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forms of alcoholic liver disease (ALD). The spectrum of alcoholic liver disease (ALD) consists of steatosis, steatohepatitis, cirrhosis and hepatocellular carcinoma depending on the duration and severity of alcohol intake ,2. Inter"} +{"text": "Knowledge of service use and costs and wider societal costs in Europe is limited; (2) Method: Using an international sample, we analysed services and costs in 357 children (4\u20136.99 years) with ASD based on parent reports. Costs were transformed into EU-28 average using purchasing power parity; (3) Results: 122 children (34%) received specialist autism services; 149 (42%) received sensory/motor therapy; 205 (57%) received speech/language therapy; 35 (10%) received play therapy; 55 (15%) received behavioural interventions; 31 (9%) received social skills training; 47 (13%) participated in therapeutic recreational activities; and 59 (17%) received other services. The total number of hours for these services combined over two months was M = 34 . Estimated total costs of health-related services were M = 1210 EUR (SD = 2160 EUR); indirect societal costs were M = 1624 EUR (SD = 1317 EUR). Regression analyses suggested that costs rise with age and presence of intellectual disabilities, but not with severity of autism; (4) Conclusions: The high extent of community-based services indicates good accessibility but also considerable variation in the receipt of services. The costs of autism services are considerable. Further research is needed to investigate whether services received match individual needs. Autism spectrum disorder (ASD) refers to a range of lifelong neurodevelopmental conditions characterized by the presence of early appearing symptoms in two core domains: impairments in reciprocal social communication and the presence of restricted interests and repetitive behaviours DSM-5; ICD-11) . ASD aff; ICD-11 https://www.who.int/news-room/fact-sheets/detail/autism-spectrum-disorders, accessed on 1 April 2020) recommend evidence-based psychosocial interventions including behavioural treatment and parent skills training programmes which can minimalize limitation in communication skills and social behavioral skills with improving well-being and quality of life for both individuals with ASD and their parents. Based on current best evidence, guidelines developed by Autism-Europe [It is important to provide individuals with ASD and their families with support to live their best possible life. There is no cure for autism nor one care package that suits everyone. People with autism require different support at each age of their lives, and it is therefore essential to ensure the right type of evidence-based therapy at the right time. Relevant guidelines often emphasize general principles in the absence of more specific evidence. One relevant policy overview by World Health Organization , we analDetails on study procedures were described separately , while aType of therapy or intervention ;Institutional stay ;Outpatient treatment ;Dietary supplement and medication ;Special diet ;Working hours spent on treatment as described above, including driving, of all private care givers (weekly average in hours);Work situation (working or not working);Reduced hours due to the child\u2019s needs (in percentage);Employing anybody privately to help care for the child ;Any additional assistant/aide in school/at home for the child ;Care giver investment:TIME-A used assessments by blinded clinicians as well as reports by parents/caregivers collected at several time points. For the current study purpose, only data collected at baseline on scores of the ADOS and ADI-R, IQ level, as well as costs and concomitant treatments were included. Parents answered a detailed questionnaire regarding services received and out-of-pocket expenses during the past two months. The following data were collected:Respondents were asked to reply with regard to the last 2 months. The limited recall time frame was used to minimalize the recall bias following other economic evaluations e.g., ,36. The https://data.oecd.org/conversion/purchasing-power-parities-ppp.htm, for 2018, accessed on 4 March 2021). All health services costs were sourced from personal communication and represent typical costs in Austria, a Central European country and one of the countries where data were collected. Heath services costs were set up to be 84 EUR per 60 min (one session) based on 1:1 setting, and discounted for group settings, assuming a group size of 5. Costs of institutional stay (310.08 EUR per day) and outpatient treatment (167.10 EUR per contact/visit) were retrieved from a report of Unit Costs of Health and Social Care [https://ec.europa.eu/eurostat/en/web/products-datasets/-/ILC_DI08, accessed on 4 March 2021), the following unit costs were obtained: 1946.08 EUR per month for full-time work where both parents had a university degree; 1391.42 EUR per month where both parents had 12 or more years of education; and 1129.42 EUR per month where at least one parent had less than 12 years of education or education level was unknown. No unit costs were imputed for medication and special diets because these costs were found to be negligible in children with ASD [https://ec.europa.eu/eurostat/tgm/table.do?tab=table&init=1&language=en&pcode=tec00118&plugin=1, accessed on 4 March 2021).Unit costs were inserted where a service was used but parents reported no expense for the service. Costs were transformed into EU-28 average using purchasing power parity , and intellectual disability (below-average intelligence) and health services costs and societal costs. Following literature that the age and severity of autism symptoms are significant predictors of costs for children at preschool age and in an = 140).A sensitivity analysis was used to determine how data retrieved from non-European countries affected the obtained health services costs and societal costs. In order to determine the robustness of our results by examining the extent to which results of health services costs and societal costs are affected by country of origin, we calculated costs including only 217 children from Europe and excluding individuals from other non-European countries and clinical judgement (n = 140), the results of which indicate that 47% of children (n = 163) had IQ below 70. The majority of individuals attended to school (62%), while 22% to full-time care and 11% to part-time care. More details can be found in the top half of The total of 357 children (83% boys) were included with a mean of age 5.4 years (SD = 0.9). As can be seen from In regard to parents\u2019 situation of work, the majority of mothers were homemakers (34%) followed by 26% being part-time employed, while the majority of fathers were working full-time (74%). Regarding education, many parents had a university degree , followed by education equivalent to high school , and less than high school . The bottom half of Of 357 children, 122 (34%) received specialist autism services; 149 (42%) received sensory/motor therapy; 205 (57%) received speech/language therapy; 35 (10%) received play therapy; 55 (15%) received behavioural interventions; 31 (9%) received social skills training; 47 (13%) participated in therapeutic recreational activities; and 59 (17%) received other services . The totThe sum of indirect societal costs was M = 1624 EUR over the last 2 months with a wide range . It can be seen that the SDs are relatively high compared to the means; sometimes higher than the means. This reflects the skewed nature of these data, which is a common phenomenon in health economic data ,41.p < 0.048) and intellectual disability (p < 0.005) on health costs attended school, 91 of included children (25%) attended kindergarten ; while 5 (1%) attended none of aforementioned. Regarding other services, 10 children (3%) had an institutional stay over the last 2 months; 24 (7%) received outpatient treatment; 55 (15%) received medication; and 38 (11%) a special diet. It can be seen from the data in n = 85; 24%); 111 had reduction in working hours (31%) due to a child care assist and required an additional aide at school or home .The results about schooling indicate that the majority of individuals from European counties . It may be explained by the fact that communication problems belong to the core autism symptoms; thus, children may benefit the most from this kind of treatment at this early stage of life. The second and most frequently chosen form of therapy was sensory and motor therapy . High use (42%) of this intervention might be due to the core nature of sensory symptoms in individuals with ASD, particularly to sensory over-responsivity . On the Estimated total costs of health-related services were M = 1210 EUR for a 2-month period, while specialist autism services contributed to these costs the most (315 EUR) followed by behavioural intervention (284 EUR) and speech/language therapy (251 EUR).Roggie and Janssen in theirThe present results indicated a high diversity among children\u2019s needs and therefore health care services used. Institutional admissions occurred in 12 cases (3% of cohort), while visits to psychiatric, somatic, or other specialized outpatient services occurred in 37 cases (10%). Even though our data indicated a relatively low mean cost of institutional stay (3 EUR) and outpatient services (1 EUR) over a period of two months when averaging across the whole sample, the wide range of costs show that there were families who incurred very high costs related to these services, whereas other families did not have these costs at all. A large and growing body of literature has investigated healthcare utilization expenditures for individuals with autism. Other research in medical and healthcare costs has emphasized the higher costs for individuals with autism compared to individuals without ,19,21,22One third (31%) of the included families in our sample experienced some costs related to medication. Even though the present data indicate a relatively low cost of medication (approx. 6 EUR) over a period of two months, the range of costs (from 0 to 290 EUR) emphasizes that there were families who incurred very high costs related to these services, and families who did not have these costs at all. There is a large volume of published studies e.g., describiSeventeen percent of the included children in our study experienced costs associated with a special diet; across all included children, the cost of special diet was on average 7 EUR over a period of two months. The broad range of these costs from 0 to 455 EUR indicates that some families have had a very high cost associated with a special diet. These results are likely to be related to a possible relationship between nutritional status and general condition of ASD children. Peretti and colleagues emphasizResults of the present study indicated the indirect societal costs to be around 1624 EUR over a period of two months. In terms of societal costs, an additional aide at school or home contributed the highest costs (621 EUR), followed by reduction in working hours (M = 524 EUR), childcare/school (M = 461 EUR), and child care help (M = 18 EUR).Our findings seem to be consistent with other research which found a high economic burden linked with ASD on society . For insFamilies of individuals with ASD face significant economic burden due to reduction or interruption of employment . The resData from our study indicate that the reduction in working hours was linked with costs of 524 EUR; child care help with additional costs of 18 EUR over a period of two months. Our findings have confirmed previous results ,30 that It was hypothesized that younger participants with a diagnosis of autism with intellectual disability will bear higher costs compared to those with older age, with broader ASD category and with intellectual disability. Regression calculation of costs confirmed that health costs change with age for children with ASD during ages 4\u20137 and with presence of intellectual disabilities, but not with societal costs. Our results indicated that health costs increased by 213 EUR per additional year of child\u2019s age and by 566 EUR for children with intellectual disability, indicating that both age and intellectual disability are significant factors related to total health costs. However, such a relationship was not observed for the social costs.Our results are in line with earlier findings. Research by J\u00e4rbrink found thThe results of our study did not confirm the predictive role of symptoms severity in the health costs and societal costs measured by ADOS total score, which is consistent with another study . HoweverLittle is known about autism-related costs in Europe. Total costs including health services costs and societal costs were estimated to be around 2834 EUR for the whole sample size compared to 2489 EUR for individuals from Europe. The results obtained from the sensitivity analysis showed that for children from European countries the pattern of services used is similar (but not exactly the same) for those from non-European countries. Children outside Europe attended more often health care services in the pre-school period, which has a direct impact of health services costs (1210 EUR vs. 740 EUR for the 2 months). Speech/language therapy; behavioural intervention; and sensory/motor therapy were associated with the highest costs for children from Austria, Israel, Italy, Norway, UK; while for the whole sample the main cost drivers were specialist autism services followed by behavioural intervention and speech/language therapy. Estimated societal costs were relatively close both in Europe and outside with the same key cost driver .The generalisability of these results is subject to certain limitations. For instance, the most important limitation lies in the fact that the study used self-reported data of costs threatened by self-reporting bias as: social desirability and recall bias , but theThe present research explores, for the first time, the costs of services received and associated costs for children with ASD bason on 5 European countries and 4 non-European countries . Total costs including health services costs and societal costs, were estimated to be around 2834 EUR over last 2 months with a wide range from 84 EUR to 26,051 EUR. Estimated total costs of health-related services were around 1210 EUR and indirect societal costs were 1624 EUR (with a wide range from 0 to 6263 EUR). Specialist autism services; behavioural intervention; and speech/language therapy were key cost driver in this group followed by sensory/motor therapy (213 EUR) play therapy (32 EUR), therapeutic recreational activities (23 EUR) and social skills training (12 EUR). Among indirect societal costs the important cost driver was an additional aide at school or home (621 EUR) followed by reduction in working hours (524 EUR), childcare/school (461 EUR) and child care help (18 EUR).The current findings add to a growing body of literature on services and costs for children with ASD by confirming that families of children with ASD bear higher costs related to the child\u2019s age and child\u2019s intellectual functioning . This study has also shown that the diversity of approaches recommended in guidelines across countries. The pattern of services used by children with ASD from European countries is similar (but not exactly the same) for those from non-European countries. The high extent of community-based services indicate good accessibility but also considerable variation in the receipt of these services. Notwithstanding the limitations, these results suggest that the costs of autism services are considerable. There is still abundant room for further progress in evaluating data on services received by individuals with ASD and associated costs for Europe. To develop a full picture of costs additional studies targeting adolescents and adults with ASD is recommended. Further research is needed also to investigate whether services received match individual needs."} +{"text": "The Centers for Medicare & Medicaid Services defines a hospital readmission as an inpatient stay that begins within 30 days of the discharge date of an index admission, to the same or a different hospital. The aims of the study were to analyze the recurrent readmissions of older persons admitted to a community hospital with diagnoses of: Chronic Obstructive Pulmonary Disease (COPD), Pneumonia (PNA), and Congestive Heart Failure (CHF). Based on the results, we will develop additional strategies that can be used to reduce the rate for hospital readmission for older patients. A retrospective chart review of hospitalizations was conducted. Among 30 readmissions, the mean age was 79.5\u00b114. The index disposition was distributed among three destinations: self-care (27%), home health organization (40%), and to skilled nursing home (33%). Most of the readmissions were for CHF (27%), COPD (10%), and PNA (13%), the only other large category include respiratory failure (10%). The readmission disposition was different from the index disposition: self-care (7%), home health organization (47%), and to skilled nursing home (20%). After hospital readmission within 30 days, older persons were more likely to be discharged to home health care organization than self-care, p<0.05. Actions that can be taken by hospitals to reduce 30-day readmissions to maintain older person independence include: clinical readiness of patients for discharge, proper infection prevention techniques, reconciling medications, good communication, and adequate patient education. This study reports that that older persons are at higher risk for unplanned hospital re-admissions and often lose their independence."} +{"text": "While Alzheimer\u2019s disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association is unclear. Using a novel, 3-step study design we examined the role of cholesterol catabolism in dementia by testing whether 1) the synthesis of the primary cholesterol breakdown products (bile acids (BA)) were associated with neuroimaging markers of dementia; 2) pharmacological modulation of BAs alters dementia risk; and 3) brain BA concentrations and gene expression were associated with AD. We found that higher serum concentrations of BAs are associated with lower brain amyloid deposition, slower WML accumulation, and slower brain atrophy in males. Opposite effects were observed in females. Modulation of BA levels alters risk of incident VaD in males. Altered brain BA signaling at the metabolite and gene expression levels occurs in AD. Dysregulation of peripheral cholesterol catabolism and BA synthesis may impact dementia pathogenesis through signaling pathways in the brain."} +{"text": "The expression of the chosen genes was confirmed by RT-qPCR technique. Thus, it can be assumed that the identified genes involved in the regulation of growth and development of muscle tissue and the processes of protein metabolism in the examined cattle breeds may be responsible for the greater gain of muscle mass in beef-breed bulls.The aim of the study was to compare the transcriptomic profiles of fully differentiated skeletal muscle derived from bulls belonging to different breeds of varying performance. Microarray analyses were performed to determine the differences in the expression profiles of genes between semitendinosus muscles of 15-month-old beef-breed bulls (Limousin\u2014LIM and Hereford\u2014HER) and dairy-breed bulls (Holstein Friesian\u2014HF). These analyses allowed for the identification of those genes the expression of which is similar and characteristic of fully differentiated muscle in beef breeds, but differs in skeletal muscle of a typical dairy breed. The analysis revealed 463 transcripts showing similar expression in the semitendinosus muscle of beef breeds (LIM/HER), in comparison with the dairy breed (HF). Among the identified genes, 227 were upregulated and 236 were downregulated in beef breeds. The ontological analyses revealed that the largest group of genes similarly expressed in LIM and HER was involved in the processes of protein metabolism and development of muscle organ. In beef breeds, some genes involved in protein synthesis and proteolysis showed an upregulation, including The online version of this article (10.1007/s13353-020-00577-1) contains supplementary material, which is available to authorized users. The quality of livestock meat is very important from an economic point of view, and hence, research has been carried out over the past few decades to increase the production of beef, accelerate the growth rate of cattle, and improve the quality of meat cattle breed and the early-maturing Hereford (HER) breed (with a large proportion of well-marbled muscle) are both beef breeds, whereas the early-maturing and poorly muscled Holstein Friesian (HF) is a typical dairy breed. The gains of muscle mass up to the 16th month of life are about 1000\u20131300, 850\u20131400, and 800\u20131000\u00a0g per day in LIM, HER, and HF breeds, respectively. The reason for these differences observed in the gain of muscle mass is not sufficiently explained, and the genes determining the rate of growth and metabolism of muscle tissue in these breeds remain to be identified skeletal muscle in cattle depending on their breed and performance. The analysis allowed for a better understanding of the genetic regulation of the development of muscle tissue, as well as determining the putative genes involved in myogenesis and development of muscle tissue in beef-breed bulls.It was assumed that the results obtained will enable the selection of those genes that are involved in the process of myogenesis and maturation of skeletal muscle and modification of their expression for achieving greater gains of muscle mass in beef-breed bulls.All the procedures related to animal experiments were approved by the Local Ethics Committee.n\u2009=\u20094), HER , and HF used as a reference. The bulls were housed, fed, and slaughtered at the age of 15\u00a0months as described earlier and total RNA isolation and validation were done as described in previous papers of 15-month-old bulls from beef breeds Limousin (LIM) and Hereford with bulls of the Holstein-Friesian (HF), a dairy breed (reference), was done using the GeneSpring software , t test with p\u2009\u2264\u20090.05 and fold change \u2265\u20091.3 as the criteria of significance. Each comparison was performed individually, in four biological repetitions. In the subsequent stage, a comparative analysis of both transcriptomes was performed, aiming at identifying common genes with different expression in the muscles of bulls from beef breeds . The data obtained from the microarray experiment were deposited in the NCBI Gene Expression Omnibus database and numbered GSE137565 (HER vs. HF) and GSE137566 (LIM vs. HF).The gene expression profile was analyzed using Bovine (V2) Gene Expression Microarray 4\u2009\u00d7\u200944\u00a0K oligonucleotide slides and Two-Color Microarray-Based Gene Expression Analysis kit . Probe labeling, hybridization, signal detection, and data extraction were done as described in a previous paper was used as a nonregulated, reference gene for normalizing the expression of the verified genes was applied. The mRNA sequences of the genes selected for validation were obtained from the NCBI Nucleotide database. Primer sequences were designed using the Primer3 and Primer-Blast software (NCBI database) and then checked using Oligo Calculator as described previously . For the purpose of publication, the color immunoblot images were converted into black and white in the Odyssey software.The protein extracts obtained from the skeletal muscle tissues were lysed with RIPA buffer supplemented with protease inhibitor cocktail and phosphatase inhibitor cocktail for 30\u00a0min at 4\u00a0\u00b0C. The lysates were cleared for 30\u00a0min at 14000\u00a0rpm, and the supernatants were collected. The concentration of protein in the lysates was determined using Bio-Rad Protein Assay Dye Reagent according to the manufacturer\u2019s instructions . The proteins (50\u00a0\u03bcg) were resolved by SDS-PAGE and transferred onto a PVDF membrane . For immunostaining, the membranes were blocked with 5% nonfat dry milk in TBS containing 0.5% Tween 20. The membranes were then incubated with the following primary antibodies: monoclonal anti-mouse GDF-8 antibody (1:100) and polyclonal goat GAPDH antibody (1:500). Then, the membranes were washed three times for 15\u00a0min and incubated further with appropriate secondary antibodies conjugated with an IRDye 680 or IRDye 800 CW fluorophore (1:5000). An Odyssey Infrared Imaging System was used to analyze the fluorescence. The scan resolution of the instrument was set at 169\u00a0\u03bcm, and the intensity at 4. The integrated optical density (IOD) was quantified using the analysis software provided with the Odyssey scanner and normalized to GAPDH. Immunoblot analysis was performed on the samples obtained from four individuals of each breed , two (**), and three (***) asterisks, respectively. The data are shown as means \u00b1 SEM (standard error of the mean).Statistical analysis of the microarray data was performed using the GeneSpring software . The results of qPCR and Western blot were analyzed using Prism 5.0 . Statistical significance was checked using the one-way ANOVA with Tukey post hoc test. The differences at the level of http://www.pantherdb.org) with a statistical overrepresentation test with Bonferroni correction; DAVID (https://david.ncifcrf.gov/), and Pathway Studio Web . In addition, during the development of data from microarrays, numerous internet databases, grouped in NCBI, such as GenBank, OMIM, PubMed, and iHOP, were used.The results were subjected to ontological analysis using the following online available databases: Panther Classification System was performed in terms of biological processes, in which products of expression of these genes might be involved. Ontological analysis demonstrated their relationship with 13 biological processes, including the following: metabolic processes 236 genes), cellular processes (161), regulation of biological processes (101), developmental processes (63), localization (54), response to stimulus (53), cellular component organization or biogenesis (39), immune system processes (35), multicellular organismal processes (26), cell adhesion (17), apoptosis (11), reproduction (5), and locomotion (1) , followed by phosphate-containing compound metabolic process (31), nitrogen compound metabolic process (27), biosynthetic process (17), catabolic process (11), generation of precursor metabolites and energy (5), coenzyme metabolic process (3), sulfur compound metabolic process (2), and vitamin metabolic process (1).Further functional classification of DEGs demonstrated that among 195 genes involved in primary metabolic processes, the highest share was exhibited by the genes involved in protein metabolic process (99), nucleobase-containing compound metabolic process (91), lipid metabolic process 20) carbohydrate metabolic process (17), and cellular amino acid metabolic process (5) Fig. . The mul0 carbohyUsing the Pathway Studio software, a network of relationships was performed for the differentially expressed genes assigned to the processes associated with protein metabolic process. This enabled a visualization of interaction between DEGs and additionally demonstrated the affiliation of genes to two major processes associated with protein metabolic process: protein synthesis 36 genes) and proteolysis (33 genes) , mesoderm development (19), anatomical structure morphogenesis (19), ectoderm development (12), apoptosis (11), cell differentiation 5), embryonic development (3), pattern specification process (2), and endoderm development (1) . Supplementary Table In addition, an ontological analysis was performed using the Pathway Studio software, which assigned the DEGs with the same direction of expression change 454 genes) to 473 biological processes and lower level of expression of 5 genes in semitendinosus muscle of beef breeds (LIM and HER), compared with the dairy breed (HF). These results confirm the results obtained with microarray analysis and exhibited the same direction of expression change as in the microarray experiment.In order to verify the results of transcriptomic analysis, validation of gene expression with the use of qPCR technique has been performed. For the purposes of result verification, seven genes were selected, demonstrating similar changes of expression in both beef breeds (LIM and HER) compared with typical dairy breed (HF), associated with the processes of muscle tissue development and protein metabolism processes. Results of verification with real-time qPCR are presented in the form of block diagrams. The level of mRNA expression is presented as \u0394\u0394Ct Fig. . The qPCp\u2009\u2264\u20090.05) difference in the expression of MSTN in bulls from LIM and HER breeds compared with HF breed bulls. Expression of the active form of myostatin (26\u00a0kDa) in the semitendinosus muscle tissue was lower in beef breeds compared with dairy breed , the key protein inhibiting the process of myogenesis, may be one of the factors influencing differences in the musculature of bulls from beef breeds , compared with bulls of the dairy breed (HF) and myostatin (mstn). The present study demonstrated higher expression of follistatin and lower expression of myostatin in beef bulls (LIM and HER) compared with bulls from dairy breed (HF) is another gene identified using the microarray technique, whose expression level was lower in bulls of beef breeds than in the dairy breed and bmpr2 in mature 15-month-old muscle tissue in LIM and HER breeds compared with HF breed assigned this gene to protein metabolism process Fig. , also kngsk3\u03b2 expression in beef breeds expression in the muscle of LIM and HER bulls and atrogin 1. The authors observed that as a result of sirt1 overexpression, reduction of the protein degradation degree occurs and their synthesis is intensified, which resulted in increased muscle mass. Koltai et al. and ctsf (cathepsin F) and fhl3 genes, which are associated with the development of muscle organ and decreased expression of genes responsible for inhibition of synthesis and intensification of protein degradation . Increased level of follistation expression and decreased myostatin expression level in skeletal muscles of beef breed bulls indicate the role of follistatin as antagonist of myostatin in the regulation of myogenesis, and it may play a significant role in stimulating development and growth of muscles in these breeds, and as a consequence greater gains of muscle mass. Moreover, the faster growth and development of muscle tissue in beef bulls can be associated with the elevated expression of fhl2 and fhl3 genes encoding FHL proteins , playing putative role in the process of skeletal muscle differentiation including formation of myotubes and expression of proteins characteristic of muscle fibers. The genes identified in this study, involved in the regulation processes of growth and development of muscle tissue and protein metabolism processes in the tested cattle breeds, may be responsible for greater muscle mass gains in bulls from beef breeds and may constitute a new cattle selection tool towards highly efficient meat production, which may be of considerable economic importance.Comparison of transcriptomic profiles of fully differentiated skeletal muscle originating from 15-month-old bulls from various breeds with different performance enabled formulation of the following conclusions. Greater growths of muscle mass in bulls from beef breeds than in the dairy breed (HF) stem from the differences in protein transformations and are associated with elevated expression of genes stimulating synthesis and inhibiting degradation of proteins (ESM 1(DOCX 73\u00a0kb)"} +{"text": "Given extended life expectancy, family caregivers are needed to provide care for older adults at home. Research has documented the deleterious effects of caregiving on mental and physical health for many. The Caregiver Health and Well-Being Initiative is a systems approach to support family caregivers of older adults by standardizing processes for identifying caregivers in ambulatory and inpatient settings, assessing caregivers\u2019 needs, and providing relevant services and resources, including caregiver health services, a Teach Back clinic for skills development, and extended goals of care conversations. N=104 caregivers have completed assessments. Participants reported the following at baseline: depressive symptoms (54%); anxiety symptoms (69%); health being affected by the care situation (59%); financial situation decreasing (58%); feeling torn between demands of their family and demands of care (63%); and some feelings of burden from caregiving (97%). Intervention components will be discussed along with a larger systems change framework for implementation."} +{"text": "Bioscience Reports 39(12) https://doi.org/10.1042/BSR20190744) would like to correct several data calculation points. In the original article, they had made a mistake in extracting the minimum allele frequency (MAF) of rs10830963 polymorphism from one included study [The authors of the original article A functional polymorphism rs10830963 in melatonin receptor 1B associated with the risk of gestational diabetes mellitus (Figures and tables have been updated in order to reflect this, and can be found in their correspondence piece ."} +{"text": "A 42-year-old patient without structural heart disease was referred for catheter ablation of salvos of outflow tract ventricular tachycardia (VT). Activation mapping of the clinical VT (VT1) revealed the earliest ventricular activation site at the right ventricular outflow tract (RVOT). Catheter ablation at this site led to a slight QRS shift of the VT morphology (VT2). Activation mapping of VT2 established the site of origin at the commissure between the right (RCC) and left (LCC) coronary cusps. This case is indicative of the presence of myocardial fibers displaying preferential conduction properties from the RCC\u2013LCC commissure to a breakout site at the RVOT. The QRS morphology was suggestive of a right ventricular outflow tract (RVOT) site of origin (SOO). An electrophysiologic study was performed in a fasting state without sedation. Antiarrhythmic drugs (\u03b2-blocker) were stopped at least five half-times before the procedure. High-density activation mapping of the clinical VT (VT1) was performed using a three-dimensional nonfluoroscopic mapping system via a multipolar catheter . A contact force-sensing catheter was used for validation of the earliest activation site and ablation (contact force up to 8 g).A 42-year-old patient was referred for catheter ablation of symptomatic salvos of idiopathic ventricular tachycardia (VT). Structural heart disease was excluded by means of transthoracic echocardiography, cardiac magnetic resonance imaging, and exercise stress testing. The electrocardiogram (ECG) during VT displayed a left bundle branch block pattern (LBBB) with an inferior axis, R-wave in lead I, and precordial transition in lead V4 and 2C. The unipolar signal at this site displayed a small initial r-wave with a steep negative dV/dT. Radiofrequency (RF) energy delivery at this site led to a slight QRS shift of the VT morphology. The ECG morphology of the second VT (VT2) was characterized by LBBB with an inferior axis, a lower-amplitude R-wave in lead I, and a precordial transition in lead V4 . Of note, the most prominent change was seen in lead V1, where the rS pattern shifted to a QS pattern with notching on the downward deflection, which is suggestive of a right coronary cusp (RCC)\u2013left coronary cusp (LCC) commissure SOO. Following the change in QRS morphology, an additional attempt of RF delivery was performed at this site but failed to suppress the arrhythmia. Meticulous activation mapping of the VT2 was subsequently performed at the RVOT, the left ventricular outflow tract (LVOT) including the coronary cusps, and the coronary venous system [great cardiac vein (GCV)]. The new activation mapping attempt revealed the earliest activation site at the RCC\u2013LCC commissure (\u221225 ms) and 2C. Catheter ablation at this site led to suppression of the arrhythmia. Of note, very low voltage and fragmented bipolar signals were recorded at the successful ablation site . On the contrary, the unipolar signal exhibited an initial r-wave with a less steep negative dV/dT as compared with during VT1. VT2 was not inducible by atrial or ventricular stimulation with or without isoproterenol infusion 30 minutes after ablation. The patient remained free from arrhythmias six months after the procedure.Activation mapping of the RVOT revealed the earliest activation site at the posterior septum (\u221223 ms) This case report is suggestive of the presence of myocardial fibers displaying preferential conduction properties from the RCC\u2013LCC commissure to a breakout site at the RVOT.1 Of 202 patients with monomorphic VT or premature ventricular contractions (PVCs) originating from the outflow tract, six patients (3%) showed changes in QRS morphology following RF energy delivery, requiring an additional RF application at a different site, which was often the LCC. Yamada et al. reported that VAs originating from the coronary cusps display preferential conduction to the RVOT and an insulated myocardial fiber across the ventricular outflow septum may exist in these cases.2 Especially, in 25% of patients with VAs of a coronary cusp origin, pacemapping from the RVOT yielded a closer match of the QRS morphology than pacing from the coronary cusp. In these cases, pacemapping identified the preferential breakout site.2 In the study by Shirai et al., a QRS morphology shift following catheter ablation at the earliest activation site was observed in 4% of cases of idiopathic outflow-tract VAs. The shifted VT or PVC demonstrated a distinct ECG QRS pattern supporting the notion that different preferential QRS exit sites within the outflow tract were operative in these cases. After remapping, the earliest activation site of the second VT or PVC moved to a different anatomical structure adjacent to the initial ablation site in 65% of cases, which was most frequently the LVOT region (coronary cusps).Tada et al. initially investigated the prevalence and characteristics of idiopathic outflow-tract ventricular arrhythmias (VAs) with altered QRS morphology following RF catheter ablation.3 An intramural SOO with preferential conduction channels to specific sites of the outflow tract may explain this phenomenon.3 The presence of preferential conduction can be unmasked by ablation at the first earliest activation site when the first preferential exit of the VT/PVC is eliminated.3 Unipolar signals displaying an rS pattern at both the earliest activation sites, as seen in our case, favors the presence of an intramural SOO.The complexity of the myocardial network around the outflow tract with the potential for preferential/alternative conduction and multiple exiting sites has been suggested to explain subtle variations in the QRS morphology of idiopathic outflow-tract VAs following RF ablation.In conclusion, a QRS morphology shift following catheter ablation of idiopathic outflow-tract VAs is not an uncommon phenomenon. Meticulous activation mapping usually reveals the true SOO in an adjacent site, which is more commonly the coronary cusps."} +{"text": "The Mong Cai pig is an indigenous breed and popularly raised as maternal line in northern Vietnam. In this study, the complete mitochondrial genome sequence of the Mong Cai pig is reported. The total length of this mitochondrial genome is 16\u00a0632\u2009bp, including 1 non-coding control region (D-loop region), two ribosomal RNA genes, 13 protein-coding genes and 22 transfer RNA genes. The phylogenetic tree of 162 pig complete mitogenomes reveals a very close relationship between Mong Cai pig in Vietnam and Bama miniature pig in southern China. This complete mitochondrial genome sequence of Mong Cai pig is useful to further genetic studies on adaptation and performance. Mong Cai pig is one of the unique and indigenous pig breeds in Vietnam. It is originated from Mong Cai district of Quang Ninh province and is farmed widely in northern Vietnam. With its high fertility, Mong Cai pigs are commonly used as basic sows for crossing with Yorkshire and Landrace pig breeds Tra . Mong CaHere, we sequenced the complete mitochondrial genome of a Mong Cai pig in Son La province, Vietnam . The ear sample was stored in the Key Lab of Agricultural Animal Genetics and Breeding, College of Animal Science and Veterinary Medicine, Huazhong Agricultural University (ID: 20151011mongcai14). The sequence was amplified using 35 pairs of primers similar to other mammalian mitochondrial genomes (Lin et\u00a0al."} +{"text": "Lipoprotein(a) has long been regarded as a risk factor for cardiovasculardisease; however, its routine use in clinical practice has been hampered bydifficulties inherent in the measurement of this complex lipoprotein. The majorchallenges relate to its size heterogeneity and related issues including (1) useof appropriate calibrators (2) standardization of calibration protocols (3)traceability and (4) reporting units. In the UK, results from the current EQAschemes for lipoprotein(a) suggest that there is considerable work required tostandardize lipoprotein(a) measurement. This is becoming increasingly pertinentwith the increasing recognition of lipoprotein(a) as an independent risk factorfor cardiovascular disease in international guidelines and the emergence ofnovel antisense therapies to effectively reduce lipoprotein(a). This articleraises awareness of the importance of measurement of lipoprotein(a) for theassessment of cardiovascular disease risk and gives guidance to clinicallaboratories regarding choice of appropriate assays. Remarkably, Lp(a)plasma concentrations within the population can therefore vary by 1000-fold. Thepathophysiology underpinning Lp(a)\u2019s role in atherosclerosis is thought to be two-fold:12,13 firstly, a pro-thrombotic effect by inhibiting fibrinolysis due to thesequence homology of apo(a) to plasminogen and secondly, a pro-atherogenic effectthrough its ability to accumulate in the intima of arteries. Epidemiological andgenetic data have now confirmed Lp(a) as an independent risk factor for coronaryheart disease, stroke and calcific aortic valve stenosis.1416Composed of an LDL-like particle, in which a single apolipoprotein B100 (apoB) iscovalently linked by a disulphide bond to a single apolipoprotein(a) (apo(a)) , Lp(a) pA personal or family history of premature atherosclerotic cardiovasculardisease (<60 years of age).First degree relatives of those with high Lp(a) plasma concentrations(>200 nmol/L).Familial hypercholesterolaemia (FH), or other genetic forms ofdyslipidaemia.Calcific aortic valve stenosis.A borderline increased (but <15%) 10-year risk of a cardiovascularevent.HEART UK (Hyperlipidaemia Education and Atherosclerosis Research Trust UK) recentlypublished a consensus statement that makes recommendations regarding the use ofLp(a) measurement in clinical practice and also reviews current and emergingtherapeutic strategies to reduce plasma Lp(a) concentrations to decrease risk ofCVD. HEART UK recommends Lp(a) measurement in the following groups: 17 to grade this risk on the basis of percentile distributions as follows:32\u201390\u2009nmol/L minor; 90\u2013200\u2009nmol/L moderate; 200\u2013400\u2009nmol/L high; >400 nmol/L veryhigh. Further studies are required to derive ethnicity-specific ranges, appropriateto the UK population as Lp(a) concentration varies by race/ethnicity.18As plasma concentrations of Lp(a) are predominantly genetically determined, they arerelatively stable over a lifetime. Therefore, Lp(a) may only need to be measuredonce, unless a secondary cause is suspected or a specific treatment is instituted inorder to lower its plasma concentration. The cardiovascular risk conferred by Lp(a)may be graded depending on the lipoprotein(a) particle concentration and HEART UKhave employed data from the ongoing Copenhagen General Population Study19 and over the past two decades the questionable performance of these assayshas hampered the incorporation of Lp(a) measurement into routine clinical practice.20 However, the recent demonstration that the genetic risk of variants in theLPA gene is fully captured by measurement of Lp(a) particlenumbers (expressed in nmol/L) using commercial immunoassays standardized andcalibrated to minimize isoform sensitivity21 shows that reliable methods for assessment of Lipoprotein(a) associated CVDrisk are available on modern high throughput platforms. There is now an urgent needfor assay harmonization to allow reliable clinical decision making.Despite the efforts of the International Federation of Clinical Chemistry (IFCC) todevelop a reference material for standardization of analytical methods (WHO/IFCCSRM-2B), shortcomings of commercially available immunoassays for this complexparticle, primarily due to their sensitivity to apo(a) isoform size variation, havelong been apparent22 The antibodies used against apo(a) are usually polyclonal and cross-reactwith the multiple KIV-2 repeats thereby overestimating Lp(a) plasma concentrationsin individuals with large isoforms and underestimating the concentrations in thosewith small isoforms.22 As a consequence of this bias, the strength of the relationship between Lp(a)and CVD risk has appeared inconsistent and has frequently been underestimated. Morerecent studies using a monoclonal antibody-based ELISA22 assayinsensitive to apo(a) isoform size variability show a consistent positiverelationship between high levels of Lp(a) and CVD, whereas earlier studies usingisoform sensitive assays have missed this important relationship. In particular, twoinfluential epidemiological studies which reported negative results, were repeated using the isoform insensitiveELISA assay and were clearly positive.23 This highlights the importance of using suitable and standardized methods forLp(a) measurement to accurately assess CVD risk.The large heterogeneity in apo(a) size between, as well as within individuals becauseof the inheritance of two different apo(a) alleles, has been a major challenge tothe accurate measurement of Lp(a).10,11 Concerted effort was made by the IFCC to select and characterize a suitablereference material and to develop a multistep standardization protocol to be used bymanufacturers and clinical laboratories. However, traceability to the WHO/IFCCSRM-2B improves assay comparability but does not eliminate the isoform sensitivityof the analytical methods.24 The target value assigned to the reference material is in nanomoles per litreof Lp(a) protein, reflecting a mole for mole interaction of antibody with apo(a).Lp(a) has historically been expressed in mass units (mg/dL) encompassing the mass ofthe entire particle, including the content of apo(a), apoB-100, cholesterol,cholesteryl ester, phospholipid, triglyceride and carbohydrate. This ismetrologically unsound because what is measured by immunoassays is the proteincomponent of Lp(a) and not its lipid and carbohydrate content. Therefore, the mostappropriate units of measurement of Lp(a) are nmol/L. Lp(a) concentrations shouldnot be converted from nmol/L to mg/dL, or vice versa, as all conversion factors areinherently isoform dependent.25Many studies have shown differences between Lp(a) assays.2628 Of the commercially availablemethods measurement are inherently isoform insensitive.methods , theDenCheck that the accuracy of the assay has been certified by the NorthwestLipid Research Laboratory in Seattle making sure the certificationapplies to the specific instrument.Do not convert results to mass units.External quality assurance programs should distribute samples with knownapo(a) isoform composition and Lp(a) values assigned by a methodvalidated to be independent of apo(a) size polymorphism and calibrationtraceable to the WHO/IFCC SRM-2B reference material.External quality assurance samples should cover the clinically meaningfulrange, especially the management threshold range of 90\u2013200 nmol/LWe suggest the following to improve harmonization of Lp(a) assays: In the UK, there is a long way to go with assay harmonization. The vast majority oflaboratories report Lp(a) concentration in mass units , with no22 However, Lp(a) particles have been found to associate noncovalently withtriglyceride-rich lipoproteins which could result in overestimation of Lp(a)measured by immunoassays based on the apo(a) capture/apoB detection approach.22,29 Another approach to circumvent the effect of apo(a) size variability, is thedevelopment of methods that are not antibody-based. Mass spectrometry methods havealso been reported30 or are under development. However, to be of the greatest clinical utility,new assays should provide the same high throughput as the analytical platformscurrently used in clinical labs as this will facilitate a more widespreadmeasurement of Lp(a).There is clearly a need for innovation in the development of isoform insensitiveLp(a) assays. One approach could be a sandwich immunoassay with antibodies detectingthe apoB component of Lp(a) or monoclonal antibodies to apo(a) directed to a uniqueepitope not present in kringle IV type 2.31,32 Currently, lipoprotein apheresis is the only reliable means of achieving asubstantial reduction of plasma Lp(a); however, its use is limited by its high cost,low capacity and lack of accessibility. Injectable antisense oligonucleotidestargeting hepatic LPA RNA have been shown to reduce apo(a)production and apo(a) assembly with apoB, leading to >90% reduction in Lp(a)particle concentrations. These agents are now in Phase 3 trials (NCT04023552) andthe results will confirm whether selective reduction of Lp(a) levels reduces CVrisk. The need for clinical laboratories to deliver timely, accurate andstandardized measurements of this enigmatic lipoprotein has become one of vitalimportance for us all to address.There is now an urgent need for the standardization of Lp(a) assays firstly, to meetgrowing demand with the recognition in international guidelines of this important,largely unmeasured cardiovascular risk factor and secondly, due to the prospect ofnovel treatments to dramatically lower Lp(a)."} +{"text": "We compared indicators of influenza activity in 2020 before and after public health measures were taken to reduce coronavirus disease (COVID-19) with the corresponding indicators from 3 preceding years. Influenza activity declined substantially, suggesting that the measures taken for COVID-19 were effective in reducing spread of other viral respiratory diseases. Public health measures, including public education and physical distancing, were implemented in Singapore to reduce transmission of coronavirus disease (COVID-19). However, instead of a lockdown, Singapore kept schools and workplaces open and did not advise the routine use of masks for persons who are well during the initial phase of the outbreak in January\u2013February 2020. We examined the effect of these COVID-19 measures on influenza incidence as a proxy to determine the overall potential reduction in respiratory virus transmission.>38\u00b0C) and cough. Data included number of visits to government primary care clinics for ILI per day, ILI samples tested per week, and percentage influenza positivity. We estimated number of influenza cases per day by multiplying ILI visits per day by the proportion of ILI patients who tested positive for influenza, which better reflects influenza infection rates than either indicator alone (We obtained routine sentinel surveillance data on influenza-like illnesses (ILI) from a national network of primary care clinics and the National Public Health Laboratory. ILI was defined as fever . Influenza activity peaked in epidemiologic week 1 of 2020 but declined to below the average of the preceding years by epidemiologic week 5 (We compared indicators of influenza transmissibility in 2020 against the average from corresponding periods in the 3 preceding epidemiologic years (2016\u20132019). We performed weekly paired difference c week 5 . Percent0) than seasonal influenza (0 of 2.2 (Public health efforts to control COVID-19 probably reduced influenza transmission in February 2020 because both viruses have similar modes of transmission through respiratory and contact routes. Even if COVID-19 has a potentially higher basic reproduction number (ROur study has several limitations. First, a decrease in influenza transmission is expected in February\u2013March, given the yearly bimodal pattern of influenza incidence in Singapore (In conclusion, we found a marked decline in ILI in Singapore after the implementation of public health measures for COVID-19. Our findings suggest that such measures are effective in reducing spread of viral respiratory diseases and could mitigate the impact of the COVID-19 pandemic."} +{"text": "As increasingly more older adults in the general population utilize smartphones to access health services, the digital divide between older adults with serious mental illness (SMI) and the general older adult population continues to widen. The purpose of this study was to examine older adult peer support specialists\u2019 and older people with SMI\u2019s perspectives of barriers and facilitators to utilizing Medicaid Safelink smartphone services. Data from two focus groups and five semi-structured interviews from older adult peer support specialists (N=10) and older adults with SMI (N=15) were analyzed using the Consolidated Framework for Implementation Science Research. A mixed methods convergent design integrated quantitative with qualitative data. Older adults with SMI (N= 15) had a mean age of 55 years and were mainly women (70%) and White (100%). Certified peer specialists (N= 10) had a mean age of 52 years (age range 45-67) and were mainly female (75%), 66% identified as White, and 33% identified as African American. Four themes that were identified across different aspects of barriers included technology knowledge, technology adoption, design features , and Safelink policies and procedures. Facilitators included free and continuous services, access to technical support, and smartphone capabilities to enable healthcare communications and facilitate the delivery of services. Improving upon the themes identified as barriers to utilizing Safelink may promote a continuum of care for older adults with SMI, closing the gap of services that occurs between in-person therapy and other interventions."} +{"text": "This review aimed to synthesize the most up-to-date evidence regarding the prevalence of urinary incontinence (UI) among adolescent female athletes. We conducted a systematic review of studies regarding UI in female athletes less than 19 years of age. This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRIMSA). The electronic databases of PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Web of Science (WOS) were searched between October and November 2020. After blinded peer evaluation, a total of 215 studies were identified and nine were included. Risk of bias was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist. This review identified a prevalence of UI in adolescent female athletes between 18% to 80% with an average of 48.58%. The most prevalent sports were trampolining followed by rope skipping. The prevalence of UI among adolescent female athletes practicing impact sports was significantly prevalent. There is a need for further research, education, and targeted interventions for adolescent female athletes with UI. Urinary incontinence (UI) is defined as any complaint of involuntary loss of urine . Mostly The younger female athletes seem to display isolated symptoms of pure stress UI which is an uncomplicated SUI without other symptoms of urge incontinence or bladder dysfunction . High-imThe underlying mechanisms by which young nulliparous female athletes show higher levels of UI as compared to their sedentary females ,17 are sElite female athletes experiencing UI at an early stage are more likely to report UI symptoms later in life . This isThe conduct and reporting of this systematic review complied with the Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) guidelines .A systematic search of electronic databases including PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Web of Science (WOS) was carried out between October and November 2020 independently by two blinded authors. No restrictions on language or publication timeline were applied. The search strategy used keywords, mesh terms, and Boolean connectors (AND/OR) including: \u201cStress urinary incontinence\u201d OR \u201curine loss\u201d OR \u201cpelvic floor muscles\u201d AND sport OR athlete OR \u201cfemale athlete\u201d. Search results were limited to species (human) and age (birth\u201318 years) and source type .Retrieved titles and abstracts were assessed for eligibility for inclusion, and duplicate entries were removed. The same two authors independently reviewed the text of the studies for eligibility. Articles published up to November 2020 were eligible for inclusion. The criteria for inclusion were: (1) study participants included adolescent females participating in sport or athletic activities; (2) study provides an assessment of UI symptoms; (3) study published in a peer-reviewed journal in any language. Randomized controlled trials (RCTs) with two or more parallel groups and crossover trials, non-RCTs were eligible for inclusion if they met the previously mentioned criteria. The criteria for study exclusion were: (1) participants > 19 years old; (2) participants who underwent any type of pelvic floor surgery; (3) participants during their pregnancy and postpartum period and; (4) systematic review, meta-analysis, or case study.For each study, data were extracted on the characteristics of the population and intervention such as: (1) last name of the first author; (2) years of publication; (3) study design; (4) sample characteristics ; and (5) instrument assessing symptoms of UI. Risk of bias was assessed independently by two authors using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist . The samThe search strategy yielded 500 potentially relevant studies. After the removal of duplicates, 321 records were screened. Of those, 215 potential titles were selected after the database filter insertion. Among those, only nine studies met the criteria for inclusion and were selected for analysis in this systematic review. The study selection flow chart is shown in 2, and 6\u201319 h of training per week. We calculated a mean of prevalence of 48.58% for all the samples that were involved in different sports. Almost all study designs were cross-sectional (n = 8) where one had a pilot cross-sectional design. The risk of bias was assessed with the STROBE checklist for cross-sectional studies [Our systematic review identified nine studies published between 2002 and 2020. The total sample was 633 female athletes, with an average age of 16.15 years, BMI ranging from 18.9 to 21.7 kg/m studies . Figure studies . ClarityThis systematic review identified a range of UI prevalence rates ranging from 18.2% to 80% and yielding a mean prevalence of 48.58%. In reports that assessed UI in one specific sport, the highest prevalence rates were found in trampolining (80%) followed by rope skipping (75%) and soccer (62.8%). On the other hand, the lowest rates of UI were found in practitioners of rhythmic gymnastics (31.8%).The main outcome for assessing UI symptoms was the International Consultation on Incontinence short form questionnaire (ICIQ-SF), which was used in 5 of the 9 studies. Only one study used a quantitative measurement of UI through the pad-test . Almost The aim of the present review was to systematically review the prevalence of UI among adolescent female athletes. Notably, we found a wide range of UI prevalence rates among young female athletes varying from 18% to 80%, with an average prevalence of UI symptoms in female adolescent athletes about 50%. Our results are slightly higher than the meta-analytic data presented by Teixeira et al. for femaOur review included a total sample of 633 young nulliparous female athletes practicing a wide range of sports. Several studies included samples of athletes practicing different sports. We applied a classification of sport impact based on the study by Groothaussen and Siener that has2 and 6 to 19 h of training per week. Collectively, these observations suggest that the high volume and intensity of training along with low energy availability could be potential risk factors for developing UI in adolescent female athletes.The benefits of sports practice early in life are well established; however, young female athletes are not immune to suffering sport-related injuries or illness . ParticuB\u00f8 and Sundgot-Borgen described that the presence of UI early in life is a strong predictor for UI later in life (ORR of 8.57) ,21. Due Limitations of this review are the small sample size, heterogeneity, and variability of outcome measures as well as the lack of reliable quantitative outcome measures for UI. The selected studies used validated questionnaires to assess urinary symptoms in young athletes. However, these questionnaires were validated in adult populations. More reliable diagnostic outcomes would improve the quality of the studies. In addition, the analysis of co-founding factors specific to the female adolescent athlete such as menstrual cycle and nutritional status would improve the quality of the studies. We recommend the use of the STROBE checklist for risk of bias study assessment to improve the scientific report of these studies and a classification of sport characteristics and impact, which would additionally improve their comparison and assessment. The development and validation of a specific questionnaire for assessing UI symptoms in adolescent females is warranted.UI during exercise and sports is a concern for young female athletes. Our findings highlight a 48.8% prevalence rate among adolescent female athletes where practitioners of high-impact sports show the highest prevalence rates. Given the high prevalence of UI among adolescent female athletes involving impact sports graded 2 and 3, concerted efforts are needed to provide early education and implement prevention measures before young female athletes experience the burden of UI. Future research is needed to guide our understanding of the underlying physiopathology and unique characteristics of the adolescent female athlete\u2019s pelvic floor muscle activity during impact sports."} +{"text": "A collaborative research team lead by an investigator from the Lyon Neuroscience Research Center and Lyon University Hospital and Lyon 1 University studied epileptogenicity of tuber and its surrounding cortex using stereoelectroencephalography (SEEG) in patients diagnosed with tuberous sclerosis complex (TSC) . A collaborative research team lead by an investigator from the Lyon Neuroscience Research Center and Lyon University Hospital and Lyon 1 University studied epileptogenicity of tuber and its surrounding cortex using stereoelectroencephalography (SEEG) in patients diagnosed with tuberous sclerosis complex (TSC) . A study cohort of eighteen patients (11 children) who underwent presurgical SEEG evaluation between 2004 and 2018 was identified from four French tertiary epilepsy centers. The electrodes were implanted bilaterally in 14 patients, and the total number of electrodes ranged from 8 to 16 per patient. The total number of tubers in each patient ranged from 3 to 30 [Epileptogenicity Index (EI) was usedThe dominant tuber was the most epileptogenic P < .001) of the five ROI. Seven patients with a focal tuber EZ organization had 80% Engel IA postsurgical outcome and the following 4 tuber characteristics: continuous interictal discharges (100%), fluid-attenuated inversion recovery (FLAIR) hypointense center (86%), stimulation \u2013 induced seizures (71%), and center-to-rim EI gradient. A combination of the first three characteristics showed a 98% specificity for a focal tuber EZ organization. Six patients with a complex EZ organization showed 40% Engel IA outcome with nearby cortex (4 patients) and distant cortex (1) as the most epileptogenic region. The authors concluded that tubers with focal EZ organization are much like type II focal cortical dysplasia, and that identification of these tubers relate to EZ hypothesis generation and invasive EEG/resection strategies. [ of the fCOMMENTARY. Talarirach and Bancaud developed \u201cstereoencephalographie\u201d in the 1960s as a tool to aid in defining the EZ. Their definition of EZ was an ictal electro-clinical concept based on SEEG recordings. Over the past 50 years, the concept of EZ has evolved due to invention of sophisticated localizing tools. Hans L\u00fcders et al. (2006) defined EZ as \u201cthe minimum amount of cortex that must be resected to produce seizure freedom .\u201d UltimaThe authors reported the following results in consideration of EZ identification in TSC: 1. A combination of the three characteristics - continuous interictal discharges, FLAIR hypointense center, and stimulation-induced seizures, showed a 98% specificity in localizing the dominant tuber; 2. Nearby cortex (4 of 6 patients) was the most epileptogenic in the presence of a dominant tuber that lacked center-to-rim gradient in EI. Importantly, these results may contribute to development of an effective implantation strategy of intracerebral electrodes in further defining EZ in TSC, as one of the challenges of using SEEG is determining targets and trajectories based on presurgical data and EZ hypothesis. Experience and skill of a functional neurosurgeon who places intracerebral electrodes to confirm/modify/reject the hypothesis of EZ may also influence outcome. The current work is a welcome and laudable contribution to further our understanding of epileptogenicity in TSC.The authors have declared that no competing interests exist."} +{"text": "The nursing home (NH) industry has experienced a shift toward care specialization. This study used NH-level panel data from 2011 to 2017 to describe unique care specialization groups in urban areas using latent profile analysis (LPA) . We focused on urban NHs because NHs specialize in care due to competition and memetic pressure, more likely to be the case for urban NHs. To identify care specialization profiles, LPA was applied using different types of specialist staffing levels and the share of special care units aimed at chronic conditions like Alzheimer\u2019s Disease and AIDs. Model diagnostics and information criterion guided selection of the best fitting model. Model stability over time, interpretability of results, and parsimony were also taken into consideration. The final results indicated a 4-profile model fit the underlying data best and the patterns remained comparatively stable over seven years. The 4-classes are uniquely identified as: high use of specialists of all types (3%), moderate use of specialists of all types (7%), mixed use of specialists and special care units (26%), and low specialization use (64%). From 2011 to 2017, the size of the \u2018low specialization\u2019 group became smaller, whereas the high and moderate groups grew larger. In addition to describing a clear trend towards increased care specialization, our findings indicated great heterogeneity in NHs\u2019 care specialization patterns in urban areas. Future studies should examine market and organizational characteristics, as well as performance outcomes for different specialization groups."} +{"text": "The genomics and genetic data of pigmented and non-pigmented Malaysian rice varieties are still limited. Hence, we performed the genome resequencing of two black rice varieties , two red rice varieties and two white rice varieties (MR297 and MRQ76) using Illumina HiSeq 4000 platform with 30x sequencing coverage. We aimed to identify and annotate single nucleotide polymorphisms (SNPs) from the genome of these four pigmented and two non-pigmented rice varieties. The potential SNPs will be used in developing the functional SNP markers related to nutritional and quality (i.e. aromatic) traits. Raw data of the pigmented and non-pigmented rice varieties have been deposited into the European Nucleotide Archive (ENA) database with accession number PRJEB29070 and PRJEB32344, respectively. Specifications Table\u2022The pigmented and non-pigmented genome data provide genomics and genetics data of Malaysian rice varieties, which can be utilized in investigating their genetic basis.\u2022Molecular markers such as single nucleotide polymorphisms (SNPs) and microsatellites can be discovered from the genomes and will be useful in facilitating genetic improvement of rice varieties in order to enhance their nutritional and quality traits.\u2022These genome data are valuable for evolutionary study and the identification of domestication genes.Value of the Data1https://www.ebi.ac.uk/ena) under the studies accession numbers PRJEB29070 (pigmented) and PRJEB32344 (non-pigmented).The genomes of four Malaysian pigmented and two non-pigmented rice varieties were sequenced using Illumina HiSeq 4000 sequencing technology, with the read length of 150\u202fbp at each end. We used a 30x depth of sequencing coverage. Approximately 88 Gb raw data sequenced were generated from the genomes of four Malaysian pigmented and two non-pigmented rice varieties. After filtering the low-quality data, we obtained 87 Gb clean reads and these clean reads were used for further analyses, such as reads mapping and SNPs calling. 22.1The genomic DNA was extracted from the young leaves of each pigmented and non-pigmented rice varieties using Murray The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} +{"text": "Elder mistreatment (EM) complexity, while described anecdotally, lacks an empirical foundation for measurement. Improved knowledge on the range and nature of concurrent issues that complicate EM intervention would inform the development of more effective solutions and enable greater precision of evaluation research. The purpose of this qualitative study was to explore factors contributing to complexity in a sample of EM cases that was selected based on difficulty reaching resolution. The sample was drawn from those reviewed by an experienced EM Multidisciplinary team (MDT) and determined to require long-term case management (n=39) beyond the capacity of the MDT\u2019s usual response. Case manager narrative documentation of ongoing assessment and social service records were qualitatively coded by two researchers. Inductive content analysis, with iterative code reconciliation, was used to identify issues and problems both related and concurrent to EM. Eighteen themes and 74 sub-themes emerged, with 93% initial coding agreement between researchers. The most frequent themes were problems with Caregiving (80%), Cognition (80%), Physical Health (80%), Behavioral Health (69%), Socialization (64%), and Finances (62%). Refusal of formal services was common (90%), yet all accepted visitation by the case manager, suggesting informal support may be effective. Diversity, interconnectedness, and emergence of issues along the duration of case management indicates a system approach to intervention design and evaluation is warranted. This research underscores the need for holistic intervention for highly complex EM, and lays the foundation for objective measure of complexity to standardize selection for specialized intervention."} +{"text": "This paper presents a semi-analytical approach for investigating the nonlinear buckling and postbuckling of spiral corrugated sandwich functionally graded (FGM) cylindrical shells under external pressure and surrounded by a two-parameter elastic foundation based on Donnell shell theory. The improved homogenization theory for the spiral corrugated FGM structure is applied and the geometrical nonlinearity in a von Karman sense is taken into account. The nonlinear equilibrium equation system can be solved by using the Galerkin method with the three-term solution form of deflection. An explicit solution form for the nonlinear buckling behavior of shells is obtained. The critical buckling pressure and the postbuckling strength of shells are numerically investigated. Additionally, the effects of spiral corrugation in enhancing the nonlinear buckling behavior of spiral corrugated sandwich FGM cylindrical shells are validated and discussed. Due to their excellent thermo-mechanical properties, functionally graded materials (FGMs) have been applied in engineering structures, such as military structures, nuclear reactors, civil engineering structures, and other technology areas . ResearcBased on Love\u2019s shell theory, Arshad et al. ,3,4 studFor corrugated cylindrical shells, some previous studies have focused on experimental and numerical analyses of the mechanical behavior of these structures. Yang et al. establisDue to their excellent load carrying capacity and conformance with manufacturing technology, spiral corrugated cylindrical shells are often used in engineering structures. According to the best of the authors\u2019 knowledge, there is currently no semi-analytical approach for investigating the mechanical behavior of spiral corrugated cylindrical shells made of sandwich FGM surrounded by an elastic foundation. This paper presents a semi-analytical approach for examining the nonlinear buckling responses of spiral corrugated sandwich FGM circular cylindrical shells using a homogenization technique . The spConsider a spiral corrugated sandwich FGM cylindrical shell with an axial length Based on the geometrical calculations, the relation between the angle of corrugation and the number of full waves of corrugation in a loop coil can be established asThe geometrical parameters of the cross section of corrugations The force and moment results of a sandwich cylindrical shell are expressed by applying the homogenization procedure for corrugated structures established by Xia et al. , as(4){The stiffness matrix terms of non-corrugated shells can be determined asBased on the coordinate transformation technique, the force and moment results of the corrugated sandwich FGM shells in the As can be recognized, the spiral corrugated sandwich FGM cylindrical shells are equivalent to the non-corrugated sandwich FGM cylindrical shells with the new stiffness matrix presented in Equation (6).Based on the nonlinear strain\u2013displacement assumption of von Karman and Donnell shell theory, the strains at the mid-plane of non-corrugated sandwich FGM cylindrical shells can be expressed as (9)\u03b5x0=uThe strains across the shell thickness at a distance From Equation (9), the deformation compatibility equation can be directly established asThe nonlinear equilibrium equations of a non-corrugated cylindrical shell based on Donnell shell theory areConsidering the first two equations of Equation (12), a stress function Substituting Equations (6) and (13) into the third equation of (12), the nonlinear equilibrium equation is obtained in a new form, asFrom the constitutive relations of Equation (6), the inverse relations can be established, taking into account Equation (13), asBy substituting Equation (15) into the deformation compatibility Equation (11), the equation can be rewritten asConsider a spiral corrugated sandwich FGM cylindrical shell under external pressure The solution of the deflection satisfying the boundary condition in Equation (17) in an approximate sense can be applied as a three-state form:Clearly, the simply supported boundary conditions in Equation (17) are approximately satisfied.Substituting Equation (18) into Equation (16), the form of the stress function Substituting the solution form of deflection Equation (18) and stress function form Equation (19) into Equation (14) and then performing the Galerkin procedure in the integral domain Unlike the cylindrical panel, the circumferential closed condition in an average sense must be satisfied for all revolution shell types, asUsing Equations (15) and (18), the closed condition Equation (23) becomesEliminating When the nonlinear amplitude of the postbuckling state The critical buckling pressure By using Equations (20)\u2013(22), the maximal deflection of a shell located at The postbuckling curves of spiral corrugated sandwich FGM cylindrical shells can be determined by combining Equation (25) and Equation (27).In this section, the accuracy of the semi-analytical approach presented for the critical buckling pressure of isotropic cylindrical shells and sandwich FGM cylindrical shells under external pressure is compared with the results reported by Shen et al. , Vuong aAs can be seen in 2 and Alumina 2, and the Poisson ratio was assumed to be a constant value of Numerical investigations were performed to predict the nonlinear buckling responses of spiral corrugated sandwich FGM cylindrical shells subjected to external pressure and surrounded by an elastic medium. The sandwich FGM corrugated cylindrical shells with the following geometrical parameters were considered: The effect of elastic foundation moduli is presented in The postbuckling curves of round spiral corrugated sandwich FGM cylindrical shells are shown in The effect of geometrical parameters of corrugation Corrugated sandwich FGM shells are homogenized to non-corrugated sandwich FGM shells;(2)The critical buckling pressure of a corrugated sandwich FGM cylindrical shell is greater than that of a corresponding non-corrugated sandwich FGM cylindrical shell;(3)The geometrical parameters of the cross section of corrugation and the material properties strongly influence the buckling and postbuckling behavior of sandwich FGM cylindrical shells.Some significant results have been obtained as follows:"} +{"text": "RAD51 (rs1801320) and XRCC2 (rs3218536) genes polymorphism having association with colorectal cancer risk. For this reason the aim of this study is to ascertain their interrelation with colorectal cancer occurrence in Bangladeshi population. In case of Bangladeshi population, no report is observed till now showing the genetic variations of A case control study was conducted where 200 colorectal cancer patients and 200 healthy volunteers were figured for this research using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). RAD51 (rs1801320), G/C heterozygous genotype was found significant . On the other hand, G/G genotype was not found statistically significant and significance was observed for GC+GG . In case of XRCC2 (rs3218536), C/T heterozygous genotype was remarked statistically significant . The T/T genotype was not recorded statistically significant but significance found for CT+TT . Moreover, it is found that the risk factor of developing CRC is observed in G/C, C/T heterozygote and GC+GG, CT+TT (heterozygote+ mutant) in RAD51 (rs1801320) and XRCC2(rs3218536) respectively although no significance is observed in case of G/G and T/T mutant. Here, in case of RAD51 (rs1801320) and XRCC2 (rs3218536) genes polymorphism with colorectal cancer risk is observed in Bangladeshi population.So, the association of In Bangladesh, cancer can be said as one of the uppermost reasons of expansion of death and morbidity in the approaching years. According to International Agency for Research on Cancer, in 2030 the death rate will be 13% and it was 7.5% in 2005 which determines the proportion is appraised to be precisely twofold compared to 2005 . Presumption says, by 2040 the figure will be expanded from 18.1 million to 29.5 million. Colorectal cancer is attributed as the most usual malignant tumours affecting the parts of alimentary canal appeared from large intestine due to unusual extension of cells having potential to invade several parts of human body . Depending on the initiating point, these types of cancers can be said either as colon or rectal cancer. Colon cancer is noticed to be identified in two-third cases and remaining one-third as rectal cancer . 75% of CRC can be remarked as sporadic. In tumour development, a part of modification in case of other genes can be observed and the occurrence of ultimate addition of supplementary malicious attributes such as intrusiveness of tissue and the ability to metastasize takes place .Several risk factors related to CRC are individual study of adenomatous polyps, one\u2019s own record of inflammatory bowel disease, genealogical account of colorectal cancer or adenomatous polyps and inherited genetic risk factors, coronary artery disease notably . Familial Adenomatous Polyposis (FAP) as well as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) also called Lynch syndrome are the most frequent inherited conditions and approximately 5 to 10% of CRCs are a sequel of accepted hereditary condition . The probability of colorectal cancer is actively governed by diet where modification in nutritional habits might diminish up to 70% of CRC implication . High meat consumption, diets with high fat specifically animal fats has also been bundled in colorectal cancer continuation . At adolescent period, several aspects like physical inactivity and corpulence, smoking, strong drink consumption are responsible for the starting of colorectal cancer. Evidence shows that continuing regular use of aspirin along with Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) lessen the probability of CRC considerably . 5-fluorouracil (5-FU) capecitabine, oxaliplatin and irinotecan are utilized predominantly in chemotherapy for the patients of CRC. Targeted therapy is regarded as an advanced sector of drug evolution. It is engaged with targeted therapy which consequences from expanded apprehension of the molecular differences necessitated in cancer occurrence. Particular molecules engaged in tumor magnification and development are featured by these drugs having divergent and generally less serious after effects compared to traditional chemotherapy drugs .RAD51 is up regulated in different cancers. Attachment of the DNA with RAD51 protein takes place at the site of a break and encompassed in a protein case which is indispensable introductory step in the restoring operation. RAD51 gene is an extremely protected well-designated DNA repair protein . The scheme of RAD51 along with molecular regulation has not yet been completely confirmed .The protein, indispensable for reconstructing the damaged DNA is formed by instructions provided with RAD51 gene which plays a fundamental role in homologous recombinational repair. It is evident from innumerable studies that XRCC2 (X-ray repair cross complementing 2) is 7q36.1 which is a member of the RAD51-related protein family. Chromosomal fragmentation, translocations and deletions are thought to be repaired by XRCC2. Additionally, this gene is found to be necessitated in the HR repair (HRR) pathway of DNA double-stranded breaks (DSBs). An association between XRCC2 (rs3218536) single-nucleotide polymorphisms (SNPs) and cancer incidence risk are found to be the most common mutation observed by numerous studies . The increment of cancer risk is appeared due to two known epigenetic causes of XRCC2 deficiency. One of them is the XRCC2 exponent methylation and epigenetic repression of XRCC2 by over-expression of EZH2 protein. Depletion of homologous recombinational repair and epigenetic repression of RAD51 paralogues including XRCC2 are accompanied by increased expression of EZH2. Over-expression of EZH2 protein between 40%-75% is found in breast cancer and EZH2 mRNA is up-adjusted, about 7.5-fold .The location of RAD51 (rs1801320) and XRCC2 (rs3218536) genes have been perceived in different ancestral groups. A case-control study on Bangladeshi population was conducted recently where the high risk association between altered gene expression of RAD51 (rs1801320) gene polymorphism and breast cancer development was detected. In different ethnicities, RAD51 (rs1801320) and XRCC2 (rs3218536) gene polymorphisms are certified to be a threat aspect of colorectal cancer and RAD51 (rs1801320) gene polymorphism in breast cancer evolution in Bangladeshi population. A possibility may arise basing on a correlation between RAD51 (rs1801320) and XRCC2 (rs3218536) polymorphisms with colorectal cancer risk in Bangladeshi population. Moreover, no related investigation has been supervised concerning this feasible association in Bangladeshi populace. We, consequently, presume to find out that predictable relationship of RAD51 (rs1801320) and XRCC2(rs3218536) genetic polymorphisms with colorectal cancer risk in Bangladeshi citizenry for the very first time.As a probable element for breast, colorectal, lung, prostate, endometrial as well as gastric cancers both Study populationRAD51 (rs1801320) and XRCC2 (rs3218536) polymorphism with clinic pathological characteristics of patients are mentioned in RAD51 (rs1801320) and XRCC2 (rs3218536) polymorphisms, patients who have primary location of cancer in rectum are found to be more susceptible to have colorectal cancer as statistical significances are observed; RAD51 and XRCC2 and in both cases the p values observed are less than 0.05. No other factors are found to be significantly associated with RAD51 (rs1801320) and XRCC2 (rs3218536) polymorphisms. Approval of the study protocol was done by the ethical committees of the respective hospitals and the research was executed according to the descriptions of Helsinki and its following editions . An informed consent document was signed by each patient and control subject after briefing the motive of the study. The genotyping scrutiny was done in the laboratory of Biotechnology, Faculty of Pharmacy, The University of Asia Pacific, Dhaka-1205, Bangladesh.A case control research was co-ordinated on 200 colorectal cancer patients and 200 healthy volunteers basing on age, weight and sex. Colorectal cancer patients were enlisted from Ahsania Mission Cancer and General Hospital and National Institute of Cancer Research and Hospital (NICRH), Dhaka, Bangladesh. After that, physical analysis of controls were picked by matching age and genetic history to colorectal cancer patients. The age of patients ranged from 13 years to 89 years (mean 51 years). Most of the patients are observed having tumour stages I, II and IV (mostly stage II). Age, sex, diet, weight, BMI, TNM staging, demographic characteristics, lifestyle factors data were stockpiled via interrogations by skilled attendants in presence of specialized doctors. The demographic characteristics of the patients and the controls are presented in Genotyping RAD51 (rs1801320) and XRCC2 (rs3218536), PCR-Restriction Fragment Length Polymorphism (RFLP) approach was applied to genotype. PCR product of 157 bp and 234 bp were obtained for RAD51 (rs1801320) and XRCC2 (rs3218536) SNPs respectively. PCR amplifications conditions are given in RAD51 (rs1801320) was dispatched with BstNI by incubating at 60\u00b0 C for 4 hours which produced two fragments 86 bp and 71 bp in case of G/G allele while for C/C allele it produced only one fragment of 157 bp. Restriction enzyme Hph1 (37\u00b0 C overnight) bisected the T/T allele of XRCC2 (rs3218536) giving two fragments of 147 bp and 87 bp but didn\u2019t divide the C/C allele that is only one fragment 234 bp was observed. These DNA fragments were blemished with ethidium bromide and pictured on 2% agarose gel electrophoresis.Genomic DNA was separated from the blood specimens assembled from all patients by the help of DNA extraction mini kit, Favorgen, Taiwan. Genomic DNA amplification was executed using the predesigned forward and reverse primers. PCR was done by following the standard protocol mentioned in published method . In case of bothStatistical analysisStatistical analyses were carried out using the SPSS software package 13.0 . Mean age for cases and controls was evaluated by using Student\u2019s t-test. Odd ratios (ORs) and the corresponding 95% confidence intervals (CI) calculated by using logistic regression analysis were used to analyse the association between the polymorphic genotypes and CRC risk, based on heterozygous and homozygous comparison models with the wild type genotype served as the reference. Odds ratios of > 1.00 specified a positive risk association and vice versa. P values of < 0.05 were significant. Study populationRAD51 (rs1801320) and XRCC2(rs3218536) with a number of 200 controls. This study included 97 males (%) and 103 females (57.5%) colorectal cancer patients with an average age of 51 and the control group covered 87 males (43.5%) and 113 females (56.5%) with an average age of 47.The study was conducted through 200 patients of RAD51 (rs1801320) polymorphismRAD51 (rs1801320). This population based case-control study was conducted to survey the prevalence of RAD51 polymorphism in Bangladeshi population of CRC patients and normal controls. The genotype frequencies in cases and controls are presented in It was evident after gel electrophoresis that DNA fragment pattern of BstNI digestion of the PCR product was done to recognize the genetic variation at XRCC2 (rs3218536) polymorphismXRCC2 (rs3218536). This population based case-control study was conducted to investigate the prevalence of XRCC2 polymorphism in Bangladeshi population of CRC patients and normal controls. The genotype frequencies in cases and controls are presented in Digestion by Hph1 shows the mutation of RAD51 (rs1801320) and CRC with present study is shown in XRCC2 (rs3218536) and CRC with present study is given in A comparison of previous association studies between HRR) genes have an extremely immediate association with cancer threat. Both RAD51 and XRCC2 proteins are fundamental constituents of DNA double strand breaks (DSBs) reconstruction by HRR. Constructional at the same time functional correspondences are noted between RAD51 and XRCC2 gene . Genomic instability is demonstrated if cell deficient with any of RAD51 or XRCC2 genes products are defective in homologous recombination. The X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2) gene plays an important role in the homologous recombination repair (HRR) pathway at the same time can be said a functional member for taking part in tumor progression . Improvement of unrepaired DNA destructions would be conducted by under expression of RAD51 gene. Replication blunders past these destructions would guide to the growth of mutations and cancer.Protein haploinsufficiency regulation by genetic polymorphisms in homologous recombination repair . Another Chinese case control study says that in CRC tissue, the expression of XRCC2 is inflated and notable interdependences are also found among positive XRCC2 expression, tumor size, Dukes\u2019 stage and TNM stage . In case of Australian population, a comparative consequence of the XRCC2 alteration to cancer threat is remarked for members of this family . Another case study on Polish population (Warsaw) also said that the feasible character of XRCC2 gene polymorphism is responsible for neoplastic diseases. Therefore, XRCC2 polymorphisms may take part dominant role in colorectal cancer tumorigenesis, conferring susceptibility to rectal tumors in Polish population . Similar relationship is also observed when studied on English population . The investigation on RAD51 and XRCC2 gene polymorphism was done by being encouraged with strong association between these genes and these gene polymorphisms may be used in several areas in colon cancer management, such as early detection of the carcinogenesis, prediction of tumor biologic behaviour and being a candidate therapeutic target for colon cancer. Evidence is yielded by this study that RAD51 and XRCC2 gene polymorphisms may be risk factors for colon cancer progress . A result of meta-analysis says that the RAD51 135 G/C polymorphism is responsible for increased risk of CRC in total using allele (OR=1.21) and recessive models (OR=1.62). However, XRCC2 rs3218536 A/G was not associated with the risk of CRC in total or in subgroups in that particular study. As claimed by the consequences of meta-analysis, the RAD51 135 G/C polymorphisms might influence colorectal cancer risk . Few reports are also made out regarding the impact of RAD51135G>C in spread of CRC in Asian populations. In a subgroup of population of Kashmir, RAD51135G>C has marked the association with CRC . On the other hand, in case of Iranian population RAD51 135G>C presumably does not impact on CRC susceptibility and other risk factors should be contemplated for furtherance of management potentials of the disease in Iran .Colon carcinoma can occur due to elevated-expression of RAD51 (rs1801320) and XRCC2 (rs3218536) genes have increased probability of colorectal cancer and both genes are significantly associated with colorectal cancer occurrence and further elucidate the relationship of multiple genotypes at the RAD51(rs1801320) and XRCC2 (rs3218536) locus with colorectal cancer occurrence. The outcomes found from our research are harmonious with various prior studies yet corresponding genotyping analysis in more racial communities is still necessary to confirm the association between SNPs and susceptibility to colorectal cancer. Our results confirmed that RAD51 (rs1801320) and XRCC2 (rs3218536) genes helps to recognize the malfunction of these proteins and can lead to successful therapies for colorectal cancer. In this study, it is observed that the risk factor of developing CRC is noticed in G/C, C/T heterozygote and GC+GG, CT+TT (heterozygote+ mutant) in RAD51 (rs1801320) and XRCC2 (rs3218536) respectively but no significance is found in case of G/G and T/T mutant. So, it can be said that a significant association between RAD51 (rs1801320) and XRCC2 (rs3218536) and colorectal cancer development is confirmed in our population. If the study can be conducted by using more samples from different areas, G/G and T/T mutant can also be found significant. However, it is the first study in Bangladesh and with a limited number of cases and controls. Therefore, RAD51(rs1801320) and XRCC2 (rs3218536) genes polymorphism and colorectal cancer risk is an important research area that needs much more attention as some statistically strong risk factors required to be excluded because of a small number of sample and control. It will also reduce the number of injuries or deaths resulting from incorrect or ineffective prescriptions prescribed for cancer patients and tend to integrate into personalized medicine.In summary, studying SNP in"} +{"text": "The 4Ms of an Age-Friendly Health System start with What Matters to the older adult. A unique method for asking that question is through film. Schaalman Senior Voices (SSV) films older adults talking about What Matters to them, and uses the films to stimulate discussion about later life with older adults in the community (n=264), with health care professions students learning to listen to older adults (n=1250), and health system executives considering implementation of the Age-Friendly Health Systems (AFHS) initiative (n=100). SSV has completed longer professional films interviewing 12 older adults. Using a mobile platform, SSV has filmed 50 older adults in the community and at health events. Outcomes of film discussions will be presented, including inspiration for older adults having conversations with family and physicians about What Matters, health care students effectively using skills in asking What Matters to enhance the care they provide, and executives considering AFHS implementation."} +{"text": "More than 19% of third-graders in Georgia had untreated dental caries (tooth decay) in 2016\u20132017 . The mosDental sealants , topicalWe developed a data visualization tool that maps county-level need for caries prevention and treatment programs and the distribution of dental safety-net programs in Georgia. This tool can be used by public health decision makers to 1) assess how well dental safety-net programs are currently allocated and 2) plan and target future programs.short). We obtained data on the prevalence of untreated tooth decay from a study that estimated this information for children aged 6 to 9 years , DeKalb (143 census tracts), Fulton (202 census tracts), and Gwinnett (113 census tracts). Level of need was based on the estimated prevalence of untreated tooth decay and the severity of a dental workforce shortage as high Dshort areas and census tracts below the median as low Dshort areas.We used data from the Health Resources and Services Administration (HRSA) on the sshort, 2) low prevalence of untreated tooth decay and high Dshort, 3) high prevalence of untreated tooth decay and low Dshort, and 4) high prevalence of untreated tooth decay and high Dshort. We designated counties in category 4 as having the greatest need for dental safety-net programs and counties in category 1 as having the least need. We designated counties in category 3 as having a greater need for dental safety-net programs than those in category 2 because of their higher prevalence of untreated tooth decay.We assigned counties to 1 of 4 categories: 1) low prevalence of untreated tooth decay and low DWe then overlaid information on current Georgia dental safety-net programs onto county need for such programs. Dental safety-net programs included 1) state-sponsored school sealant programs, 2) county-funded public health departments offering dental services, 3) federally qualified health centers offering dental services, and 4) dental hygiene programs providing community dental services. We obtained information on school sealant programs from the Georgia Department of Public Health Oral Health Program , informaOur visualization indicated good allocation of scarce dental public health resources. Of the 131 dental safety-net programs, 88 (67.2%) were in high-need counties, which is twice the number in low-need counties (43 or 32.8%). Many high-need counties, however, did not have dental safety-net programs. Among the 80 high-need counties, 52 had no programs . In high-need areas, programs were more common in the metropolitan Atlanta area than in the rest of the state. This information is important for planning purposes, although the state may not be able to immediately address the problem of dental shortages in nonmetropolitan counties because of resource constraints and the higher cost of serving areas farther away from the State Oral Health Program, which is based in Atlanta.The maps also illustrate the importance of a granular visualization in areas with diverse populations, such as metropolitan areas. If only county levels are used, small pockets of need may be missed, as in Fulton County. Visualization at the census-tract level in Fulton County provides a better assessment of need and targeting.Our mapping technique provides decision makers in Georgia with a visual tool for assessing how well current dental safety-net programs are allocated across the state and identify gaps in resource allocation where needs could be addressed in future program planning. The data used to generate these maps are publicly available for states nationwide and thus, these maps could be replicated throughout the United States."} +{"text": "We investigated the dimensional structure of mental health among aging Korean Veterans using latent profile analysis (LPA) on posttraumatic stress disorder symptoms (PTSD), late onset stress symptomology (LOSS), and psychosocial well-being (PWB). The Korean Vietnam War Veterans Study consists of 367 men . LPA identified five classes of mental health as best fitting the data. Most men were in the normal (38%) and moderate distress (31%) groups, while smaller proportions were in the low affect (13%) and severe distress (7%) groups. The resilient group (12%) had low PTSD, medium LOSS, and high PWB, and were highest on optimism, positive appraisals of military service, and social support. Negative and positive aspects of mental health outcomes were on separate dimensions rather than on a single bipolar dimension. Service providers should attempt to both reduce Veterans\u2019 negative psychological symptoms and increase psychosocial well-being. Part of a symposium sponsored by the Aging Veterans: Effects of Military Service across the Life Course Interest Group."} +{"text": "Hackman G The latest guideline suggest adjuvant radiotherapy or observation following prostatectomy with adverse pathological findings , 2. ThisThe authors founded a 74% benefit of BCRFs in the adjuvant group, and the number needed to treat was 4. There were no difference in the overall survival and in cancer-specific survival, with more grade 1 and 2 adverse events in the adjuvant group.The first results of the RADICALS trial (NCT 005541047) recently presented at ESMO Congress 2019 did not show any benefit in BCRFs (secondary endpoint), supporting the use of early salvage radiotherapy."} +{"text": "Bemisia tabaci poses a major threat to cassava production by small holder farmers in part due to their role as a vector of cassava mosaic begomoviruses (CMBs) and cassava brown streak ipomoviruses (CBSIs). In the present study untargeted metabolomics has been used as a tool to assess natural variation, similarities and attempts to identify trait differentiators among an East African cassava diversity panel that displayed tolerance/resistance to the effects of Bemisia tabaci infestation. The metabolome captured, was represented by 1529 unique chemical features per accession. Principal component analysis (PCA) identified a 23% variation across the panel, with geographical origin/adaption the most influential classification factors. Separation based on resistance and susceptible traits to Bemisia tabaci could also be observed within the data and was corroborated by genotyping data. Thus the metabolomics pipeline represented an effective metabotyping approach. Agglomerative Hierarchical Clustering Analysis (HCA) of both the metabolomics and genotyping data was performed and revealed a high level of similarity between accessions. Specific differentiating features/metabolites were identified, including those potentially conferring vigour to whitefly tolerance on a constitutive manner. The implications of using these cassava varieties as parental breeding material and the future potential of incorporating more exotic donor material is discussed.Cassava will have a vital role to play, if food security is to be achieved in Sub-Saharan Africa, especially Central and East Africa. The whitefly Viral diseases like the cassava mosaic and cassava brown streak diseases (CMD and CBSD) constitute one of the major threats for cassava production in Sub-Saharan Africa (SSA) of parent ions [M] were also excluded. The final data matrix contained 1530 unique chemical features . In order to reduce redundancy, chemical features corresponding to the isotopic species and batch corrected contained 149 observations and 1529 variables and was B. tabaci [To assess the overall biochemical variation of the Eastern African cassava elite varieties, unsupervised PCA was performed on the metabolite composition of leaf extracts. Score plot of components 1 and 2 explained 23% variation of the collection which was comprised of 26 varieties . Three m. tabaci form a tGenetic similarity was evident when analysis of SNPs was carried out to assess the natural genetic variation of the diversity panel and compared to similarities found at chemical composition level. The Ward AHC dendrogram was constructed using the genetic similarities matrix obtained by running 96 highly informative SNP locus among the complete set of the 5CP collection, which includes 31 East African cassava genotypes . These AThe number of significant chemical features differentiating each sub-group of metabolome derived dendrogram were calIn order to study whether the natural variation present in the collection can be utilised to define metabotypes representative of WF-R/WF-S phenotype and also to identify potential chemical markers linked to phenotype, a multivariate classification analysis was applied using the LC-MS untargeted data matrix as input.Supervised discriminant analysis like partial least squares (PLS) are often used for these purposes. In the present study an OPLS-DA model was chosen to incorporate both the orthogonal variation which is inherent of the metabolomics mass spectrometry data and the chemical variation of the different classes of phenotypes.Based on the whitefly abundance data available OPLS-DA p-coumaric acid and caffeic acid and neochlorogenic acid compared to the variation found in other cassavas\u2019 collections including both African and South American cultivars where >5orted by . In effeHistorical breeding efforts of African cassava, documented since in the 1930s , 11, 13 The variability introduced by environmental adaptation factors has likely to have an impact in defining the preference of whitefly adults for certain varieties or the symptoms developed under virus infection and therefore hindering/misleading the identification of true-to-type phenotype classes. This hypothesis/concern also arises when the list of potential biomarkers generated from the classification model (ultimately based on observed phenotype) is investigated further. Pair-wise comparison of the WF-R variety Nase 18 (UG4) and the susceptible Sagonja (MAL5) revealed higher similarity between them than comparison between Sagonja (MAL5) and Kalawe (MAL6), despite both Malawian lines being phenotyped as the most susceptible. Varieties UG4 (Nase 18) and MAL5 (Sagonja) presented a significant number of phenotypic biochemical markers displaying a similar pattern of accumulation in both lines.p-coumaric acid malate esters among other unknown features. Malate esters of p-coumaric and caffeic acid were the most influential in the S-plot and present at lower levels in the resistant varieties UG4, TZ3 and TZ6 whilst neochlorogenic acid accumulated in the Tanzanian varieties resistant to whitefly and viral diseases CMD and CBSD Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Figth and 25th quartiles respectively.(A) Table of calculated coefficient of variation (%) within biological replicates per each variety. Columns indicate median values of CV of all variables and the minimum and maximum CV values of each cassava variety. (B) Violin plot showing within subject coefficient of variation for each variety. Median values indicated as straight lines and top and bottom dashed lines indicate 75(TIF)Click here for additional data file.S4 FigScore plot of components 1 and 2 displaying all biological replicates of each cassava variety as small symbols and median values as large symbols. Geographical origin is denoted with different colouring: Kenya (KE) as green, Malawi (MAL) as light blue, Mozambique (MOZ) as blue, Tanzania (TZ) as orange and Uganda (UG) as purple; and number of variety indicated as different symbols: (circle) variety 1, (box) variety 2, (triangle) variety 3, (diamond) variety 4, (pentagon) variety 5, (hexagon) variety 6, (4-point star) variety 7 and (5-point star) variety 8.(TIF)Click here for additional data file.S5 Fig(PDF)Click here for additional data file.S1 File(XLSX)Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(PDF)Click here for additional data file."} +{"text": "Family caregivers play an important role in the healthcare of older adults, but their circumstances, needs, and risks are often unknown to medical professionals. Standardizing how caregivers\u2019 needs are assessed in healthcare delivery can help clinicians design care plans that take caregivers\u2019 capabilities into account and provide targeted recommendations for caregiver support. Despite the potential of caregiver assessment, little is known about its use in primary care practice. The present study surveyed a national random sample of 1,000 U.S. primary care clinicians to characterize current practices, barriers, and facilitators of caregiver assessment. A total of 231 completed responses were received. A minority of respondents (11%) reported that their practice or clinic had a standardized procedure for caregiver assessment; one in ten (10%) reported that they had personally conducted a caregiver assessment using a standardized instrument in the past year. The most common barriers to caregiver assessment were lack of time (65%), inability to have private discussions with caregivers (36%), lack of access to referral options (30%), inadequate reimbursement (30%), and reluctance of caregivers to discuss their needs (30%). The most frequently endorsed facilitators to aid future implementation included better availability of referral options (77%), easier referral mechanisms (67%), co-location of mental health specialists, care managers, or social workers (65%), and training in how to address caregiver issues (61%). Findings are discussed within the context of emerging healthcare policies and practice initiatives designed to promote caregiver assessment in health care settings."} +{"text": "The University of New England College of Osteopathic Medicine (UNECOM) Geriatrics Education Mentor (GEM) Program is in its sixth year. It's a joint project between older community living adults and 2nd year medical students within the Osteopathic Clinical Skills course. The GEM program goal is to foster understanding and importance of the person/patient-provider relationship. Pairs of osteopathic medical students (N=87 +/- 5) were assigned to an older adult GEM (mentor) volunteer (N=87 +/-5) living within a 50 mile radius of UNECOM. Snowball sampling was used to recruit the GEMs; student participation is required. Four (4) home visits were conducted over 9 months with an assigned GEM; each visit included a new assignment. Students observed, summarized, and recorded experiences communicated by the GEM for each cumulative assignment. Data from assignments were \u201cgraded\u201d and content analyses of open ended evaluation/summary questions were conducted. This program is UNE IRB approved. Student pairs completed all assignments. Assignments analysis on Blackboard revealed that students developed respect and awareness of life and medical experiences of the GEM; expressed understanding of the GEM\u2019s life experiences and goals for what \u201cmatters most\u201d. Relationships with older adults were established while students maintained professionalism and succeeded in competent and confident interactions. Documentation review from the 4 assignments aided in building students\u2019 geriatrics knowledge, attitudes and skills. Pre-clinical medical education tends to be episodic; providing an opportunity to establish longitudinal assignments over the course of the academic year with the same older adult augments relationship skills and learning in geriatrics."} +{"text": "The exposure of male individual to environmental toxicant is regarded as a channel that results in reduced sperm counts and infertility.This study investigated the ameliorative response of Sulforaphane (SFN) on Aluminum trichloride were divided into four groups (n = 8/each). Group A) received distilled water orally as placebo; Group B) received 100 mg/kgbw AlCl The sperm parameters showed a significant difference within the AlCl The present study revealed the ameliorative response of SFN on AlCl The exposure of male individual to environmental toxicant is regarded as a channel that results in reduced sperm counts and infertility . Aluminum is considered as the most common metallic element detectable in natural waters, animal, and plant tissues (3) leading to a significant upsurge in both gastrointestinal absorption and urinary elimination of aluminum in exposed individuals (4). The affinity of aluminum to other elements stimulates free radical-mediated reproductive cytotoxicity causing impairment of testicular tissues to both humans and animals (5). Aluminum compounds are widely used as by-products for the manufacture of several household cooking utensils andpharmaceutical drugs (6). Increase in the level of exposure to aluminum-containing products will boost the concentration of this metallic element in different organs thereby causing harmful effects to the well-being of humans (7).In addition, elevated concentrations of Aluminum in human sperm and seminal plasma were observed to decrease sperm viability and motility (8). Testicular Aluminum accumulations cause spermatocyte necrosis and trigger other reproductive toxicity through several mechanisms such as oxidative stress, which ultimately interferes with spermatogenesis and steroidogenesis, bloodtestis barrier, and endocrine disruption (9). The application of nutritional antioxidant supplements has increased over the years to tackle oxidative stress-induced tissue damage since they act as defense regulators and scavengers of reactive oxygen species. Sulforaphane (SFN) is the most active natural products found in crucifers such as broccoli sprout, cabbage, and kale with the potential of lowering the risk of cancer, oxidative stress-induced tissue injury, and age-related diseases (10). SFN possess antiproliferative activities and can effectively halt the initiation and progression of chemically induced tissue damage in animals (11). In addition, SFN has been suggested to have antidiabetic properties for normalizing changes in blood glucose and insulin sensitivity (12-14), and is used in cardiovascular and antihypertensive protection . It has been reported that SFN can promote elimination and detoxification of aflatoxin (17), acetaldehyde (18), methylmercury (19), acrolein (20), benzene, crotonaldehyde (21), and free radicals (22) through the Nrf2-mediated mechanism. Furthermore, some clinical studies have demonstrated the effectiveness of SFN supplements in the prevention and/or improvement of skin erythema (23), autism (24), insulin resistance (13), Helicobacter pylori-infection (25), and liver abnormality (26). SNF also has the ability to cause programmed cell death(apoptosis) and cell cycle arrest linked to their ability to regulate several proteins such as Bcl-2 and Bax family proteins, caspases, p21, cyclins, and cyclin-dependent kinases (27).This study was therefore designed to investigate the ameliorative response of SFN on the histomorphometric and enzymatic antioxidants on Aluminum chloride were obtained from the animal house, Department of Human Anatomy, Ladoke Akintola University of Technology, Ogbomosho. The rats were collected in an isolated cages in the experimental house of the Department of Human Anatomy, Federal University of Technology, Akure. They were maintained under constant 12 hr light/dark cycle.The rats were divided into four groups (n = 8/each) Group A) represent control and received water as placebo. Group B) were administered with 100 mg/kgbw AlClAll animals were observed for any behavioral anomalies, illness, and physical anomalies. The experimental procedures were conducted in accordance with the provided recommendations in the \u201cGuide for the Care and Use of Laboratory Animals\u201d prepared by the National Academy of Sciences. The rats were fed with standard rat chow and drinking water was supplied ad libitum. The weight of the animals was recorded at procurement, during acclimatization, at commencement of the experiment, and weekly throughout the experimental period using a CAMRY electronic scale .\u201cAfter the last administration, the rats were administered intraperitoneal pentobarbital sodium (40 mg/kg) and their abdominal region was opened and the testes of all the animals were immediately removed. The testicular weight of each rat were recorded. The rats were decapitated and blood samples were collected for analysis. The blood samples were centrifuged at 4\u00b0C for 10 min at 250\u201cThe spermatozoa from the cauda epididymis were obtained by cutting into 2 ml of medium (Hams F10) containing 0.5% bovine serum albumin (29). After 5 min of incubation at 37\u00b0C (with 5% COThe level of lipid peroxidation products were estimated in accordance with the method published by Adelakun and co-workers. (31). Nonenzymatic antioxidants such as reduced glutathione (GSH) and catalase (CAT) were estimated as described by Adelakun and co-workers. The SOD activity in the testes was also determined according to the method described by Adelakun and co-workers (31).\u201cThe hormonal levels of testosterone (TT), follicule-Stimulating Hormone (FSH), and Leutenizing Hormone (LH) were measured using available immunoassay (ELISA) kits according to manufacturer's instructions\u201d.\u201cThe testes of the rats were harvested and fixed in Bouin's fluid for 24 hr before being transferred to 70% alcohol for dehydration. The tissues passed through 90% and absolute alcohol and xylene for different durations before being transferred into molten paraffin wax for 1 hr each in an oven at 65\u00b0C for infiltration. The tissues were embedded and serial sections cut on a rotary microtome set at 5 microns were performed. The tissues were picked up with albumenized slides and allowed to dry on hot plates for 2 min. The slides were dewaxed with xylene and passed through absolute alcohol (two changes), 70% alcohol, 50% alcohol, (in that order), and then in water for 5 min. The slides were then stained with Hematoxylin and Eosin, mounted in DPX, and photomicrographs were taken at a magnification of 100 \u201cMorphometric studies were carried out with modification of Akang and co-workers (32). Briefly, four sections per testis and six microscope fields per section were randomly chosen for analysis. Fields were sampled as images captured on a Leica DM750 bright field microscope (Germany) via LAZ software. Volume densities of testicular ingredients were determined by randomly superimposing a transparent grid comprising 35 test points arranged in a quadratic array. Test points falling on a given testis and its ingredients were summed over all fields from all sections. The total number of points hitting on a given ingredient (lumen (EL), epithelium (EE), interstitium (EI)), divided by the total number of points hitting on the testis sections (ET) multiplied by 100 provided an unbiased estimate of its percentage volume density/volume fraction. The estimation of the volumes of seminiferous tubule EE (seminiferous EE) and EI in the testes was done in accordance with Howard & Reed (33) and Baines and co-workers\u201d (34).\u201cThis was carried out according to the method described by Adelakun and co-workers (31). Briefly, quantitative evaluation of spermatogonia, preleptotene, pachytene spermatocytes, and round spermatid cells was performed using 50 round tubules per group selected in stage VII/VIII of the seminiferous tubule cycle at All animal handling procedure and research activities was approved by the Ethics Committee of the College of Medicine, University of Lagos, Nigeria (CM/ HREC/07/19/120).Where applicable, data obtained were analyzed statistically using one-way ANOVA, followed by Dunnett's comparison test. Data were expressed as Mean In addition, there was a significant decline in the relative weight of the testes in the rat that received AlClThere was a significant decrease in the body weight in the rats administered with AlClThe spermatozoa concentration showed a significant difference within the AlClIn addition, there was a significant decrease in sperm motility in the group administered with AlClFurthermore, the spermatozoa viability was significantly decreased after AlClThe AlClThere was a significant decline in the levels of serum TT, FSH, and LH in rats treated with AlClThe rats administered with AlClThe testicular histoarchitecture of the AlClThe volume density of the germinal of the AlClConcerning the EI, the AlClThe testicular germ cell count such as spermatogonia, preleptotene and pachytene spermatocytes, and round spermatids count in the seminiferous tubules showed a significant decrease in the counts compared to the control . Although, the germ cell count after the administration of SFN and AlClAn emerging pandemic global public health issue after cancer and cardiovascular diseases is infertility due to increase in testicular cancer (35) and based on the analysis on semen parameters such as reduction in sperm counts and qualities in various countries . The exposure of male individual to environmental toxicant is regarded as the channel that results in reduced sperm counts and infertility . Aluminum is considered as the most common metallic element detectable in natural waters, animal, and plant tissues (3). Compounds of Al due to its reactivity with other elements such as Sulphur and chloride are widely used in many products such as storage utensils, household cookware, food additives, toothpaste,and pharmaceuticals (3). The enormous rate of exposure to Al increases the chances of health-related issues to human due to increase metallic concentration in various organs thereby damaging various tissue of the body including testicular tissues of animals and humans (38). Testicular weight is crucial in the evaluation of male fertility test due to its important association in sperm production (39). In our study, the decrease in body and testicular weights observed after AlClThe seminal fluid analysis were significantly declined in the AlClThe process of spermatogenesis has been implicated to be under the regulation of reproductive hormones such as TT, FSH, and LH. In this present study, our results showed a decrease in this reproductive hormone after AlClThe antioxidant defense system prevents the cells of the body against the injurious effect of Reactive Oxygen Species (ROS) produced due to exposure to environmental toxicants, ultimately inducing toxicity to the reproductive system by perturbing the pro-oxidant and thereby leading to oxidative stress (53). Our study showed that exposure to AlClThe histomorphological features of the testis are critical and usually refer to as the endpoint in the evaluation of male fertility assessment and reproductive toxicity (56). In our study, histological observation of animals that received AlClThe present study revealed the ameliorative response of SFN on AlClThe authors declare that there is no conflict of interests regarding the publication of this paper."} +{"text": "After this article was publIn rnf-5(RNAi)) appear similar.In The authors noted that these panels were duplicated due to errors in figure preparation. An updated version of The following images have also been removed in the updated figure: the second panel in right column of As noted in the figure legend, the images shown in Raw data underlying all other results reported in the article are available.The authors apologize for the errors in the published article.S1 File(XLSX)Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(XLSX)Click here for additional data file."} +{"text": "Therefore, the serious ethical concerns regarding artificial intelligence are not related to the classification of massive photo data using simple/narrow artificial intelligence (ANI).Artificial intelligence (AI) is divided into 3 groups based on capability: 1) Weak/Narrow/Simple AI (ANI), 2) Strong/General AI (AGI), and 3) Artificial Super Intelligence (ASI).3Medicine is a prominent field that has witnessed a nanotechnological revolution. However, due to the current views in philosophy and ethics, this emerging technology can be considered inconsistent or conflicting with what most ethicists in the area of medicine hold to be true. Nanotechnology and neuroscience are raising unavoidable questions concerning the ethical justification of human enhancement and intervention.4The main ethical issues are related to the use of AI in general (AGI) and superintelligence (ASI) in particular. These two groups of AI need to be audited during their advancement, as they have the capacity to develop in a versatile and unpredictable direction. Providing safety measures to prevent any direct or indirect coercion can only be possible through continuous ethical evaluations and monitoring of technological development."} +{"text": "Data comprised last year gamblers of three merged cross sectional Icelandic gambling surveys of 2007, 2011, and 2017 (N\u2009=\u20094422). For each of 15 game types (12-month time frame), a parallel multiple mediation model was applied to disaggregate bivariate associations of last year game type participation and problem gambling (Problem Gambling Severity Index) by six mediating mechanisms: (1) demographic problem gambling propensity, (2) number of game types played, (3) gambling frequency within the type, (4) maximum gambling frequency across all types beyond, (5) usual spending within the type, (6) maximum usual spending across all types beyond. Games showed two distinct profiles via which mediator they mostly impacted problem gambling: Electronic gaming machines offline, scratch cards offline, live betting online, and poker offline as well as online impacted problem gambling mostly via gambling frequency within, whereas all other types mostly impacted via the number of game types played. The applied mediation models answer the question by which mechanism game types impact problem gambling in a more exhaustive way than previous research.Bivariate associations of problem gambling with participation in particular game types often decrease when adjusting for demographics or consumption behavior . A summary of 14 peer-reviewed studies showed inconsistencies as well as conceptual and methodological challenges. The aim of this study was to expand previous research by a combination of (1) sophisticated feature-engineering, which disaggregates gambling intensity into facets In general, it is a well known fact that problem gamblers tend to invest more time and money into gambling and usually participate in a larger number of games than non-problem gamblers were applied. However, all of them were based on vastly different samples, ranging from the general population of Australia to patrons of two Las Vegas resort casinos Table\u00a0. In addiHowever, in spite of the methodological variations, the core idea of all data analyses was to examine the statistical association of participation in a specific game type and problem gambling. Therefore, participation in individual game types was applied as a predictor of problem gambling outcomes. This was done either in simultaneous model estimation with all game types and other covariates . They also underlined the importance of another construct of overall gambling intensity, the depth of involvement. Exemplary measures of depth of involvement include frequency of gambling across all game types during the last year combined . This further complicates the complex relationship between problem gambling, game types, context, individual predisposition, and behavior .In sum, the partially inconsistent empirical results of previous sophisticated regression-based studies document the complex relationship between gambling behavior and problem gambling as well as the challenges statistical modeling approaches of this relationship face. Hence, it is a major duty for further research (1) to disentangle the complexity of gambling problems and behavior as precisely as possible and (2) to provide a valid groundwork for evidence-based harm reduction measures referring to particular game types and overall gambling behavior in a given population. In a more practical sense, the inconsistent previous results also show that an unbiased evaluation of the impact of participating in particular game types on problem gambling behavior has to consider (1) demographic characteristics of the gambler and (2) his overall gambling behavior depth and breadth of involvement in regression-based models, however, not only results in the aforementioned empirical inconsistencies, but also in several methodological problems: First, the additionally inclusion of measures of overall gambling intensity (breadth or depth of involvement) in a bivariate model that predicts problem gambling by gambling participation in a specific game type only allows for indirect appraisals of the importance of the intensity measure. The extent of the decrease in statistical association of game type and outcome may be indicative for such an indirect appraisal by which a predictor variable X affects an outcome variable Y (problem gambling). In other words, mediation analyses answer the question how a predictor impacts an outcome and provide explicit point estimates and confidence intervals for specific mediating mechanisms of problem increasing gambling behaviors. Particularly this aspect qualifies parallel multiple mediation analysis to compare the importance of different plausible mechanisms within and beyond a game type, which may impact problem gambling.Against this background of empirical inconsistencies and methodological challenges, mediation analyses may solve some of the outlined problems. The core idea of mediation analyses Hayes is to exIt is worth noting that the depicted previous linear-regression models in their current way of application are similar to an old-fashioned approach of mediation analyses, the so called \u201ccausal steps approach\u201d Hayes . The criMoreover, percentile bootstrap estimation of indirect effects and their confidence intervals is able to cope adequately with some bias caused by strongly correlated mediators like in the case of measures of gambling intensity. Neglecting correlated mediators can affect the standard errors of the association of mediator and the outcome of interest . This in turn affects statistical inference with normal-theory-tests for indirect effects no explicit statistical information about the importance and confidence of specific mechanisms probably impacting problem gambling, (2) multicollinearity of gambling behaviors, (3) lack of conceptual clarity]. The proposed gambling consumption mediation model (GCMM) in the following analyses provides a novel analytical framework that includes (1) last year participation in particular game types as dichotomous predictor variable , (2) different proxy measures of gambling involvement (within and beyond the type of interest) as parallel mediators, and (3) a formative index of socio-demographic covariates that commonly increase the risk of problem gambling as another mediator that may pose an additional way via which particular game types impact an (4) outcome of problem gambling. The presented analytical approach of parallel multiple mediator models for each individual game type in the GCMM generates precise information by which specific indirect effect participation in a particular game type increases gambling problems. These empirically confirmed mechanisms can be addressed precisely by evidence-based harm reduction measures. Moreover, the applied mechanisms of the model (demographics or gambling behavior) are (1) founded in current research (Table\u00a0The aim of this study is to provide a new framework of models 2012\u20132019 by Andrew F. Hayes), a syntax oriented supplementary tool for advanced mediation analyses in SPSS and SAS, based on ordinary least squares path analysis .A conceptual map of the applied parallel mediation models for each game type is illustrated in Fig.\u00a0p-level of 5% most game types showed statistically significant changes across the years of the surveys. Only scratch cards offline and sport betting offline showed no significant changes. However, the majority of changes were based only on minuscule effect sizes with Cramer\u2019s\u00a0V values below 0.1.Table\u00a0A small effect emerged for lotto offline with increasing participation from 2007 (75.6%) to 2011 (79.4%) and decreasing participation in 2017 (68.0%). A small effect also emerged for lotto online on an Icelandic website with an increasing participation from 8.7% in 2007 to 10.5% in 2011 and 19.5% in 2017. Moreover, participation in live betting online on Icelandic or foreign websites increased from 0.8% in 2007 to 4.6% in 2017. Also sport betting online on a foreign website increased from 0.2% in 2007 to 1.2% in 2011 and 5.3% in 2017. Poker offline increased from 7.4% in 2007 to 15.5% in 2011 and decreased again to 9.6% in 2017. Participation in bingo offline changed from 8.9% in 2007 to 15.2% in 2011 and 21.1% in 2017. Dividing participation rates of 2017 by rates of 2007 showed that the mean ratio for all 8 offline game types was 1.04 with largest growth values for bingo offline (2.36) and poker offline (1.29). In contrast, the ratio of 2017/2007 prevalence rates for the 7 online game types showed a mean growth rate of 7.06 with largest values for sport betting on foreign websites (24.89), poker online on a foreign website (7.15), live betting on an Icelandic or foreign website (5.85), and other online gambling on foreign websites (4.31).p\u2009\u2264\u20090.05) but minuscule effect sizes (Eta Square\u2009<\u20090.01) for the majority of inspected attributes . The only at least small effects (0.03\u2009\u2265\u2009squared eta\u2009\u2265\u20090.01) emerged for the following attributes: The number of game types involved in increased from a mean of 1.660 in 2007 to 1.921 in 2011 and 1.944 in 2017. Frequency within bingo offline, lotto online on an Icelandic website, sport betting online on foreign websites, and live betting online on Icelandic or foreign websites increased from 2007 to 2017. Usual spending within bingo, lotto online on Icelandic websites, sport betting online on foreign websites, live betting online on Icelandic or foreign websites, and poker offline increased from 2007 to 2017. Usual spending beyond a given game type increased for every game type from 2007 to 2017.Kruskal\u2013Wallis tests of the metric and ordinal variables across the years of the surveys also showed significant within and beyond in many or even all game types. However, all relevant trends showed only small effect sizes between 2007 and 2017. Consequently, treating the entire dataset as one homogeneous population in the following analyses represents a justified step.Model estimates for unstandardized effects and 95%-percentile bootstrap confidence intervals of the parallel multiple mediation models are presented in Tables\u00a0total effects on problem gambling of last year participation in 11 of the 15 game types were of statistical relevance and 10 types were of problem increasing impact . Lotto offline was the only game type with a statistically relevant problem decreasing impact . For several game types the total impact on problem gambling was not statistically relevant: Lotto online on an Icelandic website, sport betting online on a foreign website, bingo offline, and other online gambling on foreign websites (not poker or betting).The Direct effects of game type participation on gambling problems became non significant for 8 of the 15 game types. Statistically relevant problem increasing direct effects of last year participation when simultaneously considering all other mediating impacts were left only for lotto offline, sport betting online on a foreign website, and other online gambling on foreign websites (not poker or betting). Problem decreasing direct effects occurred for sport betting online on an Icelandic website, EGMs offline, scratch cards offline, and poker offline.specific indirect effects (a*b-paths) which provides an effect size and confidence intervals for each mediator, while considering the direct path and all other mediators (indirect paths) within the model simultaneously. The metric of the unstandardized effects is determined by the scales of the X and Y variables (winsorized sum score of gambling problems), which both were similar across all analyzed game types. Hence, the size of the indirect effects is comparable across the mediators.However, total and direct effects are only of minor interest in the parallel mediation analyses at hand that try to answer the following question: By which mediator (gambling behaviors or demographic propensity) is last year participation in game type X impacting gambling problems most severely? This aspect can explicitly be tackled by the quantification of breadth or (2) mostly via frequency within.A close look at the specific indirect effects revealed two distinct profiles of decisive mediators impacting gambling problems within the different game types: (1) mostly via breadth (number of game types involved in). Breadth was the strongest mediating mechanism of gambling behavior on gambling problems for participating in:lotto offline,lotto online on an Icelandic website,betting on sport pools offline,betting on sport pools on an Icelandic website,sport betting offline,sport betting online on an Icelandic website,sport betting online on a foreign website,betting on skill games offline,bingo offline andother online gambling on foreign websites (not poker or betting).Table\u00a0frequency within. Frequency within was the strongest mediating mechanism of gambling behavior on gambling problems for participating in:EGMs offline,scratch cards offline,live betting online on an Icelandic or foreign website,poker offline andpoker online on a foreign website.Table\u00a0The decision about the most important mediating gambling behavior was unequivocal in almost all game types. For several game types there was only one relevant positive indirect effect like breadth for lotto offline or lotto online on an Icelandic website (positive a*b-path). All other mediating mechanisms did not show statistically relevant effects for these two game types or even showed problem decreasing effects such as propensity for lotto offline or online on an Icelandic website (negative a*b-path).But these negative effect sizes did not mean that the mediating path propensity was not associated with gambling problems for individuals that participated in lotto (positive b-path). Rather, the negative effect was the consequence of a negative association of gambling lotto offline and demographic problem gambling propensity (negative a-path). In other words: Individuals who participated in lotto showed a reduced level of demographic propensity for gambling problems . Consequently, the product of a*b for the mediator propensity among individuals participating in lotto offline showed negative effect sizes. Hence, this mediator could not be an important problem increasing mechanism for lotto offline, even if it was positively associated with gambling problems in general.problem reducing impacts were not plausible from a theoretical position . However, in all five depicted situations with statistically relevant negative single b-paths the products of a*b-paths were not statistically relevant. Hayes in the following situations: (1) betting on sport pools online on an Icelandic website via spending within; (2) live betting online on a foreign or Icelandic website via spending within; (3) sport betting online on foreign websites via spending within; (4) other games online (not betting or poker) on a foreign website via frequency within; (5) other games online via usual spending within. These t. Hayes , p. 520 breadth of involvement (10 game types) or (2) via frequency of gambling within that type of interest (5 game types).A simple descriptive rule of thumb to determine the most important mediator among a game type is to divide the largest statistically relevant and positive effect by the second largest relevant and positive effect within a game type . In almost all game types, this ratio was between values of 3.96 (betting on sport pools on an Icelandic website) and 2.20 (live betting online on an Icelandic or foreign website), indicating distinct orders of most important mediating mechanisms (effect size of the most important mediator outperforming the second by at least factor 2 in 14 of 15 game types). The only exception from this order was betting on skill games offline, with a ratio of only 1.64 between the mediators breadth and propensity, indicating a more equivocal profile of most important mediators among this game type. Participation in any other analyzed game type was unequivocally most strongly mediated either via (1) However, the remarkable positions of the two mediators breadth and frequency within for some game types did not disqualify the other mediators in the GCMM as redundant. On the contrary: Propensity and frequency beyond both showed statistically relevant specific indirect effects in 14 of 15 game types, spending beyond in 13 of 15 game types, and spending within in 3 of 15 game types.The presented GCMM provides, for the first time, an analytical frame work to disentangle the complex network of (1) last year participation in particular game types, (2) an outcome of problem gambling and different proxy measures of (3) socio-demographic problem gambling propensity, (4) overall gambling involvement , and (5) game type-specific gambling involvement . The chosen approach of parallel multiple mediation analyses allowed for explicit quantification of the behavioral or interpersonal mechanisms, by which participation in specific game types impacts the outcome of problem gambling. Cohort analyses of the three merged Icelandic surveys warranted treating the empirical dataset as homogeneous population even though the number of used game types increased slightly and online game types showed continuously increasing levels of participation.p-levels within the parallel mediation analyses at hand were not adjusted for multiple testing, in order to uphold statistical power of the first time application of the GCMM. Further research may apply a more confirmative approach of model testing, including model-fit-statistics, but the aim of this study was rather exploratory.A short summary of 14 peer-reviewed regression-based studies outlined inconclusive results as well as methodological and conceptual challenges that can partially be resolved by the chosen approach of parallel multiple mediation analyses for each particular game type with the proposed mediating mechanisms characterizing gambling behavior and demographic problem gambling propensity. The state-of-the-art percentile bootstrap procedure to estimate effects and confidence intervals of mediators is able to cope adequately with unspecified correlated error terms (multicollinearity of mediators), providing robust estimates of indirect effects with adequate errors of type I and II. Inconsistent results of former research may be partially caused by a lack of such robustness and statistical power of very complex models with many highly correlated predictors. Consequently, statistical mediators appears to be conceptually more convincing than the commonly applied regression-based models with many covariates, because gambling behavior in terms of regularity, diversity, and spent money or time may be part of the etiological process of developing gambling-related harms and problems\u2014not only a covariate one has to adjust for statistically.Treating different attributes of problem gambling behavior or propensity as Of course, mediation analyses are mathematically also regression-based, but the product-term a*b to quantify indirect effects provides additional information. Mediation analyses enabled us to quantify effects and confidence intervals to make precise evaluations of the most important mediating mechanisms by which behavior particular game types impact gambling problems. This information is of notable interest for testing competing models or theories Hayes and for within and beyond as well as the number of game types a person was involved in. The applied maximum function to aggregate the beyond variables was chosen to curtail high correlations with the breadth variable, which occur by the alternative sum function across all game types. Further research is needed to make an informed choice about the most appropriate aggregation, because mean or median functions could also be useful proxies. However, the combination of (1) mediation analyses and (2) precise feature-engineering revealed explicit estimates and insights which were mostly concealed or at least only implicit in former research.The outlined analytical potential of mediation analyses was combined with a very elaborate process of feature-engineering for proxy measures of gambling behavior which distinguished mechanisms of demographic propensity, usual spending and frequency frequency within these types and not by the breadth of involvement or any other mediating variable of the model. Interestingly, results support findings of previous studies in which some of these types still showed explanatory power for gambling problems despite lots of other covariates in the models see: Afifi et al. The empirical findings of the GCMM showed that last year participation in (1) EGMs offline, (2) scratch cards offline, (3) live betting online on Icelandic or foreign websites, (4) poker offline, or (5) poker online on foreign websites impacted gambling problems mostly via mechanisms of gambling To our knowledge, the GCMM represents the first analytical approach that provides explicit estimates of indirect effects and confidence intervals of the most important mediating mechanisms of a game type of interest impacting problem gambling. This data-driven information facilitates a valid evaluation of risk increasing mechanisms of game types and complements former evaluation tools impacted gambling problems mostly in a qualitatively distinct way different from the breadth mechanism\u2014namely via gambling frequency within the type of interest. Furthermore, type-specific measures of gambling frequency within EGMs and poker. Obviously, the GCMM has the potential to conceptually support, model and specify a promising line of research on gambling consumption that tries (1) to explicate the dose\u2013response-relationship of gambling intensity and measures of gambling related harm and (2) to establish evidence based thresholds of low-risk gambling intensity by risk-curve- and receiver-operating-characteristic-curve-analyses , supply and access reductions may be effective due to the simple and convincing mechanisms of the total consumption model of game type participation on gambling problems still showed stabile risk increasing or decreasing impacts. For instance, (1) lotto offline, (2) sport betting online on a foreign website, or (3) other online gambling (not betting or poker) on a foreign website showed direct problem increasing impacts. On the contrary, (4) sport betting online on an Icelandic website, (5) EGMs offline, or (6) scratch cards offline or (7) poker offline showed direct problem decreasing impacts (some kind of protective effect). Obviously, the applied mediators of the GCMM were not able to disentangle the complexity of gambling behavior exhaustively and other potential mediators may be at work that can additionally explain direct effects thoroughly. A mediation model which includes all relevant mechanisms will dissolve all direct effects (c\u2032-paths) completely. Hence, future research on mediating mechanisms on problem gambling should include additional variables, for instance psychological or psychiatric attributes or other operationalizations of propensity that include comorbidities or attributes of personality. For example, the problem increasing direct effect of lotto may be attributable to demographics and health related behavior demographic propensity, of which information is available in most monitoring datasets, and via which game type participation may positively impact ascending levels of problem gambling. Therefore, the result section was mainly narrowed to the problem increasing mechanisms, mostly disregarding problem decreasing mechanisms. Further research is needed to elaborate potential beneficial mechanisms or protective factors. Further research should also specify the applied descriptive rule of thumb (ratio of largest and second largest positive indirect effect) to discriminate both emerging mediating profiles (mostly via breadth or via frequency within) by inferential statistics. Moreover, structural equation models could be applied to explicitly include correlated mediators into the statistical model.The focus of the current GCMM was on mechanisms of (1) The aggregation of demographic information into a mediating propensity score allows for precise comparison of the indirect effect sizes of demographics and behavior. However, in other situations applying demographics as covariates or moderators may be more adequate.The analyses at hand treated gambling problems as a continuously ascending scale. Treating gambling problems as a nominal attribute with different estimates for qualitatively different groups of low, medium and high risk gamblers may be a fruitful extension of the GCMM. Additionally, modeling outcomes of gambling-related harms (Delfabbro and King mode of access and (2) certain access configurations could have remarkable impacts on the GCMM, but are currently not considered adequately . Therefore, the proposed way to distinguish game types statistically by their most important risk increasing mechanism was obviously unaffected by cursory classification in online or offline game types. At the same time, particularly for Internet gambling, it is worth noting that (1) the way or In general, the GCMM is in line with other recent research that sheds light on relevant gambling issues by advanced methods of statistical modeling . Therefore, future secondary data analyses on such datasets with the proposed modeling procedure of this study have the potential to replicate and extend the suggested blueprint at hand in different countries with diverse gambling products, contexts, and regulations.This study addressed several limitations in previous research on the complex interactions of participating in different game types, problem gambling, and individual gambling behavior or vulnerabilities. Taken together, the proposed GCMM overcomes current methodological challenges by (1) a parallel multiple mediation approach in combination with (2) sophisticated feature engineering of gambling behavior and provides explicit information about the mechanisms by which participation in specific game types mostly impacts problem gambling\u2014either mostly within or mostly beyond the type of interest."} +{"text": "While eHealth programs equip survivors with tools at where and when they need, their benefit to and engagement patterns among older adults are less known. Data come from the Springboard Beyond Cancer RCT, a cancer survivor self-management program and the corresponding qualitative evaluation/user testing (N=40). Younger survivors, but not older, preferred socially interactive and personalized long-in features which enable greater tailoring of the program. However, the older survivors who did enroll in the RCT were equally as likely as their younger counterparts to engage with one or more aspects of program. Health self-efficacy improvement from baseline to 3 months was significant among younger participants in the intervention (p<.05) but not the control arm (p=.54) (d=.20) and marginally significant among older survivors (age 60+) in intervention (p=.06) but not the control arm (p=.58) (d=.28). Results suggest that the program may benefit survivors regardless of age. Part of a symposium sponsored by the Cancer and Aging Interest Group."} +{"text": "Esophageal cancer is the eighth most common cause of cancer mortality in Japan. More than 11,000 people had died from esophageal cancer in 2018. The Japan Esophageal Society has collected the data on patients' characteristics, performed treatment, and outcomes annually.We analyzed the data of patients who had first visited the participating hospitals in 2013. In 2019, the data collection method was changed from an electronic submission to a web-based data collection using the National Clinical Database (NCD). Japanese Classification of Esophageal Cancer 10th by the Japan Esophageal Society (JES) and UICC TNM Classification 7th were used for cancer stagingA total of 8019 cases were registered from 334 institutions in Japan. Squamous cell carcinoma and adenocarcinoma accounted for 87.8% and 6.3%, respectively. The 5-year survival rates of patients treated using endoscopic resection, concurrent chemoradiotherapy, radiotherapy alone, or esophagectomy were 88.3%, 32.4%, 24.4%, and 59.3%, respectively. Esophagectomy was performed in 4910 cases. The operative and the hospital mortality rates were 0.77% and 1.98%, respectively. The survival curves showed a good discriminatory ability both in the clinical and pathologic stages by the JES system. The 5-year survival rate of patients with pStage IV in the UICC classification that included patients with supraclavicular node metastasis was better than that of patients with pStage IVb in JES classification.We hope this report contributes to improving all aspects of the diagnosis and treatment of esophageal cancer in Japan. We deeply appreciate the great contributions of many physicians in the registry of esophageal cancer cases. The Comprehensive Registry of Esophageal Cancer in Japan, 2013, was published here. In 2019, the data collection method was changed from an electronic submission to a web-based data collection using the National Clinical Database (NCD). Personal information was replaced with individual management code inside each institute, and the NCD collected only anonymized information. The registry complies with the Act for the Protection of Personal Information.We briefly summarized the Comprehensive Registry of Esophageal Cancer in Japan, 2013. Japanese Classification of Esophageal Cancer 10th by the Japan Esophageal Society (JES) [We hope that this Comprehensive Registry of Esophageal Cancer in Japan for 2013 will help to improve all aspects of the diagnosis and treatment of esophageal cancer in Japan.I.Clinical factors of esophageal cancer patients treated in 2013Institution-registered cases in 2013Patient backgroundTableAge and genderTablePrimary treatmentTableTumor locationTableHistologic types of biopsy specimensTableDepth of tumor invasion, cT (UICC TNM 7th)TableLymph node metastasis, cN (UICC TNM 7th)TableDistant metastasis, cM (UICC TNM 7th)TableClinical stage (UICC TNM 7th)II.Results of endoscopically treated patients in 2013TableDetails of endoscopic treatment for curative intentTableComplications of EMR/ESDTablePathological depth of tumor invasion of EMR/ESD specimensFigureSurvival of patients treated with EMR/ESDFigureSurvival of patients treated with EMR/ESD according to the pathological depth of tumor invasion, pT (JES 10th)FigureSurvival of patients treated with EMR/ESD according to the lymphatic and venous invasionIII.Results in patients treated with chemotherapy and/or radiotherapy in 2013TableDose of irradiation TableDose of irradiation FigureSurvival of patients treated with chemotherapy and/or radiotherapyFigureSurvival of patients treated with definitive chemoradiotherapy according to clinical stage (UICC TNM 7th)FigureSurvival of patients underwent radiotherapy alone according to clinical stage (UICC TNM 7th)IV.Results in patients who underwent esophagectomy in 2013TableTreatment modalities of esophagectomyTableTumor locationTableApproaches to tumor resectionTableVideo-assisted surgeryTableFields of lymph node dissection according to the location of the tumorTableReconstruction routeTableOrgans used for reconstructionTableHistological classificationTableDepth of tumor invasion, pT (JES 10th)TablePathological grading of lymph node metastasis, pN (JES 10th)TablePathological findings of lymph node metastasis, pN (UICC TNM 7th)TablePathological findings of distant organ metastasis, pM (JES 10th)TableResidual tumorTableCauses of deathFigureSurvival of patients who underwent esophagectomyFigureSurvival of patients who underwent esophagectomy according to clinical stage (JES 10th)FigureSurvival of patients who underwent esophagectomy according to clinical stage (UICC TNM 7th)FigureSurvival of patients who underwent esophagectomy according to the depth of tumor invasion, pT (JES 10th)FigureSurvival of patients who underwent esophagectomy according to lymph node metastasis (JES 10th)FigureSurvival of patients who underwent esophagectomy according to lymph node metastasis (UICC TNM 7th)FigureSurvival of patients who underwent esophagectomy according to pathological stage (JES 10th)FigureSurvival of patients who underwent esophagectomy according to pathological stage (UICC TNM 7th)FigureSurvival of patients who underwent esophagectomy according to residual tumor (R)Institution-registered cases in 2013.Tables 8Tables Tables Tables 15"} +{"text": "Bioscience Reports (2017) 37, https://doi.org/10.1042/BSR20170342) have realised that the vector-4 group image of The authors of the original article \u201cEffects of RNA interference-mediated gene silencing of VEGF on the ultrafiltration failure in a rat model of peritoneal dialysis\u201d (The correct The authors would like to express their apologies for any inconvenience caused to the readers of their published article by this error."} +{"text": "Sus scrofa domesticus) is one of the important farm animal contributing 7% of the country\u2019s total animal protein sources in India. In the present study, random hexamer primer was used to amplify the complete mitochondrial genome of Central Indian domestic pig and resolved the complete mitochondrial sequence by shotgun sequencing followed by de novo assembly in MIRA version 4.0.5. The sequence assembly revealed to be 15,827\u2009bp mitogenome of pig (accession no. KT965278). The mitogenome in the present study has 99% homology with previously reported mitogenome of pigs from different parts of the world. The present study is the first report of complete sequence of mitogenome of pig from Indian subcontinent. Mitogenome analysis by MITOS web server revealed similarity of gene order, organization with the other pig breeds and vertebrates, comprising of 13 protein-coding genes, 22 tRNAs, 2 rRNAs and a control region. It was concluded that modified random hexamer can be successfully used for whole mitogenome sequencing using NGS without designing mitogenome-specific primer, thereby reducing cost and labor.Domestic pig ( Sus scrofa domesticus) is domesticated since 8000 years, yet the origin and evolution of domestic pigs of India has not been established. The introgression of exotic genome under state sponsored programs to upgrade the local population using semen or live animals of exotic breeds has diluted the gene pool of local breeds, thus breed specification of the local domestic pig remains questionable. Most studies on Indian domestic pig mitochondrial DNA (MtDNA) are restricted to capillary electrophoresis (CE)-derived short sequence fragments analysis of cytocgrome b, 12S rRNA as out group using MEGA 6 . The 16,827\u2009bp length of the mitogenome of the CI domestic pig showed 99% homology with the available mitogenome sequences in the GenBank and genome annotation was performed using MITOS web server (Bernt et\u00a0al. Pig ("} +{"text": "Sterna paradisaea) a species notable for undertaking the longest migrations of any species as well as breeding in sub-polar habitats and capable of enduring extreme altitude. The complete mitogenome was 16,708\u2009bp long and was typical of other avian mitogenomes in size and content. The phylogenetic position of the Arctic tern within Charadriiformes based on the coding region on the mtDNA corresponded closely to that based on nuclear loci. The sequence will provide a useful resource for investigations of metabolic adaptations of this remarkable species.The analysis of mitochondrial DNA (mtDNA) base composition, codon usage, and genome arrangement patterns can provide insight into metabolic pathways and evolutionary history. Here, we report on the complete mitochondrial genome (mitogenome) of Arctic tern ( Charadriiformes: Laridae: Sternini) are cosmopolitan core water birds closely related to the gulls, noddies, and skimmers. The life histories of 12 generally accepted genera of terns range from that of entirely sedentary to strongly migratory species (Cramp Sterna paradisaea) holds the record for the longest roundtrip animal migration ever recorded electronically of Qiagen DNeasy extracted DNA from mitochondrial-enriched DNA fraction obtained by differential centrifugation. The Illumina MiSeq run generated 8,468,804 paired-end reads that were mapped to complete Sterna hirundo genome . In total, 1.09% of the raw reads mapped to the Sterna hirundo mtDNA and yielded two \u223c12kb and \u223c3\u2009kb contigs that covered 95.62% of the reference genome. Sanger sequencing was used, to add the missing control region (CR) sequence (1158\u2009bp) and to confirm that no CR duplications of Phylogenetic position of the newly assembled complete Arctic tern mitogenome coding sequence within the Charadriiformes was resolved in MEGA 7 (Kumar et\u00a0al."} +{"text": "South Korea has included dementia care as part of their Long-Term Care (LTC) Insurance Program since 2014. Thus, LTC workers are increasingly engaged in dementia care. The purpose of this paper is to elucidate the role of the LTC workers\u2019 occupational identity in their consciousness of human rights as well as their practice of human rights protection. Data were collected in 2018 from 303 LTC workers employed by 12 LTC facilities who completed questionnaires. Their mean age was 53.6 years. We measured occupational identity with a 15-item scale (a=.772), consciousness of human rights for persons living with dementia (PLWD) with a 27-item scale (a=.916), and practice of human rights for PLWD with a 26-item scale (a=.956). Results show that occupational identity was positively associated with consciousness of human rights and practice of human rights . The findings have implications for protecting the human rights of PLWD. Part of a symposium sponsored by the Aging Among Asians Interest Group."} +{"text": "Does change in one lifestyle factor help explain change in another factor or process ? The current modeling was a secondary analysis of a primary care feasibility study of individualized lifestyle (diet and exercise) treatment of metabolic syndrome that achieved 19% reversal over one year. Diet quality was assessed by the Healthy Eating Index (HEI) (2005 Canada); while fitness was assessed by several measures . Three occasions were examined using latent change score and latent growth curve models (in AMOS) to assess whether changes in one domain predicted changes in the remaining domains: (1) diet (measured by HEI or latent construct); (2) fitness (measured by VO2max percentiles or latent construct); and, (3) 10-year risk of cardiovascular disease (by Procam Risk score). Results showed significant improvement in all three domains separately during the intervention, with greater change between baseline and 3-month assessment and continued change between 3- and 12-months. Initial status variables on observed constructs were moderately positively correlated and change in dietary behavior was significantly related to change in fitness levels, but neither were significantly related to change in the 10-year risk of cardiovascular disease. In addition, the associations between change in diet and changes in fitness were inconsistent baseline to 3 months, and 3-12 months. These results offered new insight on relationships among interventions in a behavioural counselling program which can inform future programming."} +{"text": "Treponema pallidum in an infant or fetus, acquired during pregnancy from a mother with untreated or inadequately treated syphilis. Congenital syphilis can cause miscarriage, stillbirth, or early infant death, and infected infants can experience lifelong physical and neurologic problems. Although timely identification and treatment of maternal syphilis during pregnancy can prevent congenital syphilis a condition affecting stillbirths and infants born to mothers with untreated or inadequately treated syphilis regardless of signs in the infant or 2) a condition affecting an infant with clinical evidence of congenital syphilis including direct detection of Demographic and clinical characteristics of infants and their mothers were analyzed using Stata statistical software . On the basis of CDC\u2019s congenital syphilis prevention framework, each congenital syphilis case was assigned to one of four mutually exclusive missed opportunity categories based on the mother\u2019s prenatal care, testing, and treatment history: 1) lack of timely prenatal care with no timely syphilis testing; 2) lack of timely syphilis testing despite timely prenatal care; 3) lack of adequate maternal treatment despite a timely syphilis diagnosis;Among 1,306 congenital syphilis cases reported during 2018, 685 (52.5%) occurred in the South, 465 (35.6%) in the West, 103 (7.9%) in the Midwest, and 53 (4.1%) in the Northeast Census regions . NationaNationally, the most commonly missed prevention opportunity was a lack of adequate maternal treatment despite the timely diagnosis of syphilis during pregnancy (30.7%), followed closely by a lack of timely prenatal care (28.2%) . This naRacial/ethnic disparities existed within the highest morbidity regions. In the South, the most commonly missed prevention opportunity among white mothers of infants with congenital syphilis was lack of timely prenatal care (31.6%), whereas among black and Hispanic mothers, lack of adequate maternal treatment (37.0%) was the most common . In the Nationally, the most commonly missed opportunity for preventing congenital syphilis was lack of adequate maternal treatment, likely driven by the high numbers of cases in the South, where this missed opportunity was most prevalent. The most common missed opportunities for preventing congenital syphilis differed by geographic region. In the West, a lack of timely prenatal care was the most commonly missed opportunity, and in the Northeast, late identification of seroconversion was the most common. Regional clinical and demographic differences in mothers of infants with congenital syphilis indicate that different populations are at increased risk and might require different interventions. The high proportion of mothers with early syphilis in certain regions signals recent heterosexual transmission and the potential for future increases in congenital syphilis cases if no intervention occurs. The high proportions of symptomatic and stillborn infants in certain regions might be related to early syphilis among their mothers, given that higher rates of vertical transmission and worse infant outcomes are associated with early syphilis during pregnancy and a lack of timely prenatal care (28%), followed by late identification of seroconversions (11%); prevalences of these missed opportunities differ regionally and by race/ethnicity.Halting continued increases in congenital syphilis requires understanding the missed prevention opportunities and implementing tailored interventions based on local experience."} +{"text": "Dementia is arguably the most devastating condition of older adulthood with treatment options still elusive. Alzheimer\u2019s is the most prevalent form of dementia where cognitive deficits relate strongly to underlying brain pathology. However, there exist cases in which cognitive performance does not match the corresponding level of neuropathology. Attempts to explain this phenomenon often include the concept of cognitive reserve (CR), whereby greater CR presumably results in less impairment relative to the extent of pathology early in disease progression but also greater impairment once cognitive symptoms manifest. We examined the influence of CR proxy variables (education and occupation) on the relationship between hippocampal volume and cognitive performance on tests of executive control and memory using data from the Czech Brain Aging Study (CBAS). Participants were cognitively normal/with subjective cognitive decline but without actual impairment =66.43; M(education)=15.90; 37 men) or had amnestic mild cognitive impairment =71.37; M(education)=14.92; 85 men). We found that hippocampal volume was significantly related to executive control and memory for participants with aMCI, but only memory for CN participants. Occupational position moderated the association between memory and hippocampal volume in aMCI, with the result approaching significance (p=.07), whereby a greater link between memory problems and hippocampal atrophy was present in those previously in high occupational positions. No other moderations for occupational position or education emerged (ps>.25). We found evidence for the concept of CR using occupational position as proxy."} +{"text": "Cognitive function is an important component of healthy aging and physical activities have been shown to support late life cognitive function. However, it is unclear whether non-traditional physical activities provide additional benefits for cognitive function above and beyond traditional leisure physical activities. This study examines the associations between movement therapy and cognitive function in the US population. We used data from the waves 1, 2 and 3 (1995-2014) of the Midlife in the United States (MIDUS) study. MIDUS included a national probability sample of community-living adults aged 25-75 years old in 1995 (wave 1) and added the wave 2 cognitive functioning tests of executive function and episodic memory. We applied multivariate linear regression models to estimate the effect of movement therapy (wave 2) on the cognitive episodic memory and executive function (wave 3) while controlling the covariates . A total of 2097 individuals aged 42-92 years were included in the analysis. Movement therapy was independently associated with better episodic memory , but not with executive function , after including control variables. The results suggest that movement therapy may be an effective non-pharmacological intervention to attenuate age-related cognitive decline in middle-aged and older adults. Future research should test whether these findings can be replicated in similar populations and if confirmed, interventions should incorporate a wider range of physical activities in community-living older adults with the goal of maintaining and improving physical and cognitive health."} +{"text": "Using comparative analysis of the permeability and sorption performance of the obtained PAA cryogels and earlier developed polyethyleneimine (PEI) cryogels, we have demonstrated the advantages and disadvantages of these polymers as sorbents of heavy metal ions (Cu(II), Zn(II), Cd(II), and Ni(II)) in fixed-bed applications and as supermacroporous matrices for the fabrication of composite cryogels containing copper ferrocyanide (CuFCN) for cesium ion sorption. Applying the rate constant distribution (RCD) model to the kinetic curves of Cu(II) ion sorption on PAA and PEI cryogels, we have elucidated the difference in sorption/desorption rates and affinity constants of these materials and showed that physical sorption contributed to the Cu(II) uptake by PAA, but not to that by PEI cryogels. It was shown that PAA cryogels had significantly higher selectivity for Cu(II) sorption in the presence of Zn(II) and Cd(II) ions in comparison with that of PEI cryogels, while irreversible sorption of Co(II) ions by PEI can be used for the separation of Ni(II) and Co(II) ions. Using IR and M\u00f6ssbauer spectroscopy, we have demonstrated that strong complexation of Cu(II) ions with PEI significantly affects the in situ formation of Cu(II) ferrocyanide nanosorbents leading to their inefficiency for Cs Taking into account the difference in affinities of PAA and PEI cryogels toward Cu(II) ions, we have investigated how a polymer matrix affects the efficiency of composite sorbents containing Cu(II) ferrocyanide for cesium ion removal. Transition metal ferrocyanides are the most efficient materials for selective uptake of cesium radionuclides from liquid radioactive wastes and natural waters; however, due to their small size and low mechanical strength, they cannot be used in columns without immobilization in organic or inorganic matrices, which can be realized under dynamic conditions ,45,46,474\u2212 anion ,50. We h4\u2212 anion , but PAAA composite formed in situ had homogeneous distribution of Cu and Fe on the surface, but CuFCN crystallites were not detectable with resolution of the SEM either on PEI or on PAA cryogels. XRD patterns of the composite formed in situ c did not6]4\u2212 complex due to the very high Lewis basicity of PEI. The latter possibility was demonstrated earlier for N-containing ligands and Fe(III) cyanide complexes [\u22121 typical for Fe(II) ferrocyanide (Fe-CN deformation mode) [6]4- complex ion in the CuFCN/PEI composite was also confirmed by the singlet in the M\u00f6ssbauer spectrum (Taking into account a difference in the color of CuFCN/PAA (reddish brown) and CuFCN/PEI (dark blue) composites formed in situ, one can suggest that the PEI matrix had a significant effect on formation of Cu(II) ferrocyanide in situ. There are two possible reasons for this: (i) very strong binding of Cu(II) ions by PEI; and (ii) dissociation of solution was added dropwise under constant stirring, the obtained colloid solution of reddish brown color was fed through the column with 1 mL of PAA cryogel at a flow rate of 122 BV/h using a peristaltic pump (the stirring was continued). The CuFCN colloids were distributed over the full length of the column; iron and copper in outlet solutions were not detected by AAS. The column with the composite material (CuFCN/PAA (precipitation) cryogel) was washed with distilled water and used to investigate the dynamics of Cs+ ion sorption and Cs+ uptake in a batch. In situ formation of composites containing CuFCN was performed as follows: PAA and PEI cryogels were saturated with Cu(II) ions under dynamic conditions and washed with distilled water; in a week, 10 mL of 0.01 M K4[Fe(CN)6] solution was fed through the column at a flow rate of 8 BV/h. Finally, the composites were washed with 150 mL of distilled water, removed from the column, and air-dried for investigation of Cs+ uptake in a batch.Composite cryogels containing CuFCN were fabricated by (i) precipitation of ex situ formed CuFCN colloids on PAA-DGEBD 1:8 cryogel, and (ii) in situ formation of CuFCN in PAA-DGEBD 1:6 and PEI-DGEBD 1:4 cryogels. The composite formed by precipitation method was obtained as follows: 0.5 mL of 0.1 M Cu(NO+ ion uptake in a batch was determined as follows: 5 mg of the composite cryogel was shaken for 24 h with 5 mL of CsCl solution containing 20 mgCs/L (pH~6). The equilibrium content of cesium was determined by AAS. Dynamics of Cs+ ions sorption on CuFCN/PAA (precipitation) cryogel was studied by feeding CsCl solution containing 20 mgCs/L (pH~6) through 1 mL of monolith in insulin syringe at the flow rate of 84 BV/h using a peristaltic pump, the filtrate was collected every 5 mL and analyzed for cesium, copper, and iron content by AAS.The efficiency of CsMorphology investigations and elemental analysis of the freeze-dried composite cryogels were performed using a Hitachi TM3000 scanning electron microscope (SEM) equipped with a Bruker Quantax 70 energy dispersive X-ray (EDX) spectrometer at an accelerating voltage of 15 kV.X-ray powder diffraction analysis (XRD) of composite cryogels was carried out on a Dron-3 multipurpose diffractometer .Here we have investigated the reactivity of affordable and commercially available polyamine PAA in cross-linking reaction with diglycidyl ether of 1,4-butandiol and showed that PAA cryogels were formed at lower molar ratios of cross-linker to polymer and had better stability under the flow conditions than did PEI cryogels. Both PEI and PAA cryogels were efficient for the removal of Cu(II) and Zn(II) ions in batch and fixed bed applications to the level set by the WHO for drinking water.3 solution.Although PAA cryogels had worse chelating properties than PEI cryogels, they provided high selectivity of Cu(II) recovery over Zn(II) and Cd(II) ions, and Zn(II) ions over Cd(II) ions under equilibrium sorption conditions. PEI cryogels can be used for Co(II) and Ni(II) recovery from two component solutions in fixed-bed and selective elution of Ni(II) ions with 0.1 M HNOWe have also demonstrated that formation of stable Cu(II)\u2013PEI complex hinders in situ formation of Cu(II) ferrocyanide that results in very poor sorption efficiency of this PEI-based composite in cesium ion uptake. In contrast, PAA cryogels are applicable for composite formation via loading of ex situ formed Cu(II) ferrocyanide colloids or the in situ formation of nanosorbent with preservation of the supermacroporous structure of the matrix."} +{"text": "Using the Conservation of Resources Theory, this study examined how caregiver strain was influenced by care recipients\u2019 use of falls alert wearables. Online survey data from 486 unpaid caregivers for adults aged 50 and older were analyzed. Structural equation modeling was used to test the following hypotheses: (1) caregivers with fewer financial resources would engage in fewer resource conservation strategies ; (2) resource conservation strategy engagement would be associated less resource loss; and (3) the effect of resource conservation strategies on caregiver strain would be less salient than the effect of resources used on caregiving . The hypothesized model had a good model fit (CFI=.910), with SRMR (.060) and RMSEA (.062) being close to .05. All hypothesized paths were statistically-significant, except for the direct effect of using falls alert wearables on social support (p=.076) and caregiver strain (p=.135). As hypothesized, higher income was associated with greater likelihood of using falls alert wearables . Technology use was associated with less time spent on caregiving and had statistically-significant indirect effects on caregiver strain . The total effect of using falls alert wearables on caregiver strain was less powerful than the effect of time or social support . Study findings suggest the benefits of using falls alert wearables to alleviate time-related burdens and downstream caregiver strain among unpaid caregivers. Future efforts should investigate the relative advantage of wearables for other caregiving purposes."} +{"text": "This paper describes data of earthworm abundance and functional group diversity regulate plant litter decay and soil organic carbon (SOC) level in global terrestrial ecosystems. The data also describes the potential effect of vegetation types, litter quality, litterbag mesh size, soil C/N, soil aggregate size, experimental types and length of experimental time on earthworm induced plant litter and SOC decay. The data were collected from 69 studies published between 1985 and 2018, covering 340 observations. This data article is related to the paper \u201cEarthworm Abundance and Functional Group Diversity Regulate Plant Litter Decay and Soil Organic Carbon Level: A Global Meta-analysis\u201d [1]. Totally 340 observations from 69 studies were included. Detailed data are listed in 2A data set was compiled using literature search of peer-reviewed publications about the effects of earthworms on litter decomposition or SOC from the ISI-Web of Science and Google Scholar research database. We used three different combinations of keywords: earthworm and litter decomposition; earthworm and forest floor; earthworm and soil carbon. A total of 69 studies published between 1985 and 2018 were found , Table 5For To be included in the meta-analysis, the paper had to report the means, standard deviation (SDs) and replicate numbers of litter percent mass loss or SOC for the control treatment and the experimental treatment . For studies that did not report SD or standard error (SE), we conservatively estimated SD values as 150% of the average variance across the dataset . To eval"} +{"text": "Adult protective services and other community-based agencies respond to hundreds of thousands of elder abuse cases annually in the United States; however, few studies include elder abuse victims\u2019 voices. This study explored the most distressing aspects of elder abuse, as identified by victims themselves; to date, this is the first known study on this topic. Guided by a phenomenological qualitative methodology, this study conducted in-person, semi-structured interviews with a sample of elder abuse victims (n = 30) recruited from a community-based elder abuse social service program in New York City. To enhance trustworthiness, two researchers independently analyzed transcript data to identify key transcript codes/themes. Distressing aspects of elder abuse were identified across three key domains, related to feelings of loss (50% of codes), threats/negative consequences (55%), and client-needs/system incongruity (14%). Specifically, the first theme represented outcomes related to loss of relationships (19% of \u2018loss\u2019 codes), personhood (16%), credibility (19%), faith/trust in others (38%), and finances (8%). The second theme looked at threats to physical self (34% of \u2018threat\u2019 codes), psyche (39%), and others, including the perpetrator (27%). The third theme focused on mismatches in client/system goals (50% of \u2018incongruity\u2019 codes) and legal system involvement (50%). The findings in this study provide a comprehensive and conceptually organized range of aspects to serve as infrastructure for the development of meaningful interventions to address the needs of victims. This study represents one of the largest efforts to understand and integrate the perspectives and needs of victims into elder abuse intervention practice/research to date."} +{"text": "Pseudomonas sp. strains isolated from marine sponges have shown potential quorum sensing inhibition (QSI) activity. We sequenced the draft genomes of the three strains with the goal of determining which genes or gene cluster(s) could be potentially involved in the QSI activity. Average nucleotide identity (ANI) and phylogenetic analysis classified the three strains as belonging to the Pseudomonas fluorescens species.Three Pseudomonas sp. strains isolated from marine sponges have shown potential quorum sensing inhibition (QSI) activity. We sequenced the draft genomes of the three strains with the goal of determining which genes or gene cluster(s) could be potentially involved in the QSI activity. Average nucleotide identity (ANI) and phylogenetic analysis classified the three strains as belonging to the Pseudomonas fluorescens species.Three Pseudomonas is a Gram-negative bacterial genus belonging to the Gammaproteobacteria class, whose members are known to colonize and survive in a wide range of diverse environments, mainly due to inherent broad metabolic diversity (Pseudomonas sp. strains in the inhibition of quorum sensing (QS) signaling systems has been reported were isolated from 2 different marine sponges, belonging to the Hexactinellida class, that were collected off the west coast of Ireland as part of a marine biodiscovery cruise in May 2010. The isolation of these Pseudomonas sp. strains and their QS inhibition (QSI) activities were described previously . DNA libraries were prepared using a TruSeq exome library preparation kit. The draft genome sequencing was performed by the Beijing Genomics Institute (China) using the Illumina HiSeq 2000 sequencing platform with paired-end reads and a read length of 90\u2009bp for B98C39. The HiSeq 4000 platform, with paired-end reads and a read length of 150\u2009bp, was used for B98SK52 and B98SM8. In order to obtain high-quality reads for assembly, the FASTA/Q file manipulation tool readfq.v5 quiP (pvdThe draft genome sequences discussed in this work have been deposited at DDBJ/ENA/GenBank and the Sequence Read Archive (SRA). The corresponding accession numbers are listed in"} +{"text": "A 63-year-old man presented to our hospital with 2 days history of right-sided earache and numbness followed by the development of vesicular rash involving the right side of the face. There was no history of headache, tinnitus, giddiness or hearing impairment. Neurological examination revealed right-sided mild lower motor neuron type facial palsy (A) and vesicular rash in the distribution of maxillary and mandibular branch of trigeminal nerve without any sensorineural deafness . Routine all laboratory examinations including retroviral screening were normal. A clinical diagnosis of the Ramsay Hunt syndrome (RHS) was considered based on earache, facial paralysis and typical dermatomal distribution of rash. He was started with oral valaciclovir 1gm three times daily (TDS) for 7 days and Tab prednisolone 60mg daily for 5 days. Two days after initiation of the treatment vesicular lesions disappeared but neurological examination revealed right-sided grade IV facial nerve palsy. Ramsay Hunt syndrome or Herpes Zoster Oticus is characterized by reactivation of latent varicella zoster virus in the geniculate ganglion and subsequent spread to cranial nerve. The diagnosis is mainly clinical. The facial paralysis seen in Ramsay Hunt syndrome is often more severe with the increased rate of late neural denervation and decrease the chance of complete recovery."} +{"text": "This presentation reports an exploratory study evaluating the effect of Asian Care Training (ACT) Manual on Asian American (AA) caregivers\u2019 care capacity and knowledge growth. A total of 65 AA caregivers were recruited from community-based organizations in Los Angeles and passed the screening questionnaire, in which 44 completed the evaluation process. Participants were given autonomy to choose topics they desired to learn out of 25 topics in ACT manual and completed one-month learning. The data were collected via structured questionnaires before and after the self-learning and were analyzed with paired t-test on 5 questions about care capacity and 4 about caregiving knowledge. One-month self-learning of ACT manual enhanced participants\u2019 care capacity in 4 out of 5 sectors: confidence in caregiving ; ability to deal with emergency ; to solve concerns of the care recipients ; to communicate more smoothly . Improvements were found in 3 out of 4 sectors in knowledge: knowledge of Alzheimer\u2019s disease ; appropriated approach to displacing care recipients ; and information about caregiver support resources . This self-learning method of ACT manual was feasible for AA caregivers to broaden knowledge and care capacity while adapting with their intensive workload. This study constitutes an important step towards establishing culturally tailored self-training programs for Asian American caregivers for frail older adults via multiple platforms such as online curriculums and mHealth app."} +{"text": "Control and treated animals (dams and offspring) were immunized ip with (0.5 ml) 20% sheep red blood cell (SRBC) suspension seven days before the end of experiments. At the end of exposure, ten dams and ten offspring from each group were used for assessment of cell-mediated immunity and a similar number of animals were sacrificed for evaluating the humoral immune response and serum protein profile. Aluminum chloride exposure of dams (G2 & G3) caused significant suppression of both cell mediated and humoral immune responses in the obtained offsprings compared to the control group (G1) without any significant effect on the immune responses of these dams. Moreover, the serum total globulins, albumin/ globulin (A/G) ratio and gamma globulin fraction were significantly decreased in the treated dam\u2019s offsprings compared to the corresponding controls while the serum total protein and all serum protein fractions showed non significant difference between the control and treated dams and between the two treated dam groups themselves. There were no histopatho-logical changes observed in thymus, spleen and liver of the control and treated dams. Thymus of treated dam\u2019s offsprings (G2) showed lymphoid depletion in both cortex and medulla. Their spleens showed lymphoid depletion in the white pulps and congestion with hemosiderosis in the red pulps. Liver of treated dam\u2019s offsprings showed dilation and congestion of its central vein with degenerative changes in the hepatocytes. These histopathological changes were more severe in G2 than in G3 offsprings. It can be concluded that gestational and/ or lactation exposure of pregnant dams to AI chloride caused suppression of both cellular and humoral immune responses of their offsprings.The present study was designed to explore the immunotoxic effects of orally administered aluminum (AI) on pregnant rats (n = 60) and their growing fetuses and consequently on the animal wealth. The animals were randomly allocated into three equal groups of 20 rats each. The first group has no treatment and kept as a control (G1). The second and third groups of pregnant rats were treated orally with aluminum chloride at 345 mg/Kg b.wt. The second group (G2) received the tested compound from the 6"} +{"text": "The University of Chicago GWEP, SHARE Network , is located on the South Side of Chicago, an urban medically underserved community. SHARE Network partners with a variety of community based organizations (CBOs) to support Age Friendly care through an Age Friendly Community Education Curriculum. In a one year period, 28 events were held in 13 CBO sites. Each of these events addressed the 4Ms of Age Friendly care with a specific content focus on Mentation (5 events), Mobility (5), Medications (4), and What Matters (10), and 4 events focused on multiple domains. There were 458 attendees, 290 completed surveys (63% response rate). Eighty-eight percent of participants planned to make a healthy behavior change after participation. Age Friendly Community Education can complement health system transformation to lead to health behavior change for community-dwelling older adults in medically underserved communities."} +{"text": "Research suggests that group music-making can improve well-being and cognitive function in people with dementia and their family carers. The importance of the music facilitator\u2019s role is recognised. However, empirical studies rarely capture their experiences and perspectives. Semi-structured interviews were conducted with three music therapists and three community musicians with specialisms in dementia care. The interviews sought to gain a detailed understanding of their work with people with dementia. Interpretative Phenomenological Analysis revealed eight super-ordinate themes: (1) benefits of music-making for people with dementia; (2) challenges of working with people with dementia; (3) involving family carers; (4) musical content; (5) impact of the facilitator; (6) developing field of Arts and Health; (7) work as a privilege; and (8) potential for misuse of music. This study provides a useful basis from which to further develop concepts for the amelioration of people living with dementia and their families."} +{"text": "Korean immigrant older adults residing in areas without well-established Korean ethnic enclaves experience acculturative stress and depressive symptoms due to their lingual and cultural barriers. Expressive writing can be used as a culturally sensitive intervention to help those immigrants disclose their deepest thoughts and feelings related to their immigration and acculturation experiences. This study gathered qualitative data from the author\u2019s experimental study using expressive writing for first-generation Korean immigrant adults 60 to 88 years of age residing in Midwestern cities. Participants were instructed to write for 15-20 minutes per day in three consecutive days at their convenience in a comfortable and private setting and asked to return their writings by mail. A total of 22 participants returned their writings: 14 wrote about their past and current stressful experiences related to their immigration and acculturation, while eight wrote about their daily lives. Eight themes emerged from thematic coding processes guided by the grounded theory approach: (1) survival, resilience, hardiness, tenacity, pride; (2) lingual barriers; (3) religious faith; (4) gender difference in roles and values; (5) racial discrimination; (6) traditional strategies of acculturation; (7) family and intergenerational gap; and (8) aging. The themes illustrate the participants\u2019 lifelong efforts to shape their unique voices through heart-wrenching struggles, haunting wounds, and ethnic pride and resilience. The study findings suggest that culturally relevant programs and services are needed to facilitate social relationships and reduce lingual and cultural barriers for Korean immigrant older adults residing in non-ethnic enclaves."} +{"text": "Scientific Reports 10.1038/s41598-020-58408-6, published online 30 January 2020Correction to: The original version of this Article contained a typographical error in the Abstract.\u201cWe focused on anlyse the functional trait patterns and functional diversity components of two main assemblages that were collected with window traps (WTs) and hollow emergence traps (HETs) respectively, between three protected areas of the Iberian Peninsula.\u201dnow reads:\u201cWe focused on analysing the functional trait patterns and functional diversity components of two main assemblages that were collected with window traps (WTs) and hollow emergence traps (HETs) respectively, between three protected areas of the Iberian Peninsula.\u201dThis has now been corrected in the PDF and HTML versions of the Article."} +{"text": "We read with interest the recent article by Liao et al. who concluded that patients in the endovascular cooling (EC) group had shorter intensive care unit (ICU) hospitalization and a better neurological prognosis than those in the surface cooling (SC) group . In thei"} +{"text": "PKHD1 gene, 8 variants in the TMEM67 gene, 4 variants in the PKD1 gene, 2 variants in the HNF1B gene and 2 variants in BBS1 and NPHP1 genes, respectively. NGS is a valuable tool in the diagnostics of various forms of cystic kidney diseases. Its results changed the clinically based diagnoses in 16% (n = 5) of the children.Cystic kidney diseases are a very heterogeneous group of chronic kidney diseases. The diagnosis is usually based on clinical and ultrasound characteristics and the final diagnosis is often difficult to be made. Next-generation sequencing (NGS) may help the clinicians to find the correct final diagnosis. The aim of our study was to test the diagnostic yield of NGS and its ability to improve the diagnosis precision in a heterogeneous group of children with cystic kidney diseases. Next-generation sequencing of genes responsible for the formation of cystic kidneys was performed in 31 unrelated patients with various clinically diagnosed cystic kidney diseases gathered at the Department of Pediatrics of Motol University Hospital in Prague between 2013 and 2018. The underlying pathogenic variants were detected in 71% of patients (n = 22), no or only one pathogenic variant was found in 29% of patients (n = 9). The result of NGS correlated with the clinical diagnosis made before the NGS in 55% of patients (n = 17), in the remaining 14 children (45%) the result of NGS revealed another type of cystic kidney disease that was suspected clinically before or did not find causal mutation in suspected genes. The most common unexpected findings were variants in nephronophthisis (NPHP) genes in children with clinically suspected autosomal recessive polycystic kidney disease . Overall, 24 pathogenic or probably pathogenic variants were detected in the Cystic kidney diseases (CKD) are a very heterogeneous group of chronic kidney diseases that in pediatric patients comprise mostly inherited kidney diseases, such as autosomal recessive polycystic kidney disease (ARPKD), nephronophthisis (NPHP), renal cysts and diabetes syndrome (RCAD) or autosomal dominant polycystic kidney disease (ADPKD) . In contIn the last decade, next-generation sequencing becomes the method of choice, allowing simultaneous mutational analysis of panel of genes that can be especially useful in genetic diagnosis of young patients with unclear or doubtful phenotype, in etiologically complex syndromes, or in differential diagnosis of phenotypically overlapping syndromes. In very rare cases a combination of mutations in two genes (digenic disease), can be found in children with severe neonatal clinical phenotype . TherefoThe aim of our study was to test the diagnostic yield of NGS and its ability to improve the diagnosis precision in a heterogeneous group of children with clinically diagnosed cystic kidney diseases.Altogether, there were 31 patients with clinical diagnosis of different cystic kidney diseases\u2013ARPKD, ADPKD, NPHP, RCAD syndrome and Bardet-Biedl syndrome. The group of patients was gathered at the Department of Pediatrics of Motol University Hospital in Prague between 2013 and 2018. The characterization of the group is summarized in Clinical diagnosis of ARPKD was based on the fulfillment of established clinical criteria of ARPKD including 1) typical kidney involvement on ultrasound , with or without 2) liver involvement and 3) normal renal US of both parents consistent with autosomal-recessive inheritance [Clinical diagnosis of ADPKD was based on the presence of one or more kidney cysts in one/both kidneys with or without positive family history of ADPKD and was mostly based on expert opinion as no consensus diagnostic criteria were stated for children under the age of 15. Retrospective evaluation shows that diagnosis of ADPKD in our patients followed the international consensus statement for radiological criteria for children and young people published in 2019 ,5, whereThe clinical diagnosis of nephronophthisis was based on the clinical finding of 1) polyuria/ polydipsia or 2) renal concentrating defect or 3) biopsy findings of chronic interstitial nephritis or US findings of normal sized hyperechogenic kidneys, all together with compatible autosomal recessive inheritance . NephronHNF1B nephropathy was mainly based on the presence of cystic kidney dysplasia with/without MODY and/or hypomagnesemia and/or pancreatic malformation, together with presence of other distinctive features described in detail in [Clinical diagnosis of renal cysts and diabetes syndrome (RCAD)\u2013etail in .Clinical diagnosis of Bardet-Biedl syndrome was in our group of patients (patient n.25) based on the presence of cystic kidney disease, obesity, polydactyly and cognitive impairment as described among other features in .th percentile [Hypertension was defined as blood pressure \u226595rcentile .All children with severe cystic kidney disease or systematic disease with presence of cysts treated in the Department of Pediatrics of Motol University Hospital between 2013 and 2018 were included in our group of patients. Cases of typical ADPKD phenotype with mild manifestation and positive family history of the disease, as well as patients whose parents/legal guardians did not give informed consent, were excluded from the study.Detailed clinical, laboratory and ultrasound information of patients are summarized in The study was approved by the Ethics Committee of General University Hospital in Prague and all patients/legal guardians were consulted by geneticist prior to molecular-genetic analysis and gave written informed consent for genetic testing.PKD1, library preparation from long-range PCR products was chosen for PKD1 library preparation has been chosen. The full list of genes contained in the analyzed panel is in ribed by , PrimeSTThe bioinformatic analysis was provided by in-house bioinformatic pipeline. The analysis included detection of single-nucleotide polymorphisms (SNPs), small insertions and deletions and, in the case of panel sequencing, copy-number variants (CNV).PKD1 sequencing) and quality check of the reads and their trimming was provided by Trimmomatic 0.36 [https://github.com/lh3/bwa/tree/master/bwakit). The hs38DH genome provided by bwa.kit was used. Mapped reads were cleaned up and sorted using samtools fixmate and samtools sort, respectively . The PCR duplicates were then marked with picard MarkDuplicates 2.9.2-SNAPSHOT (Picard Toolkit by Broad Institute) and mapped reads indexed with samtools index (v1.6). For variant calling, freebayes v1.1.0-9-g09d4ecf was used [https://www.ncbi.nlm.nih.gov/snp/) and dbNSFP 3.2a (https://sites.google.com/site/jpopgen/dbNSFP).First, the quality of the FASTQ files created by MiSeq Reporter was evaluated using FastQC v0.11.5 (Babraham Institute). In the second step, cutting off the adapter (TruSeq3-PE-2) sequences (and PCR primers in case of tic 0.36 . The triwas used . The varwas used and SnpSwas used compilinThe variant prioritization was composed of automatic filtration (point 1 and 2) followed by evaluation by molecular geneticist in cooperation with nephrologist (points 3\u20135):The variant causes change on protein level (i.e. nonsynonymous sequence changes in exons) or the variant is in the intronic region in the donor or acceptor splite site.The variant has a population frequency (of European descend) lower than 0.1. 1000 Genome Project EUR population and Exome Aggregation Consortium (ExAC) was used for the assessment.in silico prediction by programs: SIFT [http://www.mutationtaster.org/), MutationAssessor [Evaluation of the variant based on ms: SIFT , PolyPhems: SIFT , LRT [18Assessor , FATHMM Assessor , PROVEANAssessor , CADD [2Assessor , ensemblAssessor , and conhttp://www.humgen.rwth-aachen.de/) and Autosomal Dominant Polycystic Kidney Disease Mutation Database: PKDB (https://pkdb.mayo.edu/).The consultation of variant with VarSome search engine containiThe consultation with attending nephrologist regarding the possible pathogenic effect of detected variants with uncertain significance on patient phenotype.trans localization in the patient.If available, analysis of variant segregation in family members. In case of recessive inheritance, analysis of variation in proband\u2019s parents to determine The copy-number variant calling was done using CNVkit 0.8.6.dev0 in all sPKHD1 gene done within our previous project. These patients were either clinically suspected to have ARPKD or had neonatal/infantile onset of the disease. The sequencing method, data analysis and variant classification used in this project were in detail described previously [PKHD1 gene) of patients 3\u20135 and 7 were already published and discussed in [PKHD1 gene alone have not been analyzed by panel or PKD1 sequencing . Patient 24 was analyzed in commercial laboratory. The complete list of patients and their respective genetic analysis are summarized in Patients 1\u201324 had had mutational analysis of the eviously . The defussed in . The patPKHD1 and HNF1B followed the genetic analysis of the PKHD1 gene in patients in whom no/one mutation in PKHD1 was found. The kits used for MLPA analysis were SALSA MLPA P341 PKHD1 mix 1, P342-PKHD1 mix 2 and SALSA MLPA P241 MODY Mix 1 (MRC Holland). The generated data were analyzed by Coffalyser.Net (MRC Holland).MLPA (Multiplex Ligation-dependent Probe Amplification) analysis was used for detection of large genome rearrangements. MLPA of NPHP1 gene found by panel sequencing. The kit used for the analysis was SALSA MLPA P387 NPHP1.The MLPA analysis was also applied in patient 29 to confirm the complete deletion of both alleles of PKHD1 confirmed the diagnosis in 10 (50%) of them. In the other 10 patients, the sequencing of PKD1 and panel of genes yielded the diagnosis in additional 5 of them . Four children harbored only one pathogenic mutation in the recessive PKHD1 gene, and the final diagnosis remained unknown.The group of 31 patients formed by patients from Motol University Hospital gathered between years 2013 and 2018 was analyzed within our project. The underlying pathogenic variants were detected in 71% of patients (n = 22), no or only one pathogenic variant was found in 29% of patients (n = 9) . The resPKHD1 and those with childhood onset, without a clinical suspicion of ARPKD, a panel sequencing and sequencing of the PKD1 gene yielded the diagnosis in 57% patients (12 of 21). The most common unexpected findings were changes in nephronophthisis (NPHP) genes in children with clinically suspected ARPKD (n = 4). The most common incorrect clinical diagnosis was ARPKD (n = 10) with four patients having genetically proven NPHP, one ADPKD de novo and further five patients having no definitive genetic diagnosis.In patients without a yield by sequencing of PKHD1 gene (14 patients), 8 variants in the TMEM67 gene (4 patients), 4 variants in the PKD1 gene (4 patients), 1 variant in HNF1B (1 patient) and 2 variants in BBS1 (1 patient). Moreover, whole gene deletion was detected in heterozygous (HNF1B gene) and homozygous (NPHP1 gene) state in two patients.Overall, 24 pathogenic or probably pathogenic SNP variants were detected in the The molecular genetic data of patients are summarized in HFN1B and NPHP1 was detected. In both genes, whole gene deletions are the most common variants described in literature [Sequencing analysis performed in 31 pediatric patients with suspected cystic kidney diseases detected causal variant in 71% (n = 22) of patients. This roughly correlates with results presented by Bullich et al. where taterature .TMEM67 variant), which was already described in 2009 by Otto et al. [NGS confirmed the clinical diagnosis in 55% (n = 17) patients and did not confirm or changed the clinical diagnosis in 45% (n = 14) of them. The most common clinical diagnosis that had to be changed thanks to the NGS results was ARPKD. Four children with a clinical diagnosis of ARPKD was diagnosed as having genetically NPHP11 and one patient (28) de novo ADPKD. The clinical and ultrasound picture of ARPKD and NPHP can be similar making the differential diagnosis difficult mainly in children with non-neonatal manifestation in ARPKD and in absence of extra-renal/hepatic manifestation such as eyes or central nervous system abnormalities present in NPHP. The less severe NPHP phenotype in our patients was caused by the fact that all children carried the allele p.Cys615Arg or had another clinical diagnosis discovered during follow-up . In three children (15%) with clinically diagnosed ARPKD only one pathogenic variant in the n et al. . Even thn et al. suggestsNo or partial genetic findings in some patients could be caused by several reasons:DZIP1L [CEP83 [Mutations in other ciliopathic genes which were not in our NGS ciliopathy panel covered by genetic analysis, e.g. regulatory regions in deep intronic sequences, untranslated regions of genes, first exons of genes or even promotor regions, that are especially important for genes coding transcription factors whose function strongly relates to expression level. Also, the causing variant could have been filtered out as variant of unknown significance (VUS) as its function is yet unknown or could have been missed by bioinformatic processing.Moreover, a combination of heterozygous mutations in two different ciliopathic recessive (or dominant) genes could theoretically cause a severe cystic kidney disease phenotype as an oligogenic inheritance where variants in different genes modify final phenotype was already described in ciliopathies (reviewed in ), as welAnother possibility for the discrepancy between clinical and genetic diagnosis is that the cystic kidney disease in a given child is non-inherited which is however very rare in pediatric patients especially if manifested in neonatal/infant age.Extra-renal manifestations, such as eye or CNS abnormalities were the best clues for the correct clinical diagnosis of patients with non-ADPKD cystic kidney diseases . NystagmThe strengths of our study are a very well clinical and ultrasound characterization of the patients, the long-term follow-up and the high number of ciliopathy genes in our panel. The genetic diagnosis consisted of several methods of sequencing and CNV detection and thus provided reliable results. We are aware of the limitations of our study\u2014the low number of patients, single-center study, lack of some non-ciliopathy genes in our panel and lack of whole-exome sequencing in the genetically unresolved patients.In conclusions, our study demonstrated that the next-generation sequencing method facilitates molecular analysis of different types of cystic kidney diseases and enables precise genetic diagnosis. Its results changed the clinical diagnosis in number of the children. The correct final genetic diagnoses enable better management of children with different forms of cystic kidney diseases and provide efficient genetic counseling.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S4 Table+, yes; -, no.(PDF)Click here for additional data file."} +{"text": "We conducted a genome-wide association study of 1317 centenarians from the New England Centenarian Study and 2885 controls using >9M genetic variants. The most significantly associated variants were correlated to 4131 serum proteins in 224 study participants. The genetic and protein associations were replicated in a genome-wide association study of 480 centenarians and ~800 controls of Ashkenazy Jewish descent and a proteomic scan of approximately 1000 participants of the same study. The analysis replicated a protein signature associated with APOE genotypes and confirmed strong overexpression of BIRC2 (p < 5E-16) and underexpression of APOB in carriers of the APOE2 allele (p< 0.05). The analysis also discovered and replicated associations between longevity variants and slower changes of protein biomarkers of aging, including a novel protein signature of rs2184061 (CDKN2a/CDKN2B in chromosome 9). The analyses show that longevity variants correlate with proteome signatures that could be manipulated to discover healthy aging targets."} +{"text": "Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory tract illness in infants and affects the elderly and the immune-compromised. RSV infection can cause pulmonary obstruction and disease, but the mechanisms contributing to these outcomes remain elusive. Despite the major health burden caused by infection, there is currently no licensed RSV vaccine and treatments are limited. The Special Issue on \u201cPathobiology of Respiratory Syncytial Virus (RSV)\u201d covers the attributes of disease pathogenesis, immunity, and vaccine development. In an article by Pedro Piedra, \u201cAntibody Response to the Furin Cleavable Twenty-Seven Amino Acid Peptide p27) of the Fusion Protein in Respiratory Syncytial Virus (RSV) Infected Adult Hematopoietic Cell Transplant (HCT) Recipients\u201d , the ant7 of the"} +{"text": "The purpose of this study was to explore the relationship between nursing home volunteer programming and quality measures and increase the knowledge base of nursing home volunteer programming in various settings. Fifty-two nursing homes were surveyed using electronic surveys and personal interviews. Questions focused on the organization of the nursing home, characteristics of the volunteer program and volunteer activities. Of the 52 facilities surveyed, 19 were not part of a chain, 37 were in urban settings, and 24 were for-profit entities. Volunteers were used in 46 nursing homes with a mean number of volunteers of 51.7 onsite an average of 4.9 days per week. Bivariate analysis revealed statistically significant correlations (p<.05) between organizational and volunteer programming characteristics and six quality measures . Statistically significant (p<.05) inverse relationships were found between volunteers providing individualized activities and the incidence of urinary tract infections and the use of psychotropic drugs. Multiple regression analysis revealed a statistically significant (p<.05) inverse relationship between personal volunteer services such as combing hair and doing nails and the use of hypnotic drugs and antipsychotic drugs. This study indicates a significant correlation between volunteer programming and quality measure scores. A larger study of these relationships is indicated."} +{"text": "Semen samples were then cryopreserved in TEST-yolk buffer and stored in liquid nitrogen at -196\u00b0C.The identification of the differentially expressed proteins (DEPs) between the control and NSTC groups was con- ducted via Scaffold software. The criteria for the selection of DEPs for validation by Western blot (WB) included: 1) proteins involved in reproductive system development and function; 2) proteins involved in the top canonical pathways; 3) proteins with a higher difference of abundance between the experimental groups; 4) proteins with a well-described function in the literatureThe authos identified 189 differentially expressed proteins (DEPs) in the dataset, from which five DEPs related to sperm function and fertilization were selected for validation by Western blot. And they indentified that underexpression of the mitochondrial complex subunits NADH:Ubiquinone Oxidoreductase Core Subunit S1 (NDUFS1) and ubiquinol-cytochrome C reductase core protein 2 (UQCRC2), as well as the underexpression of the testis-specific sodium/potassium-transporting ATPase subunit alpha-4 (ATP1A4) in the NSTC group.The results indicate that sperm mitochondrial dysfunction may explain the observed decrease in sperm concentration, total sperm count and total motile count in NSTC patients. The identified DEPs may serve as potential biomarkers for the pathophysiology of subfertility/infertility in patients with NSTC."} +{"text": "Conventionally, (p)ppGpp collectively refers to two nucleotides, ppGpp, and pppGpp in the literature. Initially, (p)ppGpp has been discovered as a transcription regulatory molecule as it binds to RNA polymerase and regulates transcriptional gene regulation. During the past decade, several other target proteins of (p)ppGpp have been discovered and as of now, more than 30 proteins have been reported to be regulated by the binding of these two signaling nucleotides. The regulation of diverse biochemical activities by (p)ppGpp requires fine-tuned molecular interactions with various classes of proteins so that it can moderate varied functions. Here we report a structural dynamics of (p)ppGpp in the unbound state using well-defined computational tools and its interactions with target proteins to understand the differential regulation by (p)ppGpp at the molecular level. We carried out replica exchange molecular dynamics simulation studies to enhance sampling of conformations during (p)ppGpp simulation. The detailed comparative analysis of torsion angle conformation of ribose sugar of unbound (p)ppGpp and bound states of (p)ppGpp was carried out. The structural dynamics shows that two linear phosphate chains provide plasticity to (p)ppGpp nucleotides for the binding to diverse proteins. Moreover, the intermolecular interactions between (p)ppGpp and target proteins were characterized through various physicochemical parameters including, hydrogen bonds, van der Waal\u2019s interactions, aromatic stacking, and side chains of interacting residues of proteins. Surprisingly, we observed that interactions of (p)ppGpp to target protein have a consensus binding pattern for a particular functional class of enzymes. For example, the binding of (p)ppGpp to RNA polymerase is significantly different from the binding of (p)ppGpp to the proteins involved in the ribosome biogenesis pathway. Whereas, (p)ppGpp binding to enzymes involved in nucleotide metabolism facilitates the functional regulation through oligomerization. Analysis of these datasets revealed that guanine base-specific contacts are key determinants to discriminate functional class of protein. Altogether, our studies provide significant information to understand the differential interaction pattern of (p)ppGpp to its target and this information may be useful to design antibacterial compounds based on (p)ppGpp analogs. Escherichia coli culture. The concentration of these nucleotides was enhanced drastically in E coli cells during amino acid starvation and these nucleotides were inhibiting rRNA synthesis ppGpp is used for two nucleotides, guanosine 5\u2032-diphosphate-3\u2032-diphosphate (ppGpp) and guanosine 5\u2032-triphosphate-3\u2032-diphosphate (pppGpp). These nucleotides are synthesized by (p)ppGpp synthetase by transferring pyrophosphate groups from ATP to GDP/GTP to form ppGpp and pppGpp, respectively . There aThe molecular dynamics simulation studies provide structural dynamic information in the solution state of a molecule. Although, glycosidic bond and ribose sugar in the nucleotide structure exhibit conformational flexibility and classical molecular dynamics simulation on nucleotides is challenging because of energy barriers and sampling of conformations are limited. Therefore, Replica Exchange Molecular Dynamics (REMD) simulation was carried out on ppGpp and pppGpp nucleotides in solution states. In REMD, several identical replicas run in parallel at different temperatures and these allow enhanced sampling of high energy conformations. Moreover, these replicas are allowed to swap their states based on Boltzmann-weighted probability at neighboring temperature state. This process is repeated iteratively during the simulation and subsequently enhanced sampling of conformations is achieved at various temperatures.3 for both molecules and upon addition of buffer, the box volume was expanded to 145262 and 150766 \u00c53 for ppGpp and pppGpp, respectively. Negative charges, due to phosphates groups of (p)ppGpp molecule, were neutralized by the addition of 20 mM Mg2+ in the simulation system. The Optimized Potential for Liquid Simulations 3 enhanced (OPLS3e) force field was selected for the simulation ppGpp-protein complexes. The structural alignment was carried out in PyMol using an atom alignment algorithm. The distribution frequency of glycosidic bonds in unbound states of ppGpp and pppGpp were plotted at 300 K simulation pose in Schrodinger. The torsion angle and phase angle values were calculated from Pseudo-Rotational Online Service and Interactive Tool (PROSIT) , 2005.The structures of (p)ppGpp-protein complexes were downloaded from Protein Data Bank (PDB). The PDB ligand code G4P for ppGpp, 0o2, and C1Z for pppGpp was used as a search term to obtain structures of ppGpp-protein and pppGpp-protein complexes, respectively. As shown in Molecular dynamics simulation is one of the most commonly used approaches to understand structural dynamics of biomolecules in solution state . It has 2+ ions during the simulation, yet higher flexibility of phosphate atoms was observed in the RMSF plot. In contrast to (p)ppGpp, the phosphate groups in cyclic messenger nucleotides show lesser flexibility due to the unavailability of free phosphate chains (2 group of guanine ring of (p)ppGpp in REMD simulation. The detailed analysis of molecular properties shows the overall quality and conformational dynamics of (p)ppGpp during the simulation ppGpp were obtained by energy minimization in Maestro. The structural coordinates of bound (p)ppGpp were extracted from structures of (p)ppGpp-protein complexes. The structural alignment of unbound state and bound state of (p)ppGpp shows substantial similarity in the guanine ring region with RMSD of atoms less than one. However, the phosphate chain shows divergence upon structural alignment which is in agreement with our simulation RMSF plot.syn conformation, however, some occurrences were observed in anti conformation. Our results on the frequency distribution of glycosidic conformation in unbound states are similar to those observed in the bound states in the crystal structure. As most of the structures of (p)ppGpp-protein complexes have anti conformation of glycosidic bond except in few cases it was found in syn conformation such as nucleosidase (6GFM) and maximum puckering amplitude (\u03bdmax) which show that ribose sugar adopts north conformation in both states ((p)ppGpp nucleotides exhibit a substantial extent of conformational flexibility because of various rotatable torsion angles present in the structure particularly a ribose ring . Therefoe (6GFM) , lysine e (6GFM) . The sugormation . Whereasd pppGpp . The fivse sugar . The ribse sugar . Additioh states . The com2+ ions. As seen by the hydrogen bonds histogram, the major interatomic polar interactions were observed in guanine ring and phosphate group atoms. The aromatic ring of guanine had\u03c0-\u03c0 base stacking interactions with the side chain of tyrosine in the structures of (p)ppGpp synthetases and nucleotide metabolic enzymes. The ribose moiety of (p)ppGpp makes comparatively fewer interactions with protein atoms which may be the consequence of the structural restrain of the ribose ring. Similarly, van der Waal\u2019s interactions were found majorly in the region of the guanine ring of (p)ppGpp ppGpp . The avaBacillus subtilis ppGpp synthetases are apparent (p)ppGpp binding proteins as these enzymes synthesize ppGpp and pppGpp from ATP and GDP/GTP, respectively. However, most of the structures determined so far are in complexes with substrate analogs as these complexes explain the catalytic mechanism. A brief structural review on (p)ppGpp synthetase proteins has been described previously hence cusubtilis ; small as aureus and one mophiles . The (p)2+ ions. Therefore, these interactions are considered as ionic interactions. The observed binding mode of (p)ppGpp to the nucleotide enzymes is similar due to an analogy of substrate nucleotide structure to the (p)ppGpp. As shown in the graph, the N1, N2, N7, and O6 atoms of the aromatic guanine ring of (p)ppGpp is a major contributor to hydrogen bond interaction with protein residues.There are six crystal structures of (p)ppGpp and nucleotide metabolic enzymes complexes available in the Protein Data Bank which includes Xanthine phosphoribosyltransferase (XPRT) , PyrimidThere are five crystal structures of GTP binding GTPase proteins in complex with (p)ppGpp available till now. These include Obg GTP binding protein , GTPase RNA polymerase was the first protein complex reported to regulate its activity by binding of (p)ppGpp . There aThere are several crystal structures of various other functional class of (p)ppGpp binding proteins reported including translation peptide chain release factor 3 (PDB: 3VR1) , acetylt2+) plays a significant role in the structural stability of nucleic acid and nucleotides by neutralizing highly negative charged phosphate groups (2+ ions assist in the specific interaction of (p)ppGpp to their target protein. As shown in the graph ppGpp synthetase, RelTt, it binds to only one chain of phosphate ppGpp but it also mediates interactions between (p)ppGpp and protein side chains. Each phosphate chain of (p)ppGpp is making interactions with one Mg2+ ion in the complex of RNA polymerase-(p)ppGpp. Altogether, we have observed Mg2+ ions in several other complexes of (p)ppGpp-protein structures except for few complexes which may be the limitation of electron density interpretation as discussed earlier ppGpp have linear phosphate chains that provide additional flexibility to adapt various conformations according to the stereochemistry of the binding site of a respective target protein. Overall, our results support the hypothesis that the conformation flexibility of glycosidic bond, ribose sugar puckering, and phosphate groups provide structural plasticity to the (p)ppGpp for binding to the various functional class of proteins. The structures of unbound ppGpp and pppGpp in solution states obtained by MD simulation are similar to that observed in the structures in bound form, hence, these structures resemble biologically active conformations of (p)ppGpp. The gyration conformation profile of glycosidic bond is in agreement with the conformation of (p)ppGpp observed in the bound state. The analysis of (p)ppGpp-protein interactions reveals that the binding pattern of these nucleotides governs the regulation for a particular class of target proteins.The original contributions presented in the study are included in the article/GK and NB conceptualized the study. GK and AP performed the study. All authors analyzed the data, wrote and edited the manuscript, and agreed on the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Sarothrura ayresi was sequenced using next generation sequencing technology. The size of the genome is reported as 16,767\u2009bp and comprises 13 protein-coding genes, 2 rRNAs and 22 tRNAs. The organization of the genome is comparable to that of other bird species. A phylogenetic comparison mapped the relative relationship of Sarothrura ayresi with respect to other species in the order Gruiformes.The mitochondrial genome of The Critically Endangered white-winged flufftail forms part of the genus Sarothrura IUCN . The speTM \u2013 Tissue MiniPrep Kit (Zymo Research Corporation), library preparation and Illumina high-throughput sequencing . Sequences were assembled using the CLC Genomics platform . The mitogenome was assembled under the de novo option, using the standard parameters. Various kmer sizes were used during optimisation and the full mitochondrial genome for the WWFT was assembled using kmer size 31. The mitochondrial assembly constituted 8597 reads out of the 18,567,330 that remained after quality trimming and removal of contaminating adapters, using the Trimmomatic software in January 2014 was selected for mitochondrial analysis. This was performed using standard extraction using the ZR Genomic DNAGallus gallus as reference was performed using MITOS and Heliornithidae (Heliornis fulica) than with members of the Gruidae (Anthropoides paradiseus) and Otidae (Otis tarda).The WWFT mitogenome constitutes the first whole mitochondrial genome entry within the Sarothruridae family. In order to evaluate its relative position within the order Gruiformes a phylogenetic tree (maximum-likelihood) was constructed to place the WWFT among species representing the Rallidae, Gruidae, Heliornithidae and Otididae Families using MEGA version 6 (Tamura et\u00a0al."} +{"text": "Recent studies have reported ERp57 overexpression in various human cancers, and altered expression and aberrant functionality of ERp57 are associated with cancer growth and progression and changes in the chemosensitivity of cancers. ERp57 may become a potential biomarker and therapeutic target to combat cancer development and chemoresistance. Here, we summarize the available knowledge of the role of ERp57 in cancer and the underlying mechanisms.Endoplasmic reticulum resident protein 57 (ERp57) has a molecular weight of 57 kDa, belongs to the protein disulfide-isomerase (PDI) family, and is primarily located in the endoplasmic reticulum (ER). ERp57 functions in the quality control of nascent synthesized glycoproteins, participates in major histocompatibility complex (MHC) class I molecule assembly, regulates immune responses, maintains immunogenic cell death (ICD), regulates the unfolded protein response (UPR), functions as a 1,25-dihydroxy vitamin D With cancer incidence and mortality rates increasing rapidly, cancer has become a global problem and is expected to become the leading cause of death worldwide in the 21st century according to the Global Cancer Statistics 2018 report The PDI family includes more than 20 members that catalyze cysteine-based redox reactions and play critical roles in productive protein folding in vitro analyses and clinical trials support that ERp57 is overexpressed in a variety of cancers. ERp57 expression is significantly different between tumor tissues and normal tissues (P < 0.05) in a wide variety of cancers, including stomach adenocarcinoma, colon adenocarcinoma, liver hepatocellular carcinoma (HCC), breast invasive carcinoma, and prostate adenocarcinoma, as shown in Figure http://ualcan.path.uab.edu/analysis.html) Recent research from In vitro, knockdown of ERp57 in HeLa cells inhibits cancer invasiveness and metastasis Some studies have demonstrated that ERp57 is a primary cellular target that inhibits cancer cell proliferation + T cells is enhanced when ERp57 is knocked out in human CD8+ T cells because ERp57 knockout in CD8+ T cells regulates the expression of multiple immune regulators and effectors on the cell surface + T cells need to be explored in detail to expand the utility of ERp57 in cancer immunotherapy strategies.Calnexin (CNX) and calreticulin (CRT) predominantly act as lectins that specifically interact with nascently synthesized glycoproteins in the ER, and ERp57 forms complexes with these proteins to accomplish efficient folding and proper formation of intramolecular disulfide bonds in glycoproteins in vivo because CRT translocation is inhibited and immunogenic cell death is abolished Immunogenic cell death (ICD), a type of regulated cell death (RCD), induces adaptive immune responses to kill cells directly Due to its disulfide isomerase activity, ERp57 forms a complex with CNX and CRT to specifically modulate the folding of newly synthesized glycoproteins by facilitating the formation of native disulfide bonds Recent data suggest that ERp57 plays an important role in the DNA repair process. ERp57, accompanied by high mobility group proteins 1 and 2 (HMGB1 and HMGB2), acts as a component of a complex that detects damaged DNA, inactivates the mismatch repair system and decreases the sensitivity of cells to thiopurine treatment Taken together, the evidence indicates that ERp57 has a protective effect on the survival of tumor cells due to its contribution to the DNA repair process, which regulates the sensitivity of the tumor to DNA-modifying chemotherapy. Thus, it may become a biomarker to predict therapeutic failure and success. However, further studies are required to confirm these findings and identify potential antitumor targets.2D3 is the active form of vitamin D, and its analogs exert inhibitory effects on the proliferation and progression of multiple cancers, including melanoma 3-membrane-associated, rapid response to steroid binding receptor, mainly located on the plasma membrane and Golgi/ER 2D3 to form a ligand-receptor complex to mediate several rapid signal transduction cascades; for example, it regulates STAT3 2+ release from lysosomes to activate autolysosomal degradation In vitro studies have revealed that knockdown of ERp57 inhibits HCC cell proliferation 1,25(OH)Mitomycin C (MMC) exerts anticancer effects by inducing DNA cross-linking in cancer cells Affymetrix microarray results suggest that cytoskeletal remodeling and the Wnt signaling pathway are the two of the top pathways disrupted by ERp57 silencing in HeLa cells 3-MARRS receptor ERp57 plays an important role in the natural history of cancer and the therapeutic process. As an ER chaperone, ERp57 is associated with CRT and CNX, participates in MHC class I molecule assembly"} +{"text": "Cervical cancer is a common gynecologic malignancy worldwide. It is the fourth for both incidence and mortality. For cervical cancer, imaging and pathology assessments are incorporated in the revised 2018 Federation of Gynecology and Obstetrics (FIGO) staging system. Uses of imaging techniques for the pre-treatment work-up of cervical cancer have been increasing. Among imaging techniques for the evaluation of cervical cancer, ultrasound is cheaper, faster and widely available than other imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI). Advanced technique in ultrasound, such as three-dimension (3D) ultrasound and color Doppler, have improved the clinical application of ultrasound in cervical cancer. Ultrasound may provide highly accurate information on detecting tumor presence and evaluating local tumor extent if performed by ultrasound-trained gynecologists; the experience of readers is also critical for correct pretreatment staging and assessment of response to treatment. Sonographic images could be useful to predict response of neoadjuvant chemotherapy, radiotherapy, chemotherapy and concurrent chemoradiotherapy in patients with cervical cancer. This review article attempted to present the most updated specific applications of ultrasound in cervical cancer. Cervical cancer is a common gynecologic malignancy among women. It is the fourth for both incidence and mortality in Global cancer statistics 2018 Patient age, performance status, para-aortic lymph node status, tumor size, and pelvic lymph node status are significantly associated with progression-free interval Cervical cancer can spread by lymphatic or hematogenous dissemination or direct extension. Staging cervical cancer is critical for approaching the most effective treatment strategy and predicting the outcomes. Stage IA cancer can be treated with cervical conization procedure or simple hysterectomy, while later stages may require neoadjuvant chemotherapy, radical surgery, radiation, chemotherapy or a combination of therapies. It is valuable to evaluate the response to treatment in cervical cancer women.For cervical cancer, imaging and pathology assessments are incorporated in the revised 2018 F\u00e9d\u00e9ration internationale de gyn\u00e9cologie et d'obst\u00e9trique (FIGO) staging system Transvaginal and transrectal ultrasound (TVUS and TRUS) are typically performed by the gynecologist with the advantage of low cost and wide availability A study enrolled 52 patients, 13 were advanced-stage disease (stage \u2265IIb) and 39 were early-stage disease (stage \u2264IIa), to evaluate the combined use of transvaginal elastography (TVES) and high-resolution TVUS in comparison with the diagnostic performance of magnetic resonance imaging (MRI) in detecting parametrial invasion in cervical cancer. It could be promising and economic for pre-operative work-up of cervical cancer by a dedicated gynecologic radiologist using TVES combined with TVUS In the cases with negative paraaortic lymph nodes on computed tomography (CT) or positron emission tomography (PET-CT), it could be necessary to perform dissection of the paraaortic lymph node in surgical staging. Obtaining an ultrasound or CT-guided tru-cut biopsy in equivocal extrauterine lesion is recommended to reduce false positive findings by imaging methods Hence, uses of imaging techniques for the pre-treatment work-up of cervical cancer have been increasing Among imaging techniques for the evaluation of cervical cancer, ultrasound is faster, radiation-free, cheaper, noninvasive, no contrast medium required and more widely available than other imaging techniques The characteristics of the cervix blood flow in normal women and in women with precancerous lesions or invasive cancers were reported by using three-dimensional power Doppler ultrasound (3D PDU) indices, including the intensity of flow at the time of volume acquisition (FI), the number of vessels within the volume of interest (VI), and both blood flow and vascularization (VFI) TVCD combined with colposcopy was used to diagnose precancerous lesions and early stage cervical cancer A thorough evaluation to determine the extent of cervical cancer should be performed if the diagnosis has been identified. There were several studies involving detection of the extension of cervical cancer lesion Table .The role of ultrasound for staging cervical cancer was reported in early 90s The accuracies of staging with TRUS and clinical staging were 83% and 78%, respectively. The sensitivity, specificity and accuracy of TRUS for extent of parametrial involvement were 78%, 89% and 87%. TRUS could be helpful applied to routine pretreatment assessment of patients with cervical carcinoma In the assessment of parametrial infiltration in cervical cancer, a study included 29 patients using MRI and 2D and 3D ultrasound examination before treatment. The result showed that 2D and 3D ultrasound had similar moderate agreement with MRI. However, 2D and 3D ultrasound examinations are more available at low cost than MRI. Ultrasound could be considered as a method for preoperative work-up of cervical cancer The agreement of clinical examination, 3D and 2D sonography with MRI for local staging of cervical carcinoma was evaluated For evaluating the tumor's volume and intra-tumoral vascularization, the study enrolled 27 patients, with cervical cancer and stage 1B1 disease, who have an initial 2D ultrasound examination and followed by 3D volumes of the cervix. The Virtual Organ Computer Aided Analysis (VOCAL) program was used to calculate the tumor volume and vascularization A recent study reported the local staging of cervical cancer for 46 patients who underwent MRI of the pelvis and high\u2010resolution TVUS A previous prospect study, included 38 cervical cancer patients, involved the TRUS in the evaluation of cervical carcinoma and comparing with spiral computed tomography (SCT) and MRI For locally advanced cervical cancer, 3-dimensional transvaginal ultrasound (3D-TVUS) was used to diagnose the extent of invasive cervical cancer and compare to that of Magnetic resonance imaging For cervical primary tumor confined to the origin, the sonographic detection rate is high; transrectal or TVUS is a highly accurate modality in classifying early-stage tumors The diagnostic performance of TVUS and MRI for assessment of presence and extent of cervical cancer was investigated by a prospective study The diagnostic performance of TVUS examination with regard to local extent and tumor size of the disease of early stage cervical cancer was investigated Assessment of the extension of the lesion has been researched Furthermore, angiogenesis, the formation of new vessels in a specific area, is required for tumor growth and progression Transvaginal Color Doppler in cervical cancer allows non-invasive assessment of tumor angiogenesis Color Doppler findings associated with risk factors was reported by a study involving neoangiogenesis measured in early cervical cancer cases Angiogenic parameters, including subjective assessment of pulsatility index (PI) and the amount of vessels within the tumor (scanty-moderate or abundant), were evaluated by transvaginal color Doppler ultrasound for 27 early stage cervical cancer patients. The risk factors were recorded. Tumors with abundant vasculization were significantly associated with parametrial involvement, lymph-vascular space involvement, pelvic lymph node metastases etc. Postoperative treatment was significantly more prevalent in patients with profuse vascularization The p53 protein expression in cervical cancer after RT correlated with transvaginal color Doppler ultrasound findings was reported by a recent study Several studies have evaluated the role of ultrasound for predicting the response to varied treatment in women with cervical cancer.The role of TVUS in early prediction of pathological response in a large series of locally advanced cervical cancer patients arranged neoadjuvant treatment followed by radical surgery was investigated by using 3D PDU Using Power Doppler vascularity index (PDVI) to predict the response to neoadjuvant chemotherapy (NACT) in bulky early stage cervical carcinoma was reported A prospective study involved 42 women with locally advanced cervical cancer referred for NACT Transvaginal Color Doppler sonography used to predict the response to chemotherapy in patients with advanced cervical cancer was reported The residual tumor in locally advanced cervical cancer patients receiving chemoradiation and radical surgery was assessed by 3D power Doppler, 2D ultrasound parameters, or contrast-enhanced indices Ttransvaginal color Doppler ultrasonography (TCD) used to predict response to preoperative chemoradiation for locally advanced cervical carcinoma patients was investigated Alterations in cervical intra-tumoral vascularization during and after radiotherapy investigated by 3D PDU was reported The evaluation of radiotherapy response of cervical cancer by suing gray scale and color Doppler ultrasonography was report It was reported that Transvaginal color Doppler sonography could be useful in predicting clinical response to concurrent chemoradiation for locally advanced cervical carcinoma The investigation of early response of locally advanced cervical cancer patients undergoing concurrent chemo-radiotherapy (CCRT) by ultrasound was reported The role of intraoperative ultrasound guidance in intracavitary brachytherapy of cervical cancer was investigated in a recent retrospectively study In a recent systematic review and meta-analysis, a decrease of uterine perforations by using ultrasound image-guided applicator insertion for cervical carcinoma patients underwent intracavitary brachytherapy was revealed TRUS guided high dose rate (HDR) interstitial brachytherapy for patients of cervical cancer was investigated For the ability of evaluating morphology and intensity of blood flow, ultrasound technique might be used to improve cervical cancer screening, and this need more studies to confirm the applications. Imaging during the primary diagnostic work-up is essential for accurately assessment of tumor extent and selecting the best therapeutic option for cervical cancer patients. Ultrasound may be a useful modality to evaluate local extent of disease in cervical cancer. This technique is limited for evaluating lymph node status. Tumor vascularization by Doppler ultrasound could be useful for monitoring and predict response to therapy."} +{"text": "The Medication-Related Osteonecrosis of Jaws (MRONJ) diagnosis process and its prevention play a role of great and rising importance, not only on the Quality of Life (QoL) of patients, but also on the decision-making process by the majority of dentists and oral surgeons involved in MRONJ prevention (primary and secondary). The present paper reports the update of the conclusions from the Consensus Conference\u2014held at the Symposium of the Italian Society of Oral Pathology and Medicine (SIPMO) \u2014after the newest recommendations (2020) on MRONJ were published by two scientific societies , written on the inputs of the experts of the Italian Allied Committee on ONJ (IAC-ONJ). The conference focused on the topic of MRONJ, and in particular on the common practices at risk of inappropriateness in MRONJ diagnosis and therapy, as well as on MRONJ prevention and the dental management of patients at risk of MRONJ. It is a matter of cancer and osteometabolic patients that are at risk since being exposed to several drugs with antiresorptive or, more recently, antiangiogenic activities. At the same time, the Conference traced for dentists and oral surgeons some easy applicable indications and procedures to reduce MRONJ onset risk and to diagnose it early. Continuous updating on these issues, so important for the patient community, is recommended. Medication-Related Osteonecrosis of Jaws (MRONJ) and its prevention play a role of great and rising importance, not only on the Quality of Life (QoL) of patients, but also on the decision-making process of the majority of dentists and oral surgeons, involved every day in MRONJ prevention (primary and secondary). The present report illustrates the update of conclusions adopted from the Consensus Conference held at the Symposium of the Italian Society of Oral Pathology and Medicine (SIPMO) on 20 October 2018, in Ancona (IT), when opinions were discussed and synthesized by 24 Italian experts. The Conference was the first national consensus to address the MRONJ disease and specific interventions , it sharThe present report was considered by the experts as convenient and worthwhile in the light of the new findings ,12,13 anThe updated Consensus Conference focused on the common practices still at risk of inappropriateness in MRONJ diagnosis and prevention, and on the dental management of patients exposed to ONJ. It is matter for the cancer and osteometabolic patients, since they are exposed to an increasing number of drugs with antiresorptive or antiangiogenic activities ,16,17,18The experts focused on the topic of MRONJ using the following 6 main subcategories (issues): (1) clinical diagnosis; (2) radiologic diagnosis; (3) primary prevention (before and during drug intake); (4) dental management; (5) drug holiday (temporary suspension vs. therapeutic suspension); and (6) therapy.The IAC-ONJ planned that a recommended practice equivalent will be advised for any inappropriate practice, within these 6 issues.Assume that the Italian Consensus adopted the previously described definition of MRONJ ,5, as be(#1) Restricting the anamnestic interview only to the assumption of bisphosphonates for diagnosing MRONJ.(#2) Carrying out routine bone biopsies when suspecting an MRONJ.(#3) Considering the presence of exposed necrotic bone, in the oral cavity, as an essential (conditio sine qua non) sign to diagnose MRONJ.(#4) Judging the presence of pain as an essential symptom for diagnosing MRONJ.(#5) Believing that all MRONJ are preceded by dental invasive procedures.(#1) Evaluate not only the intake of bisphosphonate drugs (current or past), but also further pharmacological therapies and perform a thorough physical examination and medical history, together with targeted radiologic examinations see (confirm(#2) Perform jaw bone biopsies only if there is a suspicion of metastases in cancer patients (confirmed).(#3) Take into the account not only the presence of exposed necrotic bone but considering also other clinical signs and first/second-level imaging (confirmed).(#4) Consider that the symptom \u201cpain\u201d may not always be present in MRONJ cases, especially in the early stages (confirmed).(#5) Consider that some cases of MRONJ can arise from the presence of dental-periodontal diseases or spontaneously, without any relation to invasive dental procedures (confirmed).Radiologic imaging is assumed to be a fundamental tool for diagnostic completion, defining the extent of the disease at the skeletal level, staging and the correct therapeutic planning. Even if it is well known that no specific radiological signs of disease can be defined until now, an increasing volume of evidence recognizes some radiological characteristics that, although non-specific, are associated with MRONJ ,23,24,25(#1) Starting therapies at risk of ONJ without a radiologic assessment of dental arches, remarkably in cancer patients.(#2) Omitting the radiologic assessment for those patients at risk of MRONJ in the presence of dental/endo-periodontal diseases.(#3) Prescribing to everybody exposed to therapies at risk of ONJ all imaging techniques to rule out MRONJ.(#4) Requiring radiologic exams without a specific diagnostic hypothesis.(#5) Prescribing radiological exams for MRONJ only after onset of jawbone exposure.(#6) Diagnosing MRONJ only on the basis of the clinical signs, without radiologic assessment.(#7) Prescribing high-resolution imaging for soft tissue (with contrast medium) for diagnosis of MRONJ.(#8) Planning MRONJ treatment without second-level imaging exams for assessing jawbone disease extension and severity.(#9) Monitoring the extension of the MRONJ process only by investigations of first-level exams .(#1) Evaluate clinically and radiologically any local risk factors for MRONJ for preventive dental screening in patients, remarkably cancer ones, who are candidates for therapies at higher risk of MRONJ; sometimes, MRONJ could manifest like a dental/endo-periodontal disease, or a worsening of a pre-existent disease (updated) .(#2) Perform radiological exams in all cases of dental/endo-periodontal diseases in patients at risk of MRONJ (confirmed).(#3) Reserve the indication for the execution of radiological exams of the second level to patients at MRONJ risk only in the presence of ascertained clinical or radiologic signs compatible with MRONJ (confirmed) ,9,22.(#4) Specify always the diagnostic hypothesis when prescribing radiological exams of any level in patients at MRONJ risk (confirmed).(#5) Do not delay in prescribing radiologic exams to investigate any clinical signs of possible MRONJ, independent of the presence of bone exposure or fistulas (updated).(#6) Integrate always the clinical check-up with the appropriate imaging exams for the diagnosis of MRONJ (confirmed).(#7) Prescribe radiologic exams for bone diseases without contrast medium for diagnosis of MRONJ (confirmed).(#8) Set up the MRONJ treatment after defining its extension and severity also by targeted imaging (confirmed).(#9) Use targeted imaging to monitor MRONJ during follow-up after conservative and/or surgical treatment (updated).Assuming that recently it has been confirmed that MRONJ prevention means applying the correct protocols of (1) primary prevention for both pre-treatment and in-treatment patients, and (2) secondary prevention , the ConPrimary prevention for MRONJ mainly means elimination/reduction of the oral and dental risk factors ,27,28,29A new emerging and huge aspect is that primary prevention should be performed not only prior to taking the MRONJ-related drugs but also during and after the treatment with antiresorptive agents (AR), in order to eliminate any infective outbreaks of MRONJ. It is the responsibility of the dentist to accurately assess the risk factors leading to the development of MRONJ and suggest a strategy to remove these factors or minimize the risk. The dentist must also stress the importance of maintaining effective dental hygiene , including regular check-ups, for the patient. Both are necessary to maintain oral health, reducing the outbreak of MRONJ and/or detecting possible signs of the early symptoms of this disease.Secondary prevention or early diagnosis is the second pillar in the strategy against MRONJ, since we know that MRONJ diagnosed at an early stage is more likely to be treated successfully. With respect to the diagnostic work-up, the main problem is the possible under-diagnosing of MRONJ cases without bone exposure (or fistula). A recent multicenter study ,30 has d(#1) Keeping teeth with endodontic and/or periodontal diseases at uncertain prognosis only to avoid extractive and invasive procedures, in patients at risk of MRONJ.(#2) Extracting teeth in partial or total inclusion for pure preventive purposes in patients that are candidates for treatment with drugs at risk of inducing MRONJ.(#3) Scheduling in cancer patients the first dental check-up only after diagnosis of bone metastases.(#4) Omitting in osteometabolic patients dental check-ups for oral health status assessment and relative preventive dentistry actions.(#5) Omitting periodic dental check-ups for edentulous patients or wearing removable prostheses, if they are at risk of MRONJ.(#6) Underestimating the usefulness of the imaging performed to evaluate cancer disease extension with respect to MRONJ early diagnosis (and follow-up).(#1) Extract teeth with endodontic and/or periodontal diseases, in patients at risk of MRONJ, when a conservative approach is not possible and a good tooth prognosis is not guaranteed (confirmed).(#2) Maintain teeth in partial or total inclusion, if no sign and/or symptom is present (confirmed).(#3) Schedule in cancer patients the first dental check-up as soon as possible, preferably during the tumor staging process (confirmed).(#4) Consider in osteometabolic patients a potential gradient in MRONJ risk (updated(a) Administration and duration of treatment with MRONJ-related drugs ,6,37,38;(b) Eventual presence of comorbidities and further medical therapies indirectly associated; assess, during the prescription of the MRONJ-associated drugs, the oral health status even by a questionnaire 39]; sc; sc39]; (#5) Schedule preventive dental check-ups even in patients at risk of MRONJ even if edentulous or wearing removable dentures, in order to intercept and correct any injury on the oral mucosa (confirmed).(#6) Research any sign of jawbone alterations in cancer patients, revising the pictures of the imaging investigations already performed to stage the cancer disease, in order to potentially detect eventual early signs of MRONJ, before prescribing further specific imaging (updated).Assume that the Consensus Conference has now adopted the new protocols for dental management in patients at risk of MRONJ, published in the recommendations on MRONJ by the two scientific societies SICMF/SIPMO , in whic(#1) Building an implant rehabilitation in cancer patients who have to take or are taking MRONJ-associated drugs due to advanced cancer disease.(#2) Considering as contraindicated, in an absolute sense, implant rehabilitation in osteometabolic patients taking MRONJ-associated drugs (including cancer patients treated with antiresorptive agents for CTIBL).(#3) Prescribing antibiotic prophylaxis before non-invasive dental therapies.(#4) Performing extractive procedures without removing, even if necessary, the alveolar bone, and plan the healing as a second intention .(#1) Avoid in cancer patients implant rehabilitation and plan non-surgical rehabilitation (confirmed).(#2) Plan implant rehabilitation in osteometabolic patients taking into account the cumulative dose of the drug already taken, the periodontal status, lifestyle , comorbidities and other drugs. Share with the patient a hypothetical medium to long-term MRONJ risk due to \u201cimplant presence-triggers\u201d (such as peri-implantitis and micro-cracks), beside the lower probable short-term risk due to \u201cimplant surgery-triggers\u201d ,41,42,43(#3) Recommend always, in patients at MRONJ risk, antibiotic prophylaxis when surgical procedures involving the dento-alveolar process or maxillary bones are planned (confirmed).(#4) Practice extractive or surgical procedures planning the healing as the first intention with the clot maintenance (confirmed).Assuming that a drug holiday is a controversial issue, involving both drug prescribers and oral and dental specialists, it is important to clarify that \u201cDrug holiday\u201d can have at least two meanings in the medical literature when referred to MRONJ. It can mainly mean (1) the temporary and preventative suspension of drug therapy in a patient at risk of MRONJ, before the necessary dental procedures (tooth extraction or jawbone surgery); or (2) the suspension of drug therapy due to a diagnosis of MRONJ, hypothetically finalized to stop or to slow the osteonecrosis process (a practice with scarce literature as support). This document will afford only the first meaning of a \u201cdrug holiday\u201d.It is well known that suspension of drug therapy can create different cost\u2013benefit balances, according also to the type of molecule in those two patient populations.In cancer patients with advanced disease , suspension of antiresorptive drugs has to be decided on the basis of a difficult balance between a possible positive drug effect and a potentially higher risk of a side effect anyway present . Clearly that balance could individually change on the basis of the moment along the patient cancer history and along the drug administration history: hypothetically, in the first months of drug administration for bone metastases or myeloma, the suspension is potentially more harmful for the (lack of reduction of) risk of SRE but less dangerous for the risk of triggering MRONJ; vice versa after two years of antiresorptive administration, for example, the suspension appears less dangerous for the risk of SRE (anyway present) whereas the risk of MRONJ (being higher with longer time and higher cumulative drug dose) might receive maximum benefit from the suspension.(a) -BPs have a long half-life and are able to accumulate in the bone tissue, potentially influencing the post-extractive bone tissue repair. Furthermore, for some largely used BPs , a possible antiangiogenic effect was described in the literature, potentially reducing the soft tissue repair process. Consequently, a precautionary and temporary suspension of the drug administration has been claimed by most of authors as potentially useful, even if no definitive data have been published;-\u00ae), a monoclonal human anti-RANKL inhibitor, is a drug with a short half-life and does not accumulate in the bone. A possible rebound effect on the bone turnover has been described after drug withdrawal, so that some authors advised against a (long) suspension.Denosumab , receive antiresorptive drugs at lower doses and less frequently . The fracture risk can be determined objectively and correctly by applying the DeFRA79 algorithm validated by AIFA, the Italian version of the FRAX algorithm [(b) lgorithm .-BPs are synthetic analogues of pyrophosphates, which firmly bind to the hydroxyapatite and reduce bone metabolism/remodeling . The hal-\u00ae), a monoclonal human IgG2 antibody that highly binds the receptor activator of nuclear factor-kB ligand (RANK-L), blocks the osteoclast maturation, function and survival. Its half-life is 25\u201332 days and it does not amass in the bone with a peculiar regimen (1 dose s.c. of 60 mg every six months) [Denosumab (Prolia months) ,47,48. T months) ,50. Of nOn the basis of the two different antiresorptive agents, they are classified as follows:\u00ae) without agreeing any temporary suspension with the prescriber (oncologist/hematologist).(#1) Performing dental extraction or oral surgery in patients with active cancer and myeloma bone disease and in therapy with i.v. high-dose bisphosphonates or denosumab (Xgeva(#2) Suspending indiscriminately therapy with antiresorptive drugs prescribed for osteoporosis (or its prevention), in case of necessity of extraction or programmed oral surgery, without agreeing with the prescribing physician.\u00ae) before and after the dental procedure. This combined assessment is mandatory in the absence of univocal data on the efficacy of the suspension of bisphosphonates or denosumab to reduce the risk of \u201cpost-extraction\u201d MRONJ, and in consideration of conflicting data about the possible anti-angiogenic effect of zoledronic acid ((#1) Plan, in cancer patients, combined assessment by the prescriber and by the dentist to determine whether or not there is the need for a precautionary suspension of i.v. high-dose bisphosphonate or denosumab (updated). There are two different conditions ((#2) Plan, in osteometabolic patients, a balanced and combined assessment by the prescriber and by the dentist to assess whether or not you need precautionary suspension of BPs or postponing the denosumab (Prolianditions .(a) Patient under BPs, a drug suspension may be already considered useful one week before surgical procedures. BP administration can resume once the biological process of healing of the oral tissues is completed (at least 4\u20136 weeks after surgery) ,14;\u00ae); it is still possible to take advantage of the pharmacokinetic of Prolia\u00ae in order to define a time interval in those postponable and non-critical dental/periodontal conditions requiring invasive treatment and can theoretically take place without restrictions. This \u201cdelayed dosing window\u201d lasts about 2 months, starts ideally 5 months after the last dose of Prolia\u00ae and ends at the beginning of the 7th month. If the surgical dental procedure is assessed as urgent and not procrastinable, it is recommended to apply the suspension scheme of denosumab previously described for cancer patients [(b) Patient under denosumab with respect to therapeutic strategies ,14; it f(#1) Forgetting the adoption of an adequate perioperative antibiotic regimen in case of surgical treatment of MRONJ.(#2) Performing a diagnostic bone biopsy, unless bone metastases are suspected.(#3) Applying of first-level imaging only to plan surgical treatment.(#4) Awaiting the exfoliation (self-sequestration) of necrotic exposed bone via the use of non-surgical therapies, since this process is unpredictable over time.(#5) Neglecting shaving and smoothing of the bone surfaces as a mainstay of any surgical procedure.(#6) Banishing the surgical option for MRONJ cancer patients based on general statements of residual life expectancy.(#7) Merging BP-related and non-BP-related (anti-RankL and/or targeted therapies) MRONJ patients as a whole when considering temporary interruption of medications for surgical treatment.(#8) Adopting surgical treatment of MRONJ in symptomatic cases only.(#9) Relaying on systemic bone turnover markers to predict the success of surgical therapies in MRONJ patients.(#1) Prescribe a broad-spectrum antibiotic regimen as an integral part of surgical treatment: high-dose amoxicillin/clavulanic acid (1000 mg TID), plus high-dose Metronidazole (500 mg TID), from the day before surgery and up to the 10th post-operative day. Alternatives should be used in case of reported allergy to penicillin (confirmed).(#2) Perform a diagnostic bone biopsy in case of clinical and radiological suspicion of bone metastases to the jaw or myeloma area, in order to distinguish them from site of MRONJ disease, when clinically needed (confirmed).(#3) Use second-level imaging tools, mainly computed tomography (CT), to appropriately plan the extent of jawbone disease before surgery (confirmed).(#4) Anticipate surgical treatment, whenever indicated, to reduce the surgical burden for MRONJ patients and increase the likelihood of long-term healing (confirmed).(#5) Always perform the shaving and smoothing of bone surfaces as a mainstay of any surgical procedure to prevent further bone exposure (confirmed).(#6) Plan the surgical treatment of MRONJ on an individual basis, weighing the impact and the potential benefit of surgery on the general health status of patients (confirmed).(#7) Discuss and plan the temporary interruption of any given medication in agreement with the prescriber and based on its pharmacological properties, before initiating every MRONJ surgical treatment (confirmed).(#8) Adopt the early surgical treatment also in MRONJ asymptomatic patients (confirmed).(#9) Do not rely on systemic bone turnover markers to establish individual treatment algorithms for MRONJ, but carefully examine all potential factors that are likely to influence the long-term success of therapies, including the underlying disease (cancer or non-cancer) and the type of medication used (confirmed).MRONJ is a potentially severe complication of antiresorptive and/or antiangiogenic treatment in patients with skeletal events due to various cancers as well as osteometabolic diseases; MRONJ may lead to a reduced quality of life due to jawbone infections, chronic pain, tooth loss and compromised function. Although notable progress has been made, there remain a number of controversial aspects on MRONJ, especially regarding pathogenesis, diagnosis and treatment.The present paper updated conclusions from the Consensus Conference at the Symposium of Italian Society of Oral Pathology and Medicine (SIPMO) , after the newest recommendations on MRONJ were published in 2020 by two scientific societies , written on the inputs of the experts of Italian Allied Committee on ONJ (IAC-ONJ). Some recommendations were confirmed.We defined six issues of MRONJ and submitted for every issue the current knowledge and the appropriate best practices, in order to improve the management of patients.We highlighted the importance to disclose the appropriate information about MRONJ, and the statements and recommendations presented in this paper might represent a beneficial instrument both at a national and international level to better understand and manage this singular and severe disease.In the absence of clear knowledge on the etiology and given the continuous spread of the application of new target therapies, it will be fundamental to continue the research, to report any cases using new drugs and to clarify by evidence-based medicine all the controversial aspects of MRONJ."} +{"text": "Radiotherapy is an important therapeutic approach to treating malignant tumors of different localization, including brain cancer. Glioblastoma multiforme (GBM) represents the most aggressive brain tumor, which develops relapsed disease during the 1st year after the surgical removal of the primary node, in spite of active adjuvant radiochemotherapy. More and more evidence suggests that the treatment's success might be determined by the balance of expected antitumor effects of the treatment and its non-targeted side effects on the surrounding brain tissue. Radiation-induced damage of the GBM microenvironment might create tumor-susceptible niche facilitating proliferation and invasion of the residual glioma cells and the disease relapse. Understanding of molecular mechanisms of radiation-induced changes in brain ECM might help to reconsider and improve conventional anti-glioblastoma radiotherapy, taking into account the balance between its antitumor and ECM-destructing activities. Although little is currently known about the radiation-induced changes in brain ECM, this review summarizes current knowledge about irradiation effects onto the main components of brain ECM such as proteoglycans, glycosaminoglycans, glycoproteins, and the enzymes responsible for their modification and degradation. Adjuvant chemoradiotherapy with temozolomide is a conventional protocol for the standard treatment for newly diagnosed glioblastoma multiforme (GBM) . Last deRadiotherapy (RT) represents an essential part of this post-surgery GBM treatment, and the current standard usually includes 30 X-ray fractions \u00d7 2 Gy, although multiple non-conventional RT sources and regimens are under active investigation .RT aims to destroy the residual GBM cells at the resection border and prevent the disease relapse, but it has wide biological effects on different molecular and physiological parameters in the irradiated brain tissue as well . NegativAlong with that, RT-induced lymphodepletion and subsequent suppression of immune response contribute to the insufficient efficiency of conventional RT and may be limiting the success of GBM treatment . Also, iAt present, more and more evidence is accumulating showing that TME is actively involved in the molecular fate of GBM tumor-initiating cells and tumor development, and significantly modifies the epigenetic landscape of GBM cells with unknown mechanism . IrradiaThe presented data demonstrate that different components of the GBM TME actively respond to X-ray irradiation, whereas the contribution of extracellular matrix (ECM) to radiation-induced changes in both GBM tumor and normal brain tissue remain much less investigated. The available information on this issue is very scanty and fragmentary, but it may be useful to summarize it in order to outline possible directions for future research in this scientific field.Here, the effects of experimental and clinical irradiation onto key brain ECM components in normal brain tissue and GBM cells/tumors will be reviewed.Proteoglycans (PGs) are the main components of brain ECM and play important roles in normal brain physiology and gliomagenesis . They reA major component of the brain ECM is chondroitin sulfate proteoglycans (CSPGs), which are actively involved in the organization of GBM TME and glioma invasion . The comThe few available data on radiation effects on CSPGs are quite controversial, although expression of CSPG-coding genes has a tendency to be down-regulated in non-tumor tissues and up-regulated in glioma cells or tissues upon X-ray irradiation . Cranial125I) seed results in an increase of NG2 content in the brain tissue. The U251 cells with activated NG2 expression (U251\u2013NG2) were significantly more resistant to 5 Gy irradiation compared to the NG2-negative U251 cells suggesting NG2 as an important prognostic factor for radiotherapy resistance activates the expression of CD44 in these cells is an integral component of any tissue, but it plays a particularly important role in the brain, where it represents a major component of intercellular space .Irradiation effects onto HA remain to be almost uninvestigated. The only study by Yoo et al. demonstrates that irradiation of GBM U87MG cells (2 Gy/day for 3 days) or U87MG orthotopic brain tumors (2.5 Gy/day for 3 days) results in a significant increase of HA content in GBM cell-conditioned medium and experimental tumors, respectively. The increase of HA content in tumor tissue affects the biomechanical tension in the GBM microenvironment and provides pro-invasive extracellular signaling cue due to binding with CD44 receptor and SRC activation sufficient for a mesenchymal shift of GBM cells. These findings suggest an explanation for the frequent brain tumor relapse after radiotherapy .Heparan sulfate proteoglycans (HSPGs) represent one of the main components of the neurogenic niche. Tight involvement of both the polysaccharide heparan sulfate (HS) chains and their degrading enzyme heparanase in the development of the nervous system and growth and invasion of glioma tumors are comprehensively described by Xiong et al. , 45. AmoThere is just fragmentary information on the irradiation effects onto these macromolecules.Experimental irradiation of normal mouse brain (7 Gy in a single dose) did not change expression levels of syndecan-1, glypican-1, and perlecan in short-term period (24\u201372 h) . HoweverDespite the common extracellular glycoproteins not being much abundant in brain tissue, they are intrinsic components of brain ECM. Radiation-induced changes in their expression contribute to pathological brain ECM reorganization during radiotherapy.Whole-brain irradiation of experimental animals (a single dose of 10 Gy for rats or 8 fractions \u00d7 5 Gy for 4 weeks for mice) decreases collagen IV content in brain tissue by 24 h after irradiation, while no significant changes are shown at 4 or 8 h after irradiation. Simultaneous up-regulation of expression and enzymatic activity of MMP2 and MMP9 seems to be a molecular mechanism for irradiation-induces ECM degradation .Long-term effects (6 months) of irradiation of the whole brain of Rhesus macaques (age 6\u201311 years), which had received 40 Gy , increased expression of fibronectin 1 (FN1) in brain tissue at mRNA level and protIrradiation of U87 GBM cells (2 Gy/day for 3 days) does not affect the expression of collagen type-I alpha 1 (COL1A1) and collagen type III alpha 1 (COL3A1) .Brain ECM structure is tightly determined by a complex interplay between the expression of ECM glycoproteins/PGs/GAGs and their proteolytic remodeling by matrix metalloproteinases (MMPs) and GAG-degrading enzymes , 48. RadX-ray irradiation of animal brain results in a quick (4\u201324 h) up-regulation of expression and enzymatic activity of MMPs: MMP2 and MMP9 and MMP2 . IrradiaIrradiation of U87MG GBM cells at 2\u20136 Gy doses increases expression and enzymatic activity of MMP2 in these cells and experimental orthotopic U87 tumors obtained from them . This reHeparanase (HPSE) is the main enzyme responsible for the degradation of polysaccharide chains of HS at the cell surface and ECM of all tissues. It involved in normal physiology and pathological reorganization of ECM into TME and cancer progression and metastasis , 45, 49.Gamma-irradiation of brain microvessel endothelial cells results in a significant increase in the release of heparanase, which degrades [35S]-labeled heparan sulfate from the subendothelial matrix. This was most pronounced at the 24 h after irradiation and can affect the interactions of tumor cells with endothelial cells and their microenvironment, which in turn facilitate the formation of metastasis in irradiated tissues . The relAccording to the presented data, X-ray radiation affects all key components of normal brain ECM in different extent and directions .An interesting observation is that radiation has a much pronounced effect on normal brain tissue than on tumor cells. There is a common tendency to the increased expression of glycoproteins (collagen and fibronectin) and decreased expression of main proteoglycan components of brain ECM indicating significant changes of normal structure of brain ECM . ReplaceOn the other side, GBM cells and tumors demonstrate more resistant phenotype to X-ray irradiation and completely different pattern of radiation-induced changes. Only three of fifteen ECM components respond to irradiation by activation of their expression/content . The cooThese radiation-induced changes in brain ECM and the residual GBM cells cooperate to provide a favorable microenvironment for GBM progression. Moreover, multiple studies show that radiotherapy not only serves as a therapeutic mean to eliminate glioma cells but also activates proliferation and invasion of those cells which survived irradiation. This seems to occur due to the selection of radioresistant GBM clones and their active invasion in previously irradiated GBM tumor microenvironment .in vivo, possibly through the imbalance between MMP2 and TIMP2 and ECM degradation (Molecular mechanisms of negative side effects of irradiation are tightly related to GBM TME: subcurative irradiation of primary human GBM tumors in rat brain results in the increased proliferation (3-fold), migration, and invasion of the survived GBM cells associated with increased expression of CD44 and activation of MMP2 expression ; irradiaradation . Besidesradation .Radiation induces also significant changes in immune components of brain microenvironment, which contributes to poor efficacy of anti-GBM radiochemotherapy. Irradiation results in activation of the expression of immune-associated genes in murine glioma and human glioma U87 cell line, leading to changes in immune microenvironment, glioma cells radioresistance, and treatment failure . Cranialin vivo, where the initial positive effect on inhibition of GBM tumor growth by 14 day is followed by the tumor relapse and higher mortality for the mice with a smaller tumor volume by 21 day (Thus, GBM radiotherapy possesses a double effect\u2014it directly affects brain ECM and induces GBM cells to modulate their microenvironment. The balance between these modalities might be responsible for the ambiguous functional effect y 21 day . OverallEG conceived the study, drafted, and edited the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Accidents, as the third important cause of mortality, are among main challenges of communities due their costs and irreversible damages. This study aimed to investigate the age distribution of people referred to the hospitals affiliated by Iran\u2019s ministry of health because of accidents.In a cross-sectional study, using a CDC checklist, data related to the injured people who referred to the hospitals affiliated by Iran\u2019s ministry of health in a one year period was gathered from hospital records, as well as interview and observation. The collected data was analyzed by descriptive and analytical statistics in SPSS11 software.The commonest age group involved in accidents during the year 1395 (2016) was middle-aged (37%) followed by youth (25%). The commonest accidents in children were: fall (23%), traffic accidents (19%), and burn (13%). In adolescents, the commonest accidents were: traffic accidents (32%), fall (16%), and violence and poisoning (5%). The commonest accidents in youth were: traffic accidents (35%), violence (9%), and poisoning (6%). In middle-aged group, the commonest accidents were: traffic accidents (30%), fall (12%), and violence and poisoning (7%). The commonest accidents in elderly were: fall and traffic accidents (25%), burn (4%), and violence and poisoning (3%).Making plan and policies to prevent accidents and injuries is a health priority and a key tool for improving the safety of the community. Also, informing the all age groups of the community about preventive actions is necessary.Road Traffic Injury, Trauma, Hospital"} +{"text": "How have US clinicians planned for and responded to resource limitation during the coronavirus disease 2019 pandemic?This qualitative study included interviews with 61 clinicians across the United States. While institutions planned for an explicit and systematic approach to resource allocation in crisis settings, this approach did not address many challenges encountered by frontline clinicians, leaving them to struggle with what constituted acceptable standards of care and to make difficult allocation decisions.The findings of this study suggest that expanding the scope of institutional planning to address a broader spectrum of resource limitation may help to support clinicians, promote equity, and optimize care during the pandemic. This qualitative study describes the perspectives and experiences of clinicians involved in institutional planning for resource limitation and/or patient care during the coronavirus disease 2019 (COVID-19) pandemic. Little is known about how US clinicians have responded to resource limitation during the coronavirus disease 2019 (COVID-19) pandemic.To describe the perspectives and experiences of clinicians involved in institutional planning for resource limitation and/or patient care during the pandemic.This qualitative study used inductive thematic analysis of semistructured interviews conducted in April and May 2020 with a national group of clinicians involved in institutional planning and/or clinical care during the COVID-19 pandemic across the United States.Emergent themes describing clinicians\u2019 experience providing care in settings of resource limitation.The 61 participants included in this study were practicing in 15 US states and were more heavily sampled from areas with the highest rates of COVID-19 infection at the time of interviews . Most participants were White individuals (39 [65%]), were attending physicians (45 [75%]), and were practicing in large academic centers . Three overlapping and interrelated themes emerged from qualitative analysis, as follows: (1) planning for crisis capacity, (2) adapting to resource limitation, and (3) multiple unprecedented barriers to care delivery. Clinician leaders worked within their institutions to plan a systematic approach for fair allocation of limited resources in crisis settings so that frontline clinicians would not have to make rationing decisions at the bedside. However, even before a declaration of crisis capacity, clinicians encountered varied and sometimes unanticipated forms of resource limitation that could compromise care, require that they make difficult allocation decisions, and contribute to moral distress. Furthermore, unprecedented challenges to caring for patients during the pandemic, including the need to limit in-person interactions, the rapid pace of change, and the dearth of scientific evidence, added to the challenges of caring for patients and communicating with families.The findings of this qualitative study highlighted the complexity of providing high-quality care for patients during the COVID-19 pandemic. Expanding the scope of institutional planning to address resource limitation challenges that can arise long before declarations of crisis capacity may help to support frontline clinicians, promote equity, and optimize care as the pandemic evolves. Early reports from frontline clinicians in global epicenters describing extreme shortages and bedside rationing of ventilators and intensive care unit (ICU) beds2 prompted a national conversation about how to respond to similar challenges in the United States.3 Hospitals and health care systems drew on frameworks developed by the Institute of Medicine (IOM) and other national organizations to guide care in resource-limited emergency settings.7Since the first US case of coronavirus disease 2019 (COVID-19) was diagnosed in mid-January 2020,8 Under crisis standards of care, a specialized triage team becomes responsible for rationing scarce resources and making decisions about which patients will and will not receive potentially life-saving treatments.Under the IOM\u2019s framework, resource allocation is intentionally siloed from other aspects of clinical care to ensure a fair process and spare frontline clinicians from the responsibility of having to ration scarce resources at the bedside. The IOM recommends a phased adaptation to resource limitation. Institutions first shift from conventional to contingency capacity, in which resources are adapted, optimized, and redistributed to maintain a standard of care that is functionally equivalent to usual care. If resources become so limited that a functionally equivalent standard of care can no longer be sustained, institutions then shift to crisis capacity, and care is redirected to provide the greatest aggregate benefit to the population.10 and has been iteratively refined through ethical analysis8 and community deliberation,12 there have been few opportunities to test the framework in real-world clinical settings. Reports from past pandemics14 and from early global epicenters of the COVID-19 pandemic,15 press reports,17 and perspectives published in the scientific literature19 describe some of the challenges faced by frontline clinicians. However, there is little empirical work describing the experiences and perspectives of US clinicians pertaining to resource limitation and clinical care during the COVID-19 pandemic.21 To address this knowledge gap, we conducted a qualitative analysis of interviews with US clinicians during the pandemic.Although the IOM framework reflects lessons learned during earlier pandemicsCOREQ) reporting guideline at our own institution (the University of Washington). We then expanded recruitment to include other groups of clinicians and those practicing in other parts of the country. We used a snowballing recruitment strategy in which we asked participants to identify colleagues with relevant experience who might be interested in participating in the study. We did not exclude participants who had collegiate relationships with members of the research team. Interviews were conducted between April 9, 2020, and May 26, 2020. The University of Washington institutional review board approved this study and authorized verbal in lieu of written consent. Verbal consent was obtained from all participants. We report details of our methods using the Consolidated Criteria for Reporting Qualitative Research . All but 1 interview, which included 2 participants at their request, were conducted 1-on-1, and 2 interviews were spread over 2 sittings. A semistructured interview guide independently reviewed and openly coded transcripts until reaching thematic saturation ,25 which occurred after reviewing 30 interview transcripts. One of us (C.R.B.) coded all remaining transcripts for concurrence. Throughout the analysis, the 2 investigators iteratively reviewed codes, collapsed codes into groups with related meanings and relationships, and developed larger thematic categories, returning frequently to the transcripts to ensure that emergent themes were well-grounded in the data.25 All coauthors reviewed example quotations and themes and together developed the final thematic schema. We used Atlas.ti version 8 (Scientific Software Development GmbH) to organize and store text and codes.We conducted an inductive thematic analysis26 All but 1 participant completed the online survey. The mean (SD) age of participants was 46 (11) years, and most were White (39 [65%]), were attending physicians (45 [75%]), and were practicing in large academic hospitals . Participants were practicing in 15 states across the United States and had primary affiliations with 29 different hospitals or clinics, with greater sampling of clinicians practicing in states with the highest rates of COVID-19 infection at the time of the study .We approached a total of 97 clinicians by email, of whom 75 (77%) agreed to participate and 22 (23%) declined or did not respond to our inquiry. Among those who agreed to participate, we purposively sampled 61 clinicians to participate in interviews from April 9, 2020, to May 26, 2020 .26 All bThree overlapping and interrelated themes pertaining to resource limitation and clinical care during the COVID-19 pandemic emerged from qualitative analysis, as follows: (1) planning for crisis capacity, (2) adapting to resource limitation, and (3) multiple unprecedented barriers to care delivery. Exemplar quotations are referenced in parenthesis and listed in Institutional leaders who participated in planning for crisis capacity described the challenges of adapting and operationalizing existing guidelines as well as the substantial moral weight of the task. They were relieved when it became clear that these processes would likely not be needed at their institutions .Clinicians who were involved in institutional planning described strong institutional support for their work to develop protocols to guide care should their region reach crisis capacity (quotation 1). They believed that establishing protocols in advance would allow for a more carefully considered approach (quotation 2) and would be reassuring to staff (quotation 3).Their work involved developing actionable triage algorithms based on existing frameworks (quotation 4). Group deliberation focused on both big picture ethical questions (quotation 5) as well as more granular operational details (quotation 6). Several clinicians with whom we spoke were not formally involved in institutional planning efforts but had offered input and/or developed their own protocols when they identified gaps in planning or disagreed with institutional policies (quotations 7 and 8).To support fairness and avoid bias, the plan was for triage team members to receive very limited information about individual patients when making selection decisions (quotation 9). Some clinicians involved in planning were skeptical about the feasibility of making triage decisions in the absence of detailed clinical information (quotation 10). Others expressed uncertainty about whether and how triage protocols would address more ambiguous or dynamic types of resource limitation (quotation 11). Clinicians could also be mindful of how their work might be viewed by other clinicians and the public (quotation 12) and were wary of sharing details about committee deliberations (quotation 13), plans (quotation 14), or team membership (quotation 15) with their colleagues and/or during the research interview.Clinicians who had been appointed to triage teams were usually respected leaders in intensive care, palliative care, or bioethics who were recognized for their ability to collaborate and communicate (quotation 16). Some of the intensivists and ethicists with whom we spoke saw the work of the triage team as an extension of their usual work (quotations 17 and 18), but many clinicians saw this experience as entirely new (quotation 19). Clinicians described being motivated to participate in the triage team out of a sense of duty and desire to contribute (quotation 20) but were also cognizant of the moral weight and emotional burden of the task before them (quotation 21).Clinicians involved in triage planning understood the processes they were developing to be intended exclusively for crisis settings (quotations 22 and 23) and saw the importance of optimizing resources under contingency capacity to avoid having to resort to crisis standards of care (quotation 24). While several clinicians described a period of intense planning early in the pandemic, by the time of our interviews, many were relieved to report that crisis standards of care were unlikely to be invoked at their institutions, and some had paused or disengaged from triage planning (quotations 25 and 26).Clinicians working during the pandemic were forced to grapple with multiple expected and unexpected forms of resource limitation that did not rise to the level of triggering crisis capacity. Nevertheless, these limitations could compromise care, require that they make difficult allocation decisions, and engender moral distress .Although none of the clinicians with whom we spoke reported a shift to crisis capacity at their institutions, they nevertheless described being faced with a range of expected and unexpected forms of resource limitation (quotation 27) that could arise in a haphazard manner with little warning (quotation 28). Some expressed frustration that resource shortages they were seeing in practice were not acknowledged as such by hospital or regional leadership (quotations 29 and 30) or felt unsupported by colleagues at neighboring medical centers (quotation 31). When not available from their institutions, some clinicians resorted to obtaining health care equipment through personal contacts or even fabricated it themselves (quotations 32 and 33).Clinicians were strongly motivated to avoid situations in which they would have to categorically deny needed treatment to any patient (quotation 34) and went to great lengths to develop alternative treatment options (quotation 35). This might involve using unorthodox therapies or nontraditional approaches to care delivery that could be suboptimal or potentially harmful (quotations 36 and 37). For example, some nephrologists described triaging patients for hemodialysis based on immediate need (quotations 38 and 39), delaying dialysis until there was an emergent indication (quotation 40), and/or prescribing shorter treatment times. As 1 clinician explained, \u201ceveryone gets a little bit of bad care\u201d (quotation 41). Rarely, clinicians were able to draw a clear line between acceptable and unacceptable care (quotation 42), but most focused on doing the best they could under the circumstances (quotation 43).The notion of rationing generally had negative connotations (quotation 44), and some clinicians even described erring on the side of providing more intensive interventions to avoid the appearance of rationing (quotation 45). With rare exceptions (quotation 46), clinicians did not explicitly speak of having had to ration health care resources (quotation 47). Nonetheless, some clinicians did describe situations in which they had to make difficult choices about which patients would and would not receive life-saving therapies, typically on the basis of age and/or comorbidity. This was often seen as part of the spectrum of normal clinical decision-making (quotations 48 and 49) and within their scope of practice (quotation 50). Some clinicians did describe struggling to understand what constituted acceptable practice vs rationing (quotations 51 and 52) and expressed misgivings about the approach to selecting patients for life-saving treatments during the pandemic (quotations 53 and 54).Many clinicians were fearful of having to ration resources (quotation 55). Even in lower acuity and outpatient settings, some struggled with whether it was acceptable to provide suboptimal care (quotation 56) and worried about the potential harms of disrupted care practices (quotation 57). A sense of responsibility for poor outcomes could take a substantial emotional toll (quotation 58). Some clinicians felt that explicit guidelines would be helpful in limiting this moral distress (quotation 59), while others felt personally responsible for poor outcomes regardless of whether they were adhering to institutional recommendations or requirements (quotation 60).Clinicians described multiple barriers to care delivery during the pandemic. These challenges compounded and were difficult to disentangle from the effects of resource limitation .Policies and practices were modified to limit physical interaction between staff, patients, and family members with the dual goals of reducing viral spread and conserving personal protective equipment. While necessary, policies to limit contact with patients were seen as being detrimental to care and to the experiences of both patients and clinicians (quotations 61 and 62). Decisions about something as routine as whether to perform a physical examination could expose tensions around the conflicting goals of conserving scarce resources, protecting oneself, and caring for patients (quotations 63 and 64). Visitor restrictions could complicate and disrupt the process of engaging family members in decision-making (quotations 65 and 66).The rapid pace of change and limited scientific understanding of COVID-19 (quotations 67 and 68) led to substantial uncertainty in day-to-day practice. A sense of desperation and a desire to do everything possible to save lives might lead to more aggressive treatment practices and/or greater willingness to try unproven therapies (quotation 69), reluctance to engage palliative care specialists (quotation 70), and delays in end-of-life decision-making (quotation 71).Many clinicians commented that families and patients were often quite understanding of care disruption (quotation 72), and that they were surprised at how accepting some families could be when care was compromised by the need to conserve resources and/or protect clinicians (quotations 73 and 74). However, some clinicians did describe contentious interactions with family members (quotation 75) and patients (quotation 76) who felt that care was being inappropriately withheld. Other clinicians described deliberately avoiding mention of resource limitation when talking with families (quotation 77).30 the clinicians we interviewed described how, even in the absence of formal declarations of crisis capacity, a variety of expected and unexpected forms of resource limitations severely compromised care and required that they make difficult allocation decisions at the bedside.Our thematic analysis of interviews with US clinicians who were directly involved in patient care and/or strategic planning during the COVID-19 pandemic highlights the real-world complexity of adaptation to resource limitation. Clinicians described patterns of institutional planning that mirrored the IOM\u2019s phased approach, which assumes a common understanding about what constitutes usual standards of care with a plan for a coordinated regional response when these become untenable. However, consistent with prior anecdotal reports,31 and may not be supported by societal priorities for fairness in resource allocation.35Clinicians and clinical teams went to great lengths to develop alternative treatment options and to stretch existing resources to provide at least some care to all in need and avoid having to categorically deny treatment to any patient. However, this approach could mean providing care that fell far short of the IOM standard of functional equivalence to usual care. When substituting lower-quality or delayed treatments, clinicians and clinical teams were left to grapple with what constituted an acceptable standard of care, which could be a source of self-doubt and moral distress. While most clinicians did not feel that they had been in the position of having to ration scarce resources, some nevertheless described practices, such as selection by age or comorbidity, that may be subject to implicit biases7 represent an important step toward promoting fairness through transparent allocation processes.36 However, our results suggest that a narrow focus on crisis capacity may fail to address the full spectrum and complexity of challenges to providing high-quality care encountered by frontline clinicians during the COVID-19 pandemic .In this qualitative study, many clinicians described institutional planning for crisis capacity, but this did not always address real-world challenges to providing care when resources were limited. Expanding the scope of institutional planning beyond crisis capacity may be helpful in supporting clinicians and addressing moral distress, promoting equity, and optimizing care as the pandemic evolves."} +{"text": "Shortening of the hospital stay in patients admitted with the diagnosis of acute myocardial infarction (AMI) has been observed within the last decades. Our center is the only cardiac center in the region providing tertiary care facility and hence receives all AMI patients deemed suitable for invasive assessment and management and this leads to huge required demand. Our aim is to assess feasibility and safety of the early discharge of selected proportion of AMI patients.P = 0.04) and treated more with primary percutaneous coronary intervention (PPCI) (P = 0.04). They had favorable coronary anatomy , better hospital course, and higher left ventricular ejection fraction compared to non-early discharged patients . Follow-up of those early discharged patients were promising as majority of them were asymptomatic (95%) and did well post-discharge.Out of 557 of patients presented with AMI and treated with percutaneous coronary intervention (PCI), 310 (56%) were discharged early. Men patients and pilgrims were more prevalent among the early discharge group. Early discharged patients had significantly less comorbidities compared to the other group of patients. Moreover, they presented mainly with ST-elevation myocardial infarction (Our study demonstrated data that support safety of early discharge in a carefully selected group of AMI patients. Early but safe discharge may have a huge impact on increasing bed availability, reducing hospital costs, and improving patient\u2019s satisfaction. Shortening of the hospital stay in patients admitted with the diagnosis of acute myocardial infarction (AMI) has been observed within the last decades \u20133.The current Guidelines of European Society of Cardiology for the management of acute myocardial infarction with ST-segment elevation, released in 2018, state that the selected patients may be considered (class of recommendation IIb) for early discharge (after approximately 72\u2009h), if adequate follow-up is arranged . This isHajj is a great event and it is one of the five Islamic pillars. Millions of pilgrims from different countries of the world come to the Kingdom of Saudi Arabia for performing hajj. The overcrowding, hot climate, and huge physical stress expose the pilgrims to many health hazards. Cardiovascular disease has recently emerged as the leading cause of death during hajj , 11. ThiOur tertiary center is the only cardiac center in the region providing tertiary care facility including percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) and hence receives all AMI patients deemed suitable for invasive assessment and management and this leads to huge demand on cardiac services over the few weeks of hajj time. Reduced hospital stay has been proved to reduce the hospital burden and costs \u201315.The aim of our study is to assess feasibility and safety of the early discharge of selected proportion of AMI patients. This facilitates establishment and implementation of the successful and safe early discharge program to enhance bed\u2019s efficiency, improve occupancy rate and serve more patients during hajj crowdedness.This is a prospective, single-center study reviewing the clinical details of all AMI referred to our center for early revascularization and discharged during the two hajj seasons 2018 and 2019. It is designed to be a part of the standards of patient\u2019s care, to investigate and improve quality of AMI management and outcomes among a diverse population; general and cath consents were taken and has received approval of the ethics committee/institutional review board of our institution.As mentioned earlier, our center is the only cardiac center in Makkah with cath lab facilities, which provides invasive management of AMI, and we envisage capturing almost all AMI patients suitable for invasive management. Every year, our center receives about 1000 AMI patients; a quarter of them were admitted during the hot season in Makkah (2\u20133\u2009weeks of hajj). Our study population included residence and hajj patients . They were referred either from other primary, secondary, and Al-Mashaer hospitals or presented directly through our emergency department, and underwent coronary angiogram and PCI with drug eluting stents.All patients admitted with established diagnosis of AMI during the few weeks of hajj seasons 2018 and 2019.Patients presenting with AMI where coronary angiography was not done because of preference of the patient or due to any other reason and AMI patients admitted outside hajj seasons were not included as well.Demographics. Age, gender, and status (residence/hajj)Risk factors. Diabetes (DM), hypertension (HTN), smoking, dyslipidemia, presence of chronic kidney disease, old cerebrovascular accidents (CVA), chronic obstructive lung disease (COPD), ischemic heart disease (IHD), and previous PCI/CABGClinical data. Type of AMI are as follows:ST-elevation myocardial infarction (STEMI) treated either with PPCI or with non-PPCIIHistory of pulmonary edemaIILeft ventricular ejection fraction (LVEF) in echocardiographyNon-ST-elevation myocardial infarction (NSTEMI) with high-risk features , which necessitate early revasculrizationCoronary procedure description and angiography findings. Access site , presence of left main disease (LM), single vessel disease (SVD), two or three vessel coronary artery disease (CAD), infarct-related artery (IAR), thrombus aspiration, and use of tirofiban/AggrastatThe following data for each patient were collected:AMI treated with successful PCI (TIMI flow III in infarct-related artery)Age \u2264 75\u2009yearsHemodynamic and rhythmic stabilityAbsence of comorbidities, which require continuation of hospitalizationAbsence of contraindication of dual anti-platelet treatmentSupposed cooperation, compliance, and adherence to medical treatment particularly DAPT Early discharge (24\u201372\u2009h) was planned for selected patients who were fulfilled those criteria:Alive/death with dateRecurrent symptoms of ischemiaAny bleedingRecurrent hospital admissionFollow-up of early discharged patients with telephone communications within 15\u2009days after discharge to check the safety of this strategy with collection of the following data:t test. Categorical data were given as a percentage and compared with a Chi-square test. A P value <\u20090.05 was considered statistically significant.Statistical analysis was performed by the use of the SPSS software package ; version 21.0. Continuous data were expressed as mean \u00b1 SD and compared using the Student Out of 1972 AMI consecutive patients, five hundred fifty seven were treated with PCI during their admission in our center within the two hajj seasons (2\u20133\u2009weeks of hajj) of the 2 consecutive years 2018 and 2019, respectively. Patients were distributed in to two groups: group I, 310 (56%) who were fulfilled the given early discharge criteria and discharged, and group II, 247 (44%) who were discharged late (after 72\u2009h). From the whole discharged AMI patients in the study period, 89 (16%) were discharged within 24\u2009h and 221 (40%) were discharged within 48\u201372\u2009h from admission. One hundred twenty patients (39%) were early discharged in the hajj season 2018 while 190 (61%) were early discharged in the hajj season 2019 . They also showed less prevalence of DM (161 (52%) vs 148 (60%)), HTN (181 (58%) vs 158 (64%)), history of ischemic heart disease (55 (17%) vs 53 (21%)), and previous coronary revasculrization (27 (9%) vs 34 (14%)) compared to group II patients and 212 (68%) vs 87 (35%) and 146 (59%); P = 0.04). The early discharged patients had better hospital outcomes compared to the other group as they showed less prevalence of post myocardial infarction pulmonary edema (5 (2%) vs 15 (6%); P = 0.006) and higher LVEF . Otherwise, regarding the other treatment modalities, there were no detected significant differences between the two groups for the use of thrombolytic therapy and/or tirofiban post AMI treated with PCI.As shown in Table P = 0.003). Also, patients of group I with early discharge had favorable coronary artery disease anatomy as they showed less prevalence of both left main and three vessel disease in their coronary angiography compared to those of group II (7 (2%)and 55 (17%) vs 17 (7%) and 65 (26%); P = 0.01 and 0.02, respectively) vs 171 (69%); Among 310 early discharged patients, only 187 (60%) could be contacted by phone (with help of many translators of different languages) for follow-up within 15\u2009days from the discharge date. They were questioned and found that 177 (95%) patients were totally asymptomatic, 6 (3%) had nonspecific chest pain which did not require any hospitalization, 2 (1%) had minor bleeding (epistaxis resolved spontaneously), and 2 (1%) re-admitted with heart failure symptoms. Those two patients re-admitted with heart failure had been found to have low ejection fractions with ischemic mild to moderate mitral regurge in their pre-discharge echocardiography and their follow-up echocardiography showed the same findings; however, they had mild chest infection, which predisposed to aggravation of heart failure vs 6 (2%), respectively) Fig. . No recoThe overview of most of literature investigating the issue of safety and feasibility of early discharge in AMI patients shows variable methodology and this explains that guidelines for early discharge are based just on limited data derived from randomized trials. The issue of early discharge was investigated in PRAGUE 5 study, which after pilot phase randomized 56 low-risk probands with STEMI, discharged even the next day after successful PCI. It was the first study in which mean length of hospital stay was shorter than 72\u2009h . Most ofIt has been proven that substantial reduction in-hospital length of stay has been associated with reduction of in-hospital charge with no Our center is the only cardiac center in the region providing tertiary care facilities and receives a huge number of AMI patients especially during the 2 to 3\u2009weeks of hajj seasons, subsequently this puts a big burden for the required provided service and hospital costs. The primary aim of our study is to create and implement successful safe early discharge program to improve bed\u2019s utilization efficiency and provide the best, safe, and maximum service for cardiac patients during over crowdedness of the hajj season. To the best of our knowledge, there are no similar studies conducted in our region concerned with this idea. We selected few weeks of each hajj season to conduct this study for many reasons: First, as previously mentioned, our cardiac center is the only center in the region of Makkah that has cath lab facilities and this required to provide tremendous tertiary care services to pilgrims and residents of Makkah during hajj season. Therefore, appropriate improvement of bed utilization is crucial with subsequent increase of hajj population in the successive years. Second, during this selected period, most of our AMI patients were pilgrims who had special ritual, religious emotions, and soul as most of them were doing their hajj for the first time having beliefs that longer hospital stay might reduce the opportunity to complete the hajj for which they were coming and persistently asking all the time for discharge. We believe that appropriate early post AMI discharge might grant their wishes provided it is totally safe. Third, during this short 2\u2009weeks of hajj season additional two millions of population increase within Makkah city from pilgrimage and this requires a huge health service demand. Many facilities provided by the Ministry of Health and Hajj Committee during hajj seasons to provide a tremendous 24\u2009h non-stop cardiac services included increasing manpower, raising number of working cath labs, improving working network, expanding all available services, and hence all that motivate the huge work and discharge of stable cases. We started implementation of early discharge program on hajj season 2018 and continued on 2019 to enlarge our sample size, which might help to gather more data and generalize our conclusion.Our results concluded that those early discharged patients had higher percentage of pilgrims who were in high need for early discharge to compete their hajj pillars with their groups and return back to the their home countries safely. They also showed to have low-risk AMI features including less prevalence of cardiovascular risk factors and comorbidities, which all might predict safe early discharge post revascularization. Early revascularization with PPCI with appropriate target for DBT was recorded higher among those early discharged patients and this reflects higher quality of service provided by our center to AMI patients and could help in the process of early discharging them from the hospital. Clinical features and short-term outcome of AMI patients post event are crucial once decided the discharge process and these were followed carefully during our program implementation . Reassuringly, most of our early discharged patients had favorable coronary artery disease anatomy and this encouraged their early discharge process.Follow-up data results were impressive as majority of our early discharged patients were totally asymptomatic (95%). Few percentages of those patients had non-serious symptoms and did not require any major intervention and this might reflect the early success of implementation of such program in our facility, which is considered the corner stone in the region.Finally, our current experience reflects many advantages: great compensation of the huge required hospitalization burden; provision of the best, safe, and maximum service for cardiac patients during over crisis periods; lower hospital cost; and improvement of patient\u2019s satisfaction.Our study is limited to a single center and relatively small population number (short period selected only two hajj seasons) corresponds to the conclusions of mentioned studies. There are many factors explaining limitation of our follow-up data (as 40% of our early discharged patients lost their follow-up): language barrier, wrong written contact number in our records, non-attending calls, and higher percentage of those patients were pilgrims who returned back to their countries immediately after hajj without any follow-up here. We tried to support our results with some previous randomized studies with such recommended strategies and shorter length of hospital stay.Suggested plan to establish proper educational program with help of the health promotion department supported with different language materials, which will be provided to those patients during their hospitalization regarding to their disease process, medication compliance and proper short-/long-term follow-upProper recording of correct contact numbers of the patients organized by our admission office and bed management departmentsMotivation of the primary and secondary hospitals in the regions to conduct similar programs and possible organization of better follow-up protocolsWe hope to reduce these limitations in future seasons by the following suggestions:Our results provide preliminary data to support safety of early discharge in a carefully selected group of AMI patients while providing them dedicated telephone support and follow-up. Early but safe discharge may have huge impact on increasing patient\u2019s satisfaction, bed availability and reducing hospital costs. Furthermore, a larger multi-center study in the region has been encouraged to generalize our conclusion."} +{"text": "The present study analyzes the drug-target-disease network and may prove to be a useful tool in gene-phenotype connectivity for genistein in HBV-related liver cancer. Our data also pave the way for further research on Grb2 during the development of chronic HBV infection in liver cancer.Genistein is a type of isoflavone, which has been widely described as an antitumor agent in many cancers. The present study aimed to provide information on the mechanisms of genistein's activity and thus enable a wider range of targeted therapies in hepatitis B virus (HBV)-related liver cancer. We searched the DrugBank database for direct targets of genistein, which were then analyzed through the STRING database to predict their secondary protein targets. Thirteen primary protein targets of genistein and 209 secondary protein targets-associated genes were identified. The data were integrated into the network of protein targets-associated genes and visualized with the Cytoscape software. We further carried out GO (Gene Ontology) analysis and KEGG (Kyoto Encyclopedia of Gene and Genome) pathway analysis using DAVID tool. The top 14 KEGG pathways were further assessed, and 19 overlapping genes derived from pathways of hepatitis B and cancer were discovered. The overlapping targets were further mapped in the online tool UALCAN to evaluate the survival rate of hepatocellular carcinoma (HCC) patients. We found that the overexpression of Grb2 (growth factor receptor-binding protein 2) ( Worldwide, chronic infection due to hepatitis B virus (HBV) is recognized as a major reason for hepatocellular carcinoma (HCC), with a huge financial burden to the society database, and generated 209 secondary protein targets-associated genes and constructed their protein\u2013protein interaction (PPI) network with the Cytoscape software. Primary target genes and the genes associated with them were further analyzed using DAVID online tools for KEGG (Kyoto Encyclopedia of Genes and Genomes) biochemical pathways, and finally, the top 14 KEGG pathways were picked out. Nineteen overlapping genes derived from hepatitis B and pathways in cancer on the top 14 KEGG pathways were identified. At last, the expression level and overall survival (OS) of these hub genes were analyzed with UALCAN, which is a tool to facilitate the study of survival associations and gene expression variations across tumors based on exhaustive evaluation of TCGA (The Cancer Genome Atlas) gene expression data enrichment analysis and KEGG pathway enrichment analysis were carried out using an online tool DAVID, which is an online database and analytic tool that provides information about a large list of genes or proteins and their potential functions between normal and tumor samples and assess the effect of clinicopathologic features and level of gene expression on patient survival , prolactin signaling pathway (19 genes), pathways in cancer (37 genes), hepatitis B (23 genes), focal adhesion (26 genes), erbB signaling pathway (18 genes), PI3K/AKT signaling pathway (33 genes), proteoglycans in cancer (25 genes), estrogen signaling pathway (18 genes), colorectal cancer (15 genes), FoxO signaling pathway (20 genes), AMPK signaling pathway (19 genes), mTOR signaling pathway (14 genes), and HIF-1 signaling pathway (17 genes) . Moreovehttp://ualcan.path.uab.edu). We found that expression of GRB2 (p\u2009<\u20090.0001) followed by AKT1 (p\u2009=\u20090.0015) and PIK3CA (p\u2009=\u20090.0088) was linked to worse OS for liver HCC patients (The expression level and prognostic details of 19 selected genes are accessible online (patients . The UALInvestigations carried out in the past decades have shown that genistein demonstrates synergistic activities combined with chemo-drugs (Spagnuolo et al., A system biochemistry approach integrating multiple web-based tools was applied, and associations of HBV-related HCC and biological molecules with drug targets were evaluated. We obtained 13 primary and 209 secondary target genes/proteins in DrugBank and STRING. Nineteen overlapping genes from 2 of 14 enriched KEGG pathways related to genistein-altered genes were selected. The overexpression of AKT1, PIK3CA, and GRB2 in HCC was linked to decline in OS as per UALCAN. Therefore, we hypothesized that those three genes might be potential targets by genistein during the development of chronic HBV infection into liver cancer.The PI3K/AKT signaling pathway has been found abnormally activated in HCC and affects cell behavior, including proliferation, survival, metabolism, and tumorigenesis (Chen et al., In conclusion, with the increase in number of studies on genistein by traditional experimental techniques, more and more genistein targets will undoubtedly be identified. However, there is ambiguity in determining whether the specific biological effects on genistein can be definitively assigned to the individual or simultaneous modulation of their newly established or identified targets. This analysis enabled the interpretation of the inherent mechanisms of HBV-related cancer and genistein's target identification and would ultimately aid in future studies with rational experimental likelihood for detection and validation of logical hypotheses about the role of genistein in HBV-related liver cancers in the future."} +{"text": "This talk explores the importance of a racially diverse graduate student interacting in an applied care setting with minority older adults in the Southeast relative to assessment of cognitive status and in the context of cultural mistrust and misdiagnosis. ~250 older adults (16% AA) in an applied care setting were administered a cognitive screener as part of a larger research battery. An independent samples t-test was conducted to assess differences in mean cognitive status. Non-Hispanic Whites (NHW) (M=76.8 years) were found to be more intact than AAs (M=73.27) on measures of cognitive status . Implications highlight that cognitive screeners have often been found to lack sensitivity in groups of marginalized older adults. Having an AA graduate student in these settings could be a way of mitigating the effects of culturally incompatible screening tools and bridging the gap between research and practice for AA older adults."} +{"text": "We combined Medicare claims and nursing home (NH) administrative data to determine the mortality and morbidity effect of Hurricane Irma on nursing home residents. We utilized the Centers for Medicare and Medicaid Services (CMS) Standard Analytical Files (SAFs) combined with the Minimum Data Set (MDS) to create an exposure cohort of NH residents residing in Florida facilities immediately prior to Hurricane Irma\u2019s landfall on September 10, 2017. We created a control group of residents who resided in the same NHs over the same dates in 2015, a year when there were no hurricanes. Outcome variables included 30/90-day mortality and first hospitalizations post storm. Compared to the control, an additional 260 more NH deaths were identified at 30 days and 429 more deaths at 90 days. Long stay residents (\u2265100 days) were at particular risk for mortality compared to short stay residents (<100 days). Hospitalization was also markedly increased."} +{"text": "Digital transformation creates new opportunities and is an important driver of novel and often disruptive innovation and value creation. Entrepreneurs are using digital technologies to finance innovation Opportunities and management of digital methods of funding innovation and entrepreneurship New value creation and platform innovation through digital technologiesCorporate entrepreneurship and startups within established organizations to approach opportunities and challenges of digital transformationExploitation of missing regulation of digital entrepreneurship Opportunities of Digital EntrepreneurshipThe following list of topics is neither exclusive nor exhaustive. We have structured them along three dimensions (Recker and von Briel Competence and team needs of (corporate) digital entrepreneursDigital entrepreneurial cultureThe role of universities and entrepreneurial ecosystems for digital entrepreneurshipImpacts of digital technologies on entrepreneurial decision makingUse of Social media or crowdsourcing resources by entrepreneursOrganization, organizational learning, and performance of digital startupsManagement of digital business model innovationInternationalization of digital startupsAlignment of digital capabilities and business modelsBehavior of startups in digital platform ecosystems Development and management of new digital ecosystems by startupsIndustry-specific classification schemes of startups or business models Changes in startup investment processes due to digitalizationProcesses, Organization, and Challenges of Digital EntrepreneurshipImpacts of Digital EntrepreneurshipImpacts of digital entrepreneurship on regions and countries Investments in digital innovation and their economic or societal pay-offsThe dark side of new digital business models Influences of digital entrepreneurial and innovative activities on government policy or regulationhttp://www.editorialmanager.com/buis/). Please observe the instructions regarding the format and size of contributions to Business & Information Systems Engineering (BISE). Papers should adhere to the submission general BISE author guidelines .Please submit papers by 1 March 2021 at the latest via the journal\u2019s online submission system (All papers will be reviewed anonymously (double-blind process) by at least two referees with regard to relevance, originality, and research quality. In addition to the editors of the journal, including those of this special focus, distinguished international scholars will be involved in the review process.https://www.fgf-ev.de/en/g-forum-conference-2020-karlsruhegermany/). In this paper development workshop, the special issue editors will provide feedback on early drafts or first paper versions. The submission to the G-Forum, however, is not a requirement for submitting to the special issue.\u00a0Please Note: We are closely monitoring the current situation with regards to\u00a0COVID-19\u00a0and the paper development workshop might therefore\u00a0be canceled or moved to a digital setting.There will be a special issue paper development workshop at the 24th Annual Interdisciplinary Conference on Entrepreneurship, Innovation and SMEs (G-Forum) which will take place at KIT Karlsruhe, Germany, from 30 September to 2 October 2020 (Deadline for submission: 1 March 2021Notification of the author 1: 3 May 2021Completion revision 1: 2 July 2021Notification of the author 2: 17 August 2021Completion Revision 2: 21 September 2021"} +{"text": "A questionnaire-based survey was conducted among members of the European Society for Gynaecological Endoscopy (ESGE), with the aim of increasing awareness of the diagnosis and surgical treatment of tubal disease as an alternative to in-vitro fertiliszation (IVF). Seventeen participants (34%) occasionally used a test for prediction of the ovarian reserve before surgery, and the most commonly used test was anti-mullerian hormone assay . Laparoscopy was the preferred method for staging tubal disease .Thirty-seven (76%) participants always performed salpingectomy or tubal occlusion before the first IVF attempt. Thirty (60%) of the gynaecological surgeons considered the outcome with tubal surgery and IVF to be similar in mild tubal disease, whereas for severe disease, 31/50 (62%) felt that surgery had worse outcome. Among other factors to be considered in choosing a strategy for treating infertility, 20/50 (40%) of respondents listed the stage of disease. The findings of this survey suggest that first-line treatment for women younger than 35 years old with minor tubal pathology, is tubal surgery. IVF appears to be offered if there are other infertility factors, if the patient is >38 years old and if moderate to severe tubal disease is present. Tubal disease is responsible for 30-40% of cases of female infertility. Pathology of the fallopian tubes may vary from peritubal adhesions and distorted tubal anatomy or damaged fimbriae to hydrosalpinx or tubal blockage . Pelvic st to March 31st , 2019, ESGE members were invited by the ESGE Central Office to complete a 22-item online questionnaire, accessible through the ESGE website. For some questions, more than one answer was acceptable. The invited gynaecological surgeons were not specifically infertility specialists, but they had experience in laparoscopic treatment of tubal-factor infertility. The participants received three reminders during this period. Fifty 50 gynaecological surgeons participated in the survey.A questionnaire survey was conducted to assess the approaches of members of the European Society for Gynaecological Endoscopy (ESGE). From March 1Forty-eight (96%) of the participants were specialists and two (4%) were trainees. Sixty per cent of the participants were aged 35 to 54 years; 25(50%) were experts who performed more than 90 laparoscopic procedures per year; and 19 (38%) had over 16 years of practice in endoscopic operations. Eighteen (36%) of the participants performed more than 30 laparoscopic tubal operations per year and 22 (44%) performed 10 to 30 per year. Seventeen of the participants (34%) worked in a university teaching hospital and 25 (50%) worked in a national health service hospital.According to 43 (86%) of the surveyed gynaecological surgeons, the best method for staging tubal disease was laparoscopy. Salpingectomy was the operation preferred by 30 (60%) participants, salpingoneostomy by nine (18%), tubal anastomosis by six (12%) and tubal occlusion by two (4%). Twenty-nine (58%) of the participants preferred bipolar energy for electrocoagulation during surgical treatment for tubal disease. When there is an incidental finding of hydrosalpinx 21(42%) of the gynaecological surgeons reported treatment in all cases; 18 (36%) reported treatment depending on the case; six (12%) reported no treatment; and 4 (8%) reported treatment only in case of bilateral disease. When hydrosalpinx was an incidental finding, 43 respondents (86%) preferred to inform the patient first and perform second-look surgical treatment only when there is indication, such as pain or infertility.In treatment of asymptomatic hydrosalpinx 23 (46%) gynaecological surgeons reported using no routine antibiotic treatment, 18 (36%) reported using occasional antibiotic treatment; and five (10%) reported using antibiotic treatment in all cases. When antibiotics were used for this condition, 20(40%) of the gynaecological surgeons seemed to prefer a combination of doxycycline, cephalosporin and penicillin, whilst 25 (50%) seemed to prefer doxycycline or cephalosporin only.Twenty-two (44%) participants reported using a test for predicting ovarian reserve in all cases before tubal surgery for infertility, and 40 (80%) felt the most precise and reliable test for predicting ovarian reserve is the serum anti-Mullerian hormone assay. Twenty-four (48%) reported salpingectomy as the best method for surgical treatment of hydrosalpinx in case of infertility, while 17 (34%) prefer laparoscopic tubal occlusion, six (12%)prefer salpingostomy, and three (6%) prefer hysteroscopic tubal occlusion, with permanent micro inserts to cause fibrosis and irreversible tubal occlusion, which develop within three months of insertion.Thirty-seven (76%) participants always performed surgical treatment of hydrosalpinx before the first IVF attempt, and 40 (80%) supported salpingectomy as being the best operative method regarding the outcome of a following IVF attempt. For women with mild tubal disease, good ovarian reserve and no other infertility factors, the prognosis of tubal surgery versus IVF is similar according to 30(60%) respondents. For women with moderate tubal disease 19(38%) participants felt that surgery and IVF had similar outcomes, and 17 (34%) felt that surgery had worse outcomes. In the treatment of severe tubal disease, 31 (62%) gynaecological surgeons stated that tubal surgery has worse outcomes than IVF. Twenty-two (44%) of participants reported that the combination of both methods imposes higher cost. Finally, according to 20 (40%) of the surveyed gynaecological surgeons, the stage of tubal disease is the first factor to take into account when considering strategies for treating infertility, whereas 30 (60%) felt that age and other infertility factors are most important.The results of this survey of 50 members of the ESGE on surgical treatment of tubal-factor infertility are comparable to the published literature on this subject. Thirty-eight (76%) participants favoured laparoscopy as the ideal method for the evaluation of tubal patency and the diagnosis of tubal disease, which is in line with reported practice . Almost Based on the survey responses, first-line treatment for women less than 35 years old with minor tubal pathology seems to be tubal surgery. IVF appears to be offered when there are other infertility factors, if the patient is >38 years old, and when moderate- to-severe tubal disease is present. According to the surveyed laparoscopic surgeons, tubal surgery and assisted reproductive technology in most of the cases are not competitive techniques, but usually tubal surgery is a prerequisite for the success of the IVF. Optimizing pregnancy rates and reducing the risks associated with IVF or surgical treatment should always be the main goal. The outcome of our survey is especially meaningful because of the high level of expertise in laparoscopic surgery and the high level of expertise in the laparoscopic treatment of hydrosalpinx among the participating gynaecological surgeons. On the other hand, the insufficient number of participants is a drawback, which points out the need for a future survey, better designed and with more gynaecologists with experience in laparoscopic treatment of tubal-factor infertility. Such a survey would minimize bias and produce clear answers and recommendations."} +{"text": "Family caregivers provide the majority of support for older adults and people with disabilities in the U.S. The onset of the COVID-19 pandemic forced radical changes in duties and relationships between family caregivers and care recipients. These changes can be attributed to fears of virus transmission as well as federal, state and local government mitigation strategies resulting in social distancing and quarantining limiting caregiving interactions. This qualitative investigation conducted 55 Zoom interviews over summer 2020 with family caregivers to explore their changing roles and duties during the pandemic. Researchers utilized a semi-structured interview guide to explore caregiver experiences with COVID-19. The average age of the caregiver participants was 59 and the average age of the care recipients for whom they provided care was 74. All participants provided unpaid care for family members. Interviews were conducted in English (n=40), Spanish (n=5), Somali (n=5) and Korean (n=5). Care recipients resided in a facility (70%) with the caregiver (20%), and in a separate independent setting (10%). Data from each interview were coded into themes by two researchers. Themes that emerged from the analyses included concerns about care recipient mental and physical health deterioration, lack of communication from formal providers, change in relationships with other family members, and future concerns. Implications for additional research and practice are included."} +{"text": "Home-based medical care (HBMC) is emerging in China, but research understanding the efficiency and effectiveness of this new care model is rare. In this study, researchers interviewed 17 Chinese homebound adults aged 45 and older who have received HBMC, and collected detailed information regarding their experiences and attitudes toward HBMC. Participants were recruited from healthcare institutions in Shanghai, Jinan, and Zhangqiu of China. The evaluation of patients\u2019 experiences with HBMC yielded both positive and negative aspects. Positive experiences included 1) the delivery method was convenient for homebound patients; 2) health problems could be detected timely because doctors visited patients regularly; 3) home care providers had better bedside manners and professional skills than hospital-based providers; 4) the medical insurance covered the cost of home care services. Negative experiences related to the supply and quality of care, including 1) the scope of current HBMC services was too limited to meet the needs of homebound patients; 2) the visit time was too short; 3) healthcare providers\u2019 professional skills varied greatly. Findings from this study suggest that the HBMC model benefited Chinese older adults, primarily homebound adults, in terms of convenience and affordability. There are opportunities to expand the scope of home care services and improve the quality of care. Policymakers may consider providing more resources and incentives to enhance HBMC in China. Educational programs may be created to train more HBMC providers and improve their professional skills."} +{"text": "Disease Models & Mechanisms (2019) 12, dmm040238 (doi:10.1242/dmm.040238).There was an error in The authors mistakenly used the wrong image for the FUS(1-359) vehicle panel in Both the online full-text and PDF versions have been updated and the authors apologise to readers for this error and any inconvenience it may have caused."} +{"text": "Pakistan is a developing country with high number of road traffic injuries. High magnitude of road traffic injuries highlights deficiencies in road traffic laws which are not at par with current safety requirements resultantly fail to address important risk factors such as distracted driving, non-use of seat belt and helmet. Purpose: - To assess effect of deficient traffic laws related of distracted driving, seat belt and helmet usage in term of estimate prevalence of different types of distractions and use of helmet by motorcycle riders and pillion riders and seat belts by the drivers and the passengers on National Highway in Pakistan that can lead to road crashes and increasing the injuries.Roadside survey was carried on N-5 National Highway to estimate number of distracted drivers, use of helmet by riders and pillion riders and use of seat belt by drivers and passengers.Three types of distraction were observed i.e. Mobile Phone distraction (24%); Equipment related distraction (1%) and eating related distraction (1%) amounting to 29% of drivers distracted ;car drivers (29%), other vehicle drivers (6%), motorcyclists (3%) and trailer drivers (3%). Likewise; 64% drivers were found without seat belt, LTV drivers (85%), car drivers (74%) and truck drivers (69%). Similarly; 97% passengers were found without seat belt, LTV passengers (100%), truck passenger (99%), cars passenger (97%), Oil tanker and trailer passenger (90%). Helmet violation was high with 87.4% motorcycle riders and 100% pillion riders were found without helmet. Lack of enforcement due to deficient traffic laws result in RTIs in Pakistan. There is need to improve legislation on different forms of distractions, use of seat belt among passengers and helmet use by pillion riders; so that enforcement efforts can be made to address risk factors effectively to meet Decade of Action 2011-2020 targets.Seat belt, Helmet, Distraction, Pakistan"} +{"text": "Dear Editor,We would like to thank Dr Arjun Srirampur for his interest in our work. Below please notice our replies:1. All of our diabetic patients were operated upon due to proliferative diabetic retinopathy (PDR) complications such as non-clearing vitreous hemorrhage and traction retinal detachment but there was no case of rhegmatogenous retinal detachment; therefore no tamponade was used during surgery.2. None of our patients had uncontrolled IOP during the short follow-up period (two weeks) after surgery in both groups. The corneal epithelial defect (CED) was improved in all eyes except three; and in those three eyes, lateral tarsorrhaphy and application of a lubricant ointment resulted in healing of the CED less than one month after surgery."} +{"text": "Functional disability might be related to an increased risk of dementia or could represent a prodromal stage. We examined the occurrence of functional impairments over eight years follow-up and their association with dementia incidence in 1,666 participants aged 65+ from the English Longitudinal Study of Ageing. Growth models with distal outcome were used to examine whether different trajectories of functional abilities (activities of daily living (ADL); and instrumental activities of daily living (IADL)) between 2002/03 and 2010/11, were associated with dementia incidence four years later (2014/15). Participants with an increasing number of functional impairments (Class III), were more likely to be classified with subsequent dementia compared with those with no impairments (Class I). An increased risk was also observed for individuals with raised levels of impairments (Class II). We found IADLs more sensitive than ADLs, and this may imply a more comprehensive ascertainment during the prodromal stage of dementia."} +{"text": "In 2020, the Center of Innovation for Veteran Centered and Value Driven Care (COIN) continued its monitoring and evaluation of the Veterans Administration (VA) Medical Foster Home (MFH) programs expansion into rural areas. Veterans in MFHs are provided 24/7 care by VA trained and supervised community caregivers and primary care by VA Home Based Primary Care (HBPC) teams. One year after the three-year (2017-2019) expansion funds stopped, COIN continued monitoring remaining programs. Objectives were to understand factors critical for program expansion and sustainability and the impact of COVID-19. Phone interviews were conducted with sixteen coordinators from seventeen programs. A thematic analysis approach was used to address the evaluation objectives using transcript data. Findings showed factors important to program sustainability were: 1) Program fit (finding caregivers in the community); and 2) Local VA facility support . COVID prompted losing some caregivers and prevented others from joining. Program staffing was not impacted as many program activities ceased. Recreational therapists (RTs) were significant to maintaining Veterans well-being and reducing social isolation through virtual activities. COVID required coordinators transition their supervision of MFHs to new virtual environments and HBPC to increase telehealth to new levels. Local leadership became important to monitoring local conditions and providing support to programs. The evaluation: 1) Found factors important to program sustainability were also critical to keeping programs operational during the pandemic; and 2) Stimulated future research on the suitability of MFH programs to meet challenges to resurgences of COVID or other national emergencies."} +{"text": "The literature on the contribution of elastic fibre deposition to alcohol-related liver disease (ARLD) is limited. We studied: (1) 180 liver biopsies from ARLD patients; (2) 20 ARLD explant livers; (3) 213 liver biopsies with non-ARLD injury. Elastic fibres were assessed in terms of their distribution around hepatocytes [pericellular elastosis (PCE)] and within bridging fibrous septa and scored using a semiquantitative system. We also investigated the composition of the elastic fibres in 20 cases. PCE was associated with steatohepatitis in ARLD patients and with ARLD when compared to non-ARLD cases (p\u2009<\u20090.001). Oxytalan fibres were identified in PCE in ARLD biopsies and broken dense perisinusoidal mature elastic fibres in explanted livers. Septal elastosis increased from intermediate to advanced fibrosis stage. Early septal elastosis contained oxytalan fibres, whereas septal elastosis at more advanced stages contained mainly mature elastic fibres. PCE is a typical feature of steatohepatitis in ARLD and includes oxytalan fibres. Septal elastosis is a gradual process with a transition from oxytalan to mature elastic fibres usually present in explanted livers. There may be different dynamics in the assembly and reabsorption of pericellular and septal elastic fibres, and a potential role for stratification of patients with advanced stage ARLD. The spectrum of liver injury in alcohol-related liver disease (ARLD) ranges from simple steatosis to steatohepatitis and from minimal or no fibrosis to cirrhosis2. Elastic fibres are a component of the extracellular matrix (ECM) along with collagen, glycoproteins, glycosaminoglycans and proteoglycans3. The elastic fibres are composed of a core of elastin made of tropoelastin monomers encoded by ELN and a microfibrillar mantle composed of fibrillins, glycoproteins which in humans are present in three isoforms4. The relative proportion of tropoelastin and microfibrils divide elastic fibres into three main types: oxytalan, composed of microfibrils only with no elastin core; and elaunin and mature elastic fibres, both characterized by a central cross-linked core of elastin and a surrounding microfibrillar component. Elaunin fibres have a lower amount of elastin compared to mature elastic fibres5. Oxytalan fibres can be differentiated from both elaunin and mature elastic fibres by removing the oxidation step of histochemical elastic fibre staining methods such as the orcein stain or analogues9. Oxytalan fibres do not react with this modified protocol, whereas both elaunin and mature elastic fibres remain positive. Elastogenesis begins in the late stages of development and early after birth10 and is particularly active in those tissues in which elastic properties are essential for their function such as the aortic wall and lung parenchyma4. Elastogenesis is attenuated in normal adult tissues but reactivates in a wide spectrum of disease processes10 including wound healing12. Elastin has long been known to accumulate in fibrotic livers13. Little is known however about its role in the progression of ARLD and the literature on the contribution of elastic fibre deposition in ARLD injury is limited14. Porto et al.14 showed that in the early stage of alcoholic fibrosis there is deposition of oxytalan fibres in the space of Disse in the perivenular region. The internodular bridging fibrous septa of more advanced stages contained oxytalan and elaunin fibres. Our aim was to evaluate retrospectively a large series of liver biopsies from patients with ARLD focusing on the pattern, distribution and composition of elastic fibres.Worldwide alcohol-related mortality in 2016 was high at 38.8 per 100,000 people and half of cirrhosis related deaths were due, at least in part, to alcohol useOut of our initial cohort of 303 biopsies 180 fulfilled our selection criteria and were selected for our study.Seventy-three biopsies (40.6%) showed steatosis only (mild in 36 (49.3%), moderate in 28 (38.4%) and severe in 9 12.3%). Ninety-seven biopsies (53.9%) showed steatohepatitis. Ten (5.6%) biopsies were classified as NOS of liver biopsies at the different disease stage were as follows: 0 (no fibrosis)\u2009=\u20094 (2.2%); 1 (early)\u2009=\u200984 (46.7%); 2 (intermediate)\u2009=\u200934 (18.9%); 3 (advanced stage cirrhotic transformation)\u2009=\u200913 (7.2%); 4 (advanced stage cirrhotic)\u2009=\u200945 (25%).For reference, examples of none and focal perihepatocytic elastic fibres, and PCE are demonstrated in Fig.\u00a0The correlation between pericellular elastic fibres and overall disease pattern is detailed in Supplementary Table PCE was identified in 58 32.2%) of the 180 cases studied. PCE was present in 7 (9.6%) of the 73 biopsies with steatosis, 47 (48.5%) of the 97 biopsies with steatohepatitis, and 4 (40%) of the 10 biopsies classified as NOS. When biopsies were divided into two groups according to presence or absence of steatohepatitis, PCE was significantly associated with steatohepatitis with end stage ARLD. All patients had been abstinent at the time of transplantation for at least 6\u00a0months.Most cases showed a combination of grades 2, 3 and 4 of septal elastic fibres. Grade 0 was not observed in any of these 20 cases and grade 1 was present in three cases only. PCE was not identified in most cirrhotic nodules in 18 cases. It was present very focally in occasional cirrhotic nodules after extensive examination at high magnification in 4 cases, and was easily identified at low magnification in a few (7 cases) or several (7 cases) cirrhotic nodules. The pericellular elastic fibres were often in the form of broken dense strands or in a more perisinusoidal distribution. Examples are shown in Supplementary Figure In two other cases PCE was more prominent affecting approximately half of the cirrhotic nodules in the sample examined. There was no evidence of active steatohepatitis.We next correlated our findings with the immunohistochemistry for elastin and the repeat Victoria blue stain with and without the oxidation step to explore the proportion of oxytalan, elaunin and mature elastic fibres. , in all ten biopsies showing grade 1 or grade 2 septal elastosis with the conventional Victoria blue an appreciable reduction in elastic fibre stain with the modified Victoria blue method suggested the presence of a significant proportion of oxytalan.Grade 3 or 4 septal elastosis, consisted of elastin positive septa without reduction in stain with the modified Victoria blue stain indicating that the septa were composed mostly of mature elastic fibres.PCE appears to be composed of a significant proportion of oxytalan in most of the biopsy specimens and of mature elastin in the explanted livers . Further studies are needed to better understand whether the elastification process can be used to stratify patients with advanced stage ARLD and correlate with clinical outcome.Our study was based on four cohorts of specimens; (i) a series of 303 core needle biopsy specimens from patients with known ARLD clinically; (ii) a series of 20 livers removed at transplantation for ARLD; (iii) a control group of 213 core needle biopsy specimens with a variety of liver conditions other than ARLD characterized after clinico-pathological correlation; (iv) a selection of representative cases from cohorts (i) and (ii) to investigate in more details the elastic fibres morphology and composition in terms of oxytalan, elaunin and elastin content.16: steatosis, steatohepatitis, and not otherwise specified (NOS).Our review of the first cohort of biopsies included the assessment of the overall pattern of liver injury, fibrosis stage, and pattern of elastic fibre deposition. The biopsies were divided into the following categoriesFibrosis staging was carried out using a semiquantitative scoring system (0 no fibrosis identified); 1 or early; 2 or intermediate (bridging fibrosis); 3 or advanced stage with features of cirrhotic transformation; and 4 or advanced stage cirrhotic.We assessed the presence of elastic fibres in a pericellular/perivenular distribution and within fibrous septa.Pericellular elastic fibres were classified as absent, focal and after extensive search), or pericellular elastosis (PCE) (perihepatocytic elastic strands obvious at 10\u2009\u00d7 or 20\u2009\u00d7 magnification).We classified septal elastosis into the following grades: grade 0: bridging fibrous septa with no elastic fibres; grade 1: bridging fibrous septa with delicate fibres visible only at high magnification; grade 2: elastic fibres visible at low magnification and clearly distinguishable from the residual portal or liver capsule elastic fibres, grade 3: strong elastic bundles well visible at low magnification and of similar density, blending with or indistinguishable from the to the residual portal normal or liver capsule elastic fibres; and grade 4: slender, regressive type dense elastic bundles visible at low magnification. Pericellular and septal elastosis were further investigated, in terms of their composition on a subseries of 20 cases using 6 serial sections. The sections were stained in the following sequential order with (i) anti-Elastin [BA4] antibody IHC (ab9519), (ii) Victoria blue with no oxidation step (demonstrating only mature elastin fibres and Elaunin), (iii) Victoria blue with oxidation and decolourisation step , (iv) (spare unstained back-up section), (v) Picrosirius red and (vi) Haematoxylin and Eosin. Reduction in stain between the Victoria blue with and without oxidation step was assessed as follows: minimal and focal ; partial ; marked . Septal elastin immunohistochemical stain was regarded as diffuse when present in most or all septa and patchy when approximately half of the septa were negative. Pericellular elastin stain was considered as diffuse (most hepatic plates), patchy , focal (identified at high magnification after extensive search) or absent.Details on the biopsy selection, histological categories, fibrosis scoring system staining protocols, statistical analysis and elastic fibres assessment are provided as supporting information. All methods were carried out in accordance with relevant guidelines and regulations, experimental protocols were approved by the Royal Free Hospital Ethics Committee (07/Q0501/50) and informed consent was obtained as appropriate.Supplementary Information."} +{"text": "Loneliness and social isolation present emerging public health challenges for aging populations. To inform efforts against loneliness and social isolation, research is needed to evaluate impacts of these conditions on patterns of adverse aging outcomes. We used longitudinal, repeated measures data to isolate effects of loneliness and social isolation from effects of socioeconomic circumstances and psychological vulnerabilities, rule out reverse-causation, and test dose-response in associations with morbidity, disability, and mortality. We also explored the biological basis of relationships by testing associations with biological aging. We analyzed data from more than 12,000 adults aged 50-95 in the US Health and Retirement Study (HRS) who reported on symptoms of loneliness and social isolation at 2-3 time points during 2006-2014. We measured loneliness using the 3-item Revised UCLA Loneliness Scale and social isolation using a 6-item scale. We tested associations with chronic disease, disability, and biological aging in 2016 and with mortality through 2018. We found (1) associations of loneliness and social isolation with adverse aging outcomes are not fully explained by socioeconomic circumstances and psychological vulnerabilities; (2) the direction of relationships with disability indicates temporal precedence of loneliness and social isolation; (3) there is a dose-response in associations with loneliness; and (4) there is evidence of a biological mechanism explaining associations with loneliness and social isolation. Findings add to the emerging literature on health sequelae of loneliness and social isolation. Assessment of loneliness and social isolation in surveillance and intervention with older adults can enhance risk assessment for adverse aging outcomes."} +{"text": "Digital methods are a way to engage marginalized populations, such as sexual and gender minority (SGM) adults. No study to date has leveraged these methods to engage SGM caregivers of people with dementia. We used digital methods to access SGM caregivers of people with dementia in our study of psychosocial measures of caregiving for recruitment and data collection. Posts on social media and online registries targeted SGM caregivers. The study landing page received 2201 views; 285 caregivers completed the survey. Participants learned of the study most frequently from Facebook (45%). The sample was 84% white, with gay (52%), lesbian (32%), bisexual (11%), and other sexual orientations (5%) and transgender (17%) caregivers represented. While we exceeded goals for inclusion of Latinx (26%) and Native American (4%) caregivers, the number of African American SGM caregivers was lower than projected (7%). Digital methods are effective for engaging SGM caregivers of people with dementia."} +{"text": "Crops during their early growth stages are vulnerable to a wide range of environmental stressors; thus, earlier seed invigoration and seedling establishment are essential in crop production. As an alternative to synthetic chemical treatments, plasma technology could be one of the emerging technologies to enhance seed germination and seedling vigor by managing environmental stressors. Recent studies have shown its beneficial effects in various stress conditions, suggesting that plasma treatment can be used for early crop stress management. This paper reviewed the effects of different types of plasma treatments on plant responses in terms of the seed surface environment (seed scarification and pathogen inactivation) and physiological processes (an enhanced antioxidant system and activated defense response) during the early growth stages of plants. As a result, plasma treatment can enhance seed invigoration and seedling establishment by alleviating the adverse effects of environmental stressors such as drought, salinity, and pathogen infection. More information on plasma applications and their mechanisms against a broad range of stressors is required to establish a better plasma technology for early crop stress management. Rapid seed invigoration and seedling establishment during the early growth stages of crops are necessary to prevent crop yield loss due to unfavorable environments. Seed germination and early seedling growth are the most sensitive growth stages for a crop to a wide range of environmental stressors . Once thPlasma technology has been widely designated as an advanced oxidation process . It has However, no review has yet summarized plasma applications and their protective mechanisms against a broad range of stressors. The potential applications of plasma technology for early crop stress management are largely unknown. This review evaluated the effects of the different types of plasma treatments on plant responses in terms of the seed surface environment (seed scarification and pathogen inactivation) and physiological processes (an enhanced antioxidant system and activated defense response) during the early growth stages of plants. Recent information on plasma applications and their mechanisms against a broad range of stressors was reviewed from these two perspectives. Thus, this review proposes that plasma technology has potential uses for seed invigoration and seedling establishment under stressful conditions.The seed coat regulates seed germination through its thickness and permeability. Therefore, seeds with thick coats are incapable of water uptake rapidly unless it is scarified . In part6H5NH2) or cyclohexane (C6H12). However, RF discharge delayed the germination time of maize, radish, and some legumes such as soybeans, peas, and common beans when generated from carbon tetrafluoride (CF4) or octadecafluorodecalin (ODFD) otherwise known as perfluorodecalin (2H4) .Dielectric barrier discharge (DBD) has been proven to be effective for seed germination and seedling vigor when generated under optimal conditions. DBD in air induced faster germination, leading to a better germination rate and early seedling growth of wheat, barley, and peas under laboratory conditions . A DBD wOther discharge plasmas, including corona, arc, glow, and microwave discharges, also have shown stimulating effects on seed invigoration of some crops although their maximum values differ depending on the treatment conditions of the plasma sources .These results suggest that plasma treatment can enhance the water absorption of seeds, thus leading to a better invigoration of crops. The beneficial effect of plasma treatment on seed invigoration is mainly associated with its power (W) and exposure time (min) , plasma treatments with DBD and arc discharge effectively inactivated its growth and thus reduced the fungal infection of rice by a maximum value of 51% under environmentally controlled conditions radical into hydrogen peroxide (H2O2) and an ordinary molecular oxygen (O2). Finally, CAT in peroxisomes and PODs in the cytosol detoxify the hydrogen peroxide (H2O2) by catalyzing its reduction to water (H2O). Together with these enzymes, non-enzymatic antioxidants can provide cells with highly efficient machinery to detoxify the molecular species of active oxygen. After plasma treatment, the enhancement of these antioxidant systems has recently been reported in a few crops , catalase (CAT), and peroxidase (POD), in plant cells . The antCellular antioxidant systems are effectively enhanced by plasma treatments with a low power (W) and short exposure (min) see . SimilarDielectric barrier discharge has shown positive effects on the contents of the total phenolic compounds under laboratory conditions, although its effects depend on the types of feed gas. These results indicate that plasma treatments generated with a low power and short exposure time can enhance cellular antioxidant systems through H2O2-mediated signaling activating defense-related responses and physiological processes in seeds under stressful conditions such as drought, salinity, and pathogen infection (1) reduce infection with pathogenic microorganisms in germinating seeds or growing plants (2) regulate ROS homeostasis through the antioxidant machinery of plants (3) activate other defense-related responses in plant cells and the seed surface, seed-borne pathogens, and cellular homeostasis, respectively. Although the plasma-induced effects are still poorly understood, their potential mechanisms for crop stress tolerance can be suggested based on the review of the literature on plasma-induced plant responses (Section 2). The ROS, RNS, and UV of plasma can change the physical and chemical properties of the seed surface before exposure to environmental stressors, thus enabling seeds to be more hydrophilic and permeable to water. Scanning electron microscopy studies have shown partial degradation of cellulose and formation of cracks on the surface of plasma-treated seeds . Additiog plants , 2) reguf plants , and 3) nt cells . Many stnt cells . AltogetSeed invigoration and seedling establishment under stressful conditions are highly variable depending on numerous factors, including biological and environmental factors . There is little or no information for establishing crop stress management practices using plasma technology. To our knowledge, there are only a few studies under laboratory conditions on crop tolerance to disease , droughtPlasma applications have been widely used for seed scarification, pathogen inactivation, and antioxidant system activation with proven beneficial effects on seed invigoration and seedling establishment under laboratory and greenhouse conditions. Moreover, the optimal plasma exposure can enhance crop tolerance before stress events by modulating the seed surface environment and physiological processes in seeds. This promising technology is potentially valuable for alleviating the adverse effects of environmental stressors on seed germination and seedling growth in crop production. However, information on plasma effects under stressful conditions is limited to a few crops under laboratory conditions. Further studies are necessary to fully understand the effectiveness of plasma applications to a broad range of stressors under field and greenhouse conditions. This review suggests that the power (W) and exposure time (min) are vital operating parameters of the plasma treatment that affect the phenomenon of the plasma. More experimental evidence is needed to adopt the use of the power (W) and the exposure time (min) as standardized values for the plasma treatment of various crops \u201d through the National Fusion Research Institute of Korea (NFRI) funded by government funds.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The Chinese Center of Disease Control and Prevention (CDC) executed an intensive investigation program. WHO named this novel strain of coronavirus as sever acute respiratory syndrome coronavirus 2 (SARS-CoV-2) aka coronavirus disease 2019 (COVID 19). The sufferer of this virus predominantly and typically shows the symptoms of acute respiratory infections ranging from barely noticeable cough and dyspnea to need of mechanical ventilation in excessively compromised individuals but it typically causes pneumonia thus producing pneumonia like symptoms.th leading cause of death in USA.According to World Health Organization (WHO) the ailments caused by viruses have always emerged in the past and posed masses to life threatening medical conditions. Considering the last two decades, a number of viral infections emerged as epidemic including severe acute respiratory syndrome coronavirus (SARS-CoV), H1N1 influenza, Middle East respiratory syndrome coronavirus (MERS-CoV) and when the timeline approaches the present days there is an outbreak of coronavirus once again with drastic dissemination all across the globe but this time it is the novel one, having a new strain and originating from China in the city of Wuhan with its 1MMAA: Concept, design and accountable for all work.SQ: Drafting and revision.KK: Critical analysis and final approval."} +{"text": "Purpose: To collect information on unintended drug exposure during pregnancy in early clinical drug development. Materials and methods: Questionnaire mailed in autumn 2015 to members of human pharmacology societies in Europe for anonymous responses via the online tool SurveyMonkey. Results: 53 of the ~ 700 addressees participated in the survey. 23 female trial participants and 11 female partners of male trial participants were exposed to investigational medicinal products during unintended pregnancies in a clinical trial. Most survey respondents confirmed adequate contraceptive methods by in/exclusion criteria and the use of pregnancy tests in female trial participants at screening and before the first dose. The last menstrual period was documented less frequently . A considerable proportion of respondents denied the routine use of compliance checks about the appropriate use of contraceptive methods, had no procedures in place if contraceptive methods failed, and did not train physicians in instructing trial participants about the appropriate use of contraceptive methods. Conclusion: The methods to avoid unintended pregnancies during participation in a clinical trial need improvement and should include (i) pregnancy tests, (ii) documentation of last menstrual period before the first dose, (iii) compliance checks of the appropriate use of contraceptive methods, and (iv) training of trial physicians. Procedures should be in place for what to do if contraceptive methods fail. What is known about this subject Pregnancies in early clinical drug development must be avoided Appropriate methods to avoid unintended pregnancies are to be defined in the clinical trial protocol Guidance is provided in the ICH M3(R2) and the respective European Clinical Trial Facilitation Group recommendations (CTFG 2014) What this study adds This AGAH survey revealed that unintended pregnancies occur in early clinical drug development Regulatory recommendations are not fully implemented The methods to avoid unintended pregnancies during participation in a clinical trial need improvement A series of workshops related to early-phase clinical development has been hosted by the scientific society \u201cAssociation for Applied Human Pharmacology\u201d (AGAH e.V.) in Germany since 2012. In 2015, members from the pharmaceutical industry, contract research organizations, academia, ethics committees, and the German competent authority discussed unintended exposure to an investigational medicinal product (IMP) during pregnancy in clinical trials and its prevention [In early drug development, data on reproduction toxicity are in general not yet available. According to the ICH M3R2) Guidance [ Guidance\u201cMen can be included in Phase I and II trials before the conduct of the male fertility study since an evaluation of the male reproductive organs is performed in the repeated-dose toxicity studies\u201d \u201cFor women of childbearing potential (WOCBP) there is a high level of concern for the unintentional exposure of an embryo or foetus before information is available concerning the potential benefits versus potential risks\u201d If reproduction toxicity studies are not available, and WOCBP are planned to be included in a clinical trial, the guideline recommends limiting the risk by taking precautions to prevent pregnancy by (i) pregnancy testing , (ii) use of highly effective methods of birth control, and (iii) trial entry only after a confirmed menstrual period. To enable trial participation of WOCBP, the ICH M3R2) Guidance [ GuidanceInformed consent should be based on known risks to the embryo/fetus related to reproduction toxicity. A general assessment of potential toxicity of pharmaceuticals with related structures or pharmacological effects should be provided If no relevant reproductive information is available, the potential for unidentified risks to the embryo or fetus should be communicated as well Subjects should be instructed to use adequate contraceptive measures during the period of drug exposure which could exceed the length of the trial Pregnancy tests are required during the trial to ensure compliance with the contraceptive measures planned in the trial protocol In Europe, the Clinical Trials Facilitation Group (CTFG) has issued further recommendations related to contraception and pregnancy testing in clinical trials . They arA survey was conducted (i) to collect information on unintended pregnancies during clinical trials in early drug development and (ii) to learn from current experience whether applied precautionary measures are in line with current guidances , 3 and aDefinitions used are: Drug exposure via parent (DEVP) Unintended drug exposure during pregnancy in a clinical trial The survey addressed specialists working in early-phase drug development in Germany, Belgium, France, and the United Kingdom. The questionnaire compriseThe questions covered the following topics (see questions (Q) provided in Characteristics of survey participants Number and cause of unintended pregnancies in female participants and female partners of male trial participants in clinical trials combined in one protocol (Q3\u00a0\u2013\u00a0Q8) Age of women becoming accidentally pregnant in a clinical trial (Q9) Preventive measures (Q10\u00a0\u2013\u00a0Q13) It cannot be excluded that different participants belonging to the same organization referred to the same trial protocol(s). In consequence, a qualitative rather than quantitative interpretation of results is indicated. Not all survey participants answered all questions. For the respective questions, the total number of responses is given . A total of 53 of ~ 700 addressees answered the questionnaire. The majority came from contract research organizations (19), the pharmaceutical industry (15), but also from academia (8), independent consultants (8), biotechnology (2), or regulatory authority (1). Participants were from Germany (47), The Netherlands (3), Belgium (1), Luxembourg (1), and South Africa (1). 15 survey participants reported that 23 female clinical trial participants were unintentionally exposed to IMP during pregnancy in a clinical trial they sponsored or conducted during the past 10 years. 33 survey participants denied the occurrence of such pregnancies. A total of 10 survey participants reported that 11 female partners of male clinical trial participants were unintentionally exposed to IMP during pregnancy in a clinical trial they sponsored or conducted during the past 10 years. 36 survey participants denied the occurrence of such pregnancies. These included (i) non-compliance with trial-specific contraceptive methods (9), (ii) \u00a0failure of contraceptive methods (3), and (iii)\u00a0failure of the pregnancy test to detect pregnancy at screening or before first dose (1). The main outcome of this AGAH survey demonstrates that the occurrence of unintended pregnancies is a relevant issue in early drug development despite considerable effort to avoid them. Taking into account that 53 out of ~ 700 addressees responded, it may be assumed that the unintended exposure to IMPs in early pregnancy is higher than reported here. The number of participants is not a representative sample of all parties conducting clinical trials in Europe. Participants from the same organization may have referred to the same trials. To provide (i) data with respect to a topic with considerable lack of information, (ii) data on failure of/or compliance with contraceptive methods, (iii) data on training of physicians in instructing trial participants how to use the contraceptive methods as specified in the clinical trial protocol. Despite the advice provided in the ICH M3R2) guidance guidance, 5, 6, 7If contraceptive methods fail in a clinical trial, the following procedures are useful in identifying the risk of having become or becoming pregnant and to estimate the usefulness of emergency contraception: Identification of exact kind and time point of contraceptive failure Cycle history Urine pregnancy test If possible, transvaginal ultrasound for determination of ovarian activity Blood sampling for determination of beta-human choriogonadotropin (\u03b2-HCG), estradiol, luteinizing hormone (LH), and progesterone There was agreement among participants of the workshop that good practices to avoid unintended pregnancies in early drug development comprise: Implementation of adequate contraceptive methods in the clinical trial protocol st dose, at appropriate time points thereafter, and upon completion of the clinical trial Pregnancy tests in female trial participants depending on the kinetics of the tested compound. At least screening before 1Written subject information concerning the adequate contraceptive methods to be used during the trial and the necessity avoiding DEVP as well as measures to be taken in case of possibly failed contraception before or during the trial Training of trial physicians on how to instruct trial participants about the appropriate use of adequate contraceptive methods as well as measures to be taken in case of possibly failed contraception Routine compliance checks whether enrolled subjects are appropriately using the contraceptive methods as per protocol Standard procedures in place regarding what to do if contraceptive methods failed Decision on further measures to avoid unnecessary elective pregnancy terminations Compliance with measures indicated by the CTFG publication Female clinical trial participants and female partners of male clinical trial participants must not become pregnant during early drug development; however, this AGAH survey shows that pregnancies did occur. According to the discussions during the workshop, the methods to mitigate the risk of unintended pregnancies need further improvement and should include (i) written information of the trial participants regarding contraceptive measures and the necessity of avoiding drug exposure via parent, (ii) repeated pregnancy tests, (iii) documentation of last menstrual period before the first dose, (iv) compliance checks of the appropriate use of contraceptive methods, (v) training of trial physicians. Procedures should be in place for what to do if contraceptive measures fail. Lessons learned from unintended pregnancies should result in appropriate modification of hitherto implemented procedures. This will mitigate the risk of DEVP in early-phase clinical trials. We thank Sam Welgemoed for her technical support . We thank all participants of the survey for their contributions. Survey: None. Open access provided by AGAH e.V. None. Supplemental material"} +{"text": "Following these two introductory chapters, the monograph can then be divided into four main sections: (i) the technical overview of currently available commercial SGRT Systems (chapters 3\u20135), (ii) the commissioning of the systems described in part (i) (chapters 6\u20138), (iii) the clinical application of SGRT (chapters 9\u201319), and (iv) miscellaneous topics in surface image guidance (chapters 20\u201326). While the corresponding chapters in part (i) and (ii) can be read independently of each other, I personally would have found it more helpful if the technical overview of a particular surface image guidance technology would have been followed by the chapter on its commissioning. Having said that, each of the chapters in part (i) and (ii) strikes the right balance between technical detail and brevity, making them very useful both as a reference and an introduction to the technology and how to commission a given technology of surface image guidance. Part (iii) begins with an in depth look at the clinical application of this technology to breast cancer (chapters 9\u201311), while Chapters 12\u201314 consider Stereotactic Radiosurgery and Stereotactic Radiation Therapy in depth, including a very nice chapter on the risk analysis for SGRT\u2010based SRS/SRT. Part (iii) continues with a detailed description of respiratory motion management strategies employing surface image guidance in SBRT (chapter 15), including the use of surface image guidance for SBRT without respiratory gating (chapter 16). Chapters on the use of surface image guidance in the treatment of Head and Neck (chapter 17), extremities (chapter 18), and pediatric patients (chapter 19) conclude Part (iii). Chapters 20\u201326 round out the presentation with three perspectives on the clinical implementation of surface image guidance, one from the point of view of a physicist and two from the that of a radiation therapist (chapters 20\u201322); applications of surface image guidance to proton therapy (chapter 23); integration of surface image guidance into tomographic and bore type gantry systems (chapter 24); use of consumer grade cameras and alternate approaches to surface image guidance (chapter 25); and a final chapter discussing future directions for SGRT (chapter 26).In summary, this monograph presents a very readable account of the technical features of currently commercially available SGRT technologies, considers the commissioning of each in detail, and discusses in detail the clinical implementation and use of these systems for a number of important clinical sites, such as Breast, Stereotactic Body Radiation Therapy, Stereotactic Radiosurgery and Stereotactic Radiation Therapy, and Head and Neck. Regardless of career stage, professionals in either therapeutic medical physics or radiation oncology will find this monograph beneficial. The authors of this monograph balance technical detail with clinical information regarding the technology's implementation, and, hence, those interested in SGRT will find this monograph a valuable and welcome addition to their professional library. I have enjoyed reading through this monograph and found it a cogent reference and a thorough introduction to the topic.Wolfgang A. Tom\u00e9, Ph.D., FAAPM, FASTRO, is a Professor of Radiation Oncology and a Professor of Neurology at Albert Einstein College of Medicine and the Chief of the Division of Therapeutic Medical Physics at Montefiore Medical Center ."} +{"text": "Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrosis in skin and internal organs, progressive vascular obliteration, and the production of autoantibodies. Diagnostic imaging is irreplaceable in both diagnosing and monitoring patients suffering from systemic sclerosis. In addition to routinely used methods, such as comparative X-ray of the hands or a contrast-enhanced examination of the upper gastrointestinal tract or chest, there is an array of less widespread examinations, with an emphasis on magnetic resonance imaging (MRI) and ultrasonography, not only in the evaluation of the musculoskeletal system. This article will review the various imaging modalities available for SSc imaging and assessment, focusing on their utility as tissue-specific diagnosis and treatment monitoring. Systemic sclerosis belongs to a wide spectrum of connective tissue diseases\u2014a diverse group of disorders characterised by chronic inflammation of connective tissue, usually of autoimmune origin . The mosSSc typically affects women (4:1 predilection), with the median onset at the age of 30\u201350 years. There is a higher morbidity within black patients than in other ethnical groups. A very high prevalence of SSc in Choctaw Native Americans suggests the possibility of a genetic factor in the pathogenesis of this disease. Reports of familial history of SSc or other autoimmune disorders in SSc patients have also shown support for the genetic grounds of SSc. The incidence rate seems stable over several decades in both Europe and the United States ,3,4,5. TThe diagnostic criteria for SSc are still not universal. The classification criteria of the American College of Rheumatology (ACR), presented in 1980 and updated by a collaboration of ACR and European League Against Rheumatism (EULAR) in 2013, are used most commonly. According to those criteria, skin thickening proximal to the metacarpophalangeal joints is sufficient proof of SSc. If it is not present, seven other signs should be evaluated: (1) skin thickening of the fingers (either sclerodactyly or puffy fingers); (2) fingertip lesions ; (3) telangiectasia; (4) abnormal nailfold capillaries; (5) pulmonary arterial hypertension (PAH) and/or interstitial lung disease; (6) Raynaud\u2019s phenomenon; and 7) SSc-related antibodies: anticentromere and/or anti-topoisomerase I (anti-Scl-70) and/or RNA polymerase III , al, al83], The prevalence of ischaemic heart disease related to vasospasm is increased in SSc patients. The vasospasm is often triggered by low temperature, and this symptom is sometimes labeled as the Raynaud phenomenon of the heart. It might be confirmed by visualising subendocardial hypoperfusion areas during an MRI examination .MRI \u2018wall tagging\u2019 and phase contrast techniques are useful to assess fibrosis and diastolic heart failure .Native and post-contrast T1 mapping combined with T2 mapping and LGE (late gadolinium enhancement) discriminate between several myocardial diseases and notably between myocardial fibrosis and edema. The number of studies regarding T1 and T2 mapping is rapidly increasing and the available data show that native T1 mapping detects left ventricular elevated T1 in 50% of patients with SSc while a third of them had normal conventional screening (including standard CMR). This proves that T1 mapping cardiac MRI imaging frequently detects subclinical diffuse myocardial fibrosis in systemic sclerosis patients .In patients without evidence of fibrosis (in LGE), T1 mapping parameters (extracellular volume fraction (ECV), gadolinium partition coefficient (\u03bb), pre-contrast T1, and post-contrast T1) correlated with the modified Rodnan skin score, indicating a correlation between SSc cardiac and skin fibrosis. .Moreover, T1-mapping offers incremental diagnostic value in the identification of patients with high risk of cardiovascular incidents and in addition to independently predict adverse outcomes at follow-up. Thus, CMR may be considered in cases where echocardiographic results are equivocal but the clinical picture warrants a higher index of suspicion, in order to identify high-risk patients early on and to institute prompt changes in the therapeutic management of SSc-related cardiac involvement .MRI allows to recognize one of the more common manifestations of the SSc in the GI tract\u2014lesions of the anus and rectum. Characteristic symptoms include ventral displacement of the anterior rectal wall, decreased thickness of the anal sphincter, and its reduced contrast enhancement caused by its fibrosis . In the A recent survey implies possible applications of MRI ultrafast echo-spin sequences in diagnosing interstitial pulmonary involvement\u2014a correlation between the results of MRI and HRCT was proven .In conclusion, SSc is associated with various radiological findings of specific organ and system manifestations of SSc, which may be apparent in its initial presentation and/or subsequent disease phases. This review may help clinicians and radiologists in the initial diagnosis and monitoring of progression of SSc."} +{"text": "This cohort study examines the association of participation in a summer college academic enrichment program with diversity of students in medical school and intent to practice in underserved areas. As a strategy to increase diversity, many organizations and institutions sponsor premedical summer college academic enrichment programs (SCAEPs) that may address Liaison Committee for Medical Education Standard 3.3, Diversity/Pipeline Programs and Partnerships.2 and Graduation Questionnaire.3 The AAMC Human Subjects Office exempted the study from institutional board review because it did not constitute human participant research and used deidentified data. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.This cohort study included US medical school matriculants from 2013 to 2015 who graduated through 2019 and voluntarily completed the Association of American Medical Colleges (AAMC) Matriculating Student Questionnaire5, by using program reports to the AAMC and other SCAEP participants (excluding those in SMDEP) by Matriculating Student Questionnaire self-report.2 We examined bivariate associations between SCAEP participation and sex, race/ethnicity, and first-generation college graduate (FGCG) identity and examined factors associated with sustained career intention (Matriculating Student Questionnaire and Graduation Questionnaire self-report) to practice in underserved areas by multilevel logistic regression. P values were 2-sided, and statistical significance was set at P\u2009<\u2009.05. Deidentified individual-level data linked via unique AAMC identifiers were analyzed using Stata, version 15 (StataCorp LLC).We identified SCAEP participants in the Robert Wood Johnson Foundation Summer Medical and Dental Education Program (SMDEP), which is a cost-free, 6-week national program to strengthen academic proficiency and career development of students underrepresented in health care professionsThe study sample included 29\u2009456 graduates . A total of 15\u2009050 (51%) were women, 4375 (15%) were graduates from racial/ethnic groups that are underrepresented in medicine, and 4255 (14%) were FGCGs . Among 25 of SCAEPs have shown an increase in the likelihood of application and matriculation to medical school associated with SCAEP attendance. We observed an association between SCAEPs and increased student diversity and that SMDEP participants were more likely to report sustained career intentions to practice in underserved areas. Because career intention to practice in underserved areas at graduation has established predictive validity,6 our findings may inform medical schools\u2019 investments in programs to recruit diverse students whose career goals align with national needs to increase access to care.Previous studiesOur study was limited by small numbers of American Indian or Alaska Native only and Native Hawaiian or other Pacific Islander only graduates, precluding their examination as discrete groups. In addition, we could not further disaggregate the other SCAEPs , which limits generalizability of observations for this group. In the context of the current coronavirus disease 2019 (COVID-19) pandemic and recent activism in response to anti-Black racism, SCAEPs such as SMDEP may play a particular role in medical schools\u2019 efforts to recruit and educate a diverse physician workforce that will meet national health care needs."} +{"text": "Hepatocellular carcinoma (HCC) and pancreatic cancer (PC) belong to the most lethal malignancies worldwide. Despite advances in surgical techniques and perioperative multidisciplinary management, the prognosis of both carcinoma entities remains poor mainly because of rapid tumor progression and early dissemination with diagnosis in advanced tumor stages with poor sensitivity to current therapy regimens. Both highly heterogeneous visceral carcinomas exhibit unique somatic alterations, but share common driver genes and mutations as well. Recently, circulating tumor DNA (ctDNA) could be identified as a liquid biopsy tool with huge potential as non-invasive biomarker in early diagnosis and prognosis. CtDNA released from necrotic or apoptotic cells of primary tumors, metastasis, and circulating tumor cells can reveal genetic and epigenetic alterations with tumor-specific and individual mutation and methylation profiles. In this article, we focus on clinical impact of ctDNA as potential biomarker in patients with HCC and PC. Hepatocellular carcinoma (HCC) and pancreatic cancer (PC) represent two of the most challenging visceral malignancies in oncology with rising incidence and lack of reliable biomarkers for early diagnosis, prognosis, and therapy response. PC and HCC are estimated to become the second and third respective leading causes of cancer-related death in western countries by 2030 , Topoisomerase I inhibition by irinotecan, the DNA crosslinking agents oxaliplatin and cisplatin, and the tubulin inhibitor paclitaxel 1\u20133, platelet-derived growth factor receptor (PDGFR) beta, c-KIT, and RAF/mitogen-activated protein/MEK was the sole drug approved for the treatment of advanced HCC between 2007 and 2016 with a response rate of less than 5% and an extended median overall survival of 2.5 months DNA originates from normal cells exported by exosomes as well as from apoptotic and necrotic cells with highly fragmented, double-stranded DNA of approximately 150\u2013180 base pair fragments in size being released into the bloodstream. In 1948, Mandel and Metais first reported the presence of cfDNA in human circulation followed by detection in urine, saliva, and other body fluids DNA is becoming a research hotspot with high potential as liquid biopsy marker in cancer medicine and digital droplet PCR (ddPCR) are the most promising methods for the detection of mutations in liquid biopsies. In general, plasma samples are used in preference over serum because of lower concentrations of wild-type DNA in HCC patients Table . TERT pr. detected concurrent p15 and p16 methylation in 74% of ctDNA of 23 blood samples from 92% of HCC patients with tumor p15/p16 methylation , RASSF1A, and secreted frizzled-related protein 1 (SFRP1) resulted in an increased accuracy of 93% to differentiate between HCC and healthy controls and therapy stratification in advanced non-small cell lung cancer patients (Zhang et al. Overall, ctDNA mapping of somatic driver mutations and specific epigenetic alterations has great potential in early detection and dynamic monitoring of hepatic or pancreatic carcinomas to achieve a significant decrease of mortality. However, low sensitivity of current ctDNA assays rest a major challenge.So far, ctDNA analysis in PC and HCC could reveal high frequency of common key mutations as TP53 and CDKN2A. CTNNB1 and TERT mutations and aberrant methylation of RASSF1A and CDKN2A were detected in ctDNA of HCC patients, whereas high frequency of KRAS mutations was characteristic for PC. Prospective trial data based on sufficient sample size and defined entry criteria regarding the blood draw procedure and pre-analytical variables as well as standardization of experimental techniques that demonstrate the clinical utility of ctDNA assays in PC and HCC are required."} +{"text": "Pterocarya stenoptera is a common fast\u2010growing tree species often used in the ecological restoration of riverbanks and alpine forests in central and eastern China. Until now, the characteristics of the distribution of this species' habitat are poorly known as are the environmental factors that influence its preferred habitat. In the present study, the Maximum Entropy Modeling (Maxent) algorithm and the Genetic Algorithm for Ruleset Production (GARP) were used to establish the models for the potential distribution of this species by selecting 236 sites with known occurrences and 14 environmental variables. The results indicate that both models have good predictive power. Minimum temperature of coldest month (Bio6), mean temperature of warmest quarter (Bio10), annual precipitation (Bio12), and precipitation of driest month (Bio14) were important environmental variables influencing the prediction of the Maxent model. According to the models, the temperate and subtropical regions of eastern China had high environmental suitability for this species, where the species had been recorded. Under each climate change scenario, climatic suitability of the existing range of this species increased, and its climatic niche expanded geographically to the north and higher elevation. GARP predicted a more conservative expansion. The projected spatial and temporal patterns of P.\u00a0stenoptera can provide reference for the development of forest management and protection strategies.Climate change poses a serious threat to biodiversity. Predicting the effects of climate change on the distribution of a species' habitat can help humans address the potential threats which may change the scope and distribution of species. Minimum temperature of coldest month (Bio6), mean temperature of warmest quarter (Bio10), annual precipitation (Bio12), and precipitation of driest month (Bio14) were important environmental variables influencing the prediction of the Maxent model. Under each climate change scenario, climatic suitability of the existing range of this species increased, and its climatic niche expanded geographically toward farther north and higher elevation. The GARP predicted a more conservative expansion. The results will allow researchers to identify the future suitable habitat and help in the use, management, and cultivation of P.\u00a0stenoptera.To determine the potential geographical distribution and the environmental variables influencing habitat suitability for this species, we used Maxent and GARP modeling to predict the future distribution of 22.1http://www.tropicos.org/), the Global Biodiversity Information Facility (http://www.gbif.org) and the Chinese Virtual Herbarium (http://v5.cvh.org.cn/) database; the latter holds the plant distribution records of the main herbaria of China. Some results from other field survey reports and scientific research literature for 1984\u20131995 data.Soil variables are important factors controlling plant distribution; they change over relatively short timescales based on direct and indirect effects caused by anthropogenic climate change 2.6 and 8.5 proposed by the Intergovernmental Panel on Climate Change were used for the years 2050 and 2070. The BCC\u2010CSM1.1 is recommended for use in studies of operational short\u2010term climate prediction and studies of climate change in China [see Wu et al. and refer|\u00a0>\u00a0.90) in each set was retained for further analysis. The variables in the final environmental dataset include precipitation of warmest quarter (Bio18), precipitation of wettest quarter (Bio16), precipitation seasonality (Bio15), precipitation of driest month (Bio14), precipitation of wettest month (Bio13), annual precipitation (Bio12), mean temperature of warmest quarter (Bio10), mean temperature of wettest quarter (Bio8), minimum temperature of coldest month (Bio6), temperature seasonality (Bio4), isothermality (Bio3), and mean diurnal temperature range (Bio2).Principal component analysis and correlation analyses (Pearson's correlation coefficient) were carried out to minimize the overfitting of the model and decrease the high collinearity. Only one of the highly correlated variables , Bio10 (14.1% of variation), Bio12 (23.2% of variation) and Bio14 (29.2% of variation) for those four most important variables in Maxent were generated to examine the climatic preference of a Figure\u00a0. Overall3.3P.\u00a0stenoptera and modeling methods (GARP and Maxent), showing that the climatic suitability of the existing distribution range increased, and the suitable habitats of the species expanded geographically to the north and to higher elevations , mean temperature of warmest quarter (Bio10), annual precipitation (Bio12), and precipitation of driest month (Bio14) were the most important environmental variables influencing the distribution of this species. The projected spatial and temporal patterns of P.\u00a0stenoptera can provide reference for the development of forest management and protection strategies.Under the climate change scenario, high\u2010quality distributional data play an important role in setting priorities and implementing effective protection actions. Our results indicate that the areas of suitable habitat for The authors declare no competing interest.Keliang Zhang: Formal analysis ; funding acquisition ; methodology ; writing \u2013 original draft . Huina Liu: Formal analysis ; writing \u2013 original draft ; writing \u2013 review and editing . Haolei Pan: Data curation ; investigation ; resources ; software . Yi Zhao: Data curation ; investigation ; resources ; software . Wenhao Shi: Data curation ; investigation ; resources ; software ; visualization . Silei Li: Data curation ; investigation ; resources ; visualization ; writing \u2013 original draft . Junchi Liu: Data curation ; investigation ; resources ; software ; visualization . Jun Tao: Conceptualization (lead); formal analysis ; project administration (lead); supervision (lead); writing \u2013 review and editing ."} +{"text": "IGF2BP2 is known to affect both life span and energy expenditure. The positively selected mutations detected in IGF2BP2 likely affected the functionality of the encoded protein. IGF2BP2, which has been reported to simultaneously prolong life span and increase energy expenditure, could be responsible for the evolution of shortened MLS associated with the loss of flying ability.Acquisition or loss of flying ability is evolutionarily linked with maximum life span (MLS) in mammals and birds. Although ecological factors, such as extrinsic mortality, may lead to either shortened or extended life spans through natural selection, MLS is influenced by complex molecular and metabolic processes, and the genetic changes associated with flying ability that have led to either a longer or shorter MLS are unknown. Here, we examine the parallel evolution of flight in mammals and birds and investigate positively selected genes at branches where either the acquisition (in little brown bats and large flying foxes) or loss of flight abilities occurred. Although we found no shared genes under selection among all the branches of interest, 7 genes were found to be positively selected in 2 of the branches. Among the 7 genes, only Positively selected genes at the branches of interest. It has been proposed that species with lower extrinsic mortalities have longer life spans because they can invest in long\u2010term survival receptors may have contributed to the evolution of their long life spans and the little brown bat (Myotis lucifugus), as volant species with a longer MLS in mammals; and two penguins, the Ad\u00e9lie penguin (Pygoscelis adeliae) and the emperor penguin (Aptenodytes forsteri), and eight ratites, the common ostrich (Struthio camelus), the emu (Dromaius novaehollandiae), the great spotted kiwi (Apteryx haastii), the little spotted kiwi (Apteryx owenii), the okarito brown kiwi (Apteryx rowi), the greater rhea (Rhea americana), the lesser rhea (Rhea pennata), and the cassowary (Casuarius casuarius), as nonvolant birds with a shorter MLS. We then searched for positively selected genes among the different lineages to identify genes that evolved in parallel and are related to both flying and life span. Genes detected among multiple branches where changes in flying ability had occurred are discussed for their possible roles in energy expenditure and alteration in life spans.To shed light on the parallel evolution of either longer or shorter MLSs with that of either acquisition or loss of flight ability, it is necessary to examine candidate genes that have been subject to positive selection in multiple lineages of birds that have lost their flying ability in addition to those of mammals that have evolved the ability to fly. The purpose of our research was to detect positively selected genes at the branches where the acquisition or loss of flying ability occurred, using whole\u2010genome\u2010sequenced mammals and birds, and to explore the genes responsible for shorter or longer MLSs associated with the evolution of the loss or acquisition of flying ability. We chose two bats, the large flying fox (22.1Felis catus), cow (Bos taurus), dog (Canis lupus familiaris), elephant (Loxodonta africana), horse , human being (Homo sapiens), marmoset , mouse (Mus musculus), opossum (Monodelphis domestica), pig (Sus scrofa), platypus (Ornithorhynchus anatinus), rabbit (Oryctolagus cuniculus), rat (Rattus norvegicus), and sheep (Ovis aries) were selected as nonvolant species, and the large flying fox (Pteropus vampyrus) and little brown bat (Myotis lucifugus) were selected as volant species. All genome sequences were obtained from Ensembl 98 , emperor penguin (Aptenodytes forsteri), common ostrich (Struthio camelus), emu (Dromaius novaehollandiae), great spotted kiwi (Apteryx haastii), little spotted kiwi (Apteryx owenii), okarito brown kiwi (Apteryx rowi), greater rhea (Rhea americana), lesser rhea (Rhea pennata), and cassowary (Casuarius casuarius) were selected as nonvolant species, and the American crow (Corvus brachyrhynchos), Anna's hummingbird , bald eagle , mallard (Anas platyrhynchos), budgerigar (Melopsittacus undulatus), chimney swift (Chaetura pelagica), common cuckoo (Cuculus canorus), crested ibis (Nipponia nippon), downy woodpecker (Picoides pubescens), golden\u2010collared manakin (Manacus vitellinus), killdeer (Charadrius vociferus), little egret (Egretta garzetta), medium ground finch (Geospiza fortis), peregrine falcon , pigeon (Columba livia), and zebra finch (Taeniopygia guttata) were selected as volant species. Genomes of the zebra finch, emu, and the three kiwis were obtained from Ensembl 98 , reportedly the longest\u2010living bat, and the flightless brown kiwi were not included in our analysis as their assembled genome sequences included many gaps and a sufficient number of orthologous genes was not available. Analyses for mammals and birds were conducted separately. We performed reciprocal basic local alignment search tool (BLAST) searches and obtained the highest score pairs of one\u2010to\u2010one orthologs using the BLASTp algorithm in National Center for Biotechnology Information\u00a0(NCBI) BLAST v.2.6.0+ or those that rarely fly (such as the tinamou or hoatzin). For mammals, the genome sequences of the cat . We focused on genes detected via both calculations with a gene tree and species tree, and the genes detected by both PAML and aBSREL analyses were considered candidates under positive selection. To evaluate parallel and/or convergent evolution between avian and mammalian species, we used one\u2010to\u2010one ortholog information between humans and zebra finches (the reference species in birds) inferred by BLASTp terms and pathways using the over\u2010representation test with Fisher's exact test and the Benjamini\u2013Hochberg procedure in PANTHER version 14.1 ; Visualization ; Writing\u2010original draft ; Writing\u2010review & editing . Daiki X. Sato: Formal analysis (supporting); Writing\u2010original draft (supporting); Writing\u2010review & editing (supporting). Takashi Makino: Formal analysis (supporting); Writing\u2010review & editing (supporting). Masakado Kawata: Conceptualization ; Supervision (lead); Writing\u2010original draft ; Writing\u2010review & editing (lead). Fig S1\u2010S19Click here for additional data file.Table S1\u2010S52Click here for additional data file."} +{"text": "Oreolalax major was determined using polymerase chain reaction (PCR). It includes 13 protein-coding genes (PCGs), 2 ribosomal RNA (rRNA) genes and 19 transfer RNA (tRNA) genes (GenBank accession number KU310894). The features of O. major have one more tRNA gene (MettRNA) behind the original one before ND2 which is similar to Leptobrachium boringii. Phylogenetic analyses were based on the concatenated sequences of the 13 protein-encoding genes of O. major and other related species.In this study, the near complete mitogenome sequence of Oreolalax major (Liu & Hu 1960) belongs to family Megophryidae, genus Oreolalax. It is an endemic species of China, which is distributed in Hengduan Mountains of western Sichuan and southern Gansu Provinces was collected from Wawushan Nature Reserve, Hongya , Sichuan, China in June, 2015. It was fixed in 75% ethanol and deposited in the Museum of Sichuan Agricultural University. The total DNA was extracted and purified from muscle tissue using the Ezup pillar genomic DNA extraction kit . We used twenty-three pairs of polymerase chain reaction (PCR) primers published by Zhang et\u00a0al. , 2 ribosomal RNA (rRNA) genes and 19 transfer RNA (tRNA) genes (GenBank accession number KU310894). The features of O. major have one more tRNA gene (MettRNA) behind the original one before ND2 which is similar to Leptobrachium boringii tRNA and GlutRNA genes. We regrettably did not sequence the region between 12S rRNA and Cyt b genes which contains 4 rRNA genes and 1 D-loop region because of difficult to amplify. There are two types of initiation codons used for 13 PCGs and most PCGs initiate from ATG, while others start with GTG. In addition, 5 PCGs terminate in incomplete stop codon T, the same number of PCGs use complete stop codon TAA, and the rest of PCGs end with AGG. The 12S rRNA and 16S rRNA are determined to be 936\u2009bp and 1598\u2009bp long respectively and all the tRNA genes can constitute typical cloverleaf secondary structure exclude Ser(AGY)tRNA.The near complete mitochondrial genome of The NJ analysis of the combined data set indicates that all samples of Megophryidae form a strong supported monophyletic group and all"} +{"text": "The purpose of this study was to describe the ocular findings, structural ocular complications, and vision impairment in a cohort of Lassa fever survivors in Kenema, Sierra Leone. A retrospective, uncontrolled, cross-sectional study of 31 Lassa fever survivors (62 eyes) who underwent an ophthalmic evaluation in January 2018 at the Kenema Government Hospital in Kenema, Sierra Leone was performed. Data collection included demographic information, ocular/systemic symptoms, visual acuity (VA), and ophthalmic examination findings. Main outcome measures included anterior and posterior segment ophthalmic manifestations and level of VA impairment in Lassa fever survivors. Anterior segment findings included cataract (18%) and pterygium (2%), while posterior segment manifestations consisted of glaucoma (6%), preretinal hemorrhage (2%), and lattice degeneration (2%). Findings suggestive of prior sequelae of uveitis included chorioretinal scarring (5%), retinal fibrosis (3%), and vitreous opacity (2%). Visual acuity was normal/mildly impaired in 53 eyes (85%), moderately impaired in 6 eyes (10%), and 3 eyes (5%) were considered blind by the World Health Organization (WHO) criteria. Median VA was worse in Lassa fever survivors with ophthalmic disease findings (p<0.0001) for both anterior segment (p<0.0001) and posterior segment disease (p<0.013). Untreated cataract was a significant cause of visual acuity impairment (p<0.0001). Lassa fever survivors in this cohort were found to have cataract and posterior segment findings that potentially represent sequelae of uveitis associated with visual impairment. Future studies are warranted to improve our understanding of the spectrum of ocular disease in this emerging infectious disease of public health consequence. Arenaviridae family. Lassa fever is endemic to the West Africa countries of Benin, Ghana, Liberia, Guinea, Mali, Sierra Leone and Nigeria, affecting 100,000 to 300,000 people annually, and causing approximately 5,000 deaths per year 19\u201350). The median time from the date of Lassa fever diagnosis to the date of ophthalmic examination was 10.03 years (IQR 6.0\u201312.0). Five patients (16.1%) reported eye symptoms including pain, redness, and blurry vision during the acute phase of Lassa fever. At the time of ophthalmic examination, Lassa fever survivors reported ocular symptoms including blurry vision (42%), itching (13%), pain (6%), redness (6%), tearing (6%), loss of near vision (3%), and floaters (3%) . Review Anterior segment findings included cataract (18%) and pterygium (2%). One patient had a traumatic cataract from penetrating corneal injury, which had self-sealed without surgical repair and showed evidence of uveitis with focal posterior synechiae . This siOphthalmic manifestations in the posterior segment included the presence of glaucomatous optic neuropathy (6%), chorioretinal scarring (5%), retinal fibrosis (3%), peripheral drusen (3%), preretinal hemorrhage (2%), lattice degeneration (2%), and vitreous opacity (2%) . There wVisual acuity was normal or mildly impaired in 53 eyes (85%), moderately impaired in 6 eyes (10%), and 3 eyes (5%) were considered blind according to the World Health Organization classification of visual impairment . The thrWe analyzed the impact of ocular structural complications on visual acuity, which are summarized in any ophthalmic abnormality by exam (p > 0.05). Individuals with any ocular abnormalities were likely to be older compared to patients evaluated without ocular findings . Patients who were older tended to report blurred vision symptoms than younger patients . Gender was not associated with the presence of ocular complications or blurred vision symptoms .A significant minority of Lassa fever survivors (42%) reported blurred vision and we thus assessed the relationship of this patient-reported symptom to visual acuity impairment and ophthalmic findings. No association was observed between individuals with reported blurred vision and at least moderate visual acuity impairment . In addition, no association was observed between blurred vision and evidence of Audiovestibular symptoms and joint pain have been reported in Lassa fever survivors and their relationship to ophthalmic disease was analyzed. Seven patients were found to have audiovestibular symptoms (23%) including 6 with hearing loss and 1 patient with tinnitus, which developed after acute Lassa fever. Hearing loss included bilateral disease (1), right ear (2), left ear (1) and unspecified (2). Hearing loss was not associated with patient-reported blurred vision or the presence of posterior segment or anterior segment disease findings . Joint pain was similarly unassociated with ocular findings (p > 0.05) in our series of patients, although like hearing loss, was observed in a modest proportion (26%) of patients evaluated.The ophthalmic sequelae of Lassa fever have not been well-characterized, and the aim of this study was to provide a preliminary investigation of the ophthalmic manifestations in Lassa fever survivors. Ocular involvement during the acute phase of Lassa fever has been reported to manifest as conjunctivitis, typically starting on day 7 of illness and lasting for a duration of 5 days . SubconjBlurry vision was a common visual complaint with over 40% of patients describing this symptom at the time of ophthalmic evaluation. The majority of patients (85%) had normal or mild vision impairment according to the WHO classification of visual impairment. While McCormick et al identified cases of uveitis with transient vision loss, we did not observe signs of active uveitis in our cohort of Lassa fever survivors who were evaluated . MoreoveThere are few reports in the literature documenting the prevalence and causes of visual impairment in the general population in West Africa. The Tema Eye Survey, a population-based cross-sectional study of 5,603 participants residing in an urban West African location, reported a 17.1% prevalence of visual impairment and 1.2% rate of blindness in Tema, Ghana, West Africa . RefractOther untreated ophthalmic conditions that were observed in our study of Lassa fever survivors included open globe trauma, cataract and advanced glaucoma. Specifically, cataract and end-stage glaucoma were identifiable causes of blindness (vision loss worse than 20/400) in three patients (9.7%). A dense mature cataract precluded view to the fundus in one of these patients, and thus it is unknown whether there were other posterior segment findings suggestive of cataract formation related to intraocular inflammation or if the cataract was merely age-related. The mechanism of glaucoma is unknown in the two patients with end-stage glaucoma and hand motions visual acuity; however, they did not have visible sequelae of prior ocular inflammation. In comparison, a retrospective study of a hospital population in Sierra Leone, West Africa conducted in 1989 and 1992 revealed that senile cataract was the major cause of blindness followed by uveitis despite a significant decrease in blindness from onchocerciasis . BlindneLong-term systemic symptoms were also present at the time of ophthalmologic examination, including joint pain (26%), hearing loss (16%), and headache (16%). Hearing loss is a well-documented and potentially profound sequelae of Lassa fever, and a literature review of five hospital-based and population-based studies of Lassa fever survivors revealed that approximately one-third (4%-75%) of Lassa virus-infected patients developed sudden sensorineural hearing loss . Our limAnimal studies have been utilized to better understand the pathogenesis of LASV in the eye and to investigate the possibility of LASV persistence in this immune-privileged site , 21. WalArenaviridae family include accounts of similar descriptions of chorioretinal scarring in lymphocytic choriomeningitis virus (LCMV) [The few reports of ocular involvement in other members of the s (LCMV) \u201324. Thiss (LCMV) . In parts (LCMV) . In a res (LCMV) . Mets ets (LCMV) . LCMV ins (LCMV) .Ocular manifestations in viral hemorrhagic fever disease is not limited to Lassa fever and has been described previously with other hemorrhagic fevers including Ebola virus disease (EVD) and Marburg virus disease . A singlToxoplasma gondii. Selection bias was also a potential limitation, as patients may have presented for an ophthalmic examination primarily if they reported ocular symptoms. Future controlled, longitudinal studies with larger sample sizes are planned to characterize the prevalence of ocular disease and the spectrum of ophthalmic complications associated with Lassa fever.Limitations of our study include the cross-sectional, retrospective nature of the study. Because ophthalmic examination occurred at a single time point, the patient\u2019s baseline eye disease was unknown, and we were unable to ascertain whether the patients\u2019 cataract or chorioretinal scarring occurred as an immediate consequence of Lassa virus infection. Understanding the timing of the ocular findings following acute Lassa virus infection will allow clinicians and investigators to understand the potential relationship between the ocular findings identified and Lassa fever. It is currently unknown whether the etiology of chorioretinal scarring was from prior trauma or other infectious agents such as In summary, this cross-sectional, retrospective study highlights the first detailed characterization of ophthalmic manifestations in Lassa fever survivors. Evidence of cataract and prior sequelae of intermediate and posterior uveitis were present in this cohort of Lassa fever survivors. Moderate vision impairment was present in 10% of the patients in our study, highlighting the need for further investigation into ophthalmic complications of LASV infection during the acute phase of disease and convalescence. Future studies are warranted to improve our understanding of long-term ophthalmic sequelae and the spectrum of ocular disease in Lassa fever survivors, particularly given its high annual incidence in West Africa and our ophthalmology field\u2019s mandate to understand emerging infectious diseases of public and global health consequence.S1 Dataset(XLSX)Click here for additional data file."} +{"text": "In contrast, in Li+-containing buffer, SERT showed only low force interactions. Conversely, the vestibular mutant SERT-G402H merely displayed the high force population. These observations provide physical evidence for the existence of two binding sites in SERT. The dissociation rate constant of both binding sites was extracted by varying the dynamics of the force-probing experiments. Competition experiments revealed that the two sites are allosterically coupled and exert reciprocal modulation.Crystal structures and experiments relying on the tools of molecular pharmacology reported conflicting results on ligand binding sites in neurotransmitter/sodium symporters (NSS). We explored the number and functionality of ligand binding sites of NSS in a physiological setting by designing novel tools for atomic force microscopy (AFM). These allow for directly measuring the interaction forces between the serotonin transporter (SERT) and the antidepressant S-citalopram (S-CIT) on the single molecule level: the AFM cantilever tips were functionalized with S-CIT via a flexible polyethylene glycol (PEG) linker. The tip chemistry was validated by specific force measurements and recognition imaging on CHO cells. Two distinct populations of characteristic binding strengths of S-CIT binding to SERT were revealed in Na Aa (Drosophila melanogaster dopamine transporter) (The serotonin transporter (SERT) is a member of the monoamine neurotransmitter sodium symporter (NSS) family . Its epoAa and dDATsporter) , indicatsporter) of NSS tsporter) .To date, a series of crosslinkers have been developed for covalent conjugation of functional molecules to atomic force microscopy (AFM) cantilever tips. Some conventional linkers are NHS-PEG-aldehyde , NHS-PEGForce measurements were conducted on living CHOK1 cells stably eThe validity of the tip chemistry was also shown by topography and recognition imaging (TREC) . TREC isFrom a large amount of repeated force measurements using the same conditions, two populations with distinct unbinding forces were obs3H]HT uptake was not detectable and the width (xB) of prominent energy barriers of the interaction for the individual force populations by plotting the unbinding forces as a function of the force loading rate for both S1 and S2 were in agreement with those determined for the S1 site by force spectroscopy (0.032 \u00b1 0.005 s\u20131) (We extracted the dissociation rate constant (k1 and S2 . We reli1 and S2 was empl005 s\u20131) .Dissociation of S-CIT at the central S1 site is delayed, if the vestibular S2 site is occupied by either S- or R-CIT . This obThe flexible PEG linker between the AFM tip and the CIT molecule provides the unique opportunity to explore the binding sites of different depths in transmembrane transporter. Force sensing in physiological conditions allowed for the extraction of dynamic information, thus unequivocally documenting the existence of two binding sites in SERT. Furthermore, our force experiments revealed a positive allosteric effect on the S2 site induced by the binding of S-CIT at S1 site. Given the importance of allosteric regulation in biology and pharmacology, SMFS provides a unique approach to explore transient binding sites in clinically relevant membrane transporters for addressing the modulation of interaction forces between ligands and allosterically coupled binding sites.Indeed, such an allosterically enhanced binding strength of S-CIT at the S2 site could be a critical contribution for the capture of the S2 site by X-ray crystallography. The X-ray structure of SERT bound with S-CIT verifiedWe notice that the only common amino acid residue of S2 site revealed by the crystal structure and previous studies is the arginine R104. The involvement of R104 in S2 site is partially supported by the experiment of recognition imaging . The bloFurther developed AFM techniques have provided the possibility to measure the depth of ATP binding site in mitochondrial uncoupling protein 1 (UCP1) or to reAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Globally, wetlands are in decline due to anthropogenic modification and climate change. Knowledge about the spatial distribution of biodiversity and biological processes within wetlands provides essential baseline data for predicting and mitigating the effects of present and future environmental change on these critical ecosystems. To explore the potential for environmental DNA (eDNA) to provide such insights, we used 16S rRNA metabarcoding to characterise prokaryote communities and predict the distribution of prokaryote metabolic pathways in peats and sediments up to 4m below the surface across seven New Zealand wetlands. Our results reveal distinct vertical structuring of prokaryote communities and metabolic pathways in these wetlands. We also find evidence for differences in the relative abundance of certain metabolic pathways that may correspond to the degree of anthropogenic modification the wetlands have experienced. These patterns, specifically those for pathways related to aerobic respiration and the carbon cycle, can be explained predominantly by the expected effects of wetland drainage. Our study demonstrates that eDNA has the potential to be an important new tool for the assessment and monitoring of wetland health. These aspects include: 1) identification of sensitive indicators for discriminating different types of anthropogenic disturbance ; 2) demonstrating consistency of indicator responses across different wetlands and wetland types; and 3) using temporal sampling to show whether reverse trends in indicators of anthropogenic disturbance are detectable in wetlands undergoing restoration.S1 FigFilled circles represent sample depths.(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file."} +{"text": "Dear Editor,JAK2 V617F mutation, insertion and/or deletion (indel) mutations of CALR exon 9 are the second most common driver mutations in the myeloproliferative neoplasms (MPN) of essential thrombocythemia and primary myelofibrosis and their detection is considered a major diagnostic criterion for these malignancies. It is becoming increasingly apparent that MPNs harboring CALR mutations may occur in patients with BCR-ABL1-positive chronic myeloid leukemia (CML) as evidenced by a wave of recently reported cases. The CALR-positive MPN and CML may appear concurrently with composite morphology or sequentially with either malignancy revealed as a consequence of specific treatment for one of the malignancies (Table 1CALR-mutated MPN in the remaining 12/24 (50 %) cases. Evidence exists for molecular abnormalities occurring within a single clone and in distinct clonal populations.After the JAK2 V617F mutation in all newly presenting CML cases (McCarron et al., 2012[CALR and MPL mutations in all likelihood would show a similar redundancy. Given the low incidence but increasing awareness of co-existing CML and MPN, testing for the relevant rearrangement should therefore be implemented when there is clinical, hematological or morphological evidence.While co-existence of CML and another MPN has clinical relevance with respect to selection and timing of tyrosine kinase inhibitor therapy, there is currently insufficient follow-up data to ascertain overall survival of such cases. There is limited value in assessing the The author declares no conflicts of interest."} +{"text": "Older adults\u2019 behavioral stage of change for adopting fall prevention interventions, and their use of evidence-based interventions are not well understood. A survey was administered to older adults (65 years+) (n=1063) to understand their stage of change and fall prevention behaviors. Descriptive statistics were calculated and logistic regression conducted to determine factors most related to stage. The distribution of subjects by stage was precontemplation (17%), contemplation (2%), preparation (5%), action (15%), and maintenance (61%). The strongest variable related to being in an action stage was screening positively for fall risk . The most common preventive actions for those in an action stage were taking Vitamin D (37%), and having vision tested (30%). Older adults at risk for a fall are ready to take action to prevent falls; health promotion should focus on increasing knowledge and use of different evidence-based interventions."} +{"text": "Alternative splicing generates multiple protein isoforms from one primary transcript and represents one of the major drivers of proteomic diversity in human cells . AlternaAlthough significant progress has been made in recent years, important questions still remain to be addressed. In particular, we need to determine (i) the role(s) of the majority of the splicing isoforms during physiological processes, (ii) the factors involved in their production, and (iii) how splicing is integrated with other gene expression regulatory programs.RAD6B gene and their association with melanoma pathogenesis [SMN2 gene [moso bamboo (an important forest species) by supporting the translation of a fraction of transcript isoforms targeted by nonsense-mediated mRNA decay (NMD) pathway [Trichophyton rubrum (a dermatophytic fungus) suggesting strategies employed by dermatophytes in response to antifungal therapy [This special issue collects recent insights addressing the above interrogatives. More specifically, Palombo and colleagues illustrate the function of two splicing factors (hnRNPM and SRSF3) in regulating DHX9 poison exon, with potential implications in Ewing sarcoma proliferation and sensitivity to chemotherapy , whereasogenesis , while Mogenesis , which mMN2 gene . In thei pathway . Taking therapy .This special issue also includes four reviews. In particular, Biamonti and colleagues discuss the key role played by alternative splicing in cancer cell plasticity and tumor heterogeneity . The posWe hope that the articles and reviews included in this special issue will illuminate new progresses in the field of alternative splicing and its function(s) in physiological and pathological conditions."} +{"text": "Needs during and following end-of-life (EOL) experiences are distinctive for sexual and gender minority (SGM) people and, in particular, older lesbian, gay, and bisexual women (LGB) women; however, access to supportive services is limited. This poster presents findings from a qualitative study of older (60+) LGB women who have lost a spouse or partner. This work draws on queer gerontological theory, addressing issues of individual agency, systemic silence, and marginalization by invisibility of older SGM women in order to illuminate specific areas in which policy may be changed and improved. The study analyzed participants\u2019 (n = 16) reflections on their experiences of losing a loved one, including how they sought out and received essential grief support and the type of support they would have preferred and from whom, particularly immediately following their spouse or partner\u2019s death. Thematic analysis revealed three main findings: 1) having a women-identifying support presence at the time of death for both themselves and their spouse or partner; 2) needing LGB women during EOL for support; and 3) preferring grief groups comprised of other LGB women based on their feelings of difference from gay men and heterosexual/non-SGM women and men. Findings reveal the need for a better understanding among healthcare and social work support professionals regarding LGB women\u2019s grief needs and preferences; grief options grief groups); and how to implement policy changes reflecting these needs and preferences."} +{"text": "The Saint Louis University GWEP partners with a rural Missouri critical access hospital and an urban Federally Qualified Health Center to support their transformations into an Age-Friendly Health System in their community. With an emphasis on the 4Ms, programmatic innovations include development and training of: 1) electronic health records integration of the Rapid Geriatric Assessment (RGA) for patients 65+ years old; 2) RGA-based protocol for Medicare Annual Wellness Visits (MAWV); 3) Interprofessional health care team approach; 4) Evidence-based or Evidence-Informed treatment interventions, including Cognitive Stimulation Therapy (CST), exercise and strengthening program, caregiver support, and Circle of Friends, an intervention for loneliness and social isolation. Outcomes will be presented which suggest increased assessment practices and improvement in functional and cognitive status. Successes and lessons learned regarding strategies to develop an Age-Friendly Health System in two different primary care settings will be discussed."} +{"text": "This article has been corrected: The authors requested replacement of Figure 4h (upper panel). Originally, to represent the morphology of brown adipose tissue (BAT) in the Middle-Aged group, the authors used the same image in Figure 3c (lower panel) and Figure 4h (upper panel). To avoid misinterpretation, they have replaced the Middle-Aged, Rest panel with a representative image from the original set of experiments. This alteration does not affect the results or conclusions drawn in this work."} +{"text": "Recombinant human insulin plays an important role in the gut maturation of preterm infants. This meta-analysis was carried out to assess the efficacy and safety of enteral recombinant human insulin in decreasing the time to full enteral feeding in preterm infants. The pooling of data from four clinical trials yielded a significant decrease in the time to full enteral feeding in preterm infants under both low and high doses of insulin . These findings require confirmation by further large trials that evaluate the efficacy and safety of enteral insulin, especially at supraphysiological doses. A preterm birth is categorized as the birth of a baby before 37 weeks of gestation . Around Studies on animal models suggest that maternal milk contains factors that stimulate the development of the gastrointestinal tract . These iSome clinical trials have been conducted on this topic, but they have not been systematically evaluated. In this study, we aim to evaluate the efficacy and safety of enteral human recombinant insulin in reducing the time to full enteral feeding in preterm infants. Our meta-analysis will help to determine if this intervention can prevent feeding intolerance and associated complications in this vulnerable population.This meta-analysis was conducted according to the guidelines of the Preferred Reporting Items for Systematic Review (PRISMA) . The PRIWe initially screened articles based on titles and abstracts and then screened them by reading the full text of the research articles. Two separate authors (FQ and MA) conducted the screening, and any conflicts and discrepancies were resolved through discussion with the third author (MA). We included controlled clinical trials that enrolled preterm infants and compared the efficacy of recombinant human insulin concentration with placebo or no treatment. Our outcomes of interest were the reduction in the time to full enteral feeding and the incidence of serious adverse events.2 statistic. We evaluated the efficacy of enteral insulin in two doses: (a) the physiological dose (400 \u00b5IU/mL milk) present in human colostrum (low dose) and (b) a supraphysiological dose (2000 \u00b5IU/mL milk) (high dose) [We pooled the data using RevMan 5.4 software under a random-effects model using mean differences (MDs) and risk ratios (RRs) with their 95% confidence intervals (CIs). Heterogeneity was assessed by the Igh dose) .The screening process identified four trials meeting the inclusion criteria that contributed five comparisons to the meta-analysis with a total of 388 participants ,14,15,16The quality assessment of RCTs was carried out using the revised Cochrane Risk of Bias (RoB 2.0) tool . One tri2 = 48%; 2 = 0%; The results of our meta-analysis show that the use of enteral recombinant human insulin significantly decreased the time to full enteral feeding in preterm infants at both low should be evaluated."} +{"text": "Anemia in patients with chronic kidney disease (CKD) is associated with increased morbidity and mortality, decreased quality of life, and substantial health care costs. Iron therapy is recommended, usually in combination with an erythropoiesis-stimulating agent (ESA), in many CKD patients with anemia and low iron levels to raise hemoglobin levels to a range of 10 to 12 grams per deciliter; iron deficiency is defined by a ferritin score less than 100 micrograms (mcg) per liter and transferrin saturation (TSAT) less than 20%.To examine the use of intravenous (IV) iron and it's associated economic and clinical outcomes in Medicare beneficiaries with stage 3 or stage 4 CKD and anemia.This was a retrospective cohort analysis using 2006 and 2007 Medicare 5% Standard Analytic Files (SAF). Use of therapy with IV iron and/or ESAs was identified among patients diagnosed with CKD and anemia. The study index quarter was the first quarter in 2006 during which the patient had primary or secondary diagnoses of both CKD and anemia. Based on the receipt of IV iron or ESA treatment in the index quarter, patients were classified into 1 of 4 treatment groups: IV iron and ESA; IV iron without ESA; ESA without IV iron; neither IV iron nor ESA. Therapy with oral iron was not measurable with this database. Clinical and economic outcomes, including the progression to advanced CKD stages, development of anemia, mortality, hospitalization, and net Medicare reimbursement for all-cause health care services, were examined for 1 year following the index quarter. Between-group differences were tested using Pearson chi-square for categorical variables and the Kruskal-Wallis nonparametric test for reimbursement. Multivariate logistic regression models were estimated to assess the associations of mortality, inpatient hospitalization, skilled nursing facility (SNF) admission, and hospice care with treatment regimen, controlling for patient demographic and clinical characteristics.Of the 4,310 study patients with both CKD and anemia, 2,913 (67.6%) received neither IV iron nor ESA; 984 (22.8%) received ESA without IV iron; 277 (6.4%) received IV iron and ESA; and 136 (3.2%) received IV iron without ESA in the index quarter. Logistic regression analyses showed that patients receiving neither IV iron nor ESA (reference group) were at increased risk of death compared with patients receiving both IV iron and ESA . Additionally, patients receiving neither IV iron nor ESA were more likely to be hospitalized compared with patients receiving both IV iron and ESA , IV iron without ESA , and ESA without IV iron . Further, patients not receiving IV iron or ESA were more likely to be admitted to an SNF than patients receiving both IV iron and ESA , IV iron without ESA , and ESA without IV iron . Patients receiving neither IV iron nor ESA in the index quarter had the highest mean [SD] total Medicare reimbursement per patient in the subsequent year compared with patients receiving IV iron without ESA , IV iron and ESA , or ESA without IV iron .Use rates of IV iron and ESA in a sample of Medicare enrollees with CKD and anemia in 2006 suggest that anemia management therapies may be underutilized; however, oral iron therapy use was not measurable with the study database, and therapies initiated after the index quarter were not measured. Patients not treated with IV iron or ESA had significantly higher rates of hospitalization and SNF admission than patients treated with either IV iron or ESA. Further, mortality was significantly higher in patients receiving neither IV iron nor ESA than in patients who received IV iron and ESA. Additionally, total all-cause health care costs were higher among patients receiving neither IV iron nor ESA treatment compared with patients treated with IV iron and/or ESA."} +{"text": "Due to a production error, the funder University of Bern was erroneously omitted. Statement to be added, \u201cOpen access funding by University of Bern.\u201d The corrected Funding statement appears below:\u201cData collection and publication was supported financially by the canton of Aargau. Internal funding of research time. JJ work in tobacco prevention is funded by a career development award (CDA) funded by Swiss Academy of Medical Sciences (SAMS) (YTCR-34/19). Open access funding by University of Bern.\u201dThe publisher apologizes for this mistake. The original article has been updated."} +{"text": "Arabidopsis thaliana), neighbor cues reduce the activity of the photosensory receptors phytochrome B (phyB) and cryptochrome 1, releasing photoreceptor repression imposed on PHYTOCHROME INTERACTING FACTORs (PIFs) and leading to transcriptional reprogramming. The phyB-PIF hub is at the core of all shade-avoidance responses, whilst other photosensory receptors and transcription factors contribute in a context-specific manner. CONSTITUTIVELY PHOTOMORPHOGENIC1 is a master regulator of this hub, indirectly stabilizing PIFs and targeting negative regulators of shade avoidance for degradation. Warm temperatures reduce the activity of phyB, which operates as a temperature sensor and further increases the activities of PIF4 and PIF7 by independent temperature sensing mechanisms. The signaling network controlling shade avoidance is not buffered against climate change; rather, it integrates information about shade, temperature, salinity, drought, and likely flooding. We, therefore, predict that climate change will exacerbate shade-induced growth responses in some regions of the planet while limiting the growth potential in others.When exposed to changes in the light environment caused by neighboring vegetation, shade-avoiding plants modify their growth and/or developmental patterns to access more sunlight. In Arabidopsis ( The signaling network involved in shade avoidance responses integrates information from environmental variables such as temperature, water availability, and salinity. Shade avoidance responses are changes in plant growth and/or developmental patterns elicited by modifications of the light environment caused by neighboring vegetation. Their function is to increase access to sunlight and reduce the risk of future shade .There are four strategies to achieve these goals: (a) To overtop neighbors, elevating the foliage above vegetation shade; (b) to move the position of the foliage on the horizontal plane away from the shade of neighbors; (c) to reduce the proportion of the foliage placed at the shaded base of the canopy; and (d) to modify the phenology to elude the time when deep shade is present.The growth and developmental responses inherent to each one of these strategies, respectively, include (a) enhanced elongation of the stem or petioles and the shift of leaves to a more erect position (enhanced leaf hyponasty); (b) asymmetric growth of the stem or the leaves (the phototropic response of light-grown seedlings can be included within this class of shade avoidance responses) and asymmetric branching; (c) the inhibition of branching at the base of the plant, the reduction of expansion of shaded leaves and the advanced senescence of basal leaves; and (d) the accelerated transition to reproduction (flowering) to complete the life cycle before shade becomes too deep and the delayed seed germination until shade disappears.Glycine max) (Helianthus annuus) (Triticum aestivum) (Hordeum vulgare) (Sorghum bicolor) (Zea mays) and sunflower and sunf annuus) , reduce estivum) , barley vulgare) , and sorbicolor) , and enhbicolor) and orieea mays) and sunfea mays) . Enhanceunflower . The widArabidopsis thaliana) for which the molecular events are best understood. We propose that the output of this network integrates different light, temperature, salinity, drought, and likely flooding cues and is, therefore, affected by climate change.Different species may show selected components of the shade-avoidance syndrome and shade avoidance is actually weak in shade-tolerant plants adapted to the understory of tree canopies . This reThe presence of neighbors modifies diverse features of the physical and chemical environment, including mechanical cues , which cCompared with isolated plants, the intensity of neighbor cues shows three phases of progressive strength with closer proximity to these neighbors and increased size particularly of their green organs . First, A. thaliana, sunlight activates phyB and cry1 to repress shade avoidance responses. The loss-of-function mutants of these photosensory receptors show shade avoidance responses under full sunlight shows enhanced expression of the PHYA gene and phyA accumulation, which combined with a higher specific intrinsic activity of phyA and enhanced activation of inhibitors of shade avoidance prevents hypocotyl elongation in far-red rich environments (BES1 to reduce cotyledon expansion under shade (Some of the downstream targets of PIFs are transcription factors themselves . A consp (ATHB2) , which m (ATHB2) and ARFs (ATHB2) . Also, Per shade .PIF gene expression levels. For instance, prolonged exposure to low blue light enhances the expression of PIF4 targets IAAs to degradation in the proteasome and shadHFR1 to SPA4 form a complex that acts as an E3 ubiquitin ligase substrate recognition module . In the Cardamine hirsuta, which is, therefore, more stable and helps reduce shade avoidance in this shade-tolerant species , YUC5, YUC8, and YUC9 are shade induced within 15 min in cotyledons mutant deficient in auxin synthesis gene subfamily occurs 15\u201345 min after the beginning of neighbor cues, even in the pin3 pin4 pin7 and yuc2 yuc5 yuc8 yuc9 mutants shows that both conditions elicit similar hypocotyl elongation but very different reprogramming of gene expression of leaves (9-CIS-EPOXICAROTENOID DIOXIGENASE 3 and 5 (NCED3/5) expression (a rate-limiting enzyme) and higher abscisic acid (ABA) levels levels . Gene ex) levels . Whether) levels . Intrigu) levels .Medicago sp.) or sunflower which perform heliotropism to continuously reposition their leaves according to the solar position and hence of the AN3 targets GROWTH REGULATING FACTOR1 (GRF1), GRF3, and GRF5 involved in cell proliferation (CYTOKININ OXIDASE 6 (CKX6) gene involved in the breakdown of cytokinin, a response proposed to be mediated by enhanced auxin levels in leaf primordia (HOMEOBOX PROTEIN 21 (HB21), HB40, and HB53 genes and these transcription factors, together with BRC1, increase the expression of NCED3 a known 1 (BRC1) . In turnof NCED3 (FLOWERING LOCUS T (FT) and its paralog TWEEN SISTERS OF FT (TSF) . The AraFT (TSF) . As FT eed ratio . In rapied ratio by direct binding to its promoter (ORE1 expression indirectly by binding to and enhancing the expression of ABA INSENSITIVE 5 (ABI5), ENHANCED EM LEVEL (EEL) and ETHYLENE INSENSITIVE 3 (EIN3) followed by direct activation of ORE1 by these transcription factors and REPRESSOR OF ga1-3 (RGA) (ABI5 (SOM) , ABI5 (OA) (ABI5 and the I5 (SOM) , all of I5 (SOM) . Active I5 (SOM) . In addiromoters .In many areas of the planet, plants are experiencing a temperature increase that is so fast that it jeopardizes their ability to adapt. Moreover, global temperatures will continue to rise to an extent that will depend on the adoption of strong climate actions . In paraPIF4 gene (PIF4 (PIF4 promoter (PIF7 transcript (a third temperature sensor), increasing its rate of translation and hence PIF7 protein abundance , whereas warmth has little effect on expression and increases protein stability , necessary for BES1 activity , transcriptional regulators (ARFs and BES1/BZR1), and post-transcriptional regulators fulfill crucial organ- and/or environment-specific functions.The importance of shade avoidance of liquid\u2013liquid phase separation, chromatin remodeling, and carbon allocation is beginning to emerge.The activity of key components of the shade avoidance network responds not only to neighbor cues but also to temperature, water availability, salinity, and/or oxygen availability, acting as cellular integrators of above- and belowground information.To what extent is the signaling network involved in shade avoidance responses in Arabidopsis conserved in other species?What is the specific function of the negative regulators of shade-avoidance responses that increase their expression in response to neighbor cues?Which genes provide organ specificity to core shade-avoidance proteins such as PIFs or COP1?What are the patterns and mechanisms of integration of the auxin and sugar signals moving from the cotyledons to the growing hypocotyl? Is a similar convergence observed for other interorgan communication processes such as control of bud outgrowth?Is there deep signaling integration between soil resources-sensing mechanisms affected by climate change and the perception of neighbor cues by aerial organs?Can shade avoidance responses modify the impact of climate change on plants?"} +{"text": "Central line-associated bloodstream infections (CLABSI) are associated with increased morbidity, mortality, and healthcare costs. Many CLABSIs can be prevented using evidence-based care. To make this information more accessible and actionable, we developed interactive dashboards that translate data on CLABSI-related metrics and prevention efforts into visual formats that can be easily understood by healthcare professionals.A multidisciplinary work group of data analysts, infectious diseases physicians, and infection preventionists determined the content and layout of the dashboards. A query was written to extract necessary data elements from the Electronic Medical Record and NHSN. Data was then exported and used to build the dashboards using Tableau\u00ae software. The dashboard can be filtered at the facility level or at the unit level., one intensive care unit (ICU) , and one cardiovascular ICU (CVICU) . The central line standard utilization ratio (SUR) was higher for the CVICU ( >1.5), followed by the ICU (\u22481), and the general ward (< 1). Blood culture intensity (number of blood cultures collected/patient-days) was less for the general ward (< 5%), variable for the ICU (8-14%), and persistently higher for the CVICU (11%). Compliance with daily chlorhexidine bathing was higher for both the CVICU (80%) and the ICU (75%) compared to the general ward (40-60%). The CLABSI rate per 1,000 central line-days has been downtrending for the CVICU and uptrending for the ICU. Besides lower compliance with daily chlorhexidine bathing, the examined ICU has also recently shown a higher proportion of long-term devices (40%), calculated as proportion of central lines \u2265 7 days/all central lines, compared to the CVICU (25%).We present the dashboard of one general ward Dashboards should contain meaningful outcomes and standardized process metrics that are mapped to strategic goals and be timely to support prompt identification of deviations. Our CLABSI dashboards are effective tools for communicating and tracking performance data. Filtering at the unit level allows us to identify unique unit characteristics, or \u201cfingerprints,\u201d and recognize specific areas for improvement. This enables us to develop targeted interventions for each unit.All Authors: No reported disclosures"} +{"text": "Despite evidence suggesting a decline in the physical activity of middle-aged adults, 40\u201364-year-olds participation in group exercise is actually increasing. One potential reason for this increase in activity is the increase in a range of different online group exercise formats and contexts. Recent research suggests that people join, participate, and stay involved in, exercise groups that reflect who they are - a process of social identification. The purpose of this research is to qualitatively explore participants\u2019 experiences and facilitators of social identification related to the online group exercise platform known as Zwift.Zwift participants (n\u2009=\u200917) aged between 40-64 (midlife) were recruited into the study for three stages of data collection: (stage 1) an initial semi-structured interview exploring participant exercise history and use of Zwift, (stage 2) completing a two-week post exercise diary to capture their experiences of social identification after participation, (stage 3) a follow up final interview to explore topics raised over the first two data collection steps. This generated 23\u2009hours of interviews, that were then transcribed and combined with the participant diaries resulting in 468 pages of data.Reflexive thematic analysis was used to identify themes from the data. The results from this analysis indicate the following themes from the data: (1) Online exercise as an enabling facilitator of exercise identity; (2). Online exercise provides exercise identity continuity or exercise identity creation depending on the exercisers, exercise history; (3) Online exercise identification via communities goes through phases of identification; (4) Two-way communication contributes to perceptions of identification phases of identification; and (5) Social identity leadership is demonstrated by online exercisers norms, behaviours and beliefsOverall, this research highlights three key suggestions for mid-life physical activity promotion: (1) That facilitators and processes of social identification may be context specific; (2) That social identification processes should be considered in the design of online exercise; and (3) That online exercise that enables social identification should be considered as a vehicle of maintaining/ increasing exercise participationThe study was funded by the researcher."} +{"text": "Coccinella undecimpunctata Linnaeus (1758) (Coleoptera: Coccinellidae). Tens of individuals of both sexes were discovered at a single location, indicating that the species may already be established on South Georgia. Transport connectivity with this site suggests that the species most likely arrived recently from the Falkland Islands as a stowaway on a ship. We discuss the implications of our discovery for the continued development of South Atlantic biosecurity.Biological invasions represent a growing threat to islands and their biodiversity across the world. The isolated sub\u2010Antarctic island of South Georgia in the South Atlantic Ocean is a highly protected area that relies on effective biosecurity including prevention, surveillance and eradication to limit the risk of biological invasions. Based on an opportunistic field discovery, we provide the first report of an introduced ladybird beetle on South Georgia. All specimens discovered belong to the Eurasian species Coccinella undecimpunctata. The species may already be established and reproducing on the island and likely arrived from the Falkland Islands as a stowaway on a ship. This discovery has implications for the continued optimisation of South Atlantic biosecurity and global island conservation.During a scientific expedition in South Georgia, we incidentally discovered the presence of the introduced ladybird beetle The entCoccinella undecimpunctata is established in North America (Coleoptera: Coccinellidae) on South Georgia.Among the approximately 6000 described species , sex determination relied on the sexual dimorphism of the 8th abdominal segment: males have a \u201cnotch\u201d on the posterior margin of the sternite . Cutting through the posterior tip of the abdomen to expose the reproductive system enabled determination of the sex of most individuals. For a few specimens that were kept intact (2.3t\u2010tests were used to investigate if the widths of the pronotum and of the head differed between sexes. Maps of South Georgia were based on topographic data from thematicmapping.org and South Georgia GIS (2023). Figures were assembled in Inkscape . Antarctic fur seals move between the sea and their resting areas via the sampling location and a group of moulting king penguins (Aptenodytes patagonicus) was present in the vicinity. Consequently, organic debris and feathers were abundant below and between rocks in the sampled area.In January 2023, we recorded the presence of ladybirds on the southern side of Stromness Bay, South Georgia Figure\u00a0. DespiteC.\u2009undecimpunctata Linnaeus (1758). Specimens had small and elongate bodies and of the head (1.1\u2009\u00b1\u20090.05\u2009mm) \u2013 and these were not significantly related to sex (two\u2010sided Welch 4C.\u2009undecimpunctata Linnaeus (1758) on the sub\u2010Antarctic island of South Georgia. There is little doubt that the presence of this Eurasian species is due to human activity. C.\u2009undecimpunctata may be reproducing on South Georgia given the presence of both sexes and the number of individuals found relative to search effort. However, the species was detected only in a small area and not at any other sampling site on the northern peninsulas nor in King Haakon Bay and may therefore be at an early stage of biological invasion ; data curation (lead); formal analysis (lead); investigation (lead); methodology (lead); project administration (supporting); software (lead); supervision (supporting); validation (lead); visualization (lead); writing \u2013 original draft (lead); writing \u2013 review and editing (lead). Helen E. Roy: Formal analysis (supporting); validation (supporting); writing \u2013 review and editing (supporting). Peter Convey: Conceptualization (supporting); funding acquisition (supporting); investigation (supporting); methodology (supporting); project administration (supporting); writing \u2013 review and editing (supporting). Paul Brickle: Conceptualization (supporting); funding acquisition (supporting); methodology (supporting); project administration (supporting); resources (supporting); writing \u2013 review and editing (supporting). Rosemary J. Newton: Conceptualization (supporting); funding acquisition (supporting); methodology (supporting); project administration (supporting); writing \u2013 review and editing (supporting). Wayne Dawson: Conceptualization (supporting); data curation (supporting); formal analysis (supporting); funding acquisition (lead); methodology (supporting); project administration (lead); resources (lead); supervision (lead); validation (supporting); writing \u2013 original draft (supporting); writing \u2013 review and editing (supporting).The authors declare no competing interests."} +{"text": "Diabetes mellitus is defined as a group of metabolic diseases characterized by hyperglycemia, which when untreated can lead to long-term complications, including micro- and macrovascular complications. Tight glycemic control with intensive insulin therapy has been suggested to reduce the risk of such complications in several diabetes populations; however, such an approach can also be associated with risks and challenges. There are currently several modalities available to deliver insulin and monitor glucose levels to achieve glycemic goals in diabetic patients. In July 2012, the Agency for Healthcare Research and Quality (AHRQ) published a systematic review on the comparative effectiveness of insulin delivery systems and glucose-monitoring modalities in diabetic patients receiving intensive insulin therapy. Studies from 44 publications included in the review compared the effects of continuous subcutaneous insulin infusion (CSII) with multiple daily injections (MDI) and/or real time-continuous glucose monitoring (rt-CGM) with self-monitoring of blood glucose (SMBG) among children, adolescents, or adults with either type 1 (T1DM) or type 2 diabetes (T2DM), or pregnant women with pre-existing diabetes (either T1DM or T2DM). This comparative effectiveness review evaluated which modality results in improved glycemic control, less hypoglycemia, better quality of life, and/or improved clinical outcomes. The numerous technologies and the challenges that clinicians face when determining which patient population may benefit from different insulin delivery systems and glucose-monitoring approaches motivated AHRQ to synthesize the available information to assist health professionals in making evidence-based practice decisions for their patients. The review also delineates advances in insulin delivery and glucose-monitoring systems, practical methods to achieve tight glycemic control and strategies to minimize associated risks, as well as highlights gaps in research and areas that need to be addressed in the future.To (a) educate health care professionals on the findings from AHRQ\u2019s 2012 comparative effectiveness review on insulin delivery and glucose-monitoring modalities in patients with diabetes; (b) apply review findings to make treatment decisions in clinical practice; and (c) identify shortcomings in the current research and future directions relating to the comparative effectiveness of insulin delivery and glucose-monitoring modalities for patients with diabetes.The AHRQ systematic review of randomized clinical trials reveals that both insulin delivery modalities (CSII and MDI) demonstrate similar effectiveness on glycemic control and severe hypoglycemia in children and adolescents with T1DM and in adults with T2DM. In adults with T1DM, hemoglobin A1c decreased more with CSII than with MDI with low strength of evidence, but one study heavily influenced these results. In children and adults with T1DM, the use of CSII was associated with improved quality of life compared with MDI, with low strength of evidence, while there was insufficient strength of evidence to make conclusions regarding the quality of life for adults with T2DM. The study investigators suggest that the modality to deliver intensive insulin therapy can be individualized to patient preference in order to maximize quality of life. On all measured outcomes, there was insufficient or low strength of evidence regarding pregnant women with pre-existing diabetes.The AHRQ investigators found studies comparing the effectiveness of glucose-monitoring modalities in individuals with T1DM only. The systematic review demonstrates that rt-CGM is associated with greater lowering of A1c compared with SMBG (high strength of evidence) without affecting the risk of severe hypoglycemia (low strength of evidence) or quality of life (low strength of evidence) in nonpregnant individuals with T1DM, particularly when compliance with device use is high. Additional findings suggest that the use of sensor-augmented insulin pumps (rt-CGM + CSII) is superior to the use of MDI/SMBG use in lowering A1c in nonpregnant individuals with T1DM (moderate strength of evidence). Comparison of other outcome measures did not yield firm conclusions due to low or insufficient evidence."} +{"text": "Retirement from sport is a life transition that has significant implications for athletes\u2019 physical and mental health, as well as their social and professional development. Although extensive work has been done to review the retirement experiences of athletes, relatively less work has been done to examine and reflect on this expansive body of literature with a pragmatic aim of deciding what needs to happen to better support retiring athletes. This study used scoping review methodology to review current academic reviews, gray literature articles, and support programs on athletic retirement. This review followed the Joanna Briggs Institute reviewer\u2019s manual guide on scoping reviews and adhered to the PRISMA-ScR checklist. Academic articles were identified from PubMed, Embase, Web of Science and Scopus. Gray literature articles and support programs were identified using advanced Google searches. This study identified 23 academic reviews, 44 gray literature articles, and 15 support programs. Generally, the results suggest that athletic retirement encompasses a drastic shift in identity, a loss of social networks, a lack of career ambitions, and potential risks to physical and mental health. While there was a gap in the academic literature regarding practical strategies to support retiring athletes, the gray literature suggests many creative ideas. Stepwise programming may be beneficial to help athletes: (a) make sense of their athletic experience and see retirement as an ongoing process; (b) develop a well-rounded sense of self identity and understand how to apply their unique skills and strengths in new ways; (3) gain control over their retirement transition by establishing a clear plan and adjusting to new routines and opportunities; and (4) normalize the transition experience by \u201cliving in the next\u201d and building confidence in new life directions. Future research may benefit from developing and evaluating more programming to support athletes through the retirement transition. Retirement from a high-performance sport is a life transition that has significant implications for physical and mental health, as well as social and professional development . AthletiReviews of the academic literature on athletic retirement have generated mixed findings regarding the impact of retirement from sport on mental and physical health , 11, 12.Several approaches can be used to examine individuals\u2019 retirement experiences, including approaches from the field of social gerontology where retirement is seen as a career transition that results in the termination of paid work \u201326, and Regardless of the approach taken, there appears to have been extensive work done to review the retirement experiences of athletes in both academic and non-academic settings. Despite these important advancements, relatively less time has been taken to examine and reflect on the expansive body of literature, with a pragmatic aim of deciding what needs to happen next to better support retiring athletes. Despite numerous evidence syntheses, athletes still face physical, mental, and emotional struggles after retirement with a lack of appropriate supports. Though nearly every move an athlete makes is scrutinized, relatively little attention is paid to an athlete\u2019s transition to life after sport. In light of the current state of the literature, this review presents a scoping review of the athlete retirement transition experience, focusing on existing reviews of the academic and gray literature, with a pragmatic aim to improve future practices.The objective of this scoping review is to review other academic reviews, gray literature articles, and support programs that address athletes\u2019 experience transiting into life after sport, with a pragmatic aim of identifying how athletes can be supported through the retirement process. To encompass a wide range of athlete experiences, this review includes both amateur and professional athletes. This review will address the following specific questions: (1) what are the main characteristics of academic and gray literature studies that review athletes\u2019 transition experiences? (2) what does the current body of synthesized literature say about the key barriers and enablers to a successful athletic retirement transition? (3) what does the current body of synthesized literature say about the negative and positive impacts of athletic retirement? and (4) what does the current body of synthesized literature say about the programming needed to better support athletes\u2019 transition into life after sport?other reviews as our primary evidence source [We followed the Joanna Briggs Institute reviewer\u2019s manual guide on scoping reviews, with a focus on e source . We wante source .rd, 2022, with search terms related to athletes, retirement, and reviews. Results were limited to English. We ensured our search was specific enough to yield highly relevant reviews we knew we wanted to include. To find relevant gray literature sources, several targeted advanced Google searches were conducted between August and September 2022. The advanced Google searches included search terms related to athletes, retirement, and organizations that our research team identified as highly relevant . For pragmatic reasons, only the first 50 sources were used for each advanced Google search. Our full search strategy can be viewed in The search strategy was developed by the lead authors (PV and MS). To find relevant academic sources, a search of the databases PubMed, Embase, Web of Science and Scopus were conducted on July 23For our academic search, included papers were restricted to full-text, original, peer-reviewed evidence syntheses . The reviews had to focus on athletes as their primary population . We decided to include amateur and professional athletes to encompass the wide range of athletes who experience the retirement transition process. The reviews also had to have a clear focus on athletes\u2019 retirement or transition into life after competitive sport . Although we did not constrict our paper eligibility by the type of review, the review had to include a clear search strategy . For our gray literature search, advanced google searches either identified: (a) programs that support athlete transitions, or (b) non-academic articles about athlete transitions. No restrictions were put on the date or location of included sources, although certain search terms focused on American and Canadian programs specifically.Reviews from the academic database searches were handled using Covidence reference management software. Reviews were deduplicated and imported for a 2-level screening process. During level 1 screening, titles and abstracts were double screened by two reviewers (AR and LA) using the eligibility criteria. Publications with titles and abstracts not meeting the eligibility criteria were excluded. During level 2 screening, full-text papers that passed level 1 were screened by the same two reviewers (AR and LA). Studies that met the eligibility criteria were included for full data extraction. Discrepancies during level 1 and 2 screening were discussed over several meetings with final decisions on screening made by PV. Programs and articles from the gray literature search were handled using google sheets. One reviewer (JC) scanned the advanced google searches for relevant programs and articles using the eligibility criteria. The reviewer copied and pasted relevant programs and articles into a google sheet, which was then reviewed by PV. After discussion between JC and PV on the included programs and articles, the final gray literature source inclusion was finalized by PV.Data from the included academic reviews were extracted using a data extraction form that included information on reviews\u2019 title, author, year, journal, review type, study objective, databases searched, date range searched, population limitations, setting limitations, number of papers included, paper types included , paper locations, paper populations , and the key thematic constructs identified in the review. The thematic information we extracted included information on (a) the barriers and enablers of athlete retirement transitions, and (b) the negative and positive outcomes of athletic retirement. Barriers to retirement transitions and negative outcomes after retirement were indicated using a negative text symbol high athletic identity, or (-) worsening anxiety and depression). Enablers and positive outcomes were indicated using a positive sign planned retirement, or (+) relief from pressure and expectation). The data was initially extracted by one reviewer (IH) and then reviewed and refined by the lead authors (MS and PV).articles were extracted using a data extraction form that included information on the title, author, host origination, organization mission, organization location, key themes about (a) athletes\u2019 unique experiences, (b) athletes transition challenges and enablers, and (c) strategies or programs for improving the transition experience. Data from included gray literature programs were extracted using a data extraction form that included information on the title, author, host origination, organization mission, organization location, and the program\u2019s offerings for athletes . The data was initially extracted by one reviewer (JC) and then reviewed and refined by the lead authors (MS and PV).Data from included gray literature sources were extracted using two different data extraction forms. Data from the gray literature The lead author (PV) completed a descriptive analysis of the data collected from the included papers that aligned with the objectives of this review. For the academic sources, we start by presenting an overview of the review characteristics. We then present a summary of the major findings across the reviews depending on the review topic reviews that explore the general psychosocial experiences of retiring athletes, (b) reviews that specifically explore the cognitive and mental health experiences of retiring athletes, and (c) reviews that specifically explore the musculoskeletal and cardiovascular experiences of retiring athletes. For the gray literature sources, we first present an overview of the gray literature source characteristics. We then present a summary of the major themes across the gray literature sources, including summaries about (a) the unique experiences of athletes themselves, (b) athletes\u2019 experiences with retirement, specifically, and (c) support programming for retiring athletes. All reviews were published in the last 10 years (between 2013\u20132022). In total, 10 reviews explored the general retirement experiences of athletes, 8 reviews explored athletic retirement with concussion, cognitive, and mental health concerns, and 5 reviews explored athletic retirement with musculoskeletal and cardiovascular health issues. The majority of the reviews were systematic reviews (n = 20), in addition there was a scoping review (n = 1), a critical review (n = 1), and a literature review (n = 1). Most reviews combined athletes from multiple different sports (n = 14); the remaining reviews focused on soccer players (n = 5), cricket players (n = 1), rugby players (n = 1), American football players (n = 1), and gymnasts (n = 1). Most reviews included athletes from multiple countries (n = 21), however, 2 reviews specifically focused on athletes in the United States. The number of articles examined in each review ranged from 4 articles to 219 articles, with the mode being 17 articles. Most reviews included male and female participants (n = 15), with the exception of reviews that focused on females only (n = 1), males only (n = 3), or did not report on gender (n = 4). Most reviews focused on quantitative studies (n = 16); however, several reviews included multiple study designs (n = 5). Only 1 review did not report the designs of the studies they included. The majority of reviews focused on professional and elite athletes (n = 11); several reviews featured sub-elite athletes (n = 6), such as club or high school athletes, and a substantial number of reviews did not report the level of the athletes in the studies included (n = 7).We identified 23 academic reviews of literature examining the retirement transitions of athletes. A detailed description of the academic reviews included in this overarching review is provided in the Among the 10 reviews that explored the general retirement experiences of athletes, we identified numerous barriers and facilitators that affected athletes\u2019 ability to smoothly transition into life after sport. Barriers included: (1) having a high athletic identity; (2) high perfectionism and comparison; (3) athletic career dissatisfaction; (4) involuntary retirement ; (5) amount of other life changes occurring at the same time as retirement; (6) despair about future career; (7) lack of coping strategies; (8) low social support; (9) lack of transition planning; (10) education and resource dissatisfaction; (11) previous concussions; (12) raising body mass index; and (13) onset of osteoarthritis. Facilitators included: (1) having a good sport-life balance ; (2) positive self-perception and self-control; (3) athletic career satisfaction; (4) voluntariness of retirement; (5) gradual reduction of training; (6) length of time since retirement; (7) retirement planning; (8) support program involvement; (9) planned occupation after retirement ; (10) educational attainment; (11) financial planning; (12) social support network; (13) continued relationships with coaching staff; (14) strong coping strategies crisis preparedness.In addition to barriers and facilitators that affected athletes\u2019 retirement transition, we also identified numerous negative and positive impacts of athletic retirement itself. Negative impacts included: (1) worsening anxiety and depression; (2) feelings of burnout; (3) feelings of grief, loss, and void; (4) sleep disturbance and distress; (5) adverse alcohol use; (6) adverse smoking behaviours; (7) brain atrophy and dementia; (8) difficulty establishing new a lifestyle routine; (9) adverse nutrition behaviour; (10) disordered eating; (11) body dissatisfaction; (12) compensatory exercise; (13) high incidence of osteoarthritis incidence; (14) high incidence of join pain/back pain; and (15) high incidence of skin cancers. Positive impacts included: (1) relief from pressure and expectation; (2) high capacity for resilience and toughness; (3) greater or similar long-term quality of life; (4) greater capacity in certain mental proficiencies; and (5) difficulties with transition will fade over time.Among the 8 reviews that explored the relationship between athletic retirement and cognitive or mental health outcomes, several reviews examined and found that history of concussion during sport was a significant risk factor for cognitive impairment and mental health issues among retired athletes. Only one review reported mixed findings about this association . Most reAmong the 5 reviews that explored the relationship between athletic retirement and musculoskeletal and cardiovascular health issues, 4 reviews specifically focused on osteoarthritis prevalence among retired athletes, while 1 review focused on cardiovascular disease risk . Among tS3 and We identified 15 unique programs from our gray literature search that provide information about support for athletes through their athletic retirement transition. In addition, we identified 44 unique non-academic articles that describe and provide practical advice on athletic retirement transitions. Athlete retirement transition programs were based in different regions including, Canada (n = 7), the United Kingdom (n = 2), the United States (n = 2), Australia (n = 1), and South Africa (n = 1); while some programs had a clear global presence (n = 2). A full description of the programs and articles we identified in the gray literature search can be viewed in the Based on our analyses of the gray literature, 10 features emerged as unique aspects of the athlete experience: (1) living in a highly structured environment ; (2) living in a high pressure and stimulating environment ; (3) athletics is experienced as a way of life ; (4) high identity association with being an athlete ; (5) young career termination ; (6) high focus on body function and image ; (7) experiencing injury and/or significant bodily changes ; (8) large personal sacrifices during their career ; (9) unique financial situations ; and (10) gaining distinctive skillsets that can be transferable to other life circumstances .In terms of the athletic retirement transition, 10 key challenges and 5 key opportunities emerged from the gray literature. Challenges include: (1) athletic termination as a crisis ; (2) athletic retirement as a long process, not a quick event ; (3) loss of identity ; (4) lack of purpose in day-to-day life ; (5) lack of stimulation and psychological demands ; (6) loss of significant relationships ; (7) physical adaptations ; (8) financial concerns ; (9) mental health issues, ; and (10) substance use concerns. Athletes\u2019 transition opportunities relate to: (1) exploring new social networks and lifestyle opportunities ; (2) exploring other career interests ; (3) having the chance to unwind ; (4) the stamina and strength gained in athletics ; and (5) being psychologically disciplined and accountable .Factors that influence whether an athlete has a positive or negative transition experience were found to be context dependent and related to issues such as: (1) voluntariness of retirement; (2) timing of retirement; (3) duration of the transition; (4) amount of other life changes during retirement; (5) positive or negative reflections on athletic career; (6) financial and career planning for retirement; (7) fitness and dietary planning for retirement; (8) personal brand built through athletics; (9) high athletic identity association; (10) ongoing injury issues; and (11) prioritization of retirement planning.The primary themes that emerged in relation to athlete retirement transition supports include the deliverer of support, the receiver of support, the delivery mode of support, and the content of support. Regarding the deliverer of the support, many different groups provided athletes with support, including: (1) athletic organizations; (2) third-party organizations ; (3) sports psychologists and counsellors; (4) family, friends, mentors, and peers; and (5) coaching staff and other team personnel . Regarding the receiver of supports, many different groups also accepted support, including (1) athletes themselves; (2) coaching staff; (3) athletic organizations; and (4) parents, family, friends, and partners. Regarding the delivery mode of support, avenues tend to be resource-based or systems-based . Resource-based supports include: (1) resource repositories; (2) educational information; (3) employment lists; (4) extracurricular activities lists; (5) educational opportunities lists; (6) videos with education/advice; (7) podcasts sharing lived experiences; (8) speaker series sharing lived experiences; (9) social media stories; (10) assessment tools; (11) reflection workbooks; and (12) guided journaling. Systems-based provisions include: (1) person-to-person support (online or in-person); (2) email or text-based support; (3) stepwise multicomponent programming; (4) team-integrated programming; (5) small group workshops; (6) membership to a community network; and (7) conferences or retreats. Regarding the content of support, the following issues were addressed: (1) personal wellbeing; (2) identity shifting; (3) mental health; (4) social networks; (5) personal relationships; (6) career building; (7) educational development; (8) physical health; (9) diet and exercise; (10) financial planning; (11) stories about others lived experiences; (12) education about transitioning; (13) personalized sports psychology; and (14) stepwise programming.S5 Table.Stepwise programming tended to include multifaceted interventions that featured the following steps: (1) come to terms with their retirement and see the retirement transition as a process; (2) develop a well-rounded sense of self identity and understand how to apply their unique skills and strengths in a new setting; (3) gain control over their retirement transition by establishing a future plan and adjusting to new routines and opportunities; and (4) normalize the transition experience by \u201cliving in the next\u201d and building confidence in new life direction. The contents of these steps have been fully detailed in high athletic identity is consistently associated with difficulties in transitioning into life after sport. Among elite athletes, it is not uncommon for their social networks, career ambitions, physical goals, psychological stimulation, and sense of self-worth to be distinctly tied to their sport [This paper presents a scoping review of the synthesized academic and gray literature regarding athlete retirement transitions. Our analyses of review articles from the academic literature illustrate that possessing a ir sport , 36. It ir sport , 44. Their sport , 45.ended their career on a low . In line with prior research [strong athletic identity combined with a traumatic career termination puts athletes in a very difficult scenario early in their lives [In addition to the challenge of athletic identity, the academic literature highlighted an important threat for athletes who research , 46, 47,ir lives . In lineir lives \u201351, thishealthy sport-life balance over the course of their athletic career can better transition into life after sport. Developing interests outside of sport and making time to develop contingency plans for life after sport helped ameliorate the transition. A second notable enabler was that athletes who can gain a sense of perceived control over their athletic termination, and gradually reduced their athletic participation, are able to transition better into retirement. Although supporting athletes to maintain balance, plan for their retirement, and gradually detrain themselves may seem counterintuitive to sports organizations who want the most out of their current athletes, our paper indicates that athletes who plan for retirement may actually perform better while still competing.Although identity loss, career regret, and abrupt lifestyle modifications were common conditions among retiring athletes, several key factors emerged across the academic literature as enablers of positive retirement transitions. The first notable enabler was that athletes who create a While much attention has been placed on the need to enhance athlete mental health and wellbeing , 53, lescognitive impairment, mental health issues, and osteoarthritis complications [Across the synthesized literature is a consensus that retiring athletes are at a particularly high risk of experiencing ications , 7, 36. a wide range of supports from different sources in order to address different needs. Stepwise programming, where athletes work through a series of ongoing interventions to prepare for a retirement transition, emerged as a robust enabler of a positive transition experience. Gradual, longstanding, embedded investments into retirement planning may be highly advantageous for improving athlete retirement transition outcomes. Researchers and practitioners may deeply benefit from investigating the mechanisms that best support the development of a well-rounded sense of self throughout an individual\u2019s athletic career and through the retirement transition experience.Despite indicating that retirement planning facilitated a better transition to athletic retirement, a clear gap in the academic literature exists with regard to how to develop and implement specific strategies for retirement planning based on sport and level. Fortunately, much of the gray literature focuses on these specific details, suggesting a multitude of creative ideas for how to better support athletes transition into life after sport. What is clear across the gray literature is that athletes need This review is the first of its kind to examine existing review articles from academic literature as well as current evidence from gray literature on retirement from sport. Limitations of this review include that we only included studies published in English and therefore may have excluded potential studies published in a different language. In an effort to be inclusive of the existing literature on athletic retirement, our review incorporates reviews of studies that combine different types of sport, multiple geographic regions, individuals of varying gender, and combines data on professional as well amateur athletes. Retirement experiences are likely to differ based on factors like these. Future research may benefit from focusing on developing and evaluating retirement support interventions based on characteristics of the individual athlete, the sport, as well as regional variations and other contextual factors.This review scopes the current synthesized academic and gray literature on athlete retirement transitions, with a pragmatic focus on how retiring athletes can be better supported. We identified and examined 23 academic reviews of literature examining the retirement transitions of athletes, 15 unique programs from gray literature that aimed to provide information about support to athletes through their athletic retirement transition experience, and 44 distinct non-academic articles that described and provided practical advice on the athletic retirement transition. The literature illustrates that feelings of loss, identity crisis, career regret, and difficulties with abrupt lifestyle modifications are common experiences in an athlete\u2019s retirement transition. While the academic review literature presented a gap in evaluating programs that aim to ameliorate athletic retirement, the gray literature provided multiple creative ideas for how to improve programming to support athletes\u2019 transition into life beyond sport.S1 Checklist(PDF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file."} +{"text": "We review the latest information related to the control of fruit softening in tomato and where relevant compare the events with texture changes in other fleshy fruits. Development of an acceptable texture is essential for consumer acceptance, but also determines the postharvest life of fruits. The complex modern supply chain demands effective control of shelf life in tomato without compromising colour and flavour.Solanum lycopersicum) are discussed with respect to hormonal cues, epigenetic regulation and transcriptional modulation of cell wall structure-related genes. In the last section we focus on the biochemical changes closely linked with softening in tomato including key aspects of cell wall disassembly. Some important elements of the softening process have been identified, but our understanding of the mechanistic basis of the process in tomato and other fruits remains incomplete, especially the precise relationship between changes in cell wall structure and alterations in fruit texture.The control of softening and ripening in tomato ( Solanum lycopersicum) and other fruits is essential to the successful function of the modern fresh market supply chain. Substantial losses during transportation, susceptibility to post harvest diseases and limited keeping quality, result from fruits that ripen and soften rapidly. This has led to the use of a range of natural ripening mutations in commercial tomato breeding that slow the ripening and softening processes. The best known of these is the ripening inhibitor (rin) mutation. The use of the rin mutation in commercial practice has been very important in extending tomato shelf life, but it has detrimental effects on colour and flavour and downstream genes Fig.\u00a0.Fig. 1HPlant hormones, such as ethylene, act as endogenous and exogenous cues that govern the transition stage from fruit development to ripening. Extensive studies have shown that fruit ripening is modulated by a complicated network of feedback and crosstalk among different phytohormones including ethylene, abscisic acid (ABA) and auxin and ABA 8\u2032-HYDROXYLASE (SlCYP707A2) genes, which are genes involved in ABA biosynthesis and catabolism, resulted in elevated pectin levels and improved texture and shelf life and several genes encoding major cell wall catabolic enzymes were down regulated , a gene which encodes an ABA receptor, has revealed a role for SlPYL9 in regulating ABA signalling and ripening in tomato by affecting expression of ripening-related genes involved in ethylene production and cell wall modification , \u03b2-GALACTOSIDASE (Fa\u03b2GAL4) are positively regulated by ABA and negatively regulated by auxin , CELLULASE 1 (CEL1), and CELLULASE 2 (CEL2) were significantly up-regulated by ABA treatments, thus accelerating ripening in strawberry within the QTL was cloned. This FIS1 gene encodes a GA2-oxidase, an enzyme that inactivates endogenous GAs and their precursors also participate in modulating tomato fruit ripening via an interplay with ethylene. In several recent studies GA has been demonstrated to play a negative role in regulating tomato ripening. It is associated with suppression of the expression of ripening associated transcription factors and inhibiting ethylene production , and RNA methylation. Many of these events have now been shown to be associated with the progression of normal ripening and softening in tomato and other fruits subfamily played a positive role in regulating fruit softening through the activation of the same set of cell wall related genes regulated by SlHDA1/3 proteins within the polycomb repressive complex act as repressors of gene expression via histone modifications , non-ripening (nor) and Colourless non-ripening (Cnr) , ENDO--\u0392-MANNANASE 4 (LeMAN4) and \u03b1-EXPANSIN 1 (LeEXP1), CEL2, XYLAN 1,4-BETA-XYLOSIDASE1 (XYL1) was highly ripening-related. Repression of SlFSR significantly reduced the expression of multiple cell wall modification-related genes including PL, PG, TBG4, CEL2, XYL1, PECTIN ESTERASE (PE), MANNOSIDASE (MAN1), XYLOGLUCAN ENDOTRANSGLUCOSYLASE/HYDROLASE (XTH5) and EXP1, and prolonged shelf life, but did not influence other aspects of fruit ripening. These observations reveal the potential role of SlFSR in targeted control of tomato fruit shelf life by regulating cell wall metabolism TF, SlLOB1 has been shown by Shi to act as a transcriptional activator of a broad suite of cell wall\u2013related genes and to control softening were direct targets of SlHY5. However, the interplay between SlHY5 and these regulators needs further investigation in Arabidopsis (Wang et al., In a similar way to the pectin domain, disassembly of the hemicellulose and cellulose domains in the wall also appear to be a common feature of ripening in tomato and other fruits, but the contribution of these events to texture changes is even less well understood (Pos\u00e9 et al., Cell wall enzymes and other factors - In both tomato and strawberry the expression of genes encoding enzymes with PL activity has been demonstrated to be important in softening of these fruits. In the absence of PL expression, tomato fruit softened more slowly and HG was retained at cell junctions in the pericarp (Uluisik et al., The action of PL on wall mechanical properties has been studied in onion cells. Here lateral mobility of cellulose microfibrils was greatly increased at the nm-scale after PL treatment. However, concomitant effects on wall loosening and tensile properties were absent (Zhang et al., EXP1 is silenced (Brummell et al., EXP1 expression alters the extent of pectin depolymersation (Brummell et al., EXP1 has been shown to be important in tomato softening and there is an inhibitory effect on the process when SlLOB1 (Shi et al., EXP1 are strongly suppressed in SILOB1 RNA interference lines and induced in SlLOB1-overexpressing fruits. Other cell wall-related genes that show related patterns of expression in the SlLOB1 lines included CEL2 which encodes an endo-\u03b21,4-glucanase and genes encoding an alpha-xylosidase and a \u03b2-1,4 endomannase. As already mentioned, EXPs may enhance the ability of cellulase to act on cellulose microfibrils (Zhang et al., New insights into the mechanisms involved in cell wall disassembly are now coming from studies of ripening-related TFs. Shi investigated the genes impacted by suppressing or upregulating the expression of the TF"} +{"text": "Dear Editor,1][. The 2019 Lancet paper by Colvin et al.5][. The United States Food and Drug Administration (orFDA) has issued a black-box warning for this class of drug in a setting ofCABG6][. Cardinale etal.11][ study. Markham et al.12][, and the way to which can only be paved by sustainableconcepts like multimodal analgesia.The opioid-sparing links of multimodal analgesia ought to be nurtured in the present eraof ERAS with a primary patientcentric approach of an enhanced recovery in cardiacsurgery While a traditionalist might argue fddling with the position that opioids haveenjoyed in the cardiac surgery, any degree of opioid stewardship materializes fromevidence in ERAS (an evidence-based augmented patient recovery)"} +{"text": "In the original publication , ref. , corresponding microscopic model diagrams before and after growing VACNTs, respectively. Reprinted with permission from Elsevier 2023 [36].The citation has now been inserted in the caption of Figure 3 and should read: SEM images of CF: (a) adsorption and desorption curves; (b) the pore width. Reprinted with permission from Elsevier 2023 [36].The citation has now been inserted in the caption of Figure 4 and should read: BET analysis results [36] of CF with growing VACNTs in situ: (The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "Myeloid sarcoma is a rare clinical entity that presents as an isolated proliferation of leukemic cells, concurrently with or at relapse of acute myeloid leukemia (AML), myelodysplastic syndromes/neoplasms (MDS), chronic myeloid leukemia (CML), and myeloproliferative neoplasm (MPN). Myeloid sarcoma disrupts the normal architecture of its surrounding tissues. When it forms in long bones, it can cause their pathological fracture. We recently experienced a rare case of MDS presenting with myeloid sarcoma in the femur that eventually resulted in its pathological fracture. Detailed chromosomal analysis of the bone marrow cells suggested emergence of myeloid sarcoma during the fast-paced progression of MDS just after acquiring trisomy 22. A comprehensive review of previous cases of myeloid sarcoma-associated pathological fracture indicated possible involvement of structural rearrangements of chromosomes 9 and 22. Management of myeloid sarcoma should continue to improve, and clinicians should note that myeloid sarcoma with specific chromosomal alterations needs extra medical attention to prevent pathological fracture. Myeloid sarcoma is a tumor mass consisting of myeloblasts with or without maturation involving any anatomical site. Most often, myeloid sarcoma is formed in patients with acute myeloid leukemia (AML), either at the time of diagnosis, during or after chemotherapy. This medical condition is well established in AML patients with recurrent genetic abnormalities, especially in cases of core binding factor AML that are characterized by the presence of either t8;21) or inv(16) scan was immediately taken, but did not locate any origins of fever. The complete blood counts showed white blood cells (WBC) of 6,700 /\u03bcL (13% neutrophils) and platelets of 1.02\u2009\u00d7\u200910Myeloid sarcoma is a tumor composed of immature myeloid precursor cells. It sometimes develops as a de novo isolated sarcoma without bone marrow involvement . Besides, extensive review of the past literatures on myeloid sarcoma-associated pathological fractures, we have identified 18 cases that had been reported with description of the results of cytogenetic analyses. In a sharp contrast to the chromosomal alterations seen in myeloid sarcoma in general, our detailed review elucidated that the incidence of t in myeloid sarcoma with pathological fractures (8/19 cases) is considered to be much higher than expected. Thus, we suspect the potential yet vital role of chromosomes 9 and/or 22 alterations in the development of myeloid sarcoma-associated pathological fractures. Given that the present case developed myeloid sarcoma soon after the immature myeloid cells acquired additional chromosomal alteration of\u2009+\u200922 (Fig.\u00a0As shown in Table 1In summary, we have experienced a rare case of MDS presented with a myeloid sarcoma in the right femur that eventually resulted in its pathological fracture. Reviewing the past cases, the possible involvement of the rearrangements of chromosomes 9 and 22 is suspected in the occurrence of myeloid sarcoma-associated pathological fractures. To seek the optimal management of myeloid sarcomas and prevention of associated complications, clinicians are encouraged to pay extra medical attention to the myeloid sarcoma cases involving chromosomes 9 or 22 alterations."} +{"text": "This cross-sectional study assesses the prevalence of conflicts of interest (COI) associated with guideline-recommended drugs among Infectious Diseases Society of America clinical practice guideline authors and compliance with the Council on Medical Specialty Societies and Institute of Medicine guidelines. The prevalence and nature of COI among authors of infectious diseases CPGs are poorly understood. We assessed the prevalence of COI associated with guideline-recommended drugs among Infectious Diseases Society of America (IDSA) CPG authors and compliance with Council on Medical Specialty Societies (CMSS) and Institute of Medicine (IOM) guidelines.5Conflicts of interest (COI) among clinical practice guideline (CPG) authors are commonSTROBE) reporting guideline and was determined to be exempt by the HealthPartners institutional review board because it was non\u2013human participants research.In this cross-sectional study, we searched all IDSA CPGs from June 1, 2017, to March 31, 2022 (N\u2009=\u200937). We excluded guidelines not published primarily by IDSA (n\u2009=\u200917) and guidelines without recommendations regarding specific antimicrobials (n\u2009=\u200910). We identified all CPG authors, their status as chair or co-chair, disclosed relationships, and relationship time frames. We included relationships only with pharmaceutical companies that developed or sold drugs. We extracted all drugs recommended in each CPG and excluded drugs recommended only in a clinical trial or sold only outside the US. We searched US Food and Drug Administration websites to identify drug manufacturers and approval dates. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology and a pharmaceutical company if the company manufactured a guideline-recommended drug at the time of publication. Companies associated with a manufacturer as a subsidiary or acquisition were included. Conflicts of interest described in the present tense were considered active relationships and categorized as high-level COI , for the analysis.We assessed the prevalence of COI and high-level COI and guideline compliance with the following IOM and CMSS recommendations: (1) most panel members are free of COI relevant to guideline subject matter and (2) panel chairs (or \u22651 chair if co-chairs) are free of COI relevant to guideline subject matter.Clostridioides difficile infection (CDI 2018) (21), and COVID-19 2021 (12) disclosed a relationship with any pharmaceutical company, and one-third (48 of 149 [32.2%]) had 1 or more COI or high-level COI . The ant021 (12) . Most CP021 (12) . Four CP6 We also focused on the tense of disclosures in our analysis, which is vulnerable to misclassification. To ensure that IDSA CPGs remain a trusted source, improving the review and management process for CPG COI is needed.Relationships between IDSA CPG authors and the pharmaceutical industry are common. Approximately one-third of authors disclosed relationships with manufacturers of guideline-recommended drugs, and multiple IDSA CPGs were nonadherent to CMSS and IOM standards. Our findings warrant further attention considering that even the appearance of bias in CPGs can have negative consequences\u2014public distrust in science and health care, including concerns about ties between clinicians and pharmaceutical companies, has been increasing. Study limitations are that we did not assess the accuracy of COI disclosures using third-party data, which may have resulted in underreporting of COI."} +{"text": "Antimicrobial stewardship programs (ASP) have demonstrated improvement in patient outcomes, reduction of antimicrobial adverse drug events (ADE) and a decrease in antimicrobial resistance in hospitals. Antimicrobials maintain the second highest rate of ADEs in long-term care facilities. Prescribed antimicrobials in nursing homes may be unnecessary or inappropriate in upwards of 75% of cases. There is limited evidence available quantifying the impact of pharmacist-led ASP interventions in long-term care facilities. The purpose of this project is to evaluate the effectiveness of antimicrobial stewardship interventions completed at the Salisbury Veterans Affairs Health Care System Community Living Center (SVAHCS CLC).\u00ae was proposed from May 2018 to January 2021. The primary objective is to determine the effectiveness of ASP interventions in the CLC based on acceptance rate. Secondary objectives include to assess safety of select implemented CLC ASP interventions through reported ADEs within 30 days of performed CLC ASP intervention and determine potential cost savings of the implemented ASP interventions.This is a retrospective quality improvement project. Eligible subjects included Veterans residing in the SVAHCS CLC to which an ASP intervention documented in TheraDocClostridioides difficile infection. There was a total potential cost savings of $101,704.A total of 379 interventions were included. Of these interventions, 370 were accepted (98%), 5 were accepted with modification (1%) and 4 were rejected (1%). The most common ASP interventions included lab monitoring, renal adjustment, pharmacokinetic consults and duration changes. The most common indications for many ASP interventions performed were osteomyelitis, influenza and bacteremia. Vancomycin, cefepime and ceftriaxone were the most common antimicrobials involved for which ASP interventions were performed. Of the 131 interventions assessed for safety, one Veteran experienced ADEs within 30 days of the intervention including nephrotoxicity and Most Common InfectionsASP Intervention Acceptance Rate and ADEs within 30 Days of ASP InterventionThis study demonstrates that pharmacist-led ASP interventions proposed in the SVAHCS CLC were effective with a high rate of acceptance. These interventions resulted in a low rate of ADEs and potential cost savings for the facility.All Authors: No reported disclosures"} +{"text": "Nature reveals an interaction between SWI/SNF subunits and mitotic chromatin, which is essential for establishing gene bookmarks and preserving cell identity.1 The findings deepen our understanding of how SWI/SNF complexes regulate transcriptional memory heritability for cell fate commitment and polybromo-associated BAF (PBAF) complexes that were found bound to mitotic chromatin.4 Like many transcription factors, SWI/SNF subunits are expected to be degraded during mitosis.3 It is thus reasonable that SWI/SNF subunits that interact with chromatin in dividing cells may have implications for their participation in fate commitment or propagation of transcriptional blueprint. This idea may have motivated the curiosity of Zhu and colleagues to interrogate how the inheritance of somatic phenotypes is underscored by the gene expression modulatory activity of SWI/SNF subunits that linger at mitosis.1The SWI/SNF or BAF complexes are chromatin remodelers assembled on a modular basis and in a context-specific manner to dictate gene expression patterns that influence cell state and function.1 employed a biochemical fractionation strategy to investigate the presence, subcellular localization, and interaction of SWI/SNF complexes with chromatin in synchronized mouse embryonic stem cells spanning the cell cycle. It was identified that SMARCB1 and SMARCE1 were bound to mitotic chromatin, whereas other SWI/SNF subunits, including SMARCA4 (Brg1), were disengaged or residually bound. They subsequently used live cell imaging to substantiate the observation by in situ visualization of mitotic chromatin localization of SMARCB1 and SMARCE1 alongside SOX2, a classic mitotic chromatin-bound factor. The outcome of chromatin immunoprecipitation and sequencing, which was tweaked by Cut & Run sequencing approach, revealed the promoter region as the preferential genomic location of SMARCB1 and SMARCE1 in mitotic cells and BAF170 (SMARCC2) as the earliest assembled subunits of SWI/SNF complex5 may benefit expanding the range of SWI/SNF subunits involved in mitotic bookmarking and transmission of the transcriptional memory in cell cycle stages. Knowing the expression dynamics of SWI/SNF subunits driving gene bookmarking in the M-phase of lineage stem cells and cancer cells can lend therapeutic information.For future work, it would be interesting to probe the plausible contribution of SMARCC1 (BAF155) in mitotic bookmarking as it was observed bound to mitotic chromatin, although at a mild intensity."} +{"text": "Misoprostol is a prostaglandin E1 (PGE1) analogue that has been on the World Health Organization (WHO) List of Essential Medicines since 2005.Brazil has one of the most restrictive regulations in the world related to the use of misoprostol establishing it is exclusively for hospital use with special control, and sale, purchase and advertising prohibited by law.Misoprostol is currently the reference drug for pharmacological treatment in cases of induced abortion, both in the first trimester of pregnancy and at more advanced gestational ages.Misoprostol is an effective medication for cervical ripening and labor induction.Misoprostol is an essential drug for the management of postpartum hemorrhage.The use of misoprostol is recommended for the following situations: legal abortion, uterine evacuation due to embryonic or fetal death, cervical ripening before labor induction (uterine cervix maturation), labor induction and management of postpartum hemorrhage.Misoprostol 800 mcg vaginally (four 200 mcg pills) is recommended for uterine evacuation in pregnancy loss up to 13 weeks.In cervical preparation for surgical abortion at less than 13 weeks of pregnancy, the use of misoprostol 400 mcg vaginally 3-4 hours before the procedure is recommended.The use of misoprostol alone according to the gestational age for uterine evacuation is recommended for termination of pregnancy in legal abortion.The use of vaginal misoprostol according to the gestational age is recommended for uterine evacuation in case of fetal death: at 13-26 weeks, 200 mcg every 4-6 hours; at 27-28 weeks, 100 mcg every 4-6 hours; and over 28 weeks, 25 mcg every six hours.The use of misoprostol at an initial dose of 25 mcg vaginally every 4-6 hours is recommended for cervical ripening and induction of labor with a live fetus in pregnancies over 26 weeks.The use of misoprostol for cervical ripening and induction of labor with a live fetus is not recommended in women with a previous cesarean section due to the greater risk of uterine rupture.Misoprostol is a safe and effective option for women with premature rupture of membranes and unfavorable uterine cervix, as long as they do not have contraindications for taking the medication, for example, previous cesarean section.Rectal misoprostol 800 mcg is recommended as part of the drug treatment of postpartum hemorrhage.In Brazil, misoprostol should be made available to all health services at all levels of care, and it is desirable that outpatient use be allowed, when indicated.Misoprostol is a synthetic analogue of prostaglandin E1 (PGE1) with gastric secretion inhibitory and mucosal protection properties through the production of bicarbonate and mucus. It was first approved to be used to protect the stomach mucosa in patients using non-steroidal anti-inflammatory drugs.Misoprostol is a synthetic analogue of PGE1. It is metabolized in the liver, deesterified and becomes the active metabolite, misoprostol acid. It has the ability to bind to uterine smooth muscle cells, increasing the strength and frequency of uterine contractions.Although other prostaglandins can cause myocardial infarction and bronchospasm, misoprostol is not associated with these effects. Toxic doses have not been well established and cumulative doses of up to 2,200 mcg in 12 hours are well tolerated without significant adverse effects.The Food and Drug Administration (FDA) classifies misoprostol as a category X drug in the first and second trimesters of pregnancy. Animal studies have shown a significant reduction in fertility with the use of high doses (6.25 to 625 times the maximum human therapeutic dose). In pregnant rabbits, doses of 300 to 1,500 mcg/kg of misoprostol on days 7-19 of embryogenesis have been associated with teratogenic effects.Misoprostol is used for uterine evacuation in first trimester pregnancy loss. On ultrasound examination, pregnancy loss can be characterized by the following aspects: presence of gestational sac without yolk sac or embryo and with mean diameter \u2265 25 mm; embryo with crown-rump length greater than or equal to 7 mm without cardiac activity; no embryo with a heartbeat two weeks after an examination demonstrating an empty gestational sac or no embryo with a heartbeat at 11 or more days after an examination demonstrating a gestational sac with yolk sac. In these situations, three approaches are possible: expectant management, mechanical uterine evacuation, or pharmacological evacuation.Brazil has one of the most restrictive regulations related to induced abortion - induced abortion is only legally permitted in cases of pregnancy resulting from rape, risk to the woman's life and fetal anencephaly \u2013 and to the use of misoprostol in the world. In a study of countries in Africa, Asia and Latin America, Brazil was close only to Vietnam among those with greater restrictions on access to medical abortion in the world.In cervical preparation prior to surgical abortion in pregnancies over 12-14 weeks, the use of misoprostol 400 mcg 2-3 hours before surgical treatment is routinely recommended.The use of misoprostol on an outpatient basis is considered effective and safe for the treatment of induced abortion, especially in the first 12 weeks of pregnancy. The use of misoprostol during this period has minimal adverse effects, such as diarrhea, vomiting, nausea and fever, which can be easily treated by professionals outside the hospital setting.When the diagnosis of fetal death is established, the health professional assisting this pregnant woman and her family must always be able to answer the posed questions with empathy and embracement, even if there are no answers to all. A systematic review including 14 controlled and randomized studies that evaluated the use of misoprostol in fetal death in the second and third trimesters found 100% effectiveness in uterine evacuation within 48 hours.In cases of fetal death after more than 24 weeks, labor induction depends on the conditions of cervical maturation. In patients with a favorable cervix (Bishop index \u2265 6), labor induction can be started with oxytocin without the use of misoprostol for previous cervical ripening. In patients with an unfavorable cervix and without previous uterine scar, misoprostol is the agent of choice for preparing the cervix and inducing labor.25-26 weeks: misoprostol 400 mcg vaginally or sublingually every 4-6 hours;27-28 weeks: misoprostol 100 mcg vaginally or sublingually every 4-6 hours;Over 28 weeks: misoprostol 25 mcg vaginally every six hours.In patients with previous segmental scarring and unfavorable cervix at 24-28 weeks, cervical preparation can be performed with a mechanical method followed by the use of oxytocin. The use of misoprostol seems to be an acceptable alternative at this gestational age, since the risk of uterine rupture is low. In a review study in which misoprostol was used at this gestational age, the risk of uterine rupture was 0.28% (95% CI: 0.08-1.00) in patients with a previous cesarean section versus 0.04% (95% CI: 0.01-0.20) in patients without a previous cesarean section.In the labor induction process, when the situation of the uterine cervix is unfavorable, a maturation process is recommended to shorten the duration of induction and increase the chance of vaginal delivery. When the Bishop score is less than 6, the cervix is generally considered unfavorable, and mechanical and/or pharmacological methods can be used in this process.Women planning a vaginal birth after a previous caesarean section may need labor induction. There are two concerns: reduced chances of vaginal birth after caesarean section (VBAC) and increased risk of uterine rupture. Having a previous vaginal delivery and a favorable cervix are the main predictors of induction resulting in VBAC.No previous vaginal delivery \u2013 for example, in a study, the risks of rupture during TOLAC-induced in women without a previous vaginal delivery versus a previous vaginal delivery were 1.5% and 0.6%, respectively;Use of prostaglandins \u2013 induction with prostaglandins appears to be associated with a greater risk of uterine rupture than induction with oxytocin or cervical ripening with mechanical methods followed by administration of oxytocin.Risk of rupture with prostaglandin use\u2013 Data from large randomized trials and from good quality observational studies on the effects of prostaglandins alone or in combination with other agents for cervical ripening in TOLAC are not available. Much data on prostaglandin use in women with a previous caesarean section has been derived from observational studies in which misoprostol (PGE1) was used. Reports on the use of other prostaglandins, such as prostaglandin E2, are limited by their small size, the co-administration of other agents and the lack of stratification by previous vaginal delivery.Unspecified prostaglandin\u2013 Concern over the use of prostaglandins arose following the publication of a large population-based retrospective cohort study that analyzed data from 20,095 primiparous women who delivered after a single previous cesarean section.Repeat cesarean sections without labor: 1.6 ruptures per 1,000 planned repeat cesareans;Spontaneous labor: 5.2 ruptures per 1,000 spontaneous deliveries;Induced labor (without prostaglandins): 7.7 ruptures per 1,000 labors induced without the use of prostaglandins;Induced labor (with prostaglandins): 24.5 ruptures per 1,000 labors induced using prostaglandins. Compared to repeat cesarean delivery, the relative risk of rupture with the use of prostaglandins was 15.6 (95% CI: 8.1-30.0).However, despite the very large number of cases, the information in this study is from a database and individual reviews of medical records were not performed to check other medications administered. The risk of uterine rupture reported in this retrospective study was lower in another large prospective study.American College of Obstetricians and Gynecologists (ACOG \u2013United States)Society of Obstetricians and Gynecologists of Canada (SOGC \u2013 Canada)National Institute for Health and Care Excellence (United Kingdom)In conclusion, the use of misoprostol in women with previous cesarean is not recommended given the higher risk of uterine rupture. Note that mechanical methods are available, effective and safe.Premature rupture of membranes (PROM) is one of the most common complications of term and preterm pregnancies, but there is a gap in knowledge about how management affects the cesarean rate. As gestational age at delivery is the critical factor influencing perinatal outcome, expectant management is generally adopted when far from term. In PROM at term, the risk of maternal and fetal infectious morbidity increases with longer duration of membrane rupture. Therefore, expectant management should be brief, with instructions for induction of labor.Postpartum hemorrhage affects around 2% of all patients, and in only 25% of cases the risk factors are pronounced. The obstetrician must perform prophylaxis in 100% of cases and be aware of the occurrence of PPH, even if drug prophylaxis is performed. There is strong evidence that the association of uterotonics prescribed in the immediate postoperative period of childbirth reduces blood loss greater than 500 mL: ergometrine plus oxytocin and misoprostol plus oxytocin and reduces the need for blood products .Oxytocin:In post-vaginal delivery: single dose of 10 IU intramuscularly right after birth;In cesarean section: 5 IU in slow intravenous infusion in three minutes and maintenance solution ;Misoprostol: single dose of 600 mcg rectally;Ergometrine: single dose of 0.2 mg intramuscularly.For the drug treatment of PPH, the use of misoprostol 800 mcg rectally is recommended. It is important to remember that since the onset of action of rectal misoprostol is slower than that of other uterotonics, it should be used as an adjuvant to treatment with oxytocin. Misoprostol should not be used in isolation, maintaining uterine massage until the onset of its effect, which may take 15-20 minutes. Always consider the use of tranexamic acid 1 g intravenously over 10 minutes, with the possibility of repeating the 1 g dose in 30 minutes if bleeding persists.Circular letter number 182/2021 of the Office of the President of the Brazilian Federal Council of Medicine,In obstetric practice, misoprostol has been widely used in legal abortion, uterine emptying due to embryonic or fetal death, cervical ripening and labor induction, and management of PPH. Contrary to the accumulated scientific evidence, Brazil has one of the most restrictive regulations in the world related to the use of misoprostol. The great difficulty in acquiring, storing and dispensing the medication imposed by Ordinance No. 344/1998 of Anvisa, still in force, contributes to denying the right to safer outpatient treatments for women who need it. These restrictions also hinder the availability of this medication, essential and mandatory, in obstetric care services.National Commission Specialized in Childbirth, Puerperium and Abortion Care of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Alberto Trapani J\u00faniorVice-President:Alessandra Cristina MarcolinSecretarySheila Koettker SilveiraMembros:Elias Ferreira de Melo JuniorLiduina de Albuquerque Rocha e SousaMarcia Maria Auxiliadora de AquinoMirela Foresti Jim\u00e9nezRicardo Porto TedescoTenilson Amaral OliveiraNational Commission Specialized in Antenatal Care of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Fernanda Garanhani de Castro SuritaVice-President:L\u00edlian de Paiva Rodrigues HsuSecretaryAdriana Gomes LuzMembros:Jorge Oliveira VazEliana Martorano AmaralEugenia Glaucy Moura FerreiraFrancisco Herlanio Costa CarvalhoJoeline Maria Cleto CerqueiraJose Meirelles FilhoLuciana Silva dos Anjos Fran\u00e7aMarianna Facchinetti BrockMary Uchiyama NakamuraPatricia Goncalves TeixeiraRenato AjejeSergio Hecker LuzNational Commission Specialized in Gestational Trophoblastic Disease of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Antonio Rodrigues Braga NetoVice-President:Jos\u00e9 Mauro MadiSecret\u00e1rioMauricio Guilherme Campos ViggianoMembros:Bruno Maurizio GrilloChristiani Bisinoto de SousaClaudio Sergio Medeiros PaivaElaine Azevedo Soares LealElza Maria Hartmann UbertiFabiana Rebelo Pereira CostaIzildinha MaestaJose Arimatea dos Santos JuniorMaria do Carmo Lopes de MeloRita de Cassia Alves Ferreira SilvaSue Yazaki SunTiago Pedromonico ArrymNational Commission Specialized in High Risk Pregnancy of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Rosiane MattarVice-President:Alberto Carlos Moreno ZaconetaSecretaryMylene Martins LavadoMembros:Arlley Cleverson Belo da SilvaCarlos Alberto MaganhaElton Carlos FerreiraFelipe Favorette CampanharoInessa Beraldo de Andrade BonomiJanete VettorazziMaria Rita de Figueiredo Lemos BortolottoFernanda Santos GrossiRenato Teixeira SouzaSara Toassa Gomes SolhaVera Therezinha Medeiros BorgesNational Commission Specialized in Fetal Medicine of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Mario Henrique Burlacchini de CarvalhoVice-President:Jos\u00e9 Antonio de Azevedo Magalh\u00e3esSecretaryRoseli Mieko Yamamoto NomuraMembros:Alberto Borges PeixotoCarlos Henrique Mascarenhas SilvaCarolina Leite DrummondEdward Araujo J\u00faniorFernando Artur Carvalho BastosGuilherme Loureiro FernandesJair Roberto da Silva BragaJorge Fonte de Rezende FilhoMarcello Braga ViggianoMaria de Lourdes BrizotNadia Stella Viegas dos ReisReginaldo Ant\u00f4nio de Oliveira Freitas J\u00faniorRodrigo RuanoNational Commission Specialized in Maternal Mortality of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Marcos Nakamura PereiraVice-President:Rodolfo de Carvalho PacagnellaSecretaryMelania Maria Ramos de AmorimMembros:Acacia Maria Louren\u00e7o Francisco NasrDouglas Bernal TiagoElvira Maria Mafaldo SoaresFatima Cristina Cunha PensoIda Perea MonteiroJo\u00e3o Paulo Dias de SouzaLucila NagataMaria do Carmo LealMonica Almeida NeriMonica Iassan\u00e3 dos ReisJacinta Pereira MatiasPenha Maria Mendes da RochaNational Commission Specialized in Obstetric Emergencies of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Alvaro Luiz Lage AlvesVice-President:Gabriel Costa OsananSecretarySamira El Maerrawi Tebecherane HaddadMembros:Adriana Amorim FranciscoAlexandre Massao NozakiBrena Carvalho Pinto de MeloBreno Jos\u00e9 Acauan FilhoCarla Betina Andreucci PolidoEduardo CordioliFrederico Jose Amedee PeretGilberto NagahamaLaises Braga VieiraLucas Barbosa da SilvaMarcelo Guimar\u00e3es RodriguesRodrigo Dias NunesRoxana KnobelNational Commission Specialized in Sexual Violence and Pregnancy Interruption Provided for by Law of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Robinson Dias de MedeirosVice-President:Cristi\u00e3o Fernando RosasSecretaryHelena Borges Martins da Silva ParoMembros:Aline Veras Morais BrilhanteAnibal Eus\u00e9bio Fa\u00fandes LathamD\u00e9bora Fernandes BrittoEdison Luiz Almeida TizzotIsabelle Cantidio Fernandes DiogenesKenia Zimmerer VieiraMichele Lopes PedrosaOsmar Ribeiro ColasRivaldo Mendes de AlbuquerqueRosires Pereira de AndradeSuely de Souza ResendeZelia Maria CamposNational Commission Specialized in Professional Defense and Appreciation of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Maria Celeste Osorio WenderMembros:Carlos Henrique Mascarenhas SilvaEtelvino de Souza TrindadeHenrique Zacharias Borges FilhoJuvenal Barreto Borriello de AndradeLia Cruz Vaz da Costa Dam\u00e1sioMaria Rita de Souza MesquitaMirela Foresti Jim\u00e9nezSergio Hofmeister de Almeida Martins CostaCelia Regina da SilvaAljerry Dias do RegoRosires Pereira de AndradeMaria Auxiliadora BudibCarlos Alberto Sa MarquesHilka Flavia Barra do Espirito Santo Alves Pereira"} +{"text": "The current systematic review sought to identify quantitative empirical studies that focused on the transdiagnostic factors of intolerance of uncertainty, emotional dysregulation and rumination, and their relation with depression and post-traumatic stress disorder (PTSD). The overall research aim was to examine the relationship between these transdiagnostic factors and their relation with depression and PTSD symptoms. The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Out of the 768 articles initially identified, 55 met the inclusion criteria for the current review. The results determined that intolerance of uncertainty is indirectly related to depression and PTSD symptoms, mainly through other factors including emotion dysregulation and rumination. Additionally, emotional dysregulation is a significant predictor of both depression and PTSD symptoms. Rumination is a robust factor related to depression and PTSD symptoms, this relationship was significant in cross-sectional and longitudinal studies. This review provides evidence on the transdiagnostic factors of intolerance of uncertainty, emotional dysregulation and rumination in the relationship with depression and PTSD symptoms. Depressive, anxiety, and substance use disorders are among the leading contributors to the global disease burden lack of awareness, understanding, and acceptance of emotions; (b) the inability to control behaviors when experiencing emotional distress; (c) lack of access to situationally appropriate strategies to modulate the duration and/or intensity of emotional responses to meet individual goals and situational demands; and (d) unwillingness or reluctance to experience emotional distress as part of seeking meaningful activities in life guidelines Empirical quantitative research reports published in a peer reviewed journal (2) Written in English or Spanish language, (3) Outcome measures related to depression or PTSD symptoms or diagnosis. Studies were excluded if the following criteria was met: (1) No depression or PTSD outcome measure, (2) No rumination, intolerance of uncertainty or emotional dysregulation measure, (3) Not depression PTSD comorbidity, (4) Children or adolescent sample, (5) Insufficient or inappropriate data reported , specifically USA (21 studies), and Canada (3 studies). Followed by 25.5% from European countries, 16.4% from Asia including China (4 studies), Japan (1 study), India and Iran (2 studies each), 7.2% from Oceania particularly, Australia (4 studies), and 7.2% from South America including Argentina (2 studies), Colombia and Chile (1 study each). Community-based studies were the most frequent type (39%), followed by undergraduate student sample (27.1%), clinical sample (18.6%), and trauma exposed sample (15.3%). Most of the studies were cross-sectional (66.1%), followed by longitudinal (28.6%) and a minority were experimental (5.4%).Eleven studies examined the relation between intolerance of uncertainty and depression symptomatology. Empirical evidence indicates that intolerance of uncertainty is a significant predictor of depression symptoms, even when anxiety symptoms where accounted for (Barry et al., Six studies that examined the relation between intolerance of uncertainty and PTSD symptoms. This evidence indicates that intolerance of uncertainty is a significant predictor of PTSD symptoms. These result remained significant even after covarying for other PTSD risk factors including: rumination, neuroticism, and worry (Boelen et al., When the relation between intolerance of uncertainty and PTSD symptoms DSM-V clusters was examined, there was a significant association to the avoidance, hyperarousal and emotional numbing symptom clusters (Oglesby et al., We identified 8 studies that assessed the relation between emotion dysregulation and depression symptoms. Results indicated that emotion dysregulation was positively associated with depressive symptoms, even when controlling for baseline mindfulness (Diehl et al., Seven studies assessed the relation between emotional dysregulation and PTSD symptoms. Longitudinal assessments found that emotional dysregulation was significantly associated with the probability of developing PTSD symptoms 4\u00a0months later (Fujisato et al., Thirteen studies examined the relation between rumination and depression symptoms. Results from longitudinal associations indicated that rumination predicts depressive symptoms and that depressive symptoms predict rumination at 4-year follow-up (Whisman et al., Ten studies examined the relation between rumination and PTSD. Repetitive and anticipatory rumination moderated the relationship between PTSD and MDD symptoms (Roley et al., The current systematic review sought to identify quantitative empirical studies that focused on the transdiagnostic factors of intolerance of uncertainty, emotional dysregulation and rumination, and their relation with depression and/or PTSD. This review identified 55 studies that reported the association between the transdiagnostic factors of interest in depression and PTSD symptoms.Intolerance of uncertainty was a consistent significant predictor for both depression and PTSD symptoms, as suggested by other authors (McEvoy et al., Emotional dysregulation has been found to relate to depression as well as many other psychiatric symptoms including PTSD (Aldao et al., Rumination is an important factor related to the maintenance and exacerbation of depression and PTSD symptoms (Olatunji et al., This systematic review had a number of limitations that should be taken into account when interpreting the results and addressed in future research. First, even though studies in Spanish were included in an attempt broaden the scope, the majority of the studies were conducted in North American and European countries. Furthermore, taking into consideration the evidence that culture may play a significant role in the manifestation of psychopathology Rathod, , the resThis review provides evidence that the transdiagnostic factors of intolerance of uncertainty, emotional dysregulation and rumination are consistent significant predictors for both depression and PTSD symptoms. Particularly, intolerance of uncertainty is indirectly related to depression and PTSD symptoms through other factors including emotion dysregulation and rumination. Meanwhile, emotional dysregulation is a significant predictor of both depression and PTSD symptoms. Rumination is a robust factor related to depression and PTSD symptoms, this relationship was significant in cross-sectional and longitudinal studies. Both emotional dysregulation and rumination can mediate the relationship between several risk factors including intolerance of uncertainty and depression and PTSD symptoms. This study provides insight into understanding these factors in the onset and maintenance of depression and PTSD symptomatology. Consequently, contributing to the evidence that allows the development of theoretical and empirically supported transdiagnostic models. Which may ultimately promote the development of cost-effective treatments that targets underlaying mechanism or factors, thus promoting preventative alternatives for multiple disorders."} +{"text": "Motivation is an important factor in therapy and potentially even more so in an online setting. Earlier research shows that more autonomously motivated patients have better outcomes and completion rates than more controlled motivated patients\u00b4. However, little is known about how motivation type influences treatment effect in an online setting and in patients with binge eating disorder specifically.This study set out to investigate how motivation type as per the Self-Determination Theory would affect treatment adherence and effect in a sample of 148 patients, undergoing an Internet-based Cognitive Behavioral Therapy (iCBT) for BED.The study was mixed-methods. A sample of 148 patients gave two written qualitative statements regarding their motivation for seeking treatment and reasons for choosing online therapyThe statements were transformed into quantitative units via the condensation method. The themes were categorized according to the model by Ryan and Deci based on level of autonomy and perceived locus of causality.This was compared with completion rate and outcomes on eating disorder symptomatology. Completion was designated into three groups. Low adherers - less than six sessions (n=54), high adherers \u2013 between 7 and 10 sessions (n =56) and full adherers - 10 session plus follow up (n=37).The effect of the treatment was measured via the Eating Disorder Examination Questionnaire (EDEQ) and Binge Eating Disorder Questionnaire (BEDQ).Perceived locus of causality and level of autonomy, did not affect level of adherence or outcome of treatment in either setting. This unexpected result may suggest that internet-based therapy is less dependent on motivation types, when comparing with face-to-face treatment.None Declared"} +{"text": "Correction to: Japanese Journal of Radiology (2021) 39:84\u201392 10.1007/s11604-020-01040-1In the original publication, the last sentence under heading Patients in section Materials and methods should read as:All patients gave written informed consent for the procedure.The revised Ethical approval statement should read as:Ethical approval All procedures performed in these studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments. All patients gave written informed consent for the procedure. The institutional review board of our hospital approved retrospective data analysis."} +{"text": "After this article was published, similarities were noted between this article and submIn response to queries about these concerns, the corresponding author provided the underlying data in During editorial follow-up, the following errors in article were notThere are two instances in The Nakano study involvedThe Lehmann study T stage The Matrana study T stage In Table 1:The univariate analyses instead of the multivariate analyses from Kubackova\u2019s research [An expert statistical reviewer assessed the updated PLOS ONE Editors issue this Expression of Concern.The concerns about specific results were resolved in discussions with the authors and reviewer, and the dataset received from the authors provides a level of assurance as to the provenance of this work. Nevertheless, PLOS remains concerned about similarities between and otheS1 File(XLSX)Click here for additional data file.S2 File(XLSX)Click here for additional data file.S3 File(CSV)Click here for additional data file."} +{"text": "There is a large gap between the need for anticoagulation and the use of drug therapy for this purpose in ambulatory care. Major lower-extremity orthopedic surgery such as total hip replacement and total knee replacement are associated with an increased risk of venous thromboembolism (VTE). Anticoagulant prophylaxis is necessary to reduce the risk of deep vein thrombosis (DVT), which may progress to symptomatic outcomes such as pulmonary embolism (PE). Prophylaxis and treatment of patients with symptomatic VTE occurs in 2 phases. Initial therapy focuses on rapid achievement of effective anticoagulation and usually involves subcutaneous low-molecular-weight heparin. Long-term prophylaxis with the vitamin K antagonist, warfarin, reduces the risk of recurrent VTE from about 27% (without prophylaxis or inadequate prophylaxis) to 4% during the first 3 months of observation."} +{"text": "Malnutrition is a common condition in cancer patients which is usually associated with functional limitations, as well as increased morbidity and mortality. Based on the support of the young sections of Italian Association of Medical Oncology (AIOM), Italian Association of Radiotherapy and Clinical Oncology (AIRO) and Italian Society of Surgical Oncology (SICO) merged into the NutriOnc Research Group, we performed a multidisciplinary national survey with the aim to define the awareness of nutritional issues among healthcare professionals delivering anticancer care. The questionnaire was organized in four sections, as follows: Knowledge and practices regarding Nutritional Management of cancer patients; Timing of screening and assessment of Nutritional Status; Nutritional Treatment and prescription criteria; Immunonutrition and educational topics. The modules focused on esophagogastric, hepato-bilio-pancreatic and colorectal malignancies. Overall, 215 physicians completed the survey. As regards the management of Nutritional Status of cancer patients, many responders adopted the ERAS program (49.3%), while a consistent number of professionals did not follow a specific validated nutritional care protocol (41.8%), mainly due to lack of educational courses (14.5%) and financial support (15.3%). Nearly all the included institutions had a multidisciplinary team (92%) to finalize the treatment decision-making. Cancer patients routinely underwent nutritional screening according to 57.2% of interviewed physicians. The timing of nutritional assessment was at diagnosis (37.8%), before surgery (25.9%), after surgery (16.7%), before radiochemotherapy (13.5%) and after radiochemotherapy (7%). Most of the responders reported that nutritional status was assessed throughout the duration of cancer treatments (55.6%). An important gap between current delivery and need of nutritional assessment persists. The development of specific and defined care protocols and the adherence to these tools may be the key to improving nutritional support management in clinical practice."} +{"text": "Sussex cattle breed is characterized by their distinctive solid red coat colour and white tail switch. Sussex cattle are known for being easy to handle and manage, making them an ideal choice for cattle farmers. The phenotypic characterization of this cattle breed in South Africa is unknown. Hence, the objective of this study was to characterize the morphological structure, phenotypic and body indices traits of Sussex cattle in South Africa at Huntersvlei farm, Frere State province of South Africa. One hundred and one weaners (n = 101) between 6 and 8 months old and fifty yearlings between 12 and 15 months old were used in this study. Body weight at weaning, yearling and linear body measurements such as head length (HL), head width (HW), ear length (EL), ear width (EW), sternum height (SH), withers height (WH), heart girth (HG), hip height (HH), body length (BL), rump length (RL), and rump width (RW) were measured. Moreover, the animals were assessed for coat colour and horn presence. Descriptive statistics, Pearson\u2019s correlation and Principal Component Analysis (PCA) were used to describe the Sussex cattle breed. The results indicated that male Sussex cattle had highly significant (p < 0.01) mean numeric values for the BW and morphometric traits. The results further showed that Sussex cattle had highly significant (p < 0.01) increase for the BW and morphometric traits as age advances in all sexes. Interaction effect of sex and age showed a highly significant (p < 0.01) effect with BW and measured morphometric traits, while moderately significant (p < 0.05) with EW. Male Sussex cattle showed highly significant (p < 0.01) higher mean numeric values for the body index (BI), length index (LI) and compact index (CI) indices. While female Sussex animals showed highly significant (p < 0.01) mean numeric values for area index (AI) and proportionality (PR). Body weight showed a positive highly significant (p < 0.01) correlation with the measured morphometric traits except for the moderate significant (p < 0.05) correlation with EL. Coat colour traits ranged from 15 (9.93%), 103 (68.21%) to 33 (21.85%) for light, moderate and dark colours, respectively. While horn presence traits ranged from 48 (31.79%), 42 (27.81%) to 61 (40.40%) for polled, scur and horned respectively. The PCA results extracted only two components in both sexes of the animals. The morphological variations obtained in this study could be complemented by performance data and molecular markers of single nucleotide polymorphism (SNP) to guide the overall breed characterization, conservation and development of appropriate breeding and selection strategies. Livestock plays an important role in the social, economic and cultural stability of rural households in many parts of the world . MASA 22 reporteThe experimental procedures were conducted following the University of South Africa (UNISA) Ethics code for the use of live animals in research, ethics reference number: 2022/CAES_AREC/171.This study was conducted at Huntersvlei farm also known as Rhys Evans Group (RE) in the Free State Province, South Africa. The farm is situated in Viljoenskroon, Fezile Dabi municipality; the site, temperatures, latitudes, longitude, and rainfall of the study area similar as described by Bila . HuntersAll the animals used in the study were exposed to a traditional management grazing system which allows animals to freely graze in the camps during the day and afternoon. Fresh clean water was always available in the camps. Animals received a routine inspection and dipping for herd health management purposes. The linear body measurements were taken while the animal was in a standing position with head raised up and weighed on all four feet. A functional handling facility with a crowding pen, working crush and head clamp was used for handling the animals to minimize movement during the measuring process.Morphometric traits and live body weight at two different stages were taken. The first stage was at weaning age in one hundred and one (n = 101) South African Sussex weaner animals between 6 and 8 months old. Second stage yearling age is 50 South African Sussex yearling animals are between 12 and 15 months old. The animals used in the study at weaning age were between six to fifteen months old. The live body weight at the two stages was measured using a balance weighing scale whereas linear body measurements were measured using a measuring tape calibrated in centimetres (cm). The body weight at weaning, yearling and morphometric traits, namely head length (HL), head width (HW), ear length (EL), ear width (EW), sternum height (SH), withers height (WH), heart girth (HG), hip height (HH), body length (BL), rump length (RL), and rump width (RW) were measured following the guideline defined by Lomillos and Alonso , Tyasi eTo prevent individual variations in measurements, only one individual was taking the body weight and morphometric traits. The horn presence was assessed using three point scale following the guidelines reported by Grobler et al. . Moreove2) test was used to find the significant difference on qualitative traits. Procedure of correlation (PROC CORR) was used to determine Pearson\u2019s correlation matrix. These analyses were then followed by a principal component analysis (PCA) to reduce the dimensionality of the morphometric data using the procedure of principal component (PROC PRINCOMP and PROC FACTOR). Furthermore, to examine the morphometric traits and body indices that have the most discriminating power the stepwise discriminant analysis was applied using the STEPDISC procedure (PROC STEPDISC). The significant difference was observed at P<0.05 and highly significant at P<0.01.The Statistical Analysis System version The overall summary of the collected data discoverMeans and standard deviation for the sex effect on body weight and morphometric traits is given in The overall summary of the collected data discoverMeans and standard deviation for the overall sex effect on body indices is given in In females, the BI showed a positive highly significant (p < 0.01) correlation with LI, while moderately significant (p < 0.05) correlated with PI and insignificant (p > 0.05) correlated with CI . PI showThe overall summary of the collected data discoverThe frequency and percentage of coat colour and horn presence observed in males and females of Sussex cattle at Huntersvlei farm population are presented in The frequency and percentage of coat colour and horn presence observed in males and females of Sussex cattle at Huntersvlei farm populations are presented in The predicted factor loading extracted by factor analysis, eigen-values and variation explained by each factor are presented in The CDA for morphometric traits of South African Sussex cattle are presented in The CDA for body indices traits of South African Sussex cattle are presented in This study was exclusively based on specific phenotypic and morphometric traits of Sussex cattle at Huntersvlei farm in the Free State, Province, South Africa. Phenotypic variation of local animal resources shows a genetic diversity that may be worth conserving for future uses while better understanding of the external features assists to facilitate the implementation of conservation policies intended to ensure local resources survival . FirstlyFurthermore, the results of the study showed that the coat colour both in male and female populations had a highly significant effect with males showing a maximum incident of dark coat colour while females showing a maximum incident moderate coat colour. On the other hand, the horn presence showed a significant effect amongst the sexes with males showing a maximum occurrence of horn presence and females showing a maximum occurrence of polledness. Bila and Tyasi showed tThe importance of morphological characterization of cattle breed\u2019s genetic resources cannot be emphasized. The present study is based on morphometric and certain phenotypic traits of Sussex cattle at Huntersvlei farm in South Africa. The study findings displayed the morphological and phenotypic variations between ages and genders of the Sussex cattle breed at Huntersvlei farm. It was found that the Sussex cattle breed in the study area have developed some diverse phenotypic traits such polled, scur and horns. Moreover, the Sussex cattle at Huntersvlei farm showed that the male animals had a much darker red brown colour in comparison to female animals. The correlation results shown that in male BW had highest positive association with HH, BL and WH and hence can be used as markers to predict BW using regression equations. The extracted principal components from different morphometric traits symbolize the general body size and shape of the Sussex cattle population at Huntersvlei farm. Stepwise canonical discriminant analysis showed that head width, head length, hip height, sternum height, heart girth and rump width are the suitable discriminating morphometric traits in the Sussex cattle breed. Furthermore, an investigation on the molecular characterization using molecular markers SNP will complement the results obtained from morphometric variation. Lastly these findings might be helpful in breed characterization, conservation and developing breeding and selection strategies.S1 FileIt is an Excel file with variables fully explained in column P and Q of the sheet.(XLSX)Click here for additional data file.S2 FileIt is an Excel file with variables fully explained in column E, F and G of the sheet.(XLSX)Click here for additional data file."} +{"text": "Based on studies showing the use of autologous skin cell suspensions (ASCS) leads to burn wound closure with significantly smaller amounts of harvested donor skin, the Food and Drug Administration approved the first ASCS for the reconstruction of thermal injuries in September, 2018. The benefit of needing less donor skin to heal a given soft tissue wound has led to off-label usage of ASCS in a variety of clinical situations, such as necrotizing soft tissue infections (NSTI), toxic epidermal necrolysis (TEN), and traumatic injuries with soft tissue loss among others. Here, we report on a single-institution case series of ASCS usage for closure of soft tissue wounds caused by nonthermal mechanisms.We performed a retrospective chart review of all patients treated with ASCS for an indication of non-thermal soft tissue wounds at our American Burn Association-verified academic burn center between April 1, 2018 to June 1, 2022. Descriptive demographic data were collected.+ 17 yrs, mean length of stay 46 + 30 days) were found to have undergone closure of their wounds using ASCS during the time period of the chart review. Indications were NSTI (n=2), frostbite (n=2), antiphospholipid syndrome (n=2), and TEN (n=2). ASCS was used as a sole therapy for the TEN patients while ASCS was used in combination with meshed autografting for all other patients. The mean size of wounds treated with ASCS was 2835 + 2670 cm2, and the mean ASCS take rate was 86 + 7%. No ASCS-related complications were found.Eight patients (6 male/2 female, mean age 57 These results bolster the off-label use of ASCS solutions for closure of nonthermal wounds while the surgical world awaits the results of an ongoing Phase III trial on this questionThis study seeks to contribute to the literature supporting off-label uses of ASCS in non-thermal injuries & diseases."} +{"text": "The chest bone, or sternum, protects the heart and lungs and aids in breathing motion. It is included on chest radiographs of dogs and cats, but little information is available for veterinarians on what abnormalities or diseases affect the chest bone in companion animals. We reassessed chest radiographs of dogs and cats taken in our hospital over a 2 year period to describe these changes. We found that abnormalities of the chest bone were visible in 24% of dogs and 29% of cats, with the most common abnormality being age-related degeneration. Most of the abnormalities noted were of minor clinical importance, but in some animals, conditions that could be painful or otherwise affect well-being were seen.Evaluation of the sternum is part of the routine examination of small animal thoracic radiographs. However, descriptions on frequency and type of abnormalities are lacking. This retrospective observational study aimed to describe abnormal radiographic findings of the sternum in a cross-section of client-owned dogs and cats undergoing thoracic radiography between 1 January 2019 and 1 January 2021 for reasons unrelated to diseases of the sternum. The study population consisted of 777 dogs and 183 cats . Sternal abnormalities were observed in 189/777 (24%) dogs and 53/183 (29%) cats, mostly around the intersternebral cartilages, accounting for 32/80 (40%) dogs and 20/35 (57%) cats. This was followed by an abnormal number of sternal segments . Pectus excavatum was observed in 6/777 (0.8%) dogs and 6/183 (3%) cats, and pectus carinatum in 18/777 (2%) dogs and 2/183 (1%) cats. Post-traumatic changes, such as subluxation, were observed in nine dogs (1.1%) and three cats (1.6%). Presumed prostatic carcinoma metastasis and malignant lymphoma were observed in two dogs (0.2%). Incidental radiographic sternal abnormalities are common in cats and dogs but mostly of unknown clinical relevance. An evaluation of the sternum is part of the routine examination of small animal thoracic radiographs, as it forms the ventral contour of the thoracic cavity. The sternum contributes to the bony protection of the intra-thoracic cardiopulmonary structures, as well as to the stability and breathing motion of the thorax.manubrium sterni), is wider and longer than the other sternal segments. The manubrium of the sternum is the point of insertion of the sternocephalicus muscle and has lateral shelves of bone accommodating the attachment of the costal cartilages of the first pair of ribs. The body of the sternum (corpus sterni) consists of six rectangular to cylindrical-shaped sternebrae. The most caudal last sternebra, or xiphoid process (processus xiphoideus), is flat and long, occasionally with a foramen in its caudal half. The xiphoid process is prolonged caudally by the xiphoid cartilage (cartilago xiphoidea), which supports the cranial part of the ventral abdominal wall and from which the linea alba extends caudally to the symphysis pelvis. The individual sternebrae are connected by intersternebral cartilages, forming cartilaginous joints , and the sternum is covered on the ventral and dorsal surface by thickened periosteum, forming the sternal membrane (membrana sterni). Whilst the costal cartilages of the first pair of ribs articulate directly with the manubrium of the sternum, the costal cartilages of the second to seventh ribs articulate with the consecutive intersternebral cartilages between the individual sternal segments, and both the costal cartilages of the eighth and ninth rib pairs articulate with the intersternebral cartilage between the seventh sternebra and the xiphoid process. The first eight paired sternocostal joints are synovial joints, but no synovial joint was found at the ninth sternocostal articulation The costal cartilages of the last four pairs of ribs do not directly articulate with the sternum but connect via the costal arch or are floating ribs, and these ribs are therefore considered asternal ribs ) if normally distributed or as median (range) if the distribution was skewed. Data were analyzed using IBM SPSS Statistics (Version 28). Independent samples n = 145), Labrador Retriever (n = 62), Chihuahua (n = 28), Bernese Mountain Dog (n = 26), Golden Retriever (n = 23), French Bulldog (n = 23), Labradoodle (n = 22), and German Shepherd (n = 21). One hundred and fourteen dogs were of brachycephalic breed. The three most common indications for thoracic radiography in dogs were metastasis screening (n = 252), cough (n = 94), and dysphagia (n = 57). An example of a thoracic radiographs of a dog on which the sternum was considered unremarkable is provided in The study population consisted of 777 dogs. The group of dogs had a mean age of 7.3 years and consisted of 400 males (188 neutered) and 377 females (252 neutered) of various breeds, the most common being mixed breed (n = 8), post-traumatic changes (n = 5) or shape deformity of the sternum (n = 1), and an abnormal number of sternebrae in combination with shape deformity (n = 4) or post-traumatic changes (n = 1).Sternal abnormalities were observed in 189/777 (24%) dogs . Nineteen = 108; 14%), most of which were considered degenerative type changes such as mineralisation of the sternal cartilages or formation of bony spurs . Marked degenerative changes, such as narrowing of the intersternebral cartilage space (n = 13), vacuum phenomenon (n = 13), and subluxation (n = 5), were mainly observed in the mid-section of the sternum, between the 3rd and 4th and 4th and 5th sternebrae (n = 16). The mean age of dogs with degenerative changes was significantly higher than the mean age of dogs without these changes .Abnormalities were most frequently observed in the area of the intersternebral cartilages in dogs . Less than eight sternal segments were observed 46 dogs (6%): seven sternebrae were visible in 40 dogs, six sternebrae in four dogs, and three and four sternebrae in one dog each. The latter resulted in morphologically abnormal short sternum (n = 5) or four (n = 2) sternebrae. Three dogs with lower number of sternebrae showed border effacement of the ventral thoracic diaphragmatic surface and the caudal ventral cardiac silhouette due to cranial excursion of the diaphragm, but none of these animals had evidence of peritoneopericardial herniation. Supernumerary sternal segments were observed in 16 dogs (2%), affecting predominantly medium and large breed dogs. The most common breed affected was Labrador Retriever (n = 7).An abnormal number of sternal segments was the second most seen abnormality in dogs ( sternum . The lown = 8) and Chihuahua (n = 5) were overrepresented.Pectus excavatum was observed in six dogs (0.8%), and the severity was considered mild in five dogs and moderate in one dog based on vertebral indices . Pectus excavatum involved the caudal sternum in five cases and the mid-sternum in one mixed breed dog. One case was considered likely to have a traumatic instead of congenital origin based on clinical history. Four of the five dogs with suspect congenital pectus excavatum were brachycephalic breeds, including two out of seven Pugs . Mild pen = 9, of which five were in combination with other degenerative changes) (Presumed post-traumatic changes were observed in 12 dogs (1.5%), although none of these dogs were presented for thoracic radiography because of a history of trauma or suspect traumatic lesions of the sternum; the indication in eight of these dogs was metastasis screening. The presumed post-traumatic changes mainly consisted of dislocation (changes) . These cOne Chihuahua with malignant lymphoma had multiple pathological fractures associated with osteopenia . An aggrn = 112), Maine Coon (n = 16), mixed breed (n = 11), and British Shorthair (n = 10). The most common indications for thoracic radiography in cats were dyspnea (n = 40), metastasis screening (n = 37), and post-accident trauma (n = 18). An example of a thoracic radiographs of a cat on which the sternum was considered unremarkable is provided in The study population consisted of 183 cats. The group of cats had a mean age of 7.3 years and consisted of 105 males (89 neutered) and 78 females (66 neutered) of various breeds, most commonly Domestic Shorthair (n = 3) or degenerative changes (n = 3).Sternal abnormalities were observed in 53/183 (29%) cats . Six catp = 0.002). Concurrent gas opacity in the intersternebral cartilage space or associated subluxation of sternebrae was not observed in any of the cats with signs of degenerative changes of the intersternebral cartilages.Degenerative changes, consistent of mineralization of the sternal cartilages or formation of bony spurs, were observed in 15 cats (8%). Cats with degenerative changes were significantly older than those without or sixth and seventh sternebrae (n = 5). The other nine cats with seven sternebrae had an absence of one sternal segment. One Domestic Shorthair had six individual sternebrae, caused by complete fusion of the fourth and fifth sternebrae and the absence of one sternal segment , of which seven cats had nine sternebrae. Nineteen cats had seven individual sternal segments, which, in ten cats was caused by complete fusion of the first and second sternebrae ( segment .Pectus excavatum was observed in six cats (3%), and the severity was considered mild in four cats and moderate and severe in one cat each . The typn = 2), partial fusion of sternebrae (n = 3), and narrowing of the intersternebral cartilage space without signs of degeneration (n = 1).Signs of traumatic luxation were observed in three cats (1%). One cat had undergone recent cardiopulmonary resuscitation, and the other two cases showed more chronic changes with malformed fusion of the dislocated sternebrae. One of these cats had a history of sternal fracture 10 years prior and the other cat had no known history of trauma . Other aThe sternum develops from the fusion of bilateral mesodermal bars which unite from day 25 of gestation in dogs and day 28 of gestation in cats, starting cranially at the manubrium of the sternum and ending caudally at the xiphoid process ,24. OssiAs in previous reports, pectus excavatum mostly affected the caudal sternum in dogs in our study population, which is the typical form of pectus excavatum . Komsta In agreement with a previous publication by Hassan and colleagues (2018), we observed pectus carinatum predominantly in small breed dogs, except for in one English Springer Spaniel . In thatAlthough neoplastic disease was the most common indication for thoracic radiography in dogs, only two cases presented with radiographic aggressive bone lesions affecting the sternum. One dog diagnosed with malignant lymphoma presented with pathological fractures of multiple sternebrae, the other dog was diagnosed with prostatic carcinoma and had an aggressive bone lesion affecting the second and third sternebrae. However, the sternal lesions were not biopsied in these dogs and therefore it remains unknown if these aggressive bone lesions indeed were caused by neoplastic disease. Skeletal involvement affecting the spine has been described in canine multicentric lymphoma ,30, but synchondroses sternales, mostly consistent of mineralization of the sternal cartilages or formation of bony spurs, was the most common finding in our study, with a prevalence of 14% in dogs and 8% in cats. In 13 of the dogs affected, gas opacity was observed in between the sternebrae on the left lateral view radiograph. Gas accumulation within synovial joints and intervertebral disc spaces is termed vacuum phenomenon. This gas consists of 90\u201392% nitrogen and its presence has been associated with intervertebral disc degeneration in dogs [synchondrosis sternalis in dogs, similar to the above-mentioned association between vacuum phenomenon in the intervertebral disc space and intervertebral disc degeneration in dogs [Age-related degeneration of the in dogs ,36,37. T in dogs and, in in dogs . In our Sternal dislocation is infrequently reported in veterinary literature and is most often considered to be of traumatic origin ,16,17. BOur study had several limitations. First, the retrospective design prohibits adequate correlation between radiographic findings and clinical signs. For example, it cannot be reliably determined if sternal dislocation in dogs with severe intersternebral cartilage degeneration was associated with pain or other clinical signs, because no specific history and physical examination addressing these findings were performed in these cases. Secondly, the large variety in breeds in combination with the relatively low number of cases for each disorder impedes drawing firm conclusions on any breed predispositions. Thirdly, the use of radiography instead of a cross-sectional technique such as computed tomography results in a lower sensitivity for detection of abnormalities because of the inferior contrast resolution and problems of superimposition inherent to radiography. Moreover, computed tomography would allow a better representation of the anatomy. For instance, computed tomography was reported to be useful for evaluation of thoracic asymmetry and sternal torsion in cats with pectus excavatum, which cannot be done with radiography . In addiSternal abnormalities are common incidental findings on thoracic radiographs of companion animals and were observed on thoracic radiographs of 24% of dogs and of 29% of cats in our study population. Clinically relevant abnormalities, such as severe degeneration of the intersternebral cartilage space, dislocation, or aggressive bone lesions, were only recognized in few cases, whilst most animals showed abnormalities that were unlikely to cause clinical complaints."} +{"text": "To determine the extent to which primary care physicians have been willing to incorporate computerized protocols and clinical information systems into their practices.A survey was fielded to both primary care and non hospital-based specialty group practices of five physicians or more.The types of these technologies in use and the degree to which the physicians themselves were active users.Findings (n=197 or a 38% response rate) are presented grouped by three stages of software application adoption: (1) transaction; (2) decision support; and (3) expert systems or simulation of human thought. Transaction systems, particularly applications that support practice administration such as registration, billing, and scheduling, have the highest percentage of adoption (82% to 97%). Expert systems are uncommon (3% to 6%), with slightly higher penetration of telephone triage (such as \"ask-a-nurse\") and prevention reminders applications . Within group practices, physician \"hands-on\" use of systems is low for viewing (28%), and even lower for entering patient information (6% to 8%).Emerging knowledge technologies such as medical decision support or expert systems are not widely accepted and may even threaten traditional physician domains of expertise. Explicit consideration of potential physician opposition should be included in planning pharmaceutical management strategies that depend on \"hands-on\" physician computer use to be successful."} +{"text": "Rheumatoid pulmonary nodule can be detected in up to 32% of rheumatoid arthritis (RA) patients and approximately one-third of nodules may cavitate. We aimed to evaluate characteristics of patients with RA developing cavitary pulmonary nodular (CPN) lesions under disease-modifying antirheumatic drugs (DMARDs), follow-up of both cavitary and solid nodules, and their outcome with the treatment.RA patients who presented with CPN lesions during follow-up were recruited retrospectively in this case series analysis. Total numbers and mean diameters of cavitary and solid nodules in each thorax computed tomography (CT) have been determined and followed up by two experienced pulmonary physicians. Moreover, changes in treatment after the development of the CPN lesions and characteristics of cavitary nodules were collected.Eleven patients with CPN lesions were reported. At the time of CPN diagnosis, more patients were taking leflunomide than methotrexate (81% vs 19%). Half of the patients were receiving biologic therapy and only 18% were taking anti-TNF drugs. After a median of 24 (3\u201365) months of follow-up, the regression of CPN lesions was determined in 45% (5/11) of patients. Four of these 5 (80%) patients were switched to a treatment regimen without leflunomide and three of them to nonanti-TNF biologic treatment or targeted synthetic DMARDs .CPN lesions seen in RA patients are often pulmonary manifestations of the underlying disease; however, one must rule out malignancies or infections. If lesions progress under DMARDs, it is advised to discontinue synthetic DMARDs (LEF/MTX) and switch to another biological DMARD with different modes of action Rheumatoid arthritis (RA) is a chronic inflammatory disease typically involving small joints. Pulmonary involvement is the most common extraarticular manifestation of the disease. Pulmonary disease, which is a major source of morbidity and mortality in RA, manifests most commonly as interstitial lung disease (ILD), airways disease, rheumatoid nodules (RN), and pleural effusions .The prevalence of rheumatoid pulmonary nodules, also called necrobiotic nodules, ranges from less than 0.4% in radiological studies to 32% in lung biopsies of patients with RA [Nodules usually present a diagnostic challenge rather than therapeutic. Nodules in RA patients should be evaluated similarly to those in any other patient presenting with solitary or multiple pulmonary nodules, as nodules may reflect the presence of infection, malignancy, or other inflammatory diseases. Biologic drugs are now widely used for treating RA. Various side effects, mainly infection, have been described with these drugs. The efficacy of these agents for the treatment of pulmonary involvement of disease has not been specifically evaluated in large placebo-controlled randomized trials.We report characteristics of 11 patients with RA developing cavitary pulmonary nodular (CPN) lesions under disease-modifying antirheumatic drugs (DMARDs) and follow-up of cavitary nodules and their outcome with the treatment were reported.RA patients who presented with CPN lesions during follow-up between September 2009 and April 2019 in rheumatology outpatient clinic were recruited retrospectively in this case series analysis. Diagnosis of the CPN lesions was made with computed tomography (CT) scan and indication for imaging of these patients were constitutional/respiratory symptoms or any abnormality at routine annual conventional radiography during biological treatment. Characteristics of the patients, positron emission tomography (PET), and biopsy (if available) findings were collected from patient reports. Patients without biopsy were the ones who did not accept biopsy or who had contraindication for biopsy (with cardiac failure and arrhythmia treated by the cardiac pacemaker). In addition to these, changes in treatment after development of the CPN lesion and characteristic of cavitary nodules were collected. Outcome assessment focused mainly on the number and characteristics of all nodules with the modification of treatments, but we also evaluated cavitary nodules separately. Total numbers and mean diameters of cavitary and solid nodules in each CT have been determined with the agreed decision of two experienced pulmonary physicians, who were aware of the clinical data of the patients. An increase in total nodule count or new cavitation of a solid nodule at CT was accepted as a progression of the lesion. It is also accepted as a progression of the lesion if there is a 20% or more increase of mean nodule size even though total and cavitary nodule count is stable. A decrease in total or cavitary nodule count and a 30% or more decrease in mean nodule size is accepted as regression of the lesion.The study was approved by the local clinical research ethics committee (reference number: 09.2019.592)Before initiation of biologic drugs (except rituximab), each patient was screened for tuberculosis and underwent conventional radiography, clinical pulmonary examination, and ppd/QuantiFERON test, and tuberculosis prophylaxis (9 months of isoniazid) was given to 5 of them as the results of these tests.Two patients received antituberculosis treatment after the detection of CPN; the negative QuantiFERON test turned positive during abatacept treatment in 1 patient (case 4) and biopsy of the nodule was necrotizing granuloma for the other one although tuberculosis bacilli were not detected (case 8). After antituberculosis treatment, there was no regression at the cavitary nodules.Respiratory symptoms were reported by 2 patients and constitutional symptoms by 2 patients while the others were asymptomatic during the diagnosis of CPN. All patients were seropositive, 2 patients had p ANCA (antinuclear cytoplasmic antibody)-positive, but the ELISA test for anti-MPO (myeloperoxidase) and PR3 (proteinase) were negative. Extensive examinations for microbial organisms (mycobacteria and opportunistic infections) were all negative .A total of 48 CTs were evaluated by two experienced pulmonary physicians. We are presenting CT findings showing cavitary and solid nodules of our patients in Fluorodeoxyglucose (FDG) PET/CT scan examination of nodules was performed to exclude malign conditions in 7 patients. We determined that both mediastinal lymphadenopathy (LAP) and cavitary-solitary nodules had increased uptake with a standardized uptake value (SUV) of 1.6\u20137.9 FDG. Salivary gland adenocarcinoma was detected in one of the patients with 12 FDG uptake value at the submandibular area, but biopsy from mediastinal lymph node (11 FDG) showed tuberculosis-negative necrotizing granuloma.We evaluated CTs of patients for the total (solid/cavitary) nodules at the end of 28 (3\u201365) months follow-up and 4 (36.3%) patients were diagnosed with regressed lesions while 7 (63.7%%) patients had progressive lesions compared to previous CTs and switch to biological DMARDs with different modes of action. In addition, improvement of the CPN lesions might be seen with non-TNF biologic treatment or targeted synthetic DMARDs ."} +{"text": "Scientific Reports 10.1038/s41598-021-03609-w, published online 10 January 2022Correction to: The Acknowledgements section in the original version of this Article was incomplete, where the grant number of one of the funding agencies was omitted.\u201cSP would like to acknowledge support of the National Science Centre of Poland within the OPUS programme.\u201dnow reads:\u201cSP would like to acknowledge support of the National Science Centre of Poland within the OPUS programme (2020/39/B/ST2/01524).\u201dThe original Article has been corrected."} +{"text": "In India, unsafe sex has been documented among truck drivers. This study explores the factors influencing their attitude of trucker towards condom use.A cross-sectional study design was adapted for this study in which 25 factors were chosen to assess attitude toward condom use on 7 point validated Likert scale UCLA Multidimensional Condom Attitude Scale on 5 subcomponents -Reliability, Pleasure, Stigma associated with condom use, embarrassment about negotiation and use of condom and about purchasing condom. Hundred truck drivers were recruited using convenient sampling and Mann-Whitney U and Kruskall Wallis Test were used to validate the subcomponents among those practicing unsafe sex.Positive attitudes regarding reliability and effectiveness of condom were significantly higher among adult entrants and those resting more than 10 hours during journey whereas positive attitude regarding pleasure associated with condoms and stigma towards it is significantly higher among truck drivers travelled long distances and resting more than 10 hours.Adolescent entrants, those who have not travelled long distances and not rested more than 10 hrs requires improvement in the attitude towards condom use. WHO reports globally 36.9 million people are living with HIV. 1In South-east Asia, 1.7 million people are living with HIV and number of people living with HIV in India is 2100000.2Sexual promiscuous lifestyle is common among truck drivers and therefore susceptible of acquiring HIV infection. 12There seems to be few studies highlighting the attitude toward condom use among truck drivers. This study was undertaken with an objective to assess the attitude towards condom use and its predictors among truck drivers at transhipment location in Meerut district, IndiaThis cross-sectional study was conducted at Trans-shipment area in Meerut district, India which is home to over two hundred transporters and over 500 trucks are available at any given point of time. Furthermore, a typical halt can range from thirty minutes to two days and work hours of most transporters are eleven hours.Hundred truck drivers were recruited who were having a valid driver's license from the trans-shipment area using convenient sampling procedure.A pre-tested validated questionnaire comprising closed ended questions was used to document socio-demographic-occupational profile and for assessment of attitude towards condom use University of California Los Angeles Multidimensional Condom Attitude Scale (UCLA MCAS) was used.13The truck drivers were briefed about the purpose of the study, importance of their participation, its consequential benefit to truck drivers and assurance of their confidentiality. After briefing them, the informed consent was taken from truck driver agreeing to participate and regardless of the participation, the truck drivers were given condoms and advices related to health issues. Truck drivers having wrong perception about condom were educated about the benefit of condom The pilot study, modification of questionnaire, recruitment of participants for main study and data analysis was done from a period of August 2014 to September 2015.Occupation profile: Type of truck drivers (based on distance traversed), average number of days away from home, average resting time during trip and type of entrant (adolescent or adult)Unsafe sex: Our criterion for unsafe sex was operationally defined as inconsistent use of condom with high risky sexual partners like CSW and MSM irrespective type of intercourse-vaginal, anal or oral (Fellatio) and practicing either Cunnilingus or Analingus or both.Attitude towards Condom Use: The 25 item UCLA MCAS 7-point Likert scale was used to assess the attitude towards condom use. The UCLA MCAS has 5 subscales (or domains) - Reliability and Effectiveness of Condoms, Pleasure associated with Condom, Stigma associated with condom use, Embarrassment about negotiation and use of condom and Embarrassment about purchasing condoms. 13Reliability and effectiveness subscale included 1) Condoms are an effective method of preventing the spread of Aids and other sexually transmitted diseases 2) Condoms are unreliable (reverse scored) 3) I think condoms are an excellent means of contraception 4) Condoms do not offer reliable protection (reversed score) 5) Condoms are an effective method of birth control. Pleasure associated with condoms included 1) Use of condom is an interruption of foreplay (reversed score) 2) Condoms ruin the sexual act (reversed the score) 3) Condoms are a lot of fun 4) The use of condom can make sex more stimulating 5) Condoms are uncomfortable for both parties (reversed score)Stigma associated with Condom use included 1)Women think men who use condoms are jerk (reversed score) 2)If a couple is about to have sex and the man suggests using a condom, it is less likely that they will have sex (reversed score) 3) People who suggest condom use are a little bit geeky (reversed score) 4) Men who suggest using a condom are really boring (reversed score) 5) A woman who suggests using a condom does not trust her partner (reversed score). Embarrassment about negotiation and use of condom include 1) It is really hard to bring up the issue of using condoms to my partners (reversed score) 2) When I suggest using a condom I am almost always embarrassed (reversed score) 3) It is easy to suggest my partner that we use a condom 4) I never know what to say when my partner and I need to talk about condoms or other protection (reversed score) 5) I am comfortable talking about condoms with my partner. Embarrassment about purchasing condoms include 1) I always feel really uncomfortable when I buy condoms (reversed score) 2) I don't think that buying condoms is awkward 3) It is very embarrassing to buy condoms (reversed score) 4) It would be embarrassing to be seen buying condoms in a store (reversed score) 5) It would be embarrassing to be seen buying condoms in a store (reversed score)The analysis was done in SPSS 21.The total score for each item = + + + + + + / Total Response (100)Mean score% for each subscale = (mean score \u2013 1)/Minimum value = 1 and maximum value = 7The mean score for individual participant in different subscales was computed and non-parametric test [Kruskall Wallis and Mann-Whitney U Test] were applied to find the predictors of attitude regarding condom use.The study was a component of a dissertation and Subharti Medical College Institutional Committee approved the dissertation (SMC/PG-13/2013).Of the 100 participants, most were married (72%), literate (90%), adult entrant (69%), travelled long distance (77%) average time away from home less than 10 days (71%) and resting during journey less than 10 hours (65%).The attitude among truck driver regarding reliability and effectiveness of condom is 88.3% , pleasure associated with condom is 70.3% , stigma associated with condom is 73.7% , embarrassment about negotiation and condom use is 76% and purchasing condoms is 75.8%.The mean score for attitude regarding reliability and effectiveness of condoms is significantly higher among adult entrants than adolescent entrants and those resting more than 10 hours during journey whereas mean score for regarding pleasure associated with condoms is significantly higher among truck drivers travelled long distances and resting more than 10 hours. Furthermore, the mean score for attitude regarding stigma associated with condom use is significantly higher among truck drivers travelled long distance and attitude regarding embarrassment about negotiation and use of condom was significantly higher among truck drivers resting more than 10 hours. However, mean score for attitude regarding embarrassment about purchasing condom use was significantly higher among adult entrants and those who have travelled long distance. This seems to be the first study for elaborative assessment of attitude toward condom use among truck driver population in India using UCLA Multidimensional Condom Attitude Scale. The findings of the study indicate in almost all domains the attitude of truck driver was far from satisfactory.This scale was used among 20 recruited community members assessing difference in attitude towards condom use between those consuming alcohol and does not consuming it.18The study is subjected to limitation because of small sample size recruited using convenience sample and social desirability bias may have influence on the response of the participants. Hence it is recommended the study be conducted on a large sample size using probability sampling.The age of the entrant, travelling long distances and resting time more than 10 hours were predictors significantly affecting attitude of truck drivers regarding condom use."} +{"text": "C) to the neurotoxic pathogenic form (PrPTSE) via a yet undefined but profoundly complex mechanism. Despite several decades of research on PrD, the basic understanding of where and how PrPC is transformed to the misfolded, aggregation-prone and pathogenic PrPTSE remains elusive. The primary clinical hallmarks of PrD include vacuolation-associated spongiform changes and PrPTSE accumulation in neural tissue together with astrogliosis. The difficulty in unravelling the disease mechanisms has been related to the rare occurrence and long incubation period (over decades) followed by a very short clinical phase (few months). Additional challenge in unravelling the disease is implicated to the unique nature of the agent, its complexity and strain diversity, resulting in the heterogeneity of the clinical manifestations and potentially diverse disease mechanisms. Recent advances in tissue isolation and processing techniques have identified novel means of intercellular communication through extracellular vesicles (EVs) that contribute to PrPTSE transmission in PrD. This review will comprehensively discuss PrPTSE transmission and neurotoxicity, focusing on the role of EVs in disease progression, biomarker discovery and potential therapeutic agents for the treatment of PrD.Prion diseases (PrD) or transmissible spongiform encephalopathies (TSE) are invariably fatal and pathogenic neurodegenerative disorders caused by the self-propagated misfolding of cellular prion protein (PrP TSE) of normal cellular prion protein (PrPC) (Prusiner Prion diseases (PrD) or transmissible spongiform encephalopathies (TSE) are progressively rapid and fatal neurodegenerative diseases (NDs) with a defining hallmark of vacuolation in the brain tissue , Gerstmann\u2013St\u00e4ussler\u2013Scheinker (GSS) and fatal familial insomnia (FFI) while sporadic CJD (sCJD) presents with disease aetiology from unknown origins. PrD with acquired aetiologies from exposure to pathogenic prions includes iatrogenic CJD (iCJD), vCJD, and kuru. To date, various human-to-human iCJD transmissions occurred due to incomplete decontamination of surgical equipment, corneal grafting, dura mater grafting, cadaveric pituitary-derived growth hormone or gonadotrophin, and blood transfusions denaturation, proteinase K (PK) treatment and high-performance liquid chromatography (HPLC) purification yielded the significant component of a single protein ranging 27\u201330\u00a0kDa in size (PrP 27\u201330) TSE isofoC has high endogenous expression in neurons and is encoded by only one exon out of three exons in the PrPC gene at chromosome 20 anchor at the C terminus (residue 230) and two N-linked glycans at residues 181 and 197. Nuclear magnetic resonance (NMR) examination of PrPC structure revealed an intrinsically disordered N-terminal tail (residues 23\u2013128), three \u03b1-helical regions (two of them linked by a disulphide bridge) and a short anti-parallel \u03b2-sheet , where it is packaged in extracellular vesicles and released into the extracellular environment was developed model \u2013based structure isolation of infectious prions from different prions strains for dynamic and multi-angle light scattering (DLS/MALS) analysis showed quaternary structure difference resulting in PrPTSE strain heterogeneity polymorphism fragment on SDS-PAGE gels, three different PrPres subtypes have been identified, which include type 1 (21\u00a0kDa), type 2 (19\u00a0kDa) and type intermediate is a technique that converts normal brain homogenate PrPTSE deposition are the characteristic features of prion-infected brains, the mechanism of neurotoxicity has remained elusive. However, several studies have investigated the synergistic effect generated by the interaction of PrPC and PrPTSE, providing some explanation on the neurotoxic effects of PrPTSE. Grafting neural tissue overexpressing PrPC into PrPC null mice brains and intracerebrally injecting scrapie prions produced severe histopathological changes exclusively in the grafted tissue starvation followed by ATP depletion and exosomes classified based on biogenetic pathway and size. Apoptotic bodies (500\u20135000\u00a0nm) arise from the cell fragmentation during apoptosis, microvesicles (200\u20131000\u00a0nm) from outward budding and shedding from the plasma membrane, and exosomes 40\u2013200\u00a0nm) which are released intercellularly following production via the endosomal pathway and fusion of the MVB to the plasma membrane , and many have predicted targets in crucial neuronal signalling pathways. This suggests that EVs could carry brain-associated miRNAs and into the blood play key roles in gene regulation either by inducing mRNA degradation or repression of mRNA translation. A plethora of miRNAs are present in the brain, indicating that complex physiological and neuronal development functions of miRNAs are more enriched in the brain regions, which shows the complex physiological functions of the brain , a regulator of ceramide biosynthesis, reduced exosomes as well as miRNA secretion, an effect that was reversed following overexpression \u2013infected N2a cells overexpressing murine prion protein demonstrated upregulation in the redox chaperone, protein disulphide isomerase (PDI) and ATPase (complex V). A more recent study validated mitochondrial respiratory chain deficiency in human sCJD brain temporal cortex with immunohistochemistry, demonstrating a loss of all mitochondrial complexes (I\u2013V) and Alzheimer\u2019s disease (AD). An early study of scrapie-infected hamster brain cerebral cortex transmission electron microscopy images depicted alterations in mitochondrial morphology and depletion of mitochondrial matrix and cristae \u2013derived EVs from human placenta intravenously delivered to multiple sclerosis mice demonstrated increased motor abilities, reduced DNA damage and increased myelination \u2013derived EVs injected into the bloodstream ameliorated neuroinflammation and increased cognitive function in immunocompetent mice (Leavitt et al. EV research is a burgeoning field elucidating the dynamic nature of intercellular communication in the local and distal areas of the body, and has opened a new horizon to decipher the fundamental biological processes in health and disease. Studies exploiting EVs as the biomarker source and their subsequent role in pathogenic and neurotoxic processes aid a better understanding of the complexity of PrD. The gaps in the study of proteomics and lipidomic cargo from the infectious EVs of several prion strains would help to reveal common neurotoxicity-related pathways. Moreover, the functional study of infectious prion EVs in communication with the glial cells can reveal these EVs\u2019 immunomodulatory and inflammatory effects. While secondary lymphoid organs, including the spleen, are indicated as an early accumulation site for prion replication following peripheral prion infection, isolating EVs from these organs for infectivity and cargo assessment would result in better understanding of EVs\u2019 associated roles. Future studies utilising emerging technologies to examine the nanoscale world of EVs will shed more light on this growing field, promoting strain-specific biomarker discovery for disease diagnosis and enabling the engineering of EVs for disease treatment."} +{"text": "This study aimed to use data analytics to retrospectively identify the prevalence of inpatients across a system of hospitals with a BAAL who received and tolerated the culprit or related beta-lactam (BL) without proper documentation in the allergy profile of the electronic medical record (EMR). Findings from this study could prioritize direct non-invasive delabeling opportunities as a feasible process measure for resource limited antimicrobial and diagnostic stewardship programs (ADSP).> 18 years of age, 2) inpatients at a NM System Hospital (NMSH) with > 1 overnight stay between 8/1/2020 and 8/1/2022, 3) a BAAL in the allergy profile of the EMR, and 4) received > 1 dose of a BL during the study period. Patients who only received aztreonam were excluded. The primary objective of this study was to determine the prevalence of inpatients with a BAAL who received and tolerated the culprit BL antibiotic during the study period without proper documentation in the allergy profile of the EMR. The secondary objectives were 1) to determine the prevalence of inpatients with a BAAL who received and tolerated a related BL antibiotic during the study period without proper documentation in the allergy profile of the EMR and 2) to determine the prevalence of reported BL allergy reactions and severity risk.Eligible patients were generated by a data analyst using the Northwestern Medicine (NM) Enterprise Data Warehouse. Patients eligible for inclusion: 1) adults Results of our study identified up to 751 inpatient BAALs (9.7%), including 87 BAALs of high priority, as valuable targets for early direct non-invasive delabeling, requiring minimal effort and resources from ADSP.Using data analytics to empirically assess digital allergy information could streamline the antimicrobial stewardship process, proactively identifying and prioritizing BAALs to cast a wider net and efficiently achieve process measure outcomes related to allergies compared to conventional methods of delabeling.Anju T. Peters, MD MSCI, Astra Zeneca: Advisor/Consultant|Astra Zeneca: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|Optinose: Advisor/Consultant|Sanofi Regeneron: Advisor/Consultant|Sanofi Regeneron: Grant/Research Support"} +{"text": "In the published article, there was an error in the legend for (A) Immunization and challenge schedule with prime and boost (day 0 and 21), intranasal challenge (day 42), and bleeds . On day 45 mice were euthanized for the harvesting of lungs and nasal turbinates. (B) Viral levels in the nasal turbinates of mice as measured by tissue culture infectious dose 50 (TCID50). (C) Viral levels in the left lung of mice as measured by TCID50. P-values are indicated for the significance of differences and NS denotes no statistical difference. Vaccines were Fluad (T) (blue) and Fluzone (T) (red) with saline (black) and non-infected controls (white). Yamagata-lineage challenge virus was mouse-adapted B/Florida/04/2006.\u201d\u201cMeasuring viral titers in the nasal turbinates and lungs of mice following vaccinations and subsequent challenge with Yamagata-lineage influenza B virus. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Existing data on adverse effects (AEs) of COVID-19 vaccines among people living with human immunodeficiency virus (PLHIV) are currently limited.A cohort study was conducted among PLHIV receiving care at two clinics during COVID-19 epidemics in Thailand (2021-2022). The PLHIV received various types and regimens of COVID-19 vaccines based on vaccine availability and the national policies. Data on vaccine types and AEs were collected and assessed using the online survey system.Of the 398 vaccinated PLHIV, 365 (92%) had CD4 count at enrollment \u2265 200 cells/\u00b5L, 382 (96%) were virologic suppressed, 153 received two doses and 245 received three doses of COVID-19 vaccines. Inactivated and viral vector were the most common vaccine types received by the PLHIV as the first and second doses , while mRNA vaccine was the most commonly used as a booster dose (57%). For the first and second vaccine doses, the most common AEs were fever (15% and 11%) and injection site pain (11% and 11%). The mRNA vaccine significantly caused more overall AEs, injection pain, fatigue, and rashes than the other two types, while the mRNA and viral vector vaccines significantly caused more fever than the inactivated vaccine. For a booster dose, viral vector vaccine significantly caused more injection site pain and headache than the other two types. Most of the PLHIV reported that the AE intensity was similar between the first and second doses (49%) and was more for a booster dose compared to the first dose (50%). The majority of all AEs of the first, second and booster doses spontaneously recovered without treatment or required symptomatic treatment without hospitalization . By multivariable analysis, receipt of viral vector or mRNA vaccine and age less than 40 years were independently associated with any AEs of the primary series vaccines, while having AEs from the previous dose and female sex were factors associated with any AEs of a booster vaccine.The three types of COVID-19 vaccines were generally safe among PLHIV. Most of the AEs were non-severe and did not require hospitalization. PLHIV who were elderly, female or had AEs from the previous vaccine dose should be closely monitored for AEs of the vaccines.All Authors: No reported disclosures"} +{"text": "Mental disorders, musculoskeletal diseases (MSDs) and their comorbidities are major threats to work and functional ability. The relationship between mental health and the common MSDs has not received enough attentionTo study the socio-professional characteristics of workers suffering from work related MSDTo evaluate the association of work related MSDs with anxiety and depression disordersA descriptive cross-sectional study conducted among workers with work-related MSDs who consulted the occupational medicine department of the Charles Nicolle Hospital between January 2022 and September 2022. A remote survey was conducted among these workers to screen for anxiety and depressive disorders using the Hospital anxiety and Depressive ScaleThe study population consisted of 54 workers with MSDs with a sex ratio (M/F) of 0.74. The average age was 44.4 [27-61 years]. The average professional seniority was 14.9 years\u00b17 years and the sectors with the highest prevalence of MSDs were the health sector (22%), the food industry (13%) and the textile industry (11%). The workers reported MSDs of the lumbar spine in 61%, gonarthrosis in 31%, followed by MSDs of the upper limb in 25%. The prevalence of anxiety and depressive disorders were respectively 46% and 38%. There was no significant association between socio-demographic factors and anxiety depressive disorders. The anxiety disorder was associated with MSDs of the lumbar spine .Anxiety and depressive disorders were common among workers with MSDs related to work. Interventions targeting psychological distress and work-related psychosocial characteristics may reduce their musculoskeletal pain.None Declared"} +{"text": "Toxoplasma encephalitis (TE) is the most frequent cause of expansive brain lesions among acquired immunodeficiency syndrome (AIDS) patients; however, the optimal timing of antiretroviral therapy (ART) initiation in these patients remains controversial.This was a multicenter prospective observational study, and eligible patients were recruited from eleven treatment centers in China.In total, 87 patients were included, and 38 of them were assigned to the Early ART group (initiating ART within 2 weeks after anti-Toxoplasma treatment initiation), while the remaining 49 patients were allocated to receive deferred ART (initiating ART at least 2 weeks after anti-Toxoplasma treatment initiation). Our results indicated that the incidence of immune reconstitution inflammatory syndrome (IRIS) and the number of death events were not significantly different between the two groups at Week 48. The timing of ART initiation was also found to not significantly contribute to human immunodeficiency virus (HIV) viral load control. The difference in the number of patients who maintained an undetectable HIV viral load of <50 copies/mL in each of the two groups of patients was calculated to not be statistically significant at Week 24 and Week 48 . Meanwhile, median CD4+ T-cell counts were also observed not to reach statistical significance between the two groups, both at Week 24 and Week 48 .In our study, early ART initiation was observed to not confer statistically significant differences in the incidence of IRIS, mortality, and HIV virological and immunological outcomes, when compared to deferred ART initiation.All Authors: No reported disclosures"} +{"text": "In recent decades, vagus nerve stimulation (VNS) therapy has become widely used for clinical applications including epilepsy, depression, and enhancing the effects of rehabilitation. However, several questions remain regarding optimization of this therapy to maximize clinical outcomes. Although stimulation parameters such as pulse width, amplitude, and frequency are well studied, the timing of stimulation delivery both acutely (with respect to disease events) and chronically (over the timeline of a disease\u2019s progression) has generally received less attention. Leveraging such information would provide a framework for the implementation of next generation closed-loop VNS therapies. In this mini-review, we summarize a number of VNS therapies and discuss (1) general timing considerations for these applications and (2) open questions that could lead to further therapy optimization. What VNS implementation strategies have worked best ?Moving forward, what open questions and strategies can be assessed for further optimizing VNS therapy and timing?Implanted vagus nerve stimulation (VNS) is utilized for a number of applications, including improving cardiovascular function the reactive neurostimulator (RNS) by NeuroPace and 2) VNS with AutoStim Mode by LivaNova. The former uses neural recordings for early seizure detection, while the latter uses relative increases in heart rate (characteristic of seizure activity) for a similar purpose uses brief bursts of closed-loop VNS paired with events to promote neural plasticity and recovery following disease or dysfunction . Overall, the ultimate role of closed-loop VNS for treating cardiovascular disease will be affected by a number of exciting innovations, including neurogram decoding of cardiovascular information Zanos and machWhile therapeutic intervention for disease states that are symptomatic but not perceivable is important, such disease progression is usually preceded by a series of interconnected subclinical states detect disease events and better time VNS and (2) intervene earlier in disease progression to maximize the clinical benefits of VNS (Fig.\u00a0 detect d"} +{"text": "Sorghum bicolor (L.) Moench] utilizes the cytoplasmic-nuclear male sterility (CMS) system for seed production and subsequently harnesses heterosis. Since the cost of developing and evaluating inbred and hybrid lines in the CMS system is costly and time-consuming, genomic prediction of parental lines and hybrids is based on genetic data genotype. We generated 602 hybrids by crossing two female (A) lines with 301 diverse and elite male (R) lines from the sorghum association panel and collected phenotypic data for agronomic traits over two years. We genotyped the inbred parents using whole genome resequencing and used 2,687,342 high quality single nucleotide polymorphisms for genomic prediction. For grain yield, the experimental hybrids exhibited an average mid-parent heterosis of 40%. Genomic best linear unbiased prediction (GBLUP) for hybrid performance yielded an average prediction accuracy of 0.76\u20130.93 under the prediction scenario where both parental lines in validation sets were included in the training sets (T2). However, when only female tester was shared between training and validation sets (T1F), prediction accuracies declined by 12\u201390%, with plant height showing the greatest decline. Mean accuracies for predicting the general combining ability of male parents ranged from 0.33 to 0.62 for all traits. Our results showed hybrid performance for agronomic traits can be predicted with high accuracy, and optimizing genomic relationship is essential for optimal training population design for genomic selection in sorghum breeding.Hybrid breeding in sorghum [ Heterosis is the phenomenon by which the interest . Mid-parc values . The genulations . IMPH ar1 hybrid . Therefo1 hybrid .Sorghum bicolor (L.) Moench] is one of the self-pollinated crops that is bred as a hybrid crop, particularly in the United States (US) and Australia. Beginning in the 1950s, sorghum breeding in the US started utilizing the cytoplasmic-nuclear male sterility (CMS) system to produce hybrid cultivars of R lines crossed to two female testers. The male lines used for generating single crosses are accessions included within the US sorghum association panel (SAP) that represent the genetic and phenotypic diversity of sorghum across the globe and could be used in allele mining and prebreeding (A sorghum hybrid diversity panel (SHDP) of 602 hybrids was generated by crossing 301 diverse male restorer (R) lines to two CMS female (A) testers: ATx642 (PI656029) and ATx2928 (PI629059) . The malHelicoverpa zea) and fall armyworm (Spodoptera frugiperda) infestation. Fields were watered using overhead irrigation only as needed to prevent drought stress.The hybrids and parental lines from the SHDP were planted along with the commercial check in a modified randomized complete block design with two replications in May 2019 and May 2020 at the Clemson University Pee Dee Research and Education Center in Florence, SC. The modification was done by blocking each complete replication into smaller blocks based on previously observed maturity and height phenotypes for the male parent of the hybrids to avoid shading effect of taller lines on neighboring plants. There were a total of 40 blocks per replication and each block consisted of 30 individual plots. Each plot had two rows with a row length of 6.096 m and a row spacing of 0.762 m. The experimental hybrids, their parental lines and check hybrid variety (83P17) were randomized completely for each small block nested within each replication. Preplant fertilizer was blended based on soil sample results and per field recommendations for cereal grain production. In 2019, the fertilizer blend consisted of granular muriate of potash at 300 kg haPhenotypic data were collected for days to anthesis (DTA) when about 50% of the primary panicles in the plot were at mid-anthesis. Plant height (PH) was measured from the base of the plant to the top of the representative panicle within the plot after physiological maturity. Plants were harvested when the majority of the plants in the plot reached post-physiological maturity (grain moisture below 18%) using a Wintersteiger Delta two row combine plot harvester. Harvest dates ranged from 16 to 18 September in 2019 and 17 to 25 September in 2020. Total harvest weight of the grain from each plot and the average moisture content of the harvested grain was used to calculate grain yield (GY) in bushels/acre and subsequently converted to ton per hectare lines of the female parents were used to evaluate female parent performance. The following model was used to adjust for spatial variability within each experimental year:whereThe adjusted means (BLUPs) of wherewherevcftools 8) by redist function in R ..8). Suppd by GNP .For genomic GCA and genomic GCAe shared . For thee shared . Mean prGCAs of male lines were estimated from the genomic GCA model using alThe ability to predict testcross performance in hybrids was evaluated for male general combining abilities (mGCA) using the GCA and GCAo models , Fig. 5.Hybrid sorghum breeding is based on a CMS system where male sterile females (A lines or seed parents) are crossed to restorer males (R lines or pollinator parents) to produce seed of commercial Following the wide range of diversity in the parental genotypes, the to 20%) . The comSince the possible hybrid combinations even in a medium sized breeding program far exceeds the capacity to test them in actual hybrid crosses, one of the main motivation for the use of GP in hybrid breeding is to be able to estimate hybrid genetic value of those untested hybrid crosses or only female parent (T1F) were shared between training and validation sets to understand the effect of parent testing on the accuracy of single cross predictions. While single-cross performance was predicted with high accuracy in T2 scenario, a strong decline (12\u201390%) in prediction accuracy was observed in T1F compared to T2. This is expected because the predictions from the model in T2 rely not only on kinship between male parents , as in the case of T1F, but also on information from other crosses in the training set that involves the male parent of predicted hybrid with the other female tester. Plant height showed the greatest decline in prediction accuracy in T1F, which could be due to very limited phenotypic variability among female lines for PH, and as a result, accuracy for PH could have been driven primarily by male parent. GP of sorghum hybrids using GBLUP model and cross-validation involving leave one parent out strategy (similar to our T1F) showed mean prediction accuracies (0.31\u20130.54) for grain yield that was similar to accuracy from our T1F prediction scenario (Prediction of testcross performance of inbred lines in hybrid combinations has been studied across multiple crop species ( studied . PredictThe phenotypic distribution of agronomic traits and consistent heterotic advantage of experimental Studies exploring the role of genetic diversity and genomic relationship on GP for trait phenotypic values as well as trait heterotic values are essential for optimization of training population for predicting hybrid performance. In silico simulation studies have highlighted strategies for application of rapid recurrent genomic selection combined with progeny testing to facilitate separation of heterotic groups, reduction in breeding cycle, and ultimately increase in long term genetic gain (jkac311_Supplementary_DataClick here for additional data file."} +{"text": "To examine the federal government's current health care initiatives in the Centers for Medicare and Medicaid Services (CMS) to improve quality of care and cost-effectiveness around the prescription drug benefit.The government has a unique perspective on quality and outcome. Pharmacists need a working knowledge of 3 areas: (1) Medicare Part D, (2) medication therapy management efforts, and (3) demonstration projects. All of these will make demands on health care providers but should result in better outcomes data and patient care. All of these areas also have value components, and all have strategic implications as 2006 moves into 2007.CMS does not consider managing cost and providing value to be mutually exclusive and is attempting to move America's health care toward a value based program."} +{"text": "Suicide rates in Azerbaijan rank among the top 3 highest of all Muslim majority countries. Further, approximately 40% of women in Azerbaijan report being physically or sexually abused. Women experiencing interpersonal violence report higher rates of suicide ideation and attempts (34%) than women in the general population. No prior studies have specifically explored protective factors against suicide and interpersonal violence in Azerbaijan.This study aims to address this gap and to identify culturally relevant protective factors against suicide and violence against women in Azerbaijan.A total of 51 women with lived experience and mental health providers participated in either in-depth qualitative interviews or focus groups. The interview guide for the focus groups and one-on-one interviews were developed by the study PI. A list of questions served as the basis for the discussions and was revised and expanded as the groups progressed. For the qualitative analyses, conventional content analysis following a systematic process of coding and classification was utilized.Three main protective factors against suicide were identified: 1) psychological support (33%); 2) psychoeducation to raise awareness of suicide and reduce stigma (28%); and 3) providing financial opportunities/supports (10%) and for violence against women 1) advocacy (28%); 2) psychological support (28%); and 3) changing cultural values (17%).This study fills a much-needed gap in our understanding of suicide and violence against women in Muslim populations. Our findings suggest that for intervention to be relevant and effective, prevention programming needs to span micro, mezzo, and macro levels.None Declared"} +{"text": "There is a modest but consistent association between violent behavior and schizophrenia. Persons with schizophrenia are at a modestly increased risk of committing violence ,with approximately half of victims being relativesOur study examined the factors attributed to violent behaviour within the relationship patient-caregiver in schizophrenia according to caregivers.This is a cross-sectional study among caregivers of patients with schizophrenia during the period from June to August 2022.Patients who attended our department of psychiatry at the Razi.The questionnaire was divided into three sections. The first section contained items regarding patient- and caregiver-related information.In the second section, caregivers were asked questions about their experience of violence perpetration and victimization involving their relative with schizophrenia in the past 12 months.Beyond frequency, caregivers were also asked to specify, the causes of the violence perpetrated and sufferedThe third section contained two measures, i.e. the Depression Anxiety and Stress Scales (DASS-21) and the abridged version of the Zarit Burden Interview (ZBI), assessing psychological distress and caregiving burden, respectively. The protocol of the study was approved by the ethics committee of the Razi Psychiatric Hospital.The majority of caregivers were females (63.6%), and consisted of patients\u2019 parents (50.9%).The most endorsed causes of violence victimization were symptoms of illness (57.3%), followed by refusal to adhere to treatment (49.1%), drug reaction (23.6%), and negative events; while the most reported causes of violence perpetration were refusal to adhere to treatment (42.7%), Symptoms of illness (37.3%), and limitation of patients\u2019 activities and/or liberty (32.7%).Bivariate analysis showed that lower patients\u2019 economic status (p=.042), tobacco (p=.015) and alcohol use (p=.014) as well as taking Trihexyphenidyl (p=.001) were significantly and positively associated with violence perpetration by caregivers against their relatives with schizophrenia.Multivariable analysis (Logistic regression) revealed that caregivers\u2019 levels of burden remained significantly associated with violence victimization occurrence , while only having other person in charge of caring represented a significant factor associated with perpetration of any form of violence against patients .It is important for medical staffs to provide caregivers with professional knowledge about patients\u2019 real motivation for violence in order to improve their skills of problem-solving.None Declared"} +{"text": "Clostridioides difficile infection (CDI) is a priority. Infection control measures to prevent CDI target symptomatic (infected) patients. These patients are placed on contact precautions (CP), requiring hand hygiene and use of gloves and gowns. However, asymptomatic (colonized) patients may be a reservoir for cross contamination, and evidence is scarce regarding prevention measures with this population. To address this gap, our study evaluates the effect of universal gloving (UG) for all patient contact to prevent transmission from these patients. However, the gloving intervention involves complex behavioral practices with wide variations in compliance; thus, data on intervention implementation provides critical context. Here we provide a preliminary analysis of intervention fidelity.Prevention of A cluster randomized trial (CRT) is being conducted in ten VA hospital patient units; 5 units randomized to standard of care (CP) and 5 units to the intervention (UG plus CP). A secondary outcome of the study is intervention fidelity (gloving compliance). This analysis includes monthly observation data on hand hygiene (HH) and gloving compliance for UG and HH, gloving, gowning for CP in both groups using a standardized observation tool. Compliance was calculated using the total number of compliant observations divided by the total number of observations.Table 1). Gloving compliance with UG was lower than expected and significantly lower than gloving compliance for CP in the intervention group (Table 2). Table 3 compares HH and gloving between UG (intervention group) and CP (both groups). Gloving compliance was significantly higher with CP than with UG.1012 Observations were conducted between May 2022 and April 2023. HH, gloves and gown compliance for CP did not differ between groups (Results TablesTable 1 - 3Intervention fidelity is critical to support rigor of the CRT, but our results showed lower than expected compliance for both gloving and HH despite the UG intervention. A pilot interview identified the healthcare worker requirement for practicing both HH and gloving as a barrier. Additional investigation into barriers to gloving and HH compliance within the context of a UG intervention is ongoing.All Authors: No reported disclosures"} +{"text": "Scientific Reports 10.1038/s41598-022-24353-9, published online 28 November 2022Correction to: The original version of this Article contained an error in the Funding section.\u201cThis work was supported by the funds from the National Natural Science Foundation of China (No. 81971842 to Lianbo Zhang) (grant numbers 81973120 to Liu) and National Key R&D Program of China (grant numbers #2018YFC1311600 to Liu).\u201dnow reads:\u201cThis work was supported by the funds from the National Natural Science Foundation of China (No. 81971842 to Lianbo Zhang).\u201dThe original Article has been corrected."} +{"text": "During 2013, the 11 countries of the World Health Organization (WHO) South-East Asia RegionRubella is the leading cause of vaccine-preventable birth defects ; 3 develRCV1 was introduced in five SEAR countries before 2013 and in the remaining six SEAR countries for measles and rubella elimination was established during 2016 and developed an updated framework for verification of measles and rubella elimination during 2020 obtain the highest level of national commitment from SEAR countries and support from partners; 2) strengthen routine immunization and achieve \u226595% coverage with RCV1; 3) conduct high-quality SIAs; 4) enhance surveillance sensitivity and increase collection of specimens for rubella virus detection and genotyping; and 5) leverage elimination activities to enhance measures to restore routine immunization services and reduce immunity gaps for all vaccine-preventable diseases. With the regional birth cohort representing 24% of the world\u2019s infants surviving beyond age 1 year, progress toward rubella elimination in SEAR represents an important opportunity to decrease rubella-related death, disability, and illness worldwide.During 2013, coverage with the first dose of rubella-containing vaccine (RCV1) in the World Health Organization South-East Asia Region was 12%, and only five countries in the region had introduced RCV into their routine immunization programs.By 2021, all 11 SEAR countries had introduced RCV1, and estimated regional RCV1 coverage increased from 12% to 86%; rubella incidence declined by 80%. Maldives and Sri Lanka achieved rubella elimination; Bhutan, North Korea, and Timor-Leste have halted endemic transmission of rubella virus for >36 months.SEAR has made substantial progress toward rubella elimination. To achieve regional rubella elimination by 2023, optimal and accelerated measures to implement all elimination strategies are needed."} +{"text": "Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co) at three environmentally different sites. Based on molecular and morphological analyses, we characterized their associated AMF communities. Cj was more densely colonized than Co and that root colonization intensity was significantly correlated with soil AMF diversity. The communities comprised 15 AMF genera dominated by Glomus and Paraglomus and 1443 operational taxonomic units (OTUs) of which 1067 and 1170 were in roots and soil, respectively. AMF communities were significantly different among sites, and the root AMF communities were significantly different from those of soil at each site. The root and soil AMF communities responded differently to soil pH. At the genus level, Glomus and Acaulospora were abundant in roots while Paraglomus and Redeckera were abundant in soil. Our findings suggest that AMF colonizing roots are protected from environmental stresses in soil. However, the root-soil-abundant taxa have adapted to both environments and represent a model AMF symbiont. This evidence of strategic exploitation of the rhizosphere by AMF supports prior hypotheses and provides insights into community ecology.Arbuscular mycorrhizal fungi (AMF) in the roots and soil surrounding their hosts are typically independently investigated and little is known of the relationships between the communities of the two compartments. We simultaneously collected root and surrounding soil samples from The online version contains supplementary material available at 10.1007/s00248-023-02223-9. Arbuscular mycorrhizal fungi (AMF) are ubiquitous symbiotic microorganisms that live in both the soil and in roots of their hosts upon which they bestow diverse benefits , 2. AMF AMF communities and species richness may be similar or dissimilar between the roots and surrounding soil . DiffereCamellia japonica ), and vesicles (vesicular colonization [VC]) following McGonigle et al. [Five ethanol-conserved root systems were selected randomly for the assessment of mycorrhization frequency (MF) and intensity in Cj and Co. The roots were stained with Trypan blue in lactoglycerol . Under ae et al. , except We performed statistical analysis using R v. 4.2.2 softwareWe used a permutation-based multivariate analysis of variance (PERMANOVA) in the vegan R package to examine the effects of site, host species, and compartment on the AMF community. Similar and dissimilar communities were detected by analysis of similarity (ANOSIM) based on Bray-Curtis model in the vegan R package. The AMF community was ordinated and visualized using the ggplot2 R package v. 3.4.0. Next, we applied the multinomial species classification method (CLAM) in the vegan R package to identify the AMF OTUs and genera in each compartment of the rhizosphere (root or soil) and those significantly associated with a host (Cj or Co) . We alsoParaglomus occultum AJ276082 served as the outgroup in the phylogenetic tree for which we relied on the clade only when its SH-aLRT \u2265 80% and UFBoot \u2265 95%. The tree was annotated and displayed using Interactive Tree of Life [The sequences of the top 10 most abundant OTUs (dominant) of each group of samples were aligned using MEGA11 and their maximum-likelihood phylogenetic positions were determined using an automatic model finder, tested with PhyML (SH-aLRT) and ultrafast (UFBoot) bootstraps over 1000 randomizations, all implemented in IQ-TREE 2 . ParagloL, v. 5) .The soil pH was significantly different between sites and host species but the interaction between the two factors was not significant Table . It wentrbcL for Cj and Co (ON156682\u2013ON156726) in BankIt (2569115).After excluding unconfirmed samples, for\u00a0the remaining 94 samples, Illumina MiSeq amplicon sequencing produced 1,114,607 amplicon sequences clustered into 108,048 OTUs. After quality filtering and sequence annotation, we obtained 555,657 Glomeromycota amplicon sequences of excellent quality that clustered into 1445 AMF OTUs. After being rarefied, the normalized AMF community data comprised 226,634 Glomeromycota amplicon sequences in 94 (100.00%) samples and clustered into 1443 AMF OTUs. We deposited the sequence read archives in the National Center for Biotechnology Information (PRJNA714473), the representative nucleotide sequences of the AMF OTUs generated (MZ479751\u2013MZ481498) in GenBank (SUB9891895), and the partial nucleotide sequences of Site, host species, and compartment significantly affected the composition and structure of the AMF community at the OTU level Table S. In UTCBOTU richness of the root AMF community was less than that of the surrounding soil , two unknown clades, and some unknown Glomeraceae . Arbuscles, hypha, and vesicles were observed in Cj and Co , the soil explorers (more abundant in soil than in roots), and the explorers of both, thereby validating the hypothesis of strategic taxon-based colonization in the AMF community and Chamaecyparis obtusa (Co), collected from three sites in Japan. Normalized community data was used to build these curves, 2411 Glomeromycotan amplicon sequences per sample. Despite the differences in the number of samples per group, it is noticeable that OTU richness of the arbuscular mycorrhizal fungi (AMF) community was higher in soil than rootsESM 2Online Resource 2 Venn diagrams of shared operational taxonomic units (OTUs) in roots and soil communities of arbuscular mycorrhizal fungi (AMF) associated with Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co), collected from three sites in Japan. Notice that the number of OTUs exclusively in roots of Cj (Cj Root) or Co (Co Root) has reduced considerably when data from all sites were consideredESM 3Online Resource 3 Phylogenetic tree for the placement of the dominant (top 10 most abundant) operational taxonomic units (OTUs) in the intra- and extraradical communities of arbuscular mycorrhizal fungi (AMF) associated with Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co) collected from three sites in Japan. Maximum likelihood tree was built using the representative sequences of the dominant OTUs (29 nucleotide sequences) and 53 reference nucleotide sequences downloaded from NCBI GenBank and MaarjAM databases. Best model and parameters were selected with automatic model finder in IQ-TREE 2. SH-aLRT test and ultrafast bootstrap (UFBoot) over 1000 randomizations were performed and UFboot \u2265 95% are shown at the nodes where SH-aLRT \u2265 80%. Accessions of the dominant OTUs (in bold) and scientific names of reference sequences followed by their accessions were used for labeling. All sequences contained an average of 550 bp of the small subunit ribosomal DNA between the primer pairs NS31 and AM1 (EPS 1595 kb)ESM 4Online Resource 4 Classification of AMF OTUs in two habitats using multinomial species classification method (CLAM) for the host (Cryptomeria japonica and Chamaecyparis obtusa) and the compartment (root and soil). Only root samples were used for the host-related classification while root and soil samples were used for the compartment-related classification. Generalist, similarly abundant in both habitats; x specialist, more abundant in the habitat x than the other; Too rare, the OTUs is too rare to be classified with confidenceESM 5Online Resource 5 Anatomical structures of arbuscular mycorrhizal fungi (AMF) in stained roots of Cryptomeria japonica and Chamaecyparis obtusa . a and d show vesicles and hyphae, respectively while others show different morphologies of arbusculesESM 6Cryptomeria japonica; Co, Chamaecyparis obtusa. b) The UTCBF and UTCF are mixed plantations of Cj and Co. The UTTF site is an adjacent Cj plantation and Co plantation. Table S2 Understory plant community composition of the study sites. a) + refers to the presence at the corresponding site. Table S3 Analyses of variance on soil pH, soil electrical conductivity, and host diameter at breast height a) Variables are soil pH, soil electrical conductivity (EC), and diameter at breast height (DBH) of the host tree. Factors are Site and Host. Sites are Chiba (UTCBF), Chichibu (UTCF), and Tanashi (UTTF). Hosts are Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). Table S4 Permanova on the arbuscular mycorrhizal fungi (AMF) community at the OTU level. a) Sites are Chiba (UTCBF), Chichibu (UTCF), and Tanashi (UTTF). Hosts are Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). Compartments are root and surrounding soil. Table S5 Mantel test showing the biotic and abiotic effects on the root and soil AMF communities associated with Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). Significant effects are in bold. a) Sites are Chiba (UTCBF), Chichibu (UTCF), and Tanashi (UTTF). Factors are Host and Compartment. Hosts are Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). Compartments are root and surrounding soil. Table S6 Analysis of root and soil AMF communities similarities between Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). ANOSIM p-value < 0.05 (in bold) refers to significantly different communities. Table S7 Analyses of variance on the alpha diversity indices of arbuscular mycorrhizal fungi (AMF) community. a) Variables are number of operational taxonomic units (NOTUs) and Shannon index. Factors are Site, Host, and Compartment. Sites are Chiba (UTCBF), Chichibu (UTCF), and Tanashi (UTTF). Hosts are Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). Compartments are root and surrounding soil. Table S8 Association of arbuscular mycorrhizal fungi (AMF) with host species or compartments of the rhizosphere (Root and Soil) based on the multinomial species classification method (CLAM). Table S9 Mantel test showing the biotic and abiotic effects on the root and soil AMF communities associated with Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). Significant effects are in bold. Table S10 Permanova on the arbuscular mycorrhizal fungi (AMF) community at the genus level. Table S11 Analyses of variance on root colonization by type of arbuscular mycorrhizal fungi (AMF) morphotypes. Table S12 Pearson correlations showing the association of root and soil conditions with the root colonization of Cryptomeria japonica (Cj) and Chamaecyparis obtusa (Co). Correlation values are followed by the significance probability in parentheses. Significant correlations are in boldTable S1 Summary of the study sites a) UTCBF, Chiba; UTCF, Chichibu; UTTF, Tanashi; MAP, mean annual precipitation; MAT, mean annual temperature; Cj,"} +{"text": "This reParticipants of child\u2010bearing potential in HPTN 084, the trial that enrolled individuals assigned female at birth, were required to use long\u2010acting reversible contraceptives (LARCs) with a failure rate of <1%. This stringent requirement was in response to a safety signal associated with peri\u2010conception dolutegravir (DTG) use in women living with HIV . CAB injGood participatory practice (GPP) recommends that community stakeholders contribute to protocol development to ensure locally appropriate and acceptable trial procedures . FollowiN = 101) stakeholders from HPTN 084 countries (n = 82) and the United States (n = 19) attended the consultation, with most representing community (86%), global (7%) and other (7%) stakeholder groups as defined by GPP guidelines [n = 50) (range 43\u201352) stakeholders from sub\u2010Saharan Africa responded to polling questions , National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institute on Drug Abuse (NIDA), and the National Institute of Mental Health (NIMH), under award numbers UM1AI068619 (HPTN Leadership and Operations Center), UM1AI068617 , and UM1AI068613 (HPTN Laboratory Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional funding was provided by the Bill & Melinda Gates Foundation (OPP1154174) and ViiV Healthcare. Pharmaceutical support was provided by ViiV Healthcare and Gilead Sciences.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health."} +{"text": "Objectives: Based on Sardjito Hospital surveillance data in 2020, the incidence of SSI in orthopedic implant surgery was 46 cases (4.7%), mostly in the outpatient clinic. We evaluated some of the potential risks and proposed redesign of infection prevention and control measures in April 2021 to improve the overall clean care at the orthopedic outpatient clinic. Methods: We conducted an operational study to redesign various components of clean care using a before-and-after evaluation of infection risk. The study was led by an IPC nurse and was supported by all levels of stakeholders at Sardjito Hospital, a referral and academic hospital in Yogyakarta, Indonesia, during May\u2013September 2021. Results: The redesigned components covered continuing professional development (CPD) through a workshop on clean care and wound care for doctors and nurses. The workshop also encouraged high-level management to make several important changes: (1) to redistribute medical staff schedules, (2) to start online patient registration to better distribute and decrease patient loads, (3) to set up the waiting room as well as the dressing room with strictly separate between dirty and clean areas, (4) to schedule daily general disinfection at noon during service hours, and (5) to perform routine air disinfection after daily clinic services as well as placing an additional portable HEPA filter for continuous air disinfection. After the these changes, during 2021, 7 SSIs occurred among postoperative orthopedic implant patients, a decrease of 85%. We observed more clean and neat rooms without patient overcrowding as well as easy and comfortable flow of patients and staff. Environmental pathogen germ counts decreased significantly. Conclusions: A redesign project at the orthopedic outpatient clinic reduced the incidence of postoperative SSIs and reduced the number of environmental pathogens. Overall clean care is a basic strategy in IPC for improving patient safety."} +{"text": "In April, May, and June 2003, we conducted market research with decision makers from 3 payer segments to determine their perspectives on the potential introduction of statins to the U.S. over-the-counter (OTC) market.We selected a convenience sample of survey participants based upon prominence in the market, membership size, and by willingness to participate in our study. The 12 participating managed care organizations (MCOs) cover approximately 100 million lives. The 4 pharmacy benefit managers (PBMs) cover approximately 200 million lives. The 3 large employers (one employer withheld quantitative results) provide medical coverage to nearly 1.4 million employees, both actives and retirees. Each survey participant received a verbal description of an OTC statin and a proposed patient self-management system. We asked each participant a series of questions to obtain opinions on a number of issues related to the potential introduction of an OTC statin.Our research findings can be summarized in the following key(1) MCO representatives generally view OTC statins as a low-risk and beneficial addition to drug therapy options; (2) payer policies will continue to support access to prescription statins with no change in policy following introduction of an OTC option; (3) several of the MCOs and 75% of the PBMs anticipate a sharp, short-term increase in plan costs as a consequence of OTC statin availability; (4) survey participants believe that consumer or member reaction will be mixed and that consumer advertising and physician education will be important; (5) MCOs and PBMs are eager for involvement but cautious about partnerships with pharmaceutical companies; and (6) the details of any OTC statin offering will lay the foundation for its success.Based upon interviews conducted from April through June 2003, key decision makers from 4 PBMs, 12 MCOs, and 3 large employers generally considered the introduction of an OTC statin as a low risk and a beneficial addition to drug therapy. Most believed that increased awareness would result in an initial increase in plan costs, but long-term savings would accrue through improved care and availability of lower-cost OTC options for low-to-moderate-risk patients. The key concern is how to help patients gain enough knowledge and comfort to manage their own cholesterol therapy safely and successfully."} +{"text": "Invasive cervical cancer (ICC) is an HIV-associated cancer that is preventable and precancerous stages including early ICC stages could be detected through screening offering opportunities for treatment and cure. The high incidence in women living with HIV and late presentation often at advanced stages of ICC with limited treatment facilities often result in early mortality. We sought to compare the epidemiologic characteristics and survival differences in HIV status of ICC patients in Nigeria.We conducted a cohort study at two federal academic hospital-based research sites in Jos University Teaching Hospital, and Lagos University Teaching Hospital Nigeria, between March 2018 and September 2022. We enrolled women with histologically confirmed ICC with known HIV status, and FIGO staging as part of the United States of America\u2019s National Institutes of Health/National Cancer Institute funded project titled \u2018Epigenomic Biomarkers of HIV-Associated Cancers in Nigeria\u2019. The primary outcome was all-cause mortality with assessment of overall survival (OS) and time to death after ICC diagnosis. OS distribution was estimated using the method of Kaplan-Meier and compared between groups using the log-rank test.A total of 239 women with confirmed ICC were enrolled and included in this analysis, of whom 192 (80.3%) were HIV-negative (HIV-/ICC+), and 47 (19.7%) were HIV-positive (HIV+/ICC+). The HIV+/ICC) patients were younger with median age 46 (IQR: 40\u201351) years compared to 57 (IQR: 45\u201366) among HIV-/ICC+) , with 12-month OS 84.1% (95%CI: 75% - 90%) and 67.6% (95%CI: 42%\u221284%) respectively.ICC is diagnosed at a relatively young age in women living with HIV, with a significantly lower overall survival probability compared to women without HIV. The trend of presentation and diagnosis at advanced stages in women living with HIV could partly explain the differences in overall survival. The World Health Organization (WHO) global estimates showed that 604,127 new cases of invasive cervical cancer (ICC) and 341,831 deaths occurred in 2020.Late presentation and diagnosis, lack of access to care, low resources, and ineffective treatment of ICC have contributed to the high mortality and poor survival for cases of ICC in Nigeria and most low- and middle-income countries (LMICs). \u20138 The dePrevious epidemiologic studies have focused on the survival outcomes of patients with cervical cancer based on stage at diagnosis, access to treatment by surgery or chemoradiation, but few have compared survival outcomes by HIV status., 11, 12 We conducted a cohort study at two academic hospital-based research sites in Jos and Lagos , Nigeria. We enrolled women with histologically confirmed invasive cervical cancer, with and without HIV, as part of the United States of America\u2019s National Institutes of Health/National Cancer Institute funded project titled \u2018Epigenomic Biomarkers of HIV-Associated Cancers in Nigeria\u2019 (U54CA221205) (see inclusion below).Eligible study participants were approached for enrollment at the two research sites between March 2018 and September 2022. Trained research staff screened and enrolled women aged 18 or older who were not pregnant, no history of hysterectomy, and were not undergoing cancer treatment at the time of recruitment. Participants were classified into two cohorts based on histopathological confirmation of ICC and HIV diagnosis: 1) HIV-positive women with ICC (study group: HIV+/ICC+), 2) HIV-negative women with ICC (control group): HIV-/ICC+). Participants\u2019 clinical and demographic information were obtained by interviewer-administered questionnaires at the time of enrollment into the study. The intent and procedures of the study were disclosed to the study participants and informed consent was obtained. The study protocol was reviewed and approved by the Institutional Review Boards (IRB) at UniJos (JUTH/DCS/ADM/127/XXVII/630) and UniLag (CMUL/HREC/02/22/327/V4) in Nigeria, and Northwestern University (NU) in the USA (STU00207051).The HIV status of study participants receiving care and treatment at the Presidential Emergency Plan for AIDS Relief (PEPFAR) program of the two participating institutions was extracted from the adult HIV treatment and care database. Women with unknown HIV status had rapid HIV diagnostic testing according to the national HIV testing serial algorithm, which involved the use of the Rapid Determine Test, Unigold, and STAT Pack rapid HIV diagnostic test kits. All HIV-infected women receiving care in the PEPFAR program at both study sites were on antiretroviral therapy (ART) at the time of study enrollment. Those whose HIV infection was diagnosed at enrollment were provided appropriate HIV counseling and linked to care and commencement of ART in the PEPFAR program of the participating institutions in accordance with the Nigerian National ART Guidelines.Suspected ICC cases were evaluated by the gynecologic oncology team at the Jos University Teaching Hospital (UniJos) and Lagos University Teaching Hospital (UniLag). Diagnostic evaluation of ICC included examination under anesthesia (EUA), and clinical staging according to the international federation of gynecology and obstetrics (FIGO 2009). During tAs previously reported, the pauThe primary clinical outcome analyzed in this study was all-cause mortality with assessment of overall survival and time to death after invasive cervical cancer diagnosis. Overall survival (OS) is defined as time from ICC diagnosis to death with censoring at the date of last available follow up as obtained from clinic visits or telephone contact up to September 30th, 2022. The use of telephone for cancer follow up has been documented in a prior study in Jos Nigeria and in other studies in Africa., 20Study data were collected and managed using REDCap electronic data capture tools, 22 withDescriptive statistics were used to summarize baseline subject characteristics for ICC+/HIV+ and ICC+/HIV- groups, and overall. Continuous variables were summarized using median and interquartile range (IQR) and compared between groups using the Wilcoxon rank sum test. For categorical variables, frequencies and percentages were reported, and proportions were compared using Fisher\u2019s exact test. Frequencies of missing observations were tabulated, and missing observations were not included in these descriptive analyses.Primary objective was to determine the association between HIV status and overall survival (OS) among ICC+ patients. OS distribution was estimated using the method of Kaplan-Meier, and survival estimates are reported with the corresponding 95% confidence bands, 25th, median, and 75th percentiles survival times are presented. Overall survival was compared between groups using the log-rank test. Overall survival was estimated for HIV+ and HIV- groups, and by study site.Statistical analyses were performed using R v. 4.2.2 statistical software, and usiBetween March 18th, 2018, and September 30th, 2022, a total of 239 women with confirmed invasive cervical cancer were enrolled and are included in this analysis, of whom 192 (80.3%) were HIV-negative (HIV-/ICC+), and 47 (19.7%) were HIV-positive (HIV+/ICC+).The median age at study enrollment was 53 years (IQR: 44\u201365) among the ICC+ participants overall. HIV-positive patients were younger with median age 46 (IQR: 40\u201351) years compared to 57 (IQR: 45\u201366) among HIV-negative ; had a higher level of education with only 10.6% having no formal education as compared to 32.6% in the HIV- groups (p<.001); and a higher number of lifetime sexual partners with median of 3 (IQR: 1\u20134) partners among HIV+ patients vs. 1 (IQR: 1\u20132) in the HIV- group (p<0.001). Women without HIV had a higher number of childbirths but comparable age at first childbirth (median 20 years old in both groups) and BMI (median 25 in both groups) to women with HIV. The most common histopathologic variant of ICC was squamous cell carcinoma in 80.4% of all cases and was similar among HIV+ and HIV- women . The majority of patients (68.1%) had moderately differentiated tumor grade , and the histopathologic variants and tumor grading were comparable in both groups. HIV+ women tended to be diagnosed with advanced stage more frequently (64.9%) than HIV- women (47.9%) although the difference was not statistically significant (p=0.10). Other descriptive statistics of the participants with ICC by HIV status have been summarized in Following diagnosis and enrollment of participants with ICC, types of treatments received were not significantly different for women with HIV and without HIV as shown in We also compared the survival outcomes by HIV status and founThis manuscript discusses the descriptive epidemiologic characteristics and survival outcomes of women with and without HIV diagnosed with invasive cervical cancer enrolled in two large tertiary academic medical centers in Nigeria. We found that women with HIV were 11 years younger at diagnosis of ICC compared to women without HIV. Although there were no significant differences in baseline BMI, FIGO staging at diagnosis, histopathologic variants, tumor grading and types of treatment received, we found that overall survival was significantly better in ICC participants without HIV compared to those living with HIV. Our findings were similar with a larger Zambian cohort of ICC patients that showed women with HIV were 10 years younger at diagnosis with a poorer prognosis compared to those without HIV.The relatively low survival rates in our primary analyses likely reflect the fact that treatment options for cervical cancer are greatly limited in most LMIC settings including Nigeria, with a paucity of trained gynecologic oncology specialists and limited cancer centers with chemoradiation facilities. A recent review has corroborated the poor treatment facilities, particularly the lack of radiotherapy centers to compensate the poor surgical services for gynecological cancers in sub-Saharan African settings.These chaThe paucity of trained gynecologic oncologists and limited compliance to treatment guidelines is widespread in LMICs. This has been reported in a related study in Botswana in southern Africa that showed comparable findings of women with HIV being diagnosed with ICC at a much younger age compared to women without HIV, and the hazards of early mortality were significantly higher in women with HIV. The effeThe above findings have implications given the evidence of high incidence of cervical cancer in women living with HIV. It is imOur data showed comparable histologic types of ICC and tumor grading irrespective of HIV status. As in most literature, the most common histologic variant found in both HIV positive, and HIV negative cervical cancer tumors is squamous cell carcinoma variants. A previous study report of a retrospective cervical cancer cohort found that women living with HIV were significantly more likely to be diagnosed at advanced stages of cancer compared to HIV negative women. Our dataA previous histopathologic study of ICC showed that the commonest variant in both HIV positive and negative patients is the squamous cell type, and as in our study cohort is diagnosed at younger age in HIV-infected patients compared to HIV-negative patients. The studOur study findings are unique and are based on the strength of the enrollment protocol jointly developed by investigators from both participating sites in two distinct geographic zones in Nigeria in collaboration with Northwestern University. The histologic diagnoses and tumor grading were further subjected to peer review and quality improvement through a telepathology scanning and video conferencing platform involving the two participating sites and Northwestern pathology core. To the bCervical cancer remains a significant public health concern, diagnosed at a relatively young age in women living with HIV, with a significantly lower overall survival probability compared to women without HIV. The trend of presentation and diagnosis of this cancer at advanced stages in women living with HIV could partly explain the differences in overall survival. Strategies that strengthen access to primary prevention, early detection through screening, and early provision of effective treatment should be prioritized for all women- particularly those infected with HIV.Supplement 1"} +{"text": "Frontotemporal dementia (FTD) encompasses a group of clinically, genetically and pathologically heterogeneous neurodegenerative disorders that mainly affect people under the age of 64 years. However, around 25% of those affected have a later age of onset. FTD represents 10\u201320% of all dementia cases [The clinical hallmarks of FTD include gradual yet progressive deficits in behaviour and/or language with the relative preservation of memory. Subtypes of FTD are identified clinically according to the symptoms that appear prominently at presentation. Clinical diagnoses include behavioral variant FTD (bVFTD), which accounts for nearly 60% of cases; primary progressive aphasia (PPA), which affects language; and the movement disorders progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) . With diC9orf72, progranulin (GRN) and MAPT, with C9orf72 repeat expansions being the most common. Neuropathologically, TAR DNA binding protein-43 (TDP-43), fused in sarcoma (FUS) and tau are three major proteins that cause pathological deposits in FTD post-mortem brains [C9orf72 expansions also have an additional pathology where di-peptide repeat proteins are also found deposited in patients. It is thought that disease pathogenesis is caused either by a gain of toxic function or a loss of nuclear function associated with protein dislocation from the nucleus, which in turn may lead to neuronal degeneration. FUS regulates the transcription of multiple genes, including the MAPT gene [A third of FTD cases are genetically linked with mutations occurring in"} +{"text": "No objective technique exists to distinguish necrotic from viable tissue, risking over-excision in burns and loss of wound healing potential. Using delayed fluorescence imaging of indocyanine green (ICG), a method called second window ICG (SWIG), we have shown that high dose ICG persists in burn wounds in both animals and patients 24 hours after infusion. The necrotic avidity of ICG is proposed as the underlying mechanism, although inflammation also likely has a role. The objective of this study is to examine the hypothesis at both the tissue and cellular levels.To examine the localization of ICG in burn tissue, 4-mm biopsies taken from burn patients who underwent SWIG were embedded and sequentially sectioned for H&E (tissue architecture) and LDH (tissue viability) and ICG fluorescence imaging. To examine whether ICG preferentially binds to necrotic cells, primary skin cells (fibroblasts or keratinocytes) were subjected to thermal injury at 65\u00baC for 0 (untreated), 2.5 or 5 minutes. The cells were subsequently incubated with ICG at concentrations ranging from 0.5 to 5 \u03bcg/mL at 37\u00baC for 30 minutes. A necrosis and apoptosis detection kit with Yo-Pro\u2122-1 and propidium iodide (PI) was used to differentiate live, apoptotic and necrotic cell populations in flow cytometry. The ICG florescence intensity of each cell population was measured with flow cytometry.The fluorescence microscopic imaging revealed that ICG intensity was most intense in the superficial severely thermally-injured tissue and gradually decreased with depth. This zone of high ICG intensity was co-localized with high cellularity (shown in H&E) consisting of a mixture of nonviable skin cells (shown in LDH) and inflammatory infiltrates. Using flow cytometry, the optimal concentration of ICG with the highest ICG florescence median intensity (FMI) and the best separation of live, apoptotic and necrotic cell populations was 2.5 \u03bcg/mL, which was used for subsequent flow cytometry experiments. For both fibroblasts and keratinocytes, the ICG FMI was significantly higher in the necrotic cell population than that of either the live or apoptotic cell population, suggesting higher affinity of ICG to necrotic cells. The ICG FMI of necrotic cells with longer heat exposure (5 minutes) was significantly higher than that of necrotic cells with shorter heat exposure (2.5 minutes), suggesting that the binding sites for ICG increase with the degree of thermal injury.This study demonstrates the necrotic avidity of ICG in burned skin tissue and two primary skin cell types. Further studies are needed to study the ICG binding characteristics with inflammatory cell populations and single cell suspensions dissociated from human burn tissue.This, along with our pilot study of SWIG in patients, supports the feasibility of SWIG in guiding surgical decision-making in burn excision by defining thresholds of fluorescence intensity values."} +{"text": "PLOS Biology demonstrates that combined therapy targeting enhancer of zeste homolog 2 (EZH2) and histone deacetylases (HDACs) may sensitize CRPC to both epigenetic and standard therapies.Development of resistance in castration-resistant prostate cancer (CRPC) involves epigenetic pathways. A new study in Development of resistance in castration-resistant prostate cancer (CRPC) involves epigenetic pathways involving EZH2 and HDACs. This Primer explores a PLOS Biology study showing that combined epigenetic therapy targeting these enzymes can activate cellular stress pathways, which may sensitize CRPC to both epigenetic and standard therapies. Despite advances in diagnosis and treatment, prostate cancer remains the second-leading cause of cancer-related death in men and a significant health concern. This is attributable to its high incidence (an estimated 1 in 8 men are diagnosed with prostate cancer), late stage of diagnosis and development of treatment resistance. Prostate cancer develops in the prostate gland mainly due to dysregulated androgen signaling through the androgen receptor. Androgen receptor has a critical role in regulating the growth and differentiation of prostate cells and is frequently overexpressed or mutated in prostate cancer cells. Suppression of androgen receptor signaling by androgen deprivation therapy (ADT), which involves blocking the production or activity of androgens, has been a major treatment approach for prostate cancer. However, the effectiveness of ADT is limited, and prostate cancer cells can eventually develop resistance to this therapy by finding alternative ways to activate the androgen receptor signaling pathway, leading to development of castration-resistant prostate cancer (CRPC). CRPC consequently is an advanced stage of prostate cancer with limited treatment options. Understanding the biological mechanisms involved in maintenance of CRPC and ways to directly target the resistance mechanisms are therefore critical.Development of the CRPC state involves epigenetic reprogramming in response to persistent androgen receptor targeting, wherein the epigenetic enzyme enhancer of zeste homolog 2 (EZH2) has a critical role. EZH2 is a histone methyltransferase that complexes with polycomb repressive complex 2 (PRC2) components to catalyze the trimethylation of histone H3 lysine 27 (H3K27me3), which is associated with gene repression . EZH2 ovIn addition to EZH2, another key epigenetic enzyme important in CRPC is the class of histone deacetylases (HDACs). HDACs are enzymes that remove acetyl groups from histone proteins in chromatin, which can lead to a tighter packing of DNA and a reduction in gene expression . HDACs aPLOS Biology, Schade and colleagues found that targeting the epigenetic functions of both EZH2 and HDACs together had a synergistic effect in killing CRPC cells, independent of androgen receptor activity [ATF3, which resulted in an acute cytotoxic effect both in vivo and in in vitro models of aggressive CRPCs. Schade and colleagues hypothesized that genes suppressed by EZH2 are incompletely derepressed upon inhibiting EZH2 alone because of sustained presence of deacetylated histones at the target gene regulatory elements by performing expression analysis to identify up-regulated genes and pathways, ChIP-seq, and siRNA knock-down screens. reatment . ATF3 ha results show thaFinally, combination epigenetic therapies have been a focus of research for various cancer types . While E"} +{"text": "Streptococcus infections (iGAS) among children in the United States. Colorado and Minnesota observed an increase in the number of cases in the Fall 2022. Similarly, the Pennsylvania Department of Health issued a health alert that was then lifted in February 2023. Preliminary CDC data showed that iGAS infections were higher in some areas of the country compared to pre-pandemic levels. Lehigh Valley Reilly Children\u2019s Hospital is a community teaching hospital in Allentown, Pennsylvania. A rise in the number of children admitted with GAS infections was noted in the same period compared to previous years. The aim of our study was to determine the clinical characteristics of patients admitted with iGAS and non-iGAS infections during fall and winter 2022-2023.In December 2022 the CDC issued an alert about possible increase of invasive group A st 2022 through March 31st 2023 and diagnosed with GAS infection plus those admitted with the same diagnosis between 2018 and 2022.Retrospective chart review of patients 18 years and younger admitted to Reilly Children\u2019s Hospital between September 1There were 19 children admitted to the hospital with GAS infection: 6 (32%) with iGAS and 13 (68 %) with non-iGAS infections. The iGAS infections included bacteremia without source (2), myositis (1), pneumonia (2), and vascular infection (1). Non-iGAS infections included retropharyngeal abscess (3), peritonsillar abscess (2), parotid abscess (1), submandibular abscess (1), lymphadenitis (2), mastoiditis (1), cellulitis (1), pharyngitis (1), and erythema nodosum (1). Six children required intensive care and two were transferred to higher level care. Median age was 2.2 year for iGAS infections and 4.8 years for non-iGAS. All but one patient had no underlying medical conditions. There were no patient deaths. In 2018 there were zero cases of iGAS infection; in 2019: two cases; 2020: two cases; 2021: zero cases. There were no admissions between May 2020 and April 2022 for either iGAS or non-iGAS.The number of children admitted for iGAS and non-iGAS infections in the fall and winter of 2022-2023 surpassed the preceding 4 years combined. This is reflective of what was happening in some other areas of the country as a result of reduced exposure and lack of immunity due to pandemic restrictions.All Authors: No reported disclosures"} +{"text": "Staphylococcus aureus (MSSA) bacteremia and/or abscess following sacroiliac (SI) joint injections for pain at an outpatient surgery center. Two recovered after treatment and one expired 9 days after the injection. CDPH-HAI and the LHD conducted an investigation.In February 2023, a local health department (LHD) notified the California Department of Public Health (CDPH) Healthcare-Associated Infections (HAI) Program of 3 patients hospitalized for methicillin-susceptible LHD and CDPH infection preventionist staff went on site to evaluate infection control (IC) practices. Whole genome sequencing (WGS) was performed on all available MSSA isolates at the CDPH Microbial Diseases Laboratory.Initial investigation revealed single-dose vials of one product had been used for multiple patients; this practice was discontinued. WGS found the 3 patient isolates were identical (0 single nucleotide polymorphism (SNP) difference). The same healthcare personnel (HCP) team had performed the procedures for all 3 infected patients. A site visit identified gaps in IC and injection safety practices. One HCP who provided care to all 3 patients had visible skin lesions on their hands, wore bracelets, and was unaware of a facility policy to report if they were unable to perform adequate hand hygiene. MSSA screening cultures were collected from 3 involved HCP and were positive in only the HCP with skin lesions. WGS showed that the HCP MSSA isolates were highly related to the patient isolates (0-2 SNP difference). We advised the facility to develop an IC program tailored to the procedures performed, including adverse event surveillance, adherence monitoring of hand hygiene and environmental services practices, and attention to injection safety. The MSSA colonized HCP was referred for treatment of their skin condition and decolonization and was restricted from patient care until their skin condition improved.Phylogenetic tree for MSSAA combination of injection safety and hand hygiene lapses led to MSSA transmission from an HCP to 3 patients. This cluster underscored the importance of IC programs in outpatient clinics and the risk of transmission of infectious agents from HCP to patients with gaps in IC practices. It also highlighted the contribution of WGS in investigating HAI outbreaks.All Authors: No reported disclosures"} +{"text": "Frontiers in Physiology focused on emerging research on nuclear receptors and cardiovascular function in health and disease. Unlike cell membrane G-protein-coupled receptors that elicit biological responses through second messenger signaling, nuclear receptors are a large family of transcription factors that primarily bind to genomic DNA and regulate the expression of target genes, although non-genomic actions of nuclear receptors have also been identified . These studies demonstrate that 2ME2 downregulates AT1 receptor expression in the kidney cortex and liver without impacting angiotensin II binding affinity . The blood pressure-lowering effect of 2ME2 is independent of sex in Wistar rats infused with angiotensin II. In addition, prolonged 2ME2 treatment decreases heart rate and body weight in male SHRs. Collectively, this study demonstrated that 2ME2 plays a critical role in regulating the renin\u2013angiotensin system and resting heart rate through the downregulation of angiotensinogen and AT1 receptor . Sundin et al. determined that turbulent kinetic energy of blood flow in the healthy human thoracic aorta increases with dobutamine stress and is strongly related to cardiac output. Quantification by magnetic resonance imaging (MRI) was performed to determine 4D flow-based hemodynamic parameters and turbulent kinetic energy and evaluate dobutamine stress on thoracic aortas. Findings of this study demonstrate that turbulent kinetic energy with cardiac stress could serve as a risk assessment for aortic disease development . Future studies that focus on the therapeutic potential of 2ME2 to treat hypertension and MRI-based 4D turbulent kinetic measurement to assess cardiovascular disease progression are required.Two original research articles provide novel findings on the regulation of angiotensin type 1 (AT1) receptors by the estrogen metabolite, 2-methoxyestradiol (2ME2), and quantification of turbulent flow and aortic disease development. Imig focused on PPAR and FXR dual modulating drugs for the treatment of metabolic diseases, organ fibrosis, and hypertension. Evidence from clinical studies and animal hypertension models demonstrated that PPAR and FXR agonism can lower blood pressure and decrease end-organ damage in metabolic diseases and hypertension. This review article details the emerging dual modulating drugs that combine PPAR and FXR agonism with soluble epoxide hydrolase (sEH) inhibition or Takeda G-protein receptor 5 (TGR5) agonism (Imig). In preclinical studies, these novel drugs demonstrate reduced side effects in addition to anti-hypertensive, anti-fibrotic, and anti-inflammatory actions. Ertuglu et al. focused on PPAR\u03b3 regulation in salt-sensitive hypertension and insulin resistance. This review highlights the ability of PPAR\u03b3 agonists to increase insulin sensitivity and ameliorate salt sensitivity. These findings on the role for PPAR\u03b3 in pathogenesis of insulin sensitivity and salt sensitivity were coupled with newly found effects on the immune system and vascular function . These review articles provide a framework for future studies to explore nuclear receptor-based drugs in treating metabolic and cardiovascular diseases.Two review articles in this Research Topic focused on PPAR and farnesoid X receptor (FXR) therapeutics for hypertension and PPAR\u03b3 regulation in salt-sensitive hypertension and insulin resistance. Nuclear Receptors in Hemodynamics and Blood Pressure Control presents two original articles and two review articles that highlight emerging findings in the field that could lead to enhanced cardiovascular risk detection, therapeutics for hypertension including salt-sensitive hypertension, and development of dual modulating drugs for metabolic and cardiovascular diseases. Continued understanding of the contribution of nuclear receptors to controlling organ blood flow and blood pressure is needed for the development of effective therapies to combat hypertension and other cardiovascular diseases.The Research Topic"} +{"text": "The advent of enhanced conjugate pneumococcal vaccines for adults has created a need to assess the burden of pneumococcal disease in different populations to support recommendations for vaccination. We assessed the epidemiology of invasive pneumococcal disease (IPD) in adults with underlying lung disease in Ontario, Canada.Streptococcus pneumoniae; annual audits ensure completeness. Isolates are serotyped at the National Microbiology Laboratory. Population data are from Statistics Canada, with estimates of prevalence of underlying conditions from ICES.Ontario introduced PCV7 and PCV13 for children in 2007 and 2010, and PCV13 for immunocompromised adults over 50 years in 2014. TIBDN performs population (pop\u2019n)-based surveillance for IPD in a pop\u2019n of \u223c4.5 million. Microbiology laboratories serving area residents report sterile site isolates of From 2014-2022, 2769 episodes of IPD occurred in adults; detailed clinical data are available for 2366 (85%), and serotyped isolates for 88%. Of these, 573 (24%) had no chronic underlying illness (undill); 1155 (49%) had an undill not affecting the lungs, 165 (7%) had asthma only, 409 (17%) had COPD (with/without asthma or other lung disease (OLD), 64 (2.7%) had OLD alone (most commonly ILD or bronchiectasis). Among those with asthma, 87 (53%) had another undill predisposing to IPD; compared to 290 (71%) of those with COPD and 45 (70%) of those with OLD. Persons with asthma were younger (median age 56y) than those with no or other undill (64y and 61y), and those with COPD or OLD (70 and 71y). Persons with lung disease were more likely to present with bacteremic pneumonia and less likely to have primary bacteremia or meningitis that those without or with other chrill. ICU admission and case fatality rates are in Table 1. The distribution of serotypes causing disease by conjugate vaccine types did not differ among those with lung disease and others . The incidence of disease in persons with asthma and COPD by age group is shown in Figure 2.The epidemiology of IPD differs somewhat in persons with lung disease compared to others, but conditions other than lung disease have a greater impact on incidence and outcome of IPD in adults. Enhanced PCVs likely provide cost-effective protection for 50-64 year olds with asthma/COPD.All Authors: No reported disclosures"} +{"text": "Correction: Research Involvement and Engagement (2022) 8:8 10.1186/s40900-022-00337-xSearch strategy and study selection. The revised Appendix 3: Prisma flow chart and the Search strategy and study selection section is indicated hereafter and the changes in the given section have been highlighted in bold typeface.Following publication of the original article [1], the authors reported errors in Appendix 3: Prisma flow chart and would like to correct the number of studies under the heading The incorrect Search strategy and study selection section reads:248 papers were excluded leaving a total of 23 studies from the published literature search.After full-text screening, a further The correct Search strategy and study selection section should read:249 papers were excluded leaving a total of 23 studies from the published literature search.After full-text screening, a further Appendix 3: Prisma flow chart should read:Appendix 3: Prisma flow chartAll the changes requested are implemented in this correction and the original article [ article has been"} +{"text": "Schizophrenia is a chronic psychiatric illness with symptoms in positive, negative and cognitive domain.The interplay of dietary folic acid intake with common genetic variants that influence folate metabolism, has potential implications for Schizophrenia pathogenesis and treatment.Therefore, it\u2019s deficiency has been identified as a risk factor for Schizophrenia through epidemiologic, biochemical and gene association studies.1-To assess the efficacy of folic acid supplementation on severity of symptoms and overall functional status of patients2-To assess the correlation of serum folate levels with symptom severity and overall functional status of patientsexperimental Group A which received 5mg folic/day along with anti psychotic drugs and control Group B which received only anti psychotic drugs) and followed up for 3 months. Blood sample for measuring serum folate level was obtained from the experimental group at the beginning and at the end of the study period. Scales applied were Positive and Negative Syndrome Scale(PANSS) for symptom severity and Global Assessment of Functioning scale(GAF) for overall functional status.A randomized control trial study was carried out in the inpatient department of a psychiatric tertiary care centre on 40 participants who were between the ages of 18 \u2013 55 years,met diagnostic criteria for Schizophrenia (ICD 10) and had at least 2 years of illness duration while those with a co-morbid psychiatric illness, medical illness and substance abuse were excluded. The participants were then randomly allocated into two groups (table 1) and also in GAF scores between both the groups after 3 months(table 2). At the end of the study period,a strong negative correlation(r= -0.9) was found between serum folate level and total PANSS score in the experimental group (figure 1) while the correlation between GAF score and serum folate level was strongly positive (r= 0.8) (figure 2).A significant difference was observed in PANSS scores at the end of the study between experimental group and control group( Image:Image 2:Our study is among the few to use a randomized controlled study design for assessing the effect of folic acid supplementation on severity of symptoms and global functioning in Schizophrenia,strongly suggesting the use of folic acid as an adjuvant treatment for Schizophrenia.None Declared"} +{"text": "Serial point of care ultrasound (POCUS) exams are essential to assess acute pericardial effusions which can rapidly evolve into cardiac tamponade. A typical presentation includes dyspnea, tachycardia, and chest pain. Importantly, serial cardiac exams in such high-risk patients can detect other concurrent pathologies. We present an unusual case of a patient who initially presented with an acute circumferential pericardial effusion and upon serial POCUS exams developed an unexpected Takotsubo cardiomyopathy in the setting of cardiac tamponade. A 63-year-old woman with a past medical history of Human Immunodeficiency Virus, asthma, and previously treated Hodgkin\u2019s lymphoma presented to the emergency department with 3 weeks of worsening shortness of breath. On initial assessment in the emergency department, the patient was hemodynamically unstable with a heart rate of 140 beats per minute (bpm) and a blood pressure of 88/68 mm Hg. Bedside point of care ultrasound (POCUS) was performed and demonstrated a moderate circumferential pericardial effusion with normal left ventricular function and a collapsible inferior vena-cava (IVC). Intravenous fluids were initiated with resolution of the patient\u2019s hemodynamic instability (Video S1). A computer tomography (CT) of the chest was also obtained in the emergency department which showed extensive mediastinal lymphadenopathy with right middle lobe consolidation. The patient was admitted for evaluation of the pericardial effusion and CT findings. Forty-eight hours after admission, the patient reported persistent midsternal chest pain and shortness of breath with a blood pressure of 110/60 mm Hg, heart rate of 127 bpm, and an oxygen saturation of 100% on 2-liters nasal cannula. Repeat troponin I was elevated at 1.02ng/ml (ref - <0.03 ng/ml). POCUS was performed which revealed mid-to apical left ventricular (LV) akinesis and an interval reduction of LV function along with right atrial systolic collapse, right ventricular diastolic collapse and a plethoric IVC (Video S2). Limited transthoracic echocardiogram done by the echocardiography lab shortly after confirmed the findings. These findings were concerning for Takotsubo/stress induced cardiomyopathy in the setting of tamponade physiology. The patient underwent a pericardiocentesis with removal of 240 mL of fluid with improvement of tachycardia and dyspnea. Formal echocardiography 48 hours after the procedure showed minimal residual effusion with improvement of LV function, which returned to normal within a week (Video S3). Cytology of the pericardial fluid showed inflammatory and mesothelial cells with no evidence of malignant cells. However, subsequent lymph node biopsy revealed recurrence of Hodgkin lymphoma to which her pericardial effusion was attributed. Cardiac tamponade is a pericardial syndrome characterized by impairment of diastolic filling of the ventricles causing reduction of cardiac output. The classically advanced signs of tamponade described as hypotension, distension of jugular veins, and diminished heart sounds (Becks Triad) are present in a minority of patients. The most common initial presenting symptoms are dyspnea and tachycardia, which may be present in the absence of hypotension Echocardiographic evaluation of tamponade includes: i) Quantity and quality of pericardial fluid ii) Systolic right atrial collapse iii) Diastolic right ventricular size and variability with the respiratory cycle iv) Interventricular septal shift of the left ventricle during inspiration v) Collapsibility of IVC Diastolic right ventricular collapse is specific for tamponade while IVC plethora is highly sensitive. Systolic right atrial collapse is often the earliest sign of tamponade. Comprehensive or advanced critical care echocardiography can be used to detect exaggerated respiratory cycle changes in mitral and tricuspid valve in-flow velocities as a surrogate for pulsus paradoxus In this patient the initial POCUS exam revealed a moderate sized pericardial effusion with a fully collapsible IVC making tamponade physiology less likely. When the patient developed new onset chest pain and shortness of breath this raised the concern for worsening tamponade. A repeat ultrasound revealed an unexpected finding of stress induced cardiomyopathy which can potentially be attributable to progressive tamponade development. Potentially the tamponade was further exacerbated by left ventricular dysfunction.In dog models right atrial and ventricular collapse occurred with significantly smaller volumes of pericardial fluid in the setting of induced left ventricular dysfunction Takotsubo-associated myocardial dysfunction is irrespective of vascular territories, and commonly presents as transient mid to apical akinesia, hypokinesia, or dyskinesia in the absence of obstructive coronary disease. Other findings include circumferential apical dilatation , basal hyperkinesia and a severely reduced left ventricular function This case highlights the importance of serial cardiac POCUS examinations in the evaluation of pericardial effusion. Additionally, it highlights the importance of recognizing an acute concurrent cardiac pathology that can quickly lead to a vicious cycle of cardiac dysfunction leading to decompensation. The authors confirm that consent to publish this case was obtained from the patient.All authors of this manuscript have no conflicts of interest. The authors listed have no affiliations with or involvement in any organization or entity with any financial interest in the subject matter or materials discussed in this manuscript. Video S1 Video S2 Video S3"} +{"text": "Since the development of optical coherence tomography (OCT), technological improvements have made this diagnostic imaging tool adaptable to clinical settings . OCT proA 2018 Cochrane review, \u201cOptical Coherence Tomography for Diagnosing Skin Cancer in Adults,\u201d provides an in-depth review of the accuracy of OCT for detecting skin abnormalities. Data from five test accuracy studies were obtained, permitting comparison of the index test to a reference standard. The diagnostic accuracy of OCT was assessed for melanoma (n=2) and keratinocyte carcinomas (n=3). There were insufficient data to determine the diagnostic accuracy of OCT for melanoma or cutaneous squamous cell carcinoma. In a sample of 346 lesions (n=2 studies), the sensitivity and specificity of OCT for detecting basal cell carcinoma (BCC) was potentially superior versus visual assessment and dermoscopic exam\u2014however, given a limited sample size and the high prior probability of BCC, results must be interpreted cautiously. Applied to a hypothetical population (n=1000 people), OCT had better outcomes than visual and dermoscopic exams, correctly identifying 53 more BCC lesions while reducing the incidence of false positives and unnecessary excisions by 87 [The high sensitivity and specificity of OCT for BCC diagnosis are noted in subsequent reviews and expert consensus ,4. An inThe insufficient number of studies available for inclusion, study heterogeneity, and restricted study populations limit the conclusions that may be drawn regarding the diagnostic utility of OCT . Include"} +{"text": "In recent years, there has been an increase in the number of candidates for bariatric surgery and a decrease in psychiatric contraindications.We aim to make an descriptive evaluation of unfavorable feedback concerning mental health of the candidates for bariatric surgery of the Local Health Unit of Matosinhos .Descriptive analysis of unfavorable feedback of mental health of candidates for surgical treatment of obesity.From March 2017 to August 2022, the Mental Health Service of the Local Health Unit of Matosinhos issued 347 pre-surgical feedback. In 63 cases the initial opinion issued was unfavorable: 11 cases due to a psychiatric contraindication (not meeting conditions for intervention) and 52 cases had a conditional opinion . Regarding contraindications, these were due to alcohol use disorder (n=3), binge eating (n=3), intellectual development disorder (n=2), purgative behavior (n=1), psychotic disorder (n=1) and mood disturbance (n=1). In terms of conditional opinions, the issues mencioned were lack of motivation for surgery (n=22), psychopathology (n=20), doubts about informed consent (n=8) and need for multidisciplinary discussion/coordination (n= 7).There was an increase in eligibility of candidates for surgical treatment as most of the initial unfavorable opinions were conditional. This could be explained by the decline of complications associated with bariatric surgery, but also because psychiatric disorders are now being viewed as treatable. Notably people with eating disorders are now fit for surgery after a medical or psychotherapeutic intervention.None Declared"} +{"text": "The pathogenesis of Psoriatic Arthritis (PsA) remains poorly understood. The underlying chronic inflammatory immune response is thought to be triggered by unknown environmental factors potentially arising from a defective immune function.To determine whether an impaired acute inflammatory response by Dendritic Cells (DCs) might compromise the clearance of bacteria and predispose to chronic inflammation in PsA.Mycobacterium tuberculosis, Mycobacterium avium paratuberculosis and a range of other bacteria and TLR ligands was determined. Phenotypical differences involved in cellular responses against (myco)bacteria were determined by qPCR and flow cytometry.The cytokine production by DCs from 13 healthy controls, 11 Rheumatoid Arthritis, 13 PsA and 8 psoriasis patients from The Netherlands and from 6 Scottish healthy controls and 6 PsA patients towards The secretion of the proinflammatory cytokines TNF\u03b1 and IL-6 by PsA DCs was impaired upon in vitro challenge with mycobacteria and TLR2 ligands compared to DCs from healthy controls and RA patients. DCs from psoriasis patients did not demonstrate such a dampened reaction towards mycobacteria. This impairment demonstrated by PsA DCs was associated with elevated serum CRP levels. The expression of TLR2 and other receptors known to mediate mycobacterial recognition was unaltered. The intracellular TLR(2) inhibitors SOCS3 and A20 were more highly expressed in DCs from PsA patients. PsA DCs further demonstrated up regulated levels of the autophagy-related genes ATG16L1, NOX2 and LL37; molecules implicated in the immune response against intracellular bacteria.Our findings indicate that DCs from PsA patients have a disordered immune response towards some species of (myco)bacteria. This might predicate to impaired immune responses to, and in turn impaired clearance of, these bacteria, setting the stage for the chronic inflammation of joints, entheses, skin and the gut found in PsA."} +{"text": "Mycobacterium avium complex (MAC) clinical isolates with varying catalase activity recovered from the blood of HIV patients in terms of invasiveness and intracellular multiplicity in host cells. The catalase activity in MAC isolates was also analysed in context to CD4 counts and clinical presentation of mycobacterial disease in HIV patients.The mycobacterial catalase-peroxidases protect it from the reactive oxidative metabolites and allow its survival within the host phagocytes. We compared the virulence of Catalase activity of KatG protein of 51 mycobacterial isolates from HIV patients was determined. MAC isolate with maximum catalase activity (KatG-max) was compared to isolate having minimum activity (KatG-min) for adherence, intracellular replication and katG mRNA expression by ZN staining, colony forming units (CFU) enumeration and RT-PCR respectively in A549 and HT29 cell lines.rd day of infection (doi) [p<0.001], whereas, it was comparable at 1st doi. CFU enumeration results correlated well with the levels of katGm RNA expression.Catalase activity of mycobacterial isolates was found to be inversely related to CD4 counts and unrelated to the clinical presentation of mycobacterial disease in HIV patients. The intracellular replication of KatG-max isolate was found to be 2 fold higher than KatG-min at 3The MAC isolates having maximum catalase activity and increased katGm RNA expression was favoured for its survival and replication in the host cells. High levels of catalase activity in isolates from HIV patients with low CD4 counts suggest an important role of KatG in the establishment and progression of disseminated MAC disease."} +{"text": "Conservation planning and the design of marine protected areas (MPAs) requires spatially explicit information on the distribution of ecological features. Most species of marine mammals range over large areas and across multiple planning regions. The spatial distributions of marine mammals are difficult to predict using habitat modelling at ecological scales because of insufficient understanding of their habitat needs, however, relevant information may be available from surveys conducted to inform mandatory stock assessments.Dugong dugong) abundance to create spatially-explicit models of dugong distribution and relative density at the scale of the coastal waters of northeast Australia . We interpolated the corrected data at the scale of 2 km * 2 km planning units using geostatistics. Planning units were classified as low, medium, high and very high dugong density on the basis of the relative density of dugongs estimated from the models and a frequency analysis. Torres Strait was identified as the most significant dugong habitat in northeast Australia and the most globally significant habitat known for any member of the Order Sirenia. The models are used by local, State and Federal agencies to inform management decisions related to the Indigenous harvest of dugongs, gill-net fisheries and Australia's National Representative System of Marine Protected Areas.We use a 20-year time series of systematic aerial surveys of dugong (In this paper we demonstrate that spatially-explicit population models add value to data collected for stock assessments, provide a robust alternative to predictive habitat distribution models, and inform species conservation at multiple scales. Ecological scales can vary from 10 s of km2 for isolated, sedentary species with small geographic ranges , to 100,000 s of km2 for migratory species . The scales of planning regions and ecological features are rarely congruent The data that inform conservation planning and the design of marine protected areas (MPAs) are primarily spatially explicit 2Marine mammals are some of the most highly dispersed species with geographic ranges up to 300,000,000 kmDugong dugon) occur in the shallow, protected coastal waters of some 40 countries and territories in the tropical and subtropical Indo-West Pacific. As the only herbivorous mammal that is strictly marine, dugongs are often used as a flagship species because of their high biodiversity and cultural values. Although dugongs are seagrass community specialists, their habitat needs are not yet sufficiently understood to predict their distribution at broad spatial scales using habitat modelling Dugongs (2) would require information on the distribution of: (1) seagrass habitat community composition; and (2) the various factors that influence the choice of seagrass species or habitats by dugongs. This information is currently unavailable for most of the habitats exploited by dugongs in northern Australia.Dugongs are of high cultural and nutritional value to Indigenous Australians and northern Australia is internationally recognised as supporting the most globally significant remaining dugong populations 2; almost half of their range in northern Australian waters from Moreton Bay in Queensland, the southern extremity of the dugong's range on the east coast (27\u00b050\u203221\u2033S), through the Gulf of Carpentaria (12\u00b013\u20328\u2033S) (2). These models have informed dugong conservation initiatives within the Great Barrier Reef World Heritage Area because they effectively delineate the spatial distribution of dugongs at the required scale Systematic aerial surveys have been used to monitor the abundance and distribution of dugong populations in northeast Australia since th\u00b013\u20328\u2033S) . The sur\u00b013\u20328\u2033S) to develThis paper updates and extends the spatially-explicit model of dugong distribution and relative density in the Great Barrier Reef region Marsh's group undertook systematic aerial surveys of northeast Australia in seven survey regions approximUsing the technique of Grech and Marsh (2007) Most aerial surveys were conducted in late spring or early summer when weather and sea states provide optimum survey conditions . In highsensu Marsh and Sinclair (1989) 2) making them inappropriate to use in the spatially-explicit models which we developed at the scale of 2 km * 2 km planning units. Thus the models were based on relative rather than absolute population estimates, nonetheless, relative densities among regions should be approximately comparable All the aerial surveys estimated absolute dugong abundance by correcting sightings for perception bias and availability bias We corrected the spatial data from the aerial surveys for differences in sampling intensity and area sampled between surveys using equations described in Grech and Marsh (2007) As independent data on dugong abundance at the scale of northeast Australia do not exist, we used a re-substitution approach to validate the individual spatially-explicit population models International Union for Conservation of Nature and Natural Resources Red ListWe estimated dugong distribution and relative density at a planning unit of 2 km * 2 km because this scale: (1) corresponds with the scale of the aerial survey data allowing the model to account for: (a) slight changes in altitude of the aircraft (which affects transect width at the surface); and, (b) the blind area under the aircraft; and, (2) is recommended under Criterion B of the 2; medium density 0.0015<0.25 dugongs/km2; high density areas 0.25\u22640.5 dugongs/km2; and very high density areas >0.5 dugongs/km2. We included planning units with 0 dugongs/km2 to ensure that the spatial layers extended across the entire survey region , Hervey Bay (0.43 dugongs/km2), Moreton Bay (0.19 dugongs/km2) and the northern Great Barrier Reef region (0.16 dugongs/km2). The planning units with the highest relative densities were in Moreton Bay (9.0 dugongs/km2), Torres Strait (6.49 dugongs/km2), the northern Great Barrier Reef region (6.03 dugongs/km2) and Hervey Bay (4.56 dugongs/km2). The southern Great Barrier Reef region and coastal waters of the Gulf of Carpentaria had the lowest mean (<0.07 dugongs/km2) and maximum density estimates (<1.92 dugongs/km2).The average relative dugong density in the ongs/km2 . Density2; Planning units of very high and high relative dugong density in Moreton Bay and Hervey Bay were adjacent to the mainland coast and islands . In the 2; high: 12,432 km2, medium: 63,024 km2 and low: 61,800 km2 because: (1) specialised areas of high conservation value such as calving or mating areas and migratory corridors have not been identified; and (2) density estimates are regarded as robust surrogates of habitat utilization The spatially-explicit models suggest that the broad-scale patterns of dugong distribution in coastal regions of northeast Australia are determined by the physical characteristics of their seagrass habitats: exposure to wind and wave activity, tidal ranges and seabed current stress The broad-scale patterns of dugong distribution predicted by our model can assist in the identification of important dugong habitats in data-poor areas of the Indo-Pacific. It is likely that dugongs exhibit habitat preferences similar to those in northeast Australia throughout their range , coastal waters, bays and estuaries with low wave exposure Australia aims to realise its international commitments as a signatory to the Convention on Biological Diversity through the significant expansion of its existing Marine Protected Area network throughout Australia's Exclusive Economic Zone by 2012. The central component of Australia's Oceans Policy is the development of Marine Bioregional Plans and a National Representative System of Marine Protected Areas in Commonwealth waters. Australia's Commonwealth , State and Northern Territory governments are working together to implement this initiative. The models of dugong distribution and relative density currently inform Australia's Oceans Policy and species conservation initiatives of local and State (Queensland and Northern Territory) governments across multiple scales. In the following section, we provide specific examples of the application of the models at local, regional and national scales to demonstrate the merits of using survey data collected for stock assessment in species conservation and the design of MPAs.2). Primarily, the models assist with the development of management decisions related to the harvest of dugongs at the scale of Torres Strait .One of the major outcomes of our modelling exercise was the improved understanding of the relative importance of the seven survey regions to dugong conservation in northeast Australia. Torres Strait has the greatest number of very high dugong density planning units when compared to the other survey regions of northeast Australia ; Table 3Hervey Bay also has a large proportion of very high and high dugong density planning units relative to its size ; Table 3Dugongs are listed as vulnerable to extinction under schedule 3 of the Queensland Nature Conservation (Wildlife) Regulation of 1994 and were one of several explicit reasons for the World Heritage listing of the Great Barrier Reef region The Australian Government is using the models of dugong distribution and relative abundance at the scale of northeast Australia to assisMany government agencies have developed comprehensive and dedicated monitoring programmes to estimate the size and trends of marine mammal populations for stock assessment . For example, the US Marine Mammal Protection Act of 1972 and subsequent amendments mandates the use of the Potential Biological Removal technique to estimate the maximum number of animals that may be removed from a stock Figure S1Spatially-explicit population models of dugong distribution and relative density in Moreton Bay and Hervey Bay.(TIF)Click here for additional data file.Figure S2Spatially-explicit population models of dugong distribution and relative density in the southern Great Barrier Reef.(TIF)Click here for additional data file.Figure S3Spatially-explicit population models of dugong distribution and relative density in the northern Great Barrier Reef and Torres Strait.(TIF)Click here for additional data file.Figure S4Spatially-explicit population models of dugong distribution and relative density in the Gulf of Carpentaria.(TIF)Click here for additional data file."} +{"text": "This study aims to quantify the acute exercise response to early passive and active activities in order to inform exercise prescription when designing rehabilitation programmes for the critically ill. Critical care survival is often associated with a poor functional outcome , with reThis study is a prospective randomised controlled trial with a repeated-measures crossover design. Eligible participants, requiring mechanical ventilation for 4 or more days, completed two exercise activities routinely used in early critical care rehabilitation, a passive chair transfer (PCT) and active sitting on the edge of the bed (SOEOB). The oxygen consumption and cardiovascular parameters were measured to quantify and compare the exercise response between the two activities.Data are presented as the median (interquartile range). Data for five patients have been collected, aged 68 years (23), with an ITU stay of 15 days (10.5) and duration of mechanical ventilation 8 days (12), at the point of intervention. Exercise response results are reported (Table Intensive care patients with prolonged mechanical ventilation demonstrate a higher rate of oxygen consumption when actively sitting on the edge of the bed, compared with a passive chair transfer. This may have important consequences for early mobilisation of the critically ill."} +{"text": "Ossification of the Posterior Longitudinal Ligament (OPLL) is a condition caused by new bone developing in the posterior longitudinal ligament within the spinal canal. OPLL is a common cause of myelopathy in East Asian countries. Here, we report a case with OPLL in thoracic and lumbar spine in Kermanshah, West of Iran. A 40 years old man gradually developed lower extremities paresis with defecation or voiding difficulties. Radiographic evaluation by computed tomography (CT) and magnetic resonance imaging (MRI) confirmed the mass of ossification at the posterior aspect of the T2-T4 and T12-L1 of vertebral body with spinal cord compression. Although OPLL is a common cause of myelopathy in the East Asian countries, it should be included in differential diagnosis of myelopathy in other regions.Ossification of the posterior longitudinal ligament (OPLL), Spinal canal, Myelopathy"} +{"text": "Sox genes encode for a group of transcription factors that share the presence of an HMG-type (high mobility group) box. This is a 79 amino acid motif that encodes their DNA binding domain. They were identified soon after the discovery of the mammalian testis-determining gene Sry, which also possesses an HMG box, and obtained their name from Sry (\u201cSox\u201d Sry-related box genes). The members of the Sox family are highly conserved among vertebrates and so far 26 different genes have been identified and SoxB2 (Sox14 and 21) subgroups, code for a group of highly related transcription factors expressed mainly in the developing and adult Central Nervous System (CNS) in mammals , either self-renew or exit the cell cycle and differentiate. NEPs make cell fate decisions controlled by extrinsic and/or intrinsic determinants . Neuronal fates are determined around the final cell cycle of NEPs during which neural differentiation factors regulate the cell cycle either directly or indirectly. Only recently, SoxB genes have been implicated in the regulation of cell cycle. Studies in the mouse developing cortex showed that Sox1 acts to maintain the undifferentiated state of NEPs via a mechanism involving suppression of Prox1\u2013mediated cell cycle exit and neurogenesis (Elkouris et al., The transcription factors Sox1-3 have been proposed to block neuronal commitment and thus prevent differentiation (Bylund et al., Sox2 null embryos die soon after implantation, masking a potential role for Sox2 in the CNS (Avilion et al., + cortical radial identity and plasticity (Remboutsika et al., Sox2 has found itself in the position of the most celebrated of the Sox proteins due to its role in epiblast formation (Avilion et al., This review is dedicated to the memory of Prof. Larysa Pevny."} +{"text": "Trisomy 21 affects virtually every organ system and results in the complex clinical presentation of Down syndrome (DS). Patterns of differences are now being recognized as patients\u2019 age and these patterns bring about new opportunities for disease prevention and treatment. Low bone mineral density (BMD) has been reported in many studies of males and females with DS yet the specific effects of trisomy 21 on the skeleton remain poorly defined. Therefore we determined the bone phenotype and measured bone turnover markers in the murine DS model Ts65Dn. Male Ts65Dn DS mice are infertile and display a profound low bone mass phenotype that deteriorates with age. The low bone mass was correlated with significantly decreased osteoblast and osteoclast development, decreased bone biochemical markers, a diminished bone formation rate and reduced mechanical strength. The low bone mass observed in 3 month old Ts65Dn mice was significantly increased after 4 weeks of intermittent PTH treatment. These studies provide novel insight into the cause of the profound bone fragility in DS and identify PTH as a potential anabolic agent in the adult low bone mass DS population. Although Down syndrome (DS) was initially described in 1866 Several investigators, including ourselves have reported that adults (and children) with DS have lower bone mass, expressed as BMD, especially in the lumbar spine, compared with their peers without mental retardation or with mental retardation but without DS The Ts65Dn mouse is one of several mouse models of DS that has been developed to investigate the pathology of DS phenotypes 16)65Dn (Ts65Dn) mouse model of DS at both 3 and 24 months of age To investigate bone health in DS, we determined the skeletal phenotype of the Ts at both 3 months and 24 months of age . There w2)); bone area fraction ; cortical thickness (mm); anteroposterior and mediolateral diameters (mm). Sub-region analysis of the mid-shaft of the femur revealed that trisomy significantly decreased cortical thickness in both 3-month old were used.Mice were treated with daily i.p. injections of 30 or 80 ug/kg PTH(1\u201334), or vehicle control, for 28 days. PTH increased whole-body BMD in both 3 month old WT and Ts65Dn mice as determined by DXA . In WT mIntermittent PTH treatment caused an approximately equivalent increase in BV/TV in both WT and Ts65Dn mice . PTH incThe observed increase in trabecular bone mass and volume was mediated by a PTH-stimulated increase in mineral apposition rate and bone formation . Osteoblex vivo bone marrow cultures, the differentiation capacity of osteoblasts and osteoclasts were impaired in Ts65Dn mice, demonstrating the cell intrinsic nature of the bone phenotype, and confirming both mesenchymal and hematopoetic lineages as targets of trisomy 21. Interestingly, and as reported by others The present study demonstrated that Ts65Dn DS mice have lower trabecular bone volume and trabecular number and higher trabecular separation in the proximal tibia and distal femur as well as decreased cortical thickness and strength compared with WT littermates. The low bone mass phenotype is consistent with the human DS population that also displays a low BMD due to decreased bone turnover Ts65Dn mice at 3-months and 24-months of age have significant decreases in trabecular and cortical bone. The BV/TV and trabecular number are significantly decreased at both ages. With the decreased number of trabeculae, there was a subsequent significant increase in trabecular spacing. Interestingly, trabecular thickness was not significantly affected, suggesting that the fundamental mechanism controlling the development of trabeculae is intact in trisomic Ts65Dn mice, but the rate at which they are generated is decreased. These results extend those of Blazek Other DS mouse models have been developed and their bone phenotype investigated The low bone mass phenotype of Ts65Dn male mice like people with DS is profound and is the result of decreased bone turnover. The decreased bone turnover is unexpected, given the hypogonadism and infertility associated with the disorder in humans ex vivo bone marrow cultures and in the histomorphometric analysis of tibias from 3-month old Ts65Dn mice. In ex vivo cultures, both osteoblast and osteoclast differentiation was significantly decreased in Ts65Dn compared with control. In vivo, osteoblast number per bone surface, osteoclast number per bone surface and bone formation rate were all significantly decreased. These observations suggest an intrinsic defect in both the mesenchymal and the hematopoetic cell lineages. While the defect in megakaryocyotopoiesis in DS has been well studied in humans and is recapitulated in the Ts65Dn mouse The defect in both osteoblast and osteoclast differentiation in Ts65Dn mice was observed in both th decade of life and are presenting in increasing numbers with low bone mass and fracture Histological evaluation of the bone marrow confirmed the megakaryocyte hyperplasia as has been reported in Ts65Dn mice and in DS patients Collectively, these observations provide evidence that the low bone mass observed in humans with DS and Ts65Dn mice is due to a cellular defect in both the hematopoietic and mesenchymal lineages, such that aneuploidy\u2019s effects on the available pool of precursor cells decreases their capacity for normal differentiation and function. Thus, fewer cells differentiating into functional osteoblasts and osteoclasts results in the accrual of lower bone mass, which is a mechanism fundamentally distinct from the high bone turnover observed in hypogonadal women and men, where increased numbers and activity of cells leads to low bone mass.In support of this idea, the Ts65Dn mice demonstrate a lifelong deficit in bone turnover, such that normal peak adult bone mass is never achieved. It is important to note that the serum bone turnover markers of control animals revealed the expected age-dependent increases in both formation and resorption markers, whereas markers in Ts65Dn mice do not increase with age and are consistently lower compared with control throughout the life of the mice. If this temporal difference in bone turnover is recapitulated in humans with DS, it would indicate that low bone turnover is sustained in DS resulting in lower bone accrual and is an area that we are actively investigating. Perhaps most importantly, our studies provide the first data to demonstrate the efficacy of a bone anabolic agent in the treatment of low bone mass in DS and call into question the routine use of bisphosphonates (which decrease bone turnover) in this patient population.Intermittent PTH therapy increases bone formation by stimulating osteoblast numbers at sites of bone remodeling, where old bone is replaced with new by the concerted efforts of both osteoclasts and osteoblasts Thus, these data provide a clearer understanding of the cellular mechanisms leading to the low bone mass in DS, suggest a new direction for treatment and provide a relevant animal model for continued studies of the skeleton in DS. Given the elevated fracture risk and rate in DS patients our data provide the rationale to consider bone anabolic therapies in DS patients with low bone mass.ad libitum and a 12-hr light:dark cycle. Only male mice were evaluated due to the decreased fertility of Ts65Dn male mice and the necessity of Ts65Dn female mice for colony maintenance. Animals were purchased at 6 weeks and aged as required. Some mice were aged and maintained at UAMS for up to 24 months.All animal handling and experimentation was performed in accordance with approved University of Arkansas for Medical Sciences (UAMS) institutional guidelines and protocols and approved by the UAMS Institutional Animal Care and Use Committee (IACUC). Ts65Dn male mice and wild type euploid littermate controls were purchased from the Jackson Laboratory . Upon arrival they were housed individually with food and water available For bone phenotyping, animals were sacrificed at 3 months and 24 months and long bones and spines harvested. Some three month old animals were injected with calcein (administered 8 days prior to sacrifice) and alizarin red S (Sigma) or alizarin red complexone (Sigma) (administered 2 days prior to sacrifice), for subsequent determination of dynamic parameters of bone histomorphometry with an inter-label distance of 6 days as described In Ts65Dn and WT mice, serum was extracted from blood drawn at sacrifice and serum procollagen-1 N-terminal peptide (P1NP) and tartrate resistant acid phosphatase (TRAP) measured. P1NP was measured using a commercially available enzyme immunoassay (EIA) (Immunodiagnostic Systems) and TRAP using a TRAP-5b solid phase immunofixed enzyme activity assay (Immunodiagnostic Systems) according to the manufacturer\u2019s protocol.All MicroCT analyses were consistent with current guidelines for the assessment of bone microstructure in rodents using micro-computed tomography The MicroCT slices were segmented into bone and marrow regions by applying a visually chosen, fixed threshold for all samples after smoothing the image with a three-dimensional Gaussian low-pass filter to remove noise, and a fixed threshold . Femoral cortical geometry was assessed in a 1-mm-long region centered at the femoral midshaft. The outer contour of the bone was found automatically using the built-in manufacturer\u2019s contouring tool. Total area was calculated by counting all voxels within the contour, bone area by counting all voxels that were segmented as bone, and marrow area was calculated as total area - bone area. This calculation was performed on all 25 slices (1 slice\u200a=\u200a\u223c12.5 \u00b5m), using the average for the final calculation. The outer and inner perimeter of the cortical midshaft was determined by a three-dimensional triangulation of the bone surface (BS) of the 25 slices, and cortical thickness and other cortical parameters were determined as described After MicroCT analysis, the same tibia and femora, fixed in 10% neutral-buffered formalin, were decalcified in 5% formic acid with agitation until deemed clear by the ammonium oxalate endpoint test Specimens for plastic embedding and cancellous bone histomorphometry were harvested at sacrifice and the muscle dissected away before fixation in Mallonig\u2019s fixative as we have described previously Mechanical testing was performed to determine bone strength of frozen Ts65Dn intact femora (3 month and 24 month), using standard three-point bending as we have described 6 cells per well in \u03b1-minimal essential medium (\u03b1-MEM), supplemented with 15% fetal calf serum, and 10\u22128 M 1,25-dihydroxyvitamin D3 2D3 in quadruplicate wells per treatment. Cells were fed every 3 days with half-volumes of medium, until day 14, when cells were fixed and stained with tartrate resistant acid phosphatase (TRAP) to facilitate determination of the number of TRAP-positive multinucleated (3 or more nuclei) cells formed per well.Bone marrow cells were harvested from femurs for osteoclastogenic culture as previously described 5 cells/cm2 on six-well tissue culture plates (Becton Dickinson Labware) osteoblast medium (\u03b1-MEM +15%FBS containing 10 mM BGP and 50 \u00b5M ascorbic acid). The total number of mesenchymal progenitors recruited into the osteoblastic lineage was measured by alkaline phosphatase-positive staining for colony forming unit-fibroblast (CFU-F) at day 10. Replicate cultures were fed every 3 days with half-volumes of medium, until day 28, when cells were fixed and minerals stained with Alizarin Red to facilitate determination of the number of bone nodules representing CFU-osteoblastic (CFU-OB) formed per well For osteoblastogenesis, bone marrow cells were harvested from femurs and seeded in triplicate at 2.5\u00d710All data were analyzed by either Student\u2019s t-test or one way ANOVA with post-hoc analyses by Bonferroni post-hoc test as appropriate. Parametric data are presented at mean \u00b1 SEM. Differences with P values <0.05 were considered statistically significant and are reported as such. The SigmaStat (SPSS Science) software package was used for all statistical analysis.Figure S1Age-related bone phenotype in Ts65Dn mice. (A) Micro CT reconstructions of proximal tibia and femur from 3-month (left column) and 24-month (right column) old WT (top) and Ts65Dn (bottom) mice. Low bone volume and cortical thinning is evident. (B). Paraffin-embedded decalcified histological sections of proximal tibia from 3-month (left column) and 24-month (right column) old WT (top) and Ts65Dn (bottom) mice stained with H&E. The expected age-related decrease in trabecular bone is observed in both WT (top) and Ts65Dn (bottom), however, the expected increase in marrow fat is observed in WT (top) but not Ts65Dn (bottom). In contrast, Ts65Dn mice reveal the reported elevation in marrow megakaryocyte number (TIF)Click here for additional data file.Figure S2Decreased cortical bone parameters of 24-month old Ts65Dn mice. Determination of femoral midshaft cortical parameters from Micro CT reconstructions of mid shaft femur shows significant decreases compared to WT in (A) cortical cross sectional area, (B) total cross sectional area, (C) periosteal perimeter, (D) Peak load (load tolerated at the breaking point adjusted for bone size), (E) Stiffness (deformation tolerated before breaking). Open bars WT; solid bars Ts65Dn. *, p<0.05 vs. WT control.(TIF)Click here for additional data file."} +{"text": "The G-protein coupled parathyroid hormone 2 receptor (PTH2R) is concentrated in endocrine and limbic regions in the forebrain. Its endogenous ligand, tuberoinfundibular peptide of 39 residues (TIP39), is synthesized in only two brain regions, within the posterior thalamus and the lateral pons. TIP39-expressing neurons have a widespread projection pattern, which matches the PTH2R distribution in the brain. Neuroendocrine centers including the preoptic area, the periventricular, paraventricular, and arcuate nuclei contain the highest density of PTH2R-positive networks. The administration of TIP39 and an antagonist of the PTH2R as well as the investigation of mice that lack functional TIP39 and PTH2R revealed the involvement of the PTH2R in a variety of neural and neuroendocrine functions. TIP39 acting via the PTH2R modulates several aspects of the stress response. It evokes corticosterone release by activating corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Block of TIP39 signaling elevates the anxiety state of animals and their fear response, and increases stress-induced analgesia. TIP39 has also been suggested to affect the release of additional pituitary hormones including arginine-vasopressin and growth hormone. A role of the TIP39-PTH2R system in thermoregulation was also identified. TIP39 may play a role in maintaining body temperature in a cold environment via descending excitatory pathways from the preoptic area. Anatomical and functional studies also implicated the TIP39-PTH2R system in nociceptive information processing. Finally, TIP39 induced in postpartum dams may play a role in the release of prolactin during lactation. Potential mechanisms leading to the activation of TIP39 neurons and how they influence the neuroendocrine system are also described. The unique TIP39-PTH2R neuromodulator system provides the possibility for developing drugs with a novel mechanism of action to control neuroendocrine disorders. It was discovered based on its sequence similarity to other proteins belonging to this receptor family animals administered a PTH2R antagonist as discussed below.in situ hybridization histochemistry and dopamine neurons in the arcuate nucleus , hotplate tests were performed before and after an inescapable foot shock, used as the stressful stimulus or saline) while no differences were observed between groups in the number of closed arm entries or total arm entries, suggesting an anxiolytic-like effect of TIP39 neurons, whose activity is suppressed during lactation. In addition, the TIP39-PTH2R neuromodulator system might also play a role in conveying the effect of suckling on other systems adapted in the postpartum period. PTH2Rs in the preoptic area, the lateral septum, and the periaqueductal gray could be involved in the control of maternal behaviors Dobolyi, . EmotionThere is limited information available showing that TIP39 neurons are activated in stress situations. At present, only the effects of an h-long high intensity noise stress have been reported. Medial paralemniscal and posterior intralaminar TIP39 neurons demonstrate Fos induction together with CRH neurons in response to noise stress, suggesting that TIP39 neurons could be involved in the transmission of acoustic stress derived information to CRH neurons in the PVN (Palkovits et al., c-fos in some PVG neurons (Kiyohara et al., c-fos expression in the PVG significantly outlasts the cold exposure (Miyata et al., Cold exposure but not warm ambient temperature induced The PVG is a site of stimulation-induced analgesia (Rhodes and Liebeskind, via the facilitation of copulatory behavior by current injection into the area (Shimura and Shimokochi, Fos expression following ejaculation (Wang et al., The TIP39-PTH2R neuromodulator system is present in several brain areas that are activated in males following mating (Sachs and Meisel, c-fos expression in the PIL but not in the PVG in response to reunion with their litter (Cservenak et al., Another reproductive influence reaching TIP39 neurons in the PIL was reported in mother rats. Dams deprived of their pups for a day demonstrated 2+ levels (Goold et al., via presynaptic excitation of their afferents (Dimitrov et al., in situ hybridization histochemistry (Figure via potentiation of excitatory inputs to inhibitory interneurons acting on the AVP and dopaminergic neurons, respectively.There are no indications at present that TIP39 would have any action apart from activating the PTH2R. The PTH2R elevates cAMP and in some cells also increases Cay Figure . In othey Figure . Thus, tThe TIP39-PTH2R neuromodulator system may play an important role in the regulation of several different aspects of neuroendocrine functions. TIP39 neurons in the PVG may be stimulated by stress inputs compromising the homeostasis of the animal while TIP39 neurons in the PIL may be stimulated by various reproductive events Figure . AdditioThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Drosophila are remarkably conserved. As IIS pathway governs growth and development, metabolism, reproduction, stress response, and longevity; temporal, spatial, and nutrient regulation of dilps encoding Drosophila insulin-like peptides (DILPs) provides potential mechanisms in modulating IIS. Of eight DILPs (DILP1\u20138) identified, recent studies have furthered our understanding of physiological roles of DILP2, DILP3, DILP5, and DILP6 in metabolism, aging, and responses to dietary restriction (DR), which will be the focus of this review. While the DILP producing IPCs of the brain secrete DILP2, 3, and 5, fat body produces DILP6. Identification of factors that influence dilp expression and DILP secretion has provided insight into the intricate regulatory mechanisms underlying transcriptional regulation of those genes and the activity of each peptide. Studies involving loss-of-function dilp mutations have defined the roles of DILP2 and DILP6 in carbohydrate and lipid metabolism, respectively. While DILP3 has been implicated to modulate lipid metabolism, a metabolic role for DILP5 is yet to be determined. Loss of dilp2 or adult fat body specific expression of dilp6 has been shown to extend lifespan, establishing their roles in longevity regulation. The exact role of DILP3 in aging awaits further clarification. While DILP5 has been shown associated with DR-mediated lifespan extension, contradictory evidence that precludes a direct involvement of DILP5 in DR exists. This review highlights recent findings on the importance of conserved DILPs in metabolic homeostasis, DR, and aging, providing strong evidence for the use of DILPs in modeling metabolic disorders such as diabetes and hyperinsulinemia in the fly that could further our understanding of the underlying processes and identify therapeutic strategies to treat them.The neuroendocrine architecture and insulin/insulin-like signaling (IIS) events in Drosophila, eight insulin-like peptides (DILPs) and one insulin receptor (DInR) are found. DILPs 1\u20138 have been identified mostly through their sequence homology to the mammalian insulin and the typical B-C-A domain structure as observed in mammalian insulin in the brain has provided a physiological link between those two major tissues governing nutrient sensing, metabolism, and aging pathway governs growth and development, metabolism, reproduction, stress response, and longevity. In Drosophila insulin-like peptide genes (dilp1\u20137) with diverse temporal and spatial specific expression patterns and several neurons in the brain constructs in their fat body similar to the levels observed in dSir2 RNAi flies , short neuropeptide F (sNPF) modulates metabolism and lifespan revealed an up-regulation of dilp1 and dilp2 mRNA as the result of sNPF overexpression accompanied by increased IIS in the periphery , a member of Drosophila E3 ubiquitin ligases and adaptor proteins, negatively regulates the expression of brain dilps. Neuronal and IPC-specific knockdown of dcbl results in up-regulation of dilps 2, 3, 5 whereas the Epidermal growth factor receptor (EGFR) signaling pathway mediates this regulatory effect of dCbl only on dilps 2 and 3. Thus, a likelihood of other mediators for dilp5 is speculated play a prominent role in regulating insulin secretion in \u03b2-pancreatic cells signaling -producing corpora cardiaca (CC) cells are neurosecretory cells that function to regulate metabolic processes in the fly (Rulifson et al., dilp2 overexpression strongly supported the notion that loss of DILP2 was responsible for the phenotypes (Rulifson et al., The first set of compelling evidence demonstrating the functional extent of DILPs in controlling growth, development, and glucose homeostasis was generated by the destruction of IPCs. Ablation of IPCs during the early larval stage results in severe developmental delay with a reduction of both cell numbers and body size accompanied by an increased level of circulating sugars suggesting a diabetic-related phenotype (Rulifson et al., daf-2, a gene encoding the insulin receptor homolog in C. elegans nearly doubled the lifespan of the organism (Kenyon et al., Drosophila homolog of the insulin receptor substrate CHICO similarly render cell non-autonomous effects in lifespan extension as the result of reduced IIS (Clancy et al., The role of IIS pathway in aging was first discovered when mutations of dilps and DILP2 possesses the highest homology to the mammalian insulin with a 35% identity in protein sequence (Brogiolo et al., dilp2 is associated with lifespan extension under several conditions. First, activation of dFOXO in the pericerebral fat body extends lifespan with an accompanied reduction in dilp2, but not in dilp3 or dilp5 mRNA levels (Hwangbo et al., dilp2 is associated with the extension of lifespan observed in those flies (Wang et al., dilp2 transcript levels, again indicating that the reduction of dilp2 expression was closely associated with extended longevity under those genetic conditions (Bauer et al., dilp2 expression and increased lifespan, direct modulation of dilp2 levels was needed to assess the causal relationship between dilp2 expression and lifespan control. To this end, surprisingly, while causing a severe reduction of dilp2 transcripts, targeted knockdown of dilp2 in IPCs did not result in any lifespan extension (Broughton et al., dilp3 and dilp5 expression was observed in those flies raising the possibility that a compensatory mechanism exists to modulate overall dilp expression in the IPCs. However, this compensatory increase in dilp3 and dilp5 expression could not completely account for the lack of lifespan extension in dilp2 knockdown flies as a similar increase of dilp3 and dilp5 transcripts was observed in long-lived dilp2 null mutant flies and increased dilp5 expression levels in long-lived dilp2\u20133 mutants (Gronke et al., dilp2 knockdown elicits additional genetic alterations neutralizing the effect on lifespan associated with reduced dilp2 transcripts. The extended lifespan measured in dilp2 null mutants, however, confirms a major role of DILP2 in longevity control. The absence of any change in lifespan in flies with a dilp3 deletion is intriguing as both dilp2 and dilp5 transcript levels are lowered in those flies (Gronke et al., dilp transcript levels and lifespan effects in dilp2, dilp2\u20133, and dilp3 null mutants requires further clarification with measurements of DILP peptide levels as possible compensatory mechanisms to modulate IIS and lifespan regulation. An involvement of DILP3 in longevity control is worth further investigation, however as dilp3 transcript levels appeared to be specifically reduced in long-lived flies with increased mitochondrial uncoupling in adult IPCs (Fridell et al., dilp5 null mutant appeared to have no effect on lifespan under standard diet (Gronke et al., dilp5 levels are moderated in DR-mediated lifespan extension (Min et al., dilp6 loss-of-function mutation neither had any effect on adult Drosophila survival nor on any compensatory increase in the expression of other dilps (Gronke et al., dilp6 in the adult abdominal fat body significantly extends lifespan in females in a diet-dependent manner and negatively affects expression of dilp2 and dilp5, whereas a modest effect in survival is observed when dilp6 is expressed in the pericerebral fat body. This study also shed light on the fact that the longevity effect of dFOXO when overexpressed in the pericerebral fat body requires dilp6 (Bai et al., dilp mutants has confirmed lifespan extension as the result of dilp2 deficiency suggesting a major role of DILP2 in modulating IIS. On the other hand, targeted expression of dilp6 in the adult fat body results in profound longevity and metabolic consequences that underlies its role in lifespan regulation.A significant amount of interest has been bestowed upon DILP2 as its transcript is most abundantly expressed among all dilp mutants have paved the way. IPC ablated flies exhibit high levels of trehalose, lipid and glycogen stores, accompanied by increased stress resistance (Broughton et al., dilp2 loss-of-function mutant with no change in lipid or glycogen levels (Gronke et al., dilp 1\u20134 loss of function mutants were starvation resistant recapitulating the role for dilp2 in starvation resistance (Gronke et al., dilp2 null mutants nor dilp 2\u20133, 5 deletion mutants, created by homologous recombination, were resistant to starvation (Gronke et al., dilp2 null mutants. A putative role for DILP2 in response to oxidative stress was discovered in the context of JNK signaling upon oxidative stress where dilp2 expression is repressed in IPCs (Wang et al., dilp2 RNAi hypomorphs (Broughton et al., dilp2 loss-of-function mutants (Gronke et al., dilp6 over expression in the abdominal fat body exhibit metabolic phenotypes reminiscent of those seen as a consequence of reduced IIS (Bai et al., dilp6 loss-of-function mutants only had high stored lipid levels revealing its specific role in lipid storage (Gronke et al., To aid a better understanding of the significance of DILP2 and DILP6, physiological alterations that accompanied lifespan extension in respective dilp3 or dilp5 single mutants were neither resistant to starvation or oxidative stress nor was there any change in their trehalose, glycogen, or lipid levels (Gronke et al., dilp3 overexpressors play a role in regulating triglyceride levels (Varghese et al., Unlike DILP2 and DILP6, an involvement of DILP3 and DILP5 in any physiological feature that plays a part in lifespan regulation has not been identified. Drosophila. While the exact molecular mechanisms behind DR-mediated lifespan extension are yet to be completely elucidated, several molecular pathways have emerged as important players involved in DR responses (Narasimhan et al., C. elegans, depending upon the methods of DR, lifespan extension associated with DR is largely independent of IIS (Kaeberlein et al., Drosophila (Clancy et al., chico mutants did not respond to optimal DR for additional lifespan extension indicating an overlap between IIS and DR (Clancy et al., dFOXO mutants remained sensitive to DR thus suggesting that DR acts independently of IIS (Min et al., Drosophila in order to reconcile discrepant findings as well as pinpoint a role of IIS in DR (Tatar, Through dilution of nutrient content, DR is a robust intervention that has been shown to extend lifespan in R Tatar, .Drosophila are shown to extend lifespan with changes in dilp5 mRNA levels but not dilp2 or dilp3 levels (Min et al., dilp5 mRNA and DILP5 protein levels are down-regulated in wild type flies under a yeast DR diet where only yeast is diluted while keeping carbohydrate levels constant (Broughton et al., There is emerging evidence on the role of IPCs in lifespan extension through DR, as those neurosecretory cells appear to respond to nutrient changes (Broughton et al., dilp5 knocked down by a UAS-dilp3RNAi construct that repressed expression of dilps 2, 3, and 5 and blocked the nutrient-dependent expression of dilp5, exhibited a normal response to DR under a yeast DR regime implying that DR-mediated lifespan extension works independently of DILP5 (Min et al., dilp6 in the fat body lowers dilp2 and dilp5 expression as well as the respective hemolymph peptide levels, the lifespan of dilp6 overexpressors was similar to the controls under a yeast restricted diet corroborating with the evidence that DR works independently of dilp5 and DILP5 (Bai et al., Flies with dilp5 null mutant flies that displayed a normal DR response also exhibited a compensatory up-regulation of dilp2 mRNA when raised on food with high yeast concentration while dilp3 mRNA levels were up-regulated in these flies raised on food with relatively low yeast concentration (Gronke et al., dilp5 loss-of-function flies raised on yeast DR diet. Supporting evidence for the involvement of DILPs in DR, if not a direct role, was presented when dilp 2\u20133, 5 deletion mutant flies (Gronke et al., per se but whose activity has shown to modulate DR response when over-expressed (Giannakou et al., dilp5 is modulated under DR, this change in expression could simply be a response associated with dietary alterations but does not trigger the longevity effect of DR. Further clarification is required to definitively assign a physiological role of DILP5, if any, in DR response.However, Drosophila homolog of IGF-binding protein, Imp-L2 is shown to bind to DILP2 (Honegger et al., dilps have confirmed that loss of dilp2 and over-expression of dilp6 is sufficient to extend lifespan (Gronke et al., Drosophila as a model to study cross talk between the nutrient sensing fat body and the neurosecretory IPCs has shed significant insight into a systemic control of DILP activities as the result of communication between those two tissues tightly associated with metabolism. The studies highlighted in this review have underscored the importance of measuring DILP levels in order to substantiate and validate their functional significance. Specifically, measuring circulating DILPs in the hemolymph should provide most relevant assessment on secreted DILP levels and their systemic effects (Bai et al., DILPs are involved in a myriad of physiological processes ranging from growth (Brogiolo et al., dilps 1\u20135 mimics phenotypes seen in type 1 diabetes (Rulifson et al., dilp levels in modeling type 2 diabetes (Musselman et al., dilps in Drosophila, metabolic disorders such as diabetes, hyperinsulinemia, or those affecting glucose homeostasis can be modeled in this genetic organism. These approaches will likely further characterize the molecular mechanisms behind these disorders, discover drug targets, and screen potential therapeutic modes to treat these disorders. Apart from disease models, emerging research has revealed an involvement of DILPs in stem cell biology including stem cell proliferation (LaFever and Drummond-Barbosa, dilp8 in tumor eye discs that responds to signals from peripheral tissues to mediate their growth and development has further strengthened Drosophila as a model for investigating mechanisms underlying inter-organ communication and demonstrated a role for DILP8 in cancer biology (Garelli et al., Drosophila through diverse mechanisms that are being unraveled.Ablation of IPCs or deletion of The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "This study evaluated the potential of the NAVIGATOR (Applied Physiology) haemodynamic monitor to improve consistency of cardiovascular assessments amongst ICU members with different levels of expertise and experience.n = 20) post cardiac surgery were monitored by NAVIGATOR to display heart efficiency (Eh), mean systemic filling pressure (Pms) and vascular resistance (SVR) against targets for mean arterial pressure and cardiac output set by the clinical team. Four categories of staffparticipated: nine consultants (C), eight senior registrars (SR), nine registrars (R) and 11 nurses (N) and were asked to score Eh, Pms, and SVR ranging (discrete steps of one) from -5 to 0 to 5 first without (BLIND) and then given (OPEN) access to the NAVIGATOR display. Recommendations for therapeutic interventions were noted. Agreement , disagreement (median and interquartile range of steps) and therapeutic agreement were recorded and analysed for statistical difference BLIND versus OPEN .Patients (Eh was commonly overestimated, Pms commonly underestimated with no clear trend for SVR. Agreement amongst all categories of staff increased and disagreement score decreased for Eh, Pms and SVR Table comparinThe assessment of heart function, intravascular filling and resistance state in postoperative cardiac patients was made significantly more consistent amongst different ICU staff members using the NAVIGATOR haemodynamic monitor. Such enhanced consistency could potentially make the haemodynamic management more effective with improved clinical outcomes."} +{"text": "Early diagnosis of macrophage activations syndrome (MAS) in systemic juvenile idiopathic arthritis (sJIA) may be challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication. However, the diagnostic value of the guidelines for hemophagocytic lymphohistiocytosis (HLH) (1) or sJIA-associated MAS (2) has seldom been examined.To investigate the sensitivity and specificity of diagnostic guidelines for HLH and sJIA-associated MAS in patients with sJIA who developed MAS.The study sample included 155 children with sJIA who had MAS (diagnosed and treated as such by the attending physician) and 2 control groups with potentially \u201cconfusable\u201d conditions, including active sJIA without MAS (n=303) and a systemic febrile infection requiring hospitalization (n=191). Diagnostic guidelines for HLH and sJIA-associated MAS were applied to all MAS and control patients. Because no patient had NK-cell activity and soluble CD25 determination available and bone marrow aspirate was performed in only a few patients, these 3 criteria were excluded from HLH guidelines. HLH criteria were, therefore, met when at least 4 of the 5 remaining variables were present. sJIA-associated MAS criteria were met when at least 2 laboratory criteria or at least 1 laboratory criterion and 1 clinical criterion were present. Sensitivity and specificity of guidelines in discriminating patients with MAS from control patients were assessed.The table shows the comparison of sensitivity and specificity of diagnostic guidelines.The diagnostic guidelines for sJIA-associated MAS revealed strong sensitivity and specificity, whereas HLH guidelines were highly specific, but lacked sensitivity. Sensitivity of HLH was mostly hampered by the excessive stringent threshold for cytopenia and hypofibrinogenemia, and the infrequent occurrence of splenomegaly in patients with MAS."} +{"text": "Ischemic brain injury due to stroke and/or cardiac arrest is a major health issue in modern society requiring urgent development of new effective therapies. The use of appropriate animal models is essential to study the mechanisms of ischemia-induced injury and neuroprotection. The goal of our study was to establish a reliable and reproducible model of brain ischemia in pigs for further research.in vivo SDF videomicroscopy) and histological structure (light microscopy) of brain tissue in healthy control animals and after 3 hours of brain ischemia (three different models).Eighteen pigs (18 to 22 kg) were anesthetized and randomly assigned to the one of the following groups: 1 - control, 2 - unilateral carotid occlusion, 3 - bilateral carotid occlusion, 4 - bilateral carotid occlusion + hypotension (MAP 40 to 50 mmHg). In order to investigate the effects and mechanisms of cerebral ischemia, we assessed the mitochondrial respiration (high-resolution respirometry), microcirculation . Mitochondrial respiration rates after addition of atractyloside and cytochrome c were the same in all experimental groups, suggesting that intactness of mitochondrial outer membrane was not affected by cerebral ischemia. Microcirculatory and histological alterations also demonstrated increasing derangement and reversible structural changes after bilateral carotid occlusion and vascular occlusion combined with systemic hypotension.LEAK respiration was not affected by ischemia in any model. The OXPHOS capacity with pyruvate + malate as substrates decreased by 20% and 79% compared to the control level after bilateral carotid artery occlusion and bilateral carotid occlusion + hypotension, respectively, resulting in the decrease of RCI (ADP/PM) by 14% and 73%. The OXPHOS capacity with succinate as substrate remained constant after unilateral carotid artery occlusion but decreased by 53% after bilateral carotid artery occlusion and hypotension compared to the control level ."} +{"text": "Objectives. To evaluate the feasibility of implementing a statewide children with special health care needs (CSHCN) program evaluation, case management, and surveillance system using a standardized instrument and protocol that operationalized the United States Health and Human Services CSHCN National Performance Measures. Methods. Public health nurses in local public health agencies in Washington State jointly developed and implemented the standardized system. The instrument was the Omaha System. Descriptive statistics were used for the analysis of standardized data. Results. From the sample of CSHCN visit reports (n = 127), 314 problems and 853 interventions were documented. The most common problem identified was growth and development followed by health care supervision, communication with community resources, caretaking/parenting, income, neglect, and abuse. The most common intervention category was surveillance (60%), followed by case management (24%) and teaching, guidance, and counseling (16%). On average, there were 2.7 interventions per problem and 6.7 interventions per visit. Conclusions. This study demonstrates the feasibility of an approach for statewide CSHCN program evaluation, case management, and surveillance system. Knowledge, behavior, and status ratings suggest that there are critical unmet needs in the Washington State CSHCN population for six major problems. Children with special health care needs (CSHCN) are at increased risk for poor health outcomes . The CSHThe Maternal Child Health Bureau (MCHB) defines CSHCN as \u201cthose who have or are at increased risk for a chronic physical, developmental, behavioral, or emotional condition and who also require health and related services of a type or amount beyond that required by children generally\u201d . The MCH Identifying health care problems experienced by CSHCN and their families provides information about the larger service system, while a successful system of services results in high levels of child and family health and well-being . Partner Programs that address the unique needs of CSCHN have long been a component of the public health system . Public The adoption of electronic health records and public health information systems varies across jurisdictions in the United States . Many loThe objective of this study was to evaluate the feasibility of implementing a state-wide case management, surveillance, and program evaluation system for CSHCN program using a standardized Omaha System protocol and visit report. This paper reports preliminary data from the first four months after the implementation of the standardized data collection protocol.The University of Minnesota Institutional Review Board and State of Washington Institutional Review Board approvals were obtained for this study. All local public health agencies in Washington State were invited to a statewide training on the data collection system (September 2010) and to participate in the data collection starting November 2010. The data collection period for this study ended in February 2011. Visit reports were submitted to State of Washington Department of Health CSHCN officials for program evaluations by 25 of the 35 local agencies during this time period. The Department of Health entered the deidentified data into a spreadsheet and provided the spreadsheet to the research team for analysis . The Omaha System was seleThe Problem Classification Scheme is used to identify and classify health-related issues and includes 42 problems. Problems are uniquely identified by distinctive definitions and signs and symptoms (s/sx). The Intervention Scheme is used for addressing the problems which are described using the four-level Intervention Scheme. The four terms of the Intervention scheme are: problem from the Problem Classification Scheme, category (action term), target (defined term that further specifies the intervention), and care description [The Problem Rating Scale for Outcomes is used to measure client knowledge, behavior, and status (KBS) related to each client problem. KBS ratings are documented using a Likert-type ordinal scale from 1 (lowest) to 5 (highest). The knowledge scale measures what the client understands and knows. The behavior scale measures the appropriateness of client actions. The status scale describes the level of severity of client sign and symptoms . The defThe State of Washington Department of Health together with PHNs serving CSHCN sought to develop a uniform CSHCN evaluation protocol including the development of practice standards and assessment guidelines. The purpose of their project was to generate data for overall quality improvement and outcomes reporting. They created the evaluation protocol in response to three important trends: 1) the need to respond to federal maternal-child health national performance measures, (2) the fact that many of the public health agencies had the electronic capacity to collect standardized data, and (3) many of the agencies were using the Omaha System for other maternal-child health programs . Title V the needn = 127). The client demographics were excluded from analysis because of Washington State data deidentification protocols. The only known characteristics of the sample were that the CSHCN who received PHN visits qualified for services through the HHS Title V CSHCN definitions and criteria. There were CSHCN visit reports , 314 problems and 853 interventions were documented. The most common problem identified was growth and development followed by health care supervision, communication with community resources, caretaking/parenting, income, neglect, and abuse. The most common intervention category was surveillance (60%), followed by case management (24%) and teaching, guidance, and counseling (16%). On average, there were 2.7 interventions per problem and 6.7 interventions per visit. The mean KBS ratings for each problem are reported in From the visit reports (n = 80), the most common s/sx were abnormal results of developmental screening tests (40%), inadequate achievement/maintenance of developmental tasks (40%), age-inappropriate behavior (30%), and abnormal weight/height/head circumference in relation to growth/age standards (23%). For the growth and development problem (n = 57), the most common s/sx were inability to coordinate multiple appointments/treatment plans (23%), inadequate source of health care (21%), inadequate treatment plan (21%) fails to obtain routine/preventative health care (18%), inconsistent source of health care (11%), fails to return as requested by health care provider (9%), and fails to seek care for symptoms requiring evaluation/treatment (7%). For the health care supervision problem (n = 57), the most common s/sx were unfamiliar with options/procedures for obtaining services (58%), language, cultural, educational, transportation barriers (38%), difficulty understanding roles/regulations of service providers (36%), inability to communicate concerns to provider (24%), dissatisfaction with services (20%), limited access to care/services/goods (14%), and inability to use/have inadequate communication devices/equipment (2%). For the communication with community resources problem (n = 48), the most common s/sx were difficulty providing physical care/safety (33%), difficulty providing cognitive learning experiences and activities (33%), difficulty providing preventative and therapeutic health care (31%), expectations incongruent with the stage of growth and development (19%), difficulty providing emotional nurturance (17%), dissatisfaction/difficulty with responsibilities (15%), difficulty interpreting or responding to verbal/nonverbal communication (15%), and neglectful or abusive (4.2%). For the Caretaking/parenting problem (n = 45) were low/no income (78%), ability to buy only necessities (33%), uninsured medical expenses (18%), difficulty buying necessities (18%), and difficulty with money management (11%). The most common s/sx of the income problem (n = 18), the most common s/sx were cluttered living space (44%), structural barriers (11%), homelessness (11%), structurally unsound (6%), inadequate heating/cooling (6%), steep, unsafe stairs, (6%) inadequate/obstructed exits and entries (6%), presence of lead based paints (6%), and unsafe equipment/wiring (6%). For the residence problem (n = 12), the most common s/sx were of the signs and symptoms documented in the neglect problem included inadequate/delayed medical care (25%), included lacks necessary supervision (17%), while lacks adequate physical care (8%), lacks emotional support (8%).For the neglect problem . The use of the CSHCN visit reports will generate large data sets that will enable further evaluation of the effectiveness of PHN interventions for these problems. Previous studies have described intervention tailoring and effectiveness for high risk families \u201321. Furt The use of the Omaha System enabled the aggregation of standardized CSHCN data for program evaluation. Assessments and intervention data from 25 of 35 local health jurisdictions were included in this study. The 127 visit reports were submitted to the Department of Health on the paper visit report forms. Data from electronic documentation of CSHCN assessments and interventions were not included in this study but will be available in the future. The interoperability of electronic systems continues to be a challenge. It is essential for state and local health jurisdictions, software vendors, and policy makers to work together to achieve the goals of standardized, interoperable systems to support uniform data collection for program evaluation and research.The results of this study will be used by the Washington State CSHCN program to focus nursing activities on the problems most likely to be encountered by PHNs serving the CSHCN population. Additionally, these results will be used to further refine the program evaluation process.National, state, and local officials have a responsibility to develop, support, and maintain CSHCN programs , 22. Pub With all research using large observational data sets, limitations of the data include observer bias and fidelity to documentation procedures. While the sample of 127 clients from 25 local health jurisdictions demonstrates the feasibility of the approach, bias toward submitting forms for clients with the greatest need may exist. This limitation is supported by the PHN interpretation of the findings reported in Section 5.0. Therefore, alternative explanations for the findings must be considered. In this study, many of the local health jurisdictions started to use the Omaha System for the CSHCN at the beginning of the data collection period. Documentation quality was supported by peer training and the use of KBS rating guide supplements. However, no evaluation of documentation quality was included in the program evaluation protocols. Further research is needed to create quality assurance measures that can be implemented as an integral part of program evaluation.This study demonstrates the feasibility of a structured approach to case management, surveillance, and program evaluation for CSHCN using a standardized terminology. The use of the Omaha System facilitated uniform data collection of client assessments and services across 25 of 35 local health jurisdictions in the first four months of the evaluation. Preliminary findings suggest that critical needs existed among CSHCN in Washington State. In the future, larger data sets will be used to evaluate the quality of PHN services, inform public policy, and improve the health CSHCN and their families."} +{"text": "A number of studies have outlined mechanisms by which mycoplasma infection may promote allergic lung inflammation. In addition, there is increasing evidence from human studies suggesting that mycoplasma infection contribute to asthma exacerbations, and severity with the change of cytokines. The present study evaluated the change of serum levels of eosinophil count, eosinophil cationic protein, and interleukin-5 in atopic children with Mycoplasma pneumonia infection.We recruited 145 children including 45 atopic children with mycoplasma pneumonia (Group 1), 39 non-atopic children with mycoplasma pneumonia (Group 2), 35 children with viral pneumonia (group 3), 26 non-atopic children with viral pneumonia with mycoplasma infection (Group 4). The change of total eosinophil count, serum levels of interleukin (IL)-5, eosinophil cationic protein were measured at admission and at recovery for each group by using commercial ELISA.The serum level of IL-5 at admission was increased at recovery in group 1 . However, Buserum eosinophil cationic protein concentrations were increased at clinical recovery compared to the mean serum concentration at admission .Mycoplasma infection may be associated with the mechanism by which the Mycoplasma pneumoniae contribute to the development of airway hypersensitivity.The outcomes of the present study implied changes of eosinophil and its mediators during"} +{"text": "The aims were to assess: (i) how the instruments were used in practice; (ii) which items of resource use were most frequently measured using patient-recall; and (iii) how estimates compared if more than one method of data collection was used for the same resource itemsWe conducted a review of articles citing trial-related resource use measures catalogued in the Database of Instruments for Resource Use Measurement used an instrument derived from Beecham and Knapp\u2019s Client Service Receipt Inventory or a variation thereof (81/143). Most measures relied on patient- or proxy-recall (126/146) generally administered during researcher interviews. Use of primary and secondary care was the most widely reported items of resource use (136/146). Twelve studies compared more than one method of data collection for the same resource items and 8/12 showed good correlation between medical records and patient/carer recall or at least indicated one could routinely validate the other. No single administration method was deemed superior.Patient interviews are the most common method of questionnaire administration but studies lack clarity on how they are conducted. Results indicate good precision and accuracy in recall questionnaire use; however, concerns about recall bias still exist."} +{"text": "Pathological and imaging data indicate that amyotrophic lateral sclerosis (ALS) is a multisystem disease involving several cerebral cortical areas. Advanced quantitative magnetic resonance imaging (MRI) techniques enable to explore in vivo the volume and microstructure of the cerebral cortex in ALS. We studied with a combined voxel-based morphometry (VBM) and magnetization transfer (MT) imaging approach the capability of MRI to identify the cortical areas affected by neurodegeneration in ALS patients. Eighteen ALS patients and 18 age-matched healthy controls were examined on a 1.5T scanner using a high-resolution 3D T1 weighted spoiled gradient recalled sequence with and without MT saturation pulse. A voxel-based analysis (VBA) was adopted in order to automatically compute the regional atrophy and MT ratio (MTr) changes of the entire cerebral cortex. By using a multimodal image analysis MTr was adjusted for local gray matter (GM) atrophy to investigate if MTr changes can be independent of atrophy of the cerebral cortex. VBA revealed several clusters of combined GM atrophy and MTr decrease in motor-related areas and extra-motor frontotemporal cortex. The multimodal image analysis identified areas of isolated MTr decrease in premotor and extra-motor frontotemporal areas. VBM and MTr are capable to detect the distribution of neurodegenerative alterations in the cortical GM of ALS patients, supporting the hypothesis of a multi-systemic involvement in ALS. MT imaging changes exist beyond volume loss in frontotemporal cortices. Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder characterized by upper motor neuron (UMN) and lower motor neuron (LMN) degeneration The UMN involvement in ALS cannot be easily established based on the clinical ground because of the confounding effect of LMN involvement. The UMN damage has initially been explored mainly in the corticospinal tract using conventional Magnetization Transfer Imaging (MTI) is a MR technique capable to explore the microstructure of the cerebral cortex in several neurodegenerative diseases In order to explore the topographical distribution of VBM and MTI changes in the cerebral cortex of ALS patients we performed a cross sectional study which included voxel based analysis (VBA) of T1 weighted images and MT ratio as well as a multimodal image analysis aimed to ascertain whether MT changes occur independently of regional volume loss.We examined 18 consecutive right handed ALS patients and 18 right handed healthy controls . Age and gender between groups were not significantly different (Mann-Withney U test p\u200a=\u200a0.07 for age and Pearson Chi-square p\u200a=\u200a0.17 for gender). All patients had definitive ALS diagnosis according to the revised El Escorial criteria MR data were acquired on a 1.5 T scanner with high performance gradients , equipped with an 8-channel head coil with ASSET-technology.A high-resolution 3D spoiled gradient recalled (SPGR) sequence (repetition time (TR)/echo time (TE)\u200a=\u200a28 ms/5 ms, flip Angle 40\u00b0, number of excitation 0.75, field of view (FOV) 240 mm, 192\u00d7192 matrix, 124 oblique-sagittal slices 1.5 mm thick, null gap) was acquired with (Sat) and without (No-Sat) the magnetization transfer (MT) saturation pulse. The MT pulse was a 1200 Hz off-resonance pulse.The VBM analysis was carried out by the FSL-VBM optimized protocol MT image processing was performed as described in a previous work In order to exclude the possibility that differences found in voxel-wise MTr analysis were due to brain atrophy in ALS patients compared to healthy subjects, we performed a multimodal image analysis In order to establish a correlation among clinical variables and VBM or MTr changes, ALSFRS score, MRC for upper limb, MRC for lower limb, disease duration and upper motor neuron sign score was inserted as covariate variables within different GLM design matrix.Statistical maps were superimposed onto Anatomical Automated Labeling (AAL) Atlas The research was conducted according to the principles expressed in the Declaration of Helsinki. The study was approved by the Ethics Commitee of Azienda Ospedaliera Universitaria Pisana, Pisa, Italy. Written informed consent was obtained from all the study partecipants.Results of the between group VBM analysis revealed several clusters of reduced cortical GM in ALS patients compared to healthy controls (p<0.05 FWE corrected for multiple comparisons). They were located in the superior, middle and inferior frontal gyri , in the supplementary motor area (AAL 20) and in the temporal lobe (AAL 85) . These rResults of the between group MTI analysis revealed that the MTr values were significantly lower in ALS patients than in the healthy controls in the following cortical regions: superior, middle and inferior frontal gyrus , gyrus cinguli , supplementary motor area , insula and temporal lobe .Results of the between group regional MTI analysis corrected for atrophy revealed that the MTr values were significantly lower in ALS patients than in the healthy controls in the superior, middle and inferior frontal gyri , in the gyrus cinguli , in the supplementary motor area , in the insula and in the temporal lobe .No cluster of significant association between atrophy or MTr changes and clinical scales was detected in the respective statistical maps.ALS is emerging as a multi-system disease involving several frontal-temporal structures beside motor structures and functions In order to compare the spatial distribution of atrophy and MTr changes in ALS we adopted in the present study a voxel based approach of MT data Since a region specific MTr decrease in the sensory motor cortex is observed with advancing age Although we do not know the exact meaning of the reduced MTr in the cerebral motor-related and extra-motor cortex of ALS patients, the rate of MT effect depends on the surface chemistry and the biophysical dynamics of the macromolecules, as well on the concentration of macromolecules and water The neuronal loss and degeneration in the V layer of the cortex into the precentral gyrus is considered the pathological hallmark of the UMN involvement in ALS In the present study the voxel-wise analysis of GM volume, MTr and MTr data corrected for regional atrophy failed to show any structural abnormality in the precentral gyrus of ALS patients. This result may reflect both the fact that the pathological changes in primary motor cortex of ALS patients are subtle On the other hand our and other studies showed clusters of atrophy and MTr changes in motor-related area. Clusters of decreased MTr independent of cortical atrophy were observed in the premotor cortex particularly in the superior, middle frontal gyri pertaining to the fronto parietal circuit At multimodal image analysis, the MTr decrease in prefrontal and temporal cortex of our ALS patients survived correction for local atrophy indicating that the microstructural changes exist beyond the areas of cortical atrophy. This interpretation is supported by the observation that MTI can detect microstructural changes in cortical areas unaffected by atrophy also in patients with Alzheimer disease (AD) A longitudinal evaluation of VBM and MTr data could be a further fundamental step in evaluating their spatial and temporal relationship in the progression of motor and cognitive functions in ALS and is currently under way.We recognize as main limitation of our work that we did not obtain a detailed neuropsychological profile of our patients. This hinders investigation of the relationship between behavioural and cognitive functions and regional volume or MTr of the cortical GM in specific brain structures VBM and MTI reveal regional atrophy and microstructural changes of the cerebral cortex in ALS involving not only motor-related areas but also frontotemporal cortices.MTr reduction occurs in non atrophic cortical areas suggesting that microstructural degenerative phenomena can extend beyond the tissue loss in ALS.Table S1Demographic and Clinical data.(DOC)Click here for additional data file.Table S2VBM results: clusters of cortical atrophy.(DOC)Click here for additional data file.Table S3MT Imaging results: clusters of reduced MT ratio.(DOC)Click here for additional data file.Table S4MT Imaging results: clusters of reduced MT ratio adjusted for atrophy.(DOC)Click here for additional data file."} +{"text": "A number of human diseases such as obesity and diabetes are associated with changes or imbalances in the gut microbiota (GM). Laboratory mice are commonly used as experimental models for such disorders. The introduction and dynamic development of next generation sequencing techniques have enabled detailed mapping of the GM of both humans and animal models. Nevertheless there is still a significant knowledge gap regarding the human and mouse common GM core and thus the applicability of the latter as an animal model. The aim of the present study was to identify inter- and intra-individual differences and similarities between the GM composition of particular mouse strains and humans.A total of 1509428 high quality tag-encoded partial 16S rRNA gene sequences determined using 454/FLX Titanium (Roche) pyro-sequencing reflecting the GM composition of 32 human samples from 16 individuals and 88 mouse samples from three laboratory mouse strains commonly used in diabetes research were analyzed using Principal Coordinate Analysis (PCoA), nonparametric multivariate analysis of similarity (ANOSIM) and alpha diversity measures. A reliable cutoff threshold for low abundant taxa estimated on the basis of the present study is recommended for similar trials.Distinctive quantitative differences in the relative abundance of most taxonomic groups between the examined categories were found. All investigated mouse strains clustered separately, but with a range of shared features when compared to the human GM. However, both mouse fecal, caecal and human fecal samples shared to a large extent not only representatives of the same phyla, but also a substantial fraction of common genera, where the number of shared genera increased with sequencing depth. In conclusion, the GM of mice and humans is quantitatively different (in terms of abundance of specific phyla and species) but share a large qualitatively similar core. Shifts in the composition, known as dysbiosis, of the human GM have in several studies been associated with diseases such as allergies Rodents are the mammalian model most extensively used to investigate the relationship between GM and health and disease. The reason for the popularity of mouse models is their well explored genetic and relatively close physiological similarity with humans and the ability to control a wide range of environmental factors which reduces variation in the baseline gut microbiota between individual study objects Lachnospiraceae family have been suggested as possible biomarkers to help predict predispositions to inflammatory bowel disease Many GM related disorders have been linked with bacterial dysbiosis on a higher taxonomic level proving the usefulness of sequencing the GM to e.g. phylum and family level. For example, Turnbaugh et al. showed that a switch from a low fat to a high fat, high sugar diet in mice, which was associated with obesity, lowered the Bacteroidetes/Firmicutes ratio in the gut within one day However, the usefulness of mice models for such studies would to a large extent also depend on similarities in their GM profiles at genus or species level with humans. The aim of the present study was therefore to demonstrate inter- and intra-individual differences and similarities between the GM composition of three laboratory mouse strains commonly used in research in chronic inflammatory diseases with those of humans based on more than 1.5 million high quality sequences of partial 16S rRNA gene verified with tag-encoded 454/FLX Titanium (Roche) pyro-sequencing.A total of 88 mice and 128 human GM profiles determined using tag-encoded 16S rRNA gene 454/FLX Titanium (Roche) pyro-sequencing were included in the study . All samAll animal experiments were carried out in accordance with the Council of Europe Convention European Treaty Series (ETS) 123 on the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes, and the Danish Animal Experimentation Act (LBK 1306 from 23/11/2007). The study was approved by the Animal Experiments Inspectorate, Ministry of Justice, Denmark.Human specimens used in this meta-analysis come from the independent study that was approved by The Scientific Ethics Committee of Capital Region, Denmark (reference H-4-2010-137). Written informed consent was obtained from volunteers prior to recruitment.http://www.drive5.com/usearch/). The representative sequences from each cluster were aligned with pyNAST (http://qiime.org/pynast/) and subjected to the Ribosomal Database Project (RDP)-based 16S rRNA gene annotation. For intra-individual assessment all mouse and 16 human samples from the control group were subsampled to an equal number of reads per individual (4500 reads per sample which constitutes to 85% of the second most indigent sample in the dataset). For inter-group comparison the reads were merged according to host (mouse strain/human) and subsampled to an equal number of sequences per category, respectively 80000 reads for mice strains comparisons and 600000 reads for similarity assessment between mice and humans. Both numbers constitute approximately 85% of the least numerous category. Alpha diversity measures such as rarefaction curves based on the estimated species number (97% sequence identity threshold), Chao1 and Shannon indexes were calculated for OTU tables that were unified to 4000 (first most indigent sample) sequences per sample.The dataset was analyzed using the Quantitative Insight Into Microbial Ecology (QIIME) open source software package In order to investigate the influence of the sequencing method into variance between categories, which is caused mostly by the low abundant taxa, a set of 16 samples each sequenced in 4 independent runs were compared within their quadruplicates. A set of 1000 subsampled OTU-tables was generated for each sample (3000 reads per sample). Low abundant taxa were removed until taxa similarity of all replicates within a given sample crossed 99%. An average, minimum cutoff value was therefore calculated based on 16000 subsampled OTU tables using an in-house Matlab (Mathworks) script.Principal Coordinate Analysis (PCoA) plots were generated with the Jackknifed Beta Diversity workflow based on 10 distance metrics calculated using 10 subsampled OTU tables. The -e value (number of sequences taken for each jackknifed subset) was set to 85% of the sequence number within the most indigent sample. Analysis of similarities (ANOSIM) was used to evaluate group differences using weighted and unweighted uniFrac distance metrics that were generated based on rarefied (4500 reads per sample) OTU tables. The relative distribution of the GM genera registered in 88 mouse and 16 human samples was calculated for unified, summarized at the genus level OTU tables.http://metastats.cbcb.umd.edu). From each group 14 samples were randomly chosen and combinations of group pairs were tested using 1000 permutations . The relationship between sequencing depth and shared GM, classified into phylum and genus level, between mice and humans was plotted based on multiple subsampled OTU tables composed of two categories collecting 794988 human and 714440 mouse GM 16S rRNA gene reads. Simulation of each sequencing depth was repeated 100 times and an average proportion of shared taxonomic groups between the two categories were calculated (abundance threshold for unshared taxa\u200a=\u200a0.19%).Differences in taxa abundances at phylum and genus level between categories were verified with Metastats (http://www.cytoscape.org/).A network presenting shared genera between categories was prepared for normalized OTU tables (600000 reads per category) after filtering the low abundant OTUs (abundance threshold for unshared taxa\u200a=\u200a0.19%) using the make_otu_network.py script (QIIME). The visualization of the OTU-networks was performed with an open source platform \u2013Cytoscape yielded 1753858. After removing chimeric sequences a total of 1509428 reads remained, meaning that the ChimeraSlayer algorithm Alpha diversity assessment using rarefaction curves revealed that the fecal GM of the BALB/c mice is the most rich in OTUs (species-level). The average Chao1 index calculated for 4000 reads per sample was 2.5\u20135 times higher in this group compared with other groups . SpeciesobLep/J groups where age was the only varying factor were only partially separated . The three remaining mouse strains were either devoid of bacteria from this phylum, or the bacteria were below the detection limit.All reads used in this study were classified into 9 phyla after applying the abundance threshold (0.19%), with one phylum noted as unclassified . GeneralAlistipes (12%), while in human specimens \u2013 Roseburia (12%) and unclassified genus representing the Clostridiales order (10%) were the dominating genera.The relative abundance of genera depicted for all samples individually shows explicit alterations between studies with the human specimens being the most conspicuous category . In totaMetastats analysis revealed widespread differences in the bacterial relative abundance at both phylum and genuobV-Lep/J pups and the NOD group was not detected in the adult B6. obV-Lep/J counterparts (examined in the age of 16 weeks), nor in any of the BALB/c mice. The Akkermansia genus which is the only representative group of the Verrucomicrobia phylum, was therefore the reason of discrepancies on both the phylum . The similarity of the collective mouse and human microbiomes without the abundance threshold was correspondingly 40% and 57% lower at the phylum and the genus level comparedIn Laboratory mice are commonly used as experimental models for diseases such as diabetes Qualitative and quantitative-based analysis of the three mouse strains fecal GM compared with the mice caecal and human fecal GM (PCoA and ANOSIM) disclosed significant separation of all microbial profiles. The composition of the GM has previously been shown to be influenced by multiple factors including environment and host genetics Diet is an environmental factor known to strongly influence GM composition Early priming of bacterial colonization during early life may also influence GM and immunity later in life Lastly, for adult humans and mice the influence of age on the GM profiles seems to be minor as neither human samples collected from patients at different age (18\u201350 years) nor NOD mice analyzed at different ages (14\u201330 weeks) clustered according to age. This supports the high level of GM composition stability in adult individuals which was previously documented among humans and mice Although innovations in high throughput sequencing techniques offer insight into microbial communities at an hitherto up-preceded level of details one need to be aware of constrains that comes with it, for example: sequencing depth, reads error rate and length or analysis methods In the present study the Firmicutes fraction was more abundant than the Bacterioidetes in most fecal and caecal samples, except for the BALB/c fecal samples, which showed an inverted proportion of these two phyla. Human fecal samples had relatively more Firmicutes and less Bacteriodetes compared to most mouse fecal and caecal samples. This is in accordance with earlier studies reporting that the majority of bacteria in the gut are members of these two phyla and that in mice the Firmicutes fraction seems to be much larger than the Bacteriodetes fraction As seen from Prevotella genus has been found to be inversely correlated with body weight gain, cholesterol accumulation, insulin resistance and diet-induced adiposity Odoribacter genus which relative abundance was recently shown to be increased in the caecum of mice exposed to grid floor induced stress obLep/J group that on the other hand were lacking members of the Akkermansia genus. Akkermansia muciniphila has been suggested to possess anti-inflammatory properties as it was found to be present in lower levels in humans suffering from inflammatory bowel disease compare to the healthy control group For example, the vs. humans) using 0.6 million reads per category disclosed 89% similarity between mouse and human GM genera, with 9 genera being unique for human samples and not detected in any of the three mice strains (abundance threshold 0.19%). Among these 9 genera were Faecalibacterium from the Ruminococcaeae family and Asteroleplasma from phylum Tenericutes that both have been suggested as possible indicators of a healthy human GM since disturbances in the relative distribution of common species from these genera have been linked with the etiology of Crohn\u2019s disease (CD) and ulcerative colitis (UC) Megasphera genus was also unique for humans not being detected in any of the three mouse strains. Megasphera spp. have been imputed to support the growth of colonic mucosa Mistsuokella genus has recently been identified as a GM member of lean as well as obese Indians Faecalibacterium and Dialister but also Sutterella from the Proteobacteria phylum showed poor establishment after transplanting them from human into mice GI tracks Pairwise comparison and mouse (blue node) categories generated for normalized OTU tables (600000 reads per category) after filtering the low abundant OTUs using the make_otu_network.py script (QIIME). The visualization of the OTU-networks was performed with an open source platform \u2013Cytoscape .(PDF)Click here for additional data file.Figure S2Number of GM phyla and genera shared between given categories using raw data. Number of taxonomic labels shared between given mice strains using raw data where no abundance threshold was used (A) on the genus level and (B) on the phylum level. 80000 high quality 16s rRNA reads used to represent the GM of each mouse strain were annotated to the Ribosomal Database Project database. (C) Number of phyla and genera shared between collated categories of humans and mice using raw data (600000 reads per category). Labels \u201cBALB/c (f)\u201d, \u201cBALB/c (c)\u201d, \u201cB6.V-obLep/J (16)\u201d and \u201cB6.V-obLep/J (8)\u201d stand for the gut GM of BALB/c mice determined using fecal and caecal samples and B6.V-obLep/J mice using fecal specimens sampled in 16 and 8 weeks of age respectively.(PDF)Click here for additional data file.Table S1The relative distribution of bacterial genera among categories. The relative distribution of the gut microbial genera among single human and five mouse groups . The abundance threshold within at least one of the category was set to 0.19%.(PDF)Click here for additional data file.Table S2Differences in the relative abundance of gut microbial phyla between categories. Differences in the gut microbial phyla relative distribution verified using Metastats (http://metastats.cbcb.umd.edu) for all combinations of categories. Each pairwise comparison was performed based on 1000 permutations .(PDF)Click here for additional data file.Table S3Differences in the relative abundance of gut microbial genera between categories. Differences in the gut microbial genera relative distribution verified using Metastats (http://metastats.cbcb.umd.edu) for all combinations of categories. Each pairwise comparison was performed based on 1000 permutations .(PDF)Click here for additional data file."} +{"text": "Dear Editor,Vagal paragangliomas are uncommon tumors of the parapharyngeal space, approximately 200 cases having been reported. They ariThe other manifestations are hoarseness and less commonly dysphagia, palatal weakness and tongue hemi-atrophy.4] Press Press4] A 37 years old farmer presented with hoarseness and left cervical mass beyond mandible angle. He did not claim of another symptom, on physical examination a firm mobile 2x2 cm mass was moving horizontally. Before treatment planning, we found left vocal cords paralyzed and CT scan demonstrated a heterogenous lesion next to the carotid bifurcation . PlanninThe normal carotid body is a small mass of neurovascular tissue located bilaterally in the medial valley of the carotid artery bifurcation. Although the term \"tumor\" has historically been assigned to these masses, they are not carcinomas, and the neoplastic process is actually hypertrophy of the carotid body tissue.The four main locations of glomus tissue within the head and neck are: (a) The carotid bifurcation (carotid body tumor), (b) The inferior ganglion region (ganglion nodosum) and cervical portion of the vagus nerve , (c) The jugular bulb region (glomus jugulare) and (d) The middle ear cavity (glomus tympanicum). ParagangChallenging options about surgical versus radiation treatment continues, advocating radiation for small lesions,9] and s and s9]"} +{"text": "Nosocomial infection is a constant concern in the obstetric and surgical practice in both developing countries than in developed countries.To assess knowledge, attitudes and practices of the staff of maternity services in the prevention of nosocomial infection in three community health centers in Bujumbura.A qualitative survey was conducted using a standardized questionnaire over 2 months with 76 health workers from three maternity wards of health facilities in the vicinity of all categories. Data collection consisted of two parts: first assessment of knowledge through a questionnaire and also the observation of attitudes and practices of personal hygiene.It was noted: In knowledge: Knowledge of the exact def-inition of nosocomial infection: 75% (doctors), modes of transmission of infection (manu-portage): 50%, hygiene protocols: 25%, and procedures decontamination of contaminated equipment: 16%. At the observation of practices:Compliance with hand washing before and after childbirth: 50% Use of alcohol-based solutions: 20%, antiquated equipment sterilization: 80% Compliance with the sterilization of equipment: 25% Circulation in delivery rooms disorganized: 100%, perceived risk of blood contamination (uterus): 75%, biomedical waste collected and decontaminated evil: 80%, existence of incinerators: 33.3% and participation in training in personal hygiene: 50%.There is a high risk of infectious contamination in maternity services studied for both the staff and for parturient and their newborns.None declared."} +{"text": "This study assessed the feasibility and acceptability of utilising insecticide treated plastic sheeting (ITPS) as a malaria control intervention in Papua New Guinea (PNG).\u00ae ITPS was installed in 40 homes across four study sites representing a cross section of malaria transmission risk and housing style. Structured questionnaires were completed at the time of ITPS installation (n=40) and at four weeks post installation (n=40) with the household head. Similarly, focus group discussions (FGDs) with the male and/or female household heads were completed at installation (n=5) and four week follow-up (n=4).Zero Vector\u00ae ITPS was successfully installed in a range of homes employing traditional and/or modern building materials in PNG. The ITPS installations remained intact over the course of the four week trial period and were highly acceptable to both male and female household heads. No dissatisfaction with the ITPS product was reported at four week follow-up; however, the installation process was time consuming, participants reported a reduction in mosquito net use following ITPS installation and many participants expressed concern about the longevity of ITPS over the longer term.ZeroVector\u00ae ITPS installation is feasible and highly acceptable in a diverse range of PNG contexts and is likely to be favourably received as a vector control intervention if accessible en masse. A longer-term evaluation is required before firm policy or public health decisions can be made regarding the potential application of ITPS in the national malaria control program. The positive study findings suggest a longer-term evaluation of this promising malaria control intervention warrants consideration.ZeroVector"} +{"text": "Despite the introduction of more aggressive systemic therapies for the management of rheumatoid arthritis (RA) MTP joint pain & deformity is commonly reported. Previous research has proposed that articular damage in the forefoot of patients with RA is probably caused by synovitis leading to destruction of the bone & soft tissues, which might result in the failure of a complex ligamentous system & the dynamic effect of displacement of the plantar plates (PP).In 24 patients with RA the more symptomatic forefoot was imaged using MRI, high-resolution ultrasound (HRUS) & conventional radiography (CR). The MRI & HRUS images were assessed to determine inflammation & damage at the MTP joints, the presence or absence of the PP & to identify tears of the PP & their location. CR was used to determine radiographic progression at the MTP joints.17 females and 7 males (mean (SD) age of 55.5 (10.5) years, disease duration 10.6 (8.6) years & forefoot pain score was 43.4 (27.9)) took part.Tears were not identified on HRUS. The Larsen score on the index foot correlated with the absence of PP viewed using both MRI & HRUS . MRI synovitis was not related to PP absence on either MRI or HRUS but there was good correlation between MRI bone oedema & the number of absent PP visualised using MRI & HRUS . There was also a strong correlation between MRI imaged bone erosion & PP absence confirmed using both MRI & HRUS .In agreement with existing literature, this current study demonstrates that pain & deformity at the MTP joints is highly prevalent despite good disease control. The findings indicate that PP failure is associated more with damage at the lesser MTP joints than active synovitis in patients with RA. Longitudinal follow-up of patients with RA & forefoot pain is required to establish the relationship between local inflammation, disease activity, impairment & structural changes, & identify factors that precede & result in PP pathology."} +{"text": "The endothelial glycocalyx is a recently discovered structure at the luminal side of blood vessels consisting of proteoglycans and glycosaminoglycans, which play an important role in vascular barrier function and cell adhesion. Due to its vulnerability, the endothelial glycocalyx may easily be altered by hypoxia , TNF\u03b1 22, oxidizn = 10), severe sepsis (n = 9) and septic shock (n = 18) as defined by the members of the ACCP/SCCM Consensus Conference Committee by ELISA technique and polymorphonuclear leukocyte (PMN) function by flow cytometry in eight healthy volunteers (HV) and 37 patients who were prospectively enrolled within 24 hours of onset of signs of infection, if they met the criteria for sepsis n = 0, severeP < 0.05; Figure Plasma levels of the glycocalyx components were significantly higher in septic patients than in healthy volunteers and even more pronounced in patients with severe sepsis and septic shock (all Elevated plasma levels of hyaluronan, syndecan and heparan sulfate are suggestive of a glycocalyx shedding from endothelium with increasing sepsis severity. This process might contribute to the vascular dysfunction and development of edema in septic patients."} +{"text": "The aim of the study is identification of correlations between the serum concentrations of iron and the risk of breast cancer among female BRCA1 mutations carriers and unselected breast cancer patients.The first group (99 triplet) selected for the trial were Polish women, positive for at least one of three founder mutations in BRCA1 gene dominating in Poland . Serum was collected at the time of breast cancer diagnosis. Persons with detected tumor were considered as cases and the others were considered as controls. One case and two controls were paired regarding many criteria to achieve the maximum of similarity between them.The subjects of the second group (28 triplet) selected for the trial were Polish women, positive for at least one of three founder mutations in BRCA1 gene. Serum was collected 1-2 years before breast cancer diagnosis. One case and two controls were matched for year of birth, past history of cancer, adnexectomy status and cigarettes smoking to achieve the maximum of similarity between them.The subjects of the third group were unselected cancer for the trial were Polish women. Serum was collected during breast cancer diagnosis before treatment. One case and one control were matched for year of birth (+/- 3 years), number and location of cancer among I\u00ba relatives, smoking-the number of pack years (+/- 10%), adnexectomy status, CHEK2 mutation.The proportion of cases and control in the first quartile was taken as a reference to calculate the odds ratio, confidence interval and p-value of the multivariate conditional logistic regression.The iron was quantitatively measured by ICP-MS (Inductively Coupled Plasma Mass Spectrometry), .This study shows that concentration levels of iron in blood serum are a strong factors associated with an additionally increased risk of breast cancer among BRCA1 mutation carriers and unselected breast cancer patients.For iron concentration in BRCA1 carriers (serum collected at the time of breast cancer diagnosis) all quartiles above the first one had a decreased risk of breast cancer. The results are shown in Table For iron concentration in BRCA1 carriers (serum collected 1-2 years before breast cancer diagnosis) the last quartile had a decreased risk of breast cancer. The results are shown in Table Individuals classified in the III and IV quartile had lower risk of breast cancer however results were statistically insignificant.The strongest result and lowest cancer risk was for Fe > 1350 \u03bcg/l For iron concentration in unselected breast cancer patients (serum was collected during breast cancer diagnosis before treatment) all quartiles were statistically insignificant. The results are shown in Table Individuals classified in the III quartile had lower risk of breast cancer however results were statistically insignificant.The strongest result and lowest cancer risk was for Fe > 1000 \u03bcg/l .For iron concentration in unselected breast cancer patients (serum was collected during breast cancer diagnosis before treatment) before 55 years old, third quartile had a decreased risk of breast cancer. The results are shown in Table Individuals classified in the III quartile had lower risk of breast cancer ;The strongest result and lowest cancer risk was for Fe concentration higher than 987 \u03bcg/l (III quartile) ; max 1285 \u03bcg/l (III quartile)"} +{"text": "Inflammation is a vital process induced by microbial infection or tissue injury. The main function of inflammation is to resolve the infection or repair the damage and return the body to a state of homeostasis. Acute inflammation can induce signals that result in two main functions: 1) initiation of an inflammatory cascade that helps limits the infection and 2) activation of the immune response. In this study we determined the impact of the nature and magnitude of acute inflammation on the host anti-tumor activity against Ehrlich Ascites cancer cell (EAC) line as a model system which forms either peritoneal ascites upon intraperitoneal injection.Different inflammatory signals, including agonists for toll-like receptor (TLR) 2 (zymosan) and TLR3 agonist (poly (I:C) or its clinical grade Hiltonol\u00ae), complete Freund's adjuvant (CFA), and incomplete Freunds Adjuvant (IFA), and BCG from Bacillus calmatte (TLR9 agonist) were used to induce acute inflammation 1 day after i.p. challenge with EAC.We found that Hiltonol\u00ae, poly (I:C), IFA, CFA, and BCG induced inflammatory cells associated with anti-tumor activity that resulted in significant decrease in the tumor growth measured by the total number of tumor cells after 7 days of tumor challenge. Of interest, among the test TLR agonists both poly(I:C) and Hiltonol\u00ae (TLR3 agonist) showed the highest anti-tumor effects.Provision of the proper inflammatory signal with optimally defined magnitude and duration during cancer growth will induce inflammatory cells with potent anti-tumor responses leading to significant decreases in tumor growth."} +{"text": "Studies investigating the outcome of conservative scoliosis treatment differ widely with respect to the inclusion criteria used . While tA PubMed and (incomplete) hand search for outcome papers on PT has been performed in order to detect study designs and inclusion criteria used.Real outcome papers (start of treatment in immature samples / end results after the end of growth) have not been found. Some papers investigated mid-term effects of exercises, most were retrospective, few prospective and someAn agreement of the scientific community on common inclusion criteria for future studies on PT is necessary. We would suggest the following: (1) girls only, (2) age 10 to 13 with the first signs of maturation (Tanner II), (3) Risser 0-2, (4) risk for progression 40 \u2013 60% according to Lonstein and Carlson.A SOSORT consensus paper following a 3-step Delphi process seems necessary in order to establish the inclusion criteria for future studies on PT."} +{"text": "Disseminated intravascular coagulation (DIC) is observed after not only sepsis but also trauma. DIC is associated with concomitant activation of coagulofibrinolytic disorder and systemic inflammation with endothelial dysfunction and microvascular permeability. The angiogenic factors, including vascular endothelial growth factor (VEGF), angiopoietin (Ang), and their receptors, play crucial roles in angiogenesis and microvascular permeability. The aim of the study was to assess: the relationship between angiogenic factors, their soluble receptors and organ dysfunction associated with DIC precipitated by severe trauma; and the effects of DIC-induced platelet consumption, thrombin generation and tissue hypoxia on the expression of these factors and receptors.Fifty-seven patients with severe trauma were divided into two subgroups: 30 DIC patients and 27 non-DIC patients. The serum levels of angiogenic factors were measured on admission (day 1), day 3, and day 5. We compared serum levels of these angiogenic factors between with and without DIC groups and evaluated their predictive value for organ dysfunction and outcome.DIC patients showed higher Sequential Organ Failure Assessment (SOFA) scores, soluble fibrin and lactate levels. The serum levels of VEGF, Ang1, and the sTie2 levels were lower in the DIC patients than the non-DIC patients. The serum levels of sVEGFR1, Ang2 and the Ang2/Ang1 ratio in the DIC patients were higher than in those without DIC. The sVEGFR2 levels showed no statistically significant difference between the patients with and without DIC. The levels of sVEGFR1, Ang2 and the Ang2/Ang1 ratio correlated with the SOFA score. In particular, sVEGFR1 and Ang2 were independent predictors of an increase in the SOFA score. The lactate levels independently predicted increases in the levels of sVEGFR1 and Ang2 and platelet consumption also independently predicted the increase in Ang2 levels in severe trauma patients with DIC.Angiogenic factors and their soluble receptors, particularly sVEGFR1, play pivotal roles in the development of organ dysfunction in DIC associated with severe trauma. The DIC-induced tissue hypoxia and platelet consumption plays crucial roles in inducing sVEGFR1 and Ang2, and in determining the prognosis of the severity of organ dysfunction."} +{"text": "Molecular epidemiologic findings suggest an ancient focus of TB. Mycobacterium tuberculosis in India is largely unknown. A collection of 91 isolates originating from 12 different regions spread across the country were analyzed by genotyping using 21 loci with variable-number tandem repeats (VNTRs), by spoligotyping, by principal genetic grouping (PGG), and by deletion analysis of M. tuberculosis\u2013specific deletion region 1. The isolates showed highly diverse VNTR genotypes. Nevertheless, highly congruent groupings identified by using the 4 independent sets of markers permitted a clear definition of 3 prevalent PGG1 lineages, which corresponded to the \"ancestral\" East African\u2013Indian, the Delhi, and the Beijing/W genogroups. A few isolates from PGG2 lineages and a single representative of the presumably most recent PGG3 were identified. These observations suggest a predominance of ancestral M. tuberculosis genotypes in the Indian subcontinent, which supports the hypothesis that India is an ancient endemic focus of TB.Although India has the highest prevalence of tuberculosis (TB) worldwide, the genetic diversity of Mycobacterium tuberculosis, its main causative agent, is widely disseminated and is one of the most successful human pathogens today, with 2 billion persons infected. Most of the disease's effects are now concentrated in countries with few resources; India has the highest number of cases (Tuberculosis (TB) in humans has been described since ancient times. M. tuberculosis of genetic elements named mycobacterial interspersed repetitive units (MIRUs) were used to assess consistency of the genetic relationships obtained by VNTR typing and spoligotyping at a broader evolutionary level. SNPs in the katG and gyrA genes classify M. tuberculosis isolates into 3 principal genetic groups (PGGs) thought to have evolved sequentially from group 1 to group 3 according to the previously described method . MIRU-VNTR profiles were compared to each other by using the neighbor-joining algorithm. For spoligotypes, the Jaccard index was calculated to allow for the construction of a dendrogram by using the unweighted pair-group method with arithmetic averages. The spoligotypes were compared to fingerprints in an international database , X (1 case), and T (8 cases) spoligotype families were detected among the isolates of the PGG2/3group. The single PGG3 isolate (ICC399) had a T spoligotype, which includes both PGG2 and PGG3 strains groups. This correlation, also seen in previous studies on isolates from Singapore has been observed in southern India (,,The few previously identified TbD1+ strains were isolated from patients from East Africa and South Asia. These strains have low copy numbers of IS India ,,. Also co India ,,.6110 distribution (6110 low copy-number fingerprints and of known spoligotypes (,6110 (The prevalence of these low-copy-number strains in regions of such high endemicity has raised the question of the true extent of genetic variation beyond their restricted ISgotypes ,. Moreove,,In addition to the TbD1+ isolates, 2 other major PGG1 families were well represented in this Indian collection. They were qualified as modern groups by their TbD1\u2013 status. The recently identified Delhi type (M. tuberculosis ancestral strains and the relatively poor representation of the most recent lineages in this Indian collection lend support to the hypothesis that India is a relatively ancient endemic focus of TB (M. tuberculosis complex, subsequent to the recently proposed emergence of tubercle bacilli in eastern Africa millions of years ago (The predominance of"} +{"text": "We reviewed neuromedin U (NMU) and neuromedin S (NMS) involvement in the regulation of the hypothalamo\u2013pituitary\u2013adrenal (HPA) axis function. NMU and NMS are structurally related and highly conserved neuropeptides. They exert biological effects via two GPCR receptors designated as NMUR1 and NMUR2 which show differential expression. NMUR1 is expressed predominantly at the periphery, while NMUR2 in the central nervous system. Elements of the NMU/NMS and their receptors network are also expressed in the HPA axis and progress in molecular biology techniques provided new information on their actions within this system. Several lines of evidence suggest that within the HPA axis NMU and NMS act at both hypothalamic and adrenal levels. Moreover, new data suggest that NMU and NMS are involved in central and peripheral control of the stress response. Bombesin-like neuromedins\u2014neuromedin B (NMB) and neuromedin C (NMC) and neuromedin L (NML) , for which no substantial homology with other known neuropeptides was found and its anorexigenic action have enhanced interest in physiological role of NMU and NMS and the other 8 (NMU8) amino acid residues gene, on the other hand, was identified based on its sequence similarity with NMUR1 NMU-like immunoreactivity was observed in perikaria of the dorsal nucleus of the hypothalamus and the caudal part of the infundibulum . In the rat hypothalamus expression of NMS gene was nearly 3-fold higher than that of NMU gene and protein (dot blot method) were identified in 2000 injection of NMU demonstrated a strong increase in Fos-immunoreactive nuclei in the PVN and supraoptic nucleus (SON) of the rat hypothalamus release by rat hypothalamic explants NMU also regulates HPA axis in birds. Icv administration of NMU in chicks significantly upregulated mRNA expression of CRH in the hypothalamus blood ACTH level remained unchanged into hemiadrenalectomized rats did not significantly change corticotropin levels resulted in a dose-dependent increase of plasma ACTH concentrations, an effect significantly reduced by pretreatment with anti-NMU IgG and a sustained (24 h) elevation of plasma corticosterone concentration NMU activates CRH containing neurons and stimulates CRH secretion, which in turn triggers pituitary ACTH and adrenal corticosterone/cortisol secretion. In this regard it is not astonishing that NMU and NMS are involved in central and peripheral control of the stress response. These studies were initiated by Hanada et al. who obseStress related behavior induced by icv NMU or NMS administration was also observed in cattle glycol (PEG) (\u201cPEGylation\u201d) may be helpful in these attempts (Ingallinella et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Aortic valve stenosis (AVS) is the most common valvular disease. Its evaluation is of growing interest because of its increasing incidence with the aging population. Previous studies demonstrated the usefulness of Phase-Contrast Magnetic Resonance (PCMR) images in the evaluation of AVS. However, because of the lack of automated methods for PCMR data analysis, this technique remains time-consuming and operator-dependent.Therefore, the aims of this study were 1) to develop a semi-automated method for aortic flow analysis from PCMR images, and 2) to evaluate several approaches of aortic valve area (AVA) estimation.2) and 12 healthy subjects who had the same day a trans-thoracic echocardiography (TTE) and PCMR acquisitions at the levels of the aortic valve and the left ventricle outflow tract (LVOT). PCMR data analysis included a semi-automated segmentation, based on pixels connectivity in terms of velocity sign, to delineate the aortic flow on all systolic frames, as well as a functional parameters extraction from aortic velocity and flow rate curves such as aortic maximal velocity (VmaxAo) and AVA. AVA was calculated using: 1) Hakki\u2019s formula which is a simplification of Gorlin\u2019s formula, resulting in AVA1= cardiac output divided by \u221asystolic pressure gradient, 2) the continuity equation with the most pertinent method found in previous studies in PCMR resulting in AVA2 = LVOT stroke volume (LVOT SV) divided by aortic valve velocity time integral (VTIAo), and 3) the continuity equation with another approach previously described in echocardiography but never used in PCMR. It resulted in AVA3= LVOT peak Flow rate (QLVOT) divided by VmaxAo . Hakki\u2019s formula underestimated the AVA with regard to TTE in the absence of severe stenosis. AVA3 provided the best results .The LVOT and aortic flows were successfully delineated on all phases for all subjects. Comparison of PCMR and echocardiographic Vmaxts Table in termsOur semi-automated approach for AVS evaluation from PCMR provided reproducible velocity measurements and AVA estimates in good agreement with echocardiographic values, and were able to characterize the severity of AVS."} +{"text": "Rheumatoid arthritis (RA) is a prototypic autoimmune disease characterized by a prominent humoral autoimmunity. Of particular relevance is the local production of autoantibodies such as rheumatoid factor and anti-citrullinated protein antibodies in the inflamed synovial tissue. The mechanisms underlying break of B cell tolerance and local autoantibody production remains poorly understood. This study was conducted in order to identify cellular and molecular pathways implicated in RA-specific humoral autoimmunity.Synovial tissue samples were obtained by arthroscopy from untreated individuals with RA (n=33) and inflammation matched SpA controls (n=58). Gene expression profiling was performed on tissue samples of patients with established arthritis using 44K Whole Genome Human microarrays (Agilent). Top differentially expressed genes were validated on three independent cohorts by Taqman based RT-qPCR and immunohistochemistry. Collagen-induced arthritis (CIA) and Experimental autoimmune encephalomyelitis (EAE) experiments were conducted using Bob1 knockout mice and their littermate controls.\u2212/\u2212 mice were fully resistant to CIA induction compared to their wild-type littermates. This remarkable protection from CIA is explained by failure to produce pathogenic anti-collagen autoantibodies in the absence of Bob1. In contrast, Bob1\u2212/\u2212mice were susceptible to MOG protein induced EAE and incidence and severity of clinical disease were not altered in these mice comparing to wild-type littermates, suggesting that absence of Bob1 does not impact on antigen-presentation/costimulatory capacity of B cells.Microarray screening for genes differentially expressed in the inflamed synovium, the key target of the disease process in RA, revealed a prominent and disease-specific B cell/plasma cell signature with the B cell-specific transcriptional co-activator Bob1 and its transcriptional target BCMA among the most upregulated genes. Validation by RT-qPCR on two independent cohorts representing early and established arthritis confirmed microarray data and demonstrated elevated expression of Bob1 and BCMA not only in established RA, but also at the early phase of the disease. Quantitative evaluation of immunohistochemical stainings of synovial tissue with monoclonal antibody for Bob1 revealed significant increase in Bob1 positive cells in RA synovium (p<0.01). Next we determined whether lack of functional Bob1 modifies disease onset or severity in CIA. Interestingly, the results showed that Bob1The specific increase in Bob1 expressing cells in RA synovitis and the resistance of Bob1-defecient mice to development of CIA indicate that Bob1/BCMA axis may contribute to humoral autoimmunity in RA. The relationship between an aberrant Bob1 expression and the break of peripheral tolerance in RA is currently under investigation."} +{"text": "We investigated the effects of dorsal root stimulation (flexor related dL2 and extensor related dL5) on fictive locomotion evoked pharmacologically (by 5-HT+NMDA+DA) in the isolated neonatal mouse spinal cord. In our experiments, electrical stimulation produced a wide variety of effects depending on stimulation frequency, intensity, and the drug concentrations used. At stimulation intensities near threshold we were able to produce phase advances and delays that resolved within a single step cycle. During these single-cycle alterations we observed different effects after stimulating dL2 and dL5. Stimulation of dL2 during ipsilateral extension typically produced an early onset of the next flexion and termination of current extension in the ipsilateral activity with or without rhythm disturbances on the contralateral side of the cord (subject to drug concentrations and stimulus intensity). These disturbances represented a true phase resetting characterized by a full flexor phase expression independent of ending the stimulation producing the disturbance. In contrast, stimulation of dL5 often produced a complex bilateral effect starting from a brief activation of ipsilateral extension (for the stimulus duration) with a corresponding reduction in the flexor activity followed by a reactivation of ipsilateral flexor activity (a full second burst that could represent a rebound evoked by end of stimulation) and then by an enhanced next extensor burst. Our results were consistent with the previously proposed two-level architecture of the spinal central pattern generator (CPG) consisting of a top-level rhythm generator (RG) and pattern formation (PF) circuits ,3. The a"} +{"text": "ERBB2. In this review, we will focus on the functional role of these somatic mutations that cause ERBB2 receptor activation. We will additionally discuss the current preclinical and clinical therapeutic strategies for targeting mutationally activated ERBB2.Despite the ongoing \u201cwar on cancer,\u201d cancer remains one of the major causes of human morbidity and mortality. A new paradigm of targeted therapies holds the most promise for the future, making identification of tumor-specific therapeutic targets of prime importance. ERBB2/HER2, best known for its role in breast cancer tumorigenesis, can be targeted by two types of pharmacological manipulation: antibody therapy against the extracellular receptor domain and small molecule compounds against the intracellular tyrosine kinase domain. Aberrant activation of ERBB2 by gene amplification has been shown to participate in the pathophysiology of breast, ovarian, gastric, colorectal, lung, brain, and head and neck tumors. However, the advent of next-generation sequencing technologies has enabled efficient identification of activating molecular alterations of Rising incidences of neoplasia worldwide are estimated to translate into 13 million cancer deaths by 2030 , HER3/ERBB3, and HER4/ERBB4 amplification and overexpression, (ii) molecular alterations of the receptor, and (iii) inhibition of phosphatase activity revealed more rapid and acute activation of different signaling pathways compared with the full-length receptor and the 648-CTF fragment was demonstrated to be active in patients with breast cancer who had progressed on trastuzumab therapy were found to respond to neratinib in lung epithelium revealed that the combination of afatinib and an mTOR inhibitor (rapamycin) were effective in mediating tumor shrinkage , a second irreversible inhibitor of EGFR and ERBB2, was demonstrated in Ba/F3 cells expressing an ERBB2-mutant with an insertional mutation at codon 776 and in transgenic lung cancer models , a third irreversible pan-ERBB inhibitor, is currently under clinical investigation due to promising preclinical studies or with other targeted therapies present valid options to combat ERBB2-driven oncogenesis.in vitro and in vivo experiments (Garcia-Garcia et al., Recent clinical data showed a significant overall survival benefit of patients with heavily pretreated metastatic ERBB2-positive breast cancer upon dual ERBB2 blockade through trastuzumab and lapatinib (Blackwell et al., Although activating mutations of ERBB2 were identified in various tumor types and several potential therapeutic options are at hand, specific screening for these lesions has not been translated into clinical routine yet.Despite the plethora of ERBB2 targeted compounds, we currently lack a sound understanding why tumor shrinkage is short-lived and only a relatively small percentage of patients benefit from these therapies. Major mechanisms of primary and acquired resistance to anti-ERBB therapeutics include (reviewed in Tortora, Retrospective studies on tumors expressing truncated p95HER2 fragments revealed that these tend to be resistant to any current therapeutic antibody approach as the required epitopes are missing (Scaltriti et al., In vitro analyses identified three point mutations, L755S, L755P, and T798M to confer resistance to lapatinib (Kancha et al., in vitro and in vivo (Kobayashi et al., Analogous to a commonly observed event during TKI treatment of EGFR-driven lung adenocarcinomas, lapatinib application was shown to induce secondary mutations within the ERRB2 kinase domain consequently leading to TKI resistance. During the past decades, the ERBB2 signaling cascade gained significant importance in the oncogenesis of many tumor types. The discovery of primary activating mutations and the emergence of acquired secondary mutations represent sophisticated challenges for effective treatment approaches. Our next steps in evaluating potential ERBB2-directed therapeutics clearly rely on: adequate diagnostic properties for specific patient selection and identification of tissue-specific mechanisms of resistance to initiate well-designed clinical trials of combinational treatment strategies.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Hypoxia/ischemia induces the neural stem cells (NSCs) proliferation in mammalian brain; but the mechanisms remain unknown.In this study, we investigated the effects of metabotropic glutamate receptor 5 (mGluR5) on NSC proliferation under hypoxia by 3--2,5-diphenyltetrazolium bromide (MTT) assay, diameter measurement of neurospheres, bromodeoxyuridine (BrdU) incorporation assay and cell cycle analysis. The cell death of NSCs was evaluated by terminal dUTP nick-end labeling (TUNEL) assay and Hoechst staining. The expression of cyclin D1 and the activation of mitogen-activated protein kinases (MAPKs) signaling pathway were analyzed by immunoblotting assay.The results showed that hypoxia promoted the mGluR5 expression on NSCs. Under hypoxia, mGluR5 agonist DHPG and CHPG significantly increased NSC proliferation in cell activity, diameter of neurospheres, bromodeoxyuridine (BrdU) incorporation and cell division, and expression of cyclin D1 with decreasing of cell death. mGluR5 siRNA and antagonist MPEP decreased the NSC proliferation and expression of cyclin D1 with increasing of cell death. Phosphorylated JNK and ERK increased with the proliferation of NSCs after mGluR5 agonist DHPG and CHPG treatment under hypoxia, while p-p38 level decreased.These results demonstrated that the expression of mGluR5 was upregulated during the proliferation of NSCs stimulated by hypoxia in vitro. The activation of ERK and JNK signaling pathway and the expression of cyclin D1 were increased in the process. These finding suggesting the involvement of mGluR5 in NSC proliferation and providing a target molecule in neural repair after ischemia/hypoxia injury of CNS."} +{"text": "Grid cells in the medial entorhinal cortex (MEC) encode location through firing fields that form grid-like maps of the environment. At the same time network activity in the MEC is dominated by oscillations in the theta 4-12 Hz) and gamma (30-100 Hz) bands. Our recent experimental data established that feedback inhibition between excitatory stellate cells and inhibitory fast spiking interneurons dominates the synaptic connectivity in layer II of the MEC, and that continuous attractor models derived from these properties are sufficient to explain both the network oscillations and grid firing fields [2 Hz and"} +{"text": "To the Editor: I read with interest the article by Jones-Engel et al. (Because current evidence shows that SV40 infections are identified in some humans and that the virus is associated with selected human malignancies ( In response: Dr. Vilchez (Specificity of SV40 seroreactivity in macaques has recently been demonstrated by competitive inhibition assays ("} +{"text": "To the Editor: Since 1987, morbillivirus outbreaks among pinnipeds and cetaceans in the Northern Hemisphere have caused high rates of death (Phocine distemper virus (PDV) and Cetacean morbillivirus (CeMV). PDV has been isolated from pinnipeds, and 3 strains of CeMV have been isolated from dolphins and whales (Tursiops truncatus) has been confirmed in the Southern Hemisphere (in the southwestern Pacific Ocean) (Lagenodelphis hosei) stranded off Brazil and Argentina in 1999 indicate the exposure of South Atlantic cetaceans to morbillivirus , a coastal marine and estuarine species that occurs off the Atlantic Coast of South and Central America. Serologic surveys indicate that morbilliviruses infect marine mammals worldwide , a monoclonal antibody against the nucleoprotein antigen of canine distemper virus that cross-reacts with cetacean morbilliviruses (Morbillivirus spp.\u2013specific primers were used for PCR: 5\u2032-ATGTTTATGATCACAGCGGT-3\u2032 (forward) and 5\u2032-ATTGGGTTGCACCACTTGTC-3\u2032 (reverse) (http://megasoftware.net/) was used to construct a neighbor-joining phylogenic tree based on the sequenced amplicon from this study (GenBank accession no. KF711855) and 12 other GenBank sequences that represent the 6 morbillivirus species already described in the literature. The analysis placed the Guiana dolphin strain at the CeMV clade, but segregated it from the already described dolphin morbillivirus strains PMV, DMV, and PWMV . We extracted RNA from frozen lung samples by using TRIzol Reagent according to the manufacturer\u2019s instructions and amplified a 374-bp conserved fragment of the phosphoprotein (P) gene by reverse transcription PCR. The following and PWMV . The samIn summary, sequence analysis of the morbillivirus from the dead Guiana dolphin suggests that the virus is a novel strain of the CeMV species; this conclusion is supported by phylogenic analysis and geographic distribution of the virus and by its distinct host. Emaciation, marked lymphoid depletion, interstitial pneumonia, and meningoencephalitis are common findings in morbillivirus-infected animals (Morbillivirus outbreaks have caused a high number of deaths among pinnipeds and cetaceans and are a major risk to previously unexposed nonimmune populations of aquatic mammals ("} +{"text": "Atrial fibrillation (AF) is the commonest sustained arrhythmia afflicting the adult population. Identifying and ablating triggers in the left atrium (LA) or more often the pulmonary veins (PV) with radiofrequency energy to restore sinus rhythm is fast becoming the mainstay of treatment. The success of the procedure often requires a combination of imaging techniques with an electroanatomical mapping system. We describe the use of three dimensional (3D) delayed enhancement cardiovascular magnetic resonance imaging (DE-MRI) to provide a road map of the anatomy as well as regions of scar tissues in the LA and PV for AF ablation.Images were acquired with a Siemens Avanto 1.5 tesla scanner. Standard acquisition of cardiac anatomy and function were performed as well as the atrial short-tau inversion recovery (STIR) sequences in the axial plane. In addition, 3D steady-state free precession (SSFP) axial plane, 3D magnetic resonance angiography (MRA) coronal plane and 3D DE-MRI axial plane of both LA and PV were acquired.The 3D SSFP axial plane, 3D MRA coronal plane and 3D DE-MRI axial plane of both LA and PV obtained were then incorporated into an electroanatomical mapping system which generated a 3D road map of the LA and PV together with regions of scar tissues as shown by DE-MRI. The merging of this road map with the electroanatomical map enables AF ablation to be done effectively.Together with the electroanatomical mapping system, 3D DE-MRI provides an invaluable non-invasive assessment of the anatomy and scar tissues of the LA and PV for AF ablation.No external funding."} +{"text": "Idiopathic toe walking (ITW) has been associated with ankle equinus, and while equinus has been linked with foot deformity in adults, there has been limited investigation on its impact on structural foot change in children. This study used the weight bearing lunge (WBL) test and Foot Posture Index-6 (FPI-6) to evaluate the foot and ankle measures of children with an ITW gait.Sixty children between the ages of four and eight years were grouped into an ITW (N=30) and a non-toe walking (NTW) (N=30) cohort. The ankle range of movement and FPI-6 was calculated during appropriate weight\u2013bearing test and stance.There was a highly significant difference in the WBL test measures between the ITW cohort and the NTW cohort. The FPI-6 comparison was not significant. The WBL test was also not predictive of an abnormal FPI-6 in the ITW cohort.These results demonstrate that ITW gait style impacts only on the available dorsiflexion at the ankle. The WBL measure may be utilised within the clinical setting to guide and monitor treatment interventions."} +{"text": "Staphylococcus aureus. In an adaptive response, bacteria have evolved systems to acquire the metals in the face of this competition while effluxing excess or toxic metals to maintain a bioavailability of transition metals that is consistent with a particular inorganic \u201cfingerprint\u201d under the prevailing conditions. This review highlights recent biological, chemical and structural studies focused on manganese (Mn) acquisition and homeostasis and connects this process to oxidative stress resistance and iron (Fe) availability that operates at the human host-pathogen interface.Pathogenic bacteria acquire transition metals for cell viability and persistence of infection in competition with host nutritional defenses. The human host employs a variety of mechanisms to stress the invading pathogen with both cytotoxic metal ions and oxidative and nitrosative insults while withholding essential transition metals from the bacterium. For example, the S100 family protein calprotectin (CP) found in neutrophils is a calcium-activated chelator of extracellular Mn and Zn and is found in tissue abscesses at sites of infection by The most abundant transition metals in humans are iron (Fe) and zinc (Zn) , Mn(IV) and Mn(V)] and is most strongly linked to oxidative stress resistance mediated by Mn superoxide dismutase (Mn-SOD) . This is generally expressed in nmol or ng of each metal per mg total protein and is readily measured by inductively coupled plasma mass spectrometry (ICP-MS) of acid-solubilized cells. A remarkable aspect of the inorganic fingerprint relevant to this discussion is the fact that the total Mn:Fe ratio varies by over seven orders of magnitude when various single-celled organisms are compared with one another when grown in the presence of oxygen and Fe(II), if left unregulated metal ions to the exclusion of all others or hydrogen peroxide (H2O2) atoms from enzymes harboring mononuclear Fe and 4Fe-4S cluster cofactors dissociation, essentially analogous to that which occurs in the peroxide sensor Fe-PerR H2O2 induces the OxyR regulon which includes genes encoding a manganese import pump MntH and the DNA binding iron-scavenging protein Dps .Manganese as a micronutrient is critical to the viability and virulence of many Gram-positive and Gram-negative bacterial pathogens . First, increased Mn(II) availability allows for increased metallation of Mn-SOD which efficiently catalyzes the dismutation of the superoxide anion radical to Hi) and Mn-carbonate complexes are efficient catalysts of superoxide disproportionation and the chemical mechanism of this reaction has recently been investigated in detail to one based on Mn(II) in order to protect key enzymes from inactivation by ROS. Another example of this type of cofactor replacement is the iron sequestration protein, Dps, in Kineococcus radiotolerans via cofactor substitution in the oxidative stress response functions as an antioxidant through a combination of enzymatic degradation of oxidants by Mn-SOD and other Mn(II)-containing enzymes, nonenzymatic degradation of oxidants by LMW-Mn complexes, and metalloenzyme cofactor substitution to prevent Fe-induced peroxide chemistry and subsequent enzyme inactivation Figure . The exto Figure , may repo Figure .The ability of a bacterial pathogen to obtain sufficient Mn(II) is critically important for pathogenesis and as such, Mn(II)-dependent metal sensor proteins control the expression of operons that encode additional virulence factors unrelated to the acquisition of Mn(II) are known to modest resolution reveal essentially closed, metal bound-like structures, with BtuF indicative of a slightly more open and conformationally dynamic structure that collapses around the Co(II)-ligand complex -specific cluster A-I SBPs have been reported including those from distant bacterial phyla such as cyanobacteria depending on the transporter is often too tight to measure at the protein concentrations required to make the measurement . As can be seen, determined KdMn values range from the low nM to several hundred nM, with some indication that Zn(II) may bind more weakly than Mn(II) is robust since this value was extracted from a nonstoichiometric binding isotherm acquired in the presence of 50 mM citrate as a Mn(II) competitor chelator from the SBP into the transport cavity can only enter the cytoplasm efficiently through Mn(II)-specific transporters, elucidation of the affinity of each for Mn(II) vs. noncognate Zn(II) and the rates at which Mn(II) is transported across the plasma membrane takes on added significance when considered in the context of the discovery of calprotectin (see below). This is also true from the perspective of fundamental inorganic chemistry since Mn(II) complexes will tend to be far less thermodynamically stable than \u201cisostructural\u201d Zn(II) complexes Figure Waldron. Metal tt Figure , despiteE. coli, Mycobacterium tuberculosis, or Bacillus anthracis in this case) that secretes these siderophores to capture bioavailable Fe from the host and Zn(II) to sequester these metals from the invading bacterium. For example, the S100A7 homodimer limits growth and invasion at epithelial surfaces through chelation of Zn(II) . One simple explanation is that more resistant bacteria express Mn(II) uptake systems that possess a higher affinity than CP for Mn(II) and thus will compete more effectively with CP for extracellular Mn(II). This requires knowledge of the structure and Mn(II) and Zn(II) binding affinities of CP. Initial studies established that a single S100A8/S100A9 heterodimer is capable of binding two molar equivalents of transition metal, designated S1 and S2; however, while Zn(II) could fill both sites, Mn(II) could fill only one with high affinity (S1) which is well-modeled in metal binding experiments as two functionally independent heterodimers as a competitor ligand for Zn(II) revealed KdZn1 = 0.13 nM and KdZn2 = 185 nM (\u2013Ca) and KdZn1 \u2264 0.01 nM and KdZn2 \u2264 0.24 nM (+Ca) Mn(II) site conforming to octahedral coordination geometry site, thus likely connecting Mn(II) sequestration to the biological activity of CP. Although CP may have a lower affinity for Mn(II) than bacterially encoded SBPs transport into the cytoplasm with significantly higher affinity (\u2265100-fold), a finding consistent with the Irving-Williams series and Fe(II) can influence Mn(II) acquisition and intracellular Mn(II)-dependent metalloregulation of transcription. For example, Zn(II) has been shown to inhibit Mn(II) uptake by binding irreversibly to s Figure - or Mn(II)-specific metal-sensing repressor -MntR and two related Fur family members, the peroxide sensing, Fe(II)-binding PerR levels to rise to a level sufficient level to fill the mutant PerR regulatory site with cognate Fe(II) and Mn(II) homeostasis systems may well be more relevant to bacterial cell physiology and pathogenesis than is Zn(II)-Mn(II) crosstalk. These two metals lie at the same weakly competitive end of the Irving-Williams series and the Fe:Mn ratio might be considered a reporter of microbial lifestyle, capable of altering the altering the resistance of an organism to ROS -specific in vivo. Remarkably, this Fe(II)-specificity is lost in a perR mutant strain. Here, the combined impact of increasing Fur concentrations and intracellular Mn(II) levels relative to Fe(II), leads to conditions where Fur binds Mn(II), which in turn, leads to inappropriate Mn(II)-mediated repression of the fur regulon, including genes responsible for Fe(II) uptake. Thus, PerR may directly impact Fe(II) homeostasis by modulating Fur levels in response to a change in the Mn:Fe ratio, i.e., that which might occur under conditions of high Mn(II) and Fe(II)-deplete conditions :Fe(II) ratio :Fe(II) ratios under conditions of low iron is also critical to virulence in sepsis models effluxer, MntE, that is required for virulence -Mn(II) crosstalk influences bacterial pathogenesis is not firmly established, a number of recent studies suggest that maintenance of an optimal Mn(II):Fe(II) ratio can impact the virulence of pathogenic bacteria. For example, the ability of Recent studies of bacterial transition metal physiology and crosstalk places manganese acquisition by human microbial pathogens on center stage of the host-pathogen \u201carms race\u201d proteins attached on the cell surface known to bind zinc -specific uptake systems compete for the same metal on the basis of their respective affinities, there is much more to be learned about this process. This includes elucidation of the rates and rate-limiting steps of Mn(II) transport, and structural studies of intact bacterial ABC transporters positioned at the \u201cfront line\u201d of Mn(II) acquisition. This is particularly interesting since Mn(II) is generally handicapped relative to other divalent metal ions, notably Zn(II), in chelate stability, and as a result, other factors including formation of kinetically trapped Mn(II) metalloenzyme complexes in the cell (Whittaker, Further insights into molecular mechanisms of host nutritional immunity against bacterial pathogens will continue to rely on concerted and collaborative efforts of microbiologists, coordination chemists and structural biologists in an effort to win the \u201ctug-of-war\u201d over transition metals at the host-pathogen interface through the development of intervention strategies based on metals in biology of infectious disease.John P. Lisher and David P. Giedroc wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Acinetobacter baumannii(CRAB) is an emerging pathogen of healthcare associated infection and little is known about the effectiveness of the active surveillance culture of CRAB.Carbapenem resistant This study aims at evaluating the effect of active surveillance culture of CRAB upon intensive care unit(ICU) admission on the occurrence of new CRAB bacteremia in ICU.Since February 2011, the active surveillance culture of CRAB was performed in all patients admitted to medical ICU in Seoul national university hospital. Contact precaution was applied for the patients who had positive surveillance culture results. Respiratory specimen were obtained and the isolates were cultured overnight in blood agar plates which contain imipenem. To assess the effectiveness of active surveillance culture of CRAB and contact precaution, the rate of new CRAB bacteremia was compared between baseline period(February 2012-January 2011) and intervention period(June 2011-February 2012). The new CRAB bacteremia case was defined as the CRAB bacteremia occurred later than 48 hours of ICU admission in patients without positive CRAB clinical culture in the prior 12 months and within the 48 hours of ICU admission.P=0.019).In the baseline period there were 242 total admissions to the ICU(7355 patients-days) and in the intervention period there were 266 total admissions to the ICU(5432 patients-days). During the intervention period, 21(7.9%) patients showed positive CRAB surveillance culture results. The rate of new CRAB bacteremia is 2.72 cases per 1000 patients-days in the baseline period and 0.92 case per 1000 patients-days in the intervention period(When active surveillance culture of CRAB and contact precaution for the patients of positive results were applied in a medical ICU, the rate of new CRAB bacteremia was lowered and the time betweennew CRAB bacteremia and ICU admission was lengthened.None declared."} +{"text": "In this work we present a large-scale three stage model of the early mammalian olfactory system, including the olfactory epithelium (OE), the olfactory bulb (OB) and the olfactory (piriform) cortex (OC). All neurons in the network are modeled with a single or few compartments using the Hodgkin-Huxley formalism and are implemented in the NEURON simulator for parallel execution ,2. We inThe OE model comprises families of olfactory receptor neurons (ORNs) with different sensitivities, each family expressing one type of olfactory receptor (OR) with a vector of affinity values for each ligand . These dResults from runs with network sizes comprising thousands of model neurons show that this biophysically plausible network model generates response patterns of cells reminding of their real counterparts (see Figure"} +{"text": "Loss of phosphatase and tensin homologue (PTEN) function evaluated by loss of PTEN protein expression on immunohistochemistry (IHC) has been reported as both prognostic in metastatic colorectal cancer and predictive of response to anti-EGFR monoclonal antibodies although results remain uncertain. Difficulties in the methodological assessment of PTEN are likely to be a major contributor to recent conflicting results.We assessed loss of PTEN function in 51 colorectal cancer specimens using Taqman\u00ae copy number variation (CNV) and IHC. Two blinded pathologists performed independent IHC assessment on each specimen and inter-observer variability of IHC assessment and concordance of IHC versus Taqman\u00ae CNV was assessed.Concordance between pathologists (PTEN loss vs no loss) on IHC assessment was 37/51 (73%). In specimens with concordant IHC assessment, concordance between IHC and Taqman\u00ae copy number in PTEN loss assessment was 25/37 (68%).Assessment PTEN loss in colorectal cancer is limited by the inter-observer variability of IHC, and discordance of CNV with loss of protein expression. An understanding of the genetic mechanisms of PTEN loss and implementation of improved and standardized methodologies of PTEN assessment are required to clarify the role of PTEN as a biomarker in colorectal cancer. Survival for patients with metastatic colorectal cancer (mCRC) has improved significantly over the past 15 years, largely due to improved systemic treatment options-6. In adPTEN is an important negative regulator of PI3K/AKT pathway and controls cell proliferation, survival and angiogenesis. Loss of PTEN function leads to persistent activation of the PI3K pathway and has been observed in breast, prostate, glioblastoma, endometrial and colon cancers,13. LossSeveral crucial factors make testing and interpretation of PTEN difficult. Loss of PTEN function results from several genetic mechanisms including small scale PTEN gene mutations , allelic loss at chromosome 10 and epigenetic silencing via hypermethylation of the PTEN promoter region. PTEN geFurther complicating the situation, the frequency of loss of PTEN expression increases from progression from normal colonic mucosa to adenoma, primary CRC and ultimately metastasis. The resClearly the role of PTEN is more complex than KRAS gene mutation where a single identifiable mechanism (activating mutation), largely concordant between primary and secondary tumours, confers near complete resistance to anti-EGFR MoAbs. Understanding this complexity is central to interpreting the current literature relating to PTEN and its potential role as a predictive biomarker. Recently reported cohorts of mCRC patients receiving anti-EGFR MoAbs have used PTEN loss of IHC expression to report loss of PTEN function. While this represents the functional outcome of several genetic mechanisms of PTEN loss, IHC relies on subjective interpretation and has the potential for inter reporter variation. Furthermore there is variability over the definition of 'loss of PTEN\u2019 based on IHC scoring. In the largest cohort of mCRC patients, PTEN loss was defined as no staining in any cells at any intensity, while oOur group undertook an analysis of PTEN status in the AGITG MAX study of mCRC patients to identify the rate of inter-observer variability in IHC assessment and the rate of discordance between IHC and PCR assessment of PTEN status.The MAX study design and eligibility criteria have been reported previously.The primary objective of this Phase III randomized trial was to evaluate the effect of adding bevacizumab to capecitabine (with or without mitomycin C) on progression free survival (PFS) among patients receiving first line chemotherapy for mCRC. Four hundred and seventy-one patients were enrolled between July 2005 and June 2007. We have used the TaqMan\u00ae Copy Number Assay to assess for PTEN allelic loss and have previously reported that loss of PTEN copy number was not prognostic nor predictive of outcome in the MAX trial cohort. In thisFormalin-fixed, paraffin-embedded (FFPE) samples of tumor tissue from archival specimens collected at the time of diagnosis were retrieved from storage at hospital pathology departments. For Copy Number PCR, genomic DNA was extracted from FFPE tissue sections with the use of the QIAamp DNA FFPE tissue kit . Manual micro-dissection was performed on samples with less than 80% malignant cells when visualized by microscopy. The same tissue blocks were used to make tissue microarrays (TMAs) and were assessed for PTEN expression by IHC. Researchers who assessed PTEN IHC expression were blinded to the PCR results.Immunohistochemical staining was carried out on TMAs using the PTEN monoclonal antibody 6H2.1 that has been used previously-36. EssePTEN, at cytoband 10q23.31a, location Chr.10:89727445 on NCBI build 37 (Life Technologies). The assay is a duplex PCR for the PTEN gene and the reference gene, RNaseP , set up according to the supplier\u2019s protocol and run on the Rotorgene 6000 real time PCR instrument . The results are calculated as a ratio relative to a 2-copy control using the 2-\u2206\u2206Ct method (Rotorgene software), and multiplied by 2 to give the copy number. We tested DNA from colon cancer cell lines to determine the reproducibility of the assay and to select cell lines to use as copy number controls. HT29 (ATCC) is known to have 3 copies of chromosome 10 as determined by spectral karyotyping and comparative genomic hybridization[The PTEN TaqMan\u00ae copy number assay was performed using 10 ng DNA in quadruplicate PCR. The primers provided in the assay were entirely within exon 9 of dization. For theFifty-nine tumor specimens were analysed for loss of copy number by Taqman\u00ae and for loss of protein expression by IHC. Eight samples were found to contain no tumor tissue and were excluded from further analysis..Two blinded pathologists assessed 51 specimens independently for PTEN protein expression with IHC. Pathologist JC assessed 29/51 (57%) as having PTEN expression loss, while pathologist AR assessed 17/51 (33%) as having loss of PTEN expression. Concordance between pathologists on final IHC assessment (PTEN loss/no loss) was 37/51 (73%), indicating in 14/51 (27%) of specimens there was discordance in the final assessment of IHC PTEN loss had \u22641.5 copy number and were thus classified as PTEN loss.\u00ae PCR concordance analysis. Fifteen specimens had PTEN loss on IHC of which 10 (67%) also had PTEN allelic loss on Taqman\u00ae PCR. Seventeen specimens had PTEN allelic loss on Taqman\u00ae PCR of which 10 (58%) had PTEN loss on IHC. Fifteen specimens had preserved PTEN on both IHC and Taqman\u00ae PCR analysis. Overall concordance between IHC and Taqman\u00ae copy number in PTEN loss assessment was 25/37 (68%) whether protein expression is reduced and whether such reduction confers a growth advantage is unknown. Sood et al. also demonstrated monoallelic PTEN dysfunction (by mutation or promoter methylation) resulted in loss of protein expression in only 38% of samples, while biallelic inactivation resulted in loss of PTEN expression in 80% of cases. Ali et In our cohort 25% of cases without PTEN allelic loss demonstrated complete absence of PTEN expression on IHC. These findings confirm alternative genetic mechanisms, beyond allelic loss, are responsible for loss of PTEN protein expression. Several authors have undertaken more comprehensive analysis of PTEN status on CRC specimens and provide an important insight into the often coexisting genetic mechanisms of PTEN dysfunction. Goal et al. demonstrated hypermethylation of the PTEN promoter region occurred in 10/132 (7.6%) sporadic CRC specimens, with a higher rate (19.1%) in microsatellite unstable CRCs. PTEN mutations coexisted in 4/10 (40%) of hypermethylated PTEN specimens. Eighty percent of patients with promoter hypermethylation had reduced (+1) or loss of PTEN protein expression and in the 3 cases of complete loss of PTEN staining, promoter hypermethylation coexisted with PTEN mutation or allelic loss. PerroneAlternatively, focusing on loss of protein expression at least represents the functional outcome of any such genetic insult. We have demonstrated the current limitations of IHC for this purpose. In our cohort, IHC assessment of PTEN loss by two pathologists was 33% and 57%, with overall concordance of 73%. As this was designed as a validation subset we did not ask the two pathologists to discuss the results that were not concordant, nor seek a further opinion, methods commonly described in papers reporting PTEN IHC aimed at reducing the apparent discordance rate. In all Overall the current literature highlight the difficulty in accurately measuring PTEN function to date; measurement of a single genetic insult, while minimizing inter-observer variability, does not capture the often coexisting mechanisms required for biallelic inactivation. The use of IHC, while potentially a better measure of PTEN function, is observer dependent and there remains a lack of consensus on optimal methodology and scoring.Given the limitations of PTEN assessment discussed here, it is not surprising reports of the predictive value of PTEN as a biomarker in CRC remain conflicting,17,27,31The lack of standardization in assessing loss of PTEN function appears to have contributed significantly to the conflicting results from retrospective cohort studies. Further elucidation of PTEN as a potential biomarker for colorectal cancer relies on defining PTEN loss of function and standardizing analytical methods and scoring systems. Future studies assessing PTEN function may be better served by obtaining a more comprehensive analysis of PTEN function by assessing PTEN mutation, hypermethylation of PTEN promoter, PTEN allelic loss and protein expression on each specimen. An alternative approach may be to explore improved methods of measuring reduced protein expression beyond IHC, given reduced or absent protein expression should reflect the functional outcome of PTEN loss irrespective of the genetic mechanism. Immuno-PCR may provide an option of combining the protein-specific capability of antibodies with the objective quantification of real-time PCR. This wiCNV: Copy number variation; CV: Coefficient of variability; EGFR: Epidermal growth factor receptor; FFPE: Formalin-fixed, paraffin-embedded; FISH: Fluorescent in situ hybridization; IHC: Immunohistochemistry; mCRC: Metastatic colorectal cancer; MoAbs: Monocloncal antibodies; PTEN: Phosphatase and tensin homologue; TMAs: Tissue microarrays; VEGF: Vascular endothelial growth factor.The authors declare that they have no competing interest.CH drafted the manuscript. JH conceived the study and coordinated all laboratory aspect of the study. VB participated in the design of the study and assisted with writing of manuscript. JW was involved in performing the DNA isolation and copy number PCR. NT contributed to trial conception and design as well as assisting with manuscript preparation. JC undertook the immunohistochemistry of the specimens and contributed to study design. AR undertook the immunohistochemistry of the specimens and contributed to study design. CL undertook data analysis and statistical analysis. TP conceived the study and participated in its design and coordination of all aspects of the study including drafting of the manuscript. ART designed study and assisted with manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/128/prepub"} +{"text": "The study is aimed at i) optimization of techniques for preparing microcapsules; ii) generation of multicellular tumor spheroids (MTS) by culturing tumor cells in the microcapsules; iii) study of anticancer treatment effects for both photodynamic therapy (PDT) and anti-cancer drug screening. The model allows to estimate drug doses or parameters for PDT To form MTS, tumor cell lines were encapsulated in polyelectrolyte microcapsules (200-600 \u03bcm), and cultivated for 3-4 weeks . MicrocaMTS based MCF-7 cells were prepared and used to study effects of PDT. To study the effect of irradiation parameters on cell viability, 2 photosensitizers (PS), namely photosense and chlorine e6 were used. Phototoxicity of PS depended on PS concentration and light energy density in both monolayer culture (MLC) and MTS. Study of cell morphology in MLC and MTS before and after PDT revealed that light energy density increase within the range of 30-70 J/cm2 resulted in cell apoptosis. However, cell survival in MTS was much higher than this in the MLC. MTS were also used to test some antitumor therapeutics . An enhanced cell resistance in MTS compared to MLC both for normal and Dox-resistant cells were observed. MTS were also proposed to evaluate cytotoxicity not only of novel therapeutics but also nanosized drug delivery systems ."} +{"text": "NCC is considered as potential therapeutic target for several pathological disorders like neuropathic pain and stroke disease. For understanding mechanism of action at the atomic level crystal structure provide valuable inside but lack of crystal structure of ion channel lead sequence analysis of different types of voltage dependent Ca2+ channel (VDCC) and we found identical/similar active site residues, which was confirmed by site-directed mutagenesis analysis of L-type Ca2+ channel (LCC). Based on these observations, we have developed for the first time the homology model of the closed state of NCC receptor at the ligand-sensing region by using bacterial K+ channel receptor. Further, molecular docking using different dihydropyridine (DHP) blockers identified NCC receptor hot spot binding residues, which is in consonance with that of the LCC. These residues are potential for further biochemical investigations. To understand binding and stability behavior of NCC with the DHP (amlodipine) in closed state, 50 nano second molecular dynamics simulation in lipid bilayer membrane environment were carried out. This analysis revealed the closed state stabilizing by binding of ligand into inner part of S6 region.The voltage dependent N-type Ca"} +{"text": "Post-zygotic aneuploidy is the prominent genetic feature of the human brain (1). Genomically mosaic brain results from that the excess of aneuploid neurons due to early developmental disturbances (somatic genome variations), abnormal cell cycle regulation and altered programmed cell death. As the result, aneuploidization of the brain is a likely susceptibility factor (mechanism) for brain disorders including Alzheimer\u2019s disease.The proportion of aneuploid cells was determined in brain areas differentially affected by neurodegeneration by molecular-cytogenetic and immunohistochemical techniques in brain tissues of individuals with AD and controls as described ealier (2).Increased levels of aneuploidy (monosomy and trisomy) involving chromosome 21 and chromosome X was observed in AD brain. The high level of aneuploidy involving chromosome 21 was observed in the AD cerebrum and hippocampus. In total, the incidence of abnormal (aneuploid) neural cells was significantly higher in degenerating brain areas comparing to the less degenerating area (cerebellum).Our data indicates that AD brain areas subjected to neurodegeneration are more significantly affected by aneuploidy . We propose that widespread postzygotic aneuploidization of selected brain areas is a mechanism for AD neurodegeneration. Such area-specific distribution of aneuploidy can be explained by the accumulation of aneuploid cells during postnatal life or abnormal selective pressure against non-aneuploid cells (3). Finally, these data provide for the speculation that acquired neural aneuploidy could be generated during both developing and adult neurogenesis/gliogenesis."} +{"text": "To the Editor: Diversity of genotypes among Pneumocystis jirovecii (human-specific Pneumocystis species) isolates mainly involves internal transcribed spacer (ITS) loci (Pneumocystis pneumonia (PCP). Studies of the DHPS locus have found mutations at positions 165 and 171, which confer potentially lower sensitivity to sulfonamides to mutant P. jirovecii organisms from 15 PCP patients and in 15 air samples collected 1 meter from each patient\u2019s head of the 15 pulmonary samples; none of the15 patients had received sulfonamide treatment at the time of PCP diagnosis. These results were not unexpected because frequency of finding DHPS mutants in PCP patients in Paris who had no prior sulfonamide treatment is high (Several lines of evidence suggest that P. jirovecii genotypes in pairs of pulmonary and room air samples argue in favor of P. jirovecii exhalation by infected patients. The exhalation of P. jirovecii organisms emphasizes the risk for their nosocomial transmission. Our data provide additional arguments in favor of the application of measures to prevent the airborne transmission of P. jirovecii in hospitals.Matches of"} +{"text": "Results of a recent National Insitute of Drug Abuse-funded pilot randomized controlled trial of Mindful Awareness in Body-oriented Therapy (MABT) for women in substance use disorder treatment showed improved substance use outcomes for MABT compared to treatment as usual. In addition 80% of the MABT participants maintained a daily mindful body awareness practice at nine month follow-up. The purpose of this subsequent study was to explore the perceived role of MABT and mindful body awareness practice in the recovery process.A qualitative design utilizing a focus group method was employed. Participants from the larger RCT that had completed the MABT intervention (n =18) were recruited for the focus group, and five attended. Semi-structured questions were used to explore participants\u2019 utilization of mindful body awareness practice in substance use disorder recovery, and the usefulness of various aspects of MABT delivery. Content analysis was used. Two researchers individually coded for themes across participant responses and together verified the coded themes.The primary themes were: (1) motivation to maintain body awareness practices one year post-intervention was due to improved ability to access and process emotions when using these practices; (2) exploration of uncomfortable feelings was perceived as critical for relapse prevention, as substance use was associated with escalated emotions and an inability to attend to feelings; (3) MABT facilitated awareness of inner experience and the connection between emotions and the body; they had not been able to achieve this awareness with prior therapeutic approaches. Also, three aspects of MABT were considered critical for learning mindful body awareness practice: (1) individual delivery to allow for safe exploration of emotional experiences, (2) manual/touch-based processes to learn interoceptive skills, and (3) homework to integrate body awareness practice into daily life.These findings point to the importance of studying emotional awareness in mind-body interventions, and in women\u2019s substance use disorder prevention and treatment specifically."} +{"text": "Treatment of chronic urticaria consists of antihistamines as the first-line treatment. For more severe symptoms, combinations can be necessary as well as dose augmentations. The recent guidelines suggest the possibility of using omalizumab in resistant cases. We treated 2 patients with cold-urticaria (CO), 1 with cholinergic urticaria(CH) and 11 with chronic spontaneous urticaria (CSU) with omalizumab, who had not benefited from the recommended first-line, second-line and third-line treatments.Patients were required to document their CU symptoms once daily with urticaria activity scores for 7 days (7UAS). Briefly, the symptoms were monitored in terms of numbers of wheals , and the intensity of their pruritus , for a total of 42 points. To evaluate the efficacy of the omalizumab treatment, 7UAS obtained at baseline was compared to that at the third and sixth month of the therapy. Omalizumab was given at 150 \u03bcg/month irrespective of IgE levels and increased to 300 mg if needed (no response). The concomitant medication was slowly reduced according to clinical response.The 7UAS improved significantly in all severe urticaria patients with omalizumab as early as one month (not shown) after initiation of therapy and was sustained for the 6 month observation Figure . 7UAS inOur results show that omalizumab improves significantly recommended treatment-resistant urticaria patients (13/14) in terms of clinical symptomatology (7UAS) and drug reduction in a real life setting. None of the patients reported any adverse effect."} +{"text": "A proper infection control program in the Ministry of Health's hospitals-Jeddah, Saudi Arabia has never been applied based on focused and aimed scientific plans. The objective of this study was to monitor the enforcement of a scientifically based infection prevention and control program via continuous auditing.A standardization and continuous auditing program was implemented in the year 2009 in twelve hospitals. Three auditing visits were conducted throughout this year to estimate hospital-wide compliance of the required procedures and strategies using auditing sheets based on that year's target aims.The first compliance rate for the first visit in the first year was 42% which increased to 66% during the second visit and to 78% during the third visit. During the first audit there were deficiencies in: general measures in infection control (43%), surveillance (31%), monitoring of infection control guidelines (81%), isolation practice (64%), infection control committee performance (66%) and education (46%). These deficiencies improved during the second audit as follows: (37%), (24%), (39%), (21%), (49%) and (25%) respectfully. During the third audit, deficiencies were as follows: (32%), (22%), (22%), (14%), (34%) and (9%) respectfully.A standardized infection control program for ongoing monitoring led to a significant improvement in infection control practices in all twelve hospitals in Jeddah. Consequently, these results might suggest that such a program can be applied to other Ministry of Health hospitals in the Kingdom.None declared."} +{"text": "The inherited periodic fever syndromes are single gene disorders of innate immunity which have provided invaluable insights into the regulation of inflammation. They are all extremely rare but are clinically important as they cause very significant day to day symptoms and carry a high risk of early death due to AA amyloidosis. With the exception of familial Mediterranean fever treatment was essentially ineffective until this century.The discovery in 2002 that specific IL-1 blockade completely prevented all symptoms in cryopyrin associated periodic syndrome (CAPS) transformed treatment of this rare genetic disease. Isolation of the responsible gene, NLRP3, followed by rapid advances in molecular biology and identification of the inflammasome has made it clear that CAPS is purely a disease of IL-1 dysregulation. These discoveries combined with the availability of specific anti IL-1 agents have resulted in new insights into the regulation of IL-1 beta production in humans and its long term consequences.IL-1 is now recognised to be an important mediator of inflammation in other inherited autoinflammatory diseases such as Familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), deficiency of IL-1 receptor antagonist (DIRA) and mevalonate kinase deficiency and has transformed patient prognosis and quality of life. In addition the recognition that IL-1 blockade provides complete disease control in acquired diseases of uncertain aetiology particularly Schnitzler\u2019s syndrome and systemic onset juvenile chronic arthritis (SoJIA), adult onset Stills disease and recurrent idiopathic pericarditis has made it clear that these too are autoinflammatory disorders. One of the most striking features of these diseases is that IL-1 blocking agents have been used for prolonged periods as monotherapy without serious side effects or breakthrough of inflammatory activity thus differentiating them from the commoner autoimmune disorders such as rheumatoid arthritis and vasculitis."} +{"text": "Occult hepatitis B (OHB) is not a new entity and there are many reports of patients with hepatitis B virus (HBV) evidence replication in the absence of detectable hepatitis B surface antigen (HBsAg) and occasionally other HBV serologic markers . After iEgypt has the highest prevalence of HCV infection in the world . HoweverEnd-stage renal disease (ESRD) is a significant problem in almost all countries and the prevalence has increased considerably in developing countries especially in Middle East countries. The prevalence of HCV infection among hemodialysis patients differs in different parts of Middle East countries which is 48% in Egypt . The pre"} +{"text": "Agnotecous, a cricket genus endemic to New Caledonia showing a generalized pattern of sympatry between species making sympatric speciation plausible. We obtained five mitochondrial and five nuclear markers (6.8 kb) from 37 taxa corresponding to 17 of the 21 known extant species of Agnotecous, and including several localities per species, and we conducted phylogenetic and dating analyses. Our results suggest that the diversification of Agnotecous occurred mostly through allopatric speciation in the last 10 Myr. Highly microendemic species are the most recent ones (<2 Myr) and current sympatry is due to secondary range expansion after allopatric speciation. Species distribution should then be viewed as a highly dynamic process and extreme microendemism only as a temporary situation. We discuss these results considering the influence of climatic changes combined with intricate soil diversity and mountain topography. A complex interplay between these factors could have permitted repeated speciation events and range expansion.Islands are bounded areas where high endemism is explained either by allopatric speciation through the fragmentation of the limited amount of space available, or by sympatric speciation and accumulation of daughter species. Most empirical evidence point out the dominant action of allopatric speciation. We evaluate this general view by looking at a case study where sympatric speciation is suspected. We analyse the mode, tempo and geography of speciation in Diversity hotspots in islands are characterized by very high specific richness and endemism resulting from local diversification of groups which are \u201ctrapped\u201d in very limited spatial areas Empirical case studies showed or suggested that diversifications in islands most often result from repeated events of local allopatric speciation and subsequent establishment of microendemism New Caledonia, one of most diverse island biodiversity hotspots AgnotecousHere we analyse the mode, tempo and geography of speciation in the microendemic species of the cricket genus We use a dated species-level phylogeny, analyses of diversification time-course, and age-range correlation methods to investigate the mode of speciation and causes of microendemism. We aim at discriminating between two alternative scenarios:Under a scenario of dominant allopatric speciation, the observed pattern of sympatry is caused by secondary sympatry with post-speciational movements.Under a scenario of dominant sympatric speciation, the observed pattern of sympatry results directly from recent sympatric speciation, with little or no post-speciational movements.According to the dominant mode of speciation, we will compare and discuss the pattern of microendemism and tempo of species diversification in New Caledonia with respect to the influence of climatic changes combined with intricate soil distribution and mountain topography. This study will allow us understanding the origin of microendemic distributions in an evolutionary and biogeographical perspective.Agnotecous. Each species is represented by specimens known from 1\u20137 localities (mean\u200a=\u200a1.8). Three species from different eneopterine tribes and one species belonging to another cricket subfamily were used as outgroups The molecular sampling consists of 37 individuals corresponding to 17 out of the 21 known extant species of Agnotecous, we generated a consensus sequence per Agnotecous species using IUPAC ambiguity codes under BIOEDIT v 7.0.9.0 DNA sequences were aligned under Muscle with default parameters Agnotecous at 10.5 Myr ago, and its divergence with L. santoensis at 15 Myr ago, with standard deviations of 1 Myr for each calibration point Likelihood-ratio test Agnotecous phylogeny using the software SymmeTREE , which implements a whole-tree topological approach to the study of diversification rates. Diversification rate variation within the phylogeny is reported by a range of test statistics that vary in their sensitivity to nodal depth scales Lineage Through Time (LTT) plot derived from the BEAST MCC tree was used to visualise the time-course of diversification. We tested the null hypothesis of equal diversification rates across the Agnotecous data set and using the estimated pure speciation value.We also compare the fit of rate-variable models to the null hypothesis of constant diversification by using likelihood methods based on birth-death models and model-fitting approach (BDL) implemented in the R package LASER A. petchekara is close to A. azurensis, A. humboldti and A. nekando are close to A. chopardi, and A. novaecaledoniae is close to A. sarramea (within clade B2).To compare diversification rates, we used APE Data on geographic distribution of the species were obtained from the collections of the following institutions: Mus\u00e9um national d\u2019Histoire naturelle (Paris), Natural History Museum (London), Queensland Museum (Brisbane), Osaka Museum of Natural History (Osaka), Naturhistorisches Museum (Vienna) and National Museum of Natural History (Leiden). The material examined in previous taxonomic studies of the genus was taken into account Agnotecous azurensis, aimed at generating a continuous distribution area for this species. Considering these range sizes, our sampling covers 70% of Agnotecous main potential habitat (rainforest) method test Agnotecous is not characterised by high mobility (short-winged species unable to fly), we also computed two modified indicators following Although Finally, we computed the relationship between areas and ages of species to investigate post-speciational range expansion, and test whether microendemism is mostly found in younger clades.Distribution areas and ages of clades were compared with the map of soil diversity using the GIS layers provided by Direction des Infrastructures, de la Topographie et des Transports Terrestres of the Gouvernement de la Nouvelle-Cal\u00e9donie, and past climatic events with data in Chevillotte et al. Agnotecous (Agnotecous are found around three major recent climatic events (Two main lineages (A and B) of similar age are recovered within the genus notecous . Each clc events : The genThe species-level LTT plots suggested two minor increases in diversification rates around 3.5 and 2 Myr ago , and a sThese results are not confirmed by BDL analyses: the best rate-constant model (pure birth) had an AIC of 13.16 versus 15.97 for the rate-variable model (yule-2-rate) (\u0394AICrc\u200a=\u200a3.19) see . AlthougAgnotecous. Only three species belonging to clade B2 are not sympatric with any other and slope (0.01244>0), thus rejecting a scenario of fully sympatric speciation . Values species , indicatAgnotecous, a cricket genus characterized by restricted areas of distribution . However, this case of partial sympatry is mostly a consequence of our definition of estimated range sizes, and these species are indeed not syntopic, but were found at different altitudes on the same mountain (Mont Mou: 375 m for A. minoris versus 1010\u20131140 m for Agnotecous sp.).In se study and 4, dAgnotecous?All the studies analysing the mode of speciation in New Caledonia have concluded that both the faunal and floral diversity originated from dominant allopatric speciation Recent events may have affected the post-speciational distributions of the species, resulting in secondary contacts between them. This kind of pattern was already found in other microendemic taxa showing lower levels of sympatry. For example, sympatric species occupy different microhabitats as a consequence of character displacement in Australian freshwater snails 2), and younger species show more restricted distributions. This is especially true in the clade B2 (2 (mean\u200a=\u200a100 km2), compared to the 122\u2013500 km2 for other species (mean\u200a=\u200a253 km2). Highly microendemic species are thus clearly the most recent ones show a larger distribution Click here for additional data file.Figure S2Topologies obtained in parsimony (a) and Bayesian inference (b) for mitochondrial dataset only.(PDF)Click here for additional data file.Figure S3Comparison between the phylogeny obtained from the 37 specimens and the phylogeny from the 16 consensus sequences .(PDF)Click here for additional data file.Figure S4Repartition of p-values obtained by the analyses under apTreeshape.(PDF)Click here for additional data file.Table S1Additional information on taxonomic sampling, voucher references (specimen numbers in MNHN collections) and GenBank accession numbers of the specimens included in this study.(PDF)Click here for additional data file.Table S2Primers used in this study.(PDF)Click here for additional data file.Table S3Agnotecous species.Results of the Bayesian test of monophyly for (PDF)Click here for additional data file.Table S4Details of the geographic distribution of species used in the analysis of geographical pattern of speciation.(PDF)Click here for additional data file.Table S5Results of the asymmetry tests conducted under SymmeTREE for seven test statistics.(PDF)Click here for additional data file.Table S6Results of the diversification rate change test conducted under the R package apTreeshape.(PDF)Click here for additional data file.Table S7Results of the BDL analyses and comparison of AIC values from different diversification models.(PDF)Click here for additional data file.Text S1Additional information on sequencing protocols.(PDF)Click here for additional data file.Text S2Characteristics of mitochondrial (a) and nuclear (b) datasets used in this study.(PDF)Click here for additional data file.Text S3Congruence tests between nuclear and mitochondrial data sets.(PDF)Click here for additional data file.Text S4Details about phylogenetic analyses.(PDF)Click here for additional data file.Text S5Additional BEAST parameters and details of calibrations.(PDF)Click here for additional data file.Text S6Details of the rate.estimate function used in GEIGER.(PDF)Click here for additional data file."} +{"text": "Traumatic Brain Injury (TBI) is a contributing factor to approximately one third of all injury-related deaths in USA annually. Updated statistical records for TBI in Egypt are lacking. The current research is aiming for estimating the prevalence of TBI in Egypt in order to develop a comprehensive TBI prevention program.One year period descriptive epidemiological study of moderate and severe TBI cases admitted to the emergency department, Cairo main university hospital. The Data collection sheet included personal data , incident related data and both; clinical and radiological findings.Moderate and severe injuries account for 17.2% (844) of all TBI presented cases in the 4 months for the study. Male sex was predominantly affected 79% of cases. 63% of the cases were between 19 and 55 years old and the 2 main causes were fall from height (FFH) and motor vehicle collision (MVC) which account for about 64% of cases. 17% of cases were among pediatric group (1-18 years) and FFH was the leading cause with 34% followed by MVC and stuck by or against events with the same percentages (21%). Causes of moderate and severe TBI among seniors (above 60 years) were FFH (28%), MVC (24%), and Stuck by or against events (15%).Traumatic brain injury is a serious public health problem in Egypt. Further data interpretation over wider periods of time should be conducted for better understanding of TBI prevalence is highly recommended to develop effective injury prevention program. Inefficient recording should raise the concern to establish an optimal system for data recording and interpreting."} +{"text": "Contact electrochemical transfer of silver from a metal-film stamp or a metal-coated scanning probe is demonstrated to allow site-selective metallization of monolayer template patterns of any desired shape and size created by constructive nanolithography. The precise nanoscale control of metal delivery to predefined surface sites, achieved as a result of the selective affinity of the monolayer template for electrochemically generated metal ions, provides a versatile synthetic tool en route to the bottom-up assembly of electric nanocircuits. These findings offer direct experimental support to the view that, in electrochemical metal deposition, charge is carried across the electrode\u2013solution interface by ion migration to the electrode rather than by electron transfer to hydrated ions in solution. The quest for a chemical methodology applicable to the bottom-up fabrication of planned electric nanocircuits that can be effectively addressed from the external macroscopic world continues to pose major synthetic challenges. Metal growth or deposition on or within a preformed template structure has been successfully used in the fabrication of various metallic nanoscale objects and periodic nanostructures \u201312; howe3 groups of a self-assembled OTS/Si monolayer to \u2013olecules ,16. The olecules \u20131518,27 ecules 15.contact electrochemical patterning and transfer (CEP\u2013CET), whereby OTSeo features are first printed or inscribed on a target OTS monolayer by using a stamp electrode consisting of a patterned silver film on OTS (Ag/OTS@OTS/Si) or a silver-coated SFM tip electrode, and then in-situ metallized by direct electrochemical transfer of the metal from the patterning electrode itself 30], respAll monolayer nanopatterning (CNL) and serial metallization (CET) operations were carried out in the contact mode , under controlled humidity at 55\u201365% RH. A SOLVER P47 SFM system (NT-MDT) was used in the fabrication of the OTSeo@OTS nanopatterns in 2C-coated HSC20 contact probes (Team Nanotec) were used in the inscription of the OTSeo lines, (under conditions similar to those mentioned above in relation to The serial CET experiments were perFile 1Serial CET trial experiments and comparison of imaging results obtained under different SFM imaging conditions."} +{"text": "Occluded Artery Trial (OAT) demonstrated that percutaneous coronary intervention (PCI) with optimal medical therapy does not reduce the frequency of major adverse events compared to optimal medical therapy alone when performed on days 3-28 post ST-elevation myocardial infarction (STEMI) in stable patients. However the assessment of infarct zone (IZ) viability was not used as an inclusion criterion in the this trial. Several studies in patients with stable coronary artery disease have shown that only patients with preserved myocardial viability benefit from revascularization.Therefore we decided to assess the frequency of IZ viability in patients fulfilling the criteria for randomization in the OAT trial.Until now the registry included 16 patients screened for participation in the Cardiac magnetic resonance for the Occluded infarct-related Artery Treatment (COAT) trial which is a single center randomized study conducted in the Institute of Cardiology in Warsaw to compare late revascularization with optimal medical therapy alone on days 3-28 post MI in stable patients with preserved IZ viability. Estimated enrollment into the randomized phase is 40 patients. Viability is defined as necrosis transmurality <50% in at least 4 segments of IZ on cardiac magnetic resonance. The primary end-point of the study is a change in systolic wall thickening (SWT) at 6 months. Secondary end-points include change in left ventricular ejection fraction (LVEF), wall motion score index (WMSI), end-diastolic and end-systolic left ventricular volumes .In the studied group 8 patients (50%) did not have preserved viability of the infarct zone. Patients with preserved IZ viability were randomized to late revascularization (4 patients) or optimal therapy alone (4 patients).Lack of preserved IZ viability in 50% of patients fulfilling the criteria for randomization in the OAT trial might have influenced the negative results of this trial regarding late revascularization in STEMI. Hypothesis tested in the ongoing COAT trial assumes that late opening of the occluded infarct-related artery only in patients with preserved myocardial tissue viability may lead to improvement of left ventricular function and/or volumes."} +{"text": "Arabidopsis thaliana ovules initiate within the developing gynoecium from meristematic tissue located along the margins of the floral carpels. When fertilized the ovules will develop into seeds. SEUSS (SEU) and AINTEGUMENTA (ANT) encode transcriptional regulators that are critical for the proper formation of ovules from the carpel margin meristem (CMM). The synergistic loss of ovule initiation observed in the seu ant double mutant suggests that SEU and ANT share overlapping functions during CMM development. However the molecular mechanism underlying this synergistic interaction is unknown. Using the ATH1 transcriptomics platform we identified transcripts that were differentially expressed in seu ant double mutant relative to wild type and single mutant gynoecia. In particular we sought to identify transcripts whose expression was dependent on the coordinated activities of the SEU and ANT gene products. Our analysis identifies a diverse set of transcripts that display altered expression in the seu ant double mutant tissues. The analysis of overrepresented Gene Ontology classifications suggests a preponderance of transcriptional regulators including multiple members of the REPRODUCTIVE MERISTEMS (REM) and GROWTH-REGULATING FACTOR (GRF) families are mis-regulated in the seu ant gynoecia. Our in situ hybridization analyses indicate that many of these genes are preferentially expressed within the developing CMM. This study is the first step toward a detailed description of the transcriptional regulatory hierarchies that control the development of the CMM and ovule initiation. Understanding the regulatory hierarchy controlled by SEU and ANT will clarify the molecular mechanism of the functional redundancy of these two genes and illuminate the developmental and molecular events required for CMM development and ovule initiation.In flowering plants the gynoecium is the female reproductive structure. In Arabidopsis thaliana, two rows of ovules develop from a ridge of meristematic tissue on the inner surface of the seed pod or gynoecium. Within the developing ovule primordia, much is known about molecular patterning events along the proximal to distal axis and the mechanisms of integument development In both gymnosperms and angiosperms, ovules are critical for reproductive competence. Ovules contain the female gametophyte and thus the egg cell. Additionally, upon fertilization the ovules develop into the seeds that nurture and protect the developing embryos. In Gynoecial development in Arabidopsis initiates at stage 6 of floral development single mutant is nearly wild type while the aintegumenta (ant) mutant conditions the loss of about 50% of the ovule primordia. Together the loss of both the SEU and ANT activities in the seu ant double results in the complete loss of ovule initiation, indicating a synergistic genetic interaction and suggesting a degree of overlapping function for SEU and ANT during CMM development.A number of genes have been suggested to play a role in the maintenance of meristematic potential in the CMM and for the subsequent initiation of ovule primordia from the flanks of the CMM. While no single mutant has been reported to strongly disrupt ovule initiation, several higher order mutant combinations have been reported to disrupt the initiation of ovule primordia from the CMM SEU and ANT both encode transcriptional regulators ANT encodes an AP2-type DNA binding transcription factor that is expressed in all lateral organ primordia ANT is expressed throughout the stage 6 gynoecial mound with a higher level of expression within the adaxial core ANT is strong in the ovule anlagen and early ovule primordia as they arise. ANT activity during primordium development supports organ growth by maintaining the developmental period during which cell growth and cell divisions occur ANT has also been shown to contribute to proper specification of floral organ identity and polarity specification ANT regulation have not yet been published, PHB and cyclinD3 have been shown genetically to be downstream of ANT regulation ANT in organ polarity specification and regulation of cellular proliferation and/or organ growth.SEU encodes a transcriptional adaptor protein that is expressed widely throughout the plant SEU does not have a specific DNA binding activity but rather complexes with sequence specific DNA binding proteins in order to exert its effects on transcriptional regulation AGAMOUS (AG) expression during floral organ identity specification AG transcription through the recruitment of histone deacetylase proteins seu ant mutant is not conditioned simply by a de-repression of AG, but rather that SEU and ANT function to maintain or specify adaxial fate in the gynoecium and that this fate specification is critical for proper CMM development PHABULOSA (PHB) and REVOLUTA (REV) are reduced in the adaxial core of the stage 6 gynoecium in seu ant mutant plants. PHB and REV encode transcriptional regulators of the Homeodomain Leucine Zipper Class III type (HDZip-III) that are known to play a key role in the specification of adaxial identity in lateral organs SEU and ANT activity on HDZip-III expression was due to a direct or indirect regulation of their expression or accumulation. Additionally the defects in ovule and CMM development observed in the seu ant double mutant were not rescued when PHB activity was replaced, suggesting that either that PHB could not substitute for the other HDZip-III family members or that gene functions in addition to HDZip-IIIs are required downstream of SEU and ANT for CMM development ant rev double mutant, but not in ant phb double mutant support the idea of a functional differentiation between the PHB and REV activities within the CMM SEU and ANT that remain to be elucidated.A variety of experimental data suggest that the disruption of CMM development observed in the SEU and ANT are members of gene families whose members have been shown to share redundant function SEUSS-LIKE genes, SLK1, and SLK2 genetically enhance the ant mutant phenotype with respect to ovule initiation defects ANT-LIKE family member, AIL6, shares a critical redundant function with ANT as the ant ail6 double mutants flowers display reduced medial domain development and initiate very few ovule primordia ANT and the YABBY family members YAB1 and YAB3 is suggested by the synergistic disruption of ovule initiation observed in the ant yab1 and ant yab1yab3 mutants ant shatterproof1 (shp1) shatterproof2 (shp2) crabs claw (crc) mutants implicates the SHP MADS domain transcription factors in CMM development. These studies together highlight an important role for ANT function during CMM development and ovule initiation as well as reveal a high degree of functional redundancy within this tissue.Although no single mutant has been identified that eliminates CMM development or ovule initiation, a number of double mutant or higher order mutant combinations condition a severe disruption of the CMM and CMM-derived tissues (e.g. ovules) seu ant double mutant. In particular we sought to identify transcripts whose expression was dependent on the coordinated activities of SEU and ANT gene products. We hoped to both identify novel regulators of CMM development and to examine the molecular mechanism of the functional redundancy of SEU and ANT during CMM development. Our analysis identified a diverse set of transcripts that display altered expression in the seu ant double mutant tissues. Our in situ hybridization analyses indicate that many of these genes are preferentially expressed within the developing CMM. The analysis of overrepresented Gene Ontology classifications suggests a preponderance of transcriptional regulators including multiple members of the REPRODUCTIVE MERISTEMS (REM) and GROWTH-REGULATING FACTOR (GRF) families of transcriptional regulators are mis-regulated in the seu ant gynoecia. This study is the first step toward a detailed description of the transcriptional regulatory hierarchies that control the development of the CMM and ovule initiation.A number of key regulators of CMM development may be difficult to recover with standard forward genetic approaches due to a high degree of redundancy. Identifying genes that have specific patterns of spatial and temporal expression in the CMM would generate a set of candidate genes that could then be analyzed by reverse genetic approaches. In this paper we employ a transcriptomic profiling approach to identify sets of genes that are differentially expressed in the developing carpels of the seu ant double mutant relative to either single mutant. We isolated RNA from staged and hand-dissected gynoecia to limit the developmental window of the sample to the period just before and then during ovule primordia initiation, the earliest steps of ovule development. This differentiates our work from that of the Gasser and Colombo groups that have focused on later ovule developmental stages when identifying ovule-specific transcripts In an effort to identify novel regulators of CMM development and ovule initiation we identified genes that are preferentially expressed within the CMM within the context of the gynoecium. Additionally we endeavored to prioritize genes whose expression is synergistically disrupted in the seu-3, ant-1, and seu-3 ant-1 double mutant). We first analyzed mRNA accumulation in each single mutant relative to the Col-0 wild type gynoecial samples. To identify transcripts whose steady-state levels were altered in the single mutants relative to wild type, we utilized a 1-way ANOVA and identified probe sets (transcripts) that displayed a statistically significant difference in accumulation by the genotype term. This analysis identified 120 under-expressed and 200 over-expressed transcripts in the seu single mutant and 219 under-expressed and 241 over-expressed transcripts in the ant single mutant (We utilized the Arabidopsis ATH1 Gene Chip (Affymetrix) to compare transcript levels between four different genotypes over-represented GO terms suggest a role for this gene set in transcriptional regulation and relevant developmental processes, and 2) the reduced accumulation of these transcripts in the seu ant double mutant suggests that they may be preferentially expressed in the CMM in the wild-type gynoecium and, thus, are candidates for novel regulators of CMM development.We focused our attention on the genes that displayed seu ant double mutant we used a second analytical approach (Approach II) comprised of two steps. We first selected probe sets for which the mean expression was significantly lower in the seu or ant single mutant relative to wild type . These include AT1G02800 (ATCEL2), AT3G55560 (AGF2), AT5g57720 (REM15) AT2g46870 (NGA1), AT1G68640 (PAN), AT2G34710 (PHB), AT4G37750 (ANT), AT1G70560 (TAA1), AT5G18000 (VDD), AT3G17010 (REM22), and AT4G31610 (REM34 - previously AtREM1) PHB and TAA1) has been previously shown to be reduced in seu, ant or seu ant mutant gynoecia SEU and ANT have been implicated in the repression of AG in perianth organs, the levels of AG expression were not significantly different from wild type in the seu or ant single mutant gynoecial RNA samples . The Arabidopsis B3 superfamily consists of 118 genes all of which encode proteins containing one or more B3-type DNA binding domains. The B3 superfamily is comprised of four sub-families: REPRODUCTIVE MERISTEM); LAV (LEAFY COTYLEDON2[LEC2]-ABSCISIC ACID INSENSITIVE3 [ABI3]-VAL); ARF(AUXIN RESPONSE FACTOR);REM ( and RELATED TO ABI3RAV( and VP1). Six of the seven B3 regulators that were identified in our transcriptomics approach are from the REM subfamily for which there is little functional data. Four of these genes, AT4G31610 (REM34/AtREM1), AT5G18000 (VDD), At5G57720 (REM15) and AT3G17010 (REM22), have been previously reported to display CMM-enriched expression Surprisingly, seven out of the 31 Approach II candidate genes were members of the factors [49], with experiment number (E-MEXP-3293).Two analyses were run on our data. The first was a simple 1-way ANOVA by genotype. This method identified genes with expression levels that were statically different from that of the mean of the expression values. Class variables were specified as the genotype and the genotype was modeled as a fixed effect. The data was not compared to any baseline, but the LSMeans were run for simple differences of genotype using pFDR for the multiple testing method with an alpha of 0.05. Additionally we required that log2 of the magnitude of the expression level difference between the compared genotype means was greater than 0.35. The fixation method for the data points with large residuals was set as the False Positive Rate and the LSMeans standardization rate was set for Standard Deviation. The second analysis method (Approach II) was directed at detecting genes whose expression was synergistically affected in the enes See . Gene liseu, ant, and seu ant genotypes. Each biological replicate was assayed in triplicate. Results in ADENOSINE PHOSPHORIBOSYL TRANSFERASE1 . Results shown are the average expression normalized to APT1 and the standard error of the mean for four biological replicates. APT1 was shown to be unaffected by genotype in our gynoecial RNA samples by comparison of APT1 expression levels with two other standards across the four genotypes. Statistical analysis of one way ANOVA was conducted in JMP8 using a Tukey-Kramer HSD test and a p value cutoff of 0.05. Sequences of the oligonucleotides used for qRT-PCR analysis are described in in situ hybridizations were carried out as reported previously http://www4.ncsu.edu/~rgfranks/research/protocols.html.For analysis of transcript abundances, RNA from stage 8\u201310 gynoecia isolated for microarray analysis (pre-amplification) was used. cDNA synthesis and qRT-PCR were performed as previously described Table S1seu single mutant via one way ANOVA.Genes under-expressed (reduced accumulation) in the (XLS)Click here for additional data file.Table S2Genes over-expressed (increased accumulation) in the seu single mutant via one way ANOVA.(XLS)Click here for additional data file.Table S3ant single mutant via one way ANOVA.Genes under-expressed (reduced accumulation) in the (XLS)Click here for additional data file.Table S4ant single mutant via one way ANOVA.Genes over-expressed (increased accumulation) in the (XLS)Click here for additional data file.Table S5seu single mutant.Over-represented GO categories for gene set displaying reduced expressed in the (XLS)Click here for additional data file.Table S6seu single mutant.Over-represented GO categories for gene set over expressed in the (XLS)Click here for additional data file.Table S7ant single mutant.Over-represented GO categories for gene set displaying reduced expressed in the (XLS)Click here for additional data file.Table S8ant single mutant.Over-represented GO categories for gene set over expressed in the (XLS)Click here for additional data file.Table S9seu ant double mutant via one way ANOVA.Genes under-expressed (reduced accumulation) in the (XLS)Click here for additional data file.Table S10seu ant double mutant via one way ANOVA.Genes over-expressed in the (XLS)Click here for additional data file.Table S11seu ant double mutant.Over-represented GO categories for gene set displaying reduced expressed in the (XLS)Click here for additional data file.Table S12seu ant double mutant.Over-represented GO categories for gene set over expressed in the (XLS)Click here for additional data file.Table S13Sequences of oligonucleotides used for qRT PCR analysis of candidate gene expression.(XLS)Click here for additional data file.Table S14Output from JMP Genomics (SAS) ANOVA analysis with values for estimate builder (non-additivity) model for double mutant.(XLS)Click here for additional data file."} +{"text": "To identify the origin of synchronous and metachronous urothelial carcinoma (UC) of the bladder and upper urinary tract to get a better understanding of the basic mechanism behind the multifocality of UC, which may provide a sound bases for the future development of new strategies for detection, prevention and therapy.Six patients with UC of the bladder and synchronous or metachronous UC of the upper urinary tract were studied. Genetic analysis involving the study of loss of heterozygosity (LOH) has been evaluated on their tumours using well characterised and new markers of UC .Five of the six patients demonstrated informative results. Four of five (80%) of patients had synchronous or metacharonous UC tumour and showed patterns of LOH consistent with tumorigenesis from monoclonal tumour origin. One of five (20%) patients exhibited a LOH consistent with oligoclonal tumorigenesis.These findings suggest that both the monoclonal and field cancerization theory of tumorigenesis may play a role in tumors of the urothelial tract. However, more data is needed. Urothelial carcinoma (UC) of the bladder is the fifth most common solid cancer in the industrialized world as a measure of clonality model exposed to known carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine has shown oligoclonal tumour development in 30% of mice, suggesting that the field defect means of tumorigenesis plays a significant role in cancer of urothelial tract with UC of the UUT and synchronous or metachronous bladder UC that underwent surgical excision of their tumours were identified. These patients underwent nephroureterectomy for their UUT tumour(s) and transurethral resection of their bladder tumour(s). All tumours excised were high grade UC. The patients were not treated with any radiotherapy or chemotherapy prior to their surgical resection. Patients had not received any intravesical chemotherapy or immunotherapy for the bladder tumours. Tissue sample and microdissection: Formalin fixed paraffin embedded archival tissue was cut to 5um sections, and stained with haematoxylin and eosin for microscopic evaluation. Pathological identification of tumours was done with guidance of pathologist. Laser assisted microdissection of neoplastic tissue was performed using the PixCell II Laser-Capture Microdissection\u00ae apparatus was used to amplify genomic DNA at four specific loci on two different chromosomes: 9p21 (D9S171), 9q32 (D9S177), 9q22 (D9S303) and 17p13 (TP53). D9S171 is associated with tumour suppressor gene p16, a well characterized marker of early bladder tumorigenesis was examined in 6 patients. Of the six patients, five patients showed informative results (83%) in one of the four loci studied. However, no patient showed informative results through all four loci with informative loci showed a monoclonal pattern of LOH, while only one of five patients (. (20%) showed an oligoclonal pattern of LOH. Unfortunately, the patient with the oligoclonal pattern of LOH was male, and a confirmatory x-inactivation study could not be conducted. These findings are consistent with results seen by Sidranksy et al. Habuchi while the overgrowth of one clone in late stages tumorigenesis (high-grade tumours) may result in pseudomonoclonality or intraepithelial spread. In one of case however, there was evidence for tumour that may arise independently, consistent with the field cancerization model. This suggest that although the single cell theory of tumorigenesis may be the predominate means of UC progression, the field cancerization model may also play a small albeit significant role, which must not be overlooked when considering appropriate treatments modalities, and when using molecular diagnostic techniques to diagnosis and monitor for disease recurrence."} +{"text": "Right heart catheterization (RHC) is required for definitive diagnosis of pulmonary hypertension (PH) and serial echocardiograms or RHC are necessary for long term disease management. However, RHC is invasive, costly and risky for the patient. EchocarTo evaluate the use of Cardiac MR for measuring right ventricular parameters in order to assess Pulmonary Hypertension.23 patients with PH and 12 controls underwent CMR on a 1.5T Siemens Avanto scanner. All patients underwent RHC to diagnose PH within 1 month of CMR study. The CMR protocol included cine SSFP of the whole heart and phase contrast MRI of the pulmonary valve (PV). The following conventional right ventricular (RV) functional parameters were calculated: ejection fraction (EF), end diastolic volume (EDV) and end systolic volume (ESV). Time to peak systole (TPS), an indirect measure of RV strain, was derived from the volume-time curves of the RV. PV flow analysis was performed and the following parameters were calculated: peak velocity, full-width at half maximum (FWHM), acceleration time (AT) and ejection time (ET).The results of RV functional parameters and PV flow values are shown in Tables TPS, calculated by CMR, may be a useful additional quantitative measure for diagnosis of PH and may be of value in long-term non-invasive assessment of treatment efficacy."} +{"text": "Microthrombosis has been demonstrated in early and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Markers of coagulation activation as microparticles (MPs) are an established risk factor for thrombosis. Our hypothesis was that levels of microparticles might correlate with aSAH severity, early cerebral ischemia (ECI) and delayed cerebral ischemia (DCI).Consecutive aSAH patients (age 18 to 80) admitted to our department between November 2011 and September 2012 were enrolled in the study. Total MPs (anxV+), platelet MPs , tissue factor MPs , and endothelial MPs were assessed in venous blood samples. Measurement of MPs levels were obtained at early (<3 days) and delayed phase (7 to 10 days). Multiparameter MRI was performed to evaluate ischemic damage and vasospasm at the same time points. Qualitative evaluation of severity of ischemic damage was performed on DWI sequences. Levels of MPs were evaluated comparing different groups in terms of SAH severity , ECI severity and occurrence of delayed complications (vasospasm and DCI).n = 9) when compared with WFNS 1 to 2 (n = 16) patients. Interestingly, patients with most severe ECI and DCI showed the highest values of MPs, but this trend did not reach statistical significance, probably because of the small number of patients included in the study.Twenty-five patients were included in the analysis. Overall increased levels of MPs were observed at early phase after aSAH when compared with controls. Contrarily to our hypothesis, in the early phase no significant differences of MP level were observed in WFNS 4 to 5 (Microparticles and microthrombosis may increase the severity of early and delayed ischemic damage after aSAH."} +{"text": "Studies report that women with Rheumatoid Arthritis (RA) are not wearing therapeutic footwear. It is likely they are wearing normal retail footwear. Previous research gives limited information on people\u2019s perceptions on the relationships that exist between retail footwear, well-being and quality of life (QOL). This study aimed to explore these perceptions and to identify the factors influencing footwear selection.Eleven women with RA wearing retail footwear were recruited from an out-patient podiatry clinic in the south east of England. Semi-structured interviews were carried out and a hermeneutical approach; interpretative phenomenological analysis of transcripts occurred to identify recurring themes.Six main themes were revealed from the analysis. These included: (1) the nature of foot complaints and deformities, (2) aesthetic appearance and design of footwear, (3) body image, (4) psychosocial aspects, (5) Perceptions of footwear and (6) the therapeutic value of retail shoes.Retail footwear for these women with RA has impacted on their individuality which has been shown to link significantly with their body images. Whilst footwear itself has not impacted solely on the well-being of these women; the disease process has. These consequences have been identified in their quality of life."} +{"text": "Tau pathology is characteristic of Alzheimer\u2019s disease (AD) and related tauopathies including Parkinson\u2019s disease (PD) wherein a significant percentage of PD patients who develop dementia harbor AD-like tau pathology. Tau pathology is characterized by insoluble filamentous aggregates of hyperphosphorylated tau in CNS neurons known as neurofibrillary tangles (NFTs) and neuropil threads (NTs). NFTs and NTs are implicated in mechanisms of neurodegeneration through gains of toxic functions or losses of normal tau functions. Hyperphosphorylation and decreased solubility of tau leads to a loss of the ability of tau to bind to and stabilize microtubules (MTs) which impairs axonal transport and results in neuronal dysfunction and degeneration. This presentation describes the use of MT stabilizing drugs to counteract the loss of tau function and prevent/ameliorate tau mediated neurodegeneration in a transgenic (Tg) mouse model of an AD-like neurodegenerative tauopathy. Briefly, proof of concept prevention and intervention studies of the brain-penetrant MT-stabilizing agent epothilone D (EpoD) are described in young (prevention) and aged (intervention) P301S mutant tau Tg mice (PS 19 mice) with little (young PS 19 mice) or abundant tau pathology and behavioral impairments (aged PS19 mice). In the prevention and intervention studies, EpoD treatment reduced axonal dystrophy and increased axonal MT density which led to improved neuronal integrity and cognitive performance. EpoD treatment also improved fast axonal transport in the aged PS19 Tg mice. Unexpectedly, aged PS19 mice treated with EpoD showed a marked reduction in forebrain tau pathology and increased hippocampal neuronal integrity. There were no dose-limiting side effects in the EpoD treated young and aged PS19 mice. These studies support the view that EpoD and other brain-penetrant MT-stabilizing drugs offset the loss of tau function in neurodegenerative tauopathies and therefore are potential therapeutics for the treatment of AD and related tauopathies. Finally, a new seeded transmission model of tauopathy is presented using injections of preformed tau fibrils into the brains of PS19 mice which presents new opportunities to assess the efficacy of MT stabilizers and other potential passive immunization therapies for AD and related tauopathies.Supported by grants from the NINDS/NIA."} +{"text": "The overall outcome of HIV disease may depend on the host's capacity to maintain dendritic cell (DC) homeostasis at mucosal sites, where DC populations, one of the earliest cell types to be exposed to the virus, present an inherent capacity to modulate the balance between tolerance and protection. DCs may influence mucosal B cell responses against HIV through contact and/or production of B cell growth factors such as B lymphocyte stimulator (BLyS/BAFF), which in turn modulate the outcome of CD4[superscript]+[/superscript] T cell HIV effectors/targets. Recent observations of HIV/SIV infections in non-pathogenic animal models and from mucosal vaccination of nonhuman primates suggest that maintenance of systemic integrity may be achieved through constraining highly efficient immune responses to mucosal sites.B lymphocyte disorders are important consequences of HIV infection mice Indeed, there is an increasing body of experimental evidence demonstrating the role of B cells in regulating the development, proliferation, and maintenance of CD4+ T cell HIV effectors/targets. Recent observations of HIV/SIV infections in non-pathogenic animal models and from mucosal vaccination of nonhuman primates suggest that maintenance of systemic integrity may be achieved through constraining highly efficient immune responses to mucosal sites.The overall outcome of HIV disease may depend on the host's capacity to maintain dendritic cell (DC) homeostasis at mucosalsites, where DC populations, one of the earliest cell types to be exposed to the virus, present an inherent capacity to modulate the balance between tolerance and protection. DCs may influence mucosal B cell responses against HIV through contact and/or production of B cell growth factors such as B lymphocyte stimulator (BLyS/BAFF), which in turn modulate the outcome of CD4BLyS expression levels correlate with both the extent to which the B cell compartment is compromised and HIV disease progression status. The fact that HIV elite controllers expressed relatively low levels of BLyS suggest that therapeutic blockage of BLyS in HIV progressors may restore balanced effector to regulatory cell ratios to reduce both HIV target cells and systemic immune activation that are the hallmarks of HIV disease progression."} +{"text": "We show that intracerebral injection of such isolates into C57BL/6 mice produces a disease with preservation of PrPres molecular features distinct from BSE.We previously reported that cattle were affected by a prion disorder that differed from bovine spongiform encephalopathy (BSE) by showing distinct molecular features of disease-associated protease-resistant prion protein (PrP Characterization of the infectious agent associated with BSE showed unique features. These include defined incubation periods and distribution of brain lesions after transmission to wild-type mice, not only directly from cattle, but also after natural or experimentally induced cross-species transmission (res) accumulating in the brains of animals and humans with BSE have demonstrated specific molecular features. These include a low molecular mass of unglycosylated PrPres with high proportions of diglycosylated PrPres and decreased levels of diglycosylated PrPres when compared with BSE isolates and labeling with P4 monoclonal antibody C57BL/6 female mice were injected intracerebrally with 20 \u03bcL of 10% (weight/volume) homogenates per mouse prepared from brain stem samples of 3 cattle TSE isolates. Two of the isolates were characterized, as previously described or Supersignal and visualized either on film or directly in an image analysis system . Molecular masses of PrPres glycoforms were determined as the average of the center positions of the bands from at least 3 repeated electrophoretic procedures, as measured by comparison with a biotinylated marker included on each gel. Immunologic reactivities of antibodies 12B2 and Sha31 were compared in Western blots run in parallel with the same samples with both antibodies.Frozen mouse brain tissues and fixed brain tissues were examined by Western blot analysis and immunohistochemical tests as previously described (res detection among mice analyzed by Western blot are shown in the Table.After intracerebral injection of cattle brain samples into C57BL/6 mice, disease was observed in mice with the 2 H-type isolates, as well as with the BSE sample. Survival periods of mice and results of PrPres from H-type\u2013infected mouse brains in comparison with BSE-infected mice is shown in res glycoforms in mice infected with H-type isolates than in mice infected with a typical BSE agent (1.1- to 1.5-Da difference in the unglycosylated PrPres (res protease cleavage showed that only the PrPres of mice infected with H-type isolates was recognized by antibody 12B2 (Western blot analysis of PrPd PrPres A. Studieody 12B2 B. This fHistopathologic analysis showed vacuolar lesions in the thalamus A that weres molecular signature. This evidence in favor of a new bovine prion strain in cattle suggests that BSE is not the only transmissible prion disease in cattle. The origin of such cases has not been determined (res after infection with the BSE agent. However, based on analysis of molecular features of prion diseases in cattle, this situation is similar to that in humans (Our data show that the recently identified bovine H-type isolates involve an infectious agent that can induce development of a disease across a species barrier, while maintaining the specific associated PrP"} +{"text": "Objectives: To investigate cognitive components and mechanisms of learning and memory in primary progressive aphasia (PPA) using a simple clinical measure, the Three Words Three Shapes Test (3W3S).Background: PPA patients can complain of memory loss and may perform poorly in standard tests of memory. The extent to which these signs and symptoms reflect dysfunction of the left hemisphere language versus limbic memory network remains unknown.Methods: 3W3S data from 26 patients with a clinical diagnosis of PPA were compared with previously published data from patients with typical dementia of the Alzheimer type (DAT) and cognitively healthy elders.Results: PPA patients showed two bottlenecks in new learning. First, they were impaired in the effortless (but not effortful) on-line encoding of verbal items. Second, they were impaired in the retrieval (but not retention) of verbal items. In contrast, DAT patients had impairments also in effortful on-line encoding and retention of verbal and nonverbal items.Conclusions: PPA selectively interferes with spontaneous on-line encoding and subsequent retrieval of verbal information. This combination may underlie poor memory test performance and is likely to reflect the dysfunction of the left hemisphere language rather than medial temporal memory network."} +{"text": "Research indicates a clear need for easily accessible interventions of different lengths and intensity for individuals with problematic substance use. Internet interventions with therapist support for problematic alcohol use have yielded positive results in prior studies, but have never been investigated in Sweden. This pilot study tested an online structured relapse prevention program with and without therapist support. 80 internet help-seekers from the general population were recruited through a national self-help site and randomized into three groups: 1) therapist support via secure messages (n=20); 2) a choice between therapist support via messages or live chats (n=20); 3) self-help (n=40). Baseline data showed no significant differences between the three groups concerning age, gender, Time Line Follow Back (TLFB), Alcohol Use Disorders Identification Test (AUDIT), Readiness to Change Questionnaire (RTCQ) and Quality of Life (WHOQOL). In the group with a choice between messages and chat, 35% chose chat. All follow-up data for the study have recently been collected, and results will be analyzed for presentation at the conference. This study has the potential to further broaden knowledge about internet-based interventions for problematic alcohol use, and provide information about the significance of therapist support."} +{"text": "Neurons of the striatum receive important glutaminergic input from the cortex and thalamus and massive dopaminergic innervation from midbrain dopamine neurons. The majority (95%) of striatal neurons are medium spiny projection neurons and 5% are aspiny interneurons. The projection neurons are GABAergic and form the direct and indirect striatal output pathways that have been shown to be crucial for normal motor function and appetitively motivated learning. The importance of the medium spiny projection neurons is highlighted by the severe debilitation associated with the loss of their dopaminergic input in Parkinson\u2019s disease or degeneration of these cells in Huntington\u2019s disease . Approximately half of all medium spiny striatal neurons express the dopamine D1A receptor (Drd1a) and these neurons comprise the direct output pathway to the medial globus pallidus and substantia nigra pars reticulata . Early deletion of the Drd1-expressing striatal neurons in mice results in severe motor impairment, eating deficits and reduced striatal volume . In order to separate potential developmental effects from the normal role of the Drd1a-expressing striatal cells in adult mice, we have made a mouse model that allows for the inducible deletion or expression of targeted genes specifically within the Drd1a-expressing striatal neurons using BAC transgenesis.A bacterial artificial chromosome (BAC) designated RP23-47M2 was obtained from BACPAC resources of the Children\u2019s Hospital Oakland Research Institute (CHORI). This BAC contains the Drd1a locus. Using the techniques of bacterial homologous recombination , a cassette containing the reverse tetracycline-controlled transactivator (rtTA) fused to the herpes simplex virus VP16 transactivator was inserted at the ATG start site of the Drd1a locus. Transgenic mice with the modified BAC randomly integrated into their genomes were produced by microinjection of the modified BAC into mouse zygotes at the University of Michigan Transgenic Core. Transgenic mouse lines carrying the rtTA allele were crossed with reporter transgenic mice carrying the allele for tetO-lacZ. In bi-transgenic mice this approach (TET-ON) allows for the activation of the tet operator by rtTA in the presence of doxycycline (DOX). Therefore, during DOX administration, the lacZ gene produces \u03b2-galactosidase which can be detected through X-gal staining.Drd1a-rtTA/tetO-lacZ lines were screened and at least one line to date has shown strong expression specifically within the mouse striatum. X-gal staining is present throughout the striatum, with somewhat higher levels in the medial aspects of the structure. We are continuing to screen additional lines and are determining the minimal parameters of DOX administration (dose and duration) necessary for the inducible expression of rtTA/VP16.We have made the first inducible Drd1a TET-ON mouse. This mouse, in conjunction with other transgenic models, will allow for the inducible expression or deletion of target genes specifically within Drd1a-expressing cells and will be highly useful in the study of Parkinson\u2019s and Huntington\u2019s diseases, addiction and the normal role of Drd1a-expressing cells."} +{"text": "Adverse drug reactions (ADR) appear more frequently then what is actually reported and registered. The aim was to establish an intensive monitoring system and to analyze ADR in hospitalized patients.The prospective study covered 200 patients hospitalized in the Cardiology Center, Clinical Center of Montenegro. ADR were recorded in the following way: patients were interviewed on the basis of a symptoms list and any signs which could point to eventual ADR. Secondly, lab tests and other available parameters were monitored.At the time when interviews took place, patients received on average 8.0 \u00b1 2.6 medicines (2\u201317). In total, 67 patients (33%) had 75 ADR. Twenty one ADR (28%) are classified as serious. Fifty four ADR resulted in the recovery of the patient (72%), eight had as an outcome prolonged hospitalization (11%), another eight were life threatening (11%), while five ADR (6%) were the cause of the hospitalization. The most frequent ADR which had as an outcome admission to hospital were caused by digoxin (40%), prolonged hospital stay by furosemide (38%), while the most frequent registered ADR which were life threatening were caused by streptokinase (50%).Monitoring ADR in patients using cardiovascular drugs is a matter of importance since this class of medicines is usually used by elderly patients with critical conditions and accompanying diseases. Considering increased use of cardiovascular drugs and limitations in pre-marketing trials for drug safety evaluation, post marketing evaluation of adverse drug reactions induced by this class of medicinal products seems necessary. Additional educational efforts could affirm the rationalization of the pharmacotherapy."} +{"text": "Background: Recent findings strongly promoted the hypothesis that common pelvic gynecological diseases including endometriosis and ovarian neoplasia may develop de novo from ectopic endometrial-like glands and/or embryonic epithelial remnants. To verify the frequency, the anatomical localization and the phenotype of misplaced endometrial tissue along the fetal female reproductive tract, histological and immunohistochemical analyses of uteri, fallopian tubes, and uterosacral ligaments were performed. Methods: Reproductive organs were collected from seven female fetuses at autopsy, five of them from gestational ages between 18 and 26\u2009weeks and two fetuses with gestational ages of 33 and 36\u2009weeks deceased of placental anomalies. Serial sections from areas containing ectopic glands and embryonic duct residues were analyzed by histological and immunohistochemical procedures. Results: Numerous ectopic endometrial glands and stroma were detected in the myometrium in two fetuses with low levels of expression of estrogen receptor-alpha (ER-\u03b1) and progesterone receptors (PR). The embryonic ducts were localized in the uterine broad and ovarian ligaments and under the fallopian tube serosa in six fetuses. Low levels of steroid receptors expression were found in the embryonic residues, whereas the carcino-embryonic antigen (CEA) and the tumor marker Ca 125 were not detected. The embryonic residues stromal component strongly expressed the CD 10 and vimentin proteins. Conclusion: The anatomical and the immunohistochemical features of the ectopic organoid structures identified in fetal female reproductive tract suggest that endometriotic as well as neoplastic disease in adult women may develop on the basis of misplaced endometrial glands and/or embryonic cell remnants. Endometriosis is a heterogeneous gynecological disease clinically characterized by the presence of different anatomo-clinical subtypes Giudice, . The mosIn the present study, we evaluated the incidence and the anatomical location of displaced endometrial tissue in the reproductive tract in seven female fetuses. Serial sectioning of the reproductive organs was realized followed by immunohistochemical analysis of tissue areas containing ectopic glands and embryonic cell rests. It was observed that the anatomical and the phenotypic features of the mislocated tissue components recall some pathological characteristics of both benign and malignant gynecological conditions.Reproductive organs from a series of seven human female fetuses at different gestational ages ranging from 18 to 36\u2009weeks were obtained at autopsy. All together, the causes of fetal death were placental pathology in two samples, cardiac malformations in two cases and voluntary abortions in three. The reproductive organs were carefully dissected, fixed in buffered formaldehyde, and included in paraffin.Between 200 and 400 serial sections with thickness of 5\u20137\u2009mm from each paraffin block containing uteri, fallopian tubes, ovaries, and uterosacral ligaments were prepared and stained by hematoxylin and eosin (H&E). To ascertain tissue sections containing ectopic endometrial glands and/or embryonic duct remnants, every sixth slide was separately stained and microscopically analyzed.The following antibodies were employed; rabbit anti estrogen receptor-alpha (ER-\u03b1), ; monoclonal mouse anti human progesterone receptor, clone PR 636 ; monoclonal anti human CA125, clone M11 CA125 (Dako); monoclonal anti human CD10 clone 56C6 (Dako); monoclonal anti human carcino-embryonic antigen (CEA) clone II-7 (Dako); rabbit anti human alpha-1-foetoprotein (Dako); monoclonal anti human epithelial membrane antigen (EMA) clone E29 (Dako); mouse anti human Cytokeratin 7 and monoclonal mouse anti-vimentin clone VIM 3B (Dako).Five micrometres thick sections were deparaffinized in xylene, rehydrated through graded alcohol series, and washed in PBS. For antigen retrieval, the slides were immerged in citrate buffer (pH\u2009=\u20096.0) during 25\u2009min at 96\u00b0C essentially as described , PR (14%), and ER-\u03b1 (6%) was revealed in the ectopic glandular structures localized in the uterine wall. A strong expression of CD10 (41.3%) but lower level of vimentin specific immunolabeling (20%) was observed in the stromal component surrounding the displaced glands. Representative illustrations of PR expression in orthotopic endometrial cells as well as the expression of PR, ER-\u03b1, and CD10 in the uterine ectopic glands and stroma are shown in Figures Concerning the embryonic remnants, consistent EMA immunostaining ranging between 32 and 53% was detected in the duct lining cells, while lower level of expression in duct cells of both ER-\u03b1 10\u201323%) and PR (13\u201344%) molecules was found in all samples. The stromal-like component surrounding the duct residues contained between 1 and 3% of immunoreactive cells for ER-\u03b1 and between 4 and 13% of immunoreactive cells for PR. Approximately 2\u201311% of the ductal cells and 1\u20133% of the stormal cells expressed cytokeratin 7, while CEA and CA125 molecules were not detected. Using anti alpha-1-fetoprotein antibody, close to 42% of the epithelial and duct surrounding mesenchymal cells were intensely immunoreactive on sections from two fetuses. Representative illustrations of the embryonic duct residues labeled with anti ER-\u03b1, anti PR, anti alpha-1-fetoprotein and anti CD10 antibodies are shown in Figures 0\u201323% andIn this study we show presence of misplaced endometrial glands and embryonic duct-like remnants in the reproductive organs in six of seven examined female fetuses. The phenotypic features of the ectopic glands in the myometrium of two fetuses indicate particularly weak expression of PR and ER-\u03b1 steroid hormone receptors in comparison to their high level of expression in cells lining the endometrial cavity. In these two cases, moderate level of PR expression was also revealed in the cell nuclei of the stromal component, while ER-\u03b1 receptors were not found. Overall, the presented findings are in accordance with other studies describing the levels of ER-\u03b1 and PR in misplaced glands in patients with both endometriosis and adenomyosis (Van der Walt et al., Concerning the foci of embryonic duct remnants observed, moderate expression of PR and low levels of ER-\u03b1 were uniformly revealed in the epithelial cells in all cases. Histologically, some ducts appeared dysplastic and surrounded by a dense cellular stromal layer consistently expressing vimentin and CD10 molecules. Of interest, these tubular structures in most of the samples did not clearly express cytokeratin 7, and Ca 125 protein molecules. This might be related to particular phenotypic features of coelomic metaplastic cell rests at given gestational age (Batt and Smith, de novo expression of this protein in ovarian malignancy arising from endometriosis (Horiuchi et al., In spite of the limited number of studied cases, the findings of ectopic glands and/or embryonic ducts in the reproductive tract of female fetuses is a remarkable phenomenon that could be referred to the theory of involvement of M\u00fcllerian or Wolfian cell rests in the pathogenesis of both endometriosis and particular pelvic malignancies Fujii, . At presIn conclusion, the presented data support the theory that at least some subtypes of endometriotic and gynecological neoplastic lesions may be related to anomalies occurring during the embryogenesis. These data stand in relationship with the embryological origin of certain pelvic malignancies based on the metaplastic potentiality of the secondary M\u00fcllerian system. The observed frequency of displaced embryonic structures, also suggests a complex pathogenetic mechanism in the development of endometriosis-associated neoplasms including genetic, hormonal, and/or environmental events. Consequently, further studies of endometriotic and neoplastic lesions should include novel embryonic cellular phenotypic markers, that could provide important diagnostic and predictive information to guide clinical decision making.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Our objective was to investigate the molecular mechanism underlying the processing of proBNP, levels of which are increased in heart failure ,2.Rat neonatal atrial and ventricular myocytes were cultured separately. We examined: (1) the molecular forms of secreted and intracellular BNP in atrial and ventricular myocytes; (2) levels of corin and furin mRNA in atrial and ventricular myocytes and the effect their knockdown on proBNP processing; (3) molecular forms of BNP in plasma from rats and humans with and without heart failure; (4) the structure of proBNP in humans and rats; (5) the impact of the distance between the glycosylation and cleavage sites in wild-type and mutant human proBNP expressed in rat myocytes transfected with lentiviral vectors.BNP was the major molecular form secreted by atrial (75\u00b19%) and ventricular (85\u00b19%) myocytes, and was the major intracellular form in atrial myocytes (60\u00b15%). ProBNP was the major intracellular form in ventricular myocytes (58\u00b14%). The relative levels of furin mRNA correlated with those of BNP in atrial and ventricular myocytes, and transfection of furin siRNA reduced proBNP processing in both atrial and ventricular myocytes. BNP was the major molecular form in rat plasma 90\u00b110%), whereas proBNP was the major form in human plasma (72\u00b18%). The relative fraction of human BNP in rat myocytes expressing human proBNP was 60\u00b15%, but increasing the distance between the glycosylation and cleavage sites through mutation, increased the processed fraction correspondingly (Figure 0%, whereO-glycosylation and cleavage sites in humans.These results suggest that proBNP is processed into BNP and N-terminal proBNP intracellularly, most likely by furin in rat. The level of proBNP processing is lower in humans than rats, most likely due to the smaller distance between the"} +{"text": "From a methodological point of view, these results demonstrate the suitability of computing bilateral CoP trajectories regularity for the assessment of lateralized postural control under pathological conditions.The present study was designed to assess the relative contribution of each leg to unperturbed bipedal posture in lower limb amputees. To achieve this goal, eight unilateral traumatic trans-femoral amputees (TFA) were asked to stand as still as possible on a plantar pressure data acquisition system with their eyes closed. Four dependent variables were computed to describe the subject's postural behavior: (1) body weight distribution, (2) amplitude, (3) velocity and (4) regularity of centre of foot pressure (CoP) trajectories under the amputated (A) leg and the non-amputated (NA) leg. Results showed a larger body weight distribution applied to the NA leg than to the A leg and a more regular CoP profiles with greater amplitude and velocity under the NA leg than under the A leg. Taken together, these findings suggest that the NA leg and the A leg do not equally contribute to the control of unperturbed bipedal posture in TFA. The observation that TFA do In recent years, a growing number of studies have been designed to explore the dynamical structure of the centre of foot pressure (CoP) trajectories in terms of entropy (regularity/predictability) to provide more insight into mechanisms involved in the control of bipedal unperturbed stance , with feet parallel separated by 10 cm, and their arms hanging loosely by their sides. This system includes capacitive force sensors arranged in matrix form body weight (BW) distribution, (2) amplitude (On the one hand, to quantify the amount of postural sway under each leg, the root mean square of the CoP displacements (The means of the three postural measurements recorded were used for statistical analyses. BW distribution,"} +{"text": "This review aimed to ascertain the extent to which the issue of departure from treatment protocol (DTP) is reported and addressed in published analyses of RCTs.One hundred publications of RCTs were randomly selected from those published in the BMJ, NEJM, JAMA and Lancet during 2008. Each trial report was reviewed to determine the extent and nature of reporting on DTP and whether statistical methods were used to deal with DTP for both benefit and harms analyses.Even the most basic adherence information was not presented in some trials. Forty-two publications did not state how many patients actually initiated their randomised treatment. Information about treatment discontinuation can be vague and may not allow assessment of the number of patients who completed the treatment protocol.Ninety-eight publications reported at least one form of DTP, including non-receipt of allocated treatment , incomplete treatment in those who initiated allocated treatment (78), switching trial treatments (12), starting disallowed/non-trial treatment (4), starting open label treatment out of trial (7), contamination across groups (3) and other nonadherence to treatment dose or schedule (23). Treatment providers were reported to be nonadherent when delivering treatment in 12 trials.More than half (50 (51%)) of the publications that reported DTP used some method to deal with it, but none were based on randomisation-preserving techniques. The most common method was based on per protocol (PP) analysis (46) (including one instance of using inverse probability of censoring weighting) often labelled as intention to treat (ITT) (18) or modified ITT (5), but missing data techniques (2) and as treated analyses (3) were also implemented. Less than 40% (26) of the 69 trials which presented harms analyses specifically defined harms analysis populations, and the majority of these definitions were based on actual treatment received (18). The majority (31) of the 43 trials that did not explicitly specify harms analysis population appeared to analysed harms outcomes using ITT. Twelve reports explicitly commented on the fact that DTP was likely to have influenced the observed treatment effect.DTP data presented in RCT publications, particularly related to treatment initiation and discontinuation, may be ambiguous or scant. Trialists often attempt to deal with DTP using variations of PP analysis, although they may be labelled as ITT; randomisation-preserving methods are not typically used. There appears to be confusion among trialists over the appropriate analysis population for harms outcomes in the presence of DTP."} +{"text": "Self-transcendence (ST) is one of specific human experiences often related to harmony with nature or feeling oneness with others or the self as an integral part of the whole universe. The Temperament and Character Inventory (TCI) is a widely used personality measure, and ST is one of personality dimensions and body cooperation indexed by central (CNS) and autonomic (ANS) nervous system interaction (Cahn and Polich, In summary, growing empirical evidences indicate meditation has potential to develop ST\u2014a positive relationship between self and other that transcends self-focused needs and increases prosocial characteristics (H\u00f6lzel et al.,"} +{"text": "Haemodynamic monitoring is essential for the management of critically ill patients. Currently there are various techniques available in clinical practice to measure cardiac output (CO) in ICUs including pulmonary artery catheter (PAC), oesophageal Doppler, lithium dilution cardiac output (LiDCO) and pulse-induced contour cardiac output (PiCCO) studies. In recent times PAC has been used less with less invasive methods becoming more popular. We conducted a telephone survey of the current CO monitoring practices in adult ICUs in the United Kingdom.All general adult ICUs in the United Kingdom were surveyed via telephone. The nurse-in-charge or the senior physician for the shift was consulted to ascertain which cardiac output monitors (COMs) were available for use, which was their first choice and if they used PAC in the past 12 months.A total of 225 adult ICUs were surveyed and all the replies were recorded on paper (98% response). Two hundred and eleven (96%) units used at least one form of COM while the rest of the 14 units did not use any COM tool. One hundred and two (48%) use more than one form of cardiac output monitoring. Oesphageal Doppler was most popular , followed by LiDCO and PICCO both used in 73/211 (35%) of the units, and pulse contour analysis . Seven out of 211 (3%) units still use PAC as the preferred method of COM, of these two had other COM devices available and five used PAC only. Forty-six out of 211 (22%) units were using PAC at least occasionally. In contrast, a similar survey performed in 2005 [The results show the changes in COM over the past 5 years in comparison with a previous survey in 2005 . There a"} +{"text": "National and international guidelines on antiretroviral therapy for HIV infection recently changed to recommend earlier treatment, following the publication during 2009 of two collaborative analyses of HIV cohort studies ,2. These"} +{"text": "However, the detection of other genomic variants remains a challenge due to the lack of appropriate tools for heterozygous base-calling fluorescence chromatogram data analysis. In this study, we developed a free web-based program, Mixed Sequence Reader (MSR), which can directly analyze heterozygous base-calling fluorescence chromatogram data in .abi file format using comparisons with reference sequences. The heterozygous sequences are identified as two distinct sequences and aligned with reference sequences. Our results showed that MSR may be used to (i) physically locate indel and STR sequences and determine STR copy number by searching NCBI reference sequences; (ii) predict combinations of microsatellite patterns using the Federal Bureau of Investigation Combined DNA Index System (CODIS); (iii) determine human papilloma virus (HPV) genotypes by searching current viral databases in cases of double infections; (iv) estimate the copy number of paralogous genes, such as \u03b2-defensin 4 (DEFB4) and its paralog HSPDP3.The direct sequencing of PCR products generates heterozygous base-calling fluorescence chromatograms that are useful for identifying single-nucleotide polymorphisms (SNPs), insertion-deletions (indels), short tandem repeats (STRs), and paralogous genes. Indels and STRs can be easily detected using the currently available In The detection of genomic variations is important in studying the relationships between causative genes and diseases and the relationships between predisposing genes and complex trait diseases, such as type 2 diabetes, coronary heart disease, and cancers \u20134. Strucdelligent program uses dynamic programming optimization to decode the heterozygous indels with International Union of Pure and Applied Chemistry DNA code system (IUPAC code) Another type of \u201cmixed\u201d sequence is represented by viral coinfection in the same specimen. For example, double HPV genotypes within one sample could be analyzed by EasyChip using probes designed to amplify the variable regions that are unique to each HPV genotype . To valiDEFB4 gene, which is well known for its multiple copy number variations. The PCR primers used amplified DEFB4 and its paralog, the pseudogene HSPDP3 and chromosome 8 . The LRi value of each chromatography peak was used to estimate the ratio between DEFB4/HSPDP3 and calculate the DEFB4 copy number . Second,delligent, which only processes IUPAC code data. Only MSR can map sequence data to a reference database and report the most possible mixed sequence. MSR and CHILD can estimate the ratio of sequences in a mixture. Only PolyScan can process next-generation sequencing data STR repeat structure and those of plasmid cloning, (B) MSR analyzed results are shown as the IUPAC code and decomposed sequence.Supplementary Figure 2: (A) Chromatography trace of a combined two CODIS D21S11 Locus subtype, (B) there were two 4-bp gaps in the alignment of two subtypes in CODIS D21S11 Locus.Click here for additional data file."} +{"text": "While considerable research has evaluated the effects of joint mobilisation on spinal, pelvic and shoulder biomechanics, there is a paucity of research evaluating the effects of foot mobilisation techniques (FMT) on gait. This pilot study evaluated the immediate effects of FMT on plantar pressures and temporal-spatial gait parameters.Fifteen adults (48\u00b121.4 years) that had no known balance problems or falls history participated. An instrumented treadmill system was used to measure plantar pressure and temporal-spatial gait parameters. Data were recorded for 30 seconds of steady state walking immediately before and after intervention using a standardised protocol of FMT. Repeated measures ANOVAs were used to assess the effect of FMT on gait parameters at an alpha level of .05.Of the 34 gait parameters measured, only three changed significantly after FMT. Peak pressure beneath the lateral heel (4%) and lateral forefoot (9%) was increased immediately following FMT (p<.05) and was accompanied by a delay (3%) in the time to peak pressure beneath the lateral forefoot (p<.05).Changes in plantar pressure following FMT were small and less than the reported measurement error of the treadmill system. Therefore, in this pilot study the immediate effect of FMT on gait parameters was negligible. Further research evaluating short and long term effects of FMT on specific aspects of the locomotor system are needed."} +{"text": "To the Editor: The recent article by Helms et al. described the distribution of Salmonella enterica serovar Typhimurium definitive page type 104 (DT104) infections in 29 countries from 1992 to 2001 (According to the Colindale scheme for phage typing (Emergence of phage subtype DT104A was identified in June 2004 during an outbreak of salmonellosis in Rome. This subtype had never been previously identified in Italy. All DT104A isolates were susceptible to the Enter-net panel of antimicrobial drugs (The incidence of DT104 in Italy has remained stable from 2002 through 2004. However, emergence of subtype DT104A during a recent outbreak highlights the need for subtyping in identifying communitywide outbreaks and in monitoring changing subtype patterns."} +{"text": "Several recent studies have demonstrated that endothelial to mesenchymal transition (EndoMT), a newly recognized type of cellular transdifferentiation may be an important source of myofibroblasts during the development of experimentally induced pulmonary, cardiac and kidney fibrosis. EndoMT is a complex biological process induced by members of the transforming growth factor (TGF-\u03b2) family of regulatory polypeptides in which endothelial cells adopt a mesenchymal or myofibroblastic phenotype acquiring motile and contractile properties and initiating expression of mesenchymal cell products such as \u03b1 smooth muscle actin (\u03b1-SMA) and type I collagen. Although these experimental studies provide compelling evidence for the participation of EndoMT in the development of experimentally-induced fibrotic processes the precise role of EndoMT in the pathogenesis of human fibrotic disorders requires confirmation and validation from studies of human clinical pathologic conditions. Such confirmation should lead to a change in the paradigm of the origin of profibrogenic myofibroblasts involved in human fibrotic diseases. Further understanding of the molecular mechanisms and the regulatory pathways involved in EndoMT may lead to the development of novel therapeutic approaches for the incurable and often devastating fibrotic disorders. It is generally accepted that activated mesenchymal cells or myofibroblasts play a crucial role in the pathogenesis of various fibrotic diseases including interstitial pulmonary fibrosis, systemic sclerosis and liver or cardiac fibrosis being responsible for the exaggerated production and accumulation of extracellular matrix proteins in various organs affected by these diseases -4. AlthoThe occurrence of EndoMT in experimentally induced cardiac fibrosis was originally described by Zeisberg et al. employinin vitro. The treated cells displayed a progressive loss and the eventual disappearance of endothelial-specific cell markers (CD-31 and VE-cadherin) and a parallel acquisition of mesenchymal cell markers including vimentin, collagen I and N-cadherin. These results suggested that intestinal endothelial cells exposed to an inflammatory environment may participate in the intestinal fibrotic process which accompanies intestinal inflammatory diseases. The in vitro observations were confirmed by studies of molecular co-localization in human colonic mucosa [In contrast with the extensive evidence from experimental animal models demonstrating the important participation of EndoMT in the development of tissue fibrosis studies with human endothelial cells are just beginning to appear. One such study examinedc mucosa .Another study examined the expression of cell surface markers specific for endothelial cells in mesenchymal/fibroblastic cells present in the subendothelial compartment of small vessels in lungs from patients with Systemic Sclerosis-associated pulmonary fibrosis . ConfocaIn contrast to the very extensive studies conducted to unravel the molecular mechanisms and the regulatory pathways that modulate epithelial mesenchymal transition -31, the Besides TGF-\u03b2 it has been shown that endothelin-1 (ET-1) may also participate in EndoMT. In one study, Widyantoro et al. showed tAlthough there are numerous studies which have conclusively shown the crucial involvement of members of the TGF-\u03b2 family of growth factors in initiation of EndoMT, the detailed molecular events and the intracellular cascades activated by TGF-\u03b2 that result in the remarkable phenotypic change of endothelial cells to mesenchymal cells have not been entirely elucidated. Recent studies in primary cultures of murine pulmonary endothelial cells and in cde novo mesenchymal phenotypes. These studies identified the c-Abl protein kinase (c-Abl), protein kinase C\u03b4 (PKC-\u03b4), and glycogen synthase kinase 3\u03b2 (GSK-3\u03b2) as important participants and that GSK-3\u03b2 kinase phosphorylation was a crucial event in this process [Several studies explored the underlying molecular pathways that may cause the significant loss of endothelial-specific markers while inducing strong process ,42. It i process ,44 as ilIn summary, numerous recent studies have provided strong evidence for the prominent participation of EndoMT in the generation of activated myofibroblasts during the development of experimentally induced tissue fibrosis suggesting that EndoMT plays a crucial role in fibrotic diseases. There is some early experimental evidence providing support and validation for the participation of EndoMT in the development of human intestinal fibrosis and of Systemic Sclerosis-associated pulmonary fibrosis. The firm demonstration of the occurrence of EndoMT in human fibrotic diseases and further understanding of the molecular mechanisms involved may lead to the pharmacologic modulation or abrogation of this pathway in human fibrotic disorders and may represent a novel therapeutic approach for these devastating diseases.The authors declare that they have no competing interests."} +{"text": "It has been shown in in-vitro experiments that \"withdrawal\" of tamoxifen inhibits growth of tumor cells. However, evidence is scarce when this is extrapolated into clinical context. We report our experience to verify the clinical relevance of \"withdrawal therapy\".Breast cancer patients since 1998 who fulfilled the following criteria were selected from the departmental database and the case-notes were retrospectively reviewed: (1) estrogen receptor positive, operable primary breast cancer in elderly (age > 70 years), locally advanced or metastatic breast cancer; (2) disease deemed suitable for treatment by hormonal manipulation; (3) disease assessable by UICC criteria; (4) received \"withdrawal\" from a prior endocrine agent as a form of therapy; (5) on \"withdrawal therapy\" for \u2265 6 months unless they progressed prior.Seventeen patients with median age of 84.3 (53.7-92.5) had \"withdrawal therapy\" as second to tenth line of treatment following prior endocrine therapy using tamoxifen (n = 10), an aromatase inhibitor (n = 5), megestrol acetate (n = 1) or fulvestrant (n = 1). Ten patients (58.8%) had clinical benefit (CB) with a median duration of Clinical Benefit (DoCB) of 10+ (7-27) months. Two patients remain on \"withdrawal therapy\" at the time of analysis.\"Withdrawal therapy\" appears to produce sustained CB in a significant proportion of patients. This applies not only to \"withdrawal\" from tamoxifen, but also from other categories of endocrine agents. \"Withdrawal\" from endocrine therapy is, therefore, a viable intercalating option between endocrine agents to minimise resistance and provide additional line of therapy. It should be considered as part of the sequencing of endocrine therapy. Estrogen receptor (ER) positive breast cancers after a period of response to anti-estrogens develop resistance and clinically the disease progresses. Besides the predominant role of alternative signalling pathways, domination of partial agonistic activity of tamoxifen over its antagonist activity has been implicated for acquired resistance . RegressCase-notes of the breast cancer patients treated in the Nottingham breast unit since 1998 fulfilling the following criteria were studied retrospectively:\u2022 ER positive invasive breast carcinoma proven by histology \u2022 Primary operable cancer in elderly (age > 70 years) (who were frail or refused to undergo surgery), locally advanced or metastatic\u2022 Disease deemed suitable for further hormonal manipulation\u2022 Disease progressed on a hormonal agent and thus suitable for \"withdrawal\" from an endocrine agent as a therapeutic option \u2022 Assessable lesions were deemed to have shown CB when they either had objective response in the form of complete response (CR) or partial response (PR); or had stable disease (SD) for \u2265 6 months in accordance with UICC criteria ,10\u2022 Metastatic lesions were assessed radiologically (CT scan/X-rays/bone scan) every 3 months as routine protocol in the unit\u2022 On \"withdrawal therapy\" for at least 6 months unless disease progressed priorDuration of CB (DoCB) is the duration of therapy in months only in patients who have derived CB and including patient still on treatment. Duration of treatment (DoT) is the duration of therapy in months of all patients (regardless of the type of response) and including patient still on treatmentSeventeen patients with either locally advanced primary (n = 3) or metastatic n = 14) breast cancer had \"withdrawal\" treatment as 2nd to 10th line of treatment. Patient and tumor characteristics are shown in Table 4 breast Tamoxifen may continue to provide antagonistic activity on ER nuclear signalling activity but may act as an agonist on the ER membrane signalling activity which could explain the loss of continuing CB to some patients on long-term tamoxifen therapy . There iIn an in-vivo study , athymicThe lack of response in the remaining patients on withdrawal of tamoxifen could partly be explained by the growth promoting action of natural estrogen in the body as seen in the above in-vivo study . Therefo-11 M/L or more of estradiol. This is again possible due to activation of cross-talk mechanisms and domination of mitogen-activated protein kinase or growth factors [In our study, as seen in table st 4 years followed by 12 months in year 5)[The above in-vitro concept is being explored further in clinical settings. There is ongoing recruitment to a phase III trial wherein node positive early stage patients who have completed 4-6 years of prior adjuvant endocrine therapy (a SERM/AI/both) are randomised to receive either 5 years of daily letrozole or receive intermittent letrozole regime (daily for first 9 months of 1n year 5). The ratIn locally advanced and advanced breast cancer, ideally, inhibitors of the alternative pathways would be the subsequent logical therapy following resistance to other endocrine agents. However, if the patient is unfit to receive any further anti-estrogen therapy then it is very likely that they would not be suitable for further growth factor inhibitors or indeed chemotherapeutic agents. In this circumstance, withdrawal of therapy may be the only feasible option or alternating regime of endocrine therapy and withdrawal therapy as is being tested in the adjuvant setting in the SOLE trial.Our data therefore provides some clinical evidence and emphasises the relevance of withdrawal therapy. The concept is being tested in large randomised trials in adjuvant settings. However, larger datasets and results of ongoing adjuvant trials are needed to provide confirmatory evidence for or against the concept and feasibility of withdrawal therapy in locally advanced and metastatic breast cancer.The authors declare that they have no competing interests.KLC conceived this study. Patients were under care of JFR and KLC. AA collected data, performed analysis, drafted, revised and finalised the manuscript. KLC and JFR revised and approved of the contents of the manuscript. All authors read and approved the final manuscript."} +{"text": "Diabetes related foot ulcers (DRFU) frequently require surgical debridement or limb saving, partial foot amputation. The resultant wounds are generally deep and associated with prolonged healing times. Negative pressure wound therapy (NPWT) is increasingly used to facilitate healing of these complex wounds. This retrospective audit provides outcome data on patients with post-surgical wounds managed with NPWT within our High Risk Foot Service (HRFS). There is a paucity of data on clinical outcomes of DRFU treated with this therapy.Data from patients treated for post-surgical wounds within the HRFS was extracted from our electronic data base. A manual review of the patients records treated with NPWT was conducted to determine wound severity (University of Texas grading system), time to healing (from date of surgery), duration of NPWT and complications including new or recurrence of wounds and the need for further surgical management.155 patients with post surgical wounds were managed by the HRFS between September 2006 and November 2010. Many (83%) of these were superficial ulcers (grade 1), the remainder involved tendon and or bone (Grade 2 and 3). Thirty seven patients (37 wounds) were treated with NPWT. Two were superficial (grade 1), 19 were to tendon (grade 2) and 16 were to bone (grade 3). Most (34) were clinically infected at baseline and 13 were ischaemic. Median time to healing (from the date of surgery) was 121 days. Twenty one healed and 5 cases are ongoing. NPWT was used for a median of 30 days. Two required further foot surgery before healing, 14 patients developed new ulcers (unrelated to NPWT), 3 patients who healed required below knee amputation within 2 years and 1 died during the follow-up period.NPWT is often used in our service for the management of complex post surgical wounds with close to 60% achieving complete wound closure and a low rate of major amputation. While many factors may influence this result, the increasing use of NWPT is supported in this setting. Data collection is ongoing and we plan to compare these outcomes to a historical control group and hope that this sets a benchmark for appropriate use of NPWT."} +{"text": "Cancer remains a major health concern in the management of HIV infection in areas of the world with and without access to highly active antiretroviral therapy. In the USA alone, approximately 56,000 people were newly diagnosed with HIV infection in 2006; 53% of these new diagnosis occurred in gay and bisexual men but Black/African American men (45%) ,women (27%) , and Hispanics 17%) were also strongly affected [7% were aAMC-PNs conducted activities that raised awareness in their local communities of AIDS-related malignancies, developed partnerships with local health community organizations and identified areas where further communication was needed. PNs took the lead in developing a PN brochure and in the design of several tailored recruitment strategies. The PN program is making important inroads into behavioral interventions to increase participation of minorities and underserved populations in AMC trials."} +{"text": "Addressing the problem of preventable drug related morbidity (PDRM) in primary care is a challenge for health care systems internationally. The increasing implementation of clinical information systems in the UK and internationally provide new opportunities to systematically identify patients at risk of PDRM for targeted medication review. The objectives of this study were (1) to develop a set of explicit medication assessment criteria to identify patients with sub-optimally effective or high-risk medication use from electronic medical records and (2) to identify medication use topics that are perceived by UK primary care clinicians to be priorities for quality and safety improvement initiatives.For objective (1), a 2-round consensus process based on the RAND/UCLA Appropriateness Method (RAM) was conducted, in which candidate criteria were identified from the literature and scored by a panel of 10 experts for 'appropriateness' and 'necessity'. A set of final criteria was generated from candidates accepted at each level. For objective (2), thematically related final criteria were clustered into 'topics', from which a panel of 26 UK primary care clinicians identified priorities for quality improvement in a 2-round Delphi exercise.(1) The RAM process yielded a final set of 176 medication assessment criteria organised under the domains 'quality' and 'safety', each classified as targeting 'appropriate/necessary to do' or 'inappropriate/necessary to avoid' (safety) medication use. Fifty-two final 'quality' assessment criteria target patients with unmet indications, sub-optimal selection or intensity of beneficial drug treatments. A total of 124 'safety' assessment criteria target patients with unmet needs for risk-mitigating agents, high-risk drug selection, excessive dose or duration, inconsistent monitoring or dosing instructions. (2) The UK Delphi panel identified 11 (23%) of 47 scored topics as 'high priority' for quality improvement initiatives in primary care.The developed criteria set complements existing medication assessment instruments in that it is not limited to the elderly, can be implemented in electronic data sets and focuses on drug groups and conditions implicated in common and/or severe PDRM in primary care. Identified priorities for quality and safety improvement can guide the selection of targets for initiatives to address the PDRM problem in primary care. Systematic reviews have demonstrated deficits in the quality and safety of medication use in primary care to an extent sufficient to constitute a public health threat. Three to four percent of all unplanned hospital admissions are due to preventable drug related morbidity (PDRM), with the majority attributed to high-risk prescribing and inconsistent monitoring -4. AntipThe 'Data-driven Quality Improvement in Primary care (DQIP)' research programme is designing and testing a complex intervention to improve the quality and safety of medication use in UK primary care. It is based on encouraging and facilitating primary care medical practices to systematically and continuously identify, correct or otherwise manage drug therapy risks that are potential pre-cursors to PDRM . The DQIA number of explicit medication assessment tools have been developed in recent years. The Beers criteria set lists potopics, are perceived to be priorities for quality improvement by professionals working in UK primary care.The study had two aims. First, we aimed to develop and classify by clinical importance a set of up-to-date medication assessment criteria that can be implemented in routine primary care clinical datasets to identify instances of (a) sub-optimally effective medication use for conditions commonly encountered in primary care and (b) high-risk use of drugs that have been shown to either commonly cause harm and/or cause severe harm in primary care. Second, we aimed to elicit the extent to which thematically-related medication assessment criteria, subsequently referred to as The study was conducted in three stages. First, an extensive list of candidate medication assessment criteria was generated based on a structured literature review. Second, an expert panel participating in a modified RAND/UCLA (University College of Los Angeles) Appropriateness Method (RAM) study scored these items by clinical importance based on a summary of research evidence and their clinical judgement. Candidate criteria with high importance scores were translated into a final criteria set by removing redundancies (see below). Final criteria were characterised by the type of medication use targeted, informed by available taxonomies -15. ThirPrescribing is a ubiquitous feature of medical care which makes a systematic evaluation of the literature on prescribing quality or safety unfeasible in a single research project. We therefore focussed on medication use for conditions commonly encountered in primary care and drugs with clear evidence of significant benefit or harm. The literature review drew initially on UK national clinical guidelines, prescribing advice, and safety alerts, supplemented by European or other clinical guidelines and targeted primary literature review in selected areas as detailed below.Candidate medication assessment criteria either described potentially beneficial medication use or the use of potentially harmful treatments ('safety'). Candidate 'quality' criteria targeted common conditions where there are compelling indications for drug therapy based on UK and European guidelines -25. CommIn order to identify candidate safety criteria, the drug groups reported to be most frequently implicated in PDRM hospital admissions were identified from systematic reviews and large scale studies -4,34. FoThe RAND/University of California Los Angeles (UCLA) appropriateness method is a rigorous way of combining research evidence with expert opinion , and hasimproper' not to be offered or avoided, whereas 'appropriate' is a more neutral balancing of net benefit or harm [The questionnaire aimed to classify candidate medication assessment criteria derived from the literature as either 'necessary' or 'appropriate' care table . 'Necess or harm -45. Foll or harm ,46.and three or more ratings of 1 to 3) on the appropriateness scale were rejected. Those items with median ratings of 7 to 9 were accepted as 'appropriate' and those with median ratings of 1 to 3 as 'inappropriate'.All candidate quality and safety assessment criteria were scored for 'appropriateness'. Candidate criteria with a median rating of 4 to 6 ('uncertain') or disagreement were accepted. Candidate safety assessment criteria were additionally scored on a 'necessary to avoid' scale, where items with a median rating of 1 to 3 (= clearly necessary to avoid) were accepted. Candidate criteria with median ratings of < 7 on the 'necessary to do' and > 3 on the necessary to avoid scale and those showing disagreement (defined as above) were rejected. The concept of 'necessary to avoid' was an extension to the original RAM method to differentiate between prescribing that is 'generally not worthwhile' from 'improper' in safety terms (see box 2).The ten RAM panel members were emailed the first round questionnaire and a summary of the supporting evidence base. Panellists were asked to rate each item with reference to an 'average' patient consulting an 'average' primary care clinician in 2009 based on both the evidence summary and their clinical judgement . PanelliA random sample of general medical practitioners (GPs) and eligible pharmacists in Scotland and England was invited to participate by e-mail. In order to be eligible, pharmacists had to have experience of working in medicines governance, as a prescribing advisor or as a practice pharmacist. Twenty three (64%) GPs and 13 (36%) pharmacists agreed to participate.'The described topic is a priority for collaborative quality improvement in primary care'. The term 'collaborative' was used in order to emphasise that the intended purpose of this study was to identify priority topics for quality improvement rather than measures for judging practitioners or practices as part of performance management.The Delphi questionnaire listed the medication improvement topics to be scored together with a short summary of the scientific rationale for each topic. For each item, panellists were asked to state their level of agreement with the statement and 30% or more ratings of 7 to 9) were accepted as 'priority', with median ratings of 8 or 9 defined as 'high priority'. All findings reported in this paper refer to second round ratings.As in the RAM study, all ratings used an ordinal scale of 1 to 9 (1 = strongly disagree and 9 = strongly agree). Panellists were instructed to rate topics in relation to primary care in general, rather than their own practice. The first round ratings were summarised and returned to participants by email for a second round of scoring. Topics with second round median ratings of 7 to 9 without disagreement candidate assessment criteria. Upon completion of the second rating round, 318 (82%) candidates were accepted at the 'appropriate' and 275 (71%) items at the 'necessary' level. A number of candidate criteria were duplicates, in the sense that they were designed to determine thresholds beyond which care was judged appropriate and necessary. For example, 18 candidate quality assessment criteria related to glycated haemoglobin (HbA1c) levels beyond which treatment intensification was appropriate or necessary. Removing redundant candidate criteria yielded 52 quality and 124 safety assessment criteria to be included in the final set. Forty (77%) final quality assessment criteria and 107 (86%) final safety assessment criteria were derived from candidates accepted at the 'necessary' level. The results of the RAM study are summarised in tables Table Similarly, table The majority of safety assessment criteria are drug-focussed (74%), either targeting drugs reported to be frequently implicated in PDRM hospital admissions (54% - section A) or others implicated in severe preventable harm (20% - section B). The remainder (26% - section C) target medication use in particularly vulnerable groups, namely the elderly 15%), patients with heart failure (8%) and children (4%). Over a third (36%) of final safety assessment criteria focus on potentially harmful use of NSAIDs, antiplatelets, anticoagulants and diuretics, the drug groups most frequently implicated in PDRM hospital admissions [5%, patieOver half (52%) of safety criteria target the selection of high-risk drugs (MS2 to 4), either for indications where safer alternatives exist (MS2) or in patients particularly susceptible to adverse reactions because of age/co-morbidity (MS3) or co-prescription (MS4). A further 15 (12%) criteria target omissions of drugs indicated to mitigate the risk of adverse events from high-risk treatments (MS1), while twenty (16%) criteria target inconsistent laboratory monitoring (MS8). Two (2%) criteria focus on prescribing that may jeopardise patient compliance with methotrexate dosing schedules (MS7).The majority of quality (81%) and safety (71%) assessment criteria are not restricted to the elderly (patients aged 65 years or older).Grouping of thematically related assessment criteria that were derived from candidates accepted at the 'necessary' level yielded a total of 47 medication improvement topics to be rated by the Delphi panel. Thirty-six Delphi study participants completed a first round and 26 (73%) a second round questionnaire and high-risk use, inconsistent monitoring or patient instructions for drugs implicated in preventable harm (medication use safety) in primary care. All items are classified by clinical importance (appropriateness and necessity) as the output of an extended RAM process. Key professionals in UK primary care identified eleven clusters of thematically related medication assessment criteria (topics) as 'high priority' for quality improvement initiatives. The three highest rated topics related to methotrexate dosing instructions, high-risk prescribing of NSAIDs and antiplatelets and underuse of corticosteroids in asthma.The RAM approach had advantages over the Delphi technique as an initial step in the criteria development process, because the face-to-face meeting ensured the necessary commitment of panellists to place ratings on an extensive and thematically broad list of candidate criteria that were grounded in the evidence base. The original RAM approach was extended in this study by introducing the concept of 'necessary to avoid', in order to distinguish between inappropriate ('not worthwhile') and 'improper' medication use in safety terms results in the UK are often held in bespoke systems which hinder the implementation of meaningful measures for monitoring anticoagulant use -4. SimilAlthough the DQIP criteria set has been developed for application in UK primary care, the drug groups reported to be implicated in PDRM events in primary care are similar internationally -52, and The Delphi approach allowed stakeholders in primary care to prioritise the chosen medication use topics for improvement initiatives in UK primary care. The Delphi panel was deliberately chosen to include both day to day prescribers and those involved in prescribing governance and improvement (predominately pharmacists but including GPs with a more strategic role). A limitation is that our focus on professionals involved in primary care prescribing meant that we did not seek to include either specialist or patient/public perspectives in the Delphi panel. Since there is evidence that practitioners' perceptions of a targeted behaviour as meaningful is a pre-requisite to changing behaviour we aimedIt is important to note that even those topics that were not considered to be priorities contain individual criteria that were agreed to be 'necessary' to do or avoid by the RAM panel. Examples are 'inadequate dose titration of ACEI, ARBs and beta blockers in chronic heart failure', and the 'using of warfarin without a compelling indication in atrial fibrillation with low risk of stroke'. These should therefore not be neglected. Lower priority ratings nevertheless indicate that changing and improving the corresponding medication use aspects may require targeted effort (or resources) in order to influence prescribing behaviour.NCT01425502).The DQIP medication assessment criteria set presented here has been developed using established consensus methods and complements existing medication assessment instruments by not being limited to the elderly and by targeting a wide spectrum of medication use practices implicated in common and/or severe PDRM events in primary care. As all previously published explicit medication assessment tools, the criteria set presented here does not, however, provide comprehensive coverage of all situations that put patients at risk of PDRM, reflecting the large scope and high complexity of medication use in primary care and the limitations of current UK clinical information systems. The best choice of criteria set will therefore depend on the main purpose to be addressed and will be guided by local priorities. Informed by the priority ratings of a panel of UK primary care professionals, we have selected a subset of the DQIP criteria to serve as outcome measures in a cluster randomised trial evaluating the effectiveness of a complex intervention to improve prescribing safety and the extent to which any improvements in prescribing or monitoring translate into improved patient outcomes therefore deserve further study.ACEI: Angiotensin converting enzyme inhibitor; ACOVE: Assessing care of vulnerable elders; ACS: Acute coronary syndrome; ADE: Adverse drug event; AF: Atrial fibrillation; ARB: Angiotensin receptor blocker; BB: Beta blocker; BP: Blood pressure; CCB: Calcium channel blocker; 2: CHADSScore for stroke risk assessment in atrial fibrillation based on the following risk factors: cardiac failure, hypertension, age > 75, diabetes and stroke; CHD: Coronary heart disease; CHD: Coronary Heart Disease; CHF: Chronic heart failure; CKD: Chronic kidney disease; CKD: Chronic kidney disease; COPD: Chronic obstructive pulmonary disease; COX: Cyclo-oxygenase; CVD: Cardiovascular disease; DM: Diabetes mellitus; DMARD: Disease modifying antirheumatic drug; DQIP: Data driven quality improvement in primary care; eGFR: Estimated glomerular filtration rate; FBC: Full blood count; GIP: Gastro-intestinal protective agents; GP: General practitioner; HbA1c: Glycated haemoglobin; HIV: Human immunodeficiency virus; HRT: Hormone replacement therapy; HTN: Hypertension; INR: International normalised ratio; IT: Information technology; MI: Myocardial infarction; MTX: Methotrexate; NSAID: Non-steroidal anti-inflammatory drug (includes non-selective and COXII selective agents unless stated otherwise); NS NSAID: Non-selective NSAID NYHA: New York Heart Association; PDRM: Preventable drug related morbidity; RAM: RAND appropriateness method; SABA: Short acting beta 2 receptor agonist; SD: Standard deviation; START: Screening tool to alert doctors to right treatment; STOPP: Screening tool of older person's prescriptions; TCA: Tricyclic antidepressant; TIA: Transient ischaemic attack; U&E: Urea and electrolytes; UCLA: University College of Los Angeles; UK: United Kingdom; Z-drug: zopiclone, zolpidem or zaleplone.The authors declare that they have no competing interests.The study is part of the Data-driven Quality Improvement in Primary Care (DQIP) research programme, which is led by BG. TD led the literature review, conduct of RAM and Delphi studies, data analysis and wrote the first draft of the manuscript. All co-authors contributed to subsequent drafts. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6904/12/5/prepub"} +{"text": "The purpose of this study was to determine whether the duration of antiarrhythmic therapy after discharge from the hospital following abdominal surgery is related to the incidence of atrial fibrillation (AF) recurrence in elderly patients with the occurrence of peri-operative AF.The occurrence of peri-operative AF after abdominal surgery is a clinical condition burdened by several complications, especially in the elderly -3. When The recurrence of AF needs different kind of treatment. Medical therapy includes various antiarrhythmic drugs to control heart rate and restore sinus rhythm and anticoagulation to reduce the tromboembolic risk . OveractA pilot study was conducted in 19 elderly patients (age > 65 years) who underwent abdominal surgery and with occurrence of peri-operative AF that successfully reverted to sinus rhythm. They were prospectively randomized at dismissal to receive antiarrhythmic therapy for 1 week (six patients in group A), 3 weeks (seven patients in group B), or 6 weeks (six patients in group C). Patients were followed up for an additional 4 weeks after discontinuation of antiarrhythmic therapy for detection of recurrence of AF.There was no significant difference in the recurrence of AF among groups .In elderly patients with peri-operative AF after abdominal surgery, converted to normal sinus rhythm before hospital discharge, have a benign course and the duration of antiarrhythmic therapy shorter than one week is appropriate."} +{"text": "To the Editor: The biologic role of amino acid variants at position 222 of the hemagglutinin (HA) gene of pandemic (H1N1) 2009 virus in severe infections has been extensively discussed. A recent series of studies , confirming the clustering of all the worldwide 222E variants in a well-defined subclade . The same analysis showed that D222G variants could be reconciled with 2 different phylogenetic patterns. The first less frequent pattern includes sequences appearing sparsely throughout the tree, confirming the mentioned hypothesis of sporadic mutation. In contrast, the second pattern (the majority) relates to small groups of sequences appearing in monophyletic microclusters. Among these microclusters, 2 are particularly interesting because they include only 222G sequences, isolated in different parts of the world to 2,492 complete HA sequences from the Global Initiative on Sharing All Influenza Data database (expanded Figure online,"} +{"text": "Early results of an international RCT comparing drainage, irrigation &fibrinolytic therapy (DRIFT)for prematurity-associated post-ventricular dilatation (PHVD), with standard treatment suggested no benefit in terms of avoidance of shunt dependency. There was also an increased rate of secondary bleeds in those having DRIFT. The longer term benefits or otherwise of DRIFT treatment were unknown.We randomly allocated 77 preterm infants with PHVD to either DRIFT or standard treatment . Severe disability was assessed at 2 years\u2019 corrected age.Of 39 infants assigned to DRIFT, 21 (54%) died or were severely disabled versus 27 of 38 (71%) in the standard group . Among the survivors, 11 of 35 (31%) in the DRIFT group had severe cognitive disability versus 19 of 32 (59%) in the standard group . Median Mental Development Index was 68 with DRIFT and_50 with standard care.Despite inducing an increased rate of secondary intraventricular bleeding, DRIFT reduced severe cognitive disability in survivors and overall rates of death or severe disability. A modification of DRIFT involving simple ventricular lavage and fibrinolytic therapy (limited to unblocking clogged-up drainage catheters) will now be employed in clinical practice at our unit."} +{"text": "When patients with a rheumatic disorder reach adulthood, transfer to adult-focused care is advocated (1). A successful continuation of rheumatology follow-up beyond childhood depends on how clinicians think about transfer and transition (2).To explore the attitudes of rheumatology practitioners on transfer and transition from pediatric to adult health care of adolescents with a rheumatic disorder.A survey among rheumatology practitioners attending the Pediatric Rheumatology European Society congress in 2010. Overall, 138 individuals participated, of which 59 were medical doctors (MDs) with paediatric and rheumatology background; 30 MDs with pediatric background; and 21 MDs with rheumatology background.Participants judged that, when patients with active rheumatic disorder reach adulthood, they should receive medical follow-up from an adult rheumatologist (87%). Only 19% thought that patients should stay under surveillance of a paediatric rheumatologist. Several initiating factors for transfer were marked as important: readiness of the patient according to the caregiver (62%), age (61%) and psychosocial maturity (49%). A transfer meeting with the patient (76%), a referral letter (73%), or a medical transfer file (64%) were most preferred transfer communication tools with adult healthcare. Joint outpatient clinic, phone calls, and transfer meetings without the patient were considered to be less useful. The pediatric (94%) or adult rheumatologist (83%), parents (81%) and the nurse specialist (74%) were stated as most important active participants in the transition process.This study emphasized the importance of transfer to specialized rheumatology care of adolescents with an active rheumatic disease and highlighted transfer initiators and transfer communication tools."} +{"text": "We analysed the responses using descriptive statistics; 660 individuals responded to the public and 303 individuals responded to the expert survey. We found evidence of public skepticism about the use of neuroimaging for applications such as lie detection or to determine consumer preferences and considerable disquiet about use by employers or government and about how their data would be stored and used. While also somewhat skeptical about new applications of neuroimaging, experts grossly underestimated how often neuroimaging had been used as evidence in court. Although both the public and the experts rated highly the importance of a better informed public in limiting the inappropriate uses to which neuroimaging might be put, opinions differed on the need for, and mechanism of, actual regulation. Neuroscientists recognized the risks of inaccurate reporting of neuroimaging capabilities in the media but showed little motivation to engage with the public. The present study also emphasizes the need for better frameworks for scientific engagement with media and public education.Emerging applications of neuroimaging outside medicine and science have received intense public exposure through the media. Media misrepresentations can create a gulf between public and scientific understanding of the capabilities of neuroimaging and raise false expectations. To determine the extent of this effect and determine public opinions on acceptable uses and the need for regulation, we designed an electronic survey to obtain anonymous opinions from as wide a range of members of the public and neuroimaging experts as possible. The surveys ran from 1 Am I politically right or left wing? Which of sex or money interests me most? Should I take an fMRI lie detector test? Can other people see my dreams? Can neuroimaging help me chose the right career? Can imaging identify future criminals amongst young children? The potential for new technologies to improve the health, living and economic prospects of society quite rightly attract public curiosity We are exposed, almost weekly, to reports of new, thrilling and increasingly fantastical applications of neuroimaging to unravel the complexities of our minds \u2013 Misinterpretations of neuroimaging research by the public may arise in several ways: the distortion of findings by scientists or the media to enflame interest, through commercial interests, or poor engagement of the public by researchers. Promotion of the level of public understanding of neuroscience concepts Motivated by the need for evidence-based solutions to these challenges, we surveyed the public for their thoughts on the current uses, communication of, and need for regulation of, neuroimaging research. In parallel, we also surveyed experts in neuroimaging to provide a benchmark of the scientifically accepted uses and identify where public and professional opinions might differ.We designed two short questionnaires, one for the public and one for neuroimaging experts, suitable for delivery online or on paper. The public and expert surveys were modified to reflect the respondents' likely knowledge of and degree of personal relevance in determining their opinion on each issue. There were 10 questions in the public survey and 21 questions in the expert survey , websites , tweets , and science blogs as well as to attendees at meetings (e.g. Scottish Parliament Futures Forum) and societies for public engagement (Beltane http://www.publicengagement.ac.uk/about/beacons/edinburgh-beltane). The Expert Survey was distributed via university mailing lists , professional interest websites and individual imaging research centre websites) to target individuals who routinely used neuroimaging methods . Ethics approval was not sought. A level one self-assessment indicated that there was no risk to the respondent or the researcher.The survey was posted online, using the Survey Monkey Pro web survey template, between 31p<0.05). All available data were included. Percentages are based on samples of completed response, as opposed to the entire potential sample. After main effects were examined, we examined for trends within demographic profiles. The public sample was divided into groups based on scientific interest. The expert sample was divided based on the capacity in which they used neuroimaging technology .We used descriptive statistics to characterize the composition of the sample, t-tests to examine differences between the samples and chi-squared tests to analyse main effects and the majority described themselves as professionals (60%), students (16.5%), administrator (9.8%), not working (9.8%), skilled manual (2.7%) or manual workers (1.1%). The highest educational attainment was university undergraduate degree (30%), a Masters degree (21.3%), a PhD (15.9%), a professional qualification (15.5%), minimum school leaver's exam (8.9%) or final school leaver's exam (8.1%). Most respondents to the Expert Survey were neuroscientists (27%), followed by psychologists (17%), neuroradiologists (12.5%), psychiatrists (12.5%) or medical physicists (10.5%); had been using neuroimaging for 5\u201310 years (31%), <5 years (28%) or 10\u201320 years (26%); and were based in Scotland (34%), elsewhere in the United Kingdom (32%), Europe (16%) or the United States (15%).n\u200a=\u200a39, 5%) who said that their professions involve neuroimaging and may therefore not be representative of the public profile was identified, but no differences were found between the groups (p>0.05).Almost half the sample reported themselves as at least \u2018a little\u2019 aware of neuroimaging uses (47%), followed by \u2018quite aware\u2019 (26%), \u2018no awareness\u2019 (17%) and \u2018very aware\u2019 (10%). A subgroup , but few had the same confidence in use of neuroimaging to diagnose mental illness , some thought that neuroimaging could detect lies or consumer preferences , but had less confidence in detecting racial attitudes , political views or reading minds , Most respondents reported that they would be comfortable having their brain scanned for medical purposes (96%), for scientific research (90%), but were less inclined as part of a criminal investigation (36%), for insurance purposes (9%), for marketing research (16%) or as part of a job interview (11%) Most respondents were \u2018very\u2019 or \u2018quite\u2019 concerned about the confidentiality and storage of scans (82%) and that \u2018people would know what they were thinking\u2019 (55%), being forced to have a scan (70%) or that there would be \u2018something wrong with their brain\u2019 (57%). Most were \u2018not at all \u2018or\u2019 only a little \u2018worried that having a scan would make them vulnerable to thought control (61%), Most respondents reported that newspapers (65%) and popular science publications (64%) were the most common sources for information about neuroimaging, followed by television documentary (62%), television or film fiction (59%) and online sources (46%). Of those who reported using online sources, twitter and blogs were the most popular. When asked how often they encountered information on brain imaging, responses were highly varied with about a third reporting a little , often and very often .When asked about the regulation of brain imaging, most public respondents chose legislation (85%) and professional regulatory bodies (86%), followed by increased public awareness (84%). The least favoured response was the self-regulation of brain imaging research by the scientists themselves (53%), followed by the licensing of the scientists to conduct neuroimaging research (66%).Most expert survey respondents reported using neuroimaging for neuroscience research (66%), followed by clinical research (47%), medical diagnosis (35%), neuromarketing (4%), forensic purposes (3%) and security purposes (1%). The majority of respondents were aware of the use of neuroimaging outside traditional research (86%), particularly for neuromarketing (67%) and lie-detection (68%). Moderate awareness was reported for legal uses (48%), neuroaesthetics (56%), cognitive enhancement (55%) and mind reading (45%). Few were aware that neuroimaging was being used for security purposes (11%).Most respondents report specialist peer-reviewed literature as their main source of information on neuroimaging (84%), followed by general literature (65%), popular science media (50%), research conferences (54%), science blogs (25%), newspapers (25%) and popular science websites (23%).Most respondents thought that neuroimaging could improve the understanding of cognition , or improve treatment of psychiatric illness . However, most experts thought that the ability of neuroimaging to detect lies, read minds, understand consumer or criminal behaviour was largely a thing of the future or unlikely ever to occur : 29% of When asked how often neuroimaging evidence has been presented in U.S. courts in the last 5 years, most believed it was between 10 and 30 times (24%), followed closely by 6\u201310 times (22%) and between 1 and 5 times (23%). The lowest rates were reported for greater than 100 times (15%), between 30\u201360 times (8%) and between 60 and 100 times (8%).development of new applications, changing the legal system, changing views on responsibility for criminal behavior and enhancement of mental abilities, although changing the legal system and enhancing mental abilities were considered the least likely amongst these options (innovative applications (45%), cognitive enhancement (46%), change views of criminal responsibility (34%) and change the legal system (47%).Most respondents thought that wider uses of neuroimaging would, to some extent, lead to options . These vIn terms of strategies for regulating use of neuroimaging, respondents ranked professional guidelines first (66% ranked first or second choice), followed by more funding for interdisciplinary projects integrating neuroscience and law (50%) and improved public awareness (51%), with legal regulation (16%) and self regulation (15%) being placed last.A substantial majority (87%) felt that neuroimaging was not accurately portrayed in the media. When asked why, most cited poor journalism (54%) as either a quite or very important factor, followed by exaggerated results by researchers (51%), a lack of effective scientific communication (38%) and poorly conducted research (44%). Most respondents believe that increased exposure to neuroimaging research would raise its public profile as a beneficial technology (96%), whereas 80% foresaw a public backlash on the widespread use of the technology. 92% predicted an increase in funding opportunities, but 44% anticipated the opposite trend. 69% feared the over regulation of neuroimaging in research.Having said that, although most respondents thought it was important to communicate with the public (69%), most do not regularly engage with the media (52%). Of those that do communicate their results to the public, most used media and peer-reviewed publication to do this (78%), followed by public seminars (49%), the internet (39%) and television (28%). Among those that did not engage with the public, the majority gave little opportunity (58%), little incentive (38%) and distrust of media (27%) as their main reasons, followed by a lack of public speaking training (15%) and a fear of criticism (5%). When asked how this situation might be improved, most rated as \u2018quite\u2019 or \u2018very effective\u2019: professional credit for public engagement (75%), making public communication a funding requirement (72%), increased public exposure of research (76%), and outlets for a career in the media (25%).This survey of members of the public and neuroimaging experts revealed a range of similarities and differences of opinions. About a third of the public saw articles on neuroimaging in the media once or twice a month indicating, in line with previous research Although the public and experts were generally in agreement about some points, e.g. both had little faith in uses of neuroimaging in non-medical applications and both agreed on some methods to use for regulation, the results also suggest that extensive media coverage has moderated viewpoints and awareness differentially among the public and experts. The public were concerned about data protection issues. The experts had little awareness of how often neuroimaging had been used in court in the USA and one in three experts reporting no familiarity with neuromarketing or commercial lie-detection, although the public were aware of these uses. Although the experts thought that neuroimaging results were not well communicated in the media, and recognised the dangers of public loss of trust, few experts seemed motivated to improve the situation.Who can say which, if any, of the current legal, commercial or governmental uses of neuroimaging may become in future years routine, reliable tools? Neuroimaging is a rapidly evolving discipline; insights gained from well-conducted neuropsychological imaging research are in turn influencing knowledge of human behavioural traits on which many of society's attitudes are based. Consequently, it is entirely possible that society will need to adjust its views on behaviour, culpability, consciousness, etc. in future. However, a major focus of the present study was to determine how the public perceived the current capability of neuroimaging. Limited confidence in diagnosing psychiatric illness, lie-detection and neuromarketing was found, and to a far lesser degree in revealing racial and political attitudes and inner thoughts. Interestingly, the evidence base that complex social behaviours, such as racial attitudes and basic forms of mental representation, can be inferred using neuroimaging especially with regards privacy and human rights (e.g. \u201cAnything that is voluntary is acceptable. Mandatory brain scans are not\u2026\u201d). The public distrust of other technologies used to extract sensitive information for non-health related uses has been echoed in a public survey on the acceptability of genetic testing in insurance and employment settings One of the clearest trends identified in the survey is the public disapproval of the use of neuroimaging in non-medical or scientific settings, such as in marketing research, and in employment screening. Indeed, respondents who made specific comments cited moral and ethical grounds as explanations for this standpoint Click here for additional data file."} +{"text": "The recommendations are presented with supporting level of evidence.In this report, guidelines for the evaluation, medical and surgical management of transitional cell carcinoma of testicular germ cell tumors is presented. It is categorized according to the stage of the disease using the tumor node metastasis staging system, 7 A total of 38 cases have been diagnosed in 2006, with an age standardized rate (ASR) of 0.5 cases per 100,000 representing 1% of all diagnosed cancer in Saudi Arabia High level: well-conducted phase III randomized trials or meta-analysis.(EL2) intermediate level: good phase II trials or phase III with limitations.(EL3) low level: Observational/retrospective studies or expert opinion.thedition 2010) was used.The American Joint Committee on Cancer (AJCC) TNM staging for testis cancer (7 The international Germ Cell Cancer Collaborative Group Risk Classification should bWill depend on the histological subtype as follows:"} +{"text": "Most patients undergoing cardiac surgeries are exposed to red blood cell (RBC) transfusions, in the operating room or in the postoperative period. One of the main beliefs of this therapy is the ability of the RBCs to improve tissue perfusion through oxygen supply. However, recently, this concept is being questioned by some evidence as RBC storage lesion and adverse outcomes in transfused patients. The aim of this study was to determine if RBC transfusion after cardiac surgery results in improvement of tissue perfusion.2) were collected immediately at the beginning and end of the procedure, immediately postoperative (POI), after 24 hours (1PO), 48 hours (2PO), 72 hours (3PO) and at ICU discharge. Mean values of these above-mentioned parameters were compared in patients exposed to RBC transfusions and patients not exposed through repeated-measures variance analysis.From February 2009 to February 2010, a total of 502 patients underwent cardiac surgery with cardiopulmonary bypass at InCor - University of S\u00e3o Paulo. Arterial lactate, standard base deficit (SBD), arterial bicarbonate and oxygen central venous saturation (ScVOHemoglobin values were different between groups since before surgery until just before ICU discharge and in all periods, the group not exposed to RBC transfusions presented higher values compared with the exposed group (see Figure In this prospective study, red blood transfusion did not result in improvement of tissue perfusion parameters. This finding brings to discussion the real role of blood transfusion in cardiac patients."} +{"text": "We sought to determine if a common polymorphism can influence vulnerability to LDL cholesterol, and thereby influence the clinical benefit derived from therapies that reduce LDL cholesterol.We conducted a meta-analysis of the association between a common Trp719Arg polymorphism in the kinesin-like protein 6 (KIF6) gene and the risk of cardiovascular disease (CVD), and a meta-regression analysis to measure the effect modification of this polymorphism on the association between LDL cholesterol and the risk of CVD. We used this measure of genetic effect modification to predict the expected difference in clinical benefit among KIF6 719Arg allele carriers and non-carriers in response to therapies that reduce LDL cholesterol. We then conducted a meta-analysis of statin trials to compare the expected difference in clinical benefit with the observed difference during treatment with a statin.In a meta-analysis involving 144,931 participants, the KIF6 719Arg allele was not associated with the relative risk (RR) of CVD . Meta-regression analysis involving 88,535 participants, however, showed that the 719Arg allele appears to influence the effect of LDL cholesterol on the risk of CVD. KIF6 carriers experienced a 13% greater reduction in the risk of CVD per mmol/L decrease in LDL cholesterol than non-carriers. We interpreted this difference as the expected difference in clinical benefit among KIF6 carriers and non-carriers in response to therapies that lower LDL cholesterol. The difference in clinical benefit predicted by the increased vulnerability to LDL cholesterol among KIF6 carriers agreed very closely with the observed difference among 50,060 KIF6 carriers and non-carriers enrolled in 8 randomized trials of statin therapy .The KIF6 719Arg allele increases vulnerability to LDL cholesterol and thereby influences the expected clinical benefit of therapies that reduce LDL cholesterol. A common single nucleotide polymorphism (rs20455) results in an argine to tryptophan substitution at position 719 (Trp719Arg) in the gene encoding kinesin-like protein 6 (KIF6). Some One possible explanation is that the KIF6 719Arg allele may increase the risk of cardiovascular disease (CVD), and that treatment with a statin may ameliorate this increased risk through a pleiotropic effect A biologically plausible hypothesis that can potentially reconcile these apparently conflicting findings is that the KIF6 719Arg allele may increase vulnerability to LDL cholesterol. If carriers of the 719Arg allele are more vulnerable to the deleterious effects of LDL cholesterol, then they should experience a greater increase in the risk of CVD per unit increase in LDL, and a correspondingly greater reduction in the risk of CVD per unit decrease in LDL, as compared to non-carriers. Therefore, if KIF6 carriers are more biologically vulnerable to LDL cholesterol, they should derive a greater clinical benefit per unit reduction in LDL cholesterol than non-carriers in response to therapies that lower serum LDL cholesterol levels.The primary aim of our study was to test the hypothesis that a common polymorphism can influence biological vulnerability to LDL cholesterol, and thereby influence the expected clinical benefit of therapies that reduce serum LDL cholesterol levels. To test this hypothesis, we first conducted a systematic review and meta-analysis of the association between the KIF6 719Arg allele and the risk of CVD. We then conducted a meta-regression analysis to measure the effect of the KIF6 719Arg allele on the association between LDL cholesterol on the risk of CVD. We used this measure of effect modification to estimate the expected difference in clinical benefit among KIF6 carriers and non-carriers in response to therapies that lower serum LDL cholesterol level. We then conducted a systematic review and meta-analysis of the effect of the KIF6 719Arg allele on the clinical efficacy of statin therapy. Finally, we compared the expected difference in clinical benefit predicted by the meta-regression analysis with the observed difference in clinical benefit among KIF6 carriers and non-carriers in the meta-analysis of statin trials.We searched Pubmed, Embase, Index of Science, HUGEnet, and Google Scholar, using the search terms: KIF6, rs20455, 719Arg, and Trp719Arg without language restriction; we also checked the abstracts and presentations from major cardiovascular medicine meetings held from 2004 to present First, we conducted an updated systematic review and meta-analysis of the association between KIF6 719Arg carrier status and the risk of CVD. For this analysis, we included case-control studies, epidemiologic cohort studies, and the treatment allocation arms of randomized trials of statin therapy that have reported data separately among KIF6 719Arg allele carriers and non-carriers, but excluded family-based studies. We included both the placebo allocation and statin allocation arms of the placebo controlled trials, as well as both the less intensive and more intensive treatment allocation arms of the trials that compared different treatment intensities of statin therapy. Each treatment allocation arm was considered as a separate prospective cohort study for the purposes of this analysis. For study samples that were included in more than one report, we used data from only the most recent report. In each study, Hardy-Weinberg equilibrium was assessed, as appropriate, using a chi-square test. For each prospective cohort study , we extracted the total number of KIF6 719Arg allele carriers and non-carriers, as well as the number of KIF6 carriers and non-carriers who experienced an incident CVD event during study follow-up. From each case-control study, we extracted the total number of prevalent cases and controls for both KIF6 719Arg allele carriers and non-carriers. We used these data to create 2\u00d72 tables to calculate the unadjusted relative risk (RR), and 95% confidence interval (CI), for each prospective cohort study, and the unadjusted odds ratio (OR), and 95% CI, for each case-control study (as an approximation of the RR) 2) by the effect modification was calculated as the difference in tau2 between the regression model with and without a regression term, expressed as a percentage.Next, we performed a random effects meta-regression analysis to measure the effect modification of study baseline LDL cholesterol level on the association between KIF6 carrier status (and separately KIF6 genotype) and the risk of CVD Finally, we conducted an updated systematic review and meta-analysis of statin trials that have reported results stratified by KIF6 carrier status (or KIF6 genotype). From the report of each randomized trial, we extracted data on the number of persons assigned to either treatment allocation arm and the number of incident CVD events that occurred during study follow-up in each arm, stratified by KIF6 carrier status. We used these data to create 2\u00d72 tables to calculate an unadjusted RR (and 95% CI) for the effect of statin therapy as compared to placebo (or more intensive statin therapy as compared to less intensive statin therapy) on the risk of incident CVD events, separately among KIF6 carriers and non-carriers in each study. All analyses were by the intent-to-treat principle. We then standardized the estimate of the effect of statin therapy per mmol/L reduction in LDL cholesterol across trials by multiplying the natural logarithm of the RR for each trial (and its standard error) by 1\u00f7 Y, where Y is difference in average LDL cholesterol during follow-up between the two treatment allocation arms . We then combined the adjusted RR for each trial using an inverse variance weighted random effects model We standardized the effect of statin therapy per mmol/L reduction in LDL cholesterol in order to compare the observed difference in clinical benefit in the meta-analysis with the expected difference in clinical benefit estimated from the meta-regression analysis using the same scale. Standardizing the effect of statin therapy also allowed us to include both the trials that compared statin with placebo and the trials that compared more intensive and less intensive statin therapy. In the meta-analysis, therefore, the primary measure of effect is not the clinical benefit of statin therapy per se, but rather the clinical benefit per mmol/L reduction in LDL cholesterol during treatment with a statin.2 metric Heterogeneity was measured using Cochran's Q, and the IA total of 37 case-control studies, prospective cohort studies, or randomized trial treatment allocation arms (each considered as a separate cohort), including 144,931 participants and 27,465 CVD events, were included in our meta-analysis of the association between the KIF6 719Arg allele and the risk of CVD [1]\u2013[6],2\u200a=\u200a58.7%).Among the 37 study samples included in our meta-analysis, 19 prospective cohort studies involving a total of 88,535 participants and 9,692 incident CVD events, provided information on the average baseline LDL cholesterol level of the population under study and therefore were included in our meta-regression analysis Relying on the symmetrical nature of the effect modification between any two epidemiologic exposures A total of 8 randomized trials, involving 50,060 participants and 7,307 incident cardiovascular events, were included in our meta-analysis of the effect of statin therapy, stratified by KIF6 carrier status [1]\u2013[6],The magnitude of the difference in clinical benefit per mmol/L reduction in LDL cholesterol observed among KIF6 719Arg carriers and non-carriers in response to treatment with a statin was nearly identical with the expected difference in clinical benefit per mmol/L reduction in LDL cholesterol predicted by the increased vulnerability to LDL cholesterol among KIF6 719Arg carriers from the meta-regression analysis .Our study demonstrates that the common KIF6 719Arg allele appears to increase vulnerability to LDL cholesterol, and thereby influences the expected clinical benefit from therapies that lower serum LDL cholesterol levels. Persons who inherit one or more copies of the 719Arg allele appear to be more biologically vulnerable to the deleterious effects of LDL cholesterol than non-carriers. As a result, KIF6 719Arg carriers appear to derive a greater reduction in the risk of CVD per mmol/L reduction in LDL cholesterol than non-carriers. The results of our study resolve several apparently conflicting lines of evidence to provide a biologically plausible explanation for how KIF6 carriers can derive a greater clinical benefit from treatment with a statin than non-carriers, even though this polymorphism does not have any impact on the LDL cholesterol lowering effect of statins, and is not independently associated with the risk of CVD.More generally, our study demonstrates that a common polymorphism can influence vulnerability to LDL cholesterol, and thereby influence the expected clinical benefit from therapies designed to lower serum levels of LDL cholesterol. The concept of genetically-mediated differential vulnerability to LDL cholesterol is illustrated in Our study shows that, on average, KIF6 719Arg allele carrier status is not associated with the risk of CVD. Our study also shows, however, that this association varies significantly according to the average baseline LDL cholesterol level of the population under study . FurtherOur findings do not challenge the results of a large-scale meta-analysis of statin randomized trials that found that the clinical benefit of statin therapy is determined largely by the magnitude of LDL cholesterol reduction achieved during treatment Importantly, our study shows that the KIF6 719Arg allele increases vulnerability to LDL cholesterol even though it is not, on average, associated with an increased risk of CVD. This means that all 2.5 million directly genotyped and imputed polymorphism measured in previously conducted genome-wide association studies of CVD, very few of which have been shown to be reliably associated with the risk of CVD Our study has several limitations. Most importantly, we did not have any data on the association between LDL cholesterol and the risk of CVD, stratified by KIF6 carrier status. Therefore, we could not estimate the effect modification of KIF6 on the association between LDL cholesterol and the risk of CVD directly. Instead, we estimated this effect from the meta-regression estimate of the effect modification of LDL cholesterol on the association between the KIF6 719Arg allele and the risk of CVD. We believe this approach is valid because these two estimates of effect modification are equivalent as shown in In conclusion, we found that the common KIF6 719Arg allele appears to increase vulnerability to LDL cholesterol, and thereby influences the expected clinical benefit from therapies that lower serum LDL cholesterol levels. More generally, our study demonstrates that a common polymorphism can influence vulnerability to a common modifiable risk factor for CVD even if it is not independently associated with the risk of CVD. Our study provides a roadmap for further research that could potentially lead to the discovery of polymorphisms that cause large differences in vulnerability to common modifiable risk factors for CVD and thus lead to correspondingly large differences in the clinical benefit derived from therapies used to treat these risk factors. Incorporating such polymorphism into the care of individual patients may help to guide the selection of optimal medical therapies for each individual person based on their genetic background and therefore introduce a practical clinical strategy to personalize the prevention of CVD.Table S1A list of studies included in the meta-analysis of the KIF6 719Arg allele and the risk of cardiovascular disease. The included studies are Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology study (ADVANCE); Acute Myocardial Infarction Gene Study, Dortmund Health Study (AMI Gene Study); CATHGENE Research Project (CATHGENE); deCODE CAD Study (deCODE); National FINRISK studies (FINRISK); German Myocardial Infarction Family Study I (GerMIFS I); German Myocardial Infarction Family Study II (GerMIFS II); Heart Attack in Puget Sound study (HARPS); International Heart Study (INTERHEART); Malmo Diet and Cancer Study (MDS); Washington Hospital Center catheterization study (MEDSTAR); Massachusetts General Hospital study of premature CAD (MGH PCAD); Mid-America Heart Institute (MAHI); Penn-CATH study; Registre Gironi de Cor (REGIGOR); Verona Heart Study (VHS); Wellcome Trust Case Control Consortium CAD Study (WTCCC); Ottawa Heart Study; Cholesterol and Recurrent Events (CARE); West of Scotland Coronary Prevention Study (WOSCOPS); Pravastatin or Atorvastatin Evaluation and Infection Therapy: Thrombolysis in Myocardial Infarction 22 (PROVE-IT TIMI22); Prospective Study of Pravastatin in the Elderly at Risk (PROSPER); Heart Protection Study (HPS); Justification for the Use of Statins in Primary Prevention trial: An Intervention Trial Evaluating Rosuvastatin (JUPITER); Treat to New Targets (TNT); Incremental Decrease in Events through Aggressive Lipid Lowering (IDEAL); Atherosclerosis Risk in Communities study (ARIC); Cardiovascular Health Study (CHS); Women's Health Study (WHS).(PDF)Click here for additional data file.Table S2A description of the baseline characteristics of the randomized trials included in the meta-analysis of the clinical benefit of statin therapy stratified by KIF6 carrier status. The Difference in average LDL (mmol/L) is the difference between either treatment allocation arm. Study acronyms are defined in (PDF)Click here for additional data file.Text S1Equivalent measures of effect modification.(PDF)Click here for additional data file."} +{"text": "Despite the use of hepatitis B virus (HBV) vaccines and preventive mDespite the use of hepatitis B virus (HBV) vaccines and preventive measures, infection with HBV remains a major global health problem. Patients with chronic kidney disease (CKD) are at an increased risk of acquiring HBV infections from shared dialysis equipment, increased exposure to blood products, and immunodeficiency associated with CKD 2]. In a. In a2]."} +{"text": "Differentiation of acute heart failure from infection in patients with respiratory symptoms and a history of congestive heart failure (CHF) is challenging due to overlap of clinical symptoms and X-ray findings. The BACH study found higher mortality rates if patients presenting with dyspnea were treated with antibiotics and their procalcitonin (PCT) levels were low indicating absence of bacterial infection. Yet the BACH study was observational and causal inference cannot be drawn. Herein, we analyzed the effects of PCT-guided antibiotic stewardship in CHF patients from a previous trial (ProHOSP).This is a secondary analysis of a previous randomized trial of adult ED patients with respiratory symptoms and a history of CHF. Patients were randomized to administration of antibiotics based on a PCT algorithm (PCT group) or standard guidelines without knowledge of PCT levels (control group). The primary endpoint of this analysis is the risk of adverse outcome defined as death or ICU admission within 30 days after ED admission.n = 110), PCT-guided patients had a significant reduction in antibiotic exposure , P <0.001). Furthermore, PCT-guided patients had a significant lower risk for death and ICU admission , P = 0.02). See Figure A total of 233 patients met the inclusion criteria, with 116 in the PCT-guided group and 117 in the control group. In the subgroup of patients with low initial PCT levels <0.25 ng/l (In CHF patients with suspicion of respiratory infection, use of a PCT protocol resulted in a significant decrease of antibiotic exposure and significantly improved outcomes in patients with low PCT levels indicating absence of bacterial infection. Whether inadequate antibiotic therapy in these CHF patients requiring diuretic treatment explains this difference in clinical outcomes needs verification."} +{"text": "Anser albifrons) in South Korea. Phylogenetic analyses of the complete genome sequence showed that polymerase acidic (PA) and neuraminidase (NA) genes belonged to the Eurasian lineage AIV, but polymerase basic 2 (PB2), PB1, hemagglutinin (HA), nucleoprotein (NP), matrix (M), and nonstructural (NS) genes belonged to the North-American lineage AIV. These data are beneficial for understanding the ecology and epidemiology of AIVs.In 2007, we isolated a natural recombinant H9N2 avian influenza virus (AIV) from the fecal droppings of a white-fronted goose ( Influenzavirus A genus of the Orthomyxoviridae family (Avian influenza virus (AIV) belongs to the e family . The AIVe family .Anser albifrons) in South Korea in 2007. Species identification of the fecal droppings was done by DNA barcoding using the cytochrome oxidase I gene, as described previously was isolated from the fecal droppings of a white-fronted goose virus were derived from North American lineages but that PA and NA genes were derived from Eurasian lineages. It seems that continuous reshuffling of AIV genes between North American and Eurasian lineages has been occurring in wild bird populations, producing the reassortant North American-Eurasian lineage AIV.In the present study, our results provide crucial information on the epidemiology of AIV in wild birds by increasing understanding of the role of migratory birds in exchanging AIV genes between the Eurasian and North American continents. Enhanced surveillance of the wild bird population is required to improve our understanding of the natural history of AIV in wild birds.KC693639 to KC693646.The genome sequences of A/white-fronted goose/Korea/20-36/2007 (H9N2) have been deposited in GenBank under accession no."} +{"text": "Geologic process, including tectonics and global climate change, profoundly impact the evolution of life because they have the propensity to facilitate episodes of biogeographic differentiation and influence patterns of speciation. We investigate causal links between a dramatic faunal turnover and two dominant geologic processes operating within Laurentia during the Late Ordovician: the Taconian Orogeny and GICE related global cooling. We utilize a novel approach for elucidating the relationship between biotic and geologic changes using a time-stratigraphic, species-level evolutionary framework for articulated brachiopods from North America. Phylogenetic biogeographic analyses indicate a fundamental shift in speciation mode\u2014from a vicariance to dispersal dominated macroevolutionary regime\u2014across the boundary between the Sandbian to Katian Stages. This boundary also corresponds to the onset of renewed intensification of tectonic activity and mountain building, the development of an upwelling zone that introduced cool, nutrient-rich waters into the epieric seas of eastern Laurentia, and the GICE isotopic excursion. The synchronicity of these dramatic geologic, oceanographic, and macroevolutionary changes supports the influence of geologic events on biological evolution. Together, the renewed tectonic activity and oceanographic changes facilitated fundamental changes in habitat structure in eastern North America that reduced opportunities for isolation and vicariance. They also facilitated regional biotic dispersal of taxa that led to the subsequent establishment of extrabasinal (=invasive) species and may have led to a suppression of speciation within Laurentian faunas. Phylogenetic biogeographic analysis further indicates that the Richmondian Invasion was a multidirectional regional invasion event that involved taxa immigrating into the Cincinnati region from basins located near the continental margins and within the continental interior. Late Ordovician (~450 Ma) shallow marine deposits of Laurentia record a series of dramatic faunal and biogeographic shifts including a rapid change from predominantly warm to cool water adapted taxa during the middle Mohawkian (late Sandbian) and a major regional biotic immigration event into the Cincinnati Basin during the early Richmondian (Katian) ,2. TheseDuring the Late Ordovician, the Taconian orogeny developed along the eastern margin of Laurentia as a result of diachronous collisions with an island arc and/or microplates \u20135 , carbonate deposits of eastern Laurentia reflect a heterozoan assemblage typified by cool water and/or non-photosynthetic organisms, whereas tropical-style carbonates became restricted to the continental interior and marginal basins ,7. This sequenceAlso during the M5 sequence, faunas of the Appalachian Basin transitioned from predominantly warm to cool water adapted. The biotic overturn was accomplished primarily through immigration of extra-basinal taxa into a region following regional generic extinction . For exaThe Richmondian Stage was employed as described in Wiley & Lieberman . SpeciesBecause different geologic processes operated before and after the M4/M5 sequence boundary, LBPA was employed in a time-stratigraphic framework to more accurately discern patterns of biogeographic differentiation. Stratigraphic dimension was incorporated based on equal phylogenetic split using first and last appearances of species at the level of depositional sequence. Cladogenetic events were separated into Time Slice 1 (T1), approximately corresponding to the Blountian tectophase (W-b through M4 sequences), and Time Slice 2 (T2), approximately corresponding to the Taconic tectophase (M5 though C6 sequences) . AdditioGlyptorthis indicates that the genus originated in the Southern Midcontinent region and subsequently underwent a major dispersal event into the Appalachian and Central Basins with frequent episodes of speciation via dispersal into neighboring tectonic basins during T2 , whereas the other tree is consistent with a more recent exchange of taxa between Anticosti Island and the Midcontinent region (supported by biogeographic affinities of Psubquadratus. ). These data indicate that both dispersal pathways were operational during the Richmondian Invasion.The diametrically opposed patterns of speciation and biogeographic differentiation between T1 and T2 reflect different biogeographic controls operating before and after the M4/M5 sequence boundary. This discrepancy is clearly illustrated by the divergent topology of vicariance trees between times slices and the dissimilarity of the geodispersal and vicariance trees within each time slice , 3. The The level of congruence between vicariance and geodispersal trees is indicative of the style of geologic processes impacting macroevolutionary patterns . CongrueDuring T1, the Blountian tectophase introduced siliciclastics into eastern Laurentia yet did not inhibit the production of tropical carbonates ,6. The hDispersal became the dominant mode of speciation during the Taconic tectophase of the Taconian Orogeny T2). The combination of flexural downwarping of the craton and GICE related oceanographic changes facilitated the upwelling of cool, nutrient rich water into the shallow epieric seas of eastern Laurentia ,5,9. Thi. The comThe shift in speciation regime across the M4/M5 boundary is significant because high rates of vicariance are typically associated with high rates of speciation, whereas high rates of dispersal are associated with reduced speciation . The negThe main pulse of the Richmondian Invasion into the Cincinnati Basin occurred during the C5 sequence . The retPhylogenetic biogeographic analysis of species-level patterns in Middle to Late Ordovician brachiopods indicates a shift in biogeographic patterns and macroevolutionary dynamics between the Blountian and Taconic tectophases of the Taconian orogeny . These patterns were driven largely by geologic processes related to the Taconian Orogeny and global cooling at the boundary between the Sandbian and Katian stage boundary (M4/M5 sequence boundary). Prior to the M5 sequence, tectonic activity associated with the Blountian tectophase produced increased habitat fragmentation in tropical carbonate environments, thereby facilitating high levels of vicariant speciation. In contrast, the post-M5 sequence interval corresponds to a shift in paleoceanographic conditions related to the combined effect of structural deformation from the Taconic tectophase and GICE related global cooling, whereby cool, nutrient rich water from the Sebree Trough was introduced into shallow intracratonic seas. Dispersal became the dominant form of speciation and the increased number of invasive species may have led to increased faunal homogenization between basins. High rates of dispersal in the T2 interval and a return to tropical conditions within the Cincinnati Basin facilitated the Richmondian Invasion into the Cincinnati Basin. Species-level phylogenetic biogeographic patterns suggest both intracratonic seas and marginal basins supplied invasive species into the Cincinnati Basin.Figure S1The division between TS1 and TS2 is indicated by the horizontal line.(TIF)Click here for additional data file.Table S1Numbered columns refer to nodes and tips on the stratocladograms . Coding as in Wiley & Lieberman [31].(PDF)Click here for additional data file."} +{"text": "Dear Editor,We read with great interest the report of Alcelik et al.This 64-year old woman with chronic kidney disease due to nephrosclerosis, commencing on hemodialysis before 3 years, desired to candidate for kidney transplantation. Her medical history limited to hypertension of 10 years duration and end stage renal disease with well controlled secondary hyperparathyroidism [intact parathyroid hormone (iPTH): 17O pg/ml], but increased calcium phosphorus product (about 62 over the last 6 months) due to non compliance with absorption of phosphorus binders. No signs of osteoporosis have been identified on Dexa scan. Pretransplantation evaluation of the hands (plain radiograph) identified subperiostal bone resorption at the inner part of the terminal thumb phalanges symmetrically at both hands, with preservation of peripheral cortex . MoreovePublished data point out that the earliest subperiostal bone resorption due to secondary hyperparathyroidism is demonstrated at the phalangeal tufts and the radial aspects of the middle phalanges of the second and the third hand fingers. Whereas previously, radiologic findings were more intense, improvements in therapeutic management of secondary hyperparathyroidism in hemodialysis result in significant decrease of radiologic evidence."} +{"text": "The current methods utilized to track stem cells by cardiac MR are affected by important limitations, and new solutions are needed.In vivo cine and in vivo and ex vivo multiecho T2 weighted images were obtained by 9.4T cardiac MR.We tested human ferritin heavy chain (hFTH) tagged with both myc and green fluorescence protein (GFP) as a reporter gene for in vivo tracking of stem cells by cardiac MR. Rat mesenchymal stem cells (rMSCs) were transduced with lentiviurs to overexpress hFTH. Myocardia infarction was induced by cryoinjury in rats, and the animals were immediately subjected to intramyocardial injection of 100 \u00b5l of 106 rMSCs (experiment group) or buffer solution (control group) in the border zone. ex vivo images was significantly decreased in the infarct area compared to remote normal myocardium in the experiment group, but not in the control group. GFP and myc immune-staining confirmed the presence of differentiated rMSCs around infarct area in the experiment group.Four-week follow-up cine MR showed that marked left ventricular remodeling developed in the control group. T2 relaxation time of in vivo and hFTH can be used as a MR reporter gene to track dividing and differentiating stem cells in the beating heart while simultaneously monitoring cardiac morpho-functional changes.This study was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (No.A100131) and partly by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MEST) ."} +{"text": "Chronic progressive external ophthalmoplegia (CPEO) is a classical mitochondrial ocular disorder characterised by bilateral progressive ptosis and ophthalmoplegia. These ocular features can develop either in isolation or in association with other prominent neurological deficits (CPEO+). Molecularly, CPEO can be classified into two distinct genetic subgroups depending on whether patients harbour single, large-scale mitochondrial DNA (mtDNA) deletions or multiple mtDNA deletions secondary to a nuclear mutation disrupting mtDNA replication or repair. The aim of this magnetic resonance imaging (MRI) study was to investigate whether the ophthalmoplegia in CPEO is primarily myopathic in origin or whether there is evidence of contributory supranuclear pathway dysfunction.POLG, PEO1, OPA1, and RRM2B. All subjects underwent a standardised brain and orbital MRI protocol, together with proton magnetic resonance spectroscopy in two voxels located within the parietal white matter and the brainstem.Ten age-matched normal controls and twenty patients with CPEO were recruited nine patients with single, large-scale mtDNA deletions and eleven patients with multiple mtDNA deletions secondary to mutations in There was evidence of significant extraocular muscle atrophy in patients with single or multiple mtDNA deletions compared with controls. There was no significant difference in metabolite concentrations between the patient and control groups in both the parietal white matter and brainstem voxels. Volumetric brain measurements revealed marked cortical and cerebellar atrophy among patients with CPEO+ phenotypes.The results of this study support a primary myopathic aetiology for the progressive limitation of eye movements that develops in CPEO. Chronic progressive external ophthalmoplegia (CPEO) is a slowly progressive extraocular muscle disorder characterised by bilateral, usually symmetrical, limitation of eye movements and ptosis The aim of this magnetic resonance imaging (MRI) study was to investigate whether the limitation of eye movements in CPEO is myopathic in origin or whether there is evidence of contributory brainstem dysfunction with magnetic resonance spectroscopy (MRS). Brain volumetric measurements were also performed to assess the extent of central nervous system involvement and whether this correlated with the development of extraocular neurological features in patients with CPEO+ phenotypes.The study cohort included: (i) nine patients with single, large-scale mtDNA deletions \u200a=\u200a3.0 years), (ii) eleven patients with multiple mtDNA deletions , and (iii) ten age-matched normal controls Table 1.POLG mutations (n\u200a=\u200a4) PEO1 mutations (n\u200a=\u200a3) OPA1 mutations (n\u200a=\u200a1) RRM2B mutations (n\u200a=\u200a1) c oxidase-deficient fibres in addition to prominent ragged red fibres.All patients were assessed by an experienced multi-disciplinary team of neurologists and ophthalmologists to define the clinical phenotype and disease severity Table 1.Text S1), with a high degree of intra- and inter-observer reliability (Table S1).MRI and MRS data were acquired on a 3-Tesla Philips Achieva clinical MR system using an 8-channel head coil. Proton MRS analysis was performed by an experienced research physicist (FES) to derive brain metabolite concentrations in the parietal white matter and brainstem regions: (i) choline; (ii) creatine; (iii) total glutamate and glutamine (Glx); (iv) myo-inositol; and (v) N-acetyl-aspartate (NAA). Extraocular and brain compartment volumes were measured using standardised semi-automated segmentation protocols . Group comparisons were made using the unpaired t-test. Intra-observer and inter-observer variability for the measurement of extraocular muscle and brain volumes was assessed with Pearson correlation coefficient (r). and and There was a significant reduction in extraocular muscle volumes in the CPEO group compared with normal controls for all four recti muscles Figure 1There was no significant difference in metabolite concentrations between the patient and control groups in both the parietal white matter and brainstem voxels Table 4.Carlow and colleagues observed a significant reduction in extraocular muscle volumes for the inferior rectus, medial rectus and lateral rectus Ortube and colleagues measured extraocular muscle volumes in five patients with a clinical diagnosis of CPEO Ortube and colleagues, including the relatively small number of patients that were recruited and the lack of a confirmatory molecular diagnosis. Furthermore, only a relatively small portion of the extraocular muscle belly was sampled, which could have underestimated the degree of atrophy in the recti muscles.This study has shown clear evidence of significant extraocular muscle atrophy involving all four recti muscles in CPEO. This striking observation was noted for both patients with single, large-scale mtDNA deletions and for those harbouring multiple mtDNA deletions secondary to an underlying nuclear genetic defect. In a previous report of nine patients with CPEO, Our study is the first to demonstrate objectively that the extent of extraocular muscle atrophy in CPEO is highly symmetrical between the two eyes of the same patient, reflecting the ophthalmoplegia pattern observed clinically A variable decrease in N-acetyl-aspartate (NAA) has previously been reported in the brain of patients with the Kearns-Sayre syndrome \u2013 a particularly severe clinical phenotype characterised by the development of CPEO and pigmentary retinopathy before the age of twenty years, often in association with progressive cardiac conduction block Patients with CPEO+ features had significantly reduced total grey matter and cerebellar volumes compared with controls, in keeping with the higher burden of neurological disease in this specific patient population. The prominent degree of atrophy seen in the cerebellum further highlights the particular vulnerability of this specific brain region to the deleterious consequences of mtDNA defects This comprehensive magnetic resonance study of patients with molecularly confirmed CPEO has revealed a number of important findings that are directly relevant to our understanding of the underlying pathophysiology in this mitochondrial ocular disorder. In addition to marked generalised extraocular muscle atrophy, there was clear evidence of significant CNS involvement in this disorder, which becomes clinically manifest in a subgroup of patients.Figure S1Voxel placements and proton magnetic resonance spectra.(PDF)Click here for additional data file.Figure S2Boundary delineation of extraocular muscle cross-sections.(PDF)Click here for additional data file.Figure S3Measurement protocol for brainstem and cerebellar volumes.(PDF)Click here for additional data file.Table S1Validation of extraocular muscle and brain volume measurements.(DOC)Click here for additional data file.Text S1Supplementary methods.(DOC)Click here for additional data file."} +{"text": "Malaria prevalence has recently declined markedly in many parts of Tanzania and other sub-Saharan African countries due to scaling-up of control interventions including more efficient treatment regimens (e.g. artemisinin-based combination therapy) and insecticide-treated bed nets. Although continued molecular surveillance of malaria parasites is important to early identify emerging anti-malarial drug resistance, it is becoming increasingly difficult to obtain parasite samples from ongoing studies, such as routine drug efficacy trials. To explore other sources of parasite DNA, this study was conducted to examine if sufficient DNA could be successfully extracted from malaria rapid diagnostic tests (RDTs), used and collected as part of routine case management services in health facilities, and thus forming the basis for molecular analyses, surveillance and quality control (QC) testing of RDTs.Plasmodium species detection. Additionally, 165 archived RDTs obtained from ongoing malaria studies were analysed to determine the amplification success and test applicability of RDT for QC testing.One hyper-parasitaemic blood sample was serially diluted in triplicates with whole blood and blotted on RDTs. DNA was extracted from the RDT dilution series, either immediately or after storage for one month at room temperature. The extracted DNA was amplified using a nested PCR method for DNA was successfully extracted and amplified from the three sets of RDT dilution series and the minimum detection limit of PCR was <1 asexual parasite/\u03bcl. DNA was also successfully amplified from (1) 70/71 (98.6%) archived positive RDTs (RDTs and microscopy positive) (2) 52/63 (82.5%) false negative RDTs (negative by RDTs but positive by microscopy) and (3) 4/24 (16.7%) false positive RDTs (positive by RDTs but negative by microscopy). Finally, 7(100%) negative RDTs (negative by RDTs and microscopy) were also negative by PCR.This study showed that DNA extracted from archived RDTs can be successfully amplified by PCR and used for detection of malaria parasites. Since Tanzania is planning to introduce RDTs in all health facilities , availability of archived RDTs will provide an alternative source of DNA for genetic studies such as continued surveillance of parasite resistance to anti-malarial drugs. The DNA obtained from RDTs can also be used for QC testing by detecting malaria parasites using PCR in places without facilities for microscopy. Malaria has for a long time remained a major cause of morbidity and mortality in most endemic countries particularly in sub-Saharan Africa. However, recent reports have indicated that malaria prevalence has declined drastically in some endemic countries -4. The dFollowing changes of malaria treatment guidelines in Tanzania in 2006, by introducing an ACT containing artemether and lumefantrine (ALu) ,8. HowevPlasmodium falciparum specific histidine rich protein 2 (PfHRP-2), Plasmodium lactate dehydrogenase (pLDH) or aldolase districts of Tanga region, Tanzania.This study was conducted at Amani Biomedical Research Laboratory (AMBRELA) of the National Institute for Medical Research (NIMR) at Tanga Centre in Tanga region, northeastern Tanzania. Archived RDTs were obtained from ongoing studies in Muheza and Korogwe . Other 94 RDT samples (on ParaHIT\u00aef), included 24 RDT false positive (positive by RDT but negative by microscopy), 63 false negatives (negative by RDTs but positive by microscopy) and seven negative samples (negative by both RDTs and microcopy) obtained from a cross-sectional survey conducted in May 2010 in four villages in Muheza district where high level of false positive and negative RDT results were observed in previous surveys . All 165 RDT samples were stored at room temperature in the field or laboratory for a duration of 6 - 95 days (Table The archived RDT samples included 71 RDTs (positive for both RDT and microcopy) collected at health facilities in Muheza and Korogwe districts and stored without any preservatives at room temperature (temperature ranging from 25 - 34\u00b0C). Out of these, 26 RDTs were obtained from patients enrolled in InterACT project in Muheza were ParaHIT\u00aef (Table \u00aef), which failed to amplify by PCR, had a low parasitaemia detected by microscopy . Fifty-two (82.5%) of the 63 false negative RDTs were positive by PCR. Eleven (17.4%) of the 63 false negative RDT samples which failed to amplify by PCR had low parasite density detected by microscopy .Table \u00aef Table . One posPfdhfr gene as a marker of pyrimethamine resistance using DNA extracted from RDTs was also successful and the results were similar to those observed when DNA was obtained from other sources such as cultured parasites or filter papers.Detection of microscopically negative samples was equally successful whereby, 20 out of 24 (83.3%) RDT false positive samples (which were positive by RDTs but negative by microscopy) were confirmed to be negative by PCR. Fourteen out of the 20 RDT false positive samples with negative PCR results were obtained from individuals who had taken anti-malarials (within seven days) before the survey. All seven negative RDTs (negative by both RDTs and microscopy) were also negative by PCR Table . Detectiet al, personal communication) and most likely, the decline is apparent in other parts of Tanzania as well . However, because of this current positive trend, recruitment of malaria positive patients for various studies, such as malaria drug efficacy trials has proved to be difficult. Since the region has been known as a hotspot for the emergence of anti-malarial drug resistance in Eastern Africa [Previously, malaria has consecutively been shown to be the main cause of morbidity and mortality in Tanga region, as for the rest of Tanzania -31. Howen Africa -36, it iIn this context, the study presented here has shown that archived RDTs used for malaria diagnosis in routine practice can be used as an alternative source of DNA for detection of malaria parasites and other molecular analyses. The RDTs can also be used as source of DNA as part of QC testing of RDTs instead of microscopic examination of Giemsa-stained blood smears, by comparing RTD results produced by health workers with those obtained in the laboratory based on detection of malaria parasite by PCR. Thus, after deployment of RDTs in the field, archived RDTs can also be used for QC of RDTs in addition to using Giemsa-stained blood smears, particularly in health facilities without capacity for performing malaria diagnosis by microscopy or lacking the skills and experience to prepare good blood smears as recently shown in Eastern Tanzania by McMorrow and colleagues ,25.Storage of RDTs (that were prepared in the laboratory) for one month either with or without silica gel as preservatives did not affect the quality of extracted DNA as determined by the detection limit of PCR in the diluted samples and band intensity of amplified products in comparison to known standard DNA samples which were used as control. Similarly, field samples stored at room temperature without preservatives for over 3 months were equally amplified. However, the impact of long term storage of RDTs beyond this duration on the quantity and quality of DNA is not clearly known, particularly if they are stored at room temperature without preservatives and under high ambient temperature, and humidity (as in most parts of Tanzania) which support growth of moulds that can degrade the parasite DNA. The period of three months or more shown in this and a previous study should b\u00aef and Paracheck Pf\u00ae) examined provided DNA of sufficient quality with similar amplification success although the quantity of DNA was not assessed. This is in concordance to a previous study which showed that the type/brand of RDTs did not affect the quality of extracted DNA [Both types of PfHRP-2 based RDTs (ParaHITcted DNA . Furthercted DNA . Among tcted DNA .This study showed that DNA can be extracted from routinely used and archived RDTs, and successfully amplified by PCR; thus providing an alternative source of DNA for detection of malaria parasites and possibly other molecular analyses such as surveillance of parasite resistance to anti-malarial drugs and monitoring of insidious parasite reservoirs in different interventions, such as malaria elimination programmes. Furthermore, the RDTs can be used for QC testing of RDTs deployed in the field for malaria diagnosis based on comparing the results obtained by PCR genotyping of DNA extracted from archived RDTs with the test results produced by health workers, particularly from remotely located health facilities without the capacity of microscopic examination of blood smears. Thus, availability of archived RDTs after the tests are deployed in all health facilities in Tanzania as planned by the Ministry of Health and Social Welfare will provide a good source of parasite DNA for laboratory studies.Plasmodium falciparum; PfHRP-2: Plasmodium falciparum histidine rich protein 2; RDTs: Rapid diagnostic tests; WBCs: white blood cells; WHO: World Health Organisation; \u03bcl: microlitre.ACT: artemisinin combination therapy; DNA: deoxyribonucleic acid; pLDH: Plasmodium lactate dehydrogenase; NIMR: National Institute for Medical Research; NMCP: National Malaria Control Programme; PCR: polymerase chain reaction; Pf: The authors declare that they have no competing interests.DSI, MA conceived of the study, designed the experiments, supervised the laboratory analyses and wrote the manuscript. NN, OP and LV participated in study design and supplied archived RDTs while SL and RAM conducted the laboratory analyses. MML and ICB participated in study design and supervised the study. All authors read and approved the manuscript."} +{"text": "In contrast to the RNA viruses, the genome of large DNA viruses such as herpesviruses have been considered to be relatively stable. Intra-specific recombination has been proposed as an important, but underestimated, driving force in herpesvirus evolution. Recently, two distinct field strains of infectious laryngotracheitis virus (ILTV) have been shown to have arisen from independent recombination events between different commercial ILTV vaccines. In this study we sequenced the genomes of additional ILTV strains and also utilized other recently updated complete genome sequences of ILTV to confirm the existence of a number of ILTV recombinants in nature. Multiple recombination events were detected in the unique long and repeat regions of the genome, but not in the unique short region. Most recombinants contained a pair of crossover points between two distinct lineages of ILTV, corresponding to the European origin and the Australian origin vaccine strains of ILTV. These results suggest that there are two distinct genotypic lineages of ILTV and that these commonly recombine in the field. Herpesviridae have genomes ranging in size from 124 to 241 kbp Alpha-, Beta- and Gammaherpesvirinae. Classically, sequences obtained from a single gene or multiple concatenated genes have been used for phylogenetic analyses of herpesviruses. More recently developments in high-throughput sequencing techniques have resulted in the availability of complete genome sequences for comparative complete genomic analyses of herpesviruses Herpesviruses are highly host-specific double stranded DNA viruses that have been isolated from most animal species, including mammals, birds, reptiles and fish. The Alphaherpesvirinae (genus Iltovirus) and causes acute upper respiratory tract disease in chickens Iltovirus genus (including psittacid herpesvirus 1 (PsHV1) and ILTV) separated from the mammalian alphaherpesviruses around 200 million years (Mys) ago, in agreement with the theory that herpesviruses have co-evolved with their hosts AlphaherpesvirinaeInfectious laryngotracheitis virus belongs to the subfamily In Australia three commercial live ILTV vaccines are registered for use. The SA2 vaccine strain is an attenuated ILTV field strain isolated from South Australia in 1950 Australian ILTV field strains and vaccine strains have been classified into nine genotypes (classes 1 to 9) using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis th century) In a previous report we analysed and compared the complete genome sequences of two Australian origin ILTV vaccines and a European origin ILTV vaccine strain. The genome sequences of the two Australian origin vaccines differed by only 23 nucleotide substitutions, even though one of the strains was derived from the other after more than twenty-five serial passages in cell culture and embryonated eggs. Although similar to each other, these two Australian vaccine strains showed considerable divergence (0.8% nucleotide difference) from the genomic sequence of the European origin ILTV vaccine strain. This is higher than the 0.1\u20130.5% nucleotide difference reported between the most distantly related strains of varicella zoster viruses (VZV), which is a human alphaherpesvirus with the same genomic sequence arrangement as ILTV The aim of this study was to better understand the molecular epidemiology of ILTV by analysing a broader range of ILTV sequence data, including currently available complete or partial genomic sequences of ILTV. The complete genome sequences of two Australian ILTV field strains (V1-99 and CSW-1) were determined using high-throughput sequencing and included in these analyses. Additionally, we aimed to identify the origins of the parent strain of the Australian ILTV vaccines by searching for similar genotypes among publically available nucleotide sequences from ILTV strains isolated in other countries.de novo and mapped to the complete genome sequence of the Serva vaccine strain. Sequence gaps were filled and ambiguous sequences clarified using Sanger sequencing. The size of the ILTV genomes ranges from 150,335 to 153,952 bp . The size of the strain V1-99 genome was 153,631 bp, similar to that of the Serva strain . The V1-99 and Serva strains shared 99.6% nucleotide sequence identity. The CSW-1 strain genome was somewhat smaller due to three large deletions within the unique long region and both the internal and terminal repeat regions (463 bp) (Sequencing data from the V1-99 and CSW-1 strains of ILTV obtained by high-throughput sequencing were assembled (463 bp) . Excludi(463 bp) .In order to further understand the relationship between ILTV vaccine strains and Australian field strains of ILTV, complete genome sequence alignments were performed and phylogenetic trees were inferred using the six complete genomic sequences of ILTV currently available. This analysis included a European origin vaccine (Serva), an Australian origin vaccine (SA2), two Australian field strains (V1-99 and CSW-1) and two strains from the USA (63140 and USDAref). The sequences were examined in order to identify relevant genes that could be used to differentiate between all six strains .All predicted ORFs were extracted from the complete genome alignments and separate phylogenetic trees were inferred from the nucleotide sequences of each ORF. Similarly, alignments of amino acid sequences for all the predicted ORFs were performed separately and phylogenetic trees were inferred. The UL21, 32, 34 and 43 genes of all six ILTV strains were found to share 100% nucleotide and amino acid sequence identity. The UL3, 4, 13, 14, 18, 24, 31, 33, 40 and 49 genes of the six strains had differing nucleotide sequences, but were predicted to have 100% amino acid sequence identity. The ICP4, UL27, UL36, US5 and US8 genes showed the most variability within the six strains of ILTV and the six strains could be distinguished using the nucleotide and/or amino acid sequences of these genes . The UL2All available nucleotide sequences for the ICP4 and UL27 genes of ILTV from the NCBI database were aligned and phylogenetic analyses were performed . The EurTo confirm the close relationship between the Australian origin vaccine strain and strains isolated from backyard flocks in the USA, concatenated nucleotide and amino acid sequences were generated using all available sequences for each of these strains. This included the complete sequences of the UL27, UL32 and UL10 genes from the unique long region, the UL47 and US4 genes from the unique short region, and the complete sequence of the ICP4 gene from the repeat region. Surprisingly, one of the strains isolated from backyard flocks in the USA (25/H/88/BCK) shared 100% amino acid sequence identity with the concatenated sequence of the Australian origin vaccine. Another strain isolated from backyard flocks in the USA (12/D/02/BCK) differed in only two amino acid residues from the Australian origin vaccine strain . These rA possible mosaic pattern of relationship between the genome sequences of the Australian field strains of ILTV was detected in the phylogenetic analyses of the UL27 and ICP4 genes . In addiTo confirm the mosaic patterns of these relationships and detect the suspected recombination events responsible, we performed additional phylogenetic analyses on the nucleotide sequences of the UL47 and US4 genes . As expeIn order to define recombination crossover points, Bootscan analyses were performed using complete genome alignments of five ILTV strains . Bootscan analyses of the 1874C5 and CSW-1 strains revealed pairs of crossover points in the repeat region, while the 81658 strain had multiple tightly grouped pairs of crossover points in the unique long region . Most ofA history of recombination was not detected in the sequences located in the unique short region of the genome of the eight strains of ILTV for which complete genomic sequence was available, so the sequences of this region were used to investigate the evolutionary history of ILTV. In the resulting trees, all Australian strains of ILTV clustered together and separately from European and USA strains of ILTV . The timin vivo. In this study, we sought to perform broader phylogenetic analyses of ILTV in order to understand the evolution and molecular epidemiology of the virus. We found that the parent strains of Australian origin vaccine and Australian field strains may have been imported into Australia from the USA. Moreover, with the exception of field isolates derived from bird-to-bird passage of commercial vaccines, most field strains of ILTV isolated in Australia and in other geographic areas of the world show evidence of historical recombination events between two distinct viral lineages, represented by the Serva and SA2 strains.Genome wide comparative sequence analyses of closely related strains of ILTV, or of strains from specific geographical regions, have been reported previously The Australian origin SA2 vaccine was produced using an Australian field isolate that induced comparatively smaller pocks on the chorioallantoic membrane of embryonated hen eggs In order to search for an SA2-like strain of ILTV in other geographical areas, we compared the phylogenetic tree inferred from alignments of complete genome sequences with those inferred from alignments for all individual predicted ORFs. The ICP4, UL27, UL36, US5 and US8 genes were found to be sufficiently divergent to allow differentiation between distinct strains of ILTV . ComparaThe European origin Serva vaccine strain was recently registered in Australia and rapidly became widely used by the Australian poultry industry within a relatively short timeframe The Australian field strains V1-99 and CSW-1 and the USA field strain 874C5 shared a distinct sequence segment in the unique long region. This suggests that the Australian field strains and the 1874C5 strain may have shared the same (or very similar) parent strain(s) before recombination, or that these strains may have obtained this distinctive sequence segment from some other strain in independent recombination events.Evidence of historical intra-specific recombination in alphaherpesviruses has been described previously With the exception of the USDAref and 81658 ILTV strains, which each contained three recombination crossover points, all other ILTV recombinants contained a single pair of recombination crossover points between the Serva-like and the SA2-like parental strains, as detected by bootscan analyses. Recombination networks further supported these findings, confirming that recombination events occurred in the unique long and the repeat regions, but not in the unique short region and 7. TIn conclusion, the origins of Australian strains of ILTV have been determined using complete genomic sequence analyses of multiple strains of ILTV and wider phylogenetic analyses. Moreover, evidence for significant recombination events in most field strains of ILTV was identified by recombination network and bootscan analyses. We found that the Serva-like and SA2-like lineages of ILTV have recombined frequently over the history of ILTV evolution. This, taken together with data from our previous studies Pock purified V1-99 (six passages from isolation) and a laboratory stock of CSW-1 ILTV (approximately twenty passages from isolation) de novo assembled contigs and to produce a consensus sequence using the Serva ILTV genomic sequence (Genbank accession HQ_630064) as reference. Any sequence gaps or ambiguous regions of sequence were confirmed by Sanger sequencing using BDT version 3.1 (Applied Biosystems). The complete genome sequences of the V1-99 and CSW-1 strains of ILTV have been deposited in the NCBI GenBank database under the accession numbers JX646898 and JX646899.Total viral genomic DNA preparation, high-throughput sequencing and genome assembly were performed as previously described Complete genome sequences, nucleotide sequences and amino acid sequences used in this study are summarized in To detect evidence of historical recombination events between ILTV strains, recombination networks were generated using SplitsTree 4 To estimate the time points of divergence between ILTV strains, the Minimum Evolution Table S1ILTV genome and gene sequences used in this study.(DOC)Click here for additional data file."} +{"text": "A stationary association between El Ni\u00f1o Southern Oscillation (ENSO), the Indian Ocean Dipole (IOD) and epidemics of cholera in Bangladesh has been widely assumed. However, whether or not elements of the local climate that are relevant for cholera transmission have stationary signatures of the IOD on their dynamics over different time scales is still not clear. Here we report results on the time-varying relationships between the various remote and local environmental drivers and cholera incidence in Bangladesh.We performed a cross wavelet coherency analysis to examine patterns of association between monthly cholera cases in the hospitals in Dhaka and Matlab (1983\u20132008) and indices for both IOD and ENSO. Our results showed that the strength of both the IOD and ENSO associations with cholera hospitalizations changed across time scales during the study period. In Dhaka, 4-year long coherent cycles were observed between cholera and the index of IOD in 1988\u20131997. In Matlab, the effect of ENSO was more dominant while there was no evidence for an IOD effect on cholera hospitalizations.Our results call for the consideration of non-stationary, possibly non-linear, patterns of association between cholera hospitalizations and climatic factors in cholera epidemic early warning systems. Vibrio cholerae, the bacterium that causes the disease, is known to inhabit riverine, estuarine and coastal ecosystems with specific abiotic and biotic components V. cholerae has an increased growth rate in aquatic environments with warmer temperatures, particularly when combined with a high pH and blooms of phytoplankton, aquatic plants or algae Cholera remains a major public health problem in many places, including Bangladesh, India, and a number of countries in Africa and South America V. cholerae multiplication It has been reported that the El Ni\u00f1o-Southern Oscillation (ENSO) plays a role in the interannual variation of endemic cholera in Bangladesh The Indian Ocean Dipole (IOD) is another climate mode that arises from ocean-atmosphere interactions that cause interannual climate variability in the tropical Indian Ocean Wavelet analysis is useful for epidemiological time series analyses mainly because of the non-stationarity of associations between the disease dynamics and exposure covariates Dhaka: The ICDDR,B hospital serves a large urban population within the city of Dhaka and provides free treatment for more than 100,000 cases of diarrhea each year. A surveillance system was established at the ICDDR,B in 1979 to systematically sample children and adults with diarrheal illnesses th patient was enrolled in the surveillance system, and since 1996 every 50th patient has been enrolled. Matlab. Matlab is a rural and riverine delta area situated approximately 57 km southeast of Dhaka. Every hospital visit of patients residing within the area covered by the Health and Demographic Surveillance System (HDSS), which consists of 142 villages with populations over 220,000, was registered in the hospital surveillance system The primary outcome for this study was the monthly number of patients with cholera who attended the International Centre for Diarrhoeal Disease Research, Bangladesh hospitals in Dhaka and Matlab . Dhaka: V. cholerae. The details of the laboratory procedures were described in a previous study V. cholerae of the serogroups O1 or O139 was identified in the stool specimen, regardless of the presence of other pathogens. From the surveillance data that had been collected over a 26-year period (January 1983 to December 2008) for Dhaka and 28-year period (January 1981 to December 2008) for Matlab, we retrieved the date of the hospital visit and the pathogens identified in each stool specimen. From these data, the monthly cholera cases in Dhaka and Matlab were counted separately and used for analysis.For each diarrhea patient of the ICDDR,B hospitals in Dhaka and Matlab, the stool was microbiologically examined to identify common enteric pathogens including www.jamstec.go.jp/frcgc/research/d1/iod/). The DMI values were calculated using the SST data from the HadISST dataset (http://www.metoffice.gov.uk/hadobs/hadisst/). The base period for calculating anomalies was 1958\u20132008. These values were standardized to zero mean and unit standard deviation. The strength of the ENSO was measured by monthly average SSTs in the Ni\u00f1o 3 region (Nino3) in the Pacific Ocean that we derived from the National Oceanic and Atmospheric Administration (NOAA) Climate Prediction Center data (http://www.cpc.ncep.noaa.gov). We examined the association between DMI and monthly average SST in the northern Bay of Bengal to gain some insight into the causal pathways linking the IOD to the number of cholera cases. Mean monthly SSTs in the Bay of Bengal were derived from the NOAA Optimum Interpolation Sea Surface Temperature dataset The strength of the IOD was measured by the dipole mode index (DMI), defined as the difference in SST between the western and eastern tropical Indian Ocean The daily rainfall and maximum and minimum temperature data for Dhaka and Matlab were obtained from the Bangladesh Meteorological Department. The data for the daily river levels of the Brigonga (Millbarrak in Dhaka) and Danagoda (Matlab Bazaar) rivers were obtained from the records maintained by the Bangladesh Water Development Board. The monthly means for the maximum temperature (\u00b0C) and maximum river level (m), and the total monthly rainfall (mm) were calculated from the daily records. Missing values (17 [5.4%] in Dhaka and 6 [1.9%] in Matlab) for river levels were imputed using the average values of the same month in the other years over the whole time series.Temporal patterns of association in the time series were studied using the continuous wavelet transform 0\u200a=\u200a6 months , a total smoothing window of 31 and parameter W0\u200a=\u200a6 (dimensionless parameter of the Morlet Wavelet). Further details about cross wavelets and software are described in Maraun and Kurths V. cholerae El Tor O1 biotype strain and one for the O139 Bengal strain.We also estimated the cone of influence, where inferences from the wavelet analysis outside the cone of influence are not valid because of the manipulations that were performed to generate the wavelet spectrum in the absence of data for larger period frequencies We did not stratify the analysis by age, because the seasonal patterns were the same and there was no likely reason to expect different cholera-climate associations between the age groups at interannual time scales.The associations between DMI, Nino3 and monthly average temperature, rainfall and SST in the northern Bay of Bengal were also examined by wavelet coherence analysis. All the analyses were performed with R software (version 2.0).The time series for the number of cholera patients per month, by serogroup and biotype, ambient temperature, rainfall and river level during the study period are shown for Dhaka and MatlThe time series for Dipole Mode Index (DMI), Nino3 and sea surface temperature (SST) during the same period are shown in Four-year long coherent cycles between O1 cholera and DMI were seen in 1988\u20131997 in Dhaka while thV. cholerae were similar to the result for the El Tor O1 biotype strain alone because the frequency of the O1 biotype was dominant during the study period in the Bay of Bengal The association between Dipole Mode Index (DMI) and cholera hospitalizations that we found in Dhaka was not observed in Matlab, while a consistent association between Nino3 and cholera hospitalizations was observed only in Matlab. The associations that we found between DMI and Nino3 with cholera are broadly consistent with previous finding There are some limitations in this study. First, less severe cases of cholera are less likely to have been included in the surveillance data; however, this should not pose a threat to the validity of the comparison over time, which was the subject of this study. Second, some cases could have been missed because of limitations in the capacity of the hospitals to receive the patients; particularly, during epidemics of cholera. However, in principle, the hospitals accept all patients who visit the hospital. Thus, the capacity of the hospitals should not be an important limitation of this study. Third, the wavelet analysis explores a periodical synchronicity between two time series, and so has no bearing on mechanisms. Further environmental and microbiological studies are necessary to elucidate the causal pathways of the associations.Because of the serious global consequences of cholera and its sensitivity to climate, the World Health Organization has proposed that an early warning system for cholera epidemics using climatic parameters could be developed Figure S1Monthly time series of cholera hospitalizations by (a) serotype O1 & O139 and (b) bio-type El Tor & Classical for Dhaka (January 1983\u2013December 2008).(TIF)Click here for additional data file.Figure S2Monthly time series of cholera hospitalizations by (a) serotype O1 & O139 and (b) bio-type El Tor & Classical for Matlab (November 1981\u2013December 2008).(TIF)Click here for additional data file.Figure S3Cross wavelet coherence of global and local climatic time series with cholera in Dhaka and Matlab. (A) Dipole mode index (DMI) and cholera in Dhaka; (B) DMI and cholera in Matlab; (C) Nino3 and cholera in Dhaka; (D) Nino3 and cholera in Matlab; (E) Sea surface temperature (SST) in the Bay of Bengal (\u00b0C) and cholera in Dhaka; (F) SST in the Bay of Bengal (\u00b0C) and cholera in Matlab; (G) Rainfall (mm) and cholera in Dhaka; (H) Rainfall (mm) and cholera in Matlab; (I) Temperature (\u00b0C) and cholera in Dhaka; (J) Temperature (\u00b0C) and cholera in Matlab; (K) River level (m) and cholera in Dhaka; (L) River level (m) and cholera in Matlab. Time series span from January 1983 to December 2008.(TIF)Click here for additional data file.Figure S4Cross wavelet coherence of global and local climatic time series with classical biotype and El Tor cholera in Dhaka. (A) Dipole mode index (DMI) and classical cholera; (B) DMI and El Tor cholera; (C) Nino3 and classical cholera; (D) Nino3 and El Tor cholera; (E) Sea surface temperature (SST) in the Bay of Bengal (\u00b0C) and classical cholera; (F) SST in the Bay of Bengal (\u00b0C) and El Tor cholera; (G) Rainfall (mm) and classical cholera; (H) Rainfall (mm) and El Tor cholera; (I) Temperature (\u00b0C) and classical cholera; (J) Temperature (\u00b0C) and El Tor cholera; (K) River level (m) and classical cholera; (L) River level (m) and El Tor cholera. Time series span from January 1983 to December 2008.(TIF)Click here for additional data file.Figure S5Cross wavelet coherence of global and local climatic time series with classical biotype and El Tor cholera in Matlab. (A) Dipole mode index (DMI) and classical cholera; (B) DMI and El Tor cholera; (C) Nino3 and classical cholera; (D) Nino3 and El Tor cholera; (E) Sea surface temperature (SST) in the Bay of Bengal (\u00b0C) and classical cholera; (F) SST in the Bay of Bengal (\u00b0C) and El Tor cholera; (G) Rainfall (mm) and classical cholera; (H) Rainfall (mm) and El Tor cholera; (I) Temperature (\u00b0C) and classical cholera; (J) Temperature (\u00b0C) and El Tor cholera; (K) River level (m) and classical cholera; (L) River level (m) and El Tor cholera. Time series span from November 1981 to December 2008, with the exception of river level which begins in January 1983.(TIF)Click here for additional data file."} +{"text": "As Breast Cancer and Environment Research Center (BCERC) project leaders, we would like to address what we believe represents inaccuracies and omissions in the recent article by The LIBCSP has been enormously productive, continuing even now, with > 100 scientific publications and $21 million in grant funding using LIBCSP resources. \u201d 16 times, without noting the impressive contributions of the BCERC Community Outreach and Translation Cores (COTC) projects. Advocacy and COTC in the BCERC since 2003 have resulted in extensive and innovative dissemination of knowledge and new ideas (ew ideas . Mutual As noted by"} +{"text": "Sudden cardiac death (SCD) is responsible for 11% of all deaths and 50% of all cardiovascular deaths. Hypertrophic cardiomyopathy (HCM) is the most common cause of SCD among the young patients. SCD is often the first manifestation of the disease. There are 5 major risk factors for SCD in patients with HCM. However, no single risk factor can be used as a screening test in assessment of SCD. Nowadays new non-invasive risk factors, such as T-wave alternation (TWA), are being studied. They may provide important information on the patient\u2019s susceptibility to life threatening arrhythmias.The study involved 33 hypertensive heart disease (HHD) patients and 22 HCM patients. All patients underwent echocardiography test (ECHO) and 24h Holter monitoring with mTWA evaluation using the modified moving average method. The evaluation involved maximum mTWA figures in 24h (mTWA max), mTWA figures at the heart rate of 100/min (mTWA 100) and at 5:00 am (mTWA 5:00).The common group demonstrated a weak direct correlation between the thickness of ventricular septum (IVSth) and mTWA max, as well as a weak reverse correlation between the left ventricular posterior wall thickness (LVPWth) and mTWA 100. These correlation were revealed primarily in HHD patients who demonstrated correlation between mTWA max and IVSth, between mTWA 5:00 and IVSth, LVPWth, as well as between mTWA 100 and LVPWth. The HCM patients did not demonstrate correlation between mTWA and the thickness of left ventricular wall. The patients with non-obstructive HCM (n=15) demonstrated significantly higher mTWA 100 in comparison to the patients with obstructive HCM (n=5). The presence of higher SCD risk factors in the HCM patients (n=6) did not influenced mTWA figures. The mTWA figures in the HHD and HCM patients differed insignificantly, with the only exception of higher mTWA 5:00 in the HHD in comparison to the HCM group.mTWA figures correlate with the degree of left ventricular hypertrophy, however the revealed correlations are weak. The causes of lower MTWA 100 in patients with more intensive hypertrophy (reverse correlation) as well as in patients with obstructive HCM in comparison with non-obstructive HCM call for additional studies."} +{"text": "Bordetella pertussis (DTwP). In contrast, similar studies suggest that many African females and males may have their lives saved each year by the nonspecific immunological benefits of Bacillus Calmette-Guerin (BCG) vaccination. From an immunological point of view, we hypothesise that the adverse effects of DTwP vaccine may occur because of the Th2-polarising effect of the aluminium phosphate adjuvant in the vaccine and because intramuscular administration of the vaccine may cause chronic inflammation at the site of injection. However, the Th1-polarising effect of BCG is likely to be beneficial. Sexual dimorphism affecting immune functions and vitamin A supplementation may influence both the deleterious and beneficial nonspecific effects of immunisation.A number of mainly observational studies suggest that many African females below the age of one year die each year from the nonspecific effects of vaccination with diphtheria-tetanus toxoids and killed (whole-cell) The paper discusses the immunology behind the reported nonspecific effects of DTwP and BCG vaccination: increased childhood mortality rates after DTwP and decreased mortality rates after BCG vaccination given during the course of the WHO recommended vaccine programs implemented in Guinea-Bissau and other low-income countries , 2. BothBordetella pertussis vaccine. A typical DTwP vaccine dose (0.5\u2009mL) from the Serum Institute of India contains diphtheria toxoid (25\u2009Lf), tetanus toxoid (5\u2009Lf), and pertussis toxoid (4\u2009IU), aluminium phosphate (1.5\u2009mg), and a preservative, thiomersal (0.01%). Aluminium phosphate acts primarily as an antigen-adsorbing and Th2-polarizing adjuvant \u03b3 and TNFIn spite of numerous studies, there is still only weak evidence for any effect of micronutrient supplementation on vaccine efficacy (reviewed in ). Howeve The deleterious effect of DTwP vaccination in infant females and the beneficial outcomes of BCG vaccination might reflect nonspecific immune-polarizing and nonintended regulatory effects of vaccines and sex hormones in early childhood. The data from West Africa on the nonspecific effects of DTwP and BCG vaccination in young children discussed here suggest (1) replacement of intramuscular DTwP vaccination with cutaneous vaccination or development of a DTwP vaccine live bacterial carrier such as BCG which maIn low-income countries with high rates of childhood mortality, the nonspecific effects of routine vaccinations are likely to be of increased importance due to the high disease burden. The nonspecific vaccine effects should therefore be a high-priority research area and be considered in the future planning of immunization programs in these countries to enhance the beneficial impact of immunizations on child survival.The author has no relevant affiliations or financial involvement with any organization of entity with financial interest in or financial conflict with the subject matter discussed in this paper. No writing assistance was utilized in the production of this paper."} +{"text": "Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A was associated with the presence of paradoxical heat sensation (p\u200a=\u200a0.03), and transient receptor potential vanilloid 1 1911A>G with cold hypoalgesia (p\u200a=\u200a0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia and transient receptor potential vanilloid 1 1103C>G to cold hypaesthesia (p\u200a=\u200a0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients. Neuropathic pain arises after lesions or diseases of the somatosensory nervous system and involves multiple somatosensory phenomena. In addition to spontaneous pain, these include negative and positive symptoms and signs such as hypaesthesia, hypoalgesia, thermal and mechanical hyperalgesia and allodynia The understanding of the molecular basis of neuropathic pain has been expanded by the cloning and characterization of the transient receptor potential (TRP) family of voltage-gated ion channels. Among these the TRP vanilloid 1 (TRPV1), TRP melastin 8 (TRPM8) and TRP ankyrin 1 (TRPA1) subfamilies have been found to play important roles in transduction and sensitisation in primary afferent somatosensory neurons Beside these physiological functions, TRPs are thought to play an important role in the generation of neuropathic pain, as demonstrated by in vitro and in vivo animal studies and neurophysiological and psychophysical studies in human experimental pain models and pain patients However, the contribution of a genetic variability in TRP channels on pain perception and pain generation in neuropathic pain patients is unknown. In this study we describe the results of an association analysis of polymorphisms in TRPV1, TRPM8 and TRPA1 genes with somatosensory signs of neuropathic pain patients. The aims were (1) to determine the frequencies of TRP variants in a large group of neuropathic pain patients of different aetiology and a cohort of healthy volunteers and (2) to determine the relationship of TRP gene variants and somatosensory function in neuropathic pain patients. Within this study we could demonstrate significant associations between the somatosensory function and TRP gene variants in neuropathic pain patients but no differences in the TRP frequencies compared with healthy volunteers.All subjects gave their written informed consent and the study was approved by the ethics committee of the Medical Faculty of the Christian-Albrechts-University Kiel and subsequently the Ethic Committees of the other participating DFNS centers and performed according to the Declaration of Helsinki.www.neuro.med.tu-muenchen.de/dfns/) were included in the study . The patients suffered from complex regional pain syndrome, postherpetic neuralgia, peripheral nerve injury, trigeminal neuropathy, polyneuropathy, central pain and neuropathies that did not fulfill diagnostic criteria of the above mentioned syndromes as diagnosed by expert physicians. Patient characteristics are listed in A total of 371 patients with chronic neuropathic pain syndromes, all Caucasians, who participated in the German Research Network on Neuropathic Pain established by the DFNS to determinate somatosensory function and signs of pain Whole genomic DNA was extracted from venous blood samples obtained from patients and volunteers using the Qiagen Gentra Puregene Blood Kit . The final concentration of gDNA was determined spectrophotometrically. Two SNPs in TRPV1, six in TRPM8 and three in TRPA1 genes were identified by literature review in the context of neuropathic pain and selected for detailed association analysis . Except Before statistical analysis the QST values that did not show normal distribution were transformed logarithmically In order to identify major subpopulations of patients who are characterized by a typical combination of signs, a cluster analysis was performed in those patients only from whom complete QST results were available and for bi-allelic polymorphisms each subtest and genotype were calculated using analysis of variance (ANOVA). For dominant and recessive models the t-test was used, if applicable. To correct for multiple testing each test was performed using 100,000 permutations.The frequency distribution of all polymorphisms investigated was in Hardy-Weinberg equilibrium. Moreover, after correcting for multiple comparisons, the frequency of all SNPs did not differ significantly between neuropathic pain patients, healthy controls and data from the HapMap project .First, within the group of patients who suffered from paradoxical heat sensation (PHS) heterozygous and homozygous carriers of the TRPA1 710G>A variant were significantly under-represented as compared to neuropathic pain patients without PHS . Second,Hierarchical cluster analysis detected two main clusters . ClusterZ-scores of all QST tests were stratified to all TRP variants investigated in the entire sample and in both clusters. After correcting for multiple comparisons, two TRPV1 polymorphisms, 1911A>G and 1103C>G, were identified that had a significant relationship with the somatosensory function in cluster 1 .The TRPV1 1911A>G polymorphism was significantly associated with altered heat pain thresholds (HPT). Neuropathic pain patients being heterozygote or with wild type TRPV1 1911G genotype (AA or AG) tended to show heat hyperalgesia whereas TRPV1 1911G homozygotes exhibited significantly higher, i.e. normal heat pain thresholds . Homozygous variant carriers (GG) exhibited cold hypaesthesia compared with heterozygous or wild type carriers Click here for additional data file."} +{"text": "The intestine and the intestinal immune system have evolved through a symbiotic homeostasis under which a highly diverse microbial flora is maintained in the gastrointestinal tract while pathogenic bacteria are recognized and eliminated. Disruption of the balance between the immune system and the gut microbiota results in the development of multiple pathologies in humans. Inflammatory bowel diseases (IBD) have been associated with alterations in the composition of intestinal flora but whether these changes are causal or result of inflammation is still under dispute. Various chemical and genetic models of IBD have been developed and utilized to elucidate the complex relationship between intestinal epithelium, immune system and the gut microbiota. In this review we describe some of the most commonly used mouse models of colitis and Crohn's disease (CD) and summarize the current knowledge of how changes in microbiota composition may affect intestinal disease pathogenesis. The pursuit of gut-microbiota interactions will no doubt continue to provide invaluable insight into the complex biology of IBD. The lower gastrointestinal tract of healthy adult humans contains more than 100 trillion bacteria and the impact of microbiota on these pathologies Figure .+ and CD8+ T lymphocytes, regulatory T cells, neutrophils and macrophages, resembling the pathogenic events in human colitis. Mucosal macrophages may prime the local inflammatory response through both phagocytosis of DSS and activation by bacteria products. The contribution of macrophage polarization phenotype to the development of CAC has been described using this model including the demonstration that Akt2 deficient mice are partly protected from DSS-induced colitis because of a macrophage phenotype shift from M1 to M2 in the colonic mucosa . DSS administered to the drinking water in repeated cycles triggers a state of chronic intestinal inflammation by binding to medium-chain-length fatty acids present in the mouse colon, inducing disruption of colonic epithelial barrier by cytochrome P450 . DMH is metabolized in liver and its derivatives induce the production of diazonium by gut epithelial cells. The aforementioned metabolite exerts mutagenic effects through oxidative stress and methylation events initiates acute T cell-mediated, IL-12 driven intestinal inflammation and develops numerous adenomas. Exposure of Apcmin/+ mice to DSS alone mimics CAC and results in accelerated tumorigenesis gene in humans are critically involved in familial adenomatous polyposis (FAP) and represent an early genetic aberration in sporadic colorectal cancer can be adoptively transferred into immunodeficient SCID or RAG1/2\u2212/\u2212 mice, where they traffic to the intestine and induce gut inflammation. Recipient mice repopulated with CD4+CD45RBLo T cells or total CD4+ T lymphocytes do not develop colitis, despite their ability to colonize the host gut. This phenomenon is attributed to the presence of CD25+FoxP3+ regulatory T cells within the CD4+CD45RBLo population conditions results in spontaneous colitis which is transmissible to wild-type animals (which express T-bet) upon cross-fostering or co-housing , which harbors 8 genes and 5 micro RNAs and confers protection against H. hepaticus-induced chronic colitis and inflammation-driven colon cancer activity. Resident Treg produce IL-10 which inhibits Th1 cells and monocyte effector functions associated with inflammation. Suppression of Treg activity thereby unleashes inflammation, leading to a switch in the differentiation program of Ly6Chi monocytes from anti-inflammatory M2 macrophages to inflammatory dendritic cells and M1 macrophages in the colon microbes or inhibitors of specific microbes and/or their products which \u201cnormalize\u201d the intestinal flora and can improve human health. As the current repertoire of probiotics is limited, further studies to explore the potential of fecal microbiota transplantation (FMT) therapy, the infusion of fecal bacteria from a healthy individual into a recipient patient, for the treatment of intestinal disorders are warranted. FMT has demonstrated tremendous efficacy in treating refractory The microbiome plays an important role in immunity and energy metabolism and will thus be important to determine if the microbial gut ecology may also impact on non-gastrointestinal diseases, including obesity, cancer and neurological disorders.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Early diagnosis of macrophage activations syndrome (MAS) in systemic juvenile idiopathic arthritis (sJIA) may be challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication. However, the diagnostic value of the guidelines for hemophagocytic lymphohistiocytosis (HLH) (1) or sJIA-associated MAS (2) has seldom been examined.To investigate the sensitivity and specificity of diagnostic guidelines for HLH and sJIA-associated MAS in patients with sJIA who developed MAS.The study sample included 155 children with sJIA who had MAS (diagnosed and treated as such by the attending physician) and 2 control groups with potentially \u201cconfusable\u201d conditions, including active sJIA without MAS (n=303) and a systemic febrile infection requiring hospitalization (n=191). Diagnostic guidelines for HLH and sJIA-associated MAS were applied to all MAS and control patients. Because no patient had NK-cell activity and soluble CD25 determination available and bone marrow aspirate was performed in only a few patients, these 3 criteria were excluded from HLH guidelines. HLH criteria were, therefore, met when at least 4 of the 5 remaining variables were present. sJIA-associated MAS criteria were met when at least 2 laboratory criteria or at least 1 laboratory criterion and 1 clinical criterion were present. Sensitivity and specificity of guidelines in discriminating patients with MAS from control patients were assessed.The table shows the comparison of sensitivity and specificity of diagnostic guidelines.The diagnostic guidelines for sJIA-associated MAS revealed strong sensitivity and specificity, whereas HLH guidelines were highly specific, but lacked sensitivity. Sensitivity of HLH was mostly hampered by the excessive stringent threshold for cytopenia and hypofibrinogenemia, and the infrequent occurrence of splenomegaly in patients with MAS."} +{"text": "Pain is a common problem for patients admitted to the ICU, causing patient discomfort, agitation and accidental self-extubation. For this reason the recognition of pain and its severity is extremely important. Several pain scores and protocols are in use. We aimed to elucidate current practice of pain measurements and treatment in Dutch ICUs.In March 2011, a questionnaire was sent to all Dutch adult ICUs irrespective of the number of ICU beds with active follow-up by telephone calls to optimize the participation rate.A total of 84 ICUs (84/107) returned the survey, representing a response rate of 87%. Most ICUs are community teaching hospitals and nonteaching hospitals (85%) in comparison to academic hospitals (15%). Most ICUs (94%) use a standardized pain score in the group of patients who are capable of verbal communication: the Visual Analogue Scale (57%), Numerical Rating Scale (48%) and Faces Pain Scale (5%) being the most frequently used scores. In the group of patients who are unable to communicate, ICUs less frequently use pain scores (19%), with the Critical-Care Pain Observation Tool (6%) and Behaviour Pain Scale (5%) being used most frequently. Measurement of pain was considered most important for patients with burn wounds (67%), trauma patients (64%), postoperative patients (57%) and those who receive end-of-life care (64%). Barriers to use pain measurements included the patient's inability to communicate (82%), interference with pain assessment due to sedation (79%), hemodynamic instability (64%), insufficient dosages of analgesics (60%) and the unavailability of a standard pain scoring system (51%). In addition, guidelines for management of sedation and analgesics from the Netherlands Association for Intensive Care (NVIC) had been read by only 20% of the respondents. Factors that were mentioned to be useful in contributing to an improvement in pain assessment and effective pain control included adequate analgesic dosage (87%), utilization of protocols and directives (86%), enthusiastic and motivated personnel (81%) and the utilization of standardized pain measurement tools.Most Dutch ICUs measure pain frequently (94%) in patients who are able to communicate. However, in the group of patients who cannot communicate only 19% of the Dutch ICUs use a standardized pain score. This finding applied to both academic and nonacademic ICUs, which suggests that efforts should be put into implementing pain measures in Dutch ICUs."} +{"text": "Critical transitions between alternative stable states have been shown to occur across an array of complex systems. While our ability to identify abrupt regime shifts in natural ecosystems has improved, detection of potential early-warning signals previous to such shifts is still very limited. Using real monitoring data of a key ecosystem component, we here apply multiple early-warning indicators in order to assess their ability to forewarn a major ecosystem regime shift in the Central Baltic Sea. We show that some indicators and methods can result in clear early-warning signals, while other methods may have limited utility in ecosystem-based management as they show no or weak potential for early-warning. We therefore propose a multiple method approach for early detection of ecosystem regime shifts in monitoring data that may be useful in informing timely management actions in the face of ecosystem change. Transitions between alternative states, i.e., regime shifts, have been shown to occur across an array of complex systems Several early-warning indicators have been proposed to describe the temporal dynamics of complex systems close to a critical transition Pseudocalanus acuspes and Acartia spp., two key indicator species significantly contributing to the reorganization of the Baltic Sea ecosystem and sprat (Sprattus sprattus) Pseudocalanus acuspes and Acartia spp. serve as suitable indicators for the ecosystem regime shift in the Central Baltic Sea. Furthermore, long-term temporally and spatially resolved monitoring programs Pseudocalanus acuspes and Acartia spp. biomass covering the period 1960\u20132008. Since the primary aim of the study is to investigate and evaluate potential early-warning signals, we chose to focus on and present results on method performance during the time-period immediately preceding and following the regime shift . We used data representing spring as this is the main reproductive season of the copepods We used Pseudocalanus acuspes and Acartia spp. within a 10, 15 and 20-year sliding window, following the approach by Dakos et al. We measured temporal variance and autocorrelation at lag-1 (AR(1)) in detrended time series of average spring biomass of f\u2032\u2032) as a proxy for statistically significant acceleration in the rate of change (slope) of ecological time series a priori specified degree of smoothing In a second set of methods we applied statistical methods for assessing recent trends in the zooplankton time series. Although not specifically designed for early detection of regime shifts, the idea of using trend analysis as an early-warning signal lies in the possibility of detecting a slight increase in the rate of change (either in an upward or downward trend) in advance of a critical transition in an ecological time series. The approach is based on fitting non-linear Generalized Additive Models (GAM) The third approach was not primarily designed for early detection either, but rather for the identification and detection of regime shift. It is based on the evaluation of statistical time series models including structural breaks and combines several statistical indicators into a so-called \u201cshiftogram\u201d per se but to assess how under the constraints of real ecological time series similar to ours, different approaches may or may not work, and which assumptions and drawbacks may pose the greatest challenges in terms of early-warning detection and applicability to management.The full set of early-warning methods were assessed in terms of (i) the potential for detecting early-warnings signals in the selected indicator time series, (ii) how far in advance early-warning signals could potentially be detected, (iii) associated methodological assumptions and drawbacks influencing early-detection and (iv) applicability to real ecosystem management in terms of data requirements. While the trend analysis and shiftogram approach may quantitatively evaluate the first two criteria , no predefined reference levels exist to objectively assess the performance of our ecological indicators of critical slowing down, nor the possibility to theoretically crash test the methods against a simulated (modeled) spatio-temporal data set Pseudocalanus acuspes strongly increased two years before the regime shift in 1988 one year ahead of the regime shift correlation showed p-values exceeding their upper confidence intervals one year in advance of the regime shift for both species . This mate-1980s , may simContrary to temporal indicators of slowing down, spatial approaches for detecting changes in correlation and variance patterns Pseudocalanus acuspes and Acartia spp. prior to the regime shift (f\u2032 (slope) and a positive f\u2032\u2032 (acceleration). As in the previous example, no significant trend or change point was detected when excluding also 1987.The trend analysis me shift . When reme shift , while wme shift , as illuThe trend analysis seems to be highly dependent on the length of time series and the numbers of regression splines used during fitting of the generalized additive models GAMs; . These aPseudocalanus acuspes both the Akaike\u2019s information criterion (AICC) and the p-joint significance test showed a gradual transition towards a local minimum 3\u20134 years before the regime shift transitions or more gradual changes strongly influence the shape of the local minimum and hence the degree to which these transitions can be detected sufficiently in advance; a difference illustrated by the abrupt decrease in tia spp. and the acuspes . In addiThe versatility of methods for early detection of regime shifts in ecological time series provide an important toolbox for scientists and ecosystem managers. As learned from our example, no \u2018one-size-fits all\u2019 solution to deriving and interpreting spatio-temporal patterns announcing critical transitions exists Hence, we suggest that a multiple method approach may provide a sound scientific basis for detecting and evaluating early-warning signals and thus provide timely advice for immediate management actions in the face of future ecosystem changes Figure S1Map of the Baltic Sea and its location within Northern Europe. The central part of the Baltic Sea encompasses three deep (<70 m) basins important for marine biota, the Bornholm Basin (BB), the Gdansk Deep (GD) and the Gotland Basin (GB); largely corresponding to the International Council for the Exploration of the Sea (ICES) official sub-divisions 25, 25 and 28, respectively (thin lines). Furthermore, these basins are part of a long-term spatially and temporally disaggregated zooplankton monitoring program in the Baltic Sea.(JPG)Click here for additional data file.Figure S2Temporal variance of Pseudocalanus acuspes (circles) and Acartia spp. (triangles) estimated by standard deviations (SD) and the first-order autocorrelation coefficient (AR(1)) of detrended time-series for a sliding window of 10 , 15 and 20 years. Vertical dashed bars mark the timing of the Central Baltic Sea regime shift in the late 1980s.(TIF)Click here for additional data file.Figure S3The degree of spatial correlation for Pseudocalanus acuspes (A) and Acartia spp. (B) estimated as the mean significance of spatial correlation coefficients derived from a Moran\u2019s I test across 6 (black), 8 (grey) and 10 (black) randomly assigned stations (after 1000 resamples). Vertical dashed bars mark the timing of the Central Baltic Sea regime shift in the late 1980s.(TIF)Click here for additional data file.Figure S4Smoothed indicator time-series of Pseudocalanus acuspes and Acartia spp. with GAM df\u200a=\u200a10 and df\u200a=\u200a20 from 1960\u20131987. Bootstrapped confidence intervals are shown by grey lines. Acceleration in the rate of change (slope) in each year are shown by statistically significant second derivatives (f\u2032\u2032\u2019), where black and white dots represent major downward- and upward trends, respectively.(PPTX)Click here for additional data file.Table S1Test results for recent trends and changes in trends over 3-year periods before the regime shift in 1988 using intersection\u2013union tests. P-values from a \u03c72 goodness-of-fit test indicate whether the GAM fits satisfactory to the entire time-series. Significant negative (\u2212) or positive (+) time trends in the rate of change (f\u2032), as well acceleration (+) or deceleration (\u2212) of the current trend (f\u2032\u2032) are shown. Hence, an increase in a rate of decline is indicated by negative f\u2032 and a positive f\u2032\u2032.(DOC)Click here for additional data file."} +{"text": "The survival rates for oncology patients admitted to the ICU have improved significantly. The prognostic influence of the pre-admission oncological and treatment history is being questioned, the most significant impact being related to acute physiological status. In this survey, we sought to evaluate the awareness of overall mortality rates in critically ill cancer patients among intensivists in the UK.We surveyed intensive care lead clinicians in December 2011 in order to establish: a profile of the hospital and ICU they work in; their estimate of overall ICU mortality for critically ill cancer patients; the value of six outcome indicators in predicting mortality in two subgroups of oncological candidates for ICU admission; and the local management of acutely deteriorating cancer patients potentially requiring ICU care.The ICU mortality rates estimated by survey respondents differed from those reported in the literature: for solid tumor 21% (SEM 3) versus 10 to 23%, for metastatic solid tumor 38% (SEM 4) versus 23%, hematological malignancy 45% (SEM 3) versus 33 to 43% with allograft transplant 54.8% (SEM 5) versus 39 to 50% and autograft transplant 56% (SEM 5) versus 44%. Regarding the management of cancer patients, there were conflicts reported between teams . Few units had established triage policies for the acutely ill cancer patient (5%) and it was also not common that plans were made prior to the patient's deterioration . Figure The awareness of improved outcome in critically ill cancer patients differs among physicians, and in general estimated mortalities were far higher than those reported in the literature."} +{"text": "Numerous viruses are responsible for respiratory infections; however, both their distribution and genetic diversity, in a limited area and a population subgroup, have been studied only rarely during a sustained period of time.A 2-year surveillance program of children presenting with acute respiratory infections (ARIs) was carried out to characterize the viral etiology and to assess whether using gene amplification and sequencing could be a reliable approach to monitor virus introduction and spread in a population subgroup.Using multiplex RT-PCR, 15 different respiratory viruses were detected within the 486 nasopharyngeal positive samples collected among 817 children aged <9 years old who presented with ARI during October 2006 to September 2008. A single virus was detected in 373 patients (45.7%), and two to four viruses in 113 patients (13.8%). The most frequent causative viruses were respiratory syncytial virus (RSV) (24.7%), human bocavirus (24.5%), and human rhinovirus (HRV) (15%). RSV was more prevalent in winter and among young infants. Cases of seasonal influenza A and B viruses were reported mainly in January and August. An increase in adenovirus infection was observed during the spring of the second year of the study. Sequence analyses showed multiple introductions of different virus subtypes and identified a high prevalence of the newly defined HRV-C species. A higher viral incidence was observed during the winter of 2008, which was unusually cold.This study supports the usefulness of multiplex RT-PCR for virus detection and co-infection, and for implementation of a molecular monitoring system for endemic and epidemic viral respiratory infections."} +{"text": "This review provides the available evidence on sexual dysfunctions in India. Most of the studies have concentrated on male sexual dysfunction and hardly a few have voiced the sexual problems in females. Erectile dysfunction (ED), premature ejaculation (PME) and combinations of ED and PME appear to be main dysfunctions reported in males. Dhat syndrome remains an important diagnosis reported in studies from North India. There is a paucity of literature on management issues with an emergent need to conduct systematic studies in this neglected area so that the concerns of these patients can be properly dealt with. Human sexuality is inherently related to some of the social and public health problems in India. These problems may involve contraceptive use, child abuse, sex education, legal issues of homosexuality and AIDS. These health problems have a significant impact on existing health infrastructure and budget. These problems also need to look within the context of poverty, stressful living situations, diverse cultural belief systems, quackery, ignorance and inadequate health services. However, there is little recognition of how these health problems are related to human sexuality and their dysfunctions. There is a need to understand how sexual attitudes, beliefs, and values act and influence these problems. Our cultural perspective can also shape the experience and understanding of these disorders. There isIn this review, our aim is to present sexual dysfunction from the Indian perspective. Available data, based clinical studies from India, are reviewed and important findings highlighted. Our presentation is limited to sexual dysfunction only and paraphilias will be not discussed.et al. (1959). conVerma and his colleagues (1998) analyzedA file review of 178 male patients with sexual dysfunction by Avasthi and his colleagues (2003) revealedGupta and his colleagues (2004) attempteKendurkar and his colleagues (2008) assessedAs compared to male sexual dysfunction, a few Indian studies are available in the area of female sexual dysfunction. This area remains largely unexplored. Agarwal (1977) reportedIn the review by Kulhara and Avasthi (1995), there waKar and Koola (2007) conducteIn the study among 100 consecutive women attending the Department of Pediatrics for the care of non-critical children in a tertiary care teaching hospital, Avasthi and his colleagues (2008), found 17In another cross-sectional survey of 149 married women in a medical outpatient clinic of a tertiary care hospital, Singh and his colleagues (2009), reportedet al. (2005),[et al. (2007).[Studies pertaining to Dhat syndrome, a culture bound syndrome, have mostly defined clinical features. This \u201csemen loss\u201d-related psychological distress has been extensively reviewed by Prakash 2007), and Avas07, and A. (2005), and Dhik. (2007).Wig (1960), coined tBehere and Natraj (1984) and BhatMost studies found erectile dysfunction (22-62%) and premature ejaculation (22-44%) as commonly associated psychosexual dysfunctions, while depressive neurosis (40-42%), anxiety neurosis (21-38%), somatoform/hypochondriasis (32-40%) as the most reported psychiatric disorders in patients diagnosed with Dhat syndrome.Chadda and Ahuja (1990) could not find any abnormality on urine examination except oxaluria (10%) and phosphaturia (6%). On follow-up of these patients, Behere and Natraj (1984) found that majority of the patients recovered (66%), while the rest either improved (22%) or were unchanged (12%).Behere and Natraj (1984) and BhatRegarding management of Dhat syndrome, Wig (1960) suggestePrakash and Meena (2007), providedChadda and Ahuja (1990) advocateThis review highlights the available evidence in the field of psychosexual medicine in India. It is important to mention that all studies were from a hospital setting and none from community. Only a few studies explored female sexual dysfunction. Very few studies spoke about management issues. Dhat syndrome could be an important diagnostic entity to be researched. There is a strong need to perform studies in these areas."} +{"text": "Studies of spontaneous EEG and visual or somatosensory evoked high frequency oscillations indicate that the abnormal fluctuations of cortical responsivity over time in relation to the migraine attack could be due to abnormal thalamic control. Here we searched for possible structural changes in the thalamus of migraineurs by mean of acquiring diffusion tensor magnetic resonance imaging (MRI). This MRI technique provides quantitative data on water molecular motion, as a marker of tissue structure. Materials & Method \u2013 Seventeen untreated migraine without aura (MO) patients underwent MRI scan (3-Tesla Siemens Gyroscan) during (n=7) and between attacks (n=10) and were compared to a group of 14 healthy volunteers (HV). We examined fractional anisotropy (FA) and mean diffusivity (MD) in the thalamus.Between attacks MO patients had a significantly higher FA and lower MD values in the bilateral thalami when compared to HV (p<0.05). During attacks, all MRI quantitative measurements in migraineurs were similar to those found in HV. In MO patients, FA of the right thalamus was positively correlated with the number of days since the last migraine attack .The higher thalamic FA values noted between attacks in MO patients may be related to a decrease in regional branching and crossing of fibers, which normalizes during an attack. Whether these changes could be considered as the anatomical counterpart of the cyclic functional fluctuations previously observed with the neurophysiology in migraine remains to be determined."} +{"text": "Sheep chromosome 3 (Oar3) has the largest number of QTLs reported to be significantly associated with resistance to gastro-intestinal nematodes. This study aimed to identify single nucleotide polymorphisms (SNPs) within candidate genes located in sheep chromosome 3 as well as genes involved in major immune pathways. A total of 41 SNPs were identified across 38 candidate genes in a panel of unrelated sheep and genotyped in 713 animals belonging to 22 breeds across Asia, Europe and South America. The variations and evolution of immune pathway genes were assessed in sheep populations across these macro-environmental regions that significantly differ in the diversity and load of pathogens. The mean minor allele frequency (MAF) did not vary between Asian and European sheep reflecting the absence of ascertainment bias. Phylogenetic analysis revealed two major clusters with most of South Asian, South East Asian and South West Asian breeds clustering together while European and South American sheep breeds clustered together distinctly. Analysis of molecular variance revealed strong phylogeographic structure at loci located in immune pathway genes, unlike microsatellite and genome wide SNP markers. To understand the influence of natural selection processes, SNP loci located in chromosome 3 were utilized to reconstruct haplotypes, the diversity of which showed significant deviations from selective neutrality. Reduced Median network of reconstructed haplotypes showed balancing selection in force at these loci. Preliminary association of SNP genotypes with phenotypes recorded 42 days post challenge revealed significant differences (P<0.05) in fecal egg count, body weight change and packed cell volume at two, four and six SNP loci respectively. In conclusion, the present study reports strong phylogeographic structure and balancing selection operating at SNP loci located within immune pathway genes. Further, SNP loci identified in the study were found to have potential for future large scale association studies in naturally exposed sheep populations. Haemonchus contortus, Teledorsagia circumcincta, Trichostrongyles, Nematodirus sp. impose severe constraints on sheep and goat production especially those reared by marginal farmers under low external input system. These parasites incur heavy losses to farmers in terms of body weight loss, direct cost of anthelminthic drugs, loss due to mortality, etc. For example, annual treatment cost for Haemonchus contortus alone had been estimated to be 26 million USD in Kenya, 46 million USD in South Africa and 103 million USD in India Haemonchus contortus, Trichostrongylus colubriformis, Teledorsagia circumcincta and various Nematodirus species. Considerable variation has been reported among sheep breeds on their ability to resist gastro-intestinal nematodes (GIN). For example, indigenous sheep breeds like Red Maasai 2\u200a=\u200a0.149, Avikalin sheep 2\u200a=\u200a0.41, Armidale sheep Assessment of livestock health conditions in developing countries for identification of priority diseases to be targeted for control, revealed helminth infections as one of the most important problems in sheep and goat Exploration of genetic variation either within specific regions of genome or more specifically in candidate genes involved in innate and adaptive immune pathways may help to identify a set of DNA markers significantly associated with parasite resistance characteristics. The former approach in terms of quantitative trait locus (QTL) analysis is a powerful method to understand genotype-phenotype relationship. Several QTL studies on parasite resistance characteristics have been reported in sheep. A quick evaluation of Animal QTL database Haemonchus contortus parasite).One of the important objectives of QTL studies is to identify underlying causative gene polymorphisms associated with the trait. Different QTLs reported in chromosome 3 for parasite resistance characteristics were found to be distributed all over the chromosome with varying overlapping regions. Hence, different candidate genes within chromosome 3 along with genes involved in immune related KEGG pathways (KEGG-Kyoto Encyclopedia of Genes and Genomes) could be important targets for establishing underlying causative variations. It is expected that the potential causative polymorphisms within candidate genes are members of the same overarching KEGG pathway that lead to the phenotypic expression on parasite resistance characteristics in each population. Further, the extent of genetic diversity and population sub-structure at such polymorphic loci are critical for such a genotype-phenotype association study. Population stratification has been demonstrated to result in false positive associations in various species including humans Haemonchus contortus and blood samples were collected from jugular vein under the supervision of qualified veterinarians for extraction of DNA and assessment of blood parameters. 42 days post challenge, animals were dewormed to clear parasites from the gut after the experiment. The experimental challenge in both locations did not involve animals from any endangered or protected species/breeds. Blood sample collection for DNA extraction and genotyping from remaining breeds were performed by local veterinarians in respective countries following good animal practice.All procedures for artificial challenge experiment at different locations in Argentina and Indonesia were approved respectively by the Institutional Committee for Care and Use of Experimental Animals of the National Institute of Agricultural Technology (CICUAE-INTA), Argentina (protocol number 35/2010) and Institutional Research Animal Facility, Bogor Agricultural University, Indonesia following the guidelines described in their institutional manuals. Experimental animals were challenged with infective L3 larvae of in vitro conditions. All animals were maintained together during the entire trial in dry lot or under conditions of minimum additional parasite challenge. Body weight (BW), fecal egg count (FEC) and packed cell volume (PCV) were recorded at 0, 28, 35 and 42 days after artificial infection. 136 animals from Corriedale (66), Pampinta (34), Indonesian Fat Tail (17) and Indonesian Thin Tail breeds of sheep (19) were utilized for artificial challenge at experimental stations located in Argentina and Indonesia respectively.A total of 713 unrelated sheep from 22 different breeds/populations were utilized for diversity analysis in the present study. The sheep breeds/populations were distributed in three macro-environmental geographical locations including Asia (tropics), Europe (temperate) and South America (tropics) with the assumption that level of parasite load and infections vary significantly across these regions http://www.mbio. ncsu.edu/bioedit/bioedit.html). 44 novel SNPs were identified within the candidate genes under study for which competitive allele specific PCR (KASPar) assay based on FRET chemistry were developed for genotyping . Briefly, two forward primers one specific to each allele were designed with the respective proprietary tail sequence complementing the FAM or HEX fluorescence reporting system. A common reverse primer was designed for each genotyping assay. Thermal cycling parameters and recycling conditions were followed as per manufacturer's recommendations and are available on request. Endpoint allele discrimination module incorporated within the BioRad CFX96 was utilized for calling the genotypes based on fluorescent intensity recorded for each of the two alleles. The emission data of all the samples in the plate were plotted in X and Y axis respectively for each allele and the genotypes were called based on distinct clustering. Quality of allele calling was confirmed by comparing the genotypes derived from KASPar assay with the available sequence data on individuals from the panel of unrelated animals. 38 out of 44 assays passed quality control and were subsequently utilized for genotyping large number of animals. Additionally, ten toll like receptor (TLR) genes were selected for in silico mining of SNP variations from sequences available at NCBI-GenBank database. A total of 14 non-synonymous SNPs within coding DNA regions of TLR genes were identified for development of genotyping assays using SPSS version 13.0. The first three principal components were used to draw the scattergram so as to understand underlying genetic structure and relationship of different breeds in three dimensional geometric space. The extent of population sub-structure was further explored using STRUCTURE with the assumption of different clusters, K\u200a=\u200a1\u201315, 20, 25 and 30. Five replicate runs were performed for each K under admixture model without a priori population information. The number of burn in periods and MCMC repeats used for all the runs were 50000 and 100000 respectively. To identify the optimal \u2018K\u2019, the second order rate of change of L(K) with respect to \u2018K\u2019 was calculated by following the procedure reported elsewhere Basic diversity indices like allele frequency, genotype frequency, expected heterozygosity and test for Hardy Weinberg equilibrium were calculated using PEAS www.stat.washington.edu/stephens) ST values using ARLEQUIN version 3.1 Thirteen SNP loci within candidate genes involved in different immune related KEGG pathways and located in chromosome 3 were used to reconstruct haplotypes from unphased genotypic data. Reconstruction of haplotypes and estimation of haplotype frequencies were performed using PHASE for Windows, version 2.1 , body weight change (BWC) and packed cell volume change (PCVC) measured 42 days post infective L3 larvae challenge. The data on FEC were subjected to log transformation before applying the program of least squares, LSMLMW A total of 243 sequences were generated by targeted re-sequencing of selected candidate genes to 0.315 (Hamdani) while the mean expected heterozyosity varied from 0.237 (Pampinta) to 0.315 (Indonesian Thin Tail). Among different geographical regions, mean observed heterozygosity was highest in South West Asian sheep populations (0.309) followed by European populations [0.296] while South East Asian populations had the least mean observed heterozygosity (0.270). This is consistent with the fact that the diversity remains higher around the centre of domestication while decreasing with increasing geographic distance ST to 0.469 (Pampinta/Mouflon). 21.3% of total genetic variation was found to be due to between breed differences while 77.3% was due to within breed differences. The values are much higher than that reported for European sheep (13.1%) ST values observed could be understood from the fact that the samples were derived from wide geographic locations in the present study . Further, phylogenetic analysis of pair-wise allele sharing distance revealed two major clusters with most of South Asian, South East Asian and South West Asian breeds clustering together while the European and South American sheep breeds clustered together separately were plotted on a three dimensional scattergram to evaluate the genetic structure of sheep breeds on 136 animals was used for least squares analysis under a complete fixed effect model. The effect of location of experimental stations was not found to have significant influence on fecal egg count and packed cell volume while significant effect was observed with respect to body weight change (P<0.01). Although the locations are wide apart geographically, uniform protocol was followed across different experimental stations in terms of age of lambs selected for experiment, deworming and data recording schedule, however some differences did exist in terms of quality of pasture available for grazing, etc. Higher observed body weight change in animals challenged at Aguil Experimental Station (AES), Argentina was due to better growth performance of Pampinta lambs. Higher body weight achieved by Pampinta lambs were due to their genetic differences in growth rate (average pre-weaning weight gain of 295 g/day) and weight gain (average weaning weight of 33.4 kg) as compared to other breeds like Corriedale (218 g/day and 24.6 kg) To evaluate the potential utility of the SNP loci for future association study on a large number of samples, a pilot analysis was performed with the phenotypes generated in four breeds after artificial challenge with infective L3 larvae of In conclusion, the present study reports strong phylogeographic structure in sheep across Asia, Europe and South America and balancing selection operating at SNP loci located within immune pathway genes. Although the present association analysis is preliminary in nature, the SNP loci on chromosome 3 and those within immune pathway genes indicated their potential for future large scale association studies in naturally exposed populations.Figure S1http://www.animalgenome.org/cgi-bin/QTLdb/index).(a\u2013c) QTLs related to gastro-intestinal nematode resistance in sheep (d) Chromosome-wise distribution of QTLs related to parasite resistance traits in sheep and number of SNP loci investigated in the present study (e) Quantitative trait loci (QTL) map of chromosome 3 related to parasite resistance traits in sheep Click here for additional data file.Figure S2Distribution of allele sharing distance (IBS) between pairs of individuals. Distance was plotted separately where pairs were drawn from within the same breed (blue bars) and from across the breeds (red bars).(TIF)Click here for additional data file.Figure S3Bayesian clustering of 713 sheep based on genotype data at (a) 18 non-neutral SNP loci (b) 23 neutral SNP loci under assumption of 2 to 6 clusters without a priori population information. The breed names are given below the box plot and the geographical origin indicated above the box plot with the individuals of different breeds separated by vertical black lines.(TIF)Click here for additional data file.Table S1Details of SNPs identified in silico within TLR genes of sheep.(DOCX)Click here for additional data file.Table S2ST (lower triangle) and allele sharing distance (upper triangle) among different sheep breeds.Pairwise F .(DOCX)Click here for additional data file.Table S3Global F-Statistics among different sheep populations at 41 SNP loci.(DOCX)Click here for additional data file.Table S4Results of Ewens Watterson Neutrality test at different SNP loci in various sheep breeds .(DOCX)Click here for additional data file.Table S5Analysis of molecular variance among different sheep breeds based on (right) genotypes at 18 non-neutral SNP loci and (left) genotypes at 23 neutral SNP loci.(DOCX)Click here for additional data file."} +{"text": "To the Editor: The severe acute respiratory syndrome (SARS) outbreak of 2002\u201303 and the subsequent implication of bats as reservoir hosts of the causative agent, a coronavirus (CoV), prompted numerous studies of bats and the viruses they harbor. A novel clade 2c betacoronavirus, termed Middle East respiratory syndrome (MERS)\u2013CoV, was recently identified as the causative agent of a severe respiratory disease that is mainly affecting humans on the Arabian Peninsula . Details about the bat sample are available in the RNA-dependent RNA polymerase (RdRp) gene . PCR results were positive for 5 (8%) of the 62 specimens. PCR amplicons for 4 positive specimens yielded alphacoronavirus sequences related to recently described bat alphacoronaviruses from South Africa . During 2011\u20132012, fecal pellets were collected from 62 bats representing 13 different species in the KwaZulu-Natal and Western Cape Provinces of South Africa and stored in RNARdRp fragment generated by the screening PCR to 816 nt, as described . A partial spike gene\u2013based phylogeny using this sequence yielded the same topology as that using the partial RdRp sequence are urgently needed to elucidate the emergence of MERS-CoV. Such studies should focus on the Arabian Peninsula and Africa.Neoromicia zuluensis bats, and spike gene phylogeny of the 2c betacoronavirus clade.Description of bat sampling, screened bat species, distribution of"} +{"text": "Verapamil is an off-label first-line drug in prevention of cluster headache (CH) but little is known about the optimal rate of dose escalation. The safety profile of slow dose increment in 80mg intervals has been previously documented. It is possible to achieve the effective dosage earlier with fast escalation, although the safety and tolerability are of concerns.To compare the electrocardiographic abnormalities and other adverse events between fast and slow titration (by 80mg) of verapamil in CH treatment.Electrocardiograms (ECGs) at baseline and every two weeks in parallel with the increment of the drug were performed in patients attending our clinic. Medical records and ECGs performed in CH patients between 2007 and 2011 were retrospectively reviewed.Of 169 patients, 80 followed the fast and 89 the slow regimen. The slow regimen group differed from the fast regimen group in terms of: higher proportion of chronic CH , duration of verapamil use and maximum dosage of verapamil achieved . Eighty-three (49%) patients showed ECG changes: bradycardia in 60 (36%), first-degree atrioventricular block (AVB) in 22 (13%), second-degree AVB in 1(1%), third-degree AVB in 2 (1%), junctional rhythm in 7 (4%) and bundle branch block in 3 (2%) patients. The rate of arrhythmias did not differ between two groups. Verapamil was stopped only in second- and third-degree AVB. The rate of drug discontinuation due to arrhythmias or non-ECG adverse events did not differ between groups.The occurrence of verapamil-related serious cardiac arrhythmias was rare in patients adopting fast titration regimen. Our data support the safety and tolerability of rapid escalation of verapamil in patients with CH. Regular ECG assessment is essential throughout the therapy."} +{"text": "Enzyme-replacement therapy (ERT) with alglucosidase alfa has improved the lifespan of patients with classic infantile Pompe disease, although ERT is not effective in a subset of patients who mount an immune response to the exogenous enzyme. We studied the development of antibodies in response to ERT and its effect on clinical outcomes in 11 patients with classic infantile Pompe disease treated with ERT since 1999 for a median of 4.2 years (range 3 months to 12 years).We determined the endogenous acid alpha-glucosidase expression and regularly assessed antibody formation in all 11 patients, all of whom developed antibodies. The patients who lacked any endogenous acid alpha-glucosidase production did not develop a substantially different antibody titer than those who produced an inactive form of the enzyme (n=8). However, the patient\u2019s age at the start of ERT proved to be important: none of the four patients who started ERT before 2 months of age developed titers of more than 1:6,250. Gross motor function and cardiac dimension improved less in patients with high titers and in CRIM-negative patients. The three CRIM-negative patients have died, whereas the eight CRIM-positive patients survived.Antibody formation is common. High antibody titers and a CRIM-negative status are associated with a poorer clinical outcome. Earlier initiation of ERT may prevent the formation of a severe immune response."} +{"text": "The perceptual inference of the three-dimensional (3D) external world from two-dimensional (2D) retinal input of the left and right eye is a fundamental problem or changing disparity over time (CDOT) are both binocular inputs that may have improved discrimination performance in this task. However, motion detection and therefore IOVD is relatively insensitive to velocity changes (Gottsdanker, Early motion and disparity processing in the human visual system show tuning characteristics that supplement each other. Motion processing tends to have high temporal but relatively coarse spatial resolution whereas disparity processing has high spatial and relatively limited temporal resolution Tyler, . It has In an influential paper Weiss et al. demonstrA geometric-statistical model based on motion and disparity constraints provides a flexible computational framework for binocular 3D motion perception that can capture arbitrary 3D trajectories of moving features and objects. For example, motion and disparity information needs to be combined to disambiguate local motion direction of a single line or edge moving in depth (see Figure The observations by Pierce et al. demonstr"} +{"text": "Severe hypoglycemia (blood glucose level (BGL) <40 mg/dl) is independently associated with an increased risk of mortality in critically ill patients. The impact of milder hypoglycemia (BGL <70 mg/dl) on outcome is less clear.Prospectively collected data from two observational cohorts in the USA and in the Netherlands and from the prospective GLUCONTROL trial were analyzed. Hospital mortality was the primary endpoint.n = 1,098) and strict glycemic protocol ) and 914 patients who participated in the GLUCONTROL trial and intensive insulin therapy arm ). The percentage of patients with hypoglycemia varied widely among the different cohorts. Patients with hypoglycemia experienced higher mortality than did those without hypoglycemia within each subgroup , even after stratification by severity of illness or diabetic status. Multivariable logistic regression analysis revealed that hypoglycemia had a greater impact on the mortality of surgical patients than of medical patients. The impact of hypoglycemia on mortality occurred independently of mean glucose level during ICU stay or glycemic variability.We analyzed data from 3,262 patients admitted to Stamford Hospital (ST), 2,063 patients admitted to three institutions in the Netherlands (NL; loose glycemic protocol (L, Even a single episode of mild hypoglycemia was associated with a significantly increased risk of mortality in heterogeneous cohorts of critically ill patients, independently of severity of illness, diabetic status, diagnostic category and glycemic variability."} +{"text": "The aim of genetic tests performed by Genetic Counseling at Centre of Oncology was to screen for carriers of germline mutations in BRCA1 and 2 genes who are at high risk of developing breast or/and ovarian cancer.Among the patients qualified to genetic tests there are the patients who do not meet the Amsterdam criteria of HBOC syndrome.In Genetic Counseling at Centre of Oncology we find germline mutations in BRCA1 and 2 genes in about 5% of patients. Beginning in January 2003 until now we found mutations in BRCA genes in 247 families. Not all families belong to the group of high risk of developing breast or ovarian cancer. Among them there were 23 families which did not meet pedigree and clinical criteria.Analysis of tumors which were developed by the members of families carrying germline mutations in BRCA1/2 genes revealed mainly breast (415) and ovarian (170) cancers. There were also tumors which were not typical for this mutation. The most frequent not typical tumors in the families with germline BRCA1/2 mutations were: lung cancer (38), intestinal tract tumors (26) \u2013 including stomach cancer, liver cancer (20), pancreas cancer (15) and also hematopoietic tumors \u2013 among them leukemias (17), prostate cancer (14) and other.These findings justify performing genetic tests for germline mutations in BRCA1/2 genes not only for the patients who meet pedigree and clinical criteria typical for HBOC syndrome."} +{"text": "Normal development of the mammalian embryo requires epigenetic reprogramming of the genome. The level of cytosine methylation of CpG-rich (5meC) regions of the genome is a major epigenetic regulator and active global demethylation of 5meC throughout the genome is reported to occur within the first cell-cycle following fertilization. An enzyme or mechanism capable of catalysing such rapid global demethylation has not been identified. The mouse is a widely used model for studying developmental epigenetics. We have reassessed the evidence for this phenomenon of genome-wide demethylation following fertilisation in the mouse. We found when using conventional methods of immunolocalization that 5meC showed a progressive acid-resistant antigenic masking during zygotic maturation which gave the appearance of demethylation. Changing the unmasking strategy by also performing tryptic digestion revealed a persistence of a methylated state. Analysis of methyl binding domain 1 protein (MBD1) binding confirmed that the genome remained methylated following fertilisation. The maintenance of this methylated state over the first several cell-cycles required the actions of DNA methyltransferase activity. The study shows that any 5meC remodelling that occurs during early development is not explained by a global active loss of 5meC staining during the cleavage stage of development and global loss of methylation following fertilization is not a major component of epigenetic reprogramming in the mouse zygote. The mechanism that is currently considered to best describe 5meC reprogramming should result in an almost complete loss of methylation (<1%) by the time the embryo reaches the blastocyst stage. Analysis of around 1000 CpG islands (CGIs) within ovulated eggs shows that 15% are methylated de novo methylation occurs later, upon epiblast formation (D6.5)The dominant paradigm describing the processes of epigenetic reprogramming in the embryo holds that global active demethylation of 5meC occurs within the first cell-cycle. This demethylation acts preferentially on DNA inherited from the male while passive demethylation of the maternally derived genome occurs over subsequent mitoses Reports of an active process of global 5meC demethylation of the zygotic genome within hours of fertilisation in some species . This re-analysis did not find evidence for extensive active loss of methylation in zygotes or progressive loss due to an absence of maintenance methylation across the first several rounds of cell division. Rather, it was found that the reported loss of methylation immediately after fertilisation was accounted for by changes in the conformation or structure of chromatin that resulted in antigenic masking of 5meC.Mouse zygotes, 2-cell, 4-cell and 8-cell embryos were collected directly from the female reproductive tract from B6CBF1 strain female mice . The embryos were fixed and immunostained with anti-5meC. Zygotes were collected at various times after mating and staged according to the maturation of their pronuclei , is an independent measure of the global levels of CpG methylation. Western blot analysis showed two dominant molecular weight forms of MBD1 present in oocytes and the early stages of development . ImmunolBrief acid-treatment of cells has been the most widely used method of 5meC antigen retrieval reported. Altering the duration and concentration of HCl treatment did not change the pattern of 5meC staining in PN5 zygotes (not shown) showing that the difference between anti-5meC and anti-MBD1 staining was not due to increased acid-sensitive masking of 5meC. To determine whether other forms of masking may have occurred, fixed and acid-treated zygotes were subjected to extensive tryptic digestion. This caused a loss of MBD1 staining from nuclei 1\u20137 and aTo further assess this antigenic masking, condensing chromosomes of the zygote and 2-cell embryo were triple stained for DNA (blue), 5meC (green) and MBD1 (red). Acid-treated chromosomes from the zygote had some segments of undecorated DNA and large segments decorated by MBD1, but were largely devoid of staining by anti-5meC 1. By conIt is reported that further passive demethylation of the embryonic genome occurs during the cell-cycles following fertilisation due to limited maintenance methylation of the newly synthesized DNA Asymmetric anti-5meC staining of the male and female pronucleus after acid-pretreatment has been reported These analyses were all undertaken on embryos from hybrid (B6CBF1) mice. To assess whether the strain of mouse influenced the patterns of anti-5meC staining we also examined staining in an inbred (C57BL/6j) and an outbred (Swiss Quackenbush) strain embryos. Zygotes were collected directly from the reproductive tract fixed and stained for anti-5meC and PI. Hybrid embryos were collected and processed at the same time to act as controls. This analysis showed in acid-treated zygotes there was a similar progressive loss of anti-5meC staining of both PN4 and PN5 pronuclei in all three strains . Hybrid mice were used in most experiments. In the experiments reported in 2 for the periods indicated in individual experiments. Embryos were treated with the DNA methyltransferases inhibitor N-Phthalyl-L-tryptophan Embryos were collected from the reproductive tract in Hepes-buffered modified human tubal fluid medium (Hepes-mHTF) Immunofluorescence of zygotes was performed as previously described Unmasking of the 5meC antigen was performed by brief exposure to HCl as previously described Embryos from each treatment were processed at the same time and in parallel for each experimental replicate. All treatments were exposed to the same preparations and dilutions of all reagents including primary and secondary antibodies. Similarly all preparations from an experiment were examined microscopically within the same session, and used identical microscope and camera settings. All image analysis was performed in an identical manner for all embryos within an experiment. All preparations were performed by the same experienced operator throughout the study. Semi-quantitative analysis of staining was independently confirmed by two experienced observers.Western blot analysis on embryo and oocyte extracts was performed as previously described"} +{"text": "To assess and compare attitudes of general practitioners in different European countries towards screening and early interventions in alcohol use disorders.A total of 2435 general practitioners (GPs) from 9 European countries were surveyed. The questionnaire included questions on demographic, education and training on alcohol, received by general practitioners, as well as their attitudes towards management of alcohol problems. In addition, the Shortened Alcohol and Alcohol Problems Perception Questionnaire (SAAPPQ) was used.Seventy seven per cent of GPs declared that they placed \u2018somewhat high\u2019 or \u2018very high\u2019 their priority on disease prevention of the general practitioners; 54% reported having received 4 or more hours of education and training on managing alcohol problems, and 43% reported managing seven or more patients for alcohol problems in the previous year. GPs who reported higher levels of alcohol-related CME training were more likely to report regularly asking their patients about alcohol use (chi-square (3)=14.9, p=0.002). Moreover, there was a significant association between experience of alcohol-related CME and the number of patients managed for hazardous drinking (chi-square (5)=83.6, p<0.0005). Busyness (64%) and lack of training (52%) were considered most important barriers and readily available support services (84%) most effective facilitator of early intervention.The recommendations coming from the results of the ODHIN study for improving the delivery of early alcohol intervention and the management of alcohol problems in general practice are: provide better training and infrastructure. The main barriers and facilitators of early interventions did not change throughout last 16 years."} +{"text": "The human protein encoded by the FOXO1 gene functions as a transcription factor of insulin signaling key genes. Human uncoupling proteins 3 (UCP3) are mitochondrial proteins that are involved in the control of energy metabolism and the pathophysiology of obesity. In this study we investigated the role of genetic variation in the FOXO1 and UCP3 gene in susceptibility to non-alcoholic fatty liver disease (NAFLD) and relevant metabolic traits.We genotyped nine single nucleotide polymorphisms (SNPs) for association analyses in children . Body mass index (BMI), waist and hip circumference, blood pressure, fasting blood glucose (FBG), insulin (FIN), lipid profiles were measured and performed B-ultrasound examination in all the subjects.In the NAFLD group, FOXO1A and UCP3 allele were significantly more frequent in both association studies. There was a significant difference in the overall distribution of the genotype frequencies , (FOXO1 rs2721068), and there was a significant difference in the distribution of the haplotype , might be good NAFLD markers.In conclusion, our study suggests a effect of UCP3 haplotype on NAFLD development and relevant intermediate phenotypes which predispose for NAFLD."} +{"text": "Patients with atrial fibrillation (Afib) routinely undergo a transesophageal echocardiogram (TEE) for evaluation of the left atrial appendage (LAA) to rule out thrombus prior to undergoing cardioversion or pulmonary vein isolation (PVI). Cardiac MRI (CMR) is now increasingly used for evaluation of these patients for defining pulmonary vein anatomy prior to PVI.We hypothesized that 2D and 3D non-contrast and contrast CMR is as effective as TEE in evaluating for LAA thrombus while providing simultaneous comprehensive non-invasive evaluation of the pulmonary vein anatomy within a single exam.Afib Pts underwent TEE and non-contrast and contrast CMR prior to undergoing an initial PVI procedure. CMR was performed on 1.5T GE scanner and two blinded CMR experts analyzed the images. The CMR images were analyzed under two categories: 1) the 2D non-contrast cine images showing LAA in 2 chamber and orthogonal views 2) 3D atrial contrast source-images acquired during pulmonary vein angiogram. CMR variables evaluated were the presence or absence of LAA thrombus, quality of images and the results were compared with the results of TEE in a blinded fashion.In 62% of pts (n=65) the CMR and TEE studies were performed on the same day, in 37 % of patients (n=39) the mean interval between the two studies was 7 days and in the remaining 6 patients the mean interval was 3+1months. All pts (n=110) were analyzed for the evaluation of LAA thrombus (avg time: 35 min). All (100%) of patients were in Afib and in all (100%) the images were of diagnostic quality (good correlation between the two CMR observers with only one grade difference when in disagreement). Thrombus was absent in 108 of 110 pts on TEE and CMR and present on 2 TEE and CMR images (100% concordance). In 9 cases the 2D CMR images were indeterminate where 3D contrast images were most helpful in the final rule out of LAA thrombus.CMR offers a comparable and equally specific alternative to TEE for the complete non-invasive evaluation of LAA thrombus in patients with Afib without the obligate need for sedation, radiation or nephrotoxicity. In one single examination a CMR exam can provide LAA anatomy, rule out thrombus and display the pulmonary veins in patients undergoing a PVI procedure."} +{"text": "Despite the availability of an effective vaccine, Hepatitis B virus (HBV) infection still remains a foremost health problem. Undoubtedly, finding the key routes of hepatitis transmission from the point of prevention in every country, specifically in endemic regions, is of high priority. Such efforts are especially important given that many infected patients with hepatitis are asymptomatic 2]. Iran. Iran2].HBV is transmitted through both vertical and horizontal routes. Although vertical routes have both been very common in Turkey and Iran, nowadays the horizontal routes are much more important . In otheOther studies recommend the extension of HBV vaccinations in infant and high risk group, screening during pregnancy, and implementing additional strategies Such as adding the injection of hepatitis B immunoglobulin (HBIG) to the routine vaccination in neonates of mother HBs Ag positive, extension of vaccination in adults 13]14][[14][13][[[14][13]"} +{"text": "Cross-priming serves to activate cytotoxic T lymphocytes for immune defense against viruses and tumors and plays an important role in vaccinations. Only certain dendritic cell (DC) subsets can cross-present. Several cell surface markers have been described that more or less specifically and sensitively characterize these subsets. The cell-biological mechanism(s) why a DC subset can cross-present are less clear. Theoretically, the task of cross-presentation can be divided into several mechanistic steps: (1) Antigen uptake by various endocytosis mechanisms, (2) Intracellular antigen routing into distinct organelles including the crossing of organelle membranes, (3) Antigen processing into peptides, (4) Peptide loading onto MHC molecules, and (5) Transport of these complexes to the cell surfaces for presentation to T cells. Each of these steps is dependent on numerous parameters, not only the DC subtype, but also the nature of the antigen or the presence of further signals that impact DC function or signify the presence of danger or infection.This research topic contains 10 articles by leading experts in the field of antigen presentation that cover our current knowledge on the molecular mechanisms underlying cross-presentation (Chopin et al.,"} +{"text": "The results section of the published article state thThe above definition contains an error and should instead be written as follows: 46,XY.ish der(15)tmat."} +{"text": "FRB), length (FRL), and root area index (RAI) were significantly lower for spruce than for beech in mixed stands. Vertical profiles of fine root attributes adjusted to one unit of basal area (BA) exhibited partial root system stratification when central beech is growing with spruce competitors. In this constellation, beech was able to raise its specific root length (SRL) and therefore soil exploration efficiency in the subsoil, while increasing root biomass partitioning into deeper soil layers. According to relative values of fine root attributes (rFRA), asymmetric below-ground competition was observed favoring beech over spruce, in particular when central beech trees are admixed with spruce competitors. We conclude that beech fine rooting is facilitated in the presence of spruce by lowering competitive pressure compared to intraspecific competition whereas the competitive pressure for spruce is increased by beech admixture. Our findings underline the need of spatially differentiated approaches to assess interspecific competition below ground. Single-tree approaches and simulations of below-ground competition are required to focus rather on microsites populated by tree specimens as the basic spatial study area.Scientists are currently debating the effects of mixing tree species for the complementary resource acquisition in forest ecosystems. In four unmanaged old-growth spruce-beech forests in strict nature reserves in southern Sweden and northern Germany we assessed forest structure and fine rooting profiles and traits (\u22642 mm) by fine root sampling and the analysis of fine root morphology and biomass. These studies were conducted in selected tree groups with four different interspecific competition perspectives: (1) spruce as a central tree, (2) spruce as competitor, (3) beech as a central tree, and (4) beech as competitor. Mean values of life fine root attributes like biomass ( Fagus sylvatica L.) and Norway spruce [Picea abies (L.) Karst], Pretzsch and Sch\u00fctze show evidence of species interaction and its effects on tree performance and stability. Several studies in managed mature beech-spruce mixtures in Germany and Austria found indications for vertical root system stratification Karst.] or oak expand its distribution range northwards finding evidence for vertical root system stratification in the unmanaged spruce-beech forests, (2) quantifying effects of spruce-beech competition in different mixture constellations on fine root structural traits, and (3) evaluating the competitive status of both species below ground considering different levels of interspecific competitive pressure.Our present study includes a temperate near-natural forest within the high montane zone of the Harz Nationalpark (Northern Germany) with climate and site conditions comparable to the hemi-boreal forests of our other two study sites in Southern Sweden (see Table Picea abies (L.) Karst.] and European beech (Fagus sylvatica L.) are located in the boreo-nemoral zone covered with moraine sediments whereas at the Harz site both metamorphic \u201cHornfels\u201d and sedimentary \u201cGrauwacke\u201d sandstones prevail, partly covered by loess (eolic silt sediment). All sites have comparably low amounts of fine-textured soil and are riddled with boulders. Soil traits of all three sites are comparable with a moderate to thick accumulation of organic material 5\u201312 cm; the humus type is moder to raw humus or raw humus (Siggaboda) with a high C/N ratio. Fine soil material is dominated by silt (40\u201365%) and sand (18\u201352%); the clay proportion is relatively low (8\u201317%) and the texture can be classified as sandy silt or silty sand, respectively. The soil type is a Haplic Podzol BGR, with a hdbh), tree heights, and basal area (BA) .All three mixed stands are dominated by spruce with higher mean values of stem density, diameter at breast height (A) Table . The SweForest stand structures were recorded in a 1 ha square core plot (100 \u00d7 100 m) in the center of the semi-natural forest representing a typical section of the old-growth stand. We subdivided the plot using a 20 m-grid of 7 cm and larger in winter 2004 at Siggaboda and in spring 2005 at the other sites. For each tree, species, cardinal location coordinates of the stem using above mentioned equipment and dbh with a girth tape were recorded. Subsequently, a tagging system was used for temporarily (between 2004 and 2007) marking and numbering each measured tree.Within the entire 1 ha core plot, we assessed each tree with a A) spruce as the central tree, (B) spruce as competitors, (C) beech as the central tree, and (D) beech as competitors. This design was completed by monospecies groups with comparable intraspecific competitive status that was only used as a reference for analyses of mixed species representation .We studied fine root structure of mature trees focusing on tree groups with one central tree with its mostly four\u2013five competitors . Therefore, beech-spruce tree groups representing four different types of interspecific competitive situations were selected: until the solid bedrock layer was reached. The maximum mineral soil depth sampled varied from 20 to about 40 cm. Various studies revealed that the maximum of fine roots is found in the top soil layers and vitality . We applied morphological criteria for the identification of dead root material: dead root parts exhibits a dark discoloration of the central cylinder and a decreased flexibility of root segments . The reported measurements allowed the calculation of specific root length and specific root surface area (SRA) from the ratio of fine root length (FRL) and root biomass, and fine root surface area and rooting biomass, respectively.All recorded root fragments were then dried for 48 h at 40\u00b0C and weighed in order to measure living fine root biomass , and thus variable species abundance above-ground :The data was included in a relational database running on the open source database system PostgreSQL and analyzed with the software package Statistica 9 and SAS JMP 9 (SAS Institute Inc. 2010). Differences between mean root traits were assessed either by the Kolmogorov-Smirnov-two-sample test, or by the Kruskal-Wallis H test when more than two samples or groups were compared. We used the respective tree BA per hectare of either spruce or beech as a reference unit for the comparison of fine root attributes (FRA are the life fine root attributes in terms of FRB (g m\u22122), FRL (m m\u22122), and RAI (cm2 m\u22122) of a central tree (CT) or n competitors (COMP), respectively. BA (m2 ha\u22121) is the BA of either spruce or beech, and FRAad are fine root attributes adjusted to the same BA (1 m2 ha\u22121) of either one central tree or of n competitors .where CT) or competitor (COMP) constellations of spruce and beech were further assessed by calculating relative fine root attributes in mixed groups with either CT or COMP constellations to those of pure stand groups (Equation 3). This enables the assessment of under- (<1) or overrepresentation (>1) of beech and spruce below ground growing in different mixed stand constellations under interspecific competition.The fine root representation of either central tree attained higher adjusted fine root abundance along the vertical rooting profile than the competitors exhibited significantly higher fine root abundance in both the humus layer and deeper soil layers compared to beech competitors (COMP). This was not the case for spruce with a quite equal allocation of fine root proportion along the profile for both CT and COMP constellations. A spatial separation of the fine roots of spruce and beech was visible for the deeper soil horizons (10\u201340 cm) when growing with beech as the central tree and spruce as competitors resulting in high beech and low spruce fine root quantities. This partially vertical stratification was mainly due to high plasticity of beech fine rooting as a central tree. No stratification was visible in the organic layer and top soil where both species reached their maximum abundances.For both spruce and beech, central trees (SRL and specific fine root surface area (SRA) attained values for mixed beech (CT and COMP) of SRL 12.7 \u00b1 5.5 m g\u22121 and of SRA 367.3 \u00b1 125.9 cm2 g\u22121 compared to mixed spruce of SRL 6.6 \u00b1 3.8 m g\u22121 and of SRA 253.6 \u00b1 108.1 cm2 g-1 . However, total SRL and SRA differences between CT and COMP constellations within both species were not significant.Total means of specific SRL and SRA support the idea of higher plasticity of beech fine rooting . For spruce in contrast, we did not find such changes between central spruce trees (CT) and its competitors (COMP) rooting behavior. However, significant higher SRL and SRA values of CT constellations in the humus layer and the top soil points to higher competitive investments for rooting space sequestration in the upper soil horizons of single central spruce trees (CT), whereas single beech trees (CT) invested more in deeper soil horizons with less competitive abundance of spruce roots. Comparing beech and spruce as interspecific competitors (COMP), one can observe quite similar vertical rooting behavior , beside the above mentioned fact that the overall level of beech is much higher than that of spruce.The vertical profiles of g Figure . WhereasrFRA, cf. Equation 3) in mixed CT and COMP constellations and COMP constellations on interspecific tree species representation compared to the intraspecific one (Table rFRA). Two major findings were derived: (1) spruce is underrepresented in fine root abundance in mixed stands (mean rFRA < 1) whereas beech is overrepresented (mean rFRA > 1); (2) both beech overrepresentation and spruce underrepresentation address CT constellations with beech as the central tree (B). This indicates that beech rooting was favoured by an asymmetric interspecific competition of both species when several spruce competitors grew together with a single beech tree. But this was not the case for CT constellations with central spruce and beech competitors where we found a quite symmetric interspecific competition. Combining results from the existing mixtures (means of A + D) of central spruce (CT) and competing beech (COMP) or vice versa (means of B + C) one can assess fine root representation effects of the mixtures compared to either beech or spruce pure groups. It turned out that due to the low fine root representation of spruce no existing mixture reaches the high fine root representation of pure beech. However, both mixture constellations lead to higher fine root representation compared to the pure spruce plots.For the analyses of fine root representation of the mixed stand plots in Sweden is related to the remarkably low tree abundance above ground compared to the Swedish plots. The positive relationship between tree dimension (BA) and soil exploration (FRB) on microsite and tree level has been demonstrated by Bolte and Villanueva of central beech and competing spruce in deeper soil horizons and mixed beech (12.7 m g\u22121) lie within the lower part of the range for spruce and beech (d < 2 mm) of 4.5\u201326 and 5.7\u201331.5 m g\u22121, respectively, reported by the extensive meta-analyses of Ostonen et al. are similar to those reported for mixed spruce by Bolte and Villanueva of beech does not mean that resource exploitation is more efficient compared to spruce increased SRL in deeper soil layers. This indicates additional soil exploration activities at low carbon costs in soil depths from 20 cm downwards fitting well to the findings of changed root system partitioning favouring deeper soil horizons for increasing complementary resource exploitation and \u201cunderground niche separation\u201d adjusted to the same unit of above ground performance (1 m2 BA per hectare) with adjusted values for monospecies plots is in line with other studies reporting an over-proportional reduction of fine root abundance in beech mixtures with spruce surrounding a single beech tree (CT) have a low fine root representation possibly reflecting intensive above ground competition between central beech and spruce competitors leading to increased biomass partitioning toward aboveground tree compartments. Beech fine root representation on the other hand is favored by interspecific competition with spruce. The found morphological belowground plasticity (variation of rooting depth in CT constellation and of SRL/SRA) reflects the high crown plasticity (Dieler and Pretzsch, The relative fine root representation is a measure to compare mixed species abundance (SRL and with this soil exploration efficiency in the subsoils while increasing root biomass partitioning toward deeper soil layers. Moreover, asymmetric below-ground competition was observed favoring beech toward spruce in a mixed constellation with central beech. We conclude that beech fine rooting is facilitated in the presence of spruce by lowering competitive pressure compared to intraspecific competition whereas the competitive pressure for spruce is increased by beech admixture. This is most obvious when central beech trees are admixed with spruce competitors. Our findings underline the need of spatially differentiated approaches to assess interspecific competition below ground. Since tree competition is a process that affects tree at an individual scale, stand scale analyses should be complemented by single tree approaches, above and below ground. In line with the recent development of crown competition assessments and stand simulation methods (e.g., Pretzsch et al., The results of the presented study exhibited an only partially vertical root system stratification in the subsoil in the three spruce-beech old-growth stands and depended on specific mixture constellation: beech central tree with spruce competitors. In this mixture constellation, beech was able to raise The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Headache diagnostic software (HDS), developed by Headache center, Neurology Clinic in Belgrade integrates a diagnostic expert system able to suggest the correct ICHD-II diagnosis once all clinical characteristics of a patient\u2019s headache have been collected.Purpose The aim of this pilot study was to test its diagnostic accuracy, the usefulness and applicability in the diagnosis of primary headache disorders and medication overuse headache (MOH).Forty patients with clinical diagnosis of migraine, tension type headache (TTH), cluster headache and MOH with an Internet access agreed to fill the web-based headache diary 4-6 weeks after their first consultation in Headache center. This diagnostic diary is developed exclusively based on the ICHD-II criteria, and represents the core of HDS. We analyzed the level of agreement between diagnosis given after clinical interview and obtained by HDS as well as patients\u2019 level of compliance.Patients\u2019 understanding of the diary proved highly satisfactory which was followed by good compliance (77.5%). Number of patients with one headache diagnosis was 22; 9 patients received 2 or 3 different diagnosis. All patients with a clinical diagnosis of migraine (21) had at least one migraine attack recognized by HDS; episodic TTH was less frequent diagnosed using standard clinical interview than by DHS. In all MOH (4) and cluster headache patients (3) there was complete concordance between clinical and software generated diagnosis.Web-based HDS can be considered as advanced, user-friendly, useful and reliable diagnostic tool in headache center."} +{"text": "Mycobacterium tuberculosis (MTB) strains is a worrisome trend seen during recent years. Rapid detection of MDR strains is very important to restrict their spread in the population. Gold standard methods for drug susceptibility testing (DST) of MTB are either costly or very slow. Nitrate reductase assay (NRA) is one of the methods for rapid detection of resistance. This technique is based on the capacity of M. tuberculosis to reduce nitrate to nitrite. The WHO recommends that the NRA be used as direct test on smear-positive sputum specimen or as an indirect test on Mycobacterium tuberculosis isolates grown from conventional solid cultures. We evaluated the performance of NRA as rapid, reliable & inexpensive method for drug-susceptibility testing of Mycobacterium tuberculosis against first line antitubercular drugs, Rifampicin (RIF) and Isoniazid (INH).Increase in multi-drug resistant (MDR) M. tuberculosis isolated from sputum samples of pulmonary tuberculosis patients were subjected to NRA and absolute concentration method for comparison.80 strains of Out of 80 isolates, 12 strains were resistant to INH & 11 strains were resistant to RIF and 9 strains are resistant to both INH & RIF constituting MDR strains. Sensitivities and specificities were 99%, 98% for RIF and 99%, and 100% for INH by NRA as compared to Absolute Concentration. However median time of obtaining results was shorter using NRA (9-10 days) compared to Absolute Concentration (30-40 days).Mycobacterium tuberculosis.We conclude that NRA has the potential to be a useful tool for rapid DST of"} +{"text": "The complete funding information is: \"This study was supported by Clinical Translational Science Institute (CTSI)(1UL1RR029893) seed fund to PL, Northwestern Memorial Hospital Dixon Translational Research Fund and Marsha Rivkin Center For Ovarian Cancer Research Award to JJW, and predoctoral fellowships from NYU CTSI TL1 (1UL1RR029893) and NYU Molecular Oncology and Immunology Training grant (T32 CA009161) to GD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\""} +{"text": "Selecting the treatment of choice for multilevel cervical myelopathy remains a controversial issue. The most important factor in choosing a treatment method for patients with cervical myelopathy is the sagittal curvature and the site of compressive pathology.A total of 20 cases were available for the last 4 years with acceptable follow-up (f/u) of at least one year after surgery. Clinical examinations were obtained before surgery, 3 months post-surgery and at f/u. Evaluating the operative results performed by analyzing the recovery rate using the Japanese Orthopaedic Association (JOA) scoring system.Analysis were conducted on a total 20 patients undergoing surgery via anterior approach (9 patients), posterior approach with fixation (3 patients), and anterior. Posterior approach (8 patients). Two patients underwent surgery with hybrid decompression fixation technique. There were two patients who had decreased level of the JOA score which need posterior decompression. One patient had early onset post of infection in posterior approach.Our strategy base on naderi algorithm were effective and the follow up showed stable clinical results which depended on the completely removal of the possible causes of the pathology.Cervical spine, Multilevel, Myelopathy"} +{"text": "To the Editor: Mediterranean spotted fever (MSF) is endemic in Italy, where it is a reportable disease. From 1992 to 1998, the Italian Ministry of Health was notified of approximately 8,500 cases of human rickettsioses presumed to be MSF. MSF occurs more commonly in some central (Lazio) and southern regions for ompA gene and restriction analysis under conditions previously described by Roux et al. and aligned sequence data with homologous sequences of reference strains of the spotted fever group rickettsiae retrieved from the GenBank database. Sequence analysis showed 100% similarity with the homologous sequence of Israeli spotted fever Rickettsia reference strain ISTT CDC1 (GenBank accession no. U43797). The Israeli spotted fever Rickettsia belongs to the R. conorii complex .Molecular analysis of spotted fever group"} +{"text": "Global evaluation of influenza vaccination in children indicates that current recommendations are not followed. Most children at high risk for influenza-related complications do not receive the vaccine, and increased efforts are needed to protect them. Furthermore, immunizing healthy infants 6\u201323 months of age and their close contacts should be strongly encouraged. Vaccinations are recommended for children with recurrent acute otitis media or recurrent respiratory tract infections and possibly for healthy daycare and school-age children because of the potential socioeconomic implications of influenza. Issues that need to be addressed include educating physicians and parents concerning influenza-related illness and complications, cost-effectiveness and safety of licensed vaccines, adequate vaccine supply, and availability of intranasal products. The most important of these obstacles are lack of understanding of the risks for complications and lack of knowledge of efficacy (Seven main obstacles to complying with recommendations for vaccination in children exist: 1) lack of understanding of the risk for influenza complications in children; 2) lack of knowledge of annual immunization\u2019s efficacy in primary prevention; 3) parents\u2019 negative reaction to parenteral vaccine administration (\u201cNot another shot!\u201d); 4) need for two priming doses in children <9 years old followed by annual administration; 5) fear of limited protection in younger and high-risk children; A number of studies of adult (particularly elderly) populations have shown that knowing risk factors for influenza complications, favorable perceptions of the vaccine, and clinician recommendations are the main variables predicting the administration of influenza vaccination and require annual administration to maintain protection were randomized to receive the vaccine (n = 67) or no vaccination (n = 66). During a 6-month period, 24 vaccine recipients (35.8%) experienced 32 episodes of AOM, and 42 control participants (63.6%) experienced 64 episodes. The overall efficacy of vaccination in preventing AOM was 43.7% . Recurrent AOM is common in infants and children, and its possible sequelae make prevention desirable (= 0.002) (13). Mo>6 episodes per year if >3 years; >8 episodes per year if <3 years) were randomized to receive the intranasal virosomal influenza vaccine (n = 64 with 176 household contacts) or a control placebo (n = 63 with 173 household contacts). During the influenza season, vaccinated children had fewer respiratory infections or febrile respiratory illnesses, received fewer prescribed antimicrobial and antipyretic drugs, and missed fewer school days than the controls (A second group of children who could be considered for influenza vaccine are those with recurrent episodes of respiratory tract infections (RRTIs). A large number of children without any immunologic problems experience multiple episodes of RRTIs during the first years of life; although these generally have a benign prognosis, they can cause substantial medical and socioeconomic problems in 555 school-aged children in Russia demonstrated that both were efficacious in preventing school absenteeism by reducing the number of missed school days by 47% to 56% compared to missed school days in unvaccinated children . AlThe socioeconomic importance of influenza in childhood is confirmed by economic analyses showing that vaccinating healthy preschool and school-age children can lead to health and economic benefits during epidemic and pandemic periods , and the central role of children in disseminating the infection in households and communities. The issues that need to be addressed include educating physicians and parents about the illness caused by influenza, the cost-effectiveness and safety of licensed vaccines, adequate vaccine supplies, and the availability of intranasal products. Improved compliance associated with nasal administration should increase the use of influenza vaccination. Only a heightened and regular demand for influenza vaccine will result in sufficient vaccine supplies at all times (not just on a year-to-year basis) and place us in a better position to detect a novel pandemic influenza virus strain."} +{"text": "The recent article by Prud'homme et al suggestsThe above examples clearly illustrate the role of neuropilin-1 in tumor progression in systemic malignancies and the urgent need to identify further inhibitors of neuropilin-1 expression."} +{"text": "Critically ill patients with inadequate lid closure are susceptible to developing exposure keratopathy. Protective measures can prevent this and reduce the risk of subsequent microbial keratitis and irreversible visual loss. Of two published surveys ,2, one wA team of researchers telephoned all general ICUs and other specialty critical care units in England caring for sedated, ventilated patients and asked a supervising nurse questions from a questionnaire piloted earlier in London.Two hundred and seventeen out of 267 ICUs (81%) participated. One hundred and thirty out of 217 (60%) ICUs had an eye care protocol. Sixty-six per cent of units with protocols assessed lid closure compared with 65% of those without. Geliperm application was the most common protective therapy , followed by Lacrilube . Most ICUs used a combination of methods. The total estimated incidence of ocular complications in the last year was 502. The most recent complications witnessed included corneal ulceration (23 cases), microbial keratitis (11) and chemosis (23). Cases of severe visual loss were caused by anterior ischaemic optic neuropathy following prone positioning (two cases) and microbial keratitis in a patient's only functioning eye.There is a need for protocols that encourage proper eyelid position assessment, effective protection of the ocular surface and referral to ophthalmologists in the event of any complications or any loss of corneal clarity."} +{"text": "Deciphering functional mechanisms of the Hsp90 chaperone machinery is an important objective in cancer biology aiming to facilitate discovery of targeted anti-cancer therapies. Despite significant advances in understanding structure and function of molecular chaperones, organizing molecular principles that control the relationship between conformational diversity and functional mechanisms of the Hsp90 activity lack a sufficient quantitative characterization. We combined molecular dynamics simulations, principal component analysis, the energy landscape model and structure-functional analysis of Hsp90 regulatory interactions to systematically investigate functional dynamics of the molecular chaperone. This approach has identified a network of conserved regions common to the Hsp90 chaperones that could play a universal role in coordinating functional dynamics, principal collective motions and allosteric signaling of Hsp90. We have found that these functional motifs may be utilized by the molecular chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, and protein client binding. These findings have provided support to a long-standing assertion that allosteric regulation and catalysis may have emerged via common evolutionary routes. The interaction networks regulating functional motions of Hsp90 may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based \u201cconformational selection\u201d of functional states is likely to be activated based on the nature of the binding partner. This mechanistic model of Hsp90 dynamics and function is consistent with the notion that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected residue clusters. Hence, allosteric signaling through a small network of distantly connected residue clusters may be a rather general functional requirement encoded across molecular chaperones. The obtained insights may be useful in guiding discovery of allosteric Hsp90 inhibitors targeting protein interfaces with co-chaperones and protein binding clients. The molecular chaperone Hsp90 (90 kDa heat-shock protein) is required for managing conformational development, stability and function of proteins in the cellular environment E coli homologue, HtpG Structural and biochemical studies have established Hsp90 as an ATP-dependent system that operates as a homodimer in a functional cycle associated with the ATP binding and hydrolysis Modern biophysical approaches including X-ray crystallography, electron microscopy and small-angle X-ray scattering (SAXS) have provided a more detailed characterization of the Hsp90 conformational states during progression through the ATPase cycle Computational approaches have been instrumental in revealing the atomic details of the inter-domain communication pathways which may regulate the conformational equilibrium of the molecular chaperone. We have recently reported the first computational study of the Hsp90 allosteric binding with an atomic level analysis of the conformational motions and the inter-domain communication pathways in the full-length yeast Hsp90 dimer in the apo form and complexes with ATP and ADP Mechanistic and thermodynamic models of allosteric communication have become widely accepted and broadly applied to analyze mechanisms of allosteric regulation in proteins and biological networks Structure-functional studies of Hsp90 regulation have proposed a number of functional motifs that may contribute to the regulation of Hsp90 activity, including ATP hydrolysis and allosteric interactions. Nevertheless, molecular mechanisms that control the relationship between conformational diversity and biological functions of Hsp90 lack a detailed quantitative characterization. In this work, we integrated molecular dynamics (MD) simulations and modeling of the principal collective motions with the energy landscape models and structure-functional analyses of regulatory interactions to characterize functional dynamics of the Hsp90 molecular chaperones and formulate a unifying theoretical framework that may adequately describe and rationalize molecular principles of Hsp90 dynamics and function.We begin by providing a road-map through the manuscript and formulating main questions, computational experiments conducted and hypotheses tested. In the present work, we integrated all-atom MD simulations with modeling of principal correlated motions, the energy landscape analysis and structure-functional characterization of regulatory interactions to investigate functional dynamics and mechanisms of the Hsp90 molecular chaperones. The following specific objectives were pursued in this study: (a) to quantify molecular mechanisms by which functional dynamics and allosteric motions of Hsp90 may be connected with the probabilistic nature of the underlying energy landscape; (b) to identify and characterize functional hotspots shared by the Hsp90 chaperones that could coordinate functional dynamics and \u201cconformational selection\u201d of the functional states. We proposed that conformational dynamics and functional motions of Hsp90 may be described using the energy landscape models and principles of \u201cconformational selection\u201d (or \u201cpopulation-shift\u201d) between preexisting conformational ensembles In the first section, we discussed the results of MD simulations performed for all structural forms of Hsp90. A comparative analysis of the conformational ensembles highlighted fundamental aspects of Hsp90 dynamics that may be exploited by the chaperone to accommodate functional requirements during the ATPase cycle. In the second section we characterized functional dynamics and principal collective motions of the molecular chaperone. This analysis demonstrated that a central evolutionary conserved characteristic of Hsp90 dynamics is the presence of long-range inter-domain motions that enable allosteric signaling. We concluded that allosteric interactions may provide a mechanism for structural adaptation of Hsp90 by shifting the dynamic equilibrium between the ensembles of functional states. A switch-based conformational change is a hallmark of complex biomolecular systems that function via allosteric signaling and are often regulated by a relatively small number of functional hot spots , , The crystal structures of the full-length Hsp90 dimer from three different species revealed a similar domain architecture, yet significant differences in the global conformational flexibility and the relative domain orientation Figure 1Figure S1) that may serve as stabilizing \u201chandlers\u201d in assisting the central \u201cstrap\u201d of hydrophobic residues (residues 755\u2013765) to ensure structural integrity of the M-domain and CTD of MD trajectories. The structural distribution of the protein mobility and the cross-correlation maps of protein residue fluctuations were computed along the dominant principal component (PC) modes. This analysis identified the shapes of the low frequency modes and the protein regions subjected to correlated and/or anti-correlated motions along the selected low frequency modes.Sstructural mapping of the HtpG mobility projected along the low frequency modes revealed a heterogeneous and diffuse network of structurally stable regions distributed across all domains of the extended HtpG form , the catalytic loop in the M-domain (residues 332\u2013342) and the adjacent H10 helix (residues 343\u2013366) are among functional regions that become protected upon ATP binding The full-length mammalian Grp94 in complex with either ATP or ADP has a semi-open, V-shaped conformation of the dimer , , , The ATP-bound yeast Hsp90 is characterized by structurally constrained conformation, stabilized by a dense network of both intra-monomer and inter-monomer interactions , , , 8These findings are in accordance with insights by Wolynes and coworkers Within the energy landscape framework, long-range cooperativity of allosteric interactions during allosteric transitions may favor a combination of the population-shift and induced-fit mechanisms Allosteric signaling is often enabled by a relatively small number of evolutionary conserved and sparsely connected regulatory hotspots. In this section, we describe a computational approach to identify and characterize a network of conserved functional motifs responsible for regulation of Hsp90 dynamics. We propose that functional motifs coordinating functional dynamics and collective motions of the Hsp90 chaperone may serve as central regulators of Hsp90 activity. Structurally rigid and conformationally flexible residues may often occupy proximal positions to the hinge sites, since the regions of high and low structural stabilities could participate in binding sites We focus on the low-frequency functional motions represented by the normalized mean square fluctuation (NMSF) of the Hsp90 chaperone residues, along the two lowest frequency modes. These profiles can reflect salient features of the intrinsic protein dynamics , , According to this analysis, the NMSF profiles along the two slowest modes of HtpG motions confirmed the presence of anti-correlated motions between the NTD and CTD in the open apo-HtpG form , 10. TheInterestingly, this charged linker in Grp94 (residues 287\u2013327) was deleted in the protein construct and replaced by four glycine residues in the crystal structures In the framework of the energy landscape model, this inter-domain region may facilitate cooperative interactions and efficient allosteric communication networks in HtpG. The alterations in this region observed in Grp94 may introduce a degree of inter-domain frustration that would detrimentally affect allosteric interaction networks. These findings could rationalize several important biochemical experiments REILQD-342 in HtpG . When Hsp90 dimer forms an initial complex with two Cdc37 molecules Figure S2). According to our mechanistic model, the binding sites of these motifs may recognize the \u201cincoming\u201d co-chaperone molecules, and the Cdc37 dimer would then bind the two linker regions. The regulatory elements of these motifs may then \u201cpass\u201d the binding signal information via allosteric communication pathways and trigger switching of the thermodynamic equilibrium towards a more open and flexible ADP-bound state of Hsp90 suitable for recognition of protein kinase clients.Hence, allosterically regulated conformational equilibrium of Hsp90 and co-chaperone binding are closely associated and may be modulated via the stochastic nature of the underlying energy landscape. Based on our findings and agreement with structure-functional experiments , IV-539 containing a pivotal switch point Ile-538 in HtpG emerged as a central element of the CTD regulatory motif involved in coordinating the inter-domain communications. The evidence of an efficient molecular communication between NTD and CTD regions at the interface is of special importance given a rapidly growing interest in developing novel and specific Hsp90 inhibitors targeting allosteric C-terminal nucleotide binding site Hence, we identified universal functional motifs shared by the Hsp90 chaperones in different species that could play a universal role in coordinating functional dynamics and principal collective motions of Hsp90. These motifs may also serve as central functional regulators of Hsp90 activity, including control of ATP hydrolysis, the inter-domain communications and protein client binding. We observed that recognition sites may correspond to the conformationally mobile regions along slow modes of principal motions. Moreover, the recognition sites are often strategically positioned close to the regulatory anchor motifs containing catalytic and/or hinge residues. According to our results, functional coupling of structurally stable and conformationally mobile elements in the regulatory motifs is what may enable allosteric signaling and recognition of co-chaperones and protein clients. The central result of this study is that a small number of functional motifs may be utilized by the chaperone machinery to act collectively as central regulators of Hsp90 dynamics and activity, including the inter-domain communications, control of ATP hydrolysis, co-chaperone binding and protein client recognition. Mutations, drug targeting, and probing protein binding in these regions would allow furthering pinpointing specific residues responsible for various functions including protein binding.It becomes more apparent now that functional dynamics of Hsp90 is closely associated with the ability of the molecular chaperone to bind and control activity of numerous protein clients. During client binding, the Hsp90 chaperone can adopt equilibrium between structurally different states that is maintained even after substrate loading In this work, we identified and characterized evolutionary and functionally conserved elements of the Hsp90 chaperone that may serve as key regulators of collective motions and hubs of long-range communication networks. We propose that functional clusters corresponding to stable regions in principal collective motions define minimally frustrated anchor sites (\u201chot spots\u201d). These minimally frustrated residue clusters with optimized local interactions may be critical for regulation of allosteric signalling between distant protein regions. The proximal recognition sites (\u201csoft spots\u201d) may be functionally coupled to the anchoring regulatory residues and form networks of communicating interaction clusters. These \u201csoft spots\u201d may be formed by locally frustrated residues, whose interaction networks are energetically optimized and prone to dynamic modulation by mutations or protein client binding. Hence, allosteric signaling may involve a dynamic coupling between structurally rigid and plastic clusters of residues. A switch in state at a soft cluster upon protein client binding can shift the thermodynamic balance and activate a specific network of allosterically coupled residues. This model is consistent with the central role of regulatory nodes as \u201cdiscrete breathers\u201d or independent dynamic segments in allosteric signaling Overall, the proposed mechanistic picture of Hsp90 function is consistent with studies showing that allosteric networks orchestrating cooperative protein motions can be formed by evolutionary conserved and sparsely connected groups of residues, suggesting that rapid transmission of allosteric signals through a small network of distantly connected residue clusters may be a universal requirement encoded in the molecular chaperones and possibly other macromolecular assemblies. Our analysis has also confirmed that Hsp90 homologues sharing the same fold architecture may exhibit similar dynamical characteristics, including conservation of principal collective motions. The results support a mechanistic hypothesis according to which that the interaction networks regulating collective motions of the Hsp90 chaperone may be determined by the inherent structural architecture of the molecular chaperone. At the same time, the thermodynamics-based \u201cconformational selection\u201d of Hsp90 functional states is likely to be readily modulated by co-chaperones and protein binding partners.Targeting allosteric binding sites and interrupting protein client binding with Hsp90 can produce a broad-spectrum antitumor activity and a low risk of drug resistance due to a combinatorial blockade of multiple signaling pathways. While there has been a steady progress in structural studies of the Hsp90-NTD complexes with small molecules, much less is known about the molecular basis of allosteric Hsp90 binding with co-chaperones and protein clients. A second nucleotide-binding domain has been reported to exist in the C-terminus of Hsp90, and specific inhibitors to this domain are represented by novobiocin and the related coumarin antibiotics The results of our study could guide design of experiments for probing allosteric binding of celastrol by introducing mutations in the communicating residues from the regulatory and recognition motifs of Hsp90. Integration of computational and experimental approaches may thus facilitate experimentally-guided mapping of allosteric binding states and help to specify whether Hsp90 or its co-chaperone Cdc37 is the primary target for binding of celastrol. Recent evidence suggests that Hsp90 interacts and stabilizes a growing list of protein kinases, and Cdc37 serves as the key co-chaperone for a large portion of the yeast kinome +) and chloride (Cl\u2212) counter-ions were added to achieve charge neutrality in MD simulations at physiological concentration of 0.15 mol/L. All Na+ and Cl\u2212 ions were placed at least 8 \u00c5 away from any protein atoms and from each other. The system was subjected to initial minimization for 20,000 steps (40 ps) keeping protein backbone fixed which was followed by 20,000 steps (40 ps) of minimization without any constraints. Equilibration was done in steps by gradually increasing the system temperature in steps of 20 K starting from 10 K until 310 K and at each step 15000 steps (30 ps) equilibration was run keeping a restraint of 10 Kcal mol\u22121 \u00c5\u22122 on protein alpha carbons (C\u03b1). Thereafter the system was equilibrated for 150,000 steps (300 ps) at 310 K (NVT) and then for further 150,000 steps (300 ps) at 310 K using Langevin piston (NPT) to achieve uniform pressure. Finally the restrains were removed and the system was equilibrated for 500,000 steps (1 ns) to prepare the system for simulation. An NPT simulation was run on the equilibrated structure for 20 ns keeping the temp at 310 K and pressure at 1 bar using Langevin piston coupling algorithm. The integration time step of the simulations was set to 2.0 fs, the SHAKE algorithm was used to constrain the lengths of all chemical bonds involving hydrogen atoms at their equilibrium values and the water geometry was restrained rigid by using the SETTLE algorithm. Nonbonded van der Waals interactions were treated by using a switching function at 10 \u00c5 and reaching zero at a distance of 12 \u00c5. The particle-mesh Ewald algorithm (PME) as implied in NAMD was used to handle long range electrostatic forces.MD simulations of the Hsp90 structures (each of 20 ns duration) were performed for a closed ATP-bound conformation of yeast Hsp90 (PDB ID 2CG9) \u03b1 atoms) i and j was calculated for each of the 20 ns MD simulation trajectories: snapshots from trajectories were taken every 200 ps, overall translation and rotation were removed, and only C\u03b1 was kept for analysis.Protein flexibility was analyzed by combining the results of MD simulations with the principal component analysis of conformational ensembles To obtain collective motion coordinates that represent the overall dynamics of each trajectory, PCA was performed, in which the covariance matrix Figure S1Time-Dependent History of High Occupancy Salt Bridges. Thermal fluctuations of the salt bridges in Grp94 (A) and yeast Hsp90 (B). (A) The depicted high occupancy hydrogen bond interactions in the M-domain and CTD of Grp94 are Glu564-Lys530 (in blue), Asp573-Lys493 (in red), and Glu548-Arg660 (in green). (B) The depicted high occupancy hydrogen bond interactions in yeast Hsp90 are Glu165-Arg174 , Glu355-Lys335 , and Asp506-Lys426 .(TIF)Click here for additional data file.Figure S2Allosteric Coupling of the Regulatory and Recognition Sites in the Hsp90 Chaperone. The coordinated involvement of the inter-domain charged linker, the catalytic functional loop from the M-domain and the projecting recognition loops are shown in blue spheres (only main chain is shown). The ADP-bound Hsp90 crystal structure (PDB ID 2IOP) was used for clarity of illustration. The protein structure is shown in ribbons colored according to secondary structures.(TIF)Click here for additional data file."} +{"text": "Elevated intracranial pressure (ICP) episodes are associated with poor outcome and should be prevented. We developed models to predict these episodes 30 minutes in advance, and to predict long-term neurological outcome by using dynamic characteristics of continuous ICP and mean arterial pressure (MAP) monitoring.The Brain-IT dataset Predictions of elevated ICP episodes Figure were extDynamic data in continuous MAP and ICP monitoring allows prediction of elevated ICP. Adding information of the first 24 hours of ICP and MAP to known risk factors allows accurate prediction of neurological outcome at 6 months."} +{"text": "Whereas the use of discrete pitch intervals is characteristic of most musical traditions, the size of the intervals and the way in which they are used is culturally specific. Here we examine the hypothesis that these differences arise because of a link between the tonal characteristics of a culture's music and its speech. We tested this idea by comparing pitch intervals in the traditional music of three tone language cultures and three non-tone language cultures with pitch intervals between voiced speech segments. Changes in pitch direction occur more frequently and pitch intervals are larger in the music of tone compared to non-tone language cultures. More frequent changes in pitch direction and larger pitch intervals are also apparent in the speech of tone compared to non-tone language cultures. These observations suggest that the different tonal preferences apparent in music across cultures are closely related to the differences in the tonal characteristics of voiced speech. Tonal differences between traditional Eastern and Western music are readily heard. Explanations often refer to the use of different scales The use of pitch in speech varies greatly among languages. The most obvious example is the broad division of languages into \u201ctone\u201d and \u201cnon-tone\u201d groups Based on these differences, we asked how, if at all, differences in the use of pitch in the traditional music of tone and non-tone language speaking cultures compares with the use of pitch in speech. To address this question, we compiled databases of speech and music from several tone and non-tone language cultures. The analysis focused on two aspects of pitch dynamics: the frequency of changes in pitch direction , and the size of the pitch intervals used. These aspects were chosen because they differentiate tone and non-tone language speech and play a central role in the structure of musical melodies U\u200a=\u200a9843.5, P<0.001; U\u200a=\u200a2317, P<0.001; t\u200a=\u200a-11.4, P<0.001), whereas intervals equal to or larger than a major second occur more often . The only exception in this overall pattern is major thirds (400 cents), which are more frequent in the music of non-tone language cultures (7.7% vs. 2.3%). t\u200a=\u200a\u22125.6, P<0.001), whereas larger intervals occur more often . and three that use non-tone languages . The patterns apparent in music parallel those in speech. Thus the music of tone language cultures changes pitch direction more frequently and employs larger melodic intervals. Similarly, the speech of tone language cultures changes pitch direction more frequently and employs larger prosodic intervals. Presumably tone language speech exhibits these characteristics because the lexical meaning of each syllable in a tone language is tonally determined The only exception to this pattern is the use of major thirds. Despite the greater frequency of larger prosodic intervals (\u2265200 cents) in the speech of tone compared to non-tone languages, there are fewer melodic major thirds (400 cents) in the music of tone language cultures see . A possiIn sum, co-variation of tonal characteristics in the music and speech of the tone and non-tone language speaking cultures we examined indicates an intimate relationship between these two modes of social communication, providing a way of explaining at least some aesthetic preferences in biological terms.Monophonic folk melodies from tone and non-tone language speaking cultures, all of which could be either played on an instrument or sung, were obtained from scores and MIDI format files obtained principally from National University of Singapore and the Singapore National Library Board. The tone language database comprised 50 traditional Mandarin, 20 traditional Thai, and 20 traditional Vietnamese melodies. The non-tone language database comprised 50 traditional American, 20 traditional French, and 20 traditional German melodies. To mitigate cross-cultural contamination by modern media, all compositions pre-dated 1900, often by hundreds of years.Tone and non-tone speech samples were acquired by recording monologues read by native speakers of each of the 6 relevant languages . Each speaker read 5 emotionally neutral monologues translated into the appropriate language . Prior tThe analysis of music focused on melodic slope reversals, and melodic interval size. Melodic slope reversals were defined as any change in the direction of the pitch contour of a melody. For each melody, the number of local minima and maxima was tabulated and divided by the total number of notes; this value was multiplied by 100 to give the incidence of melodic slope reversals per 100 notes. Melodic interval size was defined as the pitch difference (in cents) between adjacent notes see . The analysis of speech focused on two aspects of pitch dynamics analogous to those examined in music: prosodic slope reversals, and prosodic interval size. Prosodic slope reversals were defined as any change in the direction of the simplified pitch contour of a speech recording Click here for additional data file.Figure S2Music analysis. (A) Musical notation of the traditional American melody \u201cHome on the range\u201d. (B) The same melody reformatted for analysis. Notes are represented by black bars with open circles marking their beginnings and endings. The length of each bar is proportional to the duration of the note. Local maxima (max) and minima (min) indicate slope reversals in the melodic pitch contour; melodic interval size (i) is the vertical distance between successive notes. Dashed lines have been added to aid visualization of the melodic pitch contour.(TIF)Click here for additional data file.Figure S3Speech analysis. (A) Recording of the sentence \u201cI applied for a job that would give me a good work experience\u201d spoken in American English (B) Fundamental frequency (F0) of the recording in (A) over time . (C) F0s in Panel (B) segmented into syllables with simplified contours. Syllables are represented by black bars with open circles marking their beginnings and endings. (D) Output of the Prosogram analysis. Local maxima (max) and minima (min) indicate slope reversals in the prosodic pitch contour; prosodic interval size (i) is the vertical distance between successive syllables. Dashed lines have been added to aid visualization of the prosodic pitch contour.(TIF)Click here for additional data file.Figure S4Interval size in the music and speech of tone and non-tone language speaking cultures sorted into descending and ascending. (A) The distributions of descending (left panel) and ascending (right panel) melodic interval sizes per melody in the tone (red) and non-tone (blue) language music databases. Unisons (0 cents) are shown in both panels. (B) The distributions of descending (left panel) and ascending (right panel) prosodic interval sizes per speaker in the tone (red) and non-tone (blue) language speech databases. The left panel inset shows the percentages of large (\u2265200 cents) vs. small (<200 cents) descending prosodic intervals . The right panel inset shows the percentages of small (<200 cents) vs. large (\u2265200 cents) ascending prosodic intervals .(TIF)Click here for additional data file.Figure S5Slope reversals in the music and speech of tone and non-tone language speaking cultures sorted by the individual languages examined. (A) Box plot showing the distribution of the number of melodic slope reversals per melody in the Mandarin, Thai, and Vietnamese melodies (red), and in the English, French, and German melodies (blue). Horizontal yellow lines indicate medians; colored boxes specify inter-quartile ranges and dashed lines the ranges without outliers. (B) Box plot of the number of prosodic slope reversals per speaker in the Mandarin, Thai, and Vietnamese speech (red) and English, French, and German speech (blue). Format is the same as in (A). Crosses indicate outliers (defined as greater/lesser than 1.5x the inter-quartile range). See (TIF)Click here for additional data file.Figure S6Interval size in the music and speech of tone and non-tone language speaking cultures sorted by the individual languages examined. (A) The distribution of absolute melodic interval sizes per melody in Mandarin, Thai, and Vietnamese melodies (red), and in the English, French, and German melodies (blue). (B) The distributions of absolute prosodic interval sizes per speaker in the Mandarin, Thai, and Vietnamese speakers (red), and the English, French, and German speakers (blue). See (TIF)Click here for additional data file.Figure S7Comparison of melodic intervals arising from pentatonic vs. heptatonic scale structure. (A) Illustration of heptatonic and pentatonic scales on piano keyboards . The pattern within a single octave repeats in each octave. (B) Histogram of the percentages of all possible intervals \u2264 500 cents arising from analysis of the scales in (A). Red bars represent pentatonic scale percentages, and blue bars heptatonic scale percentages.(TIF)Click here for additional data file.Table S1Statistics comparing the number of slope reversals in tone and non-tone language music and speech databases for each possible pair of the cultures examined. (A) Statistics for melodic slope reversals in music. (B) Statistics for prosodic slope reversals in speech; n1 and n2 refer to the sample sizes of group 1 and group 2. (DOC)Click here for additional data file.Table S2Statistics for the comparisons of interval size distributions in the tone and non-tone language music and speech databases for each possible pair of the cultures examined. (A) Statistics for melodic interval size distributions. (B) Statistics for prosodic interval size distributions; n1 and n2 refer to the sample sizes of groups 1 and 2. (DOC)Click here for additional data file.Text S1Supporting Methods and Results. This file gives an overview of the methods and results used in this manuscript.(DOC)Click here for additional data file."} +{"text": "In patients with diabetes mellitus, coronary artery disease (CAD) is a major cause of mortality and results in substantial morbidity. Non-invasive detection of CAD in diabetic patients is challenged by silent ischemia and microvascular disease. Pharmacological stress CMR perfusion imaging (CMRPI) may identify evidence of flow limiting CAD at high resolution and tissue contrast. We therefore sought to test the hypothesis that stress CMRPI can provide robust prognostication to identify diabetic patients at high risk for major adverse cardiac events (MACE).Stress CMRPI was performed on 138 consecutive patients with diabetes referred for assessment of ischemia. Rest and vasodilator stress CMRPI were performed each using a bolus of 0.1mmol/Kg of gadolinium, followed by late gadolinium enhancement (LGE) and cine imaging. Myocardial ischemia was defined by the presence of a stress induced perfusion defect, reversible at rest, in the absence of LGE in the same territory. At a median follow up of 21 months (IQR 30 months), 21 MACE (15%) had occurred (14 cardiac deaths and 7 AMIs).By univariable analysis, the presence of myocardial ischemia by CMRPI portended to 3-fold increase in MACE hazards . The absence of myocardial ischemia and LGE by CMRPI indicated a low annual rate of cardiac death (0.9%, Figure Stress CMRPI provides robust prognostication for major cardiac events in patients with diabetes. While a CMR study negative in both myocardial ischemia and LGE indentifies diabetic patients with lower event rates for MACE, the presence of myocardial ischemia by CMRPI indentifies a subgroup of diabetic patients at high risk for cardiac events."} +{"text": "Xenotropic murine leukemia virus-related virus (XMRV) infects different human cells in vitro. In this study the pathogenic effect of XMRV in lymphoid tissue was investigated by infection of human tonsil histocultures.Human tonsils were obtained from healthy donors, dissected into small blocks and cultured on top of gelfoams. Tissue blocks were left uninfected or infected with an XMRV stock obtained from a 22Rv1 cell culture supernatant in the presence or the absence of AZT or Raltegravir. Viral infection was evaluated by PCR at different times in the cells migrating out the tissue and at day 14 in tissue cells. In addition, tissue cells were immunophenotyped and the expression of XMRV envelope protein was analyzed by western blot.Cells migrating out the tissue and tissue cells were positive for XMRV and both AZT and Raltegravir blocked the detection of viral DNA. Despite the presence of XMRV DNA, tissue lysates exhibited undetectable expression of XMRV env proteins by WB. XMRV infection did not modify the percentage of CD3 , CD4 (47 vs 48), CD8 (20 vs 19), or CD19 cells (29 vs 27) neither the naive/memory cell ratio, nor immune activation markers, as evaluated by the expression of HLA-DR and CD38.XMRV could specifically infect human lymphoid tissue cells although this process does not culminate in an explicit productive infection. This infection did not result in changes of T or B cells nor in immune activation, suggesting that lymphoid tissue could latently support XMRV infection."} +{"text": "Diversity of immunoglobulins and the T cell antigen receptors is achieved via the recombination activating gene (RAG)-mediated rearrangement of variable (V), diversity (D) and joining (J) gene segments, and this underpins the efficient recognition of a seemingly limitless array of antigens. Analysis of V(D)J recombination activity is typically performed using extrachromosomal recombination substrates that are recovered from transfected cells and selected using bacterial transformation. We have developed a two-colour fluorescence-based system that simplifies detection of both deletion and inversion joining events mediated by RAG proteins.This system employs two fluorescent reporter genes that differentially mark unrearranged substrates and those that have undergone RAG-mediated deletion or inversion events. The recombination products bear the hallmarks of true V(D)J recombination and activity can be detected using fluorescence microscopy or flow cytometry. Recombination events can be detected without the need for cytotoxic selection of recombination products and the system allows analysis of recombination activity using substrates integrated into the genome.This system will be useful in the analysis and exploitation of the V(D)J recombination machinery and suggests that similar approaches could be used to replace expression of one gene with another during lymphocyte development. The antigen receptor loci of B and T lymphocytes exhibit a unique mechanism of control amongst the genes of multicellular organisms. The production of functional immunoglobulin (Ig) and T cell receptor (TCR) genes is accomplished through a tightly regulated process of recombination. Variable (V), diversity (D) and joining (J) gene segments of antigen receptor loci are assembled into a functional coding unit by a series of site-specific recombination events mediated by the products of recombination activating gene (RAG)1 and RAG2 [Escherichia coli [Assays of V(D)J recombination have relied extensively upon the transfection of extrachromosomal plasmid substrates into RAG-expressing cell lines and the recovery of these plasmids in hia coli -6. Many hia coli -5. This hia coli -9, or rehia coli -12. Furthia coli . Here, wDiscosoma and enhanced green fluorescent protein (EGFP). The system was designed such that unrearranged substrates would express the DsRed gene, whereas substrates that had undergone RAG-mediated recombination would replace DsRed expression with EGFP expression. In one construct, the EGFP open reading frame was placed on the opposite strand to DsRed and the RSS motifs arranged such that the segment containing DsRed and EGFP would be inverted by RAG-mediated recombination J recombination can occur either by deletion of the DNA between RSS motifs or by inversion of the intervening segment Figure . We geneThe inversion and deletion constructs were stably transfected into two cell lines representing different developmental stages of the B cell lineage. The cell line 300-19P is a pre-B cell line, expresses RAG1 and RAG2 and is known to catalyse V(D)J recombination, whereas WEHI231 is a B cell line in which RAG gene expression has been silenced and is therefore unable perform V(D)J recombination. The expression of RAG1 and RAG2 in these two cell lines was confirmed using reverse transcription polymerase chain reaction (RT-PCR) Figure . Pools oThese transfectants were then analysed for expression of the DsRed and EGFP reporter genes at the mRNA level. RT-PCR analysis established that expression of the EGFP gene was restricted to the RAG-expressing cell line and that EGFP transcripts could be detected in cells transfected with both the inversion and deletion construct Figure . A largeOur aim was to identify V(D)J recombination at the single cell level. We therefore analysed expression of the DsRed and EGFP molecules by fluorescence. Fluorescence microscopy of the stably transfected RAG negative WEHI231 and RAG positive 300-19P cells indicated that expression of EGFP was restricted to the 300-19P cells. Furthermore, EGFP expression was clearly detectable in both the deletion and inversion transfectants Figure . ExpressThe process of V(D)J recombination has evolved to generate a repertoire of antigen receptors. Large repertoires are generated by both combinatorial diversity and by the imprecise nature of the recombination process whereby the location of the double strand break is not fixed and nucleotides can be added or deleted from the free DNA end, generating extensive diversity in complementarity determining region (CDR)3 of the antigen receptor -16. Clonin situ in the absence of selection. Previously, assays of V(D)J activity have relied heavily upon extrachromosomal recombination substrates that are transiently transfected into cells before recovery and transformation into E. coli [In the system described here, the use of the twin fluorescent protein system distinguishes individual cells that have recombined a V(D)J recombination substrate from those which carry the substrate in a configuration representing germline gene segments. The ability to assay the absence of recombination is important when testing the effects of mutations or local chromatin environment on the recombination process. Importantly, the twin fluorescent protein system allows recombination to be detected E. coli -6. Chrom E. coli ,18 and fcis-acting sequences (RSS12 + RSS23) need to be provided to ensure correct expression of the exogenous gene (unpublished results). The ability to switch gene expression from one gene to another by harnessing endogenous recombinase activity may have practical applications in the B and T cell lineage analogous to the use of the Cre/Lox system or other exogenous recombinases [Interestingly, the twin fluorescent protein system also indicates that V(D)J recombination could be used to control the expression of exogenous genes. Just 67 bp of mbinases .The inversion and deletion plasmids for selection.Murine B cell lineage cell lines (300-19P and WEHI231) were maintained in RPMI medium supplemented with 10% foetal calf serum and 50 \u03bcM 2-mercaptoethanol. The recombination substrates were transfected into pre-B (300-19P) and B (WEHI231) cell lines by electroporation. Approximately 20 \u03bcg of linearised DNA were electroporated into 10DNA and RNA were isolated from 10 ml aliquots of culture using Genelute kits as per the manufacturers' protocols. The optical density was measured at 260 nm and the concentration of the nucleic acid calculated; 500 ng of genomic DNA was used as template in a PCR reaction. Recombination events were detected by PCR using appropriate primers using the FL1 channel of a FACS Calibur flow cytometer . The mean fluorescence intensity of EGFP expression was compared between transfected and non-transfected cells and the data expressed as a fold increase in fluorescence with non-transfected cells assigned an arbitrary value of 1.The authors declare that they have no competing interests.GPC designed the overall strategy, GPC and GBS designed the constructs, GBS performed the experiments, EADW assisted with flow cytometry and GPC and GBS wrote the paper."} +{"text": "MyoG and Myf6) than the genes encoding myogenic determination factors (Myf5 and MyoD). Additionally, the functional divergence within the myogenic determination factors or differentiation factors was also under positive selection pressure. The positive selection sites were more frequently detected from MyoG and MyoD than Myf6 and Myf5, respectively. Amino acid residues under positive selection were identified mainly in their transcription activation domains and on the surface of protein three-dimensional structures. These data suggest that the functional gain and divergence of myogenic regulatory factors were driven by distinct positive selection of their transcription activation domains, whereas the function of the DNA binding domains was conserved in evolution. Our study evaluated the mechanism of functional divergence of the transcriptional regulation factors within a family, whereby the functions of their transcription activation domains diverged under positive selection during evolution.The functional divergence of transcriptional factors is critical in the evolution of transcriptional regulation. However, the mechanism of functional divergence among these factors remains unclear. Here, we performed an evolutionary analysis for positive selection in members of the myogenic regulatory factor (MRF) gene family of vertebrates. We selected 153 complete vertebrate MRF nucleotide sequences from our analyses, which revealed substantial evidence of positive selection. Here, we show that sites under positive selection were more frequently detected and identified from the genes encoding the myogenic differentiation factors ( Recent studies in evolutionary genetics have provided several lines of evidence supporting the role of positive selection in the evolution of many genes. These studies have suggested that positive genetic selection is also the major evolutionary force in addition to neutral mutations and random genetic drift MyoD), myogenic factor 5 (Myf5), myogenin (MyoG), and Myf6 (MRF4) genes. All MRFs share a conserved basic helix-loop-helix (bHLH) domain that is required for DNA binding and dimerization with other proteins, such as E protein. All four MRFs are characterized by their capacity to convert a variety of cell lines into myocytes and to activate muscle-specific gene expression Myf5 and MyoD are myogenic determination factors and contribute to myoblast determination, which is activated in proliferating myoblasts before overt differentiation. In contrast, MyoG and Myf6 are myogenic differentiation factors that contribute to the differentiation of myoblasts and act downstream of Myf5 and MyoD, though Myf6 partly acts at both the determination and differentiation levels Myf5 and MyoD have redundant functions in myoblast determination and can compensate for the functional loss of each other, Myf5 plays a more critical role during the early determination of epaxial muscle, whereas MyoD is more critical for hypaxial muscle determination Myogenesis involves two major temporally ordered steps. First, myogenic progenitor cells (myoblasts) originate from mesenchymal precursor cells, and second, these cells then terminally differentiate into mature muscle fibers Myf5, MyoD, MyoG, and Myf6 genes were duplicated from a single invertebrate gene Caenorhabditis elegansAnthocidaris crassispinaDrosophila melanogasterCiona intestinalis, it gives rise two different transcripts of MRFs (MDFa and MDFb) as a result of alternative splicing. Moreover, in cephalochordates, the amphioxus have two MRF genes: BMD1 and BMD2MyoD in ascidians suggest that the regulation pattern of multiple MyoD genes has evolved under selective pressure before the MRF genes were duplicated into multiple copies Myf5 and MyoD genes were then duplicated from one of these two lineages, whereas MyoG and Myf6 were duplicated from the other lineage during vertebrate evolution. Therefore, the functional redundancy between Myf5 and MyoD as well as between MyoG and Myf6 might be due to their common genetic origin Genome duplication is believed to be a major genetic event that occurs during the evolution of a gene family from a single gene to multiple gene copies The mechanisms underlying the evolution of the MRF gene family during their duplication remain unclear. In particular, the evolutionary forces affecting the functional divergence of the four MRFs genes have not been fully elucidated. In this study, we investigated the mechanisms underlying the evolution of the four MRF genes with particular emphasis on the selective pressures imposed on the branches and sites of MRFs during vertebrate evolution. Our study provides several lines of evidence for the role of positive selection in the functional divergence of transcription factors.Myf5 and MyoD), but not in the myogenic differentiation factors (Myf6 and MyoG) . Two amiand MyoD .Nucleotide mutations in coding sequences are important for the evolution of gene functions. The likelihood ratio (LR) tests of site models in the CODEML program of phylogenetic inference by maximum likelihood (PAML4) Typically, the relatively short period of positive selection is usually followed by long periods of continuous negative selection MyoG lineage and myogenic differentiation factors (MyoG/Myf6) play distinct roles in myogenesis. The functional divergence between these factors was estimated using the DIVERGE 2.0 program Myf5/MyoD and MyoG/Myf6 branches, which was significantly greater than 0 (p<0.01). Thus, the functional divergence between Myf5/MyoD and MyoG/Myf6 was significant. Twenty-nine residues have a stringent threshold of a posterior ratio higher than eight. Most of these sites were located in the BASIC, MYF5 domains and C-terminus, which might be critical for the functional divergence between the myogenic determination factors (Myf5 and MyoD) and myogenic differentiation factors (Myf6 and MyoG) (Myf5/MyoD lineage (branch a in MyoG/Myf6 lineage (branch b in The myogenic determination factors (nd MyoG) . The rolnd MyoG) . Using tMyoD coding sequences tree of 53 vertebrate equences was geneequences . No siteequences . Using aequences . These rMyoD and MyoG, no branch or site under positive selection was identified in the vertebrate Myf5 gene analysis, a total of 55 positive selection sites during the divergence of MRFs were identified using the site and branch-site models of PAML4. We plotted the genetic location of positively selected sites onto the protein secondary structure and three-dimensional structure . PositivdN) and synonymous (dS) substitution rates were transcribed by a single MRF gene, which was different than lower invertebrates, whereby a single MRF ortholog was transcribed Ciona intestinalisMyf5 and MyoD evolved from one of these lineages, whereas MyoG and Myf6 (MRF4) evolved from another lineage Myf6 and MyoG (Myf5 and MyoD) and the myogenic differentiation factors (MyoG and Myf6). In addition, two amino acid regions (SXXTSPXSNCSDGM and SSLDCLSXIVXRIT) might be critical in the functional gain of the myogenic determination role in Myf5 and MyoD and differentiation factors (Myf6 and MyoG) was driven by positive selection. Positive selection sites responsible for this divergent process were identified from the BASIC, MYF5 domains and C-terminus was also under positive selective pressure. The evolution processes of MyoD in all vertebrates are driven by positive selection on the BASIC and MYF5 domains also diverged under positive selection. The positive selection on the BASIC and C-terminus were identified in the bird MyoG lineage and the teleost MyoG lineage . The MRF sequences were aligned by the program MUSCLE or ClustalW, and all gaps were eliminated by manual edition and synonymous (dS) substitution rates were calculated by the Nei-Gojobrotri (Jues-Cantor) method as implemented in the MEGA5.0 program to measure the pairwise sequence distances of the three domains among different MRFs The CODEML program in the PAML4 Three-dimensional structures of the proteins were predicted using the worldwide web following the methods of a case study using the Phyre server Myf5/MyoD) and myogenic differentiation factors (MyoG/Myf6). The Type I functional divergence was measured as the coefficient of functional divergence, \u03b8 (ranging from 0\u20131), which was calculated by model-free estimation (MFE) and maximum-likelihood estimation (MLE) under a two-state model. The value of \u03b8 represents the functional divergence The DIVERGE 2.0 program Table S1Likelihood Ratio Tests for the positive selection on all MRF genes.(XLS)Click here for additional data file.Table S2Likelihood Ratio Tests for the positive selection on each of the MRFs.(XLS)Click here for additional data file.File S1Alignment results for the 153 vertebrate MRF coding sequences.(NEXUS)Click here for additional data file.File S2Alignment results for the 53 vertebrate MyoD coding sequences.(NEXUS)Click here for additional data file.File S3Alignment results for the 43 vertebrate MyoG coding sequences.(NEXUS)Click here for additional data file.File S4Alignment results for the 19 mammalian MyoG coding sequences.(NEXUS)Click here for additional data file."} +{"text": "Dear Editor,The increasing incidence of aspergillosis emphasizes to improve the diagnostic tools. AspergilA standard isolate of Aspergillus fumigatus PTCC5009 was grown in potato dextrose broth. DNA extraction of Aspergillus fumigatus, Fusarium oxysporum PTCC5115 and Aspergillus flavus PTCC5004 as control species were done according to established methods.[4] BloodThe alignment of the three DNA sequences was performed with the program Gene Works , Selection of the primer sequences was based on a close check for sequences with matching homologies in current DNA databases (Gen Bank). By using a nested PCR technique, two pairs of o primers derived from sequences of the A. fumigatus 18s rRNA gene (GenBank No.) were chosen for PCR assays. For eachThe two mentioned primers with the highest sensitivity and species specificity of Aspergillus which amplified a fragment of 404 bp, were followed by AFU5S and AFU5AS which produced an internal fragment of 335 bp. These primer-binding sites are located in the 3' part of the 18S rRNA gene and in variable region V7-V9 (AFU7AS) or V8-V9 (AFU5AS), with no sequence overlap between the primers used in the first and second PCRs to reduce contamination problems. Comparison of clinical characteristics of the patients, and their PCR results showed that IA negative patients had an age>25, WBC count>3000 while positive patients had an age<30 and WBC count=1000-2000.Our results showed that out of 30 BMT patients, six patients had positive nested PCR results (20%). So detection of Aspergillus DNA from blood is possible and helpful in diagnosis of IA and can assist in distinguishing this disease from others . Most of"} +{"text": "We surveyed intensivists to evaluate their stated use of systemic steroids in the ICU. The efficacy of steroids in septic shock and ARDS remains uncertain and clinicians' perceptions of competing indications and contraindications may jeopardize future randomized controlled trials (RCT). Knowledge of current practice will inform the design of future RCTs addressing the efficacy of systemic steroids in septic shock and ARDS.We designed and conducted a self-administered survey of intensivists practicing in academic settings with expertise in ARDS clinical research. We generated questionnaire items in focus group sessions with content experts and refined them through a standardized process of clinical sensibility, pilot and intra-rater reliability testing. Respondents used a four-point scale to grade how frequently they would administer systemic steroids in a 14 different clinical situations and reported their opinions of 16 near absolute indications or contraindications for systemic steroids. Local research staff distributed the survey to all intensivists practicing in the 11 centres (Canada and USA) with most patients enrolled in the OSCILLATE trial.In total, 103 of 125 potential respondents returned completed surveys (response rate 82%). A majority of respondents 'almost always' prescribe systemic steroids in the setting of recent systemic steroid use and low blood pressure (93%), significant bronchospasm in a mechanically ventilated patient (93%) and vasopressor refractory septic shock (52%). A majority of respondents would 'almost never' prescribe steroids in severe community-acquired pneumonia (81%), ALI (76%) and ARDS (65%). One-half (50%) would 'almost never' prescribe steroids for severe ARDS (50%). The near absolute indications selected by a majority of respondents were 'known adrenal insufficiency' (99%) and 'suspicion of cryptogenic organizing pneumonia' (89%). The only near absolute contraindication selected by a majority of respondents was 'systemic fungal infection' (52%).Certain clinical conditions may prompt intensivists to almost always prescribe systemic steroids and reduce equipoise for future placebo-controlled trials. Moreover, this survey shows that in selected academic centres a majority of intensivists do not prescribe corticosteroids for pneumonia, ALI and ARDS."} +{"text": "Objective. The aim of this study was to identify patients with Parkinson's disease who showed loss or decrease of nocturnal blood pressure fall (nondipper patients) as a marker of autonomic dysfunction. Presence or absence of orthostatic hypotension was considered to investigate whether alterations in circadian blood pressure pattern are associated with posture-related dysregulation of blood pressure. Methods. 40 patients with Parkinson's disease underwent 24-hour blood pressure monitoring. 21 patients were diagnosed with arterial hypertension and received anti-hypertensive drugs. Nondipper patients were defined as having nocturnal decrease of mean systolic and diastolic blood pressure less than 10%. Presence or absence of orthostatic hypotension was determined by Schellong's test. Results. We identified 35 nondipper patients (88%). Nondipping was detected in 20 patients with orthostatic hypotension (95%) and in 15 patients without orthostatic hypotension (79%). 18 patients with hypertensive and 22 patients with normal blood pressure values were detected. Conclusions. In conclusion 24-hour blood pressure monitoring showed a high prevalence of nondipping in 40 patients with Parkinson's disease with and without orthostatic hypotension independent of coexisting arterial hypertension and antihypertensive treatment. 24-hour blood pressure monitoring may be useful to identify non-dipping as a marker of autonomic dysfunction in patients with Parkinson's disease. Parkinson's disease is a multisystem degeneration . Beside Involvement of the autonomic nervous system (ANS) occurs in the early stages of the disease . Cardiovascular dysautonomia, especially orthostatic hypotension, is frequently reported in Parkinson's disease .Involvement of peripheral components of the ANS can be demonstrated by MIBG scintigraphy.MIBG scintigraphy shows reduced cardiac uptake of MIBG (meta-[123I]iodobenzylguanidine) representing loss of postganglionic myocardial sympathetic nerve fibers in patients with Parkinson's disease and autonomic failure . HoweverFurther effects of autonomic cardiovascular dysfunction are demonstrated in earlier studies such as baroreceptor reflex dysfunction, alterations in circadian blood pressure regulation, and supine hypertension \u201315. FindAmbulatory blood pressure monitoring is frequently used in the diagnosis and therapy monitoring of arterial hypertension and allows an evaluation of the circadian blood pressure evaluation , 18.The aim of this study was to identify patients with Parkinson's disease who showed loss or decrease of nocturnal blood pressure fall (non dipper patients) as a potential marker of autonomic dysfunction.Presence or absence of orthostatic hypotension was considered to investigate whether alterations in circadian blood pressure pattern are associated with posture-related dysregulation of blood pressure.40 patients with Parkinson's disease underwent ambulatory 24-hour blood pressure monitoring. Parkinson's Disease was diagnosed according to the criteria of the United Kingdom Parkinson's disease Society Brain Bank . None ha20 of the patients were male, 20 were female; they were aged 41 to 82 years ; disease duration (Parkinson's disease) was 1 to 152 months (mean disease duration 49 months) . 21 patiLong-term blood pressure measurements were performed with \u201cMobilograph,\u201d an oscillometric recorder . Patients were asked to maintain their normal physical activity. Nondipper patients were defined as having nocturnal decrease of mean systolic and diastolic blood pressure less than 10%. Presence or absence of orthostatic hypotension was determined by Schellong's test ; orthostatic hypotension was defined as a minimum decrease in systolic and/or diastolic blood pressure of 20\u2009mmHg or 10\u2009mmHg, respectively, on standing at the third minute .Results are presented as mean values (\u00b1 standard deviation (SD)). A correlation analysis was performed between the presence of loss of nocturnal blood pressure fall and disease duration, age and presence of arterial hypertension/use of antihypertensive medication.Ambulatory blood pressure was recorded without interruption in all patients with a mean measurement period of 23 hours . The average number of measurements obtained during the 24-hour recording was 88% (\u00b1 11). Results of the mean diurnal arterial pressure showed 18 patients with hypertensive blood pressure values and 22 patients with normal blood pressure. Beside the 21 patients who were already diagnosed with arterial hypertension 6 patients showed hypertensive blood pressure values in ambulatory blood pressure recording; thus a total of 27 patients (68%) had arterial hypertension .We identified 35 non dipper patients (88%) among 40 examined patients with Parkinson's disease; 25 patients (63%) showed nocturnal increase of blood pressure . CorrelaAutonomic test results showed 21 patients with orthostatic hypotension. Loss of nocturnal blood pressure fall was detected in 20 patients with orthostatic hypotension (95%); this was also detected in 15 patients without orthostatic hypotension (79%). We found 11 patients with supine hypertension who were non dipper (100%) and 24 patients without supine hypertension who were non dipper (83%) .We investigated ambulatory blood pressure monitorings in patients with Parkinson's disease to evaluate the circadian blood pressure profile, especially the presence or absence of loss of nocturnal blood pressure fall (non dipper). Results of earlier studies show a variable percentage of non dipper patients , mainly Our results show that most of our examined patients with Parkinson's disease were non dipper (88%); this was even found in 79% of the patients without orthostatic hypotension. In conclusion, ambulatory blood pressure monitoring could be useful to detect autonomic dysfunction even in the early stages of Parkinson's disease when orthostatic hypotension is not present. \u03b1-adrenergic receptors due to sympathetic denervation in patients with Parkinson's disease may contribute to supine hypertension during the night due to exaggerated vasoconstriction [The alterations in the circadian blood pressure profile may be caused by impairment of the autonomic regulatory mechanisms, possibly through postural dysregulation of blood pressure as mentioned in earlier reports . This dytriction , 23, 24.Presence or absence of arterial hypertension was additionally investigated in our patients to evaluate a possible association with loss of nocturnal blood pressure fall; there was no correlation between the presence of non-dipping and the presence of arterial hypertension or use of antihypertensive medication. 27 patients were additionally diagnosed with arterial hypertension or had hypertensive blood pressure values in ambulatory blood pressure recording (68%). 24-hour blood pressure monitoring should be performed in patients with Parkinson's disease and coexisting arterial hypertension, who are treated with antihypertensive medication. For prevention of an increased prevalence of end-organ damage we propose treatment of nocturnal hypertension in patients with Parkinson's disease. Treatment with antihypertensive drugs in patients with orthostatic hypotension may be complicated by worsening of the postural blood pressure fall in the upright position in these patients and thus may cause syncopes or cerebral ischemia. Consequently, vasoactive drugs should be used carefully in patients with Parkinson's disease and autonomic dysfunction. Alternatively sleeping in a 12\u00b0 head-up tilt position may be helpful . Concerning an increased cardio\u2014and cerebrovascular risk in patients with nondipping, Corn\u00e9lissen et al. showed that\u2014compared with dipping\u2014abnormal chronobiological end points such as reduced circadian standard deviation of heart rate or elevated pulse pressure are more useful to discriminate between patients who are at a higher risk and who are not . HoweverIn conclusion 24-hour ambulatory blood pressure monitoring showed a high prevalence of non-dipping in 40 patients with Parkinson's disease with and without orthostatic hypotension independent of the coexisting arterial hypertension, and antihypertensive treatment. Our data strengthens the role of ambulatory blood pressure recording for detection of non-dipping not only in patients with orthostatic hypotension, but also in patients without orthostatic hypotension. Beside other autonomic tests 24-hour blood pressure monitoring may be helpful to support the detection of autonomic dysfunction in patients with Parkinson's disease even in the early stages of the disease."} +{"text": "There is an error in the legend for Figure 3. The legend refers to figures 3a, 3b and 3c, which is not correct. Figure legend 3 should read:Figure 3: The figures display the mean % BOLD signal change for each of the 3 tasks for each delay in the ROI. The graphs show: the medial temporal cortex (V5), the supramarginal gyrus (SMG), and superior parietal lobe (SPL), the cerebellum (CBM), primary visual cortex (V1), the frontal eye fields (FEF), supplementary eye fields (mid SEF), and dorsolateral prefrontal cortex (DLPFC). The centre of mass for the regions of interest used in the analysis are highlighted within a template brain on either side of the % signal change graph for all figures and brain coordinates are presented using the Montreal Neurological Institute (MNI). T values and significance corrected cluster level P values are also displayed for each ROI."} +{"text": "Pancoast syndrome (Pancoast\u2019s syndrome) is characterized by a malignant neoplasm of the superior sulcus of the lung (lung cancer) with destructive lesions of the thoracic inlet and involvement of the brachial plexus and cervical sympathetic nerves (stellate ganglion) which causes Horner syndrome .Following trimodality treatment for (SSTs), the 5-year survival rate has significantly improved. The objective of this study was mortality and morbitity and quality of life after the resection of superior sulcus tumours following neoadjuvant chemoradiation.Between Januar 2002 and December 2012 ; 55 consecutive patients were treated with primary radiotherapy followed by surgery or with primary excision and subsequent radiotherapy in the absence of an initial histological diagnosis.In total, 55 patients participated in this study (45 men and 10 women). The median age was 60 years (range 40\u201373), median radiation dose 45 Gy (range 40\u201360) and median follow-up 50 months (range 4\u2013101). The mortality of patients given the combined treatment was 8.6% (one death due to pulmonary embolism and one death due to myocard ischemia), and the five year survival rate was 20.6% for all patients and 37% for those who underwent complete resection without N2 disease.Stage III lung cancer, classified as Pancoast tumour according to strict, consistent criteria, is best treated by primary radiotherapy; combined treatment should be used only for patients with potentially resectable cancer without N2 disease and/or malignant invasion of the first rib."} +{"text": "Despite the increasing public health burden associated with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD), the molecular mechanisms responsible for the pathogenesis of these diseases remain unclear. The goal of this study was to comprehensively profile the lung small RNA transcriptome via next-generation sequencing, and elucidate microRNAs that might contribute to COPD and ILD pathogenesis.n = 150) or ILD (n = 149), and from normal lung tissue (n = 65). 319 lung tissue samples were sequenced via multiplexing on the Illumina HiSeq 2000 (10 samples/lane) and 45 samples were sequenced on the Illumina GAIIx (one sample per lane). Reads were trimmed using the FASTX toolkit and aligned to hg19 using Bowtie. Reads mapping to a microRNA locus were grouped into those with the canonical seed and those with an alternative seed due to variation in the 5' start position (isomiRs). Negative binomial generalized linear models were used to identify microRNAs and isomiRs differentially expressed between phenotypes. The large RNA from a subset of these samples was also sequenced using the Illumina GAIIx (one sample per lane). A network was generated by identifying all microRNA-mRNA pairs that were significantly anti-correlated <0.05) and had a predicted microRNA-binding site in the mRNA 3'UTR (TargetScan 6.0).As part of the Lung Genomics Research Consortium, we sequenced the small RNA in lung tissue samples from subjects with COPD (n = 72). 2,133 genes in the network (65%) were predicted to be regulated by at least one differentially expressed isomiR. Both the canonical form and three isomiRs of miR-338-3p were significantly downregulated in ILD. Predicted targets of the canonical form of miR-338-3p were enriched in extracellular matrix genes while the predicted targets of a miR-338-3p isomiR were enriched in the Wnt signaling pathway (P<0.001), suggesting different roles for multiple forms of this microRNA in ILD.An average of 26.3 million and 7.1 million reads were sequenced per sample using the singleplex and multiplex protocols, respectively. An average of 73% of reads per sample aligned to the human genome with one or fewer mismatches at 10 or fewer locations. 287 novel microRNA precursors were predicted using the miRDeep algorithm. One of these candidates was validated by quantitative RT-PCR and found to be expressed across a range of human tissues. The expression of 309 canonical microRNAs was significantly different between patients with disease and controls (FDR <0.05). In addition, we found that 242 isomiRs from 159 different microRNA loci were also differentially expressed (FDR <0.05). We developed a network of microRNA-mRNA interactions by integrating small RNA and large RNA sequencing data generated on the same samples (Our results demonstrate the power of deep sequencing to reveal additional complexity in the microRNA transcriptome, such as novel microRNAs and isomiRs. The disease-related patterns of microRNA expression can provide insights into the molecular pathogenesis of chronic lung diseases and novel targets for therapy."} +{"text": "O. rufipogon as a reference in the characterization. Results indicated relatively rich genetic diversity (He = 0.63-0.65) in Italian rice varieties. Further analyses revealed a close genetic relationship of the Italian traditional varieties with those from northern China, which provides strong genetic evidence for tracing the possible origin of early established rice varieties in Italy. These findings have significant implications for the rice breeding programs, in which appropriate germplasm can be selected from a given region and utilized for transferring unique genetic traits based on its genetic diversity and evolutionary relationships.The characterization of genetic divergence and relationships of a set of germplasm is essential for its efficient applications in crop breeding and understanding of the origin/evolution of crop varieties from a given geographical region. As the largest rice producing country in Europe, Italy holds rice germplasm with abundant genetic diversity. Although Italian rice varieties and the traditional ones in particular have played important roles in rice production and breeding, knowledge concerning the origin and evolution of Italian traditional varieties is still limited. To solve the puzzle of Italian rice origin, we characterized genetic divergence and relationships of 348 rice varieties from Italy and Asia based on the polymorphisms of microsatellite fingerprints. We also included common wild rice Oryza sativa L., referred to as rice hereafter) is the third largest cereal crop of the world, and provides staple foods and nutrition for nearly one half of the global population [Asian cultivated rice and 1.6 million tons of total grain production. Nearly all rice varieties grown in Italy are japonica ecotype [Italy is the largest rice production country in Europe, with about 250,000 hectares of cultivation area , although no written document about these is available. The earliest rice cultivation documented in Italy can be traced back to 1468 in the wetlands of Tuscany, near Pisa [Magnaporthe oryzae). To guarantee the continued rice cultivation that was seriously threatened by this fungal disease, new varieties were introduced from China and Japan at the beginning of 19th century. These varieties were characterized by their high yielding and resistance to rice blast. As a consequence, five Italian rice varieties were cultivated in Italy in 1872: Ostiglia, Bertone, Novarese, Francone, and Giapponese. Because of the recrudescence of blast attacks that created a new crisis for Italian rice cultivation, more rice varieties were imported from Asian countries including China, India, and Japan in 1880, which led to a substantial increase in the number of Italian rice varieties in the subsequent years. A milestone of Italian rice cultivation in history was the presence of a set of varieties grouped under the general name of \u201cChinese Originario\u201d with high yield and strong resistance to blast [The first official documentation of rice introduction to Italy is related to the Spanish Presence in the Kingdom of Naples because of the ties between the Aragon family (The Kings of Naples) and the Sforza family (Dukes of Milan) in the second half of 15 century . Rice maear Pisa . At thatRice production in Italy fluctuated significantly, depending essentially on the national and international varieties used. A number of successful varieties were bred in 1926 through the systematic selection from \u201cChinese Originario\u201d or, in a few cases, improved from old American varieties. This illustrates the importance of rice improvement in Italy relying on the introduction of alien germplasm from other countries. A number of recent studies have systematically characterized the existing Italian rice germplasm for its genetic diversity , agronomOryza rufipogon Griff.) accessions were also used as a reference. The primary objectives of this study were to (i) estimate the general genetic diversity of different historical groups of Italian rice germplasm in comparison with that from other sources; (ii) determine genetic divergence of Italian rice germplasm from that of Asian rice germplasm; and (iii) trace the possible origin of Italian rice varieties based on genetic data. The answer of these questions will facilitate the continued genetic improvement of Italian rice for the sustainable rice production in the region.To solve the \u201cpuzzles\u201d of Italian rice origin, we characterized a large set of rice germplasm from extensive sources, based on the polymorphisms of microsatellite (SSR) fingerprints at 24 loci across the rice genome. The set of germplasm is represented by 183 Italian rice varieties, including nearly all traditional and modern varieties currently available in Italy, and 165 rice varieties from Asia. In addition, ten common wild rice (Oryza sativa) from Italy and Asian countries were included in this study represented the modern Italian varieties that were improved under local genetic breeding programs. The third group included the modern Italian varieties improved under genetic breeding with rice germplasm from North America. These rice varieties covered the entire range of Italian rice cultivation regions and represented nearly all rice germplasm currently available in Italy (http://www.enterisi.it/ris_schede.jsp).A total of 348 rice varieties (is study . InformaO. rufipogon) from Guangdong and Hunan Province of southern China (Wild) were also included as a reference group the Chinese group that included varieties from different Provinces of this country (encoded as China); (2) the East Asian group included varieties from Japan and South Korea (E Asia); (3) the South Asian group included varieties from India and Sri Lanka (S Asia); and (4) the Southeast Asian group comprised of varieties from different countries in southeastern Asia (SE Asia), including Cambodia, Indonesia, Laos . In addice group . Seeds of sampled rice varieties and wild accessions were germinated in an incubator at the temperature of ~25\u00b0C. The total genomic DNA was extracted from about 1g fresh leaf tissues for each seedling, separately, at about the three-leaf stage 10 days after seed germination. The extraction followed a modified cetyltrimethyl ammonium bromide (CTAB) protocol described by . http://www.gramene.org). All the forward primers were labeled by one of the following fluorophore: FAM (blue), ROX (red), or JOE (green) . Twenty-four SSR primer pairs distributed on the two arms of each of the 12 rice chromosomes were selected for analyses from The RiceGenes Database (2+), 0.2mM each of dNTPs, 0.2\u03bcM each of SSR primers, 20 ng of genomic DNA and 0.3U of Taq polymerase . The reaction procedure was programmed as following: a denaturation period of 4 min at 94\u00b0C followed by 28 cycles of 30 s at 94\u00b0C, 30 s at 55\u00b0C and 40 s at 72\u00b0C, and then 7 min at 72\u00b0C for the final extension.The polymerase chain reaction (PCR) was performed in the \u201c2720 Thermal Cycler\u201d . Reactions were carried out in a volume of 10 \u03bcL mixture, containing 1\u00d7buffer and internal lane size standard (GeneScan\u2122 -500 LIZ) for fragment separation after denaturing at 94\u00b0C for 5 min and then cooled at 4\u00b0C. The SSR fragments were separated on a capillary electrophoresis genotyper, ABI 3130xl . The separated SSR fragments were scored as genotypic data using the software Genemapper ver. 3.7 .P); (2) the effective number of alleles per locus (Ne); (3) the observed heterozygosity (Ho); (4) Nei\u2019s unbiased genetic diversity (He) [I). In addition, the number of private alleles per rice group (Npa) was also calculated to estimate the uniqueness of each group. To determine genetic relationships among cultivated rice groups (see definition in sampling of rice germplasm) from various regions, the values of Nei\u2019s unbiased genetic similarity [The genotypic data matrix from all rice varieties and wild accessions generated by the 24 SSR primer pairs was analyzed to estimate the level of genetic diversity. The following five diversity parameters were calculated: (1) the percentage of polymorphic loci (ty (He) ; and (5)milarity were calmilarity .To illustrate the relationships of different rice groups, an UPGMA dendrogram was constructed based on the unbiased genetic similarity , using tRice germplasm included in this study with different origins presented a relatively high level of overall genetic diversity, although with a considerable degree of variation among rice groups . A totalThe Nei\u2019s unbiased genetic similarity was calcFor estimate genetic relationships of rice varieties from Italy (three groups) and Asia (four groups), a dendrogram was consindica and japonica rice varieties as shown in previous studies. The NJ tree did not suggest an obvious variation pattern of the rice varieties from different regions either. However, the Italian traditional rice varieties categorized in Italy-1 , a neighbor joining (NJ) tree was constructed based on the genetic distance of all the individual rice varieties using wild rice as an out-group . In geneindica and japonica) of rice varieties in different regions, which was considered for dividing the whole group into subgroups. The newly divided Asian regions included different Provinces of China, Southeast Asia, East Asia, and South Asia with Chinese and East Asian varieties as groups. Given the abundant genetic diversity in Italian traditional rice varieties as a reference, to estimate its genetic variation and relatedness. The total number of alleles (442) detected in these varieties was unexpectedly high, compared with those detected in a previous study where 172 Italian rice varieties and 47 introduced foreign varieties were analysed using 24 SSR loci [O. rufipogon that had a much higher Ho value . We analyzed a large set of rice germplasm including 183 varieties representing nearly all Italian rice germplasm, 165 varieties from Asia, and ten accessions of wild rice in Italian rice varieties (three groups) is comparable to that (0.59) reported in a previous study on the temporal trends of variation in Italian germplasm [The level of genetic diversity and locally improved modern rice varieties share a close affinity, and showed their close linkage with rice varieties from China and East Asia. This finding reveals that the Italian rice varieties produced based on germplasm from similar sources remain much closer genetic relationships than those with germplasm from different sources such as North American . In addition, Italian rice germplasm as a whole showed a relatively distant genetic affinity with that from South Asia and Southeast Asia, where varieties, it makeindica and japonica differentiation as suggested by other studies [Notably, the Italian traditional and locally improved rice varieties have a close genetic affinity with Chinese and East Asian varieties. When alien germplasm was introduced from North America and used as breeding materials for hybridization, the genetic relationship between Italy-3 and Chinese/East Asian rice varieties became loose due to mixture of North America rice germplasm. Obviously, the evolution and divergence of Italian rice germplasm depend essentially on the introduced exotic rice varieties from different geographical sources and the breeding methods. The NJ tree based on genetic relatedness of individual rice varieties did not show particular groupings of these varieties associated with either studies ,25, or g studies ,18. HoweUnderstanding genetic relationships of the current Italian rice germplasm has its important implications in rice breeding, through properly selecting and introducing exotic germplasm into Italian rice varieties . The intindica and japonica rice varieties [Our results generally indicated a close relationship of Italian traditional and locally bred modern varieties to Chinese varieties as a whole group. However, China is a large country with the extensive cultivation of diverse types of arieties ,23,24. IOur results based on genetic similarity analysis of Italian traditional varieties with Chinese rice germplasm represented by different Provinces evidently indicated their close genetic affinity to that from northern rice cultivation regions . These rAlthough the tales such as Marco Polo\u2019s contribution to the introduction of rice from China to Italy may never be fully confirmed, results from this study provide solid genetic evidence to confirm the close linkage between Italian and Chinese rice varieties. Rice varieties from northern China may provide genetically most accessible and useful germplasm for Italian rice breeding because of their close genetic relatedness and abundant genetic diversity, even though rice varieties from other regions in Asia can also provide unique and especially valuable germplasm that has not been represented in the Italian rice gene pool. As the largest rice production country in Europe, Italy holds important and diverse rice germplasm, which guarantees the sustainable rice production and breeding in Italy and neighboring countries. Knowledge concerning the genetic diversity, origin, and evolutionary relationships of Italian rice has important implications for its effective breeding by selecting proper exotic rice germplasm. The early introduced rice varieties such as \u201cChinese originario\u201d have played an important role in Italian rice production and breeding programs. However, the origin and evolutionary relationships of these early introduced varieties have not been properly documented. Results based on SSR fingerprints of a large set of rice germplasm from Italy and Asia in this study demonstrate a close genetic relationship between Italian and Chinese rice varieties, suggesting the possible origin of Italian traditional rice from northern China. Although the conclusion on Chinese origin of Italian traditional rice still needs supports from further studies, this finding has significant implications for Italian rice improvement by including appropriate exotic germplasm in its breeding programs.Figure S1A Neighbor-Joining (NJ) tree showing individual-based genetic relationships of 348 rice varieties analyzed in this study (see Table 1 and Table S1 for detail information), using wild rice as an out-group (root). The yellow-color highlighted entries indicate the Italian traditional varieties, and the green-color highlighted entries indicate Chinese varieties. The NJ tree was constructed based on the \u201cdistance methods\u201d installed in the software PAUP ver. 4.0 [ver. 4.0 .(PDF)Click here for additional data file.Table S1Rice germplasm included in the analysis. Accession numbers and indica (i) or japonica (j) characteristics are indicated in the parentheses following the name of a rice variety. IBS = Institute of Biodiversity Sciences of Fudan University; AAV = Shanghai Agricultural Gene Center; ENR-CRR = Ente Nazionale Risi-Centro Ricerca sul Riso; RNV = Registro Nazionale Variet\u00e0 2013.(DOC)Click here for additional data file."} +{"text": "Associations between clinical outcome and patient characteristics, such as tumour gene expression, and inherited variation (single nucleotide polymorphisms) can be difficult to reproduce between ovarian cancer cohorts. Sources of variation include the size and composition of patient cohorts and treatment, which has varied over time and can vary between countries. We have undertaken a review of treatment in patients recruited to the Australian Ovarian Cancer Study (AOCS) to determine the primary treatment patterns and levels of consistency across the cohort. Australian clinical practice guidelines for the management of women with epithelial ovarian cancer were published in 2004 and AOCSAOCS collected fresh tissue, blood, epidemiological/dietary questionnaires and clinical follow-up data for women aged 18-79 diagnosed with invasive (n=1476) and borderline (n=352) cancer, and material and data are available for research, by application. Clinical data was collected through a national research nurse network at pre-specified intervals: at diagnosis, completion of primary treatment and then at 6-monthly intervals. At the end of Feb 2011 primary treatment data was complete on 99% of eligible cases and the median follow-up time was 5.1 years.Most patients with invasive cancer underwent surgery prior to chemotherapy and a small proportion had an interval debulk or other procedure (<10%). The vast majority of women with advanced stage cancer (FIGO stage II-IV) received chemotherapy and of these, over 99% (1110/1116) received a platin-based regimen. The most common regimens were carboplatin/paclitaxel (77%) and carboplatin alone (9%), most women (86%) received 6-8 cycles and 95% of women who received adjuvant chemotherapy began treatment within 6 weeks of surgery.In conclusion, the majority of women in AOCS were treated according to national guidelines, enabling the selection of cases with uniform treatment for projects investigating associations of genomic and genetic features with clinical outcome."} +{"text": "Number of studies indicates on possible role of toxic substances in development of heart malformations during cardiogenesis. The aim of our research is studying of toxic element barium content in different biosubstrates of children with CHD.29 patients boys and 12 girls), aged from 14 days to 17 years (medium age: 26 month\u00b12 month) old with CHD were examined by the spectral analysis of toxic element barium in intraoperative (23) and autopsy (6) biopsies of endocardium (22), myocardium (26), pericardium (7), aorta (10), skin (8), subcutaneous fat (8), intercostal muscles (24), fascia (2), kidneys (5), brain (2) and hair (9) by methods of the atomic emission spectrometry in the inductively coupled plasma and atomic absorption spectrometry with electrothermal atomization.A comparative analysis of barium level in different biosubstrates demonstrated it\u2019s highest content (\u0447\u0438\u0441\u043b\u0430) in muscle tissue . Whereas in other tissues the concentration was decreased or absent. Barium content exceeded toxic level in heart tissues of 72.4% of patients. The excess degree of barium content depended on biopsy topics, namely, in aorta coarctation place, valve atresia place, septal defect its level was in two, ten or more times higher than in normal heart area or great vessel area. Dependence between the barium excess degree content in the heart tissue and severity of malformation or its combinations was also established: children with exceeding level of barium in the heart tissues had significantly more (p <0.05) of combined complex CHD.Barium affinity to the myocardium, blood vessels smooth muscles and striated skeletal muscles was confirmed. Spectrum of barium content depends on the type and severity of the defect and biopsy point. Received data indicate on possible role of barium in cardiogenesis malformation, that needs deeper investigation."} +{"text": "To study the association between house dust endotoxin levels and respiratory symptoms and allergen sensitizations in children from the urban areas (Guangzhou) and rural areas (Conghua) of Guangdong province, China.20-FEV1) and allergen skin reactions were analysed by logistic regression.Three hundred and seventeen children aged 13-14 years with self-reported respiratory symptoms and 537 healthy children were selected from 854 school-children according to their response to ISAAC standardized questionnaire. These children attended the school infirmary again to complete a detailed questionnaire and medical examinations including skin prick test (SPT) to 8 common aeroallergens, lung function test, histamine bronchial provocation test and peripheral blood eosinophil counts. House dust samples were collected from living room and mattresses of 156 of these children with the agreement of their parents . The content of endotoxin in house dust was quantified using an endpoint chromogenic kinetic limulus amoebocyte lysate test. Associations between levels of house dust allergens and endotoxin and the provocation dose producing a 20% fall in forced expiratory volume in one second , and a negative association (p<0.01) between endotoxin levels and the wheal sizes of skin response to Dermatophagoides pteronyssinus (Der. p) and Dermatophagoides farinae (Der. f).The prevalence of wheeze symptom, asthma, nasal symptoms and allergic rhinitis in the children of Guangzhou were significantly higher than the children of Conghua . Endotoxin concentrations in dust samples in homes of Conghua were significantly higher than those of Guangzhou . Logistic regression analyses showed a positive association between endotoxin levels and PDThese findings suggest that exposure to higher levels of house dust endotoxin might contribute to the lower risk of allergic sensitization in children."} +{"text": "Our objective was to evaluate if the implementation of a multifaceted intervention program for quality improvement in ICUs of nonacademic hospitals would decrease mortality and the catheter-related bloodstream infection rate (CRBSI).\u00ae); (6) 3-day workshop to share the coordinating institution quality improvement practices with directors and ICU coordinators from the 17 participant institutions; (7) 3-day nursing visits from the coordinating hospital to perform advice on care practice; (8) basic life support courses, 56 vacancies per hospital, and fundamentals of critical care support, 30 vacancies; and (9) implementation of a web-based system to collect ICU and hospital mortality, SAPS3, standardized-mortality ratio (SMR) and CRBSI after June 2011. We assessed variation of SMR and CRBSI on time using weighted linear regression, and variation of mortality on time using generalized-estimating equations.A clinical practice improvement program involving 17 Brazilian ICUs of nonacademic public hospitals located far from major economic centers under coordination of a not-for-profit private hospital with the support of Brazilian Ministry of Health. We implemented the following interventions: (1) hospital visits to assess the facilities, human resources and processes; (2) workshop with hospital directors and ICU coordinators to elaborate improvement proposals based on the initial visit findings; (3) multidisciplinary videoconference lectures every 3 weeks about critical care medicine assistance and quality issues; (4) website containing project educational material, videoconference recordings, and an evidence-based practice course; (5) subscription of an electronic clinical information resource for all participating hospitals (UpToDateThe results are presented in Table A multifaceted intervention program applied to a network of ICUs in nonacademic public hospitals reduced mortality."} +{"text": "The aim of the study was to evaluate the effect of cumulative dose of glucocorticoids during 3 years on bone mineral density (BMD) and bone turnover (BMT) measurement in children suffering from inflammatory bowel disease (IBD).In cohort of 64 children with IBD (54 children with Crohn disease and 10 with Ulcerative colitis) we measured bone mineral density at the time of diagnosis and two times during follow-up. Bone turnover /osteocalcin (OC) and C-terminal telopeptide of type I collagen (CTx)/ was measured using ELISA same time as BMD. All patient were treated by glucocorticoids with average of cumulative dose 4,46g. The obtained results were analyzed using correlation analysis.\u00b1 SD). There was no change during the treatment . The level of CTX and osteocalcin paradoxically increased, but there was no statistical significance.At the time of diagnosis we observed the total body BMD Z-score \u20131,7 (mean In our study we didn\u2019t find correlation between BMD, cumulative dose of glucocorticoids, CTX and osteocalcin during period of 3 years. Insignificant increase of bone markers was established. According to our results we can speculate that bone status impairment of bone mass is independent in children with IBD on treatment with glucocorticoids regarding to inflammation itself."} +{"text": "Population fluctuations are often driven by an interplay between intrinsic population processes and extrinsic environmental forcing. To investigate this interplay, we analyzed fluctuations in coastal phytoplankton concentration in relation to the tidal cycle. Time series of chlorophyll fluorescence, suspended particulate matter (SPM), salinity and temperature were obtained from an automated measuring platform in the southern North Sea, covering 9 years of data at a resolution of 12 to 30 minutes. Wavelet analysis showed that chlorophyll fluctuations were dominated by periodicities of 6 hours 12 min, 12 hours 25 min, 24 hours and 15 days, which correspond to the typical periodicities of tidal current speeds, the semidiurnal tidal cycle, the day-night cycle, and the spring-neap tidal cycle, respectively. During most of the year, chlorophyll and SPM fluctuated in phase with tidal current speed, indicative of alternating periods of sinking and vertical mixing of algal cells and SPM driven by the tidal cycle. Spring blooms slowly built up over several spring-neap tidal cycles, and subsequently expanded in late spring when a strong decline of the SPM concentration during neap tide enabled a temporary \u201cescape\u201d of the chlorophyll concentration from the tidal mixing regime. Our results demonstrate that the tidal cycle is a major determinant of phytoplankton fluctuations at several different time scales. These findings imply that high-resolution monitoring programs are essential to capture the natural variability of phytoplankton in coastal waters. What drives fluctuations in population abundances? In the 1920s the famous zoologist Charles Elton argued that population fluctuations of many birds and mammals are most likely due to climatic fluctuations This interplay between intrinsic population processes and external forcing is exemplified by the plankton of freshwater and marine ecosystems. Theory and experiments have shown that plankton communities can display striking fluctuations, and even chaos, under constant conditions without external forcing Environmental forcing by the tidal cycle is an important driver of phytoplankton variability in coastal waters We hypothesize that these different sources of phytoplankton variability can be distinguished by investigating the time scales of phytoplankton fluctuations. For instance, phytoplankton fluctuations with a periodicity of 6 hours 12 min indicate an alternation between entrainment of sinking phytoplankton into the surface layer during high tidal current speeds and settlement of sinking phytoplankton during tidal slacks. A periodicity of 12 hours 25 min indicates changes in phytoplankton concentration due to horizontal transport of different water masses. A 24 hour periodicity would signal environmental forcing by the day-night cycle , which would be very different from the 24 hour 50 min periodicity of a mixed semidiurnal tide. At longer time scales, the spring-neap cycle and apogee-perigee cycle generate variation in the intensity of tidal mixing that could affect phytoplankton populations.Furthermore, we hypothesize that the impact of environmental forcing on phytoplankton population dynamics will depend on the relative magnitude of intrinsic population growth versus environmental forcing. For instance, settling and resuspension of phytoplankton in shallow coastal waters depends on the vertical mixing intensity generated by wind action and tidal motion To investigate these hypotheses, we analyze phytoplankton fluctuations in a high-resolution time series obtained from an automated mooring station in the coastal North Sea. The mooring measured chlorophyll fluorescence, suspended particulate matter (SPM), nitrate, salinity, temperature and irradiance at a high temporal resolution for a period of nine years. Earlier analysis of the first year of this time series showed that the phytoplankton spring bloom was initiated by an improved light availability in spring, due to a combination of enhanced solar radiation and reduced SPM concentrations We analyzed data of mooring station Warp, located in the coastal waters of the southern North Sea near the Thames Estuary . The maihttp://www.cefas.defra.gov.uk. More information on the methodology and application of SmartBuoys can be found in Kr\u00f6ger et al. At the mooring station an automated measuring platform, called a \u2018SmartBuoy\u2019, has been deployed from 30 November 2000 onwards, as part of the United Kingdom\u2019s eutrophication monitoring program in situ Seapoint fluorometer measurements versus extracted chlorophyll concentrations in the water samples had a R2 of 0.86 when averaged over all monthly samples. Although chlorophyll fluorescence is a very convenient measurement technique, it is known that the fluorescence signal can be quenched when cells are exposed to high light Chlorophyll fluorescence was measured with a Seapoint fluorometer (Seapoint Inc.). Fluorescence data were calibrated against chlorophyll concentrations in water samples taken during monthly service visits to the mooring stations. Chlorophyll concentrations were measured by filtering known sample volumes through glass fiber filters in triplicate. Pigments were immediately extracted in 90% buffered acetone and refrigerated prior to analysis. A Turner Designs Model 10AU filter fluorometer was used to measure the fluorescence of extracted chlorophyll and phaeopigment before and after acidification as described by Tett in situ Seapoint turbidity measurements versus SPM concentrations in the water samples had a R2 of 0.72 when averaged over all monthly samples.Optical backscatter was measured with a Seapoint turbidity meter (Seapoint Inc.), and converted to SPM concentration using calibration against monthly water samples. SPM concentrations in the samples were measured by filtering known sample volumes through pre-weighed 0.4 \u00b5m polycarbonate filters and subsequent rinsing with 2\u00d750 mL ultrapure water. Filters were then dried in a desiccator at room temperature and weighed until filter weight remained constant. Calibration curves of The concentration of total oxidisable nitrogen (hereafter referred to as nitrate) was measured with a NAS-3X nutrient analyzer (EnviroTech). Salinity and temperature were measured using an FSI CT sensor . Salinity measurements were calibrated using a Guildline 8400B salinometer, which had been standardized with IAPSO standard seawater. Downwelling PAR was measured at 1 and 2 m depth using two LiCor (LI-192) underwater quantum sensors (LiCor Biosciences).The SmartBuoy measurements went through a Quality Assurance protocol within the SmartBuoy Data Management System, checking all data manually for possible sensor malfunction and biofouling. For instance, fluorescence measurements directly before each monthly service were compared with those directly after monthly service to identify signatures of biofouling. Data that looked suspect were flagged and not used in the analyses.Phytoplankton species composition at the mooring station was determined on an approximately monthly basis. Water samples (150 mL) taken at 1 m depth were preserved with 2.5 mL acidified Lugol\u2019s solution, and analyzed by inverted microscope after 12 hours of settling in a 25-mL glass chamber Tidal data were obtained from a tide gauge at the nearby coastal station Sheerness . Inspect\u00b5mol quanta m\u22122 s\u22121), to remove possible effects of non-photochemical quenching of chlorophyll fluorescence. We analyzed the hourly averaged and daily averaged time series separately to investigate variability at different time scales.Because the sampling interval of the automated measurements varied between instruments and between years, we calculated hourly averages to obtain a more uniform dataset. We also calculated daily averages of all variables, where the chlorophyll data were confined to measurements made in the dark to reduce the effect of small-scale variability caused by e.g. measurement noise, intermittent turbulence or local patchiness. We used these small intervals for the moving average filter to avoid smoothing out relevant periodicities of the tidal cycle. Third, we calculated the rates of change from the difference between the data values at time t and time t-\u0394t, where \u0394t represents a single time step of one hour or one day. Because we had log-transformed the data, this procedure effectively resulted in a time series of the relative rates of change (\u2018relative growth rates\u2019) of the measured variables, since.We analyzed the rates of change of the data instead of their concentrations, because concentrations are the result of growth and decay processes during the preceding period whereas instantaneous rates of changes better reflect the conditions at the time of measurement.We used wavelet analysis We applied wavelet coherence, an extension of wavelet analysis, to investigate the \u2018coherence\u2019 of two time series http://www.pol.ac.uk/home/research/waveletcoherence/).The statistical significance of periodicities revealed by wavelet analysis was tested by comparing the wavelet power spectrum of our time series against the 95% confidence level of wavelet power spectra generated by red noise, using an autoregressive AR1 model with the same autocorrelation coefficient as our time series Our time series contained several data gaps. Small gaps of at most one data point were filled by linear interpolation. Larger gaps could not be filled by interpolation without affecting the results. Therefore, we calculated separate wavelet power spectra for all subsets of the time series with a sufficient number of consecutive data points. Wavelet analysis can accurately detect periodicities up to \u223c25% of the length of a time series Phaeocystis). Most abundant were chain-forming diatoms , and benthic diatoms .Time series of water level, chlorophyll, SPM, nitrate, light intensity, temperature and salinity all displayed strong variability at several different time scales , S8, S9.Light intensity (PAR) at 1 m depth followed the expected seasonal pattern, but with distinct daily and biweekly variation . High liWe first analyzed the tidal data measured at station Sheerness . In lineThe spring-neap cycle is clearly visible in the time series of the tidal range . Close iWavelet analysis of the hourly-averaged chlorophyll concentration of the year 2007 reveals significant periodicities of 6 hours 12 min and 12 hours 25 min during most of the year, and an additional 24-hour periodicity in late spring and summer only . LikewisComparison with the tidal data reveals that chlorophyll concentrations consistently peaked a few hours before high tide and a few hours before low tide . The timTaking the absolute value transforms the 12 hour 25 min periodicity of the water level to a 6 hour 12 min periodicity in tidal current speed. Indeed, the rate of change in chlorophyll concentration seems to fluctuate in phase with tidal current speed .This phase relationship can be tested by wavelet coherence analysis, which displays the coherence (colors) and phase angles (arrows) between two fluctuating time series. Bold black lines delineate areas of significant coherence. Arrows pointing to the right indicate in-phase fluctuations. This confirms that the rate of change in chlorophyll concentration fluctuated in phase with tidal current speed at a significant 6-hour periodicity . In otheIn Wavelet coherence analysis shows that the chlorophyll concentration fluctuated in phase with the tidal range and SPM This sequence of events, where a strong decline of the SPM concentration in late April or early May was accompanied by a large spring bloom, was also observed in the years 2001, 2003, 2004 and 2008 , S8, S9.\u22123 of chlorophyll should contribute 100 mg m\u22123 of SPM. In view of the measured concentrations of chlorophyll and SPM in our time series, this implies that phytoplankton comprised less than 5% of the SPM concentration throughout the entire year, except during the spring bloom when phytoplankton increased to \u223c20% of total SPM. However, during the spring bloom the phytoplankton dynamics diverged from the SPM dynamics, as the decline in SPM concentration was accompanied by a rise in chlorophyll concentration. For these reasons, the in-phase fluctuations of chlorophyll and SPM cannot be explained by the assumption that SPM consisted mostly of phytoplankton particles.Our results show that short-term fluctuations of coastal phytoplankton were dominated by periodicities of 6 hours 12 min, 12 hours 25 min, and to a lesser extent 24 hours, reflecting the typical periodicities in tidal current speed, horizontal displacement of tidal waters, and the day-night cycle, respectively. Likewise, SPM also fluctuated at 6-hour and 12-hour periodicities, in phase with the chlorophyll fluctuations. One possible explanation for the in-phase fluctuations of chlorophyll and SPM could be that SPM is largely composed of phytoplankton. We therefore estimated the relative contribution of phytoplankton to SPM. Assuming a phytoplankton biomass to carbon ratio of 2.5 Cylindrotheca, Paralia, Plagiogrammopsis), which combine a benthic and pelagic life style as they commonly settle on the sediment during weak mixing but are resuspended during intense tidal mixing Instead, we hypothesize that the 6-hour periodicity and in-phase dynamics of chlorophyll and SPM are explained by alternating sinking and vertical mixing of phytoplankton and SPM driven by the tidal cycle. Phytoplankton and SPM both have a particulate nature. Hence, surface concentrations of phytoplankton and SPM will decrease simultaneously due to sedimentation during weak turbulent mixing . Conversely, phytoplankton and SPM will increase simultaneously by resuspension during periods of intense tidal mixing generated by the high current speeds between each high and low tide. This explanation is supported by the in-phase fluctuations of the chlorophyll dynamics and tidal current speed . In fact\u22121\u22121Sinking rates of single diatom cells range from near zero to 10 m dSalinity, nitrate and temperature are not subject to sedimentation and resuspension by tidal mixing. Indeed, salinity, nitrate and temperature showed only minor 6-hour periodicity, but fluctuated predominantly at a periodicity of 12 hours 25 min. This periodicity matches the typical time scale of horizontal displacement of water masses moving back and forth by tidal motion. Horizontal transport of different water masses is further confirmed by the observation that salinity fluctuated in phase with water level, while nitrate fluctuated in anti-phase with water level at a 12-hour 25-min periodicity . This reAn additional process contributing to the 12 hour 25 min periodicity might be the vertical excursions of the SmartBuoy, which moved up and down with the water level. This could be particularly relevant in waters with strong vertical gradients of the chlorophyll and SPM concentrations in the upper meters of the water column, where the measurements are made. At station Warp, however, the upper meters of the water column are well mixed . TherefoIn summer, we also found a 24-hour periodicity in chlorophyll fluorescence, but not in SPM. The 24-hour periodicity was less pronounced than the periodicities at 6 hours 12 min and 12 hours 25 min. Wavelet analysis indicates that this 24-hour periodicity is independent of the tidal periodicity, because the peak of the global power spectrum was located at 24 hours sharp rather than at 24 hours 50 min. This day-night cycle is probably caused by non-photochemical quenching of the fluorescence signal during sunny days. Alternatively, this day-night cycle might reflect diurnal variation in convective mixing driven by thermal micro-stratification during the daytime and surface cooling at night. Van Haren et al. Superimposed upon the 6-, 12- and 24-hour periodicities the chlorophyll concentration also fluctuated at a significant 15-day periodicity, in phase with the spring-neap tidal cycle. A possible explanation for the 15-day periodicity in phytoplankton abundance is that the spring-neap cycle modulated the nutrient supply. This mechanism was described by Sharples et al. 2. Hence, the chlorophyll and SPM fluctuations observed at the time scale of the spring-neap cycle will probably not represent small-scale processes restricted to the local neighborhood of station Warp, but may integrate sedimentation and resuspension over a large area. The 15-day periodicity of the SPM concentration confirms recent spectral analyses of remote sensing data of the North Sea, which indicated spring-neap variations in SPM in the East Anglia plume and Rhine plume Instead, the in-phase fluctuations of both chlorophyll and SPM with the tidal range suggest that a large fraction of the phytoplankton and SPM sinks to the sediment or deeper water layers during calm conditions at neap tide, while they are resuspended by strong tidal mixing during spring tide. Station Warp is part of a large shallow outer estuary of more than 100 kmEarlier analysis indicated that the spring bloom at our coastal mooring site is triggered by improved light conditions due to a combination of enhanced solar radiation and reduced SPM concentrations in spring What caused the conspicuous decline of the SPM concentration in mid spring? It might be induced by a strong reduction in tidal range, weakening tidal mixing and thereby enhancing sedimentation of SPM. For instance, the strong SPM decline in early May 2007 occurred when spring tide coincided with apogee of the moon, resulting in a weak spring tide . LikewisThe phytoplankton spring bloom resulted in rapid depletion of inorganic nutrients, which was followed by lower phytoplankton concentrations during the remainder of the summer. This classic pattern was also observed in the earlier study of Weston et al. Prorocentrum micans and Peridinium trochoideum) aggregated near the water surface during slack water, while they became homogeneously distributed when tidal mixing intensified. Conversely, large pelagic diatoms (Coscinodiscus spp.) relied on enhanced turbulent mixing during ebb and flood currents to prevent sinking from the photic zone. In view of these studies, it seems quite plausible that the 6-hour periodicity in chlorophyll concentration observed in our tidal system may also be accompanied by a concomitant 6-hour periodicity in phytoplankton species composition, due to species-specific differences in vertical dispersal by the tidal cycle.Temporal variation in turbulent mixing may result in temporal variation in the phytoplankton community. For instance, Huisman et al. According to the intermediate disturbance hypothesis, biodiversity will be highest in ecosystems exposed to intermediate frequencies of environmental forcing The superposition of several periodic fluctuations in chlorophyll concentration and phytoplankton species composition are a challenge for the design of marine monitoring strategies. Measurements taken at fixed time intervals that are not commensurate with the natural frequencies of the tidal cycle may introduce structural biases in monitoring data. For instance, the semidiurnal tidal cycle takes slightly longer than 12 hours. Hence, if measurements are taken, say, once every day at noon, this may erroneously suggest large changes in phytoplankton concentration over a period of several days, while these data simply represent different phases of the semidiurnal tidal cycle. Likewise, the spring-neap cycle takes slightly longer than 14 days. Hence, if a water body is sampled once every two weeks, then the data may erroneously suggest large changes in phytoplankton concentration and phytoplankton species composition over a period of several months, while these data actually reflect different phases of the spring-neap cycle. To avoid such structural biases, the temporal resolution of the measurements should be sufficiently refined to capture the periodicities in the system. In practice, this implies that chlorophyll concentrations should be measured at minimum time intervals of \u223c1 hour to capture the semidiurnal tidal cycle. Alternatively, if resources are limited, one might consider measuring less frequently but always at the same moments with respect to both the semidiurnal and spring-neap tidal cycle. In those marine ecosystems where the tidal cycle is a key determinant of chlorophyll variability, it will be difficult to make sense of phytoplankton data obtained from low-frequency sampling programs ignoring the tidal periodicities.Our results show that careful investigation of the time scales of population fluctuations in relation to environmental forcing can reveal much information on the underlying processes. We found that phytoplankton fluctuations in the southern North Sea reflect different oscillatory modes of the tidal cycle, including variation in tidal current speeds (6 hours 12 min), horizontal water motion (12 hours 25 min) and the spring-neap tidal cycle (15 days). A weaker 24-hour periodicity was also observed. During most of the year, chlorophyll and SPM concentrations fluctuated in phase with the tidal cyle, indicative of alternating periods of sedimentation and resuspension. However, phytoplankton escaped from the spring-neap tidal cycle in spring, when a strong decline in SPM concentration led to improved light conditions. Hence, fluctuations of coastal phytoplankton were strongly driven by external forcing, but intrinsic population processes took over when growth rates were high during the spring bloom. Our findings illustrate that high-resolution monitoring is required to capture this natural variability, which is considered an essential first step for the reliable detection and prediction of the long-term response of coastal phytoplankton to changing environmental conditions.Figure S1Contour plots of water density. The contour plots are based on CTD profiles taken during service visits to the Smartbuoy from August 2004 to July 2006.(TIF)Click here for additional data file.Figure S2Time series measured in 2001. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. When tidal data at station Sheerness were missing, we show the tidal range at station K13A (blue dashed line) rescaled to match the tidal range at Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S3Time series measured in 2002. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. When tidal data at station Sheerness were missing, we show the tidal range at station K13A (blue dashed line) rescaled to match the tidal range at Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S4Time series measured in 2003. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S5Time series measured in 2004. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S6Time series measured in 2005. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S7Time series measured in 2006. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. When tidal data at station Sheerness were missing, we show the tidal range at station K13A (blue dashed line) rescaled to match the tidal range at Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S8Time series measured in 2008. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. When tidal data at station Sheerness were missing, we show the tidal range at station K13A (blue dashed line) rescaled to match the tidal range at Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S9Time series measured in 2009. (A) Water level (red line) and tidal range (blue solid line) at station Sheerness. When tidal data at station Sheerness were missing, we show the tidal range at station K13A (blue dashed line) rescaled to match the tidal range at Sheerness. (B) Chlorophyll concentration (green) and SPM concentration (black). (C) Nitrate concentration (dark purple) and light intensity at 1 m depth (pink). (D) Salinity (blue) and water temperature (red). In (B-D), dots show the hourly averages and lines the daily averages.(TIF)Click here for additional data file.Figure S10Coherence between fluctuations in light attenuation and SPM on a daily time scale. (A) Time series of the light attenuation coefficient Kd (pink line) and SPM concentration (black line) using daily averaged data of spring 2005. Kd is calculated from PAR measurements at 1 m and 2 m depth. (B) Wavelet coherence spectrum of the two time series in panel A. Color coding indicates the coherence of the two time series. Arrows indicate the phase angle between fluctuations of the two time series. See the legend of (TIF)Click here for additional data file.Figure S11Coherence between fluctuations in water level, salinity and nitrate on an hourly time scale. (A) Time series of water level (red line) and salinity (blue line) on an hourly time scale during 8 days in winter 2007. (B) Wavelet coherence spectrum of the two time series in panel A. Color coding indicates the coherence of the two time series. Arrows indicate the phase angle between fluctuations of the two time series. See the legend of (TIF)Click here for additional data file.Figure S12Coherence between fluctuations in nitrate concentration, tidal range and salinity on a daily time scale. (A) Time series of nitrate concentration (thick purple line) and tidal range (thin blue line) on a daily time scale during spring of 2007. (B) Wavelet coherence spectrum of the two time series in panel A. Color coding indicates the coherence of the two time series. Arrows indicate the phase angle between fluctuations of the two time series. See the legend of (TIF)Click here for additional data file."} +{"text": "The aim of the present study was to evaluate the long term follow-up of patients enrolled in the Italian Registry of cryopirin associated periodic sindrome (CAPS).The Italian CAPS Registry started in 2004 and has currently enrolled 29 patients: 16 with Chronic Infantile Neurologic Cutaneous Articular Syndrome (CINCAs), 8 with Muckles Welles syndrome (MWS) and 5 with Familial Cold Urticaria (FCU). 16 patients were treated with Anakinra (IL-1 receptor antagonist) at 1 mg/kg/day. The Child Health Questionnaire (CHQ-PF 50) was used to assess the health related quality of life.Rapid clinical and laboratory improvement was observed in all patients, but six patients who declined treatment and experienced progressive course of the disease. All the treated patients maintained persistent remission; 5 patients required an increase of the dosage to 300 mg per day. No adverse effects were recorded except injection site reactions.Until today, 8 of the 16 patients initially treated with Anakinra have subsequently switched to Canakinumab at the initial dose of 150 mg every 8 weeks.IL-1 inhibition seems to be crucial in modifying the natural history of CAPS. Long-term follow up of patients treated with Anakinra established its efficacy and tolerability. The same evaluation will be done for Canakinumab, that appears to be equally effective but whose side effects still need to be evaluated. The bimonthly administration of Canakinumab may be certainly useful, especially in pediatric population, however its long half-life implies a tight surveilance in case of infections."} +{"text": "The objective of this study was to systematically review the medical literature for the prevalence of waterpipe tobacco use among the general and specific populations.We electronically searched MEDLINE, EMBASE, and the ISI the Web of Science. We selected studies using a two-stage duplicate and independent screening process. We included cohort studies and cross sectional studies assessing the prevalence of use of waterpipe in either the general population or a specific population of interest. Two reviewers used a standardized and pilot tested form to collect data from each eligible study using a duplicate and independent screening process. We stratified the data analysis by country and by age group. The study was not restricted to a specific context.Of a total of 38 studies, only 4 were national surveys; the rest assessed specific populations. The highest prevalence of current waterpipe smoking was among school students across countries: the United States, especially among Arab Americans (12%-15%) the Arabic Gulf region (9%-16%), Estonia (21%), and Lebanon (25%). Similarly, the prevalence of current waterpipe smoking among university students was high in the Arabic Gulf region (6%), the United Kingdom (8%), the United States (10%), Syria (15%), Lebanon (28%), and Pakistan (33%). The prevalence of current waterpipe smoking among adults was the following: Pakistan (6%), Arabic Gulf region (4%-12%), Australia (11% in Arab speaking adults), Syria (9%-12%), and Lebanon (15%). Group waterpipe smoking was high in Lebanon (5%), and Egypt (11%-15%). In Lebanon, 5%-6% pregnant women reported smoking waterpipe during pregnancy. The studies were all cross-sectional and varied by how they reported waterpipe smoking.While very few national surveys have been conducted, the prevalence of waterpipe smoking appears to be alarmingly high among school students and university students in Middle Eastern countries and among groups of Middle Eastern descent in Western countries. Tobacco smoking using waterpipe - also known as narguileh, hookah and shisha - is traditional to region of the Middle East Figure 1]. The . The 1].A recent systematic review found that waterpipe tobacco smoking was significantly associated with lung cancer, respiratory illness, low birth weight and periodontal disease . An assoRecent studies have reported relatively high prevalence rates of waterpipe tobacco smoking in Middle Eastern countries, but alsoThe primary objective of our study was to systematically review the medical literature for the prevalence of waterpipe tobacco use among the general population as well as specific populations. A secondary objective was to identify the factors associated with waterpipe tobacco use.No protocol for this review has been published.Inclusion criteria were:\u2022 Cohort studies and cross sectional studies\u2022 Assessment of the prevalence of use of waterpipe for the purpose of tobacco smoking.\u2022 The target population is either the general population or a specific population of interest such as high school students, university students, and pregnant women.\u2022 Prevalence of waterpipe smoking reported separately from the prevalence of other forms of smokingExclusion criteria were:\u2022 Convenience sampling\u2022 Sampling methodology did not clearly lead to a representative sample of the target population .\u2022 No measure of prevalenceWe electronically searched the following databases in June 2008, MEDLINE (1950 onwards), EMBASE (1980 onwards), and ISI the Web of Science using no language restrictions. The search strategy was based on related systematic review, a reviewTwo reviewers independently screened the title and abstract of identified citations for potential eligibility. They then used a standardized and pilot-tested form to independently screen the full texts of citations judged potentially eligible by at least one reviewer. They resolved disagreements by discussion or using an arbitrator.Two reviewers used a standardized and pilot-tested form to independently abstract data and resolved disagreements by discussion or using an arbitrator. Abstracted data related to the following:\u2022 Study methodology: sampling frame, sampling method, recruitment method, and administration method\u2022 Methodological quality: sample size calculation, validity of tool, pilot testing, and response rate\u2022 Population: country, target population, setting (location and time period), and numbers sampled, participated, and analyzed\u2022 Results including prevalence results of waterpipe only smoking, waterpipe smoking (regardless of other tobacco products use), cigarette smoking, and factors significantly associated with waterpipe smoking.We calculated the kappa statistic to evaluate the agreement in assessing full texts for eligibility. We stratified data analysis by country and age group. We present the results by the region of the world.Figure The studies varied by whether they reported the prevalence of waterpipe only smokers (n = 5), all waterpipe smokers (n = 37) , and by the types of measure of waterpipe smoking: ever smoker (n = 16), current smoker (n = 34), and regular smoker (n = 3). Five studies reported on group waterpipe smoking while 35 studies reported on individual smoking.Ten studies reported sample size calculation. The instruments used to measure waterpipe use were: self developed instrument with no validation reported (n = 15); self developed instrument based on previously validated instruments, with no validation of the new instrument reported (n = 7); self developed validated instrument (n = 1); previously developed instrument with no validation reported (n = 1); previously validated instrument that measured \"forms of smoked tobacco products other than cigarettes\" which the authors assumed to be waterpipe smoking (n = 1) and not reported (n = 13). Fifteen studies reported pilot testing the measurement instrument. Twenty-nine studies reported response rate that varied from 18% to 62% for online administered surveys, 46% to 100% for paper-based surveys, and 70% for telephone survey.Additional file two studies of intermediate and secondary school students in Lebanon reported 25% current and 65%-66% ever waterpipe smoking ,,46-48 th%-15%,,46Our findings are consistent with national surveys conducted by the WHO and the Global Youth Tobacco Survey (GYTS) in a number of countries and the type(s) of measure of waterpipe smoking .The authors declare that they have no competing interests.EAA contributed to drafting the protocol, designing the search strategy, developing the forms, screening, data abstraction, data analysis, and drafting of the manuscript. SKG contributed to data abstraction, data analysis, and drafting of the manuscript. RO and SA contributed to data abstraction. PAJ and RH contributed to screening. JI contributed to drafting the protocol and designing the search strategy. All authors revised the article critically for important intellectual content and approved its final version. All authors had full access to all of the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. EAA is the guarantor. All authors read and approved the final draft.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/244/prepubElectronic search strategies. Provides the detailed search strategies used in the systematic reviewClick here for fileExcluded studies. Provides a list of excluded studies and the reason for their exclusionClick here for fileTables describing the characteristics of included studies measuring waterpipe smoking prevalence by world region. Provides tables describing the characteristics of included studies measuring waterpipe smoking prevalence by world regionClick here for fileResults of the Global Youth Tobacco Survey (GYTS) and World Health Organization (WHO) surveys. Provides the prevalence of waterpipe smoking in the GYTS and WHO surveysClick here for file"} +{"text": "Superficial siderosis (SS) is a rare disease which affects people in all ages and both sexes, but three times more in men. Pathological etiology is deposition of hemosiderin (a product of the breakdown of blood) in leptomeninges, subpial layer, ependymal surface and other parts of central nervous system (CNS) and typically leads to neurological dysfunction and progressive irreversible signs and symptoms. We present a 33-year-old man with complete deafness in left ear, partial hearing loss in right ear, gait imbalance, bilateral frontotemporal throbbing headache and anosmia resulted from superficial siderosis. His familial history was noncontributory.Neurological examination revealed a good alert patient with no evidence of cognitive impairment, horizontal nystagmus in both eyes with normal saccade and pursuit, normal force and tone of muscle with decreased light touch and pin prink with stocks and gloves pattern, severe dysmetria and moderate dysdiadochokinesia, generalized hyperreflexia, bilateral equivocal plantar reflexes, and ataxic gait with impossibility to perform tandem gait.Audiogram showed bilateral, high-frequency sensorineural hearing loss especially in left side.Magnetic resonance imaging (MRI) findings are shown in 2 It was first described in 1908 by Hamill; but with no access to modern technology and MRI, the only diagnostic way was biopsy.2 Using the results of 270 reported cases of SS in articles from 1908 to 2006 revealed different causes for this disease;2 some of the most frequent ones are Idiopathic (35%), head or neck trauma (13%), AVM (9%), current CNS tumor (15%), previously resected CNS tumor (6%), post CNS surgery (non-tumor) (7%), amyloid angiopathy (3%), brachial plexus injury (6%), and other cause of subarachnoid hemorrhage (6%).5 The probable cause in the presented case was recurrent head trauma in his childhood.Superficial siderosis (SS) is a rare disease affects people in all ages and both sexes but three times more in men.4 and as the result of these depositions and central nervous system involvement; there are progressive, irreversible clinical manifestations of the disease; the most common one is sensorineural hearing loss which over a period of 1 to 12 years progresses to total deafness.2 In our case, hearing loss and loss of sense of smell began at the age of 20 and over 13 years developed to complete deafness and anosmia. The second most common sign is gait imbalance and ataxia which was also in our case a remarkable, slowly progressive problem.After breaking down of erythrocytes or red blood cells exiting in CSF and CNS, hemoglobin and iron-containing heme are released in CSF and in response to this upsurge in heme levels, Bergmann glia and microglia cells produce heme oxygenase-I enzyme which breaks down free heme into biliverdin, carbon monoxide and iron. The deposition of iron in cerebral tissue is the main pathology of superficial siderosis2 The largest review of the literature to date, reported that patients presented with bilateral SNHL (95%), ataxia (88%), and pyramidal tract signs (46%);6 cerebellar dysarthria is common and nystagmus may be present.7 But, sensory symptoms or a sensory level are uncommon.8Using the result of 270 reported cases of SS, the most common features of the disease are hearing loss (81%), ataxia (81%), myelopathy (53%), urinary problems (14%), headache (14%), anosmia (14%), diplopia (4%), bowel problems (3%), and cranial nerve palsies (2%).2 and optic or trigeminal neuropathy9 also are uncommon but have been reported. In approximately one third of the cases in an earlier literature review,2 severe recurrent headaches which were indicative for symptomatic subarachnoid hemorrhage were reported; but was infrequent in recent large studies.10Extraocular nerve palsies11The first step for early detection of SS is via MRI which shows iron depositions in affected tissues as a hypointense band, and characteristic rim of intensity appearing on the cerebellum, with no enhancement These signal loss areas in T2-weighted scans are pathognomonic for the disease, but hyperintense rime is also rarely seen.11 Iron or copper chelators and steroids are other treatments but with little success.12 In one study, using oral deferiprone (a lipid-soluble iron chelator with ability to cross the blood-brain barrier) at a dose of 30 mg/kg per day has been caused reduction of hemosiderin deposition in MRI;13 and the usage of trientine also has been reported to reduce iron concentration in CSF.14There is no successful or specific treatment for SS. With early detection of source of bleeding, the surgery may be helpful.In conclusion, according to our literature review, SS with CNS involvement is a rare disorder which formed because of the deposition of hemosiderin in leptomeninges, subpial layer, ependymal surface and other parts of CNS and leads to neurological dysfunction and progressive irreversible signs and symptoms. In our case, hearing loss and loss of sense of smell began at age of 20 and over 13 years developed to complete deafness and anosmia. There is no successful or specific treatment for SS but Iron or copper chelators and steroids are some treatments with little success."} +{"text": "Identification of the genetic differences between the two lesions may assist in identifying genes that promote the invasive phenotype. To annotate these alterations we analysed 21 breast tumours containing synchronous areas of DCIS and IDC. Tumour cells were microdissected from FFPE tissue and analysed by 300K Molecular Inversion Probe (MIP) copy number arrays. Matched IDC and DCIS showed highly similar copy number profiles (average of 83% of the genome shared). Four regions of loss and four regions of gain were recurrently affected in IDC but not in the matching DCIS. CCND1 and MYC showed increased amplitude of gain in IDC. One region of loss (17p11.2) was specific to DCIS. Our data shows that DCIS is an advanced pre-invasive tumour with genetic instability and continues to evolve in parallel with co-existing IDC. In the IDC-specific regions of genomic alteration we have identified novel loci as well as genes with previous links to breast cancer progression.Ductal carcinoma"} +{"text": "Methods. A secondary school having girl students in the age group of 12\u201315 years studying in sixth to ninth standard was selected. Serum ferritin concentration was estimated by ELISA. For assessing the cognitive function mathematics score, one multi-component test for memory, attention and verbal learning and Intelligent Quotient scores of the students were used. Results. Scholastic Performance, IQ and Scores of Mental balance, Attention & Concentration, Verbal Memory and Recognition were decreased in iron deficient girls, both anemic and non anemic as compared to the non iron deficient girls.Iron deficiency anemia is most common nutritional deficiency disorder in India and remains a formidable health challenge. Girls in the period of later school age and early adolescence are prone to develop iron deficiency. Iron deficiency leads to many non-hematological disturbances which include growth and development, depressed immune function in infants; reduces physical work capacity; decreases the cognitive function in both infants and adolescents. Present study was done to know the prevalence of iron deficiency in both the anemic and non anemic school going adolescent girls, to assess the effect of iron deficiency on cognitive functions in anemic iron deficient and non-anemic iron deficient school girls in a village school situated in central India. Iron deficiency is the third greatest global health risk after obesity and unsafe sex . Anemia Iron deficiency has both physiologic and pathologic causes. Physiologic causes relate to the greater iron demands during periods of growth and development whereas pathologic causes refer to iron losses secondary to a chronic medical condition. In general, iron deficiency results when iron demands by the body are not met by iron absorption. Thus, iron deficiency can result from inadequate intake, impaired absorption, increased requirements, and chronic blood loss.More than half of the world's undernourished population lives in India and halfIron deficiency is a systemic condition which has many non ematological consequences, which occurs in relation to its severity, like decreased physical work capacity , decreasIn present study, effort has been made to assess the effect of iron deficiency on cognitive functions in anemic iron deficient and in nonanemic iron deficient school going adolescent girls in a village school.The present study was carried out in the Department of Pathology, MGIMS, Sevagram, India from July 2007 to September 2009. Approval was obtained from the Institutional Ethics Committee for the study.A secondary school in the neighborhood, having girl students in the age group of 12\u221215 years studying in sixth to ninth standard was selected. Necessary permission was taken from the school authority and girls were explained in detail about the study in the school assembly. Participation in the screening programme was voluntary. An explanatory letter and consent form was given to all the girls. Written consent was obtained from parents or guardian for participation in the screening as all participants were minor. Participants completed a questionnaire asking for significant family, medical and menstrual history, parent education, and their dietary habits.Screening for anemia and iron deficiency was done by (1) complete blood count: done by automatic cell counter, that is, Coulter for hemoglobin concentration. (2) estimation of serum ferritin concentration was done by ELISA. For this recommended protocol by the kit used was followed. Established age adjusted values for hemoglobin and serum ferritin were used.Group I\u2014participants who were anemic (Hb < 12\u2009gm%) and iron deficient (serum ferritin less than 12\u2009\u03bcg/L).Group II\u2014participants who were nonanemic (Hb \u2265 12\u2009gm%) and iron deficient (serum ferritin less than 12\u2009\u03bcg/L).Group III\u2014participants who were nonanemic (Hb \u2265 12\u2009gm%) and noniron deficient (serum ferritin levels of 12\u2009\u03bcg/L or more).The participants after screening were divided into three groups.After dividing the participants into three groups, that is, anemic iron deficient (group I), nonanemic iron deficient (group II), and nonanemic noniron deficient (group III), for assessing the cognitive function mathematics score, one multicomponent test for memory, attention and verbal learning, and intelligent quotient (IQ) scores of the students was used.For assessment of scholastic performance, the mathematics score obtained in the final term examination was noted from the report card. The score obtained were from total 100 marks.Multicomponent test of the three groups was assessed after randomization by using PGI test\u2014(Dr. N. N. Wig & Dr. Dwarka Prasad) for testing memory attention and verbal learning Both parPGI test\u2014(Dr. N. N. Wig & Dr. Dwarka Prasad), consisted of the following ten subtests: (I) remote memory, (II) recent memory, (III) mental balance, (IV) attention and concentration, (V) delayed recall, (VI) immediate memory, and (VII) verbal retention for similar pairs, (VIII) verbal retention with dissimilar pairs, (IX) visual retention, and (X) recognition.For assessing the intelligent quotient of the girl student's, Bhatia battery performance test\u2014(Dr. C. M. Bhatia) for intelligent quotient (I.Q) was used, which includes two subtest Kohl's block design and Pass along test .Statistical analysis: the data was analyzed with SPSS (version 16) statistical software. One-way ANOVAs test 63 of 100 girl students had hemoglobin levels less than 12\u2009gm% and 37 had hemoglobin levels above 12\u2009gm%. Thus, prevalence of anemia in school going adolescent girls was 63%. The overall mean hemoglobin in the study was 11.66 \u00b1 1.27\u2009g/dL.Out of the 63 girl students who had anemia, 56 girls (56%) had Hb values between 10 and 12\u2009gm%, 5 girls (5%) had Hb values between 7 and 10\u2009gm%, and rest of the 2 girls (2%) had Hb values below 7\u2009gm%. Thus, mild anemia (Hb 10\u201312\u2009gm%) was present in 56% of the study subjects, moderate anemia (Hb 7\u201310\u2009gm%) in 5%, and severe anemia (Hb < 7\u2009gm%) was present in only 2% of the study subjects.\u03bcg/L). So the prevalence of iron deficiency was 67%.Serum ferritin was done in 100 girl students between the age group of 12\u221215 years, 67 were iron deficient between nonanemic noniron deficient (group III) and anemic iron deficient (group I), it was significant between nonanemic noniron deficient (group III) and nonanemic iron deficient (group II).The difference in mathematics score was highly significant (Multicomponent test (MCT) of verbal learning, attention, memory and IQ scores of all the three groups was assessed after randomization. Tests were administered under the guidance of trained research assistant of the Department of Psychological Medicine. The person who was assessing the tests was unaware of the group assignment.P value < 0.0001) and also the scores of mental balance differed significantly between the nonanemic noniron deficient (group III) and nonanemic iron deficient (group II). The difference in scores of attention and concentration was significant between non anemic noniron deficient (group III) and anemic iron deficient (group I). And the nonanemic iron deficient (group II) and nonanemic noniron deficient (group III) also showed statistically significant difference in scores of attention and concentration.The difference in scores of mental balance between the nonanemic noniron deficient (group III) and anemic iron deficient (group I) was significant , and on comparing the scores of Verbal Retention for Similar Pairs between the non-anemic iron deficient (group II) and non anemic non iron deficient (group III) the difference was also statistically significant .Non anemic non iron deficient (group III) and anemic iron deficient (group I) when compared for scores of Verbal Retention for Similar Pairs showed significant difference and also between the nonanemic iron deficient (group II) and nonanemic noniron deficient (group III) showed statistically significant difference .The difference in scores of verbal retention for dissimilar pairs between the anemic iron deficient (group I) and nonanemic iron deficient (group III) was statistically significant , similarly the difference in scores of recognition between the nonanemic iron deficient (group II) and nonanemic iron deficient (group III) were statistically significant .The scores of recognition between the anemic iron deficient (group I) and nonanemic iron deficient (group III) showed significant difference (For assessing the intelligent quotient (IQ) of the girl students two test, that is, Kohl's block design test and Pass along test were used. After obtaining the test quotient (TQ) from these two tests the IQ was calculated.P value < 0.0001 and also between nonanemic noniron deficient (group III) and nonanemic iron deficient (group II) .The IQ levels differed significantly between nonanemic noniron deficient (group III) and anemic iron deficient (group I) with Thus, the cognitive function scores which included the mathematics score, multicomponent test scores, and IQ scores were less in iron deficient both anemic and nonanemic groups (group I and II) than the noniron deficient nonanemic group (group III).Although all the features of cognition are important but verbal learning and attention and concentration along with memory are particularly more important for academic performance.In present study, iron deficient both anemic and nonanemic students had scored less in mathematics than the normal non iron deficient students. This is in accordance to the study done by Prestonjee wherein Multicomponent test of verbal learning, attention, and memory of all the three groups was assessed after randomization. The overall total score was less in iron deficient both anemic and nonanemic groups than noniron deficient nonanemic group.Similar findings were also seen in scores of mental balance and verbal retention for similar and dissimilar pairs. There was no difference in score of recent and remote memory, delayed and immediate recall, and visual retention subsets between iron deficient (group I and II) and noniron deficient (group III).The findings suggest that iron deficiency, even in the absence of anemia causes decrease in at least some aspect of cognitive functioning.The present findings are in accordance with the findings of a randomized trial done by Bruner et al. on nonanThe difference of mean IQ scores between iron deficient both anemic and nonanemic groups (I and II) and nonanemic noniron deficient was statistically significant.Pollitt et al. , SoemantThe findings of the present study are iron deficient school going adolescent females both anemic and nonanemic had low scholastic performance in the form of low mathematics score and low scores in verbal learning, attention, mental balance, and recognition component of multicomponent test along with low IQ scores than their noniron deficient comparers. Iron deficiency independently leads to decreased cognitive scores. Iron deficiency without anemia is the initial stage and as the iron deficiency increases anemia manifests. The cognitive scores were lowest in the iron deficient anemic (group I). In iron deficient without anemia it was slightly more than group I but much less than group III, that is, nonanemic noniron deficient subjects. Prevalence of anemia was 63% while prevalence of iron deficiency anemia in present study was 50%.There is need to initiate programme for supplementation of iron and folic acid to school going adolescent girls for the prevention of hematological and nonhematological consequences of iron deficiency with government and private organizational efforts."} +{"text": "To the Editor: Approximately 3,000 cases of tickborne encephalitis virus (TBEV) disease are registered annually in Europe , aseptic meningitis (3 cases), encephalitis (2 cases), meningoencephalitis (8 cases), and meningoencephalomyelitis (3 cases) (,During the past 20 years, TBEV has reemerged in several European areas that had been disease free (The implementation of a regional active surveillance system allows the highest sensitivity in assessing the epidemiologic features of TBEV infections, which are characterized by highly disease-endemic microfoci in areas free of the problem ("} +{"text": "Down syndrome includes learning and memory deficits in all cases, as well as many other features which vary in penetrance and expressivity in different people. While Down syndrome clearly has a genetic cause - the extra dose of genes on chromosome 21 - we do not know which genes are important for which aspects of the syndrome, which biochemical pathways are disrupted, or, generally how design therapies to ameliorate the effects of these disruptions. Recently, with new insights gained from studying mouse models of Down syndrome, specific genes and pathways are being shown to be involved in the pathogenesis of the disorder. This is opening the way for exciting new studies of potential therapeutics for aspects of Down syndrome, particularly the learning and memory deficits.Chromosome copy number aberrations, anueploidies, are common in the human population but generally lethal. However, trisomy of human chromosome 21 is compatible with life and people born with this form of aneuploidy manifest the features of Down syndrome, named after Langdon Down who was a 19 Down Syndrome (DS) is the consequence of trisomy of human chromosome 21 (Hsa21) and is the most common genetic form of intellectual disability, occurring in approximately 1 in 700 live birthsThe additional copy of Hsa21 results in elevated expression of many of the genes encoded on this chromosome, with varying expression levels in different tissuesMouse models of DS are instrumental in identifying which genes contribute to DS phenotypes, and unraveling the mechanisms by which these phenotypes ariseIn this review, we highlight recent developments in understanding how overexpression of Hsa21 genes leads to many of the features of DS. We focus on key areas including brain, heart and cancer, as these are currently the most developed in our understanding of the molecular pathogenesis of DS.People with DS have learning and memory problems and exhibit differences in brain structure compared to the euploid populationdual-specificity tyrosine- (Y)-phosphorylation-regulated kinase 1A (Dyrk1A), potassium inwardly-rectifying channel, subfamily J, member 6 Gene (Girk2) and single-minded homologue 2 (Sim2), cause alterations in dendritic spine morphology and deficits in some behavioural testsAbcg1-U2af1) found on the Hsa21 sub-telomeric region in Ts1Yah mice and SIM2dopey family member 2 (DOPEY2)Down syndrome cell adhesion molecule (DSCAM)The over-expression of a number of Hsa21 genes has been implicated in learning and memory deficits in single gene transgenic mouse models, suggesting that trisomy of these genes may contribute to learning disability in DS individuals. These genes include Fig.1), suggesting that this trisomic segment contains the causal dosage-sensitive genes for these detrimental developmental phenotypesNeurodevelopment is known to be altered in people with DS. Already by mid-gestation the brains of fetuses with DS are smaller than those which do not have the condition. Cerebellar granule cells in Ts65Dn mice have reduced proliferation rates and elongation of the cell cycle length which could potentially result in a decrease in brain massElevated rates of neuronal apoptosis related to oxidative stress have been reported in DSRecently, it was proposed that DYRK1A contributes to DS neural phenotypes, such as impaired dendritic growth, by disturbing neuron-restrictive silencer factor (REST/NRSF) levelsThis is a relatively new area of research in DS that is rapidly gaining momentum, and which arises from experiments carried out in mouse models in which behavioural, neurophysiological and cellular biology changes can be quantitatively assessed during development and ageing, and then modified through pharmacological intervention.Several pharmacological interventions to enhance cognition in people with DS have been suggested, based upon efficacy in the Ts65Dn mouse occurs in people with DS, with 30-70% of DS individuals developing dementia by the age of 60APPAPP expression is also linked to enlargement of early endosomesdap160/ITSN1 (intersectin1), synj/SYNJ1 and nla/RCAN1 (runt-related tremscripthon factor 1), results in abnormal synaptic morphology and impaired vesicle recyclingNeurodegenerative phenotypes have also been observed in animal models of DSOther Hsa21 trisomic genes may also contribute to AD through different mechanisms. DYRK1A, an Hsa21 encoded kinase, phosphorylates Tau at a key priming site which may mediate its AD-related hyperphosphorylation in people with DSSix percent of children and adolescents with DS have epileptic seizuresPeople with DS have been reported to experience disturbed sleeping patterns. Studies of circadian activity in the Ts65Dn mouse model have reported conflicting results of both intactGATA binding protein 1 (GATA1) gene resulting in the synthesis of a truncated GATA1 protein termed GATA1sv-ets erythroblastosis virus E26 oncogene homolog (ERG), is required for development of the myeloproliferation defect in the Ts65Dn modelrunt-related transcription factor 1 (RUNX1) has also been proposed to regulate hematopoiesis via the phosphoinositide 3 (PI3)-kinase/AKT pathwayChildren with DS have a greatly elevated risk of developing the otherwise very rare transient myeloproliferative disorder (TMD), as well as acute megakaryocytic leukemia (AMKL) and acute lymphoblastic leukemia (ALL)Despite perturbations of hematopoietic development in the Ts1Cje, Ts65Dn and Tc1 models of DS, these mice do not develop leukaemia, even when the trisomic models also express disease-associated GATA1 mutationsmin, with mouse models of DS resulted in reduced formation of tumors, dependent on the trisomy of the Hsa21-encoded ETS2 generegulator of calcineurin (RCAN1), was shown to be sufficient to suppress tumour growth by attenuating angiogenesis via the regulation of vascular endothelial growth factor (VEGF) signalingRcan1 did not completely abrogate the effect of trisomy on tumour formation, suggesting that other Hsa21 genes also contribute to this phenotypeAlthough DS is associated with a predisposition to leukemia, people with DS have a reduced risk of developing most solid tumourscysteine-rich with EGF-like domains 1(CRELD1), a non-Hsa21 gene, contribute to the occurrence of AVSD in DSDSCAM- ZNF295 (zinc finger protein 295)] of Hsa21 may be sufficient for the development of CHDCongenital heart defects (CHD) are prevalent in 40% of children with DS and over 50% of all atrioventricular septal heart defects (AVSDs) in infancy are attributed to trisomy Hsa21DS is complex disorder and dissecting the genetic and molecular processes underlying the syndrome requires many different complementary approaches, including the study of human data and mouse and other model organisms. However, several recent breakthroughs have increased our understanding of the effects of Hsa21 trisomy. Combining information from studies of people with DS with the power of mouse models of trisomy has enabled genetic associations to be tested and continues to lead to the identification of genes that cause DS-associated pathology. Significant advances in basic research have been instrumental in determining the molecular mechanisms underlying these phenotypes leading to useful therapeutic interventions. However, many aspects of DS crucial to the health and well-being of people with the condition remain to be investigated and require study at all levels."} +{"text": "Atypical Odontalgia (AO) is a term applied to a continuous pain in the teeth or in the tooth socket after extraction in the absence of any identifiable dental cause, under the International Classification of Headache Disorders (ICHD) and somatosensory abnormalities are common features in these patients, where Quantitative Sensory Testing (QST) are helpful tools to evaluate these cases.The aim of the pilot study was to determine the effect of topical application of anesthetic cream in quantitative sensory testing (QST) findings of AO patients.Methods Ten (7 women and 3 men) consecutive AO patients with mean pain duration of 2.7 years . QST was performed in all patients at baseline and 3 minutes after topical application of anesthetic cream . QST included tests of mechanical detection threshold (MDT) and mechanical pain threshold (MPT) with von Frey monofilaments, dynamic mechanical allodynia with cotton swab (DMA1) and with toothbrush (DMA2), heat pain thermal detection (HPD), cold pain thermal detection (CPD), temporal summation (WUR) and controlled pain modulation (CPM). The present pain intensity was also recorded with visual analogue scale (VAS). Results were analyzed with non-parametric Wilcoxon test with significance level of 5%.QST mean values showed no differences after topical application of anesthetic cream, except for DMA2 (p=0.02) and WUR (p=0.02). Moreover mean pain in visual analogue scale relieved from 6,03 to 2,12 .In this pilot study significant changes in intraoral somatosensory function were observed in AO after topical application of anesthetic cream for dynamic mechanical allodynia, associated to a reduction of pain intensity. These results may reflect peripheral and central sensitization of trigeminal pathways.There were no conficts of interest in the performance of this study."} +{"text": "A suitable approach to select cancer stem cells (CSC), the black seed of melanomas would enable their characterization and elimination.Cancerous tissues from primary and metastatic lesions of patients with malignant melanomas (n=150) were investigated by cell cultures and molecular genetics. Double labelled cells were sorted by BD FACSAvia Sorter. Gene expression analysis by Real Time PCR and RNA microarray (Agilent) has been performed (n=48).90% of the cell cultures grew and cancer initiating cells could be IF FACS sorted . Colocalisation of unique GD3 sialilated glycosphingolipids and antiCD20 binding was proved. Characteristic growth pattern, spheroid forming, CSC markers was observed Figure . We founUnique GD3 sialilated glycosphingolipids with colocalised CD20 proved to be selection markers for CSC in metastatic melanomas. Our strategy paves the way for detection and characterization of cancer stem cells and provides material for therapeutic developments to eliminate the black seeds of melanomas."} +{"text": "Journal of Studies on Alcohol and Drugs (4), Alcoholism: Clinical and Experimental Research (3), and Addictive Behaviors (3). The authors who published most frequently on BI efficacy were \"Carey KB,\u201d \"Fleming MF,\u201d \"Floyd RL,\u201d \u201cMartens MP,\u201d \"Nilsen P,\u201d \"Saitz R,\" and \"Shang G,\u201d with two publications each. The quantitative approach was prevalent among studies, with randomized controlled trials the most frequent (35). The BIs were conducted mainly in clinical and health-services settings (18). However, interventions were also conducted via the Internet (5) and by telephone (4). Regarding the study population, 22 articles addressed BI for men and women, 14 addressed BI for women, and 9 addressed BI for pregnant women. The efficacy of BI in the reduction of alcohol consumption was confirmed in most research, but some studies showed a reduction only in men. Further specific research using a study population solely comprised of women is deemed necessary.The aim of this study was to systematically review the efficacy of brief intervention (BI) in reducing alcohol use in women. We performed an electronic search across all databases using Thomson Reuters (formerly ISI) Web of Knowledge to identify multidisciplinary content. The term \"brief intervention\" was associated with the words \"alcohol\" and \"women.\" We selected studies published between 2006-2010. Of the 95 studies found, 52 were excluded because they were presented at meetings or did not focus specifically on the subject of interest. Forty-three articles with the central theme of realization and/or evaluation of BI efficacy were included in the analysis. Abstracts of these papers underwent content analysis. The year 2007 had the most publications (13) as did the following journals:"} +{"text": "Cluster headache (CH) is an extremely severe and debilitating trigemino-autonomic pain syndrome.About 10% of patients with CH manifest a chronic form CH (CCH). Extracts of Boswellia serrata have been clinically studied for the treatment of many inflammatory conditions such as osteoarthritis and rheumatoid arthritis (3). The resin from Boswellia Serrata contains a number of biological actives called pentacyclic triterpene acids, which give the extract its anti-inflammatory and analgesic properties, with boswellic acid the major active ingredient (4). These acids have been demonstrated to interfere with the body\u2019s natural inflammatory response by inhibiting cytokines and leukocyte activity. The present study aims to evaluate the long-term efficacy of Boswellia Serrata on headaches and disturbed sleep in patients with CCH.In an open-label study, 4 patients with CCH and disturbed sleep received oral Boswellia Serrata.The effects were long-lasting in 3 patients (mean 15 months) and transient (6 months) in one patient. The rapid improvement of nocturnal pain within weeks is similar to the analgetic effect observed in recent trials using Boswellia Serrata in cancer pain The mechanisms of how Boswellia Serrata reduces pain in CCH remain unclear. Boswellic acids, constituents of Boswellia extract have subsequently been identified as selective redox independent noncompetitive inhibitors of both 5-lipoxygenase, the key enzyme in leukotriene biosynthesis and human leukocyte elastase. Proinflammatory cytokines, such as leukotrienes, are known to play a role in the pathophysiology of CH. This study provides Class IV evidence that oral Boswellia Serrata reduces the intensity and frequency of headaches in patients with CCH.None"} +{"text": "Reliable measurement of esophageal pressure is a prerequisite for analysis of respiratory system mechanics in spontaneous breathing patients. For that purpose, various types of balloon catheters exist that differ in material, size and shape. In physical models we studied the quality of pressure measurement via six different balloon catheters, three of them containing a second balloon for measurement of gastric pressure.2O) at different levels of superimposed pressure.Nine balloons of six esophageal catheters were investigated in three conditions: measurement of balloon pressure during initial inflations immediately after unpacking; measurement of static pressures at different filling volumes; and compliance estimation in physical models (27, 54, 90 ml/cmH2O if the balloon was filled appropriately. Overfilling of the balloon resulted in larger errors only in two catheters. Compliance estimations resulted in errors below 1 ml/ cmH2O. Superimposed pressure had no relevant effect on compliance estimation.During the initial inflation most catheters showed pressure artifacts resulting from material adhesion. Those artifacts disappeared during following inflations. Static pressure measurements could be performed with an error below 1 cmHThe reliability of pressure measurements and also of compliance estimation via the tested catheters is high. Only in two catheters was the filling volume a critical point for a precise measurement of pressure or for estimation of compliance. Immediately after unpacking, adhesion of the balloon material might prevent reliable pressure measurement, therefore before the first measurement overfilling of the balloon and retention of the excess gas seems strongly recommended."} +{"text": "Evaluate the effect of myocardial scar burden, scar location, and scar transmurality on response to cardiac resynchronization therapy (CRT)not respond to cardiac resynchronization therapy (CRT). Results from these studies have varied on the importance of scar location, transmurality, and burden on response to CRT. We analyzed cardiac MRI in patients undergoing CRT from 4 centers (two in Europe and two in the US), and hypothesized that the presence of transmural scar in the posterolateral wall (the most frequent site of left ventricular lead placement in CRT) would preclude positive response to CRT.Several recent single center studies have used late Gadolinium enhancement (LGE) MRI to predict which patients would likely Cardiac MRI was performed according to standard methods and included at a minimum, cine imaging and LGE imaging using a Gadolinium-based contrast agent. All patients met current criteria for CRT . Sixty (60) patients from 4 centers were analyzed, and any patient with infarct enhancement on LGE by visual inspection was processed into an LGE bullseye map following AHA guidelines. Total scar burden (as % of LV mass) as well as the presence of transmural scar in the posterolateral or septal segments were assessed. 48% of patients (29/60) patients had LGE and 59% of those (17/29) had transmural scar in at least one AHA segment. Positive response was assessed at 6 months both by clinical and echocardiographic (reduction of LVESV by 15%) parameters.posterolateral scar responded by clinical criteria, and only one patient with posterolateral scar responded by echocardiographic criteria . The negative predictive value for the presence of transmural septal scar or total scar burden >15% were lower (NPV = 64-67%).None of the patients with transmural non-response to CRT.The presence of transmural posterolateral scar by LGE is predictive of"} +{"text": "The primary endpoint of the model was the probability of tumor extinction following BCG induction therapy in patients with high risk for tumor recurrence. We theoretically demonstrate that extending the duration between the resection and the first BCG instillation negatively influences treatment outcome. Simulations of higher BCG doses and longer indwelling times both improved the probability of tumor extinction. A remarkable finding was that an inter-instillation interval two times longer than the seven-day interval used in the current standard of care would substantially improve treatment outcome. We provide insight into relevant clinical questions using a novel mathematical model of BCG immunotherapy. Our model predicts an altered regimen that may decrease side effects of treatment while improving response to therapy.Intravesical Bacillus Calmette Gu\u00e9rin (BCG) immunotherapy is considered the standard of care for treatment of non-muscle invasive bladder cancer; however the treatment parameters were established empirically. In order to evaluate potential optimization of clinical parameters of BCG induction therapy, we constructed and queried a new mathematical model. Specifically, we assessed the impact of (1) duration between resection and the first instillation; (2) BCG dose; (3) indwelling time; and (4) treatment interval of induction therapy \u2013 using cure rate as the primary endpoint. Based on available clinical and Adjuvant treatment of non-muscle invasive bladder cancer (NMIBC) using intravesical Bacillus Calmette-Gu\u00e9rin (BCG) after transurethral resection was established empirically almost 40 years ago in vitro experimental data to construct and parameterize a new stochastic mathematical model describing the interactions between BCG, the immune system, and tumor cells with the primary endpoint being the probability of tumor extinction. We did not aim for precise quantitative results but rather for a robust qualitative understanding that would remain valid for future models that could integrate increasing levels of detail. Herein, we assessed the impact of: (1) varying the time from resection to BCG instillation, (2) modulating the BCG dose used during intravesical instillation, (3) the indwelling time of BCG, and (4) the inter-instillation interval.Using a refined mathematical model that includes the adaptive effector functions of the immune system, we address several clinical parameters in order to learn about their impact for an optimal protocol of successful BCG immunotherapy. Specifically, we integrated available clinical and Although all parameters influenced treatment outcome, the most surprising result concerned the impact of the inter-instillation interval where simulations suggested that an interval two times longer than the seven-day interval used in the current standard of care, would substantially improve treatment outcome. Our study provides useful insight and testable hypotheses that could lead to improved management in NMIBC.Our mathematical model makes assumptions about the interactions triggered by BCG instillations and simulates the dynamics of populations of cells. Prior to initiation of BCG therapy, three cell populations are present: healthy urothelial tissue, tumor and innate immune cells. The interactions between these cell populations are negligible. The processes that take place for each of these cell populations before therapy are cell migration and/or local proliferation and death varying the time from resection to BCG instillation, (2) modulating the BCG dose used during intravesical instillation, (3) the indwelling time of BCG, and (4) the inter-instillation interval. Each probability of tumor extinction was calculated by running 1,000 stochastic simulations, such that it's resulting 95% confidence interval became reasonably small. The computer code was also employed in uncertainty and sensitivity analyses for assessing the robustness of our results . Again, we find that greater exposure of the bladder mucosa to BCG results in an increased probability of tumor extinction Click here for additional data file.Figure S2Simulation of logistic tumor growth, resection and tumor re-growth. The horizontal dashed line represents the approximate size of the tumor when the tumor is visible on the bladder wall.(TIFF)Click here for additional data file.Figure S3Simulation of population dynamics of cells during and after a six-week course of intravesical BCG therapy. BCG (panel A), tumor cells (panel B), BCG-associated tumor cells (panel C), BCG-associated tissue cells (panel D), innate effector cells (panel E), adaptive effector cells (panel F). Note the modeling of the prime/boost response of the innate and adapted immune system occurring after the third instillation .(TIFF)Click here for additional data file.Figure S4Sensitivity analyses forandof the main text.A. Sensitivity analysis of Ea\u03bc. The blue, black . The black \u200a=\u200a106, 105, 104 and 103 tumor cells. The model has been re-calibrated for each value of T(0), accordingly. These numerics suggest that our prediction of improved therapeutic outcome by a two-week inter-instillation interval is robust. C. Sensitivity analysis of T (0) \u200a=\u200a106 and 103 tumor cells, respectively.(TIFF)Click here for additional data file.Table S1State variables of the model along with their biological description. The state variables represent counts of various cell types involved in the interactions between the immune system, tumor cells and BCG.(TIFF)Click here for additional data file.Table S2Stochastic processes and their corresponding rates.(TIFF)Click here for additional data file.Table S3Parameters of the model.(TIFF)Click here for additional data file.Text S1Detailed description and numerical analysis of the stochastic mathematical model.(PDF)Click here for additional data file."} +{"text": "Because animals can transmit some diseases to people, it is wise to be cautious around animals that carry these diseases. But how do you know which animals are carrying disease? Sometimes they appear perfectly healthy. A study of 57 apparently healthy show pigs at a 2009 US state fair found that almost 20% were carrying influenza virus and at least 4 were carrying the 2009 pandemic virus. Of concern is the possibility that different types of influenza virus\u2014pandemic, swine, avian\u2014could combine in pigs and emerge as new viruses that then spread to humans. Swine workers, veterinarians, and other persons with pig contact may be at high risk for infection with pig influenza and should receive seasonal influenza vaccines, use personal protective equipment when working with healthy pigs, and limit their contact with sick pigs. Regular monitoring of influenza virus among pigs and testing of sick persons who have been exposed to pigs are needed. Within 5 months after the earliest detection of human influenza A(H1N1)pdm09 virus, we found molecular and culture evidence of the virus in healthy US show pigs. The mixing of humans and pigs at swine shows possibly could further the geographic and cross-species spread of influenza A viruses. Cross-species infections with influenza A viruses readily occur between humans and pigs. Pigs often have been infected by human epidemic viruses and South Dakota (2009). Exhibitors were eligible for the study if they reported working with pigs at least 1 cumulative hour per week and had no current immunocompromising condition. Enrolled participants completed a questionnaire and permitted collection of nasal swab specimens from their show pigs. Before data were collected, multiple institutional review boards, the Institutional Animal Care and Use Committee of the University of Minnesota and the University of Iowa, and state fair officials approved the study.After acquiring informed consent, we recruited persons t) values <35 were considered positive for influenza Avirus; specimens with Ct values of 35 to <40 were suspected to be positive; and specimens with Ct values >40 were considered negative. In a blinded fashion, aliquots of swab specimens from pigs were shared with the Minnesota Veterinary Diagnostic Laboratory , where rRT-PCRs for matrix, hemagglutinin (HA), and neuraminidase (NA) genes were performed. Specimens were then shared with the National Veterinary Services Laboratory and later with CDC for further molecular and sequencing studies.We used the Centers for Disease Control and Prevention real-time reverse transcription PCR (rRT-PCR) (http://blast.ncbi.nlm.nih.gov).Positive and suspected-positive rRT-PCR specimens were cultured in shell vials on MDCK cells by using standard techniques. Sequence-based analyses of the influenza A virus isolates were performed by the CDC influenza division, using full or partial genome sequencing approaches for all 8 gene segments. Sequences were compared by using BLASTn alignment search techniques (<1 year of pig exposure (Questionnaires were completed by 121 (98%) participants. Participants were predominantly male (71%), and their median age was 34.9 years (range 9\u201375 years); 24% of participants were <18 years of age. Some pig exhibitors were children with exposure ; others Nasal swab specimens were collected from a total of 149 pigs . Almost all (97%) swabbed pigs were <1 year of age, and 40% were female. All pigs were observed to be healthy by a veterinarian before they were permitted to enter the show.In 2008, nasal swab specimens from show pigs showed no molecular or viral culture evidence of influenza A virus. However, in 2009, a number of pigs were positive for influenza A virus. Comparing the molecular results of the 3 laboratories and using conservative rRT-PCR result interpretations on which all laboratories agreed, we determined that influenza A virus was detected in 12 (12%) of 102 swine respiratory samples by rRT-PCR; 11 (19%) of these were from among the 57 pigs swabbed at the Minnesota state fair . Viral cA follow-up telephone survey of study participants identified 2 with influenza-like illness (ILI) within 7 days after the fair: an adult, with ILI with onset 1 day after his pigs arrived at the fair (and 4 days before pig swabbing), and his daughter who developed an ILI on the last day of the fair (3 days after pig swabbing). Three pigs exhibited by the child tested positive for influenza A virus.We found a 19% prevalence of influenza A virus among the 57 show pigs swabbed at the 2009 Minnesota state fair, which occurred during the second wave of the 2009 pandemic. Temporal analysis of the results indicated that most pigs with rRT-PCR\u2013positive results were sampled within 24 hours after arriving at the fair, suggesting that they probably were infected before their arrival . None ofThese detections of A(H1N1)pdm09 virus in the United States (reflecting the ease of transmission from humans to pigs) were soon followed by multiple other detections in US pigs (Of concern is that new reassortants between A(H1N1)pdm09, enzootic SIVs, and possibly other human- or avian-origin viruses might emerge and possibly spread to humans who have contact with asymptomatic pigs (Because of the possibility of novel virus generation in pigs and of human-to-pig and pig-to-human transmission of influenza virus, routine influenza A virus surveillance among pigs and influenza A virus testing of ill persons exposed to pigs is needed to ensure timely detection of novel influenza viruses in humans and pigs ("} +{"text": "Porphyromonas gingivalis include phosphoethanolamine (PE DHC) and phosphoglycerol dihydroceramides (PG DHC) lipids. These PDHC lipids mediate cellular effects through Toll-like receptor 2 (TLR2) including promotion of IL-6 secretion from dendritic cells and inhibition of osteoblast differentiation and function in vitro and in vivo. The PE DHC lipids also enhance (TLR2)-dependent murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. The unique non-mammalian structures of these lipids allows for their specific quantification in bacteria and human tissues using multiple reaction monitoring (MRM)-mass spectrometry (MS). Synthesis of these lipids by other common human bacteria and the presence of these lipids in human tissues have not yet been determined. We now report that synthesis of these lipids can be attributed to a small number of intestinal and oral organisms within the Bacteroides, Parabacteroides, Prevotella, Tannerella and Porphyromonas genera. Additionally, the PDHCs are not only present in gingival tissues, but are also present in human blood, vasculature tissues and brain. Finally, the distribution of these TLR2-activating lipids in human tissues varies with both the tissue site and disease status of the tissue suggesting a role for PDHCs in human disease.Novel phosphorylated dihydroceramide (PDHC) lipids produced by the periodontal pathogen Porphyromonas gingivalis is a periodontal pathogen strongly associated with development of destructive periodontal disease in adults. We have recently characterized the structures of novel phosphorylated dihydroceramide (PDHC) lipids produced by this organism P. gingivalis. Little is known regarding the capacity of other common human bacteria to produce these lipids and most importantly, whether these lipids can be identified in human tissues distant from sites normally colonized by these bacteria. Therefore, the purpose of this investigation was to evaluate intestinal bacterial species as well as other periodontal organisms for their capacity to produce PDHCs and to examine blood and human tissue samples for the presence of these novel TLR2-activating bacterial lipids.Bacteroides, Parabacteroides or Prevotella genera produced PDHCs and of these, most produced predominantly PE DHC lipids , whereas the remaining intestinal and oral bacteria produced negligible amounts of UnPG DHC lipids (PG DHC lipids (both the HM and LM forms) can exist with three aliphatic chains (the substituted or \u201cSub\u201d form) or can be de-esterified to a lipid class with 2 aliphatic chains (the unsubstituted or \u201cUn\u201d form) C lipids .In contrast, human tissue samples revealed significant percentages of both LM or HM UnPG DHC lipids . We nextOf note, the average total ion abundances of PDHC lipids per microgram of total lipid extract were at least 33 times higher in the control artery segments than the atheroma segments sites. We also evaluated blood plasma samples taken from periodontally healthy subjects or subjects with destructive periodontal disease. Two-factor ANOVA revealed significantly lower percentages of HM and LM SubPG DHC lipids and significantly higher percentages of HM and LM PE DHC lipids in periodontitis gingival tissue samples versus healthy samples . SimilarFor quantification of absolute PDHC lipid levels in control and periodontitis gingival tissue samples, each tissue lipid extract was supplemented with 1.5 \u00b5g of synthetic phospholipid internal standard before analysis by MRM/MS. This analysis revealed that lipid extracts of periodontitis tissue samples contained significantly higher mean levels of HM PE DHC and LM PE DHC lipids than that recovered in healthy gingival tissue samples until the time of lipid extraction. Human brain specimens were obtained as postmortem samples from the Colorado Brain Bank, Denver, CO.Porphyromonas gingivalis , Tannerella forsythia (generously provided by Dr. Sigmund Socransky) and Prevotella intermedia were grown in broth culture and after pelleting bacteria by centrifugation, the bacterial pellets were stored frozen until processing. At the time of lipid extraction, samples of bacterial pellets were removed and extracted using the same phospholipid extraction procedure.Intestinal bacterial samples that were previously stored frozen were grown on blood agar plates after demonstrating purity of bacterial isolates. The plates were scraped to recover the bacterial colonies and were extracted using the phospholipid extraction procedure of Bligh and Dyer All tissue and blood samples were stored frozen until processing. Gingival tissue, atheroma and brain samples were thawed and at least 20 mg of tissue was minced and extracted for several days in organic solvent according the method of Bligh and Dyer Individual lipid samples were analyzed using a QTrap 4000 mass spectrometer (ABSciex). A standard volume of each lipid sample (5 \u00b5l) was analyzed by flow injection and HPLC solvent was run at a rate of 80 \u00b5l/min. Using previously purified lipid preparations of each phosphorylated dihydroceramide class, the instrument parameters were optimized for detection of each lipid component based on gas phase transitions depicted in Each lipid ion transition peak was electronically integrated and the percentage abundance of each lipid class was calculated from the integrated lipid ion transition peaks. For each category of tissue or blood samples, all samples within a particular tissue or blood category were analyzed during a single analysis session. One or two-factor ANOVA, or the paired student t test was used to test for significance differences between sample categories.Table S1Ion abundances of bacterial phosphorylated dihydroceramides recovered from each intestinal and oral bacterial isolate. The individual bacterial samples were processed as described in the (DOC)Click here for additional data file.Table S2Ion abundances of bacterial phosphorylated dihydroceramides recovered from individual lipid extracts of subgingival plaque samples, and human gingival tissue, blood, atheroma and brain samples. The individual tissue and blood specimens were processed as described in the (DOC)Click here for additional data file.Table S3Ion abundances of bacterial phosphorylated dihydroceramides in lipid extracts of paired common carotid (control) and carotid atheroma samples derived from human endarterectomy samples. The individual tissue specimens were processed as described in the (DOC)Click here for additional data file.Table S4Mass spectrometric calibration parameters used to quantify bacterial lipids in bacterial or human specimens. The instrument parameters for the MRM-MS analysis are listed for the 4000QTrap Instrument (ABSciex). These parameters were defined using highly purified preparations of each PDHC lipid class.(DOC)Click here for additional data file."} +{"text": "Solanum tuberosum). Small RNAs were analysed from leaf and stolon tissues. 28 conserved miRNA families were found and potato-specific miRNAs were identified and validated by RNA gel blot hybridization. The size, origin and predicted targets of conserved and potato specific miRNAs are described. The large number of miRNAs and complex population of small RNAs in potato suggest important roles for these non-coding RNAs in diverse physiological and metabolic pathways.Micro RNAs (miRNAs) represent a class of short, non-coding, endogenous RNAs which play important roles in post-transcriptional regulation of gene expression. While the diverse functions of miRNAs in model plants have been well studied, the impact of miRNAs in crop plant biology is poorly understood. Here we used high-throughput sequencing and bioinformatics analysis to analyze miRNAs in the tuber bearing crop potato ( The recent discovery of small RNAs and their widespread roles in post-transcriptional gene regulation has changed our basic understanding of how genes are regulated during development and in different biological processes. These RNAs represent an additional layer in regulation of gene expression. The pathways and key enzyme components are well described and are highly conserved in plants and animals Increasing evidence shows that miRNAs play important roles in developmental processes and gene regulation upon biotic and abiotic stresses http://www.fao.org). Moreover, potato is being grown more extensively in developing countries with rapidly growing populations, such as those in South East Asia, so it is playing an increasing role in addressing food security issues. It is extremely important to understand the as yet poorly known molecular events in tuber development, which ultimately impact on the breeding of cultivars with improved tuber characteristics . There is a great deal of current interest and research in the molecular signals which promote tuberization in potato Potato is an important global food crop which is cultivated for its underground storage stems (tubers), rich in starch and nutrients and is unique among the major crops in tuber formation. The importance of potato globally is shown by the \u223c330 million tons production in 2010 (Solanum tuberosum group Andigena (clone ADG573) was used for small RNA library preparation and next generation sequencing. This clone was developed at The James Hutton Institute from the Commonwealth Potato Collection . ADG573 has the feature of being able to tuberize under short days (SD) but not under long days (LD), which is typical of germplasm originating from the Andes in South America. From 12 libraries of leaf and stolon materials using LD and SD conditions with three biological replicates about 60 million raw reads were obtained and further analysed. Firstly reads were quality filtered, adaptors were removed and ribosomal RNAs (rRNAs), transfer RNAs (tRNAs), small nuclear RNAs (snRNAs) and small nucleolar RNAs (snoRNAs) were filtered out from the database . These miRNAs have relatively high read numbers in our database and each originates from one locus in the genome. S. tuberosum group Andigena plants but also DM (doubled monoploid) which was used for the potato genome sequencing project S. tuberosum group Andigena \u2018Neotuberosum\u2019 clone selected for long day tuberization). PotatoMir1005047020 showed similar expression pattern in different tissues in all the plants but PotatoMir1005907528 had lower levels in roots and higher in stolons. PotatoMir1005564753 had strong expression in every tissue in the different plants. These analyses strongly suggest that the examined miRNAs exist in plants and have high expression levels in several potato tissues.To validate the presence of these miRNAs in plant tissues RNA gel blot hybridization was performed. All the examined miRNAs are highly expressed in the examined tissues . We haveWith the aim to better understand the biological role of conserved and potato specific miRNAs we searched for putative target genes by using a plant small RNA target analysis tool: psRNATarget RAP1 (Relative to APETALA2 1) RAP1) was found for all the miR172 family members as a predicted target with low expectation score and unpaired energy suggesting it to be a highly likely target. Additionally, the NL25 protein disease resistance gene transcript (PGSC0003DMT400006234) is targeted by miR482b which is present in our prediction To prove the power of our prediction we searched among the predicted targets of miR172 for the known target miRNAs play key roles in most biological processes in animals and plants The small RNA analysis of potato showed that the 24 nt length class dominates in the dataset in total number and unique sequences strongly suggesting that small RNA directed heterochromatin silencing plays an important role in this crop similar to other species Most predicted miRNAs are of 21 and 24 nt in length. 21 nt miRNAs have the canonical size for small RNAs derived from DCL1 processing but a little variation in size might originate from the inaccuracy of DCL1 processing The prediction of miRNAs in our study, in contrast with previous reports, is based on results from high-throughput small RNA sequencing. Zhang et al. (2009) predicted 21 miRNA families but our study predicted 14 additional conserved miRNA families in potato. For 6 families we have predicted more members in the same family but our high-throughput study could not confirm the prediction for 9 of the reported miRNA families. Similarly, twelve miRNA families were found in common with another study Potential targets with a wide variety of predicted functions were identified for the miRNAs in potato: transcription factors, genes with a role in defence mechanisms, kinases and ion homeostasis genes. We have predicted the mRNA/gene targets of many potato miRNAs. Some have known functions in flowering and tuberization (miR172) or guiding cleavage of transcripts of immune receptors (miR482) Solanaceae species.In summary, we have identified conserved and potato specific miRNAs and their targets for the first time at a genome-wide level. Using high-throughput sequencing technology and taking advantage of the recently published potato genome Solanum tuberosum group Andigena (line ADG573) was used for the experiments. Plants were propagated in vitro by single-node cuttings on MS 20 \u22122 sec\u22121. After the shift to cabinets, leaf (8 days at SD and LD) and stolon (12 and 16 days of SD plants) materials were collected 4\u20136 hours after dawn. For miRNA validation DM Solanum tuberosum group Andigena, Neotuberosum) and D\u00e9sir\u00e9e were used. Plants were grown in glasshouse under LD conditions for four weeks after in vitro propagation.Total RNA was extracted from leaf and stolon material using Plant/Fungi Total RNA Purification Kit according to the manufacturer's instructions. An Illumina TruSeq Small RNA sample prep kit was used for the preparation of small RNA libraries according to the manufacturer's instructions starting with 1.5 \u00b5g total RNA and Illumina GAIIX sequencer for sequencing.32\u03b3-ATP. RNA was blotted onto Hybond-N membrane using a Panther\u2122 Semi-dry Electroblotter, HEP-1 and cross-linked by N-(3-Dimethylaminopropyl)-N\u2032-ethylcarbodiimide hydrochloride 32\u03b3-ATP using T4 polynucleotide kinase to visualize miRNAs. For sequences see For RNA gel blot hybridization of miRNAs total RNA was separated by 15% polyacrylamide (19:1) gel with 8M urea and 1 \u00d7 MOPS buffer. RNA markers were end labelled by http://code.google.com/p/cutadapt/). First, low-quality ends were trimmed by applying a quality score threshold of 20. In the applied trimming method, the threshold is subtracted from all quality scores and partial sums from all indices to the end of the sequence are then computed. Sequences are cut at the indices where the sums are minimal. Adaptors were then removed by matching the first (for 3\u2032 adaptors) and last (for 5\u2032 adaptors) 8 nt of the adaptor sequences while allowing 1 nt of mismatch maximum.Quality trimming and adaptor removal of the Illumina reads were carried out using Cutadapt (http://www.phrap.org/phredphrapconsed.html). The sequences aligned to the above databases with at least 10 matched nts and a minimum alignment score of 10 were excluded from further analysis. Sequences, shorter than 17nt and longer than 35 were also discarded.Sequences were then searched against ribosomal, transfer RNAs, snRNAs and snoRNAs from Rfam, the Arabidopsis tRNA databases and plant rRNA and tRNA sequences from EMBL using cross_match (http://potatogenomics.plantbiology.msu.edu/index.html) on all of the plausible positions using Bowtie with perfect matches (0 mismatches). Then the sequences that were mapped to multiple positions in the genome were filtered based on the maximum size of potato miRNA families. The threshold was set at 30 to recover small RNAs with relatively large family sizes. 4,006,195 flanking regions of the 3,113,450 filtered sequences were retrieved from the genome using a window of 250 bps. Then the secondary structures of the flanking sequences were predicted using RNAfold Click here for additional data file.Table S1Predicted known and new miRNAs in potato. The table shows the predicted miRNAs according to the family number (family #); the super-scaffold location (chromosome id); the direction of chromosome strand where the miRNA maps (strand direction); read and precursor identification number according to the analysis ; the homologue of miRNA (miRNA family); read number for miRNAs and star sequences ; the location of miRNA and precursor RNA on the super-scaffold and the mature, precursor and star sequences. Total read numbers of each predicted miRNAs are indicated for the different tissues which were analysed. During the analysis DNA equivalent of RNA sequence was used.(XLSX)Click here for additional data file.Table S2Summary of conserved and potato specific miRNA families. The table shows the conserved miRNA families according to the family number corresponding to our analysis. The number of family members is indicated with mature miRNA and star sequences. The homologue of miRNA is shown (miRNA family) with the length of miRNA (miRNA length). For potato specific miRNAs the family number, numbers of miRNAs in the same family, mature and star sequences and miRNA length are indicated. During the analysis DNA equivalent of RNA sequence was used.(XLSX)Click here for additional data file.Table S3Predicted target RNAs of conserved and potato specific miRNAs. The table contains the miRNAs with the read number in the libraries (miRNA_Acc.), the homologue of miRNA (miRNA family) and the targeted potato transcripts (Target_Acc.) with the predicted gene functions (target gene function annotation). Expectation score (Expectation) and unpaired energy (UPE) with a low number suggest highly likely target for the miRNA. The aligned miRNA and target start and end nucleotide is indicated with the corresponding sequences. The inhibition type (Inhibition) and the number of target sites (multiplicity) are shown. On the second sheet of the table predicted targets could be found using more relaxed prediction criteria. During the analysis DNA equivalent of RNA sequence was used.(XLSX)Click here for additional data file.Table S4Predicted targets of miR172, miR482 and validated potato specific miRNAs. Details of miR172, miR482 and the validated miRNAs are shown in the table. The predicted target transcripts are below the miRNA data. For details see (XLSX)Click here for additional data file.Table S5Oligonucleotide sequences used in this study.(XLSX)Click here for additional data file."} +{"text": "Studies have suggested that selective microbial targets prevail in the fecal microbiota of infants with eczema. This study aims to evaluate and compare the composition of fecal microbiota of infants who developed eczema by 2 years of age and healthy controls.Eubacterium rectale-Clostridium coccoides group (Erec482), Clostridium leptum subgroup (Clep866 and the corresponding competitor probes), Bacteroides-Prevotella group (Bac303), Bifidobacterium genus (Bif164), Atopobium group (Ato291), Lactobacilli- Enterococci group (Lab158), Enterobacteriaceae family (Enter1432) and Clostridium perfringens (Cperf191). Linear mixed model was used to evaluate the longitudinal differences (i.e. 4 time points) of bacterial targets while adjusting for gender, mode of delivery, feeding up to 6 months, and allergic rhinitis and wheezing within the eczema group at 2 years of age.Children with eczema at 2 years old (n=26) and their matched healthy controls (n=26) were selected from the placebo group of a cohort of at-risk infants participating in an randomized double-blind placebo controlled trial on the protective effects of supplemental probiotics (first 6 months) on eczema and allergies. Children with eczema were subclassified into atopic eczema (n=12) and non-atopic eczema (n=14). Molecular evaluation of fecal microbiota were conducted using Fluorescence In Situ Hybridization-Flow Cytometry (FISH-FC) for fecal samples collected at 3 days, 1, 3, and 12 months. Probes were selected to target Clostridium perfringens were also higher when subanalyzed for non-atopic and atopic eczema compared to healthy controls.Longitudinal analyses over four time points showed that higher relative abundance of Enterobacteriaceae in children with eczema by 2 years of age. Similar observations were made when eczema group was subanalyzed into non-atopic and atopic eczema, where higher relative abundance of Enterobacteriaceae and were observed respectively as compared to healthy controls. Relative abundance of Clostridium perfringens in the fecal microbiota of infants influence the development of eczema in early childhood.Our data suggests that relative abundance of selective microbial targets particularly Enterbacteriaceaea and"} +{"text": "Arabidopsis, the onset of SCW deposition is initiated by a nexus of NAC, MYB, homeodomain and several other families of TFs, which function in a transcriptional network regulating SCW biosynthetic genes. NAC family members SND1/NST1 and VND6/VND7 have been identified as functionally redundant master regulators of SCW formation in fibres and vessels, respectively [Arabidopsis plants overexpressing SND2, an indirect target of fibre master regulator SND1, exhibited increased SCW thickness in inflorescence stem fibres, whilst dominant repression lines exhibited a decrease in fibre SCW thickness associated with a reduction in glucose and xylose cell wall sugar content [SND2 to transactivate the CesA8 promoter [SND2 may regulate cellulose biosynthetic genes during fibre SCW formation. The evaluation of this hypothesis necessitates the identification of all downstream genes potentially regulated by SND2, and the analysis of SCW chemistry and morphology in overexpression lines. The aim of this ongoing study is to further elucidate the role of SND2 in fibre SCW formation through microarray analysis of overexpression lines and by independent confirmation of the effect of SND2 overexpression on fibre SCW chemistry and morphology in Arabidopsis plants.Transcription factors (TFs) play important roles in the regulation of secondary cell wall (SCW) biosynthesis in herbaceous and woody plants. In ectively . Arabido content . The abipromoter suggeste2x35S::SND2 Arabidopsis thaliana Col-0 plants, screened them for CesA8 upregulation and phenotypically assessed several homozygous (T4) transgenic lines. Inflorescence stem fibre SCW thickness was measured from light and scanning electron micrographs, and the cell wall monosaccharide and Klason lignin composition of stems was determined relative to the wild type. We performed microarray analysis of the inflorescence stem transcriptomes of wild type and transgenic Arabidopsis plants using the Agilent 4x44k transcriptome array and confirmed the expression profiles of differentially expressed genes with RT-qPCR.We generated Arabidopsis (T4) lines showed no significant external phenotype, and we were unable to reproduce the increased fibre SCW thickness phenotype reported by Zhong et al.[CesA8 upregulation and moderate SND2 overexpression. Whole-transcriptome analysis of the line revealed the upregulation of several TFs and genes associated with SCW biosynthesis, which were reproducibly upregulated in an independent trial. We additionally observed possible ectopic artifacts and gene dosage effects associated with excessive constitutive expression of the SND2 gene. Chemical analysis revealed only minor changes in SCW monosaccharides, despite the upregulation of SCW biosynthetic genes.Transgenic ng et al.. We idenSND2 in the regulation of cellulosic and non-cellulosic components of fibre cell walls, and we provide a model for the position of SND2 in the transcriptional network regulating fibre SCW formation.Our results implicate"} +{"text": "The superficial zone (SZ) of articular cartilage is critical in maintaining tissue function and homeostasis and represents the site of the earliest changes in osteoarthritis (OA). The expression of chromatin protein HMGB2 is restricted to the SZ, which contains cells expressing mesenchymal stem cell (MSC) markers . Aging-rHMGB2 was detected at higher levels in human MSC as compared to human articular chondrocytes and its expression declined during chondrogenic differentiation of MSC Figure . LentiviThese results demonstrate that HMGB2 expression is inversely correlated with the differentiation status of MSC and that HMGB2 suppresses chondrogenic differentiation. The aging-related loss of HMGB2 in articular cartilage may represent a mechanism responsible for the decline in adult cartilage stem cell populations."} +{"text": "In darkness, the dicot seedlings produce an apical hook as result of differential cell division and extension at opposite sides of the hypocotyl. This hook protects the apical meristem from mechanical damage during seedling emergence from the soil. In darkness, gibberellins act via the DELLA-PIF (PHYTOCHROME INTERACTING FACTORs) pathway, and ethylene acts via the EIN3/EIL1 (ETHYLENE INSENSITIVE 3/EIN3 like 1)-HLS1 (HOOKLESS 1) pathway to control the asymmetric accumulation of auxin required for apical hook formation and maintenance. These core pathways form a network with multiple points of connection. Light perception by phytochromes and cryptochromes reduces the activity of PIFs and (COP1) CONSTITUTIVE PHOTOMORPHOGENIC 1\u2014both required for hook formation in darkness\u2014, lowers the levels of gibberellins, and triggers hook opening as a component of the switch between heterotrophic and photoautotrophic development. Apical hook opening is thus a suitable model to study the convergence of endogenous and exogenous signals on the control of cell division and cell growth. Arabidopsis thaliana), the formation of an apical hook structure and the presence of folded cotyledons. Light exposure initiates the transition between skoto- to photomorphogenesis is perceived mainly by phyA, phyB and cry1. phyA is important for the early steps of this transition, which is completed by phyA itself under dense canopies and by phyB and cry1 in open places to the active (Pfr) form and part of these Pfr pools migrate to the nucleus in Figure A. thaliana seedlings grown in darkness, the formation phase lasts approximately 26 h after germination while the maintenance phase, where the hypocotyl remains closed, lasts another 25 h and the concave (inner) and convex (outer) sides across the hook or 1-naphthoxyacetic acid (1-NOA) reduces hook formation and GH3 (GRETCHEN HAGEN 3) gene families and AUX/IAA (AUXIN/INDOL-3-ACETIC ACID) proteins gene encodes a N-acetyltransferase that is required for apical hook formation. The hls1 mutant fails to form the apical hook due to defects in both differential cell elongation and cell division and PIF4 see Box , interfeSo, gibberellins are crucial for apical hook formation. Gibberellins are needed to maintain DELLA levels reduced and thus PIF and EIN3/EIL1 transcription factors are available to increase WAG2 and HLS1 which regulate asymmetric auxin accumulation.ethylene overproducer mutants confer ethylene insensitivity and lack of an apical hook, while loss-of-function mutations cause hypersensitivity to ethylene and exaggerated hooks after ethylene treatment , ERS1, ERS2 (ETHYLENE RESPONSE SENSOR 1 AND 2) and EIN4 (ETHYLENE INSENSITIVE 4) receptors , the enzyme that catalyzes the first limiting step in tryptophan synthesis are higher in the inner than in the outer side lack an apical hook in darkness reporter gene which is involved in brassinolide synthesis, shows induced expression of the reporter gene by ethylene in apical hooks. Also, dark-grown det2 mutant seedlings treated with exogenous ethylene are not able to induce an exaggerated hook suggesting ethylene action requires brassinosteroids that is deficient in the perception of brassinosteroids but have activated downstream brassinosteroids responses due to a dominant mutation that stabilizes BZR1, forms and apical hook similar to that of the WT that phosphorylates ARF2 and reduces its activity, leading to the enhanced expression of auxin responsive genes and phyB . Since BBX23 is a repressor of photomorphogenesis required for hook maintenance in darkness, down-regulation of its expression enhances hook opening , which attenuates late hook opening possibly as part of a mechanism that avoids an exaggerated response of hook opening to light stimulus once seedlings are de-etiolated show impaired hook opening under far-red light, but hfr1 (long hypocotyl in far-red) and laf1 (long after far-red light) mutants are affected in hypocotyl elongation but not in hook opening under far-red light see Box . BBX23 iHY5 gene induces the expression of gibberellins-2-oxidase, the major gibberellin catabolic enzyme in plants, resulting in negatively regulation of gibberellin pathways (Weller et al., cop1 mutant of several species (Alabad\u00ed et al., Light decreases the level of gibberellins in Arabidopsis (Ait-Ali et al., In the hooks, light also affects the expression and localization of the auxin transporter ABCB19. ABCB19 localizes to the inner side of etiolated hooks but its presence fades away during hook opening under blue light (Wu et al., In summary, COP1 and PIFs are direct key targets of light signaling to control hook opening. PIFs operate downstream of gibberellins and affect auxin transport and ethylene synthesis. EIN3/EIL1 are indirect targets of light signaling, through the PIFs and DELLA pathways, operate downstream gibberellins and ethylene and affect auxin transport, synthesis and signaling. The connections between COP1 and the hormonal network that underlies the formation of the hook in darkness are not firmly established.The coordinated actions of gibberellins, ethylene and brassinosteroids control asymmetric auxin distribution to allow the correct development of the hook in darkness. This control occurs at multiple levels, including synthesis, distribution by the action of specific transporters and abundance of transcription factors involved in the control of auxin-responsive genes. PIFs and EIN3/EIL1 are key connectors of gibberellins and ethylene pathways with auxin signaling in the hooks. The repressors of photomorphogenesis PIFs and COP1 are indispensable for hook development in darkness and the activation of phytochromes and cryptochromes by light negatively regulates the activity of PIFs and COP1, leading to the opening of the hook.Considerable progress has been made in recent years in the elucidation of the signaling network that controls apical hook formation in darkness; however there still are several gaps concerning how light-regulated proteins modulate hook formation and triggers hook opening. Learning the dynamics of the hormonal networks in response to light is a challenge for future research.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "A number of neurological disorders (i.e. Schizophrenia and Parkinson's disease) that result from dysfunction of striatal signal transduction pathways underline the importance of the striatum for motor function and procedural learning. Most striatal neurons are medium spiny neurons (MSN) that receive input via dopaminergic and glutamatergic terminals and project to the basal ganglia. The MSN express dopamine receptors that are either positively (D1) or negatively (D2) coupled to adenylyl cyclase therefore dopamine directly influences intracellular levels of cAMP. Participants in cAMP mediated signalling pathways are often organized in multiprotein complexes around A-kinase anchoring proteins (AKAPs). The proximity of the cyclases and phosphodiesterases (PDEs) as well as protein kinase A ensures fine tuning of cAMP levels in a given compartment and allows for selective regulation of target proteins such as NMDA or AMPA receptors by phosphorylation.2+ concentrations.According to our results PDE10 is highly expressed in striatum and responsible for 70% of cAMP degrading activity. Therefore we asked if PDE10 participates in signalling complexes at the synapse. Indeed, the immunoprecipitation via PDE10 specific antibodies revealed interactions with AKAP150 and AKAP-interacting proteins as well as subunits of the NMDA-receptor and PSD95. In the isolated complex and in striatal slices, PDE10 can be phosphorylated by activation of PKA. This phosphorylation is short lived, probably because it is reversed by permanently active protein phosphatase 1. We observed that dephosphorylation is additionally accelerated via NMDA dependent rise in intracellular Ca"} +{"text": "This study aimed to investigate differences between the motor skills and sensory processing abilities of children between the ages of four and eight years with and without an idiopathic toe walking (ITW) gait.Children in each cohort were tested with the following norm referenced assessments:1. Bruininks-Oseretsky Test of Motor Proficiency 2nd edition (BOT-2)2. The Sensory Profile (SP)3. Six subtests of the Sensory Integration and Praxis Tests (SIPT)4. Vibration Perception Threshold (VPT)Sixty children participated in the study, 30 within each cohort. Those with an ITW gait were found to have different SP quadrant scores (p=0.002), poorer performance on the BOT-2 (p=<.001), a lower VPT (p=.001) and poorer performance on the Standing Walking Balance subtest of the SIPT (p=0.047) compared with peers.While the results did not identify a causative factor for an ITW gait, they do suggest that the toe walking gait may not be idiopathic in nature. The results of this research highlight the importance of a fuller assessment of the toe walking child compared to that traditionally conducted by podiatrists, and suggest that multiple strategies may be required to manage this gait style."} +{"text": "Meles meles) culling as a control strategy. Our study complements previous analyses of the RBCT data (focusing on treatment effects) by presenting analyses of herd-level risks factors associated with the probability of a confirmed bTB breakdown in herds within each treatment: repeated widespread proactive culling, localized reactive culling and no culling (survey-only).The control of bovine tuberculosis (bTB) remains a priority on the public health agenda in Great Britain, after launching in 1998 the Randomised Badger Culling Trial (RBCT) to evaluate the effectiveness of badger (M. bovis positive badgers initially culled within 1500 m of a farm was the strongest predictor of the risk of a confirmed bTB breakdown.New cases of bTB breakdowns were monitored inside the RBCT areas from the end of the first proactive badger cull to one year after the last proactive cull. The risk of a herd bTB breakdown was modeled using logistic regression and proportional hazard models adjusting for local farm-level risk factors. Inside survey-only and reactive areas, increased numbers of active badger setts and cattle herds within 1500 m of a farm were associated with an increased bTB risk. Inside proactive areas, the number of The use of herd-based models provide insights into how local cattle and badger populations affect the bTB breakdown risks of individual cattle herds in the absence of and in the presence of badger culling. These measures of local bTB risks could be integrated into a risk-based herd testing programme to improve the targeting of interventions aimed at reducing the risks of bTB transmission. Mycobacterium bovisM. bovis to human health is low in most developed countries, the main causes of concern related to M. bovis in industrialized countries are epizootics in domesticated and wild mammal populations M. bovis remains a significant livestock zoonosis in the European Union where some member states experience a reemergence of the disease despite significant historical efforts to implement eradication plans. In Great Britain, the disease was eliminated from most cattle herds by 1960, with the exception of infection hotspots in southwest England, after the implementation of a herd testing and slaughter policy M. bovis in wildlife host populations, acting as reservoirs of infection, in particular badgers (Meles meles) Bovine tuberculosis (bTB) remains an important public health concern worldwide as a result of deficiencies in preventing and/or controlling measures targeting the spread of its causative agent M. bovisM. bovis than younger ones Risk factors associated with bTB have been investigated in case-control studies in Europe and the USA M. bovis can infect a wide range of wild animals Trichosurus vulpecula) are the primary wildlife reservoir of bovine bTB in New Zealand Odocoileus virginianus) in Michigan Bison bison athabascae) Syncerus caffer) in Southern Africa Sus scrofa) in Southern Europe M. bovis. The Randomised Badger Culling Trial (RBCT) was launched in 1998 to evaluate the effectiveness of badger culling as a control strategy for bTB in Britain 2) trial areas recruited as matched sets of three, known as \u201ctriplets\u201d. Detailed field surveys in all trial areas for which consent was obtained to identify the most important bTB breakdown risk factors for herds within the RBCT areas.M. bovis) from \u201cunconfirmed breakdowns\u201d (incidents in which one or more cattle reacted to the tuberculin test but infection was not confirmed at postmortem or by culture). Herds with the same County Parish Holding Herd numbers (CPHH: unique herd identifier) which were registered in different treatment groups (n\u200a=\u200a14); herds which were archived before the start of the RBCT (n\u200a=\u200a22) and herds which showed no evidence of having had a bTB disclosing test during the RBCT (n\u200a=\u200a745) were removed from the VETNET records; leaving us with 1306 unique herds recorded in RBCT proactive areas, 1380 unique herds recorded in RBCT survey-only areas and 1320 unique herds recorded in RBCT reactive areas.The Defra animal health information system (VETNET) provided data on cattle bTB tests and herd breakdowns, distinguishing between \u201cconfirmed breakdowns\u201d .On the basis of details recorded in the RBCT database, farms were categorized into one of three enterprise types: beef, dairy and other . The median herd size was 72 animals . The hisM. bovis positive (+) badgers culled, the number/density of active badger setts and the number/density of neighbouring cattle herds within 500, 1000 and 1500 m of all the land parcels belonging to a farm were extracted from the RBCT geodatabase (to be) in a better position to tackle the disease\u201d Supporting Information S1Univariable models and alternative multivariable models of herd-level bTB risk.(DOC)Click here for additional data file."} +{"text": "Irritant-induced occupational asthma suspected to occur within few hours of exposure to high concentration of gas, fume or vapour at work in oil refinery establishmen lacking safety measures. There was a relationship between asthmatic and bacterial agents causing respiratory infections.The quatitative estimation of immunoglobulin E in serum of the patient was based on solid phase enzyme-linked immunosorbent assay (ELISA).37% (74/200) of refinery patients and 19.5% (39/200) of nonrefinery hospitalized patients who had a total IgE level up to 100 IU/ml or more were considered as allergic. It was noticed that IgE level among refinery allergic patients ranged between 201-728 and 106-3266 IU/ml of refinery and nonrefinary hospitalized patients respectively.The highest incidence of allergy was recorded among refinery patients. The present study revealed that the percentages of 80 and 42 pathogenic strains were isolated from 74 and 39 allergic patients with respiratory infections from refinery and nonrefinery hospitalized patients respectively. The high incidence of asthma and respiratory infections in the oil refinery plant could be due observed lacking of safety measures."} +{"text": "Hyperactivity of the type I interferon (IFN) pathway is involved in the pathogenesis of systemic lupus erythematosus (SLE). Immunoglobulin-like transcript (ILT3) is an immunohibitory transmembrane molecule that is induced by type I IFNs. ILT3 is expressed by plasmacytoid dendritic cells (PDCs), monocytoid dendritic cells (MDCs), and monocytes/macrophages. Given the pathogenic role of IFN in SLE, we hypothesized that the IFN-induced immunosuppressive ILT3 receptor may be dysfunctional in human SLE.In total, 132 European-derived and 79 Hispanic-American SLE patients were genotyped for two coding-change SNPs predicted to interfere with protein folding in ILT3 (rs11540761 and rs1048801). One hundred and sixteen control DNA samples and sera from healthy controls were also studied. We detected associations between ILT3 genotype and serum cytokine profiles. ILT3 expression levels on PDCs and MDCs from 18 patients and 10 controls were studied by flow cytometry.The rs11540761 SNP in the extracellular region was associated with decreased cell surface expression of ILT3 on circulating MDCs and to a lesser extent PDCs in SLE patients. The cytoplasmically located rs1048801 SNP was not associated with a change in DC expression of ILT3. Both SNPs were significantly and independently associated with increased levels of serum type I IFN activity in SLE patients. The rs1048801 SNP was also associated with increased serum levels of TNF\u03b1.Loss-of-function polymorphisms in ILT3 are associated with increased inflammatory cytokine levels in SLE, supporting a biological role for ILT3 in SLE."} +{"text": "Staphylococcus aureus clonal complex (CC) 398. Further typing in comparison with animal isolates identified 4 clusters: 1 related to a horse epidemic and 3 to persons who had no direct contact with animals or each other. These findings may indicate unrecognized community transmission.Nationwide surveillance identified 10 human isolates of methicillin-resistant Staphylococcus aureus (MRSA). The MRSA lineage clonal complex (CC) 398 has been reported to be common among pigs by PCR related to the horse epidemic; 3 human isolates from 2 hospital districts (A and B); 5 human isolates from 1 hospital district (C); and 7 isolates from pigs respectively, and there are differences in screening policies. In the Netherlands, people in close contact with pigs or cattle are screened at hospital admission. It remains to be investigated whether the low occurrence of CC398 and lack of direct animal contacts among CC398 case-patients are related to lower occurrence of MRSA in animals, sparse pig and human populations, or screening policies in Finland.The proportion of CC398 of all MRSA in humans was far lower in Finland (0.09%) than in the Netherlands (30% in 2007) . In addition, the presence of 2 different SCCmec types among t011 and nonexistent links in time and space between human cases may suggest unrecognized transmission chains in the community.Except for the isolates from the horse epidemic, human and animal isolates were distinguished from each other by using a combination of molecular typing techniques. Additional typing by the Open reading frames of African swine fever virus."} +{"text": "This novel virus is related to arenaviruses that cause hemorrhagic fever. Peromyscus mexicanus) captured near the site of a 1967 epidemic of hemorrhagic fever in southern Mexico. Analyses of nucleotide and amino acid sequence data indicated that the deer mice were infected with a novel Tacaribe serocomplex virus (proposed name Ocozocoautla de Espinosa virus), which is phylogenetically closely related to Tacaribe serocomplex viruses that cause hemorrhagic fever in humans in South America.Arenavirus RNA was isolated from Mexican deer mice ( Arenaviridae, genus Arenavirus) comprise Bear Canyon virus, Tamiami virus, and Whitewater Arroyo virus in the United States; Tacaribe virus (TCRV) on Trinidad; Chapar\u00e9 virus (CHPV) and Machupo virus (MACV) in Bolivia; Guanarito virus (GTOV) in Venezuela; Jun\u00edn virus (JUNV) in Argentina; Sabi\u00e1 virus (SABV) in Brazil; and 9 other species in western Venezuela is the principal host of GTOV in central Argentina is the principal host of JUNV cause hemorrhagic fever in humans and 0 of 29 other cricetid rodents captured in the municipality of Ocozocoautla de Espinosa, State of Chiapas, Mexico (P. mexicanus deer mice in western Chiapas.A recently published study reported antibody against a Tacaribe serocomplex virus in 3 (25.0%) of 12 Mexican deer mice (Baiomys musculus), and 11 Jaliscan cotton rats (Sigmodon mascotensis) were tested for arenavirus by cultivation in monolayers of Vero E6 cells and 38 antibody-negative rodents were captured on July 16, 2000, at a locality in the municipality of Ocozocoautla de Espinosa and 19C-cons and either AVNP42 (5\u2032-GCCGCGGACTGGGAGGGCA-3\u2032) or AVNP122 (5\u2032-GCCGCGGACTGGGGAGGCACTG-3\u2032). The second-round (heminested) PCR used MasterTaq Kit and either AVNP42 and oligont 1010C protein gene RNA. First-strand cDNA was synthesized by using SuperScript III Reverse Transcriptase and oligont 19C-cons (p) distances.Analyses of GPC sequences, N protein sequences, and nucleotide sequences included AV B1030026, 8 other viruses from North America, and 15 viruses from South America . Sequenc>0.95 were considered supported by the data was 96.4% identical to the nucleotide sequence of the homologous region of the N protein gene of AV B1030026.Bayesian analyses of complete GPC gene sequences , panel ANonidentities between amino acid sequences of the GPC and N protein of AV B1030026 and amino acid sequences of homologous sequences of the 8 other viruses from North America ranged from 47.8% to 52.1% and from 44.3% to 45.4%, respectively. Similarly, nonidentities between the amino acid sequences of the GPC and N protein of AV B1030026 and homologous sequences of the 8 other members of group B ranged from 24.7% to 46.8% and from 16.1% to 32.3%, respectively . NonidenArenaviridae, genus Arenavirus in the family The hallmark of the arenaviruses is their ability to establish chronic infections in their respective principal hosts. The failure to isolate arenavirus from Mexican deer mice in this study could be caused by small sample size or poor specimen quality. Alternatively, a cricetid rodent other than the Mexican deer mouse is the principal host of Ocozocoautla de Espinosa virus (OCEV).Members of the rodent family Cricetidae, subfamily Sigmodontinae (Baiomys taylori) captured in Texas and northern Mexico (The presence of OCEV in Mexico suggests that the last common ancestor of the 9 viruses in group B emerged P. mexicanus deer mouse is a relatively common species in forests of southern Mexico (The history of the State of Chiapas includes an outbreak of a highly lethal hemorrhagic fever in 1967 (It is generally accepted that humans usually become infected with arenaviruses by inhalation of virus in aerosolized droplets of secretions or excretions from infected rodents. Another source of infection may be ingestion of infected rodents (Human consumption of wild rodents is common in rural areas in some regions of Mexico. For example, Mexican deer mice and other cricetid rodents are consumed by the Tzeltal Indians in the highlands of Chiapas ("} +{"text": "Hepatitis C virus (HCV) infection is the second viral cause for chronic liver disease (CLD) in the world and nearly 170 million people are infected worldwide . The hisIn 2006, we started a project for control of hepatitis C infection in dialysis patients . Iran He"} +{"text": "Paracoccus (Alphaproteobacteria). Complex analysis of 25 strains representing 20 species of this genus led to the capture and characterization of (i) 37 insertion sequences (ISs) representing 9 IS families , (ii) a composite transposon Tn6097 generated by two copies of the ISPfe2 (IS1634 family) containing two predicted genetic modules, involved in the arginine deiminase pathway and daunorubicin/doxorubicin resistance, (iii) 3 non-composite transposons of the Tn3 family, including Tn5393 carrying streptomycin resistance and (iv) a transposable genomic island TnPpa1 (45 kb). Some of the elements were shown to contain strong promoters able to drive transcription of genes placed downstream of the target site of transposition. Through the application of trap plasmid pCM132TC, containing a promoterless tetracycline resistance reporter gene, we identified five ways in which transposition can supply promoters to transcriptionally silent genes. Besides highlighting the diversity and specific features of several TEs, the analyses performed in this study have provided novel and interesting information on (i) the dynamics of the process of transposition and (ii) structural changes in DNA mediated by transposition (e.g. the generation of large deletions in the recipient molecule upon transposition of ISPve1 of the IS21 family). We also demonstrated the great potential of TEs and transposition in the generation of diverse phenotypes as well as in the natural amplification and dissemination of genetic information by horizontal gene transfer, which is considered the driving force of bacterial evolution.Several trap plasmids (enabling positive selection of transposition events) were used to identify a pool of functional transposable elements (TEs) residing in bacteria of the genus Transposable elements (TEs) are components of nearly all prokaryotic genomes. They are mobilized to change their location in DNA by the action of a transposase (TPase), an enzyme which catalyses transposition, i.e. recombination that does not require sequence homology between the TE and the target site. The presence and activity of TEs may lead to structural changes in both the size and composition of a genome. TEs can generate (i) various mutations, such as insertions, deletions, duplications, inversions and translocations of even large DNA fragments, and (ii) replicon fusions The simplest TEs are insertion sequences (ISs), which are highly abundant in bacteria. They carry only genetic information that is necessary and sufficient for transposition and its regulation. The majority of ISs are composed of a single open reading frame (ORF), encoding a transposase, flanked by two inverted repeat sequences (IRs) that are recognized by the TPase during transposition. In most cases, the transposition of ISs causes duplication of the target site, so that the inserted element is bordered by two short (2\u201315 bp) identical direct repeat sequences (DRs) Bacillus cereusISs are also able to form more complex TEs such as (i) composite transposons consisting of random segments of genomic DNA (core region) bordered by a pair of ISs, or (ii) transposable modules (TMos) and ISCR elements composed of one IS copy, which can mobilize an adjacent DNA segment for transposition 3 and Tn7 families. Besides a transposase, the Tn3 elements contain a site-specific recombination module encoding a resolvase , while the Tn7 elements are known for their complex transposition machinery (they encode five transposition proteins) There is another widely distributed group of TEs called the non-composite transposons, which is divided into the TnLarge-scale genome sequencing projects have led to an explosion in the number of annotated prokaryotic and eukaryotic TEs . This genus currently comprises 31 species, which have been isolated from many geographical locations and from different environments. Paracoccus spp. are physiologically among the most versatile bacteria, and are able to perform a number of different growth modes. Many are aerobic chemoorganoheterotrophs utilizing a wide variety of organic compounds, including potential pollutants like acetone, N,N-dimethylformamide and methylamine Paracoccus spp. are facultative chemolithoautotrophs utilizing reduced sulfur compounds, molecular hydrogen and Fe(II) as energy sources In 2009 we initiated a project aimed at identifying functional transposable elements harbored by bacteria belonging to the genus Paracoccus spp., it is tempting to speculate that their physiological heterogeneity might result from various transposition events.Although there is no direct evidence linking the presence of TEs with important phenotypic traits of Paracoccus species were analyzed. For the identification of functional TEs we used trap plasmids, which are convenient tools enabling the direct identification of even phenotypically silent elements (reviewed by Solyga and Bartosik) P. pantotrophusP. solventivoransP. marcusiiP. methylutensPme2, ISPpa2, ISPpa3, ISPpa4, ISPso2, ISPso3 (IS5 family), ISPpa5 (IS66 family), ISPpa1, ISPso1 (IS256 family) and IS1247a, ISPme1 (IS1380 family), ISPmar4 (ISAs1 family) 3 family \u2013 cryptic Tn3434 and streptomycin resistant Tn5393Ppa1, whose transposition is mediated by two copies of Tn34341380-family element and adjacent fragments of genomic DNA of various lengths Paracoccus spp. strains. We also analyzed the structure, frequency of transposition, specific features and distribution of the captured TEs, which allowed us to draw more general conclusions concerning their evolutionary impact, as well as the direction and frequency of horizontal gene transfer in this group of bacteria.In this study, TEs residing in strains representing 20 r) derivatives of the wild-type strains of Paracoccus spp. (listed in Escherichia coli TG1 Paracoccus spp.) or 37\u00b0C (E. coli). P. homiensis DSM 17862 was cultivated in Marine Broth (Difco). Where necessary, the medium was supplemented with sucrose (10%) and with antibiotics at the following concentrations (\u00b5g\u00b7ml\u22121): kanamycin, 50; rifampicin, 50; tetracycline, 0.3\u201335 (depending on the strain).For identification of transposable elements rifampicin-resistant a silent tetracycline resistance gene tetA under the control of the bacteriophage lambda pR promoter, and (ii) the gene encoding the lambda cI repressor. Inactivation of the repressor gene (e.g. through insertion of an IS), results in constitutive expression of tetracycline resistance r version pEBB10, contains the sacB gene of Bacillus subtilis, coding for levan sucrase \u2013 an enzyme that catalyzes sucrose hydrolysis and levan extension. The products of this reaction are toxic for gram-negative bacteria. Therefore, cells carrying the functional sacB gene are sucrose sensitive (Sucs) and their cultivation in medium containing sucrose results in cell lysis sacB mutants (Sucr) (e.g. carrying inserted TEs), whose growth is not affected under these conditions, thus enabling positive selection of transposition mutants. The BHR trap plasmid pCM132TC, contains a promoterless tetracycline resistance gene tetA. In this case, the transposition of TEs containing strong promoters upstream of the tetA gene can initiate its expression, resulting in tetracycline resistance in cells carrying such mutated plasmids Ppa1 were (i) pBBR1MCS-3 oriV of pMAR4 of P. marcusii DSM 11574; oriT RK2; Kmr), (iii) pDIY703 oriV RA3; oriT of RK2; Kmr), (v) pMAO-MS oriV RA3; oriT of pIGRK of K. pneumoniae 287-w; Kmr) For the identification of TEs, the following trap plasmids were used: pMEC1 Paracoccus spp. strains by triparental mating as previously described E. coli cells was performed according to the method of Kushner DNA was introduced into Paracoccus spp. was isolated by the procedure described by Chen and Kuo Plasmid DNA was isolated using a standard alkaline lysis procedure r strains of Paracoccus spp. The overnight cultures of the transconjugants were spread on plates with solidified LB medium supplemented with tetracycline or sucrose (pMAT1 or pEBB10). Appropriate dilutions of the cultures were also spread on LB medium in order to determine the frequency of transposition. For each strain, the plasmids of at least 100 Tcr or Sucr clones were analyzed. Three classes of plasmids were distinguished carrying (i) potential insertion sequences (inserts <3 kb), (ii) putative transposons (inserts >3 kb) or (iii) point mutations (replicons of the same size as the trap plasmid). The insertion sites of the elements were localized by performing PCRs with the trap plasmid insertion derivatives (as template DNA) and previously described sets of cassette-specific primers Trap plasmids were introduced into the RifParacoccus ferrooxidans NCCB 1300066 digested with restriction endonucleases NcoI or XhoI. The digested DNA preparations, purified using a Clean Up kit (A&A Biotechnology), were then self-ligated overnight at 16\u00b0C with T4 DNA ligase (Fermentas). The ligation mixture was used as the template for amplification by PCR of the DNA flanking Tn6097 in the host genome. The synthetic oligonucleotides used in PCR were LIPCRPF2 and RIPCRPFE (Templates for inverse PCR (IPCR) were prepared from total DNA of RIPCRPFE .Dot blot analysis was performed using a Bio-Dot apparatus (Bio-Rad) according the manufacturer's instructions. To determine copy number of TEs in parental strains Southern blotting was carried out as described by Sambrook and Russell tetA gene in this vector) were analyzed to localize the TE-derived promoters. Deletion analysis was performed for two of the analyzed elements (Tn5393 and Tn6097), by removal of different parts of the inserted TE by digestion with appropriate restriction enzymes, followed by religation and characterization of the resistance phenotype. The constructed mutants contained different parts of the 3\u2032-end of the transposon, adjacent to the promoterless tetA gene. For the insertion sequences ISPam1, ISPkr1 and ISPaes3, PCR was applied to amplify (i) the terminal 3\u2032-end DNA fragments of the elements and (ii) analogous fragments with an attached short DNA region of the trap plasmid, adjacent to the target site of transposition (identification of possible hybrid promoters). The amplified DNA fragments were cloned into pCM132TC (Tcs) upstream of the promoterless tetA gene or into pCM132 upstream of promoter-less lacZ reporter gene. The presence of a promoter (tested in Paracoccus spp. hosts) resulted in a Tcr phenotype (pCM132TC) or expression of \u03b2-galactosidase (pCM132). \u03b2-galactosidase activity was measured as previously described A pool of derivatives of the trap plasmid pCM132TC (containing inserted TEs able to drive transcription of a promoterless http://www.ncbi.nlm.nih.gov/). G+C plots were created using the program Artemis 6097 and Tn6122 was assigned by the Tn Number Registry website according to the generally accepted nomenclature Nucleotide sequences of TEs were determined using a dye terminator sequencing kit and an automatic sequencer (ABI 377 Perkin Elmer). A combination of vector-derived primers and primer walking was used to obtain the entire nucleotide sequences. Similarity searches were performed using the ISfinder The nucleotide sequences of the elements identified in this study have been submitted to the ISfinder and GenBank databases. Accession numbers of the sequences are given in Paracoccus spp. we used mobilizable trap plasmids pMEC1, pMMB2, pMAT1, pEBB10 and pCM132TC carrying three types of cassette enabling positive selection of transposition events (see cI-tetA or sacB cassettes) enable the capture of all types of TEs, irrespective of their structure, specific features and genetic load. In contrast, pCM132TC only permits the identification of elements containing strong outwardly oriented promoters or those able to generate hybrid promoters, which drive the transcription of nearby genes.To identify functional TEs of ents see . The plaParacoccus spp. and pools of clones carrying mutated plasmids were obtained and analyzed as described in 3 family .The trap plasmids were introduced by conjugation into 25 strains of 3 family and 2. TThe nucleotide sequences of the captured ISs were subjected to detailed analysis. All contained a transposase gene(s) and terminally placed inverted repeat sequences (IRs). Moreover, all were able to generate DRs at the target site of transposition . Since tParacoccus spp. ISs identified in this study. Analogous analysis was also used to compare the nucleotide sequences of the terminal IRs of the ISs , which contain three conserved residues (two aspartate and one glutamate) constituting the DDE motif , that is highly conserved in the majority of bacterial TPases the ISs .1248f, ISPko1a, ISPpa3a, ISPpa5a and ISPve1a. In only four cases we found completely identical elements residing in different bacterial strains \u2013 ISPpa2, IS1247, IS1248 and ISPpa8. The identified ISs and their characteristics are presented in Preliminary analysis revealed that the vast majority (32) of the identified ISs were novel elements. In five cases, we captured ISs that were highly related to known elements \u2013 ISParacoccus spp. could be classified into the following families: (i) IS3 family (IS407 group) \u2013 4 captured elements, (ii) IS5 family \u2013 22 elements, (iii) IS6 family \u2013 2, (iv) IS21 family \u2013 3, (v) IS66 family \u2013 2, (vi) IS256 family \u2013 1, (vii) IS1182 family \u2013 1, (viii) IS1380 family \u2013 1, and (ix) IS1634 family \u2013 1.Based on the results of these comparative analyses, the ISs of 407 group of the IS3 family and IS427 group of the IS5 family) carry two overlapping ORFs and possess a conserved frameshift motif (1 of E. coli) 1 and IS3 families As shown in ft motif , which i427 group of the IS5 family is a natural point mutant, because, in contrast to other elements of this group, it carries a single large ORF encoding a functional DDE transposase.Interestingly, we found that one of the members of the IS21 and IS66 families besides the transposase gene(s). In most cases, the specific role of the predicted proteins encoded by these ORFs is unknown, although it is highly probable that they are involved in the regulation of the process of transposition. Such multi-ORF structures are typical for members of the ISfamilies .427 group of the IS5 family (8 ISs) contain, within their left IR , a sequence partially matching the consensus sequence of the integration host factor (IHF) binding site (5\u2032- WATCAANNNNTTR -3\u2032) 10427 group.We also performed a detailed inspection of the nucleotide sequences of the captured ISs in order to predict any DNA sequences that may constitute a site of interaction with host-encoded factors. This analysis revealed that the majority of the elements of the IS6097 , which was captured in P. ferrooxidans NCCB 1300066 using the trap plasmid pCM132TC. A summary of the predicted ORFs of Tn6097, including their position, the size of the encoded proteins, and their closest homologs is presented in The only composite transposon identified in this study was a novel element, designated Tn6097 into the selective cassette of pCM132TC generated 6-bp DRs. This transposon contains two identical, convergently oriented copies of ISPfe2 (1884 bp), that are responsible for its mobility (Betaproteobacteria), share 51% aa sequence identity.Transposition of Tnmobility . Using tPfe2 flank the large core region of Tn6097, comprised of 13,991 bp. The average G+C content of this region is 63.6 mol%, which is lower than that of the total DNA of the native host P. ferrooxidans NCCB 1300066 (67 mol%). The core region contains 12 ORFs whose putative products show similarity to proteins conserved in many bacteria, including some involved in the metabolism of nitrogen compounds and resistance to chemotherapeutics. Based on the predicted functions of the ORFs, they may be divided into three clusters, which can also be differentiated by the G+C content of their nucleotide sequences (data not shown).The two copies of ISP. pantotrophus5-formyltetrahydrofolate and ATP into 5,10-methenyltetrahydrofolate, ADP and phosphate, which results in the creation of carbon-nitrogen bonds due to the cyclo-ligase activity The first cluster contains four ORFs (ORF2-ORF5) encoding6097 contains four ORFs (ORF6-ORF9) arginine/ornithine antiporter (ArcD), (ii) arginine deiminase (ArcA), (iii) ornithine carbamoyltransferase (ArcB) and (iv) carbamate kinase (ArcC), respectively. The arcABCD operon of Tn6097 exhibit the highest nucleotide sequence similarity (76%) and synteny to homologous genes in plasmid pOANT03 of Ochrobactrum anthropi ATCC 49188 (accession no. NC_009671).The second cluster of TnF6-ORF9) with sig6097 consists of three ORFs (ORF10-ORF12) adjacent to the right-hand copy of ISPfe2, which encodes a putative NAD-dependent epimerase/dehydratase that is most similar (85% aa identity) to a protein of P. denitrificans PD1222 (The third putative genetic module of Tn0-ORF12) encodings PD1222 .6097 is present in one copy in the P. ferrooxidans NCCB 1300066 genome (data not shown). Using inverse PCR (IPCR) we determined the nucleotide sequence of its original target site in the host genome (see 6097 is located within a gene (disrupted upon transposition), whose predicted product shows similarity to a number of bacterial proteases. The highest identity (67%) was observed with a htpX gene of Polymorphum gilvum SL003B-26A1 (accession no YP_004302375). The transposon was flanked by 6-bp long DRs (5\u2032-GGCTCG-3\u2032), confirming that it had been incorporated into the host genome by means of transposition.DNA hybridization analysis revealed that Tn3 family of transposons. Two of the identified transposons (Tn6122 and Tn3434a) were identified as cryptic elements, solely encoding genetic information required for transposition was the presence of two putative genetic modules (responsible for transposition and resolution of cointegrates resulting from replicative transposition), which are highly conserved in members of the Tnposition .6122 (3792 bp) was captured in P. halophilus JCM 14014 using the trap plasmid pMEC1. This element is composed of (i) identical 39-bp IRs, (ii\u2013iii) two divergently oriented ORFs encoding a large transposase protein and a resolvase (TnpR) as well as (iv) an AT-rich putative recombination site (res) separating the ORFs (this region is involved in cointegrate resolution and regulation of expression of the tnpA and tnpR genes) Alphaproteobacteria: (i) Sulfitobacter sp. NAS-14.1, (ii) Ruegeria sp. PR1b and (iii) Roseovarius sp. TM1035. These transposons encode highly related transposases and resolvases, and are bordered by IRs identical to those of Tn6122 (data not shown).Tn3434a (3695 bp), identified using pEBB10 in P. aminophilus JCM 7686, is an isoform of the transposon Tn3434, that we trapped previously in P. pantotrophus DSM 11072 3434 (36 mismatches). The resolvases encoded by these elements are 100% identical, while their transposases differ in 30 aa (data not shown).The second trapped cryptic transposon, Tn3434a is also related to Tn6122. As shown in TnP. pantotrophus LMD 82.5 contains a non-composite transposon Tn5393, which is another member of the Tn3 family 3434a and Tn6122, carries two streptomycin resistance genes (strA and strB) placed downstream of the tnpR gene and their sequence identity is only 50% (14 mismatches). In contrast, the IRs of Tn5393 are much longer (81 bp with 4 mismatches between IRL and IRR), but their termini show significant similarity to those of Tn3434a, Tn6122 and other members of the Tn3 family , which was previously identified in this strain During analysis carried out in Analyses performed using trap plasmids not only enabled the capture of many functional TEs but also identified specific features of several elements, including their ability to (i) activate transcriptionally silent genes, (ii) generate deletions within the target sites of transposition and (iii) transpose at unusually high frequency.903 group of the IS5 family (ISPam1 and ISPpa8), (ii) the IS407 group of the IS3 family (ISPam3 and ISPfe1), (iii) the IS21 family and (iv) the IS256 family (ISPaes3). We also captured two transposons: (i) Tn5393 of the Tn3 family and (ii) the novel composite transposon Tn6097 bordered by two copies of ISPfe2 (IS1634 family).Using the trap plasmid pCM132TC (contains a promoterless tetracycline resistance gene as the selection cassette) we identified several TEs that are able to drive the transcription of promoterless genes placed downstream of the target site of transposition. The majority of the elements identified in this way were insertion sequences from four different groups: (i) the ISr clones, as described in 5 (IS903 group), IS3 (IS407 group) and IS21 families (256 member) (5393 of the Tn3 family) a member) , (iii) t family) , or (iv)y) which naturally occurs in strain DSM 11073.An unexpected phenomenon was observed upon selection of TctetA gene). The inserted trap plasmid was bordered by two copies of the insertion sequence IS1248 (IS427 group of the IS5 family), which strongly suggests that co-integrates were generated upon replicative transposition of this IS the appearance of a DNA band corresponding to the resolved trap plasmid. In contrast, we were never able to detect individual replicons when plasmid DNA was isolated from bacteria grown in medium supplemented with tetracycline, which strongly suggests that this antibiotic provides selection for the maintenance of the co-integrates.1248. When introduced into the strain DSM 11073, this plasmid (pCM132TC::IS1248), did not confer the Tcr phenotype, which precludes the possibility that a promoter of the IS may drive transcription of a nearby gene.DNA sequencing of the selection cassette of the resolved trap plasmid confirmed the presence of an inserted copy of IStetA gene in the co-integrate is driven by a promoter located within pKLW1. This conclusion is supported by the DNA sequence of regions flanking the original insertion site of IS1248 within pKLW1 and the detection of activity of the upstream promoter (These observations indicate that expression of the promoter .Pmar2 of P. marcusii DSM 11574 and ISPve1 of P. versutus UW400) into selection cassettes could be accompanied by deletions at the transposition target site.The transposition of the vast majority of TEs identified in this study resulted in the simple insertion of the elements into the trap plasmids and the generation of DRs. However, we found that the insertion of two ISs (ISPmar2 (IS407 group of the IS3 family) we identified only one deletion mutant . The deletion (15 bp) occurred at the 3\u2032-end of the inserted IS, and therefore the intact element was not bordered by the DRs, in contrast to the other clones tested.In the case of ISPve1 (IS21 family), which frequently generated much larger deletions within the selection cassettes of various trap plasmids. Initial analysis of a pool of Tcr clones of strain UW400 (obtained with pMEC1) revealed the presence of two types of pMEC1 mutants representing either (i) simple insertion of ISPve1 (7% of Tcr clones), or (ii) insertion of ISPve1 associated with deletions within the trap plasmid (16%). The remaining Tcr clones did not contain any TEs.More interesting was the case of ISPve1 resulted in the generation of 8-bp long DRs. Moreover, in both the insertion and deletion mutants, the element was always placed in the same orientation within the cI gene of pMEC1 and in each case, the location of the replication system was the factor limiting the range of deletions generated within the plasmid was observed for ISPaes3 of P. aestuarii DSM 19484. In contrast, the element most dynamic in transposition was Tn5393 (P. pantotrophus LMD 82.5), which transposed into the selection cassette of the trap plasmid pCM132TC at a very high frequency (10\u22123). This is in agreement with our previous observations performed in the strain LMD 82.5 with pMEC1 In most cases, the frequency of transposition of the captured TEs ranged from 10rain see . The lowP. pantotrophus DSM 11072. Surprisingly, in this case, the vast majority of the transconjugants (92%) did not contain pMEC1 (9.4 kb) but they carried a very large replicon (>50 kb), that was not originally present in DSM 11072. The remaining transconjugants (8%) contained intact pMEC1. DNA hybridization followed by DNA sequencing revealed that the large nascent plasmids are in fact insertion mutants of pMEC1. They were generated by transposition into the trap plasmid of a large previously described composite transposon TnPpa1 3 family transposon Tn3434, which border the core region of the element containing a set of genes conserved in the chromosomes of many bacteria Ppa1 into pMEC1. Intriguingly, all the transposon insertions were detected in randomly tested Kmr transconjugants, i.e. without applying positive (tetracycline) selection for the identification of transposition events. DNA sequencing of several insertion derivatives of pMEC1 confirmed that transposition of TnPpa1 had targeted random parts of the trap plasmid. In each case the inserted element was bordered by DRs, of a length typical for other members of the Tn3 family (5 bp) (data not shown).TnPpa1 is able to transpose as frequently into other replicons. For this purpose, several mobilizable plasmids were transferred into strain DSM 11072R. The plasmids contained different replication systems derived from (A) three broad host range replicons \u2013 (i) RA3 , (ii) RK2 (pCM132TC) and (iii) pBBR1 , as well as from (B) three plasmids originating from Paracoccus spp. \u2013 (i) pMAR4 of P. marcusii DSM 11574 (pDG12), (ii) pAMI7 of P. aminophilus JCM 7686 (pDIY703) and (iii) pTAV1 of P. versutus UW1 (pMMB2).We also tested whether TnPpa1 into plasmids containing replication systems of pMAR4 and pAMI7 as well as into all derivatives of RA3 , but not into the other tested plasmids (data not shown). This strongly suggested that the observed transposition phenomenon is dependent on the nature of the incoming replicon.Analysis of the plasmid content of the obtained transconiugants revealed massive transposition of TnSouthern blotting and DNA hybridization analysis were performed to examine the copy number and genomic location (plasmid/chromosome) of the identified TEs in their natural hosts.Paracoccus spp., which most probably reflects the replicative transposition of some of these elements. As shown in 427 group of the IS5 family , (ii) the IS903 group of the IS5 family , (iii) the IS407 group of the IS3 family , and individual members of (iv) the IS21 family (ISPve1a) and (v) the IS66 family (ISPpa7). Some of the detected IS copies displayed different signal intensities in the hybridization analysis, which most probably reflects divergence in the nucleotide sequences of closely related elements or the presence of truncated copies of the same element (data not shown).The analysis revealed that most of the identified insertion sequences were present in multiple copies in 5 family , (ii) the IS6 family and (iii) the IS256 family (ISPaes3), as well as for the identified transposons .In contrast, a low copy number (1\u20132 copies) was observed for all members of (i) the IS5 group of the ISP. aminophilus JCM 7686, P. halophilus JCM 14014, P. kondratievae NCIMB 13773T, and P. marcusii OS22 that were available in 2009, when this project started. In total, we tested approximately 7000 individual clones to identify trap plasmid insertion derivatives. However, despite the complexity of this analysis, it is obvious that not all the TEs residing in Paracoccus spp. were defined; we only identified those that are the most dynamic in transposition, i.e. elements of highest evolutionary impact. As a result, we captured 41 elements representing (i) insertion sequences, (ii) an IS-driven composite transposon and (iii) non-composite transposons of the Tn3 family.The genus Paracoccus spp. As expected, the vast majority of the captured elements were insertion sequences. We identified 47 elements, representing 10 IS families: IS3, IS5, IS6, IS21, IS66, IS256, IS1182, IS1380, IS1634 and ISAs1. Interestingly we did not encounter elements of the IS1, IS4, IS91 or IS110 families, which are widely distributed among other bacteria In total, together with our previous studies Paracoccus spp. were members of the IS5 family (26 elements), while only single elements from the ISAs1, IS1182 and IS1634 families were captured. However, dot blot DNA hybridization revealed that TEs are much more abundant in Paracoccus spp. than we had expected. These results suggest that each tested strain carries elements belonging to several different families .Southern blotting and DNA hybridization analysis revealed that most of the ISs identified in 6097 carries two putative conserved genetic modules. Specific functions of closely related modules have previously been determined in other bacterial hosts. One of the modules carries most probably genes involved resistance to daunorubicin and doxorubicin (used in the treatment of some types of cancer arcABC genes), which enable bacteria to grow anaerobically in the presence of arginine. The enzymes mediate the conversion of arginine to ornithine, NH3, and CO2, with the generation of ATP. It has been shown that this pathway constitutes a major source of energy for several microorganisms, e.g. strains of Mycoplasma spp., Pseudomonas spp. and Bacillus spp. TnP. ferrooxidans NCCB 1300066 (host strain of Tn6097) is unable to grow anaerobically in the presence of arginine (data not shown), which suggests that the arcABCD operon may be not functional. It has been previously demonstrated that anaerobic expression of the closely related operon of Pseudomonas aeruginosa, requires a transcriptional activator 6097. It is therefore possible that the ADI module of Tn6097 may be functional exclusively in the strains encoding a compatible transcription regulator.However, we have observed that 3 family, which represent different stages in the evolution of this group of transposons. It is believed that the Tn3 transposons originate from progenitor IS elements , which acquired an additional genetic module involved in site-specific resolution of cointegrates (intermediates of replicative transposition) as well as other genes whose products can directly affect the phenotype of their host We have also identified several non-composite TEs of the TnParacoccus spp. we identified two cryptic transposons (Tn6122 and Tn3434a) that contain the conserved module for site-specific recombination. We also captured the transposon Tn5393 (closely related to Tn3434a), which apart from the resolvase module, carries two additional streptomycin resistance genes of P. pantotrophus DSM 11072, which can be considered a composite transposon generated by two copies of the non-composite Tn3434Ppa1 provides evidence that the Tn3-family transposons (similarly to ISs) are able to mobilize large segments of genomic DNA for transposition. The generation of such composite elements seems to be very rare because of transposition immunity (a phenomenon that is thought to apply to members of the Tn3 family), which precludes transposition of more than one copy of the element into a single replicon Ppa1, composed of two identical copies of Tn3434, has a unique structure and, to our knowledge, is the only element of this type identified so far.The next step in the evolution of TnPpa1 is able to transpose into random sites of several mobilizable plasmids with unusually high frequency, not previously observed for any other bacterial TE. Our observations strongly suggest that the massive transposition of TnPpa1 might result from the specific features of the transferred plasmids. Irrespective of the precise mechanism of TnPpa1 transposition, it is clear that targeting of mobilizable or conjugal plasmids contributes to the dispersal of this element among bacterial populations. Within its core region, TnPpa1 carries a number of genes , whose presence may potentially improve the ecological fitness of the host cells Alphaproteobacteria In this study, we found that Tn\u22123) of another member of the Tn3 family: the streptomycin resistance Tn5393 (P. pantotrophus LMD 82.5) \u2013 far higher than that observed for other non-composite members of this family (3434 was 10\u22126) 5393 explains the wide dissemination of this transposon in many bacterial isolates In this study, we also observed very frequent transposition , and (ii) a transposon of the Tn3 family (the aforementioned Tn5393).We showed that activation of nearby genes is a typical feature of insertion sequences of the ISr phenotype (activation of the promoterless tetA gene of pCM132TC) were examined in detail. This analysis revealed that transposition-mediated delivery of promoters to transcriptionally silent genes can occur in at least five ways , which was prone to generate deletions within target DNA molecules . This indicates that transposition may significantly shape plasmid genomes and promote plasmid diversity, which could have significant evolutionary implications.Another interesting phenomenon observed in this study was connected with the insertion sequence ISolecules . The tra21 family identified in this study, including ISPve1a, an isoform of ISPve1 from P. bengalensis DSM 17099 (99% identity at the nucleotide sequence level). The high frequency of deletions generated by ISPve1 (in comparison with \u201cpure\u201d insertion events) might therefore be a specific feature of this element. Alternatively, it might result from the presence of host factors, which stimulate such deletions. The latter hypothesis is supported by data recently published by Kusumoto et al.Pve1 and the strain P. versutus UW400 are necessary to determine the likelihood of these two possibilities.Interestingly, this \u201cdeletion\u201d phenomenon was not observed for other members of the ISPme1Paracoccus spp. It should also be borne in mind that many TEs (including composite transposons and TMos) cannot be distinguished in bacterial genomes by classical in silico sequence analysis, unless they have been inserted into a highly conserved genetic context (e.g. a trap plasmid selection cassette), to enable precise definition of their termini. For this reason, the identification of functional TEs using trap plasmids may produce many interesting and surprising findings even when carried out in bacteria whose genomes have been fully sequenced.To conclude, the analysis performed in this study together with our previous work concerning the identification of diverse TMos generated by a single copy of ISParacoccus spp. has also generated considerable interesting and unique data concerning the dynamics of the process of transposition of IS-families identified in Paracoccus spp. . The sequences used for the comparisons were obtained from the ISfinder database (http://www-is.biotoul.fr/is.html). Sequence alignments were performed with the Pictogram program . The size of the letter in Pictogram represents the frequency of the occurrence of that nucleotide at each position. In the consensus sequences, shown below each Pictogram, uppercase letters indicate conservation within the IS family, lowercase letters indicate the predominant nucleotides, and dots indicate non-conserved residues. The family and group specific DDE motifs determined by multiple alignment of the amino acid sequences of the transposases of ISs present in the ISfinder database has been shown in the middle of the figure (Paracoccus spp.(TIF)Click here for additional data file.Table S1Oligonucleotides used in this study.(DOC)Click here for additional data file.Table S2ORFs located within Tn6097 of Paracoccus ferrooxidans NCCB 1300066.(DOC)Click here for additional data file.Table S3Rate of transposition of the TEs of Paracoccus spp. identified in this study.(DOCX)Click here for additional data file."} +{"text": "To establish the clinical spectrum of food related gastroenteropathy in children.30 children with allergic bowel disease were identified from general and paediatric allergy outpatient clinics and studied retrospectively from the bowel as well as other allergy and management point of view.24 of the children (80%) exhibited symptoms of gastro-oesophageal reflux disease, 28 children (93%) had lower GI symptoms and 23 children (77%) had significant sleep problems. 19 out f the 30 children (63%) had other atopic disorders. The most common food trigger was cow\u2019s milk others included egg, soya, wheat, fish, and nuts. Family history of atopy was seen in 24 children (80%). Skin prick tests were positive in only 7 children (23%) suggesting this is a non-IgE mediated phenomenon. Management of these children included diet exclusion, anti-reflux and anti-allergy medication. 12 children (44%) responded poorly to treatment and required steroids and 8 (30%) required biopsies. In families with more than one child with allergic gastroenteropathy, diagnosis and treatment with anti-reflux, diet exclusion and anti-allergy medication was started much earlier (2m-2yrs) in the younger sibling.In children the triad of upper and lower GI symptoms, other atopic disorder and a strong family history of atopy suggests a diagnosis of allergic bowel disease . This condition is diagnosed commonly as Gastroesophageal reflux disease with milk allergy but this fails to recognise the significant mid and lower bowel component in most of these children, which can be considered as an allergic inflammatory bowel disease. It is neither necessary nor essential to biopsy all these children in view of the response to anti allergy and anti inflammatory measures as well as the large number of children with this problem. Biopsies when positive may have esoinophils, hence this may represent the milder end of the spectrum of eosinophilic gastrointestinal disorder (EGID). The management of allergic gastroenteropathy ranges from dietary exclusion, anti-reflux & anti-allergy medication to immunomodulators in severe cases."} +{"text": "The purpose of this study was to analyse assessment of the axilla in patients with primary operable breast cancer in a one-stop symptomatic breast unit.A retrospective review of 229 patients diagnosed with new primary operable breast carcinoma over a 12-month period. All patients underwent axillary ultrasound (US). All cases with normal US had subsequent sentinel lymph node biopsy (SLNB). All cases with abnormal US underwent fine needle aspiration cytology (FNAC). Findings were correlated with SLNB and axillary node clearance histology.A total of 128 patients had normal US and subsequent SLNB, this was positive in 29 (23%); 12 (40%) had micro metastases; primary tumour size was >2 cm in 22 (76%). Positive predictive value for US and FNAC was 97%. Negative predictive value was 75%. False positive and negative rates for US axilla are discussed with analysis of tumour subgroups and pattern of positive nodes.The combination of US and FNAC is a powerful predictive tool of axillary disease . Disappo"} +{"text": "Traumatic brain injury (TBI) is a major cause of permanent disability and death in young patients. Controversy exists regarding the optimal cerebral perfusion pressure (CPP) required in TBI management. A tool for monitoring autoregulation and determining an optimal CPP is the pressure reactivity index (PRx), defined as a moving correlation coefficient between the mean arterial blood pressure (MAP) and intracranial pressure (ICP) at a frequency of at least 60 Hz. This requirement of high frequency has constrained its use to a few academic centers. An association was shown between outcome and continuous optimal CPP based on 4 hours of PRx . We presA total of 182 patients from the Brain-IT [On the Brain-IT database, LAx resulted in an optimal CPP for 90% of the first 48 hours. Table The differences in optimal CPPs derived from PRx and LAx were not clinically significant. LAx allowed for recommendations to be computed for longer periods. Significantly better outcome Table was obse"} +{"text": "The purpose was to assess factors that may influence the use of IM modalities by ID physicians in their practice.In a 2010 national survey of 1000 practicing ID physicians, participants were asked to report the extent to which the following considerations played a role in their recommendation/referral of IM modalities: (1) Knowledge of how and when to use them; (2) Amount of clinical research showing clear benefit; (3) Insurance; (4) Cost; (5) Reliable referral base; (6) Concern for professional reputation; (7) Fear of judgment from colleagues; (8) Insufficient regulatory oversight of supplements; and (9) Potential drug interactions with botanicals/supplements.A total of 311 (31%) ID physicians responded to the survey. The mean age was 49 and 64% of respondents were male. Their responses to the questions are listed below.For ID physicians, factors that were considered a major influence on the use of IM modalities included: potential drug interactions, clinical research, knowledge of IM modalities, and regulatory oversight. Factors that played a minor/no role in the use of IM modalities included fear of judgment and concern for professional reputation."} +{"text": "Objective: The immunochromatographic rapid tests facilitate the early diagnosis of dengue by providing evidence of the presence of virus specific proteins (antigens/ antibody) in human blood. Many products for rapid dengue diagnosis are available in the market; the performance of few selected products was evaluated and compared with enzyme linked immuno sorbent assays (ELISA).Methods: Sera from a large number of patients (n=184) admitted to National Institute of Blood Diseases & Bone Marrow Transplantation (NIBD) were used to determine the efficiency of non-structural (NS) 1, IgA, IgG and IgM based rapid test devices for dengue diagnosis.Results: The dengue NS1 antigen based device was least efficient while among the antibody based devices the dengue IgA rapid test (RDT) was comparatively better . This device could detect both primary and secondary dengue infection and was found to be the most sensitive device at all point of sample collection.Conclusion: The dengue IgA RDT could be a cost effective and efficient rapid test device for timely dengue diagnosis at all levels of healthcare settings. DHF is a vasculopathy characterized by capillary leakage and haematological deregulation; may result in fatal outcomes.8 An early and accurate diagnosis of dengue is important which assist not only in patient management by directing clinical attention but also in initiating community scale preventive measures for vector control to alleviate further dengue transmission. Commercial ELISA tests as well as immunochromatographic tests (RDT) that detect anti-dengue antibodies and the dengue NS1 antigen in plasma/sera have provided a new avenue for diagnosing dengue.9,10 In addition to this, the inexpensive and accurate dengue RDTs may also be useful in dengue epidemiological studies in resource limited countries. The primary and secondary dengue infections are diagnosed by the detection of either IgM or IgG or both in patient\u2019s serum.8 These anti-dengue antibodies appear late in serum i.e. after 5-6 days of infection so NS 1 protein is detected in routine diagnosis during this period. The NS1 antigen appears in high concentration during the first few days of illness and it stays in serum after the infection subsides i.e. up to 14 days.10,11 Beside viral antigen detection a newer approach to dengue diagnosis is the use of anti-dengue IgA based RDT devices.12 IgA is the principal secretory antibody and human serum contains very low concentration of IgA1. During secondary dengue infection considerable increase in serum anti-dengue IgA is observed. The anti-dengue IgA is documented as the first antibody to appear in case of secondary dengue infection prior to IgG and IgM production while in case of primary infection it is produced after the anti-dengue IgM antibody due to class switching.13In the past few decades dengue has become a global health problem infecting millions of individuals annually.14 In this report three commercially available rapid diagnostic test devices were compared. Serological tests for dengue NS1 antigen, dengue IgA, dengue IgG/ IgM antibodies were carried out to demonstrate the potential application of these kits in early laboratory diagnosis of dengue infection with the special emphasis on utility of dengue IgA RDT as one of the new dengue diagnostic markers.12 The results were also compared with more specific and sensitive gold standard methods of dengue diagnosis i.e. IgG and IgM capture ELISAs.In Karachi, most of the clinical diagnostic facilities are using commercial immunochromatographic rapid tests (RDT) from international manufacturers relying only on the supporting literature on the efficiency of these devices. No local data on the efficacy and sensitivity of most of these tests is documented.Study design: A panel of 184 dengue disease suspected human serum samples was used for the evaluation of efficacy of dengue immunochromatographic tests (RDT).8 The study was conducted during the period of August to December 2010 at National Institute of Blood Diseases (NIBD). A signed informed consent form and detailed questionnaire were obtained from patients involved in this study following institutional review board (IRB) policies. Age range of the study population was 2-65 years.8 In the present study any sample positive for either dengue specific-antigen (NS1) or antibodies (IgM or IgG or IgA) by RDT screening was considered as positive dengue case. All samples were characterized using dengue acute diagnostics: NS1 Ag Rapid Test , ASSURE\u00ae dengue IgA Rapid Test and dengue Duo Cassette . The efficiencies of all these devices were evaluated by comparing with dengue IgM capture ELISA and dengue IgG capture ELISA . Complete blood count (CBC) was performed; after proper mixing by automated hematological analyzer; Sysmex XE-2100 ; to evaluate the clinical parameters of dengue diagnosis .A probable dengue case may be a patient with presentation of defined clinical symptoms and history of acute febrile illness of 2\u20137 days with or without haemorrohage.Dengue Antibodies ELISAs: Dengue IgM-Cap ELISA and IgG-Cap ELISA were used to detect dengue antibodies as per manufacturer\u2019s instruction. Briefly, 100 \u00b5l/well of patient sera (diluted 1:100) and controls were added to the assay plate coated with either anti-human IgM or anti-human IgG to capture the IgM or IgG. Both plates were incubated for one hour at 37C. Then the plates were washed and 100 \u00b5l/well of enzyme conjugate was transferred to the assay plates except the blank wells. After 10 minutes, the reaction was stopped by addition of 100 \u00b5l/well 1 M phosphoric acid. The OD values were determined at 450 nm. A sample was defined as positive when ratio of sample absorbance and calculated cut-off value was > 1.Dengue NS1 Ag Rapid Test: Dengue NS1 Ag Rapid Test is a one-step chromatographic assay which uses murine monoclonal antibodies to capture dengue virus NS1 antigen in human serum or plasma and detected by NS1 antigen polyclonal antibodies conjugated with gold colloid. Assays were conducted and results were interpreted according to the instruction of manufacturers.Dengue IgA Rapid Test: ASSURE\u00ae Dengue IgA Rapid Test (WO 2009/139725 ) is a reverse flow technique (US Patent-6316205) immunochromatographic rapid test for the qualitative detection of anti-dengue IgA from patient\u2019s biological samples . In this platform, test sample migrates upwards from the sample well and eventually form antibody-antigen complexes with dengue virus antigens in the test window. The bound antibody-antigen complexes is subsequently detected by goat anti-human IgA gold conjugate carried by chase buffer that flows downwards giving a pink-purplish color line in the test window. Control line which contains protein L captures human IgA from patient\u2019s sample and binds with the anti-human IgA-gold conjugate, resulting in pink-purplish color line in the control window. The appearance of control line indicates the proper addition and migration of serum sample and chase buffer. The test was performed as per manufacturer\u2019s instruction for use (IFU) and results were interpreted according to the intensity scale provided with the kit box without knowledge of the results of other tests.Dengue Duo IgM/IgG Cassette: Dengue Duo Cassette is a lateral flow based immunochromatographic rapid test for the qualitative detection of anti-dengue IgM and IgG from patient\u2019s biological samples . The device is designed to detect IgM antibodies to dengue, as well as elevated IgG titers that are indicative of a secondary infection. The rapid tests were read and interpreted according to the manufacturers' instructions. The positivity of individual marker were calculated separately (IgM or IgG) as well as in combination (IgM and IgG).Statistical analysis: The quantitative variables were expressed as mean, standard deviation, confidence interval and minimum and maximum range. The qualitative variables were mentioned as percentages. The sensitivity and specificity of immunochromatographic tests were analyzed by 2x2 table using MedCalc statistical software, version-11.5 . Kappa value was used to test the efficiency and reliability of the rapid devices.Characteristics of the study population: The characteristics of the study population (n = 184 cases) that contributed acute sera to the test panel is shown in Sensitivity and specificity of dengue immunochromatographic tests versus reference dengue tests: The sensitivities and specificities of three RDTs against the reference tests i.e. dengue IgM-cap ELISA and IgG-cap ELISA are presented in Immunochromatographic tests sensitivity in primary or secondary infection: The detection of both dengue primary and secondary infected patients by dengue IgA RT was significantly higher than Panbio IgM/IgG Duo RDT and is presented in Sensitivity of Immunochromatographic tests by day of illness: The sensitivity of three RDTs was also evaluated based on the duration of onset of dengue fever, categorized into 6 groups and 86.05% (80.95%) respectively. Additionally, the level of detection of infection at all stages of disease by IgA RDT was far better false negative results. Dengue NS-1 antigen can be found in patient\u2019s serum until the production of anti-NS-1 IgG or in some instances a few days after defervescence. The variable levels of NS-1 antigen in different phases of infection might be due to the immune-complex formation of NS1 antigen with anti-dengue IgG resulting in less sensitive dengue detection in acute-phase secondary infection as reported previously.21We conclude that the serological testing for early diagnosis of dengue infections could be accomplished by using IgA based RDT at all heath care settings during any stage of infection cycle. Moreover, it partially overcomes the limitations associated with ELISAs like handling of single sample without delay."} +{"text": "The cGMP-dependent protein kinase (PKG) is widely expressed in mammalian tissues and serves as an integral component of second messenger signaling in a number of biological contexts including vasodilation, motility and memory . PKG assHere we report the 2.5 \u00c5 crystal structure of a regulatory domain fragment containing both tandem cGMP binding sites of PKG I\u03b1 (amino acids 78-355). The overall domain topology of this structure shows a distinct and segregated architecture. The cGMP binding sites are separated by an extended central helix and offer limited interdomain communication. However, a previously uncharacterized helical domain (switch helix) promotes the assembly of a dimeric interface between PKG I\u03b178-355 protomers. Disruption of this interface by alanine scanning mutagenesis in full length PKG resulted in a marked reduction of activation constants.Our results offer new insight about PKG holoenzyme assembly as they provide the first detailed molecular view of tandem cGMP-binding domains and characterize the switch helix as a critical site of interchain communication between PKG protomers. The biological integrity of PKG appears to be mediated by this interface as it is necessary for the maintenance of kinetic fidelity. This structure highlights the critical importance of dimer communication in PKG biology and will likely serve as an improved platform for the strategic development of therapeutic agents aimed at treatment and prevention of cGMP-dependent pathologies."} +{"text": "This is a case report of a previously undescribed 20q chromosomal deletion (del(20q)) in marginal zone lymphoma (MZL). A 54-year-old Caucasian male presented with an enlarging neck mass and multiple violaceous skin nodules over his chest. Biopsy of the neck mass and cervical lymph nodes revealed MZL. Cytogenetic evaluation of both lymph node and bone marrow tissue revealed del(20q). This was an unexpected finding, as del(20q) is associated with myelodysplastic syndromes and myeloproliferative neoplasms and rarely seen in diffuse large B-cell lymphoma, follicular lymphoma, and T-cell lymphoma, but has not previously been described in MZL. We describe the case presentation and histologic findings and discuss the significance of this novel finding. Del, near 20q12 . There wNodal MZL is one of three subtypes of MZL and its incidence is relatively rare, comprising only 1.5% of all lymphomas , charactThe finding of a del(20q) in both the lymph node tissue and bone marrow samples was an unexpected finding in this case; a diagnosis of nodal MZL could confidently be made by lymph node histological features, IHC and flow cytometric immunophenotyping. The literature has not previously reported del(20q) in MZL. This finding may represent a specific cytogenetic abnormality in this nodal MZL with an aggressive morphology and high-stage disease. In conclusion, this case of nodal MZL with 20q deletion is a novel finding which can expand the breadth of knowledge of chromosomal abnormalities in MZL."} +{"text": "Salmonella enterica serovar Bovismorbificans from isolates associated with the 2011 hummus-borne multistate outbreak. All six genome sequences indicate the presence of two plasmids, one of which demonstrates similarity to the 93-kb pSLT2 IncF-type plasmid of Salmonella\u00a0enterica serovar Typhimurium.We present six draft genome sequences of Salmonella outbreak investigations [http://www.cdc.gov/salmonella/outbreaks.html]). In August through November of 2011, sesame seed paste (tahini) and hummus containing a rare serotype of Salmonella enterica caused illness in 23 people in 7 states and the District of Columbia pattern that was distinctly different from those of other isolates of serovar Bovismorbificans recorded in the Pulse Net Database from patient stool samples, two from hummus samples (SAL616 and 617) from the District of Columbia Public Health Laboratory, and one clinical isolate (SAL682) from the Michigan Department of Health.There are more than 40,000 cases of salmonellosis reported in the United States each year (see the CDC reports of de novo assembly of the paired-end reads to 100 contigs. The genomes were annotated by use of the RAST server (Genomic DNA from each strain was extracted from overnight cultures using QIAcube (Qiagen). The DNA library was constructed according to the Illumina recommended protocol for Nextera XT DNA sample prep and sequenced using Illumina Miseq . CLC bio software version 6.0.1 was used for the trimming and T server .S.\u00a0enterica serovar Typhimurium. In addition to this virulence plasmid, an integration and conjugative element (ICE) similar to ICESb1 found in Salmonella bongori .The draft genome sequence accession numbers for these six"} +{"text": "Massive fluid resuscitation followed by hypoperfusion abnormalities in the ICU is a risk factor for development of intra-abdominal hypertension (IAH). The aim of our study was to determine what influence would have the control of daily fluid balance on the incidence of IAH in patients after extensive abdominal surgery or after abdominal trauma.n = 22) or after abdominal surgery (n = 60). During first 7 days the fluid intake and balance was monitored and corrected at 6-hour intervals not to exceed 1,500 ml positivity over 24 hours . IAP was measured from admission twice daily . A sustained elevation of the IAP above 12 mmHg in two consecutive measurements was considered as IAH.A prospective observational study included a total of 82 adult patients , number of patients with intra-abdominal pressure (IAP) above 12 at admission: 23 (28%), admitted to a single ICU with the diagnosis of abdominal trauma (The incidence of IAH in relation to daily fluid intake and daily fluid balance is shown in Figure The incidence of IAH in patients after abdominal surgery or abdominal trauma may exceed the value of 40%, especially in situations associated with massive fluid resuscitation . We have"} +{"text": "Migraine is 2-3 times more prevalent in women than in men, with frequent perimenstrual attacks. TRPV1 receptors on sensory nerve endings of the trigeminal track are important in mediating migraine attacks by releasing the vasodilator calcitonin gene-related peptide (CGRP). Variation in estrogen levels during the menstrual cycle may have an influence on the sensitivity of the TRPV1 receptor or on the amount of CGRP in perivascular nerve terminals and hence on CGRP release. Capsaicin, the active ingredient of hot chili peppers, stimulates the TRPV1 receptor and causes CGRP-dependent vasodilatation ["} +{"text": "To compare the presence and quantity of cervicovaginal HIV among HIV seropositive women with clinical herpes, subclinical HSV-2 infection and without HSV-2 infection respectively; to evaluate the association between cervicovaginal HIV and HSV shedding; and identify factors associated with quantity of cervicovaginal HIV.Four groups of HIV seropositive adult female barworkers were identified and examined at three-monthly intervals between October 2000 and March 2003 in Mbeya, Tanzania: (1) 57 women at 70 clinic visits with clinical genital herpes; (2) 39 of the same women at 46 clinic visits when asymptomatic; (3) 55 HSV-2 seropositive women at 60 clinic visits who were never observed with herpetic lesions; (4) 18 HSV-2 seronegative women at 45 clinic visits. Associations of genital HIV shedding with HIV plasma viral load (PVL), herpetic lesions, HSV shedding and other factors were examined.10 copies/mL) was closely associated with HIV PVL and HSV shedding but not the presence of herpetic lesions .Prevalence of detectable genital HIV RNA varied from 73% in HSV-2 seronegative women to 94% in women with herpetic lesions . In paired specimens from HSV-2 positive women, genital HIV viral shedding was similar during symptomatic and asymptomatic visits. On multivariate regression, genital HIV RNA (logHIV PVL and HSV shedding were more important determinants of genital HIV than the presence of herpetic lesions. These data support a role of HSV-2 infection in enhancing HIV transmissibility. Herpes simplex virus type-2 (HSV-2) infection is lifelong and a common cause of genital ulcers In vitro studies provide evidence of the effect of HSV-2 infection on HIV replication The frequency of recurrent episodes of clinical herpes and of subclinical viral shedding varies both between individuals and over time within the same individual The objectives of this study were to compare the presence and quantity of cervicovaginal HIV in HIV seropositive women living in Mbeya Region, Tanzania with clinical episodes of herpes, subclinical HSV-2 infection and without HSV-2 respectively; to examine the association between genital shedding of HIV and HSV-2; and to investigate factors influencing the quantity of HIV genital shedding.As part of a study of the determinants of HIV super-infection in Mbeya Region, Tanzania, an open cohort of 600 female barworkers aged 18 to 35 years was established in late 2000. Study procedures have been described previously Treponema pallidum particle agglutination assay and the rapid plasma reagin test .A diagnostic algorithm including two different enzyme-linked immunosorbent assays and a Western Blot assay was used to determine HIV serostatus. Type-specific serological testing for HSV-2 was also performed by enzyme immune assay . Syphilis testing was carried out using the Serodia HIV-1 plasma viral load (PVL) was quantified by transcription polymerase chain reaction (PCR) , with a detection threshold of 50 HIV-RNA copies/ml.T pallidum, H ducreyi and HSV A single dry swab was taken from genital ulcers and multiplex PCR (M-PCR) was used for the detection of 6 cells for HIV-1 DNA. Cervicovaginal specimens were also tested for prostate specific antigen (PSA) using the VITROS immunodiagnostic product PSA reagent and calibrator packs on the automaton Ortho-Clinical Diagnostics VITROS Eci , and for traces of haemoglobin using Multistix 8 SG strips .Cervicovaginal secretions (CVS) were collected from all women at every study visit using standard vaginal lavage procedures Trichomonas vaginalis by direct microscopy of a wet mount preparation and Candida albicans by wet mount preparation and gram stain.Vaginal swabs were tested for CVS specimens collected from HIV seropositive women at 3-monthly study visits were excluded from analyses if (i) the woman had a genital lesion of non-herpetic origin (12 specimens were excluded for confirmed syphilis and 7 specimens excluded for chancroid), (ii) there were traces of haemoglobin in the specimen or (iii) the specimen was positive for PSA. Specimens from (i) were excluded as HSV shedding may have been influenced by other ulcerative STIs, and those from (ii) and (iii) were excluded as any HIV-RNA or HIV-DNA found in the genital tract may not have been attributable to genital shedding from the woman. Specimens were categorised into four study groups according to the woman\u2019s HSV-2 serostatus and the presence or absence of confirmed herpetic genital lesions at the time of specimen collection. Women who experienced PCR-confirmed herpetic lesions at one or more study visits contributed to two study groups: Group 1 included CVS specimens collected in the presence of herpetic lesions; Group 2 , included specimens taken from the same women at follow-up examinations at least 6 months after or 6 months before the visits at which herpetic lesions were detected. In Group 3 (\u201cnever lesions\u201d) a random sample of specimens were taken from HSV-2 seropositive women who never had herpetic genital lesions or a history of genital lesions at any of the study visits. Group 4 (\u201cHSV-2 negative\u201d) was randomly chosen from specimens taken from women not infected with HSV-2.10) transformations were applied to plasma and genital viral loads for HIV and HSV-2 to obtain approximately normal distributions, geometric means (GM), and 95% confidence intervals (95%CI). Differences in mean viral loads between groups were assessed using a random effects linear regression model to account for correlations within subjects. Correlations between viral loads were assessed using Spearman\u2019s rank correlation coefficient.Differences between study groups in proportions of CVS specimens with HIV-1 (RNA and DNA) and HSV DNA above the detection threshold were tested using random effects logistic regression modelling to account for correlations within subjects. Analyses of quantity of genital viral shedding were restricted to specimens with viral loads above the threshold of detection. Logarithmic .Initial analyses suggested that HSV shedding was a strong determinant of genital HIV shedding. We regrouped specimens of HSV-2 seropositive women in the subclinical and never lesions groups according to the presence of HSV shedding (asymptomatic HSV shedders) or absence of HSV shedding (HSV non-shedders). We then used random effects linear regression, accounting for multiple observations from the same individual, to examine the association of log-transformed HIV genital viral loads with HSV shedding status as well as other potential risk factors, including age, laboratory-diagnosed non-ulcerative sexually transmitted infections (STI), signs or symptoms of sexually transmitted diseases (STD), enlarged lymph nodes and HIV plasma viral load. In this analysis, specimens with HIV or HSV genital viral load below the threshold of detection were assigned a value of half the threshold.Analyses were performed using Stata 11.0 . The study was approved by the national ethics review committee of the National Institute for Medical Research of the United Republic of Tanzania and the LSHTM Ethics Committee . It was conducted within the framework of the Mbeya Medical Research Programme. All participants provided written, informed consent to participate in the study.Analyses were based on 221 eligible CVS samples from 131 HIV seropositive women. The four study groups comprised 57 women at 70 study visits with clinically manifest genital herpes (Group 1), 39 of the same women at 46 study visits when they did not have visible ulcers (Group 2), 55 HSV-2 seropositive women at 60 study visits who were never observed with herpetic lesions (Group 3), and 18 women at 45 study visits who were HSV-2 seronegative (Group 4) .Thirty-five women contributed to both Groups 1 and 2; four other women in Group 2 were not sampled at the time of clinical herpes. Three women were HSV-2 seronegative (Group 4) and later seroconverted, two with an episode of clinical herpes (Group 1) and one with no episode of clinical herpes (Group 3). Thirty-three women contributed more than one specimen to the same study group (up to 7 specimens from one HSV-2 seronegative woman).Mean age was around 28 years for HSV-2 positive women and 25 years for HSV-2 negative women. Slightly higher proportions of women were using hormonal contraception among those who had never had lesions, and those who were HSV-2 negative, but this difference was not statistically significant (p\u200a=\u200a0.35).C Albicans was most common in the never lesions group (p\u200a=\u200a0.08), but other STI or clinical signs of STD at the time of specimen collection did not differ significantly by study group in samples from women uninfected with HSV-2 and highest in samples from women with confirmed herpetic lesions. TPPA seropositivity, indicating past or current syphilis, was also lower in the HSV-2 uninfected group (p<0.001), and dy group .The prevalence of detectable genital HIV RNA was lowest in the HSV-2 negative group (73%) and highest in the clinical herpes group (94%) . The gen6 cells) and the lowest in the never lesions group (GM\u200a=\u200a141 copies per 106 cells) . The pattern was less clear than for HIV RNA, but the highest viral load was seen in the clinical herpes group (GM\u200a=\u200a252 copies per 106 cells) .All women with detectable genital HIV RNA also had detectable plasma HIV RNA. Among women with detectable genital HIV RNA, quantities of plasma and genital HIV RNA were significantly correlated .As expected, the prevalence of detectable genital HSV DNA varied substantially between the three study groups of HSV-2 positive women, with a much higher prevalence among women with clinical herpes (77%) than in the subclinical herpes (20%) and never lesions (12%) groups (p<0.001). HSV DNA viral load showed a similar, though non-significant trend .Of the 35 women who had specimens taken during clinical episodes of herpes and also at visits when they were asymptomatic, 30 (86%) had detectable HIV RNA on both occasions, while all 29 women with paired specimens analysed for HIV DNA were positive on both occasions. There was no evidence of a difference in the quantity of genital HIV shed between clinical and subclinical phases of herpes . AlthougTo explore whether signs of clinical herpes or HSV-2 viral shedding were more important determinants of HIV shedding, we re-categorised the specimens into four new groups: clinical herpes, HSV-2 seropositive with detectable genital HSV DNA shedding (asymptomatic HSV shedders), HSV-2 seropositive without detectable genital HSV shedding (HSV non-shedders at that visit), and HSV-2 seronegative. In all four groups, the majority of specimens had detectable HIV RNA and HIV DNA, and the prevalence was highest in samples taken during clinical or subclinical shedding episodes . OverallAmong specimens with HSV DNA shedding (with or without lesions), the genital viral loads of HIV RNA and HSV DNA were positively correlated . The correlation of genital HIV DNA and HSV DNA was weaker , as was the correlation between plasma HIV RNA and genital HSV DNA . A positive correlation between genital and plasma viral loads of HIV was seen in all women . While tGenital HIV RNA viral load increased with quantity of HIV PVL (p<0.001) and presence and quantity of genital HSV DNA . AlthougSimilarly, genital HIV DNA viral load increased with both HIV PVL (p<0.001) and genital HSV DNA viral load . AlthougIn this study we determined the frequency and quantity of cervicovaginal HIV and HSV using specimens collected from 131 HIV infected women who were followed up every three months for up to 30 months. The prevalence of detectable genital HSV DNA in asymptomatic HIV positive women was similar to studies from elsewhere in Africa The main objective of our study was to determine whether genital shedding of HIV occurred more frequently in the presence of genital herpetic lesions. A strength of the study was the long follow-up period, providing an opportunity to observe women both during and between clinical episodes of herpes. Clinical herpes was associated with higher levels of genital HIV shedding, but only partially as there were episodes of herpetic ulceration where HSV genital shedding was not recorded, and conversely episodes of HSV genital shedding in asymptomatic women. In the multivariate analysis, we clearly saw that herpetic ulcers were not independently associated with genital shedding of HIV RNA , whereas there remained a clear association between HSV genital shedding and genital shedding of HIV RNA , suggesting that this increase was related to the quantity of genital HSV and the HIV plasma viral load rather than to the presence or absence of herpetic lesions. In paired specimens taken from women with clinical herpes and from other study visits when they were asymptomatic, no difference was seen in HIV genital shedding at the two visits. When the original study groups were rearranged to examine the effect of genital HSV shedding, there was a clear difference in HIV genital shedding between HSV shedders and non-shedders, but no additional increase in HIV shedding in those with clinical herpes. Similarly, when risk factors for HIV genital shedding were examined in a multivariate regression analysis, the quantity of genital HIV RNA or DNA was significantly associated with HIV plasma viral load and HSV shedding, but after adjustment for these factors was not associated with clinical herpes.Our findings are consistent with results from a study carried out in Bangui, Central African Republic, where among HIV positive women shedding HSV, there was a significant correlation between genital HIV RNA shedding and genital shedding of HSV The observational design of these studies limits inferences about causality, but stronger evidence concerning the effect of herpes on HIV infectivity comes from seven recently completed randomised controlled trials of herpes suppressive therapy. Four trials, using valacyclovir or high dose acyclovir (800 mg b.i.d.), found significant reductions in PVL as well as significant reductions in rectal and cervicovaginal HIV-1 RNA concentrations Our results are consistent with previous reports of an association between HSV-2 shedding and HIV PVL, and suggest that clinical and subclinical herpetic reactivations might increase genital HIV shedding not only through a direct viral interaction at the genital level, but also through their systemic effect on plasma HIV viral load In this study we used cervicovaginal specimens as a marker of genital shedding, and did not find evidence of increased HIV shedding in the presence of genital lesions. However, HIV shedding may also occur directly from a herpetic lesion, and we cannot exclude the possibility that overall HIV infectivity is increased in the presence of lesions, particularly as 64% of herpetic lesions seen in this study were found on the vulva T pallidum or H ducreyi) were excluded from this analysis, as were specimens with traces of blood or semen, although we cannot rule out the possibility that some HIV or HSV detected in CVS originated from infected sexual partners. Some CVS were collected from women with non-ulcerative STI, and this may have led to underestimation of the association between herpetic lesions and HIV shedding, as cervicovaginal secretion of HIV-1 has been associated with the presence of non-ulcerative STI such as gonorrhoea and Chlamydia and found to decrease after effective treatment Genital specimens from women with ulcers of other confirmed aetiology (Increased genital HIV-1 viral load has been shown to be associated with immunosuppression in some studies In conclusion, this study adds to the accumulating evidence that HSV-2 infection increases genital shedding of HIV, and may therefore increase the infectivity of HIV infected individuals to their sexual partners. Our data suggest that the increase in HIV shedding is related to the quantity of HSV shedding rather than to the presence of clinical lesions of herpes. These findings emphasise the importance of developing and evaluating effective interventions to control herpes in populations where HSV-2 may account for a substantial proportion of HIV transmission."} +{"text": "Energy therapies in the hospital setting are met with various levels of acceptance due to questions of efficacy and evidence base. This prospective randomized controlled study quantifies the impact of one form of energy therapy on post-operative anxiety and pain in the lumbar spine surgery population.After meeting inclusion and exclusion criteria, patients that consented to participate in the study were randomized into standard post operative care (Control), standard post operative care plus a Healing Touch therapy intervention (Treatment), and standard post operative care plus an attention-control intervention (Sham). Patients were asked to complete the Visual Analog Anxiety Scale, Visual Analog Pain Scale, and Hospital Anxiety Depression Scale (HADS) both prior to and after receiving four consecutive sessions of Healing Touch intervention, attention-controlled intervention, or the standard of care. Baseline data were compared among the three groups using the chi-square test. The Sham and Treatment group were compared in terms of average change in HADS, anxiety and pain scores using the t-test.A total of 75 patients were included: 25 in the Control group (33%), 24 (32%) and 26 (35%) in the Sham and Treatment groups, respectively. The three groups were similar in terms of baseline factors (p>0.05). Results from comparing the Sham and Treatment group in terms of the change in anxiety and pain scores showed marginally statistically significant differences in anxiety scores in session 2, statistically significant differences in anxiety in session 3, and statistically significant differences in pain scores measured in sessions 2, 3 and 4. No differences were observed between the two groups in terms of the change in HADS (p>0.05).Healing Touch demonstrated a statistically significant reduction in post-operative pain and is a viable adjunct in the care of patients undergoing lumbar spine surgery."} +{"text": "To develop a tool for self-assessment of HH resources, practice and promotion in healthcare facilities (HCF), based on the key components of the WHO Multimodal Hand Hygiene (HH) Improvement Strategy (MHHIS).A task force (TF) of HH experts developed the tool and identified the following desired features: 1) to reflect the 5 components of the WHO MHHIS; 2) to include measurable indicators based on scientific evidence and expert consensus; 3) to be in the format of a user-friendly questionnaire; 4) to be associated with a score; 5) to be usable repetitively over time. Tool development steps were: 1) identification of indicators, score and format; 2) usability and reliability pilot testing; 3) review and finalization.The tool was named HH Self-Assessment Framework (HHSAF) and structured in 5 sections corresponding to the WHO MHHIS components . 27 indicators were included and points assigned according to available evidence and importance attributed by experts. WHO implementation tools suited to the improvement of each indicator were referred to within the HHSAF. A score of maximum 100 points was established per each HHSAF section. According to the overall score, 4 HH situation levels were identified: inadequate; basic; intermediate; advanced. Additional leadership criteria for HH reference centres were included. The draft was finalized according to results of usability and reliability tests.Through a thorough development process, all desired features identified for an optimal HH self-assessment tool at HCF level were successfully fed into the HHSAF.None declared."} +{"text": "Human species and guinea pigs have to obtain vitamin C (VC) from food because they are unable to synthesize ascorbic acid due to the absence of the gene that encodes L-gulonolactone oxidase (Gulo). The spontaneous bone fracture (sfx) mouse is a mouse model which is deficient in the synthesis of VC because of the deletion in Gulo gene. Because muscle forces are a strong determinant of bone structure, particularly during the process of growth and development, we examined the gene expression of muscle in sfx mice.In order to identify the genes that regulate muscle development through Vitamin C (VC) pathway, we analyzed the gene expression profile in mouse muscle from femur. For microarray analysis, muscle from three age-matched, wild-type +/+ Balb/By, inbred strain mice (WT) and 3 female and 3 male homozygous sfx/sfx mice were used.Our results indicated that 1) The expression of Myogenic factor 6 (Myf6) gene in sfx mice is increased in both female and male mice, while the increase in male mice is much higher than that in female mice. 2) Some of dystrophin relevant genes are also affected in the sfx mice. The expressions of adenylate kinase (Ak1), creatine kinase sarcomeric mitochondrial (Ckmt2), and calcium-and integrin-binding protein 2 (Cib2) are decreased. The expression of creatine kinase muscle type (Ckb) and Cdc42 binding protein kinase beta (Cdc42bpb), on the other hand, although at a low level are increased in both sfx and wild type mice. Pathological analysis suggests that the diameters of male and female of sfx mice are smaller than that of Wt mice.Suggesting a deficiency in muscle development and potentially function.There is a significant difference in myopathy and gene regulations in muscle of sfx mice between female and male mice."} +{"text": "The most significant SNP, rs7952106 , was in the DRD2 locus on chromosome 11. In a gene-based association analysis, MIR4301 (micro-RNA4301), which resides in an intron of DRD2, was the most significant gene . Examining 27 of the previously reported SBP associated SNPs, 4 SNPs were nominally significant. A genetic risk score was constructed to assess the aggregated genetic effect of the published SBP variants, demonstrating a significant association (P=0.05). In addition, we also assessed whether these variants are associated with SCI, validating the use of SBP as an endo-phenotype for SCI. Three SNPs were nominally associated, and only rs2357790 (5\u2019 CACNB2) was significant for both SBP and SCI. None of these SNPs retained significance after Bonferroni correction. Taken together, our results suggest the importance of DRD2 genetic variation in the modulation of SBP, and extend the aggregated importance of previously reported SNPs in the modulation of SBP in an African American cohort, more specifically in children with SCD.In pediatric sickle cell disease (SCD) patients, it has been reported that higher systolic blood pressure (SBP) is associated with increased risk of a silent cerebral infarction (SCI). SCI is a major cause of neurologic morbidity in children with SCD, and blood pressure is a potential modulator of clinical manifestations of SCD; however, the risk factors underlying these complications are not well characterized. The aim of this study was to identify genetic variants that influence SBP in an African American population in the setting of SCD, and explore the use of SBP as an endo-phenotype for SCI. We conducted a genome-wide meta-analysis for SBP using two SCD cohorts, as well as a candidate screen based on published SBP loci. A total of 1,617 patients were analyzed, and while no SNP reached genome-wide significance (P-value<5.0x10 Sickle cell disease (SCD) is an inherited hemoglobin disorder affecting approximately 1 in 600 individuals of African American ancestry in the United States and contStudies of familial aggregation provide significant evidence that blood pressure is a highly heritable trait ; howeverThis study includes two unrelated admixed African American ancestry SCD cohorts. Study protocols of both cohorts were approved by the Institutional Review Board (IRB) of Johns Hopkins University and Boston Medical Center. Additionally, IRB approval was acquired from all of the participating sites for subject enrollment and conducted in accordance with institutional guidelines.http://sitstudy.wustl.edu/) . These studies suggest that the DRD2 locus is plausibly involved in the regulation of SBP. Our results support these findings and the suggestive association from the DRD2 region SNPs may represents a true signal associated with SBP in SCD patients.) have reactive oxygen species (ROS)-dependent hypertension [44]. In addition, the pression and showRecently, several large and well powered studies from European ancestry populations have identified 29 genomic loci associated with blood pressure -23. We sCACNB2 (5\u2019) locus showed the consistent nominal significance for both SBP and SCI .A quantile-quantile (Q-Q) plot showing the distribution of observed \u03c7The black diagonal line indicates expected results under the null hypothesis.(TIFF)Click here for additional data file.Figure S2Comparison of the effect size of variants from the reported regions associated with SBP in the ICBP meta-analysis and SCD cohort.(TIFF)Click here for additional data file.Figure S3Power calculation to detect genome-wide significant SNPs for systolic blood pressure in the combined SIT Trial and CSSCD cohort, utilizing 1617 SCD samples.The authors thank the staff, clinicians and patients for their participation in the Silent Infarct Transfusion (SIT) Trial study. Genotyping services for the SIT Trial were provided by the Center for Inherited Disease Research (CIDR) at Johns Hopkins University and the Division of Blood Disorders at the Centers for Disease\u00a0Control and Prevention (CDC). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.(TIFF)Click here for additional data file."} +{"text": "The consistent retention of habitat variables in our predictive models supports the area of refuge hypothesis which posits reduced extinction rates in the Coral Triangle. This does not preclude support for a center of origin hypothesis that suggests increased speciation in the region may contribute to species richness. In addition, consistent retention of sea surface temperatures in models suggests that available kinetic energy may also be an important factor in shaping patterns of marine species richness. Kinetic energy may hasten rates of both extinction and speciation. The position of the Indo-Pacific Warm Pool to the east of the Coral Triangle in central Oceania and a pattern of increasing species richness from this region into the central and northern parts of the Coral Triangle suggests peripheral speciation with enhanced survival in the cooler parts of the Coral Triangle that also have highly concentrated available habitat. These results indicate that conservation of habitat availability and heterogeneity is important to reduce extinction of marine species and that changes in sea surface temperatures may influence the evolutionary potential of the region.Range overlap patterns were observed in a dataset of 10,446 expert-derived marine species distribution maps, including 8,295 coastal fishes, 1,212 invertebrates (crustaceans and molluscs), 820 reef-building corals, 50 seagrasses, and 69 mangroves. Distributions of tropical Indo-Pacific shore fishes revealed a concentration of species richness in the northern apex and central region of the Coral Triangle epicenter of marine biodiversity. This pattern was supported by distributions of invertebrates and habitat-forming primary producers. Habitat availability, heterogeneity, and sea surface temperatures were highly correlated with species richness across spatial grains ranging from 23,000 to 5,100,000 km Persistent questions remain regarding the origins of the uneven distribution of marine species richness across the tropical Indo-Pacific The tropical Indian and Pacific Oceans encompass about two thirds of the earth\u2019s equatorial circumference and include two distinct marine zoogeographic regions The observation that peaks in marine species richness throughout geologic time follow changing concentrations of available habitat is an extension of the area of refuge hypothesis, one of the numerous hypotheses invoked to explain the current epicenter of marine biodiversity in the Coral Triangle In addition to area of refuge, other hypotheses used to explain the current epicenter of marine biodiversity can be summarized as: 1) center of origin A neutral hypothesis has also been tested relating to the mid-domain effect The area of refuge hypothesis was primarily formulated as an alternative to the well-established center of origin hypothesis which heavily relies on assumptions about dispersal One component of the area of refuge hypothesis is habitat heterogeneity, which has long been considered important in shaping species diversity patterns It has long been established that there are latitudinal gradients in species richness with highest species richness in the tropics linked to multiple potential factors A number of different methods have been used to examine causes of the uneven distribution of marine species across the Indo-Pacific The study range covers the entire Indian Ocean (including Red Sea and Persian Gulf) and the entire Pacific Ocean between 30\u00b0N and 30\u00b0S. All data layers were projected onto the World Cylindrical Equal Area coordinate system centered at 130\u00b0 longitude.2/grid cell, except for the grids located along upper and lower edges of the study area which cover less area. To compare the effect of area distortion, we used, five different equal area grids: small , medium , large , extra large , and largest . The use of different grid sizes was not to test for the best possible grain but to test at which grain the predictors are likely to operate The study area was divided into equal grids of different horizontal resolutions and the commonly-used Universal Transverse Mercator (UTM) grid to test the grid choice effects on relationships between predictors and species richness. Different orientations of centroid location were tested and found to have minimal effects , S2 so tThe aim of this study was to test for effects of available nearshore habitat on species diversity, and therefore, relates to pelagic, benthic, or demersal species found primarily over continental or island shelves. The total number of species maps produced in this study was 10,446 of which2) from a 200 m bathymetry layer processed from ETOPO1 raster data Using a Geographic Information System (GIS), we calculated the amount of continental shelf or shallow water area (SW) for each habitat and N\u200a=\u200atotal habitat area .The SST layer was developed from the monthly long-term SST data derived from the National Oceanic and Atmospheric Administration Optimum Interpolation dataset. This product was constructed from two intermediate climatologies to produce a 1\u00b0 resolution dataset with a 1961\u20131990 base period y is fitted as a Poisson variable. Using the log of y we fit the GLM as below:o, \u03b21\u03b2, 2\u03b2, 3\u03b2, and 4\u03b2 are the parameter estimates. For SLM, we used maximum likelihood estimation of spatial simultaneous autoregressive error model in the form:Range overlap maps and environmental layers were combined to form grid matrices with the corresponding values of species richness, habitat availability , two habitat heterogeneity indices , SST and NPP in each cell. Statistical analyses were performed to test the relationship between the environmental variables versus four different species richness subgroups: combined all species, all fish species, all habitat-forming species , and all invertebrate species. We modeled the influences of habitat area and heterogeneity to each subgroup using both a generalized linear model (GLM) and a spatial linear model (SLM) to account for spatial autocorrelation \u03b2 is the vector of coefficient for intercept and explanatory variable X; \u03bb is the spatial autoregression coefficient; W is the spatial weights; \u03bc is the spatially-dependent error term; and \u03b5 is the error vector. Likewise, the Poisson response variable y was also fitted as a log function.2R values were used as a guide to model selection by evaluating the amount of variation explained. Since an equivalent 2R does not exist in spatial analysis with a logistic regression, we used pseudo-2RIWe performed SLM with spatial distance weights derived from five nearest-neighbor cells. We used five and not eight nearest neighbors since most of the cells are isolated creating coastal and island effects. The presence of isolated cells will create a bias in spatial weight distance calculation. To normalize the data, all variables (dependent and independent) were log-transformed. Pearson correlation coefficients were generated for all between-variable comparisons. We tested individual habitat predictors versus each subgroup using single-predictor models. Then we used multiple-predictors model to test the effects of the combination of different habitats in each subgroup. The effects of multiple predictors were further explained by identifying the minimal-adequate model using backwards elimination method. Model fit was assessed using t-values (GLM) and z-values (SLM) for both single and multiple-predictor relationships. In GLM, adjusted Species richness across the Indo-Pacific showed the expected pattern of highest richness in the Coral Triangle . The cenGreatest shallow water area (SW) and longest coastline (CL) per unit area , 3A wereAverage SST values were highest (over approximately 29\u00b0C) around and east of the Solomon Islands and northern Australia and were also high (over approximately 28\u00b0C) in eastern central Indonesia, western Sumatra and northwestern Madagascar . SpeciesPredictor variables were consistently highly correlated with one another at all scales, with some notable exceptions . SW and Species richness of all taxonomic sets was significantly correlated with most environmental variables at all scales in single predictor GLM and SLM with the exception of insignificant correlations with SST at the smallest grid sizes, insignificant correlations with NPP at nearly all grid sizes, and HDIa and some other variables at the larger grain sizes . CL mostI indicated significant autocorrelation at all grains sizes except the largest grain size. As expected with increasing grains size and decreasing sample sizes, R2 and pseudo-R2 increased (less variation to explain) and AIC values decreased with larger grain sizes (less entropy to account for). However, when comparing equal grain sizes between GLM and SLM the correction for significant autocorrelation always improved the model (higher pseudo-R2 versus R2 and lower AIC). CL was consistently retained in all SLM for all taxonomic sets at all grain sizes except in the largest grain size. In SLM across all taxa most consistently retained were SW at smallest and largest grain sizes, HDIa at smallest grain size and variably in large grain sizes, HDIn and SST mostly at all grain sizes except small and medium, and NPP negatively correlated and variably retained at larger grain sizes.Multiple regression results were similar to single predictor results in that many environmental variables were significant and retained in models . GLM andRange overlap of 10,44The pattern of species richness in this study is dominThe high correlation among our predictor variables and the I test shows significant effects of autocorrelation in our data (R2 than R2) and more entropy removed from the model (lower AIC). When comparing models based on the same grid size, correction for autocorrelation resulted in a lower AIC, and therefore, SLM is the preferred model The choice of best predictors for species richness is influour data similar our data consisteR2 values increase with increasing grid size over the same area since there is less variation to explain with smaller sample sizes is not statistically defensible le sizes . Similar2 a habitat heterogeneity index similar to HDIn may suffice in addition to CL as a proxy for habitat availability. Differences in how the different habitat complexity indices behave in models are a result of the form of complexity they emphasize. Our HDIa index is based on the relative proportion of area for our different habitat types in a grid. Heterogeneity is negatively correlated with shallow water area and the available kinetic energy predictor variable (SST) are consistently retained as positive significant predicator variables across species groups and grid sizes, accounting for autocorrelation . Coastliter area because ter area . HDIn ister area . FurtherThe position of the Indo-Pacific Warm Pool appears to be a primary reason that available kinetic energy, as exemplified by SST, is most consistently retained in models with autocorrelation considered . LatitudOur results suggest that kinetic energy, habitat availability, and habitat complexity are all important in shaping species richness patterns across the Indo-Pacific but the relationship of these variables to area of refuge, area of accumulation, and center of origin hypotheses is not straightforward. The striking pattern of diminishing species richness away from the epicenter in the Coral Triangle was a factor in formation of both the center of origin and area of accumulation hypotheses, both mediated primarily by dispersal out of or into the Coral Triangle An alternative explanation for the pattern of increasing species richness into the Coral Triangle from the east and the correlation of SST with species richness is that the position of the Indo-Pacific Warm Pool is only a coincidence and does not influence speciation and extinction rates. If speciation within the Coral Triangle is the dominant factor then dispersal out of the Coral Triangle would rely on stepping stones of available habitat counter to prevailing currents over geologic time periods. There is some evidence for gene direction out of the Coral Triangle Habitat availability is central to both the center of origin and area of accumulation hypotheses but also to the neutral and eclectic hypotheses as well. The observed correlations among species richness, habitat availability, and habitat heterogeneity may simply be a function of the well-known species-area relationship This complex view of the area of refuge hypothesis supports the concept that both area of available habitat and complexity of available habitat are potentially important in models seeking to predict and conserve tropical marine species diversity. Shallow water area, as a measure of available habitat, is a significant component in shaping species richness in the region across different taxonomic groups. However, the largest shallow water area (the Sunda and Arafura shelves), does not coincide with the location of highest species richness . Available habitat in terms of shallow water area alone is not the optimal explanation for variation in species richness because coastline length and habitat heterogeneity are significant explanations for variation in species richness . BellwooAnother factor that may profoundly influence the role that available shallow water area plays in shaping biodiversity in the Coral Triangle is local extinction from glacial maxima and concomitant sea level lows. Marine life was extirpated on the extensive tropical sea floor represented by the Sunda and Arafura shelves several times during the Pleistocene Tittensor et al. (2010) th century Our findings further support previous studies based largely on different distribution databases Available habitat and habitat complexity both significantly explain variation in species richness, and therefore, the loss of these attributes may reduce diversity. Advances in our understanding of the different components of area of refuge may help more clearly define distinctions between available habitat and complexity of habitat. For example, more accurate mapping of presumptive keystone structures such as seagrass beds, mangrove areas, and coral reefs may improve the accuracy of habitat diversity indices. Testing additional types of habitat indices may also improve our understanding. Finding a practical alternative to grid-based spatial analyses may also improve resolution of the degree to which habitat availability components and factors such as SST explain variation in species richness. It is clear that habitat-based conservation efforts targeted at preserving biodiversity should aim to preserve both area and complexity of habitats. This effort is most crucial in the Coral Triangle where species richness is at its peak but it may also be very important in preserving the evolutionary potential of isolated islands, particularly those in the Indo-Pacific Warm Pool. Habitat destruction is a key factor linked to species threats in the Coral Triangle but fortunately, destruction is less intense at present in the islands of Oceania Figure S1Distribution pattern of shallow water extent in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified into 10 classes based on the amount of shallow water area recorded in each cell such that cells in red have the largest amount of shallow water area, and cells in blue have the lowest amount of shallow water area. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S2Distribution pattern of coastal length extent in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified into 10 classes based on the amount of coastal length recorded in each cell such that cells in red have the largest amount of coastal length, and cells in blue have the lowest amount of coastal length. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S3Distribution pattern of the habitat heterogeneity index using area in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified into 10 classes based on the index values recorded in each cell such that cells in red have the largest index values, and cells in blue have the lowest index values. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S4Distribution pattern of the habitat heterogeneity index using number in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified into 10 classes based on the index values recorded in each cell such that cells in red have the largest index values, and cells in blue have the lowest index values. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S5Distribution pattern of the mean sea surface temperature in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified into 10 classes based on the index values recorded in each cell such that cells in red have the highest temperature, and cells in blue have the lowest temperature. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S6Distribution pattern of the mean net primary productivity in the Indo-Pacific at UTM grids shifted into different orientations. The grids were classified into 10 classes based on the index values recorded in each cell such that cells in red have the highest productivity, and cells in blue have the lowest productivity. (A) UTM shifted north/south, (B) UTM shifted east/west, (C) UTM shifted northeast/southwest.(PDF)Click here for additional data file.Figure S7Combined adjacent cells (red color) against the regular sized cells (yellow color). (A) Small grid, (B) Medium grid, (C) Large grid, (D) UTM, (E) UTM shifted north/south, (F) UTM shifted east/west, (G) UTM shifted northeast/southwest. There are no adjacent cells that were combined in extra large and largest grids.(PDF)Click here for additional data file.Figure S8The two types of basemaps used in this study. (A) Visualization basemap consisting of 200 m depth and 100 km buffer, (B) Bathymetry basemap showing the 200 m depth used in analyses of species richness versus independent variables.(PDF)Click here for additional data file.Figure S9Distribution pattern of coastal length extent in the Indo-Pacific at different grid scales. The grids were classified into 10 classes based on the amount of coastal length recorded in each cell such that cells in red have the largest amount of coastal length, and cells in blue have the lowest amount of coastal length. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Figure S10Distribution pattern of the habitat heterogeneity index using area in the Indo-Pacific at different grid scales. The grids were classified into 10 classes based on the index values recorded in each cell such that cells in red have the largest index values, and cells in blue have the lowest index values. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Figure S11Distribution pattern of the habitat heterogeneity index using number in the Indo-Pacific at different grid scales. The grids were classified into 10 classes based on the index values recorded in each cell such that cells in red have the largest index values, and cells in blue have the lowest index values. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Figure S12Distribution pattern of the mean sea surface temperature in the Indo-Pacific at different grid scales. The grids were classified into 10 classes based on the index values recorded in each cell such that cells in red have the highest temperature, and cells in blue have the lowest temperature. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Figure S13Distribution pattern of the mean net primary productivity in the Indo-Pacific at different grid scales. The grids were classified into 10 classes based on the index values recorded in each cell such that cells in red have the highest productivity, and cells in blue have the lowest productivity. (A) Small grid, (B) Medium grid, (C) Large grid, (D) Extra large grid, (E) Largest grid.(PDF)Click here for additional data file.Table S1Single predictor Generalized Linear Model (GLM) and Spatial Linear Model (SLM) results at different UTM grid orientations. The predictors are shallow water area (SW), coastline length (CL), habitat diversity based on area (HDIa), habitat diversity based on number of patches (HDIn), sea surface temperature (SST), and net primary productivity (NPP). Values under predictor variables are t-values for GLM and z-values for SLM. Asterisks indicate significance value of P: *(<0.05), **(<0.01); ***(<0.001); ns (not significant). UTM NS\u200a=\u200acentroid shifted on a North-South plane, UTM EW\u200a=\u200acentroid shifted on an East-West plane and UTM NE\u200a=\u200acentroid shifted along a Northeast-Southwest plane. Sample size for each grid (n) is shown. The highest adjusted 2R (GLM) and pseudo-2R value within each grid size are highlighted in boldface.(PDF)Click here for additional data file.Table S2Multiple predictor Generalized Linear Model (GLM) and Spatial Linear Model (SLM) results at different UTM grid orientations. The predictors are shallow water area (SW), coastline length (CL), habitat diversity based on area (HDIa), habitat diversity based on number of patches (HDIn), sea surface temperature (SST), and net primary productivity (NPP). Values under predictor variables are t-values for GLM and z-values for SLM. Asterisks indicate significance value of P: *(<0.05), **(<0.01); ***(<0.001). UTM NS\u200a=\u200acentroid shifted on a North-South plane, UTM EW\u200a=\u200acentroid shifted on an East-West plane and UTM NE\u200a=\u200acentroid shifted along a Northeast-Southwest plane. Sample size for each grid (n) is shown. 2R values are for GLM results, while pseudo-2R (p\u20132R) values are for SLM results.(PDF)Click here for additional data file.Table S3List of families with the number of species distribution maps used in this study.(PDF)Click here for additional data file.Table S4Single predictor Generalized Linear Model (GLM) and Spatial Linear Model (SLM) complete results at different grid sizes. The predictors are shallow water area (SW), coastline length (CL), habitat diversity based on area (HDIa), habitat diversity based on number of patches (HDIn), sea surface temperature (SST), and net primary productivity (NPP). Values under predictor variables are t-values for GLM and z-values for SLM. Asterisks indicate significance value of P: *(<0.05), **(<0.01); ***(<0.001); ns (not significant). Sample size for each grid (n) is shown. The highest adjusted 2R (GLM) and pseudo-2R value within each grid size are highlighted in boldface.(PDF)Click here for additional data file.Text S1Methods and results for UTM grids shifted to different centroid orientation.(PDF)Click here for additional data file.Text S2Sources for species range used in producing the distribution maps.(PDF)Click here for additional data file."} +{"text": "Fever is a common observation during critical illness ,2 and maAn online scenario-based questionnaire survey was distributed to medical and nursing members of the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS-CTG) and their intensive care colleagues. Main outcome measures: the choice of drug and preferred threshold temperature for intervention with antipyretics in clinical practice and in a clinical trial.There were 588 email invitations distributed through the ANZICS-CTG and Research Coordinator mailing list. Four hundred and forty-seven responses were received from 308 nurses (69%), 137 doctors (31%), and two others (0.5%). The majority of respondents having more than 8 years of experience 62%) worked in mixed medical and surgical units (84%) in a metropolitan or tertiary hospital setting (77%). The primary findings of our survey suggest that fever management is highly variable. Most clinicians administer an intervention to reduce temperature at or below 39\u00b0C (Figure % worked This survey suggests there is considerable clinical variability in fever management in patients with sepsis and without neurological injury or hyperthermic syndromes. At present, no particular management strategy is known to be superior to any other and it remains possible that current practice may be harming substantial numbers of patients. A temperature threshold of up to 40\u00b0C may be acceptable to clinicians for the design of a future randomized controlled trial. Further observational data may be informative for the design of such clinical trials."} +{"text": "Time-series data collected over a four-year period were used to characterize patterns of abundance for pelagic fishes in the northern Gulf of Mexico (GoM) before (2007\u20132009) and after (2010) the Deepwater Horizon oil spill. Four numerically dominant pelagic species were included in our assessment, and larval density of each species was lower in 2010 than any of the three years prior to the oil spill, although larval abundance in 2010 was often statistically similar to other years surveyed. To assess potential overlap between suitable habitat of pelagic fish larvae and surface oil, generalized additive models (GAMs) were developed to evaluate the influence of ocean conditions on the abundance of larvae from 2007\u20132009. Explanatory variables from GAMs were then linked to environmental data from 2010 to predict the probability of occurrence for each species. The spatial extent of surface oil overlapped with early life habitat of each species, possibly indicating that the availability of high quality habitat was affected by the DH oil spill. Shifts in the distribution of spawning adults is another factor known to influence the abundance of larvae, and the spatial occurrence of a model pelagic predator (blue marlin) was characterized over the same four-year period using electronic tags. The spatial extent of oil coincided with areas used by adult blue marlin from 2007\u20132009, and the occurrence of blue marlin in areas impacted by the DH oil spill was lower in 2010 relative to pre-spill years. Pelagic fishes that frequent open oceans are valuable economically and influence the structure and resilience of offshore ecosystems 6 (\u00b120%) barrels of oil into the northern Gulf of Mexico (GoM) [9). Oil trajectory models predicted that surface or near surface oil covered a large region of the continental shelf and slope In April 2010, the Deepwater Horizon [DH) oil spill resulted in the release of approximately 4.4\u00d710Thunnus atlanticus), blue marlin (Makaira nigricans), dolphinfish (Coryphaena hippurus), and sailfish (Istiophorus platypterus). We first explored temporal variability during early life by contrasting larval abundances of each species before (2007\u20132009) and after (2010) the DH event. Next, generalized additive models (GAMs) were developed from 2007\u20132009 data to assess habitat associations, and then to predict the probability of occurrence the following year (2010) in relation to surface oil . Finally, patterns of occurrence for a model pelagic predator (blue marlin) over the same four-year period were examined using pop-up archival transmitting (PAT) tags, and light-based geo-locations from tags were used to compare the distribution of adults before and after the DH oil spill. Our working hypothesis was that the distribution and abundance of pelagic fishes in our study area, both early life and adult stages, may have changed in 2010 due to changes in habitat condition or other activities related to the DH oil spill. We fully recognize that natural environmental variability is known to influence the distribution and abundance of pelagic fishes in the northern GoM The aim of the present study was to assess possible impacts of the DH oil spill on four pelagic fishes that commonly inhabit outer shelf and slope waters of the northern GoM: blackfin tuna and the oceanographic factors that influence the abundance of larvae, inter-annual variability was investigated with separate models for June and July. In June surveys, a significant year effect was observed for all four species: blackfin tuna (p\u200a=\u200a0.030), blue marlin (p\u200a=\u200a0.001), dolphinfish (p\u200a=\u200a<0.001), and sailfish (p\u200a=\u200a0.006). Despite the fact that the mean density of each species was lower in June 2010 than any of the other June surveys , this yea concentration, depth, distance to feature, feature classification, salinity, sea surface temperature, sea surface height anomaly) on the occurrence of larvae varied across species and within species when contrasting June and July models and 44.3% (July). Final GAMs for dolphinfish retained three explanatory variables in the June model and four in the July model, with depth being the only variable common between the two models. Percent deviance explained for dolphinfish GAMs was 13.2% (June) and 13.5% (July). Final GAMs for sailfish included three common explanatory variables in June and July models , and percent deviance explained was 20.3% (June) and 15.3% (July).GAMs based on presence/absence data developed for each species indicated that the influence of 7 oceanographic factors varied markedly among species . The spaectively . High qu2 in both June and July.The spatial extent of surface oil from the DH event was viewed in relation to the total available area of high quality habitat predicted with GAMs to determine whether suitable habitat of each species was exposed to oil contamination. In June 2010, the estimated overlap between high quality habitat and surface oil was relatively low for blue marlin (0%) and sailfish (4.5%). Conversely, percent overlap for blackfin tuna and dolphinfish was considerably higher, with 15.3% and 13.9% of the predicted high quality habitat exposed to surface oil in the northern GoM. Species-specific patterns for July 2010 were similar, and again the percentage of high quality habitat exposed to surface oil was considerably lower for blue marlin (0.2%) and sailfish (7.2%) when compared to blackfin tuna (19.4%) or dolphinfish (11.4%). Given the predicted overlap observed for blackfin tuna, it is not surprising that the areal coverage of high quality habitat exposed to surface oil was relatively large, exceeding 60,000 km2 (9.3%) of the core use area in 2007\u20132009 was exposed to surface oil in 2010. Based on daily mean positions, we also observed that use of a region subsequently closed to fishing in 2010 by the National Oceanic and Atmospheric Administration and after (2010) the DH oil spill . From 20Both the abundance and percent occurrence of fish larvae for selected pelagic fishes declined in 2010 relative to the three years prior to the DH oil spill, suggesting that changes in environmental conditions, possibly linked to the presence of oil and dispersants, may have contributed to observed inter-annual variability. Previous studies have demonstrated a clear relationship between these contaminants and the demographics of a wide range of marine organisms including invertebrates, fishes, birds, and mammals Although results from this study suggest a possible connection between reduced abundance of pelagic fish larvae in 2010 and the DH oil spill, inter-annual variability is relatively common for cohorts of pelagic larvae in the GoM Variability in mesoscale circulation has been shown to influence the spatial distribution of larvae in the GoM Determining the primary cause of annual fluctuations in the abundance of pelagic fish larvae is challenging, and establishing a direct link between the abundance of larvae and the DH oil spill is not possible given the data available. However, our estimates of overlap between surface oil and high quality habitat of billfish, dolphinfish, and tuna larvae, support the premise that highly suitable nursery areas (or spawning areas) of these taxa were impacted by the DH oil spill. Oil contamination occurred across several hundred thousand square kilometers of suitable habitat of pelagic fish larvae, accounting for approximately 10\u201320% of the available high quality habitat for blackfin tuna and dolphinfish in the northern GoM. Estimates of percent overlap were lower for billfish larvae , and suitable habitat for these taxa appeared to be more limited in coverage and farther offshore , possibly out of reach of significant oil contamination from the DH oil spill. While the presence of surface oil may have impacted larval survival within a restricted area, the majority of the high quality habitat for each species occurred in areas of the northern GoM unaffected by the oil spill. Therefore, anticipated effects of the DH oil spill on early life survival or reduced larval abundance are expected to be relatively modest, which interestingly is in accord with observed annual patterns of abundance.Apart from early life processes that directly impact the dispersal and survival of larvae, differences in the demographics (age structure) and abundance (spawning stock biomass) of spawning adults can also influence the abundance of larvae within a given area The influence of direct and/or indirect effects of the DH oil spill on the abundance and distribution pelagic fishes is currently unresolved, and caution must be exercised when interpreting time-series data that are limited in scope and duration. While larval abundances of all four species examined were lower in 2010 relative to the three-year baseline sample, abundance in 2010 was statistically similar to at least one of the other years surveyed, suggesting that observed declines are within the bounds of expected natural variability. Despite the fact that we cannot explicitly link observed inter-annual trends in the abundance of larvae to the DH oil spill, we can conclude that large areas of high quality habitat of pelagic fishes were exposed to oil contamination. In turn, oil contamination may have contributed to observed temporal patterns of abundance, but the main driver of observed temporal patterns is unknown.Ichthyoplankton surveys were conducted over a four-year period (2007\u20132010) from approximately 26.5 to 28.0\u00b0N latitude and 87.5 to 92.0\u00b0W longitude in the northern GoM. Summer surveys were conducted each year during the same two months , which corresponds to the primary spawning periods of many pelagic fishes in the GoM Thunnus atlanticus (family Scombridae), blue marlin Makaira nigricans and sailfish Istiophorus platypterus (family Istiophoridae), and dolphinfish Coryphaena hippurus (family Coryphaenidae). Density at each station was determined by combining numbers of individuals in both 500 and 1200 \u00b5m mesh nets and adjusted to reflect a sampling depth of 0.75 m. Average volume of water sampled with both nets at each station was approximately 3500 m3. Percent occurrence at the species level was also determined and based on the number of stations where selected taxa were present divided by the total number of stations sampled.Fish larvae were sorted in the laboratory, and density and occurrence were determined for blackfin tuna Thunnus) to species was based on sequence variability of mitochondrial DNA [41) and High Resolution Melting (HRM) assays based on fixed nucleotide differences among species Thunnus larvae to determine the abundance of blackfin tuna (T. atlanticus) in our collections. Two congeners were also present in our collections , and blackfin tuna accounted for nearly 90% of the Thunnus larvae collected.Fish larvae were identified visually to family level based on anatomical and morphometric features Temporal differences in the densities of larvae collected over the four-year period were compared with a Kruskal-Wallis (rank sums) one-way analysis of variance (ANOVA). This non-parametric method does not assume a normal distribution, which was required due to the large number of zero values in our data set (skewed distribution). Species-specific models were developed for each species in both June and July to investigate temporal differences in larval density for all four species. Non-parametric multiple comparison tests (Wilcoxon method) were run to determine which factor levels or years differed from others. Statistical significance for all tests was based on \u03b1\u200a=\u200a0.05.a, depth), and parameters related to mesoscale oceanographic features were used to investigate the influence of environmental conditions on the occurrence of each species. Presence/absence models were fit with a binomial distribution using a logit link function in R software feature) . MesoscaA manual backwards stepwise procedure based on minimizing the Akaike Information Criterion tags were deployed opportunistically on blue marlin from sport fishing vessels in the GoM from 2007\u20132010, following methods previously described Daily mean position estimates from the primary spawning season of blue marlin (May\u2013July) were compared before (2007\u20132009) and after (2010) the DH oil spill. PAT tag data from deployments prior to the DH oil spill (n\u200a=\u200a13) ranged from 60 to 365 days. Daily mean positions of adult blue marlin after the spill were based on geo-location estimates generated from 1-year tag deployments on blue marlin (n\u200a=\u200a4). These fish were tagged in summer/fall 2009 and the tags released from fish during or after July 2010. Our analysis is based on the assumption that individuals return to the same general spawning area the following year, which is supported by long-term tag deployments on blue marlin and white marlin before or after 2010 . GriddedFigure S1Spatial and temporal variability in the density of pelagic fish larvae collected from 2007 to 2010 for A) blackfin tuna (Thunnus atlanticus), B) blue marlin (Makaira nigricans), C) dolphinfish (Coryphaena hippurus), and D) sailfish (Istiophorus platypterus). June (red) and July (blue) survey shown and colored lines represent the observed margin of the Loop Current during each sampling trip (coded by color). Density (larvae. 1000 m\u22123) denoted by circle size.(TIF)Click here for additional data file.Figure S2Response plots from final presence/absence generalized additive models (GAMs) based on June data for A) blackfin tuna (Thunnus atlanticus), B) blue marlin (Makaira nigricans), C) dolphinfish (Coryphaena hippurus), and D) sailfish (Istiophorus platypterus).(PDF)Click here for additional data file.Figure S3Response plots from final presence/absence generalized additive models (GAMs) based on July data for A) blackfin tuna (Thunnus atlanticus), B) blue marlin (Makaira nigricans), C) dolphinfish (Coryphaena hippurus), and D) sailfish (Istiophorus platypterus).(PDF)Click here for additional data file.Figure S4Map showing the region closed to fishing on June 21, 2010 by the National Oceanic and Atmospheric Administration due to the Deepwater Horizon oil spill.(TIF)Click here for additional data file.Figure S5Long-term tracks (ca. 1 year) of individual A) white marlin and B) blue marlin (Makaira nigricans) from pop-up archival transmitting (PAT) tags deployed in the Gulf of Mexico. Blue shading depicts kernel density (95% volume of utilization distribution shown) based on daily mean positions the first month of the deployment (dark blue) and the same month the next year (light blue). Colored symbols represent quarterly geo-location estimates for each individual over the deployment period and all geo-location data were generated using state-space models that implemented the Kalman filter algorithm from light-based location data generated from PAT tags. Estimated weights of white marlin (ID: WM-09-01) and blue marlin (ID BM-10-02) shown here were 30 and 120 kg, respectively.(TIF)Click here for additional data file.Table S1(DOCX)Click here for additional data file."} +{"text": "Although postsynaptic and transmembrane currents over local neuronal populations are considered the main factors for shaping local field potential (LFP) and current source density (CSD) fluctuations , high-frFirstly, we employ a spiking network model of the CA3 and CA1 hippocampal areas that reproduces key features of SWRs based on synchronous CA3 population bursts and strong, fast-decaying CA1 recurrent inhibition . The emein vivo, from multiple locations in areas CA3 and CA1 of the rat hippocampus while animals run on a linear track with resting areas at both ends. The spiking activity of detected place cells, firing in sequence during the running sessions, is replayed in either forward or reverse order during SWRs occurring at the resting areas [Next, we apply our analysis to a set of LFPs and unit activity, recorded ng areas . We tracThis work provides a deeper understanding of the nature of extracellular fields and offers a new approach to the decoding of ongoing cell assemblies based on extracellular current flows. Differences in the emerging SWR field activity may play an important role in information processing during memory consolidation."} +{"text": "Nitric oxide (NO) maintains cardiovascular health by activating soluble guanylate cyclase (sGC) to increase cellular cGMP levels. Cardiovascular disease is characterized by decreased NO-sGC-cGMP signaling. Pharmacological activators and stimulators of sGC are being actively pursued as therapies for acute heart failure and pulmonary hypertension. Here we review molecular mechanisms that modulate sGC activity while emphasizing a novel biochemical pathway in which binding of the matricellular protein thrombospondin-1 (TSP1) to the cell surface receptor CD47 causes inhibition of sGC. We discuss the therapeutic implications of this pathway for blood flow, tissue perfusion, and cell survival under physiologic and disease conditions. Cardiovascular disease is the number one cause of death worldwide and remains a burdensome health problem. Understanding the underlying molecular mechanisms of cardiovascular disease will provide valuable information for the design of novel drugs for pharmacological therapies.As a central player of the canonical NO-sGC-cGMP pathway, sGC controls important physiological functions such as smooth muscle relaxation, platelet aggregation, and hemostasis NO is formed via two primary pathways. NO is generated when endothelial nitric oxide synthase (eNOS) is activated by Cain vitro and cell lysates further mediates membrane localization of sGC in cardiomyocytes . Riociguat raises the potency of sGC activation by NO and has been approved for the treatment of pulmonary arterial hypertension mice but not in CD36\u2212/\u2212 mice that putatively inactivated/inhibited sGC through phosphorylation at a yet to be determined residue signaling and cystathionine \u03b3-lyase (CSE) and hydrogen peroxide (H2O2) that in turn modify proteins and adversely alter their function . TSP1 is a more potent stimulator of ROS compared to the classic activators phorbol myristate acetate and angiotensin II. The CD47 targeting peptide 7N3 that contains the Val-Val-Met sequence also increased VSMC O\u00b7\u22122 production -mediated activation of sGC and subsequent dephosphorylation of myosin light chain 2 (the kinase responsible for vasoconstriction) while increasing immuno-reactive F-actin in cultured VSMC TSP1\u2212/\u2212 mice maintained a more normal cardiovascular profile compared to wild type animals with less change in right ventricular systolic pressure, less right ventricular hypertrophy and less pulmonary vascular smooth muscle cell hyperplasia. This observation was further associated with less pulmonary ROS production 10SDG2600345 (Elsa D. Garcin), 13PRE17000045 (Franziska Seeger) and 13POST14520003 (Natasha M. Rogers) and by the Intramural Research Program of the NIH/NCI (David D. Roberts). This work was further supported by the Institute for Transfusion Medicine, the Hemophilia Center of Western Pennsylvania and the Vascular Medicine Institute (Jeffrey S. Isenberg).Jeffrey S. Isenberg is Chair of the Scientific Advisory Boards of Vasculox, Inc. and Radiation Control Technologies, Inc. and holds equity interest in the same. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The female genital tract is an important site of HIV acquisition, but the epithelial and submucosal tissue factors associated with HIV susceptibility have not been defined.Ectocervical biopsies were obtained from HIV-exposed seronegative (HESN) women (n=20) and HIV-seronegative lower risk controls (n=20). Epithelial thickness and tissue distribution of immunological markers were assessed in situ by immunohistochemistry and measurement of mRNA expression was performed by quantitative PCR.The thickness of the ectocervical epithelium was significantly higher in HESN vs. lower risk subjects. CD4 and DC-SIGN mRNA expression was significantly lower in HESN than lower risk women, and in situ immunohistochemical analysis confirmed the reduced CD4 expression in HESN participants. In addition, immunohistochemistry demonstrated lower CCR5 and higher Langerin expression in the HESN subjects.A thicker epithelial barrier and altered expression of HIV binding receptors in the ectocervix of HESN women may contribute to protection against HIV transmission."} +{"text": "NUAK2 as a member of the AMPK family has several intriguing aspects both as an oncogene and as a tumor suppressor gene. Here we review genomic aberrations of melanomas focusing on acral melanomas to emphasize the possible roles of NUAK2 in tumorigenesis in general and suggest that NUAK2 has pivotal roles in acral melanomagenesis.Recent technological advances in cancer genomics make it possible to dissect complicated genomic aberrations of melanomas. In particular, several specific genomic aberrations including 11q13 amplification and KIT aberrations have been identified in acral melanomas. We recently identified NUAK2 at 1q32 as a promising oncogene in acral melanomas and reported its significant roles in tumorigenesis in melanoma cells using both The identification of genes that participate in oncogenesis has facilitated recent development of molecular targeted therapies against cancer (reviewed in -3). In tThe SNF1/AMP-activated protein kinase (AMPK) family functions to control the balance of cellular metabolisms, and is activated by the cellular AMP:ATP ratio that is regulated by metabolic stresses such as hypoxia and glucose deprivation , 18. AMPRecent tenacious efforts by investigators have accelerated the elucidation of genomic alterations in melanoma cells. The first step to decipher enigmas in complex genomic alterations in melanoma cells had started by taking advantage of techniques that had been utilized to elucidate chromosomal abnormalities in hematopoietic malignancies -39. ThosAcral melanomas occur on nailbeds and plantar regions such as the palms of the hands and soles of the feet . The hisCGH combined with analyses of clinical parameters are a powerful approach to identify genomic loci that have significant impact on the clinical outcome of melanoma patients. Both the classical cytogenetic approach and the CGH approach share the same implication that the long arm of chromosome 1 and the short arm of chromosome 6 may have a profound effect on the tumorigenesis of melanomas since both chromosomal regions have a significant impact on the clinical outcome of patient survival Fig. 50, 61], 6150, 6NUAK2 is the fourth member of the AMPK family of kinases and shares a similar catalytic domain of the sucrose-non-fermenting protein kinase (SNF1)/AMP-activated protein kinase (AMPK) family of serine/threonine protein kinases. The NUAK2 gene resides at 1q32 and encodes 630 amino acid residues that are translated into a protein of approximately 76 kDa . In geneCaenorhabditis elegans, participates in maintaining the integrity of components of myosin filaments. Disruption of unc-82 by mutations causes defects in cytoskeleton reorganization during embryogenesis [The amount of knowledge about the regulation and function(s) of NUAK2 is quite limited compared to AMPK-\u03b11 and AMPK-\u03b12. However, several important functions related to myosin filaments and cytoskeleton organization have been revealed. Myosin phosphatase target subunit 1 (MYPT1) was identified as a specific substrate for NUAK2. MYPT1 is phosphorylated by NUAK2 at sites other than Thr696 and The853, which are known as Rho-kinase (ROCK) phosphorylation sites . Furtherogenesis . Anotherogenesis . As the ogenesis , 81. Musin vitro and tumor growth in vivo in melanomas, and the extent of those reductions of cell proliferation varies depending on the different genomic aberrations of melanoma cells [in vivo from the profile of the proliferating cell population [Disruption of the normal regulation and function(s) of NUAK2 may lead to the dysregulation of proliferation and migration in cancer cells. However, the exact effects and mechanisms participating in tumorigenesis remain to be elucidated due to the lack of sufficient molecular studies of NUAK2. Several conflicting results on tumorigenesis including cell proliferation, apoptosis and migration have been reported. The knockdown of NUAK2 using siRNA or shRNA reduces cell proliferation ma cells . Anotherpulation . Over-expulation . This fupulation , 84. Howpulation . NUAK2 apulation . CD95 stP = 0.0036), and multivariate analysis using multiple Cox regression analysis also showed the impact of NUAK2 on relapse-free survival . Interestingly, those impacts of NUAK2 on melanoma patient survival are significant at relapse-free survival of acral melanomas compared to weak significances at Non-CSD melanomas and overall survival. Those observations lead to the speculation that NUAK2 has more profound effects on cell migration resulting in worsening relapse-free survival of acral melanoma patients as suggested by both a migration assay and a wound healing assay [UV irradiation is one of the major causes of cutaneous melanomas, but acral and mucosal melanomas are protected from exposure to UV irradiation due to their anatomical locations. Thus, the molecular pathogenesis of acral and mucosal melanomas should be different from that of cutaneous melanomas arising from sun-exposed areas such as Non-CSD melanomas, and causes other than UV irradiation, such as reactive oxygen species (ROS), may play an important role in the melanomagenesis of acral and/or mucosal melanomas. The HGF/SF transgenic mouse model is prone to develop cutaneous melanomas following UV irradiation . In thatng assay .The recent identification of KIT mutations in acral, mucosal and CSD melanomas led to the development of therapeutic modalities using imatinib mesylate to target KIT activation. Although initial studies achieved only poor responses using imatinib mesylate against melanomas, the stratification and appropriate selection of patients based on KIT activation by mutations and amplifications have improved responses of melanoma patients to imatinib mesylate , 98. As"} +{"text": "Gastric tube after esophagectomy can be the site of local recurrence or the development of second primary tumor which implies poor prognosis. The study presents an extremely rare case of a patient after Ivor-Lewis esophagectomy for squamous cell carcinoma, in whom there was detected local recurrence in the anastomosis associated with metachronous primary tumor in gastric tube. Esophageal reresection with the upper part of the stomach was performed. Left colonic segment supplied by middle colic vessels transposed through retrosternal route was used as new esophageal substitute. Esophagectomy with lymph node dissections combined with adjuvant therapy remains the basic method of esophageal cancer surgical treatment. The stomach is the most commonly used esophageal substitute after esophagectomy. Owing to the availability of new, more precise diagnostic techniques and to the improvement of the late outcomes of esophageal cancer treatment, there increases the detectability of the cases of second primary malignancies in the stomach . The coeThe surgical treatment of a cancer diagnosed in the gastric tube after esophagectomy is a difficult and rarely undertaken surgical challenge associated with the risk for severe complications and high mortality.A female patient, MZ, aged 61\u2009years, referred primarily for surgical treatment due to esophageal cancer detected in the epicardial region. Endoscopic examination revealed a primary tumor located 30\u2009cm from the incisors. Endoscopic evaluation of the stomach lumen was impossible due to esophageal stricture at the tumor level. Histopathological examination of tumor specimens led to the diagnosis of squamous cell carcinoma. Preoperative thoracic computed tomography (CT) detected neither tumor infiltration on the surrounding tissues nor the enlargement of the regional lymph nodes in the thorax and abdominal cavity.Based on the results of diagnostic investigations which confirmed the possibility of local excision of the tumor, the patient was qualified for surgical treatment.3N0M0, Stage II A). Microscopically esophageal and gastric rings were free from neoplastic cells. The proximal resection margin was 4\u2009cm. Eighteen lymph nodes of the following groups were removed: upper thoracic paraesophageal lymph nodes (2), right thoracic paratracheal lymph nodes (1), bifurcation lymph nodes (2), middle thoracic paraesophageal lymph nodes (2), right pulmonary hilar lymph nodes (1), lower thoracic paraesophageal lymph nodes (2), diaphragmatic lymph nodes (1), posterior mediastinal lymph nodes (2), lesser curvature lymph nodes (3), left gastric artery lymph nodes (1), and common hepatic artery lymph nodes (1). All lymph nodes were free of cancer cells. The patient\u2019s postoperative course was uncomplicated and she was discharged from hospital after 17\u2009days. After surgery, the patient did not report for further treatment at an oncological center.Partial Ivor-Lewis esophago-gastrectomy was performed with conventional two-field en block lymphadenectomy using a gastric tube as an esophageal substitute. The esophagogastroplasty was performed in the right pleural cavity. The postoperative histopathological examination showed squamous cell carcinoma keratodes G-2 invading the adventitia without lymph node metastasis (pTThe follow-up endoscopy performed 6\u2009months after esophagectomy showed: (A) mucosa at the site of anastomosis: uneven, congested with superficial lesions covered with fibrin, unchanged esophageal mucous membrane proximal to anastomosis. About 3\u2009cm below the anastomosis was a stocky polyp of 10 to 12\u2009mm in diameter (B) surrounded by normal gastric mucosa. Congested mucosa without lesions were in the gastric tube distal segment. The results of histopathological examinations revealed: (A) gastric mucosa segment with the features of foveolar hyperplasia, (B) polyp from the gastric tube - squamous cell carcinoma keratodes . The result of CT after esophagectomy was . En bloc dissection of residual esophagus was performed to the level of the apex of the chest and then the esophageal stump was cut 8\u2009cm above the anastomosis Figure\u2009. The esopT2N0Mx (primary focus), the tumor sounded by normal gastric mucosa; and (c) lymph nodes from the thoracic area (7) and neck (4) without tumor cells.The results of postoperative histopathological examination were (a) distal esophageal stump with anastomosis: recurrence of squamous cell carcinoma keratodes G-2, tumor emboli in lymphatic vessels, proximal esophageal stump free of tumor infiltration; (b) tumor located in gastric tube, squamous cell carcinoma Eight weeks after surgery, in the course of the second cycle of chemotherapy, dysphagia developed. Endoscopy revealed no anastomotic stenosis. Within a 3-week period an effective endoscopy-guided dilatation with a balloon was performed twice. Six months after reoperation no recurrence of the neoplastic process was observed in follow-up diagnostic tests.The use of the stomach as an esophageal substitute after esophagectomy is commonly accepted by the majority of surgeons ,5. The sIn the case of metachronous tumors located in the gastric tube the therapeutic management depends on the depth of tumor infiltration to the gastric wall -12. In tet al.[Gastric tube resection requires reconstruction of gastrointestinal tract with the useof colonic or small intestine conduit. In such situations colon graft is preferred owing to its proper length, reliable blood supply, and fewer complications ,12,15. Iet al.. The nonGastric tube resection with the creation of a new esophageal substitute from the colon is a difficult but possible treatment option in selected cases of recurrence or second primary cancer of the stomach detected in postoperative follow-up..Written informed consent was obtained from the patient for publication of this report and any accompanying imagesThe authors declare that they have no competing interests in this paper.SJ composed the case report, prepared and edited this manuscript, contributed it conception, collected the data and conducted a literature search. \u0141P and MW participated in the data collection and gave final approval for this version of the manuscript. All authors read and approved the final manuscript."} +{"text": "Nilaparvata lugens and Laodelphax striatellus are two of the most important pests of rice. Up to now, there was only one mitochondrial genome of rice planthopper has been sequenced and very few dependable information of mitochondria could be used for research on population genetics, phylogeographics and phylogenetic evolution of these pests. To get more valuable information from the mitochondria, we sequenced the complete mitochondrial genomes of BPH and SBPH. These two planthoppers were infected with two different functional Wolbachia (intracellular endosymbiont) strains (wLug and wStri). Since both mitochondria and Wolbachia are transmitted by cytoplasmic inheritance and it was difficult to separate them when purified the Wolbachia particles, concomitantly sequencing the genome of Wolbachia using next generation sequencing method, we also got nearly complete mitochondrial genome sequences of these two rice planthoppers. After gap closing, we present high quality and reliable complete mitochondrial genomes of these two planthoppers.N. lugens (BPH) and L. striatellus (SBPH) are 17, 619 bp and 16, 431 bp long with A + T contents of 76.95% and 77.17%, respectively. Both species have typical circular mitochondrial genomes that encode the complete set of 37 genes which are usually found in metazoans. However, the BPH mitogenome also possesses two additional copies of the trnC gene. In both mitochondrial genomes, the lengths of the atp8 gene were conspicuously shorter than that of all other known insect mitochondrial genomes . That two rearrangement regions (trnC-trnW and nad6-trnP-trnT) of mitochondrial genomes differing from other known insect were found in these two distantly related planthoppers revealed that the gene order of mitochondria might be conservative in Delphacidae. The large non-coding fragment (the A+T-rich region) putatively corresponding responsible for the control of replication and transcription of mitochondria contained a variable number of tandem repeats (VNTRs) block in different natural individuals of these two planthoppers. Comparison with a previously sequenced individual of SBPH revealed that the mitochondrial genetic variation within a species exists not only in the sequence and secondary structure of genes, but also in the gene order (the different location of trnH gene).The mitogenomes of The mitochondrial genome arrangement pattern found in planthoppers was involved in rearrangements of both tRNA genes and protein-coding genes (PCGs). Different species from different genera of Delphacidae possessing the same mitochondrial gene rearrangement suggests that gene rearrangements of mitochondrial genome probably occurred before the differentiation of this family. After comparatively analyzing the gene order of different species of Hemiptera, we propose that except for some specific taxonomical group (e.g. the whiteflies) the gene order might have diversified in family level of this order. The VNTRs detected in the control region might provide additional genetic markers for studying population genetics, individual difference and phylogeographics of planthoppers. The mitochondrial genome is the most commonly used molecular marker for phylogenetic studies, population genetics and dynamics, phylogeography and evenThe order Hemiptera is the largest group of the hemimetabolous insects and inclNilaparvata lugens and the small brown planthopper (SBPH), Laodelphax striatellus (Hemiptera: Delphacidae) are two of the most important pests in rice fields of many Asian countries. By transmitting virus diseases [Wolbachia[Wolbachia strains, we also obtained nearly the complete mitochondrial genomes of BPH and SBPH. The Wolbachia strain wStri infecting SBPH can induce complete Cytoplasmic Incompatibility (CI), a reproductive modification that typically results in embryonic lethality between crosses of infected males and uninfected females. On the other hand, the Wolbachia strain wLug infecting BPH cannot induce CI at all.The brown planthopper (BPH), diseases and causdiseases . These tWolbachia which caWolbachia,24. WhiltrnH gene) were verified using natural populations. In addition, comparing mitochondrial genome of SBPH sequenced in this study with a previously sequenced individual revealed a remarkable variability between these two individuals.After gap-closing, the complete mitochondrial genomes of these two most important rice piercing and sucking type pests, BPH and SBPH were determined. We analyzed the nucleotide composition, codon usage and genomic rearrangement of these two mitochondrial genomes and compared them with mitochondrial genomes of other hemipteran species. Some special characteristics of mitochondria of these two planthoppers in \u2018A + T\u2019 rich regions; location of N. lugens (BPH) mtDNA and another scaffold containing 3 contigs of L. striatellus (SBPH) were identified in the assemblage of the wLug and wStri genome which were reported so far. The unusual length of the mitochondrial genome in N. lugens is partly due to a long putative control region and a long repeat region containing three repeats of trnC gene of BPH, trnS2 (UCN) of SBPH which harbor a simple loop in the dihydrouridine (DHU) arm and trnH of SBPH could have a loop-stem structure like trnT of BPH that forms a loop is found in many Hemiptera [trnS1 (AGN) has a completed loop-stem structure while that of trnS2 (UCN) has a loop. In contrast, the trnS1 (AGN) has a loop and trnS2 (UCN) has a completed loop-stem structure in previously reported SBPH [trnH gene of SBPH which formed a weak loop-stem structure of the T-arm (T\u03a8C) in this study possessed a stable loop-stem structural of the T-arm (T\u03a8C) in previous study [All of the tRNA genes have the typical cloverleaf secondary structure, except for emiptera ,18,27-30emiptera . For SBPted SBPH . Furtherus study .trnS2 (UCN) (SBPH) and 57 bp for trnS1 (AGN) (BPH) to 71 bp for trnK (BPH and SBPH) and trnV (BPH) and rrnL . They are located between trnL1 (CUN) and an A+T-rich region, separated by trnV.The length of all tRNA genes ranged from 56 bp for trnC-trnW and nad6-trnP-trnT) associated with tRNAs and PCGs were found in both of BPH and SBPH . But the most striking feature was the different locations of the trnH gene in two individuals of SBPH. The trnH gene is located between nad5 and nad4 genes in this study just as in all other hemipteran species sequenced so far, but Song and Liang (2009) previously reported that this tRNA gene is located between nad4L and nad6 genes . This feature is common in hemipteran insects [The mtDNAs of BPH and SBPH contain the full set of PCGs usually presented in animal mtDNA. Except for the Insects were the shortest in insects known so far. In fact, the longest atp8 gene (228 bp) was found in Bemisia tabaci (Hemiptera: Aleyrodidae) [Pachypsylla venusta) [Lymantria dispar) [atp8 gene had a length of about 160 bp. Taking into account the length of atp8 gene of planthoppers discovered in this study, it seems that the length distribution of atp8 gene in Hemiptera was wider (From 99 bp to 228 bp) than that of all other orders of insects reported so far. The sequence alignment of atp8 gene with other insects revealed that nearly 60 bp length of sequence in the 3\u2032end of this gene was lost in these two planthoppers. Does the short length of this gene change the structure of its encoded protein? Does length change of this gene alter the functions or efficiency of this gene? These aspects are worth further studying.It is worth mentioning that the lengths of rodidae) . In almovenusta) to 183 b dispar) . In mostThe abundance of codon families and Relative Synonymous Codon Usage (RSCU) in PCGs rrnS and trnI-trnQ-trnM gene cluster in the A+T-rich region. This poly \u201cT\u201d structure might be conservative in Delphacidae and be responsible for the control of replication and transcription of mitochondria.Neuroctenus parus) to 86.3% (Aleurodicus dugesii). These two extreme A+T content species were inferring gene arrangement [The composition of the majority strand (J-strand) of SBPH mtDNA is A = 7099 (43.2%), T = 5581 33.97%), G = 1527 (9.29%) and C = 2224 (13.54%). The composition of the J strand of BPH mtDNA is A = 7393 (41.96%), T = 6165 (34.99%), G = 1661 (9.43%) and C = 2400 (13.62%). Similarly to most hemipteran insects, the nucleotide compositions of the two planthopper mitogenomes are significantly biased toward A and T . Comparing with 48 mitochondrial genomes of hemipteran species, we found that there is considerable variation in base composition among different hemipteran species: ranging from 68.9% to 0.2765 (Lycorma delicatula) with the BPH and SBPH mtDNA exhibiting a slight different AT-skew (0.0909 for BPH and 0.119171 for SBPH). The GC-skews of hemipteran species vary from \u22120.2827 (Acyrthosiphon pisum) to 0.2086 (Neomaskellia andropogonis) with the BPH and SBPH mtDNAs exhibiting very similar GC-skew (\u22120.1826 for BPH and \u22120.1842 for SBPH). Similarly, the AT/GC-skew values exhibit different ranges among three suborders: AT-skew: Heteroptera, 0.0642 - 0.2181,\u2009Sternorrhyncha,\u2009-0.1812\u2009- 0.0956, Auchenorrhyncha, 0.0623\u2009-T\u20090.2765;\u2009GC-skew:\u2009Heteroptera,\u2009-0.2656\u2009-(\u22120.0965),\u2009Sternorrhyncha,\u2009-0.2810\u2009-\u20090.2086,\u2009Auchenorrhyncha,\u2009-0.2827 - (\u22120.0783).The hemipteran AT-skews vary from \u22120.1812 of Sternorrhyncha, all species of Aleyrodidae exhibit converse AT/GC-skew values Figure\u00a0 as descrrrnL gene and rrnS gene with the entire mitochondrial genome, PCGs show more significant positive correlation (R2 = 0.9674) than rrnL gene (R2 = 0.8873) and rrnS gene (R2 = 0.7189) , complete trnH gene (62 bp), two intergenic nucleotides and a portion of nad4 gene (96 bp). All sequenced individuals have an identical sequence of the trnH gene which was the same with that of the mitochondrial genome of SBPH sequenced in this study. Considering the low probability of many different sites in the trnH gene related sequences caused by PCR or sequencing, we still cannot exclude the possibility that some sporadic individuals of SBPH possessing the same location of trnH gene as previous study exist in some special regions in China. Anyway, according to the mutation sites of all sequences of the region compassing trnH gene, 16 haplotypes of the sequence were identified were observed in natural populations and one ATP synthase gene (atp8). Because of the different locations of trnH gene, positions of the start codon of nad5 and nad6 genes and the end codon of nad4 and nad6 genes had been changed. Comparing the region (from nad5 to nad6) of mitochondrial genomes of SBPH with that of previous study, we found the differences were 57 bp deletion in the front of nad5 gene, 21 bp deletion at the end of nad4 gene and 84 bp insert in the front and 55 bp deletion at the end of nad6 gene. Furthermore, there also existed 21 bp absent in the nad2 gene and 60 bp absent at the end of atp8 gene of mitochondrial genome of these two SBPH, the other eight PCGs and two ribosomal RNA genes represented significant difference in the evolution rates showed the fastest mutation rate among these genes. The mutation rates of the other PCGs ranged from 0.0022 to 0.0076. The evolution rate of rrnS gene (0.8%) was five times faster than rrnL gene (0.16%). In general, except the trnH and two trnS genes, the other tRNA genes were conserved (only few of them have single variant site).Excluding five length distinct genes detected in the control region might provide additional genetic markers for studying population genetics, individual difference and phylogeographics of planthoppers. The comparative analyses of two sequenced mitochondrial genomes of SBPH revealed that rearrangements of genes in the mitochondrial genome could have occurred in the same species. On account of the different locations of trnH gene, the start and end codon of its neighboring genes had been changed. Even the same tRNA gene (e.g. trnS1 (AGN) and trnS2 (UCN) genes) could form different secondary structures in these two different individuals of SBPH. All these characteristics reveal that great divergence of mitochondrial genome could occur in different individuals of a species.The rearrangement of mitochondrial genome of planthoppers reported in this study adds more examples of the rearranged pattern of genes in the mitochondrial genomes of hemipteran insects studied so far. The fact that the rearrangement was conserved in Delphacidae suggests that gene rearrangements of mitochondrial genome probably occurred before the differentiation of this family. Compared with other hemipterans and other insects, the extreme short lengths of Laodelphax striatellus and Nilaparvata lugens for mitochondrial genome sequence were collected in China. Other natural populations which were used to validating location of trnH of SBPH and detecting the variable number of tandem repeats (VNTRs) in control regions of BPH and SBPH were collected in different locations of China generated from the PCR-free random shotgun-sequencing libraries of average insert size 500 bp, one scaffold composed of three contigs of mitochondrial genome of SBPH and one scaffold composed of four contigs of mitochondrial genome of BPH were generated were determined based on alignments and secondary structures of rRNA sequences of other hemipteran species. The boundaries of the ribosomal rrnL gene were assumed to be delimited by the ends of the trnL1 (CUN) and trnV. The 3\u2032 end of rrnS gene was assumed to be delimited by the start of trnV while the 5\u2032 end was determined through comparison with orthologous genes of other hemipteran species sequenced so far. The base composition, the Relative Synonymous Codon Usage (RSCU) values of BPH and SBPH were calculated with MEGA 4 program [After finished the gap closing work, we annotated the mitochondrial genomes of BPH and SBPH. All PCGs were identified by ORF Finder implemented at the NCBI website with the invertebrate mitochondrial genetic codes. Finally pair-wise comparisons with orthologous proteins from other hemipteran insects were performed to better define the limits of PCGs. The transfer RNA (tRNA) genes were identified using both of the tRNAscan-SE and ARWE program .trnH rearrangement types really exist in natural populations, we sequenced a region of mitochondrial genome encompassing the trnH gene from 309 individuals of SBPH which were collected from 15 natural populations and also checked the Wolbachia infection status of each individual to calculate the frequency of each haplotype of the sequence of this region. The sequences of each haplotype are deposited in the GenBank database under the Accession No. KC006945 - KC006960.After downloaded other mitochondrioal genome sequence were not calculated for the variant length of these genes in these two individual mitochondria.The mutation rates of each gene between mitochondrial genomes of two individuals of Click here for fileNilaparvata lugens and Laodelphax striatellus used in this study. Collection information for natural populations of Click here for file"} +{"text": "S)-PD172938 and arylated analogues with hypnotic sedative activity, obtained in good overall total yield (50%) and high enantiomeric purity (95% ee). The synthetic routes developed herein are particularly convenient in comparison with the current methods available in literature and are particularly promising for large scale applications.New bifunctional chiral ammonium salts were investigated in an asymmetric cascade synthesis of a key building block for a variety of biologically relevant isoindolinones. With this chiral compound in hand, the development of further transformations allowed for the synthesis of diverse derivatives of high pharmaceutical value, such as the Belliotti ( The enantiomeric excess was determined by derivatization of the compound into methyl ester 12 or amide 16.File 11H NMR, 13C NMR and HPLC traces.Complete experimental details and procedures, spectroscopic data, copies of"} +{"text": "Azadirachta indica L.) leaf has been widely used in ayurvedic system of medicine for fertility regulation for a long time. The molecular mechanism by which neem leaf regulates female fertility remains poorly understood. Animal studies suggest that aqueous neem leaf extract (NLE) induces reactive oxygen species (ROS) - mediated granulosa cell apoptosis. Granulosa cell apoptosis deprives oocytes from nutrients, survival factors and cell cycle proteins required for the achievement of meiotic competency of follicular oocytes prior to ovulation. Under this situation, follicular oocyte becomes more susceptible towards apoptosis after ovulation. The increased level of hydrogen peroxide (H2O2) inside the follicular fluid results in the transfer of H2O2 from follicular fluid to the oocyte. The increased level of H2O2 induces p53 activation and over expression of Bax protein that modulates mitochondrial membrane potential and trigger cytochrome c release. The increased cytosolic cytochrome c level induces caspase-9 and caspase-3 activities that trigger destruction of structural and specific proteins leading to DNA fragmentation and thereby oocyte apoptosis. Based on these animal studies, we propose that NLE induces generation of ROS and mitochondria-mediated apoptosis both in granulosa cells as well as in follicular oocyte. The induction of apoptosis deteriorates oocyte quality and thereby limits reproductive outcome in mammals.Neem ( Azadirachta indica L.) has been considered as one of the most important medicinal plants worldwide. The medicinal utility of this plant are listed in ancient documents \u2018Charak-Samhita\u2019 and \u2018Susruta-Samhita\u2019 that are considered as the foundation of the Indian system of natural treatment, Ayurveda during final stages of folliculogenesis and ovulation, while their effects are neutralized by active enzymatic antioxidant system in rat ovary of NLE leaf extract-induced egg apoptosis in rat\u201d funded by Department of Science and Technology, Ministry of Science and Technology, Government of India, New Delhi.Author SKC is the Principal Investigator of a project entitled \u201cStudies on neem ("} +{"text": "Myocardial infarction was experimentally induced in rat hearts and harvested immediately, 7, 14 and 28 days after the infarction induction. Anterior wall infarct samples underwent biaxial tensile and uniaxial compressive testing. Orientation of collagen fibres was analysed following mechanical testing. In this paper, we present the tensile and compressive stress\u2013strain raw data, the calculated tensile and compressive moduli and the measured angles of collagen orientation. The presented data is associated with the research article titled \u201cCharacterisation of the mechanical properties of infarcted myocardium in the rat under biaxial tension and uniaxial compression\u201d [1]. Specifications TableValue of the data\u2022Full presentation of biaxial mechanical data and collagen fibre orientation for healing myocardial infarcts.\u2022The presented data demonstrates the mechanical and structural anisotropy of the healing myocardial infarcts.\u2022First report to characterize the compressive properties of the healing rat myocardial infarcts.\u2022Presentation of collagen fibre orientation in healing myocardial infarcts.\u2022The presented mechanical and structural data can be utilised in constitutive modelling of healing myocardial infarcts for rats.1The data being shared describe the mechanical and structural properties of healing rat myocardial infarcts from individual samples in several post-infarct time points: immediately (i.e. 0 day), 7, 14 and 28 days after the induction of myocardial infarction. The mechanical data are composed of biaxial tensile stress\u2013strain relationships , Fig. 4,2The details of the experimental work and materials are provided in"} +{"text": "To the Editor: Marburg virus (MARV) and Ravn virus (RAVV), collectively called marburgviruses, cause Marburg hemorrhagic fever (MHF) in humans. In July 2007, 4 cases of MHF occurred in miners at Kitaka Mine in southern Uganda. Later, MHF occurred in 2 tourists who visited Python Cave, \u224850 km from Kitaka Mine. One of the tourists was from the United States (December 2007) and 1 was from the Netherlands (July 2008); 1 case was fatal (Rousettus aegyptiacus bats (Egyptian fruit bats).Longitudinal investigations of the outbreaks at both locations were initiated by the Viral Special Pathogens Branch of the Centers for Disease Control and Prevention in collaboration with the Uganda Wildlife Authority (UWA) and the Uganda Virus Research Institute (UVRI). During these studies, genetically diverse MARVs and RAVVs were isolated directly from bat tissues, and infection levels of the 2 viruses were found to increase in juvenile bats on a predictable bi-annual basis Figure. R. aegyptiacus colonies in the area. Although minor colonies of small insectivorous bats were found, the only identifiable colony of R. aegyptiacus bats was found inside the re-opened Kitaka Mine, albeit at much reduced size, perhaps 1%\u20135% of that found before depopulation efforts.In October 2012, the most recent known marburgvirus outbreak was detected in Ibanda, a town in southwest Uganda. Ibanda is \u224820 km from the Kitaka Mine and is the urban center that serves smaller communities in the Kitaka area. This MHF outbreak was the largest in Ugandan history: 15 laboratory-confirmed cases occurred were positive for marburgvirus RNA by quantitative reverse transcription PCR (32/233 [13.7%] adults and 21/167 [12.6%] juveniles; Of the 400 Phylogenetic analysis of viral RNA genome fragment sequences in this study showed high marburgvirus genetic diversity, including the presence of RAVVs and MARVs. Sequences for isolates from 3 bats were nearly identical to those of the MARV isolates obtained from patients in the 2012 Ibanda outbreak (Photographs taken during August 2008\u2013September 2009 of bat extermination efforts at Kitaka Mine, and table showing demographic characteristics of bats captured during a Marburg hemorrhagic fever outbreak investigation at the mine in November 2012, Uganda."} +{"text": "Although extensively studied and indeed emotionally discussed for more than two decades the role of C-reactive protein (CRP) in cardiovascular disease remains controversial. Three major questions are still not yet resolved. (1) Is CRP a clinically relevant marker of cardiovascular risk? (2) Is CRP even more than a risk marker, that is, a risk factor in cardiovascular disease? (3) Finally, is CRP a cardiovascular drug target?This special issue comprises four review articles and three research articles that reflect the ongoing controversy over the subject. The review articles discuss CRP as a cardiovascular risk marker, CRP in animal models, CRP in its native and nonnative conformation, and CRP in human arteriosclerosis. The research articles deal with CRP as a cardiovascular risk marker in non-ST elevation acute coronary syndrome and with CRP as a drug target. The discussion climaxes in two research articles describing the use of CRP specific antisense oligonucleotides (ASOs) for the treatment of cardiovascular disease in animal models. The conclusions are indeed contradictory. When looking at the two articles, three general points may have to be taken into consideration. (1) Is the statistical power of the animal experiments adequate to draw definitive conclusions? (2) Are there off-target effects of the ASOs that may confound the results? And (3) is it necessary to design studies incorporating multiple on-target ASOs?Specific CRP inhibition followed by use of CRP inhibitors in controlled clinical trials may be the only way to prove or disprove a causative role for CRP in cardiovascular disease."} +{"text": "To the Editor: The earliest clinical cases of Zika virus infection were reported from continental South America in 2015 tests specific for dengue . Of these 50 patients, 30 (60%) were female. Most of these patients reported illness onset during December 9\u201327, 2015 were female. A total of 22 (8%) samples were positive for dengue; 2 were positive for chikungunya. Of the remaining 252 patients, 50 (20%) had 27, 2015 Figure 1The most commonly reported signs and symptoms were fever (86%), exanthema (72%), and headache (62%). The clinical characteristics of these infections showed no statistically significant difference with those associated with dengue and chikungunya virus infections and with cases found to be negative for all 3 viruses, suggesting that the negative cases could represent Zika virus infections Table. OBy using Vero E6 cells (American Type Culture Collection), we isolated Zika virus from 9 samples . Phylogenetic analysis of 5 Zika virus sequences placed these isolated (GenBank accession nos. KU724096\u2013100) within the Asian lineage, the lineage involved in the spread of Zika virus in the Americas Figure 2By using molecular methods, we confirmed diagnoses in 27% of patients during this outbreak. The distribution of positive results suggests that Zika virus was the predominant etiologic virus in this cohort, but we cannot firmly conclude this because most specimens tested negative for Zika, dengue, and chikungunya viruses.Although results from patient sampling and laboratory testing are not comparable, an assessment in Puerto Rico was able to detect Zika virus RNA by rRT-PCR or IgM by ELISA in 19% of 155 patients with suspected Zika virus infection (Several reasons might exist for the high proportion of specimens testing negative for Zika virus. Viremia is often low and short-lived in persons infected with Zika virus (The Panama Ministry of Health is following up with known pregnant women of the Guna Yala region who report Zika virus infection symptoms and is testing urine samples by using Zika virus\u2013specific rRT-PCR within 14 days of symptom onset. Pregnant women confirmed to have Zika virus infection will receive ultrasound monitoring; however, the test has relatively low positive predictive value for detecting microcephaly (Distribution of symptoms by patients with Zika, dengue, and chikungunya virus infections in the Guna Yala region of Panama, November 27, 2015\u2013January 22, 2016; epidemiologic curve for the outbreak of Zika virus infection in this region; and maximum-likelihood tree of the Zika virus isolated during the outbreak."} +{"text": "Alcohol screening and brief interventions (SBI) have a history and good evidence of efficacy in primary care settings . EfficacThis study aimed to discuss, and present for debate, challenges and opportunities relating to alcohol SBI in new settings from published and previously unpublished studies of recent SBI implementation in Scotland and England.A narrative review was conducted of evidence from diverse studies including research into training and implementation of alcohol SBI outside of primary care .The challenges and opportunities can be conceptualised in terms of questions that should be asked before considering implementation of alcohol brief interventions in a new setting: (1) Is there a need for SBI delivery in this service? (2) How are practitioners currently addressing alcohol use - how when, where does SBI fit in? (3) Will SBI work/do harm in this setting? (4) Will SBI be perceived as legitimate by practitioners and acceptable to service-users? (5) Will practitioners have the ability to deliver SBI? (6) What support will be needed? (7) What will support routine implementation of SBI in this setting?Careful consideration should be given to every aspect of the design, purpose, context and evaluation of alcohol SBI in any given setting preferably by robust stepwise research prior to widespread implementation. Avoiding assumptions, including about screening methods and intervention goals, is likely to be important for effectiveness, implementation and avoiding unintended harms."} +{"text": "The body sodium imbalance (dysnatremias) may be associated with increased mortality of critically ill patients. Evidence suggests that changes in the serum sodium level on admission to the intensive care unit (ICU), may lead to a poor outcome.The objective of this study was to evaluate the ability of APACHE II and serum sodium levels to predict mortality of surgical critically ill patients.One hundred and ninety-five surgical patients admitted to the ICU in the post-operative phase were retrospectively studied. The patients were divided into survivors (n=152) and nonsurvivors (n=43). APACHE II, and serum sodium levels at admission, 48-h and discharge were recorded. The capability of each index to predict mortality of surgical patients was analysed by receiver-operator characteristic curves (ROC). Odds ratios (OR) and 95% confidence interval (CI) for hyponatremia (Na< 136 mmol/L) and hypernatremia (Na>144 mmol/L) were calculated.Comparison of data between survivors and nonsurvivors is summarized in Table Even though APACHE II was the most effective index to predict mortality in the surgical critically ill patients, the serum sodium levels on admission may also be used as predictor of outcome."} +{"text": "Chronic migraine (CM) affects 2% of the population and Botox is the only licensed treatment for prevention of adult patients with CM.In the UK, National Institute for Clinical Excellence (NICE) approved its use on the NHS in patients who failed three preventive medications.NICE recommends continuing treatment beyond cycle 2 in those with 30% reduction in headache days (negative stopping rule) and the treatment is stopped when migraine become episodic (positive stopping rule).However, the long-term outcome ie duration of required treatment remains uncertain.To ascertain the duration of treatment with Botox for the prevention of chronic migraine in responders as per NICE criteria.Adult patients with CM attending the Hull migraine clinic were offered Botox based on clinical needs and maintained a headache diary.Data were extracted for headache, migraine, and headache-free daysResponder rate was assessed applying NICE criteriaPatients (N=67) who commenced treatment between July 2010 and June 2012 were followed up for at least 18 months.30 Patients stopped treatment at Cycle 2 as per negative stopping rule by NICEOf 37 responders, only 12 were still on treatment at 18 months. Nearly half of the patients stopped treatment by the 4th Cycle (positive stopping rule).We continue to follow all patients who receive Botox for prevention of chronic migraine and aim to present 2 year follow up on a larger cohort at the EHMTIC September 2014."} +{"text": "Electronic medical records (EMR) form a rich repository of information that could benefit public health. We asked how structured and free-text narrative EMR data should be combined to improve epidemic surveillance for acute respiratory infections (ARI).Eight previously characterized ARI case detection algorithms (CDA) were applied to historical EMR entries to create authentic time series of daily ARI case counts (background). An epidemic model simulated influenza cases (injection). From the time of the injection, cluster-detection statistics were applied daily on paired background+injection (combined) and background-only time series. This cycle was then repeated with the injection shifted to each week of the evaluation year. We computed: a) the time from injection to the first statistical alarm uniquely found in the combined dataset (Detection Delay); b) how often alarms originated in the background-only dataset ; and c) the number of cases found within these false alarms (Caseload). For each CDA, we plotted the Detection Delay as a function of FAR or Caseload, over a broad range of alarm thresholds.CDAs that combined text analyses seeking ARI symptoms in clinical notes with provider-assigned diagnostic codes in order to maximize the precision rather than the sensitivity of case-detection lowered Detection Delay at any given FAR or Caseload.An empiric approach can guide the integration of EMR data into case-detection methods that improve both the timeliness and efficiency of epidemic detection. Epidemics of acute respiratory infections (ARI), whether due to influenza Electronic data offer the opportunity for more timely and complete gathering of health information compared to what has historically been achieved through manual, paper-based reporting To gain insight on the conduct of surveillance in an EMR environment, we previously evaluated how EMR entries should be assembled to discover individuals with ARI The Institutional Review Boards of the Veterans Administration (VA) Maryland Health Care System and the University of Maryland approved this study. The study was granted a waiver of consent as risks were limited to information confidentiality and the work would not have otherwise been feasible, given the large number of EMR records screened for possible ARI. All EMR information was anonymized and de-identified prior to simulations and analyses, which used only daily case counts.Historical EMR data were extracted from the Veterans Integrated Service Technology Architecture (VistA) repository using the MDE software and transferred to a Structured Query Language (SQL) relational database .th Revision, Clinical Modification, ICD-9) either used by the original Centers for Disease Control and Prevention (CDC) \u201cBioSense\u201d surveillance system Outpatients with possible ARI were identified by applying previously developed ARI case-detection algorithms (CDAs) et al. To create a plausible ARI outbreak to be discovered by the surveillance system, we developed an epidemic model of influenza . The model included 30 contiguous ZIP codes centered on Baltimore, Maryland, and consisted of a coupled series of differential equations to describe the overall epidemic http://www.r-project.org). Starting on the day when the synthetic epidemic was injected into a CDA-specific authentic background time series, and then daily for a total of 80 days, a statistical outbreak detection method (see below) was applied in parallel to corresponding time series that included either: a) both background and epidemic cases W2c We computed three performance benchmarks at any given statistical alert threshold: 1) the Detection Delay, the time from the injection of the synthetic outbreak to the first true positive alarm, averaged for the 52 surveillance cycles of the evaluation year; 2) the false alarm rate (FAR), the average daily number of unique alarms issued in the background-only time series during the evaluation year; 3) the Caseload, defined as the total yearly number of cases included in the above false alarms. Corresponding Detection Delays, FARs and Caseloads were obtained for a range of statistical alert thresholds adjusted iteratively to focus on a FAR range felt to be of practical use for surveillance i.e. 0\u201310%.The activity monitoring operating characteristic (AMOC) curves The surveillance advantages of adjusting the ICD-9 codes used to identify ARI cases can be visualized by comparing the AMOC curves obtained using a \u201crespiratory\u201d code set used by a surveillance system of national scope Case detection that relied solely on text analyses of clinical notes resulted in outbreak detection performance roughly on par with that of the VA-adapted set of ICD-9 codes Time series of background casecounts. 8-year background time series are provided for each of the CDA outlined in the (TXT)Click here for additional data file.Datafile S2(CDA 2) Time series of background casecounts.(TXT)Click here for additional data file.Datafile S3(CDA 3) Time series of background casecounts.(TXT)Click here for additional data file.Datafile S4(CDA 4) Time series of background casecounts.(TXT)Click here for additional data file.Datafile S5(CDA 5) Time series of background casecounts.(TXT)Click here for additional data file.Datafile S6(CDA 6) Time series of background casecounts.(TXT)Click here for additional data file.Datafile S7(CDA 7) Time series of background casecounts.(TXT)Click here for additional data file.Datafile S8(CDA 8) Time series of background casecounts.(TXT)Click here for additional data file."} +{"text": "A subset of patients with autoimmune diseases including rheumatoid arthritis (RA) and lupus appear to be exposed continually to interferon (IFN) as evidenced by elevated expression of IFN induced genes in blood cells. In lupus, detection of endogenous chromatin complexes by the innate sensing machinery is the suspected driver for the IFN, but the actual mechanisms remain unknown in all of these diseases. We investigated in two randomized clinical trials the effects on RA patients of baminercept, a lymphotoxin-beta receptor-immunoglobulin fusion protein that blocks the lymphotoxin-\u03b1\u03b2/LIGHT axis. Administration of baminercept led to a reduced RNA IFN signature in the blood of patients with elevated baseline signatures. Both RA and SLE patients with a high IFN signature were lymphopenic and lymphocyte counts increased following baminercept treatment of RA patients. These data demonstrate a coupling between the lymphotoxin-LIGHT system and IFN production in rheumatoid arthritis. IFN induced retention of lymphocytes within lymphoid tissues is a likely component of the lymphopenia observed in many autoimmune diseases.NCT00664716.ClinicalTrials.gov Systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren\u2019s syndrome, systemic sclerosis, myositis and multiple sclerosis patients have circulating blood cells with elevated levels of RNA from IFN-induced genes, i.e. an \u2018IFN signature\u2019 We have investigated the effects of inhibition of the lymphotoxin-LIGHT system in RA using a soluble lymphotoxin-beta receptor immunoglobulin fusion protein called baminercept. LTBR is a central component of a signaling system whereby lymphocytes instruct stromal cells to differentiate into specialized vasculature and certain reticular networks Unexpectedly, we found that baminercept reduced the IFN signature in RA patients. The reduced IFN signature in RA patients following baminercept treatment is the first time outside of high dose steroid therapy that an IFN signature was decreased by a pharmacological treatment not targeting IFN itself. Taken together with the known effects of LTBR inhibition, these studies not only link the LTBR axis to IFN production in man, but also provide potential insight into the nature of the IFN signature.Two randomized phase IIb controlled studies of the effects of baminercept in rheumatoid arthritis were conducted. One study enrolled patients with an inadequate response to disease-modifying antirheumatic drug therapy (DMARD-IR) and the other involved patients with an inadequate response to tumor necrosis factor inhibition (TNF-IR) and an IFN score calculated and type II IFN (IFN\u03b3) and, furthermore, each IFN is capable in many contexts of inducing the expression of the other IFN class Elevated levels of type I IFN or an IFN-like inducing activity can be found in the sera of a subset of the SLE patients with a transcriptional IFN signature; however, in RA the results range from not detectable to low levels relative to SLE sera SLE patients with a high IFN signature tend to be lymphopenic In rodents, blockade of the LTBR system leads to lymphocytosis within several weeks most likely due to loss of high endothelial venule addressin expression and reduced entry into the lymph nodes and mucosal environments In mice, lymphocytosis following LTBR blockade results from elevated T and B cells counts Given the emphasis on plasmacytoid DC as the source of the IFN signature in SLE, we examined RNA levels in the blood of two known pDC markers, CLEC4C (BDCA2) and LILRA4 (ILT7). LILRA4 levels increased following baminercept treatment, yet CLEC4C levels were unchanged scoring system. Overall, baminercept was well tolerated was a multicenter, phase IIb, double-blinded, placebo-controlled study of RA patients who lacked an adequate response to TNF-blocking therapy and had discontinued TNF blocking treatment for at least 90 days. The study dosed 114 patients with subcutaneous injections q2w of either placebo (38) or baminercept 200 mg (76). This study was terminated early due to poor efficacy in the DMARD-IR study; however, 81 patients completed the 3 months of dosing and another 15 patients received at least 2 months of treatment. Study was conducted between March 2007 and October 2008 at 40 sites in the United States, Canada, Belgium and United Kingdom.Investigators for both baminercept studies are listed in the supplemental materials in SLE data were from registry representing a collection of 292 SLE patients from the Hopkins Lupus Center in the US. Patients were eligible if they were aged 18\u201375 years and met the American College of Rheumatology Revised Criteria for Classification of Systemic Lupus Erythematous. Baseline data were used in this study and patients were under standard clinical practice. Normal controls for RNA analyses were composed of healthy volunteer donors from Biogen Idec. Control group had equal numbers of males and females and was not exactly gender balanced with the predominantly female composition of both the RA and SLE cohorts.The RA studies were approved by the appropriate institutional review boards or ethics committees and all patients provided written informed consent Click here for additional data file.Checklist S1CONSORT Checklist.(PDF)Click here for additional data file.Protocol S1Trial Protocol.(PDF)Click here for additional data file.Protocol S2Trial Protocol.(PDF)Click here for additional data file."} +{"text": "Preoperative quantitative assessment of coronary angiography (CAG) and real-time graft size and graft flow assessment using epigraftic ultrasonography in the operative field have been performed to ascertain the patency in the right coronary artery bypass grafting (CABG).This study aims to evaluate the efficacy of the quantitative coronary artery and graft assessment to increase the patency of the right CABG.CABG was performed in 200 patients from January 2010 to December 2014. Ninety-three patients underwent all of preoperative CAG, real-time graft assessment and postoperative CAG with a total of 93 grafts anastomosed to the right coronary artery. Severity of coronary artery stenosis was evaluated by CAG. The size of target right coronary artery was measured by ultrasonography in the operative field. Parameters about graft flow were obtained from flow velocity curve in all the graft. The grafts were divided into two groups: patent grafts and failing grafts . All factors were compared in these two groups and evaluated by logistic analysis and receiver operating characteristic (ROC) curve analysis.The overall patency as measured by postoperative CAG was 94.6% (88/93). There were 7 failing grafts including 5 occlusion and 2 competitive slow flow. Logistic regression analysis revealed that the percentage of graft size measured by ultrasonography divided by the size of the right coronary artery (graft-RCA size mismatch) and the pulsatility index (PI) were independent predictors of early graft failure . ROC curve analysis revealed that graft-RCA size mismatch > 2.08 and PI > 4.55 were predictors of graft failure.In this series, epigraftic ultrasonography depicted graft flow clearly. Combination of preoperative quantitative coronary artery assessment and real time graft assessment was essential to predict graft failure during the CABG. This technique may increase the patency of the right coronary artery bypass grafting."} +{"text": "The condition accounts for almost half of all nail issues yet continues to be largely under-reported and untreated. This study will investigate the antifungal efficacy of eucalyptus oil A longitudinal prospective study was used to monitor the changes in toenail mycotic infections over a four-month period, using undiluted eucalyptus oil as a topical antifungal agent. Data were collected from 22 participants (14 men and 8 women) aged between 40 and 84 with a total of 70 toenails, 35 with nail matrix infection and 35 without. To review the effect of eucalyptus oil on the clinical appearance of the fungal infected nail plates, toenails were monitored at four-weekly intervals for a period of four months. The participants\u2019 satisfaction with the therapy was assessed using the OnyCOE-t questionnaire.Of the 70 nails analysed, the patterns of infection were classified as proximal subungual onychomycosis (49%), distal lateral subungual onychomycosis (47%), white superficial onychomycosis (3%), and total dystrophic (1%). Almost half of all participants (45%) had onychomycosis affecting only one toenail. Only 23% of participants had previously treated the infection and the mean duration of infection was 10 years and 3 months.Nails with superficial onychomycosis (n=2) were found to have 86% clearance of infection after four months. One third of all nails (n=11) with distal lateral subungual onychomycosis and 50% (n=17) of nails with proximal subungual onychomycosis demonstrated a zone of clearance at the proximal nail plate tissue, suggesting a fungistatic effect of the eucalyptus oil.Topical eucalyptus oil is more effective as an antifungal treatment for fungal infected toenails without nail matrix infection. Eucalyptus oil may provide an acceptable and cheaper alternative to prescription topical antifungal agents, for people with white superficial onychomycosis or distal lateral subungual fungal nail infections."} +{"text": "UGT1A1*28 was not questioned in our study.There is an error in the second sentence in the third paragraph of the \u201cGenetic differentiation and haplotype diversity for DMET Plus markers\u201d section of the Results. The correct sentence is: Although, the array captures many of the functional variants described for these genes, unfortunately The S5 TableMinor Allele Frequencies (MAF) for 1,647 genetic markers. The markers are those included in the DMET Plus array and for all populations: Europeans (Hapmap CEU), Africans (Hapmap YRI and LWK), Native Americans (Zapotecas), Brazilians and Mexican mestizos (Guanajuato (GUA); Guerrero (GUE); Sonora (SON); Veracruz (VER) and Yucatan (YUC)).(XLSX)Click here for additional data file."} +{"text": "Systematic review and meta-analysis of published studies of alcohol use among young people (age 15\u201324 years) in eastern Africa to estimate prevalence of alcohol use and determine the extent of use of standardised screening questionnaires in alcohol studies.2 statistic (DerSimonian-Laird).Five databases were searched for publications until 30th June 2013. Results were summarised using the guidelines on preferred reporting items for systematic reviews and meta-analyses (PRISMA) and on quality assessment using the modified quality assessment tool for systematic reviews of observational studies (QATSO). Heterogeneity was assessed using the IWe identified 2785 potentially relevant studies, of which 56 were eligible for inclusion. Only two studies (4%) used the standardised Alcohol Use Disorder Identification Test (AUDIT) questionnaire, and six studies (13%) used the Cut down, Annoyed, Guilt, Eye opener (CAGE) questionnaire. The reported median prevalence of alcohol use was ever-use 52% [interquartile range (IQR): 20\u201358%], use in the last month 28% (IQR: 17\u201337%), use in the last year 26% (IQR: 22\u201332%), and problem drinking as defined by CAGE or AUDIT 15% (IQR: 3\u201336%). We observed high heterogeneity between studies, with the highest prevalence of ever use of alcohol among university students and female sex workers . Current use was most prevalent among male sex workers .Reported alcohol use and problem drinking were common among diverse groups of young people in eastern Africa, indicating the urgent need for alcohol-focused interventions in this population. Few studies have used standardised alcohol screening questionnaires. Epidemiological research to investigate alcohol-focused interventions in young people should aim to apply such questionnaires that should be validated for use in this population. Harmful alcohol use is a significant public health problem that often begins early in adult life. Globally, an estimated 2 billion people drink alcohol and 76 million have alcohol use disorders (AUD) WHO . The meaet al. et al. et al. et al. et al. et al. Factors associated with alcohol use include religion, personal income, education level, peer influence, having older sexual partners, stress and relatives and friends using alcohol estimate the prevalence of alcohol use among specific groups of young people (15\u201324 years) in eastern Africa; (ii) determine the extent of use of standardised alcohol screening questionnaires [Alcohol Use Disorder Identification Test (AUDIT), Cut down, Annoyed, Guilt, Eye opener (CAGE) in identifying alcohol use and AUD in this region; (iii) assess the quality of research papers included in the review; and (iv) describe factors associated with initiation and persistence of alcohol use among young people in eastern Africa.).Five databases were searched for publications to 30th June 2013. We used the following key terms: AND (young people OR adolescent OR teenage OR youth) AND . , and consensus on potential eligibility reached. Studies were eligible if they were conducted in eastern Africa ; and included prevalence of alcohol use for young people aged 15\u201324 years.et al. et al. Guidelines on preferred reporting items for systematic reviews and meta-analyses (PRISMA) were used (Moher We used a data extraction form to collect the following information from each eligible article: (i) country; (ii) year the study was conducted; (iii) year of publication; (iv) study population ; (v) sample size; (vi) definition of alcohol use ; (vii) prevalence of alcohol use and AUD (problem drinking as classified by CAGE and AUDIT); (viii) factors associated with the initiation and persistence of alcohol use; (ix) alcohol use screening questionnaires applied; and (x) complications associated with alcohol use.et al. A descriptive quality assessment of the final papers included in the meta-analysis was conducted using the modified quality assessment tool for systematic reviews of observational studies (QATSO) (Wong 2 statistic (DerSimonian-Laird) and reported the prevalence for studies in four groups: (i) ever use of alcohol; (ii) alcohol use in the last year, (iii) alcohol use in the last month (current use) and (iv) problem drinking as defined by CAGE and AUDIT .We identified 4013 published study citations from five databases, of which 1228 were duplicates. Thus, 2785 abstracts were screened for initial eligibility to identify studies conducted in eastern Africa. We identified 696 relevant abstracts of studies conducted in eastern Africa. We conducted further screening for studies reporting on alcohol use and identified 285 abstracts for full article review. Of these 285 abstracts for full article assessment, we could not access six full articles, 11 were review articles and five were conference posters.Thus, we reviewed 263 full-text papers and identified 56 eligible for inclusion in the review. The main reason for exclusion was that the paper did not report information on alcohol use from the target population, that is, young people aged 15\u201324 years, or that young people were included but we could not separate the prevalence in this age group from that in older people , and two were case\u2013control studies. Almost all studies were conducted in four countries: Ethiopia (n = 19), Kenya (n = 15), Tanzania (n = 10) and Uganda (n = 8); the remaining four studies were conducted in Rwanda (n = 2), Seychelles (n = 1) and Eritrea (n = 1). Most studies reported current alcohol use, 17 studies reported ever use of alcohol, four studies reported alcohol use in the last year, and five studies reported problem drinking. Only two studies used the AUDIT alcohol use screening questionnaire used probability-based sampling and had a response rate above 80% . However, 17 studies did not report the response rate and street children (21% vs 11%) and high in male university students (53% vs 50%). There was significant heterogeneity based on I2 statistics in all subgroups, and therefore, we do not report pooled prevalence.Figure vs 17%).Four studies reported the prevalence of alcohol use in the last 12 months. These showed similar levels as found for reported current alcohol use. Three studies were from the general population with a pooled prevalence of 30% (95%CI: 27\u201333%) and one from university students . One study reported gender-specific prevalence; it was high among males (34% vs. 9%(IQR: 9\u201320%) in the general population, 28% (IQR: 13\u201344%) vs 19%(IQR: 7\u201332%) among healthcare service attenders, 60% (IQR: 56\u201363%) vs. 41% (IQR: 24\u201358%) in secondary schools, and 43% vs. 28% in a university. There was no significant heterogeneity in studies conducted among university students except one study among female university students among female bar workers and 47% (95%CI: 40\u201353%) among male sex workers. Median prevalence in the general population was 3% (IQR: 1\u201315%); two of the studies in the general population were from Ethiopia and showed low levels of problem drinking (1\u20133%), but a study from Tanzania reported a rather high median prevalence of 15% (95%CI: 10\u201320%).et al. et al. et al. In this review, eight studies reported problematic drinking, two studies applied AUDIT, and six (13%) used CAGE to screen for problem drinking; two of the studies that applied CAGE and one study that applied AUDIT did not report scores according to age groups and female sex workers (66%) and lower among the general population and primary school students. Few studies reported alcohol use in the last year, and median prevalence in the general population was 29%. Reported current alcohol use was highest among male sex workers (69%), followed by the university students (33%), and was lowest in the general population and secondary school students with the exception of one study in the Seychelles that reported a high prevalence of 61%. Problem drinking was highest among groups known to engage in high-risk behaviours (such as bar workers and sex workers). Generally, reported alcohol use across all definitions of use was highest among groups known to engage in high-risk behaviours, followed by university students. Individuals attending healthcare services and general populations and secondary school students reported the lowest prevalence. Studies included in this review were of good quality; however, about two-thirds employed face-to-face interviewing approaches, an approach prone to social desirability bias that could lead to underreporting of alcohol use.vs. students vs. sex workers). We also attribute these variations to social influence and peer pressure ; it is, however, not widely used for the assessment of AUD among young people in general populations. In our review, only two studies used the internationally recommended AUDIT alcohol screening questionnaire (Mbatia et al. et al. The use of effective and validated instruments for the screening and assessment of alcohol use is essential to guide research and is important for the design and evaluation of interventions. AUDIT is validated and recommended by WHO for use at the primary healthcare settings and for the assessment of AUD in developing countries (Saunders Reported alcohol use among young people in eastern Africa is common and varies between different populations. The prevalence of AUD was highest among populations known to engage in high-risk sexual behaviours, but was also high among students in some of the studies. The studies reviewed lacked data about initiation and persistence of alcohol use, and little information was available about risk factors associated with alcohol use, and AUD. Notably, only few of the studies reviewed used internationally recommended and validated screening questionnaires such as AUDIT. Future epidemiological studies on alcohol use among young people should apply these questionnaires to facilitate comparison. However, such questionnaires have not been evaluated among young people in Africa, and studies closing this knowledge gap are therefore also required. Future studies should also determine factors responsible for initiation, persistence, and patterns of use in preparation for potential interventions. There is an urgent need of targeted interventions for groups of young people with a particularly high risk of alcohol use and AUD such as college students and young sex workers."} +{"text": "Background Exposure to high levels of Aluminium (Al) leads to a neurodegenerative disorders , which may be mediated through over generation of free radicals. So in the present study we investigated the ability of both Quercetin and Omega 3 to ameliorate Al adverse effect on brain antioxidant through monitoring the main brain antioxidant enzymes on molecular and cellular levels.Forty male albino rats were used, they were divided into 4 groups; Control, Aluminum Chloride (AlCl3) supplemented group that orally supplemented with 100mg of AlCl3 per Kg b.w. for two months. Quercetin group treated as ALCl3 group and orally supplemented with 100 mg/kg b.w. Quercetin for two months according to Hui et al. [Our results indicate a significant increase in superoxide dismutase (SOD) activity and MDA level and a significant decrease in the activities of catalase (CAT), glutathione reductase (GR) and glutathione peroxidase (GPX) and levels of reduced glutathione (GSH) in brain tissues in AlCl3 supplemented group when compared with control or Quercetin and Omega 3 supplemented groups Table . At the Both Quercetin and Omega 3 has the ability to overcome the Al induced oxidative stress in brain, manifested by the significant reduction in free radicals concentration and induction of the activity and gene expression of the brain antioxidant enzymes."} +{"text": "Patients with inflammatory bowel disease (IBD) demonstrate an inflammatory response which bears some similarities to that seen in ischaemic heart disease (IHD). The nature of the association of IBD with IHD is uncertain. We aimed to define the extent and direction of that association.This retrospective cohort study examined records from patients aged \u2265 15 years with IBD from 1987\u20132009 (n = 19163) who were age and gender matched with patients without IBD (n = 75735) using the General Practice Research Database. The primary outcome was the hazard ratio for IHD.A higher proportion of IBD patients had a recorded diagnosis of IHD ever, 2220 (11.6%) compared with 6504 (8.6%) of controls. However, the majority developed IHD prior to IBD diagnosis (1404 (63.2%) of IBD cases and 3090 (47.5%) of controls). There was increased IHD incidence in the first year after IBD diagnosis. Mean age at IHD diagnosis was statistically similar across all IBD groups apart from for those with Ulcerative Colitis (UC) who were slightly younger at diagnosis of angina compared to controls and coronary heart disease . Of those developing IHD following IBD diagnosis, UC patients were at higher risk of IHD (unadjusted HR 1.3 (95% CI 1.1\u20131.5), p<0.001) or MI (unadjusted HR 1.4 (95% CI 1.1\u20131.6), p = 0.004).Although IHD prevalence was higher in IBD patients, most IHD diagnoses predated the diagnosis of IBD. This implies a more complex relationship than previously proposed between the inflammatory responses associated with IHD and IBD, and alternative models should be considered. The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn\u2019s Disease (CD) are disorders of uncertain origin. In both UC and CD, an exaggerated immune response to unknown antigens is evident and a nuThere is a well-described association between rheumatoid arthritis (RA) and increased cardiovascular mortality, mainly as a result of ischaemic heart disease (IHD)., 10 AtheThere are sufficient shared characteristics to the inflammatory responses seen in IBD and RA to hypothesise that the recognized association between RA and IHD might also exist for IBD and IHD. Previous cohort studies have examined the risk of IHD in patients with IBD and have variously found no effect, or a slihttp://www.cprd.com/home/) between 1987 and 2009. For each subject with IBD, a further 4 subjects were identified and matched for age and sex but without IBD. All cohort members were followed from the start date (i.e. the date their GPRD record began) until the earliest occurrence of one of the following endpoints: recorded code of IHD, death, date of exit from GPRD registered GP practice, or end of study period (31.12.2009). Patients with less than (1) 2 years up-to-standard enrolment with the GP or (2) 1 year of computerized prescription history or (3) no health contacts during their complete period of follow-up were excluded from the cohort. Patients whose date of death or date of transfer out of a GPRD-registered practice preceded date of IBD diagnosis were excluded from the cohort. Patients <15 years of age at entry were excluded.The study population for this retrospective cohort study consisted of around 2.1 million male and female patients with an active registration at practices contributing to the General Practice Research Database , or Crohn\u2019s Disease (CD), or inflammatory bowel disease (not otherwise specified) (IBD (nos)) recorded on the database since 1987; patients with ICD-10 Read Codes (K50-K51) records of both UC and IBD were coded as UC; CD plus IBD were coded as CD; individual records which included both UC and CD were included only in analyses of IBD (nos). Prevalent IBD cases on 01.01.1987 were excluded. The index date was defined as the date of first recording of IBD. Lifetime IBD severity was determined using an algorithm based on IBD drug-use and surgical intervention (colectomy/stomata) developed by team members with clinical and research expertise in IBD.Age, sex and practice matched controls were allocated the same index date as their matched case. Because IHD has not been subjected to the same specific validation studies as IBD, our operational definition was developed using advice from clinicians with special interest in cardiovascular disease to include the following: Read Codes for IHD Coronary Heart Disease (CHD) was considered for the purpose of this study to be synonymous with IHD and Read Codes for coronary heart disease (including coronary artery disease) were included.Data was accessed within limits set out by the Medical Research Council licence agreement for academic access with Medical Research Ethics Committee ethical approval. The proposal was approved by the Independent Scientific Advisory Committee of the GPRD (protocol number 10_003).a priori hypothesis, that IHD followed IBD, was conducted on a subset which included cases of IHD following IBD and their associated matched controls (COHORT B: n = 77540).Descriptive analysis of baseline characteristics and exploration of the direction of association between IBD and IHD was conducted using the whole cohort of patients aged over 15 years . Subsequent analysis of the The relative risks of ischaemic heart disease (IHD) and its sub-entities myocardial infarction (MI) and angina), as well as CHD were estimated as hazard ratios (HRs) for patients with IBD compared to non-IBD patients, using Cox proportional hazard models. Models were subsequently adjusted for age, gender, socio-economic status , comorbidity and concomitant drug use, IBD disease severity, and smoking status. We carried out both forward and backward stepwise covariate selection within the cox proportional hazard model. All covariates were initially included with entry testing based on the significance of the score statistic, and removal testing based on the probability of a likelihood-ratio statistic based on conditional parameter estimates. Models were tested for interactions between fitted variables. Precision of estimates is reported using 95% confidence intervals. Data management was performed using Stata 10IC. Cox regression proportional hazard computations and Kaplan-Meier survival analysis were conducted using SPSS 21.Data were examined from electronic primary care records from 221 general practices across the UK from patients with a first diagnosis of IBD recorded from 1st January 1987 to 31st December 2009 . FollowiOf 19163 IBD cases, a total of 2220 (11.6%) had an IHD diagnosis ever, compared with 6504 (8.6%) of those without IBD. Of these IHD diagnoses, 4494 (51.5%) occurred prior to IBD diagnosis (1404 (63.2%) of IBD cases and 3090 (47.5%) of controls) . AccordiA total of 17358 patients were excluded from subgroup analysis where IHD preceded IBD or, for controls, the matched IBD date . Subset In order to examine the subset in a way that was consistent with previous research, the inciThis is the first study to fully examine both the strength and direction of association between development of ischaemic heart disease (IHD) and IBD. An increased incidence of IHD, angina, MI, and CHD diagnoses was seen in the first year after IBD diagnosis but the mean age of diagnosis comparing IBD cases with non IBD cases was not statistically different, apart from those with Ulcerative Colitis (UC) who were slightly younger at diagnosis of angina and coronary heart disease. Of those developing IHD following an IBD diagnosis, patients with UC were at slightly higher risk of a diagnosis of IHD or MI although results were not significant after adjustment for the role of covariates. Most notably, we found that although overall prevalence of IHD was higher in those with IBD, in the majority of cases the diagnosis of IHD actually predated that of IBD.This is the largest British cohort study to examine this issue. It used the General Practice Research Database which is an appropriate and reliable resource for IBD research, having been used for at least 19 studies published in peer-reviewed journals since 2000. The diagnostic reliability of IBD diagnosis and the year of IBD diagnosis in the GPRD has been confirmed in a recent validation study. Other GPAs others have highlighted , there iThe temporal relationship between IBD and IHD may be weakened by differences with which the diagnosis of each is recorded in the GPRD. IHD is a diagnosis made in the majority of cases fairly soon after the onset of symptoms, because of an event requiring admission to hospital . Nevertheless, among those with stable angina, nearly half have symptoms for 6 months or more before diagnosis. For IBD It is possible that IHD cases may have been missed or incorrectly coded within GPRD. Unrecorded diagnoses are increasingly unlikely within UK general practice due to policy and fiscal incentives to assess, monitor and treat cardiovascular disease, althoughThis is the first known study to examine the temporal relationship between IHD and IBD and we found that the majority of IHD cases predated IBD diagnosis. Previous research has predominantly focused attention on incident cases of IHD occurring at or after diagnosis of IBD. It is notable that the overall risk of prevalent (i.e. whole cohort) IHD was almost identical to a recent Danish study at 2.1 IBy identifying and quantifying both the strength and direction of association between IBD and IHD, this study provides important insights into the burden of IHD in the IBD population. This is relevant for basic scientists exploring the temporal causal pathway, and clinicians who should be aware of the risks of IHD in patients with IBD and vice versa.S1 FigTotal number of patients showing time from IBD diagnosis (T0) to the first cardiovascular event according to IBD type and age categories.(TIF)Click here for additional data file.S2 FigTotal number of patients showing time from IBD diagnosis (T0) to the first cardiovascular event according to IBD type and gender categories.(TIF)Click here for additional data file.S3 FigTotal number of patients showing time from IBD diagnosis (T0) to the first Coronary Heart Disease (sub-group of CVD) event according to IBD type.(TIF)Click here for additional data file.S4 FigTotal number of patients showing time from IBD diagnosis (T0) to the first Ischaemic Heart Disease (sub-group of CVD) event according to IBD type.(TIF)Click here for additional data file.S5 FigTotal number of patients showing time from IBD diagnosis (T0) to the first Angina (sub-group of CVD) event according to IBD type.(TIF)Click here for additional data file.S6 FigTotal number of patients showing time from IBD diagnosis (T0) to the first Myocardial Infarction (sub-group of CVD) event according to IBD type.(TIF)Click here for additional data file.S7 FigTotal number of patients showing age at onset of Cardiovascular Disease according to IBD type.(TIF)Click here for additional data file."} +{"text": "Our data provides first evidence that the genetic factors associated with pigmentation traits are risk loci of UM susceptibility.While the role of genetic risk factors in the etiology of uveal melanoma (UM) has been strongly suggested, the genetic susceptibility to UM is currently vastly unexplored. Due to shared epidemiological risk factors between cutaneous melanoma (CM) and UM, in this study we have selected 28 SNPs identified as risk variants in previous genome-wide association studies on CM or CM-related host phenotypes (such as pigmentation and eye color) and tested them for association with UM risk. By logistic regression analysis of 272 UM cases and 1782 controls using an additive model, we identified five variants significantly associated with UM risk, all passing adjustment for multiple testing. The three most significantly associated variants rs12913832 , rs1129038 and rs916977 are correlated (r BAP1, CDKN2A, or BRCA2 explain only about 3% of UM population-specific risk678310Uveal melanoma (UM) is the most common primary adult intraocular cancer142\u2009>\u20090.5), which were still significant following adjustment for multiple testing established in recent GWASs for association with CM or related host phenotypes (including skin and eye pigmentation) , in a po testing : rs12913esting 12. As showOCA2, which codes for P protein involved in melanin synthesisHERC2, is a key pigmentation \u201cregulator allele\u201d that impacts the expression of OCA2 via a long range enhancer mechanismOCA2 expression resulting in darkly pigmented melanocytes. The C-allele conversely reduces expression of OCA2 producing lightly colored melanocytes3The locus at 15q13.1 determines pigmentation of eyes and skin by regulating the expression of 2\u2009=\u20090.48) , that waIt is important to note that our study has limited power and hence may reduce the ability to detect associations exerting smaller risk effects. It is possible that there are other associations among the selected variants that are likely missed in this study due to relatively small size of our UM case population. The most significant associations at HERC2/OCA2 locus , as wellGNAQ mutation signatures were observed in posterior (choroid) versus anterior UM tumors , likely reflecting divergent UM pathways related to toxic pheomelanin synthesisAlso, the relatively small size of our case population did not allow for stratifying the associations by the primary location of tumors, and this will need to be explored in subsequent large consortia analyses. The molecular effect of pigmentation on different UM subtypes has recently been suggested, as different A limitation in this study is an inability to assess the effect of pigmentation phenotype information in our sample populations as the HERC2/OCA2 locus exerts a purifying selection effect in European ancestries21The identification of novel germline genetic loci involved in UM susceptibility in our study provides the first evidence of a link between the inherited genetics of pigmentation and UM risk. It has been established that lighter pigmentation and chronic sun exposure impact the development of choroid nevi, which occur in ~7% of the US population and are a known precursor for UMFor cases, the study originally employed 286 UM patients. Fourteen of these failed the genotyping or quality control, resulting in 272 UM cases available for association analysis. The vast majority of patients were ascertained from the ophthalmology, medical oncology or clinical cancer genetics clinics at Ohio State University. Four patients were referred to our research program from an outside institute. UM patients with family history of UM were excluded. The study was approved by The Ohio State University cancer institutional review board. DNA for patients and controls were extracted from peripheral blood lymphocytes by a simple salting out procedureOut of available specimens from 3500 participants currently ascertained by OSUMC Human Genetic Sample bank, for our analysis we selected 760 controls that were individually matched as closely as possible to cases by gender and age . The DNATo test the association of common genetic variants (MAF\u2009>\u20090.05) with the risk of UM, a total of 29 SNPs were selected through the comprehensive search of published GWAS data on melanoma risk, nevi-driven phenotypes, pigmentation, hair color, skin color and other melanoma risk etiologies. The selection criteria focused on variants with the most significant associations (in particular those surpassing GWAS level of significance) reported from each of these published GWAS. The complete list of selected variants with association information from prior studies is in For the genotyping of 29 selected variants, the highly multiplexed Sequenom MassARRAY system was used according to the manufacturer\u2019s protocol. Quality control (QC) measures included duplicates (8 per each 384-well plate) and non-template controls (2 per plate) resulting in >99% observed concordance with no evidence of cross-contamination. Post-genotyping filtering criteria were as follows: exclusion of SNPs with minor allele frequency (MAF) <5%, exclusion of SNPs with a call rate <95%, exclusion of samples with a call rate <95%, and exclusion of SNPs with significant departure from Hardy-Weinberg equilibrium (p\u2009<\u20090.001). The filtering steps excluded one variant with MAF\u2009<\u20090.05, resulting in genotype information on 28 variants for 272 UM patients and 735 matched controls.2 tests (1 degree of freedom). All analyses were performed in PLINK2\u2009=\u20091) determined from European ancestries in the recent data release of 1000 Genomes Project Phase 3 (October 2014), as indicated in The association of UM risk with the selected 29 common genetic variants in the analysis of 272 cases and 1782 controls was estimated as odds ratios (OR) with 95% confidence intervals (95% CI), using unconditional logistic regression in an additive model where two copies of the minor allele have twice the effect of one copy. The genotype model (separate indicators for heterozygotes and rare homozygotes), dominant model (indicator for heterozygotes and rare homozygotes combined) and recessive model (indicator for homozygotes) were also assessed but not reported as they presented no significant additional information not captured by the additive model. All models were adjusted for continuous age at diagnosis (cases) or at the time of inclusion in the study (controls) and gender. Deviations of the genotype frequencies in the controls from those expected under Hardy-Weinberg equilibrium were evaluated by \u03c7IMPUTE2 was used for imputationThe imputed variants were tested for UM association using logistic regression implemented by the SNPTEST software under an additive model. Genotype uncertainties from imputation were accounted for in the model using genotype dosages. Notably, there were a number of variants comparably significant to our top genotyped associations . To asseHow to cite this article: Ferguson, R. et al. Genetic markers of pigmentation are novel risk loci for uveal melanoma. Sci. Rep.6, 31191; doi: 10.1038/srep31191 (2016)."} +{"text": "In silico functional analysis revealed that many genes in these families might be associated with the regulation of responses to environmental stimuli via transcriptional regulation of the response genes. Moreover, these genes had diverse endogenous expression patterns in switchgrass during seed germination, vegetative growth, flower development, and seed formation. Interestingly, several members of the ERF and DREB families were found to be highly expressed in plant tissues where active lignification occurs. These results provide vital resources to select candidate genes to potentially impart tolerance to environmental stress as well as reduced recalcitrance. Overexpression of one of the ERF genes (PvERF001) in switchgrass was associated with increased biomass yield and sugar release efficiency in transgenic lines, exemplifying the potential of these TFs in the development of lignocellulosic feedstocks with improved biomass characteristics for biofuels.The APETALA2/ethylene response factor (AP2/ERF) superfamily of transcription factors (TFs) plays essential roles in the regulation of various growth and developmental programs including stress responses. Members of these TFs in other plant species have been implicated to play a role in the regulation of cell wall biosynthesis. Here, we identified a total of 207 AP2/ERF TF genes in the switchgrass genome and grouped into four gene families comprised of 25 AP2-, 121 ERF-, 55 DREB (dehydration responsive element binding)-, and 5 RAV (related to API3/VP) genes, as well as a singleton gene not fitting any of the above families. The ERF and DREB subfamilies comprised seven and four distinct groups, respectively. Analysis of exon/intron structures of switchgrass AP2/ERF genes showed high diversity in the distribution of introns in AP2 genes versus a single or no intron in most genes in the ERF and RAV families. The majority of the subfamilies or groups within it were characterized by the presence of one or more specific conserved protein motifs. Panicum virgatum) is an outcrossing perennial C4 grass known for its vigorous growth and wide adaptability and, hence, is being developed as a candidate lignocellulosic biofuel feedstock is a large group of regulatory protein families in plants that are characterized by the presence of one or two conserved AP2 DNA binding domains. AP2/ERF TFs are involved in the transcriptional regulation of various growth and developmental processes and responses to environmental stressors. The AP2 domain is a stretch of 60\u201370 conserved amino acid sequences that is essential for the activity of AP2/ERF TFs have been suggested to be associated with the regulation of cell wall biosynthesis in some tissues Arabidopsis AP2/ERF TFs were excluded from our subsequent analysis.We used representative genes from appropriate rice gene families as the basis to search for orthologs in switchgrass. The amino acid sequences of AP2 domain-containing rice genes represented three families: AP2 (Os02g40070), ERF (Os06g40150), and RAV (Os01g04800). These proteins were used to query the derived amino acid sequences of all switchgrass AP2/ERF TFs using tblastn against the switchgrass EST database . The exon\u2013intron organizations in these genes were visualized by the gene structure display serverThe genomic and coding DNA sequences of the identified AP2/ERF TFs were retrieved from the Phytozome (The transcript data for the AP2/ERF superfamily TFs were extracted from the publicly available switchgrass gene expression atlas (PviGEA)Arabidopsis AtSHN2 (At5g11190) and rice OsSHN (Os06g40150) was identified by tblastn or blastp against the switchgrass EST database or draft genome (Phytozome v1.1 DOE-JGI) followed by cluster and multiple sequence alignment analysis to discriminate the most closely related gene for cloning. For construction of overexpression cassette, the open reading frame (ORF) of PvERF001 was isolated from cDNA obtained from ST1 clonal genotype of \u2018Alamo\u2019 switchgrass using gene-specific primers flanking the ORF of the gene and cloned into pANIC-10A expression vector by GATEWAY recombination and watered three times per week, including weekly nutrient supplements with 100\u2009mg/L Peter\u2019s 20-20-20 fertilizer. Transgenic and non-transgenic control lines were propagated from a single tiller to produce three clonal replicates for measuring growth parameters and quantitative [pyrolysis molecular beam mass spectrometry (py-MBMS)] analysis of lignin content was performed as previously described particle size and sugar release efficiency was determined via NREL high-throughput sugar release assays on extractives- and starch-free samples with least significant difference (LSD) procedure was used while PROC TTEST procedure was used to examine the statistical difference between the expression of target genes in transgenic vs non-transgenic lines using SAS version 9.3 . Pearson\u2019s correlation coefficient to determine the relationship between relative transcript levels and growth parameters was calculated by SAS.Arabidopsis along with the presence of conserved B3 domain suggest that these proteins might be categorized as putative AP2/ERF TFs. The characteristic features of these genes are summarized in Table S2 in Supplementary Material. The amino acid sequences of AP2/ERF TFs showed wide variation in size (ranging from 119 to 666 amino acids) and sequence composition. Twenty-two of these TFs contained two AP2 DNA-binding domains and hence were classified under AP2 family. Five of the AP2/ERF proteins had a B3 conserved domain at the C-terminus in addition to the common AP2 domain, and these genes were grouped into the RAV family. Three of the remaining 180 proteins, namely PvERF049, PvERF160, and PvERF177 with a single AP2 domain, which is more similar to the amino acid sequences of AP2 domains in the AP2 family TFs, were also grouped under the AP2 family. Moreover, one AP2/ERF protein showed a distinct AP2 domain different from all other switchgrass AP2/ERF proteins but with higher shared sequence similarity with the previously identified genes in rice and Arabidopsis. The remaining 176 proteins were grouped into ERF family, which was further subdivided into either one of two subfamilies (ERF and DREB) based on sequence similarity in the AP2 domain. The ERF subfamily members included 121 proteins while DREB had only 55 proteins .To confirm the classification and evaluate the sequence similarities between the switchgrass AP2/ERF TFs, a dendrogram was constructed by NJ method using the whole amino acid sequences of the proteins. The analysis showed distinct clustering of the proteins into specific groups and families as previously described in other species Figure . SpecifiTo complement the cluster analysis-based classification, the exon\u2013intron structures of AP2/ERF genes were evaluated. The schematic representations of protein and gene structures of switchgrass AP2/ERF superfamily are presented in Figure Analysis of amino acid sequence conservation in the whole proteins of AP2/ERF superfamily showed the presence of unique conserved motifs shared between proteins within families, subfamilies, or groups Figures . MoreoveGene ontology analysis of switchgrass AP2/ERF TFs, based on rice reference sequences, predicted candidate genes\u2019 molecular functions, putative roles in the regulation of diverse biological processes, and their cellular localization containing expression data for about 78,000 unique transcripts in various tissues was recently developed displayed increased expression level at radicle emergence whereas the other two (PvERF049 and PvERF203) showed increased expression at coleoptile emergence. The expression of the RAV genes and the singleton gene were apparently relatively less variable throughout the seed germination process revealed apparent differential expression pattern between the organs and different stages of vegetative development . Moreover, the expression pattern of AP2/ERF genes during reproductive development also showed differential expression between the reproductive tissues from the initiation of inflorescence meristem to the maturation of the seeds .PvERF95, PvERF98, PvERF101, and PvERF102) and one gene in group II (PvERF148) of the DREB subfamily showed highest expression in vascular bundles and internode tissues followed by internode portions where active lignification is expected and X showed the highest expression in the vascular bundles followed by youngest internode sections , one gene in group VI-L (PvERF088), and three genes in group VII had high expression in vascular bundles. Contrastingly, some genes in the ERF subfamily belonging to group V (PvERF001 and PvERF002) and VI (PvERF068) showed the highest expression in the basal fragments of the fourth internodes (E4) that is under less active lignification. Other genes including PvERF178 (VI); PvERF110 (VII), PvERF115 (VII), and PvERF164 (VII); and PvERF038 (IX) had notably high relative expression in roots than in other tissues. Compared to the ERF family genes, the expression of AP2 genes was highly diverse with some genes having high specificity to roots and vascular bundles. The expression of the two RAV genes analyzed was uniformly low throughout whereas the singleton gene was highly expressed in the LBs, LSH as well as the vascular bundles, and young internode sections and rice OsERF057 (OsSHN) in ERF subfamily group V, for overexpression analysis in switchgrass. This gene was selected since the expression of its Arabidopsis homolog in transgenic rice resulted in modified cell wall composition and the C-terminal motif (cm) specific to the Arabidopsis SHINE clade of TFs and OsERF012 and OsERF057 and tiller height (R\u2009=\u20090.73 at P\u2009=\u20090.06)] . However, no tangible difference was observed in the rate of leaf chlorophyll leaching between transgenic and the control lines (data not shown). Subsequently, we analyzed whether the changes in leaf morphology might be accompanied by changes in the expression level of genes in the cutin and wax biosynthesis pathway, in which none were observed . Moreover, overexpression of PvERF001 in transgenic switchgrass showed relatively reduced expression of some lignin (PvC4H and PvPAL), hemicellulose (PvCSLS2), and cellulose (PvCESA4) biosynthetic genes, as well as some of the transcriptional regulators (PvMYB48/59 and PvNST1) of cell wall biosynthesis . The total lignin content in R1 tillers determined by Py-MBMS of cell wall residues and in leaves determined by phloroglucinol\u2013HCl staining did not show sizeable difference between the transgenic and non-transgenic control lines . Similarly, analysis of the S/G lignin monomer ratio in transgenic lines did not significantly change as compared to that of the non-transgenic control line . However, significant improvement in glucose release efficiency was observed in lines 7 (10%) and 8 (16%) relative to the non-transgenic control line , and Populus (66). All three species along with switchgrass have a singleton in their genome. Consistent with the previous report in rice , also known as the cytokinin responsive factor (CRF) domain in Arabidopsis that is also shared by rice ERF genes belonging to same group in rice ERF subfamily displayed LWSY conserved motif (M21) at the C-terminal and thus may play similar roles. No information is available in the literature on some of the conserved motifs identified here including M8, M13, M14, M15, M17, and M24 , which might potentially be specific to switchgrass.AP2/ERF TFs that function as repressors or activators of specific target genes are distinguished by the presence of conserved motifs called repression domains (RD) that are highly conserved, or by the presence of activation domains which are generally less conserved , DREB , and AP2 genes during the initiation of seed germination as well as in vascular bundles and internode sections. Moreover, the observed robust expression of 14 DREB, 17 ERF, and 3 AP2 genes in tissues or organs undergoing active lignification but less robust expression in less lignified tissues (leaves) also supports this assertion , reduced lignification, and enhanced carbohydrate content (cellulose) in the wood of transgenic lines hinting that these TFs may indeed interact with the transcriptional machinery regulating cell wall biosynthesis (EjAP2-1) is an indirect transcriptional repressor of lignin biosynthesis via interaction with EjMYB1 TFs gene resulted in improved enzymatic saccharification efficiency via increased level of starch was expressed mainly in the abscission zone and functionally associated with the regulation of the pedicel abscission zone-specific transcription of genes including cell wall-hydrolytic enzymes required for abscission was proposed to have a native association with cell wall regulatory and biosynthetic pathways, yet this was not experimentally verified exhibiting reduction in plant height but increase in the number of tillers (Zhou et al., PvERF001 showing increased plant height but no difference in number of tillers. This suggests that ERF genes might functionally be highly diversified and PvERF001 may be part of a different pathway than we anticipated such as regulation of responses to biotic stress or other abiotic stress or regulation of cell elongation or division in coordination with the cytokinin pathway, with the latter perhaps explaining the observed increase in biomass and vegetative growth in transgenic lines.A recent study involving overexpression of rice homolog of PvERF001 highlight the potential of these TFs for improvement of bioenergy feedstocks.In summary, the expression profiling of the switchgrass AP2/ERF genes provides baseline information as to the putative roles of these genes and thus a useful resource for future reverse genetic studies to characterize genes for economically important bioenergy crops. With the current advancements in switchgrass research and establishment of efficient transformation system, this inventory of genes along with the information provided here could facilitate our understanding regarding the functional roles of AP2/ERF TFs in plant growth and development. Furthermore, it would aid in the identification of potential target genes that may be used to improve stress adaptation, plant productivity, and sugar release efficiency in bioenergy feedstocks such as switchgrass. The increased biomass yield and sugar release efficiency from overexpressing WW designed and performed the experiments, analyzed the data, and wrote the manuscript. MM participated in experimental design and data analysis, assisted with revisions to the manuscript and coordination of the study. GT, RS, SD, and MD assisted with performing lignin and sugar release assays and contributed in revision of the manuscript. CS conceived the study and its design and coordination, and assisted with revisions to the manuscript. All authors read and consented to the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.http://journal.frontiersin.org/article/10.3389/fbioe.2015.00101The Supplementary Material for this article can be found online at Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file."} +{"text": "XPD, XPB and TTD-A, code for subunits of Transcription Factor (TF)IIH. Interpreting XPD mutations in the context of available biochemical data led us to propose adverse effects on CDK-activating kinase (CAK) subunit of TFIIH and TFIIH-mediated functions as a relevant mechanism in preeclampsia. In order to gain deeper insight into the underlying biologic mechanisms involving TFIIH-mediated functions in placenta, we analyzed NER/transcription and global gene expression profiles of normal and preeclamptic placentas and studied gene regulatory networks.Preeclampsia is a significant cause of maternal and fetal mortality and morbidity worldwide. We previously reported associations between trichothiodystrophy (TTD) nucleotide excision repair (NER) and transcription gene mutations in the fetus and the risk of gestational complications including preeclampsia. TTD NER/transcription genes, XPD and XPB were consistently expressed from 14 to 40 weeks gestation while expression of TTD-A was strongly negatively correlated with gestational age. Analysis of gene expression patterns of placentas from a case-control study of preeclampsia using Algorithm for Reconstruction of Accurate Cellular Networks (ARACNE) revealed GTF2E1, a component of TFIIE which modulates TFIIH, among major regulators of differentially-expressed genes in preeclampsia. The basal transcription pathway was among the largest dysregulated protein-protein interaction networks in this preeclampsia dataset. Within the basal transcription pathway, significantly down-regulated genes besides GTF2E1 included those coding for the CAK complex of TFIIH, namely CDK7, CCNH, and MNAT1. Analysis of other relevant gene expression and gene regulatory network data also underscored the involvement of transcription pathways and identified JUNB and JUND (components of transcription factor AP-1) as transcription regulators of the network involving the TTD genes, GTF2E1, and selected gene regulators implicated in preeclampsia.We found high expression of TTD NER/transcription genes in normal human placenta, above the mean of their expression in all organs. Our results indicate that TTD NER/transcription genes are expressed in placenta during gestational periods critical to preeclampsia development. Our overall findings suggest that impairment of TFIIH-mediated function in transcription in placenta is a likely mechanism leading to preeclampsia and provide etiologic clues which may be translated into therapeutic and preventive measures. Preeclampsia is a complex disorder affecting about 7% of all pregnancies and a major cause of severe intrauterine growth restriction (IUGR) and preterm birth . Preecla6) recessive disorder and XPB in placenta compared to skin and other tissues. XPD expression was also higher in placenta than skin and most other tissues but the difference did not reach statistical significance with gestational age . In our GTF2E1, which codes for a component of TFIIE, as the most interconnected gene in the network revealed0588 revGTF2E1 with 120 significant interactions and those coding for all three components of the CAK complex of TFIIH, namely CCNH , CDK7 and MNAT1 (which codes for MAT1) are inferred to be the master regulator(s) in the network defined as gene(s) with the highest number of significant interactions with other genes within the network. In our analysis, the top gene in the network in terms of the largest number of interactions was -6) between GTF2E1 and FLT1 siRNA datasets suggesting similar consequences for inhibition of FLT1 tyrosine protein kinase and inhibition of transcription in the endothelial cells transcriptome dataset GSE27871) [871 [27] We analyzed the reactome database to identGTF2E1) and gene regulators implica) Figure\u00a0. These a) Figure\u00a0, highligAlthough singular observations of certain pregnancy complications were noted in individual case reports of TTD patients (as illustrated in our recent genetic epidemiologic study ), gestata and three XP The reactome dataset was alsoIn order to infer potential common transcriptional regulatory networks of selected genes and gene regulators implicated in preeclampsia, analysis of the ENCODE Chip Seq derived regulatory network data was condaReferences for most XPD mutations analyzed in our previous report can be found in Table four of Cleaver et al. [r et al. .The authors declare that they have no competing interests.RM and AD conceived the study and analyzed the data. XA and VN helped with data analysis and interpretation. AK helped with data preparation and analysis. All authors read and approved the final manuscript.2 scale) of three TTD NER/transcription genes in normal human tissue array including placenta in GSE 96 [NER/transcription gene expression profiles in normal human placenta. Panel a. Bar graph depicting expression (relative fluorescence intensity shown on logn GSE 96 . Red barn GSE 96 . CirclesClick here for file"} +{"text": "Acromegaly is a rare endocrine disorder with excess growth hormone (GH) production. This disorder has important metabolic effects in insulin resistance and lipolysis. The objective of this study was to explore transcriptional changes induced by GH in adipose tissue.Patients with acromegaly (n=9) or non-functioning pituitary adenoma (n=11) were prospectively observed from March 2011 to June 2012. The patients underwent clinical and metabolic profiling including assessment of HOMA-IR. Explants of adipose tissue were assayed ex-vivo for lipolysis and ceramide levels. Adipose tissue was analyzed by RNA sequencing (RNAseq).IGF1, IGFBP3) as well as several novel transcriptional changes, some of which may be important for GH signal regulation (PTPN3 and PTPN4) and the effect of GH on growth and proliferation. Several transcripts could potentially be important in GH-induced metabolic changes. Specifically, induction of LPL, ABHD5, ACVR1C could contribute to enhanced lipolysis and may explain the suggestive enhancement of adipose tissue lipolysis in acromegaly patients as reflected by glycerol release from the explants of the two groups of patients (p=0.09). Higher expression of SCD and TCF7L2 could contribute to insulin resistance. Expression of HSD11B1 was reduced and GR was increased, predicting modified glucocorticoid activity in acromegaly.There was evidence of reduced insulin sensitivity based on the increase in fasting glucose, insulin and HOMA-IR score. We observed several previously reported transcriptional changes (We identified the acromegaly gene expression signature in human adipose tissue. The significance of altered expression of specific transcripts will enhance our understanding of the metabolic and proliferative changes associated with acromegaly."} +{"text": "Gliomas are mostly incurable secondary to their diffuse infiltrative nature. Thus, specific therapeutic targeting of invasive glioma cells is an attractive concept. As cells exit the tumor mass and infiltrate brain parenchyma, they closely interact with a changing micro-environmental landscape that sustains tumor cell invasion.in situ in Invading Glioma Cells (IGCs) compared to tumor core, as well as changes in host cells residing within the infiltrated microenvironment relative to the unaffected cortex. IGCs were found to have reduced expression of genes within the extracellular matrix compartment, and genes involved in cell adhesion, cell polarity and epithelial to mesenchymal transition (EMT) processes. The infiltrated microenvironment showed activation of wound repair and tissue remodeling networks. We confirmed by protein analysis the downregulation of EMT and polarity related genes such as CD44 and PARD3 in IGCs, and EFNB3, a tissue-remodeling agent enriched at the infiltrated microenvironment. OLIG2, a proliferation regulator and glioma progenitor cell marker upregulated in IGCs was found to function in enhancing migration and stemness of GSCs. Overall, our results unveiled a more comprehensive picture of the complex and dynamic cell autonomous and tumor-host interactive pathways of glioma invasion than has been previously demonstrated. This suggests targeting of multiple pathways at the junction of invading tumor and microenvironment as a viable option for glioma therapy.In this study, we used a unique microarray profiling approach on a human glioma stem cell (GSC) xenograft model to explore gene expression changes Glioblastoma (GBM), the most malignant glioma tumor, is highly invasive with a median survival of 16 months despite combined surgical resection, radiotherapy, and chemotherapy. Although the molecular signature of glioma has been investigated in detail The brain consists of numerous cell types forming tissue scaffolds that guide invasion Glioma stem cells (GSCs) are a subpopulation of cells in the tumor capable of self-renewal that can give rise to a heterogeneous tumor in vitro would affect cell physiology and gene expression. Traditional laser capture microdissection studies of glioma invasion focused on glioma specimens from human patients, dissecting neoplastic astrocytes as the invading cells at the rim of the tumor core Ideally, one would perform between\u2013group differential expression analysis for each cellular compartment. However, experimental methods for isolating the IGCs and their microenvironment cellular compartment are neither timely nor cost effective, and isolating them in situ. Subsequently, we found several genes in multiple pathways that may facilitate invasion which were validated at the protein level in xenografted GSCs and in clinical samples from GBM patients. Importantly, OLIG2, a proliferation regulator and glioma progenitor cell marker was upregulated in the IGCs relative to the tumor core. Inhibition of OLIG2 expression reduced migration and stemness and provided functional confirmation as a potential therapeutic target in glioma invasion. Overall, the novel approach in this study allowed us to construct and evaluate a more complete picture of multiple pathways within the area of glioma invasion than has been previously demonstrated.In the present study we used an innovative laser microdissection (LMD) enrichment strategy and gene expression analysis. Differentially expressed genes (DEGs) of IGCs and their microenvironment were simultaneously detected allowing us to deduce functional networks that characterize glioma invasion Following signed informed consent, tumor tissue was obtained from patients (aged \u226518 years) undergoing medically indicated resection of malignant gliomas at the National Institutes of Health as part of a clinical trial approved by the Institutional Review Board (NCI-02C0140). NCI Animal Care and Use Committee (ACUC) approved all animal experiments.Primary glioma stem cells were cultured in NBE medium as previously described GSCs migration was assessed by the xCELLigence RTCA DP device, according to the manufacturer instructions .An intracranial orthotopic model in SCID mice was utilized for the generation of infiltrative glioma xenograft tumors Raw data for this experiment has been deposited in the Gene Expression Omnibus (accession number GSE53717).The probe for each gene was designed and synthesized by NanoString nCounter technologies to match the Affymetrix probe target region . HousekeThe standard immunohistochemistry of paraffin sections and western blotting were performed as previously described in vitro cell migration assay (P\u22640.01). When laminin was used for chemotaxis, only 0923 cells showed significant migration (P\u22640.01). In haptotaxis conditions with fibronectin, only 1228A1 cells demonstrated significant migration (P\u22640.01). None of the GSCs migrated in chemotaxis with fibronectin. Intracranial tumors generated by 0923 and 1228A1 GSCs demonstrated an extensive infiltration into the surrounding cerebral cortex in glioma invasion enrichment analysis. GO terms that were overrepresented and had at least a 30% overlap with at least one other category were identified as significant and 9 genes of cell polarity were downregulated STAT3, which is downregulated, acts as a hub in the EMT network interacting with all other networks. On the other hand, majority of genes (13 out of 18) associated with neurophysiological process and in the cell cycle were upregulated CTNNB1), which plays a central role in the canonical Wnt pathway, acts as a major hub interconnecting with genes and gene products associated with tissue remodeling and wound repair For every dataset, we focused on a subset of genes associated with significant cellular processes and canonical pathways SEMA5A-Plxnb3, AQP4-Dag1, and FGF2-Sdc2) Further analysis identified 17 potential protein-protein binding interactions between the IGCs and the microenvironment residing host cells and PDGFA proteins in the invasive glioma cells was confirmed (Pdgfra was only detected in host cells residing at the AOI (Shh) protein was only observed at the brain cortex and barely detected at the AOI or tumor core transcription factor, is selectively expressed in a subgroup of glioma cells and required for glioma formation in a murine GBM model OLIG2 expression by the IGCs in situ may suggest their stemness, which supports their invasive capability in vivo. We thus investigated whether OLIG2 could serve as a therapeutic target in invading glioma cells. We examined the effect of OLIG2 knockdown (shOLIG2) on the differentiation state, self-renewal, proliferation, cell migration and in vivo invasion of GSCs. As demonstrated in NANOG, OCT4 and SOX2 in 0923 shOLIG2 GSCs were significantly decreased compared to the shControl cells. Immunofluorescence labeling as previously demonstrated GFAP and TUJ1 in 0923 shOLIG2 cells in a more pronounced manner than in shControl cells and SOX9. Our analysis revealed . These probes were designed to only capture human or mouse genes, and a significant (70\u201380%) proportion was indeed validated, and is in line with previous reports using pure samples Previous studies of global gene expression in GBM invasion used LCM of patient specimens did not distinguish changes in the microenvironment at the site of invasion CDK1, BUB1, FBX05, ADAM23 and PLXNA4, associated with cell cycle, cell adhesion or neurophysiological processes were found in both datasets. Though upregulated genes within the cell cycle functional category can imply activation of cellular proliferation, we observed the presence of inhibitory proteins of APC such as BUB1 and FBX05, which could promote cell cycle arrest PLXNA4, a semaphorin receptor required for guidance of newly differentiated neurons, was also common to both datasets Many of the DEGs common for both xenografted GSCs were at a low fold-change, but were nonetheless statistically significant. We then looked at the intersection of our DEGs with those previously reported in the invasive rim of 4 human GBMs in an attempt to correlate our xenograft data to a closely related one derived in a clinical setting EPHA2 and EPHA3 in maintaining the undifferentiated state of GSC has been reported EFNB3 enrichment at the AOI accompanied by EPHA4 expression in the IGCs. Cell contact-mediated bidirectional EFNB3/EPHA4 signaling and migration of interneurons during cerebral cortex development has been previously reported, suggesting the possible usage of this interaction during glioma invasion EFNB3 in the cerebral cortex may provide the switch between cell-cell adhesion and cell migration by A-Disintegrin-And-Metalloproteases (ADAM)-mediated shedding ADAM10, ADAM15 and ADAM19 at the AOI.Being exploratory and hypothesis generating, our analysis suggests some potential protein-protein interactions that have never been explored between glioma cells and host cells at the AOI. Recently the role of OLIG2 positive tumor cells within the AOI strongly suggests that the invasive niche contains GSCs OLIG2 in 0923 GSCs decreased the expression levels of their NSC markers , and reduced their self-renewal and proliferation abilities. Exposure of these cells to differentiation conditions reveals the potential of the shOLIG2 GSCs to differentiate more profoundly into distinct populations of glial and neuronal lineages than GSCs which express OLIG2. Moreover, OLIG2 knockdown inhibited their migration potential in vitro and in vivo. Recently, Siebzehnrubl et al. SOX2 and OLIG2 are induced by ZEB1-miR-200 feedback loop in GBM. Our data support their model, as non-invasive cells in the tumor mass express relatively low levels of OLIG2. Our in vitro data further show that OLIG2 can modulate TWIST and SNAI2 protein expression, the central regulators of EMT cancer invasion OLIG2, TWIST and SNAI2 expression within the AOI of xenografted 0923 GSCs.The presence of CHI3L1 (YKL40), CD44, and STAT3in situ contains both invasive and post-invasive (colonizing) glioma cell populations. We postulate that as cells exit the tumor mass and infiltrate brain parenchyma, OLIG2 expression is enhanced, and as they colonize brain parenchyma, expression of EMT markers is diminished.In epithelial cancer, EMT is evoked during tumor cell invasion and metastasis, leading to the generation of cancer cells with stem cell-like characteristics. Metastases are accompanied by a re-differentiation and a MET type transition, both of which are proposed to be a driving force of metastasis, suggesting that MET allows for growth and colonization of the invasive cell in situ. This study revealed several distinct glioma pathways as well as many previously characterized developmental and neurophysiological processes that had never been described in glioma. These multiple pathways serve as a rich reservoir for therapeutic targets that warrant further investigation. Firstly, our data shows that direct targeting of proteins such as CD44CHI3L1PARD3 may be ineffective at this stage of disease as they are already downregulated in glioma cells at the AOI. On the other hand, the identification of molecules selectively expressed by invasive glioma cells such as OLIG2 may allow the development of therapeutic strategies that specifically target this population of cells EFNB3 may be equally amenable to therapeutic targeting.While our approach of filtering out cross-hybridizing genes may have resulted in the loss of some differentially expressed genes, the exploratory nature of this study enabled us to capture for the first time multiple pathways that take place at the junction of tumor invasion and microenvironment Specific therapeutic targeting of glioma invasion is a field in its infancy. Within the tumor-bearing CNS, complex, dynamic and synchronized interactions between glioma tumor cells and tumor-microenvironment residing cells may sustain glioma cell invasion. Recently, Sottoriva et al. detected the multiple coexisting cell lineages and expression subtypes at the individual GBM patient. They also suggested that these IGCs are a heterogeneous population of malignant cells that survived treatment Figure S1Migration in vitro and in vivo of 0827A2 GSCs. (A) Migration activity of 0827A2 GSCs was tested using the xCELLigence RTCA system. The bars represent the average cell indices at 13 h for the indicated conditions of at least 3 experiments. Asterisks indicate significant differences in the migration of the cells compared to the control [cells in NBE medium in both upper and lower chambers (NBE/NBE) in uncoated well (\u2212/\u2212)] as determined by t-test. Error bars indicate standard error of the means. (B) Migratory nature of xenografted 0827A2 GSCs. H&E stained section depicting restricted infiltration of GBM cells. Inset depicts 10\u00d7 magnification, representative infiltration area. Unsupervised hierarchal clustering in (C) human and (D) mouse arrays of 0827A2 GSCs xenografts shows that the regions are not completely segregated while a clean separation was observed in human and mouse arrays of both 0923 and 1228A1 GSCs xenografts (demonstrated in (TIF)Click here for additional data file.Figure S2Gene ontology and pathway analysis of host cells at the area of invasion (tumor microenvironment). (A) Gene ontology analysis of the microenvironment dataset. Please see legend of (TIF)Click here for additional data file.Figure S3Distinguishing invading human GSCs from mouse cells. Frozen section of xenograft glioma derived from intracranial injection of 1228A1 GSCs were stained with OLIG2 (red), hNuclei (green) and DAPI (blue). Invading GSCs were distinguished by either nuclear size or human-nuclear staining (white arrows). Magnification \u00d740.(TIF)Click here for additional data file.Figure S4OLIG2, PARD3 and Efnb3 expression in xenografted 1228A1 GSCs. Frozen sections of xenograft glioma derived from intracranial injection of 1228A1 GSC were stained with (A) OLIG2, (B) PARD3 or (C) Efnb3 . DNA was stained with DAPI (blue). At the left side of each panel: intracranial tumor histology and when available a whole brain tile at same scale. Solid line box (tumor core) and dashed line box (area of invasion) identify magnified (\u00d740) images on right as indicated.(TIF)Click here for additional data file.Figure S5EPHA4, WISP1 and Shh expression in xenografted GSCs. Frozen sections of xenograft gliomas derived from intracranial injection of 0923 (Upper panel) or 1228A1 (Lower panel) GSCs were stained with (A) EPHA4, (B) WISP1 or (C) Shh . Please see legend of (TIF)Click here for additional data file.Figure S6Downregulated expression of EMT associated genes in invasive glioma cells of xenografted 1228A1 GSCs. Frozen sections of xenograft glioma derived from intracranial injection of 0923 GSC were stained with (A) CD44, (B) CHI3L1 or (C) ITGA6 . Please see legend of (TIF)Click here for additional data file.Figure S7PDGFA and mPdgfra expression in xenografted GSC. Frozen sections of xenograft glioma derived from intracranial injection of 0923 (Upper panel) or 1228A1 (Lower panel) GSC were stained with (A) PDGFA and (B) mPdgfra (both in red). Please see legend of (TIF)Click here for additional data file.Table S1NanoString Codeset Details.(XLS)Click here for additional data file.File S1Table S2: Pathway Maps in Invading GSCs and the Tumor Microenvironment. Table S3: Potential Protein-Protein Interactions between Invading GSCs and Their Microenvironment Residing Cells. Table S4: Differentially expressed genes in invading GSCs (array data). Table S5: Differentially expressed genes in the tumor microenvironment (array data). Table S6: Glioma invasion-related genes common with previously reported study by Kislin et al. (reference (DOC)Click here for additional data file."} +{"text": "External quality assurance (EQA) systems are essential to ensure accurate diagnosis of TB and drug-resistant TB. The implementation of EQA through organising regular EQA rounds and identification of training needs is one of the key activities of the European TB reference laboratory network (ERLTB-Net). The aim of this study was to analyse the results of the EQA rounds in a systematic manner and to identify potential benefits as well as common problems encountered by the participants.The ERLTB-Net developed seven EQA modules to test laboratories\u2019 proficiency for TB detection and drug susceptibility testing using both conventional and rapid molecular tools. All National TB Reference laboratories in the European Union and European Economic Area (EU/EEA) Member States were invited to participate in the EQA scheme.A total of 32 National TB Reference laboratories participated in six EQA rounds conducted in 2010\u20132014. The participation rate ranged from 52.9% - 94.1% over different modules and rounds. Overall, laboratories demonstrated very good proficiency proving their ability to diagnose TB and drug-resistant TB with high accuracy in a timely manner. A small number of laboratories encountered problems with identification of specific Non-tuberculous Mycobacteria (NTMs) (N = 5) and drug susceptibility testing to Pyrazinamide, Amikacin, Capreomycin, and Ethambutol (N = 4).The European TB Reference laboratories showed a steady and high level of performance in the six EQA rounds. A network such as ERLTB-Net can be instrumental in developing and implementing EQA and in establishing collaboration between laboratories to improve the diagnosis of TB in the EU/EEA. Tuberculosis (TB) remains an important public health problem globally and within the European Union (EU) despite significant progress made in the past decade. In 2013, 64 844 TB cases were reported in 28 EU and two European Economic Area (EEA) countries, 6% less than in 2012 and reflecting a decrease in 19 countries [Timely and accurate diagnosis of active TB is a prerequisite for any successful TB control programme and an essential part of the action framework to eliminate TB in low-incidence countries . The labTo ensure compliance with existing international standards of laboratory diagnostics , all labThe introduction of new drug susceptibility testing methods, including rapid culture and molecular tools, and genotyping methodologies necessitated the development of novel as well as modification of existing EQA schemes (eg for rapid molecular tools). A series of recent reports revealed specific problems related to a lack of standardisation in second-line drug (SLD) susceptibility testing and multilocus MIRU-VNTR genotyping \u201315. The A situation analysis of national TB reference functions across the EU formed tThe aim of this study was to systematically analyse the implementation of the EQA scheme across the network from 2010 to 2014, assess performance of the laboratories, identify common problems and discuss the potential benefits of the scheme for the participants.A total of six EQA rounds were conducted from 2010 to 2014 . All 34 The ERLTB-Net developed seven modules covering various types of laboratory techniques: (1) microscopy; (2) primary isolation; (3) identification; (4) drug susceptibility testing; (5) nucleic acid amplification testing (NAAT) for rapid detection of Mycobacteria; (6) molecular drug susceptibility testing using cultures; and (7) molecular drug susceptibility testing using crude DNA extracts .Mycobacterium species and drug susceptibility profiles) were used. Specimen panels included strains with varying DST profiles (M. tuberculosis suspensions treated with chloroform [M. tuberculosis complex (MTBC) strains as well as non-tuberculous mycobacteria (NTM) in various combinations.Artificial sputa (spiked with mycobacteria) were used for preparation of slides (for microscopy) and specimens for primary isolation and rapid NAAT-based detection; all specimens in the latter panels contained equal concentrations of Mycobacteria. For identification and DST, strains with validated characteristics and methods used for species identification (Module 3).Reports received from participating laboratories were analysed against reference results as determined by the EQA provider (NRL Germany and INSTAND e.V), and the percentage of correct results in each module was calculated by dividing the number of correct results by the total number of tests in the module. This provided the score for the given laboratory in the given module. If not all tests within a given module were performed , the overall score was adjusted accordingly. Laboratories scoring \u226580% were issued performance certificates for individual modules. Their individual performances were referred to as \u201cgood\u201d (scores 80.0\u202699.9%) and \u201cexcellent\u2019(100.0%) and overall performance of laboratories achieving 80% score was collectively termed \u201cgood\u201d. Scores under 80% were considered to indicate poor performance for the specific module(s) and no EQA certificate was issued .Error rates for specific methods were calculated as a proportion of incorrect results relative to a total number of individual tests performed by all laboratories across all rounds; for example in Modules 5 and 6 data was analysed by individual drugs. Proportions were compared using the chi-square test using GraphPad Prizm . A p-value < 0.05 was considered as significant.Mycobacterium species identification module in round 1 comprising 94.1% of laboratories within the network (The number of participating laboratories varied across EQA rounds and modules with the largest number of laboratories (N = 32) participating in the network . These 3Performance characteristics of participating laboratories in the EQA rounds 1\u20136 are summarised in The proportion of laboratories using Ziehl-Neelsen (ZN) staining for smear microscopy (Module 1) varied from 46.0% to 58.0% with the remaining laboratories using primarily auramine fluorescent staining; a small number of laboratories (varying from 1 to 4 in different rounds) used the Kinyoun method.There were minor variations in the numbers of laboratories participating in the proficiency testing for microscopy in different rounds with the largest number (N = 27) taking part in round 5 and the smallest (N = 23) in rounds 2 and 4. In rounds 2\u20136, laboratories demonstrated good and excellent performance with only a small number of laboratories failing to achieve the 80% threshold. The proportion of laboratories that were awarded certificates was 80.8% in round 1 and 96.2% in round 6. There were no significant differences in error rates and overall performance characteristics between laboratories using different smear staining methods .M. tuberculosis complex from NTM and identify Mycobacteria species using a range of phenotypic and/or molecular tools. The number of participating laboratories varied from 23 (round 3) to 29 (round 1). Overall scores were good and excellent with only one laboratory in rounds 4 and 6 failing to achieve the 80% threshold. The proportion of laboratories reporting results of species identification varied from 64.3% to 95.7% in different years and largely depended on the composition of the EQA panels (MTBC or NTM) as not all laboratories identify the same spectrum of NTM species routinely on primary specimens. Common problems encountered by the laboratories included reporting the presence of mycobacteria in negative specimens , and inability to detect NTM in positive specimens (N = 2).Within module 2, laboratories were requested to detect the presence of mycobacteria in artificial spiked sputum specimens using bacteriological culture, and (if routinely performed) differentiate In module 3, participants performed species identification of mycobacterial cultures using phenotypic or molecular tools or a combination of both based on standard protocols adopted in those laboratories. The number of participating laboratories ranged from 21 (Rounds 2 and 5) to 32 (Round 1).M. tuberculosis complex with M. bovis caprae and M. bovis BCG being the most problematic species.Within this module, performance varied considerably with a total of three laboratories across all rounds achieving low scores of 20\u201340% and one laboratory misidentifying all specimens in round 5. The majority of participating laboratories, however, demonstrated either good or excellent performance. The proportion of laboratories that were awarded certificates varied from 85.2% (round 4) to 100% (round 6). Common problems experienced by the laboratories included misidentification of NTM and misidentification of species within the M. tuberculosis cultures for sensitivity to five first-line drugs (FLD) and additionally to fluoroquinolones (FQ), capreomycin (CAP), amikacin (AMK), and kanamycin (KAN) (Modules 3\u20135) or FQ, CAP, and AMK (Modules 2 and 6) using any validated phenotypic method routinely used in the laboratory. All but one laboratory used automated liquid culture-based systems for DST for second line drugs; for FLD including PZA methods varied and included Bactec MGIT960 as well as the proportion method on solid media and resistance ratio method on semi-solid and liquid media for PZA.In module 4, laboratories were requested to test five (modules 1\u20132 and 5\u20136) or ten (modules 3 and 4) The number of laboratories taking part in module 4 varied from 22 (Rounds 5 and 6) to 31 (Round 1) and overall performance was good with only two laboratories failing to achieve 80% in one round (round 2). Only susceptibility to rifampicin (RIF) and isoniazid (INH) was tested by all participating laboratories; other drugs were tested by a smaller number of laboratories in accordance with their routine practices. Importantly, the proportion of laboratories routinely testing for susceptibility to pyrazinamide (PZA), FQ and AMK increased over the five years from 65.0%, 56.6%, and 52.2% to 100.0%, 77.3%, and 77.3%, respectively, confirming the ability of many laboratories to detect extensively drug-resistant (XDR) strains.Error rates varied substantially between drugs . PZA wasThis module was designed to test proficiency of laboratories in rapidly detecting MTB complex bacteria in sputum specimens using nucleic acid amplification tests (NAAT). The number of participating laboratories ranged from 19 (Round 4) to 22 (remaining rounds) and performance was good with all but two laboratories (in Rounds 5 and 6) achieving scores >80%. The proportion of laboratories using GeneXpert methodology for TB detection in primary specimens increased from 35.0% in 2011 to 65.2% in 2014. Other methods used for TB detection in primary specimens included BD ProbeTec DTB used by up to 13.6% of laboratories in different years, and Cobas TaqMan GT Mycobacteria Direct , and Artus PCR kit .There were no differences in error rates and overall performance characteristics between GeneXpert and other NAAT methods for rapid MTB complex bacteria identification.In Module 6, proficiency of laboratories in rapidly detecting resistance to selected first and second-line drugs on cultures was tested. The number of participants remained relatively stable over five years and ranged from 18 (Round 1) to 22 (Round 2). Nearly all laboratories used line probe assays (LPAs) for molecular DST. A small number of laboratories (<10%) used in-house validated assays including targeted gene sequencing and pyrosequencing,Performance was good with only one laboratory in round 6 failing to achieve the 80% threshold score. The proportion of laboratories adopting technologies for rapid DST for second-line drugs increased from 66.7% (round 2) to 85.0% (round 6). Overall concordance with reference results was high, exceeding 99% for all drugs . Unlike M. tuberculosis strains, and therefore inactivated non-hazardous crude DNA extracts isolated from fully sensitive, poly- and multidrug-resistant strains were used. Module 7 panels were only included in rounds 3 and 4 and results were obtained from 26 and 24 laboratories, respectively.The primary aim of this module was to test the proficiency of the laboratories in rapid detection of highly drug-resistant Overall performance was good with a total of 8 errors reported . All laboratories achieved scores >80%. Errors were not confined to any specific drug and were lower for RIF (0.3%) and higher for INH (1.0%) . ConcordThe primary aim of this study was to systematically analyse the performance of national TB reference laboratories for detection, identification and drug susceptibility testing for TB diagnosis across the EU/EEA through a comprehensive series of EQA rounds, identify common problems and discuss the potential benefits of the EQA scheme developed within the EU-wide TB reference laboratory network.Overall, laboratories demonstrated good proficiency with scores consistently exceeding the 80% threshold in the vast majority of the laboratories. Steady high performance in both phenotypic and rapid molecular methods over five years with only 27 individual module result failures shows an ability of national TB Reference laboratories to diagnose TB and drug resistance TB with high accuracy in a timely manner. The principal results of our study were in agreement with another report demonstrChallenges with microscopy and species identification in rounds 1\u20133 have been addressed through corrective actions including additional training and laboratory visits. No major problems were detected in primary isolation (module 2). An in-depth analysis of laboratory performance for phenotypic DST has allowed us to identify methodological problems with specific anti-TB drugs including PZA, EMB and, interestingly, KAN and AMK. This is largely in agreement with earlier reports demonstrating a lack of standardised methodologies and drug concentrations for PZA (type of media) and KAN ,19,20 anProficiency of laboratories in identification and DST using rapid molecular tools proved to be good and excellent. High scores were achieved by the laboratories in molecular DST on cultures and crude extracts and there was a significant increase in the number of laboratories adopting molecular techniques (particularly the GeneXpert system), which is critical for the timely detection of MDR strains and prevention of transmission ,5.Our study identified several common challenges in EQA schemes with relatively low participation rates being one of them. Significant variability of participation rates (52.9\u201394.1%) across modules and/or EQA rounds can be in part explained by the fact that not all laboratories perform all the tests routinely ; data collected outside the current study suggests that up to 25% of NRLs are not routinely engaged in primary laboratory work (unpublished data). A small number of laboratories encountered challenges in sending the results within the agreed timeframe or were unable to take part due to financial constraints . This highlights the importance of adequate management and careful financial planning including allocation of funds for participation in EQA schemes. Other problems encountered in individual laboratories preventing them achieving the 80% threshold included clerical errors (mislabelling etc), incorrect interpretation of molecular and phenotypic tests results, as well as cross-contamination issues. These problems may be indicative of more general problems in the laboratory practice and should be taken into account in the laboratory quality management.Laboratory services play a crucial role in improving the delivery of health care and reducing the prevalence of TB and drug-resistant TB in particular. Quality assessment through proficiency testing is a fundamental tool used to ensure accuracy of test results by comparing quality between laboratories, evaluating performance and detecting errors so that corrective actions, including additional training and support visits, can be taken in a timely manner to restore the high quality of services.M.tuberculosis genotyping [Overall, results of our study and earlier reports on proficiency testing and EQA schemes for notyping ,14 demonParticipating laboratories benefited from the developed EQA program in a number of ways including free of charge EQA and performance certificates essential for their accreditation by relevant national bodies, availability of training for their staff members as well as targeted actions including direct consultations with the EQA providers and support visits from scientists within the network who were able to provide additional expertise and help to NRLs where needed. Steadily high performance during the implementation period suggests that aforementioned network activities addressing the challenges identified through the analysis of EQA results were effective. Sustainability of EQA and training activities at EU/EEA level as well as their further development through inclusion of novel validated methodologies (eg Next Generation Sequencing) are crucial for ensuring timely and high-quality laboratory diagnosis of TB in the EU/EEA.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file."} +{"text": "Cerebral near-infrared spectroscopy (NIRS) represents an exciting prospect for the non-invasive monitoring of cerebral tissue oxygenation in traumatic brain injury (TBI). Earlier attempts at clinical application of cerebral NIRS demonstrated that further work was needed . The bas\u00ae computational light modelling software (developed at the University of Birmingham) [The optimal depth for grey matter target tissue (grey-white matter junction) was ascertained by reviewing a series of brain CT scans of patients who had sustained a TBI. Set (average) measurements were derived from these identifying the target depth of the grey matter strip from the point of probe placement. Currently there are five commercially available cerebral NIRS systems. Table mingham) . The novWe reviewed 32 trauma series CT brain images and the average depth to grey matter was derived as 21.37 mm from the surface (Figure Based on the computational modelling of our work, the FORE-SIGHT NIRS device by CAS Medical source detector layout provides the greatest sensitivity at depth for the purposes of cortical monitoring in trauma. Variations in the layout have a significant impact on the quality of signal detected."} +{"text": "IL1RAPL1, PIR, GABRQ, GPRASP2, SYTL4) with cadherin, protocadherin and ankyrin repeat gene families most commonly altered . Other genes related to neurogenesis and neuronal migration , were also identified.Classical autism or autistic disorder belongs to a group of genetically heterogeneous conditions known as Autism Spectrum Disorders (ASD). Heritability is estimated as high as 90% for ASD with a recently reported compilation of 629 clinically relevant candidate and known genes. We chose to undertake a descriptive next generation whole exome sequencing case study of 30 well-characterized Caucasian females with autism from multiplex families. Genomic DNA was used for whole exome sequencing via paired-end next generation sequencing approach and X chromosome inactivation status. The list of putative disease causing genes was developed from primary selection criteria using machine learning-derived classification score and other predictive parameters . We narrowed the variant list to 10 to 20 genes and screened for biological significance including neural development, function and known neurological disorders. Seventy-eight genes identified met selection criteria ranging from 1 to 9 filtered variants per female. Five females presented with functional variants of X-linked genes ( PTEN tumor suppressor gene ; d1 = peak height of digested DNA from the first allele and u1 = peak height of undigested DNA from the first allele; d2 = peak height of digested DNA from the second allele and u2 = peak height of undigested DNA from the second allele. Highly skewed XCI is defined as >80% calculated ratio for either one of the AR gene alleles in the digested DNA sample. To ensure the reproducibility of XCI results and equal amplification of both alleles, the digestion, PCR amplification, and genotyping were repeated up to three times in several samples.The digestion process preferentially degrades activated (unmethylated) over inactivated (methylated) DNA. Undigested DNA is preferentially amplified and produces larger peak heights. The peak height values for digested DNA is normalized using peak height values for the undigested DNA for each subject. The percentage of XCI for each XCI status for each subject was assigned to one of the three mutually exclusive categories: (i) randomly selected inactivation of either allele from each X chromosome (XCI = 50%:50% to 64%:36%); (ii) moderately skewed inactivation favoring 1 allele of one of the X chromosomes (XCI = 65%:35% to 80%:20%); and (iii) highly skewed inactivation of a single allele representing one X chromosome (XCI > 80%:20%). The relative frequency of random, moderate, and highly skewed XCI categories was determined for the females with autism. The binomial frequency distribution of X-linked gene variants (present or absent) among females with autism spectrum disorder exhibiting moderate and high levels of XCI skewness were approximated using Yates\u2019 chi-squire test and odds ratios were calculated with 95% confidence intervals.The top genes chosen were based on the final selection criteria identified for each female and evaluated for biologic function and whether each gene was previously reported as a clinically relevant candidate or known gene for autism . The X cCCDC64 in subject HI0605) and some novel ] in 77% of the remaining females. In most females, we found more than one gene that could contribute to the causation of autism. This compares with a recent report of molecular findings among 2000 consecutive patients (primarily pediatric age) referred for clinical whole exome sequencing for evaluation of suspected genetic disorders at a large USA medical center in which 25% received a molecular diagnosis. About 60% of the diagnostic mutations were not previously reported [In summary, we shared our experience using a descriptive next generation whole exome sequencing case study approach examining 30 well-characterized Caucasian females with autism between 5 and 16 years of age recruited from multiplex families enrolled at the AGRE for research purposes. Interpretation of DNA findings are limited due to an inability to study other affected and non-affected family members to determine whether the gene variants were de-novo or inherited in origin for correlation with clinical phenotypes and lack of Sanger sequencing confirmation. Using strict selection criteria, four females (13%) were found to possess single gene variants of known candidate genes for ASD with a high likelihood of causality. We also identified multiple plausible candidate genes [some known (e.g., reported . By phen"} +{"text": "Left ventricular ejection fraction (LVEF) is the primary risk stratification tool used for therapeutic decision making related to device therapy. However, an influence of right ventricular dysfunction on cardiovascular events is becoming apparent. The incremental prognostic value of right ventricular ejection fraction (RVEF) on future arrhythmic events among those being considered for device therapy has not been well examined. In this study we evaluate the significance of MRI-based measurement of RVEF versus other clinical and MRI-based variables for their ability to predict Sudden Cardiac Death (SCD) or Appropriate ICD therapy.Consecutive patients with cardiomyopathy were evaluated for device candidacy. All patients underwent a standard Late Gadolinium Enhancement (LGE) MRI protocol followed by a blinded core-laboratory based quantification of left ventricle (LV) and right ventricle (RV) volumes, ejection fraction (EF) and total hyperenhancement (HE). Patients were stratified according to the presence or absence of significant RV systolic dysfunction, defined as an RVEF \u226445%. All patients were followed for the occurrence of SCD or appropriate ICD therapy. The secondary outcome was heart failure admission or non-sudden cardiac death. All clinical and MRI-based variables were evaluated for associations with the primary and secondary outcomes with Cox proportional multivariable regression analysis also performed.A total of 318 patients were followed over a median of 467 days. At the end of follow-up 49 patients (15.4%) suffered a primary outcome (10 SCD and 39 appropriate therapies). Baseline clinical characteristics were similar among those with and without the primary outcome with the exception of prior history of ventricular arrhythmia and ischemic etiology (p < 0.05). Following adjustment for etiology, LVEF, LVEDV, and Total HE, those with an RVEF\u226445% were more likely to experience the primary outcome and the secondary outcome of interest.Patients with right ventricular dysfunction, defined as RVEF\u226445% by cardiac MRI, are at an increased risk of future arrhythmic events. Similarly, these individuals are at an elevated risk of heart failure admission and non-sudden cardiac death.This research was supported by the Imaging in Cardiovascular Therapeutic grant from the Ontario Research Fund and the Canada Foundation of Innovation."} +{"text": "In order to improve the tracking accuracy, model estimation accuracy and quick response of multiple model maneuvering target tracking, the interacting multiple models five degree cubature Kalman filter (IMM5CKF) is proposed in this paper. In the proposed algorithm, the interacting multiple models (IMM) algorithm processes all the models through a Markov Chain to simultaneously enhance the model tracking accuracy of target tracking. Then a five degree cubature Kalman filter (5CKF) evaluates the surface integral by a higher but deterministic odd ordered spherical cubature rule to improve the tracking accuracy and the model switch sensitivity of the IMM algorithm. Finally, the simulation results demonstrate that the proposed algorithm exhibits quick and smooth switching when disposing different maneuver models, and it also performs better than the interacting multiple models cubature Kalman filter (IMMCKF), interacting multiple models unscented Kalman filter (IMMUKF), 5CKF and the optimal mode transition matrix IMM (OMTM-IMM). Bayes filtering algorithms have been broadly used in target tracking systems ,2,3,4, wBlom and Shalom have proposed the interacting multiple model (IMM) algorithm based on a generalized pseudo-random algorithm to decrease the error of single model algorithm, which will improve the quick response and accuracy of target tracking . The IMMIn this paper, the interacting multiple models five degree cubature Kalman filter (IMM5CKF) based on a five degree cubature Kalman filter and IMM algorithm is proposed to improve the tracking accuracy, model estimation accuracy and quick response of target tracking algorithms. The negative weights of 5CKF go to 0 when the system dimensions go to \u221e, so 5CKF is more stable than UKF . The simThe five degree cubature Kalman filter is proposed to improve the accuracy of the traditional Cubature Kalman Filter . It choox, P is the covariance of x. The five degree Cubature Kalman Filter includes two steps, time update and measurement update.Supposing state variables (1) FactorizeThe Cholesky decomposition of (2) Evaluate the cubature points:(3) Evaluate the propagated cubature pointsThe sample points are obtained by propagating the cubature points through the state equation as:(4) Estimate the predicted pointsState prediction (5) Estimate the predicted error covariance:(1) Factorize:(2) Evaluate the cubature points:(3) Evaluate the propagated cubature pointsThe sample points are obtained by propagating the cubature points through the observation equation:(4) Estimate the predicted measurement:(5) Estimate the innovation covariance matrix:(6) Estimate the cross-covariance matrix:(7) Estimate the Kalman gain:(8) Estimate the updated state:(9) Estimate the corresponding error covariance:In the paper, the proposed IMM5CKF includes the merits of the 5CKF algorithm and IMM algorithm. The main character of IMM5CKF is that it calculates the state distribution and error covariance matrix by choosing an odd number of special cubature points with equal weights, and the negative weights go to 0 when the dimension of the system goes to The mixed initial value and measure value of position and velocity are used to contrast the performance of the filtering algorithms. The RMSE defined in state vector The RMSEs of the IMM5CKF, IMMCKF, IMMUKF, 5CKF and OMTM-IMM are shown in In this paper, IMM5CKF is proposed to enhance the tracking accuracy, model estimation accuracy and response sensitivity of nonlinear maneuvering target tracking problems. The algorithm introduces a five degree cubature Kalman filter into interacting multiple models which simultaneously disposes of all the models through a Markov Chain. A classical target tracking problem is utilized to demonstrate that the IMM5CKF can indeed improve the quick response sensitivity of target tracking algorithm, and it exhibits more accurate than IMMCKF, IMMUKF, CKF and OMTM-IMM. In our future research, the study may focus on multisensor navigation and positioning systems. The proposed algorithm should be suitable for the complex real environments according to the analysis."} +{"text": "Left ventricular late gadolinium enhancement (LV-LGE) is a known incidental cardiac magnetic resonance (CMR) finding in atrial fibrillation (AF) patients and has recently been associated with increased mortality . While LA 1:2 observational case-control study was conducted with a dataset of cases with new onset ischemic stroke after 1st CMR scan and controls matched by age and sex. Cases and controls were selected from a database of 762 AF patients without any prior history of MI who underwent cardiac MRI exams between June 2006 and January 2013. We manually reviewed the electronic medical records of all patients with CMR and sequentially selected the first identified age and sex matched controls (subjects without stroke event after their CMR scan). Two experienced readers scrutinized the CMR scans of cases and controls for presence of left ventricular delayed enhancement. We then collected all comorbidities and conducted univariate (Chi-square test/t-test as appropriate) and multivariate analyses to examine the association between LV-LGE and occurrence of stroke.Out of 762 patients, we identified 14 cases (1.8%) with new onset ischemic stroke after the first MRI scan. Of these cases, 2 (14%) were found to have LV-LGE. We age and sex matched these 14 cases with 28 controls in a 1:2 fashion. Description of demographic variables and univariate measures of association are presented in Table In this case-control study of AF patients without a history of MI, an incidental finding of LV-LGE is shown to predict the risk of stroke, especially in the case of patients with a higher CHADS2 score.Not applicable."} +{"text": "Furthermore, our study indicates that the structure of CsA during dissociation from the protein possesses a distribution of conformations different from those in solution under equilibrium condition.The immunosuppressive drug cyclosporin A (CsA) binds to its receptor protein cyclophilin 18 (Cyp18) in two distinct kinetic phases, while the mechanism remains elusive. Stopped-flow measurements coupled with titration and competition experiments were used to investigate the puzzling two-phase process of CsA and Cyp18 interaction. This study leads to the dissection of different conformational fractions of either direct fast binding or slow binding with rate-limiting conformational inter-conversion and the real-time measurement of Berkeley Modenna method[-1 (The slow binding conformer may need to convert to the active conformer before binding to Cyp18 (Model II). Thus, the rate of slow binding represents the apparent converting rate. When the concentration of CsA is lower than that of Cyp18, the slow binding conformers will bind to Cyp18 once they convert to the active conformation with the rate of kna method was usedethod[-1 . This reOur work provides the evidence that the two-phase binding kinetics of CsA to Cyp18 is caused by the ligand conformational heterogeneity. This leads to the dissection of different conformational fractions of either direct fast binding or slow binding with rate-limiting conformational inter-conversion. Moreover, the competition experiment described in S1 FigTime courses of Cyp18 intrinsic fluorescence intensity upon to the adding of THF(A) or LiCl/THF(B). (A) Time courses of Cyp18 intrinsic fluorescence with (Red) or without (Black) subtraction of reference curve (only THF). The arrows show the procedures of the experiments and the curves before and after subtraction of reference curve. (B) Time courses of Cyp18 intrinsic fluorescence with (Red) or without (Black) subtraction of reference curve (only LiCl/THF). The arrows show the procedures of the experiments and the curves before and after subtraction of reference curve.(PDF)Click here for additional data file.S2 Fig(PDF)Click here for additional data file.S3 Fig\u22123 s-1.The values shown in the inset represent the different ratios of CsA to CypA. The k value was 8.25 \u00b1 0.03 x 10(PDF)Click here for additional data file.S4 FigBlack curves are plotted by the data converted from (PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 Tables-f and kf-s used for fitting was board (highlight), whereas the fitting showed closed value to the predicted, this indicated the conformational selection model was the most dominant process of CsA binding to Cyp18 in aqueous solution.The range of k(PDF)Click here for additional data file."} +{"text": "The aim of our investigation was to determine effect of the internal carotid arteries (ICAs) tortuosity (S-shape), kinking and coiling on the arterial blood flow by magnetic resonance imaging and ultrasound (US).50 healthy volunteers (control group) and 43 patients with carotid abnormalities (CAs) were examined on 1.5T MR-scanner using routine MR protocol and quantitative MR angiography (qMRA) for estimate of the arterial blood flow velocity and cross sectional area of the ICA. We observed the cross sectional area and the values of peak velocity, mean velocity, flux velocity of arterial blood flow at one cardiac cycle at cervical and intracranial segments of the ICA ."} +{"text": "Immune reconstitution inflammatory syndrome (IRIS) is a common cause of death and even more common cause of morbidity in patients started on highly active antiretroviral therapy (HAART). At present, very limited data is available about IRIS in the local population so the present study was conducted to determine the incidence, clinical manifestations, risk factors and outcomes of IRIS in south Indian HIV/AIDS patients.Study was a prospective surveillance method to identify IRIS from two ART centers in Mysore city, India for a period of two years. HIV patients who are initiated with HAART were included for the study and were followed up for a period of six months. Data were analyzed using SPSS version 21.s (11%) and other opportunistic infections (27%). The major manifestation of IRIS were fever (44%) followed by lymphadenitis (36%). Statistically important predictors for occurrence of IRIS were male gender and low CD4 count. Two deaths were attributable to IRIS and 54% of them required hospitalization.Out of 798 people followed 82 patients had experienced IRIS with an incidence rate of 10%. Among them 48% were unmasking and rest were paradoxical worsening. Diagnosis included tuberculosis (44%), herpes zoster (18%), cryptococcal meningitiPatients with advanced immunodeficiency at HAART initiation are at greatest risk of developing IRIS and should be appropriately screened and monitored. Educational programs on recognizing and treating these conditions should be initiated in ART access programs."} +{"text": "Infaunal communities of benthic macro-organisms (\u2265 1mm length) were studied from 81 samples collected across nine sites to the north and south of the Orange River in the Benguela upwelling ecosystem in 2003, with a view to describing communities and understanding the drivers of regional community structure, as well as to document diversity and to examine geographic affinities. Although the fauna was dominated by polychaetes and peracarid crustaceans, patterns in community structure could only weakly be explained by the measured environment (~35%). This is attributed to the generalist nature of the species recovered, which were widely distributed amongst different sediments, water-depths and latitudes. The fauna is dominated by species that enjoy a widespread regional and global distribution and is characterised by relatively low diversity, which is discussed. Coastal-upwelling ecosystems are amongst the most productive in the world, where pelagic systems are characterised by short diatom-based food chains leading to industrial scale fisheries . Biomass2 l-1), and sometimes high levels of hydrogen sulphide in the pore water [sensu [cf 8]. Macrofaunal diversity within OMZs is also low, and communities show a remarkable homogeneity in composition across wide spatial scales; a fact that is attributed to the lack of biogenic structures and large burrowers ).The results of this study suggest that the fauna of the soft-sediment environment off southern Namibia and off Namqualand is characterised by relatively low diversity and by species with a generalist habit and wide distribution. Further work on measuring a wider suite of environmental variables is desirable, and studies into the detailed taxonomic identity of all material collected is encouraged.S1 Fig(TIF)Click here for additional data file.S2 FigNumber of identified species recovered in one or more of the nine regions (a) or sediment textural groups (b) sampled off southern Namibia and off Namaqualand during 2003.(PPTX)Click here for additional data file.S1 TableList of the identified species recovered from the samples collected off southern Namibia and off Namaqualand during 2003, with an indication of their presence (1) or absence (0) in on-line distributional databases . Information from other sources also indicated, where appropriate. A summary of the known distribution of each species is also indicated.(DOCX)Click here for additional data file.S2 TableList of additional genera, not included in (DOCX)Click here for additional data file.S3 TableMean abundance and standard error (per sample) of the top ten most commonly represented families at each of the sites sampled off southwestern Africa during 2003.(DOCX)Click here for additional data file.S4 TableAverage (root-root) abundance per sample of those macro-infaunal taxa identified by the SIMPER routine in PRIMER 6 as being responsible for 90% of the identity of each of the water-depth zones . The weighted mean water-depth (m) occupied by each of the identified species is also shown.(DOCX)Click here for additional data file.S5 TableAverage (root-root) abundance per sample of those macro-infaunal taxa identified by the SIMPER routine in PRIMER 6 as being responsible for 90% of the identity of each of the sediment textural groups identified by Folk (1954) sampled off southwestern Africa during 2003. The weighted mean sediment particle size (\u03bcm) occupied by each of the identified species is also shown.(DOCX)Click here for additional data file.S6 Table(XLSX)Click here for additional data file."} +{"text": "Focal left atrial tachycardia (FLAT) although a common cause of supraventricular tachycardia(SVT) among children, the one's arising from left atrial appendage (LAA) present a unique challenge for successful ablation because of anatomical location. We present two children with FLAT arising from the epicardial LAA, successfully mapped and ablated through percutaneuous epicardial approach. The LAA is one of the major sources of FLATs in children . HoweverA 12 year old girl presented with history of recurrent episodes of palpitations and fatigue. She had left ventricular dysfunction secondary to (TIC). Tachycardia was refractory to multiple antiarrhythmic drugs and was referred for RFA. Patient was in incessant atrial tachycardia and baseline 12 lead electrocardiogram (ECG) revealed negative P waves in leads I and avL, positive P wave in leads V1, III and avF and isoelectric P wave in lead II . ActivatThe second case was a 6 year old boy presented to us with incessant atrial tachycardia at the rate of 190 per minute with 1:1 AV conduction and TIC. The 12 lead ECG showed negative P waves in leads I and avL and positive P waves in the inferior leads and in lead V1 . He had There have been several case series of successful catheter ablation of an LAA tachycardia using different approaches -6. To thThus, the epicardial catheter ablation may be an alternative approach to endocardial catheter ablation in atrial tachycardias with an LAA origin without the need for subjecting these patients to surgical ablation."} +{"text": "Recent reports suggest that within the heterogeneous population that constitutes a melanoma, certain cell types exhibit molecular and functional features similar to stem cells. These melanoma-initiating cells (MICs) have the ability of unlimited self-renewal, multilineage differentiation and the potential to initiate and maintain tumor growth . FurtherMICs were enriched by Fluorescence Activated Cell Sorting using the metabolic marker Aldehyde Dehydrogenase (ALDH) and by establishing melanoma spheres in non-adherent culture conditions from 20 human melanomas. Expression of SOX2 and of HH pathway components was determined by real time PCR and Western blot analysis. Modulation of the HH signaling was performed by stable expression of lentiviral vectors encoding short-interference RNAs specific for SMO or GLI1 (to inhibit HH), and PTCH1 (to activate HH). Functional analysis of SOX2 was performed by stable overexpression and silencing using lentiviral vectors.SOX2 promoter in melanoma cells. Functionally, we show that SOX2 is required for HH-induced melanoma cell growth and MIC self-renewal. We present evidence that SOX2 is highly expressed in a population enriched for cancer stem cells in patient-derived melanomas. Knock-down of SOX2 sharply decreases self-renewal of melanoma spheres and of ALDHhigh melanoma stem cells. Consistently, ectopic expression of SOX2 in melanoma cells is sufficient to enhance stemness in vitro. SOX2 silencing also inhibits cell growth and induces apoptosis in melanoma cells. Most importantly, depletion of SOX2 drastically impairs tumorigenicity of ALDHhigh MICs in orthotopic xenografts.We find that the HH signaling regulates the expression of SOX2 and the downstream effectors of the HH signaling, the transcription factors GLI1 and GLI2, bind to Our data identify SOX2 as a novel mediator of the HH signaling in melanoma cells and indicate that SOX2 is a critical factor for the survival of MICs. These findings could provide the basis for novel therapeutic strategies based on the inhibition of SOX2 for the treatment of human melanomas."} +{"text": "Reprogramming of metabolic pathways and abnormal acetylation of DNA are two common features of cancer, including prostate cancer (PCa).CWR22Rv1 cells (a castrate-resistant human PCa cell line) were treated with a polyherbal mixture of botanicals (PHBs) consisting of 10 herbal extracts [de novo lipid biosynthesis through the phosphorylation of acetyl-CoA carboxylase and by inhibiting the expression of fatty acid synthase and SREBP1c. Also via AMPK, the PHBs inhibit the activity of mTORC1 complex by phosphorylating raptor, decreasing the activity of S6K. These effects can be mimicked by treatment of AICAR (activator of AMPK) and over-expression of AMPKalpha, and attenuated by compound C (AMPK inhibitor) and siRNA silencing of AMPK. Furthermore, the PHBs increase the cellular pools of acetyl CoA via mechanisms that may include ATP-citrate lyase. Coordinately, there are increases in acetylation of histone 3 and expression of the tumor suppressor proteins p21 and p27, a mechanism that most likely involves the down regulation of class I and II histone deacetylases and up regulation of histone acetyl transferase via ERK1/2 signaling. The inhibitory effects on cell proliferation can be attributed in part to the synergistic activity of some of the individual components in the PHBs as determined by the Chou-Talalay method [in vitro.Our results show that the PHBs can modify lipogenesis in CWR22Rv1 cells by enhancing the activation of AMPK, with concomitant decreases of Bioactive nutrients derived from multiple herbs inhibit the growth of androgen-deprived castrate resistant PCa cells via multiple mechanisms, one of which involves up regulation of AMPK signaling."} +{"text": "P. falciparum resistance mechanism to ACT has become a global research goal. The selective pressure of ACT and the possibility that some specific Pfcrt and Pfmdr1 alleles are associated with treatment failures was assessed in a clinical trial comparing ASAQ to AL in Nanoro. Dried blood spots collected on Day 0 and on the day of recurrent parasitaemia during the 28-day follow-up were analyzed using the restriction fragments length polymorphism (PCR-RFLP) method to detect single nucleotide polymorphisms (SNPs) in Pfcrt (codon76) and Pfmdr1 genes. Multivariate analysis of the relationship between the presence of Pfcrt and Pfmdr1 alleles and treatment outcome was performed. AL and ASAQ exerted opposite trends in selecting Pfcrt K76T and Pfmdr1-N86Y alleles, raising the potential beneficial effect of using diverse ACT at the same time as first line treatments to reduce the selective pressure by each treatment regimen. No clear association between the presence of Pfcrt and Pfmdr1 alleles carried at baseline and treatment failure was observed.The adoption of Artemisinin based combination therapies (ACT) constitutes a basic strategy for malaria control in sub-Saharan Africa. Moreover, since cases of ACT resistance have been reported in South-East Asia, the need to understand Plasmodium falciparum resistance to antimalarial drugs is the main challenge for malaria control in endemic countries. To overcome resistance to chloroquine (CQ), artemisinin-based combination therapies (ACT) have been recommended by the World Health Organization (WHO) for the treatment of uncomplicated malaria to distinguish between recrudescence and new infections constitutes another limit of this study and could partially explain why no significant difference was observed between the two groups (recrudescence and new infections). In this study the prevalence of mutation in Pfmdr1-D1246Y was extremely low and it was difficult to correlate the presence of this mutation and treatment outcomes. No samples carried mutation in Pfmdr1-S1034C and Pfmdr1-N1042D as reported by several studies throughout Africa [Our findings suggest also no association between the presence of s report . The Pfmfantrine . Therefos report . Furthert Africa , 30.Pfcrt K76T and Pfmdr1-N86Y alleles, raising the potential beneficial effect of using diverse ACT at the same time as first line treatments to reduce the selecting pressure by each treatment regimen. No association between the presence of Pfcrt and Pfmdr1 alleles carried at baseline and ASAQ treatment failure was observed.AL and ASAQ exerted opposite trends in selecting S1 Fig(XLSX)Click here for additional data file."} +{"text": "Quantitative real-time reverse transcription-polymerase (qRT-PCR) is a widely used technique to characterize changes in gene expression in complex cellular and tissue processes, such as the cytoprotection or inflammation. The selection of an adequate internal reference gene for accurate and consistent analysis of gene expression is of major importance. Carbon monoxide (CO) affects several metabolic pathways and de novo protein synthesis is crucial in the cellular responses to the gasotransmitter. Herein a selection of commonly used reference genes was analyzed to identify the most suitable internal control genes to evaluate the effect of the CO on gene expression in cultured cortical astrocytes. The cells were exposed to CO by incubation with CORM-A1 (CO releasing molecule A1) and four different algorithms were applied to better evaluate the stability of eight putative reference genes. Our results indicate that Gapdh and Ppia (peptidylpropyl isomerase A) is the most suitable gene pair for normalization of qRT-PCR results under the experimental conditions used. Pgk1 (phosphoglycerate kinase 1), Hprt1 (hypoxanthine guanine phosphoribosyl transferase I), Sdha , Tbp (TATA box binding protein), Actg1 (actin gamma 1) and Rn18s (18S rRNA) genes presented less stable expression profiles in cultured cortical astrocytes exposed to CORM-1 for up to 60 min. Analysis of the effects of CO on the expression of Bdnf and bcl-2 gave different results depending on the reference genes used. A significant increase in the expression of both genes was found when the results were normalized with Gapdh and Ppia, in contrast with the results obtained when the other genes were used as reference. This study highlights the need for proper and accurate usage of reference genes in quantification of qRT-PCR results in studies on the effect of CO in gene expression."} +{"text": "Permanent neonatal diabetes mellitus (PNDM) is a rare disease which is defined as the onset of diabetes before the age of 6 months with persistence through life. Patients with KCNJ11 or ABCC8 gene mutations have the opportunity to switch to oral sulfonylurea therapy. There were limited studies about the genetic analysis and long term follow-up of PNDM.Report four cases of PNDM, including their genetic mutations, treatments and long-time follow-ups. All of the patients and their parents got gene analysis include INS, KCNJ11 or ABCC8 gene.None of the patients and their parents suffered from any genetic mutations of these three common genes. One of the children got continuous subcutaneous insulin infusion (CSII) and the others got multiple injections of insulin (MII). The PNDM patients had persisted after 35 months to 60 months of follow-up, 3 patients maintained almost stable blood sugar level, and 1 patient had poor sugar control.All of PNDM patients are suggested undergo genetic evaluation. For patients without KCNJ11 and ABCC8 gene mutation, oral sulfonylurea might not be considered. CSII is a useful tool for overcoming the difficulties of diabetes, and can also improve quality of life."} +{"text": "Liocarcinus depurator we assessed the contribution of historical and contemporary processes on population connectivity patterns across three main oceanographic discontinuities along the Atlantic-Mediterranean transition: Gibraltar Strait, Almeria-Oran Front and Ibiza Channel. A partial fragment of the cytochrome oxidase I gene was sequenced in 366 individuals collected from localities at both sides of each discontinuity during three time periods. Although localities showed genetic fluctuations through time, a significant gradient was detected along the coast for all sampling periods. Significant inter-annual differences identified within the Alicante area, north of the Almeria-Oran Front, were associated with shifts in the relative contribution of Atlantic and Mediterranean water masses. The persistence of a clinal pattern in the Atlantic-Mediterranean transition area together with local fluctuations suggests a complex balance of dispersal and selection.Spatial genetic studies often require sampling broadly separated areas, difficult to access simultaneously. Although comparing localities surveyed at different time periods might result in spurious genetic differentiation, there is a general believe on the stability of genetic structure through time, particularly if sampled localities are isolated or very distant. By analysing spatial and temporal genetic differentiation of the portunid crab Spatial genetic studies have increased in the last decades in many taxa while temporal genetic studies, despite being essential to understand biodiversity distribution, are still scarce. Landscape genetics and phylogeography are both concerned with understanding the distribution of genetic variation across natural environments1358The large population sizes of marine organisms generally result in little genetic differentiation despite restricted gene flow, and molecular markers show practical limitations in making inferences for recent timescales and single time point samples111314Three oceanographic discontinuities along the Atlantic-Mediterranean transition in the south and eastern Iberian Peninsula have been shown to restrict gene flow in several marine species. The connection of the Mediterranean Sea and the Atlantic Ocean through the Gibraltar Strait is characterized by the inflow of surface Atlantic water and outflow of deeper Mediterranean water1791419121423182512Liocarcinus depurator showed that the Almeria-Oran front did not represent a significant barrier to gene flow, whereas Ibiza Channel acted as the main genetic barrierL. depurator across the three main oceanographic discontinuities along the Atlantic-Mediterranean transition. A partial region of the mitochondrial DNA cytochrome oxidase subunit I (COI) was analysed in 366 individuals from five areas situated at both sides of each discontinuity and sampled during three time periods , and another including haplotypes mostly found in the Mediterranean (Ldep02 and related haplotypes) and were thus referred as the Atlantic (ATL) and the Mediterranean (MED) haplogroups, respectively the present study evidences that contemporary processes impact local genetic diversity and modify connectivity between populations. Temporal variability of oceanographic discontinuities should not be overlooked when defining connectivity patterns because this could mislead conservation decisions (e.g. when designing networks of marine protected areas)28Liocarcinus depurator populations under strong influence from Atlantic waters and decaying diversity going into the Mediterranean, suggests an Atlantic origin of the species. Many phylogeographic studies identify genetically differentiated units that can be attributed to vicariance or selection reducing gene flowCOI haplotypes for L. depurator can be related to an abrupt decline of sea temperature in north Atlantic waters around 38\u201340 kya14L. depurator probably diverged due to vicariance events and posterior range expansions, as observed in other species influenced by climatic fluctuations during the Quaternary3435Changes in environmental conditions and historical shifts of species distributions can shape genetic variation, as shown by spatially-explicit demographic modelling of genetic differentiationLiocarcinus depurator epipelagic larvae could drive genetic connectivity of this species by moving along with surface currents4et al.The greater diversity observed in samples under stronger Atlantic influence using microsatellite loci suggesting genetic exchange from the west side of the Almeria-Oran front towards the east and northet al.The largest fluctuations in haplotype frequency across time were found in ALAC located between two main oceanographic discontinuities, the Almeria-Oran front in the south and the Ibiza Channel in the north. The ALAC07 sample showed a relatively high frequency of individuals from the Atlantic (ATL) haplogroup, whereas ALAC09 and ALAC13 were clearly dominated by haplotypes from the Mediterranean (MED) haplogroup. A strong genetic break between Almeria-Oran front and Ibiza Channel and higher proportion of Atlantic genotypes was also observed in the comber pointed to the effect of variable reproductive success, and highlighted the unpredictable nature of connectivity in coral reef fishes43Clupea arenguset al.et al.Liocarcinus depurator as well as in other species with high dispersal capabilities gene fragment was amplified using the universal primers LCO1490 and HCO2198et al.2 (25\u2009mM), 0.5\u2009\u03bcl dNTP\u2019s (1\u2009mM) and 0.4\u2009\u03bcl (10\u2009\u03bcM) of each primer. PCR products of 2013 samples were cleaned with ExoSAP (1.2\u2009U Exonuclease and 1.2\u2009U Shrimp Phosphatase per \u03bcl) at a proportion of 1:2 (ExoSAP:PCR product) and sequenced at the Scientific and Technical Services of the University of Barcelona (Spain) or at Macrogen Inc. .Muscle tissue from each individual was preserved in pure ethanol on board of the vessel. Total DNA extraction was performed for 2009 and 2010 samples using Chelex 10% as in Estoup ST values and their significance assessed performing 1000 permutations with Arlequin v. 3.5P-values were corrected for multiple comparisons using the false discovery rate (FDR) as in NarumST pairwise distances with GenAlEx v6.5et al.Sequences were visually inspected, aligned and trimmed, to obtain a final alignment of 527\u2009bp, with BioEdit v7.2.5Liocarcinus depurator haplotypes were estimated by Bayesian Inference (BI) using MrBayes v 3.2L. depurator COI sequences was reconstructed using the median joining methodThe phylogenetic relationships between http://www.socib.eu/) and buoys located within the different sampling areas salinity data as a proxy for identifying Atlantic and Mediterranean water masses ."} +{"text": "Classical methods for determining malignant disease prognosis are based upon characterizing the morphology and location of tumor cells. While this analysis provides important information about a patient's disease it fails to capture the biological complexity of the tumor microenvironment and the contribution of the anti-tumor immune response. Basic histological quantification of T lymphocyte density, cytotoxicity, and memory by CD3, CD8, and CD45RO, respectively, has demonstrated that increased infiltration of T lymphocytes is associated with statistically significant improvement in patients' disease-free survival (DFS) and overall survival (OS) in colorectal carcinoma (CRC). Delineating the location of T lymphocytes into two areas within the primary tumor, the center and the invading margin is termed Immunoscore.In this study we examined whether tumor genotype could predict the clinical outcome of patients with CRC and if combining Immunoscore with analysis of the tumor genotype could further enhance the accuracy of predicting clinical outcome. We analyzed 200 primary colorectal tumor samples for mutations in 50 common driver genes, including those implicated in models of colon carcinogenesis . Each mutation was then assessed for prediction of DFS. Patients presented with a mean of 4 \u00b1 2 mutations. The most common mutations were in KRAS (58%), TP53 (49%) and APC (37%). Neither, a single mutation or the number of mutations significantly predicted clinical outcome.We examined whether mutations in the primary tumor were associated with presence of metastasis. Mutational profiles were remarkably similar between primary tumors from patients whether or not they had metastatic progression at the time of surgery. None of the 50 major cancer genes was more frequently mutated in patients with metastasis. However, using integrative analysis we found that tumors from patients with metastatic disease downregulated adaptive immune genes including those involved in co-stimulation, proliferation and positive regulation of T cells. Furthermore when analyzing the ability to predict patients' OS using Immunoscore in these late stage tumors, high Immunoscore still distinguished patients with better clinical prognosis. These data suggest immune contexture accurately predicts clinical outcome regardless of tumor stage. Further analysis of pre-existing immunity together with the analysis of tumor genotype may provide better understanding of tumor progression and invasion."} +{"text": "Nigeria is expected to be the nation with the 11th highest population of older persons by 2015. This demographic transition will have implications for the medical care services. Currently, there is no geriatric social health insurance policy nor comprehensive geriatric healthcare services in the country. The minimal health system response may be due to lack of comprehensive knowledge of geriatric disease burden, pattern and healthcare needs. This paper aims to describe the trend and pattern of geriatric health research publications, and to review the current geriatric health policies in Nigeria.A systematic review of published reports in PubMed was performed for the period of January 1990 to April 2014. The review of current geriatric health policies was conducted by document analyses of an annotated national bibliography on digitized health policies and guidelines.A total of 38 policies and guidelines of the Federal Ministry of Health were reviewed and none of them targeted geriatric health. The systematic review identified 52 eligible studies out of 3519 studies. Twenty-five studies (48%) were community-based studies, twenty (38%) were conducted in hospital settings, while only one was carried out in an old people\u2019s home and four were narrative literature reviews. Twelve studies (23%) were done in a rural area, 24 (46%) in an urban area and 11 (21%) report findings from both locations.One study reported the health of the elderly and economic policies (1), elderly destitution (1), health implication of ageing (1), attitude to ageing (2), care for the elderly (3), quality of life and life satisfaction (3), nutrition (2) and physical activity (1). The morbidity pattern reported from the reviewed articles were as follows: medical morbidities (8), geriatric emergencies and admissions (2), dental problems (5), surgical morbidities (1), nosocomial infection (1), mental health morbidities (6), orthopaedic (2), otorhinolaryngology (3), urology (1) and visual morbidities (5).The findings underscore a geriatric health research and policy needs. It is recommended that resources be invested into collaborative research for the development and implementation of evidence based geriatric health policies."} +{"text": "Cervical spine arthritis is a well-recognized complication of juvenile idiopathic arthritis (JIA). It is usually present in patients with more severe disease.To evaluate the prevalence of symptomatic cervical spine involvement and their association with MRI findings in children with JIA.The study was a retrospective study of all patients with JIA followed at University Children's Hospital Ljubljana from September 2010 to January 2013. We reviewed the charts of 206 patients with JIA diagnosed according to the ILAR criteria. Clinical, laboratory data and MRI of cervical spine where available were collected and reviewed.206 patients, 143 girls (69%) and 63 boys (31%) with JIA were followed at University Children's Hospital Ljubljana from September 2010 to January 2013. Twenty-two out of 206 (11%) patients had pain in the neck and/or limited range of motion of cervical spine. Twelve out of 206 (6%) patients had persistent cervical spine symptoms, MRI of the cervical spine with application of paramagnetic contrast was performed in those. The results revealed inflammation of atlantoaxial (AA) joint without subluxation in 6/206 (3%) patients. Among 6 patients with AA joint inflammation were 5 girls and one boy. Three of them had RF negative polyarthritis, two persistent oligoarthritis and one girl had juvenile psoriatic arthritis. Five out of six (83%) patients were ANA positive and none of them had positive HLA B-27 antigen. In four out of six patients (66%) with AA joint inflammation, the neck pain was an initial manifestation of JIA. Five out of six patients (83%) were treated with anti-TNF alpha agents and demonstrated good clinical recovery.The prevalence of AA joint inflammation in our cohort of patients with JIA was 3%. Cervical spine involvement could present as an initial manifestation of JIA and in 83% of our cases demonstrated good clinical response on treatment with anti-TNF alpha agents.None declared."} +{"text": "Borrelia burgdorferi sensu lato. The most important for human pathogenicity are B.garinii, B.afzelii and B.burgdorferi sensu stricto. Indirect laboratory diagnostics of LB is based on serological methods such as Enzyme-Linked ImmunoSorbent Assay (ELISA) and Western Blot Assay (WB) that detect specific antibodies. Another method in the diagnostics of LB is a new test LymeSpot. This test is based on Enzyme-Linked ImmunoSpot Assay (ELISPOT). We present our first experience with the test LymeSpot.Lyme borreliosis (LB) is multisystem infectious disease with various clinical manifestations. In Europe, LB is caused by gram-negative spirochetal bacteria of the complex B. burgdorferi sl.From November 2013 to June 2014 we performed LymeSpot on the group of 42 patients who were tested for suspicion of LB presence. LymeSpot is based on specific cell immune response of T-lymphocytes after stimulation by Borrelia antigens. The result is a number of antigen specific effector T-cells producing IFN-\u03b3 in the form of spots. We compared the results of LymeSpot test with the level of specific IgM and IgG antibodies detected by ELISA and WB with using recombinant antigens From the number of 42 patients we detected positive LymeSpot test only in 4 of them , a cutoff value in 3 patients . From the group of 42 patients were simultaneously performed ELISA and WB in 26 persons. In this group we found positive LymeSpot in 4 patients and cutoff value in 2 patients. In the group of 4 patients with positive LymeSpot was detected higher level of IgM antibodies in 3 patients and only IgG antibodies in 1 patient. They were patients with clinical manifestations of LB who were treated with antibiotics afterwards. Among 20 patients with negative results of LymeSpot these findings correlated with antibody response in 8 patients (40%). In this group we detected seronegative finding (IgM-IgG-) or finding of passing through LB (IgM-IgG+). In other 12 patients with negative LymeSpot test we detected serological finding of beginning (IgM+IgG-) or running LB (IgM+IgG+). They were mostly patients without clear symptoms of LB, patients with long-term positivity of IgM antibodies without clinical manifestations of LB or patients after antibiotic therapy.Our first experience shows that results of LymeSpot test better correlate with clinical findings and LB activity as well as can be effective marker of success of antibiotic therapy."} +{"text": "The majority of distal radius fractures are associated with an ulnar styloid fracture -3. ThereBecause of its close association with the Triangular Fibrocartilage Complex (TFCC), fractures of the ulnar styloid might indicate possible TFCC disruption with subsequent DRUJ instability ,8,9. StuBone fragments resulting from non-union could also provoke irritation and pain ,10 due tAs the results of treatment of chronic instability of DRUJ following a distal radius fracture are more unpredictable , it is a"} +{"text": "Breast cancer is the second most lethal cancer in women. Further, death rates for African American women are the highest for any racial/ethnic group. Hormone receptor status is one of the major prognostic factors and a determinant of treatment options for breast cancer, thus suggesting the importance of molecular level characterization for precision treatments. In this study, we have identified transcriptome level differences correlating to receptor specific molecular subtypes of breast cancer in African American women.http://cancergenome.nih.gov/), yielding transcriptome level analysis between four specific subtypes of breast cancer (Table Clinical and gene expression data from 18 African American women samples were obtained from The Cancer Genome Atlas (TCGA: The samples were analyzed using One-way ANOVA with Welch's correction for unequal sample sizes with type 3 sum of squares. Genes with ANOVA p-value < 0.01 and with relative expression fold change > |2.0| were considered significantly altered; this yielded 90 differentially expressed genes between cancer subtypes in our dataset (Figure BRCA1, SMAD3, SMAD4, EGFR and MDC1 genes[MDC1 showed altered expression for all subtypes of breast cancer and a significant p-value for the Luminal A subtype compared to the Triple negative subtype. The MDC1 protein has been previously implicated in the DNA damage response[The biological interaction network included important DNA repair sub-networks consisting of response and signIn conclusion, our results highlight a significant difference in the transcriptome levels of critical DNA repair proteins among the different breast cancer subtypes in African American women. The differentials that were observed stress the importance of molecular level characterizations to understand this disease. Understanding the protein interactions involved in this network will have a major role in predicting best courses of action and aid in precision medicine-based approaches to treating breast cancer."} +{"text": "We report on the derivation of a diploid 46(XX) human embryonic stem cell (HESC) line that is homozygous for the common deletion associated with Spinal muscular atrophy type 1 (SMA) from a pathenogenetic embryo. By characterizing the methylation status of three different imprinted loci , monitoring the expression of two parentally imprinted genes (SNRPN and H19) and carrying out genome-wide SNP analysis, we provide evidence that this cell line was established from the activation of a mutant oocyte by diploidization of the entire genome. Therefore, our SMA parthenogenetic HESC (pHESC) line provides a proof-of-principle for the establishment of diseased HESC lines without the need for gene manipulation. As mutant oocytes are easily obtained and readily available during preimplantation genetic diagnosis (PGD) cycles, this approach should provide a powerful tool for disease modelling and is especially advantageous since it can be used to induce large or complex mutations in HESCs, including gross DNA alterations and chromosomal rearrangements, which are otherwise hard to achieve. Parthenogenesis is the process by which an oocyte is stimulated to divide and develop into an embryo without being fertilized. It can be artificially induced by triggering unfertilized eggs to resume meiosis without undergoing cell division, or achieved spontaneously following failed fertilization. The resulting embryos, which contain only maternal chromosomes, are unviable due to poor development of extra embryonic tissues \u20137. Yet, This study was approved by the Ethics Committee at Shaare Zedek Medical Center (IRB 87/07) for the derivation of HESC lines from genetically affected PGD derived embryos, in compliance with protocols approved by the National Ethics committee.The SMA HESC line was established from a PGD derived embryo that developed into a fully grown hatched blastocyst by day 7 following fertilization. At this stage the inner cell mass (ICM) was mechanically isolated by manual cutting with an ultra-sharp splitting blade (Bioniche). The intact ICM clump was placed on a feeder cell layer of mitomycin C-inactivated mouse embryonic fibroblasts and cultured in HESC media . Outgrowths of proliferating cells were manually propagated using the cut-and-paste method. Following 5\u20137 passages, the newly established HESC line was further propagated by collagenase type IV (Gibco) and then frozen for future use as described in ..31]. In S1 FigDifferential expression of SNRPN but not H19 in SZ-SMA5, is different from wild-type HESC control (WT) and corresponds to the maternal only origin of SZ-SMA5 cell line.(TIF)Click here for additional data file.S2 FigSequencing results (shaded) of 4 randomly selected probes from the SNP array were used to validate the CytoScan 750K array data obtained for SZ-SMA5. For each probe heterozygosity rate , allele variations, and SNP array result are indicated, illustrating high accuracy of the assay for whole genome homozygosity detection.(TIF)Click here for additional data file.S1 File(DOCX)Click here for additional data file."} +{"text": "Several classes of antimicrobial nanoparticles (NPs) and nanosized carriers for antibiotics delivery have proved their effectiveness as alternative agents to combat the antimicrobial resistance experienced with conventional drugs. Gold nanostructures find extensive applications in nano electronics and nanomedicine.The present study involved the synthesis of gold nanoparticles using a sodium cholate, as both reducing and capping agent and characterization by UV- Visible spectroscopy and High ResolutionTransmission Electron Microscopy (HRTEM). The antibacterial activity on significant bacterial species was evaluated by micro broth dilution method. The mechanism for antibacterial action of the gold nanoparticles were studied by reactive oxygen species (ROS) generation that causes oxidative stress to microbial cells and release of intracellular enzyme lactate dehydrogenase into extracellular medium (LDH assay) indicative of loss of cell membrane integrity.80) of the nanoparticles on E. coli, S. typhi, P. aeruginosa, K. pneumoniae, ranged from 20 to 40\u00b5g/mL. The ROS generation was directly dependent on the concentration of the nanoparticles and no detectable enzyme leakage was recorded.The synthesized gold nanoparticles showed characteristic peak at 541 nm by UV- Visible spectroscopy with particle size of 10nm as confirmed by HRTEM. The minimum inhibitory concentration (MICThe results showed appreciable antibacterial activity of gold nanoparticles against the tested species and the possible mechanism of antibacterial activity may be due to increased intracellular ROS generation causing oxidative stress to the bacterial cells while LDH assay indicated that nanoparticles caused no damage to the cell membrane integrity."} +{"text": "Within the focal point of focused ultrasound (FUS), high pressure fluctuations cause shear stress on cells and tissues with energy dissipation leading to heating of the targeted tissue. The extent of the mechanical and thermal effects strongly depends on the ultrasound parameters and also potentially the acoustic properties of the tumor. High temperatures lead to coagulative necrosis with little immunogenic response as tumor antigens most likely denature during the ablation. As antigen presentation by activated dendritic cells (DCs) is necessary to activate T cells during an anti-tumor immune response, we hypothesize that non-ablative FUS treatment can be used to increase tumor immunogenicity by activating molecules that enhance intratumor dendritic cell (DC) infiltration and T cell activation. One of the first steps in this process is an activated stress response, including surface calreticulin (CRT), high mobility group protein B1 (HMGB1) release, ATP secretion and heat shock protein 70 (HSP70) surface expression and release. Using non-ablative FUS, antigen release can be stimulated by mechanical stress, thermal stress, or both. Here, we examine the stress response following non-ablative FUS treatment in three murine tumor models with varying consistencies and determine the causative agent of the stress.in vivo in three subcutaneous tumor models in C57BL/6 mice, varying the mechanical and thermal energies to determine which protocol results in the greatest anti-tumor immunity. We investigated CRT surface expression, ATP release and both intra and extracellular expression/release of HMGB1 and HSP70. Since the effect of FUS treatment may vary depending on the cancer cell type, we investigated three different mouse cancer cell lines varying in consistency from solid to fluid . Animals were sacrificed 24 hours post-treatment and tumors were excised for stress response analysis by flow cytometry. Plasma was also obtained for analysis of soluble proteins by ELISA. Stress response was compared to non-treated tumors (control) as well as to in vitro treatment of a cell pellet with the same FUS parameters. For all FUS treatment a Philips Therapy and Imaging Probe System was used.We tested a range of non-ablative FUS treatment protocols in vivo model of 3LL 24 hours following FUS treatment that delivers high thermal energy when compared to other treatment settings and no treatment in surface expression of HSP70 in an"} +{"text": "ADG) of growing animals. The objective of this study was to identify commercial single nucleotide polymorphism (SNP) panels that could improve the predictability of days on feed (DOF) to reach a target United States Department of Agriculture (USDA) grade given animal, diet, and environmental information under feedyard conditions. The data for this study was comprised of crossbred heifers (n = 681) and steers (n = 836) from commercial feedyards. Eleven molecular breeding value (MBV) scores derived from SNP panels of candidate gene polymorphisms and two-leptin gene SNP (UASMS2 and E2FB) were evaluated. The empty body fat (EBF) and the shrunk body weight (SBW) at 28% EBF (AFSBW) were computed by the Cattle Value Discovery System (CVDS) model using hip height (EBFHH and AFSBWHH) or carcass traits (EBFCT and AFSBWCT) of the animals. The DOFHH was calculated when AFSBWHH and ADGHH were used and DOFCT was calculated when AFSBWCT and ADGCT were used. The CVDS estimates dry matter required (DMR) by individuals fed in groups when observed ADG and AFSBW are provided. The AFSBWCT was assumed more accurate than the AFSBWHH because it was computed using carcass traits. The difference between AFSBWCT and AFSBWHH, DOFCT and DOFHH, and DMR and dry matter intake (DMI) were regressed on the MBV scores and leptin gene SNP to explain the variation. Our results indicate quite a large range of correlations among MBV scores and model input and output variables, but MBV ribeye area was the most strongly correlated with the differences in DOF, AFSBW, and DMI by explaining 8, 13.2 and 6.5%, respectively, of the variation. This suggests that specific MBV scores might explain additional variation of input and output variables used by nutritional models in predicting individual animal performance.Cattle body composition is difficult to model because several factors affect the composition of the average daily gain ( USDA) Choice or Canadian AAA graded meat versus lower quality grade meat CT was asAn analysis indicateIn conclusion, our analysis indicates that it is possible (and desirable) to incorporate genomic information into mathematical nutrition models to enhance their predictability by accounting for individual makeup differences. This incorporation, however, may require profound modifications of nutrition models to accommodate new concepts, such as genome wide associated studies , 55, to S1 File(ZIP)Click here for additional data file."} +{"text": "In 2008 the Paediatric Rheumathology European Society (PReS) promoted an International Project for the study of Autoinflammatory Diseases (AID) named Eurofever whose main purpose is to create a web-based registry for the collection of clinical, laboratory and response to treatment information in patients with AID.To implement the Registry with the new recently described AID and genes and modify the web-system to make it suitable for the collection of longitudinal data.With the technical help of Paediatric Rheumatology INternational Trial Organization (PRINTO) web-masters, we were able to revise the electronic case report forms bringing 2 main novelties: i) inclusion of the more recently described AID and the relative clinical manifestation ii) modification of drug layout. In this process information on safety and efficacy has been included. Very soon Centres will be asked to update on a yearly base the information regarding each patient with particular focus on modification of the clinical picture, onset of complication/sequelae, treatment, adverse events if present, laboratory and instrumental findings.At present baseline demographic information from 3089 (M:F=1513:1576) patients from 101 centers in 38 countries are available. In 77% complete clinical information from disease onset to diagnosis and response to treatment is also available. For each disease the number of enrolled patients is: FMF 894 pts ; TRAPS 268 pts (226 complete); CAPS 284 pts (208 complete); MKD 189 pts (165 complete); Blau's disease 71 pts (22 complete); PAPA 27 pts (22 complete); NLRP-12 mediated periodic fever 14 pts (9 complete); DIRA 3 pts ; CANDLE 2 pts (1 complete), Schnitzler 1 pt and Majeed 2 pts (both complete). Among multifactorial autoinflammatory diseases: PFAPA 612 pts (380 complete); CRMO 417 pts (394 complete); pediatric Bechet disease 92 pts (72 complete) and 217 patients with undefined periodic fever (182 complete). Longitudinal electronic data capture is now ready and online for authorized PRINTO members.A common registry for collection of patients with AID is available and the enrollment is ongoing. This project represents the first attempt of a common registry for different autoinflammatory syndromes. The longitudinal collection and analysis of data coming from the Registry will improve our knowledge in the field of autoinflammation both on the natural history of the single disease and the efficacy and safety of the treatment commonly used in the clinical practice with particular regards to biologics."} +{"text": "Pompe disease (OMIM 232300) is an AR glycogenosis due to deficiency of the lysosomal enzyme alpha-glucosidase (GAA). As a result, glycogen storage occurs in muscles and patients present a wide clinical spectrum ranging from early onset severe cardiomyopathy (EOPD) to adult onset forms (LOPD). Severe loss of GAA activity correlates with early onset and severe phenotypes. Residual enzyme activity warrants later onset and a slowly progressive course, although a strict correlation is not always observed. Patients with Classic infantile Pompe disease show hypotonia, macroglossia, respiratory insufficiency and early death for cardiorespiratory failure.The availability of enzyme replacement therapy (ERT) with alglucosidase alfa ( human recombinant GAA) has changed the natural history of the disease allowing most children with EOPD a longer survival and a longer preserved muscle performance with increased quality of life in LOPD.The experience of the Regional referral Center for Metabolic Diseases, University of Catania, concerns 11 patients ( 9 months to 65 years at the time of the diagnosis). Their clinical and laboratory follow-up included eye tracking and Muscle MRI.EOPD, with a severe clinical picture since the first weeks of life and cardiomyopathy was observed in a newborn who died at age 4 months, despite early started and high dosage ERT. Another girl with EOPD is on ERT since the age of 9 months and, today, after 7 years of treatment shows only mild signs of muscle weakness and no cardiac involvement.Five more LOPD patients on ERT had a significant improvement of blood parameters including transaminases, LDH and CPK. No progression of muscle impairment was seen after 5 to 8 years of treatment, except for one 35 years old man, who was already severely compromised and did not show any benefit in terms of respiratory ventilation.In a recently performed Italian survey of classical Pompe disease treated with ERT, a substantial improvement in cardiac parameters and gross motor function was observed, even if residual muscle weakness still exist and gross motor function remain below age-appropriate levels.The different response to ERT depends on several factors mainly on timing of treatment (worse outcome if started later than 5 months of age) and cross reactive immune material (CRIM-negative status associated with less good response to ERT).Although some residual mild weakness is present in treated patients, ERT has demonstrated its effects on respiration, lowering nocturnal apneas and allowing patients a better quality of life."} +{"text": "Road traffic injury (RTI) has assumed major public health importance world-wide and the burden is heavier on the health-care infrastructure of countries in Sub-Saharan Africa. In Nigeria, RTI is the leading cause of trauma related morbidity and mortality. While there are some published epidemiological reports on RTI in the region, studies on the mechanism of causation of road traffic crashes (RTC) are not available.Over a 9-month period, we prospectively captured the 571 victims of RTC presenting to a single tertiary health care center in Nigeria. Data collected include demographic data, Mechanism of causation of RTC, Injuries sustained and outcomes.Over three-quarters of the victims are young people and half were either traders (27.5%) or students (20%). Pedestrians, motorcycle riders and open truck occupants (people sitting at the rear loading compartment of trucks) often had fatal injuries. Analysis of collision patterns showed that lone crashes were the most frequent though car-to-motorcycle crashes caused a quarter of the deaths. Host factors were responsible for four-fifths of the crashes while vehicular and environmental factors accounted for the remaining. On binary regression analysis, head injured victims had higher odds of dying than the non-head injured (Odds ratio = 6.5).This paper elucidates the mechanisms of causation of and types of injuries sustained following RTC in Nigeria and thus provide opportunities for prevention and control of this unacceptable situation. Worldwide, Road Traffic Injury (RTI) has assumed major public health concern as it is responsible for an increasing number of morbidity and mortality. The World Health Organization (WHO) has attributed this increase to rapid urbanization and motorization and has aptly identified RTI as the price humanity must pay for modernization . The cosAll RTI victims who presented to University of Ilorin Teaching Hospital between October 2006 and June 2007 were prospectively captured. Biodata of victims, details of how the RTI occurred (mechanism of causation), the location of the victim during the incident (host status), the types of injuries sustained and eventual outcome was documented. Age categorization: The age of the victims were categorized into three groups for statistical analysis. Host status: The host status was also categorized as riders of motorcycles (two wheeler vehicles); drivers of cars, buses or trucks (four wheeler vehicles); passengers of motorcycles; passengers of four wheeler vehicles; pedestrians and open truck occupants . Crash mThere were 571 patients over the nine month period consisting of 427 males and 144 females (M:F ratio = 3:1). There was no statistical significant difference in outcome between the sexes (p = 0.439). Median age was 30 years (range 6 months to 84 years). Over three-quarters of victims were young people, with another one-fifth being middle-aged and only 0.5% were elderly. There was however no significant statistical difference in outcomes between the age categories (p = 0.168). Majority of victims were either engaged in business or trading (27.5%) or were students (20%). The least involved group was the professional (2%). There were a total of 388 crashes consisting of 310 single patient and 78 mass (>1 victim) involvements (single: mass crash ratio = 4:1). Two crashes which involved 15 and 11 casualties constituted the highest mass crash casualty.Pedestrians, motorcycle riders and open truck occupants represenOf the various collision patterns, lone crashes (Solitary crash involving only one vehicle with no collision with another vehicle or pedestrian) were the most frequent on our roads accounting for about 29% of 388 crashes and were responsible for the highest casualty of 199 patients (35%) . Car-to-Soft tissue injuries constituted the largest (35%) injuries . Head inThe African region has been identified to carry the highest road traffic death rate of all continents , 4. SoutAbout 43% of victims in this study were passengers of 4 wheeled vehicles, 28.4% were on motorcycles (rider and passengers), and 14.5% were pedestrians. These three groups of road users are particularly prone to RTI in the developing countries . The motEighty percent of crashes were due to host factors and accounted for 74% of morbidity and about 84% of mortality. Over-speeding/inappropriate speed constituted the major host problem (80%). Odero's presentation also identified human error as leading cause with over-speeding topping the list in Kenya, Uganda, South Africa, Ghana, Zimbabwe, Ethiopia and Tanzania . AlcoholThe following recommendations are suggested to policy makers to reduce the occurrence of and injuries from RTI: 1) Enforcement of helmet use by motorcyclists, seat belts by drivers and passengers of 4 wheeled vehicles and a law against travelling on the back of trucks and Lorries. 2) Strict regulation and enforcement of speed limit. The Federal Road Safety Corps should be equipped with speed detectors in their patrol cars and our roads must have speed detectors at strategic points with camera facilities. 3) Appropriate road engineering with road signs and conspicuously displayed speed limits to guide road users. Provision of road shoulders and service lanes will prevent broken down vehicles from being impediments to traffic. 4) Construction of new roads to open new network of roads so as to decongest the major roads. 5) Regular road maintenance to eliminate potholes. 6) House to house waste collection coordinated by the local government authority should be introduced to replace the current practice of refuse tanks dumped on major roads. 7) Use of \u201cTokunbo\u201d tires must be banned urgently.This paper has elucidated the mechanisms involved in causation of RTIs, the injury spectrum seen in involved victims and the relationships of these variables to outcome of clinical management of the victims. Several opportunities for control are also put forward based on the findings in the study."} +{"text": "Nature Communications7: Article number: 10578 10.1038/ncomms10578 (2016); Published 02232016; Updated 03212016The original version of this article contained an error in the spelling of the author Eugen Buehler, which was incorrectly given as Eugen Beuhler. This has now been corrected in both the PDF and HTML versions of the article."} +{"text": "Active JIA of the knee can lead to bony overgrowth and leg length discrepancies in children with JIA. Fixed flexion deformities of the knee result in loss of inner range quadriceps strength, abnormal gait and reduced independent function and participation in sports and activities.Our objective was to review the use of stretch and cast procedures alongside Intra-articular steroid injections (IAI) for active JIA of the knee resulting in fixed flexion deformities (FFD) of greater than 15 degrees.A retrospective review was undertaken of all patients presenting to Great Ormond Street Hospital NHS Foundation Trust between 2005-2013 with active JIA of the knee resulting in FFD and loss of knee extension range of movement (ROM) greater than -15 degrees extension and underwent a stretch and cast procedure alongside IAI for treatment of their disease. ROM was assessed pre and post procedure. Patients received their IAI under general anaesthetic, and then the physiotherapists carried out a stretch and cast procedure.The stretch and cast procedure included patella mobilisations, gentle and prolonged knee extension passive stretching, and casting with a fibre-glass cast for 72 hours. All patients then received 2 weeks of intensive physiotherapy strengthening. ROM and inner range quadriceps strength were measured at the end of these 2 weeks post procedure.30 patients had a FFD of between -15 and -90 degrees (mean -30) extension at the affected knee(s). A total of 35 joints were injected and underwent the stretch and cast procedure plus physiotherapy strengthening. Post intensive rehab the patients all had improved or normal ROM (mean -7 degrees) and improved muscle strength in order to maintain this improvement. This was maintained at 4-6 month follow up in 94% of patients. The 2 patients who did not maintain range of movement had poor compliance to their physiotherapy home exercise programme.ROM improved following procedure in all patients, indicating that stretch and cast treatment is an effective intervention for the management of fixed flexion deformities secondary to active JIA. Ongoing strengthening of inner range quadriceps is vital to maintain this improved range of movement and restoration of function and normal gait.None declared."} +{"text": "Rare diseases; clinical practice guidelines; recommendationshttp://www.rarebestpractices.eu) is a 4-year project (2013-2016) funded by the EC FP7. The project aims at improving clinical management of patients with rare diseases (RD) and at narrowing the existing gap in quality of healthcare among countries.RARE-Bestpractices (http://www.rarebestpractices.eu) involves 9 EU countries, including 15 partners from academic institutions, governmental bodies, patient organizations and networks, which will exploit the added value of integrating different contributions and viewpoints.RARE-Bestpractices and systematic reviews.http://rarejournal.org)Project expected outputs include: 1) identification of challenges to be considered in deriving high quality standards for CPG on RD; 2) transparent procedures and criteria for the evaluation of CPG and their collection in a publicly searchable database; 3) identification of notation criteria to improve user understandability and implementation of CPG; 4) production of mechanisms to assess RD clinical research needs; 5) development of training activities targeted to key stakeholders to disseminate process and tools for developing and evaluating CPG; 6) the publication of a new scientific journal for RD; in fact, one main criterion for ERNs should be the competence to produce CPG and actively disseminate them among Centers of Expertise."} +{"text": "Asthma is the most prevalent of all childhood diseases and accounts for the majority of hospitalizations and school absences in children . Current1262 children enrolled in the Canadian Healthy Infant Longitudinal Development (CHILD) Study with complete skin prick test and wheeze data at one year were grouped into four clinically relevant phenotypes: atopy + wheeze, atopy only, wheeze only, and control. Bacterial 16S rDNA from 3-month and 1-year stool samples of 319 children in these four phenotypes was extracted, amplified, and subjected to high throughput Illumina sequencing. Quantitative polymerase chain reaction (qPCR) and short chain fatty acid (SCFA) analysis were also conducted on 44 children in the two extreme phenotypes (atopy + wheeze vs. control).16S sequence analysis of our sample cohort (319 subjects) identified bacterial populations that differed in abundance in the atopy + wheeze group at 3-months of age but not at 1-year of age. Additionally, significant changes in the abundance of certain bacterial genera were found in the atopy + wheeze group when compared to controls by qPCR at 3-months of age only. Changes in stool short chain fatty acid production between the atopy + wheeze group and the control group were also observed at 3-months of age only.Shifts in the relative abundance of certain gut bacterial populations and differences in the levels of stool SCFAs before 3-months of age are associated with atopy and wheeze at one year of age."} +{"text": "Suppressor of cytokine signaling (SOCS) proteins are the negative regulators in cellular signal transduction system. SOCS family proteins consisting of 8 proteins (CIS and SOCS1-7) inhibit JAK/STAT protein activity to maintain proper cytokine functions. Initially identified for the negative feed-back function of cytokine signal transduction, suppressors of cytokine signaling (SOCS) have emerged as multi-functional protein involved in the regulation of development, apoptosis and oncogenesis. Recent reports showed that SOCS can be also affected by cytokine and other cell signaling factors to regulate cancer development and progression as well as cell death. The present study was aimed to investigate various effects of SOCS1 protein on the tumor suppressive function. We have found that SOCS1 promotes radiation-induced apoptosis of colon cancer cells through cell cycle arrest at G1 involving activation of p53 and p21 induction. SOCS1 also exhibits radiosensitization effects on the growth of implanted colon tumor cells in nude mice. As a mechanism of anti-tumor action of SOCS, we now present the data on the suppressive effects of SOCS1 on tumor cell migration and invasion. Notably SOCS1 over-expression and knock-out inversely regulates the expression of EMT markers such as E-cadherin and vimentin along with modest morphological change of cells from epithelial to fibroblast shape, representing EMT process. Data on the invasion and EMT signaling pathways suggest that SOCS1 potentially regulates tumor cell invasion and metastasis in vitro and in vivo in colon cancer models. SOCS1 may be not only a useful predictive factor for radiation response but also a possible drugable target for human colon cancer."} +{"text": "Evaluation of segmental instability in DLS is essential for spinal surgery to make the decision \"fusion or not fusion.\" Some previous studies have shown radiographic data regarding segmental instability in DLS. However, little is known about segmental motion of wedging segments in DLS. To evaluate the segmental instability of wedging segments using dynamic films and the impact of osteophyte formation on segmental motion in degenerative lumbar scoliosis (DLS).A total of 101 patients complaining of neurogenic claudication owing to lumbar spinal canal stenosis (LCS) were enrolled and divided into 2 groups based on their coronal spinal deformity; Cobb angle of >10 degree (DLS group) or <10 degree (LCS group). The following parameters were measured on anteroposterior films: lateral translation, degree of osteophyte formation, and range of motion (ROM) in lateral bending films. The facet joint space discrepancy was measured on computed tomography images. The radiographic parameters were compared between 85 wedging segments (>5 degrees) in DLS group and 150 nonwedging segments in LCS group.Mean lateral translation was significantly greater in the DLS group (P<0.01 for each level). Average joint space discrepancy was significantly greater in the DLS group . ROM was significantly greater in the DLS group with the same degree osteophyte formation. Degree of osteophyte formation was inversely correlated with ROM in the DLS group (R(2)=0.5696).The present study indicated that wedging segments in DLS had greater motion than nonwedging segments in LCS. However, the osteophyte formation provided restabilization for the wedging segments in DLS, suggesting that evaluation of osteophyte formation is an important factor in surgical decision making for DLS."} +{"text": "The new tendency in rehabilitation involves non-invasive tools that, if applied early after stroke, promote neurorecovery. Repetitive transcranial magnetic stimulation and transcranial direct current stimulation may correct the disruption of cortical excitability and effectively contribute to the restoration of movement and speech. The present paper analyses the results of non-invasive brain stimulation (NIBS) trials, highlighting different aspects related to the repetitive transcranial magnetic stimulation frequency, transcranial direct current stimulation polarity, the period and stimulation places in acute and subacute ischemic strokes. The risk of adverse events, the association with motor or language recovery specific training, and the cumulative positive effect evaluation are also discussed.Abbreviations: AAT = Aachen Aphasia Test, BDNF = brain-derived neurotrophic factor, IFG = inferior frontal gyrus, M1 = primary motor cortex, MRI = magnetic resonance imaging, NIBS = non-invasive brain stimulation, PET = positron emission tomography, rTMS = repetitive transcranial magnetic stimulation, SLT = speech and language therapy, STG = superior temporal gyrus, tDCS = transcranial direct current stimulation, NIHSS = National Institutes of Health Stroke Scale After an injury, there are changes in motor and sensitive cortical somatotopies, both in the damaged region and the remote areas from ipsi- and contralateral hemisphere. An increased activation in contralesional primary motor cortex (M1), bilateral ventral premotor cortex and supplementary motor area are commonly found in stroke patients [3]. While the healthy subjects show greater activity in the contralateral hemisphere to the moving hand, stroke patients assume a bilateral pattern in general [4]. Due to its intrinsic plasticity, the brain has the capacity to restructure its neural networks and to reconfigure its activity after an ischemic or haemorrhagic stroke. The metabolic and functional cerebral alteration can be observed by functional imaging studies (positron emission tomography (PET) scan and functional magnetic resonance imaging (fMRI), and also by transcranial magnetic stimulation mapping of the motor area [5]. These mechanisms are activated differently depending on stroke size and location. Small ischemic or haemorrhagic lesions may be compensated by the recruitment of residual language areas and the increase in perilesional activity. By contrast, the larger lesions in the language regions are followed by the recruitment of homotopic non-dominant areas [6]. In the recovery of aphasia, three models of neuroplasticity were framed by prior research: (1) activation of perilesional language areas in the dominant hemisphere, (2) recruitment of homologue area in the non-dominant hemisphere, and (3) improper recruitment of different regions in the non-dominant hemisphere [5]. Secondary to the decrease of transcallosal inhibition, some right hemispheric areas may deploy an inhibitory effect over the residual perilesional areas in the left hemisphere, interfering with the language recovery. Based on these data, a new model for the recovery of aphasia was proposed based on the suppression of non-dominant hemisphere activity and the stimulation of the perilesional areas in dominant hemisphere [5]. However, the role of right language homologues in the early recovery after stroke seems to be transient, to an extent perilesional neuronal recruitment occurs [4]. Transcranial direct current stimulation (tDCS) of the brain is an electrophysiological method which may be used to modulate the neocortical excitability. A direct current generator is connected to two patch electrodes (an active and a reference one) positioned over the scalp, to stimulate the subjacent tissue with low amplitudes currents (0.5 - 2.0 mA) and to modify the threshold for discharge of cortical neurons. The modulation of cortical excitability is polarity-dependent: \u201canodal stimulation\u201d (increased in network excitability) \u2013 when the active electrode generates a positive potential compared to the reference electrode; \u201ccathodal stimulation\u201d (decreased in network excitability) \u2013 when the active electrode generates a negative potential . Repetitive transcranial magnetic stimulation (rTMS) is another therapeutic tool that can contribute to the modulation and reconfiguration of different cortical areas. In contrast to tDCS, rTMS results in the induction of action potentials and depolarization of the neuronal membrane. The principle of transcranial magnetic stimulation is to produce a perpendicular magnetic field, by a stimulating coil, which induces an electric field, which, in contact with the cerebral tissue, is transmitted as an electric current, parallel to the generating coil. The depth of the stimulation depends on the type of coil and the intensity of the stimulation. The excitatory or inhibitory effect is correlated with the frequency of rTMS: high frequencies (\u2265 5 Hz) are excitatory, while low frequencies (\u2264 1 Hz) are inhibitory . By modulating cortical excitability with respect to neural plasticity, these two non-invasive brain stimulation (NIBS) techniques represent potential therapeutic tools in recovery after stroke [10-14]. This model suggests that the balance between the left and the right hemisphere of stroke patients is altered by an increased interhemispheric inhibition from the unaffected hemisphere to the affected hemisphere. Accordingly, a therapeutic effect may be obtained either by increasing the excitability of the affected hemisphere, or by decreasing the excitability of the unaffected hemisphere [10]. The mechanism of excitability enhancement in the motor cortex underlies the motor learning and the use-dependent plasticity, which are impaired in the affected hemisphere. Other positive effects of the NIBS are the enhancement of neural coupling between the primary and secondary motor areas in the affected hemisphere, the reduction of the hyperactivity in the primary and secondary motor areas in the unaffected hemisphere, and the excitability modulation in both hemispheres [10].There are two main directions of NIBS treatment in neurorehabilitation: the motor deficit and the speech disorders. The improvement of motor and language performances is based on interhemispheric competition theory [15]. The major disadvantage is the deterioration of bimanual movement due to the reduction of transcallosal inhibition that controls that kind of movement. This possible consequence may be prevented by applying a low frequency rTMS concomitant with anodal tDCS over the affected hemisphere [16]. The neural modulation induced by NIBS and the improvement of motor and speech deficits can be sustained by subsequent motor training and speech therapies .The advantages of inhibitory NIBS over the intact hemisphere are the uniform response and the lower risk of potential epileptic seizures, which are more probably to appear after rTMS in the infarcted area . The genetic polymorphism can be involved and may explain the different response of stroke patients to this therapy. BDNF is one of the factors strongly involved in synaptic plasticity of the human motor cortex [9]. The consequence of BDNF val66met, a common single nucleotide polymorphism, is the reduced secretion of BDNF [19]. This is clinically expressed by a poorer retention in short-term motor learning and slower cognitive and motor recovery . Therewith, the individual variation in response to rTMS may be explained by the difference in BDNF concentration [20]. Although it was demonstrated that the early rehabilitation facilitates motor recovery after stroke, the application of NIBS in acute stages is controversial [21]. In this respect, a recent Cochrane meta-analysis evaluated the efficacy and safety of rTMS in recovery after stroke regardless of the duration of illness [22]. Nineteen randomized controlled trials (RCTs) with a total of 588 patients were included. Even if the rTMS treatment was not associated with a significant improvement in activities of daily living, or a significant improvement of motor function, a positive trend was noted, larger and homogeneous RCTs being needed in order to confirm the results [22]. The majority of the clinical studies evaluating the role of rTMS in rehabilitation were performed in subacute and chronic stroke patients, few data being available for acute stroke [22]. Also, epileptiform discharge on EEG and seizures, can be noted especially after high-frequency rTMS (10 Hz) [11].The most encountered adverse events reported in clinical trials evaluating rTMS are transient or mild headache (2.4%), anxiety (0.3%), neurocardiogenic syncope after initial exposure to rTMS (0.6%), exacerbation of pre-existing insomnia (0.3%) and local discomfort at the site of the stimulation [23]. In 2005, Khedr and colab. applied 3 Hz, in 10 daily stimulation sessions on the affected side in 26 patients with acute cortical stroke and in 26 patients with acute subcortical stroke (recruited between the fifth and tenth day post-stroke). The evaluation of motor recovery showed an improved function in the paretic hand in both groups [24]. Liepert and colab. showed that one session of 1 Hz rTMS therapy on the contralesional hemisphere in 12 patients with acute subcortical stroke (mean 7 days), disclosed an enhancement in the hand functioning at Nine Hole Peg Test (a transient improved dexterity of the affected hand), but no change in the grip strength [25]. In 2010 Khedr and colab. published another study on 48 acute stroke patients which supported 3 Hz, 130% resting motor threshold intensity, or 10 Hz, 100% resting motor threshold intensity, in 5 daily stimulation sessions on the ipsilateral hemisphere. The improved hand function persisted for 12 months after rTMS treatment [26]. Participants were divided in two groups \u2013 the study group (5 patients) \u2013 stimulated in the right pars triangularis, and the control group (5 patients) \u2013 stimulated in vertex (sham stimulation). The results pointed out an improvement of Aachen Aphasia Test (AAT) scores in patients from the study group, but not in those with sham stimulation. Compared with baseline, a larger activation index was observed on PET scan in the right hemisphere in the control group compared with the study group, 2 weeks after rTMS, suggesting that inhibitory magnetic stimulation of the right-hemispheric Broca homologue followed by SLT might be a feasible and effective complementary therapy for post stroke aphasia [26]. Weiduschat studied the effect of 1 Hz rTMS stimulation together with subsequent speech and language therapy (SLT) in 10 right-handed patients at 16 weeks after stroke [27]. The patients were included between 2-12 weeks after the onset. This group was compared with a sham stimulation group . The assessment included Computerized Picture Naming Test, Boston Diagnostic Aphasia Examination and Aphasia Severity Rating Scale. After a follow-up period of 15 weeks, no differences in naming accuracy between the two groups were noted, but reaction time was slightly faster in real rTMS group [27].Waldowski and collab. studied the effects of 1 Hz rTMS over pars triangularis and pars opercularis from the right inferior frontal gyrus (IFG), followed by 45 min/ day SLT, in 13 right-handed patients with aphasia [18]. Forty patients received 3 weeks of motor training on the paretic upper limb (45 minutes daily) preceded by 30 minutes of 1 Hz rTMS (stimulated group) or by 30 minutes of sham rTMS over the contralesional M1 (control group). The functional assessment of the paretic hand (by Wolf Motor Function Test and NIHSS) performed before, immediately after and at the 3 months follow-up revealed no statistically significant differences between the two groups [18]. In a randomized, sham-controlled, double-blind study, Seni\u00f3w and colab. evaluated the association of low-frequency rTMS of the contralesional M1 area with physiotherapy [13]. In 2013, Heiss et al. analyzed for the first time the consequences of the inhibitory NIBS over the contralesional IFG in left-handed aphasic patients. They reported the results of a randomized controlled trial comparing the effect of combined rTMS/ SLT in 29 right-handed patients with left hemisphere infarcts and 2 left-handed patients with right hemisphere infarcts. The start of treatment was between 25 and 93 days after stroke onset. Fifteen right-handed patients received 10 sessions of inhibitory 1 Hz rTMS over the triangular part of the right IFG (20 min each) followed by 10 sessions of SLT, while 14 right-handers with heterogeneous aphasia forms received 10 sessions of 20 min rTMS over the midline at the vertex (sham stimulation). Two left-handers were treated according to the same protocol with real rTMS over the left hemisphere. The speech performance was evaluated by AAT, and the language activation patterns were assessed with PET scan prior to and after the treatment. The results showed better recovery of language function in right-handed patients after real rTMS than in sham-treated right-handers. Furthermore, a shift of network activity towards the left, ipsilesional hemisphere was observed in treated right-handers, while the sham group maintained the activation in the contralesional hemisphere. Both left-handed volunteers also improved, the PET scan showing a very small interhemispheric shift (less than in rTMS-treated right-handers) and a consolidation of active networks in both hemispheres [12]. In both groups, the inhibitory NIBS was followed by SLT 45 min/ day. The global AAT and naming subtests disclosed better scores, which correlated with a PET activation in the left hemisphere in rTMS group post-treatment compared to the sham group [12]. Another RCT compared the effect of 1 Hz real rTMS versus sham stimulation over the right pars triangularis, in 24 patients suffering of subacute stroke [28]. The tDCS was initiated 4 to 8 weeks after stroke onset. Each of the 6 daily stimulation sessions was followed by a robot-assisted arm training. Motor arm function was assessed with the Fugl-Meyer motor score and language impairment with the AAT. The motor function improved in all patients (in a significant manner in 3 cases), and aphasia improved in 4 patients [28]. Hesse and colab. evaluated the role of anodal tDCS on the ipsilesional side in the recovery after stroke in 10 patients [29]. In all patients, the reference electrode was placed on the contralateral supraorbital region, the sessions of stimulation lasted 30 min/ day for 10 days and were completed by online SLT. The application of Korean-Western Aphasia Battery evidenced a significant improvement in auditory verbal comprehension after right cathodal tDCS compared to sham and left anodal tDCS, with an overall improvement in Aphasia Quontient and spontaneous speech across groups [29]. In 2011, You and collab. evaluated the role of tDCS in 21 aphasic patients with subacute stroke divided in 3 equal groups: the patients in the first group received anodal tDCS on the left Wernicke\u2019s area , the subjects from the second group received cathodal tDCS on the right Wernicke\u2019s area and the other 7 participants were sham stimulated [NIBS could be a useful therapeutic tool in the early rehabilitation after stroke. Both methods may enhance the neuroplasticity in the injured area and reestablish the balance between different regions of the brain. The association with specific motor tasks and SLT reinforces the effect of NIBS and partially restores the damaged neural networks.Larger RCTs are needed in order to confirm the effectiveness of NIBS, but the small clinical studies published so far showed encouraging results in motor and speech recovery."} +{"text": "Previous studies reported that patients in end-of-life (EOL) care may still receive aggressive treatment in the Intensive Care Unit (ICU). Despite To characterize factors associated with death in the ICU in patients accompanied by a palliative care team (PCT) in a tertiary private hospital in Brazil.Retrospective analysis of prospectively collected data based on a standardized questionnaire of PCT. All 628 questionnaires from June 2008 to December 2013 were included. Two groups were compared: patients that eventually died in the ICU versus patients that died outside the ICU.Out of 443 patients who died; 76 12.1%) died in ICU and 367 (58.4%) outside the ICU setting. a comparison between groups is shown in Table 2.1% diedNon-cancer patients died more frequently in the ICU (p = 0.03). We observed the presence of conflicts among patients who died in ICU: conflicts between family members (family-family conflicts) and between family and the attending physician (family-physician conflicts) were equally common, but there were a significant number of conflicts originating between family and nurse staff Figure .Figure 1Explicit directives of EOL care were more commonly explicitly written in non-ICU patients . As expected, we also observed that a remarkable percentage of ICU patients received advanced life support until death (42%). There were no association between death in the ICU and age, late PCT consultation (less than 3 days before death) and prolonged hospitalization .Circumstances associated with death in the ICU of patients assisted by PCT included a non-cancer diagnosis, conflicts as reason to referral, being in the ICU or receiving life support at the time of the initiation of PCT consultation, and the lack of written advanced directives of EOL care. Further studies are needed to evaluate whether modifying these circumstances may be related to a different EOL care."} +{"text": "World leaders remain committed to globally-coordinated oral poliovirus vaccine (OPV) cessation following successful eradication of wild polioviruses, but the best timing and strategy for implementation depend on existing and emerging conditions.Using an existing integrated global poliovirus risk management model, we explore alternatives to the current timing plan of coordinated cessation of each OPV serotype . We assume the current timing plan involves OPV2 cessation in 2016 followed by OPV1 and OPV3 cessation in 2019 and we compare this to alternative timing options, including cessation of all three serotypes in 2018 or 2019, and cessation of both OPV2 and OPV3 in 2017 followed by OPV1 in 2019.If Supplemtal Immunization Activity frequency remains sufficiently high through cessation of the last OPV serotype, then all OPV cessation timing options prevent circulating vaccine-derived poliovirus (cVDPV) outbreaks after OPV cessation of any serotype. The various OPV cessation timing options result in relatively modest differences in expected vaccine-associated paralytic poliomyelitis cases and expected total of approximately 10\u201313 billion polio vaccine doses used. However, the expected amounts of vaccine of different OPV formulations needed changes dramatically with each OPV cessation timing option. Overall health economic impacts remain limited for timing options that only change the OPV formulation but preserve the currently planned year for cessation of the last OPV serotype and the global introduction of inactivated poliovirus vaccine (IPV) introduction. Earlier cessation of the last OPV serotype or later global IPV introduction yield approximately $1 billion in incremental net benefits due to saved vaccination costs, although the logistics of implementation of OPV cessation remain uncertain and challenging.All countries should maintain the highest possible levels of population immunity to transmission for each poliovirus serotype prior to the coordinated cessation of the OPV serotype to manage cVDPV risks. If OPV2 cessation gets delayed, then global health leaders should consider other OPV cessation timing options. The Global Polio Eradication Initiative (GPEI) continues to make progress toward the primary goal of interrupting all global transmission of the three wild poliovirus (WPV) serotypes . After aOPV comes in different formulations. Trivalent OPV (tOPV) protects against all three serotypes and represents the current vaccine of choice for OPV RI and the vaccine used for SIAs up until 2004. In 2005, the GPEI began using serotype 1 monovalent OPV (mOPV1) and later some serotype 3 (mOPV3) for some SIAs, because of their higher seroconversion for the mOPV serotype than achieved by the same serotype component of tOPV, particularly for the first dose , 16. In The inactivated poliovirus vaccine (IPV) currently represents the only vaccine alternative to OPV. While the killed, injectable IPV provides very good individual protection from paralytic poliomyelitis and boosts intestinal immunity in individuals with immunity from a prior live poliovirus infection , it does not protect as well against asymptomatic participation in poliovirus transmission\u00a0as OPV, particularly in settings with more intense fecal-oral transmission, and it does not spread beyond the vaccine recipient \u201328. ConsRecognizing the risks associated with OPV2 cessation, the GPEI established 6 prerequisites for OPV2 cessation, including the need to validate the elimination of persistent cVDPV2s , which rWe use an integrated global model of long-term poliovirus risk management options described in detail elsewhere . Brieflystatus quo of OPV use in most countries to characterize incremental cost-effectiveness ratios (ICERs) and incremental net benefits (INBs) using 2013 United States dollars ($). The global model estimates financial costs associated with RI and SIAs, including any outbreak response SIAs (oSIAs) before and after OPV cessation [The global model estimateessation . The gloessation and the essation , includiessation and emphTo model the global population and poliovirus transmission, the global model assumes Table\u00a0status quo) option assumes OPV2 cessation on April 1, 2016, consistent with the current target date [All options assume tOPV intensification from January 1, 2015 characterized by an increased proportion of planned, preventive SIAs using tOPV instead of bOPV , 39. Theget date , and OPVget date . For theget date , 39 untiget date , 39, whiget date and the Due to the assumed sufficiently high frequency of SIAs leading up to OPV cessation of any serotype for all OPV cessation options, none of the options lead to any subsequent cVDPV cases. With only a small number of paralytic cases from WPV1 remaining in the model during the first year of the time horizon , VAPP cases represent the main source of paralytic poliomyelitis in the model for 2015\u20132019. Table\u00a0With respect to vaccine dose estimates, our results include the entire world , assume relatively high effective wastage, and assume sustained high SIA frequency up until cessation of the last OPV serotype . Most scTable\u00a0The INBs represent a more informative metric for this analysis. OPV23 cessation in 2017, OPV123 cessation in 2019, and OPV123 cessation in 2019 with tOPV-only from 2017 all result in the same expected financial costs for vaccination as the current timing plan because they involve different OPV formulations without affecting the overall duration of OPV or IPV use in any of the income levels. Thus, for these alternative OPV cessation timing options the incremental costs reflect only treatment costs (or savings) associated with additional incurred (or prevented) paralytic cases. Given the relatively small number of paralytic cases involved in any of these options, their INBs remain close to 0. The INB estimate of approximately -$4.5 million for OPV123 cessation in 2019 (with or without tOPV-only from 2017) suggests that if the excluded logistical costs of coordinating OPV cessation once instead of twice amount to more than $4 million , then some economic justification exists for this original path of coordinated OPV cessation of all three OPV serotypes. OPV123 cessation in 2019 with tOPV-only from 2017 yields almost the same INBs as OPV123 cessation in 2019, which involves some continued bOPV SIAs , because the cases would occur for all OPV cessation timing options. However, longer transmission of WPV1 and/or cVDPV2 will affect the feasibility of some of the options and expected SIA frequency and costs. Some reduction in SIA frequency may remain sufficient to keep population immunity high enough to avoid cVDPVs after OPV cessation, although too much reduction or inconsistency in SIA quality would result in cVDPVs , and insOur analysis leads to the realization that flexibility in national vaccine licensing for the transition period may prove helpful. While under the current plan the GPEI continues to encourage countries to pursue licenses of bOPV for RI use after OPV2 cessation, our analysis suggests potential value in simultaneously pursuing national licenses for RI use of bOPV or mOPV1, and potentially also securing licenses now to use any mOPV serotype for outbreak response if ever needed. In addition, given uncertainty about the status of population immunity for serotype 2, our results underscore the importance of developing contingencies with manufacturers to continue tOPV production past the current planned OPV2 cessation target of April 2016.All countries should maintain the highest possible levels of population immunity to transmission for each poliovirus serotype prior to the coordinated cessation of the OPV serotype. If OPV2 cessation gets delayed, then global health leaders should consider other OPV cessation timing options."} +{"text": "The fat signal can lead to misinterpretation and poor visualization of epicardial enhancement. In previous work fat was suppressed by using two appropriately timed fat-selective RF pulses which re-invert and invert fat signal but this technique was sensitive to off-resonance and heart rate variations. The goal of the present work is to make two improvements to fat-saturated LGE: (1) increase robustness against B0 and B1 variations by using asymmetric adiabatic RF pulses, and (2) increase robustness against heart rate variations through dynamic timing of fat-selective RF pulses.Late Gadolinium Enhancement (LGE) allows imaging of infarction and cardiomyopathies by measuring the accumulation of contrast agent within the myocardium. The shortened T1 (10\u03bcT) and pulse duration (40 ms). Mz magnetization depends on the repetition time of the IR pulse and therefore in cardiac gated sequences depends on the patient heart rate. Heart rate variation leads to a shifting of the inversion time (TIfat) at which the fat signal is nulled. Therefore a heart rate independent nulling of fat signal was developed by measuring the length of each R-R interval during the examination and time-shifting the fat-selective inversion pulse accordingly and 3.0T (300 ms). With appropriate TI selection the technique led to nulling of signal from healthy myocardium and from fat. The cases without contrast injection had poor blood-myocardium contrast due to the lack of Gd but fatBenefits of fat-saturated LGE imaging include avoiding image wrapping of subcutaneous fat and therefore reduced possible misdiagnosis Figure ), and in"} +{"text": "It was more effective following vaccination with live than killed vaccines. In conclusion, application of synbiotic Biomin Imbo, as a feed-additive adjuvant promotes acquired humoral immune responses of broiler chickens. Increased susceptibility of birds to avian pathogens in intensive husbandry system has emphasized on necessity of improvement of innate and specific immune responses of birds by the fast establishment of a beneficial microflora and immune stimulator factors to guarantee healthy and low-price products. During this study, 192 one-day-old broiler chicks (Ross-380) in four groups with three replicates per group were used to investigate effectiveness of synbiotic Biomin Imbo on immune responses of the chickens following routine vaccination against Newcastle disease (ND), avian influenza (AI), infectious bronchitis (IB) and infectious bursal disease (IBD). The results of this study indicated that supplementation of Biomin Imbo in diet enhanced humoral immune responses significantly in the case of ND, IB, IBD ( Finding novel antigens as well as adjuvants is the most beneficial methods to induce an optimal protective immunity against human1 and poultry diseases including avian infectious bronchitis (IB), infectious bursal disease (IBD), Newcastle disease (ND) and avian influenza (AI) which cause significant economic losses in poultry industry worldwide.2,3 Interest in the dietary use of prebiotics and probiotics blossomed in the late 1800s/ early 1900 and the growing enthusiasm on the beneficial effects of pre-, pro- and synbiotics was motivated near the turn of the 20th century.4 Ban of antibiotic growth promoters (AGPs) due to increased bacterial resistance and drug residues in poultry production together with consumer's demand for \"natural\" products have encouraged findings of alternatives for AGP. In order to preserve gut microbiota and to promote host innate defenses, administration of synbiotic as alternative approach for promoting of performance and immune responses in modern poultry husbandry widely accepted.5,6 Probiotics affect the intestinal microbial balance and subsequently improve performance and reduce mortality in broiler chickens.7,8 Probiotics also protect chickens against avian pathogens,9,10 activate immunocytes and stimulate systemic immune responses11 including promoting the endogenous host defense mechanisms12 and enhancement of production natural antibodies13 as well as specific antibodies.14 On the other hand, prebiotics may control or manipulate microbial composition and/or activity, therefore combination of probiotics and prebiotics improve the survival rate of probiotics in digestive tract contributing to the stabilisation and/or enhancement of the probiotic effects.15,16 Under the present circumstances, improvement of post-vaccination immune responses against the most economically important poultry diseases, in particular IB, IBD, ND and AI is topic for research. Ideologically, synbiotics would have more beneficial effects than these elements alone.17-20 Therefore, the present project was undertaken to study the immuno-modulatory effects of the synbiotic Biomin Imbo on antibody responses during a routine vaccination of broiler chickens against IB, IBD, ND and AI as well as to compare its immunomodulatory effectiveness in vaccination with live and killed vaccines.In the 21Chickens and experimental design. One hundred and ninety-two one-day-old broiler chicks (Ross-308 strain) were randomly allocated into four groups: (A) vaccinated + diet containing Biomin Imbo, (B) vaccinated + diet not-containing Biomin Imbo, (C) environmental control (unvaccinated + diet without Biomin Imbo), and (D) Biomin control (unvaccinated + diet containing Biomin Imbo). Three replicates were considered for each group (16 chicks per replicate). After leg labeling, the chicks of each replicate were housed in separated boxes and nutritional requirements , ambient temperature, lighting, ventilation as well as other environmental conditions fully met the requirements laid down in the technical instructions of Ross-308 broiler management.21 Vaccinated groups (A and B) and unvaccinated groups (C and D) were kept in separated houses.Enterococcus facium IMB 52; 5 \u00d7 1011 CFU per kg), cell wall fragments of useful micro-organisms, prebiotic (fructo-oligosaccharides) and phycophytics was used as recommended by manufacturer . Synbiotic Biomin Imbo containing of probiotic level (below log2-3), chickens of the groups A and B were vaccinated and on 11-days and second vaccination (only live vaccine) was carried out on 21-days of age using clone 30 strain of ND virus by eye-drop route as a recommended route inducing higher antibody titer with the closest-rang.22 In the case of AI, one vaccination is carried out on 11-days-old using killed (H9N2) vaccine by subcutaneous injection as a routine vaccination for broilers in the region. In the case of IBD, optimal time for first vaccination was estimated3 and D78 vaccine was used on day 16 and repeated on day 24 of age (based on MDA of the chicks). In the case of IB, as protection significantly (p < 0.05) correlated with levels of local respiratory antibody and not with serum antibody23 therefore, regardless to the potential negative effects of MDA against IB virus, Ma5 vaccine was used via eye-drop for vaccination of one-day-old chicks against IB on day 1 and is repeated on day 18 of age using the same vaccine.2,24Sampling. As level of MDA titer is very important for determination of the best timing of vaccination against IBD as well as ND. On day 1 (one-day-old chicks), blood samples were collected from half the chicks of each replicate as previously described.25,26 On day 7 and then at weekly intervals until 42 days of age, blood samples were collected from jugular veins and brachial vein, respectively as previously described.27,Serum antibody titers assessment. Antibody level was determined using weekly serum samples of each bird separately in each replicate and treatment. Hemagglutination inhibition test (HI) was used for evaluation of antibody titers against ND and AI, as it has been reported that HI test is an excellent indicator of the immune status and disease resistance of a flock especially to assess protective response following vaccination,27,28 while the indirect enzyme-linked immunosorbent assay was used for evaluation of antibody titers as recommended for IB29 and IBD.3,29,30Statistical analysis. SPSS software was used for analyzing of the results under completely randomized design employing one-way ANOVA analysis of variance and the means of different treatments were compared with Bonferroni, Duncan multiple range and repeated measure tests. Significance differences were taken at p < 0.05 level. Newcastle disease antibody titer. Antibody titers against ND of the chickens of different groups are shown in Avian influenza antibody titer. Antibody titers of the chickens against AI are shown in p = 0.160).Infectious bronchitis antibody titer. Status of MDA and acquired antibody titer against avian infectious bronchitis are shown in nd vaccination and peaked around 42 day of age. In comparison to groups A and B (vaccinated groups), antibody titers of chickens treated with Biomin Imbo (group A) differed significantly (p = 0.020) from those of group B during day 28 to end of experiment antibody titer than those of vaccinated but not treated with Biomin Imbo diet. 31,32 but also leads to immuno-modulation of humoral immune responses as well as cellular immune responses,33 however debates on their potential side effects (cytotoxic and moderate genotoxic effects) is open.34 Comparison of a growth promoters, prebiotics, probiotics as well as synbiotics on their preventive effects in colonization of salmonella in poultry revealed that antimicrobial agents allowed higher colonization as compared to prebiotics and probiotics,9 but Biomin controls the intestinal colonization of Salmonella enteritidis in chickens.35In general, dietary supplementation of synbiotic Biomin Imbo not only ameliorate performance of poultryEnterococcus faecium) of Biomin Imbo enhances humoral immune responses against sheep red blood cells (SRBC).36 Biomin Imbo also increases most parameters of blood profile including total protein37 and higher protein promotes induction of specific antibody titer against avian pathogens. Dietary inclusion of synbiotic Biomin Imbo increased growth performance and improved intestinal morphology, nutrient absorption38 and resistance of birds to pathogens or diseases.37 Comparison of the synbiotic with another probiotic indicated that the synbiotic had much more beneficial effects than probiotic alone5 as well as prebiotics alone39 or AGP alone.40 Enhanced effects of Biomin Imbo on antibody titers of the chickens against ND, AI, IB and IBD were observed during this study and is in agreement with previous reports that the serum antibody responses to oral and systemic administration of antigens were significantly enhanced by probiotics supplementation.41 Due to the immunomuadulatory effects of vitamin E, future synbiotics may include vitamin E as well.42With regards to immunomodulatory effects of Biomin Imbo, there are some reports that probiotic (nd vaccination). Analyzing of the results, as shown in p = 0.100) until 21 day of age; b) From day 21 up to end of the experiment, difference between vaccinated and unvaccinated groups due to vaccination was significant (p = 0.010); c) Comparison between antibody titers of chickens of group A (vaccinated and treated with Biomin Imbo) and those of chickens of group B (vaccinated but not treated with Biomin Imbo) was significant on the day 35 (p = 0.049) and on the day 42 (p = 0.048) of age. Continuously reduction of ND antibody titer of chickens of unvaccinated groups (C and D) and its remaining at undetectable level during experimental period confirmed that neither environmental nor cross contamination had occurred. Antibody titers of vaccinated chickens (groups A and B) increased following first vaccination (live + killed) and reached the highest level on day 35 of age is the highest available titer that could be induced by vaccinations (two live + one killed vaccines) as mean titers 4 to 6 log2 for single live and at least log2-8 for live plus killed vaccine was reported by OIE.43 Higher ND titers of chickens treated by Biomin Imbo is observed in our study is also in agreement with those of log2-7.2 and mean titer of log2-7.5 was reported for mentofin treated chickens.44 The beneficial effects of Biomin Imbo could be more evident in undesirable circumstances due to intensive husbandry systems. However, the enhancement effects of Biomin Imbo on humoral immune responses against ND observed during this study is also been reported for an another probiotics14 as well as other synbiotics.The results obtained during this study is in agp = 0.150) until 21 day of age; b) From day 21 up to end of the experiment, difference between vaccinated and unvaccinated groups due to vaccination was significant (p = 0.020); c) Difference between group A (vaccinated and treated with Biomin Imbo) and group B (vaccinated but not treated with Biomin Imbo) was not significant (p = 0.160). Regarding lack of significant increasing effects of Biomin in the case of AI, it may be attributed to the mechanism of this product on providing a better condition for multiplication of live vaccines whereas a killed vaccine was used in the case of AI. High antibody titers observed during this study (-5.6) of chicken group A could be attributed to enhancement effects of Biomin Imbo on antibody titers of the chickens as it has been reported that optimal nutritional status may enhance immune function indicated by increased vaccine response following vaccination against influenza.37,45As shown in is study for chic24 As shown in p < 0.05).33 As maternal IBV antibodies are in low concentrations in the tear secretions than in sera, therefore, the interference between MDA and virus of vaccine may happen in a very low level. However, in the eye-drop or spray routes, invasion of the gland by virus of vaccine without the involvement of blood borne circulation after infection by the conjunctival and intranasal routes, would explain why the high levels of MDA of one-day-old chicks did not impair immunization.46 Lack of rising of antibody titers of unvaccinated chickens (groups C and D) during experimental period indicated that there was neither environmental nor cross contamination. Late rising of antibody titer (28 days post-1st vaccination and 10 days post-2nd vaccination) of the vaccinated chickens (groups A and B) and reaching the highest level at six weeks age were observed during this study is in agreement with the studies reporting that antibody peaked around 45 day of age following vaccination on day 1 and on day 25. Our observation on enhancement effects of Biomin Imbo on humoral response against IB is in agreement with the results reported for an another synbiotic.33 Recent studies indicate that supplementation of vitamin E may also enhances higher immune responses against IB.42Humoral immunity has a key role in protection of chickens against IB.3 Maternally-derived antibody transferring rate (up to 73.00%) from breeders to yolk/chicks not only varied among different chickens' line but also MDA varied among one-day-old chicks even from same broiler breeder flock47 and depending on the range of MDA, finding optimal timing of primary vaccination would be too difficult. Although there are several methods for predicting the timing of initial vaccination,30,48 in routine vaccination program for intensive poultry husbandry system, primary vaccination against IBD may equalized MDA of the chicks and good immune response may be obtained following booster dose. Generally, infectious bursal disease with clinical signs occurs around three to six weeks of age3 and the birds are most susceptible at 30 to 35 days old. Therefore, an ideal vaccination program must induce protective antibody titer at this age as occurred during this study Differences among the groups were not significant (p = 0.100) until day 28 of age; b) From day 28 up to end of the experiment, difference between vaccinated and unvaccinated groups due to vaccination was significant (p = 0.020); c) Difference between group A (vaccinated and treated with Biomin Imbo) and group B (vaccinated but not treated with Biomin Imbo) was significant (p = 0.036) only on day 42 of age. Humoral antibody plays a key role in protection against IBD.is study and IBD In conclusion, Application of synbiotic Biomin Imbo enhances antibody responses following vaccination against ND, AI, IB and IBD but it is more effective in live than killed vaccines and could be used as a feed-additive adjuvant for improving innate and acquired immune responses in chickens."} +{"text": "We also update the information about the inhibition properties of single pgip gene products against microbial PGs and the results, including field tests, showing the capacity of PGIP to protect crop plants against fungal, oomycetes and bacterial pathogens.Polygalacturonase inhibiting proteins (PGIPs) are cell wall proteins that inhibit the pectin-depolymerizing activity of polygalacturonases secreted by microbial pathogens and insects. These ubiquitous inhibitors have a leucine-rich repeat structure that is strongly conserved in monocot and dicot plants. Previous reviews have summarized the importance of PGIP in plant defense and the structural basis of PG-PGIP interaction; here we update the current knowledge about PGIPs with the recent findings on the composition and evolution of To this end, pathogens produce a wide array of plant cell wall degrading enzymes (CWDEs), among which endo-polygalacturonases are secreted at very early stages of the infection process . Most of these genes have been identified as pgip genes on the basis of sequence identity but only a few of them have been shown to encode proteins with PG-inhibitory activity.Early characterization of a polygalacturonase-inhibiting activity was reported in 1970s . These proteins do not interact in vitro, although VvPGIP1 reduces symptoms caused by BcPG2 upon co-infiltration in leaves. The number and sources of PGs tested is also limited; only a few studies have been carried out against PGs of bacteria and insects possessing non functional pgip genes . Recently, a wheat gene with some sequence similarity to pgip genes has been reported and was shown to be involved in the defense response against Fusarium graminearum forms with PG from A. niger (AnPGII), F. phyllophilum (FpPG) and C. lupini (ClPG). Site-directed mutagenesis has shown that the residues involved in the interaction are located in the concave surface of the inhibitor suggesting that the protein is highly versatile in recognizing different epitopes of various PGs Bnpgip1 or Bnpgip2. Arabidopsis plants overexpressing Atpgip1 or Atpgip2 showed a significant reduction of disease symptoms caused by B. cinerea PGIP (PcPGIP) capable of inhibiting the PGs secreted by B. cinerea, showed a reduction of disease lesions caused by this fungus both on ripening fruit (15% reduction) and leaves (about 25% reduction). The initial establishment of infection was not affected in the transgenic plants but the later colonization of the host tissue was significantly reduced , Vvpgip1 (from V. vinifera), Capgip1 [from pepper (Capsicum annum)] and Brpgip2 (from B. rapa) have been obtained in transgenic tobacco. Plants expressing PvPGIP2 showed about 35% reduction of symptoms caused by B. cinerea that are highly resistant to blue mold disease. These transgenic plants expressing PvPGIP2 represented the first example of PGIP-expressing plants subjected to field trails. Recently, transgenic rice expressing OsPGIP1 showed also improved resistance against Rhizoctonia solani in field experiments caused by Solanum tuberosum) plants expressing the gene StPGIP1 from S. torvum showed a 50% reduction of wilt disease symptoms caused by Verticillium dahliae and a normal plant growth plants constitutively expressing the pear PcPGIP gene represent an interesting example of the potential of PGIP for protection against pathogens other than fungi and oomycetes. These plants show a delayed development of the Pierce's disease (PD) caused by bacterial pathogen Xylella fastidiosa of the symptoms as compared to wild-type plants plants overexpressing BrPGIP2 showed higher resistance against P. carotovorum and produced normal looking pods-like structures with no viable seeds. Combination of crossing with non-transgenic plants did not restore fertility of the transgenic plants, suggesting that mechanisms such as ploidy changes occurring during the tissue culture stage or changes in cell-wall architecture of sexual organs are responsible for the abnormality , transformed with Ripgip from raspberry (Rubus idaeus L.) and apple transformed with pear PcPGIP transformed with bean Pvpgip2 transformed with bean Pvpgip1 to transform both durum and bread wheat by particle bombardment. PvPGIP2 was correctly targeted to the apoplast and the transgenic plants did not show any major morphological and growth defects. Transgenic wheat showed a significant reduction (46\u201350%) of foliar spot blotch symptoms caused by the hemibiotrophic fungal pathogen Bipolaris sorokiniana and improved resistance (25\u201330%) against the hemibiotrophic fungal pathogen F. graminearum E3 ligase that is involved in several stress responses, including Pi starvation, and flowering (Sato and Miura, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Different reports of shared manifestations for malignancy and rheumatic diseases in children since 1970s indicate the presentation of malignancies, particularly ALL, with musculoskeletal (MS) symptoms.To evaluate the rate and the characteristics of hematological malignancies in Iranian children with joint manifestations based on two different scopes of data collection since 1981.In this retrospective review, we considered two different aspects of evaluation within two pediatric tertiary centers in Iran: 1- Children's Hematology/Oncology Research Center, 2- Pediatric Rheumatology Center.Here we report the results of 3 studies conducted through 1981-2006, followed by current (IV) study performed since 2006. Findings of four different studies are mentioned in detail, in Table The relative increase in the rate of malignancy in this review (period of 1981-2012) could be an alarm to perform BM aspiration in children with joint manifestations harboring the following as \"Red Flags\": (i) Boys at the age of 5-7, (ii) Large joint involvement and (iii) Arthralgia at presentation. According to recent recommendations by ACR for early aggressive treatments in JIA patients, this precautionary measure may minimize the potential dangers and consequences of misdiagnosis prior to initiation of any treatment.None declared."} +{"text": "Glycine max) because of ruptured cell walls. Using RNA-Seq, we examined the seed coat transcriptome from three stages of immature seed development in two pairs of isolines with normal or defective seed coat phenotypes due to the net pattern. The genome-wide comparative study of the transcript profiles of these isolines revealed 364 differentially expressed genes in common between the two varieties that were further divided into different broad functional categories. Genes related to cell wall processes accounted for 19% of the differentially expressed genes in the middle developmental stage of 100\u2013200 mg seed weight. Within this class, the cell wall proline-rich and glycine-rich protein genes were highly differentially expressed in both genetic backgrounds. Other genes that showed significant expression changes in each of the isoline pairs at the 100\u2013200 mg seed weight stage were xylem serine proteinase, fasciclin-related genes, auxin and stress response related genes, TRANSPARENT TESTA 1 (TT1) and other transcription factors. The mutant appears to shift the timing of either the increase or decrease in the levels of some of the transcripts. The analysis of these data sets reveals the physiological changes that the seed coat undergoes during the formation of the breaks in the cell wall.The plant cell wall performs a number of essential functions including providing shape to many different cell types and serving as a defense against potential pathogens. The net pattern mutation creates breaks in the seed coat of soybean ( Plant cells are surrounded by cell walls which provide tensile strength, mechanical support, protection from insects and pathogens, prevention of water loss, and that participate in cell to cell communication Glycine max) has been well characterized, and contains features in common with the majority of the legumes: an epidermal layer of palisade cells, or macrosclereids, a sub-epidermal layer of hourglass cells, or osteosclereids, a few layers of parenchyma, and an aleurone layer The seed coat, or testa, of the mature soybean of the cell wall leading to higher levels of this transcript in the defective seed coats at the middle weight range of 100\u2013200 mg seed weight The effect on PRP1 transcript levels was assumed to be a downstream effect of the net pattern mutation. In this report, we present the global gene expression analysis of the net pattern cell wall mutant in soybean using transcriptome analyses of three different stages of seed development at 50\u2013100 mg, 100\u2013200 mg, and 400\u2013500 mg. By comparing RNA-Seq data from the two lines containing the defective seed coat trait compared to their standard counterpart isolines using Bowtie alignments The isolines in the background of cultivar Clark are referred to as Clark standard (CS) which exhibits an intact seed coat and Clark defective (CD) that contains the defective seed coat mutation that had been backcrossed into the Clark standard line. Likewise, Harosoy standard (HS) is compared to the Harosoy defective (HD) isoline that contains the defective seed coat mutation. The genotypes and phenotypes of these two isoline pairs is presented in Next-generation high throughput sequencing of the transcriptome (RNA-Seq) was used and the cDNA libraries were constructed from seed coats from 50\u2013100 mg, 100\u2013200 mg and 400\u2013500 mg seed weight stages in standard and mutant isolines of Clark and Harosoy cultivars. Each library was sequenced on the Illumina GAII or HiSeq 2000 platforms. The number of raw sequence reads obtained from all four isolines, at different seed weight stages are presented in As presented in As shown in A selection of 29 of the 364 differentially expressed genes at the 100\u2013200 mg seed weight stage are shown in As presented in The expression levels of PRP1 and PRP2 at different seed weight stages were previously demonstrated by The graphical representations of the expression levels of the other differentially expressed genes shown in It is clear from the 68 graphs of the gene expression patterns shown in There were 21 hormone regulated genes that were differentially expressed in the seed coat of wild type and defective isolines of both Clark and Harosoy background includinThe expression pattern of two other hormone regulated genes in ie., if expression of a particular gene was higher in the standard isoline of Clark, then it was lower in the standard isoline of Harosoy) .Two zinc finger domain (C2H2 type) containing protein genes that had TT1 (TRANSPARENT TESTA1) annotations were approximately 6-fold and 15-fold more highly expressed in the defective seed coats of the Clark and Harosoy lines, respectively, at the 100\u2013200 mg seed weight stage & 4. TheAlong with the two TT1 gene models, there were 14 total transcription factor genes that showed differential expression in seed coats of standard and defective isolines in both of the Clark and Harosoy backgrounds at the 100\u2013200 mg stage . The mosWe provide an overview of the genes that are affected by the \u201cnet pattern\u201d mutation which affects the structural integrity of the soybean seed coat. As shown in Allergens, thaumatin-like proteins, and cysteine-rich domain containing proteins have also been reported to play important roles in various functions related to the cell wall While we have concentrated on the 51 cell wall related genes that were significantly differentially expressed in both varieties, we note that there are 920 additional cell wall related genes that did not show differential expression in the seed coats of either of the two isoline pairs. Thus, there are many processes related to the cell wall that are not affected at the transcript level by the net-pattern mutation.Auxin is a plant growth regulator that is required for cell expansion, division and differentiation. Auxin pathway related genes have been reported to regulate several cell wall related genes in Arabidopsis Glycine maxThe proline-rich proteins are composed of small tandem repeats such as PPVYK or PPVEK, where the second proline is often hydroxyproline I alleles), as compared to black Clark isolines . LikewisOur RNA-Seq data show excet al., WRKY transcription factors are involved in regulation of downstream genes encoding the NAM, ATAF1/2, and CUC2 (NAC) and CCCH type (C3H) zinc finger TFs that activate secondary wall synthesis Arabidopsis thaliana, these were expressed in specific cell types of roots, stems and seeds that undergo suberization Transcription factors are important players for controlling the flow of genetic information from DNA to RNA and ultimately affecting the growth and physiology of the plant. In this study, there were approximately 240 differentially expressed transcription factor genes at different seed weight stages \u2013S4. ThesIt is likely that the defective seed coat mutation in soybean sets in motion changes in many pathways related to the cell wall. Some of the differential expression may be a temporal shift in developmental appearances of transcripts. Notably, in the case of the TT1 homolog, it appears that the decline in its transcript levels was delayed in the defective seed coats relative to the standard seed coats , thus leGlycine max. There were approximately 1300 significantly differentially expressed genes affected by this mutation in each isoline pair with 364 in common between the two isolines of different genetic backgrounds. The cell wall structural protein genes including proline-rich proteins (PRP1 and PRP2) and glycine-rich proteins were among the transcripts affected by the mutation as well as a number of transcription factors. Some of the transcript patterns indicate that a developmental shift in timing of gene expression underpins the differential gene expression changes at mid-maturation as shown by graphical presentation of expression patterns for 82 out of 364 genes that were significantly differentially expressed in both the Clark and Harosoy backgrounds. In summary, the mutation appears to set in motion a complex series of events, many manifested at the transcript level, that lead to changes in physiology and ultimately structure of the cell wall. The information on potential candidate genes for this mutation and the regulated genes will not only be helpful in understanding cell wall physiology in soybean, but could also provide a platform for improvement in bioenergy crops like sorghum, maize and Miscanthus.We present an overview of genes whose expression was affected by the \u201cnet pattern\u201d mutation in soybean. Two isolines of different genetic backgrounds were used to understand physiology related to this mutation that causes defective cracks in the seed coats. Twelve samples representing three stages of seed coat development from each of the four lines were subjected to the power of next-generation sequencing to obtain millions of transcript reads that were mapped to all 78,773 high and low confidence gene models of Glycine max used in this study were a black seeded Clark line, Clark defective seed coat, Harosoy standard and Harosoy defective seed coat. The defective seed coat mutation was originally found in two PI (plant introduction) lines, PI 339.994 and PI423.730B and these lines were backcrossed to the black seeded Clark line (UC9) to create an isoline UC412 containing this mutation. The same mutation was also backcrossed into the Harosoy line to create an isoline UC508. The L or PI numbers represent the official USDA isoline or plant introduction numbers, respectively. The UC number is an internal number used by our laboratory. Detailed information on these lines is presented in The isolines of For RNA extraction, immature seeds were harvested over the course of several weeks. The individual seeds were pooled and sorted by weight. Following this, each seed was dissected, separating the cotyledon and embryo from the seed coat, and placed in separate 15-ml polypropylene centrifuge tubes . All tissue was then frozen in liquid nitrogen and placed in storage at \u221280\u00b0C until it could be lyophilized. RNA of seed coats of seeds from the 50\u2013100 mg, 100\u2013200 mg and 400\u2013500 mg seed weight stages of each isoline was extracted separately using the RNA for 5 ml volumes from \u223c30 mg (50\u2013100 mg and 100\u2013200 mg seed weight stage) and \u223c70 mg (400\u2013500 mg seed weight stage) dry weight. The modified protocol used here is based on the protocols of McCarty The 75 bp and 100bp reads were mapped to the 78,773 Glyma cDNA gene models (JGI/Phytozome) using Bowtie et al. Coding region gene models were collected from the masked soybean genome from Phytozome version 6.0 and the soybean genome version 1.0 GFF file of the soybean genome DESeq (available via Bioconductor) is an R package to analyze count data from high-throughput sequencing data such as RNA-Seq and test for differential expression 32P]dATP by random primer reaction method Total RNA was extracted from the frozen tissue including 4\u20135 day old soybean hypocotyls minus their cotyledons and seed coats of 100\u2013200 mg seeds from four lines using a standard phenol chloroform method with lithium chloride precipitation The data have been entered into Gene Expression Omnibus at that National Center for Biotechnology Information as Accession Series GSE54903.Figure S1The Distribution of Expression Levels in RPKMs of Differentially Expressed Genes in the Clark Isoline Pair at Three Different Seed Weight Stages. (A) 50\u2013100 mg in Clark Standard (B) 50\u2013100 mg in Clark Defective (C) 100\u2013200 mg in Clark Standard (D) 100\u2013200 mg in Clark Defective (E) 400\u2013500 mg Clark Standard (F) 400\u2013500 mg Clark Defective.(TIFF)Click here for additional data file.Figure S2The Distribution of Expression Levels of Differentially Expressed Genes in the Harosoy Isoline Pair at Three Different Seed Weight Stages. (A) 50\u2013100 mg in Harosy Standard (B) 50\u2013100 mg in Harosoy Defective (C) 100\u2013200 mg in Harosoy Standard (D) 100\u2013200 mg in Harosoy Defective (E) 400\u2013500 mg Harosoy Standard (F) 400\u2013500 mg Harosoy Defective.(TIFF)Click here for additional data file.Figure S3Williams (Phytozome) and Wayne (NCBI) cultivars showed 100% sequence homology.The Nucleotide and Amino Acid Sequence Alignment for PRP1. (A) Alignment of PRP1 nucleotide sequence from NCBI (J02746) and PRP1 sequence (Glyma09g12200.1) from Phytozome database (B) Alignment of PRP1 amino acid sequence from NCBI with PRP1 amino acid sequence from Phytozome database. The nucleotide and amino acid sequence from (TIFF)Click here for additional data file.Figure S4The Nucleotide and Amino Acid Sequence Alignment of the PRP2 Gene. (A) Alignment of PRP2 nucleotide sequence from NCBI (J05208) and PRP2 sequence from Phytozome database (Glyma09g12260.1) (B) Alignment of PRP2 amino acid sequence from NCBI with PRP2 amino acid sequence from Phytozome database. There is difference of one tandem repeat in the amino acid sequence. The PRP2 protein is shorter in Williams (Phytozome) as compared to Wayne (NCBI) cultivar.(TIFF)Click here for additional data file.Figure S5The Genome Organization of PRP1 and PRP2. As in the Phytozome database, PRP1 and PRP2 are on chromosome 9 and the distance between these genes is \u223c146 kb.(TIFF)Click here for additional data file.Figure S6The Expression Pattern of 13 Selected Differentially Expressed Genes in the Seed Coat of Wildtype and Defective Isolines in Both Clark and Harosoy Backgrounds. The genes over expressed in the defective isolines . CS: Cla(TIF)Click here for additional data file.Figure S7The Expression Pattern of 16 Selected Differentially Expressed Genes in the Seed Coat of Wildtype and Defective Isolines in Both Clark and Harosoy Background. The genes overexpressed in the Standard isolines . CS: Cla(TIF)Click here for additional data file.Figure S8The Expression Pattern of 11 Fasciclin-like Arabinogalactan Gene in the Seed Coat of Wildtype and Defective Isolines in Both Clark and Harosoy Background. These genes showed higher expression in defective isoline as compare to wildtype isoline . CS: Cla(TIF)Click here for additional data file.Figure S9The Expression Pattern of Cell Wall Genes Overexpressed in the Seed Coats of Defective Isolines in Both Clark and Harosoy Background. These graphs present data for 25 additional cell wall related genes not previously shown in (TIF)Click here for additional data file.Figure S10The Expression Pattern of Cell Wall Genes Overexpressed in the Standard Seed Coats of Both Clark and Harosoy Background. These graphs present data for 3 additional cell wall related genes not previously shown in (TIFF)Click here for additional data file.Figure S11The Distribution of Differentially Expressed Genes in the Seed Coats of Either (A) Clark or (B) Harosoy Backgrounds at the 50\u2013100 mg Seed Weight Stage. The number of differentially expressed genes was (A) 720 genes in Clark isolines and (B) 48 genes in Harosoy isolines. In both backgrounds, there were major categories related to the cell wall.(TIFF)Click here for additional data file.Figure S12The Distribution of Differentially Expressed Genes in Seed Coats of Either (A) Clark or (B) Harosoy Backgrounds at the 100\u2013200 mg Seed Weight Stage. The number of differentially expressed genes was (A) 173 genes in Clark isolines and (B) 156 genes in Harosoy isolines at 100\u2013200 mg seed weight stage. In both backgrounds, one of the major categories was related to the cell wall.(TIFF)Click here for additional data file.Figure S13The Distribution of Differentially Expressed Genes in Seed Coats of (A) Clark or (B) Harosoy Backgrounds at the 400\u2013500 mg Seed Weight Stage. The number of differentially expressed genes was (A) 417 genes in Clark isolines and (B) 1068 genes in Harosoy isolines. In both backgrounds, the cell wall related genes occupied 5% of the chart area.(TIFF)Click here for additional data file.Figure S14The Expression Pattern of Differentially Expressed Transcription Factor Genes That Showed Higher Expression in the Seed Coat of Defective Isolines in Both Clark and Harosoy Background. Overexpressed in defective isolines. CS: Clark Standard, CD: Clark Defective, HS: Harosoy Standard, HD: Harosoy Defective.(TIF)Click here for additional data file.Figure S15The Expression Pattern of Differentially Expressed Transcription Factor Genes That Showed Higher Expression in the Seed Coat of Standard Isolines in Both Clark and Harosoy Background. Overexpressed in standard isolines. CS: Clark Standard, CD: Clark Defective, HS: Harosoy Standard, HD: Harosoy Defective.(TIF)Click here for additional data file.Figure S16The Distribution of Differentially Expressed Transcription Factor Genes into Different Classes in Clark at the 50\u2013100 mg Seed Weight Stage. The 59 differentially expressed transcription factor genes were divided into 12 classes based on functional annotations.(TIFF)Click here for additional data file.Figure S17The Distribution of Differentially Expressed Transcription Factor Genes in (A) Clark or (B) Harosoy Backgrounds at the 100\u2013200 mg Seed Weight Stage. (A) The 16 differentially expressed transcription factor genes were divided into 9 different classes (B) The 12 differentially expressed transcription factor genes were divided into 10 different classes based on functional annotation.(TIFF)Click here for additional data file.Figure S18The Distribution of Differentially Expressed Transcription Factor Genes in Different Classes in (A) Clark and (B) Harosoy Backgrounds at the 400\u2013500 mg Seed Weight Stage. (A) The 43 differentially expressed transcription factor genes were divided into 10 different classes (B) The 111 differentially expressed transcription factor genes were divided into 15 different classes based on functional annotation.(TIFF)Click here for additional data file.Table S1The Total Number of Expressed Genes in Seed Coats of the Different Isolines. The total number of expressed genes at \u226510 RPKM or \u22651 RPKM in different backgrounds at different seed weight stages are presented in this table. CS: Clark standard, CD: Clark defective, HS: Harosoy Standard and HD: Harosoy defective.(DOCX)Click here for additional data file.Table S2Significantly Differentially Expressed Genes Found in the Seed Coats of Either Clark or Harosoy Backgrounds at the Indicated Stages of Seed Development.(XLSX)Click here for additional data file.Table S3The 364 Significantly Differentially Expressed Genes Found in Common in Both Clark and Harosoy Backgrounds as Defined in (XLSX)Click here for additional data file.Table S4The 109 Significantly Differentially Expressed Genes Common in Both Background But with Expression in Opposite Directions as Described in (XLSX)Click here for additional data file."} +{"text": "Early diagnosis of macrophage activations syndrome (MAS) in systemic juvenile idiopathic arthritis (sjia) may be challenging because it may mimic the clinical features of the underlying disease or be confused with an infectious complication. However, the diagnostic value of the guidelines for hemophagocytic lymphohistiocytosis (HLH) or sjia-associated MAS has seldom been examined.To investigate the sensitivity and specificity of diagnostic guidelines for HLH and sjia-associated MAS in patients with sjia who developed MAS.The study sample included 362 children with sjia who had MAS (diagnosed and treated as such by the attending physician) and 2 control groups with potentially \"confusable\" conditions, including active sjia without MAS (n = 404) and a systemic febrile infection requiring hospitalization (n = 345). Diagnostic guidelines for HLH and sjia-associated MAS were applied to all MAS and control patients. Because no patient had NK-cell activity and soluble CD25 determination available and bone marrow aspirate was performed in only a few patients, these 3 criteria were excluded from HLH guidelines. HLH criteria were, therefore, met when at least 4 of the 5 remaining variables were present. Sjia-associated MAS criteria were met when at least 2 laboratory criteria or at least 1 laboratory criterion and 1 clinical criterion were present. Sensitivity and specificity of guidelines in discriminating patients with MAS from control patients were assessed.The table shows the comparison of sensitivity and specificity of diagnostic guidelines.The diagnostic guidelines for sjia-associated MAS revealed strong sensitivity and specificity, whereas HLH guidelines were highly specific, but lacked sensitivity. Sensitivity of HLH was mostly hampered by the excessive stringent threshold for cytopenia and hypofibrinogenemia, and the infrequent occurrence of splenomegaly in patients with MAS.None declared."} +{"text": "Quantification of interstitial (diffuse) myocardial fibrosis by T1 mapping may prove useful in a range of conditions. Both native T1 maps and extracellular volume fraction (ECV) are being increasingly used clinically and have been shown to be sensitive to a wide range of conditions and associate with worse prognosis. However, quality control by T1 phantoms is essential and thei2-agarose gel phantoms [NiClphantoms were prephantoms . PhantomBoth high resolution and low resolution sequences had similar T1 means, standard deviation and coefficient of variation (CoV) for blood and myocardium native and post-gadolinium may require further investigation.There was significant stability of the NiClNIHR Cardiovascular Biomedical Research Unit of Royal Brompton & Harefield NHS Foundation Trust and Imperial College London."} +{"text": "To the Editor: Feline morbillivirus (FeMV) was first reported in Hong Kong and mainland China in 2012 of the L gene of the US strains (We generated amplicons from 10 (3%) of 327 samples; 3 samples were from cats with CKD and 7 from cats without CKD. Sequencing results confirmed that these 493 bp amplicons correspond to unique strains of FeMV . Approximately 15 months later, we obtained a follow-up urine sample from the still healthy cat, performed reverse transcription PCR (RT-PCR), and generated amplicons by using RT-PCR and rapid amplification of cDNA ends. The major morbillivirus surface antigen is the HA glycoprotein, and we used pan-FeMV HA gene primer sets to detect additional viruses , and antibodies to FeMVUS5 were detected in nonpermeabilized cells Figure 2US1 is closely related to viruses from Asia, highlighting the global distribution of FeMV clustered phylogenetically in a basal sister relationship with all other viruses from Asia and the United States (We used complete genome and H gene sequences in a comprehensive phylogenetic analysis. FeMV of FeMV , panel Ad States , panel BEcologic surveys continue to identify novel viruses that are homologous to known paramyxoviruses in many wildlife species, including bats and rodents (The detection of FeMV sequences in a clinically healthy animal after 15 months is a novel and surprising observation but is consistent with the known propensity for morbilliviruses to persist in vivo (Technical Appendix. Methods for the molecular and serologic detection of feline morbillivirus in clinical samples."} +{"text": "Ribavirin (RBV) is a synthetic nucleoside analogue used for the treatment of a number of viral diseases. RBV inhibits inosine 5\u2032-phosphate dehydrogenase (IMPDH), the enzyme required for synthesis of guanosine monophosphate (GMS) as well as DNA and RNA synthesis. Based on this mechanism of action, RBV is also used in the treatment of solid tumors, lymphoproliferative disease and some inflammatory diseases such as Crohn's disease. A number of nucleoside analogs including RBV diffuse across cell membranes through a membrane transporter protein called equilibrative nucleoside transporter-1 (ENT1). Our recent publication demonstrated that an autophagy response induced by hepatitis C virus (HCV) in a cell culture reduces RBV uptake and antiviral activity by diminishing the surface expression of ENT1 [Human ENTs are the nucleoside transporter proteins expressed on the cell membrane that occur as four isoforms ENT1-ENT4). These proteins play important roles in transporting nucleosides- and nucleotides-based small molecule drugs. The expression of ENT1 is critical for salvage of natural nucleotides and nucleosides for nucleic acid synthesis, neurotransmission, and regulation of cardiovascular activity . The exp. These pTaking into consideration the previously mentioned autophagy related mechanism that regulates the expression of ENT1, it is reasonable to speculate that cellular autophagy status could regulate the uptake and response to nucleoside based treatment of viral infection or cancer. RBV has been used for the treatment of a number of viral infections with modest antiviral activity. The decreased antiviral activity of RBV against virus disease could be related to the degree of cellular autophagy response and expression of ENT1. Based on our results, we propose that inhibiting cellular autophagy response should improve the RBV uptake and antiviral activity against other viruses. One report showed that RBV has a potent antitumor activity against metastatic breast cancer . The celThe responses to gemcitabine treatment of pancreatic cancer have been shown to be correlate with reduced expression of ENT1 transporter. Over expression of ENT1 enhances the gemcitabine response in human pancreatic cancer, tumor cells lacking ENT1 expression are highly resistant to gemcitabine . This is"} +{"text": "There is an emerging evidence that critical illnes induces an alteration in the immune response of patients that makes them more susceptible to the development of nosocomial infections and influences its clinical response.The aim of this study is to characterize the immunocompetence status of critically ill patients undergoing mechanical ventilation and to determine impaired immune patterns associated with an increased risk of developing ventilator-associated pneumonia (VAP) and a poorer clinical evolution.All immunocompetent patients over 18 years old admitted to the Intensive Care Unit of the Hospital Universitario and Politecnico la Fe , undergoing mechanical ventilation for more than 48 hours were included. Patients with clinical suspicion of ventilator-associated respiratory infection were considered as cases and compared with a selection of controls matched by age, comorbidities, severity scales and days of mechanical ventilation. At the moment of intubation and each 72 hours until the moment of extubation, clinical surveillance was performed and respiratory samples were taken to evaluate clinical and microbiological response. Samples of plasma and mini-BAL were also taken for immunoglobulins IgG1 - IgG4, IgM, IgA and IgE determination. Comparison of numerical and categorical variables was performed with the Mann-Whitney U test. Results were expressed as medians with interquartile (25% to 75%) ranges (IR) in brackets.16 cases and 14 controls were considered for analysis. Response to antibiotic treatment was evaluated in cases and patients were classified in responders (7 cases) and non-responders (8 cases). Initial empirical antibiotic treatment was more accurate in responders patients . At the moment of orotracheal intubation and beginning of mechanical ventilation, VAP patients showed lower serum IgA levels (figure A), lower serum IgG1 and IgM and lower respiratory levels of IgG1, IgG2 and IgA, without statistical signification. At the moment of VAP diagnosis, responders patients showed higher levels of IgG2 (figure B), lower serum IgG1 and IgM and higher levels of IgA (figure C).Our findings show the protective role of IgA and IgG2 against the inflammatory aggression of mechanical ventilation and in the response against ventilator-associated pneumonia.This study was supported by the Spanish Society of Pneumology and Thoracic Surgery (SEPAR 129/2011)."} +{"text": "The aim of the present study was to investigate the correlation between initialalveolar bone density of upper central incisors (ABD-UI) and external apical rootresorption (EARR) after 12 months of orthodontic movement in cases withoutextraction. 1) andafter 12 months of treatment (T2). ABD-UI and EARR were measured bymeans of densitometry. A total of 47 orthodontic patients 11 years old or older were submitted toperiapical radiography of upper incisors prior to treatment . No statistically significant correlation was found between initial ABD-UI andEARR at T Based on the present findings, alveolar density assessed through periapicalradiography is not predictive of root resorption after 12 months of orthodontictreatment in cases without extraction. Radiographs were taken using the RX Timex 70 C and Pro 70-Intra x-rayequipment operating with 70 kVp, 7 mA and a 0.25-second exposure time.oC). Intermediate washing was standardized at 30 seconds and fixing timewas standardized at 10 minutes.All procedures were approved by the State University of Maring\u00e1 Institutional ReviewBoard, Brazil (190 \u2044 2008). Each volunteer was submitted to periapical radiography ofthe upper incisor region either immediately prior to or immediately after bracketbonding , a trapezoidal region of interest was outlined in the alveolar boneprocess of the apical region of upper central incisors to estimate optical densityexpressed in grey level values ranging from 0 (black) to 255 (white).1 and TLT2; CLT1 andCLT2) were measured at a precision of 0.1 mm with the aid of CorelDRAWX4 software.,,,,,2 wascalculated using the following equation:,,Tooth length (TL) and crown length (CL) of upper incisors #11 and #21) at bothevaluation times was also employed.Although no statistically significant differences were found between the first andsecond measures, the mean of each variable was used in the subsequent statisticaltests to minimize random error.2. Significance level was set at 5% (P< 0.05) for all statistical tests.Neither EARR nor ABD-UI had normal distribution (Lilliefors test). Thus,nonparametric Spearman correlation test was used to determine potential correlationsbetween initial ABD-UI and EARR at TNo significant differences were found between teeth #11 and #21 regarding EARR andABD-UI. After 12 months of treatment, mean EARR was 3.5% . Three p,,,,Apical root resorption can occur in the early stages of orthodontic treatment,especially in upper incisors which generally undergo greater movement in comparison toother teeth.,Periapical radiography is the method of choice to assess apical root resorption stemmingfrom orthodontic treatment, mainly due to the cost-benefit ratio of this method.Periapical radiographs are known to have greater reliability in comparison to lateraland panoramic radiographs.,-In previous studies employing dual-energy x-ray absorptiometry (DXA), systemic BMD(lumbar spine and femur) was not correlated with maxillomandibular alveolar BMD.,,,A study investigating alveolar density of anterior and posterior regions of the maxillaand mandible found that only the densities of the anterior maxilla and posteriormandible were correlated.The dentoalveolar complex of each patient is unique in terms of size, orientation anddensity, and associations between EARR and alveolar density and morphology have not yetbeen established.,,,As cortical bone is denser than trabecular bone, a number of studies have investigatedassociations between bone density and root resorption in an indirect manner by analyzingthe proximity of roots and cortical bone during orthodontic movement.Kaley and PhilipsHoriuchi et al,,It makes sense to measure the total displacement of a tooth by the root apex which iswhere pathological resorption occurs.Based on the present findings, alveolar density in the apical region of upper incisorsassessed by means of periapical radiographs is not predictive of root resorption 12months after orthodontic treatment in cases without extraction."} +{"text": "Hypertrophic cardiomyopathy is the most common monogenic disorder in cardiology. Despite important advances in understanding disease pathogenesis, it is not clear how flaws in individual sarcomere components are responsible for the observed phenotype. The aim of this article is to provide a brief interpretative analysis of some currently proposed pathophysiological mechanisms of hypertrophic cardiomyopathy, with a special emphasis on alterations in the cardiac mechanical properties. Hypertrophic cardiomyopathy (HCM) is a relatively rare inherited cardiovascular disease that affects approximately 1 in 500 young individuals and that accounts for 35% of sudden cardiac death cases in young athletes and myosin binding protein C (MYBPC3) are the most commonly involved genes, followed by troponin I (TNNI3), troponin T (TNNT2), essential myosin light chain (MYL3), regulatory myosin light chain (MYL2), alpha tropomyosin (TPM1), and cardiac actin (ACTC) . Myocardial deformation analysis in the form of magnetic resonance imaging (MRI) has revealed strain dissimilarities between the endocardial and epicardial layers of the left ventricle (LV) wall and among different LV segments or slow (MYH7). There are certain developmental, environmental, epigenetic and hormonal factors that regulate the expression of MYH6 and MYH7, which are encoded by a gene cluster on chromosome 14 Gupta, . MYH7 isSeveral studies have examined the mechanical properties of the epicardial and endocardial layers . In general terms, patients with unexplained syncope, documented ventricular tachycardia or aborted SCD, positive family history for SCD, maximal LV wall thickness >30 mm and abnormal drop in blood pressure during exercise, treated with an implantable defibrillator . The mechanisms analyzed in this paper shed some light on the relation of mutations to disease phenotype, although they may not necessarily apply to all patients. A better understanding of the pathophysiological mechanisms leading to hypertrophy will contribute to the further improvement of treatment and to risk stratification for sudden cardiac death.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "AbstractReduced fetal growth is seen in about 10% of the pregnancies but only a minority has a pathological background and is known as intrauterine growth restriction or fetal growth restriction (IUGR / FGR). Increased fetal and neonatal mortality and morbidity as well as adult pathologic conditions are often associated to IUGR. Risk factors for IUGR are easy to assess but have poor predictive value. For the diagnostic purpose, biochemical serum markers, ultrasound and Doppler study of uterine and spiral arteries, placental volume and vascularization, first trimester growth pattern are object of assessment today. Modern evaluations propose combined algorithms using these strategies, all with the goal of a better prediction of risk pregnancies.Abbreviations: SGA = small for gestational age; IUGR = intrauterine growth restriction; FGR = fetal growth restriction; IUFD = intrauterine fetal demise; HIV = human immunodeficiency virus; PAPP-A = pregnancy associated plasmatic protein A; \u03b2-hCG = beta human chorionic gonadotropin; MoM = multiple of median; ADAM-12 = A-disintegrin and metalloprotease 12; PP-13 = placental protein 13; VEGF = vascular endothelial growth factor; PlGF = placental growth factor; sFlt-1 = soluble fms-like tyrosine kinase-1; UAD = uterine arteries Doppler ultrasound; RI = resistence index; PI = pulsatility index; VOCAL = Virtual Organ Computer\u2013Aided Analysis software; VI = vascularization index; FI = flow index; VFI = vascularization flow index; PQ = placental quotient Considered by the American College of Obstetricians and Gynecologists \u201cthe most common and complex problem in modern obstetrics\", fetal growth restriction still needs clear criteria because intrauterine fetal growth is not defined by clear parameters but mainly estimated on the basis of multiple factors. Research in this field is trying to find predictive parameters, with the goal of reaching an early diagnosis, which would lead to a better management of the condition [2]. Intrauterine growth restriction is defined as the pathologic inhibition of intrauterine fetal growth and the failure of the fetus to achieve its growth potential [3]. While the majority of such pregnancies will have a physiologically normal fetus that is simply small for gestational age (SGA), pathological fetal growth-restriction is a different category and the ability to differentiate such a condition from SGA is limited. A healthy fetus with estimated weight or birth weight below the 10th percentile according to population standards is commonly defined as SGA [5]. Pathological SGA is known as intrauterine growth restriction (IUGR) or fetal growth restriction (FGR). Fetal development is evaluated through comparison between estimated fetal weight or birth weight and references or standards for different gestational ages [6].Impaired fetal growth is seen in about 10% of pregnancies [ Why detecting intrauterine growth restriction?9]. IUGR is associated with increased fetal and neonatal mortality and morbidity, being linked to immediate perinatal adverse events and also to adult pathologic conditions [14]. Former studies showed that cerebral palsy was found to be 4-6 times more frequent in newborns below the 10th percentile compared to those between the 25th and the 75th percentile [15]. A strong association between FGR and stillbirth was also confirmed [16]. From the moment FGR was recognized as a cause of perinatal death, almost 50% of stillbirth were identified as FGR [17], resulting in a decrease of unexplained stillbirth from 67-70% to 15% [18]. Therefore, fetal growth impairment identification triggers a 4-time reduction in neonatal complications and death [14]. Fetal growth is known to be an important predictor of pregnancy outcome and reflects the interaction between physiological and pathological factors influencing the fetus [19]. In addition, the investigation of possible IUGR/FGR has the objective of an early detection and appropriate management that could lower the percentage of stillbirths and other perinatal complications, hoping that the identification of low risk fetuses would decrease the number of unnecessary surveillance [11]. In about 75% of the cases, IUGR remains unrecognized until birth and the diagnosis comes retrospectively, whereas in low-risk pregnancy the detection rate is about 15% [ IUGR: risk factors21]. The main factors assessed in clinical practice include: maternal factors , fetal factors , adnexal factors [22]. The risk factors for IUGR comprise a wide range of conditions and their assessment should be seriously taken into account, as they are easy to perform and are routinely used during pregnancy [23]. Further diagnostic tests could have a better relevance in a selected high-risk population [24]. However, these clinical factors have shown a different impact for each individual case and their relevance, as effective screening tools have not been proved yet [25]. A positive history for risk factors of IUGR can raise the problem of an increased surveillance with the specific goal of an early detection of growth insufficiency [26]. For this purpose, biochemical serum markers, Doppler study of uterine arteries, placental volume and vascularization as well as first trimester growth pattern, were the object of study for IUGR/FGR assessment. As presented above, IUGR/FGR is linked to serious pregnancy complications and early assessment of the condition is a main topic of research today. Furthermore, preventive measures like administration of low dose aspirin showed efficacy in IUGR treatment if administered before the 16th week of gestation [ Serum markers linked to IUGR27]. The impaired spiral artery transformation is leading to weak development of the utero-placental circulation and is implied in the pathology of preeclampsia and IUGR [21]. The placentation process starts with the migration of trophoblastic cells that invade the walls of spiral arteries and transform them from small caliber high resistant vessels into wide caliber low resistant vessels that deliver blood at low pressure to the intervillous space. Then, the utero-placental circulation develops in two stages: the first stage (until the 10th week of gestation) consists in endovascular plugging of the spiral arteries by trophoblastic cells, subsequently followed by invasion and destruction of the intradecidual spiral arteries; the second stage (between 14-16 weeks of gestation) consists in the invasion of the inner miometrial part of the spiral arteries [21]. Several serum analytes have been studied in hope of finding a relevant marker linked to IUGR, but none of them proved to be sufficiently accurate to be used in routine clinical practice as single predictive marker. The combined approach using clinical data, serum markers, biophysical parameters showed increased predictive relevance [28]. Maternal serum analytes were first studied with the aim of screening for aneuploidies during the first or second trimester of pregnancy and their use was then further extended in many studies to evaluate their utility as markers for impaired placentation. The trophoblastic invasion failure is thought to be responsible of the changes in the concentration of serum placental products [29]. Furthermore, in the group of 4390 women with singleton pregnancy evaluated by Spencer et al. in 2005 the maternal low levels of serum PAPP-A at 11-13 weeks of gestation resulted significantly associated to adverse pregnancy outcomes [30]. Low levels of PAPP-A were mentioned as predictors of IUGR also by Goetzinger et al. in 2009 and Poon et al. in 2009 . The sensitivity of detecting IUGR for a first trimester PAPP-A level below the 5th percentile ranges only between 8% and 33% and PAPP-A as single marker is an insufficient screening tool for IUGR [33]. Pregnancy associated plasma protein A (PAPP-A), an Insulin\u2013like Growth Factor Binding Protein Protease whose levels depend on placental volume and function, was assessed in several studies with congruent results. In 2000, Ong et al. evaluated 5584 singleton pregnancies at 10-14 weeks of gestation and measured maternal serum free beta human chorionic gonadotropin (\u03b2-hCG) and PAPP-A, concluding that low levels of maternal serum PAPP-A or \u03b2-hCG were associated with subsequent development of pregnancy complications [34]. Later, Gotzinger et al. showed that high levels of \u03b2-hCG were linked to SGA fetuses [31]. Overall, the predictivness of free \u03b2-hCG is unsatisfactory today [25]. Dugoff et al. evaluated 34271 pregnancies at 11-14 weeks of gestation and proved that maternal serum free \u03b2-hCG was mildly reduced in pregnancies that subsequently developed IUGR [36]. In 2008, in the name of the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada, Gagnon et al. reviewed the obstetrical outcomes associated with abnormal levels of single or multiple maternal serum markers used in the screening for aneuploidy. PAPP-A, alphafetoprotein, \u03b2-hCG, estriol, unconjugated estriol, inhibin-A were the analytes assessed and among the conclusions an unexplained low PAPP-A (< 0.4 MoM) and/or a low hCG (< 0.5 MoM) in first trimester were associated with an increased frequency of adverse obstetrical outcomes [37]. As in the first trimester biochemical screening starts as early as 8wa, the detection of a low level of hyperglycosylated human chorionic gonadotrophin correlated with a low PAPP-A and resulted a marker of impaired placentation, showing 90% specificity and 69% sensitivity when adjusted for mean arterial pressure and parity .41]. In 2007, Chaftez et al. showed that low levels of first trimester PP-13 were associated with preterm birth in women with IUGR [42]. In 2008, Spencer et al. found poor association between PP-13 and pregnancy outcome like IUGR [43]. In 2008, using the integrated assessment of PP-13, PAPP-A and uterine artery Doppler at 11-13 weeks of gestation, Poon et al. determined a 20% detection rate of FGR at a false positive rate of 5% [44]. Placental Protein 13 (PP-13) is a peptide involved in placental implantation and vascular invasion and remodeling [45]. Soluble fms\u2013like tyrosine kinase-1(sFlt-1) on the other hand, inhibits the effects of VEGF and PlGF by blocking their interaction with the specific receptors. The imbalance between the anti-angiogenic and angiogenic factors seems to be linked of preeclampsia and IUGR [45]. The recent meta-analysis performed by Conde-Agudela et al. in 2013 including 53 studies and 39974 women evaluated 37 new biomarkers among which: Angiogenesis-related biomarkers , Endothelial function/oxidative stress-related biomarkers ; Placental proteins/hormone-related biomarkers and other markers like metabolomics and genetic biomarkers. Overall, none of the 37 novel biomarkers evaluated showed a significant accuracy for predicting IUGR [45]. Angiogenic factors implied in placentation like Vascular Endothelial Growth Factor (VEGF) and Placental Growth Factor (PlGF) were also evaluated in many studies [ Ultrasound markers21]. The Doppler ultrasound sampling of uterine arteries (UAD) is a useful non-invasive method for the assessment of the interaction between fetal and maternal hemodynamic compartment. Starting from the early studies of Campbell et al. and Trudinger et al. in the 1980s, this procedure has been reported in numerous following surveys and showed to be a promising technique for the prediction of the IUGR risk [46-48]. In case of an incomplete trophoblastic invasion of the spiral arteries, the maternal compartment failsed to transform from a high resistance to a low resistance flow district and this impairment is associated with the development of preeclampsia and IUGR. In these cases, a Resistence Index (RI) or a Pulsatility Index (PI) above the 90th-95th percentile and/or the presence of unilateral or bilateral notching is associated with a value of the RI >0,58 or a value of the PI >1,45 [49]. Therefore, in 1994 North et al. and in 1998 Irion et al. stated that UAD was not a reliable screening test for nulliparous women [51]. Further studies performed in the 2000s have evaluated UAD between 10-14 weeks of gestation finding low positive predictive values for IUGR and a slightly better prediction value for preeclampsia with IUGR or IUGR alone with delivery in less than 32 weeks [55]. Most of the studies published to date, disregarding if performed during the first or second trimester, agree that UAD modifications are linked to IUGR but are not a reliable single predictive marker for defining a low risk category [56]. An interesting approach proposed by Gomez et al. in 2006 showed that the sequence of changes in the uterine flow between the first and second trimester correlates with subsequent appearance of IUGR and the highest risk is held by women with persistent low vascular indices [54]. The early studies that assessed UAD were performed during the second trimester of gestation, between weeks 18-23 [49-54]. Although an increased resistance in the uterine arteries is associated with poor obstetric outcome like preeclampsia, IUGR or prematurity, the positive predictive value was found to be only 15% for IUGR [57]. Hung et al. evaluated color and spectral Doppler of the spiral arteries between 13-19 weeks and 20-25 weeks concluding that spiral artery Doppler assessment was not a sensitive tool for detection of IUGR in a low risk population [58]. Furthermore, in studies comparing normal outcome pregnancies versus complicated pregnancies, spiral arteries sampling failed to show any statistically significant predictive value, making spiral arteries Doppler study an insufficient method for screening of IUGR [59].Spiral arteries have been subjected to assessment during the first trimester. M\u00e4kikallio et al. found that spiral arteries impedance decreased starting with the 5th week of gestation and uterine and arcuate artery lost their tonus starting with the 8th week .62]. In a region of interest, three indices are mostly calculated and used: Vascularization Index (VI): the ratio between color vessels and total vessels , representing the percentage of blood vessels in a region of interest; the Flow Index (FI): the sum of a color vessel\u2019s signal intensity divided by the number of color vessels, representing the amount of blood corpuscles in the vessels in a region of interest; the Vascularization Flow Index (VFI): the ratio between the sum of the color vessel\u2019s signal intensity and the total tissue vessels, representing the total number of blood corpuscles in the total tissue volume. In 2004, Merce et al. showed that the 3D-Power Doppler study of the placental vascularization in normal pregnancies is reproducible and seems to be a useful tool in performing \u201ca placental biopsy\" [63]. In 2008, Guiot et al. used this technique in the assessment of the 3rd trimester pregnancies complicated with IUGR and compared them to normal pregnancies, correlating VI, VFI and FI values to Umbilical Artery Doppler abnormalities (elevated Systolic/Diastolic ratios and absent End Diastolic Velocity), and the results showed that modifications in vascularization indices could be detected earlier than Umbilical Artery Doppler abnormalities [64]. In 2009, Noguchi et al. performed \u201cplacental vascular sonobiopsies\" starting with the second trimester, comparing normal and growth restricted pregnancies and proving the differences in vasculature [65]. Against these evidences, in vitro phantom studies performed by Raine-Fenning et al. and Schulten-Wijman et al. in 2008 questioned the technical and methodological aspects of this procedure, doubting the reproducibility\u00ac\u00ac\u00ac\u00ac [67]. On the other side, the sheep model study conducted by Olivier Morel et al. in 2010 demonstrated a good correlation between true uterine blood flow and flow parameters, as well as a good reproducibility of the technique [68]. The introduction of Virtual Organ Computer\u2013Aided Analysis software (VOCAL) proved useful in the quantification of blood vessel volume and of the flow in an acquired volume [69]. Another way of determining early fetal growth was proposed by Hafner et al. who compared Placental Quotient (PQ) [Placental Volume / Crown Rump Length] assessed during the first trimester with Uterine Artery Doppler at 22 weeks and concluded that PQ has low sensitivity in diagnosis of IUGR in low-risk population, comparable with that of Uterine Artery Doppler, but has the advantage of possible first trimester assessment [70]. In 2013, these authors refined their research showing that Placental Bed Vascularization Index assessed by 3D Power Doppler could be used for a quick and reliable first trimester assessment of severe pregnancy risks because it shows a 66,2% detection rate for severe pregnancy complications, higher than the 50% sensitivity of second trimester Uterine Artery Doppler [71]. In regard to placental volume assessment Rizzo et al. showed in 2009 that first trimester evaluation of placentas in a high risk group with low PAPP-A proved a good correlation between reduced placental volume and low fetus weight (<10th percentile) with Umbilical Artery Doppler modifications [ The multiparameter approach21]. The combined approach reflects various pathological pathways: Doppler ultrasound of the uterine arteries shows inadequate invasion of the spiral arteries and impaired secretory placental function is reflected by the disturbances of biomarker levels [72]. Preeclampsia is associated with IUGR and models of prediction by combining ultrasound assessment of uterine arteries, biochemical markers and maternal history were published concerning the assessment of both conditions, but the need for the development of a model for prediction of SGA without preeclampsia emerged [74]. With the purpose of identifying SGA fetuses not related to preeclampsia, Karagiannis et al. used a model of prediction containing Uterine Artery Doppler Pulsatility Index at 11-13 weeks of gestation, Mean Arterial Pressure, maternal serum PAPP-A, free \u03b2-hCG, Placental Growth Factor, PP-13, ADAM-12 and Fetal Nuchal Translucency. Although the study did not distinguish between the constitutional and pathological SGA, it raised the problem of increased surveillance for the whole population at risk for SGA, improving perinatal outcome by individualized management in late-second trimester and third trimester. The study also proved a good detection rate for SGA of 73% for those requiring delivery before 37 weeks and of 46% for those requiring delivery after 37 weeks [28]. Investigators tried to improve the prediction of IUGR by combining Doppler indices with biochemical and clinical parameters due to the insufficient predictive value of each marker alone [26]. A thorough history should be taken to all pregnant women at the first antenatal visit because risk factors determination results are easy and inexpensive. Different single approaches in the screening of this condition have been proposed but did not show sufficient sensitivity, therefore, combined models are proposed with the goal of a better predictive value. Large-scale prospective studies are required to prove the power of such integrated approaches in clinical practice.Although it is a public health problem with around 10% incidence in the pregnancy population, FGR is still a matter of debate starting from the definition, the multifactorial origin, the low levels of prediction, the questionable references like customized or uncustomized growth charts, and the methods of diagnosis and management. The main trajectory of research is towards the first trimester diagnosis, as the optimal interval in which a prophylactic treatment would influence placentation ends in the 16th week ["} +{"text": "However, the exact mechanisms of the selectivity and toxicity have remained obscure. Here we discuss the current knowledge on the role of mutSOD1 in mitochondrial dysfunction in ALS from the novel perspective emphasizing the misregulation of dismutase activity in IMS as a major mechanism for the toxicity.In amyotrophic lateral sclerosis (ALS), mitochondrial dysfunction is recognized as one of the key elements contributing to the pathology. Mitochondria are the major source of intracellular reactive oxygen species (ROS). Increased production of ROS as well as oxidative damage of proteins and lipids have been demonstrated in many models of ALS. Moreover, these changes were also observed in tissues of ALS patients indicative of important role for oxidative stress in the disease pathology. However, the origin of oxidative stress in ALS has remained unclear. ALS linked mutant Cu/Zn-superoxide dismutase 1 (SOD1) has been shown to significantly associate with mitochondria, especially in the spinal cord. In animal models, increased recruitment of mutant SOD1 (mutSOD1) to mitochondria appears already before the disease onset, suggestive of causative role for the manifestation of pathology. Recently, substantial Amyotrophic lateral sclerosis (ALS) is a fatal paralyzing disease characterized by the selective degeneration of motor neurons in the spinal cord, brain stem and motor cortex. The majority (\u223c90%) of ALS cases are sporadic whereas some 10% of patients have dominantly inherited familial ALS (FALS). However, the forms share clinical features. The suggested causative factors for the motor neuron degeneration include oxidative stress, neuroimmune reactions, protein aggregation are products of normal oxygen metabolism in cells as superoxide and hydrogen peroxide which is a highly reactive oxidant mitochondria. Further in vivo studies revealed that mutSOD1 in spinal cords of G93A SOD1 rodents is destabilized and bound to the inner mitochondrial membrane which oxidizes it to Ot Figure . Cells lA substantial proportion of SOD1 is found in the mitochondria which all have a role in mitochondrial import and accumulation (Kawamata and Manfredi, A mitochondrial import mechanism for SOD1 independent of CCS has been described in yeast (Varabyova et al., For maturing into an active enzyme, SOD1 requires three post-translational modifications: the insertions of zinc and copper, intramolecular disulfide bond formation, and dimerization. Zinc is deposited close to the active site stabilizing the structure (Potter et al., Full activation of human SOD1 requires CCS (Wong et al., in vitro (Tiwari and Hayward, in vivo studies did not assess the localization of reduced mutSOD1, one could expect that it would be accessible to mitochondria where a part of that pool could be oxidized. In cell culture, oxidation of Cys111 residues led to accumulation of several SOD1 mutants in mitochondria (Ferri et al., In ALS, mutSOD1 is recruited to mitochondria especially in the spinal cord (Higgins et al., Furukawa and O\u2019Halloran suggestein vitro (Rodriguez et al., Most forms of mutSOD1 show instability 2O2 (He et al., The IMS-located SOD1 has been suggested to be inactive in the intact mitochondria and activated through oxidative modification of its critical thiol groups by yet poorly known mechanisms (I\u00f1arrea et al., Insertion of copper is required for the activity of SOD1 and altered copper homeostasis is a common feature in mutSOD1 mice (Tokuda et al., in vivo, suggesting that formation of heterodimers may be physiologically relevant in FALS patients as well. It has been proposed that the heterodimers comprise a pool of more soluble and more toxic SOD1 whereas homodimers form less toxic aggregates (Weichert et al., 2O2 production is not known and warrants further elucidation. In the model proposed (Figure 2O2 leads to cytC catalyzed peroxidation and mitochondrial damage.In addition to proper folding and metal acquisition, dimerization is critical for dismutase activity. Mutant and wtSOD1 are able to form either homo- or heterodimers both in animal and cell culture models (Furukawa et al., Under physiological conditions SOD activity in IMS is suppressed by redox state control. However, upon mitochondrial stress SOD1 may undergo oxidative activation and compete with cytochrome C for superoxide released in the IMS, leading to increased ROS production. In ALS, mutSOD1 accumulates in IMS, thus contributing to the misregulation of dismutase activity. The presence of endogenous wt enzyme may provide dismutase activity to inactive mutant by heterodimerization. Here we propose that aberrant regulation of dismutase activity in IMS as a major mechanism for the toxicity should be further evaluated in future studies. Furthermore, the possible involvement of mitochondrial IMS dismutase activity misregulation in sporadic ALS warrants careful assessment.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Neisseria meningitidis serogroup X isolates from sub-Saharan Africa and Europe showed that serogroup X emergence in sub-Saharan Africa resulted from expansion of particular variants within clonal complex 181. Virulence of these isolates in experimental mouse models was high.The epidemiology of meningococcal disease varies by geography and time. Whole-genome sequencing of Neisseria meningitidis, varies substantially by geography and time. The disease can occur as sporadic cases, outbreaks, and large epidemics. Most cases occur in what has been termed the \u201cmeningitis belt\u201d in sub-Saharan Africa, where the World Health Organization estimated that 12,464 suspected cases occurred during the 2013 meningitis season and that 1,131 were fatal . Molecular typing of meningococci has used multilocus sequence typing (MLST) to determine CCs on the basis of the polymorphism of 7 housekeeping genes , which runs on the Bacterial Isolate Genome Sequence Database (BIGSdb) platform from culture grown overnight on gonococcal medium base agar plates with Kellogg supplements . Among genes involved in iron acquisition, the isolates from Africa, unlike those from France, lacked the carriage , panel BluxCDABE operon expressed by the PporB meningococcal promoter but differed in LNP13407 (obtained in the 1990s), and we detected 23 genes for which alleles were identical in all isolates obtained since 2006 and in LNP13407 but differed in LNP14354 . fHbp (encodes factor H binding protein), lpt3 (encodes the phosphoethanolamine transferase), and lot3 . All serogroup X isolates obtained since the outbreak of 2006 (including those from the BIGSdb platform) harbored the lpt3 allele 45, which differs from allele 136 by the deletion of 2 codons (encoding Glu-211 and Ser-222 residues). These isolates do not react with the monoclonal antibody that recognizes immunotype L3,7,9 on the lipooligosaccharide (Most of these 41 genes encode hypothetical proteins; several encode proteins that are involved in meningococcal survival in the blood , panel CN. meningitidis serogroup X isolates in the meningitis belt of Africa supports the emergence of virulent serogroup X isolates and the belief that CC181 may be considered a hyperinvasive genetic lineage of meningococci. The occurrence of the periodic epidemic waves may be caused by the emergence and spread of successive new clones of meningococci with enhanced virulence and an ability to escape population immunity. Our data underline the need for whole-genome sequencing for reliable tracking of meningococcal isolates and emphasizes the need for an effective vaccine against serogroup X (The extensive characterization of"} +{"text": "In There are errors in Notes: GDPpc: Gross Domestic Product per capita; QALYs: Quality Adjusted Life Years. Notes: These five countries were selected to reflect the range of results obtained in the incremental cost-effectiveness ratios (ICERs) in the 30 Latin American and Caribbean countries analysed . Each point represents 1 of the 1000 simulated ICERs in the probabilistic sensitivity analysis for each country. Probabilities of being Cost-Saving, or Cost-Effective at 1 and 3 GDPpc for all countries can be seen in"} +{"text": "It is imperative for staff involved in clinical trials to receive appropriate education and training relating to their particular roles to be able to fulfil GCP requirements and ensure successful trial conduct . However, little is known about the ways training is being provided to trial staff.To investigate and summarize training methods currently used in RCTs of health-care interventions.A systematic review was undertaken to identify articles reporting methods and practices of staff training within RCTs. A set of codes was used for the systematic organisation of extracted data.7471 records were screened and 89 studies were identified; 78 (88%) focused on training in an individual RCT and 11 (12%) were network-based. Studies were mainly conducted in USA (55%) and internationally (27%). Most were multi-centre (94%) and funded by non-commercial funders (70%). Different combinations of live (face-to-face and remote) and recorded (text-based and multimedia) training methods were used. Training was mainly provided at a group-level (51%), by trainers from the research team (65%). Intervention delivery/fidelity (49%), protocol and trial-related procedures (39%), trial data (36%), patient recruitment (31%) and outcome assessment (18%) were the top five training objectives. Evaluation information was present in 88% of studies, however, a detailed evaluation was only given in 12% of them. Information on the cost of training was only reported in 4.5% of studies.There is substantial variability in the reported training process across RCTs of various intervention types, disease areas and sample sizes."} +{"text": "There is an error in affiliation #3 for authors Xiaofan Guo and Hongning Zhou. Affiliation #3 should be: Yunnan Provincial Key Laboratory of Vector-borne Diseases Control and Research (in establishment) of Yunnan Institute of Parasitic Diseases."} +{"text": "Pinus koraiensis mixed forest, the responses of composition and structure of Pinus koraiensis mixed forests to climatic changes are unknown and the key climatic factors controlling the composition and structure of Pinus koraiensis mixed forest are uncertain.Although some studies have indicated that climate changes can affect Pinus koraiensis mixed forests along a latitudinal gradient and an elevational gradient in Northeast China. In order to build the mathematical models for simulating the relationships of compositional and structural attributes of the Pinus koraiensis mixed forest with climatic and non-climatic factors, stepwise linear regression analyses were performed, incorporating 14 dependent variables and the linear and quadratic components of 9 factors. All the selected new models were computed under the +2\u00b0C and +10% precipitation and +4\u00b0C and +10% precipitation scenarios. The Max Temperature of Warmest Month, Mean Temperature of Warmest Quarter and Precipitation of Wettest Month were observed to be key climatic factors controlling the stand densities and total basal areas of Pinus koraiensis mixed forest. Increased summer temperatures and precipitations strongly enhanced the stand densities and total basal areas of broadleaf trees but had little effect on Pinus koraiensis under the +2\u00b0C and +10% precipitation scenario and +4\u00b0C and +10% precipitation scenario.Field survey was conducted in the natural Pinus koraiensis mixed forest. Although the Pinus koraiensis would persist, the current forests dominated by Pinus koraiensis in the region would all shift and become broadleaf-dominated forests due to the dramatic increase of broadleaf trees under the future global warming and increased precipitation.These results show that the Max Temperature of Warmest Month, Mean Temperature of Warmest Quarter and Precipitation of Wettest Month are key climatic factors which shape the composition and structure of Pinus koraiensis is a pine species endemic to the region including East Russia, Korea, Japan and Northeast China Pinus koraiensis - broadleaf mixed forest is one of the major vegetation types and the typical conifer - broadleaf mixed forest and plays important role in carbon cycling in Northeast China Pinus koraiensis patches and the expansion of some broadleaf tree species from 1986 to 1994, and indicated that the reason for the shrinkage of Pinus koraiensis patches and the expansion of some broadleaf tree species might be the effects of climate change Pinus koraiensis or its mixed forest Pinus koraiensis would shift Northward under the HadCM2 climatic change scenario and under the average of another five climatic change scenarios Pinus koraiensis to become broadleaf forests in Changbai Natural Reserve of Northeast China under the CGCM2 climate change scenario Pinus koraiensis mixed forest are uncertain.A field study of the North East China Transect (NECT) has observed the shrinkage of Pinus contorta and Pinus sylvestrisPinus koraiensis reflects the stand age of a Pinus koraiensis mixed forest, because the mean diameter of Pinus koraiensis in a stand naturally increases over time Linear or quadratic regression models can be built to simulate the relationships of compositional and structural attributes of plant communities with climatic and non-climatic factors, and such studies have been conducted in grasses, tropical trees, According to the recent CMIP5 (phase five of the Coupled Model Inter-comparison Project) climate change scenarios, the global temperature averaged in 2081\u20132100 is projected to likely exceed 2\u00b0C (RCP6.0 and RCP8.5 emission scenarios) above 1850\u20131900; although unlikely to exceed 4\u00b0C in all other RCP emission scenarios than RCP8.5 Pinus koraiensis mixed forests to spatial climatic changes, a field survey was conducted in the natural Pinus koraiensis mixed forests along a latitudinal gradient and an elevational gradient in Northeast China. The mathematical models were built for simulating the relationships of compositional and structural attributes of the Pinus koraiensis mixed forest with climatic and non-climatic factors, and two scenarios of the +2\u00b0C and +10% precipitation and +4\u00b0C and +10% precipitation were used to predict the possible changes of composition and structure in Pinus koraiensis mixed forests under the future global climatic change. The objectives of this study are to: (1) build mathematical models to quantify the responses of the composition and structure of Pinus koraiensis mixed forests to the climatic factors; (2) discover the key climatic factors which control the composition and structure of Pinus koraiensis mixed forest. Additionally, we hypothesized that the composition and structure of Pinus koraiensis mixed forests would significantly be affected and Pinus koraiensis mixed forests would be overtaken by broadleaf-dominated forests in the region under the future global warming and increased precipitation.To examine the responses of composition of and structure of All necessary permits were obtained for the described field studies. This study was approved by State Key Laboratory of Vegetation and Environmental Change, Institute of Botany, the Chinese Academy of Sciences; Shengshan National Nature Reserve; Liangshui National Nature Reserve; Dongsheng Forestry Bureau; Changbai National Nature Reserve and Kuandian National Nature Reserve.Pinus koraiensis mixed forests without recent disturbance. All the broadleaved trees are deciduous and most of the conifers are evergreen (except for Larix) in the study region. From June to August is the warmest quarter (summer) and January is the coldest month of the year in the study region. Rainy season begins at May or June and ends at September, and the summer (from June to August) precipitation occupies 60% of annual precipitation This study was conducted in the Augusts of 2010 and 2012 in Northeast China, including ten sites: Kuandian, Dongsheng, Liangshui, Shengshan and Changbai from A to F . The forIn each plot, every living tree higher than 1.4 m was identified to species and then measured for its circumference with a tape measure at its breast height (1.3 m). The measured circumference of each tree was converted into its diameter at breast height (DBH) and calculated into its basal area using the circle formulas.Pinus koraiensis mixed forest were extracted from each plot. The fifteen attributes were: Mean DBH of Pinus koraiensis (MeanDBHPinus), Total Basal Area of Pinus koraiensis , Stand Density of Pinus koraiensis (StandDensityPinus), Total Basal Area of Acer and Fraxinus , Stand Density of Acer and Fraxinus (StandDensityAcer-Fraxinus), Total Basal Area of Quercus , Stand Density of Quercus (StandDensityQuercus), Total Basal Area of Abies and Picea , Stand Density of Abies and Picea (StandDensityAbies-Picea), Total Basal Area of Larix , Stand Density of Larix (StandDensityLarix), Total Basal Area of Ulmus , Stand Density of Ulmus (StandDensityUlmus), Total Basal Area of Betula and Stand Density of Betula (StandDensityBetula) (Fifteen attributes of yBetula) .One-way ANOVA and correlation and regression analyses were performed using SPSS 13.0. Standard errors within sites were detected by one-way ANOVA with descriptive options. Significant differences (p<0.05) between sites were detected using One-way ANOVA with post-Duncan's test.Pinus koraiensis mixed forest. The independent factors used in the regressions were linear and quadratic components of Max Temperature of Warmest Month (TempWarmestMonth), Min Temperature of Coldest Month (TempColdestMonth), Mean Temperature of Warmest Quarter (TempWarmestQuarter), Mean Temperature of Coldest Quarter (TempColdestQuarter), Precipitation of Wettest Month (PrecipWettestMonth), Precipitation of Driest Month (PrecipDriestMonth), Precipitation of Wettest Quarter (PrecipWettestQuarter), Precipitation of Driest Quarter (PrecipDriestQuarter) and MeanDBHPinus. The 14 dependent variables were BasalAreaPinus, StandDensityPinus, BasalAreaAcer-Fraxinus, StandDensityAcer-Fraxinus, BasalAreaQuercus, StandDensityQuercus, BasalAreaAbies-Picea, StandDensityAbies-Picea, BasalAreaLarix, StandDensityLarix, BasalAreaUlmus, StandDensityUlmus, BasalAreaBetula and StandDensityBetula included in its regression model.Pinus values under current climate, under the +2\u00b0C and +10% precipitation scenario and under the +4\u00b0C and +10% precipitation scenario. In order to examine the concordances between the simulated and observed values under current climate, scatter plots with simple error bars and regressions were generated using Sigmaplot 10.0. To represent the variations of stand densities and basal areas of Pinus koraiensis, other conifers and broadleaves under current climate under the +2\u00b0C and +10% precipitation scenario and under the +4\u00b0C and +10% precipitation scenario, vertical bar charts with error bars were generated using Sigmaplot 10.0.The selected models were computed using the currently observed MeanDBHPinus koraiensis mixed forest were predicted to be zero firstly increased and then decreased with increasing latitude, while the stand density of broadleaved trees decreased with increasing latitude and altitude , while Acer and Fraxinus and Pinus koraiensis serve as late successional species during the succession of Pinus koraiensis mixed forest Pinus (which represents the stand age of a Pinus koraiensis forest) Pinus and BasalAreaAcer-Fraxinus, suggesting that Pinus koraiensis and Acer and Fraxinus are late successional species and naturally increase in their total basal areas over time. However, negative relationship existed between MeanDBHPinus and StandDensityPinus when MeanDBHPinus was below 47.6 cm Pinus koraiensis but the negative effects of summer temperatures on other conifers (Abies and/or Picea and Larix) and the positive effects of summer temperatures on some broadleaved trees (Acer and/or Fraxinus and Quercus) were observed (Pinus koraiensis trees compared with other conifer trees (Abies and/or Picea and Larix); (2) increased summer (growing-season) temperatures may enhance the growths of many broadleaved trees (Acer and/or Fraxinus and Quercus).Climate warming has positive and negative effects on plants. Prolonged growing seasons and increased growing-season temperatures have been found to enhance the growth of some plants, especially the growth of many deciduous broadleaved trees observed . Our resPinus koraiensis were observed (Pinus koraiensis populations. We suggest that the Pinus koraiensis in the region may not necessarily maintain itself under the +2\u00b0C and +10% precipitation and +4\u00b0C and +10% precipitation scenarios if proper migrations of local populations do not occur in time.A wide-ranged pine species is usually composed of many genetically-different local populations. Each local population has evolved to adapt to its local climate, and has its unique response curve to climate change observed , and thePinus koraiensis within 150 years in current Pinus koraiensis mixed forest under climate warming scenarios Pinus koraiensis could persist for at least 300 years under the warming climate Pinus koraiensis would persist, while the broadleaf trees would overtake Pinus koraiensis to become dominant species under either of the two warming scenarios (Studies using a forest gap model alone usually predicted the extinction of cenarios .Pinus koraiensis mixed forests to the climatic factors. TempWarmestMonth, TempWarmestQuarter and PrecipWettestMonth strongly affected the stand densities and total basal areas in Pinus koraiensis mixed forest and therefore they are suggested to be key climatic factors which shape the composition and structure of Pinus koraiensis mixed forest. The composition and structure of Pinus koraiensis mixed forests were significantly affected, and although Pinus koraiensis would persist, the current forests dominated by Pinus koraiensis in the region would all shift and become broadleaf-dominated forests due to the dramatic increase of broadleaf trees under the future global warming and increased precipitations.These results show that some mathematical models were successfully built to quantify the responses of the composition and structure of"} +{"text": "Magnetic Resonance Imaging of the Small Bowel is becoming increasingly popular as the first imaging modality for the diagnosis and follow-up of small bowel diseases. The aim of this work was to evaluate the role of recent MRI sequences and techniques in evaluation of small bowel disease.The study population included 24 patients who were referred to multiple radiology centers by gastroenterologist for magnetic resonance enterography (MRE) for evaluation. The examination was done on 1.5 Tesla superconducting magnet MRI.All studied patients had small bowel lesions. 15 patients were neoplastic (64%) and 9 patients were inflammatory (36%). Among 15 cases of small-bowel neoplasm; 12 were malignant; and 3 were benign. The malignant cases were classified as follows; lymphoma (6 patients); adenocarcinoma (4 patients); GIST (1 patients) and carcinoid tumour(1 patient). Nine patients out of 24 had inflammatory bowel diseases. Eight cases out of 9 proved to be specific inflammatory disease and 1 chronic non specific ileocolitis. Seven cases out of 8 proved to be Crohn\u2019s disease and 1 proved pathologically to be TB of small bowel. The final diagnosis was confirmed by surgical or endoscopic data and follow up.MRE is accurate non-invasive modalities in assessing the intra-luminal, parietal and extra-luminal small bowel tumour without the need for ionizing radiation. MR signal appearances of the lesions, combined with the contrast enhancement behavior and the characteristic of the stenosis, can help in differentiating neoplastic from other non-neoplastic diseases of small bowel."} +{"text": "The presence of joint inflammation in juvenile idiopathic arthritis (JIA) patients can be made by physical examination and confirmed by imaging. The discrepancy between physical examination and MRI for evaluation of synovitis in a target joint is possibly explained by the fact that clinical measures mostly reflect overall disease activity instead of measures specific for the joint imaged by MRI.To compare clinical disease activity of the major target joint upon physical examination with a validated MRI score for the knee in JIA.MRI datasets and corresponding clinical parameters of disease activity of the knee were analyzed in 167 JIA patients . Local physical examination of the knee included absence or presence of swelling, warmth, pain or limitation-of-motion (LOM) as assessed by experienced pediatric rheumatologists. A blinded radiologist (6 years of experience in MRI in JIA) analyzed synovial hypertrophy (SH) on a scale from 0-12 on all MRI datasets following the validated Juvenile Arthritis MRI Scoring system (JAMRIS). SH was \u2018present\u2019 when the total JAMRIS score was >2. Diagnostic accuracy of the local physical examination parameters for detection of arthritis was determined with MRI as reference standard.Sensitivity and specificity of the parameters scored by local physical examination compared with MRI varied from 39-71%. The overall positive predictive value for synovitis was very low (21-28%), while the negative predictive value was relatively good (71-74%). Median time between the clinical assessment and the MRI was 38 days (IQR 28-53 days). Subgroup analysis on 51 patients with <31 days (median 25 days) between clinical assessment and MRI did not improve the diagnostic accuracy.The presence of swelling, warmth, pain or LOM on physical examination did not predict the presence of synovitis upon MRI. The time between clinical assessment and MRI appeared to have no influence on the diagnostic accuracy of the physical examination inflammation parameters. While the discrepancy between physical examination and MRI persists, follow-up studies are warranted to unravel the difficulties in assessment of disease activity.None declared."} +{"text": "For multimodal pain therapy (MPT), a bio-psycho-social therapy approach for patients suffering from chronic pain, a core outcome set (COS) is currently lacking. Following the recommendations from initiatives such as Outcome Measures in Rheumatology (OMERACT) and Harmonizing Outcome Measures for Eczema (HOME), the study \u201cValidation and Application of a patient relevant core set of outcome domains to assess multimodal PAIN therapy\u201d (VAPAIN) aims to develop an accepted and valid COS for MPT.An online survey consisting of two rounds was conducted using the mOMEnt software provided by the COMET initiative. 25 stakeholders in MPT were nominated by their associations and asked to participate. During both rounds, participants were asked to rate the importance of proposed domains regarding a) effectiveness trials (ES) and b) daily record keeping (DRK). Domains to be rated were identified through a systematic review of reported outcomes in MPT studies. During round 1, survey participants were allowed to name additionally relevant outcomes and were asked to name the number of minimal/maximal number of outcome domains to be included in the COS. During round 2 participants received feedback regarding their own previous ratings and also regarding ratings from other participants had to name which outcomes should be included in the COS.All participants completed round 1, but only 22 round 2 (88% response rate). The maximal and minimal number of outcome domains to be included in the COS ES was 9 and 4, and for the COS DRK 6 and 3. Pain intensity/severity (18/22), health-related quality of life (17/22), and pain-related disability (11/22) was named most frequently by the survey participants as being part of the COS for ES. Pain intensity (15/22), psychological distress (9/22) and both analgesic medication intake and pain-related disability (7/22) were named for the COS DRK.The results of this online survey regarding outcomes in studies evaluating MPT are mostly in line with the results from the preceding systematic review on outcome domains. Furthermore, the domains for the COS for effectiveness trials and daily record keeping were not fundamentally different. The identified preliminary outcome domains will be consented during a face-to-face meeting (consensus conference) in a moderated group discussion to determine a COS for MPT."} +{"text": "Rationale. Visual impairment is one of the most common clinical manifestations of multiple sclerosis (MS). Some multiple sclerosis patients complain of poor vision although the Snellen visual acuity is 20/20. This study reveals that sensitive measurements like visual evoked potential (VEP) and optical coherence tomography (OCT) can evidence subclinical disturbances of visual pathway. These methods examine the relation between the visual function (VEP) and retinal nerve fiber layer (RNFL) thickness, as a structural biomarker for axonal loss in patients with multiple sclerosis (MS). The findings in this study indicate the utility of combining structural and functional testing in clinical research on patients with MS.Purpose. To detect visual impairment in a population of visually asymptomatic patients affected by clinically definite multiple sclerosis (MS) and to compare the utility of optical coherence tomography (OCT) versus visual evoked potentials (VEP).Material and methods. Fourteen patients (28 eyes) affected by clinically definite MS, without a history of optic neuritis and asymptomatic for visual disturbances, were initially fully examined from an ophthalmic point of view and then measured by OCT (RNFL thickness) and VEP.Patients with a history of glaucoma or other retinal or optic nerve disease were excluded.Results. Of fourteen patients (28 eyes), VEP was abnormal in 11 cases and OCT (RNFL thickness) was abnormal in 5 cases , while 3 patients had no abnormalities on neither tests.Conclusions. Optical coherence tomography (OCT) is less sensitive than visual evoked potentials (VEPs) in detecting visual subclinical impairment in patients with multiple sclerosis (MS). VEP remains the preferred test for the detection of clinical and subclinical optic neuritis. OCT may provide complementary information to VEP in cases with clinical definite MS and represent a valuable research instrument for the study of optic nerve disease in populations. The findings in this study reveal the utility of combining structural and functional testing in clinical research on patients with MS.Abbreviations: multiple sclerosis = MS, optical coherence tomography = OCT, visual evoked potential = VEP, retinal nerve fiber layer = RNFL, best corrected visual acuity = BCVA. Just over a decade ago, MS clinical trials did not include visual outcomes, but experts recognized the need for more sensitive measures of visual function . Optical coherence tomography is used to monitor retinal ganglion cell axon loss in glaucoma, diabetic retinopathy, traumatic optic neuropathy, chiasmal lesions and optic neuritis [4-8]. Recently, OCT has been studied in patients with multiple sclerosis (MS). Two studies showed that the eyes without a history of optic neuritis among MS patients have decreased RNFL thickness compared with the eyes of control subjects, suggesting that retinal ganglion cell axonal loss occurs separately from acute optic neuritis in MS patients .Optical coherence tomography (OCT) is a noninvasive high-resolution technique that uses near-infrared light to generate cross-sectional tomographic images of tissues, including the retinal nerve fiber layer (RNFL) .This suggests that OCT can be used to monitor axonal injury and visual dysfunction in MS and may be an useful outcome measure in clinical trials [15]. In this study, we compared OCT versus VEP in the detection of visual dysfunctions in a population of visually asymptomatic patients with clinically definite MS.The alteration in visual evoked potential (VEP) latencies by using pattern stimuli is considered one of the most characteristic electrophysiological signs observed in patients with MS .The retinal nerve fiber layer (RNFL) measurements were obtained after 3 consecutive scans centered on the optic nerve head. OCT software Cirrus, Carl Zeiss Meditec generated a mean RNFL thickness measurement for 360 degrees around the optic disc, four retinal quadrants and 12 clock for our segment (30 degrees for each hour position). All scans were performed without pupil dilatation [VEPs were elicited by checkerboards reversing at 2 Hz on a television monitor located 1 m from the patient.15].VEP measurements were obtained with the patient wearing a visual aid, if needed and the fellow eye was occluded. A fixation spot was used on the center of the screen during stimulation. The latency of the first major positive peak in the VEP (P100 wave) was measured. Most investigators currently interpreted pattern reversal VEP based almost entirely on the latency of P100. A P100 latency >115ms was considered abnormal .Multiple sclerosis is a progressive disease in which subclinical RNFL thinning may occur, even in patients who have not been clinically diagnosed with optic neuritis [20]. Visual evoked potentials (VEP) remain the preferred test for the detection of clinical and subclinical optic neuritis [1].The alteration of the visual evoked potential (VEP) latencies during pattern stimulation is considered one of the most characteristic electrophysiological signs in patients with MS, visually affected or unaffected [20].The study showed that in patients affected by MS with no history of optic neuritis and no visual symptoms, there is a large prevalence of visual pathway involvement [2]. The greatest predictor for RNFL in the unaffected eye was the RNFL in the fellow affected eye [1].Clinically, it will be helpful to establish the baseline RNFL thickness and functional measurements in all MS patients at the time of the MS diagnosis. Change in RNFL thickness and/or visual function over time is likely the best approach in monitoring the disease progression [3].Based on OCT studies in MS, RNFL thickness is reduced significantly among patients (92 \u00b5m) versus controls (105 \u00b5m) and is particularly reduced in MS eyes with a history of optic neuritis (85 \u00b5m) [3].Combining information from structural and functional tests and following individuals longitudinally is probably the best strategy for assessing and monitoring the optic nerve involvement in patients with MS [4]. Imaging the RNFL allows a direct measurement of the unmyelinated axons of the central nervous system. The capacity to image central nervous system axons quickly and noninvasively, to minimize expense, and to correlate structural abnormalities with visual dysfunction add to the appeal of OCT as an imaging biomarker and outcome measure in clinical trials .The validation of OCT as an imaging biomarker in MS is important because several aspects of the information it generates are unique [The important correlation between the functional and anatomic aspect confirms the value of VEP and OCT to appreciate the subclinical involvement of the optic nerve."} +{"text": "The management of Adhesive Capsulitis(AC) is controversal. Both capsular distension after intraarticular injection and mobilization therapy are known as highly effective treatment of painful and limited shoulder joint. The aim of this study was to determine the synergistic effect of intensive mobilization technique combined with capsular distension for patients with adhesive capsulitis in improving shoulder ROM, pain and function.A total of 28 subjects suffering from AC were randomized into two groups. Group A received fluoroscopically guided capsular distension with steroid injection followed by intensive mobilization technique twice per week for 4 weeks and group B only received capsular distension with steroid injection.Patients were assessed using the Shoulder Pain and Disability Index (SPADI), Constant-Murley Shoulder Function Assessment Score (CS), Active Range of Motion(AROM) and Verbal Numeric Score(VNS). All measurements were obtained before injection and mobilization and 4 weeks after the procedures in order to compare with effects of the treatments.All measured value was significantly difference in group A and B(P<.05). Only external rotation ROM was not significantly difference in group B. The statistical differences were observed between group A and B in SPADI, CS, AROM and VNS (P<.01).Treatment using steroid injection with distension followed by intensive mobilization technique is recommended rather than injection treatment alone for the treatment of AC. In order to maximize the effectiveness of the two treatments further studies for optimal mobilization techniques will be needed."} +{"text": "Therefore, the current study demonstrated importance of mechanical factor in stem cell differentiation and showed promising protection of brain from HI injury using ELCs treatment.Neonatal hypoxic-ischemic (HI) brain injuries disrupt the integrity of neurovascular structure and lead to lifelong neurological deficit. The devastating damage can be ameliorated by preserving the endothelial network, but the source for therapeutic cells is limited. We aim to evaluate the beneficial effect of mechanical shear stress in the differentiation of endothelial lineage cells (ELCs) from adipose-derived stem cells (ASCs) and the possible intracellular signals to protect HI injury using cell-based therapy in the neonatal rats. The ASCs expressed early endothelial markers after biochemical stimulation of endothelial growth medium. The ELCs with full endothelial characteristics were accomplished after a subsequential shear stress application for 24 hours. When comparing the therapeutic potential of ASCs and ELCs, the ELCs treatment significantly reduced the infarction area and preserved neurovascular architecture in HI injured brain. The transplanted ELCs can migrate and engraft into the brain tissue, especially in vessels, where they promoted the angiogenesis. The activation of Akt by neuropilin 1 (NRP1) and vascular endothelial growth factor receptor 2 (VEGFR2) was important for ELC migration and following Hypoxic and ischemic (HI) brain injuries which result from lacking of oxygen or blood supply lead to permanent neuron damage and neurological deficit. During birth, HI insults in developing brain, such as asphyxia and ischemic stroke, are the leading cause of neonatal mortality and lifelong functional loss among newborns . The und ex vivo expanded EPCs or ECs showed therapeutic effect in several disease models, including neonatal HI brain injury, stroke, myocardial infarction, and vascular injury after angioplasty [Endothelial progenitor cells (EPCs) in circulation system are positively correlated with the outcome of hypoxic brain injury, and the more EPCs in circulation showed better recovery . The defioplasty \u201317. The ioplasty .Although the usage of EPCs is promising in brain therapy, the shortage of autologous EPCs limits its clinical application. We previously demonstrate the induction of endothelial differentiation by synergistic biochemical and biomechanical stimulations in human placenta-derived multipotential cells (PDMCs) . The appHuman liposuction aspirates were obtained from healthy donors with informed consent to protect the information and rights of patients as approved in accordance with procedures of the institutional review board of the National Cheng Kung University Hospital (NCKUH). The human ASCs were isolated following the protocol described previously . Briefly2) for 24 hours immediately after the EGM induction. The LSS was created by a flow chamber which allowed medium to flow through the cell-seeding glass slide and applied LSS to cells [The combined chemical and mechanical stimulation was used to induce the ELCs as previously established induction protocols . For theto cells . The endto cells . The lev5 cells) were trypsinized and resuspended with 1\u2009mL complete medium and added onto the polymerized Matrigel (BD Biosciences). After incubation in 5% CO2 incubator for 5 hours, the formation of tube-like structure was observed and quantified in the tube length using phase contrast microscope.Forming tube-like structure which is an important indicator of endothelial function was measured in ASCs, early EPCs, and ELCs as previously described . In brie5\u2009cells/100\u2009\u03bcL each time. The pups returned to dam for recovery for one week before the brain samples were harvested.The Sprague-Dawley (SD) rats were provided by the animal center in NCKU with the approval of the experiment procedure by the Institutional Animal Care and Use Committee at NCKU. Neonatal HI brain injury is created according to previous study . Concise\u03bcm-thick slice for the following staining. The corresponding plates 15, 18, 27, 31, and 39 in rat brain according to the rat brain atlas were stained with 0.1% cresyl violet solution for 1 hour to reveal neurons [Damage severity of brain was determined by the volume of ischemic region on outer surface and Nissl staining at P14. The rat brains were perfused with normal saline and 4% paraformaldehyde. Upon isolation, each brain was given a score based on the lesion size of outer surface of brain. The size of the lesion was divided into 3 grades, score one (lesion size less than 1/3 hemisphere), score two (the lesion size greater than 1/3 but lesser than 1/2), and score three (the lesion size greater than 1/2 hemisphere) . After d neurons .The integrity of neurovascular structure was assessed by immunofluorescence staining. The brain slices were incubated with the primary antibodies against neuronal nuclear antigen for identifying neuron and against rat endothelial cell antigen-1 for identifying vessels. To further verify the mechanism of the protection effect of different treatment, the marker of angiogenesis, isolectin IB4 antibody , was used to visualize new forming vessels. The antihuman nuclei antibody was utilized to recognize transplanted human cells in rat brain. The primary antibodies were labeled by fluorescent-labeled secondary antibodies , and the signals were observed at excitation-emission wavelengths of nm 470 to 505\u2009nm and 596 to 615 with a tissue scanning fluorescent microscope using a 20x objective lens.4 per well) are loaded into the upper compartment of Boyden chamber; the migration ability of the cells through 8\u2009\u03bcm-pore membranes (Neuro Probe) to the lower compartment which filled with medium with or without hypoxia mimetic reagent desferrioxamine will be measured. The cells are cultured in Boyden chamber for 6 hours, and then the cells on the lower surface of membrane will be fixed by 4% paraformaldehyde (Sigma) and stained with Giemsa to quantify the transmigrated cell numbers. To further clarify the mechanism of boosting migration ability of ELCs under hypoxic condition, the ELCs were pretreated with neuropilin-1 (NRP1) blocking peptide or inhibitor of VEGFR 1 hour before being loaded into the chamber. The migrating cell area was quantified by ImageJ software.The ability of stem cells to migrate into lesion site is important for tissue protection and regeneration. The injured brain area will release environmental cue to trigger the migration of the stem cells. We use Boyden chamber assay to compare the chemotaxis and transmigration ability of different cells. Shortly, different cells (2 \u00d7 10 in vitro hypoxic condition was achieved by treating the ASCs or ELCs with 50\u2009mM DFO. The cells were cultured in hypoxic condition for 6 hours with or without the pretreatment of DG2 (20\u2009\u03bcM) for 1 hour, followed by the collection of cell lysates. The gene expression level of VEGFR1, VEGFR2, CD31, vWF, angiopoietin 1 (ANG1), and neuropilin 1 (NRP1) was measured using RT-PCR with the primer sequence listed in previous study [\u03b2-actin [To further illustrate the underlying signaling under hypoxic condition, theus study . The act, Sigma) . The p-Ap < 0.05.For all experiments at least 3 independent groups were performed to demonstrate the consistency outcome. All data were expressed as the mean \u00b1 standard SEM. Statistical analysis was performed using the one-way analysis of variance (ANOVA) with Fisher's test of the Origin statistic software . The statistical significance was defined as The endothelial differentiation for early EPCs and ELCs was induced from human ASCs using biochemical and biomechanical stimulations. After EGM induction, the early EPCs did not show obvious change in morphology and remained spindle shaped which was similar to undifferentiated ASCs . InsteadThe therapeutic effect of ASCs and ELCs was tested using neonatal HI brain injury model in rats. The severity of brain injury was compared among the rat pups receiving different treatments, including PBS, ASCs, and ELCs. The brain score determined based on infarction size on the outer surface of brain showed sever damage after HI insult in PBS group . TransplWe further investigated the integrity of neurovascular structure by immunofluorescence staining of specific antibodies against neuron (NeuN) and vess in vivo local hypoxic environment that may have different responses in ASCs and ELCs. We further used in vitro Boyden chamber assay to investigate themigration ability of various cells under normal and hypoxic conditions. The transmigrated cells were labeled in dark blue color after migrating from the loaded upper compartment of chamber to the lower compartment with or without adding DFO for studying the cell mobility in normoxia (vehicle) and hypoxia (DFO) (The HI injured brain created ania (DFO) . The ELCia (DFO) . To illuia (DFO) . The chaia (DFO) . The levia (DFO) . The resTo confirm the role of NRP1 and VEGFR2 in promoting ELCs migration and remaining of endothelial differentiation under hypoxic condition, blockage of NRP1 or VEGFR signals in ELCs was tested by using specific NRP1 blocking peptides (DG2) or a small molecular targeting tyrosine kinase receptor (BIBF1120), respectively. Under regular condition (normoxia), the transmigration ability of ELCs was slightly decreased with the inhibition of NRP1 (DG2) or VEGFR (BIBF1120) signaling . The enhTo further confirm the signaling in brain tissue after receiving different therapeutic cells, the p-VEGFR2 and p-Akt were coimmunofluorescent staining with the angiogenesis marker IB4 . The appIn this study, we demonstrated the ASCs can be differentiated into endothelial lineage by synergistic stimulation of growth factor and shear stress. The therapeutic effects of both ASCs and ELCs were tested in HI injured brain. Main finding of present study supported that transplantation of ELCs showed better capacity than ASCs in preserving neurovascular structure after HI brain injury in rats. The ELCs were able to migrate and incorporate into the vascular structure in brain tissue. In addition, the ELCs can promote the angiogenesis in the impaired area as compared to ASCs. The involvement NRP1 and VEGFR2 is important for ELCs to facilitate the migration ability under hypoxic condition through Akt pathway.The angiogenic potential in early EPCs and late EPCs is comparable; there is divergence in their functions . Early EThe cell-based therapy using EPCs shows protective effect on restoring blood flow and preventing tissue damage. Upon transplantation, the EPCs home the ischemic site and incorporate into the damaged vessel structure. Studies address the fact that there are two main mechanisms for the therapeutic effect of EPCs therapy. First, the EPCs have potential to differentiate into mature ECs . After aThe crosstalk between ECs and neuron are prominent for the normal structure and function of nervous system. The ECs in central nerve system are highly specialized which connect tightly with each other and form blood barrier . The bloSeveral chemoattractants will be secreted in the injured tissue after HI insult to recruit circulating cells into the damaged area. VEGF is an important chemotactic factor for EPCs to participate in cell mobilization . VEGF acThe current study demonstrates the importance of chemical and mechanical factors in inducing the differentiation of ELCs from ASCs and the potential of using ELCs in protecting rat neonatal HI brain injury. Both ASCs and ELCs therapies can prevent the brain from HI insult by decreasing the infarction volume. Yet, ELCs showed a promising outcome in protecting the architecture and integrity of neurovascular unit. The transplantation of ELCs preserved not only the networks of vascular structure, but also the number of neurons. The mechanism for protective effect in ELCs may act through the increase of migration capacity and neovascularization after HI injury. The increase of NRP1 and VEGFR2 was identified with phosphorylation of Akt signaling in ELCs under hypoxic condition. Inhibition of NRP1 signal diminished the promotion of ELCs transmigration and Akt phosphorylation under hypoxia. Inhibition of VEGFR2 totally abolished the cell migration and endothelial differentiation in ELCs. Taken together, these results indicate that shear stress induced ELCs can be a promising cell resource for autologous cell therapy in HI brain injury."} +{"text": "To The Editor: Woodrats (Neotoma spp.) are natural hosts of Whitewater Arroyo virus (WWAV) and other Tacaribe serocomplex viruses (family Arenaviridae) in the western United States and northern Mexico . Virtually all serum samples were acute-phase specimens, and a specific diagnosis was achieved for only 55 (31.8%) of the 173 study participants.Serum samples were tested for IgG against WWAV, Amapar\u00ed virus (AMAV), an arenavirus that is antigenically closely related to the Tacaribe serocomplex viruses known to cause hemorrhagic fever of the 173 study participants. None of the 173 study participants were positive for IgG against AMAV or LCMV. The IgG titers against WWAV in the positive samples were 320 (n = 1), 1,280 (n = 3), and \u22655,120 (n = 4). WWAV was the apparent homologous virus in the 7 persons with antibody titers \u22651,280. The apparent homologous virus in the person with the titer of 320 could not be determined from ELISA data. The presence of IgG against WWAV in acute-phase serum samples implied past infection with WWAV or an arenavirus antigenically closely related to WWAV.The state of residence , sex ratio , and mean age of antibody-positive persons reflected the characteristics of the entire study population. The clinical features in each of the antibody-positive persons included fever, headache, myalgia, and thrombocytopenia. The diagnoses given for these persons were acute parvovirus infection (n = 1) by IgM assay, adult respiratory distress syndrome (n = 1) by clinical progression, and not determined (n = 6).The results of this study indicate that a small fraction of the adult population in the southwestern United States has been infected with North American Tacaribe serocomplex virus(es). We note that the dominant epitopes in ELISA for IgG against arenaviruses are associated with the viral nucleocapsid (N) protein, and that amino acid sequence of the N protein of WWAV and amino acid sequences of N proteins of other Tacaribe arenaviruses from Arizona or New Mexico showed differences as high as 15.1% in a previous study (,It might be the case that human IgG against some Tacaribe serocomplex viruses in the southwestern United States does not react strongly against WWAV in ELISA. If so, the true prevalence of antibody against North American Tacaribe serocomplex viruses in this study might be >4.6%. Accordingly, future work should include development of broadly reactive assays for detection of human IgM and human IgG against North American Tacaribe serocomplex viruses, including those associated with wild rodents in Mexico ("} +{"text": "Non-alcoholic fatty liver disease (NAFLD) affects almost one third of adults in European countries. A well-known factor of influence is overnutrition and insulin resistance . In conRecently, Marta Benet and colleagues from Barcelona and Valenica in Spain have published a transcriptomic signature to identify compounds with an increased risk of inducing steatosis . ). in vitIn this context the identification of the steatogenic FOXA1/HEX/SREBP1C signature by Benet and colleagues (2014["} +{"text": "Brown adipose tissue (BAT) has long been known to dissipate energy as heat and contribute to energy expenditure, but its presence and physiological role in adult human physiology has been questioned for years. Recent demonstrations of metabolically active brown fat depots in adult humans have revolutionized current therapeutic approaches for obesity-related diseases. The balance between white adipose tissue (WAT) and BAT affects the systemic energy balance and is widely believed to be the key determinant in the development of obesity and related metabolic diseases. Members of the transforming growth factor-beta (TGF-\u03b2) superfamily play an important role in regulating overall energy homeostasis by modulation of brown adipocyte characteristics. Inactivation of TGF-\u03b2/Smad3/myostatin (Mst) signaling promotes browning of white adipocytes, increases mitochondrial biogenesis and protects mice from diet-induced obesity, suggesting the need for development of a novel class of TGF-\u03b2/Mst antagonists for the treatment of obesity and related metabolic diseases. We recently described an important role of follistatin (Fst), a soluble glycoprotein that is known to bind and antagonize Mst actions, during brown fat differentiation and the regulation of cellular metabolism. Here we highlight various investigations performed using different Obesity is a major health problem spreading at an epidemic pace throughout the world without any sign of abatement. According to the World Health Organization report, more than 1 billion adults (~ 15% of world population) are overweight [body mass index (BMI) > 25] lineage and are called beige cells or brite (brown-in-white) cells have recently been identified in adult humans superfamily is comprised of over 30 members that include several structurally dimeric cytokines such as TGF-\u03b2, activins, and bone morphogenic proteins (BMPs)/growth and differentiation factors (GDFs) which are evolutionarily highly conserved , also termed as growth/differentiation factor-8 (GDF-8) is a member of the TGF-\u03b2 superfamily that regulates skeletal muscle mass is a secreted glycoprotein that has been recognized for many years as a high affinity binding and neutralizing protein for several members of the TGF-\u03b2 superfamily including activins and Mst entitled \u201cComposition and methods for treating or preventing metabolic syndrome disorders\u201d is in process. Authors declare no other potential conflict of interest."} +{"text": "OnabotulinumtoxinA (OnabotA) was approved for treatment of chronic migraine (CM) following the PREEMPT trials, 2, and Written informed consent to publication was obtained from the patient(s)."} +{"text": "Mycobacterium tuberculosis, innovations in TB drug discovery and evolving strategies to bring new agents with best performance is an essential investigation. Taking this into account, there is a pressing need to develop new and more effective anti tubercular agents. The coordination of metal with organic drugs is a promising strategy that has been successful in many cases with different pharmacological activities. The emergence of new cases and the adverse effects of first and second-line antituberculosis drugs have led to renewed research interest in metal drug complexes in the hope of discovering new antituberculosis drugs. The aim of the present study is to assess the antituberculosis activity of Ni (II) and Cu (II) complexes of polymer ligand poly (3-nitrobenzylidene-1-naphthylamine-co-methacrylic acid).Tuberculosis (TB) is a disease that produces several million deaths annually. With the appearance of multi drug resistant microbial strains of M. tuberculosis H37 Rv strain by microplate alamar blue assay (MABA) method using pyrazinamide as standard.Antituberculosis activities of the ligand and its complexes were assessed against The minimum inhibitory concentration values of the ligand and its complexes on comparison with standard indicate that the complexes exhibit promising antituberculosis activity. Cu (II) complex shows more activity (10 \u00b5g/ mL) followed by Ni (II) complex (20\u00b5g/ mL) and ligand (35 \u00b5g/ mL).Among the synthesized compounds, the Cu (II) complex may be used as therapeutic substitute in the treatment of tuberculosis by replacing the routine drugs."} +{"text": "Unequal distribution of dermal collagen and elastic fibers in different orientations is reported to be one of the multi focal causes of scar related complications.To study the correlation pattern between the variables of dermal collagen in horizontal (CH) and in vertical (CV) directions as well as that of dermal elastic fibers in horizontal (EH) and vertical (EV) directions.Current research comprised of histo-morphometrical study of 120 skin samples collected in horizontal and vertical orientations from anterior chest area and lateral chest areas of formalin embalmed human cadavers (n = 30). The quantitative fraction of dermal collagen and elastic fiber content was obtained by tissue-quant image analysis. Spearman correlation coefficient (r) was computed to determine the linear association between the variables (CH/CV/EH/EV). The results were interpreted according to the degree of association after taking into consideration the significant correlation (p < 0.01 or p < 0.05) with respect to coefficient (r) values.Significant positive correlation between CH and CV and between EH and EV were observed in both anterior and lateral chest areas . However, the negative correlations were observed between CH and EH for anterior chest area (r = -.55) and between CV and EV at lateral chest area (r = -.43).Positive correlation among dermal collagen and elastic fibers between horizontal and vertical directions, and their negative correlation within same direction could be one of the factors for the speckled behavior of scar related complications in the chest area."} +{"text": "Provisional evidence-based classification criteria for Familial Mediterranean Fever (FMF), Cryopyrin Associated Periodic Syndrome (CAPS), Tumor Necrosis factor Receptor Associated Periodic Syndrome (TRAPS) and Mevalonate Kinase Deficiency (MKD) have been recently developed based on data coming from the Eurofever registry. However, no consensus on how to combine clinical criteria with results of molecular analysis has been reached so far.To understand how physicians involved in the clinical care of patients with Autoinflammatory diseases (AIDs) classify patients with inherited periodic fever in daily practice.By using the Delphi and Nominal Group Technique, we started a process made of three consecutive e-mail surveys. In the first survey, clinicians/biologists and other health professionals working in the field of autoinflammation were asked to identify the variables that they consider as important, in their clinical practice, for the diagnosis of patients with inherited periodic fever. This survey was open not to influence the experts.We sent the first survey to 124 experts. The overall rate of response was 107 (86%): 101 experts responded to be interested in the survey and 88 completed and confirmed it for at least one disease; 6 experts responded not to be interested. No clinical variable was chosen by all the experts for any disease the five most cited clinical variables for FMF were recurrent fever (80% of experts), abdominal pain (67%), arthritis (53%), thoracic pain (47%) and arthralgia (36%). The five most cited clinical variables for CAPS were fever (75%), urticarial rash (71%), hearing loss (49%), ocular involvement (40%) and arthralgia (35%). The five most cited clinical variables for TRAPS were long lasting fever (92%), rash (84%), periorbital edema (59%), myalgia/myositis (57%), and abdominal pain (55%) while the five most cited clinical variables for MKD were abdominal pain (61%), fever (59%), skin rash (41%), diarrhea (43%) and arthralgia (39%). A confirmatory genetic test resulted a relevant element for the diagnosis of FMF, TRAPS, CAPS and MKD while the response to treatment for FMF and CAPS.The preliminary results of the first Eurofever Delphi Survey show a high rate of response by Expert, underlying the interest of the scientific community in this topic. A wide heterogeneity in their response was observed. At the end of the Delphi process, we will obtain different set of clinical criteria whose performance will be tested in comparison to already existing criteria in a cohort of patients affected by AIDs. The final step will be a Consensus among experts (geneticists and clinicians) in order to define the best combination of clinical and genetic data for the definitive classification of patients with inherited periodic fevers."} +{"text": "Medical errors are particularly frequent in Neonatal Intensive Care Units (NICUs) , increasWe carried out our study from 2011 and 2012 in Department of Medical and Surgical Neonatology of Bambino Ges\u00f9 Children\u2019s Hospital. We recorded throughout retrospective methods nursing reports to detect an error or incidents. We used voluntary reporting, non punitive, of medical errors by health care providers.From 2011 and 2012 we detected 29 adverse events in Neonatal Department; 15 (58%)of whom were therapeutic errors concerning of drug process: 2 (13%) order, 1 (7%) preparation, 7 (46%) prescription, 5 (33%) administration (Figure The voluntary reporting system represents the best option to detect the human errors. In our experienced the introduction of shared protocols, of the nurse staff training, and the following of the JCHAO directives have been achieved to identify all procedures performed for patient care. To reduce the ADRs the Paediatric Investigation Plans should be required by the Paediatric Committed to guarantee safer and tolerated drugs, especially for newborns."} +{"text": "Contemporary inhabitants of the Balkan Peninsula belong to several ethnic groups of diverse cultural background. In this study, three ethnic groups from Bosnia and Herzegovina - Bosniacs, Bosnian Croats and Bosnian Serbs - as well as the populations of Serbians, Croatians, Macedonians from the former Yugoslav Republic of Macedonia, Montenegrins and Kosovars have been characterized for the genetic variation of 660 000 genome-wide autosomal single nucleotide polymorphisms and for haploid markers. New autosomal data of the 70 individuals together with previously published data of 20 individuals from the populations of the Western Balkan region in a context of 695 samples of global range have been analysed. Comparison of the variation data of autosomal and haploid lineages of the studied Western Balkan populations reveals a concordance of the data in both sets and the genetic uniformity of the studied populations, especially of Western South-Slavic speakers. The genetic variation of Western Balkan populations reveals the continuity between the Middle East and Europe via the Balkan region and supports the scenario that one of the major routes of ancient gene flows and admixture went through the Balkan Peninsula. It is believed that part of the Illyrians was assimilated and the other part was forced to move south - into the territory of present-day Albania th until 19th century the Peninsula was under the Ottoman control The Balkan Peninsula has been continuously settled by anatomically modern humans (AMH) since the Upper Paleolithic era Today, the Western Balkan territory is inhabDuring the last two decades the variation of uniparentally inherited markers such as mitochondrial DNA (mtDNA) and the non-recombining part of Y chromosome (NRY) have been exploited in population genetic studies in order to disentangle the problems of the diversity and dispersal of humans both in global and local contexts The study of the variation of mtDNA in the population of Bosnia and Herzegovina has shown - like in case of the variation of NRY - that the majority of detected mtDNA hgs among Bosnians belong to the common West Eurasian gene pool The aim of this study was to characterize, in a larger geographical context, the autosomal gene pool of eight Western Balkan populations from six countries - Bosnia and Herzegovina, Croatia, Serbia, former Yugoslav Republic of Macedonia, Montenegro and Kosovo. All studied samples were characterized also for mtDNA and NRY diversity. One of the main questions we address here is whether the whole genome approach with the accent on the variation of autosomal SNPs is in concordance with the information about genetic affinities of the populations of Western Balkan region, revealed by the studies of uniparental markers.Genome-wide autosomal markers of 70 Western Balkan individuals from Bosnia and Herzegovina, Serbia, Montenegro, Kosovo and former Yugoslav Republic of Macedonia . The genome-wide SNP data generated for this study can be accessed through the data repository of the National Center for Biotechnology Information \u2013 Gene Expression Omnibus (NCBI-GEO): dataset nr. GSE59032, 2>0.4) were excluded from the analysis in the window of 200 SNPs (sliding the window by 25 SNPs at a time). The final dataset consisted of 220 727 SNPs and 785 individuals from African, Middle Eastern, Caucasus, European, Central, South and East Asian populations was reduced with the exclusion of East and South Asians and Africans, in order to increase the resolution level of the populations from the region of interest for the same dataset used for PCA were estimated between populations, and regional groups for all autosomal SNPs, using the approach of Weir and Cockerham ST values for the populations specified in Pairwise genetic differentiation indices between different ethno religious groups of Western Balkan region with Middle Eastern populations. The Ottoman rule over the Balkans during 15\u201319 cc AD led inter alia to the conversion of the local people to Islam, the largest number of whose assumed descendants live in contemporary Bosnia and Kosovo ibd sharing for each of these populations and Middle Eastern populations . The details of the dataset has been characterized in The analysis was designed to compare patterns of shared tracts that are identical by descent (http://faculty.washington.edu/browning/beagle/beagle.html) ibd between pairs of individuals. The fIBD algorithm was applied to the 22 autosomes in 10 iterations and the IBD threshold was set to 1e\u201310. Since the power of the fIBD algorithm to detect segments shorter than 1 centiMorgan (cM) is low, we considered only ibd segments longer than 1cM. We summarized ibd sharing for six classes of ibd segments . We estimated an average number of ibd segments per pair of individuals for Muslim and non-Muslim populations of Western Balkan vs Middle Eastern populations algorithm implemented in BEAGLE software package and non-Muslim of the Western Balkan populations share around 1.5 ibd segments per pair with the population from the Middle East patterns of ibd sharing with Middle Eastern populations for shorter classes of ibd segments . This is slightly higher with Turks, and lower with Saudis, Syrians, Iranians and Palestinians and only Bosniacs have higher ibd sharing with Turks (p\u200a=\u200a0.0097 for 5\u20136 cM ibd segments) we first analyzed the number of dle East . This isulations . Next, wstinians . For lonegments) . Howeveribd segments reveals similar patterns of ibd sharing for Muslim and non-Muslim Western Balkan populations with populations of Middle East, providing thereby little support to a gene flow scenario during the conversion to Islam (15\u201319 cc AD) in the Balkans. Our analysis of ibd sharing agrees with other analyses of the Western Balkan populations, the influence of the clan structure to the present genetic variation should be seen the most in the Y chromosomal gene pool of the studied populations \u2013 this, however, is not the case. To conclude: the linguistic or religious differences seem to have had no impact on the present variation of uniparentally inherited or autosomal markers in a region.Compared to the rest of the Western Balkan populations, the Kosovars have a somewhat different cultural and demographic background. All studied Western Balkan populations, except Kosovars, belong to the South Slavic branch of the Indo-European (IE) language family n Balkan . Howevern Balkan , suggestn Balkan , Text S1We have analyzed and present here the new data of genome-wide autosomal diversity of five Western Balkan populations. The variation analysis of 660K autosomal SNPs of 70 individuals from Western Balkan populations revealed that the genetic uniformity that has been shown by studies of uniparentally inherited markers of these populations can be seen also at the whole-genome level. Thus, culturally diverse Western Balkan populations are genetically very similar to each other. These results, together with the high-resolution analysis of the variation of mtDNA and NRY, let us to affirm that the genetic profiles of Western Balkan populations resemble that of their closest geographical neighbors, and in the global context are in concordance with the geographical distribution of the studied population.The major variants of the gene pool of present-day Western Balkan populations have developed from a common source without being influenced by major population-specific bottlenecks. In a more general perspective, our results reflect clear genetic continuity between the Middle Eastern and European populations. It has been suggested recently that the Neolithic migrants from Anatolia took mainly the maritime coastal route and island hopping to reach Europe The autosomal analysis as well as mtDNA and NRY data presented in this study contribute to an existing database and for understanding the origins of the peopling of this part of Europe.Figure S1ADMIXTURE plots of autosomal SNPs of Western Balkan region in a global context on the resolution level of 3 to 15 assumed ancestral populations (K). A. Box and whiskers plot of the cross validation (CV) indexes of all 15\u00d7100 runs of ADMIXTURE; B. Log-likelihood (LL) scores of all 15\u00d7100 runs of ADMIXTURE. Inset shows the variation in the fractions of runs that reached the highest LL values; C. Bar plot displaying individual ancestry estimates for studied populations.(TIF)Click here for additional data file.Figure S2Principal component (PC) analysis (PC1 versus PC2) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S3Principal component (PC) analysis (PC1 versus PC3) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S4Principal component (PC) analysis (PC1 versus PC4) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIFF)Click here for additional data file.Figure S5Principal component (PC) analysis (PC1 versus PC5) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S6Principal component (PC) analysis (PC2 versus PC3) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S7Principal component (PC) analysis (PC2 versus PC4) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S8Principal component (PC) analysis (PC2 versus PC5) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S9Principal component (PC) analysis (PC3 versus PC4) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S10Principal component (PC) analysis (PC3 versus PC5) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S11Principal component (PC) analysis (PC4 versus PC5) of the variation of autosomal SNPs in Western Balkan populations (highlighted) in Eurasian context (see (TIF)Click here for additional data file.Figure S12Principal component (PC) analysis based on the frequencies of mtDNA (panels A and C) and NRY haplogroups (panels B and D) of Western Balkan (WB) populations in a context of selected Central and South Europeans and Iranians from the Middle East Click here for additional data file.Figure S13Average total length of genome shared identical by descent between Bosniacs, Kosovars and Near Eastern populations. Panels A-E indicate five length classes of ibd segments: 1\u20132, 2\u20133, 3\u20134, 4\u20135, 5\u20136 cM, respectively. Bosniacs and Kosovars are tested Muslim populations from Western Balkans; Macedonians, Montenegrins, Bosnian Croats and Serbs, Croatians, Serbians are non-Muslim populations from Western Balkans, used as a background. Red color of the Western Balkan population name and red circle around the symbol of Middle Eastern population indicates significantly higher ibd sharing between these populations as compared to non-Muslim background.(TIF)Click here for additional data file.Figure S14Median-joining network of mtDNA hg H lineages of Western Balkan populations: A: subhg H1 and its sub-branches; B: other subhgs of hg H. A total number of 19 H1 and 49 other H haplotypes are reported. Numbers on links indicate the mutations: blue color indicates HVS1 and HVS2 mutations, black color coding region mutations. Polymorphic nucleotide sites are numbered according to Reconstructed Sapiens Reference Sequence. Node size is proportional to absolute haplotype frequency, as it is reported in figure legend.(TIFF)Click here for additional data file.Figure S15Median joining network of mtDNA hg U lineages. A total number of 34 U haplotypes are presented. A diagnostic mutation A1811G has been added into the network, but not genotyped in the sample. For further details, see the legend of (TIF)Click here for additional data file.Figure S16Median joining network of mtDNA lineages for hgs J and T in the Western Balkan region. A total number of 24 J and 10 T haplotypes are presented. For further details, see the legend of (TIF)Click here for additional data file.Figure S17Median joining network of mtDNA lineages of hgs HV, V and R0a. A total number of 11 V, 8 HV and 2 R0a haplotypes are reported.For further details, see the legend of (TIF)Click here for additional data file.Figure S18Median joining network of mtDNA lineages from hgs W, I and N1b. A total number of 6 W, 1 I and 3 N1b of haplotypes are reported. For further details, see the legend of (TIF)Click here for additional data file.Figure S19Phylogenetic tree of mtDNA K1a13a complete sequences. Two samples of Bosnian Croats (BHCB15 and BHCHZ20), and two from Croatia [Croatia.m.(S)199 and Croatia.m.(S)34] are sequenced in this study, the others are from Phylotree mtDNA Build 15. The mutations are given relative to the Reconstructed Sapiens Reference Sequence.(TIF)Click here for additional data file.Figure S20Phylogenetic tree of mtDNA N1a complete sequences. One sequence of Croatian from Croatia is sequenced in this study, the others are from Phylotree mtDNA Build 15. The mutations are given relative to the Reconstructed Sapiens Reference Sequence.(TIF)Click here for additional data file.Figure S21Phylogenetic tree of mtDNA R0a2 complete sequences. Macedonian (MAC16) and Croat from Bosnia and Herzegovina (BHCCB19) are sequenced in this study, the others are from Phylotree mtDNA Build 15. The mutations are given relative to the Reconstructed Sapiens Reference Sequence.(TIF)Click here for additional data file.Table S1Sample of populations used for autosomal analyses.(XLS)Click here for additional data file.Table S2The ethnolinguistic characteristics of studied Western Balkan populations.(XLS)Click here for additional data file.Table S3F3-statistic calculated for all possible triplets of f3 of TreeMix dataset.(XLSX)Click here for additional data file.Table S4Average number of IBD segment per pair of individuals.(XLSX)Click here for additional data file.Table S5MtDNA HVS-1 and HVS-2 haplotypes of analyzed Western Balkan populations relative to Reconstructed Sapiens Reference Sequence.(XLSX)Click here for additional data file.Table S6Y chromosome variation in Western Balkan populations.(XLSX)Click here for additional data file.Table S7MtDNA gene and nucleotide diversity of analyzed Western Balkan populations.(XLSX)Click here for additional data file.Table S8st-distances of mtDNA HVS1 variation between Western Balkan populations.F(XLSX)Click here for additional data file.Table S9Results of AMOVA and Mantel test based on mtDNA HVS-1 haplotype or haplogroup frequencies.(XLSX)Click here for additional data file.Table S10Estimated coalescense time for the most frequent mtDNA haplogroups in studied Western Balkan populations.(XLSX)Click here for additional data file.Text S1Description of the sample and methods of the analyses of mtDNA and NRY.(DOCX)Click here for additional data file.Text S2Results of the analyses of mtDNA and NRY variation.(DOC)Click here for additional data file."} +{"text": "In recent years, emerging evidence has shown the potential risks of arterial hyperoxia, but observational studies failed to indisputably demonstrate its impact on clinical outcome of critically ill patients. Importantly, the lack of a clinical definition of hyperoxia and methodological limitations hamper the interpretation and clinical relevance of these studies.We aimed to systematically evaluate previously used metrics for defining hyperoxia and associations with outcome of intensive care unit (ICU) admission.2). Worst PaO2 was defined as the PaO2 associated with the lowest PaO2/FiO2 ratio. In logistic regression models, we analysed the associations between hospital mortality and severe hyperoxia (PaO2> 200 mmHg) defined by either identified metric, calculated over the total ICU admission.Arterial blood gas (ABG) analyses between July 2011 and July 2014 were extracted from the patient data management system (PDMS) database of three large tertiary care ICUs in the Netherlands. Data from all admissions where more than one ABG was available were supplemented with anonymous demographic and admission and discharge data from the Dutch National Intensive Care Evaluation (NICE) registry. Identified oxygen metrics from a systematic review of the literature included the first, highest, worst, and mean arterial oxygen tension died before hospital discharge. All identified metrics showed statistically significant associations between severe hyperoxia and hospital mortality. The risk estimates differed substantially between the metrics used for defining hyperoxia (P < 0.001). The strongest effects were found for the mean and the highest PaOIn this multicenter cohort study, severe arterial hyperoxia was associated with hospital mortality and this association was independent of the used metric for hyperoxia. However, the metric choice greatly influences the effect size for hospital outcome.This work was financially supported by an unrestricted grant issued by the Netherlands Organization for Health Research and Development (ZonMw).ADDIN EN.REFLIST"} +{"text": "Patent foramen ovale (PFO) occurs in a quarter of the population but half of those with cryptogenic stroke (CS). Difficulty in identifying the pathogenic PFO versus the innocent bystander has contributed to controversy surrounding outcomes following PFO closure. We aimed to investigate whether right atrial flow patterns could help define the mechanism for CS in the setting of PFO.3, temporal resolution:50-55ms, 20 phases, SENSE, factor 2) was used. Analysis was performed with GTflow v2.0 (Gyrotools). Contours were placed manually in the superior vena cava (SVC) and inferior vena cava (IVC) in the axial plane at the junction with the right atrium. Net flow was assessed at these points. The relative position of the SVC and IVC at these points was measured. A pathline analysis of atrial flow was performed .4D flow cardiac magnetic resonance (CMR) was performed in 10 subjects with proven PFO and CS and in 10 controls with normal trans-thoracic echocardiograms. CMR was performed at 3T with a 6-channel cardiac array. A retrospectively ECG-gated and respiratory-gated TFE sequence x240mm(FH)x142mm(LR), spatial resolution:3mmBody mass index (BMI) and heart rate (HR) were comparable but blood pressure was higher in the PFO/CS group with three patients taking anti-hypertensives (Table). Four variations of right atrial flow were observed Figure :a) vortical b) helico-vortical c) helical [SVC and IVC flow twist together in a helix]d) multiple vortices [arising variably from SVC and IVC flow]Vortical flow was most prevalent in the control group whilst the PFO/CS subjects were more likely to show one of the other flow patterns (Graph). Peak systolic and diastolic flow in both SVC and IVC were comparable between groups. However, peak diastolic flow in the IVC occurred earlier in the cardiac cycle when corrected for heart rate in the PFO/CS group than controls . The antero-posterior distance between the SVC and IVC was comparable between groups. The right-left distance between the SVC and IVC was greater in the PFO/CS group than the controls A spectrum of right atrial flow patterns can be seen in the normal heart. The relative position of the SVC and IVC may influence the generation of these. Our findings suggest that variant flow patterns in the right atrium may contribute to the pathogenesis of CS in the presence of PFO, we hypothesise, by promoting a passage for paradoxical embolism. Further work is needed to better define the subsets of CS patients in whom the PFO should be regarded as pathological.Academy of Medical Sciences and Newcastle Hospital Charities."} +{"text": "The frequency of contact allergens is often regionally different and hence it regional identification is important for the prevention of allergic contact dermatitis (ACD).Aim of this study was evaluation of the frequency of particular positive results of patch test (APT).A total number of 127 patients from Outpatient Allergic Clinic MED-ALL Medical Centre (age 2-76 years old) with suspected ACD were examined using the most common allergens from the patch tests from the European Standard Series including nickel, pallatium, chrome, cobalt, fragrance-mix I and II, balsam of Peru, formaldehyde and propolis and one extra allergen -- house dust mite (HDM). The data obtained were subjected to statistical analysis.The highest positivity of APT was seen against HDM (67%), then nickel (51%), chrome (40%), cobalt (39%), pallatium (16%), propolis (16%), fragrance-mix I , balsam of Peru , fragrance-mix II formaldehyde . In the group of patients with positive results with HDM higher percentage is in younger group<18 years old (70%) with almost 68% of cases with strong positive results (++ or +++).HDM allergens play an important role in determining the clinical severity of allergic dermatitis and should be included in basic patch test series."} +{"text": "At present there are two methods to determine the chromosome health of unborn fetus in pregnant women. One is through maternal serum screening that is considered as simple but less sensitive method and the second options involves invasive methods like amniocentesis or chorionic villus sampling (CVS) for women who are found to be positive in maternal serum screening. Recent studies have demonstrated that non-invasive prenatal testing (NIPT) using cell-free fetal DNA (cfDNA) present in circulating maternal blood is considered as one the most effective method of screening for trisomy 21.The single nucleotide polymorphism (SNP) based Non-invasive Pre-natal test, being offered by Quest Diagnostics in technical collaboration with Natera Inc to determine chromosomal copy number by looking for specific patterns of (SNPs). This second generation technology analyzes cfDNA in a single reaction targeting 19,500 single nucleotide polymorphisms which are the most informative portions of an individual\u2019s DNA selected across all the analyzed chromosomes.et al., 2013 paper on total of 242 cases that include thirty two cases aneuploidy included trisomy 21 (n=25) which were correctly identified with 100% sensitivity and 100% specificity with no false positive and false negative. Another study by Zimmerman et al., 2012 study on 166 samples from pregnant women, including 11 trisomy 21, three trisomy 18, two trisomy 13, two 45, X, and two 47,XXY samples including 146 low risk pregnancies. The study also correctly reported the chromosome copy number of all five chromosomes in 145 samples that passed a DNA quality test.Two published study demonstrated in the women undergone both invasive chorionic villus samplings followed by karyotyping in conjunction with non-invasive prenatal testing the efficacy of test. Data from Nicolaides The studies had demonstrated that SNP based NIPT is considered as an effective method of screening for common chromosomal abnormalities with detection rate of more than 99% and false positive rate of less than 0.1%. The initial finding shows NIPT approach has potential to avoid invasive procedure and can be provided an option to high risk pregnancies i.e. those with advanced maternal age, screens positive for biochemical screening and history of pregnancies with previous aneuploidies."} +{"text": "Addiction is associated with medical consequences, due to direct drug effects, poor adherence to health-care recommendations, and poor quality of care. But little is known about how the spectrum of illicit drug use in primary care patients affects quality of medical care measures for chronic conditions. The objectives of this study were to determine the association between drug use and quality measures indicating failure to meet criteria for good blood pressure (BP) and blood glucose (BG) control among primary care patients identified by screening as using illicit drugs who also have hypertension and/or diabetes.The study population was adult patients presenting for primary care visits in an urban, safety-net hospital with recent illicit drug use or prescription drug misuse identified by screening and either hypertension or diabetes mellitus. The outcomes were failure to control: a blood pressure (primary), defined as systolic BP of 140 or higher or diastolic BP of 90 or higher, and b) blood glucose (secondary), defined as hemoglobin A1c of 8 percent or higher and Healthcare Effectiveness Data and Information Set [HEDIS] measures). Main independent variables were: days of drug use in the past month; drug type ; and severity of use . We fit separate longitudinal logistic regression models for each measure of drug use and each outcome.Overall, 40 percent (66/164) of the sample with hypertension failed to meet criteria for BP control and 42 percent (26/62) of those with diabetes failed to meet criteria for BG control. No significant associations were detected for any measure of drug use and BP or BG control, except those reporting cocaine use had higher odds of failing to meet criteria for BG control compared to those reporting marijuna use (adjusted odds ratio (AOR) 8.8, 95% CI: 1.9, 41.9). Higher severity of drug use was associated with higher odds of failing to meet criteria for BG control in an unadjusted model ; however, this association was not significant after controlling for age, gender, and race/ethnicity.In this cohort of primary care patients with drug use, type of drug but not frequency of use or severity was significantly associated with failure to meet quality measure criteria for control of hypertension and diabetes.Trial registrationidentifying number NCT00876941"} +{"text": "In nerve transfer, we transfer a physiologically active nerve to a distal, more important but irreparably paralyzed nerve. This surgical procedure is best done early within 6 months of the injury. Nerve transfer can be broadly classified into four categories: (1) Extraplexal; (2) Intraplexal and (3) Targeted nerve transfer.Prime extraplexal donors are the spinal accessory, phrenic and intercostal nerves. There are many combination of nerve transfer, depending upon the loss of action and available motors.For shoulder abduction: 1) Spinal accessory to supra-scapular: this transfer can be done from a dorsal approach; 2) Triceps branch of radial nerve to axillary from an anterior approachFor elbow flexion: 1) Spinal accessory to biceps and brachialis split sural nerve transfer: this extraplexal transfer involves using a reversed sural nerve graft and the two ends are used for the biceps and brachialis separately; 2) Ulnar to brachialis and median to bicepsFor Elbow extension: 1) Ulnar nerve to triceps; 2)Intercostal to TricepsFor wrist extension: Median nerve to ECRB branch of Radial nerveFor Finger extension: Transferring the FDS branch of median to posterior interosseous nerveFor distal Ulnar nerve neurotisation to prevent Claw deformity and sensation:Pronator quadratus branch of median to deep motor branch of Ulnar nerve"} +{"text": "We found that non-functional alleles of white, unable to produce a coding transcript, could reactivate in trans the expression of a wild type copy of the same gene silenced by heterochromatin. This new epigenetic phenomenon of transcriptional trans-reactivation is heritable, relies on the presence of homologous RNA\u2019s and is affected by mutations in genes involved in post-transcriptional gene silencing. Our data suggest a general new unexpected level of gene expression control mediated by homologous RNA molecules in the context of heterochromatic genes.In order to study the role played by cellular RNA pools produced by homologous genomic loci in defining the transcriptional state of a silenced gene, we tested the effect of non-functional alleles of the trans-reactivation. We found that genes, unable to produce a functional coding transcript, but with the potential of transcribing other RNA\u2019s within their gene body, strongly reactivate the transcription of a wildtype copy of the same gene silenced by heterochomatin. This new epigenetic phenomenon is heritable, relies on the presence of diffusible RNAs able to carry and transfer epigenetic information and is affected by mutations in genes involved in Post-Transcriptional Gene Silencing. Our data strongly suggest that homologous non-coding RNA can reactivate the expression of genes silenced by heterochromatin, thus defining a new unpredicted level of gene expression control in the context of heterochromatic genes.We discovered a new epigenetic phenomenon we called In recent years it has become increasingly evident that the expression of eukaryotic genomes is far more complex than it had been previously explored. An emerging body of evidence, coming from next generation sequencing approaches, is showing that the genomes of all studied eukaryotes are almost entirely transcribed, generating an enormous number of non-coding RNAs (ncRNAs) . The ENCparamutation v) (C). All autosomal lines tested carried an X chromosome with a w1118 allele. In order to clean the lines from the w1118 allele, we back crossed the original lines with deletions of the w gene (Df(1)w), before testing them for their interaction with the w* suppressing alleles. To help follow the transmission of individual chromosomes, female chromosomes are represented in pink while male chromosomes are shown in blue.Detailed description of cross schemes and fly genotypes tested as experimental and control classes to measure (JPG)Click here for additional data file.S5 Fig(A) Loss of function mutations in smaug (smg1) and pumilio (pum13), two RNA binding protein involved in mRNA destabilization in flies, are embryonic lethal. Thus, the ability of smg1 and pum13 loss of function alleles to modify the levels of eye pigmentation (trans-reactivation) we scored in wm4h/w* females (+) was tested in heterozygosis (pum and smg). Polytene chromosome FISH using genomic probes covering the entire w gene (with the exception of the first intron) and coding sequences for the hsp70 gene (mapping chromosome 3R) on homozygous wwt/wwt(B), and transheterozygous wm4h/\u0394w(C) combinations. FISH signals for white (red) and hsp70 (green) genomic sequences are indicated by arrowheads. The asterisk indicate the region of pericentric heterochromatin. The X indicates the chromosome where the w gene maps.(JPG)Click here for additional data file.S6 Figtrans-generational inheritance of wm4htrans-reactivation from (F1) trans-heterozygous wm4h/w* females when crossed with parental w*/Y (A) or \u0394w /Y (B) males. To help follow the transmission of individual chromosomes, female chromosomes are represented in pink while male chromosomes are shown in blue. (C) Trans-generational inability of a wild type w+ allele (coming from an OreR stock) to trans-reactivate in F2 the wm4h locus. Eye pigment quantification and representative eye pictures of the parental (P), F1 and F2 progenies for each genotype tested are shown.Detailed description of cross schemes and fly genotypes tested as experimental and control classes to measure (JPG)Click here for additional data file.S7 Fig(A) and control (B) classes to measure trans-reactivation of wm4h during the process of gynogenesis. (C) Cross scheme used to test in heterozygosis the ability of loss of function alleles (Mut) to modify trans-reactivation. (D) Eye pigment quantification was conducted on adult flies of the indicated genotype and the Log2 ratio of wm4h/w* trans-reactivation in the mutant background over the normal levels of wm4h/w* trans-reactivation was used as a measure of the influence of the mutation tested in the onset of trans-reactivation. To help follow the transmission of individual chromosomes, female chromosomes are represented in pink while male chromosomes are shown in blue.Detailed description of cross schemes and fly genotypes tested as experimental (JPG)Click here for additional data file.S1 Tablew* alleles tested for their ability to modify in trans-heterozygosity the wm4h eye color variegation. Stocks that increased eye color variegation are highlighted in orange (Suppressors), the ones that did not have any effect are highlighted in light red (-). Tested white genomic deletions are highlighted in light grey. Finally, the mutation class, the mutagen employed and the Nature of the lesion, for each w* allele tested is reported when known.Genotypes of stocks carrying the (DOCX)Click here for additional data file."} +{"text": "The prevention and treatment of caries and non-carious lesions by means of remineralization has been studied for many decades. The theoretical basis for remineralization as a means of caries prevention and treatment is based on the retention of protein matrix in dental enamel at early stage of caries (white spot) and on the possibility of its remineralization.The detection of new structural formations and emerging information about morph-chemical properties of human and animal enamel have facilitated identification of a new approach not only to for caries prevention but also the creation of new, more effective formulations for oral health hygiene as well as, structural and metabolic reparation of tooth enamel.For ultrastructure and morph-chemical tooth enamel reconstruction, we applied dentifrice gel ROCS Medical Minerals which contains calcium glycerophosphate, magnesium chloride and xylitol. Participants were 10\u201330 years old, without any significant medical conditions. Each patient received 15 applications of the gel. Total of 57 subjects were divided to 4 groups depending on the diagnosis. All the subjects had indications for remineralizing therapy.st group consisted of 15 patients with early stage of caries (white spot).\u2022 The 1nd group was made up of 19 patients with systemic hypoplasia (spotted form).\u2022 The 2rd group consisted of 10 young subjects with significant hypersensitivity without any visible lesions .\u2022 The 3th group consisted of 13 subjects with hypersensitivity due to wedge-shaped lesions, abrasion or enamel erosion.\u2022 The 4The application of gel containing the new mineral complex of magnesium and calcium resulted in a positive remineralizing effect which was obtained in patients with early stages of caries as well as those with non-caries lesions. Further, white spots (early stage of caries) completely disappeared in 80% cases after 15 applications of the dentifrice. Thus, it appears that 15 procedures of remineralizing therapy with ROCS Medical Minerals are enough for mineralizing of white hypoplastic spots. Most patients with hypersensitivity (82% and 93% in two groups) noticed significant reduction of painful reactions after two 15-minutes applications. Finally, all subjects noticed a significant improvement of teeth appearance .In conclusion, the results suggest high efficacy of the mineral magnesium-calcium remineralizing complex in patients with early stages of caries as well as those with non-carious lesions."} +{"text": "Recent studies in the United Kingdom ,2] have have2] hWe surveyed Scottish intensive care trainees to ascertain whether such deficits are widespread and persistent.Trainees were invited to complete a web-based questionnaire on three occasions in June 2014. Responses in the form of ticked boxes or free text were collated and analysed for trends.Ninety-nine trainees replied, of whom 96 were based in anaesthesia, one in emergency medicine and two in allied medical specialties. Alarmingly, 70 respondents (71%) had been involved in managing an airway emergency in a patient with a tracheostomy or laryngectomy, 63 (90%) on a critical care unit and 40 (57%) on a general ward. Deficits in staff training and equipment were identified as contributory by 28 (40%) and 10 (14%) respondents, respectively. Most trainees (68%) felt quite confident in caring for neck breathers, with confidence increasing as training progressed. However, the majority of trainees accrued such confidence through exposure to these patients on theatre lists (80%). Only a minority had participated in simulated emergencies (33%) or a formal training course (14%). Almost half (49%) rated their training as deficient or absent and the vast majority (96%) felt there was a place for more formal tuition in caring for patients with a tracheostomy or laryngectomy.Our findings suggest that we are failing to prepare trainees for the challenges of managing airway emergencies in neck breathers. Divergence of anaesthesia and intensive care training in the UK may further compound this problem by reducing exposure to controlled subglottic airway management in theatre. The Scottish Intensive Care Society Trainee Committee has sought to address these deficits in training and reduce the burden of avoidable harm by incorporating sessions on tracheostomy management into its educational programme."} +{"text": "High numbers of tumour infiltrating lymphocytes has been associated with a significantly improved prognosis. Some of the key cell types involved are Cork Cancer Research Centre (CCRC) has long utilised an ablative cancer treatment that involves delivering a pulse of electrical energy (electroporation) directly to the tumour. This treatment results in the formation of reversible pores in the cell membrane, allowing up to a 1000 fold increase in chemotherapy drug absorption (Electrochemotherapy). A significant benefit of this non thermal ablation is the release of tumour associated antigens into the microenvironment, leading to activation of APCs and subsequent cross presentation of the antigens to circulating T and B cells. While ECT facilitates the priming of a favourable immune response, the combination of iCOS antibody, capable of stimulating T cell proliferation, causes a very robust mediated regression of treated tumours. In addition, ICOS is involved in humoral immune responses and increases the production of IL-4.+ and CD8+ T cells, CD45R+ B cells and CD11c+ DCs, post treatment.Preclinical work in aggressive murine models has yielded very encouraging results. The combinational therapy has achieved cures in both colorectal (CT26) and metastatic lung (LLC) cancer cell lines. Follow up immunohistochemical staining confirmed the presence of tumour infiltrating CD3"} +{"text": "Sedation management during weaning from mechanical ventilation is an important task for ICU nurses. Nurse-led sedation protocols have a favorable impact on weaning outcome , 2.To identify sedation practices among ICU nurses and to determine barriers towards use of sedation protocols.A cross-sectional, self-administrated survey was developed. Consensus on content validity was achieved through a Delphi procedure among experts. The survey was distributed and collected during the annual congress of the Flemish Society of Critical Care Nurses (Dec. 2014).423 attendants completed the survey (response rate: 66%) of which 342 ICU nurses were included for further analysis. These are employed in general (73%) or university hospitals (27%) and are working in mixed (66%), surgical (18%) or medical (13%) ICUs.Short working agents are most frequently chosen for analgo-sedation. A majority of respondents administer sedatives in continuous infusion with bolus doses (81%). Less than half of nurses have a sedation protocol (44%) but only minority consistently uses it (8%). Nurses in university hospitals reported higher availability of sedation protocols compared to general hospitals . Patient-targeted protocols are most available (53%). They are mostly developed particularly by MDs (79%) and nurses (52%). Level of sedation is generally evaluated per 2 hrs (56%) and with use of a RASS scale (59%). Daily interruption of sedation (DIS) is applied variably and usually to evaluate the neurological status (86%) and to shorten the duration of ventilation (44%). 78% of nurses report not to apply DIS at night. Patients' discomfort is the most important barrier to execute DIS (49%). Nearly half of respondents pointed out respiratory deterioration is the greatest concern during DIS (47%). For 40% of nurses it is risk of self-extubation and removal of the catheters. Agitation/confusion (66%) and lack of comfort and pain (46%) are the most frequently reported problems associated with sedation reduction.There appears to be a considerable discrepancy between recommendations and sedation practice. This data demonstrate room for quality improvement initiatives."} +{"text": "Few studies have investigated the use of viscoelastic devices for monitoring of treatment with LMWHs and to our knowledge there are no studies comparing different LMWHs or different visocoelastic methods.Enoxaparin (Klexane) and tinzaparin (Innohep) were added to 2 ml citrated blood from 10 intensive care patients to obtain plasma concentrations of 0, 0.5, 1.0 and 1.5 IU/ml enoxaparin and tinzaparin, respectively. The study was approved by the local ethics committee and with written consent (relatives). Clot formation and clot retraction was studied using ROTEM and ReoRox.ROTEM analysis showed prolonged clot formation (CT) with increasing concentrations of enoxaparin and tinzaparin (more so). ReoRox analysis showed that the initiation of clot formation COT1) increased with increasing doses of enoxaparin and tinzaparin (more so), as did the progression of clot formation (COT2 - COT1), thus resulting in a prolongation until complete clot formation (COT2). See Table increaseClot initiation was prolonged with both drugs and detected by both ROTEM and ReoRox. Clot formation was more decreased with tinzaparin than enozaparin and only detected by ReoRox."} +{"text": "Impaired right ventricle (RV) function is associated with worse outcome in ARDS. Pulmonary artery pressure waveform analysis provides information about phenomena that affect RV performance. In particular, pulmonary vascular wave reflection (WR) is directly related with RV stress. We hypothesised that open lung ventilation (OLV), compared with conventional ARDS-net ventilation (CV), would improve conditions for RV performance in an ARDS model. This hypothesis was tested by measuring pulmonary vascular wave reflection (WR).To evaluate the effect of two mechanical ventilation (MV) strategies on WR in an experimental model of ARDS.8 anesthetized and muscle relaxed pigs were submitted to a two-hit lung injury model combining repeated lung lavages with injurious MV. After lung injury was induced, animals were randomized (4 pigs in each group) to one of two strategies of MV: OLV, PEEP 2cmH2O above the PEEP corresponding with the maximal dynamic compliance in a decreasing PEEP trial after a recruitment manoeuvre; or CV, PEEP adjusted according to the ARDSnetwork table. In both groups tidal volume was 6ml/kg, respiratory rate to maintain PaCO2 between 55-65 mmHg and FIO2 to maintain PaO2 55-80 mmHg.1 and quantify WR. The following indexes of WR were calculated: Backward wave amplitude (APbw); Reflection index (RI) which is the ratio between the backward wave amplitude and the sum of backward and forward wave amplitude. Evaluation was done before (BL) and after lung injury (ARDS) and after 4 hours of management in the respective MV strategy.Pulmonary artery (PA) flow and pressure waveforms (1000Hz sampling rate) were acquired by a high-fidelity microtip manometer and an instantaneous transonic pulmonary flow probe placed in the main PA by a small lateral thoracotomy. These signals were used to separate the forward and backward components of the pressure waveformWe did not find any significant changes by induction of ARDS but both APbw and RI were lower in OLV comparing with CV.In this experimental ARDS-model OLV decreased WR in the pulmonary vascular system comparing with CV, indicated that OLV could reduce the stress on the RV and improve conditions for RV performance."} +{"text": "Traumatic injury of the central nervous system (CNS) has severe impact on the patients\u2019 quality of life and initiates many molecular and cellular changes at the site of insult. Traumatic CNS injury results in direct damage of the axons of CNS neurons, loss of myelin sheaths, destruction of the surrounding vascular architecture and initiation of an immune response. Class III semaphorins (SEMA3s) are present in the neural scar and influence a wide range of molecules and cell types in and surrounding the injured tissue. SEMA3s and their receptors, neuropilins (NRPs) and plexins (PLXNs) were initially studied because of their involvement in repulsive axon guidance. To date, SEMA3 signaling is recognized to be of crucial importance for re-vascularization, the immune response and remyelination. The purpose of this review is to summarize and discuss how SEMA3s modulate these processes that are all crucial components of the tissue response to injury. Most of the functions for SEMA3s are achieved through their binding partners NRPs, which are also co-receptors for a variety of other molecules implicated in the above processes. The most notable ligands are members of the vascular endothelial growth factor (VEGF) family and the transforming growth factor family. Therefore, a second aim is to highlight the overlapping or competing signaling pathways that are mediated through NRPs in the same processes. In conclusion, we show that the role of SEMA3s goes beyond inhibiting axonal regeneration, since they are also critical modulators of re-vascularization, the immune response and re-myelination. Class III semaphorins (SEMA3s), apart from their classical axon repulsive properties, exert regulatory functions in a variety of non-neuronal cells associated with CNS trauma.Neuropilins (NRPs) are pleiotropic receptors involved in multiple signaling pathways controlling tissue remodeling following CNS trauma.Semaphorin signaling is regulated at several levels, including receptor complex formation, proteolytic cleavage and interaction with extracellular matrix molecules.Interfering with class III semaphorin signaling might be beneficial for axonal re-growth, re-vascularization, re-myelination and manipulation of the immune response following CNS trauma.The semaphorin family consists of secreted and transmembrane glycoproteins that are involved in many cellular functions. Semaphorins (SEMAs) are subdivided into eight classes based on amino acid sequence similarities and structural features. The first two classes of SEMAs are found in invertebrates, class III till VII belong to vertebrates, while class VIII semaphorins are only expressed by viruses injuries due to their presence in neural scar tissue. The expression of SEMA3s following CNS trauma is suggested to be important in both the acute and sub-acute/chronic phases of scar formation. To date there is data showing Sema3A mRNA up-regulation as early as 1 day after CNS penetrating lesions and a small CSPG called Decorin. ChABC digests the chondroitin sulphate (CS)\u2014 glycosaminoglycan (GAG) chains of CSPGs, while decorin suppresses multiple repulsive proteoglycans in the extracellular matrix. Among the repulsive molecules that could be affected from treatment with the above approaches is SEMA3A which in earlier in vitro, but was unable to enhance axonal regeneration and functional recovery after SCI in vivo from Sema3A-induced apoptosis after optic nerve axotomy enhances axonal regeneration in an in vitro model of cerebral ischemia. VEGF rescued cultured CNS neurons from hypoxia and glucose deprivation induced apoptosis and receptor complexes consisting of NRPs and VEGFRs , there is degeneration of the vascular architecture and the hypoxic regions display dysregulated hyper revascularization. Interestingly, the newly formed blood vessels are not capable to reach the neural retina. The inflammatory and ischemic stress induced expression of Sema3A by RGCs prevented revascularization of the eye since RGC-derived Sema3A repelled blood vessels and inhibited EC growth , which in turn, inactivates integrin receptors. Secondly, Sema3E induces the activation of ADP-ribosylation factor 6 (Arf6) positive vesicles that promote internalization of integrin receptors. In contrast to these functions of SEMA3s as inhibitors of angiogenesis and integrin functions, Sema3C promotes angiogenesis in vitro by activation of integrins and their receptors are key modulators of the immune response secrete cytokines that can be toxic for CNS neurons, while the non-classical anti-inflammatory type 2 macrophages (M2) can promote neuroregeneration across neuronal repulsive substrates signaling, which is NRP1-independent, exerting anti-proliferative and immunosuppressive effects that induce fibrosis and non-canonical signaling pathway which is NRP1-dependent and can antagonize canonical signaling As mentioned earlier in this review blockage of SEMA3s signaling might favor revascularization and thus the innate ability of the organism for effective clearance and recycling of the excessive inflammatory cells through the circulatory pathway; and (2) NRP1 receptors of inflammatory cells may become available for TGF-\u03b2 signaling, which suppress the immune response perhaps more sufficiently than SEMA3s. Therefore, the role of SEMA3s in modulating the immune response after traumatic CNS injury needs to be investigated in more detail.Trauma of the CNS induces mechanical forces that cause loss of OLs and demyelination of axons at and surrounding the injury site. The loss of myelin sheaths decreases the conduction velocity of action potentials and could result in axonal degeneration. The reestablishment of myelin sheets around demyelinated axons and around newly sparsely formed regenerating axons, a process called remyelination, is therefore important to regain neuronal function after brain and spinal cord injuries axonal regeneration; (2) re-vascularization; (3) immune response; and (4) re-myelination (Figure axonal rIn the sub-chronic and chronic phase of CNS injury SEMA3s may inhibit axonal regeneration by inducing apoptosis of neurons and by preventing axons to penetrate scar tissue. They may also restrict re-vascularization by SEMA3B inhibition of the recruitment of pericytes that normally stabilize new blood vessels and by SEMA3A mediated elevation of the vascular permeability of blood vessels even when the expression of VEGFA declines. This increased vascular permeability may have a direct impact on the chronic immune response where SEMA3s are shown to inhibit the proliferation of recruited T-lymphocytes and antagonize the synthesis of cytokines such as IL-2, IL-4, IL-10 and IFN\u03b3. Furthermore SEMA3A induces apoptosis of microglia that express NRP1 and thereby influence the survival and axonal regeneration capacity of injured CNS neurons. Additionally SEMA3A induces cell death of M2 macrophages and could thereby induce a \u201cpro-inflammatory\u201d M1 macrophage environment in the scar. An intriguing but yet not fully established hypothesis is that SEMA3s might modulate TGF-\u03b2 non-canonical signaling via NRPs at inflammatory cells near the scar tissue. Finally, re-myelination is also affected by SEMA3s at the chronic stages of injury. In particular SEMA3A inhibits the recruitment and differentiation of OPCs and inhibits the mobility of migrating Schwann cells. In contrast, SEMA3F promotes OPC migration and remyelination. Lastly, SEMA3A signaling via NRP1 might antagonize furin-processed SEMA3F, EGF and PDGF signaling pathways that all posses the ability to stimulate remyelination.Since the discovery of Sema3A in 1993, SEMA3s signaling and their receptors were increasingly recognized to be involved in key processes influencing axonal outgrowth and guidance. However, substantial evidence indicates that SEMA3s also participate in cell-to-cell communication systems that underlie angiogenesis, inflammation and re-myelination. It will be necessary to combine the knowledge obtained from the research fields of vascular biology, cancer biology, immunology and glial biology in order to better understand the role of SEMA3s signaling in CNS trauma. A combinatorial approach involving these fields of research may be necessary in order to move closer towards a therapy for traumatic CNS injury. SEMA3s are an important target in strategies that aim to repair traumatic spinal cord and brain injuries, however the sometimes overlooked pleiotropic nature of their NRP receptors needs to be addressed/understood in a more thorough fashion in future studies.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Growing demand of resources increases pressure on ecosystem services (ES) and biodiversity. Monetary valuation of ES is frequently seen as a decision-support tool by providing explicit values for unconsidered, non-market goods and services. Here we present global value transfer functions by using a meta-analytic framework for the synthesis of 194 case studies capturing 839 monetary values of ES. For 12 ES the variance of monetary values could be explained with a subset of 93 study- and site-specific variables by utilizing boosted regression trees. This provides the first global quantification of uncertainties and transferability of monetary valuations. Models explain from 18% (water provision) to 44% (food provision) of variance and provide statistically reliable extrapolations for 70% (water provision) to 91% (food provision) of the terrestrial earth surface. Although the application of different valuation methods is a source of uncertainty, we found evidence that assuming homogeneity of ecosystems is a major error in value transfer function models. Food provision is positively correlated with better life domains and variables indicating positive conditions for human well-being. Water provision and recreation service show that weak ownerships affect valuation of other common goods negatively (e.g. non-privately owned forests). Furthermore, we found support for the shifting baseline hypothesis in valuing climate regulation. Ecological conditions and societal vulnerability determine valuation of extreme event prevention. Valuation of habitat services is negatively correlated with indicators characterizing less favorable areas. Our analysis represents a stepping stone to establish a standardized integration of and reporting on uncertainties for reliable and valid benefit transfer as an important component for decision support. Goods and services obtained from nature\u2013ecosystem services (ES)\u2013are essential for human well-being , 2. ManyDespite this critique ES are valued in prominent assessments of natural capital , 18, 19,A first major critique refers to benefit transfer in its basic form. Benefit transfer averages monetary values (point estimates) from study sites and transfer them to a similar unsampled area by accounting for land use/land cover types only , 28, 29.A second critique originates from the complexity and heterogeneity of human-environmental systems. Due to the variation in site characteristics, e.g. socio-economic or biophysical feature , 31, andWith this publication we i) provide a conceptual base supporting the establishment of a standardized integration and reporting on uncertainties of benefit transfer. Building on this we ii) assess the transferability of monetary values of ES and identify major sources of uncertainty by using meta-analytical value transfer functions.We generated a spatially explicit database of 194 globally distributed cases studies covering 839 monetary values of ES from peer reviewed data collections , 36. We We combined two, peer reviewed databases with monetary valued ES , 36, seer >0.75 or r< -0.75) and Spearman\u2019s rho (\u03c1>0.75 or \u03c1< -0.75), for two categorical covariates chi-square test and for testing categorical and continuous one-way ANOVA. From 291 covariates 93 remaining were combined with the maps of standardized monetary values by overlay operation in ArcGIS. Combined maps were used as input for the value transfer functions . A BRT computes the relative influences (importance) of covariates for a BRT model, i.e. they identify major determinants of the variance in monetary values of ES. BRT also provide elasticity curves that account for non-constant marginal value changes over distinct socio-ecological conditions and thus quantify the change of monetary values in response to an alteration in one covariate (i.e. ceteris paribus) ; see S2 We tested different parameter of the BRT algorithm such as learning rate, tree complexity, minimal number of observations in terminal nodes and number of trees see , and choStatistical significant value transfer functions could be computed for 12 ES types based on 839 monetary values . Most important covariates were quantified and monetary values in unsampled areas extrapolated . If therIn an additional step confidence intervals were estimated to examine generalization failure of value transfer functions from training data . We reruFor the discussion of the results we conceptualized three major sources of uncertainty of value transfer functions: (i) Sample error, such as measurement error in input studies for value transfer functions or publication selection bias; (ii) errors originating from statistical estimation of BRT models (model performance and suitability of chosen approach for benefit transfer); and (iii) transfer error from generalization that encompasses distortions due to value transfer without fully accounting for site and study characteristics. Only covariates with >1% were analyzed for the six groups of covariates. Additionally, in a fourth point we provide information of the spatial application of the value transfer functions.All studies considered in the synthesized database come froThe final 12 cross-validated value transfer functions explain from 18% (water provision) to 44% (food provision) of the variance of monetary values . FurtherResults from the quantification of the importance of covariates for the value transfer functions indicate which site and study characteristics need to be considered in order to minimize transfer error from generalization. In The application of the value transfer function for spatial extrapolation of values in unsampled areas results in a map shown in In the following section we discussed the results in detail for 6 out of 12 ES. Food and water provision, climate and extreme events regulation as well as recreation and habitat service were selected, because they represent the highest variance of monetary values from each ES group , see Available input data: With 158 monetary values the largest data set is available for food provision. The majority of case studies examine fish provision (51%) in lower latitudes (93%) and in coastal ecosystems or inland wetlands (69%). Lower latitudes are most likely food-insecure regions with a high vulnerability to climate change . CoastalModel uncertainty: The value transfer function shows the lowest uncertainty and explains 44% of the variance in the data. Estimations of the confidence intervals show that for 91% of the terrestrial earth surface monetary values can be computed with low and medium uncertainty (1 to 80 Int.-$-2007 per ha), due to a high number of data points .Importance of covariates: Most important covariates are climate indicators (22%), followed by geographic and nature endowment (15%) and valuation methods (15%). Further influential are social covariates such as better life domains of human well-being (12%) and religion (3%) as well as the economic covariate agricultural subsidies (3%).2 per grid cell). Variance explained by distance to sea (9%) is a logical consequence from the distribution of studies and the focus on fish as food resource. In more landlocked areas the importance of fish in the food supply reduces and so does the monetary valuation of fish. Moreover, the type of biome explains 6% of the variance, but does only partly coincide with the land use classification used on the case studies itself. These show that coastal wetlands, coastal systems and cultivated areas (aquaculture) are most valued, and confirm previous findings from [Ecology: Covariates indicating climate and those on geographic and nature endowment show low values in areas with prevailing unfavourable growing conditions and low human-induced alteration of ecosystems <11%) or high amounts of alternative food products , followed by benefit transfer (17%) and group valuation (5%). With group valuation significant lower values are derived. Most studies (75%) based on group valuation were conducted for fish in India, a country where fish consumption represents only 2% of protein intake , which mSociety: The valuation of food increases with a lower unemployment rates (<10% of labour force) and a high number of people in working age (15\u201359 years), good education system as well as with improving sustainable well-being measured by years of life satisfaction achieved per unit of resource used (Happy Planet Index). These covariates directly relate to the better life domains of the Organisation for Economic Co-operation and Development (OECD), which are essential metrics for human well-being . This shEconomy: With increasing subsidies in agricultural sector the value for food provision decreases. Subsidies distort markets by promoting the production of agricultural commodities beyond market demand, thus, they encourage farmers and fishermen to rely on them instead of consumer wants .Application of value transfer function: Spatial extrapolation of values shows for food the highest uncertainties and lowest values are in India and parts of Africa . On contAvailable input data: For water provision one of the smallest datasets was available (26 case studies). Most of the case studies were conducted in climate sensitive lower latitudes (63%). Climate change is affecting the hydrologic cycle and directly impacts the water resource base, usage, and management, in particular in lower latitudes .Model uncertainty: The value transfer function for water provision shows the highest uncertainties and explains 18% of the variance . ConfideImportance of covariates: Most influential are ecosystem-based covariates that indicate biodiversity and water availability (67%), followed by type of biome (3%). Further important are covariates of social and economic indicators (22%).2 per grid cell), in particular, agricultural frontier areas of cropland foster high values for water provisioning . Third, deforestation explains 3% of the variance and is positively correlated with water values. Water availability, moreover, depends on the spatial (3%) and temporal allocation of water resources (2%). The more unequal rivers and lakes are distributed in an area the higher is the value for water provision. Seasonal variability or long-term climatic changes cause extended periods of droughts or water abundance. The type of biome explains 3% of the variance. However, the applied land use classification system differs from the actual biome type of the case studies. Taking case study based classification into account coastal wetlands and freshwater (rivers/lakes) show highest values, confirming [Ecology and society: Areas of high biodiversity threat and conservation value are positively correlated with monetary values and explain 21% of the variance. Biodiversity and water supply are strongly interrelated , 53. Drinfirming , 28, 29.Economy: The portion of privately owned forests is positively correlated with water provision value (5%). This confirms that weak ownerships might affect valuation of other common goods negatively . SimilarApplication of value transfer function: Spatial extrapolation of values shows the most certain and highest values in areas of high population growth and increasing pressures on water security, for instance in China, India, Java, eastern USA, south Mexico and Western Central America, south coast of Western Africa, and Mediterranean Europe . TransfeAvailable input data: From a total of 36 case studies , carbon sequestration was most frequently examined (68%), followed by other greenhouse gases (<2%) or remain unspecified (24%). The majority of studies were carried out in tropical and temperate forests (25%) as well as inland and coastal wetlands (45%). These biomes are seen as regions highly suitable for carbon sequestration , 59. MorModel uncertainty: With 38% of variance explained in monetary values the transfer model for climate regulation represents the third best prediction performance . For mosImportance of covariates: The most important covariates are ecosystem-based variables of nature threats (49%). Also relevant but explaining less of the variance are covariates indicating input measures of climate sensitive economic sectors (20%) and other economic variables (6%), followed by scale (7%), methods (6%) and social variables (4%),3) exist. Furthermore, the economic covariate inequality of income (6%) shows that the more unequal income is distributed the higher the value for climate regulation.Ecology and economy: Covariates of nature threats show that high values are associated with areas of high risk that unique biodiversity will soon be lost (30%) and high risk of erosion (19%). Covariates indicating input measures of climate sensitive economic sectors (e.g. energy production and water business) are positively correlated with monetary values for climate regulation. Most important covariates are: proportion of electricity production from hydroelectric sources (12%), annual mean of solar radiation (6%) and the water storage capacity of dams per country (2%). Values are high, for instance, in areas of lower latitudes where up to 99% of electricity is produced by hydroelectric power plants and where big artificial constructed water reservoirs , followed by direct market prices (16%) and avoided costs (11%). For direct market prices the highest values and for benefit transfer and replacement costs the lowest ones can be observed.Society: Social covariates of relevance are population density per country (2%) or the age of population (2%). Population density is negative correlated with monetary values. Surprisingly, case studies in countries with on average older population report higher values of climate regulation. One might hypothesize older people may have made in their lifetime perceiving changes in climatic conditions and associated consequences, thus, valuing climate regulation service higher than younger persons. This might be an indication for the \u201cshifting-baseline\u201d hypothesis, i.e. shifts of the reference points of human perception for estimating changes .Application of value transfer function: Applying the value transfer function shows that the most certain and highest values are computed for areas under threat of habitat alteration due to climate change or other land degradation processes. Examples are areas like the Sahel Zone, tropical islands and mountains, Mediterranean ecosystems, Eastern USA and parts of Europe . On contAvailable input data: The majority of case studies (82%) were conducted in areas of high vulnerability to extreme events and sites which are increasingly exposed to extreme events due to climate change \u201363. In 4Model uncertainty: The value transfer function for prevention of extreme events represents medium prediction performance and explains 21% of the variance in monetary values . TransfeImportance of covariates: The impact of extreme events depends on both ecological conditions and societal vulnerability. We found that with 64% the highest explanatory power is represented by covariates showing the inherent conditions of ecosystems, followed by socio-economic characteristics (33%) and covariates dealing with the spatial and temporal scale (3%).Anthropogenic pressure on the ecosystem: Extreme event prevention is valued high in areas with advanced anthropogenic alteration of ecosystems characterized by highly changed biomass (HANPP 13%), high agricultural induced soil erosion rates (10%), degraded freshwater resources and riverine biodiversity (10%), dense infrastructure (5% market access), dense settlements with major markets (4% Anthromes) and high population density (3%). Hence, the risk awareness to weather extremes and natural hazards increases with number of people potentially effected and higher level of land-use and degradation. The more risk aware a society is, the more weight it places on strategies that preserve or build ecosystem resilience, and the higher the value it would allocate to ecosystem configurations that are more robust . This isSpecies richness and unemployment: We also found that areas with high species richness (4%) and high level of conservation priority (3%) show high valuation for extreme event prevention. These areas are characterized by high population, the highest population growth rates globally , 56 and Application of the benefit transfer function: Using the value transfer model for spatial estimations of extreme event prevention show that the most certain and highest valuations are situated in densely populated areas with advanced anthropogenic altered environments . The larAvailable input data: The database for the ES recreation services captures with 96 the most case studies. The majority of studies were conducted in major non-religious and Christian sites (73%) as well as lower latitudes (77%). Studies in developing countries < 4024 US-$) are underrepresented (26%). Subcategories of recreation services investigated are tourism (41%), hunting (<1%), ecotourism (<1%) and unspecific recreation (47%).Model uncertainty: The value transfer function for recreation services is with 33% variance explained the fourth most certain model . ConfideImportance of covariates: With 32% ecosystem-based covariates are the most influential group. In comparison with other value transfer functions, however, this is the lowest value . Further2 and a soil moisture index of 1 to 1.6. This corresponds to areas in the (sub-) tropics, see Ecology: More homogeneous environments receive lower values for recreation. The value transfer function shows that areas are low valued with intensive agricultural use (6%), a high number of people living on degraded land (2%) and low number of terrestrial protection areas (4%) and biodiversity (2%) as well as low ethnic diversity (1%). Surprisingly there is a negative effect of marine protection areas (4%) and length of coastlines (1%). This is due to the low number of case studies carried out in coastal areas (17%) and marine protection areas (16%). Furthermore, covariates on land use/land cover types explain 9% of the variance and show that wetlands and freshwater areas (river/lakes) are highest valued. The most important climatic covariates are solar radiation (3%) and soil moisture (2%). The latter one is strongly correlated with precipitation. Highest monetary values are shown for areas with 100 to 190 W/mEconomy and society: Economic covariates show that recreation is highly valued in wealthy countries. These countries are characterized by high market access (3%), low GDP growth (3%), low consumer prices (2%), positive trade balance and a high level of export to import ratio (3%). In wealthy countries the access to a greater share of ES and substitutes is provided, thus, the basis for recreation given. However, in areas with a high unemployment rate (6%) recreation values are high, too. We hypothesize these are sites where tourism is already established and an important economic factor. With increasing portion of privately owned forests the value for recreation is higher (1%). This shows that with the granting of property rights the valuation of common goods might be positively affected and emphApplication of value transfer function: Applying the value transfer function shows that the most certain and highest values are in the USA, most of the Mediterranean area, Caribbean islands, and Colombia . These aAvailable input data: The database for habitat service contains one of the smallest numbers of case studies .Importance of covariates: The group of ecosystem-based covariates contributes with 90% to the value transfer function . These aEcology and society: Habitat services are valued less in marginal areas, i.e. harsh growing conditions due to low soil quality (24%), arid climate zones with high drought potential (16%) and high UV exposure (26%). Marginal areas are mostly sparsely populated (1%) and characterized by low market access (3%). Also those areas are the home of poor people , 73 withApplication of value transfer functions: Spatial extrapolation shows the most certain values in low valued marginal areas like the highlands and drylands of Asia and sub-Saharan Africa, transition zones of the grassland to deserts of Australia as well as southern Latin Americas Andes Mountains, and the highlands and drylands of North America .Although \u201cmoney\u201d is seen as a well-known and easily understandable indicator, monetary valuation of ES is ambiguous and shows only a fraction of the multiple characteristics that give utility to the beneficiary . ApplyinThe data availability and the quality of input studies determine the sampling error. We only included valuation studies that were reviewed by experts as a minimal assurance of study quality. Although the peer review approach is often criticized it is also appreciated as an efficient method that increased the scientific progress over the past decades . The majAnother concern with respect to the input data refers to the aggregation of the monetary values. In order to create a comparable data base for spatially explicit value transfer modelling, monetary values need to be disentangled. Only values measured under marginal changes in the socio-ecological system were considered . We utilUtilizing BRT for spatially explicit, meta-analytic value transfer functions have inherent causes of error, too. Although this method is acclaimed to be one of the most sophisticated approaches for benefit transfer , 82 the The spatial application of the value transfer functions in unsampled areas generates transfer errors from generalization, which are determined by uniformity, spatial extent and resolution as well as temporal aspects , 83. We Regionalization error encompasses extrapolation errors due to generalization from a local case study to a wider region . All valThe major achievement of this study is, first, to clearly distinguish between major sources of uncertainties and to quantify patterns in the influence of different study- and site-characteristics that affect value transfer functions and predicted ES values. Second, the study identifies regions for which sufficient knowledge on our natural capital is available, i.e. a statistically defensible benefit transfer model can be applied in combination with uncertainty values. Third, we provide global maps of the \u201cwhite spots\u201d on our knowledge on accounting natural capital and ES. This provides guidance for future analysis and concerted action on the assessment of natural capital and ES within the work program of IPBES and the The integration of the presented value transfer functions in a fully automated spatial benefit transfer tool, such as the Ecosystem Valuation Toolkit , would bS1 FigThis map is the completion of the (TIF)Click here for additional data file.S2 FigTreemaps A) to L) represent models with covariates greater than 1%, their relative influence (or importance) and response. Rectangle groups delimited by bold black lines and numbered from 1 to 7 reflect groups of covariates mentioned in the main article (1) scale, 2) economy, 3) policy, 4) society, 5) ecology, 6) valuation methods, 7) rest <1%). The sizes of rectangles show the relative influence of covariates on a BRT model, in percentage. Rectangle colours illustrate the strength of relationship between monetary values and covariates. Greenish colours symbolize positive correlation and reddish negative, expressed in International-$-2007 per hectare. Multiple colours can occur for nonlinear effects of variables. Bluish colours represent categorical variables and show the maximum range between the levels.(TIF)Click here for additional data file.S3 FigThe graphs show the model performance for twelve parameter configurations. In the table below these configurations are specified. In addition to learning rate (lr), number of trees (nt) and minimal number of observations in the terminal nodes (mintn), there is also the selected model visualized. The selected model represents the final BRT model used for value transfer. It reduces the deviance of residuals in the model (squared error loss) the most and thus explains the variance of monetary values best.(TIF)Click here for additional data file.S1 TableThe table gives an overview of the case study references that were included for the boosted regression trees.(PDF)Click here for additional data file.S2 TableThe table shows sources of covariates either from valuation databases , 36 or f(PDF)Click here for additional data file.S1 Text(PDF)Click here for additional data file.S2 Text(PDF)Click here for additional data file."} +{"text": "Parkinson Disease (PD) is a neurodegenerative disease for which no cure is available yet. It is the second largest neurological disease affecting an estimated 571 per 100,000 people in Europe with rising prevalence due to the aging population sensory cues from the music as well as from the dance partner reported no adverse events during dance classes reported one single fall with no injury , ParkinsonFonds (20094), and EU (ERC-291339). EV received research-funding from ZonMw (630000012), Parkinson Vereniging (2013R16), ParkinsonFonds (20094), and the Hersenstichting (F2013141).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Ablation of adult neurogenesis in mice has revealed that young adult-born granule cells (abGCs) are required for some of the behavioral responses to antidepressants (ADs), yet the mechanism by which abGCs contribute to AD action remains unknown. During their maturation process, these immature neurons exhibit unique properties that could underlie their ability to influence behavioral output. In particular, abGCs in the DG exhibit a period of heightened plasticity 4\u20136 weeks after birth that is mediated by GluN2B-expressing NMDA receptors. The functional contribution of this critical window to AD responsiveness is unclear. Here, we determined the behavioral and neurogenic responses to the AD fluoxetine (FLX) in mice lacking GluN2B-containing NMDA receptors in abGCs. We found that these mice exhibited an attenuated response to FLX in a neurogenesis-dependent behavioral assay of FLX action, while neurogenesis-independent behaviors were unaffected by GluN2B deletion. In addition, deletion of GluN2B attenuated FLX-induced increases in dendritic complexity of abGCs suggesting that the blunted behavioral efficacy of FLX may be caused by impaired differentiation of young abGCs. Adult hippocampal neurogenesis is a process that results in the generation of new neurons in the dentate gyrus (DG) throughout life Gross, . After tDuring the maturation process, abGCs exhibit distinct properties that could underlie their ability to influence behavioral output of Grin2b. In the presence of Cre, exon 9 gets excised. Western blotting performed using an antibody that targets the C-terminal domain downstream of exon 9 has shown decreased GluN2B expression following Cre recombination, demonstrating that excision of exon 9 results in the complete absence of GluN2B, not merely a truncated protein product was injected once per day for 2 days just prior to the start of AD treatment. For dendritic morphology analysis, AD treatment began ~5 weeks after TMX administration and BrdU was injected 4 times over 8 h the day before AD treatment began. For all mice, FLX (18 mg/kg/day in water) or vehicle was delivered by oral gavage and in the drinking water (160 mg/mL) at a schedule of 5 consecutive days gavage followed by 2 consecutive days of water, then repeated for the duration of treatment.All behavioral experiments were conducted in male mice 18\u201324 weeks of age.In the novelty suppressed feeding (NSF) test, chronic AD treatment decreases latency to feed in the center of a novel arena after overnight food deprivation is a behavioral despair test during which the mobility of mice suspended by their tail is measured. A depressed-like state is characterized by greater immobility while ADs are able to decrease immobility consisting of both open and closed arms and were given 5 min to explore. The test was video recorded and activity was measured using TopScan software. Their preference for open (anxiogenic) or enclosed (anxiolytic) spaces was used to assess anxiety Hogg, .http://fiji.sc/Fiji) where dendritic length was measured using the freehand trace tool and Sholl analysis was conducted using the Sholl analysis plug-in with parameters previously described , brains postfixed, cryoprotected, and sections (35 \u03bcm) of the entire DG were labeled for BrdU, glial fibrillary acidic protein (GFAP), neuronal nuclei (NeuN), doublecortin (DCX), Ki-67, or green fluorescent protein (GFP) , as previously described , while an encoding region immediately preceding the first transmembrane domain of GluN2B is flanked by loxP sites . TMX injection in adult mice leads to deletion of GluN2B and expression of YFP in neural precursor cells (NPCs) and their subsequent progeny or in an assay of anxiety that was insensitive to FLX in this strain of mice (EPM). While some studies in rodents do find that chronic AD treatment results in an anxiolytic phenotype in the EPM -dependent mechanism. Chronic SSRIs have been shown to increase BDNF in the DG . RH is supported by the National Institute of Mental Health (R37 MH068542 [MERIT]), the National Institute on Aging (R01 AG043688), the National Institute of Neurological Disorders and Stroke (R01NS081203), NYSTEM (C029157), and the Hope for Depression Research Foundation (RGA 11-024). MK was supported by a NIH grant (K01MH099371), a NARSAD Young Investigator Award from the Brain & Behavior Research Foundation, and NYSTEM (C029157).RH receives compensation as a consultant for Roche and Lundbeck. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Mortality of ICU patients is a global parameter reported as an end-point in numerous studies. However, causes and characteristics of patients' death are studied only in particular pathologies such as sepsis, cardiac arrest or ARDS , 2)..2]).The aim of our study was to analyse causes and circumstances of death in a general ICU population.We performed a prospective observational study. Every ICU included all death occurring during a month randomised in the year of the study. Demographic data were collected as well as circumstances of death (organ failure and organ support at this time). An organ failure was defined by a SOFA sub-score \u2265 3. Population of the study was dichotomised in expected death and unexpected death . Data are expressed as median and IQR. Comparisons were made by a Mann-Whitney or chi-squared tests as appropriate. A p value < 0.05 was considered as statistically significant.Ninety-six ICUs included 698 dead patients during the study time. Main characteristics of the population and their comparison between expected (n=473) and unexpected deaths (n=225) are reported in the table.At the time of death, 586 (84%) patients presented at least one organ failure: cardiovascular (58%), respiratory (31%), renal (33%), neurologic (30%), liver (8%) and coagulation (8%). At the same time, an organ support was used in 440 (63%) patients: catecholamines (63%), mechanical ventilation (85%), renal replacement therapy (28%) and liver dialysis (1%). Comparison of these parameters between groups is reported in the figure.Patients who died in ICU presented, most of the time, at least one organ failure. Expected death patients exhibited more neurologic and respiratory failures whereas cardiovascular failure was more prominent in unexpected death. In the latter group of patients, the proportion of organ support was higher corresponding to a greater intensity of care."} +{"text": "The PI3K-AKT pathway has been shown to complement activation of the MAPK pathway in melanocyte transformation in preclinical models. We have utilized clinical specimens and cell lines to examine the regulation, functional role, and clinical significance of the PI3K-AKT pathway in melanoma.All analyses of clinical specimens were performed under protocols approved by the MD Anderson Institutional Review Board. Identities of cell lines were confirmed by STR-fingerprinting, and cell lines were genotyped by sequenom analysis for hotspot mutations. Reverse phase protein array (RPPA) analysis was performed by the MD Anderson RPPA Core Facility.Proteomic analysis of frozen melanoma clinical specimens and cell lines demonstrated that phosphorylation (activation) of AKT (P-AKT) correlated inversely with PTEN protein expression. Confirmatory analysis of PTEN expression by an immunohistochemical (IHC) assay on archival tumor samples identified a linear correlation between PTEN measurement by IHC and RPPA. Significantly increased expression of P-AKT was observed in melanomas with complete loss of PTEN protein expression compared to tumors with any other pattern of PTEN expression. Integrated analysis of BRAF/NRAS mutation status, PTEN expression, and clinical outcomes was performed using lymphadenectomy specimens from patients who underwent surgery for stage IIIB/C melanoma. Complete loss of PTEN expression correlated with shorter overall survival and time to brain metastasis on univariate and multivariate analyses. Testing of human melanoma cell lines demonstrated that cells with baseline or compensatory activation of the PI3K-AKT pathway were generally resistant to apoptosis induction following BRAF or MEK inhibition. Extended molecular profiling found that a subset of melanoma cell lines with de novo and acquired resistance to MEK inhibitors are characterized by increased expression of PGC1alpha and a metabolic phenotype of high oxidative phosphorylation (OxPhos). The resistant high OxPhos cell lines all demonstrated synergistic growth inhibition and apoptosis induction with combined targeting of MEK and mTORC1/2. mTORC1/2 inhibition decreased PGC1alpha expression in vitro and in vivo, and caused cytosolic localization of MITF. Treatment with a MEK inhibitor and an mTORC1/2 inhibitor demonstrated marked synergy in a BRAF-mutant, MEK inhibitor resistant human melanoma cell line in vivo.Activation of the PI3K-AKT pathway correlates with clinical outcomes and resistance to MAPK pathway inhibitors in melanoma. These findings support the rationale to determine the clinical benefit of inhibiting the PI3K-AKT pathway in this disease."} +{"text": "We hypothesize that changes of shape of arterial blood pressure (ABP) high-frequency waveform signal can be reflective of body's response to stress, in particular to hemorrhage.To apply Machine Learning (ML) and sequential pattern extraction to ABP waveforms to reliably detect slow bleeding.62 healthy pigs are anesthetized, intubated, ventilated, and instrumented prior to and during a controlled bleeding at a rate of 20 ml/min. ABP is recorded at a 250 Hz rate. To estimate the likelihood of bleeding, our algorithm:(1) Extracts 10 s disjoint intervals of ABP waveform and standardizes the time series to zero mean and unit standard deviation;(2) Discretizes the standardized data into a sequence of symbols each reflective of a particular value of the standardized ABP;(3) Identifies which sequential patterns of symbols are present in the current interval data from among patterns previously extracted from training data using SPADE algorithm ;(4) Feed the identified sequential patterns into previously trained ML classifier (Random Forest) to predict current bleeding status of the subject. The procedure is empirically evaluated using leave-one-pig-out crossvalidation.Figure In addition, our method enables easy interpretation of learned patterns. An example in Figure ML and sequential pattern extraction enables effective monitoring of ABP waveforms for indications of hemorrhage. The presented approach can be used to enhance current practice of hemodynamic monitoring while helping clinicians interpret patterns of patients' physiological response to stress.Work partially supported by NSF (award 1320347) and by NIH (grant NR013912)."} +{"text": "Magnetic resonance (MR) conditional pacemakers are increasingly implanted into patients who may need cardiovascular MR (CMR) subsequent to device implantation. While the safety profile appears good, limited data exists regarding the indication and outcome of these examinations for clinical management.CMR and pacing data from consecutive patients with MR conditional pacemakers performed at our centre was retrospectively reviewed. Images were acquired at 1.5T (Siemens Magnetom Avanto). The indication for CMR and any resulting change in management was recorded. The quality of CMR was rated by an observer blinded to clinical details and data on pacemaker and lead parameters collected pre- and post- CMR.45 CMR scans on 42 patients performed between 2011 and 2014 were assessed. All scans were completed successfully with no significant change in lead thresholds or pacing parameters. Steady state free precession (SSFP)cines were non-diagnostic in 6/45 (13%) scans, but diagnostic in all patients when using gradient echo sequences (GRE). Late gadolinium enhancement imaging was performed in 39 patients and appeared less susceptible to artefact than cine images.The CMR data resulted in a new diagnosis in 19 (42%) of examinations, clinical management was changed in a further 14 (31%).CMR in patients with MR conditional pacemakers provided diagnostic or management-changing information in the majority (73%) of our cohort. The use of gradient echo cine sequences, which are less susceptible to metal artefacts, can reduce rates of non-diagnostic imaging.The study was funded by the NIHR Cardiovascular BRU. CER is supported by the British Heart Foundation."} +{"text": "To compare the effectiveness of constraint induced movement therapy versus motor relearning programme to improve motor function of hemiplegic upper extremity after stroke.A sample of 42 patients was recruited from the Physiotherapy Department of IPM&R and Neurology OPD of Civil Hospital Karachi through non probability purposive sampling technique. Twenty one patients were placed to each experimental and control groups. Experimental group was treated with Constraint Induced Movement Therapy (CIMT) and control group was treated with motor relearning programme (MRP) for three consecutive weeks. Pre and post treatment measurements were determined by upper arm section of Motor Assessment Scale (MAS) and Self Care item of Functional Independence Measure (FIM) Scale.Intra group analysis showed statistically significant results in all items of MAS in both groups. However, advanced hand activities item of MAS in MRP group showed insignificant result . Self-care items of FIM Scale also showed significant result in both groups except dressing upper body item in CIMT group and grooming and dressing upper body items in MRP group showed insignificant p-values.CIMT group showed more significant improvement in motor function and self-care performance of hemiplegic upper extremity as compared to MRP group in patients with sub-acute stroke assessed by the MAS and FIM scales. Thus CIMT is proved to be more statistically significant and clinically effective intervention in comparison to motor relearning programme among the patients aged between 35-60 years. Further studies are needed to evaluate CIMT effects in acute and chronic post stroke population. Stroke is the third leading cause of death and the most common cause of disability in the developed and developing countries. In Pakistan it is the leading cause of mortality and morbidity after cancer and ischemic heart disease.3Rehabilitation of upper extremity is a challenge, various therapeutic strategies like neurodevelopmental technique (NDT), splinting, biofeedback and electrical stimulation are designed, however the best method to improve upper limb function is still not clear.9This study is a randomized controlled trial carried out to evaluate the effectiveness of CIMT over motor relearning programme. Constraint induced movement therapy (CIMT) is proved to be effective in western countriesIn this randomized controlled trail 42 males and females stroke patients having first attack of stroke and hemiplegic upper extremity had functional level of \u2265 20 degrees of wrist extension and \u226510 degrees of extension of all digits were included. Subjects were between 35-60 years of age and diagnosed with ischemic or hemorrhagic strokes confirmed by CT/MRI scan. Patients were excluded if they had cognitive deficit, recurrent or cerebellar strokes, severe aphasia, balance and equilibrium problems, severe shoulder pain affecting therapy or other neurological deficits.The research was started after approval from institutional review board (IRB) of Dow University of Health Sciences (DUHS). Sample was recruited from Physiotherapy department of Institute of Physical Medicine & Rehabilitation (IPM&R) and Neurology OPD of Civil Hospital Karachi through non-probability purposive sampling technique. Informed consent was taken from the patients. Then patients were randomly allocated to CIMT group and MRP group by using computer-generated random numbers kept in sealed envelopes. Each group had 21 patients. After baseline assessment, patients in CIMT group were asked to perform tasks only with the hemiplegic upper extremity with the unaffected hand restraint in a mitt. The patients in MRP group were asked to perform tasks with both affected and unaffected upper extremities. Tasks were attempted in different positions like supine lying, sitting and standing.th visit. All the exercises were demonstrated to the patients by the therapist and were performed under the supervision of the therapist. Details of exercises are given in Both interventions consisted of 6 sessions per week, two hours duration of each session, for three consecutive weeks. Pre and post treatment evaluation of motor function of hemiplegic upper extremity was determined by using upper arm section of Motor Assessment Scale. Upper limb section of MAS includes, Upper arm function item, hand movements item and advanced hand activities item. An activity of daily livings (ADLs) was measured by using self care item of Functional Independence Measure Scale (FIM) which includes 5 items for quantitative data. A Non parametric Wilcoxon Signed Ranks test was conducted to find the significance of interventions used within the groups . To test the significance of changes in scores on each of the outcome measures between the groups , a Non parametric Mann Whitney test was used both at the baseline and at the end of 3A sample of 42 patients participated in the study and no patient dropped out. There were total 28 male participants (66.67%) and 14 (33.33%) female participants in both groups, the distribution of males and females in each groups was almost equal. The mean age of the participants was 49.67 years (SD = 7.01) in CIMT group and 49.47 years (SD = 8.19) in MRP group. Total patients who suffered from ischemic stroke were 32 (76.2%) and number of patients having hemorrhagic stroke were 10 (23.8%) respectively. At the end of third week, mean scores significantly increased in all items of both outcome measures (MAS and FIM) in both CIMT and MRP groups. However, mean value in CIMT group was greater than in MRP group, showing better improvement in CIMT group & III. Ird week. Post treatment P-value showed statistically significant results in all items of MAS and FIM Scale accept dressing upper body item.For inter-group analysis a non parametric Mann Whitney test was used at baseline and at the end of 3This study showed the effectiveness of constraint induced movement therapy (CIMT) over motor relearning programme (MRP) to improve motor function of hemiplegic upper extremity in sub-acute stroke patients. The affected patients in the present study were between two weeks to three months post stroke. CIMT initiated within 2 weeks of stroke onset is more effective in upper extremity rehabilitation.12This study results are in agreement with Myint et al. (2008)9In the present study an alteration was made from the original protocolCIMT is considered to attain its beneficial effects by 2 associated but independent mechanisms: overcoming learned nonuse and use-dependent neural plasticity.18The second mechanism by which CIMT has been established to give good functional results is use-dependent neural plasticity.20CIMT group showed more significant improvement in motor function and self-care performance of hemiplegic upper extremity as compared to MRP group in patients with sub-acute stroke assessed by the MAS and FIM scales. Thus CIMT is proved to be more statistically significant and clinically effective intervention in comparison to motor relearning programme among the patients aged between 35-60 years. Further studies are needed to evaluate CIMT effects in acute and chronic post stroke population."} +{"text": "Maturity Onset Diabetes of the Young 3 (MODY3) is the most common monogenic form of diabetes, characterized by early age of onset (before the age of 25), autosomal dominant transmission and severe defect in insulin secretion ,2. MODY bmf gene expression knockout on beta cell mass and islet organisation in a transgenic mouse model of MODY3.To study the role of Bmf (Bcl-2 modifying factor) in the pathogenesis of MODY3, immunohistochemical staining of male and female pancreatic islets for insulin- and glucagon-positive expression utilising confocal microscopy followed by Image J analysis were used to investigate the effect of Bmf gene expression knockout was observed to significantly increase beta cell mass in DN-HNF1a-expressing transgenic male pancreas (p=0.04) but had no observable effect on transgenic female pancreas. Surprisingly, islet disorganisation was seen in both male and female transgenic mice and was not rescued by bmf knockout.Data generated from this study indicate a possible role for Bmf in beta cell mass reduction and thereby the pathogenesis of MODY3 but demonstrates no effect on islet organisation. These data can be built upon by further research to examine in greater detail how Bmf contributes to the characteristic loss of beta cell mass in MODY3 and in mediating DNHNF1a-induced apoptosis."} +{"text": "We assessed and compared abiotic preferences of aquatic macroinvertebrates in three river basins located in Ecuador, Ethiopia and Vietnam. Upon using logistic regression models we analyzed the relationship between the probability of occurrence of five macroinvertebrate families, ranging from pollution tolerant to pollution sensitive, and physical-chemical water quality conditions. Within the investigated physical-chemical ranges, nine out of twenty-five interaction effects were significant. Our analyses suggested river basin dependent associations between the macroinvertebrate families and the corresponding physical-chemical conditions. It was found that pollution tolerant families showed no clear abiotic preference and occurred at most sampling locations, i.e. Chironomidae were present in 91%, 84% and 93% of the samples taken in Ecuador, Ethiopia and Vietnam. Pollution sensitive families were strongly associated with dissolved oxygen and stream velocity, e.g. Leptophlebiidae were only present in 48%, 2% and 18% of the samples in Ecuador, Ethiopia and Vietnam. Despite some limitations in the study design, we concluded that associations between macroinvertebrates and abiotic conditions can be river basin-specific and hence are not automatically transferable across river basins in the tropics. Benthic macroinvertebrates have often been used for water quality monitoring and assessment Most macroinvertebrate-based water quality assessment methods have been developed in temperate climate regions where relationships between environmental variables and the occurrence of macroinvertebrate taxa are well documented. Due to the infancy of the macroinvertebrate-based monitoring and assessment in the tropics The aim of this study was to assess if abiotic preferences of aquatic macroinvertebrates differed between three river basins in the tropics. We investigated associations between physical-chemical variables and macroinvertebrate occurrences in one Ecuadorian, one Ethiopian and one Vietnamese river basin. Five representative macroinvertebrate taxa, ranging from pollution tolerant to pollution sensitive were selected and their preferences towards environmental conditions were compared using regression-based ecological models.\u22121), dissolved oxygen concentration (mg.L\u22121), pH (-), stream velocity (m.s\u22121) and water temperature (\u00b0C) (Samples were taken in the Chaguana river basin (Ecuador), Gilgel Gibe river basin (Ethiopia) and Cau river basin (Vietnam) \u2013S3. In eure (\u00b0C) .Benthic macroinvertebrates were sampled, identified and quantified according to the method described in Gabriels et al. Boxplots were used for data exploration. The first series of boxplots visualized the seasonality of the physical-chemical variables per river basin. The second series of boxplots summarized for each macroinvertebrate family and per physical-chemical variable and river basin the conditions under which the taxon was present and absent. Boxplots were constructed with the R software The univariate associations between explanatory variables were assessed with pairwise Spearman's rank correlations, which is often used in ecology due to its nonparametric nature The occurrence of five macroinvertebrate families was related to the physical-chemical water quality conditions using a regression-based model and these relationships were compared between three river basins situated in the tropics. Logistic regression models (LRMs) were used to infer relationships between occurrences of five aquatic macroinvertebrate families and environmental data. LRMs have been frequently used to model the presence or absence of a species in relation to environmental variables A hierarchical backward elimination model selection method was carried out to build the LRM. The starting model included five physical-chemical variables , season and river basin (represented as country). In addition to the main effects, two-way interactions between the physical-chemical variables and the river basin as well as between season and river basin were included and S2. Residual plots and the extended Hosmer-Lemeshow test for LRMs based on GEE The outcome of the LRM per family was visualized as the estimated probability that the family was present as a function of a physical-chemical variable. The explanatory variables different from the one on the x-axis, were set to their river basin specific medians and the season to \u201cdry\u201d. The river basin-specific observed range of the corresponding physical-chemical variable were plotted as horizontal boxplots below the response curves and were subdivided between presence and absence points. The gray-colored ends of the response curves indicate extrapolation outside the observed range of the corresponding physical-chemical variable.For the data exploration, the effects of season and river basin on the continuous physical-chemical variables were assessed using a linear regression model fitted with GEE for accounting for the clustered sampling scheme. Only few p-values were reported in the main text to prevent information overload, all p-values were summarized in The observed range of physical-chemical water quality conditions was not always equal between river basins. Seasonal effects were observed for all physical-chemical variables and the seasonal effect of conductivity and stream velocity was similar for the three river basins \u2013S8. DissThe prevalence values, known as the relative frequencies of occurrence of taxa , i.e. the effect of water temperature on the occurrence differed between river basins . AlthougThe effect of water temperature on the probability of occurrence of Baetidae differed between river basins p<0.01; . Indeed,Associations between the DO concentration, pH, stream velocity and water temperature relative to the probability of occurrence of Hydroptilidae were similar across river basins . Only thThe associations between water temperature (p<0.01), stream velocity (p\u200a=\u200a0.02) and DO concentration (p\u200a=\u200a0.02) and the probability of occurrence of Libellulidae differed between river basins . WhereasAssociations between stream velocity and S54,\u22121 for optimal health For pollution tolerant macroinvertebrate families (e.g. Chironomidae (TS2)) only few significant associations between physical-chemical conditions and the occurrence of the families were found suggestiHabitat suitability of macro-invertebrates probably depends on more factors than those included in our statistical analysis. For instance, additional to the variables that were included in our analysis, Al-Shami et al. Seasonal changes of environmental variables were taken into account The outcome of the LRM per family was visualized as the estimated probability that the family was present as a function of a physical-chemical variable e.g. \u20135. WithiThe fact that river basin dependent associations were found is not surprising. For instance, Bonada et al. Since the range of the observed physical-chemical conditions were not always equal between river basins, in some cases extrapolations outside the observed range were shown . For insNo relation was found between the occurrence of Leptophlebiidae and stream velocity in the Ethiopian and the Vietnamese river basin. However, according to the data Leptophlebiidae occurred in both river basins in upstream sampling sites with a moderate to high stream velocity. The reason for the non-significant relation is the prevalence of the present-points. In the Vietnamese and Ethiopian river basin, Leptophlebiidae were only present in 18% and 2% of the samples, respectively. Consequently, the occurrence of Leptophlebiidae seems statistically not associated with stream velocity. Therefore, due to unbalanced dataset prevalence it is possible that not all models obtained represent true ecological relations Presence and absence data are commonly used in macroinvertebrate research e.g., as they As an alternative to the conventional taxonomic division of the benthic invertebrates one can use functional traits to categorize macroinvertebrate assemblages e.g., . Such a Overall, LRMs based on GEE are a flexible way to model the probability of occurrence of macroinvertebrates as a function of environmental variables. We revealed similar as well as dissimilar abiotic preferences of macroinvertebrates between the three river basins, but these estimated probabilities are restricted to the observed range of the predictor within each river basin. In conclusion we found that associations between macroinvertebrates and abiotic conditions can be river basin-specific.Figure S1Sampling sites in the Chaguana river basin in Ecuador.(DOCX)Click here for additional data file.Figure S2Sampling sites in the Gilgel Gibe river basin in Ethiopia.(DOCX)Click here for additional data file.Figure S3Sampling sites in the Cau river basin in Vietnam.(DOCX)Click here for additional data file.Figure S4Boxplots showing the seasonality (dry (blue) and wet (red) season) of the stream velocity.(DOCX)Click here for additional data file.Figure S5Boxplots showing the seasonality (dry (blue) and wet (red) season) of the water temperature.(DOCX)Click here for additional data file.Figure S6Boxplots showing the seasonality (dry (blue) and wet (red) season) of the conductivity.(DOCX)Click here for additional data file.Figure S7Boxplots showing the seasonality (dry (blue) and wet (red) season) of the pH.(DOCX)Click here for additional data file.Figure S8Boxplots showing the seasonality (dry (blue) and wet (red) season) of the dissolved oxygen.(DOCX)Click here for additional data file.Figure S9Boxplots indicate the observed stream velocity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Chironomidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S10Boxplots indicate the observed water temperature in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Chironomidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S11Boxplots indicate the observed conductivity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Chironomidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S12Boxplots indicate the observed pH in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Chironomidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S13Boxplots indicate the observed DO concentrations in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Chironomidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S14Boxplots indicate the observed stream velocity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Baetidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S15Boxplots indicate the observed water temperature in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Baetidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S16Boxplots indicate the observed conductivity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Baetidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S17Boxplots indicate the observed pH in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Baetidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S18Boxplots indicate the observed DO concentrations in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Baetidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S19Boxplots indicate the observed stream velocity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Hydroptilidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis).(DOCX)Click here for additional data file.Figure S20Boxplots indicate the observed water temperature in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Hydroptilidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S21Boxplots indicate the observed conductivity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Hydroptilidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S22Bottom: Boxplots indicate the observed pH in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Hydroptilidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis).(DOCX)Click here for additional data file.Figure S23Boxplots indicate the observed DO concentrations in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Hydroptilidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S24Boxplots indicate the observed stream velocity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Libellulidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S25Boxplots indicate the observed water temperature in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Libellulidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S26Boxplots indicate the observed conductivity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Libellulidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S27Boxplots indicate the observed pH in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Libellulidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S28Boxplots indicate the observed DO concentrations in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Libellulidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S29Boxplots indicate the observed stream velocity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Leptophlebiidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S30Boxplots indicate the observed water temperature in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Leptophlebiidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S31Boxplots indicate the observed conductivity in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Leptophlebiidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis).(DOCX)Click here for additional data file.Figure S32Boxplots indicate the observed pH in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Leptophlebiidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S33Boxplots indicate the observed DO concentrations in Ecuador (red), Ethiopia (green) and Vietnam (blue) at which Leptophlebiidae are found to be present (denoted by P on the left axis) and absent (denoted by A on the left axis). The sample sizes per boxplot are shown on the right axis.(DOCX)Click here for additional data file.Figure S34The probability of Chironomidae being present in relation to the stream velocity measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S35The probability of Chironomidae being present in relation to the water temperature measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S36The probability of Chironomidae being present in relation to the conductivity measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S37The probability of Chironomidae being present in relation to the pH measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S38The probability of Chironomidae being present in relation to dissolved oxygen (DO) concentration measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S39The probability of Baetidae being present in relation to stream velocity measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S40The probability of Baetidae being present in relation to water temperature measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S41The probability of Baetidae being present in relation to conductivity measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S42The probability of Baetidae being present in relation to pH measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S43The probability of Baetidae being present in relation to dissolved oxygen (DO) concentration measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S44The probability of Hydroptilidae being present in relation to stream velocity measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S45The probability of Chironomidae being present in relation to the Hydroptilidae measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S46The probability of Hydroptilidae being present in relation to the conductivity measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S47The probability of Hydroptilidae being present in relation to pH measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S48The probability of Hydroptilidae being present in relation to dissolved oxygen (DO) concentration measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S49The probability of Libellulidae being present in relation to stream velocity measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S50The probability of Libellulidae being present in relation to the water temperature measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S51The probability of Libellulidae being present in relation to the conductivity measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S52The probability of Libellulidae being present in relation to pH measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S53The probability of Libellulidae being present in relation to dissolved oxygen (DO) concentration measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S54The probability of Leptophlebiidae being present in relation to stream velocity measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S55The probability of Leptophlebiidae being present in relation to the water temperature measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S56The probability of Leptophlebiidae being present in relation to the conductivity measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S57The probability of Leptophlebiidae being present in relation to pH measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Figure S58The probability of Leptophlebiidae being present in relation to dissolved oxygen (DO) concentration measured in Ecuador , Ethiopia and Vietnam . The gray-colored ends of the response curves indicate extrapolation outside the observed physical-chemical range in the corresponding river basin.(DOCX)Click here for additional data file.Table S1Seasonal differences per physical-chemical variable and per country. A p-value less than 0.05 demonstrates a significant difference between seasons for the mean physical-chemical variable that is considered for a specific country. Significant relations are indicated in bold.(DOCX)Click here for additional data file.Table S2Country-wise differences per physical-chemical variable and per season. A p-value less than 0.05 demonstrates a significant difference between countries for the mean physical-chemical variable that is considered for a specific season. Significant relations are indicated in bold.(DOCX)Click here for additional data file."} +{"text": "Diabetic polyneuropathy (DPN) has an insidious and non-homogeneous installation making it difficult to determine its onset. Therapeutic and preventive actions should target patients depending on their DPN severity status. Methods for supporting the decision making process of classifying patients can improve early health actions.Analyze the use of 2 artificial intelligence methods for classifying the DPN severity degree: (a) fuzzy modeling and (b) multiple correspondence analysis (MCA) and Kohonen map.Retrospective analysis of 195 patients. The fuzzy model determined a DPN degree score (0-10) by the combination of fuzzy sets derived from clinical variables , using if-then rules to combine the inputs with the output sets (Mamdani process), with membership functions determined by a team of 4 DPN specialists. The MCA method grouped 16 DPN-related categorical variables into micro and macro-classes (groups) after the algorithm learned the grouping pattern of the variables in the patients' cohort. A Kohonen map was used to better represent the clusters of variables that could identify different DPN severities.Loss of tactile and vibration perceptions were decisive for classification of DPN severity using the fuzzy system, and its sensitivity and specificity in discriminating patients with and without DPN was very high (ROC=0.985). The MCA and Kohonen map identified 4 macro-classes of variables: (1) DPN absence, (2 and 3) intermediate status , and (4) severe .The fuzzy model contributes to the early detection of DPN using typical clinical variables, and although this method strongly relies on the specialist subjectivity, it is very reliable. Software for classifying DPN severity using this Fuzzy model is available and can be easily implemented in any clinical setting as a decision support system. The MCA"} +{"text": "The still unclear mechanisms causing ventilator-induced diaphragm dysfunction (VIDD) are considered intrinsic to the diaphragm muscle fibers. VIDD delays and complicates weaning from mechanical ventilation (MV) and accordingly contributes to prolonged ICU stay by 50%, with older patients being more affected than the young. The main aim of this study was to measure the effects of aging and 5 days of MV on rat diaphragm muscle fiber structure and function. We also aimed to investigate the biological age of the old rats to obtain data useful to design future experimental studies focusing on the effects of age in an ICU setting.We used a unique ICU rat model, which allows us to maintain the vital parameters stable under deep sedation and MV for long durations . Diaphragm fiber cross-sectional area (CSA) and force-generating capacity (specific force = absolute force / CSA) were measured in young (6 months) and old (28 to 32 months) F344/ BN hybrid rats in response to 5 days of deep sedation and volume-controlled MV. To investigate the biological age of the old rats, we performed a second set of experiments, comparing muscle fiber CSA and specific force in fast and slow-twitch distal hind limb muscles in three different age groups: young adults (6 months), middle aged (18 months) and old rats (28 months).P < 0.001) of the diaphragm fibers in response to 5 days of MV in both young and old animals. Maximum force decreased 39.8 to 45.2% (P < 0.001) in both young and old animals compared with controls, resulting in a dramatic loss of specific force. This increase in CSA and the concomitant decrease in specific force observed in both young and old diaphragm fibers are compatible with an ineffective compensatory hypertrophy in response to the MV. The comparison of the limb muscles fibers from young, middle aged and old animals confirmed the 28 to 32 month rats to be senescent from a skeletal muscle point of view.This study demonstrated an unexpected increase in CSA (These results demonstrate intrinsic changes in diaphragm muscle fibers of significant importance for the prolonged and complicated weaning from MV. Moreover, the increased number of frail diaphragm muscle fibers observed after MV in old age, both controls and mechanically ventilated, offers a further age-related possible mechanism which may be of significant clinical importance. These results also provided useful information to design future experimental studies focused on the effect of age in an ICU setting, pharmacological intervention strategies as well as mechanisms underlying rat strain differences."} +{"text": "The objectives of the study were (1) to explore the pattern of public spending on road safety programmes corresponding to 5-E strategy , and (2) to investigate road safety policy directions.The government budget documents from 5 ministries including Ministry of Transport, Education, Interior, Public Health and Royal Thai Police were reviewed. Two researchers identified budget used in road safety projects with 5-E strategies independently; the kappa analysis was used to test inter-rater reliability. Information from Thai Health Promotion Foundation and Road Safety Fund was also gathered using a developed excel-based template. Semi-structured interviews were conducted among road safety experts. Some mathematical and statistical analyses were applied to evaluate the efficiency of road safety policy.Thailand devoted around 18 billion Baht each year to prevent road traffic accidents. The majority of public budget was allocated to engineering strategies (50%), followed by enforcement (23%), emergency medical services (12%), evaluation (8%) and education (7%). The road safety experts, however, suggested that the strategies of education, enforcement and particularly evaluation are Thailand\u2018s key success factors. Thus, an area-based road safety information system should be developed. Data Envelopment Analysis suggested an inefficiency of law-enforcement system in Thailand by comparison with other countries worldwide.Despite insufficient data and evidence to clarify the outcomes of road safety policy and programmes, it is possible to conclude that (1) there is an underinvestment in road safety in Thailand and (2) the government allocates budget inappropriately. This study suggests allocating more public spending on road safety management data systems that empower local service providers to access and analyse current accident information. Investing in strategies of education and enforcement effectively influencing road user behaviour would be the right way to achieve the ultimate goal."} +{"text": "Even with the availability of new and more effective diagnostic procedures over the past decades, autopsy remains one of the most reliable methods to validate clinical diagnoses. The aim of this review was to determine whether autopsy plays a role in extending knowledge about the cause of death in patients with cirrhosis who died in the ICU.We conducted a retrospective review of medical records and postmortem findings in critically ill patients with cirrhosis who were admitted to a major university teaching medical ICU (MICU) between August 2007 and August 2013. Agreement between diagnoses before death and postmortem findings were compared using the Goldman system [n = 19, 45%).Of 641 patients admitted with diagnosis of cirrhosis, 86 (13%) died in the MICU. Forty-five (52%) patients underwent an autopsy. Forty-two autopsy reports were available for review, three histologic and microbiological reports were missing. Major missed diagnoses were present in seven patients (17%), four in class I (10%) and three in class II (7%) (Table Despite declining rates worldwide, autopsy remains an important tool for quality and safety assurance. In this retrospective study, autopsy showed that knowledge of the correct premortem diagnosis would have altered therapy in 10% of critically ill cirrhotic patients."} +{"text": "There is an error in the first sentence of the Introduction. The correct sentence is: Behavioral studies indicate involvement of the prefrontal cortex and medial temporal lobe (MTL) during memory tasks that require short-term (200ms- 30s) information retention [1\u20134]. The publisher apologizes for this error."} +{"text": "There are errors in Equation (3). In the description of Equation (3), the equilibrium frequencies PIX are incorrectly defined in terms of pi, where in fact they should be defined in terms of phi. Please see the corrected description of Equation (3) here."} +{"text": "The differential diagnosis of hypertrophic phenotype remains challenging in clinical practice, in particular between hypertrophy cardiomyopathy (HCM) and increased left ventricular wall thickness (LVWT) due to systemic hypertension. Diffuse myocardial fibrosis is the characteristic feature in HCM, whereas hypertensive response is underpinned by addition of myofibrils in otherwise normal myocardial tissue. Late gadolinium enhancement (LGE) imaging provided important new way of differentiation between these two entities by separating those cases with evidence of regional fibrosis. Whereas approximately 60% of patients with HCM reveal visually discernable LGE, T1 mapping is highly discriminative, irrespective of the presence of LGE.Sixty patients with diagnosis of unequivocally hypertrophic cardiomyopathy and fifty patients with hypertensive cardiomyopathy underwent routine cardiac MRI protocol including assessment of function and scar (3-Tesla). T1 values were measured conservatively within septal myocardium in midventricular short-axis slice prior to administration of 0.2 mmol/kg of gadobutrol.HCM group showed higher LV mass and maximum LVWT than the hypertensive group . There was LGE in 20% of hypertensive and in 84% of hypertrophic cardiomyopathy (p < 0.001). Patients with HCM showed significantly higher T1 values compared to hypertensive patients . Native T1 values were concordant to LVWT and LV mass . T1native held superior diagnostic accuracy compared to conventional functional parameters and the presence of LGE to discriminate between hypertrophic or hypertensive cardiomyopathy comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital National Health Service Foundation Trust. Dr. Rocio Hinojar was supported by the Fundacion Alfonso Martin Escudero."} +{"text": "Hyperfibrinolysis (HF) is a major issue of trauma-induced coagulopathy but has also been described in many other medical or surgical settings such as cardiopulmonary surgery, gastro-intestinal bleeding, liver transplantation and post-partum hemorrhage.The aim of this study was to describe the HF in a cohort of patients experiencing severe bleeding from trauma and non-trauma source and to highlight the differences between both groups.\u00ae) between 2010 and 2014 were included. Demographic and clinical parameters, standard laboratory and ROTEM\u00ae results were collected. HF diagnosis was established when the 60 minute clot lysis index (CLI60) was below 85% of the maximum clot firmness. HF was classified as fulminant HF (immediate breakdown of the clot within 30 minutes), intermediate HF (breakdown of the clot between 30 and 60 minutes) and late HF (complete clot lysis after more than 60 minutes). Data are expressed as n (%) and median [interquartile range].We conducted an observational, retrospective study in two academic trauma centers from a French university institution. All patients diagnosed with HF on rotational thromboelastometry (ROTEMSixty-four patients were included (39 trauma and 25 non trauma). Overall mortality was 64% . Median ISS for trauma patients was 49 . Patients severity assessed with SAPS II was not different between groups whereas 28 day survival was greater in non-trauma patients (Figure to 73 vsFulminant HF is more frequent in trauma patients and is associated with an increased mortality. The decreasing incidence of HF observed during the study period might be due to the systematic prehospital administration of tranexamic acid in trauma patients since 2011 in our city area."} +{"text": "Virus replication efficiency is influenced by two conflicting factors, kinetics of the cellular interferon (IFN) response and induction of an antiviral state versus speed of virus replication and virus-induced inhibition of the IFN response. Disablement of a virus's capacity to circumvent the IFN response enables both basic research and various practical applications. However, such IFN-sensitive viruses can be difficult to grow to high-titer in cells that produce and respond to IFN. The current default option for growing IFN-sensitive viruses is restricted to a limited selection of cell-lines (e.g. Vero cells) that have lost their ability to produce IFN. This study demonstrates that supplementing tissue-culture medium with an IFN inhibitor provides a simple, effective and flexible approach to increase the growth of IFN-sensitive viruses in a cell-line of choice. We report that IFN inhibitors targeting components of the IFN response significantly increased virus replication. More specifically, the JAK1/2 inhibitor Ruxolitinib enhances the growth of viruses that are sensitive to IFN due to (i) loss of function of the viral IFN antagonist (due to mutation or species-specific constraints) or (ii) mutations/host cell constraints that slow virus spread such that it can be controlled by the IFN response. This was demonstrated for a variety of viruses, including, viruses with disabled IFN antagonists that represent live-attenuated vaccine candidates , Influenza Virus), traditionally attenuated vaccine strains and a slow-growing wild-type virus (RSV). In conclusion, supplementing tissue culture-medium with an IFN inhibitor to increase the growth of IFN-sensitive viruses in a cell-line of choice represents an approach, which is broadly applicable to research investigating the importance of the IFN response in controlling virus infections and has utility in a number of practical applications including vaccine and oncolytic virus production, virus diagnostics and techniques to isolate newly emerging viruses. Knockout of viral IFN antagonists is also a method of engineering viruses to specifically target cancer cells for oncolytic virotherapy Virus infection triggers the cellular interferon (IFN) response to produce Type 1 IFN's alpha and beta (IFN\u03b1/\u03b2). Secreted IFN\u03b1/\u03b2 can stimulate the JAK-STAT pathway in an autocrine or paracrine manner to activate hundreds of IFN-stimulated genes (ISGs), many of which have antiviral activities that elicit an antiviral state Despite the advantages of disabling a virus's IFN antagonist, it can be difficult to grow such IFN-sensitive viruses to high-titer in tissue culture cells that produce and respond to IFN Inhibitors of the IFN response were prepared as 10 mM stocks in dimethyl sulfoxide (DMSO) and used at the indicated concentrations. Inhibitors were purchased from Selleck Chemicals except MRT68844 and MRT67307, which were gifts of MRC-Technology and Philip Cohen (University of Dundee) respectively. Cell-lines derived from a variety of mammalian species were utilized: human (A549 and MRC5) monkey (Vero), mouse , rabbit (RK13), dog (MDCK) and pig (PKIBRS2). These cells were obtained from the European Collection of Cell Cultures (ECACC) with the exception of the PKIBRS2 cells, which were obtained from the Institute of Animal Health (UK) 4 units/ml of purified \u03b1-IFN to activate the IFN signaling pathway and GFP expression from the IFN response (ISRE) promoter. Forty-eight hours post-IFN stimulation GFP expression and cellular cytotoxicity were measured as described above. Each assay was conducted in triplicate and the mean and standard deviation (StDev) determined.The A549/pr(IFN-\u03b2).GFP and A549/pr(ISRE).GFP reporter cell-lines were used to test the effect of IFN inhibitors on IFN induction or IFN signaling. A549/pr(IFN-\u03b2).GFP were seeded into a 96 well plate and media supplemented with a TBK1 inhibitor or the IKK2 inhibitor (TPCA-1) at the indicated concentrations or equivalent volumes of DMSO. Two hours post-inhibitor treatment cells were infected with a stock of PIV5V\u0394C rich in defective interfering particles (DIs) to optimally activate the IFN induction pathway and expression of GFP under the control of the IFN-\u03b2 promoter Standard plaque assays were conducted in the appropriate cells using a 0.6% (w/v) avicell overlay Eight small molecules that have previously been described to inhibit the cellular IFN response were obtained; four inhibitors that target components of the IFN induction pathway: TBK1 inhibitors BX795, MRT68844, MRT67307 Bunyaviridae family are being developed as attenuated vaccines via NSs knockout Effect of the inhibitors on viral plaque formation was examined using A549 cells infected with recombinant Bunyamwera virus (BUN\u0394NSs), in which the NSs IFN antagonist has been inactivated rendering the virus IFN sensitive The six effective inhibitors were used to examine their effect on BUN\u0394NSs growth kinetics and all six inhibitors significantly improved virus titers . At 48 hWe next sought to determine if two inhibitors targeting different components of the IFN response could further boost BUN\u0394NSs growth if used in combination with each other or to supplement the medium of infected A549/PIV5-V cells. The IKK-2 inhibitor TPCA-1 and JAK1/2 inhibitor Ruxolitinib were tested. However combinations resulted in no further increases in plaque size in A549 cells and in fact a small decrease in plaque size was observed when the inhibitors were used in combination compared to Ruxolitinib or PIV5-V expressing cells alone . One posA limited number of cell-lines have regulatory approval for vaccine manufacture e.g. MRC5 Respiratory Syncytial Virus (RSV) and Influenza are examples of viruses currently being developed as IFN-sensitive attenuated vaccine candidates We also tested two traditional vaccine strains, measles (MeV) Edmonson and the Mumps (MuV) Enders, which have been generated empirically using nonsystematic attenuation methods in vitro. In the initial plaque formation screen the JAK1/2 inhibitor Ruxolitinib was the most effective and hence was taken forward for further study. Moreover, all the results obtained for Ruxolitinib were essentially mirrored with the IKK2 inhibitor TPCA-1 (data not shown). The plaque assays and growth curves performed required incubation with the inhibitor for multiple days. To ensure our results were not affected by loss of activity of the drug, we used the A549/pr(IFN-\u03b2).GFP and A549/pr(ISRE)GFP reporter cell-lines to measure the activity of the drug over time; confirming that the inhibitory effect of both Ruxolitinib and TPCA-1 was stable up to at least 7 days in tissue-culture the cost of the inhibitor and (ii) the harvested virus stocks will contain the inhibitor which may affect experiments to address both basic science questions and regulatory problems for medical applications in humans, although in this latter regard it is noteworthy that Ruxolitinib is approved for clinical treatment of myelofibrosis in vivo, they may also prove useful in studies designed to investigate the importance of the IFN response in controlling virus infections in animal models.These results provide proof of principle that supplementing tissue-culture medium with IFN inhibitors provides a simple, effective and flexible approach to enhance virus growth in cell-lines of choice. IFN inhibitors targeting different components of the IFN response significantly increased replication and yield of a variety of viruses; including examples of potential vaccine candidates with disabled IFN antagonists , traditionally attenuated vaccine strains and wild-type viruses . In addition JAK1 inhibitors have recently been shown to enhance the growth of oncolytic vesicular stomatitis virus (VSV) in cancer cells resistant to oncolysis"} +{"text": "The genes encoding the E3 ubiquitin protein ligase Parkin (PARK2) and the mitochondrial serine/threonine kinase PINK1 (PARK6) are mutated in clinically similar, autosomal recessive early onset Parkinson\u2019s disease (PD) forms. Over the past ten years, a number of studies in different model systems have demonstrated that PINK1 and Parkin regulate jointly several processes relevant to maintenance of mitochondrial quality, including mitochondrial trafficking and dynamics, mitophagy and biogenesis. By using a combination of approaches of cell biology, confocal imaging and biochemistry in different cell models, we recently showed that loss of protein import efficiency triggers recruitment of Parkin by PINK1 in proximity of the translocase of outer mitochondrial membrane (TOM). We provided evidence that the degradation of specific TOM subunits plays a key role in initiating the autophagic degradation of damaged mitochondria. We also showed that PINK1 and Parkin interact with the TOM machinery on polarized mitochondria. Our results suggests that this interaction modulates the import of the multifunctional mitochondrion-protective matrix enzyme 17beta-hydroxysteroid dehydrogenase 10, which is depleted in Parkin-deficient mice and Parkinson\u2019s disease patients. Electron and confocal microscopy, and calcium imaging approaches used to characterize the endoplasmic reticulum (ER)-mitochondria interface, a compartment previously linked to neurodegenerative processes, revealed enhanced juxtaposition between these organelles, associated with increased ER-to-mitochondria calcium transfer in cells from Parkin-deficient mice and patients with PARK2 mutations. Our current work aims at investigating the relevance of mitochondrial quality control mechanisms regulated by PINK1 and Parkin in different cell types of the central nervous system, to evaluate the contribution of each of them to the physiopathology of autosomal recessive Parkinson\u2019s disease."} +{"text": "Observation of the kinetics of tissue enhancement after the injection of a bolus of tracer has been used for the analysis of perfusion and related variables. In general, a gradient of concentration in the exchanging vascular compartment between the arterial and venous ends is represented in models via focus on maintaining the detailed balance between the advective and diffusive exchange processes. Conventionally, this is by considering the exchange in an Eulerian framework, based on considering the exchange within each compartment as a separate unit model ). HereinEight patients (age 63 \u00b1 12 years) underwent first-pass perfusion (FPP) rest and regadenoson stress cardiac MRI (CMR) , followed by invasive coronary angiography. Images were obtained at 4 slice locations and 3 short-axis slices of the left ventricle for the wall) using a TurboFLASH readout with centric k-space reordering [The results of a representative patient (66 year old man) with history of hypertension, hyperlipidemia, Diabetes Mellitus and known coronary artery disease with prior stents on maximal medical therapy are shown in Figure A novel method combining aspects of TH model and a Lagrangian approach allows quantification of the transit of tracer through myocardial tissue, and may serve to identify physiologically significant coronary artery disease. Larger studies to validate this approach are warranted.NIH R01 HL083309."} +{"text": "Atherosclerosis, a chronic inflammatory disorder of the arteries, is responsible for most deaths in westernized societies with numbers increasing at a marked rate in developing countries. The disease is initiated by the activation of the endothelium by various risk factors leading to chemokine-mediated recruitment of immune cells. The uptake of modified lipoproteins by macrophages along with defective cholesterol efflux gives rise to foam cells associated with the fatty streak in the early phase of the disease. As the disease progresses, complex fibrotic plaques are produced as a result of lysis of foam cells, migration and proliferation of vascular smooth muscle cells and continued inflammatory response. Such plaques are stabilized by the extracellular matrix produced by smooth muscle cells and destabilized by matrix metalloproteinase from macrophages. Rupture of unstable plaques and subsequent thrombosis leads to clinical complications such as myocardial infarction. Cytokines are involved in all stages of atherosclerosis and have a profound influence on the pathogenesis of this disease. This review will describe our current understanding of the roles of different cytokines in atherosclerosis together with therapeutic approaches aimed at manipulating their actions. Atherosclerosis is now recognized as an inflammatory disorder of medium and large arteries initiated by risk factors such as high plasma cholesterol levels and hypertension in vitro studies using cell culture model systems have made a major contribution in advancing our understanding of the roles of cytokines in the cellular processes associated with atherosclerosis, the major focus of this review will be on the outcome from studies using animal model systems. In particular, two mouse models, the apolipoprotein (Apo) E-deficient mice and the low-density lipoprotein receptor (LDLr)-deficient mice Cytokines are a diverse group of low-molecular weight proteins with over 100 identified so far. Cytokines are clustered into several classes such as the interleukins (IL), chemokines, colony-stimulating factors (CSF), tumor necrosis factors (TNF), the interferons (IFN) and transforming growth factors (TGF) 2Atherosclerotic plaques tend to form particularly at the inner curvatures and branch points of arteries that are often associated with disturbed blood flow, and is augmented by other factors such as high plasma low-density lipoprotein (LDL) concentration, hypertension and toxins from cigarette smoke The activated ECs release a range of chemokines and other cytokines that then cause the recruitment of circulating immune cells, particularly monocytes and T lymphocytes 3C, XC) high [express high levels of CC-chemokine receptor (CCR)-2, believed to be pro-inflammatory in nature and their levels increase in hyperlipidemia) and less frequent Ly6Clow [express CX3C-chemokine receptor 1 and perceived to carry out a homeostatic function) high monocytes involves immobilization of CCL5 and CXCL1 on proteoglycans and P-selectins on ECs Chemokines are a large family of structurally related, chemoattracting cytokines that are divided into subgroups on the basis of the position of the amino terminal cysteine residues is also associated with reduced macrophage recruitment and the alternatively activated M2 (thought to be derived from Ly6Clow-monocytes and produces anti-inflammatory cytokines such as IL-10 and TGF-\u03b2) that aid in the resolution of inflammatory responses \u2212/\u2212 model system drives M2 macrophage polarization and inhibits atherosclerosis progression In the arterial intima, monocytes can differentiate to macrophages or dendritic cells (DCs) depending on the cytokine signal received with macrophage colony-stimulating factor (M-CSF) a major facilitator of macrophage differentiation LDL tends to diffuse passively through EC junctions and its retention is aided by interaction of its apoB moiety with components of the extracellular matrix such as proteoglycans Macrophages express pattern recognition receptors (PRRs), such as scavenger receptors (SRs), toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLR), that participate in foam cell formation and/or elicit an inflammatory response against foreign particles or endogenously produced danger signals in vivo; for example, IFN-\u03b3 and TNF-\u03b1 promote this whereas IL-1RA and IL-33 are inhibitory. The formation of foam cells involves dysfunction of a homeostatic mechanism that controls the uptake, intracellular metabolism and efflux of cholesterol by macrophages \u2212/\u2212 mice in vivo and macrophages in vitro by decreasing modified LDL uptake, reducing intracellular content of cholesteryl esters and stimulating cholesterol efflux As shown in 4Cholesterol is toxic to cells and mechanisms exist to maintain homeostasis. For example, derivatives of cholesterol, such as oxysterols, activate liver X receptors (LXRs) that then stimulate cholesterol efflux by inducing the expression of ABCA1 and ABCG1 Defective lipid homeostasis is instrumental in the amplification of the inflammatory response and activation of the immune response Antigen presenting cells, such as macrophages and DCs, are essential for the adaptive immune responses as they engulf and process antigens, and present them on the cell surface in association major histocompatibility complexes (MHC) for recognition by T-cells SMCs also play an important role in atherosclerosis and more advanced lesions are generally covered with a fibrous cap, composed of SMCs and ECM components produced by them, and lipid-rich necrotic core 5The continued inflammatory response ultimately leads to the destabilization of atherosclerotic plaques via the action of pro-inflammatory cytokines. Indeed, studies in mouse model systems have shown that IFN-\u03b3, IL-18, GDF-15 and TWEAK destabilize plaques whereas TGF-\u03b2 causes stabilization , Table 46Inflammation plays a pivotal role in all stages of atherosclerosis: endothelial dysfunction; recruitment of immune cells; modification of LDL; foam cell formation; apoptosis of foam cells; plaque rupture; and thrombosis. The inflammatory response in atherosclerosis is regulated by both the innate and adaptive immune system via the action of cytokines. Our understanding of the roles of such cytokines has recently advanced considerably mainly via studies using mouse model systems None."} +{"text": "India\u2019s agricultural output, economy, and societal well-being are strappingly dependent on the stability of summer monsoon rainfall, its variability and extremes. Spatial aggregate of intensity and frequency of extreme rainfall events over Central India are significantly increasing, while at local scale they are spatially non-uniform with increasing spatial variability. The reasons behind such increase in spatial variability of extremes are poorly understood and the trends in mean monsoon rainfall have been greatly overlooked. Here, by using multi-decadal gridded daily rainfall data over entire India, we show that the trend in spatial variability of mean monsoon rainfall is decreasing as exactly opposite to that of extremes. The spatial variability of extremes is attributed to the spatial variability of the convective rainfall component. Contrarily, the decrease in spatial variability of the mean rainfall over India poses a pertinent research question on the applicability of large scale inter-basin water transfer by river inter-linking to address the spatial variability of available water in India. We found a significant decrease in the monsoon rainfall over major water surplus river basins in India. Hydrological simulations using a Variable Infiltration Capacity (VIC) model also revealed that the water yield in surplus river basins is decreasing but it is increasing in deficit basins. These findings contradict the traditional notion of dry areas becoming drier and wet areas becoming wetter in response to climate change in India. This result also calls for a re-evaluation of planning for river inter-linking to supply water from surplus to deficit river basins. Indian summer monsoon rainfall (ISMR) over India contributes approximately 80% of the annual precipitation during June-September (Jun\u2013Sep) . India\u2019s). The hydrologic simulations were performed with a Variable Infiltration Capacity (VIC) model [S1 Text). The model was validated with satellite-based observation from the European Space Agency-Climate Change Initiative (ESA-CCI) soil moisture data [The gridded daily rainfall data (mm/day) from the India Meteorological Department (IMD), for the years 1901\u20132004 at a resolution of 1\u00b0 were useS1 TextC) model in energure data ,29. The The spatial variability of the mean and extreme of the ISMR exhibit opposing trends. In the present case, rainfall associated with a return period of 50 years was consWe address the first point with hydrological simulations over entire India and by computing the water yield sum of . The resTo reconfirm our conclusions, we conducted a trend analysis of the ISMR over water surplus and deficit river basins in India . The majTo investigate the systematic nature and consistency of the opposing trends in the spatial variability of the mean and extreme ISMRs, we selected five regions of equal grid-size from different agro-climatic zones in the surplus (deficit) river basins strongly contradict the traditional notion of wet (dry) areas becoming wetter (drier) over India. Our conclusion corroborates a study conducted by Greve et al. , who repS1 FigThe spatial variability of the mean does not exhibit a trend pre-1950 (a) and a significant decrease post-1950 (b). The spatial variability of extremes does not exhibit a trend pre-1950 (c) and a significant increase post-1950 (d).(TIF)Click here for additional data file.S2 Fig(a) The spatial variability of the mean monsoonal rainfall (blue), with the black solid line indicating the fitted trend line, and (b) the spatial variability for rainfall extremes (blue) with the black line representing the linear trend. The respective Mann-Kendall trend and associated p values are individually presented for each panel.(TIF)Click here for additional data file.S3 Fig(a) Correlation between the simulated and observed soil moisture from 1979\u20132004. (b) Normalized Root Mean Square Error (nRMSE) for the same period.(TIF)Click here for additional data file.S4 FigTrends in temperature (a), ET (b) and soil moisture (c) over India during 1951\u20132004, respectively. (d) shows a scatter plot of ET and temperature over India. The values inset the figures represent magnitude of the correlation (R) and slope for the respective variables. All the values are significant at 10% significance level.(TIF)Click here for additional data file.S5 Fig(a) Ratio of convective to total precipitation obtained from TRMM for all of India. (b) Trend in the spatial variability of the Indian Summer Monsoon Rainfall for the stratiform precipitation obtained from MERRA database over the Indian region (blue), where the black line indicates the fitted trend (linear) line. The Modified Mann-Kendall trend is insignificant at the 5% level. (c) is similar to (b) except for the trend in convective precipitation, which is significant at the 5% level. The spatial data obtained from TRMM and MERRA were re-gridded to IMD at a 1\u00b0 resolution using a linearly interpolated technique.(TIF)Click here for additional data file.S6 Fig(TIF)Click here for additional data file.S7 Fig(a) The trend in the spatial variability of convective precipitation (blue) during 1951\u20132004 for ERA-20c reanalysis data, where the black line indicates the fitted trend (linear) line. The modified Mann-Kendall trend is significant at the 5% level. (b) is similar to (a) but shows stratiform precipitation, for which the trend is insignificant at the 5% level. Trends in convective precipitation (c) and stratiform precipitation (d) during 1961\u20132004 for JRA-55 reanalysis data. The modified Mann-Kendall trend is insignificant at the 5% level for both convective and stratiform precipitation. The spatial data obtained from ERA-20c and JRA-55 were regridded to a 1\u00b0 resolution (same as the IMD data resolution) using a linearly interpolated technique.(TIF)Click here for additional data file.S8 Fig(a) Spatial correlation for the monsoonal mean and (b) spatial correlation for the seasonal maxima. (c) The trend in the spatial correlation of individual grid points over the given region estimated with a 30-year overlapping moving window for the monsoonal mean. (d) same as (c) but for seasonal maxima.(TIF)Click here for additional data file.S9 Fig(TIF)Click here for additional data file.S1 TextContains complete description of methods and also the Tables.(DOCX)Click here for additional data file."} +{"text": "The use of medication during pregnancy should be taken with caution, especially because of its implications for maternal and fetal health. The mycophenolate sodium (MFS) is used to avoid possible rejection of transplanted tissues and organs by inhibiting T and B lymphocyte proliferation.To evaluate the effects of maternal immunosuppression by MFS on physiological parameters in rats.The rats were divided into three groups: rats treated with water (CONT=10) rats orally treated with MFS (20mg/Kg) daily for 15 days until a positive diagnosis of pregnancy (MICO-1=10) and rats orally treated with MFS (20mg/Kg) daily for 15 days prior to and during 21 days of pregnancy (MICO-2=10). It was weekly evaluated body weight, blood glucose, and water and food intake (before and during pregnancy). Statistical significance was p <0.05.In the pre-pregnancy period, although there were no changes in body weight values, the continuous treatment with MFS decreased food and water consumption and also increased blood glucose (MICO-2). During pregnancy period, these rats presented a reduction of the body weight, maintaining a mild hyperglycemia level (about 170 mg/dL)The continued use of MFS during pregnancy can be considered toxic, damaging the maternal health, lead to mild hyperglycemia state plus some toxic data (low food and water intake). This study shows that MFS use is not recommended during pregnancy freely and should be replaced by another immunosuppressant."} +{"text": "One of the challenges facing us in India, translating recent discoveries of chronic disease associated SNPs into clinical domain for prevention, is the lack of knowledge about the frequency of the polymorphism in our population. Hence, using available HapMap data has become a norm. However, it is anticipated that population genomics in India could be different from the HapMap Caucasian population. Relative disease risk prediction based on relevant SNPs, both for personalized medicine and for population genetics, has little value without accurate information of population allele frequencies. We report allele frequency of 384 SNPs directly related to chronic disease risk and metabolic traits in the Indian population.We report the allele in a random sample of 146 individuals and compare them with the data reported in HapMap Caucasian population (n = 112). Genotyping was performed using Illumina golden gate genotyping assay following DNA extraction from saliva. Allele frequencies were determined by direct gene count method.GWAS studies confirmed 384 SNPs to be associated with disease risk (364) of Diabetes Type 1 and 2 (54 & 118 respectively), Coronary artery disease(71), myocardial infarction(9), cardiac failure(24), sudden cardiac arrest(38), atrial fibrillation(9), hypertension(18), obesity(10), metabolic syndrome(2) and stroke(11); or were associated with metabolic traits (20). The master table of their \u2018rs\u2019 id, chromosomes, location and association is presented. Of the 384 SNPs, 44 were not in H-W equilibrium and were omitted. HapMap data were not available for 13 SNPs. We are reporting their allele frequencyon the Indian population for the first time. Of the remaining 307 disease association SNPs, statistically significant difference (p<.05) from HapMap Caucasian population was observed in 53% of them (164 of 307) and the difference of >10% (considered major in population genetics) was found in 42% (130 of 307). Of the 20 metabolic association SNPs, 50% (10 of 20) had statistically significant difference and in all of them it was >10%.We are reporting the largest repository, documenting disease and related SNP and allele frequencies in Indian population. We have also highlighted clear differences with HapMap data and would caution against indiscriminate use of HapMap for bench-to-bedside application of genetic knowledge in our population."} +{"text": "In 2011, the University of Michigan\u2019s Center of Excellence in Public Health Workforce Studies and the Association of Public Health Laboratories (APHL) assessed the workforce and program capacity in U.S. public health, environmental, and agricultural laboratories of 105 laboratory directors participated. A laboratorian was defined as a person whose principal work was in a governmental public health, environmental, or agricultural laboratory; positions could be reported as one-quarter fractions of full-time equivalents. For each program area, the director was asked if they had adequate capacity to perform necessary services for that program area. Estimates were categorized as follows: full = 100% capacity to perform; almost full = 75%\u201399%; substantial = 50%\u201374%; partial = 25%\u201349%; minimal = 1%\u201324%; and none. Fifty-six (71%) of the laboratories self-identified as a public health (49), environmental (three), or agricultural (four) laboratory; 23 (29%) self-identified as some combination of these categories; and one did not specify laboratory type.In 2011, a total of 6,656 employees, of whom 5,555 (83%) were laboratorians in one of the eight job classifications identified, worked in the 80 responding laboratories; the remaining 894 employees (13%) were administrative support staff, and 207 (4%) were information technology staff . The disFor those laboratories indicating any capacity in a given program area , more than half reported either no, minimal, or only partial capacity to perform necessary activities in toxicology (65%), agricultural chemistry (80%), agricultural microbiology (80%), clinical chemistry/hematology (68%), and education and training (55%). Conversely, more than 75% of laboratories reported substantial to full capacity in emergency preparedness and response (89%), safety and/or security (91%), bacteriology (91%), administration/operations (86%), molecular biology (92%), quality assurance (83%), serology/immunology (85%), and regulation and inspection (80%); however, fewer than half reported substantial to full capacity in agricultural chemistry (20%), agricultural microbiology (20%), clinical chemistry/hematology (32%), toxicology (35%), and education and training (45%) . SeveralMore than half of laboratories (42 [53%]) anticipated that up to 15% of their workers would retire, resign, or be released within 5 years, whereas 27 (34%) laboratories predicted a loss of 16%\u201325%, 10 (13%) predicted a loss of 26%\u201350%, and one anticipated losing more than 75% within 5 years. The lack of opportunities for promotion and lack of a career path for advancement were the two most common barriers to recruitment; both were reported by 76% of responding laboratories. Other major barriers to recruitment were inadequate salary scale (59 [74%]), hiring policies/procedures (54 [68%]), and complexity of the administrative bureaucracy (49 [61%]). Lack of promotion opportunities and career path for advancement were reported as obstacles to worker retention by 66 (83%) and 64 (80%) of laboratories, respectively, as was inadequate salary scale by 58 (73%) of laboratories.The public health, environmental, and agricultural laboratory workforce is a vital component of the nation\u2019s public health infrastructure. Laboratory capacity is essential for protection against health hazards and provision of essential community services . The 201The lack of many laboratories\u2019 ability to provide training to their staff is a concern because access to continuing education is essential to ensuring a well-trained public health workforce. This might be particularly true for laboratorians because only one quarter of laboratorians have a graduate or professional degree. Laboratory directors and public health, environmental, and agricultural laboratory workers reported lack of opportunities for promotion and a clear career path to advancement as the most common barriers to worker recruitment and retention , which mThe assessment of laboratories\u2019 program area capacity should be based on the Laboratory System Improvement Plan (LSIP) standards, which were developed by APHL and CDC to assess laboratory performance ,8. HowevThe findings of this report are subject to at least three limitations. First, only three quarters of laboratory directors completed the survey; nonresponders might have differed systematically from responders and yielded dissimilar results if they had participated. Second, the questions used to assess program area capacity in the laboratory were subjective, and their interpretation might have varied by respondent. Finally, some subjective questions have objective correlates, such as assessment of equipment quality.What is already known on this topic?The public health, environmental, and agricultural laboratory workforce is a vital component of the nation\u2019s public health infrastructure. Well-trained laboratorians are essential to providing protection against newly emergent diseases and other health hazards through diagnostic testing; reporting and surveillance; chemical, toxicologic, and environmental analysis; emergency preparedness; and provision of other vital services for the community.What is added by this report?Data from a 2011 National Laboratory Capacity Assessment indicate that national public health laboratory capacity needs to improve in several areas to achieve optimal testing and response capacity. Laboratory workers need better access to training and educational opportunities to ensure a well- qualified laboratory workforce.What are the implications for public health practice?Agencies at the local, state, and federal level should collaborate to improve laboratory capacity, including worker training and education, and encourage the development of a greater number and type of available laboratory degree programs.Healthy People 2020 public health infrastructure objective no. 11 (PHI-11) aims to increase the proportion of tribal and state public health agencies that provide or ensure comprehensive laboratory services to support essential public health services (The services . The Nat"} +{"text": "Juvenile Dermatomyositis (JDM) is the most common idiopathic inflammatory myopathy in childhood, a systemic vasculopathy that usually affects skin and skeletal muscle but also can affect gastrointestinal tract and other organs. Diagnosis is based on Bohan and Peter's criteria and the goals of treatment include control of skin and muscle symptoms and prevention of disease complications. Stepwise aggressive treatment decreases JDM activity and improves long-term outcome.Muscle involvement in JDM can be assessed by electromyography (EMG), magnetic resonance imaging (MRI) and/or muscle biopsy.Muscle biopsy assesses the presence of lymphocytic inflammatory infiltrate, perifascicular atrophy, muscle fibers necrosis and it allows studying the overexpression of major histocompatibility complex (MHC) class I in the sarcolemma and sarcoplasm of the muscle cell. In healthy muscles, there is no MHC class I expression but in inflammatory myopathies there is a distinctive and generalized overexpression, not limited to the affected areas, it appears before the inflammatory infiltrate occurs and it is not modified by immunosuppressive treatment.To assess MHC I overexpression on muscle biopsy of our patients with JDM.Descriptive retrospective review of our JDM patients with muscle biopsy at diagnosis between January 2000 and December 2011. In all cases, muscle biopsy techniques were performed with hematoxylin-eosin, trichrome, oxidative enzymes , neonatal myosin and MHC class I.12 patients were included, 8 of them were girls (66%). All children had cutaneous and muscular clinical features at diagnosis. All MRI were pathological before treatment. EMG was performed in 9 patients, being altered in 8 of them (88%). Childhood Myositis Assessment Scale (CMAS) was done in 6 children with a median score of 30.5/52 (range 12-50/52). We found pathological muscle biopsy in 8 children (66%). Mild endomisial inflammation was found in 5 (41%) patients and moderate inflammation in 4 (33%). No vasculitis was found, but 7 (58%) patients had necrotic muscle fibers in biopsy. Immunohistochemical staining for MHC class I was positive in all cases, even in those children with normal muscle biopsy.MHC class I overexpression is present in muscle biopsy of all our patients with suspected JDM, even those with negative EMG or normal CMAS score. Although it is an invasive technique, muscle biopsy including MHC class I staining should be performed in all patients with suspected JDM in order to achieve more accurate diagnostic and establish an early and aggressive treatment.None declared."} +{"text": "Many patients die and majority of those who survive remain in a vegetative state2. There is paucity of data on the clinical characteristics and outcome of patients with status myoclonus treated with hypothermia from resource-limited centres in South Asia.Generalized status myoclonus following out of hospital cardiac arrest (OHCA) has been associated with poor prognosisTo study the clinical characteristics and outcome of patients with status myoclonus following out of hospital cardiac arrest and treated with hypothermia.Retrospective chart review of patients surviving > 24 hours following OHCA in an urban community hospital in South India, between January 2006 and December 2012. All patients received therapeutic hypothermia (32-34\u00b0C) for 24 hours. Data on the clinical characteristics of patients developing status myoclonus and their outcome were studied in detail. Based on the cerebral performance category (CPC) score at hospital discharge, the neurological outcome of patients was classified into favorable and unfavorable .Out of the 124 patients surviving > 24 hours, 52 (42%) developed status myoclonus. Baseline and general characteristics were similar in patients with and without status myoclonus (Table Status myoclonus following out of hospital cardiac arrest was associated with unfavorable outcome. Majority of deaths in patients who developed status myoclonus was secondary to WLST, which may indicate self-fulfilling prophecy."} +{"text": "Data have been retrieved from several databases mentioned in details in the text. Determination and analysis of the structural and functional impact of TAFI and its expression could help elucidate the contribution of the TAFI pathway to acquired hemostatic dysfunction and will form the basis of potential therapeutic strategies to manipulate this pathway. An inhibition of TAFI (e.g. by FXI inhibitors) will offer the therapeutic possibilities to improve the decreased fibrinolysis and increase the efficiency of fibrinolytic therapy in thrombotic disorders including cancer.The data in this paper is related to the research article entitled \u201cThrombin-activatable fibrinolysis inhibitor Thr325Ile polymorphism and plasma level in breast cancer: A pilot study\u201d Specifications TableValue of the data\u2022in silico analysis of the structural and functional characterization of TAFI and its expression.This data provides a comprehensive \u2022The data are useful for understanding the effect of TAFI variants on its structure and function.\u2022This data may provide insight for determining the role of future drug treatment to inhibit TAFI function especially in cancer cases.11.1Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) represents the molecular link between the coagulation and fibrinolytic pathways TAFI activity is generated during the blood clotting process via binding to thrombin, thrombin\u2013thrombomodulin complex, or plasmin, which in turn cleave TAFI protein at Arg114 into N-terminal activation peptide and catalytic domains, leading to exposure of the active site cleft of activated TAFI (TAFIa) 1.2The plasma concentration of TAFI appears to be under the control of genetic factors and non-genetic factors 1.3in silico analysis predicted these two coding SNPs to be functionally neutral using polymorphism phenotyping (PolyPhen) version 2 and MutPred web-based programs According to several databases, TAFI gene contains multiple variants; all are rare with minor allele frequencies (MAF) of less than 0.001 except two common natural variants rs3742264 and rs1926447 at positions 46073959 and 46055809 with MAF of 0.31 (T) and 0.22 (A), respectively,"} +{"text": "G protein coupled receptors (GPCR) comprise a large family of transmembrane proteins involved in the regulation of signal transduction through the cell membrane in response to various extracellular stimuli. GPCR have become important targets of many drugs for treatments of very different diseases. During the last decade several fluorescence-based methods have been implemented for the characterization of signal transduction via GPCRs, starting from ligand binding and including several steps leading up to a response on the level of gene regulation. We have proposed the fluorescence anisotropy (FA) and fluorescence intensity (FI) assay to investigate fluorescent ligand binding properties to different GPCRs . The implementations of budded baculoviruses that display G protein-coupled receptors on their surfaces have significantly increased sensitivity and applicability of these assays . The developed novel assay systems opened new possibilities for real-time monitoring of ligand binding to their receptors for understanding their particular kinetic properties. These assays are also compatible for homogenous HTS suitable fo ligand screening. There has been implemented assay systems for receptors of peptides like melanocortin (MC4R) and neuropeptide Y (NPY1R) as well as for receptors of monoamines like dopamine (D1DAR) and serotonin (5-HT1AR)."} +{"text": "The shoulder joint is the foundation for excellent upper extremity function. It contributes to stability and basic movements like rotation and elevation of the arm. Shoulder fusion should not be accepted even for total palsy, and nerve repair should be recommended as long as an available donor nerve exists.In planning the reconstructive procedure for shoulder function, accurate biomechanical analysis of individual glenohumeral (GH) and scapulothoracic (ST) joint is imperative, especially concerning serratus anterior muscle (SA) function.Priority of nerve repair and selection of donor nerve for shoulder function are the most important key points especially in C5~7, C5~8 and total palsy depending on accompanying reconstruction of elbow and finger function including conventional nerve transfer (NT) and free muscle transfer.Many previous articles of shoulder reconstruction with nerve repair following brachial plexus injuries were concluded from global shoulder motion that combine GH and ST motion, and emphasized only suprascapular nerve (SSN) repair. I emphasized SSN and long thoracic nerve (LTN) repair except in C56 palsy. The axillary nerve (Ax) can be ignored because simple AX palsy does not result in serious paralysis of shoulder function.Postoperative range of shoulder motions following SSN repair, in decreasing order according to individual donor nerve was; phrenic never (PN), spinal accessory nerve (SAN), C5 root and contralateral C7 (CC7 ) root. For LTN repair; the decreasing order of post operative range of shoulder joint movements were intercostal nerve (ICN), PN, SAN, C5 root and CC7 root. PN to SSN and ICN to LTN transfer achieved the most satisfactory outcome in total palsy; however, other combinations of nerve repair and AX repair did not provide significantly better shoulder motion.Dynamic shoulder XP is useful to differentiate between GH and ST motion for pre- and postoperative evaluation.I will introduce our techniques of the representative nerve repairs for shoulder reconstruction."} +{"text": "Wall shear stress (WSS) may be associated with the onset and development of aortopathy in the presence of bicuspid aortic valve (BAV) . The use of 'aortic atlases' of 3D WSS vectors allows for systematic analysis of WSS differences between large patient cohorts. In this study, a comparison is performed between WSS atlases of BAV patients, BAV patients with aortic dilation, patients with BAV stenosis, and healthy controls with tricuspid valves. The aim is to test the hypothesis that WSS atlases can identify regions of significantly altered WSS that are associated with different expression of BAV and aortopathy.Prospectively ECG and respiratory gated 4D flow MRI was performed in 10 healthy controls, 10 BAV patients, 10 BAV patients with aortic dilation (as defined by aorta diameter > 4 cm), and 10 patients with BAV stenosis (table Figure WSS atlases demonstrate the ability to regionally detect that all BAV patients exhibit significantly elevated WSS compared to healthy volunteers with tricuspid valves.NIH NHLBI grant R01HL115828; American Heart Association Scientist Development Grant 13SDG14360004."} +{"text": "Staphylococcus aureus (MRSA) clonal complex 398 septicemia in persons who had no contact with livestock. Whole-genome sequencing of the isolated MRSA strains strongly suggest that both were of animal origin and that the patients had been infected through 2 independent person-to-person transmission chains.We describe 2 fatal cases of methicillin-resistant Staphylococcus aureus (MRSA) clonal complex (CC) 398 is associated with livestock and can spread to humans who have contact with animals . On the basis of these data, a phylogenetic tree was constructed from single-nucleotide polymorphism differences in genome sequences of isolates from the 4 patients and from the isolates obtained during the previous study by using the S0385 complete genome sequence (GenBank accession no. AM990992.1) as reference (tet(M) and czrC determinants (similar to most MRSA strains from clade IIa) and lacked the \u0278Sa3 phage and the nursing home . Transmission of MRSA CC398 in hospitals and institutions has been reported elsewhere, which underscores its potential to spread through person-to-person contact (In conclusion, the organism implicated in these 2 fatal cases was by all accounts spread from person to person. These findings suggest that this clonal complex can be of high pathogenicity and is readily transmissible among humans."} +{"text": "Investigators from 4 pediatric hospitals in Canada analyzed the clinical presentation and electrophysiological data of 12 children with hereditary neuropathy with liability to pressure palsies (HNPP), caused by PMP22 gene deletion. Investigators from 4 pediatric hospitals in Canada analyzed the clinical presentation and electrophysiological data of 12 children with hereditary neuropathy with liability to pressure palsies (HNPP), caused by PMP22 gene deletion. Peroneal palsy was the most common presentation (42%) followed by brachial plexus palsy in 25% of their cases. Complete nerve conduction studies were available in 10/12 cases and it demonstrated 3 major patterns: multifocal demyelination at areas of nerve entrapment without generalized demyelinating polyneuropathy (20%), isolated generalized sensorimotor polyneuropathy (20%), combined focal demyelination at the area of entrapment and demyelinating polyneuropathy (60%). All patients had electrophysiological evidence of unilateral or bilateral carpal tunnel syndrome, although it was not always symptomatic. Electrophysiological findings are useful in diagnosis of HNPP, especially in children with heterogeneous clinical presentation. [COMMENTARY. HNPP is the third most common type of hereditary motor and sensory neuropathy . The typ"} +{"text": "Estonian concentrated HIV epidemic started in August 2000 when rare HIV-1 CRF06_cpx was introduced into the population of intravenous drug users (IDUs). The majority of these HIV-positive subjects are likely co-infected with HCV but the prevalence of HCV and its genotypes during HIV concentrated epidemic in Estonia is largely unknown. The Estonian HIV database collects clinical and laboratory data (including HCV) of HIV-positive patients on medical care. Of 4500 patients on medical care 3500 are entered into Estonian HIV database .Aim: to describe the prevalence of HCV infection and the distribution of the HCV genotypes among HIV-positive subjects infected during HIV concentrated epidemic in Estonia.nd of January 2014 and it comprised subjects diagnosed HIV-positive from 2000.Data for present analyses was extracted from Estonian HIV database on 2In total 2,420 of 3,476 (70%) HIV-positive subjects were HCV antibody positive and 1,184 (64%) were HCV RNA positive. More than half of HCV-positives were men (66%) and the median age was 32 years (inter quartile range 30-36 y). The prevalence of HCV was higher in subjects verified to be HIV-positive between 2002 and 2010 as compared to between 2011 and 2013 . The prevalence of HCV-positivity was equally high in subjects reporting the use of intravenous drugs (88%), the use of other narcotics but intravenous drugs (69%) and persons who have not reported the use of illegal drugs (71%). In total 640 subjects had HCV genotype data available. The dominating genotypes were Ib (53%) and IIIa (36%), however, in recent years the prevalence of genotype Ia is raising (from 2.6% in 2005 to 25% in 2013). The distribution of HCV genotypes between different IDUs and non-IDUs was similar. Altogether 5% of HCV RNA positive subjects received HCV treatment and all except one admitted the drug usage. Of 59 subjects 48 (81%) received both HCV and HIV therapy.Decreased prevalence of HCV-positive subjects among HIV-positives may suggest a lowered HIV transmission through intravenous route during the last years. The high prevalence of HCV in persons who did not report the use of illegal drugs might indicate under-reported drug usage in this population."} +{"text": "Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of the endothelial cell-derived tumor Kaposi's sarcoma and of the lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman's disease. The life cycle of KSHV includes a latent and a lytic/productive phase that both contribute to tumorigenic activity. Major threats for infected tumor cells are attacks of the immune system and the induction of endogeneous cell death programs in response to the virus infection. KSHV opposes these threats for example by hiding from the immune attack by entering the latent infection phase where only few genes are expressed and replication is absent or in the productive phase by the downregulation of major histocompatibility complex class I on the surface of infected cells. Moreover, KSHV uses several different strategies to counteract endogenous cell death programs such as apoptosis and necroptosis.KSHV encodes more than 87 ORFs (open reading frames) and numerous ribosomal-loaded not previously annotated RNAs . ORF actIn another RTCM-based study the effects of all KSHV-encoded genes on the inhibition of p53 were investigated. The tumor suppressor p53 is a major regulatory molecule of apoptosis and cell cycle progression. Three structural proteins namely ORF22 (envelope glycoprotein gH), ORF25 (major capsid protein) and ORF64 (tegument protein) were identified as potent inhibitors of p53 signaling [Finally, viral DNA establishes a pathogen associated molecular pattern (PAMP) that can trigger the host innate immune responses by stimulating production of type I interferons (IFNs). This leads to repression of viral replication and elimination of virus infected cells by apoptosis. Systematic analyses of all KSHV-encoded genes identified the tegument protein ORF52 as a potent inhibitor of this pathway . ORF52 aAltogether, the transfection studies summarized here indicate that KSHV encodes a large repertoire of genes regulating survival of the infected cell in all stages of the viral life cycle Figure . In the"} +{"text": "The kidneys are known as a target of hepatitis viruses. The renal impairment associated with hepatitis B virus (HBV) could be represented by lesions of glomeruli, or by injury of the renal tubules. Membranous nephropathy is the most common form of glomerulonephritis associated with HBV infection. We aimed to develop a prospective study that evaluated the relation between serum levels of 8-hydroxy-2-deoxiguanosine (8OHdG) and total antioxidant status (TAS) in patients with membranous glomerulopathy associated with HBV infection.The study included a group of 18 patients with chronic infection with HBV and membranous nephropathy with nephrotic syndrome, without renal failure (eGFR >60mL/min/1.73sqm), and a group of 20 patients with chronic infection with HBV without membranous glomerulonephritis. The patients did not receive any treatment for the mentioned diseases before the inclusion in the study. The groups were similar for demographic and nutritional status characteristics. The assessment of 8OHdG, a metabolite of oxidative damage of DNA, was made by ELISA method. TAS was determined by spectrophotometric method.In patients with chronic HBV infection and membranous nephropathy, 8OHdG (ng/mL serum) had higher levels than in patients with chronic HBV infection without renal disease . Serum levels of TAS (mmol/L serum) were significantly lower in patients with membranous glomerulopathy compared with those without nephropathy . A statistically strong negative correlation was determined between 8OHdG and TAS in patients with glomerulopathy associated with HBV infection.The negative association between serum levels of 8OHdG and TAS in patients with membranous nephropathy induced by HBV infection suggests an important role of oxidative stress in the development of renal diseases. The adjustment of imbalance between levels of reactive oxygen/nitrogen species and those of antioxidants in the human body could represent a goal for a better management of renal diseases."} +{"text": "Platanista gangetica (the Ganges and Indus river dolphin), is the sole surviving member of the broader group Platanistoidea, with many fossil relatives that range from Oligocene to Miocene in age. Curiously, the highly threatened Platanista is restricted today to freshwater river systems of South Asia, yet nearly all fossil platanistoids are known globally from marine rocks, suggesting a marine ancestry for this group. In recent years, studies on the phylogenetic relationships in Platanistoidea have reached a general consensus about the membership of different sub-clades and putative extinct groups, although the position of some platanistoid groups has been contested. Here we describe a new genus and species of fossil platanistoid, Arktocara yakataga, gen. et sp. nov. from the Oligocene of Alaska, USA. The type and only known specimen was collected from the marine Poul Creek Formation, a unit known to include Oligocene strata, exposed in the Yakutat City and Borough of Southeast Alaska. In our phylogenetic analysis of stem and node-based Platanistoidea, Arktocara falls within the node-based sub-clade Allodelphinidae as the sister taxon to Allodelphis pratti. With a geochronologic age between \u223c29\u201324 million years old, Arktocara is among the oldest crown Odontoceti, reinforcing the long-standing view that the diversification for crown lineages must have occurred no later than the early Oligocene.The diversification of crown cetacean lineages occurred throughout the Oligocene, but it remains an ongoing challenge to resolve the phylogenetic pattern of their origins, especially with respect to stem lineages. One extant monotypic lineage, Multiple lines of evidence point to the Oligocene epoch as an important period for the origin and early evolutionary history of crown group Cetacea . This inPlatanista gangetica . The inclusion of Squalodontidae and Waipatiidae in Platanistoidea, as suggested by Currently, phylogenetic studies of Platanistoidea have reached a general consensus about the inclusion three groups (two of which are completely extinct): Allodelphinidae, Squalodelphinidae and Platanistidae , it is both the oldest allodelphinid and among the oldest crown Odontoceti known. The results of our phylogenetic analysis continue to support a monophyletic Platanistoidea, along with traditional sub-clades (including a monophyletic Allodelphinidae), which underscores the importance of Oligocene cetaceans in documenting the early diversification of crown Cetacea.Here we describe t Alaska \u20136. ArktoArktocara yakataga was scanned using Nikon Metrology\u2019s combined 225/450 kV microfocus X-ray and computed tomography (CT) walk-in vault system at Chesapeake Testing in Belcamp, Maryland, USA. Using this vault CT scanner system, we collected CT slices at 0.63 mm, resulting in three-dimensional reconstruction increments of 0.30 mm. We mounted the holotype skull vertically in the vault CT scanner system, with the posterior side down to minimize scanning width. Also, we collected CT scan data for the right periotic (YPM 13408) of Allodelphis prattiArktocara cranium that will be available for viewing and download on the Smithsonian X 3D website (http://3d.si.edu). These 3D files, along with the original DICOM files, are also archived at Zenodo (http://zenodo.org) at the following DOI: 10.5281/zenodo.51363. While the CT data were useful for making 3D models of the holotype, the density of the fossil material prevented the CT scanner from clearly determining internal morphology of the skull, failing to clarify indistinct sutures between skull elements.The holotype of Arktocara yakataga using Notocetus vanbenedeniPhocageneus venustusSqualodon calvertensisWaipatia maerewhenuaZarhachis flagellatorPlatanista gangetica. The stem cetacean taxon Georgiacetus vogtlensis was used as the outgroup. We removed an undescribed specimen (OU 22125), and added 4 allodelphinid taxa (Zarhinocetus errabundus (Goedertius oregonensisAllodelphis pratti and Arktocara yakataga), raising the number of OTUs used in the analysis to 86. We also added codings for four periotic characters (288\u2013291) for Pomatodelphis inaequalisZarhachis flagellator, based on material available at the Smithsonian Institution (see \u2018Specimens observed\u2019). We did not add codings for taxa that we could not directly observe, and therefore some platanistoid taxa were excluded from the analysis, including Huaridelphis raimondiiNinjadelphis ujiharaiAllodelphis woodburneiWe tested the phylogenetic placement of rabundus GoedertiWe performed a cladistic search in TNT* using all characters as unordered and equally weighted. We then conducted subsequent statistical support analyses by searching for successively longer trees to calculate bremer decay indices and 100 bootstrap replicates. The complete matrix in .txt format, as well as a description of character states are avaiFollowing http://zoobank.org/\u201d. The LSID for this publication is: urn:lsid:zoobank.org:pub:0194A593-DBE0-47CA-A41F-04A37931BA2F. The electronic edition of this work was published in a journal with an ISSN, and has been archived and is available from the following digital repositories: PubMed Central, and LOCKSS.The electronic edition of this article conforms to the requirements of the amended International Code of Zoological Nomenclature, and hence the new names contained herein are available under that Code from the electronic edition of this article. This published work and the nomenclatural acts it contains have been registered in ZooBank, the online registration system for the ICZN. The ZooBank LSIDs (Life Science Identifiers) can be resolved and the associated information viewed through any standard web browser by appending the LSID to the prefix \u201cAllodelphis pratti (YPM 13408); Allodelphis sp. ; Goedertius oregonensis (LACM 123887); Goedertius sp. ; Notocetus sp. (USNM 206286); Phocageneus venustus ; Phocageneus sp. ; Platanista gangetica (USNM 23456); Pomatodelphis bobengiPomatodelphis sp. (USNM 360054); Squalodon calvertensis ; cast of Waipatia maerewhenua (USNM 508061); Zarhachis flagellator ; Zarhachis sp. ; cast of Zarhinocetus errabundus (USNM 526600); Zarhinocetus errabundus .Definitions. Crown group Platanista refers to the crown clade arising from the last common ancestor of all lineages descending from Platanista, including two subspecies of Platanista gangetica because these familial level groupings are not the explicit focus of this study, and we defer to future work that can better substantiate their taxonomic scope and better test their monophyly was discovered and collected in 1951 by United States Geological Survey (USGS) geologist Donald J. Miller (1919\u20131961), who was mapping what was then the Yakataga District of Alaska (now the Yakutat City and Borough) between 1944 and 1963. Archival notes housed with the specimen at USNM state that Miller found the specimen in the Poul Creek Formation within the then-Yakataga District . Therefore, we delimit the area for the type\u2019s provenance to exposures of the Poul Creek Formation in the Yakutat City and Borough, Alaska, USA, in a grid ranging approximately from 60\u00b022\u2032N, 142\u00b030\u2032W to 60\u00b000\u2032N, 143\u00b022\u2032W , which belongs, based on one equivocal synapomorphy, to the node-based Platanistoidea: width: width of the premaxillae >50% of the width of the rostrum at the antorbital notch (character 51[1]). More convincingly, Arktocara belongs to Platanistoidea based on its affinities to other members of the Allodelphinidae that possess unequivocal synapomorphies of the Platanistoidea (see \u2018Discussion\u2019 for further comments on the relationship of Allodelphinidae within the Platanistoidea). We also note that, for the purposes of this diagnosis, we use a broad definition of Waipatiidae that includes Otekaikea spp. ; an occipital shield bearing a distinct sagittal crest (character 118[1]); length of the zygomatic process as percent of the greatest width of the maxillae across the postorbital processes <30% (character 152[1]); lacking a dorsal condyloid fossa (character 119[0]); and lacking any asymmetry in the vertex (character 98[0]).Arktocara also differs from Waipatiidae and Platanistidae in having: frontals posterior to the nasals and between the premaxillae wider than the maximum transverse width across the nasals (character 95[0]); and lacking an anterior transverse ridge and large tympanosquamosal recess, with middle sinus still inferred to be present (character 144[1]). Arktocara further differs from Waipatiidae in having: a lacrimal that wraps around the anterior edge of the supraorbital process of frontal and slightly overlies its anterior end (character 37[0]); maxilla forming the dorsolateral edge of the internal opening of the infraorbital foramen (character 43[0]); ventromedial edge of the internal opening of infraorbital foramen formed by maxilla and palatine (character 44[1]); a nuchal crest weakly convex anteriorly in dorsoposterior view (character 117[1]); a lateral end of the groove for the mandibular branch of the trigeminal nerve wrapping laterally around posterior end of pterygoid sinus fossa and opening primarily anteriorly (character 148[0]); the angle formed by the basioccipital crests in ventral view between 15\u201340\u00b0 (character 157[1]); and in lacking a premaxillary crest or posterior maxillary crest adjacent to the nasal (character 72[0]).Arktocara differs from all Platanistidae and Squalodelphinidae in having the anterolateral corner of the maxilla overlying the supraorbital process of frontal being thin and of even thickness to parts posteromedial (character 64[0]). Arktocara also differs from all Platanistidae in having: the apex of the postorbital process of frontal projected posterolaterally and slightly ventrally (character 46[0]); the ratio of the greatest width of the premaxillae to the greatest width of maxillae at the level of postorbital processes between 0.49\u20130.38 (character 76[1]); a shallow emargination of the posterior edge of zygomatic process by the sternomastoid muscle fossa in lateral view (character 111[1]); the width of the squamosal lateral to the exoccipital in posterior view as a percent of the greatest width of the exoccipitals <15% (character 112[0]); fossae for the preorbital lobe of the pterygoid sinus present in the orbit (character 134[1]); shallow posterior portion of the periotic fossa of the squamosal (character 151[1]); posteroventral-most point on the basioccipital crest forming a closely appressed flange with a narrow crease separating exoccipital dorsally from the rest of crest (character 156[1]); and lacking a pneumatic maxillary crest overhanging medially (character 65[0]). Finally, Arktocara differs from all Squalodelphinidae in having: a narrower width of the premaxillae at the antorbital notches as a percent width of the rostrum at the antorbital notch (50\u201364%) (character 51[1]).Arktocara differs from all other Allodelphinidae in having: a reduced postglenoid process of the squamosal (character 114[1]); and the posteroventral-most point of the basioccipital crest forming a closely appressed flange separating the exoccipital dorsally from the rest of the crest by a narrow crease (character 156[1]). Arktocara differs from Allodelphis pratti and Goedertius oregonensis in having: both premaxillae extending posterior to the nasals (character 58[1]); and the ratio of the greatest width of the premaxillae to greatest width of the maxillae at the level of the postorbital processes between 0.49\u20130.38 (character 76[1]).Arktocara also differs from Goedertius oregonensis and Zarhinocetus errabundus in having: the width of the premaxillae between 50\u201364% of the width of the maxillae a the level of the antorbital notches (character 51[1]); a uniformly thin anterolateral corner of the maxilla overlying the supraorbital process of the frontal (character 64[0]); length of the zygomatic process of the squamosal \u226430% of the width of the maxillae at the postorbital processes (character 152[1]); lacking a rostral basin (character 50[0]), lacking a posterior dorsal infraorbital foramen placed posteromedially near the posterior extremity of the premaxilla (character 60[0]); lacking a dorsal condyloid fossa (character 119[0]) and having a symmetrical cranial vertex (character 98[0]).Arktocara also differs from Allodelphis pratti and Zarhinocetus errabundus in having: two anterior dorsal infraorbital foramina (character 49[1]); and a shallow emargination of the posterior edge of the zygomatic process by the sternomastoid muscle fossa in lateral view (character 111[1]). Arktocara further differs from Goedertius oregonensis having: a fused lacrimal and jugal (character 39[1]); the apex of the postorbital process of the frontal directed posterolaterally and slightly ventrally (character 46[0]); a triangular or anteroposteriorly widened falciform shaped postorbital process of the frontal (character 47[2]); one posterior dorsal infraorbital foramina of the maxilla (character 59[1]); nuchal crest weakly convex anteriorly in dorsoposterior view (character 117[1]); and the posterior edge of the vomer terminating on the basisphenoid (character 154[0]).Arktocara further differs from Zarhinocetus errabundus in having: the transverse width of the nasal >70% the length of the nasal (character 91[2]); a distinct sagittal crest on the occipital shield (character 118[1]); and in lacking an anterior transverse ridge and large tympanosquamosal recess (character 144[1]).Arktocara displays the following apomorphies: a weakly developed antorbital notch (character 10[0]); straight lateral margin of the right premaxilla posterior to premaxillary foramen (character 56[1]); a U-shaped nasal frontal suture (character 94[2]); and a greatly reduced postglenoid process of the squamosal (character 114[1]).Lastly, Etymology. The species epithet \u2018yakataga\u2019 derives from the Tlingit name for the point of land along the southeast coast of Alaska between modern day Kayak Island and Ice Bay. This point, currently called Cape Yakataga, is located directly southwest of Watson Peak and represents the southeastern boundary of a floodplain drained by the Bering Glacier. The name Yakataga was first published by Anatomical terminology follows Arktocara yakataga (USNM 214830) consists of an incomplete skull, measuring 23 cm in preserved length. The majority of the rostrum is missing, with an asymmetric transverse break approximately 2\u20135 cm anterior to the antorbital notch. The skull also lacks both nasals, jugals, tympanoperiotics, and the right occipital condyle and deep , with a broadly open and deep mesorostral canal . While there is material missing around the antorbital notch, the posterior margin of the right antorbital notch appears to be real, demonstrating it to be weakly developed, forming an L-shape with the lateral margin of the rostrum . Though In ventral view, there is clearly a fossa for the preorbital lobe of the pterygoid sinus , as well as for the hamular lobe of the pterygoid sinus (fossa anterior to the choanae). Also present are an extremely shallow tympanosquamosal recess for the middle sinus, and a middle pterygoid sinus fossa anterior to the periotic fossa . There iBoth of the premaxillae are symmetrical, and overlie either the maxillae or the frontals for their entire preserved length . In lateOn the vertex, the posterior termination of the premaxilla lies on the frontal as an asymmetrical, spatulate lobe, tapering posterolaterally and bordered medially by frontal and the nasal fossa of the frontal, and laterally the maxilla . There iOnly a small portion of rostral maxilla remains, including part of the maxillary flange on the left side, and just over 5 cm of the body of this element on the right side. In anterior view, the maxilla preserved on the rostrum slopes dorsally from the lateral edge to the premaxillary suture . The preIn ventral view, the hard palate of maxilla curves dorsolaterally from the midline to the lateral edge, where it flattens out on the maxillary flange . No alveIn dorsal view, the frontals are mostly covered by the maxillae, with the exception of exposures on the postorbital processes and the vertex . The posThe frontal-maxillary suture is also indistinct along the lateral edge of the vertex, where the maxilla rises dorsomedially to the edge of the vertex\u2019s tabular surface . The sutMost of the medial margin of the antorbital process is composed of the lacrimal. In dorsal view, a narrow margin of the lacrimal emerges from beneath the maxilla as a thin plate along the lateral and anterior edges of the antorbital process . In ventAllodelphis pratti . For further discussion of the lateral lamina of pterygoid as a platanistoid feature, see discussion in \u201cPlatanistoid systematics.\u201dPlatanistoids bear a bony structure on the ventral side of their skulls: a thin, bony lamina that extends from the ventral surface of the hard palate and runs parallel to the posterior lateral lamina of the pterygoid to finally attach to the alisphenoid medial of the squamosal in the ear region. The holotype of Both of the palatine bones are missing large portions, including the palatine surface, maxillary process, palatal crest, and lateral lamina. However, in ventral view a prominent pterygoid sinus fossa for the hamular lobe is formed by the palatine, anterior to the medial pterygoid lamina and posterior to the palatine groove of the maxilla . These gPlatanista and an undescribed platanistoid USNM 214911 was estimated using the formula created by n weight . It is lic necks . Though Arktocara, or whether it is more broadly observed in other allodelphinids . Also, the missing nasals and palatines suggest that their sutures to adjacent skeletal elements were unfused. We assessed skeletal maturity based on long-established osteological indicators, particularly the fusion of cranial sutures and textural surface of the occipital condyles . Most suArktocara is the sister taxon to Allodelphis, nested within a broader clade of Allodelphinidae, which includes Zarhinocetus and Goedertius. This is the first phylogenetic analysis to include these latter two genera, which were not included in Zarhinocetus and Allodelphis among their allodelphinid sample of Platanistoidea. Our analysis yields robust support for the monophyly of Allodelphinidae, with higher support values than those recovered for the node-based clade of Platanistoidea (sensuWaipatia and both species of Otekaikea\u2014Otekaikea species from their definition of Waipatiidae. We recommend defining Waipatiidae more inclusively (both species of Waipatia and Otekaikea).The phylogenetic analysis resulted in 430 most parsimonious trees, all with a score of 1960, consistency index of 0.233 and retention index of 0.631. The strict consensus tree, which was created from the 430 trees, shows a similar topology to the equally weighted analysis of lue <50) . Like Ta0) sensu, yet in Though it is beyond the scope of this study, the incorporation of molecular data into future analyses of odontocete systematics will help to better resolve the relationships among extant cetaceans, and consequently their fossil relatives. See below for further comment on the implications of these results on the systematics of Platanistoidea.Inia, Pontoporia, and Lipotes were more closely related to Delphinoidea than to Platanista and is slightly overlapped by the pterygoid (though not the maxilla) .Dalpiazina ombonii (Champsodelphis by Longhi (1898), was later reviewed by and given its new genus by ombonii . However, in their implied weighting strict consensus, Squalodon was added to Platanistoidea. Allodelphinidae was not included in their analysis. sensu stricto based on 6 synapomorphies: presence of the posterior dorsal infraorbital foramina of the maxilla (character 59); C-shaped or weakly curved parabullary sulcus (character 169); presence of the articular rim on the periotic (character 186); presence of the anterior spine of the tympanic bulla (character 195); presence of the anterolateral convexity of the tympanic bulla with anterolateral notch (character 196); and presence of the ventral groove (median furrow) of bulla anteriorly (character 212). Arktocara.In contrast to hectori , both OtGoedertius oregonensis, Ninjadelphis ujiharai, and Zarhinocetus donnamatsonaeIn a broad review of Allodelphinidae, Waipatia maerewhenua + Waipatia hectori + Otekaikea marplesi + Otekaikea huata), Allodelphinidae and a polyphyletic Squalodelphinidae. We note that, for Phocageneus venustus, we followed Waipatia and Otekaikea is consistent with Waipatia, differing from the results in Waipatia maerewhenua and Otekaikea marplesi. Our results are consistent with Squalodelphis fabianii as a basal member of Platanistoidea and an unnamed clade of Notocetus vanbenedeni + Phocageneus venustus as the sister group to Platanistidae. A more detailed coding of Squalodelphinidae in future work, especially one that includes Huaridelphis raimondii, will provide more insight into the relationships among this group.Our phylogenetic analysis herein addresses some of the shortfalls of previous studies by including type genera belonging to all potential platanistoid families that have been presented in recent phylogenetic analyses i.e., . We resoWe diagnose a node-based Platanistoidea by the following synapomorphies: moderately elevated coronoid process (character 33*); premaxillae >65% of width of rostrum at antorbital notches (character 51*); alisphenoidal-squamosal suture coursing along groove for mandibular branch of trigeminal nerve in ventral view (character 147[1]); lateral groove or depression with profile of periotic becoming slightly to markedly sigmoidal in dorsal view (character 166[1]); anteroposterior ridge on dorsal side anterior process and body of periotic (character 167[1]); parabullary sulcus on the periotic weakly to strongly curved and c-shaped ; and ventral surface of the posterior process of the periotic not flat along a straight path perpendicular to its long axis Of these synapomorphies, the two marked by an asterisk (\u2217) are equivocal across the group, demonstrating character state reversals or independent origins . Two characters are ambiguous and show independent origins (characters 169 and character 191), but we argue remain useful for characterizing this group.Allodelphis pratti, where there is no distinguishable rim lateral to the posterior process and separated by a sulcus , the anterolateral convexity of the tympanic bulla with anterolateral notch (character 196), and the ventral groove (median furrow) of bulla anteriorly (character 212) are all ambiguous characters, represented by two states each across Platanistoidea. All of the latter traits are present in Allodelphis pratti and Zarhinocetus errabundus, with perhaps the exception of the ventral groove of the anterior surface of the bulla in Allodelphis pratti, which could not be determined from the photos of the referred specimen (UCMP 83791) provided by Only one of the six synapomorphies presented by a sulcus . In ZarhSqualodelphis fabianii and an unnamed sub-clade that includes Notocetus vanbenedeni + Phocageneus venustus + Platanistidae. Allodelphinidae in our study is supported by the following synapomorphies: rostral constriction anterior to the antorbital notch (character 9[1]); premaxillae in dorsal view contacting along midline for approximately half of the entire length of the rostrum and partially fused (character 14[3]); buccal teeth entocingulum absent (character 24[1]); greatest diameter of largest functional tooth <3% of greatest width of maxillae at postorbital processes (character 25[2]); angle of anterior edge of supraorbital process and the median line oriented anteromedially (character 35[1]); dorsolateral edge of internal opening of infraorbital foramen formed by maxilla (character 43[0]); posterolateral sulcus shallow or absent (character 57[1]); lack of premaxillary crest or posterior maxillary crest adjacent to nasals (character 72[0]); temporal fossa roofed over by lateral expansion of the maxillae (character 101[1]); palatines partially covered by pterygoid dividing it into medial and lateral exposures (character 121[1]); lateral lamina of palatine (character 122[1]); lateral end of groove for mandibular branch of trigeminal nerve wrapping laterally around posterior end of pterygoid sinus fossa and opening anteriorly (character 148[0]); lack of anterior bullar facet (character 172[1]); elevated caudal tympanic process of periotic with ventral and posterior edges forming a right angle in medial view (character 178[1]); tubular fundus of internal acoustic meatus (character 182[1]) angle between posterior process of periotic and long axis of pars cochlearis \u2264135\u00b0 from dorsal or ventral view (character 189[1]); and ventral surface of posterior process of periotic convex along a straight path perpendicular to its long axis (character 191[2]). Based on the published descriptions and illustrations provided by Allodelphis woodburnei, Ninjadelphis ujiharai, and Zarhinocetus donnamatsonae) each possess all of the allodelphinid synapomorphies presented by our analysis.Our analysis recovered Allodelphinidae as a well-supported sub-clade within a node-based Platanistoidea, rooted in a polytomy with Waipatia and Otekaikea where the palatine is poorly preserved or missing), and a tympanic bulla with elongated and pointed anterior process, among others. Nevertheless, our diagnosis is consistent with Allodelphis pratti where only one premaxilla is separated from the corresponding nasal by a tiny exposure of maxilla, to further \u201cderived\u201d states in Ninjadelphis and Zarhinocetus where the premaxillae are further retracted anteriorly onto the facial region and away from the nasals. However, it is unclear in the more \u201cprimitive\u201d state of Allodelphis whether the lack of contact between the premaxilla and nasal could be a result of diagenetic breakage, or individual variation. Furthermore, speculations on the more \u201cderived states\u201d in taxa such as Ninjadelphis, are based on specimens with incomplete premaxillae. In Goedertius oregonensis, the premaxillae are not separated from the nasals. This condition is likely also true for Arktocara yakataga: although the nasals are missing, the premaxillae directly abut the nasal fossa of the frontal, and therefore would most likely have been in direct contact with the nasals. Further extensive comparative work on allodelphinid taxa will heAllodelphis pratti, in part due to obstruction by unprepared matrix. However, in Arktocara yakataga, though there is no obvious indication of a postorbital lobe of the pterygoid sinus, the deep and broad fossa surrounding the ventral infraorbital foramen and the sphenopalatine foramen anteromedial of the orbit suggests the presence of a preorbital lobe.Second, Allodelphis pratti was referred to the Platanistidae by Ninjadelphis is the only allodelphinid specimen with an associated scapula, and it is missing the coracoid process. This agreement with Otekaikea huata), the character may still be relevant for diagnosing Platanistoidea . Though the type specimen of Arktocara lacks tympanoperiotics, it is closely allied with Allodelphis pratti, whose periotic shares three more of the platanistoid synapomorphies: presence of lateral groove or depression with the profile of the periotic becoming slightly to markedly sigmoidal in in dorsal view (character 166[1]); anteroposterior ridge developed on anterior process and body of periotic in dorsal view (character 167[1]); and a curved C-shaped parabullary sulcus . Therefore, in the absence of tympanoperiotics associated with new cranial material of Arktocara, we are confident that these elements would share many features with Allodelphis pratti, the sister taxon of Arktocara.Of the 7 supporting synapomorphies for Platanistoidea in our study, none of the unequivocal synapomorphies are preserved and demonstrated on the skull of Arktocara in morphology is Allodelphis pratti , (B) Platanista gangetica (USNM 23456) and (C) USNM 214911, an undescribed platanistoid. This feature (highlighted in red), is a pointed lamina projected anteromedially from the anterior margin of the falciform process (highlighted in blue), posterior to the lateral lamina of the pterygoid and anterior to the posterolateral lamina of the alisphenoid that articulates with the base of the falciform process USNM 2345 and (C) Click here for additional data file.10.7717/peerj.2321/supp-2Figure S2Goedertius. (A) USNM 335406, (B) USNM 335765, (C) USNM 314421, (D) USNM 13673.Photographs of undescribed platanistoid specimens housed in the Vertebrate Paleontology collections of the National Museum of Natural History, Smithsonian Institution, Washington D.C. All of the skulls are referred in this paper to the allodelphinid genus Click here for additional data file.10.7717/peerj.2321/supp-3Table S1Zarhinocetus errabundus, Goedertius oregonensis, Allodelphis pratti and Arktocara yakataga). Also added were codings for four periotic characters (288\u2013291) for Pomatodelphis inaequalis and Zarhachis flagellator.0, primitive state; 1, 2, 3, derived states; 0/1, a variable between 0 and 1; 1/2 a variable between 1 and 2; 1/3, a variable between 1 and 3; ?, missing character or taxon not coded for this character. Following Click here for additional data file.10.7717/peerj.2321/supp-4Appendix S1Following Click here for additional data file."} +{"text": "The hyperglycemic condition from dysregulated glucose homeostasis has been defined stress hyperglycemia. Following burn trauma it persists in a hypermetabolic flow phase as a response of burn itself and sepsis. Serial Sequential Organ Failure Assesment (SOFA) score is recommended from American Burn Association for evaluation of organ dysfunction/failure.The aim of this study is to test the relation of serial SOFA score evaluation and probability of critical hyperglycemia during burn injury.-rd,7-th,14-th and 21 -st day after burn injury.This is an observational prospective cohort study. Population is composed of adults hospitalized in ICU of the Service of Burns near University Hospital Center, Tirana, Albania for 5 years(2010-2015).Patients are grouped according glucose values on three categories: Patients with Euglycemia ( 80-120 mg/dL), Moderate Hyperglycemia (121-180 mg/dL) and Critical Hyperglycemia (> 180 mg/dL ).Test characteristics and performance as well as AUC are calculated for SOFA score on the 3The prevalence of Critical Hyperglycemia in adult burn patients is 6.9%. Using the value 6 as the cutoff SOFA scoring for dysfunction/ failure, serial SOFA score evaluation and presence of critical Hyperglycemia have a good correlation. On the 14-th day after burn the values of Area Under the Curve, Positive Likelihood Ratios and Positive Predicted Values (PPV) are the better values as complementary information to clinical assessment Figure .Figure 1In patients with clinical sepsis after severe burns the probability for Critical hyperglycemia is higher after the first week This tells us that 2 of 5 patients with sepsis after the first week of the illness will demonstrate critical hyperglycemia. Hyperglycemia is a sign of sepsis in severely burned adult patients."} +{"text": "Critically ill patients frequently suffer from intensive care unit (ICU) acquired weakness (ICUAW). Evoke muscle contraction by electrical muscle stimulation (EMS) may help to prevent their overall strength diminishing by conserving muscle strength and mass.The aim of the study was to investigate the effects of daily EMS-therapy on muscular strength in ICU patients, compared to a protocol based standard physiotherapy.The interventional randomized controlled trial included critically ill patients at high risk for ICUAW selected by SOFA score \u2265 9 and onset of critical illness in less than 72 hours. Randomization was administered to EMS group or a physiotherapy group (protocol base physiotherapy). EMS-therapy was applied for 20 minutes 7 days/week to 8 bilateral muscle groups by an experienced physiotherapist. Medical-Research-Council (MRC) score for muscle strength and grip strength measured by hand-dynamometer were recorded on the first day patients were adequately awake and on the day of their ICU discharge. Non-parametric tests were performed. Ethic vote (Charit\u00e9 EA 2/041/10).50 patients, 33 males and 17 females with a median age of 52 (10/90) years and a SOFA score of 13 (10/15) at admission where included in the study. Randomization resulted in 21 to 29 subjects for EMS and controls respectively. Time-points of muscle strength measurements were \u201cfirst day being awake\u201d at median day 11 (7/19) and discharge form ICU, median day 26 (17/33). Patient characteristics and time-points of recorded parameters were without significant differences between the intervention (EMS) and control group (data not shown). Overall subjects fulfilled criteria for ICUAW on their first day of being awake and significantly improved their MRC score and grip strength until their ICU discharge. Surprisingly we could not show direct group differences between EMS- and control group for MRC score and grip strength. By focusing separately on the course of strength for EMS- and control group we found an increase in MRC score for both groups between the first and second measurement.Grip strength in nonEMS treated patients rose significantly whilst patients receiving EMS couldn't show significant improvements between measurements.Our patients managed to increase their grip- and general strength levels significantly from their first day of being adequately awake until the day of their ICU discharge. Further subgroup analysis however indicates that EMS therapy may not be more beneficial in increasing grip or MRC-measured strength compared to the standard physiotherapy protocol within our study. The missing grip strength improvement of the EMS group between the first day of being awake and ICU discharge may be attributed to greater muscle strength at time of awakening without significant power to show group differences.DFG KFO 192/2 TP3"} +{"text": "Respiratory muscle weakness is common in mechanically ventilated patients and impairs liberation from ventilation. Inspiratory muscle training (IMT) might accelerate liberation from mechanical ventilation. We undertook to summarize previously published IMT protocols and the impact of IMT on respiratory muscle function and clinical outcomes.We searched multiple databases using a sensitive search strategy combining MeSH headings and keywords for studies of IMT during MV. Studies were adjudicated for inclusion and data were abstracted independently and in duplicate. Methodological quality was assessed using the GRADE system.n = 5) or after difficult weaning (n = 5); one study implemented IMT within 24 hours of intubation. IMT was associated with greater increases in maximal inspiratory pressure compared with control , I2 = 0%). There were no significant differences in the duration of MV , I2 = 71%) or the rate of successful weaning . The GRADE quality of evidence was low for all these outcomes; risk of bias was high for most studies and summary effects were imprecise and inconsistent. No serious adverse events related to IMT were reported.Eleven studies met the inclusion criteria; of these, six were randomized controlled trials and five were observational studies. A variety of IMT techniques were employed including inspiratory threshold loading (eight studies), biofeedback to increase inspiratory effort (one study), chair-sitting (one study) and diaphragmatic breathing pattern training (one study). Threshold loading was achieved by application of an external device (six studies) or increases in the inspiratory pressure trigger setting (two studies). Most studies implemented IMT in the weaning phase (IMT in mechanically ventilated patients appears safe and well-tolerated and improves respiratory muscle function. IMT was not associated with accelerated liberation from mechanical ventilation. However, because the included studies had important methodological limitations and employed varying methods of IMT, we cannot draw firm conclusions about the effect of IMT on clinical outcomes."} +{"text": "Twenty one fully sequenced and well annotated insect genomes were used to construct genome content matrices for phylogenetic analysis and functional annotation of insect genomes. To examine the role of e-value cutoff in ortholog determination we used scaled e-value cutoffs and a single linkage clustering approach.. The present communication includes (1) a list of the genomes used to construct the genome content phylogenetic matrices, (2) a nexus file with the data matrices used in phylogenetic analysis, (3) a nexus file with the Newick trees generated by phylogenetic analysis, (4) an excel file listing the Core (CORE) genes and Unique (UNI) genes found in five insect groups, and (5) a figure showing a plot of consistency index (CI) versus percent of unannotated genes that are apomorphies in the data set for gene losses and gains and bar plots of gains and losses for four consistency index (CI) cutoffs."} +{"text": "This article gives an overview of recent publications and potential indications of Positron emission tomography/ Magnetic resonance (PET/MR) imaging of prostate cancer. Several original research articles showed that a combination of these functional imaging modalities can improve diagnostic accuracy of MR imaging or [18F] choline has been examined to a large extent during the past years; however, with partly controversial results. A large meta-analysis defined possible indications of PET/CT examinations of the prostate including initial staging of patients with newly diagnosed prostate cancer and high-risk of nodal extension and suspected recurrent prostate cancer after surgery or radiotherapy indicated by a rising PSA-level. Another indication of a PET/CT scan of the prostate might be a history of negative biopsies in patients with a strong suspicion of prostate cancer to plan a focused re-biopsy in carefully selected cases [PET and PET/CT imaging of prostate cancer with the radiotracers C or [18F18F] choline PET/MR imaging in patients with prostate cancer [11C] and [18F] choline was shown that PET and MR image quality was sufficient and without significant differences in the detection of hyper-metabolic lesions and with excellent correlation of standardized uptake values derived from PET/MRI and PET/CT [18F] choline PET/MRI were reported for detection of prostate cancer relapse after external beam radiotherapy [68Ga] labeled prostate-specific membrane antigen (PSMA) ligand. Recent studies demonstrated the technical feasibility of PET/MR imaging with this new tracer and found a superiority of PET/MRI over PET/CT by using this tracer [68Ga] labeled tracer yielded some difficulties and requires further investigation before routine use choline PET/MR imaging was performed after PET/CT. The images illustrate the combined findings of anatomical sequences together with diffusion-weighted imaging and PET imaging.Figure legends: Images from a patient with biochemical failure after radical prostatectomy and fromIn conclusion, the results published so far on PET/MRI of prostate cancer are promising and justify further research in this field. It will be necessary to plan and conduct large prospective studies in order to ascertain the additive value of PET/MRI in comparison to the available diagnostic tools in prostate cancer diagnostics."} +{"text": "Simian foamy virus (SFV) is a retrovirus ubiquitous in non-human primates (NHPs) that can be transmitted to humans, mostly through severe bites. In the past few years, our laboratory identified more than 50 hunters from Central Africa infected with zoonotic SFVs. Analysis of SFV complete sequences obtained from 5 of these individuals had revealed that the env gene was the most variable one. Furthermore, recombinant SFV strains have been recently shown; some of them involved the env gene. This led us to investigate the env gene variability of zoonotic SFV strains, looking especially for possible recombinants. We sequenced the complete or the surface glycoprotein region (SU) of SFV env gene amplified from blood DNA of: 1) a series of 40 individuals from Cameroon or Gabon infected with a gorilla or chimpanzee FV strain; 2) one gorilla and 3 infected chimpanzees living in the same areas than the hunters. All sequences were aligned and analysed by phylogenetic (neighbour-joining and maximum likelihood) and recombinant detection methods . Phylogenetic analyses revealed the existence of two different env variants among both gorilla FV and chimpanzee FV strains. These were present in zoonotic as well as in NHP strains. These variants differ greatly (more than 30% variability) in a 750 bp long region located in the receptor binding domain of the SU; the rest of the gene is very conserved (less than 5% variability among strains from the same species). Within a given variant, protein sequences of the SU are very conserved and stable which may reflect functional constraint. Recombination analyses highlighted that these variants could have emerged through recombination events."} +{"text": "Radium-223 is an alpha emitter, licensed in 2013 for treatment of symptomatic bone metastases in metastatic castration resistant prostate cancer. The treatment consists of 6 intravenous administrations and ongoing patient management before, during and after treatment. In our institution, this service is led by the nuclear medicine departmentThe ALSYMPCA trial, published in 2013, demonstrated improved overall survival (14.9 vs 11.3 months) and prolonged time to first symptomatic skeletal event (15.6 vs 9 months) for patients administered Radium-223 vs placeboImaging plays a key role in the selection criteria and response assessment for this new therapeutic modality. We present an educational review of the spectrum of multimodality imaging techniques employed for pre-therapeutic assessment and also for therapeutic response assessment\u2022 A brief overview of the criteria for treatment with radium-223 will be provided\u2022 Examples of CT and MRI scans of patients suitable for treatment, including pre and post therapeutic findings\u2022 Isotope bone scans of patients before and following treatment, demonstrating the effect of radium-223 on skeletal lesions.Radium-223 is an emerging innovative treatment for symptomatic bone metastases from castrate resistant prostate cancer and may well be the standard of care in the future. Cancer imagers should be aware of the suitability criteria for treatment, which will help inform discussions when patients are being considered for this treatment. They should also be aware of the multimodality imaging findings on post therapeutic response assessment studies."} +{"text": "Multiple epidemiologic studies have consistently reported association between increased coffee consumption and a lowered risk of Type 2 diabetes mellitus. However, the mechanisms behind this finding have not been fully elucidated.We investigate the effect of coffee (caffeinated and decaffeinated) on glucose effectiveness and insulin sensitivity using the stable isotope minimal model protocol with oral glucose administration in healthy men.Fifteen healthy men underwent 5 arms randomized crossover single-blinding (researchers) clinical trial. They consumed decaffeinated coffee, caffeinated coffee (with and without sugar), and controls \u2013 water (with and without sugar) followed 1 hour by an oral glucose tolerance test (75 g of available carbohydrate) with intravenous labeled dosing interpreted by the two compartment minimal model (225 min). One-way ANOVA with Bonferroni adjustment were used to compare the effects of the tested beverages on glucose metabolism parameters.Decaffeinated coffee resulted in 29% and 85% higher insulin sensitivity compared with caffeinated coffee and water, respectively, and the caffeinated coffee showed 15% and 60% higher glucose effectiveness compared with decaffeinated coffee and water, respectively. However, these differences were not significant (p >0.10). In overall analyze (0 \u2013 225 min) there were no significant differences on glucose effectiveness, insulin sensitivity, and glucose and insulin area under the curve between the groups. The beneficial effects of coffee did not seem to act in the short-term (h) on glucose metabolism parameters mainly on insulin sensitivity indices. The benefits of coffee consumption occur in the long-term (yrs.) as has been shown in the reduction of Type 2 Diabetes Mellitus risk in epidemiological studies. The clinical relevance of the present findings is that there is no need to avoid coffee as the drink choice for healthy people.The findings of this study demonstrate that the consumption of caffeinated and decaffeinated coffee with or without sugar has no acute effects on glucose metabolism in healthy men. Further researches, including long-term interventional studies, are needed to fully elucidate the mechanisms behind the coffee effects on reduced risk for Type 2 diabetes mellitus."} +{"text": "The third and fourth authors, Delphine Magis (DM) and Jean Schoenen (JS), should be noted as contributing equally to this work."} +{"text": "The creatinine values in Tables S1 Tablem/z), retention time (sec) and abundance (intensity) of 58 metabolites. The information of sex and age on 50 individuals is indicated on top.Plasma collected from marmoset was analyzed for metabolomics by high-resolution mass spectrometry as described in Methods. The mass spectrometry data includes ion mass Click here for additional data file."} +{"text": "There was an error in the figure legend of Figure 4. Please see the corrected Figure 4 here: The corrected Figure 4 caption reads:Grand-average ERP waveforms for the Grasping Small and the Grasping large conditions. The plots show ERPs time locked to glasses opening.The corrected Figure 3 caption reads:Scalp distribution of ERP differences between Grasping Small and Grasping Large conditions.In the last sentence of the \"Electrophysiological recording and data processing\" section in Materials and Methods, some of the stimulus appearance sites were listed incorrectly. The corrected sentence is: Based on visual inspection of grand average waveforms and amplitude scalp maps, the following ERP components were statistically analyzed: amplitude and latency of P300, namely the positive peak evoked 200\u2013400 ms following stimulus appearance at parietal sites ; amplitude and latency of N400, namely the negative peak occurring at 300\u2013500 ms after object appearance at frontal , fronto-central , and central sites; and mean amplitude of the sustained negativity observed in 400\u2013800 and 1200\u20132000 time windows at frontal , fronto-central , central , and parietal sites."} +{"text": "Malignancies of biliary tract have been rarely reported in HIV disease.We report 3 cases of biliary tract malignancy associated with HIV infection from Prayas Amrita clinic, an NGO based HIV clinic in Pune, India. Two of the cases were diagnosed with gall bladder malignancies (GBM) and the third one had cholangio carcinoma (CC). All presented with advanced stage of malignancy with metastases and had poor prognosis. All were males with median age at presentation being 47 years (range - 46-48 years) They were diagnosed to have HIV for a median duration of 102 months (range: 69-118 months) . Median nadir CD4 count was 77cells/cmm (range: 71\u2013163 cell/cmm). They were on first line ART for median 63 months (range: 41\u201372 months). A patient with GBM was Hepatitis B co infected. Prior AIDS related events of anemia, immune thrombocytopenic purpura and tuberculosis were present in the patient with CC and progressive multifocal leukoencephalopathy was in one of the patients with GBM. Being managed in resource limited setting; the absence of other risk factors is corroborative and lacks evidence.These 3 cases of biliary tract malignancies were seen recently in a relatively short span of time. All were men in late forties, infected with HIV for a long time and had no other known risk factors. This could be a pointer towards changing scenario of malignancies among HIV infected patients associated with prolonged survival."} +{"text": "Increasing number of patients with post-herpetic neuralgia (PHN) leads to clinical observation of the fact that it worsening the condition of patients with other chronic pain syndromes such as migraine and tension-type headache (TTH).The aim of this study was assessment of cephalgic pain severity and quality of life (QoL) in patients with primary headaches in comparison with those who additionally suffers of PHN.12 patients with PHN and comorbid migraine and TTH and 14 patients with migraine and TTH only (4 and 10) as controls were assessed for headache pain severity by visual analog scale (VAS) and QoL by short form (SF-36) screening tools.Patients with PHN had worse results of headache pain intensity and QoL vs patients of control group. Headache pain severity in PHN group was 7-8 vs 5-6 in control group, and QoL scoring was lower in PHN group vs control.PHN as the reason of central sensitization leads to further increase of the other chronic pain syndromes, such as primary headaches, elevate the cephalgic pain and decrease the QoL.No conflict of interest."} +{"text": "Scientific Reports5: Article number: 1448510.1038/srep14485; published online: 09292015; updated: 02022016The original version of this Article contained a typographical error in the Abstract.\u201cShort diffusion distance of few hundreds of nanosecond was also observed in thin films.\u201dnow reads:\u201cShort diffusion distance of few hundreds of nanometer was also observed in thin films.\u201dThis has now been corrected in the PDF and HTML versions of the Article."} +{"text": "Investigators from Washington University St. Louis studied the impact of electroencephalographic monitoring of neonates with Hypoxic Ischemic Encephalopathy (HIE) and their degree of MRI injury and neurodevelopmental outcomes when increasing seizure burden was present. Investigators from Washington University St. Louis studied the impact of electroencephalographic monitoring of neonates with Hypoxic Ischemic Encephalopathy (HIE) and their degree of MRI injury and neurodevelopmental outcomes when increasing seizure burden was present. Investigators performed a randomized controlled trial to investigate the effect of seizure burden on neurodevelopmental outcomes in infants with recognized electrographic seizures versus infants with clinically recognized seizures. Researchers found 15/35 neonates in the electrographic seizure group (ESG) and 20/34 neonates in the clinical seizure group (CSG) to have seizures. The researchers found that the ESG presented with a lower cumulative seizure burden (SB) than the CSG (p=0.02) likely due to faster identification and subsequent treatment of seizures. The investigators found no difference between ESG and CSG groups regarding developmental outcome due to the power of the study. However, analysis of the cohort as a whole indicated that an increasing SB correlated with worsened outcomes on the Bayley Scales of Infant Development III (p=0.03). The investigators also showed that greater SB in the cohort was associated with a worse MRI injury severity. [COMMENTARY. Neonatal seizures are prevalent in infants with HIE . However"} +{"text": "In the fourth paragraph of the Discussion section, reference #37 and #5 are switched. The paragraph should read as follows: \"Although this study did not identify any IS6110 positives, previous studies have identified the presence of this locus in New World primates [5]. However, the IS6110 mobile element has been found to be homologous in some related soil mycobacteria [37], and targeting this element with PCR has previously produced false-positives [38].\""} +{"text": "Background: Hypospadias is one of the most common congenital abnormalities in the male which is characterized by altered development of urethra, foreskin and ventral surface of the penis. Androgen receptor gene plays a critical role in the development of the male genital system by mediating the androgens effects.Objective: In present study, we looked for new variations in androgen receptor promoter and screened its exon 1 for five single nucleotide polymorphisms (SNP) in healthy and hypospadias Iranian men.Materials and Methods: In our study, at first DNA was extracted from patients (n=100) and controls (n=100) blood samples. Desired fragments of promoter and exon 1 were amplified using polymerase chain reaction. The promoter region was sequenced for the new variation and exone 1 screened for five SNPs using restriction fragment length polymorphism technique.Results: The results showed a new single nucleotide variation (C\u2192T) at -480 of two patients\u2019 promoter region (2%). None of the mentioned SNPs were detected in patients and controls groups (0%). Conclusion: This finding indicates that new single nucleotide polymorphism in androgen receptor promoter may have role in etiology of hypospadias and development of this anomaly.This article extracted from Ph.D. thesis. (Nasim Borhani) Hypospadias is the most common congenital malformation of the male external genitalia in which the urethral meatus opens on the ventral side of the penis . It affeAR gene is located on chromosome Xq11-12 and consists of eight exons, in which exon 1 encodes the transactivation domain that activates transcription of several different AR-responsive downstream genes , and in addition, AR gene promoter region was scanned for new variations in hypospadias disease in Iranian population.Impaired signaling through the androgen receptor (AR) leads to failure of urethral fold formation and fusion and consequently leads to hypospadias . The AR am genes , 7. The am genes , 9. ThesPatients and controlsThe patients in this analytical association study refered to the Mofid\u2019s children Hospital between March 2012 to August 2012. The patients should have criteria including diagnosis by urologist and having no sign of other genetic or congenital disease or genital malformations; (the properties distribution of patients in our study are listed in =100) and control group (n=100) were taken using venoject tube containing EDTA (0.5 M). The controls were selected from healthy males in Shahid Beheshti School of Medicine. The control samples should not have any sign of genetic disease, genital malformations or any addiction. Peripheral blood samples of hypospadic patients (nDNA extraction and polymerase chain reaction (PCR)AR transactivation domain were amplified using the primer pair: 5\u2019TCCAGAGCGTGCGCGAA GTG3\u2019 (sense) and 5\u2019CCGACTGCGGCTGT GAAGGT3\u2019 . Genomic DNA was extracted from peripheral blood of patients and controls using the whole blood extraction kit . Nucleotides -756 to -366 of the AR 5\u2019 promoter region (based on Ensemble.org genome browser) were amplified using the primer pair: 5\u2019TCTCCAAA GCCACTAGGCAG3\u2019 (sense) and 5\u2019ACCGAA GAGGAAAGGGCAGCTC3\u2019 (antisense). Nucleotides +604 to +888 of the Restriction fragment length polymorphism (RFLP) analysisFor transactivation domain genotyping, PCR, RFLP and 8% polyacrylamide gel electrophoresis (PAGE) were used. The RFLP reaction condition was detailed and presented in Promoter region sequencingFor AR promoter region sequencing, PCR products were purified using DNA extraction kit and then scanned for variations using direct sequencing .Ethical considerationsThe informed consent was obtained from all adult participants (control groups) and from the parents or legal guardians of minors (patients). This study had been reviewed and approved by a certified Ethical Committee in Shahid Beheshti University of Medical Sciences.RFLP resultsThe 285 bp PCR product containing five SNP sites was digested using suitable enzymes; SsiI, PstI, CaiI, SfaNI, and BseG1. The two SNPs rs62636528, and rs62636529 produce gain of sites compared to wild type allele, while rs78686797, rs139767835, and rs145326748 supposed to have loss of sites in digestion with the mentioned enzymes . The SsiSequencing resultsAR gene promoter region was scanned for new variations in subjected samples and a new single nucleotide polymorphism (SNP) was detected in two patient samples (2%) at position -48oC\u2192T (the normal sequence and two sequences curves with a new nucleotide variation are shown in AR gene is a member of the nuclear receptor superfamily that is located on Xq11-12. This receptor plays a critical role in male sexual differentiation by mediating the biological effects of androgens (AR amount or structure may disrupt this patterning (AR for the first time in hypospadic patients and we found a new single nucleotide polymorphism in two patients at -480 using direct sequencing. There have been many reports on AR promoter sequencing. ndrogens . Early det al scanned AR gene promoter and untranslated region in 44 clinical prostate cancer specimens and 36 normal controls; but they did not find any different sequence variations (et al screened promoter region of androgen receptor gene in 240 men with idiopathic infertility and 30 healthy men and this study did not show presence of any deletions or mutations in infertile or healthy men and they suggested that AR gene promoter mutation are not common in men with idiopathic infertility (AR gene promoter region of 100 healthy men suggested that DNA sequence alterations are rare in the human androgen receptor gene promoter (In 2006, Waltering riations . Likewisertility . Furtherpromoter . et al in which mutation screening of genomic DNA of men with hypospadias did not show any point mutation in AR gene exons (et al reported that the majority of patients with hypospadias did not carry androgen receptor gene mutations. In addition Sasagawa et al suggested that alteration of the AR gene is rare in males with isolated hypospadias, cryptorchidism, micropenis, or idiopathic male infertility (et al reported that none of the studied hypospadic patients in their research had AR gene mutations (AR gene mutation is rare in hypospadic patient (Additionally, we did not find any of mentioned single nucleotide polymorphisms in control and patient groups using PCR and RFLP techniques. This finding may declare that these five polymorphisms are not be involved in hypospadias etiology. These data are consistent with the previous report by Muroya ne exons . Also Hiertility . Furtherutations . Likewis patient , 17. et al it was found that a SNP in the AR gene region was associated with susceptibility to severe hypospadias. They concluded that AR rs5919436 polymorphism may act as a new gene marker for increased susceptibility to severe hypospadias in Caucasians (AR gene with the hypospadias; and suggested that expanded CAG repeat length has a role in modifying the risk and development of hypospadias (In addition, In a recent study by Adamovic ucasians . BesidesAR gene expression in the genital system due to decreasing the transcription machinery affinity for binding toward regulatory elements.In addition, in another study on Chilean population, the CAG and GGN polymorphisms in the AR gene has been investigated and showed that in isolated hypospadic boys, there are longer CAG alleles in their AR gene that might be associated with the development of hypospadias . Taken t"} +{"text": "One of the most pressing health-related challenges is the worldwide epidemic of type 2 diabetes and associated complications such as nephropathy. Indeed, type 2 diabetic patients account for the majority of individuals with chronic kidney disease requiring renal replacement therapy. This not only suggests inadequacy of current drug therapies but also failure of endogenous protective mechanisms. Stem cells are known to play pivotal roles in repair and regeneration of damaged/dysfunctional tissues. Our initial observations suggested that initiation and progression of type 2 diabetes mellitus is associated with progressive reduction in endothelial progenitor cells in the obese diabetic db/db mice. Thus, the present study was intended to more fully explore the status of components of stem cells in the setting of type 2 diabetic nephropathy and whether the diabetic milieu affects the survivability of these cells.Male 16-week-old obese diabetic db/db mice (and their db/m controls) were used for this study. Accordingly, indices of glycemic status , kidney function were determined in the context of assessment of components of stem cells in peripheral blood and renal tissue. In addition, we measured apoptotic cell death in components of stem cells.+Ckit+CD31-) mesenchymal stem cells and endothelial/epithelial progenitor cells compared to those of db/m controls. Further, kidney cells prepared for experimental groups also showed reductions in components of stem cells. Using annexin V in association with markers of each component of stem cells revealed significant increases in apoptosis for HSC, MSC and EPCs in cells prepared for kidneys of db/db and db/m mice. Collectively, the results suggest that apoptosis of components of stem cells likely contributes to eventual manifestation of renal failure in type 2 diabetes mellitus.The db/db mice showed significant increases in insulin resistance index and hemoglobin A1c in association with marked increase in albuminuria but reduction in creatinine clearance in association with significant increases in apoptotic and necrotic cell death of kidney cells. The peripheral blood cells of db/db mice displayed significant reduction in hematopoietic stem cells (HSC; Sca1The observation of a similar pattern of decline in stem cell components in the peripheral blood and the kidney suggests that monitoring of blood levels of stem cells subsets may be predictive of failure of their renoprotective features. Further, strategies aimed at reducing apoptosis of stem cell components and \u201cempowering\u201d them through genetic modulations could potentially serve as effective strategies to prevent end-stage renal failure in type 2 diabetic patients."} +{"text": "Chronic kidney disease (CKD) caused by renal fibrosis is an important public health concern. It is therefore necessary to understand the molecular pathogenesis of renal fibrosis in order to develop novel therapeutic strategies. KLF4 is the most extensively studied factor among the various members of the Kr\u00fcppel-like factor (KLF) family of zinc finger-containing transcription factors. Many studies have demonstrated that KLF4 inhibits the activation of myofibroblasts and exerts an inhibitory effect on fibrosis. However, other studies have indicated that KLF4 may promote renal fibrosis. These controversial results suggest that KLF4 may be crucially involved in the development of renal fibrosis, although the underlying mechanism(s) remain unclear. Here, we summarize the recent progress made in understanding the role of KLF4 in renal fibrosis. Together, these findings suggest that KLF4 may participate in the development of renal fibrosis, but that its inhibition of fibrosis is greater than its promotion of the condition, which suggests that KLF4 may serve as a novel therapeutic target for renal fibrosis. Renal fibrosis is characterized by excessive proliferation of fibroblasts and increased deposition of extracellular matrix (ECM), which together lead to extensive scarring (fibrotic tubular and glomerular sclerosis), renal artery stenosis and chronic inflammatory cell infiltration family consists of 17 zinc finger-containing transcription factors, among which KLF4 is the most extensively studied is an important participant in a broad spectrum of inflammatory networks that regulate the cytokine activity in renal fibrosis regulates the expression of VSMC differentiation markers by cooperating with its co-activator, myocardin, or its co-repressor, phosphorylated KLF4 (Wang et al., renal physiological functions and the progression of fibrosis (Chen et al., in vivo models of unilateral ureteral obstruction, a decrease in KLF4 expression was observed (Chen et al., Recently, Chen et al. showed that KLF4 was indeed involved in the regulation of The role of KLF4 in renal fibrosis is complex. For instance, KLF4 can induce the transformation of primary fibroblasts (Rowland et al., Because KLF4 is expressed in kidney cells (Hayashi et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The dynamical fluctuations in the rhythms of biological systems provide valuable information about the underlying functioning of these systems. During the past few decades analysis of cardiac function based on the heart rate variability has attracted great attention, resulting in more than 17000-publications (PubMed list). However, it is still controversial about the underling mechanisms of HRV. In this study, we performed both linear (time domain and frequency domain) and nonlinear analysis of HRV data acquired from humans and animals to identify the relationship between HRV and heart rate (HR). The HRV data consists of the following groups: (a) human normal sinus rhythm (n = 72); (b) human congestive heart failure (n = 44); (c) rabbit sinoatrial node cells ; (d) conscious rat (n = 11). In both human and animal data at variant pathological conditions, both linear and nonlinear analysis techniques showed an inverse correlation between HRV and HR, supporting the concept that HRV is dependent on HR, and therefore, HRV cannot be used in an ordinary manner to analyse autonomic nerve activity of a heart. Greek Physicians and scientists were the pioneers who measured pulse rate; however, it was not much accurate till the invention of pulse watch in 1707 .The autonomic nervous system (ANS) controls heart rate, hear rate variability (HRV) and breathing. Heart Rate Variability (HRV) analysis is a non-invasive technique used to evaluate the balancing action of sympathetic and parasympathetic branches of the autonomic nervous system , 4,5. OvOver the last 35 years, various linear and non-linear techniques have been developed to extract the valuable information from cardiac interbeat interval time series data, aiming to help clinician for prognostication of illness and assessing malfunctioning of the autonomic nervous system. However, often contradictory results have left clinicians skeptical and there exists no clear consensus about HRV analysis measures . In 1996The main purpose of this study is to identify the relationship of HR with both linear and nonlinear metrics of HRV. The human and animal data sets were analysed under following conditions: (a) human normal sinus rhythm n = 72); (b) human congestive heart failure (n = 44); (c) rabbit sinoatrial node cell (SANC) (n = 67); and (d) conscious rat (n = 11). Both nonlinear and linear methods showed that HRV is primarily dependent on HR. There is an inverse correlation between the HRV and HR: a larger HRV was correlated with a lower HR, and the vice versa. Such a correlation was observed both in the human data at variant pathological conditions and variant animal species. This study provided support to the concept of a previous study[; (b) humHRV analysis can be done by many ways and a wide range list of techniques explored since 1960 are described in detail by the North American Society of Pacing Electrophysiology and the task force for European Society of Cardiology . This stMeasures included in linear time domain parameters are derived from direct RR interval measurement for standard deviation of all normal to normal RR intervals (SDNN), and from differences of RR interval for root mean square of successive NN interval differences (RMSSD) (RMSSD) . SpecifiIn which \u2018I\u2019 is RR intervals, Where \u2018I\u2019 is RR intervals and \u2018N\u2019 is the total number of RR intervals.The frequency domain measures used in this study included: Very low frequency (VLF), low frequency (LF), high frequency (HF) and total power. VLF is a band of power spectrum range \u2265 0.04 Hz. Normally this measure shows overall activity of numerous slow mechanisms of sympathetic activity. LF is a band of power spectrum ranging between 0.04 and 0.15 Hz. This parameter reflects both sympathetic and parasympathetic function. HF is a band of power spectrum range between 0.15 and 0.4 Hz. Generally this measure reflects parasympathetic function. Total power is a short term estimate of the total power of power spectral density in the range of frequencies between 0 and 0.4 Hz. In this parameter sympathetic activity is a main contributor when its shows overall autonomic activity .m or 30m and m = 2(100\u2013900 data points) will yield statically reproducible and reliable results. He also describe that ApEn can be applied to any system having at least 50 data points. ApEn algorithm counts similar sequences to given sequence of length m, including the sequence itself to avoid natural logarithm of zero within the calculations. As a result, ApEn can sensitive to the size of data. To overcome this, a variant of the ApEn algorithm called Sample entropy (SamEn) [Approximate entropy (ApEn) and sample entropy (SamEn) were used to analyse the nonlinear behaviour of HRV , 13,14. (SamEn) , which gThe data sets used in the study comprised of both human and animal data and in We used RR-interval time series data of human normal sinus rhythm (n = 72), human congestive heart failure(n = 44), rabbit SANC and conscious rat(n = 11) subjects.In human groups, HRV in terms of SDNN and RMSSD is high in normal sinus rhythm then in In frequency domain analysis we used Total Power(TP) (high frequency (HF)+low frequency (LF)+very low frequency (VLF)) to analyse RR-interval time series data of human normal sinus rhythm (n = 72),human congestive heart failure(n = 44), rabbit SANC and conscious rat(n = 11). HRV in terms of Total Power in human groups is high in the normal sinus rhythm then conIn nonlinear time series analysis we used Approximate Entropy and Sample Entropy to analyse RR-interval time series data of human normal sinus rhythm (n = 72),human congestive heart failure(n = 44), rabbit SANC and conscious rat(n = 11). In human groups, HRV in terms of Approximate Entropy and Sample Entropy is high in normal sinus rhythm then conThe baseline cycle length also varied widely between preparations . In humaIn the Figs Heart rate variability analysis is a non-invasive technique used to assess the cardiac autonomic control under physiological and pathophysiological conditions , 4, 7. TMonfredi et al , used liIn this study, we investigated the relationship of linear (time domain and frequency domain) and nonlinear HRV parameters with heart rate using RR-interval time series data from human and animals. The RR-interval time series comprised of human (72 NSR and 44 CHF subjects) and animal subjects . The research findings indicate that both linear and nonlinear HRV methods showed an inverse correlation between the HRV and HR: a larger HRV was correlated with a lower HR, and the vice versa. Such a correlation was observed both in the human data at variant pathological conditions and in different animal species. The inverse correlation of nonlinear HRV measures along with linear ones with HR is the salient feature of this study. The outcomes of this study strong the evidence of relationship between HRV with HR and are in line with outcomes of Monfredi and co-authors. It is suggested that in future studies HR should be taken into consideration at which HRV analysis is being performed."} +{"text": "For the first time, complete genome sequences of four lineage III peste des petits ruminants (PPR) viruses originated from the Middle East and East Africa are reported here. The availability of complete genome sequences from all four lineages (I to IV) of the PPR virus (PPRV) would greatly help in a comprehensive understanding of the molecular evolution and emergence of PPRV. Phylogenetic analysis of the partial F gene (322\u00a0nt) (Peste des petits ruminants (PPR) is an important infectious viral disease of domestic and wild small ruminants and endemic in the Middle East, Africa, and Asia (http://(322\u00a0nt) has defi(322\u00a0nt) , 5. AvaiThe complete genomes of four PPRV isolates from the Middle East, Oman 1983 and UnitPhylogenetic analysis of all the available (at GenBank as of August 2014) complete genome sequences of PPR viruses , including the four viruses sequenced in this study , has grouped them into four genetically divergent lineages that are similar to the phylogenetic study using partial F, N, and H genes. Complete genomes of PPRV isolates sequenced in this study were confirmed to be of lineage III. Therefore, this study demonstrated the co-circulation of lineages III and IV in East Africa . FurtherKJ867543 (Uganda 2012), KJ867540 (Ethiopia 1994), KJ867545 (UAE 1986), and KJ867544 (Oman 1983).The complete genome of the PPRV isolates have been deposited in GenBank under accession no."} +{"text": "In this connexion novel radiopharmaceuticals for the noninvasive molecular imaging of early disease states and monitoring of treatment responses in vivo by means of PET/CT, SPECT/CT and PET/MRI are indispensable prerequisites to further advance and strengthen the unique competence of radiopharmaceutical sciences. In the era of personalised medicine the diagnostic potential of radiopharmaceuticals is directly linked to a subsequent individual therapeutic approach called endoradiotherapy. Depending on the \u201cradioactive lantern\u201d (gamma or particle emitter) used for radiolabelling of the respective tracer molecule, the field of Radiopharmaceutical Chemistry can contribute to the set-up of an \u201cin vivo theranostic\u201d approach especially in tumour patients by offering tailor-made (radio)chemical entities labelled either with a diagnostic or a therapeutic radionuclide.The fields of molecular biology, immunology and genetics have generated many important developments that advance the understanding of the induction and progression of oncological, cardiological and neurological diseases as well as the identification of disease-associated molecules and drugs that specifically target diseased cells during therapy. These insights have triggered the development of targeted radiopharmaceuticals which open up a new dimension of radiopharmaceutical sciences in nuclear medicine. Radiopharmaceuticals, also called radiotracers, are radiolabelled molecules, bearing a \u201cradioactive lantern\u201d, and used as molecular probes to address clinically relevant biological targets such as receptors, enzymes, transport systems and others. Positron emission tomography (PET) and single photon emission computed tomography (SPECT) realised in the in vivo and facilitates to predict and monitor successful therapy strategies. The definition of \u201cmolecular probe imaging\u201d is highlighted in detail in this special issue : \u201cAt the heart of all nuclear imaging, radiopharmaceutical science is the design, synthesis and evaluation of compounds containing suitable radionuclides that can be used in vivo to trace (follow) a particular physiological or biochemical phenomena\u201d [Early-stage noninvasive molecular imaging enables to look at the biodistribution of molecular probes al issue 1]. Ind. Indin venomena\u201d .In fact, according to reports of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) more than 33 million diagnostic nuclear medicine examinations are performed annually worldwide. The annual frequency of diagnostic nuclear medicine examinations and of nuclear medicine treatments in health-care level I countries have thus increased tremendously, from 11 per 1,000 population in 1970\u20131979 to 19 per 1,000 in 1997\u20132007 and for therapeutic nuclear medicine procedures from 0.17 per 1,000 population in 1991\u20131996 to 0.47 per 1,000 in 1997\u20132007 [(i)reasonable pharmacokinetic behaviour adjusted to the physical half-life of the used radionuclide(ii)ability to penetrate and cross biological membranes and permeability barriers(iii)usage of chemical as well as biological amplification strategies (iv)in vivo stabilityavailability of radiopharmaceuticals with high specific activities and To succeed in the design of targeted high-affinity radiopharmaceuticals that can measure the alteration of a respective biological target several aspects need to be considered:et al. have started a project on targeting the cannabinoid receptor subtype 2 (CB2) with a promising 11C-labelled 2-oxoquinoline derivative [11C]KP23. The CB2 receptor has been shown to be up-regulated in activated microglia and therefore plays an important role in neuroinflammatory and neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis and Alzheimer\u2019s disease could be confirmed, the cellular externalisation of the radioactivity was not improved , PET/CT and PET/MRI , or in a therapeutic radiopharmaceutical (then labelled with 131I) for targeted systemic radionuclide therapy (endoradiotherapy) with identical chemical structure. Similarly to the high efficiency of the combination of radiological diagnostics and radiation therapy, this combined in vivo theranostic approach with targeted radiotracers provide the potential to significantly improve the management of many diseases and the application of individually adapted therapy strategies. One contribution at the current basic research front on Folate Receptor Targeted \u03b1-Therapy using Terbium-149 addresses the mentioned in vivo theranostic approach and is described by M\u00fcller C et al. who discuss the potential matching pairs of diagnostic and therapeutic folate receptor (FR)-targeted radiotracers bearing different radioisotopes of terbium and positron emitters or particle emitters , respectively. This results either in diagnostic radiopharmaceuticals for SPECT/CT is used for the treatment of different tumours. EGFR can thus be considered as an ideal biological target for combinatorial diagnostic and therapeutic approaches using corresponding radiolabelled cetuximab conjugates. Here Sihver W et al. summarises the hitherto developed radiolabelled cetuximab conjugates for EGFR-targeted diagnosis and therapy (The neurotensin receptor (NTS1) is an attractive biological target for the molecular imaging and endoradiotherapy of NTS-positive tumours owing to the overexpression in a range of malignancies. One contribution shows an example of a ogenesis 8]. Ano. Ano177L therapy 9]..177Lu-la68Ga]Ga-PSMA-HBED-CC was developed at the DKFZ and is the most promising PET tracer for the imaging of prostate cancer to date and clinical trials are currently going to be initiated. Therefore, novel important preclinical data of [68Ga]Ga-PSMA-HBED-CC and relevant aspects of its radiopharmaceutical good manufacturing practice (GMP)-compliant production are presented in this special issue (68Ga) as well as with the beta-minus particle emitters yttrium-90 (90Y) and lutetium-177 (177Lu) which are clinically relevant for systemic radionuclide therapy has gained highest clinical impact during recent years. The new PET radioligand [al issue 11]. On. On68Ga]therapy) 12]. . 68Ga]GaThe GMP-compliant production and quality control of radiopharmaceuticals have to conform to all aspects of the relevant EU-GMP regulations and radiation protection rules. Specific guidance on current good radiopharmacy practice (cGRPP) for the small-scale preparation of radiopharmaceuticals has been recently published by the EANM radiopharmacy committee . One repet al. provides information about radiolabelling procedures of NPs or polymers intended for PET imaging and their potential use as drug delivery systems have been designed and used for various purposes, such as magnetic resonance imaging (MRI), computed tomography (CT) and optical imaging (OI) or simply for improved drug delivery. The question is: What is the ideal nanodimensional architecture usable as drug delivery system or for multimodality imaging by means of PET/CT and PET/MRI? In detail the review article of Stockhofe systems 15]. A . A et alRadiopharmaceutical Chemistry Between Imaging and Endoradiotherapy covers a broad spectrum of representative internationally recognized research and development projects and nicely shows the complexity of the multidisciplinary field radiopharmaceutical sciences located in between nuclear chemistry, radiochemistry, organic chemistry, bioorganic and -inorganic chemistry, labelling chemistry, medicinal chemistry, radiopharmacology and nuclear medicine. The special issue published in Pharmaceuticals intends to reach and attract rather extended readership including students, PhD students and young scientists and talents from medicinal disciplines such as nuclear medicine, radiology and radiation therapy, but especially from natural sciences such as chemistry, pharmacy, biotechnology, technical engineering and physics who are looking for highly innovative translational research conceptions in radiopharmaceutical sciences.In summary this comprehensive special issue"} +{"text": "This article also provides supplementary information to the research article, i.e., within-group comparisons between baseline and outcome cortical thickness and subcortical volume measures, between-group tests of performance changes in cognitive benchmark tests (www.cambridgebrainsciences.com [4]), correlation analyses between performance changes in benchmark tests and training-related structural changes, correlation analyses between the time spent training and structural changes, a scatterplot of the relationship between cortical thickness measures derived from the occipital lobe as control region and the chronological order of the MRI sessions to assess potential scanner drift effects and a post-hoc vertex-wise whole brain analysis with FreeSurfer Qdec (https://surfer.nmr.mgh.harvard.edu/fswiki/Qdec [5]).The data and supplementary information provided in this article relate to our research article \u201cTask complexity and location specific changes of cortical thickness in executive and salience networks after working memory training\u201d Participants could train from home and their progress and compliance was monitored throughout the training time. Eight participants dropped out so the final sample size for both groups was n=20 each . Training-related changes in working memory span and executive functioning as well as in cortical thickness and subcortical volume in regions of interest of cognitive control networks were assessed. Cortical thickness and subcortical volume indices were derived with the FreeSurfer longitudinal analyses stream 48 healthy participants (19\u201340 years of age) were pseudo-randomly (with the provision to match groups for age and sex) allocated to an adaptive training or an active control group 2.1post-hoc whole brain vertex-wise analyses in Qdec to test for the effects of group (adaptive training versus active control group) and time of assessment effects (baseline versus outcome) on cortical thickness measures. Cortical thickness indices were derived from the T1-weighted anatomical images smoothed with a kernel of 10. Multiple comparisons were controlled with a False Discovery Rate (FDR) of 5%. There were regions on both hemispheres with significant clusters of group effects across time (see We conducted a time see but no r"} +{"text": "Thymic epithelial tumors (TETs) are comprised of a spectrum of histologically distinct tumors that also exhibit differences at the molecular level . SurgerySomatostatin receptors are expressed in TETs and can be detected by octreotide scan . PalmierHistone deacetylases (HDACs) regulate gene expression through chromosome remodeling. Belinostat is a HDAC inhibitor that has been evaluated in a phase II trial in patients with advanced TETs after failure of platinum-containing chemotherapy . Among 2Thymic epithelial tumors express insulin-like growth factor-1 receptor (IGF-1R), particularly recurrent or advanced tumors and those with aggressive histological subtypes . CixutumMultiple case reports have described responses to the multikinase inhibitors, sorafenib and suniDespites preclinical data demonstrating overexpression of epidermal growth factor receptor (EGFR) and KIT Milciclib, an inhibitor of cyclin-dependent kinase 2/cyclin A complex and tropomyosin receptor kinase A (TrkA) is being evaluated in two phase II studies in patients with recurrent B3 thymoma and thymic carcinoma (NCT01011439 and NCT 01301391).A phase II study is evaluating the role of the mammalian target of rapamycin (mTOR) inhibitor, everolimus in patients with TETs previously treated with chemotherapy. (NCT02049047).In conclusion, although the presence of targetable mutations detected by current techniques of molecular profiling is low, whole genome and exome sequencing has the potential to uncover novel biological targets. Although many trials of targeted agents have yielded disappointing results, the unprecedented activity of sunitinib in thymic carcinoma and the disease stabilizing effect of cixutumumab in thymoma provides an impetus to continue to explore the role of novel biological agents in TETs.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Pulmonary embolism (PE) is a known cause of morbidity and mortality in oncology patients. Whilst much of the literature focuses on the detection of incidental PE in this cohort of patients (approximately 4%), little is written about the rate of positive CT Pulmonary Angiograms (CTPA) when PE is clinically suspected. We wanted to assess the rate of positive CTPA specifically amongst oncology patients with suspected PE in our teaching hospital.We retrospectively analysed all consecutive CTPAs carried out for clinically suspected PE over a 12 month period in all patients under our oncology services.A total of 230 oncology patients had a CTPA to exclude PE and 40 were positive (17.4%). Of the positive CTPAs, most showed multiple PEs. The commonest cancer patients to undergo CTPA were lung (38), breast (34) and lymphoma (26) patients, and the highest incidence of positive CTPA were in breast (7/34), ovarian (2/9) and pancreatic (2/5) carcinoma. CTPAs carried out in colorectal carcinoma patients had the lowest probability of being positive (1/15).The published rate of positive CTPA for clinically suspected PE in the general population is 15-20%. Our study shows that despite the widely held view that oncology patients are more prone to pulmonary thromboembolic disease, the incidence of positive CTPA is in fact similar to the general population. Our threshold for imaging oncology patients should therefore be the same as in the general population."} +{"text": "Noninvasive ventilation (NIV) in the management of chronic obstructive pulmonary disease (COPD) patient with acute hypercapnic respiratory failure is considered a first-line therapy. However, higher mortality was shown in patients receiving transition from NIV to invasive mechanical ventilation than in patients receiving invasive mechanical ventilation from the first management. We tried to find parameters associated with early NIV failure in patients presenting to ED with acute exacerbation of COPD.Medical records of 218 patients with acute exacerbation of COPD visiting Asan Medical Center and managed with NIV during their stay in the ED from January 2007 to December 2013 were analyzed.NIV was successful in 191 (87.6%) and 27 (12.4%) failed NIV treatment. Of the variables obtained before NIV treatment, heart rate and pH were significant factors associated with early NIV failure. Of the variables obtained after 1 hr of NIV treatment, heart rate and pH were still significant.Presence of tachycardia and severe acidosis before NIV treatment, and persistence of tachycardia and severe acidosis after 1hour of NIV treatment predicted early NIV failure."} +{"text": "Aspiration can cause a diverse spectrum of pulmonary disorders some of which can lead to death but can be difficult to diagnose.The medical records and autopsy findings of 57 consecutive patients in whom aspiration was the immediate cause of death at Mayo Clinic over a 9-yr period, from January 1 2004 to December 31 2012 were analyzed.The median age at death was 72 years and included 39 (68%) males. The most common symptom before death was dyspnea (63%) and chest radiography revealed bilateral infiltrates in the majority (81%). Most common precipitating factors for aspiration were depressed consciousness (46%) and dysphagia (44%). Aspiration-related syndromes leading to death were aspiration pneumonia in 26 (46%), aspiration pneumonitis in 25 (44%), and large airway obstruction in 6 patients (11%). Aspiration was clinically unsuspected in 19 (33%) patients. Antimicrobial therapy had been empirically administered to most patients (90%) with aspiration pneumonia and aspiration pneumonitis.We conclude aspiration-related deaths occur most commonly in the elderly with identifiable risks and presenting bilateral pulmonary infiltrates. One-third of these aspiration-related pulmonary syndromes were clinically unsuspected at the time of death. Aspiration is defined as inhalation of oropharyngeal or gastric contents into the larynx and lower respiratory tract Using a computer-assisted search of medical records we identified 57 patients undergoing an autopsy at the Mayo Clinic over a 9-year period from January 1, 2004 to December 31, 2012 and were identified to have aspiration-related pulmonary disease as the immediate cause of death on postmortem examination. This cohort comprised 1.2% of 4,623 autopsies that included examination of the lungs over this period, Aspiration-related pulmonary syndromes encountered in this cohort included aspiration pneumonia, aspiration pneumonitis and large airway obstruction. Aspiration pneumonia was diagnosed by: 1) clinical and radiologic features of pneumonia and 2) pathologic findings of aspiration and acute bronchopneumonia sometimes accompanied by microabscesses and granulomatous inflammation at postmortem examination. Aspiration pneumonitis was diagnosed by: 1) acute onset of respiratory symptoms with new pulmonary infiltrates on chest imaging and 2) pathologic evidence of acute lung injury combined with the presence of foreign material or foreign body giant cell reaction at postmortem examination. Large airway obstruction was defined as acute respiratory failure related to the presence of large particulate material causing large airway obstruction confirmed on postmortem examination. Patients who died from drowning and amniotic fluid aspiration were excluded. Other forms of aspiration-related pulmonary syndromes including diffuse aspiration bronchiolitis and exogenous lipoid pneumonia were not encountered in this autopsy study. We identified the time of aspiration event based on available medical history as well assessment of clinical course and emergence of new pulmonary infiltrates on chest imaging. The current study was approved by the Mayo Foundation Institutional Review Board .Medical records were examined in detail and the following data were retrieved: age, sex, clinical presentation, risks for aspiration, radiologic findings, events leading up to death, and autopsy findings. We also determined clinician's diagnosis as to the cause of death based on review of all available medical records including clinical notes as well as the clinician diagnoses listed on death certificates. The clinician diagnosis and the type of aspiration-related pulmonary syndrome causing death was assigned based on a review of all available data by consensus of the two authors (XH and JHR).Continuous data are presented as median and range , when appropriate, and frequency, percentages for categorical variables.Of 57 patients with aspiration-related deaths, 39 (68%) were male Table 1.One or more precipitating factors for aspiration were identified in all 57 patients and mainly included depressed consciousness in 26 patients (46%), dysphagia in 25 patients (44%); 6 patients had two risk factors Table 2.The type of aspiration-related pulmonary syndrome leading to death were classified as aspiration pneumonia in 26 (46%), aspiration pneumonitis in 25 (44%), and large airway obstruction in 6 (11%). All six large airway obstruction cases died within 72 hours of aspiration. Among the 19 aspiration pneumonitis cases in whom the time of aspiration event could be identified retrospectively, 14 (74%) died within 72 hours. In contrast, among 22 cases of aspiration pneumonia in whom the time of initial aspiration event could be identified, only 6 (27%) died within 72 hours.Among 27 patients who suffered aspiration in the hospital were 10 aspiration pneumonia, 14 aspiration pneumonitis and 3 large airway obstruction cases. In the remaining 30 patients with aspiration likely occurring outside of the hospital were 16 aspiration pneumonia, 11 aspiration pneumonitis and 3 large airway obstruction cases.Main symptoms recorded preceding death included dyspnea (63%), decreased consciousness (19%) Table 1.Fifty-three patients (93%) underwent chest radiography, 16 of whom also had undergone chest computed tomography (CT); four patients had no chest imaging available prior to death. Bilateral distribution of parenchymal abnormalities was seen in 44 patients (83%). The predominant radiologic findings were patchy alveolar infiltrates and/or atelectasis in 46 patients (87%); remaining seven patients exhibited mixed patterns of interstitial, consolidative, and ground-glass opacities. These chest imaging findings were relatively nonspecific.During the hospital course, 35 patients underwent invasive mechanical ventilation (non-invasive ventilation in two patients including one with aspiration pneumonia and another with aspiration pneumonitis); 20 patients had aspiration pneumonitis, 14 patients had aspiration pneumonia and, 1 patient had large airway obstruction. Extracorporeal membrane oxygenation was also employed in one patient with aspiration pneumonitis. Bronchoscopy was performed in 16 patients, including one procedure performed at an outside hospital and one patient who underwent the procedure twice. Three of these patients were found to have evidence of aspiration and 12 patients underwent the procedure for clearance of airway secretion; the bronchoscopic inspection was normal in the remaining patient.Staphylococcus aureus , Enterobacter species (two patients), Streptococcus(one patient), Nocardia (one patient), Klebsiella pneumoniae complex coexisting with Enterococcus (one patient), and Candida (one patient with lymphoma). Microbial culture results were available in 14 patients with aspiration pneumonitis , 9 of whom had potential pathogens identified including Staphylococcus aureus , Escherichia coli , Enterobacter species , Klebsiella species (two patients), Citrobacter koseri (one patient) and Streptococcus species (one patient). Antimicrobial therapy had been administered to 23 patients (88%) with aspiration pneumonia and 22 patients (92%) with aspiration pneumonitis, including three in each group treated with antifungal drugs.Microbial culture results were available in 19 patients with aspiration pneumonia, nine of whom had potential pathogens identified including Aspiration was included among diagnostic possibilities by clinicians at the time of death for 38 patients (67%). Nineteen patients (33%) whose aspiration was clinically unsuspected included nine who died from aspiration pneumonitis, nine with aspiration pneumonia, and one with large airway obstruction Table 3.With the exception of few reported cases, aspiration-related deaths have not been methodically investigated Our data also show that dysphagia related to neurologic disorders comprise the commonest precipitating factor for aspiration-related deaths, followed by depressed consciousness related to sedation. These findings are in agreement with prior studies showing neurologic disorders and sedation to be common precipitating factors for aspiration Dyspnea was the most common symptom recorded for patients in this study and is similar to a prior study describing the presence of this symptom in almost half of 36 aspiration cases confirmed on lung biopsy specimens Aside from large airway obstruction-related death which is very familiar to clinicians According to our data, aspiration pneumonia is the most common type of aspiration-related pulmonary syndrome leading to death. There were more patients with underlying neurological disorders in our study for whom the median age was 72 years old compared to two prior studies Staphylococcus aureus, Enterobacter species rather than anaerobes. This was similar to that previously reported in the literature Our data demonstrated the common isolated pathogens in aspiration pneumonia were Pathogenic bacteria were recovered in a portion of patients with aspiration pneumonitis, a disease entity generally thought to involve aspiration of sterile gastric contents. There are several potential explanations for this finding. Any form of aspiration is likely to include entrance of oral secretions into the lung. Emerging data on human microbiota have demonstrated that multiple species of bacteria can exist in the stomach as well as lungs of healthy individuals Irwin and colleagues Aside from the issue of correctly diagnosing aspiration-related syndromes, our study has some implications on the prevention of aspiration-related deaths. The patients at risk appear to be identifiable such as those with neurologic impairment and dysphagia. Optimal strategies in managing patients identified to be at risk generally require multidisciplinary expertise in maintaining adequate hydration and nutrition while minimizing the risks of aspiration. These options many include tube feeding, oral and bronchial hygiene measures, positioning, antimicrobial and other pharmacologic therapies This study included consecutive patients undergoing autopsy during a nine year period and the diagnostic criteria were based on combined clinical and autopsy findings. We, however, acknowledge that the limitations of this study including the retrospective design which limited the analysis to clinical data available in medical records and autopsy results. There are likely many patients who died from aspiration but did not undergo a postmortem examination and were undiagnosed. There is a selection bias in autopsy studies which tend to enrich for atypical and diagnostically challenging cases. Microbiology data were limited to standard respiratory cultures obtained at postmortem examination and may not have recovered some pathogens such as anaerobic bacteria. Furthermore, aspiration pneumonia and aspiration pneumonitis can sometimes be difficult to distinguish.Aspiration-related deaths most commonly occur in the elderly with identifiable risks and often manifesting bilateral pulmonary infiltrates. In one-third of these patients aspiration as the cause of death was unsuspected by clinicians."} +{"text": "Natural killer (NK) cells are highly effective in controlling tumour growth, in mice, but have no significant effect in humans. The reason(s) of this phenomenon is(are) unclear.The effects of cancer cells on NK cells during target-effector cell conjugation was investigated utilising standard immunological methods including flow cytometry, chromium release and enzyme-linked immunosorbent assays while gene expression was evaluated by quantitative reverse transcriptase-polymerase chain reaction.We found that this phenomenon was associated with the different susceptibility of human and mouse NK cells to autologous tumour cell-induced NK cell abnormalities (NKCA). The latter includes CD16 down-regulation and NK cell depletion. Induction of NKCA by leukaemia and solid tumour cells was influenced neither by IL2 treatment nor by HLA class I antigen expression, but was abrogated by a 10 day culture. Following a 10 day of PBMCs culture, NK cells became resistant to leukaemia and solid tumor cell induced NKCA but maintained their cytotoxic activity. Actinomycin D restored the susceptibility of long term NK (LTNK) cells to NKCA suggesting that the generation of resistance to NKCA required RNA transcription. TAPI-0, a functional analogue of the tissue inhibitor of metalloproteinases (TIMP) 3 inhibited cancer cell induced NKCA underlying a role for a restricted number of metalloproteinases in the generation of this phenomenon. Finally, we found an association of TIMP3 gene and protein over-expression with the reduced susceptibility of LTNK cells to cancer cell induced NKCA.This study provides evidence that TIMP3 plays a role in the protection of LTNK cells from cancer cell induced NKCA."} +{"text": "Lohith et al. recently identified increased metabotropic glutamate receptor 5 (mGluR5) expression in the frontal cortex (FC) of subjects with fragile X syndrome. These results are consistent with postmortem findings in cerebellar vermis and FC of subjects with autism , suggesting that increased mGluR5 signaling is common to multiple autism spectrum disorders. Increased mGluR5 signaling may be associated with reduced phosphorylation of fragile X mental retardation protein (FMRP), which could result in the inactivation of this protein. In the current study, we report on reduced expression of phosphorylated FMRP in cerebellar vermis of adults and children with autism and in FC of adults with autism. Moreoveet al. . Taken t [et al. suggest [et al. .Increased mGluR5 expression in autism and FXS is associated with reduced or absent expression of fragile X mental retardation protein (FMRP) ,3 and frr >0.3) we used analysis of covariance (ANCOVA) to co-vary their effects. In none of these cases were significant differences between controls and subjects with autism in phosphorylated FMRP changed by the presence of these covariates. Our new finding of a reduction in phosphorylated FMRP in the cerebellar vermis of children with autism may be associated with increased activity of mGluR5, which could result in dephosphorylation of FMRP, and its subsequent ubiquitination and degradation [We have recently completed a preliminary study of serine 499 phosphorylated FMRP protein levels in the cerebellar vermis in adults (n = 5 controls and 5 adults with autism) and children (n = 3 controls and 4 children with autism), and in the superior frontal cortex in adults (n = 6 controls and 10 adults with autism) and children (n = 6 controls and 8 children with autism). All values were normalized against neuronal specific enolase (NSE) and data were expressed as ratios of phosphorylated FMRP/NSE. We found significant reductions in phosphorylated FMRP/NSE in the vermis of adults and children with autism when compared with controls (Figure\u00a0radation support ANCOVA: Analysis of covariance; APP: Amyloid beta A4 precursor protein; BA9: Brodman area 9; FMRP: Fragile X mental retardation protein; FXS: fragile X syndrome; mGluR5: Metabotropic glutamate receptor 5; NSE: Neuronal specific enolase; RAC1: Ras-related C3 botulinum toxin substrate 1; STEP: Striatal-enriched protein tyrosine phosphatase.The authors declare that they have no competing interests. SH Fatemi has several patents on the use of Reelin as a diagnostic marker for neuropsychiatric disorders but has not derived any financial gains from these patents.SHF conceived of the study, participated in its design, supervised conduct of all experiments, and contributed to the drafting of the manuscript. OGR, MKY performed western blotting experiments. TDF performed western blotting experiments and contributed to the drafting of the manuscript. All authors read and approved the final manuscript."} +{"text": "Metabolic reprogramming is one of the strategies adopted by cancer cells to survive hypoxic conditions. Recent findings suggest that hypoxic cancer cells derive the energy that they need through glycolysis using glucose mobilized from intracellular glycogen reserve. Glycogen phosphorylase (GP) is the major rate-determining enzyme for glycogen mobilization in many normal cells under the condition of starvation or physical exercise. The lysosomal alpha-glucosidase (GAA) has also been implicated in glycogen mobilization since deficiency of this enzyme is known to result in Glycogen Storage Disease Type II (Pompe disease). Although a role for GP in the mobilization of glycogen by cancer cells depleted of oxygen had been demonstrated, whether a similar role for GP (and GAA) could be demonstrated under deprivation of both glucose and oxygen is not yet known. This issue is addressed in this study by examining the intracellular level of glycogen in the absence and presence of pharmacological inhibitors of GP and/or GAA.2) in the presence or absence of glucose for 3 hours. The effect of these hypoxic conditions on intracellular glycogen level was examined in the presence and absence of inhibitors for glycogen phosphorylase [CAS 648926-15-2] or lysosomal alpha glucosidase (castanospermine or miglitol).The Hela, HEK293 and HT29 cancer cell lines were subjected to hypoxic conditions only when cultured cancer cell were deprived of both glucose and oxygen for 3 hours. The hypoxia-induced lowering of intracellular glycogen was alleviated by the presence of glycogen phosphorylase inhibitor (CAS 648926-15-2) but not alpha glucosidase inhibitor (castanospermine or miglitol). The simultaneous presence of inhibitors for both enzymes did not have a synergistic effect in preventing hypoxia-induced glycogen mobilization as compared to that observed for (CAS 648926-15-2) alone. Hypoxia had no significant effect on both"} +{"text": "TDP43 is a ubiquitously expressed prevalently nuclear protein involved in RNA splicing, RNA stability and miRNA processing. Amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and inclusion body myopathy (IBM) are characterized by TDP43 being depleted from the nucleus and accumulating in cytoplasmic inclusions, which are the pathological hallmark of the disease \u2013 these diseases are also defined as \u201cTDP43 proteinopathies\u201d. Mutations in TDP43 have been found to be causative of a proportion of ALS cases reinforcing the primary importance of this molecule in disease pathogenesis. The pathogenic mechanism by which TDP43 acts is unclear, and both loss of nuclear function (LOF) and gain of function (GOF) mechanisms have been proposed. We here discuss how we used muscle tissue, which provides high quality RNA of patient disease tissue, to investigate the consequences of TDP43 mislocalization. Further, we characterize two novel mouse TDP43 mutant lines, carrying ENU-induced mutations in order to study the effects of TDP43 mutations expressed at physiological levels in the mammalian central nervous system. One mutation (deltaRNA) strongly reduces the RNA-binding capacity of the protein; the second mutation (C-TERM) is in the glycine-rich C-terminal domain where the majority of human pathogenic mutations are found. Our results underline the importance of studying models with physiological expression levels of TDP43 mutations and shed light on the different effects on RNA metabolism caused by the TDP43 loss and gain of function."} +{"text": "Heart failure (HF) is characterised by alterations in fatty acid and glucose metabolism. We aimed to determine if myocardial lipid is increased in HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction (EF), and assess whether it is related to cardiac structure and function.1H MR spectroscopy to quantify myocardial lipid/water (%).25 HFrEF due to dilated cardiomyopathy (DCM), 18 HFpEF and 28 normal volunteers were prospectively recruited. All subjects underwent cardiovascular magnetic (MR) resonance at 3T for the determination of left ventricular (LV) volumes and function, and cardiac As expected DCM patients had significantly increased LV volumes and reduced EF, whilst HFpEF patients had significantly increased LV mass to end-diastolic volume ratio (LV mass/EDV). Importantly, cardiac lipid was increased in both HFrEF and HFpEF when compared to normal controls , with HFpEF group having the highest level of cardiac lipid (Table This is the first study to demonstrate that myocardial steatosis occurs in both HFrEF and HFpEF and is related to parameters of LV remodeling. This suggests that myocardial lipid may play a role in the pathophysiological processes of LV remodeling in both HFrEF and HFpEF. Cardiac lipid accumulation may be a potential therapeutic target in these conditions.N/A."} +{"text": "To compare thin section CT characteristics of the early local tumour recurrence after the resection of squamous cell carcinoma (SCC) with those of the stump deformity or granulation tissue.Twenty nine consecutive patients with local recurrence after definitive SCC operation from April 2006 to September 2012 were included. Pre- and post-operative CT from these patients were retrospectively reviewed and compared with those in age- and gender-matched 29 patients with stump deformity or granulation tissue at stump site after the definitive SCC operation, by two chest radiologists.p< 0.001). The univariate analysis showed that the size of soft tissue and the distance between soft tissue and stump site were associated with the predictive factors of local recurrence (p< 0.001). On the receiver operating characteristic analysis, the optimal cut-offs of the size of soft tissue and the distance between soft tissue and stump staples were 6mm and 5mm, respectively.Local recurrence were commonly observed as round/oval shape, peripheral eccentric lesion or central contour bulging lesion on CT, while the stump deformity or granulation tissue were commonly demonstrated as irregular or flat shape, focal wall thickening. The size of suspected soft tissue and the distance between stump staples and suspected soft tissue were significantly different between two groups (median; 19mm and 3mm; 18mm and 0mm, respectively, The proper knowledge of stump recurrence regarding the size and the distance around the stump on CT imaging will help us achieve an early and higher diagnostic rate of recurred SCC."} +{"text": "Bicuspid aortic valve (BAV) is the most common congenital heart defect affecting 1-2% of the US population. BAV has been associated with progressive secondary pathologies, such as aortic valve calcification, stenosis, regurgitation, aortic root dilatation, and/or aortic aneurysm. However, not all patients exhibit symptoms or develop aortopathy and the exact link between BAV morphology and disease progression is not fully understood. Magnetic resonance imaging (MRI) has been previously used to characterize BAV hemodynamics. However, studies have been hampered by the need for lengthy manual data analysis thereby limiting reproducibility and/or integration into a clinically feasible workflow.This work develops and applies a novel semi-automated technique to characterize geometry and hemodynamics of the aorta and the aortic valve based on 2D bSSFP cine and 4D flow MRI data. The protocol was applied to a cohort of 30 BAV and 30 control subjects. The table summarizes the preliminary analysis of the demographics of the subject cohort. The analysis was performed at several cross-sectional locations across the ascending aorta (see figure Geometric metrics (summarized in the table) were found to be significantly larger in the BAV subjects than in the control group (preliminary results are summarized in table A semi-automated protocol for the combined analysis of the aortic valve geometry and hemodynamics in the aorta was developed to analyze MRI data obtained with 2D cine and 4D flow MRI. Application of this protocol and a preliminary analysis performed on the subset cohort of 12 BAV and 12 control cases revealed elevated mean velocity, jet angle and forward flow displacement in BAV subjects in the proximal ascending aorta. This study provides a roadmap for comprehensive large cohort assessment of correlations between geometry and hemodynamics associated with BAV disease.NHLBI grant R01HL115828, K25HL119608 and PURA scholarship."} +{"text": "The prevalence of different biotic processes and historical contingency due to priority effects are in the focus of ongoing discussions about community assembly and non-random functional trait distributions.We experimentally manipulated assembly history in a grassland biodiversity experiment (Jena Experiment) by applying two factorially crossed split-plot treatments to all communities: (i) duration of weeding (never weeded since sowing or cessation of weeding after 3 or 6 years); (ii) seed addition (control vs. seed addition 4 years after sowing). Spontaneous colonization of new species in the control treatment without seed addition increased realized species richness and functional richness (FRic), indicating continuously denser packing of niches. Seed addition resulted in forced colonization and increased realized species richness, FRic, functional evenness (FEve) and functional divergence (FDiv), i.e. higher abundances of species with extreme trait values. Furthermore, the colonization of new species led to a decline in FEve through time, suggesting that weaker competitors were reduced in abundance or excluded. Communities with higher initial species richness or with longer time since cessation of weeding were more restricted in the entry of new species and showed smaller increases in FRic after seed addition than other communities. The two assembly-history treatments caused a divergence of species compositions within communities originally established with the same species. Communities originally established with different species converged in species richness and functional trait composition over time, but remained more distinct in species composition.Contrasting biotic processes increase functional convergence between communities initially established with different species. Historical contingency with regard to realized species compositions could not be eradicated by cessation of weeding or forced colonization and was still detectable 5 years after application of these treatments, providing evidence for the role of priority effects in community assembly. A deeper insight into the mechanisms which control community assembly is central to understand ecosystem functioning and the maintenance of biodiversity. Functional diversity, i.e. the extent of trait differences among co-occurring species In natural ecosystems, the importance of biotic processes causing trait convergence and divergence in community assembly is difficult to disentangle because abiotic processes may also cause trait convergence or counterbalance biotic trait divergence In the present study, we used experimental plots of a grassland biodiversity experiment cessation of weeding after six years (2007), no seed addition,(S6+) cessation of weeding after six years (2007), seed addition (2005),(S3\u2212) cessation of weeding after three years (2004), no seed addition,(S3+) cessation of weeding after three years (2004), seed addition (2005),(S0\u2212) never weeded, no seed addition, and(S0+) never weeded, seed addition (2005).Plots were mown twice per year and the mown plant material was removed.Species richness, species identities and visually estimated species cover using a decimal scale A trait matrix comprising species mean traits related to spatial and temporal niche dimensions and to strategies of regeneration was compiled for all observed species based on information in the floristic literature Bray-Curtis dissimilarities n-dimensional trait space occupied by the species in a community n-dimensional trait space n-dimensional trait space Measures of functional trait diversity quantify the distribution of species in a multidimensional space whose axes are defined by functional characteristics. Three components of functional trait diversity were calculated separately: functional richness (FRic), functional evenness (FEve) and functional divergence (FDiv) http://www.r-project.org) including the packages FDnlmeLinear mixed-effects models were applied to test for effects of the experimental factors on the response variables measured in the 5-year study period in the split-split-plot colonization experiment. Block and plot identity, subplot pair and subplot were treated as random factors in a nested sequence. Although the factors species richness and number of functional groups are nearly orthogonal in the Jena Experiment, the design of the experiment is not completely balanced because it is not possible to vary species richness and functional group number completely independently. Starting from a constant null model the fitting sequence of fixed terms followed the a-priori hypotheses of the biodiversity experiment starting with the number of initially established species (log-linear term), the number of functional groups (linear term), factors for the split-plot variables colonization period (with three factor levels) and seed addition (with two factor levels) and their interactions with the main experimental factors. Finally, a term for the different study years and its interaction with the previously mentioned experimental factors was entered. The maximum likelihood method was used and likelihood ratio tests were applied to assess the statistical significance of model improvement. The statistical software R after colonization of new species , Table 2Realized functional evenness (FEve) after colonization declined with an increased number of initially established species , Table 2Realized functional divergence (FDiv) after colonization decreased with an increased number of initially established species , Table 2Average between-community dissimilarity in species composition was highest for communities initially established with a large number of species. Average between-community dissimilarity in functional trait composition did not depend on the initially established plant diversity . BetweenThe average within-plot dissimilarities (between different seed addition \u00d7 colonization period combinations) in species and functional trait composition were smaller than between communities . Within-In spite of sustained efforts to understand patterns of community assembly, the importance of different biotic processes is poorly disentangled so far. We used the opportunity to study biotic processes of community assembly under relatively homogeneous environmental conditions in split-plots of a large grassland biodiversity experiment opened for colonization by new species and removed dispersal limitation through a seed addition treatment Species gain and increase in functional richness (FRic) after the opening of experimental communities for colonization by new species was reduced by a higher number of initially established species and a longer colonization period (shorter duration of weeding). The negative effects of a higher initially sown plant diversity on the spontaneous colonization of new species may be attributable to the lower stability of low-diverse communities even in the absence of weeding Functional richness (FRic), which quantifies the volume of functional space filled by a community, increased in parallel to species gain in sub-plots without seed addition, but the increment of FRic was flattened in subplots with a higher number of initially sown species . The conPrevious studies have reported that experimental communities initially sown with different plant diversity and opened to colonization converged in species richness and functional or phylogenetic composition while keeping different species composition It becomes increasingly apparent that multiple processes are involved in community assembly. A number of recent studies have shown that patterns of functional trait composition depend on environmental conditions and the traits considered Figure S1Between- and within-community coefficients of variation of realized species richness, FRic, FEve and FDiv.(DOC)Click here for additional data file.Text S1Reference list for data on specific leaf area of particular plant species included in the matrix of functional traits.(DOC)Click here for additional data file."} +{"text": "Pectus Excavatum affects between 1:400 - 1000 live births. Little academic focus has been directed to the anatomical subgroups of this condition. No anatomical classification and subgrouping has been formulated. Current surgical strategies utilize a 'one size fits all' philosophy with variations of the Nuss or Ravitch procedureOur aim was to stratify patients with Pectus Excavatum by providing an anatomical classification that would guide treatment. The novel classification we propose provides a framework for use with current and evolving medical technologiesBetween April 2006 - March 2015, 24 patients presented to our institute with symptomatic Pectus Excavatum. All presented with symptoms of dyspnoea /fatigue/dysphagia. All patients underwent Prospective evaluation of exercise and anatomical characteristics by: Spirometry; Cardiopulmonary exercise tolerance (CPEX) testing & Non-contrast axial/sagittal CT scan of the thorax & 3D reconstruction. We propose an Anatomical classification based on 2D and 3D CT imaging: Classification A : No depression of manubrium, posterior angulation of sternal bodyClassification B: (1) Horizontal depression of manubrium and sternal body with no angulation (2) Depression of manubrium with posterior angulation of sternal bodyClassification C: Complex asymmetrical torsion of manubrium and body of sternum associated with asymmetrical distortion and depression of rib cage9 patients (38%) had a Type A defect. We recommend this sternal body angulation to be corrected with Ravitch Procedure, Transverse osteotomy and midline screw fixation bar. 14 (58%) patients had a Type B2 defect, which we recommend should be repaired as a Type A defect but elevation of the whole sternum using a transverse screw fixation bar.Our classification provides a framework for evaluation of the pathological anatomy of Pectus Excavatum. This classification has been shown to have utilitarian value in planning surgical strategy. The model will provide opportunities for future development of surgical technique and provides a descriptor that will allow academic discussion"} +{"text": "The ability to non-invasively establish patency of cerebral spinal fluid (CSF) flow between adjacent central nervous system (CNS) compartments is of importance in the diagnosis and treatment of patients with various areas of CSF flow obstruction. Recent advances in magnetic resonance imaging (MRI) technology allows for real-time magnetic labeling of CSF to directly visualize flow through different compartments.The presence of CSF flow was examined at the aqueduct of Sylvius (AS), the foramen of Monro (FM), the floor of the third ventricle (3rd V), and the foramen magnum (FMag) using a modification of arterial spin labeling (ASL). The studies were compared with clinical information and classified as true positive, true negative, false positive, and false negative based on expectation of patency.A total of 68 flow studies were done on 44 patients. High correlation with true positive was seen at all four sites. No flow was visualized in 25 readings of the AS; in 9 of those cases we expected flow to be present. Table Establishing qualitative patency between adjacent CSF compartments using MRI is possible with a modified ASL technique. This technique has excellent (above 80%) sensitivity, specificity, and negative likelihood ratio in three out of the four regions studied."} +{"text": "Investigators from the University of Western Australia report the diagnostic yield of performing next generation sequencing in a heterogenous cohort of patients with neuromuscular disorders (NMD) presenting at or before birth. Investigators from the University of Western Australia report the diagnostic yield of performing next generation sequencing in a heterogenous cohort of patients with neuromuscular disorders (NMD) presenting at or before birth. Forty-five patients from 38 unrelated families with fetal akinesia (9 families), arthrogryposis (13 families) and severe congenital myopathies (16 families) underwent whole exome sequencing (23), targeted sequencing (7) and both (8). Ten of these families were consanguineous. A conclusive genetic diagnosis was achieved in 18/38 families (47%). Autosomal recessive was the most common mode of inheritance (15), however dominant (1), de novo (1) and X linked (1) were also identified. Mutations were found in eight previously known neuromuscular disease genes and four novel neuromuscular disease genes .RYR1 are associated with the arthrogryposis and fetal akinesia phenotype while missense mutations in RYR1 are associated with central core myopathy phenotype . The study also led to the identification of novel neuromuscular disease genes involved in sarcomere assembly and muscle dysfunction. [This study highlights the widening spectrum of phenotypes associated with mutations in known neuromuscular genes. For example, null mutations in the COMMENTARY. Fetal akinesia deformation sequence , arthrogryposis , and severe congenital myopathies comprise a very heterogeneous group, both phenotypically and genetically, that present at or before birth . Prior tThis study used a combination of whole exome sequencing and targeted exome sequencing of known neuromuscular genes. Functional studies were done in cases of novel genes when feasible . A previ"} +{"text": "Heparin is diluted in parenteral nutrition bags and administered over a period of 24 hours with in-line filtration. However, there are no data on heparin stability in parenteral nutrition bags, especially on its compatibility with 50% dextrose mainly present in bags. The aim of our n = 6 per type) were infused over a period of 24 hours with and without in-line filtration. Heparin activity was measured using a chromogenic anti-Xa method in bags just being prepared (references for other measures) and after 24-hour infusion and in effluents at the end of infusion line after 24 hours.We prepared both types of bag: parenteral nutrition bags whose composition was defined in the unit, including sodium heparin (77 UI/ml); and bags containing only sodium heparin diluted in 50% dextrose (193 UI/ml). These bags (Our results show values of heparin activity measured in bags and effluents with and without in-line filtration after 24-hour infusion for both types of bag assessed Tables and 2. RWe conclude that there is no loss of heparin activity when drug is infused over 24 hours for both types of bag prepared, with and without in-line filtration, showing heparin activity remains stable during this period and there is no interaction of drug with other nutrient components of bags, especially 50% dextrose."} +{"text": "ECMO is widely used through the world, but is still surrounded by important complications, most of them at the site of the surgical approach.We describe and assess the effectiveness, the feasibility and the security of exclusive percutaneous peripheral veno-arterial ECMO including the distal reperfusion of the homolateral lower limb.It is a monocentric, retrospective and observational study. Twenty nine patients were implanted between July 2012 and March 2014. The indications for ECMO were acute phase of myocardial infarction (n = 8), post-cardiotomy cardiogenic shock (n = 12), acute myocarditis (n = 1), cardiac rhythm disorders (n = 1), bridge to cardiac transplantation or long-term circulatory support (n = 7). The insertion was performed in hybrid operating room. After puncture of the common femoral artery (CFA) the superficial femoral artery (SFA) was opacifiated. An anterograde 6F introducer was placed in the SFA under fluoroscopic control. The arterial and venous cannulae were then introduced through guide wires placed under fluoroscopic control. The distal perfusion of the homolateral lower limb was performed through a connection between the arterial cannulae and the introducer placed initially. Femoral arterial cannula was surgically removed at the end of the assistance to avoid vascular complications, the others by compression.The mean duration of circulatory support was 9,5 days (from 1 to 52 days). Thirteen deaths occurred (45%). Bleeding of the groin required a haemostasis procedure in two cases only (5%). One external iliac artery dissection and two acute thrombosis of the oxygenator (one of which was reversible) (5%) occurred. Neither infection, nor lower limb acute ischemia occurred. A percutaneous atrioseptostomy was performed in catheterization room in eight patients who presented an acute pulmonary edema (21%), which all resumed.These results suggest that the implantation of exclusive percutaneous peripheral veno-arterial ECMO is efficient, reproducible and minimally invasive. The pre-positioning of the distal reperfusion should be systematic. Surgical ablation of the arterial femoral cannula is necessary, but complications related to an initial surgical approach could be avoided during the time of assistance."} +{"text": "Disturbances of cerebral venous hemodynamics define development of child headache. However directed by the diagnosis and subsequent treatment these disturbances are not considered. The absence of diagnostics algorithm and norms of cerebral venous blood flow limits the possibility of timely therapy at children.The studies of headache caused by venous hemodynamics disturbance.600 patients (3-17 years old) who complained of headache have been examined. The data of a blood flow velocity in deep cerebral veins of a brain: in straight venous sinus, vein of Galen, sinuses cavernous defined by Transcranial Color-Coded Duplex.Headache caused by cerebral venous dysfunction notes in 47% of children. The surveyed children had typical headache (100%) of holding apart character in occipital and parietal areas after a dream (69%) ,after physical activity(14%) and a long static pose have been revealed(17%).\u201cVenous\u201d headache at children often can be similar to dizziness. The attacks of headache which are coming to an end with vomiting are revealed at 25% of children. Children also complained of nasal bleeding as a fountain (60%) during a night or day dream (40%), noise in ears (53%), ocular pathology refraction(43%) and expressed vegetative symptoms (80%).We have found clinical signs of the connective tissue dysplasia syndromes at 67% of children.Structural cerebral abnormalities were revealed at 9% patients of them by MRI .\u201cMarkers\u201d of disturbances in cerebral venous hemodynamics was venous outflow in deep brain veins. The research of parameters of a cerebral hemodynamics was carried out in the conditions of functional rest and after dynamic tests. We suggest modified Valsalva, orthostasis and head-down tilting tests in children .Definition of cerebral venous hemodynamic normal indicators in children of different age groups is very important for identification and treatment of headache with cerebral venous disturbances.No conflict of interest."} +{"text": "The differential diagnosis of patients in the emergency department who show symptoms of sepsis and suspected pneumonia may be difficult because of the low sensitivity and specificity of supine chest X rays (SCXR) and physical examination.A retrospective assessment of the usefulness of lung ultrasound (LU) in the diagnosis of pneumonia in patients with signs and symptoms of sepsis and respiratory disease.2 groups of patients were considered:Group A: 22 patients with a positive first SCXR (SCXR1) for pneumoniaGroup B: 18 patients with a negative SCXR1 for pneumonia, but who were subsequently diagnosed with pneumonia during their hospital stay following a second SCXR (SCXR2) or CT.Lung ultrasound examination was performed within 24 hours of admission, searching for direct and indirect echographical signs of pneumonia: focal B lines (FBL), pleural effusion (PE) and images of lung consolidation (LC).See table In our observational study, LU showed high sensitivity in the diagnosis of pneumonia:95% in patients already diagnosed using SCXR, and 100 % of early diagnosis of pneumonia in patients whose diagnosis was subsequently confirmed during hospitalization."} +{"text": "However, full analyses of T cell receptor (TCR) sequences have been difficult because of the inefficiency of T cell cloning, heterogeneity of T cells or the heterodimeric structures of TCRs. Here, we revealed complete landscapes of cancer antigen-specific TCRs using a novel TCR cloning system; hTEC10 -derived peptide vaccine for advanced hepatocellular carcinoma (HCC). The peptide-specific cytotoxic lymphocytes (CTLs) were detected and sorted as single cells from the patients' peripheral mononuclear cells (PBMCs) after in vitro stimulation. cDNAs of paired TCR chains were amplified from the single cells, cloned into retroviral vectors, and transduced in the T cell strain or PBMCs. The avidities of the obtained TCRs were evaluated by comparing antigen-specific cytotoxicities. This system was also applied to the healthy controls and the participants of the Phase I clinical trial of human telomerase reverse transcriptase (hTERT)-derived peptide vaccine for prevention of HCC recurrence after radiofrequency ablation (RFA) therapy.AFP-specific CTLs were induced in 4 patients whose clinical responses were CR , long SD , SD (91 days) and PD (46 days), respectively (long SD is defined as SD over 6 months). Totally, 347 specific TCR clones that consisted of 10 kinds of TCR gene rearrangements were amplified. The TCRs obtained from the CR patient and the long SD patient possessed higher avidities than that from the SD patient, the PD patient and the healthy controls without HCC. Similarly, we could obtain highly reactive 122 TCR clones consist of 10 different gene arrangements from 3 patients who were treated with hTERT vaccine and prevented from the recurrence until 24 weeks after RFA. These results indicated that the inductions of TCRs with high avidities reflected the good clinical responses, and high-avidity TCR might be retrieved from vaccinated patients with good clinical responses, not from patients with poor responses or healthy individuals."} +{"text": "The primary aim of this commentary is to describe trauma-related dissociation and altered states of consciousness in the context of a four-dimensional model that has recently been proposed . This model categorizes symptoms of trauma-related psychopathology into (1) those that occur within normal waking consciousness and (2) those that are dissociative and are associated with trauma-related altered states of consciousness (TRASC) along four dimensions: (1) time; (2) thought; (3) body; and (4) emotion. Clinical applications and future research directions relevant to each dimension are discussed. Conceptualizing TRASC across the dimensions of time, thought, body, and emotion has transdiagnostic implications for trauma-related disorders described in both the Diagnostic Statistical Manual and the International Classifications of Diseases. The four-dimensional model provides a framework, guided by existing models of dissociation, for future research examining the phenomenological, neurobiological, and physiological underpinnings of trauma-related dissociation. Putnam notes suAccordingly, this commentary will review the relevance of each of the four dimensions of consciousness to the theoretical, neurobiological, and clinical underpinnings of trauma-related phenomenology in the context of a four-dimensional model (4-D model) outlining a dissociative and a non-dissociative dimension of each of the four dimensions of consciousness those that occur within NWC and (2) those that exhibit a dissociative presentation associated with the experience of TRASC. Experiences of NWC and TRASC can be further classified along four dimensions of consciousness: (1) time (reliving flashbacks [TRASC] versus intrusive memories and reminder distress [NWC]); (2) thought ; (3) body ; and (4) emotion see . It shouThe model makes four predictions: (1) the experience of TRASC will be less common than will be presentations of normal waking consciousness given that states of normal waking consciousness, by definition, are the most common phenomenological state of human beings; (2) TRASC are expected to be less intercorrelated than states of normal waking consciousness as the experience of TRASC is frequently experienced as more \u201ccompartmentalized\u201d; (3) measures of TRASC are expected to be more strongly correlated with other measures of dissociative symptomatology; and (4) experiences of TRASC are predicted to be more specific to an etiology implicating early life adversity and repeated traumatization. Emerging evidence provides support for these predictions in the context of a subjective past and anticipated future. Accordingly, under normal circumstances, time is experienced as continuously moving forward. However, traumatized individuals often relive their traumatic memories through flashbacks and lack the ability to live in the \u201cnow,\u201d reflecting a key dissociative process associated with TRASC. Such reliving events are in contrast to intrusive memory recall most frequently associated with reminder distress and not involving an altered state of consciousness or a dissociative process but rather represent a state of normal waking consciousness traumatized individuals with frequent symptoms of emotional numbing and shutdown and (2) traumatized individuals that solely exhibit general negative affect to identify specific maps of bodily sensations and to explore the relation of these maps to the experience of different emotional experience. These findings will then need to be related not only to the underlying neural deficits of emotion processing but also to treatment outcomes. Moreover, investigating how specific neural networks involved in the consciousness of emotion can be directly targeted through the use of real-time fMRI or EEG-based biofeedback in conjunction with pharmacotherapeutic and psychotherapeutic approaches will be an important avenue for future investigation.In summary, this commentary describes a 4-D model that categorizes symptoms of trauma-related psychopathology into (1) those that occur within normal waking consciousness and (2) those that are dissociative and associated with TRASC along four dimensions of consciousness: (1) time; (2) thought; (3) body; and (4) emotion. Conceptualizing TRASC across these four dimensions has transdiagnostic implications for trauma-spectrum disorders involving dissociation and is relevant to efforts to identify key factors related to the development and maintenance of trauma-related symptoms described both in the DSM and the International Classification of Disease. It will be crucial for future research to examine directly these symptoms along each dimension of consciousness and to identify further their neurobiological and physiological underpinnings, and to determine their role in treatment outcome (also see Sar, Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file.Click here for additional data file."} +{"text": "Background. The current study was designed to reveal possible associations between the polymorphisms of the vascular endothelial growth factor (VEGF) gene (rs2010963) and its receptor, kinase insert domain-containing receptor (KDR) gene polymorphism (rs2071559), and markers of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Patients and Methods. 595 T2DM subjects and 200 control subjects were enrolled. The carotid intima-media thickness (CIMT) and plaque characteristics (presence and structure) were assessed ultrasonographically. Biochemical analyses were performed using standard biochemical methods. Genotyping of VEGF/KDR polymorphisms was performed using KASPar assays. Results. Genotype distributions and allele frequencies of the VEGF/KDR polymorphisms were not statistically significantly different between diabetic patients and controls. In our study, we demonstrated an association between the rs2071559 of KDR and either CIMT or the sum of plaque thickness in subjects with T2DM. We did not, however, demonstrate any association between the tested polymorphism of VEGF (rs2010963) and either CIMT, the sum of plaque thickness, the number of involved segments, hsCRP, the presence of carotid plaques, or the presence of unstable carotid plaques. Conclusions. In the present study, we demonstrated minor effect of the rs2071559 of KDR on markers of carotid atherosclerosis in subjects with T2DM. Type 2 diabetes mellitus (T2DM) is considered a major epidemic of this century. It is estimated that its prevalence will increase worldwide from 371 million people in 2013 to 552 million people in 2030 . The genotype distributions in both patients with T2DM and controls were in Hardy-Weinberg equilibrium for the KDR gene polymorphism [rs2071559: T2DM and controls ]. No statistically significant differences in the VEGF rs2010963 and KDR rs2071559 genotype distribution frequencies were observed between T2DM patients and controls.The genotype distributions in both patients with T2DM and controls were in Hardy-Weinberg equilibrium for both VEGF gene polymorphisms [rs2010963: T2DM between patients with T2DM and controls (32.3% versus 33%). However, the C allele frequency of the KDR rs2071559 polymorphism was significantly lower (p = 0.04) in T2DM subjects as compared to the controls (49% versus 54%).The observed minor allele frequency (MAF) distributions were mostly in agreement with the 1000 Genomes Project data in the European population. The C allele frequency of the VEGF rs2010963 showed no significant difference (Higher VEGF serum levels were demonstrated in subjects with T2DM with the CC genotype (rs2010963) compared to those with other (CG + GG) genotypes . MoreoveThe comparison of atherosclerosis parameters was performed with regard to different genotypes of the VEGF polymorphism rs2010963) upon enrolment. In our study, we did not demonstrate any association between the rs2010963 and either CIMT, the sum of plaque thickness, the number of involved segments, hsCRP or the presence of carotid plaques, or the presence of unstable carotid plaques and CIMT. Variations in the VEGF gene were reported to be weakly associated with CIMT . None ofAdditionally, we also demonstrated an association between the rs2071559 of KDR and the sum of plaque thickness in subjects with T2DM, whereas no association between tested polymorphism of VEGF (rs2010963) and markers of carotid atherosclerosis was demonstrated. The rs2010963 polymorphism of the VEGF gene was not demonstrated to exert a significant influence on the risk of subclinical atherosclerosis manifested by the presence of endothelial dysfunction by brachial artery reactivity and increased CIMT in a series of patients with rheumatoid arthritis . ContrarIn our study, the effect of either rs2071559 of KDR or rs2010963 on VEGF serum levels was demonstrated. These findings are in accordance with our previous studies in which subjects with recent MI history (up to 9 months after MI) were enrolled , 16, 25.In contrast to the minor effect of the rs2071559 of KDR and the absence of the rs2010963 of the VEGF, an association of either rs2071559 or rs2010963 with MI has recently been reported in Caucasians with T2DM , 16, 24.To conclude, in our study we demonstrated a minor effect of the rs2071559 of KDR on markers of carotid atherosclerosis in subjects with T2DM, whereas we failed to demonstrate an effect of tested polymorphism of the VEGF gene (rs2010963) on markers of carotid atherosclerosis."} +{"text": "Actinomycosis is a chronic infection due to anaerobic filamentous bacteria (Actinomyces), which occurs mostly in the cervicofacial region as a chronic granulomatous infection. We report the case of Mr KI, 17 years old, without past medical history, presented a painful ulceration on the right side of the chest wall which evolved since 2 months. The onset of symptoms was a nodule which ulcerated after 2 months with extruding yellowish pus. The examination objectified ulcerated and burgeoning lesion in right parasternal region from what came yellowish pus mixed with sulphur granule (A). A painful subcutaneous nodule was noted under the right breast. An examination of the oral mucosa was entirely normal as well as the rest of the physical examination. Histopathologic studies (hematoxylin-eosin staining) revealed the presence of inflammatory cells surrounding basophilic sulfur granules which were composed of a large number of filaments arranged in a radiating pattern (B). The chest x-ray was normal. The chest scan showed an infiltration of the anterior and right lateral wall without bone and lung injury. The results of aerobic and anaerobic culture showed mixed flora. The histopathologic findings led to the diagnosis of actinomycosis of the wall chest. Treatment was based on oral amoxicillin + clavulanic acid (1g + 125 mg 3 times daily). The size of the ulcerative lesion gradually decreased and completely healed by 4 weeks. Then antibiotherapy was continued for four months. No evidence of recurrence of this lesion was found after 24-month of follow-up."} +{"text": "Eosinophilic esophagitis (EoE) is a chronic/recurrent inflammatory disease of the esophagus characterized by the association between symptoms of esophageal dysfunction and a prominent eosinophilic infiltrate >15/HPF) of the esophageal epithelium 5/HPF of . The nat"} +{"text": "Evidence of the association of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) with the full range of cardiovascular diseases (CVDs) is limited. We examined their relationship with the first clinical presentation of the 12 most common CVDs in an unselected population-based cohort of men and women.We analysed CArdiovascular disease research using LInked Bespoke studies and Electronic health Records (CALIBER) data, which links primary care and hospital and mortality data in England, from 1997 to 2010. We assembled a cohort of men and women initially free from CVD at baseline and included all patients with PMR and/or GCA (PMR/GCA) diagnosis, matched by age, sex and general practice with up to 10 individuals without PMR/GCA. Random effects Poisson regression analysis was used to study the association between PMR/GCA and the initial presentation of 12 types of CVDs.The analysis included 9776 patients with PMR only, 1164 with GCA only, 627 with PMR and GCA and 105\u2005504 without either condition. During a median of 3.14\u2005years of follow-up 2787 (24.1%) individuals with PMR/GCA and 21\u2005559 (20.4%) without PMR/GCA developed CVDs. Patients with PMR/GCA had lower rates of unheralded coronary death , transient ischaemic attack and coronary and death composite . No associations were observed for other CVDs or cerebrovascular diseases, and in patients with only PMR or GCA. No evidence of interaction by age or sex was found. Estimates decreased with longer PMR/GCA duration and findings were robust to multiple sensitivity analyses.In this large contemporary population-based cohort the presence of PMR and/or GCA was not associated with an increased risk of CVDs or cerebrovascular diseases regardless of PMR/GCA duration. Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are two chronic inflammatory diseases with similar genetic and acute-phase response patterns that affect predominantly women aged \u226550\u2005years.3The inflammatory nature of the two conditions and presence of clinical or subclinical arteritisBecause one in two patients diagnosed with GCA will also develop PMRIn this longitudinal population-based study of individuals registered in primary healthcare practices with linked information to hospital, registry and mortality data, we examine the association between PMR and GCA and the 12 most common clinical initial presentations of CVD. We also assess whether associations differ according to disease duration, sex, age or presence of other autoimmune diseases.All patients with prospectively recorded PMR and/or GCA diagnosis between January 1997 and March 2010 were identified in the CALIBER dataset.13\u201316For each patient with PMR/GCA, up to 10 individuals matched on age (\u00b15\u2005years), sex and practice were randomly selected among those who, on their matched inclusion date, had contacted the medical practice within 1\u2005year and had not been diagnosed with the disease (concurrent sampling). At the start of the observation period all patients were \u226518\u2005years old, free of prior CVD and had been registered with their practice for \u22651\u2005year.Patients with recorded diagnosis of PMR and/or GCA were identified from electronic medical records using Read and ICD-10 codes (see online supplementary table S1). Those with supporting information for PMR or GCA diagnosis or under the care of a rheumatologist within 6\u2005months) were included in primary analyses (see online supplementary figure S1 and table S3). Patients without supporting information for diagnosis were included in sensitivity analyses. Individuals were initially categorised as having PMR and/or GCA (PMR/GCA group) or not having either condition. Because it is uncertain whether the two conditions are different presentations of the same disease, they were then divided into subgroups of those diagnosed only with PMR, only with GCA or with GCA regardless of previous or later PMR diagnosis during follow-up . Patients were further classified into incident and prevalent cases, depending on whether the first recorded diagnosis was made before or after/on study entry.https://www.caliberresearch.org/portal/.Baseline covariates considered were: sociodemographic , cardiovascular , \u22652 prescriptions in the past year , immunosuppressant drug, oestrogen oral contraceptives and hormone replacement therapy), diagnosis with another autoimmune diseases (see online supplementary table S4) and year of study entry. As in previous CALIBER analyses,http://www.caliberresearch.org/portal/.The primary study endpoints were the initial presentation of 12 fatal and non-fatal cardiac and arterial vascular diseases of heterogeneous pathophysiology identified across the four linked data sources in CALIBER: the CPRDFor individuals with PMR/GCA the observation period began on the date on which the patient fulfilled all the study inclusion criteria, or the date of first recorded diagnosis for patients with incident PMR/GCA (see online supplementary figure S2). For individuals without PMR/GCA, it started on the entry date of the matched individual with PMR/GCA. For all patients the study ended on the date of cardiovascular endpoint diagnosis, death, practice deregistration, last practice data collection date or diagnosis of PMR/GCA (for patients who contributed follow-up to both the PMR/GCA and non-PMR/GCA groups).Incidence rates of events per 1000 person-years of follow-up with 95% CIs were calculated in patients with and without PMR/GCA, separately for individuals with prevalent or incident PMR/GCA, and for patients exclusively diagnosed with PMR or GCA. Associations between PMR/GCA and every study endpoint were assessed with random effects Poisson regression accounting for clustering between practices. Missing values of covariates were multiply imputed (see online supplementary text S1). Models were initially adjusted for age and sex, then additionally for cardiovascular factors. To explore possible pathways or mediators of any increase in risk, estimates were further adjusted for: (i) lipid and blood pressure lowering medication; (ii) diagnosis of another autoimmune disease; and (iii) anti-inflammatory and/or immunosuppressant drugs.In secondary analyses: (i) evidence of interactions with sex and age were assessed using Wald tests for interaction; (ii) the relationships with prevalent and incident PMR/GCA were studied; (iii) associations were assessed separately for patients who had only one of the two diseases and for those who had GCA regardless of PMR diagnosis. Furthermore, to examine the association between disease duration and CVD, the follow-up of patients with incident PMR/GCA was split into duration periods . Patients with prevalent disease who had a first diagnosis recorded \u22655\u2005years before study entry were included in the \u22655\u2005year period group. Those with prevalent disease of shorter duration (<5\u2005years) were excluded from this analysis because of uncertainty about exact disease duration.Sensitivity analyses comprised: (i) exclusion of patients with another autoimmune disease; (ii) restriction to patients with \u22656\u2005months of follow-up; and (iii) exclusion of 2\u2005years of follow-up prior to PMR/GCA diagnosis for patients who contributed to the exposed and unexposed groups (to account for delays in diagnosis); (iv) inclusion of patients without supporting information for PMR/GCA diagnosis; (v) exclusion of patients of <50\u2005years of age; (vi) inclusion of first cardiovascular events irrespective of other earlier CVD presentations; (vii) comparison of estimates in the periods before and after the introduction of the pay for performance scheme\u00a0in England ; and (viii) restriction to patients with evidence of active disease (baseline c-reactive protein (CRP) >3.0\u2005mg/mL or elevated erythrocyte sedimentation rate (ESR)).Statistical analyses were done with Stata (V.13.1).Approval was granted by the Independent Scientific Advisory Committee of the Medicines and Healthcare Products Regulatory Agency and the MINAP Academic Group. We registered the protocol at clinicaltrials.gov (NCT02062021).In total 11\u2005567 patients with PMR/GCA and supporting diagnosis information and 105\u2005504 non-PMR/GCA patients free of CVD were identified . Of patiDuring follow-up, 2272 (23.2%) patients with PMR only, 348 (29.9%) with GCA only, 167 (26.6%) with both conditions and 21\u2005559 (20.4%) without either disease experienced one of the 12 CVDs. The incidence of fatal and non-fatal CVDs was slightly lower in patients with than without PMR/GCA , greater differences being observed for heart failure, PAD and stable angina. The small number of CVD events in the subgroup of patients with GCA limited the power to examine differences in rate ratios between patients with PMR and GCA for some CVDs. However, no evidence of increased risk of CVD was observed for those with a higher number of events (see online supplementary table S8) and for composites endpoints .Exclusion of individuals diagnosed with another autoimmune disease or patients aged <50\u2005years, inclusion of patients with >6\u2005months of follow-up and censoring of follow-up 2\u2005years before the diagnosis of PMR/GCA in patients who contributed to both, PMR/GCA and non-PMR/GCA groups, did not alter the results (see online supplementary table S8 and figure S10). Patterns of association remained unchanged when PMR/GCA individuals were included irrespective of whether disease supporting information was recorded (see online supplementary figure S11). Analyses comparing estimates before and after the introduction of the pay-for-performance system of CPRD, those of first presentation of CVD and those restricted to patients with evidence of active disease also showed similar patterns of associations (see online supplementary figures S12 and S13 and table S10).This is to date the largest population-based longitudinal study comparing the initial presentation of a wide range of symptomatic CVDs in patients with and without PMR and/or GCA using contemporary data (1998\u20132010). The large sample size, the longitudinal design and the information available allowed examination of associations in individuals with prevalent and incident PMR/GCA, pure and concomitant PMR and GCA, different duration of disease and adjustment for sociodemographic and cardiovascular factors. In contrast to a previous CALIBER study conducted in the same population in which we reported increased rates of the initial presentation of several CVDs in patients with rheumatoid disease (awaiting publication), no evidence of increased risk of any of the 12 CVD presentations investigated was found in the presence of PMR/GCA.This study has several strengths. The longitudinal population-based design provided evidence of temporality and enabled investigation of associations with duration of PMR/GCA since diagnosis. The large sample size allowed conducting separate analyses for patients with incident and prevalent PMR/GCA and pure and concomitant PMR and GCA, and investigation of sex and age interactions. The time period covered 1997\u20132010) provided epidemiological evidence from a population diagnosed and treated in recent years. The analysis of linked electronic health records spanning primary, hospital and disease registry data improved disease and cardiovascular endpoint ascertainment,10 providStudy limitations include the possibility of PMR/GCA misclassification . In our study, PMR/GCA was defined based on recorded physician diagnosis in primary care and hospitals. Information on American College of Rheumatology classification criteria or histology was not available in the dataset for diagnosis confirmation. However, to reduce the likelihood of PMR/GCA misclassification in patients >60\u2005years of age with incident seronegative rheumatoid arthritis or malignancies,There are several possible explanations for the absence of increased risk of CVD observed in patients with PMR/GCA regardless of disease duration. PMR/GCA affects an old population who might die before a detrimental effect of chronic systemic inflammation on the arteries becomes symptomatic.7Discordance with previous studies that found evidence of increased risk of CVD in patients with PMR/GCA could be related to their inclusion of patients with a history of CVDs and/or primarily diagnosed and treated in tertiary health facilities, and to betterThe chronic inflammatory nature of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) and the presence of clinical or subclinical arteritis might lead to an increased risk of cardiovascular diseases (CVDs). However, findings from the few available studies investigating these associations are heterogeneous and inconsistent.In this large, contemporary longitudinal population-based study of patients treated at primary and hospital levels, we examined the associations between prevalent and incident PMR/GCA and pure and concomitant PMR and GCA, and the 12 most common clinical presentations of CVDs. Regardless of PMR/GCA disease duration, presence of pure or concomitant PMR and GCA was not associated with an increased risk of CVD. No evidence of interaction by sex or age was found.The study findings suggest that, under current clinical practice targeted to patients with PMR and/or GCA, including early and long-term administration of anti-inflammatory and immunosuppressant drugs to control chronic systemic inflammation associated with PMR/GCA, and management of cardiovascular factors with primary prevention, cardiovascular patient risk is similar to the risk of patients without PMR/GCA.In conclusion, regardless of disease duration, diagnosis of pure or concomitant PMR and GCA was not associated with increased risk of CVDs in a large, contemporary population-based sample suggesting that, within the framework of current clinical practice, these diseases do not represent an important risk factor for CVD."} +{"text": "The mechanism by which transmyocardial revascularization (TMR) offers clinical benefit is controversial. We hypothesized that TMR ameliorates vasoconstriction in patients with ENDCADThis study was undertaken to demonstrate that transmyocardial laser revascularization in patients with advanced CAD improves results of combined operations CABG+ TMR through reduction of vasoconstrictionWe investigated vessels of coronary microvascular network of patients with ENDCAD and analyzed the histological changes in two groups: in group of patients died after sole CABG (1-st group - 8 heart specimens) and group of patients died after combined operations CABG+TMR (2-nd group - 6 heart specimens).These data are compared with hospital results in two large groups of patients with ENDCAD: with isolated CABG (1-st group -33 operations) and CABG+TMR (2-nd group - 87 operations), operated in 2011-2012.in all hearts after sole CABG was identified coronary arteriolar vasospasm that decreases coronary and bypass flow and thus increase the probability of thrombi formation. All cases after CABG+TMR revealed vasodilatation in lased areas. Reduction in the occurrence of vasospasm in cases with CABG+TMR can prevent graft and coronary occlusion. High indices of hospital mortality (12.1%) and morbidity(33.3%) in cases with sole CABG can be explained with coronary spasm in patients with advanced CAD. On the other hand, reduced hospital mortality (1.15%) and morbidity (2.3%) in the second group(CABG+TMR) can be explained by laser-influenced vasodilatation of distal coronary bed. Elevated resistance of the coronary bed hinders the effectiveness of the graft and myocardial blood flow(MBF). We suggest, that intraoperative effectiveness of TMR based of denervation, dilatation of microvascular network of the myocardium and intraoperative improvement of perfusion.elevated resistance of myocardial microcirculation(vasoconstriction) in patients with advanced CAD inhibit the effectiveness of the CABG. In cases with TMR effectiveness is most likely due to vasodilatation of vasoconstriction of myocardial microcirculation"} +{"text": "Therapeutic temperature modulation (TTM) is widely used in the care setting to improve outcomes of patients with traumatic brain injury (TBI). Through fever prevention, both oxygen utilization and caloric expenditure are reduced, so metabolic efficiency can be maximized . HoweverA retrospective review was conducted looking at SICU patients managed with a normothermia protocol, with particular attention paid to the anti-shivering portion of the protocol. Serum magnesium (Mg) levels were assessed prior to initiation of TTM and Bedside Shivering Assessment Scale (BSAS) scores were collected.n = 10 of 20). Serum Mg levels at the initiation of TTM were observed to negatively correlate with the level of shivering, as indicated by the BSAS scoring system (P = 0.02). See Figure Twenty patients receiving TTM for TBI were evaluated (March to October 2013). One-half of the patients maintained targeted BSAS scores <1 for the full duration of TTM (The literature suggests the positive impact of TTM on patient outcomes can be maximized with shivering prevention . Current"} +{"text": "Ebstein's anomaly consists of varying degrees of tricuspid dysplasia and displacement into the right ventricular (RV) cavity, along with changes in ventricular function predominantly affecting the RV. Measuring alterations in contraction pattern and dyssynchrony may provide insights into ventricular performance in this disease. We sought to quantify right and left ventricular (RV and LV) deformation and dyssynchrony in a cohort of patients with Ebstein's anomaly in comparison with normal controls using cardiovascular magnetic resonance myocardial feature tracking (CMR-FT).Twenty-six patients with uncorrected Ebstein's anomaly and 10 normal controls were prospectively studied. LV and RV global longitudinal myocardial strain (GLSLV and GLSRV) and time to peak strain (TPKLV and TPKRV) were calculated from the 4-chamber cine CMR images. Intraventricular dyssynchrony (IntraVD) was calculated as the difference between the segments with the longest and shortest TPK divided by the global TPK value of the respective ventricle: (IntraVD) = TPKlongest-TPKshortest/TPK global. The ratio of global TPKRV and TPKLV was measured as interventricular dyssynchrony (InterVD).Mean patient age was 28 \u00b1 15 . GLSRV was significantly reduced in patients (-15.7 \u00b1 5.2) as compared to controls , while there was no significant difference in GLSLV or global TPKRV and TPKLV between patients and controls ."} +{"text": "There are errors in S10 Figmean annual runoff are shown. Statistics describing annual variability in runoff in these scenarios is shown in Table 2 and illustrated graphically for 4FRI scenario in S8 Fig.Effects of increasing (a) pace and (b) extent of thinning treatments of ponderosa pine forests in Salt-Verde watersheds on increases in mean annual runoff (acre-feet/year). In (a) total area thinned is held constant at 301,000 ha to show influence of increasing the area thinned per year. In (b) duration of thinning treatments is held constant at 25 years to show influence of increasing the total area thinned across the scenario. In order to illustrate scale effects, only increases in (TIFF)Click here for additional data file."} +{"text": "Surgical Site Infections (SSI) are the most frequent healthcare-associated infection in developing countries with incidence rates up to 30%. Prevention of SSI is complex and faces multiple challenges, especially in resource limited settings. Since 2013, WHO in collaboration with Johns Hopkins University, has been leading the Surgical Unit Safety Program (SUSP) in 5 African hospitals, one of which is the AIC Kijabe Hospital, a private teaching facility in rural Kenya.The SUSP intervention incorporated a bundle of 6 SSI prevention measures selected as priority by the site leaders embedded within adaptive work to improve the safety culture. Implementation was achieved with local adaptation and creation of tools for advocacy, training, leadership and front-line staff and patient engagement. SSI surveillance and process measures evaluation reflecting the intervention have been carried out throughout the study period for about 18 months, based upon a WHO protocol using standardized definitions.Preliminary data show that the crude SSI rate significantly decreased from 9.3% (38/406 patients) before to 5% (18/353) post-intervention. Patients receiving post-operative antibiotics decreased from 50% to 26%; hair removal with shaving decreased from 25% to 2% of patients; theatre discipline improved with a drop in the average number of door openings per operation from 55 to 40.Implementation of a SSI prevention bundle and creation of a safety climate was successfully achieved at AIC Kijabe Hospital with tangible reductions in SSI rates and improvement of process measures. Local production of alcohol-based products for surgical hand and surgical site preparation was an innovative approach to overcome availability and cost barriers. Engagement of senior staff coupled with structured management of patient safety programs helped inculcate these concepts into the local culture and practice and are crucial for the long term sustainability.None declared."} +{"text": "Quantitative MR myocardial strain analysis is typically performed using rectilinear or Cartesian grid tagging, and regional contractility is visually assessed by the deformation of the grid1. However, it is difficult to visually isolate circumferential and radial components of displacement and strain from parallel straight lines on short axis images. This study evaluates the potential of a polar coordinate tagging system2 for quantification of circumferential myocardial displacement in a variety of clinical conditions.33 subjects including 12 patients with congenital heart disease (CHD), 11 with cardiomyopathy (CM) and 10 healthy volunteers (HV) underwent cardiac SSFP cine and myocardial tagging in the mid-ventricular short axis plane with grid tags (line separation 5-7 mm), circular tags (5 mm separation) and radial tags . Visual assessment of circumferential and radial displacement was performed by two observers for each of the six mid short axis segments. Scores were assigned for: overall tag quality , strain , confidence in the findings and ease of interpretation . Quantitative analysis of global and segmental circumferential strain was performed using a semi-automated tool previously described3.Healthy volunteers Figure had the Polar tagging has advantages for the visual and quantitative assessment of myocardial strain. Compared to rectilinear tagging, radial tags are easier to interpret for isolation of circumferential and radial components of myocardial motion. Overall tag quality, strain, confidence in assessment and ease of interpretation of the image were highest in healthy volunteers, second highest CHD patients and lowest in CM patients.n/a."} +{"text": "We consider parks in a landscape context (including surrounding 30 km) and evaluate both mean and inter-annual variation in 25 biologically relevant climate variables related to temperature, precipitation, frost and wet day frequencies, vapor pressure, cloud cover, and seasonality. We also consider sensitivity of findings to the moving time window of analysis . Results show that parks are overwhelmingly at the extreme warm end of historical temperature distributions and this is true for several variables . Precipitation and other moisture patterns are geographically more heterogeneous across parks and show greater variation among variables. Across climate variables, recent inter-annual variation is generally well within the range of variability observed since 1901. Moving window size has a measureable effect on these estimates, but parks with extreme climates also tend to exhibit low sensitivity to the time window of analysis. We highlight particular parks that illustrate different extremes and may facilitate understanding responses of park resources to ongoing climate change. We conclude with discussion of how results relate to anticipated future changes in climate, as well as how they can inform NPS and neighboring land management and planning in a new era of change.US national parks are challenged by climate and other forms of broad-scale environmental change that operate beyond administrative boundaries and in some instances are occurring at especially rapid rates. Here, we evaluate the climate change exposure of 289 natural resource parks administered by the US National Park Service (NPS), and ask which are presently (past 10 to 30 years) experiencing extreme (<5 Recent scientific reviews of the US National Park Service (NPS) suggest the agency needs to manage its parks for changing climatic and ecological baselines in a landscape context Climate change is a principal factor driving the imperative for progressive management aimed at achieving a specified \u2018desired future condition\u2019 (DFC) Recommendations to both scale up and consider changing baselines n\u200a=\u200a289), including a 30 km buffer around each park\u2019s boundary Our analyses were performed for all natural resource parks considered by the NPS Inventory & Monitoring Program\u2019s landscape dynamics monitoring project, NPScape (2 at the Equator and 2000 km2 at 70\u00b0N latitude) for each month \u00d7 year, 1901\u20132012. Although this dataset is spatially coarse, at least relative to the size of some parks , it offers for all NPS geographies the highest spatiotemporal resolution of observed climate over the 20th and 21st centuries. We selected for analysis monthly averages of daily temperature , percentage cloud cover, and vapor pressure (haP), as well as total monthly precipitation (mm) and monthly frequencies of frost days and wet days (rain days per month). We used the monthly climate variables to calculate a series of biologically meaningful variables, including 19 standard bioclimatic variables Gridded climate data were obtained from the Climatic Research Unit (CRU) high-resolution time series version 3.21 (TS 3.21) Although correlations exist among some of these variables, we include the full suite in our analysis because the relevance of individual climate variables can vary dramatically by park resource . As such, the elimination of certain variables due to high statistical correlations would adversely restrict the value of these analyses for park interpretation. Furthermore, the data presented here are percentiles calculated from HRV (see below), not the raw climate variables. Hence, whether variables are correlated is not simply a question of correlation at one point in time; it is a complex question of how sensitive correlations are across the entire 1901\u20132012 period of analysis, interacting with the moving time window of summarization.For each biologically relevant variable, over the entire time series (1901\u20132012), we used three moving windows to calculate a series of running means and standard deviations (SD). Hereafter we refer to these as \u2018moving window means\u2019 and \u2018moving window standard deviations\u2019. These statistical distributions are what we use to estimate HRV. For example, with the 10 year window, we calculated the mean and SD for 103 windows to create the HRV distribution. The three windows were designed to encompass both near- and long-term management and planning considerations, as well as important climatic periods and cycles. In the NPS, many implementation plans have short horizons (<10 years), while strategic plans forecast out 10 to 20 years th percentile for the most recent 10 year moving window of annual mean temperature signifies that the value of this climate variable during this time period was greater than 90% of all annual mean temperature 10 year moving window values). Hereafter we refer to these estimates as \u2018recent percentiles\u2019.For each variable, moving window size, and summary statistic , we calculated the area-weighted mean for each park, based on the spatial intersect of park areas of analysis with the CRU lattice. Using processing logic contained in the NPScape climate grid analysis toolset We then averaged the recent percentiles of the most recent 10, 20, and 30 year moving windows and computed the maximum difference in percentile (max \u0394) among windows; this resulted in \u2013 for each park, variable, and summary statistic \u2013 both an overall measure of recent climate change exposure with respect to HRV, and an estimate of how sensitive that measure was by comparing the different moving window sizes. Note that our measure of variability (moving window SD) does not reveal any information regarding extreme events, such as droughts, heat waves, and storms, which can also impact park resources An example of these steps with annual mean temperature (Bio1) is shown for Grand Canyon National Park . In thisth percentile (low) or greater than the 95th percentile (high), and all intervening percentiles as \u2018average\u2019. We tallied the total number of temperature and precipitation variables that met either of these conditions and categorized each park as extreme low or high on temperature and precipitation if at least one variable in each class was low or high. Parks were considered \u2018mixed\u2019 if they possessed low and high estimates of temperature, or low and high estimates of precipitation. Then, considering only the low and high variables, we calculated the maximum value of their max \u0394\u2019s to provide a maximum estimate of sensitivity to window size. Given the thresholds used to define \u2018extreme\u2019, the maximum possible value for max \u0394 is 15%.Given the number and complexity of variables considered in our analysis, we performed two multivariate analyses in an effort to produce more integrated summaries of recent percentiles. Principal component analyses were used to identify a small set of uncorrelated axes for each combination of summary statistic and measure (mean percentile and max \u0394 percentile). We also conducted a threshold-based classification analysis of mean percentiles, on both the moving window mean and SD, to characterize which parks were extreme on their annual, monthly, or quarterly temperature or precipitation variables. In this classification analysis, as well as in other evaluations of individual climate variables, we define \u2018extreme\u2019 as either less than the 5For a subset of parks spanning the contiguous US, we conducted another sensitivity analysis using local weather station data to examine the degree to which CRU results differ from those obtained using direct climate observations. For local station data, we identified 18 United States Historical Climatology Network stations located within park boundaries that similarly span the 1901\u20132012 period of analysis Lastly, as part of the CRU-based classification analysis, for each climate variable we used a Monte Carlo simulation to test whether the number of extreme parks was significantly different than random expectations. To conduct this test, we first randomly selected 100000 samples of size 289 from a uniform distribution to develop a sampling distribution of the expected number of extreme parks under the null hypothesis . Using that sampling distribution, we then computed the probability of obtaining the observed number of extreme parks for each climate variable.th percentile in 99% of parks), while recent percentiles associated with the annual number of frost days (Frs12) are correspondingly quite low are greater than the 95th percentile), with low sensitivity to moving window size (125 parks (43%) have a maximum difference in percentile that is less than 5%). This general pattern holds for parks from the Pacific Islands to Alaska to the East Coast of the US.Focusing on two common climate variables, annual mean temperature (Bio1) and annual precipitation (Bio12), geographic distributions of recent percentiles are illustrated for moving window means and stanth to 75th percentiles and 233 parks (81%) are within the 5th to 95th percentiles. Hence, only 56 parks (19%) are extreme (<5th percentile or >95th percentile) with respect to annual precipitation.Corresponding results for annual precipitation are rathth to 75th percentiles and 275 parks (95%) are within the 5th to 95th percentiles. Annual precipitation is similar: 188 parks (65%) are within the 25th to 75th percentiles and 277 parks (96%) are within the 5th to 95th percentiles. Hence, only about 10 parks are extreme with respect to either annual mean temperature or annual precipitation, and these parks differ between the two variables triggered by any one of the temperature or precipitation variables, most parks are presently dominated by extreme high temperatures (235 parks (81%) are higher than the 95th percentile), and \u2013 independent of temperature \u2013 some also by either extreme high precipitation (78 parks (27%) are higher than the 95th percentile) or low precipitation (43 parks (15%) are lower than the 5th percentile) . Excludicentile) .The number of parks that are extreme high or low on each temperature or precipitation variable considered in the classification analysis are reported in th percentile) or low (<5th percentile) on temperature or precipitation variables , Bio1 and 10 , and Bio11 Management and planning decisions will be greatly informed by an overall assessment of vulnerability that integrates the present climate change exposure analyses with others that consider both the sensitivity and adaptive capacity of park resources to climate change a priori knowledge of how major climate drivers have changed in recent time. For resources influenced by climate variables that are presently well within the bounds of HRV, parks might decide that limited funding should be redirected to study other resources that are sensitive to variables approaching the limits of HRV. Parks might also decide to monitor variables with recent extreme percentiles to assess rates of change and detect when and where they become \u2018novel\u2019 with respect to 1901\u20132010 HRV. Beyond applications related to monitoring and management, results offer park interpreters scientific information that may be translated and communicated to the public.Our measures of climate change exposure support broad-scale vulnerability assessments in the NPS, but they also help individual parks understand and interpret which of their major climate drivers are beginning to approach the limits of 1901\u20132012 HRV. Such insights facilitate discussion of how climate change may impact diverse park resources and values , which are often sensitive to different measures of exposure, but they are not intended to replace more detailed analyses required for site-level management and planning within park boundaries. Many parks are in areas of complex topography and indeed this heterogeneity has important implications for climate adaptation In approaching the 100-year anniversary of its creation in 2016, the NPS is poised to enter its next century of natural resource stewardship and science. The new century brings new challenges in terms of stewarding park resources in the face of environmental drivers that operate beyond park boundaries. Climate change further challenges us to develop new, ecologically viable desired conditions to guide the preservation of park resources in this new era of change. While such challenges remain paramount, more integrative research and education in the climate and landscape arenas will contribute to solutions.Appendix S1Mean percentile and maximum difference in percentile (in parentheses) for moving window means: annual mean temperature (Bio1), mean diurnal range (Bio2), isothermality (Bio3), temperature seasonality (Bio4), maximum temperature of the warmest month (Bio5), and minimum temperature of the coldest month (Bio6).(PDF)Click here for additional data file.Appendix S2Mean percentile and maximum difference in percentile (in parentheses) for moving window means: temperature annual range (Bio7), mean temperature of the wettest quarter (Bio8), mean temperature of the driest quarter (Bio9), mean temperature of the warmest quarter (Bio10), and mean temperature of the coldest quarter (Bio11).(PDF)Click here for additional data file.Appendix S3Mean percentile and maximum difference in percentile (in parentheses) for moving window means: annual precipitation (Bio12), precipitation of the wettest month (Bio13), precipitation of the driest month (Bio14), precipitation seasonality (Bio15), precipitation of the wettest quarter (Bio16), precipitation of the driest quarter (Bio17), precipitation of the warmest quarter (Bio18), and precipitation of the coldest quarter (Bio19).(PDF)Click here for additional data file.Appendix S4Mean percentile and maximum difference in percentile (in parentheses) for moving window means: mean annual percentage cloud cover (Cld1), cloud seasonality (Cld4), vapor pressure of the warmest quarter (Vap18), annual number of wet days (Wet12), number of wet days of the warmest quarter (Wet18), and annual number frost days (Frs12). NA\u2019s associated with Frs12 indicate that the variable is undefined .(PDF)Click here for additional data file.Appendix S5Mean percentile and maximum difference in percentile (in parentheses) for moving window standard deviations: annual mean temperature (Bio1), mean diurnal range (Bio2), isothermality (Bio3), temperature seasonality (Bio4), maximum temperature of the warmest month (Bio5), and minimum temperature of the coldest month (Bio6).(PDF)Click here for additional data file.Appendix S6Mean percentile and maximum difference in percentile (in parentheses) for moving window standard deviations: temperature annual range (Bio7), mean temperature of the wettest quarter (Bio8), mean temperature of the driest quarter (Bio9), mean temperature of the warmest quarter (Bio10), and mean temperature of the coldest quarter (Bio11).(PDF)Click here for additional data file.Appendix S7Mean percentile and maximum difference in percentile (in parentheses) for moving window standard deviations: annual precipitation (Bio12), precipitation of the wettest month (Bio13), precipitation of the driest month (Bio14), precipitation seasonality (Bio15), precipitation of the wettest quarter (Bio16), precipitation of the driest quarter (Bio17), precipitation of the warmest quarter (Bio18), and precipitation of the coldest quarter (Bio19).(PDF)Click here for additional data file.Appendix S8Mean percentile and maximum difference in percentile (in parentheses) for moving window standard deviations: mean annual percentage cloud cover (Cld1), cloud seasonality (Cld4), vapor pressure of the warmest quarter (Vap18), annual number of wet days (Wet12), number of wet days of the warmest quarter (Wet18), and annual number frost days (Frs12). NA\u2019s associated with Frs12 indicate that the variable is undefined .(PDF)Click here for additional data file."} +{"text": "Here we review zebrafish modeling for two broad groups of inherited conditions that each share genetic and molecular pathways and overlap phenotypically: neurodevelopmental disorders such as Autism Spectrum Disorders (ASD), Intellectual Disability (ID) and Schizophrenia (SCZ), and neurodegenerative diseases, such as Cerebellar Ataxia (CATX), Hereditary Spastic Paraplegia (HSP) and Charcot-Marie Tooth Disease (CMT). We also conduct a small meta-analysis of zebrafish orthologs of high confidence neurodevelopmental disorder and neurodegenerative disease genes by looking at duplication rates and relative protein sizes. In the past zebrafish genetic models of these neurodevelopmental disorders and neurodegenerative diseases have provided insight into cellular, circuit and behavioral level mechanisms contributing to these conditions. Moving forward, advances in genetic manipulation, live imaging of neuronal activity and automated high-throughput molecular screening promise to help delineate the mechanistic relationships between different types of neurological conditions and accelerate discovery of therapeutic strategies.Zebrafish are a unique cell to behavior model for studying the basic biology of human inherited neurological conditions. Conserved vertebrate genetics and optical transparency provide Therefore these genes may be associated with earlier onset cases of CMT, which can occur anywhere between birth and adulthood is a large gene and mouse Shank3 knockout models exhibit variable phenotypes depending on whether a mutation is expressed in a predominant isoform . Because brain regions mediating human cognitive symptoms may lack parallels in zebrafish, modeling has focused on embryonic development and disorder comorbidities that still allow testing of etiological theories for these developmental disorders. These studies have paved the way for comprehensive functional assessments that link cellular- and circuit-level phenotypes to changes in behavior.CHD8 mutations was shown to have a dose-dependent affect in producing macrocephaly (knockdown) and microcephaly (overexpression) that supports a role for KCTD13 copy number variants causing head size phenotypes interacts with canonical and non-canonical Wnt signaling and zdisc1 morphants and mutants exhibit disorganized axon tracts at larval stages that can be rescued by activating Wnt signaling mutants, recapitulating a mutant mouse Cntnap2 model and suggesting that in the absence of cntnap2ab larvae fail to maintain inhibitory neuronal populations. This inhibitory decrease was shown to increase seizure susceptibility in \u2212/\u2212cntnap2ab mutants by applying a GABA receptor antagonist signaling in Fragile X Syndrome knockout models in mice, a zebrafish fmr1 knockdown model showed behavioral deficits that were ameliorated when treated with an mGluR inhibitor and shank3a exhibit hyposensitivity with concomitant neuronal cell death and morphological changes in skin innervating sensory neurons knockdowns and sodium channel, voltage gated, type II, alpha (scn1lab) knockouts display hyper-excitable phenotypes that are characterized by extended or disorganized swimming with epileptiform-like activity in the brain , HSP, SMA or spinal muscle atrophy (SMA), ALS, as well as some forms of CATX which have phenotypic and mechanistic overlap , a molecular motor for transporting microtubule-mediated cargo, have been reported in both CMT2 encoding atlastin-1 cause an early onset form of HSP are the primary cause of axonal degeneration in Charcot-Marie-Tooth Neuropathy (CMT2), and MFN2 has been implicated in the fusion and transport of mitochondria in neurons , and early lethality by 1 year of age cause a spectrum disorder classified as Costeff syndrome and includes optic atrophy, ataxia, extra pyramidal dysfunction, and increased urinary excretion of 3-methylglutaconic acid morphants show decreases in PC progenitors while cwf19-like 1 (cwf1911) morphants show disruptions in overall hindbrain morphology mutations that cause Spinocerebellar ataxia type 13 mutations rarely covert carrier cells into cancer cells unless in a p53 mutant background (Kaufman et al., It is also common, though not necessarily well-represented in the literature, for knockout models to lack phenotypes. In a zebrafish study that generated mutant lines with 32 distinct lesions in 24 genes, most of the mutants exhibit a wild-type phenotype (Kok et al., in situ hybridization data and determine the relative enrichment of gene expression in brain regions and spinal cord (Figure Both developmental and degenerative diseases are associated with dysfunction in specific regions of the CNS Figure . None-th0 mutant models of inherited neurological disorders (Jao et al., 0 mutants (Bernier et al., 0 generation. Combined with a large repertoire of behaviors that develop within 5 days of fertilization and diverse transgenic lines for rapid screening of cellular phenotypes, F0 CRISPR zebrafish mutagenesis promises to contribute significantly to our understanding of genetic variation linked to nervous system disorders.Because of the large number of rare mutations linked to inherited nervous system diseases, an important frontier for disease modeling is strategies that leverage to make stable Fin vivo or create conditional mutant alleles, several groups have also recently pioneered the use CRISPR/Cas9 for more sophisticated genome engineering. One novel strategy effectively \u201cenhancer traps\u201d a gene of interest by replacing the last exon with an engineered last exon encoding the C-terminal end of the coding sequence in frame with a cleavable p2A sequence followed by a fluorescent reporter (Li et al., Shank3 autism model, rescuing the mutant Shank3 protein in the adult was sufficient to rescue social interactions and excessive grooming but not anxiety and repetitive motor behaviors (Mei et al., To model specific patient missense mutations and to better understand the basic biology of disease genes by tagging them in vivo calcium imaging with genetically encoded calcium indicators- (GECIs; Chen et al., The development of approaches that enable monitoring of behavior-relevant neural circuits in the intact larvae will be a boon for modeling inherited neurological disease (Ahrens et al., In addition to genetic screens, due to their small size and their tendency to absorb drugs added directly to the water, zebrafish larvae are uniquely amenable for high-throughput drug screens (Rihel et al., The continued expertise and innovations of zebrafish genetic and developmental tools will continue to make zebrafish an attractive neurological disease model. Going forward, combining standard assays that allow comparisons across models with newer approaches would be ideal to enable a better understanding of the molecular, cellular, and systems-level groupings of these neurological conditions. Finally, zebrafish will certainly contribute to consortia of research groups that use multiple animal models for discovering essential molecular to circuit level mechanisms underlying neurological disease.RAK conducted all meta-analyses, made all figures and wrote introductory and developmental disorder sections and conducted extensive edits to coordinate sections. AJA wrote the bulk of the neurodegenerative section with the exception of the ataxia section that was written by EB. DMJ wrote comorbidity section that centered on GI distress in developmental disorders. QY wrote the lessons learned section. JED conceived the scope of the review, wrote frontiers section and helped RAK to conduct extensive edits to coordinate sections.This work was supported by support from the National Institutes of Health Institute of Mental Health R03MH103857 to JED and from the Institute of General Medicine, an IMSD graduate fellowship from parent grant R25GM076419 to DMJ.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "To examine both migraine and pulmonary hypertension (PH) we developed a hypoxic mouse model. Under hypoxic conditions (four weeks at 10% O2) mice develop typical symptoms of PH, characterized by an increased muscularization of arterial blood vessels in the lung. The vessel remodeling can be prevented by the chronic application of 5-HT2B receptor antagonists. We found that hypoxic mice also develop increased sensitivity towards the 5-HT2 receptor agonist meta-Chlorophenylpiperazine (mCPP). In contrast to the control group (normoxic mice kept at 20% O2) at low doses of 1 \u00b5g / kg body weight, mCPP triggers plasma protein extravasation (PPE) in the dura mater in hypoxic mice. Dural PPE is a quantifiable indicator of migraine-like events in animal models.The sensitization towards mCPP may coincide with structural remodeling processes in arterial blood vessels of the dura mater, possibly exhibiting similarities to vascular alterations in the lung. A prerequisite in the investigation of vascular alterations in the dura mater is a thorough understanding of the normal organization of dural vasculature in mice and of the extent of its normal biological variance.Histological examinations of the length of dural vessels were performed to quantify and statistically analyze inter- and intraindividual differences.Interindividual differences: The arteriole total lengths are 15% far from the arithmetic mean.Intraindividual differences: The difference in the length of arterioles represents 12% of the total length of the arterioles.On the basis of these results examinations of dural vessel of hypoxic mice can be investigated.No conflict of interest."} +{"text": "Patients with repaired tetralogy of Fallot (TOF) frequently have right bundle branch block. However, the contribution of cardiac dyssynchrony to dysfunction remains controversial. To better understand this phenomenon and ultimately study therapies, we developed a method to quantify left (LV), right (RV) and inter-ventricular cardiac dyssynchrony using standard cine CMR.30 patients with repaired TOF and 17 healthy controls underwent cine CMR. Patients were imaged twice to assess inter-test reproducibility. Circumferential strain vs time curves were generated with a custom feature tracking algorithm for 12 LV and 12 RV segments in 4-7 slices encompassing the ventricles. For each segment, the temporal offset (TO) of the strain curve relative to a global reference curve derived from the controls was calculated and expressed as a percent of the cardiac cycle. The intra-ventricular dyssynchrony index (DI) for each ventricle was computed as the standard deviation (SD) of the TOs (more dyssynchrony increases the SD). The inter-ventricular DI was calculated as the difference in median RV and median LV TOs. Regional dyssynchrony was quantified in 3 LV and 3 RV regions using median TOs.Compared to controls, patients with repaired TOF had a greater LV, RV and inter-ventricular DI Figure . The grePatients with repaired TOF suffer from left, right and inter-ventricular cardiac dyssynchrony which can all be quantified from standard cine CMR with good inter-test reproducibility. Future studies need to determine whether these patients may benefit from resynchronization therapy.This work was supported by a National Institutes of Health (NIH) Director's Early Independence Award (1DP5OD012132-01), and NIH grant number KL2 RR033171 from the National Center for Research Resources and the National Center for Advancing Translational Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH."} +{"text": "The correct legend is given below. The article has since been corrected and reposted in the issue.In Figure 1 of the article \u201cPulmonary Fibrosis in Antineutrophil Cytoplasmic Antibodies (ANCA)-Associated Vasculitis: A Series of 49 Patients and Review of the Literature\u201d,Representative high-resolution computed tomography showing typical features of the 3 major patterns of PF associated with AAV. Predominantly basal, subpleural reticular pattern with macrocystic honeycombing lesions in usual interstitial pneumonia (A). Centrilobular and paraseptal emphysema predominating in the upper lobes (B). Ground-glass opacities in a patchy distribution in nonspecific interstitial pneumonia (C), and reticular subpleural changes in the lower lobes, associated with few microcystic lesions suggesting honeycombing (D) in combined pulmonary fibrosis and emphysema syndrome."} +{"text": "Solanum lycopersium L.) is the most widely grown vegetable in the world. It was domesticated in Latin America and Italy and Spain are considered secondary centers of diversification. This food crop has experienced severe genetic bottlenecks and modern breeding activities have been characterized by trait introgression from wild species and divergence in different market classes.The tomato using a custom-made Illumina SNP-panel. Most of the 175 successfully scored SNP loci were found to be polymorphic. Population structure analysis and estimates of genetic differentiation indicated that landraces constitute distinct sub-populations. Furthermore, contemporary varieties could be separated in groups that are consistent with the recent breeding aimed at market-class specialization. In addition, at the 95% confidence level, we identified 30, 34 and 37 loci under positive selection between landraces and each of the groups of commercial variety . Their number and genomic locations imply the presence of some extended regions with high genetic variation between landraces and contemporary varieties.Our work provides knowledge concerning the level and distribution of genetic variation within cultivated tomato landraces and increases our understanding of the genetic subdivision of contemporary varieties. The data indicate that adaptation and selection have led to a genomic signature in cultivated landraces and that the subpopulation structure of contemporary varieties is shaped by directed breeding and largely of recent origin. The genomic characterization presented here is an essential step towards a future exploitation of the available tomato genetic resources in research and breeding programs.The online version of this article (doi:10.1186/1471-2164-14-835) contains supplementary material, which is available to authorized users. Solanum lycopersicum L.) was probably domesticated in Mexico from wild species that originated in the Andean region, although other hypotheses have been also put forward for each K value. (JPEG 723 KB)Additional file 7: Figure S1: Estimation of the optimum number of clusters. Estimation of the optimum number of clusters of tomato accessions according to the analysis of variance of the log-likelihood values of the genotypes based on STRUCTURE and CLUMPP analyses. (XLSX 52 KB)Additional file 9: Table S8: Pairwise estimates of Fst and Nei\u2019s standard genetic distance (Dst) between predefined groups or between groups of tomato accessions as inferred by the Bayesian analysis implemented in the STRUCTURE software. (XLSX 16 KB)Additional file 10: Table S9: Heterogeneity in F-Statistics among loci. (XLSX 11 KB)Additional file 11: Table S10: Candidate loci under positive selection between landraces varieties and the different market-classes of contemporary varieties. (XLSX 10 KB)Additional file 12: Table S11: Marker names and their genomic information. (XLSX 22 KB)"} +{"text": "Circulating strains cluster geographically and belong to at least 5 distinct clades. Mastomys natalensis) is the only known reservoir of LASV. Most human infections result from zoonotic transmission. The very diverse LASV genome has 4 major lineages associated with different geographic locations. We used reverse transcription PCR and resequencing microarrays to detect LASV in 41 of 214 samples from rodents captured at 8 locations in Sierra Leone. Phylogenetic analysis of partial sequences of nucleoprotein (NP), glycoprotein precursor (GPC), and polymerase (L) genes showed 5 separate clades within lineage IV of LASV in this country. The sequence diversity was higher than previously observed; mean diversity was 7.01% for nucleoprotein gene at the nucleotide level. These results may have major implications for designing diagnostic tests and therapeutic agents for LASV infections in Sierra Leone.Lassa virus (LASV) is endemic to parts of West Africa and causes highly fatal hemorrhagic fever. The multimammate rat ( Arenaviridae), the etiologic agent of LF (Lassa fever (LF) belongs to a group of viral hemorrhagic fevers characterized by a febrile syndrome and high case-fatality rates , a natural host and reservoir of this pathogen and high-density resequencing microarrays to detect LASV and amplify fragments of NP, GPC, and L genes. The obtained amplicons were sequenced and compared with previously published sequences from Sierra Leone to obtain a more complete and updated picture of the strains circulating in this country.Mastomys sp. were further identified down to species level by using molecular methods as described previously . Thirteen locations were selected for study in the LF-endemic region of eastern Sierra Leone. The geographic coordinates of the sampling locations and details of rodent trapping methods are available in the online Technical Appendix . Traps wRNA from 10 mg of spleen of each rodent was extracted with TRIzol following the manufacturer\u2019s recommendations. The samples were stored at \u201380\u00b0C.RNA were reverse-transcribed by using the SuperScript III Reverse Transcriptase kit (Life Technologies) according to the manufacturer\u2019s instructions, and RT products were stored at \u201320\u00b0C. Specific oligonucleotide primer pairs were used for the PCR targets of interest at finalThe resequencing pathogen microarray (RPM) analysis was conducted by using Tropical and Emerging Infections microarrays . The RPM-TEI microarray enables detection of 84 biothreat agents, including all lineages of LASV (http://tree.bio.ed.ac.uk/software/figtree).We conducted the sequence alignment using the MUSCLE algorithm implemented in the MEGA 6.0 software package ; Cricetomys sp. (3 [1.4%] rodents); and Mus sp., Praomys sp., and Hylomyscus sp. (1 [0.5%] rodent each).We collected 681 small mammals during the field survey. Of these, we analyzed 214 for this study on the basis of RNA availability at the time of the study Table 2.We screened all samples for LASV by RT-PCR using pan\u2013Old World arenavirus (OWA) primers .In addition, we screened a randomly selected subset of 51 samples , Largo (8 samples), Bumpeh (7 samples), Ngiehun (4 samples), Koi and Yawei (3 samples each), Taiama (2 samples), and Saama (1 sample) . No LASVAll positive samples came from multimammate rats, which is considered the sole vector species for LASV was closely related to that of strains from Barlie . In another example, 1 GPC sequence originating from Liberia (523) clustered with Sierra Lone clade A sequences. In some cases , such unusual clustering patterns may be explained by cross contamination or mislabeling of the samples. They also might result from relative proximity of all sampling sites and inadvertent anthropogenic transfer of rodents. Massive population movements that occurred in Sierra Leone during the 1991\u20132002 civil war could contribute to the process of mixing multimammate rat subpopulations carrying different LASV strains most likely originated from the Yawei village area because they cluster closely. A few other human isolates for which no location information is available also clustered with Yawei isolates on the basis of GPC and L sequences, suggesting their origin in the same area. These sequences were obtained in 2002 from United Nations peacekeepers stationed in this part of Sierra Leone (Recent epidemiologic data show that LF was detected in 10 of 13 districts in Sierra Leone, which suggests that the infection is much more common that previously recognized (Molecular characterization of isolates from a wider geographic area of the country is needed to fully understand the diversity of the LASV strains in Sierra Leone and its impact on disease distribution and risk. Such information would be useful for developing efficient viral detection technologies, for example, enabling design of PCR primers and antibodies specific for a broad range of LASV types. These diagnostic tests are extremely relevant to disease surveillance and monitoring and evaluation of interventions to prevent primary LASV infection in humans. More extensive information about sequence diversity affecting the antigenicity of the virus or the function of its RNA-dependent RNA polymerase may help in the development of vaccines and antiviral drugs. It will also lead to deeper understanding of the biology and pathogenesis of LASV.Rodent trapping procedures; coordinates of sampling locations; and list of all analyzed samples."} +{"text": "Figure S1 is incorrect. Please view the correct The seventh sentence of the second paragraph of the Discussion section is also incorrect. The correct sentence is: Only sample 74 had a serine (S), polar neutral, at position 429, while the other samples had phenylalanine (F), which is neutral and hydrophobic.Figure S1Average temporal distribution of precipitation and suspected or confirmed dengue cases.(TIF)Click here for additional data file."} +{"text": "To summarize a first stage of research on implementation of a peer leader suicide prevention program by testing the utility of a method for tracking and reporting each school's success in retaining and preparing Peer Leaders.Peer leader programs that prepare opinion leaders to spread healthy practices through their social networks reduce high-risk sex behaviors and show promise in preventing adolescent substance use and suicidal behavior. However, knowledge of implementation processes is very limited. To address this limitation, we drew on the Stages of Implementation Completion (SIC) framework to measure a key phase of peer leader implementation.40 high schools were randomly assigned to either immediate Sources of Strength (n = 20) or waitlist (n = 20). The schools were underserved by mental health services and over-represented by youth at high risk for suicide . In the 20 implementing schools, 656 students (18-71 per school) received Peer Leader (PL) training. Adult mentors facilitated PL meetings to reinforce program concepts and help PLs plan and execute activities to spread healthy coping practices. Using a framework derived from the Stages of Implementation Completion (SIC), school reports of PL meeting dates/attendance were codified as indices of school success in retaining and preparing PLs. Surveys with 5,712 students showed wide school-level variation in success of PLs in reaching their classmates with the prevention concepts. In analytic models examining predictors of school-level exposure, a higher proportion of student population trained as PLs and greater retention of PLs predicted higher population exposure to the prevention program, congruent with diffusion of innovations theory, whereas frequency of meetings did not.Identified an efficient method (derived from the SIC) for assessing a school's success in preparing/retaining peer leaders. This approach shows promise in providing schools actionable data to increase impact of peer-led programs.NIH R01MH091452."} +{"text": "Although the in vivo anti-tumor efficacy of cannabinoids is mimicked in continuously cultured cancer cells in vitro, cannabinoid potency for direct elicitation of apoptosis in cancer cells is far lower, indicating that other mechanisms (perhaps other cell types within the tumor) are involved in vivo. We have recently obtained evidence that: 1) CB2 agonists mediate inhibition of primary tumor growth and metastasis in vivo, 2) significant infiltration of TAMs occurs within the developing tumor in this murine model, 3) administration of a CB2 agonist increases populations of pro-inflammatory M1 macrophages in both the primary tumor and in the spleen of tumor bearing mice, and 4) a concurrent increase in the proportion of CD8+ cytotoxic T lymphocytes is also observed within the primary tumor upon CB2 agonist treatment.In human breast cancers, tumor infiltration by tumor associated macrophages (TAMs) correlates with multiple markers of poor prognosis: higher tumor macrophage counts are associated with higher tumor grade, higher tumor vascular density, and reduced overall survival. TAMs sesentation. Recent"} +{"text": "Acute aortic dissection is the most common life-threatening vascular disease, with sudden onset of severe pain and a high fatality rate. Clarifying the detailed mechanism for aortic dissection is of great significance for establishing effective pharmacotherapy for this high mortality disease. In the present study, we evaluated the influence of biomechanical stretch, which mimics an acute rise in blood pressure using an experimental apparatus of stretching loads in vitro, on rat aortic smooth muscle cell (RASMC) death. Then, we examined the effects of azelnidipine and mitogen-activated protein kinase inhibitors on mechanical stretch-induced RASMC death. The major findings of the present study are as follows: (1) cyclic mechanical stretch on RASMC caused cell death in a time-dependent manner up to 4 h; (2) cyclic mechanical stretch on RASMC induced c-Jun N-terminal kinase (JNK) and p38 activation with peaks at 10 min; (3) azelnidipine inhibited RASMC death in a concentration-dependent manner as well as inhibited JNK and p38 activation by mechanical stretch; and (4) SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor) protected against stretch-induced RASMC death; (5) Antioxidants, diphenylene iodonium and tempol failed to inhibit stretch-induced RASMC death. On the basis of the above findings, we propose a possible mechanism where an acute rise in blood pressure increases biomechanical stress on the arterial walls, which induces RASMC death, and thus, may lead to aortic dissection. Azelnidipine may be used as a pharmacotherapeutic agent for prevention of aortic dissection independent of its blood pressure lowering effect. With the rapid progress of population aging in most developed countries, the number of patients with atherosclerosis has remarkably increased; this is becoming an extremely serious problem requiring urgent attention It is well recognized that aortic dissection occurs when a small tear generated in the inner aortic wall extends along the wall of the aorta and causes blood to flow between the layers of the tunica media and adventitia of the aorta, forcing the layers apart. Despite the pathophysiological interpretation, the detailed mechanism for aortic dissection still remains unclear. Various efforts have been recently made to clarify the possible reasons for aortic dissection. Collins et al. reported that progressive loss of smooth muscle cells is observed in the specimens of acute aortic dissection characterized by aortic medial degeneration Azelnidipine has been approved for the treatment of patients with hypertension and is extensively used in developed countries In the present study, we used an experimental apparatus of stretching loads in vitro that can simulate sudden increases of blood pressure and observed RASMC death induced by biomechanical stretch. Furthermore, we investigated whether azelnidipine inhibited stretch-induced VSMC death. The effect of azelnidipine on changes in intracellular signaling by biomechanical stretch was also examined to provide a possible mechanism by which azelnidipine may be used as a pharmacotherapeutic agent for the prevention of aortic dissection independent of its blood pressure lowering effect.The study design was approved by an ethics review board of guidelines for the use of laboratory animals of Nara Medical University (No. 11011) and this study conducted in accordance with the guide for the Care and Use of Laboratory Animals as adopted and promulgated by the United States National Institutes of Health.2 in a humidified incubator. RASMCs were used for experiments between the third and sixth passages. The cells were cultured in collagen I-coated (70 \u00b5g/cm2) silicon chambers . When the cell confluency in culture was estimated to be 70\u201380%, the medium was replaced with unsupplemented DMEM. The cells were further cultured for 24 h and then subjected to cyclic mechanical stretch for a given time period using the computer-controlled mechanical Strain Unit . After cyclic stretch, the medium was replaced with DMEM-containing 0.1% FBS. For western blot analysis, a portion of the RASMCs were lysed immediately after stretch stimulation and lysate proteins were collected in the manner described earlier RASMCs were isolated from the thoracic aorta of 8-week-old male Sprague\u2013Dawley rats by enzymatic digestion, as previously described Materials were purchased from Wako (Kyoto) or Nacalai Tesque (Kyoto) unless stated otherwise. Azelnidipine (CS905) was from Daiichi Sankyo, Inc (Osaka). The antibodies used for western blot analyses were as follows: anti-phospho-SAPK/JNK (Thr183/Tyr185) antibody and anti-phospho-p38 MAP kinase (Thr180/Tyr182) antibody were purchased from Cell Signaling Technology, while ECL and ECL plus systems were purchased from GE Healthcare. Collagen I was purchased from Nippon Meat Packers, Inc. (Osaka). All chemical compounds were dissolved in dimethyl sulfoxide (DMSO) at final concentration less than 1% except for special notification.t-test was used to determine significant differences in multiple comparisons. A P value<0.05 was considered to be significant.All experimental values were expressed as mean \u00b1 standard deviation. Analysis of variance along with subsequent Student\u2019s The effect of cyclic mechanical stretch on the viability of RASMCs was firstly examined by measuring MTT reduction and LDH released. The effects of cyclic mechanical stretch on the activation of JNK and p38 (members of MAP kinases family proteins) were assessed by western blot analysis . RASMCs In order to clarify the possible mechanisms of how cyclic mechanical stretch influences cell death, the following two experiments were undertaken.The effects of azelnidipine on cyclic mechanical stretch-induced activation of JNK and p38 in RASMCs were firstly examined and the results are shown in It has been reported that azelnidipine has the effects of anti-inflammation and antioxidant in mouse aneurysmal models The major findings of the present study are as follows: (1) cyclic mechanical stretch of RASMC caused cell death in a time-dependent manner up to 4 h; (2) cyclic mechanical stretch of RASMCs induced JNK and p38 activation with peaks at 10 min; (3) azelnidipine, a calcium channel blocker, inhibited the activation of JNK and p38 by cyclic mechanical stretch in a concentration-dependent manner; and (4) azelnidipine and JNK or p38 inhibitors protected against stretch-induced RASMC death; (5) Antioxidants, DPI and tempol failed to inhibit stretch-induced RASMC death.In this work, we recall the assumption that acute biomechanical stretch applied to cultured VSMCs in vitro simulating a sudden increase in blood pressure resulted in VSMC death that led to aortic dissection. As shown in Azelnidipine is a calcium channel antagonist (blocker) that has been applied extensively to the treatment of patients with hypertension all over the world. In the present study, we found that azelnidipine inhibited RASMC death induced by cyclic mechanical stretch . Under tAmong MAP kinases, JNK and p38 were recognized to be related to cell death or apoptosis We have reported in the previous study that p38 and JNK are oxidative stress sensitive In conclusion, azelnidipine inhibited RASMC death induced by acute cyclic mechanical stretch (originating from a simulated increase in blood pressure in vitro). JNK and p38 in RASMCs were activated by cyclic mechanical stretch; however, the activation was inhibited by azelnidipine. Similar to azelnidipine, pharmacological inhibition of JNK and p38 activation by mechanical stretch suppressed cyclic mechanical stretch-induced RASMC death. It is expected that the mechanism of acute aortic dissection will be clarified from further study of the fate of VSMCs by acute cyclic mechanical stretch. Azelnidipine may be an alternative candidate for prevention of acute aortic dissection independent of its blood pressure lowering effect."} +{"text": "PGR, ABCB1, ABCG2, GSTT1, GSTM1, GSTP1, ATM, TP53 and ATP7B genes. Ten genetic modifications were significantly associated with the risk of developing ovarian carcinoma in at least one of the groups under study. PGR gene polymorphisms\u2019 impact on ovarian cancer risk was specific only for the group of the BRCA1 mutation carriers, which proves the difference in the modulation of ovarian cancer risk between sporadic and hereditary malignancies, including the breast-ovarian cancer group (as a cancer-prone group). The analyses showed also the importance of ATP7B gene in ovarian carcinogenesis, both studied variants of which significantly modulated the ovarian cancer risk in three out of four groups. Cumulative risk analysis revealed 3 unfavorable variants that significantly increased the risk of developing ovarian cancer, and also two favorable genotypes which protected against ovarian cancer.Single nucleotide polymorphisms modulate the risk of developing ovarian cancer during lifetime. In this study we analyzed 12 polymorphic variants and 2 deletions in Survival analysis for carriers of favorable versus unfavorable genotypes emphasized the importance of regulation of the cell cycle and active transport of xenobiotics during paclitaxel/cisplatin chemotherapy. The unfavorable variants could facilitate carcinogenic process and once their carriers developed malignancy, their chances of survival were smaller. Our analyses also showed a strong gene-dosage effect with the decrease of progression-free survival for the carriers of two unfavorable genetic factors."} +{"text": "Scientific Reports5: Article number: 1007210.1038/srep10072; published online: 07082015; updated: 08262015The Acknowledgements section in this Article is incomplete.\u201cRM acknowledges the Academy of Finland for support within the FiDiPro scheme.\u201dshould read:\u201cRM acknowledges the Academy of Finland for support within the FiDiPro scheme. We acknowledge financial support of the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of the University of Potsdam.\u201d"} +{"text": "Hemorrhage in association with microvascular obstruction (MVO) is a new independent predictor of adverse remodeling following acute myocardial infarction (AMI), occurring in ~35% of patients presenting with STEMI , 2. HoweMyocardial hemorrhage was induced in a porcine model of AMI by direct intracoronary injection of collagenase (col) . AnimalsAt day 1, low T2* values in the infarct region confirmed the presence of myocardial hemorrhage in the collagenase groups 2 and 3 whereas group 1 was non-hemorrhagic. Infarct size was significantly greater in group 3 compared to group 1 at all time points beyond the effects of the initial ischemic insult. Thus, hemorrhage actively contributes to the tissue remodeling processes during infarct healing. A mechanistic view of the consequences of hemorrhage post-AMI will potentially lead to better management and care of the high-risk STEMI patient population.We acknowledge funding support from the Heart & Stroke Foundation of Canada, GIA award #000334, and the D+H Sunnybrook Research Institute (SRI) Summer Student Program."} +{"text": "Efficient neutralization of HIV is a primary goal both for therapeutic and prophylactic HIV vaccines based on induction of neutralizing antibodies (NAbs) , 2. NeutAnti-HIV IgG antibodies 2F5 and 2G12, switched back to IgM isotype, showed increased avidity and neutralization efficacy . It woulin vivo in a highly specific way either by secondary immunization with protein antigens or in response to immunization with the newly formed ICs (Rheumatoid factor (RF) is an autoantibody which specifically binds Fc region of IgG , 11. Aparmed ICs , 11. Newrmed ICs .The level of RF was significantly higher in some of HIV-infected individuals compared to control groups \u201322. RFs in vivo? Measurements of RF level both in long-term non-progressors Can neutralization-enhancing RF antibodies (NeRFa) be induced after repeated immunization of humans with recombinant gp120 glycoprotein?(ii)Will the power of gp120 immunogen design \u201331 combi(iii)Could NeRFa help to improve the efficacy of previous and futu(iv)Might induction of NeRFa be a future promising method not only against malaria as suggested in Ref. , but alsStudies , 17 haveRepeated immunization with gp120 glycoprotein might lead to prolonged induction of neutralization-enhancing RF antibodies with a potential to be explored for finding the ways to extend lives of HIV-infected individuals and to stop current HIV pandemic.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In the United Kingdom (UK), major trauma networks became operational in April 2012. Based at Queen Elizabeth Hospital Birmingham (QEHB), supported by the Ministry of Defence and University of Birmingham, the National Institute of Health Research Surgical Reconstruction and Microbiological Research Centre (SRMRC) is one of the few 24/7 UK trauma research centres. Having demonstrated success in delivering time critical studies, collaboration with West Midlands Ambulance Service (WMAS) has resulted in transferring research to the scene of injury, demonstrated by the success of The Brain Biomarker After Trauma Study, \u2018Golden-Hour.\u2019Specialist WMAS staff supported by the Midlands Air Ambulance were trained for \u2018Golden-Hour\u2019 enrolling patients with a traumatic brain injury (TBI) or an Injury Severity Score (ISS)>8. Operating Procedures and consumable packs were developed allowing sampling without delaying patient care. Blood samples obtained by WMAS within one hour of injury are passed at handover to QEHB for processing. A 24/7 research team based at QEHB ensure support and sample transfer from WMAS and are responsible for consequent sampling and consenting.Introducing a 24/7 SRMRC team into both pre-hospital and hospital settings has swiftly embedded research into routine trauma care. Whilst \u2018Golden-Hour\u2019 continues, enrolment remains ahead of predicted target with over 500 samples collected and recruitment continues to improve rapidly as WMAS staff become familiar with the protocol. The study has proved the concept allowing future collaboration and grant applications, potentially resulting in further innovations for the under-researched trauma population.Delivering research pre-hospital within one hour of injury requires a highly motivated team but is achievable. Effective integration between pre-hospital and research teams are paramount for any study to succeed. As trauma care evolves and research infrastructures within trauma networks improve, there is vast potential for further engagement with the goal of delivering evidence based pre-hospital trauma care."} +{"text": "We report the complete sequences of two West Nile virus strains (FDA-Hu02 and NY99) used for the formulation of CBER/FDA RNA reference reagents and lot release panels for use with nucleic acid technology testing. Flavivirus, family Flaviviridae) is the most widely extended arbovirus in the world. WNV transmission involves a bird-mosquito enzootic cycle that can infect humans, horses, and other vertebrates who act mainly as dead-end hosts. WNV appeared for the first time in the Americas in the United States in 1999 and since then it has disseminated extensively within the country and also to other countries on the continent (West Nile virus (WNV) and NY99 (obtained from an infected flamingo in 1999). Cell culture supernatants from the second passage of the NY99 strain and third passage of the FDA-Hu02 strain in Vero cells were used for total RNA extraction using the QIAamp Viral RNA minikit (Qiagen). Reverse transcription reactions, PCR amplification, sequencing of overlapping PCR products, and sequence analysis were performed as described previously .The total lengths of the genomes of the WNV NY99 and FDA-Hu02 strains are 11,029 and 11,030 nucleotides (nt), respectively. The isolate FDA-Hu02 showed 20 nucleotide mutations plus one insertion at position 10,497 compared to prototype NY99; 5 mutations resulted in amino acid substitutions. We found no differences between the nucleotide sequences of the original NY99 isolate (AF196835) and the NY99 isolate cultivated and sequenced in our laboratory. Phylogenetic analysis classified FDA-Hu02 as belonging to genotype WN02, whereas strain NY99 is the prototype of the NY99 genotype (AY646354 and KM083619, respectively.The complete sequence of the WNV strains FDA-Hu02 and NY99 have been submitted to the GenBank under the accession numbers"} +{"text": "Cardiovascular magnetic resonance (CMR) has expanded its role in the diagnosis and management of congenital heart disease and acquired heart disease in children. However, there are limited studies evaluating the role of cardiac magnetic resonance in delineating the anatomy of coronary arteries along with assessment of first pass myocardial perfusion in children. The purpose of this study is to evaluate the extensive use of CMR for delineating coronary anatomy, evaluating first pass myocardial perfusion and late gadolinium enhancement in children with acquired and congenital heart disease.Retrospective review of 37 consecutive CMR Whole Heart T2 Prep coronary angiography studies of patients with congenital and acquired heart disease. The subjects had CMR from December, 2013 to September, 2014. Results of first pass myocardial perfusion study (at rest and with adenosine stress) and myocardial inversion recovery for delayed myocardial enhancement imaging were also reviewed.The median age at the time of CMR was 11 years with range of 3 months to 25 years; 26 male and 11 female subjects. The origins and proximal course of coronary were well demonstrated by CMR in 92% (34/37) of the cases. Five patients (13.5%) had multiple coronary artery aneurysms related to Kawasaki disease (Cardiac magnetic resonance imaging can reliably evaluate the coronary anatomy, first pass myocardial perfusion defect and myocardial scar in diverse group of children with acquired and congenital heart diseases.None."} +{"text": "Obesity is a risk factor for cardiovascular disease and mortality. Studies in both obese humans and murine models of obesity have identified changes in left ventricular (LV) mechanics , which manifest prior to global changes in cardiac function (ejection fraction) and may represent early markers of cardiovascular disease. These data are generally acquired under resting conditions, which could mask subtle differences in the early stages of disease. We sought to evaluate LV mechanics under inotropic stress conditions with the hypothesis that mechanical deficiencies with obesity would be exacerbated under stress conditions and revealed at earlier stages of disease.C57BL/6J mice were randomized to either a high-fat or control diet for varying time intervals (n=7-10 subjects per group per time point). At each interval, LV mechanics were quantified under baseline (resting) and stress conditions (40 \u00b5g/kg/min continuous infusion of dobutamine) using cine displacement encoding with stimulated echoes (DENSE) on a 7T Bruker ClinScan. Three short-axis and 1-2 long-axis slices were acquired with 11-20 frames per cardiac cycle. Peak strain, systolic strain rates, and torsion were quantified. A linear mixed model was used to compare interactions between time and group with Benjamini-Hochberg adjustments for multiple comparisons.Under rest conditions, reductions in LV peak strains Fig were obsDifferences in left ventricular mechanics in obese mice are exacerbated under inotropic stress conditions. Compared to evaluation at rest, stress CMR demonstrated a broader array of mechanical dysfunction (changes in systolic strain rates and torsion in addition to peak strains) and revealed these differences at earlier time points (16-22 vs. 42 weeks). A deficit in circumferential peak systolic strain rate at peak stress was the earliest observed marker of obesity-induced ventricular dysfunction. Thus, it may be important to evaluate cardiac function in the setting of obesity under stress conditions in order to fully elucidate the presence of ventricular dysfunction.This work was supported by a Ruth L. Kirschstein National Research Service Award (T32 HL91812); an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the NIH (P20 GM103527); the University of Kentucky Cardiovascular Research Center; the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (UL1TR000117). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources."} +{"text": "Individuals with short bowel syndrome (SBS) have reduced intestinal absorptive capacity and many require home parenteral nutrition (PN) support. One of the common causes of SBS is secondary to intestinal resections in the management of Crohn\u2019s disease (CD). Complication rates and survival in SBS secondary to CD on PN versus other etiologies remains unknown.To determine whether patients with SBS secondary to CD versus SBS secondary to other etiologies on home PN, have increased risk of hospitalizations and complications including central line associated bloodstream infection (CLABSI) and venous thromboembolism and whether there is a difference in overall survival between groups.This is a multicentre prospective cohort study using the Canadian Home Parenteral Nutrition (HPN) Registry on individuals with defined SBS separated into two cohorts: 1) Patients with SBS secondary to Crohn\u2019s disease vs. 2) Patients with SBS secondary to other aetiologies . Patient characteristics and clinical factors are presented as mean (standard deviation) for continuous variables and as frequency (percentage) for categorical variables. Comparison between groups (SBS CD vs SBS other) were performed using 2-sample t-test for continuous variables and Chi-square or Fisher exact tests when appropriate for categorical variable. Survival probabilities will be estimated using the Kaplan-Meier method.The study included a total of 379 patients with short bowel syndrome on home PN. There are 170 (45%) patients with SBS secondary to CD and 209 (55%) patients with SBS from other secondary causes. The average age of those with CD is 52 and 65% female patients. The average age of those with other causes of SBS is 56 with similar percentage of female patients (65%). There were significant differences in baseline medications with higher use of immunosuppressant therapy in those with CD. There was no significant difference in total number of hospitalizations, hospitalizations related to PN and CLABSI.Individuals with SBS secondary to CD do not appear to be at increased risk of central line infections or hospitalizations compared those with SBS from other causes.NoneNone Declared"} +{"text": "A decrease in SUV max of more than 60% in the primary tumour was identified as optimal cut-off value for predicting major pathological response and performed better than computed tomography morphologic partial response measured by a size reduction of the primary tumour of more than 30%. The same result was observed for prediction of prognosis.The authors must be congratulated on systematically assessing the role of fluorodeoxyglucose-positron emission tomography and computed tomography in predicting pathological response and prognosis of locally advanced non-small cell lung cancer (NSCLC) after neoadjuvant chemoradiotherapy . IntegraRelevant differences were identified for the subgroup of T3-4N0-1 patients compared to N2 positive patients and a decrease of <60% of SUVmax was found as an indicator of poor prognosis, particularly in N2 patients. The analysis was focused on metabolic and imaging response in the primary tumour, whereas lymph node status was analysed pathologically.Previous analyses of well-designed prospective trials looking at pre-treatment metabolic tumour volume only showed conflicting results on the impact on 5-year survival rates , whereasIn the current treatment landscape, the presented data will be challenged by several issues. Particularly, the details of pathologic reporting after neoadjuvant treatment are crucial to ensure comparability of trials. In 2020, the \u2018International Association for the Study of Lung Cancer\u2019 (IASLC) has reported a multidisciplinary recommendation for pathologic assessment of lung cancer resection specimens after neoadjuvant treatment . The autThe integration of immunotherapy in neoadjuvant treatment algorithms will leaIn summary, innovative neoadjuvant combination schemes have the potential to substantially change staging algorithms in NSCLC. The paper by Tanahashi and colleagues provides relevant confirmatory reference data on the impact of metabolic response on pathologic response rates and 5-year survival rates after neoadjuvant chemoradiation therapy."} +{"text": "Recent events in the world, wars, pandemics, have once again raised the issue of the need for competent human resources in global public health (GPH). In Georgia, there are master\u2019s degree programs in public health where global health is mostly offered as an elective or core course of the curriculum. University of Georgia (UG) is involved in the ERASMUS + project in GPH (BACE). UG initiated to create new GPH Master Program, which will be response towards local, regional and international challenges and demand.Main objective of developing GPH program was to address and meet national and international global health education needs and challenges. The aim of the study was to identify evidence-based prerequisites for the MPH in GPH (UG). We conducting document review based on the GPH competency model (GPHCM) and evaluated: 1) GPH & MPH programs of the top 20 world university ranking (THE/2022); 2) CUGH associated programs; 3) Georgian MPH programs; 4) Georgian education documents ); 5) Main directions of career development in global health. In addition, interviews with national experts were conducted using the Delph method.Study found that depending on the scope and content of the program, prerequisites for obtaining MPH in GPH varies. In addition to English competence and a high GPA, working or research experience or interviews or additional exams or other are required. In Georgia, there is no adopted GPHCM, but GNQF allows the establishment of MPH in GPH. UG new Master program (120 ECTS) will include 99 ECTS core (including research practicum & thesis) and 21 ECTS elective courses based on 6 domains of GPHCM. The program will mostly focus on population health management at a global level.Study findings suggest any undergraduates with appropriate conditions could be eligible for admission to the UG (MPH in GPH).\u2022\u2002UG admission prerequisites for Health Science undergraduates: National entrance exam, English proficiency B2, working experience and motivation letter.\u2022\u2002UG additionally admission prerequisites for Health Science undergraduates: basic knowledge epidemiology and medical terminology (if credits available or test)."} +{"text": "Pregabalin is an analogue of gamma-aminobutyric acid (GABA). Recent reports suggest illicit pregabalin use may be increasing among youth, however its addictive potential has not been well established (1).Drug seeking behavior and chronic drug use are associated with defcits in glutamate clearance and activation of postsynaptic glutamatergic receptors (2). Based upon multiple studies, we compare here the addiction and misuse risks of pregabalin with those of traditional psychoactive substances (3).Users of pregabalin were identified from 1st January 2019 to 31 December 2019 in Oran Addictology service, at west Algeria. The aim of the study was to establish the addictive potential of pregabalin and to compare the addiction risks of pregabalin with traditional psychoactive substances in west Algerian population. Clinical diagnosis was established according DSM-5 diagnosis criteria.A total of 92 cases of pregabalin abuse or dependence were identified. The principal population at risk consists of patients with other current or past substance use disorders, for the most part opioid and multi-drug users, the age group were between 17-38 years old, mostly single men. The mean daily dose of pregabalin was 1200 mg. Almost all patients experienced withdrawal symptoms when pregabalin was discontinued.The misuse of pregabalin often leads to abuse and dependence, mostly in the context of multiple drug addiction, especially in youth population."} +{"text": "Currently, Buprenorphine maintenance therapy (BMT) is an evidence-based treatment in retaining patients who are dependent on opioids. However, factors influencing retention are often measured objectively. Studies on patient\u2019s perspectives on take home BMT in developing countries are limited.This study examines the potential factors influencing treatment compliance in the early phase of Buprenorphine maintenance treatment from the patient\u2019s perspectiveParticipants (n=89) who were initiated on BMT were recruited and followed after six weeks. A semi-structured interview was conducted with 62 patients who remained in treatment and 24 patients who dropped out of the studyBased on the semi qualitative analysis some of the factors which facilitated the patient\u2019s retention in treatment were: (1) Effectiveness in blocking withdrawal symptoms (2) effectiveness in reducing their cravings and controlling their opioid use (3) decreased fear of withdrawal and/or missing doses(4) improvement in the quality of life(5) patient-related factors like family support (6) effectiveness of the treatment program. Around nine percent of patients reported family support as the reason for retention, which is not noticed in other studies. Barriers reported by the patients while on medication were: (1) negative effect experienced with medication (2) program related difficulties like distance, unavailability (3) major life event interrupting the treatment (4) patient-related factors like low mood, financial constraints.Understanding factors associated with barriers to treatment provide insights into preventable factors that contribute to premature drop out from BMT and to improve clinical practice, policy decisions, or future research."} +{"text": "Interactions between genetic and environmental risk factors (GxE) contribute to an increased risk of venous thromboembolism (VTE). Understanding how these factors interact provides insight for the early identification of at-risk groups within a population and creates an opportunity to apply appropriate preventive and curative measures.To estimate and compare GxE for VTE risk in the general Hungarian and Roma populations.The study was based on data extracted from a database consisting the results obtained previously in a three pillars complex health survey. DNA was genotyped for rs121909567 (SERPINC1), rs1799963 (F2), rs2036914 (F11), rs2066865 (FGG), rs6025 (F5), and rs8176719 (ABO) polymorphisms. Multivariable linear regression analysis was applied to test the impact of GxE on VTE risk.Interestingly, the rs121909567 (SERPINC1) SNP was not present in the general population, however the risk allele frequency was 1.4% among Roma, which might suggest a founder effect in this minority. The risk of VTE was higher among depressive Roma subjects who carried the risk variant of rs2036914 ; however, not for the general subjects. The joint presence of high level of LDL-C and rs2066865 increased the VTE risk only among Roma . A multiplicative interaction between rs8176719 and cancer was identified and higher for the Roma population . The VTE risk increased in the Roma population but was higher in the general population as a result of the multiplicative interaction between CAD and rs2036914 (F11).rs121909567 (SERPINC1) was confirmed as a founder mutation in the Roma population. As a result of higher genetic load and GxE interactions, the minority Roma population is at higher risk of VTE than the general Hungarian population.\u2022\u2002Our study revealed some evidence on the burden of the joint presence of genetic and environmental risk factors on VTE.\u2022\u2002A marginalized and segregated Roma community could need due attention for the prevention and control of CVDs."} +{"text": "Oculo-auriculo-vertebral spectrum (OAVS) is a rare condition characterized by the involvement of the first branchial arches.To investigate the ear abnormalities of a sample of patients with OAVS.The sample consisted of 12 patients with OAVS seen at the Clinical Genetics Unit, UFCSPA/CHSCPA. The study included only patients who underwent mastoid computed tomography and with normal karyotype. We performed a review of its clinical features, giving emphasis to the ear findings.Nine patients were male, the ages ranged from 1 day to 17 years. Ear abnormalities were observed in all patients and involved the external (n=12), middle (n=10) and inner ear (n=3). Microtia was the most frequent finding (n=12). The most common abnormalities of the middle ear were: opacification (n=2), displacement (n=2) and malformation of the ossicular chain. Agenesis of the internal auditory canal (n=2) was the most frequent alteration of the inner ear.Ear abnormalities are variable in patients with OAVS and often there is no correlation between findings in the external, middle and inner ear. The evaluation of these structures is important in the management of individuals with OAVS. Branchial arch disorders comprise several developmental anomalies including the oculo-auriculo-vertebral spectrum (OAVS), also known as Goldenhar's syndrome, or hemifacial microsomy OMIM 164210)2104, 5, The origin of the OAVS is unclear, but it is a complex and heterogeneous condition. Two pathophysiologic mechanisms have been proposed for the OAVS: a reduced blood flow, and focal hemorrhage in the development region of the first and second branchial arches around 30 to 45 days of pregnancy, in the blastogenesis periodAlthough external ear anomalies have been described in OAVS patients - to the point of being inclusion criteria - middle and especially inner ear alterations have received little attention in the literatureThe sample comprised 12 patients with the OAVS seen at the Clinical Genetics Unit, UFCSPA/CHSCPA. The inclusion criteria were alterations in at least two of the following bodily regions: oro-cranial-facial, ocular, auricular, and vertebral, according to Str\u00f6mland et al.'s criteria (2007)p<0.05 were considered statistically significant. The institutional review board approved this study (Opinion no. 581/08 of 25/01/2008).The registries of patients were reviewed to gather clinical data and the results of diagnostic tests . Fisher's exact test (bicaudate) was applied to compare the frequencies were found. The software was the PEPI program. Values of There were 9 male and 3 female subjects. The ages at the first visit ranged from 1 day to 17 years (10 were aged 1 year or less). Most of these patients were referred from the pediatrics unit (n= 7); two others were referred from the plastic surgery unit, one from the cardiology unit, one from the otorhinolaryngology unit, and one from the pediatric surgery unit. Eight subjects had two of the inclusion criteria, three subjects had three, and one had four. All subjects had ear anomalies, affecting the external ear n= 12), the middle ear (n= 8), and the inner ear (n= 3). Microtia was the most frequent finding - it was observed in all cases (ranging from grades I to IV). It was mostly unilateral, to the left, and grade III. Four patients had bilateral microtia (33%). The most common middle ear anomaly was opacification (n= 2), and displaced (n= 2) and malformed ossicular chains (n= 2). Agenesis of the inner ear canal (n= 2) was the most frequent inner ear anomaly. The most common finding in the temporal bone was a non-aerated mastoid (n= 5). Additional alterations in other organs or systems consisted of low height (n=4), craniofacial anomalies (n= 11), ophthalmologic anomalies (n= 2), esophageal/ pulmonary anomalies (n= 6), cardiac anomalies (n= 7), abdominal anomalies (n= 4), skeletal anomalies (n= 6), and cerebral anomalies (n= 5) , the mid.Figure 1External ear malformations in OAVS patients ranged from slightly dysmorphic to absent ears (or anotia - the most severe form of microtia)Because the ossicles of the ear develop from the dorsolateral terminations of the cartilage in the first (Meckel's cartilage) and second (Reichert's cartilage) branchial arches, anomalies of these structures are often found in the OAVS. Anomalies in the stapedial and tympanic tensor muscle suggest that these structures originate from the first and second branchial archesAlthough external middle ear anomalies are well known, inner ear alterations are rarely observed; these anomalies vary widely and range from mild to severePoorly pneumatized mastoid antrumEnlarged cartilaginous portion of the Eustachian tube lumen and absence of the cartilaginous lateral lamina of the Eustachian tubeLengthened mastoid antrumPreauricular appendages and pitsEar anomaliesAtresia/stenosis of the outer ear canalUndeveloped tympanic membraneMicrotia/anotiaIncomplete development of the tympanic cavityImmature and malformed ear ossiclesAbsent oval and round windowAbsence of the tympanic tensor muscleAbnormal path of the facial nerve and absence of the chorda tympani nerveDistorted and hypoplasic cochleaAbsence of the cochlear aqueductImmature vestibular system and absence/fusion of semicircular canalsDisplaced endolymphatic ductWidened vestibular aqueductAbsent/abnormally coursing facial nerve canalSmall, wide, and/or duplicated inner ear canalAgenesis of the inner ear canalDuplicated inner ear canalThe frequency of these anomalies in our sample (25%) was similar to previously reported rates (27% to 36%)As mentioned above, the most frequently reported ear anomalies in the OAVS are external and middle ear abnormalities. Thus, secondary conductive hearing loss predominates in these patientsSurgery is difficult because of the complexity of this condition and the number of factors that may affect the outcome of surgical therapy. On the other hand, hearing loss is generally unilateral in the OAVS; the majority of patients develop speech, and their level of hearing enables them to be socially active. However, patients with bilateral mixed profound hearing loss or pure sensorineural hearing loss required more advanced forms of treatment, such as cochlear implants or bone anchored hearing aidsEar anomalies are frequent and varied in OAVS patients; often there is no correlation among external, middle, and inner ear findings. Therefore, it is important to assess these structures using radiologic methods (such as computed tomography of the mastoid) when managing patients with OAVS."} +{"text": "Autoimmune diseases of central nervous system (CNS) are wide spread in children. In some cases, mental disturbances in such patients are barely noticeable in the beginning, which hinders early detection of risks in the child\u2019s mental development.The study focuses on comparative analysis of the structure of mental disorders in pediatric patients with autoimmune diseases of CNS.Research includes two cases: girls aged 14 and 16, one with acute disseminated encephalomyelitis (ADEM), disease onset at 4 years and 11 months, and another with multiple sclerosis (MS), disease onset at 5 years and 5 months. The following methods were used: analysis of patient\u2019s medical record, interview with neurologists, pathopsychological assessment.Common features in both cases: 1) organic brain disorders; 2) patients do not demonstrate intellectual deterioration, can master regular school curriculum; 3) detected mental disturbances reflect risks for mental and personality development. Specific features: 1) the patient with MS demonstrates polymorphism of mental disorders, while the patient with ADEM \u2014 homogeneity of mental disorders; 2) main problems of the patient with MS are related to self-regulation, which makes the general picture similar to pseudo-frontal syndrome; the patient with ADEM has major neurodynamic disturbances, which has similarity to psychoorganic syndrome; 3) predictors of personality disorders detected in case of MS determine the negative prognosis for mental development.The delineated features evidence for further psychological study of CNS autoimmune diseases and formulation of criteria for clinical psychological assessment. These patients need to be monitored by psychologists to prevent personality disorders.No significant relationships."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-80366-2, published online 21 January 2021Correction to: The original version of this Article contained an error in the Methods section, regarding ethical approvals. The data of three patients included from Hino hospital were not covered by the original ethical approval, which read:\u201cThis study was approved by the institutional review board, and the requirement of written informed consent was waived because of the study\u2019s retrospective design .\u201dThese patients provided their consent separately and an additional ethical approval was issued by the IRB of Hino Municipal Hospital. Additional information on the approval for study execution by the other participating centres was also included in the corrected version. The approval statement now reads:\u201cThis study was approved by the institutional review boards of Keio University School of Medicine Ethics Committee , National Hospital Organization Tokyo Medical Center , Saiseikai Utsunomiya Hospital , Japanese Red Cross Shizuoka Hospital , Inagi Municipal Hospital (dated 23/06/2020), Hiratsuka City Hospital , and Hino Municipal Hospital IRB (dated 24/03/2021). The requirement of written informed consent was waived because of the study\u2019s retrospective design.\u201dThe original Article has been corrected."} +{"text": "Hydrocephalus is reported in approximately one-tenth of neurosarcoidosis patients. However, data on clinical characteristics and outcome are lacking. In this retrospective study, we present 11 patients with neurosarcoidosis and hydrocephalus on neuroimaging. Median age was 52\u00a0years and seven were female (64%). Presenting symptoms consisted of headache in 8 out of 11 (73%), vertigo in 5 (46%), gait abnormalities in 4 (36%), diplopia in 2 (18%) and decreased visual acuity in 1 (9%). Cranial imaging showed obstructive hydrocephalus in 10 (91%) and non-obstructive hydrocephalus in 1 (9%) out of 11, obstruction occurred at the level of the fourth ventricle in 6 out of 10 (60%). Treatment consisted of glucocorticoids in all the patients with additional methotrexate or azathioprine in 6 (55%) and infliximab in 1 (9%) patient. Neurosurgical intervention was performed in 10 out of 11 (91%) patients. Treatment led to remission, improvement or stabilization of disease in 9 out of 10 (90%) of patients. One patient died due to cerebral herniation despite neurosurgical decompression and CSF shunting. Median modified Rankin scale score at last follow-up was 2 (range 0\u20136). A systematic review and meta-analysis of studies on hydrocephalus due to neurosarcoidosis identified 36 patients that compared to our patients had a lower median age at onset and a higher mortality. Acute obstructive hydrocephalus due to neurosarcoidosis is a potentially fatal medical emergency requiring neurosurgical intervention and initiation of immunosuppressive therapy. If patients survive the initial phase, the outcome is generally favorable. Sarcoidosis is an inflammatory disorder that can involve multiple organ systems . InvolveWe retrospectively reviewed all case records from adult patients that were seen between June 2015 until June 2020 at the Neurology Department at the Amsterdam University Medical Centers a tertiary referral center for neurosarcoidosis. We included patients diagnosed with (1) neurosarcoidosis and (2)Detailed history and neurological examination were retrieved from patient files in an electronic database including presenting symptoms, age of onset of symptoms, results of ancillary investigations and data on treatment and treatment response and outcome of hydrocephalus in neurosarcoidosis.A literature search was performed in PubMed using the following terms: (\u201csarcoidosis\u201d [MeSH Terms] OR sarcoid* [tiab] OR \"Neurosarcoidosis\" [Supplementary Concept] OR neurosarcoid* [tiab]) AND . We included articles written in English describing one or more adult patients that were published in the last 25\u00a0years. The search was followed by a manual search in the reference lists of the publications found. The study conforms with the World Medical Association Declaration of Helsinki, 7th revision 2013 Fortaleza. Ethical approval is not required in the Netherlands for a retrospective study with anonymized patient data such as used in our study.Between June 2015 and June 2020, 303 patients were analyzed because of suspected neurological involvement of sarcoidosis at our outpatient department or clinical department. Of these, 153 patients (50%) were diagnosed with neurosarcoidosis had a history of sarcoidosis of which one had a history of neurosarcoidosis-associated myelitis (9%) and three used immunosuppressive therapy at symptom onset. Presenting symptoms were headache in eight (73%), vertigo in five (46%), abnormal gait in four (36%), diplopia in two (18%) and decreased visual acuity in one patient (9%). Time from symptom onset of hydrocephalus-related symptoms to first neurological evaluation was 15\u00a0weeks (interquartile range 3\u201338). Abnormalities on neurological examination included nystagmus and impaired consciousness each in four (36%), papilledema and ataxia each in two (18%) and bilateral sixth nerve palsy in one patient (9%). Neurological examination showed no abnormalities in two patients (18%). Median time from onset of symptoms to diagnosis of neurosarcoidosis was 4 months (range 0\u201334). Other organ systems involved were lymph nodes in four patients (36%), lungs in three (27%) and eyes, liver and bones, respectively, in one patient.Serum angiotensin-converting enzyme (ACE) was analyzed in five patients and was elevated in none of them, soluble Interleukin 2 receptor (sIL-2R) was evaluated in two patients and was elevated in both. Cerebrospinal fluid (CSF) analysis was performed, commonly after external ventricular drain placement, in nine and showed an elevated leukocyte count in eight (89%) patients and elevated total protein in five (56%). One patient had a normal CSF analysis. CSF oligoclonal bands were present in the one patient in which they were tested.Results of cranial imaging were re-evaluated for all patients [ten magnetic resonance imaging (MRI) and one computed tomography (CT)] and showed hydrocephalus in all. The hydrocephalus was non-communicating/obstructive in ten patients and communicating in one. Obstruction was at the level of the fourth ventricle in six patients (60%), the foramen of Monro in three (30%) and the cerebral aqueduct in one 10%). In one patient, there was tonsillar herniation due to the obstruction hydrocephalus was performed in seven patients with no history of sarcoidosis, and showed abnormalities suggestive of sarcoidosis in all of them. Biopsy was performed in all patients. Leptomeningeal biopsy was performed in one patient and showed non-caseating granulomas (definite neurosarcoidosis), lymph node biopsy was performed in eight patients and showed non-caseating granulomas in seven (probable neurosarcoidosis) and was inconclusive in one (possible neurosarcoidosis), in one patient liver biopsy was performed and showed non-caseating granulomas (probable neurosarcoidosis). In the patient with possible neurosarcoidosis, chest CT was highly suggestive of sarcoidosis.Fluor-18-deoxyglucose positron emission tomography (The median follow-up was 23.5\u00a0months (interquartile range 3\u201350\u00a0months). Immunosuppressive treatment was initiated in all 11 patients and consisted of corticosteroid pulse therapy in 7 (64%), corticosteroid maintenance therapy in 9 (82%) and second-line therapy, methotrexate or azathioprine, in 4 patients (36%). Neurosurgical intervention was performed in 10 out of 11 patients (91%) and consisted of external ventricular drain placement followed by ventriculoperitoneal shunt in 3 (30%), ventriculoperitoneal shunt in 5 (50%), ventriculostomy in 3 (30%) and cyst fenestration in 1 patient (10%). All but one patient were treated both with immunosuppressive agents as well as a neurosurgical intervention. Of these ten patients, three underwent neurosurgical intervention prior to immunosuppressive treatment, three received immunosuppressive treatment prior to neurosurgery and in four, neurosurgical and immunosuppressive treatments were initiated simultaneously. Medication was changed during follow-up due to insufficient response to initial therapy, side effects or a relapse of symptoms during follow-up in 5 out of 11 patients (45%). One patient had multiple relapses of symptoms. The relapse of symptoms of neurosarcoidosis was recurrence of hydrocephalus in four (80%) and meningitis without hydrocephalus and myelitis each in one patient (20%). Treatment changes included restarting or increasing the dosage of corticosteroid maintenance therapy in three (80%), corticosteroid pulse therapy in three (60%) and initiation of second-line therapy in five . Third-line therapy (infliximab) was started in one patient (20%). Two patients underwent a second neurosurgical intervention because of failure of CSF shunt or ventriculostomy.Neurological examination at the end of follow-up was available in ten patients and focal neurological deficits were present in only one patient and were attributable to sarcoidosis-associated myelitis. Outcome of neurosarcoidosis at last follow-up was classified as remission in two (18%), improvement in five (45%) and stable disease in three (27%). One patient (9%) died following cerebral herniation as a result of the hydrocephalus. Median modified Rankin scale (mRS) score at last follow-up was 2 (range 0\u20136).Literature review yielded 95 articles of which 46 were assessed for eligibility based on title and abstract. Of these articles, five consisted of case series of neurosarcoidosis patients that included patients with hydrocephalus but did not report clinical characteristic, ancillary investigations, treatment and outcome of this subgroup \u201342. The 18FDG-PET. These investigations can help ascertain a potential biopsy site outside of the central nervous system. Histopathological evidence of non-caseating granulomas is necessary for a diagnosis of probable or definite neurosarcoidosis [Our study shows that hydrocephalus is a rare but potentially fatal manifestation of neurosarcoidosis that requires a combination of neurosurgical intervention and immunosuppressive treatment. In the absence of a positive history of (neuro)sarcoidosis, the differential diagnosis of acquired hydrocephalus is diverse and includes among others inflammatory, (post-) infectious, (post-)hemorrhagic and (post-)traumatic disorders and intracranial tumors such as colloid cysts or malignancy , 43, 44.coidosis .Presenting symptoms of hydrocephalus in neurosarcoidosis are (sub)acute and related to increased intracranial pressure. Hydrocephalus in neurosarcoidosis is often non-communicating and caused by obstruction of the outflow from the fourth ventricle or of the cerebral aqueduct due to a chronic meningitis. Acute obstructive hydrocephalus can be fatal and an emergency neurosurgical intervention such as CSF shunting, ventriculostomy or decompression should be considered in all patients. Corticosteroid treatment in adjunct to neurosurgical intervention should be strongly considered in all patients. Intensification of immunosuppressive treatment is required in case of a relapse of symptoms, as a persistent or recurring granulomatous chronic meningitis can lead to an additional site of obstruction or shunt failure through obstruction of the CSF shunt . AlthougAs compared to our case series, the mortality was higher (9% versus 22%) and more patients had a diagnosis of definite neurosarcoidosis (10% versus 58%) in the review of the literature. The difference in mortality may be explained by publication bias as multiple articles reported on patients with sudden death. A previous review of the literature found an even higher mortality of 75% in patients with neurosarcoidosis who presented with seizures and had hydrocephalus . HoweverThis study has several limitations. First, patients evaluated were referred to our tertiary center. This may introduce selection bias leading to overestimation of the impact of hydrocephalus in neurosarcoidosis. Second, the retrospective design of our study resulted in heterogeneous assessment of disease activity as well as missing data in some patients. This prohibits drawing firm conclusions regarding outcome and treatment effect. Third, as mentioned above there might be publication bias regarding hydrocephalus in neurosarcoidosis. Nevertheless, our retrospective single-center cohort study and systematic review provides valuable information on a rare disease as hydrocephalus in neurosarcoidosis.In conclusion, hydrocephalus due to neurosarcoidosis is a medical emergency as onset is often (sub)acute and the hydrocephalus is obstructive in nature. Initiation of treatment should be prompt and include both neurosurgical interventions to lower intracranial pressure and immunosuppressive therapy to reduce granulomatous inflammation. If patients survive the initial phase outcome is generally favorable."} +{"text": "Broad-range metagenomic cell-free DNA testing (Karius\u00ae) can identify a variety of pathogens from a single blood sample to help in diagnosis of deep seated and bloodstream infections. Few studies have evaluated the impact of Karius testing on clinical decision making when compared to more conventional diagnostic methods.We performed a retrospective cohort study of adult patients who had Karius tests at University of Iowa Hospitals and Clinics between 01/2020 and 10/2021. Chart review was conducted to obtain patient characteristics and clinical course including patient age, immunocompromising conditions, involvement of Infectious Disease (ID) consultant, reason for the test, and final diagnosis. Results of the Karius tests and conventional tests were compared for concordance. Clinical impact and change in management due to Karius testing were determined using previously established criteria outlined by Hogan et al.:239-245)Out of 26 patients who had Karius testing, 20 patients (77%) had an immunocompromising condition, the most common of which was hematologic malignancy . Twenty-four patients (92%) had received a formal ID consultation prior to the test. The most common finding prior to testing was the presence of pulmonary infiltrates on imaging . Karius testing was positive in 18/26 cases (69%). Organisms detected by Karius and conventional testing were concordant in 9/18 cases (50%). Karius test result had a positive clinical impact in 3 cases (12%), an indeterminant impact in 1 case (3%) and no impact in 22 cases (85%). Reasons for a positive impact are as follows: 1 case with initiation of antituberculosis therapy due to earlier diagnosis of tuberculosis, 1 case with de-escalation of antifungal therapy based on negative Karius results, and 1 case of clearance for urgent lung transplantation based on negative Karius results in the setting of mobile echo density on echocardiogram in the absence of other stigmata of endocarditis.The impact of Karius testing on patient management appears limited. Further studies will be needed to identify patient populations or disease factors in which this testing have clinical impact.All Authors: No reported disclosures."} +{"text": "Death at home is preferred by most people and has become a key indicator of the end-of-life care quality; however cultural attitudes about death and dying may vary by race and ethnicity. This study describes racial and ethnic variation in place of death among Medicare beneficiaries aged 50 years and older who died in 2018 with a dementia diagnosis and without a dementia diagnosis . Among those with dementia, 60% died at home, with the highest percentage for non-Hispanic white (62%) beneficiaries, followed by Black/African American (55%), Hispanic (61%), Asian American/Pacific Islander (58%), and American Indian/Alaska Native (58%) beneficiaries. Among those without dementia 61% died at home, with the highest percentage for non-Hispanic white (60%) beneficiaries, followed by Black (57%), Hispanic (65%), Asian American (65%), and American Indian (60%) beneficiaries. Among those who died at home, about half without dementia received hospice care compared to the majority with dementia."} +{"text": "Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS.Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (The online version contains supplementary material available at 10.1007/s13311-022-01237-4. Despite decades of research, there remains a significant unmet need for effective treatments for amyotrophic lateral sclerosis (ALS). The reasons are manifold, but two key considerations have emerged . First, SOD1) gene (SOD1-ALS) ., 24.Pre-The date of emergence of clinically manifest ALS will be defined as the date when the participant first experienced the relevant clinical symptom or, in the absence of symptoms, the date when neurological examination first detected evidence of UMN and/or LMN signs indicative of ALS, whichever is sooner.SOD1 genetic testing to determine or confirm their SOD1 variant. Recognizing the complexities of predictive genetic testing and the potential for emotional, psychosocial, legal, and financial implications [In the ATLAS study, participants undergo centralized ications , 29\u201331, SOD1 result and anticipating or learning about a NfL level increase, additional counseling is available as needed throughout the study. Genetic counseling will be performed by qualified individuals as per local standard clinical practice; acknowledging that exact qualifications for providing genetic counseling differs around the world [During screening for enrollment in Part A of the study, genetic counseling sessions are required before a DNA sample is collected for testing and at the time that the results are communicated. These sessions, which focus primarily on genetic testing, also include in-depth discussions about NfL \u2014 specifically, the uncertain but potential implications of above-threshold NfL levels for the risk of imminent clinical disease. Given the potential for continued psychosocial and emotional impact, especially after receiving a positive he world . In addiSOD1 variant genetic analysis results and their NfL levels \u2014 is paramount. If disclosed, positive SOD1 test results and elevated NfL levels could be used in discriminatory ways, with potential implications for both the study participant and their biological relatives in many spheres of life, including finances, insurance , eligibility for educational and recreational activities, family planning, and employment status [The protection of participants\u2019 privacy \u2014 in particular, their t status , 33, 34.SOD1 variant carriers in the Pre-fALS study. The utility of this critical observation from the Pre-fALS study underscores the importance and value of high-quality natural history data in advancing therapy development for rare diseases [The ATLAS study incorporates unique design elements to evaluate whether presymptomatic initiation of tofersen can delay the emergence of clinically manifest ALS and/or reduce the loss of clinical function over time. ATLAS is the first interventional trial in ALS that uses neurofilament as an enrichment marker for study eligibility and a trigger for initiation of study treatment. The design of ATLAS was built upon the premise that elevations in NfL precede the emergence of clinically manifest ALS, as observed in rapidly progressive diseases .ATLAS has the potential to aid in the identification and understanding of early markers of disease activity beyond NfL. The collection of CSF (at baseline for Part A and prior to every dose in Parts B/C/D) and urine/blood will enable the identification of other potential fluid markers of disease activity. Similarly, comprehensive electromyography (EMG) at screening for Part A and Part B may inform the timing of NfL elevation relative to the emergence of EMG abnormalities and the relative sensitivity of these two biomarkers. Through these biomarker assessments, ATLAS will help to inform the conduct of presymptomatic trials in other subsets of the ALS population.SOD1 variants is continuously evolving due to limited reporting and heterogeneity across carriers. To account for this, an independent Mutation Adjudication Committee was formed to adjudicate eligibility of non-protocol-defined SOD1 variants based on the most up-to-date information at the time. The use of clinically manifest ALS as a primary endpoint is not without challenges, given potential perverse incentive to receive open-label tofersen in Part C; it is for this reason that we have established an independent EAC to confirm the emergence of clinically manifest ALS.A list of variants associated with high/complete penetrance and rapid disease progression was defined in the protocol based on the totality of information ascertained in the literature, genetic databases, and clinical experience. However, characterization of Pre-fALS study, ATLAS aims to take into account two key considerations: (1) when and how participants are informed of their genetic risk, and (2) how participants\u2019 privacy, especially regarding their SOD1 genetic variant and NfL biomarker status, can be protected. For both study sites and participants alike, education, training, and resources are essential to help address these concerns. Specifically, the ATLAS study has implemented genetic testing and counseling processes along with firewalls and strategies to protect participant privacy in the context of a clinical research study.Recognizing the potentially serious and life-long implications of positive genetic testing results on study participants and their families, the study also necessitated the development of a supportive infrastructure to inform, support, and protect prospective participants. Informed by experience from the SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease through elevated plasma NfL. Recognizing that therapeutic intervention in earlier phases of ALS has the potential to yield the greatest clinical benefit, ATLAS, together with data from the VALOR study and its open-label extension study, will inform the optimal timing of treatment initiation in SOD1-ALS. As the first interventional trial in presymptomatic ALS, ATLAS has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS and other neurodegenerative diseases.The ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of Supplementary file1 (PDF 536 KB)Supplementary file2 (PDF 589 KB)Supplementary file3 (PDF 545 KB)Supplementary file4 (PDF 599 KB)Supplementary file5 (PDF 535 KB)Supplementary file6 (PDF 616 KB)Supplementary file7 (PDF 553 KB)Supplementary file8 (PDF 580 KB)Supplementary file9 (PDF 553 KB)Supplementary file10 (PDF 629 KB)Supplementary file11 (PDF 563 KB)Supplementary file12 (PDF 563 KB)Supplementary file13 (PDF 619 KB)Supplementary file14 (PDF 598 KB)Supplementary file15 (PDF 600 KB)Supplementary file16 (PDF 571 KB)Supplementary file17 (PDF 545 KB)Supplementary file18 (PDF 625 KB)Supplementary file19 (PDF 562 KB)Supplementary file20 (PDF 527 KB)Supplementary file21 (PDF 527 KB)Supplementary file22 (PDF 607 KB)Supplementary file23 (PDF 329 KB)Below is the link to the electronic supplementary material."} +{"text": "The emotional, behavioral and psychosocial effects of chaotic environments following wars and armed conflicts in terms of exposure to trauma and displacement is well recognized. School-age children who are directly exposed to or witnessed negative effects of armed conflicts show an array of emotional and behavioral problems.Our study aimed to examine the mental health conditions of children living in war and conflict zones and attending primary schools in Agdam.The study sample comprised of 617 children , residing in the conflict areas in the southwestern of Azerbaijan. The children were evaluated with the previously validated Azerbaijani version of the Strengths and Difficulties Questionnaire (SDQ) Teacher Form.About a third of children (32.7%) had abnormal total scores, and a fifth (21.4%) were in borderline range. The SDQ subscale scores included emotional problems (19.4%); conduct problems (20.3%), hyperactivity/inattention (12.2%), peer relationship problems (31.1%), and pro-social behavior difficulties (13.1%). As a result, externalizing problem scores were higher in males (p<.001) and internalizing problems in females (p<.05). Due to correlation analysis, age is negatively and significantly related with externalising (p<.05), internalising (p<.01), and total difficulty (p<.05) scores.The findings of the study show that more than half of the children living in the war zone in Azerbaijan suffer from mental health problems and highlight the need for child mental health services and family supports in the region.No significant relationships."} +{"text": "Inflammatory Bowel Diseases (IBD) are increasing globally with westernized countries experiencing a dramatic increase in cases of ulcerative colitis and Crohn\u2019s disease. The corresponding rise in the comorbidities of anxiety and depression are linked to inflammation and microbiome dysbiosis; impacting the gut-brain axis (GBA). Another facet of the GBA are the tryptophan metabolites serotonin (5HT) and kynurenine (Kyn). 5HT and Kyn are metabolites implicated in anxious behaviours and memory deficiencies with dysbiosis influencing metabolite production. In inflammatory conditions, upregulation of Kyn impacts brain homeostasis as Kyn has both positive and negative brain metabolites. As disease outcomes are tied to the severity of depression/anxiety, characterization of the behavioural and tryptophan metabolite profile of an IBD model can allow us to develop better IBD therapies.To characterize the anxiety and memory phenotype with corresponding assessment of tryptophan metabolites 5HT and Kyn across tissues of interest in an spontaneous colitis model.-/-) lack the protective mucin 2 layer in the distal colon, allowing for direct contact between the gut contents and the gut epithelial layer. Over time this contact results in the development of spontaneous colitis. Muc2-/- n=12 per sex were compared to C57Bl/6 mice for behaviour and tryptophan metabolites across brain, colon and serum. Open Field Test and Light/Dark tests were used to assess anxiety levels, Novel Object and Radial Arm maze were performed to assess memory deficits. Mice underwent one anxiety and one memory test and were euthanized following their last maze. Enzyme-linked immunosorbent assay (ELISA) assessment of 5HT and Kyn were performed on brain, colon and serum samples. T-tests were performed and graphs created using PRISM (v9.4.1).Mucin 2 knockout mice (Muc2-/- mice had decreased anxiety (p=0.0113) compared to C57Bl/6 wild type mice in the light/dark maze. Muc2-/- displayed no significant differences in novel object preferences or the number of memory errors in novel object recognition test and radial arm maze respectively. Serum kynurenine was found to be significantly elevated (p=0.0444) in Muc2-/- mice. The sex factor has to be mentioned here in the results not in the conclusions.Muc2-/-and wild-type mice with depressed anxiety responses and heightened serum kynurenine, however the implications of these findings require further investigation. Understanding how inflammation is driving behavioural alterations can provide pathways to ameliorate the behavioural comorbidities in IBD patients suffering from anxiety of memory deficits.IBD is increasing globally and problems with mental health is often comorbid. Within our model we were able to show that behavioural and biochemical differences do exist between our Muc2None Declared"} +{"text": "There is a need for improved communication in assisted living communities (ALCs) for staff and family caregivers of persons with dementia. This study is a cluster randomized trial in 10 ALCs of a PC education (PCEAL) program for dementia care providers facilitated by hospice nurse educators. Baseline, 3- and 6-month data was collected for documentation of advance care planning (ACP) discussions. The PCEAL program had a moderate effect on ACP discussions at the 3-month follow in the treatment (N=17) compared to the control group (N= 6) . The findings indicate that the PCEAL program potentially improves ACP discussions with family members of persons with dementia. We will discuss recommendations for tailoring the PCEAL program to include other direct and administrative staff and to elicit the perspective of families about quality of communication."} +{"text": "We evaluated the concordance of lymphoproliferative disorder (LPD) diagnoses made initially at Kamuzu Central Hospital (KCH) with a limited immunohistochemistry panel and telepathology consultation with University of North Carolina (UNC) at Chapel Hill and second review at UNC with an extensive immunohistochemistry panel available.The prospective KCH Lymphoma Study in Lilongwe has been enrolling patients with LPDs since 2013. Diagnoses are made by pathologists in Malawi and supported by US pathologists and Malawian clinicians at weekly telepathology conferences. Diagnostic tissue blocks are sent quarterly to UNC for secondary review and further confirmatory studies. Concordance of diagnosis from primary to secondary review was scored as: exact match (level 1), differences in granularity of the diagnosis (level 2), a change in classification but not in treatment (level 3), and a change to the diagnosis that would have altered the treatment course (Major Discordance). Cases with insufficient tissue for review at UNC were excluded from concordance evaluation.Three hundred eighty-eight adult patients were enrolled (June 2013-May 2019). Three hundred twenty-seven tissue blocks were sent to UNC for review and 292 LPDs diagnostic samples had sufficient quality for concordance review. The five most common LPDs were diffuse large B-cell lymphoma , Burkitt lymphoma , classical Hodgkin lymphoma , Multicentric Castleman disease , and low grade non-Hodgkin lymphoma . Level 1, 2 and 3 concordance represented 175 (60%), 49 (17%) and 50 (17%) cases, respectively, and a Major Discordance was identified in 18 cases (6%).With a limited, selected immunohistochemistry panel and telepathology consultation, 94% of cases were accurately classified in real-time, leading to appropriate therapy. The evaluation of concordance provides a measure of quality assurance of the telepathology program, confidence in diagnoses for involvement in interventional trials, and useful data for understanding the epidemiology of LPDs in Malawi."} +{"text": "Osteoporosis is common amongst elderly patient populations and is associated with significant morbidity and mortality. We aimed to assess whether national clinical guidelines regarding the identification, assessment and management of osteoporosis and fragility fracture risk were being adhered to on a female later life psychiatry ward. We then aimed to improve the detection and treatment of osteoporosis amongst this patient cohort and subsequently conducted a re-audit of adherence to relevant clinical guidelines.In July 2021, the electronic health records of the 20 most recently discharged patients from a female later life psychiatry ward were reviewed. The proportion of patients who appropriately received FRAX screening, DEXA scanning and pharmacological management of osteoporosis and fragility fracture risk was recorded. The results were compared to standards identified in national clinical guidelines from the National Institute for Health and Care Excellence (NICE) and the National Osteoporosis Guideline Group (NOGG). In addition, the proportion of patients who had FRAX scores communicated to their general practitioners on discharge was recorded. Recommendations were made based on audit findings, and several changes to ward processes were implemented including incorporating fracture risk scoring in a structured ward round template and displaying information posters about osteoporosis in clinical areas. A re-audit was completed in February 2022 using the same methodology as baseline to re-assess adherence to the audit standards.All included patients were female and aged >65 years, and therefore eligible for consideration of fragility fracture risk according to NICE guidelines. 88% (15/17 patients) of those without pre-existing osteoporosis had FRAX scores calculated during their admission on re-audit compared to 50% (8/16 patients) at baseline. 73% (11/15 patients) had FRAX scores communicated to their GP on discharge at completion of the audit cycle compared to 25% (2/8 patients) at baseline. At completion of the audit cycle 10% (1/10 patients) with intermediate fragility fracture risk received measurement of bone mineral density during admission while 30% (3/10) had this recommended to their GP on discharge. None of the high-risk patients (n = 4) were started on bisphosphonate therapy.On completion of the audit cycle, we found excellent compliance with national guidelines regarding the identification of osteoporosis and fragility fracture risk, which demonstrates the feasibility of considering this aspect of physical health in the setting of a later-life psychiatry ward. Areas for improvement include the assessment and management of patients identified as having intermediate or high risk of osteoporosis and fragility fractures."} +{"text": "We used canonical correlation (n=424) to examine the relationships between a set of physical function measures time, stair climb time and stair climb power) and a set of cognitive measures (Trail Making Test B (sec), Digit Symbol Substitution Test (DSST), the Montreal Cognitive Assessment, and California Verbal Learning Test). Canonical correlation derives synthetic variables comprised of linear combinations within each set of variables that maximize the correlations between synthetic variables. The FSST was most strongly correlated with the cognitive synthetic variable (- 0.42). The DSST score was the cognitive measure most strongly correlated with the physical synthetic variable (0.48). It is notable that only the timed cognitive and physical tests are inter-associated"} +{"text": "The rural areas of southwestern Indiana are challenged with insufficient healthcare workers in the long-term care industry. The University of Southern Indiana (USI) Geriatric Workforce Enhancement Program (GWEP) is collaborating with state agencies to address shortages in licensed administrators, activity professionals and social service designees. These roles, vital in the nursing facility, hold educational requirements through the Indiana State Department of Health (ISDH) and the Indiana Professional Licensing Agency (IPLA). USI gerontology faculty addressed workforce challenges in five phases: 1) Evaluation of state educational requirement and comparison to current USI gerontology courses; 2) Development of new coursework to support state requirements; 3) Expansion of preceptor pool; 4) Proposal to state agencies; 5) USI curriculum modifications. Faculty evaluated the educational and training requirements for these roles and compared the requirements with current courses. Preceptors were needed for students\u2019 field experiences; a preceptor pool was developed through funded training. The requirements and course alignment were included in the program proposal to the state agencies. Upon ISDH, IPLA and University New Program Development Committee approval, additional instructors were recruited. Results of this initiative include a: 1) Fully approved and launched Administrator-in-Training (AIT) residency embedded in curriculum at undergraduate and graduate level; 2) Fully approved Activity Professional Certificate Program; 3) Pool of 10 certified preceptors; and 4) Onset of the social service designee certificate program. This collaborative partnership developed between USI, ISDH and IPLA ensure state agency requirements are met academically for students entering the long-term care workforce."} +{"text": "Scientific Reports 10.1038/s41598-021-86979-5, published online 01 April 2021Correction to: The original version of this Article contained an error. In the Materials and methods section, under the subheading \u2018Study design\u2019, the approval number of the Ethics Committee was incorrect.As a result,\u201cThe study was conducted with the approval of the Ethics Committee of Nagoya University Hospital and enrolled in the jRCT (CRB4180004).\u201dnow reads:\u201cThe study was conducted with the approval of the Ethics Committee of Nagoya University Hospital .\u201dThe original Article has been corrected."} +{"text": "Photobacterium damselae subsp. piscicida (Pdp) causes photobacteriosis in fish and important financial losses in aquaculture, but knowledge of its virulence factors is still scarce. We here demonstrate that an unstable plasmid (pPHDPT3) that encodes a type III secretion system (T3SS) is highly prevalent in Pdp strains from different geographical origins and fish host species. We found that pPHDPT3 undergoes curing upon in vitro cultivation, and this instability constitutes a generalized feature of pPHDPT3-like plasmids in Pdp strains. pPHDPT3 markers were detected in tissues of naturally-infected moribund fish and in the Pdp colonies grown directly from the fish tissues but were undetectable in a fraction of the colonies produced upon the first passage of the primeval colonies on agar plates. Notably, cured strains exhibited a marked reduction in virulence for fish, demonstrating that pPHDPT3 is a major virulence factor of Pdp. The attempts to stabilize pPHDPT3 by insertion of antibiotic resistance markers by allelic exchange caused an even greater reduction in virulence. We hypothesize that the existence of a high pressure to shed pPHDPT3 plasmid in vitro caused the selection of clones with off-target mutations and gene rearrangements during the process of genetic modification. Collectively, these results show that pPHDPT3 constitutes a novel, hitherto unreported virulence factor of Pdp that shows a high instability in vitro and warn that the picture of Pdp virulence genes has been historically underestimated, since the loss of the T3SS and other plasmid-borne genes may have occurred systematically in laboratories for decades.The marine bacterium Photobacterium damselae subsp. piscicida (hereafter dubbed Pdp), a bacterium of the family Vibrionaceae, was first isolated in 1963 from natural populations of white perch (Morone americana) and striped bass (Morone saxatilis) affected by an unknown bacterium in the Chesapeake Bay ) were used. TSA-1 plates supplemented with Cm5 + Kan50 and sucrose (15% [wt/vol]) were used to select double mutant colonies containing the kan gene plus the cat gene.The coding sequence of each of the two rivative . Two fra plasmid was inse plasmid . The catPdp. The high in vitro instability of pPHDPT3-like plasmids warns that the picture of Pdp virulence genes has been historically biased and underestimated. The realization of the prevalence of plasmids encoding the T3SS and additional genes in Pdp will surely change our view of this pathogen from now on.This study provides evidence that pPHDPT3 plasmid constitutes a novel, hitherto unreported virulence factor of"} +{"text": "Describe the progress of developing and monitoring global physical activity policy from the 1990s through the release and implementation of Global Action Plan for Physical Activity-GAPPA;Present findings of a systematic review of instruments for physical activity policy analysis;Describe the methods and progress after 1-year implementation of the Global Observatory for Physical Activity-GoPA! physical activity policy inventory;Present the preliminary findings and lessons learned after 1-year implementation of the Global Observatory for Physical Activity-GoPA! physical activity policy inventory.Physical inactivity is one of the most important factors contributing to global morbidity and mortality, but despite both importance and the recent launch of a WHO action plan, public health policy around physical activity remains poorly developed and monitored.Description of the problemPhysical inactivity accounts for as many as 5 million deaths per year globally but has yet to be addressed effectively by most governments or the World Health Organization(WHO). Many efforts led by WHO, national governments, networks, and academics from the 1990s to the present have tried to turn physical activity into a public health priority. Since its launch in 2015, the Global Observatory for Physical Activity-GoPA! has monitored the progress of national physical activity surveillance, policy and research. The GoPA! Policy Inventory created in 2017, contributes to physical activity policy monitoring and aims to collect data worldwide.In this symposium we will address several key questions about physical activity policy by examining different initiatives such as GAPPA and the experience of monitoring policy globally with the GoPA! policy inventory. We will examine whether it is feasible to track physical activity policy at the global and country levels, if the existence of ?good? physical activity policy is associated with less physical inactivity and how policy indicators may be used for advocacy and guidance in the coming years.Findings show that PA policy monitoring has and still varies substantially by geographic area and country income group. Effectiveness and implementation of PA policies remains challenging worldwide. PA policy indicators can enhance understanding of the links between policy and population levels of PA.GoPA! is committed to continue improving PA policy monitoring for informing and encouraging policy to address physical inactivity worldwide.Agenda and PresentersIntroduction: Michael Pratt (10-minutes)Talk 1: Developing and monitoring physical activity policy: 1990 to today \u2013 Michael Pratt (15-minutes)Talk 2: Instruments for the analysis of national-level physical activity and sedentary behaviour policies: a systematic review \u2013 \u017deljko Pedi\u0161i\u0107 (15-minutes)Talk 3: The GoPA! Policy Inventory: Progress and methods - Andrea Ramirez (15-minutes)Talk 4: The GoPA! Policy Inventory: preliminary findings and lessons learned \u2013 \u017deljko Pedi\u0161i\u0107 (15-minutes)Q&A from the audienceConclusion by discussant Adrian Bauman (20-minutes)"} +{"text": "Group Name: Working Group on Neonatal Infectious Diseases of the Section of Neonatology of the Dutch Paediatric SocietyBackground: Central-line\u2013associated bloodstream infections (CLABSIs) are a main focus of infection prevention and control initiatives in neonatal care. Standardized surveillance of neonatal CLABSI enables intra- and interfacility comparisons, which can contribute to quality improvement. To date, there is no national registration system for CLABSI in neonatal care in the Netherlands. Across neonatal intensive care units (NICUs), several different sets of CLABSI criteria and surveillance methods are used for local monitoring of CLABSI incidence rates. To achieve standardized CLABSI surveillance, we conducted a consensus procedure with regard to nationwide neonatal CLABSI surveillance criteria. Method: A modified Delphi consensus procedure for the development of nationwide neonatal CLABSI surveillance criteria was performed between January 2016 and January 2017 in the Netherlands. An expert panel was formed by members of the Working Group on Neonatal Infectious Diseases of the Section of Neonatology of the Dutch Paediatric Society. The consensus procedure consisted of 3 expert panel rounds. Figure Result: The expert panel achieved consensus on Dutch neonatal CLABSI surveillance criteria, which are summarized in Figure 2. Neonatal CLABSI is defined as a bloodstream infection occurring >72 hours after birth, associated with an indwelling central venous or arterial line and laboratory confirmed by 1 or more blood cultures. In addition, the blood culture finding should not be related to an infection at another site and one of the following criteria can be applied: (1) a bacterial or fungal pathogen is identified from 1 or more blood cultures; (2) the patient has clinical symptoms of sepsis and (2A) a common commensal is identified in 2 separate blood cultures or (2B) a common commensal is identified by 1 blood culture and C-reactive protein (CRP) level is >10 mg/L in the first 36 hours following blood culture collection. Conclusion: The newly developed Dutch neonatal CLABSI surveillance criteria are concise, are specific to the neonatal population, and comply with a single blood-culture policy in actual neonatal clinical practice. International agreement upon neonatal CLABSI surveillance criteria is needed to identify best practices for infection prevention and control.Funding: NoDisclosures: None"} +{"text": "The AgingME Geriatrics Workforce Enhancement Program (AgingME GWEP), a statewide collaboration led by the University of New England and the University of Maine, is guided by an annual statewide survey of community and professional stakeholders. The aim of this research is to identify training and resource gaps related to age-friendly healthcare and topics of interest. Of the 245 survey respondents, 15% indicated existing knowledge of the 4Ms framework. The top sources of 4M\u2019s framework exposure included trainings or webinars (30%) and web-based resources (19%). Of those with knowledge of the 4M\u2019s, 33% of providers and 29% of older adults/community members reported employing the 4Ms in their professional practices and personal lives, respectively. Respondents also noted the need for more training on how to use technology to locate healthcare information (33%), using technology to reduce isolation and loneliness among older adults (29%), and keeping providers connected with older patients (26%). Additional write-in responses (11%) suggest a need for general technology training and improving access to technology overall. Respondents' (N = 157) top five categories for needed aging-related training topics were community resources for older adults (15%), aging-in-place (14%), exercise and nutrition (11%), improving provider/patient communication (9%), and 4M\u2019s of age-friendly healthcare overview (8%). Responses also identified themes related to improving patient/provider communications, availability of resources, and ageism that could be addressed through upcoming GWEP activities. Results indicate a need to facilitate the translation of 4Ms knowledge into practice and increasing technology training and access."} +{"text": "Pandemic is accompanied by \u201cinfodemic\u201d that is related to higher anxiety . We suggest that indefinite and stressful situation of pandemic provoke magical thinking leading to lower adherence with recommendations for self-isolation.The aim was to reveal the structure of beliefs about reasons, manifestation and consequences of coronavirus and their relationship with magical thinking, anxiety and COVID-19-related behaviour.In April 2020 (2-3 weeks of self-isolation regimen) 402 adults aged 18-64 years old filled checklist including beliefs about pandemic , Magical Ideation Scale Eckblad, Chapman, 1983) as well as scales measuring anxiety and protective behaviour in pandemic and monitoring of information about coronavirus .Factor analysis revealed three groups of radical beliefs about coronavirus . Belief about the particular meaning of coronavirus was associated with the magical thinking (r=.21), less anxiety about infection (r=-.19) and poorer adherence to self-isolation (r=-.26). Belief in the negligence as a cause of coronavirus was more typical for those with better adherence (r=.18) while catastrophic beliefs about the consequences of pandemic were related to frequent monitoring of the information about the pandemic (r=.24), and anxiety regarding future negative consequences of the pandemic (r=.46).Dysfunctional beliefs about coronavirus could be a factor of poorer adherence related to magical thinking and could be addressed in psychological interventions. Research is supported by the Russian Foundation for Basic Research, project No. 20-04-60072."} +{"text": "We tested the following genotype-related mechanisms generating race-dependent disparity in Alzheimer\u2019s Disease (AD) risk: i) the frequencies of SNPs with genotypes associated with AD are higher in the Black subpopulation; ii) the effects on AD risk of genotypes associated with increased AD risk is higher in the Black subpopulation; iii) there is a small group of SNPs with a large difference in the effects on AD race-dependent risk generating disparities; alternatively, the disparities are generated by a collective effect of multiple SNPs with minor or moderate effects. We modified the GWAS algorithm to use it with the Cox regression multivariable model and the outcome accounting for race-related differences in AD risk. Using the modified GWAS we have identified loci in charge for the disparity between Whites and Blacks and used the results along with SNPs of a special interest which were identified from the literature in the Cox multivariable regression model and generalized Oaxaca-Blinder approach. The following genes had the strongest effects on racial disparities: i) NYAP1 neuronal tyrosine-phosphorylated phosphoinositide-3-kinase adaptor; ii) RPA3-UMAD1 loci RPA3 replicates protein A, interacting with gastric tumor and hepatocellular carcinoma; iii) TOMM40 associated with an increased risk of developing late-onset AD; iv) ACE - responsible for making the enzyme which converts angiotensin which regulates blood pressure; v) PSME3IP1 - proteasome activator subunit 3 interacting protein 1; vi) MARCHF1 regulator of glucose-tolerance and lipid storage and vii) LINC01146 which belongs to coagulation cascade pathway and linked to hepatocellular carcinoma."} +{"text": "Cognitive Stimulation Therapy (CST) is an evidence-based treatment for people living with dementia that is not in widespread use in the United States. To better understand barriers and facilitators to implementation of CST, we conducted virtual focus groups of newly trained facilitators of Cognitive Stimulation Therapy (CST). Of 12 facilitators trained, representing two settings of care (The Program for All-inclusive Care of the Elderly and a Continuing Care Retirement Community), 4 facilitators, representing Social Work n = 2, Speech Therapy n = 1, and Recreation Therapy n = 1, participated. We analyzed interview transcriptions using framework analysis guided by constructs from the Consolidated Framework for Implementation Research (CFIR). Themes that emerged across constructs were 1) balancing competing personal, stakeholder, and organizational needs; 2) lack of mastery experiences and the need for opportunities for more practice, reflection, and feedback from trainers; 3) building a community of facilitators to provide peer support; 4) logistical concerns; and 5) identifying appropriate participants who would most benefit from CST. The barriers to implementation imposed by the ongoing COVID-19 pandemic were also a cross-cutting theme. Many of these barriers are readily managed, and professionals who implement CST in their sites should be aware of and take into consideration these barriers and facilitators."} +{"text": "Pharmacists play an important role in infection control and antimicrobial stewardship teams in hospitals and the community. The need for education on antimicrobial resistance (AMR) and clinical infectious diseases (CID) is increasing. However, the status of Japanese pharmaceutical education on CID and AMR is unclear.We conducted a nationwide cross-sectional survey of pharmaceutical department in Japanese universities between February and March 2022. Data on the following were collected using questionnaires: 1) basic information; 2) number of faculty members with experience in CID; 3) lecture times for CID and AMR; 4) self-evaluation of CID and AMR education; and 5) the most important issues in CID and AMR education. Descriptive analyses were conducted.Among the 74 participating universities, 44 (59.5%) universities responded. The median number [IQR] of faculties of infectious disease education was 7 [4\u201312], and clinical faculties was 3 [1\u20136]. Twenty-seven (62.8%) of the universities had faculties with clinical experience in infectious diseases. Lectures time for CID and AMR varied among the universities.Respondents indicated that CID and AMR lectures were insufficient, compared to microbiology basic lectures. Additionally, insufficient lecture time and specialists were the most common responses as the most important issues in CID and AMR education.University background and questions regarding CID and AMR lectures (N=44)Boxplot of lectures time for clinical infectious disease and antimicrobial resistance educationSelf-evaluation of clinical infectious disease and antimicrobial resistance educationThis study revealed that educational status and resources for CID and AMR education varied widely, and that practical lectures on CID and AMR may be insufficient. We suggest that the entire core curriculum and resources, including the number of faculties, needs to be examined and improved.The most important issues in clinical infectious disease and antimicrobial resistance education.All Authors: No reported disclosures."} +{"text": "Our previous systematic review on the health benefits of different sport disciplines included 69 studies published before 2013. We found moderately strong evidence of health benefits for running and football while the evidence for other sport disciplines was either inconclusive or tenuous. The purpose of this report is to update the evidence base on published studies through 2013-2019.A systematic literature search of observational and experimental studies on the association between the participation in sport and health outcomes was conducted through electronic databases: MEDLINE via PubMed, Scopus, and Web of Science. The inclusion criteria were: participants heathy adults; type of studies cross-sectional, cohort or intervention designs; study group participation in specific sport disciplines; non-participation comparison group; health-related outcome variables in terms of mortality, morbidity, disease risk factors and function. Studies on sport injuries were excluded.A total of 3909 titles and abstracts of studies published between 2013-2019 were identified for potential inclusion. The study selection process yielded 30 studies for further assessment. These studies included 26 different sport disciplines with 54 sport vs. no sport comparisons. The most prevalent sports were cycling (10 studies) and running (8 studies). Together with the previous systematic review the combined data includes 99 studies, 40 sport disciplines and 159 sport vs. no sport comparisons. Significant health benefits were found for a range of sport disciplinesThe updated systematic review provides new relevant data for an extended analysis of the health benefits of different sport disciplines and strengthens the existing evidence base for the promotion of health through participation in sports."} +{"text": "Nature Communications 10.1038/s41467-022-34321-6, published online 04 November 2022Correction to: The original version of this Article contained an error in the caption of Figure 3a, which incorrectly read \u2018showing ratios of rapid intensification (RI) cases satisfying the critical environmental thresholds divided by entire samples satisfying thresholds (blue histograms) and the analogous ratios for cases where the critical thresholds are not met (red histograms)\u2019. The correct version replaces sentence with \u2018showing the probability of rapid intensification (RI) for cases satisfying the critical environmental thresholds (blue histograms) and the probability of RI for cases where the critical thresholds are not met (red histograms)\u2019. This has been corrected in both the PDF and HTML versions of the Article."} +{"text": "ALS Forum is an online support group for those who have motor neuron disease or amyotrophic lateral sclerosis (ALS). It provides information, advice, connection, care, and assistance to persons living with ALS and their family caregivers. This study aimed to analyze the online discussion posts by caregivers of persons with ALS and assess their perceptions, experiences, and challenges of using assistive technologies (AT). Posts were extracted from the ALS caregiver discussion forum via web scraping using Python in March 2022. The extracted posts are dated between June 2005 and January 2022. The total number of posts and replies generated during this period was 52,292 by 2,397 unique users. Additional searches were conducted using assistive technology-related keywords to create the text dataset. A total of 263 posts by 137 unique users were identified. After the initial review, 186 posts were included in the final analysis. Thematic analysis revealed six major themes: (1) Uses of AT ; 2) Barriers and Facilitators ; 3) Usability (hardware and software-related); 4) Sharing Experience on AT; 5) Giving Advice; 6) Seeking Information on AT. The findings are consistent with previous literature that online health discussion forums provide access to rich data that contains lived experiences of patients and caregivers. The findings may inform the design of future assistive technology that incorporates the patients\u2019 and caregivers\u2019 perspectives to increase the adoption and long-term sustainability of the technology for people living with ALS and their caregivers."} +{"text": "A 54-year-old man presented with cough and 3-month history of pain in bilateral knees and fingers. Physical examination revealed digital clubbing and b an(1). 95%-97% of the cases are caused by underlying conditions; the most common being non-small cell lung carcinoma (2). Screening for underlying conditions, particularly lung cancer, should be performed after hypertrophic osteoarthropathy diagnosis.Hypertrophic osteoarthropathy is characterized by digital clubbing accompanied by arthralgia and periostosis and typically involving the tibia and fibula NoneHK wrote the manuscript, and AO and KS critically revised the manuscript for the intellectual content. All authors have read and approved the final manuscript.Written informed consent was obtained from the patient.Ethical approval was waived by the Ethics Committee of Tokyo Metropolitan Bokutoh Hospital."} +{"text": "Previous research has established the role of lifelong learning in promoting psychological wellbeing and active aging. Population aging necessitates an understanding of the unique opportunities and challenges around formal and informal learning in later life. This paper will share findings from a mixed methods study with the MIT AgeLab 85+ Lifestyle Leaders, a panel comprised of octogenarians and nonagenarians from across the United States. Drawing on an online survey and virtual focus groups with 29 Lifestyle Leaders from January 2021, findings suggest the Lifestyle Leaders most often learned new things from talking with others (46%) and reading print (54%) or online (54%) sources. The majority were familiar with attending in-person lectures or classes (89.7%) and were now using videoconferencing to do these (78.6%). A majority (56.7%) had or are currently participating in a lifelong learning program. Most consider themselves lifelong learners and described this around remaining curious and engaged with life, choices around what one learns, and greater enjoyment of learning. In the survey, a plurality of Lifestyle Leaders indicated the top two challenges affecting their ability to learn were sensory burdens (35%) and their energy level (32.4%); focus group data revealed that recall also is a barrier. Focus group data further highlighted generational experiences around early life learning and career paths, specifically how gender roles, diagnoses of learning disabilities, and evolving digital technology have affected these and changed over the course of their lifetimes."} +{"text": "People with schizophrenia have a life expectancy that is 10\u201320 years shorter than the general population. The high incidence of metabolic syndrome, cardiovascular disease and diabetes mellitus in this patient group are thought to be major \u2013 and potentially modifiable \u2013 factors contributing to this premature mortality. Therefore, annual monitoring of physical health parameters is recommended by organisations including the Scottish Intercollegiate Guidelines Network (SIGN). The SIGN guideline on schizophrenia advises that the following parameters are checked annually for patients with schizophrenia who are on anti-psychotics: ECG, blood glucose, lipid profile, prolactin, BMI/weight, smoking status and blood pressure. Traditionally, this monitoring is overseen in the community by general practitioners. This audit aimed to capture how the COVID-19 pandemic impacted on the annual physical health monitoring of patients under the care of NHS Borders Community Rehabilitation Team.A retrospective audit was performed by reviewing notes of the 100 patients on the NHS Borders Community Rehabilitation team caseload. Notes from the years of 2019, 2020 and 2021 of all 100 patients on the caseload were reviewed, for documentation of the following seven parameters as recommended by SIGN: ECG, blood glucose, lipid profile, prolactin, BMI/weight, smoking status and blood pressure. Results were then entered manually into a secure spreadsheet. Permission for this audit was granted by NHS Borders.Initial results for the parameters of: ECG, blood glucose, lipid profile and prolactin levels demonstrate that routine monitoring of all four domains has decreased since the start of the COVID-19 pandemic. In 2019 the following numbers of patients had monitoring in these domains: ECG 56 (56%); blood glucose 84 (84%); lipid profile 74 (74%) and prolactin levels 62 (62%).During 2020, the number of patients having monitoring in all four domains fell: ECG 31 (31%); blood glucose (72%); lipid profile 64 (64%) and prolactin levels 48 (48%). During 2021, monitoring levels remained low: ECG 30 (30%); blood glucose 71 (71%); lipid profile 62 (62%) and prolactin levels 43 (43%).Data collection for the parameters of blood pressure, BMI/weight and smoking status is ongoing.Initial results indicate that the COVID-19 pandemic has negatively impacted on the routine physical health monitoring of patients under the care of the community rehabilitation team in NHS Borders. These results imply opportunities to treat and prevent conditions such as diabetes mellitus and hypercholesterolemia are being missed, further perpetuating an existing health inequality for patients with severe and enduring mental illness."} +{"text": "Inflammatory bowel disease (IBD) advanced training programs in Canada are heterogenous in their education, structure, and case exposure, resulting in differences in trainee experience. While competency based medical education (CBME) is becoming the primary educational framework in residency training, there is no CBME-based curriculum for IBD advanced training programs. Adopting a CBME framework for IBD fellowships may help standardize training to increase competence.The purpose of this study was to develop a CBME-based curriculum for IBD advanced training programs in Canada.Strategic groups consisting of 25 IBD experts were assigned to develop 15 entrustable professional activities (EPAs), which were then refined by experts in medical education and curriculum development. Acceptable EPAs were assessed using an electronically administered round-less Delphi panel. Panel members evaluated each EPA using a Likert scale, which asked participants to consider appropriateness of each EPA for an advanced IBD curriculum. A consensus strength greater than 70% was the acceptable threshold for inclusion into the final curriculum. Milestones were modelled after CanMED roles for each EPA.Of the 15 initial EPAs, nine were recommended for the roundless Delphi panel by the selection committee: (1) identification, diagnosis, and treatment of new onset IBD; (2) assessment and treatment of outpatients with IBD; (3) the endoscopic evaluation of disease activity and the effective communication of endoscopic findings for patients with IBD; (4) provide effective inpatient management and coordinate transition to outpatient care for patients with IBD; (5) recognize and institute preventive health maintenance strategies in patients with IBD; (6) management and treatment of special populations with IBD; (7) identification, diagnosis, and treatment of the various extraintestinal manifestations of IBD; (8) Engage health care systems to improve the quality of care for patients with IBD; (9) engage in scholarly activities related to IBD. Eight of the nine EPAs achieved a consensus score greater than 70%, with the EPA, \u2018engage in scholarly activities related to IBD\u2019 failing to meet this cut-off. Associated milestones were developed for the eight final EPAs.This study was the first attempt to develop a CBME-based IBD curriculum in Canada. With proper funding and guidance, we hope our model can be implemented across Canada in IBD advanced training programs. These methods may also help facilitate the development of CBME curricula for other advanced training programs.NoneNone Declared"} +{"text": "Mediterranean ports are sources of significant economic activity and at the same time they act as recipients of considerable anthropogenic disturbance and pollution. Polluted and low-in-oxygen sediments can negatively impact benthic biodiversity and favour recruitment of opportunistic or invasive species. Macrobenthic communities are an important component of the port biota and can be used as environmental quality indicators. However, a baseline database for benthic biodiversity in Mediterranean ports has not yet been widely established.Mollusca were the most abundant group (34%) in all ports. The highest percentage of opportunistic taxa per station was found before the touristic period in the shipyard of Heraklion port (89.3%).Macrobenthic assemblages were recorded in three Mediterranean touristic ports under the framework of the ENPI CBC MED project MAPMED (MAnagement of Port Areas in the MEDiterranean Sea Basin). Samples were collected from Cagliari , Heraklion and El Kantaoui (Tunisia) ports during February, May and September 2012. The sampling stations were selected according to the different sectors within each port . A total of 277 taxa belonging to 12 phyla were found, of which the 96 taxa were present in all three ports. El Kantaoui port hosted the highest number of macrobenthic taxa. Mediterranean ports are sources of significant economic activity and they strongly support local, regional and national economic development. The Mediterranean Sea hosts about 480 ports and terminals and is one of the busiest maritime areas of the world . ShippinThis dataset includes macrobenthic taxa identified in three touristic ports in the Mediterranean, located at Cagliari , Heraklion and El Kantaoui (Tunisia) . SamplinMAPMED: MAnagement of Port areas in the MEDiterranean sea basinDr Eva Chatzinikolaou , Dr Panagiotis Damianidis (taxonomic identification), Dr Christina Pavloudi (taxonomic identification), Dr Katerina Vasileiadou (taxonomic identification), Dr Sarah Faulwetter (taxonomic identification), Kleoniki Keklikoglou (taxonomic identification), Wanda Plaiti (taxonomic identification), Dimitra Mavraki (data management), Stamatina Nikolopoulou (data management) and Dr Christos Arvanitidis .Mediterranean touristic ports: Cagliari , Heraklion and El Kantaoui (Tunisia).During this study, differences in macrobenthic assemblages were examined across three levels: a) geographical differences (three countries), b) use-sectoral differences (3-5 stations within ports) and c) temporal differences (three seasons in relation to the touristic period).This project has been financed by the European Union under the ENPI CBC Mediterranean Sea Basin Programme in the framework of the project \u201cMAnagement of Port areas in the MEDiterranean Sea Basin\u201d (MAPMED) (Grand Contract 6/2019-25/ 7/2011). This publication has been supported by the LifeWatchGreece infrastructure (MIS 384676), funded by the Greek Government under the General Secretariat of Research and Technology (GSRT), ESFRI Projects, National Strategic Reference Framework (NSRF) and from LifeWatch ERIC.Five replicates of sediment samples were collected from each station using a box corer (13.5 cm \u00d7 13.5 cm \u00d7 16 cm) manually operated from a small boat. A Garmin 60 CS portable GPS and a depth meter were available on board to record the exact position and depth of each station respectively. The sediment samples were sieved through a 0.5 mm sieve and then fixed and preserved in 5% formaldehyde buffered with seawater and stained with Rose Bengal. The benthic organisms were sorted out of the sediment under a stereoscope, counted and identified down to the lowest possible taxonomic level.http://www.marinespecies.org/aphia.php?p=match) on 10-03-2021.All scientific names were standardised against the World Register of Marine Species using the Taxon Match tool (2) located on the southern coast of Sardinia . The port of Heraklion and it is located on the northern coast of Crete (Greece). The port of El Kantaoui on the eastern Tunisian coast. Both the ports of Heraklion and Cagliari host a leisure marina, large passenger, cruise and cargo vessels, while El Kantaoui port offers moorings only for smaller fishing boats, luxury yachts and boats for sporting activities. Heraklion port has also a shipyard section.Three Mediterranean touristic ports were selected as study sites and they are presented in Fig. ion Fig. C is medioui Fig. D is a smSampling stations were selected in order to achieve good spatial coverage in each port and also to represent sectors with different uses according to the Water Management Units in MAPMED Action Plans MAPMED 2015). Four stations were selected in the port of Heraklion, five stations in the port of Cagliari and three stations in the port of El Kantaoui , Annelida (28.2%) and Arthropoda (24.2%) were also highly represented, while each of the remaining groups contributed less than 5% in the benthic assemblages studied was calculated for each station as the percentage of abundances for eta taxa in the teta taxa . The higAdditional statistical analysis has been applied to the species composition matrices of the specific dataset by Data range: 2012-2-13 \u2013 2012-9-25.Three seasonal sampling campaigns were carried out during 2012: one in winter (February), one in spring before the beginning of the touristic season (May) and one in late summer after the touristic season (September).Benthic communities and environmental parameters in three Mediterranean ports .5% formaldehyde buffered with seawater.Hellenic Centre for Marine Research (HCMR), Institute of Marine Biology, Biotechnology and Aquaculture (IMBBC), Heraklion, Crete, Greece.Open Data Commons Attribution LicenseCreative Commons Attribution (CC-BY) 4.0 License. All data in the database can be freely used provided it is fully cited even if only partially used.This work is licensed under a Benthic communities and environmental parameters in three Mediterranean ports .https://www.gbif.org/dataset/9b11f305-fb7a-4a65-826e-7fb97af06e5fhttp://ipt.medobis.eu/resource?r=mapmed_ports1Benthic communities and environmental parameters in three Mediterranean ports .Darwin Core Archive.UTF-8http://ipt.medobis.eu/resource?r=mapmed_portsMedOBIS (Mediterranean node of Ocean Biodiversity Information System),Integrated Publishing Toolkit (IPT) which has been established through the LifeWatchGreece Research Infrastructure and is hosted in the Institute of Marine Biology, Biotechnology and Aquaculture (IMBBC) of the Hellenic Centre for Marine Research (HCMR). The data are also harvested by and made available through the Ocean Biodiversity Information System (OBIS).The dataset is available as a DarwinCoreArchive and all fields are mapped to DarwinCore terms.The dataset is available via the This publication refers to the most recent version of the dataset available through the IPT server or MedOBIS. Future changes to the dataset due to quality control activities might change its content or structure.The current publication refers to the \"occurrence\" source file (txt file) that is associated with the particular dataset. Additional details about the sampling events can be found in the \"event\" source file (txt file) associated with the same dataset."} +{"text": "The current coronavirus pandemic (Covid-19) is posing new critical challenges on mental health due to widespread social alarm as well as long lasting \u201cphysical distancing\u201d as a result of public health protection measures or voluntary conduct. In a period of uncertainty, certain rewarding behaviors, such as the use of the Internet, exercise among other coping strategies might have increased considerably. We will share the results of an international cross-sectional investigation on the impact of physical-distancing on such potentially addictive behaviours to mitigate the pandemic effects, while identifying the most risky patterns and vulnerable populations. The studied sample consists of 3161 participants from Italy (41%), Spain (16%), the UK (12%), Lithuania (12%), Portugal (11%), Japan (6%), and Hungary (4%). Results are currently being analysied.No significant relationships."} +{"text": "Depressive symptoms affect the physical and cognitive health of approximately 20% of older adults. These symptoms have strong, bidirectional ties with physical activity levels and mobility disability. Physical activity has a positive impact on mood and depression and is highly recommended for symptom management across all ages. However, it\u2019s unclear whether elevated depressive symptoms interfere with potential benefits that physical activity has on other health outcomes like mobility loss. The Lifestyle Interventions and Independence for Elders (LIFE) Study randomized over 1,500 older adults (aged 70+) to either a physical activity (intervention) or successful aging (control) program with an average of 2.2 years of follow-up. Our analysis used Cox proportional hazards models to evaluate whether elevated depressive symptoms -11 scale with a cutoff score of 16/22 points) moderated the relationship between intervention status and the primary outcome . In a secondary analysis of 1,534 older adults , we confirmed significant main effects of both the physical activity intervention and elevated depressive symptoms on incident major mobility disability but found no evidence of moderation . Results indicate that the benefits of the intervention were comparable between those with and without significant depressive symptoms at baseline, supporting the inclusion of individuals with depression in clinical trials. In addition to potential symptom relief, promoting physical activity in older adults with depression is important for protecting against mobility loss."} +{"text": "Persons Living with HIV (PLWH) with chronic kidney disease progress to end-stage renal disease (ESRD) at a faster rate than HIV-negative individuals. Unfortunately, there is increasing data to suggest that PLWH are less likely to be waitlisted. We reviewed the transplant care continuum among PLWH at the Medical University of South Carolina (MUSC).st, 2012 and December 31st, 2021. Cases were included if a PLWH and ESRD had not died before being referred for kidney transplant, had evidence of pursuit of kidney transplant, and sufficient data of their transplant process were available in the medical record system. Descriptive statistics were used to analyze demographic and clinical characteristics as well as the transplant care continuum of PLWH and ESRD at MUSC.This was a retrospective review of PLWH and ESRD who either received care at MUSC Health Care System or were referred for Kidney transplant at MUSC between May 157 PLWH and ESRD were included in the analysis. Of these, 45 (79%) were referred for kidney transplant (Table\u00a01). The median age at the time of referral was 52 (range 26 - 78), 33 (73%) were males and 42 (93%) were of the Black race. The most common causes of ESRD were Multifactorial (36%), HIV-Associated Nephropathy (24%) and unknown (16%). Almost all patients had hypertension (96%) and 29% of patients had diabetes. Additionally, prevalent comorbidities include psychiatric conditions (53%), history of substance use (43%) and history of tobacco use (36%). Of those referred for kidney transplantation, 32 (71%) started a transplant evaluation, 24 (53%) completed the transplant evaluation, 22 (49%) were waitlisted, and 13 (29%) were transplanted. Common reasons why patients did not complete transplant evaluation included not meeting HIV criteria for transplant (9%), having too many comorbidities (9%), and not completing testing (9%).Clinical Characteristics of the 45 HIV Patients with ESRD Who Were Referred to Kidney Transplant at MUSCClinical Data on Transplant Care Continuum, n = 45The majority of PLWH with ESRD seen at MUSC were referred for kidney transplant and started the evaluation process. More is needed, though, to assist patients in completing the transplant evaluation process and making it to the transplant waitlist, with the ultimate goal of transplantation.All Authors: No reported disclosures."} +{"text": "Psoriazis and major depressive disorder (MDD) have a high degree of overlap, and inflammatory citokines like tumor necrosis factor alpha, interleukins 1, 2, 6 and 10, and C-reactive protein have been involved in their common pathogenesis. The prevalence of MDD in patients with psoriazis has been reported to range between 28% to 67%.To monitor the core symptoms evolution in patients diagnosed with psoriazis and MDD during antidepressant treatment.Four patients diagnosed with psoriazis and MDD (according to the DSM-5 criteria) were monitored during 6 months using Physician Static Global Assessment (PSGA), Hamilton Depression Rating Scale (HDRS)-17 items, and Global Assessment of Functioning (GAF). All patients underwent specific psoriazis and antidepressant treatment .All patients significantly improved their depressive symptoms during sertraline or escitalopram treatment , while their global functioning increased . The PSGA score decreased and reached a level of signifiance at week 24 . The duration of active periods of psoriazis was less longer during the 6 months of monitoring than in the 6 months previous to the antidepressant initiation . No treatment discontinuation due to low tolerability was reported.Antidepressant treatment with selective serotonin reuptake inhibitors is efficient and well tolerated in patients with MDD and psoriazis. The duration of active symptoms of psoriazis tends to be less longer than previous to the antidepressant initiation."} +{"text": "Byssinosis is a disabling occupational lung disease caused by cotton dust. It is a well-known occupational respiratory disease in cotton industry workers caused by cotton dust pollution. Many studies have been documented the effects of cotton dust onpulmonary function among workers employed in cotton-spinning mills. However, little data exist on the prevalence of this disorder in female workers particularly in western part of India. The present study was conducted to analyze the effects of exposureto cotton dust on pulmonary functions among female workers. The study was designed to assess the effects of exposure to cotton dust on lung functions among female cotton industry workers. Study group comprises 50 Female workers of cotton industry andcontrol group comprises 50 age matched females who were neither worked in cotton industry nor exposed to cotton dust. Information was collected using standardized questionnaires, physical examination and spirometric measurements. Student's T test was usedto find the difference between spirometric parameters. All the respiratory parameters were reduced in cotton industry workers as compared with control subjects (p<0.0001) and no significant differenceof SpO2 between groups. Cotton dust exposure makes huge impact on respiratory parameters of the cotton industry workers. This deterioration in respiratory health deteriorates with increasing duration of exposure. The health hazards caused by cotton dust shouldbe controlled by creating awareness among the workers & employers. Byssinosis is a crippling occupational lung disease caused by cotton dust. It is a well known occupational respiratory disease among cotton mill workers induced by cotton dust pollution. Byssinosis also called Brown Lung or Brown Lung disease is a typeof Pneumoconiosis caused by dust from cotton fibers. Inhaled dust stimulates histamine release which causes constriction of the air passages, making breathing difficult over time. Inhalation of the dust particles depends on its aerodynamic diameter, surroundingair's velocity, and breathing rate of the person. The inhaled fine cotton dust particles would get sedimented in the gas-exchange part of the lung tissue, where air flow is slow. These fine particles get lodged in the respiratory bronchioles within the centralpart of the acinus. The duration of exposure to cotton dust, type of dust, concentration of dust and the size of dust particle influence the effect on lungs . The preThe present study was conducted in department of physiology, Nootan Medical College & research Centre, Sankalchand Patel University, Visnagar, Mehsana district. This study composed of two groups which contains totally 100 subjects. Group A(Study group) comprises 50 Female workers of cotton industry. The workers were selected from different cotton textile industries of Mehsana district. Group B (control group) comprises 50 age matched females who were neither worked in cotton industrynor exposed to cotton dust. Female subjects of cotton industry, relatives of patients attending various outpatient departments in the age group of 18 - 40 years, who come forward for the study voluntarily and satisfied the inclusion criteria, wererecruited. Subjects on medication for Cardiovascular respiratory illness and Central nervous system (CNS) disorders, subjects with past and present history of CVS disorders, diabetes, psychiatric illness, subjects with history of drug abusing,smoking were excluded.A elaborate clinical history of these volunteers were taken such as relevant past history, family history, drug history, personal history like alcoholism, smoking etc. A structured questionnaire was given to all volunteers (subjects) to obtain the detailsof occupational history and history of past or present respiratory illnesses. The present study was approved by the Institutional ethics committee and an informed consent was taken from all the subjects after explainingthe test procedures and the goal of the study in local language. The anthropometric measurements such as height, weight, Body mass index (BMI), body surface area (BSA), lean body mass (LBM), Fat % were recorded for each subject by using standard procedure[7 - check with author]. SpO2 (Oxygen saturation) was measured with a digital handheld pulse oximeter to investigate oxygen saturation (blood oxygen level) in blood. Participants rested at least15 minutes before examination of SpO2. PFT was done with the help of spirometer (RMS Helios 401). The following variables were evaluated for spirometry: FVC (L) , PEF (L/S) (Peak expiratory flow), FEF 25-75% (Forced expiratory flow),FEV1 (L) (Forced expiratory volume in first second of FVC), MVV (Maximum voluntary ventilation), and FEVI/FVC (%). The subjects were briefed about the procedure of conduction of spirometry and demonstration was given before initiation of procedure. The subjectswere instructed to take deep inspiration from outside and then to expire as forcefully and as fast as she can inside the mouthpiece and recorded the activities. Using all aseptic techniques, the pulmonary function tests were conducted on subjects in standingposition and wearing nose clips. Each test was repeated three times and the best results among the three were considered for analysis. Experiments were done in accordance with revised Helsinki Declaration of 2000.Statistical analysis was performed with SPSS (version 17.0). Results are expressed as mean \u00b1 standard deviation (SD) and assessed using Student's t-test. P-value < 0.05 was considered statistically significant.Table 1(see PDF) describes baseline (anthropometric) characteristics of the subjects. It can be seen that majority of the subjects were adults and all the subjects were females. There was no significant difference between the two groups (control & studygroup) in terms of anthropometric measures. Table 2(see PDF) describes the lung function parameters (Spirometry) of study and control group subjects. All the respiratory parameters were reduced significantlyin cotton industry workers as compared with control subjects (Group B) (p<0.0001). The mean predicted values of FEV1 and FVC parameters were reported in Table 1(see PDF). Predicted value of FEV1 in study subjects were decreased significantly (p<0.0466),predicted FVC value was also decreased in study group however it was not statistically different (p<0.0802). The prevalence of various respiratory symptoms was shown in Table 2(see PDF) and the most common finding was reported is dyspnea followed by chesttightness & cough (16% & 20% respectively). No such symptoms were noted in control group (Group B). Figure 3(see PDF) shows Mean value of SpO2 (Oxygen saturation) in study and control groups. No significant difference of SpO2 between study and controlgroups (p<0.6612). Table 3(see PDF) shows duration of Cotton dust exposure among cotton industry workers. In the present study majority of the subjects had an exposure of at least 10 years or more showing an increased risk of developing lung diseases relatedto byssinosis.Women working in the cotton industry are more susceptible to various health problems much to their counter parts in other sectors. In the present study the anthropometric parameters of study and control group showed no significant difference thus makinggroup comparable. In the present study, Forced vital capacity (FVC) was significantly decreased in cotton industry workers. This is supported by a report of Fishwick and Jadhav A.J et al ,9.StudiThe Present study showed a strong coalition between cotton dust exposure in the cotton industry environment and lung function abnormalities. The pulmonary parameters are decreased significantly in the subjects working in cotton industry. This suggeststhat more aggressive measures must be taken in the workplace and enforcing the use of personal protective equipment, such as respirators and face masks. The health hazards caused by cotton dust should be controlled by creating awareness such as regular healthcheck-ups, personal protective measures and proper ventilation among the employees & employers and thereby ensuring the quality of life of the cotton textile industry workers."} +{"text": "The links between body image disturbances and distorted relationships with parents were supposed since the early conceptualizations of AN by Hilde Bruch. The empirical studies however were concerned with perceptual aspects of body image and much less is known about how the attitudinal aspects and the body-related behaviors are affected.To study the attitudinal and behavioral aspects of body image in adolescents with AN in relation to perceived parental care and the attachments to close people.The Body Investment Scale (BSI), Parental Bonding Instrument (PBI) and Attachment Style Questionnaire (ASQ) were used. 53 girls with Anorexia Nervosa were compared to 63 controls (adjusted by age).Girls with AN scored significantly higher on BIS Body attitude (p<.001) and Protection scales (p<.01), while displayed equal results on Body Care scale. They displayed lower Confidence in relationships (p<.01), higher Need for approval, Discomfort and preoccupation in close relationships (p<.05). No differences were found on PBI, excerpt for AN group perceiving less paternal control (p<.05). The correlation analysis, while showing a number of similar correlations within groups, suggests that in AN group positive Body image was more closely linked to perceived early care, especially from father (r=.6), in contrast with controls. In current relationships negative Body image for AN is stronger related to Discomfort and Need for approval (r>0.6), while Discomfort with Touch is less linked to problems in relationships than in controls.Results suggest the importance of studying the father\u2019s mediating role in the formation of body attitudes in AN.No significant relationships."} +{"text": "Perceived control is an important psychosocial resource for healthy aging. Using data from the National Study of Daily Experiences , we examined aging-related changes in stressor control across 10 years and compared these trajectories with measures of general control . Over 8 consecutive days in waves conducted in ~2008 and ~2017, people reported their perceived control over four types of stressors . Longitudinal analyses revealed declines in stressor control across 10 years (p<.001), driven by declines in home stressors specifically. The rate of decline did not depend on baseline age. General control trajectories showed unique patterns of age differences in aging-related change such that declines were steeper among older adults (p<.001). Results suggest that stressor control is a distinct domain of control beliefs with aging-related declines that differ based on type of stress experienced."} +{"text": "Growing evidence has shown that genetic factors play crucial roles in the disorder of eye development and the progression of ocular diseases . Ocular The eye consists of three main types of tissues: 1) refracting tissues that focus incoming light onto light-sensitive tissues , 2) light-sensitive tissues that convert detected light into electrical signals and transmit them to the brain (including the retina and optic nerve), and 3) support tissues that provide the architectural support for the shape of the eyeball . These pThis topic summarizes ten original research articles that explored the genetic effects and mechanisms of genetic factors contributing to eye development and disease from diverse aspects, providing new insights into treating eye diseases . AccordiInherited eye diseases affect approximately one in 1,000 people worldwide, but the molecular mechanisms underlying most of them remain unclear . IdentifWei et al. identified mitochondrial mutations (OPA1 and LHON-mtDNA) in nearly half of patients with ethambutol-induced optic neuropathy (EON), a well-recognized ocular complication associated with ethambutol treatment in tuberculosis patients. Since some patients with EON have severe and permanent visual loss even without the known risk factors, their findings that mitochondrial genetic variations are major predisposing factors for the development of EON provided a better understanding of EON and additional support for genetic counseling.Zhang et al. found variants in BMP4 contribute to a novel phenotype of pathologic myopia rather than syndromic microphthalmia that have been reported in a previous study , the second leading cause of pediatric lens surgery after congenital cataracts, could be caused by mutations in cbEGF-like domains of fibrillin-1 (FBN1) . HoweverLuo et al. presented work on the role of the mouse double minute 2 (MDM2) gene single nucleotide polymorphism (SNP) T309G in the development of epimacular membranes (EMMs), relatively common sight-threatening conditions characterized by fibrocellular proliferation along the surface of the internal limiting membrane (ILM) of the retina. They first reported that the MDM2 SNP309\u00a0G allele was a risk allele for EMM in a Chinese population. Their observation provides new insights into the molecular mechanism underlying these pathologies.Since the experimental studies of many inherited eye disorders in human beings are limited, the availability of genetically engineered animal models is very valuable for exploring the pathogenic mechanisms of these conditions and developing translational therapies.Zhao et al. generated a knock-in mouse model with lanosterol synthase (Lss) G589S mutation, which can recapitulate human congenital cataract resulting from G588S mutation in human LSS. Mice with homozygous Lss G589S mutation exhibited disrupted lens fiber differentiation at early-stage of lens development and down-regulated cholesterol synthesis signaling pathways. Their findings elucidate the important roles of LSS in lens development, contributing to a better understanding of LSS defects and disturbed sterol signaling in cataractogenesis and the development of therapies for cataracts.Hejtmancik et al. generated and characterized the Kcnj13 knockout mouse and RPE-specific conditional Kcnj13 knockout mice. Their work provides a potential mouse model system for elucidating the pathology of these diseases and developing gene therapy trials.Mutations in KCNJ13 are responsible for both snowflake vitreoretinal degeneration (SVD) and Leber congenital amaurosis (LCA) . ExistinASRGL1) has been reported as a causing mutation for retinitis pigmentosa (RP), an inherited retinal degenerative disease for which there is currently no cure could be reprogramed into functional retinal ganglion cells (RGCs) in vivo by Math5 and Brn3b together, two crucial transcription factors (TFs) involved in retinal ganglion cell (RGC) generation and differentiation and the optic nerve are the common features shared by all forms of glaucoma . In vivontiation . Their sHou et al. profiled a single-cell transcriptome atlas of human RPE (hRPE) cells and provided a map of disease-related genes in the hRPE. They found two subpopulations, the macular RPE and peripheral RPE clusters which exhibited substantial differences in gene expression patterns and functions, play crucial roles in the potential treatment of retinal diseases. Their work provides important information for understanding the cellular mechanisms and treating pathological conditions of the hRPE associated with ocular diseases.These research articles on the topic show that elucidating the genetic underpinnings of ocular disorders leads to a better understanding of these diseases, which will contribute to clinical diagnosis, genetic counseling, early intervention and targeted treatment. The application and advancement of integrated multi-omics will further improve our knowledge of complex traits and provide new insights into the pathogenesis of ocular diseases. New genetic methodologies based on automated methods are expected to be developed for accurate and routine diagnosis of eye diseases that have highly diverse genetic causes and are difficult to identify. And gene and cell therapies will open new doors for the treatment of currently incurable eye disorders."} +{"text": "Chronic functional gastro-intestinal disorders can affect cognitive functioning of patients (1). Wong et al (2) showed attentional and executive function impairment, Aizawa et al. (3) found impairment of cognitive plasticity and activity of frontal and temporal arias of brain during performing tests in these patients.Assessing of cognitive functioning of the female patients with chronic functional constipation.42 Rome IV adult female patients with chronic functional constipation and 26 adult normative female volunteers were tested with Brief Assessment of Cognition in Schizophrenia (BACS).Both groups were comparable by age In both groups subjects demonstrated normal level of cognitive functioning but the scores of the patients were closer to the lower level than the scores of the volunteers. The difference was significant in composite scores and in several other scores (Tab.1). Table1.The findings of the study once more indicate some link between gastrointestinal dysfunction and cognitive functioning. Even these slight decrease in some aspects of cognition from normal population could have negative impact on everyday functioning. The origin of this link is still under question.No significant relationships."} +{"text": "Mapping positional features from one-dimensional (1D) sequences onto three-dimensional (3D) structures of biological macromolecules is a powerful tool to show geometric patterns of biochemical annotations and provide a better understanding of the mechanisms underpinning protein and nucleic acid function at the atomic level.We present a new library designed to display fully customizable interactive views between 1D positional features of protein and/or nucleic acid sequences and their 3D structures as isolated chains or components of macromolecular assemblies.https://github.com/rcsb/rcsb-saguaro-3d.Bioinformatics online. Mapping positional features from 1D sequences onto 3D structures of biological macromolecules facilitates interrogation of relationships between shape and function. Sequence to structure mapping enables identification of spatial correlations and geometric patterns among protein or nucleic acid annotations that would be obscured if they were analyzed solely using linear polymer sequences. Over the last few years, various libraries, web applications and software tools have been developed to compute alignments among structures, and protein and gene sequences, and visualize positional features over the different levels of molecular organization from genome to macromolecular assemblies. 3DBIONOTES annotatiIn this work, we present a new TypeScript/JavaScript module designed to create custom interactive views between 1D sequence positional features and 3D structures of macromolecules over the web. The main motivation behind this development is to provide the structural bioinformatics community with a flexible and fully customizable tool that can be adapted for use in various contexts. To achieve this end, the library exposes multiple event callbacks that allow software developers to define bidirectional interactions between 1D positional features and 3D atomic coordinates of experimental structures (from PDB) or computed structure models ; the US Department of Energy [DE-SC0019749]; and the National Cancer Institute, National Institute of Allergy and Infectious Diseases and National Institute of General Medical Sciences of the National Institutes of Health [R01GM133198] .Conflict of Interest: none declared.btac317_Supplementary_DataClick here for additional data file."} +{"text": "Oesophageal cancer survivorship is afflicted by cancer cachexia related weight loss and nutrition impact symptoms. Identifying the factors which predict cancer cachexia specifically is warranted in order to identify those at risk and render the right kind of support. We aimed to assess if preoperative and postoperative body mass index (BMI) adjusted weight loss grading system (WLGS) is predictive of cancer cachexia at one year after surgery for oesophageal cancer.p\u2009<\u20090.05 together with a clinically relevant difference of 10-points in mean scores was considered as a significant difference.Data were used from a prospective nationwide cohort study on patients operated on for oesophageal cancer in Sweden between 2013 and 2018 included at one year after surgery. The study exposure is BMI adjusted weight loss graded into one of five distinct weight loss grades (grades 0\u20134), defined in accordance with the WLGS by combining BMI and percentage weight loss, assessed at two clinical time points: preoperative and at 6 months post-surgery for oesophageal cancer. The study outcome is subjective measures of cancer cachexia one year after surgery, assessed using the cancer-cachexia specific questionnaire EORTC QLQ-CAX24. Multivariable linear regression models calculated mean score differences (MD) with 95% confidence intervals (CI) adjusted for predefined confounders. Statistical significance at Among a total of 232 patients, the highest grade of preoperative WLGS 4 was associated with significantly worse physical decline than lower grades of WLGS 1 and WLGS 2 . Those with preoperative WLGS 2, 3 and 4 reported lower scores on the adequacy of information on weight loss provided to them than those with preoperative WLGS 0. Those with the highest postoperative WLGS 4 had greater eating and weight loss worry than WLGS 2 and WLGS 3 and worse physical decline than WLGS 0 .Higher grades of both preoperative and postoperative WLGS are predictive of cancer cachexia related physical decline one year after surgery for oesophageal cancer. Additionally, preoperative and postoperative WLGS were also predictive of inadequate information concerning weight loss and more worry regarding eating and weight loss, respectively. The WLGS may be an effective risk prediction tool for postoperative cachexia related physical decline in patients undergoing treatment for oesophageal cancer emphasizing its usability in the clinical setting. Despite improving survival rates with multimodal treatments such as chemotherapy and radiotherapy, an extensive surgical procedure remains the cornerstone of curatively intended treatment for oesophageal cancer , 2. CancOesophageal Surgery in Cancer patients: Adaptation and Recovery (OSCAR) cohort, a nationwide and prospective study of patients who were operated on for oesophageal cancer in Sweden from 2013. The data collection for the OSCAR study is ongoing. The OSCAR study is explained in detail elsewhere . Th. Th14]. n) and proportions (%). Multivariable linear regression models were used to calculate the association between preoperative and postoperative WLGS and the cachexia scale scores from QLQ-CAX24. A linear model was used since a pre-established cut-off is not available for cachexia scores and mean scores difference (MD) of 10 or more points (10%) were tested for statistical significance. A 10-point difference was regarded as clinically relevant based on previous research [Descriptive statistics were presented as counts , age at operation (continuous), comorbidities (Charlson comorbidity score 0/1/\u22652), histological sub-type (adenocarcinoma and high-grade dysplasia/squamous cell carcinoma), pathological tumour stage (0-I/II/III-IV) and neoadjuvant therapy (yes/no). For the postoperative WLGS at six months after surgery in addition to the above confounders, type of operation , postoperative complications (Clavien-Dindo score (CDS); low grade (0-II)/high grade (III-IV), enteral and/or parenteral nutrition support for at least 1 week postoperatively (yes/no) was adjusted for. Statistical analysis was conducted using SAS 9.4 software .n\u2009=\u200925) or other reasons (because they did not want/had the energy to participate (n\u2009=\u2009119), were too sick (n\u2009=\u200928), other reasons (n\u2009=\u20091)). In total, 253 (58% of eligible) completed the EORTC QLQ-CAX24 questionnaire, and 232 had complete data concerning WLGS before operation and clinical data from medical charts, hence were included in the analysis.Between January 2013 and 15 May 2019, a total of 839 patients underwent surgery for cancer of the oesophagus in Sweden. Of those, 636 patients were alive at the one-year follow-up, 113 were unreachable and one patient was excluded owing to cognitive impairment, leaving a total of 522 patients eligible for inclusion in the OSCAR cohort and 438 eligible for the current study as 84 were included in the cohort before the EORTC QLQ-CAX24 questionnaire was introduced. Among those identified as eligible, 173 (39%) declined to participate for reasons namely, cancer recurrence had a higher comorbidity score than those in the other categories of WLGS 1\u20134 (15.1% to 23.1%). More patients (43.5%) with WLGS 4 had a higher pathological tumour stage (III-IV) than those with the least WLGS 0 (31%). As many as 91.3% of patients in the WLGS 4 received enteral or parenteral nutrition support compared to 77.5% in the WLGS 1 from the five weight loss grades were reported in the eating and weight loss worry dimension MS 30 to 38) and food aversion dimension (MS 28 to 34) [Table 0 to 38 aAmong the dimensions of the QLQ-CAX24 as per the five grades of postoperative WLGS at six months after surgery, the highest MS were reported in the eating and weight loss worry dimension MS 21 to 38) and food aversion dimension (MS 21 to 33) [Table 8 and fooThis population-based prospective cohort study on patients who underwent surgery for oesophageal cancer, exploring if the WLGS is a predictor of long-term cancer cachexia indicated that higher grades of both preoperative and postoperative WLGS are associated with cancer cachexia related physical decline at one year after surgery for oesophageal cancer. Additionally, higher grades of preoperative WLGS were also associated with inadequate information on weight loss aspects of cancer cachexia. Meanwhile, higher grades of postoperative WLGS was also predictive of eating and weight loss worry among patients. The results signify that the WLGS maybe a useful predictor of specific cancer cachexia related decline in oesophageal cancer patients.Several methodological aspects in the present study add to its strength. The population-based nationwide data collection with a longitudinal design minimised selection bias and increased generalisability of the results. The OSCAR cohort is comprised mostly of male patients, which is typical for oeophageal cancer and hence considered representative of the disease demographics and generalisable. Adherence to a strict protocol for data collection further reduced the scope for bias, and another added strength is the unique home-based data collection which reduced missing values. However, selection bias through non-participation of those who were unreachable and declined participation in the study cannot be neglected and may be considered a potential limitation. The choice of the WLGS as the assessment tool for the exposure and EORTC QLQ-CAX24 for the assessment of the outcome is also a strength in the present study. The WLGS has marked a crucial step in redefining clinically important weight loss where BMI is included and has thus been included in the current international clinical practice guidelines for nutrition and cancer . MoreoveIn our study, both the higher grades of preoperative and postoperative WLGS was predictive of physical decline at one year after surgery for oesophageal cancer. In the treatment of patients with oesophageal cancer, resection surgery remains the cornerstone of curatively intended treatment . The surOur results highlight that the WLGS may be a good risk prediction model for the cancer cachexia related physical decline in patients undergoing treatment with oesophageal cancer emphasizing its usability in the clinical setting. The persisting and long-term issues concerning eating and weight status are also a major challenge for health care and the WLGS is a more clinically relevant and robust tool for cachexia related physical decline after surgery for oesophageal cancer.Table S1Table S2"} +{"text": "Night work has been widely studied for the associations with diseases, sickness absence (SA) and disability pension (DP), but less for sustainable working life. We aimed to investigate the longitudinal changes in sustainable working life among those with or without baseline night work.Using data from Swedish national registers, sustainable working life was defined as employment during follow-up without interruptions due to SA/DP, unemployment, and old-age pension. Survey data for two cohorts were utilized to assess night work at baseline (yes/no) in 1998-2003 and 2004-2006, respectively. The final samples for the two cohorts were 34680 and 19637, respectively. Group-based trajectory models were applied.Among those born before 1959 , a five-trajectory solution was best for those with and without night work. The trajectory groups were stable sustainable working life (38-42%), stable unsustainable working life (24-25%), early (13%) or later (13%) decreasing sustainable working life, and between sustainable and unsustainable working life (7%). Among those born after 1958 , four trajectories were detected for those with night work: stable sustainable working life (81%), stable unsustainable working life (6%) and increasing (7%) and decreasing (5%) sustainable working life. For those without nightwork, a three-trajectory solution was best: stable sustainable working life (83%), stable unsustainable working life (6%) and between sustainable and unsustainable working life (11%).Sustainable working life was similar across baseline night work statuses of older cohort but differed in younger cohort. The findings suggest that at least night work at one time point does not affect sustainable working life. However, night work at early stages of working life could be accompanied with lifestyle counselling for sleep and recovery.\u2022\u2002Trajectories of sustainable working life seem similar for those with or without night work adding to the understanding of effects of such work to health.\u2022\u2002From public health perspective, counselling employees with night work already at early stages of working life for health behaviours including sleep and recovery could support sustainable working life."} +{"text": "This review describes the recently FDA-approved drugs (in the year 2022). Many of these products contain active moieties that FDA had not previously approved, either as a single ingredient or as part of a combination. These products frequently provide important new therapies for patients with multiple unmet diseases. The diverse small molecules are described according to the date of approval and their syntheses is discussed. This review comprises classical chemical scaffolds together with innovative drugs such as a deuterium-containing drug. The constant research for innovative therapies leads every year to molecules that are approved by the United States Food and Drug Administration (FDA), a federal agency of the U.S. Department of Health and Human Services.Novel building blocks and their connections have been explored much in recent years allowing drug hunters to explore a much bigger chemical space .Small molecule drugs are organic compounds with low molecular weight. For a long time, they have been the backbone of the pharmaceutical industry. There are several benefits that make small molecules important drugs in therapy, such as the possibility of oral administration and cell membrane permeability which allow them to reach specific tissue and targets. For this purpose, small molecule drugs can be designed in order to acquire, for example, specific affinity and selectivity .The goal of this review is to highlight the chemical entities approved in the year 2022 for clinical use. The approved drugs (and their synthesis) are listed according to their chronological approval date . This pa11) (brand name Quviviq\u00ae) is a 1,2,3-triazole derivative with an expected global sales to 2026 of $1052 million pyrimidine 14 in the presence of diisopropylethylamine (DIPEA) to give the intermediate 15 which underwent the deprotection of carboxylbenzyl protecting group under acidic conditions (HBr) to afford 16. The free primary amino group of 16 reacted with the propane-1-sulfonyl chloride 17 to provide the sulfonamide 18. The last stage (yield: 74%) involved the removal of tosyl group by using lithium hydroxide or sodium hydroxide in ethanol to generate Abrocitinib (19).Approved in January 2022 (14 January 2022), abrocitinib was approved for the treatment of hereditary hemolytic anemias sta sta16] s41) was authorized for the treatment of seizures in cyclin-dependent kinase-like 5 deficiency disorders to provide PSMA-617 (52).Its structure is composed of PSMA-617, a human prostate-specific membrane antigen (PSMA)-targeting ligand, conjugated to the beta-emitting radioisotope lutetium, Lu 177 (177Lu) . The syn177Lu) ,23. The 67, brand name Vivjoa\u00ae) was approved in April 2022 (26 April 2022) with the indication of reducing the incidence of recurrent vulvovaginal candidiasis (RVVC) in females with a history of RVVC who are not of reproductive potential [The antifungal oteseconazole at \u221265 \u00b0C to afford derivative 57. The following Henry reaction provided the mixture of nitro alcohols 59 and 60 (S enantiomer of 59) in the presence of 5% mol of organocatalyst 58. The enantiomeric ratio of the couple 59:60 was 90:10. The organocatalyst 58 proved to be the most effective in stereoselectivity among the many others tested. The subsequent catalytic hydrogenation of the mixture of nitro alcohols led to the corresponding amines 62 and 63. The conversion of 62 and 63 to the corresponding tetrazoles 64 and 65 was mediated by trimethylsilyl azide and trimethyl orthoformate in the presence of acetic acid. The last step involves a Suzuki coupling between the aryl bromide of 64 and 65 and the boronic ester 66 catalyzed by (diphenylphosphino) ferrocene] dichloropalladium (II) to generate the desired oteseconazole 67. The authors claim that an enantioenriched (95.9%) form of 67 was obtained via diastereomeric recrystallisation with (S)-Camphor sulfonic acid ,26 25,26\u00ae) was approved in April 2022 (28 April 2022) for the treatment of certain classes of obstructive hypertrophic cardiomyopathy [Mavacamten which upon reaction with trimethylsilyl isocyanate 70 is converted to isopropylurea 71. The reaction between 71 and dimethyl malonate in the presence of sodium methoxide as base gave 1-isopropyl barbituric acid 72. The subsequent conversion to chloride derivative 73 is mediated by POCl3 using triethylbenzylammonium chloride (TEBAC) as phase transfer catalyst. The last stage is the nucleophilic addition of (S)-methylbenzylamine (74) to 73 in order to afford mavacamten 75. Last step yield was 69% [Its synthesis 29] sta sta29] s\u00ae) was approved in May 2022 (3 May 2022) for the treatment of Helicobacter pylori infection sta sta35] s\u00ae) was approved in September 2022 (9 September 2022) and for the treatment, as in the case of tapinarof, of plaque psoriasis [Deucravacitinib (brand name Sotyktusoriasis . It is esoriasis .It is a deuterated drug launched by Bristol Meyers Squibb selectiv89 which is firstly methylated with methyl iodide and later converted into amide by ammonolysis to afford the intermediate 90. The treatment of 90 with DMF-DMA followed by condensation with hydrazine hydrate yielded the triazole 91 which was then methylated in presence of methyl iodide and potassium hexamethylsilazide to generate compound 92 in a good regioselectivity (8:1) over compound 93.Its synthesis 38] sta sta38] s92 was subjected to catalytic hydrogenation to give the substituted aniline 94 which was then mixed with the pyridazine 95 and aqueous potassium triphosphate resulted in a better yield and milder conditions if compared to the triad XantPhos/Pd2(dba)3/Cs2CO3. Last step yield was 76%.Pure compound azine 95 in the pApproved in September 2022 (21 September 2022), gadopiclenol is used to detect and visualize lesions, together with Magnetic Resonance Imaging (MRI), with abnormal vascularity in the central nervous system and the body ori ori42] o\u00ae dichloropalladium (II)] between halide 124 and alkyne 125 provided the derivative 126. The subsequent nucleophilic attack (resulting in inversion of configuration) of 126 to mesyl-protected alcohol 127 afforded the pyrrolidine derivative 128 which was subjected to BOC-removal by addition of HCl to give 129. The final step involves another nucleophilic attack (acylation) of 129 to acryloyl chloride (130) followed by neutralization with sodium bicarbonate to yield futibatinib (131).Its structure contains a pyrazolo-pyrimidine scaffold and the synthesis 53,54] ,54 53,54Sulfonamide-containing drugs (four entities) are arising among the approved molecules in 2022. Sulfonamides were among the first examples of carboxylic acid isosteres to show utility in drug design .\u00ae, In the previous year (2021), only odevixibat (brand name Bylvay19), a pyruvate kinase enzyme activator , a potassium-competitive acid blocker (P-CAB) represented by vonoprazan and a selective prostaglandin E2 receptor agonist . None of these molecules in the synthesis of folic acid which is essential for the further production of DNA in the bacteria [Historically, the first sulfonamide drug was prontosil rubrum . This cobacteria . Anotherbacteria .Interestingly, none of the sulfonamides approved by FDA in 2022 belong to the last two groups of inhibitors, creating novel opportunities in hitting novel and diverse targets.Moreover, a key-feature that would help in the design of novel bioactive compounds is the fact that sulfonamides possess high hydrolytic stability .In this work, all small molecule drugs that were approved by the FDA in 2022 were discussed. For each compound, the biological activity and the chemical synthesis were provided. It appears that sulfonamide-containing drugs are dominating the year 2022 with four molecules approved. Their physicochemical and pharmacodynamic properties still play an important role many years after the discovery of the first sulfonamides endowed with antibacterial activities.Deuterium-containing drug deucravacitinib represents, on the other hand, an example of novel approaches in drug discovery incorporating an unusual isotope to provide drug stability.The discovery of pyrimidinedione mavacamten for the treatment of cardiomyopathy and the huge forecasted sales for thisThe combination of drugs, for example vonoprazan (in combination with amoxicillin and clarithromycin) and taurursodiol (in combination with sodium phenylbutyrate) is still a valid weapon for the treatment of unmet medical diseases.The 15 FDA-approved small molecules in 2022"} +{"text": "Sphenoid sinus mucocele (SSM) caused by obstruction of sinus ostium while sphenoid sinus retention cyst (SSRC) is due to obstruction of mucinous gland ostium which could enlarge to obstruct the sinus ostium and lead to acute sinusitis or mucocele,Incidence of isolated SSM is about 2% out of paranasal sinus (PNS) mucocele, but there is no specifically occurrence rate regarding SSRcWe herein describe one case of SSM and two cases of SSRC with sudden unilateral visual loss that recovered following endonasal endoscopic sinus surgery.A 25-year-old man with left-sided vision loss (light perception (LP), afferent pupillary defect (APD)) occurred within 24 hours, was referred after 10 days of the attack.Magnetic resonance imaging (MRI) showed a mass with rim enhancement obstructing the sphenoid sinus ostium . ComputeA 12-year-old boy with a history of gradual visual loss of left eye over 2 month-period was referred because of left sphenoid sinus mass in MRI with no Gadolinium uptake that was compatible with SSRC. There was no obvious compression of the optic nerve in the CTS or MRI .(28-year-old woman) showed up with total visual loss (LP and APD) of the right eye over 34 day period and retro-orbital pain. She had a similar attack 4 years earlier treated with 2-week administration of Dexamethasone. MRI showed an RC in the sphenoid sinus touchingAll patients were referred by ophthalmologist with the first diagnosis of retrobulbar optic neuritis (RON) following incomplete recovery with administration of glucocorticoids. The patients underwent endoscopic endonasal approach and the cysts were removed. Total vision and visual field recovery were achieved in case 1 and 3 and partial recovery in second case.Isolated inflammatory diseases of SS are infrequent comparing to other paranasal sinuses. However neglected sphenoiditis could lead to critical complications by affecting adjacent vital structures such as cranial nerves II, III, IV, VIVisual loss and blindness often occur following circulatory disorders of the optic nerve caused by prolonged mucocele pressure that erode the bone and put the nerve in jeopardyMucocele could show four patterns of MRI signal intensity according to the protein concentration revealing its chronicityA high index of suspicion is needed for proper diagnosis of this entity especially for neurologists and ophthalmologists who are usually first physicians visiting sudden visual loss cases."} +{"text": "Scientific Reports 10.1038/s41598-022-10708-9, published online 05 May 2022Correction to: The original PDF version of this Article contained errors in the Results section under the subheading \u2018Pulse width\u2019, where the confidence intervals of the median relative perception thresholds The confidence intervals of the median relative attention thresholds The confidence intervals of the median relative intolerance thresholds Table 2 shows the results of linear regression The original PDF version of this Article has been corrected."} +{"text": "The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) showed the benefits of blood pressure (BP) lowering for secondary stroke prevention in stroke survivors for the first time after a long dispute in the last century and trigIn the present post hoc analysis of RESPECT, Kitagawa et al. examined the effect of intensive BP lowering on recurrent stroke subtype risk in patients with a history of ischemic stroke, accounting for 84% of the overall participants in RESPECT . The majAnother major finding of the RESPECT sub-analysis was that the risk of recurrent ischemic stroke was almost identical between two treatment groups with different BP lowering targets . The uncAs the adverse events of intensive BP lowering, the authors of the RESPECT sub-analysis indicated caution regarding falls and renal dysfunction . Acute kThe current guidelines recommend systolic BP control aiming at <130\u2009mmHg or 120\u2013130\u2009mmHg for adults who experience ischemic stroke \u201312. RESP"} +{"text": "Drawing on the life course perspective and multi-channel sequence approach, this research identifies long-term financial hardship and income security patterns among older adults and examines their relationship with depressive symptoms. Data were from the 2010 to 2018 HRS with 3,077 older workers aged 62\u201371 in 2010. Four clusters of key sequences were identified: 1) High food and low medical insecurities with private pension plans (43%); 2) Moderate food and low medical insecurities with gradually acquired private pension plans (13%); 3) High food and low medical insecurities with both private and employment-based pension plans (40%); 4) High food insecurity with employment-based pension plans(3%). Regarding the association with depressive symptoms, a group of people who experienced high food and low medical insecurities with private pension plans and those who experienced moderate food and low medical insecurities with gradually acquired private pension plans were more likely to have depressive symptoms compared to those high food and low medical insecurities with both private and employment-based pension plans. These findings highlight the heterogeneity of long-term patterns of financial hardships and patterns of income security, including the limited accessibility for a pension plan through their occupation and that an individual pension plan may not be sufficient to ensure mental health in later life. The results imply the importance of dual security of private and employment-based pensions on their mental health and provide important insights for future tailored income support programs for older adults."} +{"text": "Alzheimer's disease (AD) is the most common dementia syndrome in the elderly and a devastating neurodegenerative disease without any cure available currently. AD patients usually present insidious onset and progressive cognitive impairments with unique post-mortem diagnostic brain pathology including accumulation of amyloid beta (A\u03b2) and hyper-phosphorylated tau proteins and highlights both basic and clinical studies in the relevant field. In total, seven original research articles from investigator groups across the world using multiple state-of-art scientific approaches reported AD- or ADRD-related metabolic signaling alterations in rodent models or human subjects.The current Research Topic \u201cZhao et al.) analyzed plasma metabolites profile in the MCI patients by using a high-resolution mass spectrometry metabolomics approach. The results indicate an association between dysregulated sphingolipid metabolism and behavioral performance in the MCI patients, providing insights into development of novel blood biomarker for MCI.The Qi Guo group examined the relationship between AD polygenic risk score (PRS) and longitudinal decline of cognition function in older adults with type 2 diabetes (T2D). Interestingly and contrary to the authors' hypothesis, the analysis revealed no significant association between the AD PRS and multiple measurements in older adults with T2D such as cognitive decline, hippocampal volume, and A\u03b2 burden. Their findings indicate a complex relationship between AD genetic susceptibility and cognitive impairments in T2D.The Lior Greenbaum group reported that global knockout of the mRNA translation factor eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) led to improvement of cognitive function in a mouse model of AD without affecting the brain A\u03b2 pathology. The study provides further evidence to suggest that targeting eEF2K signaling dysregulation might be a feasible therapeutic approach for ADRDs.The laboratory of Tao Ma biometric components and the gray matter volume (GMW) in different brain regions. They found that decreased GMV across all the examined brain regions in the MetS patients is correlated best with waist circumference. Surprisingly, posterior cerebellum is the brain region mostly correlated to the MetS biometric components.Weise et al. analyzed the data of the MCI participants from the AD Neuroimaging Initiative (ADNI) study and reported a correlation of higher body mass index (BMI) with greater regional cerebral metabolic rate for glucose (rCMGgl) and slower cognitive decline in MCI. Such association is not related to leptin levels. Future studies are necessary to illustrate the mechanisms underlying such correlations between brain glucose utilization and body weight.Smith et al.) reported their unexpected findings revealing novel roles of the AD risk gent Abelson interactor family member 3 (Abi3) in metabolism. They found that the Abi3 knockout mice exhibited impaired energy expenditure, increased body weight and body fat, and impaired glucose tolerance and insulin sensitivity. The study may contribute to our understanding of the metabolic factors in AD development.The laboratory of Jungsu Kim (Kurano et al. examined postmortem human brains to understand potential association of the bioactive lipid regulation with the AD pathology. The study showed distinct pattern of bioactive lipid modulation correlated to AD pathogenesis.Frontiers in Aging Neuroscience is to increase overall interest in this under- investigated area of research and bring investigators from both basic science and clinical research fields. We are encouraged and excited by the findings reported in these articles and look forward to future in-depth studies on the topic to facilitate our underlying of the mechanisms underlying aging and ADRDs.In summary, accumulating evidence indicates a link between metabolic signaling dysregulation and cognitive impairments associated with aging and Alzheimer's disease. An important goal of this Research Topic in TM wrote the manuscript. RC and SM edited the manuscript. All authors contributed to the article and approved the submitted version."} +{"text": "Many elder abuse interventions and tools designed to screen for abuse exclude older adults with cognitive impairments (CI) due to the challenges associated with screening and whether the older adult with CI can reliably report elder abuse. However, it has been shown that older adults with CI are among the most vulnerable to experiencing elder abuse. VOICES is an innovative, automated tablet-based elder abuse screening and prevention intervention that is self-administered by the older adult in the provider\u2019s waiting room or office. The VOICES Elder Abuse Intervention (EAI) provides screening, educational modules, and brief psychoeducational intervention to enhance and improve identification of elder abuse when there are no visible signs of abuse. The VOICES EAI was already proven successful in terms of feasibility and acceptability in cognitively intact older adults in a busy emergency department setting with . In this study we tested the VOICES EAI with (N=30) participants 60 and above with cognitive impairment at a geriatric center using the Montreal Cognitive Assessment (MoCA) to determine cognitive capacity. Experts in the field of geriatrics and cognitive impairment assisted in grouping participants within three cognitive categories: Mild cognitive impairment (MoCA 23-25), mild dementia (MoCA 16-22) or moderate dementia (MoCA 8-15). Of the (N=30) participants, 29 were able to successfully use the VOICES EAI independently, and most participants were satisfied with the tool. We will discuss the findings of this preliminary study and the implications for future research with older adults with CI."} +{"text": "The advent of the SARS-CoV-2 virus necessitated behavior changes for most older adults. Changes were largely associated with voluntary or enforced compliance with social distancing policies. Whereas the value of social distancing for mitigating the spread of the dangerous SARS-CoV-2 virus is not the subject of serious debate among public health advocates, policies that encouraged or enforced social distancing have been met with skepticism in the general public. Understanding patterns in behavior changes may be helpful to public health professionals and policymakers who develop health communication and revised guidelines in the efforts to contain the spread of the SARS-CoV-2 and future public health infections. Our study examined patterns in behavior changes. This study had two aims. First, using survey responses from 661 adults living in rural areas about changes they made to 20 different behaviors, we identified four classes of behavior changes: (1) non-social distancers (10.7%), (2) social distancers (54.0%), (3) social distancers making civic exceptions (24.0%), and (4) social distancers making religious exceptions (11.3%). Second, polytomous logistic regression was used to predict the probability of membership in those latent patterns of behavior change. Predictor variables included demographic variables and variables theoretically predicted to covary with patterns of behavior change . This study provides insight into behavior changes during the outbreak of the SARS-CoV-2 virus that may be used by practitioners to understand variations in how people responded to the outbreak."} +{"text": "The ductus venosus (DV) carries oxygen-rich blood from the umbilical vein (UV) to the heart, bypassing the fetal liver. In 1:500 to 1:2500 pregnancies, the DV is either missing or it drains at an atypical site. The types of DV abnormalities are grouped according to the drainage site (intra- or extrahepatic) and whether they bypass the liver . The presence of a DV abnormality increases the risk of other fetal defects, especially cardiac and genetic abnormalities (3).In the image, color Doppler is used to demonstrate normal DV anatomy and five typical abnormalities:Figure Figure Figure Figure Figure Figure Figure"} +{"text": "ESCs can be obtained from the inner cell mass of the blastocysts and give rise to all the embryonic three germ layers, however, the critical ethical predicament limits ESCs clinical applications. iPSCs possess the same differentiation capacity as ESCs but avoid ESCs usage-associated ethical dilemmas. Therefore, the generation of iPSCs Stem cells inhabit specialized microenvironments called \u201cstem cell niches\u201d that maintain a hypoxic and low level of reactive oxygen species (ROS) environment. The stem cell niche is essential for preserving stem cell stemness and self-renewal potency. ROS has been considered for a long time to be implicated in stress and various disorders and has been redefined as a vital signaling molecule with multifaceted functions in modulating stem cell biology and differentiation .2O2) and the superoxide anion radical (O2.-), are produced primarily by NADPH oxidases and controlled by growth hormones, cytokines, cytokines, mitochondrial electron transport chain. There are more than 40 enzymes involved in this process. H2O2 is implicated in a vast majority of redox-associated modulation of biological activities reactions and form oxidative alteration on biological macromolecules, and ultimately activate key redox signaling and its related biological functions. Two key ROS signaling molecules hydrogen peroxide /protein kinase B (Akt) pathway. This finding is the main attribute in cyclic mechanical stress-mediated PDLSCs\u2019 osteogenic differentiation.The cyclic mechanical stress was found to boost the ROS level and induce the expression of nuclear factor erythroid-2-related factor-2 (Nrf2) and its downstream molecules including heme oxygenase 1 (HO1) and NADPH dehydrogenase quinone 1 (NQO1), which ultimately promoted the osteogenic differentiation in human periodontal ligament stem cells (PDLSCs) . In thisSinenko et al. covers the recent advances in the physiological functions of the intracellular ROS as a signaling molecule and a secondary messenger of a wide range of cellular signaling in modulating the potency and differentiation of stem cells as well as the development of invertebrate Drosophila.A well-written review paper from Sheng et al. showed that a novel natural antioxidant compound, Caffeic acid (CA) efficiently delayed the aging events in the Drosophila gut, which is associated with the aberrant function of intestinal stem cells (ISCs) and the subsequent dysplasia. This beneficial antioxidant effect is attributed to the potency of CA to suppress oxidative stress-induced JNK signaling.A study by Drosophila as a proper genetic model for studying the mitochondrial electron transport chain and mitochondrial ROS-associated biological functions and the necessity of translating various pathophysiological aspects in Drosophila that are enigmatic in humans. While editing this Research Topicr, we hoped that the contributed research work would serve as an inspiration for scientists in the field to investigate further mechanisms and applications of ROS signaling in flies that could be translational for promoting ROS-mediated enhanced stem cell function and clinical applications.These studies underscored the importance of Wang et al. demonstrated the beneficial effects of the bone marrow mesenchymal stem cell-derived exosomes on the pathogenesis of osteoarthritis through targeting the competitive endogenous RNA (ceRNA) networks represented in LYRM4-AS1/GRPR/miR-6515-5p signaling pathway.Moreover,"} +{"text": "Delusions are a key feature of schizophrenia psychopathology. From a phenomenological approach, Jaspers (1913) differentiates between \u201cprimary\u201d or true schizophrenic delusions, defined as an unmediated phenomenon that cannot be understood in terms of prior psychological origin or motivation, and \u201csecondary\u201d delusions, understandable from the patient\u2019s mood state or personality. Primary delusions have been considered the hallmark of reality distorsion dimension in schizophrenia, disregarding a possible affective patwhay to delusional belief.The present study was aimed at elucidating the psychopathological trajectories to delusion in schizophrenia through the investigation of both affective and schizotypal trait dispositions.Seventy-eight participants affected by schizophrenia were administered the Peters Delusional Inventory (PDI), the Positive and Negative Affective Scale (PANAS), the Experience of Shame Scale (ESS), the Referential Thinking Scale (REF), the Magical Ideation Scale (MIS) and the Perceptual Aberration Scale (PAS).The severity of delusional ideation (PDI) was positively related to both affective and schizotypal traits . Moreover, referential thinking (REF) mediated the relationship between \u201cmagical ideation\u201d (MIS) and delusions severity , whereas experience of shame (ESS) was a moderating factor in the between referential thinking and delusion severity .The study findings suggest that in schizophrenia patients, severity of delusions is underpinned by an intertwining of both affective and schizotypal pathways.No significant relationships."} +{"text": "The link between social connectedness and dementia risk and resilience has been examined using a diverse set of measures. Though different measures of connectedness reflect distinct social processes and underlying mechanisms , few studies have compared them. Using data from two social network studies of older adults (N=283), we compare associations between 29 measures of social connectedness and general cognitive function (MoCA), and non-verbal (Rey) and episodic memory (Craft). Measures of social participation and social support were unassociated with cognitive outcomes, net of controls. Quality of friendships (p<.05), family relationships (p<.01), and marriage (p<.05) were sporadically associated. Measures indicating large, diverse, and expansive networks were strongly and consistently related to all cognitive outcomes . We discuss implications for theories of cognitive reserve."} +{"text": "Spouses often assume the role of informal caregivers for older adults living with mild cognitive impairment (MCI). These couples represent a population with low levels of physical activity, however, there is limited research regarding promotion of physical activity among these dyads. The purpose of this study was to evaluate the feasibility of a dyadic intervention, hypothesized to enhance physical activity via mutual support. We recruited three dyads (mean age: 66 [MCI] and 67 [spouse] years) from a local memory clinic. The dyads were asked to engage in physical activity together for 16 weeks. The weekly intervention consisted of 150 minutes of moderate-to-vigorous physical activity (MVPA) on their own and two lower body strength training sessions per week, one videoconferencing-supervised and one on their own. The adherence rate to the weekly MVPA and strength training was 88% and 83%, respectively. However, the percentage meeting the goal of 150 minutes/week of MVPA as measured using a Fitbit was 31% and 73% among those with MCI and spouses, respectively. There were no issues with the retention rate (100%) or safety; satisfaction scores were high . Exit interviews revealed three key themes: (1) value of the program , (2) difficulties , and (3) suggestions to improve the program (incorporating various types of strength training). Our dyadic intervention was feasible to support regular physical activity for older adults living with MCI and their spouses. Future work will incorporate participants\u2019 feedback to optimize the intervention."} +{"text": "ASD with epileptic seizures (ES) and/or specific epileptic activity on EEG (EEG SEA) and repetitive movements and vocalizations (RMV) can be determined by different variants of genetic polymorphism or by different variants of gene expression, determined by different influences.To study the features of the clinical phenotype of ASD in preschool and school-age children with ES, EEG SEA and RMV.: The study group was divided 116 children aged 2-10 years with ASD into three subgroups: subgroup A - 23 children with a history of ES, subgroup B - 35 children with EEG SEA without ES, subgroup C - 19 children with ASD having EEG SEA, RMV . The control group consisted of 39 children with ASD non a history of ES and EEG SEA.: Children with ASD, complicated by severe and frequent ES are charactered by impaired social reciprocity and communication against the background of regression / stagnation of speech and motor skills development . Disoders of communication and repetitive behavior in ASD in children of different ages are represented by different monoqualitative syndrome (phenotypes). Movement stereotypes predominated in children with ASD without ES and without EEG SEA . In children with ASD and EEG SEA, motor stereotypes and repetitive behavior were equally common .: Disorders of social reciprocity, communication, repetitive behavior are diagnostically significant for ASD complicated by ES, ASD with EEG SEA.No significant relationships."} +{"text": "Emotion globalizing is an individual difference variable referring to the extent to which daily variations in an individual\u2019s current emotions spillover into their evaluations of life satisfaction. The present research sought to: 1) extend the conception of emotion globalizing to stressor-related emotions, 2) examine age differences in these processes, and 3) differentiate associations with evaluations of life satisfaction and day satisfaction. To do so, we used daily diary data from two adult lifespan community samples . Multilevel models revealed older (compared to younger) adults exhibited less negative (but not positive) emotion globalizing and stressor-related emotion globalizing. No age differences were revealed in the association between stressor-related emotions and day satisfaction. These findings support and extend assumptions underlying the mechanisms of emotion globalizing and inform theories of emotional aging."} +{"text": "The International Health Regulations (IHR) 2005 are an international legal instrument adopted by World Health Organization General Assembly to strengthen global health security and empower the countries to prevent and respond to public health threats.This study was done within the Joint Action on Strengthened International Health Regulations and Preparedness in the EU (SHARP JA) with the aim to assess the strengths and weaknesses in preparedness and IHR implementation in order to develop and improve countries\u2019 IHR capacities. Desk-based review and analysis of available data from the States Parties Annual Report tool (SPAR) from 2019 were done. Data (for 13 IHR capacities with 24 indicators) were analyzed for 15 countries participating in SHARP JA with gross national income (GNI) less than 90% of the EU average.The overall capacity for IHR implementation in low GNI countries is 69%, ranging from 33% in Bosnia and Herzegovina to 84% in Spain. The highest capacities are recognized in the area of Legislation and financing - 78%, IHR Coordination & NFP Functions - 77%, Food Safety - 76%, and Health service provision - 76%. The weak areas with the need for further improvement are recorded in the Points of entry (PoE) - 51%, Risk Communication - 52%, Chemical events - 60%, National health emergency framework - 65%, Surveillance - 66%, and Human Resources - 67%. The overall IHR capacity of low GNI countries is lower compared to the SHARP JA countries and the European average (76% and 73% respectively).The results have shown the strongest and the weakest points of the IHR implementation in low GNI countries. This indicates the need for capacity building and further development in identified areas .\u2022\u2002The assessment of the strengths and weaknesses in preparedness and IHR implementation is the key prerequisite for identifying countries\u2019 needs for their capacity enhancement.\u2022\u2002Special attention should be given to the strengthening low GNI countries\u2019 capacities."} +{"text": "There is emerging literature about older adults\u2019 experience of loneliness during the COVID-19 pandemic in long term care (LTC) facilities due to isolation protocols. Additionally, staff challenges while providing care for older adults in LTC has also been highlighted. While the literature emphasizes negative pandemic experiences, a gap exists with understanding resilience during the pandemic in LTC settings. The aim of this qualitative descriptive study was to explore the experience of resilience in a Continuing Care Retirement Community (CCRC) among residents, their family members, and staff. We conducted 19 in-person interviews and 1 via Zoom in fall 2021 with 5 residents (65 and older), 5 family members, and 10 staff . A conventional content analysis was employed. While we did hear how the pandemic had a negative impact on everyone, the main themes of resilience identified were: 1) overcoming the pandemic together (sense of community); 2) experience and adaptation (over time being able to adapt to the disruption in their life); 3) staying safe (engaging in precautions and self-care strategies); and 4) positivity . Study findings can inform CCRC administrators on how to support residents, their family, and staff during future pandemics and other challenging times that may disrupt normal routines."} +{"text": "This study examines the psychosocial impact of COVID-19 on cognitive aging Middle Eastern/Arab Americans immigrants and refugees in Michigan. Sociopolitical experiences as an immigrant and/or refugee may have unique effects on late-life cognitive health. Given that social engagement reduces the risk of ADRD, this study sought to examine the consequences of COVID-19 socialization restrictions on familial and communal support systems for aging Middle Eastern/Arab immigrants and refugees. Three focus groups discussions with 8-10 participants each (N=31) conducted at local Arab organizations and religious institutions were conducted followed by inductive analysis. Preliminary results indicate two prominent themes: 1) Social and Familial Hardships; and 2) Isolation. Narratives illustrate the prevalence of psychosocial ADRD risk from COVID-19. Findings are discussed within a stress framework to advance universal and unique elements of Arab immigrant and refugee cognitive aging."} +{"text": "In Alberta, Canada, we quantified the rate of potentially inappropriate oral antibiotic prescribing in emergency departments for viral infections or conditions not likely requiring antibiotics from 2010-2020 and assessed the impact of two Choosing Wisely Canada (CWC) campaigns (2015/2016 and 2018) discouraging inappropriate antibiotic prescribing in emergency medicine.We linked emergency department adult and pediatric records from the National Ambulatory Care Reporting System and medication dispensations from community-based pharmacies in the Pharmaceutical Information Network. From January 2010 to February 2020, we identified emergency department visits for 5 conditions that were potentially inappropriately treated using antibiotics per CWC recommendations . We used an interrupted time series design to detect changes in antibiotic prescribing by fitting Autoregressive Integrated Moving Average (ARIMA) models to account for secular trends and seasonality, allowing for change in slopes to measure the effect of each CWC intervention.Antibiotics were commonly prescribed in emergency departments for bronchitis (proportion of visits with antibiotics: 57%) and asthma (22%) in adults; bronchiolitis in children (43%); pharyngitis (39%) and acute otitis media (54%) in adults and children. Based on visual inspection, the proportion of emergency department visits for each condition where antibiotics were dispensed remained relatively consistent. The ARIMA models demonstrated mixed impacts on potentially inappropriate antibiotic prescribing associated with two interruptions: the 2015/2016 CWC recommendations and subsequent 2018 CWC Using Antibiotics Wisely campaign. Following each interruption, antibiotic prescribing was slightly reduced for bronchitis and bronchiolitis (not significant) , but unchanged for asthma and pharyngitis , and slightly increased for acute otitis media (not significant) .Rates of potentially inappropriate antibiotic prescribing remained constant over the past 10 years in Alberta. Campaigns to rethink antibiotic use in emergency medicine may have resulted in small decreases in antibiotic use; however, further initiatives building upon existing campaigns are required to substantially reduce rates of inappropriate antibiotic prescribing."} +{"text": "Children with acute brain damage make up a large group of patients who require multi-stage rehabilitation. Rehabilitation requires the creation of special conditions for psychiatric care and psychological and pedagogical correction of the consequences of severe damage to the nervous system.To identify the options for mental activity during the restoration of the level of consciousness in children after acute severe brain damage.210 children under the age of 18 with severe brain damage . Clinical-psychopathological, pedagogical methods were used; additionally diagnostic scales, questionnaires.4 groups were formed: 1st 37 (18%) patients had manifestations of mental activity with physical, cognitive and social capabilities in the minimal consciousness \u201c+\u201d ; 2nd 67 (32%) - manifestations of physical and cognitive abilities with minimal consciousness \u201c-\u201d (a- / hyperkinetic mutism without reactions); 3rd 95 (40%) - only the manifestation of physical capabilities at the exit from the vegetative status. 4th 11 (10%) - a low manifestation of mental activity in the form of physical capabilities with a vegetative status.4 variants of mental activity in children after acute severe brain damage have been identified: from minimal involuntary reactions or their absence in vegetative status to voluntary actions according to the instructions of an adult in minimal consciousness \u201c+\u201d. Taking into account the variability of mental activity helps to differentiate the methods of psychiatric and psychological-pedagogical assistance in the recovery of children already in the early stages of rehabilitation."} +{"text": "A key facet of innate immunity in plants entails the recognition of pathogen \u201ceffector\u201d virulence proteins by host Nucleotide-Binding Leucine-Rich Repeat Receptors (NLRs). Among characterized NLRs, the broadly conserved ZAR1 NLR is particularly remarkable due to its capacity to recognize at least six distinct families of effectors from at least two bacterial genera. This expanded recognition spectrum is conferred through interactions between ZAR1 and a dynamic network of two families of Receptor-Like Cytoplasmic Kinases (RLCKs): ZED1-Related Kinases (ZRKs) and PBS1-Like Kinases (PBLs). In this review, we survey the history of functional studies on ZAR1, with an emphasis on how the ZAR1-RLCK network functions to trap diverse effectors. We discuss 1) the dynamics of the ZAR1-associated RLCK network; 2) the specificity between ZRKs and PBLs; and 3) the specificity between effectors and the RLCK network. We posit that the shared protein fold of kinases and the switch-like properties of their interactions make them ideal effector sensors, enabling ZAR1 to act as a broad spectrum guardian of host kinases. Arabidopsis thaliana, the extracellular domains of leucine-rich repeat receptor kinases form a complex and multi-layered network through physical interactions to regulate their roles in a wide range of biological functions also form extensive networks, both with other NLRs and distinct receptor classes, to mediate immunity against a broad range of pathogens was first characterized for its genetic requirement in the recognition of the Pseudomonas syringae acetyltransferase effector HopZ1a (zed1 (hopZ-ETI-deficient1) mutant as also being deficient in HopZ1a ETI Kinase7) to suppress immunity in thaliana . Membersthaliana . Severalthaliana , all of or AvrAC . ZRK3 is HopF2a) and ZED1 HopF2a) . OverallX. campestris effector AvrAC provided crucial mechanistic insights into ZAR1 activation, culminating in the first structure of a plant resistosome . HoweverA. thaliana has no apparent effect on PTI or plant development also share a similar distribution pattern to AtZAR1 orthologs and have been identified across several angiosperm lineages (Solanum lycopersicum (tomato), the Magnoliid Liriodendron chinense (Chinese tulip tree), and the monocot Colocasia escuelenta (taro), among others are able to interact with their corresponding ZRKs , a member of the RLCK XII family of proteins and a paralog of ZED1, to mount an immune response against the Xanthomonas perforans YopJ family effector XopJ4 , sesame (Sesamum indicum), rice (Oryza sativa), false flax (Camelina sativa), canola (Brassica napus), and N. benthamiana , Natural Sciences and Engineering Research Council of Canada Postgraduate Awards (CB-M and BL), an Ontario Graduate Scholarship (CB-M), and the Centre for the Analysis of Genome Evolution and Function (DSG and DD).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-13850-6, published online 14 June 2022Correction to: The original version of this Article contained an error.As a result of an administrative mistake the incorrect number of the IRB approval was included in this manuscript. The study was performed under two protocols approved by the Institutional Review Board of Seoul National University Dental Hospital: CRI14037 and CRI20004. As a result, in Methods, under the subheading \u2018Subjects\u2019,\u201cThe study was approved by the Institutional Review Board of Seoul National University Dental Hospital and informed consent was obtained from all individual participants included in the study (CRI 08027).\u201dnow reads:\u201cThe study was approved by the Institutional Review Board of Seoul National University Dental Hospital and informed consent was obtained from all individual participants included in the study (CRI14037 and CRI20004).\u201dThe original Article has been corrected."} +{"text": "Depressive symptoms in schizophrenia have a high prevalence \u2013 up to 20-60 %, at the different illness stages. Non-pharmacological treatment, namely rTMS, seems like a promising approach that lacks side-effects typical for antidepressants. RTMS is widely applied in the treatment of depression, however the studies within schizophrenia domain are still rather fewThe aim was to examine a potential of neurophysiological data for prediction of the effects of rTMS in the treatment of patients with schizophrenia with depressive symptoms20 male patients with schizophrenia were examined at the stage of incomplete remission with predominance of prolonged (more than 6 months) treatment resistant depressive symptoms. An examination fragments)) was repeated twice - before and after a course of 10 Hz rTMS .Poor outcome was associated with initially higher coherence in alpha and lower - in beta1 EEG bands. The amplitudes of non-target N100 and mismatch negativity didn\u2019t differ the groups of responders and nonrespondersThe disturbances within brain networks of beta1 and alpha generators merit attention as potential neurophysiological markers with predictive value in rTMS treatment of patients with schizophrenia with depressive symptoms.No significant relationships."} +{"text": "As the restaging [18F]FDG PET showed intense [18F]FDG uptake in the urinary bladder at the resection site concerning for recurrence, the lesion was subsequently resected and histopathology showed extensive granulation tissue with foreign body-type giant cell reaction with no suspected foreign bodies or neoplasia.Foreign body-type giant cell reaction is typically a biological and immunological reaction to the presence of foreign bodies such as catheters, parasites or biomaterials with a collection of fused macrophages (giant cell). We reported an unusual case of [ The main limitation of Lugano criteria with a high false-positive rate of FDG avid lesions is well recognized post-initial resection and chemotherapy, with histopathologic findings of foreign body-type giant cell reaction.We present a case of intense FDG PET/CT in May 2021, an intensely hypermetabolic bladder wall lesion at the prior resection site was identified with a maximum standard uptake value (SUVmax) of 67.9 (SUVmax of radiourine was 32.3), with a ratio of 30.9 and 25.1 when scaled to uptake of blood pool and liver . In the present case, the markedly intense uptake (SUVmax of 68) is rarely observed, likely indicative of rapid tumor response to chemotherapy with extensive tumor necrosis and active inflammatory process.The inflammatory process with foreign body-type giant cell reaction is known to be associated with increased [18F]FDG avid lesion with foreign body-type giant cell reaction could occur without the presence of a foreign body and may be indicative of rapidly dying tumor cells in initial response to chemotherapy. We concluded that the intensity of [18F]FDG uptake in the suspected lesion in diffuse large B cell lymphoma following chemotherapy may be nonspecific and should not be used as the diagnostic criterion for malignancy.In conclusion, highly ["} +{"text": "The 2019 coronavirus epidemic (CoViD-19) in Italy originated in Lombardy, on February 21, 2020. Crowding has been defined as a worldwide problem and causes reduced quality of care. It is due and identified by three orders of factors: those at the access (input); those related to the patient\u2019s process (throughput); and those at the exit from the ED (output).We evaluated all the population who went to ED for mental disorder. Due to the high level of care needed and the simultaneous exposure to risk factors, an excessive duration of ED process can be counterproductive.We evaluated all patients accessing our ED for mental disorder from February 22 to May 1, 2020 and during the same period of the previous year.We enrolled 345 patients. The Crowding input factors are lower in the pandemic period: reduced attenders (142 vs 203) and reduced average waiting times (40 min vs 54 min). The Crowding throughput factors have instead worsened: LOS (length of stay) for both visit rooms (383 vs 271 min) and holding area (1735 min vs 797 min). The Crowding output factors also worsened: the percentage of access block is higher during the pandemic (100% vs 20%). The Total Access Block Time is significantly higher in the CoViD period for both the visit rooms (3.239 vs 649 min) and the holding area (590 vs 185 min).The pandemic period presented a worsened crowding for these patients due to the Access Block."} +{"text": "Composite child feeding indices (CCFIs) developed from various relevant measures of dietary intake by infants and young children have several potential applications in nutritional epidemiological studies for the development and deployment of precise public health nutrition interventions against child undernutrition. The predictive utility of some CCFIs (computed from varying formulation components) for child nutritional status were compared. The purpose of the study was to identify the most suitable among them for possible standardization, validation, and adoption by nutritional health researchers. Using cluster sampling, data from 581 mother\u2013child pairs were collected. Multivariable regression analyses were applied to the data obtained through a community-based analytical cross-sectional survey design. Three of the CCFIs were found to be significantly associated with only wasting (WHZ) from the linear regression models after adjusting for potential confounders and/or correlates. None of the CCFIs was consistently predictive of all three measures of child nutritional status, after controlling for potential confounders and/or correlates, irrespective of the choice of regression method. CCFI 5 was constructed using a dimension reduction technique\u2014namely principal component analysis (PCA)\u2014as the most optimal summary index in terms of predictiveness for child wasting status, validity, and reliability (Cronbach\u2019s \u03b1 = 0.80) that captured relevant dimensions of optimal child food intake. The dimension reduction approach that was used in constructing CCFI 5 is recommended for standardization, validation, and possible adoption for wider applicability across heterogeneous population settings as an optimum CCFI usable for nutritional epidemiological studies among children under five years. Child food intake and/or nutrition-related factors are estimated to be associated with about 45% of global mortality amongst pediatric populations under five years . The seeIYCF indicators are widely utilized within the nutritional epidemiological research (NER) community. They constitute some of the key indicators reported by nutritional epidemiologists, pediatricians, public health nutritionists, and researchers in global, national, regional, and community nutrition study reports. However, NER literature is replete, with study findings of inconsistencies in the predictive utility of the individual IYCF indicators for child nutritional status, contrary to the association theoretically postulated and espoused by the developers and users alike within the NER community ,12,13. FThe purpose of this study was to compare the predictive utility of some CCFIs (computed from varying formulation components) for child nutritional status using a cross-sectional study data set obtained from a resource-constrained study setting in northern Ghana, a West African country in Sub-Saharan Africa (SSA).The northern region of Ghana has the country\u2019s highest prevalence rate of stunting according to the Ghana Demographic and Health Survey 2014 report and the A community-based analytical cross-sectional design was used for this study conducted in June 2018. Together with their children (6\u201323 months), 634 mothers of reproductive age (15\u201349 years) were selected using a two-stage cluster sampling technique from stunting-endemic districts of the northern region of Ghana. There are several languages and dialects spoken in northern Ghana. However, the major languages spoken in the selected study districts are Dagbani (Dagombas), Gonja, and Nanumba. The study participants were drawn from 25 communities across five of the districts in the northern region with a relatively high prevalence of stunting (\u226530%) amongst children under five years of age .n = 284. The required minimum sample size was estimated to be n = 568 based on the assumption of a correction factor of 2.0 due to the design effect for cluster sampling [The final sample size used for the statistical analyses of the study data was 581 and was determined from the standard formula for one-point sample estimation ,44. The sampling . The calsampling .A local field research team , recruited mostly from the northern region and provided with training prior to the pilot and definitive surveys, was led by the principal investigator to conduct an interviewer-administered survey of 634 mother\u2013child pairs. The training exercise was to ensure high intra- and inter-rater reliability ,46. The Self-reported dietary intake indicators of child breastfeeding and complementary feeding status and/or practices were used to construct five CCFIs with varying components and scoring guides as summarized in Measures of child nutritional status were the outcome variables in this study. The heights/lengths and weights (anthropometric measurements) of the children and mothers were measured to determine nutritional status. The following measurements were used to calculate the anthropometric (bodily) indicators of underweight, stunting and wasting status, respectively: WAZ (weight-for-age), LAZ (length-for-age), and WLZ (weight-for-length: SD < \u22122) for the children and BMI (body mass index) for the mothers using the WHO Anthro Software Version 3. Computed Z-scores were based on the 2006 WHO growth standards, expressed as standard deviation units from the median value for the WHO growth reference groups . ImprobaThe independent variables of interest in this study were the CCFIs in the continuous and categorical forms, constructed from various indicators of infant and young child feeding practices. The determinants (independent variables) of undernutrition in the northern region of Ghana in this study were classified into proximal or immediate, intermediate, or underlying and distal or basic factors based on an adapted version of the UNICEF hierarchical conceptual framework as descrThe child feeding practice indicators of this study were estimated from self-reported 24 h food recall (24HFR) ,7. Each Minimum acceptable diet (MAD) was defined as the proportion of children who received both the MMF and MDD for their age category, as classified by the WHO. Intake of micronutrient-rich foods (MRF) was also estimated for vitamin A and iron (Fe), using the 17 food groups as classified by the FAO . ChildreAppropriate complementary feeding (ACF) was a composite child feeding index (CCFI) constructed from TICF, MMF, and MDD as previously described ,30. ACF,n = 634) were coded, entered, and screened using IBM SPSS Software (Version 27). Cases with missing values and/or implausible Z-scores were deleted from the dataset. The cleaned data set (n = 581) were evaluated for compliance with the key assumptions underlying multivariable regression analyses. These diagnostics included sample size adequacy, missing values, univariate outliers, multivariate outliers (Cook\u2019s distance), normal distribution of residuals (P-P plot), linearity (scatter plots), homoscedasticity , multicollinearity (variance inflation factor (VIF)), and independence of observations or residuals (Durbin\u2013Watson statistic) [Responses from the interviewer-administered questionnaires n = 4 were coatistic) .t-test and Pearson\u2019s chi-square ((\u03c72) tests . The means and standard deviations (SD) and relative frequencies were reported for the continuous and categorical forms of the CCFI component variables, respectively. Bivariate analyses were conducted also to determine associations between each categorical independent variable (IV) and the categorical form of the dependent variables (less than \u22122 SD for stunting and wasting) using Pearson\u2019s chi-square ((\u03c72) tests at p < 0.05. Pearson correlation coefficient (r) and simple linear regression were used to measure the strength, direction, and significance of the relationships between the covariates and the continuous form of the DVs at p < 0.05 [Descriptive analyses were performed to summarize the characteristics of the study participants, all the other covariates or factors (independent variables (IVs)), and prevalence of the dependent variables using mean and standard deviation for the continuous variables, counts, and relative frequencies (percentages) for the categorical variables. Bivariate analyses were also performed to examine the distribution of each CCFI using ANOVA and p < 0.05 ,66.p < 0.05. However, explanatory variables that were considered to have clinical relevance from literature search and were also statistically significant at p < 0.10 were included in the multivariable regression models [A predictive statistical modelling approach was used to analyze the association between each CCFI and the measures of child nutritional status , accounting for the effects of potential confounders (relevant factors and/or covariates) in the model specifications ,68. Multn models ,69. The 2 for the logistic regression models. The coefficient of determination (R2) was used as a measure of goodness of fit and parsimony for the multiple linear regression models [The overall model performance were assessed using the Hosmer\u2013Lemeshow goodness of fit test and the Nagelkerke Rn models ,71. Two-Content and construct validity of the five CCFIs were assessed qualitatively by the authors based on consensus, cognizant of inferences from the previous studies . InternaSensitivity (what-if) analyses of the study results were conducted to assess the robustness of the final parsimonious models based on the form of the CFFI used and the exclusion of breastfeeding status from CCFI 1 formulation ,76,77.In accordance with the requirements of the Helsinki Declaration, ethical clearance was obtained from the Ghana Health Service Ethics Review Committee (GHS-ERC: 011/11/17) in Accra, Ghana, and the Ethics Committee of Bielefeld University (EUB 2018-083) in Bielefeld, Germany. Community and household entry protocols for the study area were followed accordingly to gain access to the study participants. Written informed consent prior to enrolment was obtained from each mother by endorsement with a thumb print and/or signature on the consent forms provided after explaining the purpose and scope of the study to the participants in their native languages. Verbal consent was also obtained from the household heads in accordance with their cultural values and community normsCharacteristics of study participants and prevalence of child nutritional status are as follows:The majority of participating mothers (55.2%) were aged 25\u201334 years, farmers (55.6%), married (97.2%), and currently breastfeeding (96.4%). The majority of children (89.9%) weighed less than 2.5 kg at birth, with 32.2% being stunted .p < 0.05). Of the five CCFIs, the child age group of 9\u201311 months had the highest median score (50th percentile) for CCFI 1, all the three age groups had the same median score for CCFI 2, child age group of 12\u201323 months had the highest median score for CCFI 3, child age group of 9\u201311 months had the highest median score for CCFI 4, and child age group of 12\u201323 months had the highest median score for CCFI 5 , maternal age and height, child age group, usage of insect-treated nets (ITN), and the number of occupants per the child\u2019s household, which were significantly associated with child stunting status in the bivariate analysis. Religion, tribe (ethnicity), marital status, maternal body mass index (BMI), child age group, child gender (sex), child health status (morbidity in the last two weeks and frequency of diarrhea in the last six months), child immunization status, frequency of prenatal care (PNC) services attended, and the source of power (energy) for household utility were significantly associated with child wasting status in the bivariate analysis. The district of residence, community, tribe, type of community , maternal BMI and height, child age group and gender, child health status (morbidity in the last two weeks), the source of power (energy) for household utility, and the number of people per room in the household were significantly associated with child underweight status in the bivariate analysis. Child gender, child\u2019s recent morbidity status, and maternal BMI were consistently associated significantly with wasting status in the multivariable regression models, alongside with CCFI 1, 4, and 5.None of the CCFIs in the continuous form was consistently predictive of all three measures of child nutritional status after controlling for potential confounders and/or correlates. The continuous forms of CCFI 1, 4, and 5 were significantly predictive of only wasting (WHZ) from the linear regression models after adjusting for potential confounders and/or correlates .The continuous form of the CCFIs were all not significantly predictive of child stunting (HAZ), wasting (WHZ), and underweight (WAZ) status in the bivariate regression models except CCFI 2 for stunting (logistic regression) and underweight status (linear regression); CCFI 3 for stunting (linear and logistic regression), wasting (linear regression), and underweight status (linear regression), CCFI 4 for wasting (linear regression) and underweight status (linear regression), and CCFI 5 for stunting (linear and logistic regression), wasting, and underweight status (linear regression). Only CCFI 3 and CCFI 5 were consistently associated with child nutritional status in the bivariate analyses irrespective of the type of regression method used except for the simple logistic regression analyses between CCFI 3 and wasting or underweight status and that between CCFI 5 and wasting status .There was consistency in the predictive outcomes of the continuous forms of the CCFIs irrespective of the choice of regression methods (linear or logistic) used except CCFI 1 for wasting (multivariable), CCFI 2 for stunting (bivariate) and underweight status (bivariate), CCFI 3 for wasting (bivariate) and underweight status (bivariate), CCFI 4 for wasting (multivariable and bivariate) and underweight status (bivariate), and CCFI 5 for wasting status (multivariable and bivariate) .There was consistency in the predictive outcomes of the continuous forms of the CCFIs for child nutritional status compared with the adjusted (multivariable) and unadjusted (bivariate) models except CCFI 1 for wasting (linear regression); CCFI 2 for stunting (logistic regression) and wasting status (linear regression); CCFI 3 for stunting (linear and logistic regression), wasting (linear regression), and underweight status (linear regression); CCFI 4 for underweight status (linear regression); and CCFI 5 for stunting (linear and logistic regression) and underweight status (linear and logistic regression). Only the continuous form of CCFI 1 exhibited Simpson\u2019s paradox, that is, a spurious reversal of statistical significance, strength, and/or direction of association for the prediction of wasting (WHZ) in the linear regression model. The bivariate association between CCFI 1 and wasting was not statistically significant, but after controlling for the potential confounders and/or correlates, CCFI 1 became significantly associated with wasting .None of the CCFIs in the categorical form was consistently predictive of all three measures of child nutritional status , irrespective of the regression method (linear or logistic), after controlling for potential confounders and/or correlates .The categorical form of each CCFI was not significantly predictive of child stunting (HAZ), wasting (WHZ), and underweight (WAZ) status in the bivariate regression models except CCFI 1 for stunting (linear and logistic regression) and underweight status (linear and logistic regression); CCFI 2 for underweight status (linear regression); CCFI 3 for stunting (linear and logistic regression), wasting (linear regression), and underweight status (linear regression); CCFI 4 for stunting (linear and logistic regression) and underweight status (logistic regression); and CCFI 5 for stunting (linear and logistic regression), wasting, and underweight status (linear regression). None of the categorical forms of the CCFIs was consistently associated with all the three measures of child nutritional status in the bivariate analyses for both linear and logistic regression model specifications .There was consistency in the predictive outcomes of the categorical forms of the CCFIs irrespective of the choice of regression methods (linear or logistic) used except CCFI 2 for underweight status (bivariate), CCFI 3 for wasting (bivariate) and underweight status (bivariate), CCFI 4 for underweight status (bivariate), and CCFI 5 for wasting (bivariate) and underweight status (bivariate) .There was consistency in the predictive outcomes of the categorical form of the CCFIs for child nutritional status compared with the adjusted (multivariable) and unadjusted (bivariate) models except CCFI 1 for stunting (linear and logistic regression) and underweight status (linear and logistic regression); CCFI 2 for underweight status (linear regression); CCFI 3 for stunting (linear and logistic regression), wasting (linear regression), and underweight status (linear regression); CCFI 4 for stunting status (linear and logistic regression); and CCFI 5 for stunting (linear and logistic regression), wasting (linear regression), and underweight status (linear regression). None of the categorical forms of the CCFIs exhibited Simpson\u2019s paradox .CCFI 1 and CCFI 5 had the lowest and highest Cronbach \u03b1 values, respectively, in correspondence with the number and relevance of the test item components used in their construction . Breastf2) used to assess the trade-off between the goodness of fit and parsimony for the multiple linear regression models explained 6.7% of the variance in child wasting status for CCFI 1, 7.5% for CCFI 4, and 7.5% for CCFI 5 used in the modeling. The adjusted coefficient of determination (adjRr CCFI 5 .The purpose of this study was to compare the predictive utility of CCFIs (computed from varying formulation components) for child nutritional status . After controlling for potential confounders and/or correlates in the regression models, CCFI 5, which was constructed using a dimension reduction statistical technique, namely PCA, was found to have a relatively higher predictive utility for child wasting status compared to CCFI 1, which was constructed following the seminal formula of Ruel and Menon . It was In most of the studies that adopted the Ruel and Menon approachTo the best of our knowledge, no study has adopted the PCA approach to construct CCFI. However, similar epidemiological and public health studies that used dimension reduction as a statistical technique to generate a summary index for predictive modeling purposes found it to be robust and clinically useful ,80,81.Acute undernutrition also referred to as wasting status (WHZ/WLZ) is one of the key nutritional health indicators used in the construction of the Global Food Security Index (GFSI) and Global Hunger Index (GHI) for the classification of populations prone to food insecurity, hunger, and/or malnutrition. The consistency and suitability of the CCFIs especially CCFI 5 for predicting wasting status can also therefore be useful as a public health tool to rapidly identify undernourished children under five years under acute food shortage or emergency situations.The measurement validity of the CCFIs as constructed in this study were generally rated subjectively as ranging between low and very good even though the test items of the sub-domains covered the relevant aspects of optimal child food intake, namely breastfeeding and complementary feeding ,74. CCFIThe Cronbach alpha values of CCFI 1, 4, and 5 were indicative of low to very good internal consistency as a measure of reliability (or homogeneity of the test items) of the construct representing optimal young child food intake ,82,83. TThe findings from the sensitivity analyses and model performance evaluations agree with studies that suggest that the choice of statistical method, form of the predictors in the regression models, and the selection criteria for inclusion or exclusion of one or more IVs in regression models could influence the inferences obtainable ,85. ThisThis study is the first attempt to compare the predictive utility of variously formulated composite child feeding indices (CCFIs) that reflect the multidimensionality of optimal child dietary intake for identifying infants and young children at risk of undernutrition . Even though the cross-sectional design used for this study precludes it from establishing causality, the reliability, validity, model performance, and sensitivity analyses conducted provides additional confidence in the study results. It also highlights some important conditions that potentially debunk or otherwise accentuate the robustness of the postulated association between CCFIs and child nutritional status measures.Some possibly unmeasured confounders and residual confounding coupled with potential reporting bias (under- or overestimation from 24 HDR) and probable covariate selection bias may have suppressed or otherwise potentiated the effects of the CCFIs on child nutritional status ,87. The No internal and external model validation analyses were conducted; thus, the practical utility and generalizability of the CCFIs identified to be predictive of wasting status (WHZ) of children under five years cannot be proffered from this study. No clinical utility or practical epidemiological significance evaluation of the predictive models were conducted because none of the CCFIs was consistently predictive of all the three measures of child nutritional status (undernutrition) in this study after adjusting for potential confounders. No interaction analyses were conducted to assess the moderation effects of covariates such as child age and gender on the association between CCFI and wasting.The predictive utility of CCFIs for child nutritional status is sensitive to the components and/or various measures of child feeding practices used in their formulation and construction. After adjusting for the potential confounders measured, CCFI 1, CCFI 4, and CCFI 5 were significant predictors of wasting status of children under five years.The dimension reduction approach (PCA), which was used in formulating and constructing CCFI 5, is recommended for internal and external validation and possible adoption for wider applicability across heterogeneous study settings as the potentially optimum composite child feeding index usable for nutritional epidemiological studies among children under five years. Just as the hunger index (HI) and global food security index (GFSI) are used for ranking the vulnerability to malnutrition across communities, countries, and geographical regions, CCFI 5 could be used for a similar purpose.More robust study designs and validation methods should be considered for exploration to address some of the limitations widely known to be inherent in cross-sectional design studies and self-reported dietary intake measurement instruments during the validation of these study findings. A comparative study of the effects of the choice of various regression methods on the predictive utility of CCFIs for undernutrition, with or without the dichotomization (or categorization) of continuous data, is also recommended as explored by Sauzet et al. in an ob"} +{"text": "This talk will explore: 1) the conceptual importance of select interpersonal factors inherent to Black culture and bereavement, and 2) the impact of these factors on grief in a Black bereaved sample. 103 Black adults aged 45+ were administered items assessing cultural and bereavement-specific factors. Using linear regressions, closeness (p<.001), suddenness (p=.020), anger (p<.001), and communalism (p<.001) predicted reported levels of grief. This study identifies factors which substantially dictate the experienced levels of grief of bereaved Black adults in the latter half of life. With cultural factors notably impacting the Black bereavement experience, individuals seeking to work with this population must adopt strategies to keep bereaved Black adults connected to their communities throughout their loss. Resources to support Black adults in maintaining healthy continuing bonds with the deceased through abrupt or unsettling losses also appear paramount."} +{"text": "Reminiscence therapy (RT) is a multi-sensory treatment that uses a combination of sight, touch, taste, smell and sound to help persons with dementia (PWD) remember events, people and places from their past lives. Currently, digital technologies such as mobile applications and immersive solutions including virtual and augmented reality, are gaining momentum as supplementary tools for RT. This paper presents a usability study of a web-based and virtual reality application to understand the limitations and opportunities of digital platforms for facilitating engaging experiences for PWD towards recalling memories, while easing the therapy process for the caregivers. A total of ten healthcare caregivers were recruited from the Geriatric Dementia Unit and Geriatric Transitional Unit in Ontario Shores Center for Mental Health Sciences, Ontario Canada. Usability feedback from the caregivers were collected from the interviews after the completion of the System Usability Scale (SUS) questionnaire. Institutional caregivers found both web-based and virtual reality (VRRT) usable with SUS score above average (68/100), but required improvements related to the onboarding training of caregivers. The interview revealed four overarching themes related to the VRRT: (1) Ease of use; (2) Positive impact on caregiving; (3) Potential of reduction in responsive behaviors; (4) Feasibility for promoting social connection during COVID-19 pandemic. Next steps will focus on improving the user experience and expanding the application for immersive VR supporting head-mounted displays, hand tracking, and physiological measures, as well as conducting an usability study with PWD to expand our understanding of using RT digital tools with various levels of immersion."} +{"text": "This case series describes the kinetics of humoral deficiency in patients with relapsed refractory multiple myeloma treated with bispecific antibodies, the infectious complications, and response to COVID-19 immunization. We report on the kinetics of humoral deficiency among patients with RRMM treated with bsAb, the infectious complications, and response to COVID-19 immunization.Bispecific antibodies (bsAb) targeting novel antigens are a promising class of therapeutics for relapsed refractory multiple myeloma (RRMM).6 and antibiotic prophylaxis was prescribed per current institutional guidelines. Statistical analysis details are provided in the eMethods in the In this case series, we included patients with RRMM treated in early phase 1 and 2 clinical trials of bsAb at our institution between January 1, 2019, and December 31, 2021. Patients self-reported their sex and race and ethnicity; the latter data were collected due to the high incidence of multiple myeloma among racial and ethnic minority groups. Serial immunoglobulin levels and infections confirmed by clinical, imaging, microbiologic, or histopathologic evidence were captured retrospectively from the start of therapy until last follow-up or 3 months after study exit. Cytokine release syndrome and immune effector cell\u2013associated neurotoxicity syndrome were graded per American Society for Transplantation and Cellular Therapy criteria,reporting guideline for case series.The Medical College of Wisconsin Institutional Review Board approved this study and waived the need for informed consent owing to its retrospective design. This study followed the Forty-two patients contributing 49 treatment periods (7 patients were counted twice) were included in our analysis . The The overall cumulative risk of infections increased with increasing duration of therapy with risk at 3 months of 41%; at 6 months, 57%; at 9 months, 64%; at 12 months, 67%; and at 15 months, 70%. The most common infections were bacterial (44 of 81 [54%]), followed by viral (33 of 81 [41%]) and fungal (4 of 81 [5%]) infections. Respiratory tract infections accounted for 41 of 81 infections (51%). Four deaths were attributed to infections, including 2 patients who died within 90 days of treatment . On multThe findings of this case series highlight the prolonged hypogammaglobulinemia and increased risk of infectious complications with a 70% cumulative infection risk in patients with RRMM treated with bsAb therapy. The risk of infection was associated with the degree of hypogammaglobulinemia and increased with treatment. We also noted an increasing rate of seroconversion with COVID-19 booster vaccination series. Our study is limited by the small sample size and heterogenous patient population treated with differing dose escalations and combinations with other myeloma therapies; nevertheless, our findings underscore the changing continuum of humoral immunodeficiency and infection risk with this growing class of therapeutics in RRMM."} +{"text": "HIV rapid testing services is one among key interventions in the controlling of HIV/AIDS. Despite availability of quality standards, the quality of HIV rapid testing services remains questionable since non-laboratory testers are allowed to conduct testing while they are not specialized in providing testing services.To evaluate the compliance to the quality standards of HIV rapid testing services provided by non-laboratory testers in Makete District, TanzaniaAn explanatory descriptive study employing quantitative approach of data collection was used. An observation of 23 non-laboratory testers performing HIV rapid tests, observation of HIV testing points and documents review was done in 23 testing points to collect data. Data were analyzed using a programmed excel sheet and a three-point scale was used to determine the level of compliance to quality standards.Analysis shows that out of 23 testing points visited, the level of compliance to quality standards was lower for 22 (95.6%) testing points and moderate in 1 (4.4%) testing point. None of the testing point was highly complied to quality standards for HIV rapid testing services.The quality of HIV rapid testing services provided by non-laboratory testers is below the established quality standards for HIV rapid testing services. HIV rapid testing services is among key interventions in the controlling of HIV/AIDS since it provides chances to access HIV care, treatment, prevention, and support services.5Several studies have been conducted to evaluate the quality of HIV rapid testing services. An auditing study conducted in Caribbean and African countries, which involved 968 HIV testing points demonstrated that 20% of the testing points scored level 0; 46% of the testing points scored level 1; 31% of the testing points scored level 2; while 3% of the testing points scored level 3 and none of the testing point that had high level of compliance to quality standards such that none of the testing points scored level 4.6Furthermore a study conducted in 102 private health facilities in Kampala Uganda to evaluate the quality of HIV rapid testing services demonstrated that the quality of HIV rapid testing services is below the recommended quality standards.7Tanzania has also adopted the WHO quality standards for the implementation of HIV rapid testing services.The study was conducted at Makete District Council in Njombe Region, Southern Tanzania. HIV Records for 2016/2017 show that Njombe Region has the highest HIV prevalence (11.4%) in Tanzania.Purposive sampling technique was used to select both public and private health facilities where by all HIV rapid testing points were studied and non-laboratory testers who provided services on the day of the study were observed when performing actual HIV rapid tests.An on-site checklist for document review and observation adopted from WHO by the Tanzania Ministry of Health was used to collect quantitative data. The main areas of observations included: personnel training and certification; physical facility; safety; pretesting phase; testing phase; documentation and records as well as external quality assessment.Ethical clearance to conduct this study was obtained from Research and Ethics Committee (REC) of Muhimbili University of Health and Allied Sciences (MUHAS). Permission to conduct the study was requested from the District Medical Officer of Makete District and officer in charges of the respective health facilities. Study participants were informed about the purpose of the study, procedures, risk and benefits for them to participate in the study. Informed written consent was obtained from each study participant after agreeing to participate in the study.Data were collected manually and entered into excel sheets and they were cleaned and validated. All descriptive data were analyzed using programmed excel sheets and data were presented in frequency tables of numbers, percentages and level of compliance to quality standards for HIV rapid testing service. Summation of each response of the open ended question in each quality standard was used to determine the average compliance for each quality standard. A three-point scae was used to determine the level of compliance to all quality standards for HIV rapid testing services for each testing points whereas testing points scored level 4 (score of 90% or higher) were defined as highly complied to quality standards; level 3 (score of 80% \u2013 89%) were defined as moderately complied to quality standards; level 2 (60% \u2013 79%), level 1 (40% \u2013 59%) and level 0 (less than 40%) were defined as lower complied to quality standards.Most of the HIV testers (34.8%) worked on wards, Reproductive and Child Health section (21.7%) and Care and Treatment Centre (13%). The majority of the testers (52%) were from the district level health facilities while about 22% of them were from dispensaries. Majority of the testers (78%) worked in the government health facilities and the remaining 22% worked in private health facilities. Most of testers were women (78.3%) while 21.7% were men. All testers (100%) had ordinary level of secondary education whereas among them 69.6% testers had certificate level of education and 30.4% had diploma level of education. Only one study participant (4.4%) was clinical officer, 30.4% were enrolled nurses and 34.8% were Medical attendants while 30.4% were assistant nursing officers.Evaluation results show that out of 23 testing points visited, the level of compliance to the quality standard was lower for 22 (95.6%) testing points. Two (2) testing points (8.7%) scored level zero, 13 (56.5%) testing points scored level one and 7 (30.4%) scored level two. The level of compliance to HIV rapid testing quality standards was moderate in 1 (4.4%) testing point. None of the testing point had high level of compliance to the HIV rapid testing quality standards, meaning that no testing point attained level four. Average compliance for each quality standard was also determined by observing how non-laboratory testers and testing points operations comply with such standards. These standards include: personnel training and certification; physical facility, safety, pretesting phase, testing phase, documentation and records as well as external quality assessment. The average compliance to personnel training and certification quality standards was 15% whereas: only 9 (39%) out of 23 non laboratory testers that provided HIV rapid testing services on the day of the study received comprehensive training on HIV rapid testing using the nationally approved curriculum; only 2 (9%) non-laboratory testers were trained on external quality assessment (EQA)/proficiency testing (PT) process; only 5 (22%) non-laboratory testers were trained on safety and waste management procedures and practices. No any non - laboratory tester has been certified or licensed through a national certification program to perform HIV rapid testing services.Average compliance to physical facility quality standards was 65% whereas: 16 (66%) testing points have designated area for providing HIV rapid testing services; 11 (48%) testing points were clean and organized for testing; 22 (96%) of testing points had sufficient lighting; none of the testing points store test kits in temperature-controlled environment and there was no device to monitor temperature in all visited testing points and 18 (78%) testing points had sufficient and secure storage space for test kits and other testing consumables.Average compliance to safety standards was 56% whereas: only 2 (9%) testing points had SOPs to manage spills of blood and other body fluids; only 4 (17%) testing points had SOPs to address accidental exposure to potentially infectious body fluids through a needle stick injury, splash or other sharps injury; all 23 (100%) testing points had personal protective equipment (PPE) and testers properly used PPEs through the testing process; 13 (57%) testing points had hand-washing facilities such as water and liquid soap. Only 6 (26%) testing points handled properly waste materials such as sharps, infectious and non-infectious waste and only 13 (56%) testing points disinfect working area with the appropriate disinfectant such as chlorine.The average compliance to pre testing phase standards was 63% whereas: only 9 (39%) testing points had national guidelines for HIV testing services; all 23 (100%) testing points use national algorithm and approved HIV rapid kits; expired HIV rapid test kits such as uni-gold were available in 9 (39.1%) testing points; only 4 (17%) testing points had a standard process for stock management; only 4 (17%) testing points had posted job aides on client sample collection; 19 (82%) testing points had sufficient supplies for client sample collection and in only 9 (39%) testing points, client's identifiers were recorded in the HIV testing register and on test devices as per national guidelinesThe average compliance for testing phase standards was 53% whereas: only 5 (54%) testing points had SOPs on HIV testing procedures and posted at the testing area; timers were available and used routinely in only 1 (4.3%) testing point; sample collection devices such as capillary tube, loop, disposable and pipettes were used accurately in 22 (95%); testing procedures such as correct use of buffer and reading of results on time were adequately followed in 16 (70%) testing points and positive and negative quality control specimens were routinely used in 13 (57%) testing points. Retest for verification was done in 4 (67%) health facilities out of 6 health facilities visited.Average compliance to documentation and records standards was 92% whereas: 20 (87%) testing points had standardized register for documentation, which contain key elements in the registers such as client demographics, kit names, lot numbers, expiration dates and tester name. The final HIV results were recorded correctly in 16 (70%) testing points; client documents and records were securely kept throughout all phases of the testing process in 22 (95%) testing points.Average compliance to External Quality Assessment was 40% whereas: 11 (48%) testing points were enrolled in Proficiency Testing (PT) program; out of 11 testing points enrolled into PT program, only 4 (36%) testing points implement corrective action in case of unsatisfactory PT results; 21 (91%) testing points received periodic supervisory visit and written supervision report was available in only 1 (5%) testing point.This study has shown that the level of compliance to the quality standards for HIV rapid testing is below the recommended standards. Majority of observed HIV testing points scored level one and none of the testing point was highly complied to quality standards, meaning that no testing points scored level four. The results of this study are similar with the study conducted in Kampala Uganda to assess the quality of HIV counseling and testing services, which demonstrated that the quality of HIV testing services is below the recommended standards.13In this study, the highest average compliance score was seen on documentation and records followed by physical facility that included availability of conducive designated areas for provision of HIV rapid testing services and the lowest average compliance score was seen on personnel training and certification, followed by External Quality Assessment, testing phase, safety and pre testing phase. In addition, this study revealed that availability of new National HIV register that require all key elements to be documented in one register has contributed to improved documentation and record keeping for different data hence results into higher score for documentation and records quality standards. Furthermore, this study shows that most of the non-laboratory testers did not receive comprehensive training to perform HIV rapid testing services and none of them were certified/licensed to perform HIV rapid test through the National Certification Program. This situation has resulted into the lower score for the personnel training and certification quality standards, which was below the recommended quality standards for HIV rapid testing services, which requires that services should be provided by testers who received comprehensive training as well as evaluated for their competence and certified to provide testing services.7In this study we observed low compliance to the quality standards for External Quality Assessment (EQA) and about half of the testing points were enrolled into proficiency testing program and most of the testers were not trained to perform samples for proficiency testing. A study conducted in South Africa to evaluate the quality management system for HIV rapid testing services reported similar findings indicating that the compliance to EQA standards was low and only two clinics out of eleven clinics were enrolled into proficiency testing program. 6In this study, non-adherence to testing procedures including the use of small volume of buffer and non-adherence on time to read result whereby timers were not used during testing were observed. Similar findings were reported in a study conducted in Zambia National Reference Hospital in which the use of inadequate volume of specimen and use of incorrect volume of buffer leading into poor quality of test results was reported.11Our study has shown that a few testing points had guidelines for HIV testing services and Standard Operating Procedures (SOPs). These guidelines and SOPs are important documents for providing guidance and procedures needed to be followed during testing hence lack of guidelines and SOPs compromises the quality of HIV rapid testing services.19Some of the testing points were temporarily closed during data collection period due to lack of trained testers to provide service, and probably such testing points could have useful information regarding the practice of implementation of HIV rapid testing services in studied facilities. Furthermore, due to resource constrains only six facilities were studied, which might have limited the data collected. However, we believe that this study provides valuable insights regarding the quality of HIV rapid testing services provided by non-laboratory testers in the rural setting district in Tanzania.The quality of HIV rapid testing services provided by non-laboratory testers in Makete District is below the established quality standards set for provision of HIV rapid testing services. Most of the non-laboratory testers were not trained, evaluated for their competencies and were not certified or licensed to provide HIV rapid testing services. Some of HIV rapid testing points do not have Guidelines and SOPs that guide provision of HIV rapid testing services, which compromises the quality of HIV testing services. The Ministry of Health and Management of the health facilities should invest more efforts in training and strengthening of certification of non-laboratory testers, increasing enrolment of testing points into proficiency testing and strengthening supervision of testing points in order to improve compliance to quality standards."} +{"text": "Self-isolation regime is an effective measure to contain the pandemic , but the psychological factors predicting compliance with stay-at-home recommendations (CSHR) are understudied. We hypothesized that 1) defensive optimism and constructive optimism will have opposite effects on CSHR, 2) the effect of defensive optimism will be mediated through a decrease of anxiety (fear of infection).. The purpose of this study was to assess the direct and indirect (through the fear of infection) effects of defensive optimism (belief that coronavirus problem is exaggerated) and constructive optimism (belief that people\u2019s efforts help to prevent infection and spread of the virus) on CSHR, controlling for dispositional optimism.. A longitudinal study (from 10/4/2020 till 2/6/2020) was conducted on a sample of 306 university students using a single-item measure of CSHR, LOT-R , the scales of defensive and constructive optimism , and anxiety in a pandemic situation questionnaire .. During seven-week interval CSHR has decreased dramatically while the other variables remained stable. Using SEM we have showed that CSHR at the end of study (T2) is predicted by the CSHR (T1) and through it by the defensive optimism and constructive optimism . Negative effect of defensive optimism on CSHR is also mediated by the fear of infection (T2), reducing it. Dispositional optimism is associated only with constructive optimism.. Defensive and constructive optimism/ pessimism are essential in explaining health-related behavior.No significant relationships."} +{"text": "Age-friendly community initiatives (AFCIs) have become key policy efforts aimed at improving quality of life for older residents, but there is limited evidence about the process. This mixed methods study draws on survey and demographic data from 350 municipalities in Massachusetts to characterize communities by these categories: 1) not interested in AFCIs (n=109); 2) interested in learning more about AFCIs (n=84); 3) planning for age-friendly action (n=71); and 4) maintaining an AFCI (n=86). Interview data from key-informants contextualize the process of developing an AFCI. Thematic analyses suggest that progression through AFCIs is self-defined by the accumulation of momentum. Communities committed to AFCIs have higher proportions of vulnerable residents . Municipal resources correlate with more advanced stages of AFCIs. Implications of the variability across AFCIs, including the effort required for moving from concept to execution of AFCIs, will be discussed."} +{"text": "Vaccination is one of the main mitigation strategies to protect people from COVID19 mortality. People incarcerated in jails experienced disparate rates of COVID19 infection compared to people in the community, thus operationalization of COVID19 vaccine delivery in jails was prioritized in several states, including Massachusetts (MA). The goal of this project was to track COVID19 vaccine ordering in MA jails and compare numbers and types of COVID19 vaccines ordered by MA jails to those in the MA community, with specific attention to the Centers for Disease Control and Prevention\u2019s (CDC) guidelines for COVID19 vaccines.MA jails received COVID19 vaccines free of charge through the MA Department of Public Health. We requested de-identified, facility-level data from the MA DPH including: number of vaccines ordered by each jail, type of vaccine, and date of the vaccine order from December 2020 - January 2022. We obtained COVID19 vaccines distribution data for the MA general population from the CDC.Vaccine orders were available for 13/14 MA jails. A total of 23,060 vaccines were ordered from the MA DPH between December 2020 - January 2022. January 2021 marked the highest number of vaccine orders by the jails, and all other months were orders < 33% of the January 2021 order. Moderna COVID vaccines were most frequently ordered by the MA jails (88%), followed by Janssen (11%) then Pfizer (1%). In the general population, Pfizer was the most frequently distributed vaccine type (59%), followed by Moderna (37%), then Janssen (4%).Prioritization of jails in MA led to a strong initial push for vaccine distribution which then waned. Potential reasons for the drop in orders include: the initial vaccine orders in January 2021 may have lasted several months, people entering jail after spring 2021 may have received vaccines in the community, and clinical and administrative fatigue may have limited continued robust vaccine protocols. Tracking COVID-19 vaccine orders by jails is a way to assess equitable vaccine operationalization. As recommendations for vaccination evolve, public health and carceral leaders should collaborate to ensure consistent low-barrier COVID19 vaccine access in jailsAll Authors: No reported disclosures."} +{"text": "Since the Global Polio Eradication Initiative (GPEI) was established in 1988, the number of reported poliomyelitis cases worldwide has declined by approximately 99.99%. By the end of 2021, wild poliovirus (WPV) remained endemic in only two countries (Pakistan and Afghanistan). However, a WPV type 1 (WPV1) case with paralysis onset in 2021, was reported by Malawi a year after the World Health Organization (WHO) African Region (AFR) was certified as WPV-free and circulating vaccine-derived poliovirus (cVDPV) cases were reported from 31 countries during 2020\u20132021 the nonpolio AFP (NPAFP) rate,African Region. Among 28 priority countries in AFR, 50% met both national surveillance indicator targets in 2020 and 79% met the targets in 2021 . Subnational surveillance performance also improved in AFR; both surveillance indicator targets were met in 52% of first subnational administrative level areas in 2020 and 75% in 2021 , eight met both national surveillance indicator targets in 2020 and all but one (Djibouti with stool adequacy of 75%) met both targets in 2021. Most EMR countries performed well at the subnational level, but gaps were apparent in Djibouti. In 2020, a total of 140 WPV1 cases were detected in EMR countries (56 in Afghanistan and 84 in Pakistan), compared with five in 2021 (four in Afghanistan and one in Pakistan). Cases of cVDPV2 in EMR countries declined from 516 in 2020 to 68 in 2021, and cVDPV1 cases declined from 31 in 2020 to three in 2021 .European Region. In the WHO European Region (EUR), surveillance performance was assessed in Tajikistan and Ukraine. In 2020 and 2021, Tajikistan met both national indicators, whereas Ukraine met only the stool adequacy target. In Tajikistan, the proportion of the population living in areas that met both indicators increased significantly from 2020 to 2021.South-East Asia Region. Surveillance performance was assessed in the WHO South-East Asia Region (SEAR), country of Burma (Myanmar),Western Pacific Region. In the WHO Western Pacific Region (WPR), surveillance performance was assessed in Papua New Guinea and the Philippines. In 2020 and 2021, the Philippines met the NPAFP rate indicator, and Papua New Guinea did not meet either of the surveillance indicators. None of the subnational areas in Papua New Guinea met the indicator targets in either year; in the Philippines, 20.5% of the population lived in subnational areas in which both surveillance indicators were met in 2021 in 22 countries in 2021.Poliovirus environmental surveillance is the systematic collection and testing of sewage specimens to identify poliovirus circulation. Because paralysis occurs in <1% of poliovirus infections, environmental surveillance can detect poliovirus circulation even in the absence of confirmed paralytic polio cases to 75 across 30 sites in 2021 (53% from Afghanistan). During 2020\u20132021, 27 cVDPV emergence groups (24 cVDPV2 and three cVDPV1) were detected in sewage samples collected in 32 countries, including 22 (69%) from AFR, seven (22%) from EMR, two (6%) from WPR, and one (3%) from EUR.In Afghanistan, WPV1 was isolated from only one environmental surveillance sample in 2021 compared with 35 samples from 15 sites in 2020 comprises 145 quality-assured poliovirus laboratories in the six WHO regions. GPLN laboratories implement standardized protocols to 1) isolate polioviruses ; 2) conduct intratypic differentiation (ITD) to distinguish between WPV, Sabin virus, and VDPV (134 laboratories); and 3) conduct genomic sequencing (28 laboratories). Poliovirus transmission pathways are monitored through sequence analysis of the viral protein 1 (VP1) capsid protein from virus isolates. The accuracy and quality of testing at GPLN laboratories are monitored through a comprehensive standardized quality assurance program of onsite reviews and proficiency testing accounted for 18 of 140 (13%) WPV1 isolates from AFP patients in 2020 and two of six (33%) in 2021.All priority countries faced setbacks in surveillance performance in 2020 because of the COVID-19 pandemic and associated risk mitigation measures surveillance, the primary means of tracking poliovirus transmission, is supplemented by environmental surveillance of sewage samples. The COVID-19 pandemic negatively affected polio surveillance.Analysis of 2020\u20132021 AFP surveillance data from 43 priority countries experiencing or at high risk for poliovirus transmission found that national AFP surveillance performance improved from 2020 to 2021 in many priority countries, particularly in the World Health Organization\u2019s African Region; however, substantial national and subnational gaps persist.Surveillance gaps need to be identified and addressed to ensure timely detection of poliovirus circulation and achieve eventual eradication."} +{"text": "This study assesses the extent to which changes in mental health among older adults from pre- to during the pandemic varied by cognitive functioning and the role that decreases in social resources played in this association. We use data from the National Social Life, Health, and Aging Project (NSHAP)\u2014a population-based panel study of older U.S. adults that has surveyed respondents every 5 years since 2005\u2014and the NSHAP COVID-19 supplement, conducted between September 2020 and January 2021 . Results from linear regression models suggest that (1) higher cognitive functioning in 2015 was associated with greater loneliness during the pandemic; (2) this association is explained in part by a decrease in emotional support during COVID-19 ; and (3) cognitive status did not moderate links between social resources with happiness nor loneliness. Results emphasize the importance of social resources for older adults\u2019 mental health, regardless of cognitive ability."} +{"text": "The nursing home population is vulnerable and medically complex, yet little is known about models of medical service provision and associated quality outcomes. The goal of this study is to examine the association between physician (MD) and nurse practitioner (NP) accessibility and practice sensitive outcomes. This project used data from the Translating Research in Elder Care (TREC) longitudinal study and the routinely collected Resident Assessment Instrument \u2013 Minimum Data Set version 2.0 (RAI-MDS 2.0) to test the association between the availability of MDs and NPs in nursing homes (NH) and clinically-relevant resident outcomes of antipsychotic medication (APM) use without indication of psychosis, physical restraint use, hospitalization and emergency department (ED) transfers, and polypharmacy. Eight models were created using logistic regression to test the association between the access measures of daily presence of MD or NP on unit and MDs being involved in care planning and each of the four resident outcomes. The sample consisted of 10,888 residents across 320 units in 92 facilities. Staff from 277 (86%) units reported an MD or NP visited daily and 318 (99%) units reported that the MD or NP could be reached when needed. Following adjustment for multiple confounding variables, there were no associations between either measure of access and any of the resident outcomes. Although we did not find any associations between our measures of access and resident outcomes, additional research which more directly measures physician and NP activities in the NH is required."} +{"text": "Improving the quality and timely access of home health care is a new quality measure and particularly crucial in high-risk ADRD adults following hospitalization. However, a significant portion of older patients waits longer than 2 days to receive home healthcare. In this study, we examine how the quality of home health agency and race are associated with the delay in care among ADRD patients receiving home healthcare and how this delay mitigates the risk of rehospitalization. We find that Black patients in low rated home health agencies have 28% higher odds of delay in care compared to White patients in high rated home health agencies (Odds ratio (95% CI) =1.28 (1.21 - 1.36)). Timely initiation of home health care also reduces the risk of rehospitalization in minority older adults with ADRD."} +{"text": "There is evidence that maternal perinatal depression is associated with adverse neurodevelopmental and mental health outcomes in children. No study has yet examined the association between maternal depressive symptoms during pregnancy and the postpartum period and the risk of oppositional-defiant disorder (ODD) in children and adolescents.This study aimed to investigate whether there is an association between perinatal depressive symptoms and the risk of ODD in offspring from age 7 to 15 years.We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a population-based prospective birth cohort study in the UK. Offspring ODD at the age of 7, 10, 13 and 15 years were assessed by using parental reports the Development and Well-Being Assessment (DAWBA). We applied Generalized Estimating Equation (GEE) modelling to examine associations across the four time points.adjusted\u00a0OR = 3.59 (1.98-6.52).Maternal postnatal depressive symptoms were associated with more a two-fold increased risk of ODD overall. Third trimester depressive symptoms (measured at 32 weeks of gestation) increased risk of ODD by 72%. Offspring of mothers who had depressive symptoms both during pregnancy and in the first year of postpartum period have a four-fold increased risk of ODD over time (Offspring of mothers with perinatal depressive symptoms are at an increased risk of developing behavioural disorders."} +{"text": "Long-acting injectable antipsychotics (LAIs) can reduce relapse and hospitalization risk but they are not widely used in first psychotic episode (FEP) patientes.To examine the effcacy of two of the most used second generation LAI antipsychotics to reduce hospitalization rates.We evaluated in a naturalistic study a sample of patients (n=277) with a FEP. We carried out a mirror-design study to compare the number of hospitalizations and days in hospital before and after the introduction of LAI paliperidone (3 monthly) or LAI aripiprazol. In our Early Intervention Services (Lehenak) antipsychotic treatment is not protocolized and is established for each patient according to the psychiatrist criteria.We review the oucome of 277 FEP treated in our Early Intervention Service \u201cLehenak\u201d with LAI paliperidone 3 monthly (n=156) or LAI Aripiprazol (n=121)Both LAI paliperidone 3 monthly and LAI aripiprazol had a postive impact on hospitalIzation rate, decreasing them significantly after their introduction. These data also support a more extensive use of LAI paliperidone 3 monthly in FEP.Presenting author has received honouraria for lectures or advisory boards from Janssen, Otsuka, Lundbeck and Angelini in the last five years"} +{"text": "Obsessive-compulsive disorder (OCD) is associated to a wide range of symptomatic expression and treatment response variability [1]. Sensory perception has been identified as an emerging factor in this process [2]. Sensory vulnerability and atypical sensory experience were identified as risk factors for the development of OCD [3] and a sensory subtype of the disease was proposed in which there is a positive correlation with early onset sensory symptoms, male gender and family background [4]. Adding to the atypical sensory profile, obsessions are frequently experienced as partially perceptual.Our main goals are to characterize the sensory perception in OCD patients; assess the prevalence and intensity of the sensory properties of the obsessive thoughts and explore the how sensory perception, obsessive thoughts and obsessive dimensions/clusters are interrelated.Patients with OCD diagnosis, aged 18 to 65 years and no comorbid mental disorder (except depression) will be recruited. The study battery will include participant form with demographical and clinical features, assessment of depressive and anxiety symptoms (HAM-A and HAM-D) evaluation of clinical outcome measures and obsessive dimensions/clusters and Obsessive Beliefs Questionnaire-44 (OBQ-44)), assessment of sensory perception and sensory properties of obsessive thoughts (Sensory Perception Quotient (SPQ 21) and Sensory Properties of Obsessive Thoughts Questionnaire (SPOQ)).The results will help us understand the interaction between perceptual and cognitive processes in OCD.Better definition of OCD psychopathology and the establishment of a sensory subtype may indicate the need of specific therapeutic indications or a different escalation of treatment measures.No significant relationships."} +{"text": "Tobacco use intersects with the COVID-19 pandemic not only in terms of health consequences, but also on public health systems, economies, and the environment.The global tobacco supply contributes significantly to environmental pollution of the natural ecosystems. The damage is compounded by tobacco consumption and its resultant waste, which leaves a significant carbon footprint on the environment, undermining the planet\u2019s ecological stability and intensifying climate change. Furthermore, tobacco use exacerbates inequalities and adds burdens to COVID-19-related mortality, which are major challenges to recovery from the COVID-19 pandemic.he pandemic has provided a chance to combat tobacco use and accelerate efforts to alleviate these challenges and accelerate progress toward Sustainable Development Goals (SDGs). The MPOWER measures from the World Health Organization Framework Convention on Tobacco Control (WHO FCTC) can play an integral part to boost sustainable and equitable COVID-19 recovery \u2014 Monitor tobacco use (article 20); Protection from tobacco smoke (article 8); Offer help for tobacco cessation (article 14); Warn about the dangers of tobacco (article 11); Enforcing bans on tobacco advertising, promotion, and sponsorship (TAPS) (article13); and Raise tobacco taxes (article 6).To accelerate recovery, it is critical to call for actions for governments and policy-makers to strengthen synergies and policy actions to emphasise tobacco control across equity, public health, climate actions, and counteract against the tobacco industry during and beyond COVID-19 as global authorities pledge to achieve the SDGs.\u2022\u2002Global authorities must create better synergies on policies with a prime focus on reinforcing tobacco control to recover from the pandemic.\u2022\u2002The WHO FCTC MPOWER measures can play an integral part in COVID-19 recovery to fight tobacco use and accelerate progress toward SDGs."} +{"text": "Eradication is an all-or-nothing affair. The aspirational goal set by the World Health Assembly in 1988 of eradicating poliomyelitis by 2000 was not achieved.It is thus tempting to consider eradication of poliomyelitis two-thirds complete, with wild poliovirus type 1 in Pakistan and Afghanistan being the final hurdle to finishing the \u2018polio end-game\u2019. But this is sadly not the case. The protracted eradication efforts and perpetually underperforming vaccination programmes using oral live attenuated Sabin poliovirus vaccine (OPV) have birthed calamitous outbreaks of types 1, 2 and 3 circulating vaccine-derived poliovirus (cVDPV) in countries in every World Health Organization region since the first recorded cVDPV outbreak in Haiti in 2020.6 The unprecedented surge in reported confirmed human infections and increasing number of countries with cVDPV detections, either human infections or through environmental surveillance, is cause for great concern to bivalent oral polio vaccine , while introducing at least one dose of inactivated poliovirus vaccine (IPV) for every child, was necessary to reduce the ongoing risk of cVDPV2 outbreaks. Unfortunately the tardy rollout of IPV and outbreak response campaigns using monovalent OPV type 2 have increased the risk of cVDPV outbreaks.We must not bury our heads in the sand. Novel, genetically more stable oral polio vaccines used under emergency authorisation for cVDPV2 outbreak response provide a glimmer of hope, but this alone is not enough."} +{"text": "The aim of the present study was to investigate emotional regulation and attachment in adolescents with anorexia nervosa (AN).Anorexia Nervosa (AN) is an eating disorder (ED) characterized by self-starvation driving by weight, shape, and eating concerns and extreme dread of food, eating, and normal body weight. Dysfunctional emotional processing and regulation play an important role in the development and maintenance of eating disorders (EDs). Difficulties with emotional awareness and regulation in EDs are hypothesized to have their origins in childhood attachment.The study population (N=20) consists of two research groups of patients with AN (group A) and general population controls (group B), matched for gender and age. The age of patients was 12-18 years. All adolescents were female. This study examined the attachment states of mind, assessed by the Adult Attachment Interview (AAI), and emotion regulation difficulties, measured by the Difficulties in Emotion Regulation Scale (DERS).Group A reported significantly higher attachment insecurity (82% vs 50%) than group B. Group A show higher DERS total than group B.Study results show a crucial role of attachment insecurity and emotional dysregulation in the development and maintenance of AN. Developing interventions to improve emotional management skills in the treatment of patients with AN can be an important component in improving treatment outcomes."} +{"text": "When the Global Polio Eradication Initiative (GPEI) was established in 1988, an estimated 350,000 poliomyelitis cases were reported worldwide. In 2020, 140 wild poliovirus (WPV) cases were confirmed, representing a 99.99% reduction since 1988. WPV type 1 transmission remains endemic in only two countries (Pakistan and Afghanistan), but outbreaks of circulating vaccine-derived poliovirus (cVDPV) occurred in 33 countries during 2019\u20132020 rateSurveillance performance in 42 priority countries that had recent WPV or cVDPV transmission or that were deemed at high risk for poliovirus transmission were reviewed. In the World Health Organization (WHO) African Region (AFR), the percentage of priority countries that met targets for both national NPAFP rate and stool adequacy indicators was 67% in 2019 and 48% in 2020 . Both suAll 10 of the assessed priority WHO Eastern Mediterranean Region (EMR) countries met targets for both indicators in 2019, and all but one did so in 2020. Subnational surveillance performance remained high in most EMR countries, but gaps were apparent in Yemen and Libya, where 44% and 53% of the population, respectively, lived in areas that met both surveillance indicator targets in 2020 . From 20In the WHO European Region (EUR), surveillance performance was assessed in the two priority countries of Tajikistan and Uzbekistan. In 2019 and 2020, only Tajikistan met both surveillance indicator targets at the national level. In both years, Uzbekistan met only the stool adequacy indicator target. Subnational surveillance performance was poor in both countries in 2020 ; in UzbeSurveillance performance was assessed in Burma (Myanmar),In the WHO Western Pacific Region (WPR), surveillance performance was assessed in Malaysia and Philippines. Both countries met the NPAFP indicator target in 2019 and 2020, and neither met the stool adequacy indicator in 2019; however, Malaysia did meet the stool adequacy indicator in 2020. During 2019\u20132020, approximately one quarter of Malaysia\u2019s population and <3% of Philippines\u2019 population lived in areas that met both indicator targets ; cVDPV1 Genomic sequence analysis identified 41 cVDPV emergences from AFP cases (39 type 2 cVDPV emergences) in 18 countries in 2019 and 34 cVDPV emergences (32 type 2 cVDPV emergences) in 25 countries in 2020. More than one half (22 of 41) of cVDPV emergences detected in 2019 continued to be detected during 2020.Environmental surveillance is the systematic testing of sewage samples to identify populations shedding polioviruses; environmental surveillance in some locations, might be more sensitive to detection of poliovirus transmission than AFP surveillance, given that paralysis occurs in <1% of poliovirus infections to 599 isolates (57% in Afghanistan) resulting from two 2019 cVDPV2 emergences and seven additional new cVDPV2 emergences in 2020.In 2019, 10 WPV1 genetic clusters (isolates with \u226595% genetic relatedness) were detected in environmental sites from four provinces in Afghanistan and four provinces in Pakistan is an essential component of poliovirus surveillance. It comprises 145 quality-assured poliovirus laboratories in the six WHO regions. GPLN laboratories implement standardized protocols to 1) isolate polioviruses ; 2) conduct intratypic differentiation to identify WPV, Sabin polioviruses, and VDPV (134 laboratories); and 3) conduct genomic sequencing (28 laboratories). Poliovirus transmission pathways are monitored through sequence analysis of the capsid protein (VP1) coding region from isolates. The accuracy and quality of testing at GPLN laboratories are monitored through an annual accreditation program of on-site reviews and proficiency testing was detected in Afghanistan and Pakistan in 2019 (176 cases) and 2020 (140 cases). Orphan isolates indicate possible gaps in AFP surveillance; in 2019, orphan isolates accounted for five of 176 (3%) WPV1 isolates from AFP patients (two in Afghanistan and three in Pakistan) and in 2020 for 18 of 140 (13%) (11 in Afghanistan and seven in Pakistan).From 2019 to 2020, national NPAFP rates and stool adequacy declined overall in priority countries; subnational surveillance performance declined overall except for WPR countries. Although the total number of WPV1 cases decreased globally from 2019 to 2020, the increase in orphan WPV1 isolates between 2019 and 2020 in both countries suggests gaps in AFP surveillance. The COVID-19 pandemic substantially affected polio eradication activities in 2020 surveillance supplemented by environmental surveillance of sewage samples.Analysis of 2019\u20132020 AFP surveillance data from 42 countries at high risk for poliovirus transmission indicated that national and subnational nonpolio AFP rates and stool specimen adequacy declined in many priority countries.The findings provided in this report can help guide improvement efforts to restore timely and sensitive field surveillance activities, which were adversely affected by the COVID-19 pandemic."} +{"text": "Medications with anticholinergic properties are commonly used by older adults despite being associated with dementia.The anticholinergic total standardized daily dose (TSDD) is a continuous measure of exposure that has been associated with an increased risk of dementia at values >1095 over ten years in epidemiologic studies. We sought to determine a cumulative (cTSDD) and annualized (aTSDD) in a sample of community-dwelling older adults enrolled in the ongoing Reducing Risk of Dementia Through Deprescribing (R2D2) trial (NCT04270474). Participants were 65 years or older without dementia, attended at least one primary care visit within 12 months prior to enrollment, and were current users of strong anticholinergics according to the 2012 Anticholinergic Cognitive Burden Scale. Prescribed and over-the-counter medication details were collected during the baseline visit through self-report and included strength, frequency, units/dose and duration. The aTSDD was calculated for each participant assuming continuous use patterns throughout the year. The cTSDD was calculated by summing the aTSDD across the number of years since initiation. Of 66 participants, the median cTSDD was 2425 (IQR 5131), and 48 (72%) exceeded the threshold of dementia risk (>1095). Additionally, the aTSDD had a median of 730 (IQR 547), with 60 (90%) exceeding the threshold of dementia risk while 11 (17%) exceeded dementia risk threshold of 1095 considering 1 year of exposure. Both measures identified the majority of anticholinergic users exceeding dementia risk thresholds despite some disagreement between the two approaches. However, both methods have potential for research and clinical applications."} +{"text": "In 2020, the Los Angeles County Department of Public Health launched Healthy Brain LA (HBLA). HBLA is a multi-pronged project designed to promote cognitive health, reduce the risk of dementia, and help develop a dementia-focused strategic plan for Los Angeles County (LAC) that prioritizes the needs of those impacted by dementia and cognitive impairment and their caregivers. To support this effort, the HBLA team analyzed weighted data from the 2019 and 2020 California Health Interview Survey (CHIS) to better understand the profile of adult caregivers of individuals with dementia and cognitive impairment. CHIS is a publicly available, population-based, web and telephone survey that asks California residents about a wide range of health topics, yielding representative data on all 58 counties in the state. In 2019-2020, an estimated 1.6 million adults provided care to individuals aged 18 years or older in LAC. About 322,880 of those caregivers provided care for individuals with dementia and cognitive impairment, representing 2% of LAC\u2019s adult population. Many of these caregivers were female (59%), Latino/Hispanic (44%), and between 50-64 years of age (32%). Most of them experienced challenges, such as financial stress (61%), physical/mental health problems (18%), or a change in job status (27%), due to caregiving. These data provide the first local estimate of dementia and cognitive impairment caregiving in nearly 15 years. Results offer critical information about this population that will be used by the HBLA team and its partners to guide efforts to effectively meet the needs of caregivers in LAC."} +{"text": "Developing a level 1 accredited geriatric emergency department during the pandemic was challenging. The greater challenge has been to support rural critical access hospitals on their journey of becoming level 2 accredited geriatric emergency departments. This has been accomplished through a novel collaborative approach between the level 1 accredited emergency department, a newly established Geriatric Center of Excellence at Dartmouth-Hitchcock Health and a HRSA funded Geriatric Workforce Enhancement Program. This talk will focus on bringing together system partners and funders who have a history of success through: (a) development, testing and dissemination of tool kits and implementation guides; (b) boot camp training that includes interprofessional team training, QI and specific geriatric content training; (c) implementation support and coaching using data and QI methodology through learning collaboratives; (d) scaling successful models of evidence based geriatric care; (e) expertise in implementation science; (f) expertise in evaluation and (g) disseminating findings to achieve our goals."} +{"text": "Background: Due to the increasing amount of published data suggesting that endometrial carcinoma is a heterogenic entity with possible different treatment sequences and post-treatment follow-up, the Polish Society of Gynecological Oncology (PSGO) has developed new guidelines. Aim: to summarize the current evidence for diagnosis, treatment, and follow-up of endometrial carcinoma and to provide evidence-based recommendations for clinical practice. Methods: The guidelines have been developed according to standards set by the guideline evaluation tool AGREE II . The strength of scientific evidence has been defined in agreement with The Agency for Health Technology Assessment and Tariff System (AOTMiT) guidelines for scientific evidence classification. The grades of recommendation have been based on the strength of evidence and the level of consensus of the PSGO development group. Conclusion: Based on current evidence, both the implementation of the molecular classification of endometrial cancer patients at the beginning of the treatment sequence and the extension of the final postoperative pathological report of additional biomarkers are needed to optimize and improve treatment results as well as to pave the route for future clinical trials on targeted therapies. The Polish Society of Gynecological Oncology (PSGO) has developed the following recommendations for diagnosis, preoperative assessment for surgical treatment, radiotherapy, systemic treatment, treatment of recurrent disease and post-treatment surveillance of patients with endometrial carcinoma according to standards set by a guideline evaluation tool Appraisal of Guidelines for Research and Evaluation (AGREE) II .Recommendations apply to women over the age of 18 who suffer from endometrial carcinoma .The recommendations are intended for gynaecologists, gynaecological oncologists, surgeons, pathologists, geneticists, radiotherapists, clinical oncologists, general practitioners, palliative care specialists and allied health care professionals.Nomination of a multidisciplinary development group .Identification of scientific evidence.Formulation of guidelines.Assessment of coherence with ESGO/NCCN guidelines.Evaluation of guidelines by external reviewers.Integration of external reviewers\u2019 comments with the original content of the guidelines.The PSGO guidelines were developed using a six-step process:The strength of scientific evidence was defined in agreement with The Agency for Health Technology Assessment and Tariff System (AOTMiT) guidelines for scientific evidence classification Table 1Table 1.The grades of recommendation were based on the strength of evidence and level of consensus of the PTGO development group as described in Any clinician intending to apply PSGO guidelines is expected to perform a careful medical evaluation of individual clinical circumstances to determine the best course of patient care and/or treatment.For the first time, recommendations were developed according to standards set by the guideline tool Appraisal of Guidelines for Research and Evaluation (AGREE) II in gynaecologic oncology.The strengths of the guidelines are they are comprehensive and up-to-date.The limitation is the uncertainty of how many of the authors using guideline AGREE II were methodological experts.Recommendations indicate an urgent need for changes in the system of financing health services in Poland.The 2005 WHO classification (5th edition) identifies 10 histological subtypes of endometrial cancer 3,4,5,66,7,8 (sttype I\u2014endometrioid carcinoma (adenocarcinoma) .type II\u2014non-endometrioid carcinoma, which includes serous carcinoma, clear cell adenocarcinoma, undifferentiated and dedifferentiated carcinoma, mixed carcinoma of the endometrium and carcinosarcoma is recommended for(1)Women with postmenopausal bleeding whose endometrial thickness is > 3 mm (strengt(2)Women with adult granulosa cell tumour undergoing fertility-sparing treatment (with preservation of the uterus) (strengt(3)Women with bleeding during tamoxifen treatment lasting up to 5 years .The endometrial thickness cut-off at which biopsy in asymptomatic women in the general population and in those with increased risk of endometrial cancer *, which would have acceptable sensitivity and specificity, has not been established. Thus, an individual approach is recommended (expert opinion) (strength of evidence V) (grade of recommendation 2B). * Note: The management of endometrial hyperplasia (a precancerous condition) is a separate subject not covered by this recommendation.The sensitivity of endometrial biopsy is 89% and the false-negative rate is 10% .The report should specify the histological type, and for endometroid carcinoma, its differentiation grade assessed in two categories: low-grade (G1/G2) and high-grade G3) [ 3,4,5,6,65,6,7,8The existing scientific evidence indicates(1)The advantage of the new molecular classification over the former based solely on the type of endometrial cancer and grading in making therapeutic decisions at the beginning of treatment ,21,22 (s(2)A significantly higher concordance between pre- and postoperative results for the new molecular classification based on the ProMisE classifier and/or sequencing compared to previously considered features (type and grading) ,26,27,28(3)High sensitivity and specificity of the ProMisE classifier ,30 . A similar requirement applies to high-risk patients with comorbidities who do not qualify for surgical treatment (grade of recommendation 2A).A detailed description of the ProMisE classifier and comprehensive endometrial carcinoma diagnosis algorithm NGS+IHC is included in The centres where the diagnostic minimum (ProMisE molecular classification) cannot be performed may, in the transitional period, use existing criteria: type and grading (does not apply to the decision on fertility-sparing treatment and management of nonoperable cases) (grade of recommendation 3).The report should include a verified histological type, and for endometroid carcinoma, verified grading assessed in two categories: low-grade (G1/G2) and high-grade G3) [ 3,4,5,6,65,6,7,8If molecular classification was not performed at the time of the biopsy, it must be performed for the final report (at least a basic variant of ProMisE) (grade of recommendation 2B).LVSI invasion is a very important predictive factor indicating individual risk of recurrence and a decisive factor in the choice of adjuvant therapy and does not include LVSI within the tumour and in the immediate vicinity of the tumour margin is magnetic resonance imaging (MRI) with contrast ,36 .In justified cases, expert ultrasound can replace magnetic resonance imaging in the assessment of changes in the pelvis (grade of recommendation 2B).FIGO staging for endometrial carcinoma is shown in Standard surgery is a simple total hysterectomy with bilateral salpingo-oophorectomy (BSO) **; peritoneal fluid sampling for cytological examination is not recommended ,38 and total robotic hysterectomy (TRH)) does not compromise the prognosis and has a significant advantage in perioperative and postoperative outcomes over open surgery ,40 increases the number of complications and does not improve results (strengt(1)Sparing treatment in women who want to preserve fertility and who have met the criteria * and achieved complete clinicopathological remission after hormone therapy (strengt(2)No oophorectomy in women < 45 years old who have met the criteria ** ,43,44 and exclusion of metastatic disease (CT of the abdomen and chest); bioptate G1 TP53wt or every G when POLE strengt.HNPCC) (Lynch syndrome).** Criteria: age < 45; FIGO I/II\u2014necessary exclusion of FIGO IIIC by systematic lymphadenectomy or sentinel lymph node procedure in the group at high risk of metastases in radiologically negative lymph nodes (see indications for lymphadenectomy); and high risk of ovarian cancer excluded such as for BRCA1/2 mutation carriers or hereditary nonpolyposis colorectal cancer , does not affect overall survival and the time-to-recurrence; it is, however, associated with a significant number of complications risk of metastases in radiologically negative lymph nodes (grade of recommendation 1).The goal of lymphadenectomy is to rule out the highly probable FIGO IIIC in this group of patients. The potential up-stage change is of prognostic significance ;Non-endometroid carcinoma (high risk);TP53abn, every histological type (high risk);High-grade endometroid carcinoma excluding POLEmut (high risk) ,21,22 are as follows:Furthermore, in the group of patients at high risk of metastasis, lymphadenectomy should include the removal of radiologically negative pelvic and para-aortic lymph nodes up to the left renal vein because it increases overall survival (strengtThe sentinel lymph node procedure can be considered to assess the status of the nodes (pN) ,55 is recommended ,62 and external beam radiation therapy (EBRT) are recommended (strength of evidence V) (grade of recommendation 1).There is a lack of randomised studies comparing different methods of radiotherapy (EBRT/BT) in the radical treatment of inoperable FIGO stage I/II endometrial cancer.Retrospective cohort studies have shown that the use of BT HDR in the radical treatment of inoperable endometrial cancer improves overall survival (OS) and progression-free survival (PFS) time .Low-grade endometroid carcinoma with myometrial invasion > 50% excluding POLEmut (high-intermediate risk).Non-endometroid carcinoma (high risk).TP53abn, every histological type (high risk).High-grade endometroid carcinoma excluding POLEmut (high risk) ,21,22 with significant risk factors for metastasis to the lymph nodes, the following are recommended:In other cases, only BT should be used (expert opinion) (strength of evidence V) (grade of recommendation 2B).It is recommended that the intensity-modulated radiation therapy (IMRT)/VMAT technique or conformal radiotherapy be used in the area of the reproductive organs and lymph nodes. HDR brachytherapy should be planned based on CT or MRI performed after the insertion of the applicator (expert opinion) (strength of evidence V) (grade of recommendation 2B).Simple TLH/TRH/TAH with BSO is recommended; peritoneal fluid sampling for cytological examination and systematic lymphadenectomy is not recommended is allowed only when the patient\u2019s general condition is good and when the operator can perform complete cytoreduction , the recommended method of surgical treatment is en-block cancer resection with reconstruction of the gastrointestinal tract or * radical hysterectomy (expert opinion) (strength of evidence V) (grade of recommendation 2B).Systematic lymphadenectomy, in these cases, is not recommended ,50 (strength of evidence V) (grade of recommendation 2B).CAUTION: This applies to preoperative apparent FIGO I/II cases in which FIGO IIIA or IIIC was diagnosed postoperatively as a result of surgical staging and successfully resected cases of operable FIGO IIIB.Radiochemotherapy is a method of choice ,69 (grade of recommendation 2B). In POLE and MMRd endometrial cancer subtypes, EBRT alone is recommended because the addition of chemotherapy (CHT) before and during irradiation is of no benefit in this group of patients who are not eligible for surgery , the method of choice is EBRT including uterus and lesions in the pelvis depending on their location and/or metastatic para-aortic lymph nodes combined with BT (uterus) (expert opinion) (strength of evidence V) (grade of recommendation 2B).It is recommended that the IMRT/VMAT technique or conformal radiotherapy be used in the area of reproductive organs and pelvic lymph nodes. HDR BT should be planned based on CT or MRI performed after the insertion of the applicator. In cases where radical treatment is not feasible, the method of choice is systemic treatment with or without palliative radiotherapy (expert opinion) (strength of evidence V) (grade of recommendation 2B).In patients with incomplete resection or disseminated cancer, i.e., cases with unresectable metastases to the lungs or liver with a multifocal spread in the abdominal cavity (FIGO IVB) or with unresectable recurrence, the method of choice is systemic treatment (+/\u2212 radiotherapy) ,74,75,76The type of therapy should be selected individually considering the histological type, receptor status and/or molecular profile.For patients with low-grade endometroid carcinoma, it is recommended to determine the expression of E/P receptors (receptor status) because hormone therapy is a preferred option in this group (the percentage of objective responses (ORR) is 21.6%: ER + 26.5% and PR + 35.5%) (does not apply to cases with rapid progression of the disease) after the use of aromatase inhibitors is low (7%), but due to the high (44%) clinical benefit (stabilisation and response) , a carboplatin and paclitaxel regimen is recommended [p = 0.046) [In the arm of patients receiving trastuzumab, a significantly longer median PFS was achieved, reaching 12.6 vs. 8.0 months (strengt= 0.046) (strengtp = 0.013) [p = 0.041) [A particular benefit of trastuzumab was observed in the first line of treatment with PFS of 17.9 vs. 9.3 months (strengt= 0.041) is the most favourable (recommended) therapeutic option in the group of HER2-positive patients (grade of recommendation 1).The standards for determining the status of the HER2 receptor are included in Based on the results of a randomised phase III trial may only take place in clinically justified situations or when there are limitations in the availability of immunotherapy (grade of recommendation 3).When choosing chemotherapy, the patient should be informed of a significantly worse prognosis (expert opinion) (grade of recommendation 2B).In the entire population of patients with recurrent or advanced endometrial cancer, regardless of MMR/MSI status, the use of a combination of a PD-1 inhibitor (pembrolizumab) with a multiply tyrosine kinase inhibitor against VEGFR1, VEGFR2 and VEGFR3 (lenvatinib) was superior to chemotherapy (reduction in the risk of recurrence by 46% (HR of 0.54) and the risk of death by 38% (HR of 0.62)). The objective response rate (ORR) was 32%. The rate of serious adverse events was 89%, and 33% of patients discontinued therapy (strengtIn a single-arm study (strengtThe objective response rate (ORR) was 44% for dostarlimab or disseminated cancer (FIGO IVB) or with unresectable recurrence who progressed after platinum-based chemotherapy (at least one cycle), the treatment of choice is immunotherapy ,74,75 (sMMRd)/MSI-H cancers may be treated with PD-1 inhibitors (dostarlimab or pebrolizumab) or with a combination of PD-1 inhibitor (pembrolizumab) and lenvatinib (grade of recommendation 1). Due to the high percentage of treatment discontinuation observed in the combo therapy of pembrolizumab and lenvatinib, monotherapy with PD-1 inhibitors is the preferred option in this group of patients (expert opinion\u2014strength of evidence V) (grade of recommendation 2B).In the group of patients with a mismatch repair proficiency (MMRp), the treatment of choice is a combination of a PD-1 inhibitor (pembrolizumab) with lenvatinib (strength of evidence IIA) (grade of recommendation 1).There is no evidence that any post-treatment surveillance regimen for endometrial cancer improves patient survival time.The randomised TOTEM study assessed the role of intensive (INT) vs. minimalist (MIN) surveillance after the treatment of patients with endometroid carcinoma of the endometrium (strength of evidence V) (grade of recommendation 2B).Extrapolating the results of the TOTEM study and expeHNPCC) (Lynch syndrome).Hereditary nonpolyposis colorectal cancer proteins [EPCAM deletions (EPCAM-MSH2) and thus has Lynch syndrome [In this group, every 8th woman has a germinal mutation in the proteins are detected in 3% of Lynch syndrome cases [me cases and MSH2 (33%) and the lowest for mutations in MSH6 (26%) and PMS2 (10\u201312%) [The lifetime risk of developing colorectal cancer in the female population is 4.7% (strengt(10\u201312%) ,87 (streMSH2 (51%) and MSH6 (49%) and the lowest for the mutations in MLH1 (34%) and PMS2 (12\u201324%) [The lifetime risk of developing endometrial cancer in the general population is 2.9% (strengt(12\u201324%) ,86,87,88MSH2 mutation are affected the earliest (mean age 47) and MSH6 mutation carriers the latest (mean age 53) [Hereditary endometrial cancer is diagnosed in the fourth and fifth decades of life. Carriers of the age 53) verified pathologically;One is a first-degree relative of the other two;At least two successive generations affected;At least one relative is diagnosed before the age of 50;Familial adenomatous polyposis has been ruled out;Tumours should be verified by pathologic examination are as follows:Other rare hereditary syndromes predisposing to endometrial cancer are described below.PTEN germline mutations (<1%) increase the risk of developing endometrial cancer by 25% and susceptibility to treatment with platinum compounds and PARP inhibitors. In contrast, biallelic inactivation of is rare (Lynch syndrome) in BRCA1/2 (HBss/HBOC/HOC) and in PTEN (Cowden\u2019s syndrome) should result in genetic testing among relatives to identify carriers of the germline mutation.Confirmation of mutations in In the case of Lynch syndrome, each family member with a confirmed mutation (regardless of gender) should undergo colonoscopy screening according to the Polish Society of Oncological Surgery (PSOS) recommendations (expert opinion) (strength of evidence V) (grade of recommendation 2B).Women (Lynch syndrome and Cowden syndrome) should be encouraged to have children early and be offered prophylactic hysterectomy after the completion of reproductive plans ,87,92 (strength of evidence V) (grade of recommendation 2B).BRCA1/2 (HOC/HBOC/HOC) [Prophylactic oophorectomy and salpingectomy are recommended in Lynch syndrome ,87 (streBOC/HOC) (strengtPTEN (Cowden syndrome) germinal mutation, a prophylactic oophorectomy and salpingectomy are not recommended [In the case of ommended (strengtBRCA1/2 germline mutation (HOC/HBOC/HOC), prophylactic hysterectomy is not recommended [In the case of the ommended (strengt"} +{"text": "Cognitive training has the potential to help older adults maintain or improve their cognitive abilities, but there has been debate regarding how susceptible cognitive outcomes in these studies are to placebo effects. Some previous research has found that expectations can shape performance on study outcomes, although this is not always a consistent finding. The degree to which perceived intervention efficacy can lead to changes in the performance of objective outcome measures typically assessed in these studies is unclear. The aim of the current study is to explore the effects of perceived effectiveness of cognitive training on actual improvements in a large sample of older adults. The current study utilized data from the Intervention Comparative Effectiveness for Adult Cognitive Training Trial. Two hundred and thirty older adults (Mean age = 72) were randomized into one of four training conditions: (1) a web-based brain game suite, Brain HQ, (2) a strategy video game, Rise of Nations, (3) Instrumental Activities of Daily Living (IADL) training, or (4) an active control condition of puzzle solving. Reasoning, memory, processing speed, and IADL performance were measured before and after the intervention. Perceived efficacy of training in those outcome domains were also measured. Bayesian ANOVA analysis showed strong evidence of group differences in perceived efficacy within all outcome domains across the training conditions whereas Bayesian regression showed moderate to strong evidence against influences of perceived efficacy on changes in performance. Discussion will focus on implications of those results on behavioral and cognitive intervention designs."} +{"text": "A mental health promotion programme called \u2018Healthy Me\u2019, was a collaboration between Action Mental Health (AMH) MensSana, Child and Adolescent Mental Health Services (CAMHS) in the Southern Health and Social Care Trust and the Royal College of Psychiatry (RCPsych) in Northern Ireland in 2014. Adapting \u2018Healthy Me\u2019 for delivery in special schools was recommended in evaluation of this pilot programme. A co-produced pilot adapted \u2018healthy me\u2019 programme, for young people with ID was taken forward by Action Mental Health (AMH) MensSana and Intellectual Disability Child and Adolescent Mental Health Service (ID CAMHS) in the Southern Health and Social Care Trust (SHSCT). To determine the feasibility of adaptation and delivery of the programme for the needs of the ID population. To inform changes to be made before wider roll-out. To promote children's social and emotional well-being and emotional literacy through the teaching of problem-solving, coping skills, conflict management and managing feelings. To evaluate the effectiveness of this intervention with children being able to retain learning, information and ideas.Pre programme quiz July 2021 (young people)Post session 1\u20135 quizzes (young people)Post programme quiz October 2021 (young people)Simple visual blob tree (young people)Outcome MeasuresPre programme initial outcome measure (parent) The Mood, Interest and Pleasure Questionnaire-short form (MIPQ-S) July 2021Pre programme initial outcome measure (parent) non standardised, based on the strength and difficulties questionnaire (SDQ) and the Child and Youth Resilience Measure-Revised Person Most Knowledgeable version (PMK-CYRM-R) July 2021Post programme repeated outcome measure (parent) MIPQ-S October 2021Post programme repeated outcome measure (parent) Based on SDQ & PMK-CYRM-R October 2021EvaluationSix participants identified at outset and four attended and engaged consistently, young people aged between 14 and 17 years. Participants were supported 1:1 to fill in a simple evaluation forms after sessions rating their enjoyment and what they had learnt. Repeating the MIPQ-S with parents highlighted some improved scores indicating positive affect and elevated interest and pleasure.The programme will be offered to in the next stage of the pilot to Special Schools in NI. It is hoped to show that similar positive gains can be made in the school settings for children and young people with intellectual disability in terms of promoting positive mental health and social and emotional well-being."} +{"text": "Dear Editor et al. \"The Prevalence of HPV Genotypes in Iranian Population: An Update\", which pathologically mostly lead to Squamous intraepithelial lesions (9). Our findings suggested which Pap smear report is most associated with each serotype of HPV; however, the \"No Inflammation\" state is the most common among all serotypes (39.4%). Detailed HPV PCR test and Pap smear cross-tabulation results are shown in . We recommend cytologists report the presence of Anucleated squamous or Keratinized cells and exudates in the positive smears in order to prevent HPV-related Cancers in the population.Thus Type 16 is the most serotype involving in HPV infections among the average Iranian population , 6, 7, 8"} +{"text": "ABSTRACT IMPACT: This project will use human neuron models and bioinformatics techniques to elucidate mechanisms of cocaine neurotoxicity, which will allow treatments to be developed for minimizing or preventing neurological damage caused by cocaine abuse and overdose. OBJECTIVES/GOALS: The goals of this project are to identify genes and gene networks altered by cocaine exposure in neurons (short term), and to use these pathways to understand mechanisms of cocaine neurotoxicity for the establishment of therapeutic targets (long term). METHODS/STUDY POPULATION: To study the molecular effects of cocaine, we generated preliminary proteomics and next-generation RNA sequencing (RNAseq) data from human postmortem prefrontal cortex (Broadmann area 9 or BA9) of 12 cocaine overdose subjects and 17 controls. Future directions for this project include RNAseq analysis of neuronal nuclei sorted from human postmortem BA9 and a human induced pluripotent stem cell-derived neuron (hiPSN) model of cocaine exposure from the same postmortem subjects from whom we have brain samples. RESULTS/ANTICIPATED RESULTS: We found alterations in neuronal synaptic protein levels and gene expression, including the serotonin transporter SLC6A4, and synaptic proteins SNAP25, SYN2, SYNGR3. Pathway analysis of our results revealed alterations in specific pathways involved with neuronal function including voltage-gated calcium channels, and GABA receptor signaling. In the future, we expect to see an enhancement in neuron-specific gene expression signatures in our sorted neuronal nuclei and our hiPSN model of cocaine exposure. The hiPSN model will help elucidate which effects are due to acute versus chronic exposure of cocaine. DISCUSSION/SIGNIFICANCE OF FINDINGS: Transcriptomic signatures found with this analysis can help us understand mechanisms of cocaine neurotoxicity in human neurons. With this work and future proposed studies, we can discover targetable molecular pathways to develop drugs that can reduce or reverse cocaine-related impairment."} +{"text": "Whereas previous studies have investigated life regrets, little attention has been paid to the important accomplishments older adults include in their autobiographic life narratives. Phenomenon such as the memory positivity effect suggest that accomplishments should be observed. We used a Health and Retirement Study 2017 Life History Mail Survey to examine the characteristics of participants over age 65 who reported accomplishments (max = 3), what was reported, and whether early-life decisions about balancing family and work are associated with the reports. Women, whites, and people with at least high school education and normal cognitive status were more likely to report accomplishments (67%). We categorized reports as family-related (39%), personal (19%), combined family/personal (25%) or other (16%). Multinominal logistic regression models revealed that participants who themselves favored family over work in early life or whose spouse decided for family, were more likely to report family-related accomplishments."} +{"text": "Solanum (9), Ribes (8), Berberis (7), Hypochaeris (7) and Oxalis (6). Perennial herbs are the predominant life form (40%), followed by shrubs (35%), trees (14%), and annual and biannual herbs (11%). Fruits (35.8%), roots (21.5%) and leaves (20.0%) are the parts of plants consumed the most. Nine different food preparation categories were identified, with \u2018raw\u2019 forming the largest group (43%), followed by \u2018beverages\u2019 (27%), \u2018savoury preparations\u2019 (27%), and \u2018sweet\u2019 (13%). Almost all native Chilean WEPs have reported traditional food uses, while only a few of them have contemporary uses, with food products mainly sold in local and specialised markets. Species\u2019 richness, taxonomic diversity and family representation have similar patterns to those observed for the world flora and other countries where surveys have been carried out. Some Chilean native WEPs have the potential to become new crops and important sources of nutritious and healthy products in the food industry. However, there are still many gaps in knowledge about their nutritional, anti-nutritional and biochemical characteristics; future research is recommended to unveil their properties and potential uses in agriculture and the food industry.Wild Edible Plants (WEPs) still play a vital role in the subsistence of many traditional communities, while they are receiving increasing recognition in tackling food security and nutrition at the international level. This paper reviews the use patterns of native WEPs in Chile and discusses their role as future crops and sources of food products. We conducted an extensive literature review by assessing their taxonomic diversity, life forms, consumption and preparation methods, types of use , and nutritional properties. We found that 330 native species were documented as food plants, which represent 7.8% of the total flora of Chile. These species belong to 196 genera and 84 families. The most diverse families are Asteraceae (34), Cactaceae (21), Fabaceae (21), Solanaceae (20) and Apiaceae (19), and the richest genera in terms of number of species are The benefits derived from biodiversity are also at the heart of the Convention on Biological Diversity , with 109 WEPs (33.5%), followed by Rosids (Fabids (49 spp.) + Malvids (37) + Vitales (0)), with 86 WEPs (26.5%). Monocots contain 48 WEPs (14.8%), while gymnosperms and Monilophytes have only 3 WEP species each . The perAccording to our revision, the main consumed parts of Chilean native WEPs are fruits and infructescences (35.8%), roots (21.5%), leaves (20.0%), seeds (9.1%), and stems (7.0%) . InfloreThe most frequent form of consumption was raw (43% of species) among the nine different categories , followeThe relation between the organs consumed and the preparation forms showed tJubaea chilensis (Molina) Baill., an endemic Chilean palm tree; fruits and seeds are eaten fresh and used in sweet dishes; the sap is boiled to produce syrup , [binomial name + edible], [binomial name + beverages] and so on. All queries were made both in Spanish and English.Initial data were obtained from the database on the uses of Chilean native flora ) by Rodr\u00edguez et al., (2018) [http://www.plantsoftheworldonline.org/ (accessed on 12 February 2022)). The nomenclature follows the International Plant Name Index [The taxonomy of the species was updated based on the catalogue of the flora of Chile and by rme Index and the me Index , with whme Index , rgdal vme Index , dplyr vme Index and doByme Index .Life forms and origins of Chilean native plants were obtained from the catalogue of the flora of Chile . To infeWe considered all species naturally occurring in Chilean territory and used as food and beverages as native wild edible plants (WEPs). According to the Economic Botany Data Collection standard (EBDCS) , plant uThe flora of Chile has a high number of native WEPs, some of which were domesticated by the original peoples of south-western South America before the Spanish conquest . In contrast, others were transformed or are the progenitors of important main crops that are part of the world food base, such as potatoes, quinoa, and Chilean strawberries. However, many more WEPs have the potential to become new crops and sources of new industrial food products in the future.Innovation based on Chilean WEPs requires strengthening both the biochemical studies to characterise the nutritional content of species in detail and agriculture research for the domestication of species and the development of breeding programmes enabling the creation of new crops.However, in the face of future social, cultural, economic, environmental and climatic change scenarios, the food development of native Chilean WEPs must be responsibly supported by sustainable consumption and food innovation, which require access to plant genetic material and the cultivation of these plants in line with international access and benefit-sharing agreements and the creation of sustainable value chains."} +{"text": "During October 2019, the West Virginia Bureau for Public Health (WVBPH) noted that an increasing number of persons who inject drugs (PWID) in Kanawha County received a diagnosis of HIV. The number of HIV diagnoses among PWID increased from less than five annually during 2016\u20132018 to 11 during January\u2013October 2019 . KanawhaAfter suspension of the KCHD syringe services program (SSP) in March 2018 and a community-based SSP in April 2021 (because of concerns about program administration), a state lawAn HIV outbreak case was defined as a confirmed HIV diagnosis on or after January 1, 2019 in a PWID living in Kanawha County at the time of diagnosis. Investigators conducted qualitative interviews with 26 PWID and 45 community partners (including service providers),***As of October 27, 2021, 85 persons met the HIV outbreak case definition; 54 (52%) patients were male, 67 (79%) were aged 20\u201339 years at diagnosis, and 77 (91%) were non-Hispanic White. Forty patients (47%) had experienced unstable housing during the past year, and 73 (86%) had previous or current hepatitis C infection. Among 80 living persons, 20 (25%) had an HIV care visit during the preceding 90 days,Interview and medical record data indicated that methamphetamines and heroin were the most frequently injected drugs, and polysubstance use was common (57 [88%] of 65 patients). PWID reported reusing or sharing syringes, mainly because of limited access to sterile syringes after SSP closures. PWID expressed medical mistrust because of experiences of stigma and discrimination in health care settings. Medical record abstraction revealed that HIV screening tests were performed at fewer than one third of health care encounters before diagnosis, and none of the patients had been prescribed preexposure prophylaxis (PrEP). Prescriptions of naloxone for overdose prevention and medications for opioid use disorder were documented at fewer than a quarter of opioid-related health care encounters.Recommendations based on investigation findings and HIV surveillance data are guiding response activities."} +{"text": "Scientific Reports 10.1038/s41598-021-82092-9, published online 19 February 2021Correction to: The original version of this Article contained errors. Legends for Table 1 and Table 2 were reversed.Table 1 legend \"List of all strains examined in this study with their GenBank accession numbers (BOLD ID). Geographic position and description of sample sites indicated.\"Hantzschia from studied material with similar taxa.\"now reads: \u201cComparison of species and strains of Hantzschia from studied material with similar taxa.\"Table 2 legend \"Comparison of species and strains of now reads: \"List of all strains examined in this study with their GenBank accession numbers (BOLD ID). Geographic position and description of sample sites indicated.\"These errors have now been corrected in the PDF and HTML versions of the Article."} +{"text": "This systematic review assesses variation in international and national guidelines on respiratory protection for health care professionals during the COVID-19 pandemic. We assessed variation in international and national guidelines on respiratory protection for HCPs in hospital settings during the first year of the COVID-19 pandemic.Conflicting evidence surrounding SARS-CoV-2 transmission, particularly airborne transmission, may have contributed to heterogeneous recommendations for respiratory protection across countries and organizations.PRISMA) reporting guideline. Infection prevention and control guidelines on respiratory protection for HCPs published from January 1 to December 31, 2020, by leading organizations in 4 countries and 2 international organizations were collected through a monthly consultation of their official websites were excluded and 59 guidelines (51.8%) were included. In January 2020, all initial guidelines recommended respirators for HCPs in direct contact with patients with suspected or confirmed COVID-19 infection . After F3 The most recent assessment of the clinical evidence for the risk of transmission of acute respiratory infections to HCPs caring for patients undergoing AGPs dates back to a 2012 systematic review of a limited volume of studies .4 More evidence is still needed to clearly define what AGPs are and the level of risk associated with different procedures.5In this systematic review, we observed 4 strategies regarding the use of respirators: (1) systematic: recommended for care of COVID-19 patients, as in German guidelines; (2) flexible: recommended with use of MFs in the absence of available respirators, as in US and ECDC guidelines; (3) unit based, as in UK guidelines; and (4) recommended exclusively during AGPs, as in French and WHO guidelines. These discrepancies may reflect controversies related to SARS-CoV-2 transmission routes.6 Some guideline updates may have been dated incorrectly, representing the main study limitation.Initial uncertainties surrounding asymptomatic transmission of SARS-CoV-2 and the initial global shortage of MFs may explain some of the early delays in universal face-masking recommendations. The growing recognition of the role played by asymptomatic HCPs and the publication of a major positioning paper may have triggered the extension of face masking.Over the course of the COVID-19 pandemic, contextual factors may have generated variability in recommendations owing to a lack of scientific evidence. Inconsistencies in respiratory protection guidelines between neighboring countries created confusion over optimal measures. Strong collaborations between national and international organizations are critical in such circumstances."} +{"text": "Ebolavirus cause severe and often lethal disease in humans: Sudan ebolavirus (SUDV), Bundibugyo ebolavirus (BDBV), Ta\u00ef Forest ebolavirus (TAFV), and Zaire ebolavirus (EBOV) .,25.24,25While substantial progress has been made in the development of EBOV vaccines, multiple questions remain unanswered including the following: (1) what is the durability and the immediacy of immune responses generated by different vaccines; (2) what are the specific correlates and thresholds of protection; (3) do any interactions or interferences exist between vaccines and potential therapeutics; (4) what is the safety of these vaccines in special populations, particularly pregnant women and the immunocompromised; and (5) can vaccines be formulated to be stable for long-term storage at 2 to 8\u00b0C, which would be useful in endemic areas [Another major hurdle is mitigating the economic risks for manufacturers and distributors of EBOV vaccines since the demand may not be high enough to warrant stockpiling. Outbreaks also tend to occur in resource-poor countries leaving little financial incentive for commercial development. In January 2021, the International Coordinating Group (ICG) comprised of public and private benefactors established an Ebola vaccine stockpile in Sweden with the goal of manufacturing 500,000 doses. Stockpiling is an important step toward controlling EBOV outbreaks as it is critical for ensuring timely access to vaccines for at-risk populations .Ebolavirus: EBOV. Although multivalent vaccines have and are being developed, no studies have specifically evaluated immune responses or efficacy against other Ebolavirus species . Future work should focus on the development of vaccines that confer protection across all medically relevant species of the genus Ebolavirus, bearing in mind that intraspecies mutations may also arise that impact vaccine effectiveness.Lastly, the most advanced vaccines are solely indicated for protection against one species of"} +{"text": "ABSTRACT IMPACT: The pathophysiologic features of a metabolomic endotype that predicts patient outcomes due to sepsis have the potential to direct new therapies that target immune dysregulation and bioenergetic insufficiency. OBJECTIVES/GOALS: Acute respiratory failure (ARF) requiring mechanical ventilation is a frequent complication of sepsis and other disorders. It is associated with high morbidity and mortality. Despite its severity and prevalence, little is known about metabolic and bioenergetic changes that accompanying ARF. METHODS/STUDY POPULATION: In this study, semiquantitative and quantitative ultrahigh performance liquid chromatography mass spectrometry (UHPLC MS) analysis was performed on patient serum collected from the Trial with Acute Respiratory failure patients: evaluation of Global Exercise Therapies (TARGET). Serum from survivors (n=15) and nonsurvivors (n=15) was collected at day 1 and day 3 after admission to the medical intensive care unit as well as at discharge in survivors. Pathway analysis of the biochemical changes was performed to determine whether the disruption in specific metabolic pathways can identify the bioenergetic and metabolomic profile of these patients. RESULTS/ANTICIPATED RESULTS: Significant metabolomic differences were related to biosynthetic intermediates of redox cofactors nicotinamide adenine dinucleotide (NAD) and NAD phosphate (NADP), increased acyl-carnitines, and decreased acyl-glycerophosphocholines in nonsurvivors compared to survivors. The metabolites associated with poor outcomes are substrates of enzymatic processes dependent on NAD(P), while the abundance of NAD cofactors rely on the bioavailability of dietary vitamins B1, B2 and B6. Changes in the efficiency of the nicotinamide-derived cofactors\u2019 biosynthetic pathways also associate with an alteration of the glutathione-dependent drug metabolism as characterized by the substantial differences observed in the acetaminophen metabolome. DISCUSSION/SIGNIFICANCE OF FINDINGS: This metabolomic endotype represents a previously unappreciated association between severity of outcomes and micronutrient deficiency, thus pointing to new pharmacologic targets and highlighting the need for nutritional remediation upon hospitalization to improve patient outcomes due to ARF."} +{"text": "Senior adults\u2019 reliance on the visual frame of reference for spatial orientation is a manifestation of an age-related shift in cognitive style from field independence to field dependence. We implemented a virtual reality rod and frame test (VR-RFT) to assess visual field dependence (VFD) in n=39 young adults (20-30 years old) and n=43 seniors (60 years old and above). The subjects were asked to determine subjective visual vertical (SVV) for 19 angles of frame tilt (running from -45 degrees to 45 degrees in steps of 5 degrees). The strong VFD of seniors was manifested not only by the increased error in the determination of SVV (SVVE) but also in its distribution. For small and large frame tilt angles, seniors\u2019 SVVE skewness and kurtosis were greater than those of young adults. The SVVE median dependence on frame tilt may be accounted for with a phenomenological model whose two parameters describe the strengths of primary (P) and secondary (S) visual attractors which subjects use to infer SVV: the edges of the frame and its imaginary diagonals. For young adults, these parameters were: PY=14.91 and SY=12.51. For seniors, we observed an over 50% increase in the strength of the primary attractor PS=26.31 while the strength of the secondary one was only weakly affected by aging: SS=13.74. We demonstrate that the asymmetry between the strength of attractors significantly contributes to SVVE made by seniors at large frame tilts. We hypothesize that a variant VR-RFT may be used in rehabilitation to reduce excessive VFD."} +{"text": "Given the growing prevalence of Alzheimer\u2019s Disease and related dementias, and the intensity of this population\u2019s care needs, it is imperative that health plans (HPs) increase their dementia-capability. The Dementia Cal MediConnect (Dementia CMC) project proposes an innovative model of health care advocacy that can create dementia-capable systems change. The Dementia CMC project was a partnership (2013 \u2013 2018) between local Alzheimer\u2019s organizations and ten managed care HPs in California. It used the following model of health care advocacy: 1) Identify dementia-capable best practices to set as systems change indicators; 2) Identify and leverage public policies in support of systems change indicators; 3) Identify and engage champions; 4) Develop and advocate for a value and business case to improve dementia care; 5) Identify gaps in dementia-capable practices; 6) Provide technical assistance, tools, and staff training to address the gaps in dementia-capable practices; and 7) Track systems change. Systems change data was collected through participant observation with HPs and interviews with key informants. HPs reported making systems changes toward more dementia-capable practices such as: better pathways for identification and diagnosis; better identification, assessment, support, and engagement of caregivers; and improved systems of referral to Alzheimer\u2019s organizations. Some indicators of systems change were inconclusive as a result of variability in HP practices and the lack of common record systems between HPs and providers. The application of this advocacy model has led to systems changes that can be replicated to improve care for people living with dementia and their caregivers."} +{"text": "Adequate sleep in hospitalised children is important for a variety of physiological and psychological processes associated with growth, development, and recovery from illness and injury. Hospitalisation often prioritises clinical care activities at the expense of age-appropriate sleep. Nurses and the wider healthcare team contribute to this paradox. However, through conscious practice and partnering with mothers, nurses are able to enact change and promote sleep.To adopt, adapt or contextualise existing guidelines to develop an evidence-based practice guideline to promote sleep-friendly ward environments and routines facilitated by nurses, and in partnership with mothers.A six-step methodology for guideline adaptation was followed, as recommended by the South African Guidelines Excellence project: (1) existing guidelines and protocols were identified and (2) appraised using the AGREE II instrument; (3) an evidence base was developed; (4) recommendations were modified, (5) assigned levels of evidence and grades of recommendation; and (6) end user guidance was developed. Expert consultation was sought throughout.Existing relevant guidance comprised 61 adult-centric recommendations. Modification of the evidence base led to six composited recommendations that facilitate sleep in hospitalised children: (1) prioritising patient safety; (2) collaborating with the mother or caregiver to promote sleep; (3) coordinating ward routine and (4) environment to improve sleep; (5) work with clinical and non-clinical staff; and (6) performing basic sleep assessments. Practice recommendations were aligned to the South African regulatory framework for nursing.Hospitalisation is a time of physiological and psychological dysregulation for children, which is amplified by poor sleep in a hospital. Nurses have the opportunity to promote sleep during hospitalisation by implementing this African-centric guideline in partnership with mothers. Sleep is crucial to the developmental processes of children Beebe , and is In critically ill adults, length of stay is adversely affected by in-hospital sleep disruption was created. A guideline is a rigorously developed document that informs healthcare decisions through actionable recommendations existing guidelines and protocols were identified and (2) appraised using the AGREE II instrument; (3) an evidence base was developed; (4) recommendations were modified and (5) assigned levels of evidence and grades of recommendation after which (6) end user guidance was developed. Expert consultation was sought throughout the process, particularly during the fourth and sixth stages of development. This methodology for guideline modification follows the recommendations made by the South African Guidelines Excellence (SAGE) project approach and staff. Involving mothers was crucial to the continuity of sleep for the child as sleep practices are known to vary by culture and the website of the National Institute for Clinical Excellence (NICE United Kingdom [UK]), were performed to identify relevant guidance or policy documents. Keywords and MeSH terms included sleep, controlled environment, care, quiet (time), hospital, sleep and guideline or protocol. The search strategy was constructed using the P-C-C approach to aid definition of search terms and inclusion and exclusion criteria as summarised in Step 2: Appraisal of the existing guidelines: Identified sources were then screened for scope and purpose, and rigour of development using Domains one and three from the AGREE II instrument , contextualisation and finally adaptation resulted in the identification of 88 sources, whilst other methods identified 2345 sources (mostly grey literature). After de-duplication, a total of 2433 sources were screened by title and abstract or executive summary using the criteria described in The authors of the above sources were contacted and provided additional information that led to the identification of Elliott and the AGREE II safety and other special considerations, (2) collaboration with the bedside carer to promote individualised sleep, (3) coordination of the ward routine and (4) ward environment to improve sleep, (5) collaborating and communicating with staff and other persons to protect sleep and finally (6) performing a basic sleep assessment.The majority of modifications to the recommendations involved contextualisation, mainly for differences in resources and target population. As an example, original recommendations about a visitor policy were contextualised to accommodate the expected presence of a mother or other bedside carer. A sleep assessment tool for children was identified .A flowchart summary of recommendations is presented in The flowchart was incorporated into a poster summary together with an aide memoir: (1) safety first, (2) then a mother\u2019s love; (3) next comes time; (4) low noise, dim light and calm. Pack the phone away, (5) collaborate with us; (6) then make sure sleep was enough.Sleep is disrupted during paediatric hospitalisation Safety, (2) collaboration with the bedside carer to promote individualised sleep, coordination of the (3) ward routine and (4) ward environment to improve sleep, (5) involvement of the wider ward team and (6) sleep assessment. These recommendations and the supporting evidence-base are well-described in The second recommendation, concerning collaboration with the bedside carer, was adapted from original recommendations that encouraged family members and visitors to rest at home , we noted that children\u2019s sleep needs differ in quantity by age, generally decreasing from infancy towards puberty sleep during hospitalisation. However, nurses are ideally positioned to capitalise on time spent in hospital to aid children\u2019s sleep through engagement and partnering with families, to promote health and enact their role as patient advocates. The guideline described throughout this article seeks to guide nurses to actively engage in sleep promotion for the hospitalised child. This evidence-based African-centric approach of partnering with families during hospitalisation exemplifies collaborative healthcare and holds the promise of benefits that extend beyond discharge home in resource-constrained contexts."} +{"text": "The dynamic interplay between dementia and psychological trauma can exert powerful effects on nursing home residents\u2019 behavioral symptoms and quality of life. Our objectives in this exploratory study were to assess care aides\u2019 perceptions of how often they worked with residents with past psychological trauma, the types of trauma encountered, and reasons for these beliefs. We conducted semi-structured cognitive interviews (n = 10) with care aides in June 2019 to inform the development of a trauma needs assessment (4 questions) that we included in a large survey of nursing staff (2019 - 2020). Care aides (n = 3761) were sampled from 91 randomly selected urban nursing homes stratified by health region, owner operator model, and size. We completed basic statistics and content analyses. Care aides identified residents they believed to have psychological trauma histories and provided reasons for their beliefs. Approximately 12% of the reported traumatic events were disclosed to staff. The most common, broad categories of trauma to emerge during analysis were abuse (40%) and war exposure (30%). Each had sub-categories. The most common categories of signs of trauma were re-experiencing symptoms such as flashbacks and nightmares (28%), and avoidance of specific triggers, such as water or intimate care (24%). The majority of the reported signs of trauma were persistent and distressing for staff and residents. Some behaviours assumed to be responsive behaviours of dementia may relate to traumatic stress symptomatology. Implementing trauma-informed supports for residents and care aides is essential to person-centred care and optimal quality of life."} +{"text": "The authors wish to make the following correction to their paper . In the All ingredients were assessed by Weender analysis. Dry matter (DM), crude ash (CA), crude protein (CP) and ether extract (EE) were analyzed in all feedstuff. Crude fiber (CF), neutral detergent fiber (NDF) and acid detergent fiber (ADF) were analyzed in the solid feed. In concentrate feed and TMR starch was analyzed and in concentrate feed additionally sugar was analyzed."} +{"text": "Although mindfulness therapies have demonstrated benefits for reducing stress and improving psychological symptoms in family dementia caregivers, the mechanisms underlying these salutary effects are unknown. We report a causal mediation pathway to improvement of stress symptoms in family dementia caregivers with Mentalizing Imagery Therapy (MIT), which employs mindfulness and guided imagery tools to reduce stress and improve understanding of self and others. In a randomized controlled trial of short-term 4-week MIT (N=24) versus a psychosocial support group (N=22), MIT demonstrated superior benefit for reducing perceived stress (p=.006). Increased trait mindfulness was a causal mediator of this effect (p=.02). Neuroimaging pre and post intervention found that increased mindfulness was associated with strengthened connectivity of the dorsolateral prefrontal cortex with an emotion regulation network (p<.001). The results are discussed in light of theories of cognitive control and may inform the design of future studies aimed at reducing family caregiver stress."} +{"text": "Structural isolation such as living alone poses a mental health risk in diverse groups of older adults, including older immigrants. Given that those living with others might also be disengaged, the present investigation included eating alone as another source of isolation and examined the impact of the combination of living and eating alone. The proposes of the study were to examine (1) how living and/or eating alone would impact mental distress, (2) whether the impact would be mediated by feelings of loneliness, and (3) if there would be gender differences in the mediation effect. The data were drawn from the Study of Older Korean Americans (SOKA), which surveyed older Korean immigrants in five states during 2017\u22122018. The living/eating arrangement was classified into four-groups: living/eating with others (57%), living with others/eating alone (12.4%), living alone/eating with others (7.3%), and living/eating alone (23.1%). Using the PROCESS macro, we tested the mediation effect of loneliness and the moderation effect of gender in the relationship between the typology and mental distress controlling for background/health characteristics and social capital related variables. Two groups had sociodemographic, health, and social capital disadvantages. Analyses demonstrated that mental distress was linked with living with others/eating alone and living/eating alone, of which relationships were mediated by loneliness only among women. Findings suggest that not only structural isolation but also disengagement with others need to be considered to understand emotional well-being in older immigrant population and gender difference."} +{"text": "QuickDASH for use in assessment of limb function in patients with upper extremity lymphedema using modern psychometric techniques.This study aimed to evaluate and improve the accuracy and efficiency of the QuickDASH, and then fit the data to Samejima\u2019s graded response model (GRM) and assessed the assumption of local independence of items and calibrated the item responses for CAT simulation.We conducted confirmative factor analysis (CFA) and Mokken analysis to examine the assumption of unidimensionality for IRT model on data from 285 patients who completed the QuickDash (r\u2009=\u20090.98). Items 2 (doing heavy chores) and 8 (limiting work or daily activities) were the most frequently used. The correlation among factor scores derived from the QuickDASH version with 11 items and the Ultra-QuickDASH version with items 2 and 8 was as high as 0.91.Initial CFA and Mokken analyses demonstrated good scalability of items and unidimensionality. However, the local independence of items assumption was violated between items 9 (severity of pain) and 11 (sleeping difficulty due to pain) (Yen\u2019s Q3\u2009=\u20090.46) and disordered thresholds were evident for item 5 (cutting food). After addressing these breaches of assumptions, the re-analyzed GRM with the remaining 10 items achieved an improved fit. Simulation of CAT administration demonstrated a high correlation between scores on the CAT and the QuickDash items we can obtain estimates that are very similar to those obtained from the full-length QuickDash without the need for CAT technology.By administering just these two best performing The online version contains supplementary material available at 10.1007/s11136-021-02979-y. The disabilities of the arm, shoulder, and hand (DASH) outcome measure is a widely used patient-reported outcome measure (PROM) assessing different disorders of the upper limb as well as the extent of impairments .QuickDASH (Online Appendix A), was developed in 2005 and comprises 11 items from the original 30-item DASH while still maintaining a strong correlation with the original DASH scores , whQuickDASH substantially, we found that a more efficient and precise estimation of disability level and symptom severity for American lymphedema patients can be achieved. In the meanwhile, the Concerto, as an emerging open-source CAT delivery platform, makes this CAT QuickDASH application in a real clinic setting possible [Ultra-QuickDASH mainly consisting of two best performing items and maintaining efficient and accurate estimations could be used as a CAT technology-free version of QuickDASH. Its application and promotion can break the obstacles of complex technology on health care professionals and providers on the use of\u00a0CAT QuickDASH, making this super shortened instrument more convenient to apply into routine clinic practices.By utilizing CAT simulation based on the IRT framework to shorten the possible . All theQuickDASH Questionnaire (PDF 676 kb)Supplementary file1 Supplementary file2 (PDF 690 kb)QuickDASH Questionnaire (PDF 213 kb)Supplementary file3 Revised Below is the link to the electronic supplementary material."} +{"text": "The International Federation of Gynecology and Obstetrics (FIGO) stage remains the standard staging system for the assessment of endometrial cancer (EC) prognosis. Thus, we aim to identify the significant genes or biomarkers associated with the stage of endometrial cancer, which may also help reveal the mechanism of EC progression and assess the prognosis of patients with EC.We compared the mRNA expression levels of EC patients with stages I and II as well as stages III and IV in the Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) of EC patients at different stages were selected by volcano plot and Venn analysis. Gene Ontology (GO) and Pathways were applied to analyze the identified genes. Protein protein interaction (PPI) network was employed to identify the correlation. The survival analyses based on TCGA database were conducted for further screening. The Human Protein Atlas, quantitative PCR and immunohistochemistry were utilized to confirm the differences in expression of DEGs in endometrial cancer samples at different FIGO stages.CKMT1A was identified as a candidate gene. Through survival analyses, we found that CKMT1A may be a poor prognostic factor in the overall survival of endometrial cancer patients. GO and Pathways revealed that CKMT1A is closely associated with the metabolic process. More importantly, Human Protein Atlas and quantitative PCR confirmed the differences in expression of CKMT1A in endometrial cancer samples at different FIGO stages.CKMT1A is a newly identified essential tumor progression regulator of endometrial cancer, which may give rise to novel therapeutic strategies in the management of endometrial cancer patients to prolong its prognosis and prevent tumor progression.In summary, this study shows that Endometrial cancer (EC) is one of the most common malignant tumors in the female reproductive tract . AccordiSOX11) hypomethylation is an independent poor prognostic marker in EC and poor histological differentiation . In a multivariate analysis, histological differentiation and FIGO stage were found to be the independent predictors of tumor progression among the patients with endometrial cancer and the difference of stage were independent prognostic factors for the OS of patients with endometrial cancer Click here for additional data file.S2 TableLogFC: FoldChange.(DOC)Click here for additional data file.S3 TableLogFC: FoldChange.(DOC)Click here for additional data file.S4 TableBP: Biological Process; MF: Molecular Function; CC: Cellular Component; FDR: false discovery rate.(DOC)Click here for additional data file.S5 TableFDR: false discovery rate.(DOC)Click here for additional data file.S6 Table(DOC)Click here for additional data file.S7 Table(DOC)Click here for additional data file."} +{"text": "However, very few studies addressed its role in amyotrophic lateral sclerosis (ALS). Dominguez et al.3 recently brought some negative findings on this topic: (i) the genetic inactivation of receptor-interacting protein kinase (RIPK)1 did not protect against motor neuron degeneration in the superoxide dismutase (SOD)1 model of ALS and (ii) phosphorylated (p)-RIPK1 did not accumulate in the spinal cords of ALS compared to non-ALS patients. These findings raise doubts about the implication of necroptosis in the pathophysiology of ALS. In contrast, other studies detected robust activation of RIPK1, RIPK3, and mixed lineage kinases domain-like (MLKL) proteins in preclinical as well as clinical studies of ALS7. The discrepancies between these studies5 and others8 might be explained by (i) the use of western blotting in whole-tissue extracts8 versus in situ immunolabelling targeting motor neurons7, (ii) the removal of circulating blood cells\u2014a rich source of necroptotic markers9\u2014in some studies but not in others, (iii) the various time frame of tissue sampling, which matches or not the transient expression of necroptotic markers10, or (iv) technical limitations in the availability and specificity of in vivo tools of detection of necroptotic markers8.Interest in potential implications of necroptosis Fig. \u2014i.e., a 7, including in situ experiments focusing selectively on the cells of upmost interest, i.e. motor neurons of the anterior horn of the spinal cord7. In contrast, the studies showing the absence of activation of necroptosis assessed only one molecular step of the cascade (p-RIPK1 or unphosphorylated RIPK1)5 were often untargeted on specific neural cells, and not always targeting the phosphorylation of key necroptotic markers, which are fundamental to demonstrate the execution process of necroptosis -\u03b114.Altogether, the final conclusion about the role of necroptosis in ALS and the interplay between the various molecular mediators and cell subtypes involved would deserve further descriptive clinical findings on larger cohorts of ALS patients, as well as preclinical studies. Such research should combine pharmacological or genetic modulations of necroptotic signaling in ALS models to uncover the pathophysiological mechanisms potentially at play in the occurrence of ALS and define the key check points of putative intervention"} +{"text": "In recent years several new drugs have been approved for treatment of heart failure and type 2 diabetes. Despite their life-prolonging benefits, uptake of new drugs is often slow among older patients with frailty due to under-representation of frail older adults in pivotal clinical trials and concerns for adverse events. To optimize pharmacotherapy, timely evaluation of the drug benefits and risks is urgently needed. We propose a novel drug monitoring framework that prospectively evaluates the effectiveness and safety of newly marketed drugs for frail and non-frail patients in real-world databases. This framework utilizes a validated claims-based frailty index (CFI) to find early signals for effectiveness and safety of new drugs by updating the analysis at regular intervals as new data become available. In this symposium, we present early results of this prospective monitoring framework for 2 new drug classes using Medicare claims data from the approval date until the end of 2017: 1) angiotensin receptor-neprilysin inhibitor (ARNI) (approved in July 2015) for heart failure with reduced ejection fraction (HFrEF) and 2) sodium-glucose cotransporter-2 inhibitors (SGLT2i) (approved in March 2013) for type 2 diabetes. We first show the uptake of ARNI and SGLT2i over time among the eligible Medicare beneficiaries by clinical characteristics, including frailty. Subsequently we present the results of sequential cohort analysis for the effectiveness and safety results of ARNI and SGLT2i. After these presentations, the panel will discuss the strengths, limitations, and challenges of implementing our monitoring framework in real-world databases."} +{"text": "GamePlan4Care (GP4C) is a web-based adaptation of the Resources for Enhancing Alzheimer\u2019s Caregiver Health II (REACH II) caregiver intervention, redesigned and reformatted for online delivery. The goal of GP4C is to create an online family caregiver support platform that facilitates self-directed exposure to evidence-based skills-training and support for dementia caregivers. This approach of utilizing technology enhanced with live support has the potential for scalability and sustainability. In preparation for an ongoing randomized clinical trial, the GP4C platform underwent industry standard user interface/user experience (UI/UX) testing with dementia caregivers as part of an iterative design process. Testing of caregiver\u2019s reaction to technical and content-related aspects of the system was conducted with 31 caregivers. The thematic analysis revealed three themes for technical aspects and two themes for content aspects (satisfaction and engagement). We will discuss technical and content modifications resulting from UI/UX."} +{"text": "Maine has a growing number of age-friendly community initiatives (AFCIs); 116 communities are actively working to adapt the social, service, and built environments for aging and 71 have formally joined the AARP Network of Age-Friendly States and Communities. During COVID, rural municipalities were faced with dynamic changes that limited older resident\u2019s access to services and social engagement. To overcome these limitations, it is critical for emergent AFCIs to have tools and strategies to maintain and further enhance healthy environments and resilient communities. This study uses group interviews with 6 leaders of established AFCIs and 6 leaders of emergent AFCIs to explore how the Lifelong Fellows Program, a peer mentoring model that matches experienced leaders with newly formed initiatives, was able to spur development of new strategies to build community resilience. Prominent themes were (1) engaging new local and regional partners; (2) intergenerational volunteerism; (3) fun and flexibility; and (4) relationship-building."} +{"text": "A 14-year-old male adolescent, with no notable medical history presented to a medical consultation with pain and swelling in the left testicle of 5 months duration. Physical examination revealed scrotal varicosities, with small testicular volume. Doppler ultrasound (US) of the left pampiniform plexus and the renal vessels confirmed varicocele grade 3, and revealed an associated nutcracker phenomenon . Computed tomography (CT) scan with contrast showed also the compression of the left renal vein (RV) between the superior mesenteric artery (SMA), and the abdominal aorta (AO) confirming the nutcracker phenomenon (NCS) (1) . Our patient was treated by inguinal varicocelectomy and had a partial resolution of symptoms after. He was then referred to a nutritionist to increase BMI in order to treat the NCS, before proceeding to invasive methods. Doppler ultrasound of the renal vessels must be performed in case of left varicocele to assess for an associated NCS (2)."} +{"text": "We report 4 cases of COVID-19 in kidney transplant recipients (KTRs) 2 of them after 2 doses of Covishield vaccine and another 2 after a single dose. The study is approved by the Institutional Ethics committee. We also abided by the Declaration of Helsinki and Declaration of Istanbul principles. None of them reported any minor or major side effects postvaccination. The probable exposure was community acquired in all the 4 cases. Three patients were on triple immunosuppression. Three cases required critical care admission and received steroids, remdesivir, anticoagulation, and investigational therapies as anti-COVID-19 therapy during the stay. Patient 1 died and patients 2 and 3 are on mechanical ventilation with a poor prognosis has been reporting global peaks in India in April 2021. The enormous task of vaccinating such a bulk population has become more difficult in the state where health resources for managing coronavirus disease 2019 (COVID-19) are rapidly emptying amid the COVID-19 surge. Indian advisories have approved 2 vaccines: Oxford\u2013AstraZeneca COVID-19 (Covishield) and BBV152 (Covaxin) as of April 2021. The efficacy of these vaccines has been reported lesser compared with the mRNA vaccines in general population.The authors express our sincere gratitude to all the resident doctors and healthcare staffs who are tirelessly doing a mammoth job of managing the COVID-19 cases in India, despite facing resource crisis."} +{"text": "In this study, the gamma radiation properties of four types of surgical-grade stainless steel were investigated. The effective atomic number Z Technological development in various fields has increased the quality of life of patients by improving health services. In some circumstances, medical interventions require the use of metal materials with biocompatible compositions and properties, such as stainless steel. Stainless-steel materials are used as biocompatible mineral components for rebuilding teeth, manufacturing medical devices used in surgeries and other applications ,2. StainFour different samples of stainless steel were studied in this work. The chemical compositions and densities of the stainless steel used in this study are shown in The main parameter of photon penetration in samples is the mass attenuation coefficient Equation 23]:(1):(1)\u03bcm, wi relative to the total number of atoms of all elements in the alloy, and ith element in the alloy.Equation shows thEquation 23]: (3: (3\u0394(\u03bcm)Equation [23]:(4)The effective atomic number Equation .(5)ZeffThe half-value layer 24,25],25Zeff),I and The linear and mass attenuation coefficients were evaluated by using an X-ray fluorescent (XRF) system. The XRF energies produced from pure metal plates were irradiated to the annular source of radioactive The mass attenuation coefficients of surgical stainless-steel samples obtained in the photon energy range of 17.50\u201325.29 keV using XRF beams from Mo, Pd, Ag and Sn are listed in HVL is an important parameter in the design of radiation protection and refers to the thickness of the sample required to absorb half the value of the radiation falling on it. The results of theoretically and experimentally calculated HVL values are presented in An experimental XRF system and the WinXCOM program were used to evaluate the mass attenuation coefficient ("} +{"text": "A large number of common cold outbreaks in Hong Kong schools and childcare centers during October\u2013November 2020 led to territorywide school dismissals. Increased susceptibility to rhinoviruses during prolonged school closures and dismissals for coronavirus disease and varying effectiveness of nonpharmaceutical interventions may have heightened transmission of cold-causing viruses after school attendance resumed. Many countries implemented school closures and dismissals in 2020 as a public health measure to reduce spread of coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In Hong Kong, schools were dismissed after the Lunar New Year holiday in late January 2020 and remained dismissed until late May; during early July\u2013late September, schools were dismissed again in response to a surge in cases of COVID-19 , panel A>3 students in the same class each developing >2 symptoms of respiratory tract infection within 4 days occurred in Hong Kong schools despite a wide range of infection control measures being in place. Staff and students wore face masks at all times; lunch hours were cancelled, desks were spaced out, and group activities were limited ("} +{"text": "Scalds are the most common mechanism of burn in children, and a significant proportion of these injuries are associated with bathing. Burns sustained while bathing present a unique opportunity for injury prevention; previous studies have examined lowering water heater temperatures, however reputable infant bathing educational resources do not explicitly recommend avoiding running water and the risks that it could pose. In an effort to inform prevention programs, this study seeks to determine the incidence and circumstances of running water in bathing scald burns at our institution.A retrospective review was performed of records from an American Burn Association verified center over a ten year period (1/1/2010 to 12/31/2019). This center treats both children and adults and is affiliated with an academic hospital in a major urban center. The burn database was queried for scald injuries in children less than three years involving bathing. The Child Advocacy and Protective Services team provides inpatient consultation for all children less than three years old with burn injuries allowing us to analyze the specific events surrounding the bathing scald burns in this cohort.A total of 123 patients met inclusion criteria. Three bathing safety risk factors were specifically noted in the chart review: (1) running water, (2) lack of caregiver presence for duration of bathing, and (3) failure of caregiver to check water temperature before bathing. Of the cases identified, 107 (87%) had clear documentation of running water as part of the history of injury, 66 (54%) cases involved failure of caregiver to check the water temperature before bathing and 53 (43%) cases did not have a caretaker present for the duration of the bath. In cases with only one risk factor, running water was identified in 34 (94%) out of 36 cases, and in cases with one or two risk factors, running water remained the primary risk factor with 38 (90%) out of 42 cases. When looking at the combination of risk factors, only three (2%) cases had no risk factors while 77 (63%) involved two or more risk factors.The vast majority of bathing burn injuries in this series involved running water. In addition, a significant number of scald burns occurred from running water alone, even without the other identified risk factors. Conversely, only 2% of scald burns associated with bathing featured none of these three risk factors, suggesting that these injuries could be greatly impacted by safe bathing education."} +{"text": "Genetic networks that regulate meristem transitions were recurrent targets of selection during crop domestication and allow fine-tuning of plant architecture for improved crop productivity. Solanum lycopersicum) and that were recurrent targets of selection during crop domestication and breeding. Fine-tuning the activity of conserved regulators of meristem transitions allows re-balancing vegetative to reproductive growth to customize plant architecture for improved crop productivity.Flowering plants display enormous architectural diversity that mainly results from differences in the position and organization of branches within vegetative and reproductive shoot systems. Where and when branches develop are tightly linked to the onset of flowering, which triggers the release of lateral buds from apical dominance and the outgrowth of additional branches. The transition to flowering depends on the activity of apical meristems, which are small groups of stem cells located at the growing tips of shoots. During vegetative growth, apical meristems produce vegetative organs including leaves and stem until endogenous and environmental signals prompt the transition to reproductive development, which often culminates in the production of an inflorescence, the flower-bearing shoot. It becomes clear that the rate at which meristems transition from the vegetative to the reproductive phase determines the number and pattern of branches in shoots and inflorescences . Not surConserved regulators of meristem transitions were recurrent targets of crop domestication and breeding.Changes in the activity of conserved meristem regulators result in quantitative variation in shoot and inflorescence architecture.Tuning the expression of conserved meristem regulators by genome editing allows engineering plant architecture for crop improvement.de novo domestication of wild species.Targeting conserved meristem regulators by genome editing facilitates the rapid improvement of underutilized crops and Meristem maturation and plant architecture are omnigenic traits and dependent on genotypic context and environmental conditions.vegetativeness that changes gradually during plant development and pepper (Capsicum annuum)) and multiflowered inflorescences (e.g. tomato and related wild species). The evolution of Solanaceae inflorescence diversity involved changes in the rate of meristem maturation, which are driven by an increased transcriptional divergence of conserved regulatory genes during a critical developmental window that marks the transition to reproductive development that is released in the axil of the last leaf. This process of floral termination and sympodial meristem release is reiterated indeterminately and results in the production of modular structures that consist of a shoot with a terminal flower, resulting in a compound shoot that is characteristic for sympodial plants. In tomato, sympodial growth is recapitulated in inflorescences where each inflorescence meristem releases a sympodial inflorescence meristem at its flank before terminating in a flower, which results in the zig-zag arrangement of flowers on the tomato inflorescence.self-pruning (sp) mutation, which transformed indeterminate tomato vines into determinate bushes with concentrated fruit set that allows mechanical harvesting in large-scale field production and belongs to the CETS gene family (SP encodes an antiflorigen that acts as a repressor of flowering and antagonizes the activity of SINGLE FLOWER TRUSS (SFT), another CETS gene and homolog of Arabidopsis FLOWERING LOCUS T (FT). SFT encodes the universal flowering hormone florigen and triggers the transition of meristems to reproductive growth , the ortholog of Arabidopsis LEAFY , a flowering repressor that belongs to the CETS gene family and other closely related wild species rapidly transition to flowering is associated with higher SFT expression and accelerated flowering in short days and antiflorigen (TFL1) takes place through competition for bZIP transcription factors that are bound to cis-regulatory elements of floral identity genes -engineered sp null mutants to obtain highly compact and early yielding varieties that are optimized for indoor cultivation by genome editing transforms sympodial meristems into inflorescence meristems that terminate in single flowers and MACROCALYX (MC) are mutated mutants carry mutations in the homeobox transcription factor gene S/SlWOX9, a homolog of Arabidopsis WUSCHEL-RELATED HOMEOBOX9, WOX9 , which is a homolog of Arabidopsis UNUSUAL FLORAL ORGANS and encodes an F-box protein that interacts with the transcription factor FA to form a floral specification complex and trigger floral differentiation develop highly branched inflorescences with dozens of flowers but have been largely avoided by breeders due to low fruit set . These nX9, WOX9 . Naturaled genes . This derescence . Completntiation . S/SlWOXntiation . Loss ofAN depends on the activity of TERMINATING FLOWER (TMF), which encodes an ALOG (Arabidopsis LSH1 and Oryza G1) transcriptional regulator that directly represses AN expression genes and the quadruple tmf tfam123 mutant was shown to develop single-flowered inflorescences on all shoot systems transcriptional regulators (BOP1\u20133), which are co-expressed with TMF during vegetative meristem stages and decline toward floral identity mutation induces strong inflorescence branching and reduced fruit set in specific genetic backgrounds (j2 mutation is caused by a Rider transposon insertion in a SEPALLATA (SEP) class MADS -box transcription factor gene and induces inflorescence branching in genetic backgrounds that carry a secondary mutation in the homologous gene ENHANCER OF JOINTLESS2 (EJ2) results in flowers with elongated sepals while complete loss of EJ2 activity from CRISPR null mutations lead to leaf-like sepals. Importantly, j2 and ej2 single mutants develop unbranched inflorescences, but epistasis between the homologous genes causes excessive inflorescence branching and low fertility in j2 ej2 double mutants. Expression analyses of j2 ej2 double mutants uncovered misexpression of meristem stage-enriched marker genes at transition and floral stages of meristem maturation suggesting that j2 ej2 branching results from delays in meristem maturation (LONG INFLORESCENCE (LIN) also affect inflorescence architecture and lead to inflorescences with additional flowers and longer internodes that weakly branch. Triple j2 ej2 lin mutants give rise to inflorescence meristems that fail to achieve floral identity and produce cauliflower-like inflorescence tissue similar to the an mutant, demonstrating that J2, EJ2, and LIN genes synergistically regulate inflorescence complexity. Interestingly, the Arabidopsis genome encodes four SEP gene homologs, which redundantly regulate floral organ differentiation , breeders reported that the causative kgrounds . The j2 S2 (EJ2) . The secanscript . The natturation . Mutationtiation . Hence, j2 andW ej2 mutations by selecting additional genetic loci that suppress inflorescence branching /SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1)-class MADS-box transcription factor gene (SISTER OF TM3 (STM3) leads to lower STM3 expression and suppression of branching. Both EJ2 and STM3 copy number variants were present as cryptic variants in the domesticated tomato germplasm before j2 andW ej2 collided during modern breeding, illustrating how standing genetic variation contributes to breeding. Complete loss of STM3 activity in CRISPR-induced stm3 null mutants leads to late flowering indicating that STM3 promotes meristem maturation toward the transition to flowering branching in a gene dosage-dependent manner , determinate shoot growth from a mutation in CsTFL1 is modulated in a day-length sensitive manner by the homologous gene CsTFL1d (The genetic networks that regulate meristem transitions are highly plastic and tightly linked to environmental changes . Howevernditions . The del equator . However CsTFL1d . In toma CsTFL1d . The und CsTFL1d .de novo domestication has been tested in wild relative species of tomato and rice (cis-regulatory regions allows the generation of quantitative phenotypic variation, for example, allelic series of domestication genes that can be used to fine-tune agricultural traits (Understanding the genetic changes that were selected by humans for adapting plants to new climatic regions can outline strategies for the development of novel genotypes for agriculture during climate change. Pan-genomes of crops and their wild ancestors allow the identification of genes and networks that were altered during domestication and breeding to modulate architectural plasticity. The standing genetic variation that is preserved in crop germplasms already presents a rich resource for adapting crops to new growth conditions. However, introducing genetic variation to new genotypic backgrounds can be challenging due to genetic linkage with deleterious alleles and often leads to unexpected phenotypic outcomes due to genetic interactions . Genome and rice . By targand rice . Genome and rice . Finallyl traits . TogetheHow are the effects of conserved meristem regulators modified in different genetic backgrounds, and what is the identity of the interacting genes?How do we uncouple the gene networks that regulate successive stages of meristem maturation to independently exploit shoot and inflorescence architecture for crop improvement?Is architectural diversity in crop populations mainly established by quantitative variation in a small number of conserved regulators or rather by variation in a large and diverse set of genes?What is the genetic architecture of plasticity in meristem development that relays environmental change to plant architecture?What is the impact of domestication and breeding on plasticity in meristem maturation?"} +{"text": "This Correction follows an Expression of Concern relating to this article previously published by Portland Press.Biosci Rep (2018) 38(6): BSR20181414; DOI: 10.1042/BSR20181414) would like to correct The Authors of the original article \u201cAntioxidative and antiphotoaging activities of neferine upon UV-A irradiation in human dermal fibroblasts\u201d (The Authors state that this error had occurred during the figure making process, and confirm that it does not affect the conclusions of their study. The correct version of"} +{"text": "Little is known about the disparities in patient experience of home health (HH) care related to social vulnerability. This study examined the relationships of patient Medicare-Medicaid dual eligible status and race and ethnicity with patient experience of HH care. We analyzed national data from the Home Health Care Consumer Assessment of Healthcare Providers and Systems (HHCAHPS), Outcome and Assessment Information Set, Medicare claims and Area Health Resources File for 11,137 Medicare-certified HH agencies (HHA) that provided care for Medicare beneficiaries in 2017. Patient-reported experience of care star ratings (1-5) in HHCAHPS included 3 domains with each dichotomized into high (4-5) and low (1-3) experience of care. The proportion of patients with dual eligibility and the proportion of racial/ethnic minorities were summarized at the HHA level. HHA with higher proportion of dual eligible patients were less likely to have high experience of care rating in professional care delivery , effective communication , and specific direct care issues . HHA with higher proportion of racial/ethnic minorities were also less likely to have high patient experience of care rating across all three domains . Disparities in patient experience of HH care exist and they are associated with low income and racial/ethnic minority status, indicating substantial unmet needs among these socially vulnerable patients."} +{"text": "OBJECTIVES/GOALS: This study\u2019s goal is to examine the feasibility and acceptability of using VRM to impact the APP of adults in the inpatient setting. Aims include examining the: 1) feasibility of VRM for APP management; 2) acceptability of using VRM for APP management; and 3) experience of VRM for APP management. METHODS/STUDY POPULATION: To comprehensively examine participants\u2019 experience of using VRM for APP, this study will employ a convergent mixed-methods design in which living kidney donors (N = 45) will be recruited to serially use VRM during their hospital stay. Feasibility and acceptability will be evaluated using descriptive and inferential statistics evaluating patient-reported outcome (PRO) measures taken pre-, post- and 1-hour post-VRM, PRO measures extracted from the participant\u2019s electronic health record and data on VRM use. Semi-structured interviews will allow formulation of inferences based on participants\u2019 experience of VRM for APP management and their insights on content, deployment, and clinical use of VRM. RESULTS/ANTICIPATED RESULTS: This in-process study expects: 1) an adequate sample of participants undergoing living kidney donor surgery who agree to enroll with retention of >90% of participants (Aim 1); 2) participants to report VRM as an acceptable and suitable treatment, feel \u201cpresent\u201d and interested in the VR environment, and feel comfortable using VRM in the hospital (Aim 2); and 3) to provide insight into participants\u2019 experience of VRM for APP, understanding of extended VRM use for APP analgesia, examination of key variables affecting participants\u2019 experience of VRM for APP and feedback about VRM procedures and protocol to inform future VRM use for APP management (Aim 3). DISCUSSION/SIGNIFICANCE OF IMPACT: Results of the proposed study will inform future clinical testing and deployment of VRM, guide future use of VRM as an adjunct for inpatient APP management, and provide insight into inpatients\u2019 experience of VRM for APP analgesia."} +{"text": "We examined cross-sectional and prospective associations of sleep duration and insomnia symptoms with measures of cognitive function among older adults aged 45-75 y from the Boston Puerto Rican Health Study, a longitudinal cohort of 1500 participants of Puerto Rican ancestry. We found, statistically significant cross-sectional associations of sleep duration (hours) and an executive function domain before and after controlling for covariates ; between sleep duration and global cognition before and a trend after controlling for covariates . In longitudinal associations, sleep duration (time2) was significantly associated with global condition at time3 after controlling for time2 global cognition. In conclusion, we found hours of sleep and insomnia symptoms significantly associated with various cognitive factors. A public health focus on sleep hygiene may improve cognitive health outcomes in older Puerto Rican adults."} +{"text": "ABSTRACT IMPACT: Better understanding how clinicians make decisions about pain management, particularly since our prior research has demonstrated that opioids prescribed at discharge is the strongest predictor of opioids taken, is critical to decrease high-risk medication prescribing while preserving high-quality care. OBJECTIVES/GOALS: (1) Identify major biological, psychological, and social determinants of medical and surgical residents\u2019 pain management decisions; (2) Determine salient themes regarding the experience of residents in the management of acute and chronic pain METHODS/STUDY POPULATION: Focus groups of internal medicine and general surgery residents at an academic, tertiary care training hospital located in an urban setting were conducted. Due to the COVID-19 pandemic, all focus groups were conducted virtually and occurred during required didactic sessions to facilitate participation. All interviews were recorded and transcribed. Two reviewers independently reviewed and coded the data following the principles of constructivist grounded theory. RESULTS/ANTICIPATED RESULTS: 42 residents participated in ten focus groups ranging in size from two to five individuals. Six themes emerged demonstrating salient BPS factors in pain management decisions: (1) patient and clinician expectations determine what is considered normal/acceptable; (2) inability of pain scales to reliably capture patient pain; (3) desire for more objective methods of pain assessment, while simultaneously recognizing that pain is an inherently subjective experience; (4) difficulty in determine when pain is 'real\u2019 or 'legitimate'; (5) lack of education and protocols regarding pain management; (6) the importance of engaging other services such as acute pain service or nurse educators in complicated situations. Junior residents often expressed doubt in the appropriateness of their approaches and decisions. DISCUSSION/SIGNIFICANCE OF FINDINGS: Surgical and medical trainees routinely treat pain and may struggle, particularly in the early phases of training, to determine if pain levels are appropriate. There is also a lack of education and/or best practices for assessing and managing pain. These areas represent high-value, clinician-focused targets for future interventions to improve care."} +{"text": "Psychosocial care for residents with serious mental illness (SMI) requires understanding of co-morbidities and careful attention to needs, rights, and preferences. Analyses of social services directors (SSDs) responses (n=924) to the National Nursing Home Social Service Director Survey considered perceived roles and competence to provide care stratified by the percentage of NH residents with SMI. Depression screenings and biopsychosocial assessments were common roles regardless of the percentage of residents with SMI. About one-quarter lacked confidence to train colleagues in recognizing distinctions between depression, delirium and depression (23.4% unable) or to develop care plans for residents with SMI (26% unable). A bachelor\u2019s degree or less was associated with less perceived competence in care planning compared to those with a master\u2019s degree. SSDs reported less involvement in referrals or interventions for resident aggression in homes with a high proportion of residents with SMI."} +{"text": "With the development of real-time and visualized neuroimaging techniques, the studies on the central mechanism of acupuncture analgesia gain increasing attention. The experimental pain models have been widely used in acupuncture-analgesia neuroimaging studies with quantitative and controlled advantages. This review aimed to analyze the study design and main findings of acupuncture neuroimaging studies to provide reference for future study. The original studies were collected and screened in English databases and Chinese databases . As a result, a total of 27 articles were included. Heat stimulation and electroacupuncture were the mostly used pain modeling method and acupuncture modality, respectively. The neuroimaging scanning process can be divided into two models and five subtypes. The anterior cingulate cortex and insula were the most commonly reported brain regions involved in acupuncture analgesia with experimental pain models. Acupuncture has been used for alleviating pain in China and other oriental countries for thousands of years. It has been accepted as an alternative or complementary therapy for pain in western countries. Nearly half of the 64 recommended indications of acupuncture by WHO , Chinese Biomedical Literature Database (CBM), the Chongqing VIP Database (VIP), and the Wanfang Database (WF). The literature search was conducted from database inception 11th Nov 2020. Details of search terms were modified for each database and depicted in The article was included if (1) it was an original article, (2) experimental pain stimulation was conducted on participants, (3) participants received acupuncture as intervention, and (4) the study was performed with neuroimaging techniques . ArticleThe process of the data selection is described in Information including the year of publication, the corresponding author , the trial place, the method of modeling, the acupuncture intervention , the pain assessment, the neuroimaging techniques, and the results of brain regions involved in acupuncture analgesia were extracted.A total of 27 neuroimaging studies with experimental pain models performing on healthy participants were included in this review.The first study was published in 1980 in Chinese. Sixteen of these 27 studies were conducted in China, and 9 studies in the United States. There were 13 corresponding affiliations mentioned; the top two were Massachusetts General Hospital (6 studies) and Peking University (4 studies).The pain modeling methods included heat stimulation (11 studies), electrical stimulation (4 studies), pressure stimulation (3 studies), injections of hypertonic saline (2 studies), potassium iontophoresis stimulation (2 studies), cold pain stimulation (1 study), video stimulation (1 study), tactile stimulation (1 study), stabbing stimulation (1 study), and capsaicin allodynia stimulation (1 study) on healthy participants .Thirteen studies chose manual acupuncture (MA), and 12 studies chose electroacupuncture (EA) as the intervention method. Besides, the transcutaneous electrical nerve (TENS) and transcutaneous electric acupoint stimulation (TEAS) were applied in one study, respectively .Hegu (LI 4) (9 studies), Zusanli (ST 36) (8 studies), and Sanyinjiao (SP 6) (4 studies) were the most frequently used acupoints in these studies .Fifteen studies assessed the pain with the Visual Analogical Scale (VAS), and three studies applied the Gracely Sensory and Affective Scales (GSAS). Other pain assessment scales are shown in Twenty-one studies applied fMRI, two studies used event-related potentials (ERP), two studies used electroencephalogram (EEG), one study used arterial spin labeling (ASL), and one study used both fMRI and PET as neuroimaging techniques .Similar scanning processes were sorted together regardless of the scanning time and repetition times. Scanning processes can be divided into model 1 and model 2 based on whether the pain stimulation was a part of task scanning. Subsequently, according to the sequence of pain stimulation, model 1 was divided into three subtypes [model 1-A .The reported deactivated/activated brain regions are shown in This review mainly described the current status of the central mechanism research of acupuncture analgesia based on the experimental pain model and neuroimaging techniques.Since early 1980, researchers have applied the electrical experimental pain model to investigate the central mechanism of acupuncture analgesia based on the ERP technique (Hegu (LI 4) (9 studies) were theThis review showed that VAS is the preferred scale for assessing pain. Using VAS was previously recommended in both research and clinical practice with the advantages of its simplicity and adaptability was the most used technique of these 27 studies. fMRI indirectly measures brain activity by detecting associated changes in blood flow (hemodynamic response) , affective , and cognitive factors The selection of the types of experimental pain could be broadened but not limited to the neuropathic pain on the skin. (2) Researchers can evaluate the pain from multimodal dimensions and using more objective assessment methods to guarantee the objective results and profoundly shape the experience of pain. (3) Researchers can use the neuroimaging technologies to compare the central mechanisms of EA and MA at different acupoints, different stimulations, and different intensities, to give the reference for the selection of the clinical treatment.ZF and LS designed the study. MP, CS, and QY participated in screening studies. YT and XK extracted the data from the included studies. HZ and CS performed the analysis plan. MP, SR, and YT drafted the article. ZF revised the draft. All authors have read and approved the publication of the final article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Remarkable advances have been reached in the understanding of the genetic basis of Parkinson\u2019s disease (PD), with the identification of monogenic causes (mPD) and a plethora of gene loci leading to an increased risk for idiopathic PD. The expanding knowledge and subsequent identification of genetic contributions fosters the understanding of molecular mechanisms leading to disease development and progression. Distinct pathways involved in mitochondrial dysfunction, oxidative stress, and lysosomal function have been identified and open a unique window of opportunity for individualized treatment approaches. These genetic findings have led to an imminent progress towards pathophysiology-targeted clinical trials and potentially disease-modifying treatments in the future.In this review article we will summarize known genetic contributors to the pathophysiology of Parkinson\u2019s disease, the molecular mechanisms leading to disease development, and discuss challenges and opportunities in clinical trial designs.The future success of clinical trials in PD is mainly dependent on reliable biomarker development and extensive genetic testing to identify genetic cases. Whether genotype-dependent stratification of study participants will extend the potential application of new drugs will be one major challenge in conceptualizing clinical trials. However, the latest developments in genotype-driven treatments will pave the road to individualized pathophysiology-based therapies in the future. Parkinson\u2019s disease (PD) is an age-related neurodegenerative disorder characterized by the progressive degeneration of nigrostriatal dopaminergic neurons and extranigral brain regions due to the accumulation of certain \u03b1-synuclein species , LRRK2 (Leucine Rich Repeat Kinase 2), and VPS35 (VPS35 Retromer Complex Component) cause an autosomal dominant form of mPD whereas mutations in PRKN (Parkin), PINK1 (PTEN-induced kinase 1), and PARK7 (oncogene DJ-1) (among others) are associated with autosomal-recessive mPD gene are an unequivocal and frequent risk factor for the development of PD and a promising future drug target.PD is caused by complex interactions between genetic and environmental factors. Mutations in mPD Lill . Althoug Cookson . The ideGBA converge to distinct molecular mechanisms and can be divided into (i) \u03b1-synuclein aggregation resulting in the formation of Lewy bodies has already been proven useful in in-vitro, rodent, and primate models against GBA gene encodes the protein glucocerebrosidase (GCase), a lysosomal hydrolase, which converts glucosylceramide to ceramide and glucose . Interestingly, GD patients have a higher incidence of parkinsonism, and heterozygous mutations in the GBA gene increase the risk of developing PD and \u2018PD risk factor\u2019 GBA variants, which show an association with PD risk but are not considered causative for GD are comparable with IPD whereas carriers of severe GBA variants (sGBA-PD) have a clearly increased risk of dementia with an earlier onset and a more rapid cognitive decline substrate reduction (as often considered for the treatment of GD), (ii) external GCase augmentation, and (iii) the enhancement of GCase activity . Substrate reduction can be achieved by different mechanisms: Glucosylceramide synthase inhibitors decrease glycosphingolipid levels and are used to treat the hematological and visceral presentations of GD patients. The clinical trial GZ/SAR402671 (NCT02906020) showed that the glucosylceramide synthase inhibitor venglustat sufficiently crossed the blood brain barrier (BBB) in humans and R15-006 (NCT02914366) tested the safety, efficacy, and tolerability of ambroxol in PD phenotype, but show a relatively mild cognitive and motor decline during the overall disease course with an increase of LRRK2 kinase activity. The LRRK2 protein has a complex multidomain structure and belongs to the family of protein kinases, which play a fundamental role in the control and regulation of complex cellular processes by transferring phosphate groups to target proteins. The kinase domain of LRRK2 shares similarities with mitogen-activated protein (MAP) kinases, which play a central role in mediating cellular stress. Even though the precise mechanism of LRRK2 is poorly understood, the disease-causing GOF mutations allows heuristic treatments by inhibition of its activity. Currently, two main strategies exist for LRRK2-targeted treatment strategies: (i) pharmacological inhibition of LRRK2 activity and (ii) silencing of the LRRK2 gene by the use of ASOs. Both options aim to reduce LRRK2 activity in the CNS whereby ASOs may bypass potential peripheral adverse effects of kinase inhibitors due to its intrathecal application in blood. A trial with DNL151, a second LRRK2 inhibitor, is still actively recruiting healthy volunteers the enhancement of PRKN or PINK1 expression, (ii) the prevention of Parkin or PINK1 inactivation, and (iii) the control of the downstream Parkin/PINK1 signaling pathway (Gaki and Papavassiliou PRKN or PINK1 mutation carriers) as listed in Table PRKN/PINK1 mutation carriers, heterozygous PRKN/PINK1 mutation carriers, and two IPD groups defined by the statistical extrema as determined by a mitochondrial PRS . Both studies have multimodal neuroimaging in common that will be applied as a surrogate marker for examining beneficial effects of in-vivo brain energy metabolism, i.e., by determining the change of energy equivalents using 31Phosphorus Magnetic Resonance Spectroscopy Imaging (31P-MRSI).Mitochondrial dysfunction is one of the main concepts in PD pathogenesis. Mitochondria play a fundamental role for a plethora of cellular processes relevant for the supply of energy, the overall cellular homeostasis, and neuronal survival. The first evidence for a role in PD derived from environmental studies illustrating the effect of neurotoxic agents in inhibiting the mitochondria's electron transport chain (ETC) . The disease-modifying management of PD is herewith more challenging due to the absence of validated and dynamic mechanism-based biomarkers.SNCA and high energy phosphates such as ATP levels (31P-MRSI) (Bonvento et al. Biomarkers in clinical PD trials are mainly required to demonstrate target engagement and to quantify disease progression. Stratification of PD patients based on their primarily involved disease mechanisms is one substantial prerequisite for targeted therapies (Reden\u0161ek et al. The genetic discoveries in PD have aided the deepened understanding of clinical manifestations, underlying pathogenesis, and the potential for targeted therapies (Br\u00fcggemann and Klein"} +{"text": "A 28-year-old primigravida with 22.3 weeks of gestation came for dedicated level II ultrasonography for anomaly scan to the antenatal clinic of AVBRH, Sawangi (India). The previous antenatal check-up was not done. The patient neither had a history of maternal systemic diseases like diabetes or hypertension nor history of any trauma or drug intake during pregnancy. There was no family history of congenital anomalies. On obstetric examination, the uterus was of about 20 weeks in size. On ultrasonography, single live intrauterine foetus with an average gestational age of 21 weeks 5 days corresponding to effective foetal weight of 396 grams showing right foot abnormality with persistent adduction and inward rotation suggestive of clubfoot with mild pylectasis of left kidney was noted. However, there was no obvious abnormality of left foot. There was amniotic band in right lower quadrant of gravid uterus."} +{"text": "KMT2A gene. Clinical features can be inconclusive in mild and unusual WDSTS presentations with variable ID (mild to severe), facies and other associated malformations . Interpretation and classification of rare KMT2A variants can be challenging. A genome-wide DNA methylation episignature for KMT2A-related syndrome could allow functional classification of variants and provide insights into the pathophysiology of WDSTS. Therefore, we assessed genome-wide DNA methylation profiles in a cohort of 60 patients with clinical diagnosis for WDSTS or Kabuki and identified a unique highly sensitive and specific DNA methylation episignature as a molecular biomarker of WDSTS. WDSTS episignature enabled classification of variants of uncertain significance in the KMT2A gene as well as confirmation of diagnosis in patients with clinical presentation of WDSTS without known genetic variants. The changes in the methylation profile resulting from KMT2A mutations involve global reduction in methylation in various genes, including homeobox gene promoters. These findings provide novel insights into the molecular etiology of WDSTS and explain the broad phenotypic spectrum of the disease.Wiedemann\u2013Steiner syndrome (WDSTS) is a Mendelian syndromic intellectual disability (ID) condition associated with hypertrichosis cubiti, short stature, and characteristic facies caused by pathogenic variants in the Wiedemann\u2013Steiner syndrome is a rare severe autosomal dominant disorder, characterized by intellectual disability (ID), developmental delay, hypertrichosis cubiti and distinctive facial features ,5,6,7,8.The introduction of next-generation sequencing (NGS) and the implementation of human phenotype ontology (HPO) have revolutionized diagnostics for rare diseases . ReverseKMT2A (lysine methyltransferase 2A) gene (MIM# 159555), located on chr11q23, previously known as MLL (mixed lineage leukemia). Germline and somatic KMT2A variants are, respectively, associated with WDSTS and multiple neoplastic diseases, along with gene structural rearrangements that are common in acute leukemia and and22] ap-value < 0.01.In order to identify the regions that are differentially methylated between the subjects with WDSTS and controls, we used the DMRcate package and seleKMT2A pathogenic variants may disturb the normal process of H3K4me3 deposition coupled at gene promoters. The methylome analysis did highlight a substantial change in the global methylation pattern in WDSTS samples, and resulted in 87% hypomethylated and 13% hypermethylated probes. Our studies reported that the expression of several homeobox containing genes (including HOX or HOX-related genes) is consistently altered in the blood of WDSTS patients. If also present in other tissues, dysregulation of normal methylation of homeobox gene expression may explain part of the ID, facies and associated malformations observed in WDSTS patients. These provide novel insights into the molecular etiology of WDSTS and likely explain the broad phenotypic spectrum of the disease.In conclusion, the identified WDSTS DNA methylation episignature is added to the list of Mendelian NDDs with known DNA methylation episignatures that can be used for screening and diagnosis of NDD patients."} +{"text": "Biomarkers ideal for geroscience trials could be those simultaneously identified using targeted and discovery assays and which strongly associate with complementary disease (multimorbidity) and longevity outcomes. To identify a tractable set of biomarkers for use in geroscience trials, we used the Cardiovascular Health Study (CHS), whose participant makeup closely aligns with the Targeting Aging with MEtformin (TAME) trial. In ~4800 CHS participants, quantitative assays of nine a priori-identified biomarkers were used to construct a biomarker index which strongly associated with the TAME primary outcome of mortality and multimorbidity over 6 and 10 years of follow-up. In ~3000 CHS participants, 1300 proteins were measured with unbiased aptamer proteomics and associated with survival to age 90 over 25 years of follow-up. Proteins in the biomarker index were identified as some of the strongest associated with survival to 90. This convergent evidence suggests these biomarkers may be well-suited for geroscience trials."} +{"text": "An important quality marker for end-of-life services is congruence with patient\u2019s preferred place of care, but this congruence in place of care is less likely for those facing structural inequalities . As homelessness among older adults in the United States grows , the urgency in understanding place of care in palliative care with unhoused patients grows. This presentation illustrates results from an organizational case study of a novel homeless palliative care team and focuses on a qualitative content analysis of charts of patients over 50 receiving care both before and during the COVID-19 pandemic (n=27). Findings highlight (1) the interplay between environmental factors, psychosocial resources and constraints, and medical acuity in determining where care can take place, (2) facilitators for care in marginal settings such as emergency shelters and encampments, and (3) where opportunities for more equitable age-friendly healthcare system interventions exist."} +{"text": "BRCA2) pathogenic sequence variants (PSVs) have increased levels of serum prostate specific antigen (PSA) at diagnosis, increased proportion of high Gleason tumors, elevated rates of nodal and distant metastases, and high recurrence rate; BRCA2 PSVs confer lower overall survival (OS). Distinct tumor PSV, methylation, and expression patterns have been identified in BRCA2 compared with non-BRCA2 mutant prostate tumors. Several DNA damage response and repair (DDR)-targeting agents are currently being evaluated either as single agents or in combination in patients with PC. In this review article, we highlight the biology and clinical implications of deleterious inherited or acquired DNA repair pathway aberrations in PC and offer an overview of new agents being developed for the treatment of PC.Prostate cancer (PC) is the second most common cancer in men worldwide. Due to the large-scale sequencing efforts, there is currently a better understanding of the genomic landscape of PC. The identification of defects in DNA repair genes has led to clinical studies that provide a strong rationale for developing poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents in this molecularly defined subset of patients. The identification of molecularly defined subgroups of patients has also other clinical implications; for example, we now know that carriers of breast cancer 2 ( PSA decline of greater than 50% was observed in 50% of patients with BRCA1/2 and 3% of those with non-BRCA biallelic DDR gene alterations. Similar to olaparib, rucaparib was approved by the FDA for use amongst mCRPC patients with germline and/or somatic BRCA1/2 mutations undergoing prior progression on AR signaling inhibitor or taxane. Europe still awaits approval . Multiple phase I and phase II trials are evaluating immune checkpoint inhibitors in combination with treatments such as abiraterone and cabozantinib [NCT04477512], radiation therapy , and an experimental IL-8 directed monoclonal antibody [NCT03689699]. In addition, perioperative ipilimumab in combination with castration prior to radical prostatectomy has demonstrated feasibility with longer follow-up ongoing .DNA sequencing efforts have changed the molecular classification of prostate tumors and are leading to precision medicine strategies as well as defined prognosis and clinical features of molecular subsets of PC. Nevertheless, prospective studies demonstrating clinical value of biomarkers for prognostication or prediction of response are warranted. Somatic and germline DNA testing for patients with advanced PC should be considered in view of the therapeutic consequences for the patient and the possibility of pursuing targeted screening in this population. Metastatic tumor biopsies are recommended to obtain information regarding mCRPC tumor features. Germline samples are easily collected and analyzed, but still half of the patients with somatic DDR defects would not be identified. Liquid biopsies may be used to monitor for the detection of secondary mutations that may restore the function of a gene previously altered.PARP inhibitors represent one of the recent biggest therapeutic developments for PC patients. Combination of PARP inhibitor with AR-targeting agents is worthy due to the cross-regulation of both pathways and the central role of hormonal therapy in PC. Immunotherapy has shown still limited efficacy in these patients. However, immunotherapy combinations will probably overcome intrinsic resistance of PC to immunotherapy. Ongoing studies that assess the role of immunotherapy in PC are NCT04104893, NCT04019964 and NCT03570619."} +{"text": "OBJECTIVES/GOALS: The aim was to examine whether nicotine patch was more effective in encouraging abstinence from cigarettes smoking compared to placebo. METHODS/STUDY POPULATION: Randomized controlled trials involving the general teenage age group smokers who were current smokers-\u201csmoked less than 100 cigarettes over their lifetime and smoked at the time of the interview. Databases were searched for relevant studies reported in English that employed a randomized design published since 2000. Two authors extracted data and assessed quality. The primary outcomes and prioritization were continuous abstinence at 3, 6 and 12-month follow-up or more for the number of patients who responded to treatment, defined as a reduction/abstinence. Heterogeneity between studies did not preclude combined analyses of the data. RESULTS/ANTICIPATED RESULTS: 4 of 266 publications were included. Four studies reported positive effects on smoking cessation at end of treatment: (1) nicotine patches improved continuous abstinence at 6 weeks \u2013 9 weeks months; (2) nicotine patch improved continuous abstinence at 3 to 6 months; (3) nicotine patches improved continuous abstinence 6 and 12 months; (4) nicotine patches improved continuous abstinence at 6 months \u2013 12 and 24 months (5). All studies showed, continuous abstinence at follow up differed in percentage between groups both at 6 weeks through 24 months, with NRT (Nicotine patch) intervention groups achieving higher rates in most of the studies compared to placebo intervention group. Conclusions: NRT intervention methods seem to increase smoking abstinence in those treated for smoking cessation. Further and larger sample size studies are required to make stronger the base of evidence. DISCUSSION/SIGNIFICANCE OF IMPACT: Four randomized controlled trials investigating the effectiveness of smoking cessation interventions, for teenagers who smoke cigarettes were identified for inclusion in this review. Four of the studies reported significant effects on smoking cessation, providing evidence of effectiveness of NRT (nicotine patch), behavioral support and combinations of the two, although not all trials intervention treatments found an effect. The four studies reported important intervention effects at both the short and long follow-ups required: 6 weeks up to the 24 months, thereby, providing stronger evidence to support the effectiveness of NRT intervention on smoking cessation. All studies showed some evidence of improved smoking abstinence outcomes. The four studies had in common that the smoking cessation interventions provided a combination of intent to treat prevention, and of all the clinical trials none of them suggested a negative effect of smoking cessation treatment on substance use outcomes using NRT. However, the studies used reliable methods and reported their cases properly, but the small number of studies reviewed for the systematic review makes the conclusion about the effectiveness of these interventions uncertain. The papers visibly stated how the trials protected against bias, as indicated by the Yes (low risk). No (high risk) and U as \u201cunclear risk.\u201d All four studies conducted a random sequence generation of participants enrolled into the study sample."} +{"text": "This special issue is devoted to the celebration of the century anniversary of Xiamen University (XMU) (6 April 2021) and the establishment of the LSA Editorial Office in Xiamen (3 July 2021), a collection to highlight the recent exciting research works performed in XMU or by XMU alumni, from all aspects of optics and photonics, including basic, applied and engineering research and applications. The guest editors are three XMU alumni who are active researchers in these areas: Professor Minghui Hong from National University of Singapore, Professor Zhongqun Tian and Professor Junyong Kang from XMU.1; (2) Development of mode-locked fibre lasers towards visible-wavelength2; (3) A new route for stress recording based on the Force-induced charge carrier storage effect in mechanoluminescence materials3; (4) Identification of unconventional host\u2013guest complexation at nanostructured interface by surface-enhanced Raman spectroscopy4; (5) Quantification of electron accumulation at grain boundaries in perovskite polycrystalline films by correlative infrared-spectroscopic nanoimaging and Kelvin probe force microscopy5; (6) Improvement of detection in graphene/silicon heterojunction photodetectors through engineered tunnelling layer with enhanced impact ionization6; (7) Innovative approaches to determine the embedded electronic states at nanoscale interface via surface-sensitive photoemission spectroscopy7; (8) Development of AlGaN materials and optoelectronic devices that lead to the significant revolutions of solar-blind UV detection technology8; (9) Development of novel concepts and techniques in AlGaN-based LEDs for effectively controlling and tailoring the crucial properties of nitride quantum structures9; (10) Design of light-responsive and corrosion-resistant gas valve with non-thermal effective liquid-gating positional flow control10; (11) Design of nano/micro structures and macro-optical systems to enhance the detection sensitivity of surface-enhanced Raman and infrared spectroscopies11; (12) Demonstration of transmitting high-dimensional orbital angular momentum state at the single-photon level utilizing non-zero quantum discord12; (13) Development of hybrid laser processing technologies and their applications in the precision engineering of transparent hard materials13; (14) Demonstration of X-ray-charged bright persistent luminescence for multidimensional optical information storage by inkjet-printing NaYF4:Ln3+@NaYF4 nanoparticles14.XMU is a renowned university continuously featuring creativity and dedication. It was the first university established by an overseas Chinese (Mr. Tan Kah Kee) and has been selected for the \u201cDouble First-class Initiative\u201d Scheme, as one of the leading pioneers in achieving China\u2019s ambition of building world-class universities. XMU is also the first prestigious Chinese university to set up an overseas branch campus , which has been honoured as the \u201cshinning pearl\u201d of \u201cBelt and Road Initiative\u201d. Rooted in XMU, the motto \u201cPursue Excellence, Strive for Perfection\u201d, has been widely extended to all over the world through more than 400,000 of XMU graduates. During the century-long growth, XMU has achieved significant progress in the field of optics and photonics and become pioneers in several aspects: Development of laser holography that greatly promoted the anti-counterfeiting technology in China; study of entangled photon pairs that lead to quantum communications and optical micromanipulations, as well as the creation of facial recognition techniques based on the light beams; Development of surface-enhanced Raman spectroscopy (SERS) that not only conquers the material and surface limits of SERS, but also realizes the fast detection of trace hazards in the field of food safety; Improvement of efficiency for light-emitting diodes (LEDs) via creative pathways, including deep ultraviolet LEDs and high colour rendering warm-white LEDs. Research scholars across different disciplines in XMU are working on optoelectronic materials and devices, with interests in the designs and syntheses of luminescent materials, quantum dots, electrochromic materials as well as their applications in solid-state lighting, emissive displays, sensing, smart windows and photovoltaic cells. Experiments based on synchrotron-radiation light source as well as other advanced techniques are combined with computations/simulations to deeper understand the composition-structure-property coupling mechanism of functional materials, providing guidelines for developing high-performance materials and optoelectronic devices. This collection features some recent representative achievements in optical and optoelectronic sciences and technologies, contributed by XMU scholars and alumni. The innovative reports include: (1) Enhancement of deep ultraviolet emission by regulating the orbital state couplingEnlightened by Light, Xiamen University, this 100-year-old university will become more elegant with greater academic excellence, especially in optics and photonics research."} +{"text": "The authors have demonstrated an exciting evolution of neoadjuvant chemotherapy (NAC) trends after radical cystectomy (RC) in the USA in the present study . During"} +{"text": "We aim to investigate the effectiveness of repetitive Transcranial Magnetic Stimulation (rTMS) in reducing consumption and craving among patients with Substance Use Disorder (SUD) and comorbid depressive disorder.Dorsolateral prefrontal cortex (DLPFC) is greatly involved in SUD evolution (1). Research has turned to targeting this brain area with rTMS; a non-invasive brain stimulation technique that modulates cortical excitability by sending pulsatile electromagnetic fields through the skull and into the brain (2). rTMS is an FDA approved and safe treatment option for treatment-resistant depression (TRD) (3).Fifty-four patients were admitted over six-month period of time (June 2019- December 2019) to the inpatient unit of Erada center for treatment and rehabilitation of SUD in Dubai. All patients who fulfilled ICD-10 diagnoses of Depressive disorder and SUD were screened for further assessment.Positive drug screen was confirmed through urine analysis. Hospital Anxiety and Depression Scale (HADS) and Brief Substance Craving Scale (BSCS) were applied to all participants. Patients were contracted for 5-times weekly High frequency (10 Hz) rTMS for 4 weeks . Those who managed to complete their contracted TMS sessions were matched for age and sex with similar number of patients who received standard treatment as usual (TAU). Stimulation was as per FDA clearance for rTMS application in TRD.Eight patients were excluded (previous head trauma). A total of 46 patients had TMS mapping; nine of whom completed 20 sessions.Opioids was the most commonly used drug in almost 52% of patients (n = 14), followed by amphetamines in almost 30% (n = 8) and Cannabis in 18.5% (n = 5).Among those who completed 20 rTMS sessions; HADS scores on anxiety and depression fell by 85% and 78% respectively. BSCS score fell by 98%. Relapse rate (defined by positive drug screen) at 3 months was 33%.For those who completed 10 sessions; there was only 50% reduction on BSCS scores and 66% relapse rate. There were no data available on their HADS scores (only collected at baseline and at completion of 20 sessions).Those who only had TAU; there were no reduction in their BSCS (average score of 7 at both baseline and after 2 weeks).Our findings suggest that rTMS may be an effective and safe treatment for both depressive disorder and craving for SUD which is supported by other studies .Our study is probably the first of its kind within Middle East population with addiction problems."} +{"text": "CDHR1 alleles, and compare the associated phenotypes with previous reports.To describe the clinical and electrophysiological features of adult-onset macular dystrophy, due to novel combinations of CDHR1 were reviewed. Data analysed included best corrected visual acuity (BCVA), fundus images: autofluorescence (AF) and optical coherence tomography (OCT); full field electroretinography (ERG) and pattern ERG (PERG).The clinical records of patients with macular dystrophy and biallelic variants in CDHR1: p.(Gly188Ser), p.(Met1?), or p.; one patient was compound heterozygous for two previously unreported variants: c.297+1G>T in trans with p.(Pro735Thr). The range of BCVA at the last clinic review was (6/5\u20136/60). Autofluorescence showed macular flecks of increased AF in mild cases and patches of reduced AF in severe cases. The OCT showed attenuation of the ellipsoid zone (EZ) in mild cases and loss of the EZ and the outer nuclear layer in severe cases; one patient had subfoveal hyporeflective region between the EZ and the retinal pigment epithelium. The full field ERG was normal or borderline subnormal in all cases, and the PERG was subnormal in mild cases or undetectable in severe cases.Seven patients from six pedigrees were ascertained. One patient was homozygous for a known synonymous variant p.(Pro261=), four were compound heterozygous for the p.(Pro261=) variant and a novel allele of This report corroborates previous observations that genotypes distinct from those causing pan-retinal dystrophy can cause a milder phenotype, predominantly affecting the macula, and expands the spectrum of these genotypes. The findings in this cohort suggest a potential macular susceptibility to mild perturbations of the photoreceptor cadherin. CDHR1\u2014OMIM 609502) is a transmembrane protein, expressed at the base of the rod and cone outer segments, and maintains outer segment structure , has been associated with adult-onset macular dystrophy.The present study corroborates the association between the p.[Pro261=] variant and macular dystrophy and presents novel alleles associated with the macular dystrophy phenotype.Our study adds CDHR1 to the list of candidate genes to screen in patients with likely autosomal recessive macular dystrophy.Figure S1_legendFigure S1"} +{"text": "Although potential anticancer activities of benzimidazole-based anthelmintic drugs have been approved by preclinical and clinical studies, modes of binding interactions have not been reported so far. Therefore, in this study, we aimed to propose binding interactions of some benzimidazole-based anthelmintics with one of the most important cancer targets (Tubulin protein). Studied drugs were selected based on their structural similarity with the cocrystallized ligand (Nocodazole) with tubulin protein. Quantum mechanics calculations were also employed for characterization of electronic configuration of studied drugs at the atomic and molecular level. Order of binding affinities of tested benzimidazole drugs toward colchicine binding site on tubulin protein is as follows: Flubendazole > Oxfendazole > Nocodazole > Mebendazole > Albendazole > Oxibendazole > Fenbendazole > Ciclobendazole > Thiabendazole > Bendazole. By analyzing binding mode and hydrogen bond length between the nine studied benzimidazole drugs and colchicine binding site, Flubendazole was found to bind more efficiently with tubulin protein than other benzimidazole derivatives. The quantum mechanics studies showed that the electron density of HOMO of Flubendazole and Mebendazole together with their MEP map are quite similar to that of Nocodazole which is also consistent with the calculated binding affinities. Our study has ramifications for considering the repurposing of Flubendazole as a promising anticancer candidate. Microtubules play a key role in the invasion and metastatic spread of tumor cells, depending on its crucial roles in mitosis, signaling, trafficking, proliferation, and migration of eukaryotic cells . Drugs tThe success rate for new anticancer drugs from Phase I trial to commercial use by FDA approval is estimated to be around 6.7% from 2003 to 2011, taking about 8.3 years as an average . The ovede novo drug compounds and constitutes nowadays 30% of the newly marked drugs in the United States . DespiteIn vitro and in vivo studies revealed the potential of some members of benzimidazole anthelmintic drugs to suppress tumor progress through inhibition of multiple biological targets such as tubulin polymerization and angiogenesis (Benzimidazole anthelmintic drugs having over 40 years of safe use as over the counter medications . They arogenesis .Nocodazole (NZO) is a benzimidazole-based experimental drug targeting both protein kinases and microtubules. It is used as a lead compound for the discovery of novel CBSIs . In thishttps://pubchem.ncbi.nlm.nih.gov/). The nine tested compounds underwent energy minimization after examining the structure and the formal charges on atoms using a 2D depiction model. The partial charges were also automatically calculated. Structure of the co-crystallized NZO obtained from two subunits of the target tubulin protein (B and D subunits) and the nine tested benzimidazole drugs were imported together in the same database and saved in the form of MDB file to be docked in two separate processes for each subunit pocket, B and D, respectively.Docking studies using the Molecular Operating Environment (MOE) software package were perhttp://www.rcsb.org/). All steps for the preparation of the target protein for docking calculations were done. The addition of hydrogen atoms with their standard 3D geometry to the system, automatic correction to check for any errors in the connections and types of atoms, and fixation of the potential of the receptor were also performed. The selection of the same active site of co-crystallized inhibitor in the protein structure was done by using Site Finder where dummy atoms were created at the same binding site of the pocket.The X-ray structure for tubulin protein (PDB: 5CA1) complexed with the native NZO was obtained from the Protein Data Bank were used to approximately describe the polarity of colchicine binding pocket. All simulations were performed using GAUSSIAN 09 Revision C.01 based Becke\u2019s three-parameters Lee-Yang-Parr hybrid functional (B3LYP) was emplion C.01 on Swinb2O616). Hydrophobic interactions were also observed between Leu253 and the benzene and imidazole moieties. The 2D graphic views of binding interactions between studied benzimidazole ligands and NZO with the target protein are deposited in Crystallographic data of co-crystallized NZO complexed with tubulin protein (PDB: 5CA1) revealed the existence of two binding sites for NZO inside the protein, subunits B and D, respectively. It was obvious that subunit D is larger than subunit B in size. By analyzing the binding modes (3D graphic views) of NZO inside the two subunits , it was By studying the binding site in both B and D subunits, it was concluded that the crucial amino acids for binding interactions between CBSIs and the two subunits are Glu198 and Val236, besides Asn165 for B subunit and Cys239 for D subunit. The refined NZO was also docked among other studied benzimidazole drugs into subunits B and D to validate the molecular dynamic model used in conducting the current study. For the B subunit, the docked NZO showed almost a fingerprint binding mode as the original co-crystallized one. Interestingly, loss of binding interactions between the oxygen atom of its carbonyl group and Cys239 was also noticed. Furthermore, as expected, the binding interaction between N (3)-benzimidazole and Glu198 was lost in two subunits (B and D) as a result of using the neutral form of refined NZO in contrary to the protonated form of native NZO. The other nine benzimidazole drugs were refined and docked into NZO binding pocket subunits (B and D), respectively. Results revealed that all of the tested drugs, except for Thiabendazole (8) and Bendazole (9) members, showed very similar binding modes to the native NZO due to the great structural similarity. Regarding B subunit, Flubendazole (5) showed a nearly similar fingerprint binding mode compared to the native and docked forms of NZO. Concerning D subunit, surprisingly, Albendazole (2), Ciclobendazole (3), Flubendazole (5), and Oxfendazole (7) showed the binding interaction with Cys239 similar to the native NZO which was lost in the docked NZO itself. Especially Ciclobendazole (3) and Oxfendazole (7) showed a fingerprint binding interaction with Cys239 with the same direct and indirect pathways. It was concluded that Flubendazole (5) showed the highest similarity in binding modes compared to the native NZO in both B and D subunits of protein pocket. Furthermore, Thiabendazole (8) and Bendazole (9) lost some of the binding interactions compared to the native NZO due to the differences in the structure of side chains of their benzimidazole moieties but maintained the binding interactions with both Val236 and Asn165. By reviewing molecular dynamics scoring and other parameters listed in 2O616) calculated at 3.14\u00a0\u00c5 which is comparable to the same bond formed at 2.70\u00a0\u00c5 by the native NZO.Another confirmatory tool for validating the binding interactions between the tested ligands and the target protein is through measuring the lengths of H-bonds involved. By representing the 3D filling positions of our tested compounds inside the deep protein pockets of two subunits B and D compared to the co-crystallized inhibitor, we observed a very close similarity between all in each subunit confirming the same binding mode and structural similarity between them as shown in Moreover, the large size of the two pockets of subunits B and D, especially D subunit, gives us an idea about the possible drug modifications especially at the side chain of thiophene ring of NZO to obtain larger compounds that can occupy the binding pockets more efficiently maintaining the same essential binding interactions with the crucial amino acids and at the same time forming extra binding ones for better inhibition.It is well known that outermost electrons are those involved in the binding interaction between a ligand and target protein, we therefore, computed the electron density of the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), and the molecular electrostatic potential (MEP) map. Figures of the electron density distribution of HOMO, LUMO, and MEP are depicted in The electron density of HOMO in NZO was found to be localized mainly on benzimidazole moiety, while the electron density of LUMO was solely localized on the thiophene side chain. The electron density of HOMO and LUMO of all other studied drugs are delocalized except for Mebendazole (1), Fenbendazole (4), and Flubendazole (5) in the case of HOMO and Oxibendazole (6) in case of LUMO. The electron density of HOMO of Mebendazole (1) and Flubendazole (5) is quite similar to that of NZO which is consistent with the calculated binding affinities [Flubendazole (5) > Oxfendazole (7) > NZO (docked) > Mebendazole (1)]. Despite of this consistency, the binding affinity does not solely depend on the energies and the electronic density distribution of HOMO and LUMO, but also on other determinants such as hydrogen bonding, electrostatic interactions, hydrophobic and Van der Waals forces and presence of clusters of water. We also noted that the electrons of HOMO are localized mainly on the benzene moiety and the aromatic side chain of Fenbendazole 4) in a different pattern to that observed with NZO.The MEP maps of all studied compounds revealed that one of benzimidazole nitrogen acts as an electron donating site capable of forming H-bond with amino acids in colchicine binding sites. Whereas the other benzimidazolyl nitrogen is electrophilic moiety acting as H-donor group. Interestingly, the MEP map of Mebendazole (1), Albendazole (2) and Flubendazole (5) are quite similar which is also consistent with the calculated binding affinities, where Flubendazole (5) > Oxfendazole (7) > NZO (docked) > Mebendazole (1) > Albendazole (2) > Oxibendazole (6) > Fenbendazole (4) > Ciclobendazole (3) > Thiabendazole (8) > Bendazole (9). Lack of 5 (6) substitution on the benzimidazole pharmacophoric group leads to a significant change in the MEP of Thiabendazole and Bendazole. Weaker binding affinities of these two drugs can be ascribed to the change in electronic configuration due to the absence of 5 (6) substitution.Among the nine tested members of benzimidazole anthelmintic drugs, Flubendazole (5) exhibits the most similar binding interactions, scoring, electron density distribution, and electrostatic map to that reported for NZO in tubulin protein (PDB: 5CA1). This suggests that Flubendazole (5) would be the most active member exerting antitumor activity mainly at CBS. At the same time, more structural modifications are required for FDA approved benzimidazole anthelmintic drugs and the original NZO inhibitor to obtain larger compounds with better fitting and binding modes inside the two large pockets of subunits B and D respectively."} +{"text": "This Correction follows an Expression of Concern relating to this article previously published by Portland Press.Fragaria ananassa methanolic extract in a rat model of cadmium chloride-induced neurotoxicity\u201d (Biosci Rep (2018) 38(6), DOI: 10.1042/BSR20180861) would like to correct The authors of the original article \u201cProtective effects of The authors have stated that the overlapping images had been selected from the same group in error, and further confirm that this error does not affect the conclusions of their study. The correct version of"} +{"text": "An increasing number of people are affected by various neurodegenerative diseases each year, impacting the quality of life of millions of people worldwide. However, considerable knowledge gaps in the mechanistic understanding of these diseases present a challenge to address this threat to human life successfully. Recent endeavors in basic research, clinical trials, and other research areas have provided vital insights to discover novel biomarkers for improved diagnosis and better treatment options for patients suffering from such diseases. Articles published as part of the Special Issue \u201cBiomarkers in Neurodegenerative Diseases\u201d highlight the recent advances in this field and emerging strategies to counter such diseases in the future.Three research articles published in the Special Issue focused on molecular mechanisms involving Alzheimer\u2019s disease (AD). First, Paik et al. used human SH-SY5Y neuroblastoma cells to show the neuroprotective role of Somatostatin-14 (SST). The possible mechanism involves the ability of SST to regulate the intracellular calcium levels and Collapsin Response Mediator Protein 2 (CRMP2) phosphorylation . NaturalKessler and others show a correlation between dysregulation of Monopolar Spindle 1 Kinase (MPS1) and tumor aggressiveness in glioblastoma multiforme (GBM) patients . The resOne key aspect of neurologic disorders includes complications arising from traumatic brain injuries (TBIs). In this regard, Alam et al. investigated the role of quinpirole in dopamine D2 receptor (D2R) activation using a mouse model simulating TBI . This stFulgenzi et al. provide an excellent update in the investigation of chelation therapy involving EDTA as a potential treatment for neurologic disorders. They studied more than 300 patients from a broad age group to monitor their toxic metal burdens before and after receiving EDTA as part of the therapy . InformaOne of the critical challenges for better treatment outcomes is correctly identifying the causes behind indicators of different neurologic conditions. Chien and coworkers used an artificial neural network to distinguish between dopamine transporter single-photon emission computed tomography (DAT-SPECT) images obtained from patients with Parkinson\u2019s disease or parkinsonism resulting from other illnesses with high (more than 80%) accuracy .Apart from these original research papers, the Special Issue also contains an excellent collection of review articles highlighting recent progress, challenges, and future directions in the field. For example, the review articles published by Jacopo Meldolesi and B\u0103la\u0219a et al. are excellent resources summarizing the significant advances made in fluid and imaging biomarkers for the early detection of neurodegenerative disorders in recent times ,9. The aI hope that these excellent research works and review articles published as part of the Special Issue will provide an invaluable reference for further research to counter the menaces posed by neurologic disorders in the future."} +{"text": "The presence of 2 ventricular signals caused by structures near the His bundle region is rare. Some associative and dissociative maneuvers for dissociating a certain electrical signal from others of known origin are used to ascertain the source of an unknown potential. Figure 1 was obtained. The arrow points to a signal after the ventricular potential on the His-bundle (HB) catheter that was consistently seen in sinus rhythm . What could be the origin of this second unexpected potential?A 64-year-old man with recurrent episodes of wide QRS tachycardia with the absence of overt structural heart disease underwent an electrophysiological evaluation. An echocardiogram showed mildly depressed left ventricular function. During an electrophysiological study, the electrogram in 2 A wide range of diagnoses are possible, including (1) intermittent accessory pathway (AP) conduction with an antegrade 2-for-1 phenomenon, (2) intermittent fused premature ventricular complexes (PVCs) arising from the diseased tissue near the HB region, (3) intermittent right bundle ectopy, (4) intermittent nodoventricular (NV) conduction, (5) intermittent atriofascicular (Mahaim fiber) conduction, (6) fragmented ventricular potential, or (7) basal septal or periaortic ventricular late potentials and local abnormal ventricular activities (LAVAs).3 Mahaim fibers or the NV pathway may also produce a second HB deflection after the ventricular potential on the HB catheter because of the retrograde conduction of the right bundle.2 Other antegrade-conducting unusual AP connections from the right atrial appendage to the right ventricular outflow tract may also cause complex signals on the HB catheter. A 2-for-1 phenomenon can occur when the atrial impulse simultaneously travels down the AP (activating the annular ventricular myocardium) and the atrioventricular node (AVN) and the HB . Afterward, the ventricular activation wavefront may travel back toward the base .1The presence of 2 ventricular signals caused by structures near the HB region is rare.5 The atrial extra-stimulus testing might give us some important clues. The timing of the extra potential is expected to correlate with either the degree of pre-excitation or the amount of fusion (if a PVC or fascicular beat occurs). If the candidate signal is ventricular or otherwise associated with pre-excitation , then causing a delay to signal activation would cause less pre-excitation.2 In the current case, there was a delay from the atrial signal to both the HB and the candidate potential without a change in the degree of pre-excitation an atrial extra-stimulus beat that showed more decrement in conduction down the AVN. A relatively fixed relationship was seen with V to this potential (single arrows), with a further delay with S2 (double arrow) in activating the tissue responsible for the extra (unexplained) potential. However, it would be difficult to explain the phenomenon via the effects of atrial pacing with a Mahaim fiber.2 For this to occur, a very similar decrement in conduction down the Mahaim fiber and the AVN is needed. The delay to the extra potential despite AH prolongation excluded all AP-related diagnostic possibilities in the current case, including NV pathways.8 Electroanatomic mapping revealed periaortic fibrosis that was consistent with this unusual potential , and then 4 different ventricular tachycardia (VT) morphologies were induced .Some associative and dissociative maneuvers for dissociating a certain electrical signal from others of known origin are used to ascertain the source of an unknown potential.11 These VTs from small regions of the periaortic scar can mimic idiopathic VT but are suggested by multiple VT morphologies .12 Several methods have been studied to invoke dynamic substrate changes in critical regions to target ablation, including decrement-evoked potential mapping,5 which involves a drivetrain and an S2 pacing protocol identifying sites of decremental LAVAs. This small periaortic site was then targeted for radiofrequency ablation . During ablation, the amplitude of this potential decreased, and all VT morphologies were no longer seen. Electrophysiologists must have a thorough understanding of how unexplained potentials can be analyzed using pacing maneuvers and by observing changes of association and dissociation that occur between these unknown signals and other known potentials .1 These techniques are useful in identifying the culprit sites and targets for ablation for several arrhythmias.2Periaortic fibrosis is increasingly recognized as a distinct clinical substrate for scar-related VT in the presence and absence of overt structural heart disease."} +{"text": "From th studies .Medline (Pubmed) search using the following: \u201cvascularization maxillary sinus cadavers\u201d, completed with the revision of the bibliographical references of the selected articles in order to identify further relevant studies. Inclusion criteria: (1) Published between 2008 and 2015. (2) Cadaver Studies. (3) Studies that evaluate the position of the anatomical position of the anastomosis between arterial branches of the posterior superior alveolar artery and the infraorbitary artery. Exclusion Criteria: (1) Non cadaveric studies. (2) Foetal and paediatric studies.Eight articles were selected.The vascular anastomosis is frequently found in the lateral wall of the maxillary sinus. Its position and depth are variable, as well as its trajectory and morphology. Pre-surgical determination of its precise anatomical variations is of the utmost importance to avoid vascular damage and complications during external sinus lifts osteotomies."} +{"text": "The temporomandibular disorders (TMD) are one of the main concerns regarding orofacial pathologies and there are an ascending number of cases. They are characterised as a group of pathological conditions that may affect the temporomandibular joint (TMJ), the masticatory musculature and/or other adjacent anatomical structures, leading to pain and dysfunction . The mulA 24-year-old female patient with a history of temporomandibular disorder and bruxism she presented an non-assisted mouth opening (UMO) of 28\u2009mm and an assisted mouth opening with pain in the masseter and TMJ bilaterally of 29\u2009mm, after the clinical assessment with the DC/TMD protocol we arrived at a diagnosis of disc displacement without reduction (DDwR) with limited opening, degenerative joint disease in the left TMJ, arthralgia (II), myofascial pain (III) in the masseter with pain referred to other anatomical regions. All the assumptions of the Helsinki Declaration have been fulfilled and an informed consent for clinical case of Clinica Dent\u00e1ria Egas Moniz approved by the ethic commission of Instituto Universit\u00e1rio Egas Moniz. The treatment plan consisted of cognitive behavioural therapy (CBT), prescription of muscle relaxants, occlusal splint especially for reduction of overload due to bruxism, infiltration with 1\u2009ml of hyaluronic acid of high molecular weight in the TMJ bilaterally followed by articular mobilisation techniques and neuromuscular and myofascial techniques. The patient was instructed to continue with the physiotherapy.The follow up was made 2\u2009months after with 8 sessions of physiotherapy and 1 more hyaluronic acid infiltration bilaterally as protocoled session, we could observe an absence of temporomandibular joint pain, UMO of 42\u2009mm, decreased crepitation, decreased intensity of myofascial pain (I) and (DDwR) without limited opening.The multidisciplinary dentist-physiotherapist team combines inputs from different professions with the aim of promoting the best patient care and represents an added value for the management of the signs/symptoms of patients with temporomandibular dysfunction."} +{"text": "Health and social care providers are ill-equipped to address the complex needs of individuals growing older with IDD and their families when dementia is suspected or diagnosed. Addressing the growing need for professionals to acquire practical diagnostic, treatment, and management methods requires an interorganizational and interprofessional approach. A consortium of aging and IDD organizations developed a successful Project ECHO model to create a virtual community of practice connecting a hub team and participating spoke sites. This paper reviews reasons for the model\u2019s success, including: (1) curriculum providing practical solutions to complex problems, (2) integration of interprofessional team approach, (3) \u201call teach, all learn\u201d model promoting sharing among participants, and (4) the inclusion of case studies engaging participants in developing solutions and strategies to improve the quality of life of clients and families. Implications of this model and recommendations for future professional educational programs are presented."} +{"text": "For people living with HIV, there are multiple barriers to engagement with care. This study qualitatively examines the role of use of alcohol and other drugs (AOD) on the health and management of Human Immunodeficiency Virus (HIV) disease among older African Americans (\u226550 years). It draws on interviews conducted with twenty-seven older African Americans living with HIV in the Louisville, Kentucky area. Interviews were transcribed verbatim and then analyzed using constructivist grounded theory analytic techniques. Participants\u2019 understandings of their AOD use fell on a continuum of problematic use to use for self-care. Regardless of where participants fell on this continuum, they faced a) environmental impacts of AOD use and b) current or historic discrimination from the health care system. The analysis focused on gaining a deeper understanding of the intersection of AOD use and engagement in the HIV care continuum. This revealed six major phases, which occurred at various stages of the continuum: (1) Linking AOD use as the cause of HIV diagnosis (2) Having AOD use facilitate denial of HIV, (3) Experiencing problematic use, (4) \u201cTesting the Waters,\u201d (5) Relying on AIDS Service Organizations (ASO) and medical providers and (6) Maintaining health and/or using AOD for self-care. We discuss the ways that stigma along the lines of race, gender, and age intersect with co-occurring conditions such as substance use disorders in complex and multifaceted ways. Recommendations include assessing a patients\u2019 AOD use in relationship to the HIV care continuum to assess patients\u2019 experiences and barriers within systems of care."} +{"text": "Following publication of the original article , the autThe incorrect author name is:Chayma (given name) Saheli (family name)The correct author name is:Sahli (given name) Chaima (family name)The author group has been updated above and the original article has been"} +{"text": "Dear Editor,Our immune gene model is of great help to predict the prognosis of colon cancer patients. The model genes could be used as prognostic markers and potential new targets for colon cancer patients.Colon cancer is a common tumor with high incidence worldwide.Different genes were analyzed by colon cancer data from TCGA database, and immune\u2010related genes were extracted. The immune differential genes were combined with the clinical data, and the model was constructed and evaluated. The model genes were enriched and analyzed. Single\u2010cell expression data of model genes were extracted, grouped according to the amount of each gene expression, and the percentage of infiltration of each cell phenotype in different groups was observed. The model genes were compared with immune checkpoints and immune cells. Analyzing the relationship between the key genes of the model and clinical information and using HPA database to verify model genes.Three hundred ninety\u2010six immune differential genes were screened, and the corresponding heatmap and volcanic maps were plotted Correlation analysis between the expression of model gene CD19 and patient age. (B) Correlation analysis between model gene expression and tumor anatomical location. (C) Correlation analysis between model gene expression and occurrence of mismatch repair. (D ) Correlation analysis between the expression of model gene UCN and the occurrence of lymphatic invasion. (E) Correlation analysis between the expression of model gene and the occurrence of microsatellite instability. (F) Correlation analysis between model gene expression and tumor TNM staging. (G) Correlation analysis between model gene expression and lymphatic metastasis. (H) Correlation analysis between model gene expression and distant metastasis. (I) Correlation analysis between model gene expression and clinical stage of patients. (J) Correlation analysis between CD3E gene expression and tumor recurrence after treatment. (K) Correlation analysis between UCN gene expression and initial treatment effect. (L) The expression of prognostic\u2010related immune differential genes in colon cancer tumor tissues and normal tissuesClick here for additional data file."} +{"text": "The application of femtosecond lasers in ophthalmology has enabled precise and reproducible tissue cutting, which is expected to improve the outcomes of surgical treatment, particularly in anterior segment surgeries such as cornea, cataract, and refractive surgery.As we have introduced in the call for papers for this Special Issue, the articles published cover topics focused on the application of femtosecond lasers in anterior segment surgery, including the development of the technologies behind femtosecond lasers and their application in ophthalmic surgery, the efficacy and safety of anterior segment surgery using femtosecond lasers, and imaging techniques associated with the application of femtosecond lasers.Femtosecond lasers have been increasingly used in cornea and refractive surgery. The laser can be used to create customized trephination edges for deep anterior lamellar keratoplasty and penetrating keratoplasty and for allowing ultrathin cut for Descemet stripping automated anterior lamellar keratoplasty. It can also be helpful for improving the consistency and reproducibility of refractive surgery, including laser-assisted in situ keratomileusis (LASIK), small incision lenticule extraction (SMILE), intrastromal corneal ring segment implantation, and astigmatic keratotomy.Femtosecond laser cataract surgery (FLACS), in which a femtosecond laser is employed for corneal incision, anterior capsulotomy, lens fragmentation, and liquefaction, is also expected to improve the reproducibility and safety of cataract surgery. In this Special Issue, the authors contributed 10 original papers and one review article regarding the use of femtosecond lasers in anterior segment surgery.The authors have reported the results of their research on various topics related to femtosecond lasers in anterior segment surgery: (1) extrusion of femtosecond laser-implanted intrastromal corneal ring segments in keratoconic eyes: prevalence, risk factors, and clinical outcomes; (2) clinical observation of silicon hydrogel contact lens fitted immediately after SMILE; (3) preliminary results of a novel standardized technique of femtosecond laser-assisted deep anterior lamellar keratoplasty for keratoconus; (4) long-term evaluation of capsulotomy shape and posterior capsule opacification after low-energy bimanual femtosecond laser-assisted cataract surgery; (5) anatomical and visual outcomes after LASIK performed in myopic eyes with the WaveLight\u00ae refractive suite ; (6) correlation analysis of refractive and visual quality after wavefront-optimized laser in situ keratomileusis for 50% and 100% angle kappa compensation; (7) comparison of femtosecond laser-assisted cataract surgery and conventional phacoemulsification in shallow anterior chambers and glaucoma; (8) characteristics of facial asymmetry in congenital superior oblique palsy according to trochlear nerve absence; (9) a modified femtosecond laser technique for anterior capsule contraction syndrome; and (10) evaluation of astigmatic correction using a vector analysis after combined femtosecond laser-assisted phacoemulsification and intrastromal arcuate keratotomy. This Special Issue also includes one review article on the application of femtosecond lasers in anterior segment surgery.We believe these papers will provide readers with valuable information on the application of femtosecond lasers in anterior segment surgery and new ideas for research on related topics."} +{"text": "The COVID-19 pandemic has renewed interest in endemic human coronaviruses (HCoV), which are responsible for an estimated 5-10% of acute respiratory infections (ARI) in temperate climate zones A total of 4,375 specimens from children and adults, who had presented with acute respiratory symptoms to a sentinel physician between October 2019 and September 2020, were examined by qPCR see . EndemicBB wrote the manuscript with support from DYO and RD; BB is responsible for data acquisiton; BB and DYO analysed the data; RD is responsible for the virological section of the sentinel system; TW and RD supervised the project.The authors declare that no competing interests exist."} +{"text": "Typhoid fever, also known as typhoid, is a life-threatening bacterial infection that remains a global health concern. The infection is associated with a significant morbidity and mortality rate, resulting in an urgent need for specific and rapid detection tests to aid prevention and management of the disease. The present review aims to assess the specificity and sensitivity of the available literature on the immunodiagnostics of typhoid fever. A literature search was conducted using three databases and manual searches through the references of identified full texts to retrieve relevant literature published between 1 January 2011 and 31 December 2020. Of the 577 studies identified in our search, 12 were included in further analysis. Lipopolysaccharides (LPS) and hemolysin E (HlyE) were the most frequently studied antigens. The specimens examined in these studies included serum and saliva. Using blood culture as the gold standard, anti-LPS IgA gave the highest sensitivity of 96% (95% CI: 93\u201399) and specificity of 96% (95% CI: 93\u201399) for distinguishing between typhoid cases and healthy controls, whereas the combination of anti-LPS and anti-flagellin total IgGAM gave the highest sensitivity of 93% (95% CI: 86\u201399) and specificity of 95% (95% CI: 89\u2013100) for distinguishing typhoid cases and other febrile infections. A comparably high sensitivity of 92% (95% CI: 86\u201398) and specificity of 89% (95% CI: 78\u2013100) were shown in testing based on detection of the combination of anti-LPS (IgA and IgM) and anti-HlyE IgG as well as a slightly lower sensitivity of 91% (95% CI: 74\u2013100) in the case of anti-50kDa IgA. Anti-50kDa IgM had the lowest sensitivity of 36% (95% CI: 6\u201365) against both healthy and febrile controls. The development of a rapid diagnostic test targeting antibodies against lipopolysaccharides combined with flagellin appeared to be a suitable approach for the rapid detection test of typhoid fever. Saliva is added benefit for rapid typhoid diagnosis since it is less invasive. As a result, further studies could be done to develop additional approaches for adopting such samples. Salmonella enterica serovar Typhi (S. Typhi). The life-threatening disease has been a public health problem in developing and underdeveloped countries for generations. A systematic analysis by typhoid and paratyphoid collaborators estimated that 10.9 million cases of typhoid fever occurred globally in 2017, resulting in 116.8 thousand deaths AND [\u201cantigen\u201d OR \u201cantibody\u201d] AND [\u201cdiagnosis\u201d OR diagnostic\u201d] AND [\u201cspecificity\u201d OR \u201csensitivity\u201d]. An additional search was conducted by manually screening the references of the retrieved literature.The literature search was conducted in January 2021 according to the modified preferred reporting items for systematic reviews and meta-analyses guidelines . The seaArticles were excluded if (i) the studies were published before 1 January 2011, or after 31 December 2020; (ii) the studies were published in languages other than English or Malay; (iii) the studies did not mention the types of antigens used. We limit the studies to post 2011 (10 years) as the older literatures are not relevance to represent current diagnostic performance of the newly developed assays. Only studies that analyzed samples of at least two groups consisting of healthy controls and typhoid patients confirmed by positive blood culture were included in this systematic review. The retrieved literature was downloaded into Mendeley reference manager and duplicates were identified and removed. The references were distributed to four authors, who independently reviewed the titles and abstracts. A satisfactory agreement for the screening process was assessed between the reviewers. All four reviewers performed full-text screening and summarized the findings. Data from the selected sources were collated and summarized using a standard charting table consisting of six domains: (i) detection assays; (ii) biomarker; (iii) biological specimens; (iv) sample size; (v) specificity and sensitivity; (vi) year of publication.The number of true positives (TF), true negatives (TN), false positives (FP) and false negatives (FN) was independently retrieved from each article by three investigators and entered into an Excel datasheet. Discordant findings were assessed through discussion and when in doubt, the authors sought verification. Using blood culture as the reference standard, we calculated the sensitivity and specificity for each of the studied biomarker. Sensitivity was calculated by dividing the number of true positive outcomes with the sum of true positive and false negative outcomes. Specificity was calculated by dividing the number of true negative outcomes with the sum of true negative and false positive outcomes. Performance comparison of the immunodiagnostic assays was presented using forest plots based on control groups.The risk of bias for all included studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool . The QUAThe present systematic review provides an overview of the performance of immunodiagnostic tests for typhoid fever and found that tests based on anti-LPS in combination with anti-flagellin offered the best diagnostic performance for the diagnosis of typhoid fever and that anti-HlyE could be an alternative option with a performance comparable to that of anti-LPS. Our results highlight the limitations of the ongoing immunodiagnostic development and provide baseline information for future studies to select appropriate biomarkers in the development of RDTs for typhoid fever. Based on the good performance of anti-LPS and anti-HlyE, these two antigens appear to be suitable options for the development of future POCTs for typhoid fever. The currently low number of studies using saliva samples for detection suggests that more studies could explore the development of alternative approaches implementing such samples, which have the advantages of less invasive sample collection, which would help to boost accessibility and facilitate efficient testing in a community, especially during a disease outbreak and in areas where access to laboratory-based testing is not available."} +{"text": "This study aimed to assess the impact that the COVID-19 pandemic has had on the Hertfordshire Community Perinatal Team (CPT) group interventions and the innovations made.The CPT is a multidisciplinary mental health service that runs three groups: Circle of Security (CoS), Emotional Coping Skills (ECS) and a peer support group - Wellbeing and Lifestyle. The service has received an increase in referrals during the COVID-19 pandemic.Methods: Team member and client semi structured interviews were conducted with answers transcribed in real time and analysed. Patient clinical records were accessed via PARIS and analysed in order to identify patient demographics within each group and whether these had changed during the pandemic. Clinical outcome measures and client feedback were evaluated to see whether the change in groups is impacting their clinical effectiveness.Results: Innovations made by the CPT include: groups becoming virtual, launching of the new Circle of Security Group which helps women tackle the \u2018Ghosts in the Nursery\u2019 and strengthen maternal bonds, restructuring existing groups, breakout room forums and incorporating communication platform apps such as Whatsapp. The Wellbeing and Lifestyle Group increased in size and reach (7 women from 7 areas in 2019 vs 12 women from 12 areas in 2021) with an increased retention rate (71% in 2019 vs 100% in 2021) and a decreased attrition rate (29% in 2019 to 0% in 2021). The Emotional Coping Skills group experienced similar changes (10 areas represented in 2019 vs 15 different areas in 2021) with an increased retention rate (58% in 2019 vs 100% in 2021) and decreased attrition rate (42% in 2019 vs 0% in 2021).The Hertfordshire Community Perinatal Team has responded to the pandemic by innovating existing groups and creating new forums; many of which will continue on even after the pandemic ceases. The groups have acted as a lifeline for women breaking up the monotony and isolation of lockdown life and providing an invaluable space for women to be heard."} +{"text": "Despite two decades of palliative care services, there remains numerous barriers to patient and caregiver use of palliative care. For many years, policymakers believed lack of funding for palliative care was the primary obstacle to accessing palliative care services. In 2017, we undertook a randomized controlled trial to test the effectiveness of a home-based palliative care (HBPC) program within accountable care organizations and in partnership with an insurance company that covered the cost of HBPC. After 20 months, we had recruited just 28 patients. This symposium will: (1) describe outcomes from various approaches undertaken to engage primary care physicians and recruit patients and their caregivers into this trial; (2) present barriers to HBPC referral identified from a qualitative study of primary care physicians; (3) present findings from a qualitative study of patient- and caregiver-identified barriers to HBPC; (4) describe physician and patient barriers to research participation; and (5) discuss implications of these findings for researchers and healthcare providers. Information presented in this symposium will inform researchers and policy makers about challenges and facilitators to recruiting patients, caregivers, and physicians to participate in research studies as well as inform healthcare practitioners of potential obstacles to increasing patient access to HBPC."} +{"text": "Insomnia and obstructive sleep apnea (OSA) are two prevalent sleep disorders which share nocturnal sleep disturbances, impairments to daytime activity and quality of life, and high healthcare and social costs. The treatment of both disorders is often limited by the relatively low acceptance or long-term adherence to cognitive and behavioral therapy for insomnia (CBTi) or continuous positive airway pressure (CPAP) therapy, respectively.Unsurprisingly, the review published by Sweetman et al. on comor(1)Refine the diagnosis and measurement of COMISA to assess both the independent and the shared symptoms of insomnia and OSA disorder.(2)Investigate the potential bi-directional relationships in COMISA in order to identify the predictors of the greatest response to insomnia or OSA treatments.(3)Examine the efficacy of the combined treatments for COMISA, administering both cognitive and behavioral therapy for insomnia (CBTi) and continuous positive airway pressure (CPAP) therapy.(4)Explore the mechanism(s) underlying the relationship between obstructive sleep apnea and insomnia.(5)Define the role of circadian rhythms in COMISA.(6)Clarify the moderating role of sex, race, age, and regional differences.(7)Assess the clinical evolution of insomnia during OSA treatments.Based upon recent randomized controlled trials, some issues that should be considered in the future research agenda include :(1)RefinCo-morbid insomnia and sleep apnea (COMISA) represent a clear model of bi-directional relationships between two different disorders. The review by Sweetman et al. is able"} +{"text": "When a trainee is unable to advance the tip of the tracheal tube through the vocal cords and the patient's pulse oximeter signals declining oxygen saturation (SpOThis oxygenation technique has proved consistently successful provided (1) the ETT tip is immediately supraglottic (retro-epiglottic) and (2) glottic closure (laryngospasm) has been prevented by prior administration of a muscle relaxant drug.In the late 1990s, members of our department began employing NLPAWS to ventilate adult patients (following anesthetic induction or cardiac arrest) via an orally inserted tracheal tube when PPV could not be administered because of a large leak at the facemask-skin interface. Such occurrences most often resulted from (1) the patient having a full beard or sunken cheeks, (2) the anesthetist having small hands or a lack of experience, or (3) use of a missized facemask .1 In approximately 20% of these cases, however, PPV failed because of airway obstruction (not air leak). A solution to this problem was found to be using a laryngoscope to guide the ETT tip to the same immediately supraglottic position that had always been a part of NLPAWS use during nasotracheal intubation.2 Two advantages of this technique of rescue ventilation compared to similar use of a laryngeal mask airway (LMA) are (1) faster access to an ETT and (2) suitability of almost any ETT size.At first, we used NLPAWS to permit ventilation through an oral ETT inserted a distance approximating the length of an appropriately sized oral airway.2 and PEEP 20 cm H2O) to reverse a rapid decline in blood oxygenation (SpO2 88% \u2192 42%) and elevate it to 58% during the time required for a replacement ETT to be brought to the patient's negative-pressure intensive care unit room.Very recently, members of our department have learned to use NLPAWS to enable PPV (1) in the presence of a leaking LMA (5 cases); (2) via a nasal airway fitted with an ETT adaptor during upper GI endoscopy ; and (3) via a correctly inserted ETT (4 cases). In 3 cases in the last category, the problem was simply that that the air syringe reserved for inflating the ETT cuff had been misplaced. In the fourth case, however, NLPAWS use may have been lifesaving. ETT cuff rupture occurred (probably from contact with a prominent incisor) during intubation of a patient with severe COVID-19 pneumonia. NLPAWS enabled sufficient Ambu ventilation (100% OWe are not aware of any instance of gastric aspiration occurring during NLPAWS use by a member of our department. Risk of this complication may be similar to risks associated with PPV performed using a facemask plus oral airway."} +{"text": "Inflammation is originated by tissue injury and triggers several biochemical reactions that sensitize the nervous system for pain perception. Chronic inflammation induces adaptive changes that can cause altered pain signal processes. Indeed, inflammatory mediators provokes structural and functional changes in the peripheral or central sensory circuits, resulting in pain like behaviors, such as hyperalgesia, allodynia, and spontaneous pain. Accumulating evidence suggests that central sensitization is driven by neuroinflammatory processes mediated by activation/proliferation of resident microglia and glial cells with the consequent release of inflammatory mediators; furthermore, several recent studies are relating the role of non-neuronal cells of the peripheral nervous system with the modulation of neuroinflammation involved in the development and maintenance of chronic pain.Boccella et al.).Currently treatments for chronic pain are quite unsatisfying. Therefore, there is a need for research aimed at discovering novel biological targets for new pharmacological approaches. Recently the authors collectively participated in the study of neuropathic pain and the role of HCAR2 expressed by Schwann cells in a sciatic nerve ligation model. in arthritis by using different mouse models mimicking pathophysiology of rheumatoid arthritis in humans and integrative methodology with special emphasis on pain. They provide the first evidence that HK-1 mediates several arthritic inflammatory mechanisms and pain by direct activation of primary sensory neurons not via its classical NK1 receptor.\u27a2 Li et al., summarize the current knowledge of the role of microglia during sepsis by showing the contribute of these cells in long-term sensorial and cognitive deficits. The Authors appropriately illustrate the activation of microglia in the Central nervous system by describing specific neurotransmissions and molecular pathways which may promote the cognitive damage and chronic pain during sepsis.\u27a2 Pacini et al. test the effects of the natural antioxidant thioctic acid which is clinically used as racemic mixture. The Authors report preclinical and clinical evidences suggesting positive properties of thioctic acid in the treatment of low back pain with a more relevant efficacy of (+)-thioctic acid as compared to (+/\u2212)-thioctic acid on pain, on time of onset of therapeutic effects.\u27a2 De Caro et al., show the anti-inflammatory and analgesic properties of Perampanel, the selective non-competitive AMPA receptor antagonist in acute (tail flick and hot plate tests) and chronic pain (Chronic constriction injury). They also suggest the involvement of the cannabinergic system in Perampanel actions.\u27a2 Scuteri et al., provide a systematic review and meta-analysis assessing the efficacy of essential oils in pain. They describe the literature search conducted on databases relevant for medical scientific literature, i.e., PubMed/MEDLINE, Scopus, and Web of Science following the PRISMA criteria. Among a total number of 30 studies included, three investigated neuropathic pain conditions.\u27a2 Borges et al., review recent clinical and preclinical studies investigating the epidermal growth factor receptor (EGFR) signaling pathway in chronic pain states. EGFR inhibitors are known for their use as cancer therapeutics however recent evidence suggested their clinical use for treating chronic pain. Here, the Authors provide an overview of EGFR signaling, highlighting possible mechanisms by which EGFR and its ligands may influence pain hypersensitivity and modulate inflammatory mediators of pain.\u27a2 Brik et al., investigate the behavioral and biochemical changes after intra-articular injection of sodium monoiodoacetate (MIA). This model mimics the degenerative changes observed in osteoarthritic patients. The Authors have characterized grading changes after injection of 1, 2 or 3\u00a0mg of MIA over a 28-day period. They report significant dose- and time-dependent changes in both gene expression and protein secretion levels of inflammatory factors.\u27a2 Mazzitelli et al., provide a direct evidence for the modulation of pain-like behaviors and spinal neuronal activity by basolateral amygdala-central nucleus (BLA\u2013CeA) signaling and central nucleus-corticotropin releasing factor (CeA\u2013CRF) neurons on under normal conditions and in an arthritis pain model.\u27a2 Ma et al., reveal the (fat-mass and obesity-associated protein) FTO-triggered epigenetic mechanism of matrix metallopeptidase 24 (MMP24) upregulation in the spinal cord after spinal nerve ligation (SNL). They show that blocking the SNL-induced increase of MMP24 in the spinal cord mitigate pain hypersensitivity both in the development and maintenance phase without altering the basal/acute responses or locomotor functions. The Authors suggest that MMP24 may be an endogenous initiator of neuropathic pain and could be a potential target for this disorder\u2019s prevention and treatment.\u27a2 Bruno et al., indicate that \u03b2-adrenergic receptors (\u03b2-ARs), mainly \u03b22-and \u03b23-ARs, contribute to tumor proliferation and progression and cancer-associated pain in a mouse model of cancer pain generated by the para-tibial injection of K7M2 osteosarcoma cells. This study highlights the ability of \u03b2-ARs antagonists in modulating both tumor growth and the neuroinflammation, showing a new therapeutic targets for cancer therapy and associated pain.\u27a2 In this Research Topic, different signaling implicated in neuroinflammation and chronic pain and possible therapeutic approaches have been described:"} +{"text": "Natural disasters and COVID-19 likely add complexity to caregiving efforts, yet little is known about these effects. We will discuss our findings exploring additional needs and challenges experienced by caregivers during hurricanes, floods, and COVID focused on US Gulf Coast states. We interviewed caregivers of both Veterans (n=13) and non-Veterans (n=11). The presentation will include an overview of 1) types of resources needed or used related to storms and to COVID, including social support and access to information for both emergency planning and recovery; 2) caregiver experience before, during, and after the disaster including psychological effects on caregivers and addressing special health needs; 3) comparisons of challenges during storms versus COVID including emotional impact and access to health and specialty care; and 4) additional resources used by caregivers of Veterans. We will also address how these data are informing national caregiver support programs."} +{"text": "Public health measures implemented to mitigate the spread of COVID-19 have transformed the physical and social environments in which we live. The effects of these policies on persons living with dementia (PLWD) and their care partners (CPs) are not fully understood. This study explores the experiences, attitudes, and perceptions of caregiving dyads during the COVID-19 pandemic. Cross-sectional survey data were drawn from a larger longitudinal study examining the relationship between PLWD aged 65+ and their CPs being conducted in a metropolitan city significantly affected by COVID-19. Interviews with were conducted remotely via videoconferencing and telephone. Data on sources and types of care provided for the PLWD, relationship quality and conflict, and caregiver stress were collected and analyzed using descriptive statistics and tests of independence. Preliminary results from PLWD (n=8) and CPs (n=13) confirmed a reduction in social interaction with family members and friends. CPs reported they (n=5) or other family members (n=2) changed their schedules to provide care for the PLWD. CPs reported increased conflict with the PLWD regarding care provision, going out or welcoming visitors, and home management. In contrast, PLWD reported a lack of conflict among household members (n=6) and the perception of good changes (n=2) and increased quality time with CPs. Preliminary findings provide empirical evidence of the effects of pandemic public health policies on dyads enrolled in this study and reveal differences in perceived relational conflict between PLWD and their CPs. Further research is needed to better understand the experiences of dyads and develop supportive interventions."} +{"text": "Service users of secure forensic units can be prone to weight gain due to various reasons including medications, physical illnesses, sedentary habits and mental health difficulties. They in turn are at greater risk of obesity related health problems like Diabetes, Hypercholesterolaemia, Ischaemic Heart Disease, Depression among others.Our project was aligned with government's plan to improve prevention and screening for the obesity and metabolic syndrome among the patients of medium secure facilities by 2020.Our primary objective was to gather and analyse the data on current metabolic parameters such as weight, body mass index (BMI), blood pressure (BP) and biochemistry markers of the service users on a 18 bedded Male medium secure long term rehabilitation ward.Our secondary objective was to suggest healthy weight interventions that would help patients to loose weight and to explore the effects of these interventions on biochemistry markers and vital signs parameters.We collected cross sectional data in given period of time (mid-March 2020). Seventeen service users were included in the final sample. Following initial data collection, we suggested various healthy weight interventions for the patients and repeated data collection after four months (July 2020).Interventions offered:Healthy eating group1:1 sessions with doctors and pharmacistsGym referralsDietician referralsRelaxation groupBaselineFourteen patients on the ward (n = 14) were found to be either overweight or obese. Two patients (n = 2) had high BP, twelve patients (n = 12) had deranged lipid profile, six (n = 6) had high blood glucose (existing Diabetes).Following interventionFourteen patients (n = 14) remained either overweight or obese. Nine patients (n = 9) lost weight following the intervention. Eight patients (n = 8) gained weight over 4 months. In both of the patients (n = 2) with raised BP the readings came back to normal after the intervention. One (n = 1) patient with normal BP at the baseline had high blood pressure following intervention.Our service evaluation projects revealed that majority of the patients on the ward had deranged metabolic parameters such as increased BMI, abnormal blood tests and high BP.Following our intervention more than a half of the patients lost weight whilst other half gained weight during the period of observation, which we suspect is associated with significant physical activity restrictions during the coronavirus pandemic. In both patients with high BP at the baseline it has improved following the intervention.We would continue implementing healthy weight interventions on the ward and across the unit."} +{"text": "Public health measures implemented to mitigate the spread of COVID-19 have transformed the physical and social environments in which we live. The effects of these policies on persons living with dementia (PLWD) and their care partners (CPs) are not fully understood. This study explores the experiences, attitudes, and perceptions of caregiving dyads during the COVID-19 pandemic. Cross-sectional survey data were drawn from a larger longitudinal study examining the relationship between PLWD aged 65+ and their CPs being conducted in a metropolitan city significantly affected by COVID-19. Interviews with were conducted remotely via videoconferencing and telephone. Data on sources and types of care provided for the PLWD, relationship quality and conflict, and caregiver stress were collected and analyzed using descriptive statistics and tests of independence. Preliminary results from PLWD (n=8) and CPs (n=13) confirmed a reduction in social interaction with family members and friends. CPs reported they (n=5) or other family members (n=2) changed their schedules to provide care for the PLWD. CPs reported increased conflict with the PLWD regarding care provision, going out or welcoming visitors, and home management. In contrast, PLWD reported a lack of conflict among household members (n=6) and the perception of good changes (n=2) and increased quality time with CPs. Preliminary findings provide empirical evidence of the effects of pandemic public health policies on dyads enrolled in this study and reveal differences in perceived relational conflict between PLWD and their CPs. Further research is needed to better understand the experiences of dyads and develop supportive interventions."} +{"text": "The effects of the COVID-19 pandemic on both those experiencing homelessness and those with life-limiting illnesses is of great public health concern. This presentation details the findings from an organizational case study aimed at investigating COVID-related changes to the service environments in which unhoused palliative care patients receive care. Through ethnographic field observation and interviews with a homeless palliative care team and their community partners , findings included 1) decreased staff capacity due to de-congregated care; 2) efforts to extend care in community settings due to relocation barriers; 3) conflict between reducing viral risk and honoring unique population needs; and 4) provider perceptions of COVID-19 as an \u201cequalizer.\u201d Findings illustrate the impact of emergency response within housing and healthcare systems on unhoused patients\u2019 care and offer potential pathways to quality end-of-life care for homeless populations."} +{"text": "Previous research has established the role of lifelong learning in promoting psychological wellbeing and active aging. Population aging necessitates an understanding of the unique opportunities and challenges around formal and informal learning in later life. This paper will share findings from a mixed methods study with the MIT AgeLab 85+ Lifestyle Leaders, a panel comprised of octogenarians and nonagenarians from across the United States. Drawing on an online survey and virtual focus groups with 29 Lifestyle Leaders from January 2021, findings suggest the Lifestyle Leaders most often learned new things from talking with others (46%) and reading print (54%) or online (54%) sources. The majority were familiar with attending in-person lectures or classes (89.7%) and were now using videoconferencing to do these (78.6%). A majority (56.7%) had or are currently participating in a lifelong learning program. Most consider themselves lifelong learners and described this around remaining curious and engaged with life, choices around what one learns, and greater enjoyment of learning. In the survey, a plurality of Lifestyle Leaders indicated the top two challenges affecting their ability to learn were sensory burdens (35%) and their energy level (32.4%); focus group data revealed that recall also is a barrier. Focus group data further highlighted generational experiences around early life learning and career paths, specifically how gender roles, diagnoses of learning disabilities, and evolving digital technology have affected these and changed over the course of their lifetimes."} +{"text": "Herein we reportthe first alkynylation of quinolones with terminalalkynes under mild reaction conditions. The reaction is catalyzedby Cu(I) salts in the presence of a Lewis acid, which is essentialfor the reactivity of the system. The enantioselective version ofthis transformation has also been explored, and the methodology hasbeen applied in the synthesis of the enantioenriched tetrahydroquinolinealkaloid cuspareine. A) derivativessuch as ciprofloxacin B are well known as broad-spectrumbacteriocidal agents6 -catalyzed alkylations usingorganomagnesium and organoaluminum reagents -catalyzed alkynylation ofquinolones has not been accomplished so far.31On the contrary, the use of readily available and structurallydiverse terminal alkynes as pronucleophiles, along with the mild reactionconditions, offers an attractive strategy for the synthesis of structurallydiverse quinolone derivatives. Several examples of this approach,including Cu(I)-catalyzed alkynylations of (thio)chromonesHerein we report the first example of the direct Cu(I)-catalyzedalkynylation of 4-quinolones with terminal alkynes as pronucleophiles1c. This 1a and phenylacetylene 2a in the presence ofbase DIPEA and catalytic amounts of Cu(I) salt. On the basis of ourgroup\u2019s experience with Lewis-acid-promoted Cu(I)-catalyzedconjugate additions,35 we evaluated the effect of severalLewis acids to enhance the electrophilicity of the quinolone substrate 1a. Excellent conversion to the desired addition product 3a was observed in the presence of a stoichiometric amountof tert-butyldimethylsilyl triflate (TBDMSOTf) afterstirring overnight (Supporting Information) confirmed the conditions in entry 1 as the mostoptimal. Next, we evaluated the effect of the protecting group ofthe quinolone substrate on the reaction outcome.At the start of this work, the optimization studies were carriedout for the alkynylation reaction between Cbz-protected quinolone 3a were obtained when trimethylsilylhalides were used instead (entries 9 and 10). The use of strongersilicon-based Lewis acids such as trimethylsilyl (TMS) and triethylsilyl(TES) triflates resulted in moderate reaction rates (entries 11 and12), whereas the boron-based Lewis acid BF3\u00b7Et2O did not improve the reaction outcome either (entry 13).The superiority of TBDMSOTf over other explored silyl triflates canbe rationalized by the higher stability of a possible TBDMS-enolateintermediate formed during the reaction.No conversion was observed whenunprotected or benzyl-protectedquinolones were used (entries 3 and 4). Moreover, replacing the Cbzprotecting group on the quinolone substrate by a Boc group resultedin a significant drop in the conversion (entry 5). Further studiesconfirmed that the presence of a copper salt and a stoichiometricamount of a Lewis acid are mandatory to promote the reaction to completion.No conversion of quinolone was observed in the absence of copper saltor using only a catalytic amount of a Lewis acid (entries 6\u20138).With silyl-based Lewis acids other than TBDMSOTf, a lower substrateconversion was obtained (entries 9\u201313). Only traces of theaddition product Having the optimizedconditions in hand (entry 1), we moved tostudy the scope of the reaction. For this purpose, various alkynesand quinolones were tested 2.3ab\u20133aj). An excellent yield was also obtained withheteroaromatic alkyne 3ak. Similar results were obtainedwhen using cyclopropyl-, isobutyl-, and ester-substituted alkynes. Surprisingly, the linearterminal alkyne 1-pentyne was unreactive under the optimized reactionconditions (3ao). The limited reactivity of alkyl alkynesand the lack of reactivity of linear alkynes are consistent with theliterature observations in other Cu-catalyzed reactions.37 Various quinolones can be usedwith this catalytic system. Excellent yields were obtained for quinolonesboth with activating and with deactivating groups present in the quinolonering (3eg\u20133ig) and for those withdisubstituted substrates (3jg and 3kg).The reaction was successfully extendedto several aromatic terminalalkynes bearing electron-donating and electron-withdrawing groupsand four-, three-, and two-substituted aromatic rings -cuspareine (5)without racemization, allowing the determination of the absolute configurationof the stereogenic carbon by comparing the optical rotation of cuspareinewith literature data.17The hydrogenation of In summary, an efficientmethodology for the alkynylation of quinoloneswith readily available terminal alkynes has been accomplished. Thismethodology tolerates the presence of several functional groups inboth the quinolone and alkyne reagents and complements the previouslydeveloped arylation and alkylation reactions of quinolones. We havealso demonstrated the feasibility of an enantioselective version andapplied the current methodology to the synthesis of the enantioenrichedHancock alkaloid (+)-cuspareine. Further studies are under way, aimingto improve the enantioselective variant and shed light on the underlyingmechanism."} +{"text": "This study provides one of the first population-based studies investigating associations between social isolation, especially its two sub-dimensions (family isolation and friendship isolation), and sleep quality among older adults in China. We address three major research questions: 1) Does the risk of poor sleep quality vary by social isolation status? 2) Are the associations between social isolation and sleep quality mediated by mental disorders (depressive symptoms and loneliness) and physical impairments (pain and comorbidity)? and 3) Does the isolation from family members and friends differ in explaining sleep quality? We analyzed data from the 2014 wave of the China Longitudinal Aging Social Survey (CLASS), in which 7,597 respondents (aged 60-98) had complete information on measures of sleep quality (self-rated sleep difficulty), social isolation , and other analytical variables. Logistic regression models were estimated to predict the risk of sleep difficulty and Karlson-Holm-Breen (KHB) decomposition method was employed to test potential mediating effects. Results showed that social isolation, both family and friendship isolation, was significantly associated with higher risks of having sleep difficulty. The adverse effect of family isolation was found to be stronger than that of friendship isolation. Although both mental disorders and physical impairments mediated significant shares of associations between social isolation and sleep quality, physical impairments explained a lesser extent of them than mental disorders. These findings will be helpful for health policymakers and practitioners to design effective intervention strategies to help older adults with sleep problems."} +{"text": "Salmonella typhimurium (HKST) on intestine against IR was investigated. Through mouse intestinal organoids and whole body irradiation of mice, we found that the pretreatment with HKST significantly preserved the structure of small intestine upon IR exposure and promoted the proliferation of intestinal cells post-IR. Further study revealed that the radioprotective effects of HKST were involved in DNA damage response (DDR) signaling. Moreover, the stimulation of DDR signaling by HKST upon radiation damage was mediated by Wnt signaling, in which the inhibition of Wnt signaling diminished the radioprotective effects of HKST. To sum up, our study suggested HKST as a potential radioprotectant used for prevention of IR-induced GI toxicity.Gastrointestinal (GI) toxicity caused by ionizing radiation (IR) is a dose limiting factor in radiotherapy and a great threat for individual nuclear-related military missions. However, there are currently no available strategies to effectively prevent the damage on the intestine induced by IR. In the present study, the protective activity of Heat Killed Patients received radiotherapy and victims from nuclear accidents unavoidably suffer from the damage induced by ionizing radiation (IR) . Acute rEscherichia coli O111: B4 LPS, the coagonist of TLR4 and TLR2, exerts stronger immune stimulation effects than that from TLR2 or TLR4 agonist used alone or in combination Gastrointestinal (GI) toxicity caused by ionizing radiation (IR) appears to be a limited factor in radiotherapy and a great threat for those exposed to high dose radiation. However, there are currently no available strategies to effectively prevent or mitigate the damage on intestine induced by IR. Our study demonstrated that Heat Killed"} +{"text": "My Sister\u2019s Keeper is an online education and support group created by women of color in response to disproportionate stresses related to COVID-19 experienced by women of color. The current study aims to examine the Stage 2 evidence that an online support group formed by members of the community may help mediate inequity-related stressors and increase receptiveness to health-related recommendations. To begin to develop this evidence, a thematic analysis of 8 in-depth individual interviews was performed. Resulting themes included: 1) feeling empowered; 2) solidarity in sisterhood ; 3) being focused (on women of color) yet being inclusive; 4) currency of knowledge ; and 5) preferring virtual accessibility to stay connected. Preliminary data suggest that social support offered through an online platform dedicated to women of color can promote health during the pandemic and possibly beyond."} +{"text": "The current study examines how cohort differences across two age-matched groups of midlife and older women from the Health and Retirement Study are associated with well-being and self-perceptions of aging (SPA). Women aged 51\u201360 (n=2318) and 61\u201370 (n=1650) were selected from the 2008 and 2018 waves. No significant cohort differences were identified for life satisfaction or positive SPA . The 2008 cohort of midlife women reported significantly higher negative SPA compared to 2018 (p<.05). Linear regression analyses find that cohort and SPA are significantly associated with life satisfaction in both age groups, and that the association of negative SPA differs by cohort for the midlife women (p<.01). Implications are discussed within the life course developmental framework."} +{"text": "Tumour cells maintain a local hypoxic and acidic microenvironment which plays a crucial role in cancer progression and drug resistance. Urease is a metallohydrolases that catalyses the hydrolysis of urea into ammonia and carbon dioxide, causing an abrupt increase of pH. This enzymatic activity can be employed to target the acidic tumour microenvironment. In this study, we present the anticancer activities of urease mimetic cobalt (III) complexes on A549 cells. The cells were treated with different doses of cobalt (III) complexes to observe the cytotoxicity. The change in cellular morphology was observed using an inverted microscope. The cell death induced by these complexes was analysed through ATP proliferation, LDH release and caspase 3/7 activity. The effect of extracellular alkalinization by the cobalt (III) complexes on the efficacy of the weakly basic drug, doxorubicin (dox) was also evaluated. This combination therapy of dox with cobalt (III) complexes resulted in enhanced apoptosis in A549 cells, as evidenced by elevated caspase 3/7 activity in treated groups. The study confirms the urease mimicking anticancer activity of cobalt (III) complexes by neutralizing the tumour microenvironment. This study will motivate the applications of transition metal-based enzyme mimics in targeting the tumour microenvironment for effective anticancer treatments. The last few decades have seen an upsurge in cancer research. Many developments and milestones have been achieved in discovering compounds with effective anticancer therapeutic properties. Although a lot of such potent drugs such as doxorubicin and cisplatin were discovered several years ago and are still used clinically to treat different kinds of cancers; they are often limited by severe side effects on healthy cells ,2. RecenRecently, some researchers have focused on targeting the microenvironment surrounding tumour cells ,15,16,17Urease is widespread in nature and is present in various forms in several bacteria, fungi, and algae . It is c2\u00b76H2O , tris(2\u2013aminoethyl)amine , triethylaminetetramine , and urea were used as obtained. The complexes were prepared following literature methods Cl (III) and [Co(tren)Cl2]Cl (IV)) was measured from the culture media of the treated and untreated groups. 100 \u03bcL of the culture media was withdrawn from treated and untreated groups at fixed time intervals and the urease mimetic activity was measured using the urease activity kit from Merck Sigma-Aldrich, MAK120, following the protocol provided.The urease mimetic activity of the chloro complexes, (Cl (II) and [Co(trien)Cl2]Cl (III). The crystals were analysed by SC-XRD analyses and were found to be structurally similar to the initial compounds. The crystal structures are presented in 2]Cl was similar to the starting material, the [Co(tren)(NO2)2]Cl crystallised as a polymorph in a different space group. The most prevalent polymorph for this compound exists in orthorhombic space group (Pbca), and the only reported monoclinic form (A2) was isolated serendipitously Cl (IV) induced cleavage of urea into ammonia was reported by some of us recently. The increasing alkalinity was monitored spectrophotometrically with the aid of a pH dependent indicator, phenolphthalein Cl (IV) and [Co(trien)Cl2]Cl (III) were found to be slightly basic as compared to the other groups. This prompted us to measure the urease mimetic activity of the chloro complexes under treatment conditions. Therefore, confluent cells in culture dishes were treated with the optimised dose of the cobalt (III) complexes (32 \u03bcM) in the presence of urea (2 mM). The results were compared to cells treated with urea alone (2 mM) (untreated group) to negate any background absorbance that may arise due to the culture medium or urea. A total of 100 \u03bcL of the culture medium was withdrawn at fixed time intervals, and the urease mimetic activity was measured using the urease activity kit from Sigma Aldrich as per the protocol available with the test kit. The increase in absorbance at 670 nm at fixed time intervals for the cobalt treated groups was compared to the untreated group. The results are presented in 2]Cl (IV) and [Co(trien)Cl2]Cl (III) depicted a gradual increase in absorbance at 670 nm, and after 24 h of treatment, the absorbance, and hence the urease mimetic activity for [Co(tren)Cl2]Cl (IV) was significantly higher than [Co(trien)Cl2]Cl (III). Similar trends have been reported for catalytic studies as well [2]Cl (IV) performing better than [Co(trien)Cl2]Cl (III) for A549 cells.The ammonia generated because of urease mimetic activity in treatment groups was ascertained by pH measurements of the cell culture media after 24 h of treatment of A549 cells with the cobalt (III) complexes. Interestingly, the culture media from the cells treated with Cl (IV) and [Co(trien)Cl2]Cl (III) over 24 h complexes for MCF7 cells were completely surprising and conflicting. There was no appreciable change in absorbance at 670 nm for the cells treated with [Co(tren)Clver 24 h . The abs2]Cl (III) and [Co(tren)Cl2]Cl (IV) complexes outperformed other Co complexes (2)2]Cl (II) and [Co(trien)(NO2)2]Cl (I) complexes exhibit poor catalytic urease activity as well, owing to the strong affinity and poor lability of the nitro group towards cobalt [The WS1 cells in the control and treated groups were seen to be healthy with no significant difference observed in growth and proliferation . The LDHomplexes A. The [Cs cobalt .2]Cl (III) and [Co(tren)Cl2]Cl (IV), while the nitro complexes were dropped out. To ascertain the urease-like anticancer activity of the cobalt complexes, the cells were treated with the complexes alone and with the addition of urea. The resulting alkalinity of urease activity has been shown to enhance the activity of weakly basic anticancer drugs, such as doxorubicin. Such drugs\u2013enzyme combinations and conjugates are gaining increasing attention in recent times Cl (III) and [Co(tren)Cl2]Cl (IV))\u2013urea combination as well as the combinations with doxorubicin, induced profuse toxicity in cells and reduction of ATP. These findings further support our claim that urease mimetic activity of the cobalt complexes induces anticancer effects by facilitating doxorubicin action, as observed in the LDH assay. The results are presented in A similar trend was observed with ATP of WS1 and A549 cells. No significant ATP proliferation was observed in WS1 cells depicting the safety of complexes against normal cells ; howeverThe A549 cells which were incubated with the cobalt complexes alone and in combination with urea and doxorubicin for 24 h showed distinct morphology in a concentration dependent manner compared to the control. The cells showed signs of cell death, with deformed membrane integrity, losing inter-cellular contact, vacuolation, rounding of cells and detachment from the culture plates . The toxAs observed in LDH and ATP assays, cell viability significantly reduced in A549 cells on treatment with the cobalt complexes and the urea and doxorubicin combinations . The celIII and IV) in combination with urea and doxorubicin. The luminescent signals elevated in these groups compared to control and authenticate the role of caspases in inducing cell death complexes towards cancer cells. Such altering of the microenvironment can also be manipulated to enhance the activity of weakly basic drugs. Under acidic conditions, basic drugs, such as doxorubicin, tend to sequester in the acidic extracellular environment, thus failing to diffuse into the hydrophobic cell membrane. This often results in loss of therapeutic activity and drug resistance. In this study, we report a combination therapy of the cobalt (III) complexes with doxorubicin. The combination is proposed to be working synergistically, wherein the cobalt (III) complexes hydrolyse urea to generate ammonia, thus neutralizing the acidity in the tumour microenvironment. This subsequently, enhances the diffusion of doxorubicin into the cells, thereby, improving the overall cytotoxic activity. The cobalt complexes do not directly target the cancer cells; rather, they act on the extracellular microenvironment, disrupting the physiological factors that enable tumour growth. Thus, they exert a target specific cytotoxic action controlled by the surrounding pH. This can also be attributed to the low toxicity of the complexes towards normal cells that operate under strictly controlled pH conditions. To further confirm the mechanism of apoptotic action, caspase 3/7 expression was determined in treated groups. Even though the cell death stimulus induced by caspase 3 and 7 differs, they are yet considered universal executioner caspases ,53,54. AUrease activity was long viewed as detrimental, and research was mainly focused on inhibiting the enzyme\u2019s activity; however, the undesirable urease activity can be utilized to neutralize the acidity in tumour microenvironments, thereby leading to enhanced therapeutic efficiency. We have presented the preliminary results of the cytotoxicity induced by urease mimetic cobalt (III) complexes on lung cancer cells. The cytotoxicity results correlate well with the observed urease mimetic activity. The complexes reported in this study are found to be nontoxic towards normal cells, making them an ideal drug candidate for treating cancer cells. To further understand the application of these complexes as anticancer drugs, their dose responses on MCF-7 and HKESC-1 were also studied. With moderate toxicity on MCF-7 but commendable action against HKESC-1 cells, it can be concluded that the active complexes (III and IV) were not cell line specific and further research is warranted to understand the reason behind these specificities. Moreover, synthetic enzyme mimics based on transition metal complexes serve several advantages over the actual enzyme; they are robust, with long shelf life, and often can greatly reduce the cost of manufacturing. The urease, like the action of the cobalt (III) complexes, also improves the therapeutic activity of weakly basic drugs, such as doxorubicin, by inducing apoptosis as seen by the expression of caspase3/7 in treated groups; however, the conflicting results obtained with MCF7 cell lines warrant further investigation using in vivo and clinical models. The concept introduced in this article is worthwhile and deserves further investigation."} +{"text": "ABSTRACT IMPACT: Being explicit about the prevention of falls throughout an older adults\u2019 episode of care may further help reinforce the role of physical therapy providers in falls prevention and improve dissemination of this knowledge. OBJECTIVES/GOALS: The purpose of this study was to determine older adults\u2019 awareness of and perspectives about the role of physical therapy providers for falls prevention and determine potential barriers and facilitators to utilization of preventive rehabilitation services METHODS/STUDY POPULATION: We used a qualitative descriptive phenomenological approach to emphasize participants\u2019 perceptions and lived experiences. Four focus groups were conducted with 27 community-dwelling older adults (average age = 78 years). Focus groups were recorded, transcribed, condensed, and coded using thematic analysis. RESULTS/ANTICIPATED RESULTS: Surveys indicated 37% of participants experienced a fall in the last year and 26% reported suffering an injury. Four main themes and six subthemes surrounding older adults\u2019 perceptions of physical therapy providers\u2019 roles for falls prevention emerged: (1) Awareness of Falls Prevention ; (2) Being Able to Get Up from the Floor; (3) Limited Knowledge about the Role of Physical Therapy Providers in Falls Prevention ; and 4). Barriers to Participating in Preventive Physical Therapy Services . DISCUSSION/SIGNIFICANCE OF FINDINGS: Older adults lack awareness about the role of physical therapy services in falls prevention, perceiving services are only to treat a specific problem or after a fall. Physical therapists should be explicit about the role of physical therapy in falls prevention for all older adults undergoing rehabilitation, regardless of the reason."} +{"text": "Using whole-genome sequencing and combining genome sequence data derived from national surveillance databases, we identified additional emm12 GAS clones similar to those associated with prior SF outbreaks, emphasizing the need for continued surveillance for epidemic emergence in the USA.Scarlet fever (SF) has recently been associated with group A streptococcal (GAS) strains possessing multidrug resistance and specific streptococcal exotoxins. We screened a local surveillance collection of GAS All raw genome sequences generated in this study are publicly available from the National Center for Biotechnology Information (NCBI) under BioProject accession number PRJNA608028. In addition, sequences from BioProjects PRJNA471864, PRJNA395240, PRJNA416675, PRJEB2675 and PRJNA13551 were used in comparative phylogenomics analysis, as indicated in Streptococcus (GAS) was an important cause of morbidity and mortality in children during the 19th and early 20th centuries [emm type 12 (emm12) and harbour two mobile genetic elements (MGE): an integrative and conjugative element (ICE-emm12) encoding tetracycline and macrolide resistance and a prophage (\u03d5HKU.vir) encoding two exotoxins (SSA and SpeC) and the DNase Sda1 [emm12 SF clone [emm12 SF outbreaks have been identified in additional emm types, including emm1 GAS strains [emm12 background to enhance colonization in a mouse model [emm12 clones is warranted, given their persistence in multiple outbreaks.Epidemic scarlet fever (SF) caused by group A ase Sda1 . SubsequSF clone . MGE ass strains . Several strains . Most reemm12 isolates. Molecular typing of GAS isolates from January 2013\u2013July 2018 was performed to determine emm type. A total 300 emm12 GAS isolates were identified and underwent antimicrobial susceptibility testing to tetracycline and erythromycin using disc diffusion [emm12 isolates (n=22) and any isolate resistant to both erythromycin and tetracycline using an Illumina MiSeq (300\u2009bp PE). Raw sequencing reads were assembled using SPAdes and queried for the presence of exotoxin, DNase and resistance genes using a custom algorithm as previously described [emm12 strains (n=22) and previously sequenced emm12 GAS strains from the Centers for Disease Control and Prevention (CDC) Active Bacterial Core Surveillance (ABCs) , Hong Kong/PR China and the UK see .emm12 GAS isolates from Houston, TX screened for antimicrobial resistance, a total of 14 (5\u200a%) were identified with resistance to erythromycin or tetracycline and a single isolate (TSPY1687 \u2013 pharyngitis from 2018) was identified to be resistant to both antibiotics. Consistent with previous reports on GAS [emm12 GAS isolates sequenced by the CDC ABCs and discovered three additional isolates with erythromycin and tetracycline resistance genes demonstrated a close relationship of all four US isolates to groups of strains from previous SF outbreaks in Hong Kong and PR China and tet(M), and differed by a single prophage that was devoid of any exotoxin or DNase genes and emm1 (17.1\u200a%) lineages [emm12 GAS strains similar to the original outbreak strains in Asia [emm12 GAS strains more closely related to those from the UK were identified in Australia [emm12 SF-like clone in the USA using our local GAS strain surveillance and shown additional clones circulating within the US population using publicly available national surveillance databases. SF is a notifiable disease in many Asian countries and the UK but not the USA. Interestingly, none of the four emm12 SF-like clones identified in our study were derived from SF cases. TSPY1687 was isolated following a case of pharyngitis in an 8-year-old child in 2018 but lacked rash or other symptoms (e.g. strawberry tongue) associated with SF. Likewise, the three CDC ABCs emm12 SF-like strains were from cases of invasive disease in 2015 but at opposite ends of the country . Unlike in our local surveillance, we are unable to further query electronic medical records for additional signs and symptoms in the CDC ABCs cases. Inasmuch as GAS whole-genome sequencing analyses have shown that invasive strains are derived from the population of pharyngeal strains [emm12 SF clones in the US population. At this time, it is unclear if more robust prospective surveillance for GAS pharyngitis would identify additional cases in the USA. Alternatively, it is also possible that the small number of emm12 SF-like clones identified in our analysis represent individual importation events from outbreak regions. Importantly, our data confirm a worldwide spread of emm12 SF clones and suggest that additional factors apart from GAS strain contribute to the development of SF. In summary, our findings emphasize the role of GAS surveillance, antimicrobial susceptibility profiling and heightened awareness of possible SF in Houston and the USA.A rapid rise in the incidence of SF in the Republic of Korea, PR China and Hong Kong marked the beginning of an epidemic in Asia. Extensive surveillance identified GAS strains of primarily emm12 76.\u200a% and em in Asia . Most reustralia . We have strains , our finClick here for additional data file."} +{"text": "Here, we present the results from a population study that evaluated the performance of massively parallel sequencing (MPS) of short tandem repeats (STRs) with a particular focus on DNA intelligence databasing purposes. To meet this objective, 247 randomly selected reference samples, earlier being processed with conventional capillary electrophoretic (CE) STR sizing from the Austrian National DNA Database, were reanalyzed with the PowerSeq 46Y kit (Promega). This sample set provides MPS-based population data valid for the Austrian population to increase the body of sequence-based STR variation. The study addressed forensically relevant parameters, such as concordance and backward compatibility to extant amplicon-based genotypes, sequence-based stutter ratios, and relative marker performance. Of the 22 autosomal STR loci included in the PowerSeq 46GY panel, 99.98% of the allele calls were concordant between MPS and CE. Moreover, 25 new sequence variants from 15 markers were found in the Austrian dataset that are yet undescribed in the STRSeq online catalogue and were submitted for inclusion. Despite the high degree of concordance between MPS and CE derived genotypes, our results demonstrate the need for a harmonized allele nomenclature system that is equally applicable to both technologies, but at the same time can take advantage of the increased information content of MPS. This appears to be particularly important with regard to database applications in order to prevent false exclusions due to varying allele naming based on different analysis platforms and ensures backward compatibility.The online version contains supplementary material available at 10.1007/s00414-021-02685-x. Throughout the past decades, short tandem repeat (STR) loci have become the most important genetic markers in forensics. They can be analyzed at a reasonable cost/time ratio and provide high enough statistical discrimination power to identify individuals in the majority of crime and human identification cases . TraditiHere, we evaluated the performance of an MPS-based STR-typing system consisting of the PowerSeq 46GY panel analyzed on a MiSeq FGx sequencer for DNA intelligence databasing purposes using a random subset of the Austrian National DNA Database as an example. The PowerSeq 46GY kit includes all loci required for national and international DNA intelligence databasing in the United States and Europe. We evaluated concordance and backward compatibility to extant CE-based genotypes, stutter display, and heterozygote balance and provide new population data to increase the body of STR variation that is currently being collected and catalogued in various environments e.g., , 10)..10]).All 248 buccal swab reference samples included in this study derived from the Austrian National DNA Database in accordance with the Austrian Data Protection regime. They were analyzed in line with Austrian legislation and with permission of the Austrian Federal Ministry of the Interior. Legal requirements with respect to sample storage as well as the permission to go back to DNA extracts for re-testing are regulated by the Austrian Federal Security Police Act, which also contains specific legal provisions for scientific purposes to provide biometric data, including DNA data, in anonymized form to universities for research. The samples were randomly selected by executive authorities of the Austrian Federal Ministry of the Interior. The selection criteria were based on male sex, Austrian nationality, and birthplaces. The samples were made anonymous to the analyzing laboratory by using barcode information.DNA was extracted from buccal swab samples using the Chelex 100 method , and stoTo determine the amount of genomic DNA, a real-time quantitative PCR (qPCR) assay targeting specific AluYb8 sequences was used . A spikeSTR analysis was performed using the AmpFlSTR NGM SElect Express kit (TFS) and the The PowerSeq 46GY kit (Promega) was used to co-amplify 22 aSTRs , 23 Y-STRs (data not shown), and amelogenin. This extended STR panel aims to target forensic markers to comply with the European Standard Set (ESS) deletion Supplementary file2 (PDF 134 KB)Supplementary file3 (PDF 96 KB)Supplementary file4 (PDF 175 KB)Supplementary file5 (PDF 174 KB)Supplementary file6 (PDF 138 KB)Supplementary file7 (PDF 122 KB)Supplementary file8 (XLSX 1015 KB)Below is the link to the electronic supplementary material."} +{"text": "Tuberous sclerosis, angiomyolipoma and lymphangioleiomyomatosis are a group of diseases characterized by mutation in tuberous sclerosis genes (TSC 1-2). TSC mutation leads to continuous activation of the mTOR pathway that requires adaptation to increased ATP requirement. With limited treatment options, there is an increasing demand to identify novel therapeutic targets and to understand the correlations between mTOR pathway activation and the lack of cell death in the presence of TSC mutation. In the current study, we demonstrate deregulation of p53 controlled and mitochondria associated cell death processes. The study also reveals that treatment of TSC mutant cells with the drug candidate Proxison combined with reduced concentration of rapamycin can increase production of reactive oxygen species (ROS), can modify miRNA expression pattern associated with p53 regulation and can reduce cell viability.The online version contains supplementary material available at 10.1007/s10495-021-01670-4. RecentlIn a previous study of lymphangioleiomyomatosis (LAM) TSC mutaTSC mutations are particularly disruptive in the phosphoinositide 3 kinase (PI3K)/Protein kinase B (PKB or AKT)/mTOR pathway, as the mTOR pathway is inhibited by the complex of two proteins Hamartin (TSC1) and Tuberin (TSC2). Mutation in the TSC genes allows continuous activation of mTOR resulting in slow growing neoplasms . The mTOBased on the above we theorized that investigation and modulation of p53 and mitochondrial function associated cell death pathways might provide a better understanding of the molecular background of TSC mutation induced diseases and the results might lead to identification of additional targets for therapy.Materials and methods are detailed in the Supplementary material . Briefly, LAM tissue samples were obtained from lung transplant donors for generation of cell lines . ParaffimTOR is downstream of the PI3K and AKT enzymes that transduce signals from growth factor activated receptor kinases . To inveTo understand the significance of the results, a linear regression-based prediction algorithm analysis was usedTo confirm that deregulation of the pro- and anti-apoptotic pathways are not a unique feature of the AML derived S102 cell line, 4 primary LAM tissue derived cell lines in TSC2 mutant cell lines revealed a distortion in the pro- and anti-apoptotic balance. The cell death processes are blocked in TSC mutant cells despite p53 activation combined with the drug candidate Proxison (3\u00a0\u00b5M) can result in cell death. Although further studies are required, combined inhibition of the mTOR pathway and TRXR can potentially lead to a more effective therapy.Supplementary file1 (DOCX 7450 kb)Below is the link to the electronic supplementary material."} +{"text": "The purpose of this study was to generate a selective radiosensitising effect by the intra-hepatic-arterial infusion of misonidazole (MISO). MISO (10 mg) was infused after transcatheter hepatic-arterial embolisation into the livers of rabbits bearing VX2 liver cancer. This procedure was followed by 15 Gy electron irradiation. Evaluation of tumour volume and histological examination was carried out on the 7th day after treatment. The greatest tumour response was obtained in the group which received MISO followed by radiation and was characterised by extensive fibrosis around the tumour and nearly complete tumour necrosis. Liver cell regeneration was also noted in adjacent liver tissue. The advantages of regional infusion of MISO following hepatic-arterial embolisation are: (1) Selectivity increased radiosensitivity of liver cancer alongside very low drug concentration in the plasma. (2) Reduced or absent deleterious side effects of MISO with higher tumour/normal tissue ratios of drug concentration. (3) Reduced cost due to the lower dosage of MISO required for regional infusion."} +{"text": "ABCB4 mutations and low biliary phospholipid concentration with symptomatic and recurring cholelithiasis. This syndrome is infrequent and corresponds to a peculiar small subgroup of patients with symptomatic gallstone disease. The patients with the LPAC syndrome present typically with the following main features: age less than 40 years at onset of symptoms, recurrence of biliary symptoms after cholecystectomy, intrahepatic hyperechoic foci or sludge or microlithiasis along the biliary tree. Defect in ABCB4 function causes the production of bile with low phospholipid content, increased lithogenicity and high detergent properties leading to bile duct luminal membrane injuries and resulting in cholestasis with increased serum gamma-glutamyltransferase (GGT) activity. Intrahepatic gallstones may be evidenced by ultrasonography (US), computing tomography (CT) abdominal scan or magnetic resonance cholangiopancreatography, intrahepatic hyperechogenic foci along the biliary tree may be evidenced by US, and hepatic bile composition (phospholipids) may be determined by duodenoscopy. In all cases where the ABCB4 genotyping confirms the diagnosis of LPAC syndrome in young adults, long-term curative or prophylactic therapy with ursodeoxycholic acid (UDCA) should be initiated early to prevent the occurrence or recurrence of the syndrome and its complications. Cholecystectomy is indicated in the case of symptomatic gallstones. Biliary drainage or partial hepatectomy may be indicated in the case of symptomatic intrahepatic bile duct dilatations filled with gallstones. Patients with end-stage liver disease may be candidates for liver transplantation.Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of Low phospholipid associated cholelithiasisABCB4 gene mutationCholelithiasis with ABCB4 gene mutation-associated cholelithiasisABCB4 mutations with symptomatic and recurring cholelithiasis in young adults (e.g. <40 years).Low phospholipid-associated cholelithiasis (LPAC) is characterized by the association of ABCB4 mutations in the whole population of patients with cholelithiasis.The exact prevalence of LPAC remains unknown. The disease is more common in young adults, the usual age at the onset of the symptoms is typically lower than 40 years. The male to female ratio is estimated at approximately 1:3. However, at present, the literature data and our results did not allow to determine the frequency of Up to 10% of the European and American population carry gallstones, approximately 25% of cases have symptoms and less than 2% present with severe complications (cholangitis or pancreatitis). Based on previous epidemiological data, we consider that LPAC syndrome is infrequent and corresponds to a peculiar subgroup of patients with symptomatic gallstone disease [LPAC presents as a peculiar form of cholelithiasis characterized by cholecystitis, cholangitis and intrahepatic gallstone disease, and/or acute pancreatitis associated with biliary microlithiasis. Most patients report a history of cholesterol gallstones amongst their first-degree relatives. Intrahepatic hyperechoic foci are characteristic sign of the LPAC syndrome. Intrahepatic gallstones or sludge and increased serum gamma-glutamyl transferase (GGT) activity are frequently present. It suggests that the biliary symptoms experienced by these patients are probably caused by cholesterol crystal deposits and bile duct inflammation but not directly and exclusively related to the presence of detectable gallstones. Increased cholesterol saturation index and a defect in the hepatic transport and biliary secretion of phospholipids in patients with an intrahepatic cholesterol gallstone disease or an acute pancreatitis associated with biliary microlithiasis have been shown in another studies ,4.ABCB4 mutations presented also with an history of intrahepatic cholestasis of pregnancy and 14% had fetal complications) [The typical biliary pain in patients with LPAC syndrome often leads to decision of cholecystectomy. The majority of patients is our series (90%) underwent cholecystectomy but recurrence of the symptoms was observed in half of them, despite cholecystectomy . The onscations) . Prophylcations) . Of noteMDR3 (now referred to as ABCB4) gene, the phosphatidylcholine translocator across the canalicular membrane, are thought to be responsible for progressive intrahepatic cholestasis type 3 (PFIC 3) [Phospholipids are the major carrier and solvent of cholesterol and they exert a protective effect against bile salt-induced biliary mucosa injury. Homozygous and heterozygous mutations in the (PFIC 3) , and het(PFIC 3) -11. DefeABCB4 gene mutations in 60 consecutive adult patients who had been referred to our liver unit because of symptomatic or complicated cholelithiasis and we characterized more precisely the clinical phenotype associated with these mutations [ABCB4 gene analysis because of clinical history compatible with the syndrome that we previously described . Multivariate analysis showed that among patients with cholelithiasis three independent factors were predictive of a mutation at the ABCB4 locus: a recurrence of symptoms after cholecystectomy (adjusted OR = 8.5), intrahepatic hyperchoic material (adjusted OR = 6.1), and age <40 years (adjusted OR = 3.0) [Among the 32 patients suspected of having the syndrome, 18 presented a point mutation at the Finally, more recent data shows that the LPAC syndrome is more frequent in females and that biliary symptoms occur earlier in female who present a nonsense mutation .ABCB4 gene using polymerase chain reaction (PCR) amplification and DNA sequencing of exons 2 to 28 and all splice junctions. We identified 14 heterozygous and homozygous point mutations amongst these 18 patients. None of these mutations was detected in a control panel of 140 chromosomes demonstrating that they did not correspond to polymorphisms (SNPs). Affected patients with heterozygous mutations exhibited 1bp-insertion, 1bp-deletion, nonsense mutations or missense mutations resulting in a frameshift predicted to cause premature messenger RNA termination, a loss of protein function and single-nucleotide substitutions, while affected patients with homozygous mutations demonstrated only missense mutations. Most mutations were localized in the central part of the molecule, close to nucleotide binding domain 1 (NBD1), or in adjacent transmembrane domains and intracellular loops .Patients were screened for mutations in the st intracellular loop and resulted in a substitution in a conserved cluster of four amino-acids at position 169\u2013172, required for the adenosine triphosphatase activity of the molecule. This mutant resulted in a complete loss of drug-induced P-gp ATPase activity. The Phe165Ile mutation was localized in the same part of this intracellular loop and may therefore give rise to a similar defect. The Glu528Asp mutation was localized close to the NBD1. The glutamic acid is included in a small amino-acid cluster localized before the walker B motif which is required for drug-induced ATPase activity. These mutations indeed induced a loss of function of the molecule in vitro. It should be noted that the two unrelated patients in whom the Thr175Ala mutation was identified originated from Northern Europe, so they may have inherited a founder mutation from a shared ancestor. This mutation has also been recently identified in adults with cholangiopathy and intrahepatic cholestasis of pregnancy [The definition of a disease-causing mutation (DCM) is problematic when functional assays to determine the phenotypic effects of specific variants are not available or have not been performed. To date, two of the missense mutations (Glu528Asp and Thr175Ala) detected in patients with the LPAC syndrome had been analyzed previously in a homolog of ABCB4 in yeast ,14. The regnancy . The mutregnancy .ABCB4 sequence alterations leading to predicted premature truncation of the protein, small deletions or insertions and non-conserved missense mutations were considered as potential DCMs. Even if this restriction was taken into account, a certain number of arguments strongly supported a pathogenic role for ABCB4 gene mutations. These mutations are indeed detected at high frequency in patients with LPAC syndrome; they affect only highly conserved amino acids between human and rodent homologues of the gene and no mutation was detected in an independent control panel of 140 chromosomes. In addition, LPAC syndrome was observed in patients exhibiting the same or similar nonsense or missense mutations: in a mother and her elder son with an identical heterozygous nonsense mutation (1327insA); in independent patients from non-consanguineous families with the same homozygous missense mutation (Ser320Phe or Ala934Thr), while their heterozygous parents were asymptomatic; in patients with a similar nonsense mutation (1006-1016insT and 1006-1016delT) and in unrelated patients with the same missense mutations (Pro1161Ser). For all these reasons, these mutations could be considered as causing the LPAC syndrome.Only ABCB4 mutations may lead to cholesterol cholelithiasis when residual ABCB4 activity and subsequent biliary phospholipid secretion fall below a critical threshold which may depend on the type of mutation and on other host or environmental factors, including probably bacterial infection of the bile ducts .These results and data in the literature therefore strongly suggest that ABCB4 gene point mutation, defects in the promoter region or large DNA rearrangements might also be involved in some patients presenting with LPAC syndrome. Alternatively, defects in other regions of the gene or in other genes may also be involved, and some evidence from animal studies has pointed to Abcb 11 , Abcc 2 or Abcg5/Abcg8 as other possible candidate genes underlying susceptibility to cholelithiasis [The mutation screening method used in our two studies was unable to detect major DNA rearrangements, and nor did the analysis include the promoter or other potential regulation regions of the gene. As 44% of LPAC patients did not present ithiasis -19 or phithiasis .in vitro to enhance cholesterol crystallization. This mechanism explains the early and higher prevalence of gallstones in female Mdr2 -/- mice and provide a rationale for substitution of more hydrophobic bile salts with ursodeoxycholic acid in LPAC patients [It has also been shown that substantial amounts of cholesterol are secreted by Mdr2 (-/-) mice on a cholate-supplemented diet and microscopic examination of the gallbladder reveals massive amount of cholesterol crystals and that after 12 weeks, 50% of the Mdr2 (-/-) mice on chow also developed gallstones composed of needlike \"anhydrous\" cholesterol crystals and mucin ,22. Indepatients .ABCB4 gene mutations and sequence diversity in 34 consecutive patients with primary sclerosing cholangitis. We found no ABCB4 gene mutations and no abnormal SNP frequency in these unselected PSC patients [ABCB4 from that observed in healthy Caucasian controls [ABCB4 genetic variation in the pathogenesis of the PSC, although an implication of ABCB4 cannot be ruled out in a subgroup of these patients.As a recent study reported that Mdr2 KO mice develop liver lesions mimicking sclerosing cholangitis characterized by biliary strictures and dilatations , we alsopatients . These dcontrols . Thus, tCholesterol cholelithiasis was also demonstrated in patients with progressive familial intrahepatic cholestasis-3 (PFIC3) and some of their relatives ,26, and etc.) should remind of this rare monogenic form of cholelithiasis (e.g. LPAC syndrome) for which genetic testing may be offered by several genetic laboratories.In patients with symptomatic cholelithiasis, the presence of additional hepatobiliary manifestations , computing tomography (CT) abdominal scan or magnetic resonance cholangiopancreatography;\u2022 Intrahepatic hyperechogenic foci along the biliary tree by US;\u2022 Hepatic bile composition ;ABCB4 gene analysis.\u2022 Other inflammatory bile duct diseases which may lead to biliary symptoms and/or intrahepatic gallstones .ABCB4 genotyping should be used to confirm the diagnosis of LPAC syndrome in young adults who present with a symptomatic cholelithiasis and should allow familial screening.ABCB4 genotyping confirms the diagnosis of LPAC syndrome in young adults, long-term curative or prophylactic therapy with UDCA should be initiated early to prevent the occurrence or recurrence of the syndrome and its complications. UDCA was shown to up-regulate the expression of the protein at the canalicular membrane, minimize the toxicity of the endogenous hydrophobic bile acids and increase the pool of protective hydrophilic bile acids.Special diet is not required. In all cases where the In the case of associated hypercholesterolemia, statins should be preferred to fibrates which increase the lithogenicity of the bile.Cholecystectomy is indicated in the case of symptomatic gallstones but not when only sludge is present in the gallbladder.Biliary drainage or partial hepatectomy may be indicated in the case of symptomatic intrahepatic bile duct dilatation filled with gallstones.Patients with end-stage liver disease may be candidates for liver transplantation.Drugs that may induce ABCB4 expression.Typically, the clinical course is progressive, with multiple recurrence despite the operative intervention(s) until UDCA treatment is started.The majority of patients with LPAC syndrome described in the literature do not develop recurrence or end-stage liver disease under medical treatment.ABCB4 gene defect in LPAC syndrome and replace it in the context of ABCB4 gene-associated liver diseases in adults including attenuated form of PFIC 3, \"atypical intrahepatic cholestasis of pregnancy\", LPAC syndrome which might lead to adulthood biliary cirrhosis or bile duct dilatations associated with gallstones. A genetic test based on the present results may permit the molecular diagnosis of LPAC syndrome and the screening of high-risk subjects. Depending on the results, long-term curative or prophylactic UDCA therapy may be initiated early to prevent the occurrence or recurrence of this syndrome and its severe complications.In summary, our results strongly support the role of an"} +{"text": "Exogenous purines M) can modulate the cytotoxicity of methotrexate (MTX) in cultured cells, protecting cells at low MTX concentrations M) and markedly potentiating its effect at higher concentrations. The ability of hypoxanthine (HX) to modulate the effects of two antifolates-ICI 198583 (an inhibitor of thymidylate synthetase) and piritrexim -was investigated using cultured mouse leukaemic cells, L1210. HX (10(-4) M) was found to potentiate only the cytotoxicity of DHFR inhibitors (MTS and PTX), increasing cell kill by 20-70 fold to the level achieved by an equivalent concentration (10(-5) M) of ICI 198583 alone. Agarose gel electrophoresis of DNA extracted from cells exposed to antifolates for 24 h demonstrated that the chromatin was cleaved into multimers of 200 base pairs. This pattern of DNA cleavage indicates cell death via apoptosis. The degree of DNA fragmentation was found to be closely linked to cytotoxicity. DNA fragmentation increased from 50% in cells treated with 10(-5) M MTX or PTX to 70% when HX was added with the drugs, a level achieved by 10(-5)M ICI 198583 alone. HX potentiation of cytotoxicity was correlated with a substantial increase in dATP in conjunction with low dTTP pools. The specific potentiation of DHFR inhibitors by HX may be due to their inhibition of purine synthesis with a concurrent rise in PRPP levels. Addition of HX with MTX substantially raised intracellular purine levels via the salvage pathway as indicated by ribonucleotide pool measurements. ICI 198583, on the other hand, stimulated de novo purine synthesis with or without added HX. Treatment with MTX plus HX or ICI 198583 (with or without HX) caused a reduction of dTTP pools to 8% of untreated control and excess dATP accumulation. The subsequent elevation (to 300% of control) of the dATP pool may provide a signal for endonucleolytic fragmentation of DNA and subsequent cell death."} +{"text": "Eighty-four patients with breast cancer at high risk of bone metastases were investigated with magnetic resonance imaging (MRI) of the thoracolumbar spine. Of 58 patients with normal limited skeletal surveys (LSS) and bone scans (BS), 4 (7%) had MR images compatible with malignant infiltration. Fourteen patients had abnormal bone scans with normal or non-diagnostic plain films; 7 of these patients (50%) had MR images compatible with malignant infiltration. Twelve patients had single or multiple wedge collapses of uncertain aetiology on plain film; MR demonstrated metastatic disease as the cause of wedge collapse in 7 (58%). MRI may define a group of patients with extra-osseous relapse who have occult metastatic disease. Although the detection rate in patients with primary breast cancer is low (4/45), MRI is of value in determining the cause of wedge collapse in postmenopausal women with breast cancer and may elucidate the cause of an abnormal bone scan with normal or non-diagnostic plain films."} +{"text": "Between January 1991 and December 1992 a phase I trial of superficial photodynamic therapy (PDT) using topical application of 5-aminolaevulinic acid (ALA) was undertaken to treat Bowen's disease, superficial basal cell carcinomas (BCCs) and metastatic skin secondaries from breast (adenocarcinoma) or pinna (squamous cell carcinoma). Promising results were obtained with 36 areas of Bowen's disease, with a complete response rate of 89% at a median follow-up of 18 months. The treatment of BCCs was less successful, with 50% complete responses in 16 lesions at a median follow-up of 17 months. Metastatic nodules responded poorly. The treatment was well tolerated and discomfort during light irradiation could be reduced by prior application of 'Emla' cream. Lesions wept for 1-2 weeks following treatment and healed over a period of approximately 2 months. For large areas of Bowen's disease, particularly in anatomically difficult areas and in elderly patients, PDT using ALA may constitute a single simple alternative outpatient treatment to existing therapies. Further work is required to improve the results with BCCs."} +{"text": "The oncogenicity of Duck hepatitis B virus (DHBV) is unclear since hepatocellular carcinomas (HCCs) have been reported only in domestic ducks in Qidong, an area of China where hepatitis B virus (HBV) and aflatoxin B1 (AFB1) are risk factors for liver cancer in man. In order to better define the association between DHBV infection, AFB1 and HCC we analysed a series of 16 duck liver samples collected from local farms in Qidong. HCC was found in eight and cirrhosis in one of these samples. Furthermore bile duct proliferation, characteristic of AFB1 exposure in ducks and other animal species, was found in these ducks. Integration of DHBV DNA into cellular DNA was observed in only one out of four DHBV positive HCCs, indicating that viral integration is not prerequisite for tumour development. In four remaining HCCs the polymerase chain reaction (PCR) failed to show any DHBV DNA suggesting that liver tumours do occur in polymerase chain reaction (PCR) failed to show any DHBV DNA suggesting that liver tumours do occur in these ducks in the absence of DHBV infection. In addition, AFB1-DNA adducts were detected by hplc-immunoassay in one such DHBV-negative tumour. In summary we demonstrate that risk factors other than DHBV, including AFB1 exposure, may be important in duck liver carcinogenesis in Qidong."} +{"text": "Electrophoretic isoenzyme separation provides much more precise information than measurement of alkaline phosphatases (AP). Use of this technique for 83 patients with Hodgkin's disease revealed that the presence of the alpha 1 fraction was very significantly correlated with the stage of disease extension (P less than 0.01) and above all with the presence of general symptoms (P less than 0.001). Repeat measurements performed during patient follow-up demonstrated a close association between presence of alpha 1 AP and existence of progressive disease. While the mechanism of appearance of this abnormal alpha 1 AP fraction is not linked to Hodgkin-specific liver lesions, this test provides much more interesting data than classical measurement of total alkaline phosphatases (TAP)."} +{"text": "For the exceptional self-renewal capacity, regulated cell proliferation and differential potential to a wide variety of cell types, the stem cells must maintain the intact genome. The cells under continuous exogenous and endogenous genotoxic stress accumulate DNA errors, drive proliferative expansion and transform into cancer stem cells with a heterogeneous population of tumor cells. These cells are a common phenomenon for the hematological malignancies and solid tumors. In response to DNA damage, the complex cellular mechanisms including cell cycle arrest, transcription induction and DNA repair are activated. The cells when exposed to cytotoxic agents, the apoptosis lead to cell death. However, the absence of repair machinery makes the cells resistant to tumor sensitizing agents and result in malignant transformation. Mismatch repair gene defects are recently identified in hematopoietic malignancies, leukemia and lymphoma cell lines. This review emphasizes the importance of MMR systems in maintaining the stem cell functioning and its therapeutic implications in the eradication of cancer stem cells and differentiated tumor cells as well. The understanding of the biological functions of mismatch repair in the stem cells and its malignant counterparts could help in developing an effective novel therapies leaving residual non-tumorigenic population of cells resulting in potential cancer cures. Gurdon first introduced the concept of stemness state of the cells while successfully achieving the generation of all cell lineages of a living tadpole after transferring the nuclei from intestinal epithelial cells of feeding Xenopus tadpoles to activated enucleated eggs ,2. TheseThe multipotency of stem cells to maintain tissue homeostasis and its differentiation into mature cell types is under a tightly controlled system and is associated with restricted expression profile. The expression of transport proteins \u2013 ABC (ATP-binding cassette) transporter proteins and multidrug resistant proteins that protect cells against toxins and are associated with the efflux of xenobiotic toxins, low rate of cell division and active DNA repair are the innate properties of normal development of stem cells. Besides hormonal stimulation, DNA damage is one of the key factors for stem cell activation. DNA accumulates errors either from environmental factors, which could be the exposure to radiation, chemicals or drugs, viruses and bacteria or DNA replication errors . This woCancer stem cells (CSCs) were first identified in 1990s in hematological malignancies, mainly acute myelogenous leukemia (AML) and also in other subtypes like AML M0, M1, M2, M4 and M5 and chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL) and multiple myeloma . CSCs arIn the hematopoietic and solid tumors side population (SP) containing CSCs constitute the fraction of total population of cells that shows that CSCs is a common phenomenon for all the malignancies. SP can be identified by the efflux of fluorescent dyes by ABC transporter proteins which are the major multidrug resistant genes. In the absence of DNA repair capacity, the drug resistant pluoripotent cells accumulate mutations and show increased cell survival .To maintain the genomic integrity and normal functioning of stem cells, several DNA repair pathways come into interplay and provide the robust defense to the cell. Absence of these repair processes have a great impact on the diminution of stem cells and increased chance for stem cell differentiation and malignant transformation due to altered gene expression.AGT repair is a DNA repair protein encoded by MGMT (O6-methylguanine DNA methyltransferase) removes DNA adducts from O6 methylguanine. The failure in the repair system results in G to A transition and DNA strand break observed in hematopoietic tumors, breast, ovarian and retinoblastomas ,14.In NER, the damaged DNA bases are recognized by XPC (xeroderma pigmentosum complementation group C) and RAD23B whereas XPA, RPA (replication protein A), RNA polymerase II transcription factor 11A and XPG excise the fragment of 27\u201330 nucleotides surrounding the damaged bases. The gap is further restored by DNA polymerases and ligases and replaces it with the correct sequence. Defective NER leads to xeroderma pigmentosum (skin cancer) .It comprises of short and long patch pathways where DNA glycosylases generate apurinic/apyrimidinic (AP) followed by its 5' excision by AP endonucleases (APE-1) and remove damaged bases. Double-stranded breaks have the potential to be the most disruptive form of DNA damage ,17.Double-stranded breaks have the potential to be the most disruptive form of DNA damage. The DNA double strand breaks (DSBs) produced by free radicals generated during oxidative respiration, ionizing radiation, DNA replication, malfunction of recombination activating gene complex during V(D)J recombination in T and B lymphocytes are brought in closed proximity by Ku70-Ku80 heterodimer and kinase activity by DNA dependent protein kinase catalytic subunit (DNA-PKcs) of DNA-PK complex followed by its ligation by XRCC4-DNA ligase IV, SCID (Severe Combined Immunodeficiency) is associated with defective NHEJ repair system .The DSBs are repaired by misalignment, deletions, and rearrangement. ATM, a PI-3 Kinase binds DNA and phosphorylates multiple proteins. BRCA1 activated by ATM (ataxia telangiectasia) facilitates BRCA2 and RAD51 binding of the overhang followed by the attraction of RAD52/RAD54 with the help of BLM/WRN proteins. The homologous recombination is facilitated by large protein complexes at the DSBs. High incidence of leukemia, breast-ovarian, Werner's and Bloom's syndrome with severe premature aging and cancer is seen in defective HR repair system ,19.It is a genome surveillance system in bacteria, yeast and mammals by maintaining genomic integrity. The MMR pathway is the form of DNA repair responsible for the elimination of specific mismatched and/or unmatched bases and insertion-deletion loops (IDLs) where DNA synthesis is liable to errors, either as a part of DNA replication before cell division, or as part of DNA repair (unscheduled DNA synthesis) . AlthougMismatch in eukaryotic DNA is recognized by two heterodimeric complexes of Mut S related proteins \u2013 MSH2/GTBP (Mut S\u03b1) and MSH2/MSH3 (Mut S\u03b2) . Mut S\u03b1 Proliferating cell nuclear antigen (PCNA) has been identified as DNA polymerase processivity factor and has a role in repair at or prior to excision steps as a strand discriminating factor . Bi \u2013 diDNA exonuclease and helicase unwind, nick and degrade the error \u2013 containing strand. After dissociation of MMR complex, PCNA, which still binds at the end of error containing primer strand, recruits replication complex and thus re-initiation starts with the help of DNA polymerase.The mutations characterized by point mutations, insertions or deletions in the length of DNA microsatellite repeat sequences throughout the genome resulting in microsatellite instability (MSI) is a hallmark of defective DNA MMR system which result in malignant transformation .The maintenance of MMR system decreases the error rates by 100 to 1000 fold during DNA replication. Since it has tremendous importance in the carcinogenesis, this review presents a discussion on the role of DNA mismatch repair system as a therapeutic potential in eliminating the cancer stem cells.The maintenance and longevity of stem cell phenotype is characterized by the presence of efficient MMR system, which result in accurate DNA replication, restore normal DNA after its damage and remove replication defects at microsatellite sequences by repairing the DNA polymerase slippage products.-/- and Mlh2-/- phenotype, mice develop stem cell-derived-lymphoid malignancies and all lymphoid tumors show MSI [-/- primary murine hematopoietic cells with wild type into lethally irradiated mice with temozolomide, a methylating agent. MMR deficiency as evident by MSI was observed in early progenitor colony forming unit (CFU) and Sca+Kit+Lin- derived clones, which explain the alteration in growth and survival of hematopoietic stem cells and its long-term repopulation capacity because of accumulation of genomic instability [-/-, Msh2+/+, Msh2-/+ mouse embryonic stem cells following prolonged low level radiation treatment. The cells deficient in active MMR system survive promutagenic genomic insults by alkylating and oxidating agents that contribute to neoplastic transformation as in hereditary non-polyposis colorectal cancer (HNPCC) [The MMR deficiencies because of the mutations in wild type MMR allele with Msh2show MSI . The sertability . In anot (HNPCC) . The six (HNPCC) .The loss of MMR genes directly or indirectly alters signal pathways, loss of strictly regulated expression of cytokine receptors, transcription factors and cell cycle regulation . Unlike The mitotic homologous recombination can result in chromosomal translocations, deletions or inversions with deleterious consequences in the adult or during development. Loss of MMR adds up an additional level of genetic instability in a form of chromosomal rearrangements commonly observed in hematological malignancies. High incidence of lymphoma is reported in Msh2 deficient mouse embryonic stem cells .-/- mouse ES cells after exposure to temozolomide but not cisplatin and contributed to failed repair mechanism and apoptosis in a p53 dependent manner [The Msh2 low and deficient mouse ES cells showed poor or complete elimination of repair function and demonstrated the resistance against the toxic effects of an ethylating agent, N-ethyl-N-nitrosourea (ENU). The ENU-induced mutagenicity under the fully or partially deficient conditions accelerated the lymphomagenesis . Toft ett manner .-/- mouse embryonic stem cells showed two-fold resistance to the cytotoxic effects of cisplatin as compared to wild type cells [In a study by Fink et al., Msh2pe cells . On the pe cells . Howeverpe cells , increasIn most of the malignancies CSCs constitute less than 1% of total cell population. They are in quiescent state and most of the conventional chemotherapeutic drug therapies are effective in actively dividing cells, so for complete eradication of CSCs, the therapeutic agents either should kill cells independently of the cell cycle or selectively induce cycling of cancer cells. Moreover, therapy should target pathways uniquely used by CSCs. CSCs express various drug transporter proteins which efflux the cytotoxic drugs and protect them from damage. The inhibitors to these transporters make the CSCs sensitive to chemotherapy. Since normal stem cells also express some of these transporters so non selective inhibition of these multidrug resistant genes also kill normal stem cells. The characterization of stem cells markers would help in identification of CSCs from normal stem cells have important implications in elimination of CSCs by specifically targeting the tumor cells . Table 2The wild type MMR expression blocks the homologous recombination between the diverged DNA sequences throughout the genome and thus prevent the stem cell to accumulate further genetic instability. Hematological malignancies and lymphoma arise due to chromosomal rearrangements because of loss of MMR proteins . The effMost of the human cancers are identified having mismatch repair deficiency that result in defect in cell cycle and altered growth as in case of hematological malignancies. The defective MMR status in a damaged cell directly contributes to the resistant phenotype against the cytotoxic effects of chemotherapeutic drugs and thus these CSCs survive chemotherapy Fig . The actThe maintenance of genomic stability is the prime requirement for the stem cell phenotype and its normal functioning. The increased mutation rate and absence of MMR may give rise to stem cell failure, a proliferative advantage and cancer stem cells formation. The cancer stem cells having MMR deficiencies make them insensitive to the treatments against the cytotoxic agents and would increase the risk of relapse and metastasis. The importance of MMR in designing the therapeutic strategies specifically targeting the tumor cells is being explored and pursued in the clinical trials.The author(s) declare that they have no competing interests.The manuscript was written and finalized by the author."} +{"text": "Ploidy and cell proliferation determined by flow cytometry were assessed on colorectal cancers from patients admitted to two Italian cancer research centres. A total of 181 patients were followed prospectively for 4 years at the Istituto Regina Elena (IRE) of Rome and at the Istituto Nazionale Tumori (INT) of Milan. Fresh (at the IRE) or frozen (at the INT) tumour material and similar procedures were used for subsequent sample preparation. Similar frequencies of aneuploid tumours (63% vs 66%) and superimposable median DNA indices (1.6) were observed for the two case series. In both series, DNA ploidy was generally unrelated to clinico-pathological factors, except for a higher frequency of aneuploid tumours in Dukes' D (88%) than in Dukes' A stage (33%) in the IRE experience. DNA ploidy was a weak prognostic indicator at 3 years but not at 4 years in the IRE case series, and it never exhibited a clinical relevance in the INT experience. Conversely, multiploidy was an indicator of worse relapse-free and overall survival at 4 years in the IRE and INT case series."} +{"text": "Some environmental factors of possible aetiological importance for primary liver carcinoma (PLC) in males were analysed in a case-control study including 83 cases of hepatocellular carcinoma (HCC), 15 cases of intrahepatic cholangiocellular carcinoma (CC), 3 cases of haemangiosarcoma and 1 case of unspecified sarcoma in the liver--102 cases in total. Two matched controls were used in each case. One case with haemangiosarcoma was exposed to polyvinyl chloride. The case with unspecified soft-tissue sarcoma was exposed to phenoxy acids. A 4-fold increase in the risk of HCC was seen in alcoholics, and regular drinking gave a 3-fold increase in the risk. Exposure to organic solvents gave a 2-fold increase in the risk of HCC. No increased risk was observed for cases exposed to various other chemicals. Three cases of HCC had a previous diagnosis of porphyria acuta intermittens (PAI), versus no control. Six cases of HCC had a previous diagnosis of porphyria acuta intermittens (PAI), versus no control. Six cases with PLC had polyphyria cutanea tarda (PCT) which in 4 cases was related to alcoholism and in one case to haemochromatosis."} +{"text": "Cervical intraepithelial neoplasia (CIN) grades I to III lesions (n = 94) and squamous cell carcinomas of the uterine cervix (n = 27) were analysed for MHC class I and II expression and presence of HPV genotypes. MHC class I and II expression was studied by immunohistochemistry and HPV typing was performed by general primer- and type-specific primer mediated PCR (GP/TS PCR). Both techniques were performed on paraffin embedded tissue sections. Results show disturbed MHC class I heavy chain expression in CIN I to CIN III, as well as in cervical carcinomas. Upregulated MHC class II expression on dysplastic epithelial cells was also found in the different CIN groups and carcinomas. Prevalence of HPV genotypes increased with the severity of the lesion, mainly due to the contribution of the HPV types 16 and 18. No correlation could be established between the presence of specific HPV genotypes and any MHC expression pattern in the different CIN groups or cervical carcinomas. In some cases these data were confirmed by RNA in situ hybridisation showing HPV 16 E7 transcripts in the same dysplastic/neoplastic cells from which MHC status was determined. The results indicate that local differences may exist in the type of cellular immune response to HPV induced lesions."} +{"text": "Cremophor EL, a pharmacologically inactive solubilising agent, has been shown to reverse multidrug resistance (MDR). Using flow cytometric evaluation of equilibrium intracellular levels of daunorubicin (DNR), we found that eight other surface active agents will also reverse MDR. All the active detergents contain polyethoxylated moieties but have no similarities in their hydrophobic components. The properties of three polyethoxylated surfactants that showed the lowest toxicities, Cremophor, Tween 80 and Solutol HS15, were examined in more detail. The concentrations of Tween 80 and Solutol required to reverse DNR exclusion were 10-fold lower than for Cremophor. However while concentrations greater than or equal to 1:10(2) of the former two surfactants resulted in breakdown of cells, even 1:10 of Cremophor did not lyse cells. Studies of the effects of Cremophor on the uptake and efflux of DNR in normal and MDR cell types showed that Cremophor increases intracellular DNR primarily by locking the rapid efflux from the cells. This blockage of drug efflux may be mediated by a substantial alteration in the fluidity of cell membranes induced by Cremophor, as shown by decreased fluorescence anisotropy of a membrane probe. Consistent with these data, coinjection of adriamycin plus Cremophor into mice carrying a multidrug resistant P388 transplantable tumour significantly increased the survival time of the mice compared with adriamycin treatment alone."} +{"text": "Human papillomavirus (HPV) typing and quantitation by polymerase chain reaction was performed on exfoliated cells from 133 women referred for colposcopy because of an abnormal smear. High levels of HPV 16 correctly predicted cervical intraepithelial neoplasia (CIN) grade II-III in 93% of its occurrences, but only 59% of cases of CIN III were associated with high levels of this type. Eighty-four per cent of CIN III lesions contained high levels of at least one of HPV types 16, 18, 31, 33 and 35, but the other types were less specific for CIN III than HPV 16. Overall HPV testing compared favourably with cytology for predicting high-grade CIN lesions, but it would appear that some combination of the two modalities will produce better performance than either alone. In particular, HPV testing appears to be helpful in determining which women with mildly abnormal smears have high-grade underlying lesions in need of immediate referral for colposcopy."} +{"text": "The chemosensitising effect of the nitroaromatic radiosensitiser misonidazole (MISO) on the alkylating agent cyclophosphamide (CTX) has been investigated in a C3H mammary carcinoma in CDF1 mice. The selective cytotoxicity against aerobic and hypoxic cells was measured indirectly, using a local tumour control (TCD50) assay. The hypoxic fraction was calculated from the dose difference between the TCD50S for tumours irradiated either in air or under clamped conditions. The relative survival of tumour cells after drug therapy was expressed as a surviving fraction (SF). CTX (100 mg kg-1) was found to be considerably more toxic towards hypoxic than aerobic cells (SF 4% versus 52%). MISO (1000 mg kg-1) was almost exclusively toxic to hypoxic cells (SF 22%). When MISO and CTX were administered simultaneously a decrease in the surviving fraction was observed. The effect on aerated cells was found to be 10-fold more than expected from addition of toxicities, suggesting a chemosensitising effect on these cells by MISO when used in combination with CTX. No synergistic effect was found on radiobiologically hypoxic cells. The exact role of hypoxia for the development of chemosensitisation seems to be complex and requires additional research in the future."} +{"text": "A large body of theoretical work suggests that analyses of variation at the maternally inherited mitochondrial (mt)DNA and the paternally inherited non-recombining portion of the Y chromosome (NRY) are a potentially powerful way to reveal the differing migratory histories of men and women across human societies. However, the few empirical studies comparing mtDNA and NRY variation and known patterns of sex-biased migration have produced conflicting results. Here we review some methodological reasons for these inconsistencies, and take them into account to provide an unbiased characterization of mtDNA and NRY variation in chimpanzees, one of the few mammalian taxa where males routinely remain in and females typically disperse from their natal groups. We show that patterns of mtDNA and NRY variation are more strongly contrasting in patrilocal chimpanzees compared with patrilocal human societies. The chimpanzee data we present here thus provide a valuable comparative benchmark of the patterns of mtDNA and NRY variation to be expected in a society with extremely female-biased dispersal. Human societies show significant variation in post-marital residence practices. About 70% of human societies practice some form of patrilocality, with men remaining in and women migrating from their natal household, clan, lineage, village, or other cultural unit subsumed within a larger group of people sharing a common culture and language, often termed a `trib\u00e9 in traditional societies One study of Hill tribes of northern Thailand showed the predicted differences between patrilocal and matrilocal tribes in patterns of mtDNA and NRY variation At least three factors may contribute to the discrepant findings of prior research comparing contemporary patterns of genetic variation and post-marital residence practices. First, analyses of mtDNA and NRY variation have been performed at a broader scale of social organization than that at which sex-biased migration actually takes place. For example, the different patterns of mtDNA and NRY diversity shown by matrilocal and patrilocal tribes in Thailand versus India may occur because only in Thailand do members of the migrating sex sometimes move out of their own tribe to join another. Migration outside the tribe is actually a rare event in traditional societies, as different tribes can have very different languages and cultures A second factor complicating attempts to compare patterns of mtDNA and NRY variation is that estimates of genetic differentiation between populations are sensitive to variables that reduce the level of within-group variation, with decreased variation resulting in larger genetic differentiation. For example, an early study of global genetic variation found that genetic differentiation among continents was larger for the NRY than the mtDNA Finally, a third possible reason for the contradictory findings of prior research is that we do not know for how long and how consistently each of the sampled societies has practiced their particular form of post-marital residence. One of the societies in the Central Asian study has practiced its contemporary form of post-marital residence for several centuries In contrast to the complex situation in human populations, patterns of sex-biased migration in animals are often well known from long-term behavioral observations. The currently available genetic studies of animal populations, however, furnish limited insights into how sex differences in migration affect mtDNA and NRY variation. Long-term behavioral observations indicate that migration out of bonobo groups is extremely female-biased Here we examine patterns of mtDNA and NRY variation in four groups of wild chimpanzees located in Uganda and separated by 10\u2013165 km. Chimpanzees live in communities consisting of 20\u2013150 individuals, and as a result of over 180 total years of human observation at multiple field sites, their migration patterns are well understood ST based genetic differentiation estimates, we use the recently developed standardized measure of genetic differentiation We compare the patterns of variation in chimpanzees with those inferred from published data on patrilocal human tribes belonging to five different larger cultural/geographic regions, hereafter termed \u2018tribal groups\u2019 P\u200a=\u200a0.008, two-tailed) . Chimpanzees thus have reduced levels of NRY diversity relative to mtDNA diversity compared with patrilocal humans.We found that the average NRY haplotype diversity of the four chimpanzee communities was significantly lower than that of the 20 patrilocal human tribes . However-tailed) , suggestWe found extensive sharing of mtDNA variants among chimpanzee communities that strongly contrasted with complete community specificity of NRY haplotypes . In contStandardized genetic differentiation produced broadly similar results, with chimpanzees showing significantly larger standardized NRY genetic differentiation than three of five patrilocal human tribal groups . HoweverThe more similar standardized than unstandardized NRY/mtDNA genetic differentiation ratios between chimpanzees and patrilocal human tribal groups suggest that in addition to differences in the extent of female-biased migration, other factors which reduce NRY relative to mtDNA within-group variation have affected chimpanzees more strongly than the patrilocal human tribal groups. One possibility is that the effective population size of males relative to females may be smaller in chimpanzees than it is in humans. To test this hypothesis, we used parentage assignments in the chimpanzee communities and published human data sets to compare sex differences in effective population size in both species. We found that the ratio of male to female variance in lifetime reproductive success (LRS), an important factor influencing sex differences in effective population size, is actually similar in chimpanzees and in humans living in traditional societies . Taken tWhatever the reason for the discrepancy between unstandardized and standardized NRY/mtDNA genetic differentiation ratios, standardized NRY and mtDNA genetic differentiation were still more strongly contrasting in chimpanzees than in patrilocal human tribal groups. This suggests that migration is more female-biased between chimpanzee communities than between patrilocal human tribes within a tribal group. Additional analyses of patrilocal humans which are conducted on the scale over which sex-biased migration actually occurs, e.g., villages within a tribe rather than tribes within a tribal group, will be necessary to test this hypothesis. Alternatively, the recent history of patrilocality in most human populations may have prevented the build-up of such extremely contrasting patterns of mtDNA and NRY variation. For humans, the absence of higher NRY than mtDNA genetic differentiation at the continental and global scale may indicate that migration is not female-biased at these broad geographical distances www.ncbi.nlm.nih.gov) accession numbers for the chimpanzee mtDNA sequences are EU077270-EU077418. Supplementary We examined mtDNA and NRY variation in four communities of chimpanzees (number of mtDNA/NRY-chromosomes sampled in parentheses): the Sonso (28/16) community of Budongo Forest Reserve, the Ngogo (94/41) and Kanyawara (20/10) communities of Kibale National Park, and the Mugiri (7/6) community of Semliki National Park. We also analyzed previously published data from five patrilocal Dravidian tribes from India (Vanne (32/23), Pokanati (59/25), Panta (37/21), Kapu (22/16) and Akhutota (32/21)), five patrilocal Mundari tribes from India , Munda (23/23), Kharia (21/13), Bhumij (40/39) and Asur (30/28)), three patrilocal Hill tribes from Thailand (Akha (91/21), Chiang Rae Lisu (53/9) and Mae Hong Son Lisu (42/22)), four patrilocal tribes from the lowlands of Western New Guinea (Awyu (12/10), Citak (40/28), Mappi (18/10) and Muyu (10/6)), and three patrilocal tribes from the highlands of Western New Guinea (Dani (21/12), Ketengeban (22/19) and Una (51/46). Subjects were sequenced at the first hypervariable control region of the mtDNA and genotyped at microsatellite loci on the NRY. The chimpanzees were sequenced at 473 bases and genotyped at 9 microsatellite loci following procedures described elsewhere U tests to compare average mtDNA haplotype diversity, NRY haplotype diversity, and the ratio of NRY/mtDNA haplotype diversity between the chimpanzee communities (N\u200a=\u200a4) and the patrilocal human tribes (N\u200a=\u200a20).We used Arlequin 3.10 Unstandardized genetic differentiation was calculated in an AMOVA framework, with the number of different alleles used as the distance metric for both mtDNA and NRY. We examined the overlap in the 95% confidence limits generated by bootstrapping genetic differentiation values in a locus-by-locus AMOVA to evaluate whether (a) genetic differentiation between the chimpanzees and each of the five patrilocal human tribal groups were significantly different and (b) genetic differentiation of NRY and mtDNA were significantly different within chimpanzees and patrilocal human tribal groups.a and b at a locus, in one of the populations these alleles were recoded as c and d), and calculated an AMOVA FST for this transformed data set . This transformation does not affect within-population variation, but maximizes between-population variation. We then calculated standardized genetic differentiation by dividing the original unstandardized AMOVA FST by the AMOVA FST obtained for this transformed dataset. We included only variable loci when calculating both unstandardized and standardized genetic differentiation. The inclusion or exclusion of non-variable loci does not affect the unstandardized AMOVA, but including non-variable loci when calculating the AMOVA for the transformed data set results in AMOVA values that are determined more by the ratio of variable to non-variable sites, and less by the levels of variability of the variable loci. This would push maximum genetic differentiation possible towards 1, and result in standardized genetic differentiation values that are nearly identical to their unstandardized counterparts. To determine 95% confidence intervals for the standardized genetic differentiation, we divided the lower 95% confidence limit of the original unstandardized genetic differentiation value by the upper 95% confidence limit of the transformed genetic differentiation, and divided the upper 95% confidence limit of the original unstandardized genetic differentiation by the lower 95% confidence limit of the transformed genetic differentiation. For all tests, loci had to have less than 5% missing data to be included in calculations.To calculate standardized genetic differentiation, we first transformed the data such that each population had its own set of unique alleles and females (IF). IM and IF are commonly used to estimate variance in lifetime reproductive success when the sampling of male and female reproductive output is incomplete and the data indicate the sexes have different mean lifetime reproductive success, when in reality they must be equal To estimate variance in lifetime reproductive success, we calculated the variance in the number of offspring divided by the square of the mean number of offspring, for both males Click here for additional data file."} +{"text": "A retrospective analysis was performed of 18 patients with primary malignant germ cell tumours of the mediastinum treated with platinum-based chemotherapy between 1977 and 1990. All seven patients with pure seminoma were treated initially with chemotherapy and four of these patients received additional mediastinal radiotherapy. Only one patient relapsed; his initial therapy had included radiotherapy and single-agent carboplatin and he was successfully salvaged with combination chemotherapy. With a follow-up of 11 to 117 months (median 41 months) all seven patients with seminoma remain alive and disease free giving an overall survival of 100%. Eleven patients had malignant non seminoma; following chemotherapy eight of these had elective surgical resection of residual mediastinal masses. Complete remission was achieved in nine (82%) patients, however, one of these patients died from bleomycin pneumonitis. With a follow-up of 12 to 113 months (median 55 months) eight of 11 (73%) patients with malignant mediastinal teratoma remain alive and disease free."} +{"text": "The past ten years parallels have been drawn between the biology of cancer and pulmonary fibrosis. The unremitting recruitment and maintenance of the altered fibroblast phenotype with generation and proliferation of immortal myofibroblasts is reminiscent with the transformation of cancer cells. A hallmark of tumorigenesis is the production of new blood vessels to facilitate tumor growth and mediate organ-specific metastases. On the other hand several chronic fibroproliferative disorders including fibrotic lung diseases are associated with aberrant angiogenesis. Angiogenesis, the process of new blood vessel formation is under strict regulation determined by a dual, yet opposing balance of angiogenic and angiostatic factors that promote or inhibit neovascularization, respectively. While numerous studies have examined so far the interplay between aberrant vascular and matrix remodeling the relative role of angiogenesis in the initiation and/or progression of the fibrotic cascade still remains elusive and controversial. The current article reviews data concerning the pathogenetic role of angiogenesis in the most prevalent and studied members of ILD disease-group such as IIPs and sarcoidosis, presents some of the future perspectives and formulates questions for potential further research. The interstitial lung diseases (ILDs) are a heterogeneous group of diffuse parenchymal lung diseases comprising different clinical and histopathological entities that have been broadly classified into several categories ,2 includThe scope of this review article is to summarize the current state of knowledge regarding angiogenic and angiostatic activity in the most important and prevalent members of ILD disease-group such as IIPs and sarcoidosis, discuss its pathogenetic role and present some of the future perspectives and limitations based on authors' assessment or originated from the statements of original authors.de novo formation of blood vessels from angioblasts or endothelial progenitor cells, process that mostly occurs during embryogenesis [Angiogenesis is the process of new capillary blood vessels growth and is instrumental under both physiologic and pathologic conditions. Physiologic conditions include embryogenesis, growth, tissue repair after injury and the female reproductive cycle whereas pathologic angiogenesis can occur in chronic inflammatory and fibroproliferative disorders and tumorigenesis of cancer. Angiogenesis is similar to but distinct from vasculogenesis which describes the ogenesis . On the 2-terminus a three amino-acid motif (ELR) such as IL-8/CXCL8, epithelial neutrophil activating protein (ENA)-78/CXCL5, growth-related genes , granulocyte chemotactic protein (GCP)-2/CXCL6 and neutrophil activating protein (NAP)-2/CXCL7, originally promote angiogenesis [Molecules that originally promote angiogenesis include members of the CXC chemokine family, characteristically heparin binding proteins which on structural level have four highly conserved cysteine amino acid residues, with the first two cysteines separated by one nonconserved amino acid residue. CXC chemokines display unique diverse roles in the regulation of angiogenesis resulting from dissimilarity in structure. Therefore, members that contain in the NHogenesis ,12. Therogenesis ,12. Anotogenesis ,14. Its ogenesis . Finallyogenesis . In addiogenesis -19.By contrast, other members of the CXC chemokine family that do not contain the angiogenic ELR motif (ELR-) behave as potent inhibitors of angiogenesis. Platelet factor-4 (PF-4)/CXCL4 was the first chemokine described to inhibit aberrant angiogenesis. Furthermore, the angiostatic ELR- members of the CXC chemokine family include the interferon (IFN)-\u03b3 inducible protein (IP)-10/CXCL10, monokine induced by IFN-\u03b3 (MIG)-2 and IFN-\u03b3-inducible T-cell a chemoattractant (ITAC)/CXCL11 . The latSeveral transcription factors play instrumental role in promoting angiogenesis and sensing the environmental cues that drive this process. Strieter et al. identifiThe past ten years parallels have been drawn between the biology of cancer and pulmonary fibrosis. The unremitting recruitment and maintenance of the altered fibroblast phenotype with generation and proliferation of immortal myofibroblasts is reminiscent with the transformation of cancer cells -37. A haThere is increasing evidence supporting the notion that vascular remodeling in fibroproliferative disorders appears to be regulated by an imbalance between angiogenic and angiostatic factors. Seminal observation implicating angiogenic activity as an important aspect of progressive fibrosis was originally made by Turner-Warwick in 1963, when she demonstrated the presence of anastomoses between the systemic and pulmonary microvasculature in lungs of patients with IPF . DespiteKeane and colleagues were the first addressing this crucial issue. They demonstrated increased angiogenic activity in a large number of IPF lung specimens ,42 and sOriginal attempt to prove an association between abnormal vasculature and regional heterogeneity characterizing IPF was performed by Renzoni and coworkers . Fueled Lappi-Blanco et al. addressed this crucial issue ,54. TheyThere is a great lack of knowledge regarding this issue which has been largely ignored. Renzoni et al. were theTowards this direction, Simler et al. performeA second attempt to correlate local and systemic expression of angiogenic mediators with clinical biomarkers of disease severity and activity was recently published by Pignatti et al . They inFinally, Strieter et al. recentlyThe vascular remodeling phenomenon has been also described in the experimental model of bleomycin-induced pulmonary fibrosis. The role of neovascularization during the pathogenesis of experimental pulmonary fibrosis was originally raised by Peao and coworkers . In lineFueled by the prospect that anti-angiogenic treatment could be beneficial for pulmonary fibrosis, Hamada et al. tested tThe latter results have clear therapeutic implications since inhibition of angiogenic mediators or administration of angiostatic chemokines reduced lung collagen deposition and attenuated the exaggerated matrix remodeling. On the basis of this concept, neutralization of proangiogenic environment should be pursued. However, the latter statement should be treated with caution for the following reasons: 1) Findings derived from the bleomycin model of pulmonary fibrosis may not be applicable to human disease since pathogenetic components seen in bleomycin-induced pulmonary fibrosis do not demonstrate areas compatible with fibroblastic foci, the leading edge of human fibrosis. In addition, there are clear limitations to this model in terms of its self-limiting nature, the rapidity of its development and the close association with inflammation that accompanies the lung injury . Regardi2 terminus. While CXCR3/CXCR3 ligands inhibit angiogenesis, CXCR3 ligands play a pivotal role in orchestrating Th1 cytokine-induced cell-mediated immunity via the recruitment of mononuclear and CD4+ T-cells expressing CXCR3 and consequently via the granuloma formation (1). So far, there are only few studies in the literature implicating angiogenesis in the immunomodulatory cascade of sarcoidosis and correlating its immunopathogenesis with members of the angiostatic group of CXC chemokines. These studies are discussed in the following lines.Recent immunological advances on sarcoidosis have revealed a T helper 1 (Th1) and T helper 2 (Th2) paradigm with predominance of the Th1 response in its immunopathogenesis ,68. The The concept of disparate activity of the IFN-\u03b3-induced CXC chemokines in the context of Th1-like immune disorders, such as sarcoidosis, was originally raised by Agostini et al. who docuThe aforementioned studies substantiate the assertion that IFN-\u03b3-induced CXC chemokines are strongly involved in the immunomodulatory cascade of sarcoidosis implicating angiostasis with Th1 immune response. However, there are several arguments that should be addressed. The majority of the studies cited above have investigated the ability of CXCR3 ligands to promote Th1-dependent immunity and not to inhibit angiogenesis. Studies have shown that angiostatic CXC chemokines are more likely to contribute to the granuloma formation through their chemotactic rather than angiostatic properties. The contention of \"immunoangiostasis\" (promotion of Th1 response and at the same time inhibition of angiogenesis) as it has been coined out by Strieter et al. may possIIPs are a heterogeneous group of diffuse parenchymal disorders resulting from damage to the lung parenchyma by varying patterns of inflammation and fibrosis. On the other hand several patients with sarcoidosis develop irreversible lung damage and pulmonary fibrosis which culminates to a fatal outcome. Several theories and mechanisms have been delineated regarding the pathogenesis of fibrotic lung disorders. Recent evidence support the concept that inflammation is subsequent to injury and that fibrosis occurs as a polarization of the Th2 immune response of the body to repeated injury to the lung (\"multiple hits\" hypothesis) ,73.Putting the aforementioned data together, we tentatively present the three current theories regarding the role of aberrant vascular remodeling in the fibrogenic process. The first hypothesis is based on the idea that the hypervascularity observed in the least fibrotic areas has a role in the regeneration of the alveolar septa damaged by the fibrotic process and is a compensatory response to the decreased vascularity seen within the fibroblastic foci Figure . In thisAlternative hypothesis regarding the role of vascular remodeling during the process of ECM remodeling has also emerged. This theory supports the premise that newly formed microvessels enhance the exaggerated and dysregulated ECM deposition, support fibroproliferation and inhibit normal epithelial repair mechanisms . Human ,52 and aThe third theory supports the notion that the role of angiogenesis in the pathologic process of pulmonary fibrosis is overestimated and that aberrant vascular remodeling is just a bystander or a consequence of fibrogenesis. The latter idea is based on the assertion that CXC chemokines may exert their anti-fibrotic activities through pathogenetic pathways different from those of angiogenesis . The afoBased on the above data we can state that although several study groups have investigated aberrant vascular remodeling in the pathogenesis of pulmonary fibrosis, the relative roles played by new vessel formation and vascular regression in IPF and subsequently in other fibrotic lung disorders are still elusive and controversial. However, to address this issue further investigation in the context of large prospective multicenter studies using highly standardized techniques is sorely needed. The emergence of massive genome screening tools (DNA microarrays) coupled Several lines of research have been proven inadequate to demystify the relative role of angiogenesis in the etiopathogenesis of chronic fibroproliferative disorders. The question originally raised still remains unanswered: \"A pathogenetic hallmark of just a bystander?\" However, the status of knowledge regarding the contribution of newly formed vessels in the initiation and/or progression of the sequential events of abnormal injurious response, paradoxical apoptosis and exaggerated matrix remodeling has been greatly elevated by several studies. So far, a number of investigations give credence to the view that a chemokine imbalance favoring angiogenesis supports fibroproliferation and inhibits normal repair mechanisms. Alternatively, the regional vascular heterogeneity in IPF can be explained as a compensatory response (vascular regression) to the striking hypovascularity described in areas of active fibrosis. Currently, angiogenesis represents one of the most fruitful applications in the therapeutic minefield of fibrotic lung disorders. The lack of an effective treatment option challenges chest physicians to think beyond conventional therapeutic strategies and apply fresh approaches. Blockage of multiple angiogenic mediators may provide a way forward. Whether our hopes will be fulfilled or disproved remains to be seen.Basic fibroblast growth factor (bFGF)Bronchiolitis obliterans-organizing pneumonia (BOOP)Bronchiolitis obliterans syndrome (BOS)Cryptogenic organizing pneumonia (COP)Epithelial neutrophil activating protein (ENA)-78Extracellular matrix (ECM)Farmer's lung disease (FLD)Granulocyte chemotactic protein (GCP)Growth-related genes (GROs)Hypoxia inducible factor-1a (HIF-1a)High resolution computed tomography (HRCT)Idiopathic pulmonary fibrosis (IPF)Interferon-\u03b3 (IFN-\u03b3)(IFN)-\u03b3 inducible protein (IP)-10(IFN)-\u03b3 inducible T cell-a chemoattractant (ITAC)Idiopathic interstitial pneumonias (IIPs)Interstitial lung diseases (ILDs)Matrix metalloproteinases (MMPs)Macrophage inflammatory protein (MIP)-2Monokine induced by IFN-\u03b3 (MIG)-2Natural killer (NK) cellsNeutrophil activating protein (NAP)-2Nuclear factor-\u03baB (NF-\u03baB)Non-specific interstitial pneumonia (NSIP)Platelet factor-4 (PF-4)Pigment epithelium-derived factor (PEDF)Systemic sclerosis (SSc)Usual interstitial pneumonia (UIP)Vascular endothelial growth factor (VEGF)von Willebrand factor (VWF)The author(s) declare that they have no competing interests.AT and DB were involved with the study conception. AT and SA performed the data acquisition and interpretation. AT prepared the manuscript. DB was involved in revising the article for important intellectual content. All authors read and approved the final manuscript."} +{"text": "The effects of the major human serum bile acid, glycochenodeoxycholic acid (GCDC), as well as unconjugated chenodeoxycholic acid (CDC), on the MCF-7 human breast cancer cell line have been studied in vitro under oestrogen and bile acid deprived culture conditions. GCDC increased the growth of the breast cancer cells over the range 10-300 microM. At concentrations in excess of the bile acid binding capacity of the medium cell growth was prevented. In contrast 10 microM CDC tended to reduce cell growth. Oestrogen (ER) and progesterone (PgR) receptors, pS2 and total cathepsin D were quantified by monoclonal antibody based immunoassays. Ten to 100 microM GCDC and 10 microM CDC down-regulated ER protein and this was accompanied by induction of the oestrogen-regulated proteins PgR, pS2 and possibly cathepsin D, including increased secretion of the latter two proteins into the culture medium. All these changes were quantitatively similar to those observed with 10 nM oestradiol. The bile acid effects on ER and PgR were not due to interference with the assay procedures. Cells incubated with 50 microM GCDC or 10 microM CDC had higher pmolar concentrations of the bile acids than controls. This study suggests that naturally occurring bile acids influence the growth and steroid receptor function of human breast cancer cells."} +{"text": "Somatostatin (SMS), a naturally occurring peptide is known to inhibit the production of certain protein molecules and to diminish the ability of peripheral blood mononuclear cells to proliferate. We tested the effects of three forms of SMS on the bioactivity of both lymphotoxin (LT) and tumour necrosis factor (TNF). We also tested the effects of these agents on production of cytotoxins by peripheral blood mononuclear cells. We found the 28 amino acid form of SMS significantly enhanced the bioactivity of both LT and TNF (10(-9) M concentration) when tested in mouse L cells. The 14 amino acid form of SMS enhanced LT (10(-9) M concentration) activity but not TNF activity. The first 14 amino acid form of SMS-28 did not affect bioactivity of the cytotoxin. In contrast, the naturally occurring 14 amino acid form of SMS (10(-8) M concentration) significantly diminished production of cytotoxin by human peripheral blood mononuclear cells. Cytotoxin produced by the latter was shown to be a combination of both LT and TNF. Similarly after SMS exposure, the cytotoxin produced remained a mixture of LT and TNF in roughly similar proportions. It thus appears that certain forms of SMS can enhance the bioactivity of cytotoxins, but at the same time decrease the production of these cytotoxins."} +{"text": "Alterations in the p53 gene were analysed in 39 patients with locally advanced breast cancers (LABCs) (stage III-IV) with inflammatory signs in most cases (UICC stage T4d = 32 patients) by molecular and immunohistochemical (IHC) approaches. All patients were included in the same therapy protocol. Using polymerase chain reaction (PCR) and a single-strand conformational polymorphism migration technique (SSCP), the presence of mutations in exons 2-11, covering the entire coding sequence of the p53 gene, was evaluated. Using the mouse specific anti-human p53 monoclonal antibody (PAb 1801), we also looked for overexpression of the p53 protein in tissue sections. In 16 cases shifted bands were reproducibly identified by PCR-SSCP, and all but one were in exons 5-8, the usual mutational hotspots. Fifteen of these 16 samples were sequenced and 14 of the suspected mutations (36%) were confirmed. Most of them (12) were single nucleotide substitutions, and transitions were more frequent (eight cases) than transversions (four cases). Fourteen of the tumour samples were positively stained with the monoclonal antibody PAb 1801, 11 with nuclear staining only, two with mixed cytoplasmic and nuclear staining and one with cytoplasmic staining only. Staining patterns were very heterogeneous in terms of the percentage of positive cells (10-75%) and their distribution in the tissue section (isolated foci or dispersed cells). In 11 of the 14 mutated cases a positive immunostaining was observed. The presence of a p53 mutation was significantly associated with larger tumour diameter and the presence of clinical metastases (stage IV) . A non-statistically significant trend of association was observed between p53 mutation, negative oestrogen receptors and lower response rate to therapy. Our results in this group of patients and the heterogeneity of the staining of tumour cells in tissue sections suggest that p53 mutations could be a late event in this non-familial form of breast cancer."} +{"text": "We have investigated the capability of differentiation of Ewing's sarcoma (ES) towards a neuronal direction through the establishment of four extraosseous ES cell lines and by in vitro stimulation with dibutyryladenosine cyclic monophosphate (db-cAMP) of eight ES lines. All except one of the lines expressed the molecule defined by 5C11, the antibody specifically reactive with ES. Two ES lines expressed a 200 kilodalton (kD) neurofilament protein (NFP) although their original tumours were negative for NFP. Elongation of cytoplasmic processes and increased NFP expression were observed after db-cAMP treatment of these lines and microtubules in the cytoplasmic processes were ultrastructurally demonstrated. Six lines were NFP negative, but three lines changed their morphology after induction of 200 kD NFP expression by db-cAMP treatment. The other three showed no definitive differentiation after db-cAMP treatment. Chromosomal analysis of the new ES lines showed the typical t in one line and a +der(22) in two lines. No correlation was observed between the chromosomal abnormality and the differentiation capability. We conclude that ES is a heterogeneous group of tumours with respect to capability of differentiation into the neuronal lineage, but it is clearly distinguished from peripheral primitive neuroectodermal tumours by its 5C11 reactivity."} +{"text": "We report the natural killer (NK) and lymphokine activated killer (LAK) cell activities in peripheral blood lymphocytes (PBL) from untreated patients with Hodgkin's disease (HD) and from healthy donors. The frequency of LAK cell precursors was also studied using limiting dilution analysis (LDA). About 75% of the HD patients had normal NK activity. There was a higher percentage of low NK responders in patients with lymphocyte depletion histologic grade of the disease and those who were in clinical stage IV, suggesting a correlation of decrease in NK activity with poor prognosis. We found efficient LAK activity against the NK-sensitive K562 cells and NK-resistant VIP (melanoma) and T-24 (bladder carcinoma) tumour targets in both low and normal NK responder HD patients, irrespective of the histopathological grade and clinical stage of the disease. In concordance with their good LAK cell activity, HD patients showed a frequency distribution of LAK cell progenitors in the PBL comparable to that of healthy donors."} +{"text": "Intra-tumoural heterogeneity of proliferation has been assessed by taking multiple biopsies from 30 colorectal cancers. Following in vivo IUDR labelling, dual parameter flow cytometry was used to measure tumour DNA index (DI) and labelling index (LI) and to derive DNA synthesis time (Ts) and potential doubling time (Tpot). Heterogeneity was seen for all parameters under investigation. Overall coefficients of variation (CV) and logarithmic transformation of Ts and Tpot (due to their non-gaussian distributions) indicate that LI (CV 25%) was the most variable parameter. Intra-tumoral heterogeneity in Tpot (lnTpot CV = 22%) was less than inter-individual variation (CV = 63%), suggesting that this variation should not be a limitation to the possible usefulness of this technique as an independent prognostic indicator. Correlations of Tpot values were examined between the shortest, the median and the value for a pooled homogenate sample from a single tumour. Using an homogenate, it was possible to accurately predict classification of tumour Tpot values as being below the median ('fast tumours') in 15 of 19 cases (79%). The data suggest that assaying an homogenate may allow a more rapid analysis of a multiply sampled tumour."} +{"text": "The reactivity of murine monoclonal antibodies (McAbs) directed against the monomorphic determinants of Class I and Class II antigens of the major histocompatibility complex (MHC), and against antigens expressed by discrete populations of leucocytes was studied using the indirect immunoperoxidase technique on serial tissue sections of 16 benign and 17 malignant primary human breast tumours. Class I antigens (detected by the McAb 2A1) were consistently associated with stromal leucocytes, fibroblasts and vascular endothelium, but expression on epithelial cells particularly of malignant provenance, was more variable. Class II antigens (detected by TDR 31.1) were present upon a variety of cell types which also included sporadic expression on malignant and benign epithelia. The distribution of leucocytes grossly monitored with 2D1 (reactive with a common leucocyte antigen) was largely interepithelial and periductal in benign lesions. Leucocytes were generally more numerous in malignant tumours, where they were largely confined to the stroma. The majority (approximately 75%) of leucocytes were T lymphocytes (reactive with UCHT1), some of which appeared to react with TDR 31.1 and were therefore activated. Ratios of helper/inducer (OKT4+) and suppressor/cytotoxic (OKT8+) subsets generally exceeded unity in malignant neoplasms. There was no correlation between the extent and distribution of T cells and the HLA status of the epithelial cells. Leucocytes detected by the monoclonal antibody OKM1 which reacts with monocytes/macrophages, granulocytes and large granular lymphocytes were numerically few and again mainly confined to the stroma. In a limited number of tests, leucocytes detected with HNKl, reactive with a differentiation antigen expressed on some cells which mediate natural and antibody-dependent cellular cytotoxicity in vitro although detectable interepithelially in benign tumours, were virtually absent from malignant tissue. HNK1 also cross-reacted with myoepithelial cells in the ducts of benign lesions."} +{"text": "Small cell bronchial carcinoma (SCC) xenografts with differing sensitivity to cyclophosphamide (CY) were investigated using a variety of techniques. Two xenografts (HX78 and HX88) were relatively sensitive to CY, one xenograft (HX72) was inherently resistant to CY and a fourth xenograft (HX78Cy) was a CY induced resistant subline of HX78 and was unstable when maintained without CY exposure. Conventional light microscopy, cytology and electron microscopy examination of the xenografts revealed appearances consistent with SCC. An antikeratin antibody demonstrated the presence of keratin in the inherent and the induced resistant xenografts (and in the unstable revertant) but not in the two sensitive xenografts; the presence of keratin suggested squamous differentiation. Monolayer culture morphology of the sensitive HX78 and the unstable revertant was anchorage independent with the cells forming floating aggregates; the induced resistant subline of this xenograft (HX78Cy) showed, by contrast, flattened, angular adherent cells. Beta HCG production was detected in the monolayer culture supernatant of sensitive HX78 cells; the level of production of beta HCG was increased in the induced resistant HX78Cy cells. Karyotype and flow cytometry studies were also performed. The morphological responses of small cell lung cancer to treatment are discussed."} +{"text": "We have examined the incidence of Harvey ras mutations in human squamous cell carcinomas (SCC) of the upper aerodigestive tract using the polymerase chain reaction (PCR) followed by direct sequencing. No mutations were detected at codons 12, 13, 59 or 61 of this gene in any of six papillomas, five erythroplakias, 56 squamous cell carcinomas, and 16 SCC cell lines. Some of the SCC were lymph node metastases (three) or tumours which had recurred following radiotherapy (seven). We conclude that Harvey ras mutations are not a common event in the pathogenesis or recurrence of SCCs from Caucasian subjects, in contrast to the situation with Indian populations ."} +{"text": "We have examined two new oestrogen receptor (ER) assays--an enzyme immunoassay (EIA) and an immunocytochemical assay (ICA) in a large series of primary breast tumours to compare their potential as predictors of (1) response to endocrine therapy and (2) survival in patients developing advanced breast cancer. Response to endocrine therapy was categorised at 6 months (UICC criteria). ER-ICA appears the better predictor of response to endocrine therapy than ER-EIA. Combining ICA and EIA results did not improve the prediction of response. With both assays patients with ER positive tumours survived longer from the time of diagnosis of advanced disease than those with ER negative tumours. The predictive power of these assay for progression of disease appears slightly better for the ER-ICA."} +{"text": "To evaluate the association between mood and anxiety disorders in Hashimoto disease and Euthyroid Goitre in a case control study.Cases included 19 subjects with Hashimoto disease in euthyroid phase, 19 subjects with euthyroid goitre, 2 control groups each of 76 subjects matched (4/1) according to age and sex drawn from the data base of a community based sample. Psychiatric diagnoses were formulated using the International Composite Diagnostic Interview Simplified, according to DSM-IV criteria. All subjects underwent a complete thyroid evaluation including physical examination, thyroid echography and measure of serum free T4 (FT4), free T3 (FT3), thyroid-stimulating hormone (TSH) and anti-thyroid peroxidase autoantibodies (anti-TPO). Results: Subjects with Hashimoto disease showed higher frequencies of lifetime Depressive Episode , Generalized Anxiety Disorders and Social Phobia whilst no differences were found between subjects with goitre and controls.The study seems to confirm that risk for depressive disorders in subjects with thyroiditis is independent of the thyroid function detected by routine tests and indicates that not only mood but also anxiety disorders may be associated with Hashimoto disease. Clinical and epidemiological studies seem to indicate that an association between high levels of thyroid autoantibodies may be implicated in the increased frequencies of mood disorders observed in thyroid disease, independently of impairment of thyroid function -3. A stuThe aim of the present study was to compare 2 clinical samples of subjects, one with Hashimoto disease (in euthyroid phase) and the second with euthyroid goitre versus controls drown from a community sample, in order to clarify whether the association of mood and anxiety disorder in Hashimoto disease is evident prior to impairment of thyroid dysfunction.Cases: 19 subjects, 18 females, mean age 39.7+/-12.6, with Hashimoto disease in euthyroid phase and 19 subjects, 16 females, mean age 38.1+/-10.4, with euthyroid goitre, all of whom were attending the Endocrinological Unit of the Department of Internal Medicine, University of Cagliari, Italy.Two control groups, each of 76 subjects aged 18\u201364 years, were obtained by matching each \"case\" with four \"controls\" randomly selected on the basis of demographic characteristics (sex and age) from the data base of a larger population enrolled during a previous epidemiological study aimed at defining the prevalence of psychiatric and thyrTwo standardized forms were used to acquire information concerning: demographic data, state of health and use of social and health services. Psychiatric diagnosis was made using the Italian Simplified version of the Composite International Diagnostic Interview (CIDIS) . The comAll subjects underwent a complete thyroid evaluation including physical examination, thyroid echography and measure of serum free T4 (FT4), free T3 (FT3), thyroid-stimulating hormone (TSH) and anti-thyroid peroxidase autoantibodies (anti-TPO). FT4 and FT3 were measured by means of a chromatographic method based on separation of free T4 on Lisophase columns ; TSH was measured by a chemiluminescent method with normal values ranging from 0.3\u20133.0 \u03bcU/ml. Thyroid echography was performed using a \"real time\" echograph , Generalized Anxiety Disorders , Social Phobia and Primary Sleep Disorders ; a tendency towards an increased frequency of Panic Disorder was observed, although statistical significance was not reached . No differences were found in the evaluation of lifetime prevalence of DSM-IV Psychiatric Disorders between patients with Euthyroid goitre and controls (Table 1).This study seems to indicate an association between the presence of a lifetime diagnosis of mood or anxiety disorder and Hashimoto disease without functional thyroid impairment. No difference was observed in mood and anxiety disorders between goitre cases and controls.These findings are congruent with the results of a previous study that indThe above-cited community survey found that subjects with at least one lifetime diagnosis of anxiety disorders presented anti-TPO+ more frequently than subjects without mood or anxiety disorders. However, no specific anxiety diagnosis was found to be associated with anti-TPO+, although General Anxiety Disorder showed a strong trend toward association (P < 0.058). Anxiety Disorder Not Otherwise Specified was more frequently observed with anti-TPO+, but this is only a sub-threshold condition. A previous research carried out on celiac patients indicated thyroid autoimmunity as possible risk factor for panic disorder . In the Indeed, these 3 surveys seem to indicate a congruent trend of possible risk for anxiety disorders such Generalized Anxiety Disorder, Social Phobia and Panic Disorder in Hashimoto Disease.To our knowledge, the data concerning the association between sleep disorders and Hashimoto disease is the first such evidence published in literature, although it may be consistent with a dysregulation of sleep architecture in subjects with sub-clinical thyroid impairment .A sub-clinical dysfunction of axis thyrotropin releasing hormone (TRH) thyroid stimulating hormone (TSH) with consequent alteration of circadian rhythms of TSH has been hypothesized in several depressive disorders. Indeed, this hypothesis may explain why some forms of mood disorders were associated with anti-TPO+ without hypothyroidism, as defined by blood routine tests. A slight reduction in thyroid hormone secretion such as that found in sub-clinical hypothyroidism may affect cognition and mood . At variAlternatively, autoimmunity may be implicated in some form of extra-thyroid disease associated (even indirectly) with the depressive symptomatology.In Hashimoto disease the onset of vasculitis is frequently observed and would seem to be directly correlated to the duration of the illness .In this disease brain perfusion modifications would appear to be of an aspecific nature; recently however, Spect examination revealed a marked compromising of the left cingulum posterioris, thus related in the etiology of associated affective disorders .Recent evidence suggests that thyroid autoimmunity may be affected by the Hypothalamic-pituitary-adrenal axis (HPA) through the balance of proinflammatory and antiinflammatory cytokines ,16. In lThe potential of this study is limited by the small sample size, particularly regard to psychiatric diagnoses less frequently observed in the general population, such as Panic Disorder; the extension of the findings is therefore rather limited.This study seems to indicate an association between the presence of a lifetime diagnosis of mood or anxiety disorder and sleep disturbance and anti-TPO+. The findings obtained suggest the need for further longitudinal studies aimed at clarifying the association between anxiety and depressive disorders and anti-TPO+."} +{"text": "The prognostic role of drug-induced amenorrhea (DIA) was restrospectively evaluated in 221 out of 254 consecutive premenopausal patients treated with adjuvant CMF or a CMF-containing regimen; 33 patients were eliminated because of lack of menstrual data. All patients had metastatic axillary nodes; drug regimens were: CMF x 9 courses +/- Tamoxifen (TM) and CMF x 6 courses; median age was 43 (range 26-54). Premenopausal status was defined as last normal menses within the 6 weeks preceding initiation of chemotherapy: DIA as cessation of menses for at least 3 months not later than 3 months from the end of chemotherapy. DIA occurred in 166,221 (75.1%) patients and was strictly related to the age of the patients; also, the older the patients the shorter the time required to develop DIA. At median follow up of 69 months, Mantel-Byar analysis showed a longer disease free survival (DFS) for patients who developed DIA as compared with non amenorrheic women (P less than 0.001). DIA prognostic value was independent of age, number of involved nodes, tumour size and number of CMF cycles, as assessed by the Cox model , in which DIA was entered as a time dependent covariate."} +{"text": "Nuclear deoxyribonucleic acid (DNA) content of hepatocellular carcinoma (HCC) in 41 South African and 47 Japanese patients at autopsy was analysed by dual-wavelength microspectrophotometry. The DNA distribution patterns were classified as type I, II, III or IV and as low ploidy or high ploidy , according to the degree of dispersion. We found a significantly higher incidence of high ploidy in South African HCC than in Japanese HCC. Moreover, type IV was significantly more frequent among South Africans than among the Japanese. These findings demonstrate that large differences in biological characteristics and clinical behaviour of HCC between South Africa and Japan may reflect differences in DNA distribution patterns which we observed between these two races."} +{"text": "The cell kinetics of 82 squamous cell carcinomas of the head and neck were studied by in vivo administration of the thymidine analogue, bromodeoxyuridine (BrdUrd). Ploidy, BrdUrd labelling index (LI), duration of S-phase (Ts), potential doubling time (Tpot) and S-phase fraction (SPF) were measured by flow cytometry on 50 microns paraffin embedded sections. The range of values obtained compared well with other in vivo cell kinetic studies of head and neck cancer. Aneuploid tumours had a significantly higher BrdUrd labelling index and SPF, and a short Tpot than diploid tumours. To validate the use of 50 microns sections for measuring cell kinetic parameters by flow cytometry a comparison of values obtained by 50 microns sections and small blocks of tissue was made. No significant difference was found between the two methods. Reproducibility of values between two consecutive thick sections was also good. We conclude that reproducible cell kinetic measurements can be made in tumour samples using 50 microns sections of BrdUrd labelled tissue."} +{"text": "This study was designed to compare two different modalities of TBI which are currently used in clinical practice. The same dose of 750 cGy was given to CBA mice either in a single dose at a low dose rate (4 cGy min-1) (STBI) or in a fractionated regimen (six fractions of 125 cGy three times a day) at a higher dose rate (25 cGy min-1) (FTBI). After TBI completion we simultaneously studied the in vivo radiation response of bone marrow cells, two murine bone marrow clonogenic cells (CFU-S and GM-CFC) and peripheral blood lymphocytes and granulocytes for a period of 1 month. The percentage of spleen erythrocytic and granulocytic colonies was also determined. No significant differences were observed between the two groups in the first 48 hours after irradiation except in bone marrow cell numbers, probably due to differences in the overall treatment time between the two TBI schedules. After the first 48 hours the repopulation patterns of the different cells were very similar in both groups. These findings suggest that the different dose rates and fractionation used in this study caused similar radiation damage to the murine haemopoietic system. Moreover, no significant repopulation occurred during the longer overall treatment time of the fractionated regimen. These preliminary results must be corroborated with a larger range of doses before any firm conclusion can be drawn."} +{"text": "Nine primary pulmonary carcinomas, one metastatic carcinoma, and two malignant pleural mesotheliomas have been analysed for the expression at the mRNA level of metalloproteinases (MPs) and tissue inhibitors of MPs (TIMPs). In situ hybridisation showed TIMP-1 and TIMP-2 transcripts predominantly over tumour stroma and gelatinases evenly distributed over both stromal and tumour cells. While both TIMP-1 and TIMP-2 were expressed in non-neoplastic lungs (NNL) as well as in carcinomas, stromelysin 3 (ST3), 92 kDa gelatinase and interstitial collagenase were expressed only by carcinomas. Expression of these MPs by carcinomas was independent of histologic type and such tumour features as fibrosis or necrosis. The consistent expression of ST3 by all of the carcinomas examined and absence of its expression in NNL indicates that ST3 production is likely associated with the malignant phenotype. However, since 92 kDa gelatinase and interstitial collagenase transcripts were found in some but not all tumour samples, their expression is not a uniform feature of pulmonary carcinomas. The possible prognostic significance of the expression of the latter two enzymes by carcinomas remains to be established."} +{"text": "Antigenic modulation of major histocompatibility and tumour associated antigens was observed in neoplastic cells obtained from patients with pleural and abdominal effusions of breast and ovary carcinomas following a single intracavitary dose of 18 x 10(6) U recombinant IFN-alpha. This regimen resulted in antigenic modulation in seven out of 11 tested cases, suggesting a potential, although limited, responsiveness of at least a fraction of breast and ovary carcinoma cells to in situ biomodification with IFN-alpha."} +{"text": "Drug resistance in haemopoietic cells may be partly related to the expression of the glutathione-s-transferase (GST) pi and mdr-1 genes. We have used RNA slot blotting techniques to investigate the expression of GST pi in peripheral blood and bone marrow of eleven normal subjects, nine patients with myelodysplastic syndrome (MDS), eighteen patients with acute myeloblastic leukaemia (AML), and thirty-two patients with chronic lymphocyte leukaemia (CLL). We found increased expression of GST pi in 8 of 9 MDS, 12 of 18 AML and in the peripheral blood of 24 of 32 CLL relative to normal controls. Increased expression of GST pi can occur at any stage of disease and shows no clear relation to mdr-1 expression except, possibly, in CLL. In 3 AML patients GST pi transcript levels were the same or lower on relapse compared to presentation. Upregulation of the GST pi gene could not be demonstrated in 2 CLL patients in response to treatment with intermittent chlorambucil."} +{"text": "The QR regressor tumour (QR-32), a fibrosarcoma which is unable to grow progressively in normal syngeneic C57BL/6 mice, was able to grow progressively in 13 out of 22 mice (59%) when it was subcutaneously coimplanted with gelatin sponge. We established four culture tumour lines from the resultant tumours (QRsP tumour lines). These QRsP tumour lines were able to grow progressively in mice even in the absence of gelatin sponge. The ability of QRsP tumour cells to colonise the lungs after intravenous injection and to produce high amounts of prostaglandin E2 (PGE2) during in vitro cell culture was much greater than that of parent QR-32 cells. These biological characteristics of QR-32 cells and QRsP tumour cells were found to be stable for at least 6 months when they were maintained in culture. We also observed that QR-32 cells were able to grow progressively in five out of 12 (42%) mice after coimplantation with plastic non-adherent peritoneal cells obtained from mice which had been intraperitoneally implanted with gelatin sponge. These host cells reactive to gelatin sponge increased the production of high amounts of PGE2 by QR-32 cells during 48 h coculture. Preliminary in vitro studies implicated the involvement of hydrogen peroxide and hydroxyl radical as some of the factors necessary to induce QR-32 cells to produce high amounts of PGE2 and to accelerate tumour progression."} +{"text": "We have found that elevation of preoperative serum sialyl-Tn antigen (STN) levels is associated with a poor prognosis for gastric cancer patients, and these high levels remain in the advanced stage of the disease. We have now examined findings with the combined assay of STN and carcinoembryonic antigen (CEA) levels with regard to prediction of the prognosis of gastric cancer patients. Serum CEA levels and STN levels were determined preoperatively in 349 Japanese patients with gastric cancer. The patients were divided into four groups: (A) the CEA (-) STN (-) group ; (B) the CEA (-) STN (+) group ; (C) the CEA (+) STN (-) group ; and (D) the CEA (+) STN (+) group . Clinicopathological features and the prognosis of these groups were examined. The distribution of two markers showed no significant correlation. The patients in the CEA (+) STN (+) group (group D) had more advanced disease than the patients in CEA (-) STN (-) group (group A); tumour size was larger, serosal invasion was prominent, lymphatic and vascular involvement was frequent and the tumour was more infiltrative. Lymph node metastasis and hepatic metastasis were more common. Total gastrectomy was usually performed, and the non-curative rate was higher. The 5-year survival of patients in the CEA (+) STN (+) (group D) was 14.5 +/- 9.5%, that is lower than that of patients in any other group . This combined assay of these markers will aid in estimating the prognosis and selecting appropriate drugs and care for gastric cancer patients."} +{"text": "Growth in soft-agar bilayer cultures of human tumour cells derived from 4 in vitro continuous cell lines, from 21 xenografts carried in athymic mice, and from 197 samples of fresh human solid tumours of various histologic types was analyzed by computer-assisted image analysis. Replicate cultures for each specimen were assessed on successive days of incubation for the number and volume of growth units within multiple size categories. Our results confirm the recent finding of others that there is an upper limit of approximately 10(9) microns 3 to the cumulative growth unit volume obtainable in a 2 ml bilayer soft agar culture system. Since this upper limit to the carrying capacity of the closed culture system exists, the extent of growth within the cultures is determined in a fundamental way by the cumulative volume of growth units initially inoculated into cultures. A growth index of greater than or equal to 16-fold was only seen when initial cumulative growth unit volume was less than 10(7) microns 3 per culture dish. Computer-assisted volume analysis (CAVA) appears to be a useful quantitative method to study the growth of human tumour cells in soft agar cultures."} +{"text": "As yet, there is no reported study of chromosome allele loss in fibrolamellar carcinoma (FLC), a distinct, rare variant of hepatocellular carcinoma (HCC). We searched for evidence of allele loss in FLC using 18 DNA probes for 10 chromosomes and compared the pattern of loss with our series of HCC. Two of the probes, lambda MS32 (1q42-43) and cMS621 (5p) showed allele losses in one tumour, while other probes showed no loss. The frequency of allele loss in FLC was much lower than in HCC, which may be associated with their different prognoses."} +{"text": "Two hundred and twenty-two women with advanced cancer of the breast were asked to complete two previously validated self-assessment questionnaires and the Rotterdam Symptom Checklist (RSCL) in order to determine the prevalence and persistence of affective disorders in this group of patients. Fifty-six (27%) of 211 women who completed the HADS and 33 (22%) of 204 who completed the RSCL rated as probable cases of an anxiety state and/or depressive illness. One hundred and fifty-five patients completed the questionnaires again 1-3 months later. Twenty-one (13%) were persistently anxious or depressed as judged by the HADS compared with 14 (10%) on the RSCL. When both questionnaires were considered together, approximately one third of patients had scores suggestive of an affective disorder and in one third of these it was persistent. Only 30 patients (43% of cases) were detected as 'cases' by both questionnaires and this finding warrants further investigation."} +{"text": "Transcriptome data from quantitative PCR (Q-PCR) and DNA microarrays are typically obtained from a fixed amount of RNA collected per sample. Therefore, variations in tissue cellularity and RNA yield across samples in an experimental series compromise accurate determination of the absolute level of each mRNA species per cell in any sample. Since mRNAs are copied from genomic DNA, the simplest way to express mRNA level would be as copy number per template DNA, or more practically, as copy number per cell.Here we report a method (designated the \"Percellome\" method) for normalizing the expression of mRNA values in biological samples. It provides a \"per cell\" readout in mRNA copy number and is applicable to both quantitative PCR (Q-PCR) and DNA microarray studies. The genomic DNA content of each sample homogenate was measured from a small aliquot to derive the number of cells in the sample. A cocktail of five external spike RNAs admixed in a dose-graded manner was prepared and added to each homogenate in proportion to its DNA content. In this way, the spike mRNAs represented absolute copy numbers per cell in the sample. The signals from the five spike mRNAs were used as a dose-response standard curve for each sample, enabling us to convert all the signals measured to copy numbers per cell in an expression profile-independent manner. A series of samples was measured by Q-PCR and Affymetrix GeneChip microarrays using this Percellome method, and the results showed up to 90 % concordance.Percellome data can be compared directly among samples and among different studies, and between different platforms, without further normalization. Therefore, \"percellome\" normalization can serve as a standard method for exchanging and comparing data across different platforms and among different laboratories. E. coli. Statistical approaches have been proposed for ratiometric data to improve inter-microarray variations, especially of non-linear relations : an Excel spreadsheet file containing 2 hr data (15 GeneChip data) of the total of 60 Affymetrix Mouse 430-2 GeneChip raw data of the TCDD study consisting of 20 different treatment groups in triplicate ]: an Excel spreadsheet file containing 4 hr data (15 GeneChip data) of the total of 60 Affymetrix Mouse 430-2 GeneChip raw data of the TCDD study consisting of 20 different treatment groups in triplicate ]: an Excel spreadsheet file containing 8 hr data (15 GeneChip data) of the total of 60 Affymetrix Mouse 430-2 GeneChip raw data of the TCDD study consisting of 20 different treatment groups in triplicate ]: an Excel spreadsheet file containing 24 hr data (15 GeneChip data) of the total of 60 Affymetrix Mouse 430-2 GeneChip raw data of the TCDD study consisting of 20 different treatment groups in triplicate ]: an Excel spreadsheet file containing 2 hr Percellome data (15 sample data) of the 60 samples of the TCDD study ]: an Excel spreadsheet file containing 4 hr Percellome data (15 sample data) of the 60 samples of the TCDD study ]: an Excel spreadsheet file containing 8 hr Percellome data (15 sample data) of the 60 samples of the TCDD study ]: an Excel spreadsheet file containing 24 hr Percellome data (15 sample data) of the 60 samples of the TCDD study (cf. Figure Click here for fileExcel spreadsheet file containing 15 Affymetrix MG-U74v2 A GeneChip raw data of the uterotrophic response study (cf. Figure Click here for fileExcel spreadsheet file containing Percellome data of the same 15 samples of the uterotrophic response study (cf. Figure Click here for file"} +{"text": "The morphological appearance, incidence and prognostic significance of human chorionic gonadotrophin (HCG)-containing cells in seminomas were examined in a retrospective series of 228 orchidectomy specimens, obtained between 1958 and 1972. Sections from each tumour were stained with haematoxylin and eosin (H & E) and immunocytochemically for HCG. In 33 (14.5%) of the tumours HCG-containing cells were observed, but in only 12 were these recognised in an initial study of the H & E stained sections. HCG staining was seen predominantly in syncytiotrophoblastic giant cells and rarely in \"mulberry\" cells and mononuclear seminoma cells. Of the patients whose tumours included HCG-containing cells 23% died of their disease within 2 years of orchidectomy, compared with only 8% of the patients whose tumours lacked this feature. It is concluded that immunocytochemical staining for HCG should form part of the routine histological assessment of seminomas, and that the presence of HCG-containing cells indicates a more aggressive disease."} +{"text": "An analysis of the primary tumour histopathology was performed on 103 patients managed by orchidectomy and surveillance for stage I seminoma. Patients have been followed for 14-141 months (median 62 months) after orchidectomy. Seventeen patients relapsed, the probability of remaining relapse free at 5 years being 82% . No patients died of progressive germ cell tumours. The only significant histological factor predicting relapse was the presence of lymphatic and vascular invasion. Four of 42 patients with neither lymphatic or vascular invasion recurred, nine of 53 patients with either lymphatic or vascular invasion recurred and three of eight cases with both lymphatic and vascular invasion recurred (P = 0.05-trend). Though initial recurrence was usually of moderate volume and confined to para-aortic nodes, eight patients were treated with chemotherapy either because of the extent of their initial relapse (four cases), or because of subsequent relapse (four cases). In view of the difficulties of identifying patients at risk and of detecting early relapse, surveillance for stage I seminoma should remain a research protocol."} +{"text": "The \"Sir Charles Bell Society (SCBS)\" is an inThe SCBS began as an informal group in 1992 during the VIIth International Facial Nerve Symposium in Cologne. At this initial meeting, 74 attendees confirmed the need for a multinational approach. The original 74 attendees were to be considered as \"Founding Members\" and they drafted a Statement of Purpose: \"The SCBS is to be an international forum for clinicians of all medical specialties and researchers in basic or clinical science who have a special interest in the facial nerve and its disorders. This unique international multi-disciplinary organization is dedicated to the collection, dissemination and exchange of ideas relating to the facial nerve and its diseases.\" Their first charge was to aid Professor Naoki Yanagihara in organizing the \"VIIIth International Facial Nerve Symposium\" to be held in Japan in 1997.The SCBS was officially recognized June 23, 1993, incorporated in the state of California as a non-profit mutual benefit corporation organized under the non-profit mutual benefit corporation law meeting the criteria of: Internal Revenue Code Section 501 C (6) with FEDERAL Employee Identification Number: 94-320802 and California Corporate Number; 1917755 SCOBS.Membership includes otolaryngologists, plastic-reconstructive surgeons, neurologists, neurosurgeons, basic science researchers, physiotherapists, audiologists, anatomists, psychologists, psychiatrists, radiologists, and internists. At present there are over 229 members from 32 countries.The scientific impact is based on the interdisciplinary discussion of problems dealing with the facial nerve. An international meeting is held every four years in different countries. Main topics of discussion and international exchange are:\u25b6 Facial nerve regeneration following different kind of lesions\u25b6 Changes of the Central Nervous System following different kind of nerve lesions\u25b6 Surgical and conservative methods for treatment of facial nerve diseases\u25b6 Evaluation of grading systems.An important aspect of the SCBS is that these problems are discussed on an interdisciplinary platform.The last meeting of the SCBS was held in 2005 in Maastricht/Netherlands during the \"Xth International Facial Nerve Symposium (Chairman: Hans Manni)\" with election of Rainer Laskawi (Germany), President; Jacqueline Diels (USA), Secretary; Paul Mulkens (Netherlands), Treasurer, Mihael Podvinec (Switzerland) is Webmaster and Kedar Adour (USA) President-Emeritus. The next meeting will be held in Rome in 2009."} +{"text": "Placental and placental-like alkaline phosphatase (PLAP) levels in the culture media of 87 cell lines of neoplastic and 'normal' origin were measured by a conventional immunosorbent enzymatic assay (IAEA) and by a new immunoradiometric assay (IRMA). The IRMA detected immunoreactive PLAP in 37 of 80 (46%) human epithelial and germ cell cultures, while the IAEA detected PLAP in only 25 (33%). Of the 52 non-germ cell tumour cultures, the IRMA detected expression in 24 (46%) and the IAEA in only 16 (31%). In 17 cases (21%) the IRMA recorded levels double that of the IAEA, while in five cultures (6%) the reverse was true. The IRMA was much more robust than the IAEA and had considerably lower inter- and intra-assay coefficients of variation (3.75-8.5% vs 5.2-46%). Detection of PLAP(-like) expression by IAEA is dependent on neoplastic expression of enzymatically functional molecules and quantification assumes constant enzyme kinetics. PLAP-like material has a higher catalytic rate constant than PLAP and thus will give higher values on a stoichiometric basis in an IAEA. The higher detection rate and levels of PLAP-like material in neoplastic cultures when measured by the IRMA clearly demonstrate ectopic expression of non-enzymatic PLAP and PLAP-like genes. The incidence of PLAP(-like) expression by non-germ cell and possible germ cell tumours has been underestimated and its utility as a tumour marker should be re-examined using assays which measure antigen mass rather than phosphatase activity."} +{"text": "Inconsistent findings on the efficacy of psychosocial interventions in cancer may be due to their lack of specificity. The aim of this study was to identify priorities of psychosocial need among cancer patients currently receiving treatment in Western Sydney (NSW) as a prelude to targeted intervention. A sample of 188 patients , with various solid tumours, completed a self-report ranking questionnaire listing eight major areas of psychosocial need based on a literature search of relevant studies. The resulting ranking of priorities was: family (1), dealing with emotional stress (2), getting information (3), money (4), work (5), social life (6), sex life (7), and dealing with hospital staff (8). These priorities were independent of demographic characteristics, including time since diagnosis, suggesting that support in the areas of major need may be just as important during follow-up as it is at diagnosis. Males reported less distress than females, and patients with cancer of the head/neck or breast reported most distress. To be maximally effective, psychosocial intervention for cancer patients should focus on the principal areas of family interaction, effective stress management, and access to information."} +{"text": "Helix pomatia agglutinin (HPA)- and Concanavalin A (Con A)-binding carbohydrate expression were studied on 32 tumour samples from primary adenocarcinoma of the breast and 12 samples from lymph node metastases. Live cells were spilled from each of the fresh samples and the extent of fluorescent-labelled HPA and Con A-binding was assessed by flow cytometry. The extent of brightness was expressed in a defined quantitative fashion and the percentage of positive cells was accurately determined from a sample of 10,000 cells per tumour. Correlation of binding with clinicopathological features showed that HPA but not Con A related to lymph node involvement (P = 0.001) in tumours of higher grade (II and III). Spilled tumour cells (non-lymphocytes) were selected from the lymph nodes and the presence of HPA binding cells in the involved lymph nodes was found to relate to positive HPA binding in autologous primary tumours (P = 0.002). Dual-label analysis of HPA and Con A binding showed characteristic features for each tumour. The study demonstrates the use of flow cytometry as a simple and effective technique in detecting differences in lectin binding in live spilled cells from fresh breast cancer tissues. This method may prove to be particularly useful if performed preoperatively on cells in fine-needle aspirates."} +{"text": "The present investigation shows the effect of vitamin A deficiency on the initiation and postinitiation phases of benzo(a)pyrene-induced lung carcinogenesis in male Wistar rats. Lung tumours were induced by giving three intratracheal instillations, one week apart, of 10 mg benzo(a)pyrene per instillation. Maximum tumour incidence (100%) and tumour burden per rat was found in rats which were kept on vitamin A deficient diet for 4 weeks prior to the first administration and 8 weeks after the last administration of benzo(a)pyrene. Rats in which vitamin A deficiency was terminated after the last administration of the carcinogen had 83% tumour incidence, whereas corresponding control pairfed animals had 39% incidence of tumours. These data represent the values obtained 32 weeks after the last administered dose of the carcinogen and indicate the role of vitamin A, both in the initiation as well as in the postinitiation phases of lung carcinogenesis."} +{"text": "The clinical significance of neuron-specific enolase (NSE) as a tumour marker was evaluated in 54 patients with seminoma. Before orchiectomy NSE was elevated in six out of 21 patients with stage I seminoma and 11 out of 16 patients with metastases. After orchiectomy NSE normalised in all evaluated stage I cases, but was still elevated in six out of 12 patients with metastatic disease. NSE monitored the effect of cisplatin-based chemotherapy in patients with metastases. In some patients, increased serum NSE was found together with raised levels of human choriogonadotropin (HCG) and lactate dehydrogenase (LDH), while in others only NSE was elevated. No false positive NSE values were observed. NSE seems to be a clinically worthwhile serum tumour marker for monitoring seminoma patients, with a sensitivity and specificity of the same order as HCG."} +{"text": "Pancreatic ductal adenocarcinomas are characterised by a dense connective tissue reaction. To test the hypothesis that stroma components are synthesised and produced by the tumour cells themselves, eight cell lines as well as six xenografted tumours from human ductal adenocarcinomas of the pancreas were examined for the expression of extracellular matrix proteins (ECM), using cDNA probes and antibodies to collagen types I, III and IV, vitronectin, fibronectin, undulin and laminin. All tumour cell lines and xenografted human pancreatic tumours expressed at least one of the examined ECM at the RNA (collagen type IV > laminin = fibronectin = vitronectin > collagen type III > undulin > collagen type I) or protein level (collagen type IV = collagen type III > vitronectin > laminin > collagen type I = fibronectin > undulin). In nude mouse tumours expression of laminin and collagen I was most pronounced in well-differentiated carcinomas. In a few tumours, collagen type III, vitronectin and undulin were expressed on the luminal side of the neoplastic glands, suggesting loss of normal polar differentiation. Incubation with fetal calf serum modulated ECM RNA levels to a varying extent in all but one cell line (AsPC-1). The results suggest that human pancreatic ductal adenocarcinomas cells are capable of synthesising and producing extracellular matrix proteins in vitro and in vivo, but that the extent and pattern of ECM expression differs between the various tumours and conditions tested."} +{"text": "Serum levels of TAG 72 were measured in 726 serum samples from patients with benign and malignant gynaecological conditions in order to evaluate the clinical usefulness of TAG 72 alone or in combination with other tumour markers. Sixty-six per cent of patients with ovarian cancer showed abnormal concentrations of TAG 72 antigen. A good correlation was also found between serial TAG 72 values and the clinical course of disease during chemotherapy and follow-up. In cervical and endometrial cancer abnormal TAG 72 values occurred in 23% and 14% of cases, while none of the patients with breast cancer had abnormal TAG 72 levels. Among patients with benign disease only one out of 12 patients (8%) with benign ovarian tumours and one of 15 patients with uterine fibromyomatosis (7%) showed high TAG 72 serum levels. However, the determination of TAG 72 did not increase the sensitivity of CA 125 and squamous cell carcinoma antigen (SCC), in ovarian and cervical cancer, respectively. The systemic administration of recombinant interferon alpha-2b to 15 patients with ovarian cancer and different basal levels of TAG 72 did not increase serum levels of the antigen."} +{"text": "Serial image guided 31P magnetic resonance spectroscopy (MRS) studies were performed in eight patients with non-Hodgkin's lymphoma to determine the changes in phosphorus metabolites that occur in vivo in response to chemotherapy. Pre-treatment spectral characteristics were different in high and low grade lymphoma. A larger inorganic phosphate (Pi) peak was seen in high grade NHL relative to phosphomonoesters (PME) or beta adenosine triphosphate (beta ATP), producing significant differences in the PME/Pi and Pi/beta ATP metabolite ratios, and probably reflecting a larger hypoxic cell fraction within the high grade lymphomas. Consistent metabolite changes were seen with treatment, and before reductions in tumour bulk had occurred. Alterations in tumour energetics with changes in Pi and beta ATP, and increases in phospholipid turnover reflected as an increase in the phosphodiester (PDE) resonance were detected. Changes were seen between days 10 and 27 in low grade lymphoma treated with oral alkylating therapy and between days 1 and 5 in lymphoma treated with intensive combination chemotherapy. Increases in the PDE/beta ATP metabolite ratio may be an early indicator of response to chemotherapy in human tumours. These studies illustrate the feasibility and clinical potential of image guided 31P MRS as a means of assessing response to therapy."} +{"text": "Sequential methotrexate (Mtx) absorption studies were undertaken in 127 children undergoing treatment for childhood non-T acute lymphoblastic leukaemia (ALL) to determine whether serum drug concentration, clearance and dosage affect event free survival (EFS). Higher serum concentration and area under the plasma concentration curve (AUC) were not associated with an improved EFS. Methotrexate clearance was not found to be of prognostic significance. Patients who tolerated only low 6-mercaptopurine (6-MP) doses because of neutropaenia and those who randomly were prescribed higher doses of Mtx had a lower rate of leukaemia relapse after the completion of therapy. This suggests that the use of maintenance therapy in maximally tolerated doses may be associated with an increased survival in childhood ALL."} +{"text": "Prognostic information is essential for the evaluation, judgement and optimal treatment of patients with squamous cell cancers (SCCs) of the upper aerodigestive tract. Using immunohistochemical and flow cytometric techniques, we have studied the significance of cellular expression of the Ki-67 antigen, epidermal growth factor receptor (EGFR), the transferrin receptor (TFR) and DNA ploidy status in a prospective analysis of patients with SCCs of the head and neck region. All 42 fresh tumour samples expressed both EGFR and TFR to varying degrees. Receptor expression was most marked on the peripheral invading margin of cancer cell islands although staining was also demonstrated in a random fashion within cellular islands and consistently along the basal cell layer of overlying stratified squamous epithelium. The percentage of cancer cells that reacted with the Ki-67 monoclonal antibody was assessed as low (less than 10%) in 15 samples (35.8%), intermediate (10-30%) in 19 samples (45.2%) and high (greater than 30%) in eight samples (19.0%). Eleven of 15 samples (73%) with a low percentage reactivity were DNA diploid, whereas seven of eight samples (87.5%) with a high percentage reactivity were DNA aneuploid. Poorly differentiated SCCs were significantly more often aneuploid than were either moderately or well differentiated tumours. Our results suggest that EGFR and TFR are widely distributed on SCCs, especially on proliferating cells at the invading tumour margin. In addition, there is a close spatial correlation between cells expressing EGFR, TFR and those expressing the Ki-67 antigen. Tumours in which the staining intensity for both EGFR and TFR was intense invariably expressed the Ki-67 antigen in a high proportion of cells. Further patient follow-up will be important in determining whether intense EGFR and TFR staining, combined with a high percentage reactivity with Ki-67 antibody and DNA aneuploidy, will ultimately define a subset of head and neck cancer patients with a poor clinical outcome."} +{"text": "ABCA4), connexin 36 (CX36), c-mer tyrosin kinase receptor (MERTK) and photoreceptor cell retinol dehydrogenase (RDH12) were investigated in order to identify mutations leading to autosomal recessive (ar) gPRA in 29 breeds of dogs.Generalized progressive retinal atrophy (gPRA) is a hereditary ocular disorder with progressive photoreceptor degeneration in dogs. Four retina-specific genes, ATP binding cassette transporter retina analysis, representing a simple method with comparatively high reliability for identification of sequence variations in many samples. Conspicuous banding patterns were analyzed via sequence analyses in order to detect the underlying nucleotide variations. No pathogenetically relevant mutations were detected in the genes ABCA4 (for 9 breeds), CX36 (for 12 breeds), MERTK and RDH12 (for 9 breeds).Based on the ar transmittance of gPRA in the breeds investigated, informative sequence variations provide evidence allowing indirect exclusion of pathogenetic mutations in the genes Single strand conformation polymorphism (SSCP) analysis is a simple and cost-effective method with high reliability for the identification of base substitutions or other sequence variations like small deletions or insertions in large cohorts of individuals . We usedABCA4), connexin 36 (CX36), c-mer tyrosin kinase receptor (MERTK) and photoreceptor cell retinol dehydrogenase (RDH12) for mutations leading to ar gPRA in 29 breeds of dogs. The ABCA4 gene encodes the ABCR or RIM protein (RmP), thought to act as a flippase for N-retinylidene phosphatidylethanolamine (N-retinylidene-PE), thereby facilitating the transport of all-trans-retinal from the disk lumen to the photoreceptor cytoplasm dCTP (10 mCi/ml) was included. PCR products were digested depending on the lengths of the fragments with different restriction enzymes [see All PCRs were performed under standard PCR conditions -12 in a 2 see . For SSCymes see in orderTL conceived the experimental outline, collected blood samples, conducted the experiments, analyzed the data and drafted the manuscript. SMP, BK and SED carried out parts of the experiments and were involved in analyzing the data. JTE and GD participated in design and coordination of the study and helped to draft the manuscript. All authors read and approved the final manuscript.ABCA4, CX36, MERTK and RDH12 genes in different dog breeds and indirect exclusion of the genes as causing gPRA, respectively. The data provided represent the results of the mutation screening of the candidate genes ABCA4, CX36, MERTK and RDH12.Sequence variations in the Click here for filePrimers, conditions for PCR amplification and restriction enzymes used before SSCP analyses. The data provided represent the information for PCR amplification and restriction of PCR products which were used in SSCP analyses.Click here for file"} +{"text": "The testis is the third common site of relapse after primary treatment of childhood acute lymphoblastic leukaemia, but in adults relatively few testicular relapses of acute lymphoblastic leukaemia have been reported. In the present investigation the differences in the behaviour of leukaemia in immature and mature rat testis and the interactions of testicular and leukaemic cells were studied. Intraperitoneal injection of rat T-leukaemic cells to sexually immature animals induced testicular infiltrations in 100% of animals in 17 days. The infiltrations were small and located perivascularly in the interstitial tissue. Intraperitoneal injection of T-leukaemic cells to sexually mature animals induced testicular infiltrates in 42% of the animals. Leukaemic cells injected directly to the lymph sinusoids of sexually immature and mature testis proliferated rapidly causing testicular enlargement. The M(r) > 5 K fraction of extracts of 50 days old normal rat testes inhibited 3H-TdR incorporation of both normal and leukaemic ConA-stimulated rat lymphoblasts significantly. The same fraction of extracts of testes of 25 days old rats did not have any effect on 3H-TdR incorporation. The normally occurring pubertal increase in the lymphocyte inhibitory effect of the M(r) > 5 K fraction of testis extracts on 3H-TdR incorporation of PBL was prevented following either intraperitoneal or intratesticular injection of rat leukaemic lymphoblasts administered at the age of 25 days. The present observations suggest that physiological pubertal changes in the permeability of vascular endothelium and immunosuppressive effect of the testis may be important explanatory factors for the smaller number of testicular relapses in men compared to boys seen after treatment of ALL."} +{"text": "In the Edinburgh Randomised Breast Screening Project (EBSP) to December 1988 there were 500 cancers in the study population invited to screening and 340 cancers identified in the control population. The size and negative lymph node status characteristics of invasive cancers from the two populations were significantly different (P less than 0.05). The cancers detected by screening were predominantly 'early stage', with 16% noninvasive (PTIS) and 42% invasive stage I (pT1 node negative), whereas cancers were frequently 'late stage' (more than pT2) and inoperable in nonattenders (44%) and controls (36%). Grouped according to customary size ranges of invasive cancers, the proportion of cases lymph node positive differed in those screen detected compared with controls, but the benefit in favour of screen detection was not constant. In comparisons of cancers detected at prevalence and incidence screens, as a test of conformity with screening theory, no significant differences were apparent according to size and lymph node status, yet the characteristics of histological type of cancer discriminated significantly (P less than 0.05). When these same histological characteristics were used to compare survival, the capacity to separate invasive cancers into two groups having good and poor survival probabilities was evident, with a significant improvement for the screen detected poor survival group compared with controls (P less than 0.05)."} +{"text": "Immunoreactive inhibin-like material (ILM) was measured by radioimmunoassay (RIA) in serum and gastric juice samples of 23 fasting normal men, 27 men with chronic superficial gastritis (CSG), and 21 men with carcinoma of stomach . Serum ILM levels in carcinoma of stomach patients (367 +/- 55.5 ng ml-1) were significantly higher than in normal men and in patients with CSG . Sixty two per cent and 86% of patients with carcinoma of stomach showed elevated ILM levels which were higher than the highest noted in patients with CSG and normal men respectively."} +{"text": "Thyroid dysfunction is a well-recognised side-effect of treatment with interleukin-2 (IL2). We assessed the correlation between the development of abnormal thyroid function and tumour response in 13 patients receiving IL2 and interferon-2 alpha for advanced malignancy. Seven patients had normal thyroid function during treatment, and all of these patients have since died of progressive disease. Of six patients who did develop thyroid dysfunction during treatment, one patient has died of progressive disease. However, statistically we were unable to confirm a definite correlation between the development of thyroid dysfunction and survival in this small group of patients."} +{"text": "Widely disseminated neuroblastoma in children older than infancy remains a very poor prognosis disease. Even the introduction of marrow ablative chemotherapy with autologous rescue has not significantly improved the outlook for these children, presumably because of a failure to eradicate minimal residual disease. One additional approach which may hold promise is the use of immunomodulation with cytokines such as IL2 in the setting of minimal residual disease (MDR), for example after intensive chemotherapy and ABMT. However, considerable variability in the susceptibility of neuroblastoma cells to natural killer (NK) and lymphokine-activated (LAK) killing has been observed, and it is presently unclear how NK and LAK cells recognise neuroblastoma cells. In this paper we examine expression of cell adhesion molecules on neuroblastoma to determine which of these modify interaction with NK and LAK cells. We find that LFA-3 (CD58), the ligand for CD2 is of predominant importance in predicting susceptibility of neuroblastoma to the cytotoxic actions of NK and LAK cells, while expression of ICAM-1 (CD54) may also modify susceptibility. These findings were confirmed by blocking experiments in which co-culture of target cells with ICAM-1 and LFA-3 reduced LAK and NK cytotoxicity. Study of the immunophenotypic features of each patient's neuroblastoma cells before induction of MRD may be valuable in determining the likely effect of IL2 in predicting disease reactivation."} +{"text": "Antipsychotic medications are widely prescribed for the treatment of psychotic disorders but carry a variable propensity to increase weight. Thus metabolic dysfunction is the primary cause of premature death in psychosis patients. A system-based approach to understanding the molecular mechanisms behind metabolic dysfunction can potentially provide scope for tailored interventions and alternative treatment pathways that avert such risks on an individual basis. The aim of this study is to identify transcriptomic predictors of high Body Mass Index (BMI) and blood glucose in first episode and chronic psychosis patients.100 first-episode and 100 chronic cases of psychosis meeting ICD-10 criteria (F20-29 and F30-33) were recruited as part of 2 independent studies from 3 NHS Trusts: South London and Maudsley (SLAM), Oxleas and Sussex. Cases were ethnically mixed and aged between 18\u201365. All participants gave informed consent for biological sampling and a range of physical health assessments. Blood glucose was measure using HbA1c while height and weight data were also taken and used to calculate BMI. For FEP subjects biological measures were taken at baseline, 3 months and 12 months post recruitment. RNA samples were collected at the baseline timepoint via PAXgene blood tubes and interrogates, using the Illumina HumanHT-12.v4 beadchip array. Samples were run at the National Institute for Health Research\u2019s (NIHR) Biomedical Research Centre for Mental Health (BRC-MH) at the Institute of Psychiatry, Psychology and Neuroscience. A total of 4756 probes passed a stringent quality control across the 200 samples.Quantitative data on BMI and hba1c levels were used to assess the predictive efficacy of variables grouped by source in first episode psychosis patients. All the predictor categories were included in the initial model, although individual categories were then dropped one at a time. This leave-one-out strategy allowed the direction, impact and relative contribution of the different feature classes to be assessed. Gene-expression and clinical features were consistently associated with the lowest Mean Squared Error after 100 iterations of K-fold cross-validation and after 11 different values of the alpha parameter across 500 imputed datasets. Hba1c or BMI was used as the clinical predictor, depending on whether Hba1c or BMI was used as the target variable. Unattributed surrogate variables derived from surrogate variable analysis (n=6) were analysed within the technical feature set. Having established that gene expression has inherent value as a predictor of metabolic status the same analytical steps were repeated for the discretised versions of these traits (ie. diabetes and obesity). Top-ranking gene transcripts were compared between the quantitative and discretised models. Rank lists of transcripts were subsetted to allow the power distribution across ordered transcripts to be profiled.The top performing transcripts identified are undergoing validation analysis in the chronic sample. Results will be conveyed in terms of sensitivity and false positive rates (ie. the area under the Receiver Operating Characteristic curve). We will undertake further validation through trajectory analysis of gene-expression profiles in followed-up patients."} +{"text": "PRJEB18926), and paired antibody heavy and light chain variable region-encoding transcripts of memory B cells of three subjects . The nucleotide compositions of the corresponding 5\u2032-ends of sequences encoding the CDR3 are presented for transcripts with an origin in 47 different IGHV alleles. These data have been used The highly variable complementary determining region 3 (CDR3) of antibodies is generated through recombination of immunoglobulin heavy chain variable (IGHV), diversity, and joining genes. The codons encoding the first residues of CDR3 may be derived directly from the IGHV germline gene but they may also be generated as part of the rearrangement process. Data of the nucleotide composition of these codons of rearranged genes, an indicator of the degree of contribution of the IGHV gene to CDR3 diversity, are presented in this article. Analyzed data are presented for two unrelated sets of raw sequence data. The raw data sets consisted of sequences of antibody heavy chain-encoding transcripts of six allergic subjects (European Nucleotide Archive accession number Specifications TableValue of the data\u2022These data are useful for further development of processes used to infer the immunoglobulin gene repertoire of an individual, and for interpretation of the results of such analyses.\u2022These data are useful for further development of processes used to infer new germline gene sequences.\u2022These data are useful to investigators of antibody repertoire as they suggest avenues to identify the existence of, to this date, unrecognized alleles of immunoglobulin germline genes.\u2022These data are useful for interpretation of sequence diversity in the ascending strand of CDR3 of na\u00efve and antigen-specific immune repertoires.1This article present data of nucleotide composition in antibody heavy transcripts originating in 47 different immunoglobulin heavy chain variable (IGHV) germline genes/alleles [1]. The22.1Peripheral blood and bone marrow samples of six allergic subjects were collected , and used to construct libraries of antibody H chain V domains, as previously described 2.2PRJEB18926) generated in our laboratory, constituted the main data set. They were processed as previously described FASTQ raw data files Another, unrelated set of raw sequence data was downloaded from the European Nucleotide Archive may however also encode the first base of codon 108. Thereby, the nucleotide composition was analysed also at this position for transcripts originating in any of these four germline genes/alleles.Most of the studied IGHV genes may contribute to nucleotides of the first three codons that encode the CDR3 . The structures were visualized using MacPyMol 1.8.0.6 .Example structures of antibodies encoded by genes with a particular germline gene origin were identified using IMGT/3Dstructure-DB"} +{"text": "Literature has confirmed the pathogenic role of cadmium (Cd) and its exposure in the induction of dyslipidemia implicated in the development and increasing incidence of cardiovascular diseases. The current study explored whether polyphenolics isolated from virgin coconut oil (VCO) prevent Cd-induced dyslipidemia and investigate the underlying mechanism of action, in rats.Rats were pretreated with VCO polyphenols 2 weeks prior to concurrent Cd administration (5 mg/kg) for 5 weeks. Subsequently, serum concentrations of lipid and lipoprotein cholesterol and cardiovascular risk ratios were determined. Hepatic activities of superoxide dismutase (SOD) and catalase (CAT) as well as reduced glutathione (GSH) and malondialdehyde (MDA) contents were analyzed.Sub-chronic Cd administration significantly increased the serum levels of total cholesterol, triglycerides, low density lipoprotein cholesterol and very low density lipoprotein cholesterol while markedly reduced high density lipoprotein cholesterol. Hepatic activities of SOD and CAT as well as GSH content were suppressed by Cd, whereas MDA level was obviously increased. The co-administration of VCO polyphenol with Cd remarkably restored lipid profile and cardiovascular risk ratios and stabilized antioxidant defense systems comparable to control group.This is the first study presenting that polyphenols isolated from VCO prevent Cd-induced lipid abnormalities and cardiovascular risk ratios by improving antioxidant defense systems. Cadmium (Cd) is a widespread environmental and occupational pollutant that has emerged as a major cause of pathobiochemical events and damage in a number of organs. Cadmium concentration has increased in the biosphere through mining, smelting, agricultural and industrial activities , gallic acid, and 1, 1-diphenyl-2-picrylhydrazyl (DPPH) were obtained from Sigma-Aldrich Chemical Co. . Folin-Ciocalteu reagent was purchased from Merck Co. . Solvents such as n-hexane and methanol were purchased from Loba Chemie Pvt. Ltd. Mumbai, India. Reagents used for the assays were commercial test kits and products purchased from Randox, UK. All other chemicals used were obtained from local commercial suppliers.Cadmium . They were kept in cages with wood-chip bedding and allowed free access to standard pellet diet and clean water, ad libitum. The rats were acclimatized one week prior to initiation of the treatment and were handled in a humane manner according to the approved animal experimental procedures of NIH Guidelines for the Care and Use of Laboratory Animals were used as experimental animals in the present investigation. The rats were housed in animal facility of the Department of Biochemistry, Ebonyi State University, Nigeria, under standard conditions according to the method of Nevin and Rajamohan (2004)oC) to remove moisture. The floating oil was gently scooped out and filtered into an air-tight container. This oil which was prepared without refining, bleaching and deodorizing, was used for the isolation of polyphenols administered to rats in the current study.The coconuts were purchased from the Central market, Abakaliki, Ebonyi State Nigeria, in November, 2016. The VCO was extracted from coconuts (Extraction of polyphenols from VCOin vitro antioxidant activity of the polyphenol fraction was determined.Polyphenols in VCO were extracted according to the method described by Nevin and Rajamohan (2004)In vitro antioxidant assay of polyphenol fractionDetermination of total phenolic contentTotal phenolic content of the VCO polyphenol fraction was estimated by Folin\u2013Ciocalteu colorimetric method radical according to the method described by Blois (1958)Ferric reducing antioxidant power (FRAP) assay3+) to ferrous ion (Fe2+) complex. The reducing power was calculated using the following formula: The total antioxidant activity of the VCO polyphenol fraction was evaluated using the ferric reducing antioxidant power (FRAP) assay described by Oyaizu = 100 \u00d7 (absorbance of the control - absorbance of the sample)/absorbance of the control.Experimental designAfter 1 week of acclimatization, rats were randomly divided into 6 groups (n=8) as follow:Group 1 : received clean water for 7 weeks.Group 2 (polyphenols=PF control): received PF for 7 weeks.Group 3 (Cd control): received Cd for the last 5 weeks of experimental period : received PF for 7 weeks + Cd for the last 5 weeks.Group 5 (PF + Cd II): received PF for 7 weeks + Cd for the last 5 weeks.Group 6 (PF + Cd III): received PF for 7 weeks + Cd for the last 5 weeks.The rats were pretreated daily with polyphenols 2 weeks prior to concurrent administration of Cd (5 mg/kg) daily for 5 weeks. At the end of the treatment period (7 weeks), all animals (fasted) were slightly anaesthetized using diethyl ether and blood samples were collected from retro-orbital venous plexus by capillary tubes into plain sample bottles and allowed to clot. The clotted blood samples were centrifuged (3000g for 15 min) for separation of serum used for analysis of lipid profile, total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C) and high density lipoprotein cholesterol (HDL-C). The liver was dissected out after sacrifice by decapitation, washed in cold saline solution, dried using tissue paper, homogenized in 0.1M phosphate buffer and centrifuged (4000 g for 20 min). The obtained supernatant was used for analyses of hepatic antioxidant enzyme activity (SOD and CAT), and GSH and MDA content.Biochemical analysesoC using RANDOX kits. The hepatic activity of SOD was assayed by the method of Arthur and Boyne (1985). The activity of catalase was assayed by the method of Sinha (1972)Determination of biochemical parameters was carried out using standard commercially available kits purchased from RANDOX, UK. Lipid profile parameters were analyzed in serum stored at 4Cardiovascular risk indicesThe coronary risk index (CRI), cardiovascular risk index (CVRI) and atherogenic index (AI) were calculated using the following formulae = LDL cholesterol/HDL cholesterolCoronary Risk Index (CRI) = Total cholesterol/HDL cholesterolCardiovascular risk index (CVRI) = Triglyceride/HDL cholesterolStatistical analysispost-hoc test . A p<0.05 was considered significant. Results are expressed as mean \u00b1 SEM. Statistical evaluation was conducted by one-way ANOVA followed by Tukey\u2019s Effects of administration of VCO polyphenols and Cd on lipid profile parameters in treated ratsEffects of administration of VCO polyphenols and Cd on coronary and cardiovascular risk indices in treated ratsAntioxidant activity of polyphenol fractionEffect of administration of VCO polyphenols, and Cd as well as their co-administration on hepatic markers of oxidative stress in treated ratsThe hepatic markers of oxidative stress are depicted in Cadmium is a non-essential heavy metal known to induce a broad spectrum of toxicological effects and biochemical disruptions posing serious hazards to health. Published papers indicate that Cd toxicity triggers lipid and lipoprotein abnormalities which play undeniable roles in the pathogenesis of CVD and diabetes complications , while CAT decomposes H2O2 to water and molecular oxygen 0122 and Moreover, evidence shows that lipid ratios are important in predicting cardiovascular risk (Gasevic et al., 2014Conclusively, this is the first study to assess beneficial health effect of polyphenols extracted from VCO in Cd-induced dyslipidemia. This study confirmed previous findings that Cd can adversely affect lipid and lipoprotein profile. It has provided evidence that dyslipidemia induced by Cd exposure may be attenuated by antioxidant property of VCO polyphenols in rats. The authors declare no conflict of interest"} +{"text": "This article presents the psychosocial risk factors identified in the cases of 20 children less than four years of age who were victims of fatal or near-fatal physical abuse during a 12 month period in the Commonwealth of Kentucky. These data are related to the article \u201cHistory, injury, and psychosocial risk factor commonalities among cases of fatal and near-fatal physical child abuse\u201d Specifications TableValue of the data\u2022These data reveal commonalities among cases of fatal and near-fatal child abuse and highlight the high prevalence of psychosocial risk factors among caregivers.\u2022prior to each child\u05f3s fatal or near-fatal event, these data may assist medical providers, psychologists, social workers, and legal representatives in collaboratively assessing risk for maltreatment and intervening to prevent future injury.By identifying indicators of maltreatment that were present \u2022These data open doors for further exploration of risk factors for maltreatment, and may guide future research efforts to better inform strategies for child abuse prevention.1Psychosocial risk factors identified in 20 cases of physical child abuse are presented in 2n=10) or near-fatal (n=10) child abuse in the Commonwealth of Kentucky The Institutional Review Boards at the University of Louisville and the Kentucky Cabinet for Health and Family Services (KY CHFS) approved this research. Our retrospective record review included 20 children younger than four years of age who had been victims of fatal ("} +{"text": "Turdus merula) populations as 15.7% inside USUV-suitable areas but found no significant effect for the other 14 common bird species investigated. Our results show that the emergence of USUV is a further threat for birds in Europe and that the large-scale impact on population levels, at least for common blackbirds, must be considered.Usutu virus (USUV) is an emerging mosquitoborne flavivirus with an increasing number of reports from several countries in Europe, where USUV infection has caused high avian mortality rates. However, 20 years after the first observed outbreak of USUV in Europe, there is still no reliable assessment of the large-scale impact of USUV outbreaks on bird populations. In this study, we identified the areas suitable for USUV circulation in Germany and analyzed the effects of USUV on breeding bird populations. We calculated the USUV-associated additional decline of common blackbird ( In addition, we selected a new set of 10,000 random background points for each model. We weighted background points and occurrence points equally in each of the 300 BRT models, which we averaged for the final USUV distribution map. We converted the continuous distribution map for USUV to a binary map with areas that are suitable or unsuitable for USUV. Following Pigott et al. (We applied an ensemble boosted regression tree (BRT) approach using R software and 10 subsets for test datasets (comprising 90% of the presence and background observations) each. We used the training datasets to assess the ability of the models to predict the test dataset with the area under the curve (AUC) statistic. We averaged the AUC values of the models across the 10 models of each split sampling dataset and finally across the 300 average AUC values. Furthermore, we applied a pairwise distance sampling procedure to avoid AUC inflation due to spatial sorting bias, which is considered to give a more realistic quantification of the model performance especially regarding its transferability (Cyanistes caeruleus), common chaffinch (Fringilla coelebs), Eurasian magpie (Pica pica), European greenfinch (Chloris chloris), black redstart (Phoenicurus ochruros), great tit (Parus major), common blackbird, house sparrow (Passer domesticus), Eurasian tree sparrow (Passer montanus), common swift (Apus apus), common house martin (Delichon urbicum), carrion crow (Corvus corone), common wood pigeon , European robin (Erithacus rubecula), and common starling (Sturnus vulgaris). The dataset consisted of 317,533 unique observation datasets with anonymized sampling locations at the level of postal code regions in Germany, each giving information on the number of specimens per bird species and sampling site. Bird abundance data were collected within the citizen science program Stunde der Gartenv\u00f6gel (Hour of the Garden Birds) in Germany. This program is organized by the German BirdLife partner Naturschutzbund Deutschland (Nature and Biodiversity Conservation Union) and its counterpart Landesbund f\u00fcr Vogelschutz in Bayern (Bavarian Society for the Protection of Birds). During the second weekend of May each year, German citizens were requested to count the maximum number of specimens per bird species observed in their gardens in a time frame of 1 hour. We used the data for the 15 most commonly detected bird species, with at least 247,000 observed specimens each during 2006\u20132016, for further analyses: Eurasian blue tit ; this year was the last time bird abundance data were collected before the first epizootic outbreak of USUV in Germany (2 of the country (2.7%). The EuroLST bioclimatic variable with the strongest influence on USUV risk was the annual mean temperature, contributing 71.4% to the variation in the ensemble of models. The next most influential variables were mean temperature of the coldest quarter of the year (8.9%), temperature seasonality (7.2%), and minimum temperature of the coldest month (5.2%). The other 5 variables had <5.0% effect each on USUV risk: mean temperature of the warmest quarter (2.8%), mean diurnal range (1.6%), temperature annual range (1.3%), maximum temperature of the warmest month (1.2%), and isothermality (0.4%) Figure 2Eleven of 15 bird species analyzed did not show a statistically significant difference in the population development between the areas suitable and unsuitable for USUV since 2011. We determined overlapping 95% bootstrap CIs between USUV-suitable and USUV-unsuitable areas for 2016 Figure 3,During the past 2 decades, an ongoing spread of USUV and a continuous circulation of the virus after initial establishment have been observed in different countries in Europe (2 (8 million breeding pairs each having approximately 3 fledglings per year [2), >167,119 birds died due to USUV since 2011; this estimate does not include other population effects like immigration compensating a part of the USUV-related population decline. The estimate is substantially higher than the one determined in the study by Bosch et al. and a statistically significant lower population index in the USUV-suitable area compared with the USUV-unsuitable area (nonoverlapping CIs between both areas). We observed no significant effect for the other 14 bird species included in the study. Five years after the first detection of USUV in southwest Germany, the circulation of the virus resulted in an additional decline of \u224815.7% in the common blackbird populations compared with the development of populations not affected by USUV. Avian populations are under different threats, including changes of land use and climate change (Additional information regarding the analysis of Usutu virus in Germany."} +{"text": "Combined effects of climate change and deforestation have altered precipitation patterns in the Amazon. This has led to changes in the frequency of extreme events of flood and drought in recent decades and in the magnitude of the annual flood pulse, a phenomenon that influences virtually all aspects of river-floodplain ecosystem dynamics. Analysis of long-term data revealed abrupt and synchronous changes in hydrology and fish assemblage structure of a floodplain lake near the confluence of Amazon and Negro rivers. After an intense drought in 2005, the assemblage assumed a different and fairly persistent taxonomic composition and functional structure. Declines in abundance after 2005 were more pronounced for species of all sizes having equilibrium life history strategy, large species with periodic life history strategy, and for all trophic levels except primary consumers. Our results suggest that the extreme drought triggered changes in the fish assemblage and subsequent anomalous hydrological conditions have hampered assemblage recovery. These findings stress the need to account for climatic-driven hydrological changes in conservation efforts addressing aquatic biodiversity and fishery resources in the central Amazon. Climate change is impacting biodiversity and ecosystem services on a global scale46789111213Hydrology in the middle reaches of the Amazon is regulated by precipitation in catchments that span a vast portion of the basin6616Consequences of hydrological changes on the Amazonian fish fauna are poorly understood. Only a few studies have examined impacts of recent climatic change on aquatic ecology in the Amazon, and these have analyzed responses to drought over relatively short time intervals18Here we investigate temporal changes in fish assemblage structure during the period of 1999\u20132014, when the central Amazon experienced abnormally large inter-annual hydrological variation. To evaluate trends in inter-annual and intra-annual hydrologic variation, we analyzed river discharge data from 1950 to 2014 using principal components analysis (PCA). Multivariate ordination methods also were used to assess taxonomic and functional assemblage structures, the latter according to two ecological aspects: life-history strategies and trophic positions. Fish abundance data were obtained from standardized fish surveys conducted in a floodplain lake near the confluence of Negro and Amazon rivers . We applMultivariate ordination of hydrological data produced a dominant gradient in the first axis (PCA1) that contrasted annual flood pulses with lower amplitudes, dry seasons with higher water levels, and longer periods of rising water level with the opposite set of conditions . In the Taxonomic and functional composition of the fish assemblage differed markedly before and after 2005 ; the rel5,7\u2009=\u200913.54, P\u2009=\u20090.001; trophic levels: RM-ANOVA F 4,8\u2009=\u200914.527, P\u2009<\u20090.001; The 2005 drought significantly affected abundance (capture per unity effort CPUE) of most groups and 2 (secondary consumers), all of which shifted to lower values after 2005 and then remained relatively stable . HoweverThe year of 2005 corresponded to the first extreme drought that occurred within our field study time frame and after which a set of changes occurred in the river hydrological regime26273031Significant changes in Amazon floodplain fish assemblages after the 2005 drought have now been reported by two different studies, this supports the hypothesis that recent extreme climatic events have altered key environmental factors affecting fish ecology. The Amazon has undergone unprecedented shifts in rainfall and hydrology over the last 10\u201312 years101186sensu ref. 35Hemiodus sp., Curimatella alburna, Triportheus angulatus), and would be especially affected by reduced habitat connectivity during longer dry seasonsBrycon spp., Colossoma macropomum, Prochilodus nigricans, Semaprochilodus spp.), and therefore should be particularly sensitive to changes in flood-pulse timing as well as lateral connectivity.The similarity of response functions obtained for hydrological and biological time series, together with concordance of their change points and the fundamental importance of seasonal flood pulsing for fish ecology, strongly implies that hydrology was the main driver and Brazil\u2019s National Agency for Water (http://hidroweb.ana.gov.br). Temporal components of the annual flood pulse were defined based on analysis of water level recorded over 100 yearsstats library and prcomp function4949Daily records of the water level in the Negro River in Manaus were obtained from the website of Porto de Manaus Company as defined for the hydrological analysis (see previous paragraph).vegdist function in vegan library. PCoA analysis was performed using stats and BiodiversityR.Taxonomic structure - In total, 97 common species out of 196 total species were included in the data matrix for analysis ; Equilibrium-large ; Intermediate-small ; Periodic-large ; Periodic-small . Fishes with an opportunistic life history strategy essentially were missing from our samples, because they were too small (<60\u2009mm SL) to be caught by the standardized sampling method (gillnets). Further details on criteria used to categorize species according to life-history traits can be found in Life history - For all 97 species, we obtained information on five life history traits that were considered likely to influence how populations respond to patterns of environmental variation and allow assignment of species into life history strategies3052Consumer trophic level 1- herbivorous and detritivorous species (n\u2009=\u200926); Consumer trophic level 1.5- omnivorous species (n\u2009=\u200921); Consumer trophic level 2- invertivorous and planktivorous species (n\u2009=\u200926); Consumer trophic level 3- piscivorous species (n\u2009=\u200924) (Trophic level - Each species was assigned one of the four trophic levels: (n\u2009=\u200924) . Furtherdecostand function in the vegan library to reduce influence of more abundant groups but keeping proportionality before performing PCATemporal variation in life history and trophic assemblage structures was assessed using PCA25The effect of 2005 and 2010 droughts on abundance (CPUE) of each functional group was tested by Repeated-measures analysis of variance (RM-ANOVA) using two analytical designs: i) years before 2005 compared to years after 2005; ii) years after 2005 drought compared to after 2010 drought . Assumptions regarding data normality and homoscedasticity were met for this analysis.To evaluate temporal changes of fish assemblage (PCA and PCoA object scores) and temporal trends of abundance (CPUE) of each functional group, we applied a statistical procedure recently proposed to identify regime shifts in time series data254949nlme package and gnls functionAICcmodavg library and AICc function25Response functions and significance of shifts were tested using generalized nonlinear least-squares regression, a method that allows dealing with nonlinear relationships and non-normal errors25The possible driving factors of assemblage dynamics were inferred by comparing the type of response function between environmental and assemblage structure changesHow to cite this article: R\u00f6pke, C. P. et al. Simultaneous abrupt shifts in hydrology and fish assemblage structure in a floodplain lake in the central Amazon. Sci. Rep.7, 40170; doi: 10.1038/srep40170 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."} +{"text": "There is an error in the third sentence of the Abstract. The correct sentence is: This study aimed to describe features of Australian commercial chicken farms, with particular interest in free range farms, by conducting on-farm interviews of 25 free range layer farms, nine cage layer farms, nine barn layer farms, 15 free range meat chicken farms and 15 barn meat chicken farms in the Sydney basin bioregion and South East Queensland."} +{"text": "Individuals with schizophrenia typically suffer a range of cognitive deficits, including in executive functioning (EF) and working memory (WM) . Such difficulties are strongly predictive of functional outcomes, but there is a lack of effective therapeutic interventions [3].Transcranial direct current stimulation (tDCS) is a novel neuromodulatory technique with emerging evidence of potential pro-cognitive applications; however there has been a dearth of understanding of mechanistic effects of this intervention [4].The aim of this study was to evaluate the neurophysiological effects of tDCS during WM and EF assessment in individuals with schizophrenia.We utilized functional magnetic resonance imaging (fMRI) to evaluate the impact of tDCS on WM and EF in individuals with schizophrenia, randomized to receive either \u2018real\u2019 or \u2018sham\u2019 (placebo tDCS). Participants completed a WM (blocked 0\u20133 back) and an EF (color-word Stroop) during 30 min of 2mA tDCS applied to Broadman area 10/46 (anode 35cm2); with cathode placed on right supraorbita. Sham stimulation was applied for 30 sec. tDCS was applied during fMRI (online) [5].In addition to whole brain, we also conducted task relevant region of interest analysis (ROI) to compare mean frontal and prefrontal (Broadman are 10/46 mask) and anterior cingulate cortex (ACC) activity between the two groups during tDCS. All analyses were restricted a p-value of 0.05, following family wise-error correction (FWE).There were no between-group differences in socio-demographic or clinical characteristics (Tab 1.) Participants did not differ on WM task performance during online tDCS (Tab 2). However, there were significant between-group differences in manipulation of information with the real tDCS performing significantly better than sham, controlled for baseline after consolidation [6].During WM the ROI analysis demonstrated increased activation underneath the site of the anode in the medial frontal gyrus in the real tDCS group, as compared to sham. There was a positive correlation between with consolidated performance and the activity in the medial frontal gyrus.Further, tDCS demonstrated significantly reduced activation in the left cerebellum.During EF task, increased performance was associated with decreased activity in the ACC [5].This is the first tDCS study to examine the brain activity during WM and EF assessment in individuals with schizophrenia using fMRIThis data suggests that biasing the membrane potential of neuronal populations in the frontal cortex seems to improve their response to other inputs i.e. decreased BOLD activation in the WM and EF network. Although the mechanism of action of tDCS is not clear yet [6], one may speculate that if the BOLD response represents synaptic activity [7], including input from other areas, then tDCS might increase the probability that a synaptic input will generate a response in an output neuron, without the need of any additional energy expended by the cell. tDCS offers a potential new therapeutic approach to the treatment of cognitive deficits."} +{"text": "Progranulin deficiency in humans is associated with neurodegeneration. Its mechanisms are not yet fully understood. We performed a Yeast-2-Hybrid screen using human full-length progranulin as bait to assess the interactions of progranulin. Progranulin was screened against human fetal brain and human bone marrow libraries using the standard Matchmaker technology (Clontech). This article contains the full Y2H data table, including blast results and sequences, a sorted table according to selection criteria for likely positive, putatively positive, likely false and false preys, and tables showing the gene ontology terms associated with the likely and putative preys of the brain and bone marrow libraries. The interactions with autophagy proteins were confirmed and functionally analyzed in \"Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy\" Specifications TableValue of the data\u2022Progranulin Y2H interactors are useful for comparison of interactors obtained with different methods or with different libraries.\u2022Progranulin interactors give insight into its putative functions.\u2022Progranulin Y2H results can be used to build protein networks and signaling paths.1The full Y2H table contains all of the information and data from the screen and the blast analysis, as well as the sequence of the inserts. If the blast analysis gave two identically scoring hits for a prey sequence, both hits can be found in the full table. A description of the columns is given in comments of the column headers (full table) and explained in the \"Info\" and in the \"The short table shows a summary of the results sorted according to the libraries (brain and bone marrow) and marked with different colors to indicate likely positive hits (green), putative hits (white), possibly wrong hits (yellow) and false hits (red), based on the selection criteria explained in the \"The tables \"GO terms\" and \"GO slim\" contain the results of the Gene Ontology over-representation analysis of likely positive and putative preys.22.1The Y2H screen was done for human fetal brain and bone marrow libraries with the Matchmaker GAL4 system (Clontech) by ImaGenes GmbH using Gateway Invitrogen plasmids for human full length progranulin as bait as described in 2.2http://genetrail.bioinf.uni-sb.de/) https://david.ncifcrf.gov/home.jsp) and subsequently IDs were submitted to ORA using all genes in the database as background. ORA parameters were set to p-value threshold tp=0.05 and Bonferroni \u03b1 correction (Results in http://www.pantherdb.org/). The results are in The gene ontology terms associated with the Y2H progranulin-preys were obtained by means of over-representation analysis (ORA) using the web-based GeneTrail tool ("} +{"text": "Upon publication of the original article it was hAdditional file 1:Location of epigenetic clock CpGs in relation to the nearest glucocorticoid response element (as shown by within GR ChIP-Seq peaks in a lymphoblastoid cell line) and their methylation changes in response to the glucocorticoid receptor agonist dexamethasone. (XLSX 69 kb)"} +{"text": "Deficits in cognitive functions lead to mental retardation (MR). Understanding the genetic basis of inherited MR has provided insights into the pathogenesis of MR. Fragile X syndrome is one of the most common forms of inherited MR, caused by the loss of functional Fragile X Mental Retardation Protein (FMRP).MicroRNAs (miRNAs) are endogenous, single-stranded RNAs between 18 and 25 nucleotides in length, which have been implicated in diversified biological pathways. Recent studies have linked the miRNA pathway to fragile X syndrome. Here we review the role of the miRNA pathway in fragile X syndrome and discuss its implication in MR in general."} +{"text": "To the editor: We read with concern the reports of two human cases infected with swine influenza virus (SIV) that both occurred in October 2016 in Europe [Eurasian avian-like SIV A(H1N1)v were identified in both patients. In Europe, these viruses circulate widely in the pig population . The virThese two cases are the first severe human cases of SIV A(H1N1)v reported to the European Centre for Disease Prevention and Control (ECDC) or the World Health Organization Regional Office for Europe (WHO/Europe) since the 2009 influenza A(H1N1) pandemic, apart from a few sporadic detections in mild or asymptomatic persons during research projects . The detThe 2009 pandemic was the latest of several pandemics caused by a swine-origin influenza virus . The twoPeople who develop influenza-like symptoms after exposure to pigs should be promptly assessed for influenza infection. Specimens should be characterised virologically and isolates should be shared with the WHO Collaborating Centres. Early treatment with neuraminidase inhibitors should be considered and patients isolated to reduce risk of further transmission, in line with relevant national recommendations. Follow-up of other exposed individuals and contacts of the index cases should be considered to identify further cases and to detect any human-to-human transmission of the virus. A rapid sharing of such information nationally as well as internationally through the European Union\u2019s Early Warning and Response System (EWRS), the International Health Regulations or direc"} +{"text": "There is an error in the first sentence of the fifth paragraph in the \"Methods\" section. The correct sentence is: We compared baseline characteristics (at the time of first-line ART failure), rates of key adverse events, treatment discontinuation and virologic suppression among patients receiving second-line ART and concomitant tuberculosis therapy who received super-boosted lopinavir (with ritonavir 400 mg twice daily) and patients who received standard boosted lopinavir (with ritonavir 100 mg twice daily)."} +{"text": "The objective of this study was to compare trajectories of antipsychotic response before and after relapse following response from a first episode of schizophrenia or schizoaffective disorder.The current analysis included patients with a diagnosis of first-episode schizophrenia or schizoaffective disorder who met the following criteria: (1) referral to the First-Episode Psychosis Program between 2003 and 2013; (2) treatment with an oral second-generation antipsychotic according to a standardized treatment algorithm; (3) positive symptom remission; (4) subsequent relapse in association with non-adherence; and (4) reintroduction of antipsychotic treatment. The following outcomes were used as an index of antipsychotic treatment response: change in the Brief Psychiatric Rating Scale (BPRS) total score and number of patients who achieved positive symptom remission, including 20% and 50% response improvement.A total of 130 patients were included in the analyses. All patients took the same antipsychotic in both episodes. Antipsychotic doses in the second episode were significantly higher than those in the first episode (P=0.03). There were significant episode-by-time interactions for all outcomes of antipsychotic treatment response over 1 year in favor of the first episode compared to the second episode. Results remained unchanged after adjusting for antipsychotic dose.The present findings suggest that antipsychotic treatment response is reduced or delayed in the face of relapse following effective treatment of the first episode of schizophrenia."} +{"text": "Timing of pulmonic valve replacement (PVR) following repaired Tetralogy of Fallot (rTOF) is determined by the severity of right ventricular (RV) dilation. While it is known that cardiovascular magnetic resonance (CMR) can more accurately quantify RV size than 2D-echocardiography (2DE), many centers have not fully integrated serial CMR assessment into the management of these patients, despite guideline recommendations. The aim of this study is to determine the extent to which visual assessment of RV size using 2DE would wrongly classify individuals that should be considered for PVR.CMR and 2DE results were obtained from 61 patients with a history of rTOF. Patients were first classified into events and non-events , based on three cutoffs of RV volume determined by CMR . For each event and non-event group, patients were then reclassified based on presence of greater-than-moderate RV dilation determined qualitatively by 2DE. The net reclassification index (NRI), a measure of prediction improvement, was calculated for each of the three CMR cutoff values. Negative NRI values suggest poorer prediction with 2DE, while positive values suggest improved prediction. Hypothesis testing was conducted with McNemar's method.A cutoff of greater-than-moderate RV dilatation determined by 2DE yielded negative NRI for all three CMR event cutoffs . All three NRI were also negative for non-events (Table Regardless of the RV cutoff value used to trigger referral for PVR, visual assessment of RV size using 2DE results in significant misclassification of both individuals with rTOF who should be referred for PVR and those who should not be referred for PVR. Visual determination of RV size based on 2DE cannot substitute current guidelines recommendations for using CMR to determine timing of PVR. Solutions to increase CMR availability or the identification of appropriate surrogates are needed for the management of these patients."} +{"text": "NUT midline carcinoma (NMC) is a very aggressive and lethal type of squamous epithelial cell cancer caused due to fusion of BRD4and NUT genes. The gene fusion results into a new fusion protein that promotes oncogenesis. The detailed molecular mechanismsunderlying the NMC are still not clear and new findings are urgently required to complement the current efforts. AbnormalmicroRNAs (miRNA) expression promotes tumour formation by modulating the functional expression of critical genes other than theparent genes involved in tumour cell proliferation or survival. Here, using Insilco methods, miRNA targeting the transcripts of parentgenes (BRD4 and NUT) and the BRD4-NUT fusion gene were predicted. We investigated a situation, wherein abnormal miRNAexpression in malignant cells could arise due to deletion and fusion of genomic regions encompassing the target site of miRNAgenes. A set of 48 dysregulated miRNAs targeting the critical genes other than the parent genes (BRD4 and NUT) was identified.Functional enrichment analysis of KEGG pathways of target genes of these Ex-miRNAs implicates their role in cancer pathways.Amplification in the expression level of these miRNAs can be used for NMC diagnosis and prognosis. NUT midline carcinoma (NMC) is a fatal form of undifferentiatedepithelial cancer affecting both children and adults .CommonlMicroRNAs (miRNAs) play a critical role in regulating targetgenes and are involved in the initiation and progression of cancer. miRNAs Here, we have idetified the miRNA targeting the transcripts ofparent genes (BRD4 and NUT) and the BRD4-NUT fusion gene.We hypothesize that some of the miRNAs regulating theirrespective BRD4 and NUT gene expression may not be requiredafter the BRD4-NUT gene fusion, as the regions targeted by thesemiRNAs are deleted. This may lead to an apparent amplificationin the miRNAs, which in turn may regulate the pathways leadingto cancer. A comparative study of miRNAs regulating fused geneand its parent gene was performed and their target genes werediscovered. A functional enrichment analysis of KEGG pathway of target genes of these Ex-miRNAs shows its role in cancerpathways.BRD4 gene (Refseq: NM_058243.2), NUT gene (GenBank:AF482429.1) and BRD4-NUT fusion gene (GenBank: AY166680.1)transcript sequences were retrieved from the NCBI Nucleotidedatabase. In order to locate the deleted regions in the fusion genetranscript, the mRNA sequences of parent (BRD4 and NUT) werecompared against the fusion gene (BRD4-NUT) using align twosequences option of NCBI- BlastN tool. Prediction of miRNAstargeting the BRD4, NUT and BRD4-NUT fusion gene transcriptswas performed using MIRDB (http://mirdb.org/miRDB) [It is generally accepted that fusion genes are translated intofusion proteins, which are drivers of cancer pathway activation.On the other hand, it is well established that alterations inmiRNA expression promote tumour formation. The dysregulatedmiRNAs modulate the functional expression of critical genesother than the parent genes involved in tumour cell proliferationor survival . Recent We predicted and compared the miRNA targeting the BRD4and NUT transcripts region before and after the gene fusionevents. Sequence alignment of parent BRD4, NUT and fusionBRD4-NUT mRNA sequences, using NCBI Blast tool, revealedthat 2818 bases (54%) from 3\u05f3 region of BRD4 and 170 bases from5\u05f3 region of NUT were deleted in the BRD4-NUT gene fusiontranscript . miRNAs In order to predict the Ex-miRNA, BRD4 (1-2830 region) andNUT (170-3795 region) of fused gene were subjected to miRNAprediction using miRDB. Out of 34 miRNAs of BRD4, 28 miRNAwere no more required to target the same gene, when comparedto its fused form. This situation arises because of the deletion of2818 bases from 3\u05f3end of BRD4 . SimilarA set of 18, 33, and 34 miRNAs were predicted to target theBRD4-NUT fusion gene transcript, BRD4 and NUT mRNArespectively. Comparative analysis of these miRNAs andfunctional enrichment of pathway revealed that a set of 48miRNA might be dysregulated to target the critical genes otherthan the parent genes (BRD4 and NUT), causing the cancer.Amplification in the expression level of these miRNAs can beused for NMC diagnosis and prognosis."} +{"text": "This article contains the data on farmers' determinants of binary choices for manure use and fertiliser use at their fields in semi-arid northern Ethiopian Rift Valley. The data includes (i) a schematic diagram that represents local farmers' distinctions of the crop field types in terms of the distance from their houses and soil fertility and (ii) a table that describes a representative farmer's crop sequences and soil fertilisation methods in two consecutive years. Details about the literature review of the previous case studies on farmers' determinants of manure application technique adoption conducted in some parts of sub-Saharan Africa where cattle dung is used for manure are also summarized in a table. A table shows descriptive statistics of the independent variables used in the empirical analyses. Summary statistics of 4 binomial logit models and 4 multinomial logit models are indicated in a table, which represent model fit. Last two tables exhibited in this article show the logit analyses. Specifications TableValue of the data\u2022The data include the figure that describes local farmers' distinctions of the crop field types in terms of the distance from their houses and soil fertility in semi-arid northern Ethiopian Rift Valley.\u2022The data include the table that shows a representative farmer's crop sequences and soil fertilisation methods.\u2022These data are a benchmark for farmers' determinants of manure application and fertiliser use at their crop fields in Ethiopian lowlands including semi-arid Ethiopian Rift Valley.\u2022These data can be compared to the similar type of analyses conducted in other areas.1This article includes a schematic diagram representing local farmers' distinctions of the crop fields in terms of the distance from their houses and soil fertility , table t22.1Adama and Boset districts in Oromia region, Ethiopia, are classified into five agroecological sub-zones 2.2The following two-step procedures were used to select sample plots: in the first step, we set a goal to select 150 households from each maize growing sub-area. The target numbers of households were equally split by the number of sub-zones in each sub-area: four and two sub-zones in the MD and MM sub-areas, respectively, and were allocated to each sub-zone. Semi-structured questionnaires were prepared for interviewing randomly selected household heads in November and December 2012. After eliminating questionnaires with invalid data, we had data from 146 and 173 household heads living in the MD and MM sub-areas, respectively. It was found these 146 and 173 household heads had 313 continuous maize cropping fields and 302 other than maize cropping fields . In the second step, we randomly selected 262 CMCFs (131 for MD and 131 for MM sub-areas) and 262 OCMFs (131 for MD and 131 for MM sub-areas) from these 313 CMCFs and 302 OCMFs to match the numbers of the plot data between CMCFs and OCMFs and between MD and MM sub-areas. The total number of the plot data became 524 (262 CMCFs+262 OCMFs).2.3n=262) had three fertilisation options: (i) no fertilisation (n=39), (ii) manure application (n=220), and (iii) fertiliser use (n=3), while the OCMFs (n=262) had three fertilisation options: (i) no fertilisation (n=4), (ii) fertiliser use (n=153), and (iii) both compost and fertiliser use (n=105). The following two empirical exercises were conducted by using different econometric models:(i)manure: 1=used, 0=not used), two binomial logit models were formulated for CMCF and OCMF subdatasets . Another two binomial logit models were created with and without variable crop for the pooled dataset ; andTo analyse farmers' determining factors in binary manure use options fertilisation: 1=no fertilisation, 2=manure application, 3=fertiliser use, 4=both manure and fertiliser use), two multinomial logit models were built for the CMCF and OCMF subdatasets . Another two multinomial logit models were formulated with variable crop (model B3) and without variable crop (model B4) for the pooled dataset. Hausman test or Small-Hsiao test To assess the farmers' determinants of four fertilisation options , Bayesian information criterion (BIC), and the % correctly estimated values were examined. To test the validity of the subsampling method, the sum of squared residuals obtained from the pooled dataset and subdatasets to test the equality of coefficients were compared between the models Independent variables selected in this study were based upon the literature on technology adoption studies of manure/fertiliser use , Table 32.4Summary statistics showed t"} +{"text": "Severe bacterial infections can lead to both acute and chronic inflammatory conditions. Innate immunity is the first defense mechanism employed against invading bacterial pathogens through the recognition of conserved molecular patterns on bacteria by pattern recognition receptors (PRRs), especially the toll-like receptors (TLRs). TLRs recognize distinct pathogen-associated molecular patterns (PAMPs) that play a critical role in innate immune responses by inducing the expression of several inflammatory genes. Thus, activation of immune cells is regulated by cytokines that use the Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathway and microbial recognition by TLRs. This system is tightly controlled by various endogenous molecules to allow for an appropriately regulated and safe host immune response to infections. Suppressor of cytokine signaling (SOCS) family of proteins is one of the central regulators of microbial pathogen-induced signaling of cytokines, principally through the inhibition of the activation of JAK/STAT signaling cascades. This review provides recent knowledge regarding the role of SOCS proteins during bacterial infections, with an emphasis on the mechanisms involved in their induction and regulation of antibacterial immune responses. Furthermore, the implication of SOCS proteins in diverse processes of bacteria to escape host defenses and in the outcome of bacterial infections are discussed, as well as the possibilities offered by these proteins for future targeted antimicrobial therapies. Cytokines are signaling molecules secreted by cells to elicit a particular effect on the behavior and communication of surrounding cells family of proteins apparently are modulators of a variety of diseases including those with autoimmune etiologies, inflammation, allergies, bacteria, and cancer. SOCS regulate signaling pathways on an intracellular level to potently and specifically inhibit cytokine and growth factor signaling that have evaded detection by complement or antibody and protein tyrosine phosphatases (PTPs) are negative regulators that activate the JAK/STAT pathway effectors of PRRs , led to the blockage of cytokine expression. In addition to IFN-\u03b2 signaling, which is involved in the GAS-induced SOCS1, the TLR4/MyD88 pathway was observed to play a crucial role in stimulating SOCS1 by forming a complex with JAK1/STAT1 and E. faecalis stimulated an increase in SOCS1 and SOCS3 mRNA transcripts in mouse macrophages by triggering NF-\u03baB and MAPK signaling pathways to regulate the production of pro-inflammatory cytokines and arabinogalactan, and an external layer of hydrophobic mycolic acids and NLRs via TLR2/MyD88-activation of macrophages augment SOCS3 expression, and dislocation of the MyD88/TLR2 pathway modulated SOCS3 expression T3SS and its encoded virulence factor SpiC trigger SOCS3 up-regulation via the ERK1/2 pathway for inhibition of the JAK/STAT inflammatory signaling cascades for its continued survival in macrophages. GAS, which causes various systemic diseases induced SOCS1 that participates in the GAS' evasion of host immune responses in murine macrophages by dampening cytokine expression leading to rapid bacterial infection , the spirochetal agent of Lyme disease, stimulates the expression of SOCS1 and SOCS3 in macrophages to possibly control its inflammatory disorders (Khor et al., B. burgdorferi via CD14 signaling induced SOCS1, SOCS3, and CIS as mediated by the p38 MAPK pathway to control the development of chronic inflammatory etiologies (Dennis et al., Results from studies by Uchiya and Nikai (Uchiya and Nikai, M. tuberculosis, M. avium, and M. bovis (Gao et al., M. bovis infection stimulated SOCS1 and SOCS3 in mouse macrophages, which mediated the inhibition of IFN-\u03b3-stimulated phosphorylation of STAT1 and thereby the subsequent inhibition of growth and activation of macrophages required for the control of this intracellular pathogen (Gao et al., M. tuberculosis (Sahay et al., Various mycobacteria manipulate IFN-\u03b3-driven immunity by inducing SOCS1 and SOCS3 to evade the immune response or hamper the disease control. Augmentation of SOCS1 and SOCS3 levels and their subsequent inhibition of IFN-\u03b3-induced STAT1 were found to alleviate the immune response for several mycobacterial species like in vitro and in vivo (Galm et al., SOCS proteins regulate cytokine signal transduction for maintaining immune functions but still contribute to the onset of immunological diseases and inflammation (Yoshimura et al., in vitro by interacting with the IFN-\u03b3 signaling complex and functionally reducing the phosphorylation of STAT1, which further resulted in inhibiting the production of pro-inflammatory cytokines and chemokines (Jo et al., The regulation of the levels of pro- and anti-inflammatory cytokines and chemokines by the immune system is critical in limiting or modulating the host defense against invading pathogens. SOCS proteins as negative regulators of JAK/STAT represent a promising target for anti-inflammatory therapies (Turkson and Jove, Staphylococcus aureus (Hennessy et al., The exploitation of host SOCS proteins and manipulation of their functions by bacterial pathogens make them particularly attractive therapeutic targets. Therapeutic approaches targeting host-directed immunomodulatory components against bacterial infections have already been described (Finlay and Hancock, A better understanding of the control mechanisms involved in SOCS modulation of immune responses and inflammation is key to developing effective targeted therapeutics and vaccines. Each SOCS protein contributes either to the negative regulation of cytokine signaling or the regulation of many biological processes. The expression of SOCS proteins can define host susceptibility to infection by facilitating accelerated bacterial growth or protecting the host from severe inflammation. However, the direct action of the SOCS-mediated inhibition in inflammatory response is yet to be fully elucidated, thus limiting the progress being made scientifically and clinically by microbiologist and immunologists. Additionally, factors such as increased virulence, mutations and antibiotic resistance over time pose recurring challenges in the control of epidemic bacterial diseases worldwide. Admittedly, SOCS-targeted therapy for bacterial-induced inflammation is provocative, but yet one that should be considered exploring. So far, inhibiting the action of JAKs by small composites or drugs show reparative potential (DiGiandomenico et al., SD did the literature search and exploration and wrote the manuscript. DB and RS helped with writing and reading the manuscript. SS read and edited the manuscript. VD edited the manuscript and coordinated the project. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The last confirmed wild poliovirus (WPV) case in Democratic Republic of the Congo (DRC) had paralysis onset in December 2011 (1\u20136). AVDPVs are classified as circulating (cVDPVs) when there is evidence of community transmission; immunodeficiency-associated VDPVs (iVDPVs) when isolated from persons with primary immunodeficiency ; or ambiguous (aVDPVs ) when the identity is uncertain is held in a global stockpile for response to poliovirus type 2 outbreaks after the switch , 11 of DRC\u2019s 26 provinces reported 118 cases of acute flaccid paralysis (AFP) with VDPVs isolated in stool samples (1\u20136). UHistorically, the routine immunization program in DRC has not met global standards . TheThe first cVDPV2 patient in Maniema province had paralysis onset on March 26, 2017, in Kindu health zone (6). TheThe Advisory Group approved the release of mOPV2 for two SIAs targeting 276,076 children aged <5 years in eight health zones surrounding and including Kindu and Kunda in June and July (6). ResThe first patient in the cVDPV2 outbreak in the Haut Lomami outbreak area had paralysis onset on February 20, 2017 in Malemba-Nkulu health zone (6). TheThe Advisory Group recommended mOPV2 for two SIAs targeting 513,820 children aged <5 years in 12 health zones , including and surrounding the health zones where cases were reported (6). The SIAs were conducted in June and July (6). ResJust after the Advisory Group\u2019s approval in October 2017, the first of 13 additional, genetically linked cVDPV2 cases were confirmed in Ankoro and Manono health zones in Tanganyika province, with paralysis onset from September 14 to December 22, 2017 . In-deptAfter the December 2017 SIAs, two new VDPV2 emergences were confirmed in Haut Lomami and Tanganyika provinces. The first was in an AFP case with paralysis onset 15 November 2017 in Lwamba health zone (Haut Lomami province); this case has been classified as an aVDPV2 and the occurrence a VDPV2 event (8). TheThe emergence and circulation of VDPVs during many years and over a broad geographical area is evidence of widespread suboptimal poliovirus immunity in major portions of DRC were of insufficient geographic scope to confine the outbreak was established in late 2017 in Kindu (Maniema province) and in Lubumbashi (Haut Katanga province adjacent to Haut Lomami) and will continue. The risk for VDPV emergence in DRC will remain until population immunity is increased and maintained. The immediate goal is to interrupt VDPV transmission in the outbreak areas so that efforts can be turned toward improving polio vaccination and surveillance in other high risk areas in DRC.Democratic Republic of the Congo has had cases of polio caused by vaccine-derived polioviruses (VDPVs) documented since 2004. The emergence of these VDPVs, which cause paralysis similar to wild polioviruses, can occur where population immunity to poliovirus is suboptimal. After an outbreak of 30 circulating VDPV type 2 (cVDPV2) cases during 2011\u20132012, only five VDPV2 cases were reported during 2013\u20132016. In 2017 , 25 cases of VDPV were reported from three provinces, Haut Lomami, Maniema, and Tanganyika. Among the 25 VDPV cases, 22 were classified as cVDPV2, with 20 associated with an emergence that started in Haut Lomami province and spread to Tanganyika province and two associated with a separate emergence in Maniema province. Despite response efforts, transmission of these VDPVs has not yet been interrupted.Risk for VDPV emergence in DRC will remain unless population immunity to poliovirus is increased and maintained. Efforts are being made as part of the current VDPV outbreak response to overcome long-standing constraints to polio vaccination. Such efforts will be extended to other regions of the country once transmission in the current outbreak areas is interrupted."} +{"text": "In 12 patients, this approach was not applied because of cardiac insufficiency. Videothoracoscopy and decortication after thoracotomy ensured the recovery of functions.Our study shows the different therapeutic procedures in 64 patients with pleural effusion due to MRSA pneumonia. The thoracostomy tube associated with pleural washing was decisive in 10 simple effusion patients. Video-assisted thoracic surgery allowed a complete resolution of the disease in 22 complex parapneumonic effusion patients. In 20 of 32 patients with frank pus in the pleural cavity, the videothoracoscopic insufflation of carbon dioxide (CO"} +{"text": "The anatomical and functional information of a cardiac mass collected by cardiovascular magnetic resonance (CMR) imaging could be clinically important by affecting diagnosis, management and prognosis. Whether CMR impacts clinical care in those with known or suspected cardiac masses is not entirely clear.We identified consecutive patients referred to the University of Minnesota Medical Center (\"Minnesota\" cohort) between January 1, 2007 and December 31, 2013, and the University of Pittsburgh Medical Center between October1, 2009 and May 30, 2014 (\"Pittsburgh\" cohort) who were diagnosed with a potential cardiac mass before or after CMR. Final diagnoses were defined by clinician's opinion of histopathology or clinical evidence. Significant clinical impact was defined as CMR establishing a new diagnosis, affecting surgical procedures, or causing medication change as documented in the medical record.We identified 34 patients with masses in the Minnesota cohort n = 1621) and 58 patients in the Pittsburgh cohort (n = 3358). Overall, CMR resulted in significant impact in 71% (24/34) of the patients in the Minnesota cohort and 72% (42/58) in the Pittsburgh cohort (Table 621 and 5CMR of cardiac masses significantly impacts clinical management by facilitating accurate diagnosis and directing clinical management in a substantial percent of patients who had undergone prior evaluations with traditional imaging such as echocardiography. In addition, it also led to avoidance of surgical interventions in masses deemed to be benign or identified as thrombus. CMR is an essential step in the evaluation of majority of patients with cardiac masses or those suspected to be at high risk for developing cardiac masses."} +{"text": "The development of novel targeted agents aimed at selective inhibition of dysregulated oncogenic pathways has been a major focus and advancing area in translational oncology research. In acute myeloid leukemia (AML) the first successes have been in targeting mutations in the receptor tyrosine kinase FLT3. Small molecule inhibitors targeting FLT3 have been in clinical use for the past two decades with many patients showing favorable initial responses; however, development of resistance occurs almost universally. Here we describe mechanisms of resistance to FLT3 inhibitors and ongoing studies aimed at overcoming it.Mutations in FLT3 (FMS-like tyrosine kinase 3) are the most common genetic alteration in patients with AML occurring in approximately 30% of adult and 15% of pediatric patients at the time of diagnosis ; howeverPreclinical studies demonstrating robust anti-leukemic effects of FLT3 inhibition lead to development of ATP-competitive tyrosine kinase inhibitors (TKIs) targeting mutated FLT3 for clinical use. First generation agents with activity against FLT3 such as sunitinib, sorafenib, and midostaurin were multi-kinase inhibitors that also targeted related receptors such as PDGFR and KIT. Given the multi-kinase nature of these compounds, their use was limited due to poor potency against FLT3 and increased toxicity due to off-target activity. To address these concerns, the second-generation TKI, quizartinib (AC220) was developed with increased potency against and selectivity for FLT3. Initial responses to treatment with single-agent quizartinib were promising with 44% of relapsed or refractory FLT3-ITD AML patients achieving a composite complete remission in a phase II study ; howeverFurther analysis of patient samples to better understand mechanisms of relapse revealed secondary point mutations in the FLT3 kinase domain in patients who relapsed during quizartinib monotherapy.The most common quizartinib-resistance conferring mutations occur at the D835 and F691 loci and confer cross-resistance to the first-generation inhibitor sorafenib \u201319. MutaDevelopment of secondary point mutations represent the best characterized mechanism of acquired resistance to FLT3 inhibition; however, resistant FLT3-ITD cells lacking secondary point mutations have been frequently identified indicatiActivation of parallel signaling pathways independent of the FLT3 receptor also plays a role in resistance to FLT3 inhibition. For example, upregulation of the receptor tyrosine kinase AXL has been implicated in resistance to TKIs in a number of tumor types \u201331. SimiThe above findings highlight some of the challenges to successful translation of FLT3 inhibition to clinical application. A number of new inhibitors and dual inhibition strategies have been developed to overcome these barriers. Two of the newer generation FLT3 inhibitors that have advanced the furthest in clinical development are crenolanib and gilteritinib. Crenolanib is a type 1 TKI that is highly selective for FLT3 and PDGFR and retains a high level of activity against D835 mutant FLT3 and to a lesser degree against the F691 gatekeeper mutation . In clinThe ongoing struggles to translate the preclinical promise of FLT3 inhibition into successful clinical use underscore the importance of a deep understanding of the biology of target receptors when developing translational strategies. As it is unlikely that FLT3 inhibition alone will be sufficient to induce durable remissions, ongoing research should be aimed at devising rational combination strategies with other targeted agents based upon understanding of the molecular mechanisms at play. Other promising preclinical lines of investigation include combination with MEK inhibitors or targe"} +{"text": "In late August and early September of 2017, Hurricanes Harvey and Irma swept through the Caribbean and made landfall in the continental United States. As Texas and Florida readied for direct impacts of the storms, nearby states prepared for the arrival of internally displaced persons. During the weeks surrounding the storms, the Tennessee Department of Health (TDH) supported all-hazards situational awareness for public health partners by enhancing syndromic surveillance activities, i.e., the monitoring of symptom combinations or other indicators within a population to inform public health action data from 70 hospitals across Tennessee using the Electronic Surveillance System for Early Notification of Community-Based Epidemics (ESSENCE) patient visits by Texas residents and 1,041 (0.4%) visits by Florida residents. The number of ED visits by patients from Texas remained stable during the monitoring period (average 7.3 per day). In contrast, there was an increase in patients from Florida visiting Tennessee EDs beginning 3 days before Hurricane Irma made landfall in the continental United States. The increase peaked on the day of impact in Florida (September 10) at 116 ED visits, and returned to baseline levels (between 10\u201320 patients per day) within 1 week . The incSyndromic surveillance data are often used to identify clusters of illness based on geography or time (At TDH, ESSENCE is the only easily accessible information source capable of rapidly collecting health information on out-of-state patients. This initiative allowed TDH to observe where and when out-of-state patients were seeking ED care in Tennessee and to monitor the need for targeted messaging and resources to heavily affected areas. Additionally, close surveillance of chief complaints among out-of-state patients provided assurance that no unusual patterns in illness or injury were occurring.Enhancing syndromic surveillance during these storms was an important strategy for improving situational awareness among public health stakeholders and will be incorporated into future response activities by TDH."} +{"text": "MMWR Recommendations and Reports, \u201cPrevention of Measles, Rubella, Congenital Rubella Syndrome, and Mumps, 2013: Summary of Recommendations of the Advisory Committee on Immunization Practices (ACIP),\u201d an error occurred in the third sentence of the first paragraph under the heading \u201cMeasles Component\u201d on page 8. That sentence should read:In the 1967), live attenuated vaccines containing the Edmonston B (available in the United States from 1963 through 1975), and Schwarz strain (available in the United States from 1965 through 1976).\u201cBecause of increased efficacy and fewer adverse reactions, the vaccine containing the Enders-Edmonston vaccine strain replaced previous vaccines: inactivated Edmonston vaccine (available in the United States from 1963 through"} +{"text": "Odocoileus virginianus) in Illinois, USA, to investigate the potential effect of landscape on social network structure by weighting the edges of seasonal social networks with association rate (based on proximity inferred from GPS collar data). At the local level, we found that sociality among female deer in neighboring social groups (n = 36) was mainly explained by their home range overlap, with two exceptions: 1) during fawning in an area of mixed forest and grassland, deer whose home ranges had low forest connectivity were more social than expected; and 2) during the rut in an area of intensive agriculture, deer inhabiting home ranges with high amount and connectedness of agriculture were more social than expected. At the global scale, we found that deer populations (n = 7) in areas with highly connected forest-agriculture edge, a high proportion of agriculture, and a low proportion of forest tended to have higher weighted network closeness, although low sample size precluded statistical significance. This result implies that infectious disease could spread faster in deer populations inhabiting such landscapes. Our work advances the general understanding of animal social networks, demonstrating how landscape features can underlie differences in social behavior both within and among wildlife social networks.Intraspecific social behavior can be influenced by both intrinsic and extrinsic factors. While much research has focused on how characteristics of individuals influence their roles in social networks, we were interested in the role that landscape structure plays in animal sociality at both individual and population levels. We used female white-tailed deer ( Loxodonta africana) ) density ,20, pred density , and hun density ,23. The was low , African drought , oribi . Female white-tailed deer represent an interesting model to explore social behavior because they form matrilineal social groups )S1 FigWe randomly selected an increasing number of locations for each dyad, calculated association rate, and repeated this 100 times. The solid line represents the seasonal association rate . The dashed lines represent the association rate that we would expect for a dyad with one more or one less association than what we observed for our focal dyad across the entire season; if the mean subsampled association rate was within these bounds, then the error associated with the number of locations should not interfere with our rank order of association rates. The value in the upper right corner is the number of locations at which the association rate was within the dashed lines.(DOCX)Click here for additional data file.S2 FigBoxes represent the median (centre line) and the first and third quartiles (the range that contains 50% of the data). Whiskers represent the highest (lowest) value that is within 1.5*interquartile range. Points represent outliers and vertical lines delineate seasons. Data were pooled over study area and year (2004\u20132009).(DOCX)Click here for additional data file.S3 FigThe upper map is a conductance surface, where white represents forest and black represents absence of forest . The lower map represents current density (white is high current and black is low current) across the forest conductance surface between pairs of sites . The white box outlines the study area; the map outside of the box was later clipped to remove current density that was likely biased high due to the arbitrary placement of the 50 sites.(DOCX)Click here for additional data file.S4 FigWhite represents high current density of forest, agriculture, or the edge between forest and agriculture, and black represents low current density. Current density is analogous to random walkers moving across the landscape between sites located around the perimeter of the buffered study areas .(DOCX)Click here for additional data file.S5 FigWe used a Box-Cox power transformation on the dependent variable to redu(DOCX)Click here for additional data file.S6 FigWe estimated home range overlap as the volume of intersection (VI) of 95% kernel utilization distributions for each(DOCX)Click here for additional data file.S7 FigAn example of a) the configuration of forest and non-forest , and b) the corresponding current density of forest in a portion of the Carbondale, IL study area. Areas of high current density (the probability of movement through a cell) tend to be where corridors of forest are surrounded by non-forest .(DOCX)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 TableCoefficients with 95% CI that did not overlap zero are in bold font.(DOCX)Click here for additional data file.S5 TableCoefficients with 95% CI that did not overlap zero are in bold font.(DOCX)Click here for additional data file."} +{"text": "This article provides descriptive detailed (pre and post) values of physical capacity variables, NT-proBNP, physical activity levels and quality of life in patients with pulmonary arterial hypertension (PH) by New York Heart Association (NYHA) class before and after an 8-month exercise intervention. The data are supplemental to our original Randomized Controlled Trial (RCT) entitled \u201cBenefits of skeletal-muscle exercise training in pulmonary arterial hypertension: The WHOLEi+12 trial\u201d [1]. Specifications TableValue of the data\u2022Data presented here provide the descriptive overview of the PH patients by NYHA class involved in an exercise RCT.\u2022We describe the changes in physical capacity-related primary outcomes (peak watts in leg and bench press) and the changes in physical capacity-related secondary outcomes of the PAH patients by NYHA class involved in the RCT (control vs. intervention).\u2022We describe values of physical activity (PA) levels (min/day in inactivity and moderate-vigorous PA) of PH patients by NYHA class involved in the RCT (control vs. intervention).\u2022We show the values of health related quality of life of PH patients by NYHA class involved in the RCT (control vs. intervention).\u2022This data could be useful to physicians to make comparisons with other cohort datasets and so to contribute to the knowledge of the PA effect in PH patients by NYHA class.1NCT02288442) conducted from January 2015 to June 2016 at the Hospital 12 de Octubre following the Consolidated Standards of Reporting Trials (CONSORT) guidelines Descriptive values of physical capacity-related variables, NT-ProBNP, cardiopulmonary exercise capacity, PA levels and HRQoL of PAH patients involved in the RCT 220 PH patients were involved in the intervention group of the RCT and 20 PH patients in the control group. The RCT intervention lasted 8 weeks and included 3 main components: aerobic and muscle resistance, and specific inspiratory muscle training. All sessions were supervised by experienced fitness instructors. Data outcome (by order of aquisition) were: i) blood sampling for NT-proBNP determination, PImax, 6MWD, muscle power, 5-STS, and distribution of HRQoL questionnaire (1st day); ii) cardiopulmonary exercise testing ; and iii) seven days of accelerometry recording for objective PA determination. Please see Gonzalez-Saiz et al. (2017)"} +{"text": "Human cytomegalovirus (CMV) remains the most common infection affecting organ transplant recipients. Despite advances in the prophylaxis and acute treatment of CMV, it remains an important pathogen affecting the short- and long-term clinical outcome of solid organ transplant recipient. The emergence of CMV resistance in a patient reduces the clinical efficacy of antiviral therapy, complicates therapeutic and clinical management decisions, and in some cases results in loss of the allograft and/or death of the patient. Common mechanisms of CMV resistance to ganciclovir have been described chiefly with the UL97 mutations. Here we evaluate Incidence of ganciclovir resistance in 144 CMV-positive renal transplant recipients and its association with UL97 gene mutations. Active CMV infection was monitored by viral DNA quantification in whole blood, and CMV resistance was assessed by UL97 gene sequencing. Six mutations in six patients were detected. Three patients (2.6%) of 112 patients with history of ganciclovir (GCV) treatment had clinical resistance with single UL97 mutations at loci known to be related to resistance . three patients who were anti-CMV drug na\u00efve had single UL97 mutations (D605E) without clinical resistance. Our results confirm and extend our earlier findings on the specific mutations in the UL97 phosphotransferase gene in loci that have established role in ganciclovir resistance and also indicate that clinical ganciclovir resistance due to UL97 gene mutations is an issue in subjects with history of with ganciclovir treatment. D605E mutations remains a controversial issue that needs further investigations. Human cytomegalovirus (CMV) is a member of the Betaherpesviridae subfamily that belongs to Herpesviridae family, a significant human pathogen . The preIn immunocompetent individuals, primary infections are mostly subclinical and self-limited. In contrast, infections in immunocompromised persons including organ transplant recipients are accompanied by some important morbidity and mortality . CMV remIt was in the 1980s that Resistance of CMV to antiviral agents was first observed in the laboratory. OccurreAmong The 3 common antiviral drugs, ie, GCV, foscarnet, and cidofovir, ganciclovir targets both UL97 and the UL54 gene where foscarnet and cidofovir target just UL54 gene , 13. In Since GCV is the first-line treatment for CMV infections in immunocompromised patients , and ComPatients and methodsPatient population and CMV isolates0C until tested. In accordance with Shahid Beheshti University of Medical Sciences law, only patients who consented to the review of their medical records were included.The aim of this study was to investigate prevalence of GCV resistance in CMV-positive renal transplant recipients and its association with UL97 gene mutations. We utilized clinical specimens submitted to one of the private Virology Laboratory in Tehran for CMV quantitative measurement. A total of 144 post kidney transplant patients (from different transplant centers in Tehran), with quantitative PCR > 2000 copies/mL were included in the study for UL97 sequencing. After obtaining whole blood from patients\u2019 plasma viral DNA was extracted using QIAamp DNA Minikit (Qiagen), in accordance with the manufacturer\u2019s instructions. Viral DNA purification efficiency was analyzed by means of a dual-color detection system supplied with the kit and then they were stored at -20 UL97 gene analysisDrug resistance was evaluated for the UL97 region only by a readily available assay using detection methods previously reported , BrieflyPatients and virus isolates3 to 8\u00d7106 copies/mL serum) were studied. One hundred and forty-four CMV isolates , from 144 immunocompromised patients (post kidney transplantation) with viral load >2000 copies/mL . Clinical data and results of genotypic studies are summarized in Definition of drug resistance and UL97 gene mutation Definition of drug resistance: (no improvement (or with relapses) in CMV viremia or clinical disease during prolonged antiviral therapy especially in the presence of risk factors. Generally, prolonged therapy means 6 or more weeks of cumulative antiviral drug exposure, including more than 2 weeks of ongoing full dose therapy at the time of evaluation). Analysis of CMV DNA by sequencing revealed the presence of 6 single UL97 gene mutations in six patients who had received treatment with GCV .Three patients (2.6%) of 112 patients with history of GCV treatment had clinical resistance with single UL97 mutations at loci known to be related to resistance including an Ala-to-Val mutation at codon 594, MET-to-Thr mutation at codon 460 , and His-to-Gln mutation at codon 520. 3 patients had UL97 mutation without clinical resistance. No clinical resistance or UL97 mutation were observed among patients who were anti-CMV drug na\u00efve. The 6 patients with UL97 mutations were followed for 6 month to see the outcomes.Ganciclovir resistance and clinical outcomeDemographic and clinical characteristics and the outcomes of the 3 patients with UL97 confirmed mutations without clinical resistance and 3 patients with UL97 mutations and clinical drug-resistant are presented in In 3 patients with UL97 mutations without clinical resistance no relapses were seen.Our goal in this study was to determine incidence of ganciclovir resistance in CMV-positive renal transplant recipients and its association with UL97 gene mutations in Iranian post kidney transplant patients. In this study, we analyzed viral DNA in the blood of 144 post kidney transplantation patients (32 patients were anti-CMV drug na\u00efve) with CMV (> 2000 copies/mL) in order to determine incidence of GCV resistance and identify mutations in the CMV UL97 gene associated with clinical resistance to GCV. Clinical GCV resistance with UL97 conformed mutations were detected in 3 of 112 patients (2.6%) with history of GCV treatment. No clinical resistance or UL97 mutation were observed among patients who were anti-CMV drug na\u00efve. GCV has been the drug of choice for treatment of systemic CMV disease. However, long-term therapy, ongoing active viral replication due to factors such as the lack of prior CMV immunity (D+/R-), high levels of immunosuppressive therapy, and suboptimal drug concentrations increase the risk of development of GCV resistance. The UL97 gene is by far the most frequent site of mutations conferring GCV resistance, and extensive work by a number of groups established that nucleotide changes associated with GCV resistance are clustered at codons 460, 520, and 590 to 607. These mutations are A594V, M460T, and H520Q , 15. In The outcome of patients with CMV disease because of ganciclovir-resistant CMV is generally poor, manifested by a high rate of allograft loss as illustrated in our study and those of others -30. In oIn conclusion, CMV disease caused by drug resistant virus is not an uncommon consequence of widespread and increasing rate of GCV use and increase in the incidence of drug-resistant CMV could be subsequent issue. The observations in this study may therefore foreshadow the emergence of drug-resistant CMV as an entity that could threaten the outcome of transplantation. The morbidity of clinical disease because of drug-resistant CMV, the complexity of its treatment, and the poor outcome of patients should be taken into consideration in the determination of concise role of different mutations and their association with clinical resistance and afterword development of optimized strategies for prevention of drug-resistant CMV and also development of drugs with less toxicity."} +{"text": "Bencao (materia medica) literature review is the very first step in the standard authentication procedure of Chinese medicinals. As an important part of China\u2019s cultural heritage, these various bencao (materia medica) texts represent centuries of accumulated wisdom in combating disease and preserving health. In this short review, bencao (materia medica) classics of China are broadly divided into three major categories in our routine practice: mainstream bencao (materia medica), thematic bencao (materia medica) and regional bencao (materia medica). The overall significance and current situation of exploration of bencao (materia medica) literature are summarized as well.Books that record the sources and applications of medicinal materials are commonly known as The Chinese term \u201cbencao\u201d, which literally means \u201crooted in herbs\u201d, reflects the fact that most medicinal materials are derived from botanical sources. Bencao (materia medica) texts of past dynasties primarily describe three aspects of Chinese medicinals: medicinal materials, medicinal properties, and medicinal principles. As an important part of China\u2019s cultural heritage, these various bencao (materia medica) texts represent centuries of accumulated wisdom in combating disease and preserving health. The Complete Collection of Traditional Texts on Chinese Materia Medica, a 410-volume and 246,000-page collection complied by the Association of Chinese Culture Research, includes more than 800 bencao (materia medica) classics from 220 BC to 1911 AD. This collection highlights the value of traditional Chinese medicine (TCM) as a rich source for knowledge-based medical rediscovery due to its documentation of clinical experiences over thousands of years, and also illustrates the monumental challenge of selecting the best parts of TCM for modern innovation bencao (mbencao (materia medica) literature is uniquely developed in Chinese medicine, and represents a tremendous historical and cultural resource as well as an important reference point for clinicians, medical historians, and scientists in disciplines such as new drug discovery and Chinese medicinal authentication. Authentication is fundamental for Chinese medicinal standardization, and bencao (materia medica) literature review is the very first step in the standard authentication procedure of Chinese medicinals bencao (mbencao (materia medica) classics of China are broadly divided into three major categories: (a) mainstream bencao (materia medica): the most influential bencao (materia medica) classics from key historical periods, (b) thematic bencao (materia medica): specialized bencao (materia medica) texts dedicated to specific topics, and c) regional bencao (materia medica): bencao (materia medica) texts focused on medicinal materials from specific regions.In practice, bencao (materia medica) literature. They are the most influential classics from key historical periods.The Divine Husbandman\u2019s Classic of Materia Medica (Shen Nong Ben Cao Jing) This is the earliest extant bencao (materia medica) text, compiled in the Eastern Han Dynasty (25\u2013220 AD). This text records 365 medicinals and summarizes medicinal experiences up to the Han Dynasty. Medicinals are classified into three categories based on their medicinal effects and toxicity. Entries for each medicinal substance include nomenclature, properties, compatibilities, and medical applications. Descriptions of production regions and the ecological environment of some medicinal plants are also recorded briefly.Collection of Commentaries on the Classic of the Materia Medica (Ben Cao Jing Ji Zhu) Tao Hongjing, a physician of the North and South Kingdoms period (420\u2013589 AD), compiled this text by preserving and annotating The Divine Husbandman\u2019s Classic of Materia Medica (Shen Nong Ben Cao Jing) and adding another 365 medicinals. It records 730 medicinals and established the framework of bencao (materia medica) compilations adopted by later generations. In this book, medicinal substances are further classified into seven categories based on their natural properties: jades/stones, herbs, trees, insects/beasts, fruits/vegetables, crops, and medicinals with names but without actual applications.Newly Revised Materia Medica (Xin Xiu Ben Cao) In 659 AD, commissioned by the government of the Tang Dynasty (618\u2013907 AD), this text records 850 medicinals and is considered to be the earliest national pharmacopoeia in China.Materia Medica Arranged According to Pattern (Zheng Lei Ben Cao) Compiled by a physician named Tang Shenwei and published in 1108 AD, this is the most praiseworthy bencao (materia medica) of the Song Dynasty (960\u20131279 AD) as it comprehensively summarizes herbal knowledge up to that time. There are three versions of this book currently in circulation. It records 1746 medicinals and is the only bencao (materia medica) text from the Song and previous dynastic periods that survived intact. It features clearly preserved quotations from previous works and stands out as an important reference point for bencao (materia medica) knowledge leading up to the Song Dynasty.Compendium of Materia Medica (Ben Cao Gang Mu) Written by Li Shizhen, a physician of the Ming Dynasty (1368\u20131644 AD), this text was first published in 1596. It records 1892 medicinal substances. This massive and influential compilation represents the highest academic achievement among all the ancient Chinese bencao (materia medica). It not only comprehensively summarized medical knowledge up to the sixteenth century in China, but also contributed greatly to the development of natural sciences in the world.Over the past 2000\u00a0years, five monumental works stand out in the genre of bencao (materia medica) refer to specialized bencao (materia medica) texts dedicated to specific topics, such as medicinal processing, authentication, dietary therapy, and medicinal properties. Examples include Grandfather Lei\u2019s Treatise on Herbal Processing (Lei Gong Pao Zhi Lun) and Origins of the Materia Medica (Ben Cao Yuan Shi). The former is the first monograph on Chinese medicinal processing, written in about 500 AD in the North and South Kingdoms period; it summarizes the literature and experiences of the ancient practice of processing. The latter stands out in the history of bencao (materia medica) as an outstanding monograph on macroscopic identification, written by Li Zhongli in the Ming Dynasty (1368\u20131644 AD). It is characterized by detailed illustrations and descriptions of diagnostic features of raw medicinal materials. Other examples of thematic bencao texts include the Materia Medica of Dietary Therapy (Shi Liao Ben Cao) of the Tang Dynasty and the Materia Medica for Decoctions (Tang Ye Ben Cao) of the Yuan Dynasty (1279\u20131368 AD). The former was dedicated to the theory and practice of dietary therapy, and the latter to the theory of medicinal properties and clinical experience.Thematic bencao (materia medica) texts record knowledge related to medicinal substances derived from specific local regions. Examples include the Materia Medica from Steep Mountainsides (Lu Chan Yan Ben Cao) and the Essentials of Raw Herbs in Lingnan (Sheng Cao Yao Xing Bei Yao). The former was the first regional bencao (materia medica) with color illustrations dedicated to local medicinal plants; compiled in 1220 AD in the Song Dynasty, it focused on the area around modern-day Hangzhou. The latter was compiled in 1711 AD in the Qing Dynasty (1644\u20131911 AD); it records botanical medicinals used in the Lingnan region, a geographic area located in the southern part of China.Regional Bencao (materia medica) tradition provides a rich record of knowledge that has been gradually refined for centuries, opening a window into the cultural tradition of scholarship and textual research that defines TCM. Bencao (materia medica) literature such as the Compendium of Materia Medica (Ben Cao Gang Mu) illustrates important developments in the broader history of natural sciences in China, and this text has been translated into European languages since 1735 AD. In recent decades, exploration of bencao (materia medica) literature has facilitated dramatic medical discoveries, such as the anti-malarial drug artemisinin from sweet wormwood [bencao (materia medica) literature remains underestimated outside of the TCM community. Therefore, in addition to other aspects of TCM, attention is needed to preserve the cultural resources that lie at the heart of bencao (materia medica).However, at present, the overall significance of daodi medicinal materials, medicinal authentication and Chinese medicinal processing are closely connected to bencao (materia medica) literature [bencao (materia medica) research depends upon a multidisciplinary approach that protects the past while embracing the future.Although our research efforts related to terature \u20139, the f"} +{"text": "Oxytocin and vasopressin mediate a range of physiological functions that are important for osmoregulation, reproduction, social behaviour, memory and learning. The origin of this signalling system is thought to date back ~600\u2009million years. Oxytocin/vasopressin-like peptides have been identified in several invertebrate species and they appear to be functionally related across the entire animal kingdom. There is little information available about the biology of this peptide G protein-coupled receptor signalling system in insects. Recently over 200 insect genome/transcriptome datasets were released allowing investigation of the molecular structure and phylogenetic distribution of the insect oxytocin/vasopressin orthologue \u2013 inotocin peptides and their receptors. The signalling system is present in early arthropods and representatives of some early-diverging lineages. However, Trichoptera, Lepidoptera, Siphonaptera, Mecoptera and Diptera, lack the presence of inotocin genes, which suggests the peptide-receptor system was probably lost in their common ancestor ~280\u2009million-years-ago. In addition we detected several losses of the inotocin signalling system in Hemiptera , and the complete absence in spiders (Chelicerata). This unique insight into evolutionarily patterns and sequence diversity of neuroendocrine hormones will provide opportunities to elucidate the physiology of the inotocin signalling system in one of the largest group of animals. Insects constitute the largest and most diverse group of organisms on earth, contributing to at least half of the global species diversity1a-, V1b- and V2-receptors. Oxytocin and vasopressin signalling is involved in a variety of vital functions both in the periphery and the central nervous system. Oxytocin plays crucial roles in reproduction including uterine contraction or milk ejection, and functions as neurotransmitter in complex social behaviour such as bonding, stress or anxiety66910Here we took advantage of this opportunity to investigate the repertoire of oxytocin/vasopressin-like peptides, namely inotocin peptide hormone precursors, and their cognate family of receptors. Although this peptide G protein-coupled receptor (GPCR) signalling system is thought to date back more than 600\u2009million yearsIn the present study we analysed over 260 invertebrate species of insects and other arthropods for the presence of the inotocin peptide GPCR signalling system. By sequence mining of publicly available genome and transcriptome datasets it was possible to identify and annotate peptide precursor and receptor coding sequences. Furthermore we carried out sequence analyses for conserved motifs on the sequences that were found and performed a phylogenetic analysis of the inotocin receptors. This revealed a unique insight into the phylogenetic distribution and aspects of the evolution of the oxytocin/vasopressin-like peptide GPCR signalling system in arthropods.in 12 out of these 23 species that contain partial sequences we found putative inotocin receptor sequences as well; in the 11 remaining species we cannot exclude the possibility that these inotocin precursor sequences may have been derived as artefacts or sequencing errors] that shared similarity to the neurophysin domain of oxytocin/vasopressin-like precursors (Scolopendra subspinipes (centipede), Atelura formicaria (silverfish) and Leptinotarsa decemlineata (beetle) and three different precursor genes/transcripts in Calanus finmarchicus (crustacean) . The twoX4CPXG contain an alanine or serine residue instead of glycine in position 9; in addition we identified three sequences of putative decapeptides that contain a 4-residue tail before the processing site, i.e. CYIINCIDND in Scolopendra subspinipes, CFITNCPVGG within Lepeophtheirus salmonus and CFITNCPVGS within Caligus rogercresseyi. One unusual sequence had neither an amidated glycine nor a typical amidation processing site (Speleonectes cf. tulumensis - CFILDCPLM-IRN) and hence it remains doubtful whether this precursor will actually be processed to a mature inotocin-like peptide.Sequence analysis of all putative inotocin precursors revealed that there is some degree of conservation within parts of the cysteine-rich C-terminal neurophysin domain . HoweverX4CPXG whereof X4CPXG . NotablyLimulus polyphemus (3 subtypes), Ixodes scapularis (3 subtypes), Metaseiulus occidentalis (2 subtypes), Varroa destructor (2 subtypes), Achipteria coleoptrata (2 subtypes), Platynothrus peltifer (5 subtypes) and Strigamia maritima (2 subtypes). Additionally we found 4 different subtypes in crustaceans, e.g. Daphnia magna , appear to be conserved, which allows distinguishing them from CCAP receptors that contain alanine and valine/leucine/phenylalanine, respectively (AXNPV/L/F) in these two positions (To distinguish inotocin receptors from closely related crustacean cardioactive peptide (CCAP) receptors, which share a high degree of sequence similarity and evolved by gene duplication before Protostomia and Deutorostomia have separated, we aimed to identify sequence motifs exclusively present in the inotocin receptors. Firstly we prepared an alignment of 68 CCAP receptors of insects available at NCBI and 68 invertebrate and vertebrate oxytocin/vasopressin-like receptors that have been previously analysedositions . To confositions .in silico mining strongly relies on raw sequence data quality, completeness of genomes and sampling size, some orders (for instance Mantophasmatodea and Strepsiptera) only contained a few sampled species and hence the apparent absence of the inotocin signalling system in these orders should be treated carefully. Furthermore we identified inotocin precursor and receptor sequences in one species (Arachnocampa luminosa) of the order Diptera (flies), which most likely was due to a contamination of the dataset (FITNCPXG (with some exceptions) is distributed among Chelicerata, Myriapoda, Crustaceans and early-diverging lineages of Hexapoda; the putative peptide CLITNCPKG is almost exclusively present in the monophyletic insects group Polyneoptera (inclusive orders of Zoraptera to Isoptera), and the putative peptide CLITNCPRG is prevalent amongst the latest diverged lines of insects (orders Thysanoptera to Coleoptera).Having identified both inotocin peptides and receptors it was of interest to map their presence across all sampled arthropod species. In 105 species we were able to identify both an inotocin-like precursor as well as the cognate receptor, and in another 64 species we could establish evidence for the presence of the inotocin peptide GPCR signalling system by identification of either peptide or receptor. In addition there are 100 species that showed no evidence for the presence of inotocin precursor sequences or receptors . Bearing dataset . The tax dataset . For exaHalyomorha halys (both inotocin precursor and receptor) and the large milkweed bug Oncopelcus fasciatus (inotocin precursor only); in Auchenorrhyncha it was found in the plant/leaf/froghoppers, but not in cicadas. In a total of 62 analysed species of Hymenoptera, all sawflies, wasps (30 species) and ants (20 species) were identified to contain components of the inotocin signalling system. In agreement with the scientific literature10There are some heterogeneous groups of which some species do and others don\u2019t contain components of the inotocin signalling system; for instance in Hymenoptera and Hemiptera there appear to be losses of inotocin precursor and receptor genes . In Hemi1617Tribolium castaneum11Locusta migratoria22Oxytocin and vasopressin peptide ligands and their cognate receptors comprise one of the oldest and best-studied peptide GPCR signalling systems. Being present across a range of distantly-related animal species and dating back more than 600\u2009million years in evolution, it has been an intriguing model system for comparative endocrinology and neurophysiology199C. elegans, possess oxytocin/vasopressin-like precursor and receptorsIn this project, we analysed the presence or absence of ligands and receptors of the inotocin signalling system in Arthropoda and compared these data to the recently established phylogeny10Speleonectes cf. tulumensis we did not find the dibasic amidation signal between the peptide and neurophysin domain. There are a few exceptions, for instance the Colorado potato beetle (Leptinotarsa decemlineata) which has two copies of inotocin prepropeptides that encode two different inotocin-like peptides (CLITNCPKG and CLITNCPIG) while all other analysed beetle datasets showed evidence only for one copy of the prepropeptide encoding for the putative mature inotocin peptide CLITNCPRG. Interestingly, six of the identified multi-copy receptor species were found within the subphylum Chelicerata and one in Myriapoda, but not a single species within the Hexapoda. We also analysed four different Daphnia magna transcripts of inotocin receptors, which are probably the result of alternative splicing since these sequences are almost identical except for minor deletions/insertions in intracellular loop 3 as well transmembrane domains 3 and 5. The presence of multiple copies in some of the species could be explained by whole genome or large scale duplication events, which have been reported for Limulus polyphemus26Ixodes scapularisCalanus finmarchicusStrigamia maritima3133343534After defining a global map for the phylogenetic distribution of inotocin peptide GPCR signalling system in insects and other arthropods, we aimed to analyse the molecular structure of inotocin peptides and receptors. The vast majority of all sampled species contain one gene encoding for the inotocin receptor and one for the precursor (referred to as prepropeptide). All of the identified prepropeptides have a similar structure containing a signal peptide, a mature inotocin domain, an amidation/processing signal and a neurophysin domain . Only wiin silico mining approaches10Scolopendra subspinipes, Lepeophtheirus salmonis and Caligus rogercresseyi are decapeptides. Such unusual \u2018longer\u2019 oxytocin/vasopressin-like analogues have previously been identified in C. elegans39Ciona intestinalisStyela plicataXIXNC) and are similar to the ancestral vasotocin sequence were used to perform off-line database searches using tblastn and blastp (version 2.2.31) with an E-value cut-off of 10\u2009e\u22124 and default parameters \u22124) were discarded and other hits were manually annotated and verified.Selected published oxytocin/vasopressin-like and inotocin precursor amino acid sequences (Accessions: \u22124) were assigned and confirmed based on two unique sequence criteria: (i) presence of a conserved motif at the end of transmembrane domain 2 and at the beginning of extracellular loop 1 (XPQX2WX5-6F), and (ii) presence of a CXNPW motif in transmembrane domain 7 was used to perform alignments analysis of peptides, precursor proteins and receptor sequences. Signal peptides, mature peptide domain, amidation signal and neurophysin domain were assigned based on homology to query sequences. For the preparation of sequence logos the free WebLogo tool (http://weblogo.berkeley.edu/) was used.ClustalO .Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."} +{"text": "Specifications TableValue of the data\u2022The data presents specific surface area and pore size distribution of vanadium oxides hollow microspheres.\u2022The SEM images of the solvothermal reaction products using different volume ratio of isopropanol/ethylene glycol was characterized by field emission scanning electron microscopy and showed an appropriate amount of ethylene glycol is important for the formation of uniform microspheres structure.\u2022The FESEM images and TEM images of the microspheres prepared with different solvothermal reaction time were characterized by field emission scanning electron microscopy and transmission electron microscopy and showed the morphology of core-shell microspheres.12 adsorption-desorption isotherm and the corresponding pore size distribution curves (inset) data. The SEM image in The 22.1Brunauer\u2212Emmett\u2212Teller (BET) absorption and the pore size distribution were measured on an Xtended Pressure Sorption Analyzer at 77\u202fK. The specific surface area and pore diameter distribution of the samples were analyzed by BET and Barrett-Joyner-Halenda (BJH) methods. The morphology of the sample was determined using field emission scanning electron microscopy and transmission electron microscopy ."} +{"text": "The data presented in this paper shows the spatiotemporal expansion of Dire Dawa City (eastern Ethiopia) and the ensuing land use land cover changes in its peri-urban areas between 1985 and 2015. The data were generated from satellite images of Thematic Mapper (TM), Enhanced Thematic Mapper-Plus (ETM+) and OLI with path/raw value of 166/053 by using Arc GIS 10.1 software. The precision of the images was verified by geolocation data collected from ground control points by using Geographic Positioning System (GPS) receiver. Four LULC classes with their respective spatiotemporal dimensions were clearly identified in the analysis. Built up area had shown an overall annual increment of 15.8% (82\u00a0ha per year) from 517\u00a0ha in 1985 to 2976\u00a0ha in 2015. Expansion took place in all directions but it was more pronounced along the main road towards other nearby towns, recently established business/service areas and the Industrial Park. Barren land, farmland and vegetation areas showed speedy decline over the years. Specifications TableValue of the data\u2022The data is helpful to Dire Dawa City administrators to speculate the extent of the spatiotemporal expansion of Dire Dawa and its potential impacts on the surround areas.\u2022The data provides information on the status of urban expansion towards rural peri-urban areas around Dire Dawa City.\u2022The data is vital to model urban expansion towards rural peri-urban areas surrounding Dire Dawa City to mitigate its adverse impacts on the livelihoods of the people inhabiting the area and the ecosystem.\u2022The data is useful to researchers, urban planners and experts working in the field.1The data in this article provides information on the spatiotemporal expansion of Dire Dawa City (eastern Ethiopia) and the ensuing LULC changes in its peri-urban areas between 1985 and 2015. 2landsat images of 30\u00a0m spatial resolution and path/row values of 166/053 as well as GPS-based ground survey records were vital data sources for this data article. The images were geo-referenced with World Geodetic System (WGS) 1984 datum and Universal Transverse Mercator (UTM) projection system zone 37 North. The analysis comprised of layer stacking, radiometric correction, image enhancement, haze reduction, band combination and false color combination. Google earth maps of each year were used for GPS-based ground verification with a minimum of 20 spatially distributed ground control points in the area. Reconnaissance survey and researchers\u05f3 experience of the study area were also vital. With this pre-assessment, four LULC classification schemes such as built up area, farmland, vegetation and barren land were identified considering the standard classes defined by the US Geological Survey as well as the study detail and objectives TM (1985), ETM+ (2005) and OLI (2015) dry season"} +{"text": "Global efforts to eradicate polio began in 1988, and four of the six World Health Organization (WHO) regions currently have achieved poliofree certification. Within the remaining two regions with endemic poliomyelitis (African and Eastern Mediterranean), Afghanistan, Nigeria, and Pakistan have never interrupted transmission of wild poliovirus (WPV). The primary means of detecting poliovirus transmission is surveillance for acute flaccid paralysis (AFP) among children aged <15 years, combined with collection and testing of stool specimens for detection of WPV and vaccine-derived polioviruses (VDPVs)Two principal indicators measure the quality of AFP surveillance. The first is the nonpolio AFP (NPAFP) rate ; an NPAFP rate \u22652 is considered sufficiently sensitive to detect WPV or VDPV cases if poliovirus is circulating. The second indicator is the collection of adequate stool specimens from \u226580% of patients with AFP cases were reported in AFR in 2017. The four WPV1 cases that occurred in AFR in 2016 were reported from Borno state in Nigeria . Among tAmong the 21 EMR countries, 15,951 AFP cases were reported in 2016, and 19,035 in 2017. Two EMR countries (Afghanistan and Pakistan) reported WPV1 cases in 2016 (33) and 2017 (22). The number of WPV1 cases reported by Afghanistan remained constant (13 in 2016 and 14 in 2017); the number reported from Pakistan declined from 20 (2016) to eight (2017). In 2016, one cVDPV2 case was reported in EMR, in Pakistan. In contrast, during 2017, 74 cVDPV cases were reported from EMR. All cases were type 2 and occurred in Syria; the most recent case occurred in September 2017 , resultiSewage sample testing supplements AFP surveillance by identifying poliovirus transmission that might occur in the absence of detected AFP cases isolate and identify poliovirus, 2) conduct intratypic differentiation (ITD) to identify WPV or screen for Sabin (vaccine) poliovirus and VDPV genotype was the only WPV1 genotype circulating globally and was detected in Afghanistan and Pakistan. West Africa B1 (WEAF-B1) genotype was last detected in Nigeria in 2016. Sequence analysis associated with the SOAS genotype indicates that WPV1 cases might have been missed by AFP surveillance in 2017; orphan WPV1 isolates (those with less genetic relatedness [\u226498.5% in VP1 gene] to other circulating viruses) were associated with three of 22 WPV1 cases reported from Afghanistan and Pakistan, indicating possible gaps in AFP surveillance. In 2017, cVDPV viruses with extended divergence from the parental Sabin strain were also isolated from stool specimens of AFP cases and from environmental samples in three countries.The number of reported WPV cases declined to the lowest point ever in 2017; however, reported cVDPV cases increased from 2016 to 2017 because of major cVDPV2 outbreaks in the Democratic Republic of the Congo and Syria. Although most national-level surveillance quality indicators improved in 2017, considerable variation exists at subnational levels, particularly in inaccessible areas, and timely detection of circulating polioviruses can be hampered if active surveillance efforts are not rigorous. Repeated detection of WPV and cVDPV from sewage samples in locations where poliovirus cases have not been detected or where sewage detections have preceded detection in persons can provide early evidence of viral circulation within a community . Strong supervision and monitoring of surveillance performance, especially at subnational levels, is important to achieve high-quality surveillance that can detect poliovirus transmission. Environmental surveillance has been an important supplement to AFP surveillance and, when carefully conducted in populations covered by sewage networks, can improve detection of circulating virus, particularly in high-risk areas with suboptimal AFP surveillance , the fewest number ever reported globally. Polio cases caused by circulating vaccine-derived polioviruses increased from four in 2016 to 96 in 2017 because of large outbreaks in Syria and the Democratic Republic of the Congo. Although surveillance performance indicators are improving at the national level, gaps remain, including at subnational levels. As polio cases decline, sensitive and timely surveillance becomes even more important. As long as polioviruses circulate in any country, all countries remain at risk."} +{"text": "Heredity: The gene family that cheats Mendel. Published 20, June 2017sp (spore killing) and rsp (resistant to sp) genes in Neurospora bread molds\" with the sentence: \"Example: sk (spore killer) and rsk (resistant to sk) genes in Neurospora bread molds\" on panel B of Figure 1. Please note that this correction does not affect the results and conclusions of the original paper.The gene names in the example of the two-gene model provided on panel B of Figure 1 were incorrectly spelled and abbreviated. We have corrected this error by replacing the sentence \"Example: The corrected Figure 1 is shown here:The originally published Figure 1 is also shown for reference:The article has been corrected accordingly."} +{"text": "Introduction. Postoperative pancreatic fistula formation remains the major complication after distal pancreatectomy. At our institution, we have recently developed a novel bovine serum albumin-glutaraldehyde sealed hand sutured fish-mouth closure technique of the pancreatic remnant during distal pancreatectomy. The aim of this study was to analyze the impact of this approach with regard to technical feasibility and overall postoperative outcome. Patients and Methods. 32 patients who underwent a bovine serum albumin-glutaraldehyde sealed hand sutured fish-mouth closure of the pancreatic remnant during distal pancreatectomy between 2012 and 2014 at our institution were analyzed for clinically relevant postoperative pancreatic fistula formation (Grades B and C according to ISGPF definition) and overall postoperative morbidity. Results. Three out of 32 patients (9.4%) developed Grade B pancreatic fistula, which could be treated conservatively. No Grade C pancreatic fistulas were observed. Postpancreatectomy hemorrhage occurred in 1 patient (3.1%). Overall postoperative complications > Clavien II were observed in 5 patients (15.6%). There was no postoperative mortality. Conclusion. The performance of a bovine serum albumin-glutaraldehyde sealed hand sutured fish-mouth closure of the pancreatic remnant was shown to be technically feasible and may lead to a significant decrease of postoperative pancreatic fistula formation after distal pancreatectomy. Distal Pancreatectomy (DP) is performed as the standard procedure in patients with malignant, cystic, or neuroendocrine tumors and/or chronic pancreatitis in the body and tail of the pancreas . ContinuWe retrospectively analyzed 33 consecutive patients who underwent a bovine serum albumin-glutaraldehyde (BioGlue) sealed fish-mouth closure of the pancreatic remnant during distal pancreatectomy for primary malignant or cystic tumors of the pancreas as well as for chronic pancreatitis at the Department of General, Visceral and Transplantation Surgery, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Campus Virchow, between January 1, 2012, and January 1, 2015. All operations were performed by five experienced visceral surgeons who were all educated about the technical steps of this novel procedure as part of the inclusion criteria of this study. This study was performed in accordance with the Declaration of Helsinki and its amendments and approved by the institutional ethic committee.DP was performed as open surgery in each patient. The extent of the pancreatic resection, as well as the need for additional lymphadenectomy and splenectomy, was determined based on the underlying disease and/or cancer stages. The pancreatic resection was performed in all cases using electrocautery in an incision line, which creates a fish-mouth shaped cutting surface of the pancreatic remnant . After aThe levels of amylase and/or lipase in the blood and in the intra-abdominal drains were routinely measured on the 2nd and 5th postoperative day or immediately in the presence of laboratory or clinical signs of infection. Oral food intake was usually begun on the second postoperative day depending on the patient condition and bowel function. The drains were usually removed within 6 postoperative days if the output was clear and if there were no signs or symptoms of infection. We did not perform a standardized Somatostatin analogue prophylaxis for POPF prevention and pancreatic enzyme were only supplemented in the event of clinical signs of exocrine pancreatic insufficiency.We also did not use a standardized protocol for POPF treatment. The drains were left in situ or replaced interventionally and continuous rinsing of the drain was initiated until the drain secretion was clear and the amylase/lipase had declined back to normal values. A cessation of oral food intake and/or eventually octreotide administration during POPF treatment was decided on individual basis in each patient.The patients who had undergone an additional splenectomy received haemophilus, pneumococcal, and meningococcal vaccination according to current guidelines .All patients were observed in our outpatient department for a postoperative period of at least 30 days.Data collection in all patients included relevant information on their medical history, the pathological examination with regard to the underlying disease and resection margin status and the overall postoperative clinical outcome with documentation of any significant procedure related morbidity, the need for reintervention or reoperation, and the length of hospital stay. Postoperative morbidity was classified according to the Clavien-Dindo classification . POPF anBesides a general analysis of the technical feasibility of this novel approach the primary outcome of our study was to investigate the rate of clinically relevant POPF equivalent to POPF Grades B and C. All other complications within 30 days of the operation were also recorded.Statistical analysis was performed using PASW statistics 19 . Continuous variables were reported using mean or median values where appropriate with range, whereas categorical variables were described using frequencies and percent.Between January 1, 2012, and January 1, 2015, 32 consecutive patients underwent a bovine serum albumin-glutaraldehyde sealed fish-mouth closure of the pancreatic remnant during distal pancreatectomy.There were 15 males (47%) and 17 females (53%) with a median age of 62 years (32\u201377). The indication for distal pancreatectomy was pancreatic adenocarcinoma in 11 patients (34%), intraductal papillary mucinous neoplasm (IPMN) of the pancreas in 7 patients (22%), chronic pancreatitis in 3 patients (9%), neuroendocrine tumors (NET) of the pancreas in 2 patients (6%), mucinous cystic neoplasms (MCN) of the pancreas in 3 patients (9%), cyst adenoma in 4 patients (13%), cyst adenocarcinoma in 1 patient (3%), and leiomyosarcoma in 1 patient (3%). Two of the 32 patients (6%) underwent endoscopic retrograde cholangiopancreatography (ERCP) with endoscopic papillotomy (EPT) and endoscopic pancreas stent placement prior to the operation .A splenectomy was performed in 27 of the 32 patients (84%). Seven patients (22%) underwent an additional multivisceral resection with partial or total gastrectomy in 4 patients (13%), colon resection in 5 patients (16%), and/or partial adrenalectomy in 3 patients (9%). The mean operation time was 199 minutes (116\u2013282 minutes). No patient required intraoperative administration of packed red blood cells. The pancreas tissue texture was found to be soft in 13 patients (41%) and hard in 19 patients (59%) according to the intraoperative assessment of the operating surgeon. Major postoperative morbidity > Clavien II occurred in 5 of the 32 patients (16%). Three patients (9%) developed a clinically relevant POPF Grade B. Each of the three patients could be treated conservatively with a however prolonged hospital stay of 40, 71, and 93 days. No Grade C pancreatic fistulas were observed. Postpancreatectomy hemorrhage Grade A occurred in one patient (3%) as an intraluminal bleeding, which did not require therapeutic consequences. Two patients underwent reoperations, due to an insufficiency of a colon anastomosis in one patient and an abdominal fascial dehiscence in another patient. There was no postoperative mortality. The median length of hospital stay was 12 days (7\u201393) .Postoperative pancreatic fistula formation remains the most relevant complication after distal pancreatectomy with a major impact on postoperative quality of life as well as on health care costs. In patients with an underlying malignant disease POPF may in addition lead to a delayed onset of further essential adjuvant treatment which has been identified as an independent risk factor for early peritoneal recurrence and decreased overall survival .Numerous surgical techniques have therefore been described in an attempt to possibly decrease the incidence and impact of POPF. However, even two recent prospective randomized trials failed to identify an ideal technique for the procedure with the pancreatic remnant. The DISPACT trial compared a stapler versus hand-sewn closure of the pancreatic remnant and the incidence of clinically relevant POPF Grades B and C was reported with 20% and 21% in each group . AnalogoThe creation of a fish-mouth shaped cutting margin of the pancreatic remnant may of course be challenging especially in a rather thin gland and may also be associated with an increased bleeding tendency . Also thThe use of bovine serum albumin-glutaraldehyde (BioGlue) as a sealant is of course rather expensive especially in comparison to widely used fibrin glue. However, several studies showed that the use of fibrin for sealing the cutting surface after PD or DP as well as for occlusion of the main pancreatic duct was not associated with a reduction of POPF , 35. In Complications of bovine serum albumin-glutaraldehyde (BioGlue) application reported in cardiovascular and pulmonary surgery include nerve damage, local or embolic vascular obstruction, and foreign body reactions , 37. L\u00e4mIt should of course be noted that any kind of additional physical barrier may lead to a delayed onset or at least clinical presentation of POPF . As partA reduction in the incidence of POPF may of course not just be achieved by restricting on surgical technical factors alone. Several studies have reported an improved postoperative outcome if EPT or pancreatic stent placement were performed prior to DP . This po"} +{"text": "We report the results of pathologic examinations of 2 fetuses from women in Colombia with Zika virus infection during pregnancy that revealed severe central nervous system defects and potential associated abnormalities of the eye, spleen, and placenta. Amniotic fluid and tissues from multiple fetal organs tested positive for Zika virus. In October 2015, Colombia confirmed its first case of autochthonous Zika virus infection with brain tissue loss, including absence of cerebral hemispheres . Amniotic fluid sampled at 17 weeks was positive for Zika virus by real-time reverse transcription PCR (rRT-PCR). The fetus was at 20 weeks of gestation when evaluated.Case 2 involved a 15-year-old pregnant resident of Bogot\u00e1 who reported symptoms compatible with Zika virus disease, including generalized rash for 2 days and myalgia, after travel to a municipality with prevalent Zika virus infections, with onset occurring at 16\u201320 weeks of gestation. She had an uncomplicated obstetric history with 1 prior live birth. Prenatal care started in week 26; an ultrasound at that time showed a fetus with abnormal clefts in the cerebral hemispheres of the brain , with cleft walls separated and filled with cerebrospinal fluid (open lip). Follow-up ultrasound indicated large regions of parietal and temporal brain parenchymal loss. The fetus was evaluated and Zika virus diagnosis confirmed at 27 weeks of gestation.Autopsies of fetal organs and placenta with anatomic pathology and microscopic evaluation were performed for both fetuses. Tissue samples were fixed in 10% neutral-buffered formalin and fixed in paraffin; 4-\u03bcm-thick cuts were stained with hematoxylin and eosin for morphologic analysis with light microscopy. RNA was extracted from fresh tissue by using a TRIzol plus RNA purification kit . We used rRT-PCR for the detection of Zika virus (NS5) and 1-step RT-PCR for the detection of the envelope protein\u2013coding region (360 bp) were performed as previously described , which highlights the potentially long window of vulnerability to adverse outcomes among pregnant women with Zika virus infection.\u2013Persistent viremia in maternal serum has been previously reported (Given the epidemic levels of Zika virus disease being reported in Colombia and the severe outcomes associated with congenital infection, we call attention to the importance of healthcare providers reporting cases of Zika virus disease for adequate public health surveillance. Recommendations might include enhanced surveillance of acute cases among pregnant women and stillbirths and abortions related to Zika virus disease during pregnancy, as well as adverse outcomes among live births. Collecting information on congenital Zika virus infection is important to helping public health authorities effectively address this new health threat and make evidence-based decisions, which will benefit Colombia and other countries throughout the world."} +{"text": "Energy Information Administration\u05f3s International Energy Statistics (http://www.eia.gov/cfapps/ipdbproject/IEDIndex3.cfm?tid=44&pid=44&aid=2) and the Barro-Lee Educational Attainment Dataset (http://www.barrolee.com). These data can be used to examine the relationships between economic growth and different forms of energy consumption.The data presented in this article are related to the research article entitled \u2018Economic Growth, Fossil Fuel and Non-Fossil Consumption: A Pooled Mean Group Analysis using Proxies for Capital\u2019 The dataset is made publicly available to promote further analyses. Specifications TableValue of the data\u2022The data are useful for analysing the relationship between economic growth and different forms of energy consumption.\u2022The data are publicly available, but are dispersed within several different sources.\u2022The data are collected for 53 countries with varying levels of economic development.\u2022Other researchers may find the data useful for different types of analysis in areas such as environmental and development economics.1The data comprises real gross domestic product (GDP) and physical capital from the World Bank, fossil fuel and non-fossil fuel consumption from the U.S. Energy Information Administration and human capital from the Barro-Lee Educational Attainment Dataset for 53 countries over the period 1990\u20132012. Real GDP and physical capital stock are in millions of 2005 US dollars, fossil and non-fossil fuel consumption are both measured in trillions of British thermal units and human capital is in millions.2The data on real GDP were obtained from the World Bank\u05f3s World Development Indicators (WDI) The data on physical capital were constructed by accumulating real gross fixed capital formation (obtained from the WDI) assuming a constant depreciation rate using the perpetual inventory method Hit) were constructed as follows:Lit=total labour force sit=average years of schooling (obtained from r=return to education, set at 10% following The data on human capital (All the data were converted into logarithms for the purposes of the analysis"} +{"text": "Maintaining genome stability is essential for preventing various human diseases including cancer. Previous studies have elucidated multiple cellular mechanisms for genome maintenance, which can be classified into two major groups: one that deals with replication-associated abnormalities, and the other that repairs various DNA lesions. The replication fidelity maintenance mechanisms involve DNA polymerases and the DNA mismatch repair pathway. While replicative DNA polymerases and the mismatch repair system are responsible for correcting mispairs generated during DNA replication , 2, tranCell and Bioscience presents a series of reviews attempting to provide an overview of the latest breakthroughs and developments in the field. Specifically, this series focuses on (1) novel regulation of DNA damage response by ubiquitinating and deubiquitinating enzymes ; (2) the impact of bulky DNA lesions on error-prone or error-free transcription ; (3) the genome maintenance function of Fanconi anemia proteins ; (4) new factors and mechanisms of DNA break end joining (Wang and Xu); (5) mutagenic and tumorigenic activities of APOBEC3B ; and (6) nonsense RNA-mediated cellular surveillance pathway .Building on the previous discoveries, recent investigations in the field have revealed new insights into the mechanisms of the genome maintenance systems. In this thematic series, It is our sincere hope that this thematic series brings our readers enlightenment and offers sufficient introductory information to help them appreciate the new breakthroughs and developments in the field."} +{"text": "Arabidopsis thaliana. The first analysis was of two gene families with key roles in regulation of oil quality and in particular the accumulation of oleic acid, namely stearoyl ACP desaturases (SAD) and acyl-acyl carrier protein (ACP) thioesterases (FAT). In both cases, these were found to be large gene families with complex expression profiles across a wide range of tissue types and developmental stages. The detailed classification of the oil palm SAD and FAT genes has enabled the updating of the latest version of the oil palm gene model. The second analysis focused on disease resistance (R) genes in order to elucidate possible candidates for breeding of pathogen tolerance/resistance. Ortholog analysis showed that 141 out of the 210 putative oil palm R genes had homologs in banana and rice. These genes formed 37 clusters with 634 orthologous genes. Classification of the 141 oil palm R genes showed that the genes belong to the Kinase (7), CNL (95), MLO-like (8), RLK (3) and Others (28) categories. The CNL R genes formed eight clusters. Expression data for selected R genes also identified potential candidates for breeding of disease resistance traits. Furthermore, these findings can provide information about the species evolution as well as the identification of agronomically important genes in oil palm and other major crops.Comparative genomics and transcriptomic analyses were performed on two agronomically important groups of genes from oil palm versus other major crop species and the model organism, Elaeis guineensis, is a major global crop that can benefit considerably from the application of modern genomic advances. According to recent industry statistics, the annual global production of palm oil increased by almost 600% over the period 1990\u20132017, from 10.5 to 62.9 million tonnes Alignment of two oil palm FATBs with orthologs from A. thaliana and Z. mays. [C] Protein sequence alignment of the orthologous cluster OG1.5_1281 of stearoyl-acyl carrier protein desaturases (SAD) aligned using MUSCLE to produce more than 70% identity between oil palm and A. thaliana and maize proteins.[A] Alignment of two oil palm FATAs with orthologs from (PDF)Click here for additional data file."} +{"text": "The role of the diet as well as the impact of the dietary habits on human health and disease is well established. Apart from its sleep regulatory effect, the indoleamine melatonin is a well-established antioxidant molecule with multiple health benefits. Convincing evidence supports the presence of melatonin in plants and foods with the intake of such foods affecting circulating melatonin levels in humans. While numerous actions of both endogenous melatonin and melatonin supplementation are well described, little is known about the influence of the dietary melatonin intake on human health. In the present review, evidence for the cardiovascular health benefits of melatonin supplementation and dietary melatonin is discussed. Current knowledge on the biological significance as well as the underlying physiological mechanism of action of the dietary melatonin is also summarized. Whether dietary melatonin constitutes an alternative preventive treatment for cardiovascular disease is addressed. The role of the diet as well as the impact of the dietary habits on human health and disease has been described since the antiquity , A strong inverse relationship exists between endogenous melatonin levels and cardiovascular disease reduces BP values of hypertensive men , intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and endothelin-1 (ET-1) while it increases endothelial nitric oxide synthase (eNOS), nuclear erythroid 2-related factor 2 (Nrf2), NAD(P)H quinone oxidoreductase 1 (NQO-1), catalytic glutamate cysteine ligase (GCLC) and heme oxygenase-1 (HO-1) in a rat model of a smoke-induced vascular injury play an important role in the pathological process of pulmonary hypertension and subsequent heart failure which, in turn, activates tumor necrosis factor-\u03b1 (TNF\u03b1)/STAT3 pathway hypertrophy and cardiac fibrosis with the hallmarks of the heart failure administration or other forms of preparations ; FN: conception, literature choice, figures and tables, revised the final draft manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Japanese encephalitis (JE) virus is the most important vaccine-preventable cause of encephalitis in the Asia-Pacific region. The World Health Organization (WHO) recommends integration of JE vaccination into national immunization schedules in all areas where the disease is a public health priority . TInformation on JE surveillance and immunization programs was obtained from several sources. Health officials from 18 WHO countries with endemic JE who attended the 7th Biregional Meeting on Prevention and Control of JE in 2016 were surveyed; abbreviated surveysRepresentatives from all 24 countries with JE virus transmission risk completed the surveys.During 2015, WHO received reports of 4,087 JE cases from 20 (83%) of 24 countries; 3,549 (87%) of these cases were reported from four countries . No other country reported more than 115 cases.Twelve (50%) of the 24 countries had a JE immunization program in 2016 ; 10 virus is a leading cause of encephalitis in Asia. The World Health Organization recommends integration of JE vaccination into national immunization schedules in all areas where the disease is a public health priority.A review of surveillance and immunization program data in the 24 countries with JE virus transmission risk found that in 2016, 22 countries conducted at least some surveillance for JE, and 12 had implemented a JE immunization program. This represents substantial progress in JE prevention and control measures, but challenges remain, including incomplete case reporting, misclassification of cases, lack of immunization program monitoring data, and inadequate monitoring of JE vaccination coverage following vaccine introduction.Strengthened surveillance, continued commitment, and adequate resources for JE vaccination should help maintain progress toward prevention and control of JE."} +{"text": "The correct sentence should read: Left ventricular mass index (LVMi) was calculated using the Devereux-modified cube formula based on linear measurements of interventricular septum thickness, left ventricular cavity diameter and posterior wall thickness as assessed by the American Society of Echocardiography (ASE) method and indexed to body surface area (in m"} +{"text": "In 2015, birth testing for certain asymptomatic HIV-exposed infants was included in the South African National Consolidated Guidelines for the first time.in utero and intrapartum HIV-infected infants failed to recognise:The notion that a single HIV polymerase chain reaction (PCR) test performed at 6 weeks of age would detect virtually all 4the HIV-related mortality that occurs prior to testing at 6 weeks of agethe reduced sensitivity of HIV PCR tests as a consequence of the increase in the number and duration of drugs used for prevention of mother-to-child transmission of HIV (PMTCT) prophylaxis.There is increasing evidence that both fixed dose combination (FDC) maternal PMTCT prophylaxis and daily dose nevirapine (NVP) infant prophylaxis (Option B or B+) contribute towards reduced detection of perinatal HIV infection at 6 weeks of age. The literature demonstrates that:in utero infected infants at 5 days and 2 weeks of age respectively.6 No HIV PCR sensitivity data for 6-week-old HIV-exposed infants, tested at discontinuation of 6 weeks of daily dose NVP, are available.a single perinatal dose of NVP reduced viral load to below the limit of detection in 38% and 17% of 7the probability of a positive HIV PCR at age 6 weeks in perinatally HIV-infected infants is decreased with multi-drug maternal and/or infant PMTCT prophylaxis8in non-breastfed infants, HIV DNA and RNA PCR sensitivity at 1 month of age for perinatally infected infants was 89%9in formula-fed infants who received 6 weeks of postpartum zidovudine (AZT), with or without other antiretrovirals, 32% of intrapartum-infected infants tested HIV DNA PCR negative at 6 weeks of age but tested positive at 3 months of age10prophylaxis reduces HIV DNA concentrations at birth complicating early identification of infected infants for initiation of early treatment12there are case studies illustrating the challenges of \u2018false negative\u2019 and \u2018indeterminate\u2019 HIV PCR results in early infant diagnosis in the context of current PMTCT prophylaxis and calling for revised diagnostic guidelines.in utero and intrapartum HIV infections in the context of current PMTCT interventions. It is too late to diagnose infants who die prior to 6 weeks of age and to achieve early combination antiretroviral therapy (cART) initiation by 7.4 weeks of age as was done on the Children with HIV Early Antiretroviral Therapy (CHER) trial to reduce early morbidity and mortality.13 It is too early to diagnose in utero and intrapartum infections suppressed by daily dose NVP and/or maternal prophylaxis via the placenta and/or breastmilk.The 6-week test, conveniently scheduled at the same time as the 6-week expanded programme for immunisation (EPI) visit, is therefore too late and too early to detect all in utero and intrapartum HIV infections) can never approach 100% because it detects in utero infection only and cannot detect intrapartum infection, namely an infection transmitted at the time of labour and delivery and essentially in the window period at birth. Prior to the implementation of PMTCT and the use of standardised HIV assays, Dunn et al.\u2019s meta-analysis demonstrated that 38% of all perinatal infections were detectable at birth.14 With World Health Organization (WHO) Option A prophylaxis and a single dose of NVP at birth for infants, Lilian et al. demonstrated that 76% of all early HIV infections were detectable at birth.15 This increase was attributed to more sensitive viral detection assays and a proportional increase in in utero to intrapartum infections as a result of PMTCT prophylaxis targeting intrapartum infections during late pregnancy and delivery. As the majority of women deliver in health facilities in South Africa, identifying all HIV-infected women at delivery coupled with birth HIV PCR testing would yield three-quarters of all perinatal HIV infections with close to 90% coverage.The HIV PCR sensitivity at birth for detecting perinatal HIV infections , low birth weight (LBW < 2500 g) or symptomatic HIV-exposed neonates and those born to women who were unbooked or received a late diagnosis of HIV (e.g. at delivery) or received < 4 weeks of antiretroviral PMTCT prophylaxis or had viral loads > 1000 copies per millilitre or were co-infected with tuberculosis during pregnancy. The Western Cape PMTCT guidelines also recommend targeted birth testing that include additional and slightly modified high-risk factors.17 These high-risk factors predict vertical transmission but not necessarily in utero transmission, and therefore the birth HIV PCR test may be negative.The 2014 South African National Consolidated Guidelines recommend targeted birth testing, namely HIV PCR testing of only those HIV-exposed neonates identified as being at high risk of HIV transmission.in utero and intrapartum infections, on every HIV-exposed infant can be offset by following 2010 WHO guidelines to use HIV rapid tests (HRT) from 9 months of age.18 As the majority of HIV-exposed, uninfected infants demonstrate seroreversion by 9 months of age by testing HRT negative, only those with positive HRT would require HIV PCR tests.19 This approach reduces the number of HIV PCR tests required for symptomatic infants or those requiring testing post-cessation of breastfeeding.Universal birth testing of all HIV-exposed infants may be simpler to implement than targeted birth testing. The cost of performing two early HIV PCR tests, to detect To avoid morbidity and mortality, all positive HIV PCR results require urgent action to (1) confirm the HIV-infected status on a second blood sample and (2) initiate cART. Healthcare facilities require good communication with the laboratory to access positive results within 2\u20137 days and systems for patient follow-up to see all HIV PCR-positive patients as soon as possible. As neonates usually return to their primary healthcare clinic and not the maternity unit for follow-up after birth, ensuring that birth HIV PCR test results reach patients will be pivotal to successful implementation of birth testing. Point of care (POC) HIV diagnosis would facilitate same-day identification of HIV-infected neonates.The results of the second, confirmatory viral detection assay should not delay cART initiation but should be obtained as early as possible because, once cART is initiated, it becomes progressively more difficult to detect HIV either by HIV PCR or viral load testing. The availability of two different POC assays for detection of HIV would facilitate same-day identification and confirmation of HIV infection in neonates.1 fewer cases of intrapartum infection may be identified owing to the viral load lowering effect of the daily dose NVP infant prophylaxis. The 2014 National Consolidated Guidelines cater for this in high-risk infants only by recommending a third HIV PCR at 16 weeks of age where prolonged infant prophylaxis (e.g. daily dose NVP for 12 weeks) has been used.1 The probability that the sensitivity of diagnostic virological assays is affected by antiretroviral prophylaxis has prompted American guidelines to recommend an additional HIV PCR test be performed 2\u20134 weeks after combination antiretroviral infant prophylaxis has been discontinued if negative HIV PCR results were obtained during prophylaxis.20 As for all HIV-exposed and uninfected infants, HIV PCR testing is recommended whenever clinical features suggestive of HIV infection are present and 6 weeks after cessation of breastfeeding (if < 18 months old). If, at 6\u00a0weeks after weaning, the child is \u2265 18 months old, a HRT or HIV enzyme-linked immunosorbent assay (ELISA) test should be performed instead of an HIV PCR test.If the birth HIV PCR test is negative, an HIV PCR test at 10 weeks of age is recommended to detect as many cases of intrapartum infection as possible. If the HIV PCR test is repeated at 6 weeks of age, as per national guidelines,In an evolving PMTCT environment, ongoing monitoring is necessary to assess the impact of early diagnosis of HIV infection in neonates and to ensure that an evidence-based, effective diagnostic algorithm is deployed."} +{"text": "Escherichia coli O103 strains shed in the feces of cattle. We report here the genome sequences of 43 strains of enterohemorrhagic E.\u00a0coli (EHEC) O103:H2 isolated from feedlot cattle feces. The genomic analysis will provide information on the genetic diversity and virulence potential of bovine EHEC O103.The enterohemorrhagic pathotype represents a minor proportion of the Escherichia coli (EHEC). The organism is shed in the feces of cattle, which can contaminate the hide and then carcass at slaughter, creating the potential for foodborne illness in humans and intimin (eae) genes, the combination of these and presence of other major virulence genes, including enterohemolysin (ehxA), vary among EHEC O103 strains isolated from bovine feces , genome size, and number of contigs per genome are summarized in We report here the draft whole-genome sequences of 43 strains of EHEC O103:H2 isolated from feces of feedlot cattle in the United States . BacteriThe 43 strains deposited here will add to the limited publicly available genetic information on EHEC O103. These genomes will be a valuable resource for investigations into the genetic features of this major foodborne pathogen, including research into the genome evolution of EHEC O103 compared to other EHEC serogroups, and insights into specific factors allowing for adaptation to a bovine host. This work will also provide an opportunity to study the potential virulence risk of these EHEC O103 strains to humans.The whole-genome shotgun sequence has been deposited at DDBJ/ENA/GenBank under the accession numbers listed in"} +{"text": "Androgen deprivation therapy (ADT) has been the standard of care for advanced prostate cancer (PCa) for decades, yet men with this condition inexorably develop resistance to ADT and progress to metastatic castration-resistant PCa (mCRPC) . Second It was shown previously that AR transcriptionally upregulates multiple DNA damage response (DDR) genes -5, and tin vitro [in vitro. We used multiple subcutaneous and orthotopic in vivo CRPC models, including an ENZ-responsive PDX model to validate the superiority of lead-in combination ENZ+OLA treatment compared to concomitant administration [We initially identified a subset of 10 HR genes which were upregulated in CRPC in 2 independent public data sets, and showed that 7 of these upregulated genes were contained within a 15 HR gene subset which was downregulated by ENZ in microarray analysis [The causative mechanisms for susceptibility of cancers with BRCA mutations to PARP inhibitor \u2014 mediated synthetic lethality are complex, and recent studies have pointed to the need to expand the concept of BRCAness in tumors beyond germline BRCA1 or BRCA2 mutations to include mutations in genes that modulate HR and confer PARP sensitivity . Our rec"} +{"text": "Persons who experience symptoms of psychosis following a brain injury live with a complex dual diagnosis that is often accompanied by substantial distress and disability. However, a comprehensive examination of the clinical presentation of PFTBI using standardised clinical measures has not been reported in the literature. This information is vital for accurate diagnosis and effective treatment.Patients with PFTBI (n =10) and schizophrenia (n =98) participated in a comprehensive clinical assessment that included the Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID-I/P), the Positive and Negative Syndrome Scale (PANSS), the Scale for the Assessment of Positive Symptoms (SAPS), the Scale for the Assessment of Negative Symptoms (SANS), and the Thought Language and Communication Index (TLC).The clinical profiles of the PFTBI group met symptom/course criteria for: schizophrenia (n = 6), schizoaffective (n = 2), schizophreniform (n = 1), and paranoid psychosis (n = 1). PFTBI patients had a significantly reduced PANSS negative score relative to schizophrenia patients. No other significant differences between PFTBI and schizophrenia clinical profiles were found.The clinical profile of PFTBI appears to be comparable to schizophrenia/ schizoaffective disorder except with respect to negative psychotic symptoms. Reduced negative symptoms in PFTBI have previously been reported in a small number of case studies, and thus warrant further investigation as a diagnostic distinction in this patient group."} +{"text": "The carotid surgical experience of Cheltenham General Hospital over a 13 year period (1968-81) is presented. This includes 42 operations for stenosis, and 12 further operations for carotid body tumour, carotid aneurysm, subclavian steal syndrome and trauma to the internal carotid artery. The operative techniques and complications are briefly discussed and reasons advanced for a more agressive approach to the problems of extra-cerebral carotid disease in this country."} +{"text": "The early differentiation of Alzheimer\u2019s disease (AD) from frontotemporal dementia (FTD) may be difficult. The Tower of London (ToL), thought to assess executive functions such as planning and visuo-spatial working memory, could help in this purpose.Twentytwo Dementia Centers consecutively recruited patients with early FTD or AD. ToL performances of these groups were analyzed using both the conventional statistical approaches and the Artificial Neural Networks (ANNs) modelling.p < 0.05) The use of hidden information contained in the different items of ToL and the non linear processing of the data through ANNs allows a high discrimination between FTD and AD in individual patients. However, the discriminant validity of AS checked by ROC curve analysis, yielded no significant results in terms of sensitivity and specificity (AUC 0.63). The performances of the 12 Success Subscores (SS) together with age, gender and schooling years were entered into advanced ANNs developed by Semeion Institute. The best ANNs were selected and submitted to ROC curves. The nonlinear model was able to discriminate FTD from AD with an average AUC for 7 independent trials of 0.82.Ninety-four non aphasic FTD and 160 AD patients were recruited. ToL Accuracy Score (AS) significantly (The use of hidden information contained in the different items of ToL and the non linear processing of the data through ANNs allows a high discrimination between FTD and AD in individual patients."} +{"text": "It Specifications TableValue of the data\u2022ilr transformation for other food compositions and interested researchers.The data include the sequential binary partition of fatty acid profiles in CoDa and could be useful for calculating balances and the \u2022The correlation among fatty acids expressed in percentages may help other researchers for finding spurious relationships.\u2022The information may facilitate the comparison of conventional multivariate techniques and compositional, regardless of the field, and promote international collaborations in data analysis.\u2022Presentation in the Simplex can be an appropriated way of graphing compositional data and treatments\u2019 effects.1ilr transformations based on it Fatty acid profiles were obtained through analysis of their FAMEs by GC according to the procedures recommended in the Commission Regulation (EU) No 2015/1833 ilr transformed values (or coordinates) were subjected to similar multivariate Cluster Analysis (based on the Euclidean distance and the Ward method) (The data matrix consisted of 10 rows (five treatments in duplicate) and 19 columns (fatty acids). Values were first tested for outliers and normality. The data were plotted in the Simplex , analysedinates) [10], [1 method) [12].TabCoDaPack v. 2.01.14 , XLSTAT 2014 were used for data processing and graph drawing."} +{"text": "Objective: To characterize various dysgraphic symptoms in parietal agraphia. Method: We examined the writing impairments of four dysgraphia patients from parietal lobe lesions using a special writing test with 100 character kanji (Japanese morphograms) and their kana (Japanese phonetic writing) transcriptions, and related the test performance to a lesion site.Results: Patients 1 and 2 had postcentral gyrus lesions and showed character distortion and tactile agnosia, with patient 1 also having limb apraxia. Patients 3 and 4 had superior parietal lobule lesions and features characteristic of apraxic agraphia (grapheme deformity and a writing stroke sequence disorder) and character imagery deficits . Agraphia with impaired character recall and abnormal grapheme formation were more pronounced in patient 4, in whom the lesion extended to the inferior parietal, superior occipital and precuneus gyri.Conclusion: The present findings and a review of the literature suggest that: (i) a postcentral gyrus lesion can yield graphemic distortion (somesthetic dysgraphia), (ii) abnormal grapheme formation and impaired character recall are associated with lesions surrounding the intraparietal sulcus, the symptom being more severe with the involvement of the inferior parietal, superior occipital and precuneus gyri, (iii) disordered writing stroke sequences are caused by a damaged anterior intraparietal area."} +{"text": "Intermittent catheterisation is the preferred method of managing the neurogenic bladder in patients with spinal cord injury. However, spinal cord physicians experienced problems when trying to implement an intermittent catheterisation regime in some spinal cord injury patients in the northwest of England. We present illustrative cases to describe practical difficulties encountered by patients while trying to adopt an intermittent catheterisation regime. Barriers to intermittent catheterisation are (1) caregivers or nurses are not available to carry out five or six catheterisations a day; (2) lack of time to perform intermittent catheterisations; (3) unavailability of suitable toilet facilities in public places, including restaurants and offices; (4) redundant prepuce in a male patient, which prevents ready access to urethral meatus; (5) urethral false passage; (6) urethral sphincter spasm requiring the use of flexible-tip catheters and \u03b1-drenoceptor\u2013blocking drugs; (7) reluctance to perform intermittent catheterisation in patients >60 years by some health professionals; and (8) difficulty in accessing the urethral meatus for catheterisation while the patient is sitting up, especially in female patients. These cases demonstrate the urgent need for provision of trained caregivers who can perform intermittent catheterisation, and improvement in public facilities that are suitable for performing catheterisation in spinal cord injury patients. Further, vigilance should be exercised during each catheterisation in order to prevent complications, such as urethral trauma and consequent false passages. Health professionals should make additional efforts to implement intermittent catheterisation in female spinal cord injury patients and in those >60 years."} +{"text": "In the associated research article in vitro. We provide data demonstrating the use of nanoscale secondary ion mass spectroscopy (NanoSIMS) to identify specific ions in bulk dried NP. NanoSIMS is also used to visualize 40Ca microdomains in the z dimension of optic nerve that has been subjected to a partial optic nerve transection. The associated article 40Ca microdomains in optic nerve from animals treated with various nanoparticle preparations and provides further interpretation and discussion of the findings.Before using nanoparticles for therapeutic applications, it is necessary to comprehensively investigate nanoparticle effects, both A sample raw NanoSIMS spectra of bulk dried NP and associated spatial resolution data demonstrate the ability to detect 56Fe within NP. NanoSIMS can be used to detect 40Ca microdomains in the z dimension of optic nerve following partial optic nerve transection.The oxidative stress indicator carboxymethyl lysine was assessed in an astrocyte-like immortalized M\u00fcller cell line (rMC1 cells). Cells were stressed with H2in vitro, assessed using ImageJ image analysis software software .Fig. 1CeRaw NanoSIMS spectra and specz-dimension of an optic nerve field of view (FOV) following partial optic nerve transection, collected using NanoSIMS. All procedures involving animals conformed to the National Health and Medical Research Council of Australia Guidelines on the Use of Animals in Research and were approved by the Animal Ethics Committee of The University of Western Australia .Fig. 3Pa"} +{"text": "Improving quality of maternal care as well as patients' safety are two important issues in health-care service. Therefore, this study aimed to assess the culture of patient safety at maternity units.This cross-sectional study was conducted among staffs working at maternity units in seven hospitals of Ilam city, Iran. The staffs included in this study were gynecologists and midwifes working in different positions including matron, supervisors, head of departments and staffs. Data were collected using the Hospital Survey on Patient Safety Culture (HSOPSC).This study indicated that 59.1% of participants reported fair level of overall perceptions of safety and 67.1% declared that no event was reported during the past 12 months. The most positively perceived dimension of safety culture was teamwork within departments in view of managers (79.41) and personnel (81.10). However, the least positively perceived dimensions of safety culture was staffing levels.The current study revealed areas of strength (teamwork within departments) and weakness among managers and personnel. In addition, we found that staffs in Ilam's hospitals accept the patient safety culture in maternity units, but, still are far away from excellent culture of patient safety. Therefore, it is necessary to promote culture of patient's safety among professions working in the maternity units of Ilam's hospitals. Decreasing maternal mortality rate is recognized as an essential priority in health-care systems , 2. ImprThis cross-sectional study was conducted among staffs working at maternity units in seven hospitals of Ilam University of Medical Sciences during year 2016. The staffs included in this study were gynecologists and midwifes working in several positions including managers, supervisors, head of departments and staffs. The total number of 350 staffs was invited to take part in the current study and 299 agreed to participate in the survey. Participants were informed about the aim, benefits and importance of the survey as well as their voluntary participation rights. Written informed consent was obtained prior to actual data collection. Data were collected using series of self-administrated questionnaires including socio-demographic characteristics and the Hospital Survey on Patient Safety Culture (HSOPSC). The socio-demographic and individual characteristics include age, gender, education, working hours per week, ward, organizational position, organizational tenure, work experiences in the current ward and type of employment. The Hospital Survey on Patient Safety Culture (HSOPSC) released by the Agency for Healthcare Research and Quality (AHRQ) to help hospitals assess the safety culture within their organization. The HSOPSC contains 42 items with 5 point Likert responses scale ranging from strongly disagree (1) to strongly agree (5). HSOPSC questionnaire contains both positively and negatively worded items. The average percent-positive score for each dimension was calculated and negative items were reverse scored prior to computing percent positive response. This questionnaire is designed to measure 12 dimensions of patient safety culture and these dimensions are: Supervisor/manager expectations and actions promoting safety (4 items), Organizational learning-continuous improvement (3 items), Teamwork within units (4 items), Communication openness (3 items), Feedback and communication about error (3 items), Non-punitive response to error (3 items), Staffing (4 items), Hospital management support for patient safety (3 items), Teamwork across hospital units (4 items), Hospital handoffs and transitions (4 items), Overall perceptions of safety (4 items), Frequency of event reporting (3 items) and Two outcome variables. The two outcome variables compose of \u201cOverall perceptions of safety\u201d and \u201cFrequency of event reporting\u201d. The HSOPSC questionnaire was validated in Persian language and shown a good validity and reliability to be used in Iran's hospitals . HoweverMean age of participants in this study was 33.52 (SD= 6.37) years old and 84.1This study assessed culture of patient's safety in hospitals of Ilam University of Medical Sciences. Creating culture of patient safety requires assessment of safety culture using appropriate tool. This study measured culture of patient safety using HSOPSC questionnaire which is one of the best tools in this area . The curThe results of this study showed acceptable levels of overall perception of safety culture among both managers and personnel with higher perception among managers. This finding implies that health-care workers in Ilam's hospitals accept the patient safety culture in maternity units, but still are far away from excellent culture of patient safety. Maternal wards are among very important units in each hospital, which require special attentions. Therefore, it is necessary to promote culture of patient's safety among professions working in the maternity units of Ilam's hospital. There are several limitations in this study, which need to be addressed. One of the limitations in this study was lack of evidences in maternity units to compare the results. Therefore, future studies are recommended to assess the culture of patient safety in maternal care units using HSOPSC questionnaire. Another limitation in this study is use of self-reported data.International reports on maternal mortality rate has shown constant decreasing pattern during the last 15 years;Programs aimed at decreasing maternal mortality rate has always been a priority in the Iranian health system and some of these programs are promoting mother and child-friendly hospitals that offer maternal care using professional midwifery staffs;Promoting patients' safety and risk management are of great importance in maternity care units due to the fact that every procedure in this field will affect two individuals (both mother and baby).This study assessed culture of patient's safety in hospitals of Ilam University of Medical Sciences for the very first time and revealed areas of strength and weakness among managers and personnel;The most positively perceived dimension of safety culture was attributed to \u201cteamwork within department\u201d among both managers and personnel. While, the least positively perceived dimension was \u201cstaffing\u201d and \u201cnon-punitive response error\u201d, respectively;Positive perception toward \u201cstaffing\u201d was higher among managers compared to personnel and \u201cnon-punitive response error\u201d was almost equal between two groups.The authors declare no competing interests."} +{"text": "This article evaluated the autosomal dominant polycystic kidney disease (ADPKD) modifiers to chronic kidney disease (CKD) such as allelic and nonallelic agents. Also, our study evaluated the role of the endotelin-1 which considered in some studies as the predictor of the ADPKD.Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common life threatening inherited kidney disease which its prevalence is approximately 0.5 to 1 in 1000 subjects of general population ,3. FurthThe heterozygous mutations in PKD 1 (approximately 78%) and PKD 2 (approximately 13%) genes are responsible for the vast majority of the ADPKD incidence and no mutation detected (NMD) ADPKD exists in the other patients (9%) and increase in kidney size are as modifiers. Furthermore some laboratory factors such overt hematuria, macroalbominuria, high level of serum copeptin concerned as predicting factor for chronic kidney disease (CKD) in ADPKD . The vasEndotelin-1 (ET-1) is another agent that has been reported to exert multiple effects on renal function . Some stIn summary, the progression of ADPKD to CKD depends on multiple factors include allelic and non-allelic factors that can be use in prevention of the CKD in these patients and need further researches for achieve to this issue.The authors contributed equally to the manuscript.The authors declared no competing interests.Ethical issues have been completely observed by the authors.None."} +{"text": "Nature Communications 10.1038/s41467-017-00717-y, published online 18 September 2017Correction to: The original version of this Article omitted the Acknowledgements section:\u201cThis work was sponsored by the Australian Research Council (ARC) Laureate Fellowship (FL120100029) and the Centre of Excellence program (CUDOS CE110001010). We acknowledge the support of the ANFF ACT.\u201dThis has now been corrected in both the PDF and HTML versions of the Article."} +{"text": "Studies have shown that physiologic factors such as decreased LAA velocity and increased stasis are associated with thrombus formation in the LAA and may be better predictors for stroke. Currently available diagnostic tools such as TEE, however, are limited as they do not completely assess the complex 3D LAA blood flow and are invasive. As a result, the impact of AF on global and regional atrial 3D flow dynamics is poorly understood. In addition, it is unclear if the stimulus for LAA thrombus formation is driven by hemodynamic changes in the LAA alone or more broadly associated with AF induced flow alterations affecting the entire left atrium (LA). It was the aim of this study to test the potential of novel 4D flow MRI tools for the characterization of LA and LAA flow dynamics.Atrial fibrillation (AF) is associated with increased risk of stroke due to development of left atrial appendage (LAA) thrombus. Clinical risk scores (CHA4D flow MRI was employed to measure in-vivo time-resolved 3D blood flow velocities in 75 subjects: 30 AF patients in sinus rhythm (AF-sinus), 30 AF patients in AF (AF-afib) and 15 normal controls. Data analysis included 3D segmentation of the LA and LAA to isolate the velocity data in the LA and LAA figure . Peak veLA and LAA mean velocity, stasis, and peak velocity were significantly different between controls, AF-afib patients, and AF-sinus patients not just in the LAA but in the in the entire left atrium. An individual assessment of LAA and LA flow may thus help to better identify patients at risk for thromboembolism beyond current clinical risk scores."} +{"text": "Phaseolus vulgaris L.). In this study, 41 rhizobia isolates were obtained from the root nodules of MAC 13 and MAC 64 climbing beans grown in upper and lower midland agro-ecological zones of Eastern Kenya. Eastern Kenya was chosen because of its high production potential of diverse common bean cultivars. The rhizobia isolates were characterized phenotypically on the basis of colony morphology, growth and biochemical features. Rhizobia diversity from the different regions of Eastern Kenya was determined based on the amplified ribosomal DNA restriction analysis (ARDRA) of PCR amplified 16S rRNA genes using Msp I, EcoR I, and Hae III restriction enzymes. Notably, native rhizobia isolates were morphologically diverse and grouped into nine different morphotypes. Correspondingly, the analysis of molecular variance based on restriction digestion of 16S rRNA genes showed that the largest proportion of significant (p < 0.05) genetic variation was distributed within the rhizobia population (97.5%) than among rhizobia populations (1.5%) in the four agro-ecological zones. The high degree of morphological and genotypic diversity of rhizobia within Eastern Kenya shows that the region harbors novel rhizobia strains worth exploiting to obtain strains efficient in biological nitrogen fixation with P. vulgaris L. Genetic sequence analysis of the isolates and testing for their symbiotic properties should be carried out to ascertain their identity and functionality in diverse environments.The increasing interest in the use of rhizobia as biofertilizers in smallholder agricultural farming systems of the Sub-Saharan Africa has prompted the identification of a large number of tropical rhizobia strains and led to studies on their diversity. Inoculants containing diverse strains of rhizobia have been developed for use as biofertilizers to promote soil fertility and symbiotic nitrogen fixation in legumes. In spite of this success, there is paucity of data on rhizobia diversity and genetic variation associated with the newly released and improved mid-altitude climbing (MAC) bean lines ( Rhizobia bacteria play a significant role in provision of agricultural ecosystem services due to their ability to form symbiotic association with a wide range of leguminous plants that results in biological nitrogen fixation . Some ofMimosa genus and chickpeas (Cicer arietinum L.), while Bradyrhizobium strains are often found to nodulate soybeans (Glycine max L. Merrill), cowpeas (Vigna unguiculata L.) and green grams (Vigna radiata L.). However, in some cases, cross inoculation by both genera has been documented in some legumes such as mungbeans (V. radiata L.) and this is considered advantageous and economical to farmers growing different types of legumes (Rhizobia-legume symbiosis is a host-specific association and hence the need to determine the strains and the diversity of rhizobia associated with specific type of legume for better exploitation of the benefits associated with the rhizobia biofertilizers . Rhizobisa genus . Until racterium . However legumes .P. vulgaris L.), the MAC beans establish a mutual and a beneficial symbiotic partnership with Rhizobium leading to the formation of root nodules that catalyze nitrogen fixation from the atmospheric air , restriction fragment length polymorphism (RFLP) and amplified fragment length polymorphism (AFLP) have been used to evaluate the diversity of rhizobia . In addiIn this study, we hypothesized that there exists a large heterogeneity among the rhizobia isolates nodulating MAC beans grown in different AEZ with contrasting environmental conditions in Eastern Kenya. The aim of this study was to isolate, characterize morphologically and genetically and determine the diversity of the rhizobia populations associated with MAC 13 and MAC 64 climbing beans grown in different AEZ of Eastern Kenya.Field trapping of rhizobia was carried out during the first rainy season between March and August 2015 in four different sites of Eastern Kenya with contrasting agro-climatic conditions using MAC 13 and MAC 64 climbing beans as the host plants. Eastern Kenya was chosen because of its high production potential of diverse common bean cultivars . The fouTen healthy and undamaged root nodules of MAC 13 and MAC 64 climbing beans from each site were selected and used in the isolation of rhizobia following the standard protocols described by Rhizobium. Based on the differences in the observed morpho-cultural, Gram stain and growth features, the isolates were placed into different morphotype groups.Using the standard microbiological techniques described by Hae III, EcoR I and Msp I . Three reference strains; Rhizobium tropici CIAT 899, Rhizobium etli USDA 2667 strain and Rhizobium leguminosarum strain 446 were used. The three reference Rhizobium strains were obtained from the Microbiological Resource Centre (MIRCEN), University of Nairobi, Kenya.The molecular study involved 41 rhizobia isolates and was carried out at the Department of Microbiology, Kenyatta University. The analysis of genetic relatedness of the native isolates from Eastern Kenya was carried out using amplified rDNA restriction analysis (ARDRA) of the 16s rRNA genes using three restriction enzymes The extraction of total genomic DNA of rhizobia isolates was carried out following modification of a method outlined by Escherichia coli , 0.6 \u03bcl dNTP (10 mM), 0.3 \u03bcl of each Y1 and Y3 primers (10 \u03bcM), 0.6 \u03bcl 5% Tween 20, 0.15 \u03bcl Taq DNA polymerase (Biolabs) and 1.5 \u03bcl of DNA template. The sequences of the primers used for PCR amplification of the 16S rRNA gene were: Y1 forward primer (5\u2032-TGGCTCAGAACGAACGCTGGCGGC-3\u2032) that corresponds to positions 20\u201343 and Y3 reverse primer (5\u2032-TACCTTGTTACGACTTCACCCCAGTC-3\u2032) corresponding to positions 1482\u20131507 for 16S rDNA sequence of hia coli . A negatHae III, EcoR I, and Msp I restriction enzymes (Biolabs) (Polymerase chain reaction products of the isolates and reference strains were digested using Biolabs) . A masteH) was also used to determine the rhizobia diversity in different AEZ of Eastern Kenya.The data on rhizobia genetic diversity based on the different band patterns formed after PCR restriction were coded in binary form and analyzed as described by Table 1). Morphotype III was the most abundant (29%) and morphotype II accounted for a partly 2% of the total number of isolates. All isolates were Gram negative rods and did not absorb Congo red dye when incubated in the dark on YEMA-CR medium . Notably, all isolates turned BTB indicator from deep green to yellow when grown on YEMA-BTB indicating that the isolates were acid producers and fast growers . The colony color varied with milky white, cream white, cream yellow and watery colonies being observed which were either opaque or translucent with either firm gummy or smooth mucoid texture . Most of the isolates had a mucoid texture due to the production of excess EPSs. As expected, all isolates had an entire colony margin but the colony elevation varied consistently with convex and raised colonies being observed on YEMA media . The morphological characteristics of the reference strains Rhizobium tropici CIAT 899 and Rhizobium etli USDA 2667 were closely similar to those of morphotype III while Rhizobium leguminosarum strain 446 closely resembled morphotype V (Table 1).From the field trapping experiment using MAC 13 and MAC 64 climbing beans, 41 pure rhizobia isolates were obtained, which were placed in to nine distinct morphotype groups based on their morpho-cultural and biochemical features . Restriction of the 16S rRNA amplicons of the climbing bean rhizobia isolates using enzymes EcoR I , Hae III and Msp I produced multiple band patterns. Restriction enzyme Msp I produced the most diverse polymorphic patterns.The PCR amplification of the 16S rDNA region produced a single band of approximately 1500 bp (Na = 1.92 \u00b1 0.08) and effective alleles (Ne = 1.55 \u00b1 0.10) compared to other populations (Table 2). Rhizobia isolates from ELM had the highest percentage polymorphic loci (92.31% P) while isolates from EUM and TLM recorded the lowest at 61.54% P. The mean Shannon\u2013Wiener diversity (H) estimate showed that the four rhizobia populations from Eastern Kenya were genetically diverse with rhizobia population from ELM having the highest genetic diversity estimate of H = 0.47 (Table 2). The rhizobia population from zone TLM recorded the lowest genetic diversity estimate of H = 0.31. The average expected heterozygosity (He) varied among the four populations and ranged from 0.21 for rhizobia population from TLM to 0.32 for ELM population (Table 2).Based on ARDRA analysis of 16S rRNA amplicons, rhizobia population from ELM had the highest average number of different alleles within populations . The variation among the rhizobia populations from the four AEZ (2.5%) and two Counties (0.5%) were, however, not significant (Table 3).Analysis of molecular variance (AMOVA) for the four rhizobia populations in Eastern Kenya showed a significantly high genetic variation . Isolates from TUM zone were the most distributed and appeared in all the four quadrants, while isolates from ELM zone were the least distributed .The principal coordinate analysis (PCA) of 41 native isolates from the four zones of Eastern Kenya and three rhizobia reference strains showed considerable differentiation . Rhizobia populations from ELM and TUM clustered together with a bootstrap value of 85% while rhizobia populations from EUM and TLM clustered with a bootstrap value of 82%.Based on the pairwise population matrix of Nei unbiased genetic distance and Euclidian similarity index, the neighbor joining dendrogram clustered rhizobia populations from Eastern Kenya into two main groups . Cluster I comprised of majority of the isolates while cluster III had only one isolate ELM5. The reference strain Rhizobium tropici CIAT 899 which was placed in cluster I, clustered together with native rhizobia isolates ELM33 and TLM32, indicating their close genetic relationship. Native isolates TUM26, TLM28, and EUM23 clustered together despite originating from different AEZ of Eastern Kenya. Rhizobium etli USDA 2667 strain was also placed in cluster I and was grouped together with TLM27 and TUM 41 isolates . The native isolate EUM7 clustered closely to Rhizobium leguminosarum strain 446 in cluster II but in a separate sub-branch.Based on the genetic distance after amplified rDNA restriction analyses and Euclidian similarity index, the phylogenetic tree clustered the native rhizobia isolates into three main clusters I, II, and III estimate of rhizobia populations from Eastern Kenya based on genetic distance of ARDRA pattern analysis showed that the isolates were genetically diverse with rhizobia population from ELM zone having the highest genetic diversity estimate compared to TLM zone, which recorded the lowest diversity. This variation in rhizobia diversity could be due to the differences in agroclimatic and soil conditions of the four sites studied in Eastern Kenya. These results reinforce the promiscuous nature of P. vulgaris L. to nodulate with diverse strains of Rhizobium genetic variation distributed within regions (89%) than among regions (11%) in S. meliloti and S. medicae obtained from drought and salt affected regions of Morocco. Moreover, The analyses of molecular variance (AMOVA) based on amplified 16S rDNA restriction profiles showed a highly significant genetic variation of native rhizobia isolates within rhizobia populations and not among the four populations nor across the two regions (Counties) of Eastern Kenya. Based on ARDRA fingerprints, the low level of genetic differentiation of MAC bean rhizobia could suggest that the rhizobia population within the region is weakly structured. This could be due to the absence of physical barriers to limit gene flow . Human aAgrobacterium, Bradyrhizobium, Rhizobium, and Ensifer). Based on the evolutionary relationship of 41 isolates inferred using Neighbor-Joining method, some of the native isolates clustered closely with the three reference rhizobia strains used in this study. The phylogenetic tree showed a diverse genetic variation among the native rhizobia isolates as evident by the different clusters and sub-clusters.The principal coordinate analysis (PCA) also showed low level of genetic differentiation of native rhizobia isolates from Eastern Kenya and thus showing congruent results with the dendrogram. However, the grouping and distribution patterns of the native isolates did not correspond to the AEZ, and this is an indicative of the likelihood of a common evolutionary origin of the isolates. Similarly, Rhizobium tropici CIAT 899 and R. etli USDA 2667 in cluster I. For instance, native isolates TLM 27 and TUM 41 clustered together with R. etli USDA 2667 while isolate TLM 32 clustered with R. tropici CIAT 899. These indicate the close genetic relationship between some of the native rhizobia isolates to R. tropici CIAT 899, R. etli USDA 2667 and R. leguminosarum strain 446 genetic variation distributed within populations (97%) than among populations (2.5%) in four AEZ of Eastern Kenya. Despite the high diversity shown within the rhizobia population, the Pairwise Population Matrix of Nei unbiased genetic distance of rhizobia populations in the study region showed a narrow range, which is an indication of a weakly structured genetic population and a highly conserved genetic structure of rhizobia within the study area. Further molecular studies using either full or partial gene sequences of bacterial genome, which is more sensitive and has a higher resolution power, needs to be carried out to establish the true diversity of native rhizobia isolates up to the species and strain levels.In this study, 41 rhizobia isolates were obtained from the root nodules of mid-altitude climbing (MAC) beans and based on morpho-cultural and biochemical characteristics, the isolates grouped into nine morphotypes indicating the diverse nature of rhizobia nodulating with MAC beans. Cluster analysis based on genetic characteristics obtained after PCR-ARDRA profiling, showed a larger proportion of significant (JK, OO, JM, and EN conceived and designed the research and data collection tools and participated in drafting the manuscript. GK and SM collected the data, participated in data analyses, and wrote the manuscript. EN performed the data analyses. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Sertoli cells (Sc) are unique somatic cells of testis that are the target of both FSH and testosterone (T) and regulate spermatogenesis. Although Sc of neonatal rat testes are exposed to high levels of FSH and T, robust differentiation of spermatogonial cells becomes conspicuous only after 11-days of postnatal age. We have demonstrated earlier that a developmental switch in terms of hormonal responsiveness occurs in rat Sc at around 12 days of postnatal age during the rapid transition of spermatogonia A to B. Therefore, such \u201cfunctional maturation\u201d of Sc, during pubertal development becomes prerequisite for the onset of spermatogenesis. However, a conspicuous difference in robust hormone (both T and FSH) induced gene expression during the different phases of Sc maturation restricts our understanding about molecular events necessary for the spermatogenic onset and maintenance. Here, using microarray technology, we for the first time have compared the differential transcriptional profile of Sc isolated and cultured from immature (5 days old), maturing (12 days old) and mature (60 days old) rat testes. Our data revealed that immature Sc express genes involved in cellular growth, metabolism, chemokines, cell division, MAPK and Wnt pathways, while mature Sc are more specialized expressing genes involved in glucose metabolism, phagocytosis, insulin signaling and cytoskeleton structuring. Taken together, this differential transcriptome data provide an important resource to reveal the molecular network of Sc maturation which is necessary to govern male germ cell differentiation, hence, will improve our current understanding of the etiology of some forms of idiopathic male infertility. Spermatogenesis is a complex process where every step of male Germ cell (Gc) development are essentially supported by somatic Sertoli cells (Sc) . In respIn rodents, upto 3\u20135 days after birth, Sc keep proliferating and attract the gonocytes towards the basement membrane for establishing the spermatogonial stem cell (SSC) niche . NeonataTo understand the regulatory mechanism of spermatogenesis, it is imperative to explore the changing landscape of gene expression during various phases of Sc maturation. Microarray is a powerful technique to study differentially expressed genes in large numbers . DiffereRattus norvegicus) were procured from colony maintained by Small Animal Facility, National Institute of Immunology, New Delhi, India. Animals were maintained in a standard day night cycle with stable temperature and humidity and provided food and water ad libitum. All the animal experimentations were approved by Institutional Animal Ethics Committee (IAEC) and performed following standard guidelines of \u2018\u2018Committee for the Purpose of Control and Supervision of Experiment on Animals (CPCSEA),\u201d Government of India.Wistar outbred rats (In vitro hormone treatment was performed on day 4.Sc cultures were prepared from 5 days and 12 days old rat testes as described earlier . BrieflySc from mature rat testes (60 days old) were isolated and cultured as described earlier . BrieflyOn day 4, Gc contamination were found to be less than 5% in Sc cultures of all age groups. Purity of Sc in culture were identified by vimentin staining whereas Peritubular Cell (PTc) or Leydig Cell (Lc) contaminations were determined by the alkaline phosphatase or the 3\u03b2-HSD activity respectively, as described by us before .\u22127M T in combination = FT media) in pulsatile manner (30min of FT pulse/3hr)The doses of both o-FSH and T were previously found bioactive in cultured Sc obtained from all three age groups studied ; 2) genes downregulated in 12d but upregulated in 60d , and 3) genes upregulated in both 12d and 60d . For each sample, the calculated quantity of each gene was normalized with the endogenous control Ppia (Cyclophilin A). The relative quantities of mRNAs for all target genes were determined by 2-\u0394\u0394Ct method as reported by us before [In order to authenticate the array data the expression patterns of some of the genes were validated by quantitative reverse transcription PCR (q-RT-PCR) with additional sets of Sc culture obtained from all three age groups with consistent hormonal treatments (pulsatile FSH and T in combination for 11hr) and were compared with that of the array data. The genes considered were divided in five groups: 1) FSH responsive genes like SCF, GDNF, ABP, Transferrin and Dmrt1 in both 5d and 12d as reported earlier either by us or others . T respos before ,19. It iPostnatal maturation of testicular Sc is critical in regulating male fertility. Therefore, it becomes essential to investigate the genes expressed by Sc during this phase of development. Our microarray results have indicated differential expression of genes associated with cyto-architecture, metabolism, cytokines, chemokines, growth factors, MAPK signaling and Wnt signaling among others. Taken together, this differential transcriptome data provide an important resource database to reveal the molecular network of Sc maturation which is necessary to govern male germ cell differentiation. This information will improve our current understanding of the etiology of some forms of idiopathic male infertility with persistent immature Sc even in adulthood.S1 FigThere are 96 genes common between our data and Zimmerman\u2019s data and these genes are mainly involved in signal transduction, cell-cell communication, energy and metabolism and cell growth.(TIF)Click here for additional data file.S2 FigA) Entity based clustering analysis of co-expressed genes identified four clusters of co-expressed genes. (B) Gene Ontology (GO) based functional analysis of genes grouped under four clusters. Functional analysis was performed for molecular function (MF), cellular components (CC) and biological processes (BP).((TIF)Click here for additional data file.S1 Table(XLS)Click here for additional data file.S2 Table(XLS)Click here for additional data file.S3 Table(XLS)Click here for additional data file.S4 Table(XLS)Click here for additional data file."} +{"text": "Introduction: For many years, amblyopia was regarded as a disorder of the visual system in which an organic cause could not be identified. Optical Coherence Tomography opens new horizons in understanding the etiopathology of amblyopia and seems to highlight morphologic anomalies in the retina of the amblyopic eye. Purpose: The objective of this paper is to analyze the macular thickness, optic nerve changes, and choroidal thickness found in patients diagnosed with amblyopia based on trials reported in the literature.Material and methods: This study analyzes 30 clinical trials regarding amblyopia evaluation with Optical Coherence Tomography. The research articles analyzed were published between 2006 - 2016 and were identified on PubMed database.Results: 19 research studies focused on macular and nerve optic changes, 7 on choroidal changes and 6 on retinal changes after occlusion. The results were discussed according to the type of amblyopia, alteration of macular thickness, optic nerve changes, ganglion cell layer changes, and alteration of choroidal thickness. Conclusions: The results are of great variability, and it seems that macula and choroid involvement is more frequently suggested compared with optic nerve involvement.Abbreviations: OCT = Optical Coherence Tomography, RNFL = Retinal Nerve Fiber Layer, GCC = Ganglion Cell Complex, ACD = Anterior Chamber Depth, BCVA = Best Corrected Visual Acuity The results are often contradictory because, as Kim says, when conducting an OCT in patients with anisometropia it is important to correct the magnification of the device according to refraction and axial length of the eye. Also, results differ depending on the device used [3].Another limitation regarding correct interpretation of OCT in children emerges from the inexistence of international established normative values of macular and retinal nerve fiber layer (RNFL) parameters in children ;- Wang (2012) stated that the average thickness of the foveola is thicker than in normal eyes, but other regions have no significant difference [5];- Wu (2013) showed in his study that hyperopic anisometropic amblyopic eyes have a thicker foveola than the contralateral eyes [6];- Araki (2014) concluded that there are significant differences between amblyopic and fellow eyes that are independent of abnormalities in the visual cortex. He showed that the macular outer retinal thickness (1 and 3 mm regions) is significantly thicker in \u201elazy eyes\u201d [7].- Demircan (2015) discovered that in patients age 5-42 years the mean central macular thickness in the amblyopic eyes was thicker patients under 12 years [After studying anisometropic and strabic ambliopic patients:9];- The Sydney Childhood Eye Study (2009) affirmed that in children aged 6 to 12 years, central macular thickness may be increased in \u201elazy eyes\u201d, although it is uncertain if this precedes or follows the development of amblyopia [10]; - Al-Haddad (2011) showed in his study that the mean macular thickness was significantly increased in amblyopic eyes compared with fellow eyes. This difference remained significant in the anisometropic group but not in the strabic group. The mean RNFL thickness was similar in amblyopic and fellow eyes [11];- In 2013 Tugcu claimed that in patients with combined (anisometropic and strabismic) amblyopia and in patients with anisometropic amblyopia the thickness of ganglion cell complex (GCC) was significantly increased in both amblyopic and nonamblyopic eyes compared to healthy patients. The strabismic amblyopia group presented with significant reduction in GCC thickness and increased foveal thickness compared to nonamblyopic eyes. He did not found significant differences in morphological and functional measures among amblyopic groups but he detected significant differences in the retinal morphology of both amblyopic and nonamblyopic eyes compared with healthy control subjects [12];- Rajavi (2014) showed that the average foveal thickness of children with moderate and severe amblyopia was 10 microns thicker compared with the congener eye or the control group. Also, male patients had a mean macular thickness thicker than female patients and there was no correlation between the types of amblyopia and macular morphology changes [13]. - Szigeti (2014) revealed that there are subtle changes that affect the outer nuclear layer of the fovea suggesting the possible involvement of the photoreceptors [Concerning deprivational amblyopia:2]; - Kim (2013) investigated OCT changes in deprivational amblyopia due to congenital cataract and concluded that the mean macular thickness in amblyopic eyes was not different from the contralateral eye or control group, but noticed a thickening of the nasal RNFL compared with the fellow eye or control group [14]. - Long (2016) stated that 3 months after surgery, unilateral pediatric cataract patients show no significant interocular anatomical parameters differences except for anterior chamber depht (ACD) and that the parameters evaluated by OCT were not significantly correlated with the final BCVA [15-18].Also, there are scientists like Kee (2006) Repka (2009), Firat (2013) and Yakar (2015) who claim the inexistence of differences between amblyopic patients and the control group in their studies regarding macula morphology .Wu (2013) affirmed in his study that hyperopic anisometropic amblyopic eyes have thicker peripapillary RNFL than the contralateral eyes .Some scientist such as Kee (2006), Repka (2009), Huynh (2009), Firat (2013), Yalcin (2014), Demircan (2015) and Yakar (2015) claimed that there are no differences in RNFL and optic nerve disc morphology between amblyopic patients and control groups [\u2022 Choroidal thickness20-25]. However, Celik (2016) stated that, in young Turkish adults with hyperopic anisometropic amblyopia, the subfoveal choroidal, ganglion cell complex, macular and RNFL thickness measurements were not statistically significant between hyperopic anisometropic amblyopic eyes and normal fellow eyes [25].Morphological changes of the choroid evidenced with the help of OCT were studied by some researchers who certified that in amblyopic patients the subfoveolar area is significantly higher than in the congener eye or control group [\u2022 Are there morphologic changes after occlusion?26-30]. 6 studies were identified regarding the effect of optical correction and occlusion on the retina, optic nerve and choroid morphology. Oner (2016) analyzed central choroidal thickness before and after 6 months of occlusive treatment and reported no thickness reduction of the central choroid after amblyopia treatment. While Miki (2010), Tugcu (2013), and Yassin (2015) did not found differences between macular thickness and RNFL thickness before and after occlusion therapy, Pang (2011) stated that the central macular thickness was reduced after treatment compared with peripheric macular thickness in which changes were not noticed [31].Also, Liu (2010) stated that some children with various types of amblyopia who failed to achieve normal visual acuity after treatment show macular abnormality on OCT examination [Today, with the help of OCT, a new controversy regarding the presence of morphologic retinal changes in patients diagnosed with amblyopia arises. This opens new horizons in better defining amblyopia and can confirm if ocular structure are affected or not. In the last years, scientists have been trying to determine if morphologic changes in the macula, optic nerve, or choroid of amblyopic patients exist. The results are of great variability and, it seems that macula and choroid involvement is more frequently suggested compared with optic nerve involvement.DisclosureNone."} +{"text": "Transthoracic echocardiography (TTE) and focused cardiac ultrasound (FCU) are now considered essential skills and a requirement of training for physicians working in the intensive care unit (ICU) . TTE is Out of 114 ICUs, 69 (61 %) completed the survey, including 23 (33 %) that admitted cardiothoracic surgical patients and 44 (67 %) that did not. The proportion of ICUs performing TTE (94 %) and LU was high (83 %) but the use of TOE was low (33 %). The proportion of ICU consultants performing TTE, LU, and TOE was lower , respectively. The level of expertise (diagnostic versus focused) was highest in TTE (32 %) compared with TOE (22 %) and LU (12 %).The proportions of intensivists untrained in TTE and LU was 41 % and 30 %, respectively. Perceived barriers included lack of organized training (38 %) and time for training (25 %). Other barriers included a perceived lack of need for training (18 %), insufficient equipment (14 %), and resistance from other ultrasound providers (4 %). The most commonly reported training programs were tertiary courses, such as provided by the Australasian Society of Ultrasound in Medicine (68 %) and University of Melbourne (59 %), rather than board examinations or hands-on workshops.We conclude that although TTE and LU are used frequently in Australasian teaching ICUs, many ICU physicians are yet to be trained due to lack of ICU training programs and time for training. Although tertiary courses are popular and provide training to diagnostic level, they are lengthy and depend on trainers and patient caseload and are not, therefore, scalable. An attractive alternative is to begin training in medical school and to train more physicians in basic ultrasound with shorter, more efficient, and hands-on courses utilizing the internet and ultrasound simulators , advanci"} +{"text": "Objective: The study aims to assess the spectrum of cognitive and behavioural disorders in patients affected by Amyotrophic Lateral Sclerosis (ALS) according to the recent consensus criteria [9]. The study also intends to assess the impact of physical disability on cognitive and behavioural abnormalities.Methods: Detailed neurological, neuropsychological and neurobehavioral evaluations were administered to 23 ALS patients, 11 Lower Motor Neuron Disease (LMND) patients and 39 healthy controls. Strong et al.\u2019s criteria [9] were applied to diagnose the presence of cognitive/behavioural impairment. Clinical and neuropsychological scores were used for group comparisons and correlation analyses.Results: In comparison with LMND and controls, a subgroup of ALS patients (\u223c30%) manifested executive dysfunction, which was severe enough to classify them as cognitively impaired. Action naming difficulties and short-term memory deficits were also observed. Aspontaneity, disorganization and mental rigidity reached clinical relevance in 20% of ALS patients. A small percentage of ALS patients (13%) also had comorbid dementia. The cognitive or behavioural status was not related to the clinical features of ALS.Conclusion: The use of consensus criteria for cognitive and behavioural impairment and the comparison with the LMND group proved useful in defining the spectrum of non-motor manifestations of ALS."} +{"text": "Although multiple serum antiretinal autoantibodies (ARAs) have been reported in patients with paraneoplastic and non-paraneoplastic autoimmune retinopathy ((n)pAIR), not all retinal antigens involved in (n)pAIR are specified. This study aims to serologically identify patients with presumed (n)pAIR through determination of both known and unknown ARAs by autoantibody profiling.An antigen suspension bead array using 188 different antigens representing 97 ocular proteins was performed to detect ARAs in serum samples of patients with presumed (n)pAIR (n = 24), uveitis (n = 151) and cataract (n = 21). Logistic regressions were used to estimate the associations between ocular antigens and diagnosis. Validation of interphotoreceptor matrix proteoglycan 2 (IMPG2) and recoverin antigens was performed by immunohistochemistry and immunoblot, respectively.Samples of patients with presumed (n)pAIR exhibited a broad spectrum of ARAs. We identified retinal antigens that have already been described previously (e.g. recoverin), but also identified novel ARA targets. Most ARAs were not specific for (n)pAIR since their presence was also observed in patients with cataract or uveitis. High titers of autoantibodies directed against photoreceptor-specific nuclear receptor and retinol-binding protein 3 were more common in patients with presumed (n)pAIR compared to uveitis . The presence of all other ARAs did not significantly differ between groups. In patients with presumed (n)pAIR, anti-recoverin autoantibodies were the most prevalent ARAs. Validation of bead array results by immunohistochemistry (anti-IMPG2) and immunoblot (anti-recoverin) showed concordant results in (n)pAIR patients.Patients with (n)pAIR are characterized by the presence of a broad spectrum of ARAs. The diagnosis of (n)pAIR cannot be based on the mere presence of serum ARAs, as these are also commonly present in uveitis as well as in age-related cataract patients. Paraneoplastic and non-paraneoplastic autoimmune retinopathy ((n)pAIR) is a rare blinding retinal disorder of unknown pathogenesis. It is presumed that antiretinal autoantibodies (ARAs) are involved in the pathogenesis of (n)pAIR and damage ocular tissue causing poor visual outcome. Symptoms associated with (n)pAIR are progressive visual loss , visual field loss frequently associated with a ring scotoma or loss of the peripheral field, and decreased amplitudes on electroretinogram (ERG). \u20134Paraneoplastic autoimmune retinopathy (pAIR) includes two subgroups: cancer associated retinopathy (CAR) and melanoma associated retinopathy (MAR). In pAIR the presence of the same auto-antigens in both retinal tissue and malignant tissue has previously been described (e.g. recoverin). \u20137 The prMultiple serum ARAs have regularly been reported in affected patients , althougCurrently, antigen bead arrays are being used to profile autoantibody reactivity in body fluids. With thiOur study aimed to serologically identify patients with presumed (n)pAIR through determination of ARAs. For this purpose, we used a bead array-based multiplex assay for autoantibody profiling using 188 ocular antigens representing 97 different retinal proteins.Serum samples were either collected during routine diagnostic analysis for the presence of anti-recoverin autoantibodies in the Laboratory of Medical Immunology of the Erasmus University Medical Center between April 2013 and August 2015 or were obtained from biobank of our department. The study was approved by the local ethical committee from the Erasmus University Medical Center and adhered to the tenets of the Declaration of Helsinki. The ethical committee decided that no informed consent of patients was required for the use of the remainder of the diagnostic material, as the samples were anonymized and the patients were not subjected to additional risk or procedures. Samples which were obtained from the biobank included signed informed consent from all participants. All whole blood samples were centrifuged after at least 30\u2019 clotting time at 3,000 rpm for 10 minutes, and serum was stored at -80\u00b0C.According to the recently published report on the nomenclature of (n)pAIR, the general term autoimmune retinopathy (AIR) is recommended to indicate the non-paraneoplastic autoimmune retinopathy (npAIR) subtype. In our present series we indicate the specific subtype(s) of AIR pAIR) to prevent any misunderstanding regarding nomenclature. The diagAn additional group of presumed pAIR (CAR or MAR) patients (N = 7) in whom ERG or visual field tests were not performed , but who fulfilled all other inclusion criteria, was included separately. An additional required criterion for these patients comprised the development of a malignancy before or within 3 months after presentation with ocular problems.We collected various clinical data of the patients with presumed (n)pAIR, including patient demographics (age and gender) and ocular characteristics such as complaints of photopsia, complaints of nyctalopia, subjective or objective problems with colour-vision, unilateral or bilateral visual problems and the presence of a malignancy in the medical history or during follow-up.Controls consisted of two groups: 21 serum samples from cataract patients without retinal damage and 151 samples from patients with uveitis of different causes. Patients with age related cataract were included as controls rather than healthy people, as this disorders does not involve retina nor exhibits retinal damage, and represents a clinical setting in which the tests might be employed. Samples of control patients were collected at the department of Ophthalmology of the Erasmus University Medical Center between February 2009 and April 2015. Patient demographics (age and gender) and known malignancies of these patients were registered.Escherichia coli, with an affinity tag consisting of six histidines and an albumin binding domain from streptococcal protein G (His6ABP) and one bead identity went through the coupling process without addition of antigen . After incubation, the coupled beads were washed and stored in a blocking reagent before combining all bead identities to create a bead array in suspension. Samples were distributed across 96-well microtiter plates, together with triplicate aliquots of a sample pool and a buffer blank in each plate for determination of the intra- and inter-reproducibility. Serum samples were diluted 1:250 in assay buffer before being mixed with the bead array. Incubation was performed at room temperature for 2 hours followed by detection of the IgG reactivity by a fluorophore conjugated anti-human IgG Fab fragment and measured in a FlexMap3D instrument (Luminex Corp.).Autoantibody profiling was performed in all serum samples from patients with presumed (n)pAIR (n = 24), uveitis (n = 151) and cataract (n = 21). Antigens used for the autoantibody profiling were selected based on potential relevance to ocular diseases according to literature and previous positive retinal immunohistochemistry staining, resulting in 188 antigens (human protein fragments) representing 97 unique proteins. The protein fragments were produced within the Human Protein Atlas and designed to represent unique parts of each target protein., 43 ProtHis6ABP) . ImmobilFor validation purposes, samples that tested positive for anti-recoverin autoantibodies on the antigen bead array, and all samples from patients with presumed (n)pAIR, were analysed on a recoverin specific immunoblot . Membrane strips coated with recombinant human recoverin were incubated with a sample buffer for 5 minutes. After aspiration of the sample buffer, the membrane strips were incubated with diluted serum samples for 30 minutes on a shaking platform. Subsequently membrane strips were washed three times, incubated with secondary antibodies (enzyme conjugated anti-human IgG), washed again for three times and stained with a substrate solution which was capable of promoting an enzymatic colour reaction. To identify positive reactions, assessment of visible bands was performed relative to the included control. Results from the antigen suspension bead array and the recoverin specific immunoblot were compared.\u00ae , followed by hydration in graded alcohols and blocking for endogenous peroxidase in 0.3% hydrogen peroxide. For antigen retrieval, slides were immersed and boiled in Citrate buffer\u00ae, pH6 for 4 min at 125\u00b0C and then allowed to cool to 90\u00b0C. Automated immunohistochemistry was performed essentially as previously described, using an Autostainer 480 instrument\u00ae (Lab Vision). Ant Ant46] AOur study shows that patients with (n)pAIR are characterized by the presence of a broad spectrum of various ARAs. We identified ARAs that have already been described in previous studies, such as anti-recoverin autoantibodies, but also identified new retinal targets. Our findings illustrate that serum ARAs are not only present in patients with (n)pAIR, but also in patients with cataract and uveitis. Though some ARAs appeared to be specific for (n)pAIR, their prevalence and consequently their sensitivity as markers for (n)pAIR were low. This autoantibody screening using 188 antigen provides insight into the autoimmune repertoire of patients with (n)pAIR and a base for further validation with independent methods for protein analysis and independent sample cohorts.A gold standard for the determination of ARAs is currently lacking. DifferenIn addition, information on clinical relevance of the specific ARAs and their pathological titres are lacking. A combination of different ARAs was observed in some cases and therefore their individual effects on retinal tissue could not be distinguished.In our study, we performed statistical analyses using different cut-off levels. By using a high cut-off value, a ratio > 25, false positive results were minimized and retinal targets with a high specificity for (n)pAIR were found. The low cut-off value, a ratio of >2 (indicating ARAs with at least twice the reactivity of the negative control), was used for a more sensitive approach, limiting the exclusion of possibly relevant ARA targets with a lower titre. However, with both cut-off values, no ARAs were found eligible for diagnostic purposes. Some ARAs were specific for (n)pAIR, but had low prevalence while others were more frequently identified but lacked specificity.In concordance with previous findings, positive results of serum anti-recoverin autoantibodies were not only observed in patients with presumed (n)pAIR, but also in patients with uveitis and cataract. Furthermore, no association between the presence of autoantibodies directed against recoverin and the presence of a malignancy was found. A discrepancy between the antigen suspension bead array results for anti-recoverin and the anti-recoverin immunoblot was found in three control patients (one with cataract and two with uveitis). The difference in results could be explained by the different techniques used for determination of ARAs imposing differences in analytical performance. Possibly, the number and/or availability of recoverin antigenic epitopes differed between the antigen suspension bead array and the immunoblot technique. The protein fragments we used in this study to screen for autoantibody reactivity in serum were designed to represent unique parts of each target protein. The binding of the autoantibodies towards their target may be influenced by the protein folding of antigens and may differ in comparison to full-length protein arrays or peptide arrays. Both linear and conformational epitopes, recognized by some ARAs, might be missed for some proteins, preventing recognition by certain autoantibodies.The identification of new ARAs in (n)pAIR is in line with findings from previous studies using Western blot analysis for the determination of ARAs., 48 AlthOur present study focused on the autoantibodies prevalent in serum, which reflects systemic production and is probably not influenced by potential production or accumulation of specific autoantibodies within the eye. Analysis of local, intraocular retinal autoantibodies might show an entirely different pattern and may differ in clinical importance compared to retinal autoantibodies found in the peripheral circulation. The importance of locally produced autoantibodies has already been shown in cerebrospinal fluid for the central nervous system. In addition, it is unknown which autoantibodies penetrate from the circulation, through the blood retina barrier, into the retina and cause a local inflammation. Further research addressing the intraocular presence of specific retinal autoantibodies might elucidate the clinically relevant autoimmune processes directed against the retinal tissue in (n)pAIR.A gold standard for the definitive diagnosis of (n)pAIR is currently lacking. Also in this study, the diagnosis of presumed (n)pAIR was based on clinical symptoms. To compensate for this inaccuracy, we used strict inclusion criteria and selected a uniform cohort of patients with unexplained visual loss, visual field defects and decreased or absent ERG while other diagnostic possibilities leading to this configuration of clinical characteristics were (so far as possible) excluded. The presence of ARAs was found in all our patients with presumed (n)pAIR and therefore all fulfilled the criteria for the diagnosis of (n)pAIR.Although the mere presence of ARAs supports the diagnosis of (n)pAIR, it has been stated that there are no specific ARAs which would be exclusive for (n)pAIR and none of the ARAs were identified to be of higher diagnostic value than other ARAs., 9, 14 OIn conclusion, our study identified a heterogenous reactivity pattern of ARAs in serum of patients with (n)pAIR, although the presence of ARAs was not discriminatory between (n)pAIR, cataract and uveitis and exhibited a low sensitivity. Therefore, the diagnosis of (n)pAIR cannot be based on the mere presence of serum ARAs and such presence thus warrants careful interpretation. The determination of ARAs in intraocular fluid might provide more insight into the pathogenesis of (n)pAIR and might indicate more sensitive and specific diagnostic tools. Therefore, future research on the prevalence of ARAs in ocular fluid represents an important next step.S1 Table(DOCX)Click here for additional data file.S1 FigARAs not prevalent in patients suspected of paraneoplastic and non-paraneoplastic autoimmune retinopathy are not shown.* GNAS;GNAZ;GNA11-15;GNAL;GNAQ;GNAI1-I3;GNAO1;GNAT1-T3.(EPS)Click here for additional data file."} +{"text": "Gadus morhua) and turbot in Denmark. Phylogenomic analyses revealed that these two ranaviruses are nearly identical and form a distinct clade at the base of the ranavirus tree branching off near other fish ranaviruses.Ranaviruses have been isolated from Atlantic cod ( Cod iridovirus (CoIV) is the earliest isolation of a ranavirus in fish. It was isolated from wild Atlantic cod in Danish coastal waters in 1979 during an investigation of ulcers in cod . Ranavirg for 20\u00a0min, and total nucleic acids were purified using a DNeasy blood and tissue kit (Qiagen). The DNA libraries were prepared using the Nextera XT DNA kit (Illumina), and sequencing was performed using a V3 chemistry 600-cycle kit on a MiSeq platform (Illumina). De novo assembly of the paired-end reads in SPAdes (The Rmax and CoIV isolates were propagated in bluegill fry (BF-2) cells as previously described and harvn SPAdes producedIridoviridae core genes (The genomes of Rmax and CoIV were annotated using GATU with epire genes revealedThe isolation of nearly identical ranavirus strains from two different marine species, hundreds of kilometers and 20\u00a0years apart, indicates the persistence of a ranavirus strain of unknown virulence in the marine environment. With the exception of the grouper iridoviruses in Asia , the impKX574343 and KX574342, respectively.The complete genome sequences of Rmax and CoIV have been deposited in GenBank under the accession numbers"} +{"text": "This article provides original data on median dietary intake of 18 amino acids from amino acid medical foods, glycomacropeptide medical foods, and natural foods based on 3-day food records obtained from subjects with phenylketonuria who consumed low-phenylalanine diets in combination with amino acid medical foods and glycomacropeptide medical foods for 3 weeks each in a crossover design. The sample size of 30 subjects included 20 subjects with classical phenylketonuria and 10 with a milder or variant form of phenylketonuria. Results are presented for the Delis-Kaplan Executive Function System and the Cambridge Neuropsychological Test Automated Battery; the tests were administered at the end of each 3-week dietary treatment with amino acid medical foods and glycomacropeptide medical foods. The data are supplemental to our clinical trial, entitled \u201cGlycomacropetide for nutritional management of phenylketonuria: a randomized, controlled, crossover trial, 2016 (1) and \u201cMetabolomic changes demonstrate reduced bioavailability of tyrosine and altered metabolism of tryptophan via the kynurenine pathway with ingestion of medical foods in phenylketonuria, 2017 (2). This data has been made public and has utility to clinicians and researchers due to the following: 1) This provides the first comprehensive report of typical intakes of 18 amino acids from natural foods, as well as amino acid and glycomacropeptide medical foods in adolescents and adults with phenylketonuria; and 2) This is the first evidence of similar standardized neuropsychological testing data in adolescents and adults with early-treated phenylketonuria who consumed amino acid and glycomacropeptide medical foods. Specifications TableValue of the data\u2022The data presented are the first comparison of how ingestion of medical foods comprised primarily of single amino acids or intact protein from glycomacropeptide (a 64-amino acid glycophosphopeptide isolated from cheese whey) affect the dietary intake profile of amino acids.\u2022The dietary intake of 18 amino acids provides useful information to clinicians and researchers related to typical amino acid intake of individuals with phenylketonuria.\u2022The data from the standardized neuropsychological tests can be compared with pharmacological studies using these same tests to contrast the effectiveness of dietary management with pharmacological treatment in subjects with phenylketonuria \u2022These data are useful to clinicians and researchers evaluating the safety and efficacy of glycomacropeptide medical foods in the nutritional management of phenylketonuria.1Summary data for dietary intake of amino acids and assessment of neuropsychological and executive function are presented for subjects with phenylketonuria enrolled in a randomized, controlled, crossover trial conducted from November 2010 to July 2015 2Thirty subjects with early-treated phenylketonuria, 20 with classical and 10 with a milder or variant form of phenylketonuria, completed the clinical trial 3Daily amino acid intake from the whole diet, medical foods, and natural food was calculated from consecutive 3-day food records at the end of the 3-week amino acid medical foods and glycomacropeptide medical foods treatments . Amino aNeuropsychological testing to assess executive function, the Delis-Kaplan Executive Function System\u2122 , and the Cambridge Neuropsychological Test Automated Battery was conducted by research staff trained in the administration of standard psychological assessments under the supervision of a licensed psychologist after following the amino acid medical foods and glycomacropeptide medical foods treatments for 3 weeks , Table 3Department of Health and Human Services Grants R01 FD003711 from the FDA Office of Orphan Products Development to Ney, P30-HD-03352, T32 DK007665 to Ney, and by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000427. Cambrooke Therapeutics, Inc. donated the glycomacropeptide medical foods used in this study.This work was supported by"} +{"text": "The physical examination showed violaceous petechial purpuric patches, coalescing by area, ulcerated nodular lesions extended to both lower limbs, with presence of necrosis in center of lesions (Vasculitis is an inflammatory disease of blood vessels characterized by the alteration or destruction of the vessel wall. A 55 year\u2019s old woman, followed for diabetes and hypertension, presented to our consultation complaining of generalized pruritic lesions, without fever arthritis or any other systemic manifestations. The patient reported the concept of taking Oxicam; Brexin lesions Figure 1A lesions Figure 1B"} +{"text": "Resistance to intravenous immunoglobulin (IVIG) occurs in 10\u201320% of patients with Kawasaki disease (KD). The risk of resistance is about two-fold higher in patients with elevated gamma glutamyl transferase (GGT) levels. We sought to understand the biological mechanisms underlying IVIG resistance in patients with elevated GGT levels.We explored the association between elevated GGT levels and IVIG-resistance with a cohort of 686 KD patients (Cohort I). Gene expression data from 130 children with acute KD (Cohort II) were analyzed using the R square statistic and false discovery analysis to identify genes that were differentially represented in patients with elevated GGT levels with regard to IVIG responsiveness. Two additional KD cohorts (Cohort III and IV) were used to test the hypothesis that sialylation and GGT may be involved in IVIG resistance through neutrophil apoptosis.ST6GALNAC3, a sialyltransferase, as the most differentially expressed gene, we hypothesized that sialylation and GGT are involved in IVIG resistance through neutrophil apoptosis. We then confirmed that in Cohort III and IV there was significantly less reduction in neutrophil count in IVIG non-responders.Thirty-six genes were identified that significantly explained the variations of both GGT levels and IVIG responsiveness in KD patients. After Bonferroni correction, significant associations with IVIG resistance persisted for 12 out of 36 genes among patients with elevated GGT levels and none among patients with normal GGT levels. With the discovery of Gene expression analyses combining molecular and clinical datasets support the hypotheses that: (1) neutrophil apoptosis induced by IVIG may be a mechanism of action of IVIG in KD; (2) changes in sialylation and GGT level in KD patients may contribute synergistically to IVIG resistance through blocking IVIG-induced neutrophil apoptosis. These findings have implications for understanding the mechanism of action in IVIG resistance, and possibly for development of novel therapeutics. Kawasaki disease (KD) is an acute systemic vasculitis of infants and children, that occurs world-wide , but theIn this study, we explored the association of GGT level and IVIG resistance in KD patients to try to understand the biological mechanism of action underlying these two clinical findings. With our systematic analyses of gene regulation and associated clinical findings and outcomes, we hypothesize: (1) neutrophil apoptosis induced by IVIG plays a pivotal role in IVIG responsiveness; (2) changes in sialylation and GGT levels in acute KD patients may contribute together to IVIG resistance by blocking IVIG-induced neutrophil apoptosis.The normal ranges of GGT and alanine aminotransferase (ALT) are shown in Table A in A cohort with 686 subjects with KD (Cohort I) was used to explore the associations between GGT levels and IVIG resistance. All subjects in this cohort were enrolled at Rady Children\u2019s Hospital in San Diego after obtaining written parental informed consent and patient assent as appropriate. All subjects were treated with 2 g/kg of IVIG (Gammagard\u00ae) over a 10\u201312 hour period as per the pharmacy\u2019s standard protocol. The study protocol was conducted in accordance with the Declaration of Helsinki and was approved by Institutional Review Boards of UCSD and Stanford University. KD subjects in this study were: a) patients with fever for no more than 10 days, plus at least four of the five principal clinical criteria, b) patients meeting fewer criteria but with coronary artery abnormalities (CAA) (Z-score \u22652.5 for left anterior descending [LAD] and/or right coronary arteries [RCA]) documented by echocardiogram, and c) patients with fewer than 4 clinical criteria but meeting the American Heart Association (AHA) criteria for incomplete KD by laboratory criteria [We performed gene expression profiles of whole blood obtained from a sub-cohort of 146 KD subjects (Cohort II) as previously described . Of thesFor each of the 31,000 genes in the 130 subjects, the explained variations in GGT levels or IVIG responsiveness were estimated using R square of linear regression or the McFadden's pseudo- R square , 19 of lCorrection for multiple hypothesis testing on the explained variations was performed using the permutation-based false discovery rate (FDR) analytical method . FDRs ofThe study population was divided into two sub-cohorts, one with normal and the other with elevated GGT levels, using age-specific reference ranges established in our clinical laboratory with 587 KD subjects. Approved by the institutional review board of Korean University Medical Center, the medical records of KD patients from January 2008 to December 2013 were reviewed. The diagnosis and treatment of KD was based on AHA criteria . CAA werThe absolute neutrophil count (ANC) (mature and immature (band) forms) were calculated for both the UCSD and Korean cohorts.All statistical analyses and plots were performed using R 3.2.2 and ggplThe 575 IVIG responders and 111 IVIG non-responders in Cohort I had similar demographic and clinical characteristics . SubjectIVIG resistance was examined according to GGT levels quintiles . IVIG reOf the 130 KD subjects with gene expression data in Cohort II, 100 were IVIG responders and 30 were IVIG non-responders. At the time of diagnosis, 45 subjects had normal serum GGT levels, and 85 had elevated GGT levels with IVIG resistance persisted for 12 out of the 36 genes among patients with elevated GGT levels and none among patients with normal GGT levels or elevated GGT levels (85 subjects including 62 IVIG responders and 23 non-responders). After applying the Bonferroni correction, significant associations percentage reduction in neutrophil count than responders. A similar pattern was observed in Cohort IV, which included 222 IVIG non-responders and 365 IVIG responders . We further delineated changes in ANC by stratifying patients into quintiles according to the ANC at presentation ..ST6GALNAactoside , 35. Neuin vitro , suggestin vitro . These oin vitro . Circulain vitro , 39.Despite the fact there have been reports of KD occurring in the presence of Autoimmune neutropenia (AIN), 41, forST6GALNAC3 leads to increased enzymatic activity of ST6GALNAC3, producing more GD1\u03b1, which in turn binds to siglec-9 and prevents its recognition by Nabs-siglec-9 in IVIG; (2) elevation of GGT levels will increase the degradation of extracellular glutathione (GSH) to provide cysteine for de novo synthesis of intracellular GSH, reducing the intracellular reactive oxygen species (ROS) in neutrophils. Reduction of ROS in neutrophils decreases neutrophil apoptosis induced by IVIG in the presence of GM-CSF and IFN- \u03b3 [Naturally occurring antibodies (Nabs) against siglec-9 (Nabs-siglec-9) are found in IVIG and can induce apoptosis in neutrophils \u201344. MoreTo the best of our knowledge, we are the first to integrate multifaceted data sets of expression profiles, clinical parameters and outcomes to explore KD pathophysiology. We demonstrated that KD subjects with elevated GGT levels have a unique gene expression pattern that overlaps with the gene expression pattern associated with IVIG resistance. Our study suggests that reduction of circulating neutrophils is one of the hallmarks of the therapeutic effects of IVIG.ST6GALNAC3 and elevated GGT levels may lead to reduced neutrophil apoptosis, and consequently IVIG resistance Nabs against siglec-9 (Nabs-siglec-9) in IVIG can induce apoptosis in neutrophils and contribute to the efficacy of IVIG in the treatment of KD. (2) Increased sialylation of gangliosides block IVIG-mediated neutrophil apoptosis and lead to persistent inflammation and IVIG resistance.If confirmed, our findings may account for the variable effectiveness of different IVIG lot preparations , 49, potS1 FigNumbers below the x axis are numbers of subjects whose ANC increased after IVIG treatment. Of the 13 IVIG responders with ANC increased after IVIG, 12 fell into the lowest quintile of acute phase neutrophils, and none in the last three quintiles.(TIF)Click here for additional data file.S2 FigLoess curve analyses of neutrophil reduction or the percentage reduction in neutrophil count as a function of the pretreatment ANC .(TIFF)Click here for additional data file.S3 Fig(TIF)Click here for additional data file.S1 FileTable A in S1 File. The standard range for normal GGT (IU/L); Table B in S1 File. The standard range for normal ALT (IU/L); Table C in S1 File. The clinical characteristics and laboratory values for subjects selected for gene expression analysis; Table D in S1 File. Association of 12 genes with IVIG response in subgroup with normal and elevated CRP levels; Table E in S1 File. Association of 12 genes with IVIG response in subgroup with normal and elevated CRP levels.(PPTX)Click here for additional data file."} +{"text": "HSPD1 gene that encodes the HSP60 subunit of the HSP60/HSP10 chaperonin complex. Investigations of the molecular mechanisms underlying these disorders have revealed that different degrees of reduced HSP60 function produce distinct neurological phenotypes. While mutations with deleterious or strong dominant negative effects are not compatible with life, HSPD1 gene variations found in the human population impair HSP60 function and depending on the mechanism and degree of HSP60 dys- and mal-function cause different phenotypes. We here summarize the knowledge on the effects of disturbances of the function of the HSP60/HSP10 chaperonin complex by disease-associated mutations.Heat shock protein 60 (HSP60) forms together with heat shock protein 10 (HSP10) double-barrel chaperonin complexes that are essential for folding to the native state of proteins in the mitochondrial matrix space. Two extremely rare monogenic disorders have been described that are caused by missense mutations in the E. coli bacteria stacked back to back ) lists 95 missense variations for the protein product of the canonical HSPD1 transcript. This website provides high quality exome sequencing data from more than 60,000 unrelated adults without severe pediatric disease. Of the 95 HSPD1 missense variations 60 have only been seen in one single allele and only 9 have been observed in more than 10 of the ~120,000 alleles recorded , this variation may be disease-associated with reduced penetrance. The most frequently observed amino acid variation in HSP60, HSP60-p.Gly563Ala, has been found in homozygous form in one sporadic Danish spastic paraplegia patient has been reported (Hansen et al., Effects of expressing the SPG13- and MitCHap60-associated mutant proteins on mitochondrial morphology have been assessed in Cos-7 cells transfected with cDNAs encoding the disease-associated mutant proteins (Miyamoto et al., ShRNA-mediated knock-down of HSP60 in human HEK293 cells decreased the steady state levels of the mitochondrial medium-chain acyl-CoA dehydrogenase (Corydon et al., Knock-out of both HSP60-encoding alleles in mice is not compatible with life. Such embryos died early during development (Christensen et al., E. coli 85 proteins that display obligate dependence on folding assistance by the bacterial chaperonin complex have been characterized (Kerner et al., Proteins like UQCRC1 or SOD2 thus appear to depend more than others proteins on folding assistance by the HSP60/HSP10 complex. For de novo mutations in the HSPD1 and HSPE1 genes in sporadic diseases. Clinical geneticists should therefore be aware of this and it will be important to collect the knowledge of these rare cases to be able study genotype/phenotype relationships and to assess the disease-causing nature of variations.Different mutations in HSP60 or its partner protein HSP10 lead to distinct phenotypes of neurological disorders with a clear mitochondrial dysfunction pattern. These diseases are very rare as deleterious effects of mutations in these essential genes are not compatible with normal embryonal development (Christensen et al., Besides being affected by mutations, the activity and function of the HSP60/HSP10 complex can also be regulated by its expression levels. The regulation of the transcription levels of both proteins occurs via different elements in the bidirectional promoter. SP1 elements provide robust house-keeping levels of expression and on top of that heat-shock elements, mitochondrial unfolding protein response elements, and STAT3 elements further modulate expression adapting it to specific situations (Zhao et al., Indeed, dysregulation of HSP60 expression in hypothalamus has been implicated with type 2 diabetes mellitus (Kleinridders et al., Finally, posttranslational modifications of the HSP60/HSP10 complex may regulate the activity of the complex. Like other molecular chaperones HSP60 is a highly modified protein with a long list of PTMs recorded in the UniProt database (Consortium, PF and PB have both contributed to writing the draft and producing the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Non-traumatic out of hospital cardiac arrest (OHCA) is the leading cause of death worldwide, acute coronary syndromes accounting for up to 2/3 of cases. Urgent angiography with a view to primary percutaneous coronary intervention (PPCI) is a class IB recommendation according to international guidelines. Diagnosis and management of patients with unobstructed coronaries or unidentified culprit lesion on angiogram is challenging. Cardiac magnetic resonance (CMR) with its superior tissue characterization is a well-established diagnostic technique. We sought to assess the additive role of CMR in diagnosis and management of patients with an inconclusive coronary angiogram and to determine which findings on CMR best predict clinical impact.We retrospectively analysed our database to collect data on consecutive patients surviving non-traumatic OHCA, undergoing urgent coronary angiogram and CMR. We focused the analysis on patients with an inconclusive angiogram, defined as the evidence of unobstructed coronaries or of coronary artery disease (CAD) without a clear culprit lesion. Clinical impact of CMR was defined as a change in diagnosis, as compared to that made on a multi-parametric pre-CMR basis , or a change in management, which could be a change in medication or the performance/avoidance of invasive procedures .Out of 157 patients surviving OHCA referred for CMR after urgent angiogram, we identified 104 patients with inconclusive angiogram (66%): 67 patients (64%) had unobstructed coronaries and 37 (36%) had CAD with no clear culprit. Diagnosis based on CMR findings was ischemic heart disease in 42 patients (40%), non-ischemic heart disease in 30 (29%), a structurally normal heart was found in 25 patients (24%) and non-specific findings in 7 (7%). Overall, CMR had a clinical impact in 68/104 patients (65%), determining a change in diagnosis in 17% of patients, a change in management in 31% and both a change in diagnosis and management in 17%. CMR led to myocardial revascularization in 18% of patients and to ICD implantation in 16%; based on CMR findings, an invasive procedure was avoided in 17% of patients. In a multivariate model that included clinical and imaging parameters, LGE and segmental regional wall motion abnormality were the strongest independent predictors of CMR clinical impact (Table CMR had an additive clinical impact on diagnosis and management in 65% of patients surviving OHCA with an inconclusive coronary angiogram. LGE and segmental regional wall motion abnormality were the best independent predictors of clinical impact following CMR. CMR should be enclosed in the clinical-diagnostic work-up of this subgroup of OHCA survivors."} +{"text": "Scientific Reports 10.1038/s41598-017-14674-5, published online 06 November 2017Correction to: The original version of this Article contained an error in the Abstract.\u201cChanges in miRNA expression glomerular of capillaries during antibody-mediated rejection (ABMR) are poorly understood and could contribute to the deleterious inflammation and fibrosis of ABMR via suppression of target genes.\u201dnow reads:\u201cChanges in miRNA expression of glomerular capillaries during antibody-mediated rejection (ABMR) are poorly understood and could contribute to the deleterious inflammation and fibrosis of ABMR via suppression of target genes.\u201dThis error has now been corrected in the PDF and HTML versions of the Article."} +{"text": "Ovis orientalis), 22 wild goat (Capra aegagrus), nine Indian gazelle (Gazella bennettii) and eight Goitered gazelle (Gazella subgutturosa) during the national survey for wildlife diseases in Iran. Serum samples were evaluated using serologic antibody tests for Peste de petits ruminants virus (PPRV), Pestiviruses [Border Disease virus (BVD) and Bovine Viral Diarrhoea virus (BVDV)], Bluetongue virus (BTV), Bovine herpesvirus type 1 (BHV-1), and Parainfluenza type 3 (PI3). Sera were also ELISA tested for Pestivirus antigen. Tissue samples including spleen, liver, lung, tonsils, mesenteric and mediastinal lymph nodes and white blood cells (WBCs) were tested using polymerase chain reaction (PCR) for PPRV, Foot and Mouth Disease virus (FMDV), Pestivirus, BTV, Ovine herpesvirus type 2 (OvHV-2) and BHV-1. Serologic tests were positive for antibodies against PPRV (17%), Pestiviruses (2%) and BTV (2%). No antibodies were detected for BHV-1 or PI3, and no Pestivirus antigen was detected. PCR results were positive for PPRV (7.8%), FMDV (11%), BTV (3%), OvHV-2 (31%) and BHV-1 (1.5%). None of the samples were positive for Pestiviruses.A molecular and serological survey of selected viruses in free-ranging wild ruminants was conducted in 13 different districts in Iran. Samples were collected from 64 small wild ruminants belonging to four different species including 25 Mouflon ( Habitat fragmentation, hunting, and infectious diseases often threaten biodiversity and may contribute to significant declines in wildlife populations , 2. ThesWide climatic variations and untouched landscapes in Iran support a diverse mammalian fauna including 191 species from 93 genera and ten orders , 11. WilMost of the wild ruminants in Iran are on the International Union for the Conservation of Nature (IUCN) Red List as a direct result of infectious diseases, illegal hunting and drought .Goitered gazelle, listed by the International Union for Conservation of Nature (IUCN) red list as vulnerable, are found in the Zargros region of Iran. Indian gazelle, protected in Iran but a considerable population of Indian gazelle are found in the Kavir National Park . Both WiMorbillivirus (family Paramyxoviridae) closely related to the eradicated rinderpest virus, causes the disease Peste des petits ruminants (PPR) which is considered to be one of the most significant livestock diseases in the Middle East, Africa and Asia [The majority of pathogens that cause disease outbreaks in wild ruminants worldwide are viral . Peste dand Asia , 17. PPRand Asia . Multipland Asia , 20. PPRand Asia , 22.Foot and Mouth Disease (FMD) is caused by a single-stranded negative sense RNA virus that belongs to the genus Aphthovirus from the Picornaviridae family. The FMD virus (FMDV) contains seven different serotypes, O, A, C, Asia 1, Southern African Territories (SAT) 1, SAT 2 and SAT 3 . MoleculPestivirus infections in animals are caused by a group of viruses from the Flaviviridae family, genus pestivirus. Three different pestiviruses have been described, namely, bovine viral diarrhoea virus (BVDV), Border disease virus (BDV) and Classical Swine Fever Virus (CSFV) . BVDV anOrbivirus from the family Reoviridae. There are 24 antigenically distinct serotypes in the genus and differing levels of cross reactivity have been observed between different serotypes[Culicoides midges [Another important infection seen in domestic and wild ruminants is Bluetongue virus (BTV) an serotypes. Epidemiserotypes. Sero-epserotypes\u201344. Howeserotypes. BTV cirs midges , 46 withs midges .Malignant Catarrhal Fever (MCF) is caused by members of subfamily Gammaherpesvirinae, genus Macavirus . AlcelapInfectious bovine rhinotracheitis virus (IBRV) and parainfluenza type 3 virus (PI3V) are the main viral respiratory diseases in livestock worldwide , 57.Paramyxovirus family, is one of the most common viral respiratory infections in cattle. Although PI3V can cause primary respiratory disease in cattle, it usually leads to the development of secondary bacterial infections in the respiratory tract of large ruminants [Infectious bovine rhinotracheitis (IBRV), caused by Bovine herpesvirus 1 (BHV-1), is associated with several clinical features in cattle. BHV-1 can produce a lifelong latent infection with occasional reactivation of the virus followed by viral shedding for several days. A serological positive response in animals is evidence of a latent infection . Parainfuminants . Both seuminants .The exteuminants .The aim of this study was to investigate if there is evidence of these commonly seen livestock viruses in wild ruminants in the national parks and protected regions of Iran using serological and molecular techniques.Ovis orientalis), 22 wild goat (Capra aegagrus), nine Indian gazelle (Gazella bennettii) and eight Goitered gazelle (Gazella subgutturosa).The study animals comprised wild ruminants from four different species including 25 Mouflon each indWhole blood was collected from the jugular vein, by cardiac aspiration or from the thoracic or abdominal cavities during fresh field necropsies by an authorized veterinarian from the Iran DOE. The collected blood was divided into two tubes, with and without anti-coagulant (EDTA) and labelled. Samples were transported, refrigerated, to the Virology laboratory at the Faculty of Veterinary Medicine at the University of Tehran within 24 hours.The names of the regions and their geographic information system coordinates for all sampled animals and the age and sex of wildlife species tested in this study are shown in Tables At the laboratory, serum was separated by centrifugation at 2000 RPM for 10 min. White blood cells from each blood sample was separated for antigen detection and RNA/ DNA isolation for molecular detection.WBCs were isolated using Ficoll-Hypaque density gradient separation method. In brief, five mL of blood was diluted two-fold in sterile phosphate buffered saline (PBS) then added into the 10 mL of Ficoll-Hypaque (Sigma Aldrich), centrifuged for 400 \u00d7 g at room temperature for 30 min. The cells were isolated and washed twice with PBS . AliquotThe study was approved by the Research and Ethics Committee of Iran Department of Environment. Animals were shot by authorized hunters and autopsied by veterinarians who specialized in wildlife studies during the national programme for survey of wildlife diseases. The hunting licences were issued by the Iran Department of Environment for the DOE qualified hunters.Serological tests used to detect antibodies included the following: a) PPR cELISA kit , b) pestivirus blocking ELISA kit (BVDV) and (BDV) , c) Bluetongue competitive ELISA and d) Bovine Herpesvirus 1 (BHV-1) ELISA kit and e) virus neutralization test (VNT) for parainfluenza type 3 . PestiviIn all serological ELISA tests positive and negative control sera were included in each plate. In addition to the control samples (provided within the ELISA kits), two more known positive and negative samples were included in each round of ELISA or VNT tests. The positive and negative-control serum samples were serum from animals who had been tested at the diagnostic virology unit at the Razi Vaccine and Serum Research Institute or Virology laboratory at the Faculty of Veterinary Medicine at the University of Tehran, Iran and kept as standard control samples. Each of these serum samples were previously evaluated in different assays. For virus neutralization test, each serum sample was tested in two independent assay runs and serum samples with a titre of 1/64 or higher were considered positive . All of White blood cells and the fresh/frozen tissues from all animals were subject to DNA and RNA isolation. RNA extraction was performed using QIAamp Viral RNA Mini kit according to the manufacturer's instructions. The cDNA was synthesized from extracted RNA using Moloney Murine Leukemia Virus-Reverse Transcriptase (MMLV-RT) and random primers . Total DNA was isolated from the above mentioned samples using QIAamp DNA Mini Kit according to the manufacturer's instructions. The synthesized cDNA and isolated DNA were saved as aliquots and stored at \u221280\u00b0C for further analysis.Previously published PCR protocols were used to detect; a) PPR , b) FMD Serological exposure of the 64 wild ruminants to PPR, BVD and BD, BTV, BHV-1, PI3 and pestivirus antigen is shown in The PCR results for PPRV, FMDV, Pestivirus, BTV, OvHV-2 and BHV-1 are shown in Four mouflon, two wild goats and one Indian gazelle were positive for FMDV by PCR on tonsil samples. The only positive Indian gazelle for FMDV was from Tooran and the positive Mouflon were from Tooran (n = 1), Khojir (n = 2) and Angooran (n = 1). Two FMDV positive wild goats were from Khojir National park and Mujen protected region. All positive PCR tests for PPRV, FMDV, BHV-1 and four of the OvHV-2 samples were confirmed by sequencing. Edited nucleotide sequences were compared to the nucleotide sequence database for similarity using BLASTn search tool and was shown to have significant homology to the available sequences for the listed viruses. \u2013S5 FilesThis is the first survey of viral diseases in wild ruminants in Iran. It will provide valuable information for future research in disease ecology and risks associated with transmission of these viruses between wildlife and livestock.Studies have shown that PPRV is endemic in Iran and the other neighbouring countries with multiple devastating outbreaks occurring in domestic and wild ruminants , 22. MorBorder disease is considered as an endemic disease in domestic sheep and goats in Iran and so MFoot and mouth disease has been reported in Mouflon, wild goats and Indian gazelles in several countries , 35. As Previous work in southeast Iran identified the serological existence of Bluetongue virus in domestic sheep with no reports of clinical signs , 44, 78.In this survey all of the seropositive and PCR positive BT samples were seen in Mouflon from Bamo National Park. The locality of this survey overlaps geographically with the district where a high prevalence of BTV is seen in livestock .There was no serological evidence for PI3 and IBR, the main viral infections of Iranian livestock, and there was just one Indian gazelle positive for BHV 1 using PCR. These viruses mainly cause disease in intensively managed livestock populations, so the lack of seroprevalence was expected in wildlife. In addition, BHV 1 infection is rarely seen in small ruminants and the clinical form is mainly associated with intensive feedlot or dairy production industries .PCR tests showed a high prevalence of OvHV-2 in Mouflon. The virus does not produce clinical signs in small ruminants and there have been no reports of clinical disease in wild and domestic sheep and goats , 81. In In conclusion, while there is clear evidence that transboundary disease viruses particularly FMDV, BTV and PPRV are circulating in wild ruminants. Further studies are required to investigate the transmission pathways and disease ecology between wildlife and livestock.S1 FileGenBank accession numbers are shown at the left side of the figure and Iranian isolates are identified with double asterisk marks.(PDF)Click here for additional data file.S2 FileGenBank accession numbers are shown at the left side of the figure and Iranian isolates are identified with double asterisk marks.(PDF)Click here for additional data file.S3 FileGenBank accession numbers are shown at the left side of the figure and Iranian isolates are identified with double asterisk marks.(PDF)Click here for additional data file.S4 FileGenBank accession numbers are shown at the left side of the figure and Iranian isolates are identified with double asterisk marks.(PDF)Click here for additional data file.S5 FileGenBank accession numbers are shown at the left side of the figure and Iranian isolates are identified with double asterisk marks.(PDF)Click here for additional data file."} +{"text": "SH2 domain-containing tyrosine phosphatase-2 (PTPN11 or Shp2) is a ubiquitously expressed protein that plays a key regulatory role in cell proliferation, differentiation and growth factor (GF) signaling. This enzyme is well expressed in various retinal neurons and has emerged as an important player in regulating survival signaling networks in the neuronal tissues. The non-receptor phosphatase can translocate to lipid rafts in the membrane and has been implicated to regulate several signaling modules including PI3K/Akt, JAK-STAT and Mitogen Activated Protein Kinase (MAPK) pathways in a wide range of biochemical processes in healthy and diseased states. This review focuses on the roles of Shp2 phosphatase in regulating brain-derived neurotrophic factor (BDNF) neurotrophin signaling pathways and discusses its cross-talk with various GF and downstream signaling pathways in the retina. PTPN11 gene is a 593 amino acid non-transmembrane protein tyrosine phosphatase (PTP) encoded by Shp2 plays prominent biological roles in regulating several signal transduction cascades affiliated with its function in the early development of vertebrates, cell proliferation, differentiation, transcription regulation and metabolic control as well as multiple GF signaling networks by the Shp2 phosphatase and its implications in the retina.In the retina, Shp2 is well expressed in the ganglion cell layer (GCL) and inner nuclear layer (INL) and its reactivity has been detected in photoreceptors are secreted proteins that regulate neural growth, survival and function by negatively affecting the induction of various cellular apoptotic pathways. Retinal ganglion cells (RGCs) express various neurotrophic factors and are also supported by neurotrophic factors obtained locally from the Muller cells and retrogradely from the brain through axonal flow , the prominent structural constituent of caveolae Figure . Shp2 waThe role of other significant caveolar proteins such as Cavin family members particularly polymerase I and transcript release factor (PTRF) which participate in caveolae formation through its interaction with Cav-1, have not been extensively investigated and their potential cross-talk with Shp2 remains to be explored and in the RGCs In cerebellar granule neurons, Shp2 suppressing functions are reported to abolish axonal regeneration by paired immunoglobulin-like receptor PIR-B/Shp mediated TrkB inhibition , another member of the neurotrophin family, exerts its survival-promoting effects by stimulating neural development and differentiation through MAPK cascade signaling in human glial cells in response to EGF treatment. Zhang et al. demonstrThe EGF-inhibitory impact of Shp2 was also investigated in a glioma cell line (SNB19). Despite lack of proliferation ability of SNB19 in response to EGF stimulation, it was found that interfering Shp2 mutant could reverse the cell\u2019s ability to proliferate following EGF induction signaling cascade which has major functions in cellular processes such as proliferation, differentiation and apoptosis downstream signaling including Ras, Raf, MEK and MAPK cascade. Insulin receptor substrate 1 (IRS-1), one of the major IR substrate is a multisite docking protein which interacts with SH2 domain-containing proteins such as Shp2. Milarski and Saltiel showed tPTPN11 gene mutation (Tartaglia et al., PTPN11 gene in animal studies resulted in extensive retinal degeneration, cell death and optic neuropathy during various developmental stages highlighting its regulatory function in retinal neuroprotection and progenitor retinal cell fate (Cai et al., Shp2 involvement in regulating retinal survival signaling pathways links dysregulation of this phosphatase to various physiological and pathological conditions. Under glaucomatous stress Shp2 leads to preferential RGC degeneration by inhibiting BDNF/TrkB downstream signaling through dephosphorylation and deactivation of TrkB (Gupta et al., in vivo and in vitro studies implied that the major effect of the phosphatase is mediated through its regulatory effects on various GFs and their downstream effectors which activates multiple signaling pathways. In this review we outlined and analyzed the existing evidence regarding Shp2 involvement in BDNF and other GF-dependant signaling networks with a specific focus on the retinal neuronal cells.Shp2 plays an emerging and important role in the retinal development and its preservation. Preliminary Although significant breakthroughs in the functional characterization of Shp2 have provided more knowledge of the physiological importance of the phosphatase, other areas of future study including manipulating Shp2 expression in retinal and other neuronal cell lineage or development of specific phosphatase inhibitors will further define the mechanisms through which Shp2 positively or negatively mediates various retinal signaling pathways. Another fascinating aspect would be considering Shp2 as a potential molecular target to modulate other neuronal signaling pathways thereby serving as mechanism-based therapy. The involvement of Shp2 in broad range of biochemical actions may make it a challenge to develop any specific therapeutic strategy to isolate a particular neuroprotective role. However, prospective investigations probing Shp2 protein expression, post-translational modifications, sub-cellular localization and interactome changes will unravel the role of this protein in various neurodegenerative disease and retinal disorders.The review was conceptualized, written and edited by each of the authors. Supervisor: SLG.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "To the Editor: Zika virus infection is an emerging arboviral disease linked to an increased risk for severe neurologic outcomes and devastating adverse fetal complications, including pregnancy loss and congenital microcephaly (A 51-year-old man (patient 1) who regularly traveled to Samoa, a Pacific island with known Zika virus transmission, returned to New Zealand in late January 2016. He reported having been sexually abstinent while overseas. After 1 week he experienced onset of fever, rash, arthralgia, and ankle edema. Aware of the symptoms of mosquito-borne illnesses prevalent in his region of travel, he assumed he had a mild case of chikungunya and sought no medical attention.A 53-year-old woman (patient 2) who was the sexual partner of patient 1 experienced onset of sore throat, fever, arthralgia, and rash 17 days after her partner\u2019s return to New Zealand (10 days after he had onset of symptoms). She had had no recent overseas travel, had no blood transfusions, and was unaware of having any mosquito bites. Four days after symptom onset, she visited a general practitioner, whose investigations revealed mild neutropenia, normal liver and renal function, no evidence of streptococcal throat infection, and a demonstrated immunity to measles.The rash subsequently spread, and small joint arthralgia worsened. The patient returned to the general practitioner 9 days after symptom onset. Disclosing her partner\u2019s travel history and symptoms and reporting having unprotected sexual intercourse with him after his return to New Zealand (before and during the time he was symptomatic), she enquired about the possibility of Zika virus infection. After discussing the matter with a clinical microbiologist and securing the consent of the woman and her partner, the general practitioner ordered tests for arboviruses common in the male partner\u2019s region of travel. All laboratory tests for chikungunya and dengue viruses were negative for both patients. Testing for Zika virus RNA was performed by using real-time reverse transcription PCR (rRT-PCR) in accordance with published methods (9). Sert] 25). Semen collected on days 35 and 76 also tested positive . Semen samples collected on days 99 and 117 tested negative for Zika virus RNA. Attempts at virus isolation from the semen sample collected on day 23 failed to cultivate infectious particles.Laboratory investigations for Zika virus RNA in patient 1 demonstrated negative rRT-PCR results for serum (first tested 19 days after symptom onset) and for urine (first tested 21 days after symptom onset). Serologic testing performed on day 21 detected Zika IgM and IgG (IgG titer 1:320). Semen collected on day 23 tested positive for Zika virus RNA (cycle threshold [CAedes species of mosquito capable of transmitting Zika virus infection is established in the country (It is very unlikely that transmission of Zika virus infection to patient 2 occurred through a mosquito bite. Although occasional interceptions of exotic mosquito species have occurred at international ports of entry into New Zealand, neither of the"} +{"text": "The purpose of this study was twofold: (1) to compare whether children from polygamous family structures significantly differ from children from monogamous family structures with regard to the frequency of parent-child conflict, and (2) whether children from these two structures employ different patterns of family conflict resolution.To address these questions, a random sample of 212 high school students (60.8% monogamous) completed a self-administered survey. The results of MANOVA show no significant differences (p > 0.05) between these two structures with regard to the frequency of parent-child conflict. The results also show similar conflict management styles between these two family structures within each of the following five domains .This study is unique in that it is the first empirical research to be conducted in the field of conflict resolution among youth and adolescents in polygamous marital structures and therefore, further investigation is needed to replicate these results utilizing different cross-cultural populations practicing polygamy."} +{"text": "A key factor in determining the likely outcome for a patient with colorectal cancer is whether or not the tumour has metastasised to the lymph nodes\u2014information which is also important in assessing any possibilities of lymph node resection so as to improve survival. In this review we perform a wide-range assessment of literature relating to recent developments in gene expression profiling (GEP) of the primary tumour, to determine their utility in assessing node status. A set of characteristic genes seems to be involved in the prediction of lymph node metastasis (LNM) in colorectal patients. Hence, GEP is applicable in personalised/individualised/tailored therapies and provides insights into developing novel therapeutic targets. Not only is GEP useful in prediction of LNM, but it also allows classification based on differences such as sample size, target gene expression, and examination method. Colorectal cancer (CRC) is one of the most common causes of cancer-related deaths worldwide . Currenthttps://www.verywell.com, Updated 9 April 2017). In another report, nearly 30% of CRC cases with no record of their lymph node metastasis (LNM) status were found during the five-year follow-up to have died because of tumour recurrence. The authors of the latter study concluded that the presence of the occult lymph node metastases (micrometastases) that were not detected by routine examinations might be the cause [Curative surgery improves the CRC patient\u2019s status at least in early stage, but the healing process is not adequate by itself . For exahe cause .The prevalence of micrometastases in patients with early CRC has recently been widely investigated. Published data indicate that even patients with stage I, who seem to have localised disease, may harbor micrometastases that were missed during the clinicopathological tests . In line(1)(a)chromosomal instability (CIN) ,(b)CpG island methylator phenotype (CIMP) ,(c)microsatellite instability (MSI) .A model that consists of three molecular subtypes including:(2)(a)CMS1 (14%), microsatellite instability (MSI) and immune hyperactivation,(b)CMS2 (37%), epithelial involvement, wingless-type MMTV integration site family member (WNT) and MYC pathway interaction,(c)CMS3 (13%), epithelial and metabolic involvement,(d)CMS4 (23%), invasive and metastatic activation of transforming growth factor\u2013\u03b2 (TGF-\u03b2) .A model of four consensus molecular subtypes (CMSs). The members of this model show the following discriminating features:Like other cancer types, CRC occurs by multiple misregulation of oncoproteins or tumour suppressors that impair the intra- and extra-cellular signal balances. The two most applicable models in this field are as follows:These models facilitate the identification of germline mutations of the genes involved in DNA mismatch repair (MMR) including MutS protein homolog 2 and 6 , MutL protein homolog 1 (MLH1), and PMS1 homolog 2 (PMS2), which all cause MSI in patients with hereditary HNPCC/Lynch syndrome . As in MAs previously mentioned, DNA mutations have a huge impact on prognosis and survival rates. However, the impact of thousands of detected mutations on cancer progression has not yet been elucidated, and we are not sure whether some of these mutations cause the cancer (driver mutations) or emerge because of the cancer (passenger mutations). Currently, gene expression profiling of the primary tumours has received a great deal of attention due to its ability to create a detailed picture of the genetic and epigenetic alteration status of tumours.What is the actual value of the gene expression signatures for the prediction of key events such as recurrence or LNM in CRC patients? This question has been the subject of numerous previous studies . GeneralThe detection of high-risk patients with recurrent CRC is arguably the main challenge. In this regard, applying molecular assessment tools could be helpful in identifying cases of occult micrometastasis and potential suitability of adjuvant therapy ,41. AccoOver the last decade, gene expression profiling by microarray has been a pioneering method in the detection of disease-related molecules. Compared with other standard techniques such as RT-PCR, which is not able to evaluate a large number of targets at once, microarray screening provides fast and reliable data with high accuracy from various samples. With microarray, it is now possible to analyse the whole expression pattern of a human genome within 48\u201372 h, thus gathering precious details about related molecular subtypes .Using cDNA microarray technology, Kwon et al. (2004) examined and compared the expression profiling of 4608 genes in 12 CRC tumours versus in noncancerous tissues . AccordiWang et al. (2004) tried to identify new prognostic markers for cancer relapse by DNA chip technology. Their achievement was a 23-gene panel allowing prediction of recurrence in Dukes\u2019 B patients. The panel also provided insight regarding the underlying biological mechanism of rapid metastases; some of these genes are involved with tumour development and cell proliferation. For example, Tyrosine 3 mono-oxygenase tryptophan 5-monooxygenase activation proteins (YWHAH) and Regulator of chromosome condensation 1 (RCC1) are the most important genes governing the G2 checkpoint of the cell cycle and chromosome condensation initiation, respectively . In the Arango et al. (2005) proved that the downregulation of Ras homolog gene, a small GTPase protein known to regulate the actin cytoskeleton, was correlated with shorter survival. This approach is not only useful in Dukes\u2019 C patients\u2019 recurrence predictions but also can be used in the design of clinical management algorithms .Meeh and colleagues used digital long serial analysis of gene expression to elucidate the differences between node-negative and node-positive colorectal tumours. They reported that the development of node-positive CRC occurs, in part, through elevated levels of epithelial Fibronectin 1 (FN1). They suggested that the progression of the CRC from node-negative to node-positive disease may be facilitated partially by FN1 deregulation and the subsequent enhancement of tumour cell migration .In 2009, Watanabe and colleagues determined that gene expression programming could be a useful tool in predicting recurrence in stage III colorectal cancer, and also identified calcineurin binding protein 1 (CABIN1) among discriminating genes that may play a key role in the development of recurrence . AdditioThe other family involved in cancer metastasis is the Forkhead box proteins (FOX). For example, FOXC2, also known as Forkhead Box C2 (FKHL14), has been found to be significantly elevated in patients with lymph node involvement and correlated with the degree of LNM . UpregulIn 2011, Salazar and colleagues developed a robust gene expression classifier (ColoPrint) that can predict relapses in patients with early-stage CRC. According to their study, this method can identify patients with stage II CRC who will experience a recurrence within five years after surgery . The tecBesides ColoPrint, Lenehan et al. (2012) have developed a molecular prognostic examination able to identify tumour recurrence within three years in CRC cases having curative surgery. From analysing the expression changes of 18 key genes involved in regulation of cell signal transduction, gene expression, invasion, growth, angiogenesis, apoptosis, and antioxidation, they identified five genes that could be used in the prediction of tumour recurrence in CRC patients: BMI-1 polycomb ring finger oncogene (BMI), Vascular endothelial growth factor A (VEGFA), Ribosomal protein S10 (RPS10), Ets variant 6 (ETV6), and H3 histone, family 3B (H3F3B). However, the test was validated in stage I and II patients and the authors concluded that \u226512 lymph node samples would be required for accurate prognostication .The results of another study on 196 genes in CRC patients determined that use of the expression pattern of main genes such as Annexin A3 (ANXA3), C-type lectin domain family 4 member M (CLEC4D), Lamin B (LMNB1), proline rich and Gla domain 4 (PRRG4), TNF alpha induced protein 6 (TNFAIP6), Lamin B1 (TNFAIP6), Vanin 1 (VNN1), and Interleukin 2 receptor subunit beta (IL2RB) that participate in tumour initiation and development could act as novel biomarkers for early detection of CRC . In lineGEP has been investigated for its potential to predict the outcome of patients in other cancers, too. M\u00e9ndez et al. (2011) identified five genes (Receptor accessory protein (1REEP1), Ring finger protein 145 (RNF145), CTONG2002744, Myosin VA (MYO5A), and FBXO32) that were differentially expressed between node-positive and node-negative oral squamous cell carcinomas (OSCC), and suggested that this model is applicable for identification of occult metastasis in patients . SimilarAs already discussed, the GEP platform provides a unique opportunity to examine tens of thousands of different candidate genes at a given time. However, like other laboratory methods, GEP technology is limited. The data obtained from GEP are very simple and only consist of the candidate genes. GEP is not able to detect the interactions or signaling crosstalks. Therefore, other data analyses must be performed to elucidate the underlined network, for example, behind the antitumour drug resistance. Thus, different perceptions may be derived from a single raw data point. The other limitation of the GEP approach is the sample type and the method of preparation. The DNA of different types of cells and tissues of the body undergo multiple modifications and express various genes; hence, the quality of DNA extraction and isolation is directly related to the GEP output. This noise is usually resolved by increasing the sample size, but in particular cases, other alternatives such as RNA sequencing technology ,53 or siOverall, for prediction of tumour recurrence and metastasis, GEP analysis has marked advantages compared to routine clinical exams. Using microarray technology, various genes are identified that allow prediction of LNM in CRC cases. Based on this approach, a new classification of CRC has been introduced that reflects the different biological pathways and distinct prognostic features, allowing preselection of patients who would benefit from adjuvant therapies. However, more investigations are also needed to identify the genes associated with poor prognosis profiles, since these may actually prove interesting potential targets for rational development of new cancer drugs."} +{"text": "Arabidopsis thaliana is the most widely used model organism for research in plant biology. While significant advances in understanding plant growth and development have been made by focusing on the molecular genetics of Arabidopsis, extracting and understanding the functional framework of metabolism is challenging, both from a technical perspective due to losses and modification during extraction of metabolites from the leaves, and from the biological perspective, due to random variation obscuring how well the function is performed. The purpose of this work is to establish the in vivo metabolic profile directly from the Arabidopsis thaliana leaves without metabolite extraction, to reduce the complexity of the results by multivariate analysis, and to unravel the mitigation of cellular complexity by predominant functional periodicity. To achieve this, we use the circadian cycle that strongly influences metabolic and physiological processes and exerts control over the photosynthetic machinery. High resolution-magic angle spinning nuclear magnetic resonance (HR-MAS NMR) was applied to obtain the metabolic profile directly from intact Arabidopsis leaves. Combining one- and two-dimensional 1H HR-MAS NMR allowed the identification of several metabolites including sugars and amino acids in intact leaves. Multivariate analysis on HR-MAS NMR spectra of leaves throughout the circadian cycle revealed modules of primary metabolites with significant and consistent variations of their molecular components at different time points of the circadian cycle. Since robust photosynthetic performance in plants relies on the functional periodicity of the circadian rhythm, our results show that HR-MAS NMR promises to be an important non-invasive method that can be used for metabolomics of the Arabidopsis thaliana mutants with altered physiology and photosynthetic efficiency. Arabidopsis thaliana play a central role in understanding biological functions across plant species and in characterizing phenotypes associated with genetic mutations have been overlaid for assignment purpose.(TIF)Click here for additional data file.S3 FigReference spectra of glucose (purple), sucrose (green) and fructose (red) have been overlaid for assignment purpose.(TIF)Click here for additional data file.S4 Fig\u03b1-glucose and \u03b2-glucose has been overlaid on experimental data with purple colour.Reference spectra of (TIF)Click here for additional data file.S5 FigLeaves were collected at different time points throughout 24h light/dark period (Time points are same as mentioned in (TIF)Click here for additional data file.S1 TableHR-MAS NMR conditions used in earlier studies for obtaining metabolic profile in various plant materials.(DOCX)Click here for additional data file."} +{"text": "With the rapid development of computer science and technologies in recent years, there has been dramatic advance in anterior segment imaging.As we have mentioned in the call for papers for this special issue, manuscripts are covering the topics of anterior segment imaging techniques including anterior segment optical coherence tomography (OCT), specular microscopy, corneal topography, confocal microscopy, and ultrasound biomicroscopy (UBM). These techniques have enabled precise visualization and objective assessments of anterior segment structures; thus, these devices have become essential tools for better diagnosis and treatment of anterior segment diseases including corneal disorders, cataract, glaucoma, and even disorders of the lacrimal system. Future development of novel modalities, that is, en face OCT or ultrahigh-resolution OCT, is expected to allow more detailed visualization at a microscopic level, which would provide even more understanding of anterior segment pathology at a cellular level. In this special issue, the authors contributed 15 original articles and 4 review papers regarding technologies of the anterior segment imaging and clinical application of the imaging devices.The authors have contributed the results of their original researches on various topics on anterior segment imaging: (1) agreement between gonioscopic examination and swept source OCT imaging; (2) preliminary outcomes of accelerated corneal collagen cross-linking using topography-guided ultraviolet-A energy emission; (3) anterior segment changes before and following laser peripheral iridotomy of iris bombe in patients with uveitic secondary glaucoma; (4) anterior segment measurements with swept source OCT before and after ab interno trabeculotomy; (5) effects of a new type implantable collamer lens implantation on vision-related daily activities; (6) corneal epithelial remodeling after transepithelial photorefractive keratectomy for myopia; (7) measurement of anterior chamber volume in cataract patients using swept-source OCT; (8) biomechanical findings in contact lens-induced corneal warpage; (9) quantitative analysis of lens nuclear density using OCT with a liquid optics interface; (10) rotating Scheimpflug imaging indices in different grades of keratoconus; (11) evaluation of outflow structures in vivo after the phacocanaloplasty; (12) evaluation of corneal epithelial thickness in asymmetric keratoconic eyes and normal eyes using Fourier domain OCT; (13) central corneal thickness measured using spectral-domain OCT and associations with ocular and systemic parameters; (14) anterior segment changes in pseudophakic eyes after pars plana vitrectomy with silicone oil or gas tamponade using UBM imaging; and (15) UBM comparison of ab interno and ab externo intraocular lens scleral fixation.This special issue also includes review articles on the following topics: (1) application of Scheimpflug imaging in glaucoma management; (2) anterior segment imaging in ocular surface squamous neoplasia; (3) applications of anterior segment OCT in cornea and ocular surface diseases; and (4) the role of anterior segment OCT and UBM in corneal and conjunctival tumors.We hope these articles will provide readers with useful information on anterior segment imaging and new ideas for researches on related topics."} +{"text": "Multicellular organisms rely on the precise and consistent regulation of gene expression to direct their development in tissue- and cell-type specific patterns. This regulatory activity involves arrays of DNA-binding transcription factors and epigenetic factors that modify chromatin structure. Among the chromatin modifiers, trithorax (trxG) and Polycomb (PcG) group proteins play important roles in orchestrating the stable activation and repression of gene expression, respectively. These proteins have generally antagonistic functions in maintaining cell and tissue homeostasis as well as in mediating widespread transcriptional reprogramming during developmental transitions. Plants utilize multiple trxG factors to regulate gene transcription as they modulate their development in response to both endogenous and environmental cues. Here, I will discuss the roles of trxG factors and their associated proteins in post-embryonic plant development. The development of multicellular organisms is driven by precise patterns of gene transcription that are tightly regulated in a spatial and temporal manner. Establishing and sustaining specific transcription states at gene loci are complex, multi-step processes. They require repertoires of sequence-specific DNA-binding transcription factors as well as epigenetic factors that alter chromatin structure and thereby affect accessibility by the transcriptional machinery. Epigenetic regulators classified as trithorax group (trxG) and Polycomb group (PcG) factors are critical for maintaining the stable transcription patterns at developmental regulatory loci by organizing chromatin in an active or inactive state, respectively . trxG anDrosophila as positive regulators of PcG developmental target genes (Table 1). The chromatin remodeling proteins include members of the SWI/SNF, ISWI, and CHD families that utilize ATP to alter nucleosome assembly and distribution AP2 domain transcription factor (TF) genes, which are essential for root stem cell niche maintenance maintenance. The RAM generates the entire underground root system and has a stereotypical organization. Four rarely dividing cells known as the quiescent center (QC) act as a niche that maintenance .Figure 1A). The SET domain protein SET DOMAIN GROUP 2 (SDG2) is the major H3K4 trimethyltransferase in Arabidopsis and is necessary for genome-wide H3K4me3 deposition and BRAHMA (BRM) also regulate RAM activity in Arabidopsis. PKL acts antagonistically to the PRC2 PcG factor CURLY LEAF (CLF) to maintain RAM stem cell activity -CLAVATA (CLV) signal transduction pathway. The homeobox TF gene WUS is expressed in the core of the meristem and confers stem cell identity on the overlying cells . In contrast, the SAND domain-containing proteins ULTRAPETALA1 (ULT1) and ULT2 restrict shoot and floral stem cell activity by limiting the size of the WUS expression domain , FLOWERING LOCUS D (FD) and SOC1, which promote the transition to flowering and APETALA1 (AP1), which confer floral meristem (FM) identity on the primordia that form on the flanks of the primary SAM to reproductive organs (flowers). The timing of this dynamic meristem cell fate switch is critical for plant reproductive success and occurs in response to endogenous pathways such as the age, GA and autonomous pathways (APs) as well as environmental cues including photoperiod, vernalization and temperature . The MADlowering . FT protmary SAM .FLC, SOC1 and FT are crucial to the timing of the floral transition, and a number of trxG factors are involved in these processes . Because the role of epigenetic factors in FLC regulation during vernalization has been extensively reviewed couple removal of repressive histone marks with deposition of active marks and transcription initiation/elongation to sustain high levels of FLC expression. ATXR7/SDG25 also represses the floral transition by binding to the FLC promoter and augmenting both H3K36me3 and H3K4me3 accumulation , a core component of the Arabidopsis COMPASS-like complex (AtCOMPASS) that also binds the FLC locus and promotes its expression by elevating H3K4me3 levels . SVP forSE (SVP) . SVP expcription . BRM repactivity . Thus thFLC transcription is crucial for the transition from the vegetative to the reproductive state. The JmjC domain-containing H3K27 demethylase REF6/JMJ12 promotes flowering independently of photoperiod by repressing FLC transcription that produces floral meristems (FMs) instead of leaves. A small suite of floral homeotic transcription factor genes then specifies the identity of each floral organ \u2013 sepals, petals, stamens, and carpels \u2013 from the outside to the inside of the flower . The actAPETALA3 (AP3) and AGAMOUS (AG) that specify petal, stamen, and carpel identity in the developing flower , which recruit SYD to the AP3 and AG loci by activating AP3 and AG expression, antagonizing CLF activity at the two loci by reducing H3K27me3 deposition and enhancing H3K4me3 deposition (The plant specific TF LFY and the MADS domain TF SEPALLATA3 (SEP3) play crucial roles in activating the expression of MADS box-containing floral homeotic genes such as g flower . SYD and AG loci . At the AG loci enhance ult1 FM phenotypes, and ALP1 promotes floral organ identity gene expression in the absence of LFY . It is becoming clear from recent research that members of all of these categories of proteins play important roles in regulating landmark post-embryonic developmental processes such as meristem maintenance and floral induction. Moreover some trxG factors, such as BRM and ATX1, mediate multiple developmental processes during plant growth whereas others appear to have more restricted roles. The coupling of a core set of reiteratively used trxG components together with stage-, tissue- or process-specific trxG components may provide a flexible mechanism for tailoring the basic process of transcription activation to discrete gene networks in response to changing endogenous and environmental signals during the life cycle.A variety of trxG factors exist in plants that carry out diverse biochemical activities to promote active gene expression states: chromatin-remodeling ATPases, histone methyltransferases, AtCOMPASS core components, histone demethylases, as well as DNA-binding and accessory proteins (Although significant progress has been made in determining the roles of trxG factors in plant development, many gaps in our understanding remain. It still remains to be determined how many trxG complexes exist in plants, not to mention their full composition and whether that composition is static or changes depending on the developmental stage or tissue. The DNA binding proteins that recruit trxG factors to developmental regulatory loci are only beginning to be identified, while elucidating the chromatin signatures of plant stem cell populations can provide a valuable starting point for determining how tissue- and stage-specific epigenetic states are ultimately achieved during development. Finally, much work remains to decipher how developmental switches between trxG and PcG activities are implemented at individual loci as well as broadly across the genome to coordinate widespread transcriptional reprogramming. Further investigation in these areas will provide a more complete picture of how plants are able to maintain and as necessary adjust their gene expression programs during development in response to a wealth of endogenous and environmental cues.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Introduction: Considering importance of fatty acids in developing coronary artery disease (CAD) and lack of information about saphenous vein which is commonly used as coronary arterial bypass, in this study we investigated differences in fatty acids composition between saphenous vein and aorta tissues in patients with CAD.Methods: Biopsy samples of aortic tissues and saphenous veins as well as blood samples were obtained form 42 patients with CAD. Fatty acids composition of the tissues was determined using gas chromatography and also serum lipid profile was evaluated by commercial kits.Results: Levels of palmitic acid (16:0) were significantly higher in aorta in compared with saphenous (P < 0.001). Also levels of most unsaturated fatty acids were statistically higher in saphenous tissue than aorta tissue (P < 0.05). Mean levels of linoleic acid (18:2 n-6) was higher in aorta tissue in comparison with saphenous tissue (P = 0.01). We observed positive correlations between serum levels of LDL-C with elaidic acid and linoleic acid levels in saphenous. Evaluation of aorta tissue fatty acids revealed that palmitoleic acid (16:1) had positive and arachidonic and linoleic acids had negative correlations with serum HDL-C levels.Conclusion: Our results revealed difference between fatty acids composition of aorta and saphenous vein tissues and existence of correlations between the fatty acids levels with serum lipid profile. The saphenous vein had higher poly-unsaturated fatty acids in compared to aorta tissue and thus this vein is not at risk of atherosclerosis and can be used as coronary arterial bypass. Although many studies have evaluated effects of dietary fatty acids as well as plasma levels of them on coronary atherosclerosis,12 but there is no enough information about fatty acids content and their possible roles in the tissues which are involved in the atherosclerosis.Many studies have been conducted to investigate lipid accumulation in the arterial wall of patients with atherosclerosis but many questions about mechanisms of dyslipidemia and progression of atherosclerotic lesions have been remained unanswered.14 However existence of higher free cholesterols than cholesterol esters in the plaques15 which is in contrary with the finding about high ratio of cholesterol esters/free cholesterol in plasma,16 led to arise theory of coming the lipids from vessels growing into the plaque.17 On the other hand higher levels of fatty acid synthesis in atherosclerotic arteries in compared with intact arteries highlights possible role of fatty acid metabolism in tissues which are involved in atherosclerosis.18It has been reported that cholesterol as one of the major lipids in atherosclerotic plaques which possesses fatty acids, enters from the blood rather than in situ synthesis.19 Also Bahrami et al20 have demonstrated lower levels of unsaturated fatty acids and higher amounts of saturated fatty acids in atherosclerotic aorta in compared with the internal mammary arteries. Furthermore different fatty acids composition of aorta artery and adipose tissue between patients with and without CAD has been shown previously.21 These finding emphasize on importance of local fatty acids composition in developing atherosclerosis and CAD. However there is no information about fatty acids composition of saphenous vein which is commonly used as coronary arterial bypass and also has structural differences with arteries.22 The aim of this study was to investigate differences in fatty acids composition between saphenous vein and aorta tissues, as well as associations between the fatty acids levels with serum lipid profile in patients undergoing CABG.In a study it has been reported that the fatty acids composition of coronary arteries was significantly different between sudden cardiac death and traffic accident victims.2 and the patients with class II and III obesity (BMI \u226539 kg/m2) were not involved. The exclusion criteria were: having acute inflammation, auto-immune diseases, kidney and liver diseases, diabetes, anemia or malignant tumors. Also patients with prior CABG as well as aortic or mitral valve replacement were excluded from the study.Frothy-two individuals (mean age: 53.2\u00b17.5 years), documented as CAD patients were included in this study. All patients had at least two vessels coronary artery disease (\u226550% stenosis) based on the angiographic data and were scheduled for CABG at Shahid-Madani heart hospital in Tabriz, a northwest city of Iran. Also we recruited patients with body mass index (BMI) \u226434.9 kg/mBiopsy samples (1-2 g) were obtained during the surgery from aortic tissues and saphenous veins and then were dissolved in hexane and kept frozen at - 70\u00b0C in glass vials for fatty acid measurement. Also in order to lipid profile analysis, approximately 5 mL of venous blood samples in the fasting state at 8:00 am were taken from all participants and the serums were separated using centrifugation.23 and the percentage of each fatty acid was determined using gas chromatography. In brief, the solution of fat extract in hexane was evaporated under a stream of nitrogen to near dryness, and the lipids were esterified with methanol during catalysis with acetyl chloride. Then fatty acid methyl ester derivatives were separated on a 60- x 0.25-mm Teknokroma TR-CN100 column using gas chromatograph system equipped with a split injector and a flame ionization detector. The oven temperature program was 170-210\u00b0C, 1\u00b0C/min, and then isothermal for 45 minutes. The combined inter- and intra assay of variation was 2.1% for palmitic acid (16:0), 2.7 for linoleic acid (18:2n-6), 18.6 for eicosapentaenoic acid (EPA), and 11.2 for docosahexaennoic acid (DHA). The known fatty acids from Sigma chemicals was employed as standards to peak retention times identification. The levels of fatty acids were calculated as the percentage of each fatty acid of the total.Fatty acids were extracted using the Bligh and Dyer methodThe levels of triglycerides (TG), total cholesterol (TC) and high density lipoprotein-cholesterol (HDL-C) determined by enzymatic colorimetric method with an automated chemical analyzer . Low-density lipoprotein-cholesterol was calculated using the Friedewald formula.t test was used to compare fatty acids levels between saphenous vein and aorta tissues in each patient. Also the Pearson correlation test was applied to investigate possible associations between the fatty acids levels with serum lipid parameters. P values <0.05 were considered significant. SPSS V.16 software was used for the statistical analysis.The data are reported as mean \u00b1 standard deviation (SD). Normal distribution of the data was confirmed by Kolmogorov-Smirnov test. The paired Demographic and clinical characteristics of the studied population are shown in In studied patients mean levels of total cholesterol was higher than normal range (214 \u00b1 45 mg/dL) and mean levels of triacylglycerol, 178 \u00b1 50 mg/dL, was borderline high . Also thP < 0.001). Levels of most unsaturated fatty acids were statistically higher in saphenous tissue than aorta tissue (P < 0.05). On the other hand, mean levels of linoleic acid (18:2 n\u20106) was higher in aorta tissue in comparison with saphenous tissue . Comparing the mono-unsaturated fatty acids levels between saphenous and aorta demonstrated that levels of palmitoleic acid and oleic acid as well as its trans isomer (elaidic acid) were significantly lower in aorta than saphenous vein. The poly-unsaturated fatty acids levels were also different between the two vessels as we observed significantly lower proportions of the trans isomer of linoleic acid (18:2 t), linolenic acid (18:3 n-9) and docosatrienoate acid (22:3 n-3) in aorta in compared to the saphenous. Based on our knowledge, there is no report on differences of fatty acids composition between saphenous and aortic tissues of CAD patients. However, in accordance with our results, in previous studies higher levels of palmitic acid and also lower levels of poly-unsaturated fatty acids in phospholipids of aorta and coronary arteries of patients with CAD in compared with control individuals have been reported.21 Moreover in a study on fatty acids composition of aorta and internal mammary of patients with CAD same as our results, lower levels of unsaturated fatty acids and higher percentage of palmitic acid in aorta samples than internal mammary have been reported.20 Moreover they also found statistically different levels of stearic acid (18:0), arachidonic acid (20:4n-6) and eicosapentaenoic acid (20:5-n3) between aorta and internal mammary arteries.20 We did not find such differences between aorta and saphenous vein maybe due to structural differences between saphenous vein and internal mammary artery.The assessment of fatty acids contents in saphenous vein and aorta of CAD patients indicated that the fatty acids composition between these vessels was different. We found higher concentration of palmitic acid as saturated fatty acid in aorta in compared with saphenous vein were found in aorta tissue as compared to the saphenous vein. Higher levels of linoleic acid in aorta and coronary arteries of individuals with CAD compare to non-CAD subjects and also in aorta in compared with internal mammary artery in patients with CAD have been shown previously.20 However there is no enough information about pattern of fatty acids modification and its role in atherosclerosis pathogenesis.Such differences between fatty acids composition of aorta artery and saphenous vein could be partly due to structural differences between arteries and veins but some part of these differences could also be because of atherosclerosis and cardiovascular complications that the aorta was involved. Reports about different fatty acids composition between aorta and internal mammary of patient with CAD confirm this possibility.33 and thromboxane A2 production.34 In our previous study we also found negative correlations between levels of linoleic acid in epicardial and subcutaneous adipose tissues with serum levels of HDL-C and a positive correlation between this fatty acid content in subcutaneous adipose tissue with serum LDL-C in patients with CAD.35 There are wide evidences that the HDL-C and LDL-C are protective and risk factors for atherosclerosis and its complications, respectively37 and on the other hand linoleic and arachidonic acids have been documented as atherogenic fatty acids which cause inflammation and platelet aggregation.32 So finding the associations between these fatty acids with LDL-C and HDL-C seems reasonable. Moreover, we observed a positive correlation between the HDL value and palmitoleic acid in aorta which confirms the protective effect of palmitoleic acid as MUFAs against CAD.39In this study we detected inverse correlations between serum HDL-C with linoleic acid levels in saphenous and aorta tissues and also with arachidonic acid levels of aortic tissue. Besides, linoleic acid levels in saphenous vein were positively correlated with LDL-C in serum. The negative correlation between HDL-C and arachidonic acid could be explained by results of previous study reported that in CAD patients, HDL-hypocholesterolemia decreases ability of platelet to produce nitric oxide (NO) and consequently reduction in NO levels itself inhibits arachidonic acid metabolism. NO induces the inhibitory influence through various direct and indirect ways such as inhibition of cyclooxygenase activities40 Moreover results of a 25-year follow up study conducted in seven countries, have been showed positive correlation between dietary intake of elaidic acid and serum cholesterol.41 These reports confirm our finding about existence of positive correlation between elaidic acid in saphenous and serum total cholesterol.It has been demonstrated that elaidic acid (18:1t) is cholesterol elevating factor.43 exerts its effects partly via changing serum lipid profile and consequently vessel wall fatty acids composition. Although observed differences in fatty acids composition between aorta and saphenous vein tissues and also between aorta tissues of CAD and NON-CAD patients21 as well as aorta and internal mammary arteries of CAD patients20 emphasize that in addition to diet, local lipid metabolism and existence of atherosclerosis can be determinative factors for fatty acid composition of vessel walls. However the ways that different dietary intake or lipid metabolism could influence tissue fatty acids composition still remain to be elucidated. However, in our study we did not have information about dietary habits and life-style which could possibly affect the fatty acids composition of the tissues. Although it should be noted that in the present study the comparisons were done between two tissues of each patient, so any confounding factor such as dietary habits which could affect the evaluated parameters, affects the parameters of both saphenous and aorta tissues in same patient and consequently could not affect the overall result of our study. Another limitation of our study was lack of proper control without CVD because of impossibility of taking such samples from healthy individuals. However further studies could be conducted on immediately dead persons without CVD or animal models.Considering the association between fatty acids composition of aorta and saphenous tissues with serum lipid profile that was found in the present study, it can be concluded that composition of dietary fatty acids which has been suggested as important factor for CAD developmentIn this study due to the unavailability of healthy individuals saphenous and aorta tissues we could not compare the results with control. Also due to difficulty in finding patients our study was conducted with almost small sample size. Another limitation of our study was lack of information about diet of patients as it can has effect on fatty acids composition of saphenous and aorta tissues.In conclusion our results revealed difference between fatty acids composition of aorta and saphenous vein tissues in CAD patients and existence of correlations between the fatty acids levels and serum lipid profile. Owing our results about higher levels of PUFAs in saphenous vein compared to aorta tissue, it is likely that the vein has almost low risk for atherosclerosis and may be able to be used as coronary arterial bypass.All authors declare no competing financial interests exist.Approval for this study was granted by the ethical committee of Tabriz University of Medical Sciences and the informed written consent was obtained from all participants The work was supported by a grant from the Cardiovascular Research Center, Tabriz University of Medical Sciences. This article was extracted from the M.Sc. thesis of Mirhamid Paytakhti Oskouei."} +{"text": "A patient aged 58 years, presented with 2 months history of an erythematous, painful and bleeding nodule, after labial herpes (A). The dermoscopic examination confirms the diagnosis of a pyogenic granuloma (B). The dermoscopic criteria are: the reddish homogeneous area (green line) whose color varied from completely red to red with whitish zones which is corresponded to proliferating vessels. A white collarette (yellow line) corresponds to the hyperplastic adnexal epithelium that embraces the lesion at the periphery. The white lines (blue line) like a double rail which is corresponded to a fibrous septa that criss-cross the lobules. And finally ulceration or hemorrhagic crusts (black line) which are frequently observed in pyogenic granuloma."} +{"text": "Many alien plants use animal vectors for dispersal of their diaspores (zoochory). If alien plants interact with native disperser animals, this can interfere with animal-mediated dispersal of native diaspores. Interference by alien species is known for frugivorous animals dispersing fruits of terrestrial plants by ingestion, transport and egestion (endozoochory). However, less attention has been paid to possible interference of alien plants with dispersal of diaspores via external attachment , interference in aquatic ecosystems, or positive effects of alien plants on dispersal of native plants. This literature study addresses the following hypotheses: (1) alien plants may interfere with both internal and external animal-mediated dispersal of native diaspores; (2) interference also occurs in aquatic ecosystems; (3) interference of alien plants can have both negative and positive effects on native plants. The studied literature revealed that alien species can comprise large proportions of both internally and externally transported diaspores. Because animals have limited space for ingested and adhering diaspores, alien species affect both internal and external transport of native diaspores. Alien plant species also form large proportions of all dispersed diaspores in aquatic systems and interfere with dispersal of native aquatic plants. Alien interference can be either negative or positive . I propose many future research directions, because understanding whether alien plant species disrupt or facilitate animal-mediated dispersal of native plants is crucial for targeted conservation of invaded (aquatic) plant communities. Dispersal of plant diaspores by animals (zoochory) is a globally important mechanism regulating species diversity of plant communities. Key disperser species include birds, mammals, and fish\u2013of which many forage on plant diaspores, transport them internally during digestion, and defecate viable diaspores in new locations alien plant species may interfere with both internal and external animal-mediated dispersal of native diaspores; (2) interference by alien plants also commonly occurs in aquatic ecosystems; and (3) interference by alien plants can have both negative and positive effects on native plants. I focus on zoochory of plant diaspores by vertebrate animals. \u201cAlien species\u201d is used as the terminology throughout this study to refer to all non-native, invasive, introduced or exotic species that established a self-sustaining reproductive population outside their native geographic area feed selectively on Eurasian grasses in Canada and mule deers (Odocoileus hemionus) remove fruits of an alien succulent faster than those of a native species in the same genus studying interference of alien plants with ectozoochory by itself, and simultaneously with interference of endozoochory in single model systems; and (2) comparing the relative effectiveness of alien and native diaspores for endo- and ectozoochory in choice and attachment experiments AND TS = (seed OR diaspore* OR fruit OR nut); combined with either TS = (frugivor* OR endozoochor*) or with TS = (ectozoochor* OR epizoochor* OR exozoochor*). This resulted in respectively 376 and 36 studies that addressed dispersal of alien plants for endo- and ectozoochory. Addition of the term TS = (aquatic OR wetland OR freshwater OR riparian) reduced the publication counts to respectively 16 and 6, indicating that a low percentage of all studies involved aquatic habitats.To compare study effort on alien interference between habitats and among disperser animals, I performed a standardized search for publications reporting the presence of alien and native aquatic diaspores in single samples of feces or attached to native vertebrate animals in ISI Web of Science. On the 11th of January 2018 I entered the following search string: TS = and 55% for ectozoochory . In 5 of the 19 reports on endozoochory and 8 of the 15 reports of ectozoochory more alien than native diaspores were dispersed. However, these numbers should be interpreted with caution because variation among geographic locations and studied species was large, and studies reporting only dispersal of native diaspores were not included.All aquatic studies jointly reported 34 cases of potential interference by alien plants with dispersal of native diaspores\u2014by native disperser animals\u2014and in aquatic ecosystems Tables , 2. The The presented cases illustrate that patterns of alien interference thus far primarily described in terrestrial ecosystems may also apply to aquatic ecosystems. Future research should focus on under-examined disperser animals like fish, bats and reptiles although the phenomenon has been primarily studied for endozoochory by frugivorous birds and mammals in terrestrial ecosystems, alien species may also interfere with ectozoochory and this warrants further studying; (2) interference of alien species with zoochory can similarly be found in aquatic ecosystems; (3) alien plant species can also provide resources such as food or nesting habitat to animals, which can increase densities of native disperser animals or attract new disperser animal species. Through these mechanisms alien plants can also positively affect dispersal of native plants, which warrants further studying. This study illustrates that the impacts of alien plant species on native plant species, whether positive or negative, can vary among native plant species relying on different dispersal mechanisms. Understanding species interactions is crucial for effective conservation, especially in invaded ecosystems.CvL designed the study, collected and analyzed the data, and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "To respond to the World Health Assembly call for dissemination of lessons learnt from countries that have begun implementing the International Health Regulations, 2005 revision; IHR (2005).In November 2015, we conducted a systematic search of the following online databases and sources: PubMed\u00ae, Embase\u00ae, Global Health, Scopus, World Health Organization (WHO) Global Index Medicus, WHO Bulletin on IHR Implementation and the International Society for Disease Surveillance. We included identified studies and reports summarizing national experience in implementing any of the IHR (2005) core capacities or their components. We excluded studies that were theoretical or referred to IHR (1969). Qualitative systematic review methodology, including meta-ethnography, was used for qualitative synthesis.We analysed 51 articles from 77 countries representing all WHO Regions. The meta-syntheses identified a total of 44 lessons learnt across the eight core capacities of IHR (2005). Major themes included the need to mobilize and sustain political commitment; to adapt global requirements based on local sociocultural, epidemiological, health system and economic contexts; and to conduct baseline and follow-up assessments to monitor the status of IHR (2005) implementation.Although experiences of IHR (2005) implementation covered a wide global range, more documentation from Africa and Eastern Europe is needed. We did not find specific areas of weakness in monitoring IHR (2005); sustained monitoring of all core capacities is required to ensure effective systems. These lessons learnt could be adapted by countries in the process of meeting IHR (2005) requirements. First introduced in 1969, IHR is global legislation requiring countries to link and coordinate specific actions.,,IHR (2005) also requires all countries to develop, strengthen and maintain eight core public health capacities.Although IHR (2005) describes what must be achieved by countries, there is limited knowledge on how countries should proceed in achieving the core capacities. To fill this gap and accelerate implementation of IHR (2005), the World Health Assembly in 2015 identified a need to evaluate and share the lessons learnt from countries that have implemented IHR (2005).,,This systematic review was conducted in accordance with Enhancing Transparency in Reporting the Synthesis of Qualitative Research guidelines, using a predefined protocol .Box\u00a01Component 1A: National legislation and policyComponent 1B: FinancingComponent 2A: IHR coordination, communication and advocacyComponent 3A: Indicator-based surveillanceComponent 3B: Event-based surveillanceComponent 4A: Rapid response capacityComponent 4B: Case managementComponent 4C: Infection controlComponent 4D: Disinfection, decontamination and vector controlComponent 5A: Public health emergency preparedness and responseComponent 5B: Risk and resource management for IHR preparednessComponent 6A: Policy and procedures for public communicationsComponent 7A: Human resource capacityComponent 8A: Policy and coordination of laboratory servicesComponent 8B: Laboratory diagnostic and confirmation capacityComponent 8C: Laboratory biosafety and laboratory biosecurity (biorisk management)Component 8D: Laboratory-based surveillanceIHR: International Health Regulations.Source: International Health Regulations (2005).Two authors independently screened all abstracts, articles and reports and then matched the full texts selected during screening against the inclusion criteria. The reference lists of relevant articles and reviews were also searched for additional studies and reports. Articles meeting the inclusion criteria were included in the review. Three authors completed the data extraction using standardized extraction tables.,Two authors independently read and assessed the quality of included studies using the Critical Appraisal Skills Programme qualitative research checklist.,\u2013,We used the Cochrane qualitative systematic review method, including meta-ethnography, to synthesize qualitative data.\u2013http://www.who.int/bulletin/volumes/96/2/16-189100). A more detailed summary of the included articles and themes identified is available from the corresponding author. Some articles reported national experience in IHR (2005) implementation in multiple countries. In total, 77 countries were represented from all WHO Regions: 23 from Western Pacific, 16 from Europe, 14 from Africa, 11 from the Americas, eight from Eastern Mediterranean and five from South-East Asia from central government, subnational levels of government, civil society and the scientific community.,,2. Developing appropriate policies and allocating responsibilities for the workforce is needed at both central and subnational levels of government.,,3. Legislation and policies should strive to incorporate and balance global, regional, national and subnational priorities for health security.,,4. For sustainable financing, detailed long-term national strategic plans with budget allocations should be developed in partnership between government, national stakeholders, and non-state actors .,5. The national health system and sociocultural context of a country will determine priorities for funding and other resource needs for IHR (2005) core capacity development, emergency response and the health workforce.,,6. Creating and empowering a national secretariat responsible for mobilizing and securing resources from state and non-state actors can help ensure sustainable and continuous financing.,,1. Existing regional and global intergovernmental organizations can be recruited to collaborate and co-manage international epidemics.,,2. A strong programmatic structure at the national and subnational levels, including intersectoral national technical working groups, can assist with comprehensive and effective coordination.,,3. Establishing roles, responsibilities and terms of reference of national focal points within national legislation, and disseminating information inside government, to national stakeholders, and to WHO, improves coordination and communication.,,,4. Adequately resourced communication channels and standard operating procedures, from the subnational to the inter-governmental level, facilitate the timely transmission and retrieval of information.,1. It is important to create and empower a national government entity to coordinate disease surveillance and control efforts.,2. Strategic plans for disease surveillance at both the national and subnational levels can enable long-term sustainability of these efforts.,,3. Key communicable diseases need to be categorized based on epidemiological context .,4. Surveillance at the subnational level can be sustained by developing legislation that outlines the requirements, mechanisms can develop capacity for collection, analysis and use of data at subnational levels.,,6. A unified and dynamic surveillance system to track alerts, updates and early warnings and response, and using technologies appropriate to the national context , encourages appropriate information use and accurate reporting.,,,7. Standardizing passive data collection, management and validation procedures across all reporting sites, and actively searching for potential surveillance intelligence through local communication channels , improves the usability and timeliness of data.,1. Defining criteria for an emergency public health event assists with the initiation of an appropriate and timely response.,,,2. Establishing roles, responsibilities and terms of reference for a multidisciplinary response unit supports coordination of public health emergency responses at the national and subnational levels.,,3. Including national and international stakeholders in the development of guidelines for rapid and emergency response facilitates wide technical ownership and financial support.,4. Designing and resourcing health facilities to minimize nosocomial infection transmission improves the efficacy of response without encouraging further spread .Box\u00a03,1. Comprehensive national and subnational budgeted plans for preparedness of emergency public health events are needed to support timely action.,2. Exercises, drills, assessments and evaluations can test capacity to implement the response plans and ensure they are adequate and operational.,,3. A national reserve of medicines, vaccines and laboratory supplies and reagents helps with management of public health emergencies.,,1. An intersectoral system for risk communication of public health emergencies, functioning at all levels of government, ensures timely action and response.,,2. Risk communication systems should be bidirectional, with linkages to national and international public health partners, to collect and disseminate information about threats.,,3. Regular and emergency information to national and international stakeholders assists in building and maintaining effective communication channels and relationships.,,4. Standard operating procedures ensure personnel are ready to investigate and communicate emerging epidemics and support preparedness for activation of early warning systems.,,,5. Using a combination of media to send and receive information ensures wide access and use.,,1. Identifying competency gaps in the workforce ensures that training and resources are targeting the highest priority needs .,,2. Selecting appropriate media for developing competencies based on health system context and social and cultural preferences can increase the efficacy of training.,,3. Establishing workforce oversight mechanisms for long-term maintenance of current and future needs assists with sustainability of individual training efforts.,,4. Nationally agreed strategies to recruit, train and retain health workforce can help support IHR (2005) competency development at all levels of the health system.,,,,1. It is important to create a governmental entity at the national level to coordinate national strategic plans for laboratory response and develop national standards, guidelines and operating procedures for laboratory surveillance at national and subnational levels.,,2. Regional and global reference laboratories can be helpful when developing laboratory surveillance networks.,,3. Validated criteria and mechanisms to accredit laboratories for core surveillance tasks help ensure high-quality testing.,4. Laboratory training, routine assessments and feedback, and quality assurance systems can help improve surveillance capacity and function of national and subnational laboratories.,5. Bidirectional flows of data, specimens and communication between national and subnational levels of government improve laboratory system effectiveness and adequate public health investigation.,,6. Specific policies, strategies, regulations and standard operating procedures for high-containment biosafety laboratories help ensure the safety and efficacy of laboratory testing.,,1. Conducting a baseline needs assessment can help to identify the status of a country\u2019s health system and actions needed to meet IHR (2005) requirements.,,2. Ensuring flexible systems can improve response to known epidemics and detection of new threats.,,3. A country\u2019s\u2019 sociocultural, epidemiological, health system and economic context and priorities will guide national implementation of IHR (2005) core capacities.,4. Although early warning systems are part of core capacity in surveillance, they also affect coordination, risk communication and response for new epidemics.,,,5. Having a skilled workforce in place, from frontline staff to senior management, is important for ensuring sustainable expertise, implementation and commitment.IHR (2005): International Health Regulations, 2005 revision: WHO: World Health Organization. Notes: Framework for the analysis was based on the eight core capacities of the International Health Regulations (2005).,\u2013,\u2013,,,\u2013,,,\u2013,,,,\u2013A total of 33 articles from 60 countries reported experience implementing the national legislation, policy and financing core capacity.\u2013,,,\u2013,\u2013,\u2013,,,,,,,,,,,,,Experience implementing the coordination and communications capacity was reported in 33 articles from 51 countries.\u2013,\u2013,,,\u2013,,,,,,,,,,\u2013,,,Forty articles from 63 countries reported experience implementing the surveillance core capacity.\u2013,,,,,,\u2013,,,,,,,Experience implementing the response core capacity was reported by 27 articles from 47 countries.,,,,\u2013,,,,,,,,,Thirteen articles from 37 countries reported experience implementing the preparedness core capacity.\u2013,,,,,,,\u2013,,,,,,,,A total of 23 articles from 36 countries reported on implementing the risk communication core capacity.,,\u2013,\u2013,,,\u2013,\u2013,\u2013,\u2013,,\u2013,,,,,,,,A total of 37 articles from 49 countries reported experience implementing the human resources core capacity.\u2013,,,\u2013,,,,\u2013,,,,,,,,,Experience implementing the laboratory core capacity was reported in 26 articles from 44 countries.We identified five global lessons learnt that related to multiple IHR (2005) core capacities . Some maWe found substantial documentation of lessons learnt from implementing IHR (2005) core capacities globally. Although many factors affected implementation in a country, the structure of the health system, sociocultural factors, economic status and type of governance, we were able to extract some common themes. We found few gaps in implementation in direct relation to the IHR (2005) core capacities. Nonetheless, additional research could be useful in evaluating countries\u2019 core capacity performance against actual disease epidemics. Specifically, we did not identify any documentation evaluating IHR (2005) core capacity development with national performance in preventing, detecting and responding to disease epidemics. This type of evaluation could provide useful data for future revisions of the IHR. Moreover, defining fundamental data needs for new treatments and vaccines could help develop national research capacity to shorten the development window during future disease epidemics. Finally, additional documentation of experience from Eastern Europe and Africa could help fill knowledge gaps.,Countries had different national health plans outlining how to organize their systems and strategies for managing threats and hazards.Most countries reported some experience in implementing communicable disease surveillance as part of IHR (2005).,,Although complementary in nature, the preparedness and response core capacities were often implemented independently of one another. For example, areas requiring coordination across both of these core capacities, such as case management or infection control, were not well-documented. Taking a holistic approach to IHR (2005) core capacity development could avoid these issues.,,,Risk communication focuses primarily on effective communication strategies during disease epidemics. Some of the articles we identified primarily discussed communication systems.Global strategy on human resources for health: workforce 2030.,,The World Health Assembly recently approved the \u2013Laboratory networks are an essential part of national and regional health systems. Global laboratory networks are in place for polio, immunization programmes and influenza.\u2013,\u2013Given the many priorities in development, and limited national budgets to achieve them, external funding opportunities often help mobilize political commitment and national action. Experience from South Africa suggested that while external funding sources can be inflexible and unsustainable within national governance frameworks, such funding could create momentum in generating domestic financing and accelerate progress in implementing IHR (2005).,Along with financial and technical support, additional international measures could help accelerate IHR (2005) core capacity development. For example, since past disease epidemics affected regional and global economic growth, economic issues are relevant.This study has several limitations. We focused only on IHR (2005) core capacities and not on the core capabilities of points of entry, zoonotic events, food safety, chemical events and radiation emergencies.Despite considerable progress, countries that are yet to implement IHR (2005) core capacities may have insufficient human and financial resources to meet their obligations in the near future. Recent global epidemics have galvanized high-level political commitment towards ensuring global health security. We can leverage this commitment by mobilizing resources and securing wider collaboration to apply the lessons outlined here and accelerate the development of IHR (2005) core capacities globally."} +{"text": "Sholl analysis confirmed regular pattern of dendritic branching. The total length of dendrites was around 2100 \u03bcm with the average length of individual branching (intermediate) segment around 22 \u03bcm and for the terminal segment around 100 \u03bcm. Even though each experimental group underwent the same strictly defined protocol in tissue preparation and Golgi staining, we found inconsistency in dendritic volume and soma surface. These changes could be methodologically influenced during the Golgi procedure, although without affecting the dendritic length and tree complexity. Since the neuronal activity affects the dendritic thickness, it could not be excluded that observed volume inconsistency was related with functional states of neurons prior to animal sacrifice. Comprehensive analyses of tree complexity and dendritic length provided here could serve as an additional tool for understanding morphological variability in the most numerous neuronal population of the striatum. As reference values they could provide basic ground for comparisons with the results obtained in studies that use various models of genetically modified mice in explaining different pathological conditions that involve MSNs.In this study we have provided a detailed quantitative morphological analysis of medium spiny neurons (MSNs) in the mice dorsal striatum and determined the consistency of values among three groups of animals obtained in different set of experiments. Dendritic trees of 162 Golgi Cox (FD Rapid GolgiStain Kit) impregnated MSNs from 15 adult C57BL/6 mice were 3-dimensionally reconstructed using Neurolucida software, and parameters of dendritic morphology have been compared among experimental groups. The parameters of length and branching pattern did not show statistically significant difference and were highly consistent among groups. The average neuronal soma surface was between 160 \u03bcm The medium spiny neurons (MSNs) are the most numerous striatal neurons. Data about their morphology are needed to understand basal ganglia circuitry structure and function in normal conditions and in related disorders kindly provided by the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany , group 2 (n = 4) and group 3 (n = 5). All work with the animals used in this study was performed in accordance with the governmental and institutional ethical guidelines and with the approval of Ethics Committee from Max Planck Institute for Evolutionary Anthropology in Leipzig and School of Medicine University of Zagreb.Brain tissue was processed separately in three sets of experiments performed at different times and defined as group 1 before euthanizing. Brains were not perfused and were removed quickly from the skull to avoid any damage to the tissue. After rinsing, the tissue was sliced in approximately 10 mm thick blocks. The blocks were stained with the FD Rapid GolgiStain\u2122 kit . They were first immersed in the impregnation solution (A and B) which was replaced after 6\u201312 h and then kept in dark for 15\u201316 days. Afterwards, the blocks were put in Solution C which was replaced after 24 h and kept in dark for the next 48\u201360 h. Cryomicrotome was used to cut 200 \u03bcm thick slices. Slices were mounted on a gelatin-coated microscope slides, stained, and dehydrated and coverslipped with Permount. The tissue obtained from group 3 was additionally treated with Toluidine blue stain before dehydration.Tissue preparation and staining were all done by the same person (U.B.) following the FD Rapid GolgiStain\u2122 kit manufacturer\u2019s protocol.z-axis motorized Olympus BX61 microscope equipped with x-y motorized stage guided by MAC5000 stage controller .In total 162 MSNs were three-dimensionally reconstructed using motorized microscope-computer based system and the Neurolucida software version 10 . System was composed of Only neurons with cell bodies located in the dorsal part of striatum within the middle third of the section thickness were included in the analysis. Figure By using a Neurolucida software extension NeurolucidaExplorer, from each reconstructed neuron the following parameters of somato-dendritic morphology have been extrapolated to numeric values: (1) cell surface; (2) number of primary dendrites; (3) total number of segments; (4) total dendritic length; (5) average length per dendrite; (6) average number of segments per dendrite; (7) average length and volume of individual intermediate (branch); (8) terminal; and (9) incomplete segment.For the analysis of segment length and volume, each segment was defined as branch (intermediate), terminal, or incomplete per group using average values per neuron as raw data. We applied the STATISTICA software for statistical analysis. The dendritic variables were tested separately using one-way analysis of variance .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Vibrio parahaemolyticus (Vp) is found naturally in coastal saltwater. In the United States, Vp causes an estimated 35,000 domestically acquired foodborne infections annually (Vibrio Surveillance system. Vp isolates are distinguished by serotyping (>90 serotypes have been described) and by pulsed-field gel electrophoresis (PFGE).annually , of whicVp serotypes O4:K12 and O4:K(unknown) comprise the Pacific Northwest (PNW) strain and, within the United States, had not been associated with shellfish outside the Pacific Northwest before 2012. During May\u2013July 2012, Vp of the PNW strain associated with shellfish from Oyster Bay Harbor in New York caused an outbreak of 28 illnesses in nine states. Simultaneously, Vp of the PNW strain caused an outbreak of illnesses on a cruise ship docked on the Atlantic Coast of Spain; illness was associated with cooked seafood cooled with ice made from untreated local seawater. All Vp isolates from ill persons in the U.S. and Spanish outbreaks that were further subtyped were indistinguishable by PFGE facilitates identification of Vibrio species. Consumers can reduce their risk for Vp infection by avoiding eating raw or undercooked shellfish, especially oysters and clams.\u2020This PNW strain is possibly becoming endemic in an expanding area of the Atlantic Ocean. The mechanisms for this introduction are not known. During the 2014"} +{"text": "Myriad roles of mucins in normal tissues have been well documented, including lubrication of the epithelial surfaces; protection from physical damage; facilitation in cell-cell signaling and suppression of inflammatory activity. Pathological expression of mucins has been noted in cancer development and progression. This study sought to identify and quantify the types of mucins produced during various histological grades of colon cancer and to assess the diagnostic significance.Formalin fixed, paraffin-embedded tissue blocks, comprising three (3) normal colon and twenty-two (22) colon cancer tissues, were retrieved from the archives of the histopathology department of the Komfo Anokye Teaching Hospital. They were stained with Haematoxylin and eosin (H&E) for diagnosis and grading of tumours. Tissues were pre-digested with diastase and stained with Alcian blue (pH 2.5)/Periodic Acid Schiff to characterize the mucin variants present.Our findings indicated that normal colonic tissues expressed exceptionally high amount of acid mucin and low amount of neutral mucin. However, there was a general decrease in mucin expression in colon cancers compared to normal colon tissues. Additional findings suggested that as cancer progresses from low grade to high grade of adenocarcinoma of the colon, there was generally a considerable decrease in the acid mucin production and an increase in the neutral mucin expression. In contrast, a sizeable subpopulation of high-grade adenocarcinomas of colon showed a rather opposite mucin expression pattern- increase in acid mucin and a decrease in neutral mucin.As colonic cancer progresses, there are corresponding changes in the mucin types and content such that there are decrease in acid mucin and increase in neutral mucin expressions. Initiation and development of cancers, particularly colonic cancer is a very complex one with several variables playing crucial roles in sustaining the viability of the cancer. Even though initiations of colonic cancers are well attributed to genetic imbalances, which could be inherited or somatTwenty-five formalin fixed, paraffin embedded (FFPE) colonic tissues, which were retrieved from the archives of Histopathology Unit of the Department of Pathology, Komfo Anokye Teaching Hospital, Kumasi-Ghana, following ethical approval from both the hospital and Committee for Human Research, Publication and Ethics of School of Medical Sciences, KNUST. Two tissue sections at 3\u03bcm from each FFPE tissue block were produced. One batch of the sectioned FFPE colonic tissues was stained with Haematoxylin and Eosin (H&E) and were histologically diagnosed and graded by three independent pathologists. The second batch of the sectioned FFPE colonic tissues was dually stained with Alcian blue, pH 2.5 to demonstrate acidic mucins (sulfated and carboxylated) and Periodic Acid Schiff (PAS) to demonstrate glycogens and mucins. In order to exclusively demonstrate neutral mucins, dewaxed colonic sections were pretreated with diastase for 60 minutes to digest at existing glycogen in the tissue . PositivHaematoxylin and eosin (H&E) based diagnosis and grading colonic cancer tissues: Normal colon and colonic cancer tissues were H&E stained to confirm the diagnosis and grades of the tumours. Five of the 22 colonic cancers were diagnosed and graded as Grade 2, Well Differentiated Adenocarcinoma (G2WDA); 13 of the 22 colonic cancers as Grade 2, Moderately Differentiated Adenocarcinoma (G2MDA); 3 of the 22 colonic cancers as Grade 2 Adenocarcinomas (G2A) and only 1 case as Grade 3 Poorly Differentiated Adenocarcinoma (G3PDA) ( (G3PDA) . The colDifferential mucins staining with Alcian Blue/Diastase-Periodic Acid Schiff staining: in order to correlate the mucin content/amount and types with different grading of colonic cancers, we performed Alcian blue (pH 2.5)/Diastase-Periodic Acid Schiff staining. The sensitivity and specificity of the staining mucin staining were tested using appropriate controls. This was also part of the quality assurance procedure. Quality controls for mucin demonstration For a positive control, normal colon stained blue for acid mucins using Alcian Blue (pH 2.5), Diastase Periodic Acid Schiff (DPAS) staining on prostate, and DPAS/Alcian blue (pH 2.5) staining on colon (results not shown). For a negative control, liver tissues stained negative for Alcian Blue (pH 2.5), indicating absence of acid mucins, but stained magenta in DPAS, indicating the presence of neutral mucins. Further, an omission of the periodic acid oxidation step in DPAS resulted in a negative staining on human liver (results not shown).Mucin content/amount and types in colonic cancers: in this study, the total mucin content in 22 colonic cancer cases was semi-quantified after double Alcian blue (pH 2.5) and Diastase-PAS staining. The mucin types were also determined in each case. Both mucin content and types were estimated and correlated with tumour grade mucins but scanty neutral mucins;It is widely postulated that sulfated mucins play a role in the control of cell division;Production of mucins, in general, is remarkably reduced in adenocarcinomas of colorectal tissues.We, in this study, demonstrated that there is a progressive decline of acid mucin from low-graded to high graded adenocarcinoma of colorectal with corresponding increase in neutral mucins;We also demonstrated for the first time that a subgroup of moderately differentiated adenocarcinomas had rather an increase in acid mucins coupled with decrease neutral mucins in humans.The authors declare no competing interest."} +{"text": "Based on a two-end-member mixing model, all target consumers relied on energy sources from coupled benthic and planktonic pathways, but the predominant energy source for most species was highly variable across seasons, showing seasonal trophic shift of littoral consumers. Seasonality in energy mobilization of consumers focused on two aspects: (1) the species number of consumers that relied mainly on planktonic carbon showed the lowest values in the fall and the highest during spring/summer, and (2) most consumer species showed seasonal variation in the percentages of planktonic reliance. We concluded that seasonal trophic shifts of fishes and invertebrates were driven by phytoplankton production, but benthic resources were also important seasonally in supporting littoral consumers in Meiliang Bay. Energy mobilization of carnivorous fishes was more subject to the impact of resource availability than omnivorous species.We evaluated the seasonal variation in the contributions of planktonic and benthic resources to 11 littoral predators in eutrophic Lake Taihu (China) from 2004 to 2005. Seasonal fluctuations in consumer \u03c3"} +{"text": "GABAergic and glutamatergic systems play an important role in the neurobiology of schizophrenia, and changes in their markers are reported in both postmortem human brain and in animal models. Recent studies have demonstrated that abnormalities in DNA methylation may underlie the alterations in various indicators of GABAergic and glutamatergic functions in schizophrenia. As our group previously found decreased NR2 protein plasma levels and downregulation of parvalbumin (PVALB) mRNA in first episode of psychosis (FEP) patients, we hypothesised that changes in DNA methylation may be responsible for these indicators of glutamatergic and GABAergic deficits in FEP patients.Blood samples were collected from patients in FEP (n = 35) after their first contact with the mental health assistance, siblings (n = 21) and population-based controls (n = 35). Bisulfite conversion and pyrosequencing were used to determine methylation levels in 4 CpG sites in promoter sequence of PVALB and 5 CpG sites at GRIN2B (gene which encodes NR2).We found hypermethylation at a CpG site within the PVALB promoter sequence in patients and their siblings compared to population-based control group (p< 0.001) while overall hypomethylation was found in the 5 CpGs analysed within GRIN2B promoter sequence (p < 0.01).Our PVALB findings are consistent with our previous studies showing that PVALB promoter methylation is elevated in schizophrenia and, additionally this is the first evidence showing changes in GRIN2B promoter methylation in psychosis. These results together suggest that these epigenetic findings may relate to the reduction of protein expression of indicators of glutamate and GABA systems seen in this disease."} +{"text": "This article contains the clinical characteristics of the paradoxical embolized patients and the following up results. Data included are related to the article \u201cParadoxical embolism: Experiences from a single center\u201d Specifications TableValue of the data\u2022These data provide the clinical characteristics and follow-up results of paradoxical embolism.\u2022Most patients had one or more risk factors for thrombosis and inducing or exacerbating factor.\u2022Long term coagulation is necessary and effective for paradoxical embolism.1The data presented include the clinical characteristics of the paradoxical embolized patients, the administrated treatment and the following up results .2Twelve patients diagnosed of paradoxical embolism in Fuwai Hospital from January 1994 to October 2015 were included. All clinical data related were collected from medical records, such as (1) demographic data; (2) case history and risk factors for thromboembolism; (3) clinical, laboratory and imaging findings of deep venous thrombosis, pulmonary embolism and systemic arterial embolic events; (4) imaging findings of an abnormal communication that allowed right to left shunt; (5) treatment and outcome; (6) follow-up data. Follow-up data were obtained from hospital records or by telephone interview with the patients or their family members. Follow-up ended on November 1st, 2015 There was no conflict of interest to declare."} +{"text": "Our study samples showed high levels of proinflammatory cytokine levels in all patient groups but only high levels of \u03b11-antichymotrypsine in VD patients compared to controls. There is no significant correlation between the laboratory and clinical variables except for a link between IL-1\u03b2 and NPI scores of AD. In conclusion, this study yielded evidence of some shared mechanisms underlying AD and VD and thus motivates further studies of inflammatory markers in various types of dementia and MCI.In the past years, the possible involvement of inflammation in the pathogenesis of dementia has been the subject of several investigations. However there are restricted data about the profile of the inflammatory and soluble proteins in well evaluated Alzheimer\u2019s disease (AD), vascular dementia (VD), mild cognitive impairment (MCI) and healthy controls. There are also no reliable data regarding the relationship between the overlapping protein levels and cognitive or functional decline. We measured levels of IL-1"} +{"text": "The early recognition of risk factors for the occurrence of palatally displaced canines (PDC) can increase the possibility of impaction prevention. To estimate the risk of PDC occurrence in children with dental anomalies identified early during mixed dentition. The sample comprised 730 longitudinal orthodontic records from children with an initial mean age of 8.3 years (SD=1.36). The dental anomaly group (DA) included 263 records of patients with at least one dental anomaly identified in the initial or middle mixed dentition. The non-dental anomaly group (NDA) was composed of 467 records of patients with no dental anomalies. The occurrence of PDC in both groups was diagnosed using panoramic and periapical radiographs taken in the late mixed dentition or early permanent dentition. The prevalence of PDC in patients with and without early diagnosed dental anomalies was compared using the chi-square test (p<0.01), relative risk assessments (RR), and positive and negative predictive values (PPV and NPV). PDC frequency was 16.35% and 6.2% in DA and NDA groups, respectively. A statistically significant difference was observed between groups (p<0.01), with greater risk of PDC development in the DA group (RR=2.63). The PPV and NPV was 16% and 93%, respectively. Small maxillary lateral incisors, deciduous molar infraocclusion, and mandibular second premolar distoangulation were associated with PDC. Children with dental anomalies diagnosed during early mixed dentition have an approximately two and a half fold increased risk of developing PDC during late mixed dentition compared with children without dental anomalies. According to the guidance theory, local conditions, such as maxillary lateral incisor agenesis or microdontia, are related to canine displacement,,,,,The study by Sacerdoti and Baccetti,-,Ectopic eruption of maxillary canines has two major clinical concerns: the consequent impaction of the canine and the possibility of incisor external root resorption,,,Conversely, when there is an early orthodontic diagnosis of PDC, simpler clinical approaches such as deciduous canine extraction and rapid maxillary expansion can lead to spontaneous canine eruption in a high percentage of childrenThis retrospective longitudinal study was approved by the Research Ethical Committee of the Hospital for Rehabilitation of Craniofacial Anomalies, University of S\u00e3o Paulo (HRAC-USP) (379/2010). The patient records were anonymized and de-identified prior to analysis. The initial sample was composed of the orthodontic files of 810 children treated from 1980 to 2005 at the Society for the Social Promotion of Cleft Lip and Palate Patients (PROFIS). Inclusion criteria were: presence of an initial panoramic radiograph taken during the first transitional period or inter-transitional period of mixed dentition, according to the Van der LindenThe final sample was composed of 730 orthodontic records from children with an initial mean age of 8.3 years (SD=1.36), from both genders . A rough estimate of the ethnic background of the sample based on facial photograph was: White (84%), Black (12%), and Asian (4%). The experimental and control groups included 263 and 467 records, respectively, and were composed based on the analyses of the initial panoramic radiographs and dental casts to investigate the presence of the following dental anomalies: 1. Agenesis of any permanent teeth, except for third molars; 2. Microdontia of maxillary lateral incisors; 3. Infraocclusion of deciduous molars; 4. Distoangulation of mandibular second premolars; 5. Tooth transpositions.All the records were analyzed by a single calibrated examiner (ML). The examiner was precalibrated showing an agreement index ranging from 90 to 100% (Kappa test). The maxillary lateral incisor was considered as presenting microdontia when the maximum mesiodistal crown diameter was smaller than the same dimension of the opposing mandibular lateral incisor in the same patient, using the dental castsThe sample was divided into two groups. The dental anomaly group (DA) was composed of 263 patients with at least one dental anomaly identified in the initial or middle mixed dentition. Records from children without these dental anomalies in the early/middle mixed dentition (n=467) composed the non-dental anomaly group (NDA). Age and gender distribution in both groups is presented in Panoramic radiographs from late mixed dentition and/or early permanent dentition were evaluated to assess risks for the development of PDC in both groups. Considering the findings of Ericson and KurolThe frequency of PDC development was calculated in DA and NDA groups. Intergroup comparisons were performed using the Chi-square test with a significance level of 5%. In order to measure the strength of associations between occurrences of early-diagnosed dental anomalies and PDC, the relative risk (RR) at the 95% confidence interval and the positive and negative predictive values (PPV and NPV) were calculated. Additionally, the frequency of PDC development was separately calculated for each dental anomaly and compared with the control group using the Chi-square test (p<0.01) and relative risk assessment.Seventy-two individuals were affected by PDC (9.86%) with a male:female ratio of 1:3 in the combined DA and NDA groups (n=730). In this subgroup of individuals with PDC, 29.1% (n=21) showed bilateral expression, 31.9% (n=23) unilateral right expression, and 38.9% (n=28) unilateral left expression.The DA group presented PDC frequency of 16.3% compared with 6.2% of the NDA group . This diStatistically significant associations were observed between increased frequencies of PDC development and some of the dental anomalies were separately evaluated . The relThe frequency of RME performed during the mixed dentition was similar in both DA and control groups . No otheThis study evaluated longitudinal records from patients with early-diagnosed dental anomalies to estimate risks for developing PDC during the late mixed dentition.,,Previous cross-sectional studies showed an association between PDC and other dental anomalies including small maxillary lateral incisors, tooth agenesis, deciduous molar infraocclusion, and other slight tooth ectopia,,The present study is the first to evaluate a large sample with longitudinal records for dental anomalies that could be used as markers to estimate PDC risks,,Small maxillary lateral incisors and mandibular second premolar distoangulation were the main risk factors for PDC among the early-diagnosed dental anomalies . These r,,Deciduous molar infraocclusion was also confirmed to be a risk factor for PDC ; this as,,No significant differences were observed between PDC development in individuals with agenesis of maxillary lateral incisors or second premolars, and the NDA group . Peck, PA limitation of this study is the possibility of false-positive diagnosis for PDC using panoramic radiographs,Our results show that small maxillary lateral incisors, distoangulation of mandibular second premolar, and deciduous molar infraocclusion are early risk markers for PDC. Pediatric and orthodontic population with such dental anomalies diagnosed during the early mixed dentition should be carefully monitored during the critical age period for early diagnosis and intervention of maxillary canine ectopic eruption. The recognition of risk markers for the occurrence of PDC can increase the possibility of early diagnosis and intervention. Future longitudinal studies could contribute to identify other potential risk indicators for PDC including family history, female gender, hypodivergent pattern, and enamel hypoplasiaChildren with some dental anomalies diagnosed during the early mixed dentition have an approximately two and a half fold increase in risk of developing PDC during the late mixed dentition compared with children without these dental anomalies. Microdontia of maxillary lateral incisors, mandibular second premolars distoangulation, and deciduous molar infraocclusion constitute early risk markers for PDC development. When the maxillary canines are not palpable, a panoramic radiograph is highly recommended in 10-year-old children with clinically or radiographically diagnosed DA in order to investigate PDC."} +{"text": "Novel insights into the epigenetic control of chronic liver diseases are now emerging. Recent advances in our understanding of the critical roles of DNA methylation, histone modifications and ncRNA may now be exploited to improve management of fibrosis/cirrhosis and cancer. Furthermore, improved technologies for the detection of epigenetic markers from patients' blood and tissues will vastly improve diagnosis, treatment options and prognostic tracking. The aim of this review is to present recent findings from the field of liver epigenetics and to explore their potential for translation into therapeutics to prevent disease promoting epigenome reprogramming and reverse epigenetic changes. If taken literally this could include all of the events involved in the regulation of gene expression. However for the purpose of this review discussion will be limited to those regulatory mechanisms that operate at the level of DNA methylation, histone modifications and the activities on non-coding regulatory RNA molecules. But in addition, readers should be aware of the critical role that transcription factors play in determining gene expression and cell phenotype. Transcription factors, which operate by recognising specific DNA motifs in the promoter/enhancer regions of genes and then modulate the activity of RNA polymerase II, are increasingly featuring as important drug targets in chronic liver disease. Typical examples being the peroxisome proliferator-activated receptors and the farnesoid X receptor for which ongoing clinical trials are determining efficacy in non-alcoholic fatty liver disease (NAFLD) and autoimmune liver disease de novo methyltransferases, establishing methylation patterns during development DNA methylation is a direct chemical modification of DNA in which methyl groups are predominantly added to cytosine residues within the context of a CpG dinucleotide DNA is packaged into chromatin of which the unit structure is the nucleosome which is comprised of two copies each of histones H2A, H2B, H3 and H4 that assemble into an octamer around which 146\u2013147\u00a0bp of DNA is tightly wrapped. The nucleosome is a highly dynamic structure and dictates the degree to which DNA is accessible for transcription; this being determined by its degree of compaction and by post-translational modifications (PTMs) on the N-terminal tails of its constituent histones The vast majority of the human genome is transcribed, however only 2% encodes proteins. The vast majority of the transcriptome consists of non-coding RNAs (ncRNAs) that have regulatory functions and include micro RNAs (miRNA), small nucleolar RNAs (snoRNAs), small interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs) and the long non-coding RNAs (lncRNAs). The miRNAs are an extensively studied class of single-stranded 18\u201322 nucleotide ncRNAs that fine-tune expression of the genome either by decreasing the stability or suppressing translation of messenger RNAs Here we will consider recent advances in the role of DNA methylation, histone modifications and ncRNAs in chronic liver diseases and in particular how new knowledge of these epigenetic mechanisms may be exploited for improving the management of the two major liver disease endpoints, fibrosis/cirrhosis and cancer.2The liver must adapt on a daily basis to a constant flux of environmental variations including circadian oscillators, nutritional/metabolic fluxes, exposure to xenobiotics, viral infections, alterations in the microbiome and the demands for epithelial repair and regeneration. Using a deep sequencing approach, Vollmers and colleagues systematically mapped the epigenetic changes occurring over 24\u00a0h in the mouse liver via its induction of hepatic reactive oxygen species (ROS) promotes H3K9 acetylation leading to increased expression of alcohol-metabolising enzymes that induce further ROS and acetylation potentially establishing feed-forward epigenetic re-landscaping HDAC3 is an important circadian regulated epigenetic writer critical for hepatic triglyceride homoeostasis and when deleted in mice results in steatosis, inflammation and fibrosis via its ability to influence DNMT activity and in addition recruits the histone acetyltransferases p300/CBP to induce IL-8 and proliferating cell nuclear antigen (PCNA) which are involved in inflammation and cell proliferation respectively Hepatitis C virus (HCV) infection promotes multiple changes in DNA methylation including at enhancer elements associated with altered expression of genes implicated in cancer and control of stem cells Hence, in summary the epigenetic landscape of the liver is acutely sensitive to environmental cues resulting in modifications that impact on its circadian controlled patterns of gene expression. In obesity and alcoholic disease the disturbance to the hepatic epigenetic landscape may promote microenvironments in which steatosis advances to inflammation, fibrosis and cancer.3Myofibroblasts are the major cellular drivers of liver fibrosis and appear during conditions of liver damage and/or infection mainly through the process of hepatic stellate cell (HSC) transdifferentiation. The conversion of quiescent HSC to their activated myofibroblast state involves vast changes in transcriptome expression that dramatically alter the phenotype and behaviour of the cell. In the past decade we have begun to shed light on the epigenetic events that reprogram the HSC transcriptome, thus revealing new regulators of fibrogenesis as well as potential biomarkers for tracking disease progression.3.1in-vivo transdifferentiation of HSC can be recapitulated in a cell culture model in which isolated HSC are maintained for several days on plastic in serum-containing media. In this widely used model, HSC transdifferentiation was accompanied by a >\u00a020% methylation change (hypo- or hyper-methylation) in ~\u00a0400 methylated regions including DNMT3A and DNMT3B 4) induced liver fibrosis 4 mouse fibrosis model Many of the regulatory events associated with DNA methylation in the PPAR\u03b3 gene promotor has also been shown to be relevant in human disease. In a well phenotyped cohort of patients with biopsy proven NAFLD Zeybel et al. demonstrated that hypermethylation at discreet CpG dinucleotides within the human PPAR\u03b3 gene promotor could be used to stratify patients with mild fibrosis (Kleiner score 0\u20132) from those with severe fibrosis (Kleiner score 3\u20134) in vivo models of chronic liver disease (bile duct ligation (BDL), CCl4 and methionine-choline deficient (MCD) diet) de novo methyltransferases DNMT3A/B expression, diminution of TET protein expression and remodeling of the HSC DNA methylome. Moreover, culture activated HSC and ex-vivo purified HSC from CCl4 injured rats also demonstrated increased DNMT3A and DNMT3B, with knock-down of the latter enzymes resulting in reduced fibrogenic features. Of note, similar fibrosis-associated epigenetic changes were observed in mechanistically distinct examples of chronic human liver disease supporting the concept that fibrosis is in part driven by alterations in the balance between the DNMTs and TETs As previously explained DNA methylation is a dynamic epigenetic marker that is regulated by DNMT and TET enzymes that stimulate CpG methylation and demethylation respectively 3.2Schistosoma mansoni and BDL induced liver fibrosis in vivo delivery of histone methyltransferase inhibitors to HSC can potently inhibit liver fibrosis 4-induced liver damage in vivoHistone acetylation is associated with active transcription and is under the control of HATs and HDACs. Niki et al. first described the anti-fibrotic effects of HDAC inhibitors showing that trichostatin A (TSA) treatment of cultured HSC suppressed fibrogenic gene expression and proliferation 3.34 exposure or BDL, this observation being confirmed in human liver with advanced fibrosis in vivo relevance in vivo and in vitro during liver fibrosis, with HOTAIR knockdown suppressing HSC activation. The authors further demonstrated that HOTAIR downregulates miR-29b expression, attenuating its control on epigenetic regulation, leading to enhanced phosphatase and tensin homolog (PTEN) methylation, which contributes to the progression of liver fibrosis A large number of miRNAs have been described that both promote and suppress HSC transdifferentiation 4Hepatocellular carcinoma (HCC) is the 3rd leading cause of cancer deaths worldwide and treatment options are severely limited. There is a clear need for the identification of the molecular drivers of HCC if progress is to be made in developing new medicines. Deep sequencing studies have been instrumental in identifying gene mutations and potential disease drivers in HCC. Alongside these genetic approaches is an increasing awareness of the role of epigenetic regulators in HCC which have strong potential for drug and biomarker design.4.1DNA methylation changes are common in human cancers and it was therefore unsurprising that 3700 hypomethylated promoters were identified in HCC tumour samples in vivo. Reduced SMPD3 expression was associated with early HCC recurrence following resection in vivo in a xenograft HCC HepG2 model. CDKN2A, DLEC1 and RUNX3 promoters were all confirmed to be demethylated in HCC lines following Guadecitabine treatment and correlated with inhibition of cell growth. Importantly, in contrast to decitabine, Guadecitabine was able to overcome the inhibitory effects on cell growth by macroH2A1 (variant of histone H2A), highlighting Guadecitabine as a potential HCC therapeutic, particularly in advanced disease There is vast potential for alterations in DNA methylation in HCC to be exploited for future drug and biomarker development. The de-methylating agent decitabine has been used to validate the expression of hypermethylated TSG in primary HCC and also re-expression of genes in HCC cell lines. 13 candidate TSG were identified in this study including DGK1, LDHB, NEFH, SMPD3, ACTL6B and PRPH. Functional characterisation of 2 candidates, SMPD3 and NEFH, revealed that overexpression leads to inhibition of cell proliferation, whereas by contrast knockdown increased tumour formation 4.2in vitro and in vivoHistone modifying enzymes offer much promise for HCC therapy since they are tractable targets for the design of small molecule inhibitors. The H3K27 methylase EZH2 is up-regulated in HCC tissue and is associated with cancer progression, invasion and proliferation 4.3Previous and emerging studies in HCC are now beginning to incorporate ncRNAs into our molecular understanding of HCC pathogenesis and progression As the complexity of these molecular interactions unravel, we can begin to appreciate that in most scenarios these modulators likely work together as a network of epigenetic regulators. This highlighted by a study demonstrating how HULC and MALAT1 combine in complex with TRF2 to significantly increase telomerase activity and microsatellite instability in liver cancer stem cells NCT02603224).Therapeutic targeting of ncRNA in HCC is now an imminent challenge. Emerging pre-clinical studies utilizing sophisticated drug delivery nanoparticles and animal proof of concept models such as this study successfully targeting the lncRNA TUG1 show promise for therapeutic development of antisense oligonucleotides 5The hepatic epigenome is remarkable in its capacity to adapt to dietary, metabolic, xenobiotic and microbial challenges in order to maintain cellular and functional homeostasis. However, when this capacity is breached epigenetic adaptions can become problematic and contribute to disease pathogenesis. We are now aware of how key components of the epigenetic machinery such as DNA methylation, histone PTMs and ncRNAs alter their expression or function in the context of fibrosis/cirrhosis and liver cancer. The next steps are to convert this information into bespoke medicines that either prevent disease-driving epigenome reprogramming or that reverse specific disease-promoting epigenetic changes. Furthermore there is vast potential to use the appearance of liver-derived epigenetic markers in the patient circulation for the diagnosis and prognostic tracking of chronic liver disease using no more than a few drops of blood, avoiding the need for biopsy or complex and expensive imaging modalities."} +{"text": "Scientific Reports6: Article number: 34474; 10.1038/srep34474 published online: 09292016; updated: 05082017.As the authors of references 25 and 26 also employed plasma-assisted molecular beam epitaxy for the synthesis of hexagonal boron nitride films, the authors would like to make the following changes to the Introduction section of their Article:23,24,25,26 and atomic layer deposition27 of hBN on metal substrates; this approach must typically be complemented by complex protocols for the removal and transfer of the grown films\u201d.\u201cIn addition the direct growth of hBN on a two-dimensional material (HOPG) offers an alternative to chemical vapour depositionShould read:23,24, MBE25,26 and atomic layer deposition27 of hBN on metal substrates; this approach must typically be complemented by complex protocols for the removal and transfer of the grown films\u201d.\u201cIn addition the direct growth of hBN on a two-dimensional material (HOPG) offers an alternative to chemical vapour deposition"} +{"text": "The variables were related to brightness, color, physical aspects, soluble and total collagen as well as chemical traits. The physiological stage was defined as a classification variable in order to proceed ANOVA tests and comparison of means (P<0.05). Multivariate analysis was used to identify patterns of similarity and differentiation between samples of different physiological stages . The results revealed that meat quality varies according to different physiological stages, especially between lambs (a) and cull ewes (c). As a consequence, the physiological stage at slaughter should be taken into consideration to cote the quality of meat from indigenous sheep raised in tropical regions. The results contribute towards sensorial evaluation and the characterization of potential food products derived from indigenous sheep bred under tropical climate in developing countries.This study configures a first report regarding the variability of meat quality of locally adapted Pantaneiro sheep depending on different physiological stages and breeding systems. Pantaneiro sheep are raised in Brazil under a tropical wetland ecosystem denominated Pantanal. Twenty-nine Pantaneiro sheep from different sex and physiological stages were sorted into three groups, simulating three of the most representative ovine meat products commercialized by South American industries: a) non castrated male lambs (n = 11); b) wethers (n = 9); c) cull ewes (n = 9). Animals from each physiological stage were submitted to different breeding systems, resembling farming strategies adopted in several developing countries of South America. The effect of physiological stages on the quality of meat was accessed using 16 variables measured in the The Midwest of Brazil presents the highest growth rates of sheep farming in the country . This reSeveral factors limit sheep breeding to play a more significant role on rural development and become a source of financial income in developing countries such as Brazil , 3. The Progress has been reported, but market and merchandising of sheep products in many developing countries still contrast with global market trends which requires urgent adjustments \u201313There is considerable lack of information regarding breed, geographical provenance, breeding system and traceability of age category , which may denote the quality of meat after slaughter.Food originated from indigenous breeds of sheep is an option to access and develop alternative markets \u201316. HoweIt is reasonable to consider that the diversification of products and market niches require efforts towards characterization , 19\u201321. The quality of meat has been an important subject , includiStill, in countries such as Brazil, three top products derive from sheep farming: meat from lambs (a), wethers (b) and cull ewes (c). Demands for each one of these products vary according to local market trends in different macro regions of South American countries . PhysicoConsidering some of the aspects of indigenous sheep farming, this study was designed to generate a first report on meat quality of Pantaneiro sheep, encompassing physicochemical and sensory characterization of the most common physiological stages commercialized in South American sheep industries.All protocols of experimental procedures were approved by the Animal Experimentation Ethics Committee (CEUA) of the Federal University of Grande Dourados (UFGD), The criteria to slaughter lambs (a) and wethers (b) was the body condition, which ranged from 2.5 to 3.0 . Cull ew-1 [The uncastrated lambs (a) were weaned with average weight of 19.5\u00b14.10 kg and finished in feedlots with an 80% concentrate and 20% forage (20%) diet . The die-1 . Lambs (Cynodon spp. (Tifton85) and supplemented (1% of body weight) with the same concentrate used for lambs (water ad libitum). These animals were slaughtered at the age of 12.5\u00b11.18 months. The cull ewes (c) were kept in extensive systems with tropical pastures of Brachiaria brizantha cv. Piat\u00e3 with ad libitum mineral salt. Cull ewes (c) were slaughtered at the age of 68\u00b113 months (The wethers (b) were kept in tropical pastures based on 3 months .All animals were slaughtered after 16-hours of fasting (solids). Desensitization was carried out by electronarcosis (8 seconds of 220-V discharge) followed by cutting of jugular veins and carotid arteries with subsequent evisceration. Lambs (a), wethers (b) and cull ewes (c) showed initial average weight of 19.64, 19.90 and 45.04 kg, respectively. Final average weight was 35.72, 43.04 and 49.58 kg, respectively longissimus thoracis et lumborum (LM) and semimembranosus (SM) muscles were removed for meat quality analysis. All samples were analyzed with one replicate, and the final value of each variable was determined calculating a simple average for each variable.After slaughter, the carcasses were stored in a cold room at 4\u00b0C during 24 hours. Subsequently, the Evaluation of meat was performed based on color, physical characteristics, soluble and total collagen and chemical characteristics Tables The color was evaluated in lyophilized samples, submitted to acid digestion, filtration, neutralization, dilution and oxidation for colorimetric reaction. The results were based on the hydroxyproline values from absorbance readings performed in a spectrophotometer with a wavelength of 570 nm. The sample color was evaluated after 30 minutes of exposure to air to allow myoglobin reaction with oxygen . BrightnThe physical characteristics of meat were evaluated regarding water retention capacity (%) according to the method described by . The sheThe pH and temperature of the warm and the cold carcass were monitored using a digital thermometer and pH-meter with a Testo 205/206 penetration probe. The determination of the soluble and total collagen content (%) followed the method described by modifiedRegarding the chemical composition of meat, moisture was evaluated according to the method 950.46 . Total nlongissimusthoracis et lumborum (LM) and semimembranosus (SM) muscles. This was done using a univariate approach (PROC GLM) (p<0.05). Analyses were performed using the software SAS 9.2 . A multivariate method was used to standardize data (PROC STANDARD procedure) and to develop clustering analysis (PROC FASTCLUS procedure) assuming three clusters.The experimental design was arranged as an exploratory study. Animals were sampled from an on farm conservation flock and sorted according to pre-established physiological stages. The Shapiro-Wilk test was performed to verify the residue data normality, and the Bartlett test was performed to verify homogeneity of variances. Similar to a nested analysis approach, the effect of physiological stages (fixed effect) (lambs (a), wethers (b) and cull ewes(c)) was evaluated on the versus SM) regarding each physiological stage (The meat from lambs (a) showed different values compared with cull ewes (c) with only one exception of the LM muscle al stage . Means bWater retention capacity, shear force and losses of weight after cooking presented similar averages (P>0.05) between physiological stages The highest concentration of total collagen was found in the meat from cull ewes. Physiological stages presented different values of total collagen All variables related to chemical composition were effected (P<0.05) by the physiological stage. The chemical analysis showed significant differences between means of lambs and cull ewes, except for the ash content of the SM muscle.The meat from wethers showed the same ether extract content than the cull ewes, regardless of the muscle type Lambs showed greater moisture content in the LM muscle Considering all 15 variables used to evaluate the quality of meat from different physiological stages, only three variables may present similar aspects to the meat of lambs (a). The meat of some cull ewes (c) maybe similar to the meat of wethers (b). However, no cull ewes (c) presented similar meat quality compared to lambs (a) In general, the variables related to brightness (L*), the intensity of yellow (b*) and red (a*) varied according to physiological stages There is a trend to believe that many physical aspects of meat vary according to the age of animals at slaughter , 40. AgiCarcasses from older animals are associated to greater stability and texture of muscle fiber showing less soluble collagen . The samIn general, meat from different physiological stages showed appropriate quality values of collagen and pH, configuring soft meat The chemical characteristics of meat also differed between physiological stages The variation of meat quality regarding muscle types was considered to be random. However, diversifying aspects related to flavor and nutritional aspects of indigenous sheep meat was observed between different physiological stages.Fine discrimination observed with multivariate analysis Evaluation of meat from indigenous Pantaneiro sheep of different sex and physiological stages revealed suitable standards of meat quality produced in a rough and typically unique tropical ecosystem. Notable differences were observed between the quality of meat originated from lambs and cull ewes. This fine discrimination opens the door to valuable validation of how meat quality relates to sensorial aspects and consumer preferences regarding the preparation of dishes and consumption.Characterization of food products derived from locally adapted livestock in developing countries is an effort towards the development of new products with added value which may enhance merchandising, marketing strategies and consumption.S1 FileProtocols of experimental procedures were approved by commuittes(PDF)Click here for additional data file."} +{"text": "Data presented within this article supports the findings of the manuscript \u201cA systematic review of fantasy driven vs contact driven internet-initiated sexual offences: Discrete or overlapping typologies?\u201d [1]. Inclusion and Exclusion criteria of study selection, PICO Formulation of Study Appraisal, as well as the Study Characteristics and Methodology of included studies are presented. Specifications TableValue of the data\u2022The data allows for interpretation and assessment of studies examining the behavior of internet-initiated sexual crimes against minors, including study characteristics and methodology.\u2022The data enables comparison of two distinct classification of internet-initiated offences commonly referred to in the literature: fantasy vs contact driven crimes.\u2022Studies within this field primarily rely on the use of decoy victims, i.e. adults posing as children/young people who engage in proactive investigations. This data enables researchers to identify those studies that use decoy and real child victims.1The data set contains information on the Inclusion and Exclusion Criteria for Study Selection , and PIC2The process of study selection is defined in n = 5).Studies included in Broome et al."} +{"text": "Scientific Reports 10.1038/s41598-017-05445-3, published online 20 July 2017Correction to: This Article contains errors in the Materials and Methods section under subheading \u2018Sample selection\u2019.\u201cAll participants provided informed consent that explicitly allowed their coded genome sequencing data to be shared with other investigators\u201d.should read:\u201cUniv. of Pennsylvania samples were obtained from The Coriell Institute for Medical Research (CIMR). Collection of blood/tissue samples followed diagnostic consensus, using two informed consent forms: a) one with annual Univ. Miami IRB approval defining (with language appropriate for Old Order Amish) how their cells would be preserved for medical research on Major Affective Disorders; and, b) the Informed Consent Form required by the Institute for Medical Research (CIMR), later Coriell - National Institute for General Medical Sciences (NIGMS) Human Genetic Cell Repository (HGCR).The CIMR/NIGMS Informed Consent Forms makes no reference to specific diseases, types of genetic analysis that will be performed in future studies. Analysis of whole-genome re-sequencing data from consented individuals in this pedigree was also approved by the IRB of the Weill Cornell Medical College and the Perelman School of Medicine at the University of Pennsylvania. All other participants provided informed consent that explicitly allowed their coded genome sequencing data to be shared with other investigators\u201d."} +{"text": "Recently, Seddik Hammad from Heidelberg University published an interesting report about a frequent misinterpretation in research on liver fibrosis : in mic4 mediated pericentral killing of CYP2E1 positive hepatocytes, which after repeated CCl4 administration leads to fibrotic bridging of pericentral areas . Hammadal., 2017).in vitro systems in toxicology aim for mimicking some of the zonated features of the liver lobule (Frey et al., 2014[Studies of hepatotoxicity often rely on the correct interpretation of histology (Schenk et al., 2017; Reif etal., 2014; Leist e"} +{"text": "The extent to which poor academic achievement is associated with later schizophrenia is unclear. The aim of the present study was to update our prior meta-analyses which examined academic achievement in youth aged 16 years or younger who later developed schizophrenia or schizophrenia spectrum disorders (SSD) and those who did not . We also conducted a new meta-analysis on published studies that reported on general academic achievement in youth at-risk for schizophrenia/SSD aged 16 years or younger compared to typically developing youthIn addition to the five studies included in our earlier meta-analyses, a further three prospective investigations of birth or genetic high-risk cohorts were identified that reported results using objective measures of general academic achievement and of mathematics achievement for individuals who did and did not develop schizophrenia/SSD in adulthood. For our new meta-analysis we identified a total of seven studies that met the following inclusion criteria: (1) written in English; (2) objective measure of general academic achievement consisting of scores on least two core academic subjects at age 16 years or younger; (3) results provided for youth at high risk for developing schizophrenia/SSD in adulthood by virtue of having at least one first-degree relative with the disorder or reporting psychotic like-experiences (PLEs); and (4) sufficient data to calculate effect sizes.Meta-analyses showed that by age 16 years, individuals who later developed schizophrenia/SSD presented with significantly poorer general academic achievement (d=-0.26) and mathematics achievement (d=-0.21). Findings also indicated that during adolescence, youth with a family history of schizophrenia/SSD and youth reporting PLES were characterised by significantly lower general academic achievement than healthy peers .These results show that poor academic achievement precedes illness onset, and may represent an easily identifiable non-specific marker of biological, psychological and social risk processes underpinning the development of schizophrenia/SSD."} +{"text": "Although some studies have suggested that transfusion recipients may have better medical outcomes if transfused with red blood cell units stored for a short time, the overall body of evidence shows mixed results. It is important to understand how using fresher stored red blood cell units for certain patient groups may affect blood availability.Based on the Stock-and-Flow simulation model of the US blood supply developed by Simonetti et al. 2014, we evaluated a newly implemented allocation method of preferentially transfusing fresher stored red blood cell units to a subset of high-risk group of critically ill patients and its potential impact on supply.Simulation results showed that, depending on the scenario, the US blood total supply might be reduced between 2-42%, when compared to the standard of care in transfusion medicine practice. Among our simulated scenarios, we observed that the number of expired red blood cell units modulated the supply levels. The age threshold of the required red blood cell units was inversely correlated with both the supply levels and the number of transfused units that failed to meet that age threshold.To our knowledge, this study represents the first attempt to develop a comprehensive framework to evaluate the impact of preferentially transfusing fresher stored red blood cells to the higher-risk critically ill patients on supply. Model results show the difficulties to identify an optimal scenario. Observational studies have estimated the effects of red blood cell (RBC) storage time on clinical outcomes among different patient groups. Some studies have shown that transfusing certain high-risk patients, such as cardiac surgery patients, with RBC units that have been stored for prolonged time may increase the risk of adverse outcomes \u20136. OtherResults from randomized clinical trials (RCT) have varied in their outcomes. The RECESS RCT from the National Heart, Lung, and Blood Institute found noBased on the Stock-and-Flow simulation model of the US blood supply developed by Simonetti et al. 2014 , we explThe US blood supply model developed by Simonetti et al. evaluateThe Collector attempted to supply the Hospital with enough young RBC units to meet the HRGs expected demand of blood for the next day. The Hospital received blood from the Collector to fulfill any need of blood demand regardless the RBCs age, while maintaining an inventory of 6 days of supply. Transfers of blood from the Collector to the Hospital occurred by using \u2018standard\u2019 phenotype compatibility rules . We defiThe daily predictions of supply and demand were derived using aggregated blood donation information from America\u2019s Blood Centers (ABC) , and updWe used the annual average daily (AAD) age of RBCs as a summary measure for the overall evaluation of the performance of the blood system for each simulated scenario. Specifically, we used the weighted AAD age of RBCs, which represented the distribution of RBC units among different blood ages. Other measures of performance were \u2018unmet RBC units by age\u2019 and \u2018percentage of unmet RBC units by age\u2019 for HGRs and BBRs. \u2018Unmet RBC units by age\u2019 represented the amount of RBC units that failed to meet the age requirement derived from the literature \u20136. \u2018PercWe identified three HRGs\u2014Cardiac Surgery (CS), Trauma (TR) and Intensive Care Unit (ICU) patients , 5\u2014from To evaluate the impact on supply of transfusing a subset of HRGs with fresher stored RBCs, we compared the baseline blood recipients to several selected scenarios in context, we may help understanding the effect on the US blood supply if transfusing fresher storedRBC units is proven beneficial to improve recipient outcomes. However, under current assumptions, we demonstrated how the newly developed allocation method allows a relatively efficient distribution of blood while preferentially providing fresher stored RBCs to the high-risk blood recipient except for some disruptions in the US blood supply observed in certain simulated scenarios. Most importantly, implementing \u2018ad-hoc\u2019 models can help assist stakeholders and the blood community to make informed decisions that may impact the availability of blood in the US blood supply.S1 FigA flowchart of the \u2018Threshold Method\u2019 (TM) algorithm to illustrate the mechanism of allocating blood into the system 1) from the Hospital to the HRGs recipients; and 2) from the Collector Bank to the Hospital, on each day of the Monte Carlo simulation.(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S3 Fig(DOCX)Click here for additional data file.S4 FigThe Annual Average Daily (AAD) number of RBC units available in the system for: (A) Total Supply , average values (red), and percent reduction in total supply with respect to baseline scenario (BBR-LO) (above bars for scenarios 2 to 11); (B) Expired RBC Units, and percentage of expired units at collector only are shown on bars; (C) Unmet RBC Units by Age by blood type at the hospital, the percentage of unmet units by age (above bars), and mean age of the transfused blood at the hospital . The scenarios are sorted in a descending order according to their total supply. Error bars represent 95% confidence intervals.\u201d(DOCX)Click here for additional data file.S5 FigDescription of each element of the half-pie chart from inner to the outer layer as follows: 1) percentage of total RBC units transfused among elderly for the overall HRGs (blue) versus BBR (tan); 2) percentage of total RBC units transfused decomposed by HRGs ; 3) allocation method used for each recipient group ; 4) mean age of the blood transfused to each recipient group and the percentage of \u2018met\u2019 (green) and \u2018unmet\u2019 (red) RBC units by age for HRGs only (in parenthesis); and 5) mean age of the overall transfused blood given to HRGs (bold red).(DOCX)Click here for additional data file.S6 FigThe mean age of blood for the overall transfused blood at the hospital is shown above the bars.(DOCX)Click here for additional data file.S7 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 TableScenario illustration, group description, and allocation method used for each scenario are also presented.(DOCX)Click here for additional data file."} +{"text": "G2 and the McMaster techniques for counting of gastrointestinal nematode eggs in the faeces of alpacas using two floatation solutions (saturated sodium chloride and sucrose solutions). Faecal eggs counts from both techniques were compared using the Lin\u2019s concordance correlation coefficient and Bland and Altman statistics. Results showed moderate to good agreement between the two methods, with better agreement achieved when saturated sugar is used as a floatation fluid, particularly when faecal egg counts are less than 1000 eggs per gram of faeces. To the best of our knowledge this is the first study to assess agreement of measurements between McMaster and FECPAKG2 methods for estimating faecal eggs in South American camelids.This study aimed to compare the FECPAKThe online version of this article (10.1186/s13071-018-2861-1) contains supplementary material, which is available to authorized users. Parasitic gastroenteritis caused by gastrointestinal nematodes (GINs) is responsible for significant clinical and subclinical problems in domesticated South American camelids (SACs), alpacas and llamas, resulting in economic losses arising from lowered production of fibre, meat and/or leather , 2. AlthIn SACs, the burden of GINs can be assessed using various coprological methods originally developed for domestic ruminants , with esG2 method uses a floatation-dilution approach similar to the McMaster technique, but involves capturing digital images of samples without the use of a microscope. Digital images of samples are stored, ready for assessment by trained technicians for identification and counting nematode eggs [G2 methods assessed using the Lin\u2019s concordance correlation coefficient [epiR package [The arithmetic means of EPG were calculated for faecal egg counts obtained using the two methods and differences in arithmetic means were tested using the Wilcoxon signed rank test. A G + 15)] , and agrfficient . To provfficient . These l package implemen package .G2 methods . Using sugar solution, more samples had at least more than one EPG using the McMaster technique compared with FECPAKG2 in the proportions of positive samples tested by both methods when salt solution was used plots showing line of perfect concordance (dotted line) and estimated concordance (solid line) between McMaster and FECPAKG2 methods using salt solution (a) and sugar solution (b). (TIF 520 kb)"} +{"text": "Left ventricular (LV) fractal dimension (FD) on cardiac magnetic resonance (CMR) balanced steady-state free precession (SSFP) cines has already proven to be useful in making a diagnosis of non-compaction cardiomyopathy. Normal FD values for SSFP cines have been established (Captur 2015).Fast gradient echo (fGRE) sequences have different contrast between blood pool and myocardium, which affects measurement of FD. However, if FD could be measured on fGRE it would allow for retrospective analysis of scans acquired before implementation of SSFP or in patients with devices that underwent fGRE.The aim of this study was to establish a correlation between FD measured on SSFP and fGRE sequences in the same subjects.Twelve participants of Barts Cardiovascular Registry who underwent cardiac magnetic resonance (CMR) imaging with 1.5T scanners for various clinical reasons had cine short axis stack (SAX) acquired with both SSFP and fGRE sequences.We measured FD in 57 corresponding (positioned in the same LV location) SAX cine slices on SSFP and fGRE using dedicated MATLAB script and an Osirix \"LVFractalAnalysisFilter\" plugin written in Objective-C with equivalent architecture. The same region-based level-set segmentation and fractal procedure was implemented. Briefly: the scale parameter specifying the size of the neighbourhood (sigma) was set to 2%; size of the initial contour was set to 6 \u00d7 9 pixels; and maximum initial grid-size for fractal analysis was 45% of the original size of the region of interest estimated through the application of a scaled bounding box.We used Pearson's correlation coefficients and two-way random single measures of consistency intraclass correlation coefficients (ICC) to compare FD from SSFP and fGRE, first for values derived in MATLAB and then in Osirix.FD on fGRE was around 6.5% larger than on SSFP in MATLAB and 4.3% in Osirix (p < 0.001 and p < 0.05). There was a good agreement between the FD derived from SSFP and fGRE sequence in both MATLAB and Osirix tools .Detailed results are presented in the table and the figure.This proof-of-principle analysis shows a significant correlation between FD on SSFP and fGRE sequences. FD measured on fGRE may have utility as a research tool and further ground-truth validation of the method is encouraged."} +{"text": "To clarify the prognostic role of tumour protein 53 (TP53) mutations in patients with oesophageal adenocarcinoma (OAC) as there is a need for biomarkers that assist in guiding management for patients with OAC.A systematic review was conducted using MEDLINE, Embase, PubMed and Current Contents Connect to identify studies published between January 1990 and February 2015 of oesophageal cancer populations (with OAC diagnoses >50% of cases) that measured tumoural TP53 status and reported hazard ratios (HR), or adequate data for estimation of HR for survival for TP53-defined subgroups. Risk of bias for HR estimates was assessed using prespecified criteria for the appraisal of relevant domains as defined by the Cochrane Prognosis Methods Group including adherence to Grading of Recommendations, Assessment, Development and Evaluation and REporting recommendations for tumor MARKer prognostic studies guidelines, as well as assay method used (direct TP53 mutation assessment vs immunohistochemistry) and adjustment for standard prognostic factors. A pooled HR and 95% CI were calculated using a random-effects model.2=33%). A greater prognostic effect was observed in a sensitivity analysis of those studies that reported survival for OAC-only cohorts and were assessed at low risk of bias .Sixteen eligible studies (11 with OAC only and 5 mixed histology cohorts) including 888 patients were identified. TP53 mutations were associated with reduced survival (HR 1.48, 95% CI 1.16 to 1.90, IPatients with OAC and TP53 gene mutations have reduced overall survival compared with patients without these mutations, and this effect is independent of tumour stage. Oesophageal adenocarcinoma (OAC) remains one of the few GI malignancies where molecular information is not taken into account to guide patient management.Current clinicopathological staging fails to accurately identify patients with OAC with good or poor prognosis.Recent genomic findings have identified a high tumour protein 53 (TP53) mutation rate in OAC, but the prognostic impact of this remains unclear due to conflicting reports in the literature.This is the first dedicated systematic review and meta-analysis regarding the prognostic impact of TP53 mutations in patients with OAC including 16 studies with >850 patients.We identify a significant negative prognostic impact of TP53 mutations on overall survival of patients with OAC.A greater prognostic effect can be corroborated in studies that report tumour-stage adjusted survival for OAC-only cohorts and are assessed at being at low risk of bias.This study suggests that TP53 gene mutations have a clinically important negative prognostic impact on patients with OAC.In light of recent genomic findings highlighting a central role of this gene in OAC pathogenesis and drugs currently in development and testing that directly target this gene, a role for identifying TP53 mutations in OAC can be suggested.The incidence of oesophageal adenocarcinoma (OAC) has increased faster than any other cancer since the 1970s in many Western countries with highest incidence rates found in Northern and Western Europe, Northern America and Oceania,Fewer than half of the patients with a new diagnosis of OAC are eligible for curative treatment, and OAC continues to have one of the highest cancer case-fatality rates with population-based 5-year survival rates typically around 15%.The tumour-suppressor gene tumour protein 53 (TP53) , which encodes the p53 protein and is sometimes called \u2018the guardian of the genome\u2019,18Recent large-scale whole-genome and whole-exome sequencing studies have shown that both OAC and dysplastic BO harbour a very high TP53 mutation rate of up to 70%,We aimed to resolve the existing uncertainty regarding the prognostic value of TP53 for staging OAC by conducting a systematic review and meta-analysis of all published data with subgroup analysis of studies assessed as low risk of bias, and studies using direct TP53 gene mutation analysis techniques to determine TP53 mutation status, since these are the most accurate methods for determining tumoural TP53 mutations.Gastroenterology), American Society for Clinical Oncology and American Association for Cancer Research from 1990 to 2015.The electronic bibliographic databases MEDLINE, Embase, PubMed and Current Contents Connect were searched to identify eligible studies published between January 1990 and 8 February 2015 using MeSH terms and text words for adenocarcinoma*, o/esophagus* or o/esophageal*, TP53* or p53* or 17p13* or 17p*. In an attempt to minimize the risk of publication bias, conference abstracts and proceedings were searched through Web of Science, Embase and Scopus using the terms o/esophagus* and p53*. Further, the following major GI and oncological conferences were searched for relevant reports: Digestive Disease Week scanned the search results (title and abstract) and retrieved full text publications using the criteria outlined below to identify eligible studies. Reference lists of relevant studies identified from the search including reviews were further screened to identify studies that may not have been identified by the strategy outlined above.Study inclusion criteria were prospective or retrospective clinical studies of OAC populations that assessed TP53 mutation status and/or p53 expression in primary tumours, and compared overall survival for TP53 mutation versus TP53 non-mutation subgroups with calculation of HR and 95% CIs, or reported adequate data for their estimation. To include all available data, we also included studies of oesophageal cancer cohorts that included patients with squamous cell carcinoma if at least \u226550% of the patient cohort had a diagnosis of OAC.Study exclusion criteria were studies of TP53 DNA germline mutations or autoantibody detection in blood; and reports available in abstract form only that did not report adequate information to determine study eligibility or to assess study methods for risk of bias.If studies did not report sufficient data to calculate HRs or in case of missing/unclear data, the corresponding author was contacted by email to request this information. If the same research unit (identified from author names and institution) published multiple reports with overlapping patient recruitment time periods, HR estimates were extracted from the most recent publication with the largest patient numbers to avoid duplication of data.Three investigators reviewed eligible studies and extracted the following variables into a standardised data extraction form: author's name; publication year; country where study was conducted; number of patients included and general patient demographics; tumour histology (number and proportion of OAC tumours included); treatment modality ; tissue specimen type ; TP53 assay methods , immunohistochemistry (IHC), and type of antibody, dilution for IHC); criteria or cut-point used to define TP53 mutation status for the survival analysis; study prevalence of TP53 \u2018mutation\u2019 and \u2018non-mutation\u2019 subgroups; median survival of all patients and by TP53 mutation status; unadjusted and adjusted HR with 95% CI and corresponding p values where available. For consistency and to facilitate further quantitative analyses, the authors\u2019 definitions for TP53 \u2018mutations\u2019 were used for studies performing only IHC as the respective studies did not use uniform staining classification criteria. As such, nuclear p53 protein overexpression was interpreted to represent TP53 mutations by all authors of the included studies, although loss of p53 protein expression has also been associated with tumoural TP53 gene mutations.http://www.gradeworkinggroup.org),et al's27All studies were assessed for risk of bias for the study estimate of the impact of TP53 on survival by appraising six domains using prespecified criteria adapted from the Grading of Recommendations, Assessment, Development and Evaluation TP53 mutation database (R17)10.1136/gutjnl-2015-310888.supp1Supplementary materialsTo estimate the effect of TP53 mutation status on OAC survival, we calculated a pooled HR and 95% CI using the generic inverse variance method. If the HR was not reported, it was estimated from the corresponding Kaplan\u2013Meier curves using the Parmar method.2 statistic.27Because different TP53 mutation analysis methods were used across studies, we expected heterogeneity in study estimates of the TP53 mutation effect on survival, and thus we applied a random-effects model to estimate the HR.Sensitivity analysis was performed to assess the impact of tumour histology and assay type on survival by repeating the pooled HR analysis in the following subgroups: (i) OAC-only versus OAC-mixed study populations; (ii) IHC versus direct TP53 gene mutation analyses; and (iii) studies assessed as having low versus high risk of bias. Differences between subgroups were assessed with a test for interaction.34ggplot2 package.metafor and forestplot for R.38Descriptive statistics as well as quantitative analysis of the IARC TP53 mutation database to guide risk of bias assessment were performed using R statistical softwareThe search strategy yielded 323 studies, of which 16 met our eligibility criteria . Study cHalf of the studies (n=8) assessed TP53 mutation status by IHC,The clinicopathological variables and survival times reported in the included studies are summarised in HRs were reported in nine studies and extrapolated from five studies. In addition, individual patient data were available for two studies to calculate tumour stage-adjusted HR and 95% CIsFour studies2=33%, p heterogeneity=0.1). The analysis of studies including pure OAC patient cohorts showed similar results with low heterogeneity compared with studies performing direct TP53 gene assessments (sequencing and SSCP) or LOH analyses . This difference was borderline statistically significant (p for interaction=0.05). A similar effect was seen in the subset of studies containing pure OAC cohorts . This effect size was similar in the three studies with low risk of bias that contained pure OAC cohorts and the study appraised as being at low risk of bias were significant sources of heterogeneity .This study indicates that mutated TP53 negatively impacts overall survival in patients with OAC, independent of tumour stage. This effect is estimated as a relative increase in hazard of death of 48%, with up to a 211% increase when studies of mixed histology cohorts or high risk of bias are excluded. This corresponds to a reduced survival time of approximately 7\u2005months based on median survival from the included studies. This effect size is similar to the difference in median survival of stage IIIA compared with stage IIIC OAC.55To our knowledge, this is the first comprehensive systematic review and meta-analysis of the prognostic impact of TP53 mutations in patients with OAC that includes an assessment independent of tumour stage. Two previous systematic reviews and meta-analyses of various prognostic biomarkers in OAC have included an analysis of TP53 mutations.This study is timely because recent whole-genome sequencing studies have shown a high mutation rate of TP53 in OAC.58One potential explanation for earlier conflicting results for the prognostic significance of TP53 status in OAC is the use of different and potentially less accurate assay methods for TP53 mutation detection. Our study identified considerable variability in IHC methods across the included studies, such as the use of different antibodies, antibody dilutions and variable scoring systems for immunopositivity. Further, none of the included studies used loss of p53 expression as a method for interpreting the presence of TP53 gene mutations.22Recent genomic studies have found that TP53 gene mutations remain the most common genetic alteration in both OACet al,The two main limitations of this study that may affect the validity of our findings are the quality of the primary studies and data limitations to explore potential confounders. First, more than half of the studies were assessed as high risk of bias based on criteria defined by Hayden Further studies are warranted to better estimate the size of the prognostic effect independent of tumour, node, metastasis staging. Given the substantial amount of heterogeneity identified, adherence to REMARK guidelineshttp://www.clinicalTrials.gov identifier NCT00525200; http://www.p53.at) has recently completed recruitment. Moreover, multiple therapeutic options directly targeting the TP53 gene are either currently in clinical trials or are already clinically available.One approach to collect high-quality data is to include TP53 mutation analysis using targeted gene sequencing in the baseline analysis of trials of OAC therapies. If validated, TP53 analysis could be used to stratify patients in future trials. Stratifying patients based on TP53 mutation status may also have a role in clinical practice to guide treatment selection. For example, data suggest that TP53 mutation status may predict response to standard chemotherapeutic regimens such as fluorouracil or cisplatin,In summary, OAC remains one of the few GI malignancies for which molecular information is still not used to guide patient management. This study suggests that TP53 gene mutations have a clinically important negative prognostic impact on patients with OAC, which is relevant in light of recent genomic findings highlighting a central role of this gene in OAC pathogenesis and drugs currently in development and testing that directly target this gene. High-quality studies with large patient cohorts using modern sequencing technologies for TP53 mutation analysis are needed to confirm the independent prognostic effect of this frequent gene mutation."} +{"text": "This data aimed to audit the dental sciences related articles published in Iranian Journal of Basic Medical Sciences (IJBMS) from 2007 to 2015 over a 9 year period performed using web-based search. The data were analyzed for topic of dental sciences, type of article, international collaborations, source of funding, number of authors and authorship trends. Out of the total 18 data related to dental sciences, original articles (12), review articles (4) and short communications (2) contribute the major share. Regarding the relationship with dental sciences, the maximum number of data were related to oral pathology and microbiology (16) followed by oral medicine and radiology (7) and periodontics (7). Among the data related to dental sciences, oral cancer (3) and gingival and periodontal diseases (3) followed by dental plaque and caries (2) and orthodontic tooth movement (2) form the major attraction of the contributors. The largest numbers of data related to dental sciences were received from Mashhad University of Medical Sciences, Mashhad (4) and Tehran University of Medical Sciences,Tehran (2).The present data were compared with previous bibliometric studies done related to dental sciences Specifications TableValue of the data.\u2022These date describe the majority of dental sciences articles published as original articles (12),review articles (4) and short communication (2)\u2022These data describe specialty wise majority of dental articles related to oral pathology and microbiology (16) followed by oral medicine and radiology (7),periodontics (7), community dentistry (2),orthodontics (2), prosthodontics (1) and oral and maxillofacial surgery (1).\u2022These data describe topic wise majority of dental articles related to oral cancer (3) and gingival and periodontal diseases (3) followed by dental plaque and caries (2) and orthodontic tooth movement (2)\u2022The data presented in this paper can be used as a guide for conducting similar studies around the globe.These data describe the dental sciences related articles published in a Basic Medical Sciences Journal from Iran.1See 2http://ijbms.mums.ac.ir/ .Bibliometric information about dental sciences articles data in a clinical medical journal from Iran and ayurveda journals from India is evident in the literature The data published were analyzed for topic of dental sciences, type of article, international collaborations, source of funding, number of authors and authorship trends.The data regarding articles in press (articles that are not yet assigned to an issue) in IJBMS were excluded. The contents of the data were grouped into seven individual dental sciences specialities such oral pathology and microbiology, oral medicine and radiology, oral and maxillofacial surgery, periodontics, prosthodontics, orthodontics and community dentistry. The data was scrutinized for dental sciences related topic. The datas which are interdisciplinary in approach were counted under all the dental sciences specialities it belonged. The data were checked for authorship trends according to the institution of the first author.The data was analyzed using descriptive statistics."} +{"text": "Since 2011, the New York City (NYC) Department of Health and Mental Hygiene (DOHMH) has typically been notified of three or fewer cases of hepatitis A virus (HAV) infection each year among men who have sex with men (MSM) who reported no travel to countries where HAV is endemic. This year, DOHMH noted an increase in HAV infections among MSM with onsets in January\u2013March 2017, and notified other public health jurisdictions via Epi-X, CDC\u2019s communication exchange network. As a result, 51 patients with HAV infection involving MSM were linked to the increase in NYC.Confirmed cases were defined as symptomatic HAV infections with onset after December 31, 2016, in NYC residents who reported being MSM or having sexual contact with MSM, and reported no travel to areas of high or intermediate HAV endemicity. Probable cases were defined as onset of symptomatic HAV infection after December 31, 2016, in NYC residents who, irrespective of travel, reported being MSM or having sexual contact with MSM. For the period January 1\u2013August 31, 2017, DOHMH identified 46 cases in MSM or persons with sexual contact with MSM; 36 confirmed and nine probable cases occurred in 45 MSM patients and one was in a female (confirmed case) who reported sexual contact with a bisexual male resident of a New York county outside New York City. Fifteen (33%) of the 46 patients were hospitalized, and three (7%) reported previous receipt of hepatitis A vaccine. Nineteen (41%) patients had traveled domestically during their incubation period, and eight (17%) had traveled to Western European countries where outbreaks of HAV infection among MSM are ongoing (NYC routine surveillance identified another case of HAV infection (in addition to the 46 NYC patients), in a man who was hospitalized in New York City but resided in the New York county that had been visited by the female patient. Several Colorado jurisdictions also contacted DOHMH to report increases in HAV infections among MSM. In total, 51 patients were linked to the increase in NYC, either through epidemiologic or laboratory evidence, including five non-NYC patients .Three of the 46 NYC patients and the one patient from Oregon reported sexual contact with four NYC outbreak patients . The OreSerum specimens from 25 NYC MSM patients, the NYC female patient, and the New York (non-NYC) MSM patient were sent to CDC\u2019s Division of Viral Hepatitis Laboratory for molecular sequencing. Sequences of HAV isolated from the serum of 24 patients, including four of the eight who had traveled to Europe, matched the strains of genotype IA HAV circulating among European MSM: HAV16\u2013090 (14 patients), VRD_521_2016 (eight), V16\u201325801 (two); two patients had sequences matching three Colorado MSM patients, and one had a unique sequence .Only three patients with HAV infection reported previous receipt of HAV vaccine; this ongoing investigation highlights the importance of HAV vaccination among MSM, and of determining MSM status during HAV investigations. One patient received 1 dose (as postexposure prophylaxis), but the doses for the other two patients were unknown; both reported previous receipt of HAV vaccine but did not know the number of doses. Since 1996, the Advisory Committee on Immunization Practices has recommended that all MSM receive 2 doses of HAV vaccine administered at least 6 months apart ("} +{"text": "Nature Communications7 Article number:11362 10.1038/ncomms11362 (2016); Published 05062016; Updated 09292016.The HTML version of this Article previously published omitted Supplementary Data 8. This has now been corrected in the HTML version of the Article; the PDF was correct from the time of publication."} +{"text": "The A2AAR is widely expressed on cells of the immune system and numerous in vitro studies have identified its role in suppressing key stages of the inflammatory process, including leukocyte recruitment, phagocytosis, cytokine production, and immune cell proliferation. The majority of actions produced by A2AAR activation appear to be mediated by cAMP, but downstream events have not yet been well characterised. In this article, we review the current evidence for the anti-inflammatory effects of the A2AAR in different cell types and discuss possible molecular mechanisms mediating these effects, including the potential for generalised suppression of inflammatory gene expression through inhibition of the NF-\u03baB and JAK/STAT proinflammatory signalling pathways. We also evaluate findings from in vivo studies investigating the role of the A2AAR in different tissues in animal models of inflammatory disease and briefly discuss the potential for development of selective A2AAR agonists for use in the clinic to treat specific inflammatory conditions.The production of adenosine represents a critical endogenous mechanism for regulating immune and inflammatory responses during conditions of stress, injury, or infection. Adenosine exerts predominantly protective effects through activation of four 7-transmembrane receptor subtypes termed A"} +{"text": "Altered immune response is associated with many psychiatric disorders, but whether and how these changes confer increased risk remains unclear. In schizophrenia, robust association between illness risk and the MHC region general, and complement component 4 (C4) specifically, has been demonstrated, along with evidence from both gene enrichment and other genetic analysis highlighting the broader role of genetic variation in additional immune related networks to schizophrenia risk.In a series of recent studies from our group, we examined the effects of immune-related genetic variation, based on gene ontology, implicated in neural function both behaviourally in samples of ~1200 cases and controls, and cortically in samples of ~150 cases and controls.We found that (1) increased predicted C4A RNA expression predicted poorer performance on measures of memory recall and a pattern of reduced cortical activity in middle temporal cortex during a measure of visual processing ; (2) variation in a curated gene set associated with both increased Schizophrenia risk and immune function were associated with both variation in both episodic memory and general cognitive ability.Based on these findings we conclude that schizophrenia risk associated with variation within immune related genes is likely to be conferred at least partly via effects on cognition, and the molecular mechanisms involved may include effects on inflammatory response."} +{"text": "TNNT1) was found in the Amish populations in Pennsylvania and Ohio. This single nucleotide substitution causes a truncation of the ssTnT protein at Glu180 and the loss of the C-terminal tropomyosin (Tm)-binding site 2. As a consequence, it abolishes the myofilament integration of ssTnT and the loss of function causes an autosomal recessive nemaline myopathy (NM). More TNNT1 mutations have recently been reported in non-Amish ethnic groups with similar recessive NM phenotypes. A nonsense mutation in exon 9 truncates ssTnT at Ser108, deleting Tm-binding site 2 and a part of the middle region Tm-binding site 1. Two splicing site mutations result in truncation of ssTnT at Leu203 or deletion of the exon 14-encoded C-terminal end segment. Another splicing mutation causes an internal deletion of the 39 amino acids encoded by exon 8, partially damaging Tm-binding site 1. The three splicing mutations of TNNT1 all preserve the high affinity Tm-binding site 2 but still present recessive NM phenotypes. The molecular mechanisms for these mutations to cause myopathy provide interesting models to study and understand the structure-function relationship of TnT. This focused review summarizes the current knowledge of TnT isoform regulation, structure-function relationship of TnT and how various ssTnT mutations cause recessive NM, in order to promote in depth studies for further understanding the pathogenesis and pathophysiology of TNNT1 myopathies toward the development of effective treatments.Troponin T (TnT) is the sarcomeric thin filament anchoring subunit of the troponin complex in striated muscles. A nonsense mutation in exon 11 of the slow skeletal muscle isoform of TnT (ssTnT) gene ( A nonsense mutation in TNNT1 was first identified in the Old Order Amish in the C-terminal end segment, partial deletion (W287ter) or error-splice out of exon 17 encoding this segment in cardiac TnT have been found to cause cardiomyopathy , slow skeletal muscle (TNNT1) and fast skeletal muscle (TNNT3) isoforms of TnT expresses exclusively slow skeletal muscle TnT together with cardiac forms of TnI and myosin express only cardiac TnT in the cardiac muscle. Analysis of cardiac function demonstrated that toad hearts generated lower maximum stroke volume but significantly higher resistance to the increase of afterload than that of frog hearts contains 14 constitutively expressed exons and three alternatively spliced exons encoding a short segment of 2 or 3 amino acids between the T1 and T2 regions of mammalian cardiac TnT each encoding a segment of 14 amino acids also occurs in TNNT3 gene undergoes a high to low molecular weight, acidic to basic isoelectric point splice form switch during development due to alternative inclusions of N-terminal exons , but not type 2, Charcot-Marie-Tooth disease was reported in 9 Palestinian patients from 7 unrelated families with recessively inherited NM did not report notable clinical symptom (Johnston et al., TNNT1 myopathies may cause conditional slow TnT deficiency with symptoms such as experiencing conditional fatigue intolerance and other slow muscle-related dysfunctions.Genetically modified mice with a knockdown of the expression of slow TnT exhibited decreased muscle resistance to fatigue (Feng et al., The potential cytotoxicity of non-myofilament associated slow TnT fragments (Jeong et al., The transient expression of cardiac TnT and embryonic splice forms of fast skeletal muscle TnT in embryonic and neonatal skeletal muscle may explain the postnatal onset of ANM (Jin et al., TNNT1 myopathy patients should be able to readily rescue muscle growth and functions. The maintained slow fiber cellular environment and active regeneration also indicate that translational read-through of the nonsense stop codon in the muscles of ANM and S108ter patients may effectively restore muscle function and growth.Soleus muscle of slow TnT knockout mouse maintains a slow fiber cellular environment and exhibits signs of active regeneration (Wei et al., TNNT1 myopathies is no longer considered as a isolated disease of the Amish, and the power of genetic testing is anticipated to identify more myopathic mutations of the gene, researchers are urged to add joint effort in TnT gene expression and structural-function relationship studies, including the utilization of genetically modified mouse models of the human diseases, toward the development of effective targeted treatment of these lethal muscle diseases.Since TNNT1 myopathies demonstrate an excellent example for what we can learn from pathogenic mutations of a myofilament protein as well as how knowledges learned from protein structure-function relationship research can help us to understand the pathogenesis and pathophysiology of genetic diseases. Therefore, we hope this focused review will benefit readers with the vision beyond TNNT1 myopathy studies.In conclusion, AM: Drafting and revising the text, making figures, approval submission; JJ: Deciding the topic and contents, drafting and revising the text, making figures, approval submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "We present a review of the literature on Primary Progressive Aphasia (PPA) together with the analysis of neuropschychological and neuroradiologic profiles of 42 PPA patients. Mesulam originally defined PPA as a progressive degenerative disorder characterized by isolated language impairment for at least two years. The most common variants of PPA are: (1) Progressive nonfluent aphasia (PNFA), (2) semantic dementia (SD), (3) logopenic progressive aphasia (LPA). PNFA is characterized by labored speech, agrammatism in production, and/or comprehension. In some cases the syndrome begins with isolated deficits in speech. SD patients typically present with loss of word and object meaning and surface dyslexia. LPA patients have word-finding difficulties, syntactically simple but accurate language output and impaired sentence comprehension. The neuropsychological data demonstrated that SD patients show the most characteristic pattern of impairment, while PNFA and LPA overlap within many cognitive domains. The neuroimaging analysis showed left perisylvian region involvement. A comprehensive cognitive, neuroimaging and pathological approach is necessary to identify the clinical and pathogenetic features of different PPA variants."} +{"text": "DEAR EDITOR1Studies of quality of life measures in scar patients reveal significant interference with physical comfort as well as in social and professional life. The lay population often refers to a scar as an unsightly healed wound. Conversely, surgeons tend to think of surgical scars as an expected outcome of a violation of the dermis. Before initiating treatment, the physician must take the time to understand and diagnose each element. The extent of scar must be considered along with the patient\u2019s intent in getting treatment.2,3This is a prospective study of 50 cases of scar revision performed in our department from 2011- 2014. Mature scars more than 2mm in diameter broad were included in the study. Patients were analysed in terms of patient satisfaction with the post-operative outcome. Patients were followed up for a minimum period of 6 months. Exclusion criteria were (i) pregnant patients, (ii) paediatric patients and (iii) patients with a follow up period of <6 months. Patients were analysed regarding their satisfaction with their post-operative outcome in the form of scar related parameters and psychological parameters. Post-operative patient satisfaction was assessed using pre and post procedure Vancouver Scar Scale scores.The largest number of cases were seen in the age group 16-30 years (78%), of which 21 patients (53.8%) were satisfied with the outcome of their corrective procedure. The preponderance in this age group could be due to the fact that young adults are highly conscious regarding their appearance . Among 2The incidence of post-operative satisfaction was slightly higher among 25 unmarried enrolled patients (60%) compared to 25 studied married patients (52%). No significant difference in post-operative satisfaction could be found in patients with decreased (n=10) or unchanged scar visibility (n=10) following operative procedure. Scars which were converted to lie parallel to Relaxed Skin Tension Lines (RSTL) were seen to have the maximum satisfaction with post-operative results (83%) compared to other patients (72%). However the small number of patients in the category (5 and 8 patients) precludes any statistically significant difference to be obtained. Eighteen patients noticed gain of function of the affected part following scar revision (n=38).All patients with gain of function in the affected part showed satisfaction with their post-operative outcome. The highest incidence of post-operative satisfaction correlates with anxiety relief following correctional procedure (84% of 13 enrolled patients). The highest post-operative satisfaction was seen to correlate with alleviation of depression following correctional procedures (89% of 19 studied patients). No significant difference was seen in post-operative satisfaction rates in patients with either increased or high self-esteem following surgical procedure. However patients with low self-esteem demonstrated lower satisfaction rates compared to their counterparts (40% vs. 56% and 60%). The highest percentage of post-operative satisfaction was seen in patients with improved social acceptance following correctional procedure (73%) when compared to others (50% and 30%). Patients with change of 4 or more between pre and post operative Vancouver Scar Scale scores were satisfied with the outcome of the revisional procedures while those with scores less than 4 were either dissatisfied or neither satisfied nor dissatisfied with the outcome. Post-operative satisfaction in an individual is multifactorial. Females appear to be marginally more satisfied as compared to males with their post operative outcomes. Patients who underwent correctional procedures for cheek scars showed maximum satisfaction post operatively probably because the cheek is an exposed area and defects if an are promptly visible. Even a small improvement in a scar in such a cosmetically important area can bring great satisfaction to the patient.4,5 Following scar revisional procedures, marked reduction in anxiety and depression as compared to pre-operative status was noticed. Also, patients with low self esteem tended to be unsatisfied with their post operative outcome. Increased social acceptance, either real or apparent, could be a major factor leading to this conclusion. Patients in whom scars came to lie parallel to or within RSTL\u2019s post operatively, as compared to pre-operative status in which they did not, showed the maximum level of satisfaction with their corrective procedures.The authors declare no conflict of interest."} +{"text": "Coxiella burnetii infection(s). Use of these methods and development of criteria to define and treat such infections, especially cardiovascular infections, will improve the prognosis for patients previously thought to have chronic Q fever.Modern diagnostic methods enable clinicians to look beyond a diagnosis of chronic Q fever and discern whether patients instead have persistent focalized We read with interest the article by Kampschreur et al. (Coxiella burnetii infection(s). The obsolete term chronic Q fever should be abandoned to prevent confusion between endocarditis, vascular infections, osteoarticular infections, lymphadenitis, genital infection, and pericarditis, which occurred in 68%, 20%, 7%, 6%, 3%, and 1%, respectively, of 494 patients with persistent focalized infection(s) who we followed during 2007\u20132015 at the French National Referral Center for Q Fever in Marseille, France (unpub. data).Kampschreur et al.\u2019s use of the term chronic Q fever is misleading because it may lead to inadequate treatment of persistent focalized Another example of the deleterious effect of the Dutch Q Fever Consensus Group guidelines is the absence of screening echocardiography in the standard work-up for patients with Q fever in the Netherlands and by avoiding drug side effects in patients with isolated elevated serologic test results. Clinicians should look beyond a diagnosis of chronic Q fever to determine whether a patient might have persistent focalized infection(s). The term fever in Q fever has evolved from a pathologic picture per se to a clinical epiphenomenon; it is now time to evolve from the concept of chronic Q fever to one of persistent focalized C. burnetii infection(s) (Accurate identification of persistent focalized"} +{"text": "Magnetic resonance (MR) imaging has become an important diagnostic tool for the detection of impaired myocardial motion, which has been considered as a common consequence of most ischemic or non-ischemic heart diseases. Both cine DENSE and TPM have been independently adopted to delineate abnormal regional myocardial motion patterns for the estimation of the progression of cardiovascular diseases or for the evaluation of individual cardiovascular responses to treatments. However, although the similarities and differences between cine DENSE and TPM are well understood from a technical point of view, the interchangeability of those two imaging techniques in cardiovascular risk stratification is still not fully understood. The aim of the present study was to test the hypothesis that clinical metrics derived from cine DENSE and TPM are correlated for characterizing regional myocardial motion.This study complied with HIPAA regulations. Thirteen healthy volunteers and 4 asymptomatic recipients of heart transplant (HTx) were recruited following the approval of the institutional review board (IRB). For each participant, two-dimensional (2D) cine DENSE and TPM were performed at basal, midventricular and apical locations at the left ventricle (LV) with the short-axis view. DENSE-derived myocardial metrics, including peak radial strain (Err), circumferential strain (Ecc), first principal strain (E1), second principal strain (E2) and twist were measured and correlated with TPM-derived indices, including peak radial velocity (Vr), circumferential velocity (V\u03a6) and time to peak (TTP) in systole and diastole using Pearson correlation coefficient (r).DENSE and TPM data were successfully acquired in 17 participants and resulted in 51 data points for comparisons. On a per-slice basis, peak Err had moderate correlations with peak Vr in systole and in diastole . Peak E1 was moderately associated with Vr-sys and Vr-dia . Peak twist was moderately correlated with peak V\u03a6 in diastole . See figures DENSE and TPM can provide correlated clinical metrics for quantitatively characterizing regional myocardial motion from different technical aspects."} +{"text": "ER causing neuropathology and memory loss in AD. This review highlights molecular signatures of UPRER and its key molecular alliance that are affected in aging leading to the development of intriguing neuropathologies in AD. We present a summary of recent studies reporting usage of small molecules as inhibitors or activators of UPRER sensors/effectors in AD that showcase avenues for therapeutic interventions.Alzheimer\u2019s disease (AD), a neurodegenerative disorder, is most common cause of dementia witnessed among aged people. The pathophysiology of AD develops as a consequence of neurofibrillary tangle formation which consists of hyperphosphorylated microtubule associated tau protein and senile plaques of amyloid-\u03b2 (A\u03b2) peptide in specific brain regions that result in synaptic loss and neuronal death. The feeble buffering capacity of endoplasmic reticulum (ER) proteostasis in AD is evident through alteration in unfolded protein response (UPR), where UPR markers express invariably in AD patient\u2019s brain samples. Aging weakens UPR Alzheimer\u2019s disease (AD), the most common form of dementia faced by more than 40 million people worldwide, significantly affect morbidity and mortality in aged people imposed on the neuronal cell due to misfolded protein aggregates. Also, we have discussed various therapeutic interventions targeting the molecules involved in UPR pathways aiming at averting the neuropathologies of AD.The expression pattern of neurodegenerative pathologies shows distinct molecular signatures, such as misfolded A\u03b2 aggregation and tau protein hyperphosphorylation in the brain microenvironment like nutrient deprivation, changes in redox potential, calcium homeostasis, hypoxia and accumulation of unfolded/misfolded protein triggers the UPRER embodies a complex network comprised of three stress-responsive transmembrane proteins, Protein Kinase RNA like ER kinase (PERK), Inositol Requiring Element 1 (IRE1) and Activating Transcription Factor 6 domain models expressing aggregation-prone mutant tau variants, XBP-1 was identified to be playing a similar protective role ensuing after accumulation of unfolded peptide load is well documented. The pathway focuses on invigorating folding and degradation of misfolded peptides in mitochondrial matrix through the execution of retrograde transcriptional activation , but also showed reduction in beta-amyloid aggregation in worms and transgenic mouse models of AD revealed a deranged glucose metabolism in brain regions. Aging registers diminished brain glucose utilization that surges in AD instates mitigating effect on hexosamine pathway (HBP), due to which O-GlcNAcylation is compromised with hyperphosphorylation on tau protein when fed with the drug metformin showed mitigated levels of GRP78 with ensuing gain in lifespan, additionally the expression of GLUT1 and its association with the beginning of UPRER exerted neuroprotective effect , has been known to inhibit BACE1 translation through dephosphorylation of eIF2\u03b1-P resulted in establishing long-term hippocampus memory (Mart\u00ednez et al., 2+ equilibrium, thereby maintains the proper signaling in brain. The disruption in neuronal physiology is quite evident in age-related AD where ER dysfunctions are prominently expressed in the form of imbalance in proteostasis. Advancements in studies based on AD models have clearly shown how we can intervene the molecular pillars of UPRER and its associated signaling cascades to manage neurodegeneration in age-related AD. The present review is an attempt to revise functional relevance of the studies conducted in the field of management of age-related AD through therapeutic interventions on the UPRER pathway and its associate\u2019s molecules. Studies reinforce that the strategies where intervening the molecules, which are involved in transposing effects of aging on neurodegeneration, will cause reduction in probability of AD pathology. The manifestation of ER proteostasis is a direct indication of healthy nervous system. Progression in AD witnesses glucose hypo-metabolism in brain, reduction in glucose transporters in neurons and endothelial cells of blood brain barrier in direct proportion with the amount of neurofibrillary tangles. Type 2 diabetics with higher insulin resistance are at a greater risk of AD. Recent reports elucidate that managing UPRER can exert neuroprotective effect in AD (Smith and Mallucci, mt can impede plaque formation. Aliev et al., also demonstrated link between cancer and AD where mtDNA over-proliferation and deletion induces cell cycle dysregulation prompting oncogenic pathway (Aliev et al., ER, being a central organelle in nerve cells, coordinates with the cellular homeostasis by managing translation/modification of proteins and CaER in aging-induced neuropathology in AD can be ventured upon, so that pharmacological as well as genetic tools could underscore the significance of UPRER as well as UPRmt in aged brain.We still need extensive and efficient model systems where the molecular intricacies of weakened UPRSR and RM conceived the idea. SR, ATJ, AA and RM contributed to writing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "These models display progressive locomotor defects, disrupted organisation of the tubular ER and length-dependant defects in the axonal mitochondrial network. Here we compare our findings with those associated with more common forms HSP including: Spastin, Atlastin-1 and REEP 1 which together account for over half of all cases of autosomal dominant HSP. Furthermore, we discuss recent observations in other HSP models which are directly implicated in mitochondrial function and localization. Overall, we highlight the common features of our rare models of HSP and other models of disease which could indicate shared mechanisms underpinning neurodegeneration in these disorders.Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative conditions characterised by retrograde degeneration of the longest motor neurons in the corticospinal tract, resulting in muscle weakness and spasticity of the lower limbs. To date more than 70 genetic loci have been associated with HSP, however the majority of cases are caused by mutations that encode proteins responsible for generating and maintaining tubular endoplasmic reticulum (ER) structure. These ER-shaping proteins are vital for the long-term survival of axons, however the mechanisms by which mutations in these proteins give rise to HSP remain poorly understood. To begin to address this we have characterized Hereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative disorders characterised by the retrograde degeneration of the longest motor neurons (MNs) in the corticospinal tract, leading to muscle weakness and spasticity of the lower limbs.Historically HSP was grouped into two classifications: \u2018pure HSP\u2019 exclusively exhibiting lower limb spasticity and \u2018complicated HSP\u2019 in which patients presented with additional symptoms including dementia, seizures and amyotrophy in vivo studies consistently reveal that loss of ER-shaping proteins causes profound disruption to the organisation of the ER. Expression of an SPG3A mutant form of Atlastin-1 was found to alter ER-morphology in HeLa cells from a reticular to a more tubular organisationDrosophila nervous system results in visible fragmentation of the ERER-shaping proteins comprise intramembrane hairpin-loop domains by which they localise to and insert into the ER membrane. Spastin, Atlastin-1 and REEP1 are hairpin-loop domain containing ER-shaping proteins which account for ~50% of all autosomal dominant cases of HSP (AD-HSP). Spastin gene mutations cause spastic paraplegia 4 (SPG4) subtype, which represent about 40% of AD-HSPin vivo we have recently reported on models of HSP which we have generated and characterised in the fruit fly, Drosophila melanogasterDrosophila orthologs of RTN2 and ARL6IP1 (Rtnl1 and Arl6IP1 respectively). Gene knockdown models were selected as they likely reflect the loss-of-function genetic variants expressed in SPG12 and SPG61 patients. Mutations in RTN2 include a complete gene deletion and a frameshift mutation predicted to produce a highly truncated protein, suggesting that SPG12 acts via a haploinsufficiency mechanismTo begin to understand the role of ER-shaping proteins in MNs Drosophila MNs. Specifically, mitochondria appear increasingly elongated within axon bundles and mitochondrial load within neuromuscular junction synaptic boutons is significantly reduced in loss of Arl6IP1 and loss of Rtnl1 Drosophila . Importantly, these MAMs mediate mitochondrial fission in which the ER functions to mark mitochondrial constriction sites prior to the recruitment of mitochondrial fission factors such as dynamin related protein 1 (Drp1)s of HSP . In contWhile our Rtnl1 and Arl6IP1 models of HSP represent very rare forms of disease, family which act as microtubule motor proteins involved in the transport of membranous organelles. Mutations in KIF5A cause Charcot-Marie Tooth Disease Type 2 (CMT2) and SPG10Together these data suggest that disruption to the neuronal mitochondrial network, either directly via mitochondrial mutations or indirectly via disrupted tubular ER, underpins much of the axonal degeneration associated with HSP. Altered mitochondrial distribution could disrupt the bioenergetics of different cellular compartments, given the peculiar morphology of neurons with long axons and the requirement for energy at axonal terminals this may cause failure of normal neuronal function. This work illustrates how models of very rare forms of disease may provide novel insights into the molecular mechanisms underpinning HSP more generally and suggest novel targets for therapeutic investigation for these currently untreatable neurodegenerative disorders."} +{"text": "In 2016, CDC saw an increase in cases of acute flaccid myelitis (AFM); 144 persons in 37 states and the District of Columbia were confirmed to have AFM. After investigations in California (3 when corrected for red blood cells). A confirmed case must have an MRI demonstrating lesions restricted primarily to the gray matter of the spinal cord, in addition to acute onset of flaccid limb weakness , but MRI results indicated alternative etiologies . The case that met the probable case definition had pleocytosis (CSF WBC = 7/mm3), but MRI findings were inconsistent with AFM, and no other plausible diagnosis was identified.The 2015 Council of State and Territorial Epidemiologists and CDC case definition for probable AFM requires acute onset of flaccid limb weakness and cerebrospinal fluid (CSF) pleocytosis or gastrointestinal illness (one patient), with onset dates for those illnesses occurring during August 14\u2013September 13. Their illness began a median of 2 days (range = 2\u20135 days) before onset of focal limb weakness; three patients experienced tactile or measured fever preceding onset of neurologic symptoms . Among p3 (range = 50\u2013207), and initial viral testing at the hospital included CSF reverse transcription\u2013polymerase chain reaction (RT-PCR) assays for enterovirus (three patients) and West Nile virus (WNV) (two patients), polymerase chain reaction (PCR) assay for herpes simplex virus (two patients), and enzyme immunoassay to detect immunoglobulin M (IgM) or immunoglobulin G (IgG) for WNV (three patients). All results were negative. All four CSF specimens were negative on TGen amplicon sequencing assay . Serum collected from one patient at initial evaluation was negative for WNV IgM and IgG on a hospital immunoassay; serum collected from the same patient 47 days after onset of focal limb weakness and from two additional patients were negative for WNV IgM and St. Louis encephalitis IgM at the Arizona State Public Health Laboratory.CSF was collected from all four patients with confirmed AFM. Median CSF WBC count was 133/mmThree of the four patients had nasopharyngeal (NP) swabs available from initial evaluation that were forwarded to CDC; one specimen was positive for enterovirus/rhinovirus on a panviral respiratory PCR panel at the admitting hospital laboratory and for EV-D68 at CDC. RNA extracted from NP swabs from all three patients was positive by the TGen amplicon sequencing test for EV-D68 (GenBank Bioproject); an NP specimen from a patient who did not meet the AFM confirmed or probable case definitions also was positive for EV-D68 by the same assay.Stool specimens were collected from two patients at the time of initial evaluation; vital cultures of these specimens were negative on viral. One available specimen and three additional specimens, collected 28, 47, and 63 days after onset of focal limb weakness, were sent to CDC for four enterovirus/parechovirus RT-PCR assays. A stool specimen, collected at day 28 from the patient who did not have an NP swab available, was positive for coxsackievirus A10.This cluster of AFM at one children\u2019s acute care hospital is the largest cluster identified to date in Arizona and is part of a nationally identified increase in AFM cases. Although no statewide surveillance system specific to AFM is available, this cluster was detected by physician reporting, highlighting the need for physicians to remain vigilant for this emerging disease and to report cases that fit the AFM case definition to their local health department. Metagenomic analyses identified EV-D68 in NP swabs from the three patients for whom specimens were available, along with a specimen from a patient who did not meet the AFM case definition; therefore, no single etiology or risk factor was associated with only confirmed cases. Patient and family history of asthma was the most common comorbidity reported among confirmed AFM cases and should be considered in future case investigations. Expanded analysis of infectious, postinfectious, and noninfectious etiologies might provide further insight into the mechanism of AFM."} +{"text": "Epidemiology of drug resistant HIV has focused on trends and less attention has been given to identification of factors, especially behaviors including substance use, in acquisition of drug-resistant HIV. From 2009 to 2012 The Metromates Study enrolled and followed for one year men who have sex with men (MSM) seeking testing for HIV in a community clinic in Los Angeles assessing those testing positive for acute and recent HIV infection. Behavioral data were collected via Computer-Assisted Self-Interview from 125 classified as newly HIV infected and 91 as chronically infected (newly HIV-diagnosed); specimens were available and viable for resistance testing for 154 of the 216 HIV positives with new diagnoses. In this community clinic we found prevalence of resistance among MSM with new HIV-diagnosis was 19.5% (n = 30/154) with no difference by recency of HIV infection. Sexual partnership characteristics were associated with resistance; those who reported transgendered sex partners had a higher prevalence of resistance as compared to those who did not report transgendered sex partners , while those who reported having a main partner had a lower prevalence of drug resistance . In multivariable analyses adjusting for HIV recency and antiviral use, reporting a main partner decreased odds , reporting a transgendered partnered increased odds ; and being African American increased odds of drug resistance . This suggests African American MSM and TG individuals in Los Angeles represent pockets of exceptional risk that will require special approaches to prevention and care to enhance their own health and reduce their likelihood to support transmission of drug resistance in the US. Among those with a new diagnosis of HIV infection, some are infected by a strain of HIV-1 resistant to one or more drugs, known as primary or transmitted drug resistance (TDR) but evidBetween 2009\u20132012 321 MSM enrolled in the NIDA funded Metromates Cohort Study conducted at The Los Angeles LGBT Center, a community-based organization providing sexual health services, social services and HIV care in Los Angeles. Men at least 18 years of age reporting sex with a man in the past 12 months who sought HIV testing at the LGBT Center were offered an opportunity to undergo a consent process including a written consent with a full description of the study with choices about if and how to participate in specimen donation, and then were provided a copy of their written consent form . Those who tested HIV-positive provided a specimen for testing of recency of infection using the Vironostika detuned assay (BioSystems Laboratory in San Francisco) a validated assay for use of detection of early HIV infection, 14; negA Computer-Assisted Self-Interview (CASI) assessed sexual partner type ; types of sexual activity ; substance use . Also assessed was use of ARV drugs for treatment, pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP), substance use, and sexual behavior. \u201cTreatment status\u201d was determined from reports of date starting ARVs as some men started ARVs before enrollment due to a lag between communication of an HIV positive test result and study enrollment. Initiation of care was not an exclusion criteria for this analysis. The questions and scales used in this study were developed from two previous studies of men with acute HIV infection or previous diagnosis; with careful attention to included comparable questions/measures to the previous cohort that identified behavioral factors associated with resistant HIV \u201317. The http://hivdb.stanford.edu/). Samples were classified as \u201cresistant\u201d if results indicated reduced sensitivity to at least one class of ARVs.HIV genotyping was performed using stored plasma samples collected at study enrollment. The testing of those assessed as acutely infected (n = 104) was conducted at the HIV Genotyping Laboratory at Johns Hopkins University (JHU) and the other new diagnoses at University of California Los Angeles (UCLA) School of Medicine (n = 69). Testing at JHU was conducted using the ViroSeq HIV Genotyping System v2.8 . This system provides HIV sequences for the region encoding HIV protease (amino acids 1\u201399) and HIV reverse transcriptase (amino acids 1\u2013335). Testing at UCLA was done using the UltraSens Viral Isolation kit (Qiagen) according to the manufacturer\u2019s protocol. The Reverse Transcriptase (RT) and Protease (PRO) genes were amplified and sequenced according to the previously published protocol of Snoeck et al. using SuperScript III RT (Invitrogen) for RT and KOD high fidelity polymerase (Novagen) for PCR. PCR products were directly sequenced using the BigDye v3.1 Kit (Applied Biosystems) according to the manufacturer\u2019s protocol using the primers described in Snoeck et al. SequencDifferences in ARV drug resistance to at least one class of HIV drugs by demographics and behaviors were evaluated using t-tests, Wilcoxon rank sum, chi-square methods, Fisher\u2019s exact tests and multivariable logistic regression analysis. Behaviors included in the analyses were selected based on findings from the research team\u2019s previous work with this population and this topic, 17 as wAmong the 154 recently HIV-diagnosed MSM with testable plasma the mean age was 30 years, nearly half identified as Hispanic (48%), followed by white (29%) and African American (17%); 58% were identified as having an acute/recent HIV-infection. The median number of sexual partners in the past 12-months was eight [interquartile range (IQR) 4\u201320], with a median of two anonymous partners and one one-time partner. More than half the participants reported substance use in the past 3 months, including marijuana (41%), methamphetamine (20%), cocaine (15%), and opioids (3%). Eleven (7%) reported sex with both men and women; and 30 (19.5%) reported a transgender partner in the last 12 months; 30 (19.5%) reported transactional sex in the past 3 months. Between screening and enrollment 30 men (19%) had initiated ARV therapy. Among these HIV positive men more methamphetamine use was reported among newly infected than chronically infected .Drug resistance to at least one class of ARVs was identified in 30 (19.5%) of the 154 participants. Most of the resistance was to NNRTIs: 25/30 cases of resistance. The prevalence of ARV resistance did not vary significantly by HIV diagnosis group althoughReporting a main partner decreased odds of drug resistance , reporting a transgendered partnered increased odds ; and being African American increased odds of drug resistance .The prevalence of drug resistance of 19.5% among MSM in Los Angeles with new HIV diagnosis is relatively high compared to other reports even wheThe increased risk of resistance among men who have sex with transgendered (TG) partners is a new finding. TGs represent a marginalized group of individuals among whom adherence to HIV treatment is particularly poor and who Our findings point to the role of the main partner in providing protection against acquiring resistant virus and the increased risk with having casual partners. Clearly the more exposures, the more likely one of these is to someone with a resistant virus. Yet this also suggests that sexual networks are playing an increasingly important role in the transmission of resistance. It points to the need to counsel men without main partners that when they have unprotected sex with casual partners whose HIV status or use of therapy is unknown they may be at higher risk of acquiring resistant virus and that this has the potential to affect their therapeutic options.Our finding that African American MSM were more likely than other MSM in Los Angeles to acquire resistance raises continuing concerns about the epidemic among African American MSM. These men are most likely to acquire HIV in general in the US\u2013with African Americans representing half of all new infections in 2009 and AfriGiven the challenges of enrolling individuals into studies at the time of their HIV diagnosis and identifying those with acute or recent infection in any community, the sample size for this study was relatively small. This limited the power to more sensitively detect factors associated with resistance that were low prevalence. Although the study used computer-assisted interviewing and emphasized the conduct of the study in the most sensitive way for individuals with new HIV diagnosis, behavioral reports are always prone to mis-reporting and that could result in misclassification of participants in the analysis. Finally, the study and was initiated and tools developed in 2008 and earlier, when awareness of and well-developed tools for studying transgender individuals were not yet evolved fully limiting our ability to better study how them.Our findings support the rationale for examining behavioral characteristics of resistance because we could not confirm findings from earlier studies that identified strong use, notably methamphetamine use, as a driver of multi-resistant HIV suggestiThese findings indicate trends in HIV transmission patterns among MSM in Los Angeles. As a case of multi-drug resistant HIV has been documented among an individual on pre-exposure prophylaxis with emtricitabine (FTC)\u2013tenofovir disoproxil fumarate (TDF) that was identified as transmitted and not acquired there cl"} +{"text": "The mechanistic data presented in this interesting review suggests that long-term exposure to safe levels of ultra-violet radiation (UVR) has protective effects against the development of obesity and cardiovascular dysfunction beyond those induced by the cutaneous synthesis of vitamin D3 through factors such as the induction of cutaneous NO secretion . Evidenc"} +{"text": "This article contains one NVivo 10\u00ae file with the complete 432 projects design documents (PDD) of seven waste management sector industries registered as Clean Development Mechanism (CDM) under United Nations Framework Convention on Climate Change (UNFCCC) Kyoto Protocol Initiative from 2004 to 2014. All data analyses and sample statistics made during the research remain in the file. We coded PDDs in 890 fragments of text, classified in five categories of barriers (nodes): technological, financial, human resources, regulatory, socio-political. The data supports the findings of author thesis [4] Specifications TableValue of the data\u2022The UNFCCC raw data source is mixed up, disconnected, fragmented, and laborious.\u2022This data is all inclusive . Therefore, any other CAQCA can be immediately made for the WM sector.\u2022The data is standardized by UNFCCC, which means that it can be easily appended, replaced, compared or transposed to the others 14 sectors and 4.000 projects .\u2022The dataset is an instructive example of a Computer Assisted Qualitative Content Analysis (CAQCA) using the features of a CAQCA Software1Despite a clear indication that waste management research needs a more system-oriented approach This data article shares, in a single NVivo 10\u00ae software file, 432 large waste management projects design documents (PDD) from 2004 to 2014 1)the entire PDD documents;2)a qualitative data analysis (QDA) aiming the study of the project's designers declared barriers;3)results of a primary search for the stated barriers (890 text fragments);4)we code (hermeneutic) fragments into five barriers categories: technological, financial, human resources, regulatory, and socio-political.The sample selected from CDM Project Search site of UNFCCC The data is standardized following the main UNFCCC guidelines for any project 2The computer assisted qualitative content analysis (CAQCA) drives the data file design. CAQCA is a well-known methodology largely used in social applied and human sciences The use of software to treat a large volume of data produced almost in real time had a significant impact on research institutions and doctoral programs because part of those research without the QDAS would be impractical and impossible. This fact explains why the more Universities offers the QDAS at an institutional level The search criteria used to the content selection (raw data) from the UNFCCC Project Search site The projects have many possible statuses . We choose the registered status because no other guarantees UNFCCC consent for the registered operation. At last, the sort by reference number is strategic considering that the computer database key-index system is more reliable than registration date.The results by the host country and year are in the original article There is also an abnormal concentration of 124 projects in 2012 After the simple search for the term \u2018barrier\u2019 that returned more than a thousand occurrences, took place the coding second part by semantic-hermeneutic analysis of fragments. Some of these fragments proof meaningless and discarded. The rest classified in categories for future interpretation and pattern identification."} +{"text": "Functional neurological changes after surgery combined with diffusion tensor imaging (DTI) tractography can directly provide evidence of anatomical localization of brain function. Using these techniques, a patient with dysgraphia before surgery was analyzed at our hospital in 2011. The patient showed omission of kana within sentences before surgery, which improved after surgery. The brain tumor was relatively small and was located within the primary sensory area (S1) of the inferior parietal lobe (IPL). DTI tractography before surgery revealed compression of the branch of the superior longitudinal fasciculus (SLF) by the brain tumor. These results suggest that the left SLF within the S1 of IPL plays a role in the development of dysgraphia of kana omission within sentences."} +{"text": "Prostaglandins E2 and F2 alpha were measured by gas liquid chromatography--mass spectrometry (glc-ms) in extracts of primary tumours from 78 patients with early breast cancer. These levels have been related to factors of established prognostic value and the patients disease-free interval. Although there was a wide variation in amounts of both prostaglandins extracted from different tumours, no significant relationship was observed between levels of prostaglandins and oestrogen receptors (ER), tumour size, presence of lymph node involvement and disease-free interval following primary treatment. It therefore seems unlikely that the level of these particular prostaglandins within breast carcinomas plays a fundamental role in the prognosis of the disease."} +{"text": "The present study tests whether a combined treatment of acupuncture and transcutaneous electrical nerve stimulation (TENS) is more effective than acupuncture or TENS alone for treating knee osteoarthritis (OA).Thirty-two patients with knee OA were randomly allocated to four groups. The acupuncture group (ACP) received only acupuncture treatment at selected acupoints for knee pain; the TENS group (TENS) received only TENS treatment at pain areas; the acupuncture and TENS group (A&T) received both acupuncture and TENS treatments; the control group (CT) received topical poultice (only when necessary). Each group received specific weekly treatment five times during the study. Outcome measures were pain intensity in a visual analogue scale (VAS) and knee function in terms of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC).The ACP, TENS and A&T groups reported lower VAS and WOMAC scores than the control group. Significant reduction in pain intensity (P = 0.039) and significant improvement in knee function (P = 0.008) were shown in the A&T group.Combined acupuncture and TENS treatment was effective in pain relief and knee function improvement for the sampled patients suffering from knee OA. Osteoarthritis (OA) is the most common form of joint disease and most often affects the knee ,2. OA ofThe present study aims to test whether TENS or a combined treatment of acupuncture and TENS is more effective than acupuncture or TENS alone for treating knee OA in older patients.Outpatients aged 60 years or older with knee OA were recruited from the Meiji University of Oriental Medicine Hospital. The patients had been clinically and radiologically diagnosed of knee OA according to the criteria of the American College of Rheumatology. Further inclusion criteria for the present study were: (1) knee pain lasting for six months or longer; (2) no radiation of knee pain; (3) radiographic evidence of at least one osteophyte at the tibiofemoral joint (Kellgren-Lawrence grade \u2265 2); (4) normal neurological functions of lumbosacral nerve, including deep tendon reflexes, voluntary muscle action and sensory function; and (5) not receiving acupuncture treatment for more than six months. Exclusion criteria were: (1) major trauma or systemic disease; and (2) receiving conflicting or ongoing co-interventions. Patients under drug treatment were included if there had been no change in medicine and its dosage for one month or longer. This study was approved by the Ethics Committee of the Meiji University of Oriental Medicine.All enrolled patients gave their written informed consent. According to a block randomised allocation table , the enrolled patients were allocated to (1) the control (CT) group, (2) the acupuncture (ACP) group, (3) the transcutaneous electrical nerve stimulation (TENS) group or (4) the acupuncture and TENS (A&T) group.The design of this study was a randomly controlled clinical trial using a block randomised procedure. Each patient received a total of five treatments, once per week, and follow-up was measured for ten weeks after the first treatment.The CT group patients did not receive any specific treatment, but when necessary, were allowed to use topical poultice containing methylsalicylic acid.Liangqiu (ST34), Dubi (ST35), Zusanli (ST36), Yinlingquan (SP9), Xuehai (SP10) and Yanglingquan (GB34). Disposable stainless steel needles were inserted into the muscle to a depth of 10 mm using the 'sparrow pecking' acupuncture technique by acupuncturists who had four years of acupuncture training and three to eight years of clinical experience. When the subject felt dull pain or the acupuncture sensation (de qi) was achieved, the needle manipulation was stopped and the needle was left in place for ten more minutes.The ACP group patients received acupuncture treatment at selected acupoints for 15 minutes on the OA affected knee. The selected acupoints are widely accepted for treating knee pain -13, name2 and 5688 mm2 were respectively placed on the site with the most tenderness and the opposite side of the site. Two electrodes were different in size (ratio: 1:7). The smaller one was placed on the site of tenderness. The intensity of TENS stimulation was adjusted so that a tingling sensation 2\u20133 times of the subject's sensory threshold was produced.The TENS group patients received treatment at the OA affected knee for 15 minutes from a single-channel portable TENS unit , which sends between two electrodes a premixed amplitude-modulated frequency of 122 Hz (beat frequency) generated by two medium frequency sinusoidal waves of 4.0 and 4.122 kHz (feed frequency). Surface disposable electrodes of 809 mmThe treatment for the A&T group combined the treatments for the ACP and TENS groups. The patients received 15 minutes of TENS, and then 15 minutes of acupuncture treatment at the OA affected knee.We confirmed that the patients in all groups did not receive any other co-interventions including analgesics, anti-inflammatory agents or topical hyaluronic acid injection during the study period.Primary outcome measures were: (1) pain intensity, quantified with a 10 cm visual analogue scale and (2) pain disability measured with the Western Ontario and McMasters Universities Osteoarthritis Index . The WOMThe VAS scores were measured immediately before the first treatment and subsequently at one, two, three, four, five and ten weeks after the first treatment. The WOMAC scores were measured immediately before the first treatment and subsequently five and ten weeks after the first treatment. Each VAS and WOMAC score was measured immediately before treatment of the specified week.Repeated measures analysis of variance (ANOVA) was used to study the changes in the VAS and WOMAC scores in the three groups. Changes in the time course among groups were considered significant when the interaction was significant at a level of 0.013 (0.05/4). After detection of significant changes in the overall time course with repeated measures ANOVA, pair comparisons were detected with Bonferroni correction. StatView for Windows (version 5.0) or SYSTAT 10 (SYSTAT Inc) was used for the statistical analysis. The results with P values of less than 0.05 were considered statistically significant.A total of 32 patients were randomly allocated to four groups for specific treatment. Before the treatments, no significant difference was found in baseline variables including age, disease, pain duration, and pain intensity VAS scores among the four groups.i.e. deterioration of symptoms). The total dropout rate was the same in every group. The analyses were performed on the 24 patients who completed the study and provided required information compared to the CT group during treatment Table . The treThe present study demonstrated that acupuncture and TENS treatments were effective in pain relief. TENS is a common modality for treating musculoskeletal pain . TENS exOur other studies consistently showed that combined treatment of acupuncture and TENS was more effective than separate treatments ,25. TENSThe present study clearly demonstrated that combined acupuncture and TENS treatment is effective for pain relief in terms of VAS and knee function improvement in terms of WOMAC in patients suffering from knee OA. Large scale clinical trials are warranted.ACP: acupuncture group; ANOVA: analysis of variance; OA: osteoarthritis; QOL: quality of life; ROM: range of motion; TENS: transcutaneous electrical nerve stimulation; VAS: visual analogue scale; WOMAC: Western Ontario and McMaster Universities Osteoarthritis IndexThe author(s) declare that they have no competing interests.KI was responsible for study design, acupuncture treatment, manuscript preparation and submission. SH was responsible for patient recruitment. HO was responsible for all statistical design and data analysis. YK was responsible for manuscript review. HK was responsible for study design, critical manuscript review and patient recruitment. All authors read and approved the final manuscript."} +{"text": "Unique germline mutations in BRCA1 and BRCA2 account for inherited predisposition to breast and ovarian cancer in high-risk families. In Jewish high-risk individuals of Ashkenazi (east European) descent, three predominant mutations, 185delAG and 5382insC (BRCA1) and 6174delT (BRCA2), seem to account for a substantial portion of germline mutations, and two of these mutations (185delAG and 6174delT) are also found at about 1% each in the general Jewish-Ashkenazi population. We identified a novel BRCA1 mutation in two Jewish-non-Ashkenazi families with ovarian cancer: a thymidine to guanidine alteration at position 3053, resulting in substitution of tyrosine at codon 1017 for a stop codon (Tyr1017Ter). The mutation was first detected by protein truncation test (PTT) and confirmed by sequencing and a modified restriction digest assay. Allelotyping of mutation carriers using intragenic BRCA1 markers revealed that the haplotype was identical in these seemingly unrelated families. No mutation carrier was found among 118 unselected Jewish individuals of Iranian origin. Our findings suggest that this novel mutation should be incorporated into the panel of mutations analysed in high-risk families of the appropriate ethnic background, and that the repertoire of BRCA1 mutations in Jewish high-risk families may be limited, regardless of ethnic origin."} +{"text": "An ascitic form of plasmacytoma (MP-5563) in C3H mice has proved stable on transplantation. A simple linear relationship was demonstrated between the serum level of the paraprotein produced and the total number of plasmacytoma cells within the ascitic fluid."} +{"text": "The kinetics, specificity and morphology of cytolethal responses have been studied in human glucocorticoid-sensitive and -insensitive lymphoid cell lines (HLCL) and fibroblasts following treatment with high (10(-3)M) and low (10(-6)M) doses of steroid. The high dose cytolethal response appears non-specific occurring in all cell lines with every steroid tested. By contrast, the low dose cytolethal response requires an active glucocorticoid and a sensitive HLCL. However, both high and low concentrations of steroid induce virtually identical morphological changes in dying cells and similar changes can be induced in cells killed by deliberate feed exhaustion. Although the morphological features in each case resemble apoptosis, the \"programmed\" physiological form of cell death, the intracellular events leading to cytolysis seem likely to differ. The earliest morphological changes presaging cell death comprise rounding up of cells and condensation of nuclear chromatin. Nuclear changes progress rapidly thereafter and appear to result from detachment of chromatin from the nuclear matrix. The low dose cytolethal response requires the continuous presence of glucocorticoid for periods in excess of 24h, prior to which cell growth appears unaffected. The constancy of this latent interval suggests glucocorticoids may influence some replication control mechanism unrelated initially to macromolecular biosynthesis."} +{"text": "We examined the localization of basic fibroblast growth factor (bFGF) in a series of human breast carcinomas using immunohistochemistry. Staining was observed in tumour cells in 15 out of 54 (28%) tumours and in the adjacent stroma in 34 out of 54 (63%) tumours examined. No correlation was observed between positive staining of these two compartments. The relationship between bFGF staining and expression of the metalloprotease stromelysin-3, and between bFGF and microvessel density, was examined. A statistically significant correlation (P < 0.003) was observed between bFGF staining of the stromal compartment and high expression of stromelysin-3 metalloprotease mRNA by stromal cells. In contrast, no correlation was observed between bFGF and intratumour microvessel density (IMD). These results raise the possibility that bFGF may be involved in the induction of stromelysin-3 mRNA expression in breast cancer stroma."} +{"text": "Patients treated with tamoxifen (TAM) for primary breast cancer often manifest de novo or acquired resistance, possibly through changes in drug metabolism. Using solid-phase extraction methods and reversed-phase high-performance liquid chromatography separations, levels of TAM and metabolites 4-hydroxytamoxifen (4OH) and desmethyltamoxifen (DMT) have been measured in plasma and tumour tissue from breast cancer patients treated with TAM for at least 3 months. Patients were categorized into those with tumours responding to TAM and those showing de novo or acquired resistance. Levels of TAM, 4OH and DMT in both plasma and tissue samples were correlated with clinical response, length of treatment and patient weight. Interesting results included accumulation of 4OH in tumour tissues over time in all patients, with significance reached in the acquired resistance group. In addition, significantly lower levels of 4OH and DMT were found in plasma taken from responding patients after 3 months of treatment when compared to non-responding patients, and a small group of ER-poor patients showed significantly lower levels of all three species in plasma when compared to other patients. Whilst not explaining TAM resistance in all cases, these differences could account for the development of resistance to TAM treatment in certain subgroups of patients. \u00a9 2000 Cancer Research Campaign"} +{"text": "A possible variable is the influence of growth conditions on discerning candidates. The present study examined the influence of growth conditions on the expression of chromosome 3 genes in the tumorigenic EOC cell lines, OV-90, TOV-21G and TOV-112D using Affymetrix GeneChipChromosome 3 gene expression profiles were extracted from U133A expression microarray analyses of the EOC cell lines OV-90, TOV-21G and TOV-112D that were grown as monolayers, spheroids or nude mouse xenografts and monolayers derived from these tumors. Hierarchical cluster analysis was performed to compare chromosome 3 transcriptome patterns of each growth condition. Differentially expressed genes were identified and characterized by two-way comparative analyses of fold-differences in gene expression between monolayer cultures and each of the other growth conditions, and between the maximum and minimum values of expression of all growth conditions for each EOC cell line.An overall high degree of similarity (> 90%) in gene expression was observed when expression values of alternative growth conditions were compared within each EOC cell line group. Two-way comparative analysis of each EOC cell line grown in an alternative condition relative to the monolayer culture showed that overall less than 15% of probe sets exhibited at least a 3-fold difference in expression profile. Less than 23% of probe sets exhibited greater than 3-fold differences in gene expression in comparisons of the maximum and minimum value of expression of all growth conditions within each EOC cell line group. The majority of these differences were less than 5-fold. There were 17 genes in common which were differentially expressed in all EOC cell lines. However, the patterns of expression of these genes were not necessarily the same for each growth condition when one cell line was compared with another.in vivo and in vitro growth conditions of tumorigenic EOC cell lines appeared to modestly influence the global chromosome 3 transcriptome supporting the notion that the in vitro cell line models are a viable option for testing gene candidates.The various alternative The molecular genetic analysis of ovarian cancer has been facilitated by the establishment and characterization of spontaneously immortalized epithelial ovarian cancer (EOC) cell lines that have been derived from malignant cells by long-term growth in cell culture . In our in vitro EOC cell line models. Recently, our group has reported on global differences in gene expression between EOC cell lines that were cultured as monolayers, spheroids, or nude mouse xenografts suggesting that microenviroment could impact the transcriptome [in vitro model with the potential for identifying and testing chromosome 3 tumor suppressor genes because of extensive loss of heterozygosity of the 3p arm [A possible variable in the application of EOC cell line models is the influence of growth conditions on discerning and then characterizing gene candidates which initially exhibit differential gene expression in criptome . To furtcriptome . We havecriptome ,8,14,15.criptome . Both OVcriptome ,16. Karycriptome ,5. In pae 3p arm but has The present study was focused on addressing the magnitude and extent of transcriptome modifications for different EOC cell line models that may be influenced by tumor microenvironment. As each cell line exhibits unique molecular genetic characteristics comparisons of chromosome 3 transcriptome modifications were made with respect to gene expression profiles generated with each growth condition within each experimental cell line model.The EOC cell lines were derived from a stage III/grade 3 clear cell carcinoma TOV-21G), a stage IIIc/grade 3 endometrioid carcinoma (TOV-112D), and from the ascites fluid of a stage IIIc/grade 3 adenocarcinoma (OV-90), all from chemotherapy na\u00efve patients, as described [1G, a sta\u00ae HG-U133A microarray analyses of the OV-90, TOV-21G and TOV-112D EOC cell lines that were each grown under different conditions as described previously [. These conditions include monolayer cultures (L), spheroid cultures (S), nude mouse xenografts at subcutaneous (TSC) or intraperitoneal (TIP) sites, and monolayer cultures of subcutaneous (LSC) and intraperitoneal (LIP) xenografts, as described previously [\u00ae experiments, was achieved from the raw expression data using the MAS5 software (Affymetrix Microarray Suite\u00ae) by multiplying the value for an individual probe set by 100 and dividing by the mean of the raw expression values for the given sample data set as described previously [Chromosome 3 gene expression profiles were extracted from normalized Affymetrix GeneChipeviously . The sof and the UniGene Homo sapiens database, based on UniGene Build 198 . Additional mapping information was obtained from the University of California Santa Cruz (UCSC) Human Genome Browser database, March 2006 (NCBI Build 36.1) hg 18 assembly . Based on these databases, 1147 probe sets were identified that mapped to chromosome 3, representing 735 genes and ESTs. Chromosome 3 alignment of probe sets (represented genes) was determined based on the UCSC Human Genome Browser database, where 535 probe sets mapped to genes on the chromosome 3p arm and 612 probe sets mapped to genes on the chromosome 3q arm.The normalized data set was then used to extract the expression profiles associated with probe sets representing chromosome 3 genes. Probe sets corresponding to chromosome 3 genes were identified using the Affymetrix NetAffx Batch Query tool The normalized expression data sets were also rescaled to eliminate systematic biases due to low expression values. Low values with A-calls are considered to be technical noise, which may influence fold-difference comparisons and overestimate expression differences that result from high variability of low expression values. Probe sets containing A-calls may also reflect either absent expression or poorly designed probe sets . To redu. In order to determine the significance of the differential expression, modified t-tests were performed with Bioconductor's limma package, where p-values from the resulting comparison were adjusted for multiple testing as described [genefilter package was used to filter out probe sets with insufficient variation in gene expression across all tested samples for the analysis of each EOC cell line data set. In the remaining expression values, a log base 2 scale of at least 0.5 for the interquartile range was required across all tested samples for each EOC cell line group as described. Hierarchical clustering analysis was performed with R's cluster package, using the Pearson correlation distance.Hierarchical cluster analysis was performed on normalized and rescaled gene expression data analyzed using Bioconductor, an open-source software library for the analyses of genomic data based onescribed . This meTwo-way comparative analyses based on fold differences of expression values were performed on normalized and rescaled gene expression data derived from each EOC cell line. The expression values with at least one high-reliability score or P call for each EOC cell line sample set were evaluated in two-way comparative analyses. Differentially expressed genes were defined as those which exhibited at least a 3-fold difference in two-way comparative analyses with expression value for monolayer culture and each growth condition, or between the maximum and minimum value of expression observed within a set of data for each EOC cell line.Hierarchical cluster analysis of chromosome 3 gene expression data from each EOC cell line grown in monolayer cultures (L) and alternative growth conditions such as spheroid cultures (S), nude mouse xenografts at subcutaneous (TSC) or intraperitoneal (TIP) sites, and monolayer cultures of subcutaneous (LSC) and intraperitoneal (LIP) xenografts is shown in Figures To further characterize the gene expression profiles and identify the genes that may be influenced by the growth conditions, we applied a two-way fold-difference comparative analysis approach. As monolayer cultures are often used in molecular genetic assays of cancer derived cell lines, we compared gene expression values of the EOC cell lines grown as monolayer cultures with each of the alternative growth conditions comprised of spheroid cultures (S), nude mouse xenografts at subcutaneous (TSC) or intraperitoneal (TIP) sites, and monolayer cultures of subcutaneous (LSC) and intraperitoneal (LIP) xenografts. We performed two-way comparison analysis based on fold-differences using the expression values which contained at least one high reliability score per probe set for each EOC cell line. Using this criterion, the expression values of 692 (60.3%), 739 64.4%), and 693 (60.4%) probe sets from the total of 1147 chromosome 3 probe sets for OV-90, TOV-21G and TOV-112D, respectively, were evaluated for fold-differences of the expression values exhibited by all alternative growth conditions. Two-way comparative analysis was performed between the maximum and minimum values of expression observed for probe sets for each EOC cell line group. A minimum 3-fold cut-off was used to characterize differences in gene expression. Overall less than 23% of probe sets exhibited greater than 3-fold differences in gene expression in this comparative analysis in any EOC cell line group and both subcutaneous (TSC) and intraperitoneal (TIP) xenografts exhibited the lowest values of expression of this gene xenograft sample and the lowest value was observed with intraperitoneal (TIP) xenograft in gene expression in each EOC cell line group tested irrespective of growth condition. It was also reflected in the two-way comparative analyses where a 3-fold cut-off was applied. Although we have previously shown that replicates of Affymetrix GeneChip\u00ae expression data derived from the EOC cell lines grown as monolayer cultures were highly reproducible [\u00ae expression microarrays of the EOC cell lines, we have used a lower threshold level of 15 rather than 50 or 100 depending on the GeneChip\u00ae used [In this study, we described chromosome 3 transcriptome changes for three well characterized EOC cell lines that each responded differently in relation to various growth conditions such as in three dimensional spheroid culture and nude mouse xenograft models, relative to the conventional monolayer culture. However, the alternative oducible ,6, a lowoducible ,17. Unliip\u00ae used -10. A loip\u00ae used .TP53, whereas TOV-21G harbors a somatic mutation in KRAS and exhibits microsatellite instability. OV-90 also is monoallelic for the 3p arm, however this gross genomic anomaly did not significantly impact on global patterns of gene expression of the chromosome 3p arm as assayed by Affymetrix expression analyses of this cell line and the other EOC cell line used in the present study [The EOC cell line lines exhibited unique patterns of gene expression as shown by the hierarchical cluster analysis. These unique differences are also reflected in a previous global analyses of gene expression from the entire Affymetrix U133A microarray . These Ent study ,15. The ARPC4 and NCK1), cell growth and division (CDC25A and SKIL), and extracellular signaling/cell-cell junctions (Additional file TMEM158, HEG1, PLOD2 and ATP13A3, were recently found differentially expressed greater than 3-fold in a comparative analysis of primary cultures of normal ovarian surface epithelial cells and malignant serous ovarian tumors [Given the molecular genetic differences in the EOC cell lines, it is not surprising that there were few similarly differentially expressed genes found in common with all of EOC cell lines. Indeed there were only 17 genes in common in all three EOC cell lines which exhibited differential expression greater than 3-fold in all comparative analyses (Additional file in vitro and in vivo growth conditions may all still be significantly different when each is compared with normal cells [S100A6, was found differentially expressed relative to culture conditions and further validated by RT-PCR and immunohistochemistry [in vitro model systems for studying gene candidates, our results in the present study show that a high correlation of gene expression in the transcriptomes generated from ovarian cancer cell lines propagated in different contexts. Overall these results attests to the validity of the EOC cell lines as an in vitro model for studying gene candidates but point out that some genes may be influenced by microenvironment, a factor that should be taken into consideration when investigating the molecular biology of specific genes. As our EOC cell lines are amenable to propagation in alternative growth conditions one could assay and further investigate the magnitude of transcriptional effects for specific candidate genes of interest and their consequences at the protein level to further understand the biological relevance gene expression differences associated with microenvironment.Future experiments are required to determine if the differences observed in the EOC cell lines grown in alternative conditions are biologically relevant or a reflection of experimental design. The magnitude of the differences in gene expression observed in the EOC cell lines grown under the various al cells . The EOChemistry . While tin vivo and in vitro growth conditions affords the opportunity to study gene expression of candidates in contexts that more closely mimic tumor growth in vitro. However, the analyses of chromosome 3 transcriptomes are highly comparable within each EOC cell line context. These observations would argue that gene expression studies using monolayer cultures of ovarian cancer lines is still a viable option for initial studies involving the characterization of gene expression pattern of candidate genes.The ability to culture tumorigenic EOC cells under different The authors declare that they have no competing interests.NALC participated in the study design of expression analysis, performed the data analysis, and drafted the manuscript. MZ performed experiments involving the growth of the EOC cell lines in different conditions. DMP participated in the study design. A-MM-M supervised the growth conditions assays and participated in the study design. PNT conceived the chromosome 3 study and study design, and drafted the manuscript. All authors have read the manuscript and approved the final manuscript.The pre-publication history for this paper can be accessed here:Table S1: Genes exhibiting greater than 3-fold difference in gene expression in common in all EOC cell lines.Click here for file"} +{"text": "Cytotoxic drug resistance developing after chemotherapy is thought to be the main cause of treatment failure in several human tumours, including small cell lung cancer (SCLC). Cell lines showing drug resistance following prolonged exposure to a single agent frequently acquire resistance to several functionally unrelated drugs, the phenomenon of multi-drug resistance (MDR). Classical MDR is thought to arise from changes effecting a reduction in intracellular availability of cytotoxic drugs. We describe a flow cytometry (FCM) technique to monitor the MDR phenotype in drug resistant variants of SCLC and non-SCLC cell lines. The technique is based on a multiparametric analysis of the nuclear binding of a model chemotherapeutic agent, the fluorescent dye Hoechst 33342 (Ho342), which is capable of supra-vital staining of DNA in intact, viable cells. A laboratory derived drug resistant SCLC cell line, H69/LX4, showed a significant (30%) reduction in nuclear binding compared to the parental line H69/P. Exposure to verapamil (VPL) rapidly increased (within 2 min) nuclear binding of Ho342, and the new equilibrium of nuclear staining, attained within 20 min, remained lower than the level achieved in the parental cell line, suggesting some ability of H69/LX4 to limit the effect of the drug efflux blocker. A drug resistant large cell carcinoma line showed only a small reduction (10%) in nuclear binding when compared to the parent line, and this difference was not altered by VPL. A drug resistant adenocarcinoma line showed less than 10% difference in nuclear binding compared with the parental line and neither line was significantly affected by VPL treatment. Our findings suggest that different mechanisms of resistance may occur in lung tumours of different tissue types. This technique may be extended to the rapid and direct examination of biopsy specimens of human solid tumours for evidence of multi-drug resistance."} +{"text": "Several cobalt(II), copper(II) and nickel(II) complexes of nicotinoylhydrazine-derived compounds were prepared and characterised by physical, spectral and analytical data. These compounds and their complexes have proven to be antibacterial. The screening data show the metal complexes to be more potential/bactericidal than the uncomplexed compounds against one or more bacterial species."} +{"text": "From 1980 through 1988, biliary surgery was performed in 197 patients with acute gallstone disease andconcomitant elevation of serum glutamic oxalacetic transaminase (SGOT) or serum glutamic pyruvictransaminase (SGPT) of over 300 Karmen units. In 137 patients, anatomic inspection and liver biopsywere performed during the acute stage of the disease. Impacted and floating bile duct stones were foundin 69 (50%) and in 43 (32%) of the 137 patients, respectively. The main liver histology was necrosis ofliver cells. After surgery, high serum transaminase fell rapidly with immediate recovery in 99% of thepatients. In the remaining 60 patients, their signs and symptoms settled soon after initial conservativetreatment and surgery was performed after an average time of 21 days. At laparotomy, impacted bileduct stones were found in 2 (3%) and liver histology revealed regeneration of liver cells.\t\tThese findings suggest that marked elevation of serum transaminase in patients with acute gallstonedisease might be due to an acute inflammatory liver cell injury caused by impacted bile duct stones ormigrating stones, which would be transient and reversible after early resolution of the bile ductobstruction."} +{"text": "As these complexes are candidates for a novel class anti-HSV drugs, further studies on their mutagenicity are of particular interest. In the present paper we present data showing that Zn(pic)2 and Zn(asp)2 do not express mutagenic effect in both prokaryotic and eukaryotic (Saccharomices cerevisiae) test systems.Former studies showed that complexes of Zn(II) with picolinic and with aspartic acids, Zn(pic)"} +{"text": "Radiotherapy of tumours proximal to normal CNS structures is limited by the sensitivity of the normal tissue. Prior to the development of prophylactic strategies or treatment protocols a detailed understanding of the mechanisms of radiation induced CNS toxicity is mandatory. Histological analysis of irradiated CNS specimens defines possible target structures prior to a delineation of cellular and molecular mechanisms. Several lesions can be distinguished: Demyelination, proliferative and degenerative glial reactions, endothelial cell loss and capillary occlusion. All changes are likely to result from complex alterations within several functional CNS compartments. Thus, a single mechanism responsible cannot be separated. At least four factors contribute to the development of CNS toxicity: (1) damage to vessel structures; (2) deletion of oligodendrocyte-2 astrocyte progenitors (O-2A) and mature oligodendrocytes; (3) deletion of neural stem cell populations in the hippocampus, cerebellum and cortex; (4) generalized alterations of cytokine expression. Several underlying cellular and molecular mechanisms involved in radiation induced CNS toxicity have been identified. The article reviews the currently available data on the cellular and molecular basis of radiation induced CNS side effects. \u2002\u2002http://www.bjcancer.com \u00a9 2001 Cancer Research Campaign"} +{"text": "To evaluate visual outcome following pars plana vitrectomy (PPV) and intraocular foreign body (IOFB) removal through the sclerocorneal tunnel combined with simultaneous cataract extraction and sulcus-fixated intraocular lens (IOL) implantation as a single procedure in penetrating ocular trauma with IOFB and traumatic cataract.Eighteen cases of penetrating ocular trauma with retained IOFB and traumatic cataract who underwent PPV, IOFB body removal and cataract extraction with posterior chamber IOL (PCIOL) implantation in the same sitting, between June '04 and December '05 were retrospectively analyzed. All the foreign bodies were removed through the sclerocorneal tunnel.All the 18 patients were young males, with an average follow-up period of 12 months. In 12 cases the foreign body was intravitreal and in six cases it was intraretinal but extramacular. Thirteen cases had a best corrected visual acuity ranging from 20/20 to 20/60 at their last follow-up. Five cases developed retinal detachment due to proliferative vitreoretinopathy (PVR) changes postoperatively and were subsequently managed by surgery.Primary IOL implantation with combined cataract and vitreo-retinal surgery is a safe option reducing the need for two separate surgeries in selected patients with retained IOFB and traumatic cataract. This combined procedure provides good visual outcome with early rehabilitation in young working patients. Open globe injury with or without intraocular foreign body (IOFB) often has a poor visual outcome owing to possible endophthalmitis and/or vitreo retinopathy with the varied and unsterile wounds associated with it.\u20133 ManageMethods for removal of the traumatic cataract include lensectomy, conventional extra-capsular cataract extraction (ECCE), manual small-incision cataract surgery (SICS) and phacoemulsification. Unlike lensectomy other methods of cataract extraction offer a better visual rehabilitation because of implanted intraocular lens (IOL).\u20138 Most sTo avoid such complications, in this series we performed cataract extraction by manual SICS , removed the foreign body through the same tunnel and implanted a posterior chamber IOL (PCIOL) over the anterior capsular rim. The aim of the study was to evaluate visual outcome following pars plana vitrectomy (PPV) and IOFB removal through the sclerocorneal tunnel combined with simultaneous cataract extraction and sulcus-fixated IOL implantation as a single procedure in penetrating trauma with IOFB and traumatic cataract.Medical records of patients with penetrating eye injury and IOFB attending the retina clinic between June 2004 and December 2005 were reviewed. Out of 28 consecutive patients, 10 patients were excluded from this study because of absence of cataract, presence of associated endophthalmitis, severely injured lens with vitreous in the anterior chamber and evidence of zonular dehiscence.Eighteen patients with clinically significant lens opacification and IOFB with or without concomitant vitreoretinal pathology were included in the study. Primary repair was done in all cases except three, where the wound was self-sealed and they were taken up for vitreoretinal procedure directly. All patients underwent a complete general ophthalmologic examination prior to the surgical procedure. Preoperative visual acuity, site of entry of foreign body (FB), capsular and zonular integrity was assessed. Ultrasound B-Scan and/or X-ray of orbit were performed in all patients to locate and evaluate the IOFB. Keratometry and biometry of the injured eyes were done. If keratometry and biometry was not possible on the injured eye, fellow eye measurements were used. In all cases manual SICS was performed before the vitreoretinal procedure. A 6 mm frown-shaped sclerocorneal tunnel was made, followed by continuous curvilinear capsulorrexis and hydrodelineation. The lens nucleus was prolapsed into the anterior chamber and removed through the tunnel by sandwich method.\u201311 Rest 12Sclerotomies and conjunctiva were closed with 6-0 vicryl and 2 mg dexamethasone and 2 mg gentamicin sulphate were injected subconjunctivally. Postoperatively all patients received topical antibiotics and steroid for four weeks with gradual tapering. Oral ciprofloxacin 500 mg twice daily along with nonsteroidal anti-inflammatory agents was given in all cases with addition of systemic steroids when necessary. In each case recording of best corrected visual acuity (BCVA), intraocular pressure measurement, slit-lamp biomicroscopy and indirect ophthalmoscopy was done postoperatively. Cause of decreased vision was assessed considering site of entry of FB, site of lodgment of FB and postoperative complications like RD in each case.All our patients were young males with mean age of 24.5 years. The minimum follow-up period was four months, the maximum being 18 months with median follow-up time of 12 months. In 12 out of 18 cases the FB was intravitreal and in six cases it was intraretinal but extramacular. Thirteen out of 18 cases had BCVA between 20/20 and 20/60. Anatomical success was achieved in 13 out of 18 cases with 11 patients having visual acuity 20/30 or better with first vitreoretinal procedure. With the second vitreoretinal procedure four out of five patients had anatomical success .et al.[We reviewed the visual outcome and complications in 18 patients with penetrating intraocular injury, significant cataract and retained IOFB, who underwent manual SICS, PPV, removal of IOFB and implantation of PCIOL. This simultaneous procedure was chosen to get rid of cataract, which diminished the visualization of posterior segment and for prevention of lens-induced uveitis due to a ruptured lens capsule. We found no significant correlation in \u2018duration between injury and vitreoretinal procedure\u2019 which is well supported by other studies.14\u201319 ButSclerocorneal tunnel and sclerotomy have their advantages and disadvantages as a route for removal of IOFB. Enlargement of sclerotomy carries risk of hypotony, vitreous hemorrhage, peripheral vitreous incarceration into the wound intraoperatively, and RD postoperatively. Removal of the FB through sclerocorneal tunnel may damage or sacrifice the integrity of the posterior lens capsule and anterior capsular rim, but large FBs are easily removed through the sclerocorneal tunnel.\u201319et al.[et al.[et al.[et al.[Except few isolated case reports with large IOFBs, so far there is no data on removal of cataract and FB through the same route. In our experience, IOFB can be safely removed through the sclerocorneal tunnel and IOL can easily be implanted into the cilliary sulcus. In our study, the final BCVA was 20/30 or better in seven out of 18 cases, between 20/40 and 20/60 in six cases and counting finger (CF) at 1 meter (1 m) or less in five cases. This was very well comparable with similar studies.\u201381314 Az813et al. reportedl.[et al. reportedLate onset of RD in our series was seen in five out of 18 cases. The incidence of RD in the intraretinal FB group in this series was seen in five out of six cases. The possible causes of this overwhelming incidence of RD in the intraretinal FB group might be increased manipulation of FB and retinal penetration increasing the chance of proliferative vitreoretinopathy (PVR) changes postoperatively. These ch3Combined cataract and vitreous surgery with FB removal and IOL implantation offers not only faster visual rehabilitation but also24According to our clinical experience, the surgery that combines cataract extraction, IOFB removal and IOL implantation is a safe and desirable operation in patients with IOFB and significant lens opacities. The main advantage of this procedure is rapid visual rehabilitation with a single surgery, reducing the cost and patient discomfort. Randomized controlled studies involving larger number of patients with longer follow-up period may be needed to establish these facts."} +{"text": "A population-based case-control study of oral contraceptive use and breast cancer was carried out among young women (less than 43 years of age) at Group Health Cooperative of Puget Sound, Seattle, Washington. Use of oral contraceptives before first pregnancy did not materially differ between cases or controls. The rate ratio estimate of breast cancer incidence in women who had used oral contraceptives before first pregnancy compared to those who had not was 0.9 . There were no meaningful patterns of association between breast cancer and duration of use or formulation of oral contraceptive used before first pregnancy."} +{"text": "Connective tissue growth factor (CTGF) is a major chemotactic and mitogenic factor for connective tissue cells. The amino acid sequence shares an overall 28\u201338% identity to IGFBPs and contains critical conserved sequences in the amino terminus. It has been demonstrated that human CTGF specifically binds IGFs with low affinity and is considered to be a member of the IGFBP superfamily (IGFBP-rP2). In the present study, the expression of CTGF (IGFBP-rP2) in human leukaemic lymphoblasts from children with acute lymphoblastic leukaemia (ALL) was investigated. RNA samples from tumour clones enriched by ficoll separation of bone marrow or peripheral blood mononuclear cells (MNC) from 107 patients with childhood ALL at diagnosis and 57 adult patients with chronic myeloid leukaemia (CML) were studied by RT-PCR. In addition MNC samples from children with IDDM and cord blood samples from healthy newborns were investigated as control groups. Sixty-one percent of the patients with ALL (65 of 107) were positive for CTGF (IGFBP-rP2) expression. In the control groups, no expression of CTGF (IGFBP-rP2) in peripheral MNC was detected, and in the group of adult CML patients only 3.5% (2 of 57) were positive for this gene. The role of CTGF (IGFBP-rP2) in lymphoblastic leukaemogenesis requires further evaluation, as does its potential utility as a tumour marker. \u00a9 2000 Cancer Research Campaign"} +{"text": "The aim of this study was to examine the relationship between the pharmacokinetics of daunorubicin (DNR), overexpression of P-glycoprotein (Pgp) and treatment response in acute leukaemia. Twenty-seven patients with acute leukaemia received DNR as part of induction therapy. The plasma and cellular levels of DNR and its metabolite daunorubicinol (DOL) were determined using high-performance liquid chromatography. There were no significant differences between patients who went into complete remission (12/23) compared with those who did not respond for the following pharmacokinetic parameters: DNR and DOL plasma AUC (area under the curve) and DNR plasma half-life and clearance. There was a significant difference in the cellular DNR and DOL AUC between responders and non-responders (P < 0.02). Seven patients were Pgp positive and 18 Pgp negative. There was no correlation between patient response and the presence of Pgp (P > 0.1), nor was there any correlation between the cellular concentration of DNR or DOL and Pgp (P > 0.3). To our knowledge this is the first report examining the relationship between DNR pharmacokinetics, patient response and Pgp expression. Our data indicated that acute leukaemia patients responding to chemotherapy had higher cellular DNR and DOL than non-responders; also, overexpression of Pgp appeared not to be the sole explanation for the lower cellular DNR levels as expected from in vitro studies."} +{"text": "Immunohistochemical, cytochemical and ultrastructural data showing vivid angiogenesis and numerous mast cells (MCs) in the bone marrow of 24 patients with active multiple myeloma (MM) compared with 34 patients with non-active MM and 22 patients with monoclonal gammopathy of undetermined significance (MGUS) led us to hypothesize that angiogenesis parallels progression of MM, and that MCs participate in its induction via angiogenic factors in their secretory granules. \u00a9 1999 Cancer Research Campaign"} +{"text": "The performance of the Lung Imaging Fluorescence Endoscope (LIFE) system was compared with conventional bronchoscopy in 158 patients: 68 patients with invasive cancer, 42 patientswith abnormal sputum cytology findings (12 early cancer and 26 dysplasia), 17 cases withresected lung cancer and 31 smokers with symptoms. The respective results of conventionalbronchoscopy and LIFE for detection of dysplasia were; sensitivity 52% and 90% (biopsybasis), 62% and 92% (patient basis). Fluorescence bronchoscopy may be an importantadjunct to conventional bronchoscopy to improve the localization of subtle lesions ofbronchus."} +{"text": "Preoperative bronchoscopic findings of thyroid carcinoma with tracheal invasion wereexamined and compared with the histopathological findings. Tracheal sleeve resectionwas performed in 20 cases. The bronchoscopic findings were classified into 5 types:confirmed tumor in the tracheal lumen (5 cases), extramural compression of the tracheaplus mucosal change (9 cases), extramural compression of the trachea (2 cases), mucosalchanges only (3 cases), normal findings (1 case). Pathological findings revealed that theextent of invasion in the tracheal wall varied according to each of the above bronchoscopictypes. The number of tracheal rings with adventitial invasion averaged 0.8 (maximum2) more than preoperative bronchoscopic findings of the number of tracheal ringswith mucosal invasion. This study demonstrated the necessity of resective 2 more trachealrings than is indicated by the bronchoscopic findings."} +{"text": "Recently trans-dicarboxylato platinum(IV) complexes with mainly acetate,trifluoracetate or short-chain carboxylate groups (<11 carbons) in the axial position have beendescribed in the literature. In this paper we report on the synthesis and characterization of a new class of ethylenediamineplatinum(IV) compounds that have high lipophilic long-chain carboxylate ligands either in the axialor equatorial position. The platinum(IV) compounds with the lipophilic trans-carboxylate ligands inthe axial position were prepared by acylation of the trans-dihydroxo platinum(IV) species using anacyl halide in the presence of pyridine. In contrast to previous publications[1] the yields wereexcellent (up to 94%!).A series of new ethylenediamine (en) platinum(IV) complexes of the type Pt"} +{"text": "A slowly progressive Heymann nephritis (SPHN) was induced in three groups of rats by weekly injections of a chemically modified renal tubular antigen in an aqueous medium. A control group of rats received the chemically unmodified version of the antigen in an aqueous solution. One group of SPHN rats were pre- and post-treated with weekly injections of IC made up of rKF3 and rarKF3 IgM antibody at antigen excess (MIC) . One group of SPHN rats were post-treated with MIC 3 weeks after the induction of the disease and one group of SPHN animals received no treatment. The control group of rats received pre- and post-treatment with sonicated u/c rKF3. The incidence of immune-complex glomerulonephritis (ICGN) in the untreated SPHN rats was 87%, in the pre- and post-treated animals 13%, and in the post-treated-only rats 20%. Rats receiving sonicated ultracentrifuged rKF3 antigen did not develop ICGN. The present experiment demonstrates that the development of SPHN can be not only prevented but also effectively terminated by our newly developed modified vaccination technique."} +{"text": "In the present study we describe the effect of Zn(pic)2 and Zn(asp)2 on thereplication of VZV and on the infectivity of free virions. The experiments are done using BHK-21cells, a clinical isolate of VZV and Zn-complexes in concentration of 10 \u03bcM. When Zn-complexesare present during the whole period of infection, the yield of infectious virus progeny decreases upto 98%. The infectivity of VZV is completely restored after the removal of zinc. The virucidal effect ismanifested at the 2nd h of contact, when 90% of the virions are inactivated. The results show thatboth Zn(pic)2 and Zn(asp)2 specifically inactivate free VZV virions with no effect on viral replication.Zn(II) picolinate and aspartate, Zn(pic)"} +{"text": "In vivo and in vitro antitumour activity of Htbh,Thiiobenzyhdrazide (Htbh) and its Cu(II) complexes,"} +{"text": "Evidence in the literature suggests that hyperthermia (HT) or inhibitors of calmodulin can increase the sensitivity of rodent cells to bleomycin (BLM) by interfering with DNA repair functions. In an attempt to explore methods of improving the efficacy of thermochemotherapy we have investigated the individual and combined effects of HT (44 degrees C) and the calmodulin inhibitor trifluoperazine on early plateau phase monolayer cultures of mouse EMT6 tumour cells for simultaneous exposures to BLM. Early plateau phase cultures are relatively resistant both to HT and to BLM. The selected HT and TFP regimens were non-toxic. Comparing the sensitizing effect (given by the ratio: Do BLM/Do BLM + modifier) of the various regimens on BLM-treated cells, we found that: TFP alone had a marginal effect (ratio 1.3), HT alone showed significant potentiation (ratio 19) and the combination of HT and TFP strongly sensitized (ratio greater than 110) cells to BLM cytotoxicity. We propose that the use of calmodulin inhibitors in thermochemotherapy is worthy of further evaluation."} +{"text": "To the Editor: Verotoxin-producing Escherichia coli (VTEC) of serogroup O157 causes severe gastrointestinal and renal illness; clinical signs may be mild diarrhea, hemorrhagic colitis, or hemolytic uremic syndrome (HUS). Typically, 10%\u201315% of reported VTEC infections quickly progress to HUS identified 18 cases of verotoxin-producing SF-O157 infection in Scotland, 13 of which were associated with a nursery. HUS developed in 8 of the 18 patients; those with thrombotic microangiopathy were admitted to the renal unit of a specialist pediatric hospital, which immediately reports cases of HUS to HPS as part of national surveillance (t test showed that nadirs for serum albumin were significantly higher for children with SF-O157 HUS (p = 0.03; Statistical analysis by Our study highlights a number of lessons. Medical practitioners rarely have the opportunity to recognize patients at such an appreciable and predictable risk of progressing rapidly to anuric renal failure as they do when they see children with early O157 infection. Failure to appreciate the potential gravity of O157 infection and the possible development of HUS may result in avoidable illness and even death. Our investigation of the prehospital management of SF-O157 and non\u2013SF-O157 in this cohort found no difference in pharmacologic intervention or duration of delay in admission to hospital.Our study has limitations. A number of patients in the cohort were prescribed antimicrobial drugs and/or antimotility drugs or were sent home from the local hospital without hospital admission or further monitoring; such actions potentially exacerbate clinical outcomes (Our data suggest that infection with SF-O157 results in less severe colitis than does the more common non\u2013SF-O157 infection. Less severe colitis could result in a lower risk for renal disease because less verotoxin would be translocated into the bloodstream and bound to the kidneys. However, patients infected with SF-O157 had anuria for longer periods and consequently had longer sessions of peritoneal and hemodialysis. Although unknown bacterial or host inflammatory cytokines may contribute to enhanced disease progression, this observation is surprising and requires further investigation. Additional research is needed to learn more about the virulence of SF-O157 strains and establish other host factors that contribute to disease progression."} +{"text": "A total of 85 spontaneous rat fibrohistiocytic tumours were evaluated histologically and assessed for the presence or absence of metastases. The overall incidence in controls from 2-year carcinogenicity studies was 2.7%. The tumours occurred principally in the subcutaneous and deep soft tissues, and generally appeared after 18 months of age. Four histological types were recognized: histiocytic (17%), pleomorphic (33%), cellular (17%) and very fibrous (33%). Histiocytic tumours were highly malignant, and most produced metastases. Pleomorphic and cellular neoplasms occasionally produced metastases and must be regarded as potentially malignant. Very fibrous lesions were essentially benign. The close resemblance, both histologically and biologically, between rat and human fibrohistiocytic neoplasms supports the use of the fibrohistiocytic concept in laboratory-animal pathology. Study of these rat tumours may provide insight into the development of human fibrohistiocytic neoplasms."} +{"text": "Serum carcinoembryonic antigen (CEA) concentrations were found to be raised in 28 of 72 black patients (39%) with hepatocellular cancer (HCC). The degree of elevation was slight or moderate, except in 3 patients in whom values greater than 20 ng/ml were recorded. No significant correlation could be demonstrated in individual patients between the serum CEA concentration and various tests of liver function. The mean CEA value in the patients with cirrhosis in the non-tumorous liver was slightly higher than that in those without cirrhosis, but the difference did not reach statistical significance. There was no correlation between serum CEA and alpha-foetoprotein (AFP) levels."} +{"text": "The effects of histone deacetylase inhibitor (HDACi) treatment on SV40 transcription and replication were determined by monitoring the levels of early and late expression, the extent of replication, and the percentage of SV40 minichromosomes capable of transcription and replication following treatment with sodium butyrate (NaBu) and trichostatin A (TSA).The HDACi treatment was found to maximally stimulate early transcription at early times and late transcription at late times through increased numbers of minichromosomes which carry RNA polymerase II (RNAPII) transcription complexes and increased occupancy of the transcribing minichromosomes by RNAPII. HDACi treatment also partially relieved the normal down-regulation of early transcription by T-antigen seen later in infection. The increased recruitment of transcribing minichromosomes at late times was correlated to a corresponding reduction in SV40 replication and the percentage of minichromosomes capable of replication.These results suggest that histone deacetylation plays a critical role in the regulation of many aspects of an SV40 lytic infection. Structural and biological changes in chromatin structure are brought about by changes in the activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs) which add or remove acetyl groups from lysine residues on histone tails respectively. It has been well established that inhibition of HDAC activity is characterized by two important changes within the cell (i) an increase in the amount of hyperacetylated histones and (ii)Streptomyces and a potent inhibitor of HDAC activity. NaBu has been extensively used as a HDAC inhibitor (HDACi), though it is far less efficient (required in millimolar quantities) in its inhibition capabilities as compared to TSA (required only in nanomolar quantities). DNA micro array studies have shown that almost 7 % to 10% of genes undergo altered gene expression on HDACi using TSA for one hour. The cells were then washed twice in chilled PBS and extracted using the Hirt method of viral DNA extraction or RPA 70 [replicating Minichromosomes]). \u0394CT was expressed either as a percentage of minichromosomes containing the epitope for a particular antibody. Statistical analysis was performed using two tailed Student's t test.\u00ae polyacrylamide gel under denaturing conditions and electroblotted onto PVDF membrane . Antibodies used for western blotting were goat polyclonal anti GAPDH (sc-20357); Santa Cruz Biotechnology; rabbit GST-fusion anti VP1 [Protein extracted from untreated, NaBu treated and TSA treated 48 hour wild type 776 SV40 virus infected cells were harvested and lysed using 1\u00d7 RIPA buffer. Protein levels were determined with the Micro BCA\u2122 Protein Assay kit . The proteins were separated on a 4\u201320% PAGEranti VP1 and antiRNAP II: RNA Polymerase II, NaBu: sodium butyrate; TSA: trichostatin A; HDACi: HDAC inhibitors; ISF: immune selection and fragmentation; ISFIP: ISF followed by a second immunoprecipitation; ReChIP: re-chromatin immunoprecipitation; GAPDH: glyceraldehydes-3-phosphate dehydrogenase; VP1: viral protein 1; P.I.: post-infectionThe author(s) declare that they have no competing interests.LB performed the experiments and wrote the manuscript. BM edited the manuscript and provided input into the experiments. Both authors read and approved the final manuscript."} +{"text": "To test the role of serotonin in chemotherapy-induced nausea and emesis, ten cancer patients were pretreated with the serotonin synthesis inhibitor para-chlorophenylalanine (PCPA). PCPA (2 g 8 hourly for 2 or 3 days prior to cisplatin) reduced the spontaneous urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), inhibited the increase in urinary 5-HIAA induced by cisplatin and markedly attenuated the acute period of nausea and vomiting associated with the cytotoxic drug. These results indicate that gastrointestinal serotonin mediates cisplatin-induced emesis and that the amount of serotonin released by cisplatin is a major factor in determining the severity of the acute period of emesis experienced by the patient."} +{"text": "Between January 1981 and December 1985, 122 patients with non-seminomatous germ cell tumours (NSGT) were seen at a regional referral centre. Of these, a total of 98 patients received chemotherapy for metastatic disease. Treatment was given within collaborative EORTC Urology group studies, all of which involved cis-platin-containing schedules. Ninety patients had tumours of testicular origin, and their 2 year actuarial survival rate is 91%; 8 had tumours of extragonadal origin and their 2 year actuarial survival is 25%. Patients with testicular tumours were subdivided by volume of metastatic disease using the recommendations of the Testicular Cancer Subgroup of the MRC Urological Cancer Working Party and survival was significantly worse in the group with very large volume metastatic disease compared with the groups with large volume metastases and small volume metastases . There were 31 patients with Stage I disease at presentation; of these 6 were treated by prophylactic abdominal radiotherapy and 25 were managed by a policy of surveillance only. Seven of these Stage I patients (23%) relapsed with metastatic disease (median 8 months); all have been successfully treated with chemotherapy. These data confirm that the majority of patients now presenting with metastatic NSGCT are curable with chemotherapy, but that a small proportion with very large volume metastases or extragonadal tumours require alternative chemotherapy schedules."} +{"text": "Cytological studies in the light microscope showed that thioacetamide (TAA) depressed the mitotic index in cultures of skin fibroblasts at the lowest concentrations used (100 \u03bcg/ml). At high concentration (1 mg/ml), TAA tended to cause aberration in nuclear morphology. Ethylenethiourea (ETU) had no effect on either mitotic index or nuclear morphology at 1 mg/ml. Fibroblast cultures treated with 1 mg/ml TAA and cultures grown in the presence of 2 mg/ml ETU were studied by electron microscopy. In some TAA-treated cells there was unfolding of the nuclear membrane and enlargement and granulation of the nucleolus, but these effects were not correlated. In all cells, TAA caused severe and characteristic damage to the majority of mitochondria, whether or not there were nuclear aberrations. The organelle showed extensive swelling of the cristae of the inner membrane and an increase in matrix density. Ultrastructure of other cell components appeared to be unaffected by this treatment. In ETU-treated cells some less severe swelling of inner mitochondrial membranes was seen and only in a minority of cells, whilst all other cell structures appeared normal. Similar membrane swelling and increase in matrix density was seen in isolated rat liver mitochondria after incubation with TAA, indicating a direct antimitochondrial effect of the carcinogen.When yeast cells were treated with TAA and ETU, primary antimitochondrial activity of these compounds was apparent from (1) inhibition of growth in non-fermentable medium, (2) selective blockage of mitochondrial protein synthesis and (3) induction of mitochondrial mutations. TAA was much more effective than ETU in all these respects."} +{"text": "Sir,In a recent letter criticising one of several IARC Interphone studies investigating possible associations between mobile phone use and brain tumour risk, Editors NoteThe Editor-in-Chief of British Journal of Cancer now considers the correspondence published in Volume 94 Issue 9 and above closed."} +{"text": "Purpose: Soft tissue sarcomas (STS) account for less than 1% of all malignancies and constitute a heterogeneous tumor entity in which malignant fibrous histiocytomas (MFH) represent one-third and are characterized by a lack of type-specific differentiation. A defective mismatch repair (MMR) system cause the familial cancer syndrome hereditary non-polyposis colorectal cancer (HNPCC), and since occasional MFH have been described in HNPCC patients we assessed the contribution of defective MMR to the development of MFH.Methods: MMR status was characterized in a series of 209 histopathologically reviewed MFH. Tissue microarray sections from the tumors were immunohistochemically stained for the MMR proteins MLH1, MSH2 and MSH6, and cases with aberrant staining were further characterized for microsatellite instability.Results and Discussion: Two of the 209 STS\u2013a storiform-pleomorphic MFH and a myxofibrosarcoma\u2013showed concomitant loss of MSH2 and MSH6, but retained staining for MLH1 on both cases. The myxoid tumor also had a microsatellite unstable phenotype. These findings, together with previous observations of defective MMR in pleomorphic STS, indicate that these tumors may be part of the HNPCC-associated tumor spectrum and demonstrate that MMR defects occur in a small subset of STS."} +{"text": "Girls who engage in strenuous physical activity are often amenorrheic and have recently been reported to be at a reduced risk of breast cancer. To determine whether moderate amounts of exercise affect menstrual cycle patterns and ovulatory frequency in young postmenarcheal girls, the menstrual cycles and physical activity patterns of 168 high school girls were monitored for a 6 month period. Anovulatory cycles were associated with later age at menarche, fewer elapsed years since menarche and greater levels of energy expended per week in physical activity. After adjusting for age at menarche and years since menarche, there was a significant dose-related trend in the risk of anovular menstrual cycles associated with increasing levels of physical activity (1-sided P = 0.03). Major determinants of average cycle length were weekly average energy expenditure , age at menarche (an increase of 0.7 days per year of age) and race (Asians having cycles about 1.9 days longer than Caucasians). Because a major determinant of breast cancer risk may be the cumulative number of ovulatory cycles, these data suggest that regular participation in moderate physical activity, by reducing the frequency of ovulatory cycles in adolescence, may provide an opportunity for the primary prevention of breast cancer."} +{"text": "The structure of circulating chromogranin A (CgA) of phaeochromocytoma patients was characterised and compared with that of CgA extracted from tumours. Size exclusion chromatography experiments provided evidence that CgA is present in the blood of different patients, as well as in tumour extracts, as multiple forms having different hydrodynamic sizes of 600 kDa (CgA-I), 100 kDa (CgA-II) and 55 kDA (CgA-III). The amount of each CgA form as a proportion of the total antigenic material was different in different patients. Western blot analysis of chromatographic fractions indicated that these forms are made up by polypeptides of similar molecular weight (about 60-70 kDa). All CgA forms express the epitopes recognised by two monoclonal antibodies (A11 and B4E11), directed against residues 68-70 and 81-90 of human CgA. However, their relative immunoreactivity was markedly different. No evidence for the presence of multimeric complexes in the CgA-I fraction was obtained by various immunological and biochemical methods. These results suggest that circulating CgA in phaeochromocytoma patients consists of at least three forms that appear to be made up by polypeptides with similar molecular weight and different hydrodynamic properties and immunoreactivity. We hypothesise that different conformations and shapes contribute to the heterogeneity of circulating CgA."} +{"text": "After the 1999 West Nile (WN) encephalitis outbreak in New York, 2,300 overwintering adult mosquitoes were tested for WN virus by cell culture and reverse transcriptase-polymerase chain reaction. WN viral RNA and live virus were found in pools of Culex mosquitoes. Persistence in overwintering Cx. pipiens may be important in the maintenance of WN virus in the northeastern United States."} +{"text": "The prevalence of primary liver cancer (PLC) varies throughout the world. It has been attributed to variations in incidence of the predominant histological type, hepatocellular carcinoma (HCC). The incidence of PLC types other than HCC such as cholangiocellular carcinoma (CCC) is far less known, especially in low-incidence areas. The aetiology of HCC and other PLC types is obscure, with the exception of the association between HCC and cirrhosis as well as chronic viral hepatitis. The present retrospective incidence and aetiology study concerns a well-defined population from a period with a high autopsy frequency. Preserved biopsy specimens were re-evaluated histopathologically and patient records were studied. Among 590 histologically verified cases of PLC, HCC constituted 90%, CCC 8% and a mixed form of these types 1%. At the end of the study period the annual age-standardised incidence rate of HCC was 3.6 cases per 100,000 inhabitants. Other PLC types were hepatoblastoma (n = 3), fibrolamellar carcinoma (n = 2), angiosarcoma (n = 1) and infantile haemangioendothelioma (n = 1), each constituting less than 1% of the PLC cases. Comparing HCC with CCC we found that cirrhosis (70%) and alcoholism (21%) was significantly more frequent in HCC, and cholelithiasis was significantly more common (60%) in patients with CCC. In the majority of the PLC cases with liver cirrhosis this disorder was unknown before diagnosis of the tumour."} +{"text": "Malignant pericarditis, when associated with massive pericardial effusion, presents a critical condition in lung cancer patients. Because this condition often arises in terminally ill patients, intensive therapy such as multi-drug combination chemotherapy is rarely appropriate. This study evaluated the clinical relevance of intrapericardial administration of carboplatin for controlling malignant pericardial effusions associated with non-small-cell lung carcinoma (NSCLC). The method used for 10 eligible patients consisted of draining the pericardial effusion and infusing 300 mg/body of carboplatin in 50 ml of saline through an in-place catheter into the pericardial space and clamping the catheter for 40 min. Nine of the 10 patients showed satisfactory results, and 8 experienced complete regression of the effusion. No major or minor adverse effects were observed. Pharmacokinetics analysis revealed that the concentration of free platinum in the pericardial fluid was very high while that of total platinum in the circulating plasma was very low, assuring the usefulness of the intrapericardial instillation of carboplatin in terminally ill patients for controlling malignant pericardial effusion when the systemic delivery of cytotoxic agents is inappropriate. \u00a9 2000 Cancer Research Campaign"} +{"text": "The present study evaluated serial serum measurements of tissue polypeptide-specific antigen (TPS) in comparison with prostate-specific antigen (PSA) for assessment of tumour progression in patients with advanced prostate cancer receiving intermittent androgen suppression therapy (IAS). Twenty-three men were recruited into an IAS trial consisting of an initial 8 months of androgen suppression, followed by cycles of treatment cessation and resumption of therapy upon increases of PSA > 20 ng ml(-1) to prolong the hormone responsiveness of the tumour cells. Periods of androgen suppression resulted in reversible reduction in serum testosterone (< 1.8 nmol I(-1)) and PSA (< 4 ng ml(-1)) and decreases in tumour volume (mean reduction for first cycle 24 +/- 10%), indicating partial growth arrest and apoptotic regression of the tumours. In contrast to PSA values, non-specifically elevated TPS values were found in 8 of 23 patients. In 15 of 23 patients, TPS fell during periods of apoptotic tumour regression and increased simultaneously with testosterone and preceded the increases in PSA by 2 months during the period of treatment cessation. Although TPS represents a highly sensitive marker of tumour proliferation in this IAS clinical model of controlled tumour regression and regrowth, its low specificity compared with PSA limits its usefulness to monitoring of prostate cancer patients with proven absence of non-specific elevations of this marker."} +{"text": "The presence of tumour cells in the blood circulation may predict disease recurrence and metastasis. We have evaluated the specificity and sensitivity of detecting hepatoma cells in blood using nested polymerase chain reaction with primers specific for the alphafetoprotein (AFP) gene. The nested polymerase chain reaction amplified a 270-base pair AFP DNA fragment from cDNA of Hep 3B hepatoma cells. In a reconstitution experiment, AFP mRNA was detected from peripheral mononuclear cells isolated from 10 ml of blood containing as few as ten Hep 3B cells. Peripheral mononuclear cells from the blood of 20 hepatoma patients were analysed, and 19 patients showed positive AFP mRNA expression. Seven of 13 samples from hepatitis patients also showed positive AFP mRNA expression. All five paired samples of peripheral blood or umbilical cord blood from pregnant mothers and their babies, respectively, showed positive AFP expression. None of 22 control samples was positive. The presence of AFP mRNA in the blood of hepatitis or hepatoma patients suggests the presence of circulating hepatoma cells or hepatocytes in the circulation. The high incidence of AFP mRNA in the blood of hepatoma patients supports the notion of early haematogenous spreading of the disease."} +{"text": "The cytoreductive effects of anti-transferrin receptor (anti-TfnR) immunotoxins (ITs) and of ricin toxin against tumour micromasses have been evaluated in a multicellular tumour spheroid (MTS) model. More than 600 (656) MTSs obtained with human breast carcinoma (MCF7) or rat glioblastoma (9L) cell lines were treated individually with ITs or toxin and the effects induced by the treatment were measured for each MTS as volume variation vs time by applying the Gompertz growth model. Two dose-dependent patterns of MTS growth were observed in MTSs of both cell lines in response to IT or toxin treatment: (1) complete inhibition of MTS growth ('sterilisation'); and (2) partial/complete inhibition ('heterogeneous response'). Within the range of IT or toxin concentrations resulting in partial inhibition of MTS growth, the sensitivity of treated MTSs was extremely heterogeneous (the cytoreductive effects varying between 0.1 and 4 logs of cells killed for a given IT or toxin concentration). Analysis of the post-treatment regrowth kinetics indicated that treated non-sterilised and control MTSs reached the same final limiting volumes. However, the doubling time estimated for the surviving cells of treated MCF7 and 9L MTSs ranged between 15 and 50 h, indicating that each MTS had individual growing potential. In conclusion, our results indicate that at substerilising IT concentrations individual heterogenicity of MTSs may greatly influence the cytoreductive potential of ITs. An implication of our study is that the efficacy of an IT treatment in eradicating disseminated micrometastases may not be predictable a priori. The MTS model that we describe in this paper may help in dissecting out factors limiting the effect of ITs in three-dimensional tumours."} +{"text": "Twenty-seven patients with Hodgkin's (n = 19) and non-Hodgkin's (n = 8) lymphomas underwent cytological and colposcopic screening of the uterine cervix. Colposcopically directed cervical punch biopsies were taken from all patients in whom a colposcopic abnormality was detected. Lymphoma patients were compared with 79 controls with normal cervical cytology and no known haematological abnormality. Colposcopically directed punch biopsies were taken from the cervical transformation zone of all controls. Significantly more lymphoma patients (19%) than controls (3%) had CIN II or III (P less than 0.01) and cervical human papillomavirus infection, as judged by the presence of koilocytes . All six lymphoma patients with CIN had Hodgkin's disease (HD), and five had received combination chemotherapy. Half of the cases of CIN in lymphoma patients and all the cases of CIN in control patients were not detected by cervical cytology. This study suggests that female patients with HD are at increased risk of CIN, and that cervical cytology alone may be an inadequate form of screening for these patients."} +{"text": "Ontogenetic study on the expression of cytokeratin (CK) polypeptides within particularsubsets of rat thymic epithelial cells (TEC) has been performed by a large panel of anti-CKmonoclonal antibodies (mAbs) using the streptavidin-biotin immunoperoxidase method.Simultaneous presence of two or more CK subunits in the same TEC has been demonstratedby double immunoflouorescence labeling. The obtained results showed that the expressionof CK polypeptides in fetal and neonatal thymus differed from the adult patterns. The maindifference was observed in expression of CK10, 18, and 19 polypeptides. During fetalontogeny, CK10 and 18 are markers for most medullary TEC or a subset of medullary TEC,respectively, whereas CK19 is mainly a pan-TEC marker. In the adult animals, they arelocalized in the cortical and a subset of medullary TEC (CK18), subcapsular/perivascular andsome medullary TEC (CK19), or in a subset of medullary TEC and Hasall\u2019s corpuscles (HC)(CK10). The switch in their expression in the cortex was observed during the first two weeksof postnatal life."} +{"text": "In the present study, we investigated telomerase activation and its implications in plasma cell dyscrasias including monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM) and plasma cell leukaemia (PCL). All 5 patients with MGUS exhibited normal levels of telomerase activity in their plasma cells. Elevated telomerase activity was found in the samples from 21/27 patients with MM and 4/4 with PCL. In addition, 4 myeloma cell lines all expressed high levels of telomerase activity. The expression of telomerase reverse transcriptase (hTERT) and telomerase RNA template (hTER) was positively associated with the levels of telomerase activity in MM/PCL. Tankyrase expression was upregulated, concomitant with the induction of hTERT and activation of telomerase in MM/PCL. The present findings indicate that MGUS cells may not be immortalized and that activation of telomerase plays a role in the malignant transformation from MGUS to MM. \u00a9 2001 Cancer Research Campaign"} +{"text": "Two P388 cell lines with acquired resistance to daunorubicin have been shown to exhibit cross-resistance to anthrapyrazolone (NSC 357885). The degree of cross-resistance observed in these cell lines (58 and 150 fold) is similar to those observed towards daunorubicin (34 and 142 fold). However the decreased drug accumulation observed for daunorubicin in the resistant cell lines (4-6 fold) is not observed for anthrapyrazolone. Similarly, verapamil can increase daunorubicin accumulation in resistant cells but has no effect on anthrapyrazolone accumulation. It is concluded that in contrast to daunorubicin, decreased anthrapyrazolone accumulation is not the resistance mechanism operative in daunorubicin resistant cell lines towards anthrapyrazolone."} +{"text": "Directly observed therapy short course (DOTS) is the internationally recommended strategy to ensure cure of tuberculosis; it has become the standard for the diagnosis, treatment and monitoring of tuberculosis worldwide and has been implemented in 182 of 211 countries, covering more than 77% of world's population(The present study included patients with pulmonary tuberculosis (previously treated within RNTCP then included under CAT II) who failed DOTS CAT II treatment at various centers mainly from eastern and north-eastern parts of Uttar Pradesh and some even from surrounding states like Madhya Pradesh, Bihar and Uttarakhand. The study period extended from June 2004 to December 2005. Informed consent was taken from all subjects. All cases were critically evaluated by detailed clinical history including history of antitubercular treatment (ATT) taken before inclusion in DOTS. History regarding their socioeconomic background, smoking, alcohol intake and drug abuse was recorded and cause for their inclusion in CAT II was evaluated. Pretreatment sputum bacillary count was noted from their records. Leading questions were asked regarding non-adherence to CAT II treatment and the causes were sought into. They underwent thorough clinical examination, radiological and bacteriological evaluation. The radiographs were classified based on the report of American Thoracic Society., in CAT III , default in previous DOTS therapy and relapse [The reason for inclusion of these 95 cases in CAT II was treatment failure in CAT I . Thirty-8, 8.4%) . Since tThe pretreatment sputum bacillary load was 1+ in 22 cases (23%), 2+ in 31 (33%) and 3+ in 42 (44%) cases . MaximumThere were 35 cases (37%) who had taken CAT II treatment irregularly and finally became CAT II treatment failure cases (18 cases had interrupted treatment in the intensive phase while 17 in continuation phase and 80% of the non-adherence occurred for more than 1 month). The most important causes of interruption were the lack of relief of symptoms (37%), intolerance/toxicity (17%), inability to come for drug administration during intensive phase due to loss of earning and poor general condition (15%) and migration (14%).The study included 95 cases of failed CAT II (previously treated within RNTCP), who reported to our hospital for further treatment. The majority of patients (80%) were from economically productive age group (15-44 years) and from lower socioeconomic status. There were 32 patients who were initially wrongly categorized in CAT I since they had already received ATT for >1 month from local practitioners before inclusion in CAT I; they should have been categorized in CAT II directly, which could have been one of the important reason for the ultimate CAT II failure.n = 51) belonged to already failed CAT I cases and this could be one of the important reason for CAT II failure., drug intolerance (17%) and migration (14%). Another important factor was non-willingness to come thrice weekly for the drug administration (9%) during the intensive phase and most of the cases were from low socioeconomic strata and to them earning was more important than spending time at DOTS center for treatment. This factor becomes still more important when the symptoms of the disease are alleviated by initial treatment.The average contact of tuberculosis patients was as high up to seven to eight in our study and as nucleus of Indian household is very compact and transmission of disease is easier, presence of a resistant case in such a situation increases chances of primary drug resistance.The above study was prompted by large number of DOTS failure coming to our department and it throws some light on some of the problems of DOTS CAT II. The important causes of CAT II failure were previous CAT I failure, initial wrong categorization in CAT I, initial heavy bacillary load and non-adherence to treatment."} +{"text": "Mice were injected with tritiated misonidazole (750 mg/kg-1), killed after 24h and the excised tissues prepared for autoradiography (ARG) to identify sites of accumulation. The previously reported high grain count associated with bound misonidazole metabolite(s) was observed in the liver. The ratio of grain count in the emulsion above the centrilobular hepatocytes to the count over connective tissue (stroma) was 12. A higher count ratio for 'target' cells to stroma was observed in the following cells/tissues: meibomian gland , oesophagus (keratinised layer 60), incisor (enamel organ 17), nasal septum . For some of these tissues the explanation might appear to lie with localised hypoxia, but for others which were probably normoxic there is as yet no obvious reason for these findings."} +{"text": "Serum alpha-foetoprotein (AFP) and serum carcinoembryonic antigen (CEA) levels were measured, serially whenever possible, in 70 patients attending the Institute of Radiotherapy, Rotterdam, on account of testicular (65) or ovarian (4) germ cell tumours or, in one case, an endodermal sinus (yolk sac) tumour in the mediastinum. In 15 patients the disease was active; in the others it was in remission. Patients with active disease had raised serum AFP levels which correlated well with disease activity; no patient without evidence of active disease had raised serum AFP levels. None of the patients with active disease was found to have raised serum CEA levels. There was no correlation between serum AFP and CEA levels in patients with germ cell neoplasms, but good correlation between serum AFP levels and disease activity. Serum CEA levels did not correlate with disease activity, and serial determinations would therefore not be useful in monitoring progress in this group of diseases."} +{"text": "Serial determinations of serum alpha-foetoprotein (AFP) concentrations are well established in monitoring the response to therapy of malignant germ cell tumours. Using a radioimmunoassay (RIA) with a sensitivity down to 2kul-1 the majority (57%) of 28 patients with non-AFP producing germ cell tumours had measurable immunologically-reactive AFP in their serum while on treatment. Follow-up for 11-43 months (mean 27) without evidence of tumour activity indicated that this immunologically-reactive AFP was unlikely to be produced by tumour. In patients where the initial serum AFP was raised prior to chemotherapy the AFP concentration did not fall to the normal range at the end of the treatment in 16 (32%) of 41 patients. Follow-up of these patients for 9-48 months (mean 27) has resulted in 5 (12%) relapses in this group. Serum AFP greater than 20kul-1 three months after stopping chemotherapy was a good indicator of residual active tumour and 4 (57%) of 7 patients in this group relapsed. The production of detectable serum AFP is probably related to the type of chemotherapy used and only 7 (14%) of 51 patients treated for gestational choriocarcinoma had detectable AFP concentrations while on cytotoxic chemotherapy. The problem of interpretation of serum AFP concentration in patients with malignant germ cell tumour stresses the need to determine whether there are differences between AFP produced by germ cell tumours and that produced at other sites as a basis for a sensitive assay system able to discriminate between them."} +{"text": "Human dialysable Transfer Factor (TFd) extracted from lymphocytes of patients with transitional cell carcinoma of bladder (TCCB) was replicated in culture by lymphoblastoid cell lines. The effectiveness of two such TFdLs produced in vitro in transferring sensitivity to TCCB was assessed in the lymphocyte migration test (LMT) using formalin-treated TCCB cells as antigen. The results, showed that one TFdL transferred sensitivity in 5/14 cases and the other in 12/15, not only to leucocytes of healthy individuals but also to leucocytes of TCCB patients. Preliminary results showing an in vivo transfer of sensitivity are discussed."} +{"text": "RNA extracted from the spleens of tumour-bearing (TLRNA) and tumour-immune (ILRNA) mice was shown to transfer to normal lymphocytes (NL) the ability to produce factors that blocked specific tumour-cell cytotoxicity and mediated specific antibody-dependent cell cytotoxicity (ADCC). Aliquots of normal C3H mouse lymphocytes were treated with TLRNA or ILRNA and cultured in vitro in the absence of tumour antigen. Supernatants were collected at 24h intervals and tested in a microcytotoxicity assay for blocking and ADCC activities. Factors that inhibited tumour destruction by specifically sensitized lymphocytes at the level of both the tumour cells and effector cells were demonstrable in culture supernatants of NL pretreated with TLRNA (50 or 100 microgram/4 X 10(6) cells) but not ILRNA. However, treatment of NL with either RNA resulted in the production factors that mediated tumour-specific ADCC. Cytotoxicity testing and absorption studies of the tumour cell and a control cell (LM) indicated that factors mediating ADCC and blocking at the target-cell level were specific for the tumour. Suppressor activity at the effector-cell level was not absorbed by tumour cells and represents a separate and distinct mechanism of immunosuppression. These data indicate that RNA faithfully transfers \"suppressive\" as well as \"positive\" types of immune responses that have been reported previously for lymphocytes obtained directly from tumour-bearing and tumour-immune animals."} +{"text": "Itis suggested that the lower biological effects of IRIM compared to ICR are a consequence of the larger kineticinertness of the iridium(III) center with respect to ruthenium(III).Some biological aspects of the new complex imidazolium bisimidazole tetrachloro iridate(III)-IRIM- the iridium(III) analogue of ICR, were considered. More in detail the conformational effects produced by IRIM on DNA and the cytotoxic properties of IRIM on some selected human cell lines were measured.Dialysis experiments and DNA thermal denaturation studies are suggestive of poor binding of IRIM to DNA;formation of interstrand crosslinks is not observed. In any case CD measurements suggest that addition ofincreasing amounts of IRIM to calf thymus DNA results into significant spectral changes, that are diagnosticof a direct interaction with DNA. A number of experiments carried out on the A2780 human ovarian carcinoma,B16 murine melanoma, MCF7 and TS mammary adenocarcinoma tumor cell lines strongly point outthat IRIM does not exhibit significant growth inhibition effects within the concentration range 10"} +{"text": "Local free cell (eosinophils and macrophages) and extracellular (acid mucopolysaccharides) reactions were studied by histochemical techniques in 72 primary lung cancers (Group A), 17 pulmonary metastases and 5 lung tumours of unknown origin (Group B). Strong cellular reactions were more frequent in Group A than in Group B, whereas extracellular reactions were more frequent in Group B than in Group A. In both groups the degrees of eosinophilic infiltration and accumulation of acid mucopolysaccharides tended to be negatively correlated. In contrast, macrophages and eosinophils showed a positive correlation in the primary cancers, but none in the other tumours. The extracellular material had physical and chemical properties of the sulphated acid mucopolysaccharides. From its distribution it appeared to be derived from fibroblasts and/or tumour cells."} +{"text": "The occurrence of aberrations involving chromosomes 11 and 17 in malignant tissues of breast cancer patients has not yet been studied systematically. Using fluorescence in situ hybridisation (FISH) with centromere-specific probes, we determined chromosome 11 and 17 status in interphase nuclei from primary and/or metastatic breast cancer cells. In all cancerous specimens obtained from 30 patients, FISH identified cells with clonal chromosomal abnormalities, with aneuploidy rates ranging from 6% to 92% (median 59%). There was a gain of centromeric signals for chromosome 11, most likely corresponding to hyperploidy; aberrations of chromosome 17 in specimens from 26 patients (87%) were hyperploid as well; however, four cases (13%) showed loss of chromosome 17 centromeres. All specimens contained heterogeneous aneuploid cell populations with excessive gain of signals in some cases. The pattern of aneuploidy did not appear to correlate with tumour grade/stage and was comparable in primary tumours and corresponding metastatic axillary lymph nodes, indicative of genetic instability early in tumour development. Screening with a panel of FISH probes may lead to enhanced sensitivity and specificity in detecting malignant cells, as demonstrated in this study with effusions which could not be conclusively interpreted as being malignant by cytological criteria."} +{"text": "To elucidate the role of ras gene mutations during the early stage of colorectal tumour progression, K-ras gene mutations were analysed in 32 benign adenomas and 36 adenomas with focal carcinoma in the colorectum by microscraping of histologically pure regions from tissue sections, polymerase chain reaction-restriction fragment length polymorphism and in part by direct sequencing. Several regions were scraped out and analysed when an adenoma contained areas with different grades of dysplasia. The frequencies of K-ras gene mutation in mild dysplasia, moderate dysplasia and focal carcinoma were 19% (7/36), 51% (25/49) and 39% (14/36) respectively. The K-ras gene status was heterogeneous in 4 of the 11 benign adenomas from which multiple samples were obtained, and mutations were always found in the regions with more advanced dysplasia in these adenomas. Thirteen of the 36 adenomas with focal carcinoma showed heterogeneity of mutations between the adenoma region and the focal carcinoma. Seven of which had mutations only in the adenoma region. These findings indicated that the K-ras gene mutations occur during the late stage of adenoma progression and may confer a more advanced morphological phenotype of adenoma, but these mutations are not mainly involved in malignant transformation from adenoma to carcinoma."} +{"text": "Methotrexate (MTX) shows consistent cytotoxicity for melanoma cells in vitro but it is ineffective in clinical use at equivalent concentrations in vivo. This apparent paradox has been investigated by cell culture techniques and results quantified by cell number. In an in vitro model of high dose MTX therapy followed by leucovorin rescue (HD-MTX-LCR) there was survival of both melanoma and choriocarcinoma cell lines but not of an acute lymphocytic leukaemia cell line. The 70H metabolite of MTX was identified by HPLC in plasma samples of melanoma patients treated by HD-MTX-LCR, in which MTX concentrations approximately 10(-5) M were maintained for 24 h. However, metabolism per se is unlikely to account for the lack of response to MTX clinically. In vitro 70H MTX (10(-7) - 10(-6) M) was two orders of magnitude less cytotoxic for melanoma than MTX (10(-9) - 10(-8) M). The cellular accumulation of [3H]-MTX, using a rapid gradient centrifuge technique for separation of melanoma cells from medium, was reduced in the presence of 70H-MTX. The results suggest that reduced cellular uptake of MTX combined with biochemical rescue of tumour cells may partially explain the paradoxical lack of clinical response of melanoma to the drug."} +{"text": "The extracellular pH (pHe) of solid tumours is often lower than in normal tissues, and this may influence the uptake and/or activity of anti-cancer drugs. The cytotoxicity of mitoxantrone, paclitaxel and topotecan was therefore assessed at low pHe and after manipulation of intracellular pH (pHi) in murine EMT6 and in human MGH-U1 cells. The cytotoxic efficacy of all three agents was reduced at pHe 6.5 as compared with pHe 7.4. The ionophore nigericin and inhibitors of membrane-based ion exchange mechanisms that regulate pHi were used to cause intracellular acidification. Combined use of the cytostatic drugs with pHi modifiers reduced their cytotoxicity under both physiological and low-pHe conditions. The uptake into cells of mitoxantrone (a weak base) was inhibited at pHe 6.5 as compared with pHe 7.4, and smaller effects of low pHe to inhibit uptake of topotecan were also observed. DNA analysis of cell cycle distribution revealed that intracellular acidification, as observed during incubation at low pHe and/or using pHi modifiers, resulted in accumulation of cells in G1 phase, where they may be more resistant to these drugs. Reduced uptake of weak bases (mitoxantrone) at low pHe and altered cell cycle kinetics upon acidification are the postulated causes of reduced cytotoxicity of the agents investigated."} +{"text": "Nuclear and cytoplasmic oestrogen receptors (REN and REC) were sought in 5 normal cervices and in 43 specimens of squamous carcinoma of the cervix. All 3 tissues components of the 5 normal cervices contained both REN and REC. Thirty-five (81%) of the tumours contained receptors, but in only 9 (21%) were they found in both subcellular compartments. Twenty-four tumours (56%) had only REC and 2 had only REN. The potential therapeutic significance of these findings is not yet known, but it seems possible that tumours with an intact receptor mechanism might benefit from oestrogen therapy and have a more favourable prognosis."} +{"text": "We evaluated West Nile (WN) virus seroprevalence in healthy horses, dogs, and cats in New York City after an outbreak of human WN virus encephalitis in 1999. Two (3%) of 73 horses, 10 (5%) of 189 dogs, and none of 12 cats tested positive for WN virus-neutralizing antibodies. Domestic mammals should be evaluated as sentinels for local WN virus activity and predictors of the infection in humans."} +{"text": "In order to identify the possible role of the DCC gene in neoplasms of the human female reproductive tract, messenger RNA expression of the DCC gene was examined by reverse transcriptase-polymerase chain reaction, and expression of the DCC gene product was detected immunohistochemically. While histologically normal endometrium, cervical epithelium and ovary expressed detectable mRNA of the DCC gene, three of eight (37%) endometrial carcinomas, one of two (50%) cervical carcinomas and 9 of 22 (41%) ovarian malignant tumours had significantly reduced or negligible DCC expression, and another endometrial carcinoma and two other ovarian tumors underexpressed DCC when compared with histologically normal endometrial or ovarian tissues. Impaired DCC mRNA expression was detected more frequently in grade 3 ovarian epithelial tumours than in grade 1 tumours (P = 0.002). Loss of expression of the DCC gene product detected by immunohistochemistry significantly correlated with the loss of mRNA expression in ovarian carcinomas (P = 0.01 by chi-square test) or in both endometrial and ovarian carcinomas combined (P = 0.001). Loss of heterozygosity of the DCC gene was also evaluated by restriction fragment polymorphism analysis of the polymerase chain reaction-amplified DNA fragment. Loss of heterozygosity of the DCC gene was detected in one of seven (14%) informative cases of endometrial carcinomas, 1 of 11 (9%) informative cases of cervical carcinomas and two of six (33%) informative cases of ovarian tumours. These results demonstrate that inactivation of the DCC gene, especially by the loss of expression, plays a significant role in the aetiology of neoplasms of the human reproductive tract."} +{"text": "Signal transduction pathways activated by injury play a central role in coordinating the cellular responses that determine whether a cell survives or dies. GADD153 expression increases markedly in response to some types of cellular injury and the product of this gene causes cell cycle arrest. Using induction of GADD153 as a model, we have investigated the activation of the cellular injury response after treatment with taxol and cisplatin (cDDP). Activation of the GADD153 promoter coupled to the luciferase gene and transfected into human ovarian carcinoma 2008 cells correlated well with the increase in endogenous GADD153 mRNA after treatment with taxol but not after treatment with cDDP. Following treatment with cDDP, the increase in endogenous GADD153 mRNA was 10-fold greater than the increase in GADD153 promoter activity. Likewise, at equitoxic levels of exposure (IC80), cDDP produced a 5-fold greater increase in endogenous GADD153 mRNA than taxol. The tyrosine kinase inhibitor tyrophostin B46 had no significant effect on the ability of taxol to activate the GADD153 promoter, but inhibited activation of the GADD153 promoter by cDDP in a concentration-dependent manner. Tyrphostin B46 synergistically enhanced the cytotoxicity of cisplatin; however, the same exposure had no significant effect on the cytotoxicity of taxol. We conclude that (1) taxol and cDDP activate GADD153 promoter activity through different mechanisms; (2) the signal transduction pathway mediating induction by cDDP involves a tyrosine kinase inhibitable by tyrphostin B46; and (3) that inhibition of this signal transduction pathway by tyrphostin synergistically enhances cDDP toxicity."} +{"text": "In 104 patients with gastric cancer the serum proteins carcinoembryonic antigen (CEA), C-reactive protein (CRP), alpha 1-acid glycoprotein (AGP) (orosomucoid) and alpha 1-antichymotrypsin (ACT) were measured pre-operatively. The estimated median survival of patients with both raised CEA and ACT was only 5 weeks in contrast to 64 weeks for those with both proteins normal. An intermediary group with one of these proteins raised and the other normal had an estimated median survival of 15 weeks. Similar results were obtained by considering a combination of CEA with either AGP or CRP. For these data the results were not explicable in terms of associations between survival time and patient's age, stage, operative procedure, histological classification or site of primary tumour."} +{"text": "The expression of complex carbohydrates recognised by Helix pomatia lectin has been shown to predict unfavourable prognosis in breast and other cancers. It has been suggested that the prognostic significance of HPA binding may be through recognition of either Tn epitope or blood group A antigen GlcNAc-->R). In this study, the expression of glycoproteins terminating in alpha-GalNAc residues was investigated immunohistochemically using HPA and two monoclonal antibodies--BRIC 66 and BRIC 111 (anti-Tn). In paraffin sections, 74/87 (85%) of breast cancers expressed HPA-binding ligands, while 28/87 (32%) were positive for BRIC 66 binding and 25/87 (29%) expressed Tn. Distribution of staining patterns were distinctive and different with the three markers. BRIC 66, BRIC 111 and HPA binding to glycoproteins derived from breast cancer homogenates and to blood group A and Tn positive glycoproteins in Western blots confirmed the immunohistochemistry data. The results suggest that the prognostic significance of HPA binding in breast cancer is unlikely to be simply through recognition of blood group A antigen or Tn epitope on cancer cells. Breast cancers may express a complex profile of related but distinct glycans sharing similar terminal immunodominant sugar GalNAc, which may be implicated in aggressive biological behaviour."} +{"text": "The transformation of Wistar rat embryo cells in vitro has been studied in passaged cultures using two criteria for transformation: (1) the ability of cells to form colonies in soft agar and (2) the ability of cells to form tumours in young syngeneic animals. In general there was good correlation between the two criteria. Spontaneous transformation was observed in all untreated cultures by 44 weeks although, by not allowing the cells to become confluent, the tendency was for cultures to transform earlier (i.e. 15-21 weeks). It was noticeable that despite untreated cultures having been in vitro for different lengths of time, most cultures transformed after a similar number of passages (42-50). Treatment of the embryo cells with the alkylating agent nitrosomethylurea (NMU) or benzopyrene (BP) sometimes resulted in transformation after a shorter period in vitro than the controls (minimum 12 weeks) although some treated cultures took longer. Transformed cells produced transplantable fibrosarcomata in syngeneic hosts and those arising from NMU transformed cells were histologically different from those arising from spontaneously transformed cells. The significant of spontaneous transformation in in vitro rat cell transformation systems is discussed."} +{"text": "P < 0.0001). However, TIMP-1 expression was not increased in NPA and SW579 cells, both of which are derived from poorly differentiated thyroid tumours. Immunohistochemical study showed strong TIMP-1 staining in the stroma cells of advanced stages of carcinomas. Overexpression of TIMP-1 by gene transfer resulted in a significant suppression of the malignant phenotype of NPA cells as judged by an in vitro tumour invasion assay. These results suggest that high levels of TIMP-1 transcripts in advanced stages of thyroid carcinoma likely come from stroma rather than thyroid cancer cells, and TIMP-1 may function as a thyroid tumour invasion/metastasis suppressor. \u00a9 1999 Cancer Research CampaignTumour cell invasion and metastasis is a multistep process that involves the degradation of extracellular matrix proteins by matrix metalloproteinases (MMPs). Tissue inhibitors of metalloproteinases (TIMPs) act as negative regulators of MMPs and thus prevent tumour cell invasion and metastasis by preserving extracellular matrix (ECM) integrity. In the present study we examined the expression of one member of TIMPs, TIMP-1, in 39 thyroid tumour specimens and two thyroid carcinoma cell lines (NPA and SW579). We also investigated the effect of high TIMP-1 expression on the invasive potential of NPA cells. Northern blot analysis showed that TIMP-1 mRNA levels correlated directly with tumour aggressiveness: the highest number of TIMP-1 transcripts was found in stages III and IV vs benign goitre ("} +{"text": "Rh2(tfacam)4 was tested both in vitro (U937 and K562 human leukemia cells and Ehrlich ascitic tumor cells) and in vivo for cytostatic activity and lethal dose determination, respectively. This is the first rhodium tetra-amidate to have its biological activity evaluated. The LD50 value for Rh2(tfacam)4 is of the same order as that of cisplatin, and it was verified that the rhodium complex usually needs lower doses than cisplatin to promote the same inhibitory effects.The rhodium (II) complexes Rh"} +{"text": "Equimolar concentrations of cysteamine and reduced glutathione protected against the cytotoxicity of 5 mM misonidazole (MISO), whereas 5mM ascorbate enhanced its toxicity to hypoxic CHO and HeLa cells in vitro. Protection (reappearance of a shoulder region) could also be seen when cysteamine was added at later incubation times. These changes in toxicity were accompanied by changes in drug metabolism, as evidenced by radiochromatograms of cell extracts obtained after treatment with 14C-labelled MISO. In contrast, radiochromatograms obtained from cells treated with toxic levels of MISO (75 mM) under aerobic conditions indicated no drug metabolism. Both toxicity and drug metabolism could be immediately halted by introducing O2 during hypoxic exposure to MISO. These observations are discussed in terms of a possible model for the metabolism-mediated toxicity of MISO and the roles which sulphydryls and O2 may play."} +{"text": "Optimized functional results are difficult to achieve following hand injuries. This prospective study was undertaken to evaluate the functional outcome after surgical stabilization of metacarpal and phalangeal fractures.Forty-five fractures of digits of hand in 31 patients were managed by surgical stabilization. Five fractures were fixed with closed reduction and percutaneous Kirschner wire fixation; 10 with external fixator; 26 with open reduction and Kirschner wire fixation; and four with open reduction and plate and screw or screw fixation.Final evaluation of the patients was done at the end of three months. It was based on total active range of motion for digital functional assessment as suggested by the American Society for surgery of hand. Overall results were excellent to good in 87%. Better total active range of motion (excellent grade) was observed in metacarpal fractures (47%) versus phalanx fractures (31%); closed fractures (57%) versus open fractures (27%); and single digit involvement (55%) versus multiple digits (29%). Excellent total active range of motion was observed with all four plate and screw/ screw fixation technique (100%) and closed reduction and percutaneous kirschner wire fixation (60%). Twenty-two complications were observed in 10 patients with finger stiffness being the most common.Surgical stabilization of metacarpal and phalangeal fractures of hand seems to give good functional outcome. Closed fractures and fractures with single digit involvement have shown a better grade of total active range of motion. Fractures of metacarpals and phalanges constitute between 14-28% of all visits to the emergency department.Forty-five metacarpal and phalangeal fractures of the hand in 31 patients aged 14 yrs or more were included in the prospective study conducted during the period 2004-2005. Unstable metacarpal and phalangeal fractures, intraarticular fractures, avulsion fractures, fracture dislocations and open fractures with sharp and clean wounds were included in the study. An unstable fracture was defined as one in which the patient was able to move the adjacent joints by less than 30% of the expected normal range of motion.The fractures were reduced and fixed using various implants including Kirschner wires, external fixators, plates or screws depending on fracture site, configuration and associated soft tissue damage. The fractures were divided into four groups depending on the type of internal fixation.Group I (n=5): The closed reduction and percutaneous Kirschner wire fixation was done in patients with fractures of the middle phalanx, proximal phalanx and metacarpal when closed reduction was possible.Group II (n=10): Open/closed reduction and external fixation was performed for open fractures with sharp and clean wounds.Group III (n=26): Open reduction and Kirschner wire fixation was done in fractures where closed reduction was not possible Figures \u20134. RetroGroup IV (n=4): Here open reduction with plate and/or screw fixation was performed for long oblique or spiral fractures of both metacarpals and phalanges Figures \u20138. The aThe hand was kept elevated and patients were encouraged to perform movements of the fingers and hand to prevent edema and stiffness. Antibiotics were given for 48h and prolonged in cases of open fractures. The Kirschner wires and external fixation devices were removed between 3 to 6 weeks. Active assisted mobilization was started after removal of Kirschner wire / external fixator usually at three to six weeks. Wax bath and contrast bath were given. Continuous passive motion (CPM) was not used. Patients were followed weekly for the first month and fortnightly for the next two months before final evaluation at three months.The mean age of the patients was 35.6 years (range 14-74 years). The most common mode of trauma was assault and roadside accidents (60%). In all, 43 digits were involved and there were a total of 45 fractures. Twenty-two patients had only a single digit involvement while two digits were involved in six patients and three digits in three patients. Fracture site and configuration in metacarpal and phalanges is shown in The functional outcome after fracture treatment was assessed by calculating total active range of motion (TAM).Metacarpal fractures (n=32) had an excellent n=15, 47%); and good TAM in 94% of fractures [Figures 5, 47%; aOverall end results of hand fractures in 31 patients managed by surgical stabilization were excellent in 14 (45.16%); good in 13 (41.93%); fair in three (9.68%); and poor in one(3.23%).A total of 22 complications were observed in 10 paResults in various groups according to TAM are tabulated in Many factors, such as delicate handling of tissues, preservation of gliding planes for tendons, prevention of infection and early and appropriate physiotherapy other than accurate reduction and fixation affect recovery of good mobility.5et al.et al.A higher incidence of excellent TAM n=13, 57%) was observed in closed fractures as compared to open fractures n=6, 27%). Pun , 27%. Pu% was obset al.Closed reduction and percutaneous Kirschner wire fixation was done where fracture could be reduced and maintained by closed means. Of the five fractures treated, three achieved excellent TAM (60%). Belskey et al.et al.External fixator was used for surgical stabilization of 10 open fractures. Advantage of external fixation is that no joint transfixation is required and hence patient does not develop any stiffness of the adjacent joints. Sixty per cent (n=6) of the fractures treated by this technique achieved excellent to good TAM. The results are comparable to those reported by FreelandOpen reduction with Kirschner wire fixation was done for stabilization of 26 fractures using three different techniques. (a) Retrograde insertion of Kirschner wire (n=16) with transfixation of joint was first advocated by Vomsaal.Open reduction and plate fixation was done in two fractures and two patients were treated with screw fixation. Excellent TAM was obtained in all four fractures treated by these techniques. Bosscha and SnellenFinger stiffness was the most commonly observed complication in the present series. Only one case of open fracture developed superficial infection. None of the cases developed osteomyelitis. Two patients with multiple fractures developed angulation at fracture site as the Kirschner wire was removed four weeks postoperatively before any radiological union. The movements, however, were almost full at all joints. Two cases of multiple fractures developed hypertrophic nonunion after Kirschner wire fixation. The cause was thought to be inadequacy of Kirschner wire fixation, which cannot check movements at fracture site completely. Ikuta and Tsugeet al.The results of the present study following surgical stabilization of fractures of metacarpals (94% excellent to good) and phalanges (54% excellent to good) were observed to be superior to those reported by Duncan Limitation of the study: The sample size is very small in some groups for statistical comparison.Surgical stabilization of metacarpal and phalangeal fractures of the hand seems to give good functional outcome. Closed fractures and fractures with single digit involvement are important determinants to achieve a better grade of total active range of motion."} +{"text": "The concentration of bound sialic acid in the sera of 56 normal subjects and 65 subjects with breast cancer was measured, in order to determine (1) whether serum sialic acid concentrations are raised in breast cancer and (2) whether the concentration of sialic acid in serum reflects tumour stage. The amount of sialic acid in serum was compared to serum carcinoembryonic antigen (CEA) values. Urinary hydroxyproline and serum alkaline phosphatase concentrations were used as indicators of bone and liver involvement. Erythrocyte sedimentation rate (ESR) was also measured. Significantly elevated serum sialic acid concentrations were found in breast cancer, and showed correlation with tumour stage. Serum sialic acid values did not correlate with CEA values. The results suggest that measurement of serum sialic acid concentrations may be of adjunctive value in assessing tumour stage."} +{"text": "We have studied the incidence of microsatellite instability at three trinucleotide repeats and seven dinucleotide repeats from five chromosomal regions, in a group of 30 mammographically detected 'early' invasive breast cancers and correlated its occurrence with clinicopathological parameters. The myotonic dystrophy (DM-1) trinucleotide repeat was analysed in 48 additional cases. In 4 out of 78 (5%) paired tumour-normal DNA samples we found evidence of somatic microsatellite instability at DM-1: a novel allele of a different size was seen in the tumour DNA which was not present in the normal DNA sample. All four tumours that showed evidence of instability were from the core group of 30 cases (13%) and were well or moderately differentiated, oestrogen receptor-positive, infiltrating ductal carcinomas. Two of these tumours were unstable at nine of ten loci studied, both trinucleotide and dinucleotide repeats. DNA prepared from different normal tissues showed no evidence of instability, for all four instability cases. These data indicate that microsatellite instability is specific to the tumour DNA and is an early event in the genesis of some sporadic breast cancers."} +{"text": "To date, cytogenetic studies on pancreatic carcinoma are rare, and little is known about the frequency of cytogenetic aberrations in primary carcinomas compared with metastatic tumour cells. We therefore evaluated the frequency of chromosomal aberrations in 12 primary pancreatic carcinomas and in effusion specimens from 25 patients with pancreatic cancer by using interphase fluorescence in situ hybridization (FISH) and a panel of four centromeric probes. Hyperdiploidy and chromosomal imbalances, predominantly affecting chromosome 8, were a constant finding in metastatic effusion cells, whereas concordant gain of chromosomes or relative loss of chromosome 18 characterized primary pancreatic carcinomas. The potential role of oncogenes located on chromosome 8 for pancreatic cancer progression was further investigated by double-hybridization studies of aneuploid effusion cells with a probe to 8q24 (MYC) and a centromeric probe to chromosome 8, which demonstrated amplification of the MYC oncogene in two of ten cases (20%). Finally, a potential application of basic findings in the clinical setting was tested by searching for micrometastatic cells in effusions from pancreatic cancer patients primarily negative by FISH. Two-colour FISH in combination with extensive screening seems to be a useful tool to unequivocally identify micrometastatic cells by demonstrating hyperdiploidy and intranuclear chromosomal heterogeneity."} +{"text": "Diabetic maculopathy, the leading cause of vision loss in patients with type 2 diabetes, is characterized by hyper-permeability of retinal blood vessels with subsequent formation of macular edema and hard exudates. The degree of hyperglycemia and duration of diabetes have been suggested to be good predictors of retinal complications. Intervention studies have determined that while intensive treatment of diabetes reduced the development of proliferative diabetic retinopathy it was associated with a two to three-fold increased risk of severe hypoglycemia. Thus we hypothesized the need to identify downstream glycemic targets, which induce retinal vascular permeability that could be targeted therapeutically without the additional risks associated with intensive treatment of the hyperglycemia. Betacellulin is a 32 kD member of the epidermal growth factor family with mitogenic properties for the retinal pigment epithelial cells. This led us to hypothesize a role for betacellulin in the retinal vascular complications associated with diabetes.A disintegrin and metalloproteinase (ADAM)-10 which plays a role in the cleavage of betacellulin was seen in the retinas of diabetic mice and humans.In this study, using a mouse model of diabetes, we demonstrate that diabetic mice have accentuated retinal vascular permeability with a concomitant increased expression of a cleaved soluble form of betacellulin (s-Btc) in the retina. Intravitreal injection of soluble betacellulin induced retinal vascular permeability in normoglycemic and hyperglycemic mice. Western blot analysis of retinas from patients with diabetic retinopathy showed an increase in the active soluble form of betacellulin. In addition, an increase in the levels of These results suggest that excessive amounts of betacellulin in the retina may contribute to the pathogenesis of diabetic macular edema. The incidence of diabetes world-wide, is expected to reach epidemic proportions by 2025. Progression of diabetic retinopathy often results in diabetic macular edema, which is a consequence of the breakdown of the blood-retinal barrier, increased retinal vascular permeability and leakage of plasma from small blood vessels in the macula leading to loss of central vision. While epidemiological studies have suggested that glycemic control plays a major role in the development of vascular complications of diabetesBetacellulin (BTC) is a 32 kD member of the epidermal growth factor (EGF) family that was originally isolated from the conditioned medium of a mouse pancreatic \u03b2-cell tumor lineRecombinant human VEGF was a kind gift from Genentech, CA and recombinant betacellulin was purchased from R&D. Antibodies: polyclonal anti-mouse and anti-human betacellulin antibody (R&D), monoclonal anti-ADAM-10 and HRP-conjugated anti-rabbit, anti-mouse IgG antibodies (Amersham Pharmacia Biotech) and anti-goat IgG (Santa Cruz). Post mortem human eyes were obtained from he National Disease Research Interchange (NDRI), Philadelphia. Postmortem time ranged from 3\u201310 hours.Lysates from mouse or human retina prepared using sonication on ice with RIPA buffer (Boston Bioproducts) containing EDTA free protease inhibitors (Roche) were subjected to SDS-PAGE. Proteins were probed with antibody and detected with either a HRP-conjugated anti-rabbit or anti mouse IgG antibody followed by ECL. The blots were restripped with Restore\u2122 solution (Thermo Scientific) for 30 minutes and reprobed as indicated.6\u20138 week old C57BL6 mice were used in this study. The animals were cared for in accordance with the ARVO statement for the Use of Animals in Ophthalmic and Vision research. All experimental procedures used aseptic sterile techniques and were approved by the Animal Care and Use Committee of the Cleveland Clinic (ARC08792).6\u20138 week old mice were rendered diabetic with 3 consecutive daily intraperitoneal injections of STZ (55 mg/Kg) freshly dissolved in citrate buffer (pH 4.5). Control mice were given injections of buffer alone. Development of diabetes (defined by blood glucose greater than 250 mg/dl) was confirmed 1 week after the initial injection (One Touch\u00aeltra\u00aeTest Strips and One Touch\u00aeUltraMini\u2122glucometer).Vascular permeability in the retina was quantitated after 3\u20134 weeks of diabetes using an Evans blue quantitation technique as described previously Steptozotocin-induced diabetic mice with hyperglycemia (fasting blood sugar \u2265200 mg/ml) were examined for increases in retinal vascular permeability using an Evans Blue leakage assay. As described previously To determine if the increase in soluble active betacellulin seen in diabetic mice could contribute to increased vascular permeability we examined whether increased concentration of betacellulin in the retina could induce retinal vascular leakage in normal mice. Intravitreal injections of increasing doses of recombinant soluble betacellulin (0\u2013300 ng) resulted in increased retinal hemorrhage and diabetic macular edema (DME), we wanted to determine if the effect of betacellulin was VEGF-dependent. No increase in VEGF was observed in mouse retinas injected with betacellulin indicatiBetacellulin is expressed as a membrane anchored precursor protein (pro-betacellulin) containing an extracellular N-terminal ectodomain, a transmembrane domain and a cytoplasmic domainadisintegrin and metalloproteinase-10) can mediate the constitutive and activated shedding of pro-betacellulinRecent studies have determined that ADAM-10 , characterized by an absolute insulin deficiency as a consequence of destruction of the insulin secretory pancreatic \u03b2 cells of the islets of Langerhans; and type II diabetes and type II (30% incidence)ADAMs and ADAM-10 in particular have been recently reported to be novel regulators of vascular permeabilityWe have examined betacellulin levels in the plasma and found no significant increase in betacellulin in the circulating plasma of patients with PDR (n\u200a=\u200a23) . While tNeurod-Btc gene therapy to be a promising approach to induce islet regeneration for the treatment of insulin-dependent diabetesRecent studies have suggested Figure S1Betacellulin induces retinal vascular leakage independent of VEGF. Retinas from mice injected intravitreally with PBS or betacellulin (200 ng) or no injection (control) were evaluated for VEGF protein 24 hours post injection.(0.74 MB TIF)Click here for additional data file.Figure S2No significant increase in circulating plasma betacellulin in patients with proliferative diabetic retinopathy. Plasma was prepared from whole blood from patients with no diabetes, diabetes with no evidence of retinopathy and proliferative diabetic retinopathy and analyzed by ELISA for betacellulin.(0.54 MB TIF)Click here for additional data file."} +{"text": "It is universally acknowledged that if cancer is to be controlled, prevention and down staging are essential. In the year 2000 about 10 million new cases were registered, while 6.3 million people died from cancer worldwide. Stamps are regarded as a very useful and educative tool in fighting cancer by creating awareness and raising money for treatment and research. This year (2003) is the seventy-fifth anniversary of the issue of the first anticancer stamps in 1928, so an up-to-date review of the field of oncophilately is timely. Cancer is posing a serious social and economic problem globally since it was estimated by various organisations including It is necessary to take effective preventive measures and cancer awareness among the general population is essential. It is universally recognised that the anticancer stamps can play an excellent role in various ways as to create awareness and to collect money for treatment and research. This is because philately or stamp collection is still one of the most popular hobbies. Due to their universal circulation and appeal, stamps are powerful and effective messengers. It is also possible to use stamps issued for some other purposes in describing various aspects of cancer as will be exemplified later on. Only one report and two Five Swedish stamps on King Gustaf V issued in 1928 are regarded as the first anticancer stamps because the entire amount collected from sales was donated for cancer control (stamp 2). This was followed by a set of three Danish stamps issued in 1929 (stamp 3). Norway is the third country with a semipostal issue in 1931 (stamp 4) in the aid of Norwegian Radium Hospital. Since then, numerous countries have published several regular or semipostal stamps (stamps 5\u20138). Record shows that by the year 1964, 46 countries had issued 110 stamps and by tStamps are available on lung cancer (stamp 13), which is the most common cancer in terms of both incidence and mortality in 2000 . It is tBreast cancer is the most prevalent cancer in the world among females in 2000 . Many stFigure 1is stamp .Stamps have also been published on other cancers like prostate cancer . Passive smoking is also very dangerous. Evidence suggests that nonsmoking women married to smokers experience an excess risk of developing lung cancer in the order of 20%. A Japanese stamp may be used to illustrate this aspect (stamp 24).Excessive drinking causes liver, oral, pharynx, larynx and oesophageal cancers, and may increase the risks of colorectal and breast cancers. Simultaneous drinking and smoking habits are much more dangerous. Alcoholic beverages consumption potentiates the effects of tobacco smoking on cancers of the mouth, pharynx, oesophagus and larynx and has been estimated to account for about 3% of all cancer deaths. Stamps issued by many countries warn people about the use of alcohol (stamps 25 and 26).The British Surgeon Dr Percivall Pott demonstrated the earliest example of occupational cancer in 1775, showing a greater incidence of scrotal cancer among young chimneysweepers who were exposed to tar. Lord Shaftesbury, the great social reformer, worked for the well-being of these poor lads. A British stamp is available in his memory, depicting the hand of a chimneysweeper holding the brush (stamp 27). The stamp showing a picture of aniline (stamp 28) illustrates the need for care to be taken to minimise exposure to this chemical, because as early as in 1895, Rehn was the first to observe increased rate of bladder cancers among aniline dye workers. The stamp 29 describing the structure of benzene may be similarly used to show the need to take care in handling benzene, since it is proved to be a potent human carcinogen causing leukaemia with a latency period of about 15\u201320 years. It is widely used as a solvent in leather, petroleum and other industries. Polyaromatic hydrocarbons (PAH) are found in exhaust gases from automobiles run by petrol and diesel, from railway locomotives and in smoke, dust and exhaust gases from various factories. It is advisable to use protection to prevent inhaling of exhaust gases from automobiles as described in a Swedish stamp (stamp 30).92235U (stamp 31) and development of cancer dates from early observations on survivors of the atomic bombs in Japan.The relation between ionising radiation from various sources including radioactive substances such as Ultraviolet radiation from sunlight is the major risk factor for skin cancers and that of lip. Stamps showing sunrays and flares (stamp 32) may be used to make people aware of the dangers of overexposure to sunrays.Figure 3Links have already been established between some viral infections and the development of cancers such as Epstein\u2013Barr virus and Burkitt lymphoma, hepatitis B and C and hepatocellular (liver) carcinoma, human papilloma virus (HPV) and cervical cancer in females, human immunodeficiency virus (HIV). AIDS patients infected with HIV have higher incidence and death rates from malignancies like Kaposi's sarcoma, non-Hodgkin's lymphoma, etc. Hence awareness regarding HIV infection is very important from a cancer preventive perspective also. So far about 65 countries have issued over 120 anti-AIDS stamps (e.g. stamps 33\u201336).Catharanthus rosea) may be used to point out that some important alkaloidal drugs like vincristine and vinblastine have been isolated from the plant (stamp 40). Taxol has been isolated from Taxus brevifolia (Pacific Yew tree) and Taxus baccata (stamp 41).Figure 4Nowadays, three chief treatment modalities \u2013 surgery, radiotherapy and chemotherapy \u2013 are used in all sorts of combinations. Bangladesh has issued a beautiful stamp depicting the picture of a crab attacked with these three modes of treatment (stamp 37). One can find individual stamps on surgery (stamp 38), radiotherapy (stamp 39) and chemotherapy. Anticancer drugs are obtained by chemical synthesis or from natural sources such as plants. A French stamp on the Madagascar periwinkle plant and using \u2018smokeless\u2019 tobacco products like crude leaves, snuff, etc.Limit alcohol consumption to a minimum, if at all (stamps 26 and 43).\u03b2-Carotene present in various yellow, green or orange fruits and vegetables is converted to vitamin A in the liver. Hence it is recommended to eat fresh vegetables and fruits rich in these substances and vitamins like carrot, beans, gourd, broccoli, cauliflower, tomato, etc. (stamp 47) and a variety of fruits (stamp 48).Both vitamin A (stamp 45) and vitamin C (stamp 46) are considered as antioxidants and possess potential cancer chemopreventive properties by inhibiting precancerous changes and damages of DNA leading to cancer. The protective effects of dietary fibre present in vegetables against a number of cancers like colorectal, oesophageal and stomach have been demonstrated. Hence it is advisable to eat vegetables rich in roughage like jackfruit (stamp 49), beans (stamp 47), ladies finger, etc.Curcuma longa (stamp 50) is the source of turmeric, which contains the yellow natural colouring agent namely curcumin which may have chemopreventive properties have been shown in lab studies to have antitumour as well as tumour promotion inhibitory activities. Onions and ginger have also been shown to possess similar properties.Constituents of Camellia sinensis (stamp 52). Tea is one of the most ancient and next to water the most widely consumed liquid in the world. Many phytochemicals including polyphenols catechin compounds like epigallocatechin gallate (EGCG), etc. present in tea leaves have shown potential chemopreventive and antioxidant properties.Tea is a beverage made from the leaves of the plant species Figure 5Diet has a vital role in the prevention of about 30\u201340% of all cancers (Being very underweight or overweight increases the risk of cancer. Obesity (stamp 53) is associated with the endometrium, breast, kidney, colorectal and gallbladder cancers. Thus it is advisable to maintain a healthy body weight.An active lifestyle is recommended. Physical activity decreases the risk of colon and breast cancers. Walking, cycling, gardening, household chores, climbing the stairs, practising yoga (stamp 54), etc. are recommended.Early detection of cancer is very important to save lives (stamp 55). Annual check-up (stamp 56) of oral cavity, skin, lymph nodes, routine examinations of blood for detection of any abnormalities in its constituents (stamp 57) and chest X-ray (stamp 58) are internationally accepted tests for earlFor women: Breast awareness is important (Indian stamp 59) and clinical breast examination by a physician may be helpful where there is no national screening programme. It is also suggested to carry out mammography (stamp 60). Cervical PAP test (stamps 61 and 62) should be carried out in adult females at regular intervals.For men: Population-based prostate-specific antigen (PSA) testing can reduce mortality in countries where urological follow-up and treatment are available. US Postal Service issued a semifiscal stamp in 1998 on this aspect , electron microscope (stamp 64), X-ray instruments (stamp 65), radiotherapy instruments (stamps 66 and 67), ultrasonography (USG) (stamp 68), computed topographic (CT) scanning (stamp 69), magnetic resonance imaging (MRI) (stamp 70), nuclear medicine imaging (scintigraphy) (stamp 71), mammography, etc. In 1992, Macedonia had brought out a set of four stamps with the message of early cancer detection in one of them and with the picture of diagnostic equipment in the other three (stamps 72\u201375).Many scientists and physicians appear on stamps for their outstanding contribution in the fight against cancer. WC Roentgen (1845\u20131923) \u2013 discoverer of X-rays in 1895 and the first recipient of the Nobel prize in 1901 (stamp 76). Henri Becquerel (1852\u20131908) (stamp 77) \u2013 discoverer of the phenomenon of spontaneous emanations later termed radioactivity by Madame Marie Curie. Radiotherapy has originated from this discovery. Madame Marie Curie (1867\u20131934) and Pierre Curie (1859\u20131906) \u2013 world-renowned French scientists who discovered radium in 1898, which was the first radioactive substance used for the treatment. Madame Curie appeared in about 100 stamps either alone or with her husband Pierre Curie (stamps 81 and 82). In 1938, France and its 21 colonies issued the latter stamps (81 and 82) as a tribute to the 40th anniversary of this discovery. The surtax of these stamps was given to the International Union Against Cancer. Pierre Curie was also remembered alone in some stamps. Irene Joliot Curie (1897\u20131956), elder daughter of Madame Curie, and Frederic Joliot (1900\u20131958) son-in-law of Madame. Curie \u2013 joint discoverers of artificial radioactivity (stamp 83). Based on their discovery, a number of artificial radioisotopes have been prepared some of which find use in cancer. George N Papanikolaou (1883\u20131962) (stamps 62 and 84) \u2013 discoverer of PAP test for early diagnosis of cervical cancer that has saved the lives of millions of women worldwide. Moritz Kaposi (1837\u20131902) (stamp 85) \u2013 famous physician who identified in 1872 a special type of sarcoma that was named after him as Kaposi's sarcoma. Rudlof Virchow (1821\u20131902) (stamp 86) \u2013 founder of cellular pathology. He discovered and named gliomas and giant cells. He had also named many common tumours.Postage stamps and cancellations are available on world-famous organisations like International Union Against Cancer (UICC) (stamps 81 and 82), World Health Organization (WHO) (stamp 87), etc.Starting from 1933, UICC organises International Cancer Congress every fourth year where scientists, clinicians, nurses, etc. from all over the world meet. Special commemorative stamps have been issued on these occasions by various countries: 8th held in Russia in 1962 (stamp 88), 9th held in Japan in 1966 (stamps 39 and 89), 12th held in Argentina in 1978 (stamp 90), 14th held in Hungary in 1986 (stamp 85) and 16th held in India in 1994 (stamp 91).Thus our fight against cancer will continue till we achieve success (stamp 92). Research is ongoing globally, and newer concepts, improvements in therapeutic modalities and new drugs are being added continuously. Recent global efforts in DNA decoding (stamp 93) and human genome mapping leading to genome genetic engineering (stamps 94 and 95) will help to identify and repair the defective genes (gene therapy of cancer). The message that should reach everybody is that cancer will be defeated \u2013 sooner or later \u2013 as is beautifully demonstrated in a French stamp issued in 1970 picturing a smiling lady cured of cancer overcoming the threat of death displayed underneath (stamp 96).It is therefore convincingly demonstrated that, in addition to specific anticancer stamps, various other stamps can be used to describe different aspects of cancer. The significant role of stamps in raising awareness among people regarding this dreadful disease has been highlighted."} +{"text": "The ultrastructure of 16 tumours derived from spontaneously transformed cell lines established from young and old C57 and C3H mouse organs is described. Three types of tumour were found: myxoid (fibrosarcomatous), consisting of cells with long processes and much interstitial material; leiomyomatous, consisting of a bundle of smooth muscle-like cells with less interstitial material; or epithelial-like consisting of closely packed round cells with little interstitial material. The cell types in the tumours were similar to those found in the tissue culture cell lines from which they were derived."} +{"text": "The Src family kinases possess two sites of tyrosine phosphorylation that are critical to the regulation of kinase activity. Autophosphorylation on an activation loop tyrosine residue (Tyr 416 in commonly used chicken c-Src numbering) increases catalytic activity, while phosphorylation of a C-terminal tyrosine (Tyr 527 in c-Src) inhibits activity. The latter modification is achieved by the tyrosine kinase Csk , but the complete inactivation of the Src family kinases also requires the dephosphorylation of the activation loop tyrosine. The SH3 domain of Csk recruits the tyrosine phosphatase PEP, allowing for the coordinated inhibition of Src family kinase activity. We have discovered that Csk forms homodimers through interactions mediated by the SH3 domain in a manner that buries the recognition surface for SH3 ligands. The formation of this dimer would therefore block the recruitment of tyrosine phosphatases and may have important implications for the regulation of Src kinase activity. Members of the Src family of protein tyrosine kinases, such as c-Src, Lck, Fyn and Hck, are key players in many signalling pathways that regulate cell growth, proliferation and motility The kinase domain of Csk is responsible for the recognition of the Src family kinases as its specific substrates, resulting in phosphorylation of the C-terminal tail The SH3 domain of Csk interacts with several tyrosine phosphatases Pursuing the observation that Csk is dimeric at high protein concentration in vitro FL) migrates as a dimer by size exclusion, the removal of the SH3 domain (CskSH2KD) or the SH3 and SH2 domains (CskKD) resulted in proteins that no longer appear to dimerize and instead elute as apparent monomers by gel filtration , CskSH2KD (residues 68\u2013450) and CskKD (residues 187\u2013450) were expressed in bacteria and purified as described The constructs of human Csk, CskPurified Csk proteins were subjected to analytical gel filtration using a Superdex S200 column or SMART S200 column . Column calibration was performed using molecular weight standards ."} +{"text": "We analysed oestrogen receptor (ER) and progesterone receptor (PR) expression in a retrospective series of 21 low-grade endometrial stromal sarcomas (LGSSs). Archival formalin-fixed and paraffin-embedded material was analysed by immunohistochemistry. ER and PR were measured with monoclonal antibodies and the peroxidase-antiperoxidase method and a score was calculated as for breast carcinoma based on both the percentage of positive tumour cell nuclei and the staining intensity. ER were seen in 15 (71%) and PR in 20 (95%) of tumours respectively. ER expression was scored as high in three (14%), moderate in four (19%), and low in eight (38%) tumours. Six (29%) tumours did not stain for ER and all of these were positive for PR. PR expression was scored as high in eight (38%), moderate in ten (47%) and weak in two (10%) LGSSs. Only one (5%) LGSS did not stain for PR (this tumour was positive for ER). ER and PR expression in LGSS is heterogeneous. This may have implications for hormone therapy in the management of these tumours. These results suggest that ER and PR should be routinely quantified in LGSSs by immunohistochemical methods. \u00a9 2000 Cancer Research Campaign"} +{"text": "The objective of the study was to review the natural history of patients with a malignant pleural effusion but without obvious evidence of a primary, to assess the value of investigations used to look for a primary and to assess the response to palliative chemotherapy. This was done by a retrospective study of patients' notes at the Lung Unit, Royal Marsden Hospital, Sutton, Surrey. Improvement in tumour-related symptoms (and duration) on chemotherapy was assessed by the patient before the first course of chemotherapy and following each course using simple descriptive criteria as follows: (1) complete disappearance of symptoms (CR); (2) good improvement in symptoms (PR); (3) minor or no change in symptoms (NC); (4) worse symptoms (PD). Pleural effusion objective response (and duration) according to Hamed definition: success defined as a continued absence of reaccumulation of pleural fluid on all follow-up radiographs; any reaccumulation was regarded as a treatment failure. Overall survival was measured from the date of histological/cytological diagnosis to death. The study included 42 patients, 27 males and 15 females with a median age of 55 years. A primary was found in 15 patients (36%), and considered to be lung cancer. A total of 11/32 (34%) had a thoracic computed tomography (CT) scan with abnormalities compatible with a diagnosis of lung primary. When thoracic CT scan was negative, fibre optic bronchoscopy was always negative (0/13). Abdominal and pelvic CT scan, abdominal ultrasound, pelvic ultrasound and mammograms failed to reveal the primary. Twenty-three patients underwent local treatment and 37 received systemic chemotherapy. A total of 29/37 (78%) patients achieved symptomatic improvement and 32/37 (86%) an objective response of their pleural effusion on chemotherapy . The median survival of the whole group was 12 months (3-60+ months). In this series the thoracic CT led to a diagnosis of lung primary in 34% of the cases. Other radiological examinations and bronchoscopy were unhelpful. Chemotherapy achieved symptom relief in 78% of patients."} +{"text": "Analysis of human tumour-derived cell lines has previously resulted in the identification of novel transformation-related elements and provided a useful tool for functional studies of different genes. To establish the utility of such cell lines as indicators of change relevant to urothelial cancer, we have characterised the expression of five genes within a panel of human bladder carcinoma cell lines. Using single-strand conformation polymorphism (SSCP) and direct sequencing, p53 mutations were identified in 7/15 (47%) cell lines reflecting events reported in bladder tumours. Immunohistochemical analysis of p53 in cultured cells and in paraffin-embedded sections of xenografts from the cell line panel revealed discordant results. An absence of p53 nuclear staining was associated with an exon 5 mutation in EJ and with multiple p53 mutations found in J82. Two cell lines positive for p53 staining in the absence of detectable mutation displayed overexpression of MDM2 in Western blot analysis. Loss or aberrant Rb expression was recorded in 5/15 cell lines. Absence of E-cadherin was recorded in 5/15 cell lines with loss of alpha-catenin in immunoprecipitated E-cadherin complexes of CUBIII. Western blot analysis of APC revealed a truncated protein in 1/15 (CUBIII) cell lines. The characterisation of oncogenic events within this panel of human bladder carcinoma cell lines establishes a representation of change observed in bladder tumours and better defines the genotypic background in these experimental human cell models of neoplastic progression."} +{"text": "Two human deaths caused by Australian bat lyssavirus (ABL) infection have been reported since 1996. Information was obtained from 205 persons (mostly adults from south Brisbane and the South Coast of Queensland), who reported potential ABL exposure to the Brisbane Southside Public Health Unit from November 1,1996, to January 31, 1999. Volunteer animal handlers accounted for 39% of potential exposures, their family members for 12%, professional animal handlers for 14%, community members who intentionally handled bats for 31%, and community members with contacts initiated by bats for 4%. The prevalence of Lyssavirus detected by fluorescent antibody test in 366 sick, injured, or orphaned bats from the area was 6%. Sequelae of exposure, including the requirement for expensive postexposure prophylaxis, may be reduced by educating bat handlers and the public of the risks involved in handling Australian bats."} +{"text": "Furthermore, strong correlations were found between the levels of both uPA and PAI-1 in the cytosols and their levels previously measured with ELISAs based on commercial reagents. In both Cox univariate and multivariate analysis, high cytosolic levels of uPA or PAI-1 were significantly associated with increased rates of relapse and death. The levels of uPA and PAI-1 in the pellet extracts also provided prognostic information, although to a lesser extent compared with the cytosolic extracts. The prediction of prognosis on the basis of uPA and PAI-1 assessed by an alternative ELISA once again emphasizes the established prognostic role and usefulness of these parameters in selection of breast cancer patients at high or low risk of recurrence. \u00a9 1999 Cancer Research CampaignTo evaluate the clinical relevance of urokinase-type plasminogen activator (uPA) and its type-1 inhibitor (PAI-1) measured by a recently developed enzyme-linked immunosorbent assay (ELISA), we analysed both components in samples derived from 892 patients with primary breast cancer (median follow-up 99 months). The assays were performed in cytosolic extracts as well as in corresponding detergent extracts of pellets obtained after ultracentrifugation, which was carried out when preparing the cytosolic fractions for routine steroid hormone receptor determination. Statistically significant correlations were found between the cytosolic levels and those determined in the pellet extracts (Spearman correlation coefficient"} +{"text": "Recent studies have shown that various gastrointestinal tumours express substantial amounts of vasoactive intestinal peptide (VIP) receptors. Based on these observations, we have developed a receptor scintigraphy using [123I]VIP as a radioligand. An initial series performed at our institution showed promising potential for visualization of various gastrointestinal adenocarcinomas by means of [123I]VIP. In this article, we now report the results obtained in 80 consecutive patients with colorectal adenocarcinoma. Eighty consecutive patients with histologically verified colorectal cancer underwent scanning by means of [123I]VIP . Thirteen patients were free of tumour after complete resection of Dukes' C cancer, eight patients presented with primary and 14 with locally recurrent tumours but were free of metastases. Ten patients had locally recurrent disease and liver, lung or lymph node metastases. Disease confined to organ metastases was present in 35 patients. The size of the primary or recurrent tumours ranged between 3 and 6 cm, and the size of metastases was between 1 and 13 cm in diameter. Scan results were evaluated independently by two nuclear medicine physicians in a blinded way, and results were then compared with computerized tomography (CT)scans not older than 4 weeks. Seven out of eight primary (87%) and 21 out of 24 (82%) locally relapsing cancers were imaged with [123I]VIP. Negative VIP scans were obtained in all 13 patients in whom the cancers had been curatively resected. All patients with lymph node metastases showed positive VIP scans (four out of four), and positive scans were obtained in 25 out of 28 (89%) patients with liver metastases and in two out of three cases with lung metastases. In four patients with relapsing cancer, the VIP scan indicated the presence of disease before CT, and in two patients the diagnosis of scar tissue instead of a local recurrence of rectal cancer as suggested by CT could be established. We conclude that [123I]VIP receptor scanning is a sensitive method for radioimaging of colorectal cancer with the potential to provide valuable additional information to conventional radiological methods."} +{"text": "To study pathophysiological roles of mesothelial barrier functions in protection against cancer cell invasion, we isolated mesothelial cells from the rat abdominal cavity and then cultured them with 10(-6)M all-trans-retinoic acid (RA) for 10 days. Mesothelial barrier function assessed by measuring transcellular electrical resistance (TER) and the expression of 7H6 tight junction-associated antigen at the cell border were induced by the treatment . Then we quantified the attachment and penetration of rat mammary cancer cells (SST-2 cells) into the mesothelial cell monolayer by prelabelling of the cancer cells with fluorescent dye and by observing optical sections at different heights using a laser confocal scanning microscope. When SST-2 cells were overlaid onto the mesothelial cell monolayer treated with RA, the number of cancer cells found at the basal level of the monolayer was significantly reduced. These results showed that enhanced mesothelial barrier function at least partially prevents the penetration of cancer cells into mesothelial cells and suggested that 7H6 antigen serves as a reliable immunocytochemical marker for monitoring mesothelial barrier function."} +{"text": "Anthracenyl-amino acid conjugates represent a novel chemical class of topoisomerase (topo) inhibitor. NU/ICRF 505 is a lead compound that stabilises topo I cleavable complexes and is actively cytotoxic at low microM concentrations. In this study, endonucleolytic DNA cleavage was used as a marker of apoptosis to investigate mechanisms of cell death produced by this compound. NU/ICRF 505 (5 microM) induced a substantial increase in the level of DNA fragmentation in HL60 cells but only after a 48 and 72 h drug exposure (compared with 6 h after treatment with camptothecin), as determined qualitatively by conventional gel electrophoresis and quantitatively by spectrofluorimetry. This effect was substantially reversed by co-treatment with zinc (1 mM). Subsequent studies with the human lung (NX002), ovarian (A2780) and colon (HT29) cancer cell lines yielded evidence of formation of higher molecular weight DNA fragments in NX002 and A2780 cells in response to NU/ICRF 505 (5 microM). Co-treatment with zinc (1 mM) caused a small decrease in DNA fragmentation. These data suggest that the induction of apoptosis may play an important role in the mechanism of cytotoxicity of NU/ICRF 505 in HL60 cells and that other pathways of cell death may also be operative in NX002 and A2780 in conjunction with apoptosis."} +{"text": "The relationship between the bioenergetic status of human glioma xenografts in nude mice and morphometric parameters of the perfused vascular architecture was studied using (31)P magnetic resonance spectroscopy (MRS), fluorescence microscopy and two-dimensional digital image analysis. Two tumour lines with a different vascular architecture were used for this study. Intervascular distances and non-perfused area fractions varied greatly between tumours of the same line and tumours of different lines. The inorganic phosphate-nucleoside triphosphate (P(i)/NTP) ratio increased rapidly as mean intervascular distances increased from 100 microm to 300 microm. Two morphometric parameters - the percentage of intervascular distances larger than 200 microm (ivd200) and the non-perfused area fraction at a distance larger than 100 microm from a nearest perfused vessel (area100), - were deduced from these experiments and related to the P(i)/NTP ratio of the whole tumour. It is assumed that an aerobic to anaerobic transition influences the bioenergetic status, i.e. the P(i)/NTP ratio increased linearly with the percentage of ivd200 and the area100."} +{"text": "The characteristics of lung cancers induced by inhaled chromate were studied in 13 consecutive autopsies on male ex-chromate workers. In addition to histopathology, we examined: (1) the relationship between the occurrence of lung cancer and the amount of chromium (Cr) deposited in the lung as determined by atomic absorptiometry and (2) the chronological changes in five precancerous lung lesions followed by bronchoscopy till death. Twenty-one cancers were identified, including 16 lung tumours observed either during follow-up or at autopsy. Of these 16 tumours, 13 were found in six subjects, implying a high frequency of multiple cancers. Eleven (69%) out of the 16 tumours were of squamous cell type (including carcinoma in situ), this being twice as frequent as in age-matched controls. A further characteristic was predominance in the central part of lung (69%). The lung Cr burden was very much higher in patients with lung tumours than in those without (8-28 micrograms g-1). Five of the precancerous lesions followed by bronchoscopy originated at bronchial bifurcations. Four of these cases showed a return to normal histology at autopsy even without therapy, and the other did not progress."} +{"text": "Background: Morbidity and mortality after surgical treatment of bileduct stones increase with age and associated diseases. A proposed alternative therapy is endoscopic sphincterotomy (ES) with the gallbladder left in situ, and we elected to compare this option with standard open surgery in high-risk patients.Methods: 98 patients (mean age 80 years) with symptoms likely to be due to bileduct stones or a recent episode of biliary parcreatitis were randomised to be treated either by open cholecystectomy with operative cholangiography and (if necessary) bileduct exploration (n=48) or by endoscopic sphincterotomy alone (n=50).Findings: The procedure was accomplished successfully in 94% of the surgery group and 88% of the ES group, and there were no significant differences in immediate morbidity (23% vs 16%) or mortality (4% vs 6%). During mean follow-up of 17 months biliary symptoms recurred in three surgical patients, none of whom underwent repeat surgery, and in 10 ES patients, seven of whom had biliary surgery. By multivariate regression analysis endoscopic sphincterotomy was an independent predictor of recurrent biliary symptoms .Interpretation: In elderly or high-risk patients, surgery is preferably to endoscopic sphincterotomy with the gallbladder left in situ as a definitive treatment for bileduct stones or non-severe biliary pancreatitis."} +{"text": "Microsatellite instability (MSI) was examined at 36 loci, and found in 9 (43%) of the 21 prostatic cancers. A loss of heterozygosity had occurred in five cases (24%). MSI did not correlate with clinical stage, but might play a role in the development of a subset of prostate cancers."} +{"text": "Development of incisional hernia after open abdominal surgery remains a major cause of post-operative morbidity. The aim of this study was to determine the current practice of surgeons in terms of access to and closure of the abdominal cavity in elective open surgery.Twelve surgical departments of the INSECT-Trial group documented the following variables for 50 consecutive patients undergoing abdominal surgery: fascial closure techniques, applied suture materials, application of subcutaneous sutures, subcutaneous drains, methods for skin closure. Descriptive analysis was performed and consensus of treatment variables was categorized into four levels: Strong consensus >95%, consensus 75\u201395%, overall agreement 50\u201375%, no consensus <50%.157 out of 599 patients were eligible for analysis (85 (54%) midline, 54 (35%) transverse incisions). After midline incisions the fascia was closed continuously in 55 patients (65%), using slowly absorbable , braided sutures with a strength of 1 . In the transverse setting the fascia was closed continuously in 39 patients (72%) with slowly absorbable braided sutures with a strength of 1 .In the present evaluation midline incision was the most frequently applied access in elective open abdominal surgery. None of the treatments for abdominal wall closure (except skin closure in the midline group) is performed on a consensus level. Approximately 700.000 open abdominal procedures are performed annually in Germany and 4.000.000 in the United States . DevelopThere is still controversy about the best strategy for abdominal wall closure due to inconsistent and incomplete evidence provided by several randomized controlled trials (RCT) -8 as wel1. Is midline incision still the most frequently applied access to the abdominal cavity in elective situations?2. Has consensus for abdominal wall closure already been established in surgical routine?The primary objective of this cross sectional study was therefore to identify current practice of abdominal cavity access and closure in elective surgery.Twelve of the 25 participating centres of the INSECT-Trial group agreed in contribution to data acquisition (see acknowledgment). The local ethics committees of participating centres granted ethical approval for the study These include hospitals of all levels of health care , thus ensuring representative study results. Surgeons at these hospitals were asked to assess surgical access and closure methods of 50 consecutive patients who underwent surgery at their service. Patients who underwent more than one operation during the study period were excluded.The study was designed as a cross-sectional cohort study and performed between July and August 2005. A standardized data entry form was designed in order to collect the following information: patient's gender and age, setting of surgery (elective vs. emergency surgery), surgical approach (open vs. laparoscopic surgery), history of previous abdominal surgery, type of applied abdominal incision (transverse vs. midline), suture material used for fascia closure , the technique used for fascia closure , the use of subcutaneous suture and subcutaneous drainage, and the method of skin closure. Classification of suture strengths was reported according to the United States Pharmacopeia XXII (1990).All data entry forms were sent in an anonymous fashion to the Study Centre of the German Surgical Society and analyzed accordingly using Statistical Analysis System (SAS) version 9.1. Descriptive statistics were used in univariate analyses.The treatment of patients were categorized into four levels of consensus according to a classification of Hoffmann et al. :1. Strong consensus: treatment applied in >95% of cases2. Consensus: treatment applied in 75\u201395% of cases3. Overall agreement: treatment applied in 50\u201375% of cases4. No consensus: treatment applied in <50% of casesA total of 599 patient data entry forms out of 600 with an equal distribution of genders and a mean age of 57 years (SD 19 years) were available for analysis. An open approach was chosen in 375 patients (63%), a laparoscopic in 224 patients (37%). After exclusion of patients with previous open abdominal surgery, an emergency procedure, and laparoscopic procedures, a total of 157 patients with primary elective laparotomy were available for further analysis , midline incisions were performed in 85 patients (54%), transverse incisions (crossing the midline) in 54 patients (35%) and miscellaneous incisions in 13 patients (8%).Fascia closure for midline incisions was performed with a continuous suture in 55 patients (65%) and interrupted sutures in 16 patients (19%), respectively. In 13 (15%) of these patients a combination of both techniques was applied. Monofilament sutures were applied for fascia closure in 51 patients (60%), braided sutures in 32 patients (38%). Non-absorbable sutures were chosen in four cases (5%), slowly absorbable sutures in 47 patients (55%), and moderately rapid absorbable sutures in 33 patients (39%). Sutures with the strength of 0 were used in two patients (2%), with strength of 1 in 48 patients (57%), and with strength of 2 in 31 patients (36%).Subcutaneous suture was performed in 48 patients (57%) and a subcutaneous drain was placed in 19 patients (22%). Skin closure of patients who received midline incisions was performed with staples in 67 cases (79%).In terms of consensus levels all technical features for closure of midline incisions met the level of \"overall agreement\", except the item of skin closure for which the level of \"consensus\" was reached Table .Abdominal fascia of patients who had a transverse incision (n = 54) was sutured continuously in 39 patients (72%), interruptedly in eleven patients (20%), and with a combination of both techniques in two patients (4%). Suture material with the strength was 0 were chosen in 6 patients (11%), with a strength of 1 in 30 patients (56%) and with a strength of 2 in 17 patients (31%). Monofilament sutures were applied for fascia closure of 25 patients (46%) and braided sutures for 27 patients (50%). In two patients (4%) non-absorbable sutures, in 22 patients (41%) slowly absorbable sutures, in 29 patients (54%) moderately rapid absorbable sutures, and in one patient (2%) rapidly absorbable sutures were applied.Thirty-nine patients (72%) received a subcutaneous suture; a subcutaneous drain was placed in 12 patients (22%). Skin closure of patients who received midline incisions was performed with staples in 39 cases (72%).All technical features for closure of transverse incisions reached the level of \"overall agreement\" Table .In the present analysis midline incision is still the most frequent access to the abdominal cavity in elective surgery. No consensus for fascia closure either for midline or transverse incisions in daily practice of abdominal surgery was detected (>75% of surgeons acting similarly). Use of staples for skin closure after midline incisions was the only item that reached the level of consensus.Our finding that midline incisions are the most frequently applied access in open abdominal surgery is in accordance with previous reports . While tThe lack of consensus for abdominal wall closure strategies after midline incisions demonstrates persistent uncertainty within the surgical community. Several RCTs -8 and meAccording to our data, there is no consensus in closure of transverse incisions either. Closure technique of the abdominal fascia with a continuous suture and skin closure with staples were the only items that almost reached the level of consensus (both performed in 72%). In contrast to midline incisions, however, so far no randomized trial has been solely conducted in order to investigate closure techniques in this setting. Hence, the ideal closure strategy is still to be determined. From some trials comparing closure techniques in midline incisions ,18,19 paThe results of our study might be affected due to bias. The participating hospitals of the INSECT-Trial who agreed to contribute to this study may be a subgroup of hospitals dedicated to clinical research and therefore act differently to other hospitals (e.g. surgeons agree to randomize their patients). However, it is unlikely that such an effect might have systematically shifted the results in favour of consensus.A cross-sectional consecutive data collection of real patient data seems to be the optimal design to answer our initial study questions. Selection bias within the hospitals is prevented due to a consecutive recruitment and measurement bias due to standardized data collection. Furthermore, surgeons of the INSECT-Trial group were trained in data collection during specific preparatory INSECT-Trial meetings . Other sCurrently, no clinical guidelines are available for abdominal wall closure after any type of incision. Further well designed pragmatic randomized controlled trials are necessary to support a development of such evidence-based guidelines and to change the current practice. Otherwise a reduction of incisional hernias seems unfeasible and treatment remains on the level of \"overall agreement\". The results of the recently published INSECT-Trial certainly contribute to the body of evidence on abdominal fascia closure techniques. FurtherIn conclusion, midline incisions were the predominant type of abdominal access in the present study of participating centers of the INSECT-Trial. There is no consensus regarding the strategy for closure of the abdominal fascia after midline and transverse incisions.The authors declare that they have no competing interests.NNR: Study design, data analysis and interpretation, drafting of the manuscript PK: Study design, data acquisition, data analysis, revsion of the manuscript. MKD: Data acquisition, analysis and interpretation, revsion of the manuscript. CS: Study design, data acquisition, data interpretation, revision of the manuscript. KR: Study design, data acquisition, data interpretation, revision of the manuscript. HS: Study design, data acquisition, data interpretation, revision of the manuscript. CMS: Study design, data acquisition, data analysis and interpretation, drafting of the manuscript.The pre-publication history for this paper can be accessed here:"} +{"text": "In the recent past, compliance with 21CFR11 has become a major buzzword within the pharmaceutical and biotechnology industries. While commercial solutions exist, implementation and validation are expensive and cumbersome. Frequent implementation of new features via point releases further complicates purchasing decisions by making it difficult to weigh the risk of non-compliance against the costs of too frequent upgrades. This presentation discusses a low-cost interim solution to the problem. While this solution does not address 100% of the issues raised by 21CFR11, it does implement and validate: (1) computer system security; (2) backup and restore ability on the electronic records store; and (3) an automated audit trail mechanism that captures the date, time and user identification whenever electronic records are created, modified or deleted. When coupled with enhanced procedural controls, this solution provides an acceptable level of compliance at extremely low cost."} +{"text": "The transcription factor, milk protein binding factor (MPBF/Stat5), is a member of the STAT family of signalling molecules which mediates prolactin signal transduction in lactating mammary gland by binding to GAS (gamma-interferon activation site) DNA elements. We have determined the levels of STAT factors in nuclear extracts from a variety of human breast tissues including carcinoma and normal 'resting' breast by electrophoretic mobility-shift assay. The results show that the level of STAT binding activity is low in normal 'resting' breast and benign lesions while carcinoma samples have significantly higher (P < 0.01) amounts of STAT binding activity. Supershift analysis suggests that Stat1 and possibly other members of the STAT family of signalling factors, including Stat3, are activated in breast cancer tissues."} +{"text": "The main results of these studies can besummarized as follows: (1) exogenous or endogenous catecholamines suppress PBL functions through alpha-2-receptor-mediatedmechanisms, lymphocytes of the spleen are resistant to adrenergic in vivo stimulation,(2) direct or indirect cholinergic treatment leads to enhanced ex vivo functions of splenic and thymic lymphocytesleaving PBL unaffected, (3) cholinergic pathways play a critical role in the \u201ctalking back\u201d of the immune system to the brain,(4) acetylcholine inhibits apoptosis of thymocytes possibly via direct effects on thymic epithelial cells, and maythereby influence T-cell maturation, (5) lymphocytes of the various immunological compartments were found to beequipped with the key enzymes for the synthesis of both acetylcholine and norepinephrine, and to secrete theseneurotransmitters in culture supernatantsFor several years, our group has been studying the"} +{"text": "Autoimmunity and inflammation are associated with marked changes in lipid and lipoprotein metabolism in SLE. Autoantibodies and cytokines are able to modulate lipoprotein lipase (LPL) activity, a key enzyme in lipid metabolism, with a consequent \u201clupus pattern\u201d of dyslipoproteinemia characterized by elevated levels of very low-density lipoprotein cholesterol (VLDL) and triglycerides (TG) and lower high-density lipoprotein cholesterol (HDL) levels. This pattern favors an enhanced LDL oxidation with a subsequent deleterious foam cell formation. Autoantibodies and immunocomplexes may aggravate this oxidative injury by inducing accumulation and deposition of oxLDL in endothelial cells. Drugs and associated diseases usually magnify the close interaction of these factors and further promote the proatherogenic environment of this disease."} +{"text": "The isoenzyme Mu of glutathione S-transferase (GSTM1) is dominantly inherited, and the prevalence of this isoenzyme in the population is about 60%. The lack of GSTM1 has been linked with cancer risk. The frequency of the phenotypes of this isoenzyme in melanoma (MM) patients (n = 197) is reported here. A significantly higher proportion of individuals in the control group (n = 147) had measurable GSTM1 than MM patients ; there was a higher proportion of positive phenotypes in general among women than among men. Odds ratio analysis indicated that individuals with this polymorphic variant have an approximately 2-fold risk of developing these cancers. GSTM1 phenotype distribution depends on age, smoking habit and tumour pathology. A group of MM patients with dysplastic naevi was also studied."} +{"text": "A study was made of the relationship between the intrinsic radiosensitivity of human cervical tumours and the expression of the DNA repair enzyme human apurinic/apyrimidinic endonuclease (HAP1). The radiosensitivity of clonogenic cells in tumour biopsies was measured as surviving fraction at 2 Gy (SF2) using a soft agar assay. HAP1 expression levels were determined after staining of formalin-fixed paraffin-embedded tumour sections with a rabbit antiserum raised against recombinant HAP1. Both measurements were obtained on pretreatment biopsy material. All 25 tumours examined showed positive staining for HAP1, but there was heterogeneity in the level of expression both within and between tumours. The average coefficients of variation for intra- and intertumour heterogeneity were 62% and 82% respectively. There was a moderate but significant positive correlation between the levels of HAP1 expression and SF2 . Hence, this study shows that there is some relationship between intrinsic radiosensitivity and expression of a DNA repair enzyme in cervical carcinomas. The results suggest that this type of approach may be useful in the development of rapid predictive tests of tumour radiosensitivity."} +{"text": "Between January 1977 and January 1988, 19 patients with non-Hodgkin's lymphoma (NHL) involving the ileocaecal region were cared for by the CRC Wessex Medical Oncology Unit. Fifteen of these patients had primary ileocaecal NHL (stages IE or IIE) and four had secondary involvement of this region (stage IV). The commonest clinical presentation was with abdominal pain and a palpable mass in the right iliac fossa. Bulky (greater than 10 cm) disease was a particularly common feature, and complete surgical removal was possible in only seven patients. All patients had intermediate (18) or high grade (one) NHL using the Working Formulation. The commonest histological subtype was diffuse large cell. Seventeen patients received postoperative therapy, comprising local radiotherapy in one and combination chemotherapy in the remaining 16. Eleven of the 19 patients remain disease-free 6-60 months from diagnosis. Because of the high incidence of bulky disease at this site, postoperative therapy may be indicated, even for patients with apparently completely excised stage I disease."} +{"text": "Sir,We read with great interest the article by The diagnosis of chronic pancreatitis was based on the radiologic data obtained by means of either endoscopic retrograde cholangiopancreatography or computed tomography.DNA was extracted from 20\u2009ml of the serum by using the QIAmp Blood Kit (Qiagen) and the mutations in codon 12 of the K-ras gene were searched as described previously (BstNl restriction enzyme (PCR-RFLP).As positive controls, we used DNA from neoplastic tissues of 10 patients with pancreatic carcinoma by using the DNeasy Tissue Kit (Qiagen). For molecular analysis, DNA was amplified in the codon 12 region introducing a restriction site (GACCT) for digestion with DNA from peripheral blood resulted not mutated in the 40 patients with chronic pancreatitis and in the 30 with pancreatic carcinoma, while DNA from pancreatic neoplastic tissue resulted mutated in 70% of the samples.To verify our results, all the samples were analysed by direct sequencing using Big Dye terminator v 1.1 cycle sequencing Kit and performing runs on ABI Prism 310 genetic analyzer (Applied Biosystem)Despite what was mentioned in Maire's article, we failed to find any mutations in all patients analysed, as well as we failed to correlate K-ras mutations with the levels of tumour markers such as Ca 19.9, CA242, CA50, CEA.The results of the present investigation lead us to these conclusions: (1) the eventual presence of cancer cells in peripheral blood may be a rare event, even if numerous reports support the detection of K-ras abnormalities in the serum, (2) neoplastic cells are supposed to circulate in clusters, and consequently their cognition could be hampered by a single blood sample extraction. (3) Large amounts of nonmutated DNA, coming from leucocytes held in the buffy coat layer, might also mask some vestiges of the mutant type of K-ras gene."} +{"text": "Saccharomyces cerevisiae, has been established as part of our new drug discovery programme. Use of this assay has provided the first direct evidence that TOP1 and RAD52 proteins are involved in the mode of action of bisdioxopiperazine ICRF compounds, which thus express a mode of action quite distinctive from the other known TOP2 inhibitors evaluated. The functional assay is based on a comparison of pairs of yeast differing in their phenotypes by specific traits: the expression or lack of expression of ectopic human DNA topoisomerase I, with or without that of the RAD52 gene. Amongst a series of anticancer agents, inhibitors of topoisomerase I (camptothecin) were identified as such in yeast expressing human topoisomerase I, whilst the presence or absence of RAD52 protein permitted the discrimination of compounds generating double-stranded DNA breaks, either directly (bleomycin) or involving DNA adduct formation (cisplatin), or indirectly with DNA damage mediated via inhibition of the topoisomerase II enzyme (etoposide). Notably, however, both the RAD52 protein and the lack of TOP1 enzyme appeared implicated in the cytotoxic activities of the series of bisdioxopiperazine ICRF compounds tested. This functional assay in a living organism therefore appears to provide a valuable tool for probing distinctive and specific mode(s) of action of diverse anticancer agents. \u00a9 1999 Cancer Research CampaignA screening procedure which permits identification of compounds based on their activities against specific biological targets directly in a living organism,"} +{"text": "The uptake, retention and effects of aluminium chloro sulphonated phthalocyanine (AlSPc) were measured in two cell lines, UV-2237 a murine fibrosarcoma and the non-tumorigenic NIH/3T3 fibroblast line. The behaviour of cells treated with AlSPc was compared with that of those treated with haematoporphyrin derivative (HpD), a photosensitizer often used in photodynamic therapy (PDT) of cancer. AlSPc absorbs light strongly in the red region, is taken up by cells in a dose dependent fashion and is retained in vitro over a period of days (5 days after exposure greater than 40% remains cell-associated versus less than 25% of HpD). Additionally AlSPc was less cytotoxic to cells, maintained in darkness or exposed to room light, compared to HpD (100% viability versus 0% viability 3 days after 60 min exposure to room light). However red light (approximately 600-700 nm) caused greater toxicity in AlSPc-treated cells (100%) than in similarly exposed HpD-treated cells (less than 60%). No significant differences were detected between the responses of the fibrosarcoma and the fibroblast cell lines. These characteristics of AlSPc suggest that it may prove to be a useful photosensitizer for PDT of cancer and this possibility is discussed."} +{"text": "This investigation first set out to analyse which cellular proliferative and apoptotic factors, in addition to the clinical prognostic factors, are most predictive in patients with non-small-cell lung carcinomas (NSCLC). To this purpose, we related the proliferative factors proliferating cell nuclear antigen (PCNA), cyclin A, cyclin D1, cyclin-dependent kinase 2 (cdk2), cdk4 and the proportion of cell cycle phases in NSCLC to the survival times of 150 patients. Additionally, we associated the expressions of Fas, Fas ligand and caspase-3 in NSCLC to patient survival. Immunohistochemistry was used to determine the proteins and flow cytometry to assess the proportion of cell cycle phases. Patients with PCNA-positive carcinomas had significantly shorter survival times than patients with PCNA-negative carcinomas . Corresponding results were obtained with the factor cyclin A (64 vs 92 weeks), with the factor cdk2 (76 vs 89 weeks), with the factor cdk4 (62 vs 102 weeks) and with the proportion of S phases (86 vs 121 weeks). Patients with an expression of the apoptotic factors had a more favourable prognosis than patients with negative carcinomas. The median survival times of cancer patients with Fas expression was 86 weeks and of those without Fas expression only 69 weeks. Corresponding results were obtained with the Fas ligand (87 vs 41 weeks) and caspase 3 (87 vs 34 weeks). In order to determine whether a combination of factors can yield improved prognostic information, we investigated all possible combinations of the proliferative and apoptotic factors. Patients with tumours having a high proliferative activity, but which did not express apoptotic factors had the shortest survival times while patients with a low proliferative activity and a high expression of apoptotic factors had the most favourable outcome. A multivariate analysis (Cox model) of the cellular and clinical prognostic factors indicated that stage, lymph node involvement, Fas, PCNA and cyclin A are the most important prognostic factors for the clinical outcome of patients with non-small-cell lung carcinomas. \u00a9 2000 Cancer Research Campaign"} +{"text": "Epidemiological evidence has implicated Chinese salted fish as a human nasopharyngeal carcinogen. In the present study, 221 Wistar-Kyoto rats aged 21 days were randomly assigned to one of three experimental groups. Rats in group 1 (high dose group) were fed a powder diet of one part Chinese salted fish to three parts certified rat chow during the first 18 months. Similarly, rats in group 2 (low dose group) were fed a powder diet of one part salted fish to five parts rat chow for 18 months. Rats in group 3 were given rat chow only throughout the 3-year experiment. Four malignant tumours of the nasal cavity were observed among rats fed the experimental diets (three and one respectively in the high and low dose groups). No comparable tumours were observed in controls, compatible with the historical control rate of zero. Our results, therefore, further strengthen the hypothesis that Chinese salted fish is a human nasopharyngeal carcinogen; they also establish Wistar rats as a viable animal model for carcinogenicity studies of this food in the laboratory."} +{"text": "From 1996 through 1999, 35 deer mice (Peromyscus maniculatus) were captured in 25 urban and suburban homes in southwestern Montana. Mice were captured throughout the year except for January; seven mice (20%) from seven (28%) of the homes were seropositive for Sin Nombre virus. The infected mice were mostly adult males captured in the spring and fall."} +{"text": "A new autofluorescence (AF) system for bronchoscopy that operates as compact as aconventional white light bronchoscopy system is described. The system is also capable of whitelight illumination and excitation of aminolevulinic acid (ALA) induced fluorescence. Changing between white light and (auto-) fluorescence mode is easy and always possible. Broad band excitation with blue light delivers highintensity illumination at the distal end of the bronchoscope . A specialoptical observation technique makes the AF directly visible to the eye instead of indirecttechniques used in other AF systems. A compact (160 g)and sensitive camera can be used for documentation."} +{"text": "No numerical aberration of chromosomes that might be specific for prostate cancer has so far been established. We used fluorescence in situ hybridisation (FISH) with centromere-specific probes for chromosomes 7, 8, 17, X and Y to establish the distribution of centromere copy numbers in frozen-stored or freshly prepared samples of benign prostate hypertrophy (BPH) and to detect numerical aberrations of these chromosomes in 28 prostate cancers from Japanese men. There was no significant difference in the data of centromere copy numbers between fresh and frozen-stored tissue. The most common aberration in prostate cancers was a gain of chromosome 8 (57%), with numerical aberration of chromosome 7 being the second most frequent anomaly (50%). Numerical aberration of chromosome 7 is most significantly associated with a higher Gleason score (GS) (P < 0.005) or with lymph node metastasis (P < 0.001). Numerical aberration of several chromosomes, including chromosomes 7 and/or 8, was common in aggressive prostate cancers. Loss of chromosome Y was detected in only 4% of cases. FISH analysis thus proved to be a useful method for detecting numerical aberrations of individual chromosomes, with application to touch preparations of frozen-stored tissue having the advantage of exact sampling of cancer foci. The results suggest that numerical aberration of chromosome 7 is associated with aggressive tumour behaviour and poor prognosis of patients with prostate cancer. The association between genetic change and chromosomal abnormality should be studied in detail."} +{"text": "Idiopathic juxtafoveolar retinal telangiectasis (IJRT) group 1A usually affects one eye of young and middle aged male patients.1 TelangieA 40-year-old healthy male was referred to us for visual distortion and inability to see in the upper left field of vision in the right eye (OD) for six weeks. Medical work-up and laboratory tests excluded the presence of any systemic ailment including hypertension and diabetes mellitus. The best-corrected visual acuity was 20/30 OD and 20/20 in the left eye (OS). Anterior segment examination showed no cell or flare in the anterior chamber or in the anterior vitreous in both eyes (OU). Intraocular pressure (IOP) was 15 mmHg OU. Dilated fundus examination OD showed abnormal telangiectatic blood vessels and hard exudates temporal to the fovea as well as cystic appearance in the foveal area . The funOver the next one year the patient was followed closely without improvement in vision (following laser treatment) or change in the fundus appearance. However, 15 months after the initial examination, his vision dropped to 20/50 OD with significant increase in macular edema clinically and on OCT . The cenOn the basis of biomicroscopic and fluorescein angiographic patterns, Gass and Blodi have classified IJRT into three groups: Group 1 Laser photocoagulation and photodynamic therapy of the telangiectatic capillaries in IJRT group 1A are reported to be effective in reducing the foveolar edema and exudation.\u20134 Howeveet al. and Maia et al. successfully treated their patients of group 1 IJRT with intravitreal injection of triamcinolone acetonide.[There was dramatic improvement in vision two weeks following intravitreal triamcinolone injection in the present case. The vision improved along with resolution of macular edema that was confirmed on clinical examination and on OCT. Li cetonide.6 Both thOur experience with this patient demonstrates that intravitreal triamcinolone acetonide may be considered an additional therapeutic option besides photocoagulation in the management of IJRT group 1A, especially when the latter treatment is ineffective. Moreover, OCT is a useful non-invasive tool that helps in diagnosing the disease and following it over the years. Further long-term case controlled prospective studies evaluating the safety and efficacy of this treatment modality for patients with IJRT group 1A are warranted."} +{"text": "In vivo growth characteristics of myeloid leukaemia induced by whole-body irradiation of CBA/H male mice were examined in the strain of origin by procedures expected to enhance or depress immunological responses. Syngeneic growth in vivo was not modified by attempted active immunization with radiation-inactivated cells or by sublethal whole-body irradiation of recipients before inoculation of small numbers of clonogenic cells. Since the growth stimuli involved in in vivo repair of severely damaged normal haemopoietic tissue also did not modify the growth of the radiation-induced leukaemia cells in syngeneic passage, their growth in vivo in the irradiated primary hosts can be regarded as autonomous by the stage at which leukaemia was diagnosed. Challenge inocula in the \"immunization\" experiments were 1-9 clonogenic cells from 4 different passaged lines and in the whole-body radiation experiments, 1-10(3) clonogenic cells derived from 11 different primary hosts and 4 different passaged lines."} +{"text": "Introduction and aim. Management of complicated wounds after tumor extipiration of pelvic and proximal lower limb musculoskeletal sarcoma represents an essential component in the outcome of these patients. The authors present modified vertical rectus abdominis musculocutaneous (VRAM) flap techniques to reconstruct extensive defects after debridment of these complicated wounds. Material and Methods. Over a period of 4 years (2002\u20132005), 5 men and 2 women were managed. Median age was 21 years (range 15\u201349). The patients were managed for complicated lower trunk, groin, and upper thigh wounds after resection of three pelvic chondrosarcomas as well as two pelvic and two proximal femur osteosarcomas. The modifications included a VRAM flap with lateral and tongue-like extension design of the skin paddle (5 cases) or a delayed extended VRAM flap (2 cases). Results. All flaps showed complete survival and healing with no ischemic events providing stable coverage. All patients were ambulant with good limb functions in terms of walking and gait after adequate rehabilitation, 2 needed support with crutches. Conclusion. The modified VRAM flaps offer reliable reconstructive tools for coverage of complex groin and thigh defects by providing larger well-vascularized soft tissue with acceptable donor site. Limb salvage remains a major objective in contemporary management ofbony and soft tissue sarcomas of the pelvis and lower extremities , 2. RadiSeven consecutive patients with complicated wounds secondary to resection of pelvicand proximal lower extremity musculoskeletal sarcoma were managed with modified VRAM flaps between2002\u20132005. The medianage of the patients in this series at the time of surgery was 21 years (range15\u201349) and included 5 men and 2 women. The modifications included VRAM flapwith lateral and tongue-like extension design of the skin paddle (5 cases) or adelayed extended VRAM flap (2 cases). All the patients have been treated with amultidisciplinary approach; the management of osteosarcoma patients included a 4-month course of neoadjavant chemotherapyfollowed by resection of the primary tumor and postoperative 3-month course of chemotherapy;while chondrosarcoma patients (3 pelvic) were offered surgical resection only.The complications, which necessitated management by the plastic andreconstructive surgeons, included infection and wound dehiscence with ultimateexposure of metal prosthesis (4 patients) and necrosis of thigh flaps (3patients). The median interval duration between the primary operation and thereconstructive procedure for the complicated wounds was 16 days (range: 13\u201336).All patients underwent thorough clinical assessment, adequate debridment andirrigation of the wounds, followed by immediate coverage of the resultantdefects (median size 7 \u00d7 17\u2009cm) usingmodified VRAM flaps.This technique was used to cover exposed metal plates dueto wound breakdown after osteosarcomas resection of proximal femur where lengthof the flap was predominantly required than its width. An ipsilateralparasternal skin paddle was designed 10\u2009cm cephalic to the costal margin and 2\u2009cm from the lateral sternal edge. The pinch test, originally described byTaylor et al. , was useThis technique was used in cases after resection ofchondrosarcomas and osteosarcomas of the pelvis, which necessitated thedevelopment of large subcutaneous thigh flap to allow adequate exposure andvascular exploration to achieve adequate oncological resection. Extensive full-thicknessthigh flap necrosis occurred in these patients which necessitated adequatedebridement and coverage of the resultant defect utilizing a contralateral,laterally oriented VRAM with a tongue-like skin extension. The contralateralmuscle was selected due to the sacrifice of the ipsilateral inferior epigastricpedicle as part of the radicality of the primary tumor resection. The lateralorientation of the skin paddle was designed to be oblique (45\u00b0) tothe longitudinal axis of the rectus muscle to provide an average extra lengthof 5\u2009cm. The tongue-like extension ofthe skin paddle was designed throughout the whole length of the muscle taperingtowards the pivot point of the flap at the entry of the inferior epigastricpedicle. The fasciomusculocutaneous component of the VRAM flap was harvestedutilizing the standard technique with elevation of the laterally oriented partof the flap in the fascial plane. Theorigin and insertion of rectus muscle were transacted leaving the vascular pedicle asthe sole tether point; this significantly increased the arc of rotationallowing more muscle mass to be transposed to the wound. Incising the skinbridge between the donor and recipient defect to lay open the tunnel connectingthe recipient and the donor site followed this. The tongue-like skin extension provided the roof foropened tunnel after rotation of the flap to settle to the defect; allowing moreroom for the pedicle and providing coverage for the medial part of the defect.In all patients, the donor site was closed primarilyafter reinforcement of the abdominal wall using an onlay prolene mesh, suctiondrains were used both at the recipient and donor sites. All patients weremobilized within 2 weeks postoperatively under supervision of the orthopaedicand physical therapy team. The mean duration to postoperative chemotherapy was3 weeks. The mean follow-up period was 26 months at which patients were followed up with assessment of the oncological outcome, durability of soft tissue reconstruction, and finally assessing the functional outcome using Enneking system,All flaps showed complete survival and healing withno ischemic events, hence providing stable coverage. Mild infection wasobserved in 1 patient; no haematomas were detected. All patients were ambulantwith good limb functions in terms of walking and gait after adequaterehabilitation; 2 needed additional support with crutches. All patients showedgood emotional acceptance; and no pain has been observed during ambulation inall patients. One patient developed incisional hernia at the donor site that requiredrepair 1 year later; otherwise, no other donor site morbidity was noted.Another patient died of haematogenous metastatic spread after completeresection 15 months later. There was no hypertrophic scar formation or flapbreakdown experienced on long-term follow-up in any of the patients.Limb preservation has become a more realistic andnecessary goal in the management of patients with musculoskeletal sarcoma ofextremities . RadiatiThe reconstructive options to provide coveragefollowing debridment of these complicated wounds would be local, distant flaps,or free-tissue transfer. VRAM flaps havebeen used successfully in coverage of defects of the chest wall, groin, hip,perineal, vaginal, and gluteal regions with good functional outcomes \u201317. The The delayed phenomenon has been used for many yearsto enhance functional blood flow through vasodilatation of the arterial networkand avoidance of complete vasoconstriction caused by catecholamine release, andhence it increases the flap reliability especially in high-risk patients , 24. TheThe authors believe that these modifications willprovide reliable extralength of soft tissue, which is tension free with a widerarc of rotation, better filling of dead space with well-vascularized tissue soas to resist infection, and stable coverage with good functional outcome.Other modalities described for management ofcomplicated infected wounds as skin grafting or vacuum-assisted closure wouldnot be suitable due to the presence of dead space and exposed hardwareprosthesis after debridement , 4, 27. The use of free-tissue transfer is rare in theseclinical scenarios; on the other, hand-free osteocutaneous fibular flaps wereperformed for primary skeletal reconstruction after tumor extipiration ofsarcoma of the lower extremities rather tIn conclusion, the modified VRAM flaps would offerreliable reconstructive tools for coverage of complicated primary wound withnecrosis and breakdown after radical resection of pelvic and proximal lowerlimb musculoskeletal sarcoma. They offer larger well-vascularized soft tissuewith acceptable donor site, more durable coverage with no delay in thepostoperative adjuvant therapy, good functional outcome, together with overallimprovement in the survival."} +{"text": "A method was developed for delineating the structure ofparamagnetic metal complexes. The selective disappearanceof cross-peaks in proton-carbon shift correlated 2D NMRmaps was shown to uniquely depend upon the scalar and/ordipolar interaction between ligand nuclei and the unpairedelectron(s), thus providing a means of identifying bindingsites. Copper(II) was shown to form metal complexes withboth Penicillin (PNC) and Pilocarpine (PLC) and the structureof the two 1:2 complexes in water solution at physiologicalpH were determined."} +{"text": "Solid tumours develop an acidic extracellular environment with high concentration of lactic acid, and lactic acid produced by glycolysis has been assumed to be the major cause of tumour acidity. Experiments using lactate dehydrogenase (LDH)-deficient ras-transfected Chinese hamster ovarian cells have been undertaken to address directly the hypothesis that lactic acid production is responsible for tumour acidification. The variant cells produce negligible quantities of lactic acid and consume minimal amounts of glucose compared with parental cells. Lactate-producing parental cells acidified lightly-buffered medium but variant cells did not. Tumours derived from parental and variant cells implanted into nude mice were found to have mean values of extracellular pH (pHe) of 7.03 +/- 0.03 and 7.03 +/- 0.05, respectively, both of which were significantly lower than that of normal muscle . Lactic acid concentration in variant tumours (450 +/- 90 microg g(-1) wet weight) was much lower than that in parental tumours (1880 +/- 140 microg/g(-1)) and similar to that in serum (400 +/- 35 microg/g(-1)). These data show discordance between mean levels of pHe and lactate content in tumours; the results support those of Newell et al (1993) and suggest that the production of lactic acid via glycolysis causes acidification of culture medium, but is not the only mechanism, and is probably not the major mechanism responsible for the development of an acidic environment within solid tumours."} +{"text": "Automated Flow Injection Gas Diffusion (FIGD) promotes theselective transmembrane diffusion of MAs and NH3 from aqueoussample under strongly alkaline , chelated (EDTA) conditions into a recycled acidic acceptor stream. The acceptor is then injected onto an ion chromatograph where NH3 and the MAs are fully resolved as their cations and detectedconductimetrically. A versatile PC interfaced control unit and data capture unit (DCU) are employed in series to direct the selonoid valve switching sequence, IC operation and collection of data. Automation, together with other modifications improved bothlinearily andprecision (<8%) of FIGD-IC at nanomolar concentrations, compared with the manual procedure. The system was successfully applied to the determination of MAs and NH3 in seawater and in trapped particulate and gaseous atmospheric samples during anoceanographic research cruise.The automation and improved design and performance of FlowInjection Gas Diffusion-Ion Chromatography (FIGD-IC), a novel technique for the simultaneous analysis of trace ammonia (NH"} +{"text": "A simple, rapid histone agglutination test (HAT) is described. It consists of incubation in microplates or in microtubes of blood lymphocytes isolated from cancer patients and patients with non-malignant diseases with microquantities of histone fraction F2A1. Positive reaction is shown by massive agglutination of lymphocytes of the patients tested (126 subjects): this test was positive in 76% of cases. All controls (59 subjects) were negative."} +{"text": "By analogy with the case of [Pt(en)2]Cl2 it is suggested that Auen acts as a minor groove binder.Reactions of the complexes bisethylendiammine gold(III) and bisethylendiammine platinum(II) with calfthymus DNA were comparatively analysed. Both complexes bind DNA non-covalently most probably on the basis of electrostatic interactions. Binding of either complex at low ratios results into modest modifications of B-type DNA conformations, as detected by CD. Far larger CD alterations are observed at high ratios. The gold(III) chromophore is scarcely perturbed by DNA addition Binding of [Au(en)"} +{"text": "During a 15-month period, we used in vivo bromodeoxyuridine (BUDR) infusion to study cell kinetics in 112 consecutive patients with various types of malignant tumours: acute leukaemia (50 patients), gastric cancer (42) and brain gliomas (20). The in vivo BUDR method requires that a single tumour sample be taken 4-6 h after infusion and that bivariate flow cytometry (FCM) be employed to measure simultaneously the percentage of BUDR-labelled cells and their mean DNA content (following propidium iodide staining). This technique rapidly furnishes the labelling index (LI) and the DNA synthesis time (TS), from which the tumour potential doubling time (Tpot) and production rate are calculated. The procedure took 6-9 h to complete and there was no immediate toxicity from BUDR administration. Successful LI and TS determinations were obtained in 89 (80%) and 80 (72%) of the 112 patients, respectively. Correlations were sought between kinetic parameters and a number of pathological and clinical ones. In 34 patients with acute non-lymphoblastic leukaemias who were uniformly treated for remission (CR) induction and maintenance, proliferative activity, as measured by Tpot and FTR, was greater in responsive than in non-responsive patients, and in those who experienced CR for over 8 months than in those who had a shorter CR. Proliferative activity was also greater in patients with advanced gastric cancers than in those with more limited disease. No correlations between kinetic and clinical and pathological parameters were found in gliomas. These data indicate the in vivo BUDR infusion coupled with FCM measurements can be performed in clinical settings to obtain kinetic data rapidly in quite large patient series. This will probably allow the inclusion of kinetic data in clinical trials aimed at evaluating the prognostic relevance of these data."} +{"text": "Long-term cognitive and educational sequelae have been inconsistently reported in children who received cranial irradiation (CRT) to prevent central nervous system (CNS) disease in acute lymphoblastic leukaemia (ALL). This study investigates a large and representative sample of survivors of ALL and compares them with non-irradiated survivors of cancer and healthy control children to determine the effect of CRT on cognitive and educational ability. Three groups of children were studied: Group 1 (n=100) survivors of ALL treated with chemotherapy and CRT, group 2 (n=50) children with a variety of malignancies treated with chemotherapy alone, group 3(n=100) healthy children. Cognitive and educational abilities of these groups were evaluated using standardised psychometric techniques. Significant differences in cognitive and educational abilities were found between the children in group 1 (chemotherapy + CRT) and the two control groups, with the children receiving CRT performing less well in a range of tests. Greatest differences were detected for tasks dependent on language function including verbal IQ, reading and spelling. Within group 1 a younger age at treatment (less than 5 years) and a higher dose of CRT (24 Gy vs 18 Gy) were predictive of poor long-term outcome for cognitive and education ability. In contrast, children who received chemotherapy alone, with or without intrathecal methotrexate, performed similarly to healthy controls. No gender differences were detected for these measures."} +{"text": "Alterations in DNA ploidy accompany hepatocellular carcinoma (HCC). However, changes in DNA content are also seen in regenerating liver and with increasing age. Thus, to investigate the role of DNA ploidy changes in development of HCC, flow cytometric DNA content determinations were done in a rat model system of peroxisome proliferator-induced HCC. Paraffin blocks of liver isolated from 18 Fisher 344 male rats fed ciprofibrate for 20 weeks (4), 40 weeks (4) or 20 months (10) were examined. Livers from age-matched control rats were also examined. From the 20 month ciprofibrate group, nine neoplastic nodules (NNs), 27 HCCs and four non-tumorous surrounding tissue controls (NTCs) were examined. Significant DNA tetraploid populations were seen in both the NNs and NTCs. A significant increase in the percentage of DNA diploid cells was observed in the NN samples. No significant difference in the percentage S-phase cells was seen. Emergence of cell populations with new DNA ploidy classes (8c or DNA aneuploid) as compared with NTCs was only seen in HCCs (7 of 27), and five of these seven were DNA aneuploid, as distinct from DNA tetraploid, populations. A total of 16 of 24 HCC samples that were adequate for cell cycle analysis had average percent S-phase greater than the mean of the NTCs plus three standard deviations. Although a direct role cannot be inferred, these results support the hypothesis that increases in the fraction of diploid cells is an important early event in the development of rat HCC and that further alterations in DNA ploidy and increased proliferative fraction accompany the development of HCC."} +{"text": "Copper(II) complexes of several hydroxyflavones were prepared and characterised through their physico-chemical properties. The nuclease activity of three synthesised complexes is reported. These copper(II) complexes present more nuclease activity than the ligands and the copper(II) ion."} +{"text": "We examined hepatic artery ligation combined with an angiogenesis inhibitor, TNP-470, in the treatment of VX2 tumour inoculated into the liver of rabbits. Effects on tumour growth were correlated with arterial collateral development in this system. Three treatment methods were compared: (1) the left hepatic artery was ligated at the liver hilum (ligation group); (2) TNP-470 (40 mg per body) was infused continuously for 7 days via the common hepatic artery (TNP group); (3) the left hepatic artery was ligated and TNP-470 was infused continuously for 7 days via the common hepatic artery (ligation + TNP group). These treatments were started 12-14 days after tumour inoculation. The day of initiating treatment was defined as day 0. Although there were no significant differences in tumour volume among the three treated groups on day 7 after treatment, tumour volumes in the ligation + TNP group were significantly smaller than in the ligation group and the TNP group on day 14 after treatment. The vasculature and arterial collaterals around the tumour were demonstrated by the perfusion of a silicon rubber solution, Microfil. In the ligation + TNP group, the new microvasculature around the tumour decreased compared with the ligation group. The TNP-470 inhibition of microvascular proliferation may limit the development of collaterals that communicate with new feeding arteries. These results suggest that transarterial embolization combined with TNP-470 may enhance the anti-tumour effect of transarterial embolization alone in the treatment of liver tumours."} +{"text": "The hormonal mechanisms involved in the development of gynaecomastia accompanying the treatment of multiple myeloma in adult men have been investigated by studying levels of circulating testosterone (T), oestrone (EI), oestradiol (E2), sex-hormone binding globulin (SHBG), prolactin (PRL) and the gonadotrophins LH and FSH, before, during and after development of gynaecomastia in 4 men. These have been compared with 5 closely matched men who did not develop gynaecomastia during similar treatment for myeloma. Levels of circulating T fell, and levels of E1 and E2 rose during treatment periods in all subjects, and the changes were statistically significant in subjects developing gynaecomastia, which resolved as levels of sex steroid returned towards normal following cessation of treatment. We conclude that treatment of adult men for myeloma results in testicular dysfunction with a reduction in circulating T and a rise in circulating oestrogens. These changes are most marked in subjects developing gynaecomastia in whom the normal breast tissue is stimulated by a subtle, transient oestrogen:androgen imbalance in favour of oestrogens."} +{"text": "Twenty-four symptomatic patients with advanced non-small cell lung cancer (NSCLC) were treated with cisplatin-based chemotherapy . Patients were assessed for symptom relief as well as for objective response. Although only five patients achieved an objective response (21%), 18 patients (75%) reported a complete disappearance or good improvement in at least one of their tumour-related symptoms. The overall symptomatic response rate was 67% with 16 patients feeling better or much better on treatment. The toxicity of treatment (primarily myelosuppression and nausea and vomiting) was mild and hair loss was minimal. The high incidence of symptomatic relief seen in this study, even in the absence of objective response, suggests that moderate dose chemotherapy may have a role in the palliation of NSCLC."} +{"text": "Activation of the RET tyrosine kinase domain occurs in a proportion of thyroid papillary carcinomas. Three chromosomal rearrangements have been described, of which PTC1 is the commonest. Wide differences (2.5-25%) in frequency of PTC1 in different populations have been reported; it is not clear whether these are due to environmental factors, racial differences or technical reasons. We have developed a simple and rapid reverse transcriptase nested polymerase chain reaction (RT-nPCR) method enabling the detection of gene expression from single 5 microns sections of formalin-fixed paraffin wax-embedded archival material. We have applied this approach to detect expression of the RET tyrosine kinase domain, allowing identification of RET activation resulting from any rearrangement, whether characterised or not, or from overexpression. A retrospective study was performed on 22 adult and 21 childhood papillary carcinomas. Thirteen of 22 (59%) adult and 10 of 21 (48%) childhood carcinomas showed evidence of RET activation, demonstrating a major role for the RET oncogene in UK thyroid papillary carcinogenesis. This study also shows a similar frequency of RET activation in both children and adults. The use of a technique that allows reliable amplification of RNA from archival material, using primers chosen in different exons so that amplified products are readily distinguished from genomic DNA, will allow correlation of translocations and chromosomal rearrangements with a variety of specific tumour types."} +{"text": "A lymphocyte stimulation assay is described which detects immune reactivity to antigens derived from the CaSki cervical carcinoma cell line. Taking a stimulation index of greater than 4.1 as positive, the peripheral blood lymphocytes of 14/20 patients (70%) with untreated dysplasia or carcinoma-in-situ, 8/19 patients (42%) with untreated macroinvasive squamous cell carcinoma of the uterine cervix and 8/38 controls (21%) showed positive reactions. Statistical analysis revealed a significant difference between the group of patients with dysplasia or carcinoma-in-situ and the controls. The sera of patients and controls were simultaneously tested for the presence of tumour-directed antibody. There was no correlation between the occurrence of cellular immune reactivity and of serum antibody, both directed to cervical carcinoma antigens. Cellular immune reactivity tended to occur more frequently in patients with preinvasive stages of cervical carcinoma, and serum antibody in patients with macroinvasive carcinoma."} +{"text": "These data stimulate further epidemiological and functional studies focusing on the role of homocysteine and folate metabolism in lymphoma tumorigenesis.Primary central nervous system lymphomas (PCNSL) frequently reveal genomic instability. We analysed different functional genetic variants affecting the folate and homocysteine metabolism important for DNA integrity in 31 PCNSL patients and 142 controls. We found significantly less carriers of the methionine synthase c.2756A>G (D919G) missense polymorphism among the patients (0.16 S-adenosylmethionine (SAM) as a cosubstrate in DNA methylation.Primary central nervous system lymphomas (PCNSL) are highly malignant non-Hodgkin's lymphomas (NHL). The vast majority of them are of the diffuse large B-cell type . GeneticFigure 1We performed a case\u2013control study using DNA samples of 31 German patients with PCNSL of the DLBCL-subtype .The Hardy\u2013Weinberg equilibrium was confirmed for all polymorphisms. Allele frequencies of the control group did not significantly differ from those reported in the literature or \u03c72-analysis . Further, we did not find any significant association of the other polymorphisms or combinations with PCNSL.The CBS 844ins68 polymorphism was detected more frequently in patients (26%) than in controls (14%). However, the difference did not reach statistical significance in regression analysis is associated with a lower risk of developing colorectal cancer and types of systemic NHL against PCNSL and encourage future studies investigating the influence of genetic and dietary conditions of homocysteine and folate metabolism on cancerogenesis."} +{"text": "Serologic and molecular evidence indicates that peste des petits ruminants virus (PPRV) infection has emerged in goats and sheep in the Ngari region of southwestern Tibet, People\u2019s Republic of China. Phylogenetic analysis confirms that the PPRV strain from Tibet is classified as lineage 4 and is closely related to viruses currently circulating in neighboring countries of southern Asia. Peste des petits ruminants (PPR) is an acute and highly contagious viral disease contracted by small ruminants such as goats and sheep and causing high rates of illness and death. The disease is endemic in parts of sub-Saharan Africa, the Middle East, and Asia. The PPR virus (PPRV) genogroup consists of 4 lineages in the Ngari region, where animals having clinical signs of PPRV infection had been reported by local authorities. The second group included 298 animals in Gar and Bulang counties in the same region and in 2 counties bordering the Ngari region (Nyima in Nagqu region and Zhongba in Shigatse region). The third group contained 520 animals in 5 counties within 3 separate regions . We examined 1,536 animals (771 goats and 765 sheep) and collected serum samples from each. A competitive ELISA that used a monoclonal antibody to the N protein . Rates oField samples, including organ and swab specimens, were obtained from 49 goats and sheep suspected of being infected with PPRV. These animals inhabited 4 counties in the Ngari region . Two reverse transcription\u2013PCRs (RT-PCR) and 1 newly developed and validated real-time quantitative RT-PCR (qRT-PCR) were conducted to determine whether the animals had viral RNA .The study confirmed 11 outbreaks in 4 counties in the southwest Ngari region in Tibet. Nine of the 11 occurred in southern Rutog County, northern Ge\u2019gyai County, and Gerze County, and samples from these 9 were seropositive for PPRV , panel AThe nucleic acid sequences obtained from the PCR products were aligned with sequences from PPRV strains available in GenBank. Partial sequencing (448 bp) of the F gene showed that 20 of 21 samples were identical over the portion of the genome that was characterized (GenBank accession no. EU816772). One (GenBank accession no. EU815053) differed from other Ngari sequences by 1 nt. The Ngari sequences showed a level of nucleotide identity with other PPRV strains of 88.8%\u201398.8%. Strains of PPRV from Tibet were classified as lineage 4 and were closely related to the India/Bsk/Guj/05 strain isolated in India in 2005 , panel AIn this study, PPRV was found by collecting samples from animals in the field and detecting infection by using competitive ELISA and RT-PCR. Our research provides valuable data on PPRV infection in small ruminants in Tibet. Infection was observed in 4 counties in the Ngari region of southwestern Tibet. Most outbreaks occurred in Rutog and Ge\u2019gyai counties; 1 outbreak was confirmed in Gerze County and another in Zada County. Epidemiologic and serologic evidence suggests that the infection first emerged in Rejiao village in southwestern Rutog from November 2005 through March 2006. PPR likely existed for several years without being recognized in Tibet because veterinarians, animal health workers, and livestock owners in the area are unfamiliar with its clinical and pathologic features. Also, this disease is frequently confused with other diseases that cause respiratory problems and death in small ruminants (The molecular epidemiologic techniques provided data suggesting cross-border transmission of PPRV infection into Tibet. PPR infection has been recognized in many Asian countries bordering southwestern China, including India ("} +{"text": "Single cell suspensions of two allogeneic tumours (W-256 and Y-P388) injected intravenously produced macrocolonies in the lungs of rats. Colony forming efficiency was low in 6-week or older rats but was markedly increased by 1000-1500 rad local thoracic irradiation (LTI) given 7-14 days before the tumour cell injection, or by antilymphocytic serum (ALS) but not by sublethal whole body irradiation (WBI). Similarly, LTI increased the incidence of pulmonary metastases produced by a solid tumour growing in the leg muscle. Stimulation of CFE by LTI was a strictly local phenomenon and not due to effects of irradiation on thymus, spleen or other tissues of the rat. LTI failed to increase CFE in immunized rats. It is concluded that (1) LTI stimulates clonogenic growth of tumour cells arrested in the lungs, by causing inflammatory reactions accompanied by regenerative cellular proliferation of lung tissue, which increases the \u201cplating\u201d efficiency of tumour cells, (2) the increase in CFE in lungs is not due to suppression of immunity to tumour growth by LTI."} +{"text": "The full spectrum technique in the fourier domain was studied forsimultaneous determination of Cu(II), Pb(II) and Cd(II) with 4-(2-pyridylazo) resorcinol (PAR). A program called SPGRFSQ. was designed to perform the calculations. Seven error functions were calculated for deducing the number of factors. Data reduction was performed using principal component analysis (PCA) algorithm. Experimental results showed the method to be successful even where there was severe overlap of spectra."} +{"text": "Knowledge and awareness about childhood autism is low among health workers and the general community in Nigeria and other Sub-Saharan African countries. Poor knowledge and awareness about childhood autism, especially among health workers can compromise early recognition and interventions which had been known to improve prognosis in children with autism. In formulating policy and designing interventions for these children, there is need to develop a reliable tool that can be used in assessing baseline knowledge about childhood autism among health workers and the impact that future continued education and awareness campaign may have on such baseline knowledge. Knowledge about childhood autism among health workers (KCAHW) questionnaire was designed for this purpose.The KCAHW questionnaire is a nineteen (19) item self-administered questionnaire that is divided into four domains. KCAHW questionnaires were distributed to fifty (50) psychiatric nurses involved in community mental health services in South-Eastern Nigeria to complete. After two weeks period, the KCAHW questionnaires were re-administered to the same fifty (50) psychiatric nurses to assess their knowledge about childhood autism and to assess the test-retest reliability and internal consistency of this questionnaire.KCAHW questionnaire showed good test-retest reliability when the mean domain and total scores at first and second time administration were compared. The four mean domain scores and the mean total scores at first and second time administration were significantly correlated. The questionnaire also had a good overall internal consistency when the mean scores of the four domains were correlated with mean total scores .The KCAHW questionnaire is a reliable tool for assessing knowledge of health workers about childhood autism. It would be a useful tool in improving early recognition of features of autism among affected children in Sub-Saharan African and other developing countries of the world where knowledge and awareness about childhood autism is low. Since Leo Kanner's paper titled, \"Autistic disturbances of affective contact\" about seven decades ago , awareneEarlier survey on knowledge about childhood autism among health care workers had been by Stone . The stuRhoades et al exploredThe above surveys coming from the United States of America (USA), an environment where knowledge and research about childhood autism are more widely spread than what obtains in sub-Saharan Africa point to the need to assess knowledge and awareness in this environment and put in place programs to increase such knowledge and awareness with the ultimate aim of helping children with ASD.It had been presumed that in view of the rarity of presentation of childhood autism cases in pediatric health facilities in developing countries especially Sub-Saharan Africa, health care workers especially the nurses who are often in charge of various Primary Health Care (PHC) facilities in rural communities in Africa might not be well versed with the condition. Subsequently, early identification at the community level and intervention which have been shown to improve the prognosis of these cases ,21,22 maThis presumption was put into test in May 2007, when African Network for the Prevention and Protection Against Child Abuse and Neglect (ANPPCAN), Nigeria Chapter in collaboration with the World Bank carried out a survey to ascertain the level of knowledge and awareness of health care workers and the general public in Enugu State, South Eastern Nigeria on autism and implemented a project aimed at increasing the level of awareness on autism.The results of the survey showed that there is a very low level of awareness on autism among the general public and a low to average level of awareness among various categories of health care workers, with highest level of awareness noted among those health workers working in psychiatric facilities. Attempt was made then, to increase the level of awareness on autism through a workshop organized for the stakeholders and a radio phone \u2013 in program for the general public. However, one of the problems encountered during the survey was the unavailability of easily understandable and reliable questionnaire for measurement of the health care workers baseline knowledge of autism, aimed at early identification of cases in the community . The KCAIt had therefore been established that knowledge and awareness on autism and ASD is low in south-eastern Nigeria and there had been recent outcry in Nigeria to promote knowledge and awareness about childhood autism among the health care workers and the general community .In doing this, there is need for baseline assessment of present knowledge, facilities in place for intervention among other things. This would ensure proper planning. Promoting awareness at the community level should begin with various health workers who are involved in community health services. They can be trained to become trainers of other category of people in the community towards early recognition of children with childhood autism.For proper design of community campaign and continued education needed for these health workers, the need arises to design a reliable tool that can be used in measuring their baseline knowledge about childhood autism and the possible impact that future continued education and campaign may have on the knowledge of these health workers about childhood autism.Knowledge and awareness about childhood autism may vary from one geographical region to another. The same tool can be used to assess variation in knowledge of the disease condition over different geographical regions, given an index of geographical locations where immediate attention need to be focused as regards health workers and community education.\"Knowledge about Childhood Autism among Health Workers (KCAHW) Questionnaire\" for use in various communities of developing countries where knowledge about childhood autism is limited among the health workers working at the community level.The above reasons inform the design of This article is aimed at describing the content of KCAHW questionnaire and reporting the test-retest reliability and internal consistency of the questionnaire.Location of the study was at Federal Neuro-Psychiatric Hospital, New Haven, Enugu (FNHE), Nigeria. FNHE is a specialist Psychiatric Hospital located in the South-Eastern region of Nigeria. The hospital is involved in community mental health service collaboration with various PHC facilities located in the rural communities of South-Eastern Nigeria. This community mental health care service in various PHC facilities in this region of the country is overseeing by the psychiatric nurses employed by the hospital.Ethical approval for this study was obtained from the ethical committee of FNHE, Nigeria.A total of fifty (50) psychiatric nurses employed by FNHE, Nigeria and who are involved in the community mental health services of the hospital participated in the study. There were 12 males and 38 females. The fifty nurses included in the study had had a minimum of five years of practice in general psychiatry nursing and possessed diploma qualification in general nursing and psychiatry nursing. It should be noted that only psychiatric nurses were used as the sample for this study because in the context of our environment in Nigeria and other sub-Saharan African countries, they are supposed to be the most likely health care workers who attend to cases such as autism and ASD and still supervise health care services at primary care level.In addition to the socio-demographic questionnaire, KCAHW questionnaire was distributed to consented fifty (50) psychiatric nurses to complete. After a period of two (2) weeks, the KCAHW questionnaire was re-distributed to the same fifty (50) psychiatric nurses to complete. The questionnaires were completed by the respondents and collected from them there and then at each point of administration to prevent them from consulting any study material or discussing with their colleagues before filling in their responses.This is a self administered questionnaire that contained a total of nineteen (19) \u2013 item questions. Each of the item questions has three (3) options to choose from with only one of these three options being correct. The correct option on each item question attracts a score of one (1), while the other two options that are incorrect attract a score of zero (0) each.The KCAHW questionnaire is further divided into four (4) domains:Contained eight (8) item questions that addressed the impairments in social interaction usually found in children with childhood autism. A maximum and minimum score of 8 and 0 respectively are possible in this domain.Contained only one (1) item question that addressed impairment in area of communication and language development, which is part of symptom presentation in children with childhood autism. A maximum and minimum score of 1 and 0 respectively are possible in this domain.Contained four (4) item questions that addressed area of obsession and compulsive pattern of behavior found in children with childhood autism, a pattern of behavior which had been described as restricted, repetitive and stereotyped. A maximum and minimum score of four (4) and zero (0) respectively are possible in this domain.Contained six (6) item questions that addressed information on what type of disorder is childhood autism, possible co-morbid conditions and onset of childhood autism in affected children. A maximum and minimum score of six (6) and zero (0) respectively are possible in this domain.Therefore, a maximum and minimum total score of nineteen (19) and zero (0) respectively are possible when the four domain scores are added together.The content of the questionnaire and the scoring system are shown in Appendices 1 and 2.The mean total score on KCAHW questionnaire among a particular sample population or community is a measure of level of knowledge about childhood autism among that particular sample population or community.The mean scores in each domain and the mean total scores generated when KCAHW questionnaires were administered the first and second time were compared with paired t-test statistical analysis to assess the test-retest reliability of the KCAHW questionnaire.Then, the mean inter-domain scores during the first and second time administration of the questionnaire were correlated with the mean total scores and cronbach's alpha was calcA total of fifty (50) psychiatric nurses employed by FNHE, Nigeria and who are involved in the community mental health services of the hospital participated in the study. There were 12 males and 38 females with mean age of 32.6 years. The mean scores in the four domains of KCAHW questionnaire and mean total scores of 9.6 and 9.8 on first and second time administration of KCAHW questionnaire respectively which gave indices of level of knowledge on childhood autism in that particular sample population are shown in Table The paired t-test analysis comparing these mean scores and the 95% Confidence Interval (95% C.I) for the differences in the mean scores are shown in Table The correlation co-efficient for the four mean domain scores and mean total scores at first and second time administration of KCAHW questionnaire are shown in Table The internal consistency of KCAHW questionnaire was assessed by correlating different mean domain scores with the mean total scores at first and second time administration of the questionnaire and calculating the cronbach's alpha. The cronbach's alpha value of 0.97 obtained following the correlation is acceptable based on Nunnaly's recommendation .The ten by ten correlation matrix table of the four mean domain scores and mean total scores at first and second time administration of the KCAHW questionnaire is shown in Table The content of KCAHW questionnaire had been described. The test-retest reliability of the questionnaire is good based on the significant correlations in the mean domain and mean total scores at first and second time of administration. The KCAHW questionnaire also showed a good internal consistency as revealed in the cronbach's alpha value obtained for mean domain scores correlation with the mean total scores both at first and second time of administration.The imperative need to increase the level of knowledge and awareness among health workers and of the general community in Sub-Saharan African and other developing countries of the world about childhood autism necessitated the design of a reliable measuring tool that can be used to assess baseline knowledge of health workers on childhood autism and also subsequently the impact the future campaign and continuous education may have on the knowledge of these health workers about childhood autism, especially those group of health workers at primary health care facilities who are closer to the communities.KCAHW questionnaire could also be used to compare knowledge about childhood autism among different categories of health workers, if there is an indication for such. The variation in knowledge about childhood autism among health workers that could exist in various geographical regions of Sub-Saharan African and other developing countries where awareness about autism and ASD is low could also be assessed with KCAHW questionnaire.The limitation of administering the KCAHW questionnaire is that it could only be completed and collected immediately from the respondents upon administration. This is to prevent consultation of study materials or discussion with colleagues which can influence the respondents' response to the questions contained in the questionnaire. The KCAHW questionnaire would therefore serve the purpose only of a point time assessment of knowledge.KCAHW questionnaire is a reliable tool for assessing knowledge of health workers about childhood autism, aimed at early recognition of the condition in the primary care settings. It would be a valuable tool in assessing baseline knowledge of health workers about childhood autism in Sub-Saharan African communities and other developing countries where public awareness about childhood autism is low and policy and interventions are being planned for children affected by childhood autism. The level of knowledge of health workers about childhood autism, especially those working in the rural communities in this environment and other developing countries is an essential ingredient for early recognition and intervention which had been noted to improve prognosis in the affected children ,17,18. KPOE is affiliated with African Network for the Prevention and Protection against Child Abuse and Neglect (ANPPCAN), Nigeria Chapter and ANPPCAN, Nigeria Chapter received sponsorship from the World Bank in May 2007 for a survey on level of awareness of autism and implementation of program to raise awareness on autism in Enugu State, South Eastern Nigeria.All authors contributed to the conception of the study. MOB, POE and AOA are involved in writing and revision of the manuscript. All authors approved the final draft of the manuscript.Please do not consult formal text books to answer these questions.Thank you for your time.The following behaviors best describe a child with Childhood Autism:i. Marked impairment in use of multiple non-verbal behaviors such as eye to eye contact, facial expression, body postures and gestures during social interaction?(A) Don't Know, (B) Yes, (C) Noii. Failure to develop peer relationship appropriate for developmental age?(A) Don't Know, (B) Yes, (C) Noiii. Lack of spontaneous will to share enjoyment, interest or activities with other people? (A) Don't Know, (B) Yes, (C) Noiv. Lack of social or emotional reciprocity? (A) Don't Know, (B) Yes, (C) Nov. Staring into open space and not focusing on any thing specific?(A) Don't Know, (B) Yes, (C) Novi. The child can appear as if deaf or dumb? (A) Don't Know, (B) Yes, (C) Novii. Loss of interest in the environment and surroundings?(A) Don't Know, (B) Yes, (C) Noviii. Social smile is usually absent in a child with Autism?(A) Don't Know, (B) Yes (C) Noi. Delay or total lack of development of spoken language?(A) Don't Know (B) Yes (C) Noi. Stereotyped and repetitive movement (e.g. Hand or finger flapping or twisting)?(A) Don't Know (B) Yes, (C) Noii. May be associated with abnormal eating habit?(A) Don't Know, (B) Yes, (C) Noiii. Persistent preoccupation with parts of objects?(A) Don't Know, (B) Yes, (C) Noiv. Love for regimented routine activities? (A) Don't Know, (B) Yes, (C) Noi. Autism is Childhood Schizophrenia? (A) Don't Know, (B) Yes, (C) Noii. Autism is an auto-immune condition? (A) Don't Know, (B) Yes, (C) Noiii. Autism is a neuro-developmental disorder? (A) Don't Know, (B) Yes, (C) Noiv. Autism could be associated with Mental Retardation?(A) Don't Know, (B) Yes, (C) Nov. Autism could be associated with Epilepsy? (A) Don't Know, (B) Yes, (C) Novi. Onset of Autism is usually in, (A) Neonatal age, (B) Infancy, (C) Childhoodi Marked impairment in use of multiple non-verbal behaviors such as eye to eye contact, facial expression, body postures and gestures during social interaction?(A) 0 (B) 1 (C) 0ii Failure to develop peer relationship appropriate for developmental age?(A) 0 (B) 1 (C) 0iii. Lack of spontaneous will to share enjoyment, interest or activities with other people? (A) 0 (B) 1 (C) 0iv Lack of social or emotional reciprocity? (A) 0 (B) 1 (C) 0v Starring into open space and not focusing on any thing specific?(A) 0 (B) 1 (C) 0vi. The child can appear as if deaf or dumb? (A) 0 (B) 1 (C) 0vii. Loss of interest in the environment and surroundings?(A) 0 (B) 1 (C) 0viii. Social smile is usually absent in a child with Autism?(A) 0 (B) 1 (C) 0i. Delay or total lack of development of spoken language?(A) 0 (B) 1 (C) 0i. Stereotyped and repetitive movement (e.g. Hand or finger flapping or twisting)?(A) 0 (B) 1 (C) 0ii. May be associated with abnormal eating habit?(A) 0 (B) 1 (C) 0iii. Persistent preoccupation with parts of objects?(A) 0 (B) 1 (C) 0iv. Love for regimented routine activities? (A) 0 (B) 1 (C) 0i. Autism is Childhood Schizophrenia? (A) 0 (B) 0 (C) 1ii. Autism is an auto-immune condition? (A) 0 (B) 0 (C) 1iii Autism is a neuro-developmental disorder? (A) 0 (B) 1 (C) 0iv. Autism could be associated with Mental Retardation?(A) 0 (B) 1 (C) 0v. Autism could be associated with Epilepsy? (A) 0 (B) 1 (C) 0vi Onset of Autism is usually in (A) 0 (B) 0 (C) 1A total maximum score of 19 and a minimum score of 0 are possible. The average score on the KCAHW questionnaire among a particular sample population give an index level of knowledge about childhood autism in that particular population."} +{"text": "Elevated serum levels of the beta-subunit of human chorionic gonadotrophin (hCG) were measured in 50% of patients with locoregional recurrences or progressive vulvar carcinoma (n = 14). At diagnosis of vulvar cancer, however, the incidence of elevated serum levels was low (5%) in 104 patients. The rising serum levels during progression of disease indicate that the synthesis of the beta-subunit hCG can be increased in vulvar carcinoma."} +{"text": "In the northern hemisphere winter of 2003\u201304 antigenic variant strains (A/Fujian/411/02 \u2013like) of influenza A H3N2 emerged. Circulation of these strains in the UK was accompanied by an unusually high number of laboratory confirmed influenza associated fatalities in children. This study was carried out to better understand risk factors associated with fatal cases of influenza in children.Case histories, autopsy reports and death registration certificates for seventeen fatal cases of laboratory confirmed influenza in children were analyzed. None had a recognized pre-existing risk factor for severe influenza and none had been vaccinated. Three cases had evidence of significant bacterial co-infection. Influenza strains recovered from fatal cases were antigenically similar to those circulating in the community. A comparison of protective antibody titres in age stratified cohort sera taken before and after winter 2003\u201304 showed that young children had the highest attack rate during this season . Clinical incidences of influenza-like illness (ILI) in young age groups were shown to be highest only in the years when novel antigenic drift variants emerged.This work presents a rare insight into fatal influenza H3N2 in healthy children. It confirms that circulating seasonal influenza A H3N2 strains can cause severe disease and death in children in the apparent absence of associated bacterial infection or predisposing risk factors. This adds to the body of evidence demonstrating the burden of severe illness due to seasonal influenza A in childhood. Influenza A virus is a cause of severe morbidity and mortality worldwide Human seasonal influenza A viruses evolve rapidly through genetic mutation, allowing them to escape previously acquired immunity This study investigated fatal cases of influenza H3N2 in children during the emergence of A/Fujian/411/02 in the UK in winter 2003\u201304. The goals of the study were: to investigate whether any of the case fatalities had underlying disease or risk factors; to evaluate how laboratory confirmed infections were recorded in death certification; to describe the clinical and pathological findings in relation to circulating virus strains; and to investigate whether the high number of laboratory confirmed fatalities was reflected in measures of morbidity in primary care, age specific attack rates and age specific all-cause mortality. We reviewed the antecedent illness history, underlying risk factors, clinical findings and observed pathology at autopsy. Age-stratified serological data were combined with community based clinical morbidity data to provide an assessment of the overall population immune susceptibility, attack rates and impact of A/Fujian/411/02-like influenza in comparison with other winter seasons in which new H3N2 antigenic variants emerged.This study was conducted as part of a public health inquiry by the Health Protection Agency and Health Protection Scotland into paediatric deaths, where it was agreed that ethical approval for linking personal clinical outcome information to virus strains was not required. Nationally representative, anonymised, age stratified residual sera were obtained from the HPA serum bank held in Preston NHS hospital. Ethical approval was given by the HPA for the collection of these samples.st September 2003 to 30th May 2004) with laboratory confirmation of influenza virus infection reported to HPA. Most specimens were initially tested at referring hospitals, and all were subsequently tested at the national influenza laboratory, HPA Centre for Infection, Colindale (HPA CfI). Microbiological findings deemed significant are included.A case was defined as a death in child less than eighteen years of age during the 2003\u201304 influenza season . The activity took place within the context of a national public health enquiry into influenza associated childhood deaths in winter 2003. Children without risk factors recognized by UK Joint Committee on Vaccination and Immunisation to increase the risk of influenza related complications were classified as \u201cpreviously healthy\u201d. U.K. risk factors for severe influenza from 2003\u201304 are given in reference 12. Verification of the certified cause of death in each fatal case was performed by matching cases to Office of National Statistics (ONS) death registration records held at HPA.http://www.hpa.nhs.uk/web/HPAweb&HPAwebStandard/HPAweb_C/1195733836222.The Weekly Returns Service (WRS) of the Royal College of General Practitioners is a clinical information system based upon a network of sentinel general practices located throughout England and Wales Viruses were grown in either MDCK or MDCK-SIAT1 cells and subtyping was performed by RT-PCR, if no virus isolate was available Nationally representative, anonymised, age stratified residual sera were obtained with ethical approval from the HPA serum bank held in Preston NHS hospital. The number of sera tested from 2003 was 88 (ages 0\u20134), 196 (ages 5\u201317), 293 (ages 18\u201344), 185 (ages 45\u201364) and 101 (ages 65+). The number of sera from 2004 for each age group was 70 (ages 0\u20134), 160 (ages 5\u201317), 273 (ages 18\u201344), 199 (ages 45\u201364) and 98 (ages 65+).Haemagglutination inhibition (HI) assays to assess protective antibody titres in human sera were performed using standard protocols and antigenically representative viruses. A titre of >1/40 was taken as protective.Seventeen fatal cases of laboratory-confirmed influenza A in children under eighteen years were reported to HPA between September and December 2003. This period corresponded with peak circulation of influenza during the winter 2003\u201304. The median age of fatal cases was two years, with a range from four months to seventeen years; the majority (64%) were under five years. Ten (58%) deaths were in females. The duration of illness prior to death varied, with a median duration of three days (range 0\u201314 days). Four (24%) deaths were sudden with either no recognized antecedent illness or illness of less than 6 hours duration. A further four (24%) occurred within forty-eight hours of onset of symptoms, five (29%) were ill for three to four days prior to death, three (18%) were ill for a week prior to death, and one individual was unwell for over ten days. Eight (47%) children died following hospitalization and nine (53%) died in the community. In the cases with recognized antecedent illness, eight (57%) had fever, eleven (79%) had respiratory symptoms (cough/chest infection/croup), three (21%) had vomiting and/or diarrhea, two (14%) had clinically recognized sepsis. Two (14%) children were markedly confused prior to collapse .Among the sixteen cases for whom underlying health status information was available none was recorded as having a known risk factor for severe influenza, although two cases (both over two years) had a history of febrile convulsions In nine cases (53%) influenza A detection occurred by more than one method , either in respiratory clinical samples or from post-mortem tissues. In eleven (64%) cases influenza A virus isolates were recovered. The cultured viruses were analyzed for their antigenic characteristics; all isolates were found to be antigenically similar to each other and to virus isolates recovered from non-fatal cases matched for age, week of infection and geographical location (controls) as well as to other circulating strains from the same locality (data not shown). Influenza AH3N2 was detected by RT-PCR only in five (29%) cases.Staphylococcus aureus and Streptococcus pneumoniae in blood were identified in the two cases of clinical sepsis and one case had Streptococcus pneumonia bacterial pneumonia. No other significant bacteriological findings were described. Enterovirus and norovirus were also detected by RT-PCR in two cases.Staphylococcus aureus or Streptococcus pneumoniae and myocarditis in two cases (12%). Eight cases (47%) showed abnormalities of the lymphoid system, including seven (41%) with enlargement of the lymph nodes (LN), thymus or spleen, six (35%) with hemorrhagic LN, thymus or spleen and two (12%) with \u201cstarry sky\u201d LN indicating an infiltration of macrophages in the lymphoid tissue. No metabolic disorders were recognized ante or post mortem, although one case showed unusual large fiber laryngeal musculature of uncertain significance.Autopsy reports were available for all cases . All casDeath registration information was not available for one case. By routine death registration only nine of sixteen fatal cases (56%) were coded with influenza (ICD10 J10\u2013J11). Seven of these specifically mentioned influenza A on the death certificate and a further certificate mentioned \u201cinfluenza\u201d when text was searched manually. Two (13%) of the deaths were registered as pneumonia (J18); two (13%) as other respiratory disorders (J98); two (13%) were registered as sudden infant death (SIDS) and one as acute myocarditis, without mention of influenza (I40). Septicemia (A41) and myocarditis were identified as contributing causes to death on three certificates. No death certificate indicated any chronic medical conditions known to increase the risk of severe disease from influenza infection.We sought to establish whether young children showed particular susceptibility to A/Fujian/411/02-like virus infection during this winter season by analyzing sera from summers 2003 and 2004, prior and subsequent to the emergence of this antigenic drift variant. Serum samples in a nationally representative age-stratified serum cohort were analyzed for the presence of protective antibodies . The numTo assess the morbidity of influenza in different age groups we analysed observational clinical data from primary care recorded by GPs of the Weekly Returns Service (WRS). This is a national sentinel network which has been recording influenza-like illness (ILI) for over 40 years, and for which linked clinical-virological surveillance has been operational since 1994. The all-age incidences of ILI in England and Wales over a ten year period from 1994\u20132004, together with incidence rates in children ages 0\u20134 and 5\u201314 years is shown in Winter 2003\u201304 was marked by an unusually high number of severe and fatal cases of influenza in the young, following the emergence of the influenza A H3N2 antigenic drift variant A/Fujian/411/02 The range of clinical complications in UK fatal cases can be grouped into categories including (1) fulminant progression to death after an initially mild illness, (2) invasive bacterial infection, (3) respiratory tract complications and (4) non respiratory complications including myocarditis and encephalopathy. Extrapulmonary complications of myocarditis and encephalopathy were not accompanied by the detection of viral RNA from brain or heart tissue by RT-PCR, although virus was recovered from the nasopharynx. The pathological conclusions rest on histology findings, which suggests that tissue damage may occur through mechanisms other than direct viral replication, as has been previously suggested Staphylococcus aureusThe clinical microbiological findings add to the debate about the importance of bacterial co-pathogens in influenza associated fatality. Only three (18%) of the fatal cases showed evidence of significant bacterial co-infection. This is similar to findings from fatal cases in the US 2003\u201304 and also to preliminary information from the current outbreak of swine-origin influenza A H1N1, where a minority of paediatric hospital admissions had possible or probable bacterial infection In this case series over 40% of death certificates had no mention of influenza as a direct or indirect cause of death, and in over 70% of cases the diagnosis of influenza was not made until post mortem tissue was examined. The burden of influenza in young children is therefore under recognized, precisely because few influenza infections are recognized clinically A risk-factor based influenza vaccination program for children would not prevent these fatal cases as the reasons underlying susceptibility to severe disease remain cryptic. Further studies on the outcome of seasonal influenza in children will help us to predict the impact of future epidemics and will assist understanding of the outcome of infections in the immune na\u00efve host during influenza pandemics."} +{"text": "The differential p53 overexpression in different subtypes of intestinal metaplasia and gastric cancer suggests that type III intestinal metaplasia is the commonest lesion in dysplasia-carcinoma transition, particularly in the intestinal type of gastric cancer."} +{"text": "Higher concentrations of PSA and hK2 were found in tumours expressing steroid hormone receptors , and both PSA and hK2 correlated directly with PR levels. A negative correlation between patient age and PSA was also found. Both proteins were present in nipple aspirate fluid at relatively high concentrations which were positively correlated . The molecular weights of the immunoreactive species quantified by the hK2 and PSA assays were established by high-performance liquid chromatography (HPLC) and were consistent with the known molecular weights of hK2 and PSA. Together these data provide the first evidence, to our knowledge, that both malignant breast tissue and normal breast secretion contain measurable quantities of hK2, and that the degree of hK2 expression or secretion is directly proportional to the expression of PSA and steroid hormone receptors. hK2 expression may therefore be a marker of steroid hormone action in breast tissue. \u00a9 2000 Cancer Research CampaignThe recent demonstration of human glandular kallikrein (hK2) expression in a breast carcinoma cell line has suggested that this putatively prostate-restricted, steroid hormone-regulated protease may also be expressed in breast epithelium in vivo and secreted into the mammary duct system. Given that the only substrate yet identified for hK2 activity is the precursor of prostate-specific antigen (PSA), the expression of which in breast carcinomas may be associated with favourable prognosis, our purpose was to examine the expression pattern of both hK2 and PSA in breast tumour tissues. Cytosolic extracts of 336 primary breast carcinomas prepared for routine oestrogen receptor (ER) and progesterone receptor (PR) analysis, as well as 31 nipple aspirates from six women with non-diseased mammary glands, were assayed for hK2 and PSA using immunofluorometric assays developed by the authors. In the tumour extracts, measurable hK2 and PSA concentrations were detected in 53% and 73% of cases respectively, and were positively correlated to each other ("} +{"text": "DCC is the most likely target of LOH because loss or reduction of DCC expression has been found in many types of cancers. However, few reports have focused on sequence mutations of this gene. We investigated sequence mutations and expression of DCC in primary gastric cancers. We studied mutations in 25 of the 29 DCC exons by PCR-SSCP in 17 primary gastric cancers exhibiting LOH on 18q21. No mutations of DCC were found in any of the tumours, although 78% (47/60) of the primary tumours showed apparent loss or reduction of DCC expression by immunohistochemistry. Analysis of methylation status of DCC revealed that methylation frequently occurred in both primary tumours and corresponding non-cancerous gastric mucosae . Methylated status of DCC was significantly correlated with the loss of DCC expression in primary tumours (P< 0.01). These results indicate that DCC is frequently silenced, probably by epigenetic mechanisms instead of sequence mutations in gastric cancer. \u00a9 2001 Cancer Research Campaign http://www.bjcancer.comLoss of heterozygosity (LOH) on chromosome 18q21 is frequently found in various human cancers, suggesting the presence of tumour suppressor gene(s) in this chromosomal region."} +{"text": "To identify and implement strategies that help meet safety monitoring requirements in the context of an observational study for artemether-lumefantrine (AL) administered as first-line treatment for uncomplicated malaria in rural Tanzania.Pharmacovigilance procedures were developed through collaboration between the investigating bodies , the relevant regulatory authority (Tanzania Food and Drugs Authority) and the manufacturer of AL (Novartis Pharma AG). Training and refresher sessions on the pharmacovigilance system were provided for healthcare workers from local health facilities and field recorders of the Ifakara Health Demographic Surveillance System (IHDSS). Three distinct channels for identification of adverse events (AEs) and serious adverse events (SAEs) were identified and implemented.st September 2007 to 31st March 2010, 57 AEs were reported . The remaining seven were due to anti-pyretic or anti-parasite medications. Twenty patients experienced SAEs; in 16 cases, a relation to AL was suspected. Six of the 20 cases were reported within 24 hours of occurrence. In all cases reported after AL, 5 cases (vomiting), 16 cases (itching and/or rash) and others were difficult breathing, convulsion and headache (10 cases). The four AEs that occurred after SP were mild erythematic skin lesions that did not progress to Stevens-Johnson syndrome. The AEs seen following treatment with penicillin and amoxicillin were both rashes.Training was provided for 40 healthcare providers (with refresher training 18 months later) and for six field recorders. During the period 1Safety monitoring and reporting is possible even in settings with weak health infrastructure. Reporting can be enhanced by regular and appropriate training of healthcare providers. SMS text alerts provide a practical solution to communication challenges.Experience gained in this setting could help to improve spontaneous reporting of AEs and SAEs to health authorities or marketing authorization holders."} +{"text": "Fibreoptic bronchoscopy in previously untreated patients with malignant lymphoma provided diagnostic information in 8 of 25 cases with radiological evidence of intrathoracic involvement. There was a marked difference in the pattern of endobronchial involvement between Hodgkin's Disease (HD) and Non Hodgkin's Lymphoma (NHL) which specifically infiltrated the bronchus-associated lymphoid tissue. Bronchoalveolar lavage was abnormal in only one patient with Hodgkin's Disease in whom the presence of many Sternberg-Reed cells suggested occult dissemination of otherwise localised disease."} +{"text": "One hundred and seven patients with biliary pancreatitis undergoing operation from 1976 to 1989 werereviewed. To clarify the reason for failure to respond to conventional supportive therapy, 73 patients (68%) who underwent emergency surgery were retrospectively divided into two groups according to the severity of the pancreatitis evaluated at laparotomy and compared. Sixty-two had minimal or mild pancreatitis (Group I), among whom 44 (71%) had life-threatening acute biliary tract disease. All underwent biliary surgery and 4 (6%) subsequently died, 2 due to acute obstructive suppurative cholangitis. Eleven had hemorrhagic necrotizing pancreatitis (Group II), among whom 7 had complications of acute pancreatitis such as pancreatic ascites or abscess. These underwent pancreatic and/orbiliary surgery and 3 (27%) died of multi-organ failure.\t\tThere appears to be two types of biliary pancreatitis refractory to conventional supportive therapy, which differ in the extent of surgery required and in mortality: (1) minimal or mild pancreatitis with persistent life-threatening acute biliary tract disease (biliary type), and (2) more severe pancreatitis (pancreas type) early in the course of the disease."} +{"text": "The analyses were carried out with the aid of ion-exchange chromatography. The molar proportions of 5 bases detected in acid hydrolysates of tumour tRNA (N"} +{"text": "The measurement of carcinoembryonic antigen (CEA) in serum and endoscopic brush specimens was evaluated for the differential diagnosis of malignant and nonmalignant gastric disease. Brush specimens were studied from 33 patients with gastric cancer and 36 patients with benign gastric lesions or apparently normal gastric mucosa. Demonstrable CEA immunoreactivity was found by radioimmunoassay in brush specimens from 24/33 cancer patients (73%) and from 23/36 patients with benign lesions (64%). Patients with CEA+ tissue in the immunoperoxidase test had somewhat higher CEA concentrations in the brush specimens than cases with CEA- biopsy tissue, although overlap was considerable. Thirty-five per cent of cancer patients had both a positive tissue CEA reaction and a CEA/DNA ratio greater than 10 ng/micrograms, whilst patients with benign lesions had only 15% of positives by these criteria (0.01 greater than P greater than 0.001). The serum CEA concentration was above the upper normal level of 5 ng/ml in 2/39 patients, both of whom had gastric cancer. The CEA immunoreactive material from benign and malignant lesions eluted in gel filtration on Sephadex G-200 in the same volume as CEA purified from liver metastases of cancer of the colon, showing that a glycoprotein sharing immunological and physicochemical properties with CEA is present both in malignant and nonmalignant lesions of the gastric mucosa, and that there is considerable overlapping in the amount of CEA. The estimation of CEA in gastric-brush specimens is therefore of limited value in the differential diagnosis of benign and malignant gastric lesions."} +{"text": "Peripheral blood leucocytes from chronic myeloid leukaemia patients in remission were tested for inhibition of migration in presence of solubilized membrane antigens from leukaemic cells in 15 cases. Eight out of 9 autochthonous combinations (88-8%) and 35/49 allogenic combinations (71-4%) showed inhibition of migration. Antigens prepared from relapse leukaemic cell samples in 4 cases showed inhibition of migration of autochthonous as well as allogeneic remission leucocytes. The same batch of CML antigens inhibited migration of normal leucocytes at the level of 22-2%. The difference between inhibition of migration shown by remission leucocytes and normal leucocytes in presence of CML antigens was statistically significant. Solubilized antigens, similarly prepared from normal leucocytes, showed inhibition of migration of remission leucocytes to the extent of 15% only. The difference between the reactivity of CML remission leucocytes to normal and CML antigens was also statistically significant. No enhancement of migration of remission leucocytes was seen with CML antigens."} +{"text": "The macrophage electrophoretic mobility test described by Caspary and Field (1971) and modified by Pritchard et al. (1973) was investigated in various models of cell-mediated immune conditions in the guinea-pig and in cancer in man. No positive results were obtained in 92 guinea-pig experiments. Only 17 of 154 experiments on 74 patients gave definite positives in experiments with human cancer and a few positive results were obtained with normal healthy subjects."} +{"text": "Forty-four (44) patients with Burkitt's lymphoma received identical combination chemotherapy on the basis of body surface area. Patients with renal dysfunction, more common in those with abdominal tumours, were at significantly greater risk of developing severe leucopenia (less than 1000 cells/dl) than those with normal renal function (P less than 0.0001). Similar results were seen in a series of 8 patients with normal marrows treated with only i.v. cyclophosphamide and intrathecal methotrexate. Giving a lower initial dose of cyclophosphamide seemed to reduce the risk of severe leucopenia in 5 additional patients with evidence of renal dysfunction. The mechanism is postulated as delayed excretion of the active metabolites of cyclophosphamide. Adjustment of the chemotherapeutic dose should be considered when treating patients with renal dysfunction."} +{"text": "We compared antimicrobial resistance patterns of Salmonella enterica serovar Typhimurium (ST) of isolates from humans (n = 715) and cattle (n = 378) in the Pacific Northwest from 1982 through 1997. The major changes in antimicrobial resistance can be attributed to the widespread clonal dissemination of multidrug-resistant definitive phage type 104 ST."} +{"text": "Twenty-seven patients with malignant neoplasia were injected intradermally with the methanol extraction residue (MER) fraction of tubercle bacilli. Two schedules of treatment were used: every other week and once a month; 1-10 courses of MER were administered to the patients. The skin reactivity to 3 recall antigens, as well as to the injected MER itself, was used to monitor the immune response. Improvement of skin reactivity occurred in 9 of 18 patients tested with recall antigens. Five of 6 patients treated every other week improved in their immune capacity whereas only 4 of 12 patients improved on the monthly schedule. Thus, repeated injections given every other week were more effective in increasing the cutaneous reactivity than monthly injections of MER. The side-effects of MER treatment were tolerable."} +{"text": "High levels of loss of distal markers on 17p13.3 in breast cancer suggested the presence within the region of at least one tumour-suppressor gene. Here we describe the derivation of two biallelic polymorphisms from the 17p telomeric yeast artificial chromosome (YAC) TYAC98. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex PCR analysis demonstrated that the high level of allelic imbalance observed in breast tumours represented loss of constitutional heterozygosity (LOH) and that this LOH extended to the telomere. Lung carcinoma (but not Wilms' tumour)-derived DNA again revealed a high level of loss of subtelomeric 17p sequences. Telomeric microsatellite polymorphisms from other chromosome arms did not show such elevated loss in either tumour type. This suggested that the 17p loss observed did not reflect a general telomeric instability and provided further evidence for the presence of a breast cancer tumour-suppressor gene in the distal region of 17p13.3."} +{"text": "They co-evolved into an intricate splicing code together with additional functional constraints, such as tissue-specific and alternative splicing patterns. We used orthologous exons extracted from the University of California Santa Cruz multiple genome alignments of human and 22 Tetrapoda organisms to predict candidate enhancers and silencers that have reproducible and statistically significant bias towards annotated exonic boundaries.Auxiliary splicing sequences play an important role in ensuring accurate and efficient splicing by promoting or repressing recognition of authentic splice sites. These Tetrapoda enhancers and silencers were clustered into 15 putative core motifs based on their Markov properties. Most of these elements have been identified previously, but 118 putative silencers and 260 enhancers (~15%) were novel. Examination of previously published experimental data for the presence of predicted elements showed that their mutations in 21/23 (91.3%) cases altered the splicing pattern as expected. Predicted intronic motifs flanking 3' and 5' splice sites had higher evolutionary conservation than other sequences within intronic flanks and the intronic enhancers were markedly differed between 3' and 5' intronic flanks.A total of 2,546 Difference in intronic enhancers supporting 5' and 3' splice sites suggests an independent splicing commitment for neighboring exons. Increased evolutionary conservation for ISEs/ISSs within intronic flanks and effect of modulation of predicted elements on splicing suggest functional significance of found elements in splicing regulation. Most of the elements identified were shown to have direct implications in human splicing and therefore could be useful for building computational splicing models in biomedical research. Eukaryotic genes contain intervening sequences or introns that need to be removed from precursor messenger RNA (pre-mRNA) in a complex process termed splicing. During pre-mRNA splicing, relatively short exonic sequences are recognized by spliceosome, a large RNA-protein complex. During splicing, introns are removed and exons are joined together to form mature RNA. In addition to splice site (SS) signals at the exonic 5' and 3' ends, accurate discrimination of exons and introns requires additional auxiliary elements -3. Thesein vivo or in vitro selection methods have been employed to identify these motifs in the genomic sequences. For example, the RESCUE-ESE (Relative Enhancer and Silencer Classification by Unanimous Enrichment), a computational approach used in conjunction with experimental validation, predicted specific hexanucleotide sequences as candidate ESEs based on significantly higher frequency of occurrence in exons than in introns and also significantly higher frequency in exons with weak SSs than in exons with strong SSs we have found 88 5'SS-related and 330 3'SS-related ISEs/ISSs [see Additional File Tetrapoda superclass 3'SS and 177 (6.95%) 5'SS supporting motifs are novel and have not been previously reported in systematic screens detecting such elements. Among our predicted elements, 51.81% were octamers and 41.08% of sequences were heptamers as compared to only 6.76% hexamers and 0.35% pentamers, suggesting that motifs of larger size play important role in splicing regulation. We detected intersections with some of the cis-acting elements reported in the previous studies, but not nearly as dramatic as we saw between the intronic elements predicted for primates and Tetrapoda non-eutherian (an outgroup) clades. It demonstrates high reproducibility of our results obtained for various vertebrate lineages and supports the existence of highly conserved splicing regulatory code across vertebrates. This result also suggests the implications of elements found in regulating human splicing and may help explaining human hereditary disorders caused by mutations modulating such elements. We have established the higher evolutionary conservation for the predicted intronic cis-acting elements within mammalian intronic flanks which indicates their functional significance in exon definition. The elements found contain many of the known cis-acting factor binding sites with functionality supported by experiments with splicing reporter constructs. All these lines of evidence suggest active involvements of the predicted elements in control gradient directing spliceosome to the proper exons in the process of pre-mRNA splicing [Using the orthologous exons currently available for 23 cis-acting elements with the secondary pre-mRNA local structure in the vicinity of the SSs, except for slightly increased single strandedness detected for 5' and 3' ISSs deep inside introns. This observation is in contrast to the earlier reported [We did not observe statistically significant association for the predicted groups of reported , where kA remarkable intersection between the 5'SS ISSs and the 5'SS ESSs [see Additional File [Homo sapiens), Chimpanzee (Pan troglodytes), Rhesus (Macaca mulatta), Mouse (Mus musculus), Rat (Rattus norvegicus), Rabbit (Oryctolagus cuniculus), Dog (Canis familiaris), Cow (Bos taurus), Armadillo (Dasypus novemcinctus), Elephant (Loxodonta africana), Tenrec (Echinops telfairi), Opossum (Monodelphis domestica), Chicken , Frog . The \"threaded blockset alignments\" [ against reference human chromosomal assemblies using the BLAT program [We parsed and extended blocks of orthologous with human reference exons from multiple sequence alignment of 17 vertebrate genomes obtained from UCSC genome browser . The folgnments\" , built u program . Having program ,35 and d program to make Otolemur garnetti), Tree Shrew (Tupaia belangeri), Guinea Pig (Cavia porcellus), Shrew (Sorex araneus), Hedgehog (Erinaceus europaeus), Cat (Felis catus), Horse , Platypus (Ornithorhynchus anatinus), Lizard (Anolis carolinensis). The blocks from a total of 28 vertebrates multiple genome alignments are normally shorter than blocks from 17 vertebrates multiple genome alignments, therefore chances are higher that the block extension may not produce the correct exonic boundaries. Only the exons associated with the species not obtained through the first round should be processed in the second round.This exon set was extended with exons derived from processing of 28 vertebrates multiple genome alignments obtained from UCSC genome browser from theTetrapoda organisms. For these purposes we have examined 489,668 extended exons in primates clade (Human (Homo sapiens), Chimpanzee (Pan troglodytes), Rhesus (Macaca mulatta), Bush Baby (Otolemur garnetti)) and 476,218 extended exons from non-eutherian Tetrapoda organisms (Opossum (Monodelphis domestica), Chicken , Frog , Platypus (Ornithorhynchus anatinus), Lizard (Anolis carolinensis)) taken as the most distant outgroup among Tetrapoda organisms relative to primates.To establish the firm ground for using sequences from distantly related organisms in predicting common SS proximal elements and to estimate implication of elements found in modeling human splicing we conducted independent search for the elements in two distantly related clades of primates and non-eutherian Homo sapiens), Chimpanzee (Pan troglodytes), Rhesus (Macaca mulatta), Bush Baby (Otolemur garnetti)) and rodents (Mouse (Mus musculus), Rat (Rattus norvegicus), Guinea Pig (Cavia porcellus)) clades.To estimate the increased conservation of the intronic elements found within the intronic flanks we have used the Prank tool to Through the literature search we collected the test set of 185 human genes previously linked to autism spectrum disorder and genes implied in environmental response . A set odepth correspond to the density of an oligonucleotide of size depth present at a certain positions within genome. A significant deviation of an oligo density in the proximity of SSs as compare to background locations is strongly indicative of important functionality of elements related to splicing [We measured a statistically significant bias for all the possible oligonucleotides of size equal or less than 8 bp in the vicinity of true 5' and 3' SSs compared to distant \"background\" locations as shown in Figures splicing ,15,33.\u03b1 = 0.011 using \u03c72 test involved 87,380 statistical hypotheses testing for all possible oligos of size less or equal to 8 bp located at certain position relative to a SS. Following the Bonferroni correction for multiple hypothesis testing we reduced the significance level to \u03c72 tests for the SS vicinity counts \u2265 63 or deep intronic/exonic counts \u2265 63 are statistically significantComparing oligo counts at the significance level of under conditionsorSkip value 29 nt, as shown in Figure Skip = 0 nt in Figure Skip = 29 nt in Figure Comparative measurements between the regions shown in Figure Extended orthologous exons associated with the same multiple genome alignment block frequently contain identical conserved oligonucleotides at certain positions relative to SSs, especially within exons. These conserved elements violate our assumption of independence of the sequences used for analysis of statistical significance; therefore within a block we counted unique element at certain position relative to SSs only once, disregarding all other identical motifs conserved since speciation from a common ancestor. To prevent substantial element underscoring in a counting round, since many of the elements at a certain position relative to a SS were sorted out due to evolutionary conservation, we shifted an element position by one within a counting region for each consecutive sequence as shown in Figure where mod is a modulo operation, counting round could be 0,1 or 2 and the sequence index goes from 1 to 2,333,379. Elements shifted by one position within the region are normally different and therefore not sorted out for being similar, which allows combining more elements in the region associated with a block under the same evolutionary pressure.These predicted groups of elements were clustered with the Mixture of Hidden Markov Models (MHMM), an unsupervised clustering method capable of modeling dependencies between neighboring positions in active motif cores [see Additional File . To accelerate finding average PU value for an element we calculated them only for the contexts of 11, 15, 20, 25 and 30 nt according to [The PU values for the predicted octamers surrounded by \u00b1 30 nt context were calculated as described in using RNrding to were makAC designed and implemented the framework to search for splicing regulatory elements and tested the application. CH initiated the study, provided many valuable suggestions steering the project and was the head of the lab where the work was done. IV provided necessary expertise to formulate the study objectives, obtained experimental data to support newly found elements and extensively edited the manuscript. All authors read and approved the final manuscript.Report and analysis of splicing regulatory elements found. Contains list of all the elements found along with their statistical significance and overlap between their groups. Functional analysis for these elements in context of alternative splicing constructs is reported. We provided brief description for an unsupervised clustering method used to group the elements found and grouped the elements within possible functional motifs. We also report elements found for primates and outgroup. Subset of novel elements is reported.Click here for file"} +{"text": "Paraffin wax embedded formalin-fixed benign breast disease tissue taken from 17 patients (15 with microcystic disease and 2 with fibroadenoma) was studied for the presence of tissue bound prolactin using a rabbit antiserum against human prolactin applied in conjunction with a highly sensitive modified version of the dinitrophenyl (DNP)-hapten sandwich staining (DHSS) procedure. Sections taken from 14 of the 15 cases showing apocrine cystic changes exhibited strong prolactin staining restricted to the cytoplasm of metaplastic apocrine cells lining the cysts. Normal lobules and ducts and blunt duct proliferations were all negative, as were also the two cases of fibroadenoma. In contrast 6 out of 8 cases of breast cancer examined showed heterogenously distributed cytoplasmic staining in the cancer cells. Maximal prolactin staining in the apocrine cells was observed at antiserum dilutions as high as 1:60,000. This compared favourably with a 1:120,000 dilution that gave maximal levels of staining in the prolactotrophs present in serial sections taken from formalin fixed paraffin wax embedded post mortem human anterior pituitaries. In both types of tissues the specific staining was abolished by pre-absorption of the antiserum with human prolactin (10 micrograms ml-1). No staining was observed when the anti-prolactin serum was either omitted or substituted with DNP-labelled normal rabbit serum. Apocrine metaplasia in cystic disease of the breast has recently been found to be associated with an increased breast cancer risk. The strong and selective presence of immunohistochemically demonstrable prolactin in the metaplastic cells may be of significance in view of the hormone's known growth stimulating effect on the breast epithelium."} +{"text": "Environ Health Perspect 117:A150\u2013A156 (2009)], a statement reads, \u201cThe primary global impact of oil sands comes through the release of greenhouse gases created when about 800 million cubic feet of natural gas is burned daily to create heat for extraction and upgrading, says Stringham.\u201d To clarify: This statement refers to the global impact of oil sands production. As noted in the preceding paragraph of the article, most of the greenhouse gas emissions related to oil sands overall come from burning the fuel derived from these reserves.On p. A155 of the April Focus article ["} +{"text": "Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized by the immunological destruction of intralobular bile ducts and serum anti-mitochondrial antibodies (AMA). Based upon previous work of oral tolerance and autoimmunity, we hypothesized that feeding the mitochondrial autoantigens of PBC would alter the clinical course and the level of antimitochondrial antibodies. The bovine pyruvate dehydrogenase complex (PDC) was purified and 5 mg fed in gelatin capsules to 6 patients with early stage PBC for 6 months. Antimitochondrial antibodies and liver biochemistries were measured at every 3 months for 12 months. The clinical trial was completed for all patients except for 1 who showed deterioration of pre-existing skin rash during treatment, which disappeared within 2 weeks after treatment was discontinued. However, after 1 year, neither the titers of AMAs nor liver biochemistries were significantly changed by this treatment. This is the first trial to test the efficacy of oral tolerance induction in PBC. However, the data, which limited in scope, did not demonstrate efficacy and further highlights the difficulties in showing continuing evidence of tolerance induction in autoimmunity."} +{"text": "The immunofluorescent reaction of peripheral blood cells from 10 multiple myeloma, 10 Hodgkin's and 11 lymphosarcoma cases with antiviral (Rauscher) murine leukaemia (AMR) and antihuman stem cell leukaemia plasma (AHS) antisera was studied. Cells from 25 of these patients were reactive at least once with AMR and AHS or AHS alone. Absorption studies suggested that this cytoplasmic immunofluorescent reaction involved cellular isoantigens. Serial studies on multiple myeloma, Hodgkin's and lymphosarcoma cases with significant fluorescence, showed that the fluorescent cell count variation was correlated with the presence of active disease."} +{"text": "Insulin resistance has been extensively investigated during the past decade because of its proposed role in initiating a cluster of cardiovascular risk factors including hypertension. Insulin resistance is an inherited genetic trait that precedes hypertension in Dahl salt-sensitive (S) rats, and is not present in Dahl salt-resistant (R) rats. Owing to the co-existence of insulin resistance and salt sensitivity of blood pressure in Dahl S, but not R rats, Dahl S rats are used to elucidate the role of dietary salt as a potential link in exacerbating both phenotypes . In light of available data, examining the impact of dietary salt on insulin resistance in Dahl S rats in terms of salt concentration and duration of exposure helps answer the following question: What percentage of dietary salt and for what duration of exposure would we expect an enhanced insulin resistance in Dahl S rats? This commentary gathers all available research done on insulin resistance in Dahl S rats in an attempt to unravel dietary salt contribution to insulin resistance in Dahl S rats. Over the past decades, insulin resistance and compensatory hyperinsulinemia have been proposed as the common disorder underlying a constellation of risk factors referred to as the metabolic syndrome or syndrome X . InsulinTo be able to address the above questions, Dahl S rats have been examined at various stages (weanlings and fully developed hypertensive rats) and with various dietary salt regimens . Weanling Dahl S rats when examined before developing hypertension and prior to sodium loading were found to be significantly insulin resistant as evidenced by their higher plasma insulin levels compared to weanling Dahl R rats . This imKnowing that Dahl S rats are genetically insulin resistant as evidenced by the presence of insulin resistance in weanling Dahl S rats as well as in fully hypertensive Dahl S rats, it's time to address our third and fourth questions which inquire about the role of salt in insulin resistance and whether a specific salt concentration and/or duration of exposure is required for salt to play a role in insulin resistance in Dahl S rats. Controversial reports in the literature have been documented with some studies proposing no effect of dietary salt in advancing insulin resistance and others proposing a significant role of salt in suppressing insulin signaling and precipitating insulin resistance in Dahl S rats. That's why, it is important to analyze all available data in terms of salt concentration and duration of exposure. Salt loading in Dahl S rats did not further increase their insulin resistance when fed 3% NaCl for 1 week , or 8% NNot only did 4 weeks of high salt diet of 8% NaCl exaggerated insulin resistance ,6and conSalt-induced oxidative stress and inflammation might be the mechanism by which high dietary salt concentration of 8% suppresses insulin signaling and precipitates insulin resistance in Dahl S rats. Inflammatory mediators enhanced by high dietary salt include the tumor necrosis factor-alpha or JNK might possibly interfere with normal insulin signaling via a number of mechanisms including: i) disruption of insulin-induced insulin receptor substrate-1 (IRS-1) and phosphoinositide-3 kinase (PI3K) phosphorylation and cellular distribution, ii) reduction in glucose transporter (GLUT4) expression levels, or iii) reduction in GLUT4 translocation to the plasma membrane -11. SuppWhile one would expect suppressed insulin signaling in Dahl S rats, Ogihara et al., reported that Dahl S rats had an enhanced insulin signaling manifested by an enhanced tyrosine phosphorylation of the insulin receptor, insulin receptor substrates, activation of PI3K and phosphorylation of Akt compared to Dahl R rats. These effects could be simply attributed to the fact that the authors starved the rats for 12 hours prior to the experiment. It is well documented that 12-hour of fasting upregulated hepatic insulin receptors in Sprague Dawley rats (from which Dahl rats were derived) Insulin resistance in Dahl S rats precedes hypertension, 2) Insulin resistance in Dahl S rats is significantly enhanced after 4 weeks of 8% NaCl, which represents the threshold for a salt-induced suppression in the insulin signaling pathway, 3) Salt-induced insulin resistance in Dahl S rats (after 4 weeks of 8% NaCl) is accompanied by an enhanced oxidative stress and inflammatory responses that is manifested by increased levels of TNF-alpha and JNK proteins, 4) Increased TNF-alpha and JNK levels might disrupt the insulin signaling pathway at the level of the insulin receptor substrates' association with either upstream or downstream molecules in the insulin pathway or via suppressing GLUT4 expression and/or translocation. Finally, it is worth mentioning that the promoter regions of the insulin receptor substrates \u20131, and \u20132 comprises putative sodium-responsive elements that might be acted upon by excess salt to suppress their corresponding activity, expression and/or function ,17. Muta"} +{"text": "The assessed lack of validated reference genes emphasizes the importance of a systematic study for their identification. For selecting candidate reference genes we have developed a simple The expression stability of 32 genes was assessed by qRT-PCR using a set of cDNAs from 24 different plant samples, which included different tissues, developmental stages and temperature stresses. The selected sequences included 12 well-known HKGs representing different functional classes and 20 genes novel with reference to the normalization issue. The expression stability of the 32 candidate genes was tested by the computer programs geNorm and NormFinder using five different data-sets. Some discrepancies were detected in the ranking of the candidate reference genes, but there was substantial agreement between the groups of genes with the most and least stable expression. Three new identified reference genes appear more effective than the well-known and frequently used HKGs to normalize gene expression in wheat. Finally, the expression study of a gene encoding a PDI-like protein showed that its correct evaluation relies on the adoption of suitable normalization genes and can be negatively affected by the use of traditional HKGs with unstable expression, such as actin and \u03b1-tubulin.The present research represents the first wide screening aimed to the identification of reference genes and of the corresponding primer pairs specifically designed for gene expression studies in wheat, in particular for qRT-PCR analyses. Several of the new identified reference genes outperformed the traditional HKGs in terms of expression stability under all the tested conditions. The new reference genes will enable more accurate normalization and quantification of gene expression in wheat and will be helpful for designing primer pairs targeting orthologous genes in other plant species. Arabidopsis (using the large public collection of data from Affymetrix GeneChip experiments) -1) \u00d7 100 -1) \u00d7 100, where m is the slope of linear regression model fitted over log-transformed data of the input cDNA concentration versus Ct values according to the linear equation y = m*log(x) + b. Moreover, the Mx3000PTM software system computed the R2 value (Coefficient of determination), which represents an indicator of the quality of the fit of the standard curve to the plotted data points. The R2 values calculated for all the standard curves in each of the two biological replicates were higher than 0.994, indicating a strong linear relationship between the detected Ct values and the correspondent relative amount of template in all the amplification reactions from pooled cDNA. By plotting the Ct values of five different data-sets: 1) all 24 samples including tissues, developmental stages and temperature treatments; 2) 18 samples relative to different tissues and developmental stages; 3) six samples consisting of two temperature treatments (4\u00b0C and 33\u00b0C), each for 24 and 48 h and their controls; 4) six samples relative to the single floral organs from fully emerged spikes; 5) six samples referring to vegetative tissues and developmental stages . These data sets were used to evaluate the expression stability of the genes belonging to the four families by 18 primer pairs, 14 of them targeting specific gene transcripts of the gene families (five each for actin and \u03b1-tubulin and two each for ADP-ribosylation factor and translation elongation factor) and four primer pairs which amplified multiple transcripts for each of the four gene families . Table t differences (\u0394Ct = Ctmax-Ctmin) obtained by the 18 primer pairs for each of the five data-sets considered, whereas the complete statistics obtained by ANOVA analysis are reported in Additional file t values gives a straightforward indication of the expression stability of a particular gene; most genes with the lowest CV values showed also the lowest values of Ct range (\u0394Ct) and MST (Mean Square of Treatments) and 13 lowly expressed genes, with mean Ct values above this value , Ta2776 (RNase L inhibitor-like protein), Ta54448 and Ta54733 (Proteins of unknown function), and Ta44405 (\u03b2-tubulin), with mean Ct values between 26 and 24 cycles and moderately expressed (10 genes with more than 300 EST). Of the 13 reference genes with low Ct values, only three including more than 300 ESTs were considered moderately expressed in UniGene, whereas the expression level of the remaining 10 genes was low (<300/>100 ESTs) or very low (<100 ESTs). In our opinion, these data indicate a substantial agreement between the gene expression levels evaluated by qRT-PCR analyses and those estimated by the number of ESTs included in each corresponding UniGene cluster. Ta54963 (GABA-receptor associated protein), Ta54238 (Ubiquitin-conjugating enzyme), Ta35497 (Cyclophilin), Ta53967 (Vacuolar ATP synthase 16 kDa proteolipid subunit) exhibited the lowest gene expression variation (less than 3 cycles), while Ta44405 (\u03b2-tubulin), Ta38797 (Histone) and Ta1698 (NADP-isocitrate dehydrogenase) showed the most variable expression (more than 5 cycles).In order to avoid possible errors due to the interaction of co-regulated genes, further analyses were carried out on 32 genes involved in distinct biological processes and metabolic pathways; they comprised 28 genes selected on the basis of their uniform expression detected in UniGene and TIGR and a single gene for each of the four gene families. The expression levels could be grouped into two arbitrary categories: 19 highly expressed genes, whose mean CAs discussed in the previous paragraph, it was evident that none of the 32 selected candidate reference genes showed a constant expression under all the tested conditions in wheat. Hence, as expected, it was not possible to find an all purpose reference gene, and it would be necessary to select the most suitable one for normalizing gene expression considering the peculiar and specific experimental conditions. The relationships between expression stability of the 32 candidate genes and different types of tissues and/or experimental conditions were tested by running the programs geNorm and Normrd, Cell division control protein, AAA-superfamily of ATPases), Ta2291 , Ta53899 , Ta4045 , Ta2776 , Ta53967 , Ta54963 and Ta53919 , Ta2291 , Ta54238 , Ta54948 , Ta2776 , Ta30797 , Ta54227 and Ta4045 , Ta54227 , Ta54238 , Ta53891 , Ta54447 , Ta2291 , Ta53919 and Ta55512 , whereas Ta1698 (NADP-isocitrate dehydrogenase) and Ta44405 (\u03b2-tubulin), with M values of 0.63 and 0.59, were the least stable genes tested in our study are plotted in figure se) Fig. . The ranse) Fig. . The ranse) Fig. , and theThe high expression stability of a gene indicates that the use of a single internal control is appropriate, but some studies require the normalization based on two or more stable internal control genes. The geNorm program, in addition to the gene stability measure M, computes a normalization factor (NF) and assesses the optimal number of reference genes for generating that factor. The pairwise variations Vn/Vn+1 between two sequential normalization factors (NFn and NFn+1) are used to determine the necessity of adding the next more stable control gene for reliable normalization. Pairwise variations were calculated using geNorm for each data set to determine the optimal number of internal control genes for normalization Fig. . In all nd, ADP-ribosylation factor), Ta2776 , Ta35284 , Ta53919 , Ta53967 , Ta54171 , Ta54963 , Ta54733 and Ta4045 ; the two least stable genes were Ta44405 (\u03b2-tubulin) and Ta38797 (Histone), with stability values of 0.150 and 0.198 respectively, the same identified as the worst genes by geNorm. The best combination of two genes suggested by NormFinder was that of Ta54227 and Ta2291, which improved the stability value to 0.030, indicating a more reliable normalization than that based on single genes. Similar results were obtained for 18 samples including tissues/organs at different developmental stages of wheat, with the lowest stability value (0.032) for Ta54227 (Table NormFinder (the second adopted program based on a model approach) ranks the best candidate references genes according to their minimal combined inter- and intra-group variation of expression. The results obtained by NormFinder analysis for the five data sets are shown in Table The stability ranking of the reference genes across the five analysed data sets obtained by geNorm and NormFinder was not identical for the genes with the most stable expression Table . In partThe expression levels of the target gene TaPDIL1-1 were used as an example to show the effect of using different normalization genes on estimating its relative expression. TaPDIL1-1 encodes the typical PDI (Protein Disulfide Isomerase) which accomplishes several metabolic functions, the most important consisting in disulfide bond formation and isomerization during the folding of secretory proteins ,40. PrevNormalization of the expression of TaPDIL-1-1 using the reference genes selected by the three methods based on geNorm and NormFinder programmes did not detect significant differences in the relative expression of the gene of interest in all the four analysed data sets Figs. and 6. AArabidopsis to identify new reference genes, which has been based on the data furnished by the microarray datasets [in silico method exploiting UniGene and TIGR, two publicly available databases of wheat sequences enclosing non-redundant EST-indices. The method consists of two steps, each exploiting the peculiar features of these wheat-specific databases. Basically, an effective reference gene has to fulfil three main requirements: 1) moderate to high level of expression ; 2) expression in several tissues and developmental/physiological states; 3) low variation of gene expression across different tissues and developmental, physiological and environmental conditions [T. aestivum UniGene database (see Methods), which were accomplished by 177 out of the 42,256 sequence clusters therein contained. The second step consisted in the scanning of the TIGR wheat gene index database (TaGI version 11) for the identification of the TC (Tentative Consensus) or group of TCs corresponding to each of the 177 clusters previously selected in UniGene. The identification of TCs was important because these outputs are more effective for gene functional annotation and for designing gene specific qRT-PCR primers. The frequency of each TC or group of TCs linked to the 177 selected UniGene clusters was determined and was used to pinpoint the most suitable candidate reference genes to be included in a preliminary screening.To the best of our knowledge, the present research represents the first effort aimed to the identification and systematic comparison of a large number of potential reference genes and of the corresponding primer pairs specifically designed for gene expression studies in wheat, in particular for qRT-PCR analyses. As mentioned in the \"Introduction\", so far most studies on gene expression in wheat have been carried out using single reference genes, without any preliminary validation of their expression stability has been one of the most suitable reference genes in a set of tissue samples in rice, whereas the expression of UBQ10 was unstable [ACT2/7 was stably expressed, whereas ACT11 showed variable profiling [Among the 177 ol genes ,20,52. Tunstable . A similt values [Since the search for suitable reference genes is both time-consuming and cost intensive, several computer programs based on different statistical approaches have been developed to assist the selection of a reference gene among several HKGs. The software geNorm has been reported in 2002 and has t values . Accordit values , this apt values ,56, or tt values . The chot values ,57,58. St values and Normt values and compAs discussed by different authors ,57-59, sThe mathematical model of gene expression used by NormFinder enables to estimate both the overall variation of the candidate normalization genes and the variation between subgroups of the sample set. This approach has been reported to perform in a more robust manner than geNorm and has been shown to be less sensitive to the presence of co-regulated genes , therefot 24.79), whereas that of Ta2291 (mean Ct 21.97) and of Ta54227 (mean Ct 21.56) is high, they are suitable as reference genes in a large data set of wheat samples, but also for the normalization of target genes with contrasting expression levels.Expression stability analyses showed that the most stable reference gene identified by NormFinder and geNorm was not the same for the five data sets analysed Table . Even thth among the 32 candidate reference genes , \u03b1-tubulin (Ta25534), \u03b2-tubulin (Ta44405), Ubiquitin (Ta50503), GAPDH (Ta30768), Cyclophilin (Ta35497), Translation elongation factor (Ta53964), Translation initiation factor (Ta54280), Ribosomal protein (Ta27771) and Histone (Ta38797), in fact most of them classified as the least stable genes both by geNorm and NormFinder in the five data sets analysed , Ta2291 (ADP-ribosylation factor) and Ta2776 (RNase L inhibitor-like protein) resulted the best and most stable reference genes to normalize gene expression in different tissue and development stages of wheat; they outperformed all traditional HKGs such as \u03b1-tubulin (Ta25534), \u03b2-tubulin (Ta44405), Ubiquitin (Ta50503), Actin (Ta54825), GAPDH (Ta30768), Ribosomal protein (Ta27771) and Histone (Ta38797). Although in our experimental conditions a single reference gene was adequate to normalize the qRT-PCR data, the use of normalization factors generated from the expression data of two or three most stable genes should be considered in future studies to improve the accuracy and reliability of expression analysis. The set of qRT-PCR specific primers for the novel and more stable reference genes developed in this study will enable more accurate normalization and quantification of gene expression in wheat. Moreover, the design of suitable primer pairs for their orthologous genes could contribute to the development of reference genes with stable expression in other plant species.In the present research we compared 20 novel candidate reference genes and 12 commonly used HKGs suitable for gene expression normalization in wheat. Both new and traditional reference gene sequences were fetched by an qRT-PCR: quantitative Real-time RT-PCR; HKG: Housekeeping gene; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; RT: Reverse transcriptase; EST: expressed sequence tag; TIGR: The Institute for Genome Research; PDI: Protein disulphide isomerase; TPM: transcripts per million; TC: tentative consensus sequence; Mv: mean value; V: variance; SD: standard deviation; CV: coefficient of variation; SSH: Suppression Subtractive Hybridization; CS: Chinese Spring; TEF-1\u03b1: Translation Elongation Factor-1\u03b1; ADP-RF: ADP-ribosylation factor; GO: Gene Ontology; ANOVA: analysis of variance; MST: mean square of treatments; MSE: mean square errors; NF: normalization factor; NCBI: National Center for Biotechnology Information.ARP performed all the sample preparations and experimental procedures and participated in data analysis. MC supervised the study, performed data analysis and draft the manuscript. OAT performed data analysis, revised the manuscript critically and participated in tables and figures drawing. EP revised critically the manuscript and gave financial support to the study. All authors read and approved the final manuscript.List of articles reporting the application of reference genes for qRT-PCR normalization in wheat. The list was obtained by a PubMed search from January 1996 to March 2008 and includes 26 articles reporting 16 reference genes.Click here for fileRT-PCR primers used in this research. Table showing UniGene clusters and linked TC sequences of the reference genes used in qRT-PCR analysis, their primer sequences and characteristics of the corresponding amplicons.Click here for fileUniGene clusters and corresponding TC sequences of 177 selected candidate reference genes of wheat. The file reports the transcription profiles of the genes corresponding to the UniGene clusters in six wheat tissues calculated as a value representing the number of transcripts per million (TPM). Mean value (Mv), Variance (V), Standard deviation (SD) and Coefficient of Variation (CV) were determined on the expression values (TPM) of the 177 Unigene clusters in the six wheat tissues. The highest and lowest expression values, the relative expression (percentage) in the six wheat tissues and the number of ESTs included in each UniGene cluster are also reported. The frequency was determined for each TC or group of TCs linked to the 177 selected UniGene clusters.Click here for fileClassification of the 177 selected candidate reference genes of wheat on the basis of their putative functions. File showing the UniGene clusters and corresponding TC sequences of the 177 selected candidate reference genes of wheat and their putative functional annotation determined on the basis of their orthologous genes of rice and relative GO annotations.Click here for fileLevel of expression of the 177 selected candidate reference genes determined on the basis of the number of EST sequences included in each UniGene cluster. File showing UniGene clusters and corresponding TC sequences of the 177 selected candidate reference genes of wheat sorted in ascending order on the basis of the number of EST sequences included in each UniGene cluster.Click here for fileUniGene clusters and corresponding TC sequences of ten genes of the actin and \u03b1-tubulin families. Gene transcription profile of each UniGene cluster in six wheat tissues is reported as a value representing the number of transcripts per million (TPM). Mean value (Mv), Variance (V), Standard deviation (SD) and Coefficient of Variation (CV) were calculated on the expression values (TPM) of the ten Unigene clusters in the six wheat tissues. The highest and lowest expression values, the relative expression (percentage) in the six wheat tissues and the number of ESTs included in each UniGene cluster are also reported. The frequency was determined for each TC or group of TCs linked to the 177 selected UniGene clusters.Click here for filewcor14 and TaHSP101B.Expression analysis by RT-PCR of the genes Agarose gels of RT-PCR products of wcor14 and TaHSP101B genes after 35 PCR cycles in six samples consisting of two temperature treatments (4\u00b0C and 33\u00b0C) for 24 and 48 h and their controls . The transcripts of the constitutively expressed gene encoding actin (UniGene cluster Ta54825) were amplified as control. M = part of the DNA molecular weight marker XIV (Roche), the most intense band is 500 bp in length.Click here for fileSpecificity of qRT-PCR amplification. Figures A1\u2013A3 report the dissociation curves of 42 selected reference genes showing single peaks, they were obtained from three technical replicates of 18 cDNA pools representing different tissues and developmental stages of wheat. Figures B1\u2013B3: Agarose gels (2%) showing amplification of a specific PCR product of the expected size for each candidate reference gene.Click here for filet values for 46 primer pairs and 24 tissue samples used in this research.PCR efficiency and C The file shows PCR efficiency and Ct values of two biological replicates performed on 24 tissue samples; three technical replicates were carried out for each of the 46 primer pairs. The 24 tissue sample comprised: 1) Roots from plants with single shoot and three leaves unfolded ; 2) Shoots1 = single shoots and leaves from plants at Feekes scale 1.3; 3) Shoots2 = shoots at the beginning of tillering ; 4) Shoots3 = shoots from plants with formed tillers ; 5) Shoots4 = shoots at the beginning of erect growth ; 6) flag leaves at booting stage ; 7) stems at booting stage ; 8\u201310) Spikes1\u20133 = spikes collected at intervals of 10\u201312 days ; 11\u201316) single floral organs from fully emerged spikes ; 17\u201318) Seeds 1\u20132 = seeds collected 15 (medium milk stage) and 30 (hard dough stage) days after anthesis; 18\u201324) six samples consisting of two temperature treatments (4\u00b0C and 33\u00b0C) for 24 and 48 h and their controls .Click here for filet values obtained in five different data-set. Expression stability of the genes belonging to four families evaluated by statistical analysis of raw CANOVA analysis and statistics determined on raw Ct values obtained by 18 primer pairs which amplified either specific or multiple (m) gene transcripts of four gene families in five different data-sets: 1) all 24 samples including tissues, developmental stages and temperature treatments; 2) 18 samples relative to different tissues and developmental stages; 3) six samples consisting of two temperature treatments (4\u00b0C and 33\u00b0C), each for 24 and 48 h and their controls; 4) six samples relative to the single floral organs from fully emerged spikes; 5) six samples referring to vegetative tissues and developmental stages .Click here for fileRanking of the expression stability of the reference genes as calculated by geNorm in four data sets. geNorm output charts of M values for the 32 selected reference genes in four data sets: (A) = 18 tissues and developmental stages; (B) = six samples consisting of two temperature treatments (4\u00b0C and 33\u00b0C) for 24 and 48 h and their controls; (C) = six floral organs from fully emerged spikes; (D) = six vegetative tissues and developmental stages .Click here for fileDetermination of the optimal number of control genes for accurate normalization calculated on the basis of pair-wise variation (V) analysis in four data sets. geNorm output charts of V values for the 32 selected reference genes in four data sets: (A) = 18 tissues and developmental stages; (B) = six samples consisting of two temperature treatments (4\u00b0C and 33\u00b0C) for 24 and 48 h and their controls; (C) = six floral organs from fully emerged spikes; (D) = six vegetative tissues and developmental stages .Click here for file"} +{"text": "Two hundred and eleven patients with node-positive stage II and III breast cancer were treated with eight cycles of adjuvant chemotherapy comprising cyclophosphamide, doxorubicin and oral ftorafur (CAFt), with and without tamoxifen. All patients had undergone radical surgery, and 148 patients were treated with post-operative radiotherapy in two randomized studies. The impact of haematological toxicity of CAFt on distant disease-free (DDFS) and overall survival (OS) was recorded. Dose intensity of all given cycles (DI), dose intensity of the two initial cycles (DI2) and total dose (TD) were calculated separately for all chemotherapy drugs and were correlated with DDFS and OS. Patients with a lower leucocyte nadir during the chemotherapy had significantly better DDFS and OS (P = 0.01 and 0.04 respectively). Dose intensity of the two first cycles also correlated significantly with DDFS (P = 0.05) in univariate but not in multivariate analysis, while the leucocyte nadir retained its prognostic value. These results indicate that the leucocyte nadir during the adjuvant chemotherapy is a biological marker of chemotherapy efficacy; this presents the possibility of establishing an optimal dose intensity for each patient. The initial dose intensity of adjuvant chemotherapy also seems to be important in assuring the optimal effect of adjuvant chemotherapy."} +{"text": "Loss of mismatch repair proteins or overexpression of nucleotide excision repair proteins (ERCC1) was not detrimental for the cellular sensitivity to BBR 3464. Moreover, interesting differences in the kinetics of formation and removal of DNA lesions at the single-gene (N-"} +{"text": "Trans-[PtCl2(isopropylamine)] is a novel trans-platinum compound that shows cytotoxic activity in several cisplatin resistant cell lines. The aim of this paper was to analyse, by means ofmolecular cell biology techniques and total reflection X-ray fluorescence (TXRF), the cytotoxic activity, theinduction of apoptosis, the cellular uptake and the DNA binding of trans-[PtCl2(isopropylamine)] in the cisplatin resistant cell line A2780cisR. The results show that this drug is more cytotoxic and induces a higher amount of apoptotic cells than cisplatin in A2780cisR cells. However,the intracellular accumulation and extent of binding to DNA of trans-[PtCl2(isopropylamine)] is lower than that of cis-DDP. Moreover, trans-[PtCl2(isopropylaminae)] is partially inactivated by intracellular levels of glulathione. The resultsuggest that circumvention of ciplatin resistance by trans-[PtCl2(isopropylamine)] in A2780cisR cells might be related with the ability of this drug to induce apoptosis."} +{"text": "To investigate the underlying mechanisms of carcinogenesis, we have developed a technique to determine the frequency of genetic changes in prostatic carcinoma tissue. We have demonstrated that at a ratio of between 1:4 and 1:9 mutant-normal alleles, the signal from a mutant TP53 allele is not apparent after polymerase chain reaction (PCR) amplification and further direct sequencing or single-strand conformation polymorphism (SSCP) analysis. To bypass this problem, which is inherent in the heterogeneity of the prostate tissue and of the tumour, we selected areas of graded prostate tumours (Gleason score) from cryosectioned preparations and microdissected these cells (20-100 cells). After anionic resin removal of proteins, PCR amplification of TP53 gene exons 5/6 and SSCP analysis, an abnormal SSCP band shift was observed in suspected tumour cells, compared with microdissected stromal cells used as an internal control, while (1) a crude preparation of tissue DNA carrying the tumour did not show any abnormality and (2) immunostaining by a set of monoclonal antibodies against TP53 protein remained negative. Nucleotide sequence analysis of the different bands confirmed the presence of a mutation in the TP53 gene exon 6 position 13,336 in an abnormal band for one specimen, while no mutation was detected in the normal SSCP band. By targeting recognised tumour cells we can find DNA mutations which are undetectable using the standard technique of whole-tissue DNA extraction, particularly in a heterogeneous tumour such as carcinoma of the prostate."} +{"text": "The resultsindicate that all these antibiotics effectively bind copper(ll) at physiological pH. Cyclic voltammetryinvestigations and kinetic studies of H2o2 disproportionation and hydroxyl radicals detection made it possibleto support the mechanism of oxidative reactivity of cupric complexes of aminoglycosides, which involvesCu(1) and Cu(lll) redox states and metal-bound, rather than free radical species. The mechanism of thisprocess appears to be complicated, and may have deleterious side-effects by leaking radical intermediates.The presence of these reactive oxygen species may be responsible for modulating the biological activity ofthese drugs.The majority of aminoglycosidic antibiotics anchor Cu(ll) ions by {NHphe in both the presence and absence of hydrogen peroxideshowed that the complexes with H2o2 are the most efficient oxidants, converting dG to its 8-oxo derivative,generating strand breaks in plasmid DNA and multiple cleavages in tRNAphe. Some of these reactions mayplay a role in aminoglycoside-induced ototoxicity and nephrotoxicity; moreover, they may suggest thatCu(ll)-aminoglycosides are potentially dangerous genotoxic agents.These complexes were also screened for their antibacterial activity and bioassays were engaged to findout the possibility of Cu(ll)-kanamycin A complexes to induce tumor necrosis factor (TNF), interferon (IFN)and interleukin-10 (IL-10) in human peripheral blood leukocytes. The aim of these studies was to comparethe biological action of antibiotic alone and complexed with copper(ll) ions in both neutral and oxidativeenvironment.The interactions of copper(ll) complexes of aminoglycosides with oxidation-susceptible biomolecules:2\u2019-deoxyguanosine, plasmid DNA and yeast tRNA"} +{"text": "Concentrations of circulating immune complexes (CIC) were measured serially during chemotherapy of 22 patients with gestational trophoblastic tumours (GTT) and 11 patients with malignant teratoma (MT) by the polyethylene glycol precipitation and CIq solid-phase assays. Results were correlated with tumour response as measured by serum concentrations of human chorionic gonadotrophin (hCG) and alpha-foetoprotein (AFP). CIC concentrations correlated with disease status in the early stages of treatment in 4/22 patients with GTT and 5/11 with MT. CIC assays were less sensitive than hCG and AFP as a monitor of disease, and also less specific, in that 8 patients with GTT and 5 with MT developed raised CIC concentrations during chemotherapy in spite of sustained complete remission. Measurements of CIC concentrations by present methods are neither sufficiently sensitive nor specific to be of clinical value as a tumour marker in GTT and MT, and this casts doubt on their potential value in other malignancies. Attention should be directed to identification of the components of CIC, some of which may be more cancer-specific."} +{"text": "The leukaemic lesions in intact and ovariectomized mice of strain ICRC, induced with 20-methylcholanthrene (20-MCA) in combination with or without hormones were investigated for the presence of mouse leukaemia virus (MuLV) by (i) bioassays and (ii) electron microscopy. The different experimental groups treated with 20-MCA were (i) intact females, (ii) ovariectomized females, (iii) ovariectomized females with pituitary graft, (iv) ovariectomized females with 10 mug oestradiol/day for 30 days and (v) ovariectomized females with 1 mug oestradiol together with 1 mg progesteron/day for 30 days. It was possible to transmit nearly all these experimentally induced leukaemias to syngeneic mice through acellular extracts, compared with very poor transmissibility of spontaneous leukaemias in the ICRC strain, indicating functional activation of viral agents on combined treatment with carcinogen and hormones. Potency of the acellular leukaemic extract from the mice of group (ii) without the ovarian hormones was much weaker than that from mice of the other experimental groups. The leukaemogenic activity of MuLV was enhanced on serial transmission in syngeneic hosts. Leukaemic lesions of ovariectomized mice treated with 20-MCA and oestradiol were also transmissible to the sucklings of allogeneic mice of strain C3H-MTV, C57-BL and Dba-MTV. The cell-free supernatant medium of the cultures of these leukaemic lesions induced leukaemias on back inoculation into syngeneic mice. Electron microscopic studies of lesions induced with carcinogen and oestradiol consistently showed abundant intracytoplasmic type A particles. Numerous intracytoplasmic type A particles as well as some type B particles were found in the leukaemic tissues of ovariectomized females treated with MCA and oestradiol combined with progesterone. Type C particles, characteristic of MuLV were seen in the leukaemic tissues of all other experimental groups. These findings indicate a significant influence of the physiological condition of the host, particularly the hormonal make up, on expression and activity of specific viral agents."} +{"text": "A series of 155 cases of hepatic hydatid disease, occurring in 121 patients, were operated on at the Navaland Veterans Hospital of Athens. Ultrasonography and computerized axial tomography provided thepreoperative diagnosis in 89 and 93 percent of the cases respectively in recent years. Thirty one percentof the cases presented with complications, the commonest of these being infection of the cyst (10percent) and rupture of the cyst into the bile ducts (17 percent). Total cystectomy was performed inthree cases and removal of the endocyst with its content in the remaining 152. The remaining cavity waseither externally drained (57 cases), or filled with omentum (omentoplasty \u2014 95 cases). External fistulaand infection of the residual cavity occurred in 32 and 56 percent after simple drainage and in 4 and 2percent respectively after omentoplasty. Differences are statistically significant (p < 0.001).Hospitalization was also significantly longer after drainage than after omentoplasty (p < 0.01).Obstructive jaundice after intrabiliary rupture of the cyst was more successfully managed afteradditional choledochoduodenostomy than after simple drainage of the common bile duct.Intrapericoneal recurrence of hydatid disease occurred in two cases. The conclusion of the present studyis, that ultrasonography and computerized axial tomography provide an acceptable rate in the diagnosisand that omentoplasty offers a very low complication rate in the management of hydatid cystic disease ofthe liver."} +{"text": "The aim of our research is to evaluate the advantage by the combined use of fiberopticbronchoscopy and laryngeal mask during the performance of percutaneous dilatationaltracheostomy in an intensive care unit.Patients: 16 adult patients who were candidates to middle-long term mechanicalventilation.Environment: Intensive Care Unit of a Community General Hospital.Results: We experienced 3 minor complications (2 minor bleedings and 1 neck emphysema).Difficulties were found in 3 patients with particular anatomical conformation.Conclusion: The combined use of fiberoptic tracheo-bronchoscopy with the laryngealmask permits a better endoscopic visualisation of the operatory field, providing a moresecure and precise procedure."} +{"text": "The aims of this study were: (1) To examine the presence of alphafetoprotein (AFP) bearing tumour cells in PBSC harvests from advanced GCT patients obtained after multiple cycles of induction chemotherapy. (2) To determine whether induction chemotherapy contributed to in vivo purging of the tumour. We evaluated cryopreserved PBSC samples from 5 patients with advanced stage II/III AFP producing GCT. PBSC were separated after the first, second and third cycles of induction chemotherapy. Those samples were analysed using the nested reverse transcription polymerase chain reaction (RT-PCR) method to detect AFP mRNA. Although, in all patients, AFP mRNA was detected in PBSC samples after the first or second cycle of induction chemotherapy, but was not detected in 3 of 4 samples after the third cycle of chemotherapy. Although it is not clear whether tumour cells contaminating PBSC fraction contribute to disease relapse, PBSC harvested after at least 3 cycles of induction chemotherapy might be recommended to avoid such a possibility. \u00a9 2001 Cancer Research Campaign"} +{"text": "There was an error in the last sentence of the legend to Figure 4.-/- (thin line histogram).The correct text should read: Representative histograms were shown to analyze relative bacterial number in macrophages (MAC) and neutrophils (Neu) between WT (gray-filled histogram) and Rip2"} +{"text": "Primary pancreatic lymphoma (PPL) is an extremely rare neoplasm, which may be confused with pancreatic adenocarcinoma. So far only about 150 cases of PPL have been reported.We present our experience of 3 cases of PPL over a 4-year period.All the patients presented with vague abdominal pain of duration ranging from 1\u00bd months to 3 months. Two patients had diagnosis confirmed histologically by CT-guided core biopsy or Fine needle aspiration procedure. We were able to avoid unnecessary laparotomy in 2 patients using preoperative guided Fine needle aspiration Cytology, although the third patient did undergo a Whipple\u2032s procedure as the diagnosis of PPL was not considered during the initial workup.There is no significant difference noted with regard to patient\u2032s age or duration of symptoms between patients with either pancreatic adenocarcinoma or PPL. The differential diagnosis of PPL includes pancreatic adenocarcinoma and secondary involvement of pancreas from extra-nodal lymphoma. Combination of two things is suggestive of Pancreatic lymphoma: (1) Bulky localized tumor in pancreatic head (2) Absence of significant dilatation of main pancreatic duct strengthens a diagnosis of pancreatic lymphoma over adenocarcinoma. Majority of patients can be managed with chemotherapy with much better prognosis compared to patients with pancreatic adenocarcinoma. Larger series of patients are needed to evaluate whether chemotherapy, eventually followed by involved-field radiation therapy, is the treatment of choice for PPL. Gastrointestinal (GI) tract is the most common site of extra-nodal non-Hodgkin\u2032s lymphomas (NHLs), accounting for 15% to 20% of all NHL cases.14 SignifiTo date, approximately 150 cases of PPL have been reported in the English-language medical literature. There isWe present our experience of treating primary pancreatic lymphoma in patients at our hospital. Medical records of patients identified during a retrospective review of prospectively maintained database in the cancer institute of our hospital were retrieved after obtaining informed consent from the concerned patients. A pathologist reviewed slides and blocks to reconfirm the diagnosis. Literature was accessed on the Internet through PubMed search using the string 'primary pancreatic lymphoma.'Over a period of 4 years, we have diagnosed and treated 3 cases of primary pancreatic lymphoma . All theHematoxylin and eosin-stained sections from tumor in all the 3 patients showed monotonous population of small round cells in sheets separated by sparse fibrous septae infiltrating the pancreatic parenchyma . NeoplasTwo patients received chemotherapy for 4 cycles followed by radiotherapy (45 Gy in 20 fractions for 1 patient and 30 Gy in 18 fractions for the other) using antero-posterior and postero-anterior pair beams. One patient who was diagnosed following Whipple\u2032s procedure received adjuvant chemotherapy with CHOP regimen (6 cycles) alone.All the patients are currently on follow-up and are so far free of disease recurrence.Diagnostic criteria for PPL include presence of main mass in the pancreas with lymph nodal involvement confined to the peri-pancreatic region with no hepatic or splenic involvement; absence of superficial lymphadenopathy and mediastinal lymph node enlargement; and a normal leukocyte count in peripheral blood.9Literature suggests a strong male predominance .10There iMost common presenting symptom reported in literature is abdominal pain, found in about 83% of cases, followed by (in order of frequency) abdominal mass (58%), weight loss (50%), jaundice (37%), acute pancreatitis 12%), small-bowel obstruction (12%) and diarrhea (12%).131013]"} +{"text": "Roquinimex (Roq) is an immunomodulator known to stimulate cellular immune responses. It is currently used for immunotherapy after bone marrow transplantation (BMT). One of the major features of this compound is an enhancement of natural killer (NK) cell activity and numbers. We studied the in vitro effect of Roq on human peripheral blood NK and adherent lymphokine-activated killer cell (ALAK) activities. In cultures supplemented with recombinant interleukin 2 (rIL-2) (1000 U ml-1) and Roq a significant increase in NK and LAK function was observed without a parallel increase in cell numbers. We also examined the generation of NK cells from human bone marrow (BM) immature progenitors, obtained by purging with 4-hydroperoxycyclophosphamide (4HC). NK cell numbers and activity were both increased when cultures with rIL-2 (10 U ml-1) were supplemented with Roq. These results confirm findings obtained in vivo and in vitro in the murine system and suggest that Roq is an active agent on these lymphoid populations. These properties and good tolerability make Roq an attractive tool for immunotherapy."} +{"text": "We discuss the evaluation of the Engaging Older Adult Learners as Health Researchers (ENGOAL), a program designed to educate older adults from underserved and underresourced communities about geriatric health and research methods, enabling them to become Research Partners. Quantitative and qualitative data were collected for evaluation from 21 participants aged 53-79. We used All Aspects of Health Literacy Scale and an adaptation of Stanford Patient Education Research Center Chronic Disease Self-Efficacy Scale to assess pre-post and follow-up changes, using repeated measures analyses. Results suggest notable increases in self-efficacy, but only small improvements in subjective health literacy. Themes identified through qualitative analysis of interviews with participants included: (1) Finding our Voices (2) Race and Health (3) Faith and Health (4) Communicating with Providers and (5) Sharing and Advocacy. Emerging community leadership of participants are further evidence of confidence gains in our participants."} +{"text": "The evaluation on the characteristic dataset and figures presented here, are related to our latest research data entitled \u201cFabrication of chitosan based magnetic nanocomposite by click reaction strategy; evaluation of nanometric and Cytotoxic characteristics\u201d [1]. FTIR, Vibrating Sample Magnetometer (VSM) measurements, Xray diffraction (XRD) information and the resulted figures for structural confirmation of the prepared chitosan based nanocomposite are presented in this article. The morphological changes of the Fibroblast, Saos, MCF7 and Hela cell lines after treatment with the mention compound were displayed. The additional adsorption data for the synthesized nanobiocomposite were also demonstrated with graphs. The resulted FT-IR spectra and the corresponding data of the synthesized products were presented in The magnetic nanocomposite was prepared using chitosan. To prepare functionalized chitosan, the chitosan was azidated using chloroacetyl chloride and sodium azide. Then click reaction which has been incorporated in our recent studies ,3 and als) of 25.4 (emu/g) has super paramagnetic characteristics. Moreover; the corresponding data were presented in Magnetization experiments of the prepared magnetic nanocomposite (MNC) were obtained using VSM technique at room temperature. As can be seen in 3O4 nanoparticles theory were performed. The isotherm plots were used to calculate the specific surface area and the average pore diameter of the chitosan/magnetic nanocomposite and the difference between adsorption and desorption steps.For evaluating the cell cytotoxicity of the prepared sample (MNC) according to the literature , some kn"} +{"text": "Qualitative research on positive coping approaches actually used by caregivers can inform interventions that can be feasibly implemented. Absent from previous qualitative research is how caregivers respond to strain in the relationship, specifically. Eight focus groups were conducted with a purposeful sample of racially and ethnically diverse family caregivers in Los Angeles (n=75). An additional 8 in-depth follow-up interviews were conducted. Content analysis was used to understand the mechanisms employed by caregivers to cope with strain and tension in the caregiving relationship. Preliminary results revealed twenty-two individual themes, which were subsequently grouped into four main superordinate themes: 1) Self-care; 2) Adaptation of behaviors and feelings; 3) Seeking and utilizing assistance and respite; and 4) Education and support groups. This work can help inform the design of programs to support caregivers and prevent potentially harmful behaviors, through understanding the experiences of caregivers in their own words."} +{"text": "Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer (BC). It is so named because it lacks expression of estrogen/progesterone receptors and does not overexpress the human epidermal growth factor receptor 2 (HER2). While only 15\u201320% of all BC cases are classified as TNBCs, they account for over 50% of BC mortality. TNBCs include the BRCA1/2- defective BCs and largely overlap with the basal-like BC group. As of today, no targeted therapies are available for these BC subtypes and despite advances in cytotoxic therapies they still carry a grim prognosis, with relapses typically occurring as soon as 3 years after treatment [TNBCs trace their origin to the genomic instability (GI) associated with defects in DNA repair (notably homology-directed repair (HDR)) and thus, compared to other BCs show increased rates of pathologic complete response following chemotherapy . Yet, deDNM2 was associated with lower relapse-free survival and very short times (3\u20135 years) to relapse after chemotherapy in TNBC. Below we provide a mechanism that explains how increased DNM2 expression may shape resistance in later stages of the disease and why it is so uniquely important for the outcome in TNBC.We have recently shown that the efficiency of HDR depends on dynamin 2 (DNM2), a large GTPase best known for its role in intracellular molecular trafficking [RAD51 might similarly reverse the HDR defects induced by DNM2 deficiency. However, although we successfully rescued the DNM2 inhibition-induced HDR phenotypes in all other cells, this was not the case for cells derived from advanced TNBCs, which remained strikingly dependent on DNM2 function for their survival after treatment with chemotherapy. We concluded that in the absence of BRCA and other proteins that control recruitment of RAD51 to the sites of DNA damage and/or stalled replication forks, RAD51 trafficking to the nucleus and subsequent cell resistance to chemotherapy was largely dependent on DNM2. This reasoning is supported by observations of aberrant cytoplasmic-to-nuclear ratios of RAD51 in late-stage TNBCs, suggesting the importance of RAD51 trafficking between nucleus and cytoplasm for the aggressiveness of TNBC [High genomic instability (GI) is a characteristic feature of TNBCs. One mechanism often employed by TNBCs to counteract GI is overexpression of RAD51, a protein central to HDR . As a DN of TNBC .Recent single-cell sequencing of longitudinal TNBC samples has showIn summary, increased DNM2 and associated intra-cell trafficking explain how DNA repair-deficient cells could acquire both resistance to chemotherapy and mobility, thus providing one possible solution to the triple-negative paradox of BC (Figure"} +{"text": "Here, we investigate cross-seeding of full-length human Tau (FL Tau) with fibrils assembled from K18 and K18\u0394K280 fragments of Tau in the presence of poly-L-glutamate (poly-Glu) as an enhancer of Tau aggregation. To study cross-seeding between Tau polypeptides and the role of the conformational memory effect in induction of Tau amyloid polymorphism, kinetic assays, transmission electron microscopy, infrared spectroscopy and limited proteolysis have been employed. The fastest fibrillization was observed for FL Tau monomers seeded with preformed K18 amyloid yielding daughter fibrils with unique trypsin digestion patterns. Morphological features of daughter FL Tau fibrils induced by K18 and K18\u0394K280 seeds were reminiscent of the mother fibrils , respectively) but disappeared in the following generations which became similar to unpaired FL Tau amyloid fibrils formed de novo. The structural evolution observed in our study was accompanied by disappearance of the unique proteolysis profile originated from K18. Our findings may have implications for understanding molecular mechanisms of the emergence and stability of Tau amyloid strains.Amyloid aggregates of Tau protein have been implicated in etiology of many neurodegenerative disorders including Alzheimer's disease (AD). When amyloid growth is induced by seeding with preformed fibrils assembled from the same protein, structural characteristics of the seed are usually imprinted in daughter generations of fibrils. This so-called conformational memory effect may be compromised when the seeding involves proteins with non-identical sequences leading to the emergence of distinct structural variants of fibrils (amyloid \u2018 In A and B, lane 1 shows molecular weight marker. Note different pattern of bands in the range of 15 to 20 kDa in lane 3.(TIF)Click here for additional data file."} +{"text": "The study examined attitudes towards Advance Care Planning (ACP) as a potential mediator in the association between acculturation and willingness to use nursing home in Korean American older adults (aged 60 and older). Data were driven from a cross-sectional study of 235 community-dwelling Korean American older adults (aged 60 and older) in 2013. Multivariate regression models of willingness to use nursing home were entered in the following order: (1) demographics, (2) health, (3) acculturation, and (4) attitudes towards advance care planning. The mediation effect of attitudes towards ACP in the relationship between acculturation and willingness to use nursing home was separately examined using the bootstrapping method. Higher acculturation was associated with positive attitudes towards ACP and more likelihood of using nursing home. The proposed mediation model was fully supported: positive attitudes towards ACP served as an intervening step between acculturation and willingness to use nursing home. The mediating role of attitudes towards ACP yields implications for developing culturally sensitive advance care planning education program targeting older individuals."} +{"text": "A 39-year-old man presented with a productive cough, a history of chronic dyspnea and recurrent lower respiratory tract infections. Physical examination and laboratory tests were unremarkable. A chest X-ray (A) showed an enlarged tracheal diameter (white arrows), with multiple cysts in the lower lobes (red arrows). A computed tomography scan of the chest (B) showed the dilatation of both the trachea and the two main bronchi (white arrows) with multiple diverticulae (blue arrows). It also revealed bilateral cystic bronchiectasis involving both lower lung zones (red arrows). A possibility of Mounier-Kuhn syndrome (MKS) was considered. MKS is a rare condition characterized by recurrent lower respiratory tract infections and tracheobronchial dilation that is due to atrophy of the muscular and elastic tissues in the trachea and main bronchial wall. The patient underwent bronchoscopy which demonstrated tracheal dilation with diverticulae and enlargement of both main bronchi confirming the diagnosis of MKS."} +{"text": "We discuss the evaluation of the Engaging Older Adult Learners as Health Researchers (ENGOAL), a program designed to educate older adults from underserved and underresourced communities about geriatric health and research methods, enabling them to become Research Partners. Quantitative and qualitative data were collected for evaluation from 21 participants aged 53-79. We used All Aspects of Health Literacy Scale and an adaptation of Stanford Patient Education Research Center Chronic Disease Self-Efficacy Scale to assess pre-post and follow-up changes, using repeated measures analyses. Results suggest notable increases in self-efficacy, but only small improvements in subjective health literacy. Themes identified through qualitative analysis of interviews with participants included: (1) Finding our Voices (2) Race and Health (3) Faith and Health (4) Communicating with Providers and (5) Sharing and Advocacy. Emerging community leadership of participants are further evidence of confidence gains in our participants."} +{"text": "The management of multiple chronic conditions (MCC) in older adults living in the community is complex. Little is known about the experiences of interdisciplinary primary care and home providers who care for this vulnerable group. The aim of this study was to explore the experiences of healthcare providers in managing the care of community-living older adults with MCC and to highlight their recommendations for improving care delivery for this group. A qualitative interpretive description design was used. A total of 42 healthcare providers from two provinces in Canada participated in semi-structured interviews. Participants represented diverse disciplines and settings . Thematic analysis was used to analyze interview data. The experiences of healthcare providers managing care for older adults with MCC were organized into six major themes: (1) managing complexity associated with MCC, (2) implementing person-centred care, (3), involving and supporting family caregivers, (4) using a team approach for holistic care delivery, (5) encountering rewards and challenges in caring for older adults with MCC, and (6) recommending ways to address the challenges of the healthcare system. Healthcare providers highlighted the need for a more comprehensive integrated system of care to improve care management for older adults with MCC and their family caregivers. Specifically, they suggested increased care coordination, more comprehensive primary care visits with an interprofessional team, and increased home care support."} +{"text": "Recent data from an individual patient data (IPD) meta-analysis of 17 randomized control trials including >100,000 women living in low- and middle-income countries found that multiple micronutrient supplementation (MMS) in pregnancy reduced the risk of low birth weight, preterm birth, and being born small for gestational age. Further, MMS reduced the risk of neonatal and infant mortality for females, and there was no evidence of increased risk among the 26 subgroups examined. The 2016 WHO antenatal care guidelines, which were released before the IPD meta-analysis, did not universally recommend MMS, noting: \u201cThere is some evidence of additional benefit \u2026 but there is also some evidence of risk.\u201d The guidelines suggest that MMS may increase the risk of neonatal mortality based on an exploratory subgroup analysis of 6 randomized trials. However, we identified several issues with this subgroup analysis. In this report we correct and update the subgroup analysis and show that there is no evidence that MMS increases the risk of neonatal mortality. There is growing scientific consensus that MMS containing iron and folic acid (IFA) is superior to IFA alone. The WHO guidelines currently state that \u201cpolicy-makers in populations with a high prevalence of nutritional deficiencies might consider the benefits of MMN [multiple micronutrient] supplements on maternal health to outweigh the disadvantages, and may choose to give MMN supplements that include iron and folic acid.\u201d This equivocal guidance has created confusion about the best course of action for public health programs in low- and middle-income countries. Given the new evidence, WHO should review their statements regarding the potential neonatal mortality risks and re-evaluate the overall potential benefits of implementing MMS as a public health program. Micronutrient deficiencies in pregnancy are common and are associated with adverse birth outcomes . PrenataThe 2016 WHO antenatal care guidelines do not universally recommend MMS, noting: \u201cThere is some evidence of additional benefit of MMN [multiple micronutrient] supplements containing 13\u201315 different micronutrients (including iron and folic acid) over iron and folic acid supplements alone, but there is also some evidence of risk\u201d (1) corrected the Bhutta et al. estimate, which is consistent with the updated 2017 Cochrane Review (2) included the omitted MINIMat study (3) added 2 recently published trials (lipid-based supplements arms excluded) (4) included 2 trials that used a 60 mg Fe/d control but were excluded due to using a 250 \u00b5g/d folic acid dose addexcluded) , 7; and cid dose , 9. The cid dose and was cid dose . The Fawcid dose trial wacid dose neonatalcid dose \u201316, and cid dose .and the effect of additional micronutrients. The lower dose of iron in the MMS (30 mg/d) as compared with the control arm (60 mg/d) may explain negative effect estimates seen in some trials. The 2017 Cochrane Review examined the effect of MMS on perinatal mortality stratified by iron dose in the MMS and control arms with an IFA control arm containing high-dose iron (60 mg/d). These trial designs simultaneously address 2 questions about the effect of a lower dose of iron rol arms . Among trol arms . We argudecrease the risk of infant mortality for infants born to women without access to a skilled birth attendant (\u223c18% risk reduction) . The IPDOur update of the WHO subgroup analysis showed no increased risk of neonatal mortality and the results are consistent with the findings of the updated 2017 Cochrane Review and our recent IPD meta-analysis which found that MMS did not increase the risk of neonatal mortality overall or in any of 26 subgroups of pregnant women and newborns . In fact"} +{"text": "SLE and Serum Complement: Causative, Concomitant or Coincidental?2017, 11: 113-122The Open Rheumatology Journal, The revised last paragraph of conclusion in abstract is mentioned below:It is clinically important to find novel ways to assess disease activity in SLE. Increased serum levels of cell-bound complement activation products may more accurately reflect disease activity than conventional serum C3 and C4 monitoring.The original last paragraph of conclusion provided was:It is clinically important to find novel ways to assess disease activity in SLE. Reduced serum levels of cell-bound complement activation products may more accurately reflect disease activity than conventional serum C3 and C4 monitoring.The revised last paragraph of conclusion is mentioned below:With recent studies demonstrating that increased levels of serum cell-bound complement activation products may more accurately reflect disease activity than conventional complement C3 and C4 monitoring, we believe that this is an important area for future SLE research and look forward to further studies on research in the complement in SLE.The original last paragraph of conclusion provided was:With recent studies demonstrating that reduced levels of serum cell-bound complement activation products may more accurately reflect disease activity than conventional complement C3 and C4 monitoring, we believe that this is an important area for future SLE research and look forward to further studies on research in the complement in SLE."} +{"text": "Parkinson\u2019s disease (PD), a common neurodegenerative disorder affects approximately 1% of the population over 65. PD is a late-onset progressive motor disease characterized by tremor, rigidity (stiffness), and bradykinesia (slowness of movement). The hallmark of PD is the selective death of dopamine-containing neurons in the substantia nigra pars compacta which send their projections to the striatum and the presence of cytoplasmic aggregates called Lewy bodies [1-2]. Most cases of PD are sporadic but rare cases are familial, with earlier onset. The underlying mechanisms and causes of PD still remain unclear."} +{"text": "Macromolecular complexes are essential to intracellular signal transduction by creating signaling niches and enabling a chain of reactions that transmit external signals into various cellular responses. Analysis of SMYD3 interactome indicates this protein lysine methyltransferase might be involved in calcium dependent signaling pathways through forming complexes with the phospholipase PLCB3, calcium/calmodulin dependent kinase CAMK2B, or calcineurin inhibitor RCAN3. SMYD3 is well-known as a histone H3K4 methyltransferase involved in epigenetic transcriptional regulation; however, any roles SMYD3 may play in signaling transduction remain unknown. KEGG pathway enrichment analysis reveals the SMYD3 interacting proteins are overrepresented in several signaling pathways such as estrogen signaling pathway, NOD-like receptor signaling pathway, and WNT signaling pathway. Sequence motif scanning reveals a significant enrichment of PXLXP motif in SMYD3 interacting proteins. The MYND domain of SMYD3 is known to bind to the PXLXP motif. The enrichment of the PXLXP motif suggests that the MYND domain is likely to be a key interaction module that mediates formation of some SMYD3 complexes. The presence of the PXLXP motifs in PLCB3 and CAMK2B indicates the potential role of the MYND domain in mediating complex formation in signaling. The structural basis of SMYD3 MYND domain-mediated interactions is unknown. The only available MYND-peptide complex structure suggests the MYND domain-mediated interaction is likely transient and dynamic. The transient nature will make this domain well-suited to mediate signaling transduction processes where it may allow rapid responses to cellular perturbations and changes in environment. The N-tThe structure of SMYD3 in complex with a MAP3K2 peptide provided the structural basis for SMYD3-substrate complex formation . The weak interaction suggests the MYND-mediated interactions are transient in nature. Transient interactions usually show a fast bound-unbound equilibrium and can readily switch between different binding partners (Perkins et al., MYND domain-based interactions show relatively low binding affinities with KThe structural basis of SMYD MYND domains-mediated interactions is unknown. Based on the structural superposition , the pepIn contrast to binding specificity, MYND domains also show promiscuous binding. Many MYND domains are capable of binding to multiple targets, and single peptide motifs can be recognized by different MYND domains. The MYND domain of BS69 is able to bind to MGA, E1A, and EBNA2 proteins (Ansieau and Leutz, Motif scanning using ScanProsite (de Castro et al., The significant enrichment of PXLXP motif in SMYD3 interacting proteins suggests that the MYND domain is likely to be a key interaction module that mediates the formation of some SMYD3 complexes. The presence of PXLXP motifs in PLCB3 and CAMK2B indicates the potential role of the MYND domain in mediating complex formation in signaling including the aforementioned estrogen signaling pathway, GnRH signaling pathway, NOD-like receptor signaling pathway, and WNT signaling pathway. In PLCB3 there are two PXLXP motifs, PPLRP at residues 265\u2013269 and PSLEP at residues 530\u2013534 . The for2+ concentrations; as intracellular Ca2+ concentrations rise, the holoenzyme is released from the cytoskeleton and enters the cytosol (Swulius and Waxham, CAMK2B has only one PXLXP motif, PCLSP at residues 476\u2013480. This motif is located at the variable segment of CAMK2B . The varPseudomonas aeruginosa-induced intracellular calcium signaling and regulates the activation of PKC and the nuclear transcription factor NF-\u03baB in human bronchial epithelial cells (Bezzerri et al., Analysis of SMYD3 interactome reveals SMYD3 might be involved in signal transduction pathways in addition to epigenetic gene regulation. Most enriched KEGG pathways are associated with the signaling processes in cancer. Among them, the WNT signaling has been shown to affect the maintenance of stemness and metastasis of cancer cells (Zhan et al., Caenorhabditis elegans orthologs, Bra-1 and Bra-2, have been shown to participate in BMP and TGF\u03b2 signaling pathways (Kurozumi et al., The MYND domain might be a key complex-forming module in SMYD3 complexes. The PXLXP motif to which the MYND domain may bind is significantly enriched in SMYD3 interacting proteins. However, there is no significant difference in the enrichment between the interactors involved in signaling transduction pathways and epigenetic transcriptional regulation suggesting that the MYND domain does not have any particular binding preferences in either of these processes. No MYND domain has been directly linked to signaling, but some MYND domain-containing proteins such as BRAM1 as well as its SMYD3 interacting proteins were retrieved from four protein-protein interaction databases including GPS-Prot (Fahey et al., Pathway enrichment analysis of SMYD3 interactors was performed using STRING web-based analyzer (Szklarczyk et al., The presence of PXLXP motif in SMYD3 interacting proteins was scanned using ScanProsite (de Castro et al., All datasets generated for this study are included in the article/supplementary material.ZY and YZ contributed conception and design of the study, performed the database and statistical analyses, and prepared the figures. ZY wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Candida spp., the rate of acute kidney injury (AKI) defined by a creatinine above 3.5\u2009mg/dl or the need of any form of renal replacement therapy (RRT) was around 20% in the bacteria group versus above 40% in the candida group, while having similar Acute Physiology and Chronic Health Evaluation (APACHE) II scores [d-glucan (BDG) could be a very good candidate associated to PCT. Indeed, BDG could be even a better candidate as its molecular weight ranges from several hundred thousand to 10 million daltons and does not pass through any membrane [Candida albicans that increases serum BDG without candidemia [In their recent systematic review, Cortegiani et al. found that serum procalcitonin (PCT) concentrations were higher in patients with bacteremia as compared to candidemia . QualityAndrea Cortegiani, Mariachiara Ippolito and Antonino GiarratanoCandida spp. receiving CRRT and blood purification techniques should be addressed in future studies. Another interesting aspect would be the impact of CRRT in the trend of PCT values in these patients, since almost all the included studies reported the values at the beginning of the diagnostic process [We would like to thank Dr. Honore et al. for discussing the potential role of acute kidney injury (AKI) and continuous renal replacement therapy (CRRT) as potential confounders on the different values of procalcitonin (PCT) in patients with bacteremia versus candidemia in the intensive care unit (ICU) in our systematic review . We eval process . However process \u20139. These"} +{"text": "The efficiency of organotin(IV) complexes as photostabilizers was determined by monitoring the changes in the weight, growth of specific functional groups , viscosity, average molecular weight, chain scission and degree of deterioration of the polymeric films upon irradiation. The results obtained indicated that organotin(IV) complexes stabilized poly(vinyl chloride) and the dimethyltin(IV) complex was the most efficient additive. The surface morphologies of poly(vinyl chloride) films containing organotin(IV) complexes were examined using an atomic force microscope and scanning electron microscopy. These showed that the surface of polymeric films containing organotin(IV) complexes were smoother and less rough, compared to the surface of the blank films. Some mechanisms that explained the role of organotin(IV) complexes in poly(vinyl chloride) photostabilization process were proposed.Three organotin(IV) complexes containing ciprofloxacin as a ligand (Ph The market for poly(vinyl chloride) (PVC) has grown significantly over the years due low production cost and its large versatility ,2,3. HowA UV light of a wavelength longer than 190\u2013220 nm is not expected to be absorbed by PVC since it only contains single bonds . CommercAs a continuation of our research in the field of polymers ,38,39,403SnL, Me2SnL2 and Bu2SnL2; 2SnL2 and Bu2SnL2) and triorganotin (Ph3SnL) were used. Also, the substituents on the Sn were varied as small (Me) and bulky (Bu and Ph) groups.Three organotin-ciprofloxacin complexes complex is the least sterically hindered among the additives used and, therefore, it acts as a better primary photostabilizer compared to the others. Triphenyltin complex shows the least photostabilization effect presumably due to the presence of bulky phenyl groups.Photodegradation of PVC produces low molecular weight fragments as well as hydrochloride (HCl) that lead to a weight loss . The wei\u22121), C=O (1722 cm\u20131) and C=C (1602 cm\u22121) , can be used to evaluate the changes in PVC average molecular weight [\u03b7]=The PVC molecular weight was calculated from the intrinsic viscosities using Equation (6).Three organotin(IV) complexes containing ciprofloxacin as a ligand have been used as photostabilizers to inhibit the photodegradation of PVC films, upon irradiation with ultraviolet light for a long period. Various methods such as the growth of certain functional groups in the infrared spectra, percentage of weight loss, variation in molecular weight, chain scission and degree of deterioration were used to determine the efficiency of organotin(IV) complexes. In addition, the atomic force and scanning electron microscopy were used to assess the surface morphology of poly(vinyl chloride) films. The organotin(IV) complexes used act as efficient photostabilizers and reduce the photodegradation rate of poly(vinyl chloride). It is believed that organotin(IV) complexes act as hydrogen chloride scavengers, peroxide decomposers, free radical scavengers and UV absorbers. For future research using organotin complexes as PVC photostabilizers, the possible leakage of tin should be assessed in order to allow the long-term use of such additives."} +{"text": "The discovery of the involvement of defined molecular pathway(s) in tumor development and therapeutic targeting of such pathway(s) has revolutionised cancer treatment. More than 50 targeted therapeutic agents have been approved by the Food and Drug Administration (FDA) in the last two decades . Unlike ALK G1202R mutation. It is also highly permeable through the blood brain barrier and hence effective in targeting central nervous system metastasis. Recently published results of the global phase II study has shown superior objective response rate (ORR) and intracranial ORR in comparison to the first and second generation ALK TKIs [V600E/K melanoma patients that relapse on monotherapy [Anaplastic Lymphoma Kinase (ALK) exemplifies the use of targeted therapeutic agents in combating cancer, as well as the challenges that arise in terms of resistance mechanisms against such agents in clinical settings . A numbeALK TKIs . As the ALK TKIs . OrganicALK TKIs , 9. One otherapy . However"} +{"text": "In the third (HSP90(Cyt)) and fourth (HSP60(Mit)) panels of Both the HTML and PDF versions of the article have been corrected. This error appears only in print and in PDF versions downloaded on or before March 28, 2019."} +{"text": "Although significant animal suffering caused by preventable diseases is frequently seen in developing countries, reports of this are scarce. This report describes avoidable animal suffering owing to a suspected canine distemper (CD) outbreak in unvaccinated dogs owned by low-income families in Mozambique that killed approximately 200 animals. Affected dogs exhibited clinical signs, and gross and microscopic lesions compatible with CD. Immunohistochemical staining confirmed the presence of canine distemper virus (CDV) in the kidney of one dog from the cohort. This brief communication again illustrates that large outbreaks of CDV in unvaccinated dogs occur and that large-scale avoidable suffering and threats to the health of dogs and wild canines continue. Mass vaccination supported by government and non-government organisations is recommended. Morbillivirus within the subfamily Paramyxovirinae.Canine distemper (CD) is a highly contagious, acute or subacute systemic viral disease that has a high mortality rate in dogs and wild canines. It is caused by canine distemper virus (CDV), which belongs to the genus et al. et al. et al. et al. et al. et al. et al. Vaccination remains the principal strategy for protection, and once clinical signs develop, treatment is limited to supportive care. Even in settings where a diagnosis is rapidly reached, a high standard of care is available and high levels of vaccination are achieved, CD outbreaks continue to occur amongst domestic dogs .The most obvious gross post-mortal lesions were cachexia (3/3), mucopurulent exudate in the trachea and bronchi (2/3), focal pneumonia (3/3), cyanotic heart (2/3), splenic atrophy with increased consistency (2/3), pale kidneys (3/3) and contracted bladders with multifocal haemorrhages in the mucosa (2/3).Histopathological examination of the lung, bronchi and bronchioli showed extensive areas of severe purulent inflammation (2/3). Splenic and lymph node tissues appeared moderately active to highly active (2/3). In the grey matter of the cerebellum, multifocal blood vessels showed notable leukostasis, predominantly with lymphocytes and a few macrophages, and there were also mononuclear infiltrates visible in the perivascular spaces in these areas. There was mild gliosis in the tissue. A few blood vessels in the meninges also showed perivascular cuffing with mononuclear leukocytes, predominately lymphocytes (2/3). A few multifocal aggregates of neutrophils were visible in the parenchyma of the liver, and a mild degree of leukostasis was evident in the sinusoids. The portal regions showed the presence of leukocytes (3/3). Focally extensive severe interstitial inflammation of a chronic lymphoplasmocytic appearance was seen in the prostate (3/3).The history of the disease, the clinical signs and gross and histopathological presentations raised the probability of the presence of a CDV infection. To support this putative diagnosis, immunohistochemistry was performed, which confirmed the disease through positive immunoreactivity to CDV antigens in one of these three cases.et al. et al. The incidence of CDV infections worldwide has decreased thanks to the introduction of the highly protective CDV-modified live virus (MLV) vaccines more than 60 years ago (Martella This report illustrates the highly contagious nature of the disease and the threat to animal welfare posed by non-vaccination. Valuable wildlife would also potentially be threatened by this disease in dogs."} +{"text": "This methodological paper discusses the process of co-creating a documentary film with seven formerly homeless older adults, highlighting some of the tensions carrying out community-based participatory research (CBPR). This paper is part of a larger study that explored \u2018finding home\u2019 through a series of individual and group audio and video-recorded interviews with seven adults (aged 50+) with diverse homeless histories. In addition to the main findings, participants shared their experience of filmmaking and CBPR. Findings revealed four main tensions: 1) openness of sharing stories versus privacy and anonymity; 2) balancing participation/engagement and over-burdening; 3) negotiating interpersonal conflict and community building; and 4) ethical issues surrounding copyright and ownership of the film. Ultimately, we advocate for more CBPR film projects, as they not only provide a rich contextualized window into people\u2019s everyday lives but serve to advance the voices of marginalized populations beyond traditional academic circles."} +{"text": "OBJECTIVES/SPECIFIC AIMS: Acculturation and discrimination are associated with negative health outcomes including functional disability. The effect of these on functional disability in older African immigrants in the United States is not well understood. The purpose of this study is to describe and examine the experiences of acculturation, racial discrimination and functional disability in older African immigrants. METHODS/STUDY POPULATION: This study will use cross-sectional quantitative and qualitative mixed methods design. We plan to recruit 150 older (>55 years) participants through the African Immigrant Health Study and community-based organizations serving African immigrants. We will use the PROMIS physical function measure to assess functional disability, the Everyday Discrimination scale and the Psychological Acculturation scale will be used to measure discrimination and acculturation respectively. Higher scores indicate greater severity. RESULTS/ANTICIPATED RESULTS: We have recruited 12 participants so far. The mean age is 57 years and mean length of stay in the United States is 23 years. Mean disability score is 6.5 (range 1\u201338). Mean discrimination is 8.2 (range 4\u201315). The prevalent acculturation strategy of these participants (7) is marginalization (neither identified with the American nor African cultures). DISCUSSION/SIGNIFICANCE OF IMPACT: Preliminary results indicate pervasive discrimination and marginalization of study participants. Exploring these experiences can inform preventive strategies of coping and health behaviors that can decrease the negative effects of discrimination, acculturation and functional disability in African immigrants."} +{"text": "Roughly one-third of dissolutions among married persons aged 50 and older occur through divorce rather than widowhood, reflecting the rising gray divorce rate and lengthening life expectancies. We use data from the 1980 Vital Statistics and the 2017 American Community Survey (ACS) to estimate the divorce and widowhood rates among married individuals (aged 50+) in 1980 and 2017 to track how much the widowhood rate has declined and the divorce rate has risen. In 1980, women\u2019s widowhood rates exceeded their divorce rates at all ages. For men, the rate of divorce outpaced the rate of widowhood through ages 50-54. By 2017, divorce rates were higher for women through ages 55-59 and for men through ages 60-64, coinciding with the growth in gray divorce. We also examine subgroup variation in the 2017 patterns and the sociodemographic correlates of having experienced divorce versus widowhood during the past year using the ACS data."} +{"text": "This study aims to understand the roles that psychosocial factors play on the longitudinal associations between sensory (including hearing and vision) loss and cognitive decline. Specifically, we hypothesized that (1) loneliness mediates the associations between sensory loss and cognitive decline; and (2) social support moderates the associations between sensory loss and cognitive decline. We used longitudinal parallel process (LPP) modeling with data from the Health and Retirement Study (HRS) and the Aging, Demographics, and Memory study (ADAMS). Age variable centered at its mean age of 82. In the most parsimonious model, loneliness fully mediated the associations between vision loss and the average cognitive status at age 82 (p < .05). Social support moderated the associations between vision loss and the average cognitive status at age 82 . No moderation or mediation effect was found for the psychosocial factors on the associations between hearing loss and cognition."} +{"text": "The last poliomyelitis cases reported in Papua New Guinea occurred in 1996. Papua New Guinea is one of 37 countries (or areas) of the World Health Organization Western Pacific Region that were certified free of indigenous wild poliovirus in 2000. On June 22, 2018, the National Department of Health confirmed an outbreak of poliomyelitis caused by circulating vaccine-derived poliovirus type 1 (cVDPV1) following isolation of genetically linked virus from a patient with paralysis and nonhousehold community contacts. The index patient was a boy aged 6 years from Lae, Morobe Province, with onset of paralysis on April 25 and history of having received 2 doses of Sabin oral poliovirus vaccine (OPV).cVDPVs can emerge in underimmunized populations when Sabin vaccine poliovirus is extensively transmitted person-to-person and reverts to neurovirulence (Round 1 and Round 2) with bivPapua New Guinea was at risk for delayed detection of poliovirus because of an insufficient surveillance system for acute flaccid paralysis (AFP) and delays in seeking health care, often because of geographic inaccessibility. After the initial cVDPV1 case was detected, active AFP case-finding at health facilities was intensified. The annual national nonpolio AFP rate, a key indicator of surveillance sensitivity (A December outbreak response assessment concluded that cVDPV1 transmission likely continues, given the dates of isolation of cVDPV1 from environmental surveillance and the most recent confirmed case. Additional SIAs are planned in Papua New Guinea in 2019. Because of the outbreak, on July 12, 2018, CDC issued a Level 2 Travel Health Notice recommending that all travelers to Papua New Guinea be fully vaccinated against polio. Before traveling to Papua New Guinea, adults who completed their routine polio vaccine series as children are advised to receive a single, lifetime adult booster of polio vaccine."} +{"text": "Following publication of the original article , the autOriginally, the sentence was stated as:(ii) exhibited no evidence of prostate cancer as determined by blood test (PSA < 4 mg/dL)The correct sentence is:(ii) exhibited no evidence of prostate cancer as determined by blood test (PSA < 4 ng/ml)"} +{"text": "Rhinusa and Gymnetron, two closely related groups of weevils that feed and develop inside plant tissues of hosts within the families Scrophulariaceae and Plantaginaceae. We found strong evidence for phylogenetic conservatism of host use at the plant family level, most likely due to substantial differences in the chemical composition of hosts, reducing the probability of shifts between host families. In contrast, the use of different plant organs represents a more labile ecological trait and ecological niche expansion that allows a finer partitioning of resources. Rhinusa and Gymnetron weevils initially specialized on plants within Scrophulariaceae and then shifted to the closely related Plantaginaceae; likewise, a gall inducing behavior evolved from non-galler weevils, possibly in response to resource competition, as galls facilitate larval development by providing enhanced nutrition and a favorable microhabitat. Results from trait-dependent diversification analyses suggest that both use of hosts within Plantaginaceae and parasitism on fruits and seed capsules are associated with enhanced diversification of Rhinusa and Gymnetron via low extinction rates. Our study provides quantitative evidence and insights on the ecological factors that can promote diversification in phytophagous insects that feed and develop inside plant tissues.Weevils (Coleoptera: Curculionoidea) represent one of the most diverse groups of organisms on Earth; interactions with their host plants have been recognized to play a central role in their remarkable diversity, yet the exact mechanisms and factors still remain poorly understood. Using phylogenetic comparative analyses, here we investigate the evolution of host use and its possible role in diversification processes of Comprising approximately 5,800 genera and more than 60,000 described species , weevilsRhinusa and Gymnetron (Curculionidae: Curculioninae), endophagous parasitic weevils whose larvae feed and develop within tissues of plant species in the families Scrophulariaceae and Plantaginaceae. The genus Rhinusa comprises approximately 40 species with a Palearctic distribution as host plants assess phylogenetic conservatism in host use by plant family and in different modes of parasitic behavior; (2) estimate ancestral states of traits associated with host plant use; and (3) assess possible effects of these traits on speciation and extinction rates within the Rhinusa/Gymnetron species complex. These analyses should provide valuable insights into the evolution of different traits of host plant use and their role in diversification processes of phytophagous insects that feed and develop inside plant tissues.Here, we use a previously inferred phylogeny from mitochondrial and nuclear DNA sequence data in conjuRhinusa representing approximately 80% of recognized species, with representatives from the three main taxonomic groups proposed by Gymnetron from the Palearctic and Afrotropical regions (approximately 40% of recognized species). Additionally, since some of the analyses performed in this study require ultrametric trees, we performed a Bayesian analysis for the same dataset of concatenated sequences using BEAST 2.1.3 ST 2.1.3 .We used Mesquite 3.1 to assesUsing the same host plant use categorization as for phylogenetic conservatism analyses, ancestral states were reconstructed across the random sample of 1,000 post burn-in trees from the analysis performed with MrBayes. We used the Bayesian approach reversible jump MCMC (rjMCMC), implemented in BayesTraits 2.0 ; the advFor comparison with the rjMCMC approach and to account for differential speciation, extinction and character transition rates in the reconstruction of ancestral states, we additionally performed ancestral state reconstructions using maximum likelihood under binary and multi-state speciation and extinction models (BiSSE/MuSSE) in the RRhinusa/Gymnetron species complex. We independently used the model to assess the effect of host plant family use (Scrophulariaceae or Plantaginaceae) and the mode of parasitism as gall or non-gall inducer. The model estimates six parameters; speciation (\u03bb) and extinction (\u03bc) rates for states 0 and 1 and transition rates from state 0 to 1 and vice versa (q01 and q10). Similarly, a multi-state speciation and extinction (MuSSE) model was employed to assess the effect of different modes of parasitism on either roots, stems or fruit/seed capsules. The MuSSE model is an extension of the BiSSE model to discrete traits with more than two states or combinations of binary traits analyzed simultaneously . Eight parsimony steps were observed against 14 expected steps at the lower confidence limit under 10,000 character randomizations of the null model. When host plant use is categorized according to the plant parts being parasitized and as gall inducer vs. non gall inducer, the distribution of characters over the Bayesian consensus tree is marginally significant at the 0.05 confidence level, that is, in both cases the difference between the expected (null model) and observed number of parsimony steps is only one. A similar trend was observed for the results from the estimation of Pagel\u2019s lambda parameter, which indicate a strong phylogenetic signal for host use by plant family (\u03bb = 1) but less phylogenetic signal for both host use as either gall or non-gall inducer and parasitic mode on different plant structures , providing enhanced nutrition and a favorable microhabitat which facilitates larval development. The use of restricted sets of host plants is phylogenetically conserved, most likely because of substantial differences in the chemical composition of their hosts, thus reducing the probability of host shifts. In contrast, the utilization of different plant organs represents a more labile ecological trait that allows a finer partitioning of resources; this ecological niche expansion is associated with enhanced diversification rates in weevils exhibiting a parasitic behavior on fruits and seed capsules. Our results show that ecological factors such as host plant use and specialized endoparasitic habits can promote diversification via low extinction rates in phytophagous insects that require plant tissues for the completion of their reproductive cycle.10.7717/peerj.6625/supp-1Supplemental Information 1Extinction rates associated with (A) use of either Scrophulariaceae or Plantaginaceae as host plant families and (B) use of different plant organs: roots, stems or fruits and seed capsules.Click here for additional data file.10.7717/peerj.6625/supp-2Supplemental Information 2Extinction rates associated with use of Plantaginaceae taxa as hosts (A) and use of fruits and seed capsules (B) estimated with MCMC analyses (BiSSE and MuSSE models) from pruned simulated trees. The red line indicates the true parameter value used to simulate the tree.Click here for additional data file."} +{"text": "We deeply appreciate the great contributions of many physicians in the registry of esophageal cancer cases. The Comprehensive Registry of Esophageal Cancer in Japan, 2012, was published here, despite some delay. The registry complies with the Act for the Protection of Personal Information. The encryption with a HASH function is used for anonymity in an unlinkable fashion.We briefly summarized the Comprehensive Registry of Esophageal Cancer in Japan, 2012. Japanese Classification of Esophageal Cancer 10th [We hope that this Comprehensive Registry of Esophageal Cancer in Japan for 2012 will help to improve all aspects of the diagnosis and treatment of esophageal cancer in Japan.I.Clinical factors of esophageal cancer patients treated in 2012Institution-registered cases in 2012Patient backgroundTableAge and genderTablePrimary treatmentTableTumor locationTableHistologic types of biopsy specimensTableDepth of tumor invasion, cT (UICC TNM 7th)TableLymph node metastasis, cN (UICC TNM 7th)TableDistant metastasis, cM (UICC TNM 7th)TableClinical stage (UICC TNM 7th)II.Results of endoscopically treated patients in 2012TableDetails of endoscopic treatment for curative intentTableComplications of EMR/ESDTablePathological depth of tumor invasion of EMR/ESD specimensFigureSurvival of patients treated with EMR/ESDFigureSurvival of patients treated with EMR/ESD according to the pathological depth of tumor invasion, pT (UICC TNM 7th)FigureSurvival of patients treated with EMR/ESD according to the lymphatic and venous invasionIII.Results in patients treated with chemotherapy and/or radiotherapy in 2012TableDose of irradiation TableDose of irradiation FigureSurvival of patients treated with chemotherapy and/or radiotherapyFigureSurvival of patients treated with definitive chemoradiotherapy according to clinical stage (UICC TNM 7th)FigureSurvival of patients underwent radiotherapy alone according to clinical stage (UICC TNM 7th)IV.Results in patients who underwent esophagectomy in 2012TableTreatment modalities of esophagectomyTableTumor locationTableApproaches to tumor resectionTableVideo-assisted surgeryTableFields of lymph node dissection according to the location of the tumorTableReconstruction routeTableOrgans used for reconstructionTableHistological classificationTableDepth of tumor invasion, pT (JES 10th)TablePathological grading of lymph node metastasis, pN (JES 10th)TablePathological findings of lymph node metastasis, pN (UICC 7th)TablePathological findings of distant organ metastasis, pM (JES 10th)TableResidual tumorTableCauses of deathFigureSurvival of patients who underwent esophagectomyFigureSurvival of patients who underwent esophagectomy according to clinical stage (JES 10th)FigureSurvival of patients who underwent esophagectomy according to clinical stage (UICC 7th)FigureSurvival of patients who underwent esophagectomy according to the depth of tumor invasion, pT (JES 10th)FigureSurvival of patients who underwent esophagectomy according to lymph node metastasis, pN (JES 10th)FigureSurvival of patients who underwent esophagectomy according to lymph node metastasis, pN (UICC 7th)FigureSurvival of patients who underwent esophagectomy according to pathological stage (JES 10th)FigureSurvival of patients who underwent esophagectomy according to pathological stage (UICC TNM 7th)FigureSurvival of patients who underwent esophagectomy according to residual tumor (R)Institution-registered cases in 2012Tables\u00a0Tables\u00a0Tables\u00a0Tables\u00a022"} +{"text": "Since the early reports of neurofibrillary Tau pathology in brains of some Huntington\u2019s disease (HD) patients, mounting evidence of multiple alterations of Tau in HD brain tissue has emerged in recent years. Such Tau alterations range from increased total levels, imbalance of isoforms generated by alternative splicing (increased 4R-/3R-Tau ratio) or by post-translational modifications such as hyperphosphorylation or truncation. Besides, the detection in HD brains of a new Tau histopathological hallmark known as Tau nuclear rods (TNRs) or Tau-positive nuclear indentations (TNIs) led to propose HD as a secondary Tauopathy. After their discovery in HD brains, TNIs have also been reported in hippocampal neurons of early Braak stage AD cases and in frontal and temporal cortical neurons of FTD-MAPT cases due to the intronic IVS10+16 mutation in the Tau gene (MAPT) which results in an increased 4R-/3R-Tau ratio similar to that observed in HD. TNIs are likely pathogenic for contributing to the disturbed nucleocytoplasmic transport observed in HD. A key question is whether correction of any of the mentioned Tau alterations might have positive therapeutic implications for HD. The beneficial effect of decreasing Tau expression in HD mouse models clearly implicates Tau in HD pathogenesis. Such beneficial effect might be exerted by diminishing the excess total levels of Tau or specifically by diminishing the excess 4R-Tau, as well as any of their downstream effects. In any case, since gene silencing drugs are under development to attenuate both Huntingtin (HTT) expression for HD and MAPT expression for FTD-MAPT, it is conceivable that the combined therapy in HD patients might be more effective than HTT silencing alone. HTT gene, while individuals with expansions of 40 or more repeats develop HD. Carriers of 36\u201339 CAG repeats have lower penetrance and later onset of the disease is an autosomal dominant neurodegenerative disorder caused by a mutation in the gene that encodes for the protein Huntingtin (Htt). This mutation consists on an abnormal expansion of a CAG triplet (>35) in exon 1 of the gene that encodes for a stretch of polyglutamine (polyQ) in the N-terminal region of the protein and in the nucleus where gene expression can get altered that was first discovered in 1975 by Weingarten when it was co-purified along with tubulin and/or neuropil threads primary Tauopathies that are a major class of Frontotemporal Lobar Degeneration (FTLD) neuropathology and can present clinically with several forms of Frontotemporal Dementia (FTD)\u2014like Frontotemporal Dementia with parkinsonism linked to chromosome 17\u2014(FTDP-17), progressive supranuclear palsy syndrome (PSP) or corticobasal degeneration (CBD); and (b) secondary or non-primary Tauopathies like Alzheimer\u2019s disease (AD) in which neurofibrillary Tau neuropathology occurs in addition to the amyloid-\u03b2 (A\u03b2) plaques. The various Tauopathies affect different brain regions and cell types and they also show differences in the ratio of Tau isoforms present in the Tau filaments was found in the cortex of HD patients and this is accompanied with the appearance of lower molecular weight (35 and 39 KD) bands and FTLD with Tau+ inclusions (FTLD-Tau), alteration of alternative splicing of exon 10 produces an imbalance in 4R-Tau and 3R-Tau isoforms proteins participate on constitutive splicing while also regulating alternative splicing. Some members of this family promote the inclusion of exon 10, while others suppress it. Several studies have shown that SRSF1 (ASF/SF2), SRSF2 (SC35), SRSR6 (SRp55), and SRSF9 (SRp30c) promote exon 10 inclusion, while SRSF3, SRSF4, SRSF7, and SRSF11 suppress its inclusion could also be responsible for the 4R-Tau/3R-Tau imbalance as it has been shown to modulate exon 10 splicing and to interact with FUS, one major component of mHtt inclusions and Tau deposits stained with antibodies that recognize 3R-Tau, 4R-Tau or pathologically phosphorylated Tau (AT-8 and pS199) has been detected in cortical and striatal sections of HD patients or 103Q mHtt and Tau fused with non-fluorescence halves of a fluorescence reporter protein, Blum et al. also known as Tau Nuclear Rods (TNRs) in the striatum and cortex of HD patients Brain Bank , the Neurological Tissue Bank of the IDIBAPS Biobank , the Banco de Tejidos Fundaci\u00f3n Cien and the Netherlands Brain Bank . Written informed consent for brain removal after death for diagnostic and research purposes was obtained from brain donors and/or next of kin. Procedures, information and consent forms have been approved by the Bioethics Subcommittee of Centro Superior de Investigaciones Cient\u00edficas .Both authors (MF-N and JL) revised the literature and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "On January 7, 2019, three patients arrived at the Community Regional Medical Center emergency department in Fresno, California, after snorting white powder they thought was cocaine. One (patient A) was in cardiac arrest, and two (patients B and C) had opioid toxidrome . After sAfter notification of the initial three cases, a multiagency response was implemented by FCDPH; Fresno County Sheriff-Coroner\u2019s Office; Fresno Police Department; Fresno County Department of Behavioral Health; Community Regional Medical Center; University of San Francisco-Fresno; and the Drug Enforcement Administration. Initial actions included 1) disseminating a news release targeting the media and other emergency departments; 2) holding a multiagency press conference; 3) conducting media interviews; 4) informing law enforcement, prehospital providers, and the public about naloxone distribution and use; 5) educating persons on the proper disposal of old or new but unused medications through the Fresno County Department of Behavioral Health/California Health Collaborative drop-off containersOn January 12, 2019, a similar drug overdose incident was reported in Chico, California, in which postmortem toxicology testing for one person confirmed fentanyl (Death rates involving cocaine increased by approximately one third during 2016\u20132017. In 2017, nearly three fourths of cocaine deaths also involved opioids, with the arrival of synthetic opioids driving much of this increase (In the days following the multiagency press conference, FCDPH disseminated a California Health Alert Network message to approximately 700 Fresno County providers about free online medication-assisted treatment waiver training and encouraged use of the Controlled Substance Utilization Review and Evaluation System prescription drug\u2013monitoring program for opioid users."} +{"text": "Variation in reproductive lifespan and female fertility have implications for health, population size and ageing. Fertility declines well before general signs of menopause and is also adversely affected by common reproductive diseases, including polycystic ovarian syndrome (PCOS) and endometriosis. Understanding the factors that regulate the timing of puberty and menopause, and the relationships with fertility are important for individuals and for policy. Substantial genetic variation exists for common traits associated with reproductive lifespan and for common diseases influencing female fertility. Genetic studies have identified mutations in genes contributing to disorders of reproduction, and in the last ten years, genome-wide association studies (GWAS) have transformed our understanding of common genetic contributions to these complex traits and diseases. These studies have made great progress towards understanding the genetic factors contributing to variation in traits and diseases influencing female fertility. The data emerging from GWAS demonstrate the utility of genetics to explain epidemiological observations, revealing shared biological pathways linking puberty timing, fertility, reproductive ageing and health outcomes. Many variants implicate DNA damage/repair genes in variation in the age at menopause with implications for follicle health and ageing. In addition to the discovery of individual genes and pathways, the increasingly powerful studies on common genetic risk factors help interpret the underlying relationships and direction of causation in the regulation of reproductive lifespan, fertility and related traits. Reproductive life span from the onset of puberty, age-specific fertility rates, and twinning frequency all contribute to fertility.12 This genetic contribution to reproductive traits and diseases can result from rare mutations in specific genes and common variation at many sites in the genome each with small effects. In the last decade, genome-wide association studies (GWAS) have transformed our understanding of genetic contributions to these complex traits and diseases.13 The results of these studies have led to discovery of novel genes and pathways influencing specific traits and diseases, new discoveries in disease epidemiology, and the discovery or repurposing of candidate therapeutics.13 Results for GWAS studies for reproductive traits , breast cancer and cardio metabolic disease.28 At the other end of the distribution, delayed puberty is associated with short stature and lower bone mineral density.29Menarche occurs with maturation of the reproductive endocrine system and denotes the onset of menstrual cycles and sexual maturity for women. It usually occurs between 9 and 14 years of age. The average age at menarche has declined over the last century in high income countries including Europe and North America.30 These include mutations in genes for kisspeptin (KISS1), GnRH (GNRH1), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and their respective receptors. Some rare mutations for IHH have been implicated in less severe delayed puberty and may contribute to the population variability in AAM.11 In contrast, activating mutations in KISS1 and kisspeptin receptor (KISS1R), and paternally inherited mutations in two imprinted genes Makorin ring-finger 3 (MKRN3) and Delta-like 1 homologue (DLK1) can result in central precocious puberty (CPP).32MKRN3 is an intronless gene located on the long arm of chromosome 15 in a cluster of imprinted genes in the region associated with Prader\u2013Willi syndrome.31MKRN3 is expressed from the paternal allele in the arcuate nucleus and inhibits the secretion of GnRH during the prepubertal period in childhood.33 Mutations associated with CPP31 include a four-base deletion in the proximal promoter of MKRN3 identified in a girl with non-familial idiopathic CPP who exhibited pubertal development around the age of seven.34 The deletion was associated with reduced promoter activity in vitro.34DLK1 is located on chromosome 14 and encodes a transmembrane protein with multiple epidermal growth factor repeats. Like MKRN3, DLK1 is expressed from the paternal allele and paternal inheritance of a complex genomic rearrangement including the translation start site of DLK1 was associated with isolated familial CPP.32 The association of CPP with loss-of-function alleles in two paternally expressed genes supports a role for imprinting affecting the timing of puberty.32The timing of puberty varies between individuals and is a highly polygenic trait with both rare and common variants contributing to the variation in age at menarche (AAM). Rare mutations in genes that disrupt the development and function of the gonadotrophin-releasing hormone (GnRH) pathway, pituitary hormones, and their receptors can result in idiopathic hypogonadotropic hypogonadism (IHH) and the absence of puberty.30 The Lin-28 Homologue 28 (LIN28B) at 6q21 was the first of the many loci identified from five independent GWAS for AAM.35 The most recent GWAS conducted in \u223c370,000 women of European ancestry identified 389 independent signals explaining \u223c7.4% of the population variance in age at menarche , and genes disrupted in rare disorders of puberty GNRH1 and KISS1.36 Analyses of the data sets for genetic effects on gene expression demonstrated positive enrichment for AAM-associated variants in five central nervous system tissues, notably the pituitary gland and hypothalamus36 supporting an important role of central mechanisms in reactivation of the hypothalamic pituitary axis and onset of puberty. Expression of 205 genes in these tissues were regulated by AAM-associated variants including higher expression of LIN28B in the pituitary gland associated with later AAM.36 Formal analysis of overlap in signals for AAM and genetic effects on gene expression in blood identified evidence for causal or pleotropic effects for 60 regions36 with the variant(s) associated with AAM driving variation of a specific genes in each region.GWAS of AAM in healthy women in European and Non-European populations have identified key genetic factors regulating puberty timing as reviewed previously.37 GWAS in 67,029 women identified 10 significant association signals for age AAM, including signals in two novel regions not reported previously in European women and one novel Japanese-specific signal in a previously reported region near PTPRD. More variants had larger effects on early, compared with late menarche timing, consistent with evidence in European studies.37In Japanese women, the mean age at menarche was 13.9 years with a strong secular trend for decreasing age at menarche to a mean age of 12.3 years for women born after 1965.38 The age at menopause (ANM) has a strong genetic component with more than 50% of variation due to genetic factors.39 A genomic analysis for age at natural menopause was conducted in ~70,000 women with a range of effect sizes from 0.07 to 0.88 years per allele. Exome array analysis identified genome-wide significant evidence for association with two correlated low-frequency missense variants in DNA helicase B (HELB). Although interpretation of the GWAS results have limitations because specific target genes in each region are yet to be determined, the results implicate a substantial role for DNA damage repair in reproductive ageing40 including repair of double strand breaks, mismatch repair and base-excision repair. Pathway analysis also suggested enrichment for a set of genes associated with POI, including MCM8, POLG and MSH5.40Menopause is defined as the permanent cessation of menstruation resulting from the loss of follicular activity. Menopause generally occurs between ages of 40\u201360 years with the average age of ~51 years in western countries.NLRP11, TMEM150B and BRSK1.41 A recent GWAS study for ANM in 43,861 Japanese women identified 16 independent genome-wide significant signals , cardiovascular disease, and effects on gynaecological, gastrointestinal, musculoskeletal, and respiratory conditions.14 The relationships are complex with non-linear relationships between AAM and T2D and cardiovascular disease.42 Early menarche increases risk for both T2D and cardiovascular disease while later menarche also increases risk for cardiovascular disease, but is neutral for T2D.11 BMI also plays a role for many of the same health outcomes. Following adjustment for body composition and socio-economic status, associations with early menarche remained significant for 14 health outcomes and associations with late menarche were significant for eight health outcomes.14 Early menarche was associated with higher risks for uterine fibroids, endometriosis and earlier natural menopause.Variation in AAM and ANM have wide-ranging effects on human health. In a study in the UK Biobank, age at menarche was associated with 26 adverse health outcomes.BRCA1, MSH6 and CHEK2 that also predispose to familial cancers.39 In addition, later age at menopause results in longer exposes to high levels of oestrogen for women. Poor DNA damage response that increases cancer risk might be expected to lead to earlier menopause, opposite to the evidence from epidemiological studies. Using the available genetic data from studies for breast cancer and age at menarche, predicted age at menopause from genetic variants showed increased risks of breast cancer with later age at menopause40 and the effects were greater in oestrogen receptor positive breast cancer. Genetic variants associated with DNA damage repair genes had smaller effects than other markers.40 Taken together, the results suggest that increased exposure to oestrogen with increased reproductive lifespan is the predominant effect on risk for breast cancer.Later age at menopause is associated with increased risks for breast, ovarian and endometrial cancer. Many of the genetic markers influencing menopause are related to DNA damage repair genes including 43 Successful reproduction denoted by age at first birth (AFB) and the associated behaviour of age at first sexual intercourse (AFS) are both moderately heritable and genetically correlated.44 Estimates from the UK Biobank for SNP-based heritability for AFS and AFB were 0.242 (s.e.\u2009=\u20090.010) and 0.290 (s.e.\u2009=\u20090.015) respectively. There was a strong genetic correlation between AFS and AFB (rg\u2009=\u20090.86) and moderate genetic correlations between menarche and both AFS (rg\u2009=\u20090.22) and AFB (rg\u2009=\u20090.24).44 GWAS identified 34 genome-wide significant signals associated with AFS in women with replication in deCODE data for the Icelandic population, and in the Women\u2019s Genome Health Study. The signals include association with intronic SNPs in the oestrogen receptor 1 (ESR1) gene that are also associated with AFB and with the number of children ever born. The ESR1 SNPs associated with AFB are unrelated to SNPs at this locus associated with puberty timing and breast cancer. On chromosome 3, the SNP rs2188151 associated with AFS is highly correlated with a missense variant in the semaphorin protein SEMA3F. The SNP also influences expression (is a cis-eQTL) for the RNA binding protein RMB6. The AFS decreasing allele is associated with later age at menarche, earlier AFB and greater numbers of children born.44Fertility traits in human populations are under genetic control.45 Follow-up analyses identified a number of genes in the genomic regions associated with AFB and number of children born that could be prioritised for functional studies. The critical SNPs on chromosome 1 associated with AFB and number of children ever born are correlated with likely functional nonsynonymous SNPs in two genes; the CREB-regulated transcription co-activator 2 (CRTC2) which acts downstream of FSH in ovarian granulosa cells, and CREB protein 3 like 4 (CREB3L4) which is highly expressed in reproductive tissues in both females and males.45 The lead SNP (rs2777888) for AFB on chromosome 3 is associated with altered DNA methylation or expression of several genes with a role in cell cycle progression and/or sperm function.45 Further functional experiments will be necessary to determine the specific genes and mechanisms of action of the large number of genetic variants influencing these important traits.A large study of genetic effects on reproductive behaviour in 62 cohorts of European ancestry identified 10 independent genomic loci associated with AFB in women, men or both.46 POI is generally defined as the onset of menopause in women under the age of 40 years. Genetic mutations have been reported in a number of candidate genes, although many reported results have not been replicated.47 There is good evidence for deleterious effects of mutations in Bone Morphogenetic Protein 15 (BMP15), Progesterone receptor membrane component 1 (PGRMC1) and the pre-mutation in the Fragile-X mental retardation 1 (FMR1) locus on the X chromosome.47 Mutations in other genes, present in low frequencies in some populations, are likely to influence POI including GDF9, Folliculogenesis specific bHLH transcription factor (FIGLA), and Newborn ovary homeobox gene (NOBOX).47 The 5-prime untranslated region of the FMR1 gene contains a CGC repeat that varies in length and expansion of the repeat to >200 copies causes Fragile-X syndrome. Repeat expansion to the pre-mutation range is associated with premature menopause, but there is no influence of shorter repeat lengths in the normal range or the longer repeats that cause Fragile-X syndrome.48Ovarian reserve is one of the crucial elements of female fertility Fig. and seve47 Although GWAS have identified multiple loci associated with POI in Chinese, Korean, and Dutch women,47 the small samples studied (<1000) have low statistical power and none identified signals exceeding 10\u22126. Pathway analysis of suggestive GWAS loci for ANM do show enrichment for known POI genes.39 There are ~80 gene disorders influencing extremes of reproductive function. The genes are involved in diverse biological processes, including control of the cell cycle, DNA damage response and repair, hormone signalling and gonadal development. Genetic variants in or near many of these genes have variable effects from very early menopause to alterations of just a few weeks.39 Future studies involving larger data sets and meta-analysis of combined GWAS will be necessary to identify risk loci associated with POF.A total of six GWAS have been conducted to identify the risk loci in POI in different populations as reviewed in detail elsewhere.49 DZ twins arise from the ovulation of two follicles after a complex process of follicle growth, selection and ovulation. The frequency of DZ twinning ranges from 6\u201315 per 1000 live births and varies with maternal age and ethnicity.50 DZ twinning is influenced by genetic factors and the DZ twinning rate for sisters of women with spontaneous DZ twins is ~2.5 times higher than the twinning rate in the general population.50 Direct evidence for genetic variants influencing rates of DZ twinning were first identified in animal studies. Domestic sheep generally have 1\u20132 offspring at each pregnancy. Linkage and positional cloning identified mutations in autosomal and X-linked genes that increased ovulation and twinning rates in heterozygous carriers.53 The mutations responsible were identified in the genes for Bone Morphogenetic Protein Receptor Type 1B (BMPR1B) and BMP15, respectively; a receptor and ligand in the ovarian signalling pathway for BMP15.53 Multiple mutations have now been reported in both BMP15 and the closely related signalling molecule growth differentiation factor 9 (GDF9).54 Physiological and genotype-phenotype studies of strains carrying the different mutations demonstrate the importance of BMP signalling, and the balance between BMP15 and GDF9 in follicle survival, maturation, and control of ovulation.54The spontaneous dizygotic (DZ) twinning rate is associated with fertility and comparisons with the frequency of monozygotic twins provide a useful index of fertility in a population.BMP15 and GDF9 have alternative phenotypes depending on whether they are heterozygous or homozygous (carried as one or two copies respectively). Increased ovulation rates occur in heterozygous carriers of the mutations as described above. In contrast, homozygous carriers with two copies of the loss-of-function mutations in BMP15 and GDF9 in sheep have streak ovaries and are completely infertile.54 These genes are candidates for infertility in women and studies in women with primary ovarian insufficiency (POI), also known as premature ovarian failure (POF), have identified mutations in both genes associated with POI.55 Confirmation through segregation studies is difficult in families with infertility disorders, but molecular and functional studies for several of these variants suggest loss-of-function effects consistent with the view that two functional copies of BMP15 are required for an adequate ovarian reserve in women.55 Low-frequency variants in GDF9 are associated with increased risk for DZ twinning in women heterozygous for these variants.56 Similar studies found no evidence that rare and low-frequency variants in BMP15 influence DZ twinning.57 Mutation screening of BMPR1B in mothers of DZ twins identified a coding variant (p.Gln294Glu) altering the same amino acid as a sheep BMPR1B functional variant.58 This mutation was not seen in other families and is of unknown significance.Some mutations in 56 In a search for common genetic variants influencing DZ twinning, a GWAS in 1980 mothers of spontaneous DZ twins and 12,953 controls identified significant association with DZ twinning for SNPs close to Follicle-Stimulating Hormone Beta Subunit (FSHB) and SMAD Family Member 3 (SMAD3).59 The risk alleles for the SNPs close to FSHB and SMAD3 increased the frequency of twin births in the Icelandic population by 18 and 9%, respectively. The lead SNP associated with DZ twinning on chromosome 15 maps to the first intron of SMAD3, strongly expressed in the human ovary, where it promotes granulosa cell proliferation and steroidogenesis.59 The region of chromosome 15q22.33 also includes SMAD Family Member 6 (SMAD6). A major gene increasing ovulation rate and twinning in cattle maps to the equivalent genomic region on bovine chromosome 10 (the location of both SMAD3 and SMAD6).60 Recent analysis of gene expression in granulosa cells from carriers and non-carriers of the cattle gene demonstrated a six-fold increase in expression of SMAD6 in gene carriers.61 SMAD6 is an inhibitor of BMP/SMAD signalling and over-expression of SMAD6 is consistent with loss-of-function mutations in BMP signalling increasing ovulation rate in sheep. Further research is required to determine whether variants associated with DZ twinning on chromosome 15 act through effects on SMAD3, SMAD6 or some other mechanism.Rare and low-frequency variants account for only a small proportion of variation in DZ twinning.63 PCOS is the most common cause of infertility64 and also increases the risk for type 2 diabetes, gestational diabetes, venous thromboembolism, cerebrovascular and cardiovascular disease and endometrial adenocarcinoma.65 The aetiology of PCOS remains unclear with diagnostic criteria proposed for PCOS66 including the National Institutes of Health (NIH), Rotterdam and Androgen Excess Society (AES) criteria. Familial aggregation and twin studies suggest genetic factors play a strong role in pathogenesis of PCOS with heritability estimates of 70%.66Polycystic ovary syndrome (PCOS) is a complex, hormonal and metabolic disorder affecting 5\u201320% of women of reproductive age globally and characterised by hyperandrogenism, ovulatory dysfunction, polycystic ovarian morphology and gonadotropic abnormalities.67 Additional studies69 identify 16 independent signals in 15 genomic regions associated with PCOS including signals near important reproductive hormone genes FSHR, LHCGR and FSHB.70 The signals also include variants in or near three epidermal growth factor genes and genes associated with diabetes.70 As with similar studies in other reproductive diseases, the total heritability explained by GWAS identified PCOS risk SNPs is relatively low (<10%).65The first GWAS conducted in Chinese patients in 2011 has direct clinical applications for planning lifestyle modification as a prevention strategy and inclusion of metformin in treatment plans for PCOS.68 Discovery of additional genetic factors and further characterisation of the signals identified will provide greater insight into the pathogenesis of the complex phenotypes in PCOS.Mendelian randomisation is an analytical method using genetic variation to investigate the likely causal relationship between an exposure trait (or risk factor) and a health outcome. Genetic variants are inherited independently and fixed at birth and subject to less confounding than other measured risk factors. Increasing evidence of association between genetic variants and many common traits means Mendelian randomisation models can use genetic variants associated with a risk factor to infer relationships with a health outcome. The models assume the genetic variants used have strong evidence for association with the risk factor and do not influence the outcome through other unrelated biological pathways. In PCOS studies, Mendelian randomisation demonstrated causal roles for higher BMI, greater insulin resistance and reduced sex hormone binding globulin concentrations in serum.7 The disease affects 7\u201310% of women and is associated with pain and infertility. Early twin studies identified evidence for genetic effects on the liability for hysterectomy,71 one of the most commonly performed surgical procedures for women. Major indications for hysterectomies in reproductive age women are endometriosis (30%) and uterine leiomyomas (>50%).73 Subsequent studies in twins on genetic influences on the liability for endometriosis estimated the heritability at ~50%.75Endometriosis is a complex disease characterised by ectopic lesions of tissue resembling endometrium in the peritoneal cavity.78 The most recent meta-analysis is the predominant receptor for oestrogen action in the endometrium.80 Genomic signals associated with endometriosis include regions flanking the gene for ESR1, signals upstream of follicle-stimulating hormone beta subunit (FSHB) known to increase FSH concentrations,79 and near the oestrogen-regulated and early response gene (GREB1) first identified in breast cancer cell lines and tumours.81 Other regions include candidate genes with roles in cell migration, adhesion and proliferation including Cell Division Cycle 42 (CDC42), Cyclin-Dependent Kinase Inhibitor 2B Antisense (CDKN2B-AS1) and Kinase insert domain receptor (KDR).84Genomic regions and genes associated with endometriosis risk are reviewed in detail elsewhere.sis Fig. identifi85 On chromosome 1, studies on genetic regulation of gene expression in blood86 and endometrium86 show the critical SNPs in this region influence expression of both the long non-coding RNA LINC00339 and CDC42. There are chromatin interactions between risk SNPs and gene promoters for both LINC00339 and CDC42.86 Luciferase reporter assays support the effect of genetic differences on the interaction between the regulatory element and the promoter of CDC42.86 Formal analysis of the overlap of signals for endometriosis risk and genetic effects on gene expression provides strong evidence that key SNPs associated with endometriosis on chromosome 1 and chromosome 12 regulate LINC00339 and vezatin VEZT expression, respectively.87Mechanisms leading to formation of lesions are poorly understand, but one source for cells initiating these lesions is thought to be cells shed from the endometrium and deposited in the pelvic cavity through retrograde menstruation.TACR3 and age at menopause), rare, low-frequency and common variants all influence the same trait.11 In other examples , rare variants cause hypogonadotropic hypogonadism while common variants influence age at menopause.11 These differences, and evidence for the different effects on ovulation rate and streak ovaries for heterozygous and homozygous mutations in BMP15 and GDF9 in sheep54 show disruption of gene function or altered regulation of the same genes can have different effects on reproductive traits and diseases.Genetic studies discussed above demonstrate the complex variation contributing to the timing of puberty, menopause, ovarian function and twinning. Genetic contributions include the effects of multiple common variants with small effects on reproductive traits and disease, and rare variants with large effects contributing to failures in development, precocious puberty, delayed puberty, premature ovarian failure and increased twinning. In some cases and genes associated with POI.40 Further research will help to understand the relationships between ovarian development, disorders of puberty, DZ twinning, POI, and age at natural menopause.Potential overlap for other traits includes genes influencing both DZ twinning and POI and endometriosis and ovarian cancer. There is a small, but significant increase in mothers of DZ twins reaching menopause before the age of 40 compared with mothers of MZ twins.92 The association signals are located in WNT4.92 Subsequent follow-up functional studies show correlated association signals for endometriosis in this region regulate LINC00339 and CDC42 not WNT4,83 and one or both target genes may also play a role in ovarian cancer risk. There is genetic association near the oestrogen receptor 1 (ESR1) locus with four independent signals for endometriosis and five independent signals for breast cancer93 overlaps completely with an association signal for ovarian cancer.94 The Polygenic risk score (PRS) combines association results from genome-wide genotyping into a single estimate of the genetic risk for a disease or trait for each individual. The PRS score is calculated from the number of risk alleles carried, weighted by the effect size estimated from the discovery sample.94 It is often standardised to a mean of zero with a standard deviation of 1 for ease of interpretation.94 The risk scores are not very informative for individual prediction, but explain sufficient variation to determine individuals at highest or lowest risk in populations, and to understand genetic contributions to related traits.13 Where samples are fully independent, calculating genetic contributions to related traits provides a powerful design reducing issues of shared environment and ascertainment in epidemiological studies. Overlap between endometriosis and ovarian cancer extends beyond the observed overlap at the chromosome 1p36 locus discussed above. Observations from epidemiological studies can be confounded due to diagnosis of endometriosis at laparoscopy close to a diagnosis of ovarian cancer. PRS analysis with genotype data from independent samples for endometriosis and ovarian cancer showed shared genetic risk between endometriosis and most histotypes of ovarian cancer95 suggesting some common molecular pathways for the two diseases including the overlap at chromosome 1p36. Prediction of individual risk is improving for some diseases with better estimates of the genetic risk factors. While not sufficiently predictive in isolation, risk scores may be used in combination with other clinical data for patient stratification. The application of risk prediction to inform breast cancer screening is being evaluated in the population based Women Informed to Screen Depending On Measures of risk (WISDOM) study.96In addition to discovery and overlap in effects for individual genes, GWAS data provides powerful approaches to understand shared genetic risk between traits and diseases. Genome-wide SNP genotype data from a discovery sample can be used to estimate the genetic variation due to common SNPs or SNP heritability, and to calculate a polygenic risk score for individuals in an independent sample.97 and number of children ever born.97 Results show a significant negative genetic correlation between number of children ever born and the age at first birth suggesting genes contributing to later first birth are associated with fewer children.97 These relationships are complex because environmental effects and demographic changes also play a role with women choosing to delay childbearing in many countries. Relationships between age at first birth and lifetime number of children are also associated with genetic effects on twinning. Mothers of twins tend to have an earlier age at first birth and raise more children to adulthood in favourable environments.99 Polygenic risk score analysis from the GWAS results for DZ twinning suggest genes contributing to DZ twinning may partly explain genetic effects on fertility. The polygenic risk score for DZ twinning was significantly associated with DZ twinning in an independent sample from Iceland.59 In this sample, the risk score for DZ twinning was associated with a higher likelihood of having children, earlier age at first birth, and greater number of children.59As noted earlier, there are significant additive genetic effects for age at first birth100 This epidemiological evidence is supported by the Mendelian randomisation analyses demonstrating the causal relationship between delayed natural menopause and increased breast cancer risk.40 Understanding these relationships is further complicated by effects of variation in body mass index (BMI). There is a strong inverse genetic correlation between AAM and BMI.36 Thirty-nine signals overlap between AAM and BMI, but most AAM signals make some contribution to adult BMI.36 Using information from different genetic studies allowed estimates of the direct effects of AAM on sex-steroid-sensitive cancers after adjusting for genetically predicted BMI. In these models, later AAM was associated with reduced risks for breast, ovarian and endometrial cancers.36 Analysis of cancer subtypes suggests effects were most strongly associated with oestrogen receptor positive breast cancer and serous ovarian cancer. The effects of earlier puberty timing on higher risks of the sex- steroid sensitive cancers might be related to longer duration of exposure to sex steroids and/or increased activity of the hypothalamic-pituitary axis associated with earlier puberty and reproductive traits including dizygotic twinning.Genetic studies can also inform complex relationships between reproductive traits and related health outcomes. A large-scale meta-analysis supported an association of early menarche and late menopause with increased risk of breast cancer and demonstrated that excess risk associated with advancing menarche by one year was higher than excess risk associated with lengthening menopause by one year.Recent studies have made great progress towards understanding the genetic factors contributing to variation in traits and diseases influencing female fertility. These genetic studies are providing important insights into the complex biology contributing to female fertility. The data emerging from GWAS demonstrate the utility of genetics to explain epidemiological observations, revealing shared biological pathways linking puberty timing, fertility, reproductive ageing and health outcomes. For example, many variants influencing menopause suggest genes and pathways with known roles in DNA damage/repair with implications for follicle health and ageing, although we do not yet have a full picture of the mechanisms responsible.The effect sizes for common variants are small and, as emphasised in this and other reviews, large studies are essential to identify a substantial fraction of common variants underlying variation for these traits and diseases. In addition, GWAS identify genomic regions, but not the specific genes and pathways regulating variation in traits and diseases. To date, we lack definitive evidence for the causal variants and target genes for most of these results. Despite these gaps, examination of potential candidate genes in the multiple regions identified through GWAS provide tantalising evidence for common pathways affecting reproductive lifespan and fertility.101 This in turn will provide much better understanding of the specific pathways regulating individual components of reproductive lifespan and fertility, and the complex interactions between pathways and health outcomes. The knowledge gained will suggest possible interventions and ways to better predict and minimise health impacts of these important life events.The challenge now is to provide functional evidence for the specific genes and pathways regulated by the genetic variation influencing fertility. Multiple lines of evidence from both functional and genomic studies will be required to identify these gene targets and the mechanisms responsible. This is becoming more feasible with advances in genomics, large-scale publically available data, and genome editing.Genetic risk scores from common variants are not able to predict disease risk for individuals. As the estimates improve from more powerful studies, they may be able to predict women at higher or lower risk for specific diseases and this may be useful in some diagnostic settings. Genetic variants associated with natural menopausal timing also influence the menopausal timing in women undergoing radiation or chemotherapy suggesting that in the future, genetic risk prediction models could be useful for counselling related to family planning, lifestyle choices or use of modern techniques for fertility preservation such as oocyte cryopreservation.Epidemiological evidence for comorbidity between traits can be difficult to interpret because of the issues of sample ascertainment. Genetic risk scores add a valuable method to gain insight into the complex relationships in the overlap between traits and diseases. These analyses will also improve as the risk scores can be derived from increasingly powerful studies to help interpret the underlying relationships and direction of causation in the regulation of reproductive lifespan, fertility and related traits."} +{"text": "The USDA Forest Service and University of California researchers have developed a simple and inexpensive passive sampler for monitoring air concentrations of HNO3. Nitric acid is selectively absorbed on 47-mm Nylasorb nylon filters with no interference from particulate NO3-. Concentrations determined with the passive samplers closely corresponded with those measured with the co-located honeycomb annular denuder systems. The PVC protective caps of standardized dimensions protect nylon filters from rain and wind and allow for reliable measurements of ambient HNO3 concentrations. The described samplers have been successfully used in Sequoia National Park, the San Bernardino Mountains, and on Mammoth Mountain in California.Nitric acid (HNO"} +{"text": "The authors note that the citation of Wright (1937) and Nei (1968) is incorrect in the \u201cModels of mutation-selection balance\u201d section in Results. Wright (1937) not only showed the equilibrium frequency of a deleterious allele for a population of infinite size (Eq 1) but also derived the full equilibrium frequency distribution of a deleterious allele under a finite effective population size. He also derived the mean (Eq 2) allele frequency of a fully recessive deleterious allele and gave approximations for large and small effective population sizes. Nei (1968) further derived the approximate variance (Eq 3) in allele frequency of a fully recessive mutation by using Wright\u2019s general formula. The authors confirm that this error does not affect the conclusions of the article."} +{"text": "Scientific Reports 10.1038/s41598-019-54295-8, published online 29 November 2019Correction to: The original version of this Article contained a typographical error in the Abstract.\u201cAccording to the Dual Dodel of Social Hierarchy, one pathway for attaining social status is through dominance (coercion and intimidation).\u201dnow reads:\u201cAccording to the Dual Model of Social Hierarchy, one pathway for attaining social status is through dominance (coercion and intimidation).\u201dThis error has now been corrected in the PDF and HTML versions of the Article."} +{"text": "With the current global downturn, the organizations need to develop new strategies and innovative approaches to ensure that every aspect of sustainability is achieved. For this purpose, the organizations need an indicator that measures the fitness if an organization. The purpose of this project is to analyze the \u2018Fitness\u2019 of an organization using the dataset related to leanness, agility and sustainability in ANFIS (Adaptive Neuro-Fuzzy Inference System) in order to determine whether the company is fit enough to sustain in global markets or not. The project does so by integrating both neural networks and fuzzy logic principles with lean, agility and sustainability principles. FIT manufacturing is the integration of Lean, Agile and sustainability manufacturing in one system as a whole which would help in attaining maximum output and sustain effectively in global markets. FIT Manufacturing adopts an integrated approach towards the use of Lean, Agility and Sustainability to achieve a level of fitness that is unique to each company. The database in the paper contains lean, agile and sustainable indices reviewed by experts. FIT does not prescribe that every aspect of Lean, Agile and Sustainability methodologies must be applied to every company, but a selective mix of components will provide the optimum conditions for a company to prosper. Specifications TableValue of the data\u2022Markets all over the globe are getting more and more competitive through the changes driven by emerging technologies which creates the need for an organization to be adaptive and compatible in order to dominate the market.\u2022FIT manufacturing is a perfect amalgamation of core principles of lean, agile and sustainable manufacturing.\u2022The data in this article helps to determine lean, agile and sustainability indices which provides an insight as to how to fit the organization is by providing a framework for the calculation of fitness index.\u2022Using this data, the efficiency and responsiveness of an organization towards the constantly changing markets can be analyzed.1This dataset consists of 5 fitness enablers, 69 fitness criteria and 205 fitness attributes. The data consists of all major dimensions or enablers of fitness such as management responsibility, manufacturing management, manufacturing technology, workforce and manufacturing strategy. The data on agile, lean and sustainability criteria, was collected from automobile components manufacturing company located in Tamil Nadu, India arranged in a matrix form , Table 52The methodologies that allowed the data presented are described in 2.1The data presented in the paper was collected from automobile components manufacturing company located in Tamil Nadu. India. The attributes pertaining to leanness, agility and sustainability criteria were obtained and rated on a scale from 1 to 10 by industry experts.2.2I.If (agility is not_agile) and (leanness is not_lean) and (sustainability is not_sustainable) then (fitness is not_fit) (1)II.If (agility is average) and (leanness is average) and (sustainability is average) then (fitness is avergge) (1)III.If (agility is agile) and (leanness is lean) and (sustainability is sustainable) then (fitness is fit) (1)IV.If (agility is agile) and (leanness is average) and (sustainability is sustainable) then (fitness is fit) (1)V.If (agility is agile) and (leanness is average) and (sustainability is average) then (fitness is avergge) (1)VI.If (agility is average) and (leanness is lean) and (sustainability is average) then (fitness is avergge) (1)VII.If (agility is average) and (leanness is lean) and (sustainability is sustainable) then (fitness is fit) (1)VIII.If (agility is average) and (leanness is average) and (sustainability is sustainable) then (fitness is fit) (1)IX.If (agility is average) and (leanness is average) and (sustainability is not_sustainable) then (fitness is avergge) (1)X.If (agility is average) and (leanness is not_lean) and (sustainability is not_sustainable) then (fitness is not_fit) (1)XI.If (agility is not_agile) and (leanness is average) and (sustainability is not_sustainable) then (fitness is not_fit) (1)XII.If (agility is not_agile) and (leanness is average) and (sustainability is average) then (fitness is avergge) (1)XIII.If (agility is average) and (leanness is average) and (sustainability is not_sustainable) then (fitness is avergge) (1)XIV.If (agility is not_agile) and (leanness is average) and (sustainability is sustainable) then (fitness is avergge) (1)XV.If (agility is agile) and (leanness is average) and (sustainability is not_sustainable) then (fitness is avergge) (1)XVI.If (agility is agile) and (leanness is not_lean) and (sustainability is sustainable) then (fitness is avergge) (1)XVII.If (agility is agile) and (leanness is not_lean) and (sustainability is not_sustainable) then (fitness is not_fit) (1)XVIII.If (agility is not_agile) and (leanness is not_lean) and (sustainability is sustainable) then (fitness is not_fit) (1)XIX.If (agility is not_agile) and (leanness is lean) and (sustainability is not_sustainable) then (fitness is not_fit) (1)XX.If (agility is not_agile) and (leanness is lean) and (sustainability is not_sustainable) then (fitness is not_fit) (1)2.3MATLAB 2016 was used for creation of Adaptive Neuro-Fuzzy Inference System. The ANFIS model was created using fuzzy logic designer with the corresponding matrices as input , Fig. 5.2.4See 3FIT manufacturing is the integration of Lean, Agile and sustainability manufacturing in one system which would help in attaining maximum output and prevent the damage caused to the environment. This paper deals with analyzing the \u2018fitness\u2019 of a company using ANFIS. The integration of the Fit principles can be employed to reduce the unnecessary cost and increase efficiency of production with less wastage in a market having mercurial demand patterns. The fitness index can be used as a benchmark to evaluate overall efficiency of an organisation."} +{"text": "The Art to Life (ATL) program aims to improve the quality of life for persons living with dementia (PWD) through art therapy, intergenerational contact with college students, and life story preservation within an adult day service. This poster will present the results of an ongoing program evaluation to determine the effects of the intervention on PWDs\u2019 engagement in (1) communication with others and (2) art/creative activity. A two-member analysis team independently coded ethnographic field notes utilizing operational definitions of PWDs\u2019 observed behavior during momentary time sampling, and recording events of communication and art engagement using the modified ENGAGE measure . Results across sessions (N=97) reveal communication engagement significantly exceeded art engagement , t (96)=20.85, p=0.001). These results suggest that engagement in reminiscence via intergenerational contact is a fundamental feature in comparison to art and creative activity within the ATL program. Exploratory qualitative content analysis of ethnographic field notes by a three-member coding team identified two key themes within the communication engagements. These emergent themes included validation of personhood and reminiscence of family ties. More studies are needed to determine if the scope and reach of intergenerational interventions may be increased through the nationwide translation of the ATL program."} +{"text": "An outbreak of feline panleukopaenia virus (FPLV) infection was diagnosed by pathology, electron microscopy and polymerase chain reaction (PCR) in vaccinated captive-bred subadult cheetahs in South Africa. Subsequent to this disease outbreak, 12 cases of FPLV diagnosed on histology were confirmed by PCR in captive African black-footed cat, caracal, cheetah, lion, ocelot and serval. Phylogenetic analyses of the viral capsid protein gene on PCR-positive samples, vaccine and National Center for Biotechnology Information (NCBI) reference strains identified a previously unknown strain of FPLV, present since at least 2006, that differs from both the inactivated and the modified live vaccine strains. A previously described South African strain from domestic cats and cheetahs was identified in a serval. Surveys of FPLV strains in South African felids are needed to determine the geographical and host species distribution of this virus. Since non-domestic species may be reservoirs of parvoviruses, and since these viruses readily change host specificity, the risks of FPLV transmission between captive-bred and free-ranging carnivores and domestic cats and dogs warrant further research. Felis domesticus). FPLVs are classified under the family Parvoviridae and are related to mink enteritis virus (MEV) and canine parvovirus (CPV) infection, the first viral disease identified in cats, is one of the most common viral diseases of domestic cats (Acinonyx jubatus) , ocelot , puma (Puma concolor), Siberian tiger , and spotted cat (Leopardus tigrinus) , arctic fox (Vulpes lagopus) and raccoon (Procyon lotor), and is genetically very similar but distinct from CPV-like viruses from dogs (Canis familiaris) and raccoons , seven cheetahs, three lions, one ocelot and two servals . Clinical signs and pathological findings were not available from many of these cases. Before the 2012 cheetah outbreak molecular diagnostic confirmation of suspected FPLV cases was not readily available in South Africa. To investigate prior suspected or confirmed cases of FPLV molecular diagnostic testing was performed on archived tissue samples from felids in the NZG Biobank (Cases A\u2013G), including both suspected and histologically typical FPLV cases. Cases were from Gauteng and North West provinces and included one African black-footed cat (Felis nigripes), a domestic cat, three cheetahs and two lions. Samples from a puma, a leopard (Panthera pardus) and an ocelot in which clinical and histological evidence of FPLV was absent (Cases i\u2013iii) were included as negative control cases. DNA was also extracted from current Fellocell\u00ae and Fel-O-Vax\u00ae vaccines. All the samples are archived at the NZG Biobank.Subsequent to the outbreak in cheetahs, animal carcasses, a rectal swab, formalin-fixed tissues or formalin-fixed paraffin-embedded tissues (FFPE) from various single or multiple cases in captive felids were submitted to the NZG for pathological examination and/or molecular diagnostic testing for FPLV infection by the owners, veterinarians and pathologists throughout South Africa (Cases 6\u201320). Submitted cases of suspected or confirmed FPLV based on clinical signs and typical macroscopic and histological findings, or diseases presenting with similar signs, included two caracals (TM Tissue MiniPrep kit (Zymo Research). DNA from FFPE samples were extracted using the MasterPure\u2122 Complete DNA & RNA Purification Kit (Epicentre) following the manufacturers specifications. Molecular analysis of the parvovirus genome from all the isolates was conducted by amplification of a ~1300 base pair (bp) region of the viral capsid protein (VP2) gene treatment, cycle sequenced using the BigDye V3.1 (Applied Biosystems) chemistry and run on a 3130 genetic analyser (Applied Biosystems). The resulting sequences were analysed and aligned using the ClustalX parvovirus reference strains. Results from NJ (10 000 bootstrap replicates) and BA (1 million generations) are presented in Clinical signs were described in detail only in the initial cheetah outbreak (Cases 1\u20135) and included pyrexia, haemorrhagic diathesis , hypersaOn necropsy examination, the cheetah cubs showed similar lesions including variable dehydration, mild acute diffuse tissue congestion, and moderate acute intestinal serosal congestion and haemorrhage . VariablEscherichia coli was obtained from the intestine from Case 1 and normal intestinal bacterial flora from Case 3. On negative contrast electron microscopy intestinal contents contained small numbers of parvovirus particles (Case 1).Histologically, extensive necrosis of the intestinal epithelium was accompanied by villous collapse, marked hyperplasia of scanty remaining epithelium, and a thick coat of fibrin, necrotic cellular debris and myriad bacteria on the mucosal surface . In addiThe pathological lesions were consistent with FPLV infection with secondary bacterial enteritis and septicaemia. Additional pathological findings included moderate diffuse acute interstitial pneumonia with moderate multifocal acute pulmonary oedema ; multifocal acute moderate necrohemorrhagic bacterial gastritis as well as lingual and gastric candidiasis, mild serosanguinous hydropericardium and hydrothorax and acute moderate segmental renal tubular necrosis (Case 2); oesophageal and gastric candidiasis and acute mild multifocal pancreatic necrosis (Case 3); and mild acute multifocal necrotising aspiration pneumonia (Case 5). All the cubs were in good body condition at the time of death and showed mild to moderate diffuse adrenocortical hyperplasia.\u00ae vaccine. Clade 2 is represented in the current dataset by one sample (Case 10), which clustered with previously described South African strains of FPLV isolated from a domestic cat (1999) and two cheetahs (2000) as well as an FPLV strain isolated from a wildcat and a mink in the USA (1995). This strain is 99.99% similar to the Fellocell\u00ae vaccine . All the samples from this study clustered separately from CPV (98% similarity) and clustered in two clades. Most of the positive cases (Clade 1) clustered closely (99.94% \u2013 100%) with reference samples from carnivores in Japan and the United States of America (USA), and were similar to the Fell-O-Vax vaccine .Clinical features, pathology, electron microscopy and molecular diagnostic tests confirmed the presence of a previously unreported strain of FPLV in the cheetah cubs in the initial outbreak (Cases 1\u20134). This strain was also detected in archived samples from a lion that died in 2006 (Case A) and an African black-footed cat that died in 2007 (Case B), as well as in samples submitted from other captive felids that died throughout the country after November 2012, including cheetahs , a caracal (Cases 15), a lion (Case 14), an ocelot (Case 12) and a serval (Case 6).et al. The testing of archived samples confirms that the strain from Clade 1 was present in felids in at least North West province before the initial cheetah outbreak and Clade 1 virus subsequently caused disease in unvaccinated felids in Gauteng and North West. Clade 1 strain apparently co-exists with the previously described strain , F10 products or swimming pool chlorine (2.67 g/L water). Biosecurity measures included staff movement from clean to infected enclosures for feeding and inspections; new and frequently changed cleaning cloths as well as overalls and boots for all staff; hand gels and body sprays of F10 products used when moving between enclosures.et al. Positive cases were detected from fresh and frozen tissue, a faecal swab and FFPE intestinal samples from 16 animals clinically and pathologically diagnosed as suffering from FPLV or suspected FPLV . Three cAlthough infections with viruses of the feline parvovirus subgroup have been reported before in several wild carnivore species, including African felids, this study reveals the first in-depth insight into strain diversity within captive felids in South Africa and the first documented cases of FPLV infection in the African black-footed cat and caracal. Further surveys are needed to determine the geographical and host species distribution as well as the genetic variability of FPLV in these species. Vaccine failure, inadequate vaccination and stress may be predisposing factors in the susceptibility to disease. Retention of the current vaccination programme as well as good hygiene practices at breeding and rearing facilities is recommended for the prevention and control of the disease."} +{"text": "Containerized plant production represents an extremely intensive agricultural practice; 40,000 to 300,000 containers may occupy one acre of surface area to which a large amount of chemical fertilizer is applied. Currently, recommended fertilizer application rates for the production of containerized nursery ornamental plants are in excess of plant requirements, and up to 50% of the applied fertilizers may run off or be leached from containers. Among the nutrients leached or allowed to runoff, nitrogen (N) is the most abundant and is of major concern as the source of ground and surface water pollution. In this report, current N fertilizer application rates for different container-grown nursery ornamental plants, the amount of nitrate leaching or runoff from containers, and the potential for nitrate contamination of ground and surface water are discussed. In contrast, our best N management practices include: (1) applying fertilizers based on plant species need; (2) improving potting medium's nutrient holding capacity using obscure mineral additives; (3) using controlled-release fertilizers; and (4) implementing zero runoff irrigation or fertigation delivery systems that significantly reduce nitrate leaching or runoff in containerized plant production and encourage dramatic changes in N management."} +{"text": "PRNP reported from several countries. The objective of this study was to investigate PRNP polymorphisms of native Ethiopian goat breeds and compare the results with other goat breeds.Polymorphisms of the prion protein gene may influence scrapie susceptibility in small ruminants through modified protein conformation. At least 47 amino acid substitutions and 19 silent polymorphisms have been described in goat PRNP in 229 goats belonging to three of the main Ethiopian native goat breeds showed a remarkably high frequency (>\u200934.6%) of p.(Asn146Ser) in these breeds, a variant involved in scrapie resistance in Cyprus. In addition, two novel amino-acid substitutions p.(Gly127Ala) and p.(Thr193Ile), with frequencies ranging from 1.5 to 7.3% were detected. Both amino acids are well conserved in prion proteins (PrP) of most species and these changes have never been reported before in goats worldwide. Residue 127 is within the N\u2013terminal domain of PrP and is probably involved in the recruitment of neural cell adhesion molecules (NCAM). Residue 193 is within the highly conserved string of 4 threonines that plays a role in determining the efficiency of prion protein conversion towards its pathological form.The analysis of the prion protein gene PRNP of Ethiopian goats. This finding increases the interest in exploring PRNP polymorphisms of native goat breeds in areas where cross breeding with foreign goats has rarely occurred.Two novel coding polymorphisms and a high frequency of a scrapie protective variant indicate a high level of genetic diversity in The online version of this article (10.1186/s12917-019-1870-4) contains supplementary material, which is available to authorized users. Camelus dromedarius) in Algeria enlarging the spectrum of animal species susceptible to prion disease [Scrapie is a fatal, neurodegenerative disease that affects small ruminants world-wide. It belongs to the group of prion diseases or transmissible spongiform encephalopathies (TSEs), such as bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in cervids and Creutzfeldt\u2013Jakob disease (CJD) in humans. Recently, a new prion disease, Camel Prion Disease (CPD) of unknown origin was detected in dromedary camels ( disease .PRNP) sequences may influence scrapie susceptibility in sheep and goats through modified protein conformation [The conversion of normal prion protein (PrP) into pathogenic PrP conformers is central to prion diseases. Polymorphisms of the prion protein gene . The variant p.(Gly127Ala) showed a frequency of 4.1% in Western Highland goats and lower frequencies in Central Highland and Long-eared Somali goats respectively. The variant p.(Thr193Ile) showed higher frequencies in Western and Central Highland breeds and a lower frequency in the Long-eared Somali goat are reported for Ethiopian goat breeds. The novel variant p. Gly127Ala) is located within the N terminal domain of PrP involved in the interaction with the neuronal cell adhesion molecule (NCAM) . A varia7Ala is lf Cyprus but absef Cyprus . Both isf Cyprus .The presence of p.(Asn146Ser) in Halep (Damascus), Ethiopian and Tanzanian native goats suggests that the allele was naturally selected in the Middle East first, and spread through the central Sahara and Ethiopia later , 36 and PRNP of Ethiopian goats compared to other breeds. However, a low genetic variation among indigenous Ethiopian goats has been detected through genetic studies on microsatellites probably due to the ancient and widespread practice of nomadism [PRNP substitution frequencies among the breeds in this study. In any case extensive cross breeding with goats coming from other countries has never been performed in Ethiopia, except for some pilot studies with Saanen goats to increase milk production [The frequency of the protective variant p.Asn146Ser) in three of the main Ethiopian goat breeds and the presence of two novel amino acid substitutions in highly conserved regions of prion protein (PrP), show a major diversity in nomadism , 40. Thi6Ser in tPRNP characterization also in sheep populations of the same areas, especially because mixed holdings are very common. A surveillance plan for the disease in both goats and sheep populations would be also important to understand the true epidemiology of scrapie in the country. The occurrence of a new prion disease in dromedaries, CPD in Algeria, could be an impetus for a surveillance plan for prion diseases in Africa since dromedaries are often bred with sheep and goats simultaneously; sharing common pastures in many African countries such as in Ethiopia. A new prion disease in a farmed animal species requires a thorough risk assessment for implementing policies to control the disease in animals and minimize human exposure [PRNP polymorphisms of goats in economically marginal areas and increase the interest in exploring the genetic variation of the PRNP gene in native goat breeds and sheep as well, in countries where cross-breeding with imported animals has never been performed.The two novel amino acid substitutions and the high frequency of the scrapie protective variant p.Asn146Ser) might indicate a lower risk of scrapie in Ethiopian goats. It could be very important to perform 46Ser migPRNP gene: Western and Central Highlands and Long-eared Somali. Somatic aspects of the different goats have been already described [n\u2009=\u200952) were sampled in the Seka, Tiroafata and Omonada districts of Jimma; Western Highland (n\u2009=\u2009110) from the Ambo and Bako districts; and Long eared Somali (n\u2009=\u200967) from the Gursum and Jijiga districts of Eastern Hararghe. The samples consisted of 75% males and 25% females with no genetic relation.Three of the main Ethiopian native goat breeds were analysed for the escribed , 16, 41.PRNP (NM_001314247.1 for the cDNA position and NP_001301176.1 for the protein variants) was performed and direct PCR fragment sequencing was carried out as previously described [Polymerase chain reaction (PCR) amplification of the open reading frame of the caprine Raw data of Ethiopian goats genotyping are reported in Additional file 1Amino acid variants are described following recommendation of Den Dunnen et al. Allelic frequencies were calculated using the Hardy-Weinberg equation. Statistical differences between the breeds were calculated with a chi-square test.Additional file 1:Prion protein gene polymorphism in native Ethiopian goats. Excel file that include all information related to each single goat in the three Ethiopian regions. For each goat, information regarding sex, age in months and the related prion polymorphisms are reported. (XLS 60 kb)Additional file 2:Table of the genotypes combinations of Prion protein gene in native Ethiopian goats.. (PDF 423 kb)"} +{"text": "Community engagement is increasingly recognized as a critical element of medical research, recommended by ethicists, required by research funders and advocated in ethics guidelines. The benefits of community engagement are often stressed in instrumental terms, particularly with regard to promoting recruitment and retention in studies. Less emphasis has been placed on the value of community engagement with regard to ethical good practice, with goals often implied rather than clearly articulated. This article outlines explicitly how community engagement can contribute to ethical global health research by complementing existing established requirements such as informed consent and independent ethics review. The overarching and interlinked areas are (1) respecting individuals, communities and stakeholders; (2) building trust and social relationships; (3) determining appropriate benefits; minimizing risks, burdens and exploitation; (4) supporting the consent process; (5) understanding vulnerabilities and researcher obligations; (6) gaining permissions, approvals and building legitimacy and (7) achieving recruitment and retention targets. Engagement therefore denotes a wide variety of activities, such as patient and public involvement events (e.g. science cafes events), consultation regarding study activities through community advisory boards . Informing and explaining a study to communities requires providing information about the researcher, the research institutions, the study concept and rationale in appropriate formats involved health care can help to build institutional trust providing potential participants with adequate information about the proposed study; (2) potential participants understanding what is proposed and (3) participants being able to make a voluntary decision to participate , Although community engagement can help identify specific vulnerabilities, there can be inadvertent consequences of community engagement that are difficult to reconcile with the limits of the protocol Lavery, . CommuniWhen seeking formal permissions, approvals and building legitimacy, focused and in-depth engagement is needed. One option is a deliberative approach that entails reaching a consensus while acknowledging differing views respecting individuals, communities and stakeholders; (2) building trust and social relationships; (3) determining appropriate benefits; minimizing risks, burdens and exploitation; (4) supporting the consent process; (5) understanding vulnerabilities and researcher obligations; (6) gaining permissions, approvals and building legitimacy and (7) achieving recruitment and retention targets."} +{"text": "In January 2016, highly pathogenic avian influenza (HPAI) A(H7N8) virus and low pathogenicity avian influenza (LPAI) A(H7N8) virus were detected in commercial turkey flocks in Dubois County, Indiana. The Indiana State Department of Health (ISDH) and the Dubois County Health Department (DCHD) coordinated the public health response to this outbreak, which was the first detection of HPAI A(H7N8) in any species ( On January 15, 2016, ISDH was notified by the Indiana State Board of Animal Health that HPAI A(H7N8) virus had been confirmed in a commercial turkey flock in Dubois County, Indiana. In accordance with USDA guidelines (ISDH and DCHD recommended that responders be monitored during the response and for 10 days after their last possible exposures for influenza-like illness (ILI), defined as either 1) self-reported fever with cough or sore throat, or 2) conjunctivitis with or without additional symptoms. All responders received instructions to seek medical attention and contact public health authorities if they developed ILI during the 10-day period. USDA monitored federal employees, contractors, and subcontractors who participated in the response. ISDH and DCHD monitored state and local responders, using adapted, unpublished USDA/CDC public health monitoring procedures for HPAI A(H5) that were first circulated in September 2015 and later updated in November 2015. Responders were classified into three risk categories: 1) no risk, 2) low but not zero risk, and 3) some risk. Responders with low but not zero risk were those exposed to infected or potentially infected birds or their environments while using appropriate personal protective equipment (PPE) were monitored for some risk exposures, 67 (40%) were monitored for low but not zero risk exposures, four (2%) were monitored with no risk status recorded, seven (4%) had no exposure, five (3%) declined to be monitored, and nine (5%) were lost to follow-up. Among the 145 persons who were monitored, 14 (10%) reported current or recent ILI symptoms, 12 (86%) of whom were tested during January 16\u201322, 2016, with a median of 1 day from onset to medical evaluation. Nine patients had nasopharyngeal/oropharyngeal specimens collected, one had a conjunctival specimen collected, and two had both types of specimens collected. Specimens were tested for influenza A virus by real-time reverse transcription\u2013polymerase chain reaction at the ISDH Laboratories; all 12 patients tested negative for influenza A virus.On January 15, 2016, Indiana activated its Emergency Operations Center with staffing consistent with the Federal Emergency Management Agency Emergency Support Functions (ESFs) appropriate to the response .ISDH\u2019s major actions during the public health response included developing a demobilization packet for responders, issuing a Health Alert Network advisory to Dubois County and surrounding counties with recommendations for health care providers, establishing syndromic surveillance queries in the Indiana Public Health Emergency Surveillance System to detect community-acquired cases, and developing recommendations for the use of antivirals.Public health monitoring procedures for H7N8 responders were successfully implemented during this outbreak; no cases of zoonotic avian influenza infection were detected. The risk for zoonotic transmission in this outbreak was thought to be low at the time. No human infections with influenza A(H7N8) viruses had ever been reported,The unpublished USDA/CDC public health monitoring procedures that were adapted for use in this outbreak were developed for responders to an HPAI A(H5) outbreak. HPAI and LPAI are differentiated based on genetic features and the extent to which these viruses produce morbidity and mortality in poultry . The updated plan will allow for passive monitoring of persons wearing PPE and responding to certain influenza A H5 and H7 viruses that have caused outbreaks in the United States but have no history of causing human infections . The updated plan will also cover all avian influenza viruses of public health concern, including both HPAI and LPAI viruses.Several challenges to human health monitoring were identified during this outbreak. First, receipt of contact information for responders by the local health department was delayed in the initial stages because of the urgency and complexity of the animal health response. Complete information for exposed responders was not received by DCHD until 5 days into the response (on January 20), although preliminary information was provided earlier. Second, tears in Tyvek suits were reportedly common because of the nature of animal handling activities; this could have resulted in misclassification of disease exposure risk. Finally, mobilization of a large number of responders within a short period raised concerns that PPE and monitoring recommendations were not being implemented consistently.Enhanced communication and information sharing among local, state, and federal agencies would improve identification of exposed persons and coordination of specimen collection, testing, and medical care for ill responders. This could be accomplished by 1) effectively communicating public health needs and recommendations to all stakeholders in the response; 2) identifying processes for early identification of exposed persons ; 3) designating a local/state/federal public health department liaison to be embedded in the unified command post to facilitate coordinated implementation of human health monitoring, including obtaining names and contact information for responders; and 4) conducting daily debriefings with safety officers in the incident command system to identify injuries or breaches in PPE that could elevate responder risk. In future outbreaks, ISDH will also recommend that responders to outbreaks of AI viruses of public health concern entering the exclusion zone (hot zone) and contamination reduction zone (warm zone) in infected premises (Prolonged or close contact with birds infected with avian influenza (AI) virus increases the risk for zoonotic infection in humans. Monitoring exposed persons for 10 days might facilitate early detection and reporting of zoonotic AI.Monitoring procedures for highly pathogenic AI (HPAI) responders were successfully implemented during a 2016 outbreak of HPAI A(H7N8) in commercial turkey flocks in Indiana. No human cases of AI were identified.Collaboration among local, state, and federal partners is essential during AI outbreak responses. Monitoring should be considered for all responders who had contact with infected birds or their environments, regardless of whether personal protective equipment was worn."} +{"text": "In November 2011, a government hospital physician in Shibganj sub-district of Bangladesh reported a cluster of patients with fever and joint pain or rash. A multi-disciplinary team investigated to characterize the outbreak; confirm the cause; and recommend control and prevention measures.Shibganj's residents with new onset of fever and joint pain or rash between 1 September and 15 December 2011 were defined as chikungunya fever (CHIKF) suspect cases. To estimate the attack rate, we identified 16 outpatient clinics in 16 selected wards across 16 unions in Shibganj and searched for suspect cases in the 80 households nearest to each outpatient clinic. One suspect case from the first 30 households in each ward was invited to visit the nearest outpatient clinic for clinical assessment and to provide a blood sample for laboratory testing and analyses.We identified 1,769 CHIKF suspect cases from among 5,902 residents surveyed (30%). Their median age was 28 (IQR:15\u221242) years. The average attack rate in the sub-district was 30% (95% CI: 27%\u221233%). The lowest attack rate was found in children <5 years (15%). Anti-CHIKV IgM antibodies were detected by ELISA in 78% (264) of the 338 case samples tested. In addition to fever, predominant symptoms of serologically-confirmed cases included joint pain (97%), weakness (54%), myalgia (47%), rash (42%), itching (37%) and malaise (31%). Among the sero-positive patients, 79% (209/264) sought healthcare from outpatient clinics. CHIKV was isolated from two cases and phylogenetic analyses of full genome sequences placed these viruses within the Indian Ocean Lineage (IOL). Molecular analysis identified mutations in E2 and E1 glycoproteins and contained the E1 A226V point mutation.The consistently high attack rate by age groups suggested recent introduction of chikungunya in this community. Mosquito control efforts should be enhanced to reduce the risk of continued transmission and to improve global health security. Togaviridae family, have been reported from several countries in Africa, Asia and the Western Pacific since 1952.[Aedes aegypti and Aedes albopictus mosquitoes are the two primary vectors transmitting CHIKV to humans.[Epidemics of chikungunya fever (CHIKF) caused by chikungunya virus (CHIKV), a mosquito-transmitted alpha virus of the nce 1952. Large ounce 1952.\u201312 Aedeso humans. Classicao humans.\u201316 Howevo humans., 17\u201319 Fo humans.\u201330During December 2008, CHIKV infection was confirmed for the first time in Bangladesh. The outbOn 5 November 2011, the primary healthcare physician managing the government hospital in Shibganj sub-district of Chapainababganj district in northwestern Bangladesh reported a cluster of 19 patients with fever, severe joint pain and/or rash to the Institute of Epidemiology, Disease Control and Research (IEDCR) of the Ministry of Health and Family Welfare. In response, a collaborative, multi-disciplinary investigation team from IEDCR and icddr,b conducted an investigation to (i) characterize the outbreak in terms of person, place and time; (ii) confirm the cause; and (iii) identify prevention and control approaches for future outbreaks.The team visited the hospital in the affected sub-district and conducted unstructured interviews with local healthcare providers, including physicians and field workers, to collect preliminary information about the clinical features, laboratory findings, and geographical distribution of affected patients. Based on these interviews, the experience of a similar outbreak in 2008, and giveGiven the lack of information regarding the prevalence of chikungunya fever from Bangladesh during the investigation period in 2011 and because the preliminary survey findings suggested a widespread distribution of suspect cases, the investigation team conducted a house-to-house syndromic survey in all of the 16 unions of Shibganj to calculate the attack rate. Using the attack rate of 34% as observed during the preliminary survey and assuming a type 1 error of 0.05, a precision of 5%, an average of 5 persons per household, a design effect of 3.0 to take into account the cluster sampling design and a non-response rate of 20% at the household level, we calculated a required sample size of at least 1,280 households from the 16 unions of Shibganj for the syndromic survey. In each To obtain clinical histories and collect biological specimens, data collectors invited one suspect case from each of the first 30 households visited in each ward to come to the nearest primary healthcare clinic to complete a clinical assessment and to provide a blood sample for testing. If a household had more than one eligible respondent, the data collectors requested the eldest household member present during the survey to select one resident for participation. Physicians on the team later interviewed and physically examined suspect cases who came to the local clinics.To test for IgM antibodies to CHIKV, trained phlebotomists collected 5 ml venous blood from each suspect case who had presented to the clinic and consented to participate. Phlebotomists stored all blood samples immediately after collection at 4\u22128\u00b0C. The samples were centrifuged on the same day and the sera were stored in the local hospital refrigerator and later transported in cool boxes to the Virology Laboratory of IEDCR. At IEDCR, each serum sample was divided into three aliquots before storing at -70\u00b0C until testing. At the beginning of the investigation, we only had 300 rapid test kits available, so we tested 300 randomly selected samples out of the 367 sera. We tested 338 randomly selected aliquots out of the 367 samples for anti-CHIKV immunoglobulin M (IgM) antibodies using an enzyme-linked immunosorbent assay (ELISA) test kit that was also available with our group during the investigation in the Virology Laboratory of IEDCR following the manufacturer\u2019s guidelines.Acute sera that had been collected from suspect cases within two days of illness onset and tested negative for IgM antibodies to CHIKV were later tested for viral RNA using quantitative reverse transcription polymerase chain reaction (RT-qPCR). The seraPhylogenetic analysis was performed as previously described. ChikunguAedes aegypti bred mainly in the water collected in artificial containers in the environment of human settlements in Asia,[Aedes albopictus bred predominantly in natural containers including coconut shells, leaf axils and tree holes, team entomologists looked for mosquito larvae in both man-made and natural water containers.[The entomological investigation was conducted during December 15\u221231, 2011 and focused on identifying vector species. Given that in Asia, while Aentainers. To collentainers.We divided the total number of suspect cases by the total number of household residents surveyed in each cluster ward within each union composed of the 80 households nearest to an outpatient clinic in the ward to calculate the attack rates by cluster. We estimated the attack rate within the sub-district by calculating the mean of attack rates for the 16 clusters combined. We also calculated the attack rates by 5-year age groups and gender. We used the number of suspect cases instead of confirmed cases to estimate the attack rate because we only collected and tested the serum samples from a sub-set of suspect cases who later came to clinics for clinical assessment and sample provision. For the sub-set of patients who came to the clinics for clinical evaluation, we described their clinical features. Since many respondents were still symptomatic during the clinical survey, we estimated the median follow-up time from symptom onset till recovery for each of the four symptoms including joint pain, joint swelling, debilitating weakness and severe myalgia. Previous authors have suggested that length of follow-up time should be extracted from the time frame where the Kaplan Meier estimate was most stable. We consiThe Institutional Review Board (IRB) of IEDCR and the Ethical Review Committee (ERC) of icddr,b considers outbreak investigations that primarily aim to control outbreaks as public health practice and approval by research ethics committee is not required. This is in line with national and international ethical guidelines including the 1991 International Guidelines for Ethical Review of Epidemiological Studies by the Council for International Organizations of Medical Sciences.\u201349 SeverWe obtained informed oral consent for voluntary participation from adults and verbal assent from children. Past experience of research in similar settings suggested that obtaining written informed consent was difficult, time consuming and resource-intensive when dealing with illiterate participants who were often very cautious, as they did not know what they were signing or whether the signed document could be used against them. As a result, verbal informed consent procedure was allowed during this emergency outbreak situation, where the majority of the affected population were illiterate and ill, as obtaining written informed consent was considered unnecessary and not in the patient and community\u2019s best interest. The investigation team member who was informing a participant signed a form stating that the appropriate information was provided and verbal consent received before beginning any information and/or sample collection or any kind of investigation.The team identified 30 suspect cases from the hospital initially. These cases resided in six different unions within Shibganj. Their median age was 35 years and 45% were males. Fever (100%), polyarthralgia (90%), malaise (83%), severe weakness (66%), rash (48%), itching (38%), and headache (35%) were the predominant symptoms. Forty percent (12/30) of these patients had evidence of IgM CHIKV antibodies in their sera when tested using the rapid assay.We surveyed a total of 5,902 individuals from 1,283 households in the 16 unions of Shibganj. Of these, 1,769 (30%) met the suspect case definition. The median age of suspect cases was 28 (IQR:15\u221242) years. The average attack rate in the sub-district was 30% (95% CI: 27%\u221233%). Attack rates varied from 10%\u221244% across the 16 selected clusters within the 16 unions of Shibganj . The meaAmong the 1,769 suspect cases, 480 (27%) were invited to participate in the clinical survey and to provide blood samples. Seventy-nine percent (377/480) of the invited suspect cases gave consent for the clinical survey and physical examination, and 367 (77%) provided a blood sample. Among the serum samples tested with the rapid test, 73% were positive for chikungunya whereas IgM anti-CHIKV antibodies were detected in 78% (264/338) of the samples that were tested by ELISA. We found that the suspect cases tested within one week of illness onset (43%) were less likely to have IgM antibodies against Chikungunya compared to the suspect cases tested more than 60 days post illness onset (98%) .Among the 377 cases interviewed during the clinical survey, the median age was 40 years (IQR:30\u221250 years); 64% (241/377) were females; and 92% (347/377) were Muslims. The main clinical symptoms included fever (100%), joint pain (88%), debilitating weakness preventing routine activities (55%), rash (51%), severe myalgia (44%), itching (33%) and joint swelling (16%) . Thirty-In addition to fever, the predominant symptoms of serologically-confirmed cases (n = 264) among those who had provided sera after coming to the clinic included joint pain (97%), weakness (54%), myalgia (47%), rash (42%), itching (37%) and malaise (31%). The rashes were found on the trunk (36%), lower limbs (36%), palms and soles (33%), upper limbs in (14%), and face (8%). Of those who developed joint pain, 93% (238/256) reported pain in multiple joints and joints of the lower limbs were involved in 90% (230/256) of the cases. Among the cases reporting joint pain, severe pain that prevented sleep was reported by 61% (156/256), moderate pain that caused pain on movement was reported by 23% (59/256) and minor pain that did not interfere with daily activities but caused discomfort was reported by 17% (43/256). Severe weakness was reported by 40% (105/264), debilitating myalgia by 36% (94/264) and severe joint swelling by 14% (37/264). On examination, team physicians found restricted joint mobility in 23% (59/256) of the serologically confirmed cases. The rashes were maculopapular in 62% (69/112), macular in 33% (37/112) and popular in 5% (6/112) of the suspect cases with rashes. The median durations of symptom persistence of joint pain was 31 days, while joint swelling persisted for 7 days, debilitating weakness and severe myalgia, each persisted for about 12 days in the majority of this sub-set of confirmed cases . FurtherTwo out of the four patients from this outbreak in Shibganj and the single patient from the concurrent outbreak in Dohar sub-district of Dhaka whose acute sera were collected within two days of illness onset had detectable Chikungunya virus RNA with RT-qPCR. However, none of them had IgM antibodies in their sera. The three viral isolates, obtained from the two outbreaks including this outbreak in Shibganj (n = 2) and in Dohar (n = 1), clustered with strains from the 2006 Indian Ocean lineage and were most closely related to the Indian/Asian geographic isolates rather than the African isolates within that lineage . The sizAedes aegypti or Aedes albopictus mosquitoes during the investigation. The team found mosquito larva from only 1/160 households surveyed and the larvae that hatched from this household in IEDCR\u2019s Entomology laboratory yielded Culex quinquefaciatus species.The team did not find any larvae of Aedes aegypti or Aedes albopictus mosquitoes during the investigation.We identified CHIKF suspect cases among 30% of the residents surveyed across the 16 unions in Shibganj during the syndromic survey. The median age of suspect cases was 28 years. The lowest attack rate was found in children <5 years (15%). Anti-chikungunya virus (CHIKV) IgM antibodies were detected by an enzyme-linked immunosorbent assay (ELISA) in 78% of the case samples tested. In addition to fever, the predominant symptoms of serologically-confirmed cases, included joint pain (97%), weakness (54%), myalgia (47%), rash (42%), itching (37%) and malaise (31%). The median durations of symptom persistence of severe joint pain was 31 days, while severe joint swelling persisted for 7 days, debilitating weakness and severe myalgia, each persisted for about 12 days in the majority of this sub-set of confirmed cases. Among the sero-positive patients, 79% sought healthcare from outpatient clinics. CHIKV was isolated from two cases and phylogenetic analyses of full genome sequences placed these viruses within the Indian Ocean Lineage (IOL). Molecular analysis identified mutations in E2 and E1 glycoproteins and contained the E1 A226V point mutation. We did not find any larvae of The clinical syndrome of fever, multiple joint pain, with or without debilitating weakness or severe myalgia was consistent with previous CHIKF outbreaks., 5, 33 TThough several outbreaks have reported an increased propensity to cause clinical illness among females, our syndAedes albopictus larvae breeding in the numerous wet earthen and clay pots that were used for pottery.[Aedes mosquito from the affected area, a finding quite inconsistent with past outbreaks. The delayed reporting of the outbreak with the consequent delay in conducting the investigation during the dry winter months of November and December possibly prevented us from detecting the vector. Given the role of environmental variables on Aedes albopictus and on the pathogen transmissibility, we believe that transmission likely stopped due to changes in weather that constrained Aedes mosquito populations during this outbreak.[Aedes larvae by December, and other outbreaks in Bangladesh have also stopped abruptly around the months of November and December.[Aedes albopictus species.[Aedes albopictus were most likely responsible for transmission,[The first recognized outbreak in Chapainababganj district in 2008 predominantly affected Hindu potters and had limited geographic spread. The outbreak was reportedly precipitated by the high concentration of pottery. During t pottery., 14, 56 pottery., 33 despoutbreak., 58 We wDecember., 33, 34 species. Another A major limitation of our investigation was that the suspect cases that presented for clinical assessment and blood collection were unlikely representative of the entire affected population. We expect that cases with severe and/or persistent symptoms were more likely to come to the clinic compared to milder cases or patients who had recovered, so our clinical descriptions of serologically confirmed cases were likely biased towards severe presentations. However, since almost half of the cases had already recovered from clinical illness during the clinical survey, we also captured some less serious disease. Given that an evaluation of the sensitivity and specificity of clinical criteria for CHIKV infection identified the syndrome combining fever and polyarthralgias to allow for the correct classification of 87% of those who had serologically confirmed CHIKV infections, our caseAedes populations.Though no recent community seroprevalence study of CHIKV has been published from Bangladesh, a post outbreak sero-survey conducted in selected outbreak affected communities under publication by the author group as well as a 1995 cross-sectional survey carried out in the neighbouring city of Calcutta, India indicated that the level of previous exposure to Chikungunya infection in the country remained low. FurthermAedes mosquitoes in the future may help provide important insight into emergence of epidemic strains in Bangladesh. Effective mosquito control using a comprehensive and integrated pest management approach targeted at every life stage of a mosquito could reduce the risk of CHIKV dissemination.[Population-based seroprevalence and risk factor surveys could help describe the true extent of previous circulation of this virus and identify factors that might put some communities at higher risk than others for outbreaks. Molecular clock analyses and monitoring the spread of genotype viruses and the proportion of the mination., 13 To eS1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 Fig(DOCX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.S1 Dataset(SAV)Click here for additional data file.S2 Dataset(SAV)Click here for additional data file.S3 Dataset(SAV)Click here for additional data file."} +{"text": "Exploring the natural occurring genetic variation of the wild barley genepool has become a major target of barley crop breeding programmes aiming to increase crop productivity and sustainability in global climate change scenarios. However this diversity remains unexploited and effective approaches are required to investigate the benefits that unadapted genomes could bring to crop improved resilience. In the present study, a set of Recombinant Chromosome Substitution Lines (RCSLs) derived from an elite barley cultivar \u2018Harrington\u2019 as the recurrent parent, and a wild barley accession from the Fertile Crescent \u2018Caesarea 26\u201324\u2019, as the donor parent have been utilised in field and controlled conditions to examine the contribution of wild barley genome as a source of novel allelic variation for the cultivated barley genepool.Twenty-eight RCSLs which were selected to represent the entire genome of the wild barley accession, were genotyped using the 9\u2009K iSelect SNP markers and phenotyped for a range of morphological, developmental and agronomic traits in 2 years using a rain-out shelter with four replicates and three water treatments. Data were analysed for marker traits associations using a mixed model approach.We identified lines that differ significantly from the elite parent for both qualitative and quantitative traits across growing seasons and water regimes. The detailed genotypic characterisation of the lines for over 1800 polymorphic SNP markers and the design of a mixed model analysis identified chromosomal regions associated with yield related traits where the wild barley allele had a positive response increasing grain weight and size. In addition, variation for qualitative characters, such as the presence of cuticle waxes on the developing spikes, was associated with the wild barley introgressions. Despite the coarse location of the QTLs, interesting candidate genes for the major marker-trait associations were identified using the recently released barley genome assembly.This study has highlighted the role of exotic germplasm to contribute novel allelic variation by using an optimised experimental approach focused on an exotic genetic library. The results obtained constitute a step forward to the development of more tolerant and resilient varieties.The online version of this article (10.1186/s12870-018-1527-7) contains supplementary material, which is available to authorized users. Breeding programmes have successfully increased yield and quality traits of major cereals including barley , 2. HoweHordeum are preserved in gene banks worldwide, second only to rice and wheat (FAO 2010) and provide an enormous potential resource for allele mining. There have been many descriptive and comparative studies examining diversity in wild and landrace barleys, but few examples utilising the allelic diversity have been reported ) and the recurrent parent ([Hv]) alleles obtained for the significant peak region were used to calculate the relative contribution (RP) of the exotic parent alleles on the trait performance as follows:The Best Linear Unbiased Estimates (BLUEs) for each trait for the donor ([2) were used to identify possible putative candidate genes underlying the predicted phenotypic variation. In this case the number of genes in the targeted regions was first estimated by looking at the physical position of the iSelect SNP markers in the newly released barley genome assembly [The position of major determinant genes related to plant phenology and morphology was estimated from previous studies and public gene databases to support the results obtained from this analysis. Additionally, some genomic regions accounting for a significantly large proportion of a trait\u2019s variance of the k-th principal component axis, \u03b3ik and \u03b4jk are the genotype and the environment scores (eigenvectors) for the k-th principal component axis, \u03c1ij is the interaction residual and \u03b5ijk is the random error.Values for yield (DY) and grain weight (TGW) for each of the RCSLs were used to investigate the effect of the exotic genome in the performance and stability of the crop across the environmental conditions imposed in the field. Genotype by environment (GE) interaction was studied by means of an additive main effects and multiplicative interaction model (AMMI) for which six environments were defined as the combination of growing season and water treatment. Using this method, the overall variation observed for yield traits such as dry yield and thousand grain weight was partitioned into genotype main effects, environment main effects and GE interaction . The modAs a result, the interaction principal components generated (IPCA1 and IPCA2) are used to graphically summarise (biplots) the GE variation observed. The AMMI2 biplot uses the genotypes and environments scores for the first two IPCA components (IPCA1 on the X-axes and IPCA2 on the Y-axes) giving information about the GE patterns observed. Genotypes with IPCA scores close to zero are more stable or widely adapted to the tested environments whereas specific adaptation of the genotypes is determined by the length of the orthogonal projection of the genotype points onto the environmental vectors. In addition, the AMMI1 biplot tests the genotypes yield potential and stability simultaneously by plotting in the same diagram the average yields (X-axes) and the first dimension measure of GE interaction (IPCA1) for both genotypes and environments (Y-axes). AMMI model was computed using Genstat 17 .Additional file 1:Table S1. RCSLs genotypes determined for 1848 SNP markers from the 9\u2009K SNP chip for barley [r barley . 2013 and (B) 2014. Accumulated rainfall (mm) values per week (x axes), air maximum and minimum average temperature values per week (\u00b1 SE). Data obtained from James Hutton Institute weather station . Field trials were established in the week 16 both years. (DOCX 28\u2009kb)Additional file 3:Figure S2. Volumetric water content (ml\u2009cm\u2212\u20093) in the soil profile at (A) 100\u2009mm, (B) 200\u2009mm, (C) 300\u2009mm and (D) 400\u2009mm depth in the full irrigated (blue), partial irrigated (green), and drought (red) water treatment in 2013 (left) and 2014 (right) field trials. Vertical dashed lines indicate beginning and end of heading time referred to days after sowing (DAS) for year. Error bars indicate standard error of the mean. (DOCX 258\u2009kb)Additional file 4:Table S2. Climate data before sowing, during seedling establishment, before heading and during heading in the 2013 and 2014 growing seasons. Air and soil mean temperature values (\u00b1 SE) and accumulated rainfall (mm) values obtained from the James Hutton Institute weather station . (DOCX 15\u2009kb)Additional file 5:Table S3. Genotypic mean values (\u00b1 SE) for the morphological, developmental and agronomic traits registered in 2013 and 2014 field trials. Genotypes are arranged in ascending order from top to bottom of the table for collar height (COL), peduncle length (PdL), ear length (EAR), seed area (SdA), seed length (SdL), seed width (SdW), heading date (HEA), number of tillers (TILL), dry yield (DY), thousand grain weight (TGW), biomass yield (BY) and harvest index (HI). Best linear unbiased estimators (BLUEs) for genotypes labelled with different letters differ significantly . Harrington mean values highlighted in bold. (XLSX 20\u2009kb)Additional file 6:Table S4. Significant quantitative trait locus (QTLs) detected on the RCSLs exotic genetic library associated with thirteen morphological, developmental and agronomic traits. One trait per tab. (XLSX 167\u2009kb)"} +{"text": "Scientific Reports 10.1038/s41598-019-48007-5, published online 16 August 2019Correction to: The Acknowledgements section in this Article is incomplete.\u201cThe authors thank Rothamsted Research (BBS/E/C/000J0100) for hosting animal work; Hannah Fleming, Bruce Griffith and Simon White for excellent support and animal care during sample collection periods (Rothamsted Research); the late Robert Orr for initial contributions towards study conceptualisation and extensive knowledge of the North Wyke Farm Platform operations (Rothamsted Research); Debbie Langton for sequencing support (University of Bristol). The authors acknowledge the support from the NIHR Health Protection Research Unit in Evaluation of Interventions at University of Bristol.\u201dshould read:\u201cThis work was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) under an Industrial Case Studentship (BB/J012483/1). The authors thank Rothamsted Research (BBS/E/C/000J0100) for hosting animal work; Hannah Fleming, Bruce Griffith and Simon White for excellent support and animal care during sample collection periods (Rothamsted Research); the late Robert Orr for initial contributions towards study conceptualisation and extensive knowledge of the North Wyke Farm Platform operations (Rothamsted Research); Debbie Langton for sequencing support (University of Bristol). The authors acknowledge the support from the NIHR Health Protection Research Unit in Evaluation of Interventions at University of Bristol.\u201dIn addition, this Article contains ambiguous wording in the Results section, under subheading \u2018Duration of carriage and hazard of clearance\u2019. To clarify the findings, the following text should be disregarded:\u201cthese trends were non-linear with categories 2 and 4 associated with a longer duration (lower hazard) compared to category 3, and category 4 (highest density) associated with the longest subsequent carriage duration (Table 3).\u201d"} +{"text": "Korean grandparents raising their grandchildren play significant roles as social and family resources in Korea. They experience caregiving stress that negatively influences their mental health while struggling with limited social support from peers, and minimal respite care and community resources. Despite a need for resources and information concerning this growing population, there is limited knowledge on Korean custodial grandparents, especially the distinctive cultural factors influencing their multigenerational caregiving experiences. This qualitative study explored Korean custodial grandparents\u2019 experiences of raising grandchildren and cultural meanings of multigenerational caregiving. Using a phenomenological approach, semi-structured interviews with 23 custodial grandparents were conducted from December 2018- January 2019 in two urban and three rural places in Korea. Among the grandparents, five were grandfathers. The mean age of the grandparents was 72 years old (range: 61-82), and the mean age of their grandchildren was 13 years old (range: 1-21). On average, the grandparents had raised 1.5 grandchildren (range: 1-3) for 11 years (range: 1.5-20). Four key themes emerged from the general structure of the lived experiences of Korean grandparents: a) intensive child care support from the grandchildren\u2019s uncle and aunt; (b) stigma of a child\u2019s divorce and custodial grandparenting; (c) different social expectations toward maternal grandparents; and (d) increased needs on financial educational support for grandchildren. The finding reinforces the significant function of collectivistic and family-based Asian culture in understanding experiences of Korean custodial grandparents. It also highlights society\u2019s view of only men carrying forward family lineage and its implications on grandparents\u2019 perceptions about multigenerational caregiving."} +{"text": "Hypertrophic cardiomyopathy (HCM) is a common genetic diseases with prevalence of 1 in 200-500 in general population, and it can result in sudden cardiac death (SCD) . FurtherIn our recent study, we sought to address this knowledge gap by evaluating cardiac Magnetic resonance (CMR) in 1423 HCM patients with preserved EF for presence and extent of scar in the LV by late gadolinium enhancement (LGE) . Our stuIn the current AHA/ACC guidelines, CMR carries a weak recommendation (class IIB) (Level of evidence C) for use to assess presence of LGE in case of patients with inconclusive SCD risk stratification by conventional factors . Several"} +{"text": "Mutational spectra and signatures indicated a major role for APOBEC cytidine deaminases and a secondary role for ADAR adenosine deaminases in generating diversity of iVDRVs. The distributions of mutations across the genes and 3D hotspots for amino acid substitutions in the E1 glycoprotein identified regions that may be under positive selective pressure. Quasispecies diversity was higher in granulomas than in recovered infectious iVDRVs. Growth properties of iVDRVs were assessed in WI-38 fibroblast cultures. None of the iVDRV isolates showed complete reversion to wild type phenotype but the replicative and persistence characteristics of iVDRVs were different from those of the RA27/3 vaccine strain, making predictions of iVDRV transmissibility and teratogenicity difficult. However, detection of iVDRV RNA in nasopharyngeal specimen and poor neutralization of some iVDRV strains by sera from vaccinated persons suggests possible public health risks associated with iVDRV carriers. Detection of IgM antibody to RV in sera of two out of three patients may be a marker of virus persistence, potentially useful for identifying patients with iVDRV before development of lesions. Studies of the evolutionary dynamics of iVDRV during persistence will contribute to development of infection control strategies and antiviral therapies.Rubella viruses (RV) have been found in an association with granulomas in children with primary immune deficiencies (PID). Here, we report the recovery and characterization of infectious immunodeficiency-related vaccine-derived rubella viruses (iVDRV) from diagnostic skin biopsies of four patients. Sequence evolution within PID hosts was studied by comparison of the complete genomic sequences of the iVDRVs with the genome of the vaccine virus RA27/3. The degree of divergence of each iVDRV correlated with the duration of persistence indicating continuous intrahost evolution. The evolution rates for synonymous and nonsynonymous substitutions were estimated to be 5.7 x 10 Primary immunodeficiency diseases (PID) are caused by genetic defects and lead to serious problems including chronic granulomas of inflammatory cells), sometimes lasting for decades and sometimes leading to severe ulcers. Initial reports (2014\u20132016), including our report of a blinded study using ultrasensitive virus detection in biopsies, proved the association between granuloma of the skin in PID patients and rubella virus. The viruses in these reports and the current report were derived from a widely used vaccine strain of the rubella virus. Work reported here shows that these vaccine-derived viruses are biologically different from the vaccine virus and that their genomes have changed. Genomic changes could be analyzed largely because the exact sequence of starting vaccine virus genome was known. These genomic differences are likely generated via mechanisms similar to those occurring during normal circulation of wild type rubella. We present data that newly recognized mechanisms for generation of sequence diversity in viruses (because of cellular deaminases) likely occurs in the generation of these vaccine-derived rubella viruses. Thousands of PID patients in the United States are likely shedding these vaccine-derived rubella viruses. Our work presented here characterizing viruses in diagnostic specimens highlights at least two areas where insufficient work has been done: 1) research on the properties of rubella virus (limited understanding of the antibody binding sites on the virus); 2) controlled research studies to assess the public health impact of viruses in populations with high immunity. Rubivirus genus, which has been recently moved from the Togaviridae to a new family, Matonaviridae [76 [7674] . Brieflyrrection .An 904-nt fragment of the E1 gene (nt 8672\u20139577 in the RV genome) was amplified from RNA isolated from a clinical sample or viral stock using the RV genotyping primers and PlatComplete sequences of iVDRV genomes have been deposited in the NCBI database under accession numbers MK787188\u2014MK787191 and MK780807- MK780812.http://accelrys.com/products/collaborative-science/biovia-discovery-studio/visualization.html; Accelrys Inc., CA).The structures of the rubella E1 protein were used as templates for computer modeling. The mutations were modeled as described earlier using the software package ECMMS for molecular mechanics modeling , 84. TheECau, Enrichment for uCa mutation signature is:We first created the list of 993 (out of 1074) mutations, in which ambiguous nucleotides were excluded from the analysis . These mMutCau\u2212counts of mutations in cytosines falling into uCa motif of the positive strand in a virus isolateConCau\u2212counts of uCa trinucleotide motifs in all 41 nucleotide sequences of the positive strand centered around the mutated positive strand cytosine basesMutC\u2212counts of mutations in cytosines of the positive strand in a virus isolateConC\u2212counts of C nucleotides in all 41 nucleotide sequences of the positive strand centered around the mutated positive strand cytosine bases.http://hci-bio-app.hci.utah.edu:8081/Bass/InosinePredict) and [Unlike the exquisitely specific to single stranded RNA and DNA APOBEC cytidine deaminases, ADARs act on adenines imbedded into double stranded RNA folds, so prediction of ADAR deamination sites should account for combination of knowledge about experimentally defined short nucleotide motifs and a potential to form double stranded structure. The prediction scores for ADAR activity on adenines were generated using the web-based tool InosinePredict (ict) and . A one-sS1 FigDouble immunofluorescent staining of granulomas with M2 macrophage-specific antibodies, CD206 (green), and either RV capsid antibody (Abcam) (red) or measles (MeV) nucleoprotein antibody 83KKII (Millipore) was performed as described in Methods. Nuclei were counterstained with DAPI. Note strong staining for RV antigen and the lack of staining for measles antigen.(TIF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S1 DataSequences are shown in DNA format (T instead of U) to maintain compatibility with other outputs of mutation signature R-script.(XLSX)Click here for additional data file.S2 DataThe alignment was prepared with Mega7.(MASX)Click here for additional data file.S3 DataThe alignment was prepared with Mega7.(MASX)Click here for additional data file.S4 DataGenetic distances was computed using the Maximum Composite Likelihood method with Mega7.(XLSX)Click here for additional data file.S5 DataData for each gene are located in a separate sheet.(XLSX)Click here for additional data file.S6 Data(XLSX)Click here for additional data file."} +{"text": "During the workshop, results from a systematic evidence review prepared by an Agency for Healthcare Research and Quality Evidence-based Practice Center to inform the workshop were presented, focusing on long term osteoporosis drug treatment. This talk will describe the goals of the systematic review, which addressed four questions: (1) What are the effects of long-term (>3 years) osteoporosis drug treatment versus control on risks of incident fractures and harms; (2) Do effects of long-term osteoporosis drug treatment vary as a function of patient, bone, or osteoporosis drug characteristics; (3) Among individuals receiving osteoporosis drug treatment to prevent fracture, what are the benefits and harms of continuing versus discontinuing treatment ; and (4) Do outcomes of drug discontinuation or drug holidays vary as a function of patient, bone, or osteoporosis drug characteristics?"} +{"text": "Women continue to have higher prevalence rates of functional impairment and depressive symptoms than men. In addition, women from certain ethnic groups experience disproportionately higher rates of ADL limitation, and are less likely to be screened for depression. The current study examines the association between race/ethnicity and depressive symptoms on functional limitations in Black, White and Hispanic women. We examined prevalence and adjusted odds of ADL limitations by race in n=9,846 women aged 50+ with low (CESD <4) and high (CESD =>4) depressive symptoms from the 2014 wave of the Health and Retirement Study. Overall, Black and Hispanic women had significantly higher rates of depression (p <.001) and ADL limitations (p<.001) than White women. Among those with high depressive symptoms, Black OR 1.98 and Hispanic OR 2.82 women have significantly higher rates of ADL limitations as compared to White women."} +{"text": "The application of image processing techniques for the analysis of CT scan images corresponding to lung cancer cells is gaining momentumin recent years. Therefore, it is of interest to discuss the use of a Computer-Aided Diagnosis (CAD) system using Computed Tomography(CT) images to help in the early diagnosis of lung cancer . We discuss and explorethe design and significance of a CAD-CT image processed model in cancer diagnosis. Small cell lung cancer and non-small cell lung cancer are commontypes of lung cancer . The genThe performance of Multilayer and Neural Network classifiertrained by 11 training algorithms with Independent ComponentAnalysis feature extraction is known . It is sA set of real patient CT scan images are obtained from the LungImage Database Consortium (LIDC) archive is used in this analysis.LIDC database contains lung cancer screening CT images fordevelopment, training, and evaluation of computer-assisteddiagnostic methods for lung cancer detection and diagnosis. TheNational Cancer Institute initiated it. It consists of 1018 cases ofdataset contributed by seven academic centers and eight medicalimaging companies has deveThe CAD System has the following features: (1) It improves thediagnosis accuracy; (2) Assist in cancer detection at its earlier stageand (3) Reduces the time of the radiologist in evaluation.It is of interest to develop a CT scan image processed model for theearly detection of lung cancer where (1) preprocessing usingintensity measure helps to locate small particles in an image such asnode, speculation and angular margin; (2) high detection andclassification accuracy is established; and (3) removes noises thatcreate false detection.The first step is pre-processing of the image to locate particles usingintensity measure. The processed image is segmented using astandard segmentation technique. Thus, cancer nodules are markedin the image. In addition to features like area, perimeter andeccentricity, other features like centroid, diameter and pixel meanintensity have been extracted during feature extraction. Theclassification module follows this where distinction between benignand malignant tumors based on CT scan images is established.Extracted features are used as training features and thecorresponding trained model is generated for the classificationfollowed by model evaluation for detection and classification withimproved accuracy, specificity and sensitivity.The salient features of the method includes (1) image preprocessingby using filtering techniques and it smoothes the image andremoves speckle noise; (2) It segments the cancer nodule from theCT scan image. The segmentation method separates and identifiesthe touching objects in the image. This feature helps in propersegmentation of cancer nodules when it is touching to other falsenodules. (3) Features extraction where features like area, perimeter,centroid, diameter, eccentricity and mean intensity are extractedfrom the image. These features are used as training features todevelop the classifier; and (4) The classification module classifiesthe detected nodule as malignant or benign by using the trainedclassification method.Strengths of the method includes: (1) The improved accuracy ofcancer nodule detection; (2) classifies the detected lung cancer asmalignant or benign; and (3) Removes the noises that create falsedetection of cancer.We describe and discuss the application of a Computer-AidedDiagnosis (CAD) system using Computed-Tomography (CT)images to help in the early diagnosis of lung cancer . We report a framework forthe development of a model for early cancer detection using CADCTimage analysis."} +{"text": "As we observe the 100th anniversary of the 1918 influenza pandemic, we are reminded ofthe importance of preparedness for and adequate response to influenza, and the criticalrole of influenza surveillance through laboratory detection. Influenza virus detectionhas helped drive the development of diagnostic and virology laboratories in the WorldHealth Organization (WHO) Western Pacific Region over the last 10\u201315 years, atthe same time strengthening their capacity to detect and respond to infectious threatsbeyond influenza. Such cross-cutting approaches are advocated under the Asia PacificStrategy for Emerging Diseases and Public Health Emergencies (APSED III), laboratory network. . GISRS monitoring of circulatinginfluenza viruses in humans enables timely detection and reporting of significantchanges in seasonal influenza viruses such as the emergence of the influenza A(H1N1)pandemic virus in 2009 and the rapid global spread of oseltamivir-resistant seasonalH1N1 viruses in 2007\u20132008. techniques developed in the past 25 years enabled therapid and specific detection of viral nucleic acid sequences, becoming the gold standardfor diagnosis and surveillance. Since 2004, PCR has been instrumental in the earlydetection of various zoonotic influenza viruses in humans, including A(H5N1), A(H5N6),A(H7N9), A(H9N2) and others in the Western Pacific Region. (NICs are mandated to maintain high technical capacity for influenza testing (As the majority of NICs in the Region actually test a broad range of infectious diseasesor are housed in institutions that do, the benefits of technical and human resourcestrengthening through GISRS have been crosscutting. Annual NIC meetings bring togetherexperts to discuss progress, obstacles and best practices, helping to strengthencountries\u2019 laboratory technical capacity through better coordination, a keystrategic action in APSED III. Molecular testing available in the GISRS laboratorynetwork has also formed the basis of regional preparedness for detection of emergingpathogens, including Middle East respiratory syndrome coronavirus (Since the 1918 pandemic and the later introduction of GISRS, regional NICs have beenmaintaining traditional methods, incorporating new technologies and building humanresource capacity to help strengthen preparedness and response to influenza. Thecross-cutting advantages generated and the benefits of sharing and collaboration throughGISRS contribute to better preparedness for future outbreaks of influenza and otherinfectious diseases."} +{"text": "Selective targeting of heteromers as a tool to modulate mu opioid receptor activity is therefore attracting growing interest and raises hopes for innovative therapeutic strategies.Mu opioid receptors modulate a large number of physiological functions. They are in particular involved in the control of pain perception and reward properties. They are also the primary molecular target of opioid drugs and mediate their beneficial analgesic effects, euphoric properties as well as negative side effects such as tolerance and physical dependence. Importantly, mu opioid receptors can physically associate with another receptor to form a novel entity called heteromer that exhibits specific ligand binding, signaling, and trafficking properties. As reviewed here, The mu opioid (mu) receptor is a G protein-coupled receptor (GPCR) that neuromodulates several physiological functions, in particular nociception , and/or disruption of physical contact by an interfering peptide. The use of interfering peptide and/or mice deficient for one receptor also significantly contributed to demonstrate the specificity of the functional changes associated with heteromer formation and to establish a causal link with behavioral outputs. In native tissue, the mu receptor heteromerizes with the delta opioid (delta) or kappa opioid (kappa) receptors or with the non-opioid receptors ORL1, cannabinoid CB1, galanin Gal1, adrenergic \u03b12a, somatostatin sst2, dopamine D1, chemokine CCR5, and vasopressin V1b. Association between the mu receptor splice variant MOR1D and the gastrin-releasing peptide receptor (GRPR) has also been reported as well as mu physical proximity with the ion channel NMDA is dynamically regulated and increased in hypertensive rats binding and ERK1/2 signaling in SK-N-SH neuroblastoma cells allosterically decreased dihydromorphine binding at the mu receptor in rat striatal membranes -C neuroblastoma cells co-expressing mu and ORL1 receptors, pretreatment with nociceptin decreased DAMGO potency and efficacy to inhibit adenylate cyclase system of the leucine rich motif responsible for the receptor V1B-\u03b2-arrestin interaction increased morphine-induced analgesia and reduced adenylate cyclase supersensitization and morphine-induced tolerance and physical dependence p38 activation in the mouse DRGs pathway and contributes to morphine tolerance hydrolysis inhibitor JZL184 increased the concentration of the endogenous ligand and enhanced social play behavior in adolescent rodents (Manduca et al., 1 receptors. Indeed, opiate hyperlocomotion and locomotor sensitization were abolished in dopamine D1 receptor in knock-out mice or following local injection of the D1 antagonist SCH23390 in the Nacc (Tao et al., Mu receptors are also involved in other aspects of opiate addiction such as locomotor sensitization and could achieve their modulatory control through heteromerization with dopamine DPharmacological and knock-out based studies linked an anxiogenic and depressant phenotype to mu receptor activation and, on the opposite, associated an anxiolytic and antidepressant phenotype with delta receptor activation (Lutz et al., Systemic administration or local micro-infusion in the Nacc of the delta agonist UFP512 promoted anxiolytic- and anti-depressant-like activity (Vergura et al., 2a heteromers in the NTS were correlated with increased blood pressure in hypertensive rats (Sun et al., 2a heteromerization induced by the mu agonist DAMGO was paralleled by increased blood pressure. Treatment with the mu antagonist CTAP antagonized DAMGO changes in normotensive rats and reduced mu-\u03b12a heteromerization and blood pressure in hypertensive rats (Sun et al., 2a adrenergic receptors thereby potentiating hypertension.Mu receptors are known to control autonomous functions. Higher levels of mu-\u03b1Interactions between mu and somatostatin receptors have been postulated to influence tumor cell growth (Hatzoglou et al., The bivalent ligand MDAN-21 composed of the mu agonist oxymorphone and the delta antagonist naltrindole tethered by a 21 amino acid long linker was developed to selectively target mu-delta heteromers (Daniels et al., More recently, the bivalent ligand MCC22 linking the mu agonist oxymorphone to the CCR5 antagonist TAK220 has been proposed to inhibit inflammatory and neuropathic pain by targeting mu-CCR5 heteromers (Akg\u00fcn et al., A major limitation to the therapeutic use of bivalent ligands is their poor capacity to cross the blood brain barrier (Le Naour et al., in vivo and their functional interactions addressed in a handful of tissue or brain areas. Moreover, heteromer expression is dynamically regulated depending on physiopathological conditions. No doubt that both novel functions and receptor pairs will be uncovered in the future, which further emphasizes their potential as innovative therapeutic targets.Our current appreciation of the role of mu heteromer is still in its infancy and their contribution to mu receptor-dependent behavior likely underestimated. So far, physical proximity has only been validated for a limited number of receptor pairs All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Augmented reality (AR), superimposing digital assets onto the real-world \u2014offers a paradigm shift in delivering immersive interventions for aging adults. Reminiscence and life review are robust intervention techniques that have decades of empirical support to boost mood and meaning in older adults. In this presentation, we demonstrate the applied research and technology development process to create an AR reminiscence and life review engine for aging adults and their caretakers. We conducted 25 needs assessment interviews with community-dwelling older adults, and assisted living facility directors, nurses, and residents. Initial analyses revealed the need for: (1) finding scalable and cost-effective solutions to alleviate time burden for caregivers; (2) increasing variety of activities that do not need much instruction; (3) producing activities that grab and maintain attention; and, (4) generating more personalized activities that do not divert too much time from caretakers. We integrated the findings to develop a working prototype AR engine called \u201cProject Phonado.\u201d From preliminary user testing, Project Phonado aids in boosting mental health and meaning in aging adults\u2014at least temporarily (immediate and one day follow-up). We will show clips of some pilot user testing of the engine and discuss the next evaluation and development steps."} +{"text": "Sphenocentrum jollyanum (SJ) seed has many health benefits due to its very potent anti-inflammatory and antioxidant properties. Despite its widespread use, it has not been validated for use in the treatment of benign prostatic hyperplasia (BPH). This study was conducted to examine histomorphological effects of SJ seed on BPH that usually causes bladder outlet obstruction.There were a total of six groups of animals each comprising 5 adult male rats. Apart from group 1 , in the remaining five groups, BPH was induced. Group 2 (negative control) was sacrificed immediately after BPH induction; groups 3 and 4 received the extract at 300 and 600 mg/kg respectively by gavages for thirty days; group 5 received finasteride (0.1 mg/kg) for thirty days and group 6 received the extract (600 mg/kg) simultaneously with the steroid administration for thirty days. The animals\u2019 were weighed before the experiment and subsequently every three days until the end of the study.The extract caused marked decrease in prostate weight of rats with BPH with histo-morphology of the tissue showing degenerated stromal and epithelial cells with few epithelial involutions of glandular tissue. Prostate specific antigen (PSA) level as well as testosterone level significantly (p<0.05) decreased in the treated groups compared to negative control. BPH animals treated with extract/finasteride exhibited remarkable increases in anti-oxidant enzymes level with concurrent decreases in peroxidative activity.SJ effectively ameliorated prostatic hyperplasia in BPH animals causing marked degenerative changes in prostate stromal and epithelial cells and also exhibited marked anti-oxidant effect. Benign prostatic hyperplasia (BPH) is a noncancerous cell growth in the prostate gland. This clinical condition elicited by uncontrolled growth of glandular epithelial and stromal cells, induces lower urinary tract symptoms (LUTS) which include weak urinary stream, incomplete bladder emptying, nocturia, dysuria and bladder outlet obstruction , an active metabolite formed by enzymatic conversion of testosterone by steroid 5\u03b1-reductase enzyme Pierre (Menispermaceae) is a perennial plant that grows naturally along the West Coast sub-region of Africa that includes Nigeria. It is deep rooted with few branches bearing fruits that contain a single large oval shaped seed , Ibadan where a voucher specimen was deposited (FHI/108203).Preparation of the petroleum ether extract of Sphenocentrum jollyanum seedoC) in three cycles using a Soxhlet extractor. The crude oil extract of SJ seed was concentrated in vacuo at 30 oC to obtain 146 g residue which was an equivalent of 9.3 % w/w. The residue was stored in an air-tight bottle kept in a refrigerator at 4 oC till used.A smooth powder was made of the dried seeds using an electric grinder. The seed powder, (1.57 kg) was extracted by petroleum ether guidelines on the use and care of animals, in experimental studies obtained from the Animal House of the University of Ibadan, Oyo State, Nigeria, were kept under standard environmental conditions of 12 hr /12 hr light/dark cycles. They were housed in polypropylene cages , and maintained on mouse chow (Livestock Feeds Nigeria Ltd) and provided with water TestosteroneThis is a steroid hormone from the androgen group and is found in mammals, reptiles and other vertebrates for three weeks , in the remaining five groups, BPH was induced. Group 2 (negative control) was sacrificed immediately after BPH induction while groups 3 and 4 received the extract at 300 and 600 mg/kg body weight (bwt) doses, respectively by gavage for thirty days; group 5 received finasteride (0.1 mg/kg) for thirty days and group 6 received the extract (600 mg/kg) with simultaneous steroids injection (BPH induction) for thirty days. The animals were weighed prior to the commencement of the experiment and subsequently every three days till the end of the experiment. Assay for testosterone and prostate specific antigen (PSA) Enzyme immunoassay technique was used for the quantitative determination of testosterone concentration and PSA evaluation was assayed utilizing the technique of Kakkar activity was assayed colorimetrically at 620 nm and expressed as \u03bcmoles of HEstimation of glutathioneThe glutathione (GSH) level was determined by the method of Ellman and hydroperoxides (HP) were measured by the method of Niehaus and Samuelsson . The tissue was thereafter treated with acetone and then cleared in xylene for 30 min to enhance the tissue transparency followed by impregnation and embedding in paraffin wax. The embedded tissue was sectioned at 5 \u03bcm, mounted on a slide and stained with hematoxylin and eosin (H&E) stains has been reported to block testosterone/prazosin- induced increase in rat prostate weight testosterone in the blood stream is noted for its key role in BPH progression. Studies showed that high levels of free testosterone promote the stimulation of 5\u03b1-reductase found mainly within the stromal cells which converts testosterone to a potent androgen, DHT that is responsible for the pathogenesis of prostate gland (Wong et al., 2000Several studies have shown that BPH is associated with increased oxidative stress which increases with increasing age (Aydin et al., 2006SJ seed extract which is recognized for its potent anti-inflammatory and antioxidant properties, effectively ameliorated prostatic hyperplasia by causing marked degenerative changes in prostatic tissue stromal and epithelial cells of the extract-treated animals. The extract also exhibited significant anti-oxidant effect with considerable prophylactic activity. However, further investigation is needed for its validation."} +{"text": "OBJECTIVES/SPECIFIC AIMS: To establish a conceptual framework todevelop a CTS-IDP with data analytics, and an e-Learning Faculty DevelopmentGuide on best practices and use of the IDP over the CTS academic life-course.METHODS/STUDY POPULATION: To accomplish our goal, we propose thefollowing methods: (1) an online survey, using a convenience sample of the 24KL2 CTSA IDP Collaborative members (conducted in 2017), to assess perceivedneeds for a universal CTS-IDP, current IDP practices, barriers to IDP use, andto discern and align each CTSA Hub\u2019s interests, expertise andcommitment to specific areas of the study; (2) A scoping narrative literaturereview, utilizing the Arksey and O\u2019Malley framework covering the timeperiod corresponding to the initiation of funding (1999) of the original K30Clinical Research Curriculum Awards through to the present CTSA funding period,incorporating Medical Subject Heading (MeSH) keywords , initially delineated by USC referencelibrarian and to be expanded by reference librarian services from the IcahnSchool of Medicine at Mount Sinai and University of Rochester, and performed onNIH searchable databases including NCBI PubMed, Central and Medline &Worldwide Science; Web of Science, ProQuest, ProQuest Abi/Inform,Google Scholar, Cochrane, Ovid MEDLINE databases, as well as Google forpublished papers in English and Spanish. For this portion of the work, we willdescribe and characterize (1) research career development or progressionconstructs, domains, and milestones; (2) establish the presence or absence ofdefined and/or pre-specified timed milestone objectives and inclusionof SWOT analytics and/or Gantt chart approaches; (3) delineate IDPs structure, toolkitsand their key features ; (4) and identify specific gaps to best address the need forpersonalized career development education. Based on this review, we willsynthesize CTS milestones, develop a time frame for meeting RCD expectations,and establish RCD benchmarks for achieving these milestones, all in consensuswith the IDP Collaborative Workgroup. RESULTS/ANTICIPATED RESULTS:Seventy-seven percent of the IDP CTSA\u2019s responded to the onlinesurvey, led by University of Rochester, and the results can be summarized asfollows: (1) 100% agreed that the IDP process is important and shouldbe considerably improved to optimize effectiveness; (2) a range of diverse IDPformats are utilized, making comparisons across programs difficult; (3)50% of CTSA hubs report only fair to good compliance with the IDPprocess; (4) a major barrier to the IDP process is lack of instruction regardinghow best to utilize; (5) poor alignment of currently available IDPs designed forbasic science PhDs with CTS investigators; (6) an absence of a CTS specific IDPto best foster RCD for this specific career trajectory. When asked: What are thebarriers to writing a detailed and thoughtful IDP, responses in order ofagreement from greatest to least were: No verification of acquired competencies,beyond self-report (56%), Static platform (38%), Notconstructed for clinical and translational researcher (31%), Noanalytical or documentation on use (31%), No instruction given toscholars on how to use it effectively and efficiently (31%), The IDPwe are using is more constructed for PhD students and postdoctoral fellows(25%), No instruction given to the scholars on why it is important asadult learners (19%), and Not constructed for early careerphysicians/scientist (13%). Additional progress has beenmade on our Scoping review: An initial ABI/Inform and PubMed USCresearch librarian conducted search using Author names yielded 72 articles, ofwhich only 2 were relevant to the topic at hand. A ProQuest\u2122 searchyielded 19 potentially relevant articles, 11 of which were of relevance to thetopic of IDPs; and a Google Scholar search yielded 18 and 25 on careerdevelopment and self-management, respectively. This has enabled us to put forthan initial model of factors that impact the purpose and design of IDPs thatincludes? DISCUSSION/SIGNIFICANCE OF IMPACT: Discussion: Our initialdata suggests that many CTSA institutions see the need to further enhance thementoring process with a more informed and personalized IDP template andprocess. Furthermore, our initial scoping review suggests a framework upon whichto build specific components of a more ideal and useful IDP to best guidementored research career development of CTS trainees. Significance: Developingand evaluating collaborative evidence-based CTS IDP and corresponding e-LearningGuide could potentially prevent or reduce important delays in RCD, a commonroadblock for the translation of clinical interventions. Ultimately, the CTS-IDPserves not only to support and frame a scholar\u2019s RCD\u201chabits of mind\u201d during training and early careerdevelopment but to also to achieve a sustainable long-term career at a CTSresearcher equipped to meet the ever challenging and dynamic researchlandscape."} +{"text": "Dear Editor,Enterobacterales, and it matched cases who had extended-spectrum cephalosporin (EC)\u2013resistant enteric uropathogens (EUs) 1:1 with controls with EC-susceptible EUs to predict a scoring system tool for EC resistance [We read with great pleasure the recently published study by Weinstein et al. . This caEnterobacterales [Escherichia coli isolates and 81.3% (608 of 748) of EC-resistant Klebsiella pneumoniae [E. coli after treatment with oral nitrofurantoin was 3.2% (1/31) at 4 weeks after finishing therapy [This clinical scoring system is highly useful for empiric antibiotic treatment for urinary tract infections (UTIs), especially the complicated ones, which often require treatment based on in vitro antibiotic susceptibility testing. The Infectious Diseases Society of America (IDSA) and the European Society for Microbiology and Infectious Diseases (ESCMID) guidelines for UTI emphasize the importance of empiric treatment of uncomplicated UTI without a urine culture and susceptibility testing. Those guidelines recommend either a single dose of oral fosfomycin, 5 days of oral nitrofurantoin, 3\u20137 days of pivmecillinam (which is only available in Europe and is not licensed for use in North America), 3\u20137 days of oral \u03b2-lactam , or 3 days of oral trimethoprim-sulfamethoxazole [ 608 of 78 of EC-r Additionally, urine cultures are regularly ordered in healthy outpatient women with urinary symptoms even though they are often of limited value given the delay in obtaining results, the cost and inconvenience to the patient, and the high predictive value of symptoms alone in diagnosing acute cystitis . In someThe clinical tool developed by Weinstein et al. to predict EC resistance included recent trimethoprim-sulfamethoxazole exposure as unexpectedly the only antibiotic found to be significantly associated with EC resistance after multivariate analysis . Althoug In conclusion, the clinical prediction tool for EC resistance developed by Weinstein et al. could be most useful in the setting of empiric treatment choice for complicated UTI, but may be used less often in the case of uncomplicated UTI, where adherence to the IDSA and ESCMID UTI treatment guidelines would be the gold standard for empiric antimicrobial treatment . One cou"} +{"text": "OBJECTIVES/SPECIFIC AIMS: The aims of this project are to: (1) examine placebo effects on subjective and objective outcome measures, (2) determine if an increase in the placebo is associated with changes in benefit, (3) evaluate if the trauma related insomnia placebo group in our study has different side effect reports compared with insomnia placebo participants in previous suvorexant trials, and (4) (Exploratory) examine associations between the placebo group\u2019s characteristics and placebo effects. METHODS/STUDY POPULATION: The parent study is a randomized double-blind placebo-controlled clinical trial of suvorexant for treatment of adults (age 18\u201355) with insomnia that started or worsened after trauma exposure. Suvorexant is a first in class orexin antagonist and is approved by the FDA for the indication of insomnia. In this 6-week trial, all participants initially take 10 mg of suvorexant/placebo, and the dose will be increased to 20 mg if participants continue to experience clinically significant insomnia symptoms 1 week after starting the medication. Sleep outcomes will be measured by polysomnography, daily sleep diary, and the Insomnia Severity Index. RESULTS/ANTICIPATED RESULTS: We hypothesize that (1) within the placebo group data both subjectively and objectively measured outcomes will similarly show improvement in insomnia symptoms, (2) the increase of the placebo medication dose will result in an increased benefit, (3) the trauma-related insomnia placebo group will have the same type and similar rate of side effects reported in previous suvorexant trials. DISCUSSION/SIGNIFICANCE OF IMPACT: Most previous studies examining placebo effects focused on pain and depression. Information obtained from this project will complement our current understanding of placebo effects by characterizing placebo effects on trauma-related insomnia. This study will inform the development of novel strategies to maximize utility of placebos in future clinical trials."} +{"text": "Context: Tuberculosis (TB) has remained a devastating global public health problem. In the continuing search for effective treatment, polyherbal remedies used as alternative medicines in the Eastern Cape Province of South Africa were surveyed.Objective: The survey collected information and documents the list of ingredients such as the name of the plants used including the non-herbal inclusions, type and dosage of polyherbal formulations used for the treatment of TB.Materials and methods: The survey was conducted over a period of 6 months using semi-structured questionnaires amidst informal conversations with the traditional healers in five communities in the study area. The chosen study area is the third infected Province with TB in South Africa.Results: A total of nine polyherbal preparations were collected. Information on the parts of the plant used, mode of preparation and the dosage used were documented. In total, the herbs belong to 20 families of which Apiaceae, Liliaceae, Strychnaceae, Rutaceae and Hypoxidaceae are the most prominent. However, members of Apiaceae were commonly mentioned for the preparation of the remedies. The two most frequently used plants were Allium sativum L. (Liliaceae) and Strychnos decussata (Pappe) Gilg. (Strychnaceae). Rhizome was the commonest parts used, followed by the roots and barks.Conclusions: This paper provides significant ethno-medicinal information on polyherbal medicines used for the treatment of TB in the study area. The therapeutic claims made on medicinal plants used for the preparations are well supported by the literature, with many of the species having antimicrobial properties. Mycobacterium tuberculosis has remained one of the most prevalent causes of mortality in developing nations, especially in the Asian and African continents. The disease remains a big problem in these countries probably due to inadequate means for the management and treatment of the disease. According to World Health Organization (2002), about 95% of the approximately eight million cases of TB occur each year in Africa having the highest incidence. However, South Africa is the third highest incidence country after India and China with about 80% of the population infected with the disease. This rate has increased by 400% over the past 15 years most especially among the people living with human immuno-deficiency virus (HIV) caused by M. tuberculosis to commonly prescribed antimicrobials has made people fall back on herbal medicines for various therapeutic purposes . Ethnobotanical surveys have extensively studied South African populations of adults and children with several illnesses Bodkin .A total of nine polyherbal medicines used for the treatment of TB were recorded and collected from the study area ; these aThe polyherbal remedies in the study area were prepared from 24 plants. The six most commonly mentioned plant families used in the preparation of the polyherbal formulations in terms of number and percentage are Apiaceae [5(25%)], followed by Liliaceae [4(20%)], Strychnaceae [4(20%)], Rutaceae [4(20%)], Solanaceae [2(10%)] and Primulaceae [2(10%)] . MembersAllium sativum L. (Liliaceae) [4(17%)], Strychnos decussata (Pappe) Gilg. (Strychnaceae) [4(17%)], Daucus carota L. (Apiaceae) [3(13%)] and Hypoxis argentea (Fiscand) (Hypoxidaceae) [3(13%)]. Other plants such as Agathosma betulina (Berg) (Rutaceae) [2(8%)], Capsicum annuum L. (Solanaceae) [2(8%)] and Rapanea melanophloeos L. (Primulaceae) [2(8%)] are used for a few polyherbal preparations in the Province as represented in The most frequently used plant parts in this study was rhizomes [10(27%)], followed by bark [8(22%)], and roots [8(22%)]. Others are leaves [6(16%)], corms (3(8%)] and vegetable [2(5%)] as shown in S. decussate, which should be chewed immediately after KWTb remedy has been administered ] and decoction [2(22%)] with the exception of nistered . This isnistered . The intMycobacterium tuberculosis. Probably, these therapies have gained popularity in both developed and developing countries because of their natural origin and fewer side effects for the treatment of various chronic and acute ailments (Ahmad et\u00a0al. The diverse uses of each plant can be explicated by the fact that, a single plant can serve many medicinal purposes or perform different functions (Lawal et\u00a0al. This paper provides significant ethno-medicinal information on polyherbal medicines used for the treatment of TB in Amathole District Municipality of Eastern Cape Province. Africa is endowed with a biodiversity of medicinal plants, many of which are currently used in the traditional management of TB. The study shows that people in the study area still depend on polyherbal medicines for the treatment and management of TB. The documented remedies reflect rich ethno-medicinal knowledge in the province. However, further test are required to validate the ethno-medicinal usage of these polyherbal remedies as anti-TB agents."} +{"text": "Data for this study originated the Oklahoma 100 Year Life Project. A total N = 7 volunteer actors were recruited to participant as actors to play the role of centenarians in a living history play based on oral historical narratives. Actors participated in preliminary (prior to play performance) and post (after play performance) focus group sessions. Focus group questions addressed four key ideas: (1) Perceptions of aging and human longevity; (2) Loss and decline in aging; (3) Narrative storytelling and; (4) Personal life goal(s). Qualitative content analysis was performed to assess general thematic evidence stemming from actor perspectives. Four predominant themes emerged suggestive of adaptation in actor perceptions about human aging and longevity. These themes included: (1.) Purpose seeking (e.g. \"It was interesting to see how much you can get out of life.\"); (2.) Age-embodiment ; (3.) Creative curiosity ; and (4.) Self-actualization . Results have implications relative to how oral historical narratives can be used to enhance the personification of aging on stage, as well as demystify personal myths about longevity. Applications for use within educational and community settings for theatrical performances will be shared."} +{"text": "OBJECTIVES/SPECIFIC AIMS: The overall goal of this project is to enhance the use of GCRA in Latina breast cancer survivors at high risk of hereditary breast and ovarian cancer to reduce disparities in GCRA uptake. The aims of the study are to (1) develop a cultural adaptation of an evidence-based TGC intervention that consists of phone genetic counseling and a booklet, (2) evaluate the impact of TGC Versus Usual Care, and (3) explore the communication patterns in TGC and genetic counseling sessions with an interpreter. METHODS/STUDY POPULATION: We are conducting a 2-phase, mixed methods study. In Phase I we will develop a cultural adaption of an evidence-based intervention (TGC) for high-risk Latina breast cancer survivors using the Learner Verification and Revision Framework (n=15). In Phase II we will use a cluster randomized design with four community sites randomized to Spanish TGC (n=2 sites) or usual care (n=2 sites) . The primary outcome is genetic counseling uptake. Among women who receive genetic counseling either through TGC (n~30) or with an interpreter (n~15), we will assess counseling quality by reviewing 20 randomly selected audiotaped sessions . We will evaluate women\u2019s HBOC knowledge and satisfaction with counseling. Communication processes and outcomes will be assessed using gold standard RIAS quantitative coding system and qualitative discourse analysis. RESULTS/ANTICIPATED RESULTS: We elicited input from transdisciplinary team members to develop an initial adaptation of a TGC print booklet and intervention protocol for use with high-risk Latina breast cancer survivors with limited English proficiency. The booklet contains low-literacy information about HBOC, risk factors, pros and cons of testing, and management strategies. Based on these materials and prior work, we anticipate TGC will consist of one 1 hour or less TGC session by phone. Participants interested in pursuing testing will receive a saliva kit and will participate in a second TGC session (30 min) to discuss test results and management options. DISCUSSION/SIGNIFICANCE OF IMPACT: Given access barriers and the shortage of Spanish-speaking genetic counselors, adapting and translating TGC intervention is a promising strategy that could reduce disparities by broadening the reach and accessibility to genetic counseling while enhancing the quality of the service for Latinas with limited English proficiency."} +{"text": "Background: Death certificate inaccuracy increases at older ages. The Long Life Family Study (LLFS) utilizes a physician adjudication committee to review the death certificate, medical records and a family narrative about cause of death. We report here the adjudication process and the prevalent underlying causes of death for a subsample of those who have died so far. Methods: We first describe the adjudication process. There were ~1,250 deaths in LLFS. We report underlying causes of death for a subset of proband generation subjects enrolled and evaluated by two LLFS study centers. Results: As of May 2019, we have adjudicated 190 deaths . Mean age 95 years (range 81-105 years). Top 5 causes of death for men: cancer (13%), coronary heart disease , dementia (13%), \"other\" (11%) and \"unknown\" (9%) and for women: dementia (21%), valvular heart disease (14%), coronary heart disease (12%), unknown (12%) and other (9%). Rate of death due to dementia was greater in women compared to men . Conclusions: In this pilot study, a significantly greater proportion of women died due to dementia compared to men. At least some portion of this difference may be due to the observation that women are known to survive chronic aging-related diseases more than men and thus have a greater opportunity to die from dementia at advanced ages. An additional cause to consider includes clinicians\u2019 gender bias in ascribing diagnoses in the medical records that were relied upon as part of the adjudication process."} +{"text": "The House Calls and Behavioral Health Integration project was an inter-agency collaboration to address depression in the older adult population by increasing knowledge and awareness of the condition and providing better access to care. Rowan Medicine, New Jersey Institute for Successful Aging (NJISA) and Jewish Family and Children Services (JFCS) partnered to deliver a comprehensive education, screening and referral program for residents of 3 senior housing facilities serving an estimated 300 elderly and disadvantaged residents. The goal of this year long project was to provide depression education for both housing residents and staff; offer on-going access to free depression screens (using PHQ-9) for residents; and refer residents to an appropriate resource depending on depression screen outcome. Depression education was provided to 15 housing staff and 78 older adult residents. A total of 34 depression screens were completed ; further evaluation of symptoms was indicated for 59% (n=20) of those screened. Seventeen of the 20 residents accepted a recommendation for a referral to supportive counseling; 3 declined. The average PHQ-9 score was 8.45 . Referrals to case management and house calls (n=4) were also made. Feedback from both housing residents and staff was positive and the project team learned valuable lessons about serving older adults in congregate living settings which has informed other programming. The project was successful in providing education, screening and referrals to residents who might not otherwise have access to specialized geriatric behavioral health interventions."} +{"text": "We examine trait and state subjective aging as antecedents of control beliefs in older adults with a daily diary design. Adults (n=116) ranging in age from 60 to 90 (M=64.71) completed a nine-day daily diary study online. Participants reported trait aging attitudes on Day 1 and daily Awareness of Age-Related Change (AARC) of loss and gain experiences and control beliefs (Locus of Control and Perceived Competence) on Days 2-9. Controlling for demographics and known antecedents of control beliefs , daily increases in AARC gain were associated with increases in both Locus of Control and Perceived Competence, and a cross-level interaction revealed that Locus of Control decreased for those with more positive ATOA on days when they reported more AARC losses. Discussion will focus on interpreting the interaction between trait and state subjective aging."} +{"text": "The relationships between physical frailty and perceived neighborhood social cohesion (PNSC) and functional disability among community-dwelling older adults are poorly understood. This study aims to (1) examine the associations of frailty and PNSC with disability; and (2) evaluate low PNSC as a risk factor in the association between frailty and disability. A sample of 1645 older adults using multi-stage sampling method in Shanghai were randomly selected in this cross-sectional study. Frailty operationalized as Cardiovascular Health Study criteria and PNSC measured as Neighborhood Cohesion Scale were independently associated with basic and instrumental activities of daily living disability. A significant interaction of frailty and PNSC on disability =4.31, P=.014) was found, using a two-way analysis of covariance (ANCOVA). Compared to robust individuals with high PNSC, pre-frailty with high PNSC was not significantly associated with disability while pre-frailty with low PNSC was associated with approximate 4-fold increased prevalence of disability . Frailty with high PNSC was associated with higher likelihood of disability and frail individuals with low PNSC stood out with 10-fold increased prevalence of disability . All analyses were controlled for demographical and clinical covariates. Our results suggest high level of social cohesion serves as a buffer against the impact of physical frailty on functional disability. These findings notably imply to the development of interventions for older frail adults from the neighborhood perspective."} +{"text": "Plants grow continuously, forming new meristem-derived organs and tissues throughout their post-embryonic life. As sessile organisms, plants need to constantly integrate and reflect environmental fluctuations in their growth and development, which can translate into high level of developmental plasticity in response to environmental changes evidences of molecular mechanisms that mediate the crosstalk between phytohormone signaling, chromatin structure and gene expression (2) how this crosstalk may link to plant developmental plasticity and robustness and finally (3) why meristems may represent central places for this crosstalk allowing plasticity and environmental memory.Phytohormone and epigenetic regulation can interact on multiple levels : (1) phyFLOWERING LOCUS C (FLC), preventing precocious floral transition 1 and 2 with histone-methyltransferase activity playing a major role in transcriptional regulation during development genes is positively regulated by BRM establishing local auxin maxima and stimulating the expression of the RAM-specifying PLETHORA genes PLT1 and PLT2 is associated with changes in jasmonic (JA), salicylic acid (SA) and ethylene responses control of cell identity genes in meristems, (2) chromatin-mediated stabilization of gene expression beyond the hormonal initial signal, (3) chromatin-governed integration of separate hormone signaling pathways.WUSCHEL (WUS) is regulated by cytokinin signaling, DNA methylation, H3K27me, or chromatin remodeling their central role in postembryonic morphogenesis, plasticity and memory, (2) their particularities for phytohomone signaling and chromatin remodeling, (3) first evidences reported for this crosstalk in SAM.The meristems represent major sites of stem cell niches in plants Scheres, . Apical Phytohormone and epigenetic pathways play overlapping/complementary roles in meristem functions and developmental plasticity or robustness, laying the basis for a biologically significant crosstalk. Importantly, meristems have been shown to be the place of epigenetic control for stem cell pluripotency, differentiation, and reprogramming in the SAM of Arabidopsis clv3 mutants (Lafos et al., Major evidence for phytohormone-chromatin crosstalk was obtained using Arabidopsis mutants, or applying phytohormones or chemical inhibitors of chromatin modifiers in various developmental processes (Yamamuro et al., In conclusion, phytohormone action and chromatin modifiers seem to be tightly interacting but the extent to which they act jointly or independently remains unclear (Ojolo et al., Current knowledge leads to the opinion that this crosstalk in meristems can integrate environmental cues for developmental outcome. Erasure of this signaling may allow continuous adjustment to new environmental conditions. Its maintenance through persistent chromatin states can however stimulate mitotic memory that could prime later organ formation. How the balance between erasure and memory is achieved remains enigmatic .While the mechanistic events could be more easily deciphered in well-established model annuals such as Arabidopsis, it is important to establish perennial models where the impact of mitotic epigenetic memory is of importance in the context of climate change. In addition to SAM and RAM, cambium, whose activity is crucial for environmentally controlled wood formation, may be an appropriate and highly relevant model (Wang et al., SM suggested and designed the opinion article. MDS and SM designed the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The scarce knowledge of multimorbidity development hampers the effectiveness of clinical interventions. We aimed to identify multimorbidity clusters, trace their evolution in a cohort of older adults, and detect the clinical trajectories of single individuals as they move among clusters over 12 years. Population-based study including 2931 persons 60+ with \u22652 diseases participating in the SNAC-K study. A fuzzy c-means cluster algorithm was used to group participants by disease patterns at baseline and follow-ups. Migration from one cluster to another was tracked over time, and the association between the clusters and mortality was tested. At baseline 52% of participants were classified into five clinically meaningful disease clusters: psychiatric and respiratory (5%), heart (9%), respiratory and musculoskeletal (16%), cognitive and sensory impairment (10%), and eye diseases and cancer (11%). The remaining 48% of participants (unspecified group) were grouped in any cluster at baseline but greatly contributed to the other clusters at follow-ups. Multimorbidity clusters that included cardiovascular and neuropsychiatric diseases presented a significantly higher mortality risk (odds ratios ranging 1.58\u20136.00) than the group not part of any clusters. Clusters characterized by cardiovascular and neuropsychiatric diseases included 25% of the study population at baseline and 28% of participants at six years, and they accounted for 51% of deaths at six years and 57% of deaths at twelve years. Multimorbidity clusters and clinical trajectories of older adults with multimorbidity show great dynamism over time. The multimorbidity clusters and trajectories identified in this study may help identifying groups with similar needs and prognosis."} +{"text": "To address their needs for proactive self-care and end of life planning, we implemented a community based educational program that promotes future care planning (FCP) for community residing older adults. Extension specialists from Iowa State University implemented two brief FCP program sessions with older adults. Topics included both short-term and long-term future care planning activities and strategies. Baseline and post program surveys were completed by 216 community dwelling older adults (M=78.21). The program was successful in getting older Iowans in the rural area start end of life care preparation as well as helping them to make changes in their health care decisions. The majority of participants (89.6 %) reported high satisfaction with the programs. We also found a high rate of change (62%) in opinion regarding future care. The implication of future care planning for is discussed with recommendations for future research."} +{"text": "The quality check and determination of permitted and non-permitted additive colors in food products is very important for customer\u05f3s right protection and health. This survey was undertaken to demonstrate the frequently use of additive colors and products targeted to color adulteration in Iranian foods and beverages. From the 1120 of the samples, 18.86% contained artificial colors, 11.89% contained natural colors and 69.25% of samples had no additive colors. Tartrazine (E102) was the only non-permitted artificial dye used in samples. Among products with additive colors, only 4.38% of samples failed to meet with national Iranian standard and 61.23% of non-compliance samples were from non-industrial sectors and mostly were saffron and food containing saffron such as saffron rock candy and saffron chicken. These places and products quality are main the concern to solve the color adulteration in Iranian food market. Specifications TableValue of the data\u2022The dataset shows the amount of additive colors in local food and beverage products.\u2022The dataset signifies the amount of permitted and non-permitted colors under Iranian laws.\u2022The dataset of this article identifies products with non-authorized colors, which can be useful for other investigators working in area of quality assurance of foods.1The dataset provided here , Table 32The Iranian national standard organization only permits seven artificial dyes of Quinoline Yellow (E104), Sunset Yellow FCF (E110), Azorubine (E122), as well as Ponceau 4R (E124), Allura Red AC (E129), Indigotine (E132) and Brilliant Blue FCF (E133) in different type of products. The prevalence use of permitted and non-permitted artificial dyes has been reported from different states of Iran, previously. The required data were collected from the results documented in Kimia Test FAM Laboratory during the five years of 2011\u20132015. The additive color of 1120 samples, which represent 30% of samples analyzed in Tehran city for additive colors, was determined using thin layer chromatography methods (TLC) according to 2634 Iranian national standard and were compared to 740 Iranian national standard for permitted food additive colors. The data were entered into an Excel spreadsheet and were analyzed by descriptive statistics"} +{"text": "The HER4 receptor tyrosine kinase is known to have promiscuous activity in malignant cells, last but not least in breast cancer. Evidently, the prognostic and predictive impact of HER4 expression depends on the expression of different receptor isotypes, the way of receptor activation (ligand dependent vs. independent), and on the complex interaction of the HER4 intracellular domain (4ICD) with intracellular regulative molecules which results in either oncogenic or rather tumor suppressive HER4 activity. Recent data suggest that HER4 unfavorably affects the endocrine treatment of postmenopausal breast cancer patients with tamoxifen and therefore might represent an additional therapeutic target in luminal breast cancer. The Human Epidermal Growth Factor Related (HER) receptor family comprises at least four cognate receptor tyrosine kinases which - as a functional unit - drive breast cancer disease and have prognostic and predictive impact . Remarkably, HER4 plays an extraordinary role in the context of HER receptor coexpression and interaction . Upon itIn contrast to its differentiation enhancing activity Her4 has also been shown to promote the proliferation of breast cancer cells , 16. It Notably, HER4 does not only affect tumor cell growth and survival but also appears to significantly impact antigen specific tumor treatments by definite intracellular molecule interaction . In thisThe finding that HER4 impairs the tamoxifen treatment efficiency has clinical implications and facilitates extended treatment strategies that involve multiple tumor cell targeting. This can in case of ER/HER4 double positive BC potentially be accomplished by a dual targeting of both receptor types using for instance tamoxifen and an HER4 specific antibody with anti-tumorigenic activity , 32. Alt"} +{"text": "Ventenata dubia, an invading non-native annual grass, in geographic and ordination space over time.The data and analyses presented here were collected at the Zumwalt Prairie Preserve (ZPP), northeastern Oregon. Vegetation composition was measured within 124 (1-ha) plots using the line point intercept method . These data include vascular plant species abundance matrices at two different time periods, seven years apart (2008/2009 & 2015/2016); boxplots of species abundance (cover and frequency) change over time; Non-parametric Multiplicative Regression (NPMR) estimated abundance of The preon space , Fig.\u00a05.2The ZPP was categorized into prairie and canyon lands and the canyon lands were excluded from this data . The remVentenata dubia foliar cover and frequency within quadrats in both NMS ordination and geographic space (R2 (\u03c7R2) values were used to evaluate model fits and differ from the conventional R2 because it is based on the exclusion of each data point from the estimate of the response at that point Ventenata"} +{"text": "The evaluation framework is developed for CO2 capture, geological utilization and storage (CCUS) project developments, including CO2 emission inventory, site suitability evaluation, and source\u2013sink matching with techno-economic models. The data shows the matched source (CO2 source)-sink (onshore aquifer site) pairs with sites distribution and levelized cost under various scenarios. Data also shows the geographic distribution of source-sink pairs, cost curve, annual cumulative CO2 storage capacity and enhanced water production under various scenarios. Potential large-scale deployments of CO2-EWR projects with low cost in the modern coal chemical industry in China are shown and identified in the dataset. This data article is related to the research article \u201cCost curve of large-scale deployment of CO2-enhanced water recovery technology in modern coal chemical industries in China\u201d .This data article presents the first systematic assessment on the potential of onshore CO The data show the details of matched source-sink pairs with potential costs. The data compiled in excel spreadsheets provides the inventory of several coal chemical processes, CO2 emission from industrial and dilute processes of each CO2 source, geographic distribution of potential integrated CCUS projects (source-sink pairs) with levelized costs and CO2 storage capacity, cumulative storage capacity and water production for the whole set of modeled CO2 sources and onshore aquifer sites in China under various scenarios of actual operating capacity in 2015, designed full capacity in 2015, and total capacity in 2016. The data can be used to identify various potential low-cost large-scale deployment of CO2-EWR projects using pure CO2 from the coal chemical industry in China. Data sheet and figures are compiled using Excel software with levelized costs, cumulative storage capacity and water production for the whole set of modeled CO2 sources and onshore aquifer sites.The systematical evaluation framework is based on the"} +{"text": "Inhibition of TORC1 has extended lifespan in multiple preclinical species. Thus drugs inhibiting TORC1 may have therapeutic benefit for aging-related conditions in humans. An aging-related condition that improves with TORC1 inhibition in old mice is immunosenescence (the aging-related decline in immune function). Immunosenescence leads to increased rates of infections including respiratory tract infections (RTIs) in the elderly. In two Phase 2 clinical trials in over 900 elderly subjects, the TORC1 inhibitor RTB101 was observed to improve immune function and decrease the incidence of RTIs. Decreasing the incidence of RTIs is important because RTIs are the fourth leading cause of hospitalization in people age 65 and above. Based on these findings, two Phase 3 studies are underway to determine whether RTB101 given for 16 weeks during winter cold and flu season decreases relative to placebo the percentage of elderly subjects with illnesses associated with RTIs."} +{"text": "Objectives: Occupational mobility at various stages in the life course may have a cumulative influence on health outcomes in later life. This study aims to (1) systematically review the association between occupational mobility and chronic illness in late life; and (2) identify potential mechanisms underlying this relationship. Methods: A systematic review of literature was carried out by searching two databases (PubMed and SocIndex) and reference lists. Eligible studies examined associations between occupational mobility and at least one measure of chronic illness among adults aged 50 years or above. Occupational disruptions were reviewed as special cases of occupational mobility. Results: Downward occupational mobility and mid-life occupational disruptions have been consistently shown to predict higher risk of chronic illness in older adults. Several potential mechanisms were identified from the literature: (1) health behaviors, including dietary practices and alcohol consumption; (2) psychosocial factors, including stress, stigma, job control, job demands, and job satisfaction; (3) economic factors, including financial incentives or constraints; and (4) other individual characteristics, including personality traits and coping skills. There is also evidence that the timing of job mobility and the duration of (each) occupation modify the association between occupational mobility and health in late life. Discussion: These findings suggest that experiencing involuntary occupational mobility at various stages in the life course can increase the risk of chronic illness in late life. Health professionals and policymakers should target more resources to disadvantaged older adults who experience involuntary occupational transition."} +{"text": "Corneal blindness is one of the major causes of blindness worldwide, for which corneal transplantation has long been the only treatment method. In addition to penetrating keratoplasty, development of partial thickness corneal transplantation techniques including deep anterior lamellar keratoplasty (DALK), Descemet's stripping endothelial keratoplasty (DSEK), and Descemet's membrane endothelial keratoplasty (DMEK) allowed improved visual anatomical outcome. Keratoprosthesis including Boston keratoprosthesis (KPro) and osteo-odonto keratoprosthesis (OOKP) also enabled visual recovery in patients with serious ocular surface destruction. However, the demands for corneal transplant can never be met because of global shortage of donor corneal tissue.We have introduced in the call for papers for this special issue that various methods of corneal tissue engineering such as cultivation and expansion of corneal tissues using novel drugs and biomaterials have been studied. These novel methods are expected to allow the production of large amount of synthetic corneal tissues for transplantation without the risk of disease transmission. Further researches on corneal tissue engineering, i.e., cell therapy for corneal tissues including the epithelium, stroma, and endothelium; development of biomaterials, drugs, and imaging techniques that can be applied to corneal tissue engineering; application of artificial corneal tissue; and anterior segment reconstruction would provide even more improved visual and anatomical results.In this special issue, the authors contributed 4 original articles and 2 review papers regarding researches of corneal tissue engineering and its clinical application.The authors reported the results of their original researches on various topics in corneal tissue engineering: (1) outcomes of Descemet membrane endothelial keratoplasty for vitrectomized eyes with sutured posterior chamber intraocular lens; (2) generation of femtosecond laser-cut decellularized corneal lenticule using hypotonic trypsin-EDTA solution for corneal tissue engineering; (3) modern corneal eye-banking using a software-based IT management solution; and (4) preliminary investigation of the mechanical anisotropy of the normal human corneal stroma.This special issue also includes review articles on the following topics: (1) application of novel drugs for corneal cell regeneration and (2) from DMEK to corneal endothelial cell therapy: technical and biological aspects.We believe these articles will provide readers with valuable information on corneal tissue engineering and novel ideas for researches on related topics."} +{"text": "Dengue prototype strains are widely used for virological study. The strains presented here have been cultured under different laboratory environments, resulting in accumulating genetic variations. Dengue prototype strains are widely used for virological study. The strains presented here have been cultured under different laboratory environments, resulting in accumulating genetic variations. We present the genomes of four serotypes of the dengue prototype strain that were continuously maintained in the laboratory. These genomes contain bases different from those of the original prototype strains in GenBank. Flaviviridae and the genus Flavivirus. Four serotypes of dengue virus are a cause of dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). The prototype strains of four dengue serotypes frequently used in the laboratory are DENV1 strain Hawaii, DENV2 strain 16681 and strain New Guinea C (NGC), DENV3 strain H87, and DENV4 strain H241. The prototype strains have been cultured and used for dengue study in laboratories since 1980 (Dengue virus (DENV) is the most prevalent arbovirus and is found mainly in tropical and subtropical regions. The virus belongs to the family Aedes albopictus cells by the cell culture laboratory of the Division of Dengue Hemorrhagic Fever Research . Five prototype strains were maintained in the laboratory for more than 10 years. The prototype strains were prepared for sequencing by using the 454 pyrosequencing GS FLX platform (Roche Applied Science) in the same run as that reported in our previous study using BLASTn version 2.7.1+ database under the accession number"} +{"text": "Infectious Diseases of Poverty claimed that undue influence on African programs by concepts developed by the Onchocerciasis Elimination Program of the Americas (OEPA) is detrimental to stopping mass drug administration (MDA) in Africa. This claim is made despite a record year for MDA stoppage in four African countries of >\u20093.5 million treatments in 2018, far exceeding any past OEPA or African Program for Onchocerciasis Control (APOC) stop MDA success.A recent article \u201cIs onchocerciasis elimination in Africa feasible by 2025: a perspective based on lessons learnt from the African control programmes\u201d in The online version of this article (10.1186/s40249-019-0558-0) contains supplementary material, which is available to authorized users. Please see Additional file Infectious Diseases of Poverty including the claims: (1) that the influence of the ongoing Onchocerciasis Elimination Program of the Americas (OEPA) is, \u201cimpeding progress towards decisions to stop intervention in many (African) areas that have reached the elimination point\u201d and (2) that the introduction of testing for antibody to the Onchocerca volvulus 16\u2009kDa antigen (OV16) in children to assess for evidence of recent transmission \u201chas delayed progress with stopping treatment which according to APOC evaluations should already be feasible for millions of people.\u201d [Professor Dadzie with other distinguished directors of the former World Health Organization (WHO) African Regional Programs against River Blindness (the Onchocerciasis Control Programme in West Africa [OCP] and the African Programme for Onchocerciasis Control [APOC]) recently published an article in claims: that thetransmission suppression, at which point the adult Onchocerca volvulus worm population is in demise; (ii) transmission interruption determined by epidemiological and entomological studies of the Simulium vector black flies, at which time MDA may be halted; and lastly (iii) Post Treatment Surveillance (PTS) for 3\u20135\u2009years, after which evaluations must successfully demonstrate lack of recrudescence, at which time transmission elimination may be declared. (3) Decisions to stop MDA and PTS based on these WHO Guidelines require transmission monitoring in children. On this point, it should be recognized that it was the WHO Geneva 2001 guidelines (not OEPA) that stipulated what we agree is a quite challenging 0.1% threshold to measure [O. volvulus 150\u2009bp tandem repeat (O150) in pools of black fly heads (the threshold being <\u20091/2000 infective flies) rather than dissection. Because a laboratory was required for the PCR, in the mid-2000s OEPA successfully operationalized the use of OV16 antibody monitoring by Enzyme Linked Immunosorbant Assay (ELISA) testing of dried blood spots since it could be performed in the same facility. This test is currently known as the \u2018OEPA\u2019 OV16 ELISA [The OEPA programmatic model consists of five basic principles , 3: (1) measure , 6, 7. T measure \u201310. Both16 ELISA . Under tThis five-step OEPA model had a positive influence in Africa due to two annual meetings that provided a forum for onchocerciasis warriors from six African countries and six American ones to exchange information. One of these meetings was the annual InterAmerican Conferences for Onchocerciasis , and the other was the annual Carter Center Program Review (held since 1996). On several occasions African country delegations attended IACO and at least one IACO an APOC Director (Dr. A. Seketeli) gave the keynote address. The Director of OEPA (Dr. M. Sauerbrey) attended at least one meeting of the APOC Technical Consultative Committee (TCC).The fruit of this African-American exchange first became apparent in 2006 when Sudan declared elimination of transmission of onchocerciasis as its goal. In doing so, Sudan embraced the 2001 WHO Geneva Elimination Guidelines and many OEPA principles to reorient its program. The national program independently took the decision to upgrade to OEPA\u2019s twice-per-year treatment strategy and successfully adapted it to the APOC Community Directed Treatment with Ivermectin (CDTI) framework. It expanded MDA to low prevalence (hypoendemic) communities included under OEPA but excluded under the APOC paradigm. A national lab was established at the Ministry of Health, and OEPA OV16 ELISA and O150 PCR were successfully deployed to allow a stop MDA decision in Abu Hamad in 2012 and completion of 3-year PTS . The AbuSimulium neavei foci. The UOEEAC defined guidelines for elimination in S. neavei areas that were ultimately incorporated into the 2016 WHO guidelines. Representatives from onchocerciasis programs in the Democratic Republic of Congo and the Republic of South Sudan regularly attend UOEEAC meetings to discuss establishing SIZs in shared (cross-border) transmission zones with Uganda. Since the Ugandan program launched its elimination policy, approximately 1.9 million ivermectin treatments have been halted in the country. Active transmission now only occurs in two of the original foci. The S. neavei vector has been eliminated from many foci. Six foci have been determined to have met the WHO criteria for elimination by successfully completing the 3-year PTS period; an estimated 1.15 million persons living in these districts are no longer at risk of acquiring onchocerciasis [In 2007, Uganda declared a goal of onchocerciasis transmission elimination from all its 16 active transmission zones (foci) just months after a high-level delegation went to Guatemala for the 2006 IACO. The 2018 publication describing the history of the Uganda program includes in its introduction a section entitled \u2018Inspiration from the Americas\u2019 . The UgaEthiopia is now in its sixth year of executing a national twice-per-year treatment policy to accelerate onchocerciasis transmission elimination. In 2017, at its third meeting, the Ethiopian Onchocerciasis Elimination Expert Advisory Committee (EOEEAC) met with representatives from the Sudan program to review binational PCR and OV16 data \u201318. OverAt its fifth meeting, the Nigeria Onchocerciasis Elimination Committee (NOEC) reviewed results of 2017 OV16/PCR assessments in Plateau and Nasarawa States and determined that the WHO Geneva guidelines for stopping ivermectin MDA had been met . It recoWe conclude by noting that 2018 was the most successful year ever for stopping MDA for onchocerciasis in Africa, and that the OEPA elimination model was important in helping that success. Last year 3.8 million ivermectin treatments for onchocerciasis were halted in Africa, 64% of the cumulative 5.9 million treatments that have been stopped since Sudan\u2019s initial Abu Hamad success in 2012. This is compared with under 1 million treatments stopped by OEPA in the Americas . These eAdditional file 1:Multilingual abstracts in the five official working languages of the United Nations. (PDF 321 kb)"} +{"text": "Mitogen-Activated Protein Kinase (MAPK) cascades are conserved signaling modules that integrate multiple signaling pathways. One level of control on the activity of MAPKs is through their negative regulators, MAPK phosphatases (MKPs). Therefore, MKPs also play an integrative role for plants responding to diverse environmental stimulus; but the mechanism(s) by which these phosphatases contribute to specific signals remains largely unknown. In this review, we summarize recent advances in characterizing the biological functions of a sub-class of MKPs, dual-specificity phosphatases (DSPs), ranging from controlling plant growth and development to modulating stress adaptation. We also discuss putative regulatory mechanisms of DSP-type MKPs, which plants may use to control the correct level of responses at the right place and time. We highlight insights into potential regulation of cross-talk between different signaling pathways, facilitating the development of strategies for targeting such cross-talk and to help improve plant resistance against adverse environmental conditions without affecting the growth and development. To rapidly adapt to various environmental challenges, plants need to balance diverse signal inputs which involves crosstalk between different signaling pathways. A common strategy for integrating these signals is through use of shared components, including mitogen-activated protein kinase (MAPK) cascades that play essential roles in signal transduction and amplification for many distinct cellular responses. MAPK cascade modules are conserved in all eukaryotes and consist of three kinase components: MAPK kinase kinases (MAPKKKs) phosphorylate dual-specificity MAPK kinases (MAPKKs), which then phosphorylate and activate the terminal MAPKs in a Thr-X-Tyr activation loop and metal-dependent protein phosphatases (PPMs), which are serine/threonine phosphatases, and tyrosine phosphatases (PTPs) Shi, . RepresePTPs are biochemically distinct protein phosphatases and include tyrosine specific phosphatases and dual-specificity (Ser/Thr and Tyr) phosphatases (DSPs) phosphatases (DSPs) belong to a subfamily of the tyrosine phosphatases (PTPs) that can dephosphorylate both phosphoserine/phosphothreonine and phosphotyrosine within the activation loop of MAPKs , synthetic auxins and auxin transport inhibitors and PDR9 genes were characterized, and these two genes encode ABC transporters implicated in the efflux of synthetic auxins mutants, which display a defect in a microtubule-associated protein in the putative kinase interaction motif (KIM) of MAPKs such that the mutation might interfere with interactions with the target MAPK(s). Therefore, it has been proposed that PHS1 may regulate multiple MAPKs; and a subset of its target kinases may be involved in the organization of cortical microtubules. To further investigate the mechanism underlying microtubule regulation, a screen for PHS1-interacting MAPKs was performed; and MPK12 and MPK18 were identified by yeast two-hybrid assays was expressed in the background of phs1-5 to examine if the phosphatase-dead form of PHS1 functions as a dominant-negative microtubule destabilizer which acts in the apical meristem to induce floral identity genes treatment, including activation of MPK6 and MPK3, production of reactive oxygen species (ROS), accumulation of a subset of PAMP-regulated transcripts, and inhibition of seedling growth DC3000 (hereafter referred to as DC3000) dephosphorylates phospho-MPK3 and phospho-MPK6 ibr5-7 suppresses the chilling-induced defense responses of chs3-1 to stabilize CHS3 protein, thus increasing the accumulation of CHS3 . IBR5 interacts with and promotes the accumulation of SNC1 and DC3000 (avrRps4) proteins. IBR5 plays a positive role in regulating R protein CHS3, as evidenced by that mutation of mkp1 mutant results in hypersensitivity to various genotoxic stresses , suggesting that MKP1 plays essential roles in genotoxic stress relief -induced nitric oxide (NO) production in guard cells , superoxide anion O2\u2212 and hydrogen peroxide levels in the TMKP1 transgenic seedlings and downregulation of two ABA-repressed genes , including hydrogen peroxide (H2O2), hydroxyl radical (HO.), singlet oxygen (1O2) and superoxide anion (mkp2 mutants was more severely inhibited by the oxidative agent methyl-viologen (MV) compared to wild type plants , mkp1 mutants produced more ROS than in wild type plants are generated from partial reduction of oxygen treatments , contributing to differences in amplitude and duration of signaling. Many examples have shown that the phosphatase activity of MKPs can be regulated by post-translational modification. Mammalian MKP1s (not an orthologue of plant MKP1s) and yeast Msg5 are phosphorylated by their own substrates MAPKs, and phosphorylation regulates not only the activities but also the abundance of the phosphatases, establishing an efficient negative feedback loop ; and phosphorylation of TMKP1 is required for the interaction , which was mainly localized in cytoplasm, the localization of both MAPKs also changed to the cytoplasm substrates but decreases phosphatase activity on the phosphotyrosine of myelin basic protein (MBP), suggesting that calmodulin differentially regulates substrate specificity but not CaMBDII mutant (W678R) can be activated by CaM, which indicates that CaMBDII plays a more important role than CaMBDI for the regulation of MKP1 binding proteins, where CaM is a CaThis review summarizes current knowledge of the roles of MKPs in multiple signaling pathways. MKPs are involved in many aspects of a plant's life cycle, including growth and development as well as the adaption to various biotic and abiotic stresses. As different signaling pathways integrate through MKPs, it is critical for MKPs to undergo precise regulation to generate correct biological outcomes. These investigations of regulatory mechanisms have provided insights into putative mechanisms that might explain how the phosphatases assist in producing specific signals. The potential combinatorial complexity of different transcriptional/post-transcriptional regulations, differential localization affecting subcellular pools of MAPKs, and the possibility to integrate information from other pathways may have profound effects on organizing the amplitude and duration of targeted kinases.As important as the MKPs appear to be, most of our knowledge regarding their functions is limited to their roles in negatively regulating MAPK signaling, and few other potential upstream and/or downstream targets have yet to be characterized. Genome-wide analyses will certainly facilitate a better understanding of MKPs-mediated signaling pathways by identification of both molecular players in the pathways as well as additional putative MKP targets. A better understanding of how plants coordinate and balance different signaling pathways in response to diverse environmental stimuli could lead to more rationally designed strategies for improving crop yield under changing environmental conditions. Promising results such as the deletion of MKP1 resulting in enhanced resistance to various biotic and abiotic stresses without compromising plant growth (Ulm et al., LJ and SP conceived the main subject of this review and wrote the manuscript. YC and LL provided the suggestions and revisions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Sleep is important for memory consolidation, hence the disruption of normal sleep patterns as a result of age-related changes in the circadian system could be one of the contributors to memory impairment among older adults. It is now well-established that light is the main environmental element that synchronizes circadian rhythms. An appropriate lighting condition can be considered as a non-pharmacological solution to improve the sleep quality of individuals and consequently their overall health and well-being. The present study investigates the effectiveness of two proposed whole-day lighting interventions (L1 and L2) applied by Tunable White Lighting Technology (TWLT) on sleep quality and cognitive performance in older adults. Both lighting interventions provide a high illuminance level (500 lux) in the morning and then the illumination is dimmed gradually throughout the day and reached 100 lux in the evening. However, while L1 offers a constant Correlated Color Temperature (CCT) of 2700K, during the L2 intervention, the CCT is changing in the range of 6500K \u2013 2700K from morning towards evening. Fifteen healthy older adults participated in a 41-day counterbalanced crossover study. Participants were exposed to each lighting condition for 9 days. Actigraphy, standard questionnaires (PROMIS and PSQI), and tests (Trail Making Test (TMT) A & B and Digit Symbol Substitution Test (DSST)) were employed to measure sleep quality and cognitive performance before, during, and after lighting interventions. Significant improvements in sleep quality and cognitive performance were found for both lighting interventions with better outcomes for L2."} +{"text": "Plant is endowed with sessile habit and nutrient acquisition mainly through the root organ, which also provides an excellent model to study stem cell fate and asymmetric division due to well-organized cell layers and relatively simple cell types in root meristem. Besides genetic material DNA wrapped around histone octamer, chromatin structure determined by chromatin modification including DNA methylation, histone modification and chromatin remodeling also contributes greatly to the regulation of gene expression. In this review, we summarize the current progresses on the molecular mechanisms of chromatin modification in regulating root development. The root system constitutes the underground world of a plant, and it takes charge of nutrient and water supply for the whole plant under normal and stress environments. The developmental status of the root system directly determines the plant survival and performance of leaves, stems, flowers, fruits, and seeds, which are closely related to animal and human life. Compared with the aerial part, the building unit of a root system is simple and mainly consists of primary and lateral roots (LRs) without substantial difference in appearance. An intact root system is derived from the tiny root apical meristem (RAM). Proliferation and differentiation of RAM give rise to different types of root cells and tissues.Transcription factors combined with phytohormones, small signaling molecules, and miRNAs play an essential role in regulating the stem cell fate and RAM maintenance during root development . For instance, active marker histone acetylation and repressive marker histone deacetylation are catalyzed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively homologs , three Su(z)12 homologs , a single ESC homolog (FIE), and five p55 homologs (MSI1\u2013MSI5). PRC1 core subunits consist of two RING1 homologs (AtRING1a/b), three Psc homologs (AtBMI1a/b/c), a Pc equivalent (LHP1), and a plant-specific component EMF1, without the Ph counterpart proteins associated with repressive genes and the trithorax group (TrxG) proteins associated with active genes and atrichoblast/non-hair cell (N) in an alternative arrangement, providing a well-characterized system for studying the relationship between root epidermal cell fate decision and positional cue from underlying cortical cells /IAA14 (mIAA14) protein with enhanced inhibiting capacity on the downstream targets ARF7/19 , which is a core component of several HDAC corepressor complexes , resulting in formation of decreased CDF4 protein gradient from differentiated columella, CSCs to QC, which is opposite to the WOX5 protein gradient and permits the exit of stem cell descendants from the stem cell state in roots family ; it downregulates auxin maxima in roots, thereby inhibiting the establishment of founder cells during LR initiation display a certain proportion of \u201cpkl-root\u201d phenotype , FUSCA3 (FUS3), LEAFY COTYLEDON2 (LEC2), and LEAFY COTYLEDON1 (LEC1) and H3K4me3 through the CW domain or PHD domain and H3K27me3 through the PHD domain and reduction in levels of gene repression mark H3K27me3 in seedling and cysteine and tryptophan residue-containing domain (CW), which usually act as histone code reader modules, and the ethylene-responsive element binding factor-associated amphiphilic repression (EAR) domain that functions as a repressive motif to recruit corepressors but is enhanced by GA biosynthesis inhibitor paclobutrazol can recognize the active mark H3K4me3 through the PHD-domain and interact with the RAWUL domain of PRC1 RING-finger proteins through the PAL domain and many additional types pathway by directly targeting the chromatin of several PIN genes and affecting auxin distribution. PLT2 overexpression can partially rescue a brm SCN defect in distinct plants will deepen our understanding of root function and phylogenesis. Root developmental progresses is closely associated with stem cell fate transition during RAM differentiation, where the dynamic change and action mechanism of epigenetic marks in specific cell lineage need to be addressed.clf mutant with curly leaf, early flowering and homeotic conversion of floral organ /Cas (CRISPR-associated) system provides an extremely powerful and labor-saving tool for targeted gene editing. This tool can be used to target several genes simultaneously for fast and efficient generation of high-order mutants (Cong et al., D-HC and YH wrote the manuscript. CJ collected the raw materials. J-PS provided important suggestions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Family members and friends are the main providers of care for persons living with dementia. However, dementia caregivers are at greater risk than other caregivers of experiencing negative caregiving consequences. Despite the development of evidence-based programs to support dementia caregivers, few health or social service organizations offer any of these programs due, in part, to a lack of knowledge about their availability. Best Practice Caregiving is a newly launched website where professionals can get detailed information about these programs. Data collected to develop Best Practice Caregiving are analyzed for a sample of 42 evidence-based dementia caregiving programs to describe similarities and differences among programs including gaps in assistance available from these programs. Results show 64% of programs are delivered to caregivers only while the remaining are delivered to the caregiver and/or persons with dementia. Nearly half (43%) of the 42 programs are delivered in-person, 38% by phone, with 17% delivered all or in part online. Most programs are delivered by professionals (86%) followed by trained lay leaders (40%) and self-guided (12%). Most programs (95%) provide assistance with coping with illness/caregiving and the relationship of the dyad. Fewer than half of the programs assist caregivers with issues regarding finances (45%), end-of-life care (43%), and medical care (40%). Data from 233 delivery organizations show the most common challenge was getting caregivers to accept and complete the program (86%). Delivery sites reported more success with funding the program than with marketing and recruiting participants (mean=6.7)."} +{"text": "Type 2 diabetes mellitus (T2DM) and Heart Failure (HF) are two complex multifactorial diseases that can coexist and strongly amplify each other, suggesting overlapping mechanisms contributing to disease state. T2DM patients with HF have a higher risk of mortality and hospitalization for HF than HF patients without T2DM. Therefore, there is an increasing necessity to find new diagnostic instruments and treatments to improve clinical outcomes in T2DM subjects with HF , current research demonstrate many additional important and possibly beneficial direct effects of these drugs on endothelial cells and cardiomyocytes. SGLT2 inhibitors can normalize elevated sodium and calcium levels in cardiomyocytes through inhibition of the cardiac sodium-hydrogen exchanger, improve vascular function and activate anti-oxidant systems and intracellular stress signals such as AMPK and reduce inflammatory pathways. Further research will have to demonstrate to what extent these cellular cardiac mechanisms contribute to the large beneficial effects of SGLT2i's in clinical trials. Despa then goes on to describe that sodium is often increased in the failing and diabetic cardiac cell. Elevated intracellular sodium can then cause oxidative stress and augments the sarcoplasmic reticulum Ca2+ leak, thus amplifying the risk for arrhythmias and promoting heart dysfunction. Alterations in Na+ extrusion and/or Na+ uptake that underlie the [Na+]i increase in heart failure and diabetes are discussed, and emphasis is placed on the emerging role of Na+ -glucose cotransporters in the diabetic heart. Doliba et al. subsequently demonstrate the functional and energetics consequences of elevated sodium in the diabetic cardiomyocyte in their pioneering studies in this field. Their work clearly indicates that raising sodium in the cardiac cell will directly result in impaired mitochondrial function, possibly explaining the often observed energetic problems in the diabetic heart. These reviews all point to the importance of ionic homeostasis and disturbances in the setting of diabetic cardiomyopathy, cardiac arrhythmias, and the elevated incidence of heart failure in T2DM patients.Liu et al. evaluated the clinical effects of Black garlic in patients with ischemic heart failure. They found that black garlic treatment improved cardiac function in terms of left ventricular ejection fraction and the scores of quality of life (QOL) and decreased circulating BNP precursor N-terminal (Nt-proBNP) by increasing antioxidant levels.The article by Koyani et al. studied the effects of saxagliptin and sitagliptin (anti-hyperglycemic drugs that have been shown to inhibit dipeptidyl peptidase 4 -DPP4) in mouse ventricular cardiomyocytes. The authors showed that saxagliptin (but not sitagliptin) impaired Ca2+ transient relaxation and prolonged action potential duration in cardiomyocytes. They suggested that these results are linked to saxagliptin-DPP9 interaction and following impairment in Ca2+/calmodulin- dependent protein kinase II (CaMKII)- phospholamban (PLB) and protein kinase C (PKC) signaling.Trotta et al. investigated the anti-hypertrophic effect of the melanocortin receptor 5 (MC5R) stimulation in cardiomyocytes exposed to high glucose. The authors showed that MC5R agonists increased viability and reduced total protein in cell stimulated with high glucose via reduced GLUT1/GLUT4 ratio at the plasma membrane and increased intracellular phosphoinositide 3-kinase (PI3K) activity. In addition, MC5R stimulation showed beneficial effects on cardiac function and hypertrophy paralleled by significantly reduced blood glucose levels in a rat model of diabetes (streptozotocin-induced).We have arrived at exciting times in the world of diabetes and heart failure. At last, several novel antidiabetic drugs have shown large cardiovascular benefits in T2DM patients. Understanding the causal mechanism of these effects are now crucial in order to further our understanding of the interaction between diabetes and heart failure, possibly also offering new therapeutic strategies to combat heart failure in the absence of diabetes.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "This study is a secondary analysis of the Outcome and Assessment Information Set (OASIS) and administrative billing records of 6,153 adults \u2265 65 years old who received home health (HH) from a not-for-profit HH agency in upstate New York in CY 2017. We evaluated the association between the use of home health services (HH) with the hazard of unplanned facility admissions among Medicare patients with and without Alzheimer\u2019s disease and related dementia (ADRD). Outcome was time from HH start of care to an unplanned facility admission of any type, including the hospital, nursing home, or rehabilitation facility. Independent variables included weekly intensity of each discipline, including skilled nursing (SN), physical therapy (PT), occupational therapy (OT), social work (SW), and home health aide (HA), separately. ADRD was identified by diagnosis (ICD-10 codes) and cognitive impairment . In multivariable Cox Proportional hazard models that adjusted for time-varying effects of HH intensity, receiving the highest intensity of SN (3.3 visits of 2.78 hours per week) and PT (2.5 visits of 2 hours per week) was related to up to a 54% and 86% decrease, respectively, in the hazard of unplanned facility admission among patients with ADRD , and decreases of 56% and 90% respectively among patients without ADRD . This is the first study in the United States showing that receiving a sufficient amount and appropriate mix of HH services was associated with substantially reduced risk of unplanned facility admission among patients with ADRD by up to 86%."} +{"text": "The oomycete-specific ITS primers published by Oomycetes, which probably results in a lower proportion of this group in metabarcoding studies. We hereby provide the updated figure (Figure Closer examination revealed that the sequence of primer ITS1oo in Figure PageBreak"} +{"text": "Therapeutic strategies to restore hearing and balance in mouse models of inner ear disease aim to rescue sensory function by gene replacement, augmentation, knock down or knock out. Modalities to achieve therapeutic effects have utilized virus-mediated transfer of wild type genes and small interfering ribonucleic acids; systemic and focal administration of antisense oligonucleotides (ASO) and designer small molecules; and lipid-mediated transfer of Cas 9 ribonucleoprotein (RNP) complexes. This work has established that gene or drug administration to the structurally and functionally immature, early neonatal mouse inner ear prior to hearing onset is a prerequisite for the most robust therapeutic responses. These observations may have significant implications for translating mouse inner ear gene therapies to patients. The human fetus hears by gestational week 19, suggesting that a corollary window of therapeutic efficacy closes early in the second trimester of pregnancy. We hypothesize that fetal therapeutics deployed prior to hearing onset may be the most effective approach to preemptively manage genetic mutations that cause deafness and vestibular dysfunction. We assert that gene therapy studies in higher vertebrate model systems with fetal hearing onset and a comparable acoustic range and sensitivity to that of humans are an essential step to safely and effectively translate murine gene therapies to the clinic. Gene replacement, augmentation, knock down and knock out strategies have been elucidated to ameliorate the effects of deleterious mutations that cause hearing loss and vestibular dysfunction in mouse models of human inner ear disease. Table Vglut3 knockout mouse after round window membrane inoculation at postnatal day 1\u20133 , compound action potentials (CAP) and acoustic startle -mediated gene transfer to the sensory epithelium by delivery through the round window membrane introduces a cryptic splice site in exon 3 of the PDZ domain scaffolding protein, harmonin and generates a frameshift with premature stop codon. The splicing machinery strongly prefers the cryptic splice site though wild type splicing is not precluded. The Ush1c c.G216A knock-in mouse accurately models the hearing and vestibular abnormalities seen in USH1C patients to interfere with pre-mRNA splicing from the cryptic splice site and enhance wild type splicing. ASO therapy restored functionally relevant levels of protein expression, improved hair cell survival, rescued ABR thresholds at low and intermediate frequencies, and corrected vestibular dysfunction . The French-Acadian mutation of the transmembrane channel-like 1 (TMC1) gene is dominantly inherited and causes progressive hearing loss in mice from 8 kHz to 22.6 kHz thresholds, a sensitive measure of outer hair cell function protein joins SANS cause Usher syndrome type 1G (Ush1g) characterized by congenital profound sensorineural hearing loss and vestibular dysfunction at birth with onset of retinitis pigmentosa by adolescence -GFP at P2.5 improved stereociliary bundle morphology in auditory and vestibular hair cells. In addition, Sans rescued mechanoelectrical transduction currents in inner and outer hair cells, modestly improved ABR thresholds from 5 kHz to 15 kHz, and completely restored vestibular function measured by circling behavior and vestibulo-ocular reflex (VOR) testing designed against the Beethoven allele was delivered by lipid-mediated transfer to the mouse inner ear at P0\u2013P2 -GFP mouse cochlea at 6 weeks of age to test the efficiency of inner ear genome editing in adult hair cells. Encouragingly, GFP expression was perturbed in 25% of the adult, Atoh1-GFP hair cells /Cas9 nuclease genome editing system further validates the early neonatal window of efficacy while offering potential for adult inner ear genetic modulation. The The literature discussed thus far demonstrates that AAV-, ASO- and CRISPR/Cas9 RNP-based therapies achieve maximal benefit for recessively and dominantly inherited forms of deafness and vestibular dysfunction when initiated from P0\u2013P5. Furthermore, initiating therapeutic strategies after P5 shows reduced efficacy or the elimination of therapeutic benefit entirely Table . The thoClarin 1 is expressed in inner and outer hair cells as well as spiral ganglion neurons in the mouse cochlea mouse under the control of the Atoh1 3\u2019 enhancer/\u03b2-globin basal promoter sequence family are potent transcriptional repressors of Atoh1 expression preventing hair cell fate commitment is one of four connexins expressed in the inner ear that link all supporting cells with adjacent epithelial cells but not hair cells and the auditory sensory epithelium degrades at P18 and the EP was significantly improved (n = 5 mutant mice). An alternative model system was developed due to the difficulty in obtaining sufficient numbers of mutant mice for extensive analysis. A plasmid encoding four short hairpin RNAs (shRNAs) against Cx-30 was electroporated into wild type mice at E11.5 that knocked down Cx-30, elevated ABR thresholds to over 90 dB SPL from 4 KHz to 20 KHz, and depleted the EP. Co-electroporation of a shRNA-resistant sequence encoding Cx-30 along with the shRNAs against wild type Cx-30 in wild type mice resulted in improved ABR thresholds and EP is a nuclear-localized, long noncoding RNA robustly expressed in a diverse array of tissues that is nonessential for mouse pre- and postnatal development (Zhang et al., MALAT1 RNA effectively reduced expression in most mouse tissues analyzed (Wheeler et al., MALAT1 ASO into the E13-E13.5 mouse amniotic cavity reduced MALAT1 RNA abundance in the inner ear through P15 establishing that the ASO gains entry into embryonic tissues and exerts its bioactive effects through the second postnatal week (Depreux et al., Ush1c mutant mice generated correctly spliced harmonin RNA in the inner ear at P22 (Depreux et al., While direct injection of bioactive reagents into the developing inner ear is formally a plausible gene therapy strategy, it is unlikely that targeted injections will be conducted into the human otic vesicle which first forms by GA 6 not long after most pregnancies are first verified (Streeter, The therapeutic modulation of inner ear gene expression by systemic and focal injections of bioactive reagents has defined authentic gene therapy strategies in mouse models of hearing loss and vestibular dysfunction. The literature establishes that therapeutic intervention in the functionally immature mouse inner ear by 5 days postnatal age leads to optimal recovery of hearing and balance. This early neonatal window of therapeutic efficacy holds irrespective of the molecular strategy, delivery modality, or viral vector serotype deployed. Moreover, a corollary prenatal window of therapeutic efficacy in humans is predicted to close by 19 weeks of GA before the onset of fetal hearing. The efficacy of fetal gene therapy to preemptively correct deleterious genetic mutations in the organogenesis stage mouse embryo before the onset of inner ear disease is an emerging research focus that has promising potential. The process of defining and validating fetal and postnatal gene therapies will be critically enhanced by rigorous evaluation in higher vertebrate model systems in which the fetal onset of hearing is a defining feature.LW, JK and JB identified the need for a comprehensive review of the literature on gene therapy to treat inner ear disease. LW, JK and JB compiled the necessary literature and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Kweni, Cengkir, Palmer and Kent). Near infrared spectral data were collected and recorded as absorbance (Log(1/R)) data in wavelength range of 1000\u20132500 nm. Those spectral data are potential to be re-used and analysed for the prediction of mango quality attributes in form of vitamin C, soluble solids content (SSC) and total acidity (TA). Spectra data can be corrected and enhanced using several algorithms such as multiplicative scatter correction (MSC) and de-trending (DT). Prediction models can be established using common regression approach like partial least square regression (PLSR).Presented dataset contains spectral data on near infrared region for a total of 186 intact mango fruit samples from 4 different cultivars ( Spectra/R in wavSpectra data set were then used to establish prediction model for the determination of inner quality attributes on intact mangos using regression approach. One of the most promising and common regression method in NIRS practices is partial least square regression (PLSR) . This me22.1The NIR instrument used to obtain spectral data is Fourier transform near infrared (FT-NIR) (Thermo Nicolet Antaris II TM). It was configured and controlled under integrated software Thermo Integration\u00ae and Thermo Operation\u00ae. The workflow has been developed and set up to run specified tasks for spectra data acquisition of intact mango samples. High resolution measurement with integrating sphere was chosen as a basic measurement ..spa) and comma separated value (.csv). Standard laboratory method also prepared for inner quality attributes measurements of mango as vitamin C, soluble solids content (SSC) and total acidity (TA). Hand held refractometer was used for SSC, automatic titrator equipment for TA and standard manual titration method for vitamin C measurement respectively. The centrifuge was also used to obtain clarified sample juice and separate suspended solids.Sample naming and labelling was required automatically for each spectra acquisition in order to distinct all 186 mango samples. Background spectra correction was carried out every hour automatically. Spectra data were recorded in form of absorbance (Log(1/R)) in wavelength range from 1000 to 2500 nm and saved in two different file extension formats: Nicolet [Once after spectra data acquisitions are completed, fruit samples were directly sliced and some part of mango pulp were taken. To measure vitamin C, a total 5g of mango pulp samples were macerated, mixed and homogenized with addition of 20 ml of meta-phosphoric acid into a beaker to prevent oxidation. Distilled water were added until 50 ml of volume was reached. Vitamin C was obtained and quantified based on its reaction with the ass (FM) .oBrix while automatic titration method with 0.1 N NaOH to an end point of pH 8.1 was used to measure TA of intact mango and expressed as mg\u2219100g\u22121 fresh mass [On the other hand, SSC and TA quality attributes were measured by making another juices from 20 g of pulp sample and maximum of 100 ml distilled water. A little filtered juice was squeezed and dropped into a hand-held refractometer to record SSC in form of esh mass ,6. Descr2.4The Unscrambler X 10.1 software with network client license.It is highly recommended to perform spectra correction and enhancement prior to prediction model development. There are several methods and approaches that can be used to enhance spectra data, among of them are Multiplicative scatter correction (MSC) and de-trending (DT). Spectra enhancements were used to correct additive and multiplicative effects in the spectra. The MSC and DT spectra corrections were carried out using 2.5The main part of NIRS application is to develop models used to predict desired quality attributes of intact mango simultaneously. Prediction models were constructed to reveal information about mango quality attributes buried in absorbance spectra data. These models were developed commonly by regressing spectra data (as X variable) and actual measured quality attributes (as Y variable) through multivariate analysis. Partial least squares regression (PLSR) was applied to develop those models and validated using full cross validation approach.2) between predicted and measured quality attributes, prediction error which is defined as the root mean square error (RMSE) and the residual predictive deviation (RPD), defined as the ratio between standard deviation (SD) of the population's actual value of Vitamin C, SSC and TA, and the RMSE of predicted quality attributes. The higher value of RPD, the greater probability of models to predict desired quality parameters or chemical constituent of samples dataset accurately [The prediction performances were evaluated by means of these following statistical parameters: the coefficient of correlation (r) and determination (Rcurately ."} +{"text": "Two multimetric indices have been developed to help address fish community (reservoir fish assemblage index [RFAI]) and individual population quality (sport fishing index [SFI]) in Tennessee River reservoirs. The RFAI, with characteristics similar to the index of biotic integrity (IBI) used in stream fish community determinations, was developed to monitor the existing condition of resident fish communities. The index, which incorporates standardized electrofishing of littoral areas and experimental gill netting for limnetic bottom-dwelling species, has been used to determine residential fish community response to various anthropogenic impacts in southeastern reservoirs.The SFI is a multimetric index designed to address the quality of the fishery for individual resident sport fish species in a particular lake or reservoir[4]. The SFI incorporates measures of fish population aspects and angler catch and pressure estimates. This paper proposes 70% of the maximum RFAI score and 10% above the average SFI score for individual species as \u201cscreening\u201d endpoints for balanced indigenous populations (BIP) or adverse environmental impact (AEI). Endpoints for these indices indicate: (1) communities/populations are obviously balanced indigenous populations (BIP) indicating no adverse environmental impact (AEI), or are \u201cscreened out\u201d; (2) communities/populations are considered to be potentially impacted; and (3) where the resident fish community/population should be considered adversely impacted. Suggestions are also made concerning how examination of individual metric scores can help determine the source or cause of the impact."} +{"text": "To assess the link between the risks of most frequent cancer sites in Poland and selected socioeconomic variables that potentially affect health outcomes throughout the life course.p\u00a0<\u00a00.05 (two-tailed tests).This is a cross-sectional ecological study. Incidence of lung, breast, and colon cancer by voivodeships in 2014 was calculated based on Polish National Cancer Registry. Socioeconomic variables in individual voivodeships were assessed based on Polish Social Cohesion Survey for 2015. Spearman\u2019s rank correlation coefficient was used to test the association of incidence rates and socioeconomic variables. The significance level was set at Statistically significant negative correlation exists between: (1) friend-/neighbour-based social capital and colon and breast cancer, (2) association-based social capital and lung cancer, (3) high religiousness and lung and breast cancer, and (4) income poverty and breast cancer. Statistically significant positive correlation exists between: (1) social isolation, living conditions poverty, poverty resulting from the lack of budget balance, and lung cancer; (2) low/no involvement in religious activity and lung and breast cancer.Our findings support public health concerns over the implication of socioeconomic environment for cancer. Cancer is one of the major contributors to health burden worldwide. In 2012 14.1 million new cases and 8.2 million deaths were reported. Lung, breast and colorectal were the most frequently diagnosed cancers have rarely been analysed. Only one study, performed in the Opole province, found statistically significant positive correlation between unemployment rate and lung cancer incidence rates among male population is conceptualized as an area-level attribute. Socioeconomic determinants are conceptualized as a group attribute that affects all individuals living within the community and the interest is drawing inferences regarding differences between areas.http://onkologia.org. Data storage enables analysis of cancer incidence and mortality by type of cancer (classified according to ICD-10), age, sex and voivodeship, as well as creating custom reports. The average completeness of the Cancer Registry in Poland has been continuously improving and is currently estimated to be 94% .The cancer risk in each of 16 Polish voivodeships was calculated as incidence rates and expressed as the number of newly registered cases of cancer in 2014 per a population of 100,000. The absolute numbers of newly registered cases of lung, breast and colon cancer in Poland by voivodeships were retrieved from the Polish National Cancer Registry (NCR). NCR is a principal data source for cancer incidence in the Polish population. Healthcare providers are legally obliged to provide annual reports to NCR about every case of cancer diagnosed within the Polish population. Principles of data collecting and institutions responsible for cancer registries in Poland are specified in two acts: the Act on Public Statistics and the Act on the Health Care Information System and an ordinance issued on the basis of the said Act. The unit responsible for the registry is the National Cancer Registration Office, which is an organizational unit of the Cancer Centre and Institute of Oncology. New cases of cancer are collected via specific cancer registration forms (MZ/N-1a form) and each voivodeship is obliged to deliver the data to a shared NCR database. The data is validated using rules enforced to the system. An online database is available at Area-based socioeconomic measurements were retrieved from the Polish Social Cohesion Survey for the year 2015 . The effect of potential confounders such as sex, age and completeness of cancer registration distribution across regions was accounted for by Spearman\u2019s partial rank correlation. The basis for the evaluation of the completeness of cancer registration in particular voivodeships was the ratio of mortality to incidence (M/I\u2013Index) calculated for each cancer site in the same period of time was used to examine the link between incidence rates of particular types of cancer and socioeconomic determinants. A significance level of The ranking of voivodeships according to incidence rates of particular cancers differs considerably Table\u00a0. The higSocial isolation, social capital, religious activity and poverty in individual voivodeships is presented in Table\u00a0Voivodeships showed wide disparities in social capital levels. The lowest ratio for high degree of association-based social capital was recorded in Pomeranian, Swietokrzyskie (16%), Lodz (14%) and Warmian-Masurian (13%), whereas the highest in Podlaskie (31%), Opole (25%) and Lublin (24%). The share of persons with high level of familial capital was lowest in West Pomeranian (19%) and highest in Swietokrzyskie (34%), Opole (31%), Lesser Poland (31%), Subcarpathian (31%), Lublin (31%). The lowest value for the indicator for high level of friends- and neighbours-based social occurred in Kuyavian-Pomeranian (21%), Lodz and Lower Silesian (23%), the highest in Lesser Poland (34%), Subcarpathian (33%) and Swietokrzyskie (32%).The attitude to faith varied from one voivodeship to another. Percentage of people who declared to be \u201cprofound believers\u201d was highest in Opole (16%), Subcarpathian (15%), Podlaskie (15), Lublin (14%), and lowest\u2014in Lubusz (6%), Lodz (7%), Kuyavian-Pomeranian (7%), and West-Pomeranian (7%). In 7 voivodeships the percentage of religiously uncommitted and nonclerical people is lower than the mean for entire Poland (39%), voivodeships with the topmost percentage of religiously uncommitted inhabitants are West Pomeranian (56%), Warmian-Masurian (54%) and Lubusz (50%).Income poverty affects inhabitants of Lublin (27%), Swietokrzyskie (24%) and Subcarpathian (21%) more often, whereas those residing in the southwest part of Poland are at a lower risk: Silesian (7%), Lubusz, Opole, Lower Silesian (11%). The same value (11%) was observed in the Mazovian voivodeship as well. Voivodeship proved to have a different impact on the risk of living conditions poverty than on income poverty. The highest rates of living conditions poverty were recorded in Warmian-Masurian (12%), West Pomeranian (12%), \u015awi\u0119tokrzyskie (11%) and \u0141\u00f3d\u017a (11%), and the lowest in Podlaskie (5%), Greater Poland (6%) and Silesian (7%). Poverty in terms of lack of budget balance more often affects the West Pomeranian households (18%). Other voivodeships with high shares of households experiencing difficulties with balancing their budgets included Lubusz (15%), Lodz (15%), Pomeranian (14%) and Warmian-Masurian (14%). The lowest values were reported in Subcarpathian (6%) and Podlaskie (7%).p\u00a0=\u00a00.007), (2) two types of poverty: living conditions poverty and poverty following a lack of budget balance , and (3) low/no involvement in religious activity . A statistically significantly strong negative correlation was found between risk of lung cancer and: (1) high level of association-based social capital , and (2) high religiousness . After age and sex adjustment the Spearman\u2019s correlation coefficients remained similar, with the exception of correlation with association-based social capital which was stronger after correcting for sex . Adjustment for completeness of cancer registry strengthened the positive association between lung cancer incidence and low/no involvement in religious activity , and made the negative associations between lung cancer incidence, family based social capital and friend- and neighbour-based social capital stronger and statistically significant . After adjustment for completeness of cancer registry the correlations between lung cancer incidence, living conditions poverty and association-based social capital were no longer statistically relevant.The relevance and magnitude of associations between cancer risk and socioeconomic variables varies greatly by cancer site Table\u00a0. Spearmap\u00a0=\u00a00.04), (2) high level of friend- and neighbour-based social capital , and (3) high religiousness , and positively related to low/no involvement in religious activity . After sex, age and completeness of data adjustment the correlations between breast cancer incidence and socioeconomic variables were not substantially modified, only correlation with income poverty became statistically insignificant.The risk of breast cancer was statistically significantly negatively related to: (1) income poverty . Adjustment for age, sex and data completeness produced fairly similar coefficients.The only statistically relevant for colon cancer was a negative correlation between colon cancer risk and high level of friend- and neighbour-based social capital imply that a low income situation (determined by revenue) does not necessarily signify other poverty forms. Time factor is, therefore, extremely important, because poor living conditions and budget difficulties result from unfavourable income situation continuing for a longer period. The strong relationship with material situation observed for association-based capital and social isolation suggests a coexistence of these factors. All of these determinants were correlated with lung cancer risk. However, the question whether poverty caused social isolation and low level of association-based social capital, or if, conversely, social isolation and low level of association-based capital caused poverty, is still to be answered.These results should be interpreted in light of relationships that may exist between the socioeconomic variables selected to the analysis. Theoretically these determinants have different meaning, but there are correlations between them, except for relationships between income poverty and other socioeconomic determinants, various forms of social capital, as well as social isolation and informal social capital . Lack of correlation between income poverty and other poverty forms and strong correlation between living conditions poverty and poverty following a lack of budget balance is well known and repeatedly discussed and influencing health care accessibility, use of cancer screening programmes and effective treatments. National policy actions which can have an important effect on the magnitude of social inequalities in cancer incidence might significantly reduce the burden and disparities in various populations and geographic areas. Our study showed that the relevance and magnitude of associations between socioeconomic variables and cancer risk vary greatly by cancer site. It provides important additional information about how socioeconomic mechanisms work. Social and economic inequalities can be avoided; therefore their limitation constitutes an achievable goal and an ethical imperative."} +{"text": "Overall growth and development of a plant is regulated by complex interactions among various hormones, which is critical at different developmental stages. Some of the key aspects of plant growth include seed development, germination and plant survival under unfavorable conditions. Two of the key phytohormones regulating the associated physiological processes are gibberellins (GA) and abscisic acid (ABA). GAs participate in numerous developmental processes, including, seed development and seed germination, seedling growth, root proliferation, determination of leaf size and shape, flower induction and development, pollination and fruit expansion. Despite the association with abiotic stresses, ABA is essential for normal plant growth and development. It plays a critical role in different abiotic stresses by regulating various downstream ABA-dependent stress responses. Plants maintain a balance between GA and ABA levels constantly throughout the developmental processes at different tissues and organs, including under unfavorable environmental or physiological conditions. Here, we will review the literature on how GA and ABA control different stages of plant development, with focus on seed germination and selected abiotic stresses. The possible crosstalk of ABA and GA in specific events of the above processes will also be discussed, with emphasis on downstream stress signaling components, kinases and transcription factors (TFs). The importance of several key ABA and GA signaling intermediates will be illustrated. The knowledge gained from such studies will also help to establish a solid foundation to develop future crop improvement strategies. Overall growth and different developmental stages of plants are under strict regulation by several classes of plant hormones. Hormone molecules are present at low concentrations in plants, and they function either at the sites of synthesis or after they are transported to different tissues of crop plants enzyme and abscisic aldehyde oxidase (AAO), respectively and AAO3 (AAO3/ABA3/LOS5) were upregulated in Arabidopsis. Furthermore, transcript levels of NCED3, ABA3/LOS5, and AAO3 were induced by abiotic stresses catalyze the deactivation reaction resulting in phaseic acid (PA) and dihydro phaseic acid (DPA) as the main ABA catabolites and in turn regulate transcription of several downstream ABA-responsive genes infection in rice by Teijiro Yabuta and co-workers was the result of an investigation of fungal from the precursor compound geranylgeranyl diphosphate (GGDP), which is aided by terpene synthases (TPSs), cytochrome P450 monooxygenases (P450s), and 2-oxoglutarate\u2013dependent dioxygenases (2ODDs) and ent-kaurene synthase (KS), which are located in the plastids are responsible for the first few steps of GA biosynthesis (conversion of GGDP to ent-kaurene). Then two P450 enzymes, namely, ent-kaurene oxidase (KO) and ent-kaurenoic acid oxidase (KAO) convert ent-kaurene to GA12. Finally, three active GAs are formed by reactions catalyzed by GA 20-oxidase (GA20ox) and GA 3-oxidase (GA3ox), that belong to 2ODDs showed drought tolerance phenotype and overexpression of GA20ox confers drought sensitivity in Arabidopsis genes and growth arrest by activating a basic leucine zipper transcription factor, ABSCISIC ACID INSENSITIVE 5 (ABI5) and activates a GA catabolic gene (GA2ox2) indirectly and represses an ABA catabolic gene (CYP707A2) which acts downstream to PIL5, leads to repression of GA biosynthesis and activation of ABI3 and ABI5 which leads to increased dormancy and hence increases the ABA level whereas it decreases the GA level by repressing GA biosynthesis genes in Arabidopsis seeds lead to changes in the plant response and therefore alter the balance of endogenous levels of GA and ABA. High temperature induces ABA biosynthesis genes module , which results in stabilization of the receptor. Conversely, opposite effect has been shown by GA by inhibiting rice SnRK2 has a link between GA and ABA signaling in rice via SnRK2-APC/CCYP707A1 and CYP707A2) -domain containing transcription factors (ATFs), Arabidopsis ABA-INSENSITIVE 4 (ABI4) and rice OsAP2-39, have key roles in the antagonistic crosstalk between ABA and GA. ABI4 positively regulates primary seed dormancy by downregulating GA biosynthesis and by inhibiting ABA catabolic genes and indirectly repressing GA biosynthesis genes (GA3ox1 and GA20ox1) , B3 domain factors LEC2, and FUSCA3 (FUS3) and modulating expression of GA metabolic genes as well as signaling cascades that regulate downstream target genes (of different classes) further add to the complexity of the already elaborate cellular communication network. This has been highlighted here with the examples of ABA and GA metabolism and their regulation. Selected genes that play significant roles in the regulation of seed dormancy and germination and various abiotic stresses were also discussed. It is evident that several positive and negative regulators of ABA and GA have direct or indirect impacts on germination and abiotic stresses. Many transcription factors and signaling components of these two phytohormones help to maintain an intricate balance between endogenous levels of bioactive ABA and GA. Furthermore, studies have identified several ABA and GA crosstalk points showing positive and negative regulation of different molecular modules associated with their metabolism and signaling. There are a few open questions that can help in formulating the future research directions. Despite the fact that there are some studies on ABA transport in different cell types and tissues, there might be many unknown pathways/transporters that are yet to be explored. Moreover, very few reports on the transport mechanism of GA are available. The antagonistic roles of GA and ABA in controlling developmental processes have been established by several pieces of evidence; however, there could be synergistic crosstalk between GA and ABA in some instances whose underlying molecular mechanisms remain undiscovered. Although several target genes of a few TFs have been established (Yaish et al., BV and PK conceived the idea and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Escherichia coli (aEPEC) has been increasing worldwide. Here, we report the draft whole-genome sequences of 10 aEPEC strains isolated in Brazil.The number of diarrhea cases caused by atypical enteropathogenic Escherichia coli (aEPEC) has been increasing worldwide. Here, we report the draft whole-genome sequences of 10 aEPEC strains isolated in Brazil. These sequences will provide an important source for future studies concerning aEPEC pathogenicity and genetic markers of potentially virulent strains.The number of diarrhea cases caused by atypical enteropathogenic Escherichia coli (EPEC), which is one of the diarrheagenic E. coli pathotypes. EPEC is subdivided into typical EPEC (tEPEC) and atypical EPEC (aEPEC) based on the presence of the EPEC adherence factor (EAF) plasmid in the former group and its absence in the latter group lesions in the intestinal epithelium, in which intimate adherence between bacteria and host cells occurs \u20138. The g\u2013The number of cases of diarrhea caused by aEPEC has increased even in industrialized countries. This information reveals the need for a thorough knowledge of the genetic traits of aEPEC organisms and their mechanisms of pathogenicity in order to develop appropriate control strategies , 10, 11.The 10 aEPEC strains we sequenced were isolated from feces of children under 5\u2009years old during epidemiological studies carried out in S\u00e3o Paulo, Brazil (1985 to 1986 and 1989 to 1990) by the Laboratory of Microbiology of the Universidade Federal de S\u00e3o Paulo (UNIFESP) and in Salvador (2003 to 2004) by the Laboratory of Bacteriology of the Butantan Institute , 13. Allde novo assembly and annotation of the genomes were performed using the software SPAdes version 3.9.1 (with the \u2013careful flag) (DNA extraction was performed using the QIAamp DNA minikit (Qiagen) according to the manufacturer\u2019s instructions. DNA libraries from each aEPEC genome were prepared using the Nextera XT library prep kit and sequenced at MicrobesNG on the Illumina HiSeq 2500 platform using 2- \u00d7 250-bp paired-end reads, achieving between 34 and 157\u00d7 depth . Trimmomul flag) , respectThese sequences will provide an important source for futures studies concerning aEPEC pathogenicity and genetic markers of potentially virulent strains. Furthermore, these data will permit comparative studies to be carried out with aEPEC strains isolated in Brazil and others isolated in different countries.PRJNA490882, and the whole-genome shotgun sequences were deposited in the GenBank database under the accession numbers shown in The reads used for assembly of the 10 aEPEC genomes were deposited in the Sequence Read Archive (SRA) at the National Center for Biotechnology Information (NCBI) under the accession number"} +{"text": "This paper focus to examine the best molecular interaction between Polyamide Thin Film Composite (PA TFC) layers with different properties of the support membrane. The support membrane of Nylon 66 (N66) and Polyvinylidene fluoride (PVDF) was chosen to represent the hydrophilic and hydrophobic model respectively in the Molecular Dynamic (MD) simulation. The Condensed-Phase Optimized Molecular Potential for Atomistic Simulation Studies (COMPASS) force field was used with the total simulation runs were set 1000 picoseconds run production ensembles. The temperature and pressure set for both ensembles were 298 K and 1 atm respectively. The validity of our model densities data was check and calculated where the deviation must be less than 6%. The comparison between hydrophobic and hydrophilic of the support membrane data was examined by the distance and magnitude of intensity of the Radial Distribution Function (RDF's) trends. The interactions of binary system (MPD/TMC) were comparing with both the tertiary system, (N66/MPD/TMC) and (PVDF/MPD/TMC)[10]. Where:N (MPD) \u2013 C (TMC): Intermolecular interaction (crosslink) between nitrogen in the MPD molecules with carbon in the TMC group There were also interactions detected between TMC-subtracts presented inwhich contributes to the better attachment of TFC layer onto support membrane. Where:Cl (TMC) \u2013 O (N66): Intermolecular interaction between chlorides in the MPD molecules with the oxygen atom in the N66 group.O (TMC) \u2013 H (N66): Intermolecular interaction between oxygen in the MPD molecules with the hydrogen atom in the N66 group.Cl (TMC) \u2013 F (PVDF): Intermolecular interaction between chlorides in the MPD molecules with the fluorine atom in the PVDF group.Cl (TMC) \u2013 H (PVDF): Intermolecular interaction between chlorides in the MPD molecules with the hydrogen atom in the PVDF group.2All simulations were performed using Material Studio (version 7.0) software from Accelrys, Inc. Models were firstly undergoing the geometry optimization and then the energy started to minimized. The molecules of the models chosen represent in"} +{"text": "Bos gaurus hubbacki), locally known as the seladang, from two captive centers. Thirty fecal samples of Malayan gaur were collected from Jenderak Selatan Wildlife Conservation Center (Pahang) and the Sungkai Wildlife Reserve (Perak) for DNA extraction and amplification with polymerase chain reactions. DNA sequences were then analyzed using neighbor joining (NJ) and maximum parsimony (MP) methods. Based on the 652 base pairs obtained, we found seven variable characters with a value of 1%. The genetic distance between the two captive centers was 0.001. Haplotype analyses detected only four haplotypes between these two captive centers. Both NJ and MP trees demonstrate that all individuals in the Jenderak and Sungkai captive centers are in the same clade. Genetic variation of the Malayan gaur in these centers is considered low, possibly because individuals share the same common parent. This sequence variation data are of paramount importance for designing a proper breeding and management program of the Malayan gaur in the future.This article contains data of the sequence variation in the mitochondrial DNA D-loop region of the Malayan gaur ( Specifications tableValue of the data\u2022The data presented here provide sequence variations of Malayan gaur in captivity.\u2022Genetic relationships among captive Malayan gaur individuals.\u2022Revealing inbreeding in which they might share the same common parent.\u2022The data are useful for decision-making in the breeding and management program of the Malayan gaur.1We present D-loop region sequence data 2The DNA chromatograms of the s"} +{"text": "Scientific Reports 10.1038/s41598-018-35051-w, published online 12 November 2018Correction to: This Article contains typographical errors in the Results section where,20), Marinimicrobium, Marinobacter and Acinetobacter (Table 1). A decrease in biodiversity is observed as the salinity of the lagoons increase (Table 1), revealing the higher salinity tolerance of Marinimicrobium and Marinobacter species compared to that of Halomonas and Acinetobacter species here reported.\u201d\u201cMassive parallel sequencing of 16S ribosomal RNA gene amplicons showed that more than 60% of the sequences found in the lagoons belonged to only four main OTUs , specifically to the Class Gammaproteobacteria: Halomonas (found worldwideshould read:20), Marinimicrobium, Marinobacter and Acinetobacter (Table 2). A decrease in biodiversity is observed as the salinity of the lagoons increase (Table 2), revealing the higher salinity tolerance of Marinimicrobium and Marinobacter species compared to that of Halomonas and Acinetobacter species here reported.\u201d\u201cMassive parallel sequencing of 16S ribosomal RNA gene amplicons showed that more than 60% of the sequences found in the lagoons belonged to only four main OTUs , specifically to the Class Gammaproteobacteria: Halomonas (found worldwide"} +{"text": "As the age of the US population increases, so does cognitive impairment (CI); therefore early detection of CI is critical for ensuring its appropriate management. As part of a NINDS Consortium to detect CI and dementia in primary care (DetectCID), we are implementing and evaluating a brief 2-step CI detection paradigm (MyCog), that can be delivered in clinics with diverse populations via the electronic health record (step 1) and iPad (step 2). We conducted focus groups with 25 clinicians and administrative leaders from academic and community primary care practices to 1) understand how CI is being assessed, and 2) evaluate the feasibility of implementing the MyCog paradigm into existing primary care workflows. Several key themes emerged from the discussions. No proactive detection strategy for CI was regularly used outside of the Medicare Annual Wellness Visits (AWV); variable assessments including the Minicog, MoCA, or MMSE were used to fulfill the AWV requirement. Regarding the feasibility of our MyCog Paradigm, our 2-step process was positively received, with the brief case-finding step 1 satisfying AWV requirements and replacing the longer assessments currently being used. Clinicians preferred that step 2 be self-administered due to limited clinician time for wellness visits, and highlighted logistical challenges such as room availability and storage and maintenance of the iPad. Overall, clinicians felt that the identification of CI was valuable and supported standardization, but indicated regular case finding was unlikely without clear guidance on clinical decision-making."} +{"text": "TOX3 (16q) at 1.5% frequency, as well as for CCND2 (12p) and ANXA11 (10q) at 1% frequency, in addition to the well-known targets ERBB2 (17q) and MYC (8q). Focal amplifications with \u226515 or \u22655 additional copies of at least one of these regions were associated with a poor overall survival among patients with stage I-III MSS CRCs . All high-level amplifications were focal and had a more consistent relationship with gene expression than lower amplitude and/or broad-range amplifications, suggesting specific targeting during carcinogenesis. Genome-wide, copy number driven gene expression was enriched for pathways characteristic of the CMS2-epithelial/canonical subtype, including DNA repair and cell cycle progression. Furthermore, 50% of upregulated genes in CMS2-epithelial/canonical MSS CRCs were driven by CNAs, an enrichment compared with the other CMS groups, and associated with the stronger correspondence between CNAs and gene expression in malignant epithelial cells than in the cells of the tumor microenvironment . In conclusion, we identify novel recurrent amplifications with impact on gene expression in CRC and provide the first evidence that CMS2 may have a stronger copy-number related genetic basis than subtypes more heavily influenced by gene expression signals from the tumor microenvironment.About 80% of colorectal cancers (CRCs) have chromosomal instability, which is an integral part of aggressive malignancy development, but the importance of specific copy number aberrations (CNAs) in modulating gene expression, particularly within the framework of clinically relevant molecular subtypes, remains mostly elusive. We performed DNA copy number profiling of 257 stage I-IV primary CRCs and integrative gene expression analysis in 151 microsatellite stable (MSS) tumors, focusing on high-level amplifications and the effect of CNAs on the characteristics of the gene expression-based consensus molecular subtypes (CMS). The results were validated in 323 MSS tumors from TCGA. Novel recurrent high-level amplifications with a major impact on gene expression were found for BRAF mutation in CMS1 and KRAS mutation in CMS3, and the low frequency of somatic copy number aberrations (CNAs) in MSI is well established. However, little is in general known about the genetic basis for the distinct gene expression-based subtypes.Colorectal cancers (CRC) can be classified into four biologically distinct and clinically relevant consensus molecular subtypes (CMS) based on their global gene expression patterns . A few gChromosomal instability is an integral part of canonical CRC pathogenesis, and the majority of CRCs are characterized by a large burden of CNAs. Chromosomal instability is associated with poor patient prognosis and resiERBB2 amplification, is a druggable target, and the HERACLES trial demonstrated a 30% response rate to dual HER2 blockade in the 5% subpopulation of HER2 positive and KRAS wild-type metastatic cancers samples on gene expression (or among top five samples on gene expression when fewer than five samples displayed amplification). Similar correspondence analyses were also performed for recurrent high-level amplifications, defined as \u226515 additional copies in >1 tumor. For selected amplified genes the gene expression was additionally assessed by Wilcoxon tests .p\u2009<\u20090.05 and fold change\u2009>\u20091.2) and calculated the proportion of upregulated genes that overlapped with in cis genes. To control for the potential impact of different numbers of samples in the subtypes, we performed random sampling (n\u2009=\u20091000) of 20 tumors from each CMS group and repeated analyses for each iteration. Enrichment was assessed in pairwise comparisons among the subtypes. For a gene to be assessed in the in cis analysis, at least three tumors had to be found in the copy number gain and copy number neutral group. For robustness, the analysis was done in three different ways: (i) by identifying significant in cis genes for the 40 tumors (20 tumors in each of the subtypes included in the pairwise comparison) and performing differential expression analysis for the 20 versus 20 tumors per re-sampling, (ii) by identifying significant gain/upregulated genes for the 40 tumors per re-sampling and using the differential expression results from the original analyses including all samples, and (iii) by identifying significant in cis genes for the 40 tumors and randomly sampling 250 genes from the original differential expression results. Furthermore, to test if the variable number of genes that were differentially upregulated in each subtype affected the analysis we also performed repeated (n\u2009=\u20091000) re-samplings of 250 genes from the original gain/upregulated gene list and among the genes originally found to be upregulated in each CMS group (CMSx versus remaining CMS classified tumors).To investigate a potential enrichment of genes with in cis-association (gain/upregulation) among upregulated genes in each of the four CMSs we identified differentially expressed genes between each subtype and the remaining subtypes using limma were used for integration analyses with CNAs. Prior to data integration, the same fraction of low-variance genes as in the inhouse dataset was excluded prior to Wilcoxon-testing. The amplification analyses were performed on 320 out of 323 tumors due to segmentation failure in 3 samples.Gene expression data from four different colon cancer cell populations"} +{"text": "To determine how intrusion of O2 into iron mound sediments influences microbial community composition and Fe metabolism, we incubated samples of these sediments in a column format. O2 was only supplied through the top of the columns, and microbiological, geochemical, and electrochemical changes at discrete depths were determined with time. Despite the development of dramatic gradients in dissolved Fe(II) concentrations, indicating Fe(II) oxidation in shallower portions and Fe(III) reduction in the deeper portions, microbial communities varied little with depth, suggesting the metabolic versatility of organisms in the sediments with respect to Fe metabolism. Additionally, the availability of O2 in shallow portions of the sediments influenced Fe metabolism in deeper, O2-free sediments. Total potential measurements at discrete depths in the columns indicated that Fe transformations and electron transfer processes were occurring through the sediments and could explain the impact of O2 on Fe metabolism past where it penetrates into the sediments. This work shows that O2 availability (or lack of it) minimally influences microbial communities, but influences microbial activities beyond its penetration depth in AMD-derived Fe(III) rich sediments. Our results indicate that O2 can modulate Fe redox state and solubility in larger volumes of iron mound sediments than only those directly exposed to O2.Fe(III)-rich deposits referred to as \u201ciron mounds\u201d develop when Fe(II)-rich acid mine drainage (AMD) emerges at the terrestrial surface, and aeration of the fluids induces oxidation of Fe(II), with subsequent precipitation of Fe(III) phases. As Fe(III) phases accumulate in these systems, O Centuries of coal extraction in the Appalachian region of the United States has left a legacy of acid mine drainage (AMD), which remains the region\u2019s greatest threat to surface water quality . The maj2, while Fe(II) oxidation might occur under conditions of severe O2 depletion .(DOCX)Click here for additional data file.S2 Fig]. Values in parentheses in depth legend indicate Shanon Indices of microbial communities at each of those depths. Values in parentheses of axis labels indicate the percentage of variation explained by a PCo.Appl Environ Microbiol 2007; 73: 1576\u20131585.(DOCX)Click here for additional data file."} +{"text": "Mission: to urge all relevant entities within the international cardiac surgery, industry and government sectors to commit to develop and implement an effective strategy to address the scourge of rheumatic heart disease in the developing world through increased access to life-saving cardiac surgery. Twelve years after cardiologists and cardiac surgeons from all over the world issued the Drakensberg Declaration on the Control of Rheumatic Fever and Rheumatic Heart Disease in Africa, calling on the world community to address the prevention and treatment of rheumatic heart disease (RHD) through improving living conditions, to develop pilot programmes at selected sites for control of rheumatic fever and rheumatic heart disease, and to periodically review progress made and challenges that remain,2Prevention efforts have been important but have failed to eradicate the disease. At the present time, the only effective treatment for symptomatic RHD is open-heart surgery, yet that life-saving cardiac surgery is woefully absent in many endemic regions. In this declaration, we propose a framework structure to create a co-ordinated and transparent international alliance to address this inequality.Elimination of RHD and relief from its debilitating consequences can only occur through interdisciplinary effort, as outlined in the Cairo Accord.Progress in the prevention of RHD has been slow during the past 15 years,6Although there is one cardiac centre per 120 000 people in the United States, there is only one centre per 33 million in Africa. Furthermore, RHD is not restricted to sub-Saharan Africa. India, Pakistan, China and Indonesia together account for 72% of the mortality rate of RHD cases worldwide.2We strongly endorse the position that building local capacity is the best solution for this serious public health problem. Many lives have been saved by humanitarian \u2018fly-in\u2019 missions, but these efforts are neither sustainable nor cost effective. The non-governmental organisations associated with these programmes are shifting focus towards building long-term partnerships with host countries to develop autonomous local services with government buy-in.It is not sufficient for governments and non-governmental organisations to support the training of cardiologists and cardiac surgeons from these regions at high-income country facilities, because they will not be trained in most of the pathologies awaiting them in their own countries and will be unfamiliar with resource-constrained circumstances.There is an urgent need for a concerted effort by all stakeholders to address the plight of the poor in these regions, who need cardiac surgery. As signatories and endorsing organisations of the Cape Town Declaration, we propose a comprehensive solution with two principal aims.Aim 1: To establish an international working group of individuals from cardiac surgery societies and representatives from industry, cardiology and government to evaluate and endorse the development of cardiac care in low- to middle-income countries.It is proposed that the international coalition will have two representatives from each of the major cardiac surgery societies , and ideally, two additional committed members. There will be at least one representative from industry and at least one appointee to represent cardiology/the World Heart Federation. The responsibilities of the coalition will include establishing criteria for centres for clinical care and training as well as selecting and endorsing the centres. The coalition will derive metrics of quality and performance for the endorsed centres of training and clinical care and will encourage standardisation of care to the extent possible.The coalition will advocate mutually agreed policies and prescriptions to relevant governmental bodies. In addition, the coalition will engage with industry and private sources of philanthropy for financial assistance with large-scale initiatives.Aim 2: To advocate for the training of cardiac surgeons and other key specialised caregivers at identified and endorsed centres in lowto middle-income countries.The case has been made above for critical providers obtaining training in settings and conditions and dealing with the cardiac pathologies that they will be encountering in their practice in their countries of origin.It is preferred that centres endorsed by this coalition be based on an alliance of four stakeholders: a programme initiator , an audited training centre in a low- to middle-income country, a committed partner institution in a high-income country, and a consortium of industry that would sign on as benefactors to the specific programme. Because regional centres in low- to middleincome countries typically operate within a resource-scarce environment, resulting in lower case numbers than needed for the training of outside residents, a facilitated capacity increase to help achieve higher case numbers would benefit all participants.Summary: It is imperative that action be taken urgently. A nucleus of one to three centres should be identified and endorsed, with co-ordination by global stakeholders, as quickly as possible. The implementation of this initiative will only be made possible by the endorsement of all the relevant cardiothoracic societies and agencies subscribing to clearly defined targets and timelines, and committing appropriate resources. The time to act is now.For Cardiothoracic Societies Joseph Bavaria Friedhelm Beyersdorf R Morton Bolman, III Kumud Dhital Robert SD Higgins James Kirklin Robert Kleinloog Bongani Mayosi Juan Mejia Jose Pomar Karen Sliwa Shinichi Takamoto Wei Wang David Wood Charles Yankah , Ghana/Germany]Liesl Zuhlke Humanitarian and government organisations Alain Carpentier Sylvain Chauvaud Afksendiyos Kalangos Richard Kamwi Ren\u00e9 Pr\u00eatre Nicole Sekarski Magdi Yacoub Industry and health economy representatives Iraj Abedian Francois Bonnici Lenias Hwenda Sidhant Jena Samukeliso Dube Jacques Kpodonu Salah Malek Markus Stirner-Schilling Patrice Matchaba Lee Chuen Neng Michael P Phalen Tim Ring Kathryn Gleason Devi Prassad Shetty Alistair Simpson Raenette Taljaard Helmut Straubinger Barry Wilson For major journals and publications Friedhelm Beyersdorf Sampath Kumar Dan Ncayiyana JP van Niekerk G Alexander Patterson Marko Turina David Williams Other signatory delegates to the Cape Town Dialogue Elena Aikawa (USA)Masanori Aikawa (USA)Henning Rud Andersen (Denmark)Manuel Antunes Eduardo Becerra (Chile)Solomon Benatar (South Africa/Canada)Richard Bianco (USA)Bojan Biocina (Croatia)Carlijn Bouten (Netherlands)Abdelmalek Bouzid (Algeria)Luke Brewster (USA)Johan Brink (South Africa)Taweesak Chotivatanapong (Thailand)Patrick Commerford (South Africa)David Cooper (USA)John Curci (USA)Manfred Deutsch (Austria)Richard Daly (USA)Frederick C de Beer (USA)Norberto de Vega (Spain)Howard Eisen (USA)Max Emmert (Switzerland)Giuseppe Faggian Volkmar Falk (Germany)Ted Feldman (USA)Giovanni Ferrari (USA)Teddy Fischlein (Germany)Robert Frater (USA)Glen Gaudette (USA)Gino Gerosa Bernard Gersh (USA)Allan Glanville Craig Goergen (USA)Claudia Goettsch (Germany)Mervyn Gotsman (Israel)Martin Grabenwoeger (Austria)Andrea Griesmacher (Austria)Christian Hagl (Germany)Ulf Hedin (Sweden)Simon Hoerstrup (Switzerland)Saeid Hosseini (Iran)Joshua Hutcheson (USA)Willie Koen (South Africa)Gennadiy Khubulava (Russia)Robin Kleinloog (South Africa)Walter Klepetko (Austria)Michael Knaut (Germany)Theodoros Kofidis (Singapore)Guenther Laufer (Austria)Nicolas l\u2019Heureux (France)Georg Lutter (Germany)Simon Maltais (USA)Simon Matskeplishvili (Russia)Jo Meinhart (Austria)Ana Olga Mocumbi (Mozambique)Elmi Muller (South Africa)Mathias Mueller (Austria)Paul Mohacsi (Switzerland)Ivan Netuka (Czech Republic)Mpiko Ntsekhe (South Africa)Minoru Ono (Japan)Otmar Pachinger (Austria)Timothy Pennel (South Africa)Olga Plattner (Austria)Bruno Podesser (Austria)Darshan Reddy (South Africa)Bruno Reichart (Germany)Hermann Reichenspurner (Germany)Hector Sanchez (Argentina)Jacques Scherman (South Africa)Stephan Schueller (United Kingdom)Jim Schurman (USA)Rainald Seitelberger (Austria)Toshi Shinoka (USA)Agneta Simionescu (USA)Dan Simionescu (USA)Francis Smit (South Africa)Ulrich Steinseifer (Germany)Cynthia St Hilaire (USA)Justiaan Swanevelder (South Africa)Hendrik Treede (Germany)Nir Uriel (USA)Devagourou Velayodamu (India)David Vorp (USA)Susan Vosloo (South Africa)Beath Walpoth (Switzerland)Georg Wieselthaler (USA)Mike Wolf (USA)Andreas Zuckermann (Austria)"} +{"text": "The use of video-recording offers important advantages in observing and assessing the relationships between specific behaviors in health care settings. The purpose of this systematic review is to investigate and synthesize the methodological characteristics of studies using video-technology for measuring interactions between the older persons with dementia and staff in long-term care facilities. We searched Medline, Embase and CINHAL databases for published articles in English using a video-recording method for both staff and persons with dementia. Quantitative research design studies were included. Among 5,605 searched papers, a total of 20 studies were selected for this review. Situations of video-recording were providing personal care (n=12), mealtime (n=6), and conversation (n=3). Concepts of measuring by video-recording were classified into two groups: 1) Staff [care practice by staff (n=13) and communication by staff (n=11)] and 2) residents . This review demonstrates that video technologies are actively used to evaluate the relationship between quality of care and health outcomes of the elderly with dementia in many international nursing studies. This study provides the foundation for a future research using video-recording technologies to examine the interactions and relationship between staff and the residents in long-term care settings."} +{"text": "We detected 2936 large and rare CNVs events . Case-control burden analysis and generalized linear regression models revealed significant association of CNVs with GSD in men, with the strongest effect observed with CNVs overlapping lipid metabolism genes . Our results indicate a clear link between CNVs and GSD in men and provides additional evidence that the genetic components of risk for GSD are complex, can be sex specific and include CNVs affecting genes involved in lipid metabolism.Gallstones Disease (GSD) is one of the most common digestive diseases requiring hospitalization and surgical procedures in the world. GSD has a high prevalence in populations with European or Amerindian ancestry (10\u201320%) and the influence of genetic factors is broadly acknowledged. However, known genetic variants do not entirely explain the disease heritability suggesting that additional genetic variants remain to be identified. Here, we examined the association of copy number variants (CNVs) with GSD in a sample of 4778 individuals (1929 GSD cases and 2849 controls) including two European cohorts from Germany ( Gallstones disease (GSD) is a multifactorial chronic metabolic disease characterized by the development of calculi inside the gallbladder composed mainly by cholesterol. GSD features a long silent progression where the accumulation of stones in the affected gallbladder can lead to clinical symptoms such as recurrent episodes of intense abdominal pain (biliary colic) and major complications, like obstruction and infection of the biliary tree (cholestasis and cholangitis), acute pancreatitis, and gallbladder cancer . At leasABCG5/8 gene ATP8B1) gene [RB1) gene [HNF1A) gene [SULT2A1) gene [APOL1 and APOL2) involved in lipid transport. In addition, we note that the 23 candidate genes were enriched with 7 genes extremely intolerant to loss-of-function genetic variation and variants within these genes are rarely found in the general population [The observed associations could not be attributed to one CNV nor to an specific gene and thus CNVs may confer risk to GSD through multiple highly rare and penetrants events. In an effort to identify genes with the strongest potential to be involved in the development of GSD by a CNV-related mechanism, we highlight 23 genes involved in lipid metabolic process, which are expressed in the small intestine and exclusively affected by CNV in cases. Direct functional links between the candidate genes and the etiology of GSD is available for: the lipid transporter ATPase phospholipid transporting 8B1, (B1) gene , the RB B1) gene , the hep1A) gene , the bilA1) gene , and thepulation . We hypoAs suggested by CNVs overlapping nonlipid metabolic process genes that are expressed in the small intestine Fig.\u00a0 and the In summary, our study provides the first evidence of association of CNVs with GSD and will contribute to better understand the etiology of this complex and common metabolic disorder.Supplementary Material"} +{"text": "Investigators from Calico Life Sciences LLC and AbbVie report the effects of a novel drug targeting the genetic basis of Vanishing White Matter Disease (VWMD). Investigators from Calico Life Sciences LLC and AbbVie report the effects of a novel drug targeting the genetic basis of Vanishing White Matter Disease (VWMD). VWMD is caused by homozygous or compound heterozygous variants in any of five genes . Collectively the five genes encode a portion of the eukaryotic translation inhibition factor 2 (eIF2) termed eIF2B that is required for normal protein translation. VWMD-causing variants are though to cause a partial reduction in eIF2B activity. Prior studies by members of the group from Calico Life Sciences had shown that ISR-inhibitor (ISRIB), a small molecule, was able to activate and stabilize eIF2B [COMMENTARY. VWMD is a chronic, episodic and progressive leukoencephalopathy with highly variable presentation. Features include essentially normal early life development followed by progressive ataxia, cognitive impairment, and spasticity. In 1997 Van Der Knapp et al., proposed four criteria for diagnosis (1) essentially normal initial motor and cognitive development, (2) chronic, progressive deterioration that often follows a mild infection or head trauma, 3) progressive cerebellar ataxia and spasticity are prominent features; epilepsy and optic atrophy may be present; cognitive impairments are less significant than motor impairments and (4) MRI findings are symmetric, with white matter signal intensity similar to cerebrospinal fluid on multiple sequences [ progressWhen clinical suspicion is high, the diagnosis of VWMD is confirmed by genetic testing for homozygous or compound heterozygous variants in genes encoding the five eIF2B subunits. Normal protein expression requires function of eIF2B to extend translated RNA sequences . While tThe other important function of eIF2B is regulation of the integrated stress response (ISR), a reprogramming of protein expression that is common for a variety of cellular stress signals. ISR both shuts down normal protein expression, and activates specific transcription factors to help protect a stressed cell. Prior work demonstrated that suppression of eIF2B activates the ISR. ISRIB efficiently activates and stabilizes eIF2B to block the ISR .VWMD is caused by diminished eIF2B activity and often worsens in the setting of illness, which may be related to improper regulation of the ISR. The current investigation examined whether ISRIB can utilize the hypoactive eIF2B found in VWMD to properly inhibit the ISR. The authors selectively edited the eIF2B gene with CRISPR-Cas9 in otherwise normal cells to recreate patient derived mutations. Cells were then treated with ISRIB. Consistent with a properly inhibited ISR, global protein expression was increased and ISR-specific transcription factors were decreased [The author(s) have declared that no competing interests exist."} +{"text": "A 78-year-old patient with a recent history of transitory ischemic attack with right upper extremity weakness was referred for computed tomographic angiography (CTA) of the neck arteries. No significant stenosis was found, but systematic 3D study of the circle of Willis Figure revealedThe vocable of \u201cfetal posterior cerebral artery\u201d (FPCA) encompasses a group of developmental variants of the posterior cerebral artery (PCA) in which a significant portion of the distal PCA remains perfused through a branch of the internal carotid artery (ICA).When a FPCA variant is present, thromboembolism in the ICA may result in paradoxical PCA territory infarction .During the choroidal stage of embryogenesis (at five weeks of gestation) the anterior brain circulation is constituted by two main branches of the ICA: the rostral branch (rICA) and the caudal branch (cICA) which prefigures the future posterior communicating artery (PcoA).The rICA feeds the anterior carotid artery (ACA) and the anterior choroidal artery (AchoA) and the cICA feeds the posterior choroidal artery (PchoA) and the future P1 segment of the PCA.During growth of the posterior cerebrum, cerebellum and brainstem acceleration arises in the development of the posterior arterial network. It progressively becomes independent from the anterior circulation and the primitive transitory carotid-basilar anastomoses completely regress.Different scenarios explain the pattern of the future definitive PCA. Most commonly Figure the middAnother scenario produces the common FPCA variants Figure , C and DA third but extremely rare scenario called the \u201ctrue fetal PCA\u201d variant Figure is repor"} +{"text": "The Research article \u201cJurassic-Cretaceous boundary bioevents and magnetochrons: A stratigraphic experiment\u201d , describes the Lower Cretaceous 2016 Chronostratigraphic Database (LOK2016CS). This database comprises the first and last occurrences of key fossil ranges in forty-one global stratigraphic sections (Table 1). This data has been published by qualified biostratigraphers in selected worldwide sections that have been carefully measured, collected and fossil species consistently identified. Regional reference sections and approved or proposed Global Boundary Stratotype Section and Point (GSSP) are included. This data set is composed of lowermost and uppermost positions of species measured in meters or feet by the research team in each section, which represent the first and last occurrences of the species. These data sets were composited into the numerical age chart, LOK2016CS (Table 2), by graphic correlation. The 2016 Geologic Time Scale was the X-axis section on the first X/Y plot so that the numerical ages were calibrated consistently with that scale. The numerical ages of each event estimate the First and Last Appearance Datums within the geographic area encompassed by the sampled sections."} +{"text": "Cardioglossa schioetzi and Leptodactylodon bicolor (both in the Arthroleptidae), in and around Ngel Nyaki Forest Reserve on the Mambilla Plateau in eastern Nigeria. The landscape comprises continuous forest on steep slopes and small riparian forest fragments in a grassland matrix. While increased fragmentation is well documented for these and other forests in the mountains of Cameroon and Nigeria over the past century, there are no previous assessments of the impact of forest fragmentation on montane amphibian populations in this region. Our estimates of genetic diversity are similar across populations within each species with levels of heterozygosity values consistent with local population declines. Except for a pair of populations (C. schioetzi) we did not observe genetic differentiation between forest and riparian forest fragment populations, nor across sites within continuous forest (L. bicolor). Our results demonstrate recent gene flow between forest fragments and the adjacent protected forests and suggest that small forest corridors connecting these may lessen the genetic consequences of at least 30 years of intense and severe fragmentation in Ngel Nyaki.Amphibians are the vertebrate group with the highest number of species threatened with extinction, and habitat loss and fragmentation are considered to be among the leading causes of their declines and extinctions. Little is known of the population biology of amphibian species inhabiting montane forests in Central and West Africa, where anthropogenic activities such as farming and cattle raising are major threats to native biodiversity. We used Amplified Fragment Length Polymorphisms (AFLPs) to assess the population genetic structure of two poorly known species, Globally, amphibians face the most extreme population declines of all major vertebrate groups \u20133. ContrAs is the case with many other taxa, habitat fragmentation likely has long-term effects on the genetic viability of amphibian populations because of the combined effects of reduced population size and increased isolation . IncreasTo begin to redress the paucity of population genetics studies of African amphibians, we focused on populations of frogs within the forests of the Nigerian Highlands of the Cameroon Volcanic Line . This isCardioglossa schioetzi and Leptodactylodon bicolor, are endemic to the montane forests of Cameroon and Nigeria, they are small (<30 mm snout\u2013vent length), have stream-adapted tadpoles, and live in leaf litter and rocky areas . Our results suggest that despite considerable habitat degradation gene flow is still occurring (or occurred recently) among forest patches in two Afromontane frog species. This illustrates the importance of these degraded riparian forest fragments to amphibian communities.In Nigeria and all along the Cameroon Volcanic Line ,89, as eS1 FigK based on the Ln(K) K = 5, whereas graph B) and bar plot D) show the better K based on Evanno\u2018s method \u0394K = 2. Each vertical bar represents an individual for which is shown the proportional genetic assignment to each cluster.Graph A) and bar plot C) depict the optimal (TIF)Click here for additional data file.S2 FigK based on the Ln(K) K = 7, whereas graph (B) and bar plot (D) show the better K based on Evanno\u2018s method \u0394K = 2. Each vertical bar represents an individual for which is shown the proportional genetic assignment to each cluster.Graph (A) and bar plot (C) depict the optimal (TIF)Click here for additional data file.S1 TableTogether, the two preferred primer combinations ESP1B/MSP3 and ESP1B/MSP6 yielded 275 loci for the 198 samples representing both species.(XLSX)Click here for additional data file."} +{"text": "Of 103 serum samples collected from dogs in South Korea, 3 (2.9%) were positive for severe fever with thrombocytopenia syndrome virus (SFTSV) and 22 (21.4%) were positive for antibodies against SFTSV. A dog-derived isolate of SFTSV clustered with many South Korea SFTSV strains in the Japanese clade. Phenuiviridae family (previously Bunyaviridae), causes severe fever with thrombocytopenia syndrome (SFTS) in China, Japan, and the Republic of Korea (South Korea) (Severe fever with thrombocytopenia syndrome virus (SFTSV), a new tickborne phlebovirus of the Haemaphysalis longicornis tick is the main vector for SFTSV, promoting its circulation and transmission , obtained from dog 16, a German shepherd; dog 22, a Belgian Malinois; and dog 56, a German shepherd were positive for the small (S [346 bp]), medium (M [859 bp]), and L segments of SFTSV by reverse transcription PCR (the L segment of dog 16 was not amplified). The sequences of the SFTSV S, M, and L segments differed from each other. The results of phylogenetic analysis of partial S, M, and L segments showed that sequences of SFTSV obtained from dogs were more related to strains from Japan than to strains from China . MoreoveWe used Vero cells to isolate the virus from positive serum. We observed cytopathic effect in only 1 of 3 positive samples. The results of phylogenetic analysis of the complete S segment indicated that the SFTSV strain isolated from dog 22 had not previously been isolated; this strain clustered with many SFTSV strains from South Korea and Japan .H. longicornis ticks are the main vector of SFTSV and the dominant tick species collected from vegetation and animals in South Korea (The detection rates of SFTSV RNA and antibodies in our study were 2.9% and 21.4%, respectively, which were higher than those observed in shelter dogs in South Korea (Although we isolated only a few SFTSV strains from animals and our results could not represent all characteristics of SFTSV, our findings could indicate that SFTSV might not be host-specific and that various SFTSV clades circulate and are distributed in South Korea. Further studies continuously surveilling animals for SFTSV, along with whole-genome analysis of dog-derived Korean isolates of SFTSV, would help clarify the mechanisms of transmission and molecular evolution of SFTSV.Additional information for severe fever with thrombocytopenia syndrome virus in dogs, South Korea."} +{"text": "We analyze possible future trends in dissolved inorganic nitrogen (DIN) export by world rivers and associated emissions of nitrous oxide (N2O). Our scenarios either assume that current trends continue or that nitrogen (N) inputs to aquatic systems are reduced as a result of changes in agriculture practices and fuel combustion technologies. The results indicate that moderate changes in the human diet in North America and Europe, reducing worldwide fertilizer use by only 16%, relative to Business-as-Usual (BAU) levels, may reduce DIN export rates to the North Atlantic and European Seas by about one third and associated N2O emissions by 36 to 77%. We furthermore calculate that relatively large reductions in NOy deposition rates in Europe (of about 80%) may reduce DIN export by rivers by a moderate 8% or less, relative to BAU levels. The potential effect of reduced NOy deposition on riverine DIN export is moderate, because most N in European rivers stems from agriculture, and not from fuel combustion. Nevertheless, the calculated 9% reduction (relative to BAU) in DIN inputs to the North Sea as a potential side effect of air pollution control may help achieve the international policy targets for reduced N inputs to the North Sea."} +{"text": "Scientific Reports 10.1038/s41598-018-28912-x, published online 17 July 2018Correction to: The original version of this Article contained errors.In the Abstract,\u201cThe clean and stable experimental platform permits the visualisation of the structure and orientation of microvilli present at the apical cell membrane under standard laboratory conditions together with registering subcellular details within a microvillus.\u201dnow reads:\u201cThe clean and stable experimental platform permits the visualisation of the structure and orientation of microvilli present at the apical cell membrane under standard laboratory conditions together with registering topographical features within a microvillus.\u201dIn the main text,24), which are visible in the zoomed-in phase image and in the overlay image .\u201d\u201cIn particular, we observe lateral striations running along the length of the microvillus unit (previously observed only using high-resolution electron microscopy at cryogenic temperaturesnow reads:24), which are visible in the zoomed-in phase image and in the overlay image .\u201d\u201cIn particular, we observe lateral striations along the entire length of the microvillus unit (previously observed only using high-resolution electron microscopy at cryogenic temperaturesThese errors have now been corrected in the PDF and HTML versions of the Article."} +{"text": "Transforming nursing home (NH) cultures\u2014from impersonal institutions to enriching communities where residents and employees thrive\u2014requires multifaceted change. NHs deploy an array of culture change (CC) practices, in three core domains: resident-centered care, staff empowerment, and physical environment. This study uses novel data on CC practice from a nationally representative panel of NHs surveyed in 2009/2010 and 2016/2017. To understand how changes in practice adoption may relate to quality changes we linked longitudinal data on the CC practice domain scores for resident-centered care, staff empowerment, and physical environment and on NH deficiencies relating to health and quality of life (QoL) and combined these with Certification and Survey Provider Enhanced Reporting baseline data. Multinomial logistic regressions incorporating survey weights and inverse probability of weight (to address CC selection) estimated the relative risk ratios (RRR) of increased CC practice corresponding with NHs having fewer or no change in deficiencies, versus increased deficiencies. NHs with much increase in staff empowerment scores had a higher likelihood of no change (compared to an increase) in health deficiencies and severe health deficiencies . With a RRR of 1.63, NHs with any improvement in resident-centered care scores appeared to have a higher likelihood of no change (compared to an increase) in QoL deficiencies but statistical significance was not reached (p=0.11). This study provides some support for the benefits of CC practices, and in particular, supports the importance of staff empowerment practices in NHs."} +{"text": "Studies of aging rarely include the older adults themselves in the process of conceptualizing questions, implementing the research, and evaluating the results. To provide opportunities for community members to become engaged in research, researchers and community stakeholders developed \u201cEngaging Older Adult Learners as Health Researchers (ENGOAL).\u201d This program educates older adults from underserved and underresourced communities about geriatric health and research methods, enabling them to become Research Partners. Two cohorts of African-American seniors (N=21) aged 53-79 have participated or are currently participating in six months of weekly classes followed by 4-6 months of research apprenticeships. Content and structure of classes will be described. Challenges and successes in providing research apprenticeships will be discussed."} +{"text": "KRT17 has been described in multi-layered epithelia as well as in tumors derived from these cells. In cancers arising from KRT17 negative single layered epithelia neo-expression of KRT17 has been associated with tumor progression. To obtain more insight into the biology of kidney cancers we have investigated KRT17 expression by immunohistochemistry in normal kidney, in papillary preneoplastic lesions and in 151 papillary and 692 conventional renal cell carcinomas placed on tissue microarray. We found a positive staining in ureteric bud and collecting duct cells in foetal kidney, in all papillary preneoplastic lesions and also in 77% of the 151 papillary renal cell tumors indicating a continuos KRT17 expression during tumor development. The neo-expression of KRT17 in conventional renal cell carcinomas, which derives from KRT17 negative proximal tubules showed a significant correlation with postoperative tumor relapse . In conclusion, the continuous expression of KRT17 from emerging fetal kidney tubules and microscopic pre-neoplastic lesions towards papillary renal cell tumors and its neo-expression in aggressive growing conventional renal cell carcinomas reflects the multiple function of KRT17 in kidney cancers with distinct natural history. This should be taken into account in clinical managements and therapy.Expression of KRT8 and KRT18 in their normal state, but this may change during inflammation, regeneration and also during tumor development. Kidney tubular cells may switch on KRT7 and KRT19, sometimes also KRT17 in addition to the expression of KRT8 and KRT18KRT7, KRT17 and KRT19 appears parallel to the reduction in degree of differentiation. KRT7 and KRT19 are upregulated during renal epithelial injury and repair leading to more plasticity of cells involved in the regeneration processes KRT8 and KRT18 expression to KRT7 and KRT19 is associated with structural remodelling of end stage kidney and increased frequency of tumors expressing both KRT7 and KRT19KRT17 in the biology of kidney cancer is not yet known. Two earlier studies on the keratin expression in distinct types of renal cell cancer using the E3 clone from DAKO did not find KRT17 expression in conventional, chromophobe and papillary renal cell tumors or renal oncocytoma Keratins are intermediate filaments playing a crucial role in the integrity and mechanical stability of single epithelial cells and epithelial tissues. The expression of keratins is regulated in a tissue-type and differentiation-specific manner KRT17 a member of type I acidic epithelial keratin family was first identified in skin basal cell epithelioma and it is considered to be a basal/myoepithelial cell keratin KRT17 occurs in complex, multilayered epithelia and it is largely retained during neoplastic transformation leading to several types of cancer derived from such epithelial cells KRT17 expression has also been detected in several tumors of non-epithelial type but not in their tissue of origin. These studies demonstrated a correlation between neo-expression of the KRT17 and tumor progression KRT17 in fetal development, regeneration and tumorigenesis and on the other hand in the progression of frankly malignant cancers.KRT17 in the biology of renal tumors we applied immunohistochemistry to a large panel of conventional RCC and papillary RCT as well as to preneoplastic lesions (PNL) associated with papillary RCT. In our study we used an antibody arised against the N-terminal protein fragment of KRT17 instead of the E3 clone from DAKO .In attempt to learn about the involvement of We have enrolled tumor samples from consecutively operated patients without selection, who undervent radical or partial nephrectomy due to kidney cancer between 2000 and 2013 at the Department of Urology, Medical School, University of Pecs, Hungary. The only criteria was the availability of clinical data, follow-up and paraffin embedded tumor material. Data on regular follow-up and tumor-specific death were obtained from the Registry of the Department of Urology. Follow-up was defined as time from operation until the last recorded control in 2018, or cancer-specific death. Patients who died from causes other than RCC were excluded from this analysis. Preoperative clinical staging included abdominal and chest computed tomography (CT) scans. Bone scans and brain CT scans were obtained only when clinically indicated. The presence of nodal metastases was confirmed by histological, whereas that of distant metastases by radiographic examination. During the postoperative period patients were surveyed every 6 months by abdominal ultrasound scans, serum creatinine and eGFR measurements, and every year by CT scans. Histological diagnoses were performed by a genitourinary pathologist (GK) according to the Heidelberg and TNM classification systems Haematoxylin and eosin stained slides were reviewed to select the representative paraffin blocks and tumor areas for TMA construction. From each tumor minimum three core biopsies with a diameter of 0.6 mm were placed in the recipient block using a Manual Tissue Arrayer . For marking the TMAs fetal and adult kidney biopsies were included.0C in a moist chamber with rabbit polyclonal anti-KRT17 antibody at 1:500 dilution. Horse-radish-peroxydase conjugated anti-rabbit, anti-mouse secondary antibody was applied for 30 minutes at room temperature and the bound antibody was visualized with AEC (Amino-ethyl-carbazol) . Tissue sections were counterstained with Mayer's haematoxylin. In negative control the primary antibody was omitted. The slides were evaluated twice at different times by two of the authors . The staining intensities were scored as low, medium or high. As we did not find substantial differences between weak or strong KRT17 expression and conventional RCC progression, we have evaluated all staining intensity as positive.Paraffin blocks of fetal and adult kidneys, pre-neoplastic lesions and TMAs were used for immunohistochemistry. After deparaffinisation and rehydration the 4 um thick sections were subjected to heat-induced epitope retrieval in citrate buffer, pH 6.0 in 2100-Retriever . Endogenous peroxidase activity and unspecific binding sites were blocked with 3% hydrogen peroxide containing 1% normal horse serum for 15 minutes at room temperature. Slides were incubated overnight at 4KRT17 expression, clinical and pathological parameters were calculated using the \u03c72 test. The effects of the different variables on the survival of the patients were estimated by Kaplan-Meier analyses. Comparisons of survival curves were made using the Log rank test. Univariate and multivariate survival analyses were performed using the Cox regression model. Patients that were alive and disease-free were censored. Differences were considered significant at p < 0.05.Data analyses were performed using a SPSS Statistics software package version 25 . Correlations between KRT17 first appeared in the ureteric bud and collecting duct of fetal kidney , the average follow-up was 60.6\u00b133.2 months. Out of the 692 patients 108 (16%) developed metastasis during the follow-up and died due to metastatic cancer. The clinical parameters and correlation with KRT17 expression is shown in Table KRT17 staining which showed a significant correlation with cancer specific death, tumor size, T-stadium, grade and stage. The Kaplan-Meier analysis indicated that patients with KRT17 positive tumor have a significantly shorter survival than those with negative tumor . The KRT17 expression was an independent negative survival factor indicating a nearly three times higher risk of disease relapse and cancer specific death .To estimate the role of KRT17 has other functions as well. KRT17 plays a role in fetal epidermal development and in cell proliferation during wound healing by regulation of protein synthesis through intracellular signaling pathways KRT17 knockout mouse embryos show a delay in closure of surface ectoderm wounds KRT17 binds and sequester TRADD (TNFRSF1A associated via death domain), a mediator of programmed cell death signaling and protects the cells from apoptosis KRT17 null keratinocytes are sensitive to TNF mediated apoptosis KRT17 expression in embryonic ectoderm reflects its commitment towards distinct epithelial lineages and that the program of gene expression characteristic of wound-activated adult keratinocyte may have a relationship to that executed by epithelial cells at specific stages of embryonic development CD44+/KRT17+ cells have stemlike properties, including the capacity for cell renewal and in vivo tumorigenicity Beyond its role to maintain cellular integrity of multi-layered epithelia KRT17 is expressed in simple (one-layered) epithelial cells of fetal and adult kidney. Each PNL of embryonal origin as well as 77% of papillary RCT showed the KRT17 positivity irrespectively of cell type. Taking into account that only 5% of papillary RCTs developed metastasis during 5-year follow-up (data not shown), the role of KRT17 in the progression of papillary RCT can be excluded. Rather, the expression of KRT17 in fetal kidney suggests that it may play a role in the cell specific differentiation of tubular cells similarly to its role in fetal epidermal development KRT17 is associated with the development of PNL and subsequently of papillary RCT. This finding indicates a molecular relationship between kidney development and papillary RCT tumorigenesis. The developmental sequences outlined by KRT17 expression support our hypothesis on the unique natural history of papillary RCT We showed in this study that KRT17 is a basal/myoepithelial cell keratin the expression of which depends on the position of cells in complex multiplayer human epithelia KRT17 has been described in bladder carcinoma, keratoacanthoma and squamous cell carcinoma, oral squamous cell carcinoma, premalignant and malignant squamous lesions of the cervix, all derived from multilayer epithelial cells KRT17 has also been found in several other types of cancer such as gastric adenocarcinoma, ovarian and breast carcinoma, papillary thyroid carcinoma but not in their corresponding normal tissue KRT17 in these cases showed a significant correlation with tumor progression and metastasis. We have identified KRT17 expression in conventional RCCs as an independent negative survival factor indicating a higher risk for postoperative tumour relapse and cancer specific death of patients. Conventional RCC derives from KRT17 negative proximal tubules of the kidney, which suggests that KRT17 has not been involved in the development of conventional RCC. Rather, the neo-expression of KRT17 in conventional RCC can be used as a predictive biomarker similar to gastric, ovarian or breast carcinoma KRT17 in gastric cancer cells inhibited cell proliferation both in vitro and in vivo conditions, reduced the migration of tumor cells and induced apoptosis by BCL2 expression. They also showed that silencing KRT17 leads to cell-cycle arrest at G1/S phase of tumor cells. The clinical, pathological as well as experimental data strongly suggest the involvement of KRT17 neo-expression in tumor progression.Expression of KRT17 is expressed in a single-layered epithelia, and that papillary RCT and conventional RCC have distinct natural history. The continuous expression of KRT17 from fetal kidney tubules towards papillary RCT in adult confirm the relationship between fetal kidney development and tumorigenesis of papillary RCT. And finally, the neo-expression of KRT17 in aggressive growing conventional RCC is significantly associated with postoperative tumor relapse. The multiple functions of KRT17 in kidney cancers unequivocally delineates papillary RCTs and conventional RCCs with distinct natural history, which should be taken into account in clinical managements and therapy.The key novel findings of this study are, that"} +{"text": "Ligand binding to death receptors activates apoptosis in cancer cells. Stimulation of death receptors results in the formation of intracellular multiprotein platforms that either activate the apoptotic initiator Caspase-8 to trigger cell death, or signal through kinases to initiate inflammatory and cell survival signalling. Two of these platforms, the Death-Inducing Signalling Complex (DISC) and the RIPoptosome, also initiate necroptosis by building filamentous scaffolds that lead to the activation of mixed lineage kinase domain-like pseudokinase. To explain cell decision making downstream of death receptor activation, we developed a semi-stochastic model of DISC/RIPoptosome formation. The model is a hybrid of a direct Gillespie stochastic simulation algorithm for slow assembly of the RIPoptosome and a deterministic model of downstream caspase activation. The model explains how alterations in the level of death receptor-ligand complexes, their clustering properties and intrinsic molecular fluctuations in RIPoptosome assembly drive heterogeneous dynamics of Caspase-8 activation. The model highlights how kinetic proofreading leads to heterogeneous cell responses and results in fractional cell killing at low levels of receptor stimulation. It reveals that the noise in Caspase-8 activation\u2014exclusively caused by the stochastic molecular assembly of the DISC/RIPoptosome platform\u2014has a key function in extrinsic apoptotic stimuli recognition. Death receptors are targets of novel cancer therapeutics. Most of them signal through flexible multiprotein platforms to either activate apoptotic or necroptotic cell death, or propagate cell survival and pro-inflammatory signals. We focused our study on the role of dynamic assembly and composition of these platforms in the initiation of cell death at the single cell level. Since the assembly is slow through the competitive nature of protein binding within the platforms core we developed a stochastic mathematical model of the death inducing signalling platform. Our model provided an explanation for delayed cell death and fractional killing upon the death receptor stimulation. Additionally, we found that the variability in the cell death response arises through the random assembly initiates a slow noise-prone ramp activation of initiator Caspase-8 spontaneously triggering the apoptotic cascade. Our computational simulations predicted high variation in the time required for cell death induction at the single cell level and highlighted a significant role of death receptor clustering in effective Caspase-8 activation. Our knowledge and data driven model captures detailed processes governing the early events of cell death initiation and can be used to guide the development of more rational combinational treatments against cancer. Apoptotic signalling cascades are designed to irreversibly lead to cell death once specific death thresholds are overcome ,2. Activin vivo studies have shown that fractional death resistance has no direct association with the amount of DRs expressed on the plasma membrane is the total number of receptors per cell and Caspase 6 (Casp6) which is triggered by stochastically activated Casp8. Pro-forms of both caspases form stable dimers at physiological concentrations . By cleaAll protein concentrations and parameters used in the model are provided in Tables D and E of Materials and Methods file .in vitro [The estimated weight of the RIPoptosome after short DR-targeted stimulation may exceed 2MDa ,24,29. Tin vitro , howeverThe composition and the time evolution of individual RIPoptosomes within single cell differed from one to another. Consequently, the size and, therefore, molecular weight of those RIPoptosomes varies as well. As an example, we display the composition change in a few randomly chosen RIPoptosomes over the first 20 min with 1 min step interval , S2 Fig.FADD recruitment to the fraction of the high molecular weight complexes is persistently increasing with post treatment time . Our simOn the contrary, ProCasp8 recruitment in the single cell is most abundant in the RIPoptosome of the lower molecular weight . The binMolecular fluctuations in the RIPoptosome composition within single cells cause the fluctuations in the active Casp8 abundance . StochasAveraged over the population the Casp8 activation time course demonstrated high dependence on the dose of the DL as well as the clustering capacity . Thus, eAs expected, the overall variability in the Casp8 activation is a function of the treatment dose . DespiteNext we studied the downstream caspase cleavage cascade, the second deterministic modelling module , which fkcat). Ubiquitination of active Casp3, which is set by XIAP, will attract proteasomal complex leading to Casp3 degradation. However, application of proteasome inhibitors does not stabilise the pool of active Casp3 and consequently does not result in reduced Casp3 proteasomal degradation. Instead, Casp3 catalytic activity is absolutely required for its own proteasomal degradation [kcat needs to be significantly higher (1.75 min-1) from the general ubiquitin-dependent degradation rate (0.04 min-1) [kcat value and ODE integration as well as semi-stochastic hybrid model was implemented in the MATLAB 2017b environment see also .S1 Figet al., 2014). Distribution for ligand free (in blue) and ligand bound receptors (in pink) in stimulated cells are followed separately. Distribution of bound receptors was approximated by splines (in red). Distribution for the trimeric Vesicular Stomatitis Virus G protein (VSVG) (in yellow) was used for the peaks calibration. Numbers above the peaks represent amount of monomeric receptor per corresponding cluster and red dots below represent the trimeric receptor complexes. The table demonstrates the conversion of the frequencies into the percentage of clusters from the total DR pool.Experimental frequency distribution of the TNFR1 cluster size on the cellular membrane of unstimulated (black line) and TNF\u03b1 stimulated HeLa cells derived by Super-resolution PALM microscopy (Fricke (TIF)Click here for additional data file.S2 FigModel generated individual RIPoptosome growth over first 20 min after DR stimulation with 5ng/mL of DL assuming receptor clustering scenario. Plots show eight individual RIPoptosomes randomly chosen from different randomly selected cells.(TIF)Click here for additional data file.S3 FigPopulation average Casp8 activation per cell simulated with model under receptor clustering and disrupted receptor clustering assumption upon stimulation with 5, 7.5, 50 and 250 ng/mL of the DL. Single cell trajectories have been averaged over 100 cells in each represented condition.(TIF)Click here for additional data file.S4 FigAverage FADD abundance per origin simulated for culture of 600 HeLa cells with clustering scenario (A) and without clustering (B) for low (5 ng/mL) and high (50 ng/mL) concentrations of the DL. (C) and (D) represent corresponding quantities for average abundance of ProCasp8 together with DED1-DED2.s.(TIF)Click here for additional data file.S5 FigResult of semi-stochastic model and full stochastic model simulation for 20 HeLa cells with clustering scenario for 50 ng/mL concentration of the DL.(TIF)Click here for additional data file.S1 File(PDF)Click here for additional data file.S1 Appendix(M)Click here for additional data file."} +{"text": "Moringa oleifera,\u201d published in this journal [I read with interest the article by Omabe et al., entitled \u201cAnion Gap Toxicity in Alloxan Induced Type 2 Diabetic Rats Treated with Antidiabetic Noncytotoxic Bioactive Compounds of Ethanolic Extract of Alloxan is one of the oldest chemicals to induce experimental diabetes. It induces type 1 diabetes through a single dose administration in laboratory animals. Alloxan acts in two ways: it selectively inhibits glucose-induced insulin secretion through specific inhibition of glucokinase, the glucose sensor of the beta cell, and it causes a state of insulin-dependent diabetes through its ability to induce reactive oxygen species (ROS) formation, resulting in the selective necrosis of pancreatic beta cells , 3. TherIn the article by Omabe et al., type 2 diabetes has been induced by a single intraperitoneal injection of alloxan, which is not correct due to its mechanism of action."} diff --git a/PMC_clustering_613.jsonl b/PMC_clustering_613.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..e0af2c3ca3ebb6c80e11a3057fbac5c32672c3bd --- /dev/null +++ b/PMC_clustering_613.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:d5c657e2c3f3a3ce4a426eadca80ebd203dc0d3edb7845ef7217286bf6ae6013 +size 46436560 diff --git a/PMC_clustering_614.jsonl b/PMC_clustering_614.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..8095056b7ac5d843e9ba660291c99f3eff96fcb2 --- /dev/null +++ b/PMC_clustering_614.jsonl @@ -0,0 +1,788 @@ +{"text": "The present paper of Alger and colls is very"} +{"text": "In the article by Li et al.,The correct version of Table The authors apologize for this error."} +{"text": "This has been corrected in the HTML version of the Article."} +{"text": "One of the most important research studies of the Urogenital Research Unit is about Testicular Migration. In the interesting paper of Logsdon and Collegues of our research group we can o"} +{"text": "Dr. Ferrucci will review accomplishments of the Intramural Research Program and make projections for the future"} +{"text": "The authors regret that the wrong version of The authors would like to apologise for any inconvenience caused."} +{"text": "The images for Figs The publisher apologizes for the error."} +{"text": "The authors wish to make the following corrections to their paper :In"} +{"text": "Following the publication of the original article we were The correct project number is 20586."} +{"text": "The project for the report seems to"} +{"text": "There are errors in the panel labels and caption for The publisher apologizes for the errors."} +{"text": "The author wishes to make the following correction to this paper . The reaThe correct new The above errors were without material impact on the final results and conclusions of our papers. The authors would like to apologize for any inconvenience caused to the readers by these errors."} +{"text": "The authors wish to make the following corrections to this paper :The authors in the Funding section of found anThe authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "After published the article the authThe correct version of the Fig."} +{"text": "In our paper The corrected figures do not affect the original conclusions of the findings."} +{"text": "The figure and legend have now been corrected in the PDF and HMTL versions of the Article."} +{"text": "To enable validation of the names of some of the newly proposed taxa described in this article, the original article should not have been updated following the publication of the corrigendum. The original version has now been reinstated."} +{"text": "There are a number of errors in the Year and Age values of Data are represented as number of patients (%)."} +{"text": "The authors wish to make the following corrections to this paper :Change in Author Names (Spelling)The authors wish to make the following correction to this paper : the autWe apologize for any inconvenience caused to the readers."} +{"text": "The presentation will provide perspective on the current state of care quality in long-term care facilities and the legislative discussions and actions of the 116th Congress."} +{"text": "The infant was ventilated at the referring hospital for recurrent apnea and was treated with intravenous antibiotics and other supportive measures. General examination at admission revealed marked hyperpigmentation of the face and geni"} +{"text": "We study identification in the limit using polynomial time and data for models of"} +{"text": "The spelling of ZMachine has been corrected to Zmachine and includes the manufacturer name and location at first mention in the Methods.The HTML and PDF versions of the Article have been corrected."} +{"text": "The tenth sentence of the Abstract has been corrected to the following: Exacerbations tended to be less frequent in the digital arm compared to usual care; 18 vs 34 events. The HTML and PDF versions of the Article have been corrected."} +{"text": "This course of action follows the advice set out by COPE (Committee on Publication Ethics), of which Biology Open is a member."} +{"text": "Following publication of the original article the authThe authors apologize for this mistake, which has now been corrected online and in the author list of this correction article."} +{"text": "Materials [The exponential factor in Equation 1) of the paper published in of the pThese changes have no material impact on the conclusions of the paper.The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "There are errors in the entries in the final columns of Tables"} +{"text": "The success of support measures as COVID-19 lockdowns are relaxed depends on the type of recovery the EU wants to achieve."} +{"text": "The authors wish to make the following corrections to their paper :In"} +{"text": "This has now been corrected in the HTML and PDF versions of the Article."} +{"text": "The original version of this article unfortunThe correct author name has been included in the author list of this Correction article and is already updated in the original article."} +{"text": "The original version of this article unfortunThe author name has been updated in the author list of this Correction article."} +{"text": "In our paper The corrected figures do not affect the original conclusions of the findings."} +{"text": "This has now been corrected in both the HTML and PDF versions of the Article."} +{"text": "The term The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Journal of Fungi is a member of the Committee on Publication Ethics (COPE) and takes very seriously the responsibility to enforce strict ethical policies and standards.We have been made aware that the Figure 2 of the title paper contains"} +{"text": "This course of action follows the advice set out by COPE (Committee on Publication Ethics), of which Biology Open is a member."} +{"text": "Following publication of the original article , the autThe publisher apologizes to the authors and readers for the error and inconvenience."} +{"text": "This has now been corrected in both the HTML and PDF versions of the Article."} +{"text": "The authors wish to make the following corrections to their paper :In"} +{"text": "The initial cross should be a male This has been corrected in the HTML and PDF version of the Article."} +{"text": "Pharmacopeia Quality Institute as one of the funders of the work.The article has been corrected accordingly."} +{"text": "In each variant of the The approach is robust: it still holds when extending the calculi with operators and extra rules to model some additional computational features."} +{"text": "The following information is missing from the Funding statement: Open Access funding is provided by the Qatar National Library."} +{"text": "In our paper All the authors have read the erratum and agree with the correction."} +{"text": "This has now been corrected in both the HTML and PDF versions of the Article."} +{"text": "We believe these issues can be addressed by removing claims of universal scope and adding critical historical and mathematical context to appropriately frame the novelty and scope of this contribution."} +{"text": "The authors wish to make the following correction to their paper :The caption of"} +{"text": "In the article by Hatano et al.,The authors apologize for this omission from their published article."} +{"text": "The International Headache Genetics Consortium was omitted from the Author list and the list of additional authors and collborators was published as a supplementary file.The author list has now been corrected and members of The International Headache Genetics Consortium are listed as authors in the list of authors and collaborators at the end of the paper."} +{"text": "The H2OThese changes have no material impact on the discussion and conclusions of the paper. The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "There is an error in the caption for The image for"} +{"text": "The authors regret that the images in the original version of Figure"} +{"text": "Instead of having affiliations The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This has now been corrected in the HTML and PDF versions of this Article."} +{"text": "In the article titled \u201cComparison of the Efficacy of Three Loading Doses of Intravitreal Injection of Conbercept with Injection Combined with PDT for the Treatment of PCV\u201d , authorsThe corrected list of affiliations is shown in the author information above."} +{"text": "The following information is missing from the Funding statement: Open Access funding was provided by the Qatar National Library."} +{"text": "The following information is missing from the Funding statement: This work was also supported by the Shenzhen Key Laboratory of Viral Oncology (ZDSYS201707311140430)."} +{"text": "This has now been corrected in both the PDF and HTML versions of the Article."} +{"text": "The authors wish to make the following corrections to this paper :The third column of The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "The authors would like to apologize for any inconvenience caused to the readers by this change."} +{"text": "This has been corrected in the HTML and PDF version of the Article."} +{"text": "In the publication of this article (Liu et al."} +{"text": "In the article by Liu et al,The authors apologize for this error."} +{"text": "This has now been corrected in both the HTML and PDF versions of the Article."} +{"text": "The correct conflict of interest statement on behalf of the author has now been included."} +{"text": "The Letter to the Editor by Riggare et alThe Editorial Office apologizes for these errors and has revised the process for dealing with letters to the Journal."} +{"text": "This has now been corrected in the PDF and HTML versions of the Article."} +{"text": "Borrelia crocidurae by Fotso Fotso and others draw attention to errors in The authors of an article previously published by the AJTMH (Monoclonal Antibodies for the Diagnosis of"} +{"text": "We apologize to the authors for any inconvenience caused to the readers."} +{"text": "In the original publication the photo of the gregarious adult locust in Fig."} +{"text": "Following publication of this article , concernIn light of concerns that the originally published The underlying data for this article is available upon request from the corresponding author."} +{"text": "Vink was omitted from the author information. This has now been corrected in both the PDF and HTML versions of the Article."} +{"text": "The authors wish to add the following correction to their paper published in International Journal of Environmental Research and Public Health .In row 2 of In row 7 of In row 15 of In row 21 of The authors would like to apologize for any confusion or inconvenience. Corrected"} +{"text": "The authors sincerely apologize for the imperfections made during the collection of data and wish to make the following correction to the previous paper ."} +{"text": "This article has been corrected at the request of the submitting author to change the name Maya Borowczak to Maya Pinzon."} +{"text": "The authors regret that the one of the affiliations (affiliation b) was incorrectly shown in the original manuscript. The corrected list of affiliations is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "We regret that the immunohistochemistry images were misplaced and the mark of magnification position was missing in the Figure"} +{"text": "The authors regret that the name of the author Heather R. Campbell was incorrectly spelt in the original manuscript. The correct spelling is listed above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Following publication of the original article [1], the surname and the family name for all the authors are corrected.The original article has been corrected."} +{"text": "After this article was publAll authors agreed with the retraction and apologize for the issues with the published article ."} +{"text": "The authors regret that the name of one of the authors (Mizuo Maeda) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Computer tomography showed opacification of the right sinonasal air spaces Written informed consent was obtained from the patient for the publication of this case report and the accompanying images, and the case report was approved by the Ethical Committees of the First Affiliated Hospital of Xi'an Jiaotong University.The authors have confirmed clinical trial registration is not needed for this submission.The authors have confirmed patient consent statement is not needed for this submission."} +{"text": "There are errors in the Funding section. The correct Funding statement is: The authors acknowledge the financial support by the University of Graz."} +{"text": "Al-Ghamdi The corrected list of affiliations is as shown below.The authors regret that affiliations The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The images of We have noticed inadvertent errors in our article published in the December 2021 issue of Aging Dis"} +{"text": "The authors would like to correct a mistake in The corrected The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original publication has also been updated."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that there was an error in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The corrected list of affiliations is as shown here.The authors regret that two affiliations (affiliations The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The corrected list of affiliations is as shown here.The authors regret that two affiliations (affiliations The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In the original manuscript, the authors regret an error in the vertical axis label for The conclusions remain unaffected by this change.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The images of We have noticed inadvertent errors in our article published in the August 2016 issue of Aging Dis :"} +{"text": "The authors regret that the name of one of the authors (Pankaj Srivastava) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that some of the author affiliations were incorrectly shown in the original manuscript. The corrected list of affiliations is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Instead of Silvia BellutiThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "New sequencing data of the iPSC line clearly indicates heterozygosity of the APP patient cells. The authors would like to apologize for not having identified this error earlier and any inconvenience caused. The error does not invalidate any of the data and conclusions previously reported. The text that requires emendation in light of this sequencing error is provided below."} +{"text": "The authors regret that the name of one of the authors (Ali Maghsoodpoor) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Hashem The corrected list of affiliations is as shown above.The authors regret that one of the affiliations (affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the name of one of the authors (Lingyun Zhong) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "They also wish to apologize to the readership of the Journal for any inconvenience caused.The revised version of"} +{"text": "In this workshop we aim to discuss the ins and outs of publishing in psychiatry with practical guidance from both sides of the couch.The executive editors of the European Journal of Psychiatry will talk about the experience of starting a journal from scratch with very limited resources and share practical tips with the participants about publishing for ECPs by ECPs.None Declared"} +{"text": "We read with interest the article by Our concerns relate to the accuracy of the information presented in Table 1 of the Although In the After reviewing the five studies referenced, we do not find support for the use of blood flow restriction pressures of 100%\u2013150% of LOP during BFR training as reported by"} +{"text": "The corrected The authors regret that in the originally published article, the plots in"} +{"text": "The authors regret that an incorrect version of An independent expert has viewed the corrected image and has concluded that it is consistent with the discussions and conclusions presented.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "This has now been corrected in both the HTML and PDF versions of the article."} +{"text": "The authors regret that the name of one of the authors (Vineet Tirth) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The corrected list of affiliations is as shown here.The authors regret that the one of the affiliations (affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "We are extremely grateful to the following members of the medical profession from Pakistan and Overseas for sparing their precious time to review the manuscript published in the Issue of September - October 2023."} +{"text": "The authors regret an error in the original article whereby identical images were presented in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In the published version of the article, The authors apologise for any inconvenience caused."} +{"text": "The Acknowledgements section is missing in the paper. The correct Acknowledgements is as follows: The authors would like to acknowledge the support of Prince Sultan University for paying the Article Processing Charges (APC) of this publication."} +{"text": "In the original article in The results and conclusions of this paper are not affected by this correction.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In this workshop we aim to discuss the ins and outs of publishing in psychiatry with practical guidance from both sides of the couch. The executive editors of the European Journal of Psychiatry will talk about their experience of starting a journal from scratch with very limited resources and share practical tips with the participants about publishing for early career psychiatrists to early career psychiatrists.None Declared"} +{"text": "The authors regret that the name of one of the authors (Piyapong Buahom) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors' regret that the name of the author Fuming Zhang was incorrectly spelt as Fumin Zhang in the original manuscript. The correct author names are listed above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "S. Sabir The authors regret that the name of the first author was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "This has now been corrected in both the HTML and PDF version of the article."} +{"text": "The authors regret that the image representing a double dose of PtNPs at 15 h in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "P. Bandlamudi The authors regret that the funding information was incorrectly shown in the Acknowledgements section of the original manuscript. The corrected funding acknowledgement is as shown below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The figures were published out of order. See here the correct figures and their captions."} +{"text": "S. Sabir The authors regret that the name of the first author was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "We are extremely grateful to the following members of the medical profession from Pakistan and Overseas for sparing their precious time to review the manuscript published in the Issue of July - August 2023."} +{"text": "This article was retracted due to the improper manipulation of NMR spectra with the help of software to obscure peaks corresponding to impurities and solvent."} +{"text": "The authors regret that the email addresses were associated with the incorrect institution. The corrected association is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "This article has been corrected at the request of the submitting author to change the name Maya Borowczak to Maya Pinzon."} +{"text": "The corrected The authors regret that in the originally published"} +{"text": "Special Account for Research Grants (ELKE) of University of West Attica.'' have not been included in the Acknowledgments section of the paper. Please add the before mentioned text in the Acknowledgments section.>.The authors regret < The acknowledgments ``This study has received financial support from the The authors would like to apologise for any inconvenience caused."} +{"text": "The Publisher apologises that upon publication of this paper the wrong graphical abstract was included.The online version of this article has been updated with the correct image"} +{"text": "Alazemi The corrected list of affiliations is as shown here.The authors regret that an affiliation (affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Validation of PPh The author regrets that the funding information was incorrectly shown in the acknowledgements section of the original manuscript. The corrected funding acknowledgement is as shown below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The withdrawal hasbeen agreed because the authors are unable to finalize the APC payment for their articlefor publication in the journal as the Version of Record."} +{"text": "There is a misalignment of The publisher apologizes for the mistake."} +{"text": "The figure has been corrected in both the PDF and HTML versions of this Article."} +{"text": "The authors regret that incorrect versions of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the author Ge Shi was not marked as the corresponding author and the affiliations were incomplete in the original manuscript. The corrected author list and affiliations are listed here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The corresponding author of [Due to duplicate publication of part of Figure 1c from , the aututhor of was the"} +{"text": "One of the biggest challenges for an organisation and for clinicians and practitioners is implementing a new program or a new practice. Following an 18 month research project and the recruitment of an Eating Disorders Coordinator the MCH and Mater CYMHS have developed and implemented a number of protocols across its service to ensure consistency in the continuum of care and to ensure that treatment is in line with the best current evidence base.Within the campus based services these have included;\u2022 Development of a protocol for the CYMHS Inpatient Unit to provide structure and consistency to the admission of patients with restrictive eating disorders.\u2022 Design and roll out of a Care Pathway for the Paediatric Medical Ward where medical crises associated with malnutrition are managed.\u2022 Guidelines for triage of such patients in the Children's Emergency Department with parameters indicative of further consultation and/or admission.\u2022 Off campus/outpatient service development has included;\u2022 The implementation of Maudsley Family Based Therapy as the model of choice giving structure and consistency to outpatient treatment.\u2022 Guidelines for community staff for medical monitoring nutritionally compromised children and adolescents.This presentation will refer to implementation science as a framework to describe the process and stages of development involved in the implementation of these projects.Children and Youth Treatment and Service Development stream of the 2013 ANZAED Conference.This abstract was presented in the"} +{"text": "The author wish to make the following correction to this paper : The aut"} +{"text": "The following information was missing from the Funding section: \"The study was supported by funding from the NIHR Oxford Biomedical Research Centre programme.\""} +{"text": "Tan et al are to be congratulated for achieving the difficult task of synthesizing the many disparate pieces of data on the subject of exchange transfusion (ET) . However"} +{"text": "The GReaNs platform is an artificial life software platform that has been previously shown to allow the evolution of networks for signal processing and animat control . The str"} +{"text": "There was an error in formatting the equation in the fourth sentence of the first paragraph of the \"Bayesian geostatistical modeling\" section of Materials and Methods. The correct equation can be viewed here:"} +{"text": "The following information was missing from the Funding section: \"The study was supported by funding from the NIHR Oxford Biomedical Research Centre programme.\""} +{"text": "The following is a statement that is missing from the funding information in the published article:\"The article processing charge was funded by the open access publication fund of the Albert Ludwigs University Freiburg.\""} +{"text": "There was an error in the placement of Figures 4 and 5. The figures were swapped and each figure belongs with the legend of the other figure."} +{"text": "The following information was missing from the Funding section: Derek Brazil and Kristine Nyhan were funded by Science Foundation Ireland as part of the UCD Diabetes Research Centre."} +{"text": "There was an error in formatting the equation in the first sentence of the second paragraph of the \"Bayesian geostatistical modeling\" section of Materials and Methods. The correct equation can be viewed here:"} +{"text": "In the fifth sentence of the section \"Matching Gradients\" of Models, the text \"Standard Methods for the Examination of Water and Wastewater 18th ed.\" is incorrect and should instead read \""} +{"text": "The following funder in the Funding Disclosure is missing information: the Hakai Network for Coastal Peoples and Ecosystems.The following is the correct funder: the Tula and Hakai Network for Coastal Peoples and Ecosystems."} +{"text": "The cause of the errors in the Correction notice was the use of the incorrect manuscript during the typesetting process of the article by PLOS."} +{"text": "The authors would like to inform the correct names for the present paper as stated above."} +{"text": "The following information is missing from the Funding Statement:\"This study was funded by the German Research Foundation (DFG) and by the University of Wuerzburg Open Access Publishing funding program.\""} +{"text": "There was an error in the spelling of the fifth author's name. The correct spelling is Anxin Wang."} +{"text": "In The incorrect information in The authors' explanation of the changes can be viewed on the Comments tab of the article page."} +{"text": "There was an error in the last sentence of the \"Microarray Processing and Data Analysis\" section of the Materials and Methods. The last sentence should read: \"The microarray data has been deposited on ArrayExpress platform under the accession number GSE49451.\""} +{"text": "A funding organization and grant to the third and last authors were incorrectly omitted from the Funding Statement. The following sentence should be read with the Funding Statement: \"This study was supported in part by the Excellence Initiative of the German Research Foundation .\""} +{"text": "The last author (VL) should be noted as one of the authors who wrote the paper."} +{"text": "The description is 'Datafiles for \"High rates of gene flow by pollen and seed in oak populations across Europe\" paper' and can be viewed here:"} +{"text": "The publication date provided in the footer of the PDF is incorrect. The paper was published in the January 2010 issue."} +{"text": "There is an error in the title of Table 1. The corrected title is: Number of mosquito collections from each community in Freetown and Monrovia"} +{"text": "A second grant from the National Natural Science Foundation of China is missing from the Funding section. The second grant number is 31271068."} +{"text": "There are four mistakes at the table derived from the (c) surface slope of The new figure is provided below:"} +{"text": "A funding organization was incorrectly omitted from the Funding Statement. The first sentence of the Funding Statement should read: \"This project was supported by the NHMRC (Project Grant 509185 to SJR and Project Grant 575534 to JB and SR)and by the Malaria in Pregnancy Consortium.\""} +{"text": "The correct names of the authors of this article are Ga\u00ebtThe Publisher and authors apologize to the readers for the inconvenience caused."} +{"text": "The number of the grant from the Natural Science Foundation of China to the sixth author is incorrect. The correct grant number is: 81020108022."} +{"text": "In the The authors apologize for the inconvenience."} +{"text": "The following information was missing from the Funding section: \"The study was supported by funding from the NIHR Oxford Biomedical Research Centre programme.\""} +{"text": "The following information was missing from the funding statement: This work was also supported in part by grants from the National Natural Scientific Foundation of China ."} +{"text": "The following information was missing from the Funding section: \"The study was supported by funding from the NIHR Oxford Biomedical Research Centre programme.\""} +{"text": "The following information was omitted from the financial disclosure:'MRT was supported by the Netherlands Organisation for Scientific Research .'"} +{"text": "There is an error in the spelling of the first name of the author listed as Xiopeng Ge. The correct spelling is Xiaopeng Ge."} +{"text": "The many approaches NIH is implementing to improve translational research will be monitored closely for success.The development of new drugs and devices is expensive with long timelines and high rate of failure. The director of NIH is concerned with these issues and has made reengineering the translational sciences a top priority . One out"} +{"text": "The version of Figure 1 in the published article is incorrect. The correct version of the Figure is available here:"} +{"text": "The original edition of the article is available here:"} +{"text": "The following information was missing from the Funding section: \"The study was supported by funding from the NIHR Oxford Biomedical Research Centre programme.\""} +{"text": "The authors would like to correct the name of the fifth author in this paper to Samad EJ Golzari."} +{"text": "The authors would like to correct the name of the third author in this paper to Samad EJ Golzari."} +{"text": "The methods of the published manuscript state th"} +{"text": "The equal contributions designation was omitted. The two authors of the article contributed equally to the work."} +{"text": "We have now corrected the online Supplemental Information and apologize for the error."} +{"text": "An error was introduced into the author list during the preparation of this article for publication. The group listed in the last line of the author list on the article page and PDF should read \"on behalf of the MTN-009 Protocol Team.\""} +{"text": "The following information was missing from the Funding section: \"The study was supported by funding from the NIHR Oxford Biomedical Research Centre programme.\""} +{"text": "The following information was missing from the Funding section: This study was also supported by the National Natural Science Foundation of China grant #81171070."} +{"text": "There was a spelling error in the name of the seventh author. The correct spelling is Anthony Antonellis."} +{"text": "There are errors in the equations of the Materials and Methods section. Correct versions of the equations can be seen here:[^][^]"} +{"text": "The authors would like to add the following to their financial disclosure: \"The study is also a Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.\""} +{"text": "The following information was missing from the Funding section: This work was supported by the Wellcome Trust ."} +{"text": "The following line was omitted from the Funding statement: \"Industry Canada MNI center of excellence in commercialization and research grant awarded to AD and AS.\""} +{"text": "The content of this Correction is superseded by the Retraction and has"} +{"text": "The following information was missing from the Funding section: \"The study was supported by funding from the NIHR Oxford Biomedical Research Centre programme.\""} +{"text": "A correct version of the text of the Methods section is available here:"} +{"text": "The authors regret the following acknowledgment was missing from the original publication of this article. The acknowledgment has been reproduced below:The study was supported by funding from the NIHR Oxford Biomedical Research Centre programme."} +{"text": "The authors would like to add the following to the funding information: \"This study was supported by Himeji Dokkyo University Grant for Special Research Projects\""} +{"text": "The authors wish to add the following sentence to the Copyright Statement:\"Please contact the corresponding author for information on the underlying research materials.\""} +{"text": "The authors wish to make the following correction to this paper : The aut"} +{"text": "The following information was missing from the Funding section: The study was also supported by the European Union FP7 project European Management Platform for Emerging and Reemerging Infectious Disease Entities ."} +{"text": "We welcome the remarks of van Tongeren and Cherrie regarding our recent editorial and see"} +{"text": "The image quality for panel A in For a better quality version of For a better quality version of"} +{"text": "The authors would like to add the following to the funding information: \"The study was supported by funding from the NIHR Oxford Biomedical Research Centre programme.\""} +{"text": "The wrong version of Figure 3 was used in the published article. Please use the following link to download the correct version of this figure:"} +{"text": "The content of this Correction is superseded by the Retraction and has"} +{"text": "Please see a corrected version of the aforementioned section and the correct value and percentage here:"} +{"text": "The authors would like to make the following addition to the Acknowledgments section of this article: \"The authors also wish to thank Christina Bakatselou for performing and providing images of the acridine orange stainings of Figure 1.\""} +{"text": "The affiliations of the authors in the original paper are corrected here."} +{"text": "All specimens and clinical data were obtained with either informed written consent or a formal waiver of consent under protocols approved by the Research Ethics Board of the BC Cancer Agency and the University of British Columbia."} +{"text": "In Figure 2Frontiers in Genetics. The current description in the legend of Figure An error has been identified in the legend of Figure The correct description in the legend of Figure"} +{"text": "The following information was missing from the Funding section: \"The study was supported by funding from the NIHR Oxford Biomedical Research Centre programme.\""} +{"text": "The authors would like to make the following addition to the Acknowledgments section of this article: \"The authors also wish to thank Dr. Vinesh Thidil Puliyappadamba for performing and providing images for the western blot in Figure 4A.\""} +{"text": "We analyze the stochastic dynamics of genetic regulatory networks using a system of nonlinear differential equations. The system of"} +{"text": "The authors would like to correct the acknowledgements of this article as follo"} +{"text": "The following information was missing from the Funding section: \"The study was supported by funding from the NIHR Oxford Biomedical Research Centre programme.\""} +{"text": "The following information was missing from the Funding section: Heart and Stroke Foundation of Canada Grant."} +{"text": "The authors would like to apologize for this omission and acknowledge the work carried out by the different groups that described the datasets by replacing the supplementary Table S1 by the one provided here which includes the details of the authors and publications:"} +{"text": "There is an error in the given name of the fifth author. The correct name is Irene Ricci."} +{"text": "We provide herein the correct structures of the compounds that were listed in"} +{"text": "After the publication of this work an errorThis has now been updated in the original version of this article."} +{"text": "The following information is missing from the Funding section: The Centro de Estudios Cient\u00edficos CECs is funded by the Centers of Excellence Base Financing Program of CONICYT."} +{"text": "The original version of this article unfortunately contained a mistake in the presentation of Fig."} +{"text": "The following information is missing from the Funding section: Publication of this article was funded by the University of Colorado Boulder Libraries Open Access Fund and Loggerhead Instruments."} +{"text": "The author list in the original version of this article (Sullivan et al."} +{"text": "In the following articles, leading researchers in the field of microbial biotechnology speculate on the technical and conceptual developments that will drive innovative research and open new vistas over the next few years."} +{"text": "There is a minor error in the vertical axis label of the lower right portion of"} +{"text": "The evidence shows contradictory information about the aging decrease of neurogenesis and its impact on cognitive performance. Some studies support this view (Drapeau et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The following information is missing from the Funding section: This study was also funded by the Roskamp Foundation."} +{"text": "The attribution for the original source of"} +{"text": "The authors would like to add the following detail to the Competing Interests and Acknowledgments stated in the published article \u201cAt the"} +{"text": "The name of the second author was incorrect in the original published article. The correct author name is Raul Y Tito."} +{"text": "There are errors in In the legend of In the fifth blot of"} +{"text": "The publishers of this journal are publishing this Expression of Concern because attribution for the synthesis and design of the luc* and Renluc* coding sequences in this article is underThe correct table and description of the method set out in Table S1 can be found in this article .The University of Queensland advises that there has been no academic misconduct but the wording of any erratum remains under dispute."} +{"text": "The following information is missing from the Funding section: This study was supported a grant from the Cancer Prevention and Research Institute of Texas to AHK. The publisher apologizes for this error."} +{"text": "There is an error in the first sentence of the Study cohort section of the Materials and Methods. The correct sentence is: We conducted a review of an electronic medical record of all 622 patients who underwent radical cystectomy for bladder cancer at Seoul National University Hospital from January 2001 through December 2011."} +{"text": "The original version of the article (Hayhurst and Ahmed"} +{"text": "Rp49 loading control in the lower panel of Figure The published version of this article contains"} +{"text": "The following information is missing from the Funding section: The article processing charge was funded by the open access publication fund of the Albert Ludwigs University Freiburg."} +{"text": "In 2010 the New Zealand Ministry of Health made a decision to roll out training in FBT across New Zealand for clinicians working with eating disorders. The expectation was that the three regional specialist services in New Zealand would subsequently provide a lead to ensure implementation of FBT across their Region.This presentation will describe the process of change to achieve uptake of FBT as a new treatment model by the existing adolescent team of the Regional Eating Disorder Service in Auckland (REDS). The steps taken to overcome the significant initial challenges and the strategies and the resources required to achieve a sustainable model of provision of FBT at REDS will be discussed as well as its implications for regional training and supervision of CAMHS clinicians across the Northern and Midland Regions of New Zealand.The positive impact of these changes on outcome data is described in more detail in the presentation \"What difference does FBT make? Results of a service audit following the implementation of FBT\".Service Initiatives: Child and Adolescent Refeeding and FBT stream of the 2014 ANZAED Conference.This abstract was presented in the"} +{"text": "The quizzes are printed at the back of this issue, and the complete articles and quizzes are available online ("} +{"text": "The author list in the original version of this article (Kumar et al. The publisher would like to apologise for this error."} +{"text": "The words red and blue are swapped in the legend of"} +{"text": "In the PDF and XML versions of the article, the points within"} +{"text": "It has been found that one of the signal models in Figs."} +{"text": "The following information is missing from the Funding section: The authors would like to express their gratitude to the Leading National Research Centre (KNOW) 2012\u20132017 for their financial support of the process of printing the article.The publisher apologizes for the error."} +{"text": "Clinical and Translational Medicine [Following publication of the original version of this article in Medicine it was b"} +{"text": "During the typesetting of the final version of the article some datPlease note that references 41 and 42 in the table legend correspond to the reference order in the original article ["} +{"text": "The data are available from the University of California Merritt repository ("} +{"text": "The accession number that gives access to the Microarray data in the last sentence of the cDNA Microarray Analysis section of the Materials and Methods is incorrect. The correct accession number is: GSE59493."} +{"text": "The correct email address is: The following information is missing from the Funding section: This study was supported by the Fundamental Research Funds for the Central Universities of China grant 2682014RC14 to XH."} +{"text": "The following information is missing from the Acknowledgements section: This study was part of a project registered at the Portuguese Foundation for Science ."} +{"text": "The following information is missing from the Funding section: Funding was received from the National Natural Science Foundation (81401385)."} +{"text": "The name of the third to last author in the authorship listing is spelled incorrectly. The correct spelling of the name is: Bernhard Hemmer. The citation from the original article remains the same."} +{"text": "The PDF file of the published article incorrectly lists the year of publication as 2007, rather than 2014."} +{"text": "To the Editor,The Editorial by Hage and Iskandrian"} +{"text": "The authors and the journal apologize for any confusion caused by this error."} +{"text": "In Equation (3) the limit The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The title for the original version of this article unfortun"} +{"text": "The following information is missing from the Funding section: Publication of this article was funded in part by the George Mason University Libraries Open Access Publishing Fund."} +{"text": "The following information is missing from the Funding section: The article processing charge was covered by the open access publication fund of the University of Freiburg."} +{"text": "The second panel from the bottom of the left side of"} +{"text": "The title of Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The following information is missing from the Acknowledgements in the published article: \u201cThe publication of this article was funded by the Open Access Fund of the Leibniz Association.\u201d"} +{"text": "The alignment of the immunoblots in"} +{"text": "It has come to our attention that during the production of the original article (Acar et al."} +{"text": "Although the focus of our article in Lipids in Health and Disease reports"} +{"text": "The following information is missing from the Funding section: QX and YC are supported by NIH grants GM60448 and EY014852 to Criss Hartzell at the Department of Cell Biology, Emory University."} +{"text": "To the Editor:I read with interest the case report by Whitlow and Davis in the November 2014 issue of the Western Journal of Emergency Medicine regarding management of high altitude pulmonary edema (HAPE) in an experienced mountaineer."} +{"text": "The authors regret to have overlooked an error in of the original version of this article . The ori"} +{"text": "The correct link to access the data is:"} +{"text": "The following information is missing from the Funding section: Publication of this article was funded in part by The Pennsylvania State University Libraries Open Access Publishing Fund."} +{"text": "After publication of the original article , it was The updated and correct author affiliations of the original article are pres"} +{"text": "The values in Table 1 and the corresponding values reported in the Sequence Alignment and Analysis subsection of the results are incorrect. The authors have provided a corrected The percent sequence identity for available aviadenovirus whole genomes are given in"} +{"text": "The original version of the article (Ali et al."} +{"text": "The red blood cell counts and platelet count data in the rest of There is an error in the representation of white blood cell counts in"} +{"text": "PLOS Biology Editors.There were some errors in the preparation of the middle panel of The corrected versions of Figs"} +{"text": "The image for The image for"} +{"text": "The correct statement is: All genotypes and phenotypes are available from the Dryad Digital Repository:"} +{"text": "This does not affect the validity of the biochemical characterization of specific interactions of the sialidase with diplacone and other naturally occurring compounds reported in the paper.The authors of Lee al. 2014 have mad"} +{"text": "Antrodia vaillantii instead of the many different Genus species that should be listed. Please view the correct There are errors in the third column of The publisher apologizes for the errors."} +{"text": "International Journal of Clinical and Experimental Pathology [The editors are retracting this article as it haathology and it i"} +{"text": "The correct link to the download is:"} +{"text": "There is an error in the title of the y axis of"} +{"text": "The original orientation of the western blot in"} +{"text": "Following publication of the original version of the aThe authors would like to add the following text:\u201cThe authors would like to acknowledge the support of the Alliance for Health Policy and Systems Research (HSR/HIS), World Health Organization which supported the development of this case study and publication of this work.\u201d"} +{"text": "The color coding of the categories in"} +{"text": "The following information is missing from the Funding section: Individual support was provided to MF in the form of a Gilead Sciences Research Scholars Program in Liver Disease Award."} +{"text": "International Journal of Environmental Research and Public Health for any inconvenience. The article [The title article is a dup article will be"} +{"text": "The following information is missing from the Funding section: This work was financially supported by the Department of Education of Liaoning province (L20120113)."} +{"text": "There are errors in the formatting of Please see the corrected Please see the corrected"} +{"text": "The following information is missing from the Funding section: This study was supported by the Liaoning Province Science and Technology Plan Project (2012225020)."} +{"text": "The incorrect version of The incorrect version of The incorrect version of"} +{"text": "There is an error in The publisher apologizes for the errors."} +{"text": "In the original version of this article errors in Figs."} +{"text": "After the publication of this article the auth"} +{"text": "The legend of Figure The corrected version of Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The order of the panel descriptions in the figure legend for"} +{"text": "After the publication of the original article in BMC P"} +{"text": "The title of the original version of this article containe"} +{"text": "The following information is missing from the Funding section: Publication of this article was funded by the University of Colorado Boulder Libraries Open Access Fund."} +{"text": "The authors regret that the affiliations of three of the authors were shown incorrectly in the original article. The corrected author list and affiliations are as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors state that the images used in the original"} +{"text": "In the original publication of the article, the corresponding authors should be Xianhai Mao and Ping Liang as given in this correction and not Qunfang Zhou."} +{"text": "The editors of the Central Asian Journal of Global Health regretfully published the article \u201cA Systematic Review of the Effects of Aromatherapy with Lavender Essential Oil on Depression\u201d with a misspelled word in the title. This mistake has been corrected. The original article has been updated to reflect this change."} +{"text": "The authors regret that an incorrect figure caption was given for The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the affiliations were incorrectly shown in the original manuscript. The corrected list of affiliations is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the figures throughout the article were incorrectly referenced. The correct references for each figure are described in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Errors were present in the published version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the name of one of the authors (Aayushi Biswas) was shown incorrectly in the original article. The corrected author\u2019s name is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The mislabelingof the structures does not affect any of the reported results."} +{"text": "The authors regret that the name of one of the authors (Anna Tomaszewska) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Due to a production error the incorrect versions of The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the authors were affiliated with the incorrect institutions in the original manuscript. The corrected author list and affiliations are as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the details of the affiliations were incorrectly shown in the original manuscript. The corrected list of affiliations is as shown herein.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "They also wish to apologize to the readership of the Journal for any inconvenience caused.The revised version of"} +{"text": "The authors regret that the name of one of the authors (Cornelia Cramer) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that Hailiang Liu\u2019s name was spelled incorrectly in the original article; the corrected version is shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The correct author affiliation list in which author affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Arrousse The authors regret that the affiliation of one of the authors (Anouar Alami) was shown incorrectly in the original article. The corrected author affiliation is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The corrected list of affiliations is as shown here.The authors regret that the one of the affiliations (affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The author would like to make the following corrections to the published paper : The tim"} +{"text": "This has now been corrected in both the PDF and HTML versions of the Article."} +{"text": "A final reflection on the importance of evaluation aspects will be proposed at the end of the workshop."} +{"text": "The published affiliation contained an incomplete university name and the corrected version is shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In the original publication of this article the foot"} +{"text": "The incorrect numbers highlighted in bold in the below table have now been updated in the HTML and PDF version of this Article with the correct numbers. The conclusions of the Article are unchanged."} +{"text": "This misrepresentation of data without appropriate attribution represents a severe abuse of the scientific publishing system. The authors did not respond to the request to retract the paper."} +{"text": "The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the name of one of the authors (Muhammad Usman Rashid) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In the original manuscript, The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors wish to make the following correction to the original paper :The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original publication has been updated."} +{"text": "The authors regret that an incorrect version of An independent expert has viewed the corrected images and has concluded that they are consistent with the discussions and conclusions presented.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The correct address is as presented here.The authors regret that the address for affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that affiliation b was incorrect in the original version of the manuscript. The correct affiliation is presented herein.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the names of the authors were listed incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that in the original version of the manuscript the affiliations of Jang Ho Kim and Ki Taek Lim were reversed. The correct affiliations are presented in this correction notice.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors would like to correct errors in their prior publication . In the The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected."} +{"text": "The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the name and affiliation of the first author (Shuduan Mao) was shown incorrectly in the original article. The corrected author list and affiliations are as shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "G values is reproduced below:The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The Royal Society of Chemistry regrets that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that incorrect details were given for The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the primary affiliation of the corresponding author (Milica Budimir) was incorrectly designated in the original manuscript. The corrected list of affiliations is as shown herein.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The corrected list of affiliations is as shown above.The authors regret that one of the affiliations (affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the author contributions were incorrectly given in the original article. The corrected author list and contributions are as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The publisher regrets the Conflict of Interest statement was not included in the published version of this article.The authors declare no conflicts of interest.The publisher would like to apologise for any inconvenience caused."} +{"text": "The authors regret that the name of one of the authors was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors wish to make the following corrections to this paper :For The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original publication has also been updated."} +{"text": "The authors regret errors in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The author regrets that the funding information was incorrectly shown in the acknowledgements section of the original manuscript. The corrected funding acknowledgement is as shown below.Dr Yuandu Hu is grateful for the Fundamental Research Funds for the Central Universities under the grant number KSRC21006532.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The corrected list of affiliations is as shown here.The authors regret that the one of the affiliations (affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Hussnain Ahmed Janjua's name was incorrectly spelled in the published article; the corrected author list is shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that affiliations a and c were incorrectly shown in the original manuscript. The corrected list of affiliations is as shown below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the contact email address for the corresponding authors was incorrect in the original article. The correct email addresses are as shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Rahimi The authors regret that the name of one of the authors (Farhad Rahmani) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that there was an error in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the first name of the third author was misspelled in the original article. The correct author names are presented here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Charge partitioning theory and methodology\u2019 by Thomas A. Manz The authors regret that there was an error in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In the original publication, the first author\u2019s name was incorrect; the correct version is shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The journal citations in ref. 10 and 11 were incorrect in the published article. The corrected references are shown below as The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The Authors regret that an incorrect version of Scheme 2 was included in the original article. The correct version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret the omission of a funding acknowledgement in the original article. This acknowledgement is given below.The research leading to this result has been supported by the project CALIPSOplus under Grant Agreement 730872 from the EU Framework Programme for Research and Innovation HORIZON 2020.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the email addresses of two authors (Dingyu Yang and Jitao Li) were shown incorrectly in the original article. The correct email addresses are as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that incorrect TEM images were shown in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors wish to amend the authorship of this article by adding an additional author, Aleksandra Wiatrowska. The full author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret an error in the final line of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that ds26, telo21 and RNA were labelled incorrectly in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors apologize for that mistake. The correct Tables In the original publication of the article, some values for the electrode arrays Flex"} +{"text": "The authors regret that Jinlong Wu was not included in the author list in the original article. The correct list of authors and affiliations is presented above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In the original version of this article, in the bottom row of Table The original article has been corrected."} +{"text": "The authors regret that the name of one of the authors (Ghassan Hassan) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The HTML and PDF versions of this Comment have now been updated with the ethics declaration."} +{"text": "The authors regret that the name of one of the authors (Zhanpeng Huang) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "This minor editorial error did not affect the results or conclusions of the manuscript.The authors apologize for the error."} +{"text": "The authors regret that the name of one of the authors (Muhammad Usman Rashid) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that there was an error in the author affiliations in the original article. The correct affiliations are given here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Wolska The corrected list of affiliations is as shown below.The authors regret that one of the affiliations (affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In 2022 the International Brazilian Journal of Urology received the highest impact factor of his history and this fact was possible because the serious peer review process of our Journal . In thisThanks a lot!!!!!"} +{"text": "One of the affiliations of the corresponding author was omitted from the original manuscript. The correct affiliations are as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that incorrect versions of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the name of one of the authors (Hafiz Husnain Akhtar) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that a footnote to indicate that Chu Chen and Guanhua Xu are co-first authors was omitted in the original manuscript.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Following publication of the original article , the autThis error is corrected in the author list of this Correction article and the original article has been"} +{"text": "The authors regret that the name of one of the authors (Khawaja Waqar Ali) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the original author list was incorrect. The correct author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that incorrect versions of An independent expert has viewed the corrected images/data and has concluded that they are consistent with the discussions and conclusions presented.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "T. Sudheesh Kumar The authors regret that there were errors in The images in the lower panel of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The assigned affiliations did not match the number of affiliations in the published proof.The Original article has been corrected."} +{"text": "The authors regret the omission of one of the affiliations of the author Jon Ustarroz from the original manuscript. The correct affiliations for this paper are as shown.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the reference for The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that there was an error in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Two authors from Walter ReedArmy Institute of Research were inadvertently left off the authorlist for this paper. The corrected author list and affiliations areas presented in this Correction."} +{"text": "The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an asterisk was not displayed next to the name of the corresponding author Chang Liu in the original manuscript. The corrected information is shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the name of one of the authors (Hao Qin) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The Data Availability statement has now been updated in both the HTML and PDF versions of the Article."} +{"text": "In the original publication of the article the affi"} +{"text": "In the published article there was an error in the primer DNA (22 nt) sequence in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors of the original article would like to correct"} +{"text": "The authors regret that there are errors in the referencing in the original tables. The corrected versions of The references themselves are correct and have not been adjusted from the original article.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the name of one of the authors (Gi Seok Jeong) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Trejgis The authors regret the omission of a funding acknowledgement in the original article. This acknowledgement is given below.Karolina Trejgis would like to acknowledge support from the Foundation for Polish Science (FNP).The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the one of the affiliations (affiliation b) was shown incorrectly in the original manuscript. The corrected list of affiliations is as shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "How did the Austrian Public Health Week start and what does it have to do with the European Public Health Week?"} +{"text": "The University was omitted in the affiliation in the published article; the revised affiliation is shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The sentence has now been updated in the HTML and PDF version of this Article with the correct citations. The conclusions of the Article are unchanged."} +{"text": "Bliss Independence model:On page 9 of (1), under the section \"Issue 6: combining more than two drugs\", the following error has been identified in the formula for the Combination Index for the Bliss Independence model in the case of a combination with more than two drugs is:The correct formula for the CI for the The authors apologize for the error."} +{"text": "Following publication of the original article , the autAll the authors apologize for these errors and all the data herein are accurate and reproducible.The original article has been revised."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that one of the affiliations (affiliation b) was incorrectly shown in the original manuscript. The corrected list of affiliations is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the versions of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "There is an error in the final sentence of the Notice of Retraction . The corThe publisher apologizes for the error."} +{"text": "The authors regret an error in The authors have repeated the experiment and provided new data for The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret the omission of a funding acknowledgement in the original article. This acknowledgement is given below.Karolina Trejgis is supported by the Foundation for Polish Science (FNP).The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In the published article there was an error in the corresponding author\u2019s surname. The corrected version is shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The correct equation is shown below:The authors regret that an incorrect equation was shown in the original article. On page 98963 of the original article, in the equation for fitting power saturation data the term The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that affiliation a was incorrect in the original article. The correct affiliations are as presented here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The legends of supplementary figures and tables have been missed out in the original publication.The original article has been corrected."} +{"text": "The authors regret that the name of one of the authors (Daniel de Lima Bellan) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the name of one of the authors (Xiaomei Zhai) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Affiliation a was incorrect in the published article; the correct version is shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret mistakes in An independent expert has viewed the corrected images and has concluded that they are consistent with the discussions and conclusions presented.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Sepsis is the second leading cause of death in the intensive care unit (ICU) and is one of the important causes of death for all hospitalized patients . Evidenc The authors declare there was no any conflict of interest."} +{"text": "There is an error in the name of one of the authors. The name Pedro Henrique Presta Dia should be listed as Pedro Henrique Presta Dias."} +{"text": "The authors regret that the name of one of the authors (Maria C\u00e9lia Pires Costa) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The corrected email address should be: The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the original version of our paper unfortunately contained incorrect data in Figure The corrections made in this erratum do not affect the original conclusions. The authors apologize for any inconvenience that the errors may have caused."} +{"text": "The authors regret that the name of the co-author Ilhwan Kim was spelled incorrectly in the original article. The correct spelling is presented herein.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Abel The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that incorrect details were given for The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Algethami The corrected list of affiliations is as shown in this Correction article.The authors regret that one of the affiliations (affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the equal author contributions and corresponding author indicators were incorrectly shown in the original manuscript. The corrected indicators are as shown in this correction notice.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Trivedi The authors regret that there was an error in the author affiliations given in the original article. The correct information is given in the affiliations section here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors have identified some minor errors in the published version of the"} +{"text": "The authors regret that incorrect images were mistakenly included in The corrected graphical abstract is presented below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an incorrect version of the SEM image shown in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that Paulo Ribeirinha\u2019s name was spelled incorrectly in the original article. The correct spelling of all author names is presented above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret the errors made in The correct figure is as follows:The authors would like to apologise for this oversight and any inconvenience caused."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that their names were displayed incorrectly in the original article. The correct author names are as presented above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the name of one of the authors (Ahed Zyoud) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The corrected email is as follows: The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "This presentation will tell you about the involvement of the next generation: young public health professionals in the European Public Health Week."} +{"text": "The correct version of The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The following information is missing from the Funding statement: We acknowledge support from the Open Access Publication Fund of the University of Wuppertal."} +{"text": "Lesly Jimenez The authors regret that the name of one of the authors (Tyrone Porter) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Following the publication of the original article the auth"} +{"text": "The authors regret that some of the affiliation and contact details were incorrect in the original manuscript. The correct affiliation and contact details are shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The editorial office regrets that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Guseva The authors regret that affiliation d was missing in the original manuscript. The correct affiliations are as presented here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the name of the author Barun Mandal was incorrectly listed as Barun Mondal in the original manuscript.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Affiliation a as published was incorrect; the correct affiliation is given below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "This manuscript is missing an Acknowledgements section. The Acknowledgements should include the following statement: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC)."} +{"text": "The authors regret that James Chen Yong Kah\u2019s name was presented incorrectly in the original article. The correct spelling of all author names is presented above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the name of one of the authors (Saurabh Usgaonkar) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The corrected list of affiliations is as shown here.The authors regret that the one of the affiliations (affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "M. Jefremovas The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that in the original manuscript there were some errors in the structures displayed in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the name of one of the authors (Fazel Shojaei) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Boersch The authors regret that there was an error in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that incorrect details were given for The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the authors affiliations were incorrectly shown in the original manuscript. The corrected list of affiliations is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "References 11 and 24 as published were incorrect; the correct versions are shown below as The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the affiliations of the authors were wrongly designated in the original manuscript. The corrected list of affiliations is as shown below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the name of one of the authors (Muhammad Usman Rashid) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "This has now been corrected in both the HTML and PDF versions of the Article."} +{"text": "Jankowski The authors regret that the title shown in the original article was incorrect. The correct title is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The correct web link to the datasets and trained models is The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the funding information given in the original manuscript was incorrectly shown. The authors declare that there was no financial support for this research.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The order of References has been corrected in the HTML and PDF versions of the Article."} +{"text": "This article contains an error in the first row and third column of"} +{"text": "The corrected list of affiliations is as shown here.The authors regret that the one of the affiliations (affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In Lin et al.,The authors apologize for the error."} +{"text": "Figs There is an error in the caption for The publisher apologizes for the errors."} +{"text": "The hazard ratio label on the first line of"} +{"text": "The original article unfortunThe correct name is included in the author list of this Correction and has already been updated in the original article."} +{"text": "Chowdhury. This has now been corrected in both the PDF and HTML versions of the Article."} +{"text": "The correct affiliations are listed in this correction notice.The authors regret that affiliation The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "This has now been corrected in the PDF and HTML versions of the Article."} +{"text": "In 2021 the International Brazilian Journal of Urology received the highest impact factor of his history and this fact was possible because the serious peer review process of our Journal (Thanks a lot!!!!!"} +{"text": "During the past decades several attempts have been made to reform the Common Agricultural Policy (CAP). The article analyses the possible new directions of CAP implementation and financing of the CAP. It discusses whether renationalisation and co-financing of the CAP would be a beneficial approach to make the policy more efficient and to help restructuring not just the CAP expenditure but the whole EU budget. The author analyses the changes in light of the new regulatory frameworks to be implemented from 2023."} +{"text": "This has now been corrected in the PDF and HTML versions of the Article."} +{"text": "Huseynzada The authors regret that the name of one of the authors (Christian Jelsch) was shown incorrectly in the original article. The corrected author list is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors wish to make the following correction to this paper .The published versions of The authors have provided the complete and high-resolution versions of The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "The authors wish to add the following to this paper :"} +{"text": "With the author(s)\u2019 decision to opt for Open Choice the copyright of the article changed on June 2021 to"} +{"text": "The authors regret that one of the affiliations (affiliation f) was incorrectly omitted in the original manuscript. The corrected list of affiliations is as shown below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors wish to make the following corrections to this paper : In the The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated."} +{"text": "The authors wish to revise in the text of The correct text is shown below:"} +{"text": "Following publication of the original article , the autAll the changes requested are implemented in this correction and the original article has been"} +{"text": "Following the publication of the original article , the autThe correct figure is shown here below and has already been included in the original article."} +{"text": "Following publication of the original article , it was The author group has been updated above and the original article has been"} +{"text": "There are errors in the images for Figs The publisher apologizes for the errors."} +{"text": "In the original publication the corrThe original article has been updated. We apologize to the authors and readers for the inconvenience."} +{"text": "The corrected version of the figure with the R group as (CH2)4Ph is shown below.The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In the original publication the labelling in middle and bottom panels of Fig."} +{"text": "The authors regret that the affiliations were incorrectly shown in the original manuscript. The corrected list of affiliations is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The contribution section and ORCIDs of the authors were missing in the original version of this article.The missing contribution statement is shown below and ORCIDs for each authors were added in the author group section above."} +{"text": "The authors regret that the image of BCP group without Cal in 12 W in the Fig."} +{"text": "The original publication of this article containeThe effect of the nerve growth factor (NGF) group in promoting damage repair has not changed and the changes do not affect the scientific significance of current article."} +{"text": "The HTML and PDF versions of the Article have now been corrected."} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The above article was originally submitted to Epidemiology and Psychiatric Sciences with the incorrect author name listed for the second author. The correct surname for the second author is Ai Koyanagi (and not Ai Konayagi). The authors would like to apologise for this error."} +{"text": "In the original publication of the article , one of"} +{"text": "The authors apologize that the original version of this paper"} +{"text": "The authors wish to correct the Funding statement of their article to:"} +{"text": "The authors regret that there was an affiliation missing in the original article for the author Cuimin Sun. The corrected and complete list of author affiliations is given in this document.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Following the publication of the original article we were The author names have been corrected in the author list of this Correction and updated in the original article."} +{"text": "The authors regret that the original version of this paper"} +{"text": "Following the publication of the original article the authThe correct authors\u2019 names are shown in the author list of this Correction and have already been updated in the original article."} +{"text": "This has been corrected in the HTML and PDF version of the Article."} +{"text": "The authors agreed with the retraction of the paper. The Editor apologizes to the readership for any inconvenience caused."} +{"text": "The contents are solely the responsibility of the authors and do not necessarily represent official views of the National Institutes of Health. The funding was omitted in the original submission and the original article has been corrected."} +{"text": "The authors regret that three of the authors were associated with the incorrect affiliations. The correct list of authors and affiliations is as shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The following information is missing from the Funding statement: Furthermore the project is part of the EDCTP2 programme supported by the European Union (grant number TMA2017GSF-1962\u2014CaDERAL). The correct Funding statement is as follows: The work reported herein was made possible through funding by the South African Medical Research Council through its Division of Research Capacity Development under the SAMRC Intramural Postdoctoral Programme from funding received from the South African National Treasury. Furthermore the project is part of the EDCTP2 programme supported by the European Union (grant number TMA2017GSF-1962\u2014CaDERAL). The content hereof is the sole responsibility of the authors and do not necessarily represent the official views of the SAMRC or the funders."} +{"text": "The authors regret that the affiliations for co-author Qianwen Zhang were incorrectly given in the original article. The correct affiliations are shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors also apologize to the readership for any inconvenience caused.The corrected version of"} +{"text": "The authors regret an errorin the version of"} +{"text": "The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The authors regret that the affiliation for co-author Xuanli Wang was incorrectly shown in the original manuscript. The corrected list of affiliations is as shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Griffith was accidently omitted from the list of members of The APRICOT and PLUM study team. This has been corrected online. The authors apologize for this error."} +{"text": "The authors of the original article have fouThis correction does not affect either results or conclusions. We apologize for the inconvenience to the readers."} +{"text": "After publication of this supplement , it was The authors names are correctly presented in the author list of this correction."} +{"text": "This has been corrected in the HTML and PDF version of the Article."} +{"text": "The key to understanding the series of supply shocks that have hit inflation is the nature of the COVID-19 recession."} +{"text": "Ghule The authors regret that an incorrect version of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Following the publication of the original article the authThe correct authors\u2019 names are shown in the author list of this Correction and have already been updated in the original article."} +{"text": "The original online version of this article was revised. The last paragraph of the abstract has been deleted."} +{"text": "For the Netherlands, the single most important EU issue is the future of the eurozone."} +{"text": "Following the publication of the original article the authThe correct author name is included in the author and reference lists of this Correction, and has already been updated in the original article."} +{"text": "The authors apologize for The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The publisher apologizes for the error. Please see the correct version of There are errors in"} +{"text": "This has now been corrected in both the PDF and HTML versions of the Article."} +{"text": "We apologize for the errors and for any inconvenience thatthis may have caused the readers of"} +{"text": "This has now been corrected in both the PDF and HTML versions of the Article."} +{"text": "The following information is missing from the Funding statement: This publication was supported by the Open Access Publication Fund of the University of Wuerzburg."} +{"text": "In the original publication of this article the capt"} +{"text": "The authors make the following corrections to their published paper . In the The corrected The corrected The authors apologize for any inconvenience caused to the readers by these changes. The changes do not affect the scholarly results. The original manuscript will be updated online."} +{"text": "The name of one of the authors was misstated during the manuscript submission and publication process. The author's name Kathryn Phillips was corrected to Kathleen Phillips. The original manuscript has been updated to reflect this change."} +{"text": "The authors regret that incorrect versions of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Following the publication of this article, the authors realized that the published version of The correctly labelled version of"} +{"text": "The authors regret that the original version of our paper"} +{"text": "Following the publication of the original article it was bThe joint first authorship and equal contribution of the three co-authors has now been marked with dagger symbols in the author list and an explanatory footnote at the end of this Correction.The original article has also been corrected as above."} +{"text": "In the original version of Banerjee et al., The original article has been updated."} +{"text": "This has now been corrected in both the HTML and PDF version of the Article."} +{"text": "Authors would like to update the list of Reposi Investigators as collaborators and update \"on behalf of the RePoSi Collaborators\" to the end of authors list.The original article has been corrected."} +{"text": "We thank Hayashi and Konishi for their comments and interest in our article . We agreThe author declares no conflicts of interests with the contents of this article."} +{"text": "This has been corrected in the HTML and PDF version of the Article."} +{"text": "In the original version of this The original article has been corrected."} +{"text": "Following the publication of the original article , the autA graphic intended to be included in Table The correct Table"} +{"text": "I found the title and description of the recent review by Griffiths et al. misleadi"} +{"text": "This paper reviews techniques and equipment for collectingprecipitation samples from the atmosphere (fog and cloud water)and from atmospheric deposits that aresuitable for the evaluation of atmospheric pollution. It discussesthe storage and preparation of samples for analysis and alsopresents bibliographic information on the concentration ranges ofinorganic and organic compounds in the precipitation andatmospheric deposit samples."} +{"text": "The relationship between the size of the primary tumour upon initial treatment and the incidence of distant metastasis during the course of the disease was investigated using data from 2648 breast cancers treated at the Institut Gustave Roussy between 1954 and 1972. This analysis suggests the existence for each tumour of a critical volume (threshold) at which the first remote metastasis is initiated. The correlation between the size of the primary tumour and the probability of metastatic dissemination was assessed as well as the influence on this correlation of two prognostic indicators: histological grade and number of involved lymph nodes. It was found that the threshold volume is strongly correlated with the number of involved lymph nodes and the histological grading."} +{"text": "The UCL media strategy as described in the letter of Fourniol has been understood by us and has been accurately described in our editorial . In fact"} +{"text": "We thank Murray and colleagues for adding their view to the \"series of unfortunate events\" outlined in the editorial and in R"} +{"text": "Because of the nature of the analysis used in this study , no conc"} +{"text": "As the title of my response to the PLoS Medicine Debate implies,"} +{"text": "On behalf of my coauthors and myself, I would like to thank Dr Bolin for initiating a discussion of dental sealants and enco"} +{"text": "After reading the excellent research article by Pedrini et al. and the"} +{"text": "In the publication of this article it was bThis sentence has been updated in the original article."} +{"text": "Journal of Women\u2019s Health Care [The Publisher is retracting this case report and literature review as the clth Care and is t"} +{"text": "The correct statement is: Sequences for both the bacterial and fungal datasets have been uploaded to NCBI ("} +{"text": "After the publication of this article the authors noticed that an incorrect version of Table"} +{"text": "The following information is missing from the Funding section: This study was supported by Scientific and Technological Project of Tianjin grant 14ZCZDSY00047 to GZ. The publisher apologizes for the error."} +{"text": "This paper describes the case of a 74 year old patient who became lithium toxic after 15 years of lithium therapy. We discuss the clinical presentation of the case and some of the possible causes of the sudden development of his toxicity. Although haemodialysis is the treatment of choice for severe lithium toxicity it is not always available. In this paper we propose that the combination of saline diuresis and Amiloride may provide a suitable alternative in the management of lithium toxicity."} +{"text": "The study was supported by funding from the NIHR Oxford Biomedical Research Centre program."} +{"text": "Published by Oxford University Press [on behalf of Infectious Diseases Society of America]. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (The authors regret these error."} +{"text": "Corrections to be noted in Volume 91 of the JOURNAL OF RESEARCH of the National Bureau of Standards"} +{"text": "I read the recent systematic review which asked some interesting questions regarding the pathogenesis of tendinopathy (Vasta et al., The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Materials would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2013:The editors of"} +{"text": "In the original publication of this article there was an error in Figs."} +{"text": "The following information is missing from the Funding section: This article was supported by the Open Access Publishing Fund of the University of Vienna. The publisher apologizes for the error."} +{"text": "Dementia & Neuropsychologia finishes the fourth year of publication andwe would like to thank our referees for sharing their expertise with us. The highquality of constructive criticisms and dedication of all our reviewers are highlyappreciated by both the editors and the authors."} +{"text": "This TJHP thematic series provide an overview of the history of the discovery of PACAP and its three receptors and summ"} +{"text": "After publication of the original article the authAn updated version of Table The original article has also been updated."} +{"text": "The following information is missing from the Funding section: The publication of this article was funded by the Open Access Fund of the Leibniz Association."} +{"text": "The numerical labels for the sites in Please see the correct"} +{"text": "Following publication of the original article it was bPlease note that the original article was corrected on the BioMed Central website."} +{"text": "The following information is missing from the Funding section: This study was supported by the Canadian Statistical Sciences Institute."} +{"text": "After publication of the original article , it was The amended version of Table"} +{"text": "The tables and their references published in the original version of this article were reg"} +{"text": "After the publication of this article the authA correct version of Fig. The original article has been corrected."} +{"text": "Published by Oxford University Press [on behalf of the Infectious Diseases Society of America]. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (The authors regret these error."} +{"text": "The change does not affect the scientific results. The manuscript will be updated and the original will remain online on the article webpage."} +{"text": "The corThe change does not affect the scientific results. The manuscript will be updated and the original will remain online on the article webpage."} +{"text": "In The online version of the article has been corrected."} +{"text": "The correlations are described correctly in Results and the conclusion of the paper is not affected. Please see the corrected Tables In Tables"} +{"text": "The following information is missing from the Funding section: We acknowledge funding from National Geographic Society for the fieldwork in Uzuncarsidere that resulted in the discovery of the specimen (grant no 7086\u201301)."} +{"text": "The results discussed in the conclusion and other contents and results of the original paper are unaffected.The correct chart is:"} +{"text": "The publisher regrets that due to an error the full text of The publisher would like to apologise for any inconvenience caused."} +{"text": "Information from the manufacturer of the topical intervention in the GSK2646264 trial outlined in this review indicate"} +{"text": "The authors wish to apologize to readers for an incorrect element in Table"} +{"text": "After publication of the original article it was bThe correct spelling of the name is included in the author list of this erratum."} +{"text": "The authors have revised the order of the author list for this article . John Ko"} +{"text": "The name now appears in the online version of the manuscript."} +{"text": "After the publication of this article the edit"} +{"text": "The heading of the first paragraph of the Results section is incorrect. The correct heading should be Number of consensus guidelines."} +{"text": "The funding organization does not affect the study results.There are errors in the Funding section. The correct funding information is as follows: This scientific work was funded under the program of Polish Ministry of Science and Higher Education ("} +{"text": "The correct statement is: Data from the Hospital Authority Statistical Report HKSAR are publicly available and can be found in the Supporting Information files or at the following URL:"} +{"text": "The following information is missing from the Funding section: This work was supported by the Biotechnology and Biological Sciences Research Council ."} +{"text": "The study was supported by funding from the NIHR Oxford Biomedical Research Centre program."} +{"text": "Following publication of the original article the authThe authors also notified Production that the affiliations assigned to William Pickett are incorrect. The correct affiliation is reflected in the author list of this Correction."} +{"text": "Upon publication of the original manuscript it was hThese errors change neither the outcome of the experiments nor the conclusions of the article; and have since been corrected in the original manuscript and acknThe corrected table is shown below:The publisher also acknowledges and apologizes for these errors."} +{"text": "In the original publication of this article , figure The publisher apologizes for the inconvenience caused to the authors and readers."} +{"text": "The following information is missing from the Funding section of the paper: Publication of this article was funded by the University of Colorado Boulder Libraries Open Access Fund."} +{"text": "Monsoon rainsHave come and goneQuintessentialRemnants of summerRambutans and DuriansDiscarded peelsBustles with activityLives of other kindsWriggling and swimmingSummer dreamsOf warm humid nightsFanning away the creatures of natureThat annoying bustle of wingsOf lives that emerged from the discardsCreatures of natureThat fly in search of mealsMeals of redWithin the mealEnvelopedIn a protective sheathLies a beingIs it alive or is it not?We argue in the summer\u2019s heatHow to define life?This being is a villainA villain of a kindMinute yet mightyAstute and elusiveAdapting and evolving"} +{"text": "There is an error in the first sentence of the second paragraph of the Discussion section. The correct sentence is: A thorough and systematic search of reviews published between 2004 and 2015 identified 49 papers on interdisciplinary team working in primary care.In"} +{"text": "Nutcracker syndrome is the compression of the left renal vein between the aorta and superior mesenteric artery. It is a rare cause of hematuria which results from the rupture of congested renal veins into the collecting system."} +{"text": "Dementia & Neuropsychologia finishes the eighth year of publication andwe would like to thank our referees for sharing their expertise with us. The highquality of constructive criticisms and dedication of all our reviewers are highlyappreciated by both the editors and the authors."} +{"text": "This study was performed to see the value of histopathological diagnosis in management of patients with duodenal biopsies; to look for correlation of histology and serology in suspected cases of coeliac disease; the reasons for taking duodenal biopsies and whether proper adequate histories are provided on the forms sent with request for histopathological view on duodenal biopsies. Here are the observations of the study followed by the discussion."} +{"text": "The name of the first author was listed incorrectly in the original article . The cor"} +{"text": "Timothy Davis is a research scientist at the Great Lakes Environmental Research Laboratory of the National Oceanic and Atmospheric Administration.EHP regrets the error."} +{"text": "The Editors are retracting this article because The online version of this article contains the full text of the retracted article as electronic supplementary material."} +{"text": "In the original publication of this article , the graThe correction details of the grant number can be found below:"} +{"text": "The following information is missing from the Funding section: This project was funded in part by the Terry Fox Foundation."} +{"text": "The number of patients and caregivers included in the study is incorrect in the Results subsection of the Abstract and the third sentence of the Results section. This study included 566 patients and 593 caregivers."} +{"text": "Both the Announcement and Full Report will appear on the cover of the issue. Information about other national health observances is available at"} +{"text": "The sequences appearing in the lower panel of"} +{"text": "This name of the author of this article was mis-"} +{"text": "Concern has been raised about the similarities between the lower panel of The authors would like to apologize for any inconvenience caused to the readers of the journal."} +{"text": "After publication of the original article the authAn updated version of Fig."} +{"text": "Due to The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "The incorrect index is listed in the caption for"} +{"text": "The following information is missing from the Funding section: This study was supported by The Italian Ministry of Health (Ricerca Corrente 2016). The publisher apologizes for the error."} +{"text": "As result of a query from a reader, the authors reviewed the data in Table The correct version of Table"} +{"text": "Errors were introduced during the production process resulting in the incorrect labelling of the genotypes in"} +{"text": "The authors of the published paper would liWe apologize for any inconvenience caused to readers. The manuscript will be updated and the original will remain available on the article webpage."} +{"text": "It has come to our attention that in the work referenced above Table The correct versions of both Table"} +{"text": "The following information is missing from the Funding section: This work was partly supported by the UK Department for International Development through the SHARE research programme consortium."} +{"text": "The author and handling Editor declare a potential conflict of interest regarding their previous collaboration on the publication which waThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The authors have revised the order of the author list for this article . John Ko"} +{"text": "The authors wish to make the following erratum to this paper . The autWe apologize for any inconvenience caused to the readers."} +{"text": "In the original publication of this article the SPIR"} +{"text": "In the HTML version of this article that was originally published the VennThe original article has been revised and the publisher apologises for the error."} +{"text": "The value of MRI in the diagnosis and management of patients with primary bone tumours has already been established.The use of MRI in the detection of metastatic spinal disease is discussed in this paper."} +{"text": "After publication of the original article , it was The updated and correct author affiliations of the original article are pres"} +{"text": "This short report describes the successful use of a new minimally invasive technique for the treatment of acute gastric artery aneurysm rupture. It emphasises the importance of persistence and multiple imaging modalities in the presence of gastrointestinal bleeding. The photographs and case history clearly illustrate the nonoperative management and highlight learning points for experienced surgeons and trainees alike in the management of this potentially fatal condition."} +{"text": "Published by Oxford University Press . This is an Open Access article distributed under the terms of the Creative Commons Attribution License (The authors regret these error."} +{"text": "The authors regret that an error appeared in their original version of The online HTML and PDF versions of this paper have been corrected. The error remains only in the print version."} +{"text": "The following information is missing from the Funding section: This work was supported in part by National Science Foundation grant 1153911 to CMB."} +{"text": "The following information is missing from the Funding section: This study was supported by Sao Paulo Research Foundation ."} +{"text": "After the publication of our paper we realiWe would like to apologise for this error and for any inconvenience this may have caused."} +{"text": "After publication of the original article the authThis has been corrected in the author list of this Correction."} +{"text": "The original version of this article should hThe updated version of the acknowledgements is present below."} +{"text": "A funding organization was incorrectly omitted from the Funding Statement. The first sentence of the funding statement should read: \"This work was supported by a grant awarded from the Children & Young People's Research Network as well as the Sir Ewen Maclean Bequest Fund in the Cardiff University School of Medicine.\""} +{"text": "Dementia & Neuropsychologia finishes the sixth year of publication andwe would like to thank our referees for sharing their expertise with us. The highquality of constructive criticisms and dedication of all our reviewers are highlyappreciated by both the editors and the authors."} +{"text": "The title of the first subsection in the Materials and Methods is incorrect. The correct title is: Ethics Statement."} +{"text": "In the originally published version of this article by Titmarsh We apologize for the error."} +{"text": "The authors have revised the order of the author list for this article . John Ko"} +{"text": "The following information is missing from the Funding section: Author SB is partly supported by the Flight Attendant Medical Research Institute Clinical Innovator Award."} +{"text": "The authors wish to apologize for an error within the scale bar of the microarray heatmap in Additional File 5 of the supplementary information. Two values were incorrectly displayed on the scale bar (11 instead of 10 and 13 instead of 12). The scale bar has been changed to reflect these corrections, and the numeric values are now evenly spaced.This correction has no influence on any analyses or interpretation of the published data and does not affect the validity of the results or conclusions of this paper."} +{"text": "The funder financed the project but will not participate in any phase of the investigation. The funder will not have any authority over any of the activities of the project."} +{"text": "The standard deviations of the oculomotor parameters in"} +{"text": "The following information is missing from the Funding section: This study was supported by the Natural Science Foundation of China (grant number 41330853)."} +{"text": "Projections from a theoretical model of concentration of methotrexate in liver are confirmed but projections of biliary excretion are not.Measurements of methotrexate have been made in the liver and plasma of 4 patients and in the bile and plasma of 1 patient receiving ["} +{"text": "This first part of \u2018The Data Librarian\u2019 describes the current situation in analytical laboratories and the need for the Data Librarian. The second part of the paper will examine the features of the Data Librarian."} +{"text": "Obstructive jaundice is most commonly due to luminal stones or lesions of the head of the pancreas and more rarely ampullary and primary common bile duct lesions. Obstruction due to lesions of the ampulla of Vater may be due to adenocarcinoma which has a significantly better long term prognosis than carcinomas located in the head of the pancreas. A case is presented where two tumours were identified at the ampulla of Vater of the resected specimen one an adenocarcinoma and the other a carcinoid tumour representing a collision tumour."} +{"text": "The absorption of nitrosamines from the bladder into the circulating blood is also described.Experiments are described which demonstrate the production of nitrosamine"} +{"text": "The Equation on the seventh line of the Figure 3 legend is incorrect. The legend with the corrected equation is available here:Click here for additional data file."} +{"text": "International Society for the Prevention of Tobacco Induced Diseases are available as a zip drive in additional file The meeting materials from the 4th Annual Meeting of the Click here for file"} +{"text": "The following information was missing from the Funding section: KPK was supported by a postdoctoral fellowship from the American Heart Association."} +{"text": "Sir,The Collaborative Group on Hormonal Factors in Breast Cancer has certainly done a disservice regarding the question of the possible connection between tobacco smoke and breast cancer by publishing their recent paper and concAn estimate of the magnitude of the passive smoking breast cancer risk and its effect on the active smoking risk can be obtained by studying the data in"} +{"text": "We report the case of a 63 year old woman who developed the complications of cholangitis and BuddChiari syndrome secondary to polycystic disease of the liver. The two complications were not presentsimultaneously, and both resolved after decompression of the liver cysts."} +{"text": "The following information was omitted from the Funding section: YT was supported by the Mitsubishi Foundation."} +{"text": "Development of new mass spectrometers and implementation of new analytical methods were the central themes of the conference. The majority of oral presentations andposters were concerned with the application of mass spectrometry to pharmaceuticaland biotechnological research."} +{"text": "Biliary cystadenoma is a rare tumor of the liver. We describe a biliary cystadenoma of the left lobe of theliver with intracystic gallstone formation. This is the first report of stone formation in biliarycystadenoma of the liver."} +{"text": "The general theme of the meeting was the application of mass spectrometry to pharmaceutical and biotechnological research. The majority of the oral presentations and posters were concerned with the development and application of all mass spectrometric techniques related to proteomics."} +{"text": "The pharmacokinetics of penicillin G and ampicillin are reviewed as they pertain to their potentialuse in in vitro therapy."} +{"text": "A case of primary leiomyosarcoma of the liver is described and the problems in diagnosis andmanagement are discussed together with a review of the available literature. These tumours have afavourable prognosis when diagnosed preoperatively and the value of electron microscopic findings inthis situation are highlighted."} +{"text": "The present review describes the work carried out during the last 20 years in the field of theradioprotective activity and toxicity of several classes of organosilicon and organogermaniumcompounds ."} +{"text": "To the Editor:Recently the usefulness of snake venom preparation in the treatment of drug-resistant human immunodeficiency virus was demonstrated in clinical practice for the first time by Alrajhi and Almohaizeie."} +{"text": "In the Funding section, what is listed as the National Geographic Society Exploration Fund should be listed as the National Geographic Society."} +{"text": "The IUPAC Commission on Automation and New Technologies has developed a scheme for the classification of analytical systems. The classification scheme is reported in this paper."} +{"text": "International Society for the Prevention of Tobacco Induced Diseases are available as a zip drive in additional file 1The meeting materials from the 3rd Annual Meeting of the Click here for file"} +{"text": "We describe a patient presenting with a myxoid liposarcoma of the lower thigh in whom an episode of acute pericarditisindicated the recurrence of widespread metastatic disease."} +{"text": "The revised Table After the publication of this work we foundWe regret any inconvenience that the incompleteness of Table"} +{"text": "In this paper we report the long term results of this procedure in the treatment of eightpatients with chronic pancreatitis (CP)."} +{"text": "The zebrafish has long been a favourite model for the study of vertebrate development. Here we provide an overview of the current state of knowledge and resources for the study of this fish, with comments on the future direction of zebrafish genomics from Professor Mark Fishman and Dr Stephen Wilson."} +{"text": "International Society for the Prevention of Tobacco Induced Diseases are available as a zip drive in additional file 1The meeting materials from the 2003 Annual Meeting of the Click here for file"} +{"text": "The paper presents the cytogenetic constitution of an ovarian ascitic carcinoma. Double minute chromatin bodies were seen in all the metaphases; their number was proportional to the number of the cells. Some properties of the double minute chromatin bodies are discussed."} +{"text": "In a case operated on for calculous jaundice the right and left hepatic ducts drained directly into thegallbladder and the cystic duct was the only route by which hepatic bile reached the duodenum.Exploration of the inside of the gallbladder was a crucial step for the discovery of the anomaly. Continuityof bile drainage was secured by the preservation of a portion of the gallbladder which contained hepaticand cystic ducts."} +{"text": "The collective findings of It is tempting to generalize about the magnitude of error and direction of bias observed by"} +{"text": "This short review comments on current informatics resources and methodologies inthe study of functional pathways in cell biology. It highlights recent achievements inunveiling the structural design of protein and gene networks and discusses currentapproaches to model and simulate the dynamics of regulatory pathways in the cell."} +{"text": "Control of emerging infectious diseases will be difficult because of the large number of disease-causing organisms that are emerging or could emerge and the great diversity of geographic areas in which emergence can occur. The modern view of the evolution of pathogen virulence--specifically its focus on the tradeoff between costs and benefits to the pathogen from increased host exploitation--allows control programs to identify and focus on the most dangerous pathogens (those that can be established with high virulence in human populations)."} +{"text": "The last data row of Table 3 is a repeat of the first. Please view the corrected table here:"} +{"text": "This paper provides some initial considerations into the design andfunction of the Data Librarian. The first part described the need for the Librarian."} +{"text": "We found some errors in the paper published in International Journal of Molecular Sciences . The tabWe apologize for any inconvenience caused to the readers."} +{"text": "International Journal of Molecular Sciences is a member of the Committee on Publication Ethics (COPE) and takes very seriously the responsibility to enforce strict ethical policies and standards.Experimental results from were fou"} +{"text": "The authors regret that a mistake was made in the headings of The authors would like to apologise for any inconvenience caused."} +{"text": "The figure has now been corrected as below in the online version of the article."} +{"text": "The second and third paragraphs of the Results section incorrectly appear in the Please see the complete, correct"} +{"text": "The authors wish to make the following correction to this paper : the cor"} +{"text": "The following information is missing from the Funding section: This study was supported by the German Research Foundation and the Open Access Publication Funds of the G\u00f6ttingen University."} +{"text": "After publication of the original article , the autThe correct versions of Figs.\u00a0The address of the authors was revised and is given in this Correction."} +{"text": "The figures and captions are in the incorrect order for Figs"} +{"text": "Unfortunately, in the original version of this AcknowledgementsThe authors thank all the field and lab assistants of CIMMYT\u2019s Global Wheat Breeding Program who collected and processed the agronomic and breeding field data as well as the image data. The data used in this study was collected under projects supported by Bill and Melinda Gates Foundation and USAID."} +{"text": "Both the HTML and PDF versions of the article have been corrected."} +{"text": "Dr. Masliah will review accomplishments of the Division of Neurosciences and make projections for the future."} +{"text": "The original version of this article had the"} +{"text": "Dr. Hadley will review accomplishments of the Division of Geriatrics and Clinical Gerontology and make projections for the future."} +{"text": "The authors have retracted this article because the legal guardians of the patient described have withdrawn consent for publication of the case and images. The scientific content of the article has been removed to protect the patient\u2019s privacy. All authors agree to this retraction."} +{"text": "The following information is missing from the Funding section: This study was funded by Partners Council for Women's Health."} +{"text": "The corrected data were provided in the new version of the"} +{"text": "The authors wish to make the following corrections to this paper :The authors wish to make the following corrections to Equations (4) and (5):The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "The Data Availability statement is incorrect. The underlying data are not provided in the published paper and its Supporting Information files. The authors have deposited the data in the Sequence Read Archive ."} +{"text": "Following publication of the original article (Sawant et al., The publisher apologises to the authors and readers for the inconvenience."} +{"text": "The following information is missing from the Competing Interests section: This publication reflects the views of the authors and should not be construed to represent the FDA\u2019s views or policies."} +{"text": "Within the Materials and Methods section of the paper by Goudarzi"} +{"text": "This presentation will cover public policy issues of significance to the aging population, focusing on the perspective of the health sciences and on policies that may improve physical and mental health."} +{"text": "The Protocol Article describes the strategies for the formation of preformed discontinuous and continuous density gradients. Most of the techniques can be applied to the use of any gradient solute but some of the detailed recommendations on continuous gradients only apply to iodixanol gradients because of variations in viscosity and rates of diffusion between different solute types. Operational variations that require consideration when dealing with specific types of biological particle are also dealt with at the end of this Protocol Article."} +{"text": "The authors apologize to the Editor of"} +{"text": "The authors regret that an error was published in the original version of The authors apologize for any confusion or inconvenience caused."} +{"text": "The following information is missing from the Funding section: This study was supported by National Institute of Health grant S10OD016219."} +{"text": "The authors apologize to the Editor of"} +{"text": "There is an error in the second sentence of the Author Summary. The correct sentence is: Imprinting has served as a model system to understand the mechanisms through which chromatin modifications can influence transcriptional regulation; comparisons between active and repressed alleles in the same cell nucleus provide an internal control for the effects of DNA sequence and exposure to diffusible regulators."} +{"text": "In the original publication of this article the figuThe publisher apologizes to the readers and authors for the inconvenience."} +{"text": "Following publication of the original article , a typesThe publisher apologizes to the authors and readers for the inconvenience."} +{"text": "This does not affect the conclusions of this paper. The corrected version of Figure In Figure"} +{"text": "The following information is missing from the Funding statement: Publication costs for the article were supported by a Case Western Reserve University VPR Catalyst Award to LCC.The publisher apologizes for this error."} +{"text": "The following information is missing from the Funding statement: The publication of this article was funded by the Qatar National Library."} +{"text": "The authors wish to correct the funding projects number of \u201cNatural Science Foundation of Jiangsu Province\u201d in the Acknowledgments section of this paper : The corThe authors would like to apologize for any inconvenience caused to the readers by this change."} +{"text": "The following information is missing from the Funding statement: This study was supported by the European Research Council Executive Agency (ERC)."} +{"text": "Home delivered and congregate meals programs are a foundation part of the OAA and are a part of each reauthorization process."} +{"text": "The authors regret that in the original version of The online HTML and PDF versions of this paper have been corrected. The error remains only in the print version."} +{"text": "The corrected scheme is shown below.The authors regret an error in The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The following information is missing from the Funding section: Publication of this article was funded by the University of Colorado Boulder Libraries Open Access Fund.The publisher apologizes for the error."} +{"text": "Following publication of the original article , a typesThe publisher apologizes to the authors and readers for the inconvenience."} +{"text": "The original article (Renoust et al., The original article has now been updated to correct the order of these figures and place them with their respective correct captions."} +{"text": "Area Agencies on Aging and the aging network are the key service organizers and providers across the nation. This session will address the goals of the aging network for the OAA reauthorization and the trends and innovations in community-based service delivery."} +{"text": "The original version of this article had the"} +{"text": "Materials is a member of the Committee on Publication Ethics (COPE) and strives to uphold the highest ethical standards.The published article has been"} +{"text": "Following publication of the original article , an erroThe publisher apologises to the authors and readers for the inconvenience."} +{"text": "This presentation will cover public policy issues of significance to the aging population, focusing on the perspective of the biological sciences and on policies that may improve physical and mental health."} +{"text": "The authors wish to make the following correction to this paper : The autWe apologize for any inconvenience caused to the readers."} +{"text": "To enable validation of the names of some of the newly proposed taxa described in this article, the original article should not have been updated following the publication of the corrigendum. The original version has now been reinstated."} +{"text": "The original version of this article had the"} +{"text": "The following information is missing from the Funding statement: PAC received research funding and honoraria from Gilead Sciences within the five years prior to the conduct of the study.The following information is missing from the Competing Interests statement: PAC received research funding and honoraria from Gilead Sciences within the five years prior to the conduct of the study."} +{"text": "This session will focus on interventions to delay biological aging with the goal of in increasing lifespan and healthspan."} +{"text": "There is an error within the equation on page 6 of the pdf ).Currently the equation reads:It should read:"} +{"text": "The following information is missing from the Funding statement: Publication was funded by the Qatar National Library."} +{"text": "The above article was originally submitted to Epidemiology and Infection with an incorrect funding number. The first funding number from the Natural Science Foundation of Jiangsu Province should have been BK20171054.This error has now been rectified in the online PDF and HTML version of the article."} +{"text": "The following information is missing from the Funding section: PD is supported by the NIHR Manchester Biomedical Research Centre."} +{"text": "Dr. Sierra will review accomplishments of the Division of Aging Biology and make projections of future growth in the field."} +{"text": "The authors wish to make the following correction to this paper : The autWe apologize for any inconvenience caused to the readers."} +{"text": "This presentation will cover public policy issues of significance to the aging population, focusing on the perspective of the behavioral and social sciences and on policies that may improve physical and mental health."} +{"text": "The metadata in the HTML format of these original articles (Eppard et al., The publisher apologises for this processing error."} +{"text": "The original version of this article had the"} +{"text": "This session will focus on the challenges faced by millions of family caregivers and the innovative approaches that the OAA and other programs are using to be supportive of caregivers."} +{"text": "The following information is missing from the Funding statement: Publication of this article was funded in part by the Kansas State University Open Access Publishing Fund."} +{"text": "The following information is missing from the Funding statement: This study was supported by the European Research Council Executive Agency (ERC)."} +{"text": "PLOS ONE article [The data published in the article are partIndian Journal of Microbiology [The microbiome data of a subset of the same healthy controls were published in an earlier paper in the The Data Availability statement for this paper is incorrect. The correct statement is: Metagenomic sequencing reads can be accessed from National Center for Biotechnology Information (NCBI) BioProject accession ID PRJNA511934. All other relevant data are within the manuscript and Supporting Information files."} +{"text": "The correct statement is: The data are available through the Zenodo repository and can be accessed at"} +{"text": "The following information is missing from the Funding statement: This study was supported by the European Research Council Executive Agency (ERC)."} +{"text": "These baseline figures have been corrected to 14%, per the data reported in the Table and main body of the article."} +{"text": "Following publication of the original article , an erroThe publisher apologises to the authors and readers for the inconvenience."} +{"text": "We generally agree with the thoughtful assessment of the role of ADE described in the letter of Marques and Drexler and espe"} +{"text": "The authors wish to make an erratum to the published version of their paper . The aut"} +{"text": "The authors wish to make the following correction to their paper :The"} +{"text": "In this correction article, the revised author list is provided and the original publication has been updated to state the contribution of Halpin."} +{"text": "The second sentence of the caption for The third and fourth sentences of the caption for The publisher apologizes for these errors."} +{"text": "The correction was made on 20 July 2018.As requested by the authors of the article"} diff --git a/PMC_clustering_615.jsonl b/PMC_clustering_615.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..b740622d76b5af22fb6085088ef9284e1f0b06ab --- /dev/null +++ b/PMC_clustering_615.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:fba91db1118564596700b636d0bc4cdf58c0981286b7cafbaeee708a2112fbb6 +size 49584582 diff --git a/PMC_clustering_616.jsonl b/PMC_clustering_616.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..2a6571198fa84b675ea3f332f79c967e950742ef --- /dev/null +++ b/PMC_clustering_616.jsonl @@ -0,0 +1,293 @@ +{"text": "There is an error in the Correction published on September 12, 2019. The correct grant number is 2019R1A2C2005989. The correct Funding statement is: This work was supported in part by the National Research Foundation of Korea Grant 2019R1A2C2005989 to KJL."} +{"text": "The author apologises that upon publication, three figures were transposed and shown placed in the wrong order within the article.Figure 4 in the article should have been Figure 3The existing Figure 5 in the article should have been Figure 4And Figure 3 in the article should have been Figure 5:"} +{"text": "The caption submitted for Figure 1 was the same as the caption for Figure 2, and incorrect.The correct caption for Figure 1 is shown below."} +{"text": "The original Figure 2 published in this article mistakenly contained a duplicate of Figure 2A in the place of Figure 2B. This has now been corrected and the correct Figure 2B inserted."} +{"text": "In Table 21 on page 62, two numbers for Basu 2012 in rows 3 and 4 were mixed up. It did not affect any other outcome or result.Rows 3 and 4 should be:We apologize for this error."} +{"text": "This article was updated to correct the CME+\u2009D3 data in the text and in Table 2."} +{"text": "Table 2 and Figure 2 as published. Within In the original publication , there w"} +{"text": "There is an error in Figure 2. The correct Figure 2 can be seen here:"} +{"text": "Text from the footnote of Table 1 was erroneously included in the title of Table 2. Please see the corrected tables here: Table 1: Table 2:"} +{"text": "There were errors in the placement of Figures 2-6.The figure published as Figure 2 is actually Figure 6.The figure published as Figure 3 is actually Figure 2.The figure published as Figure 4 is actually Figure 3.The figure published as Figure 5 is actually Figure 4.The figure published as Figure 6 is actually Figure 5."} +{"text": "The incorrect Figures 3 and 4 were erroneously included in the article. Please see the correct Figures 3 and 4 here:Figure 3: Figure 4:"} +{"text": "There was an error in Figure 5. The correct Figure 5 can be viewed here:"} +{"text": "Figures 4 and 5 were incorrectly switched. The image currently appearing as Figure 4 belongs with the title and legend for Figure 5, and the image currently appearing as Figure 5 belongs with the title and legend for Figure 4. The titles and legends are in correct order."} +{"text": "The figure images for Figures 2 and 3 are reversed and should be swapped: Figure 2 should replace Figure 3, and vice versa."} +{"text": "The legends for Figure 4 and Figure 5 are reversed."} +{"text": "There was an error with Figure 8 - it was a duplicate of Figure 6.The correct version of Figure 8 can be viewed here:"} +{"text": "There were errors in Table 1. The correct version of Table 1 is available here:"} +{"text": "Figure 2, \"Results of the whole brain seed correlation analysis for the WT and TG groups,\" was mistakenly replaced by a duplicate of Figure S2. The Figure 2 legend is correct. Please see the correct Figure 2 here:"} +{"text": "The arrowheads marking the phenotypes in Figure 4B are missing. Please see the correct Figure 4 here: The headings differentiating Figure 6A and 6B are missing. Please see the correct Figure 6 here:"} +{"text": "Figures 2 and 3 were incorrectly switched. The image currently appearing as Figure 2 belongs with the title and legend for Figure 3, and the image currently appearing as Figure 3 belongs with the title and legend for Figure 2. The titles and legends themselves are in correct order."} +{"text": "The legends for Figures 7 and 8 were swapped. The legend that appears with Figure 7 actually corresponds to Figure 8, and the legend that appears with Figure 8 actually corresponds to Figure 7."} +{"text": "The images for Figures 5, 6, and 7 were incorrectly switched. The image that appears as Figure 6 should be Figure 5, and the image that appears as Figure 5 should be Figure 7. The image that appears as Figure 7 should be Figure 6. The figure legends appear in the correct order."} +{"text": "The legends for Figures 1 and 2 were incorrectly switched. The legend that appears with Figure 1 should be with Figure 2, and the legend that appears with Figure 2 belongs with Figure 1. The figure images appear in the correct order."} +{"text": "The titles and legends for Figures 3 and 4 were incorrectly switched. The title and legend for Figure 3 should appear with Figure 4, and the title and legend for Figure 4 should appear with Figure 3. The figures themselves are in correct order."} +{"text": "There was an error in Figure 2. The correct Figure 2 can be viewed here:"} +{"text": "Table 1 was formatted incorrectly. The correct version of Table 1 can be viewed here:"} +{"text": "The titles and legends for Figures 2 through 5 were incorrectly switched. The title and legend currently appearing with Figure 2 belong with Figure 3, the title and legend currently appearing with Figure 3 belong with Figure 4, the title and legend currently appearing with Figure 4 belong with Figure 5, and the title and legend currently appearing with Figure 5 belong with Figure 2. The Figures themselves are in correct order."} +{"text": "Supporting Information Figures S6 and S7 were incorrectly switched. The image currently appearing as Figure S6 corresponds to the title and legend for Figure S7, and the image currently appearing as Figure S7 corresponds to the title and legend for Figure S6. The titles and legends themselves are in correct order."} +{"text": "Table 1 was incorrectly a duplicate of Table 3. The correct version of Table 1 is available here:"} +{"text": "There was an error in Figure 4. The correct Figure 4 can be viewed here:"} +{"text": "Figures 2 and 3 were incorrectly switched. The figure labeled as Figure 2 belongs with the title and legend for Figure 3, and the figure labeled as Figure 3 belongs with the title and legend for Figure 2. The titles and legends are in correct order."} +{"text": "Figure 1 is missing Panel C. The correct version of Figure 1 can be found here:"} +{"text": "Figures 1 and 2 were incorrectly switched. Figure 1 should appear with the title and legend of Figure 2, and Figure 2 should appear with the title and legend of Figure 1. The titles and legends of the figures are in correct order."} +{"text": "Figure 4 was replaced by Figure 3 in the published manuscript. Please view the correct Figure 4 here:"} +{"text": "Formatting errors were introduced into tables 2 and 3 during the preparation of this article for publication. Please view the correct tables here:Table 1: Table 2:"} +{"text": "The legends for Figures 3 and 4 were incorrectly switched. The legend that appears with Figure 3 should be with Figure 4, and the legend that appears with Figure 4 should be with Figure 3."} +{"text": "There were errors in Tables 1 and 3. Correct version of the tables are available here:Table 1: Table 3:"} +{"text": "Figures 2 and 3 were accidentally switched. The image appearing as Figure 2 belongs with the title and legend for Figure 3, and the image appearing as Figure 3 belongs with the title and legend for Figure 2. The figure titles and legends themselves are in correct order."} +{"text": "On the basis of available crystal structures Figure 2], we , we 2],"} +{"text": "Figures 2 and 3 were incorrectly switched. The image currently appearing as Figure 2 belongs with the title and legend for Figure 3, and the image currently appearing as Figure 3 belongs with the title and legend for Figure 2. The titles and legends themselves are in correct order."} +{"text": "KNIME is a usIn the presentation we will show some of the new features in KNIME 2.4 and give an outlook to KNIME 2.5. We also present the KNIME Community Contributions ["} +{"text": "The order of figures 13 and 14 is switched."} +{"text": "Figures 1 and 2 were switched in the original publication. The captions are correct."} +{"text": "Supplementary Figures S1 and S4 were incorrectly switched. The image currently appearing as Figure S1 belongs with the title and legend for Figure S4, and the image currently appearing as Figure S4 belongs with the title and legend for Figure S1. The titles and legends themselves are in correct order."} +{"text": "The titles and legends of multiple figures were accidentally switched. The title and legend currently appearing with Figure 1 belong with Figure 5, the title and legend currently appearing with Figure 2 belong with Figure 1, the title and legend currently appearing with Figure 3 belong with Figure 2, the title and legend currently appearing with Figure 4 belong with Figure 3, and the title and legend currently appearing with Figure 5 belong with Figure 4."} +{"text": "The images for Figures 4, 5, 6, and 7 were incorrectly switched. The image that appears as Figure 4 should be Figure 5, and the image that appears as Figure 5 should be Figure 6. The image that currently appears as Figure 6 should be Figure 7, and the image that appears as Figure 7 should be Figure 4."} +{"text": "There are errors in Equation 2. The correct version of Equation 2 can be viewed here:"} +{"text": "The images for Figures 1 and 2, as well as Figures 13 and 14, were incorrectly switched. The image that appears as Figure 1 should be Figure 2, and the image that appears as Figure 2 should be Figure 1. The image that appears as Figure 13 should be Figure 14, and the image that appears as Figure 14 should be Figure 13. The figure legends appear in the correct order."} +{"text": "There was an error in Figure 2. The correct Figure 2 can be viewed here:"} +{"text": "In Figure 1 and Figure 2, the labels for \"Helmet\" and \"No Helmet\" were reversed. Please see the corrected Figure 1 here: Please see the corrected Figure 2 here:"} +{"text": "There was an error in Figure 1. Please view the corrected Figure 1 at:"} +{"text": "The image for Figure 4 has been mistakenly replaced with the image for Figure 6. The correct image for Figure 4 can be found here:"} +{"text": "The order of the titles and legends for Figures 3 and 4 is incorrect. The title and legend currently appearing with Figure 3 belong with Figure 4, and the title and legend currently appearing with Figure 4 belong with Figure 3. The figures themselves are in correct order."} +{"text": "There was an error in Table 2. Please see the corrected Table 2 here:"} +{"text": "There was an error in Table 1. The correct Table 1 can be viewed here:"} +{"text": "The images for Figures 1 and 2 were incorrectly switched. The image that appears as Figure 1 should be Figure 2, and the image that appears as Figure 2 should be Figure 1. The figure legends appear in the correct order."} +{"text": "The image currently appearing as Figure 3 is incorrect. Please view the correct Figure 3 here: The title and legend for Figure 3 are correct as they are."} +{"text": "Figures 3 and 4 were incorrect. Correct versions of the figures are available below.Figure 3: Figure 4:"} +{"text": "Figure 1 and 2 are incorrect versions. The correct Figure 1 can be viewed here: . The correct Figure 2 can be viewed here:"} +{"text": "The legends for Figures 4 and 5 were incorrectly switched. The legend that appears with Figure 4 should be with Figure 5, and the legend that appears with Figure 5 should be with Figure 4. The figure images appear in the correct order."} +{"text": "The affiliations of the last author are incorrect. Virgilie Viasnoff is only affiliated with institutions 1 and 4, and not institutions 2 and 3."} +{"text": "There were errors in Tables 3 and 4. The correct tables can be found here:"} +{"text": "Figure 3 is incorrect. Please see the correct version of Figure 3 here:"} +{"text": "The images for Figures 3 and 4 were incorrectly switched. The image that appears as Figure 3 should be Figure 4, and the image that appears as Figure 4 should be Figure 3. The figure legends appear in the correct order."} +{"text": "There were errors in Figure 2.The correct version of Figure 2 is available here:"} +{"text": "Figures 1 and 2 were incorrectly switched. The image currently appearing as Figure 1 belongs with the title and legend for Figure 2, and the image currently appearing as Figure 2 belongs with the title and legend for Figure 1. The titles and legends are in correct order."} +{"text": "The image in Figure 2C is unreadable. The correct version of Figure 2C can be viewed here:"} +{"text": "Formatting errors occurred in Table 1 and Table 2 which have affected the understanding of the data.Please see the corrected Table 1 here: Please see the corrected Table 2 here:"} +{"text": "The image incorrectly displayed as Figure 2 is a copy of Supplementary Figure S2. A correct version of Figure 2 can be seen here:"} +{"text": "The images for Figures 3 and 4 were incorrectly switched. The image that appears as Figure 3 should be Figure 4, and the image that appears as Figure 4 should be Figure 3. The figure legends appear in the correct order."} +{"text": "There was an error in Figure 2. The correct Figure 2 can be viewed here:"} +{"text": "There is an error in Figure 1. The correct Figure 1 can be viewed here:"} +{"text": "The legends for Figures 1 and 2 were incorrectly switched. The legend that appears for Figure 1 should be for Figure 2, and the legend that appears for Figure 2 should be for Figure 1. Additionally, the legends for Figures 3 and 4 were incorrectly switched. The legend that appears for Figure 3 should be for Figure 4, and the legend that appears for Figure 4 should be for Figure 3."} +{"text": "Figure 7 is currently a duplicate of Figure 6. Please see the correct version of Figure 7 at the following link:"} +{"text": "The version of Figure 4 included in the article is a duplicate of Figure 5. Please see the correct Figure 4 file here:"} +{"text": "There were errors introduced during the preparation of this manuscript for publication. The colors represented in Figures 1 and 2 are incorrect. Please view the correct Figure 1 here and the correct Figure 2 here"} +{"text": "Figures 3 and 4 were incorrectly switched. The locations of the legends for Figures 3 and 4 are correct."} +{"text": "Images for Figures 2 and 3 were incorrectly switched. The image labeled as Figure 2 is Figure 3, and the image labeled as Figure 3 is Figure 2."} +{"text": "There was an error in Figure 3. Figure 3 was identical to Figure 2. The correct Figure 3 can be viewed here:"} +{"text": "The links for Tables S3 and S4 were swapped. The link for Table S3 redirects to Table S4 and the link for Table S4 redirects to Table S3."} +{"text": "The authors noticed an error in Panel 2A of"} +{"text": "The legends for Figures 2 and 3 were incorrectly switched. The legend that appears with Figure 2 should be with Figure 3 and the legend that appears with Figure 3 should be with Figure 2. The figures themselves are in correct order."} +{"text": "There is an error in the contents of Figure 1. Please view the correct Figure 1 here:"} +{"text": "There was an error in Figure 4. The correct Figure 4 can be viewed here:"} +{"text": "Figures 2 and 3 had their placement reversed in the article.The correct figures are:Figure 2: Figure 3:"} +{"text": "Figures 4 and 5 were incorrectly switched. The image appearing as Figure 4 belongs with the title and legend appearing with Figure 5, and the image appearing as Figure 5 belongs with the title and legend appearing with Figure 4. The titles and legends themselves are in correct order."} +{"text": "There are several errors in Table 2. Please refer to the corrected version of Table 2 here:"} +{"text": "Figures 1 and 2 were incorrectly switched. The image currently appearing as Figure 1 belongs with the title and legend for Figure 2, and the image currently appearing as Figure 2 belongs with the title and legend for Figure 1."} +{"text": "The image for Figure 4 is incorrect. Please see the correct image for Figure 4 here:"} +{"text": "Figure 8 was incorrectly made a duplicate of Figure 7. The correct Figure 8 is available here:"} +{"text": "The titles and legends for Figures 1-3 were incorrectly switched. The title and legend currently appearing with Figure 1 belong with Figure 3, the title and legend currently appearing with Figure 2 belong with Figure 1, and the title and legend currently appearing with Figure 3 belong with Figure 2. The Figures themselves are in correct order."} +{"text": "The fourth, eighth and 11th authors were incorrectly indicated as being affiliated with institutions number 2 and 3. These authors are only affiliated with institutions numbers 1 and 4 ."} +{"text": "Figure 5 is incorrect. Please view the correct Figure 5 here: The title and legend of Figure 5 are correct."} +{"text": "Figures 3 and 4 are swapped. The legends are correct."} +{"text": "There was an error in the placement of Tables 2 and 3. The Tables were switched."} +{"text": "There were errors in the placement of the figure legends. The legend published with Figure 3 should be with Figure 5. The legend published with Figure 4 should be with Figure 3. The legend published with Figure 5 should be with Figure 4."} +{"text": "Due to an error introduced in the production process, the images for figures 2,3,4, and 5 were incorrectly switched. The image that appears as Figure 3 should be Figure 2, the image that appears as Figure 4 should be Figure 3, the image that appears as Figure 5 should be Figure 4, and the correct image for Figure 5 can be seen here:"} +{"text": "Figures 1 and 4 were incorrectly switched. The image currently appearing as Figure 1 belongs with the title and legend for Figure 4, and the image currently appearing as Figure 4 belongs with the title and legend for Figure 1."} +{"text": "The correct versions of Figures 2 and 3 are available below.Figure 2: Figure 3:"} +{"text": "The figure currently appearing as Figure 7 should be labeled as Figure 8, and the figure currently appearing as Figure 8 should be labeled as Figure 7."} +{"text": "The locations of Figures 1 and 2 were reversed in the article. The legends are placed correctly. The correct figures are:Figure 1: Figure 2:"} +{"text": "Figure 4 is incorrect. Please view the correct Figure 4 here: The title and legend of Figure 4 are correct."} +{"text": "Figures 1 and 2 were incorrectly switched. The figure appearing as Figure 1 belongs with the title and legend of Figure 2, and the figure appearing as Figure 2 belongs with the title and legend of Figure 1. The titles and legends themselves are in correct order."} +{"text": "There was an error in the placement of Tables 2 and 3. The Tables were switched."} +{"text": "Figures 2-4 were incorrectly switched. The image currently appearing as Figure 2 belongs with the title and legend for Figure 3, the image currently appearing as Figure 3 belongs with the title and legend for Figure 4, and the image currently appearing as Figure 4 belongs with the title and legend for Figure 2."} +{"text": "Figures 2A and 2B were mislabeled; the terms \"Low\" and \"High\" should be reversed."} +{"text": "There were errors in Tables 1 and 3. The correct versions of the tables can be found here:Table 1: Table 3:"} +{"text": "The standard error bars are missing from the graph of Figure 3D. Please see the corrected Figure 3 here:"} +{"text": "There are errors in Figures 1 and 3. Please see the corrected figures at the following links:Figure 1 - Figure 3 -"} +{"text": "Figure 1 and Figure 3 are incorrect. The correct Figure 1 and Figure 3 can be seen here:Figure 1: [^]Figure 3: [^]"} +{"text": "A formatting error was introduced during the production process for Table 2 in the PDF version only. Please see the corrected Table 2 and Table 2 notes here:"} +{"text": "Table 2 was replaced by a duplicated version of Table 3. The correct version of Table 3 is available here:"} +{"text": "The images for Figures 4 and 5 were reversed. The legends of these figures are correct."} +{"text": "Figure 2 is a duplicate of Figure 1. Please see the correct Figure 2 here:"} +{"text": "There were errors in Tables 1 and 2. The correct versions of the Tables are available here:Table 1: Table 2:"} +{"text": "In the original Figure 1B, sequences following the SHP2 and SHP3 labels were mistakenly interchanged. The correct sequence for SHP2 is MKKVNKALLFTLIMDILIIVGG, and for SHP3 is MKKISKFLPILILAMDIIIIVGG. Please see the corrected Figure 1 here:"} +{"text": "Tables S9 and S10 were incorrectly switched. The file that appears as Table S9 should be Table S10, and the file that appears as Table S10 should be Table S9. The table legends are in the correct order."} +{"text": "The titles and legends for Figures 1 and 2 were incorrectly switched. The title and legend currently appearing with Figure 1 belong with Figure 2, and the title and legend currently appearing with Figure 2 belong with Figure 1. The images themselves are in correct order."} +{"text": "The published version of Figure 1 is incorrect. View the correct Figure 1 here:"} +{"text": "There were errors in Tables 2 and 3. The correct versions of these tables are available below.Figure 2: Figure 3:"} +{"text": "There was an error in Table 1 and Table 2 Some characters erroneously appear as question marks. Please see the corrected Tables below.Table 1: Table 2:"} +{"text": "In Figure 1, the images for 1D and 1E are missing. Please see the correct Figure 1 here:"} +{"text": "Figure 1 is cut off at the bottom of the image, so that 6 gene markers are missing. Please see the corrected Figure 1 here:"} +{"text": "There is information missing in Figures 4 and 5. Please view the correct versions of Figures 4 and 5 here:Figure 4: Figure 5:"} +{"text": "Figure 3B and Figure 4B were accidental duplications of the same data. Please see the corrected Figure 3 where panel B has been revised with the correct data:"} +{"text": "There is an error in the Western Blot for Figure 2A. Kisspeptin54 is incorrectly shown as being 54kD. The correct band size for Kisspeptin54 is 15.4kD."} +{"text": "The published Figure 5 is erroneously identical to Figure 4. The correct Figure 5 can be seen here:"} +{"text": "There was an error in Table 1. The correct version of Table 1 is available here:"} +{"text": "In part 3 of the Weight Determination section, there was an error in equation 7 titled \"Definition 1. The index weight which contains both subjective and objective information\"Please view the correct equation 7 here:"} +{"text": "Figure 4 was erroneously uploaded as a duplicate of Figure 3. The correct Figure 4 can be viewed here:"} +{"text": "The legends for Figures 1-6 were incorrectly switched. The legend that appears with Figure 1 should be with Figure 2. The legend that appears with Figure 2 should be with Figure 3. The legend that appears with Figure 3 should be with Figure 4. The legend that appears with Figure 4 should be with Figure 5. The legend that appears with Figure 5 should be with Figure 6. The legend that appears with Figure 6 should be with Figure 1. The figure images appear in the correct order."} +{"text": "There is an error in Figure 2. The correct Figure 2 can be seen here: [^]"} +{"text": "There were errors in the placement of Figures 1-3. The published Figure 1 is actually Figure 2. The published Figure 2 is actually Figure 3. The published Figure 3 is actually Figure 1. The legends are in the correct locations."} +{"text": "An error was introduced in the preparation of this article for publication. Equations 1 and 2 in the Materials and Methods section under the subheading \"0.1 Model formation\" should not begin with a minus sign. Please view the corrected equations 1 and 2 here:"} +{"text": "Panel A is missing from Figure 2. Please see the correct version of Figure 2 at the following link:"} +{"text": "The images for Figures 1 and 2 were incorrectly switched. The image that appears as Figure 1 should be Figure 2, and the image that appears as Figure 2 should be Figure 1. The figure legends appear in the correct order."} +{"text": "The images for figures 5 and 6 were incorrectly switched. The image that appears as Figure 5 should be Figure 6, and the image that appears as Figure 6 should be Figure 5. The figure legends appear in the correct order."} +{"text": "A panel in Figure 1 is missing. The correct Figure 1 can be viewed here:"} +{"text": "In Figure 2B, some of the organs are mislabeled. Please see the corrected Figure 2 here:"} +{"text": "The Titles and Legends for Figures 2 and 3 were incorrectly switched. The title and legend for Figure 2 should appear with Figure 3, and the title and legend for Figure 3 should appear with Figure 2. The figures themselves are in correct order."} +{"text": "There was an error in Figure 3. The correct Figure 3 can be viewed here:"} +{"text": "The titles and legends for Figures 1 and 2 were incorrectly switched. The title and legend currently appearing with Figure 1 belong with Figure 2, and the title and legend currently appearing with Figure 2 belong with Figure 1. The figures themselves are in correct order."} +{"text": "The images for Figures 2 and 3 were incorrectly switched. The image that appears as Figure 2 should be Figure 3, and the image that appears as Figure 3 should be Figure 2. The figure legends appear in the correct order."} +{"text": "Several errors were introduced in the formatting of Tables 1 and 2 during the preparation of this article for publication. Please find the correct versions of each table here:Table 1: Table 2:"} +{"text": "The published Figure 6 is an erroneous duplicate of Figure 5. Please view the correct Figure 6 here:"} +{"text": "Table 2 is missing from the published article and a duplicate of Table 1 was published in its place. The correct tables can be viewed here.Table 1: Table 2:"} +{"text": "Figures 1 and 2 were incorrectly switched. The image appearing as Figure 1 belongs with the label and legend for Figure 2, and the image appearing as Figure 2 belongs with the label and legend for Figure 1. The labels and legends of Figures 1 and 2 are in correct order."} +{"text": "The graphs in figures 4 and 5 were incorrectly switched. The legend of figure 5 corresponds to the image labeled figure 4 and the legend of figure 4 corresponds to the image labeled figure 5. The references to these figures throughout the manuscript are correct."} +{"text": "There was an error in Figure 2. Please see the correct Figure 2 here:"} +{"text": "The current Figure S1 is a duplicate of Figure 1. Please see the correct FigureS1 here: Click here for additional data file."} +{"text": "In Table 3, the sequence locations of marker 7B8 and marker 15D6 in the Lorraine strain have been switched.The correct sequence location for marker 7B8 in the Lorraine strain is: 2631852\u20132632252.The correct sequence location for marker 15D6 in the Lorraine strain is: 713281\u2013713837."} +{"text": "The image for Figure 5 is incorrect. The correct image for Figure 5 can be seen here:[^] The current legend for Figure 5 is correct."} +{"text": "Portions of Figures 1 and 4 were omitted. The full versions can be viewed here:Fig 1: Fig 4:"} +{"text": "The is an error in the panels for Figure 2. Please view the correct Figure 2 here:"} +{"text": "The images for figures 2,3, and 4 were incorrectly switched. The image that appears as Figure 2 should be Figure 4. The image that appears as Figure 3 should be Figure 2, and the image that appears as Figure 4 should be Figure 3. The figure legends appear in the correct order."} +{"text": "Table 3 was incorrectly uploaded as Table 2 and Table 3. The correct Table 2 can be found here:"} +{"text": "Figures 1 and 2 were accidentally switched. The image appearing as Figure 1 belongs with the title and legend for Figure 2, and the image appearing as Figure 2 belongs with the title and legend for Figure 1. The titles and legends are in correct order."} +{"text": "The content of columns four and five are incorrect in Table 1. Please see the corrected Table 1 here:"} +{"text": "The order of figures were incorrectly switched. The image that appears as Figure 1 should be Figure 3, the image that appears as Figure 2 should be Figure 1, and the image that is Figure 3 should be Figure 2. The figure legends appear in the correct order."} +{"text": "Figures 1 and 2 were incorrectly switched. The image currently appearing as Figure 1 belongs with the title and legend for Figure 2, and the image currently appearing as Figure 2 belongs with the title and legend as Figure 1. The titles and legends themselves are in correct order."} +{"text": "Figures 2 and 3 were switched in production. The image listed as Figure 3 is actually Figure 2, and the image listed as Figure 2 is actually Figure 3. The legends are correct."} +{"text": "The legends for Figures 2 through 8 are incorrect. The figure under which the legend begins \"Figure 3...\" is Figure 2, the figure under which the legend begins \"Figure 4...\" is Figure 3, the figure under which the legend begins \"Figure 5...\" is Figure 4, the figure under which the legend begins \"Figure 6...\" is Figure 5, the figure under which the legend begins \"Figure 7...\" is Figure 6, the figure under which the legend begins \"Figure 8...\" is Figure 7, and the figure under which the legend does not begin with a numeric label is Figure 8."} +{"text": "Figures 1 and 2 were incorrectly switched. The figure labeled as Figure 1 belongs with the title of Figure 2 and the figure labeled as Figure 2 belongs with the title of Figure 1. The titles themselves are in correct order."} +{"text": "The titles and legends for Figures 3 and 4 were incorrectly switched. The title and legend currently appearing with Figure 3 belong with Figure 4, and the title and legend currently appearing with Figure 4 belong with Figure 3. The images themselves are in correct order."} +{"text": "Figures 3 and 4 were incorrectly switched. The figure appearing as Figure 3 belongs with the title and legend of Figure 4, and the figure appearing as Figure 4 belongs with the title and legend of Figure 3. The titles and legends themselves are in correct order."} +{"text": "There is an error in Figure 2. A correct image for Figure 2 can be seen here: [^]"} +{"text": "There was an error in Figure 2. The correct Figure 2 can be viewed here: ."} +{"text": "In Figure 3B, the panels for 4m and 8m were erroneously switched with the lower row. Please see the corrected figure here:"} +{"text": "The image currently appearing as Figure 5 consists of Figures 4e and 4f, and belongs with the title and legend for Figure 4.In addition, Figure 5 was incorrectly omitted from the manuscript. Please see the correct Figure 5 here:"} +{"text": "Figures 2 and 3 were incorrectly switched. The image currently appearing as Figure 2 belongs with the title and legend of Figure 3, and the image currently appearing as Figure 3 belongs with the title and legend of Figure 2. The titles and legends are in correct order."} +{"text": "There was a formatting error in Table 2. The correct Table 2 can be viewed here:"} +{"text": "There are errors in Tables 1-5. The correct version of Table 1 can be viewed here: The correct version of Table 2 can be viewed here: The correct version of Table 3 can be viewed here: The correct version of Table 4 can be viewed here: The correct version of Table 5 can be viewed here:"} +{"text": "The images for Figures 1 and 2 were incorrectly reversed in the article. The legends are correct. The correct versions of these figures are available below.Figure 1: Figure 2:"} +{"text": "In Table 3 and Table 4, the values for standard deviations were incorrectly listed as negative values.The correct Table 3 can be viewed here: The correct Table 4 can be viewed here:"} +{"text": "The images for Figures 3, 4, and 5 were incorrectly switched. The image that appears as Figure 3 should be Figure 4, the image that appears as Figure 4 should be Figure 5, and the image that appears as Figure 5 should be Figure 3. The figure legends appear in the correct order."} +{"text": "The legends for Figures 3 and 4 were incorrectly switched. The legend that appears with Figure 3 should be with Figure 4, and the legend that appears with Figure 4 should be Figure 3.There were also errors in the legend for Figure 4. The correct version of Figure 4 can be seen here: [^]"} +{"text": "The figure published as Figure 2 in the original published version of the manuscript isin fact a duplicate of Figure 5. The correct Figure 2 is shown here (Figure"} +{"text": "The labels and legends for Figures 6 and 7 were incorrectly switched. The label and legend appearing under Figure 6 belong under Figure 7, and the legend and label appearing under Figure 7 belong under Figure 6. The figures themselves are in correct order."} +{"text": "Figure 2 is incorrect. The correct version of Figure 2 can be viewed here:"} +{"text": "The version of Figure 3 included in the article is a duplicate of Figure 2. Please see the correct Figure 3 file here:"} +{"text": "The images for Figures 1, 2, and 3 were misplaced. The legends for the figures are placed correctly.The correct Figure 1 can be found here: The correct Figure 2 can be found here: The correct Figure 3 can be found here:"} +{"text": "Figures 3 and 4 were incorrectly switched. The image currently appearing as Figure 3 belongs with the title and legend for Figure 4, and the image currently appearing as Figure 4 belongs with the title and legend for Figure 3. The titles and legends are in correct order."} +{"text": "The images for Figures 3 and 4 were incorrectly switched. The image that appears as Figure 3 should be Figure 4, and the image that appears as Figure 4 should be Figure 3. The figure titles and legends appear in the correct order."} +{"text": "Figure 1 and Figure 2 were old versions of the figures.Please view the correct version of Figure 1 here: Please view the correct version of Figure 2 here:"} +{"text": "Supplementary Figures 1 and 2 were incorrectly switched. The image currently appearing as Supplementary Figure 1 belongs with the title and legend for Supplementary Figure 2, and the image currently appearing as Supplementary Figure 2 belongs with the title and legend for Supplementary Figure 1. The titles and legends of the figures are in correct order."} +{"text": "The published Figure 3 was incomplete. The complete Figure 3 can be viewed here:"} +{"text": "Figures 1 and 2 were incorrectly switched. The image currently appearing as Figure 1 belongs with the title and legend of Figure 2, and the image currently appearing as Figure 2 belongs with the title and legend of Figure 1. The titles and legends are in correct order."} +{"text": "The titles and legends of Figures 1 and 2 were incorrectly switched. The title and legend currently appearing with Figure 1 belong with Figure 2, and the title and legend currently appearing with Figure 2 belong with Figure 1. The Figures are in correct order."} +{"text": "The incorrect Figure 1 appears in the online version of this article. The correct Figure 1 can be viewed here:"} +{"text": "There is an error in Figure 4. The correct Figure 4 can be viewed here:"} +{"text": "There was an error in the headings for Table 1. The correct Table 1 can be viewed here:"} +{"text": "The figure numbering in the HTML version of the original article (van Roosmalen et al. Figure 1 in the HTML version is Figure 2 in PDFFigure 2 in the HTML version is Figure 3 in PDFFigure 3 in the HTML version is Figure 4 in PDFFigure 4 in the HTML version is Figure 5 in PDFFigure 5 in the HTML version is Figure 6 in PDFFigure 6 in the HTML version is Figure 7 in PDFFigure 7 in the HTML version is a duplicate of additional Figure S3.The publisher would like to apologise for this error."} +{"text": "The images for Figs 1 and 3 are incorrectly switched. The image that appears as Fig 1 should be Fig 3, and the image that appears as Fig 3 should be Fig 1. The images for Figs 2 and 4 are also incorrectly switched. The image that appears as Fig 2 should be Fig 4, and the image that appears as Fig 4 should be Fig 2. The figure captions appear in the correct order."} +{"text": "The images for Figures 1 and 2 are incorrectly switched. The image that appears as Figure 1 should be Figure 2, and the image that appears as Figure 2 should be Figure 1. The figure legends appear in the correct order.In the section entitled \u201cValidation of RNA-Seq\u201d, S2 Fig should be referenced instead of S1 Fig.Additionally, the files linked to S1 Fig and the file linked to S2 Fig are incorrect. The file linked to S1 Fig should be the file linked to S2 Fig, and the file linked to S2 Fig should be the file linked to S1 Fig."} +{"text": "A number of figure legends are associated with the wrong figures in the published article.The legend of Figure 6 should be associated with Figure 4.The legend of Figure 4 should be associated with Figure 5.The legend of Figure 5 should be associated with Figure 6."} +{"text": "The images for Figs 5 and 6 are incorrectly switched. The image that appears as Fig 5 should be Fig 6, and the image that appears for Fig 6 should be Fig 5. The figure captions appear in the correct order."} +{"text": "The images for Figs 1 and 2 are incorrectly switched. The image that appears as Fig 1 should be Fig 2, and the image that appears as Fig 2 should be Fig 1. The figure captions appear in the correct order. The publisher apologizes for the error."} +{"text": "The legend for Table 3 incorrectly lists the measurement of 14.8ms. The correct legend is below."} +{"text": "The images for Figs 2 and 3 are incorrectly switched. The image that appears as Fig 2 should be Fig 3, and the image that appears as Fig 3 should be Fig 2. The figure captions appear in the correct order. See the corrected Figures below."} +{"text": "The first step of Fig 2 appears erroneously in the publication as a repetition of Fig 1. The correct"} +{"text": "The H4 panels in Fig 4A have been corrected. The HDAC5 panel in Fig 4A duplicates the STAT1 panel shown in Fig 5C. The HDAC5 panel in Fig 4A has been corrected.The authors would like to correct an error in Fig 4 that was introduced during the preparation of this figure for publication. In Fig 4A the two bottom left panels of H4 duplicate the G\u03b2The authors have stated that cropped blots were provided to a colleague to create the finalized image for publication. The error was introduced to Fig 4 at that point in time, and the original blots were not retained because of a change of institution. The authors confirm that these changes do not alter their findings.The revised Fig 4A can be downloaded from this correction as S1 Fig(TIF)Click here for additional data file."} +{"text": "The image for Figure 1 is incorrect. Please see the corrected Figure 1 here."} +{"text": "The original S1 Dataset was published in error. The S1 Dataset was removed from the XML and PDF versions of this article on May 18, 2016."} +{"text": "Feng Liu is not affiliated with #1 and #2, but with #1 and #3:"} +{"text": "The first 8 values in column 3 of"} +{"text": "In Table 1, the values in the Case column should be listed from 1 to 18. Please see the corrected"} +{"text": "There are undisclosed splices between lanes 2 and 3 for each panel in Additionally, there is an error in S1 File(ZIP)Click here for additional data file."} +{"text": "The images for Figs 1 and 2 are incorrect and the legend for Fig 4 is incorrect. The corrected figures and captions are provided here."} +{"text": "There are panels missing from Figs 1 and 4. Please see the corrected Figs"} +{"text": "There are multiple errors in Equations 4 and 11. Please see the corrected Equation 4 here.Please see the corrected Equation 11 here."} +{"text": "The images for Figures S3 and S4 are incorrectly switched. The image that appears as Figure S3 should be Figure S4, and the image that appears as Figure S4 should be Figure S3. Please view the correct Figures S3 and S4 below.There is an error in the Methodology. The penultimate sentence of the Literature search strategy section of the Methodology should read: Study selection criteria are shown in Box S4 and full search strategy is detailed in Boxes S1 and S2.Box S4 is omitted from the list of Supporting Information. It can be viewed below.Figure S3Forest plot of pooled estimate in females.(JPG)Click here for additional data file.Figure S4Forest plot of pooled estimates by age group.(JPG)Click here for additional data file.Box S4PubMed search strategy.(DOCX)Click here for additional data file."} +{"text": "The images for Figs 1 and 2 are incorrectly switched. The image that appears as Fig 1 should be Fig 2, and the image that appears as Fig 2 should be Fig 1. The figure captions appear in the correct order."} +{"text": "There is an error in the third sentence of the Abstract. The correct sentence is: Three promoters MeEF1A3, MeEF1A5 and MeEF1A6 were successfully isolated.There is an error in the legend for"} +{"text": "The images for Figures 2 and 3 are incorrectly switched. The image that appears as Figure 2 should be Figure 3, and the image that appears as Figure 3 should be Figure 2.\u00a0The figure legends appear in the correct order."} +{"text": "The correct concentration is 7.2 log TCID50.There is an error throughout the Methods section of this manuscript. The virus concentration is recorded incorrectly as 3.75 log TCID"} +{"text": "The images for Figs 1 and 2 are incorrectly switched. The image that appears as Fig 1 should be Fig 2, and the image that appears as Fig 2 should be Fig 1. The figure captions appear in the correct order. Please see the corrected"} +{"text": "Thus H4K20me1 is not only a downstream effector of the DCC.\u201dThere are errors in the second and third sentences from the end of the Abstract. These sentences should read \u201cH4K20me1 depletion in the The last sentence of the Introduction is incorrect. The sentence should read \u201cOur results suggest that H4K20me1 levels are important for X chromosome dosage compensation, but H4K20me1 does not act only as a downstream effector of the DCC.\u201d"} +{"text": "The images for Figures 2 and 3 are incorrectly switched. The image that appears as Figure 2 should be Figure 3, and the image that appears as Figure 3 should be Figure 2. The figure legends appear in the correct order."} +{"text": "The image for the Mn2 panel of"} +{"text": "There is an error in in Figure 3. Incorrect pictures were erroneously used in Figure 3A. Please see the corrected Figure 3 here."} +{"text": "In the Funding section, the grant number from funder Ministry of Education Science and Technology is listed incorrectly. The correct grant number is [2012R1A1A4A01015109]."} +{"text": "There is an error in S2 FileContains 1) list of probesets and genes in the PPAR\u03b1 signature; and 2) description of biosets that activate or suppress PPAR\u03b1 discussed in this study.(XLSX)Click here for additional data file."} +{"text": "It has come to our attention that Figures 2F and 7A in our article are the"} +{"text": "There are errors in Figures 2 and 3 of S1 Text(DOCX)Click here for additional data file."} +{"text": "In [1], the incorrect Figure 2 was published on page 5.Below is the correct Figure 2.The authors apologize for this error."} +{"text": "The formatting of Tables 1 and 3 have been incorrectly published in original publication.The Supplementary Tables 1 and 2 have also been incorrectly published in original publication.The original article has been corrected now."} +{"text": "This corrigendum is for correcting some errors in Tables 3 and 4. Number of subjects for variables and indicator variables was not correctly reported. A corrected Tables 3 and 4 are attached below. The authors apologize for any inconvenience that this may have caused."} +{"text": "Due to a production error, tables 1\u20136 were published incorrectly in the original version.Table 1 on missing values was incorrectly published as Table 4.Table 2 on data description was incorrectly published as Table 6.Table 3 on obstetric assistance was incorrectly published as Table 5.Table 4 on birth control methods was incorrectly published as Table 1.Table 5 on C&RT endnodes was incorrectly published as Table 2Table 6 on C&RT endnodes for Montenegro was incorrectly published as Table 3.The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "The article has now been corrected and the duplicate Table 5 has been removed, and the correct Table 4 is now included."} +{"text": "In addition, the spectra in the original figure do not match with the relevant discussion of 3N4, CaFe2O4 and CaFe2O4/g-C3N4/CNT composite. The correct image for The authors regret that mistakes were made during the preparation of The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In the original publication, Tables 1 and 2 were published incorrectly.The correct version of Tables The original publication has been corrected."} +{"text": "Supplementary Figure S2, Supplementary Figure S2, the IHC images of IGF1R were erroneously used as the results of Collagen IV. The corrected IHC images of Collagen IV were displayed as below.(1) In (2) In (3) In (4) In Supplemenary Figures S10\u2013S12 are added as the raw data of Supplemenary Figure S9.(5) In the original article, there was a mistake in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In an articleAll the transmission electron microscope images are uploaded in error and these are corrected in the figures below.Figure 1Figure 3Figure 6The authors apologize for the error."} +{"text": "The Editor-in-Chief has retracted this case report because Figure 3a and Figure 3b are the same as Figure 2 and Figure 3 respectively in which de"} +{"text": "An incorrect version of S1 Appendix and S1 File was published in error. References to these Supporting Information have been updated throughout the article. The updated S1 and S2 Appendix were the previous S2 and S3 Appendix. This article was republished on May 28, 2021 to correct these errors. Please download this article again to view the correct version."} +{"text": "The ROC curves of the CCL20-IL-17A panel in Figure 4C and 4D were the same as that in the Figure 5B and 5C.There is an image crack in the Figure 5A during a layer merging process.The authors of the original article have fouThese changes don\u2019t affect any conclusions of the original paper.The incorrect Figs.\u00a0 and 2 an"} +{"text": "In the original version of the article affiliation 1 has been missed out for an author and affiliation 1 superscript has been added in this correction.The Original article has been corrected.1,5Joong Kee Lee"} +{"text": "The authors regret that Figures 6 and 11b in ["} +{"text": "Figs 2 and 3 in the original article are inco"} +{"text": "In the Abstract and Table 4, the coefficient for the association of habit 1 with hemoglobin A1c levels should have read \u22121.65%. In Table 3, the number of male patients who performed habit 1a should have read 137. This article has been corrected.1In the Original Investigation titled \u201cFeasibility of Electronic Health Record Assessment of 6 Pediatric Type 1 Diabetes Self-management Habits and Their Association With Glycemic Outcomes,\u201d"} +{"text": "In the original publication , most ofAdditional file containing corrected tables 1 and 2Click here for file"} +{"text": "Incorrect versions of Figs 3, 4 and 6 are included in the published paper.In In In"} +{"text": "Hyperbilirubinemia is a pathological condition, very often indicative of underlying liver condition that is characterized by excessive accumulation of conjugated or unconjugated bilirubin in sinusoidal blood. In literature there are several indications associating the inhibition of the basolateral hepatic transporters Organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1 and 1B3) with hyperbilirubinemia. In this article, we present a curated human hyperbilirubinemia dataset and the respective OATP1B1 and 1B3 inhibition predictions obtained from an effort to generate a classification model for hyperbilirubinemia. These data originate from the research article \u201cLinking organic anion transporting polypeptide 1b1 and 1b3 (oatp1b1 and oatp1b3) interaction profiles to hepatotoxicity- the hyperbilirubinemia use case\u201d [1]. We further provide the full list of descriptors used for generating the hyperbilirubinemia classification models as well as the calculated descriptors for each compound of the dataset that was used to build the classification model. Specifications TableValue of the data\u2022The provided dataset is the first published dataset for generating a classification model for hyperbilirubinemia \u2022The predictions on OATP1B1 and 1B3 obtained from models of high accuracy are provided together with experimentally derived OATP1B1 and 1B3 inhibition values where available. This is of high importance considering the potential association of OATP1B1 and 1B3 inhibition with hyperbilirubinemia.\u2022The descriptors\u2019 list, as well as the generated descriptors on the data are also provided for further modeling purposes.1Here we provide the curated human dataset for hyperbilirubinemia that was used for generating a classification model for hyperbilirubinemia Apart from the hyperbilirubinemia data SMILES, we are also providing the calculated predictions of OATP1B1 and 1B3 inhibition obtained from models generated in a previous study Additionally, a table containing the list of 92 2D descriptors used for generating the hyperbilirubinemia model, with a brief explanation, is provided.22.1http://sideeffects.embl.de/). This dataset consisted of 888 compounds for 13 hepatotoxicity endpoints, among them also hyperbilirubinemia. We carefully curated the compounds according to the following rules:\u2022Inorganic compounds, salt parts, as well as compounds containing metals and rare or special atoms were removed and the chemotypes were standardized using the Standardiser tool \u2022Duplicates and permanently charged compounds were removed using MOE 2014.09 \u20222. In addition, the existing chirality was preserved.3D structures were generated using CORINA (version 3.4) The human data provided in this work originate from the publication of Liu After data curation 835 compounds (86 positives and 749 negatives) annotated for hyperbilirubinemia remained in the dataset.3All 2D MOE descriptors were calculated with the software MOE 2014.09 and out of 192 descriptors, 92 comprehensible descriptors were preselected without significant loss in the resulted hyperbilirubinemia model\u05f3s performance .Due to the evidence in literature for a link of OATP1B1 and 1B3 inhibition with hyperbilirubinemia, the predictions of OATP1B1 and 1B3 inhibition were also used as descriptors. The predictions were obtained using the OATP1B1 and 1B3 models generated in a previous study For the human hyperbilirubinemia data 829/835 compounds (i.e 99.3% of the dataset) are within the applicability domain of both OATP1B1 and 1B3 models. The applicability domain was checked on KNIME with the Enalos nodes"} +{"text": "There is an error in Panel A of Fig 3. Fig 3A should show the number 92 instead of 98 for genes only regulated by siKeap1-2*. Please see the correct There is an error in Panel B of Fig 4. Fig 4B should show Free fluid instead of Fat mass. Please see the correct"} +{"text": "The images for S2 and S3 Figs are incorrectly switched. The image that appears as S2 Fig should be S3 Fig, and the image that appears as S3 Fig should be S2 Fig. The figure captions appear in the correct order."} +{"text": "The images for Figs 2 and 3 are incorrectly switched. The image that appears as Fig 2 should be Fig 3, and the image that appears for Fig 3 should be Fig 2. The figure captions appear in the correct order. Please see the corrected Figs"} +{"text": "The peaks in the C1 range are compared with the patterns predicted for simple breaking of the C\u2014C bond and dissociation of the methyl radicals. The \u201cweighting factors\u201d for removing H and D, HD, and 2D, etc., from C2HD5 are computed and also the weighting factors for H+ and D+ for all the deuteroethanes are given.Mass spectra of seven of the nine possible deuteroethanes have been measured. When the patterns are computed on a scale to make the sums of ions equal, it is found that the abundances of molecule ions differ nearly twofold in the different molecules, and there are large differences in the patterns of the two C Schissler, Thompson, and Turkevich 3 publishWe were able to obtain samples of seven of the nine possible deuteroethanes. Two of these were synthesized by M. deHemptinne of the University of Louvain and the others were purchased from Merck Inc. Mass spectra were recorded with a 180\u00b0 Consolidated model 21\u2013103 mass spectrometer following standard operating procedures. The ionizing voltage is 70 v except as noted below.2H5+, 12.8 ev; and C2H4+, 12.1 ev. This makes the measurement insensitive. (The impurity with one less D atom than the sample may be uncertain by 10 percent of the stated amount.) The mole percent impurities listed are consistent with the purity reported by Merck in round numbers as 98 and 99 atom percent.The samples were all of good chemical purity and an isotopic analysis was made by recording the spectrum at an ionizing voltage low enough to give molecule ions but not fragment ions . Table 12H6 and the seven deuteroethanes. The contributions of ions containing C13 and of isotopic impurities from 2H6 with the conventional scale of abundances used for the C2H6 pattern.3\u00b7CD3 to 23.0 for C2H5D. Both of the highly unsymmetrical molecules CH3\u00b7CD3 and CH3\u00b7CHD2 give low values of the molecule ion. There are many other conspicuous differences between the mass spectra of the symmetrical and unsymmetrical molecules of C2H4D2 in columns 4 and 5.It is evident that on this scale there is a wide variation of the abundances of the molecule ions. It ranges from 13.0 for CH2D6 affords a notable exception. The C2D4+ ion has an abundance of 113.5 as compared with 100 for C2H4+ of C2H6. In the patterns of ethanes containing H and D two different ions contribute to many of the peaks. Thus C2H2+ and C2D+ contribute to mass 26, C2H3+ and C2HD+ to 27 etc. In the deuteroethane spectra there is no safe basis for computing the relative probability of removing H and D or several H and D atoms except in the C2HD5 spectrum. In that spectrum each peak comes from a single isotopic fragment ion.As a general rule the removal of D atoms from deuterohydrocarbons is less probable than the removal of H but C2HD5 with the peaks grouped in pairs of ions containing 1, 2, 3, etc., hydrogenic atoms. The sums of these pairs in column 4 give the relative probability of removing one to five atoms. This times the a\u2019priori probability gives, in column 6, the pattern predicted if removal of H and D were random. The experimental values divided by the theoretical give the \u201cweighting factors\u201d for removing H and D atoms and all possible combinations of these. It is seen that except for the 25, 26 pair, ions involving loss of the H atom have a weight factor greater than one and the others less than one. This is qualitatively consistent with experiments with other deuterohydrocarbons. The weighting factors for removing H and D, 1.67 and 0.86 are of the magnitudes found for CHD3 [2HD3 [2HD5 such as was found in the deuteroethylene spectra [2D6 is given and it is quite similar to the \u201csums of pairs\u201d of C2HD5 in column 4. It is not surprising that C2HD5 is more like C2D6 than C2H6.In the last column of 3\u00b7CD3 fragment ions in the C1 range will involve contributions from CH3 and from CD3 as given by the C2H6 and C2D6 patterns. However the observed pattern shows a small 17 peak from CHD2+ so there is some rearrangement.The ions in the mass 12 to 18 range involve 1 range and the patterns computed from the spectra of two symmetrical molecules. The last two rows give the basis of computation. Thus the CH3\u00b7CH2D pattern is compared with 0.59 times the patterns of CH2D\u00b7CH2D plus 0.53 times the pattern of C2H6. In some cases as in the CHD2\u00b7CD3 spectrum there is fairly good agreement between the observed and computed spectra while in CH3\u00b7CHD2 the agreement is poor. In the CH3\u00b7CD3 pattern there is a peak at 17 that comes from the rearrangement giving CHD2+ and CH2D and the residual on the 16 peak comes from the same rearrangement with the charge on CH2D.+ and D+ ions and weighting factors for H+ and D+. A small but rather uncertain correction for H2+ has been made to the mass 2 peaks of ++D+) times the apriori probability. In C2D6 it is simply the ratio of D+ of C2D6 to H+ of C2H6. There is a progressive increase in the weighting factor for H+ as the number of D atoms in the atom increases. The factors for D+ do not change progressively.2HD5 the relative abundance of the pairs of ions containing 4 or 5 hydrogenic atoms can be computed if it is assumed that the same weighting factors apply in doubly and singly charged ions. Peak 15.5 of abundance 0.57 comes from C2HD3++ and from 2D4++ will have an abundance of about 0.39. The abundance of the pair is 0.96. The 16.5 peak of abundance 0.24 is C2HD4++. C2D5++ is about 0.09 and the abundance of the pair of ions with 5 hydrogenic ions is 0.33. The abundance of C2H5++ of C2H6 is 0.54.2HD5 make contributions of about 0.39 to the 16 peak and 0.09 to the 17 peak on the basis of the above assumptions. There is no good basis for computing contributions of doubly charged ions to the 14, 15, 16, and 17 peaks of other deuteroethanes but they are a source of experimental uncertainty in the data of 2H6 the abundance of C2H4++ will be approximately like that of the pair of ions from C2HD5 of abundance 0.96.The doubly charged ions of C2 range there is no appreciable difference between the patterns of symmetrical and unsymmetrical dideuteroethylenes. In these molecules it is logical to compute \u201cweighting factors\u201d on the basis of the C2H4 or CH4 spectra. In the case of the ethanes there is no regular trend. There are large differences in the relative abundance of molecule ions and there are striking differences between symmetrical and unsymmetrical molecules. Only in the case of the C2HD5 pattern is there a logical basis for computing weighting factors for removing H and D.The mass spectra of deuteroethylenes and deutIt is consistent with the statistical theory of mass spectra of polyatomic molecules that the2D\u00b7CHD2 and CH2D\u00b7CD3 for these undoubtedly differ from the isomers available for this study. This is needed for analytical purposes. For instance there is a small uncertainty in this work because C2H2D4 is the most abundant impurity in C2HD5 and C2H3D3 is the most abundant in CHD2\u00b7CHD2. We used the patterns of CHD2\u00b7CHD2 and CH3CD3 for the corrections but it would be better to use the mean patterns of the two isomers if both were known.It will be of interest to obtain the patterns of the other deuteroethanes, CHThe experimental material in this paper was used by Miss Quinn as a Master\u2019s thesis at the University of Alabama."} +{"text": "There was an error in Figure 2. The correct Figure 2 can be seen here:"} +{"text": "There are typographical errors in Eqs , 7) and and7) an"} +{"text": "The images for Figs 2\u20135 are incorrectly switched. The image that appears as Fig 2 should be Fig 5. The image that appears as Fig 3 should be Fig 2. The image that appears as Fig 4 should be Fig 3. The image that appears as Fig 5 should be Fig 4. The figure captions appear in the correct order."} +{"text": "This article was republished on November 10, 2017 to replace incorrect versions of S2 Table and S3 Table. Please download this article again to view the corrected tables."} +{"text": "The original article omits a The authors would therefore like to acknowledge the role of Dr Laila Rashed in assisting with taking the pictures that constitute Figures 1B and 1D."} +{"text": "This article was republished on October 27, 2017 to replace incorrect versions of S1 Table and S3 Table. Please download this article again to view the corrected tables."} +{"text": "The images for Figs 4, 5, and 6 are incorrectly switched. The image that appears as Fig 4 should be Fig 5, the image that appears as Fig 5 should be Fig 6, and the image that appears as Fig 6 should be Fig 4. The figure captions appear in the correct order."} +{"text": "Impact of nucleic acid and methylated H3K9 binding activities of Suv39h1 on its heterochromatin assembly. Published 1, August 2017Due to an error introduced during the production process, the image for Figure 1 \u2013 figure supplement 1 was a duplicate of the image for Figure 2 \u2013 figure supplement 1.The correct image is shown here:The incorrect duplicated image is shown here for reference:The article has been corrected accordingly."} +{"text": "There is an error in Figure 1. The correct Figure 1 can be seen here:"} +{"text": "The images for Figs 2 and 3 are incorrectly switched. The image that appears as Fig 2 should be Fig 3 and the image that appears as Fig 3 should be Fig 2. The figure captions appear in the correct order."} +{"text": "The images for Figs 3 and 4 are incorrectly switched. The image that appears as Fig 3 should be Fig 4, and the image that appears as Fig 4 should be Fig 3. The figure captions appear in the correct order."} +{"text": "Figure 2 was published as a duplicate of Figure 4. Please find the correct Figure 2 here:"} +{"text": "The legend under Figure 1 should be associated with Figure 3. The legend under Figure 2 should be associated with Figure 1. The legend under Figure 3 should be associated with Figure 2.In the article \u201cNeutrophils assist the metastasis of circulating tumor cells in pancreatic ductal adenocarcinoma: A new hypothesis and a new predictor for distant metastasis\u201d,"} +{"text": "The images for Figures 1 and 2 were incorrectly switched. The image that appears as Figure 1 should be Figure 2, and the image that appears as Figure 2 should be Figure 1. The figure legends appear in the correct order."} +{"text": "Figure 1 is a duplicate of Figure 8. Please view the correct Figure 1 here:"} +{"text": "The titles and legend for Tables 1 and 2 were reversed.The correct Table 2 can be viewed here:"} +{"text": "Figures 1 and 2 do not appear correctly. Figure 2 should be considered Figure 1, and the correct file for Figure 2 can be viewed here: The figure titles and legends are not affected and are correct as they appear."} +{"text": "The images for Figures 1 and 3 were incorrectly switched. The image that appears as Figure 1 should be Figure 3, and the image that appears as Figure 3 should be Figure 1. The figure legends appear in the correct order."} +{"text": "The images for Figures S2 and S3 were incorrectly switched. The image that appears as Figure S2 should be Figure S3, and the image that appears as Figure S3 should be Figure S2. The figure legends appear in the correct order. Please view the correct Figure S2 here: Click here for additional data file."} +{"text": "Figure 3Ba and 3Be are identical by mistake. Please view the entire corrected Figure 3 here:"} +{"text": "The data in Table 2 are duplicated from Table 1. Please view the corrected Table 2 here:"} +{"text": "Equations 17 and 19 appear incorrectly. The corrected Equations 17 and 19 can be found here:"} +{"text": "The author affiliations were displayed incorrectly for the second and third authors. Alphonse Um Boock should be listed with affiliation number 3 and Hans Peeters with numbers 1 and 4 ."} +{"text": "Part B of Figure 3 is not in the figure. Please see the corrected Figure 3 here:"} +{"text": "The images for Figures 1 and 3 were incorrectly switched. The image that appears as Figure 1 should be Figure 3, and the image that appears as Figure 3 should be Figure 1. The figure legends appear in the correct order."} +{"text": "The images for figures 3, 4, and 5 were incorrectly switched. The image that appears as figure 3 should be figure 4, the image that appears as figure 4 should be figure 5, and the image that appears as figure 5 should be figure 3."} +{"text": "The titles and legend for Tables 1 and 2 were reversed.The correct Table 1 can be viewed here:"} +{"text": "Figure 4 was published with an error in the labels under the bars. The labels should read Experiment 3 / Experiment 4 instead of Experiment 2 / Experiment 3. Please see the corrected figure 4 here:"} +{"text": "The images for Figures S2 and S3 were incorrectly switched. The image that appears as Figure S2 should be Figure S3, and the image that appears as Figure S3 should be Figure S2. The figure legends appear in the correct order. Please view the correct Figure S3 here: Click here for additional data file."} +{"text": "The file for Movie S2 is a duplicate of Movie S1. Please view the correct file for Movie S2 here:Click here for additional data file."} +{"text": "In place of Figure 4, Figure 6 was mistakenly duplicated. The correct Figure 4 is available here:"} +{"text": "Figures 8 and 9 appeared out of order. Please view the correct Figure 9 with its legend here:"} +{"text": "In Figure 3A there was a discrepancy between the original blot and the Anti-S1 blot, as published. Please see the corrected Figure 3 here:"} +{"text": "Figures 8 and 9 appeared out of order. Please view the correct Figure 8 with its legend here:"} +{"text": "Figure 1A has a mistake in the text. The correct version of Figure 1 can be found here:"} +{"text": "The images for figures 4 and 5 were incorrectly switched. The image that appears as figure 4 should be figure 5, and the image that appears as figure 5 should be figure 4. The figure legends appear in the correct order."} +{"text": "The images for Figures 1 and 2 were incorrectly switched. The image that appears as Figure 1 should be Figure 2, and the image that appears as Figure 2 should be Figure 1. The figure legends are numbered correctly."} +{"text": "In Table 1, the data in the F73 column are incorrect. See the corrected Table 1 here:"} +{"text": "The order of Figures 3 and 4 is switched."} +{"text": "Figure 4 is a duplicate of Figure 3. Please view the correct Figure 4 here: The titles and legends for both figures are correct as they appear."} +{"text": "Figure 2 is missing a panel. Please view the correct version of Figure 2 here:"} +{"text": "BstZ17I\u2014in the Methods section as displayed in the following sentences:FOXO3 gene fragments (PCR products) had pcDNA3 sequences on the ends that corresponded to upstream and downstream sequences of the utilized restriction sites (DraIII for Arm1 and BstZ17I for Arm2) in pcDNA3.[\u2026] Therefore, FOXO3 Arm 1) was cut with BstZ17I, which is on the other side of the neomycin resistance gene in the pcDNA3 plasmid compared to FOXO3 Arm 1.[\u2026] The intermediate vector (with FOXO3 Arm 2 was amplified with the primer pair specified in Table\u00a01, producing a product that had sequences on each end that were identical to the sequences proximal to the BstZ17I site in the intermediate FOXO3 Arm 1 vector.[\u2026] The original article containsBsmI\u2014in place of where BstZ17I was mentioned in each instance.As such, the above three sentences should instead have stated the correct restriction enzyme\u2014"} +{"text": "The following information is missing from the Funding statement: This work was supported in part by the National Research Foundation of Korea Grant 2016R1D1A1B03930591 to KJL."} +{"text": "The Y-axis in both Figure 3 and Figure 4 of were wro"} +{"text": "There are errors in the Data Availability Statement; the raw data underlying Figs 2 and 3 are not provided within the paper. The authors have provided the summary level data underlying Fig 2 and the raw data underlying Fig 3 as Supporting Information files below.S1 File(XLSX)Click here for additional data file.S2 File(ZIP)Click here for additional data file."} +{"text": "The forest plots are missing from Figures 1 and 2. The complete images for Figures 1 and 2 can be seen here:Figure 1: Figure 2:"} diff --git a/PMC_clustering_617.jsonl b/PMC_clustering_617.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..3938aaefdf7df966aa8e0fc2252bfad8ac52b24f --- /dev/null +++ b/PMC_clustering_617.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:4f8fae4ce4b33c832ec2f6b435b86dc0f52f4c9327edff7d5e34175f56516e58 +size 41175220 diff --git a/PMC_clustering_618.jsonl b/PMC_clustering_618.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..4ece997f7fa2634c207ac16c29e1f4967f3a3705 --- /dev/null +++ b/PMC_clustering_618.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:5cd5c4a5eedc905bbd7cde185e6cb596116dd64a32928b321519a19aea0f2913 +size 31417471 diff --git a/PMC_clustering_619.jsonl b/PMC_clustering_619.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..fa93340d96add02de7f97f1b56e81dac0724b727 --- /dev/null +++ b/PMC_clustering_619.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:befec85b2913285fb3269821e649adba5faf254208ba5c63b34c60bfb848978f +size 31514505 diff --git a/PMC_clustering_620.jsonl b/PMC_clustering_620.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..29d548ac70c54ed67fd0912fa670da0f970483d8 --- /dev/null +++ b/PMC_clustering_620.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:b23b80bdd31a3255f58dcb8a2c384303a860d1cd09a0539e4f087b19e4b285db +size 52499913 diff --git a/PMC_clustering_621.jsonl b/PMC_clustering_621.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..d6ffd9b9c1e83f9f661d909826e2dacffa413948 --- /dev/null +++ b/PMC_clustering_621.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:bb5eefaeee222814a68a53b7c16f73151c9b948c864ff958b9d989510379ebad +size 66437261 diff --git a/PMC_clustering_622.jsonl b/PMC_clustering_622.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..0ae2705b4c2f4a255d4a3f577173d74f144b3d0d --- /dev/null +++ b/PMC_clustering_622.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:d530107c18d645edbe66c294ef2a85e9dad3b8e4d035948d930625d2605ec925 +size 38513175 diff --git a/PMC_clustering_623.jsonl b/PMC_clustering_623.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..10b92884e8295749f95fffe1d8c75ac74c99df41 --- /dev/null +++ b/PMC_clustering_623.jsonl @@ -0,0 +1,2366 @@ +{"text": "Eucalyptus. Eucalyptus leaves can alter soil chemistry and negatively affect underground macro- and microbial communities. Amphibians serve as excellent models to evaluate the effect of Eucalyptus invasion on ground-dwelling species as they predate on soil arthropods and incorporate soil microbes into their microbiotas. The skin microbiota is particularly important to amphibian health, suggesting that invasive plant species could ultimately affect amphibian populations. To investigate the potential for invasive vegetation to induce changes in microbial communities, we sampled microbial communities in the soil and on the skin of local amphibians. Specifically, we compared Batrachoseps attenuatus skin microbiomes in both Eucalyptus globulus (Myrtaceae) and native Quercus agriflolia (Fagaceae) dominated forests in the San Francisco Bay Area. We determined whether changes in microbial diversity and composition in both soil and Batrachoseps attenuatus skin were associated with dominant vegetation type. To evaluate animal health across vegetation types, we compared Batrachoseps attenuatus body condition and the presence/absence of the amphibian skin pathogen Batrachochytrium dendrobatidis. We found that Eucalyptus invasion had no measurable effect on soil microbial community diversity and a relatively small effect (compared to the effect of site identity) on community structure in the microhabitats sampled. In contrast, our results show that Batrachoseps attenuatus skin microbiota diversity was greater in Quercus dominated habitats. One amplicon sequence variant identified in the family Chlamydiaceae was observed in higher relative abundance among salamanders sampled in Eucalyptus dominated habitats. We also observed that Batrachoseps attenuatus body condition was higher in Quercus dominated habitats. Incidence of Batrachochytrium dendrobatidis across all individuals was very low . The effect on body condition demonstrates that although Eucalyptus may not always decrease amphibian abundance or diversity, it can potentially have cryptic negative effects. Our findings prompt further work to determine the mechanisms that lead to changes in the health and microbiome of native species post-plant invasion.Invasive plants are major drivers of habitat modification and the scale of their impact is increasing globally as anthropogenic activities facilitate their spread. In California, an invasive plant genus of great concern is Anthropogenic habitat modification has dramatic direct and indirect effects on wild animal populations . InvasivOne way that invasive plants impact native animal populations is by altering their microbial commensals. Plant invasions could influence the microbial community structure of native fauna by changing microbial communities that hosts are exposed to, by altering host physiology, or both . InvasioEucalyptus sp. resulting in changes in soil microbial communities and native Quercus agrifolia (Fagaceae) dominated forests in the San Francisco Bay Area. Specifically, we determined whether changes in microbial composition, diversity and stability in both soil and Batrachoseps attenuatus skin were associated with Eucalyptus or Quercus dominated habitat. To evaluate animal health across Eucalyptus and Quercus dominated habitats, we also measured and compared Batrachoseps attenuatus body condition and the presence/absence of the amphibian chytrid fungus Batrachochytrium dendrobatidis, which causes the lethal amphibian disease chytridiomycosis. Our results illustrate a decline in the richness of skin associated microbiota and a decrease in salamander body condition in Eucalyptus forest, illustrating that plant invasions may have consequences for native species.To investigate potential changes induced by invasive vegetation on environmental and host-associated microbial communities, we sampled microhabitat soil and Eucalyptus invasions on native fauna and their microbiotas. The Bay Area is home to numerous seed-producing stands of E. globulus, E. pulchella, and E. viminalis among a mosaic of mixed native evergreen forests and coastal scrublands. The discrete\u2014yet interspersed\u2014distribution of invasive and native vegetation types in the Bay Area make it an ideal location to evaluate vegetation effects on resident host-associated microbiotas while controlling for geography. In addition, multiple ground dwelling amphibians are distributed throughout the Bay Area and may be sensitive to effects of invasive Eucalyptus on the skin microbiome because of their highly-limited dispersal as it has been eroded by a nearby stream, and instead chose a new site with similar characteristics.The San Francisco Bay Area (Bay Area) provides an opportunity to test the effect of crobiome . One ampy campus . To miniBatrachoseps attenuatus skin swabs from Quercus and 28 from Eucalyptus dominated habitats . Access to off-campus sampling sites was granted by East Bay Regional Parks under permit # 965. We collected salamanders by hand using gloves through log flip surveys within ~100 m of the location coordinates. New gloves were donned between the handling of each salamander. To avoid resampling individuals and ensure that salamanders were later returned to their original capture site, we marked each capture log with the individual(s) identification number. We rinsed each salamander with 250 mL of sterile water and swabbed the dorsum with a sterile cotton swab 30 times. Following microbiota sampling, we measured each salamanders\u2019 total body length and mass. All salamanders were returned to their location of capture immediately after sampling. To characterize the microhabitat microbiota, we collected ~20 mg of soil or soil swabs directly from under the logs where each salamander was captured after releasing each individual. We collected 22 habitats . All samWe isolated DNA from skin swab samples using the DNeasy PowerSoil DNA Isolation Kit following the modifications to the manufacturer\u2019s protocol described in We performed a second PCR on microbiota amplicons to ligate dual-index barcodes paired with Illumina sequencing adaptors to the eBatrachochytrium dendrobatidis infection in our swabbed individuals, we performed real-time quantitative PCR (qPCR) reactions in duplicate following Batrachochytrium dendrobatidis zoospore standard dilution ranging from 100,000 to 0.1 genomic equivalents. These zoospore standards were prepared using the Bd-GPL strain CJB7\u2013originally isolated from Kings Canyon, CA. At least three reactions per 96-well plate were designated as negative controls, with each receiving five \u00b5L of water in lieu of template DNA. To reduce the risk of laboratory contamination we set up qPCR reactions in a laminar flow hood. We ran all qPCR reactions on an Applied Biosystems StepOnePlus Real-Time PCR System , and used the manufacturer\u2019s software for standard curve analysis. We considered an average qPCR quantification of less than one genomic equivalent per swab to be negative for Batrachochytrium dendrobatidis infection.To detect and quantify We processed raw sequencing reads using Trimmomatic to removPRJNA574188).Our microbiota sequence analysis consisted of established sequence read processing pipelines to filter erroneous reads, generate an amplicon sequence variant table, create a representative sequence phylogeny and assign taxonomy to ASVs. We chose to use ASVs rather than operational taxonomic units (OTUs), because ASVs provide greater resolution in amplicon differentiation . ASV varvegan and picante: community richness , evenness and phylogenetic diversity . We calculated these metrics in order to evaluate differences in the number of ASVs (community richness), distribution of ASV frequencies within samples (Shannon diversity index), and phylogenetic representation (Faith\u2019s phylogenetic diversity) across sample groups. To assess differences in community composition across samples, we applied the R packages GuniFrac and vegan to calculate three separate beta diversity metrics: pairwise unweighted/weighted UniFrac distances and Bray\u2013Curtis dissimilarities. We chose to include these beta diversity metrics as they account for differences in presence/absence of phylogenetic lineages among samples (unweighted UniFrac), abundance-based differences in phylogenetic lineages among samples (weighted UniFrac), and non-phylogenetic abundance-based differences among samples (Bray\u2013Curtis). In addition, we computed the core microbiomes of Eucalyptus soil, Eucalyptus salamander skin, Quercus soil and Quercus salamander skin samples.We transferred the rarefied ASV table and Newick phylogeny to R (version 3.5.1) for further analyses. A Shapiro\u2013Wilk test in R was implemented on all univariate dependent variables to evaluate normality prior to statistical model selection. We calculated three distinct alpha diversity metrics using the R packages Effects of Eucalyptus invasion on soil bacterial composition, diversity, and stability: We evaluated differences in soil community diversity, composition and community homogeneity between Quercus and Eucalyptus dominated habitats. To evaluate differences in alpha diversity between soil communities sampled in Quercus and Eucalyptus dominated habitats, we implemented community richness, Shannon diversity indices and phylogenetic diversity as dependent variables, habitat type as a fixed variable and site identity as a random variable in linear mixed models . The significance of the predictor variable was calculated with likelihood ratio tests (LRT). To characterize the strength and significance of soil community compositional and structural differentiation among habitat types, we implemented three PERMANOVA tests (R package vegan) using weighted UniFrac, unweighted UniFrac, and Bray\u2013Curtis dissimilarity matrices as dependent variables and site identity as a random variable. We produced NMDS plots using the three dissimilarity matrices to visualize clustering of samples by habitat and site identity using the R package phyloseq. To assess whether habitat type influenced variation in soil community structure, we performed three separate multivariate of homogeneity of group dispersions analyses (R package vegan) using the beta diversity metrics. For each beta diversity metric, we used a one-way ANOVA to test differences in point-to-centroid distances between soil samples obtained from Eucalyptus and Quercus dominated habitats. We implemented an indicator species analysis using the R package indicspecies to identify ASVs whose relative abundance differs between soil samples collected in Eucalyptus and Quercus dominated habitats.Effects of Eucalyptus invasion on Batrachoseps attenuatus bacterial composition, diversity and stability: To assess whether salamander skin microbiota sampled in Quercus or Eucalyptus dominated habitat differ in their overlap with microhabitat microbiota, we calculated average unweighted UniFrac, weighted UniFrac, and Bray\u2013Curtis dissimilarity values between every salamander skin sample and all environmental samples in its corresponding site. We used these dissimilarities as dependent variables in a generalized linear mixed model using a logit distribution with habitat type as a fixed variable and site as a random variable. We also evaluated whether skin microbial community diversity, composition and heterogeneity differed between Batrachoseps attenuatus sampled in Quercus and Eucalyptus dominated habitats. We assessed differences in community richness, Shannon diversity indices, and phylogenetic diversity between salamander skin communities sampled in Quercus and Eucalyptus dominated habitats using linear mixed models as described above. We ran PERMANOVA tests using weighted UniFrac, unweighted UniFrac, and Bray\u2013Curtis dissimilarities as dependent variables, habitat type as a fixed variable and site identity as a random variable to evaluate variation in community composition and structure. We produced NMDS plots using the three dissimilarity matrices to visualize clustering of skin samples by habitat and site identity. We also performed three separate multivariate of homogeneity of group dispersions analyses to evaluate how habitat type influenced variation in community structure among individuals in the same group. For each beta diversity metric, we used a one-way ANOVA to test differences in point-to-centroid distances between Eucalyptus and Quercus salamander skin microbial communities. We implemented an indicator species analysis using the R package indicspecies to identify ASVs whose relative abundance differs between salamander skin samples collected in Eucalyptus and Quercus dominated habitats. Lastly, we assessed patterns of isolation by distance (IBD) by comparing our three dissimilarity matrices of community composition to a Euclidean geographic distance matrix between sampling locations. We tested for significance of IBD through mantel tests using R package ade4 with site identity as a random factor. Lastly, we evaluated whether there were correlations between skin alpha diversity metrics and body condition using Pearson correlation tests.tebrates . We omitEucalyptus and Quercus dominated habitats . The core microbial communities of Eucalyptus dominated habitat soil samples (16 ASVs) were composed of ASV\u2019s characterized as Actinobacteria and Proteobacteria . In contrast, the core microbiome of Quercus dominated habitat soil samples was composed of eight ASV\u2019s characterized as Actinobacteria , Bacteroidetes , Proteobacteria , and Verrucomicrobia . The indicator species analysis identified 216 ASVs that differed significantly between habitat types with 122 associated with Eucalytpus soil samples and 94 associated with Quercus soil samples , weighted UniFrac , or Bray\u2013Curtis dissimilarities . Microbial community richness and phylogenetic diversity were significantly lower for salamanders in Eucalyptus dominated habitat compared to salamanders sampled in Quercus habitats but not for Bray\u2013Curtis dissimilarities but no patterns of IBD with both our weighted and unweighted UniFrac matrices .We did not observe differences in composition and structure between skin and corresponding soil samples among Eucalyptus dominated habitat was comprised entirely of ASVs assigned to the phylum Proteobacteria . The core microbiota of salamander skin samples collected in Quercus dominated habitat was richer in that it possessed 32 ASVs assigned to the phyla Actinobacteria , Chloroflexi , Proteobacteria , and Verrucomicrobia . As observed in the soil core microbial communities, salamander skin core ASVs consisted mostly of rare taxa . However, we found one skin ASV identified as Bordetella petrii to dominate skin communities in Eucalyptus (29.81%) and Quercus (20.45%) dominated habitats. The indicator species analysis identified 294 ASVs that differed significantly between habitat types with 36 associated with Eucalyptus salamander skin samples and 258 associated with Quercus salamander skin samples compared to individuals collected in Quercus dominated habitats .The core microbiota of salamander skin samples collected in samples . As obseEucalyptus and Quercus dominated habitats . Salamanders sampled in Quercus dominated habitat possessed higher body condition indices than those sampled from the Eucalyptus dominated habitat , Shannon diversity index , or Faith\u2019s phylogenetic diversity . One salamander (OHG-47_S202) tested positive for Batrachochytrium dendrobatidis with a low average infection load of 41.59 zoospore equivalents .Body condition indices differed significantly between salamanders sampled in habitat . We did ivalents . The preEucalyptus and Quercus dominated sites. Thus, the filter acting on microbial richness is likely operating at the host level, rather than the passive uptake of different soil microbial communities. At the individual level, we found differences in native salamander skin microbial diversity and body condition associated with Eucalyptus invasion. We also observed higher salamander skin microbial composition heterogeneity and relative abundances of an ASV identified to the family Chlamydiaceae in salamanders inhabiting Eucalyptus dominated habitats.We observed no differences in richness, little variation in community composition and structure, and similar differentiation between soil and skin samples across Eucalyptus sites. In addition, a small fraction of the variation in community composition among soil samples was explained by vegetation type. This finding is surprising given the documented shifts in soil microbiomes following plant invasions \u2013in the Eucalyptus samples. While we cannot differentiate among these two possibilities using 16S rRNA amplicon sequencing alone, this pattern could reflect microbial community changes due to environmental filters present in the Eucalyptus dominated habitat. Changes in the relative abundance of core bacteria and alpha diversity have been documented in previous studies assessing the effects of environmental changes on the skin microbiota of amphibians has not been established . Additionally, Batrachoseps attenuatus\u2019 high site fidelity, relatively short dispersal distances and association with fallen logs may decrease differences compared to surrounding leaf litter, which may show greater microbial composition differences between sites possess distinct skin microbial communities and biotic factors may have disproportionate effects on the persistence of distinct rare bacteria in these salamanders. The loss of bacterial species in salamanders inhabiting Eucalyptus habitat may vary by individual- and site-specific factors that were not measured in the current study. Heterogeneous responses of microbial communities have been demonstrated for soil microbes in response to silviculture and agricultural practices , it is possible that an increase in Chlamydiaceae in the skin of salamanders results from microbial dysbiosis than those in native Quercus woodland . Interestingly, we found differences in the skin microbial community of the native salamander Batrachoseps attenuatus, but no differences in soil microbial communities between Eucalyptus and Quercus habitats. We also found decreased body condition of this native salamander in Eucalyptus dominated habitats. Our findings prompt further experimental work to determine the mechanisms causing these microbial changes and their potential effect on the fitness of native fauna following invasion.To our knowledge, our study is the first to demonstrate changes in the microbial communities of native hosts associated with plant invasion (10.7717/peerj.8549/supp-1Supplemental Information 1Click here for additional data file."} +{"text": "Neoadjuvant therapy with conventional chemotherapies have visibly improved the prognosis of locally advanced pancreatic cancer (PCa). However, molecular targeted therapies that have provided durable responses in other tumor entities, have not yet found access into neoadjuvant therapy of PCa. In fact, due to the presence of the tumor burden serving as an antigen source for T cell priming, neoadjuvant chemotherapy may unleash a more potent antitumoral immune response than adjuvant or palliative chemotherapy. Despite tremendous efforts, successful therapy of pancreatic cancer (PCa) remains a major challenge . FindingCancer immunotherapy, led by immune checkpoint inhibitors (ICI) and cancer vaccines have shown notable long-term efficacy in many solid malignancies . The limAdoptive immunotherapy involves injecting antitumor-programmed immune cells into the patient. New directions are pointing to tumor lysate-pulsed dendritic cells , 12 or tThe failure of immunotherapy in PCa may be partly due to the exclusion of T cells by cancer-associated fibroblasts (CAF) and the impaired drug delivery caused by increased hydrostatic pressure and the poor vascularization in the highly fibrotic pancreatic stroma . Exploitin vitro and in the in vivo murine xenograft model and inhibited PCa growth [While metabolic plasticity has long been recognized as a hallmark of cancer, we have only recently started to exploit the differences between cancer cell and normal cell metabolism . Metabola growth .Our growing understanding of the PCa biology has led to the development of novel immunotherapies as well as drugs targeting key regulators of the stromal and tumor metabolism. However, the full potential of these agents has been hampered by the presence of therapeutic resistance, resulting from intrinsic compensatory signalling pathways and mutagenic evolution . Only co"} +{"text": "Older residents often experience disruption in family relationships and social networks due to isolation once they move into public housing communities. While the need for social contact continues, the opportunity may diminish. Older African-American women living in one housing community attempted to cope with their personal safety fears through social isolation . Women in the study (N = 25) were survivors of one or more forms of interpersonal trauma, including childhood abuse, sexual assault and domestic violence. In contrast, a few women in the same sample spontaneously formed social networks within the community. This qualitative investigation will examine how the women adapted to an isolating and unsafe environment by developing social connections. As a social determinant of health, developing healthy social networks inside a housing community can reduce fear and improve well-being and quality of life for low-income older residents who are aging-in-place."} +{"text": "Methamphetamines are commonly abused drugs for their stimulant and euphoric effects. Inhaled and intravenous use may cause damage to the respiratory system. Spontaneous pneumomediastinum is a condition where changes in intrathoracic pressure leads to alveolar rupture and dissection of air along the tracheobronchial tree. Massive subcutaneous emphysema may result from pneumomediastinum which may compromise the central airway. In this case report, we present an unusual case of spontaneous pneumomediastinum and severe subcutaneous emphysema following inhalation of methamphetamine. This case emphasizes the rising concern on the acute respiratory complications of methamphetamine use. Inhaled and intravenous use of stimulants may cause a variety of respiratory injuries. These injuries include but are not limited to nasal septum perforation, pulmonary vascular disease, pulmonary hemorrhage, thermal injury, pulmonary edema, and pneumothorax . SpontanA twenty-two-year-old previously healthy male presented to the emergency department for worsening facial and neck swelling. He noticed worsening dyspnea accompanied by facial swelling a few hours after smoking methamphetamine. Within a few minutes in the emergency room, the patient's mental status declined with more labored breathing; thus, the patient was electively intubated for airway protection. Differential diagnosis was acute allergic reaction to illicit drugs causing upper airway compromise versus acute inhalational injury. Initial chest computed tomography (CT) showed extensive pneumomediastinum with air dissecting to the peribronchovascular interstitial sheaths, interlobular septa, and visceral pleura Figures . There wMechanical ventilation was adjusted having very minimal to no positive expiratory pressure (PEEP) and prolonged expiratory phase. Placement of chest blow holes was not pursued as swelling on the face and neck improved after a few hours. The suspicion for tracheobronchial tree injury was low; thus, we did not perform bronchoscopic surveillance of the airway. Patient received empiric antibiotic treatment with ampicillin sulbactam. The patient was extubated in less than 24 hours after the improvement of peak inspiratory and plateau pressures with the positive cuff leak test. Repeat chest imaging showed decreased subcutaneous emphysema and resolution of pneumomediastinum. No dietary restriction was recommended after extubation as there was no evidence of aerodigestive organ injury. The patient was discharged after 72 hours with improved symptoms.Pulmonary complications have been reported with the use of illicit stimulants. Some recognized respiratory complications are nasal septum perforation, pulmonary vascular disease, pulmonary hemorrhage, pulmonary edema, and pneumothorax . Our casPlain chest X-ray including computed tomography (CT) is an adequate evaluation procedure after a thorough history and physical examination to exclude secondary pneumomediastinum . In one Spontaneous pneumomediastinum is often a self-limiting disease; however, due to concerns for the integrity of the aerodigestive tract, this finding usually results to unnecessary radiological investigations and antibiotic use. In one case series, spontaneous pneumomediastinum is overinvestigated and overtreated; thus, clinicians need to be more judicious with the use of hospital resources in managing patients with spontaneous pneumomediastinum . For thi"} +{"text": "Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition associated with significant mortality and morbidity. The central pathophysiological mechanisms by which repetitive cranial injury results in the neurodegeneration of CTE are poorly understood. Current well-established working models emphasize a central role for trauma-induced excessive phosphorylation and accumulation of insoluble tangles of Tau protein. In this review, we summarize recent data from preclinical animal models of CTE where a series of candidate treatments have been carefully evaluated, including kinase inhibitors, antibody therapy, and anti-inflammatory therapies. We discuss the overall translational potential of these approaches and provide recommendations for future bench-to-bedside treatment strategies. Initial symptoms manifest as non-specific cognitive and neuropsychiatric impairments, including depression and heightened aggression, and eventually progress to include a variety of motor impairments and cognitive decline . While tlistica) , it has listica) . In a relistica) . Militarlistica) . Aside fcted CTE .The initial symptoms of CTE may not occur until years or even decades after rmTBI and may affect cognitive and/or emotional domains. By one classification system, symptoms occurring in more than 50% of \u201cmild\u201d CTE (Stages 1 or 2) include impulsivity, depression, physical and verbal violence, memory loss, and suicidality. Severe CTE (Stages 3 or 4) is characterized by additional symptoms such as language impairments, visuospatial deficits, parkinsonism, and dementia-like deficits . CTE is While there remain many unknowns about the molecular and cellular pathological changes that are presumably incited by repeated cranial impact, a strong consensus has unified around the pathophysiological role of hyperphosphorylated tau (\u201cp-tau\u201d) accumulation and neurofibrillary tangle (NFT) formation . Thus, Cin vivo premortem diagnostic markers. In particular, PET imaging with radiotracers such as [F-18]FDDNP (which binds insoluble protein aggregates) has been used to identify tau and beta-amyloid patterns consistent with CTE and CTE remains somewhat enigmatic. Both tauopathies share a series of culprit tau phosphorylation sites and TBI Given the major knowledge gaps in our understanding of CTE pathogenesis, as well as limitations in available premortem diagnostic biomarkers, it is not surprising that there are currently no ongoing clinical trials for the treatment of CTE. However, in light of the proposed pathophysiological overlaps between AD and CTE, several therapies that have demonstrated preclinical success in AD models have now been applied to CTE models. This review summarizes key recent findings within this body of literature which have focused on accumulations of hyperphosphorylated tau aggregates as both a direct mediator of neuronal injury and a histological biomarker of disease severity.By definition, the vast majority of CTE diagnoses occur in individuals with a self-reported or witnessed history of contact-sport-related head injuries or military-related blast exposure . AccordiThis approach does have drawbacks: secondary injuries such as cranial fracture or intracranial hemorrhage do occur at some measurable rate . AdditioWhile the more nuanced aspects of CTE-related cellular and molecular derangements remain an active area of research, most agree that a valid preclinical model of CTE should demonstrate evidence of a phosphorylated tauopathy in response to rmTBI. In this regard, insights into CTE pathophysiology may be borrowed from transgenic Alzheimer\u2019s disease models such as TauP301L and 3xTg-AD, with the caveat that these mice develop amyloid and tau pathology even in the absence of rmTBI . Other myears of participation in a contact sport and include individuals who have only received sub-concussive impacts permeability is one of the main factors limiting the efficacy of antibody treatment in CTE and other neurological diseases. Recent advances in ultrasound technology may be used to aid immune response or drug delivery across the BBB. Unilateral focused ultrasound (FUS) has been a candidate method used to increase BBB permeability by producing transient openings in endothelial tight junctions . Recentl the BBB . In an A the BBB . In conjrvention . While trvention . Low-intrvention and AD are also involved in pathological tau hyperphosphorylation. The potent CDK inhibitor roscovitine has been studied in models of TBI and demonstrated attenuation of neurodegeneration in a model of controlled cortical impact in mice . CombiniBeyond tau hyperphosphorylation, the progression of CTE is thought to include a complex cascade of secondary inflammatory and metabolic changes that may also represent potential targets for therapeutic intervention . Ionic iThe production of reactive oxidative species and mitochondrial stress likely plays a key role in driving neuronal ischemia in CTE . These pSadly, despite increasing recognition among athletes and military personnel, there are currently no available treatments for CTE or practical clinical diagnostic markers to identify at-risk individuals. Fortunately, with a detailed neuropathological description from postmortem samples combined with preclinical models that have been inspired by the Alzheimer\u2019s field, we are closer to obtaining a comprehensive pathophysiological understanding of CTE. Like AD, CTE is a progressive neurodegenerative disease that appears to propagate via tau phosphorylation and subsequent aggregation into neurofibrillary tangles. At the same time, trauma-induced changes in circuit function may borrow from prior research in severe traumatic brain injury. While research on these related conditions may shed light on CTE pathology, it also warns of potential pitfalls. In particular, both AD and severe TBI have suftrans to pathogenic cis form has driven the development of isoform-specific phosphorylated tau monoclonal antibodies. The use of immunotherapy is one of the most promising strategies to treat CTE and other neurodegenerative diseases but suffers from poor translational efficiency. Techniques such as FUS/LIPUS may be used in conjunction with antibody treatment to improve the delivery of cis p-tau antibodies and immune agents across the blood\u2013brain barrier.Perhaps the most intuitive way to halt the progress of CTE is to inhibit processes directly affecting tau phosphorylation and aggregation. Given tau\u2019s multiple physiological functions, therapies must selectively inhibit formation and spreading of pathogenic tau. A profile of kinases directly phosphorylating tau in CTE has been developed and opened the door to a number of kinase inhibitors such as roscovitine and lithium which have shown promising preclinical results. The recent finding that tau is converted from a functional As these candidate therapies move forward to clinical phases, researchers should note the failure of dementia research to produce successful clinical trials . Why do PB and VK played significant roles in the initial manuscript drafts and subsequent revisions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The potential importance of germline genetic variation for identifying men at increased risk of prostate cancer has become increasingly recognised in recent years. We present an extensive review of the major developments in the identification of genetic loci, genes and individual variants associated with greater risk of prostate cancer, and what is currently known regarding whether these heritable prostate cancer risk factors can also inform likelihood of experiencing clinically significant rather than indolent forms of the disease. We finally discuss how these research discoveries might serve to inform clinical germline genetic testing guidelines and treatment options for prostate cancer in the future.Prostate cancer (PrCa) is a heterogeneous disease, which presents in individual patients across a diverse phenotypic spectrum ranging from indolent to fatal forms. No robust biomarkers are currently available to enable routine screening for PrCa or to distinguish clinically significant forms, therefore late stage identification of advanced disease and overdiagnosis plus overtreatment of insignificant disease both remain areas of concern in healthcare provision. PrCa has a substantial heritable component, and technological advances since the completion of the Human Genome Project have facilitated improved identification of inherited genetic factors influencing susceptibility to development of the disease within families and populations. These genetic markers hold promise to enable improved understanding of the biological mechanisms underpinning PrCa development, facilitate genetically informed PrCa screening programmes and guide appropriate treatment provision. However, insight remains largely lacking regarding many aspects of their manifestation; especially in relation to genes associated with aggressive phenotypes, risk factors in non-European populations and appropriate approaches to enable accurate stratification of higher and lower risk individuals. This review discusses the methodology used in the elucidation of genetic loci, genes and individual causal variants responsible for modulating PrCa susceptibility; the current state of understanding of the allelic spectrum contributing to PrCa risk; and prospective future translational applications of these discoveries in the developing eras of genomics and personalised medicine. Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in Europe and North America and second most common worldwide, with over 1.4 million diagnoses recorded in 2020 ,4.Although several promising molecular and genomic biomarkers for PrCa diagnosis or management have been identified in recent years , prostatNo consistent, consensus definition of aggressive PrCa has thus far been adopted within the research or clinical settings, which can hinder comparability of studies to identify risk factors and uniformity of clinical treatment application. Prior to the advent of PSA testing, aggressive PrCa had been considered to encompass only cancers which had advanced beyond the prostate itself . More reThe most clearly established risk factors for PrCa are increased age, ethnicity and family history of PrCa and certain other cancers. Familial aggregation of PrCa is one of the strongest risk factors, and provided support for the likely existence of genetic risk factors shared among families. Men with one male first-degree relative diagnosed with PrCa themselves have an estimated relative risk of approximately 2.5, and risk of diagnosis with PrCa further increases for men with multiple affected FDRs and lower ages at their diagnoses ,14,15. REvidence has also been presented for clustering of aggressive clinical presentation of PrCa within families, suggestive for heritability of aggressive PrCa phenotypes. A number of studies from the Swedish population have demonstrated increased risk of high grade PrCa observed among brothers of cases with high grade disease , with grBRCA1 and BRCA2 genes, whilst Lynch syndrome is categorised by germline mutations in DNA mismatch repair genes. A strong family history of PrCa remains a more effective indicator of PrCa risk than family history of other cancer types however, especially with respect to early-onset and lethal disease . This is consistent with previous reports that the KLK3 GWAS SNP rs2735839 is associated with Gleason score in addition to overall disease risk or remained associated with aggressive status among only patients with low PSA levels from two separate ancestral populations [KLK3 variation in PrCa susceptibility, risk of aggressive disease and serum PSA levels may therefore warrant more extensive investigation, especially in prospective or PSA na\u00efve cohorts, and may have the potential to enable the identification of a subset of individuals at lower risk of poor prognosis disease who could benefit from less interventionist treatment options.Case-only GWAS have to date reported at a genome-wide significant threshold two loci associated with Gleason score , one wit of PrCa , whilst of PrCa ,242. Thease risk ,246,247.ulations . The fulWhilst these initial case-only reports imply that caution is warranted regarding the potential for GWAS loci to be able to accurately stratify PrCa patients more likely to develop clinically significant disease, increasing evidence supports the improving ability of genetic risk scores incorporating ever larger numbers of established susceptibility variants to identify a population subset at greater lifetime risk of diagnosis with PrCa of any severity ,256,257.Although the ability of GRS to predict disease status within cohort studies has been demonstrated for various traits, their potential clinical utility to inform screening decisions for individual members of the population does however largely remain to be established at this point in time. Their potential consideration for implementation as a prospective risk-profiling tool prior to screening for PrCa may, however, soon become warranted. A polygenic hazard score (PHS) has demonstrated initial promise for the detection of clinically significant PrCa at younger age among higher PHS percentiles ,264, incAlthough many common loci have been identified which contribute substantially towards PrCa risk, rare variation is also estimated to play an important role in PrCa heritability , especiaBRCA2 gene, confirming earlier observations linking BRCA2 mutation carriers to more aggressive phenotypes through other approaches [ATM, BRCA1 and PALB2 and HOXB13. The latest National Comprehensive Cancer Network (NCCN) guidelines for germline testing also propose screening CHEK2 and PALB2 as part of their minimum recommended predisposition gene panel [TP53 plus additional DNA repair genes including BRIP1 and NBN have also been proposed for inclusion on screening panels, but await more definitive evidence to achieve consensus of utility [ATM, BRCA1, BRCA2 and potentially other DNA repair genes may inform response to PARP inhibitors [BRCA1, BRCA2 and other DNA repair genes sensitivity to platinum chemotherapy [Germline testing for rare moderate penetrance pathogenic variants in specific genes is becoming an increasingly important focus of PrCa management and treatment, with the additional promise of guiding tailored therapeutic interventions appropriate for targeting specific molecular vulnerabilities in individual patients\u2019 tumours. Although few genes have been conclusively identified to date in which rare variants confer higher risk of developing aggressive PrCa, as further larger, cross population sequencing studies and meta-analyses are performed, additional genes for which mutation carriers experience greater risk of aggressive disease and/or more favourable response to particular treatment options are likely to be established . At presne panel . The tum utility . In patihibitors ,305,306,otherapy ,308, andotherapy ,310. InvAlthough family history of the disease is usually the main reason for genetic testing of men without a diagnosis of PrCa, an appreciable proportion of PrCa patients without a family history sufficient to meet NCCN guidelines for germline genetic testing have also been demonstrated to carry rare germline putative PrCa susceptibility variants . Even grThe majority of samples included in studies investigating risk factors for PrCa to date have been from populations of European ancestry. However, given differing allelic architecture and frequencies of both rare and common variants between populations, in addition to the higher incidence and poorer prognosis of PrCa among men of African descent, reducing under-representation of additional ethnicities in PrCa research remains an unmet requirement in order to ensure applicability of discoveries across populations and pan-ethnic access to healthcare improvements ,312,313."} +{"text": "On July 28, the correctional officer had multiplebrief encounters with six incarcerated or detained persons (IDPs)Subsequently, VDH and facility staff members reviewed July 28 quarantine unit videosurveillance footage and standard correctional officer shift duty responsibilities toapproximate the frequency and duration of interactions between the correctional officerand infectious IDPs during the work shift . AlthougThe correctional officer reported no other known close contact exposures to persons withCOVID-19 outside work and no travel outside Vermont during the 14 days preceding illnessonset. COVID-19 cumulative incidence in his county of residence and where thecorrectional facility is located was relatively low at the time of the investigation , suggesting that his most likely exposures occurred in thecorrectional facility through multiple brief encounters with IDPs who later received apositive SARS-CoV-2 test result.Among seven employees with exposures to the infectious IDPs that did meet the VDH closecontact definition, one person received a positive test result. Among thirteen employees with exposures to the infectious IDPs that did notmeet the VDH close contact definition during contact tracing, only the correctionalofficer received a positive SARS-CoV-2 test result.Data are limited to precisely define \u201cclose contact\u201d; however, 15 minutesof close exposure is used as an operational definition for contact tracinginvestigations in many settings. Additional factors to consider when defining closecontact include proximity, the duration of exposure, whether the infected person hassymptoms, whether the infected person was likely to generate respiratory aerosols, andenvironmental factors such as adequacy of ventilation and crowding. A primary purpose ofcontact tracing is to identify persons with higher risk exposures and therefore higherprobabilities of developing infection, which can guide decisions on quarantining andwork restrictions. Although the initial assessment did not suggest that the officer hadclose contact exposures, detailed review of video footage identified that the cumulativeduration of exposures exceeded 15 minutes. In correctional settings, frequent encountersof \u22646 feet between IDPs and facility staff members are necessary; public healthofficials should consider transmission-risk implications of cumulative exposure timewithin such settings."} +{"text": "With advancing age, the incidence rate of Alzheimer\u2019s disease and dementia gradually increases, and mortality from either Alzheimer\u2019s disease or dementia has increased in recent decades . RecentlPostmenopausal women experience a dramatic decrease in circulating estrogen level. Due to the cardio-protective effect of estrogen, premenopausal women are exposed to a lower risk of cardiovascular disease compared to postmenopausal women. Elastic conduit arteries including the aorta are more vulnerable to either internal or external stimulation than smaller muscular vasculatures because of their anatomical characteristics. Thus, central artery stiffness measures such as pulse wave analysis (augmentation index) and aortic pulse wave velocity are used as validated surrogate markers to predict future cardiovascular morbidity and mortality. Elastic central arteries in postmenopausal women older than 60 yr of age are in particular stiffer than pre- or postmenopausal women under 60 yr of age . In a reRegular physical activity including aerobic and resistance exercise is recommended for postmenopausal women to improve not only musculoskeletal and cardiovascular function, but also cognitive function. Three months of combined circuit exercise reduce arterial stiffness and other cardiovascular disease risks in hypertensive postmenopausal women. FurtherCompared to continuous exercise, high-intensity interval exercise can be more beneficial in enhancing cognitive function via not only decreased central artery stiffness but also facilitated neurotrophic factors production and increased neurotrophic factor bioavailability in postmenopausal women. The hypoxia state in high-intensity aerobic exercise increases VEGF production. In particular, intermittent hypoxia for high-intensity interval exercise facilitates the generation of BDNF, the most important neuroplasticity marker, in the cerebrovascular endothelium. Furthermore, lactate, a byproduct of high-intensity exercise, can be used to facilitate BDNF and VEGF generation in peripheral tissues and is an additional energy resource for brain neuron activity. Both the BDNF and VEGF produced in peripheral tissues can directly facilitate neuroplasticity in the central nervous system after passing through the blood brain barrier.Future studies are warranted to comprehensively investigate the effects of high-intensity interval training on central artery stiffness, neuroplasticity, and cognitive function, and elucidate the associated physiological mechanisms in postmenopausal women, the population most vulnerable to cardiovascular events and cognitive impairment."} +{"text": "TERT promoter mutations are the most common somatic alteration identified in UBC. In this study, we analyzed different histological tissues from whole-organ mapping bladder cancer specimens to reveal TERT mutational status, as well as to discern how tumors develop. Methods: Up to 23 tissues from nine whole-organ mapping bladder tumor specimens, were tested for TERT promoter mutations including tumor associated normal urothelium, non-invasive urothelial lesions , carcinoma in situ (CIS) and different areas of muscle invasive bladder cancers (MIBC). The mutational DNA hotspot region within the TERT promoter was analyzed by SNaPshot analysis including three hot spot regions . Telomere length was measured by the Relative Human Telomere Length Quantification qPCR Assay Kit. Results: TERT promoter mutations were identified in tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC. Analysis of separate regions of the MIBC showed 100% concordance of TERT promoter mutations within a respective whole-organ bladder specimen. Polyclonal events were observed in five out of nine whole-organ mapping bladder cancers housing tumor associated normal urothelium, non-invasive urothelial lesions and CIS where different TERT promoter mutations were found compared to MIBC. The remaining four whole-organ mapping bladders were monoclonal for TERT mutations. No significant differences of telomere length were observed. Conclusions: Examining multiple whole-organ mapping bladders we conclude that TERT promoter mutations may be an early step in bladder cancer carcinogenesis as supported by TERT mutations detected in tumor associated normal urothelium as well as non-invasive urothelial lesions. Since mutated TERT promoter regions within non-invasive urothelial lesions are not sufficient alone for the establishment of cancerous growth, this points to the contribution of other gene mutations as a requirement for tumor development.Background: Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate. TERT) promoter mutations occur in 60\u201380% of all urothelial bladder cancers (UBC) independent of tumor stage and grading thus, represent the most frequent alteration in this tumor entity [TERT [TERT promoter mutations in UBC are found in 99% of tissue samples at position \u2212124 and \u2212146 base pairs upstream from the ATG transcriptional start site position and are responsible for aberrant telomerase activity [TERT mutational incidence rates in UBC several studies proposed a possible role implementing these alterations in urinary testing and as a follow-up diagnostic tool [Telomerase reverse transcriptase and CIS as well as the tumor mass [Archival material of the Institute of Pathology, Erlangen was retrospectively evaluated and available bladder cancer specimens diagnosed as MIBC were screened for mor mass . All themor mass . A schemmor mass . PatholoTERT promoter mutated tumor associated normal urothelium as well as non-invasive urothelial lesions from the whole-organ mapping bladder specimens were immunohistochemically evaluated for CK20, CD44, TP53 and MIB1 staining. CK20 and CD44 were chosen as differentiation markers, which show distinct staining patterns among normal urothelium as well as for non-invasive urothelial lesions thus, are used for routine diagnostic evaluation. P53 evaluation as well as MIB1 staining is also used for evaluation of distinguishing normal urothelium as well as for non-invasive urothelial lesions [TERT promoter mutations and used for immunohistochemistry as preformed with a Ventana BenchMark Ultra and a Dako Link 48 autostainer accreditated by the German Accreditation Office (DAKKs) according to DIN EN ISO/IEC 17020. Detail information of the used antibodies are displayed in All lesions . Whole t\u00ae 16 System, Promega, Mannheim, Germany) according to the manufacturer\u2019s instructions. The tissue component from each tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC was manually microdissected from marked areas on each consecutive tissue slide derived from its corresponding tissue block in order to achieve at least 80% purity. DNA isolation was performed using the DNA preparation kit . The usage of labelled dideoxynucleotides enables the identification of the nucleotide base at the site of interest . After a denaturation step at 90 \u00b0C for five minutes the detection was performed with capillary electrophoresis using an ABI 3500 Genetic analyzer .The digestion of the remaining primers and free deoxynucleotides after PCR amplification was performed with alkaline phosphatase and an exonuclease . . The mulinterest . Two difTelomere length was analyzed by Relative Human Telomere Length Quantification qPCR Assay Kit according to the Manufacturer\u2019s instruction. Telomere length is recognized and amplified by comparing samples to reference genomic DNA containing a 100-base pair (bp) telomere sequence located on human chromosome 17. The total as well as the average telomere length was then calculated. p-Values < 0.05 represented statistical significance.Descriptive statistical analysis was used to characterize the nominal variables in terms of frequency and percentages. A non-parametric Wilcoxon rank-sum test was used for comparison between continuous variables. All analysis was performed by GraphPad Prism 7.2 and JMP SAS 13.4 (SAS). TERT promoter mutated regions were identified. TERT promoter mutations identified among the different tissue regions within the whole-organ mapping bladder tumor specimens. Results showed that the percentages of mutated samples generally increased in a step-wise manner from 17.24% among tumor associated normal urothelium, 33.3% in hyperplasia, 14.3% in dysplasia to 46.1% of CIS specimens and 100% of all MIBC regions. Representative images of mutated tumor associated normal urothelium as well as CIS are shown in From 149 available tissue samples, 75 (50.33%) TERT promoter mutations within the whole-organ mapping bladder cancer specimens. As shown in TERT promoter mutation compared to the MIBC. Interestingly, in Bladder #9 the CIS housed a TERT \u2212124 mutation, which was also different to the MIBC (\u2212146). Detailed information of the tissue histologies as well as the mutational status for the TERT promoter for the polyclonal events are displayed in TERT promoter mutation compared to the MIBC.One objective of this study was to test for clonality events of TERT promoter mutations and total telomere length, some TERT mutated and wild type tissues as well as TERT mutated MIBC samples were analyzed. None of the determined telomere lengths were significantly different between mutated and wild type tissue samples (data not shown). To determine if there was an association between TERT promoter gene mutations throughout nine whole-organ mapping bladder cancer specimens thus, representing a full spectrum of tumorigenesis. Our results demonstrate that adjacent and non-adjacent tumor associated urothelium, non-invasive urothelium lesions as well as CIS surrounding the tumors are TERT mutated. Additionally, detection of mono- as well as polyclonal mutated specimens with identification of one or several TERT promoter mutations strengthen both clonality hypotheses. In this study, we evaluated the role of TERT promoter mutations have been identified in the vast majority of bladder tumors independent of pathological characteristics. The hot spot mutations detected in UBC and identified among this cohort locate at \u221257, \u2212124 and \u2212146 base pairs upstream from the ATG site of the TERT gene and generate novel transcription factor binding sites. Similar to the first descriptions of these mutations by Allory et al. the hot spot mutation at the \u2212124 nucleotide position was the most frequent substitution identified in our whole-organ mapping bladder cancer cohort [TERT promoter mutations in systematically collected normal urotheliums locating adjacent to non-invasive bladder tumor tissue. Additionally, even when the tumor was not mutated the associated normal urothelium showed a TERT promoter mutation. Moreover, if TERT mutations were initially observed, positive associations with bladder recurrence after therapy were shown indicating a potential use of TERT promoter gene mutations as a biomarker [TERT promoter mutations in tumor associated normal urothelium but also in non-invasive urothelial lesions adjacent to or non-adjacent to muscle invasive tumors. Considering TERT mutations in bladder tumors, it is interesting to note that we found in contrast to non-invasive tumors described above, all MIBC tissues presented with a specific mutation within a whole-organ mapping bladder specimen. Additionally, this observation also strengthens the fact that TERT promoter mutations seem to be an early and crucial event during bladder tumorigenesis and importantly are independent of pathological, histological and clinical characteristics [Evolution of especially epithelial cancers can be demonstrated by identifying distinct histologies including dysplasia or CIS sharing both mutational backgrounds with the tumor ,10. Due iomarker . In lineeristics ,15. TERT promoter gene were identified. Interestingly, all MIBC samples within its respective bladder specimen showed the same hot spot mutation. However, in contrast to MIBC polyclonal TERT mutations within the same bladder specimens were identified in tumor associated normal urothelium and non-invasive urothelial lesions. This finding supports the widely accepted idea that carcinogens in the urine could damage the urothelial layer and therefore mutational backgrounds could differ. On the other hand, four out of nine analyzed whole-organ mapping bladder tumors were monoclonal for TERT promoter mutations pointing to the fact of a possible seeding or migration of the cells [TERT promoter mutations and how they affect follow-up diagnostic tools has to be investigated in the future [Clonality is widely discussed regarding bladder tumorigenesis with poly- as well as monoclonal observations. In detail, whether the process of tumor formation is due to monoclonal events within the urothelium spreading through the bladder wall or by polyclonal, events resulting in several independent tumor clones is still under debate. Findings for both theories exist and with recent advances in molecular subtyping multifocal tumors and tumor heterogeneity will even be more important in terms of planning neoadjuvant treatment regimens for patients . We demohe cells . To whice future .TERT gene is to maintain and protect the ends of human chromosomes however, as we age they become shorter [TERT promoter mutation, functional investigations are still ongoing. In the study by Borah et al. [TERT mutated as well as wild type urothelial cell lines and observed an increased mRNA level of TERT transcripts, however neither the protein level nor the telomere length showed significant differences thus supporting non-translated mRNA. Additionally, Allory et al. [TERT between mutation carriers and wild types. These observations described above are comparable with our findings where there was no differences in telomere lengths. One further explanation could be that activation of the telomerase via mutations of the TERT promoter could also lead to other functions independent of telomere lengthening. These independent functions could affect many biological processes, including cell survival and apoptosis, DNA damage repair, mitochondrial function and stem cell activity. In addition, evidence exists that activating telomerase could also enable cells to acquire tumor-initiating mutations [TERT promoter mutations ultimately affect the urothelial tumor cells and additionally, implementing TERT promoter mutations as a diagnostic tool needs further investigation. Moreover, it was recently shown that cell lines from solid tumors with somatic TERT promoter mutations showed a significantly shorter telomere length compared to cell lines with a wild type TERT promoter [TERT promoter mutations compared to tumor associated urothelium and non-invasive urothelium as well as CIS possibly indicating a complex interplay between TERT mutational activation, telomere length variation and other cellular processes. The normal function of telomerase encoded by the shorter . With aph et al. the authy et al. observedutations . How TERpromoter . AlthougTERT promoter gene have been analyzed and thereby other TERT promoter alterations could have been missed. Limitations of our study is the retrospective nature as well as the limited, partly heterogenous sampling of the bladder cancer specimens. In addition, only hot spot mutations of the TERT promoter gene mutations occur in tumor associated urothelium, non-invasive urothelial lesions and CIS thus, highlighting a crucial and important role of the TERT gene in the development of bladder tumors. Moreover, the evaluation of distinct promoter mutant positions strengthens both theories of a mono- as well as a polyclonal development of bladder tumors. To our knowledge, we demonstrate for the first time in tissues from whole-organ mapping bladder tumor specimens containing MIBC,"} +{"text": "Contrast induced neurotoxicity (CIN) is a rare complication of cardiac catheterization and re-exposure to contrast medium carries the risk of recurrent CIN. We report a case of successful contrast re-challenge in a 60-year-old female patient who developed CIN after her first procedure of coronary angiography (CAG) which resulted in symptoms of disorientation, amnesia and cortical blindness. A non-contrast enhanced CT performed four hours after the CAG was normal, however, her MRI brain scan showed scattered tiny hyper intensities in posterior occipito-temporal and parietal regions suggesting CIN. Patient\u2019s symptoms resolved completely after 72 hours. Two months later, because of persistent exertional angina, patient was successfully re-challenged with lesser amount of contrast medium with administration of hydrocortisone prior to procedure, and PCI to LAD was completed without recurrence of CIN. Contrast induced neurotoxicity in form of fits, confusion, cortical blindness and encephalopathy is very rare complication after angiography of coronary arteries and bypass grafts.A-60-year old woman with history of hypertension, dyslipidemia and paroxysmal AF admitted for acute coronary syndrome and underwent CAG. Her CAG was performed through right radial access with 5F Judkins diagnostic catheters. There was significant tortuosity in her brachiocephalic trunk which resulted in difficult engagement of both left and right coronary systems, hence larger volume (300 ml) of contrast media (Iohexol) was administered during her coronary angiography. Patient did not have a previous history of any procedure with contrast agent exposure. Her CAG showed significant 70% & 90% tubular lesions in proximal and mid segments (respectively) of left anterior descending coronary artery (LAD) requiring intervention. However, patient started to become confused, aggressive and later developed amnesia and cortical blindness. Her neurological examination did not reveal any cranial, sensory or motor nerves abnormality. A non-contrast computerized tomography (CT) scan performed four hours after the start of symptoms showed no acute pathological findings. Her brain magnetic resonance imaging (MRI) demonstrated tiny hyperdensities in the posterior occipito-temporal and parietal regions suggesting contrast induced neurotoxicity . PatientContrast induced neurotoxicity (CIN) following cardiac catheterization is a rare but devastating complication. Its clinical presentation varies from mild symptoms of headache and vomiting to more serious presentation with seizures, hemiparesis, encephalopathy and cortical blindness.The exact mechanism of contrast induced CIN remains unknown. Disruption of blood brain barrier and direct contrast neuronal toxicity mainly in the occipital region of brain haven been postulated as a possible mechanism in many reports.8Contrast media re-challenge has not been widely reported in literature. We identified only three cases where re-challenge of contrast media did not result in recurrence of cortical blindness.9Herein, we propose that re-challenge with minimal amount of contrast medium after pre-treatment with intravenous corticosteroids can be considered in patients with previous history CIN if: i) a second procedure is mandated as was the case in our patient to have persistent angina despite optimal anti-anginal medical therapy ii) CIN resolves completely after the first contrast exposure and iii) larger volume of contrast is associated with CIN.CIN following coronary angiography is an extremely rare but usually reversible complication. Re-exposure of contrast media to patients with history of CIN carries the risk of recurrent CIN, hence it is not well documented. We successfully re-challenged contrast medium in our patient and proposed that contrast rechallenge may be considered in some patients if certain conditions are fulfilled However, it is difficult to conclude whether or not CIN will recur with contrast re-challenge but we are reassured with the fact that CIN is usually transient and resolves completely.MAS & MWA did manuscript writing. MMS edited the manuscriptSKN reviewed the manuscript. HAB gave final approval. MAS responsible and accountable for the accuracy or integrity of this study."} +{"text": "The purpose of this study was to explore demographic differences in health personality. Data consisted of 3,907 participants, 65 years and older. Multivariate analysis of variance with post-hoc testing revealed that women had higher health neuroticism scores than men, but men had higher health extraversion scores than women. Those married reported higher health agreeableness than those not married and young-old participants had higher health extraversion and health openness compared to other age groups. Regional differences included Midwest participants reporting higher health openness but lower health conscientiousness scores when compared to participants from other regions. There were also significant interactions. For example, individuals from geographic areas with predominately White Midwest residents were significantly higher on health neuroticism when compared to Northwest, South, and West regions. The results are helpful for healthcare providers who can tailor intervention approaches to specific populations."} +{"text": "Gs), net assimilation rate (A), and LOX and methanol emissions to varying MeJA concentrations (0.2\u201350 mM) in cucumber (Cucumis sativus) leaves with partly open stomata and in leaves with reduced Gs due to drought and darkness. Exposure to MeJA led to initial opening of stomata due to an osmotic shock, followed by MeJA concentration-dependent reduction in Gs, whereas A initially decreased, followed by recovery for lower MeJA concentrations and time-dependent decline for higher MeJA concentrations. Methanol and LOX emissions were elicited in a MeJA concentration-dependent manner, whereas the peak methanol emissions (15\u201320 min after MeJA application) preceded LOX emissions (20\u201360 min after application). Furthermore, peak methanol emissions occurred earlier in treatments with higher MeJA concentration, while the opposite was observed for LOX emissions. This difference reflected the circumstance where the rise of methanol release partly coincided with MeJA-dependent stomatal opening, while stronger stomatal closure at higher MeJA concentrations progressively delayed peak LOX emissions. We further observed that drought-dependent reduction in Gs ameliorated MeJA effects on foliage physiological characteristics, underscoring that MeJA primarily penetrates through the stomata. However, despite reduced Gs, dark pretreatment amplified stress-volatile release upon MeJA treatment, suggesting that increased leaf oxidative status due to sudden illumination can potentiate the MeJA response. Taken together, these results collectively demonstrate that the MeJA dose response of volatile emission is controlled by stomata that alter MeJA uptake and volatile release kinetics and by leaf oxidative status in a complex manner. Treatment by volatile plant hormone methyl jasmonate (MeJA) leads to release of methanol and volatiles of lipoxygenase pathway (LOX volatiles) in a dose-dependent manner, but how the dose dependence is affected by stomatal openness is poorly known. We studied the rapid (0\u201360 min after treatment) response of stomatal conductance ( Thexenals . The emi\u03a6M) and the total volatile emission bursts after (IT) during a period of 60 min after MeJA treatment were calculated as our previous report [To study the quantitative emission characteristics of LOX compounds and methanol, the emission maxima and all statistical effects were considered significant at p < 0.05.All experiments were replicated at least three times with different plants and all data shown are averages \u00b1 SE. Effects of MeJA dose on foliage photosynthetic and emission traits were studied by linear or non-linear regressions depending on the shape of the response. Effects of abiotic factors combined with MeJA treatment on Gs that controls MeJA entry into the leaf. This implies that environmental stresses that reduce Gs are expected to reduce the plant sensitivity to airborne MeJA as was confirmed in our study for drought stress. Furthermore, changes in Gs alter the dynamics of water-soluble stress-volatile release from the plants, and this can have significant implications for stress propagation and signaling. A model of the relationships between rapid constitutive emission of volatiles and the role of stomata and cuticle by MeJA treatment interacting with light condition was put forwarded (Our experiments demonstrate that the response to MeJA strongly depends on orwarded . On the"} +{"text": "Sadness is often thought of as unpleasant and dysfunctional. Yet, evolutionary-functionalist approaches and discrete emotional aging frameworks suggest that sadness is an emotion that helps us deal with loss and thus may become particularly salient and adaptive in late life. This talk presents findings from a multi-study, multi-method research program using age-diverse samples and experimental and longitudinal study designs. Findings show (1) intact or elevated levels of sadness responding in late life . Moreover, (2) higher levels of sadness responding are linked to adaptive outcomes in late life with some effects generalizing across age groups . Implications for future research are discussed."} +{"text": "Leishmania genus protozoan parasites. Inoculation by infected Phlebotamine sandflies results in asymptomatic infection or a diverse range of clinical manifestations. Leishmaniasis can present with tegumentary lesions or visceral disease with parasite dissemination and high mortality [Leishmania species cause this spectrum of human disease [Leishmaniasis is a vector-born disease, caused by ortality . The spe disease . HoweverLeishmania parasites encounter diverse environments, genetic adaptations may result in positive or negative trade-offs in other life-cycle stages. In addition, as humans are not the primary vertebrate reservoir, protective or pathologic immune responses may alter disease outcome but not parasite fitness. Thus, understanding how Leishmania genetics influences outcomes of human leishmaniasis requires consideration of selective pressures across life-cycle stages (Leishmania parasites to navigate its evolutionary landscape.Evolutionary biology can be applied to understand the genetic differences among parasites with different disease manifestations. Because e stages . For insLeishmania evolution provide challenges to investigating host range and parasite virulence, they also present opportunities to understand human susceptibility. The range of leishmaniasis is limited by interactions between vectors and animal reservoirs. As their habitat is altered due to climate change and social conflict, ecologic studies informed by evolutionary dynamics could predict changes in leishmaniasis distribution. Human pathogenesis varies with the infecting Leishmania species; however, infection with the same species can result in an appropriate immune response with resolution, impaired response with parasite proliferation, or excessive inflammation with immunopathology [Leishmania parasites encode mechanisms to influence host immunity, understanding molecular pathogenesis requires studies using a diverse collection of parasites. Synthesis of these approaches is needed to understand variation in leishmaniasis outcomes and improve human health.While the complex pressures shaping athology . To elucPlasmodium parasites by treating mosquito nets with anti-malarial compounds [This evolutionary complexity may prove advantageous in developing novel treatments. For example, targeting parasites in vectors and reservoirs can decrease transmission and minimize human toxicity. This strategy has shown promise against ompounds . Furtherompounds uniquely"} +{"text": "Multisite medical data sharing is critical in modern clinical practice and medical research. The challenge is to conduct data sharing that preserves individual privacy and data utility. The shortcomings of traditional privacy-enhancing technologies mean that institutions rely upon bespoke data sharing contracts. The lengthy process and administration induced by these contracts increases the inefficiency of data sharing and may disincentivize important clinical treatment and medical research. This paper provides a synthesis between 2 novel advanced privacy-enhancing technologies\u2014homomorphic encryption and secure multiparty computation (defined together as multiparty homomorphic encryption). These privacy-enhancing technologies provide a mathematical guarantee of privacy, with multiparty homomorphic encryption providing a performance advantage over separately using homomorphic encryption or secure multiparty computation. We argue multiparty homomorphic encryption fulfills legal requirements for medical data sharing under the European Union\u2019s General Data Protection Regulation which has set a global benchmark for data protection. Specifically, the data processed and shared using multiparty homomorphic encryption can be considered anonymized data. We explain how multiparty homomorphic encryption can reduce the reliance upon customized contractual measures between institutions. The proposed approach can accelerate the pace of medical research while offering additional incentives for health care and research institutes to employ common data interoperability standards. The current biomedical research paradigm has been characterized by a shift from intrainstitutional research toward multiple collaborating institutions operating at an interinstitutional, national or international level for multisite research projects; however, despite the apparent breakdown of research barriers, there remain differences between ethical and legal requirements at all jurisdictional levels . There aFor example, the International Cancer Genome Consortium endeavors to amass cancer genomes paired with noncancerous sequences in a cloud environment, known as pancancer analysis of whole genomes. The International Cancer Genome Consortium\u2019s data access compliance office was unable to establish an international cloud under the Pancancer Analysis of Whole Genomes Project because of conflicts between United States and European Union data privacy laws . These cIn this paper, we describe how traditional data-sharing approaches relying upon conventional privacy-enhancing technologies are limited by various regulations governing medical use and data sharing. We describe two novel privacy-enhancing technologies, homomorphic encryption and secure multiparty computation, that extend the capacity of researchers to conduct privacy-preserving multisite research. We then turn to analyze the effects of regulation on using these novel privacy-enhancing technologies for medical and research data sharing. In particular, we argue these privacy-enhancing technologies guarantee anonymity as defined under the EU GDPR and are, therefore, key enablers for medical data sharing. We focus on the GDPR, as it currently represents a global benchmark in data protection regulations. We argue that using these technologies can reduce the reliance upon customized data-sharing contracts. The use of standardized agreements for multiparty processing of data in concert with privacy-enhancing technologies can reduce the bottleneck on research. Finally, we turn to address how these novel privacy-enhancing technologies can be integrated within existing regulatory frameworks to encourage increased data sharing while preserving data privacy.Before examining novel privacy-enhancing technologies, it is necessary to examine the main models for exchanging medical data for research purposes and the limitations of conventional privacy protection mechanisms that are currently used to reduce the risk of reidentification. We synthesize the data-sharing models into three categories and analyze their main technological issues .The centralized model requires medical sites that are willing to share data with each other to pool their individual-level patient data into a single repository. The data repository is usually hosted by one medical site or by an external third party , playing the trusted dealer role. The main advantage of this model is that the trusted dealer enables authorized investigators to access all the patient-level information needed for data cleaning and for conducting statistical analysis. Moreover, such a data-sharing model minimizes infrastructure costs at medical sites, as data storage and computation are outsourced. However, from a data privacy perspective the centralized model is often difficult to realize, especially when medical and genetic data should be exchanged across different jurisdictions. The central site hosting the data repository represents a single point of failure in the data-sharing process. All participating sites must trust such single entity for protecting their patient-level data .k-anonymity privacy model . Although homomorphic encryption and secure multiparty computation offer privacy guarantees, there is still an orthogonal risk of reidentifying individuals from aggregate-level results that are eventually decrypted and can be exploited by inference attacks [Nevertheless, any standards will need to be continually updated to respond to new technological changes. For example, one of the most significant drawbacks of fully homomorphic encryption is the complexity of computation. This computational complexity makes it hard to predict running times, particularly for low-power devices such as wearables and smartphones. For the foreseeable future, this may limit the devices upon which fully homomorphic encryption can be used . Therefo attacks ,21,27,74A final consideration relates to ethical issues that exist beyond whether homomorphic encryption, multiparty computation, and multiparty homomorphic encryption involve processing anonymized or personal data. First, the act of encrypting personal data constitutes further processing of those data under data protection law. Therefore, health care and research institutions must seek informed consent from patients or research participants . InstituMedical data sharing is essential for modern clinical practice and medical research. However, traditional privacy-preserving technologies based on data perturbation, along with centralized and decentralized data-sharing models, carry inherent privacy risks and may have high impact on data utility. These shortcomings mean that research and health care institutions combine these traditional privacy-preserving technologies with contractual mechanisms to govern data sharing and comply with data protection laws. These contractual mechanisms are context-dependent and require trusted environments between research and health care institutions. Although federated learning models can help alleviate these risks as only aggregate-level data are shared across institutions, there are still orthogonal risks to privacy from indirect reidentification of patients from partial results . Further"} +{"text": "Approximately 400 million people throughout the world suffer from a rare disease. Although advances in whole exome and whole genome sequencing have greatly facilitated rare disease diagnosis, overall diagnostic rates remain below 50%. Furthermore, in cases where accurate diagnosis is achieved the process requires an average of 4.8\u00a0years. Reducing the time required for disease diagnosis is among the most critical needs of patients impacted by a rare disease. In this perspective we describe current challenges associated with rare disease diagnosis and discuss several cutting-edge functional genomic screening technologies that have the potential to rapidly accelerate the process of distinguishing pathogenic variants that lead to disease. Approximately 400 million individuals worldwide are directly affected by a rare disease and whole genome sequencing (WGS) in a clinical setting. While the application of these technologies has greatly facilitated the identification of disease-associated genetic variants, the rate of diagnosis for rare disease remains below 50% over the past several years now provide scalable mechanisms to assign functional properties to large catalogs of variants. These approaches can be used to rapidly distinguish clinically detected variants with an increased likelihood of pathogenicity and facilitate the prioritization of variants that warrant in-depth evaluation.One common experimental approach used to explore the functional consequences of a genetic variant has been the use of plasmid-based reporter assays. These assays can be engineered to harbor specific variant sequences within exons, introns, or even noncoding regulatory regions of a transgenic reporter gene. Individual reporter constructs can be introduced into cultured cells and transgene expression and/or function can be evaluated using relevant methods. In recent years several plasmid-based reporter approaches have been adapted to multiplexed formats that permit the characterization of thousands of genetic variants simultaneously using high-throughput sequencing-based readouts. These massively parallel genomic assays have been utilized to profile published catalogs of disease-associated genetic variants and distinguish variants with functional implications . Distinguishing the functional consequences of these variants may require assays that are capable of profiling cellular phenotypes. Advances in genome editing technology, specifically CRISPR/Cas9, have dramatically improved the ability to engineer cellular models with specific genetic alterations , inhibition (CRISPRi), or activation (CRISPRa) of protein-coding genes or the repression/activation of targeted genomic regions (CRISPRi/CRISPRa). Consequently, these screens do not perfectly model the impact of clinically detected variants. As CRISPR-based screening methods continue to advance it may become possible to functionally screen large numbers of specific variants through pooled format adaptations of precision editing technologies (Shen et al. The ability to rapidly assign experimentally determined functional properties to clinically detected genetic variants will have profound impacts on rare disease diagnosis. In addition to existing resources, clinical geneticists will have access to empirical data that will facilitate more informed decisions related to variant pathogenicity. This information will reduce the time required to analyze individual patient genomes, increase patient throughput, and ultimately translate to improved rates of diagnosis. Moreover, the barriers to generating this data are minimal as many high-throughput functional assays do not require modifications to existing laboratory infrastructure nor do they require patient specimens.The experimental strategies we discuss here are intended to complement, not replace, current standard practices in variant interpretation. Moreover, the functional assays we have described are mainly suited for Mendelian diseases. Experienced clinical geneticists will always be needed to critique experimental results and to investigate diseases with more complex genetic contributions. Rare disease diagnosis will remain a constant challenge, but bridging the gap between clinical and functional genomics could provide an accelerated path to diagnosis for many rare disease patients that are still searching for answers."} +{"text": "There is limited literature on formal caregivers\u2019 communication with persons living with dementia (PLWD) in home settings. Most research comes from studies of long-term care home settings or informal home care contexts. Yet, there are expected needs and rising demands for formal caregiver support within home care. The aim of this study was to understand better the lived experiences of personal support workers (PSWs) regarding their communication with PLWD in home settings. A hermeneutic phenomenological approach guided this research. Semi-structured interviews were conducted with 15 PSW participants. Three major themes were identified through thematic analysis: (1) challenged by dementia-related impairments; (2) valuing communication in care; and (3) home is a personal space. PSWs experienced difficulties in their communication with PLWD despite recognizing the importance of communication in providing optimal home care. This suggests that while PSWs possess good intentions, they do not possess the skills necessary to ensure effective interactions. Dementia-specific education and training are recommended to improve PSWs\u2019 communication skills and to enhance quality of care. Findings highlight further the uniqueness of the personal home space itself on PSWs experiences with communication. Aspects of the home care environment can enable, but also complicate, successful communication between PSWs and PLWD. Consequently, findings also have implications for family members of PLWD and home care employers regarding optimizing practice and improving care."} +{"text": "This review enhances the existing literature on relationships between problematic smartphone use (PSU), psychopathology, addictive personality, and online social engagement as regards young adults, giving attention to predictive determinants of addictive behavior in smartphone usage. My article cumulates previous research findings on the psychology of addictive smartphone behavior in terms of problematic use, social anxiety, and depressive stress by focusing on the relationship among mobile social media usage, smartphone addiction risk, mental health issues, and individual well-being. The inspected collected findings prove that depression and social anxiety constitute risk determinants for greater PSU and that particular categories of smartphone applications are positively related to well-being. State anxiety and motivations represent significant predictors of PSU. High PSU affects participation in social engagement. As limitations in the current review, my results point towards relevant avenues of research on social consequences of teenagers\u2019 smartphone problematic use. Future directions should clarify whether compulsive smartphone use adversely affects both mental and physical health in the long run. PSU hasPSU shapes subjective and psychological well-being, and may configure associated anxiety and depression psychopathology. Mental health and somatic symptoms are adversely impacted by PSU leading to impaired socio-emotional functioning and possibly causing psychological distress.Users\u2019 psychological features may not clarify every characteristic of PSU. High PSU affects participation in social engagement. Users\u2019 absence of social networks may hinder agreeable social communications and emotParental neglect is considerably related to teenagers\u2019 smartphone addiction. In the link between parental neglect and PSU, the former is not relevantly connected with the relational instability with peers, negatively shaping PSU. The relational instability with teachers has a fragmentary mediation impact between parental neglect and PSU . ParentsParenting style and attachment may mediate young adults\u2019 smartphone use, improving interpersonal adaptation and self-control, while articulating family well-being. Young adults\u2019 addictive personality may be shaped by parental mediation practices and self-regulation.Significant research has considered lately the psychology of addictive smartphone behavior in terms of problematic use, social anxiety, and depressive stress. My article extends previous work by focusing on the relationship among mobile social media usage, smartphone addiction risk, mental health issues, and individual well-being. Progressively relevant degrees of smartphone ownership and utilization give rise to the implicit risk for addictive behaviors and adverse health results, shaping subjective and psychological well-being. The conclusions drawn\u00a0from the above analyses are that depression and anxiety symptoms are associated with PSU severity, generating, among others, emotion dysregulation, psychological distress, poor sleep\u00a0quality,\u00a0and diminished academic performance. Personality traits, social-emotional distress, and duration of daily smartphone use constitute antecedents of PSU, impacting subjective and psychological well-being. As limitations in the current review, my results point towards relevant avenues of research on social\u00a0consequences of young adults\u2019 smartphone addiction. Future directions should clarify whether compulsive smartphone use adversely affects both mental and physical health in the long run.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation. Recent pathological studies reported some of the COVID-19 patients with lung fibrotic lung features. Clinically, the main consequence of SARS-CoV-2 infection is cytokine storm, however previous studies indicate that anti inflammation therapy have no effects on pulmonary fibrosis, thus other mechanisms need to be provided to address this issue. Early micro injuries to alveoli increase local vascular permeability which provokes edema accompanied by inflammatory cytokines which prompt cytoskeletal remodeling and alter cellular mechanical forces. If these mild injuries could not be repaired properly, then fibroblasts will be activated and subsequent excessive deposition of extracellular matrix will result in a mechanical stretched niche. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize and the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.Pulmonary fibrosis (PF), which constitutes a broad range of heterogeneous end stage interstitial lung diseases, is characterized by excessive deposition of extracellular matrix and destruction of the pulmonary parenchyma about 50\u201370\u00a0m2 Weibel , 20-time2 Weibel . In the 2 Weibel .Mechanical sensing and regulating of endothelial cells are involved in the process of lung disease (Fang et al. Taken together the mechanical stress exposed to the endothelial cells is translated to different signals for the initiation and progression of lung fibrosis.2+ to interact with specific intracellular target proteins (Donato et al. 2+ influx can be induced by mechanical stretch in human lung fibroblasts (Murata et al. 2+ mediated S1006A stimulation. Taken together, these data indicate that mechanical stress promotes fibrosis by both stimulating the proliferation and migration of fibroblasts.The migratory and proliferative fibroblasts organizing in distinct clusters is called fibroblastic foci and this depicts the typical phenotype of lung fibrosis featured by accumulation of exaggerated amounts of ECM that forms a stiff milieu where fiMacrophages are involved in the cross-talk between innate and adaptive immunity (Epelman et al. Mast cells, originate from CD34-expressing haematopoietic stem cells in the bone marrow, are best known for their roles in allergic and acute inflammatory diseases (Wernersson and Pejler \u2212/\u2212 AECIIs cannot regenerate new alveoli which resulted in sustained elevated mechanical tension that subsequently activates a TGF-\u03b2 signaling loop in stem-like AECIIs and promote fibrosis (Wu Histologically, PF develops from microscopic fibrotic areas at the very peripheral regions of lung and slowly progress inward (Plantier et al. rosis Wu . Clinicarosis Wu . The lunrosis Wu . This coAccumulating evidence suggests abnormal metabolism in PF (Rowan et al. 6A modifications of pri-miRNA-126 was involved in the process of pulmonary fibrosis (Han The term \u201cepigenetics\u201d describes heritable changes in a cellular phenotype without alterations in the DNA sequence (Berger et al. osis Han . What\u2019s osis Han which maosis Han . Indeed,osis Han . Thus, uIn this review, we highlight the importance of rigid fibrotic niche in orchestrating the mechanical response of alveolar cells in exacerbating lung fibrosis Fig.\u00a0. The alvFurthermore, mechanical stress exerts a more comprehensive impact via metabolic and epigenetic regulation, which should be a promising filed for treating PF since rapid advances have been made in developing drugs to adjust metabolic status and target the epigenetic landscape. Therefore, translating these mechanism insights into clinical utilization may enable novel approaches for alleviating lung fibrosis."} +{"text": "Because old age is associated with defects in circadian rhythm, loss of circadian regulation is thought to be pathogenic and contribute to mortality. We show instead that loss of specific circadian clock components Period (Per) and Timeless (Tim) in male Drosophila significantly extends lifespan. This lifespan extension is not mediated by canonical diet-restriction longevity pathways, but is due to altered cellular respiration via increased mitochondrial uncoupling. Lifespan extension of per mutants depends on mitochondrial uncoupling in the intestine. Moreover, up-regulated uncoupling protein UCP4C in intestinal stem cells and enteroblasts is sufficient to extend lifespan and preserve proliferative homeostasis in the gut with age. Consistent with inducing a metabolic state that prevents over-proliferation, mitochondrial uncoupling drugs also extend lifespan and inhibit intestinal stem cell overproliferation due to aging or even tumorigenesis. These results demonstrate that circadian-regulated intestinal mitochondrial uncoupling controls longevity in Drosophila and suggest a new potential anti-aging therapeutic target."} +{"text": "Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are responsible for the majority of nosocomial infections . Another study achieved successful phytomedited synthesis of green TiO2NPs that proved to be effective for treating biofilm-based bacterial and fungal infections .Seven original research articles spanning diverse disciplines describe the development of NATs for clinically-relevant MDR pathogens. One study describes the one-pot synthesis of Ag-ZnO nanoparticles at low temperatures and demonstrated remarkable antimicrobial activity of these nanoparticles against methicillin-resistant Enterobacterales (CPE). The authors showed how antimicrobial combinations synergized against most CPE expressing resistance genes. These antimicrobial combinations may facilitate the successful treatment of patients infected with CPE . Another original research article identified two potent combinations of antibiotics for clinical MRSA infection, both in vitro and in vivo . A separate study found that the compound 2,4-Di-Tert-Butylphenol isolated from an endophytic fungus substantially reduced the secretion of virulence factors and biofilm and its associated factors controlled by quorum sensing in a dose-dependent manner in Pseudomonas aeruginosa .Another research article assessed the therapeutic efficacy of antimicrobial combinations on carbapenemase-producing Streptococcus pneumoniae infections . New putative antimicrobial candidates were reported by Okella et al. They designed an antimicrobial peptide and performed target identification based on a putative antimicrobial peptide motif derived from fish. From all the peptide motifs generated in this work, the authors identified Pleurocidin (secreted by flatfish) as having strong antimicrobial potential.Furthermore, a study tested the anti-virulence activity of potential uridine diphosphate glucose pyrophosphorylase (UDPG:PP) inhibitors and showed that these inhibitors are a potential drug candidates against Le\u00f3n-Buitimea et al.). Another review explored the possibility of designing antimicrobial nanoparticle-based devices to exploit the potential of antimicrobial nanoparticles to combat MDR pathogens . Finally, a third review describes the mechanisms associated with drug resistance in pyogenic streptococci and discusses the advantages and limitations of innovative therapeutic strategies such as bacteriocins, bacteriophage, phage lysins, and metal nanoparticles .Three review articles included in this special issue address the use of NATs to face MDR bacteria. A mini-review discusses combination treatments as a pathway to develop antimicrobial therapeutics with broad-spectrum antibacterial action, bactericidal instead of bacteriostatic activity, and better efficacy against MDR bacteria (In summary, this group of articles contributes to the search for new therapeutic strategies to combat antibacterial resistance. MDR and XDR infections are growing in incidence; the main challenges facing society are now to design, develop, and evaluate new therapeutic strategies that can spearhead the development of alternative therapies against clinically-relevant MDR pathogens.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Extracellular vesicles (EVs) are lipid bilayer-enclosed microparticles that have prominent roles in the intercellular crosstalk. EVs are secreted after fusion of endosomes with the plasma membrane (exosomes) or shed from the plasma membrane (microvesicles). These microparticles modulate bone marrow microenvironment and alter differentiation and expansion of normal hematopoietic cells. EVs originated from mesenchymal stromal cells have been shown to enhance expansion of myeloid-biased hematopoietic progenitor cells. In addition, megakaryocytic microparticles stimulate differentiation of hematopoietic stem and progenitor cells into mature megakaryocytes. The ability of EVs in induction of maturation and expansion of certain hematopoietic cells has implications in transfusion medicine and in targeted therapeutic modalities. Important prerequisites for these interventions are identification the specific targets of EVs, transferred biomolecules and molecular mechanisms underlying the fate decision in the target cells. EVs are also involved in the pathogenesis and progression of hematological malignancies including acute leukemia and multiples myeloma. In the current review, we provide a summary of studies which evaluated the significance of EVs in normal hematopoiesis and hematological malignancies. Extracellular vesicle, Hematopoiesis, Hematological malignancy Microvesicles (MV) and exosomes include two important kinds of EVs . While M2Normal hematopoiesis is influenced by biomolecules that exist in EVs. For instance, EVs originated from mesenchymal stromal cells have been shown to enhance expansion of myeloid-biased hematopoietic progenitor cells. This speculation is based on an experiment in murine stromal cells where EVs derived from these cells stimulated loss of quiescence in hematopoietic stem and progenitor cells (HSPCs) and enhanced expansion of myeloid progenitors. Such effects were exerted through the MyD88 adapter protein. Notably, inhibition of TLR4 could suppress this process to some extent. Canonical NF-\u03baB pathway and subsequent induction of Hif-1\u03b1 and CCL2 were also involved in this process . Megakar3EVs also mediate different roles in hematological malignancies.3.1Both primary acute myelocytic leukemia (AML) and AML cell lines have been shown to produce exosomes that are transferred to bystander cells. These EVs contain numerous coding and noncoding RNAs which are involved in the pathobiology of AML. EVs entrance into bone marrow stromal cells results in the modulation of their potential in growth factors production. The signals transmitted by these EVs change the proliferative, angiogenic, and migratory features of cocultured stromal and hematopoietic progenitor cells . EVs als3.2Exosomes originated from patients with chronic myelogenous leukemia (CML) patients are enriched in amphiregulin (AREG), therefor inducing EGFR signaling in stromal cells. Activation of this signaling pathway leads to over-expression of SNAIL, MMP9 and IL-8. Prior exposure of stromal cells with CML cells exosomes has enhanced expression of annexin A2 which increases the adhesion of leukemic cells to the stromal monolayer, facilitating the growth and invasion of leukemic cells . CML-der3.3Microvesicles released from MSCs from patients with myelodysplastic syndrome (MDS) have been shown to alter CD34 + cells characteristics .Multiple myeloma (MM) MSCs have also been shown to produce EVs that are conveyed to MM cells, thus changing tumor growth. Exosomal levels of miRNA such as miR-15a were different between MM and normal MSCs. Besides, EVs originated from MM bone marrow MSCs had greater amounts of oncogenes, cytokines, and adhesion molecules. While these EVs enhanced MM tumor growth, normal bone marrow MSC-derived EVs suppressed the growth of MM cells . MM pati4The presence of EVs in the body fluids including saliva, urine, peripheral blood and other body fluids indicates the potential of these vesicles in diagnostic and prognostic procedures . Notably5EVs have been shown to mediate critical functions during normal hematopoiesis and in the course of initiation and progression of hematological malignancies. The cell-cell communication mediated by EVs has important effects in bone marrow milieu and regulation of innate immune responses . The abiFinally, EVs which are released into bone marrow microenvironment might affect response of malignant cells to therapeutic modalities including tyrosine kinase inhibitors. Therefore, EVs components not only predict patients' outcome and their response to therapy, but also they represent potential manipulable resources for conferring drug resistance. Alteration in exosomal level of certain proteins might also reveal responses to chemotherapy. Moreover, the exosomal content may reflect the existence of residual disease in patients thought to be in complete remission . MalignaTaken together, EVs contain several protein and RNA molecules that could alter lineage differentiation, expansion and function of bone marrow cells in both physiological and pathologic conditions. The ability of these microparticles in specific targeting of the recipient cells potentiates them as vehicles for combating drug resistance in hematological malignancies. Moreover, malignant cells-derived EVs are potential diagnostic and prognostic markers in this kind of malignancy.All authors listed have significantly contributed to the development and the writing of this article.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Data will be made available on request.The authors declare no conflict of interest.No additional information is available for this paper."} +{"text": "A 48-year-old-female presented to the emergency department with dislodgement of her percutaneous endoscopic gastrostomy (PEG) tube, necessitating bedside replacement. Replacement was done without difficulty and gastrografin radiography was obtained to confirm positioning. Radiography revealed contrast filling the colon at the splenic flexure and proximal descending colon suggestive of colocutaneous fistula formation.The patient required hospitalization with surgical consultation, initiation of parenteral nutrition, and conservative management of the fistula with surgical replacement of the PEG tube. Although rare, it is paramount for the emergency physician to be aware of this complication when undertaking bedside replacement of PEG tubes. A 48-year-old female with past medical history of failure to thrive requiring percutaneous endoscopic gastrostomy (PEG) tube placement presented to the emergency department (ED) with PEG tube dislodgement. Her PEG tube was initially placed in 2009, with surgical replacements in 2012 and 2018. Examination revealed a soft, nontender, non-distended abdomen with an open gastrostomy tract. ED course included placement of a new gastrostomy tube into the existing tract and confirmatory gastrografin radiography .The confirmatory radiography revealed contrast filling the colon at the splenic flexure and proximal descending colon suggestive of colocutaneous fistula formation, without peritoneal extravasation. This required hospitalization with surgical consultation for removal of the misplaced PEG tube, initiation of parenteral nutrition, intravenous antibiotics, and surgical reinsertion of the PEG tube after conservative management of the colocutaneous fistula. Colocutaneous fistulas are a rare complication of PEG tube insertion with incidence rates of 0.5\u20133%.CPC-EM CapsuleWhat do we already know about this clinical entity?Colocutaneous fistulas are a rare complication of percutaneous endoscopic gastrostomy (PEG) tube insertion mediated by PEG tube penetration of interposed colon between the stomach and abdominal wall.What is the major impact of the image(s)?Contrast filling the splenic flexure and proximal descending colon suggests colocutaneous fistula formation, requiring prompt recognition and surgical consultation.How might this improve emergency medicine practice?Emergency physicians change a large number of PEG tubes; therefore, recognition and awareness of this rare complication is important to clinical practice."} +{"text": "Racial and ethnic disparities in age-related cognitive function and dementia risk in the US are well recognized. However, the psychosocial drivers of these disparities and underlying mechanisms are less well studied. This symposium will highlight novel research regarding our current understanding of racial/ethnic differences in brain and cognitive aging and the underlying mechanisms of the disparities. Frist, two papers will describe results regarding racial/ethnic differences in cognitive function and brain aging markers. Few studies have assessed racial/ethnic differences in cognitive function across age groups. Indira Turney will utilize data from a multigenerational study to explore how age impacts racial/ethnic differences in cognitive function. Underlying brain mechanisms of racial/ethnic differences in cognitive outcomes are also not well defined. Sara Godina will present a systematic review of racial/ethnic differences in structural markers of brain aging and neuropathology. Second, three papers will explore how various risk factors may explain the racial/ethnic disparities in cognitive outcomes. Melissa Lamar will demonstrate the differential associations of various blood pressure indicators with cognitive change among black older adults. B. Gwen Windham will present data from two studies that illustrate differential effects of common risk factors by race and region, highlighting inherent difficulties in race-place disparity research. Finally, Laura Zahodne will present results on how psychosocial factors, beyond socioeconomic status, contribute to racial/ethnic disparities in cognitive function. Jen Manly will lead a discussion on the implications of these results for the future of dementia prevention efforts for an increasingly diverse older US population."} +{"text": "Using two studies, we examined the late life prevalence and health consequences of discrete positive emotions posited to motivate rest and recovery or pursuit of novelty and stimulation (excitement). Study 1 assessed the salience of these discrete emotions in older adults relative to younger adults over a one-week period. Multilevel models showed that older (vs. younger) adults reported higher calmness and lower excitement. Study 2 examined the longitudinal health consequences of calmness and excitement in old age , as moderated by perceived control. Multilevel growth models showed that calmness, but not excitement, buffered against 10-year declines in psychological well-being and physical health for older adults with low perceived control. Results suggest that positive emotions with disparate motivational functions become more or less (excitement) salient and have diverging implications for health in old age."} +{"text": "Indices quantifying allostatic load (AL) and biological aging (BA) have received widespread use in epidemiological and health science literature. However, little attention has been paid to the conceptual and quantitative overlap between these indicators. By reviewing literature utilizing measures of AL and BA, we highlight differences with respect to biological markers employed and approach toward scale construction. Further, we outline opportunities where AL indices might be improved by adopting analytical features of BA measures. We demonstrate the utility of this approach using data from The MIDUS National Survey, constructing three indices of allostatic load: one standard approach modeled after Gruenewald et al, 2012, and two alternative formulations informed by BA procedures. The performance of AL indices are juxtaposed against two commonly employed indices of biological aging: Klemera-Doubal Method Biological Age and Homeostatic Dysregulation. All measures were significantly associated with chronological age. Alternative AL formulations were more strongly associated with biological aging measures than with the standard approach. MIDUS participants with increased allostatic load and older biological ages performed worse on tests of physical, cognitive, perceptual, and subjective functioning. Further, MIDUS participants with history of childhood-trauma and mental-health problems were measured as having increased AL and BA. Alternative AL formulations tended to have effect-sizes equivalent to or larger than those observed for BA measures. In conclusion, indices of allostatic load and biological age approximate similar processes when constructed with comparable biomarkers and rigor, in line with their conceptual overlap as proxies of cumulative wear and tear."} +{"text": "Background: Hypoglossal nerve stimulators (HNS) are an increasingly popular form of upper airway stimulation for obstructive sleep apnea (OSA) in adults who are unable to tolerate positive pressure treatment. However, HNS use is currently limited in the pediatric population. Case presentation: We present a case series detailing the anesthetic management of three pediatric trisomy 21 patients receiving HNS for refractory obstructive sleep apnea. The patients tolerated the procedure well and experienced no complications. The average obstructive apnea\u2013hypopnea index (AHI) change was 87.4% with the HNS. Conclusions: Proper anxiolysis, safe and controlled induction, multimodal analgesia, and minimization of post-operative respiratory compromise are all necessary to ensure anesthetic and surgical success. After a tailored anesthetic regimen, proper device placement and close follow-up, our patients had a marked improvement in obstructive symptoms. Patients with trisomy 21 are predisposed to an increased risk of obstructive sleep apnea (OSA) at baseline with as many as 70% meeting criteria ,4. PersiThe HNS is one of several implantable devices that aims to improve upper airway obstruction . The proA previous case series of twenty pediatric trisomy 21 syndrome patients receiving HNS has been published examining post-operative efficacy and safety . HoweverWe present the anesthetic management of the first three patients receiving an HNS at our institution. This manuscript adheres to the applicable EQUATOR guideline. Three patients, two female and one male, underwent hypoglossal nerve stimulator placement from 2017\u20132019 at Egleston Children\u2019s Hospital of Children\u2019s Healthcare of Atlanta as part of trial NCT02344108, \u201cA Pilot Study to Evaluate the HNS in Adolescents with Down Syndrome and OSA.\u201d Currently, HNS use in pediatric populations is still investigational under the Federal Drug Administration. All legal guardians for the subjects gave their informed consent for inclusion prior to participation in this case series.Baseline demographic characteristics are presented in All patients were diagnosed with severe refractory OSA despite previous surgery and non-invasive positive pressure ventilation (NIPPV). The previous surgeries included tonsillectomy and adenoidectomy (two patients) as well as lingual tonsillectomy with turbinate reduction and adenoidectomy (one patient). Despite surgical intervention, all patients then required NIPPV therapies including continuous positive airway pressure (CPAP) in two patients and bi-level positive airway pressure (BiPAP) in one patient. All patients failed NIPPV due to poor compliance, primarily caused by inability to tolerate the CPAP or BiPAP device. Each patient underwent a drug induced sleep endoscopy prior to HNS to characterize their residual OSA. Two patients received premedication with oral midazolam for pre-operative anxiety See . One patThe average case length was 244 min (range 227\u2013260 min). Intra-operative courses were overall uneventful. Glycopyrrolate was used for secretions in two patients. One patient received bolus doses of 0.32 mcg/kg epinephrine and 0.08 mg/kg ephedrine for transient bradycardia. Multimodal analgesia was used in all patients and all All patients were extubated \u201cdeep\u201d during stage 3 of anesthesia, transferred to the post-anesthesia care unit (PACU), and placed on blow-by oxygen supplementation. One patient required post-operative oral airway placement, and one patient was placed on his home NIPPV. One patient required post-operative fentanyl and dexmedetomidine for residual pain in PACU. There was no reported post-operative nausea or vomiting. All patients were transferred to the floor for post-operative observation. No anesthetic complications were noted on follow-up. There were no reported complications to the Federal Drug Administration as no serious adverse events occurred at our institution. On follow-up PSG, all patients had notable improvement see . The aveThis case series specifically addresses the anesthetic management of HNS implants in pediatric trisomy 21 patients with refractory OSA. The patients tolerated the procedure well despite their pre-existing conditions, refractory OSA, and relatively prolonged case time. The unique nature of anesthetic management for HNS placement is in the balance between addressing the high-risk patient and operative factors with minimizing respiratory depression and adequately controlling pain. While the majority of our recommendations follow known anesthesia tenants for the care of trisomy 21 patients with OSA, we feel like our recommendations vary in three major ways: the use of premedication, inhalational induction, and deep extubation.Providing appropriate anxiolysis for parental separation in this patient population is essential. To balance preexisting OSA with the need for preoperative anxiolysis, we found judicious midazolam premedication beneficial in certain patients. Parental presence inductions or other sedative premedications are reasonable alternatives. However, caution should be exercised when administering any sedative medication to this patient population due to theoretical concern of airway obstruction. When sedative premedication is used, either continuous pulse oximetry or direct observation by the anesthesia team is recommended. Inhalational inductions are common in pediatric anesthesia in the United States and are to be used with caution in patients with a high risk of airway obstruction. Airway obstruction during stage 2 of an inhalational induction can limit oxygenation and ventilation, especially in a patient with known OSA. However, patients with trisomy 21 may benefit from an inhalational induction as it avoids awake intravenous line placement, anxiety, and fear of medical procedures. Our patient population had minimal obstruction with inhalational induction despite their refractory OSA. We believe that a smooth and controlled inhalational induction is a safe alternative in these patients. Certain equipment should be immediately available including nasopharyngeal and oropharyngeal devices, CPAP capabilities, intubating materials, and intramuscular doses of emergency medications including paralytic.The intra-operative components attempt to mitigate patient and surgical factors to optimize postoperative patient comfort and safety. We found that the use of primarily short-acting opioids such as fentanyl, multimodal pain control with dexmedetomidine and ketorolac, as well as local anesthetic injected by the surgeon at an insertion site provide satisfactory pain control while avoiding respiratory depression. Other key factors we have recognized include utilizing short-acting inhaled anesthetics such as sevoflurane to ensure timely emergence after deep extubation. We believe that low-dose dexamethasone can decrease the risk of postoperative tongue edema while also synergistically working with ondansetron to prevent post-operative nausea and vomiting, which has the potential to result in subsequent lead dislodgement . Other specific anesthetic considerations include placement of monitors and lines opposite of the operative side to avoid complications with use and secure endotracheal tube taping as the bed is turned 180 degrees. Neuromuscular blocking agents are avoided and bite block placed due to intra-operative nerve monitoring. Eye lubrication and careful pressure point padding is required given the case length. Given that sensing lead placement may be complicated by violation of the pleural space, nitrous oxide should be avoided once induction is complete.Despite the risk of postoperative airway obstruction, operative factors make extubation under a deep plane of anesthesia preferable. The coughing and bucking associated with awake extubation has the potential to cause significant impairment such as a post-operative airway hematoma or HNS lead dislodgement. While no surgical complications occurred in our group, a previous case series on HNS cite a surgical complication risk up to 10% [None of the patients experienced anesthetic complications despite their refractory OSA. There were no airway difficulties or significant post-operative respiratory depression that was not able to be managed with supplementary oxygen or home NIPPV. One patient experienced transient bradycardia without hypotension that was not associated with inhalational induction. While bradycardia is common in trisomy 21 patients during inhalational induction, this bradycardia was not thought to be related due its timing in the maintenance phase of anesthesia . The occPatient selection is an important consideration for success of this procedure. Appropriate patients should have high functional capacity with responsible and involved caretakers. As the device requires on/off capabilities, patients should be monitored during use of the device. Close follow-up immediately after implantation can identify early problems and maximize successful use. Our patients had excellent response to the HNS placement with an improvement in the obstructive AHI, meeting or exceeding previously reported percentages ,13.Pediatric trisomy 21 patients with refractory sleep apnea who present for HNS are a growing population ,13. Prop"} +{"text": "Probabilistic Programming offers a concise way to represent stochastic models and perform automated statistical inference. However, many real-world models have discrete or hybrid discrete-continuous distributions, for which existing tools may suffer non-trivial limitations. Inference and parameter estimation can be exceedingly slow for these models because many inference algorithms compute results faster (or exclusively) when the distributions being inferred are continuous. To address this discrepancy, this paper presents Leios. Leios is the first approach for systematically approximating arbitrary probabilistic programs that have discrete, or hybrid discrete-continuous random variables. The approximate programs have all their variables fully continualized. We show that once we have the fully continuous approximate program, we can perform inference and parameter estimation faster by exploiting the existing support that many languages offer for continuous distributions. Furthermore, we show that the estimates obtained when performing inference and parameter estimation on the continuous approximation are still comparably close to both the true parameter values and the estimates obtained when performing inference on the original model."} +{"text": "Orofacial pain comprises multiple pain conditions that affect oral, head, face, and neck area. Such pain can be divided into different types based on its origin, including neuropathic, musculoskeletal, neurovascular, psychogenic, and idiopathic pain. Patients with orofacial pain often show sex differences with high prevalence in women. However, mechanisms underlying orofacial pain conditions and their sexual dimorphism remain elusive. With obvious differences in anatomical structures, gonadal hormones, and immune responses between males and females, it is proposed that these factors contribute to sexual dimorphism in orofacial pain. In the Special Research Topic entitled \u201cMechanisms of Orofacial Pain and Sex Differences,\u201d we collected six relevant articles. These studies provide new insights into understanding orofacial pain and may aid target identification for future development of sex-specific therapies for orofacial pain.Bereiter et al.) investigated the effects of ovarian hormones progesterone and allopregnanolone on estrogen-exacerbated nociception in TMJ inflammation model. Using a complete Freund's adjuvant-induced TMJ inflammation model, they observed that ovariectomized female rats show reduced nociceptive behavior in the TMJ inflammation model and daily administration with estradiol benzoate causes recurrence of the nociception in the TMJ, which is rapidly attenuated by the treatment with progesterone or allopregnanolone. This study suggests that supplying progesterone or its metabolite allopregnanolone when gonadal hormone levels get lower may be an effective approach to treating estrogen-evoked inflammatory TMJ pain. It has been demonstrated that estrogen plays a critical role in the pathogenesis of TMD pain. Besides ovarian sources, estrogen can also be synthesized in brain neurons. Interestingly, acute stimulation of nociceptors in the TMJ enhances estradiol secretion in the trigeminal subnucleus caudalis in a sex-dependent manner . In a varicella zoster virus infection-induced postherpetic trigeminal neuropathic pain model, aromatase-derived estradiol attenuates such orofacial nociception by interacting with estrogen receptors to increase \u03b3-aminobutyric acid-mediated neuronal inhibition in the thalamus . In addition, pituitary hormones can regulate nociceptive transmission in different orofacial pain conditions and may contribute to sex-dependent mechanisms of orofacial pain by intermodulation with gonadal hormones .Temporomandibular disorders (TMDs) are associated with chronic orofacial pain, which includes myofascial and/or Temporomandibular Joint (TMJ) pain. Women report TMD pain around three times more than men. Previous studies have demonstrated sex differences and sex hormonal effects in peripheral and central mechanisms of orofacial pain .In a masseter muscle tendon ligation-induced myogenic orofacial pain model, it has been reported . In an immune-competent oral cancer mouse model, neutrophil-mediated endogenous analgesia occurs only in male mice , suggesting that this immune cell-mediated endogenous analgesia for treating oral cancer pain is sex-specific.Additionally, in an oral cancer patient cohort, sex differences in prevalence and severity of oral cancer pain have been identified (In conclusion, giving that there are sex differences in the underlying mechanisms of orofacial pain, we need to consider outcome measurements for each sex in future animal studies and clinical investigations of such pain conditions. Further understanding of sexual dimorphism in orofacial pain will help us develop sex-selective pain therapies and improve pain management for patients with chronic orofacial pain.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Previous research has shown that despite experiencing more negative life events, older adults maintain relatively high levels of well-being compared to their younger counterparts. This effect appears to be at least partially mediated by trait mindfulness in older adults . The current study expanded into an investigation as to how trait mindfulness might intervene on the relationship between age and other well-being indicators: anxiety and depressive symptomology. Participants included 30 older adults (aged 60-83) and 41 young adults (aged 18-35). Trait mindfulness was examined using the Mindful Attention Awareness Scale (MAAS), while depressive symptoms and trait anxiety were measured using the Center for Epidemiological Studies Depression Scale (CES-D) and the State-Trait Anxiety Inventory (STAI), respectively. Two separate mediated multiple regression models were conducted using Hayes\u2019 PROCESS Macro in SPSS. Trait mindfulness exhibited a significant indirect effect on the relationship between age and depressive symptoms , which was also seen for the relationship between age and trait anxiety . Older age predicted higher trait mindfulness, which in turn predicted diminished self-reported anxiety and depressive symptomology. Controlling for mindfulness in these models reduced the direct effect of age on depression and anxiety to non-significance. These findings imply that the relationship between age and trait mindfulness can be extended to alternative markers of well-being."} +{"text": "Social ecological models of health identify intrapersonal, interpersonal, institutional, community, and policy-level contexts as social factors influencing individual and population health outcomes. However how institutions such as Area Agencies on Aging (AAA) shape rural older adults\u2019 social networks and influence health is little explored. This research examines institutional influences of social networks for rural older adults, particularly the social connections resulting from their AAA services and programs. AAAs are local social service organizations that coordinate home- and community-based supports. Our 2020 case study of a rural AAA in upstate New York involved in-depth semi-structured interviews with AAA staff, volunteers and participants included key themes related to older adults\u2019 social networks, social wellbeing, and physical and mental health. Our findings have both theoretical implications for rural community social structure as experienced by older adults, and practical implications to build AAA\u2019s capacity to address social isolation for rural older adults. Part of a symposium sponsored by the Rural Aging Interest Group."} +{"text": "Because prescribing practices in long-term care settings may reflect regional influences, we examined how potentially inappropriate antipsychotic and antianxiety medication prescribing in assisted living (AL) compared to prescribing in nursing homes (NHs) based on their proximity, using generalized linear models adjusting for facility characteristics and state fixed effects. Data were derived from a seven state sample of AL communities and data for the same seven states drawn from publicly available data reported on the Nursing Home Compare website. In adjusted analyses, AL rates of antipsychotic use were not associated with the rates in the nearest or farthest NHs. However, AL communities that were affiliated with a NH had lower rates of potentially inappropriate antipsychotic use . In a separate model, antianxiety medication prescribing rates in AL were significantly associated with neighboring NHs\u2019 rates of prescribing . Findings suggest efforts to change prescribing in NHs may influence prescribing in AL."} +{"text": "The COVID-19 pandemic and the subsequent lockdown brought about an exogenous and unparalleled stock market crash. The crisis thus provides a unique opportunity to test theories of environmental and social (ES) policies. This paper shows that stocks with higher ES ratings have significantly higher returns, lower return volatility, and higher operating profit margins during the first quarter of 2020. ES firms with higher advertising expenditures experience higher stock returns, and stocks held by more ES-oriented investors experience less return volatility during the crash. This paper highlights the importance of customer and investor loyalty to the resiliency of ES stocks."} +{"text": "Exposure to maltreatment during childhood can lead to increased risk for poor health outcomes in adulthood. Child maltreatment and later poor health may be linked by premature biological aging. We tested whether childhood sexual abuse (CSA) is associated with telomere length (TL) in adult females. We further tested the hypothesis of intergenerational transmission of trauma by measuring TL in both CSA-exposed and non-exposed mothers and their children. TL was measured in a subset of participants and their children from a prospective-longitudinal cohort study of sexually abused females and a demographically matched comparison group. Linear regression models were used to test for associations between CSA-exposure and age-adjusted TL in females . Multilevel linear models were used to test the intergenerational effect of maternal-CSA exposure on age-adjusted TL in their children (N=124 children mean age 10.5 years across 61 mothers). CSA-exposure was not associated with TL in females. Replicating previous work in this area, maternal TL and sex were significant predictors of child TL in all models tested. Longer maternal TL predicted longer TL in children, and female children had longer TL than male children. Maternal-CSA exposure did not predict TL in children. This finding is in line with some previous results on CSA and TL measured in adulthood. Previous significant results associating child maltreatment with shorter TL in adulthood may be capturing a population of individuals exposed to either multiple types of maltreatment or maltreatment in childhood with concurrent TL measurements."} +{"text": "Measles is a highly contagious respiratory disease; both locally acquired and travel-associated cases continue to occur across the United States after the exposure (The patient recovered and was discharged home from the hospital on April 27. None of his contacts developed measles, and no additional cases were identified through heightened surveillance, which included monitoring ED syndromic surveillance data in ESSENCE-FLThe Advisory Committee on Immunization Practices recommends that adults without documentation of measles immunity who are traveling internationally receive 2 documented doses of measles, mumps, and rubella virus vaccine ("} +{"text": "Protamine sulfate is a common reversal agent of systemic heparinization used during procedures. While the exact epidemiology of adverse events is unknown, prior allergic response to protamine-containing compounds or concomitant use of neutral protamine Hagedorn (NPH) insulin is associated with an increased risk of tachyarrhythmias and bradyarrhythmias. We present a case of a 68-year-old woman with no prior history of protamine sulfate intolerance that suffered bradycardic arrest following protamine infusion.Healthcare providers should recognize the potential for life-threatening tachyarrhythmias and bradyarrhythmias following protamine reversal, especially in diabetic patients at risk for autonomic dysfunction; medication and allergy review are encouraged prior to heparin reversal, especially in diabetic patients. Protamine sulfate is a cationic polypeptide that binds to negatively charged unfractionated heparin and can be used to decrease the risk of bleeding during procedures in patients with systemic heparinization . Though A 68-year-old female with a past medical history of hypertension, peripheral artery disease, and type 2 diabetes complicated by peripheral neuropathy underwent a peripheral angiographic intervention on an occluded left femoral arterial stent, after which she received 20 mg of protamine. During the postoperative period, she experienced bradycardia and hypotension progressing to cardiac arrest. Cardiac monitoring at the time indicated no ventricular arrhythmias. Advanced cardiac life support (ACLS) was initiated and the patient received three rounds of epinephrine prior to transport to the emergency department (ED).In the ED, initial evaluation demonstrated agonal cardiac activity on cardiac ultrasound. The patient received three more rounds of epinephrine, two amps of bicarbonate, and one gram of calcium chloride. The initial cardiac monitoring demonstrated pulseless electrical activity, which progressed to ventricular fibrillation. Defibrillation was performed, resulting in the return of spontaneous circulation (ROSC).The patient was admitted to the medical intensive care unit. She was determined to be neurologically intact and targeted temperature management was not initiated. Medical history was notable for insulin NPH use. She had no prior allergic reaction to NPH, exposure to protamine sulfate, or history of food allergies.Labs showed a rise and fall in troponin I with a peak value of 6.21 mcg/L (reference range \u22640.030 mcg/L). Initial electrocardiogram (ECG) after ROSC showed diffuse ST depression suggestive of subendocardial ischemia and potential medication reactions. Healthcare providers should recognize the potential for bradyarrhythmias and tachyarrhythmias before protamine administration, particularly in diabetic patients."} +{"text": "Coronary involvement is rare but can be critical in patients with aortitis. Although cardiac ischemia can be resolved by coronary artery bypass grafting (CABG), patients complicated with cardiac ischemia, calcified aorta, and valve insufficiency pose difficult problems for surgeons.A 71-year-old woman was referred to our institution because of unstable angina. She had been previously diagnosed with aortitis and left subclavian artery occlusion. Contrast-enhanced computed tomography revealed severe left coronary main trunk stenosis, right coronary artery occlusion, and porcelain aorta. Ultrasonic echocardiogram showed severe aortic regurgitation. We performed emergent coronary artery bypass grafting, aortic valve replacement and ascending aorta replacement under hypothermic circulatory arrest.The technique of circumferential calcified intimal removal and reinforcement with felt strips was effective for secure anastomosis. Unilateral cerebral perfusion from the right subclavian artery enabled good visualization and sufficient time to perform distal anastomosis. Coronary involvement is rarebit can be critical in patients with aortitis. Although cardiac ischemia can be resolved by coronary artery bypass grafting (CABG), patients complicated with cardiac ischemia, calcified aorta, and valve insufficiency pose difficult problems for surgeons. We present a 71-year-old woman with left main coronary trunk stenosis, occluded right coronary artery, left subclavian artery occlusion, severe aortic valve regurgitation and porcelain aorta with aortitis.A 71-year-old woman was transferred to our institution because of unstable angina. She had been previously diagnosed with aortitis and left subclavian artery (LSCA) occlusion. Her past medical history included hypertension and dyslipidemia. Twelve-lead electrocardiogram showed marked ST-segment depression in the precordial and inferior leads. Contrast-enhanced cardiac computed tomography (CT) revealed severe left coronary main trunk (LMT) stenosis, which had not been detected 9\u2009months previously, right coronary artery (RCA) occlusion which had occurred previously Fig.\u00a0. These fAdditional file 1.Takayasu\u2019s arteritis (TA) is a chronic, granulomatous vasculitis that causes stenosis, occlusion and ectasia of the aorta and its branches. Although coronary involvement is rare, it can be critical. Coronary ostial stenosis (COS) with normal distal part of the artery is a specific feature of TA.In our case, the patient had not been in the active phase of TA for years. LMT stenosis progressively worsened over 9\u2009months. It is not clear whether LMT stenosis in our patient was associated with TA, because stenosis occurred in the distal part of LMT, and not at the coronary ostium. In view of her diagnosis of dyslipidemia, this might have caused LMT stenosis over a short time period.We had to perform emergent CABG because jeopardized left main coronary artery supplying the chronically occluded RCA caused global ischemia of the entire heart. Although percutaneous coronary intervention (PCI) for LMT stenosis can relieve ischemia quickly, it can be more dangerous compared with CABG because the RCA is already occluded and receives blood supply from the left coronary artery. Furthermore, PCI is not able to solve AR. Although the internal thoracic artery (ITA) is commonly used for CABG, it might not be adequate in patients with Takayasu\u2019s arteritis because stenosis often occurs in the subclavian artery. However, the ITAs have been used in young patients in whom the subclavian arteries did not have stenosis , 2. AlthAnother issue is calcified aorta, which is always a concern when surgeons try to clamp it. Transcatheter aortic valve insertion (TAVI)\u2009+\u2009off-pump CABG is the procedure of choice for patients with aortic valve stenosis, porcelain aorta and coronary ostial stenosis . HoweverAnother issue is how to acquire good visualization of the proximal arch during hypothermic circulatory arrest. The proximal aortic arch was severely calcified, and its diameter was normal. Usual elasticity of the aorta was lost. It seemed difficult to obtain good visualization and enough time to apply the abovementioned technique using usual antegrade selective cerebral perfusion (ASCP) in which three perfusion cannulas are inserted into the innominate artery, left common carotid artery and LSCA, respectively. We considered that three cannulas in the calcified proximal aortic arch with normal size would prevent us from performing any maneuvers. Although controversy exists whether UCP can provide sufficient blood supply to both the left and right hemispheres compared to usual ASCP, we believe it is acceptable in emergent surgery . In factAlthough the patient did not have active phase TA, LMT stenosis progressively worsened over a short period. The technique of circumferential calcified intimal removal and reinforcement with felt strips was effective for secure anastomosis and avoiding bleeding from the suture holes in the porcelain aorta. UCP from the RAXA provided good visualization and sufficient time to perform distal anastomosis."} +{"text": "Nearly 48 million individuals worldwide have a neurocognitive disorder with projections estimating that as many as 75 million may be afflicted by 2050.Although approximations vary, a substantial portion of those affected live in the community alone, accounting for up to one-third of cases. The true proportion of persons with neurocognitive disorders living alone in the community may be underestimated as dementias are often underdiagnosed and underreported. As the baby boom generation ages and trends towards nuclear families, geographic dispersion of families, and fewer children continue, the number of live-alone persons with neurocognitive impairment is anticipated to rise; creating increased potential for difficult, ambiguous circumstances involving the rights and needs of this population. Despite these trends, available information about this population remains limited. This symposium represents papers from social gerontology, bioethics, and policy; offering unique, but complimentary perspectives on live-alone persons with neurocognitive impairment. The four papers explore 1) how non-traditional & absent support networks impact one\u2019s ability to live alone with dementia [NIA funded], 2) social isolation and vulnerabilities of living alone with dementia [NIA-funded], 3) how bioethics can inform gerontological dementia research [NIA bioethics supplement], and 4) exploration of how law enforcement and adult protective services policies influence the precarity of living alone with dementia. Together, these papers illuminate the importance of actively including live-alone persons with dementia into research and assessing this overlooked vulnerable population from multiple research perspectives ."} +{"text": "A substantial number of studies have documented paradoxical findings when examining race differences in later life psychological well-being. Despite experiencing significant structural disadvantages, Black older adults have been found to report significantly higher overall life satisfaction and lower depressive symptoms than White adults. This study relies on double consciousness framework which allows us to understand why satisfaction with material conditions among Black older adults could differ from their evaluation of overall well-being . Based on a survey of successful aging (n=409 aged 60 years or older) conducted by the Elderly Care Research Center (ECRC) in Cleveland, Ohio, we examined race differences in coping resources, and their role in shaping overall life satisfaction, domain-specific life satisfaction, and depressive symptoms. Findings show that Blacks on average have a higher likelihood of experiencing recent negative life events than their White counterparts. Despite adverse life circumstances, Blacks older adults expressed significantly higher overall life satisfaction than Whites. They, however, reported significantly lower domain-specific life satisfaction than their White counterparts. The differences in depressive symptoms between Black and White older adults was not statistically significant. The race differences in overall life satisfaction was explained by religiosity, religious coping, and social support. Education, income, and adverse life events were found to contribute to such differences in domain-specific life satisfaction. Our findings underscore the need to consider the unique role of racialized life course circumstances and coping resources in shaping disparities in later life psychological well-being."} +{"text": "Older adults make up the majority of the U.S. patient population and age differences in information avoidance have potential implications for their ability to participate in informed medical decision making. Meta-analytic evidence suggests that older adults seek less information before making a decision than younger adults do . However, age differences in explicit information avoidance have yet to be quantified. We hypothesized that older adults would avoid decision-relevant information more strongly than younger adults do. We also examined the self-reported reasons for information avoidance and hypothesized that older adults would express more concern about unwanted information influencing their affect and decision preferences , both of which are known predictors of information avoidance . To test these assumptions, we conducted a pre-registered online study involving three different health-related decision scenarios. For each scenario, an adult lifespan sample chose to either receive or avoid information. Responses were highly correlated across scenarios and results were pooled into a single avoidance measure. Analyses indicated that concerns about consequences for decision preferences positively predicted decision avoidance (p<.001), whereas concerns about consequences for affect did not (p=.079). Contrary to predictions, older age was not significantly associated with information avoidance (p=.827). Further, self-reported concerns about the influence of unwanted information on affect and decision preferences were negatively associated with age (ps<.001). This suggests that interventions to foster pre-decisional information seeking should be tailored to the target age group."} +{"text": "The recent opioid crisis is one of the rising challenges in the history of modern health care. New and effective treatment modalities with less adverse effects to alleviate and manage this modern epidemic are critically needed. The FDA has recently approved two non-invasive electrical nerve stimulators for the adjunct treatment of symptoms of acute opioid withdrawal. These devices, placed behind the ear, stimulate certain cranial nerves with auricular projections. This neural stimulation reportedly generates a prompt effect in terms of alleviation of withdrawal symptoms resulting from acute discontinuation of opioid use. Current experimental evidence indicates that this type of non-invasive neural stimulation has excellent potential to supplement medication assisted treatment in opioid detoxification with lower side effects and increased adherence to treatment. Here, we review current findings supporting the use of non-invasive neural stimulation in detoxification from opioid use. We briefly outline the neurophysiology underlying this approach of auricular electrical neural stimulation and its role in enhancing medication assisted treatment in treating symptoms of opioid withdrawal. Considering the growing deleterious impact of addictive disorders on our society, further studies on this emerging treatment modality are warranted. Approximately 36 million people are affected with opioid use disorder globally , the distress in the first few days after abrupt discontinuation can be rather severe. Without adequate treatment, many patients are unable to complete opioid discontinuation . This stimulation provides relief from symptoms associated with opioid withdrawal, including cravings, anxiety, agitation and depression. The device can be worn up to 5\u00a0days at a time, and company officials report that symptoms have eased within an hour of wearing the device.Relatively recently, in June 2018, an additional auricular stimulation device, the \u201cDrug Relief\u201d aural neurostimulator mobile health device, developed by DyAnsys, also received FDA 510(k) premarket approval for patients dealing with opioid addictions (Fig.\u00a0Pain and emotional disturbances are common symptoms during opioid withdrawal. Of note, auricular neural stimulation had been used for chronic pain management with success in various health settings (e.g., reviewed in (Chen et al. Experimental evidence indicates that non-invasive device-generated auricular neural stimulation of certain cranial nerves, primarily vagus nerve, provides an innovative approach to alleviate opioid withdrawal symptoms. This approach may specifically help expedite the recovery phase during acute detoxification from opioids. This can ultimately reduce the need of supportive medications and can facilitate smooth transition from detoxification to commencing medication-assisted treatment in opioid dependent patients. This treatment modality has so far been associated with only minor local side effects at the device placement site. While this non-invasive modality appears to be an exciting new opportunity in alleviating the current opioid epidemic, more studies are clearly needed to further validate the potential of this intervention and support its use with the hope of helping our patients and their families."} +{"text": "Portal vein thrombosis (PVT) poses a unique challenge in liver transplant. The management of PVT differs according to the extent of thrombosis. Anastomosis of a donor portal vein to a varix is a viable option when an adequate size varix is identified on preoperative imaging or intraoperatively. Here, we describe our experience in two liver transplant cases with cavernous transformation of the portal vein where the donor portal vein was anastomosed to a varix using a donor iliac vein interposition graft. In 1985, Shaw and colleagues described successful liver transplantation in seven patients with severely reduced or absent portal flow, and since that time, portal vein thrombosis (PVT) has no longer been considered an absolute contraindication to liver transplantation . As fibrOur first patient was a 58-year-old male with primary biliary cirrhosis and nonalcoholic steatohepatitis. Portal flow was not visualized on preoperative Doppler ultrasound. Contrast enhanced CT demonstrated complete PVT with cavernous transformation and clotOur second case was a 61-year-old male with cryptogenic cirrhosis and hepatocellular carcinoma. Preoperative imaging revealed cavernous transformation with numerous portal venous collaterals most prominent in the paraesophageal and periIntraoperative portal vein thrombovenectomySMV jump graftingEstablishing renal-portal inflow from left renal vein and donor ileac vein conduitVarix-to-portal anastomoses with or without conduitPortacaval transpositionPortal vein thrombosis can range from mild partial nonocclusive thrombus to complete occlusion with cavernous transformation, and varied surgical techniques are required to handle each scenario . QualityIn all cases, we consider left renal vein ligation or ligation of other collateral vessels to enhance portal inflow. Preoperative IR-guided portal vein recanalization has been described , as has Physiologic portal inflow is associated with better 1-, 5-, and 10-year outcomes than any alternative described , and theIn summary, successful surgical management of PVT requires preoperative imaging, thoughtful planning, surgical creativity, and adherence to a practice-based algorithm for establishing portal inflow."} +{"text": "Providing interprofessional geriatric care via telehealth is a unique clinical skillset that differs from providing face-to-face care. The lack of clear guidance on telehealth best practices for providing care to older adults and their care partners has created a systems-based practice educational gap. For several years, GRECC Connect has provided interprofessional telehealth visits to older adults, frequently training interprofessional learners in the process. Using our interprofessional telehealth expertise, the GRECC Connect Education Workgroup created telehealth competencies for the delivery of care to older adults and care partners for interprofessional learners. Competencies incorporate key telehealth, interprofessional and geriatric domains, and were informed by diverse stakeholders within the Veterans Health Administration. During this symposium, comments will be solicited from attendees. Once finalized, these competencies will drive the development of robust curricula and evaluation measures aimed at training the next generation of interprofessional providers to expertly care for older adults via telehealth."} +{"text": "Changing age demographics are reshaping societies and challenging institutions of higher education to consider how they can respond to aging populations through new approaches to teaching, research, and community engagement. As well, institutions are facing a range of challenges as they look to respond to the contemporary needs of traditional-aged students. The pioneering Age-Friendly University (AFU) initiative, endorsed by GSA\u2019s Academy for Gerontology in Higher Education (AGHE), offers a framework within which institutions can begin to address these issues through more age-friendly programs, practices, and partnerships. This symposium will feature AFU advocates discussing innovate ways in which older adults can serve as teaching allies and support the educational mission of higher education. Farah (Lasell University) will discuss how older adults can engage in diverse teaching and learning activities with examples as crime scenario developers in a forensics class, conversation partners in an international oral communication class, and professional interviewers in an internship skills class. Kaye (University of Maine) will discuss how older adults can serve as citizen scientists performing critical functions in participatory research and in community-based test-beds and co-design laboratories. Ermer (Montclair State University) will discuss how older adults can engage students in discourse as guest speakers and panel participants in classes across the curriculum. Manoogian (Western Oregon University) will describe the innovative ways that older adult students (for credit or audit) mentor and engage younger student peers in course activities as well as increase their own understanding of the aging process."} +{"text": "Liquid biopsy has emerged in the last ten years as an appealing noninvasive strategy to support early cancer diagnosis and follow-up interventions. However, conventional liquid biopsy strategies involving specified biomarkers have encountered unexpected inconsistencies stemming from the use of different analytical methodologies. Recent reports have repeatedly demonstrated that integrated detection of multiple liquid biopsy biomarkers can significantly improve diagnostic performance by eliminating the influence of intratumoral heterogeneity. Herein, we review the progress in the field of liquid biopsy and propose a novel integrated liquid biopsy framework consisting of three categories: elementary, intermediate, and advanced integration. We also summarize the merits of the integration strategy and propose a roadmap toward refining cancer diagnosis, metastasis surveillance, and prognostication. Bodily fluids, such as blood, urine, cerebrospinal fluid, and saliva, contain numerous biomarkers corresponding to patient-specific pathological information. From the perspective of biodetection, any biomarkers that are highly associated with tumor growth and metastasis, including circulating proteins (CPs), circulating tumor DNA (ctDNA), circulating tumor RNA (ctRNA), extracellular vesicles (EVs), circulating tumor cells (CTCs), and tumor-educated blood platelets (TEPs), can be indicators of carcinomas. Liquid biopsy has been recognized as one of the most promising strategies for conquering cancers owing to its unparalleled advantages over classical solid biopsy in improving patient compliance, partially due to its noninvasive sample collection and reduced potential for surgical complications e.g., protein-protein, RNA-RNA or DNA-DNA combinations e.g., protein-DNA combinations This review will intensively discuss the hurdles facing liquid biopsy prior to its clinical application and propose potential solutions. Here, we propose a novel analytical framework, termed \u201cintegrated liquid biopsy\u201d, that could be a useful toolkit bridging conventional liquid biopsy and clinical requirements. \u201cIntegrated liquid biopsy\u201d is defined as integrating multiple liquid biopsy biomarkers or detection methods for improved analytical sensitivity and specificity to refine cancer management. Since a single biomarker is inefficient in accurately identifying most cancers, integrated liquid biopsy using multiple markers might be a promising method to facilitate early detection and treatment of cancer. According to the complexity of the combined data types, we categorize integrated liquid biopsy into the following three groups: 1) Elementary integration refers to the combination of biomarkers or methods of the same type,e.g., CA19-9, CEA, AFP, and prostate-specific antigen (PSA)) achieved prevalence due to its convenience and low cost + exosomes containing diverse RNA and proteins may distinguish healthy subjects from patients with pancreatic cancer Liquid biopsies have been regarded as robust tools for routinely screening and identifying tumors before symptoms appear. Historically, the detection of a single CP mutations and CA19-9 provided an improved sensitivity of 64%, compared to 30% for KRAS alone Regarding intermediate integration, CP-ctDNA integration is particularly attractive because ctDNA indicates specific genetic alterations and because the relatively high concentrations of CPs compensate for the drawback of low ctDNA abundance. Joshua et al. reported that the conjunction of Despite the popularity of liquid biopsy in a clinical setting, the conventional detection of a single biomarker has encountered numerous obstacles in assessing samples with tissue or organ heterogeneity. These reported discrepancies among different detection approaches primarily originate from the small amounts and easy degradability of these biomarkers, features that severely compromise their value in indicating abnormal clonal cell proliferation. The latest studies have revealed that a CP-ctDNA integration strategy significantly improves the sensitivity of earlier cancer detection without substantially decreasing specificity. Additionally, integrated assays of CPs and genetic alterations further localize the original organs of these cancers, which could greatly benefit further therapy. Meanwhile, the CP-ctDNA integration concept could be expanded to other liquid biomarkers, such as metabolites, mRNA transcripts, miRNAs, methylated DNA sequences, or markers in EVs to increase the efficiency of early cancer detection.N-ras and phosphatidylinositol 3-kinase mutations in ctDNA can predict drug resistance against monoclonal antibodies targeting EGFR, potential negative errors have been observed due to biological heterogeneity Surviving cancer cells tend to develop drug resistance due to mutation and evolutionary selection when different therapeutic means are employed on heterogenic tissues Figure 33. TherEGFR mutation detection in plasma, and significant improvement was observed in NSCLC patients without distant metastasis EGFR T790M detection, overcoming the limitation of low T790M abundance in the blood (58% sensitivity and 80% specificity using an FDA-approved cobas\u00ae test) Integrated liquid biopsy might be an effective means of eliminating such discrepancies and probing unknown mutations. RNA-seq is a typical form of detection included in elementary integration, and a recent ctDNA profiling method known as cancer personal profiling by deep sequencing (CAPP-seq) found a high frequency of inter- and intrapatient heterogeneity in resistance mechanisms after initial EGFR tyrosine kinase inhibitor therapy Dozens of studies employing integrated liquid biopsy have demonstrated its effectiveness in improving the sensitivity of cancer diagnosis, suggesting that this strategy is ideal for cancer management. Therefore, it is highly desirable to elucidate the biological origins and mutual interactions of different biomarkers in anticipation of clinical applications.CPs are secreted from diverse human cells, including immune cells and tumor-associated cells, and were the first such biomarkers to be exploited and commercialized. The demonstrated high specificity of CPs in reflecting tumor-associated characteristics makes them attractive for cancer surveillance. In contrast to CPs, ctDNA fragments are principally released from apoptotic or necrotic cells. Given the short circulating time of ctDNA (ranging from 16 min to 2.5 h), the dynamic and continuous monitoring of ctDNA fragments plays a paramount role in cancer prediction in vitro, it is necessary to use an indirect strategy involving an enrichment step prior to detection e EVs, comprising exosomes, microvesicles, and apoptotic bodies, are free-floating bodies enwrapped by lipid rafts and contain tumor-specific signatures of nucleic acids and proteins. Briefly, exosomes emerge by budding in multivesicular bodies and are released into the plasma by fusion of multivesicular bodies with the cell membrane, whereas microvesicles and apoptotic bodies are leaked from dying cells due to external stimulation. Notably, selective accumulation of certain functional mRNA, microRNA, and protein species in microvesicles can occur. In contrast to normal cell sprouting, CTCs are spontaneously released from primary tumors to the peripheral blood circulation, constituting seeds for subsequent metastases in distant organs epithelial cell adhesion molecule (EpCAM), human EGFR2, PSA and oncolytic viruses In vivo CTC enrichment using either an inserted metal wire or magnetic separation in vitro integration of biomimicry and nanotechnology have remarkably improved capture efficiency Integrating methods with distinctive principles to strengthen integrated liquid biopsy is likely the most reliable strategy for ideal cancer management. The quantification and characterization of CTCs/EVs represent major technological challenges in liquid biopsy due to the extremely low concentrations of these targets. All the methods developed to quantify CTCs and EVs in the peripheral blood could be categorized as biological or physical. Biological methods are typically based on antigen-antibody or ligand binding; these methods are involved in typical tests for + CTCs, which reduces cell adhesion and promotes polarization and metastasis. Meanwhile, platelets immediately adhere and mechanically protect CTCs from anoikis or destruction by forming a cell fibrin-platelet aggregate surrounding CTCs Tumorigenesis, metastasis and tumor evolution are the typical forms of cancer development, and the above-noted biomarkers can reflect the accumulation of either genetic mutations or epigenetic modifications Figure . During in vitroin silico target prediction.In summary, any detection approach based on a single biomarker reflects limited information that may result in misleading predictions regarding tumor progression. Thus, integrating multiple biomarker approaches provides comprehensive information that may compensate for the drawbacks of single biomarkers in facilitating early cancer detection and intervention Table . MeanwhiKRAS mutant cells effectively drive cancer progression after the suppression of the MEK1 mutant population by panitumumab and trametinib Early and accurate cancer diagnosis is the key to reducing the economic burden of cancer. Classical tissue biopsy has arguably presented a heavy burden according to US Medicare analysis: as of 2017, the average cost of a solid biopsy for lung cancer is $8,869, and the total cost per patient will reach $37,745 for the 20% of needle biopsies that lead to follow-up complications. Compared with single liquid biopsy alone, integrated liquid biopsy provides improved cost-effectiveness in the following ways. First, integrated liquid biopsy is less expensive per marker than its counterpart. For instance, the current cost for single ctDNA mutant detection with digital PCR is approximately $300, while the cost for elementarily integrated detection of all ctDNA mutants with DNA sequencing is < $1,000 with Illumina Several fundamental questions need to be answered prior to effective integration under physiological and pathophysiological conditions: What is the relationship between the degree of ctDNA variations and the RNA/protein abundance of hundreds of functionally coherent gene sets? What are the differences between primary circulating biomarkers such as ctRNA or CP and secondary biomarkers such as RNA/protein analysis from EVs or CTCs? Will different cancer stages and mesenchymal-to-epithelial transition (MET)) or tumor cell status (primary or circulating) significantly affect the spatial and temporal distributions of ctDNA or exoRNA? Understanding the gene regulatory networks of biomarker integration will lead to significant insights and has tremendous implications for cancer intervention and management. Therefore, for integration detection, the core purpose is to reflect the real developmental stage and increase therapy efficiency for cancer.How can users predict and confront the inconsistent results stemming from different biomarkers or detection methods in integrated detection? Considering the complexity of tumorigenesis, any single-marker-based diagnosis will have a risk of error, integrated detection may naturally increase the possibility of exposing these errors by presenting contradictory results, by which the error can be significantly reduced in further diagnosis.What types of integration could be optimal? Both elementary integration and intermediate integration can provide characteristic molecular profiles of cancers in the spatial scale. Advanced integration might provide integrated information in a higher dimension by combining these comprehensive evidences, including medical imaging, tissue diagnosis, and molecular profiling, to map the characteristics of a cancer in detail based on the complementarity of these results.How can we establish a risk prediction model using the acquired integrated data from a time series? Integration in the temporal domain will help us characterize the law of cancer progress or metastases. Therefore, combining the dynamic changes in various biomarkers with previous medical records would facilitate the prognosis analysis of cancers. It is highly plausible that this type of dynamic method focusing on the whole process, including patient diagnosis and treatment, will become the mainstream of prognostic analysis in the near future.KRAS mutation rate reached 94% in a pancreatic intraepithelial neoplasm population The feasibility of integrated liquid biopsy is largely guaranteed by the quality control and standardization of each detection method. In particular, the standardization of annotations resulting from liquid biopsy is challenging due to varied cohort compositions and diverse environmental factors when analyzing the same biomarker. For instance, noticeable discordance exists among different populations: the Integrated liquid biopsy produces data that are substantially more complicated than data from any single biomarker, requiring a canonical big data processing methodology. Deep learning has recently been introduced to assist with diagnostic and therapeutic decision making by reading patients' medical images Liquid biopsy has demonstrated unparalleled advantages over conventional tissue biopsy and medical images in terms of earlier cancer detection and better surveillance of cancer metastasis and prognosis. Different from conventional imaging approaches, which mainly reveal changes in tumor size, profiling the dynamic distribution of various tumor-associated molecular biomarkers may provide continuous genetic mutation information, which will reflect different cancer stages and provide improved guidance for clinical therapy. Furthermore, the rational integration of liquid biopsy, solid biopsy, and medical imaging would prevent discordance or disagreements caused by tumor heterogeneity or individualized analytical methodologies. This advantage would facilitate cancer prevention and early intervention.Integrated liquid biopsy covers both the integration of different detection methods and the combination of multiple biomarkers, including proteomics, genomic sequencing, and DNA methylation profiling, that could reveal mechanistic differences in the development of different cancers. During carcinogenesis, integrated biomarkers could provide an earlier diagnosis than any single biomarker alone. Furthermore, ctDNA could identify the position of the tumor by detecting DNA methylation in an accurate and noninvasive manner Socioeconomic factors should also be considered in the clinical implementation of the integrated liquid biopsy strategy. In the early stage, additional blood tests for enriching the database will carry relatively high costs. However, with the gradual growth of the database, we will benefit from the mathematical model as it provides increasingly accurate and specific guidance on cancer management."} +{"text": "Globally, conservation efforts have moved millions of people out of protected areas since the 1970s, yet quantitative studies on post-resettlement well-being remain a challenge due to poor documentation. Since 2008, the Indian forest department records demographic and financial details at the household level under standardized guidelines for resettlement. Here, we examine the food security of approximately 600 households\u2019 post-resettlement from Kanha National Park (KNP) in central India between 2009 and 2014. We compare food security of resettled households with host community households with a total of 3519 household surveys, conducted over three seasons within one year. We measure food security using food consumption scores (FCSs), coping strategies index (CSI) and household hunger scale (HHS). Food insecurity is widespread in the landscape, with over 80% of households reporting poor or borderline FCSs year-round. Additionally, we recorded food insecurity increases in monsoon for all households regardless of resettlement status. Results indicate that resettled households are comparable to their host community neighbors in FCS and all households use mild coping strategies to combat food insecurity. While widespread, food insecurity in the KNP landscape is not acute with very few (<10) reports of severe hunger (as measured by the HHS). Almost all foods are market bought (>90%) and sometimes supplemented by gathering locally prevalent greens or from kitchen gardens (forest dependency for food was negligible). Accruing assets and diversifying incomes from non-labor avenues would alleviate food insecurity for all households. The patterns of market dependence and food security associated with diversified stable incomes around protected areas is in contrast with many studies but is likely to occur in similar human-dominated landscapes. Conservation-related resettlements trace back to the establishment of Yellowstone National Park in 1872 and spread rapidly with fortress management policies to conserve endangered species habitats. Globally recognized areas of high biodiversity are inhabited by more than a billion people and populations in these regions continue to grow at a rapid pace \u20135. In InUnderstanding the impacts of conservation-related resettlement on people requires meaningful measures of human well-being. Income based metrics of well-being are unidimensional and do not reflect livelihoods reliant on goods with little economic value (for example\u2013wild foods or self-provisioning via non-economic landscape resources) , 25. MorIn India, the current resettlement policy is explicit in its goal to resettle people to expand and maintain critical tiger habitats within 50 protected areas (Tiger Reserves) with detailed resettlement records and standardized compensations . ResettlWe explore food security at resettled households compared to their neighbors at their new settlement locations across the Kanha National Park landscape to answer the following questions:Are resettled households moving into remote areas compared to all existing villages in the study site, specifically with respect to\u2013road access, food markets and forest availability?Do resettled households have comparable Food Consumption Scores (FCSs) and Coping Strategy Index (CSI) measurements to their host community neighbors? , leopard (Panthera pardus), wild dog , sambar (Cervus unicolor), chital (Cervus axis), barasingha (Cervus duvaucelii) and gaur (Bos gaurus) . We. We51]. The FCS and CSI are weighted scores based on the food groups consumed and coping behaviors exhibited in the last seven days in the surveyed household respectively , 57. We We used propensity scoring and visual inspection (of the overlap between resettled households and host community households) for all measured variables to test balance in our study sample, especially to ensure that our sampled host community households provided a comparable baseline for surveyed resettled households . AdditioIn the KNP landscape, households buy foods from weekly markets and therefore restock each week for fresh vegetables, meats and staples. For availability of market items and their prices, we visually compared market checklists as most markets in the landscape have the same produce with similar prices . We alsoWe used Euclidean nearest neighbor distances to find distances between household locations and nearest road, border of protected area (KNP core), market and built up area. We used existing GIS layers of roads, protected area borders, built up area and our GPS locations of markets , 59. We tehsil\u2014for all households) and origin village (only when modelling food access in resettled households) (http://www.r-project.org) and QGIS 2.10.0- Pisa . Data is available at (https://bit.ly/2GvxGid).To understand patterns and associations in our household level data we used cluster analyses (ClustVis PCA\u2013see ), randomseholds) . We stanResettled households have predominantly moved into existing villages in similar proportions to host community human densities across the KNP landscape . HoweverHouseholds in the KNP landscape typically access the bulk of their foods (>90%) from weekly markets at their village or a neighboring village See . Thus, rtehsil during summer, resettled households had higher mean FCSs compared to host community households . However, across all surveyed households with acceptable FCSs, vegetables were not consumed every day and meats very occasionally.Resettled households reported similar Food Consumption Scores when compared to their host community neighbors across all three survey seasons . The yeaResettled households had higher CSIs in monsoon across two administrative units (Baihar and Panderia) and higher CSIs than host community households in winter in Baihar and in summer in Panderia . MoreoveWhile resettled households consume food groups in similar frequencies to host community households, we find that approximately 80% of all households have inadequate levels of food consumption (borderline or poor) . ResettlAll households predominantly access food through market purchases (>90%) supplemented by self-provisioning year round . Only a Our results of modelling livelihood characteristics associated with resettled and host community households highlight that increasing asset index values were positively associated with FCSs year-round . PredomiApart from the above livelihood associations with FCSs, resettled households supplement market bought foods with self-provisioned foods while host community households engage in winter cropping to attain similar FCSs . Owning Our study contributes to the growing quantitative assessment of resettlement on human well-being measurements, tying together conservation and social goals , 65, 66.Our study finds widespread food insecurity for all households. However, the current state of food insecurity around KNP is not acute with very few reports of hunger and coping strategies associated with higher food access. Food insecurity is largely due to the economic inability to access high nutrient food groups (tehsil (administrative block) there were seasonally changing differences in resettled and host community household FCSs and CSIs but these require further study to understand the underlying mechanisms while host community households predominantly rely on winter cropping to end up with similar FCSs . Our resThese differences aside, both resettled and host community households with increasing assets and diversified incomes showed positive associations with FCSs. Households with incomes from poultry and agriculture had comparable positive associations with FCSs as salaried jobs. We suggest that gains from poultry farming might be an avenue for on-the-ground interventions that aid alleviation of poverty as well as food insecurity , 73. We The key objective of our study was to assess post-resettlement food security of resettled compared to their host community households at the new settlement location in the KNP landscape. Our findings suggest that the current resettlement does not constrain resettled households and that they are comparable to host community households in terms of livelihood opportunities, physical food availability and food access. Approximately 20% of our surveyed households are within the KNP buffer. Households within the administrative buffer of KNP are more similar to households outside the KNP than those previously living within the KNP core in terms of economic activities, access to the road network in the KNP landscape and commercial livelihoods . The multiuse buffer around KNP is predominantly agricultural land with more than 260 existing villages. Resettled households join existing villages outside of KNP and comprise a minor proportion of the total village population .To increase overall wealth, an obvious but difficult application of our results would be to generate more opportunities for salaried jobs and make agricultural practices more profitable. Such an obvious result seems a moot point to discuss but we do so to ensure our results are not seen as a contrast of two separate livelihoods\u2013resettled households with forest livelihoods separated from rural host community households with more wealth driven livelihoods. Our results confirm that the reality is one where rural livelihoods predominantly feature wealth accruement and market bought foods regardless of being resettled and host community households . Our stuOwning more cattle suggests that households have means to increase assets which are in turn associated with higher FCSs. Cattle are culturally important, most often as work animals and easily traded assets in times of distress. Cattle for dairy incomes are rare in the KNP landscape. Incomes from cattle might be occasional or low (dairy farming practices). Similar findings about the complicated relationship between livelihoods and cattle owning have been found in Ghana . We alsoFood security for resettled households, and their host community neighbors, in the Kanha National Park landscape will be best achieved by integrating the poorer households into the economy with more opportunities, such as steady jobs and poultry farming, for higher incomes and seasonal stability. Managers for resettlement and rural development around KNP, and in other human-dominated conservation landscapes, might consider the importance of training for employment with steady incomes in future interventions. At the national policy level, the NTCA can use the methods from our study to explore links between livelihoods and social goals in resettlement from tiger reserves across India that vary ecologically, geographically and culturally. While this study concluded that steady incomes are highly relevant for food security in the KNP landscape, other landscapes around tiger reserves might indicate the need for access to forests or efforts to improve food availability.Our study focuses on a short time-frame after resettlement to look at immediate impacts on food security as a metric of human well-being. Longer studies or studies after a decade of resettlement might provide further insight into how compensations under the current guidelines allow resettled households to integrate into their new locations. Furthermore, studies that include metrics of well-being that are difficult to quantify are important to understand social impacts on people living around protected areas , 65. StuWe conclude that there is low level of food insecurity in the KNP landscape that is largely driven by low and unstable household incomes. Resettled households are comparable to their host community neighbors in food availability . We also found that resettled households are comparable to their host community neighbors in food security (FCSs and CSIs) and that households with higher food security had more assets as well as more income sources. Resettled households have more seasonal income sources and supplement foods locally (kitchen gardens) while their more established host community neighbors rely on winter cropping incomes to attain similar food security. Our results suggest that increased opportunities for diversifying non-labor incomes could be effective to alleviate food insecurity for both resettled and host community households in the KNP landscape. This result reinforces multiple studies that highlight livelihood diversification as a means for alleviating household food insecurity , 66. OurS1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file.S3 File(PDF)Click here for additional data file.S4 File(PDF)Click here for additional data file.S5 File(PDF)Click here for additional data file.S6 File(PDF)Click here for additional data file.S7 File(PDF)Click here for additional data file.S8 File(PDF)Click here for additional data file.S9 File(PDF)Click here for additional data file.S10 File(PDF)Click here for additional data file."} +{"text": "Older adults with subjective memory complaints (SMCs) are at increased risk for episodic memory decline. Episodic memory decline is an important predictor of objective memory impairment (one of the earliest symptoms of Alzheimer\u2019s disease) and an often-suggested criterion of successful memory aging. Therefore, it is important to explore the determinant factors that influence episodic memory in older adults with SMCs. Roy adaptation model and preliminary evidence suggest that older adults with SMCs undergo a coping and adaptation process, a process influenced by many health-related risks and protective factors. This study aimed to explore the relationship between coping capacity and episodic memory, and the mediating role of healthy lifestyle between coping capacity and episodic memory in a sample of 309 community-dwelling older adults with SMCs. Results from the structural equation modeling showed that coping capacity directly affects episodic memory , and there is a partial mediating effect (60.5%) of healthy lifestyle among this sample of older adults with SMCs. This study demonstrates that coping capacity and adaptation positively correlate with episodic memory in older adults with SMCs, and that these correlations are mediated by healthy lifestyle. The results suggest that older adults with poor coping capacity should be assessed and monitored regularly, and clear lifestyle-related interventions initiated by healthcare providers that promote healthy lifestyles may effectively improve coping capacity and episodic memory in this population group. Note: First author: Feilong Wang, Co-first author: Shijie li, Corresponding author: Yanni Yang"} +{"text": "This study investigated the association between childhood socioeconomic status (cSES) risk of cognitive impairment but not dementia (CIND), cognitive impairment (dementia or CIND), and dementia and whether adult personality mediated this association. A sample of 10,289 participants (aged 50 and older) from the Health and Retirement Study (HRS) were followed across 2-year periods between 2006 - 2018. Estimates of mediation effects in Cox Proportional Hazards regressions were conducted using Mplus software to approximate the total effects of cSES on the cognitive outcomes and the natural indirect effects and natural direct effects derived when personality causally mediated this outcome. cSES was associated with increased risk of all three cognitive outcomes. Conscientiousness partially mediated the relationship between cSES and dementia, CIND, and cognitive impairment risk while neuroticism partially mediated dementia and impairment, but not CIND. Personality improved the overall model fit between cSES and both CIND and impairment, and conscientiousness was specifically associated with significantly lowered cognitive impairment risk over time. Conscientiousness and neuroticism substantially mediated the relationship between cSES and risk of impairment in old age. This research adds to lifespan models and suggests that distinct personality traits attenuate early childhood factors that contribute to lifespan development and cognitive aging. Conscientiousness in particular may act as a protective buffer mediating risk factors associated with cognitive impairment in old age."} +{"text": "Cereals and legumes play a major role in the production systems and diets of farmers in the semi-arid eastern region of Kenya. Efficient postharvest management can tremendously contribute to food security in these regions. A study was carried out in three counties in eastern Kenya to assess pre and postharvest management practices among farmers. Data was collected using semi-structured questionnaires designed and administered using Kobo Toolbox via android tablets. Results showed that farmers cultivated three main crops: maize (98%), beans 66%), and pigeon peas (28%). The most saved seed crops were beans (80%) and pigeon peas (50%). Majority of the farmers (80%) experienced pre-drying losses due to insects (48%), rodents (40%) and birds (39%). Farmers stored grain for consumption (80%) and for sale (19%). About 48% of farmers stored the grain for more than 9 months. Challenges during grain storage were insects (57%) and rodents (43%). Primary methods of grain preservation included hermetic methods (61%) followed by insecticides (33%). While progress is being made in addressing storage challenges, there still a need to continue building awareness about improved storage technologies and find solutions for pest infestations in the field and drying after harvest. Cereals and legumes are the most important food staples in Sub-Saharan Africa , beans (Phaseolus vulgaris L.), green grams (Vigna radiata L.), pigeon peas (Cajanus cajan L.), millets (Pennisetum spps), sorghum (Sorghum bicolor L.), cowpea (Vigna uncguiculata L.) and dolichos lablab (Lablab purpureus L.) to ensure self-sufficiency in the face of climate change in the Eastern region of Kenya . The surWe purposively selected 50 villages in the three counties . The number of villages per country was determined based on cereal and legume production. We targeted to interview 13 farmers randomly selected in each village. We were able to survey a total of 613 farmers . The selected farmers were interviewed using a semi-structured questionnaire with open and close-ended questions. Questions included qualitative and quantitative data focused on the socio-economic characteristics of the respondents; major cereal and legume crops produced, the quantity produced; seed sources and storage, grain drying before and after harvest, storage practices; farmers\u2019 knowledge of the causes of postharvest losses and loss prevention measures. The questionnaire was uploaded to Kobo Toolbox, deployed and administered via handheld devices (android tablets). Five enumerators collected data and received consent from individual farmers before each interview. Data collected were coded and analyzed using the SPSS 24.0 (IBM Corp., About half of the farmers were an aging demographic, above 50 years. Older farmers are usually viewed least productive because most field work require physical effort. In addition, this may be a hindrance to adoption of new technologies which has a negative impact on food security. This is a universal trend caused by youth migration to urban centers among other factors. Policy-makers need to develop programs that incentivize the youth to be involved in agriculture. The average household size was five members which is similar to the Kenyan national average of between 4.9 to 5.7 people Munene, . Bigger The three major crops grown across the three counties were maize, beans and pigeon pea. Most farmers grew at least two major crops including a cereal and a legume. This agrees with the report that farmers in semi-arid areas of eastern Kenya grow two major and one minor grain crops (Wambugu & Muthamia, There was little variation in postharvest practices among the three study sites. Ideally, rainfall in these regions is bimodal with the long rains occurring from March to May and short rains from October to December. However, all these counties have been experiencing an overall decrease in precipitation and increase in temperatures, with negative impact on crop yields (Ojwang\u2019 et al., Farmers had a good understanding of storage and its implications for food security. Studies have shown the importance of storage in enhancing food security in semi-arid areas (Nduku et al., The major challenges during storage were insects and rodents. Farmers reported using new storage technologies and insecticides to deal with these pest challenges. Farmers have relied on pesticides for grain preservation, but they have been shifting towards hermetic storage in recent years. Concerns with pesticides stem from food poisoning due to overuse and misuse of insecticides as well as their ineffectiveness linked to insect resistance (Nicolopoulou-Stamati et al., Overall, farmers have a greater understanding of postharvest practices in the three counties in Eastern Kenya. Maize and common beans are the most important crops grown by farmers in these areas. Postharvest challenges linked to drying and storage such as aflatoxins and insects are serious challenges. Farmers are increasingly accessing new technologies and solutions to deal with these issues. Maize being such a staple crop grown by all farmers, there is a need to improve and promote pre-harvest and postharvest management practices to increase the use of new technologies such as improved seed, dryers, and hermetic storages devices."} +{"text": "Durable left ventricular assist device therapy has improved survival in patients with advanced heart failure refractory to conventional medical therapy, although the readmission rates due to device-related comorbidities remain high. Left ventricular assist devices are designed to support a failing left ventricle through relief of congestion and improvement of cardiac output. However, many patients still have abnormal hemodynamics even though they may appear to be clinically stable. Furthermore, such abnormal hemodynamics are associated with an increased risk of future adverse events including recurrent heart failure, gastrointestinal bleeding, stroke, and pump thrombosis. Correction of residual hemodynamic derangements post-implantation may be a target in improving longitudinal clinical outcomes during left ventricular assist device support. Automatic and timely device speed adjustments considering a patients\u2019 hemodynamic status are potential improvements in forthcoming devices. Despite considerable improvement in available heart failure-specific medical therapies including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, aldosterone antagonists, angiotensin receptor-neprilysin inhibitors, and arginine vasopressin type II receptor antagonists, morbidity and mortality in patients with advanced heart failure remain exceedingly high .In addition to mechanical circulatory support technologies including the intra-aortic balloon pump, extra-corporeal membrane oxygenation, and percutaneous axial-flow left ventricular assist device (LVAD), cardiac replacement therapy (heart transplantation and durable LVAD) remains the gold-standard therapy for those with refractory stage D heart failure . Given tLVAD therapy improves survival in patients with advanced heart failure compared to medical therapies alone ,5; howevLVADs correct hemodynamic derangements by mechanically unloading the failing left ventricle that decreases intra-cardiac pressure and subsequently increasing systemic circulation that increases total cardiac output. However, one report showed that many LVAD patients have abnormal hemodynamics despite appearing clinically stable in the ambulatory setting . FurtherDurable LVAD technology is improving, from para-corporeal models to the implantable and smaller iterations, including both pulsatile and continuous-flow types. Notably, the dominant types in the current era are implantable continuous-flow devices 12]. Th. Th12]. 2. Notably, we can measure directly or calculate various other hemodynamic parameters using right heart catheterization, as discussed later.Nevertheless, our group recently found that many LVAD patients had abnormal hemodynamics despite showing no apparent clinical symptomology . Here, wParticularly, many LVAD patients seem to have inappropriately elevated central venous pressure indicative of sub-clinical right heart failure ,14. LVADFor several reasons, we believe that invasive right heart catheterization should be routinely performed following LVAD implantation . First, Our team recently demonstrated that the presence of abnormal hemodynamics post-LVAD implantation, even without heart failure symptoms, was associated with future instances of clinical volume overload and heart failure recurrence . As one Optimal device positioning also affects the device\u2019s ability to effectively unload the left ventricle, with malposition of the inflow cannula associated with an increased risk of future heart failure exacerbations . LateralBleeding, particularly gastrointestinal bleeding, is among the most common comorbidities during LVAD support with an estimated incidence of 25% . Some gaThe mechanism of gastrointestinal bleeding is multifactorial . In addiThe most apparent risk factor for LVAD-associated stroke is uncontrolled systemic blood pressure . This rePump thrombosis is one of the major causes of device malfunction that requires device exchange . AbnormaSeveral unique hemodynamic patterns vary by disease state including right heart failure, pulmonary hypertension, and aortic insufficiency.We should state at first that there is no comprehensive and consistently agreed-upon definition of right heart failure . Right hAs mentioned above, right heart failure remains a highly morbid complication of contemporary LVAD therapy. Despite the pump\u2019s purpose to restore systemic perfusion in the failing heart by unloading the left ventricle, adverse right ventricular remodeling resulting from longstanding left ventricular failure is common and challenging to correct by durable mechanical circulatory support alone. Following LVAD implantation, right ventricular preload dramatically increases due to improved systemic circulation. The right ventricle, however, is often unprepared for this drastic increase in flow due to maladaptive structural changes from the afterload of a chronically failing left heart. As a result, right heart failure can become apparent both early and in later periods following LVAD implantation. Furthermore, a decrease in the size of the left ventricle due to mechanical unloading also facilitates a geometrical unbalance between the left and the right ventricle, resulting in further impairment of normal right ventricular contractile mechanics .Elevated central venous pressures in the setting of normal pulmonary capillary wedge pressure are one of the hallmarks of right heart failure and tend to be difficult to correct alone through mechanical unloading . Right hInvasive right heart catheterization provides the clinician valuable information regarding right ventricular performance. Pulmonary artery pulsatility index, which is calculated as a pulse pressure of the pulmonary artery divided by the central venous pressure, is a recently proposed index of right ventricular function , with a Many patients with advanced heart failure have secondary pulmonary (combined pre and post-capillary) hypertension due to chronically elevated left-sided filling pressures . HoweverAortic insufficiency is a unique and progressive comorbidity during long-term LVAD support. Continuous left ventricular unloading leads to aortic valve closure and pressure increases in the aortic root via the outflow graft. This can lead to valvular degeneration, and subsequent continuous and eccentric valvular regurgitation . Aortic The severity of aortic insufficiency is assessed usually using conventional color Doppler echocardiography for visual estimation. Accurate quantification is challenging given non-physiologic continuous and eccentric regurgitant flow. Our group recently proposed several methods to more accurately quantify the severity of aortic insufficiency .First, we can estimate the degree of aortic insufficiency using a device flow monitor, which is equipped in the HeartWare LVAD . This stSecond, we can quantify the severity of aortic insufficiency using Doppler echocardiography obtained at outflow graft 53]. Th. Th53]. As discussed above, abnormal hemodynamics are associated with various adverse clinical outcomes during LVAD support. Furthermore, there are several hemodynamically unique comorbidities during LVAD support which have unique and specific management strategies.2. We simultaneously perform echocardiography to assess for aortic valve opening, to understand the interventricular septum position, and to determine the presence of mitral valve regurgitation at each speed interval . It. It61]. The CardioMEMS device might have the potential to be utilized in LVAD patients to monitor and adjust device parameters in response to hemodynamic status . This isReDS is another promising tool to noninvasively estimate intra-thoracic fluid levels , which mThe HeartWare LVAD provides an estimated instantaneous flow waveform that shows insights into patients and device properties. For example, low pulsatility and low mean flow indicate hypovolemia, whereas low pulsatility and high mean flow let us detect suspected device thrombosis. High pulsatility and low mean flow might indicate continuous suction, whereas high pulsatility and high mean flow indicate volume overload. LVAD flow is determined by the pressure difference between the aorta and left ventricle at a fixed device speed. When aortic pressure is assumed to be constant at the diastole phase, LVAD flow is dependent on left ventricular pressure. When left ventricular pressure increases, LVAD flow often increases. Given this mechanism, pulmonary capillary wedge pressure can be estimated by the slope of LVAD flow at the end-diastolic phase 66]. We. We66]. Future advances in durable mechanical support may include a smart pump concept, which can automatically adjust device speed by continuously monitoring hemodynamic data points. For example, a novel smart pump might automatically measure the HeartWare LVAD flow slope and adjust its rotational speed considering estimated intra-cardiac pressure . If the Despite durable LVAD support, many patients can have abnormal hemodynamics due to a variety of clinical conditions even when clinically stable. LVAD therapy has improved survival in patients with advanced heart failure, though considerable limitations remain including unacceptably high readmission rates due to these various comorbidities, including volume overload and hemocompatibility-related adverse events. Assessment and optimization of hemodynamics might be one of the modifiable targets which could reduce the burden of these common post-implant complications. Interventions to optimize the hemodynamic status by adjustments of device speed and medications might improve clinical outcomes, though further large-scale prospective randomized control trials are needed to study these interventions. In the interim, noninvasive methods that estimate hemodynamics, including CardioMEMS, ReDS, and HartWare LVAD waveform analyses, may prove to be useful in more precisely guiding daily LVAD management."} +{"text": "Previous cross-sectional research suggests that age-related decreases in Rapid-Eye Movement (REM) sleep may contribute to poorer cognitive functioning (CF); however, few studies have examined the relationship at the intraindividual level by measuring habitual sleep over multiple days. Applying a 14-day daily diary design, the current study examines the dynamic relationship between REM sleep and CF in 69 healthy older adults . A Fitbit device provided actigraphy indices of REM sleep , while CF was measured four times daily on a smartphone via ambulatory cognitive tests that captured processing speed and working memory. This research addressed the following questions: At the within-person level, are fluctuations in quantity of REM sleep associated with fluctuations in next day cognitive measures across days? Do individuals who spend more time in REM sleep on average, perform better on cognitive tests than adults who spend less time in REM sleep? A series of multilevel models were fit to examine the extent to which each index of sleep accounted for daily fluctuations in performance on next day cognitive tests. Results indicated that during nights when individuals had more REM sleep minutes than was typical, they performed better on the working memory task the next morning . These results highlight the impact of REM sleep on CF, and further research may allow for targeted interventions for earlier treatment of sleep-related cognitive impairment."} +{"text": "The house acts as both an environment of care and a vehicle to financially potentiate long-term community-based support. While housing can empower a diverse set of options for a person-centered aging process, inadequate housing can also impede healthy aging in the community. This symposium teases out the nodes where housing acts to benefit or limit safe community-based aging. The first paper in this symposium, Homeownership Among Older Adults, describes typologies of older adult homeownership and sensitively highlights trends, disparities and important considerations of homeownership in later life. The next two papers take these older adults and explores situations where their housing acts as an asset or as a burden. Identifying Cost Burdened Older Adults acknowledges that housing cost burdens look different for older adults than younger cohorts. A more precise definition of older adult housing cost burden is proposed to help researchers and policymakers better synthesize the complex relationships between older adult housing and their long-term care decisions. The Long-Term Care Financing Challenge then explores the role of home equity in expanding the community-based long-term care choice set for older adults. This paper demonstrates benefits in home equity and suggests policy implications moving forward. Finally, Cardiometabolic Risk Among Older Renters and Homeowners disentangles the relationship between housing and health by demonstrating health disparities that are associated with housing tenure, conditions and affordability. Taken together, this symposium explores the complex and multidirectional relationships between housing, long-term care and older adult health."} +{"text": "Loneliness is a distressing yet adaptive emotional experience that alerts us to socially re-engage. However, loneliness can also lead to social withdrawal and isolation. To reconcile the seemingly contradictory consequences of loneliness, we unpack the timing of the underlying processes by distinguishing between the roles of state loneliness and trait loneliness in predicting social re-engagement. Using ten days of electronic daily assessments from 95 older adults , initial findings indicate that trait loneliness moderates time-varying associations between state loneliness and prosocial behavior: On days of elevated state loneliness, older adults low in trait loneliness report increases in prosocial behavior, whereas older adults high in trait loneliness show decreases in prosocial behavior. Findings suggest that transient loneliness may motivate older adults to actively re-engage with others; chronic loneliness may undermine such adaptive responses."} +{"text": "Emerging data from epidemiological studies have confirmed elevated prevalence rates for mental health conditions among the lesbian, gay, bisexual and transgender (LGBT) populations. An estimated 2.8% of Asian Americans identify as LGBT and 26% of Asian LGBT are 40 years or older. This study analyzed the California Health Interview Survey to examine differences in psychological distress between LGBT and non-LGBT older Asian Americans, and further evaluated the role of discrimination in medical care and intimate violence on psychological distress. Regression results showed older LGBT Asians had a higher psychological distress score compared to non-LGBT Asians. After adjusting for discrimination or violence, this association no longer existed. Experiencing discrimination in medical care and intimate violence were associated with higher levels of psychological stress. This study increases our knowledge of mental health among older Asian LGBT, enhancing our ability to design culturally-targeted and trauma-informed psychosocial interventions to improve outcomes in this population."} +{"text": "Existing evidence suggests that individuals\u2019 subjective experience of cognitive decline may be a risk state for dementia. However, whether self-awareness of positive changes confer cognitive protection is unknown. We examined the extent to which awareness of positive (AARC gains) and negative (AARC losses) age-related changes explains variability in objective cognitive performance in a sample of 6,231 UK residents without cognitive impairment. We tested a structural equation model with AARC gains and losses as predictors of cognitive performance and depressive symptoms as a mediator of the association of AARC losses with cognitive performance. The model fit the data well. The correlation between AARC gains and losses was negligible, yet higher levels of both AARC gains and losses predicted poorer cognitive scores. Hence, higher AARC gains did not confer cognitive protection. This unexpected pattern of results underscores the complexity of mapping individuals\u2019 awareness onto objective outcomes."} +{"text": "Cancer cells directly control nutrient uptake and utilization in a different manner from that of normal cells. These metabolic changes drive growth, proliferation of cancer cells as well as their ability to develop resistance to traditional therapies. We review published studies with pre-clinical models, showing the essential roles of lipid metabolism in anticancer drug resistance. We also discuss how changes in cellular lipid metabolism contribute to the acquisition of drug resistance and the new therapeutic opportunities to target lipid metabolism for treating drug resistant cancers.Metabolic reprogramming is crucial to respond to cancer cell requirements during tumor development. In the last decade, metabolic alterations have been shown to modulate cancer cells\u2019 sensitivity to chemotherapeutic agents including conventional and targeted therapies. Recently, it became apparent that changes in lipid metabolism represent important mediators of resistance to anticancer agents. In this review, we highlight changes in lipid metabolism associated with therapy resistance, their significance and how dysregulated lipid metabolism could be exploited to overcome anticancer drug resistance. Many oncogenic mutations resulting in the aberrant activation of several signaling pathways can reprogram cancer cell metabolism to such an extent that metabolic reprogramming is considered one of the major hallmarks of cancer . Cancer i) overproduction of neutral lipids such as triacylglycerols stored in LD that accumulate in cancer to provide a reserve of energy; (ii) production of phospholipids is used to build cancer cell membranes to satisfy the increased demand for cancer proliferation. Moreover, phospholipids also act as lipid messengers and intracellular signaling molecules in cancer . Among r review . Particur review ,17. Humar review . Orlistar review . Besidesr review . Many enr review .Secondly, apart from lipogenesis, it was observed that FAs, either from extracellular sources or mobilized from internal lipid stores, can be oxidized in cancer cell mitochondria B. Under Furthermore, lipolysis and lipogenesis may coexist in cancer cells . Lipid mEmerging evidence also suggest that dysregulated lipid metabolism could play a role in resistance to anticancer drugs. Furthermore, the dependence of cancer cells on aberrant lipid metabolism could point to lipid metabolism being a potential source of new attractive targets to eradicate cancer cells. This review highlights the role and mechanisms of lipid metabolism reprogramming induced by anticancer drugs during the development of chemoresistance in cancer cells. In addition, we discuss the potential of reversing chemoresistance via lipid metabolism regulation.It is now well-established that lipid metabolism changes are associated with resistance to conventional chemotherapies and targeted therapies in several cancers. Lipid metabolic reprogramming of resistant cancer cells includes both changes in de novo lipogenic synthesis and/or lipolytic pathway. With some exceptions , cancer Secondly, changes in the lipid metabolism of resistant cells vary depending on the environment and cellular context. Thus, radiation resistance was associated with a significant increase in CPT1A-dependent lipolysis in nasopharyngeal carcinoma whereas radiation resistance was linked to de novo lipogenesis in head and neck squamous carcinoma ,51. MechOverall, these data indicate that changes in lipid metabolism of resistant cells are treatment specific but also environmental and cellular context-dependent resulting in a high heterogeneity of lipid metabolisms.Of note, it is interesting to stress out that lipid metabolism changes, de novo lipogenesis or lipolysis, can be unveiled upon anticancer drug exposure. Comparison of paired NSCLC tumor tissues from patients before and after Gefitinib treatment revealed a significant increase in lipid droplet content and in SCD1 expression . Upon 5-Firstly, several studies suggested that aberrant lipid metabolism could be seen as metabolic shift allowing cancer cells to adapt to treatment-induced cellular stress. Almost all anticancer drugs including conventional chemotherapies and targeted therapies induce cancer cell stress that can ultimately lead to cell death. It was reported that several cellular stressors like lack of nutrients, high levels of reactive oxygen species (ROS) promote de novo lipogenesis . Thus, lSecondly, apart from an adaptive process, cancer cell exposure to anticancer drugs can result in an enrichment of a pre-existing cellular subpopulation characterized by aberrant lipid metabolism. According to this hypothesis, lipid metabolism is a metabolic state allowing a sub-population of cancer cells to escape the effects of anticancer drugs when other cancer cells die. This subpopulation could be represented by cancer stem cells (CSCs), a highly resistant subset of cancer cells. Indeed, it is well established that even if a successful cancer therapy abolishes the bulk of tumor cells, CSCs can survive to standard cancer treatments and are at the core of clinical relapse . InteresIn many preclinical models, lipid metabolism inhibition can reverse the resistance of cancer cells to cancer drugs suggesting that lipid metabolism may play a role in drug resistance. The question is how can lipid metabolic reprogramming contribute to anticancer drug resistance?The oxidative stress induced by anticancer drugs result in peroxidation of lipid membranes, oxidative modifications of proteins and DNA. Doxorubicin, which possesses an anthracycline skeleton, generates ROS leading to DNA damage followed by anticancer activity. Likewise, vinca alkaloids increase intracellular ROS production by depleting the intracellular GSH causing DNA damages. Changes in lipid metabolism elicit a cytoprotective response to oxidative stress in several different ways: (i) lipid droplets decrease ROS toxicity thereby increasing cancer cell survival ProductiLipid droplet accumulation was evidenced to support colorectal cancer resistance to 5-fluorouracil (5-Fu) and oxaliplatin by inhibiting ER stress . Indeed,Overexpression of FAS, the key enzyme of de novo lipogenesis pathway, triggers cancer resistance to genotoxic drugs by increasing DNA repair . MechaniTargeted therapies such as MAPK inhibitors inhibit glucose uptake and antiglycolytic effects triggering energy stress conditions contributing to the promotion of cancer cell death (see above). Acetyl-CoA derived from fatty acid oxidation can fuel the mitochondrial TCA cycle to reduce energetic stress. This metabolic shift towards FAO, is often orchestrated by the AMP-dependent protein kinase (AMPK). Activation of AMPK in response to low energy levels boosts energy production through a mitochondrial FAO increase and therLipid metabolism can also interfere with the process of apoptotic cell death induced by anticancer drugs through two distinct mechanisms: (i) LDs were shown to remove apoptosis-related proteins, such as BCl-2 family members, from mitochondria by direct contact between outer mitochondrial membrane and lipid droplet surface . This pr+ CSC content in the MCF7 breast cancer cell line [A large body of evidence indicates that human cancers emerge from CSCs, which are intrinsically resistant to many anticancer treatments including conventional chemotherapies, targeted drugs and radiation. CSCs are also the main source of cancer relapse. Interestingly, lipid metabolic reprogramming contributes to CSCs expansion and survival therefore enhancing the occurrence of chemoresistance . Severalell line . Activatell line converseell line . HMG-CoAell line ,94,95,96ell line . Similarell line .Overall, these observations identify the rewiring of lipid metabolism as a novel and important mechanism of adaptive resistance to anticancer drugs.As detailed above, recent studies have shown that cancer cells develop changes in lipid metabolism, which is different from that of non-proliferative differentiated cells. These observations open up new avenues for the exploitation of lipid metabolism as a source of new therapeutic targets. Natural and synthetic agents that affect lipid metabolism in cancer is a rapidly growing field that was recently reviewed elsewhere . The focNumerous pharmacological inhibitors have been developed for almost all enzymes of lipid metabolism and some compounds are used in clinical trials in association with conventional therapies . CombinaBesides, due to the role of lipid metabolism in the acquisition of treatment resistance, targeting lipid metabolism could be used to re-sensitize cancer cells to standard treatments. FAS inhibitors have shown in-vivo and in-vitro anticancer effects and are also responsible for re-sensitization of cancer cells to conventional therapy ,106,107.One major interest in lipid targeting for cancer treatment is the possibility of using existing clinically-approved drugs originally developed for other lipid-related diseases. This drug repositioning in oncology has the main advantage of improving safety and reducing costs. Besides the anti-obesity drug, orlistat (see above), statins represent a classic example of drug repositioning in oncology. Statins are currently the most efficient drugs to reduce circulating cholesterol, with few side effects including muscle pain and occasionally liver inflammation, and thereby are used in preventing the development of cardiovascular diseases . MoleculBased on preclinical data presented above, combination therapy consisting of standard anticancer therapies and lipid metabolism inhibitors would be effective for treating resistant cancers.Lipid metabolism plays a central role in cancer resistance, not only via an increased availability of lipids conferred by adipocyte environment but also through profound changes in cancer cell lipid metabolism. It is particularly interesting to note that CSCs, cells that are known to be at the center of resistance mechanisms and relapse, have an increased dependence on lipid metabolism. This could offer a very large number of potential targets, as reported in this review. Changes in the lipid metabolism of cancer cells has been overlooked since conventional 2D cell culture is unable to recapitulate the tumor environment. Moreover, conventional culture medium does not recapitulate normal fatty acid environment as reported by Else . Optimiz"} +{"text": "Teaching point: Hoarseness is a common condition that can be the initial symptom of cardiovascular disorder. A 76-year-old women who quitted smoking ten years earlier presented with recent-onset hoarseness of the voice. She had history of pulmonary commissurotomy. Fiberoptic laryngoscopy revealed paramedian left vocal cord paralysis. Chest computed tomography showed hiatus hernia and left pulmonary artery aneurysm (largest diameter 66 mm) Figures and 2 wiThe recurrent laryngeal nerves originate from the vagus nerves at different levels. The right recurrent laryngeal nerve exits anterior to the right subclavian artery and runs underneath and behind it. On the left side, the recurrent laryngeal nerve leaves the vagus nerve on the anterior surface of the aortic arch, running inferiorly around it through the aortopulmonary window posterior to the ligamentum arteriosum. Then they both rise up between the trachea and esophagus to reach larynx and innervate the intrinsic laryngeal muscles, except the cricothyroid muscle. Because of its longer course in mediastinum, the left recurrent laryngeal nerve is more vulnerable . This neThere are various mediastinal causes for vocal cord paralysis including surgical or iatrogenic injuries, traumatic lesions, inflammatory or infectious diseases, amyloidosis, tumours, and cardiovascular diseases. Ortner syndrome refers to hoarseness resulting from left recurrent laryngeal nerve paralysis caused by cardiovascular disease . It was Pulmonary artery aneurysms are rare, predominantly involving main pulmonary arteries, and may be idiopathic or result from congenital or acquired causes. It has been reported that early pulmonary valve commissurotomy may induce pulmonary artery aneurysm development due to eccentric right ventricular outflow jet.This case emphasizes the need to investigate neck and chest when looking for a causative lesion to hoarseness."} +{"text": "Anabaena sp. ATCC 33047 is a marine, heterocyst forming, nitrogen fixing cyanobacteria with a very short doubling time of 3.8 h. We developed a comprehensive genome-scale metabolic (GSM) model, iAnC892, for this organism using annotations and content obtained from multiple databases. iAnC892 describes both the vegetative and heterocyst cell types found in the filaments of Anabaena sp. ATCC 33047. iAnC892 includes 953 unique reactions and accounts for the annotation of 892 genes. Comparison of iAnC892 reaction content with the GSM of Anabaena sp. PCC 7120 revealed that there are 109 reactions including uptake hydrogenase, pyruvate decarboxylase, and pyruvate-formate lyase unique to iAnC892. iAnC892 enabled the analysis of energy production pathways in the heterocyst by allowing the cell specific deactivation of light dependent electron transport chain and glucose-6-phosphate metabolizing pathways. The analysis revealed the importance of light dependent electron transport in generating ATP and NADPH at the required ratio for optimal N2 fixation. When used alongside the strain design algorithm, OptForce, iAnC892 recapitulated several of the experimentally successful genetic intervention strategies that over produced valerolactam and caprolactam precursors.Nitrogen fixing-cyanobacteria can significantly improve the economic feasibility of cyanobacterial production processes by eliminating the requirement for reduced nitrogen. As production hosts, cyanobacteria have several advantages over eukaryotic plants and algae, including faster growth and higher photosynthetic efficiency 68]. The ming FVA . Unfortubacteria . Among tna 33047 was usedg strain . The fluiAnC892, for the fast-growing, N2-fixing cyanobacteria, Anabaena 33047 by pooling together annotation information from diverse databases. Because Anabaena 33047 forms heterocysts under diazotrophic conditions, the iAnC892 model featured two super-compartments: vegetative cell and heterocyst. iAnC892 was able to accurately capture several aspects of the diazotrophic metabolism of heterocyst forming cyanobacteria. Reaction content comparison with Anabaena 7120 and Anabaena 29413 indicated that iAnC892 is different from these models in terms of its reaction content. Cell specific shutdown of heterocyst-LETC revealed its importance in generating ATP and NADPH at ratios optimal for N2 fixation. Similar analysis of heterocyst central carbon metabolism revealed the existence of alternative routes other than PPP that can supply reducing equivalents for N2 fixation. The usefulness of iAnC892 was further tested by using it alongside OptForce to predict genetic interventions for overproduction of valerolactam and caprolactam. The study recapitulated several of the experimentally successful strategies. Further improvement in predictions can be achieved by using flux distributions specifically generated for Anabaena 33047. Availability of species-specific flux distribution would also help pin down exchanges between vegetative cell and heterocysts which would provide a clearer picture of the energy production pathways active in the heterocyst.In this study we constructed a comprehensive GSM model,"} +{"text": "Assessment of metabolic cost as a metric for human performance has expanded across various fields within the scientific, clinical, and engineering communities. As an alternative to measuring metabolic cost experimentally, musculoskeletal models incorporating metabolic cost models have been developed. However, to utilize these models for practical applications, the accuracy of their metabolic cost predictions requires improvement. Previous studies have reported the benefits of using personalized musculoskeletal models for various applications, yet no study has evaluated how model personalization affects metabolic cost estimation. This study investigated the effect of musculoskeletal model personalization on estimates of metabolic cost of transport (CoT) during post-stroke walking using three commonly used metabolic cost models. We analyzed walking data previously collected from two male stroke survivors with right-sided hemiparesis. The three metabolic cost models were implemented within three musculoskeletal modeling approaches involving different levels of personalization. The first approach used a scaled generic OpenSim model and found muscle activations via static optimization (SOGen). The second approach used a personalized electromyographic (EMG)-driven musculoskeletal model with personalized functional axes but found muscle activations via static optimization . The third approach used the same personalized EMG-driven model but calculated muscle activations directly from EMG data . For each approach, the muscle activation estimates were used to calculate each subject\u2019s CoT at different gait speeds using three metabolic cost models . The cal Metabolic cost has been used to evaluate human performance during daily activities such as walking and athlin silico. Specifically, within the field of exoskeleton design, musculoskeletal models can eliminate the time and expense of iteratively designing and building physical prototypes. With advances in computational biomechanics, musculoskeletal models incorporating metabolic cost models have emerged as tools to estimate metabolic cost. These tools have been used to predict human movement and response to mechanical interventions . AlthougPrevious studies that estimated metabolic cost during walking have focused on using scaled generic musculoskeletal models. However, several studies have reported that personalization of anatomical and physiological characteristics of a musculoskeletal model can influence prediction of muscle forces, joint moments, and novel movements, factors that also play a role in metabolic cost calculations. This study evaluated the influence of musculoskeletal model personalization on metabolic cost estimates of walking post-stroke. To evaluate the physical realism of different metabolic cost modeling methods, we compared metabolic cost estimates to trends reported in the literature for individuals post-stroke. Experimental walking data collected from two male stroke survivors\u2013one high functioning and one low functioning\u2013were used as inputs to the metabolic cost analyses see , 2008.tf Hz (tf is the period of the gait cycle being processed (tf Hz) using a fourth-order zero-phase lag Butterworth filter. EMG amplitudes for each muscle were normalized to the maximum value over all trials and resampled to 101 time points per gait cycle, as described in The experimental data were processed using standard methods. The ground reaction and marker motion data were low-pass filtered using a fourth-order zero-phase lag Butterworth filter with a cut-off frequency of 7/tf Hz , where trocessed . On averA generic full-body OpenSim musculoskeletal model served alsqnonlin algorithm, which iteratively ran OpenSim Inverse Kinematics analyses to calculate marker location errors.Personalization of the joint functional axes for the hip, knee, and ankle of each leg was performed by following a two-step process. First, the geometry of the generic OpenSim model was scaled to match the dimensions of each subject using the OpenSim Scale Model tool and the static standing trial data. Second, marker positions and functional axes of the model\u2019s lower body joints were personalized as described in Experimental data from ten gait trials collected at each available walking speed were used to calibrate an EMG-driven model of both legs for each subject. Before performing EMG-driven model calibration, we analyzed marker data from each gait trial using the OpenSim Inverse Kinematics tool to generate joint angle trajectories. The OpenSim Inverse Dynamics tool was then used to calculate the joint moments produced by muscle forces. Next, a surrogate model of each subject\u2019s musculoskeletal geometry was generated to allow the EMG-driven model to modify musculoskeletal geometry , 2017. Tfmincon algorithm with sequential quadratic programming, we adjusted the model parameter values to best match calculated experimental inverse dynamic joint moments and published passive joint moments , Hill-type muscle-tendon model parameters , and surrogate musculoskeletal geometry parameters. Using Matlab\u2019s moments . In addi moments , S2. A dTo evaluate the extent to which model personalization affects estimated metabolic cost, we developed three musculoskeletal models for each subject with varying levels of personalization. The least personalized model was a scaled generic OpenSim model where muscle activations were calculated via static optimization using quadratic programming (SOGen) . The intTo evaluate the physical realism of each musculoskeletal model/metabolic cost model combination, we identified five experimental trends in the literature for how CoT varies as a function of other clinically relevant quantities for individuals post-stroke. The first three quantities were step length asymmetry, stance time asymmetry, and double-support time asymmetry, all of which have been reported to increase as the CoT increases . The twoWe performed statistical analyses to evaluate whether trends in CoT as a function of the five quantities described above were different between each musculoskeletal model/metabolic cost model combination and the experimental data published in p-values tended to increase as the level of musculoskeletal model personalization increased, with the EMGCal musculoskeletal model generally exhibiting the largest p-values and thus the greatest statistical similarity to experimental measurements. In contrast, the p-values tended to be comparable across the three levels of musculoskeletal model personalization.The ability to predict CoT trends consistent with experimental measurements varied across the nine modeling combinations \u20135. Overap-values < 0.05). However, when absolute values of y-intercept differences were calculated , and the subject provided written informed consent prior to participation.CP and BF performed the experiments. MA performed all model personalization tasks, prepared the figures, and drafted the manuscript. MA and MS analyzed the data. MA, MS, and BF interpreted the results of analyses. All authors revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Aging is a major risk factor for chronic diseases and is directly linked to increasing mortality and healthcare costs worldwide. A key contributing factor to the aging process is a loss of stem/progenitor cell function which leads to a dysregulated tissue microenvironment and reduced repair/regeneration . Over thThe bone marrow is an important reservoir of stem/progenitor cells which cross-talk with peripheral organs to help maintain tissue function. Hematopoietic stem/progenitor cells (HSCs) are responsible for producing blood cells throughout life and these downstream cells play an active role in maintaining tissue homeostasis. With aging reduced function of bone marrow cells correlates with dysfunction of peripheral organs. For example, the decline in immune function with age, referred to as immuno-senescence, contributes to the accumulation of senescent cells, persistent low grade inflammation, and reduced responses to injury . The bon+ bone marrow stem cells and examined 4 months later to allow cross talk between the bone marrow and heart. Young bone marrow reconstitution rejuvenated cardiac endothelial cells which contributed to improved repair and better outcome following myocardial infarction. Mechanistically, young cells which migrated to the heart expressed more Cxcl12 and Vegf, key cytokines involved in angiogenic responses. This correlated with greater expression of CXCR4 and phospho-AKT in resident cardiac endothelial cells isolated from mice receiving young vs. old bone marrow. In addition to improved angiogenesis, our lab has shown that rejuvenation using reconstitution of young cells improves multiple repair processes. Young bone marrow cell transplantation increases the proliferation of resident cardiac cells [We recently utilized this bone marrow rejuvenation approach to study the effect aging has on the repair processes initiated post-myocardial infarction . Aged miac cells , increasac cells , and enhac cells . TogetheBeyond cardiac repair, we have shown that bone marrow cells interact with other tissues and that bone marrow rejuvenation can benefit multiple organ systems. Reconstituting aged mice with young cells leads to the repopulation of the retina with young bone marrow derived microglia . Within Together our studies as well as studies by others demonstrate that introducing young bone marrow into aged mice is an effective rejuvenation strategy with systemic benefits . Bone ma"} +{"text": "The journal retracts the article, Dinitrosopiperazine-Mediated Phosphorylated-Proteins Are Involved in Nasopharyngeal Carcinoma Metastasis cited abFollowing publication, concerns were brought to the attention of the publisher regarding the figures. Some stained tissue pictures in Figure 6 are duplWe apologize to our readership that this went undetected until now."} +{"text": "Bipolar disorder (BD) is a complex and serious psychiatric disorder characterized by mood dysregulation difficulties (American Psychiatric Association Emotion-related urgency (hereto referred as ERU) is defined as a tendency to act rashly in the context of extreme emotions, including trouble inhibiting impulses and risk-taking behaviors (e.g., Cyders and Smith negative urgency (defined as the tendency to behave rashly during extreme negative emotions; e.g., Whiteside and Lynam positive urgency (defined as the tendency to behave rashly during extreme positive emotions; Cyders This brief letter suggests the importance of considering impulsivity during mixed states. Both negative and positive ERU have been implicated in BD (Giovanelli et al. We suggest increased investigation into transdiagnostic presentations and clinical implications of ERU. Indeed, recent recognition of mixed features also occurring in the context of major depressive disorders underscores the important transdiagnostic utility of ERU across mood disorders. We suggest three key areas for future research. First, it will be important to develop well-validated assessment tools to measure mixed-mood ERU across self-report and clinician-rated instrument domains. Second, it will be important to carefully assess the maladaptive behaviors that may predict, and result from, ERU during mixed states and differentiate those from more general risk-taking behavior. Third, future research should carefully consider lifespan approaches that consider ERU in the context of BD onset, risk and recurrence at critical developmental junctures. We believe the time is ripe to call greater attention to examining risky and potentially fatal consequences of impulsivity during strong and co-occurring negative and positive emotion states."} +{"text": "Sepsis survivorship is associated with cognitive decline and complex post-acute care needs. Family caregivers may be unprepared to manage these needs, resulting in decline or no improvement in patient outcomes. Using a national dataset of Medicare beneficiaries who were discharged from the hospital for sepsis and received post-acute HHC between 2013 and 2014 , we examined the relationship between unmet caregiving needs and improvement or decline in cognitive functioning. Multivariate logistic regression was used to determine associations between unmet caregiving needs at the start of HHC and changes in cognitive functioning. Unmet caregiving needs included seven items from the start of care Outcome and Assessment Information Set (OASIS). Changes in cognitive functioning were measured using the start of care and discharge OASIS assessments. Twenty-four percent of patients either declined or did not improve in cognitive functioning from HHC admission to discharge, with variation seen by unmet need type. Sepsis survivors with unmet caregiving needs for activities of daily living assistance , medication assistance , and supervision and safety assistance were more likely to decline or not improve in cognitive functioning, even after accounting for clinical and demographic characteristics. Older sepsis survivors with both cognitive impairment and unmet caregiving needs in the post-acute HHC setting are at high-risk for worsening cognition. Alerting the care team of cognitively impaired sepsis survivors with unmet caregiving needs may trigger evidence-based strategies to enhance caregiver training and reduce unmet caregiving needs."} +{"text": "Prior studies suggesting associations between cortical brain areas and gait speed has been largely cross-sectional and limited to one modality neuroimaging. Using machine learning from 506 cognitively normal BLSA participants aged 55+ who had repeated measures of brain volumes, diffusion tensor imaging (DTI), and gait speed, we examined multimodal neuroimaging predictors of gait decline, accounting for demographics, body composition, and grip strength. Significant predictors of gait decline included changes in volumes and DTI measures of gray matter in selected frontal, parietal, temporal, and subcortical areas, as well as white matter changes in both fractional anisotropy and diffusivity of tracts connecting frontal areas to subcortical motor areas. This predictive model highlights the importance of atrophy and microstructural deterioration in selected frontal and subcortical motor areas in predicting gait speed decline."} +{"text": "C. elegans. As shown in et al. 1986). Serotonin and Gao signaling, which regulate egg laying behavior, can also signal to inhibit defecation . Because evidence shows that both the egg-laying active state and the defecation motor program (DMP) are both linked to changes in forward and reverse locomotion , we reasoned there may be a similar relationship between expulsive behaviors that drive either egg laying or defecation. Our experiments document an association between HSN Ca2+ activity and a reduced frequency of defecation (Ravi and Collins 2019) [See accompanying microPub Ravi and Collins (I) 2019]. Animals lacking HSNs have a reduced defecation frequency (Garcia and Collins 2019) [See accompanying microPub Garcia and Collins (II) 2019]. We hypothesize that egg-laying and defecation behaviors are coordinated because they use the same internal hydrostatic pressure to drive expulsion of uterine or intestinal contents, respectively.We have identified a relationship between egg-laying and defecation behaviors in et al. 2002; Gilpin et al. 2015; Fechner et al. 2018), releasing waste about once per minute and ~3-5 fertilized eggs (~20 pL each) about every 20 minutes . During defecation, sequential activity of the anterior and posterior body wall muscles contracts the animal, increasing internal pressure that drives expulsion of liquid waste through the anus . Mutations that eliminate the defecation motor program still expel gut contents at much reduced frequency. This is thought to be caused by a gradual accumulation of internal pressure by ongoing pharyngeal pumping of food that eventually ejects waste through the anus independent of circuit activity or muscle contractility (Avery and Thomas 1997).Worms continuously internalize bacterial food via pumping of a muscular pharynx . Animals lacking HSNs still enter active states with strong vulval muscle contractions driving release of embryos which additionally supports this model . Electrical silencing of the postsynaptic muscles renders animals egg-laying defective with embryos often hatching inside the mother . Unlike gut contents which are more fluid, fertilized embryos are more mechanically rigid, requiring full opening of the vulva for efficient release . We propose that changes in the internal hydrostatic pressure that accompany food consumption and embryo production activate mechanoreceptors that facilitate the onset of defecation and egg-laying behaviors. As animals age, they continue to eat and grow larger, but their defecation frequency decreases . Egg laying frequency also increases with age for as long as animals have sufficient sperm for oocyte fertilization . This increase in egg laying in older adults reflects both an increase in the number of eggs expelled with each vulval opening and longer active behavior states. We propose that the timing of expulsive behaviors including defecation and egg laying is regulated by sensory mechanisms that detect changes in internal pressure and/or stretch to maintain homeostasis. Feedback of successful egg laying might also signal to the germ line to ensure the continued production of oocytes for fertilization.Our recent data suggest egg-laying behavior is regulated by a stretch-dependent homeostat. Feedback from embryo accumulation in the uterus activates the postsynaptic muscles which drives burst-firing in the presynaptic HSNs as visualized by Ca"} +{"text": "Stroke is a devastating condition characterized by widespread cell death after disruption of blood flow to the brain. The poor regenerative capacity of neural cells limits substantial recovery and prolongs disruptive sequelae. Current therapeutic options are limited and do not adequately address the underlying mitochondrial dysfunction caused by the stroke. These same mitochondrial impairments that result from acute cerebral ischemia are also present in retinal ischemia. In both cases, sufficient mitochondrial activity is necessary for cell survival, and while astrocytes are able to transfer mitochondria to damaged tissues to rescue them, they do not have the capacity to completely repair damaged tissues. Therefore, it is essential to investigate this mitochondrial transfer pathway as a target of future therapeutic strategies. In this review, we examine the current literature pertinent to mitochondrial repair in stroke, with an emphasis on stem cells as a source of healthy mitochondria. Stem cells are a compelling cell type to study in this context, as their ability to mitigate stroke-induced damage through non-mitochondrial mechanisms is well established. Thus, we will focus on the latest preclinical research relevant to mitochondria-based mechanisms in the treatment of cerebral and retinal ischemia and consider which stem cells are ideally suited for this purpose. Stroke is currently the fifth leading cause of death in the United States and can cause disabling neurological deficits including cognitive impairment, hemiparesis, sensory disturbance, and aphasia . StudiesThe ischemic cascade triggereMitochondrial dysfunction plays a key role in the pathological progression of ischemic stroke . MitochoThe body has multiple mechanisms to combat oxidative stress and clear damaged mitochondria. Cells can sequester functional mitochondria while degrading dysfunctional mitochondria via mitophagy ,16. In aThe discovery that stem cells can replace dysfunctional mitochondria in damaged cells has primed the field of stroke therapy for critical improvements in treatment outcomes . In the The ideal cell source to leverage the therapeutic benefits of mitochondrial transfer is bone marrow-derived mesenchymal stem cells (BM-MSCs). This cell type gives rise to endothelial progenitor cells (EPCs), which produce nearly all of the endothelial cells in the body . In the An in vitro stroke model proved that EPCs could successfully discharge their mitochondria . ProteinThe next step in confirming a mechanism of EPC-mediated mitochondria transfer is to assess whether endothelial cells take up these extracellular mitochondria and whether this would aid the recipient cell. In that same study, confocal microscopy demonstrated evidence of mitochondria-containing, EPC-derived extracellular vesicles within endothelial cells in the cerebral vasculature . TherefoAlthough at this point there is considerable evidence for the role of EPCs in restoring mitochondrial function via a transfer mechanism, there was still much uncertainty surrounding the benefits of stem cell mitochondrial therapy. Additional studies on EPC-derived mitochondria addressed these concerns. FACS-assisted proteome analysis of OGD-exposed brain endothelial cells reveals that uptake of EPC-derived mitochondria enhances the production of angiogenic and BBB proteins, including Serpin E1, plasminogen, FGF-4, and bFGF . These fThe ischemic conditions brought about by stroke damage endothelial cells and predispose them towards undergoing intrinsic pathway apoptosis, which is mediated by mitochondrial dysfunction . IntegraImportantly, astrocytes can also transfer their mitochondria to damaged neurons but do so in a transient fashion. Thus, they do not produce the same neuroprotective effects that occur via stem cell transplantation and cannot prevent secondary cell death . Given tExamination of the electron transport chain (ETC), specifically complexes I\u2013IV, can be performed using ETC complex inhibitors to study each portion of the chain in isolation. Mouse models with mutated mitochondria are instrumental in this investigation in order to definitively determine whether it is the mitochondria themselves that confer the neuroprotection or whether a different characteristic of the stem cell is responsible . When diThe safety of BM-MSCs compared to other sources of stem cells is relatively well established . NeverthUp to this point, we concentrated on literature that characterizes the transfer of mitochondria from stem cells to endothelial cells and neurons in the context of the ischemic brain. However, stroke patients often suffer maladies that extend beyond the brain, and complete functional improvement must address these aspects of recovery as well. A prime example of this is that ischemic stroke may cause damage to the eye, leading to visual impairment and a significant delay in recovery ,37. ImpoIt is valuable to understand the role of mitochondrial dysfunction in cerebral and ocular disease post-stroke due to the markedly similar pathology and treatment options between these two conditions . In addiThere are considerable benefits to using MSC therapy to treat ischemia-induced eye damage, such as enhanced preservation of retinal ganglion cells. The decreased cell death is likely due to improved mitochondrial function, which may be due to MSC-derived mitochondrial transfer to the retinal ganglion cells . MSC traThe interaction of creatine and phosphocreatine conversion prevents lapses in cellular energy supplies under healthy conditions. However, it is still possible for the energy supply to be damaged under ischemic conditions, worsening mitochondrial dysfunction. Creatine supplementation possesses therapeutic characteristics in various neurodegenerative disorders that may address the lack of energy supply and the normal function of the mitochondria . TherefoBased on previously mentioned studies, transferring healthy mitochondria by exogenous MSCs can potentially restore respiratory functions in ischemic retinal cells, reducing cell loss. Future studies should investigate how MSCs successfully transfer healthy mitochondria to retinal ganglion cells. Studies should also observe and describe the metabolic and proteomic properties of MSC-derived mitochondria post-transplantation into ischemic retinal cells. EPCs\u2019 affinity for BBB repair makes them a favorable MSC subtype. EPCs are known for being safe and effective to use in stem cell therapy. Additionally, their ability to donate healthy mitochondria justifies the need to further investigate its effects on retinal ischemia. However, the study presents a significant limitation. Specifically, no known study provides a detailed report regarding the physical characteristics of MSC that are involved in the mitochondrial transfer in retinal ischemia . The funStroke-induced ischemia results in insufficient oxygen delivery to cells and prevents mitochondria from performing cellular respiration. The ensuing loss of ATP is not compatible with cellular viability and ultimately precipitates mitochondrial dysfunction and cell death. In response to stroke and stroke-like lesions, cells upregulate mitochondrial synthesis to compensate for damaged mitochondria . A varieDespite the innovations in stroke therapy over the past decade, novel methods of research continue to elucidate fundamental information on the mechanistic role of mitochondria in stroke and enable the development of powerful new therapeutic strategies. A novel technology, Seahorse XFe24, measures mitochondrial respiration and allows investigators to directly detect changes in cellular energetics, rather than relying on cellular signaling . This teSeveral pharmaceutical agents, such as the dopamine D2 receptor antagonist pramipexole (PPX), facilitate neuroprotection through the action of mitochondria. Administration of PPX to transient MCAO model rats after an ischemic stroke reduces infarct volume, neurological deficit severity, mitochondrial ROS formation, mitochondrial calcium concentration, and swelling of the mitochondrial membrane, while simultaneously increasing oxygen consumption and the respiratory control ratio . TherefoThe pharmacological administration of tetrahydrocurcumin (THC) also alleviates mitochondrial dysfunction and improves functional capacity and motor coordination. THC epigenetically reduces plasma and tissue homocysteine (Hcy) levels and Hcy-induced mitochondrial oxidative stress . THC treAnother drug-based approach to mitochondrial dysfunction is the use of nicotinamide mononucleotide (NMN) to increase NAD+ levels. NMN extends the lifespan of mice with the mitochondrial disease Leigh Syndrome by normalizing NAD+ redox imbalance and lowering H1F1a accumulation in skeletal muscle . FurtherCationic arginine-rich peptides (CARPs) are another candidate pharmacological therapeutic that specifically enhance mitochondria-mediated neuroprotection in stroke. CARPs are small peptides, composed of up to 30 amino acids, that cross the BBB and localize to mitochondria in neurons. This property alone highlights their value as a pharmacologic treatment for stroke, as many other promising drugs do not effectively cross the BBB, making their administration difficult or ineffective. Once in the mitochondria, CARPs efficiently eliminate ROS that accumulate during ischemia and restore proper function of the mitochondria, rescuing the cell from free radical damage and reestablishing cellular viability .Although restoring the respiratory functions of mitochondria improves stroke outcomes, this is not the only strategy for recovery. Autophagy, the process of degrading and recycling damaged or unnecessary cellular components, can also mitigate mitochondrial dysfunction. A high salt diet is particularly dangerous because it increases the risk of hypertension-related stroke occurrence, reduces the efficiency of autophagy, and downregulates the production of the electron transport chain enzyme NDUFC2 . HoweverThe proteins ULK1, NDP52, and TANK-Binding Kinase 1 (TBK1) are also meaningful targets for stroke therapies through targeting autophagy. TANK1 recruits the ULK1 complex to the NDP52 receptor to initiate autophagy under conditions of starvation . TherefoAnother potential target of autophagy-based treatments involves the small molecule Compound R6 and its regulation of mitochondria-mediated apoptosis. The release of cytochrome c from damaged mitochondria activates the intrinsic apoptotic caspase-9/3 cascade and results in cell death . CompounAlong with autophagy, manipulating the discrete molecular mechanisms of mitochondria to enhance mitophagy is another approach to ameliorate stroke-induced mitochondrial dysfunction. Cell cycle progression in the presence of impaired mitochondria generates damaged daughter cells, further exacerbating tissue injury and delaying recovery. However, the serine/threonine kinase PINK1 and the E3 ubiquitin ligase Parkin mediate the elimination of these impaired mitochondria through induction of TBK1 to upregulate mitophagy, the targeted recycling of mitochondria. By directing TBK1 to the mitochondrial membrane, away from its role at the centromere during mitosis, PINK1 and Parkin halt the cell cycle at the G2/M phase . TherefoIn addition to enhancing TBK1-mediated mitophagy, PINK1 upregulates the Parkin-induced mitophagy pathway in the presence of damaged mitochondria. During an ischemic injury, the depleted mitochondrial membrane potential inhibits PINK1 importation to the inner mitochondrial membrane (IMM). Instead, PINK1 binds to Tom 7, accumulates on the outer mitochondrial membrane (OMM), then activates Parkin-induced mitophagy. However, the IMM-resident protease OMA1 cleaves PINK1 in the absence of Tom 7, abolishing mitophagy . Hence, While the PINK1/Parkin pathway is valuable to preserve non-neuronal cells, Parkin-induced mitophagy is not as effective in neurons as only a small fraction of mitochondria in axons undergo mitophagy . HoweverMultiple cellular pathways spur mitochondrial deterioration in ischemic stroke. Apoptosis in mitochondria is upregulated during ischemic stroke and is associated with continuous mitochondrial permeability transition pore (MPTP) opening in the inner and outer mitochondrial membranes . ROS proMitochondrial transporters are also important in preventing atherosclerosis, the accumulation of fatty plaques on the inner wall of arteries, which is a significant risk factor for stroke. Poor metabolism or excess intake of lipids intensifies atherosclerotic plaque buildup and heightens the chance of stroke and ischemic brain injury. The mitochondrial calcium uniporter (MCU) prevents lipid accumulation and maintains appropriate bioenergetics by facilitating oxidative phosphorylation in the mitochondria . HoweverAnother source of mitochondrial dysfunction that may exacerbate stroke pathology is the mitochondrial ADP/ATP carrier. Mitochondrial ADP/ATP carriers are located in the impermeable mitochondrial membrane and transport ADP into the mitochondrial matrix and ATP out for use as energy . InapproAstrocytes transfer their healthy mitochondria to neurons in the peri-infarct area post-stroke, and this endogenous neuroprotective mechanism is a candidate for stroke-therapy. In particular, the nuclear and desmosome-associated protein Pinin (Pnn) upregulates anti-apoptotic Bcl-2 expression, promotes ERK signaling, reduces pro-apoptotic cleaved caspase-3 production, and enhances astrocyte survival. Therefore, therapeutically augmenting Pnn expression may improve the endogenous capacity of astrocytes to protect neurons and repair ischemic tissue in the brain .Hyperbaric oxygen therapy (HBOT), which delivers pure oxygen to patients in special high-pressure rooms, modulates inflammation in traumatic brain injury (TBI) when given after the onset of tissue damage. However, pretreatment with HBOT also reduces cell death and improves post-stroke outcomes by inducing endogenous astrocyte-based mitochondrial transfer to neuronal cells. The prophylactic use of HBOT to enhance neuroprotection circumvents the need for invasive surgical treatment and potentially toxic drug-based approaches . AdditioMitochondrial repair for stroke highlights the integral role of mitochondrial function on cell survival and neurological improvement. Mitochondrial dysfunction closely accompanies post-stroke secondary cell death. The hypoxic environment reduces energy production, further exacerbating stroke symptoms. Identifying a reliable method of mitochondrial transfer represents the first step towards developing an effective stroke treatment and is crucial to restoring cell function . To thisWhile the benefits of stem cell therapy are clear, the mechanism is not. Determining the precise location of transfer between the donor and recipient cells will provide crucial insights into the mechanism and therapeutic actions of mitochondria. Such knowledge will guide efforts to optimize transfer conditions and maximize the beneficial effects of stem cells . To thisAlthough mitochondrial transfer is theoretically bidirectional, molecular signals released by damaged cells preferentially direct the movement of mitochondria and mtDNA from MSCs to damaged neurons . One sucDeleting mitochondria from stem cells abolishes the regenerative benefits they confer to damaged endothelial cells, supporting the hypothesis that these organelles are responsible for repair. Furthermore, transferring mitochondria directly into ischemic brain tissue restores cellular energetics, facilitates homeostasis of the central nervous system (CNS), and resolves the inflammation that causes secondary cell death . Stem ceMSCs are the most common stem cell source for mitochondrial transfer and provide a protective mechanism to save damaged cells from mitochondrial dysfunction in response to stress. The transfer of MSC-derived mitochondria to endothelial cells can repress apoptosis after an IR injury by restoring aerobic respiration. The results of studies investigating this transfer are encouraging, paving the way for stem cell transplantation therapy for ischemic stroke . An in vMSCs achieved efficacy of mitochondrial transplantation via intravenous transplantation into a middle cerebral artery occlusion (MCAO) mouse model. Here, retinal ischemia caused ganglion cells to deteriorate, impairing mitochondrial activity. These findings suggest that MSCs ameliorate mitochondrial dysfunction and ganglion cell death, as was observed 14 days after the stroke . In vitrThe effect of OGD on MSCs derived from the perivascular region, cord lining, and Wharton\u2019s jelly of the human umbilical cord also implicated a key role of mitochondria in these specific MSC tissue sources. The mitochondria in the perivascular region MSCs showed the greatest activity while the MSCs from the cord lining demonstrated the highest survival rate. These findings suggest that hUC-MSCs may be a good source for mitochondrial transplantation for ischemic stroke treatment . AdditioHuman induced pluripotent stem cells (iPSCs) are also the subject of recent studies of mitochondrial transfer. PD model astrocytes derived from human iPSCs spontaneously release healthy mitochondria in damaged neuron cultures. This iPSC-induced mitochondrial transfer significantly ameliorates dopaminergic neuron damage and imparts neuroprotective effects . iPSC\u2019s Spinal cord injury (SCI) models of mitochondrial transfer via bone marrow mesenchymal stem cells (BMSC) show promising results as well. Symptoms of both diseases are very similar: hypoxia, mitochondrial degeneration, oxidative stress, vascular injury, and axonal degeneration . HealthyThe omnipresent phenomenon of mitochondrial transfer allows for many applications in combination with stem cells. Contemporary literature details the efficacy of mitochondrial transfer in improving stroke, cardiovascular injury, spinal cord injury, and Parkinson\u2019s disease outcomes. The regenerative capacity demonstrated in a variety of tissues warrants its consideration as a primary therapeutic option. In particular, the physiological and pathological improvements seen in treating ischemic stroke illustrate the capability of mitochondrial transfer therapy. However, before moving into clinical trials, the optimal stem cell type must be identified to maximize the efficacy and potency of treatment. Further investigation is needed to discover the true potential of stem cell-based mitochondrial transfer therapy and improve long-term stroke outcomes."} +{"text": "Research has shown the amount of effort we expend towards our goals depends on a sense of self-efficacy, perception of task difficulty, and likelihood of achieving our goal. All of these processes are susceptible to the influence of affect. For example, negative moods may impede goal achievement by increasing perceptions of difficulty . Negative experiences (such as past failures) can encourage these negative moods and subsequently impact self-efficacy . Findings from self-efficacy research suggest that older adults may be particularly susceptible to the impacts of negative affect on effort mobilization, especially when tasks already seem challenging, with little chance of success. Perception of task difficulty, then, impacts the amount of effort exerted in completing the task. The present study sought to examine the factors that impact perceptions of difficulty and subsequent effort expenditure, represented by systolic blood pressure responsivity (SBP-R). Younger (N = 41) and Older (N = 163) adults completed a difficult cognitive task as part of a larger, longitudinal study, as well as measures of trait affect before study sessions. Our findings indicate younger adults exert less effort overall than older adults; however, when negative trait affect is considered, we find that higher levels of negative affect in older adults reduced task engagement. These results provide support for an effect of negative affect on task appraisals and posited age-related differences in effort mobilization."} +{"text": "Brain pathologies are increasingly understood to confer mobility risk, but the malleability of functional brain networks may be a mechanism for mobility reserve. In particular, white matter hyperintensities (WMH) are strongly associated with mobility and alter functional network connectivity. To assess the potential role of brain networks as a mechanism of mobility reserve, 116 participants with MRI from the Brain Networks and Mobility Function (B-NET) were categorized into 4 groups based on median splits of SPPB scores and WMH burden: Expected Healthy , Expected Impaired , Unexpected Impaired and Unexpected Unhealthy . Functional brain networks were calculated using graph theory methods and white matter hyperintensities were quantified with the Lesion Segmentation Toolbox (LST) in SPM12. Somatomotor cortex community structure (SMC-CS) was similar between UH and EH with both having higher consistency than EI and UI. However, UH displayed a unique increase in second-order connections between the motor cortex and the anterior cingulate. It is possible that this increase in connections is a signal of higher reserve or resilience in UH participants and may indicate a mechanism of compensation in regards to mobility function and advanced WMH burden. These data suggest functional brain networks may be a mechanism for mobility resilience in older adults at mobility risk due to WMH burden."} +{"text": "The recurrence of symptoms present before cholecystectomy may be caused by a cystic duct remnant. The resolution of cystic duct remnant syndrome may require surgical resection, but identification of the duct remnant during laparoscopic surgery may be difficult because of adhesions following the previous procedure. Open surgery, which is more invasive than laparoscopic surgery, is frequently chosen to avoid bile duct injury.The patient was a 24-year-old woman with previous laparoscopic cholecystectomy for chronic cholecystitis and repeated attacks of biliary colic. The postoperative course was uneventful, but computed tomography revealed a remnant cystic duct calculus. Ten months after surgery, the patient returned to our department for right hypochondriac pain. Laparoscopic remnant cystic duct resection was performed with intraoperative near-infrared (NIR) fluorescence cholangiography to visualize the common bile duct and remnant cystic duct. The postoperative course was uneventful and the patient was discharged on day 3 after surgery. At the 6-month follow-up, she had no recurrence of pain.Laparoscopic surgery with NIR cholangiography is a safe and effective alternative for the removal of a cystic duct remnant calculus after cholecystectomy. Post-cholecystectomy syndrome (PCS) is a recurrence of upper abdominal and right hypochondriac pain, jaundice, dyspepsia, gastrointestinal disorders, and vomiting experienced before cholecystectomy . PCS mayA 24-year-old woman with chronic cholecystitis and episodes of biliary colic underwent laparoscopic cholecystectomy at our hospital. Although preoperative computed tomography (CT) revealed a cystic duct calculus, the complete removal of the calculus could not be confirmed considering bile duct injury because there were moderate chronic inflammations around the cystic duct. The postoperative course was uneventful and without pain. Ten months later, the patient visited the outpatient clinic because of hypochondriac pain. Laboratory results showed normal liver function, and inflammation and jaundice were absent. CT revealed a cystic duct remnant calculus at the same site as before Fig. . MagnetiPCS is characterized by the recurrence of symptoms experienced before cholecystectomy . In CDRSPrevious systematic reviews have described the potential advantages of fluorescence cholangiography over conventional cholangiography during laparoscopic cholecystectomy . In addiThis patient was safely and successfully treated for a cystic duct remnant calculus by relatively noninvasive laparoscopic surgery in combination with NIR fluorescence cholangiography and ICG."} +{"text": "Viruses on \u201cPlant Virus Pathogenesis and Disease Control\u201d give new, important information addressing different aspects of this topic.Plant viruses are emerging and re-emerging to cause important diseases in many plants that humans grow for food and/or fiber, and sustainable, effective strategies for controlling many plant virus diseases remain unavailable. However, cutting-edge technological approaches in cell and molecular biology and rapidly accumulating virus sequence datasets are allowing us to gain new insights into mechanisms involved in pathogenesis and how interactions between plants and viruses affect disease development. In some cases, these offer opportunities for novel approaches to target plant viruses and help control the diseases they cause. Seven original articles in this Special Issue of Solanum lycopersicum) in several parts of the world. Klap and colleagues show further complexity associated with TBRFV-induced disease. They show that when TBRFV co-infects plants with the potexvirus, pepino mosaic virus (PepMV), more severe symptoms develop [Tomato brown rugose fruit virus (TBRFV) is a recently described and rapidly spreading tobamovirus affecting tomatoes ( develop . PepMV cGlycine max) are a globally important crop plant and soybean mosaic virus (SMV) occurs wherever soybeans are grown, in part due to its seed transmissibility. Bao and colleagues developed a GFP-recombinant SMV system to assess SMV-soybean interactions [Soybeans technology to assess the role of microRNA nbe-miR1919c-5p in infections of N. benthamiana plants by tobacco curly shoot virus (TbCSV) and its betasatellite (TbCSB) DNA [Three groups addressed the roles of non-coding RNAs in plant virus infections ,6,7. LiuThese papers are representative of the approaches and opportunities that are available now to gain a better fundamental understanding of plant virus-induced pathogenesis. Obtaining a more fundamental understanding of plant-virus interactions is necessary if we are going to develop efficacious, environmentally sound approaches to control plant diseases caused by plant viruses. We now have fantastic new tools including NGS and bioinformatics approaches to look at virus diversity and host responses to virus infection at the transcriptome but also small and large non-coding RNA levels, not only in different plant genotypes but also in different plant tissues. However, the diversity of papers here also shows that we cannot ignore virus-host biology, and we must consider biology to help us accurately interpret and use what we are finding with modern technologies."} +{"text": "Although the physical and cognitive benefits of moderate-vigorous intensity physical activity (MVPA) for older adults is well documented, this population often faces age-related functional and physical limitations impeding recommended MVPA participation. Recently, there has been a surge of interest in the independent health benefits of light-intensity physical activity (LPA) and its association with morbidity and mortality risk. LPA is the most common form of activity among older adults and its potential to combat cognitive aging needs to be investigated. The purpose of this scoping review was to catalog existing evidence on the association between device-based or technologically measured LPA and cognition among healthy older adults, identify trends in the literature, and pinpoint future areas of research. Six electronic databases were searched between January and August 2020. Eighteen published studies met the inclusion criteria: one acute exercise study, two randomized control trials (RCTs), twelve cross-sectional studies, and three longitudinal studies. Overall, n=9 studies reported a significant, positive relationship between LPA and one or more cognitive outcomes including memory, attention, executive function and global cognition (MMSE/MOCA). These heterogeneous findings can largely be attributed to the diverse study designs, inconsistent definitions of LPA and numerous assessments used to test the cognitive domains. Collectively, these findings suggest LPA may be a potential lifestyle intervention to improve cognition among healthy older adults. However, the inconsistent approaches used among these studies suggests a more concerted, unified scientific approach and rigorous methodology are needed to further understand the LPA-cognition relationship."} +{"text": "Social engagement may confer cognitive benefits in older adulthood, but studies have typically been restricted to largely non-Hispanic White (NHW) samples. Levels of social engagement vary across race such that NHW report larger social networks, more frequent participation in social activities, and greater social support than non-Hispanic Blacks (NHB). Associations between social engagement and cognition may also vary by race, but research is sparse. The current cross-sectional study examined associations between different aspects of social engagement and episodic memory performance, as well as interactions between social engagement and race among NHB and NHW participants in the Michigan Cognitive Aging Project . Social engagement was self-reported. Episodic memory was a z-score composite of immediate, delayed, and recognition trials of a list-learning task. Separate hierarchical linear regression models quantified interactions between race and each of the three social engagement variables on episodic memory, controlling for sociodemographics, depressive symptoms, and health conditions. Results showed a main effect of more frequent social activity on better episodic memory, as well as an interaction between race and social support indicating a significant positive association in NHB but not NHW. These preliminary findings suggest that participating in social activities may be equally beneficial for episodic memory across NHB and NHW older adults and that social support may be particularly beneficial for NHB. Future research is needed to determine the potential applications of these results in reducing cognitive inequalities through the development of culturally-relevant interventions."} +{"text": "Choir interventions confer psychological benefits for persons with dementia (PwD) and their caregivers. However, less is known about whether physiological function also exhibits improvements pursuant to such social-cognitive interventions. The present study, based upon a subsample of the Voices in Motion (ViM) project, explored whether participation in an intergenerational choir results in systematic improvements in gait velocity for both informal caregivers and PwD . Longitudinal burst data from the first of three cohorts spanning 4 assessments over 3.5 months was analysed using multilevel modeling. Whereas caregivers exhibited significant improvements (p<.05) in gait velocity, PwD showed no improvement. Ongoing analyses are exploring additional cohorts, and whether improvements in gait dynamically covary with reductions in comorbidities . These results underscore the potential of choir for facilitating both psychosocial and physiological function for caregivers and PwD."} +{"text": "An integrated approach for assessing ventricular pump function, diastolic compliance (EDPVR), myocontractility and pulmonary vascular resistance would be of clinical interest. In addition to pump function, MRI guided catheterization was demonstrated to accurately measure myocontractility and vascular resistance. We now extended this method for acquisition of the EDPVR. Subsequently, this approach was applied in patients with Fontan hemodynamic in which abnormalities in pulmonary vascular, myocontractile and diastolic properties are debated.The EDPVR was determined by synchronizing invasive ventricular pressures with cine and real-time MRI derived ventricular volumes and pulmonary/aortic blood flow measurements.In 7 pigs the MRI and conductance-catheter method (gold standard) were compared for measuring the EDPVR at rest and during dobutamine.Parameters of global function, myocontractility (ESPVR), vascular resistance and EDPVR were measured with MRI at rest and under dobutamine in 14 patients with Fontan circulation.Bland-Altman test showed agreement between the conductance-catheter and MRI method. In the pigs, there was in both ventricles during dobutamine a right/bottom shift of the EDPVR, the stiffness co efficient decreased slightly (p < 0.051). In the patients during dobutamine we noted failure to increase stroke volumes despite increased contractility and evidenced diastolic dysfunction. Active relaxation was inconspicuous but the EDPVR shifted towards the left/top, the stiffness constant remained unchanged. Pulmonary resistance decreased slightly (p = 0.058) and thus showed adequate response to augmented cardiac outputs.This novel MRI method provides differential information about diastolic, systolic and vascular function. The method evidenced that in Fontan patients diastolic dysfunction is an important pathophysiologic cause of heart failure."} +{"text": "Chronic stress creates vulnerability to adverse mental and physical health outcomes in later life. While claims about the negative effects of stress on health are primarily based on self-report, it is unclear how subjective stress measures (chronic or perceived stress) and other environmental or individual characteristics relate to physiological stress response. This study examines which contextual features contribute to differences in physiological stress reactivity among adults at risk of type II diabetes . Psycho-social stress was induced via Trier Social Stress Test. Using advanced selection methods, we simultaneously explore multiple predictors and illustrate how different sets of risk and protective factors contribute to normal or abnormal stress reactivity profiles. Preliminary results suggest that the top five important predictors are education, contact with friends, perceived stress, ruminative coping, and sedentary behavior. Implications for research and targeted interventions are discussed."} +{"text": "Our purpose was to document the swept source optical coherence tomography (SSOCT) findings in a patient with Shaken baby syndrome (SBS).SSOCT was obtained without sedation in a six-month-old girl with bilateral multilayered retinal hemorrhages due to SBS. It documented vitreoretinal interface abnormalities, including internal limiting membrane (ILM) detachment with retinal traction, in association with other specific changes in the inner and outer retinal layers. Six weeks later, retinal hemorrhages had substantially resolved, and there was optic disc pallor. OCT showed ILM reattachment with release of retinal traction and the development of severe diffuse retinal atrophy involving the fovea.SS OCT can provide useful information in SBS, revealing a wide variety of vitreoretinal interface, inner, and outer retinal changes not detected by clinical examination. It also may have a prognostic value over follow-up. Shaken baby syndrome (SBS), also known as abusive head trauma, refers to a constellation of clinical findings including bilateral retinal hemorrhages, subdural hemorrhage, and anoxic encephalopathy . RetinalA previously healthy six-month-old girl was brought to the emergency department for paroxysmal crying with brief episodes of loss of consciousness. On physical examination there was a bulging fontanel with associated weak axial posture. A cerebral computed tomography (CT)-scan demonstrated extensive bilateral subdural hemorrhages. The child was admitted to the Pediatric Intensive Care Unit. Ophthalmological examination revealed a poor pupillary response to bright light in both eyes. There were no external signs related to ocular trauma. Fundus examination by indirect ophthalmoscopy revealed bilateral preretinal and intraretinal hemorrhages involving the posterior pole and midperiphery. There was a bilateral boat-shaped premacular hemorrhage. This hemorrhage was larger and associated with a prominent surrounding ring-shaped white retinal fold in the right eye Fig.\u00a0. A diagnThree days after hospitalization, the patient underwent swept source OCT imaging with the DRI OCT Triton plus . Multiple SS-OCT scans could be obtained without sedation, the infant being held and her eyelids kept open by an assistant. OCT confirmed multilayered retinal hemorrhages in both eyes. It showed a dome-shaped detachment of the internal limiting membrane (ILM) overlying the macular hematoma bilaterally, with associated perifoveal retinal traction corresponding to the retinal fold seen clinically in the right eye Fig. . Other SSequential follow-up examinations showed gradual resolution of the neurological symptoms and improvement of pupillary response to light. Six weeks after initial examination, retinal and preretinal hemorrhages had substantially resolved, and there were bilateral areas of subretinal fibrosis and optic disc pallor, mainly in the right eye Fig.\u00a0.Fig. 2aSS OCT, six weeks after initial presentation, showed complete reattachment of the detached ILM, with release of retinal traction and resolution of other acute findings. There was a bilateral marked diffuse retinal atrophy involving the fovea with associated subretinal hyperreflective lesions corresponding to the areas of subretinal fibrosis seen clinically Fig. .To the best of our knowledge, this report is the first to describe the use of SS OCT in the assessment and monitoring of retinal disease associated with SBS. Thanks to the faster acquisition times of SSOCT technology, OCT scans could be obtained without sedation, although an assistant was required to hold the infant\u2019s head. Until recently, time domain and conventional or hand-held spectral domain (SD)-OCT have been rarely used in very young children with acute SBS \u20135. OCT iAnother dimension of ocular changes in SBS was described in the field of forensic pathology. OCT findings may provide valuable information suggestive of child abuse in the absence of external evidence of trauma .Our study expands the OCT spectrum of SBS to include a wide variety of previously undescribed vitreous and retinal changes, including alterations of the outer retinal layers. On follow-up OCT examination, severe retinal atrophic changes became evident after resolution of hemorrhages and other acute findings. Our data show that macular atrophy may be an important causative mechanism of severe vision loss in children with SBS.In conclusion, thanks to its faster acquisition time and deeper penetration, SSOCT may be useful in the evaluation and monitoring of ocular disease in awake young children with SBS. It can provide useful information, revealing a wide variety of vitreoretinal interface, inner, and outer retinal changes not detected by clinical examination. It also may have a prognostic value over follow-up."} +{"text": "The geometric framework for nutrition has largely been applied to macronutrients in experimental settings. Here, we utilize the framework to examine both macro and micronutrient intake patterns in observational human data. We used nutritional intake patterns of 1754 older Quebecers from the NuAge cohort to predict multi-system homeostatic dysregulation scores calculated from 30 biomarkers. Intermediate intake of both macro- and micronutrients was generally associated with lower dysregulation scores . Furthermore, there were often nutrient-nutrient interactions, such that the optimal level of one nutrient depends on the intake level of others. However, higher protein intake was generally associated with better health, and results varied substantially across different dysregulation systems. Accordingly, even though nutrition does have important effects on health trajectories during aging, it will be challenging to arrive at population-level recommendations to fine-tune nutrient intake patterns to optimize health beyond \u201ceverything in moderation.\u201d Part of a symposium sponsored by the Nutrition Interest Group."} +{"text": "The current study takes a dyadic perspective to understand how self-perceptions of aging are associated with C-reactive protein, an inflammation marker, among older adult married couples. The potential moderating role of marital support and strain are also examined. Respondents include 668 married couples who participated in the 2014 wave of the Health and Retirement Study. Actor-Partner Interdependence Models were conducted in Mplus. Age, functional limitations, income, and race served as covariates. Husbands\u2019 greater positive perceptions of aging were significantly associated with their own lower levels of inflammation. Husbands\u2019 greater positive perceptions of aging were significantly associated with lower levels of inflammation for women who reported lower levels of marital strain; this was not the case for women who reported higher levels of marital negativity. This study exemplifies how relationship factors are necessary to consider when examining age perceptions and health among marrieds."} +{"text": "The knowledge regarding hypothalamic integration of metabolic and endocrine signaling resulting in regulation of food intake is scarce in fish. Available studies pointed to a network in which the activation of the nutrient-sensing systems would result in AMP-activated protein kinase (AMPK) inhibition and activation of protein kinase B (Akt) and mechanistic target of rapamycin (mTOR). Changes in these signaling pathways would control phosphorylation of transcription factors cAMP response-element binding protein (CREB), forkhead box01 (FoxO1), and brain homeobox transcription factor (BSX) leading to food intake inhibition through changes in the expression of neuropeptide Y (NPY), agouti-related peptide (AgRP), pro-opio melanocortin (POMC), and cocaine and amphetamine-related transcript (CART). The present mini-review summarizes information on the topic and identifies gaps for future research. Two neuronal populations in the mammalian hypothalamic arcuate nucleus respond to a rise in the levels of circulating metabolites . They renucleus lateralis tuberis (NLTv), an analog of arcuate nucleus , specific fatty acid receptors (FFAR), fatty acid translocase, and lipoprotein lipase. Evidence is also available in other species like grass carp induced a rise in hypothalamic Bsx mRNA abundance (In fish, evidence regarding BSX role in hypothalamus is limited with a f nucleus as well nucleus in paralbundance .Npy and Agrp leading to a decrease in food intake (Npy and Agrp (cAMP response-element binding protein is another transcription factor hypothesized to be involved in the connection between brain metabolism and neuropeptides expression. Accordingly, in mammals, a decrease in CREB levels induced a decrease in mRNA abundance of d intake . CREB prand Agrp while leand Agrp or food and Agrp .In fish, available information regarding CREB involvement in food intake regulation is restricted to rainbow trout. In this species, CREB phosphorylation status decreased in response to raised levels of oleate , octanoaAgrp mRNA values while those of Pomc decreased, changes favoring a decrease in food intake (Forkhead box01 is likely involved in the relationship between metabolic changes in hypothalamus and the production of neuropeptides . Thus, id intake .Foxo1 to changes in nutrient levels. However, changes observed in fish would be comparable with those observed in mammalian hypothalamus under anorectic conditions like feeding a high-fat diet (In fish, FoxO1 was characterized in brain in rainbow trout and turbfat diet or treatfat diet . Akt actfat diet , which afat diet . In fishfat diet , octanoafat diet , or insufat diet but not fat diet . These rAgRP/NPY and CART/POMC neurons involved in the integration of signals from nutrient sensors also have receptors for hormones like leptin, ghrelin, insulin, CCK, or GLP-1, among others . The binbsx and mtor mRNA abundance as well as in the presence of oleate for Akt phosphorylation status, and foxo1 and creb1 mRNA abundance. No other studies characterized in fish putative interactions in hypothalamus. However, in rainbow trout treatment with different hormones alter nutrient sensing mechanisms in hypothalamus (In fish, only two studies carried out in rainbow trout demonstrated interactive effects in hypothalamus between nutrient-sensing mechanisms and hormones such as ghrelin and insulin. The presence of oleate counteracted ghrelin effects on AMPK . In the thalamus as demonThe knowledge available in fish about hypothalamic integration of information of metabolic and endocrine nature eliciting changes in expression of neuropeptides ultimately regulating food intake is limited . StudiesThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Introduction. We present a case of serpiginous choroidopathy (SC) with novel OCTA and en face OCT reflectance findings which help identify subclinical disease progression. Case Presentation. En face OCT reflectance images demonstrated outer retinal tubules (ORT) at the serpiginous lesion margins of affected and unaffected retina on multimodal imaging. OCTA findings demonstrate variable dropout of choriocapillaris in \u201cnormal\u201d retina beyond lesion borders which was not visible on standard imaging and which demonstrated a clear transition zone beyond the ORT. Discussion. This is the first report of choriocapillaris atrophy identified on OCTA not identified on traditional multimodal imaging in serpiginous choroidopathy. Damage to vasculature only visible with OCTA may help characterize the distribution of inflammation, aiding in monitoring of suppression not illustrated by traditional imaging and which may threaten the central macula. ORT in SC suggest death and reorganization of outer segments from dysfunction of the choriocapillaris and RPE, as well as serve to demarcate the area of chronic or old inflammation, supporting the hypothesis that the choriocapillaris is the primary site of inflammation in SC. Based on these findings, we recommend OCTA on all patients with serpiginous choroidopathy to monitor underlying state of inflammation and help determine immunosuppressive threshold. The pathogenesis of SC is poorly understood, with clinical and histologic studies suggesting autoimmune, infectious, vasculopathic, and retinal degenerative etiologies , 2. ReceA 37-year-old female with no past medical or ocular history presented with 2 weeks of redness, pain, and photophobia of her right eye (OD). She was diagnosed with acute anterior uveitis by an outside provider and started on topical difluprednate four times daily (QID) and cyclopentolate once daily (QD) OD. Upon presentation to our facility, she reported slight improvement in her symptoms 2 weeks into treatment.On initial examination, visual acuity was 20/20 in her right and 20/20 in her left eye (OS) with unremarkable pupillary exam and normal intraocular pressure. Anterior segment examination of the right eye (OD) revealed 2 areas of anterior corneal stromal scarring and 0.5+ anterior chamber cell without flare. One area of anterior stromal scarring and trace cell without flare was seen OS. Fundoscopy revealed 0.5+ vitreous cell without haze in both eyes (OU); healthy appearing optic nerves OU; and extensive, serpentine peripapillary chorioretinal scarring OU with extension into the macula Figures . There wThe patient rapidly improved, and immunomodulatory therapy was initiated with a standard steroid taper. At one-month follow-up, en face OCT reflectance and OCTA imaging were obtained, which demonstrated severe atrophy with outer retinal tubules and patchy dropout of choriocapillaris in areas of otherwise normal-appearing retina, respectively . Over thWe present a case of serpiginous choroidopathy (SC) imaged with OCTA and en face OCT reflectance imaging. Images were obtained and processed based upon previously described methodologies in the literature , 4.OCTA imaging showed dropout of the choriocapillaris at lesion margins and discontinuously in adjacent areas centrally which appeared normal on traditional imaging such as FA . Prior tOCT angiography allows a noninvasive assessment of choroidal and deep vasculature sometimes not evident on fluorescein angiography (FA). Recently, several small case series of OCTA in SC have suggested extensive inflammation in deep retinal vessels, RPE, and choriocapillaris. Desai et al. reported a series of 6 eyes of 3 patients with active and inactive SC. In this series, active patients demonstrated absence of choriocapillaris with thickening of overlying RPE and outer retinal layers on OCTA in areas of atrophic serpiginous lesions . InactivWe analyzed en face OCT reflectance image slabs, as well as cross-sectional OCT images. En face OCT reflectance imaging demonstrated outer retinal tubules at the quiescent serpiginous margins just adjacent to those areas of atrophic choriocapillaris on OCT which were normal-appearing on funduscopy and FA . Cross-sOn SD-OCT imaging, outer retinal tubules appear as circular areas of hyporeflectivity with a ring of hyperreflectivity contained within the outer nuclear layer. Prior investigations of outer retinal tubules have centered around age-related macular degeneration (AMD) and spectral domain OCT (SD-OCT) but never reported in SC. Of the 69 eyes with outer retinal tubules identified in one study, 81% were attributable to AMD , 11. GivSevere choriocapillaris inflammation may be the cause of outer retinal atrophy in serpiginous choroidopathy, with the presence of ORT signifying reorganization of photoreceptors localizing inflammation to this area. Current multimodal imaging without use of OCTA is widely accepted for the diagnosis and monitoring of SC. In this report, we describe a patient with OCTA findings of choriocapillaris atrophy demonstrating subclinical disease beyond serpiginous lesion borders visible on standard imaging. Loss of choriocapillaris integrity in areas outside of the serpiginous borders suggests subclinical activity which, if followed with OCTA, may aid in earlier identification of progression or more targeted timing for tapering of immunomodulatory therapy if stable. This suggests that OCTA may be more sensitive than SD-OCT and FA in identifying activity in SC and should be more widely adopted in the long-term management of these patients."} +{"text": "Understanding age-related change in cognition and identification of pathological changes requires sensitive and valid measurement of cognitive performance across time. Technological advances, such as ambulatory assessment of cognition using smartphones, have enabled intensive longitudinal methods where data is collected with many measurements over time. Our research group has developed novel ambulatory assessments that provide reliable, sensitive, and ecologically valid measurement of cognition across multiple timescales; from momentary changes to change across years. This symposium will present a spectrum of approaches to analysis of intensive longitudinal data that can inform models of cognitive aging. All three presentations will draw on data from measurement burst studies that apply our ambulatory cognitive assessment methods in community-based samples . For each measurement burst, participants undergo assessment consisting of brief surveys and cognitive tests via smartphone, up to 7 times per day across 14 days. Oravecz et al. will discuss the application of a Bayesian multilevel implementation of the double exponential model to account for retest effects while quantifying change in peak cognitive performance across time. Kang et al., will demonstrate a growth curve modeling approach for assessing the effects of between-person variables on change in cognition across measurement bursts. Harrington et al., will demonstrate a model-based cluster analysis approach, leveraging ambulatory assessments of subjective and objective cognitive function to unpack latent groups as a function of age and loneliness. Measurement, Statistics, and Research Design Interest Group Sponsored Symposium."} +{"text": "Evidence suggests a growing retirement crisis in the United States among older adults placing many of them at risk of falling into poverty. While Social Security provides income assistance to retirees, the average monthly benefit is $1,300. Among older adults nearing or in retirement, the use of public assistance programs is increasing. Using data collected by the Associated Press-NORC Center for Public Affairs Research we examine retirement preparedness, borrowing from retirement plans, and use of social welfare programs. Findings indicate increased borrowing from retirement plans due to debt, significant differences in racial and gender groups accessing and receiving services among those 75 and older. Increasing rates of unpreparedness for retirement exist among older Americans, particularly among adults of color. An increase in the use of safety net services among older adults is occurring concurrently with severe funding reductions in social welfare programming."} +{"text": "Migraine is a multifaceted brain disorder where multisensory disturbances are associated with headache. Yet sensory symptoms are conventionally justified by dysfunctions confined to the cerebral cortex, a perspective through the complex interplay of thalamocortical network would provide the entire picture, more pertinent to the central sensory processing. It is important to consider thalamus as a hub that integrates multiple domains via extensive connections among anatomically and functionally separate cortical areas. Accordingly, cortical spreading depression (CSD), implicated in migraine pathophysiology can be seen as a tool to disconnect thalamocortical network by functionally eliminating cerebral cortex. Hence, including thalamic reticular nucleus and higher order thalamic nuclei, which conveys the information transthalamically among visual, somatosensory, language and motor cortical areas, would greatly improve our current understanding of migraine. Migraine is the most prevalent brain disorder under age of 50 all around the globe and the first cause of disability due to severe headache and associated sensory disorders [1]. The characteristic features of pain are one sided, severe, pulsating headache attacks, worsening by daily movements and lasting 4\u201372 h. Accompanying sensorial symptoms suggesting hyperresponsivity in the somatosensory, visual, auditory, and olfactory systems are distinguishing features of migraine attacks and multisensory stimuli may worsen the headache severity [2]. Additionally, prior to the headache phase more pronounced sensorial disruptions can occur in the visual and somatosensory system such as scintillations, scotoma or paresthesia, numbness in the extremities. These slowly propagating sensory deficits are recognized as aura symptoms and implicated by underlying cortical spreading depression (CSD) waves [3]. CSD is a neuronal and glial depolarization wave that slowly propagates within the cerebral cortex, causing transient electrical and functional silence of the involved area. Propagation of massive depolarizations and accompanying electrical DC shift and regional blood flow increase along the cortex, left long-lasting decreased neuronal excitability and reduced regional blood flow behind . The sensory aura symptoms are considered solely due to cerebral cortical dysfunction by CSD. However, this conventional approach disregards several facts that i) propagation of CSD in gyrencephalic brains such as humans, primates and even felines is very restricted [4], ii) cerebral cortex functions in a synchrony with thalamus and brain network systems. In that sense CSD was essentially used to generate functional ablation of cerebral cortex in thalamic studies [4]. Understanding the function of cerebral cortex requires knowledge of complex interaction between the cortex and the thalamus, known as thalamocortical network. The cerebral cortex and the thalamus operate in continuous interaction during the process of any information particularly related to somatosensory, visual and auditory sensory systems, movement, language, cognition and consciousness . The thalamus sends projections to majority of the cerebral cortex, and receives cortical outputs in return. Thalamic nuclei transmitting peripheral sensory inputs to the primary cerebral cortical areas are considered as the first-order relay nuclei such as the ventral posteromedial (VPM) and lateral geniculate nucleus (LGN) that relay cephalic somatosensory inputs and visual stimuli respectively. Likewise, the higher-order thalamic nuclei receive inputs from the deep cerebral cortical layers and relay information from one cortical area to another . By this means, higher-order thalamic nuclei function as hubs that synchronize distant cerebral cortical areas via transthalamic cortico-cortical connections [7]. The deep cortical cells particularly from the 6th layer, also project to inhibitory neurons in the thalamic reticular nucleus (TRN) and modulate the frequency-dependent thalamic function [6\u20138]. The TRN consists of GABAergic inhibitory neurons and surrounds the dorsal thalamus. While the TRN exclusively projects to the thalamus and inhibits thalamic drive to the cortex, its neurons are driven by the first- and higher-order thalamic nuclei as well as the cerebral cortex . TRN involvement during CSD was demonstrated in awake, consciously behaving experimental animals . CSD induced SD waves were recorded in TRN and neuronal activation was demonstrated. It is likely that either SD in the cerebral cortex could provoke SD in TRN or SD waves propagate from cerebral cortex to the TRN, as subcortical structures are more susceptible compared to highly convoluted cerebral cortex in humans [4]. Involvement of the TRN may play a role in reduced sensory discrimination, lateral inhibition and increased response to sensory stimuli in different modalities such as light, sound and touch during migraine attacks. A subset of cortical deep projection neurons was shown to project selectively to higher order thalamic nuclei in mice and recently the higher order thalamic dysfunction was proposed to be involved in the development of migraine symptoms . Instead of attributing sensory dysfunctions merely to the cerebral cortex, alternative view proposes a complex interaction of first- and higher-order thalamocortical areas along with TRN . A minimum critical volume of 1 mm3 rodent cortical brain tissue was estimated to be depolarized to ignite CSD [11]. Even if the propagation of CSD is blocked, such a depolarized cortical focus is sufficient to create a change in ongoing cortico-thalamic drive on thalamic relay nuclei and thalamic reticular nucleus. During CSD, abrupt cessation of cortical neuronal firing, would result in decreased excitatory glutamatergic drive from cortexto the thalamus, leading to a reduced GABAergic output from TRN on to thalamic relay nuclei and increased sensory impulses through thalamic relay to the cortex . That would account for the increased sensory excitation, sensory hyperresponsivity, reduced discrimination and reduced lateral inhibition and bidirectional role of sleep in migraine. Therefore, the processing of somatosensory stimulus and sensory discrimination was investigated in migraine patients [12\u201316]. For that purpose, somatosensory temporal discrimination (STD) test was employed. STD detects the temporal threshold to perceive two consecutive somesthetic stimuli as undoubtedly distinct [12\u201314]. STD was remarkably prolonged during the migraine attack while STD threshold values outside the migraine attacks were comparable to healthy volunteers [12]. STD studies also revealed that such a prolongation was specific to migraine attacks and was not detected during tension type headache, which is another common headache disorder [14]. It is an intriguing finding that discrimination of somatosensory stimuli applied to the hand that is transmitted through a pathway via thalamic ventral posterolateral nucleus (VPL), is disturbed during migraine attacks. Indeed, migraine headache is transmitted through a different pathway via trigeminal nerve to the thalamic ventral posteromedial nucleus (VPM). Hence, it is unlikely that prolonged temporal discrimination of somatosensory stimulus applied to hand is merely mediated as a direct result of trigeminal nerve or thalamic VPM activation. Transient impairment in the ability of discriminating the exact entry of somatosensory stimuli suggested a central processing dysfunction. Further study was conducted by short afferent inhibition (SAI) paradigm using transcranial magnetic stimulation [16]. SAI evaluates integration of somatosensory input through the thalamic relay neurons in the sensorimotor cortex. The SAI results revealed that impaired sensorimotor integrity and reduced cortico-cortical inhibition between somatosensory and motor cortices were associated with migraine attacks [16]. SAI impairment during migraine attacks, indicated a disinhibition in the sensorimotor integration. Remarkably, the facilitation of motor responses to a conditioned sensory stimulus was detected even several hours prior to the onset of migraine headache [16]. Therefore, the possible involvement of higher order centers seems undisputable. In the higher order thalamic nuclei such as pulvinar, that would be manifested by the disrupted visual information processing and may be related to positive visual hallucinations superimposed on to a first-order incoming information, similar to the patients\u2019 visual auras [4]. Also, higher order visual areas and somatosensory areas are associated with medial and anterior part of the pulvinar that is a multimodal sensory integration area [17]. Therefore, loss of any incoming information by CSD from one of the interconnected cortical areas such sensorimotor cortex or visual cortex to the pulvinar would change impulse trafficking and may yield multisensory sensory symptoms synchronously and/or sequentially.Thus, the view of thalamocortical network dysfunction would clarify positive aura symptoms and simultaneous manifestation of different symptoms related to distant cortical areas such as visual, sensorimotor and language cortices interconnected through a thalamic hub. Additionally, sensorial disruptions in more than one domain accompanying migraine headache can be attributed to multisensory integration dysfunction of the higher order thalamocortical network. Involvement of TRN would contribute sensory hypersensitivity in multiple sensory modalities, lateral inhibition and sensory discrimination problems associated with migraine headache. Additionally, activation of trigeminal pain nucleus through central pathways as a result of thalamocortical dysfunction could also contribute to the development of lateralized migraine headache."} +{"text": "The proportion of women of reproductive age who are overweight or obese is increasing globally. Gestational obesity is strongly associated in both human studies and animal models with early-onset development of adult-associated metabolic diseases including metabolic syndrome in the exposed offspring. However, animal model studies have suggested that gestational diet in obese pregnancies is an independent but underappreciated mediator of offspring risk for later life metabolic disease, and human diet consumption data have highlighted that many women do not follow nutritional guidelines prior to and during pregnancy. Thus, this review will highlight how maternal diet independent from maternal body composition impacts the risk for later-life metabolic disease in obesity-exposed offspring. A poor maternal diet, in combination with the obese metabolic state, are understood to facilitate pathological in utero programming, specifically through changes in lipid handling processes in the villous trophoblast layer of the placenta that promote an environment associated with the development of metabolic disease in the offspring. This review will additionally highlight how maternal obesity modulates villous trophoblast lipid processing functions including fatty acid transport, esterification and beta-oxidation. Further, this review will discuss how altering maternal gestational diet may ameliorate these functional changes in lipid metabolic processes in the obese placenta. Throughout the gestational period, maternal nutrient handling must adapt to the increasing needs of the growing fetal-placental unit to ensure developmental processes continue in a healthy and physiological manner. For example, maternal insulin sensitivity diminishes, and fasting serum lipid levels rise late in gestation to preserve necessary macronutrients for trans-placental transport into fetal circulation ,2,3. HowFurthermore, alterations in lipid processing functions of the placenta\u2014including fatty acid (FA) transport, lipid esterification and FA beta-oxidation\u2014have been thought to modulate materno-fetal lipid transport and the resulting changes to fetal lipid exposures may underlie metabolic disease programming. This review will additionally highlight how maternal obesity modulates these lipid handling processes in the placenta and discuss how maternal diet may program these placental processes independently from increased maternal adiposity.The study of the impacts of maternal gestational environment on fetal growth and development is encompassed within the field of research known as The Developmental Origins of Health and Disease (DOHaD) ,5. This 2), whereby a BMI > 25 is overweight and a BMI > 30 is obese palmitate oxidation rates in cultured villous trophoblast cells from otherwise healthy obese Ohioan women [Maternal diet has been identified to impact placental lipid oxidative function in some obese women. Specifically, obese Hawaiian women, who consume the Pacific diet, have been found to have similar mRNA expression levels of mitochondrial and peroxisomal beta-oxidation enzymes as lean Hawaiian women Figure . This maan women . While POne potential method to quantify placental beta-oxidative function is to examine the acylcarnitine profiles of maternal blood products. Under normal physiological conditions, complete beta-oxidation occurs whereby all carbon atoms in the FA backbone are converted into acetyl-CoA molecules that are oxidized for ATP production ,96. HoweAcylcarnitine profiles have previously been examined as potential biomarkers for the early detection of other placental diseases such as pre-eclampsia ,111. SpeAccumulation of shortened acylcarnitine species has also previously been linked to an increased expression of pro-inflammatory molecules . For exaOverall, acylcarnitine analysis may represent a relatively unexplored field in placenta physiology. Analysis of differences within these profiles of obese and lean women may allow clinicians to diagnose placental mitochondrial dysfunctions in conjunction with inflammatory responses early during the gestation period. In turn, acylcarnitine biomarkers may allow clinicians to monitor the impact of dietary interventions on placental lipid handling during gestational period and modulate the course of treatment to limit the risks of offspring development of later life disease.A maternal consumption of a diet high in saturated FA species and low in PUFA species during the gestational period may promote adverse placental function that underlies the development of placental and fetal metabolic dysfunction, independent to maternal body composition. Understanding the mechanisms that underlie placental metabolic dysfunctions associated with dietary fat in obese pregnancies and the accompanying offspring metabolic disorders will require a robust understanding of placental lipid transport, esterification and oxidation . A great"} +{"text": "Human brain organoids cultured from human pluripotent stem cells provide a promising platform to recapitulate histological features of the human brain and model neural disorders. However, unlike animal models, brain organoids lack a reproducible topographic organization, which limits their application in modeling intricate biology, such as the interaction between different brain regions. To overcome these drawbacks, brain organoids have been pre-patterned into specific brain regions and fused to form an assembloid that represents reproducible models recapitulating more complex biological processes of human brain development and neurological diseases. This approach has been applied to model interneuron migration, neuronal projections, tumor invasion, oligodendrogenesis, forebrain axis establishment, and brain vascularization. In this review article, we will summarize the usage of this technology to understand the fundamental biology underpinning human brain development and disorders. The human central nervous system (CNS) develops from several distinct vesicles into multiple intertwined regions. During this process, a range of migratory streams arise where progenitors generated in one place migrate and integrate into other areas : the medial ganglionic eminence (MGE) and the caudal ganglionic eminence /CGE cells were observed to migrate into dorsal regions. Slice culture of dorso-ventral fusion organoids and time-lapse imaging analysis revealed characteristic interneuron migratory dynamics. Administration of the CXCR4 antagonist AMD3100 onto organoid slice cultures perturbed the migration, supporting a potential application of the fusion platform for drug screening.Bagley et al. also estNKX2-1::GFP reporter human embryonic stem cell (hESC) line. RNA-seq, scRNA-seq, and chromatin accessibility analysis revealed that hMGEOs exhibited a strong correlation with the transcriptional signature of the MGE tissues from of human fetal brain. By fusing human cortical organoids (hCOs) and hMGEOs, they established hMGEOs-hCOs fusion organoids, named hfMCOs. GFP+ but RFP\u2212 interneuron progenitors migrated into the neuronal layer of hCOs. Their migration can be inhibited by the application of blebbistatin, a myosin II inhibitor. Besides, functional synapses in hfMCOs were also observed by calcium imaging analysis.Further, Xiang et al. generateFurthermore, using a dorsoventral organoid fusion model, Yuan et al. showed tLong distance-projections play essential roles in brain functions. According to recent reports, corticothalamic interactions are relevant for sensorimotor interplay, selective attention, and arousal behaviors is the deadliest and most widespread primary brain tumor in adults. Their property to spread through infiltration in the host brain tissue is associated with high resistance and recurrence rate. To understand the mechanism underpinning this invasive phenotype, organoid-GBM fusion models are particularly appropriate. Ogawa et al. fused tuv\u03b25 axis as a potential mechanism for ZIKV tropism. Thus, organoid-GSC fusion models could be used as in vitro platforms to characterize GBM invasiveness and screen for potential therapeutics.Tumor-organoid fusion models have been used for preclinical therapeutic studies. Previously, the Zika virus (ZIKV) has been proven to be a potential oncolytic virus for brain tumor therapy because of its tropism towards tumor cells are the myelinating glial cells of the brain and the last type of neural cells to be generated after neurons and astroglial cells during mammalian brain development spheroids, endothelial cell (iEC) spheroids, and mesenchymal stem cells (MSCs; Song et al., in vivo vascularization during brain development, and significant improvements still need to be done before obtaining functional vascular networks in organoid cultures.During brain development, the vasculature is one of the important niche components for neural stem cells and plays critical roles in neurogenesis (Bjornsson et al., in vitro. The fusion strategy should not be limited to the fusion of brain tissues as it can be applied to assemble brain organoids with other types of organoids to study the interaction between different organs. For instance, hepato-biliary-pancreatic organogenesis has been modeled using a multi-organoid fusion approach (Koike et al., Brain organoid fusion technology allows us to study more complicated biology during human brain development and neural disorders using hESCs or patient-derived iPSCs, including interneuron migration, and neuronal projections. Using the same technique, researchers can also study other pathological processes and potential mechanisms, such as corpus callosum deformity. Assembling multiple different brain regions would be the next step towards a more complete human \u201cmini-brain,\u201d which could then be used to study biological mechanisms requiring the interaction of several brain regions AC, ZG, and LF wrote the manuscript. AC and ZG prepared the figures. SB directed the manuscript preparation and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "We discuss synergies between sequencing and imaging techniques for the discovery and validation of local molecular signaling mechanisms regulating synaptic development, plasticity, and maintenance in circuits.A key challenge in developmental neuroscience is identifying the local regulatory mechanisms that control neurite and synaptic refinement over large brain volumes. Innovative molecular techniques and high-resolution imaging tools are beginning to reshape our view of how local protein translation in subcellular compartments drives axonal, dendritic, and synaptic development and plasticity. Here we review recent progress in three areas of neurite and synaptic study In neuroscience, physical maps of synaptic connections between neurons (\u201cconnectomes\u201d) help to refine hypotheses about neural computation and provide a shared anatomical resource to guide investigations of circuit function and pathologies associated with human brain disease. Physical maps of developing circuits can also help to identify progressive structural changes across stages of neuronal and synaptic maturation. Connectomic maps are produced using volumetric electron microscopy (EM) techniques that provide dense reconstructions of all cellular processes and synaptic connections in brain tissue. Continued progress in automated sample collection, high-throughput imaging, and computational analysis molecular-genetic approaches for quantifying mRNA diversity, abundance, and regulation of the local transcriptome/translatome in targeted subcellular compartments; (2) proteomic techniques for labeling, isolating, and quantifying nascent proteins and protein-protein interaction networks in specific synaptic connections; and (3) super-resolution fluorescence microscopy for multi-scale imaging and quantitative analysis of subsynaptic molecular organization within developing microcircuits. When applied together, advanced techniques in these areas have important synergies that facilitate discovery, validation, and throughput in new experiments designed to study the local molecular regulation of neural circuit development.In this review article, we discuss a bottom-up \u201cdevelopmental molecular connectomics\u201d approach for investigating the regulation of local molecular remodeling during circuit refinement . We highNeural circuit development requires the precise formation and selective plasticity of synaptic connections distributed across each neuron\u2019s polarized geometry (axons/dendrites) at significant distances from the soma. Because each synapse is an intricate molecular machine assembled from thousands of proteins, the development of circuit connections creates a significant metabolic demand for individual neurons and perform RNA sequencing analysis of compartment-specific isolates for comparison . Such exTo address questions about directed trafficking and mRNA enrichment in specific spatiotemporal contexts, an immunopurification approach called Translating Ribosome Affinity Purification (TRAP) was developed for isolating genetically-tagged ribosomes and their associated mRNAs in targeted circuits uses the transgenic expression of synapse-specific fluorescent fusion proteins to purify specific synapse types from total synaptosomal fractions based on fluorescence-activated cell sorting granules over long distances to dendrites and axons to establish local transcriptome pools axons is developmentally-regulated and shifts during different stages of circuit refinement where mRNAs encoding essential respiratory chain complex proteins are locally translated and assembled into mitochondria in response to stimulation . The induction of hippocampal LTP/LTD Direct evidence for local (synaptic) protein production in response to synaptic stimulation comes from glutamate photouncaging experiments which drive spine growth and local protein synthesis in single activated spines to isolate proteins for quantitative analysis , genetically-encoded proximity-labeling tools have been developed to selectively tag and purify interacting protein complexes from synapses Proximity-labeling experiments with APEX2 fused to presynaptic terminal protein alpha-synuclein identified hundreds of interactors including synaptic proteins, vesicle trafficking proteins, RBPs, and translation initiation factors important for local protein synthesis has been mapped both with BioID or inhibitory (gephyrin) scaffolding molecules conjugated to BirA, the promiscuous biotin ligase was used to study the developmental maturation of olfactory projection neurons provides unparalleled image resolution for synapse analysis but is difficult to combine with conventional molecular labeling tools due to challenges imposed by the use of strong chemical fixatives and epoxy resins in the sample preparation. Further development of EM-compatible transgenic labeling tools will be useful for identifying specific molecular targets and cell/synapse types in EM images patterned excitation approaches [e.g., STimulated Emission Depletion (STED) microscopy , a structural protein at the Drosophila neuromuscular junction (NMJ) essential for the developmental positioning of Ca2+ channels and synaptic vesicles to reconstruct the relative spatial positions of pre/postsynaptic proteins in thin cryosections of brain tissue to map synaptic structure with molecular specificity and nanoscale resolution organization and antibody elution on ultrathin sectioned brain material to achieve multiplexed proteomic imaging with improved axial image resolution while further enabling correlative electron microscopy (Micheva and Smith, in situ (Lein et al., in situ RNA sequencing (FISSEQ; Lee et al., in situ hybridization methods such as multiplexed error-robust fluorescence in situ hybridization (MERFISH; Chen K. H. et al., in situ hybridization (seqFISH; Lubeck et al., in situ and has been further used to identify cell populations that are specifically active during social behaviors (Moffitt et al., in situ hybridization has been performed with expansion microscopy (Chen et al., Multi-round labeling has also been used to develop spatial transcriptomic approaches for mapping RNA identity and position in vitro using PAINT (Guo et al., in situ hybridization strategies for spatial transcriptomic imaging (Chen K. H. et al., In a step toward this goal, multiplexed super-resolution synaptic proteome imaging has been achieved using DNA-oligo-linked primary antibodies which are imaged across multiple rounds of hybridization using complementary detection oligos (Wang et al., The developmental connectomics strategy presented here enables new experiments to determine the molecular blueprint for synaptic development and plasticity in neural circuits. The application of complementary techniques in transcriptomics, translatomics, proteomics, and super-resolution structural imaging establishes an integrative framework for investigating mechanistic links between mRNA trafficking, local protein synthesis regulation, and changes in subsynaptic molecular organization underlying circuit development.Molecular sequencing experiments, both at the RNA and protein levels, generate foundational databases identifying regulators of connectome development and plasticity. Also, proteomic (Sharma et al., Several analytical approaches for integrating multiomic data have been applied to better define cell types in the mature and developing brain (Stuart et al., Though deep learning methods have thus far been developed for analyzing cell types and spatial organization, related approaches should facilitate integrative analysis of subcompartment-specific multiomic and super-resolution imaging data to characterize molecular networks driving synaptic/neurite maturation and plasticity (Poulopoulos et al., JM and CS wrote the manuscript and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Continuous, long-term monitoring with remote capabilities using wearable technology is ideal for capturing information about patient/participant symptoms synced to sensor-based information. The Real-time Online Assessment and Mobility Monitor (ROAMM) is a smartwatch framework configured to collect data in free-living settings from both sensor-based (location and movement) and responses to symptom notifications through a visual display. The symposium presents the overall framework and preliminary findings from a demonstration study in older adults with knee osteoarthritis. Karnati will present the general framework of ROAMM explaining the data flow from the smartwatch to end users (clinicians and research). He will highlight components in the design that makes the framework unique and highly flexible to serve different studies with different research questions. Rouzaud evaluated satisfaction, usability and compliance wearing a smartwatch and using the ROAMM app. Participants were compliant to ecological prompts about pain, fatigue and mood three times a day (82.5% compliance rate). Additionally, > 70% reported being satisfied with the function/usability and comfort with using ROAMM and wearing the smartwatch. Mardini examined the temporal relationship between ecological pain and derived life-space mobility features from Global Positioning System coordinates. Results suggested that higher level of knee pain in older adults was associated with lower life-space mobility. Manini examined physician perception towards an electronic health record (EHR) graphical interface of top ranked patient attributes of pain, falls, hydration and mobility patterns. Results indicated a relatively high level of usability of the EHR interface depicting smartwatch data."} +{"text": "We propose that trauma history is important context for understanding the adaptive capacity of aging adults to achieve a suitable person-environment fit. We conducted a scoping review using bibliographic databases to identify studies focused on aging in place, vulnerability and traumatic personal experiences, and aging adults\u2019 maladaptive behaviors. Our review showed little research directly exploring the connection between trauma-related needs and aging in place and limited research about the community\u2019s role in supporting those needs. Literature about the impacts of trauma revealed that trauma could stem from adverse childhood experiences and adult adverse experiences . Adults who have experienced trauma may have increased physiological and psychological conditions. Sensory sensitivities in the home environment\u2014including sounds , air quality , and lighting \u2014can substantially decrease quality-of-life. Strong emotional reactions can make interpersonal relationships, such as those with a landlord or neighbors, difficult and increase the likelihood of eviction. Aging adults with trauma histories also experience greater poverty rates, increasing the likelihood of substandard housing . Because the housing environment is a significant aspect of overall well-being, challenges to aging in place for adults with trauma histories warrants further research, as does the role of community supports in mitigating housing-related stressors. Examples may include trauma-informed approaches in universal design, the availability of safe affordable housing, community education, and funding for intermediaries who can support aging adults."} +{"text": "Suillus brevipes, a mycorrhizal fungus adapted to coastal and montane habitats in California. In order to assess whether gene copy number variation mirrored population structure and selection in this species, we investigated two previously studied locally adapted populations showing a highly differentiated genomic region encompassing a gene predicted to confer salt tolerance. In addition, we examined whether copy number in the genes related to salt homeostasis was differentiated between the two populations. Although we found many instances of CNV regions across the genomes of S. brevipes individuals, we also found CNVs did not recover population structure and known salt-tolerance-related genes were not under selection across the coastal population. Our results contrast with predictions of CNVs matching single-nucleotide polymorphism divergence and showed CNVs of genes for salt homeostasis are not under selection in S. brevipes.Gene copy number variation across individuals has been shown to track population structure and be a source of adaptive genetic variation with significant fitness impacts. In this study, we report opposite results for both predictions based on the analysis of gene copy number variants (CNVs) of Brachipodium distachyon (Zymoseptoria tritici and Aspergillus fumigatus (Copy-number variants (CNVs) are genes or genomic regions of varying size with different numbers of copies across individuals. Copy-number differences can arise through genomic rearrangements or produce functional divergence across gene copies resulting in differentially adaptive phenotypes . Furthermore, no SNP variation was found in this gene across coastal individuals strongly suggesting a selective sweep for adaptive alleles allowing colonization of saline environments in coastal California. Nha-1 homologs have been reported as important for salt tolerance in other organisms, including increased Nha-1 expression levels in Arabidopsis thaliana allowing survival in high sodium concentrations and montane California populations previously analyzed in Suillus brevipes is a dikaryotic fungus which means two haploid genomes inhabit the same cell, we therefore assumed diploidy of our samples and followed ST following ST formula is available from https://github.com/abazzical/sbrevCNV). Given the reference genome is rather fragmented .We estimated gene copy number variation from the processed Illumina reads of 27 ape package enrichment analysis on the top 1% diverged CNVs between the two Suillus brevipes reference genome , there were no significant differences in CNV number or CNV size between montane and coastal populations (Wilcoxon rank sum test P > 0.05). The vast majority of CNVs were losses across the whole genome , suggesting salt homeostasis genes are not under selection for different copy numbers in the two populations. However, as shown in the heatmap in We found 83 genes involved in salt homeostasis across the Nha-1-like gene; ProteinID 1095265) showed a range of copy numbers across individuals and its annotation incomplete and based on sequence similarity-based gene predictions and there might be adaptive CNVs related to salt tolerance in the remainder of the genome that remained undetected.Both biological and technical factors likely contributed for the absence of concordance between CNVs and SNPs in lifornia , the preS. brevipes (In conclusion, our results complement findings from previous studies on environmental adaptation in the mycorrhizal fungus"} +{"text": "Biliary and pancreatic cancers occur silently in the initial stage and become unresectable within a short time. When these diseases become symptomatic, biliary obstruction, either with or without infection, occurs frequently due to the anatomy associated with these cancers. The endoscopic management of these patients has changed, both with time and with improvements in medical devices. In this review, we present updated and integrated concepts for the endoscopic management of malignant biliary stricture. Endoscopic biliary drainage had been indicated in malignant biliary obstruction, but the concept of endoscopic management has changed with time. Although routine endoscopic stenting should not be performed in resectable malignant distal biliary obstruction (MDBO) patients, endoscopic biliary drainage is the treatment of choice for palliation in unresectable MDBO patients. Self-expanding metal stents (SEMS) have better stent patency and lower costs compared with plastic stents (PS). For malignant hilum obstruction, PS and uncovered SEMS yield similar short-term outcomes, while a covered stent is not usually used due to a potential unintentional obstruction of contralateral ducts. Percutaneous transhepatic biliary drainage was introduced ~40 years ago for the Differences in the level of obstruction of the biliary system allow for a further division of these kinds of problems into resectable or unresectable hilum or distal biliary obstructions. Computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), and even endoscopic ultrasound sonography (EUS) should be used to evaluate the stage and primary source of a malignancy ,10.Treatment plans for malignancies with different primary origins differ from one another when resectable biliary obstructive malignancy diseases are discussed. In general, routine endoscopic stenting has no obvious clinical benefits for patients with malignant distal biliary obstruction (MDBO) ,12,13,14For cholangiocarcinoma, the Bismuth classifications have beeFor hilum cholangiocarcinoma without distant metastasis, resectable tumors present the possibility of resection of the involved intra- and extrahepatic bile ducts as well as the associated hepatic lobes and caudate lobe. Some recent reports have shown excellent results after surgical resection in patients with Bismuth III and IV disease ,23, but Endoscopic stenting is the mainstream endoscopic management approach for malignant distal biliary obstruction of cholangiocarcinoma or pancreatic cancers, but most clinical studies ,24 and mIn ampullary neoplasms, EUS and intraductal ultrasound sonography (IDUS) can assess the depth of invasion as well as the intraductal extension. Importantly, surgical ampullectomy can reduce medical expenses yet have similar clinical outcomes for those that are achieved via pancreaticoduodenectomy for ampuEndoscopic biliary drainage with biliary stent placement is the treatment of choice for palliation in patients with distal malignant biliary obstruction that is caused by unresectable neoplasms, with a success rate of up to 95% ,29,30 anIn some situations, PTCD has been used as part of a rendezvous endoscopic approach. A comparison in 2016 between EUS-guided and PTCD rendezvous drainage after the failure of primary ERCP in MDBO showed that EUS rendezvous had a significantly lower success rate than the PTCD rendezvous . HoweverDifferent stent types are available for the treatment of MDBO. SEMS have a lEUS is a valuable diagnostic modality for the staging of hilum cholangiocarcinomas, particularly for the evaluation of unresectable perihilar cholangiocarcinoma for liver transplantation . PercutaSome evidence indicates that in cases of bilateral biliary opacification, bilateral drainage offers a better survival benefit when compared to unilateral drainage ,70. AfteThe evidence is still insufficient and no clear consensus has been reached regarding the benefits of unilateral versus bilateral drainage for hilar malignant obstruction, although the bilateral approach can be used by most experts using the SEMS stent-within-stent placement ,76 with Plastic stents and uncovered SEMS yield similar short-term outcomes in patients with malignant hilar strictures due to stent migration in SEMS . SEMS prEUS-guided biliary drainage via EUS-guided hepaticogastrostomy (EUS-HGS) is a good alternative for draining malignant hilar biliary obstruction following the failure of an initial ERCP. An EUS-guided rendezvous procedure with the conventional ERCP access ,86 is tyIn cases of malignant biliary obstruction, CT, MRI, MRCP, and EUS should be used for tumor staging and further drainage planning. For resectable malignant biliary obstruction lesions, routine endoscopic drainage or ERCP are not advised, except in cases of concurrent infection. Endoscopic drainage is the treatment of choice for unresectable biliary obstructions. PTCD and EUS-guided biliary drainage can serve as alternative approach methods. EUS-guided biliary drainage can provide equal clinical benefits without increasing complications in a high-tech endoscopy center. In addition, PTCD plays an important role in community hospitals, where the ERCP and/or EUS approaches are not available.For MDBO, single-stent insertion is adequate, and SEMS have better patency than plastic stents; however, the superiority of FCSEMS, PCSEMS, and UCSEMS remains under debate. For malignant hilar biliary obstructions, drainage of >50% of the liver volume should be achieved by either bilateral stenting or multi-segmental stenting, and SEMS\u2019 longer biliary patency when compared with plastic stents should be considered. The general approaches to malignant biliary obstruction are summarized in the flow chart presented in"} +{"text": "The effects of retirement on cognition are still unclear and empirical evidence is conflicting. Especially for retirement from cognitively demanding jobs, positive as well as negative effects have been reported. Leisure activity engagement has been hypothesized to play an important role in explaining the mixed evidence. In this study, we examine the interplay between job demands before retirement and changes in leisure activities before and after retirement and their relation to post-retirement cognitive functioning. Using data from the HEalth, Aging and Retirement in Sweden (HEARTS) study, cognitive trajectories before and after retirement were modeled in a multi-level piecewise model (N = 2688 observations). Post-retirement memory and reasoning ability were predicted by self-reported work demands and changes in leisure activity engagement. Results imply a stable increase in memory over the retirement transition and less steep increase in abstract reasoning after retirement. Work demands and leisure activity participation were not related to post-retirement cognitive change. Job demands and leisure activity engagement may not play an important role for short-term post-retirement cognitive functioning. These findings support the conclusion that retirement, independent of prior work demands, does not affect cognitive functioning negatively."} +{"text": "The purpose of our Geriatric Workforce Enhancement Program is to provide geriatric and primary care education and training to long-term care (LTC) providers and staff, health professions students and community members. Our LTC partners and the communities we serve are often very rural and travel to urban areas for training can be difficult. Therefore, we have developed four online training that are offered free to our partners and rural communities statewide. These programs are designed to integrate the aims of the Age-Friendly 4M\u2019s model . The LTC nurse residency program provides gerontological nursing and inter-professional leadership training , in a synchronous online environment. The asynchronous Alzheimer\u2019s Disease and Related Dementias training modules educate LTC staff and family caregivers about types, diagnosis and care of older adults with dementia (Mentation and Medication). The asynchronous Opioid Use in LTC modules were developed with partners to deliver live at LTC staff trainings about opioid stewardship (Medication). The LTC Learning Communities are monthly tele-health sessions for inter-professional LTC teams to discuss current issues and propose solutions . We have successfully leveraged different synchronous and asynchronous online modalities to increase educational opportunities for formal and informal caregivers, including those in rural areas whose educational opportunities are geographically limited. To date our programs have reached over 500 individuals across our state, increasing knowledge about geriatric concepts, communication and team leadership. Moving forward, we will continue to develop and refine educational programs that promote the Age-Friendly geriatric-focused health care."} +{"text": "The widespread consumption of \u2018western\u2019-style diets along with sedentary lifestyles has led to a global epidemic of obesity. Epidemiological, clinical and preclinical evidence suggests that maternal obesity, overnutrition and unhealthy dietary patterns programs have lasting adverse effects on the physical and mental health of offspring. We review currently available preclinical and clinical evidence and summarise possible underlying neurobiological mechanisms by which maternal overnutrition may perturb offspring cognitive function, affective state and psychosocial behaviour, with a focus on (1) neuroinflammation; (2) disrupted neuronal circuities and connectivity; and (3) dysregulated brain hormones. We briefly summarise research implicating the gut microbiota in maternal obesity-induced changes to offspring behaviour. In animal models, maternal obesogenic diet consumption disrupts CNS homeostasis in offspring, which is critical for healthy neurodevelopment, by altering hypothalamic and hippocampal development and recruitment of glial cells, which subsequently dysregulates dopaminergic and serotonergic systems. The adverse effects of maternal obesogenic diets are also conferred through changes to hormones including leptin, insulin and oxytocin which interact with these brain regions and neuronal circuits. Furthermore, accumulating evidence suggests that the gut microbiome may directly and indirectly contribute to these maternal diet effects in both human and animal studies. As the specific pathways shaping abnormal behaviour in offspring in the context of maternal obesogenic diet exposure remain unknown, further investigations are needed to address this knowledge gap. Use of animal models permits investigation of changes in neuroinflammation, neurotransmitter activity and hormones across global brain network and sex differences, which could be directly and indirectly modulated by the gut microbiome. The worldwide prevalence of obesity has tripled since 1975, accompanied by a sharp increase in obesity among women of reproductive age . MaternaObservations regarding neurodevelopmental impacts of maternal obesity have emerged more recently, building on extensive evidence linking higher maternal body mass index (BMI) to adverse offspring metabolic and cardiovascular outcomes. This literature has been reviewed elsewhere and is not examined here ,8,9. RatHuman and preclinical studies of the impacts of maternal obesity and overnutrition on offspring behaviour can be categorised into three areas: cognition, affective states and psychosocial behaviour. Although human studies have shown associations between these domains and maternal body weight and diet on offspring cognition. One of the challenges in interpreting behavioural data regarding cognition is the heterogeneity in tests and test parameters employed across studies, as noted in a recent meta-analysis and systematic review which coIncreased proinflammatory signals including IL1\u03b2 and TNF\u03b1 were found in the whole brain of male and female mouse offspring of obese mothers at P0, with mixed effects seen at P7 and P21 . ElevateResults from several studies in humans indicate that maternal obesity alters affective states in children. For example, extreme maternal obesity (pre-pregnancy BMI \u2265 40) was associated with hyper-reactivity and affective changes in children, independent of demographic variables, prenatal factors or maternal anxiety and depression . A populBy contrast, preclinical studies using affective measures in rodents show mixed results, with maternal obesity found to increase ,39,41,53Although behavioural measurements differ between studies, preclinical studies have often sought to link affective changes to dysfunctional HPA axis activity, altered neuronal plasticity and increased neuroinflammation. The HPA axis regulates physiological stress responses and modulates behaviour in response to stressful stimuli, and its function is programmed by maternal obesity. An association between hyper- and hypo-active HPA axes and anxiety- and depressive-like behaviour, respectively, has been well documented . Two stuApart from differences in experimental research protocols one possible reason for the discrepancy between the results seen in human research and the mixed results from animal models might relate to methodological differences in reporting negative emotional states in humans and rodents. Human studies tend to use parental reports regarding child emotional states, whereas studies using rodents monitor anxiety- and depressive-like behaviour using ethologically relevant tests in the offspring themselves, such as forced swim, open field, elevated plus maze, dark-light box and sucrose preference tests, which cannot fully capture the breadth of negative affective states in human children. We argue that despite these challenges, the ability to associate behavioural outcomes with neurohumoral and molecular readouts in preclinical research has merit.The potential link between maternal obesity and Autism Spectrum Disorder (ASD) has been extensively investigated over the past decade or so. Several recent meta-analyses and reviews indicate an increased risk of ASD in children of mothers who were overweight or obese at the time of conception ,50. In aDespite growing interest in the link between maternal obesity and aspects of psychosocial behaviour in children in human studies, few studies have explored this relationship in animal models. Research to date has examined social interaction, anxiety and locomotor activity. Several studies have found evidence that neuroinflammation might contribute to impaired social behaviour in offspring of overfed dams: Kang et al. reportedObesity during pregnancy alters neuroendocrine, metabolic and inflammatory status and these exposures might affect foetal development, in turn influencing behaviour, emotion and cognition. In addition to neuroinflammation, altered neuronal plasticity and dysregulated brain metabolism likely contribute. Another mechanism attracting recent attention is changes in the composition of the gut microbiome, which contains trillions of bacteria, and plays a crucial role in health and disease of the host . In the Rodent models of maternal obesity have shown evidence of hypothalamic inflammation in offspring, characterised by elevated levels of TNF\u03b1, IL1b, and IL6 in adulthood, both in rats and miceAnother possibility is the involvement of glial cells. Glial cells such as microglia and astrocytes are essential for regulating immune responses and act as metabolic sensors . SeveralIn the context of maternal obesity and effects on offspring behaviour, an experimental study showed changes in glial cell proliferation and reactivity in mouse offspring of obese mothers, characterised by astrocyte proliferation and elevated levels of IL6 in the hypothalamic arcuate nucleus (ARC) and the supraoptic nucleus (SON) compared with offspring from normal weight dams . This evLactobacillus reuteri suppressed neuroinflammation by binding to a receptor expressed on astrocytes [L.reuteri produces gamma-aminobutyric acid (GABA) which has inhibitory effects on neuronal circuity [L.reuteri regulates social behaviour in mice via the vagus nerve pathway interacting with oxytocin in the VTA [Lastly, increasing evidence suggests an intriguing relationship between glial cells and the gut microbiome. Preclinical studies using conventional and germ-free mice showed that the gut microbiota indirectly regulate homeostasis and immune reactivity of microglia . Gut mictrocytes . Neurointrocytes . Notablycircuity . A recen the VTA . In summStudies in rodents and humans link maternal obesity to neurological changes in offspring. A recent human study reported a negative association between maternal BMI and hippocampal volume in male children at 7\u201311 years of age . FurtherRecent studies using functional magnetic resonance imaging technology indicate an association between higher pre-pregnancy BMI and altered white matter microstructure , neuronaDopamine is a neurotransmitter regulating motivational and reward-related functions. A recent preclinical study showed that consumption of cafeteria diets during pregnancy induced epigenetic changes in the dopamine receptor (DAT), dopamine transporter 1 (DRD1) and dopamine transporter 2 (DRD2) genes in the nucleus accumbens (NAc) and VTA, two key regions of the dopaminergic pathway . In the Perinatal exposure to maternal obesity and poor diet induces lasting effects on the central serotonergic system in female offspring . High faEvidence from animal models shows maternal obesity programs the rat offspring\u2019s health trajectory towards obesity by impaired lipid and glucose metabolism and appetite regulators ,94. InteMaternal overnutrition also alters the endocannabinoid system through impaired leptin signalling in the hypothalamus. Interestingly, only male rat offspring of HFD-fed dams exhibited impaired leptin signalling, with epigenetic changes in promoter regions of sex hormone signalling at birth . The sexThe adverse changes in brain metabolism in offspring from obese dams include altered mammalian target of rapamycin (mTOR) signalling in the rat hypothalamus and in tOxytocin is another brain hormone for which there is evidence of a relationship between maternal obesity and aberrant offspring behaviour. Oxytocinergic neurons in the PVN project to the amygdala, hippocampus, NAc and VTA, and peripherally project to the pituitary into the blood stream ,115. OxyThe \u2018gut-brain axis\u2019 describes the complex communication network between the gut and brain, comprising the enteric nervous system, sympathetic and parasympathetic branches of the autonomic nervous system, in addition to neuroendocrine signalling pathways, and neuroimmune systems . Emerginlactobacillus spp. abundance in the infant gut [Only limited evidence is currently available for an association between maternal diet and offspring gut microbiome composition in humans. Savage et al. showed a weak but positive association between maternal diet, characterised by high vegetable intake and low processed/fried food intake, and fant gut . A recenfant gut . Exposinfant gut . A caveafant gut . We havefant gut . Therefofant gut .Staphylococcus and Lactobacillus and lower numbers of Bifidobacterium bacteria relative to normal weight mothers [Lactation is another key period that shapes the offspring\u2019s gut microbiome, immune system and behaviour. Breast milk is comprised of non-nutrient components such as immunoglobulins, oligosaccharides, growth factors, and epithelial and immune cells, which could reflect maternal health, and DNA\u2014essential bioactive compounds that foster the development of the gastrointestinal, immune and neurological systems in offspring . Indeed, mothers . A recen mothers . What isThere is now broad evidence from human and animal studies indicating that maternal obesity, overnutrition and unhealthy dietary patterns induce adverse effects on behaviour and neurodevelopment in offspring. This review has identified possible underlying neurobiological mechanisms for these effects, which include neuroinflammation, disrupted neural circuitries and connectivity and dysregulated brain hormones. Dynamic interactions between these factors shape behaviour during gestation and lactation through the offspring\u2019s exposure to maternal obesity via the placenta, gut microbiome and breast milk. Future research should continue to examine behaviour and brain changes in maternal obesity models beyond the hippocampus and hypothalamus, given recent evidence from imaging studies suggesting that aberrant behaviour might be a result of dysregulated global network in the brain, in addition to region-specific dysfunctions. In addition, future research should be targeted at characterising the intriguing sex differences evident in many maternal obesity studies, given that current preclinical studies are still skewed towards males. Human studies using advanced imaging techniques could provide a useful resource to guide animal studies to further elaborate underlying mechanisms. Further, animal models need to incorporate experimental protocols that maximise translational relevance to align with human studies in terms of dietary components, feeding duration and behavioural tests, to allow behavioural and molecular outcomes to be systematically assessed longitudinally and compared across species where possible. Studies currently underway should yield more valuable data on the longer-term effects in humans."} +{"text": "Diffuse gliomas, such as glioblastoma (GBM), represent the most common and aggressive form of brain cancer with an unfortunate dearth of treatment advances despite decades of ongoing research . PerhapsDespite this prospect, the aggressive biology and low incidence of gliomas make them poor candidates for conventional screening strategies. Case reports of serial neuro-imaging studies of GBM, with scans taken as few as 68\u2009days apart, show that even small cortical lesions can rapidly evolve into established disease within a very short clinical time frame (<\u20093\u2009months) . This shConsequently, when conceptualizing an effective screening tool for gliomas, brain health changes would need to be monitored over short intervals (days to weeks) using tools that could be practically applied to the general population. Herein lies the immense potential of using emerging non-invasive electroencephalography (EEG)-based biotracking devices to serve as agents that gather continuous health data from our nervous system Fig.\u00a0a. These With these exciting prospects in mind, several potential limitations at present are worth highlighting. Current EEG wearables, designed for niche application , only require a handful of sensors for their intended uses. The optimal quantity and spatial distribution of sensors for effective screening of central nervous system pathologies therefore still need to be defined. Additionally, the amount and timing of daily wear needed to detect subtle baseline changes would also need optimization and balance with enthusiasm to wear such devices. Despite these current unknowns, rapid and widespread acceptance of other smart wearables offers encouraging insights. For example, despite only debuting in 2015, Apple shipped >\u200940 million smartwatches in 2018 with the global wearable market expected to grow to >\u2009279 million users by 2023. This estimate of the wearable market alone could allow the detection of tens of thousands of brain tumors annually! With increasing possibilities and interest at the intersection between artificial intelligence and brain-machine interfaces , such devices may soon even become essential tools to intellectually compete in society. It is therefore possible that consumer demand for brain wearables may quickly mirror the rapid growth of their hardware manufacturers and extend far beyond current niche applications and existing smartwatch demands . Lastly,The ability of these devices to provide continuous longitudinal and personalized data, along with the advent of modern deep learning computational tools, could provide new solutions for the early detection and differentiation of various nervous system pathologies. Large-scale detection of incipient tumor formation could also provide new epidemiological insights of unappreciated risk factors and mechanisms of gliomagenesis. Deployment of these devices to existing brain tumor patients could also help monitor disease recurrence and understand treatment-related neurocognitive sequalae.Brain tumors such as GBM carry a dismal prognosis which has challenged conventional treatment paradigms for decades. Conceptualizing novel early detection-based approaches for these tumors may provide success in a patient population where conventional late-stage diagnosis and treatment have failed. While the role of early detection in the management of brain tumors is still unclear, recent innovations in personal brain wearables, artificial intelligence, and evidence for the benefits of aggressive surgery offer new opportunities to refine our clinical approach to these challenging clinical entities."} +{"text": "Under physiological conditions, a balance between oxidants and antioxidants exists. Reactive oxygen species (ROS) are continuously generated by aerobic cells and eliminated through scavenging systems to maintain redox homeostasis. Disruption of redox homeostasis results in oxidative stress and altered ROS signaling. Higher ROS levels can lead to DNA mutation and genomic instability which can play causal role in cancer development and progression. These mutations coupled with distorted redox signaling pathways orchestrate pathologic events inside cancer cells, resulting in resistance to stress and death signals, aberrant proliferation, and inefficient repair mechanisms.Cancer cells are energy intensive, owing to their high rate of proliferation. However, due to impaired TCA cycle and poor blood perfusion, cancer cells switch towards glycolytic pathway for energy generation termed as \u201cWarburg effect.\u201d Such pathways lead to a higher oxidative environment. The oxidative environment is also enhanced by tumor-infiltrating macrophages and neutrophils. Thus, cancer cells are used to a high ROS environment. This redox imbalance allows for protumorigenic cell signaling. In this issue, we explore the relation between ROS and cancer. The issue comprises of twenty original articles and comprehensive reviews.Reactive oxygen species (ROS) mediates cisplatin-induced cytotoxicity in tumor cells. However, when cisplatin-induced ROS do not reach cytotoxic levels, cancer cells may develop chemoresistance. Di Vito et al. reported the association of ferritin heavy subunit (FHC)-ROS axis with cisplatin resistance in ovarian cancer cells. Thus, implying that inhibition of FHC might be a potential approach for restoring cisplatin sensitivity of resistant ovarian cancer cells. The authors investigated whether the modulation of H-Ferritin might affect cisplatin-induced cytotoxicity in ovarian cancer cells. H-Ferritin knockdown strengthened cisplatin-mediated ROS increase and significantly restored sensitivity resistant ovarian cancer cells.via a ROS-dependent mitochondria-mediated pathway. H\u00e4m\u00e4l\u00e4inen et al. investigated the expression of redox regulator nuclear factor erythroid-2-related factor (NRF)1 and NRF2 in skin lesions like naevi and melanoma from 172 patients. NRF1 and NRF2 are transcription factors essential for maintaining redox homeostasis and coordinating cellular stress responses. The study found the association of redox microRNAs (miRs) with aggressive melanoma feature. This study opens up avenues to test these redox miRs as possible prognostic value in larger cohorts. The research article by Pires et al. described label-free mass spectrometry- (MS) based proteomics of breast cancer (BC) plasma to investigate the differences between circulating proteins between chemoresponsive and chemoresistant luminal A breast cancer. Protein-protein interaction networks were created utilizing using in silico tools. The study reports interesting findings on differences in inflammatory, complement system, and oxidative stress pathways in both BC phenotypes which holds potential clinical implications. Moreira et al. presented their findings about the antitumor effect of celastrol, a natural pentacyclic triterpenoid, in colon cancer cells with acquired resistant to cytotoxic drugs. Yang et al. have evaluated the anticancer and anti-invasive properties of alpha-lipoic acid (ALA) in gastric cancer cells. ALA is a naturally occurring thiol antioxidant which is known to exhibit antiproliferative and cytotoxic effects on several cancers. The study found that the Mucin 4 (MUC4) gene was strongly expressed in human gastric cancer tissues. ALA administration reduced the proliferation and invasion of human gastric cancer cells by suppressing MUC4 expression. Helfinger et al. reported expression of Nox4 in macrophages and the role played by them in determining the polarization and the phenotype of macrophages. In the report by Acheva et al., authors showed epithelial to mesenchymal transition (EMT) in lung cancer cells postexposure to oxidative stress of gamma radiation. The authors conclude that induction of EMT in bronchial epithelial cells by radiation requires more than single acute exposure to gamma radiation and that the presence of stromal component might enhance the effect through free radical production and accumulation.Studies by Zhao et al. in osteosarcoma cells found that metformin (drug for type 2 diabetes) suppressed the self-renewal ability of osteosarcoma stem cells (OSCs) and induced G0/G1 phase arrest by blocking the activity of cyclin-dependent kinases. Metformin triggered apoptosis in these cells, which promoted cell death Gao et al. investigated the association of nitric oxide metabolites and lung cancer incidence through a matched case-control study based on the German ESTHER cohort. The study deduced that subjects with high urinary nitrite/nitrate concentrations had an increased risk of lung cancer. Butturini et al. highlighted plant-derived Sesquiterpene as a potential for cancer therapeutics. The authors exhibited that the compound downregulated STAT3 signaling leading to an antitumor effect and correlated the anti-STAT3 activity with their ability to decrease GSH levels in cancer cells. These properties make them lead compounds for the development of a new therapeutic strategy for cancer treatment.In addition to these original works, Kim et al. listed a comprehensive report on the ROS-inducing strategy in anticancer therapy. The review by Xian et al. summarized the role of ROS in cutaneous carcinogenesis and skin cancer progression. Akanji et al. provides a comprehensive account of hypoxia-inducible factors (HIFs). In the review by Lv et al., the authors discussed recent understanding in the involvement of Glutathione (GSH) in cell death pathways such as apoptosis, necroptosis, ferroptosis, and autophagy. Goh et al. performed online literature search to identify studies reporting metabolic biomarkers of aerodigestive squamous cell carcinomas (ASCC). Akbari et al. have focused on the role of hydrogen sulfide in bladder, kidney, and prostate malignancies.In the review by Tataranni et al., the authors have addressed the therapeutic potential of dichloroacetate (DCA) in cancer therapy. DCA is a 150 Dalton, water-soluble acid molecule, analog of acetic acid in which two of the three hydrogen atoms of the methyl group have been replaced by chlorine atoms. The authors have summarized recent reports suggesting the employment of DCA in cancer therapy, in combination with chemotherapy agents, radiotherapy, and other chemical or natural compounds showing anticancer properties. Paz et al. in their review have discussed the pharmacological effects and toxicogenetic impacts of omeprazole in context of cancer. This extensive report highlights that omeprazole therapy may induce genomic instability and increase the risk of certain types of cancer and hence advocates for taking adequate precautions, especially in long-term therapeutic strategies. The review by Fiocchetti et al. focused studies conducted on Neuroglobin (NGB), a globin primarily described in neurons as an oxidative stress sensor and cytoprotective factor against redox imbalance.Although ROS sustain tumorigenesis and cancer progression, these can also be efficient therapeutic tools to fight cancer. Oxidative stress-based therapies like radiotherapy, chemotherapeutic agents, and photodynamic theory increase ROS levels in the tumor niche and take advantage of the cytotoxic face of ROS for killing tumor cells by a nonphysiologically sudden, localized, and intense oxidative burst. Clinical efficacy of anticancer therapies is often subdued by multidrug resistance (MDR). Redox therapy by using redox-active drugs or inhibitors of inducible antioxidant defense in tumor microenvironment has reported to be effective against MDR tumors. Further insight into such redox biology will enable precisely targeted manipulation of ROS for effective medical therapies against carcinomas."} +{"text": "Caenorhabditis elegans. We discuss how cell surface receptor complexes link to and modulate actin dynamics to regulate dendritic and axonal branch formation. The mechanisms of neurite branching are often coupled with other neural circuit developmental processes, such as synapse formation and axon guidance, via the same cell-cell surface molecular interactions. We also cover ectopic and sex-specific neurite branching in C. elegans in an attempt to illustrate the importance of these studies in contributing to our understanding of conserved cell surface molecule regulation of neurite branch formation.The high synaptic density in the nervous system results from the ability of neurites to branch. Neuronal cell surface molecules play central roles during neurite branch formation. The underlying mechanisms of surface molecule activity have often been elucidated using invertebrates with simple nervous systems. Here, we review recent advances in understanding the molecular mechanisms of neurite branching in the nematode An extensive neurite branching morphology is a fundamental aspect of neuronal structure. Each axon and dendrite contain numerous neurite branches that enhance neural circuit complexity by allowing for interaction with a large number of target neurons and non-neuronal cells. For example, a single neuron can synapse onto multiple target neurons due to the extensive branching of the axonal shaft. Dendrites have an extremely complex branching thereby producing a large dendritic field to receive synaptic or sensory inputs. These neurite branch networks allow for the formation of highly complex neural circuits that integrate and process information, thereby coordinating specific nervous system functions. Growing evidence suggests that dysregulation of neurite branching could underlie various neurological and neurodevelopmental disorders such as autism, schizophrenia, and Down syndrome or synaptic output functions of the posterior section of the body. These neurons extend elaborate dendritic branches throughout the body excluding the head , leading to defects in harsh touch response , an IgSF cell surface protein and their modifying enzymes , it also possesses 294 sex-shared neurons, some of which show notable sex differences in neuronal structure, branching pattern, and synaptic connectivity and regulated by conserved cell surface molecules , DD06 neurons , and PHC neurons (male-specific axon extension; Cook et al., Drosophila brain revealed several conserved, but previously unidentified, cell surface molecules that act as regulators of neural circuit formation (Li et al., Over the past decades, studies have identified numerous cell surface molecule interactions implicated in neural circuit formation processes including neurite branching. Most of these molecules possess conserved structural domains, such as LRR, Ig domains, and cadherin repeats, which mediate protein-protein interactions necessary during neuronal morphogenesis (De Wit and Ghosh, HJ and BK developed the concept. Both have written and edited the text.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Benevolence directed towards older adults can cross the line between respect and overaccommodation that undermines their physical and cognitive capabilities ; however, little research has examined the subtleties of the influence of benevolent ageism on older adults\u2019 ratings of their own functioning. Because stereotypes about older adults include the decline of mental abilities, this study examined whether their (N= 155) experiences with benevolent ageism, or overaccommodative offers of assistance and protection, influenced their own appraisals of memory abilities through their feelings of self-compassion. Older adults with fewer benevolent ageist experiences had higher rates of self-compassion, which in turn translated into better evaluations of their memory abilities. Future research should consider the potential pernicious influences that benevolent ageism has on older adults\u2019 self-evaluations and performance, consider self-compassion as a buffer in these relationships, and test whether these relationships have downstream consequences on well-being outcomes."} +{"text": "This symposium will examine positive and negative aspects of older adults\u2019 relationships and their impacts on health and well-being. We will begin by reviewing the past decade of research on family gerontology. Seidel\u2019s meta-analysis of 995 articles will identify prominent theories and methods, as well as remaining research gaps. The subsequent presentations provide current, cutting-edge research. Marini examines how associations between rumination and sleep unfold within a social context. The findings highlight how spousal support protects older adults\u2019 sleep quality from rumination, whereas support from family and friends is vulnerable to rumination. Using an actor-partner approach, Novak investigates the dynamics of support and control on health among older gay couples. Results reveal the benefits of support and risks of control for partners\u2019 diet quality and depression. Ermer adopts a dyadic perspective to examine links between self-perceptions of aging and inflammation. Results highlight how wives\u2019 inflammation is sensitive to husbands\u2019 aging perceptions, particularly if marital strain is low. Finally, Wilson characterizes age-graded patterns of relationship narratives and their protective effects on emotional well-being. The findings demonstrate how older-adult couples\u2019 narratives are less self- and present-focused, which helps explain protective linkages between age and negative mood. The symposium will conclude with remarks from discussant Katherine Fiori, a GSA Fellow and internationally recognized scholar on older adults\u2019 social networks. She will synthesize the research and put forth her new theory about the importance of peripheral ties in later life to help direct the future of research on older adults within a social context."} +{"text": "Stroke is a life-threatening disease that leads to mortality, with survivors subjected to long-term disability. Microvascular damage is implicated as a key pathological feature, as well as a therapeutic target for stroke. In this review, we present evidence detailing subacute diaschisis in a focal ischemic stroke rat model with a focus on blood\u2013brain barrier (BBB) integrity and related pathogenic processes in contralateral brain areas. Additionally, we discuss BBB competence in chronic diaschisis in a similar rat stroke model, highlighting the pathological changes in contralateral brain areas that indicate progressive morphological brain disturbances overtime after stroke onset. With diaschisis closely approximating stroke onset and progression, it stands as a treatment of interest for stroke. Indeed, the use of stem cell transplantation for the repair of microvascular damage has been investigated, demonstrating that bone marrow stem cells intravenously transplanted into rats 48 h post-stroke survive and integrate into the microvasculature. Ultrastructural analysis of transplanted stroke brains reveals that microvessels display a near-normal morphology of endothelial cells and their mitochondria. Cell-based therapeutics represent a new mechanism in BBB and microvascular repair for stroke. Stroke is currently the fifth leading cause of death in the US, and someone dies of one approximately every 4 min. Stroke occurs due to the interruption of blood flow to the brain, and is typed as ischemic or hemorrhagic. Ischemic stroke makes up approximately 87% of total strokes. Ischemic stroke survivors may not fully recover and develop long-term disabilities ,2,3, sucCerebral functional insufficiency in chronic stroke might be due to pathological changes in brain areas remote from the initial ischemic lesion, for example, diaschisis. In this review, the BBB is implicated in subacute diaschisis. Additionally, BBB competence in chronic diaschisis using a transient middle cerebral artery occlusion (tMCAO) rat model is discussed as well. BBB alterations can be demonstrated in not only the ipsilateral hemisphere, but also the contralateral hemisphere, an area with remote brain structures not directly affected by ischemia. The microvascular damage in the subacute phase likely reveals ischemic diaschisis, and should be considered in the development of treatment strategies for stroke. The direct targeting of cell delivery into the injured vasculature might be a feasible approach for stroke treatment, and endothelial progenitor cells (EPCs) serve as a promising cell source for BBB restoration in stroke. The ability to preserve the mitochondria and increase these organelles\u2019 pinocytosis via cell-based therapeutics represents a new neurorestorative mechanism in BBB repair.Microvascular damage in ischemic stroke demonstrates ischemic diaschisis. In this review, the investigation of subacute diaschisis in ischemic stroke rat models exhibits stroke-induced pathological disturbances in ipsilateral and contralateral brain areas, and causes microvascular damage with BBB breakdown in remote brain microvessels. Additionally, widespread microvascular alterations in ipsilateral and contralateral brain hemispheres suggests continued BBB damage in chronic ischemic stroke. Because of the rampant pathological microvascular changes in remote brain areas in both subacute and chronic ischemic diaschisis, such vascular damage presents as a therapeutic target for stroke. The use of bone marrow-derived mesenchymal stem cells has been initiated to treat patients with acute ischemic stroke. Here, we discuss the potential use of EPCs as an effective cell source for BBB restoration in stroke by promoting neurovascular repair and preserving the mitochondrial morphology of the microvasculature.Following an ischemic stroke, substantial alterations in both cellular and molecular activity take place due to stroke-induced cerebral pathology ,6. StrokStroke pathology due to vascular injury is time-dependent and can be classified into three types: acute (minutes to hours), subacute (hours to days) and chronic (days to months). The acute and subacute stages of ischemic stroke can be grouped into one period, as secondary cell death following both phases drastically overlap ,6,8. NotIn-depth investigations into stroke pathology have brought about the phenomenon of diaschisis, an abrupt change in activity in regions of the brain far-off from the ischemic lesion generated by stroke-induced impairments. Transhemisphere diaschisis was first recognized through blood flow and metabolism alterations in unilateral and contralateral ischemic hemispheres in the brain . After iNevertheless, in the context of the subacute phase, BBB functionality and the associated pathology in distal brain regions have received less focus . A comprThe effects of subacute diaschisis on BBB stability and associated pathological mechanisms in contralateral regions of the brain were evaluated in focal ischemic stroke rat models . Using tMoreover, BBB impairment in distal cerebral microvessels and endothelial autophagosome build-up could be correlated with the injuries observed in the ipsilateral and contralateral brain regions spurred by focal ischemic stroke . ImportaBy utilizing a focal ischemic stroke rat model, subacute diaschisis could be explored ,29,36,37A major pathologic characteristic of subacute tMCAO involves BBB impairment in the ipsilateral and contralateral striatum and motor cortex ,29,36,37Parenchymal extravasation plays a role in secondary cell death following an ischemic stroke, and can be linked to diaschisis and BBB impairment. An in vivo study illustrated that EB extravasation was amplified in the MCAO group when compared to the control group, and could be associated with exacerbated BBB integrity . A high Autophagy in capillary ECs following ischemic stroke may heavily contribute to cell impairment and BBB alteration. It is still unknown whether enhanced autophagy is part of cell survival or death in an ischemic environment. Autophagosome accumulated in ipsilateral and contralateral capillary ECs following tMCAO. Autophagy plays a pivotal role in managing cell homeostasis by the degradation of cytosolic components via an autophagosomal\u2013lysosomal pathway . ExcessiAdditionally, reactive astrocytes and activated microglia populated in remote striatum, motor and somatosensory cortices 7 days post-tMCAO, potentially indicating an inflammatory response. Inflammation is a major event in ischemic stroke ,53,54. INeuronal pyknosis was also found in subacute ischemia in remote striatum, motor and somatosensory cortices. This post-ischemia damage potentially contributes to stroke pathology and inhibits recovery processes. Secondary neuronal damage and glial cell reactions were explored via two ischemic rat models . The resIn the ipsilateral hemisphere, diminished myelin was found in brain structures with neuronal damage. Decreased myelin was found in the contralateral hemisphere with reduced striatosome size. Communication between different regions of the brain is vital to normal brain function, making white matter damage harmful ,60. In oThe magnitude of the primary stroke lesion is important in predicting patient outcomes. However, the location of the lesion is also essential, especially during chronic stages. Motor recovery and functional outcome in hemiplegic stroke patients during the chronic stage had a stronger correlation with brain lesion size and location compared to that of only lesion size . Post-stAs noted in the preceding section, BBB pathological changes occur in both the ipsilateral hemisphere and contralateral brain regions, indicating the presence of subacute ischemic diaschisis . An assoChronic parenchymal extravasation was also revealed via electron microscopy imaging in ipsilateral and contralateral hemispheres ,74. The Excessive autophagosome production in both ipsilateral and contralateral striatum and motor cortex areas was observed in previous studies, primarily in subacute post-tMCAO settings, which was also exhibited in ECs in chronic stages due to the upregulation of Belcin-1 expression ,74. IncrThe analysis of vascular damage, such as BBB impairment, in cerebral brain structures represents a key pathological feature of chronic tMCAO at the ultrastructural levels ,74. AbnoAstrocyte reactivity in both ipsilateral and contralateral hemispheres displayed significant increases in glial fibrillary acid protein (GFAP) immunoreactivity in striatal areas of the ipsilateral hemisphere, while significant increases in GFAP expression were observed in the dorsal area of the contralateral striatum despite enhanced astrocyte reactivity in the striatum regions. The overexpression of bilateral astrocyte was only present in the dorsal striatum, but the causation of this phenomenon is unknown. Astrogliosis in the striatum may indicate spatial differences in astrocyte reactivity due to the structural location of the striatal area relative to the corpus callosum. Studies have demonstrated the degeneration of transcallosal fibers in subacute and chronic stroke settings using MRI . To explInvestigation of damaged BBB integrity in the cerebral hemisphere capillaries in chronic post-ischemic rats may reveal chronic diaschisis. Large autophagosome accumulation and astrocyte degeneration led to EC impairment, ultimately inducing extensive microvascular damage and neuronal degeneration in chronic ischemia. Chronic diaschisis should be included in stroke therapeutic strategies, primarily reviving endothelial and astrocytic integrity for BBB repair. Cell therapy is a possible stroke treatment option for BBB repair by replacing dysfunctional ECs through EPC transplantation. Combining cell therapy with pro-inflammatory inhibitors may prove to be a worthy stroke treatment.Currently, the only FDA-approved treatment for ischemic stroke is tissue plasminogen activator (tPA) for dissolving the blood clot and improving blood flow in the brain. When tPA is administered intravenously up to 4.5 h after stroke onset in patients with acute ischemic stroke, it reduces mortality and increases the rates of independent ambulation when thrombolytic treatment is given early . HoweverIn MCAO-induced rat models, various cell types including bone marrow stromal cells , umbilicA feasible approach for stroke treatment may involve directly targeting cell delivery into the injured vasculature. Since pervasive BBB impairment is an important factor in ischemic stroke pathogenesis, BBB repair might serve as a primary target for cell therapy development. An early study has shown that the intrastriatal transplantation of bone marrow stromal cells in MCAO rats restored local cerebral blood flow and decreased BBB permeability . AdditioThe ability of transplanted human bone marrow EPCs (hBMEPCs) to repair the BBB in adult Sprague-Dawley rats subjected to tMCAO can be evaluated via electron microscopy . When \u03b2-With intravenously transplanted \u03b2-gal pre-labeled hBMEPCs into rats 48 h after tMCAO, the rats experienced vascular repair in the brain structures of both hemispheres via transplanted cell engraftment into the vascular wall, which helped to re-establish BBB integrity post-stroke . BBB repAt 7 days post-tMCAO, BBB damage in the ipsilateral and contralateral striatum and motor cortex was observed , consistIntravenously transplanted hBMEPCs in tMCAO rats provide beneficial effects that are visualized by quantitative mitochondrial morphology analysis within ECs and perivascular astrocytes. Mitochondrial alterations can lead to cellular energy deficits and oxidative stresses that result in cell death, and mitochondrial dysfunction can occur after stroke which results in the reduced number and size of the mitochondria in astrocytes , neuronaIn cell-treated post-tMCAO animals, numerous pinocytic vesicles found solely in engrafted hBMEPCs were present . TypicalThe pinocytic vesicles were found only in engrafted hBMEPCs within the cerebral capillaries of cell-treated post-tMCAO rats, and represent a new line of investigation for cell therapy . AdminisAlthough intravenously transplanted hBMEPCs replaced post-stroke damaged ECs, it is possible that the administered cells were involved in capillary sprouting, or might have extravasated to the brain parenchyma via paracellular migration across cell\u2013cell junctions similarly to leukocyte diapedesis in various pathological conditions, given the new vessel formation ,127. TraAdditionally, transplanted hBMEPCs might not only exogenously but also endogenously enhance post-stroke vasculogenesis, via the secretion of angiogenic or growth factors. Local transplantation of the human EC cell line improved endogenous vasculogenesis and neurogenesis by the VEGF signaling pathway . SignifiIn conclusion, \u03b2-gal pre-labeled hBMEPCs intravenously transplanted into rats 48 h after tMCAO engrafted within the capillary wall at 5 days after its administration and closely participated in the vasculature repair of the BBB in subacute stroke . The anaStroke is a devastating disease, and further investigation regarding the underlying pathophysiological changes is warranted so as to unveil an effective neurodegenerative treatment. Acute and chronic microvascular damage, as a result of ischemia, may act as a potential mechanism to target when contemplating stem cell therapy . Similar"} +{"text": "Sex and gender are important sources of variation in Alzheimer\u2019s disease and related dementias (ADRD) and associated caregiving. Women comprise 2/3 of ADRD cases and the majority of ADRD caregivers. Sex encompasses biological differences due to sex chromosomes, reproductive tract, and hormones, while gender constitutes socioculturally constructed psychosocial aspects of sex. Several lines of research have begun to interrogate sex differences, but less is known about the relation of gender and lesbian, gay, bisexual, transgender, and/or queer (LGBTQ) status with ADRD. In this symposium featuring both trainees and faculty we highlight novel research addressing these factors from multiple perspectives. Two presentations address how psychosocial characteristics and their strengths of association with brain health may vary by gender. C. Elizabeth Shaaban presents analyses testing whether gendered psychosocial factors explain sex differences in white matter hyperintensities, a neuroimaging marker of cerebral small vessel disease and risk factor for ADRD. Justina Avila-Rieger presents results testing region of birth-based spatial patterning of dementia risk among Black men and women. Next, Jason Flatt presents prevalence estimates of subjective memory problems and dementia and describe factors associated with dementia among LGBTQ older adults. Finally, gender may also impact perceptions of individuals with dementia. Shana Stites explores gender differences in AD stigma and discuss implications for who is willing to be an AD caregiver. Michelle Mielke, an expert in sex and gender differences in neurodegenerative and age-associated diseases will facilitate conversation about these results and place them in the context of current sex and gender-based ADRD research."} +{"text": "Recent conceptualizations of depression and supporting empirical work suggests that elevations and allievations of depressive symptoms can be understood from a dynamic systems perspective. Specifically, depression is proposed to result from strong-feedback loops in a system comprised of highly interdependent component parts . Supporting this perspective, individual differences in emotional interia and strong connections across emotions at micro-level timescales have been consistently associated with individual differences in depressive symptomatology such that individuals with greater emotional inertia and cross-emotion relations show higher levels of depressive symptoms. Importantly, however, individual differences do not necessarily translate to intraindividual change. The present study explores whether emotional connectivity at the daily timescale differs within individuals across a ten-year span and how these associations relate to intraindividual changes in depressive symptomatology. The results of these individual-level analyses will help further a dynamic systems perspective of depression and help inform clinical interventions for depression."} +{"text": "The SmartPrompt phone-based reminder application was designed according to neuropsychological theory and pilot testing to facilitate everyday functioning. A laboratory-based pilot of ten participants with MCI and mild dementia showed significantly greater task completion with significantly fewer checking behaviors when using the SmartPrompt versus a control condition. Younger individuals and those who engaged in more checking behaviors completed more tasks in the control condition, but these relations were not significant when using the SmartPrompt. After 15 minutes of training, caregivers achieved near perfect scores on a SmartPrompt configuration quiz. Participant and caregiver usability ratings were strong, even though participants reported relatively low computer proficiency and neutral/unfavorable attitudes towards technology. Piloting informed modifications of the SmartPrompt to enhance personalization and improved human-computer-interaction for in-home testing. Preliminary in-home test data on individually-owned smartphones and conclusions regarding barriers and facilitators to the effectiveness of the modified SmartPrompt will be discussed."} +{"text": "Dear Editor:Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disorder and affects up to 12 million individuals worldwide. Radiologic imaging is critical for successful management. Until recently, the treatments were only symptomatic but EMA in 2017 and FDA in 2018 approved Tolvaptan for ADPKD therapy. Renal imaging provide important diagnostic and management guidance in the monitoring of disease progression. In the past, standard radiographic imaging has not provided the accuracy necessary to reliably measure renal volume. With diagnostic advances, kidney volume growth is considered the principal surrogate marker predicting the decline of renal function in ADPKD; therefore the role of total kidney volume (TKV) has been investigated as surrogate endpoint in randomized clinical trials. TKV can be measured by ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI) using manual, semiautomated, or fully automated data processing techniques.Using high-resolution MRI, the Consortium of Radiologic Imaging Studies of PKD (CRISP), observational cohort study of ADPKD subjects, investigated the ADPKD progression highlighting that MRI could accurately and reliably measure TKV cystic kidneys."} +{"text": "This paper explored the effect of the type of health insurance on dentist visits among older adults in China. The data were drawn from the CHARLS-II (2013). The sample included older adults aged 60 and older =3272, n=3495). Multivariate logistic regression models indicated that in urban and rural places, respondents with a governmental/civil servants\u2019 insurance and those with an urban-employee insurance are more likely to visit a dentist in the survey year. Household registration status (hukou) does not play a significant role in dentist visits when insurance types are adjusted for. In other words, employment status, and the coverage of health insurance presented more significant effects on dentist visits. Differing from previous studies about urban-rural health disparities, this study disclosed substantial institutional influences on dental care access among older adults."} +{"text": "Pulmonary vein stenosis or occlusion is a rare but one of the most devastating complications after catheter ablation for cardiac arrhythmias, and surgical repair is an option in severe cases. The sutureless technique, which avoids direct suture of vessel walls, was initially described for congenital pulmonary vein stenosis and has been widely performed due to its good restenosis-free rate.A 52-year-old male developed left pulmonary vein occlusion after catheter ablation for atrial fibrillation. The surgical repair with sutureless technique using the left atrial appendage was performed without any complications. Postoperative computed tomography demonstrated the revascularization of the pulmonary vein.The sutureless technique using the left atrial appendage is significantly reasonable particularly in case of left pulmonary vein stenosis or occlusion after catheter ablation for atrial fibrillation since it reduces the risks of restenosis and thromboembolism. Pulmonary vein (PV) stenosis occurs as a complication of catheter ablation for cardiac arrhythmia in 1\u20133% of patients [A 52-year-old male with AF underwent catheter ablation for two times. Eight months after the second maneuver for recurring AF, he presented with hemoptysis and exertional dyspnea. Computed tomography (CT) showed multiple consolidation in the left lung and ipsilateral pleural effusion Fig. . Three-dPV stenosis often develops as a congenital anatomical anomaly or anastomotic stenosis occurring after the repair of total anomalous PV connection, and several surgical repairs including endovenectomy, re-implantation of PV with direct anastomosis, or patchplasty have been described , 3. HoweThe sutureless technique using the LAA for the left PV stenosis or occlusion after catheter ablation for AF is a significantly reasonable procedure in terms of reducing the risks of restenosis and thromboembolism. Since the long-term outcome of this technique is still unknown, careful follow-up is required."} +{"text": "Empathy for pain is a complex phenomenon incorporating sensory, cognitive and affective processes. Functional neuroimaging studies indicate a rich network of brain activations for empathic processing. However, previous research focused on core activations in bilateral anterior insula (AI) and anterior cingulate/anterior midcingulate cortex (ACC/aMCC) which are also typically present during nociceptive (pain) processing. Theoretical understanding of empathy would benefit from empirical investigation of shared and contrasting brain activations for empathic and nociceptive processing.Thirty-nine empathy for observed pain studies were selected by systematic review. Coordinate based meta-analysis (activation likelihood estimation) was performed and novel contrast analyses compared neurobiological processing of empathy with a comprehensive meta-analysis of 180 studies of nociceptive processing (Conjunction analysis indicated overlapping activations for empathy and nociception in AI, aMCC, somatosensory and inferior frontal regions. Contrast analysis revealed increased likelihood of activation for empathy, relative to nociception, in bilateral supramarginal, inferior frontal and occipitotemporal regions. Nociception preferentially activated bilateral posterior insula, somatosensory cortex and aMCC.Our findings support the likelihood of shared and distinct neural networks for empathic, relative to nociceptive, processing. This offers succinct empirical support for recent tiered or modular theoretical accounts of empathy. Empathy is a critical concept in human emotional and social experience. The ability to share in the affective states of those around us brings evolutionary advantages, enabling us to respond to the needs of others, predict their behaviour and support decision-making about our own actions and sociNociceptive (pain) processing is associated with wide-reaching patterns of neural activation which briefly encompass bilateral anterior, mid-and-posterior insula cortices, primary and secondary somatosensory cortex, inferior frontal gyri (IFG) and supramarginal gyri, as well as medial clusters in anterior cingulate/anterior midcingulate cortices (ACC/aMCC), thalami and brainstem .The Perception\u2013Action Model (PAM) of empathy , suggestHowever, current definitions of empathy suggest the involvement of automatic affective processing but also include aspects of higher order cognition. For example, empathy requires isomorphic sharing of feelings with another, but also necessitates awareness that one\u2019s state originates from observation of the target . In suppThe Russian-Doll model of empathy posits a tiered system with progressive levels of empathy from basic affective to higher order processes such as sympathetic concern and emotional perspective taking . SimilarNeuroimaging studies demonstrate a heterogeneous profile of activation foci for empathy for pain , as were supplementary and manual searches. Both authors were responsible for assessment of articles for inclusion, and decisions over article inclusion were determined by discussion, disagreements where resolved via discussion or presented to a third arbiter (A.S.). One author (N.F.) extracted the relevant coordinate data, which was cross-checked and confirmed by a second (C.R.). Studies that reported coordinates in the Talairach space were converted into MNI using GingerALE software for the purposes of analysis and reporting.P\u2009<\u20090.001 uncorrected voxelwise throughout the whole brain with at least P\u2009<\u20090.05 cluster level correction declared. We excluded papers which only reported ROI results.The criteria for inclusion were: (i) human fMRI studies published up until October 2019; (ii) original English language articles; (iii) published in a peer-reviewed journal; (iv) utilizing a paradigm including visual pain stimuli i.e. images, videos or animations of pain scenes or pain facial expressions; (v) employed an appropriate contrast with a suitable control stimulus ; (vi) coordinates were reported in the paper or supplementary material of the direct (pain > non-pain) contrast in either Montreal Neurological Institute was implemented followed by cluster-level Family-wise error (FWE) correction (P\u2009<\u20090.05) to identify relevant ALE regions as recommended in recent publications (P\u2009<\u20090.05) and a minimum cluster size of 200\u00a0mm3 as previously recommended middle frontal gyrus, and bilateral supramarginal regions .Contrast analysis comparing the ALE maps of concordant activations for each process pointed to significantly greater likelihood of activation during empathy for pain relative to directly perceived pain in 6 clusters encompassing bilateral supramarginal, IFG and occipitotemporal regions .The reverse contrast revealed six clusters indicative of increased activation likelihood estimates for directly perceived pain relative to empathy for observed pain. These regions encompassed two large bilateral clusters encompassing parietal opercular cortices (S2), posterior insula and S1. Right putamen was also evident for directly perceived pain relative to empathy. A right frontal cluster encompassing right prefrontal and dorsolateral prefrontal cortices was also elicited. Two medial clusters demonstrated increased concordance of activation in direct, relative observed, pain in aMCC .The findings of the ALE meta-analysis of empathy for pain revealed concordant activations to observed pain stimuli located in aMCC and bilateral AI which accords with previous investigations were also performed for the first time. Empathy, compared to direct pain experience, demonstrated preferential bilateral activation in supramarginal regions, which extended superiorly to the supramarginal gyrus. Although supramarginal activations are frequently reported in fMRI empathy literature, their specific relevance is often not subject to discussion or interpretation, particularly if the basic empathy contrast is not the primary aim of the research . This poContrast analyses also pointed to bilateral occiptotemporal activations that were more likely to be engaged during observed pain, but not direct pain experience. Previous fMRI research have explained these activations for empathic viewing in terms of enhanced visual processing or attenContrast analyses also revealed greater bilateral activation in ventral IFG during empathy for pain relative to direct experience of pain. The IFG is frequently activated during motor imagery or action observation type paradigms , it has ALE of directly perceived pain, compared to empathy, demonstrated preferential concordance of activation in bilateral S1, posterior insula and parietal operculum, right putamen, right prefrontal cortices and aMCC. Posterior insula and parietal opercular cortices represent the primary targets of nociceptors in the spinothalamic tract and the From a theoretical perspective, the patterns of ALE seen in conjunction and contrast analyses show alignment with a tiered theoretical understanding of empathic processing such as the Russian-Doll model or indepThe role of inferior parietal and occipitotemporal cortices for a broad range of social processing is a topic of considerable research, and a nexus of social processing extending from the angular gyrus of the TPJ anteriorly to supramarginal gyrus and posteriorly to occipitotemporal cortices was posited . Others The present study has some limitations. As mentioned, we focused on empathy for observed pain rather than more complex iterations of cognitive empathy such as paradigms which utilize learning to associate abstract cues with pain stimulation delivered to another person located outside of the scanner. The former design is more prevalent in fMRI research , allowinTo surmise the impact of the present study, elucidation of a rich functional brain network of empathy for pain, extending beyond AI and aMCC, is important for theoretical understanding of the phenomenon. The conjunction and contrast analyses reveal, for the first time, shared and distinct networks for observed and direct pain which supports the concept of tiered levels of processing of empathy as were previously theorized . The finTo conclude, the findings reveal concordance in an extensive bilateral network of brain regions for empathy for observed pain. This encompassed bilateral AI, supramarginal gyri, lateral occipitotemporal cortices IFG and aMCC, regions with functional relevance for interoception, pain processing, social cognition and self-other distinction. Utilizing novel contrast analyses for empathy for pain and direct pain experience, we demonstrated a broad network of shared brain representations which align to automaticity of response or emotional contagion, and empathy-specific activation patterns with relevance for higher order responses such as self-other distinction. Knowledge of these shared and distinct brain networks offers a novel insight into the neurobiological underpinnings of our subjective experience of empathy with relevance for theoretical, clinical and social applications.None declared.File013_nsaa090Click here for additional data file."} +{"text": "Introduction: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality in the United States. Preexisting chronic health conditions may be confer increased CVD risk, specifically fibromyalgia (FM), a chronic condition characterized by widespread pain, fatigue, stiffness, and concentration problems. CVD risk increases with normal aging; however, characteristics of FM are suggested to exacerbate health profiles in normal aging processes that may contribute to increased CVD risk. Method: The sample included 221 older adults and 55% reported an FM diagnosis. CVD risk factors were entered separately in a five-block hierarchical binary logistic regression model as predictors and included: cardiorespiratory fitness using the six-minute walk, BMI, standing and lying mean arterial pressure (MAP), and depression using the Beck Depression Inventory. Results: Logistic regression analyses revealed that poorer cardiorespiratory fitness , greater depressive symptoms and lower standing MAP were associated with higher odds of an FM diagnosis. However, no differences in lying MAP or BMI for an FM diagnosis emerged. Discussion: These data support the importance of examining the health profiles of persons with FM in the context of CVD risk. Experiences of FM may produce distinct health profiles with characteristics that serve as both protective and risk factors in the context of CVD."} +{"text": "Some lower vertebrates such as zebrafish and axolotl have incredible cardiac regenerative potential while mammals have very limited ones. Comparative studies among species have revealed that cardiomyocyte polyploidy, endothermy, and injury-induced activation of certain transcriptional factors including AP1 complexes are critical for cardiomyocyte proliferation and heart regeneration during animal evolution. Gaining insights into these evolutionarily conserved mechanisms will likely lead to achieving heart regeneration in non-regenerative mammals including humans. Regenerative potential in the animal kingdom is a fundamental topic of regenerative biology and medicine. With the development of genome science and genetics technology, many investigators started to address how regenerative potential is lost or gained during the evolutionary courses of particular animal species. It is now documented that either whole-animal or organ regeneration is achieved by activating adult stem cells , by inducing Muller glia reprogramming into neurons in adult zebrafish retinas, or by promoting cardiomyocyte (CM) proliferation in adult zebrafish hearts, and neonatal mouse, rat, and pig hearts are mononuclear diploid CMs during development, but they become mostly polyploid CMs at late gestation or early postnatal stages. The appearance of CM polyploidy conincides with the loss of cardiac regenerative potential in mice, rats, and pigs increases CM proliferation and the percentage of MNCMs in neonatal and adult mice, and results in an evident improvement in cardiac function and fibrosis after myocardial ischemic reperfusion in adult mice. Consistently, exogenous application of thyroid hormone T3 inhibits heart regeneration with evident CM polyploidization and decreased CM proliferation in zebrafish. Thus, thyroid hormone signaling promotes CM polyploidy and decreases cardiac regenerative potential during animal evolution.Another elegant work has reported that the loss of cardiac regenerative potential is highly related with CM polyploidization via phylogenetic analysis of CM nucleation and polyploidy in a large collection of non-vertebrates and vertebrates, and the percentage of MDCMs inversely correlates with metabolic rate, body temperature, and serum total thyroid hormone T4 levels for regulating CM nucleation and polyploidization, as well as non-coding DNA elements (regenerative enhancers) and binding factors (AP-1 complexes) for regulating CM proliferation. These and future studies will likely reveal a network of transcription factors and enhancers for coordinating CM proliferation and heart regeneration. In addition to these critical factors and regenerative enhancers, the field will take advantage of genome editing and chemical biology approaches to identify factors and small molecules that are sufficient for promoting non-regenerative heart regeneration in the coming years."} +{"text": "Of the estimated 16 million U.S. family members currently providing essential yet unpaid caregiving for persons with dementia (PWD), many will also make end-of-life (EOL) care decisions as surrogates, a process that can be fraught with uncertainty. Even with dementia death rates rising, many families delay advanced care planning (ACP) discussions, and surrogate decision makers often lack crucial information and support, implicating the need to further study this topic in aging. While decision aids (DA) serve as a support tool for caregivers, they can be less effective when failing to address unresolved decisional needs. Utilizing the Ottawa Decision Support Framework (ODSF), which asserts caregiver decision needs affect decision quality, this study sought to identify surrogate decision-support needs extending beyond general ACP. This mixed study used cognitive interviews and focus groups with family caregivers (N=13) and healthcare professionals (n=14) to assess their knowledge and understanding of hospice and artificial hydration and nutrition. Data were audio-recorded, transcribed verbatim, and analyzed with thematic content analysis. Three main themes were identified: DAs alone aren\u2019t enough to foster quality decision making for surrogates; individualized communication is necessary to clarify PWD and caregiver value priorities and disease trajectories; and clarification of the impact of care choices within situational contexts is quintessential. Further development is needed to create a practice protocol from these themes to inform professionals assisting surrogates in ACP at EOL. Practical implications from this study include highlighting the importance of individualized communication between PWD, providers, and caregivers in addressing EOL care decisional needs."} +{"text": "Community-dwelling older adults often experience cognitive symptoms, and three common conditions that contribute to changes in cognition are dementia, depression and delirium. Despite the clinical inter-connectedness among these medical conditions, hereafter referred to collectively as cognitive vulnerability, little is known about the potential for success of clinical interventions that simultaneously address these conditions. From the perspective of older adults with cognitive vulnerability and their families, hospital admissions and emergency department (ED) visits are disorienting and often lead to declines in functional capacity and well-being, and significant family distress, threatening continued independent living. In this Symposium, we present details about an ongoing clinical trial testing a novel in-home, multidisciplinary team care management intervention for older adults with cognitive vulnerability and their families. This care management intervention led by nurse practitioners, called the3D Team care model, aims to help reduce ED visits and hospitalizations and achieve other health-related outcomes. The first presentation will provide study background and design features as well as characteristics of study participants. The next two presentations by the3D Team nurse practitioners will provide details about how the multidisciplinary team works, and how each team member provides interventions intended to address risk factors for adverse health outcomes. The fourth presentation by the3D Team community health educator will explain how needs related to social determinants of health are addressed. The Discussant will place this clinical trial within the broader context of multidisciplinary team care for older adults with cognitive vulnerability led by nurse practitioners trained in geropsychiatry."} +{"text": "Background\uff1aGratifying the elderly health-care demands and promoting high-quality of nursing services are based on the effort of long-term care(LTC) nurses. However, the high turnover rate of LTC nurses has become very serious in China. What remains unclear is whether the organizational justice and job characteristics affect the LTC nurses\u2019 intention to stay. Objective: The aim was to investigate intention to stay among LTC nurses in relation to organizational justice and job characteristics. Method: A cross-sectional study was conducted with a convenience sample of 545 LTC nurses. Data collection was performed between July and November 2019. Data were analyzed using structural equation modeling. Results: Most of LTC nurses reported to stay in nursing or current work place, however they still had strong desire to leave if there were other job opportunities. Organizational justice and job characteristics were significant predictors of LTC nurses intent to stay. LTC nurses job characteristics partially mediates the relationship between organizational justice and intent to stay. Conclusion: This would suggest the importance of administrators/ managers understanding how to promote organizational justice, foster a justice climate and increase LTC nurses\u2019 perceived job characteristics. The organizational justice culture programs should be develop as LTC nurses retention strategy."} +{"text": "Post-traumatic bronchobiliary fistulas (BBF) are extremely rare with high morbidity and mortality rates. Accurate and timely diagnosis of these entities is critical for appropriate treatment, which usually requires a multidisciplinary approach. We describe two post-traumatic cases using a multimodality approach including computed tomography (CT), magnetic resonance imaging (MRI)/Magnetic Resonance Cholangiopancreatography (MRCP), and hepatobiliary scintigraphy with specific emphasis on the imaging features for each modality. Management of hepatobiliary fistulas is complex, involving extensive diagnostic work up followed by a conservative and/or surgical approach. Bronchobiliary fistula (BBF) is communication of biliary system and bronchial tree. It was first described by Peacock in 1850 . Post-trCase 1A 16-year-old male with history of penetrating injury (gunshot) to the right upper quadrant and right lower hemithorax complicated by biliary leak, diaphragmatic injury, and bilomas. Initial contrast-enhanced CT demonstrated multiloculated fluid collections in the right subphrenic space and small pleural effusion Figure , 1B . ThCase 2A 40-year-old male and victim of gun violence with surgical history of laparotomy, left hepatectomy, cholecystectomy and removal of two foreign bodies. Six days later, he underwent an endoscopic retrograde cholangiopancreatography (ERCP) which revealed extravasation of contrast from the common bile duct and he returned to the operating room for drainage of intraabdominal abscesses and a Roux-en-Y hepaticojejunostomy.Since then over several months he suffered from many hepatic abscesses, bilomas, cholangitis, and gram negative bacteremia, primarily managed with percutaneous drains and antibiotics. His clinical course was further complicated by misplaced drains and a biliarycutaneous fistula.Multiple admissions were made for management of the biliarycutaneous fistula, a most recent CT of the abdomen and pelvis demonstrated loculated collection in the hepatic dome extending into the right subdiaphragmatic space Figure , 2B. ThiThere is paucity of large case series in literature since post-traumatic BBFs are extremely uncommon. Most of the publications consists of case reports and small series. A systematic literature review of 68 cases published in 30 years by Liao et al. revealed only seven cases 10.2%) secondary to trauma [% secondaA significant clinical symptoms in patients with BBFs is bilioptysis. Bilioptysis is presence of bile in the sputum and believed to be pathognomonic finding for BBFs. Other common symptoms include irritating cough, fever, and jaundice .Penetrating injuries rather than blunt traumas are reported in etiology of bronchopulmonary fistulas .\u00a0Both ofInitial evaluation usually starts with CT which is useful to demonstrate liver injury, abdominal and thoracic fluid collections, as well as abnormal lung findings. The widespread availability, decreased variability between operators, imaging speed, and relatively few contraindications make it ideal in immediate traumatic assessment ,8.\u00a0HowevConventional MRI of the abdomen with MRCP (Magnetic Resonance Cholangiopancreatography) can provide good anatomical information of the biliary system. However, contrast-enhanced magnetic resonance cholangiography using hepatobiliary contrast agents was reported to demonstrate bronchobiliary fistula since it depicts biliary excretion from injured ducts . UnfortuHepatobiliary scintigraphy, similar to MR cholangiopancreatography with hepatobiliary contrast agents provide functional information. Image acquisition may be obtained for a prolonged time to trace bile movement. The precise location of bronchobiliary connection could not be confidently determined with this method even when SPECT was performed in the past. SPECT/CT as a hybrid imaging technique combining the functional information of hepatobiliary scintigraphy and anatomical information of CT overcomes the shortcoming and may clearly define fistulous tract .Management of BBF varies from a conservative approach to definitive surgical management. The conservative approach is preferred in the initial management of bile leaks. Biliary decompression or diversion using endoscopic sphincterotomy, biliary stent placement, or nasobiliary drainage and percutaneous image-guided catheter collections alone may be successful. More definitive treatment would require surgical resection of the fistula with pulmonary segmentectomy, especially in the presence of lung injury -15. ReceA multimodality approach is critical for stepwise diagnosis of BBFs. Although CT is used in initial evaluation of BBFs, hepatobiliary scintigraphy can confirm biliary leaks and differentiate bilomas from other fluid collections. Bile excretion and movement may be traced by sequential dynamic imaging. SPECT and more recently SPECT/CT may reveal connections between the bile ducts, bilomas and other structures such as bronchial tree and may play an important role in management of complex cases. MR cholangiopancreatography with hepatobiliary contrast agents also allows dynamic biliary imaging. It is an alternative to hepatobiliary scintigraphy and SPECT/CT and may demonstrate fistulous communications of the biliary system with high accuracy."} +{"text": "Motor impairments, including slow walking, are common in older age in the absence of prototypical Parkinson\u2019s disease (PD). The etiology of such disturbances is heterogeneous and multi-system in nature. Dopamine is a key neurotransmitter involving motor, cognitive and behavioral circuitry. Normal aging is associated with substantial dopaminergic losses in the brain. Dopaminergic vulnerability of aging can be augmented by genotypic changes that may further compromise dopaminergic signaling, such as polymorphisms in the COMT gene. These observations may augur dopaminergic pharmacotherapy studies to treat gait disturbances in older adults. Prior dopaminergic therapy studies have shown overall limited effects in non-PD older adults. A major limitation of these studies is the non-targeted selection calling for personalized medicine approaches. Recent dopaminergic treatment studies targeting specific sub-groups of non-PD older adults conducted by us and others will be discussed."} +{"text": "In the coming years, inevitably growing numbers of older populations will yield more older Americans with extensive medical and long-term care needs. This will lead to an increasing need for long-term services and supports (LTSS) to assist older adults with routine daily activities . There is a growing interest in understanding how social and physical environments contribute to health outcomes and the provision of services and resources for older persons with disabilities requiring assistance from LTSS. Decisions about care and subsequent experiences are likely a result of factors that extend beyond personal preference or individual factors, such as neighborhood quality, housing context, and living situations among community-dwelling older adults. Given population aging and the shift of LTSS from nursing homes toward community settings, there is a pressing need for more information about contextual factors that might help better develop supports for vulnerable older adults. This symposium will feature four presentations that provide novel insight regarding social and physical contextual factors contributing to LTSS. Presentations leverage data from the National Health and Aging Trends Study (NHATS), a nationally representative survey of Medicare beneficiaries aged 65 and older, and will describe: 1) associations between individual and home environment risk-factors, neighborhood-level social deprivation, and falls; 2) the relationship between neighborhood-level social deprivation and caregiving intensity (number of hours of caregiving per week) among community-dwelling older adults; 3) associations between living in single-family vs. multi-unit housing and social networks; and 4) community tenure among homebound older adults."} +{"text": "Novel technologies like navigation and robotic surgery are very costly and not easily available in all centres, especially in developing countries. We describe a simple method to assess the HKA alignment while performing coronal deformity correction around the knee using external fixator components which are commonly available with every centre.Coronal plane deformities of lower limb are often challenging and require a thorough pre-operative planning, accurate intra-operative assessment and execution. Intra-operative confirmation of correct restoration of lower limb alignment [Hip-Knee-Ankle (HKA) axis] is more often than not assessed by gross visual inspection, which can be fallacious. Various methods described in literature for intra-operative assessment include cable method, axis board, specialised alignment rods with a connector, computer assisted surgeries, etcApparatus required for assessment of alignment includes external fixator rods and tube to tube connector clamps . ConnectWe have shown the application of this method using external fixator set from Greens\u00ae Surgicals Private Limited. However, external fixators from any manufacturer can be utilised for this purpose. We believe this simple method can be easily used by any orthopaedic surgeon in any centre without any additional efforts or cost."} +{"text": "Neural injury in mammals often leads to persistent functional deficits as spontaneous repair in the peripheral nervous system (PNS) is often incomplete, while endogenous repair mechanisms in the central nervous system (CNS) are negligible. Peripheral axotomy elicits growth-associated gene programs in sensory and motor neurons that can support reinnervation of peripheral targets given sufficient levels of debris clearance and proximity to nerve targets. In contrast, while damaged CNS circuitry can undergo a limited amount of sprouting and reorganization, this innate plasticity does not re-establish the original connectivity. The utility of novel CNS circuitry will depend on effective connectivity and appropriate training to strengthen these circuits. One method of enhancing novel circuit connectivity is through the use of electrical stimulation, which supports axon growth in both central and peripheral neurons. This review will focus on the effects of CNS and PNS electrical stimulation in activating axon growth-associated gene programs and supporting the recovery of motor and sensory circuits. Electrical stimulation-mediated neuroplasticity represents a therapeutically viable approach to support neural repair and recovery. Development of appropriate clinical strategies employing electrical stimulation will depend upon determining the underlying mechanisms of activity-dependent axon regeneration and the heterogeneity of neuronal subtype responses to stimulation. Following injury to the adult mammalian central nervous system (CNS), neural circuits are permanently disrupted as severed axons fail to undergo spontaneous regeneration. The limited regenerative response of injured CNS neurons is due to both intrinsic and extrinsic factors. These growth-restrictive mechanisms play a large part in the poor clinical outcomes following brain or spinal cord trauma; however, despite limited regenerative capacity, mounting evidence has shown extensive spontaneous sprouting of CNS axon collaterals in the injured adult CNS.The mammalian nervous system has an intrinsic capacity for structural and functional reorganization in response to a variety of stimuli during development, learning, or in response to pathological insults . This inRecent findings suggest that manipulation of neuronal activity can drive plasticity related growth mechanisms and augment collateral sprouting, thereby enhancing the functional effect of axonal remodeling . ElectriIn contrast to most CNS neurons, neurons of the peripheral nervous system (PNS) have a more robust regenerative response to injury . This owDespite the innate regenerative potential of PNS neurons after injury, recovery of function remains limited. Several factors can hamper recovery, such as age, extent of injury and disruption of endoneurium, perineurium, or epineurium, and neuroma formation. One critical factor is the slow rate of regeneration in the adult PNS of 1\u20133 mm per day . Axons nThe innate regenerative ability of adult mammalian PNS neurons has been used as a model to study the intrinsic mechanisms underlying the regenerative program. Primary sensory neurons are located in the DRG and extend axons into both CNS and PNS. Each axon exhibits a distinct response to injury in the adult. As described above, the peripheral axon retains the ability to regenerate following axotomy. In contrast, the CNS axon of the same cell will fail to regenerate after spinal cord injury. Intriguingly, the regenerative program activated by peripheral nerve injury conditions DRG neurons to mount an enhanced regenerative response to a second injury, whether in the peripheral or central axon . The proAnother important change after conditioning lesion is the transient increase of second messenger cyclic nucleotide cAMP levels. Artificial elevation of cAMP can support a limited amount of sensory axon regeneration in the injured spinal cord . DownstrActivation of the pro-regenerative transcriptional response in the somata of regenerating neurons requires a retrograde signal from the injury site. One candidate for this rapid signal is the early influx of calcium at the injury site . Rapid cin vitro injury stimulation . Nitric (CamKII) . Piezo-m in vivo . Further in vivo . Genetic calcium . Blockad in vivo .PTEN deletion from RGCs and other CNS neurons leads to elevated PI3K/mTOR signaling, enhanced phosphorylation of S6, and an increased capacity for axonal growth after injury by high-contrast visual stimulation or via chemogenetics approaches can enhance optic nerve regeneration . In contr injury . Alternadeletion .suppressor of cytokine signaling 3 (SOCS3) increases optic nerve regeneration have been largely defined as the coordinated and complementary genes activated by peripheral conditioning paradigms in PNS neurons. These include developmental growth-associated proteins , transcription factors , and signaling pathways . In muchWhile electrical stimulation activates many of the same molecular pathways as peripheral conditioning via crush injury, it does not fully recapitulate the growth-promoting effects of conditioning. Following a subsequent peripheral injury, previous exposure to low-frequency electrical stimulation enhances the initiation of regeneration, but does not increase the rate of peripheral motor or sensory axon regeneration . The limin vivo by low frequency (20 Hz) electrical stimulation, 20 Hz trains separated by 5 min intervals arrested neurite outgrowth of primary sensory neurons in vitro stimulation of the soleus muscle in the rabbit was used to shorten the time for recovery of soleus function after axonotmesis of the soleus motor nerve . This mod injury is likeld injury .trans-spinal direct current stimulation after cervical spinal cord injury results in a strengthening of novel connections in the spinal cord. Furthermore, this paired stimulation paradigm can support the recovery of dextereous forelimb movements that depend on corticospinal function is a non-invasive and painless neuromodulation strategy that augments motor and sensory function after SCI . CervicaAmong the different approaches that have been proposed to enhance post-lesion plasticity, extrinsic manipulation of neuronal activity by electrical stimulation is an attractive therapeutic approach. Electrical stimulation has been demonstrated to engage plasticity mechanisms in several central and peripheral neural circuits and has already shown feasibility in clinical settings. Development of appropriate strategies will likely depend upon the selective activation of desired neural subtypes in a temporally and spatially organized manner. Non-targeted electrical fields have been used to trigger population responses; however, it may be that distinct electrical stimulation parameters can selectively affect neuronal subtype responses and circuit-specific functional outcomes. Whether the molecular mechanisms activated by electrical stimulation are consistent across neuronal populations is unknown. The sprouting response of corticospinal axons to electrical stimulation contrasts with the elongation observed in stimulated PNS axons. These differences may arise from disparate stimulation parameters, discrete responses of these distinct populations to electrical stimulation, or from interactions of conserved stimulation-mediated molecular pathways with the intrinsic limitations of adult CNS neurons to axon elongation. Further studies will be required to identify whether CNS-tuned parameters of electrical stimulation can drive a regenerative response in transected corticospinal axons.In the context of SCI, preclinical and clinical studies have clearly demonstrated that the stimulation of local spinal networks can drive lasting functional improvements . CorticaJJ and EH wrote and edited the manuscript. SA created the illustrations. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "We summarize how older women face intersectional experiences that affect their retirement security. These include differential trends in aging, life expectancy, labor supply, work history, retirement savings, and poverty at old age. We also highlight research showing that older women experience significantly more age discrimination than older men. affecting the ability for older women to improve their retirement security by working longer. We demonstrate through examples that these differential trends and intersectional experiences of older women have important policy implications. We provide examples of how Social Security policies, such as increases in the full benefit retirement age and changes to the retirement earnings test, have differential effects on older women. We also discuss how age and gender employment discrimination law fails to protect older women from intersectional sex-plus-age discrimination. We conclude by urging policymakers to consider how older women experience different challenges and how policy should consider their unique experiences."} +{"text": "High-grade gliomas are the most common and aggressive malignant primary brain tumors. Current therapeutic schemes include a combination of surgical resection, radiotherapy and chemotherapy; even if major advances have been achieved in Progression Free Survival and Overall Survival for patients harboring high-grade gliomas, prognosis still remains poor; hence, new therapeutic options for malignant gliomas are currently researched. Sonodynamic Therapy (SDT) has proven to be a promising treatment combining the effects of low-intensity ultrasound waves with various sound-sensitive compounds, whose activation leads to increased immunogenicity of tumor cells, increased apoptotic rates and decreased angiogenetic potential. In addition, this therapeutic technique only exerts its cytotoxic effects on tumor cells, while both ultrasound waves and sensitizing compound are non-toxic per se. This review summarizes the present knowledge regarding mechanisms of action of SDT and currently available sonosensitizers and focuses on the preclinical and clinical studies that have investigated its efficacy on malignant gliomas. To date, preclinical studies implying various sonosensitizers and different treatment protocols all seem to confirm the anti-tumoral properties of SDT, while first clinical trials will soon start recruiting patients. Accordingly, it is crucial to conduct further investigations regarding the clinical applications of SDT as a therapeutic option in the management of intracranial gliomas. Intracranial gliomas are the most common primitive malignant neoplasms of the central nervous system, accounting for approximately 24.1% of all primary brain tumors .,56.55,56"} +{"text": "This pilot study assessed a novel intervention to enhance both walking and executive function in older adults. The primary hypothesis was that eighteen sessions of frontal lobe tDCS combined with walking rehabilitation would be feasible, safe, and show preliminary efficacy. Eighteen participants were randomized to one of three intervention groups: active tDCS and rehabilitation with complex walking tasks (Active/Complex); sham tDCS and rehabilitation with complex walking tasks (Sham/Complex); or sham tDCS and rehabilitation with typical walking . Outcome measures included multiple tests of walking function, executive function, and prefrontal activity during walking as measured by functional near infrared spectroscopy (fNIRS). Of the three groups, the Active/Complex group demonstrated the broadest improvements across outcome measures including for prefrontal activity. The functional range of prefrontal activity in this group was increased considerably, as conceptualized by the Compensation Related Utilization of Neural Circuits Hypothesis. Frontal tDCS is a promising adjuvant to walking rehabilitation."} +{"text": "Older adults\u2019 psychosocial factors, including personality, are correlated with driving performance and driving cessation. However, the relationship between personality and driving styles has been examined only among young and middle-aged drivers. This study examined the relationships of personality factors and self-reported driving styles among 72 healthy older drivers aged 65-85 using the Multidimensional Driving Style Inventory (MDSI) scale to measure reckless and careless, anxious, angry and hostile, and patient and careful driving styles. Personality was accessed with the Big Five Personality questionnaire. Correlational results indicated that less conscientiousness was significantly correlated with increased reckless and careless and less patient and careful driving styles; and lower agreeableness was significantly correlated with greater angry and hostile and less patient and careful driving styles. Being a man was associated with greater reckless and careless and angry and hostile driving styles. Age was not associated with driving styles. Accordingly, three regressions were tested. After controlling for gender, only lower conscientiousness was associated with greater reckless and careless driving style . Men had a higher risk of reckless and careless and angry and hostile driving styles. Our results highlight the relationship between personality traits and self-reported driving styles among older adults, and how gender may influence some of these relationships. Future research should further investigate the associations between gender and personality traits and older adults\u2019 driving mobility and safety."} +{"text": "Certain emotion regulation (ER) strategies are often considered to be more or less demanding of cognitive resources. However, age-related differences in the perceptions of these demands are not yet understood. Older adults might perceive greater demands for certain strategies due to differences in cognitive ability and motivation to maintain emotional well-being. In the present study, we examined age and cognitive ability as predictors of perceived effort required to use ER strategies that span all families of the process model. A diverse sample of community participants (age 22-83) completed assessments of cognitive ability and perceived demands associated with ten ER strategies. Overall, response-focused strategies were rated as highest in demands whereas situation selection and savoring were perceived as least demanding. Older adults reported higher demands associated with situation selection, distraction, and detached reappraisal compared with younger adults. Cognitive ability was not associated with perceived demands for ER strategies traditionally viewed as cognitively demanding . Rather, higher cognitive ability only predicted lower perceived demands for strategies often considered low in demand: situation selection and savoring. Perceived ER success was not consistently associated with age or cognitive demands. Results suggest that older adults view some, but not all, ER strategies as more demanding than younger adults do. The role of cognitive ability in age-related changes in ER may be more complex than previously expected. Notably, the lack of findings with perceived ER success suggest effort requirements associated with ER may not impede ability to successfully regulate across adulthood."} +{"text": "E. coli and quantify ppGpp within several strains using a recently developed analytical method. We find that although the inverse correlation between ppGpp and growth rate is robust across strains and analytical methods, absolute ppGpp concentrations do not absolutely determine RNA synthesis rates. In addition, we investigated the consequences of two separate RNA polymerase mutations that each individually reduce (but do not abolish) sensitivity to ppGpp and find that the relationship between ppGpp, growth rate, and RNA content of single-site mutants remains unaffected. Both literature and our new data suggest that environmental conditions may be communicated to RNA polymerase via an additional regulator. We conclude that basal ppGpp is one of potentially several agents controlling ribosome abundance and DNA replication initiation, but that evidence for additional roles in controlling macromolecular synthesis requires further study.The molecule guanosine tetraphophosphate (ppGpp) is most commonly considered an alarmone produced during acute stress. However, ppGpp is also present at low concentrations during steady-state growth. Whether ppGpp controls the same cellular targets at both low and high concentrations remains an open question and is vital for understanding growth rate regulation. It is widely assumed that basal ppGpp concentrations vary inversely with growth rate, and that the main function of basal ppGpp is to regulate transcription of ribosomal RNA in response to environmental conditions. Unfortunately, studies to confirm this relationship and to define regulatory targets of basal ppGpp are limited by difficulties in quantifying basal ppGpp. In this Perspective we compare reported concentrations of basal ppGpp in Escherichia coli, the small molecule guanosine tetraphosphate (ppGpp) is closely tied to growth rate control. However, due to the circumstances of its discovery, ppGpp is more familiar as a stress or starvation signal. ppGpp and guanosine pentaphosphate (pppGpp), collectively called (p)ppGpp, were first identified in E. coli as compounds produced in strains that inhibit stable RNA synthesis upon amino acid starvation, a phenomenon known as the stringent response (\u20131 for ppGpp) (E. coli (How might a bacteria cell measure its own growth rate? In the model bacterium response . The souresponse . The higr ppGpp) drive prr ppGpp) . The ove(E. coli we focusE. coli in the absence of stress (between 10 and 90 pmol OD\u20131). When growth rate is varied by nutritional quality, basal ppGpp correlates inversely with growth rate. Basal ppGpp is essential in minimal media as it is required to activate transcription of amino acid pathways ppGpp0] does not vary DNA replication initiation in response to growth rate, suggesting that ppGpp participates in regulating the DNA-biomass ratio like an emergency brake.The observation that high ppGpp concentrations inhibit biomass synthesis suggests that basal ppGpp concentrations might also directly regulate all biomass synthesis pathways during steady-state growth, in addition to regulating stable RNA synthesis. This hypothetical layer of regulation would complement control of rRNA transcription, which determines the maximum rate of is PurF, or transis PurF, or the fis PurF, . Basal pis PurF, , as highis PurF, . In thisE. coli controls growth. To further encourage the recent revival of interest in the mechanisms of steady-state growth regulation and homeostasis its low abundance; (2) its chemical instability; (3) the presence of environmentally sensitive enzymes that rapidly hydrolyze and synthesize ppGpp. This means the analytical method must both chemically stabilize ppGpp and immediately denature all enzymes that synthesize or hydrolyze ppGpp. Moreover, in order to study ppGpp dynamics relevant to the rapid ppGpp response (<5 s), the method must enable fast sampling.Actual ppGpp measurements are essential for determining which cellular processes are watching the growth rate speedometer. The rarity of basal ppGpp measurements is understandable as basal ppGpp is difficult to accurately quantify. The main challenges in measuring basal ppGpp Despite these difficulties, several (p)ppGpp measurement methods have been developed, including thin layer chromatography (TLC) , high peA survey of reported basal ppGpp concentrations combined with our own measurements indicateE. coli show an inverse correlation between growth rate and basal ppGpp (15\u201390 pmol OD\u20131) . Early sol OD\u20131) . Khan aned trend . Howevered trend .Reported ppGpp concentrations may differ perhaps due to differences in strains, turbidimeter calibration, or sampling method . InteresE. coli K-12 strains using LC-MS (rph+ but not isogenic with the MG1655 reported here) has been used to demonstrate correlation between the RNA/protein ratio and the growth rate artificially elevates ppGpp, inhibits rRNA synthesis and decreases growth rate. Data from ppGpp titrations using RelA\u2032 are compared in E. coli NCM3722 in both LB medium and glucose minimal medium yields a ppGpp-growth rate curve steeper than the curve obtained in nutrient-limited NCM3722 . Howeverincreases in parallel with growth rate. E. coli mutants unable to synthesize specific nucleotides [carAB- guaB(ts)]. When growth rate was titrated with pyrimidine and purine sources, the authors inverted the correlation between ppGpp and growth rate supply? First, uracil limitation does not activate ppGpp synthesis in wild-type strains , indicatE. coli glucose cultures. Pseudomonic acid causes accumulation of uncharged tRNA and increases ppGpp. High concentrations of pseudomonic acid abruptly increased ppGpp and rapidly arrested growth, consistent with the stringent response. Low concentrations of pseudomonic acid also triggered ppGpp synthesis (up to 60\u2013100 pmol OD\u20131) and an immediate but smaller decrease in rRNA synthesis. However, the instantaneous growth rate was not perturbed in the short term by small increases in ppGpp concentrations.Steady-state correlations such as the correlation between ppGpp and growth rate imply but do not establish regulatory connections. Hypotheses inspired by correlations must be tested by environmental perturbations. \u20131) do not seem to immediately inhibit biomass synthesis (with the exception of stable RNA). This undermines any notion that basal ppGpp directly regulates the instantaneous translation rate. Finally, two additional studies demonstrate that ppGpp and the rate of stable RNA synthesis can be transiently decoupled during nutritional upshifts, suggesting that additional signals may regulate rRNA synthesis retains regulation by basal ppGpp if its two ppGpp binding sites are disrupted, we measured basal ppGpp levels, growth rates and cellular RNA in mutants , 2016. ArpoZ(wt) rpoC R362A R417A K615A; rpoC N680A K681A; We transferred mutations that disrupt ppGpp binding site 1 [rpoC2- mutant in LB medium. At first glance, this is consistent with the notion that the RNAP mutants are less sensitive to ppGpp, as apparent from the slopes of cellular RNA content vs. ppGpp (P < 10\u20136). In other words, higher ppGpp concentrations may be required to inhibit RNA synthesis in these strains. While it might be expected that the cultures expressing ppGpp-insensitive RNAP thus contain a higher RNA abundance than wild-type, we found that for every medium aside from MOPS/acetate, both mutant strains exhibit equivalent or even less RNA per OD unit than does the wild-type deserve fuller exploration as they likely hint at poorly understood facets of ppGpp biology. Disrupting either individual ppGpp binding site of RNAP did not eliminate the correlation between growth rate, RNA content, and basal ppGpp concentrations. Despite compelling evidence for basal ppGpp control of rRNA synthesis, incorporating ppGpp into quantitative models of cell behavior requires a better understanding of both transcriptional and post-translational targets. In order to advance this goal, we suggest several questions for the field:1.What targets are responsive to basal ppGpp concentrations? As basal ppGpp varies with growth rate in parallel with all biosynthetic fluxes during balanced growth, it is tempting to overextend models of ppGpp control. Targets thought to be regulated during the stringent response may prove insensitive to basal ppGpp. Experiments that monitor ppGpp during growth transitions already suggest that small changes in basal ppGpp do not immediately affect instantaneous protein synthesis or total biomass production. Studies of basal ppGpp concentrations during growth transitions are essential for distinguishing what is influenced by ppGpp. We suggest experiments that monitor protein synthesis during small controlled variations in basal ppGpp (\u00b150 pmol OD\u20131).2.What establishes basal ppGpp concentrations? It is unknown which metabolic cues drive RelA and SpoT to generate basal ppGpp.3.What regulates stable RNA synthesis during steady-state growth, aside from basal ppGpp? Our observation that RNA polymerase mutants lacking either one of the two ppGpp binding sites still exhibit an inverse relationship between RNA content and ppGpp concentrations implies that other factors also regulate RNA content, as has been suggested would also determine whether basal ppGpp is an accurate growth rate speedometer.5.Do all species with RSH proteins also maintain basal concentrations of ppGpp (or pppGpp) during steady-state growth? As RSH proteins are widely distributed and defined media to enable comparisons between labs.We further recommend the use of common reference strains (preferably All datasets generated for this study are included in the article/NI and GB conceived and designed the experiments and wrote the manuscript. NI performed experiments and data analysis. NI, NB, and MN developed the LC-MS method. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "This study compared gait speed changes after CSF tap test in patients with idiopathic normal pressure hydrocephalus presenting with various gait phenotypes . All patients improved, except those with parkinsonian gait. Gait disorders are the hallmark feature of patients with idiopathic normal pressure hydrocephalus (iNPH) /[(gait speedpost-CSF tap test\u2009+\u2009gait speedpre-CSF tap test)/2]. Univariable linear regressions evaluated the relationship between gait speed changes and each gait phenotype . Multivariable linear regressions were adjusted for age, gender, comorbidities, white matter changes assessed by the age-related white matter change scale . Frontal gait was significantly associated with gait speed improvement after CSF tap test, even after adjusting on age, gender, comorbidities, white matter changes, and MMSE . Normal gait, parkinsonian gait, and other gait abnormalities were not significantly associated with gait speed improvement, after adjusting on age, gender, comorbidities, white matter changes, and MMSE .Clinical characteristics are presented in Table This study showed that gait improvement after CSF tap test varies across gait phenotypes: frontal gait is associated with the greatest gait improvement after CSF tap test, while patients with parkinsonian gait did not show any significant gait speed changes.p value\u2009<\u20090.001). Patients with frontal gait presented the lowest gait speed at baseline and, therefore, had the greatest potential of improvement, as previously described may be explained by the following reasons. First, patients were included at an early stage of the disease course, where clinical gait abnormalities may not be evident. Second, patients have been referred, because the suspicion of iNPH was solely based on cognitive impairment and/or urinary incontinence. Third, patients may complain of gait impairments in challenging situations or balance impairments that were not clinically evident in the secure setting of a gait laboratory. Fourth, they presented fewer comorbidities that may affect gait. These results suggest that CSF tap test could also be considered at the earliest stages of iNPH when patients complain about their gait, but no clinical gait abnormality is diagnosed by physicians.The variability of the gait phenotypes in our cohort of iNPH patients may be explained by comorbidities . However, the validity of the clinical examination is not perfect and prone to an interrater variability. Having a better quantification of neurological and non-neurological comorbidities would allow a better sense of the influence of comorbidity on each gait phenotype. A post-mortem pathological examination is missing and would be of interest, especially in this cohort including mainly patients with possible iNPH (87%), who may present either a comorbid neurological condition along with iNPH or present an iNPH mimic. Finally, future studies should confirm these results by evaluating the predictive value of clinical gait phenotypes after shunting.Among gait phenotypes, frontal gait in patients with iNPH is associated with the largest gait improvement after CSF tap test. This study suggests that a clinical classification of gait phenotypes in patients with iNPH may inform about the reversibility of gait disabilities. Future studies should include long-term clinical outcomes after shunt procedure to confirm that frontal gait in iNPH patients may present a good clinical outcome in comparison to other gait phenotypes."} +{"text": "Calcifications play an essential role in early breast cancer detection and diagnosis. However, information regarding the chemical composition of calcifications identified on mammography and histology is limited. Detailed spectroscopy reveals an association between the chemical composition of calcifications and breast cancer, warranting the development of novel analytical tools to better define calcification types. Previous investigations average calcification composition across broad tissue sections with no spatially resolved information or provide qualitative visualization, which prevents a robust linking of specific spatially resolved changes in calcification chemistry with the pathologic process.Method: To visualize breast calcification chemical composition at high spatial resolution, we apply hyperspectral stimulated Raman scattering (SRS) microscopy to study breast calcifications associated with a spectrum of breast changes ranging from benign to neoplastic processes, including atypical ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. The carbonate content of individual breast calcifications is quantified using a simple ratiometric analysis.Results: Our findings reveal that intra-sample calcification carbonate content is closely associated with local pathological processes. Single calcification analysis supports previous studies demonstrating decreasing average carbonate level with increasing malignant potential. Sensitivity and specificity reach >85% when carbonate content level is used as the single differentiator in separating benign from neoplastic processes. However, the average carbonate content is limiting when trying to separate specific diagnostic categories, such as fibroadenoma and invasive ductal carcinoma. Second harmonic generation (SHG) data can provide critical information to bridge this gap.Conclusion: SRS, combined with SHG, can be a valuable tool in better understanding calcifications in carcinogenesis, diagnosis, and possible prognosis. This study not only reveals previously unknown large variations of breast microcalcifications in association with local malignancy but also corroborates the clinical value of linking microcalcification chemistry to breast malignancy. More importantly, it represents an important step in the development of a label-free imaging strategy for breast cancer diagnosis with tremendous potential to address major challenges in diagnostic discordance in pathology. Calcifications associated with breast disease are critical to breast cancer screening as they are often the only discernible indicator of risk in mammography Despite their diagnostic and prognostic potential, the morphologic and chemical features of calcifications are poorly understood, in part due to technological limitations. Morphological features of calcifications identified by mammography are insufficient for accurate diagnosis and prognosis. In addition, smaller calcifications (<0.1mm) are undetectable using mammography Moving beyond morphology and distribution patterns in breast calcification, studies utilizing X-ray diffraction and electron microprobe analysis with scanning electron microscopy (SEM) have contributed to an earlier understanding of calcification chemical differences While offering information about calcification chemistry, most spectroscopic methods average calcifications within multiple ducts within a tissue section, irrespective of the heterogeneous pathologic processes among adjacent ducts. Spatially resolved methods such as FTIR imaging have limited resolution and throughput, prohibiting visualization of calcification composition variation within adjacent ducts and lobules. Moreover, tissue protein content is recognized to correlate with malignancy We utilize the high resolution and chemical specificity SRS offers to deliver an unprecedented level of detail when analyzing calcifications. Additionally, we incorporate second harmonic generation (SHG) which has been proven effective at visualizing collagen in the tumor microenvironment -1 for total of 90 frames per stack. For SHG, a dichroic mirror (Chroma 695dcxr) is placed before the objective to allow for epi-collection of SHG signal from the sample. The SHG signal is detected by a photo-multiplier tube (Hamamatsu H10770PA-40) using 485 nm long pass and 650 nm short pass filters.A broadband femtosecond dual-beam laser system (Insight DS + from Spectra-Physics) was used for SRS and SHG Figure . The detCalcium hydroxyapatite (HAP) and 10% carbonated hydroxyapatite (CHAP) were obtained from Sigma Aldrich and Clarkson Chromatography Products respectively. Both solid controls were ground using mortar and pestle. A total of five mixtures were prepared for calibration purposes . The calibration samples were placed between a coverslip and a microscope slide for SRS imaging.Breast tissue was obtained from 17 patient archival cases (including biopsy and resection) managed by Northwest Biotrust, Seattle, WA. The initial case selection was based on the pathology report . Slides were subsequently reviewed to confirm the histologic diagnoses . Formalin-fixed paraffin-embedded tissue blocks were retrieved from archives and sectioned at 4-microns and mounted on charged slides. One section was H&E stained to identify pathological process. The adjacent section was deparaffinized and coverslipped for SRS and SHG analysis. The areas of interest were identified in the bright field based on selected areas of interest on adjacent H&E stained slides. A total of 214 breast calcifications were imaged, including: 31 non-neoplastic calcifications , 27 fibroadenoma (FA) associated calcifications, 8 atypical ductal hyperplasia (ADH) associated calcifications, 36 ductal carcinoma in situ (DCIS) associated calcifications, 112 invasive ductal carcinoma (IDC) associated calcifications. -1) and phosphate (~960 cm-1) peaks corrected for background Calibration samples with 0%, 2.5%, 5.0%, 7.5%, 10% carbonate content in calcium hydroxyapatite mixtures were imaged using the hyperspectral SRS microscope described above. Using SRS intensities at carbonate (~1070 cm-1) was used to visualize tissue morphology of the FOV the average, for a given category , was calculated with the standard deviation reported as an error bar. The differences between categories were assessed using p-values calculated from Student's t-tests. The receiver operator curves (ROC) were calculated using R software to assess the sensitivity and specificity for each parameter. Maximum Youden's index was used to determine sensitivity and specificity values.Previously, the carbonate content in hydroxyapatite has been measured using RS Figures Breast tissue submitted for pathological examination often contains calcifications in multiple ducts, which may represent various pathologic processes. In previous spectroscopic studies, multiple ducts are frequently measured together, which can average calcifications associated with different processes. Isolating individual breast ducts and detailing the histopathology within the ducts allows for correlation of variation in carbonate content with local pathology.Here, we group calcifications by specific pathological processes and not by overall case diagnosis. In Figure Figure The two cases illustrate that calcifications in the same patient case can have differing chemical composition. Although ducts are present in the same tissue section, the carbonate content associated with individual ducts is markedly different and reflects underlying pathological process. The high spatial resolution of hyperspectral SRS imaging is important to resolve calcification heterogeneity within the same patient sample and to establish the relationship between chemical composition and pathological process.Previous studies using FTIR have demonstrated that breast calcifications with lower carbonate content of CHAP correlate with malignancy Figures The neoplastic progression from benign ducts to IDC is associated with an overall decrease in calcification carbonate content Figure F and 6G Although precise quantification of the spatial distribution of carbonate in large calcifications is challenging due to sectioning artifact, our findings suggest that the carbonate content decrease on the edges of the calcifications directly reflects the changing microenvironment (i.e. higher acidity) associated with neoplastic cells and necrotic debris -1) to phosphate (~960 cm-1) ratio is used to quantify protein content in calcifications and specificity (88%) when identifying benign and invasive processes. SHG data provides a parameter separating FA from IDC cases with high sensitivity (94%) and specificity (85%). Phenylalanine to phosphate ratio provides additional separation between DCIS and IDC. Together, spectroscopy and morphology can be utilized to better establish the malignant potential in cases with ambiguous morphology on H&E alone.CHAP is not the only microcalcification species that was identified in breast cancer. Although whitlockite typically accounts for a tiny percentage of breast calcifications -1 to 970 cm-1) Typically, whitlockite can be identified using Raman spectroscopy due to unique spectral features . This problem can be addressed in future studies by imaging either fixed tissue or fresh tissue, where calcifications remain intact.Besides carbonate content of calcifications, we have elucidated the unique features that distinguish chemical composition of calcifications between FA and IDC. For the first time, we demonstrate that SHG data confirms collagen in FA makes an organic matrix upon which hydroxyapatite accumulates. This matrix observed in FA calcifications is one of the main differences between FA and IDC. This collagen matrix enables robust differentiation of FA and IDC, which exhibit similar carbonate content.In conclusion, we imaged a diverse set of breast calcifications associated with benign processes, and a range of neoplastic processes including FA, ADH, DCIS and IDC. Our findings support previous reports of carbonate content decreasing on average with increasing malignant potential. Importantly, we showed that a detailed spatial map of calcifications and their complex underlying organic matrix is highly correlated with underlying neoplastic processes and could potentially be used for breast cancer diagnosis. Additionally, the spatial heterogeneity of carbonate content could potentially be a diagnostic indicator of malignancy. Calcification underlying organic matrix, visualized using SHG in conjunction with SRS, assisted in the diagnostic differentiation of patient lesions. Our study suggests that SRS imaging of calcification can be used as an important tool for breast cancer diagnosis. The diagnosis capability will be significantly improved when combined with stimulated Raman histology (SRH), a technique that has already been shown to provide H&E equivalent information in unsectioned tissue Supplementary figures and tables.Click here for additional data file."} +{"text": "Recent changes in health care practices - shorter hospital stays, increased complexity of disease management, and greater management of chronic illnesses at home - have left family members increasingly responsible for medical tasks. Although these family caregivers represent the vital front line of care, they remain mostly excluded from the formal health care team. Based on interviews with multi-sector stakeholders representing patients/caregivers, providers, and payers, we identified several barriers to fully incorporating family caregivers into the health care team. They fall under five key themes: identification of caregivers; communication and information; time and resources; trust and cultural barriers; and Medicaid coverage. We discuss these barriers and potential solutions that could be undertaken by different stakeholder groups to improve family caregiver integration into the care team."} +{"text": "The number of older populations raising their grandchildren has increased. Past research has indicated the distress custodial grandparents\u2019 experience is related to their family relationships . Family relationships are also influenced by a variety of factors such as social history, culture, family structure, and individual differences . The current study evaluated the influence of culture on the relationship between caregiver relationship quality and mental health by examining 885 children . This study also compared the difference in cultural impact between custodial grandparents-grandchildren and biological parents-children. Measures included the Network of Relationships Inventory, Hofstede Cultural Questionnaire, and Adult Behavior Checklist. Path analysis was conducted using AMOS 26.0 which resulted in an interaction between relationship closeness and collectivism to predict custodial grandparent depressive symptoms. Custodial grandparents who reported a lower level of closeness with their grandchildren in a higher collectivistic culture reported a significantly higher level of depression symptoms than those in a more individualistic culture, particularly for custodial grandmothers. However, custodial grandparents who reported a higher level of closeness with their grandchildren in a higher collectivistic culture reported significantly lower levels of depressive symptoms than those in a more individualistic culture. Furthermore, compared to biological parents, custodial grandparents reported significantly lower levels of depressive symptoms when reporting higher collectivistic culture. These findings will inform the need for more research to assess factors of cultural features that reduce psychological problems and support family relationships to adapt psychological therapies in older adults."} +{"text": "This study examined the relationships between several attributes of living environment and attitudes towards aging among persons of age 75 years and older in Shanghai, China. The data were collected using self-administered surveys in a study of successful aging in 2018. Respondents included 139 persons of age 75 years and older living in 12 neighborhoods in Shanghai. Attitudes towards aging were measured by indices of happiness, time use and worry about the future. Using BaiduMap and GIS ArcPro, we quantified accessibility to neighborhood living resources as numbers of recreational facilities, medical facilities, parks, and grocery stores located within 500 meters of each respondent\u2019s home. The analysis found that more positive attitudes towards aging were correlated with less depressive symptom as measured by CES-D and greater numbers of neighborhood resources near home, especially greater number of grocery stores near home. In conclusion, accessibility to neighborhood resources may influence attitudes towards aging."} +{"text": "As a consequence of the Affordable Care Act\u2019s enhancements of Medicare benefits, certain recommended clinical preventive services became available to Medicare beneficiaries without cost-sharing. We study the impact of these mandates on racial/ethnic disparities in the use of preventive services among traditional Medicare beneficiaries. We analyze nationally representative data on non-institutionalized Medicare seniors from the 2006-2016 Medical Expenditure Panel Survey . Our preventive services of interest include yearly receipt of cholesterol check, blood pressure test, flu shot, endoscopy, blood stool test, clinical breast examination, mammography and prostate exam. We estimate propensity score weighted difference-in-difference (DID) models to test for differences in preventive services utilization by race/ethnicity. Among traditional Medicare beneficiaries, we do not observe significant change in the use of most preventive services for Blacks and Hispanics compared to their White counterparts. However, Hispanics have significantly increased their use of blood stool tests relative to whites. Overall, we do not find major evidence to support a differential effect of reforms on race/ethnic minorities\u2019 uptake of preventive services following the mandates. Our results suggest that despite an overall benefit trough services expansion and cost-sharing elimination race/ethnic group differences persist. As such, disparities might continue and would require additional interventions. Reduction in disparities is a stated goal of US policy for many decades and achieving equity might require additional work and more varied and targeted interventions."} +{"text": "Metastatic cancer patients undergo numerous treatment strategies with known cognitive side effects. It is unclear how medical decision-making capacity (MDC) is impacted by cognitive deficits in metastatic cancer. This study examines reliability of an objective measure of MDC compared with self-report. Participants with newly diagnosed metastasis to the brain and other sites were enrolled at the University of Alabama at Birmingham over seven years. At the study visit, participants completed a comprehensive neuropsychological battery including memory and executive functioning, and the Capacity to Consent to Treatment Instrument (CCTI) assessing medico-legal domains of MDC. The CCTI is a reliable and valid instrument containing two vignettes of hypothetical medical situations assessing four standards of consent. We examined reliability between the CCTI and self-reported MDC using Gwet\u2019s AC1 statistic. Participants with brain metastasis with impairment on the CCTI demonstrated significantly lower executive functioning and memory skills than those without impairment . There were no significant differences between intact and impaired participants with other metastases. Low reliability was observed between self-report and all medico-legal standards on the CCTI across both metastatic groups . Self-rating of MDC is unreliable in metastatic cancer patients. Patients with metastases (particularly brain metastases) may lack awareness of deficits in their MDC, so providers must affirm proper autonomy in their decisions."} +{"text": "A paradoxical double challenge has emerged in the last decades with respect to nutrition and nutrition-related clinical conditions. Hunger-related undernutrition continues to represent an unacceptable burden, although its prevalence has been encouragingly reduced worldwide. On the other hand, the prevalence of overweight and obesity, defined as fat excess accumulation with negative impact on individual health, has dramatically increased due to increasingly pervasive obesogenic lifestyle changes. Undernutrition and obesity may coexist in world regions, Countries and even smaller communities and households, being referred to as double burden of malnutrition. It is however important to point out that fat accumulation and obesity may also induce additional nutritional derangements in affected individuals, both directly through metabolic and body composition changes and indirectly through acute and chronic diseases with negative impact on nutritional status. In the current narrative review, associations between fat accumulation in obesity and malnutrition features as well as their known causes will be reviewed and summarized. These include risk of loss of skeletal muscle mass and function (sarcopenia) that may allow for malnutrition diagnosis also in overweight and obese individuals, thereby introducing a new clinically relevant perspective to the obesity-related double burden of malnutrition concept. Natu2 \u20135. Indee2 , 7, 3, 4e groups , 6, 9.Based on the above observations, new complex nutritional challenges have emerged in recent times, with epidemiological shifts and coexistence of under- and overnutrition. The latter concept has indeed been recently described under the definition of \u201cdouble burden of malnutrition\u201d, indicating that both under- and overnutrition are commonly observed not only at global level but may indeed coexist in the same world regions and often in the same Countries and communities. Coexistence of seemingly opposite nutritional patterns may obviously partly reflect social and economic inequalities, but additional important reasons should be pointed out. In particular, enhanced life expectancy is increasing older adult population worldwide, and elderly individuals are commonly more prone to undernutrition due to multifactorial reasons that include psychological, social and health-related factors \u201312. EvenThe ongoing unprecedented shift in body weight paradigms is however posing larger dramatic individual, family, socio-economic and healthcare challenges . ObesityNegative obesity- and disease-related influences on skeletal muscle mass and function maintenance are summarized below. It is increasingly clear that profound alterations in skeletal muscle metabolism may occur in obesity with potential negative impact on whole body muscle mass and function , 26. Bodprimary metabolic abnormalities and insulin resistance: although a sizable portion of the obese population is not insulin resistant, a large majority of insulin resistant persons is either overweight or obese, or it presents with excess fat accumulation in the abdominal visceral compartment , 30. Subectopic muscle fat accumulation: muscle lipid accumulation commonly results in obesity from impaired adipose tissue expansion in the presence of excess lipid availability. Skeletal muscle fat accumulation is conversely closely associated with tissue and systemic insulin resistance , 48. Mecmitochondrial dysfunction: mitochondrial changes may not occur in obese individuals and become relatively common only in relatively late stages; their onset may however lead to excess ROS production resulting in oxidative stress and related complications that may exacerbate insulin resistance and directly favor muscle loss , 31, 44.stem cell dysfunction: altered muscle stem cell function with excess adipocyte differentiation have beeIntermediate and energy metabolism changes.metabolic complications: metabolic syndrome or overt type 2 diabetes and hyperglycemia are common in insulin resistant obese individuals and their onset may exacerbate pro-oxidative and inflammatory alterations as well as mitochondrial dysfunction. These enhanced abnormalities may further promote muscle loss and functional alterations , 48;chronic disease: chronic organ failure syndromes result in enhanced inflammation and oxidative stress through various mechanisms at tissue and systemic level, thereby also synergistically promoting muscle loss and damage . Obesitysurgery: bariatric procedures are becoming increasingly common and almost invariably lead to skeletal muscle catabolism at least in the initial rapid weight loss phase characterized by profoundly negative energy balance , 58; lowComorbidities and treatment.Lifestyle and physical inactivity: low physical activity levels play a key role in the onset of obesity and physical activity is commonly further progressively reduced with disease duration, aging and increased body weight, with direct negative impact on muscle protein turnover as well as muscle fitness . ObesityBased on the above observations, a multifactorial cluster of obesity-induced or obesity\u2013associated alterations leads to skeletal muscle loss and dysfunction with low muscle strength and endurance, that are likely caused at least in part by low muscle mass, mitochondrial dysfunction with altered bioenergetics and fat accumulation with reduced muscle density. These changes become progressively more likely in patients with longer obesity duration, complications and older age, that may be per se independently associated with muscle loss and dysfunction.Skeletal muscle changes in obesity have a profound clinical impact. Obese individuals with low muscle mass and function have higher risk of developing frailty and disability, and may generally present with poorer quality of life. Importantly, low or declining muscle mass is emerging as a negative prognostic factor associated with higher morbidity and mortality in obese patients with various chronic complications and diseases and in aging , 64, 65.The potential relevance of muscle mass maintenance as a priority therapeutic target in obesity is regrettably hampered by inadequate awareness. Definition and diagnosis of this condition are problematic. Definition of sarcopenic obesity may combine obesity with the geriatric concept of primary sarcopenia, a combination of low muscle mass and function (particularly strength) that almost invariably occurs in old age. While diagnostic criteria for aging-associated primary sarcopenia have been proposed , they arOverall, despite relevant practical limitations, recognizing skeletal muscle depletion or dysfunction in obese individuals by body composition measurement techniques, strength measurement or other functional tests should be a priority to alert clinicians to enhanced risk for negative outcome \u201378.Routine nutritional screening to identify patients at risk for malnutrition is recommended in most chronic and acute disease conditions and in hospitalized patients. Validated and widely utilized screening tools include Nutritional Risk Screening-2002 (NRS-2002) . ImportaMost importantly, major guidelines have started to take nutritional needs of obese patients into account with specific recommendations for nutritional support that may combine a limitation in calorie with high protein administration aimed at preventing loss of skeletal muscle mass and function , 86. PreIn conclusion, the ongoing obesity epidemics, along with population aging and increased chronic disease prevalence is profoundly modifying fundamental clinical nutrition and healthcare priorities worldwide. A true double burden of malnutrition exists beyond coexistence of obesity and undernutrition in Countries and communities. Indeed individuals with obesity may present with true malnutrition due to inability to preserve body composition and performance with loss of skeletal muscle loss and function that exert major negative influences on morbidity and survival. Recognition of this new double burden is a relevant priority in order to more effectively identify diagnostic and therapeutic tools."} +{"text": "Isolated coronary Takayasu arteritis is a rare form of ischemic heart disease that typically appears as an aorto-ostial lesion. Although several vascular imaging modalities including ultrasonography, computed tomographic angiography, magnetic resonance angiography or catheter angiography, play crucial roles for diagnosing Takayasu arteritis, the intravascular ultrasound imaging of Takayasu arteritis is not well studied.A 55-year-old woman who was diagnosed with heterozygous familial hypercholesterolemia underwent coronary angiography due to effort angina, which showed ostial left anterior descending coronary artery (LAD) stenosis. Although directional coronary atherectomy followed by drug-coated balloon was successfully performed, 6\u2009months later restenosis occurred at the ostial LAD, and the ostial left circumflex coronary artery (LCx) progressed significantly. The intravascular ultrasound imaging in these lesions was noteworthy, in which the media was partly unrecognizable and an echo intensity similar to fibrotic intimal thickening traversed from the intima to the adventitia, thereby causing the whole image of the coronary artery to become unclear. Directional coronary atherectomy followed by drug-coated balloon procedures for both LAD and LCx lesions were performed again. Systemic examination of computed tomographic angiography found no other stenotic lesions except for those in the coronary arteries. Five months later, the LAD and LCx lesions progressed diffusely, therefore the coronary artery bypass graft was done. The histopathological findings of specimens of the coronary artery that were obtained during the bypass graft showed excessive fibrous thickening of the intima and adventitia, with granulomatous inflammation in the media, which led to the diagnosis of isolated coronary Takayasu arteritis. Systemic corticosteroid therapy was then started.We described an extremely rare case of isolated and non aorto-ostial Takayasu arteritis. The characteristic intravascular ultrasound images of diseased coronary arteries may help in the diagnosis of coronary Takayasu arteritis. Takayasu arteritis is an idiopathic chronic inflammatory arteritis characterized by stenosis, occlusion or dilatation of the aorta and its major branches, predominantly prevalent among young women . CoronarA 55-year-old woman was referred to our hospital because of chest pain on effort that had worsened in the last 3 months. The patient had no significant past medical history and was not on any medication. Family history revealed that her mother was diagnosed as having stable angina pectoris at 70. The patient had no evident physical findings of fever, lymphadenopathy, joint pain or left-right deference of blood pressure. Electrocardiogram showed regular sinus rhythm and no significant abnormalities Fig.\u00a0. The echPercutaneous coronary intervention with coronary plaque atherectomy using directional coronary atherectomy (DCA) catheter followed by paclitaxel-coated balloon was performed on the LAD lesion, and plain old balloon angioplasty was performed on the high lateral branch lesion Fig. c and d. Five months later, she suffered from chest pain on effort again and coronary angiography showed a restenosis of the ostial LAD, as well as a stenosis of the distal left main coronary artery (LMCA) and the ostial LCx Fig. e and f. Single photon emission computed tomography myocardial perfusion imaging at 6 months after the second coronary intervention revealed significant apical and lateral wall ischemia. Coronary angiography showed the restenosis of the ostial LCx and the diffuse stenotic progressions of the mid LAD and LCx was then started. Since the administration of corticosteroids, at the time of writing, the patient has been free from chest pain for 1\u2009year.Takayasu arteritis is an idiopathic chronic inflammatory arteritis characterized by stenosis, occlusion or dilatation of the aorta and its major branches, and is predominantly prevalent among young women . CoronarIVUS imaging of the lesion revealed intimal fibrotic thickening without lipid-rich plaque, in which the media was partly unrecognizable and the echo intensity similar to fibrotic intimal thickening traversed from the intima to the adventitia. The histopathologic characteristics of Takayasu arteritis are granulomatous inflammation of the media and adventitia with giant cells, diffuse productive inflammation consisting of lymphocytes and plasma cells infiltration, diffuse or nodular fibrosis accompanied by disintegration and loss of elastic fibers, and reactive intimal fibrotic thickening. These conditions caused marked intimal and adventitial fibrosis . The disDirectional coronary atherectomy is a useful method especially for bifurcated lesions . The comBoth Takayasu arteritis and familial hypercholesterolemia provoke arterial stenosis as a result of inflammatory disorder of the arterial wall; however, the correlation of these diseases is unclear , 14. TheWe here described an extremely rare case of isolated and non aorto-ostial coronary Takayasu arteritis, and IVUS images of coronary lesions in Takayasu arteritis. Characteristic IVUS images may help for diagnosing coronary arteritis."} +{"text": "Avian influenza A viruses (AIVs), as a zoonotic agent, dramatically impacts public health and the poultry industry. Although low pathogenic avian influenza virus (LPAIV) incidence and mortality are relatively low, the infected hosts can act as a virus carrier and provide a resource pool for reassortant influenza viruses. At present, vaccination is the most effective way to eradicate AIVs from commercial poultry. The inactivated vaccines can only stimulate humoral immunity, rather than cellular and mucosal immune responses, while failing to effectively inhibit the replication and spread of AIVs in the flock. In recent years, significant progresses have been made in the understanding of the mechanisms underlying the vaccine antigen activities at the mucosal surfaces and the development of safe and efficacious mucosal vaccines that mimic the natural infection route and cut off the AIVs infection route. Here, we discussed the current status and advancement on mucosal immunity, the means of establishing mucosal immunity, and finally a perspective for design of AIVs mucosal vaccines. Hopefully, this review will help to not only understand and predict AIVs infection characteristics in birds but also extrapolate them for distinction or applicability in mammals, including humans. Avian influenza A viruses (AIVs) remain one of the important viral pathogens that cause respiratory tract infections in various animal species, such as poultry and humans, and aquatic birds are considered the primordial source of AIVs infecting other animal species . InfluenInfluenza viruses undergo antigen mutations through antigen drift and shift. Circulating AIVs evolve constantly, resulting in the occurrence of new strains with variable antigenicity. Particularly, mutations occurring in the HA or NA usually cause antigenic drift, subsequently leading to an escape from earlier immune responses. Besides, an antigenic shift can take place in AIVs. In this case, co-infection of a host cell with AIVs strains of different origins can lead to the generation of novel virus subtypes via induced genetic reassortment; a newly formed HA subtype of AIVs can transmit easily in immunologically na\u00efve individuals . To dateVaccination remains one of the most effective ways to control and prevent AIVs transmission in poultry. Current influenza vaccines are generally effective against antigenically matched strains. It has been demonstrated that the antigenic mismatch between the vaccine and circulating strains or inadequate vaccine protocols can cause an antigenic drift and failed vaccination ,14. AlthThe innate immune response constitutes the first line of protection from invading pathogens. AIV infection results in a recognition of viral conserved components called pathogen associated molecular patterns (PAMPs) by host pathogen recognition receptors (PRRs), including Toll-like receptors (TLRs), retinoic acid inducible gene-I (RIG-I) receptors (RLRs), and NOD-like receptors (NLRs); the above recognition subsequently activates innate immune signaling and induces various proinflammatory cytokines as well as antiviral molecules ,19. ThenTLRs were identified as the first PRRs family that are expressed on either the plasma membrane or the surface of endosomes and lysosomes . To dateThe RLRs\u2014RIG-I and melanoma differentiation-associated protein 5 (MDA5)\u2014recognize the cytoplasmic viral non-self RNA and transcripts. RIG-I preferentially binds cytoplasmic single-strand 5\u2032-triphosphate RNA, while MDA5 is activated by long dsRNA species . Upon inThe roles of NLR signaling in bacterial infection have been broadly investigated . IAV infThe adaptive immune response comprising humoral and cellular responses at both systemic and mucosal levels constitutes the second line of defense against influenza viruses; this multifaceted immune response is complex 36]. In. In36]. Infection with influenza viruses initiates virus-specific cellular immune response involving CD4+ T and CD8+ T cells . Upon inDuring IAV infection, CD8+ T cells, a vital subset of immune cells, are activated after recognition of viral epitopes on DCs that migrate from the lung tissue to T-cell areas in the draining lymph nodes, resulting in their proliferation and differentiation into CTLs . CD8+ T The mucosal immune system plays a crucial role in controlling infection with influenza viruses in the URT . The URTAbs, particularly IgG and IgA, are the major immune components acting in the protective response to IAVs . IgG is In response to antigen stimulation, IgA class switching and IgA secretion occur in B cells stimulated by specific signals such as co-stimulatory molecules and cytokines and in Th cells via T-cell-dependent and T-cell-independent pathways . The aboAt present, the commercial vaccines against influenza available on the market mainly comprise inactivated influenza A virus (IIV) vaccine and recombinant influenza A virus (RIV) vaccine. Strains used in commercial influenza vaccines are selected based on the compositions of viruses from the surveillance, laboratory, and clinical observations . These vThe respiratory mucosa is the first target of influenza virus, constituting the first line of defense against the infection, which can effectively prevent the virus from entering . MucosalMoreover, it has been shown that mucosal vaccines induce cross-reacting Ab in the respiratory tract, providing cross-protection against heterologous virus infection. Inoculating the influenza HA vaccine together with cholera toxin B subunit (CTB) or B subunit of heat-labile enterotoxin (LTB) supplemented with cholera toxin (CT) intranasally enhanced anti-HA lgA and IgG Ab responses in nasal wash or serum, which protect mice against variant virus infection . OkamotoResearchers have been attempting to create universal influenza vaccines for providing broad and sustainable protection against diverse influenza viruses. In recent years, research on the prevention of influenza infection by nasal immunity has gained more and more attention. To effectively work in mucosal immunization, mucosal vaccines must be designed to possess the characteristics of mucosa and promote the specific immune responses to vaccine antigens in the mucosa. Currently, generating effective mucosal vaccines mainly involves the identification of efficient means for antigen delivery to the mucosal immune system and the development of safe and effective mucosal adjuvants or immunoregulatory agents.A growing number of pre-clinical studies and clinical trials have advanced our understanding of how live attenuated influenza vaccines (LAIVs) elicit mucosal antibodies via intranasal administration. Contrary to the wild-type forms, attenuated viruses have the capacity to replicate well at temperatures around 25 \u00b0C rather than at 37 \u00b0C, deterring their replication in the lower airway, including lung tissue, and the subsequent occurrence of influenza-like disease . The mosAmong developing live attenuated mucosal vaccines, the major class of vaccines, oral vaccines, are currently being assessed in clinical studies. Oral vaccines are classified into intranasal and sublingual vaccines that are developed for the control of influenza, rotavirus, norovirus and measles viruses . ExperimSuccessful development of LAIVs largely rests on the proper balance between attenuation and immunogenicity. It has been reported that serial virus passage in the host cells during vaccine development causes a decrease in the virulence of effective live attenuated vaccines for rotavirus . As a reAdjuvants can potentially increase the immunogenicity of mucosal influenza vaccines, while enhancing the efficacy of vaccines through modulating the quantity and quality of host immune responses. Commonly used adjuvants include a wide range of compounds . The comAdjuvants act via the following mechanisms: (1) a depot formation at the site of injection, which enables the vaccine agents to be slowly released and the host immunity to be constantly stimulated; (2) enhancement of the agent uptake via APCs and APC activation and maturation; (3) immune cell recruitment; and (4) innate immune receptor activation. Moreover, adjuvants can shape subsequent adaptive immunity for producing the most effective and protective responses to a given pathogen through targeting the subsets of innate immune cells and forming a unique cytokine milieu associated with Th1, Th2, and/or Th17.A number of adjuvants for inactivated influenza vaccines including TLR agonists are widely used to enhance the vaccine immunogenicity . StudiesDNA vaccines are capable of expressing immunogenic antigens in vivo, thereby inducing cellular and humoral immunities without causing host exposure to live viruses . ExtraceIt has been shown that intranasal administration of DNAs in mice leads to a fast and relatively even distribution of plasmid DNAs all over the body . DNA vacParticulate vaccines are capable of forming a close contact with the epithelial cells in the mucosa via included anchoring devices with adhesive properties or included immunomodulating factors ,121. TheRecombinant technology has been employed to engineer live vector vaccines to express target antigens. The vectors usually have minimal replicative ability to allow immune stimulation without causing infection. Delivery of vector vaccines via the mucosal routes mimics the natural infection, inducing strong mucosal, systemic, and cellular immunities against micro-organisms. Many candidate vectors. e.g., bacillus subtilis , FowlpoxAdministration of mucosal vaccines via the oral route is strongly recommended because it avoids an injection, is safe and painless, and does not require professionals for delivery. However, the efficacy of oral vaccination has proven less satisfactory due to the fact that vaccine degradation occurs in the harsh environment of the gastrointestinal tract, and mucosal tolerance suppresses immune responses to a foreign antigen. Thus, oral vaccination may require highly sophisticated formulations involving approaches for cell-specific targeting and immunomodulation. In the mucosal tissues, epithelial cells are coated by a viscous fluid called mucus containing a layer of glycoproteins (mucins). The layer of mucus serves as a physical barrier between the epithelium and invaded pathogens while harboring competitive binding sites for entrapping microbes and S-IgA Abs for binding to and neutralizing pathogens. Structurally, the intestinal epithelium formed by a single-cell layer constitutes the largest and most important barrier to the entry of foreign substances and functions as a selective barrier that only allows for nutrients and electrolytes to be absorbed while preventing the entry of intra-luminal antigens, toxins, and microorganisms ,134. TheThere exist continued efforts in developing oral live attenuated vaccines. However, compared with live-attenuated pathogen based vaccines with limitations in safety, recombinant subunit vaccines or non-living or non-infectious vector vaccines could be more attractive, albeit more difficult to deliver ,135. HenAs a major entering portal for pathogens, the nasal route becomes a promising option for mucosal vaccination due to its unique physiological and immunological characteristics. Intranasal vaccination is capable of stimulating immune responses in the nasopharynx-associated lymphoid tissue, eliciting systemic and mucosal immunities in the gastric mucosa and the respiratory and/or genital tract . Most soVaccination via the nasal cavity is the earliest mean of mucosal delivery, and nasal immunity can effectively prevent respiratory diseases. At present, mucosal immunity has made great contributions to human medicine from theory to practice, and various influenza vaccines such as LAIVs and cold-adapted influenza attenuated vaccines have been developed ,140. TheAvian influenza is a serious respiratory disease. Although currently used inactivated vaccines are effective, circulation of antigenically different strains could reduce the efficacy of vaccines due to the fact that almost all vaccines are administered via the i.m. route. The rate of antigenic variation of AIVs is accelerating, thereby increasing the risk of human infection and harm to the economy and society. Therefore, speeding up the research on AIVs vaccines and improving vaccine safety and reliability will have huge economic and social benefits. Mucosal immunity constitutes the first line of defense against AIVs; the mucosal delivery route elicits mucosal and systemic immunities simultaneously. Compared to inactivated vaccines, mucosal vaccines stimulate both cellular and humoral immunities and can be more effective in protecting against influenza variant strains, hence producing more cross-reactive and longer-lasting comprehensive immune responses. Overall, mucosal vaccines and delivery routes should play an irreplaceable role in remarkably reducing AIVs-caused burden."} +{"text": "Examining the neural correlates underlying racial differences in cognitive functioning is necessary to help clarify mechanisms and to improve the generalizability of findings related to brain-behavior relationships. This systematic review aimed to determine whether there are racial differences in structural markers of brain aging among community-dwelling, neurologically healthy adults aged 18 and older. We identified studies from searches in Ovid Medline, Ovid PsychINFO, and Elsevier EMBASE published until February 13, 2020. We included original articles that examined structural markers of brain aging and neuropathology across individuals from more than one race or ethnicity. These measures included magnetic resonance imaging, positron emission tomography amyloid and tau, cerebrospinal fluid amyloid, tau, and neurofilament light chain and computed tomography. Two reviewers independently screened full-text articles. We will present ongoing results and discuss the current state of knowledge, quality of existing studies, and gaps in the literature and highlight potentially key next steps."} +{"text": "Stem cells have improved the treatment of several diseases. Their efficacy has been widely debated over the last few decades, but their contribution to medical research has constantly increased .Recently, a pivotal study supported by the National Institute of Dental and Craniofacial Research (NIDCR), leaded by Prof. Yang Chai, investigated stem cell-based therapies for children with craniosynostosis. Authors demonstrated that Mesenchymal Stem Cells (MSCs) combined with hydrogel were able to regenerate functional cranial sutures previously undergone craniosynostosis, restoring not only skull anatomy but also neurocognitive functions in an animal model . This stSeveral research groups have worked on the role of genetic and epigenetic factors on craniosynostosis development, confirming a pivotal role of TWIST-1 gene mutations in Saethre\u2013Chotzen syndrome (SCS). The discovery of genetic and molecular pathways has increased attention on alternative treatments to surgery: the group of Prof. Stan Gronthos demonstrated that pharmacological targeting of Kdm6a/b genes activity may regulate aberrant osteogenesis by TWIST-1 mutant cranial suture mesenchymal progenitor cells via deregulation of epigenetic modifiers, thus preventing cranial prefusion and the related functional impairment . On the The use of stem cell therapy to reactivate functional sutures is a clinical breakthrough also in the light of the high incidence of resynostosis after complex cranial vault reconstruction. Nevertheless, an early combined surgical and regenerative approach to craniosynostosis, may reduce or definitely prevent several related dental and maxillofacial implications , in addiThe crosstalk among stem cell therapy and clinical outcomes has been investigated also in studies on muscular , neural Therefore, the results reached by Prof. Yang Chai and his group are a milestone that will promote novel less-invasive, stem cell-based therapeutic approaches that will benefit patients affected by craniofacial developmental disorder involving related brain and organs alterations. Overall, stem cell research has obtained an important achievement towards its future clinical application in minimally invasive therapeutic procedures."} +{"text": "Emergency providers should recognize that pneumothorax is a rare but serious complication of shoulder arthroscopy that may require a unique approach to decompression.We present a case of a 60-year-old female who presented to the emergency department with right-sided facial swelling, voice change, and shortness of breath three hours after an elective arthroscopic right rotator-cuff repair and was noted to have a right-sided pneumothorax. We also describe a potential novel approach to chest tube decompression that maintains shoulder adduction in patients with recently repaired rotator cuffs.Although most cases of post-arthroscopy pneumothoraces are reported in patients who received regional anesthesia or have underlying lung pathology, it can occur in lower-risk patients as was demonstrated in our case. We also suggest considering an alternative anterior approach between the midclavicular and anterior axillary lines for chest decompression in select patients when a traditional approach is less ideal due to the need to maintain shoulder immobilization postoperatively. Over the past few decades shoulder arthroscopy has become an increasingly common technique to treat shoulder pathology. Proponents cite a decreased complication rate when compared to open procedures.A 60-year-old female presented to the ED with right-sided facial swelling, voice change, and shortness of breath three hours after an elective, arthroscopic, right rotator cuff repair. The outpatient surgery comprised a subacromial decompression, major glenohumeral joint debridement, and rotator cuff repair for right shoulder chronic impingement syndrome, intra-articular biceps tear, and full thickness rotator cuff tear. The surgery was performed in the lateral decubitus position under general anesthesia and without regional nerve block. The anesthesia report was reviewed and showed no major complications or episodes of hypotension or desaturation. The patient reported feeling well postoperatively; however, three hours later she developed right-sided face and neck swelling , voice cThe patient denied significant past medical history including any history of smoking or underlying lung or connective tissue disease. On arrival, her vitals were heart rate 92 beats per minute, blood pressure 135/80 millimeters mercury, respiratory rate 18 breaths per minute, and pulse oximetry was 96% on room air. Her physical exam was notable for predominately right-sided facial swelling, diminished right-sided lung sounds, and crepitus of the right neck, face, and chest. A chest radiograph showed a right-sided pneumothorax of approximately 70% with mediastinal shift and extensive subcutaneous emphysema .A pigtail catheter-type chest drain was placed in the fifth intercoastal space between the right midclavicular and anterior axillary line so as to not abduct or displace the patient\u2019s shoulder given her recent rotator cuff repair. Successful expansion of the lung was noted .On the third day of admission, the chest tube was removed and the patient was discharged home without further complications. At her two-week follow-up, her shoulder was healing well and she had no significant sequelae from her pneumothorax.Only a handful of case reports and case series describe an association between arthroscopic shoulder surgery and postoperative pneumothorax3CPC-EM CapsuleWhat do we already know about this clinical entity?Pneumothoraces have been reported as a possible complication of shoulder arthroscopy.What makes this presentation of disease reportable?We present a case of a rare complication of a common procedure and suggest a less common procedural approach to treating pneumothorax.What is the major learning point?Pneumothorax is a rare but serious complication of shoulder arthroscopy that may require a unique approach to decompression.How might this improve emergency medicine practice?This variation to traditional pneumothorax decompression technique could help avoid re-injury of the rotator-cuff repair site.Emergency providers have traditionally placed tube thoracostomy drains at the fourth or fifth intercostal space at the midaxillary or anterior axillary line11Limitations to this new approach include left-sided pneumothorax , obese patients, large area of breast tissue, or use of larger caliber chest tubes. Placing the pigtail catheter at the second intercostal space midclavicular line is a viable alternative in these casesEmergency providers should recognize pneumothorax as a rare but serious complication of shoulder arthroscopy. Although most cases reported are in patients who received regional anesthesia or have underlying lung pathology, it can occur in lower-risk patients as was demonstrated in our case. Patients may present with classical findings of pneumothorax including dyspnea, decreased breath sounds, and signs of tension including mediastinal shift. Postarthroscopy pneumothoraces nearly always present with crepitus on exam or subcutaneous air on imaging. The majority of these cases tolerate decompression without issues and patients are discharged within several days without complications. Providers may consider follow-up computed tomography imaging in patients without prior lung disease to assess for underlying lung disease or structural pathology including blebs. We also suggest considering an alternative anterior approach between the midclavicular and anterior axillary lines for chest decompression in select patients when a traditional approach is less ideal due to the need to maintain shoulder immobilization postoperatively; however, more research is needed to confirm safety and efficacy."} +{"text": "Previous research has identified cancer and cancer-treatment related effects on survivors\u2019 mental impairment including memory and concentration. However, research has not systematically examined the relative impact of cancer in the context of age and other age-related health challenges common in later life. This paper compares the effects of cancer-related factors with other health challenges faced by 471 older adult long-term survivors from an NCI-funded study of a randomly selected tumor registry sample from a major comprehensive cancer center. Having had chemotherapy is associated with several cognitive outcomes including memory and concentration. Survivors who reported more cancer-related symptoms during treatment reported a greater number of cognitive symptoms even decades after treatment. Importantly, other comorbid health problems as well as social factors were found to be important in explaining symptoms of cognitive impairment in this older adult sample. These findings suggest that health care and mental health providers consider the range of health challenges, including those related to cancer and its treatment, as they provide patient centered care."} +{"text": "This special issue includes seven articles. We have a brief review of mental health issues among Asian and Pacific Island (API) communities. Two papers examine non-biological factors that may be associated with mood disorders, using a nationally representative sample of Asian Americans (AA). These papers are particularly informative because they report disaggregated results across four AA subgroups. Another two articles examine different interventions and their efficacy to improve mood and quality of life among APIs. Finally, the case of a clinical encounter during COVID-19 was examined through the lens of Asian critical theory. Although these papers differ in their focuses and methodologies, collectively, they provide valuable information about mental health issues among the API community."} +{"text": "Influenza viruses rapidly diversify within individual human infections. Several recent studies have deep-sequenced clinical influenza infections to identify viral variation within hosts, but it remains unclear how within-host mutations fare at the between-host scale. Here, we compare the genetic variation of H3N2 influenza within and between hosts to link viral evolutionary dynamics across scales. Synonymous sites evolve at similar rates at both scales, indicating that global evolution at these putatively neutral sites results from the accumulation of within-host variation. However, nonsynonymous mutations are depleted between hosts compared to within hosts, suggesting that selection purges many of the protein-altering changes that arise within hosts. The exception is at antigenic sites, where selection detectably favors nonsynonymous mutations at the global scale, but not within hosts. These results suggest that selection against deleterious mutations and selection for antigenic change are the main forces that act on within-host variants of influenza virus as they transmit and circulate between hosts. As influenza viruses replicate within infected hosts, they quickly mutate into genetically diverse populations. A small proportion of within-host variants transmit between individuals , and somSeveral recent studies have used deep sequencing to identify within-host mutations in hundreds of clinical influenza infections . HoweverHere, we compare the genetic variation of H3N2 influenza virus within and between human hosts to infer the fates of within-host mutations in the global viral population. Individual within-host mutations are challenging to track on a global scale, but by comparing large numbers of genetic variants identified within and between hosts, we can infer the evolutionary forces that act on different classes of mutations. We analyze within-host viral variation in 308 acute influenza infections from three deep-sequencing datasets , and we Evolutionary rates provide a simple, quantitative framework for comparing viral variation across scales. Under neutral evolution, we expect within-host and global evolutionary rates to be identical, and deviations from these neutral expectations shed light on how selection acts across evolutionary scales. For instance, HIV and hepatitis C virus both evolve more rapidly within than between hosts, probably because viruses acquire adaptations to specific hosts that often revert after transmission .We sought to calculate the within-host and global evolutionary rates of influenza virus. Influenza\u2019s global evolutionary rate is easily estimated from phylogenies of patient consensus sequences, which represent transmitted strains , but evoTo overcome these challenges, we developed a method to estimate rates of within-host evolution from deep sequencing of acute viral infections. In brief, we identified within-host mutations that were present in at least 0.5 per cent of sequencing reads to estimWe tested the sensitivity of this method to common technical considerations. Estimates of evolutionary rates can be influenced by the frequency threshold used to identify within-host variation . We focuIn calculating within-host evolutionary rates, we sought to limit the influence of outlier samples with unusually high within-host variation . This hiWe calculated rates of within-host influenza evolution from deep-sequencing data in three published studies that together represented 308 acute H3N2 influenza infections Dinis e. We estiTo assess sources of variation in our estimates, we calculated evolutionary rates separately for each deep-sequencing dataset . We alsoTo compare rates of evolution in acute and chronic influenza infections, we also calculated rates of influenza evolution in four chronic H3N2 infections that lasted multiple months Supplem. We findWhat kinds of mutations reach detectable frequencies within hosts? We compared how quickly synonymous, nonsynonymous, and stop-codon (nonsense) mutations accumulate within hosts. Differences in how quickly these three classes of mutations accumulate can reveal how selection acts within hosts. Most synonymous mutations are nearly neutral; many nonsynonymous mutations are deleterious; and premature stop codons are lethal. In the absence of selection, all three types of mutations accumulate at the same rate. However, purifying selection purges deleterious mutations, and positive selection increases the frequency of any beneficial mutations.We find that deleterious mutations are purged detectably but incompletely within infected individuals. Synonymous mutations accumulate about twice as quickly as nonsynonymous mutations within hosts, with some variation across genes . Stop-coHow do mutations that arise within hosts fare as they circulate between hosts? We compared rates of evolution within hosts and globally to determine how selection acts across different scales of viral evolution. Neutral mutations should have similar rates of evolution within and between hosts. Purifying selection that acts between hosts to eliminate deleterious mutations will decrease global evolutionary rates compared to rates within hosts. Conversely, positive selection that acts on a global scale will increase rates of evolution between hosts relative to their within-host expectations for beneficial classes of mutations.To calculate the global evolutionary rates of influenza virus, we analyzed H3N2 influenza sequences in the Global Initiative on Sharing All Influenza Data (GISAID) EpiFlu database, where each sequence represents the consensus sequence of one patient infection . We usedSynonymous mutations accumulate at similar rates within hosts and globally . This coIn contrast, nonsynonymous mutations accumulate more slowly globally than within hosts in all six viral genes analyzed. In addition, while stop-codon mutations accumulate at appreciable rates within hosts, they never fix during global evolution. These discrepancies in evolutionary rates within and between hosts suggest that many nonsynonymous mutations that reach detectable frequencies within hosts are later purged by purifying selection as viruses transmit and circulate between hosts.An important exception to this trend occurs in the antigenic regions of the HA gene, which evolve more rapidly on a global scale than non-antigenic regions of HA Caton e. Within The previous section shows that nonsynonymous mutations are less common among mutations that fix globally than they are within hosts. This result suggests that purifying selection eliminates many nonsynonymous within-host variants before they fix in the global population of influenza viruses. However, it remains unclear from this analysis how quickly deleterious, nonsynonymous mutations that are generated within hosts are eliminated as viruses transmit and circulate between hosts.de novo mutations are expected to be nonsynonymous. However, purifying selection reduces the fraction of nonsynonymous mutations by removing deleterious mutations after they arise and before they fix. By examining when nonsynonymous mutations are depleted from circulating viral strains, we can identify where in the evolutionary process most purifying selection takes place . The fraction of nonsynonymous mutations is even lower among between-host mutations that reach higher frequencies, and eventually, fewer than 20 per cent of the mutations that fix in these genes are nonsynonymous. Previous work has shown that rare variants in global viral populations are dominated by transient deleterious mutations , so thisMore nonsynonymous mutations are present between hosts in the viral surface proteins HA and NA. Nonsynonymous mutations are especially enriched between hosts in antigenic sites of HA, which experience strong positive selection on the global scale Murphy,. In antiOur analyses show that transient deleterious mutations make up a large proportion of influenza\u2019s genetic variation within hosts. Deleterious variation is common at the between-host scale as well and can In this study, we quantitatively compared influenza virus\u2019s genetic diversity within and between human hosts. Our results show that although viral diversity may seem low within acute human influenza infections, it is sufficient to explain the virus\u2019s rapid global evolution. Synonymous mutations accumulate at similar rates within and between hosts, as expected for neutral genetic changes. Most nonsynonymous mutations that reach detectable frequencies within hosts are eventually purged between hosts, suggesting that within-host influenza diversity consists mostly of transient, deleterious mutations that are eliminated at transmission and global evolution. Antigenic sites of HA are the only region of the influenza genome where mutations are consistently favored between hosts beyond their frequencies within hosts.Our findings show how purifying and positive selection act on viral populations at different evolutionary scales. Influenza populations within hosts accumulate genetic variation as they expand during the first few days of an infection. However, most of this variation, which is deleterious, is purged as viruses circulate between hosts. One recent study estimates that influenza\u2019s transmission bottleneck consists of one to two viral genomes , and furin vitro mutations within hosts in each influenza gene . Random To calculate rates of viral divergence per day, we normalized per-site viral divergence by the timing of sample collection. Of the 308 H3N2 samples that we analyzed, 251 had metadata describing the number of days post-symptom-onset after which the sample was collected. For the remaining samples sequenced by For comparison, we calculated rates of evolution in acute patient infections through both the \u2018point\u2019 method described above, which averages rates of evolution calculated from each patient infection, as well as through linear regression . We perfTo calculate within-host rates of evolution in antigenic sites of HA, we used the antigenic sites defined by We downloaded all full-length H3N2 influenza coding sequences in the GISAID EpiFlu database collected from 1 January 1999 to 31 December 2017 . We randWe used a molecular-clock approach to calculate global evolutionary rates. We performed linear regression of the distances from a reference sequence by the timing of sample collection to estimate the rate of between-host evolution . MoleculWe previously deep-sequenced longitudinal samples of influenza from four chronic H3N2 influenza infections . We downTo calculate the fraction of mutations that are nonsynonymous within hosts, we tallied the total number of synonymous and nonsynonymous mutations in each frequency bin for each sample. Stop-codon mutations were counted as nonsynonymous mutations in this analysis. We then summed the variants in each frequency bin across samples. We calculated confidence intervals by performing 100 bootstrap resamplings of the viral samples and plotted the 95 per cent confidence interval from these bootstrap replicates .To calculate the fraction of mutations that are nonsynonymous between hosts, we must be able to determine when the same mutation has arisen multiple times in the global influenza population. We downloaded all full-length H3N2 influenza coding sequences in the GISAID EpiFlu database collected from 1 July 2015 to 30 June 2018, together representing the 2015\u20136, 2016\u20137, and 2017\u20138 Northern Hemisphere flu seasons . We grouhttps://github.com/ksxue/within-vs-between-hosts-influenza. Sequences downloaded from the GISAID Epiflu database are not available due to data-sharing restrictions, but acknowledgement tables for the sequences we analyzed are available at https://github.com/ksxue/within-vs-between-hosts-influenza/tree/master/data/GISAID/acknowledgements/H3N2.Raw sequencing data are publicly available from the NCBI SRA database for Bioprojects PRNJA577940 , PRJNA34Virus Evolution online.veaa010_Supplementary_DataClick here for additional data file."} +{"text": "Older age has often, but not always, been associated with greater risk aversion. Some have suggested that age differences in risk may reflect age-related declines in cognitive abilities. This study investigated the robustness of age differences in risk aversion across three different risk-taking measures, after controlling for cognitive abilities. Community-dwelling younger and older adults completed self-report and behavioral measures of risk aversion and several measures of cognitive abilities. Results showed that older adults reported significantly greater risk aversion than young adults on the behavioral measure of risk , but not on the self-report measures (Framing Task and Choice Dilemmas Questionnaire). Greater risk aversion on BART was significantly associated with lower analytic thinking, slower processing speed, and worse shifting of attention. Therefore, we tested the relation between age and risk aversion on the BART while controlling for these three cognitive abilities. Age differences in risk aversion remained significant even after accounting for cognitive abilities. Our results suggest that the lack of consistent age differences in risk aversion in the literature may at least partly be due to measurement differences, which raises concerns about the construct validity of these measures of risk aversion. Moreover, cognitive decline may not explain age differences in risk. Further research is needed to understand factors that dampen and heighten risk aversion in people of diverse ages."} +{"text": "The Latinx population is disproportionately affected by HIV-infection and older Latinx persons living with HIV (PLWH) are at greater risk for neurocognitive impairment (NCI). However, no studies have examined whether intersectionality increases NCI risk. This study investigated whether LGBT status increases NCI risk in 126 PLWH who completed a comprehensive NC battery. Domain average T-scores were based on demographically-corrected norms. Multiple regressions revealed that after accounting for covariates and other dimensions of intersectionality , LGBT status significantly contributed to NCI risk in attention/working memory and executive functioning . LGBT status, a key dimension of intersectionality, should be considered in NC assessment of PLWH. Future research is needed to identify factors that may confer increased NCI risk in this population."} +{"text": "The vagus nerve-based inflammatory reflex regulates inflammation and cytokine release. Recent successful clinical trials using implantable bioelectronic devices to modulate the inflammatory reflex in patients with rheumatoid arthritis and inflammatory bowel disease have demonstrated the efficacy of targeting neural circuits as an efficient alternative to drug treatments. However, the optimal vagus nerve stimulation parameters to achieve efficacious symptomatic relief for inflammation are still unknown. In this issue of Bioelectronic Medicine, Tsaava et al. tested whether altering these electrical stimulation parameters would change circulating cytokine levels in healthy mice. They found that specific combinations of parameters produced significant increases in serum TNF while other parameters selectively lowered serum TNF levels, as compared to sham stimulated mice. These results have considerable implications for determining the optimal stimulation parameters to better treat common conditions and diseases that involve immune regulation. Recent successful clinical trials using implantable bioelectronic devices that modulate the inflammatory reflex have reported efficacy of vagus nerve stimulation in the treatment of inflammatory diseases. However, the optimal neurostimulation parameters to achieve significant cytokine changes are still unknown.In healthy mice without inflammation, specific combinations of pulse width, pulse amplitude, and frequency produce significant increases of the pro-inflammatory cytokine TNF but other parameters selectively lower serum TNF levels. Serum levels of the anti-inflammatory cytokine IL-10 were also significantly increased by selective parameters but remained unchanged with others.These findings provide guidance for design of future studies on the neural regulation of inflammation based on the selection of optimal parameters to relieve conditions and improve organ function.Bioelectronic medicine is based on neuromodulation of the nervous system restoring organ functions and health with less adverse effects than drugs, thus minimizing adherence issues (Olofsson and Tracey i) invasive with surgical implantation of an electrode around the left VN linked to a neurostimulator positioned under the collarbone or ii) non-invasive through transcutaneous cervical (on the path of the VN) or auricular stimulation, based on the innervation of the cymba conchae by the auricular branch of the VN (Peuker and Filler VN stimulation (VNS) is approved for the treatment of drug-resistant epilepsy and well tolerated vagal A-fibers are the largest and myelinated fibers and carry afferent visceral information and motor input, ii) vagal B-fibers are small and myelinated fibers carrying parasympathetic input, and iii) vagal C-fibers are small and unmyelinated and carry afferent visceral information. Antiepileptic property of VNS was supposed to be related to vagal C-fibers, but their destruction did not alter VNS-induced seizure suppression in rats (Krahl et al. Importantly, these results argue that serum cytokines may be controlled by specific fiber sets and firing patterns. The specific VN fibers mediating the inflammatory reflex are not known. The VN contains A-, B-, and C-fibers, defined in accordance to their conduction velocity, which, in myelinated fibers, is proportional to their size (Erlanger and Gasser Patients under VNS for epilepsy may experience improved seizure reduction by increasing the frequency and/or duty cycle of stimulation while VNS for heart failure is limited by the inability to activate the nerve fibers mediating therapeutic benefit without co-activation of side effect-inducing fibers (Musselman et al. The results of Tsaava et al. indicate"} +{"text": "As the US population continues to age, it is important to gain a better understanding of factors that differ between independently living older adults and those that require assisted living. Accidental falls contribute to decreased quality of life for many older adults, and considerable research has been conducted examining measures of fall-risk and potential interventions. In this pilot study, we investigated fall-risk via assessment of spatio-temporal variables associated with gait in independent and assisted-living older adults aged 65+. Two gender-matched groups of participants were tested on seven gait variables utilizing Opto-Gait technology. Each group included sixteen participants. Independent living participants were recruited through word of mouth and flyers at local senior centers. Assisted living participants all resided in one local health care facility and were recruited via word of mouth and flyers posted in the facility. A one way ANOVA with an alpha level of .05 revealed significant differences between groups in contact time, foot flat, propulsive phase, and average speed. The independent living group performed better on each variable. These findings indicate that older adults living in assisted living facilities may be at much greater risk of accidental fall than their independent living counterparts. While this study identified several key factors related to instability among old adults, additional investigation is warranted to further examine the relationships among gait, fall-risk, and differentiators between independently living and assisted living older adults in these variables."} +{"text": "This systematic review examines current randomized clinical trials of therapeutic agents to treat coronavirus disease 2019 (COVID-19). In this systematic review, we characterize the landscape of current COVID-19 trials to better quantify these potential issues.High-quality evidence generated by appropriately powered and controlled trials is needed to advance care for patients with coronavirus disease 2019 (COVID-19) and those who are susceptible to it.PRISMA) reporting guideline.3Institutional review board approval of this study was waived because it exclusively used publicly available data without any protected health information. Screening and trial selection adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses . Data analysis was performed in June 2020.We performed a data query of the ClinicalTrials.gov registry for interventional trials in any clinical phase regarding COVID-19 on June 8, 2020. Advanced search parameters included Our search yielded 674 trials after removing suspended and halted trials . Most we4We found a high rate of trial multiplicity, particularly with chloroquines, which are being tested in 143 studies. Although these overlapping trials may afford opportunities for replication and validation, the high degree of multiplicity also enhances the likelihood of finding a positive result through chance alone, potentially resulting in widespread use of an ineffective and possibly hazardous intervention.5 Because the projected participant accrual for US-only COVID-19 treatment trials is approximately 45\u2009942 participants , it seems unlikely that this target will be achieved given the intrinsic challenges of participant accrual during an active pandemic.The fragmentation of efforts could also lead to unnecessary competition for participants, which potentially compromises trial accrual and statistical power for all trials. This worrisome scenario has already occurred in China.Notably, our study is limited through the use of a single US-based clinical trials registry, potentially representing only a fraction of the worldwide COVID-19\u2013related trials portfolio. Furthermore, the ever-changing landscape of COVID-19 clinical research amid this pandemic may complicate future interpretation of this report.6 Together, these factors endanger the capacity to rapidly produce meaningful evidence that is vital during this critical time. Avoiding these pitfalls requires coordination of efforts. This could be achieved, in part, through makeshift cooperative groups to improve participant accrual and decrease duplicative efforts. Institutional review boards and regulators (including the US Food and Drug Administration) must also work together to responsibly ease roadblocks to coordinate pooled analyses across trials. These efforts should include synchronization and standardization of end points, focusing on the most meaningful and objective outcomes . It is hoped that these measures will expedite generation of high-quality prospective data to guide effective treatments while maximizing resource allocation.Although current trials have been initiated with the best intentions, the medical community must be mindful of the potential issues of incomplete participant accrual and publication bias that are introduced by enabling dozens of similar trials simultaneously."} +{"text": "This is commonly accomplished by the timed addition of soluble signaling factors, in conjunction with cell-handling steps such as the formation of 3D cell aggregates. Interestingly, when stem cells at the pancreatic progenitor stage are transplanted, they form functional insulin-producing cells, suggesting that in vivo microenvironmental cues promote beta cell specification. Among these cues, biophysical stimuli have only recently emerged in the context of optimizing pancreatic differentiation protocols. This review focuses on studies of cell\u2013microenvironment interactions and their impact on differentiating pancreatic cells when considering cell signaling, cell\u2013cell and cell\u2013ECM interactions. We highlight the development of in vitro cell culture models that allow systematic studies of pancreatic cell mechanobiology in response to extracellular matrix proteins, biomechanical effects, soluble factor modulation of biomechanics, substrate stiffness, fluid flow and topography. Finally, we explore how these new mechanical insights could lead to novel pancreatic differentiation protocols that improve efficiency, maturity, and throughput.Insulin-producing beta cells sourced from pluripotent stem cells hold great potential as a virtually unlimited cell source to treat diabetes. Directed pancreatic differentiation protocols aim to mimic various stimuli present during embryonic development through sequential changes of Cell therapies involve the transplantation of human tissues or cells to treat illnesses that progressively damage or degrade functional tissues. These treatments are typically limited by access to a reliable and cost-effective cell source. For a successful transplant, allogeneic matching requires identification, procurement and transport of donor material; and variations in quality of the donated tissue may affect therapeutic potential. Therefore, the large-scale production of biological material for cell therapies is a rapidly growing area of interest. The primary goal of such research is to produce adequate quantities of functional therapeutic cells in a cost-effective manner.Treatment of type 1 diabetes by islet transplantation is one example of a currently approved cell therapy. Here, donor islets are used to replace the insulin-secreting functionality lost from the autoimmune destruction of pancreatic beta cells. The Clinical Islet Transplantation Consortium trial (CIT-07) reported that 87.5% of patients were free from severe hypoglycemic events and achieved normal or near normal glycemic control at the 1 year end point . As with+ cells (in vivo (in vitro (The production of insulin-secreting beta-like cells from pluripotent stem cells (PSCs) is a potential solution to the donor supply issues of islet transplantation. The first report of stem-cell derived insulin-producing cells via spontaneous differentiation was almost two decades ago and reported only 1\u20132% insulin+ cells . However+ cells . Therefo+ cells . More re 20 days . One of 20 days and subs 20 days . Since teptide+) . Howevereptide+) . Maturat interactions , which cin vivo. Studies of developmental mechanobiology are challenging, and these parameters are often not considered as it is unclear what mechanics are present during human embryogenesis. Furthermore, the complexity of the in vivo microenvironment makes it difficult to control these biomechanical signals and to delineate their effects on differentiation from other correlated stimuli. Therefore, the field relies mainly on studies of biochemical pathways with in vivo mouse models or in vitro human models for information.Embryonic development is guided via highly dynamic signals from the surrounding cell microenvironment with remarkable precision and robustness. As cells differentiate, they relay different signals to neighboring cells by secreting soluble factors and matrix proteins. The soluble signaling cues associated with pancreatic differentiation have been well-studied using animal models and include the Wnt, Activin/Nodal, fibroblast growth factor (FGF), bone morphogenetic protein (BMP), retinoic acid, and sonic hedgehog (Shh), and Notch signaling pathways . HoweverCells respond to mechanical stimuli through mechanotransduction mechanisms, in which biomechanical stimuli are converted into biochemical signals . ReciproResident cells communicate with their neighbors during development by secreting soluble signaling molecules which can bias differentiation . The devin vivo cellular microenvironment is much more intricate than can be modeled by current in vitro systems. Although directed differentiation protocols that focus solely on the timed addition of soluble signaling factors can generate insulin-producing cells perhaps due to improved paracrine signaling and cell\u2013cell contacts . Paracricultures . In theiskeleton .In vitro, larger non-vascularized islets may develop central necrosis due to high metabolic demand and low oxygenation , thus retaining ECM proteins composition. Utilizing decellularized pancreas matrix scaffolds in bioartificial pancreas designs could also be a fruitful strategy to improve islet functionality by retaining pancreas stiffness and matrix architecture . HydrogeIn addition to the combinatorial effects of individual ECM components, the composition of the ECM is dynamically changing during development. While one composition may promote early pancreatic differentiation, the same composition may hinder downstream differentiation stages. During hESC differentiation, ECM and MMPs are secreted which remodels the exogenous ECM on the culture substrate . PSCs cuin vivo, a recent successful strategy has been to target specific mechanotransduction-associated pathways during directed differentiation to promote pancreatic differentiation and thus improve the capacity to produce insulin-secreting cells. Such factors include H1152 (a ROCK II inhibitor) , vertepohibitor) , and lathibitor) . Nuclearhibitor) . Timed ihibitor) . Depolymhibitor) . AltogetCells interact with ECM proteins by binding with integrin receptors spanning across the cell membrane. These receptors can then activate downstream integrin-related signaling pathways that alter cell function and bias cell specification. In pancreas development, integrin-ECM signaling regulates collective cell migration and function . When plThe surrounding ECM matrix also propagates stress which al+ endocrine progenitors, fibronectin promotes high cell spread area while laminin-coated surfaces were associated with lower spreading or stiffness (MMP-mediated degradation or UV-based) could better accommodate the constantly changing requirements for beta cell differentiation. Finally, as our knowledge progresses, increasingly complex co-culture systems involving defined compositions of PSC-derived endothelial, islet endocrine cells, and other cells present during development, may be the route to a functional cell source for islet transplantation.To address these questions, some technologies that could be used to specifically identify the effect of these factors are highlighted in Overall, better understanding the mechanobiology of pancreas development could lead to new strategies to more efficiently produce functional glucose-responsive, insulin-secreting cells for cell therapies. Interdisciplinary approaches combining advances in materials science and developmental biology could accelerate the development and scale up of culture systems tailored for diabetes cell therapy.RT conducted the literature search and drafted the manuscript in consultation with CM and CH. All authors contributed to writing the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Most studies of middle-aged adults find blacks have higher levels of psychological distress compared to whites but have lower risk of common psychiatric disorders. For instance, there is evidence of lower rates of depressive and anxiety disorders among blacks relative to whites despite large disparities in stress, discrimination and physical health in midlife\u2014commonly referred to as the black-white mental health paradox. We examine evidence of the black-white paradox in anxiety and depressive symptoms among older adults. Data come from 6,019 adults ages 52+ from the 2006 Health and Retirement Study. Unadjusted models show older blacks report more anxiety and depressive symptoms than whites. After adjusting for socioeconomic factors, everyday discrimination, chronic conditions, and chronic stress, there are no black-white differences in anxiety and depressive symptoms. Findings suggest the black-white mental health paradox only extends into older adulthood for blacks living under similar stress and health landscapes as whites."} +{"text": "Initially described as pneumonia of unknown aetiology in December 2019 in populations of Wuhan (China), the coronavirus disease (Covid-19) rapidly disseminated around the world . They alActually, nearly three billions people are confined at homes or in quarantine around the world. Brooks et al. in a recently published review including studies comparing psychological outcomes between people quarantined and not quarantined, found that quarantine had negative psychological effects such as post-traumatic stress symptoms, confusion and anger . All theShanghai government organized psychological care in four levels. At the first level, an onsite psychological support is provide to patients with severe symptoms of novel coronavirus pneumonia (NCP) by front-line medical staff, Centre for Disease Control researchers or administrative staff . The secThe current Covid-19 pandemic has tremendous consequences on population health around the world, with various degrees of mental health repercussions. Actual strategies are mainly targeting Covid-19 patients and healthy general populations, and are chiefly based on clear and secured communication as well as continuous onsite and online psychological support by appropriates professionals. However, these strategies should be disseminated to all countries, especially sub-Saharan African ones, and approved by concerned governments. Also, adequate psychological care policies have to be developed for health care workers fighting against this pandemic. All these measures would help to maintain optimal care of Covid-19 patients and prevent deleterious mental health outcomes including suicides.All authors declare no competing interests."} +{"text": "Dear Editor, Recently, Wu and colleagues published a study about hepatobiliary organoids generated from human induced pluripotent stem cells . For thSeveral studies have used human stem cells including hiPSC and reported that differentiation via definitive endoderm resulted in hepatocyte-like features associated genes, potentially limiting hepatocyte maturation, which could be investigated by monitoring TWIST and SNAIL transcription factor activity. It should be considered that hepatocytes in vivo are arranged in sheets along sinusoids is that19 is thaal., 2019). The usal., 2014; Hoehme al., 2014; Reif etin vitro systems for toxicity tests . Also, al., 2018), althouThe author declares no conflict of interest."} +{"text": "Creutzfeldt-Jakob disease (CJD) is a rare prion disease characterized by rapidly progressive dementia.A 76-year-old woman exhibited pronounced signs and symptoms of dressing apraxia for about seven weeks before the disease progressed and probable CJD was diagnosed supported by imaging and CSF findings.Dressing apraxia as the initial manifestation of CJD has been sparsely reported. This remarkably focal syndrome should be considered with view on movement and neuropsychological disorders in early CJD. Creutzfeldt-Jakob disease (CJD) is a rare prion disease mainly characterized by rapidly progressive dementia. Neuropsychological disorders however frequently occur in the initial phase of the disease with amnesia, impaired attention and frontal lobe syndrome as the most frequent . RecentlA 76-year-old woman developed difficulties in dressing. She had progressive problems dressing herself. In particular, she had difficulty handling buttons and arranging her clothing articles on her body. Dressing became more and more prolonged, and she began to manipulate her clothes incoherently until finally needing support from her husband. Her medical history included stable plasmocytoma, atrial fibrillation and residual effects from a minor stroke, and she was orally anticoagulated with phenprocoumon. Her neurological examination on admission revealed a slight right-sided motor impairment with finger tapping and slight dysarthria, which resulted from the previous minor stroke. Neuropsychologically pronounced signs and symptoms of dressing apraxia were found whereby performing simple gestures and pantomiming object use were preserved. Otherwise, there were no signs of constructional and limb ataxia, optic ataxia and visual disturbances. The MoCA test showed 28 of 30 points with slight impairment in the visuospatial items. Her family history was unremarkable. She had not had any previous neurosurgical procedures or corneal transplants [Her first cranial magnetic resonance images (MRI) showed marked cortical restriction of diffusion bilaterally (positive \u201cribbon sign\u201d), most prominent in the parietal regions Figure . A cerebWith this case report, we wish to complement the observations on neuropsychological disorders in CJD for three reasons. First, dressing apraxia as an initial and for a certain time exclusive symptom of CJD has sparsely been reported . Most re465810"} +{"text": "This study enhances the existing literature on the role of trust and online perceived risk in shaping consumer purchase decision-making in social commerce. The aim of this article is to investigate consumers\u2019 purchase decision-making process, the determinant components of social commerce purchase intentions and attitudes, the effect of perceived risk on intention to go shopping in online settings, and consumer trust and buying behavior on online retailing platforms. The insights obtained from our research extend current knowledge as regards determinants of consumer attitudes and intentions toward online purchases, consumers\u2019 perceived shopping risk and repurchase behavior when buying products online, and perceived consumer online trust and purchase decisions. Limited research has considered consumers\u2019 decision-making processes on social commerce platforms by investigating how their perceptual attitudes, behavioral intentions, and immediate gratifications affect the purchase of products and services online. Our study addresses this gap and extends prior research by focusing on the relationship between online consumer purchase intention, social commerce adoption behavior, and consumers\u2019 trust together with risk factors affecting online buying decisions, in light of the characteristics of source credibility. Our findings point toward important avenues of research on psychological determinants of consumer engagement in social media, decision mechanisms lying behind evaluation of prices, the types of perceived risk incurred, and online repurchasing behavior and intention on social commerce platforms. Subsequent directions should clarify whether adoption of mobile payment services may shape online consumers\u2019 impulsive buying behavior and decision-making, especially under the influence of online product reviews. Our study cumulates evidence that consumers\u2019 decision-making process is a dynamic performance , but thaUsing exclusively empirical sources published recently (2017\u20132019) in Web of Science- and Scopus-indexed journals, our paper fills the gap in the literature by elucidating consumers\u2019 evaluation, commitment, and choice throughout online decision-making, insisting on their cognitive processing behaviors and on how expectations shape their pre-purchase and post-purchase satisfaction.On Wu J. et al. (2017)\u2019s reading, trust is the essential component of consumer purchase intention when buying things on peer-to-peer temporary rental platforms where both hosts and renters do not know each other. The empirical evidence we reviewed supports the belief that social platform users\u2019 purchase intentions can be constituted taking into account the relationship between online trust and perceived risk. Limited research has considered consumers\u2019 decision-making processes on social commerce platforms by investigating how their perceptual attitudes, behavioral intentions, and immediate gratifications affect the purchase of products and services online.Our study addresses this gap and extends prior research by focusing on the relationship between online consumer purchase intention, social commerce adoption behavior, and consumers\u2019 trust together with risk factors affecting online buying decisions, in light of the characteristics of source credibility. As limitations in the present article, our findings point toward important avenues of research on psychological determinants of consumer engagement in social media, decision mechanisms lying behind evaluation of prices, the types of perceived risk incurred, and online repurchasing behavior and intention on social commerce platforms. Subsequent directions should clarify whether adoption of mobile payment services may shape online consumers\u2019 impulsive buying behavior and decision-making, especially under the influence of online product reviews.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Medicare is the primary insurance provider for approximately 51 million older adults, including those who seek mental health care. Medicare provider eligibility was last updated in 1989, and approximately one-third of the graduate-level mental health workforce is excluded from Medicare, despite these professionals participating in Medicaid, TRICARE, the Veterans Administration, and private insurance plans. This Medicare mental health coverage gap (MMHCG) raises concerns about older adults\u2019 access to mental health care, resulting in a policy misalignment between Medicare\u2019s provider regulations and a growing number of older adults seeking mental health care. However, little is known about the precise impact of the MMHCG. To better understand how the MMHCG impacts older adults, we interviewed 17 Medicare-insured individuals about their experiences accessing mental health services. Using a phenomenological framework to analyze our data, we found that Medicare recipients described several consequences, such as: 1) a detrimental impact on their mental health and well-being; 2) concerns about having to start over with new providers due to commencing mental health treatment only to have services interrupted once the provider is no longer Medicare-reimbursable; and 3) relying on pro bono services from Medicare-excluded providers with uncertainty about the long-term sustainability of these arrangements. The presenters will describe how these findings fit within the current Medicare mental health service context, including the direct impact on older adults\u2019 mental health. Discussion will also focus on policy implications of the findings and possible solutions for addressing the MMHCG."} +{"text": "Pathogens and pests are one of the major threats to agricultural productivity worldwide. For decades, targeted resistance breeding was used to create crop cultivars that resist pathogens and environmental stress while retaining yields. The often decade-long process of crossing, selection, and field trials to create a new cultivar is challenged by the rapid rise of pathogens overcoming resistance. Similarly, antimicrobial compounds can rapidly lose efficacy due to resistance evolution. Here, we review three major areas where computational, imaging and experimental approaches are revolutionizing the management of pathogen damage on crops. Recognizing and scoring plant diseases have dramatically improved through high-throughput imaging techniques applicable both under well-controlled greenhouse conditions and directly in the field. However, computer vision of complex disease phenotypes will require significant improvements. In parallel, experimental setups similar to high-throughput drug discovery screens make it possible to screen thousands of pathogen strains for variation in resistance and other relevant phenotypic traits. Confocal microscopy and fluorescence can capture rich phenotypic information across pathogen genotypes. Through genome-wide association mapping approaches, phenotypic data helps to unravel the genetic architecture of stress- and virulence-related traits accelerating resistance breeding. Finally, joint, large-scale screenings of trait variation in crops and pathogens can yield fundamental insights into how pathogens face trade-offs in the adaptation to resistant crop varieties. We discuss how future implementations of such innovative approaches in breeding and pathogen screening can lead to more durable disease control. R genes) e.g. fungicides, insecticides) Feeding the world population requires a stable production of safe food, which is threatened by factors such as climate change, land degradation and diseases. Pathogens and pests cause significant reductions in agricultural productivity worldwide, and control strategies remain ineffective for many pathogens Sustainable agricultural management practices critically rely on an understanding of the biology and evolutionary potential of the major crop pathogens. Emerging or re-emerging pathogens can only be contained by investigating their origins and migration routes, as well as their potential to counter-adapt to deployed control measures. Advancements in genomics, transcriptomics and proteomics have been instrumental to elucidate these questions and unravelled a broad range of molecular mechanisms governing host-pathogen interactions leading to more effective control strategies 1.1e.g. appressoria) i.e. temperature, pH, humidity) to thrive, changes in the environment can alter the pathogen's ability to cause damage 2 and ozone can affect plant disease severity e.g. wash-off of fungicides following strong rainfall). Hence, the challenge to contain pathogen damage in agriculture is to predict the emergence of virulent strains and the rise of fungicide resistance.Major crop diseases are caused by pathogens including fungi, bacteria and viruses . In addii.e. biotrophs) can feed on plant nutrients for a long period without causing apparent infection symptoms Given the possibly severe consequences, the early detection of resistance breakdowns in crops or loss of sensitivity to pesticides is critical. Detection early in the growing season and identifying previously uncharacterized pathogens remain major challenges. Classic plant disease diagnostics usually relies on visual symptom scoring by trained individuals categorizing disease severity on linear scales e.g. leaves, Disease symptoms may include any range of changes in the color, shape or functioning of the plant as it responds to a pathogen and can be visualized at specific wavelengths A. Depend1.2e.g. GF-1 from China or SPOT from Europe, can provide time-resolved phenotyping of individual fields at the meter scale Technologies suitable for screening plant diseases even in early infection stages have become widely deployed 1.3Proximal phenotyping is mostly deployed in greenhouse experiments or in well-controlled field experiments. Sensors covering a broad range of spectra can be mounted on stationary platforms or, for outdoor use, on suspension cables, robots and tractors i.e. qPCR) are often required to clearly establish what is likely to cause a disease. Interesting developments to overcome these limitations are e.g. the differential reflectance spectra (400\u20131050\u00a0nm) of sugar beet leaves, which helps distinguish three different fungal pathogens including Cercospora beticola, Erysiphe betae, and Uromyces betaeOidium neolycopersiciCorynespora cassicola and bacterial spot caused by Xanthomonas perforans on tomato in the asymptomatic phase. The multi-spectral imaging approach was successful both under laboratory and field conditions. Such robust phenotyping methods could make it possible to detect infection foci in the field. Emerging infections could then be isolated and treated individually by the deployment of specific fungicides.Current plant phenotyping technologies and image processing algorithms struggle to reliably differentiate disease symptoms originating from multiple or unknown pathogens Plant phenotyping technologies have generated data to populate public image databases with a fluorescent readout sensitive to changes in gene expression or subcellular localization. The main goal of the technology is to accelerate drug discovery by screening large antimicrobial compound libraries at a rate of thousands of compounds per week. Efforts are as well made in the development of high-throughput approaches to generate mutated versions of drug targets in vitro screening of diverse pathogen population scans is very informative about possible standing resistance, which can prevent rapid efficacy failures under field conditions High-throughput phenotyping platforms for microbial organisms have dramatically advanced in automating cell culturing, liquid handling, spotting on culture medium as dense arrays and integration of fluorescence measurements and microscopy The wealth of information on phenotypic trait variation in pathogen species combined with low-cost sequencing can be exploited for GWAS 1.5etc.) influence the outcome of infections. The complexity arises in part from complex pathogen infection cycles starting from initial host contact to transmission to new hosts The application of imaging combined with computational techniques enabled enormous progress in breeding resistant crops and detecting the emergence of new pathogen threats. To reduce complexity, most studies until now focused either on variation on the plant or the pathogen side. However, the nature of host-pathogen interactions can vary across space and time omics datasets to build biological networks (e.g. gene co-expression or protein\u2013protein interaction networks) has become a powerful approach to unravel genetic factors controlling biological interactions Arabidopsis thaliana - Xanthomonas arboricola interaction, Wang et al. Z. tritici, a large set of loci associated with pathogen virulence and reproduction on different hosts were identified Botrytis cinerea and 90 plant genotypes of eight species revealed a highly polygenic architecture of pathogen virulence and host specialization e.g. blackleg in canola) or at different growth stages. Bigger sample sizes in both host and pathogen will also improve heritability estimates (e.g. as shown in human studies Integration of different 1.6Plantago lanceolata-Podosphaera plantaginis interactions C. beticola have shown that resistant isolates have significantly lower virulence and spore production than sensitive isolates Ralstonia solanacearum mutants lacking the gene for synthesizing an exopolysaccharide virulence factor show increased growth rates compared to the wild-type strain Z. tritici. Performance of a global strain collection on twelve wheat varieties and in various abiotic conditions revealed a broad pleiotropic control of pathogen performance on and off the host How successful pathogens cope in diverse environments depends on life-history trade-offs, which arise from resource allocation dilemmas and antagonistic gene actions. A trade-off indicates that an increase in one trait is associated with a decrease in another trait. Such trade-offs are typically dependent on the host genetic background and abiotic conditions. Some pathogen strains have evolved specialization on certain hosts or climatic conditions to maximize their performance. Classic examples include the wild pathosystem of 2Technological progress in assessing susceptibility of large collections of crop plants to pathogen damage is crucial for modern resistance breeding efforts. A variety of image capture techniques allow to monitor plant damage at the cellular, leaf, whole plant or field level. Most applications focus on the visible spectrum but hyperspectral imaging platforms have recently gained the ability to detect pathogen infestation even before the appearance of symptoms. A major area of going research is to improve image analyses algorithms to detect and classify pathogen damage. Variation within individual pathogen species can be highly informative about the rise of new virulence or pesticide resistance. Robotics applied to automate the culturing of thousands of pathogen strains enables screening for metabolic variation, drug susceptibility and production of secondary metabolites improving our understanding how pathogens cope with the agricultural environment. Both high-throughput plant and pathogen phenotyping efforts can be combined with genome sequencing and GWAS applications. Unraveling the genetic basis of host resistance helps to speed up breeding efforts through marker-assisted selection. Analysis of pathogen populations can be informative about possible trade-offs in the emergence of virulence or pesticide resistance.Future directions of research should focus on a set of complementary research areas.- Create efficient pipelines merging imaging and molecular assays for pathogen detection. Such integrated systems could help farmers deploy appropriate counter-measures in the field prior to widespread damage and reduce overall pesticide application.- The susceptibility of crop cultivars to major pathogens should be re-assessed continuously to detect changes in the virulence profile of the prevalent pathogens. Rapid evolution in pathogens can lead to catastrophic resistance breakdowns and must be detected early enough. High-throughput imaging systems capturing disease symptoms should be combined with machine learning to effectively recognize changes in virulence profiles. The lack of curated and open access disease image databases is currently slowing progress.- Regional monitoring efforts of resistance breakdowns or the loss of pesticide efficacy can be achieved by high-throughput genomic screening of infected leaf material. Efficient genotyping assays focusing on major genes are likely to scale well to broad applications. Bioinformatic procedures for such genomic data analyses are largely in place. A successful implementation of such genomic monitoring will also help to detect the arrival of new pathogens early enough to deploy resistant cultivars or implement changes in pesticide application regimes.- The systematic identification of trade-offs faced by pathogens adapting to pesticides and resistant crop cultivars could lead to more durable control measures.Nikhil Kumar Singh: Conceptualization, Writing - original draft, Visualization. Anik Dutta: Writing - original draft, Visualization. Guido Puccetti: Writing - original draft, Visualization. Daniel Croll: Conceptualization, Writing - original draft, Supervision, Funding acquisition.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} +{"text": "Intracortical bone pins are introduced as gold standard for analysing skeletal motion because of eliminating soft tissue artefact. However, excluding this methodological error might be in cost of intervening movement pattern by local anaesthesia and pain of external tool within body. The purpose of this study was to examine whether intracortical bone pins alter shoulder joint kinematics or coordination. Three subjects were analysed during arm elevation/depression in frontal and sagittal planes. Retroreflective skin markers captured the motion in two sessions, before and after inserting bone pins (SKIN and PIN sessions), respectively. Thoracohumeral and scapulothoracic kinematics and scapulohumeral rhythm (SHR) were compared between two sessions. Thoracohumeral exhibited lower elevation and internal rotation in PIN session especially close to maximum arm elevation. The highest differences were observed for scapulothoracic kinematics, with higher retraction during abduction as well as higher posterior tilt, lateral rotation and retraction during flexion in PIN session. In addition, no systematic changes in SHR between subjects was found. Statistically significant lower SHR in PIN session was observed over 87-100% of thoracohumeral elevation/depression cycle in frontal plane and over 25-61% in sagittal plane. Further studies should treat carefully toward the clinical validity of shoulder joint kinematics after inserting bone pins. Retroreflective markers mounted on either skin or intracortical bone pins are used to highly accurately capture shoulder motion and evaluate the shoulder dynamics represents any changes in scapulothoracic/scapulohumeral movement and their coordination at 300 Hz.Data collection was performed in two sessions in a single day, for each participant. For session 1 (SKIN), 22 skin markers were attached to the left clavicle (5), scapula (4), humerus (7) and thorax (6) based on the model introduced by Jackson et al. . Their lAnatomical and relaxed static positions were primarily recorded for each person per session. Thereafter, each participant was asked to perform movements in SKIN session and repeat these movements in PIN session. The movements included functional motion tasks and main tasks. Functional motion tasks were arm flexion, rotation, and circumduction performed in each session to find functional joint centres and axes. Main tasks involved 10 trials of arm elevation/depression in frontal plane (abduction/adduction) and sagittal plane (flexion/extension). In S4, the location of the scapula\u2019s pin interfered with the skin markers which had to be repositioned more laterally. The post-surgery skin markers on the scapula were quasi-collinear. This resulted in the impossibility of accurate kinematics calculations. S4 data were removed.t-tests using statistical parametric mapping (SPM) were implemented, during elevation and depression separately, to determine whether any significant differences exist between SKIN and PIN sessions. The open-source SPM1d toolbox (http://www.spm1d.org) in MATLAB was used for our SPM analysis.The systems of coordinates and sequences were defined based on International Society of Biomechanics (ISB) recommendations , while thoracohumeral kinematics just altered slightly. In fact, the subjects reduced their axial rotation and the plane of elevation after inserting pins. These alterations are consistent with findings of previous studies about shoulder abnormalities. Mell et al. showed aThe changes in joint kinematics before and after pin insertion , Table 1n = 3) in our cross-comparison study, we compared the kinematics of each subject separately between SKIN and PIN sessions. In addition, the obvious differences in SHR between subjects might be due to individual movement strategies rather than different compensatory mechanisms. It is recommended that validation studies which mount both skin markers and bone-pin markers on the body estimate how they will interact with each other before data collection. Otherwise, repositioning skin markers because of interference with bone pins would deteriorate the kinematic results. In our study, one of our four available subjects was excluded due to this issue. A well-organized protocol especially for such invasive studies with small sample sizes will help in minimizing the between-subject differences derived from methodological errors. While only kinematics were assessed in the present study, electromyography and/or muscle force estimation may provide additional information about the effect of pin insertion on the upper-limb biomechanics. However, the estimation of muscle forces at the shoulder remains challenging due to co-contraction and the complex trajectories of (multi-articular) muscles (Behm et al. In addition to joint rotations, SHR was selected to look at the effect of inserting bone pins, since it can represent the movement quality index for shoulder complex for several reasons. The most important reason is that kinematic redundancy enables the central nervous system to generate a specific shoulder motion with different contribution of bony structures (Yang et al. Our results showed that inserting shoulder bone pins dominantly deteriorates the pattern and RoM of scapulothoracic joint rather than thoracohumeral joint. It was also observed that SHRmight be partially reproduced after pin insertion. Eliminating methodological errors from soft tissue artefacts using intracortical pins would not necessarily add more clinical value to the kinematic results, while the approach remains relevant to model/algorithm validation."} +{"text": "Public mental health response to coronavirus disease is essential. After reviewing systemic and local efforts in China, we found efficient coordination and human resources. We recommend better symptom assessment, monitoring of organizations, and basic needs protection. This recommendation can inform how other countries can overcome mental health challenges during this pandemic. The coronavirus disease (COVID-19) outbreak and quarantines have caused major distress in China and psycCoordination and resource allocation were compiled from local efforts at the Wuhan epicenter . On JanuThe MoE and CPS recruited professionals and volunteers across China, which suggests adequate resource allocation (The Inter-Agency Standing Committee calls for assessment of mental well-being and program evaluation of psychsocial support effectiveness (CPS published a list of approved hotline organizations based on survey evaluation of organizations (Although COVID-19 does not cause intentional harm, there are human rights issues on access to basic needs (Our review suggests that China has overcome resource shortages with coordination and resource allocation in its mental health response. The government, universities, and academic societies provide coordination, and independent organizations provide local support. We recommend integration of assessment in direct support, monitoring of organizations, and advocating for affected persons. These recommendations can inform how other countries can overcome shortage of mental health resources when facing this pandemic.Additional information on review of mental health response to COVID-19, China."} +{"text": "Zostera marina). Sampling seawater along transects extending alongshore outward from eelgrass beds, we demonstrate that eDNA provides meter-scale resolution of communities in the field. We evaluate eDNA abundance indices for 13 major phylogenetic groups of marine and estuarine taxa along these transects, finding highly local changes linked with proximity to Z. marina for a diverse group of dinoflagellates, and for no other group of taxa. Eelgrass habitat is consistently associated with dramatic reductions in dinoflagellate abundance both within the contiguous beds and for at least 15 m outside, relative to nearby sites without eelgrass. These results are consistent with the hypothesis that eelgrass-associated communities have allelopathic effects on dinoflagellates, and that these effects can extend in a halo beyond the bounds of the contiguous beds. Because many dinoflagellates are capable of forming harmful algal blooms (HABs) toxic to humans and other animal species, the apparent salutary effect of eelgrass habitat on neighboring waters has important implications for public health as well as shellfish aquaculture and harvesting.Seagrass beds provide a variety of ecosystem services, both within and outside the bounds of the habitat itself. Here we use environmental DNA (eDNA) amplicons to analyze a broad cross-section of taxa from ecological communities in and immediately surrounding eelgrass ( Seagrass species are ecosystem engineers throughout the world\u2019s coastal zones , generatIn addition to these broad ecological and chemical functions, such habitats demonstrate important antimicrobial properties. Seagrass meadows have been shown to reduce exposure to bacterial pathogens affecting humans and marine life, relative to areas lacking such meadows . AdditioZostera marina) is the dominant seagrass along temperate coasts of the Northern Hemisphere or ostrich (genus Struthio) tissue. We selected these organisms because they are absent from the sampling sites and common molecular biology reagents, but amplify well with the universal primer set used in this study. Additionally, they can be used to identify possible cross-contamination: reads from other taxa that appear in these positive control samples allow us to estimate and account for the proportion of sequences that are present in the incorrect PCR reaction (see \u201cBioinformatics\u201d below). We also amplified negative controls (molecular grade water) in triplicate alongside environmental samples and positive controls, and verified by gel electrophoresis that these PCR reactions contained no appreciable amount of DNA.Finally, we generated amplicons with the same replication scheme for positive controls, comprised of extractions from either kangaroo . We then performed sequencing on an Illumina MiSeq platform in four different sets of samples: two MiSeq V.2 runs and two MiSeq V.3 runs. We processed each batch separately through the initial bioinformatics analysis (see below). We employed hierarchical clustering on transects containing six PCR replicates sequenced across two different runs and found that these samples were each other\u2019s nearest neighbors ; thus seWe followed updated versions of previously published procedures for bioinformatics, quality control, and decontamination . This pr11), false-positive rate (P10) and commonness (psi) in a Bayesian binomial model. We then used these parameters to estimate the overall likelihood of occupancy (true presence) for each ASV; those with low likelihoods (<20%) were deemed unlikely to be truly present in the dataset, and therefore culled. 25 million reads from 3143 ASVs survived this step.To address possible cross-sample contamination , we subtLastly, we removed samples whose PCR replicates were highly dissimilar: we calculated the Bray\u2013Curtis dissimilarity amongst PCR replicates from the same bottle of water and discarded those with distance to the sample centroid outside a 95% confidence interval. Of 84 bottles of water collected, 3 technical replicates survived QC in 72 cases (86%), two replicates in 9 cases (11%), one replicate in 2 cases (2%), and zero replicates in a single case (1%) . The finPRJNA606519).All bioinformatic and analytical code is included in GitHub repositories , and proe-values of 10\u221230 (culling limit = 5), and reconciling conflicts among matches using the last common ancestor approach implemented in MEGAN 6.4 .Our analysis revealed strong habitat associations for dinoflagellates and not for other taxa (see \u201cResults\u201d). To examine patterns specifically within the phylum Dinoflagellata, we further refined our annotations for these ASVs. Specifically, we considered the geographic range of taxa involved (restricting possible annotations to those taxa known from the North Pacific) and assigned taxonomy conservatively to the level of family only in cases of >95% sequence identity between the subject and query sequence; ASVs we could not confidently assign to the level of family we excluded from further analyses. Multiple dinoflagellate sequences with identical amino-acid translations occurred within To confirm the spatial resolution of our eDNA communities, we used non-metric multidimensional scaling (nMDS) ordination of eDNA indices for all ASVs within each technical replicate . To deriTo examine the relative abundance of phyla in eelgrass habitat relative to bare substrate, we determined eDNA indices for the sum of sequences within each phylum at the two transect extremes (within-eelgrass versus bare), calculating a relative eDNA abundance measure by subtracting the mean eDNA abundance index over bare substrate for each site-month combination from the corresponding mean eDNA abundance index in the eelgrass habitat. Positive values of this measure thus denote higher abundance in eelgrass, while negative values of this index indicate higher abundance over bare substrate. To assess the statistical significance of these phylum-level differences between habitat types, we compared the distributions of mean eDNA abundance indices for individual phyla in samples taken from eelgrass relative to their counterparts taken over bare substrate, using a paired Wilcoxon signed-rank test with Bonferroni correction for multiple comparisons.k-means function of the R stats package . Next, to determine whether dinoflagellate abundance measures at intermediate alongshore transect samples were more closely associated with eelgrass habitat or bare substrate, we additionally performed Gaussian mixture modeling with two groups . We thenWe assigned over 3,000 unique ASVs to 13 eukaryotic phyla comprising a diverse set of single- and multicellular taxa including Arthropoda (arthropods), Annelida (annelid worms), Bacillariophyta (diatoms), Chlorophyta , Chordata (chordates), Cnidaria (cnidarians), Dinoflagellata (dinoflagellates), Echinodermata (echinoderms), Heterokonta (stramenopiles), Mollusca (molluscs), Nemertea (ribbon worms), Ocrophyta and Rhodophyta . This represents a broad\u2014although by no means comprehensive\u2014survey of eukaryotic communities in and around our sampled eelgrass beds.Ordination via nMDS revealed consistent differentiation between eDNA communities across transects within a sampling site and date; technical replicates consistently clustered together. An example plot of samples gathered along the transect from eelgrass to bare substrate at Willapa Bay in July shows thR2 = 0.186, p = 0.001), month , and transect distance each explain a significant portion of the variance in the dataset. Thus, despite strong effects of location and time, these results confirm that we can consistently distinguish nearshore eDNA communities (as sampled by our primers) at spatial scales of meters for each site and month of sampling. Moreover, we see a highly significant effect of proximity to eelgrass on the complement of organisms present.PERMANOVA apportioned the variance in Bray\u2013Curtis distance among samples as follows: site . Other single-celled microalgae such as diatoms (Bacillariophyta) and green algae (Chlorophyta) have no significant relationship with eelgrass.To determine the habitat preference of major taxa in our dataset at a coarse spatial scale, we classified ASVs to the level of phylum and plotted an index of their relative sequence abundance in eelgrass versus bare positions . Positivk-means clustering) to define a set of high- and low-abundance transects for each dinoflagellate sequence across all sites and months .In this subset of high-abundance transects, the negative interaction of eelgrass and dinoflagellates is taxonomically universal. The taxa represented include two unique variants from the genus species . All arep < 0.02; p > 0.85).After demonstrating a preference of all dinoflagellate taxa towards the bare substrate extreme (when highly-abundant), we then characterized their patterns as a function of distance from the edge of the contiguous eelgrass beds, using data from entire transects . ExaminiIn a broad-spectrum eDNA survey of the organisms living in and near to eelgrass, we track the relative abundance of a diverse group of taxa from thirteen phyla. We demonstrate the ability of eDNA to distinguish communities represented in samples taken only meters apart, and to reveal a significant axis of variance based on proximity to habitat type, despite strong influences of geography and time across sampling events. One major and significant pattern emerges in our analysis: dinoflagellate taxa are more common over bare substrate than within eelgrass beds when highly-abundant, and this effect extends at least 15 m beyond the edge of the contiguous beds themselves. Because ours was an observational field study, rather than an experiment, we cannot rigorously distinguish among plausible mechanisms for the observed dinoflagellate distributions. Instead, we use the patterns in our own data as well as the relevant scientific literature to evaluate a number of potential hypotheses.One plausible mechanism is that of an ecological edge effect acting in nearshore zones at the interface between eelgrass and non-eelgrass habitat. \u201cEdge effects\u201d are changes in the distribution or abundance of a species at a boundary between habitats , such tA third possibility is that predatory taxa exist in greater abundance within eelgrass beds and thereby consume dinoflagellates in larger quantities within this habitat , and is mediated locally by a variety of strains of eelgrass-associated algicidal and growth-inhibiting bacteria, particularly from Erythrobacter, Teredinibacter, Gaetbulibacter and Arthrobacter genera causes paralytic shellfish poisoning via production of saxitoxin produce yessotoxins (YTXs), whose effects on human consumers of contaminated shellfish are complex and unclear (reviewed in Alexandrium) are intensifying with recent ocean warming in the North Pacific gigas, in particular, has recently been shown to lessen the effects of eelgrass wasting disease on Z. marina , transect direction , transect position , month, technical replicate, and sequencing run.Click here for additional data file.10.7717/peerj.8869/supp-2Supplemental Information 2Click here for additional data file."} +{"text": "Cross-sectional findings showed that education differences in memory performance were moderated by frequent cognitive activity . The present study examined whether frequent cognitive activity could compensate for lower education when focusing on change in cognitive performance across nine years. The study also explored whether cognitive activity can slow down declines in retired adults as previous research suggested that retiring is associated with an increased risk of cognitive decline . Longitudinal data from the MIDUS study included N = 3,325 middle-aged and older adults. Outcome variables were two factors of cognitive performance: Episodic Memory (EM) and Executive Functioning (EF). Independent variables were years of education, work status (working vs. retired), and frequency of cognitive activity. The results suggest that cognitive activity moderated the effect of educational attainment on change in EM. Individuals with both higher education and cognitive activity showed the smallest declines in EM. Individuals with lower educational attainment but high cognitive activity had less decline in EM compared to their low education counterparts. Those who increased their cognitive activity over time showed less decline in EF. In terms of work status, working adults had less decline in EM and EF compared to retired adults and retired adults who did not maintain their cognitive activity declined more in EF. The results emphasize the importance of frequent engagement in cognitive activity across the lifespan, which can attenuate cognitive declines especially among those who have lower education or have retired."} +{"text": "Tropical rainforest disturbance and conversion are critical drivers of biodiversity loss. A key knowledge gap is understanding the impacts of habitat modification on mechanisms of community assembly, which are predicted to respond differently between taxa and across spatial scales. We use a null model approach to detect trait assembly of species at local- and landscape-scales, and then subdivide communities with different habitat associations and foraging guilds to investigate whether the detection of assembly mechanisms varies between groups. We focus on two indicator taxa, dung beetles and birds, across a disturbance gradient of primary rainforest, selectively logged rainforest, and oil palm plantations in Borneo, Southeast Asia. Random community assembly was predominant for dung beetles across habitats, whereas trait convergence, indicative of environmental filtering, occurred across the disturbance gradient for birds. Assembly patterns at the two spatial scales were similar. Subdividing for habitat association and foraging guild revealed patterns hidden when focusing on the overall community. Dung beetle forest specialists and habitat generalists showed opposing assembly mechanisms in primary forest, community assembly of habitat generalists for both taxa differed with disturbance intensity, and insectivorous birds strongly influenced overall community assembly relative to other guilds. Our study reveals the sensitivity of community assembly mechanisms to anthropogenic disturbance via a shift in the relative contribution of stochastic and deterministic processes. This highlights the need for greater understanding of how habitat modification alters species interactions and the importance of incorporating species\u2019 traits within assessments.The online version contains supplementary material available at 10.1007/s00442-020-04829-z. Habitat modification via selective logging and forest conversion to agriculture is widespread across the tropics , and interactions with other species that are characteristic of anthropogenic disturbance . The majority of the concession (~\u200990%) has been selectively logged, primarily between the 1970s and 2008 across two rotations of logging logging concession in eastern Sabah, Malaysian Borneo across all four habitats]. Each site consisted of one line transect for bird sampling and two-line transects (a minimum of 500\u00a0m apart) for dung beetle trapping (see below for further methods). Sampling for birds and dung beetles occurred at the same sites across the forested habitats and at three of the oil palm sites, however the fourth oil palm site, for each taxa, was sampled in different locations due to logistical reasons (Online resource 1a). Sampling within oil palm was restricted to mature plantations (10\u201315\u00a0years old). The environmental conditions across sampling years remained similar . Primary forests are heterogeneous in structure with a dense canopy, extended vertical strata, and an open understorey with low densities of lianas when compared to logged forests . Sampling effort was equalised across habitat types for dung beetles and birds ; Online Resource 1c; following Edwards et al. Dung beetles (Coleoptera: Scarabaeidae: Scarabaeinae) were sampled using standardised baited pitfall traps across all habitats [nMicrosites\u2009=\u2009192 ; Online Resource 1c; following Edwards et al. Unlimited-radius point counts were used to sample birds across all habitats [Functional traits that reflect the key functional roles of dung beetles and birds were assessed for use with trait assembly null models described below. We combined both behavioural and morphological (body size and bill structure) traits to capture a greater proportion of the variation across species as per Edwards et al. to creatTo assess how functional traits and species abundances influence community assembly, we used a null model approach to test for trait divergence or convergence across our disturbance gradient and landscape (n\u2009=\u20094) scale (Online resource 1), and tested whether SESRaoQ values were significantly different from zero (indicating a random trait distribution) using a student\u2019s t-test.To then be able to assess community assembly patterns across our disturbance gradient we compared the deviation of observed RaoQ from the expected null distribution, using the standardised effect size (SES) (SES_RaoQ), taking the approach of Gottelli and McGabe . SESRaoQnMicrosites\u2009=\u200940 per habitat; birds: nMicrosites\u2009=\u200948 per habitat) and landscape (nSites\u2009=\u20094 per habitat) scales. Therefore, for any given subset of the community (see variations of community subsets below), four models were run for each taxa. All null model randomisations were run with 10,000 permutations and with abundance data, which has been shown to maximise detection power . This model has the effect of removing any relationship between the traits and abundances of species co-occurring at a sampling site while maintaining the sample species richness and the total sample abundance . Importantly, this maintains the link between species abundances and traits (thus differing from model 1), while also maintaining species frequencies and total abundances, but allowing sample abundance and richness to vary . Habitat specialists were defined as those species that were unique to either oil palm or forested habitats . We analysed both subsets of species using the same null models at both the local and landscape scales. To ensure our definition of habitat association was not influenced by rare species , we re-analysed these models with singletons removed. The results mirrored those from the full community; we, therefore, present only the full community results in the main text and provide both model outputs in the supplementary material (Online resource 5).To explore whether any changes in co-occurrence patterns related to changes in interactions determined by species\u2019 habitat associations, we tested whether assembly mechanisms differed between those species shared across all habitats and those that were not (non-shared). Habitat generalists were defined as those species found in all four habitats described in the Elton Trait database, which are based on the summed proportion of five individual diet components for each species , at the local scale dung beetle communities varied considerably. Random trait assembly was found in primary and twice-logged forests, while trends in once-logged forest indicated trait convergence (t-test: P\u2009<\u20090.01) and in oil palm trait divergence (t-test: P\u2009<\u20090.01) , we found no evidence of non-random trait assembly for dung beetle communities at either spatial scales .Nesting guilds of dung beetles indicated uniform trait-based assembly across habitats for rollers, which displayed trait convergence at both scales using model 1. Insectivore communities indicated strong trait convergence across all habitats and scales .Dominant avian feeding guilds showed variation in trait-based assembly patterns using We explored the manner in which tropical land-use change influences species co-occurrence patterns to infer community assembly mechanisms in two indicator taxa. To our knowledge, this is the first assessment of dung beetle co-occurrence patterns, and the first multi-taxon, multi-spatial scale analysis of co-occurrence in relation to anthropogenic habitat change. In revealing evidence of non-random assembly at local scales in dung beetles, and variation between trait convergence and random assembly in birds across the disturbance gradient Fig.\u00a0e\u2013h, our Model 1, which can detect limiting similarity, varied across the disturbance gradient, whereas model 2, which reliably detects environmental filtering and conversion . Critically, we highlight the potential hidden effects of land-use change beyond altered community structure Below is the link to the electronic supplementary material."} +{"text": "The successful implementation of antiretroviral therapy (ART) in women living with HIV (WLWH), either for their own health or for prevention of mother-to-child transmission (MTCT), has reduced MTCT risk of HIV to <5% . Yet, inIn addition to the risk of HIV infections that occur early in life via breastfeeding, sexual transmission during adolescence and adulthood also represents a significant and ongoing mode of infection . A pediaSeveral recent studies have indicated that the early life immune system may present some advantages for elicitation of HIV-specific antibody responses. The purpose of this review is to summarize these studies and highlight the unique ability of the early life developing immune system to mount robust and durable immune responses against HIV, compared to adults. Additionally, the potential of harnessing neonatal immune ontogeny to develop an effective earlylife HIV vaccine is emphasized.Owing to maturational differences in the early life and adult immune systems, the ability of infants to generate vaccine-specific immune responses has traditionally been considered as impaired [reviewed in ]. AdditiNeonatal nonhuman primate (NHP) studies have provided encouraging results regarding the ability of infants to mount durable immune responses against HIV or simian immunodeficiency virus (SIV) vaccines \u201319. In fTo date, only a few pediatric HIV vaccine trials have been completed . While nAlthough the induction of cross-clade bNab is 1 of the major goals of any HIV vaccination strategy ,37, so fWhile elicitation of bNabs remains a priority of HIV vaccine development, a combination of neutralizing and non-neutralizing effector responses might be crucial for an efficacious vaccine. A recent study has indicated that polyfunctional antibody responses are predictive of bNab development , suggestNewborns transition from a relatively sheltered intrauterine environment to an environment with multiple antigenic exposures. To obtain survival benefits during the period of immune maturation, newborns establish a highly tolerogenic environment and exhibit a distinct immune profile than adults [reviewed in ]. TherefWhile alum has been the standard adjuvant of choice for commercial pediatric vaccines, HlV pediatric vaccine trials have reported the superiority of MF-59 adjuvant in mounting potent and durable antibody responses when compared to alum. In PACTG 230 trial, the MF-59-adjuvanted vaccine formulation was associated with durable anti-Env IgG responses, which was associated with higher breadth and durability as compared to the alum-adjuvanted counterpart . This inEmerging evidence suggests that an individual\u2019s microbiome can influence immune responses to vaccination . TherefoNeonates and infants possess unique immunological characteristics that promote the development of protective immunity via immunological and molecular pathways distinct from those of adults. Therefore, a deeper understanding of the infant immune system is needed to develop novel HIV immunization regimens tailored to the infant\u2019s immune landscape. The fact that the most recent adult HIV vaccine trial HVTN 702), done in South Africa, which tested a canarypox vector-based vaccine (ALVAC-HIV) with HIV subtype C gp120 protein adjuvanted with MF-59, was recently discontinued due to lack of efficacy highligh2, done iThe pediatric HIV vaccine protocol HVTN 135 is currently in development to assess the safety and immunogenicity of HIV CH505 transmitted-founder (T/F) gp120 adjuvanted with the TLR4 agonist GLA-SE in HIV-exposed infants. This Phase I trial will use the CH505 T/F protein that is currently being tested in an adult HIV vaccine trial, and the results from HVTN135 will determine if this vaccine is safe to be used in infants. Additionally, this trial will indicate whether infants develop a distinct immune response to this vaccine as compared to adults, hence providing valuable information for the design of future pediatric HIV vaccine trials. Ultimately, additional clinical trials will be required to assess if immunization at birth can protect infants from vertical HIV transmission during infancy and against sexual HIV transmission during adolescence."} +{"text": "Using a stress process framework model, this study is the first to comprehensively examine the role that religious/spiritual struggles play in the lives of informal dementia caregivers. A convenience sample of 156 informal dementia caregivers completed a scale measuring six domains of religious/spiritual struggles, as well as other measures of primary stressors, background/contextual variables, and mental health outcome (depression). Overall levels of religious/spiritual struggle were low, but 26 percent of the sample were classified as possible cases of clinically significant religious/spiritual struggle for at least one of the six domains. Of this group, 49 percent acknowledged struggles with ultimate meaning. Religious/spiritual struggles predicted greater self-reported depression over and above number of care recipient problem behaviors (primary stressor), caregiver sex, and caregiver personality . Although no individual domain of religious/spiritual struggle emerged as most salient, caregivers reported significantly more ultimate meaning struggles than demonic or interpersonal struggles. These findings support the growing body of research suggesting that religious/spiritual struggles serve as a secondary stressor, adding predictive power to background/contextual factors and to primary stressors for informal dementia caregiver mental health outcomes. Further research in this area may advance efforts to better equip both secular and religious professionals to provide evidence-based counsel to informal dementia caregivers."} +{"text": "Excellent pulmonary function is one of the strongest predictors of longevity across animal models and human populations. Unfortunately, none of the major age-associated pulmonary diseases \u2013 obstructive lung disease, pulmonary fibrosis, and increased susceptibility to pneumonia \u2013 have strongly effective disease modifying therapies. There is growing evidence that normal age-associated decline in pulmonary function and major age-associated pulmonary diseases are linked to the hallmarks of aging including senescence, nutrient signaling dysregulation, mitochondrial dysfunction, and telomere disorders. This presents opportunities for collaboration between gerontologists and pulmonologists to unravel age-associated developmental mechanisms and design novel treatments. In this symposium, leaders in pulmonary aging research will present novel data on links between aging and pulmonary health and geroscience-based interventions under study. Dr. Sanders will provide an overview of the scientific and clinical space and present epidemiologic associations between aging biomarkers, early pulmonary fibrosis, and mortality. Dr. Le Saux will discuss senescence and specifically how eicosanoid biology may explain organ-specific patterns of senescence-associated fibrosis. Dr. Thannickal will discuss age-associated perturbations in metabolism and mitochondrial function and targeting these pathways to improve lung function and treat pulmonary diseases. Dr. Newton will discuss mechanisms and clinical applications of telomere biology to pulmonary aging. Symposium attendees will (1) be poised to generate collaborations between gerontologists and pulmonologists to address existing knowledge gaps in mechanisms of pulmonary aging, and (2) develop a better understanding of translational opportunities to design geroscience-based diagnostics and therapeutics to improve pulmonary health with aging."} +{"text": "Ovarian cancer, cervical cancer and endometrial cancer are three relatively common malignant cancers of the female reproductive system. Despite improvements in female genital tract cancer detection and development of new therapeutic approaches, there are still poor prognoses and some do not respond to therapeutic patterns, displaying low survival and high frequency of recurrence. In an era of personalized medicine, novel therapeutic approaches with greater efficacy for these cancers represent an unmet need. One of the actionable signaling pathways is the fibroblast growth factor receptor (FGFR) signaling pathway. Several mutations and alterations in FGF/FGFR family members have been reported in human cancers. FGF/FGFR signaling pathway has become a new target for cancer therapy. This review will summarize the role of FGFR pathway and the genetic alterations of the FGF/FGFR related to female reproductive system cancer. We will describe the available inhibitors of FGFR pathway for potential treatment of female reproductive system cancer. Furthermore, we will discuss FGFR-targeted therapies under clinical development for treatment of female reproductive system cancer. Endometrial cancer, ovarian cancer and cervical cancers are three relatively common malignant tumors of the female reproductive system. Endometrial cancer that accounts for more than 95% of cases of uterine cancer is one of the most prevalent forms of gynecological cancers. It is thought to be caused by increasing estrogen levels relative to progesterone in the body. Endometrial cancer at stages I and II responds well to surgical interventions, but the disease at stages III and IV has poor prognosis with low survival rates. Ovarian cancer is the third leading gynecological malignancy worldwide and carries the highest mortality. Most ovarian cancers initiated from epithelial cells and are thus composed of poorly differentiated epithelial cells in vitro and in vivo tumor models harboring FGFR aberrations, an increasing number of researchers have selected FGFRs as targets for anticancer drug development Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinase (RTKs) encoded by four different genes FGFR1-4), among them, FGFR1-FGFR3 generate two major splice variants of immunoglobulin-like domain III, referred to as IIIb and IIIc, which are essential determinants of ligand-binding specificity , among tSome of the most striking clinical findings regarding FGFRs relate to how these receptors are implicated in female genital tract cancers. In this article, we describe recent advances of FGFR signaling pathway in endometrial, ovarian and cervical carcinogenesis and progression. Moreover, we highlight the genetic variations (including somatic mutation and gene amplification) of FGF or FGFR family members and summarize the FGFR-targeted therapies under clinical development for treatment female genital tract cancers.FGFRs in response to fibroblast growth factors (FGFs) transmit signals. The FGF family belongs to a large family of growth factors with significant expression profiles in the female reproductive tract and potentially important roles on fertility. This family is composed of 18 secreted proteins that are grouped into 5 subfamilies according to sequence homology Figure 1).Notably, dysregulation of the FGFR pathway is associated with various human cancers and is considered as an oncogenic signaling pathway FGF/FGFR signaling governs fundamental cellular processes such as cell survival, proliferation, migration, differentiation, embryonic development, organogenesis, tissue repair/regeneration, and metabolism Figure 2). Recent study suggested that the fibroblast FGF/FGFR family could interact with PI3K/AKT pathway and subsequently involve in the carcinogenesis of ovarian cancer. In endometrial cancer cell lines, loss of PTEN has been suggested as apotential mechanism of resistance to FGFR inhibition Genetic variations, especially SNPs, and genomic alterations, such as gene amplification, chromosomal translocation, and point mutation, are involved in the transcriptional upregulation of FGFR mRNAs and the functional activation of FGFR proteins during carcinogenesis . The main challenges have included (i) determining optimal diagnostic procedures for FGFR molecular alterations, and standardizing the definition of FGFRs amplification; (ii) detecting rare-frequency fusion genes involving various partners; (iii) discriminating between passenger and driver alterations; (iv) integrating the available information within a specific cellular and tumor heterogeneity context.In clinical, although anti-FGFR therapy represents a promising targeted cancer treatment, early phase clinical trials have had mixed success, with response to therapy dependent on several factors, including cancer type, tumor histology, and presence or absence of certain biomarkers Cervical cancer is the fourth most common female malignancy worldwide. Each year, more than half a million women are diagnosed with cervical cancer and the disease results in over 300,000 deaths worldwide et al. The oncogenic significance role of the FGFRs has been elucidated in cervical cancer. Choi et al. Ovarian cancer is the leading cause of death from gynecologic cancers in vitro and in vivo have shown that silencing FGFR4 and inhibiting ligand-receptor binding significantly decreased the proliferation, survival, and invasiveness and increased apoptosis of ovarian cancer cells, suggesting that FGFR4 protein expression is a new therapeutic modality for this disease and will improve its survival in clinical trials FGFR4 is a prognostic marker for advanced-stage, high-grade serous ovarian cancer. Experiments In vivo experiment has shown that FGFR inhibitor decreased the growth of FGFR2-mutated endometrial cancer xenograft models Endometrial cancer is the most common gynecologic malignancy among women in developed countries, with an estimated 63,230 new cases in 2018 et al. Table The FGF/FGFR signaling pathway is frequently deregulated in human cancers. Over the last years, several mutations and alterations in FGF-FGFR pathway have been reported in cancer et al. et al. Previous studies of germline FGFR mutations indicate that point mutations can result in differential localization and signaling et al. Besides FGFR aberrations, a number of studies have also shown that genetic variations of FGF are associated with the disease. Take FGF2 for example, our group previously found that the polymorphisms of FGF2 gene are significantly associated with obesity and osteoporosis in Chinese population Since FGF/FGFR signaling plays a crucial role in cancers, a variety of small molecule FGFR inhibitors target FGF/FGFR signaling pathway have been developed and shown significant therapeutic effects in pre-clinical and clinical studies Actually, the most clinically advanced compounds are non-selective TKIs, such as brivanib, dovitinib, lenvatinib, ponatinib, nintedanib, and cediranib. Most of these inhibitors target ATP binding pocket in the TK domains of FGFRs through reversible or covalent bonds To date, the most clinically advanced FGFR TKIs in FGFR targeted treatment is dovitinib (TKI258), which is now being tested in endometrial cancer patients with FGFR2 mutation (NCT01379534). Brivanibis another dual TKI against FGFRs and VEGFRs, which was found to be effective in metastatic solid malignancies resistant to standard therapy and is currently being developed as an anti-angiogenic agent in Phase II clinical trials AL3818 (anlotinib) is a receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptors , stem cell factor receptor (C-kit), platelet-derived growth factor (PDGFA), and fibroblast growth factor receptors . This study evaluates the efficacy of AL3818 studying tumor regression in endometrial cancer model Table 2).Several other TKIs are also summarized in Table in vitro and in vivo models of endometrial cancer characterized by FGFR activation due to genetic alteration Table 3). Phase II trials with genomic enrichment are ongoing. A number of clinical trials use AZD4547 in cancer. One recent finding revealed that combined treatment of BGJ398 and rapamycin may be a promising therapeutic strategy in the treatment of patients with ovarian cancer AZD4547 is a famous selective TKI that specific target for FGFRs (FGFR1-3) Table 3). Pre-clinical cancer models with genetic aberrations in the FGFR pathway, including FGFR2-mutated endometrial cancer, are particularly sensitive to FP-1039 mediated tumor inhibition Anti-FGFR mAbs as well as small molecules acting as traps for the ligands of the FGFR family might represent a new strategy for the treatment of tumors. Based on the identification and characterization of FGF ligands, FGF ligand traps have allowed the development of promising FGF-targeting molecules with potential implications for the therapy of FGF-driven tumors Figure A large effort to develop FGF/FGFR inhibitors as anticancer treatments is underway. The most clinically advanced anti-FGFR drugs are small-molecule TKIs, some of them are monoclonal anti-FGFR antibodies and FGF-trapping molecules. Those anti-FGFR drugs that have entered the clinical phases of development are summarized in The cancers of the female genital tract represent a leading cause of morbidity and mortality among women worldwide. Undoubtedly, in the past decade, FGF/FGFR signaling therapies are under development for the treatment of gynecologic malignancies as well as in many other solid tumors. Therefore, dissecting canonical FGF/FGFR signaling pathways is still valuable. Deregulation of the FGF/FGFR signaling axis is observed in a wide variety of human cancers In conclusion, targeting FGFR is a promising strategy in the treatment of female reproductive system cancer. It is plausible to hope that in the following years the research efforts in pre-clinical and clinical fields allow to establish an optimal treatment strategy in FGFR-addicted female reproductive system cancer population."} +{"text": "Preparedness of residents in long-term care (LTC) in the face of hurricane emergencies is a contested and largely unanswered question. Our prior work involving the U.S. Gulf Coast hurricanes of 2005-08 showed that exposure to various storms on nursing home (NH) residents resulted in significantly more deaths than reported by health care officials. This work also highlighted that evacuation of NH residents, compared to sheltering in place, was independently associated with morbidity and mortality. Hurricane Irma struck Florida on Sept. 10, 2017, prompting the evacuation of thousands of NH and assisted living community (ALC) residents. This symposium will discuss the effects of Hurricane Irma on vulnerable older adults residing in NHs and ALCs using mixed quantitative and qualitative methodologies. The first presentation will discuss morbidity and mortality of NH residents exposed to Hurricane Irma and will stratify by long stay/short stay status and hospice enrollment. The second presentation will discuss improvements and continued barriers to NH preparedness based on interviews with 30 administrators following Hurricane Irma. Using a novel methodology to identify residents of ALCs using secondary data sources, the third presentation will document AL resident morbidity and mortality risk following Hurricane Irma. The final presentation will highlight results of interviews with 70 stakeholders from small and large ALCs concerning the hurricane experiences of residents, including those with dementia. This symposium offers a multi-faceted view of a disaster\u2019s effects on LTC residents across Florida, including novel data from the NH environment and lesser-examined ALCs."} +{"text": "Background: Preterm infants with hemodynamically significant patent ductus arteriosus (HsPDA) are exposed to low cerebral tissue oxygen saturation (rScO2) values. Additionally, infants requiring surgical ligation are at risk of further changes in cerebral oxygenation and postligation cardiac syndrome (PLCS). Previous studies have assessed the effect of PDA ligation on rScO2 with variable results.Cases description: In this report we analyse near-infrared spectroscopy (NIRS) and echocardiographic findings of two patients who underwent ligation of PDA and presented low cardiac output. Literature on regional tissue oxygenation saturation (rSO2) before and after PDA ligation was briefly reviewed.Discussion: Cerebral oxygenation values before and after PDA ligation may be influenced by gestational age, vasopressor use, ductal shunt volume, time of exposure HsPDA, chronological age and the presence of cerebral autoregulation. PLCS complicates 28\u201345% of all PDA ligations and is associated with higher mortality. Cerebral and somatic NIRS monitoring in the postoperative period may enhance the identification of PLCS at early stages.Conclusion: Cerebral oxygenation in the perioperative period of PDA ligation may be influenced by numerous clinical factors. Early detection of PLCS using multisite NIRS after ligation could prevent further alterations in cerebral hemodynamics and improve outcomes. A decrease in somatic-cerebral difference and/or a significant drop in somatic NIRS values may precede clinical signs of hypoperfusion. NIRS values should be interpreted as trends along with echocardiographic findings to guide goal directed interventions. After PDA ligation, a significant reduction (>20%) in rSrO2 and somatic-cerebral difference concurred with low LVCO in both cases in the absence of hypotension, oliguria and/or delayed capillary refill. In case 1, cerebral oxygenation decreased significantly at the end of measurement period compared to preligation baseline values (60 vs. 80%). In case 2, rScO2 remained unvaried.In the aforementioned cases, rSrOEarly detection of PLCS using multisite NIRS after ligation could prevent further alterations in cerebral hemodynamics and improve outcomes. A decrease in somatic-cerebral difference and/or a significant drop in somatic NIRS values may precede clinical signs of hypoperfusion. Further studies are needed to investigate the applicability of somatic-cerebral difference in preterm infants. Our report has many weaknesses. Firstly, we describe only two cases and no conclusions can be drawn regarding our findings. Secondly, somatic-cerebral difference although physiologically founded, has not been used in preterm infants. We consider that continuous and long lasting NIRS recording is a strength of this report, as well as the review of literature on NIRS findings before and after treatment.A prospective cohort study is recommended to evaluate the utility of two-site NIRS monitoring in the detection of PLCS. NIRS values should be interpreted as trends along with echocardiographic findings to guide goal directed interventions.Written informed consent was obtained from parents of both patient for the publication of any potentially identifiable images or data included in this article.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Diurnal cortisol slopes are stress-sensitive HPA-axis biomarkers implicated in cardiometabolic health outcomes and disparities. This study used two longitudinal cohort studies (CREATE and TRIAD) with harmonized variables to comprehensively examine what types of exposure to stressors are most salient for cortisol dysregulation in later life, and whether the characteristics of stressor exposure accounts for Black-White disparities in cortisol dysregulation . Black participants reported greater stressor exposure than Whites along some dimensions but comparable exposure in others . Stressor exposure measures that captured psychological components and pervasiveness were more closely related to cortisol dysregulation than more objective measures . Everyday discrimination was associated with racial disparities."} +{"text": "This study aimed to identify accelerometer measured daily physical activity patterns and to examine how they associate with health-related physical fitness among 258 participants from the Finnish Retirement and Aging Study. Wrist-worn ActiGraph accelerometer was used and health-related physical fitness measures included body composition, cardiorespiratory fitness and muscular fitness. Based on latent class trajectory analysis, six different patterns of daily physical activity was identified on workdays and two on days off. Having low activity throughout the workday was associated with poorest health-related physical fitness, whereas a combination of low or moderate activity during working hours and increase of activity level in the evening was associated with most favorable body composition and better physical fitness compared to the other trajectories. In conclusion, a large variation in the workday physical activity patterns and health-related physical fitness was observed among aging workers."} +{"text": "Opioid overdose risk is particularly high in immigrant communities partly due to limited English proficiency . Previous studies reported that social determinants of health (SDH) have been associated with risk for opioid overdose . The current study examines the association between SDH and literacy of opioid overdose risk among the immigrant population living in a rural area. Specifically, we examine the association in various age groups including young adults (aged 20 to 34), middle-aged (aged 35 to 49), and older adults (ages 50 to 75). Data were drawn from a sample of Korean American immigrants residing in rural Alabama (N=225). The participants administered the Brief Opioid Knowledge (BOOK) Questionnaire . Multiple regression analyses were conducted for three age groups to identify predictors of opioid literacy. Overall, older adults had lower levels of opioid literacy relative to their younger counterparts. Among young adults, low English proficiency, more chronic conditions, and greater depressive symptoms were significant predictors of limited opioid literacy. For the middle-aged adults, lower levels of health literacy and more pain symptoms were associated with limited opioid literacy. Among older adults, women, those with higher English proficiency, and lower health literacy had lower levels of opioid literacy. The findings demonstrated a greater vulnerability of older immigrants to limited opioid literacy. Different predictors based on SDH of limited opioid literacy across age groups have implications for tailored health promotion strategies to reduce opioid overdose risk."} +{"text": "Background: Surgical root canal retreatment is required when peri-radicular pathosis associated with endodontically treated teeth cannot be treated by non-surgical root canal therapy (retreatment), or when retreatment was ineffective, not feasible or contraindicated. Endodontic failures maybe happen when irritants remain within the confines of the root canal, or when an extra-radicular infection cannot be eradicated by orthograde root canal treatment. Following enhanced microsurgical techniques in the last years, the success rates of surgical root canal retreatment have improved considerably.Objective: The aim of this systematic review is to gather updated data in regard to the surgical root canal (retrograde) retreatment to heal the periapical lesions.Materials and methods: The electronic databases PubMed and Google Scholar were searched in this review using specific inclusion and exclusion criteria. The search was performed in June 2019 and updated in November 2019. Among 3900 studies, 10 studies satisfied the eligibility criteria and were included in the review to be analyzed.Results: The 10 studies showed the importance of surgical root canal retreatment as a treatment option in removing infections within the root canal system and its efficiency in periapical tissue healing. These studies investigated different aspects of healing of periapical lesion after surgical (retrograde) retreatment including success rates, follow-up duration, and updated studies in surgical (retrograde) retreatment.Conclusions: Surgical root canal (retrograde) retreatment demonstrates its efficiency in reducing the period needed for healing of the periapical lesions in short-term follow-up compared to conventional orthograde retreatment. Periapical lesions are one of the common pathological conditions affecting periradicular tissues . The micThe preliminary purpose of all endodontic procedures, especially cleaning and shaping, is to eliminate necrotic tissue and infective bacteria . Large pThere are several studies that were conducted to discuss the healing of periapical lesion after nonsurgical (orthograde) retreatment or surgical root canal treatment. However, few studies have investigated the healing of periapical lesion after surgical (retrograde) retreatment. Consequently, the aim of this review was to collect all updated and available studies including imperative information concerning the surgical root canal (retrograde) retreatment to heal periapical lesions.Material and methodsThis review has been compiled according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.Research QuestionThe following was the research question for the systematic review: \u201cThe best endodontic treatment option for the healing of periapical lesions: is it surgical retrograde retreatment or conventional orthograde retreatment?\u201d.Literature SearchWith respect to the question of the study, we searched the literature and identified relevant studies. The literature search was formulated in June 2019 and then updated in November 2019. A web search was done through PubMed (2009-2019) and Google Scholar (2009-2019) with MesH terms and/or in various combinations .Relevant articles had been read and assessed by the introduction of the close meaning ideas by the study reviewers. Full articles were obtained for most of the titles and abstracts that met the inclusion criteria, the full text was accessed. From each included article, study design, interventions, and findings were extracted. Articles used were categorized into two main groups (free and restricted). Free ones have been downloaded directly by the URLs generated from the database. The restricted group has been downloaded by the institutional access of the King Abdulaziz University (KAU) library. Even though some articles did not match the main idea, they have been reviewed again & decided to be either relevant or irrelevant.Inclusion Criteria1. Native research released in the English language.2. Time framed articles released within 10 years (2009 - 2019).3. Studies carried out on human subjects only.Exclusion Criteria1. Articles that described healing of periapical lesion with management techniques excluding the surgical root canal retreatment.2. Articles that discussed healing of periapical lesion after surgical root canal retreatment by percentages and samples taken from animals.3. Review articles.Critical AppraisalEligible studies were independently analyzed by all reviewers according to the eligibility criteria as well as PRISMA guidelines. Any disagreement between the reviewers was resolved using discussion.Data Extraction and PresentationThe search strategy using the keywords and MeSH of the databases like PUBMED and Google Scholar yielded a total of 3,900 studies, of which 3,580 were either unrelated or duplicate topics. Among the potential 140 studies, the eligibility criteria were applied and ten studies were included in this systematic review. The summary of the search flow chart for this systematic review has been depicted in retreatment including success rates, follow-up duration, and updated studies in surgical root canal (retrograde) retreatment. The studies included in this systematic review were one randomized controlled trial study, two prospective studies, one retrospective study, and six case reports -19,20-25DiscussionThe systematic review presents a comprehensive compilation of evidence taken from ten articles which included original studies. The sample size was up to 376 subjects seeking endodontic retreatment by the use of surgical retrograde retreatment. All included studies confirmed faster treatment time by surgical root canal (retrograde) retreatment Table . The recAlso, Del Fabbro et al. in 2007 and Torabinejad et al. in 2009 have compared the success rates of non-surgical orthograde and surgical retrograde endodontic retreatment ,28. TheySurgical root canal (retrograde) retreatment is defined as an important invasive procedure that permits fast treatment options minus the necessity of the extensive traditional method. Surgical retrograde retreatment demonstrates its efficiency in reducing the period needed for healing of the periapical lesions and suggests benefits that will result in better recognition among patients seeking faster results in short-term follow-up, but on the long-term follow-up\u00a0showed not significant difference for healing of periapical lesions compared to conventional orthograde retreatment. However, more clinical trials are encouraged to inspect the results of surgical retrograde retreatment on the healing of periapical lesions."} +{"text": "The Long Life Family Study (LLFS) has longitudinally measured key aging phenotypes on 4,953 participants (539 pedigrees) in the USA and Denmark selected for exceptional familial longevity. On average, both generations of the LLFS sample are healthier than average for their age/sex, for many phenotypes. However, the pedigrees are heterogeneous, with different families showing familial clustering of protection for different phenotypes. Linkage analyses identified extremely strong genetic linkage peaks for many cross-sectional as well as longitudinal trajectory rates of change phenotypes. These peaks are NOT explained by GWAS SNPs (either measured or imputed). Pedigree specific HLODs and preliminary deep sequencing suggests that these peaks are driven by rare, protective variants running in selected pedigrees. Whole Genome Sequencing, a third longitudinal visit, and extensive OMICs will help us resolve the mechanisms behind these protective genetically linked variants, and could illuminate new biology and enable new therapeutics."} +{"text": "The amygdala is a central hub for fear learning assessed by Pavlovian fear conditioning. Indeed, the prevailing hypothesis that learning and memory are mediated by changes in synaptic strength was shown most convincingly at thalamic and cortical afferents to the lateral amygdala. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to regulate synaptic plasticity and memory formation in many areas of the mammalian brain including the amygdala, where BDNF signalling via tropomyosin-related kinase B (TrkB) receptors is prominently involved in fear learning. This review updates the current understanding of BDNF/TrkB signalling in the amygdala related to fear learning and extinction. In addition, actions of proBDNF/p75NTR and NGF/TrkA as well as NT-3/TrkC signalling in the amygdala are introduced. The amygdala is a telencephalic group of diverse, interconnected nuclei in the brain receptors preferentially activated by NGF (nerve growth factor), TrkB receptors activated by BDNF as well as NT-4/5 (neurotrophin-4/5) and TrkC receptors by NT-3 (neurotrophin-3) Barbacid .While many findings regarding BDNF/TrkB signalling in cellular aspects of learning were initially reported for hippocampal and cortical circuits, BDNF/TrkB pathways in the amygdala emerged soon thereafter to be prominently involved in fear learning (see below). TrkB receptor as well as BDNF mRNA and protein were detected at moderate to high levels in various amygdala subnuclei , the posterior intralaminar nucleus (PIN) and the suprageniculate nucleus (SG) or Y515 (Shc) phosphorylation site of the TrkB receptor, respectively , which drives the expression of Met-BDNF and leads to decreased activity-dependent BDNF secretion were unaffected or impaired when assessed by skin conductance response or fear-potentiated startle, respectively from tones not paired with the aversive US (CS\u2212) in a discriminative fear learning task (Meis et al. Interestingly, chronic BDNF reduction to about 50% of wild-type levels in BDNFThe LA is highly interconnected with the BA (Pitkanen et al. AR\u03b11 subunits in amygdala cell cultures, which was supposed to elicit a transient hyper-excitability in the amygdala, thereby contributing to cellular mechanisms of memory consolidation (Mou et al. +/\u2212 mice displayed neither impaired basal synaptic GABAergic transmission nor altered inhibitory synaptic plasticity in the LA. However, positive modulation of interneuron activity by noradrenaline was significantly decreased by chronic BDNF reduction (Meis et al. Beside glutamatergic synaptic transmission, BDNF/TrkB signalling also regulates GABAergic neurotransmission (Gottmann et al. Beside the basolateral amygdala, the central nucleus is now considered as an important site of associative plasticity involved in fear memory (Ehrlich et al. In conclusion, BDNF/TrkB signalling increases excitatory synaptic transmission in different subnuclei of the amygdala and enables LTP. At GABAergic synapses, acute BDNF/TrkB signalling may lead to reduced inhibition and elevated excitability necessary for memory formation, while chronic BDNF reduction results in impaired interaction of GABAergic synaptic transmission with modulatory transmitters like noradrenaline and serotonin.After fear learning, repeated exposure to the conditioned stimulus alone leads to diminished fear responses (Myers and Davis +/\u2212 mice display an age-dependent deficit in extinction learning (Psotta et al. Val/Met or BDNFMet/Met mice as well as human Met allele carriers were impaired in extinguishing a conditioned fear response, associated with abnormal fronto-amygdala activity in humans (Soliman et al. +/\u2212 mice but was mimicked by overexpression of BDNF in the BLA from the end of extinction training onward (Karpova et al. A critical contribution of BDNF signalling in extinction was recently demonstrated. BDNFNeurotrophins are at first synthesized as precursor proteins, which are processed to the mature form by proteolytic cleavage (Lessmann and Brigadski Conflicting results are available about the distribution of TrkA receptors in the amygdala. While initially neither TrkA receptor mRNA nor immunoreactive cells for TrkA receptors were detected (Gibbs and Pfaff While neither NT-3 mRNA nor immunoreactive neurons were found in the amygdala (Phillips et al. Accumulating evidence indicates that BDNF/TrkB signalling in the amygdala plays a pivotal role in fear learning and memory as well as fear extinction. In the amygdala circuitry, BDNF/TrkB signalling contributes significantly to synaptic plasticity, which is widely accepted as a cellular mechanism underlying fear memory learning. In addition, downstream molecular signalling pathways triggered by TrkB activation are well documented. However, actions of BDNF/TrkB signalling in amygdala synaptic processes involved in fear extinction learning are far less understood. While behavioural studies suggest a significant contribution of BDNF signalling within the amygdala in extinction learning, analysis of the underlying cellular mechanisms warrants further studies."} +{"text": "Filial caregivers are a part of the growing number of family caregivers in midlife and late adulthood. The responsibilities that filial caregivers navigate in midlife and late adulthood may expose them to multiple types of discrimination that may decrease their physical health, though this relationship has been understudied. As numbers of family caregivers grow, it is important to examine the potential vulnerability of younger and older filial caregivers\u2019 physical health in the context of discrimination. Informed by the life course perspective, this study compares the physical health of younger (aged 34-64) and older (aged 64-74) filial caregivers who experience discrimination. Filial caregivers from the Midlife in the United States (MIDUS-II) Survey reported on demographics, family caregiving, daily discrimination, self-rated physical health, and chronic conditions via questionnaires and phone interviews. Regression analyses showed no differences between younger and older adults\u2019 self-rated physical health or average chronic conditions. However, moderation analyses revealed that younger filial caregivers who experienced greater discrimination reported poorer self-rated physical health than their older counter parts as well as younger and older filial caregivers who experienced less discrimination. Additionally, younger caregivers with greater discrimination exposure exhibited more number of chronic conditions as compared to other caregivers. The study results highlight the impact of the intersection between filial caregivers\u2019 age and discrimination on physical health. Findings have the potential to inform programs that could promote the health of filial caregivers in the face of discrimination."} +{"text": "Although nonalcoholic fatty liver disease (NAFLD) is more prevalent in older individuals, the underlying mechanisms by which aging processes accelerate NAFLD are not fully understood. NAFLD can progress to nonalcoholic steatohepatitis (NASH), which in turn can lead to the development of cirrhotic liver disease and hepatocellular carcinoma (HCC). Since NAFLD, NASH, and HCC are rapidly increasing in the aging population, understanding the mechanism of how NAFLD progresses to NASH is crucial. NASH is emerging as the leading cause of chronic liver disease and the most rapidly growing indication for liver transplantation worldwide, with liver fibrosis being the most important predictor of liver failure in NASH . HoweverCRMertk) mouse model, the authors further showed that all-trans retinoic acid (ATRA)\u2013induced ADAM metallopeptidase domain 17 (ADAM17)\u2013mediated MerTK cleavage decreased the levels of MerTK receptor on macrophages and suppressed NASH fibrosis. ATRA is a major active metabolite of retinol stored in quiescent HSCs in healthy liver. In damaged liver, as HSCs are activated, they release retinol. Livers of subjects with NASH show lower levels of retinol than livers of subjects with simple steatosis [in vivo. However, given that MerTK is critical for maintaining tissue homeostasis in other settings, including atherosclerosis and myocardial infarction [Liver fibrosis is driven by the activation of hepatic stellate cells (HSCs) that produce collagen and other types of extracellular matrix. It has been widely reported that liver macrophages, including resident Kupffer cells and infiltrated monocyte-derived macrophages, can activate HSCs through releasing growth factors including TGF\u03b2 and PDGF . Howeverteatosis . Consistfarction , global In summary, Cai et al. uncover a previously unrecognized function of macrophage MerTK in NASH fibrosis and provide constructive insight on the potential therapeutic targeting of MerTK. However, this study opens up new questions worth exploring. Since MerTK is often seen as a protective regulator for tissue homeostasis, why doesn\u2019t MerTK signaling trigger beneficial effects, including efferocytosis, dampening of inflammation, and resolution of inflammation in the context of NASH? Moreover, some studies have shown that Kupffer cells are protective in non-NASH liver injury models. However, Kupffer MerTK is detrimental in NASH. Does MerTK express in a unique subset of Kupffer cells that promote NASH progression? Finally, what are the mechanisms of decreased liver ATRA and increased GAS6 during NASH?"} +{"text": "Coastal wetlands provide many critical ecosystem services including carbon storage. Soil organic carbon (SOC) is the most important component of carbon stock in coastal salt marshes. However, there are large uncertainties when estimating SOC stock in coastal salt marshes at large spatial scales. So far, information on the spatial heterogeneity of SOC distribution and determinants remains limited. Moreover, the role of complex ecological interactions in shaping SOC distribution is poorly understood. Here, we report detailed field surveys on plant, soil and crab burrowing activities in two inter-tidal salt marsh sites with similar habitat conditions in Eastern China. Our between-site comparison revealed slight differences in SOC storage and a similar vertical SOC distribution pattern across soil depths of 0\u201360 cm. Between the two study sites, we found substantially different effects of biotic and abiotic factors on SOC distribution. Complex interactions involving indirect effects between soil, plants and macrobenthos (crabs) may influence SOC distribution at a landscape scale. Marked differences in the SOC determinants between the study sites indicate that the underlying driving mechanisms of SOC distribution are strongly system-specific. Future work taking into account complex interactions and spatial heterogeneity is needed for better estimating of blue carbon stock and dynamics. It points to the necessity of incorporating these indirect effects for better understanding the mechanisms underlying carbon stock in coastal ecosystems. It also calls attention to spatial heterogeneity and system specificity for estimating blue carbon stock and dynamics.By comparing between two inter-tidal salt marsh sites with similar habitat conditions in Eastern China, we observed minor differences in SOC storage and a similar vertical SOC distribution pattern across the soil depths of 0\u201360 cm. Despite these similarities, we found strongly different effects of biotic and abiotic environmental factors on SOC density distribution between the two study sites. Complex interactions involving indirect effects between soil, plants and macro-benthos (crabs) can provide important additional explanatory power to the models explaining SOC distribution, suggesting that these interactions may underpin SOC distribution at a landscape scale. Marked differences in the SOC determinants between the study sites indicate that the underlying driving mechanisms of SOC distribution are strongly system-specific. Future work, taking into account spatial heterogeneity and system specificity, is needed for improving the accuracy of estimates of blue carbon stock and dynamics."} +{"text": "The current pandemic due to the coronavirus disease 2019 (COVID-19) outbreak has forced physicians to review their current clinical practice and guidelines. Although elective procedures using assisted reproductive technologies (ART) should be preferably canceled or postponed at this time, this does not always apply to urgent procedures such as those in patients with cancer. A complete oncofertility counseling balancing the benefits and risks of undergoing fertility preservation before commencing gonadotoxic therapies (chemotherapy and/or radiotherapy) should also be provided during the COVID-19 outbreak. This article briefly highlights what patients, oncologists and fertility specialists need to keep in mind during oncofertility counseling at the time of the COVID-19 outbreak. Some anticancer treatments can affect fertility , 2. OncoPatients face hurdles that can be as basic as getting to the tertiary hospital that offers both cancer care and fertility preservation treatments to more complex emotional thoughts dealing with the fear of both the known and unknown risks of complications from COVID-19 during cancer treatment and the additional fertility preservation treatments involving further hospital visits, potential surgery and in some units additional costs relating to COVID-19 testing and personal protective equipment (PPE) gear. Moreover, the anxieties from the fear of contracting the virus during hospital visits leading to isolation and quarantine are real enough for some to even consider opting out of fertility preserving treatments whilst fighting their most basic desire to procreate. For healthcare providers, the novel challenges of providing safe and optimal care while dealing with the undefined risks remain.Nonetheless, where resources allow, with extra caution and strict adherence to the COVID-19 safety protocols and local guidelines, oncofertility is a feasible option, giving hope for young patients with cancer.Newly diagnosed eligible cancer patients should discuss before commencing treatment with their oncologist and oncofertility specialists the wish to have children to see if it is possible to safely balance this option without compromising their cancer care and further increase the risk of infections by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).Outline various fertility preservation procedures that can be undertaken safely with the precautions recommended by various national and international organizations including having protected pathways.For male patients, sperm banking before starting anticancer treatments is standard of care.For female patients, embryo/oocyte cryopreservation before starting anticancer treatments is the first option to be discussed .Ovarian tissue cryopreservation in patients that cannot wait 2-3 weeks before starting anticancer treatments can be discussed .Ovarian transposition can be considered before starting pelvic radiotherapy .Temporary ovarian suppression with luteinizing hormone-releasing hormone agonists (LHRHa) during chemotherapy is an available option to protect ovarian function during treatment .Detailed oncofertility counseling should clearly discuss the additional concerns during the COVID-19 outbreak whist defining all the established safety protocols in place to minimize these risks.Triage patients for SARS-CoV-2 testing in accordance with local guidelines before starting any of the ART procedures.Train additional members of the team on how to refill the liquid nitrogen tanks in case the lab staff is quarantined.If local resource allocation allows, consider having two teams working by rota. An alternate team can take over in case one team comes in contact with an infected patient .The advances in oncofertility have given a lot of hope on preserving future fertility to cancer patients. Hence, we urge oncologists and fertility specialists to consider oncofertility counseling (which includes COVID-19-related safety concerns at this time) and work as a dedicated team to support young cancer patients optimizing their future fertility and reproductive health even during this pandemic. Let us not allow the COVID-19 outbreak to sidetrack us on this important issue.Tanya Buckshee Rohatgi has no conflicts of interest. Bhawna Sirohi has received honoraria from Bayer and Roche outside the submitted work . Matteo Lambertini acted as a consultant for Roche, and received honoraria from Theramex, Takeda, Roche, and Lilly outside the submitted work.No funding was received for this work."} +{"text": "Salmonella (NTS) enterica subspecies enterica is associated primarily with a self-limiting diarrhoeal illness, invasive bacterial infections were also reported. Human outbreaks of NTS were reported in several countries all over the world including developing as well as high-income countries. Conventional laboratory methods such as pulsed field gel electrophoresis (PFGE) do not display adequate discrimination and have their limitations in epidemiological surveillance. It is therefore very crucial to use accurate, reliable and highly discriminative subtyping methods for epidemiological characterisation and outbreak investigation.Salmonellosis is one of the most common foodborne diseases worldwide. Although human infection by non-typhoidal Salmonella Typhimurium and Salmonella Dublin that occurred in 2013 in UK and Ireland respectively.Here, we used different whole genome sequence (WGS)-based subtyping methods for retrospective investigation of two different outbreaks of Salmonella Typhimurium genomes revealed well supported clades, that were concordant with epidemiologically defined outbreak and confirmed the source of outbreak is due to consumption of contaminated mayonnaise. SNP-analyses of Salmonella Dublin genomes confirmed the outbreak however the source of infection could not be determined. The core genome multilocus sequence typing (cgMLST) was discriminatory and separated the outbreak strains of Salmonella Dublin from the non-outbreak strains that were concordant with the epidemiological data however cgMLST could neither discriminate between the outbreak and non-outbreak strains of Salmonella Typhimurium nor confirm that contaminated mayonnaise is the source of infection, On the other hand, other WGS-based subtyping methods including multilocus sequence typing (MLST), ribosomal MLST (rMLST), whole genome MLST (wgMLST), clustered regularly interspaced short palindromic repeats (CRISPRs), prophage sequence profiling, antibiotic resistance profile and plasmid typing methods were less discriminatory and could not confirm the source of the outbreak.Single nucleotide polymorphism (SNP)-based cluster analysis of Foodborne salmonellosis is an important concern for public health therefore, it is crucial to use accurate, reliable and highly discriminative subtyping methods for epidemiological surveillance and outbreak investigation. In this study, we showed that SNP-based analyses do not only have the ability to confirm the occurrence of the outbreak but also to provide definitive evidence of the source of the outbreak in real-time. Salmonella enterica, which includes more than 2600 serovars [Salmonella infections are classically divided into diseases caused by typhoidal or non-typhoidal salmonella (NTS). Typhoid fever is caused by the human restricted Salmonella enterica serovars Typhi and Paratyphi [Salmonella (NTS) serovars, predominantly cause a self-limiting diarrhoeal illness they have adapted to cause invasive extra-intestinal disease known as invasive NTS (iNTS) which can result in bacteraemia and focal systemic infections [Salmonella serovars responsible for typhoid fever kill over 250,000 humans per year [Salmonella (NTS) serovars responsible for diarrhoeal illness cause over 155,000 deaths annually [Salmonella Typhimurium and Salmonella Dublin have been associated with systemic illness [Salmonella Typhimurium and Salmonella Dublin were reported in developed countries [Foodborne salmonellosis is an important concern for public health. It is caused by the enteric pathogen serovars . Human Sfections , 4 . Thefections moreoverper year while noannually . Interesannually . Salmoneountries \u201311.Salmonella enterica and have their limitations in epidemiological surveillance, it is therefore crucial to use accurate, reliable and highly discriminative subtyping methods for epidemiological characterisation and outbreak investigation.Conventional laboratory methods such as pulsed field gel electrophoresis (PFGE) do not usually provide adequate discrimination among outbreak and non-outbreak strains of Salmonella Typhimurium and Salmonella Dublin that occurred in 2013 in UK and Ireland respectively [Here, we evaluate different whole genome sequence (WGS)-based subtyping methods (including single nucleotide polymorphism (SNP)-based cluster analysis, multilocus sequence typing (MLST), ribosomal MLST (rMLST), whole genome MLST (wgMLST), core genome MLST (cgMLST) as well as clustered regularly interspaced short palindromic repeats (CRISPRs), prophage sequence profiling, antibiotic resistance profile and plasmid typing) for retrospective investigation of two outbreaks of ectively , 12.Salmonella Dublin that occurred in 2013 in Ireland [Salmonella Typhimurium occurred in 2013 in UK [Salmonella Typhimurium and Salmonella Dublin respectively. Non-outbreak strains were also included for comparison. Details of all Salmonella Dublin and Salmonella Typhimurium isolates analysed in this study are provided in supplementary Tables We carried out retrospective investigation of a human outbreak of Ireland and anot13 in UK . We inclSalmonella Dublin [Salmonella Dublin were indistinguishable by PFGE. Although multiple loci VNTR analysis (MLVA) was of value in discriminating the outbreak strains from an epidemiologically unrelated isolate in 2013 it was not able to provide a conclusive link between the outbreak strain and a historical isolate from 2011 (11F310) since all outbreak strains had the same MLVA pattern (3-6-1-10-2-3-12) and the historical isolate had similar MLVA pattern (3\u20136\u20131-10-2-3-11/12).PFGE was of a limited value for the investigation of the outbreak of a Dublin since alSalmonella Typhimurium [Despite the technical limitation of phage typing, it was of value for investigating the outbreak of himurium and confdenovo assembly for the raw Fastq paired end (PE) reads for all Salmonella Dublin and Salmonella Typhimurium strains using two different assemblers including Velvet available at Centre for genomic epidemiology (CGE) (http://www.genomicepidemiology.org/) and SPAdes available at Enterobase (http://enterobase.warwick.ac.uk/). We then assessed the quality of the assembly for each strain was assessed using Quast assessment tool (http://quast.bioinf.spbau.ru/).We carried out https://cge.cbs.dtu.dk/services/CSIPhylogeny/) where raw reads were mapped to reference sequences using BWA software (http://bio-bwa.sourceforge.net). The depth at each mapped position was calculated using genomeCoverageBed, which is part of BEDTools (https://bedtools.readthedocs.io/en/latest/). High quality SNPs were called using mpileup which is part of SAMTools (http://samtools.sourceforge.net). Genome mappings were then compared and an alignment of the SNPs are then created by concatenating the SNPs. A maximum likelihood (ML) phylogenetic tree was then created based on the concatenated alignment of the high quality SNPs.SNP analysis was carried out using CSIPhylogeny (http://enterobase.warwick.ac.uk/) and CGE (http://www.genomicepidemiology.org/).The assembled sequences of each strain were analyzed to detect the MLST, rMLST, cgMLST and wgMLST available at Enetrobase .Prophages were determined with the draft genomes generated by Velevt and SPAdes for all http://www.genomicepidemiology.org/) to construct a phylogenetic tree based on the SNPs of detected prophages. Phylogenetic trees were constructed using assembled genomes generated by Velvet and SPAdes assemblers to check if the assembly could affect the tree.We then used CSI phylogeny available at CGE .Spacers sequence within the draft genomes of all Salmonella Dublin and Salmonella Typhimurium strains using the plasmid database; PLSDB (https://ccb-microbe.cs.uni-saarland.de/plsdb/).We determined the plasmids within the draft genomes of all Salmonella Dublin and Salmonella Typhimurium strains using ResFinder (https://cge.cbs.dtu.dk/services/ResFinder/).We determined acquired antibiotic resistance genes and mutations within the draft genomes of all Salmonella Typhimurium were grouped together in two clades and they are very closely related to strains isolated from mayonnaise . Interestingly, outbreak isolates of Salmonella Dublin displayed identical rMLST (type 1429) however, some of the non-outbreak strains showed the same rMLST. Moreover, the wgMLST was different among the outbreak strains however, the cgMLST was unique among outbreak strains and can easily separate the outbreak strain from the non-outbreak strains including the 2011 historical isolate (11F310).As illustrated in Table\u00a0Salmonella Typhimurium as illustrated in Table\u00a0On the other hand, MLST, rMLST, cgMLST and wgMLST could not discriminate between the outbreak and non-outbreak strains of Salmonella Dublin isolates including outbreak and non-outbreak strains harbour one CRISPR locus and we observed 3 to 5 unique spacers for CRISPR1 locus. Identical spacers were detected among the outbreak and non-outbreak strains as shown in Table All Interestingly, the number of spacers in three isolates changed from (4 spacers) based on Velvet to (5 spacers) based on SPAdes.Salmonella Typhimurium isolates harbour 3 CRISPR loci. Identical spacers were detected among the outbreak and non-outbreak strains as shown in Table All Salmonella Dublin strains including the outbreak strains are lysogenic for three prophages . However, phylogenetic analyses of Salmonella Dublin strains based on the SNPs of prophages showed that outbreak strains are intermixed with the non-outbreak strains based on velvet assembler and the Edwardsiella specific phage (GF-2).All Salmonella Typhimurium genomes assembled by Velvet were lysogenic for two Salmonella specific prophages (Gifsy 2 and RE-2010). All strains except one outbreak isolate (H132940750) harbour Salmonella 118970_sal3 phage.On the other hand, Interestingly, all strains harbour Edwardsiella GF-2 prophage except three outbreak isolates .Salmonella Typhimurium strains based on the SNPs of prophages showed that outbreak strains are intermixed with the non-outbreak strains using velvet assembler as shown in Table\u00a0All outbreak and non-outbreak strains of Same plasmids were determined using Velvet and SPAdes assemblers.Salmonella Typhimurium harbour 3 plasmids except the outbreak strain H133300609 which did not carry plasmid pATCC14028 but it harbours a different plasmid (pSLT_VNP20009) instead -Iaa gene. No mutations were detected against gyrA and parC genes in all isolates except one isolate (MF038630) that carried a non-synonyms mutation within the gyrase protein and it is associated with bacterial resistance to nalidixic acid -Iaa gene\u201d. No known mutations were detected against gyrA and parC -based cluster analysis of Salmonella Typhimurium strains. However, cgMLST defined the genetic relatedness among Salmonella Dublin isolates more precisely and confirmed there is no relation among the 2013 outbreak isolates and the 2011 historical isolate (11F310) of Salmonella Dublin.On the other the WGS-subtyping methods including MLST, rMLST, wgMLST, cgMLST showed limited discrimination for the outbreak and non-outbreak isolates of It was reported that MLST might not be the most suitable epidemiological tool but it iThe cgMLST bridges the classic MLST with the novel WGS-based approach since it combines the discriminatory power of MLST with large-scale data obtained from WGS enabling to exploit a considerable number of gene targets throughout the bacterial genome which would maximize the quality and resolution for surveillance and research works.Salmonella Enteritidis in Europe [A recent study showed that cgMLST has shown the robustness of cgMLST as a tool to investigate multi-country outbreak of n Europe .Escherichia coli (VTEC) O157:H7 in Canada showed that wgMLST provided higher discrimination than PFGE and MLVA [The difference between the cgMLST and wgMLST is that unlike cgMLST, wgMLST indexes the variation of pre-defined set of genes from both core and accessory genes . Anotherand MLVA .Salmonella Dublin isolates of outbreak group from the non-outbreak group. However, both cgMLST and wgMLST were unsuccessful in differentiating outbreak-related Salmonella Typhimurium isolates from outbreak-unrelated isolates.Research studies have shown that cgMLST and wgMLST are viable typing methods for outbreak surveillance. In our study, cgMLST proved to provide higher discriminatory resolution for differentiating Salmonella serovars [Salmonella subtyping is the sensitivity and accuracy of the assembly as some prophage regions might be lost during assembly. We used two different denovo assemblers (SPAdes and Velvet) and found that prophage sequence profiling could not differentiate between the outbreak and non-outbreak isolates.Bacterial genome comprises a considerable amount (10 to 20%) of prophages integrated in their core genome . Prophagserovars . HoweverSalmonella outbreaks [Salmonella enetrica outbreaks as we showed in our previous studies [Salmonella serovars.Recent studies have suggested that high throughput CRISPR typing has the potential to be used for epidemiological surveillance and investigation of utbreaks , 27. How studies , 29 howePlasmid profiles and antimicrobial- susceptibility profiling have been used as an epidemiological tool since many decades. However, it was reported that analysis of plasmid profiles provided higher discrimination in the outbreak investigations than analysis of antimicrobial-susceptibility pattern , 31. In In this study, we compared several retrospective WGS-based subtyping methods and we showed that SNP-based cluster analysis is superior to other subtying methods to define the source of outbreak in real-time.In conclusion, foodborne salmonellosis is an important concern for public health therefore, it is crucial to use accurate, reliable and highly discriminative subtyping methods for epidemiological surveillance and outbreak investigation. The rapid development of next-generation sequencing (NGS) technology and bioinformatics tools have enabled WGS of any bacterial strain feasible. Various typing tools have been proposed by using WGS data but currently, the adoption of WGS-based methods have proved to be difficult due to lack of standardization. There are many layers on obtaining WGS data and there is need of standardization from the type of sequencers used to the bioinformatics analysis. Therefore, the emerging genetic analysis techniques should be combined with conventional phenotypic and molecular methods for routine surveillance and outbreak investigation until the WGS-based methods can be fully exploited, improved and standardized.Additional file 1: Supplementary Table\u00a01. Details of Salmonella Dublin strains analysed in this study. Supplementary Table\u00a02. Details of Salmonella Typhimurium strains analysed in this study"} +{"text": "Dual-task gait performance is a marker of motor-cognitive interactions modulated by the frontal lobes. After a stroke, gait disturbances are more evident, particularly when concurrently completing a mental task and walking, an effect called high dual-task cost (DTC). Following a stroke, the potential association of high-DTC, integrity of the frontal lobes and cognitive functioning is unclear. This study screened 161 participants with stroke history from the Ontario Neurodegenerative Disease Research Initiative (ONDRI)-cerebrovascular disease cohort . Individuals scoring zero in the National Institute of Health Stroke Scale were analyzed (n=102). DTC was the percentage change in gait speed from the single to dual-task condition. Standardized normal-appearing white matter (NAWM) and grey matter (NAGM) volumes from superior, middle and inferior frontal lobe were compared between DTC quartiles using a multivariate model (MANOVA), with total frontal lobe volume as a covariate. Another model compared group performance across 5 adjusted cognitive domains . Univariate tests revealed that NAWM volume in the superior frontal lobe was significantly different across DTC quartiles. Contrast tests suggested that the first quartile had larger NAWM than the second and fourth. DTC quartiles also showed differences in attention and contrast tests indicated that the first quartile performed significantly better than second and fourth. DTC poststroke may be a proxy for structural integrity of superior frontal lobe regions and attention."} +{"text": "Microbacteriaceae from plants infested by plant-parasitic nematodes were obtained using Illumina technology. The sequence data will provide useful baseline information for the development of comparative genomics and systematics of Microbacteriaceae and facilitate understanding of molecular mechanisms involved in interactions between plants and nematode-associated bacterial complexes.Draft genome sequences of 28 strains of Microbacteriaceae from plants infested by plant-parasitic nematodes were obtained using Illumina technology. The sequence data will provide useful baseline information for the development of comparative genomics and systematics of Microbacteriaceae and facilitate understanding of molecular mechanisms involved in interactions between plants and nematode-associated bacterial complexes.Draft genome sequences of 28 strains of Microbacteriaceae (class Actinobacteria) inhabit various terrestrial and aquatic ecosystems and often occur in plants as endophytes and pathogens , 4. Alonragariae , 5\u20138.Microbacteriaceae were isolated from plant galls induced by different anguinids and from plant tissues affected by Aphelenchoides species (Corynebacterium agar (http://www.vkm.ru).Novel nematode-associated strains of species . The airium agar or Reasoium agar , 11 and For genome sequencing, DNA was extracted with a QIAamp DNA minikit from biomass grown in liquid peptone-yeast medium as described previously or usingDefault parameters were used for all software unless otherwise specified. The quality of the reads was checked with FastQC 0.11.8 . AdapterAdditional comparative phenotypic study of the sequenced strains, along with genome-wide analyses of phylogenetically closely related plant endophytes and pathogens, will facilitate understanding of their role in bacterial-nematode complexes, including mechanisms of molecular interactions between members of these complexes and plants.These whole-genome shotgun projects have been deposited in DDBJ/ENA/GenBank under the accession numbers listed in"} +{"text": "Despite some insurance plans now paying for home-based palliative care, recent reports have suggested that coverage for palliative care may be insufficient to expanding patient access to home-based palliative care. Research has yet to explore palliative care barriers from the perspective of palliative care-eligible patients and their caregivers. To identify patients and caregivers\u2019 perceived barriers to home-based palliative care and their recommendations for overcoming these barriers, we conducted a qualitative study using semi-structured individual interviews. Participants who were eligible for a randomized controlled trial of home-based palliative care were interviewed via telephone. Our interview protocol elicited participants\u2019 perspectives on home-based palliative care services; positive and negative aspects of the program explanation; and suggestions for improving messaging around home-based palliative care. Researchers used grounded theory to identify the themes within the transcripts. Two researchers independently coded the transcripts and then met to compare coding and reconciled discrepancies until 100% consensus was reached. Identified themes related to home-based palliative care referral barriers included reluctance to have home visits, timing, lack of palliative care knowledge, misconceptions of palliative care, and patients\u2019 self-perceived health condition . Themes related to recommendations for overcoming these barriers included preferring a palliative care referral from healthcare providers or from insurance company and clearer presentation of palliative care service. Findings reinforce the need for additional palliative care education among patients with serious illness and the importance of delivering the information from a trusted source."} +{"text": "Physical frailty is an age-related clinical syndrome that is related to adverse health outcomes, including cognitive impairment and dementia. Recent studies have shown structural neuroimaging correlates with frailty. However, most existing evidence relies on brain volumetric measures. Whether brain microstructure is associated with frailty and its spatial distribution have not been explored. In the Baltimore Longitudinal Study of Aging, we identified 776 cognitively normal participants aged 50 and older who had concurrent data on frailty and brain microstructure by diffusion tensor imaging (DTI), including mean diffusivity (MD) of gray matter and fractional anisotropy (FA) of white matter. We first identified neuroimaging markers that were associated with frailty score (0-5) and further examined their relationships with frailty status using multivariate linear regression. Models were adjusted for age, sex, race, years of education, and Apolipoprotein E e4 carrier status. DTI-based neuroimaging markers that were associated with frailty status were localized in the supplementary motor area of the frontal lobe, several subcortical regions , and body and splenium of corpus callosum. This study demonstrates for the first time that microstructure of both gray and white matter differs by frailty levels in cognitively normal older adults. Brain areas were not widespread, but mostly localized in gray matter subcortical motor areas and white matter corpus callosum. Whether changes in brain microstructure precede future frailty development warrants further investigation."} +{"text": "Sambucus nigra lectin-reactive) fibronectin in prediction of gestational diabetes mellitus (GDM).To evaluate the performance of first trimester maternal serum glycosylated . There was no difference in assay formats for adiponectin.There was no difference in maternal serum glycosylated fibronectin concentrations between women with consequent GDM and control women . Maternal serum fibronectin levels were significantly lower in GDM group , compared to the control group fibronectin and GDM. Meanwhile, this study provides information on the screening performance of glycosylated fibronectin in women with GDM. This study also evaluated glycosylated fibronectin levels in different BMI subgroups.According to our results, neither first trimester maternal serum glycosylated fibronectin nor serum fibronectin are effective in screening for GDM. Further larger studies in prospective settings are needed to evaluate first trimester glycosylated fibronectin as a screening method for GDM alone and in combination with other markers."} +{"text": "Central retinal artery occlusion (CRAO) represents one of the most devastating ophthalmic emergencies, since the inner two-thirds of the retina lose their blood supply. The acute obstruction of the central retinal artery is characterized by severe, sudden and unilateral painless visual loss and usually occurs secondary to an embolus of cardiovascular origin. A paradoxical thromboembolic event of the central retinal artery through patent foramen ovale is an exceptionally unusual clinical entity as well as a great diagnostic challenge since the source of initial thrombus formation requires extensive investigation. Herein, we aim to describe a patient with no significant comorbidities who experienced a paradoxical thromboembolic episode of central retinal artery associated with patent foramen ovale. Central retinal artery occlusion represents the ophthalmic analogue of ischemic stroke and is typically manifested with sudden, severe and painless loss of vision . HoweverCRAO is usually the result of an embolus, either of cardiac origin or dislodged from an unstable atherosclerotic plaque of carotid bifurcation. Subsequently, the most common risk factors for CRAO include carotid atherosclerosis, cardiac valvular disease and cardiac arrhythmias, mainly atrial fibrillation . CongeniThe most important and well-documented clinical manifestation of PFO is the cryptogenic ischemic stroke due to a paradoxical embolus. CRAO or branch retinal artery occlusion (BRAO) associated with PFO represents an unexpected site of systemic paradoxical embolism that requires high index of clinical suspicion and meticulous laboratory investigation in order to unravel the concealed initial source of thrombus generation .Herein, we aim to present a middle-aged male patient who experienced an episode of severe, painless and unilateral visual loss due to CRAO associated with PFO. We also discuss the clinical complexity of such a diagnosis as well as we briefly review the current literature regarding similar published case reports.A 62-year-old Caucasian male, with no previous ocular or neurological symptoms, experienced a sudden and painless loss of vision in the left eye while swimming. He had no significant past medical history apart from an episode of deep vein thrombosis of the left lower extremity four years ago, provoked by a non-displaced fracture of the tibia after a motor vehicle accident. He also reported a previous history of hospitalization due to an episode of acute left-sided loin pain associated with macroscopic haematuria at the age of\u00a060 years. Then the patient had been thoroughly investigated and no specific diagnosis of renal infarct of unknown origin had been made. Otherwise, he did not take any regular medication and he neither smoked tobacco nor drank alcohol.On initial examination, he was afebrile and his pulse rate was 82/min and regular. His blood pressure was 130/85 mmHg and there were no abnormalities to find in the cardiovascular or respiratory systems. No carotid or over the umbilicus bruits were audible and pedal pulses were palpable. Physical examination was otherwise normal apart from a clearly swollen left lower extremity accompanied with engorged superficial veins, hyperpigmentation and trophic skin changes. On palpation, there was no tenderness of his left calf muscles and no venous ulcerations were observed. As regards neurological examination it was also unremarkable including the muscle tone, reflexes, coordination and sensation as well as power, in all muscle groups.\u00a0Afterwards, the patient was immediately evaluated on the basis of fundoscopic examination that revealed left retinal whitening, macular edema and cotton-wool spots compatible with CRAO Figure . The aboOnce CRAO with sparing of cilioretinal artery diagnosis had been made, a meticulous investigation was performed in order to unwind the thread of this unanticipated thromboembolic event.Routine hematological and biochemical investigations were unremarkable barring the slightly elevated creatinine and urea levels, up to 1.6 mg/dL and 60 mg/dL respectively, but accordant with a prolonged history of chronic kidney disease stage III with GFR estimated at 46ml/min/1.73m2. Inflammatory markers (C- Reactive Protein and Erythrocyte Sedimentation Rate) and clotting parameters including d-dimers and fibrinogen levels were within normal values. Further investigation for autoimmune diseases, occult infectious conditions and thrombophilic disorders were also negative. More specifically, thrombophilia testing was performed including factor V Leiden, prothrombin gene mutation, antithrombin III, protein C and protein S, lupus anticoagulant screen as well as antinuclear antibodies, anti-dsDNA antibodies, anti-cardiolipin antibodies (ACA) and anti-beta 2 glycoprotein antibodies (anti-\u03b22GPI).Regarding radiological examination, a renal ultrasound confirmed the previously mentioned asymmetrical kidney size and showed a small as well as echogenic left kidney, consistent with the past history of renal infarction without apparent cause. Carotid Doppler ultrasound did not identify any extracranial vulnerable atherosclerotic plaque potentially at risk for disruption and thromboembolic ischemic retinal event. Similarly, abdominal aorta ultrasound imaging and ultrasonographic assessment of renal arteries did not depict any atherosclerotic lesions that could be possibly the source of the reported renal vaso-occlusive event.Venous ultrasound imaging unveiled no relapse of the previously recorded deep vein thrombosis although the diagnosis of post-thrombotic syndrome was made on the basis of post-thrombotic popliteal valve incompetence accompanied with significant reflex at the same level. Residual thrombi were also recognized mainly in the left popliteal vein and partially recanalization of both popliteal and gastrocnemius veins was described. Residual thrombi in left popliteal vein raised the question of whether a paradoxical embolus could explain not only the CRAO event but also the past embolic event in renal artery circulatory system.With the completion of these steps, a meticulous cardiologic examination was undertaken and included 48-hour Holter monitoring and transthoracic echocardiography followed by bubble contrast echocardiography testing. Holter monitoring results excluded the possibility that CRAO event could be correlated with an obscured supraventricular arrhythmia, predominantly an episode of paroxysmal and symptomless atrial fibrillation. Transthoracic echocardiography examination also eliminated the option that the embolic event originated from a cardiac valvular defect. Surprisingly, bubble contrast echocardiography testing revealed more than 25 saline microbubbles in the left atrium of the heart at the first three cardiac cycles while the patient was asked to perform a Valsava maneuver in a quarter of the population .The frequency and significance of PFO in association with ocular circulatory disturbances were evaluated in forty patients with acute arterial occlusions of the posterior bulb segment through transthoracic and transesophageal echocardiography by Steuber and colleagues . PFO wasCertainly, the emerging association between undiagnosed PFO and retinal artery occlusion has been predominantly reported in young patients. An example of this is the report of a 35-year-old man with branch retinal artery occlusion (BRAO) and concomitant PFO, which was firstly diagnosed during the evaluation of BRAO, by Chatziralli and colleagues . In a siHence, it could be conceivably argued that retinal artery occlusion in an otherwise healthy adult patient, should always consider the PFO as a differential that requires meticulous cardiologic examination. Despite the fact that transesophageal echocardiography (TEE) is a potentially useful and effective tool for detecting possible sources of retinal artery emboli , in our Patent foramen ovale (PFO) is a common congenital intracardiac defect that can cause right-to-left shunting under certain conditions and may predispose individuals to paradoxical embolic events from the venous to arterial district. Rarely, PFO has been correlated to central retinal artery occlusion and branch retinal artery occlusion with visual sequelae not only in young but also in advanced-aged patients at low atherosclerosis or cardioembolic risk, concomitant with a propensity for deep vein thrombosis."} +{"text": "Pharmacoresistance and adverse drug events designate a considerable group of patients with focal epilepsies that require alternative treatments such as neurosurgical intervention and neurostimulation. Electrical or magnetic stimulations of cortical brain areas for the treatment of pharmacoresistant focal epilepsies emerged from preclinical studies and experience through intraoperative neurophysiological monitoring in patients. Direct neurostimulation of seizure onset zones in neocortical brain areas may specifically affect neuronal networks involved in epileptiform activity without remarkable adverse influence on physiological cortical processing in immediate vicinity. Noninvasive low-frequency transcranial magnetic stimulation and cathodal transcranial direct current stimulation are suggested to be anticonvulsant; however, potential effects are ephemeral and require effect maintenance by ongoing stimulation. Invasive responsive neurostimulation, chronic subthreshold cortical stimulation, and epicranial cortical stimulation cover a broad range of different emerging technologies with intracranial and epicranial approaches that still have limited market access partly due to ongoing clinical development. Despite significant differences, the present bioelectronic technologies share common mode of actions with acute seizure termination by high-frequency stimulation and long-term depression induced by low-frequency magnetic or electrical stimulation or transcranial direct current stimulation. Epilepsies are characterized by unpredictable seizures and affect more than 70 million people worldwide Beghi . Focal sPharmacoresistance and TEAEs designate a considerable group of patients with focal epilepsies that requires alternative treatments such as neurosurgical intervention and neurostimulation. Whereas neurosurgical resection can only be applied to non-eloquent brain areas in a minority of patients that compared repetitive TMS with sham or placebo controls in the period from 2014 to 2018 as compared to the meta-analysis done in 2014 by the same group on a localized epileptic focus was significantly larger than in the sham patients (17%) (Xia and Storm LFS induces LTD by N-Methyl-D-aspartate (NMDA) receptor activation and the subsequent slight increase in CaNoninvasive cathodal tDCS is suggested to provoke transient and long-term effects on cortical excitability (Antal et al. Electrical or magnetic stimulations of cortical brain areas for the treatment of pharmacoresistant focal epilepsies emerged from preclinical studies and experience from intraoperative neurophysiological monitoring in patients Table . Noninva"} +{"text": "Oregon\u2019s Behavioral Health Initiative for Older Adults and People with Disabilities is entering its fifth year. This novel state-level Initiative seeks to better coordinate services and resources for older adults and people with disabilities who have behavioral health needs by assigning a Behavioral Health Specialist (BHS) for every 60,000 adults 65 + and embedding them within local service agencies around Oregon. BHS primary job functions include improving coordination and collaboration between local service agencies, providing complex case consultations (CCC), and delivering workforce development training and community education. Five years of data from Portland State University\u2019s Institute on Aging\u2019s ongoing evaluation of the Initiative suggests significant impact in terms of workforce development trainings, community education, and new community partnerships. Data are collected from BHS and Initiative stakeholders . Data collection tools include quarterly reports from the BHS, including a CCC reporting instrument; semi-structured interviews with stakeholders assessing Initiative involvement; and an electronic post-training survey (and two-month follow-up survey) for stakeholders attending BHS trainings. After five years, the evaluation appears to show the Initiative has delivered an abundance of innovative collaborations, workforce trainings, and educational opportunities aimed at better supporting the behavioral health of older Oregonians. It also highlights several persistent systemic barriers including a need for additional public funding of behavioral health, the challenges of accessing Medicare for behavioral health, and siloed agencies and organizations. Future evaluative efforts could explore adding outcomes-based assessments of the Initiative, including local-level quality improvement projects initiated by BHS within their communities."} +{"text": "Cytokine storms, defined by the dysregulated and excessive production of multiple pro-inflammatory cytokines, are closely associated with the pathology and mortality of several infectious diseases, including coronavirus disease 2019 (COVID-19). Effective therapies are urgently needed to block the development of cytokine storms to improve patient outcomes, but approaches that target individual cytokines may have limited effect due to the number of cytokines involved in this process. Dysfunctional macrophages appear to play an essential role in cytokine storm development, and therapeutic interventions that target these cells may be a more feasible approach than targeting specific cytokines. Nanomedicine-based therapeutics that target macrophages have recently been shown to reduce cytokine production in animal models of diseases that are associated with excessive proinflammatory responses. In this mini-review, we summarize important studies and discuss how macrophage-targeted nanomedicines can be employed to attenuate cytokine storms and their associated pathological effects to improve outcomes in patients with severe infections or other conditions associated with excessive pro-inflammatory responses. We also discuss engineering approaches that can improve nanocarriers targeting efficiency to macrophages, and key issues should be considered before initiating such studies. Circulating levels of pro-inflammatory cytokines correlate with the severity of many infections. Severe infections can result in uncontrolled immune responses accompanied by excessive release of pro-inflammatory cytokines, frequently referred to as a \u201ccytokine storm\u201d, that can be responsible for a significant degree of the pathology and mortality associated with severe infections Effective therapeutic strategies to prevent or suppress cytokine storms and attenuate their effects, or other conditions prone to this response, during severe infection do not yet exist Macrophages and related monocyte-lineage immune cells, which reside in most body tissues and play essential roles in regulating cytokine-mediated inflammatory responses and innate and adaptive immune reactions, are good potential targets for such strategies In this mini-review, we focus on the pathology of cytokine storms in severe infections, highlight the role of macrophage dysfunction in this process, and discuss nanomedicine-based therapies that could be used to target macrophage dysfunction to improve clinical outcomes in patients with severe acute infections.via chemotaxis in response to concentration gradients Many cytokines released during pro-inflammatory immune responses can activate specific leukocyte populations and target their recruitment to sites of inflammation e.g., CCL2 and CCL3) that promote local accumulation of other pro-inflammatory immune cells, including neutrophils, monocytes, and dendritic cells that can release more cytokines and reactive oxygen species to increase the severity of lung injury The term cytokine storm, first used in 1993 in reference to runaway inflammatory responses in graft-versus-host disease Most individuals are vulnerable to SARS-CoV-2 infection, but can exhibit a broad range of symptom severity, and several risk factors are associated with cytokine storm development, including age (> 60 years old), smoking, poor nutrition and pre-existing conditions that can affect immune responses, including obesity, diabetes, hypertension, cardiovascular and chronic lung disease, and cancer No specific therapeutic strategies have yet been developed to attenuate cytokine storm mediated pathology, despite the established link between cytokine storms and disease pathology and mortality.COVID-19 offers a compelling example of the effect of cytokine storms on pathology and mortality. The precise mechanisms responsible for the pathological changes observed in severe COVID-19 cases are not well understood, but several studies have reported that most patients with severe pathology have markedly elevated circulating levels of multiple pro-inflammatory cytokines, including IL-1, IL-6, IL-8, IL-21, TNF-\u03b1, and MCP-1 Macrophages are multifunctional and heterogeneous innate immune cells that reside in most tissues and play essential roles in innate immunity, the regulation of adaptive immunity, and pro-inflammatory responses to control the virulence and pathology of infectious diseases in vitro characterization studies Macrophages act as an initial defense against infection Macrophages can also display pathogen-derived proteolytic peptides on their type I and type II major histocompatibility complexes (MHCI and MHCII) to activate T lymphocytes that recognize these peptides and initiate a pathogen-specific adaptive immune response A rapid and well-coordinated innate immune response is the first line of defense against infection, but excessive immune responses can cause local and systemic tissue dysfunction and damage Figure 1) + macrophages containing SARS-CoV-2 nucleoprotein, which exhibit IL-6 up-regulation, have also been detected in the spleen and lymph node marginal sinuses of patients who died from COVID-19 Macrophage dysfunction can initiate uncontrolled cytokine release leading to the development of cytokine storms observed in many severe infectious diseases, including SARS and COVID-19 family Macrophage dysfunction also plays important roles in the pathology of other infections caused by viral and microbial pathogens, particularly when these infections progress to sepsis, due to overlap of monocyte/macrophage responses to these pathogens. Macrophages are normally activated in response to recognition of danger-associated stimuli produced upon recognition of various components of viral and bacterial pathogens (PAMPs) via therapies that exhibit macrophage-specific or -selective toxicity; (ii) inhibiting macrophage invasion to limit inflammatory responses at disease sites by blocking chemotactic monocyte surface receptors Both clinical and experimental findings strongly suggest that dysfunctional macrophages are a major source of inflammatory cytokines in severe infections, and thus therapeutic interventions that target these macrophages may prove beneficial in attenuating cytokine storms that contribute to the increased pathology and mortality of severe infections. Therapeutic approaches designed to manipulate macrophage responses using conventional drug delivery mechanisms have been studied in preclinical models of inflammatory diseases and cancer Table 1).Nanomedicine, the medical application of nanotechnology, has emerged as a powerful platform to resolve issues associated with conventional therapeutics, including bioavailability, tissue specificity, and toxicity in vitro studies indicate that some nanoparticles are also preferentially engulfed via clathrin- or caveolin-mediated endocytosis mechanisms via different approaches that add macrophage-specific molecules to their surfaces Nanoparticles employed for macrophage targeting approaches can vary markedly in their origin and composition, but macrophage uptake generally occurs through one of two distinct pathways: non-specific phagocytosis (passive targeting) regulated by nanoparticle physical properties, or receptor-mediated endocytosis (active targeting). Passive targeting is usually responsible for macrophage uptake of unmodified nanoparticles of medium size (10~300 nm diameter), which include most extracellular vehicles (EVs) and liposomes. These nanoparticles primarily accumulate at infection or inflammation sites as a result of phagocytosis and/or macropinocytosis by monocyte/macrophage-lineage cells that are abundantly present at these sites Figure 1). These studies used synthetic liposomes, FDA-approved nanocarriers composed of one or more lipid bilayers surrounding a hollow core that can contain therapeutic cargoes via disruption of the mitochondrial electron transport chain and cytosolic release of cytochrome C At least two studies have now examined the efficacy of nanoparticle-mediated drug delivery to transiently deplete macrophages to attenuate dysfunctional macrophage responses . EVs are natural nanoparticles (~50-500 nm) that facilitate cell-to-cell communication, and are readily engulfed by circulating monocytes and tissue resident macrophages following their infusion into mouse models of human disease ex vivo model in which perfused human lungs rejected for transplant were injured by E. coli exposure to induce severe bacterial pneumonia e.g., miR-21, miR-124) and proteins shuttled by MSC-EVs Other studies examined the potential of unmodified EVs with anti-inflammatory properties to suppress macrophage dysfunction e.g., solid-lipid, polymeric, or metallic nanoparticles) using this strategy have been developed for macrophage-targeted drug delivery in models of inflammatory and infectious diseases Functionalizing nanoparticle therapeutics with ligands or peptides that have high affinity for extracellular macrophage membrane factors can enhance their specific uptake to attenuate dysfunctional macrophage responses , which contain viral coat proteins but lack viral genetic material, have recently been considered as nanoparticle platforms for drug delivery, imaging, and vaccine approaches A growing body of evidence indicates the potential of macrophage-targeted nanomedicines to reduce excessive cytokine production during severe infection. We therefore believe that nanomedicine approaches designed to regulate macrophage-mediated inflammatory responses should receive greater consideration as alternative therapies for conditions where macrophage dysfunction has the potential to induce a cytokine storm and its associated pathological effects. To the best of our knowledge, studies have yet to examine the therapeutic potential of macrophage-targeted nanomedicines in animal models of COVID-19, the most recent disease where cytokine storms have been shown to play a central role in disease pathology and mortality. At minimum, we propose that EV and liposome studies should be performed using commercially available human ACE2 (hACE2) transgenic mice, which can serve as a model of human COVID-19 disease, to clarify whether nanomedicine-mediated macrophage depletion or attenuation of macrophage activation is beneficial in severe COVID-19 disease. Nanomedicine delivery approaches may also be useful to increase the targeted bioavailability or reduce potential side effects of anti-inflammatory small molecule drugs and antibody therapeutics currently under investigation for treatment of COVID-19 in clinical trials. It will be important to comprehensively evaluate the therapeutic effects of these and other potential nanomedicines using clinically relevant indicators, including, but not limited to, effects on survival, lung lesions, and cytokine profiles.e.g., at or immediately prior to the hyperinflammatory phase), to have a beneficial effect, since suppression of the innate immune response in the early phase virus infection is likely to be harmful. Since cytokine storm development can be highly dynamic during severe infections, serial evaluation using a well-designed cytokine panel is necessary to determine the most effective therapeutic period and the specific effects of an intervention. Combination therapies that employ both nanomedicines and conventional antiviral drug delivery may also provide synergistic beneficial effects. Finally, it is also necessary to address the potential for increased risk of immune disorders and bacterial infections that may be associated with any strategy to deplete macrophages or attenuate their activity. Even if data from animal models proven to be promising, additional preclinical studies are required to address biosafety, mechanisms of action, and optimal administration routes and doses. Clinical translation will also require the development of nanomedicine manufacturing approaches with standard processes and quality control early in these studies. The massive degree of collaboration now ongoing across diverse disciplines and industries, offers hope for an unprecedent rate of development for new therapies and therapeutics to combat severe infectious diseases such as COVID-19. We believe that novel nanomedicine approaches are a worthy target of such efforts.Some key issues should be considered before initiating such studies, however. Macrophage-targeted nanomedicines may need to be given at the correct stage of infection ("} +{"text": "Despite recommendations to include a distinct intervention phase in Adult Protective Services (APS), most APS programs close cases following investigation/substantiation phases without engaging in a defined intervention phase. This study implements and evaluates a novel APS service planning/intervention model in the state of Maine. Using an experimental efficacy trial design with stratified random sampling at the level of Maine APS offices, this study compares standard APS care with an enhanced/integrated APS intervention model involving \u201celder advocates\u201d. Advocates were trained in motivational interviewing, supported decision-making, teaming, restorative justice, and goal attainment scaling to develop capacity to work with both the older adult victim and perpetrator and to strengthen the family and social systems surrounding the victim-perpetrator dyad. This presentation will present results on the efficacy of this integrated APS/elder advocate model and discuss the challenges and successes in conducting elder abuse intervention research in collaboration with APS and APS clients. Part of a symposium sponsored by Abuse, Neglect and Exploitation of Elderly People Interest Group."} +{"text": "Unconventional oil and gas exploration generates an enormous quantity of wastewater, commonly referred to as flowback and produced water (FPW). Limited freshwater resources and stringent disposal regulations have provided impetus for FPW reuse. Organic and inorganic compounds released from the shale/brine formation, microbial activity, and residual chemicals added during hydraulic fracturing bestow a unique as well as temporally varying chemical composition to this wastewater. Studies indicate that many of the compounds found in FPW are amenable to biological degradation, indicating biological treatment may be a viable option for FPW processing and reuse. This review discusses commonly characterized contaminants and current knowledge on their biodegradability, including the enzymes and organisms involved. Further, a perspective on recent novel hybrid biological treatments and application of knowledge gained from omics studies in improving these treatments is explored. Technological advances have led to unprecedented growth in unconventional oil and gas extraction in the US over the last few decades . This enCurrent disposal methods mainly rely on reinjecting FPW into newly drilled wells or disposal into deep Underground Injection wells. Disposal into underground injection wells irreversibly removes water from the hydrological cycle and has raised concerns due to induced seismicity . AlternaAmong the 1,198 chemical compounds identified in FPW, only 14% have existing toxicity data and 24% can be detected through standard analytical methods . PresencThis review aims to summarize recent trends in biological treatment of FPW with an emphasis on organic contaminants and microbial groups involved in their degradation . We brie1, are fairly well-documented and generally involve gas chromatography paired with mass spectrometry (GC-MS), the methods developed for surface and groundwater have to be modified to account for the complex matrix in FPW using non-targeted Liquid Chromatography-Electrospray Ionization-Mass spectrometry (LC-ESI-MS) approaches, many of which provide semi-quantitative estimation of identified compounds , especially Benzene/Toluene/Ethyl Benzene/Xylenes (BTEX), are the most commonly analyzed hydrocarbons in FPW with concentrations varying from a few ormation . BTEX arormation . Microbiormation . However+) as the dominant cation, with calcium (Ca2+), magnesium (Mg2+), and potassium (K+) as minor cations, and chloride (Cl\u2013) as the major anion, along with small amounts of bicarbonate . Trace m (SO42-) . Though A meta-analysis of published data on biological treatment of oilfield wastewater found average COD removal in actual wastewaters to be about 74% when TDS was low . IncreasTreatment of a complex matrix like FPW should not only meet the requirements of the intended application but also be cost-effective. TDS greater than 40,000 mg/L leads to elevated desalination costs, thus, low TDS western brines are more likely to be treated and reused .Experiments simulating a PW spill on soil concluded that the high salt content of PW can disrupt soil structure and mobilize metal ions like copper, lead, aluminum and manganese during subsequent rainfall events . StudiesHF involves addition of several chemicals to water that regulate viscosity to perform various functions ranging from generating fissures to ensuring smooth flowback from the formation . Among aBiocides are added to prevent biofouling by sulfate-reducing bacteria during HF and to prevent growth of microbes that clog the pipelines during gas production . BiocideGA, a non-oxidizing, electrophilic biocide, inactivates bacteria by crosslinking amines present on bacterial membrane proteins . HypersaDBNPA is the second most commonly used biocide , howeverPseudomonas are frequently used amphiphilic biocides that have been found to persist in FPW . Benzalkudomonas , Thalassiabensis isolatedpduCDE) from dominant Firmicutes was predicted to be responsible for surfactant degradation under anaerobic conditions. In another study on PEG and PPG degradation under aerobic conditions in sediment-groundwater microcosms amended with PW mapped to Halanaerobium in PW samples and in laboratory experiments with an isolate, Halanaerobium congolense WG10.Non-ionic surfactants, including both unsubstituted polyglycols [Polyethylene glycol (PEG) and Polypropylene Glycol (PPG)] and substituted ethoxylates [Alkyl ethoxylates (AEOs) and Nonylphenol ethoxylates (NPEOs)], are employed as emulsifiers, corrosion inhibitors and crosslinkers in HF. These surfactants are generally present as a mixture of homologs and are identified by calculation of Kendrick mass defect from LC-MS data . A few r with PW , authorsin situ. Reaction with persulfate (added as a breaker in the fracturing fluid) and other abiotic processes were implicated in the production of these halogenated organic compounds, along with biotic transformation by iodide-oxidizing bacteria, specifically Roseovarius spp. HF operations, those based on oilfield PW with comparable TDS have also been included. The reactor configurations and dominant microbial groups identified are summarized in Activated sludge (AS) systems are the most popular form of biological reactor for wastewater treatment around the globe. A typical AS system consists of an aerated tank for mixing microbial biomass with wastewater, followed by a settling/sedimentation unit to separate biomass (sludge) from treated water. Such systems are operated in continuous flow conditions and a portion of the settled sludge is often recycled back into the aeration tank. A sequencing batch reactor (SBR) consists of a single tank to perform all the steps of an activated sludge and hence is operated in a batch mode. Both these approaches have been used to treat FPW, and a few studies have investigated the microbes found in these systems.Pseudomonas, Ochrobactrum, Corynebacterium and Burkholderia were major bacterial groups identified from the reactor sludge using a Biolog MicrologTM System.Cellvibrionaceae, Rhodocyclaceae, Rhodobacteraceae, and Phyllobacteriaceae were some dominant groups that were found to be enriched at a TDS of 50,000 mg/L.A typical membrane bioreactor (MBR) consists of an aerated tank containing sludge fed with wastewater and a submerged membrane module to filter out the treated effluent. In high salinity wastewater like PW where bacterial floc formation is disrupted, MBRs can overcome the floc settling requirement and retain the biomass in the reactor.A lab-scale MBR was acclimated to high salinity in phases using PW from different wells to investigate impact of salinity on the microbial community . Upon inIdiomarina genus and Rhodospirillaceae family in Sample A1/2 and B, respectively.Emulating the naturally occurring stratified microbial consortia (or mats) often found in hypersaline environments, engineered microbial mats have been grown and evaluated for PW treatment in the laboratory. Biological treatability of PW samples from Utica and Bakken shale was also studied using microbial mats . These sBiologically active filters (BAF) employ microbial biofilms attached to a filter media (most commonly activated carbon) to adsorb and degrade organic compounds in wastewater along with removal of suspended solids. BAF successfully removed organic matter from three different wastewaters with varying salinity and organic composition (DOC: 35.6\u2013732 mg/L) as a pretreatment to ultrafiltration and nanofiltration . This BAFlavobacteria (predominantly genus Fluviicola) and Gammaproteobacteria) over non-aerated filters .The scalability of BAF was tested using bench-scale and lab-scale columns fed with different wastewaters under different operating conditions like aeration, pretreatment, operating temperature and empty bed contact time . AeratioBioelectrochemical systems (BES) can simultaneously achieve reduction in organic carbon and salinity, making them a promising technology, and an advancement over other biological systems to treat PW. BES harness the microbial capacity to degrade organic compounds anaerobically to generate electrons. These electrons can then be transported, via a pair of electrodes (anode to cathode), to terminal electron acceptors like oxygen or the system can be maintained anaerobic to produce hydrogen.Several configurations of BES have been tested to treat PW. Microbial Fuel Cell (MFC) is the simplest design consisting of two electrodes separated by an ion-exchange membrane in which the wastewater to be treated is added to the anode. Microbial Desalination Cell (MDC) is a modification of MFC with a pair of ion exchange membranes between anode and cathode resulting in three chambers. Microbial Capacitive Desalination Cell (MCDC), like MDC, has three chambers but the middle chamber contains electrodes for Capacitive Deionization. These electrodes have a large surface area that adsorbs organic and inorganic ions under applied electrical potential . On the MCDC desalinated 18 times faster than MDC and 5 times faster in COD removal during treatment of Piceance basin PW . A literHalanaerobium prevalens and Marinobacter hydrocarbonoclasticus, both originating from the PW (Cyanobacterium aponinum and Parachlorella kessleri) with halophilic bacteria could grow in PW over a wide range of salinities and the harvested algal biomass was suitable for biodiesel production. Researchers are now looking beyond traditional methods to treat FPW. l value) . HopkinsThough biological treatment of FPW is promising and can be initiated with a readily available inoculum , most reactors need lengthy acclimation periods which may not be practical for a field-operating full-scale reactor. Reactor parameters such as temperature, mixing/oxygenation and retention time will affect both reactor performance and community composition. Faster, more effective strategies are needed to achieve a consortium that can both tolerate the varying inorganic and organic composition of FPW and efficiently remove chemically diverse contaminants. Biological processes also have the potential to create new potentially harmful contaminants, e.g., iodinated organic compounds detected in the effluent of a BAF attributed to the activity of iodide-oxidizing bacteria . Thus, iRoseovarius was shown to be capable of leaching gold from its ore in the presence of iodide, in a process more ecofriendly than traditional cyanide leaching , particularly the dominant phosphate-accumulating organism is (CAP) . In factis (CAP) . That stis (CAP) .Another application of metagenomics and metatranscriptomics to wastewater treatment involved studies of reactors degrading terephthalate, a plastics byproduct, where a preliminary multi-organism pathway postulated based on early metagenome sequencing efforts was later expanded upon with a complex network of cross-feeding relationships that highlights the multilayered nature of these systems . FinallyHalanaerobium and methanogenic archaea during later PW, when anoxic conditions develop and TDS rises , were described based on their genomes, which in turn explained the changes in key metabolites observed in the samples collected. Viral predation of these major groups was also implicated in community dynamics and nutrient cycling. Further research revealed the viral (phage) diversity in shales and phage-induced lysis of dominant Halanaerobium was shown to release intracellular metabolites that support microbes in such ecosystems have further shed light on microbes that reside in shale with the help of metagenomics and metabolite profiling combined with supporting laboratory experiments. osystems . As a byaerobium , Frackibkibacter , Marinobnobacter , Methanolophilus , and Arccobacter \u2013 have bin silico tests. Thorough molecular characterization of bioreactor communities with varying performance combined with machine learning could identify biomarkers of successful treatment and potentially enable current monitoring strategies to be augmented or even replaced by molecular methods, allowing early warning of adverse events affecting reactor performance. Eventually, molecular methods will become a key part of a wastewater engineer\u2019s toolkit.On the other hand, there are few metagenomic studies on bioreactors optimized to treat FPW or even petroleum refinery wastewater. Molecular-level understanding of FPW treatment, however, is critical to successfully targeting multiple high-priority contaminants under a wide range of environmental conditions. Accurate, predictive models of FPW treatment bioreactors would dramatically accelerate optimization by replacing empirical manual parameter adjustments with rapid Treatment of FPW is challenging due to its complex chemical composition coupled with geographical and temporal variability. The low cost and effective treatment options offered by biological treatment systems in treating municipal wastewater have made them ubiquitous. Only in the past decade have we been able to understand core microbes and microbial processes behind treatment efficacy and resilience of these systems to shocks and overloads. Many studies have shown that FPW is amenable to biological treatment and different treatment modules to treat FPW have been discussed. Several studies indicate halophiles are effective for FPW treatment, but a systematic study to identify these halophiles during operation of a reactor and understand the key degradation pathways is not available. Omics guided study of core microbes should aid in constructing a core microbial community with broad metabolic potential to handle diverse contaminants and salinities as are common in FPW. Aided with optimized reactor design and robust microbial communities, a hybrid decentralized treatment module capable of handling fluctuations in composition as well as quantity of FPW could be a reality. Such a system could reduce the impacts of accidental release, promote a sustainable hydrological cycle and safeguard the environment.SA wrote the manuscript with inputs and edits from ST and RC. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "A 59-year-old man fell onto his outstretched hands. He was diagnosed with a left-sided transscaphoid transcapitate perilunate fracture-dislocation in the setting of previous scaphoid open reduction internal fixation (ORIF), resulting in a nonunion and scaphoid nonunion advanced collapse (SNAC). Wrist salvage in the form of primary partial wrist fusion was performed and resulted in excellent clinical and functional outcomes.What are perilunate dislocations and/or perilunate fracture-dislocations?What physical and radiologic examination findings are typically encountered with perilunate dislocations and fracture-dislocations?How are perilunate dislocations and fracture-dislocations managed?When a perilunate fracture-dislocation presents in the setting of previous scaphoid nonunion and SNAC wrist, what is the best surgical option to give the best functional outcome?Perilunate dislocations and fracture-dislocations are debilitating wrist injuries resulting from high-energy trauma. Dislocations can be purely ligamentous or involve a combination of bony and ligamentous structures. When involving only ligaments surrounding the lunate, these dislocations are referred to as lesser arc injuries. When the dislocation is associated with a radial styloid or carpal bone fractures, they are referred to as greater arc injuries.Physical examination often reveals a grossly swollen wrist with limited range of motion with or without signs of acute median neuropathy. The presence of acute carpal tunnel syndrome is an indication for urgent operative intervention if closed reduction has failed. Posteroanterior radiographic evaluation may demonstrate alteration of Gilula's lines with loss of carpal height . There m,Surgical correction involves acute carpal tunnel decompression, relocation of the carpus, repair of the capsular rent, and stabilization of the carpus with percutaneous pin fixation. Controversy exists whether acute scapholunate ligament reconstruction should be performed.4We present a case of a patient who suffered a transscaphoid transcapitate perilunate fracture-dislocation in the setting of a prior scaphoid nonunion and SNAC wrist. Radiographs revealed a greater arc injury with transmission of force through the previous scaphoid nonunion site, resulting in displacement of the cannulated screw from the proximal pole of the scaphoid and 2. S"} +{"text": "Understanding food web responses to global warming, and their consequences for conservation and management, requires knowledge on how responses vary both among and within species. Warming can reduce both species richness and biomass production. However, warming responses observed at different levels of biological organization may seem contradictory. For example, higher temperatures commonly lead to faster individual body growth but can decrease biomass production of fishes. Here we show that the key to resolve this contradiction is intraspecific variation, because (i) community dynamics emerge from interactions among individuals, and (ii) ecological interactions, physiological processes and warming effects often vary over life history. By combining insights from temperature-dependent dynamic models of simple food webs, observations over large temperature gradients and findings from short-term mesocosm and multi-decadal whole-ecosystem warming experiments, we resolve mechanisms by which warming waters can affect food webs via individual-level responses and review their empirical support. We identify a need for warming experiments on food webs manipulating population size structures to test these mechanisms. We stress that within-species variation in both body size, temperature responses and ecological interactions are key for accurate predictions and appropriate conservation efforts for fish production and food web function under a warming climate.This article is part of the theme issue \u2018Integrative research perspectives on marine conservation'. A key link in these feedbacks underlying observed warming responses is population size structure, because of how it arises from, as well as influences, individual body growth and survival figures\u00a0a and 2."} +{"text": "Complication in acute kidney injury (AKI) is significantly associated with developing acute respiratory failure (ARF), while ARF is one of the most important risks for AKI. These data suggest AKI and ARF may synergistically worsen the outcomes of critically ill patients and these organ injuries may not occur independently. Organ crosstalk between the kidney and the lung has been investigated by using animal models so far. This review will focus on innate immune response and neutrophil activation among the mechanisms that contribute to this organ crosstalk. AKI increased the blood level of an inflammatory mediator in high-mobility group box 1, which induces an innate immune reaction via toll-like receptor 4. The remarkable infiltration of neutrophils to the lung was observed in animal AKI models. IL-6 and IL-8 have been demonstrated to contribute to pulmonary neutrophil activation in AKI. In addition, the formation of a neutrophil extracellular trap was also observed in the lung after the exposure of renal ischemia reperfusion in the animal model. Further investigation is necessary to determine whether targeting innate immune response and neutrophil activation will be useful for developing new therapeutics that could improve multiple organ failure in critically ill patients. Acute kidney injury (AKI) is a common complication in critically ill patients treated in the intensive care unit (ICU). Reportedly, AKI occurs in ~30\u201360% of patients admitted to the ICU and is associated with significantly poor outcomes including morbidity and mortality . ICU patThough the primary roles are different, lung and kidney functions are intimately related regarding the maintenance of homeostasis. The blood acid-base balance is regulated by carboxy dioxide excretion by the lung and bicarbonate reabsorption by the kidney. A compensative mechanism will activate when one organ fails to keep these levels within a normal range by the other organ. Thus, respiratory complication in AKI patients is particularly important. Clinical studies revealed AKI patients were twice as likely to require invasive mechanical ventilation . On the In this review, we provide a brief overview regarding (1) the clinical data on AKI and ARF/ARDS and (2) the potential mechanisms by which AKI leads to lung injury. Recently identified mechanisms of the innate immune system including toll-like receptors (TLRs) and damage-associated molecular patterns (DAMPs) were evaluated in the kidney-lung crosstalk using animal models. Neutrophil extracellular traps (NETs) was identified as another player in the innate immune response. NETs were also demonstrated to contribute to AKI-induced lung injury.Many clinical studies suggested associations between AKI and ARF/ARDS in critically ill patients. AKI often occurs in ARF/ARDS patients, while ARF/ARDS is often observed in AKI patients. First, clinical data about AKI complication in ARF/ARDS are described below. The secondary analysis of a randomized control trial conducted by the ARDS network reported AKI occurred in ~25% of ARDS patients. The mortality rate of AKI patients was significantly higher than the non-AKI patients . AnotherSecond, ARF/ARDS complication in AKI is described below. Severe ARF requiring MV was observed in more than 70% of AKI patients in a multinational, multicenter prospective observational study. MV requirement was significantly associated with higher mortality . TherefoThird, AKI and ARF/ARDS are organ failures that can be simultaneously complicated in a critically ill patient. An observational study conducted in 18 French ICUs reported ARDS occurrence as 23%, while AKI occurrence was at 31%. Hospital mortality was 14% in this population and it increased to 42% in patients with both AKI and ARDS . In a laThe pathophysiological mechanisms of respiratory failure in patients with AKI can be categorized into inflammatory and non-inflammatory mechanisms . Non-infRabb and colleagues first demonstrated increased inflammatory gene expressions in the lung after exposure of renal ischemia reperfusion injury by using microarray analysis . Faubel Although these studies suggested that the induction of an inflammatory reaction by AKI is involved in lung injury, other studies demonstrated AKI suppressed inflammatory reactions and subsequently worsened pulmonary infection. Neutrophil function against pneumonia was evaluated in the model of bacterial pneumonia in mice complicated with AKI by folic acid administration or glycerol injection (rhabdomyolysis) . NeutropTaken together, increased humoral mediators by reduced clearance and increased expression in AKI seem to contribute to lung injury. On the other hand, few studies revealed the mechanisms of the opposite direction of crosstalk, i.e., ARF/ARDS-induced kidney injury. Slutsky et al. reportedNeutrophil infiltration is a major finding in lung injury induced by AKI. A remarkable neutrophil infiltration in the lung together with increased neutrophil elastase (NE) activity in blood and lung tissues were observed in a mouse AKI model and specific NE inhibitor reduced lung injury . Toll-liin vitro caused by hypoxia stimulated neutrophils to form NETs by extracellularly released histones. In a mouse intestinal ischemia-reperfusion model, extracellular histone accumulation and NETs formation were observed in the liver rather than the intestine , that comprise DNA studded with histones and proteases, including neutrophil elastases . Extracentestine . Extracentestine . Human r animals .These findings above suggest that extracellular histones and NETs formation might be responsible for AKI-induced lung injury, although other pathways of inflammatory mediators such as IL-6 also contribute to AKI-induced lung injury. For the development of new therapeutics against organ crosstalk between the kidney and lung, targeting multiple pathways will be necessary. In addition, extracellular histones and NETs formation have not been sufficiently evaluated in human ARDS and no cThe novel coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan in December 2019, which has spread around the world. SARS-CoV-2 dominantly affects the respiratory system and recent clinical studies reported AKI as a significant comorbidity in COVID-19 . The celMultiple organ failure frequently observed in critically ill patients was previously considered as the \u201csum\u201d of each organ failure. The sequential organ failure assessment (SOFA) score, which is widely used for evaluating the severity of ICU patients, is calculated by summing up each organ injury score. No consideration for organ crosstalk can be found in these scoring systems. Several clinical studies demonstrated possible organ crosstalk in ICU patients by applying network analysis , 35. As This review covers kidney-lung crosstalk mostly regarding lung injury caused by AKI. The opposite pathological mechanism in which ARF/ARDS causes AKI should also be considered. As described above, only a limited number of basic studies reported possible mechanisms in animal experiments. In clinical studies, ARF/ARDS caused a systemic release of pro-inflammatory mediators , which could induce or worsen AKI .Mechanical ventilation-induced lung injury has been investigated so far. Low tidal ventilation strategy against ARDS is recommended based on evidence obtained by both basic and clinical studies . Does MVAM, NH, and KD contributed to the writing of the manuscript and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Endometriosis, an estrogen-dependent inflammatory disease, is commonly observed in gynecologic practice. Spontaneous hemoperitoneum is a rare but serious complication of endometriosis. Most cases of endometriosis-induced hemoperitoneum are attributable to a ruptured endometrioma or utero-ovarian vessel hemorrhage. We report a case of massive hemoperitoneum secondary to intra-abdominal bleeding from the peritoneal endometriotic deposits with spontaneous abortion that was misdiagnosed as a ruptured ectopic pregnancy.A 36-year-old Korean woman was admitted to our hospital for acute abdominal pain and vaginal bleeding. She was suspected of ruptured ectopic pregnancy on the basis of a positive serum human chorionic gonadotropin test result and ultrasonographic evidence of pelvic fluid collection. During hospitalization, her symptoms deteriorated with peritoneal irritation sign on physical examination, hypotension, and tachycardia. Emergency exploratory laparoscopy was performed and revealed active bleeding from the peritoneal endometriotic deposit, which was treated with laparoscopic electrocoagulation. The patient\u2019s postoperative course was uneventful. Spontaneous abortion was diagnosed on the basis of decreased serial serum human chorionic gonadotropin level estimation.Although rare, gynecologists should consider endometriosis-induced hemoperitoneum with spontaneous abortion in the differential diagnosis in women of reproductive age presenting with a positive serum human chorionic gonadotropin test result and acute abdomen with intra-abdominal bleeding. Endometriosis is an estrogen-dependent inflammatory disease characterized by the deposition of endometrial tissue at extrauterine (ectopic) sites. It is a relatively common condition that mainly affects women of reproductive age . CurrentA 36-year-old gravida 1, para 1 Korean woman presented to our emergency department with a 1-day history of acute abdominal pain and vaginal bleeding. Her physical examination showed lower abdominal tenderness, and her speculum examination revealed a small amount of vaginal bleeding. Her menstrual cycle was regular at 30-day intervals, and her last menstrual period had been approximately 5\u2009weeks prior to presentation.Upon admission, her vital signs were stable . Her laboratory test results showed mild anemia with a serum hemoglobin level of 10.1\u2009g/dl and hematocrit of 29.0%. Her urine pregnancy and serum human chorionic gonadotropin (hCG) (1149 mIU/ml) tests showed positive results.Transvaginal ultrasonography revealed a large amount of complex fluid and material of mixed echogenicity compatible with blood and blood clots in the pelvic cavity. The bilateral ovaries were not well visualized by ultrasonography, and a normal gestational sac was not identified in the endometrial cavity.During her hospitalization, the patient developed pallor with dizziness, and physical examination showed positive peritoneal irritation signs along with hemodynamic instability , necessitating emergency exploratory laparoscopy.Laparoscopy revealed approximately 1800\u2009ml of fresh liquid and clotted blood in the abdominal cavity. After suctioning the blood, we explored the entire abdominal cavity to identify the source of bleeding. Continuous active bleeding was observed from the peritoneal wall of the pouch of Douglas. Excisional biopsy was performed at the site of bleeding, and bleeding was controlled using electrocoagulation . The gold standard for definitive diagnosis remains visual inspection via laparoscopy and histopathological examination of biopsy specimens .Our patient presented with vaginal bleeding and acute abdominal pain and had a positive serum hCG test result. Transvaginal ultrasonography revealed hemoperitoneum without a normal gestational sac in the endometrial cavity. Considering that she presented with a positive serum hCG test result and that her serum hCG level was less than the discriminatory level (3510 mIU/ml), we could not exclude the possibility of a normal intrauterine pregnancy despite the absence of an intrauterine gestational sac on transvaginal ultrasonography . TherefoSeveral complications related to endometriosis that most gynecologists can overlook have been reported. Endometriosis-related spontaneous hemoperitoneum in pregnancy causes increased maternal and fetal morbidity and mortality, and endometriosis-related ascites often cause a diagnostic dilemma due to symptoms similar to an ovarian malignancy \u20135. In adet al. reported a case of hemoperitoneum caused by active bleeding from a peritoneal endometriotic deposit on the pouch of Douglas. The patient presented with sudden onset of lower abdominal pain from day 5 of her menstrual cycle and showed a negative serum hCG test result [Acute abdomen and hemoperitoneum are rarely attributable to intra-abdominal bleeding from endometriotic deposits, and only a few cases have been reported previously in the literature. Togami t result . Mutihirt result .Our patient\u2019s case is similar to the two aforementioned cases in that endometriosis-induced hemorrhage occurred during progesterone withdrawal , 10. TheSeveral studies have reported differences in the incidence of abortion between women with and without endometriosis or the possibility of reducing the incidence of abortion in women treated for endometriosis; however, convincing clinical evidence is unavailable . EndometGynecologists should consider hemoperitoneum secondary to intra-abdominal bleeding from endometriotic deposits with spontaneous abortion, as well as ruptured ectopic pregnancy or intrauterine pregnancy with corpus luteal hemorrhage in women of reproductive age presenting with acute abdomen and hemoperitoneum and a positive serum hCG test result."} +{"text": "Widespread transmission of a novel coronavirus, COVID-19, has caused major public health and economic problems around the world. Significant mitigation efforts have been implemented to reduce the spread of COVID-19 but the role of ambient noise and elevated vocal effort on airborne transmission have not been widely reported. Elevated vocal effort has been shown to increase emission of potentially infectious respiratory droplets, which can remain airborne for up to several hours. Multiple confirmed clusters of COVID-19 transmission were associated with settings where elevated vocal effort is generally required for communication, often due to high ambient noise levels, including crowded bars and restaurants, meat packing facilities, and long-stay nursing homes. Clusters of COVID-19 transmission have been frequently reported in each of these settings. Therefore, analysis of COVID-19 transmission clusters in different settings should consider whether higher ambient noise levels, which are associated with increased vocal effort, may be a contributing factor in those settings. Mitigation strategies that include reduction of ambient noise, softer speech practices, and the use of technology such as microphones and speakers to decrease vocal effort will likely reduce the risk of transmitting COVID-19 or other airborne pathogens. They calculated a 0.37% probability that a 10-\u03bcm droplet contains at least one virion, which suggests that the risk of transmission is significantly increased during loud speech when large numbers of respiratory droplets are emitted. Several recent studies have characterized respiratory droplets emitted during different types of speech, which are potential vectors of viral particles. et al., of social distancing impacts on COVID-19 transmission found that closing restaurant dining rooms and bars and/or entertainment centers/gyms led to statistically significant reductions in COVID-19 cases (These findings have important implications for settings with increased ambient noise where elevated levels of vocal effort are required for communication . A recen19 cases . In theiOther settings have also been associated with increased transmission of COVID-19, and there appears to be a significant association between centers of outbreaks and areas of increased ambient noise and/or elevated vocal effort in most cases. Significant outbreaks of COVID-19 have been reported in senior living centers and nursing homes . These lSignificant levels of COVID-19 transmission have also been reported in meat packing plants (These studies reveal that high levels of vocal effort due to increased ambient noise could be an important factor in the airborne transmission of COVID-19 in settings where physical distancing is limited. Broad implementation of countermeasures to promote softer speech and reduce vocal effort could have a significant impact on decreasing emission of potentially infectious respiratory droplets. This has important implications for businesses, schools, and other venues that are implementing policies to reduce the risk of COVID-19 transmission in their facilities.There is substantial evidence that softer speech and decreased vocal effort may have an impact on reducing COVID-19 transmission. This suggests that settings with lower levels of ambient noise may have reduced risks of COVID-19 transmission. Strategies to reduce the risk of COVID-19 transmission may include community-based emphasis on approaches to decrease ambient noise exposures when feasible, combined with steps to promote softer speech practices and reduce vocal effort. Masks and face coverings can provide some protection by filtering infectious respiratory droplets in situations where vocal effort is required , but oth"} +{"text": "Medicare home health providers are required to offer family caregiver training; however, there is little information regarding the impact of family caregiver training on home health care intensity. A better understanding of this relationship is necessary to inform development and prioritization of caregiver training interventions in this setting. This research assesses whether and how family caregiver need for training affects care intensity during Medicare home health. We examine 1,217 fee-for-service Medicare beneficiaries who participated in the National Health and Aging Trends Study (NHATS) between 2011-2015 and received Medicare-funded home health care within one year of survey. Using propensity score adjusted, multivariable logistic and negative binomial regression, we model the relationship between family caregiver need for activity-specific training and the number/type of visits received during Medicare home health. We found that older adults whose family caregiver required training on self-care tasks had greater odds of receiving any therapy visits , aide visits , or training visits . Older adults whose family caregiver required training on medication management had greater odds of receiving any nursing visits and incurred 1.06 additional nursing visits. Findings support the importance of connecting family caregivers to training resources. Additionally, findings suggest that home health providers should consider prioritizing training interventions which focus on caregiving activities most closely tied to resource utilization: self-care and medication management."} +{"text": "Nonalcoholic fatty liver disease is a major global health concern with increasing prevalence, associated with obesity and metabolic syndrome. Recently, quantitative ultrasound-based imaging techniques have dramatically improved the ability of ultrasound to detect and quantify hepatic steatosis. These newer ultrasound techniques possess many inherent advantages similar to conventional ultrasound such as universal availability, real-time capability, and relatively low cost along with quantitative rather than a qualitative assessment of liver fat. In addition, quantitative ultrasound-based imaging techniques are less operator dependent than traditional ultrasound. Here we review several different emerging quantitative ultrasound-based approaches used for detection and quantification of hepatic steatosis in patients at risk for nonalcoholic fatty liver disease. We also briefly summarize other clinically available imaging modalities for evaluating hepatic steatosis such as MRI, CT, and serum analysis. Nonalcoholic fatty liver disease (NAFLD) is considered to be the hepatic manifestation of metabolic syndrome and is dramatically increasing in prevalence, paralleling the global obesity epidemic Early detection of NAFLD, continuous monitoring, and early therapeutic intervention, such as lifestyle modifications as well as treatment with pharmaceutical agents can improve overall patient outcomes and potentially decrease the economic burden on healthcare costs. Other patient subgroups such as those undergoing chemotherapy or bariatric surgery are at risk of development of fatty liver and may also benefit from monitoring of hepatic fat fraction. Non-targeted liver biopsy remains the gold standard for diagnosis and grading of hepatic steatosis, fibrosis, and inflammation Here, we summarize methods in grading of NAFLD, including non-imaging biomarkers and corresponding scoring systems currently in use for managing hepatic steatosis. We then provide a comprehensive review of imaging in liver fat quantification, focusing on innovative QUS approaches studied in human subjects Table . FinallySeveral non-imaging biomarkers such as electrical impedance tomography Conventional ultrasound is the most common imaging modality for subjective evaluation of hepatic steatosis, with good sensitivity and specificity in detecting moderate to severe levels of steatosis Several QUS techniques have been studied to improve the diagnosis and classification of hepatic steatosis in NAFLD. These include controlled attenuation parameter (CAP) measured by transient elastography (TE) device; attenuation (AC) and backscatter coefficients (BSC); computerized calculation of hepatorenal index (HRI); and ultrasound envelope statistic parametric imaging . Speckle statistics include acoustic structure quantification (ASQ) and Nakagami imaging; QUS spectroscopy; speed of sound (SoS); and shear wave elastography (SWE) metrics such as dispersion and viscosity. Emerging QUS techniques, integrating statistical methods most notably attenuation-based Nakagami imaging and backscatter-derived quantitative ultrasound spectroscopy show promise and could potentially become the noninvasive imaging method of choice in screening, grading, and monitoring NAFLD patients on therapy. These techniques compared to liver biopsy, could be implemented for screening purposes, compared to an ordinal scale, or provide an accurate continuous measurement of liver fat; the latter two would be most useful for the longitudinal follow-up of NAFLD patients to assess treatment response. Limitations of QUS techniques include confounding effects of body habitus and ascites. Further, QUS cannot simultaneously quantify fat in other organs as can be done with MRI based techniques. Finally, multiple simultaneously emerging QUS techniques from different vendors may prohibit widespread-buy in and may limit inter-vendor comparisons.Controlled attenuation parameter (CAP) is the best-studied and clinically available technique for liver fat quantification, with the first clinical studies dating back to 2010 volume, which is significantly larger than the region analyzed through a liver biopsy, decreasing the potential risk for sampling bias. Limitations of CAP include poorly standardized cut-off values in classifying hepatic steatosis and the potential for CAP estimation of hepatic steatosis to be affected by differences in skin-to-capsule ratio, which may also confound other fat quantification methods. Furthermore, although CAP is an ultrasound technique, measurements are obtained without visualization of the liver. Thus, blind estimation of liver fat may result in inadvertent inclusion of masses, vessels, ducts, or uneven steatosis, any of which may limit accurate assessment. As such, there is a need for QUS parameters to be associated with radiological ultrasound machines to overcome these challenges.Measuring CAP has multiple advantages, including simultaneous assessment of hepatic steatosis and fibrosis, which is valuable in predicting progression and treatment strategies in NAFLD. Measurement of CAP is typically performed by a hepatologist in an office setting in less than five minutes. Values are obtained from a 3 Acoustic waves are attenuated differently by steatotic versus normal liver parenchyma, and this difference is quantified in AC measurements. Unlike CAP, AC values are obtained from ultrasound systems Figure . AttenuaBackscatter coefficient (BSC) is another widely studied QUS parameter first described in 1973 In conventional ultrasound, the diagnosis of hepatic steatosis is typically made by comparing the echogenicity of the liver and right kidney in the same image. Multiple factors affect this comparison, including variations in machine parameters such as gain/depth/power, time-gain- compensation settings and patient anatomy such as attenuation caused by rib shadow or subcutaneous fat, etc. These variations can result in variability of results Prior studies have shown an excellent correlation between HRI and fat fraction obtained through MRS Ultrasound-based envelope statistical imaging, also known as speckle statistics, is based on the passive parametrization of ultrasonic speckle patterns using established statistical distributions/models, which in turn relate to the structural and acoustic properties of tissues (scatterer density and size) Nakagami imaging is one of the most popular model-based speckle statistic methods, first introduced in 2000 . Only a few animal studies have explored the utility of spectroscopy techniques in evaluating fatty liver and demonstrated the potential of spectroscopy parameters to detect and characterize steatosis Quantitative ultrasound spectroscopy uses frequency-dependent parameters extracted from raw RF ultrasound data related to characterize tissue microstructures 82Speed of sound (SoS) measurement is a QUS parameter used for evaluating hepatic steatosis, and can be used to characterize tissue properties based on alterations in ultrasound echo wave speeds in various media Transient elastography and SWE are ultrasound-based elastography methods that measure liver stiffness, which have been successfully adopted clinically to detect and classify hepatic fibrosis Hepatic fat fraction estimated by MRS has proven to be an accurate substitute for liver biopsy and noninvasive imaging standard reference for liver fat quantification The MRI-PDFF is a newer method to estimate liver fat utilizing chemical-shift imaging (CSI) in a single breath-hold. Water protons precess faster than fat protons by about 3.5 parts per million (ppm) Hepatic steatosis can be detected with unenhanced and contrast-enhanced computed tomography (CT) when absolute attenuation of the liver is \u2264 40 Hounsfield units (HU), especially when hepatic fat is > 30% In conclusion, nonalcoholic fatty liver disease is a major health issue with a worldwide increase in prevalence, paralleling the global obesity epidemic. Accurate noninvasive alternatives to liver biopsy in evaluating and monitoring levels of hepatic steatosis are have evolved significantly in the past decade. Emerging quantitative ultrasound-based approaches, integrating innovative statistical methods are promising new technologies to non-invasively assess hepatic steatosis."} +{"text": "An 85-year-old man with cardiac history notable for atrial fibrillation diagnosed 10 years ago which was being treated with atenolol and warfarin presented to our institution with persistent atrial fibrillation. His echocardiogram showed ejection fraction (EF) of 56%, no regional wall motion abnormalities, mild mitral and pulmonary regurgitation, and trivial tricuspid regurgitation. Despite this treatment, he had recurrent episodes of paroxysmal symptomatic atrial fibrillation with a rapid rate requiring multiple emergency department visits and hospital admissions. Given difficulty to control the rate, he underwent atrioventricular (AV) nodal ablation and leadless pacemaker insertion. Fifteen days after the procedure, he was found to have a severe mitral regurgitation murmur. Leadless pacemakers have been shown to have lesser risk of complications such as pocket infections, endocarditis, pacemaker-induced tricuspid regurgitation, and tamponade. However, this newer technology can lead to significant mitral regurgitation due to iatrogenic LBBB and left ventricular (LV) dyssynchrony.An 85-year-old man presented to our institution complaining of recurrent fever and a mitral regurgitation murmur. He has a past history significant for atrial fibrillation being treated with apixaban status post leadless pacemaker implantation and AV nodal ablation 15 days ago, hypertension, hyperlipidemia, obstructive sleep apnea on continuous positive airway pressure, diverticulosis and diverticulitis, dental caries, melanoma in situ, and persistent pulmonary coccidioidomycosis on fluconazole.He underwent a transthoracic echocardiogram which showed normal left ventricular size and no wall motion abnormalities, LVEF of 56%, severe mitral regurgitation due to incomplete coaptation of the mitral valve leaflets Figures , mild riHis cardiac history is notable for atrial fibrillation diagnosed 10 years ago which was treated with atenolol and warfarin. Despite this treatment, he had recurrent episodes of paroxysmal symptomatic atrial fibrillation with a rapid rate requiring multiple emergency department visits and hospital admissions . Given dGiven the absence of degenerative mitral valve abnormality and no evidence of cardiomyopathy, his diagnosis of new-onset severe mitral regurgitation is the direct result of abnormal electrical conduction related to iatrogenic LBBB due to AV nodal ablation and single-chamber paced rhythm.Mitral regurgitation in majority of cases is related to primary mitral valve diseases such as mitral valve prolapse, endocarditis, or rheumatic heart disease which was not the case in our patient . Mitral In conclusion, given the prior absence of mitral valve abnormality and cardiomyopathy, this diagnosis of new-onset severe mitral regurgitation is the direct result of abnormal electrical conduction related to iatrogenic LBBB due to A"} +{"text": "Arterial stiffness assessed by arterial tonometry \u2013 in particular pulse wave velocity and augmentation index \u2013 is associated with increased cardiovascular risk. It is now possible to use cardiovascular magnetic resonance imaging (CMR) for direct imaging of aortic function. This provides a precise assessment of the elastic properties of the aorta within distinct regions of the aorta. We therefore studied what parameters of aortic function are related to arterial tonometry-derived indices of arterial stiffness.We compared aortic stiffness assessed by cardiovascular magnetic resonance (CMR) pulse wave velocity (PWV) based on flow, velocity or acceleration, and aortic distensibility (AD)) to widely used arterial stiffness estimates provided by arterial tonometry (pulse wave velocity (PWVS) and pulse wave analysis (AI)).Thirty young healthy volunteers (aged 23\u201333) underwent tonometry (Sphygmacor) for determination of carotid to femoral PWVS and radial pulse wave analysis for AI estimation. They then underwent CMR to assess aortic elastic properties.Aortic distensibility was assessed from breath-hold ECG-gated, steady state free precession (SSFP) images acquired at the level of the right pulmonary artery through the ascending and proximal descending aorta and through the distal aorta below the diaphragm to determine aortic distensability. Distensibility was calculated as the relative change in area divided by the central pulse pressure.Pulse wave velocity was measured by an ECG-gated, free breathing, spoiled gradient echo phase-encoded acquisition at the same locations as the aortic cine images. Three variations of the transit time method were used for calculation of pulse wave velocity (PWV). Arrival of the pulse wave was defined as a) the foot of the curve of mean blood velocity of the blood during the cardiac cycle b) the foot of the curve of total blood flow during the cardiac cycle c) maximum blood acceleration rate during the cardiac cycle Figure but withAortic pulse wave velocity calculated by all three MR methods yielded an inverse correlation with descending aortic distensibility Figure but PWVSPWVS and AI most closely reflect acceleration-based CMR PWV measurements of overall aortic stiffness. Arterial tonometry has been validated in large scale clinical studies suggesting this CMR method may be most useful for interpretation of clinical risk. Regional and overall aortic measures of elasticity were not strongly related. However, CMR PWV measures inversely correlated with aortic distensibility, suggesting that MR PWV values may provide a closer estimate of local aortic elastic properties."} +{"text": "Internal jugular vein (IJV) thrombosis is an unusual condition, especially when it develops bilaterally. This is a case of bilateral IJV thrombosis in a 77-year old female who presented to the emergency department with neck and arm swelling after discontinuing apixaban and undergoing an oropharyngeal procedure. The diagnosis of bilateral IJV thrombosis was made with the use of point-of-care ultrasound to evaluate bilateral jugular vein distention and bilateral upper extremity pitting edema found on her physical examination. A 77-year-old female with a history of atrial fibrillation currently taking apixaban presented to the emergency department (ED) with swelling of her neck and arms for the past seven days. Two weeks prior, she underwent an embolization of a greater palatine pseudoaneurysm, for which she stopped taking apixaban. After being discharged from the hospital, she continued to experience neck swelling, and had an upper extremity ultrasound evaluation which was negative for thrombus. She returned to the ED for worsening neck swelling. She denied shortness of breath, chest pain, fever, or a history of thromboembolic disease. Her physical exam showed pitting edema on bilateral upper extremities and bilateral jugular vein distention. Point-of-care ultrasound was performed on patient\u2019s neck and upper extremities, revealing thrombosis in bilateral internal jugular veins (IJV) as seen in the IJV thrombosis is an uncommon condition and very rare when it occurs bilaterally. Previous studies indicate that it usually occurs in patients with a history of malignancy, oropharyngeal infections, or deep vein thrombosis.What do we already know about this clinical entity?Internal jugular vein (IJV) thrombosis may develop in patients with malignancy or oropharyngeal infections.What is the major impact of the image(s)?IJV thrombosis may develop bilaterally in patients presenting with jugular vein distention without exhibiting the common causes of bilateral thrombosis of the internal jugular veins.How might this improve emergency medicine practice?Point-of-care ultrasound is effective at providing a prompt diagnosis of bilateral IJV thrombosis and should be monitored after anticoagulation is provided.Video.A) Thrombus in the right internal jugular vein (arrow) seen on transverse view. B) Sagittal view of right internal jugular vein thrombus (arrow) with color doppler showing obstruction of venous outflow and turbulence proximal to the thrombus. C) Thrombus in the distal left internal jugular vein (arrow) seen on transverse view. D) Color doppler of the left internal jugular vein thrombus (arrow) showing partial occlusion of the lumen seen on transverse view."} +{"text": "Subjective cognitive decline (SCD) is a construct of high interest in aging and dementia because individuals endorsing it are at higher risk of developing cognitive problems. It is unclear how individuals arrive at the judgement that they have SCD. Here we aimed to understand which SCD symptoms give rise to the perception of decline as older adults age. Community-dwelling adults , completed the Subjective Cognitive Decline Questionnaire (SCD-Q) online, using an online crowdsourcing site. The SCD-Q consists of one global question regarding self-perceived decline (yes/no) and 24 questions about everyday functioning which we utilized to form a memory, language, and executive functioning domain score, higher for greater perceived decline. Logistic regression revealed that memory and language domains predicted the likelihood of endorsing SCD for adults aged >64 . Only the memory domain predicted the likelihood of endorsing SCD for adults <63 . Executive functioning domain scores did not play a role in the relationship between SCD likelihood in either age group. The higher the self-perceived memory or language decline, the more likely older adults are to conclude they have SCD. Our results suggest there is an age-related trajectory in how people evaluate their cognition, with younger people only considering memory and older people considering both memory and language. Clinicians should be aware of this trajectory when examining patients with SCD. Executive functions should be specifically queried because they may not emerge from older adults\u2019 self-reported cognitive problems."} +{"text": "Engaging in physical activity (PA) in adulthood has multiple protective health effects in later ages. However, unknown are the extent to which PA habits are laid down earlier in life and persist into adulthood, and the extent to which greater opportunities for PA during adolescence stem from differences in socioeconomic status (SES) which then affect opportunities for PA. We investigated potential mechanisms underlying these relationships using the longitudinal Project Talent Twin and Sibling Study (assessments in 1960 and 2014). With this design, we are able to hold genetics constant by modeling relationships between monozygotic twins (who share 100% of their genes) and therefore isolate effects of contextual factors on later-life PA (mean age ~70). We found that higher family SES and sports participation in adolescence predicted PA 55 years later, adjusted for gender and physical limitations. This held true when partialling out genetic variation that could otherwise explain these relationships. More education also predicted later-life PA separately from family SES and partially mediated the effect of family SES on PA. While school-level resources did not predict later life PA, they did associate with adolescent sports participation . Overall, later-life physical activity was influenced by earlier life sports participation and education, with family rearing resources being more important than high school resources. As twin pair correlations suggest gender differences, future research will examine whether family or school resources differentially benefit males or females for later-life physical activity."} +{"text": "HighlightsAt the acute phase of epidermal necrolysis, patients requiring mechanical ventilation had more alveolar macrophages and higher alveolar concentrations of IL-13 than age- and sex-matched patients with the acute respiratory distress syndromePatients with epidermal necrolysis also showed longer duration of mechanical ventilation and more frequent ventilator-acquired pneumonia episodesTo the Editor,+ T lymphocytes, monocytes/macrophages, and natural killer cells. Yet, the pathophysiology of respiratory system involvement during the acute phase of EN is not well understood. The current study aimed at exploring the clinical and biological characteristics of acute lung injury during the acute phase of EN in mechanically ventilated patients.During the acute phase of epidermal necrolysis , mucosal lesions involving the tracheo-bronchial tract have been reported , 2 and aThis is a retrospective monocentric cohort study including patients with EN admitted in the intensive care unit (ICU) of the French National Reference Center for EN during 2011 and 2015 who required endotracheal intubation for acute respiratory failure. This observational cohort study was approved by the institutional ethics committee . Patients received information during hospital stay that data abstracted from their medical charts could be used for research purposes.i.e. percent of neutrophils, macrophages and lymphocytes) cell counts were measured as recommended [2 or Fisher tests for qualitative variables and the Mann\u2013Whitney test for continuous variables. Ventilator-associated pneumonia was defined according to the presence of clinical findings suggesting infection along with a radiographic infiltrate that is new or progressive and a positive distal quantitative sample [EN patients were age- and sex-matched with a historical control cohort of patients with pneumonia-associated acute respiratory distress syndrome (ARDS) . As stanommended . Cytokine sample .2/FiO2 ratios both at ICU admission and during ICU stay and lower SOFA scores at admission. Yet, EN patients had longer durations of mechanical ventilation than ARDS patients and underwent more frequent ventilator-acquired pneumonia. Total BAL cell counts were not significantly different between EN and ARDS patients . Patients received information during hospital stay that data abstracted from their medical charts could be used for research purposes.Not applicable.The dataset used during the current study is available from the corresponding author upon reasonable request.All authors declare no competing interest for this work."} +{"text": "Previous studies show that physical activity is beneficial for emotional well-being. This study extends prior research by examining whether engagement in physical activity moderates the association between daily stressor severity and daily emotional well-being. We used data from the second wave of the National Study of Daily Experiences, a sub-project of the Midlife in the United States (MIDUS) study. Respondents reported their daily experiences across eight consecutive days. Multilevel models explored concurrent and lagged interaction effects between daily stressor severity and physical activity on negative and positive affect and whether these associations differed by age. Physical activity was measured by engagement in vigorous physical activity for at least 30 minutes. Results showed significant interactions between stressor severity and physical activity on same-day negative and positive affect. Specifically, stressor severity was associated with smaller elevation in daily negative affect on physically active days compared to non-active days . Reductions in daily positive affect were greater on physically inactive days compared to active days . These associations did not differ by age, but additional findings revealed that stressor severity was associated with greater elevation in negative affect among younger respondents than older adults . These results highlight the importance of engagement in physical activity for emotional well-being under stressful situations in daily context."} +{"text": "This paper investigated whether experiencing a major asset shock changed the cognitive health trajectories of older adults (aged 65+ at baseline)? There is a robust literature supporting a relationship between potentially modifiable environmental and individual risk factors and cognitive health and emerging literature supporting a relationship between physical health shocks and later-life financial stability in both the US and internationally. This analysis employed six waves of Health and Retirement Study Core Data (2006-2014) to estimate the causal effect of major asset losses in the period of the 2008 financial crisis. We matched respondents using a rich variety of covariates including education, race/ethnicity, income, total assets, chronic health conditions, depressive symptoms, frequency of physical activity engagement, and engagement with religious activities. Using both propensity score-matched growth curve and difference-in-differences models, we found a small, but significant, negative relationship between major asset shocks and total cognition scores. We also identified a significant overall negative effect on total cognition on all older adults in this sample regardless of exposure to asset shocks. Additionally, both the frequency of asset shock exposure and magnitude of effect on total cognition scores was larger for low-income African-American and Hispanic older adults. These findings suggest in part that recovery from large economic crises may be especially difficult for older adults occupying vulnerable socioeconomic positions and that such events may accelerate the cognitive decline of those who are at or near retirement when asset shocks occur."} +{"text": "Bos mutus f. grunniens) and cattle (B. primigenius f. taurus)), which resulted in the higher loss. Further, compensation and insurance schemes were dysfunctional, with few households insuring their livestock and receiving compensation for depredated livestock over the past two years. We recommend improving herding practices and the implementation of compensation and insurance schemes to lower the economic loss faced by herders due to predation and creating positive avenues for the co-existence of snow leopards and humans.Conflict between snow leopards and humans across the trans-Himalaya is a pressing conservation concern. Conflict severely impacts the socio-economy of the local pastoralist community and threatens snow leopard survival. We investigated the socio-economic factors influencing such conflict and pastoralist attitudes towards snow leopard conservation using semi-structured interviews for a better understanding of what factors influence the variability in losses among the households in the Narphu valley, Nepal. While snow leopards caused significant losses to impoverished pastoralist households, respondents were generally accepting of their presence due to religious reasons and strict law enforcement. We observed poor herding and guarding practices with households owning larger numbers of total livestock using semi-structured questionnaires targeting herders in the Narphu valley of the Annapurna Conservation Area, Nepal. During the two years (2017/18 and 2018/19), 73.9% of the households interviewed (n = 65) lost livestock to snow leopards, with an annual average loss of two livestock per household. Of the total depredation attributed to snow leopards, 55.4% were yak , 31.7% goat, 6.8% sheep, 3.2% horse and 2.8% cattle. Results from applying Generalized Linear Mixed Models (GLMMs) revealed the total number of livestock owned and the number of larger bodied livestock species as the main explanatory covariates explaining livestock depredation. Forty-one (41%) of all herders considered snow leopard\u2019s preference for domestic livestock as the main factor in livestock predation, whereas only 5% perceived poor herding practice as the main reason for the loss. Our study found poor and changing herding practices in the valley, whereby 71% herders reported careful herding as a solution to snow leopard depredation, and 15% of herders considered the complete extermination of snow leopards as the best solution to the problem. Tolerance levels and awareness among herders towards snow leopard conservation is increasing, mainly due to the Buddhist religion and strict law enforcement within this protected area. We recommend the effective implementation of a community-based livestock insurance scheme to compensate the economic loss of herders due to predation and improved herding practices as the recommended mitigation measures for ensuring livestock security and snow leopards\u2019 conservation in the valley.Livestock depredation across the trans-Himalaya causes significant economic losses to pastoralist communities. Quantification of livestock predation and the assessment of variables associated with depredation are crucial for designing effective long-term mitigation measures. We investigated the patterns and factors of livestock depredation by snow leopards ( Panthera uncia) and Himalayan wolf (Canis lupus chanco) are key mountain species across Himalayan range countries with their presence indicative of a healthy ecosystem . Th. Th17]. The total mean attitude scores of respondents close to zero suggests that local people were very weakly accepting the presence of snow leopards, probably due to the high level of livestock losses by snow leopard . On the We found a decrease in livestock holdings with higher predation from snow leopards over the study period. Herders owning larger livestock size and larger bodied livestock incurred more economic loss due to livestock depredation. The livestock herding trend is decreasing mainly due to livestock predation by snow leopards and outmigration of village youths to urban centers. In order to reduce economic losses, we recommend encouraging small bodied livestock while encouraging other appropriate changes in livestock composition (number and livestock species). Moreover, the effective implementation of a community-managed insurance program, with education toward improvement of herding practices and equitable compensation for depredation losses would help in building positive attitudes among herders for supporting snow leopard conservation and minimize these conflicts in the Narphu valley. Similarly, conservation programs focused on empowering herders through educational programs to improve herding techniques and herder motivations would likely reduce overall losses, especially when livestock are grazed on open pastures or housed in poorly constructed corrals at night. Programs that reduce out-migration of the younger generation and encourage them towards herding could help preserve traditional herding practices in the Narphu valley. For reasons stated above, this paper highlights conflict between snow leopard and humans as a complex phenomenon requiring holistic, multi-pronged approaches for minimizing negative impacts and ensuring positive species coexistence with pastoral-dependent communities."} +{"text": "Bats play important roles as pollen disseminators and pest predators. However, recent interest has focused on their role as natural reservoirs of pathogens associated with emerging infectious diseases. Prior to the outbreak of severe acute respiratory syndrome (SARS), about 60 bat virus species had been reported. The number of identified bat viruses has dramatically increased since the initial SARS outbreak, and most are putative novel virus species or genotypes. Serious infectious diseases caused by previously identified bat viruses continue to emerge throughout in Asia, Australia, Africa and America. Intriguingly, bats infected by these different viruses seldom display clinical symptoms of illness. The pathogenesis and potential threat of bat-borne viruses to public health remains largely unknown. This review provides a brief overview of bat viruses associated with emerging human infectious diseases."} +{"text": "Coronary angiography (CAG) sometimes shows nonobstructive coronary arteries in patients with suspected angina or acute coronary syndrome (ACS). The high prevalence of nonobstructive coronary artery disease (CAD) in those patients has recently been reported not only in Japan but also in Western countries, and is clinically attracting attention. Coronary spasm is considered to be one of the leading causes of both suspected stable angina and ACS with nonobstructive coronary arteries. Coronary spasm could also be associated with left ventricular dysfunction leading to heart failure, which could be improved following the administration of calcium channel blockers. Because we rarely capture spontaneous attacks of coronary spasm with electrocardiograms or Holter recordings, an invasive diagnostic modality, acetylcholine (ACh) provocation test, can be useful in detecting coronary spasm during CAG. Furthermore, we can use the ACh-provocation test to identify high-risk patients with coronary spasm complicated with organic coronary stenosis, and then treat with intensive care. Nonobstructive CAD includes not only epicardial coronary spasm but also microvascular spasm or dysfunction that can be associated with recurrent anginal attacks and poor quality of life. ACh-provocation test could also be helpful for the assessment of microvascular spasm or dysfunction. We hope that cardiologists will increasingly perform ACh-provocation test to assess the pathophysiology of nonobstructive CAD. We often perform percutaneous coronary intervention (PCI) with coronary stent implantation for significant organic coronary artery stenosis with induced myocardial ischemia. PCI has become a useful treatment for relief of chest symptom in patients with significant coronary organic stenosis. However, coronary angiography (CAG) sometimes shows nonobstructive coronary arteries that do not need revascularization in patients with suspected angina \u201311. IndeYasue and coworkers previously reported that the intracoronary injection of acetylcholine (ACh) is a useful test for the provocation of coronary spasm \u201323. SincAlthough the etiologic mechanisms of stable angina and acute coronary syndrome (ACS) in patients with nonobstructive CAD remain obscure, coronary spasm can play an important role in the pathogenesis of these diseases , 36, 37.In this review article, we discuss the significance of ACh-provocation test as a tool for pathophysiological evaluation in nonobstructive CAD including coronary spasm.Coronary spasm usually occurs at rest, particularly from midnight to early morning \u201327. CoroACh usually causes vasodilation by releasing nitric oxide from the endothelium, and intracoronary injection of ACh in humans provokes coronary vasodilation in young healthy subjects, whereas it causes vasoconstriction in patients with coronary endothelial dysfunction such as coronary atherosclerosis \u201351. The Nonobstructive CAD includes not only angina with epicardial coronary spasm but also microvascular spasm \u20137, 62. H\u00ae (ACh chloride) was approved as an inducer of coronary spasm during CAG in 2017 in Japan. This approval will lead to more testing for provocation of coronary spasm in Japan, adaptation of the treatment based on the patient's progress, and detailed pathophysiological evaluation of nonobstructive CAD including coronary spasm.OvisotIn addition to ACh, ergonovine (ER) is also useful for pharmacological provocation of coronary spasm. According to the Japanese Circulation Society (JCS) Guidelines , the intStudies in Japan have made many contributions to the pathophysiology, diagnosis, and treatment of coronary spasm, leading to the development of the Guidelines for Diagnosis and Treatment of Patients with Vasospastic Angina by the JCS , 75\u201378. According to the JCS Guidelines for Vasospastic Angina (Coronary Spastic Angina) Fig.\u00a02)2), we caWe and others previously reported different patterns of angiographic changes including focal and diffuse spasm (severe diffuse vasoconstriction) during the spasm provocation test , 81, 82.According to the JCS Guidelines, ACh-provocation test is not recommended during emergent CAG in patients with ACS . The AmeT/C single nucleotide polymorphism in endothelial nitric oxide synthase gene were associated with ACh-provoked myocardial lactate production in patients with coronary spasm [Epicardial coronary spasm can be seen angiographically during the ACh-provocation test; however, it is unclear whether the coronary spasm causes myocardial ischemia. For this reason, we usually measure myocardial lactate production in the coronary circulation during ACh-provocation tests in the left coronary artery as a supporting diagnostic marker for the evaluation of coronary spasm-induced myocardial ischemia , 86. OurCoronary spasm can occur at sites of varying arteriosclerosis severity. We and others previously reported that coronary spasm could be associated with the progression of atherosclerosis \u201391. PatiWe previously reported that ACh-provoked coronary spasm occurring at the site of significant coronary artery stenosis was a more significant prognostic factor for MACE than ACh-provoked coronary spasm occurring at the site other than the site of organic stenosis, suggesting that coronary spasm can be associated with the cause of MACE when the coronary spasm occurs at the site of organic stenosis , 101. ThAt present, we often perform PCI with coronary stent implantation for significant organic coronary artery stenosis. Coronary spasm occurring after coronary stent implantation has become a clinical problem , 102\u2013107Recent studies reported that epicardial coronary spasm could be associated with left ventricular (LV) dysfunction \u201341. We pA previous study reported that the ACh-provocation test induced coronary spasm in 20/42 patients (48%) who had idiopathic DCM-like LV dysfunction without significant organic coronary arteries stenosis . PatientOn the other hand, ACh-provoked coronary vasomotor abnormality in our previous study was shown to be closely associated with myocardial fibrosis (expressed as late gadolinium enhancement in cardiac MRI) in patients with heart failure and without organic coronary artery stenosis , 112. CoThe coronary arterial tree consists of not only the epicardial coronary arteries, but also smaller arteries and arterioles (<\u2009500\u00a0\u03bcm). The latter feed the capillaries and play an important role in the coronary microcirculation, being the main site of regulation of myocardial blood flow , 119. EpModalities for diagnosing obstructive CAD such as CAG or CTA have improved remarkably. However, in patients with suspected angina, we can sometimes see both nonobstructive epicardial coronary arteries and non-ACh-provoked epicardial coronary spasm. Nonobstructive CAD has included not only angina with epicardial coronary spasm but also microvascular spasm or dysfunction , 124 5). We de2, respectively. These clinical features of the microvascular spasm, such as female sex, middle age, and low body mass index, are reminiscent of postmenopausal phenomena, which invites speculation of an association between the pathogenesis of microvascular spasm and age-dependent estrogen deficiency in those patients.Our report mentioned above of the 1The ACh-provocation test has several limitations. The ACh-provocation test cannot provoke coronary spasm in all patients with coronary spasm, although our previous study showed high sensitivity and specificity of the test in patients with variant angina , 21. In ACh-provocation test has several potential complications. In our institution, the number of life-threatening arrhythmias during ACh-provocation test was 9 (0.5%) of 1637 patients who underwent this test . A previAs summarized in this review, ACh-provocation test can be a safe and reliable method not only to diagnose epicardial coronary spasm but also to assess the pathophysiology of nonobstructive CAD. The ACh-provocation test is not often performed in routine clinical cardiovascular practice because multiple procedures of this test are required. However, the pathophysiology showed by ACh-provocation test can be associated with prognosis in patient with nonobstructive CAD. We can identify the high-risk patient with coronary spasm or microvascular spasm diagnosed by ACh-provocation test and treat with intensive care for the patients.We hope that cardiologists will routinely perform the ACh-provocation test to assess the pathophysiology of nonobstructive CAD."} +{"text": "Prior research has established transitions into and out of nursing homes as periods of suicide risk for older adults. Deaths by suicide were found to be 2.4 times as likely among Veterans within six months of discharge from US Veterans Health Administration (VA) nursing homes when compared with gender and age-matched Veterans from the general VA patient population . Despite these trends, suicide prevention interventions implemented during nursing home and post-acute care transitions, including those taking place from Centers for Medicare and Medicaid Services regulated nursing homes, are lacking. Suicide Awareness for Veterans Exiting the Community Living Center (SAVE-CLC) was piloted as a quality improvement intervention to reduce suicide risk for older Veterans discharging from VA nursing homes. VA clinicians from three sites provided a friendly contact by phone after discharge (n = 66) to screen for depression, facilitate a strengths-based discussion about service needs, and provide service referrals. Compared to a group of patients discharged prior to the start of the intervention , SAVE-CLC patients received more depression screening within 30 days after discharge and were seen more quickly for mental health care when indicated. Implications for suicide prevention with older Veterans and for the general population of older adults receiving short stay services in US nursing homes will be addressed."} +{"text": "Microplastics in the biosphere are currently of great environmental concern because of their potential toxicity for aquatic biota and human health and association with pathogenic microbiota. Microplastics can occur in high abundance in all aquatic environments, including oceans, rivers and lakes. Recent findings have highlighted the role of microplastics as important vectors for microorganisms, which can form fully developed biofilms on this artificial substrate. Microplastics therefore provide new microbial niches in the aquatic environment, and the developing biofilms may significantly differ in microbial composition compared to natural free-living or particle-associated microbial populations in the surrounding water. In this article, we discuss the composition and ecological function of the microbial communities found in microplastic biofilms. The potential factors that influence the richness and diversity of such microbial microplastic communities are also evaluated. Microbe-microbe and microbe-substrate interactions in microplastic biofilms have been little studied and are not well understood. Multiomics tools together with morphological, physiological and biochemical analyses should be combined to provide a more comprehensive overview on the ecological role of microplastic biofilms. These new microbial niches have so far unknown consequences for microbial ecology and environmental processes in aquatic ecosystems. More knowledge is required on the microbial community composition of microplastic biofilms and their ecological functions in order to better evaluate consequences for the environment and animal health, including humans, especially since the worldwide abundance of microplastics is predicted to dramatically increase. Plastics have been produced since the 1940s, and world production reached 360 million metric tons in 2018, which has resulted in severe plastic pollution of the environment worldwide were also enriched in microplastic biofilms and one plant pathogen (Pseudomonas syringae) were exclusively found in microplastic biofilms biofilms represent the major groups of bacteria capable of degrading PHBH represented important microbial associations within microbial communities of the plastisphere microplastic characteristics (\u201csubstrate-specific\u201d), (ii) period/succession (\u201ctime-specific\u201d), (iii) microbial community and (iv) environmental conditions Fig.\u00a0. The lasAlphaproteobacteria and Gammaproteobacteria, while Burkholderiales (formerly Betaproteobacteria) dominated on polyethylene microplastic biofilms in the North Atlantic garbage patch for microbial growth, pollutants , physicochemical parameters and aquatic biota are critical factors controlling microbial biofilm formation and succession on microplastics. In lake water, temperature, nutrient levels and suspended particle concentrations determined microbial assemblages on various plastics (Chen et al. Mytilus edulis developed a similar bacterial community composition as the mussel\u2019s gut microbiome (Kesy et al. Aquatic plants and animals play an important role in the transfer of microplastics across complex food webs (Au et al. The formation and development of the microbial community structure of microplastic biofilms to a large extend depend on \u201clocation-specific\u201d, \u201ctime-specific\u201d and \u201csubstrate-specific\u201d characteristics. However, most studies reveal that location-specific characteristics play a more important role than substrate-specific\u201d factors in shaping the bacterial community composition of microplastic biofilms (Amaral-Zettler et al. Factors influencing microbial community composition and function require further studies to better understand underlying processes and mechanisms. Most prior studies have been restricted to traditional non-degradable plastics, but the worldwide increasing use of degradable plastics means that these less refractory polymeric compounds also need to be carefully considered. A total of 127 countries have adopted some form of legislation to regulate the use of plastic bags UNEP , but mosThe advantages and limitations of current research methods for microplastic biofilms have been summarized (see Arias-Andres et al. The focus of future studies on microbial biofilms on microplastics should concentrate on functional and ecological aspects affecting aquatic food web dynamics and biogeochemical processes. Meta-transcriptomics, metaproteomics and metabolomics are now well established and important tools to assess functions and ecological roles of microbial communities Fig. . These m"} +{"text": "Frail community-dwelling older adults increasingly receive home care and continue to face barriers to participating in physical activity (PA) that could help maintain their function. Home care aides (HCAs) are well-positioned to promoting PA among older home care recipients because of their established relationship and regular interpersonal exchanges; yet, the role of HCAs in promoting and supporting PA in home care settings is seldomly studied. Using the quantitative and qualitative data from a 4-month home-based gentle PA intervention delivered by HCAs to their clients in a Medicaid-funded home care setting, the current study examined whether outcome expectations for exercise (OEE) held by HCAs led to client PA outcomes through social support for exercise (SSE) provided by HCAs. Longitudinal mediation analysis of 46 HCA-client dyads showed that higher baseline OEE held by HCAs were related to greater SSE reported by clients after the intervention , controlling for client-level covariates, including baseline OEE, age, gender, comorbidity, and whether HCA was client\u2019s family member. Unexpectedly, SSE did not have significant association with client PA outcomes nor mediated the relationship between OEE held by HCAs and client PA outcomes. Qualitative data suggested alternative factors may explain the results, such as clients\u2019 family beliefs in the intervention and clients\u2019 participation experiences (such as expectation fulfillment). Future research should consider older home care clients\u2019 family contexts to enhance our understanding of HCAs\u2019 roles in preserving the function of growing numbers of older home care recipients."} +{"text": "This knowledge is critical to understand how crust-forming processes are related to metal accumulations at specific time and conditions of Earth evolution. To this end, high-precision absolute geochronology utilising the rhenium-osmium (Re-Os) radiometric system in specific sulphide minerals is becoming a method of choice. Here, we present a procedure to obtain mineral separates of individual sulphide species that may coexist within specific mineralized horizons in ore deposits. This protocol is based on preliminary petrographic and paragenetic investigations of sulphide and gangue minerals using reflected and transmitted light microscopy. Our approach emphasizes the key role of a stepwise use of a Frantz isodynamic separator to produce mineral separates of individual sulphide species that are subsequently processed for Re-Os and sulphur isotope geochemistry. Specifications TablePolished thin sections of the arsenopyrite-pyrite-mineralised samples were studied using transmitted and reflected light microscopy in order to establish the paragenetic relationships and constrain the workflow for optiAll sulphide samples were cut into slabs that were thoroughly cleaned using silicon carbide grit, milli-Q water and ethanol to remove any metal traces potentially introduced through hammering or sawing . These clean sulphide-bearing samples were then crushed using a zirconia ceramic dish and puck and sieved through disposable home-made nylon sieves to produce 70\u2012200 mesh size fractions . Each 70An aliquot of each arsenopyrite and pyrite mineral separate was embedded in epoxy to operate a quality control of these mineral separates . The mounts were studied by reflected light microscopy. We recommend the use of a scanning electron microscope (SEM) operated in backscattered electron mode (SEM-BSE) if doubts persist regarding the quality of mineral separates. Qualitative observations may then be complemented by point wavelength-dispersive spectroscopy (WDS) quality control analyses of arsenopyrite and pyrite in the mounts using the following suite of elements: S, Fe, Ni, Cu, As.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} +{"text": "The role of fibronectin (FN) in tumorigenesis and malignant progression has been highly controversial. Cancerous FN plays a tumor-suppressive role, whereas it is pro-metastatic and associated with poor prognosis. Interestingly, FN matrix deposited in the tumor microenvironments (TMEs) promotes tumor progression but is paradoxically related to a better prognosis. Here, we justify how FN impacts tumor transformation and subsequently metastatic progression. Next, we try to reconcile and rationalize the seemingly conflicting roles of FN in cancer and TMEs. Finally, we propose future perspectives for potential FN-based therapeutic strategies. Identification of a general and suitable target that is unambiguously oncogenic or tumor suppressive is a foundation on which cancer therapeutic strategies could be designed and developed. Fibronectin (FN) A has lonAccomplishment of cancer development, a rather slow and chronic process, temporally and spatially requires various cellular activities across different tissues. Tumor cells originate from healthy, often epithelial, cells that acquire hereditary mutations or somatIn contrast to such intratumor heterogeneity, immune and stromal cells in the tumor microenvironments (TMEs) initially arise to eliminate pre-tumor abnormal cells and early transformed cells that encounter environmental stresses. Consequently, these stresses impose early transformed cells enormous selective pressures to force evolution, rendering tumor cells staying in the equilibrium stage for a long while before being able to escape immunosurveillance and make a malignant progression ,26,27. HOxygen delivery within the TMEs is inefficient mainly due to various abnormalities in the tumor vasculature . Indeed,The liberation and survival of circulating tumor cells (CTCs) is a requirement for the colonization of disseminated tumor cells (DTCs) in secondary organs and finally outgrowth and macrometastasis development ,34. Like+ bone marrow-derived cells (BMDCs) that have been driven by cytokines or exosomes secreted by the metastatic competent tumor cells in primary tissues long before extravasation of DTCs in distant tissues formed ted data] [unpubli435 DTCs . Uncouplt organs . Such pht organs ,350, likhigh CTCs colonize more and form more metastatic tumor nodules in distant organs, unless there are strategies to reverse FNhigh CTCs back to pro-epithelial phenotypes that tend to render CTCs suffer more from anoikis and mechanical stresses and injuries.Since how cancerous FN and ECM FN participate in tumor progression remains obscure and paradoxical, FN-based cancer therapies have so far only been focused on the functions of drug delivery. For example, EDA- and EDB-containing oncofetal variants have often been utilized for that purpose ,351,352.At the same stage of tumor patients, FN deposition in ECM of TMEs exacerbates tumor growth and subsequent progression. Therefore, approaches targeting such matrix-depositing FN may be ideal for effectively slowing down the tumor progression. FN secretion and deposition may due in part to tumor-infiltrating pro-tumor stromal cells including CAFs and TAMs . Ablatiohigh CTCs prior to extravasation in distant organs as DTCs. Blockade of the attachment of FNhigh CTCs to DPP IV-expressing endothelia can be an ideal strategy to prevent tumor metastasis and improve patients\u2019 prognosis. Indeed, in experimental metastasis assays, polypeptides derived either from FN harboring DPP IV-binding sites [In later stages of tumor progression, tumor cells with the metastatic potential begin to intravasate into the circulation and become FNng sites or from ng sites ,2 have bng sites . More imng sites . Intrigung sites .high CTCs become highly metastatic and capable of colonizing distant organs. The prevailing therapeutic strategies are to switch to a second line of tumor-killing drugs or combinatory therapies including immune checkpoint blockade, which may cause further genetic or epigenetic evolutions and eventually lead to another drug resistance. These problems may be avoided by finding a drug that by itself has no cytotoxic effect on tumor cells but is able to sensitize the resistant tumor cells to the original drugs. Efforts can be exerted to screening such drug from either small molecule library or a series of less harmful natural phytochemicals. By combining such drug with periFN/DPP IV binding blockade treatments, the drug-resistant tumor cells can be re-sensitized and controlled in the primary sites and FNhigh CTCs can simultaneously prevented from entering distant sites.In most cases, tumor patients receive either tradition chemo/radiotherapies or targeted anti-tumor therapies. As aforementioned, tumor patients often develop resistance to these anti-cancer drugs, driving tumor evolution, malignant progression, intravasation of tumor cells to become CTCs, and metastatic recurrence simultaneously with the upregulation of endogenous FN. Although therapy-elevated FN expression in resistant tumor cells slow down the tumor growth, the blood-borne FNIn summary, after extensively reviewing the bulk literature regarding the roles of FN in cancer progression, we provided intriguing possibilities that reasonably reconcile the seemingly paradoxical roles FN plays. We hypothesized that cancerous FN and FN mactrices in TMEs can coordinately regulate tumor transformation and malignant progression in temporal and spatial manners. Upon accomplished experimental proof of concept, FN can be carefully targeted at the right location and in the right time. We finally provided a few FN-based therapeutic strategies as future perspectives. Hopefully, this review article can attract more cancer researchers to be delved into concerted efforts in unveiling and validating what had been proposed here."} +{"text": "Despite the well-understood benefits of vaccination in older adults, national rates still fall below public health targets, especially among certain racial and ethnic groups. Recent scholarship examining healthcare use patterns in adults revealed that health care providers miss several opportunities to provide vaccination during regular healthcare encounters, including Medicare annual wellness visits. Several barriers to older adult vaccination have been identified, including lack of patient and provider understanding of the importance of vaccination, financial barriers to vaccines covered under Medicare Part D, and patient hesitancy about the safety and effectiveness of vaccines. Strategies to address these barriers will be discussed, including the use of national quality measures to strengthen incentives for adult vaccination. Part of a symposium sponsored by the Health Behavior Change Interest Group."} +{"text": "Individual sensory deficits have been associated with adverse outcomes, including dementia, in older adults. Using data from the Baltimore Longitudinal Study of Aging (BLSA) (N=259) and Atherosclerosis Risk in Communities Study (ARIC) (N=962), we examined the prevalence of one, two, or three sensory deficits among older adults \u226570 years. Any hearing loss was the most prevalent sensory deficit , followed by vision loss and olfactory loss. Hearing and vision impairments were more prevalent than hearing and olfactory losses as well as vision and olfactory losses in both age groups and studies There were few people with deficits in all three senses . Further research should investigate the potential impact of multisensory impairments on older adults."} +{"text": "PLOS Genetics publications that exemplify recent progress in human genetic admixture studies, and we discuss potential areas for future work.Throughout human history, large-scale migrations have facilitated the formation of populations with ancestry from multiple previously separated populations. This process leads to subsequent shuffling of genetic ancestry through recombination, producing variation in ancestry between populations, among individuals in a population, and along the genome within an individual. Recent methodological and empirical developments have elucidated the genomic signatures of this admixture process, bringing previously understudied admixed populations to the forefront of population and medical genetics. Under this theme, we present a collection of recent One of the major insights from the modern genomic era is the ubiquity of migration and admixture throughout human history \u20137. Admix\u2014the population origins of material within a genome. This is related to, but distinct, from genetic similarity and from genealogical ancestry, with the relationship further discussed by Mathieson and Scally [Human population movement frequently lacks historical records. Many migration events have occurred through colonization or forced displacement, and ancient admixture often predates historical records. Therefore, genetic studies provide an opportunity to understand population history and the forces generating variation. Recent empirical work has shown that studying the genetics of a wider set of human populations can yield historical insights as well as medically relevant information about health and phenotypes. The mosaic ancestry patterns of admixed populations can also be used to elucidate the mechanisms and timescales of evolution in humans more generally. For example, ancestry patterns in admixed populations have been used to infer recombination rates \u201315 and td Scally .PLOS Genetics publications. This compilation is a limited selection of work that exemplifies recent key advances and stimulates discussion about priorities for the future.Here, we highlight recent progress and discuss future directions for the study of admixed human populations . The terBroader genetic sampling of populations worldwide is increasingly being combined with advances in theory and computational methods to elucidate human history.Genetic ancestry often varies along a chromosome within an individual and between individuals within an admixed population . SummariClassic statistical methods in population genetics typically rely on allele frequencies, patterns of linkage disequilibrium (LD), and interpopulation sequence differences. However, the admixture process may distort patterns of LD, break up runs of homozygosity, and combine allele frequency distributions from distinct parental populations \u201329. Yet,PLOS Genetics that improve our understanding of the demographic processes shaping genetic variation in admixed populations and human evolutionary history. Ragsdale and colleagues (2019) generalize 1- and 2-locus genetic summary statistics in a computationally efficient algorithm able to explore complex demographic models [A number of major theoretical and methodological advances have recently been published in c models . Other rc models . Methodoc models . Identifc models \u201338. Browc models \u201341. A rec models .Intricate sociocultural practices such as marriage customs, colonization events, and phenotypic preferences direct how parental populations interact to form admixed human populations. Whereas computational methods are increasingly considering these intricacies, empirical studies of admixed populations have already made substantial progress on fine-scale demography providing insight into how sociocultural practices shape the admixture process and within-region variation.Using these new methods, empirical studies have brought to the forefront within-continent variation, particularly for historically excluded and under-sampled populations. Analyses of genomic ancestry within the context of geography have revealed between and within continent population structure . For exaEmpirical studies such as these highlight the role social processes play in shaping genetic variation; for example, male and female demographic histories can differ. Considering population structure, sex-biased admixture, and effective population size changes, Font-Porterias and colleagues (2019) clarified the dynamic demographic history of European Roma groups, including showing that they share a common South Asian origin but have complex contributions from West Eurasian groups . AnotherSelective pressures, such as those from environments and pathogens, play an important role in genetic variation and disease risk. Admixture both obscures genetic signatures of selection in source populations and provides new genetic material upon which selection can rapidly act.Despite major progress on theory and methods to study demography in admixed human populations, methodological advances to study other processes such as adaptation and phenotypic variation remains an open area with substantial room for growth. Recent admixture may obscure genetic signatures of selection in the source populations by distorting linkage, rapidly changing allele frequencies, and breaking up homozygosity ,56. TherDARC locus is protective against malaria-causing Plasmodium vivax infection, which is estimated to be one of the strongest selective pressures in recent human history. The Duffy-null allele is nearly fixed in sub-Saharan African populations and mostly absent in non-African populations, producing a classic signal in which the DARC locus is an outlier in its proportion of local African ancestry in multiple admixed populations [DARC locus is not typical of human adaptation. These local ancestry outlier approaches likely miss many loci under weaker or polygenic selection or those not highly differentiated in the sources. Additionally, outlier approaches generate false positives due to drift or long-range LD and discard other genetic information along the genome. For example, in Western African rainforest hunter\u2013gatherer populations, Jarvis and colleagues (2012) found reduced levels of switching between ancestry types in a genomic region that may contribute to adaptive phenotypes such as short stature [A common approach to identify candidate regions under selection post-admixture looks for outliers in local ancestry \u201321,59,60ulations . However stature . DespiteDespite the challenges of identifying phenotypically important loci and regions under selection in admixed populations, recent empirical studies have highlighted the importance of using admixed populations to understand how selective pressures shape genetic variation and disease risk. Discovering phenotypically important loci in admixed populations requires careful consideration of the data, including strategies to integrate genotypes, local ancestry, and information from source populations. Once phenotypically important loci are identified, admixed populations can provide insight into how these loci interact with different ancestral backgrounds and how characteristics of the source populations shape post-admixture selection.ApoE is the strongest known risk gene for late-onset Alzheimer disease; Rajabli and colleagues (2018) showed that variation in risk for Alzheimer disease across populations may be at least partially explained by the ancestral background interacting with the risk allele [In addition to looking for correlations between genotype and phenotype, phenotypically important loci in admixed populations can be identified by looking for correlation between local ancestry and phenotype when the phenotype differs in the source populations . A combik allele . The relk allele . In Latik allele . Going fNotably, these types of studies of quantitative variation and disease risk in admixed populations rely on careful consideration of the genotype and local ancestry calls, including reference-bias and characteristics of the source populations. Identifying phenotypically important loci in admixed populations is challenging in the absence of appropriate reference panels and knowledge of the source populations. The growing availability of genetic data from diverse groups shows that the unique LD structure of admixed groups and limited availability of suitable reference panels can particularly impair variant mapping and detection for novel or rare alleles. For example, Kowalski and colleagues (2019) recently analyzed a large cohort of phased genomes from African and Hispanic/Latino individuals (NHLBI TOPMed), revealing significant phenotypic associations for rare variants that were not detected with imputation using 1000 Genomes reference data .Contributing source populations also have their own distinct selective and demographic histories. Although recent admixture obscures genetic signatures of selection in the source populations, consideration of past selective pressures can help identify important loci and clarify the genetic basis of disease risk. For example, Yao and colleagues (2018) found that in African ancestral backgrounds, past selection for the Duffy-null allele may also contribute to population differences in plasma levels of chemokines involved in a variety immune processes and diseases . In IndiThe set of papers highlighted here exemplifies recent advances and important areas for future work in the study of genetic admixture and its roles in human evolution. Recent theoretical and methodological advances have improved our understanding of the dynamic and complex demographic histories of modern human populations. New empirical insights will continue to emerge with the development of approaches that consider complex sociocultural variables, account for within-population heterogeneity, and avoid reference bias. With increasing genomic and phenotypic data available from populations around the world, we are only beginning to characterize genetic underpinnings of traits, the importance of their genetic background, and mechanisms of adaptation. Importantly, as we move forward, the field must emphasize the inclusion of local communities, ensure that people maintain agency over their genomic information, prioritize infrastructure for science, and improve scientific theories by collaborating across disciplinary knowledge \u201375."} +{"text": "According to the World Health Organization, the global population is aging, but ageism may now be the most socially \u201cnormalized\u201d of any prejudice, more pervasive than sexism or racism. Ageism produces avoidant and disrespectful treatment of older adults and contributes to a shortage of college students seeking careers with older adults. To foster positive intergenerational contact and combat ageism, we organized life-story sharing by older adult community members in four undergraduate psychology courses with lifespan themes . A panel visited each class; instructors and graduate students facilitated discussion between students and panelists. Students completed pre- and post-surveys of ageism and attitudes toward aging. A majority of students recommended integrating the activity into future semesters. In free-responses, students also frequently expressed surprise that panelists reported not feeling different than they had at age 20, and that this information challenged previously held stereotypes."} +{"text": "Nineteen percent (13 million) older adults have incomes below 150% of the Federal Poverty Level, leaving them with limited means to afford basic living expenses. Public benefits can help bridge the gap allowing older adults to afford food, home energy, and health expenses. There are studies demonstrating the positive health outcomes associated with public benefits in older adults. It remains unclear how benefits may also improve subjective measures of well-being in older adults. To examine this question, baseline measures of well-being including the CFPB Financial Well-Being Scale were administered to older adults before they enrolled in benefits and again six months after receiving benefits to examine changes in well-being as a result of accessing benefits to help ease some of their financial burdens. Results revealed that older adults experience subjective, psychological improvements from benefits. These findings have implications for the social and behavioral determinants of health in older adults."} +{"text": "Older adults in the deep south are living with high food insecurity rates; this is exacerbated by challenges with rural-living, like transportation limitations and no grocery stores. To address this, we must increase emergency food assistance offerings and adopt best practices for food pantries including choice food pantry approaches, which empowers clients with some autonomy in choosing the foods they receive as part of their pantry distribution. Coalitions in eight income-limited, aging, rural Mississippi Delta counties received support from a Centers for Disease Control and Prevention Grant to enhance the food-related infrastructure in their communities through technical assistance and economic investments. A detailed process evaluation was conducted on this effort. Each coalition adopted food pantry-related policies like adding new food pantries and adapting their existing food pantries with the choice model. Both aging volunteers and clients indicated positive outcomes from the process of adding pantries and adapting existing ones."} +{"text": "Military service during early life can result in exposure to traumatic events that can reverberate throughout life. Although much attention is focused on the negative effects of military service, many veterans report positive effects. These papers explore life course effects of military service on veterans\u2019 health and well-being. Three used national US longitudinal cohorts ; two sampled veterans from Oregon or from Korea. Three compared veterans to non-veterans; two examined veterans only. Cheng and colleagues found that veterans in HRS are more likely to be risk-averse than non-veterans. Risk aversion matters because it determines how people make decisions and predicts a wide array of health and economic outcomes. Kurth and colleagues examined Oregon veterans from several wars, finding PTSD symptoms were highest among Vietnam combat veterans, the oldest cohort; there were no differences among non-combat veterans. Piazza and colleagues examined in MIDUS the impact of veteran status on cortisol, a stress biomarker, finding older veterans more likely had non-normative patterns than did younger or non-veterans. Lee and colleagues studied patterns of mental health among Korean Vietnam veterans, identifying two patterns as \u2018normal\u2019 and \u2018resilient\u2019 encompassing half the sample; these veterans demonstrated positive outcomes of military service. Frochen and colleagues compared depression trajectories between veterans and non-veterans in HRS, finding veterans had less depression than non-veterans, but among veterans, trajectories varied based on extent of service. in sum, these papers demonstrate that military service can have positive as well as negative effects on veterans\u2019 health and well-being in later life. Aging Veterans: Effects of Military Service across the Life Course Interest Group Sponsored Symposium."} +{"text": "Person-centered caregiving approaches emphasize efforts to protect and maintain the personhood of people living with dementia (PLWD). The influence on person-centered caregiving approaches on PLWD have predominantly focused on deficit-oriented outcomes, such as absence or reduction of behavioral symptoms. While important to quality of life, the absence of measurable \u201cpositive\u201d responses to person-centered caregiving approaches limit opportunities to specify sensitive and meaningful outcome measures that more holistically represent PLWD\u2019s care experiences as more than the absence of a negative outcome. To address these gaps, we conducted a secondary analysis of video-observations of PLWD (N=9) surrounding mealtime cares using a descriptive ethnographic approach. Our objectives were to descriptively summarize specific responsive behaviors demonstrated by PLWD surrounding person-centered caregiving interactions, specifying observable features of these responses and consider their utility in future video-observational research. Findings indicate PLWD contribute both verbal and non-verbal communication surrounding person-centered approaches which can be characterized as conversational , expressing preferences , emotional responses , and reflexive (mirroring of caregiver\u2019s actions), with overlap between categories. Findings suggest that PLWD not only contribute and respond in meaningful ways to person-centered interactions, but also initiate a significant number of these interactions. This study contributes to a growing body of research and advocacy that examines the personhood and abilities of PLWD and establishes the utility of observational data in studying PLWD contributions."} +{"text": "Almost a hundred and thirty years ago, Emil Kraepelin described important weight changes in patients diagnosed with dementia praecox during the acute state of psychosis outbreaks . KraepelTwenty years later Eugenie Bleuler in his seminal book \u201cDementia praecox oder Gruppe der Schizophrenien\u201d described that body weight of patients underwent irregular and severe variations from which no cause had been identified (being sometimes as much as 25 Kg), suggesting that it could not be considered as a compensation mechanism after the stressful circumstances of a psychotic outbreak . He alsoNevertheless the link faded with the introduction of chlorpromazine in 1952 like other medical conditions . HoweveWith the reintroduction of clozapine in the market, new studies regarding this association in patients diagnosed with schizophrenia or schizoaffective disorder appeared in the literature. Lamberti, without aiming at it, showed an inverse correlation between clinical symptom severity change and weight gain in 36 inpatients evaluated for 6 months with the brief psychiatric rating scale (BPRS) . LeadbetThe same approach was taken with olanzapine in patients diagnosed with schizophrenia spectrum disorders. Czobor showed a significant correlation between weight gain and improvement in 38 patients . GaryfalThe placebo effect found in some studies is remarkable regarding previous considerations. Ascher-Svanum described that patients under placebo treatment presented a significant association between greater weight gain and greater therapeutic improvement suggesting that weight gain may serve as an important indicator of improved clinical status among acutely ill patients with schizophrenia who do not receive antipsychotic medication , 24. AlsDespite the paradox that a secondary side effect of antipsychotics such as weight increase might underlie clinical improvement, these mechanisms are worth being discussed. Initially authors underlined this issue suggesting hospital diet, physical inactivity, and the psychological and physical shelter provided by hospitalization as the cause . Later sNevertheless, recent research suggests that the gut-brain axis (GBA), specifically its neurohormones, might behave as a potential pathway underlying both conditions and a key player in promoting weight gain and clinical improvement. The biological effect on the central nervous system of leptin, adiponectin, ghrelin, cholescytokinin (CCK), neuropeptide Y (NPY), glucagon like protein I (GLP-I), and insulin has accumulated further evidence . InitialGBA has been described as a pathophysiological mechanism implicated in antipsychotic-induced weight gain , 34, howConsidering specifically clozapine or olanzapine, the two pharmacological agents more related with weight gain, they seem to display a direct effect on the hormonal pathways of energy homeostasis (adiponectin and ghrelin) rather than on weight gain . Indeed Overall, previous literature suggests that GBA might be a necessary element in both conditions and so underlie the undeciphered association between weight gain and clinical improvement. However, this association lacks specific studies evaluating the issue and so further studies are required to prove its implication .The author confirms being the sole contributor of this work and has approved it for publication.CC-R has received honoraria/speaker fees/research and travel support/from Adamed, Alter, Angelini, Janssen-Cilag and Lundbeck."} +{"text": "The world\u2019s population is aging at an alarming rate, and the incidence of osteoporosis is skyrocketing. One major consequence of the decline in skeletal health is increased fracture risk in patients 65 years and older. Osteoporosis-related fractures are predicted to result in more than $25 billion in annual health care costs by 2025. For elderly patients, who demonstrate poor capacity for regeneration and a limited physiologic reserve, surgery has increased complication rates and higher risk of failed healing outcome which is potentially devastating and can result in morbidity and mortality . CurrentStem cell therapy has emerged as a potent new strategy to repair and replace injured tissue. Readily available bone marrow aspirates and adipose tissue have been used as a source for the isolation, study, and transplantation of bone forming cell populations. Despite often being called \u2018stem cells\u2019 the isolation of these cells has been largely retrospective in nature and relying on inexact separation criteria such as plastic adherence which produces highly variable and heterogeneous cellular mixtures of multiple tissue types including bone, blood vessels, blood, fat, and fibroblast cells which makes treatment outcomes difficult to evaluate or predict . In contIn our recent study, we applied this methodology to isolate human fracture derived SSCs (hSSC) from a broad cohort of patients to test if changes in SSC function were associated with patient age . We prosWe analyzed genetic regulation of aged SSC traits such as fibrogenicity by performing gene expression analysis on purified hSSCs. We utilized microarray analysis to compare global gene expression in purified hSSCs from young versus aged patients along with corresponding functional evaluation in vitro. Consistent with age-related functional changes, we found downregulation of genes related to bone formation in aged hSSCs. Moreover, aged hSSCs upregulated genes that are related to fibroblast-like extracellular matrix secretion and cellular senescence. Curiously, we also observed that the histone deacetylase Sirtuin1 was significantly downregulated in geriatric hSSCs, which hints at epigenetic mechanisms underlying hSSC aging. We showed that specific blockade of Sirt1 in young hSSCs impairs osteogenic potential in vitro. Excitingly, Resveratrol and a Sirtuin1-specific small molecule restored mineralization capacity in impaired hSSCs thus providing a rationale for future translational strategies.In summary, our report of an association between patient age and hSSC function opens new possibilities to identify diagnostic, prognostic, and therapeutic strategies for poor fracture healing and potentially even the preservation of youthful bone health and prevention of skeletal injuries. Targeted molecular therapies that inhibit cellular senescence pathways may reverse age-related fracture phenotypes without broad off-target systemic side effects of current regimens. Continued investigation of larger groups of patients will reveal if simple in vitro assays of hSSCs, or antigens associated with aged hSSCs might serve as a prognostic tool to predict healing outcome of fractures. Furthermore, analyzing hSSCs isolated from nonunions will yield insights into the involvement of hSSCs in the etiology of failed fracture healing. A more comprehensive approach including the analysis of all cells present at the fracture site might also help to elucidate the role of the stem cell microenvironment or \u201cniche\u201d in facilitating proper bone regeneration ."} +{"text": "Research shows regular physical activity (PA) is associated with better health and longevity; however, few studies consider contextual factors related to PA among African American (AA) older adults living in socioeconomically disadvantaged neighborhoods. The Physical and Cognitive Health Pilot Study (n=50) was used to examine associations between PA and level of neighborhood socioeconomic disadvantage among sedentary, AA older adults from four public housing communities in Durham, NC and Annapolis, MD . Participants were administered the Community Healthy Activities Model Program for Seniors (CHAMPS), a self-report questionnaire measuring weekly frequency and duration of PAs. Neighborhood socioeconomic disadvantage was defined by the Neighborhood Atlas Area Deprivation Index (ADI), which ranks neighborhoods according to Census block group/neighborhoods within each state and nationally. For the present sample, two of the Durham housing facilities were located in communities in the most disadvantaged block groups. Meanwhile, one Durham location and the Annapolis community were located in the least disadvantaged block groups. Bivariate correlations showed greater neighborhood socioeconomic disadvantage was associated with less participation in various PAs (p<.05). Next, ANOVA revealed the Annapolis group participated in statistically significantly more PAs, including visiting the senior center, church attendance, and light gardening (p<.05) compared to the most disadvantaged groups. The present findings suggest there are benefits to living in advantaged contexts despite lower-income status. These findings also suggest barriers within disadvantaged neighborhoods that limit access to recreational activities favorable to health status. Future research should address ways to overcome such barriers."} +{"text": "Exposure to harmful substances and chemicals such as tobacco smoke, chemicals and metal dust has been associated with increased risk of developing cancer, cardiovascular disease, and other diseases that contribute to shorter life expectancy. Associations with brain health in relation to these exposures are less well studied. We examined the relationship between brain health and prolonged exposure to different harmful substances in 498 male participants average age 68 (range 61 to 73) from the Vietnam Era Twin Study of Aging (VETSA). For self-reported tobacco smoke, herbicides/pesticides, and metal dust we created three groups reflecting recency of exposure (current/former/never). For Agent Orange we examined two exposure groups (ever/never). Brain health, defined as predicted brain age (PBAD), was evaluated by applying Brain-Age Regression Analysis and Computation Utility software (BARACUS) to magnetic resonance images collected at age 68. Tobacco smoking was significantly correlated with PBAD and remained significant in multivariate analyses adjusted for age, socioeconomic status (SES), age 20 general cognitive ability, and non-independence of twins within pairs. Never smokers had significantly younger brains than current or former smokers. PBAD did not differ for current versus former smokers. In other analyses, more advanced PBAD was associated with non-amnestic MCI. In this sample, tobacco smoking had the strongest relationship with overall brain health in late midlife compared with other types of environmental exposures, reinforcing its role in pathological aging and its importance as a public health priority."} +{"text": "Recent findings suggest that childhood exposures can lead to chronic inflammation decades later, but the mechanisms underlying this relationship are relatively unknown. We investigate how childhood exposures influence adult chronic inflammation (measured by C-reactive protein) and examine five potential mediators comprising two midlife domains: socioeconomic status (SES) and health lifestyles. Using a sample of 8,891 adults aged 51 and older from the Health and Retirement Study (HRS), the analysis tests whether these life course mediators operate differently for Black, White, and Hispanic Americans. Among the six childhood domains examined, low SES and risky parental behaviors predict adult chronic inflammation, but adult health lifestyles mediate the effects of childhood SES and parental behavior. Adult SES also mediates the effect of childhood SES. Smoking and wealth exert stronger direct and indirect effects on adult inflammation for White Americans compared to Black Americans whereas BMI and exercise exert stronger direct and indirect effects for White Americans compared to Hispanic Americans. Although education mediated the effect of childhood SES on adult chronic inflammation, its effects did not vary by race. These results demonstrate that the physiological consequences of childhood exposures are carried into late-life via adult lifestyle factors and SES. In addition, the life course antecedents of chronic inflammation are distinct for Black, White, and Hispanic Americans. Future research investigating the early origins of adult health should consider not only multiple midlife mechanisms but also how resource mediation varies by race and ethnicity."} +{"text": "The nonunion of distal phalangeal communized fracture is relatively rare in hand fractures. However, if it occurred, the surgical treatment is quite difficult because of small piece of fragmentations. We developed a new fixation method that involves the insertion of two wires and external wire compression fixation using a metal clamp. The aim of this technique was to increase the compression force between fragments and rigidity of conventional percutaneous Kirschner wire fixation. Here, we present a patient with the nonunion of distal phalangeal communized fracture who was satisfactorily treated with open reduction and percutaneous interfragmentary compression fixation with a linking external wire fixator (the Ichi-Fixator system). Such a treatment that enables compression fixation for communized distal phalangeal fracture of nonunion will clearly boost bone healing. Linked external wire-type compression fixator (the Ichi-Fixator system) enables enhanced security of fixation and facilitates the bone healing. Distal phalangeal fractures can be managed conservatively with good outcomes if diagnosed early. However, if the initial reduction is imperfect with total displacement between fragments such as communized fracture, then it may be necessary to use headless screw or Kirschner wire (K-wire) for fixation after closed or open reduction. Moreover, if conservative treatment failed, fracture site was occupied by soft tissue and fibrous connective tissues and finally become nonunion. Treatment of nonunion will need to firmly fix at fracture site after sufficient refreshment for increasing the bone union rate. The treatment options for nonunion of distal phalangeal fracture include conservative management with use of ultrasound , bone grrd distal phalangeal fracture was made based on radiographs and computed tomography scans. Anteroposterior, lateral, of the right middle finger showed dorsal displacement of the distal phalangeal fracture, with communized fracture treatment of distal phalangeal nonunion. This system enables to increase the compression force at the nonunion site compared with conventional percutaneous K-wire fixation."} +{"text": "Cardiac regenerative therapy is expected to be a promising therapeutic option for the treatment of severe cardiovascular diseases. Artificial tissues or organoids made from cardiovascular cell lineages differentiated from human induced pluripotent stem cells (iPSCs) are expected to regenerate the damaged heart. Even though immune rejection rarely occurs when iPSC-derived graft and the recipient have the same HLA type, in some cases, such as tissue transplantation onto hearts, the HLA matching would not be sufficient to fully control immune rejection. The present review introduces recent immunomodulatory strategies in iPSC-based transplantation therapies other than MHC matching including the induction of immune tolerance through iPSC-derived antigen-presenting cells, simultaneous transplantation of syngeneic mesenchymal stem cells, and using the universal donor cells such as gene editing-based HLA modulation in iPSCs to regulate T cell compatibility. In addition, we present future perspectives for proper adjustment of immunosuppression therapy after iPSC-derived tissue/organoid-based cardiac regenerative therapies by identifying biomarkers monitoring immune rejection. Cardiovascular diseases are leading causes of death and medical expenditure worldwide even recent progresses in medical treatments . TherapeAn immunological privilege of iPSCs in regenerative medicine is that autologous iPSCs which are considered to be immunologically identical with the host can be established from the host somatic cells and used for transplantation therapies . HoweverMacaca fascicularis). iPSCs from MHC-homozygous animals were differentiated into cardiomyocytes (iPSC-CMs) and subsequently transplanted to MHC-matched monkeys by direct intramyocardial injection. The grafted cardiomyocytes showed electrically coupling to the host heart and survived without immune rejection in monkeys treated with clinically relevant doses of immunosuppressants, whereas the transplantation of iPSC-CMs to MHC-mismatched monkeys even treated with immunosuppressants exhibited immune rejection of grafted cardiomyocytes with severe infiltration of T lymphocytes [Several allogeneic transplant models have been tested to validate whether the use of HLA-homozygous iPSCs can mitigate immune rejection. The experiments using cynomolgus monkeys demonstrated that immune rejection is rarely detected in allograft transplantation differentiated from major histocompatibility complex (MHC) type-matched iPSC. In transplantation experiments of retinal pigment epithelial (RPE) cells derived from monkey MHC-homozygous iPSCs, fair engraftment of RPE cells transplanted to MHC-matched animal models was confirmed without the use of immunosuppressants . Anotherphocytes .On the other hand, the benefits of MHC-matching seem to be alleviated in transplantation of iPSC-derived bioengineered heart tissues which is a promising strategy in cardiac regenerative medicine to promote therapeutic efficiency \u201323. KawaIn this context, several attempts have been made to overcome immune rejection through strategies other than HLA-matching so far. One of the promising strategies is the induction of immune tolerance in iPSC-based transplantation. There are two pathways in immune tolerance: central pathway by selective elimination of self-antigenic immune cells in the thymus and bone marrow and peripheral pathway. An important mechanism for this peripheral pathway of immune tolerance is the immunosuppression mediated by regulatory T cells (Tregs) Fig. a. Tregs Therapeutic approaches for the establishment of immune tolerance are reported so far Table . Otsuka + cytotoxic T cells against the transplants which accordingly achieved the induction of immune torelance [In addition to the induction of immune tolerance by antigen-presenting cells of identical MHC type, tolerance induction using syngeneic mesenchymal stem cells (MSCs) has also been reported Fig. b. Yoshidorelance .+ cytotoxic T cells. The modulated iPSCs were also protected from immune responses from natural killer cells because HLA-C, HLA-E, HLA-F, and HLA-G were preserved. Differentiated cells from the modulated iPSCs would be considered as an immunologically ideal cell source for transplantation therapies with enhanced immunocompatibility suppressing immune rejection after transplantation. It is also estimated that only 12 strains of iPSCs with HLA modulation theoretically cover more than 90% of the population worldwide which encourages the establishment of clinical-grade human iPSC bank covering almost all mankind [Another intriguing approach is HLA modulation in iPSCs to regulate T cell compatibility which depends on HLA types Fig. c. Xu et mankind . Even thCRISPR-Cas9 and other gene-editing systems have recently been used to create donor cells that escape interference from the immune system . As previously described, it is not only possible to genetically modify the expression patterns of HLA class I and class II, but also to apply the immune escape mechanisms that occur in nature, such as cancer cells and placentas, to prevent the expansion of T cells and NK cells and promote Treg cell responses. Recently, some groups reported the creation of universal donor cells expressing immunomodulatory transgenes that have improved viability in allogeneic transplants . On the Although aforementioned approaches may possibly solve the problems in iPSC-based transplantation immunity, it remains to be further investigated whether these approaches will sufficiently work in iPSC-based cardiac regenerative therapies considering possible severe immunological circumstances of the heart. Another immunological consideration in iPSC-based cardiac regenerative therapies is the possible transition of transplantation subjects from \u201ccells\u201d to \u201ctissue/organoids\u201d . This paIt also means that immune regulation strategies which would even work in organ transplantation would be required in future iPSC-based cardiac regenerative therapies based on iPSC-derived tissue/organoid transplantation. Given the long history of research on immune rejection in organ transplants , it woulA strategy for the alleviation of immunosuppressant-related complications is to establish a system that can detect immune rejection in daily clinical practices to precisely control the immunosuppression level Fig. . To consIn the present review, we introduced present status and possible immunological problems in iPSC-based transplantation therapies including ongoing research attempts for immune regulation such as production of \u201ccells that control the immune system\u201d and \u201ccells that get past the immune system.\u201d Further investigations on immune regulation are required for standardization of iPSC-derived cardiac regenerative therapy based on distinctive features of iPSC-based tissue/organoid transplantation of the heart."} +{"text": "With the emergence of affordable, clinical-orientated gait analysis techniques, clinicians may benefit from a general understanding of quantitative gait analysis procedures and their clinical applications. This article provides an overview of the potential of a quantitative gait analysis for decision support in three clinically relevant scenarios of early stage gait disorders: scenario I: gait ataxia and unsteadiness; scenario II: hypokinesia and slow gait; scenario III: apparently normal gait with a specific fall tendency in complex mobility situations. In a first part, we justify the advantages of standardized data collection and analysis procedures including data normalization and dimensionality reduction techniques that facilitate clinical interpretability of instrument-based gait profiles. We then outline typical patterns of pathological gait and their modulation during different walking conditions and highlight key aspects that are particularly helpful to support and guide clinical decision-making. Gait instability is prevalent in patients with balance problems, vertigo, and dizziness, and is associated with adverse health outcomes. Depending on the underlying disease entity, the risk of falling and consequent injuries is markedly increased . Falls aIn this context, quantitative, instrument-based gait analysis is a promising tool to capture and accurately assess gait function. Clinical approaches with a justifiable trade-off between the clinical benefit and infrastructural resources have been recently established. Central for clinical implementation of these techniques is application of standardized protocols for the recording, the analysis, and the interpretation of clinical gait profiles. Clinical experience and evidence from several studies emphasize that clinical gait examination should in particular assess patients\u2019 gait function during different walking conditions , 8, 15. This article provides an overview of typical alterations of spatial and temporal gait features related to three basic syndromic scenarios: (1) gait ataxia and unsteadiness of gait with fall risk; (2) hypokinesia and slow gait; (3) fall tendency in complex situations . A special emphasis is placed on the relevance of gait findings for supporting clinical differential diagnosis.\u00ae, CIR System, Franklin, NJ, USA). A multi-condition assessment protocol with walking at self-chosen walking speed (PWS), at slow speed (SS), at maximally fast speed (MS), with reclination of the head (HR), with eyes closed (EC), with performance of a serial seven dual task (DTC), with performance of a verbal fluency dual task (DTS), and while carrying an empty tray (DTM) was performed as described elsewhere [The clinical gait profiles, which are discussed in the subsequent paragraphs were recorded on a pressure-sensitive gait carpet . The healthy control group was collected by direct recruitment and covers the age spectrum from 18 to 99\u00a0years. The resulting data are arranged in a color-coded data matrix that at first glance provides a rapid overview on the individual patient\u2019s gait performance under various challenging conditions in comparison to age- and gender-matched healthy reference performance , gait paThe hallmarks of the gait impairments in patients with sensory deficits, cerebellar disorders, or functional ataxia comprise\u00a0distinct alterations in variability and support domains of walking. Accordingly, the spatial and temporal variability of stepping is typically increased in these cohorts \u2014a gait aWalking pace in patients with cerebellar and sensory ataxia is typically preserved or only slightly decreased. This observation can be explained by the fact that sensory integration for gait stabilization is speed dependent and less essential during fast locomotion . AccordiThe characteristic modulation of ataxic gait impairments during multi-condition gait assessment can further support the differential diagnosis in the context of gait ataxia. Slow walking modes accentuate gait instability in patients with vestibular and cerebellar disorders, in particular in terms of a considerably increased gait variability . As mentHypokinetic gait patterns can be observed in patients with Parkinsonism, patients with subcortical vascular encephalopathy (SAE), and patients with normal pressure hydrocephalus (NPH). The general identification of hypokinetic gait is not challenging for experienced neurologists. Typical features of gait impairments related to this syndromic category include a reduction of stepping pace, a reduced stride length, and reduced foot clearance during swing phases. Variability measures can be increased, especially in the late course of disease or when freezing-of-gait episodes are present . PatientIn hypokinetic gait disorders, alterations of gait parameters typically persist during all examination conditions. Patients with SAE or NPH show a further decline of walking performance during cognitive dual task , 26, 30\u2014Besides the interaction of sensory feedback with supraspinal and spinal locomotor regions, human postural control also relies on cognitive and attentional capacities. Patients with mild cognitive dysfunctions frequently consult clinical centers for balance problems due to apparent locomotion impairments. They typically report a slowing of gait during real-world mobility and the occurrence of falls in complex mobility situations. The clinical examination of sensory functions and simple motor tasks does not show any significant findings in these patients. Instrument-based gait analysis shows normal gait performance during single-task walking, but typically yields strikingly abnormal findings during cognitive dual-task conditions. Accordingly, walking pace and stride length become considerably decreased and walkDisturbances of mobility and gait are major symptoms of patients with balance disorders, dizziness, or vertigo. They are related to deteriorations of the functional status and to severe health outcomes, such as falls and fall-related morbidity . The cli"} +{"text": "Mild traumatic brain injury (mTBI) represents more than 80% of total TBI cases and is a robust environmental risk factor for neurodegenerative diseases including Alzheimer\u2019s disease (AD). Besides direct neuronal injury and neuroinflammation, blood\u2013brain barrier (BBB) dysfunction is also a hallmark event of the pathological cascades after mTBI. However, the vascular link between BBB impairment caused by mTBI and subsequent neurodegeneration remains undefined. In this review, we focus on the preclinical evidence from murine models of BBB dysfunction in mTBI and provide potential mechanistic links between BBB disruption and the development of neurodegenerative diseases. Traumatic brain injury (TBI) is a leading cause of death and long-term disability around the world . Based oThe BBB is a highly selective membrane that mainly encompasses endothelial cells, sealed by tight junctions, and fortified by pericytes and astrocytic endfeet . This coMore importantly, clinical data indicated that BBB impairment can persist for many years and is highly associated with long-term neurological deficits in mTBI patients . TherefoMurine models have helped us tremendously to understand the pathogenic events after mTBI, including cerebral microvascular injury and BBB dysfunction. We searched over 6,000 publications related to mTBI on PubMed and found 232 studies potentially covering cerebrovascular impairment and BBB dysfunction . Among tin vivo imaging techniques including magnetic resonance imaging (MRI) and multi-photon imaging; and (iii) additional methods such as brain water content calculation for cerebral edema (wet/dry weight ratio). Analysis of the protein and mRNA expression of tight junction protein was also reported.We surveyed the BBB dysfunction and relevant pathologic changes found in mouse or rat models, covering the acute and subacute stages that evolve within the first 2 weeks after mTBI and the chronic stage that usually takes place 2 weeks after mTBI. The methods commonly used for BBB functional analysis in murine models are (i) histological assessment using plasma proteins such as immunoglobulin G (IgG) and/or exogenous tracers such as Evans blue dye, horseradish peroxidase (HRP), or fluoresce labeled albumin; (ii) via the in vivo two-photon imaging of intravenously injected rhodamine B. They showed that BBB disruption in wild-type C57BL/6 mice occurred at a very early stage of mTBI (between 5 and 60 min), which was even exacerbated in Slit2-Tg mice when compared with controls. Similar situations were also reported from patients diagnosed with concussion in adolescent sports and military service, which can be exacerbated by repetitive mild trauma injury . There aMechanistically, impairment of BBB can initiate a series of adverse events, including the leakage of serum-derived circulating agents into the brain parenchyma and improper activation of signaling pathways . As someMild traumatic brain injury is considered a long-term risk for neurobehavioral changes, cognitive decline, and neurodegenerative disease including AD . CognitiIn this review, we focused on BBB dysfunction after mTBI in murine models and found that BBB breakdown and microvascular impairment are important pathological mechanisms for cognitive impairment after mTBI. Restoring vascular functions might be beneficial for patients with mTBI and reduce the risk of developing cognitive impairments post-insult.ZZ and YW designed the review outline, wrote and reviewed the review, did the literature search, and data extraction and interpretation. HW, XG, and BP provided critical reviews, revised the manuscript, and provided relevant insights and edits. All authors read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "During recent years, Graduate Medical Education (GME) leaders in the United States of America have witnessed many substantive changes, including movement to a single accreditation system under the Accreditation Council for Graduate Medical Education. Both MD- and DO-trained residents and faculty must now meet an increasingly stringent set of accreditation standards outlined in Next Accreditation System standards. Specifically, updated scholarly activity standards emphasize a consistent volume and quantity of quality improvement/research projects and dissemination products. The GME literature to date has frequently provided general commentaries regarding individual project strategies or oriented to settings with greater project-related resources. There have also been few articles offering scholarly activity planning strategies for community-based GME officials striving to increase scholarly activity levels.The authors propose a customizable assessment-planning framework, largely derived from their combined decades of consultation experiences with hundreds of community-based resident and faculty projects. The authors will first describe the primary elements of their proposed scholarly activity planning approach for GME leaders so often subject to worsening resource constraints. They will describe six ongoing developmental strategies with several exemplars described. Such a framework will likely require ongoing reassessments and modification.The authors hope that this proposed planning framework will offer GME administrators, faculty and residents with a pragmatic set of strategies to develop scholarly activity projects and supports. Ideally, GME leaders can use this approach to inform their design of a sustainable system-customized infrastructure of scholarly activity supports. Next Accreditation System (NAS) standards.During recent years, the nation\u2019s graduate medical education (GME) leaders in the United States have witnessed substantive changes, including movement to a single accreditation system under the Accreditation Council for Graduate Medical Education (ACGME). Both MD and DO-trained resident and faculty physicians must now meet an increasingly stringent set of accreditation standards outlined in scholarly activity (SA) projects.SA to refer to both research and systems-oriented QIPS designs. Although both academic and community-based GME physicians contend with increasing resource constraints, a growing number of authors have contended that these types of challenges may be greater (or certainly different) in community-based GME settings.One particular standard that many GME authors have struggled to address relates to the enhanced requirements for Unfortunately, GME officials still lack a uniform definition of what comprises a minimal level of SA.More GME experts have concluded that community-based physicians may typically experience greater difficulty planning and conducting SA projects due to fewer available resources .Some GME authors have implemented SA resident teams, generally comprised of residents from multiple programs with complementary SA project interests.GME administrators have appointed later-year residents to chief research/QIPS resident positions to coordinate SA projects in some settings.Many authors have argued that any such mechanisms need to be modified due to system or program-specific influences, and that a standardized rollout approach is unlikely to work across diverse GME settings.Numerous experts have already shown that customized SA planning tools can help facilitate SA project development.non-sequential and ongoing strategies to enable community-based GME leaders to facilitate increased SA levels. The authors will also describe several exemplary settings with ongoing SA infrastructure developments.The SCS authors have developed this comprehensive planning approach from their 2016-2017 experiences consulting on over 210 community-based SA projects. Resident and faculty project leaders have requested SA consultations from many of the 190+ SCS-affiliated residency programs based at 37 healthcare systems. This paper will: a) describe the key elements of the authors\u2019 suggested SA developmental planning approach, and b) discuss six The first goal of this proposed SA planning framework is to provide community-based GME leaders with a specific set of criteria to assess their current in-house project resources and complexities. The authors propose that this approach will prove especially important for GME officials striving to first develop or improve their SA project supports. The authors have repeatedly seen that many community-based leaders\u2019 success in increasing their SA levels have required a broader perspective than simply completing a series of individual projects and dissemination products. In this paper, they assert that the longer-term development of a sustainable SA infrastructure of project supports will prove integral for maintaining SA productivity in lesser-resourced GME settings.lessons learned from earlier SA projects in their healthcare system. GME experts have increasingly supported this broader type of ongoing self-learning model of SA development that entails ongoing reassessments and modification efforts.stop and start approach to SA will impede the development of a sustainable SA project support infrastructure so later project leaders may feel as if they are starting from scratch.The key elements of this planning framework are largely derived from the authors\u2019 successful workshop, online module and individual consultation experiences with community-based GME leaders. They have concluded that many faculty and residents develop idealized projects without capitalizing on on-site resources, and/or conduct projects without the cultural realities: Faculty and resident SA attitudes and beliefs, varied specialty perspectives, perceived availability of project supports and mentoring.Referring to the upper-left of Figure 1, an effective SA support infrastructure should be oriented toward first developing projects that specifically capitalize on available specific resources, such as institutional review board (IRB) guidance, health library and data-capable personnel,Referring to the middle of Figure 1, certainly each SA project will need to be developed within the context of each project team\u2019s competing role demands .Referring to the right of Figure 1, over time, both the volume and quality of SA projects and dissemination products can be expected to increase and GME leaders may be able to realistically expect that improved SA levels will eventually impact patient care processes and outcomes.The following ongoing developmental strategies are encouraged for community-based GME leaders striving to attain an organized SA project support infrastructure:Periodically assess your project planners\u2019 SA learning needs and preferences by promoting available resources in an ongoing manner.It is also been shown to be necessary to periodically gauge the key learning needs of faculty and residents concerning SA projects.The SCS authors have generally concluded that many primary care physicians tend to prefer GME or QIPS project designs than surgical/procedure-oriented clinicians more oriented to complex research designs .Plan-Do-Check-Act planning sheets, pertinent articles, project conduction checklists, etc.) can prove key for first meeting the needs and preferences of lesser experienced project learners.GME leaders can certainly improve perceptions of available SA project resources by purposefully disseminating information concerning library, electronic health record and QIPS department materials and resources.non-human subjects, exempt, expedited, full review).GME officials should also periodically consider how their respective IRB have been distinguishing different types of SA projects by perceived level of research risks or types of suggested IRB applications program.One exemplar Te4Q learner was an emergency medicine physician who completed the program in 2016 after testing a QIPS curriculum with his senior chief resident.He had subsequently delivered this curriculum to two cohorts of residents with little SCS support. His curriculum-related projects have subsequently contributed at least a dozen regional/national resident poster presentations and two SA publications to date.Systematically embed SA planning activities into your pre-existing GME processes/groups.The GME literature contains a growing number of examples of how SA experts have incorporated project planning/evaluation activities into their current GME program/staff meetings.regular part of doing business in the minds of more residents and faculty.This approach may help SA activities become perceived as a Conduct a postmortem evaluation of every SA project and attempt to derive pragmatic system-specific knowledge for future projects.football coach analogy to GME officials striving to strengthen their SA team over several years by evaluating SA project successes and lessons. This routine practice of informing project novices about earlier project successes/failures may be integral for them to develop system-compatible projects. It is also unrealistic to expect a subset of residency programs or personnel to conduct most ongoing SA projects.writing mentor mechanisms since the responsibility of project leaders to report their community-based results in the GME literature remains increasingly important.GME officials may underestimate the impetus for future projects potentially derived from completed SA projects.The growing complexities of publishing one\u2019s final project results in many GME journals due to increased article processing fees and greater publication competition certainly needs to be acknowledged.Consider how to attain maximal SA efficiencies in your GME environment.Desire To Learn online course management software. QIPS in Healthcare: Origins and Principles, b) Research and QIPS: Differences and Similarities, c) Feasible Project Design Strategies, d) Preparing your IRB Application, and e) Building a Program of Scholarly Activity as a GME Leader. Between January 2016 and March 2018, 87 users have been enrolled and made over 280 group/individual module hits.Since many community-based GME leaders continue to experience worsening resource constraints, it may only be realistic to offer workshop/training content through coordinated asynchronous and online mechanisms.A growing number of GME experts have also indicated that it may become increasingly impractical for individual settings or programs to achieve sustainable SA progress without some type of intuitional/consortium coordination.There will never likely be any standardized solutions for development of sustainable project support SA infrastructures across our nation\u2019s diverse GME settings.This paper presents a non-sequential developmental planning approach comprised of strategies for community-based GME officials striving to address emerging accreditation standards. As GME setting conditions change, leaders\u2019 implemented SA project supports may require ongoing trial and error adjustments.The authors declare no conflict of interest."} +{"text": "Studies using data from longitudinal health survey of older adults usually assumed the data were missing completely at random (MCAR) or missing at random (MAR). Thus subsequent analyses used multiple imputation or likelihood-based method to handle missing data. However, little existing research actually examines whether the data met the MCAR/MAR assumptions before performing data analyses. This study first summarized the commonly used statistical methods to test missing mechanism and discussed their application conditions. Then using two-wave longitudinal data from the Health and Retirement Study , this study applied different approaches to test the missing mechanism of several demographic and health variables. These approaches included Little\u2019s test, logistic regression method, nonparametric tests, false discovery rate, and others. Results indicated the data did not meet the MCAR assumption even though they had a very low rate of missing values. Demographic variables provided good auxiliary information for health variables. Health measures met the MAR assumptions. Older respondents could drop out and die in the longitudinal survey, but attrition did not significantly affect the MAR assumption. Our findings supported the MAR assumptions for the demographic and health variables in HRS, and therefore provided statistical justification to HRS researchers about using imputation or likelihood-based methods to deal with missing data. However, researchers are strongly encouraged to test the missing mechanism of the specific variables/data they choose when using a new dataset."} +{"text": "Infections induce dramatic rearrangements in host macro- and micronutrient processes and like\u201cAntagonistic\u201d interactions between a host and a microbe involve host defense mechanisms that maintain the host\u2019s fitness status while having a negative impact on microbial fitness. By contrast, \u201ccooperation\u201d between a host and a microbe involves host mechanisms that promote host fitness while having a neutral to positive influence on microbial fitness . These mThe role of iron regulatory pathways in immunity against pathogens has been well studied (reviewed in ). HoweveSiderophores are molecules that chelate external iron with high affinity and transport iron into microorganisms through dedicated transport systems . Thus, sCaenorhabditis elegans physiological development [Fig 1A). Microbe-derived Ent was found to bind to the alpha subunit of the host mitochondrial ATP synthase, thereby increasing mitochondrial iron levels and host development under both low and high iron conditions. We propose that this work exemplifies iron-mediating cooperative host\u2013microbe interactions because development of the host facilitates replication, nutrient acquisition, and transmission of enterobacteria. Given that other canonical virulence factors for acquiring host iron are present in commensal or beneficial microbes, future work should reassess the role of these systems with the perspective of cooperative host\u2013microbe interactions.In addition to the role of siderophores in antagonistic host\u2013microbe coevolution, siderophores are also critical for interspecies competition between members of the microbiota . These ielopment Escherichia coli and Vibrio vulnificus, suggesting that transient hypoferremia is an effective metabolic defense to restrict certain extracellular pathogens [Salmonella enterica, Burkholderia pseudomallei, Chlamydia spp., and Legionella pneumophila [During acute infections, individuals experience inflammation-dependent hypoferremia . Hepcidiathogens , 21. Intumophila \u201324.Fig 1B). Regulation of iron levels was necessary for proper microbiome composition and mucosal repair because cDC-specific hepcidin-deficient mice were slower to recover following intestinal damage [In addition to hepatocytes, myeloid cell types are also a source of hepcidin production . In respl damage . TherefoDuring infections, microbial and host-derived toxic compounds can be generated that cause tissue damage. Detoxification mechanisms serve as antivirulence mechanisms to promote cooperative defenses by preventing damage to the host without affecting pathogen burdens . During Plasmodium or subjected to intestinal perforation leading to systemic bacterial infection [Plasmodium infection [Research into heme recycling and detoxification demonstrates the importance of these pathways for cooperative defenses . Heme denfection , 30. Thinfection , therebynfection . The HO-nfection . Given tFig 1C). Weis and colleagues established that the ferritin, the intracellular iron storage protein, regulates hepatic gluconeogenesis and is critical for host survival during polymicrobial sepsis [Recent dietary and metabolic studies in animals and humans link iron metabolism to glucose homeostasis at many levels (l sepsis . Knockoul sepsis . These sCitrobacter rodentium [C. rodentium infection caused increased tissue iron levels in the WAT and insulin resistance. The insulin resistance caused a reduction in the amount of glucose absorbed from the intestine into the bloodstream, increasing the amount of glucose available to the pathogen to metabolize, which suppressed the virulence program of C. rodentium [Sanchez and colleagues found that administration of dietary iron and transient insulin resistance promotes survival of mice given oral doses of the diarrheal pathogen odentium . Dietaryodentium . Consistodentium . The worodentium . TogetheAn entire field, called nutritional immunity, has focused on iron and other micronutrients in antagonism between host and invading microorganisms . Some in"} +{"text": "Background: An estimated 25% of older adults with diabetes (DM) may have co-occurring Alzheimer\u2019s Disease and Related Dementias (ADRD), complicated by multiple treatment plans and providers. Assessing treatment burden has been limited to patients\u2019 perspectives; little is known about caregiver perceptions of treatment burden despite their important role in personal care and treatment adherence. The purpose of this qualitative study was to describe caregiver perceptions of treatment burden for older adults with DM-ADRD. Methods: This qualitative study was conducted in the formative phase of \u201cEnhanced Quality in Primary care for Elders with DM-ADRD (EQUIPED-ADRD) a pragmatic randomized controlled trial in a large, diverse healthcare system. A diverse sample of caregivers (n=15) of patients enrolled in the RCT participated in interviews about their caregiver role and perceptions of treatment burden of DM-ADRD clinical management. Qualitative data were analyzed using content analysis and themes about treatment burden were compared to domains on the Treatment Burden Questionnaire (TBQ). Results: Caregivers reported high levels of burden related to treatment plans for patients with DM-ADRD. Themes related to complexity and burden of medication management, monitoring , dietary and physical activity regimens, navigating healthcare providers and financial burden were reported. Caregivers also described high levels of emotional burden that was associated with patient\u2019s cognitive decline and family functioning stress. Conclusions: Interventions to reduce treatment burden for patients and caregiver should include activating social/nursing services, respite care and care coordination that may support caregivers especially as patient treatment increases in complexity over time."} +{"text": "Chronic condition discordance has adverse mental health implications but little is known about mechanisms accounting for these links. We considered how chronic condition discordance at the individual level and the couple level was associated with perceived control among 2,676 couples from three waves of the Health and Retirement Study. Dyadic growth curve models revealed that when wives had greater individual-level discordance, they reported lower initial health-related control and personal mastery and steeper reductions in personal mastery. When husbands had greater individual-level discordance, they reported lower initial health-related control and faster declines in health-related control and personal mastery, and wives had faster declines in personal mastery. When there was greater couple-level discordance, wives reported lower initial health-related control. Targeting increases in perceived control among older couples managing complex conditions may be beneficial. Part of a symposium sponsored by Dyadic Research on Health and Illness Across the Adult Lifespan Interest Group."} +{"text": "A standardized approach to annotating computational biomedical models and their associated files can facilitate model reuse and reproducibility among research groups, enhance search and retrieval of models and data, and enable semantic comparisons between models. Motivated by these potential benefits and guided by consensus across the COmputational Modeling in BIology NEtwork (COMBINE) community, we have developed a specification for encoding annotations in Open Modeling and EXchange (OMEX)-formatted archives. Distributing modeling projects within these archives is a best practice established by COMBINE, and the OMEX metadata specification presented here provides a harmonized, community-driven approach for annotating a variety of standardized model and data representation formats within an archive. The specification primarily includes technical guidelines for encoding archive metadata, so that software tools can more easily utilize and exchange it, thereby spurring broad advancements in model reuse, discovery, and semantic analyses."} +{"text": "Over one in four older adults (65 years and older) in the US reports falling annually with estimated medical costs of $50 billion. Evidence-based strategies exist that can reduce falls with one of the most promising being multifactorial, clinically-based initiatives such as the Centers for Disease Control and Prevention\u2019s STEADI Initiative. STEADI includes three core components for health care providers: screen for risk factors, assess modifiable factors, and intervene to reduce falls with evidence-based strategies. Barriers to implementation include competing patient demands and limited time during patient visits. Efficient, effective implementation of clinical fall prevention is important to increase the use of multifactorial interventions. In addition, understanding older adult attitudes about the preventability of falls is needed to increase patient adherence to prescribed interventions. This symposium will cover:1. Background data on older adult falls over time,2. Description of an initial implementation of STEADI in an outpatient, Southeastern clinical practice including lessons learned,3. Attitudes of older adults toward fall prevention with implications for health promotion,4. Process evaluation of an ongoing implementation of STEADI in New York State with lessons learned. Understanding practical methods of implementing the three core components of fall prevention into practice supports wider dissemination of evidence-based fall prevention, while understanding patient attitudes toward falls informs the design of health promotion approaches to increase patient uptake of prescribed interventions. Wider dissemination and increased patient adherence in combination can reduce older adult falls and their associated medical costs."} +{"text": "Late-life suicide is a complex public health issue, and older adults have a higher risk threshold than the national average . Most late-life suicide research focuses on elevated risk of older white males, and less is known about risk factors among Black older adults . Although fewer Black older adults die by suicide than White older adults, forms of suicidality do not differ between Black and White older adults . Suicide risk factors, such as psychological distress and chronic pain , are prevalent among Black older adults. According to the Interpersonal Theory of Suicide , thwarted belongingness and perceived burdensomeness inform the development of suicidal desire. These findings have been corroborated among older adult samples, though lacking racial diversity. To better understand how the IPTS functions for older adults, and probe whether suicide risk pathways operate differently depending on race, we used data from over 400 homebound older adults residing in a U.S. metropolitan area to clarify if this suicide risk pathway is similar for Black and White older adults. Race moderated the relationship between physical and psychological pain and thwarted belongingness and perceived burdensomeness, with pain among Black older adults having a greater impact on their sense of belonging and burdensomeness. Findings illuminate the need for culturally nuanced understandings of suicidality in older adulthood. The presenters will demonstrate these results and discuss implications for cross-cultural suicide prevention frameworks."} +{"text": "Assisted living (AL) communities are increasingly home to frail, chronically ill older adults who remain until death. State laws mandate that AL facilities request copies of any advance care planning documents residents have and make forms available upon request. Using secondary data from a larger study funded by the National Institute on Aging (R01AG047408) that focuses on end-of-life (EOL) care in AL, this project investigated barriers and facilitators to conducting advance care planning in AL. Data included in-depth interviews (of 86 minute average length) with 20 administrators from 7 facilities around the Atlanta metropolitan area and aggregate data collected from each facility regarding facility, staff, and resident characteristics. Findings from thematic analysis of qualitative data showed that key barriers to planning in AL included lack of staff training and reluctance among administrators and families to discuss advance care planning and EOL care. Important facilitators included periodic follow-up discussions of residents\u2019 wishes, often during care plan meetings, educating families about the importance of planning, and external support for staff training and family education from agencies such as hospice and home health. Three study facilities exceeded state requirements to request and store documents by systematically encouraging residents to complete documentation. These facilities, whose administrators discuss advance care planning and residents\u2019 EOL wishes with residents and families during regular care plan meetings, were more likely to have planning documents on file, demonstrating the potential of long-term care communities, such as AL, to successfully promote advance care planning among residents and their family members."} +{"text": "Adenosarcoma is an extremely rare malignancy of the female genital tract composed of stromal sarcoma with a benign epithelial component. Current treatment recommendations include total hysterectomy with bilateral salpingo-oophorectomy, precluding future fertility. Although most frequently diagnosed in postmenopausal women, it is occasionally present in younger women of reproductive age with desire for future fertility. In 2015, we reported the case of a 23-year-old patient diagnosed with uterine adenosarcoma, who having strong desire of future fertility, opted for fertility sparing surgery. At a follow-up five years later, we can now report her case of spontaneous pregnancy and livebirth. A review of the literature concerning fertility outcomes in patients with uterine adenosarcoma undergoing fertility sparing therapeutic options is presented. Uterine adenosarcoma (UA) is a rare gynaecological malignancy composed of sarcomatous stroma and a benign epithelial component . While tLee et al. describeA proposed fertility sparing treatment protocol includes fertility sparing surgery (FSS) consisting of a complete resection of the lesion followed by medical treatment with megestrol acetate 160 mg/day for at least 6 months. Once the desire for fertility is fulfilled, hysterectomy with bilateral salpingo-oophorectomy is recommended. A fertility sparing treatment protocol must be performed only in low-risk cases and close longterm follow-up is needed . PatientIn 2015, a nulliparous 23-year-old woman referred to our institution was diagnosed with UA stage IA according to FIGO 2009 criteria. Due to her strong desire of future fertility, after extensive counselling she opted for FSS. Hysteroscopic complete resection of the tumour was performed, followed by oral megestrol acetate 160 mg/d as adjuvant therapy . This waMullerian adenosarcoma is a rare gynaecological cancer composed of a benign epithelial component with sarcomatous stroma . Total hAdenosarcoma is an extremely rare gynaecological malignancy with only a few cases reported in patients of reproductive age. The current recommended treatment is hysterectomy with bilateral salpingo- oophorectomy, however, fertility sparing treatment options are feasible in selected patients.In cases of focal tumours without sarcomatous overgrowth and without sign of infiltration or metastasis, a fertility sparing approach may be proposed to young women diagnosed with UA and who strongly wish to preserve their fertility. There is currently insufficient evidence regarding the ideal follow up protocol for patients diagnosed with UA who are managed with FSS."} +{"text": "Diversity and inclusion are essential perspectives on university campuses. In recent years, there has been a nationwide decline in admissions resulting in changes to traditionally FTIAC driven college campuses. An environmental scan was completed at a mid-sized midwestern university to explore age-inclusive barriers and opportunities for change. In-depth interviews were held with 28 EMU stakeholders representing a wide variety of ages in leadership positions across campus. Students aged 40 and above (N=248) were also surveyed about their experiences on campus. Qualitative analysis revealed ageist attitudes about older adults and older students from at all levels of the university. Results demonstrate that initial responses to \u2018age-friendly\u2019 focused on stereotypes of older adults, but attitudes adjusted when reframed as older learners and further refined when older learners were defined as 40 and above. Additionally, there was a distinct disconnect between ageist perceptions towards older adults and older students which highlights the importance of intergenerational opportunities as an approach to combat ageist attitudes on campus. While these barriers require long-term and complicated solutions, participants described the many benefits that older learners bring to enrich the campus. Results of this research revealed opportunities to reframe aging in the context of diversity and inclusion efforts on campus. Adopting diversity efforts to include age can benefit universities in not only admissions, classroom experiences, and connections to surrounding communities."} +{"text": "Tachycineta bicolor). We address two questions: (1) do the cloacal bacterial communities differ between female and male tree swallows within a population? and (2) do pair-bonded social partners exhibit more similar cloacal bacterial communities than expected by chance? To answer these questions, we sampled the cloacal microbiome of adults during the breeding season and then used culture-independent, 16S rRNA gene amplicon sequencing to assess bacterial communities. Overall, we found that the cloacal bacterial communities of females and males were similar, and that the communities of pair-bonded social partners were not more similar than expected by chance. Our results suggest that social monogamy does not correlate with an increased similarity in cloacal bacterial community diversity or structure. As social partners were not assessed at the same time, it is possible that breeding stage differences masked social effects on bacterial community diversity and structure. Further, given that tree swallows exhibit high variation in rates of extra-pair activity, considering extra-pair activity when assessing cloacal microbial communities may be important for understanding how these bacterial communities are shaped. Further insight into how bacterial communities are shaped will ultimately shed light on potential tradeoffs associated with alternative behavioral strategies and socially-transmitted microbes.Host-associated microbial communities can influence the overall health of their animal hosts, and many factors, including behavior and physiology, can impact the formation of these complex communities. Bacteria within these communities can be transmitted socially between individuals via indirect or direct pathways. Limited research has been done to investigate how social interactions that occur in the context of mating shape host-associated microbial communities. To gain a better understanding of these interactions and, more specifically, to assess how mating behavior shapes an animal\u2019s microbiome, we studied the cloacal bacterial communities of a socially monogamous yet genetically polygynous songbird, the North American tree swallow ( Host-associated microbial communities can contribute to the overall health of their animal hosts \u20134, and mTachycineta bicolor) and house sparrows (Passer domesticus). More recent work using culture-independent methods has revealed that pair-bonded social partners experimentally blocked from making cloacal contact have significantly less similar cloacal bacterial communities compared to control pairs in black-legged kittiwakes (Rissa tridactyla) )munities . Given tStaphylococcus spp., Campylobacter spp., Salmonella spp., and Shigella spp. In our study, we used culture-independent, next-generation sequencing. We did not find that any of the cloacal bacteria they cultured were members of the core bacterial communities of birds within our study population. While Staphylococcus spp. and Lactobacilli were detected, their relative abundances were <0.001%. This suggests that culturing of cloacal bacteria may not consistently result in isolation of the most dominant bacteria in the system. It is also possible that the bacteria cultured by Lombardo et al. [Previous work examining the similarity of the cloacal bacteria of social partners in tree swallows used culture-dependent methods . The isoo et al. are rareIn conclusion, our results suggest that the cloacal bacterial communities of female and male tree swallows are similar within our study population and that pair-bonded social partners do not share more similar cloacal bacterial communities than expected by chance. Given that tree swallows exhibit high variation in rates of extra-pair activity, we argue that considering rates of extra-pair activity or the number of sexual partners per bird when assessing cloacal bacterial communities may be important for understanding how cloacal bacterial communities are structured. Also, since cloacal bacterial communities comprise bacteria derived from both the reproductive and digestive tract, diet should also be considered when assessing cloacal bacterial communities. Lastly, we suggest that pair-bonded social partners should be sampled simultaneously to control for any temporal shifts in individual behavior and physiology that may influence shifts in cloacal bacterial community structure across breeding stages."} +{"text": "The Tailored Activity Program (TAP) is a proven program delivered primarily by occupational therapists addressing dementia-related clinical symptoms including caregiver well-being. Although used in 9 countries including the United States, scaling and widespread dissemination is challenging. We discuss key revisions to TAP to facilitate dissemination including matching assessments to those used in different practice settings, translation of materials into different languages, providing worksheets to help trainees adapt TAP to local contexts and a training/certification online experience using story board, an interactive media integrated onto the Blackboard learn management system, to provide on-demand training modules. The learning platform allows learners to engage with others, preview modules and share experiences. Revisions enable greater flexibility for program adaptation yet adherence to its core principles. With over 150 trainees, we use REAIM to evaluate effectiveness of modifications and to understand implications for its reach. Part of a symposium sponsored by the Behavioral Interventions for Older Adults Interest Group."} +{"text": "Hematopoiesis and bone interact in various developmental and pathological processes. Neurogenic heterotopic ossifications (NHO) are the formation of ectopic hematopoietic bones in peri-articular muscles that develop following severe lesions of the central nervous system such as traumatic cerebral or spinal injuries or strokes. This review will focus on the hematopoietic facet of NHO. The characterization of NHO demonstrates the presence of hematopoietic marrow in which quiescent hematopoietic stem cells (HSC) are maintained by a functional stromal microenvironment, thus documenting that NHOs are neo-formed ectopic HSC niches. Similarly to adult bone marrow, the NHO permissive environment supports HSC maintenance, proliferation and differentiation through bidirectional signaling with mesenchymal stromal cells and endothelial cells, involving cell adhesion molecules, membrane-bound growth factors, hormones, and secreted matrix proteins. The participation of the nervous system, macrophages and inflammatory cytokines including oncostatin M and transforming growth factor (TGF)-\u03b2 in this process, reveals how neural circuitry fine-tunes the inflammatory response to generate hematopoietic bones in injured muscles. The localization of NHOs in the peri-articular muscle environment also suggests a role of muscle mesenchymal cells and bone metabolism in development of hematopoiesis in adults. Little is known about the establishment of bone marrow niches and the regulation of HSC cycling during fetal development. Similarities between NHO and development of fetal bones make NHOs an interesting model to study the establishment of bone marrow hematopoiesis during development. Conversely, identification of stage-specific factors that specify HSC developmental state during fetal bone development will give more mechanistic insights into NHO. Heterotopic ossification (HO) is an abnormal development of bone tissue within soft tissue. HO can be hereditary such as Fibrodysplasia Ossificans Progressiva (FOP) or acquired following traumatic injuries and burns . Among aACVR1 gene encoding a type I BMP receptor . The patIt is currently admitted that NHOs are the result of an endochondral ossification process although intramembranous ossification has also been suggested . Foley eThe development of heterotopic bones in muscles after severe CNS trauma raises interesting stem cell biology questions particularly regarding the cells-of-origin of NHO. Adult skeletal muscles contain two major types of progenitor cells participating in muscle regeneration. Myogenic satellite cells (SCs) are CD56 expressing stem cells located between the basal lamina and myofiber plasma membrane. To regenerate damaged myofibers, activated SCs proliferate, differentiate into myoblasts and fuse to form multinucleated myofibers with the support of macrophages, endothelial cells (ECs), fibroblasts and pericytes or FAPs (via a Prrx1 gene enhancer transgene) are specifically labeled, we find that following SCI, NHO are derived from Prrx1 expressing FAPs, not from Pax7 expressing SCs and central (SCI) neurologic lesions have an effect on FAPs, inducing STAT3 activation, high IL-6 secretory activity and abnormal proliferation . FurtherThe presence of ectopic hematopoietic bones developing in muscles following CNS injuries is puzzling for the hematologist since, in adults, hematopoiesis is physiologically restricted to the BM of skeletal bones.During fetal development, blood formation occurs in discrete anatomical extraembryonic and intraembryonic niches, generating different hematopoietic cell (HC) types . First HSchofield first used the term \u201cniche\u201d to describe a putative HSC-specific environment in the BM that \u201cpreserved the reconstituting ability of stem cells\u201d . SuccessWithin these niches, HSCs are maintained quiescent by a complex molecular interplay between cells from mesenchymal origin, ECs, neuronal cells and HSC progenies, such as megakaryocytes and macrophages. Diffusible factors including inflammatory cytokines and extra-cellular matrix components perfect this molecular network, subtly controlling the fate of HSCs .Apart from stromal cells, macrophages are essential to HSC regulation within niches. They are the most abundant HCs in the dorsal aorta when the number of intra-aortic hematopoietic cluster peaks, and are suggested to promote definitive HSC formation from the dorsal aorta hemogenic endothelium through pro-inflammatory signaling cascades . Among tIn the context of NHO, it is noteworthy to integrate the role of the nervous system as an important regulator of bone remodeling and hematopoiesis homeostasis. Since the discovery of skeleton innervation by Besides its role in energy homeostasis, leptin plays a major role in neuroendocrine regulation and bone metabolism. The expression of leptin receptor on adult MSCs, osteoblasts and chondrocytes, suggests direct effects on bone growth and metabolism. Leptin can also indirectly modulate bone formation through effectors downstream of the hypothalamus such as estrogen, cortisol, IGF-1 and parathyroid hormone, and through activation of local adrenergic signaling at the osteoblast level via \u03b22 adrenergic receptors (AR) . SensoryAs reported above, HSCs are mainly located in perivascular areas of the adult BM, comprising both sinusoidal and arteriolar blood vessels. The arteriolar structures are highly innervated by SNS fibers. The neuroreticular complex formed by SNS nerves and perivascular MSCs has been reported to be a central regulator of HSC quiescence within BM niches mice that lack osteoblasts and osteolineage cells, the vasculature within the nascent bones and bone marrow can sustain multilineage proliferative progenitors but not long-term HSCs. As a result, wild-type HSC transplanted in Osx embryos engraft the liver but not the nascent BM. Therefore, interactions with osteoblasts within fetal bone regulate HSC quiescence and homing ability (Cxcl12 or Kitl gene from Osx+ osteoprogenitors has more effect on hematopoietic progenitors than on proper HSCs (Lepr+ MSCs (that form osteoprogenitors) for HSCs to be maintained (In Osterix-null (Osx ability . In the per HSCs . In contintained . These rUnderstanding the development of hematopoiesis in an adult osteogenic muscle environment as observed in NHO could help gain further insights on the role of bone forming cells in this process. Identification of stage-specific factors that orientate HSC developmental state during fetal bone development must be harnessed to gain more mechanistic insights into NHO development. Similarly, understanding the cellular origin of NHO, the role of inflammation and muscle environment might contribute to a better understanding of the impact of specific niche components on fetal BM HSC properties.In the recent few years, knowledge about NHO pathogenesis has been considerably improved as accredited by the rapidly increasing number of publications in the field. These progresses were mainly due to the development of more suitable animal models and to the availability of patient samples thanks to well organized cohorts. The current review focusing on the hematopoietic features of NHO ossifications, attempts to recapitulate how a favorable environment for the development of bone with HSC niches can develop in adult muscles following central neurological lesions. It emphasizes the role of a persistent inflamed muscle environment driving FAPs to an osteogenic fate initiating the development of ossification followed by the establishment of a mature hematopoietic bone tissue.However, there are still numerous questions in respect to the molecular mechanisms underlying this complex and multifactorial pathological process. Among those, the potential differences between normal endochondral ossification and neurogenic HO in terms of signaling events, cell type involvement and environment remains unanswered. Likewise, how an inflamed adult muscle environment becomes pro-osteogenic and thereafter hematopoietic, and what is the influence of altered nervous and neuroendocrine systems as well as hypoxia in this process? Does the neoformation of hematopoietic bones in muscles mimic what happens during development and can we learn from NHO for a better identification of stage-specific factors that specify HSC developmental state during fetal bone development? Is the impaired mobility of patients a trigger in the development of NHO and does an early and adequate mobilization of patients can avoid or at least reduce its evolution?Gathering surgeons, clinicians, specialists in physical medicine/rehabilitation and researchers within a European/International consortium would be a provocative initiative for developing translational collaborative projects to better understand NHO pathogenesis and, armed with this knowledge, enable the identification of new targets to treat and if possible prevent NHO development. Moreover, such knowledge may also provide new insights for cell therapy needs and for improving treatment of blood and bone disorders.DG, FT, EO, KA, JG, H-WT, MS, J-PL, M-CL, and SB wrote the manuscript. DG, EO, M-CL, and SB prepared the figures. All authors revised the manuscript and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Family caregivers often manage complex medical/nursing tasks (MNTs) for older adults returning home after a hospitalization. The purpose of this qualitative study was to describe caregivers\u2019 experiences leveraging diverse resources to manage MNTs for older adults receiving post-acute home health care services (HHC). In-depth telephone interviews were conducted with 20 caregivers of older adults who received HHC following hospitalization. Interviews were digitally audio-recorded, transcribed, and analyzed using directed content analysis. The Theory of Dependent-Care informed the analytical framework. We organized codes using three theoretical constructs related to managing older adults\u2019 MNT care needs (\u201ctasks related to the other\u201d), accessing existing social/environmental resources (\u201ctasks related to the situation of care\u201d), and working with the healthcare system (\u201ctasks related to the system of care\u201d). Caregivers\u2019 descriptions of MNTs included the complexity and socioemotional impact of assisting in these tasks . When needed, caregivers\u2019 accessed social and environmental resources to help address the older adults\u2019 care needs. Caregivers also identified challenges and strategies for navigating and coordinating care and services within HHC and the larger healthcare system. Caregivers assisting with complex MNTs in the post-acute HHC setting need additional training and support. HHC providers can actively engage caregivers by tailoring training and support strategies, assessing social and environmental contexts and resources, and facilitating caregivers\u2019 navigation of the healthcare system. Future research could elucidate social and environmental factors associated with successful collaborative relationships among providers, older adults and their caregivers in the post-acute HHC setting."} +{"text": "Research demonstrates reciprocal relationships between personality and depression as well as the important role interpersonal conflicts play, but rarely explores these risk factors in older adults. This study aimed to examine relationships of personality traits, processes, and the impact of emotional involvement and distress during an interpersonal conflict on depression in older adults. The study also investigated whether emotional involvement or interpersonal distress moderate the relationship between personality pathology and depression. Depressed middle and older adult inpatients completed self-reports and interview-based assessments regarding personality traits , interpersonal problems (IIP-25), and depression (GDS). Narrative responses regarding an interpersonal conflict were obtained and rated for contamination themes as well as emotional involvement and distress. Overall, findings indicated that living with others predicted higher depression (p= .046) and was related to higher neuroticism and interpersonal problems. Personality traits (Neuroticism) and processes , as well as higher levels of emotional distress and involvement in an interpersonal conflict were also tied to depression in bivariate but not multivariate analyses. The moderating effects of emotional involvement or distress on the relationship between personality and depression were not supported. Depressed older inpatients who live with others appear at higher risk of depression. Personality traits and processes may be more distal risk factors for depression. Findings are discussed in relation to stress generation as well as clinical implications targeting emotional regulation."} +{"text": "Dear Editor th, they confirmed that they had identified a new coronavirus, which is a family of microRNA respiratory viruses including the common cold, and viruses such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). This new virus was temporarily named \u201c2019-nCoV\u201d. Wuhan city is a major international transport hub. This report to World Health Organization (WHO), raised global public health concern because this is the third coronavirus \u2013associated acute respiratory illness outbreak. On 31 December 2019, Chinese authorities reported the increase in incidence of severe pneumonia in Wuhan city, Hubei province of China. One week later, on January 7Currently, up to the date of submitting this letter, 4593 cases of 2019-nCoV infections have been confirmed globally, both in China and outside of China (56 confirmed in 14 countries.). WHO risk assessment of 2019-nCoV infection is Very High in China and High in other countries or severe pneumonia, Acute Respiratory Distress Syndrome (ARDS), sepsis and septic shock. Patients with pre-existing medical comorbidities develop a more severe disease and have higher mortality rates compared to patients who do not have any comorbidity.Clinical care of patients with suspected 2019-nCoV should focus on early recognition, immediate isolation (separation), implementation of appropriate infection prevention and control (IPC) measures and provision optimized supportive care. At the triage of an Emergency room, early recognition of suspected patients allows for timely initiation of IPC. 2019-nCoV should be considered as a possible etiology of influenza like illness (ILI) under certain situations according to case definitions of WHO or non-invasive ventilation (NIV) should be used in selected patients with hypoxemic respiratory failure. Hypoxemic respiratory failure due to ARDS among these patients commonly results from intrapulmonary ventilation-perfusion mismatch or shunt and usually requires mechanical ventilation. Thus, rapid sequence intubation should be performed using airborne precautions. Implementation of mechanical ventilation using lower tidal volumes (4-8 ml/kg predicted body weight) and higher positive end-expiratory pressure (PEEP) is suggested. Patients with SARI should be treated cautiously with intravenous fluids when there is no evidence of shock, because aggressive fluid resuscitation may worsen oxygenation. For resuscitation of septic shock in adults, at least 30 ml/kg of isotonic crystalloid should be infused in the first 3 hours of shock identification and in children rapid bolus of 20 ml/kg as loading dose and up to 40-60 ml/kg of isotonic crystalloid infusion in the first hour of shock identification is needed. Vasopressor should be administered when shock persists during or after fluid resuscitation. If signs of poor perfusion persist despite reaching mean arterial pressure (MAP) target (i.e. >65 mmHg) with fluids and vasopressor, consider administering an inotrope such as dobutamine. Empiric antimicrobials should be initiated within one hour of identification of sepsis to treat all likely pathogens causing SARI. Empiric antibiotic treatment should be based on the clinical diagnosis of severe pneumonia or sepsis, local epidemiology and susceptibility data as well as treatment guidelines. If influenza is also a concern and there is a local circulation of influenza virus, a neuraminidase inhibitor should be adjoined to empiric therapy. Empiric antibiotic therapy should be de-escalated on the basis of microbiology results and clinical judgment. Systemic corticosteroids should not be routinely adding to therapy unless indicated for another reason. Collection of clinical specimens for laboratory diagnosis is suggested in early outbreak period and after that it is only advised for investigational purposes. If laboratory diagnosis is considered, serology is recommended only when RT-PCR is not available. Otherwise, HCW should collect specimens from both the upper respiratory tract and lower respiratory tract for testing 2019-nCoV via RT-PCR should be developed and implemented in the emergency departments, as the frontline of treating human infections of 2019-nCov in the hospitals."} +{"text": "Increased systolic blood pressure (SBP), pulse pressure and carotid-femoral pulse wave velocity (cfPWV) are strong predictors of cardiovascular events. The aorta and carotids are both elastic arteries susceptible to arterial stiffening and its deleterious complications. The relative importance of ascending aortic and carotid stiffness on central arterial stiffness remains unclear.Our aim was to study the relationship of local arterial stiffness in the carotid and ascending aorta to central arterial stiffness assessed by cfPWV and peripheral BP.We studied 22 healthy subjects . Central arterial stiffness was determined using carotid and femoral tonometry and transit surface distances (cfPWV). Distensibility of the ascending aorta was calculated as the ratio of its transverse area change on MRI to the central pulse pressure from radial tonometry arterial waveforms using a transfer function. Carotid distensibility was calculated as the ratio of transverse area change by sonography to carotid pulse pressure by tonometry. Local stiffness indexes of carotid and aorta were calculated from distensibility by the reverse Moens-Korteweg equation. Peripheral SBP and pulse pressure were averages of 6 brachial measurements. Linear regression was used to study correlations between aortic and carotid stiffness and cfPWVAortic stiffness has a significantly stronger correlation than carotid stiffness with: age , peripheral SBP , pulse pressure , and cfPWV . In multivariate analysis with simultaneous adjustment for age, body mass index, SBP, pulse pressure, aortic stiffness and carotid stiffness, aortic stiffness is the strongest independent determinant of cfPWV (p = 0.013), SBP (p = 0.005) and pulse pressure (p = 0.01).Stiffness of the ascending aorta is a stronger predictor of cfPWV and peripheral SBP and pulse pressure than carotid stiffness among healthy individuals. This is consistent with heterogenous age-related stiffening of large arteries."} +{"text": "This study reviews the existing literature on psychiatric interventions for individuals affected by the COVID-19 epidemic. My article cumulates previous research on how extreme stressors associated with COVID-19 may aggravate or cause psychiatric problems. The unpredictability of the COVID-19 epidemic progression may result in significant psychological pressure on vulnerable populations. Persons with psychiatric illnesses may experience worsening symptoms or may develop an altered mental state related to an increased suicide risk. The inspected findings prove that psychological intervention measures for patients affected by the epidemic should be designed and personalized adequately. Preventive measures seek to decrease infection rates and cut down the risk of the public healthcare system to eventually be overburdened. Throughout the COVID-19 crisis, people with psychiatric illnesses may confront a decrease in mental health services. As limitations in the current review, by focusing only on articles published in journals indexed in Web of Science, Scopus, and ProQuest, I inevitably disregarded other valuable sources. Subsequent research directions should clarify the effectiveness of online mental health services in providing remote psychiatric interventions to individuals affected by the COVID-19 epidemic. COVID-19 has placed a significant strain on health systems on a large scale . There mAdequate conformity to spatial distancing in addition to home confinement, self-isolation, and quarantine may have the repercussion of social disconnection with adverse effects for psychological wellbeing . The manOn The COVID-19 epidemic has generated extreme stressors that may aggravate or cause psychiatric problems, affecting the brain or generating immune reactions. Emotional responses comprise intense psychosocial distress and insecurity. Such patients need timely, precise information concerning approaches for diminishing risk.COVID-19 pandemic-related, compulsory self-isolation, home confinement, and quarantine are related to poor psychological and physical health . Taking On Infectious disease outbreaks such as COVID-19 bring about mental health conditions as individuals\u2019 emotional reactions tend to comprise extreme fear and confusion, while their anxious responses may lead to socially disruptive behaviors. Symptoms such as anxiety, nervousness, and insomnia may occur in COVID-19 infected patients with psychiatric disorders.The level of risk of COVID-19 spread among persons having a severe mental illness may be more significant than that in the general population, as a consequence of constant unhealthy behaviors and standards of living . IndividAs On People with mental health disorders may be more considerably affected by the emotional reactions generated by the COVID-19 epidemic. Affected individuals are exposed to mental health disorders and suicidal ideation and behavior, resulting in pervasive emotional distress and heightened risk for psychiatric disorders. Social relationships are pivotal in suicide prevention.The swift spread of COVID-19 and important death rate may aggravate the risk of mental health issues and intensify current psychiatric symptoms, damaging their proper functioning and cognition to a greater extent . The conThe author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Long-term care residents with and without cognitive impairment may experience undertreatment of persistent pain . Certified nursing assistants (CNAs) are important sources of information about resident pain as they provide the majority of residents\u2019 hands-on care. Therefore, assessing the accuracy of CNAs\u2019 pain assessments and potential influencing factors may provide insight regarding the undertreatment of pain. Informed by prior research, this study examined resident pain catastrophizing and cognitive status as predictors of CNAs\u2019 pain assessment accuracy. CNA empathy was examined as a moderating variable. Analyses confirmed a relationship between pain catastrophizing and CNA pain rating accuracy , reflecting lower accuracy of ratings for residents higher in catastrophizing. Hypotheses predicting a relationship between resident cognitive status and CNA pain rating accuracy and moderating effects of empathy were disconfirmed. Challenges of conducting research in long-term care are discussed."} +{"text": "Objective: Using the stress-coping theory, the aims of the present study were to test what levels of caregiving intensity posed the most negative influence on caregiver burden as well as how social support moderated such associations among dementia caregivers. Methods: Data from the baseline assessment of the Resources for Enhancing Alzheimer\u2019s Caregiver Health (REACH II) (N = 637) were used. Caregiver burden , caregiving intensity (caregiving hours), and social support were the main measurements. Separate multivariate regression models were conducted with Stata 16. Results: The results showed that the relationships between caregiving hours and caregiver burden were nonlinear after controlling all of the socio-demographic variables. Further analyses showed that when caregiving hours reached 13.50 hours per day, the levels of burden were the highest. In addition, received social support, satisfaction with social support, and social network significantly moderated the relationship between caregiving hours and caregiver burden among dementia caregivers when they were examined separately. However, only social network played a significant moderator role when examining the four social support indicators simultaneously. Discussion and conclusion: These findings suggest the need for programs and practices on educating caregivers regarding how to identify, approach, and gain social support/s, especially in how to broaden the caregivers\u2019 social network while caring for a family member with dementia."} +{"text": "Carefully maintained and precisely inherited chromosomal DNA provides long-term genetic stability, but eukaryotic cells facing environmental challenges can benefit from the accumulation of less stable DNA species. Circular DNA molecules lacking centromeres segregate randomly or asymmetrically during cell division, following non-Mendelian inheritance patterns that result in high copy number instability and massive heterogeneity across populations. Such circular DNA species, variously known as extrachromosomal circular DNA (eccDNA), microDNA, double minutes or extrachromosomal DNA (ecDNA), are becoming recognised as a major source of the genetic variation exploited by cancer cells and pathogenic eukaryotes to acquire drug resistance. In budding yeast, circular DNA molecules derived from the ribosomal DNA (ERCs) have been long known to accumulate with age, but it is now clear that aged yeast also accumulate other high-copy protein-coding circular DNAs acquired through both random and environmentally-stimulated recombination processes. Here, we argue that accumulation of circular DNA provides a reservoir of heterogeneous genetic material that can allow rapid adaptation of aged cells to environmental insults, but avoids the negative fitness impacts on normal growth of unsolicited gene amplification in the young population. E. coli and asexual yeasts reveal that strains with high mutation rates outperform those with low mutation rates, showing that mutation provides an adaptive advantage to several megabases are highly focused in aged cells and are suggested to drive premature ageing and shortened lifespan , and is instead generated from chromosomal DNA at such a high rate that simple asymmetric retention of the newly generated copies in the mother cell is sufficient for CUP1 accumulation , the most transcribed protein-coding gene in muscle tissue, is also the largest producer of circular DNA per gene (Moller et al. Excitingly we have observed that the rate of copy number variation events including circular DNA formation is not completely random, which may improve this cost\u2013benefit balance for aged cells (Hull et al. By itself, an adaptive phenotype in an individual aged cell is of little use if the causal circular DNA is selfishly retained in the mother cell, as would be the case if asymmetric segregation is maintained, and we must consider how circular DNA accumulation is translated into a heritable advantage. First, once circular DNA has accumulated, segregation can be relaxed under stress allowing circles with replication origins to propagate at high copy number in the population Fig.\u00a0, step 5aThe idea that a sub-population trades short-term growth for adaptive capacity is formalised in bet-hedging (concisely reviewed in (Levy et al."} +{"text": "The primary impact of ventilation and ventilatory efforts on left ventricular (LV) function in left ventricular dysfunction relate to how changes in intrathoracic pressure (ITP) alter the pressure gradients for venous return into the chest and LV ejection out of the chest. Spontaneous inspiratory efforts by decreasing ITP increase both of these pressure gradients increasing venous blood flow and impeding LV ejection resulting in increased intrathoracic blood volume. In severe heart failure states when lung compliance is reduced, or airway resistance is increased these negative swings in ITP can be exacerbated leading to LV failure and acute cardiogenic pulmonary edema. By merely reversing these negative swings in ITP by the use of non-invasive continuous positive airway pressure (CPAP), these profoundly detrimental forces can be immediately reversed, and cardiovascular stability can be restored in moments. This forms the clinical rationale for the immediate use of CPAP for the treatment of acute cardiogenic pulmonary edema. Increasing ITP during positive pressure ventilation decreases the pressure gradients for venous return and LV ejection decreasing intrathoracic blood volume. In a hypovolemic patient even with LV dysfunction this can result in hypotension due to inadequate LV preload. Minor increases in ITP as occur using pressure-limited positive-pressure ventilation primarily reverse the increased LV afterload of negative swings in ITP and if fluid overload was already present, minimally alter cardiac output. The effect of changes in lung volume on LV function are related primarily to its effects on right ventricular (RV) function through changes in pulmonary vascular resistance and overdistention (hyperinflation). In acute lung injury with alveolar collapse, positive pressure ventilation may reduce pulmonary vascular resistance if alveolar recruitment predominates. Hyperinflation, however, impedes diastolic filling while simultaneously increasing pulmonary vascular resistance. Thus, increasing lung volume can reduce RV afterload by reversing hypoxic pulmonary vasoconstriction or increase afterload by overdistention. Hyperinflation can also impede RV filling. All of these processes can be readily identified at the bedside using echocardiography. Understanding the hemodynamic coupling of the heart and lungs plays a significant role in managing patients in the critical care setting. The basic heart-lung physiology has been discovered earlier in the collection of papers. Understanding diastolic and systolic left heart failure is of upmost importance when treating patients with a variety of other common medical conditions such as sleep apnea, ARDS and COPD as these conditions are deeply intertwined. These interactions are magnified in the setting of decreased left ventricular (LV) function. Here we seek to explain how clinical presentations affect the left ventricle and how management of these conditions can have a profound effect on LV function. For simplistic sake, the forces that cause clinically relevant heart-lung interactions are illustrated in There are multiple aspects of cardiopulmonary physiology that affect patients with heart failure. Lung volume and hyperinflation affect autonomic tone and pulmonary vascular resistance. In 1966 de Burgh Daly et al. showed that the correlation between systemic vascular resistance and ventilation was secondary to reflexes from intrapulmonary receptors altered by changes in lung volume. Lung inflation by either negative or positive intrathoracic pressure (ITP), in the setting of blocked carotid sinus and aortic arch baroreceptors, led to an immediate decrease in systemic vasomotor tone . FurtherHere we will discuss the importance of heart-lung interactions in various clinical scenarios including acute cardiogenic pulmonary edema (ACPE), ventilatory weaning, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (OSA), and acute respiratory distress syndrome (ARDS).Left heart failure can be characterized by systolic dysfunction, diastolic dysfunction, or both. In developed countries, systolic ventricular failure is most commonly associated with ischemia and hypertension, which also contributes to diastolic dysfunction. In other parts of the world, Chagas disease and rheumatic heart disease are more prevalent causes. Understanding heart lung interactions is essential for the management of all left heart failure patients. Negative intrathoracic pressure leads to increased LV transmural pressure increasing LV afterload. In patients with left heart failure, negative swings in intrathoracic pressure can markedly decrease LV ejection leading to rapid increases in LV filling pressure and secondary (hydrostatic) pulmonary edema. The spontaneous breathing efforts also represent a metabolic stress on the body. During periods of increased work of breathing, spontaneous ventilation increases oxygen demand of respiratory muscles as well as of the myocardium and may induce circulatory insufficiency and visceral organ ischemia .Based on these principles the primary treatment of acute cardiogenic pulmonary edema should be the immediate abolishment of negative swings in ITP. While hypovolemic patients may decrease their cardiac output when positive pressure ventilation is initiated due to the decrease in preload (moving leftward on the ventricular function curve), these effects are minimized if continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) are used in patients with acute heart failure, because the spontaneous inspiratory efforts remain but the negative swings in ITP are markedly diminished or abolished. Thus, CPAP and BiPAP selectively reduce LV afterload shifting the ventricular function curve upward in patients with acute heart failure without decreasing venous return. Numerous clinical trials have shown the immediate beneficial cardiovascular effects of initiating CPAP or BiPAP. These findings were reinforced by a meta-analysis by Weng et al. showing less need for endotracheal intubation and a trend toward reduced mortality when non-invasive ventilation is initiated on patients presenting with acute cardiogenic pulmonary edema . UnfortuPatients subjected to hyperinflation and increased juxtacardiac pressure will experience a drop in biventricular volumes. Furthermore, some of these effects, including decreased vasomotor tone, may be affected by induction of anesthesia during initiation of mechanical ventilation. Lung inflation with volumes less than 10\u00a0mL per kilogram of body weight leads to vagal tone withdrawal and, consequently, an increase in heart rate. This is known as respiratory sinus arrhythmia. On the other hand, lung hyperinflation with volumes greater than 15\u00a0mL per kilogram of body weight leads to vagal tone activation and sympathetic tone withdrawal. In such cases, patients exhibit a decrease in blood pressure secondary to vasodilation from a decrease in systemic vasomotor tone. Many patients with LV failure are also hypervolemic owing to increased antidiuretic hormone activation. Thus, in volume overloaded patients with heart failure, initiation of mechanical ventilation and some degree of lung hyperinflation will decrease preload, cause vasodilation and, thereby, decrease intrathoracic blood volume. In those settings, the slight decrease in LV afterload may augment LV ejection keeping cardiac output constant despite a sustained increase in ITP. These are the reasons why patients with LV failure usually tolerate intubation and positive-pressure ventilation well without secondary post-intubation hypotension .Weaning patients from positive pressure ventilation results in several processes occurring simultaneously. First, respirations change from positive swings in ITP to negative swings in ITP. This must increase venous return and LV afterload. The combined effects of these two processes lead to an increase in intrathoracic blood volume. Second, metabolic demand increases as respiratory muscles resume their normal activity. Patients with increased work of breathing during weaning will experience sympathetic hyperactivation and catecholamine surge leading to increased heart rate and hypertension, which in turn will increase myocardial oxygen demand. If the work of breathing is excessive or LV functional reserve is too limited, then the patient will fail weaning. Weaning failure will manifest as acute cardiovascular collapse, hypotension, tachycardia, and even acute cardiogenic pulmonary edema. These hemodynamic changes can be ameliorated by restricting fluids, having the patients slightly hypovolemic and treating bronchospasm prior to extubation. Optimizing bronchodilation, avoiding volume overload and controlling afterload prior to weaning trials will facilitate liberation from mechanical ventilation .Patients with COPD can also have LV failure. Both COPD and obesity are associated with terminal airway collapse with increased shunt. COPD patients are more likely to experience hyperinflation owning to the increased airway resistance combined with increased lung compliance. These patients experience limitations in expiratory flow secondary to airway collapse. Both hyperinflation and dynamic hyperinflation can increase pulmonary vascular resistance and compress the heart within the cardiac fossa. The combined effects can worsen RV dysfunction by minimizing RV end-diastolic volume (EDV) while simultaneously increasing RV afterload. Patients with LV failure need a higher LV filling pressure and EDV to sustain LV stroke volume. Since hyperinflation compresses the heart, LV end-diastolic volume also decreases, and thus cardiac output often decreases during acute exacerbations of COPD in patients with LV dysfunction .Commonly, patients with LV failure develop RV failure. In such cases, increases in transpulmonary pressure secondary to lung hyperinflation lead to increased RV afterload and decreased RV ejection and RV stroke volume leading to systemic hypotension. In these circumstances, patients may experience acute cor pulmonale and RV ischemia. COPD exacerbations can cause hypoxemia, hypercapnia and increased sympathetic tone. Passive increases in pulmonary artery pressure due to increased LV filling pressure rarely cause enough increases in pulmonary artery pressure to result in acute RV failure. These three mechanisms increase pulmonary vasomotor tone. Patients with COPD may also have chronic pulmonary hypertension leading to RV hypertrophy. Increasing RV afterload increases RV end-systolic volume and, by extension, RV EDV. Clinically, these patients may present with increased jugular venous distension during spontaneous inspiration (Kussmaul\u2019s sign) and the shift in the intraventricular septum will decrease LV end diastolic compliance leading to decreased cardiac output Mooney . LimitataCO2 beyond the apneic threshold. Furthermore, episodes of hypoxia and waking from sleep lead to sympathetic activation, which further increases LV afterload and contributes to an increase in myocardial oxygen demand. Patients with OSA have intermittent hypoxemia and formation of free radicals and inflammatory molecules that lead to vascular remodeling. The negative swings in ITP during OSA lead to a combined increase in LV afterload and systemic hypoxemia. Thus, at the time that LV wall stress is increasing, myocardial oxygen delivery is being compromised. Over months, these repetitive OSA events lead to the development of congestive heart failure and a downward shift in the ventricular function curve. Acutely, the negative swings in ITP, hypoxia, and sympathetic surge lead to increased LV afterload and reactive systemic hypertension leading to increased myocardial metabolic demand. Chronically, these factors worsen LV hypertrophy, which in turn affects LV diastolic function. OSA has been associated with LV remodeling and increased incidence of cardiovascular disease . Nocturnal CPAP or BiPAP have been shown to improve outcomes in patients with disordered sleep. Specifically, OSA patients with heart failure demonstrate improvement in daytime off-CPAP LV function if the CPAP treatment abolishes the obstructive breathing patterns .Noncardiogenic pulmonary edema or ARDS is characterized by decreased lung volumes secondary to alveolar collapse and pulmonary congestion, increased dead space ventilation, hypoxemia and increased work of breathing. Often hypoxemia is not responsive to non-invasive ventilation and intubation with positive end-expiratory pressure (PEEP) is required to sustain gas exchange and minimize receptive alveolar collapse at end-expiration. The resultant higher mean and end-inspiratory airway pressure often further increase dead space ventilation. Dead space ventilation along with hypoxic pulmonary vasoconstriction secondary to alveolar collapse lead to increased pulmonary vascular resistance. This must impede RV ejection and increase RV EDV, which in turn decreases LV diastolic compliance by the process of ventricular interdependence. Indeed, Jardin et al. demonstrated many years ago that when ARDS patients were given high levels of PEEP their LV stroke volume decreased despite a high pulmonary artery occlusion pressure, used as a surrogate of LV EDV. However, when these same patients were fluid resuscitated to restore their LV EDV to their pre-PEEP levels, LV stroke volume also returned to its pre-PEEP value even though PEEP was still being used. This seminal work clearly demonstrated that lung hyperinflation and high levels of PEEP impair LV filling by decreasing LV diastolic compliance through the process of ventricular interdependence and increased juxtacardiac ITP. These points are described elsewhere in this series in greater detail .2 and optimal cardiac output for a given blood volume. Titrating PEEP based on RV systolic function and lung compliance is an important technique to monitor for developing RV failure and preventing PEEP too low that would worsen alveolar collapse and hypoxia or PEEP too high that would worsen PVR and RV afterload and, consequently, worsen LV diastolic filling and overdistention (increasing resistance). This elusive \u201csweet spot\u201d mean airway pressure that balances these two opposing effects is often equated to the point where PEEP maximizes lung compliance. Clinical studies suggest that the highest PEEP associated with the best value of lung compliance is also associated with better RV systolic function as measured using transesophageal echocardiography, least dead space ventilation, assessed as end-tidal CO filling .aCO2 levels are all predictive of the development of cor pulmonale in ARDS. Clearly, all these effects are predictable based on the above logic. Driving pressure is a surrogate of lung stress due to its effect on hyperinflation and pulmonary vascular resistance. Likewise, higher PaCO2 levels are indicative of increased dead space and lead to pulmonary vasoconstriction and increased pulmonary vascular resistance. Mitigating these factors is critical to avoid right heart failure, RV dilation and, consequently, poor LV diastolic filling and low output heart failure (Other investigators looked at variables that are prominent in patients with ARDS that develop cor pulmonale. These investigators concluded that pneumonia being the etiology of ARDS, driving pressure, worsening P:F ratio and rising P failure .Heart-lung interactions play a crucial role in understanding and managing patients with left heart failure under most conditions independent of ventilatory mode."} +{"text": "Behavioural supersensitivity may be a result of increased glutamate sensitivity of D2-MSN and reduced sensitivity to dopamine. We propose that clozapine may address behavioural supersensitivity by modulating glutamate activity which may partially explain its unique effectiveness in the setting of treatment resistant schizophrenia. The mainstay of schizophrenia treatment is chronic antipsychotic medication to prevent relapse of a psychotic episode. These antidopaminergic drugs reduce D2 dopamine receptor-mediated transmission. It has been proposed that relapse rates following antipsychotic discontinuation may be due to withdrawal phenomenon rather than due to illness recurrence . The leai intracellular signalling, behavioural supersensitivity was reversed [Kruyer et al. studied the mechanism of antipsychotic-induced behavioural supersensitivity and did not find any change in D2-receptor expression or function in mice administered chronic haloperidol, in the ventral striatum, dorsal striatum or midbrain and concluded neither D2-receptor expression nor the hypothesized increased function of the receptor could explain behavioral supersensitivity . Insteadreversed .Based on the above, Kruyer et al. propose D2-medium spiny neurons hyperexcitation in the nucleus accumbens core underpins neuropathology during chronic antipsychotic treatment, antipsychotic discontinuation and behavioural supersensitivity, such that chronic antipsychotic treatment possibly reduces modulatory dopaminergic input making D2-medium spiny neurons hyperexcitable to incoming excitatory transmission from glutamate . BehavioAntipsychotic-induced behavioural supersensitivity is postulated to reduce the efficacy of antipsychotic medication leading to increasing antipsychotic doses, tolerance and treatment resistance. It has also been possibly linked to the development of tardive dyskinesia which is a motor disorder known to be caused by prolonged antipsychotic exposure . A recenClozapine is a unique medication acting upon multiple receptors , and is 14and may also potentiate glutamate transmission by regulating glutamate transport [It has been hypothesised that clozapine may specifically modulate brain glutamate and that this effect could contribute to its unique efficacy for patients with treatment-resistant schizophrenia , 15. Gluransport . Tanahasransport also demransport . Clozapiransport . In an aransport and thisransport . Glutamaransport . Deficitransport .However, despite the evidence for glutamatergic dysfunction in schizophrenia, specific pharmacological strategies have so far been largely unsuccessful . These aThere is indirect evidence to support that the efficacy of clozapine in refractory schizophrenia may be related to its modulatory effect on glutamate activity \u201330. HoweThe efficacy of clozapine in reversal of tardive dyskinesia can provide indirect links to understand this mechanism further. Antipsychotic-induced behavioral supersensitivity has been considered a possible aetiological factor for the development of both treatment resistant schizophrenia and tardive dyskinesia . Meta-anKruyer et al., show antipsychotic-induced behavioural supersensitivity may be a consequence of hyperexcitation of D2 medium spiny neuron in the nucleus accumbens core, due to enhanced glutamatergic transmission . TherefoKruyer et al., have suggested the potential role of deep brain stimulation and transcranial magnetic stimulation, in reducing and preventing excitatory plasticity in D2 medium spiny neuron . HoweverUnderstanding the mechanistic basis for antipsychotic-induced behavioural supersensitivity may lead to better prevention efforts (reducing both antipsychotic dose and usage) as well as facilitate targeted treatments for supersensitivity psychosis and tardive dyskinesia. Future research should specifically investigate clozapine\u2019s role in antipsychotic-induced behavioural supersensitivity and the mechanism by which clozapine (and other therapeutic approaches) may modulate glutamate-induced excitability specifically within the striatum and the nucleus accumbens. Future controlled trials should be conducted studying the effect of clozapine, electroconvulsive therapy, deep brain stimulation, transcranial magnetic stimulation and other glutamate modulating compounds for the treatment of supersensitivity psychosis with concomitant assessment of glutamate activity within the striatum and nucleus accumbens. These studies may also help identify biomarkers for treatment resistant schizophrenia and possible predictors of clozapine response.The aetiology of treatment resistant schizophrenia is likely complex and treatments that just target either dopamine or glutamate transmission are less likely to be successful . There i"} +{"text": "IntroductionIn 2019, the Centers for Medicare & Medicaid Services (CMS) combined all autologous breast flap procedures under one billing code, effective from December 31, 2024. This change will result in equal insurance reimbursement rates for popular flap options, such as transverse rectus abdominis muscle (TRAM) and deep inferior epigastric perforator (DIEP) flaps, which were previously billed separately using S-codes based on complexity.MethodsThis study aimed to analyze insurance code changes for autologous breast reconstruction flap procedures. Data were collected from the American Society of Plastic Surgeons' annual plastic surgery statistics reports, including specific insurance codes and case volumes from 2007 to 2020. A comprehensive analysis was conducted to assess recent trends in flap utilization rates, documenting any modifications or additions to the existing codes and their implementation years.ResultsThe study analyzed billing codes and case volumes for autologous breast reconstruction procedures, with a focus on the DIEP flap and other alternatives. Non-autologous breast reconstruction procedures showed consistently higher case volumes compared to autologous procedures from 2007 to 2020. Notably, the popularity of the DIEP flap surpassed that of other flap options after 2011.ConclusionThe removal of S-codes for autologous breast reconstruction by CMS and the subsequent potential decrease in insurance coverage for the DIEP flap may lead to a decrease in its utilization and a shift toward\u00a0more invasive options, like the TRAM flap. This change could result in financial burdens for patients and widen socioeconomic disparities in breast reconstruction, limiting access to preferred reconstructive methods and impacting patient autonomy and overall well-being. In 2019, the Centers for Medicare & Medicaid Services (CMS) implemented a protocol to combine all autologous breast flap procedures under a single billing code, 193464 [Currently, most plastic surgeons receive reimbursement from insurance companies for specific flap reconstruction procedures with S-codes, such as S2068 for DIEP flap surgery, S2066 for the superior gluteal artery perforator (SGAP) flap surgery, and S2067 for stacked flap surgery, where multiple flaps are stacked on top of one another to accommodate for lack of flap volume with a single flap .\u00a0This diData collectionThe primary objective of this study was to comprehensively analyze insurance code changes concerning flap procedures for autologous breast reconstruction. To achieve this, we employed a meticulous data collection approach that involved gathering relevant information from multiple reliable sources.Sources of dataWe collected the necessary data from the annual plastic surgery statistics reports, which are published by the esteemed American Society of Plastic Surgeons . These rInsurance code identificationTo ensure a robust analysis, we first identified and compiled a comprehensive list of specific insurance codes associated with autologous breast reconstruction flap procedures . This liCase volume recordsThe case volume data for the autologous flap procedures were meticulously gathered from the annual plastic surgery statistics report . These cData analysisAfter obtaining the insurance codes and corresponding case volumes, we performed a detailed analysis to assess the impact of insurance code changes on the utilization of the DIEP flap procedure. First, we identified instances of insurance code changes related to the DIEP flap procedure by comparing the codes recorded in consecutive annual plastic surgery reports. Any modifications or additions to the existing codes were noted, and the corresponding years of implementation were documented. To examine the effect of code changes on the utilization of the DIEP flap, we compared the case volumes before and after each identified code change. This allowed us to assess any fluctuations in procedure frequency and identify potential trends related to insurance code modifications.Billing codes assessed through the annual plastic surgery statistics reportThe analysis focused on the insurance codes and case volumes associated with the DIEP flap procedure and other autologous flap alternatives, as obtained from the CMS . Table 1Case volume of autologous and non-autologous breast reconstructionNon-autologous breast reconstruction procedures had a higher case volume compared to autologous breast reconstruction procedures 168,652 cases) , \"stacked\" flaps, DIEP, and superficial inferior epigastric artery (SIEA) flaps. The findings are summarized in Table In 2021, the CMS discontinued S-codes for autologous breast reconstruction, making the 193464 billing code the sole source of insurance reimbursement for reconstructive breast procedures. In anticipation of these changes, several insurance companies have pre-emptively ceased coverage for the DIEP flap under S2068; other insurance companies are expected to follow [With the removal of appropriate additional reimbursement for the DIEP flap procedure, there is concern that breast reconstruction surgeons will decrease their DIEP flap case volume and potentially revert to utilizing more invasive autologous options, such as the TRAM flap ,7. WhileThere has been an increase in the frequency of DIEP flaps performed following the introduction of S-codes . This trWithout the additional reimbursement provided by S-codes, there is fear that surgeons cannot cover the DIEP procedure costs . For theFurthermore, these insurance changes may broaden the socioeconomic disparities in breast reconstruction . PatientSociodemographic factors currently represent disparities in autologous breast reconstruction and implant-based reconstruction ,20. PatiImplant-based reconstruction is another standard method for breast reconstruction. Some individuals prefer autologous tissue options due to their more natural feel and appearance. Additionally, increased reports and awareness of breast implant illness (BII) and breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has decreased interest in implant-based reconstructive options . The decLimitationsDespite the rigorous data collection and analysis, certain limitations must be acknowledged. The reliance on aggregated case volume data from annual reports might have introduced sampling bias, and the lack of individual patient data limited our ability to explore patient-specific factors. Additionally, the focus on a specific time frame (2007 to 2020) and the potential variability in insurance coding practices should be considered when interpreting the results. Nonetheless, our research serves as a foundation for further exploration and underscores the importance of monitoring insurance code updates in the realm of plastic surgery practices.Limiting access to alternative autologous reconstructive options for those recently afflicted by a life-threatening breast cancer diagnosis revokes patient autonomy and heightens socioeconomic health disparities. Introducing and popularizing the DIEP flap was a productive step forward in the field of breast reconstruction. In recent years, the usage and popularity of the DIEP flap have skyrocketed; however, recent changes in reimbursement can potentially result in an inflection point in the number of cases performed in the future. Limiting access to this option only to those who can pay out-of-pocket may dramatically impact\u00a0our patients' physical, mental, and overall well-being."} +{"text": "Spatial transcriptomics technologies developed in recent years can provide various information including tissue heterogeneity, which is fundamental in biological and medical research, and have been making significant breakthroughs. Single-cell RNA sequencing (scRNA-seq) cannot provide spatial information, while spatial transcriptomics technologies allow gene expression information to be obtained from intact tissue sections in the original physiological context at a spatial resolution. Various biological insights can be generated into tissue architecture and further the elucidation of the interaction between cells and the microenvironment. Thus, we can gain a general understanding of histogenesis processes and disease pathogenesis, etc. Furthermore, in silico methods involving the widely distributed R and Python packages for data analysis play essential roles in deriving indispensable bioinformation and eliminating technological limitations. In this review, we summarize available technologies of spatial transcriptomics, probe into several applications, discuss the computational strategies and raise future perspectives, highlighting the developmental potential. Human organs and systems are comprised of distinct cell subpopulations whose physiological processes and functions are deeply correlated with their spatial distributions and cellular interactions. To gain a deeper understanding of tissue architecture as well as heterogeneity and to subsequently obtain biological insights into intercellular communication and microenvironment, it is crucial to decipher the disparities among tissue regions and cells in their original spatial context. Previously developed single-cell RNA sequencing (scRNA-seq) has provAlthough current cutting-edge spatial transcriptomics techniques are confronted with some drawbacks such as relatively low resolution and comparatively insufficient sequencing depth , they arSpatial transcriptomics technologies have been continuously making significant progress. Multiple technologies have emerged in recent years, and their applications and advantages and disadvantages are comprehensively reviewed. In this article, we summarize the landscapes of available spatial transcriptomics technologies, present the employment of spatial techniques in extensive fields of biomedical research and focus on the status quo of computational strategies of data analysis.Since the initial spatial transcriptomics workflow was established in 2016 , this fiLaser capture microdissection (LCM) is a micJunker and colleagues devised In summary, microdissection-based methods provide a competent approach to obtaining regions of interest from tissue samples with high sensitivity. These techniques enable focused research into the microanatomical structures and gene expression information of specific regions. However, Geo-seq, which integrates LCM and scRNA-seq (Smart2-seq), offers only a ten-cell resolution due to the limitations of microdissection-based techniques. During the laser-capturing and tissue segregation procedures of LCM, the quality of RNA molecules and the intactness of obtained cells may not be fully maintained. Additionally, microdissection is time-consuming and labor-intensive, limiting the throughput and the capacity to handle large tissue samples. Despite these shortcomings, microdissection-based technologies can still provide robust methods for gene expression profiling.In situ hybridization is a strategy that enables the visualization of RNA molecules within their original context via probes complementary to the objective transcripts rather than extracting them from tissue sections. An early iteration of in situ hybridization technique termed single-molecule fluorescent in situ hybridization (smFISH) is compeTo overcome the drawbacks of accumulating errors, Chen and colleagues devised in-situ-hybridization-based techniques allow for the visualization of RNA molecules within their original tissue context by hybridizing probes with complementary targets. This enables the detection of target genes for biological validation of bioinformatic analysis results and the study of gene expression patterns. However, the nature of FISH methods imposes an intrinsic limitation on throughput. Additionally, specific probes must be synthesized before the hybridization process, necessitating the use of ready-made kits to overcome this challenge [Overall, hallenge .In situ sequencing (ISS) method developed by Ke and colleagues enables To examine transcripts without prior knowledge of tissue, Lee and colleagues devised in-situ-sequencing-based methods enable spatial-level gene expression analysis and avoid the bias introduced by transcript extraction. However, these techniques still face challenges. For example, prior knowledge of the tissue may be required to design specific padlock probes, and read length may be limited. Additionally, in situ sequencing may not be feasible for unconventional or rare cell types and genes. Potential applications of these methods include studying gene expression regulation within tissues or cells and localizing gene variants.In contrast to traditional sequencing methods that separate cells from their spatial context, St\u00e5hl and colleagues proposedImprovement of the resolution of spatial barcoding strategies has been continuously pursued. In 2019, Rodriques and colleagues developeSlide-seq, HDST and Seq-Scope introduced above can provide much higher and even subcellular resolutions, generating more refined spatial distribution information. The approaches to improving the resolutions of Slide-seq and HDST are similar, involving bead arrays with 10-\u03bcm- and 2-\u03bcm-diameter beads, respectively , 45. It Overall, spatial-barcoding-based techniques allow for the simultaneous acquisition of gene expression and spatial location information. However, selecting the appropriate resolution requires careful consideration. Low resolution may obscure the intrinsic tissue structure and require further decomposition analysis to gain comprehensive insights, while high resolution may introduce those aforementioned challenges. Additionally, capture efficiency may be relatively low. Despite these limitations, spatial-barcoding-based techniques are widely used to study tissue architecture, tumor heterogeneity, the tumor microenvironment, etc.Spatial transcriptomics technologies are potent tools for studying the intricate structure, the dynamics of tissue and organ systems and inherent mechanisms within their original context. These technologies can provide valuable biological insights by revealing tissue architecture, developmental patterns and diseases, among which tumor biology may be one of the most extensive applications of spatial transcriptomics. Primary application scenarios of implementing spatial transcriptomics techniques are presented Fig.\u00a0 and seveDecoding intercellular interaction and identifying cell subpopulations are of fundamental significance in delineating tissue architecture and defining structural components through the establishment of a transcriptome atlas of a specific tissue or organ, thus facilitating the perception of tissue dynamics. Hildebrandt and colleagues managed Furthermore, spatial transcriptomics technologies are generally utilized in developmental biology to reveal spatiotemporal gene expression patterns and uncover tissue morphogenesis throughout the entire development course or multiple pivotal stages. Asp and colleagues profiledBeyond the above insights about tissue architecture and development, spatial transcriptomics techniques have a robust capacity for clarifying disease microenvironments and pathogenesis. Boyd and colleagues combinedA substantial part of disease research is the study of tumor biology which could be the most extensive application of spatial transcriptomics. Significant challenges in devising tumor treatment procedures are induced by tumor heterogeneity. Moncada and colleagues utilizedTo comprehensively interrogate the tissue sections, bioinformatic analyses have to be performed to unravel the intertwined and multiplexed bioinformation and minimize the impact of current technological limitations and subsequently derive biological significance more accurately from raw spatial transcriptomics data. These bioinformatics analyses range from spatially-variable genes identification and clustering analysis to gene imputation, etc., which can be handily effectuated through a substantial number of computational strategies devised in recent years. Herein, circumstantial comparisons of algorithms and usages among the existing R or Python packages are presented Table .Table 4CDistinguishing cell types and subpopulations is a fundamental task in the bioinformatic analysis of spatial transcriptomics data. This can be resolved with the help of clustering analysis where spatially-variable genes can be discovered and data dimensions can be reduced through approaches such as principal component analysis (PCA), t-distributed stochastic neighbour embedding (t-SNE) and uniform manifold approximation and projection (UMAP). These methods calculate similarity among barcode spots and define clusters within a tissue. A robust clustering procedure is provided by a widely-distributed R package Seurat , on whicWithin a certain tissue, some genes exhibit conspicuous spatially-variable expression whereas some other genes such as housekeeping genes are expressed equally among the cells. The specific pattern in which the expressions of genes spatially vary can convey indispensable bioinformatic insights into identifying cell types and subpopulations and corresponding spatial information and underlying spatial functions. Some program packages perform outstandingly in identifying spatially-variable genes. Svensson and colleagues describeA common issue in spatial transcriptomics technology is that a single barcode-capturing spot may be overlaid by multiple cells. Thus, the detected expression is an aggregation of a heterogeneous set of cells within the spot, which may impact the efficiency and accuracy of identifying cell subpopulations and delineating tissue atlas. For example, 10\u2009\u00d7\u2009Genomics Visium offers a resolution of 55\u00a0\u03bcm meaning the diameter of each capturing spot is 55\u00a0\u03bcm which is several-fold larger than a typical tissue cell. The spatial decomposition process through various deconvolution algorithms can address this discrepancy, which is to disentangle the mixture of mRNAs and subsequently predict the proportions of each cell type in one capturing spot. A spatial decomposition method devised by Ma and colleagues is termeGene imputation refers to the task of inferring lost gene expression information or \u201cdropouts\u201d caused by factors such as low protocol sensitivity, mitigating errors during gene measurement and facilitating deconvolution. Biancalani and colleagues introducThe aforementioned strategies, including spatial decomposition and gene imputation, have demonstrated considerable efficacy in enhancing the resolution of spatial transcriptomics data and compensating for lost gene expression information. Nevertheless, certain limitations persist. These approaches are based on computational models for predicting cell locations and gene information and therefore, their predictions may be subject to error, potentially resulting in imprecise and spurious results. Further investigation and refinement are necessary to more effectively leverage these technologies and derive more reliable biological insights.Cellular interaction operated within the microenvironment where cells are adjacent to each other can convey significant perceptions into tissue dynamics and the way the communication networks change when experiencing conditions such as disease. A Graph Convolutional Neural networks for Genes (GCNG) method was introduced to infer extracellular interactions from gene expression by depicting a cellular relationship graph transformed from spatial transcriptomics data and subsequently encoding gene expressions, and the graph is then convolved with expression information . Cang anCopy number variation (CNV) refers to the increase or decrease in the copy number due to gene segment rearrangements. Typically, CNVs involve segments longer than 1000 base pairs and are mainly manifested as submicroscopic deletions or duplications. CNVs are a common form of genetic variation in the human genome, with 5%\u2009~\u200910% of the genome affected by CNVs, which is much higher than other forms of genetic variation. Ascertaining the transition from benign to malignant tissue forms the foundation for improving early cancer diagnosis, as genomic instability in histologically benign tissue can signal an early event in cancer evolution. Furthermore, the spatial distribution and activity of CNVs can impact phenotype, making mapping their spatial distribution valuable for comprehending, diagnosing, and treating diseases. Previously, gene expression was utilized to infer CNVs in individual cells, successfully identifying regions of chromosomal gain and loss . EricksoGene expression within a tissue is influenced by the spatial position of cells in the tissue microenvironment. Spatial transcriptomic data can provide valuable insights into tissue regions, as they contain information on spatial position matrices, HE region staining of sections, and relative distances between individual cells, which can be used to delineate spatial regions. MULTILAYER is an algorithm that utilizes agglomerative clustering and community detection methods for graphical partitioning, enabling digital imaging of spatial transcriptomic analysis . This alSpatial trajectory analysis is an analytical method frequently employed in spatial transcriptomics to uncover dynamic cellular evolution and differentiation processes. This approach infers evolutionary trajectories and differentiation relationships between cells by analyzing their spatial positions and gene expression levels within tissue sections. The stLearn package can visualize spatial trajectories in tissue slices and infer biological processes from transcriptional state gradients across tissues . SimilarBoth spatial transcriptomics and scRNA-seq are effective methods for obtaining biological insights into tissues and diseases. However, each method has its limitations. By integrating spatial transcriptomics and scRNA-seq data, these methods can complement each other to provide comprehensive biological information. For instance, RCTD generates spatial decomposition by assigning cell types to spatial transcriptomics spots , whereasMethods for analyzing spatial transcriptomics data are generally similar and can be divided into data preprocessing and downstream analysis. Data preprocessing typically involves quality control and normalization to improve data quality for downstream analysis and obtain more reliable biological information. For spatial-barcoding-based methods, quality control aims to remove low-quality spots and genes from spatial transcriptomics data. Quality control parameters can be adjusted based on tissue type, research requirements, and other factors. These parameters may include removing spots with fewer than a certain number of transcripts, removing genes expressed in fewer than a certain number of spots, and removing spots with a high proportion of mitochondrial genes. Normalization accounts for the difference in sequencing depth among different spots. Since differences among spots in spatial transcriptomics data can be relatively large, effective normalization is essential.After preprocessing, downstream analysis can be performed. The data should first undergo dimensionality reduction and clustering analysis to distinguish spots with different features. Biological information can then be interpreted through these clusters in subsequent analysis. Algorithms such as PCA, t-SNE, and UMAP can be used for this purpose and are available in many data analysis packages. Next, gene expression patterns in the data can be analyzed, including differential expression analysis and spatially variable gene analysis, which can be performed using packages such as Seurat and SpatialDE, respectively. Additionally, cell information from tissue slices can be annotated onto spatial transcriptomics data. Since the sequencing unit of some spatial transcriptomics technologies may contain more than one cell, spatial decomposition can infer the proportion of various cells in each sequencing unit based on the data to obtain cell locations in the spatial context. This step can be achieved using packages with deconvolution algorithms such as RCTD and cell2location. Gene imputation can also predict the positions of low-expressed or missing genes in space due to possible dropout using packages like Tangram. Furthermore, personalized analysis can be conducted based on research objectives. For instance, packages such as Giotto can be used to analyze the communication between cells or spatial regions, including receptor-ligand interactions. SpatialInferCNV can perform copy number variation analysis at the spatial level, while stLearn and SPATA can be used for spatial trajectory analysis and MULTILAYER for spatial region identification. These analytical methods and packages provide excellent visualization during data analysis, facilitating step-by-step comprehension of current analytical outcomes to guide subsequent analysis. Moreover, it is essential to integrate spatial transcriptomics data with scRNA-seq data and other omics data to obtain a more comprehensive understanding of biological information.Explosive advances in spatial transcriptomics technologies have been made in recent years to expand our understanding of miscellaneous tissues and organs. However, current spatial transcriptomics methods are confronted with some challenges of low resolution, sensitivity, throughput, etc., hindering our precise perception of normal and abnormal tissues, which calls for further innovations in technologies to overcome these deficiencies. Given that each technology bears its biological strengths, we envision the integration across these technologies which complement each other in the drawbacks before a novel and robust technology is launched. With future technology revolutions, intercellular signaling could be resolved at higher and even single-cell resolution. In addition, larger-scale tissue specimens may be investigated to allow for depicting organ-level tissue topography, enabling a more holistic and consecutive interpretation of tissue structures, which latently poses challenges for accelerating bioinformatic analysis with higher efficiency and accuracy and more powerful information processing capacity. Beyond the prospective advancement in refining and optimizing current protocols of spatial transcriptomics, we also envisage the integration with multi-omics including epigenomics, proteomics, and metabolomics to shed light on the intrinsic convoluted mechanisms of cellular interactions and disease and better probe into tumor progression and growth course. In addition to advances in spatial transcriptomics technologies, innovations in data analysis strategies are also anticipated. As deep learning technology continues to progress, its application in spatial transcriptomics data analysis is expected to become more widespread. In the future, more deep-learning-based methods may be developed to process and analyze spatial transcriptomics data to improve data resolution and interpretation reliability. Furthermore, as data scale and complexity increase, visualization and interactive analysis will become important tools for spatial transcriptomics data analysis. Future spatial transcriptomics data analysis methods will need to integrate visualization and interactive analysis technologies to better understand and interpret data.Since some spatial transcriptomics techniques, especially some widespread spatial-barcoding-based techniques, are not capable of offering single-cell resolution at the spatial level and scRNA-seq cannot reflect the spatial distribution of each cell, we envision a more organic and efficient alignment of single-cell datasets and corresponding spatial information. The alignment can be achieved by mapping single cells to spatial data, where each cell is matched with a spatial location in an ideal condition. Nevertheless, current methods for integration cannot generate precise matching due to technological limitations, which calls for further breakthroughs in the effectiveness and efficiency of data integration algorithms. By integrating both datasets, we can decipher potential intercellular communication pathways, including ligand-receptor interactions and juxtacrine and paracrine signaling. This may provide insights into previously unclear physiological and disease mechanisms and help discern more refined classifications of certain diseases, facilitating precise and individualized medical treatment. Additionally, publicly-available datasets can be interrogated retrospectively with the integration of spatial transcriptomics and scRNA-seq data to obtain novel biological cues which may be concealed in the raw data before.Moreover, we anticipate the translational medicine research into the clinical significance of spatial transcriptomics, particularly with the compatibility of the 10\u2009\u00d7\u2009Genomics Visium platform with FFPE tissue blocks allowing retrospective analysis into previously opaque tissue specimens to glean more sufficient information on clinical diagnostics and prognostics as well as therapeutic methods and targets. For example, research into human DLPFC distinguished the layer-enriched genes that may be associated with schizophrenia and autism spectrum disorder, implicating the potential of neuropsychiatric disorders progression in those bearing the risk gene expression . In tumo"} +{"text": "The clinical spectrum of atrial fibrillation means that a patient-individualized approach is required to ensure optimal treatment. Cardiac computed tomography can accurately delineate atrial structure and function and could contribute to a personalized care pathway for atrial fibrillation patients. The imaging modality offers excellent spatial resolution and has been utilised in pre-, peri- and post-procedural care for patients with atrial fibrillation. Advances in temporal resolution, acquisition times and analysis techniques suggest potential expanding roles for cardiac computed tomography in the future management of patients with atrial fibrillation. The aim of the current review is to discuss the use of cardiac computed tomography in atrial fibrillation in pre-, peri- and post-procedural settings. Potential future applications of cardiac computed tomography including atrial wall thickness assessment and epicardial fat volume quantification are discussed together with emerging analysis techniques including computational modelling and machine learning with attention paid to how these developments may contribute to a personalized approach to atrial fibrillation management. Atrial fibrillation is conventionally classified according to a single domain - the temporal pattern of the arrhythmia. Whilst the use of classification systems has increased our understanding of atrial fibrillation to some extent, such an approach can overlook the importance of the interplay of factors related to the patient, their symptom severity, risk factors and the atrial electrophysiological substrate underpinning atrial fibrillation. Given these interactions, the management of atrial fibrillation necessitates the delivery of a coordinated patient-individualized care pathway to ensure optimal treatment. Whilst more research to explore the patient-specific pathophysiological basis of atrial fibrillation is necessary, the principles of patient-individualized care have been encapsulated in the 4S-AF scheme which aims to provide a structured, pathophysiology-based characterisation of a patient's atrial fibrillation comprising four domains - stroke risk, symptom severity, severity of atrial fibrillation burden and substrate severity.Within this framework, computed tomography may provide useful information to guide atrial fibrillation management by enabling assessment of cardiac structure and function. Advances in computed tomography temporal and spatial resolution have strengthened its utility in the field of electrophysiology.This review will discuss the current state-of-the-art for computed tomography in atrial fibrillation management together with potential future applications that form part of ongoing research .Fig.\u00a01Th22.1In atrial fibrillation, cardiac computed tomography has been used prior to direct current cardioversion, radiofrequency catheter ablation and left atrial appendage closure to investigate for contraindications, delineate anatomy and guide procedures.In the context of atrial fibrillation ablation procedures, pre-procedural atrial imaging can define patient-specific atrial anatomy.Prior to percutaneous left atrial appendage occlusion, pre-procedural imaging is utilised to guide left atrial appendage occluder device selection and sizing, and to facilitate procedure planning.2.2In patients with sub-therapeutic anticoagulation (missed anticoagulant doses or short duration of therapy), investigation for left atrial appendage thrombi prior to direct current cardioversion or atrial instrumentation is required.,Computed tomography can be used to differentiate between left atrial appendage thrombus and slow blood flow by comparing early arterial and delayed phase images.2.32) score. In a recent simulation study by Qureshi et\u00a0al., it has been demonstrated that left atrial appendage morphology may affect coagulation dynamics in blood flow during sinus rhythm and atrial fibrillation, and subsequent risk of thrombus formation.Cardiac computed tomography can be used to accurately characterize left atrial appendage morphology . Left at2.4Prior to radiofrequency catheter ablation of the pulmonary veins in atrial fibrillation, an awareness of a patient's left atrial and pulmonary vein anatomy can enable accurate targeting and planning through the measurement of ostial diameter, characterization of variants in pulmonary vein anatomy such as accessory pulmonary veins or common pulmonary vein ostia, and the identification of anomalies such as anomalous pulmonary venous return, pulmonary vein occlusion or the presence of a persistent left superior vena cava.Variations in pulmonary vein anatomy are common and can be easily assessed with computed tomography.2.5Pulmonary vein stenosis is a recognized complication of atrial fibrillation ablation close to or within the pulmonary vein ostia. Symptoms typically take weeks to months to manifest and include shortness of breath, dry cough and, in some instances, chest pain.2.6Injury to extra-cardiac structures is a recognized, but fortunately rare, complication of atrial fibrillation ablation. The esophagus lies adjacent to the posterior wall of the left atrium leaving it vulnerable to injury during radiofrequency catheter ablation.Methods to reduce risk of atrio-esophageal fistula formation such as active esophageal coolingThe proximity of the right and left phrenic nerves with the right superior pulmonary vein and left atrial appendage roof respectively also leaves these structures vulnerable to injury during ablation.3Advances in computed tomography image acquisition and analysis provide the opportunity for its role in atrial fibrillation assessment to expand. Techniques including computational modelling, artificial intelligence-based imaging, atrial wall thickness assessment and epicardial adipose tissue characterisation may enable an individualized precision-cardiology approach to atrial fibrillation management. This section summarizes these approaches and suggests areas where future research developments using computed tomography may address knowledge gaps in the management of atrial fibrillation.3.1The ability of cardiac computed tomography to accurately delineate atrial structure can enable the acquisition of complex three-dimensional human atrial geometry which can form the basis of computational organ-level atrial models .45 TheseComputational models could be used to characterize an individual's substrate severity and lead to personalized atrial fibrillation ablation therapy. Hwang et\u00a0al. used cardiac computed tomography to create atrial models which could be used to compare different ablation strategies for atrial fibrillation.ClinicalTrials.gov, #NCT05057507) study will aim to use computational modelling to define patient-specific mechanisms of atrial fibrillation.Computational modelling for personalized atrial fibrillation procedure planning is an area of active research, offering the potential to better understand arrhythmia pathophysiology and improve clinical arrythmia prevention, risk stratification and treatment.Future research developments using computational models will require three-dimensional anatomical geometry and cardiac computed tomography is therefore likely to play a role in the generation of these models. A key advantage of cardiac computed tomography in this setting is the high spatial resolution of image acquisition which enables accurate anatomical assessment of wall thickness and left atrial appendage morphology. Previous studies using magnetic resonance imaging to evaluate the role of computational modelling in atrial fibrillation therapy have been unable to include variations in left atrial wall thickness or appendage morphology.3.2Machine learning is likely to be beneficial for personalized atrial fibrillation care in the future.Improved image quality with machine learning-based reconstruction algorithms may improve the ability to assess thin structures such as the atrial wall.The ability of cardiac computed tomography to characterise atrial structure may prove to be of prognostic importance as structural parameters such as left atrial volume3.3Changes in the structure and electrical behavior of the left atrium are associated with conditions which predispose to atrial fibrillation, although it is also recognized that these changes may occur in response to atrial fibrillation itself.Furthermore, we have developed reference values for left atrial wall thickness measurements on computed tomography, measured left atrial wall thickness at two locations (roof and floor) using computed tomography in 100 persistent atrial fibrillation patients., measured thickness around the pulmonary vein antra in patients undergoing repeat ablation procedures and found that antral wall thickness was higher in areas of pulmonary vein reconnection., found no association between left atrial wall thickness measurements and pulmonary vein isolation success rates.Studies have also been performed to examine for an association between left atrial wall thickness measurements and atrial fibrillation ablation success rates. Zuo et\u00a0al.The use of computed tomography to assess atrial wall thickness and provide non-invasive substrate determination may enable us to identify areas where the risk of recurrence is potentially higher and personalize therapy to improve outcomes. The utility of computed tomography-derived left atrial wall thickness in guiding catheter ablation approach has been demonstrated by Teres et\u00a0al., who found that personalized ablation approaches adapted to left atrial wall thickness allowed pulmonary vein isolation with lower radiofrequency delivery, fluoroscopy, and procedure times.3.4Cardiac computed tomography enables a three-dimensional assessment of the volume, thickness, and attenuation of the epicardial adipose tissue C.71 Some,Several studies have shown that patients with atrial fibrillation have increased epicardial adipose tissue thickness, mass and volume compared with patients without atrial fibrillation . A meta-,,,Recently, assessment of the pericoronary adipose tissue attenuation has gained attention due to its association with subsequent cardiac events.Notably these studies have considered only single-plane analysis or peri-atrial fat attenuation limited to the posterior left atrium. Furthermore, cut-off values to accurately define abnormal epicardial adipose tissue attenuation have not been defined and vary between research studies. Further mechanistic studies are therefore needed to study the role of global peri-atrial fat and fat attenuation in atrial fibrillation pathogenesis.In a study by Zhang et\u00a0al., it has been shown that the radiomic characteristics of epicardial adipose tissue may improve the identification of patients who have atrial fibrillation compared to quantification of epicardial adipose tissue volume.At present it is unknown whether changes in epicardial adipose tissue are a cause or consequence of atrial fibrillation. Epicardial adipose tissue, which contains ganglionated plexi, actively secretes cytokines and adipokines which may lead to inflammation and atrial remodelling. The secretion of pro-fibrotic factors by epicardial adipose tissue may contribute to atrial myocardial fibrosis and this may act as a substrate for atrial fibrillation.4Cardiac computed tomography can provide important anatomical information for patients with atrial fibrillation and has been used in the pre-, peri- and post-procedural stages of management. New techniques such as computational modelling and machine learning are improving our understanding of the development of atrial fibrillation and responses to therapy. In the future information such as atrial structure, atrial wall thickness, and epicardial adipose tissue from computed tomography may be used to provide a personalized approach for the management or prevention of atrial fibrillation.MCW has given talks sponsored by Canon Medical Systems, Siemens Healthineers and Novartis. SN receives research funding from Siemens for computed tomography image analysis. SEW has consulting agreements with EPD/Phillips, GSK and Biosense Webster."} +{"text": "Most mental disorders, when examined individually, are associated with an increased risk of cardiometabolic complications. However, these associations might be attributed to a general liability toward psychopathology or confounded by unmeasured familial factors.To examine whether the associations between psychiatric diagnoses and increased risk of cardiometabolic complications are attributable to a general liability toward psychopathology, or confounded by unmeasured familial factors.We conducted a cohort study in Sweden and identified all individuals and their siblings born in Sweden 1955-1962 with follow-up through 2013. After excluding individuals who died or emigrated before 1987, the final sample consisted 672 823 individuals. We extracted ICD-coded diagnoses (recorded 1973-1987) for ten psychiatric conditions and criminal convictions when participants were aged 18-25 years, and ICD-coded diagnoses (recorded 1987-2013) for five cardiometabolic complications when the participants were 51-58 years old. Logistic regression models were used to estimate the bivariate associations between psychiatric conditions or criminal convictions and cardiometabolic complications in individuals. A general factor model was used to identify general, internalizing, externalizing, and psychotic factors based on the psychiatric conditions and criminal convictions. We then regressed the cardiometabolic complications on the latent general factor and three uncorrelated specific factors within a structural equation modeling framework in individuals and across sibling pairs.Each psychiatric conditions significantly increased the risk of cardiometabolic complications; however, most of these associations were attributable to the general factor of psychopathology, rather than to specific psychiatric conditions. There were no or only small associations between individuals\u2019 general psychopathology and their siblings\u2019 cardiometabolic complications, suggesting that the associations were not attributable to genetic or environmental confounding factors shared within families. The same pattern was evident for the specific internalizing and psychotic factors.Individuals with mental disorders in early life had an increased long term risk of cardiometabolic complications, which appeared attributable to a general liability toward psychopathology. Sibling analyses suggested that the elevated risk could not be attributed to confounds shared within families.This highlights the importance of transdiagnostic and lifestyle based interventions to reduce the risk of cardiometabolic complications, particularly in patients with several mental disorders.None Declared"} +{"text": "Transcranial magnetic stimulation (TMS) is a non-invasive FDA-approved therapy for major depressive disorder (MDD), specifically for treatment-resistant depression (TRD). Though offering promise for those with TRD, its effectiveness is less than one in two patients . Limits on efficacy may be due to individual patient variability, but to date, there are no established biomarkers or measures of target engagement that can predict efficacy. Additionally, TMS efficacy is typically not assessed until a six-week treatment ends, precluding interim re-evaluations of the treatment. Here, we report results using a closed-loop phase-locked repetitive TMS (rTMS) treatment that synchronizes the delivery of rTMS based on the timing of the pulses relative to a patient's individual electroencephalographic (EEG) prefrontal alpha oscillation indexed by functional magnetic resonance imaging (fMRI). Among responders, synchronized rTMS produces two systematic changes in brain dynamics: a reduction in global cortical excitability and enhanced phase entrainment of cortical dynamics. These effects predict clinical outcomes in the synchronized treatment group but not in an active-treatment unsynchronized control group. The systematic decrease in excitability and increase in entrainment correlated with treatment efficacy at the endpoint and intermediate weeks during the synchronized treatment. Specifically, we show that weekly biomarker tracking enables efficacy prediction and dynamic adjustments through a treatment course, improving the overall response rates. This innovative approach advances the prospects of individualized medicine in MDD and holds potential for application in other neuropsychiatric disorders."} +{"text": "BMC Cardiovascular Disorders invites authors to submit articles investigating what drives and affects Cerebrovascular disorders to improve patient care.Cerebrovascular disorders pose a global health concern. Advances in basic and clinical research, including induced pluripotent stem cell models and multi-omic approaches, have improved our understanding and management of these disorders. However, gaps in our knowledge remain. BMC Cardiovascular Disorders welcomes submissions to its new \u201cCerebrovascular Disorders\u201d collection to help further our understanding of such conditions and open new avenues for risk stratification and therapeutic intervention.Cerebrovascular disorders comprise a range of distinct pathologies, including ischaemic and haemorrhagic stroke, transient ischaemic attack, and other intracranial vascular disorders , and significantly increase the risk of vascular dementia. Cerebrovascular disorders represent a significant medical and economic challenge anticipated to rise due to the increasing age of the global population . The pasHDAC9 large-vessel stroke risk to screen for histone deacetylase (HDAC) small molecule inhibitors ) We look forward to the \u201cCerebrovascular Disorders\u201d article collection bringing together basic and clinical research to develop our understanding of what drives and affects such conditions to improve patient care."} +{"text": "Climate change poses new threats to plant production as environmental stresses increase significantly. Biotic and abiotic stress that have adverse effects on plant growth and crop productivity and can be major constraints on yield. This will particularly affect major food crops, including legumes and cereals. Biotic and abiotic stresses, such as salinity, drought, chemical toxicity, extreme temperatures and oxidative stress are often interrelated and become serious threats to agriculture. These extreme conditions induce cellular damage and disruption of plant growth and development by a series of morphological, physiological, biochemical and molecular changes. For example, these extreme stresses are often leading to oxidative damage and excessive creation of reactive oxygen species (ROS) in plant cells. Usually, plants interact with these extreme conditions by their innate antioxidative defense system that including enzyme and non-enzyme elements . HoweverTherefore, enhancing the productivity of these important crops is important for the food security of growing populations worldwide. High heterozygosity imposes severe limitations on breeding new varieties of major food crops with desired traits. Conventional plant breeding and genetic research have significantly evolved in recent decades. However, to meet the growing human population\u2019s food demand, especially for major staple cereal and legume crops, genetic gain must be enhanced, making it necessary to exploit genetic diversity within cultivated crops and wild relatives. With modern technologies, plant breeders can use these additional resources of diversity to address problems like biotic and abiotic stresses and yield by combining methods from genomics, and advanced analytics in cereal and legume breeding programs on a massive scale. This topic explores how the recent advances in genomics and plant biotechnology approaches are helping researchers to answer questions related to crop improvement. Therefore, we encouraged contributions to this Research Topic to advance and disseminate knowledge across various facets of this critical field. Our goal is to illuminate the molecular mechanisms that underlie biotic and abiotic stress tolerance, enhance comprehension of plant stress biology, with a particular focus on legumes and cereals. This effort ultimately contributes to bolstering sustainable agriculture and global food security. In this topic, recent advances in genomics and stress tolerance studies of cereals and legumes are presented in six publications, contributed by 52 authors.2+), which plays a crucial role in transmitting signals and regulating numerous physiological processes. This is accomplished through Ca2+ sensors and their target proteins, as highlighted by previous research IQM genes using genome-wide bioinformatics analysis and molecular biology techniques. They discussed the phylogenetic relationships, gene structure, conserved motifs, chromosome location, evolutionary pattern analysis, yeast two-hybrid analysis, and expression profile in response to abiotic stress and hormones of the soybean IQM family. Their results provide a theoretical basis for subsequent functional analysis of soybean IQM genes and insights into improving soybean resistance to biotic and abiotic stresses. Furthermore, Hu et al. indicated that the multiple members of CDPKs in wheat (Triticum aestivum) have diverse and vital functions in plant growth, development regulation and stress responses. They reported that every TaCDPKs member has a specific function. Their results clearly provide an important foundation for in-depth exploring the function and the signaling pathways of CDPK family members, especially the interactions between TaCDPKs and TaNOXs in wheat.Many complex signaling pathways are involved in the response of plants to biotic and abiotic stresses . For exaresearch . SpecifiXue et\u00a0al. performed a research toward deep RNA sequencing to depict long non-coding RNAs (lncRNAs) profiles in rice associated with BPH feeding using the resistant Near-Isogenic Line (KW-Bph36-NIL). They elaborated insightful information on the genome-wide differentially expressed genes (DEGs) and differentially expressed lncRNAs (DELs) expression profiles of rice under BPH invasion by high throughput sequencing. They suggested that NILs could be used in BPH resistance breeding programs.Insect pest infestation is a serious threat to cereal crops and causes extensive damage to crop production annually. The brown planthopper (BPH) is a major threat to rice production. Host-plant resistance is a key component of pest management strategies to reduce the damage caused by BPH in rice production worldwide. Maanju et\u00a0al. to determine the genetic diversity and population structure of corn leaf aphid (CLA) Rhopalosiphum maidis (Fitch) resistance in barley to identify sources of resistance against R. maidis that considered as a common pest of cereals worldwide. In this study, 10 aphid specific simple-sequence repeats (SSR) markers were used to investigate the genetic diversity and population structure of 109 barley genotypes against R. maidis. Cluster analysis from the agro-morphological features grouped all the germplasm in four subpopulations and approximately 87.52% of the 109 barley genotypes shared a common major allele at any locus and finally they identified two genotypes having high resistance against CLA which highlighted their potential for inclusion in the future CLA resistance breeding programs.A study was undertaken by Park et\u00a0al. analyzed the transcriptome changes associated with the callus formation process in soybean under the influence of wounding signals and phytohormones. They identified key genes associated with transcription factors, biosynthesis, transporters, and signaling pathways related to phytohormones. The obtained results demonstrated the importance of the coordinated interplay of wounding, auxin, cytokinin, and brassinosteroid signaling pathways to activate the genes involved in determining the fate of meristematic cells. This study provides insights into the regulatory network of callus formation in soybean.With the aim of uncovering facts related to the biological mechanism underlying soybean callus induction and developmental process, Wu et\u00a0al. reported the analysis of the sugar beet WD40 proteins. They identified 177 bvWD40 from sugar beet and analyzed their evolutionary characteristics, protein structure, gene structure, protein interaction network and gene ontology. They concluded that BvWD40-82 gene is a salt-tolerant candidate gene. Transgenic Arabidopsis thaliana seedlings expressing BvWD40-82 showed enhanced tolerance to salt stress by elevating the contents of osmolytes and antioxidant enzyme activates, maintaining intracellular ion homeostasis and increasing the expression of genes related to salt overly sensitive (SOS) and abscisic acid (ABA) pathway. The obtained results hypothesized the importance of BvWD40-82 as a promising candidate gene for improving crop stress resilience.Salinity is a major environmental stress on crop productivity. Understanding the molecular and physiological mechanisms underlying salt stress tolerance will facilitate efforts to improve crop performance under salinity. In line with this aim, Biotic and abiotic stresses will remain major concerns for future food production and sustainability. The use of the most recent technologies in leveraging genomics, phenomics, machine learning approaches and plant biotechnology along with conventional breeding strategies is the most appropriate way to identify multifactorial interactions networks involved in plant defenses against stress conditions towards improving abiotic and biotic stress tolerance in major crops.PL: Writing \u2013 review & editing. MH: Writing \u2013 review & editing. RT: Writing \u2013 review & editing. MR: Writing \u2013 review & editing. HS: Writing \u2013 review & editing. H-JJ: Writing \u2013 review & editing."} +{"text": "Saccharomyces cerevisiae has been studied in hopes of understanding its causes and identifying conserved pathways that also drive aging in multicellular eukaryotes. While the short lifespan and unicellular nature of budding yeast has allowed its aging process to be observed by dissecting mother cells away from daughter cells under a microscope, this technique does not allow continuous, high-resolution, and high-throughput studies to be performed. Here, we present a protocol for constructing microfluidic devices for studying yeast aging that are free from these limitations. Our approach uses multilayer photolithography and soft lithography with polydimethylsiloxane (PDMS) to construct microfluidic devices with distinct single-cell trapping regions as well as channels for supplying media and removing recently born daughter cells. By doing so, aging yeast cells can be imaged at scale for the entirety of their lifespans, and the dynamics of molecular processes within single cells can be simultaneously tracked using fluorescence microscopy.For several decades, aging in Key featuresThis protocol requires access to a photolithography lab in a cleanroom facility.Photolithography process for patterning photoresist on silicon wafers with multiple different feature heights.Soft lithography process for making PDMS microfluidic devices from silicon wafer templates. Saccharomyces cerevisiae, the traditional method of manual microdissection of mother and daughter cells in order to count replicative lifespan has been largely supplanted by the use of microfluidic devices, which efficiently trap individual mother cells in place while removing newly budded daughter cells . As a reference, yeast cells growing in the device can be seen in Paxman et al. (2022). Age-dependent aggregation of ribosomal RNA-binding proteins links deterioration in chromatin stability with challenges to proteostasis. eLife ("} +{"text": "Plasmodium malaria parasites [P. falciparum and highlight critical future questions to answer.Isoprenoid precursor synthesis is an ancient and fundamental function of plastid organelles and a critical metabolic activity of the apicoplast in arasites \u20133. Over arasites , due in arasites ,6. In th Malaria parasites retain a non-mevalonate/methylerythritol phosphate (MEP) pathway for isoprenoid precursor synthesis in the apicoplast organelle. This pathway synthesizes two 5-carbon isoprene subunits, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), whose sequential condensation is critical for making diverse longer-chain isoprenoids required for a variety of key cellular functions that include protein prenylation, dolichol synthesis for protein glycosylation, and biosynthesis of mitochondrial ubiquinone and heme A . Core enPlasmodium therefore requires the apicoplast and the pathways that support and maintain this key organelle.Within the apicoplast, isoprenoid precursor synthesis requires the support of several additional metabolic pathways. The final 2 enzymes in the MEP pathway, IspG and IspH, contain essential Fe-S cluster cofactors that receive electrons from apicoplast-targeted ferredoxin, which also contains an Fe-S cluster. These critical Fe-S cofactors are produced by the apicoplast Suf pathway, which is therefore essential for isoprenoid synthesis \u201310. One Plasmodium focused almost exclusively on cellular roles for isoprenoids outside of the apicoplast, since exogenous IPP can rescue parasites from loss of the apicoplast and the attendant ablation of endogenous IPP synthesis. Nevertheless, multiple prior papers reported that MEP pathway inhibitors like fosmidomycin (FOS) blocked apicoplast biogenesis and prevented elongation of the organelle in blood-stage parasites . Sev. Sev4]. The foundational discovery that exogenous IPP could rescue parasites from apicoplast-specific dysfunctions and organelle loss enabled many opportunities to probe the functional properties of the apicoplast and its constituent proteins . BecauseP. falciparum [Plasmodium will be required for organelle maintenance due to a critical role in IPP synthesis and/or in other aspects of apicoplast biogenesis apart from IPP synthesis. Future studies of apicoplast functions can test this prediction and extend or revise its validity to different parasite stages in distinct host environments, where additional apicoplast pathways like type II fatty acid synthesis can produce essential outputs [Current knowledge specifies IPP and coenzyme A (CoA) as the only biosynthetic outputs of the apicoplast that are essential for blood-stage lciparum ,19,20. Ulciparum ,19. Base outputs ,22 that Plasmodium, this paradigm of metabolic interdependence does not appear to hold throughout the phylum Apicomplexa. Toxoplasma gondii parasites express 2 PPS homologs but neither appears to localize to the apicoplast [T. gondii, loss of isoprenoid precursor synthesis has no apparent impact on apicoplast biogenesis [Plasmodium and Toxoplasma presumably reflect the differing selective pressures that guided evolution of these parasites over the 600 Myr timeline of their divergence from a common ancestor. Multiple PPS homologs are also retained by other hematozoan parasites that are more closely related to Plasmodium than Toxoplasma, but a possible role for PPS in apicoplast biogenesis is unexplored in these organisms. Understanding the similarities and differences in isoprenoid metabolism between broader apicomplexan parasites can unveil and unravel the biochemical forces that have spurred evolution of intracellular parasitism along distinct pathways.The MEP pathway for isoprenoid precursor synthesis is a hallmark of apicoplast retention in apicomplexan parasites . Althougicoplast ,23,24. Aogenesis ,25. ThesP. falciparum parasites that we hope will stimulate future studies in these areas.Below, we lay out several key questions at the frontier of our understanding of the apicoplast and isoprenoid metabolism in Why does apicoplast biogenesis require long-chain linear isoprenoids? We hypothesize that these lipids are critical to tune the biophysical properties and flexibility of apicoplast membranes, such that their deficiency impairs membrane expansion during organelle biogenesis. It remains unknown if these isoprenoids are enriched in specific or all apicoplast membranes and/or serve other roles in organelle biogenesis. It may be possible to test our hypothesis with small-molecule dyes whose fluorescence properties are sensitive to variations in membrane fluidity, together with chemical rescue experiments using a homologous series of progressively longer-chain polyprenols to bypass loss of PPS.How are isoprenoids transported into and out of the apicoplast? Isoprenoid precursors synthesized in the apicoplast, including IPP and DMAPP, are required and utilized outside the organelle. Chemical rescue experiments suggest that IPP and longer isoprenoids can enter the apicoplast. Charged metabolites face an unfavorable energetic barrier to diffuse across the 4 hydrophobic membrane bilayers that encircle the apicoplast, but specific protein transporters that enable their passage into and out of the organelle remain undefined.What prenyl synthase supports the biosynthesis of ubiquinone required in the Plasmodium mitochondrion? Ubiquinone, which has a polyprenyl tail, is critical for function of the mitochondrial electron transport chain. A mitochondrial-targeted polyprenyl synthase has been identified in T. gondii [Plasmodium remain obscure and poorly studied. Apicoplast PPS was proposed to play this role in Plasmodium [. gondii , but theasmodium , but theasmodium .Are there additional metabolic uses of isoprenoids by malaria parasites beyond currently defined products? Plasmodium lacks enzyme homologs for terpene and carotenoid biosynthesis, and recent work found no evidence to support IPP incorporation into carotenoids [otenoids ,3,15. Ne"} +{"text": "Patients with traumatic brain injury (TBI) or head trauma present challenges for emergency physicians and neurosurgeons. Traumatic brain injury is currently a community health issue. For the best possible care, it is crucial to understand the various helpful therapy techniques in the pre-operative and pre-hospital phases. The initial rapid infusion of large volumes of mannitol and a hypertonic crystalloid solution to restore blood pressure and blood volume is the current standard of care for people with combined hemorrhagic shock (HS) and traumatic brain injury. The selection and administration of fluids to trauma and traumatic brain injury patients may be especially helpful in preventing subsequent ischemic brain damage because of the hemodynamic stabilizing effects of these fluids in hypovolemic shock. Traumatic brain injury is an essential factor that may lead to disability and death in a patient. Traumatic brain damage can develop either as a direct result of the trauma or as a result of the initial harm. Significant neurologic problems, such as cranial nerve damage, dementia, seizures, and Alzheimer's disease, can develop after a traumatic brain injury. The comorbidity of the victims may also be significantly increased by additional psychiatric problems such as psychological diseases and other behavioral and cognitive sequels. We review the history of modern fluid therapy, complications after traumatic brain injury, and the use of fluid treatment for decompressive craniectomy and traumatic brain injury. The term \"traumatic brain injury\" (TBI) is most often used to describe brain dysfunction brought on by external trauma. Many types of traumatic injuries happen worldwide, and traumatic brain injury is one of the most contentious health issues in modern society . The CenAn essential part of surgical treatment is administering perioperative fluids, although this process is frequently not completely understood and is still primarily empirical. There are lingering concerns regarding its effectiveness and potential consequences ,11. FluiMethodologyWe undertook a\u00a0search through PubMed, CENTRAL and other government sources in November 2022 using keywords such as \"traumatic brain injury\", \"fluid resuscitation\", \"brain injury\", \"brain trauma\", and \"colloid solutions\"((( traumatic brain injury [Title/Abstract]) OR (\"traumatic brain injury\" [MeSH Terms]), (\"fluid resuscitation\" [Title/Abstract])) OR (\"fluid resuscitation\" [MeSH Terms]), ((\"brain injury\" [Title/Abstract]) OR (\"brain injury\" [MeSH Terms]) AND (\"brain trauma\" [Title/Abstract]) OR (\"brain trauma\" [MeSH Terms]). One reviewer independently checked the papers retrieved based on title and abstract against the inclusion criteria before moving on to the full texts. Another reviewer also reviewed 20% of these studies to validate inclusion studies. The selection of studies Figure dependedThe evolution of modern fluid therapyThe importance of intravenous fluid therapy in treating cholera initially emerged in the 1830s, thanks to William Brooke O'Shaughnessy's findings on the blood observations of his suffering cholera patients ,25. It wCrystalloidsSmall, water-soluble molecules that make up a crystalloid fluid can quickly diffuse across semi-permeable barriers. These solutions' tonicity and sodium content (which affects how they are distributed throughout the body compartments) together greatly influence their features . They reColloidsColloids are liquids that impose oncotic pressure on semi-permeable membranes because they are composed of larger, more soluble molecules that are difficult to penetrate. Through osmosis, water is retrieved from the interstitial and international classifications of functioning based on their shape, molecular weight, capillary permeability, and ionic charge. They exit the intravascular region and act for a specific time . All colTraumatic brain injury and fluid therapyOedema development is not significantly impacted by clinically appropriate fluid restriction. The first investigation on human fluid therapy showed that decreasing the standard maintenance volume by 50% for neurosurgical patients causes an increase in serum osmolality over about a week . TherefoFluid treatment for decompressive craniectomyBased on experience, it is suggested that decompressive craniectomy in traumatic epidural hematoma patients improves these patients' outcomes . The genPhysiological reactions in the perioperative stageThe effects of surgery alone and the resulting adjustments to the hormonal environment inside the body are exacerbated in critically ill patients by a systemic inflammatory response that leads to capillary leak development. As a result, the interstitium endures losses that are challenging to balance and frequently display oedema. Additionally, nutritional support and actions that alter acid-base homeostasis can actively or inadvertently influence the fluid and electrolyte imbalances that result in severe illness . The effTable Traumatic brain injury (TBI) is a greater community or social health problem that increases mortality and disability. Traumatic brain injuries can result from physical attacks, sports-related injuries, traffic accidents, etc. The development of therapeutic procedures for TBI recovery has been ongoing for many years, even though there is currently no effective treatment for TBI rehabilitation. For the best possible care, it is crucial to understand the various helpful therapy techniques in the pre-operative and pre-hospital phases. There are still questions concerning the benefits and dangers of perioperative fluid therapy. The rapid infusion of large crystalloids to restore blood volume and blood pressure is now the standard treatment for patients with combined traumatic brain injury (TBI) and hemorrhagic shock (HS). Crystalloid fluid therapy is more effective than colloid fluid therapy in patients with TBI. There are no standards of care or evidence-based guidelines for managing fluid treatment in patients having decompressive craniectomy."} +{"text": "Suicide is a major health problem, mostly related to mental health disorders. However psychological autopsies have revealed the presence of unexpected suicide factors such as dietary patterns particularly folate intake. Which is a naturally occurring form of B9 essential for neurogenesis, nucleotide synthesis and methylation of homocysteine.The aim of our study is to identify the link between folate intake and suicidality.Our literature review was based on the PubMed interface and adapted for 2 databases: Science Direct and Google Scholar using the following combination ( suicide [MeSH terms]) AND (folate [MeSH terms]) AND (prevention [MeSH terms]).Stress-induced neuronal dysfunctions interact with genetic and environmental factors, including diet, to precipitate mental health disorders in vulnerable or predisposed individuals especially mood disorders.In one hand, studies showed delayed onset of clinical improvement even treatment resistance in depressive patients treated with fluoxetine associated with low folate levels.In the other hand Folate depletion has been linked to serotoninergic metabolism disturb.Moreover, co-administration of methylfolate, a highly absorbable form of folic acid, has been found to augment the effects of SSRIs .A duration-response analysis (1-mg dosage) revealed a 5% decrease in suicidal events per month of additional treatment.Accumulating data have shown that these nutrients can enhance neurocognitive function, and may have therapeutic benefits for depression and suicidal behaviors . But the pathological mechanism remains unclear that\u2019s why further studies are needed for a better comprehension and efficiency.None Declared"} +{"text": "Other distinct clinical features include keratocystic odontogenic tumors, dyskeratotic palmar and plantar pitting, and skeletal abnormalities. Clinicopathological findings of the syndrome are very diverse, and many symptoms manifest during a certain period of life. We present the compelling whole-body bone scan and"} +{"text": "Synthetic glucocorticoids (sGCs) are a well-investigated and standard drug therapy for disorders associated with CNS inflammation. Less is known about treating psychiatric disorders associated with neural autoantibodies. Our aim is to elucidate the repositioning of sGCs in psychiatric diseases that co-exist with neural autoantibodies. We used PubMed to identify articles for this narrative review. To our knowledge, no randomized, placebo-controlled trials have yet been conducted on applying sGC to treat neural autoantibody-associated psychiatric disorders. We describe initial results of cohort studies and single cases or case series often associated with autoantibodies against membrane-surface antigens demonstrating a largely beneficial response to sGCs either as monotherapy or polytherapy together with other immunosuppressive agents. However, sGCs may be less efficient in patients with psychiatric diseases associated with autoantibodies directed against intracellular antigens. These results reveal potential benefits of the novel usage of sGCs for the indication of neural autoantibody-associated psychiatric disease. Further large-scale randomized, placebo-controlled trials are needed to discover whether sGCs are safe, well tolerated, and beneficial in subgroups of neural autoantibody-associated psychiatric diseases. The term drug repurposing refers to employing old drugs for a new purpose, as for another disease category. Two additional subconditions of drug repurposing beyond its superordinate concept are distinguished, namely, drug repositioning and drug reformulation. Drug repositioning means employing an old formula for a new indication, whereas drug reformulation requires either the application of a novel dosage or a novel route, or even both. In our review, we focus on the drug repositioning of steroids in psychiatric disease limited to those patients presenting serum and/or CSF neural autoantibodies. In our review article, we refer only to synthetic glucocorticoids as they are currently applied in treating diseases involving CNS inflammation. sGCs orchestrate various cellular functions, such as inflammation application. We excluded patients with neurological disorders apart from dementia, internal medicine diseases, such as pancreatitis, autoimmune encephalitis with a mixed neuropsychiatric or no pure psychiatric symptoms, and psychiatric syndromes associated with non-neural antibodies, such as thyroid antibodies. The efficacy of sGCs has been proven in patients with autoimmune encephalitis associated with membrane-surface autoantibodies antibodies]. Concerning autoimmune encephalitis following the Graus criteria . There is evidence that the origin of neural autoantibody-associated psychiatric disease is organic, as in autoimmune encephalitis antibodies and partly responsive to polyimmunotherapy, including sGCs who underwent this therapy for autoimmune dementia of patients Table , whereasA large recent chart review study by Endres et al. showed tDifferent sGC mechanisms with a major impact on neural autoantibody-associated psychiatric disease should be mentioned. First, sGCs can enhance emotional memory by increasing hippocampal activity during the encoding of emotional stimuli , our review data point to a new direction in psychiatry that has emerged in recent years and should be pursued further. However, the use of sGCs must be seriously reconsidered when potent alternative immunotherapeutic drugs such as IVIGs and plasmapheresis are available, in case side effects such as exacerbation of psychiatric symptoms should occur. In every case, a critical risk\u2013benefit evaluation should be made especially in cases with isolated psychiatric syndromes and lacking neural autoantibody detection in CSF."} +{"text": "Waiting and stopping are essential and distinct elements of appropriate behavioral control with its dysfunction implicated in various impulsivity related mental disorders. Although rodent and human studies have investigated both phenomena, the role of preparing to stop in waiting impulsivity has rarely been investigated. Furthermore, convergent evidence from multi-modal investigation tools remains a poorly utilized approach in addressing such questions.Here, we conducted two separate, but hierarchical studies, using functional magnetic resonance imaging (fMRI) to map the neural circuit involved in waiting impulsivity and proactive stopping, and subsequently provide mechanistic and causal evidence of disruption of this circuit by transcranial magnetic stimulation (TMS). In the second study, based on our fMRI study data, we attempted to investigate possible causation between the LIFG and waiting impulsivity by modulating LIFG, i.e. non-invasively producing a \u201cvirtual lesion\u201d with an inhibitory transcranial magnetic stimulation (TMS) protocol called continuous theta burst stimulationWe recruited 41 healthy volunteers who performed an adapted version (1CSRT) of the well-established 5 choice serial reaction time task to capture waiting impulsivity. We developed a novel task measuring proactive inhibition. We scanned participants while completing these two tasks. Our fMRI data showed a strong association between LIFG activity and waiting impulsivity on the 1CSRT task. We conducted a single-blind, randomized, between-subjects design of cTBS of the LIFG on a sample of 51 healthy volunteers who completed an adapted version of the 1CSRT task (2CSRT task). Our a priori hypothesis was that cTBS would transiently decrease local cortical activity of the LIFG and increase the frequency of premature responses on both fixed and delayed cue-target interval trials on the 2CSRT task.We first show a shared neural network comprising the pre-supplementary motor area and bilateral anterior insula underlying both waiting impulsivity and proactive stopping. We further demonstrate activity in dorsomedial prefrontal cortex and left inferior frontal gyrus (LIFG) negatively correlated with waiting impulsivity in trials with additional target onset delay. We demonstrate active stimulation significantly increased waiting impulsivity.In these two studies, we validated a novel task measuring proactive inhibition. We further validated the significance of task structure for assessing distinct aspects of impulsivity, which is of translational interest. We further established a causal role of lIFG for waiting impulsivity thus highlighting the integrity of LIFG and related neural circuitry required in waiting impulsivity.None Declared"} +{"text": "In November 2022, the Centers for Disease Control and Prevention updated a 2016 practice guideline for opioid prescription.The 2022 Centers for Disease Control and Prevention guideline reiterates that clinicians should prescribe opioids at the lowest effective dose for the expected duration of pain warranting opioid use. The guideline also endorses patient-centered approaches to the initiation or taper of opioids. Clinicians should discuss benefits and risks of opioids and consider patient preference. The 2022 guideline further suggests that clinicians \u201cevaluate benefits and risks with patients within 1-4 weeks of starting opioid therapy for subacute or chronic pain or of dosage escalation.\u201d This recommendation is particularly relevant to the chronic management of patients who begin opioids for hidradenitis suppurativa, erosive lichen planus, or chronic ulcerating conditions, or even in the emergency department, where opioids are frequently prescribed for cellulitis and abscess.Postsurgical pain management comprises the majority of opioid prescriptions among dermatologists.An added 2022 recommendation outlines the use of prescription drug monitoring or high-sensitivity screening questions to mitigate opioid prescriptions to patients at higher risk for substance use. This recommendation is accompanied with the caveat that prescription drug monitoring data should be used with \u201call patients rather than differentially on the basis of assumptions about what [clinicians] will learn about specific patients.\u201d The 2022 guideline also uses five new guiding principles, which emphasize an individualized, flexible, and multidisciplinary approach to opioid prescription. The fifth guiding principle encourages culturally informed communication to promote access to affordable, diversified pain management regimens and recognizes the role of bias in pain management. The 2022 guideline update is an important step toward thoughtful, safe, and patient-centered opioid stewardship. Dermatologists should continue to build on this national policy update and consider more specific opioid appropriateness recommendations for chronic, nonsurgical dermatologic conditions.None disclosed."} +{"text": "N-glycans stabilized the ligand-binding domain dimer via cation/anion binding and modulated receptor gating properties using electrophysiology. Our findings provide vital structural and functional insights into the unique KAR gating mechanisms.Kainate receptors (KARs) belong to the family of ionotropic glutamate receptors (iGluRs) and are tetrameric ligand-gated ion channels that regulate neurotransmitter release and excitatory synaptic transmission in the central nervous system. While KARs share overall architectures with other iGluR subfamilies, their dynamics are significantly different from those of other iGluRs. KARs are activated by both full and partial agonists. While there is less efficacy with partial agonists than with full agonists, the detailed mechanism has remained elusive. Here, we used cryo-electron microscopy to determine the structures of homomeric rat GluK2 KARs in the absence of ligands (apo) and in complex with a partial agonist. Intriguingly, the apo state KARs were captured in desensitized conformation. This structure confirms the KAR desensitization prior to activation. Structures of KARs complexed to the partial agonist domoate populate in domoate bound desensitized and non-active/non-desensitized states. These previously unseen intermediate structures highlight the molecular mechanism of partial agonism in KARs. Additionally, we show how"} +{"text": "Magnetic resonance imaging (MRI) has several advantages over computerized tomography (CT) in the treatment planning of central nervous system (CNS) malignancies. The adoption of hybrid MRI and linear accelerators (MRLs) has allowed for more effective tumor control and reduced unnecessary neurotoxicity through precise daily adaptations. In this review, we provide a summary of the evidence for MRLs in the management of various CNS tumors. Additionally, we discuss the potential of multiparametric MRI and genomically guided radiotherapy to enhance patient outcomes.Magnetic resonance imaging (MRI) provides excellent visualization of central nervous system (CNS) tumors due to its superior soft tissue contrast. Magnetic resonance-guided radiotherapy (MRgRT) has historically been limited to use in the initial treatment planning stage due to cost and feasibility. MRI-guided linear accelerators (MRLs) allow clinicians to visualize tumors and organs at risk (OARs) directly before and during treatment, a process known as online MRgRT. This novel system permits adaptive treatment planning based on anatomical changes to ensure accurate dose delivery to the tumor while minimizing unnecessary toxicity to healthy tissue. These advancements are critical to treatment adaptation in the brain and spinal cord, where both preliminary MRI and daily CT guidance have typically had limited benefit. In this narrative review, we investigate the application of online MRgRT in the treatment of various CNS malignancies and any relevant ongoing clinical trials. Imaging of glioblastoma patients has shown significant changes in the gross tumor volume over a standard course of chemoradiotherapy. The use of adaptive online MRgRT in these patients demonstrated reduced target volumes with cavity shrinkage and a resulting reduction in radiation dose to uninvolved tissue. Dosimetric feasibility studies have shown MRL-guided stereotactic radiotherapy (SRT) for intracranial and spine tumors to have potential dosimetric advantages and reduced morbidity compared with conventional linear accelerators. Similarly, dosimetric feasibility studies have shown promise in hippocampal avoidance whole brain radiotherapy (HA-WBRT). Next, we explore the potential of MRL-based multiparametric MRI (mpMRI) and genomically informed radiotherapy to treat CNS disease with cutting-edge precision. Lastly, we explore the challenges of treating CNS malignancies and special limitations MRL systems face. Central nervous system (CNS) tumors pose unique and significant challenges for oncologists. As the understanding of CNS tumors continues to improve, innovative approaches and advancements in radiotherapy techniques are needed to take advantage of these insights to improve patient outcomes. The integration of magnetic resonance imaging (MRI) with linear accelerators (MRLs) has allowed for adaptive magnetic resonance-guided radiotherapy (MRgRT), which has emerged as a promising modality for increased personalization in radiation therapy for treating CNS tumors.MRI plays a central role in both the diagnosis and evaluation of CNS tumors due to its excellent soft tissue imaging and ability to visualize the boundaries between the tumor and normal tissues ,2. High-2 fluid-attenuated inversion recovery (FLAIR) sequence and a true fast imaging with steady-state free precession (TRUFI) sequence [The advent of MRLs marked a revolutionary step in the field of MRgRT for CNS tumors ,7. In adsequence of a heaIn the subsequent sections, we discuss the unique challenges and limitations associated with treating adult patients with CNS tumors using traditional radiotherapy methods and how MRgRT offers a potential solution to address these issues. Specifically, we explore the role of MRgRT in the treatment of glioblastoma (GBM) and the unique ability of MRLs to detect subtle soft tissue changes and plan adaptation to improve tumor targeting and reduce dose to surrounding healthy tissue . FurtherIn accordance with the guidelines established by the Radiation Therapy Oncology Group (RTOG), the postoperative GBM target includes both the surgical cavity and the adjacent edema . This apAlthough conducting MRI scans throughout RT to account for these changes would be ideal, it is not feasible due to limited scanner availability and cost constraints. Unfortunately, CT-guided radiotherapy (CTgRT) does not adequately account for parenchymal changes because of its inadequate soft tissue contrast. MRLs may offer a solution, as they allow for superior soft tissue contrast to detect subtle geometric changes and for online plan adaptation to account for tumor and post-operative bed changes during therapy. The need for geometric plan adaptation is highlighted in a prospective study involving 61 GBM patients who underwent chemoradiotherapy (CRT) and received diagnostic brain MRIs at planning, fraction 10, fraction 20, and one-month post-CRT. Significant anatomical changes were observed throughout therapy . The stup = 0.036) versus 20.6 Gy (p = 0.005), respectively [A recent study investigated the potential benefits of adaptive radiotherapy for GBM patients using an MRL system . The stuectively . MultiplIn summary, treatment of GBMs with MRLs is associated with improvements in dosimetry and treatment planning due to its ability to detect subtle soft tissue changes and facilitate plan adaptation. Additionally, MRLs can account for changes in the tumor and tumor bed throughout treatment to ensure better target coverage while minimizing unnecessary dose to normal brain parenchyma. Future studies are needed to determine if this translates into better disease control durability and if better normal tissue sparing results in quality-of-life improvements for these patients.SRT is an important modality in the management of brain metastases and other intracranial tumors . An MRL Several studies have explored the dosimetric feasibility of MRgRT for intracranial SRT ,18,19,20Another study examined the dosimetric feasibility of direct post-operative MRL-based SRT for resection cavities of brain metastases, concluding that direct post-operative MRL-based SRT is dosimetrically acceptable, with benefits including increased patient comfort and logistics . StreamlCollectively, the above studies indicate that MRgRT using an MRL has the potential to offer dosimetric and logistical advantages over conventional linear accelerators for intracranial SRT treatment. However, further clinical investigations are necessary to evaluate the clinical benefit of this technology.Spine SRT plays a critical role in managing metastatic disease by alleviating pain, preventing pathological fractures, and reducing neurological morbidity. Stereotactic body radiotherapy (SBRT) has been shown to provide improved efficacy compared with conventional radiotherapy methods . For spiMRLs offer several advantages over CTgRT, including MR imaging in treatment position to allow for easier fusion with the planning CT and superior spinal cord delineation during setup compared with cone-beam CT (CBCT) ,23. DosiSeveral clinical trials are currently investigating the use of MRL in spine SRS/SBRT. These studies will provide valuable insights into the feasibility and effectiveness of this technique for spine treatment. For example, a phase I/II trial is examining the use of Stereotactic MR-guided Adaptive Radiotherapy (SMART) for treating various disease sites, including the spine (NCT04115254). Additionally, the Pilot Study of Same-session MR-only Simulation and Treatment with SMART for Oligometastases of the Spine (NCT03878485) focuses specifically on spine treatment.As more clinical data emerge from these studies, the potential benefits of MRL in spine SRT will become clearer. The integration of MRI with linear accelerators for spine treatment may lead to improved tumor targeting, reduced normal tissue exposure, and better patient outcomes. Ultimately, these advancements may help optimize radiotherapy for patients with metastatic spine disease and contribute to the ongoing evolution of spine SRT techniques.HA-WBRT is a promising technique that aims to achieve the local control benefits of whole brain RT for both macro- and micro-metastatic lesions, while reducing neurotoxicity by specifically avoiding the hippocampus . HA-WBRTParticularly for patients with numerous brain metastases of radioresistant histology, HA-WBRT with a simultaneous integrated boost to gross disease may be an effective strategy ,56, one One of the fundamental goals of radiotherapy is maximizing the dose to target tissue while minimizing the dose to surrounding OARs. In a significant first step towards this aim, MRLs have facilitated treatment plan adaptation to observable anatomic changes throughout therapy. MRLs, however, may be able to enable biological plan adaptation by leveraging MRI\u2019s capability to track biological and physiological changes through advanced mpMRI techniques. These techniques may allow radiation oncologists further insight into a tumor\u2019s biology as it responds to RT over the course of treatment.The treatment paradigm of radiotherapy has traditionally been based on empirical large cohort data rather than individual biology, resulting in a one-size-fits-all approach. However, recent advancements in genomics and radiomics have begun to pave the way towards a more personalized approach based upon individual tumor biology. The synergy between genomically informed radiotherapy, treatment of high-risk sub-volumes based on extraction of radiographic data, and daily mpMRI-guided plan adaptation has the potential to usher in a new treatment paradigm in radiation oncology. Pre-treatment genomic and radiomic analyses of the tumor may improve patient selection for MRL-based dose escalation ,57,58. DThe currently active phase II Habitat Escalated Adaptive Therapy (HEAT), With Neoadjuvant Radiation for Soft Tissue Sarcoma (NCT05301283) is an example of a cutting-edge study utilizing genomic and mpMRI radiomic biomarkers to guide the initial treatment and adaptive treatment approach for high-grade soft tissue sarcomas. Utilizing a similar approach for CNS tumors appears to be technically feasible currently. For example, genomic-adjusted radiation therapy (GARD) could be similarly utilized to identify GBM patients who could benefit from higher doses with MRIMRL is poised to take a central role at the forefront of this paradigm shift to allow for plan adaptation based not only upon geometric shifts but also on a tumor\u2019s evolving treatment response throughout therapy. An ultra-personalized treatment approach like this allows for total dose, dose distribution , and fractionation changes throughout the course of therapy to improve clinical outcomes for patients. Historically, daily MRgRT plan adaptation has been utilized to manage interfractional geometric changes. However, MRI is also capable of assessing biological and physiological information using advanced mpMRI techniques ,67,68,69One such technique is diffusion-weighted imaging (DWI), which enables the detection of water mobility changes . These a1 relaxation time following a bolus injection of gadolinium [1, T2, and ADC [Dynamic contrast-enhanced (DCE) MRI is another functional imaging technique that investigates perfusion by dynamically evaluating changes in the Tdolinium ,83. Thisdolinium . DCE hasdolinium . As a redolinium . DCE has and ADC . While D and ADC .Additional MR-based techniques, such as magnetic resonance spectroscopic imaging (MRSI) , chemicaAlthough none of the CNS-specific trials within Genomics provides another powerful avenue towards personalized radiation treatment, which when combined with the advances in image guidance listed above, may provide an even more sophisticated approach for challenging malignancies such as GBM. Several such signatures have been introduced as a potential means for genomically guided RT ,109,110.In summary, MRL can be leveraged by incorporating genomically guided RT and mpMRI radiomics to enable a biologically adaptive RT paradigm. Various mpMRI techniques, including DWI, DCE, MRSI, and CEST, have the potential to offer valuable insights into tumor biology and physiology, ultimately leading to more personalized and effective treatment strategies. Using these technologies to identify intratumoral heterogeneity and tumoral sub-volumes at risk may allow for focal dose escalation or avoidance, respectively. As research and development continues in this area, we expect significant advancements in the application of these techniques, potentially revolutionizing the management of CNS tumors.MRgRT offers significant advancements for image-guided radiation therapy (IGRT) and personalized oncology in CNS tumor treatment, but there are certain limitations to be considered. These include substantial financial and time investments for training and operation, development of MR-safety protocols, and unique physical challenges related to the concurrent use of MR and external beam radiotherapy ,116,117.Treating CNS tumors on an MRL presents several unique challenges. The complex anatomy of the CNS, with its highly radiosensitive normal tissues, requires precise targeting and dose delivery. The proximity of critical structures, such as the optic nerves, brainstem, and spinal cord, demands meticulous treatment planning and delivery. Furthermore, CNS tumors often exhibit infiltrative growth patterns, making it almost impossible to accurately delineate tumor boundaries.MRL systems suffer the same limitations as diagnostic MRIs. As such, they\u2019re sensitive to the magnetic susceptibility artifacts that arise from air\u2013tissue and boneGeometric distortion represents one of the most difficult challenges to account for with any MRgRT. Geometric distortion occurs due to imperfections in the magnetic field, gradient nonlinearities, and magnetic susceptibility differences at tissue interfaces . This caTreatment of CNS tumors on MRLs represents a promising direction for the advancement of personalized cancer care. MRLs provide excellent soft tissue visualization, real-time monitoring of targets and normal tissues with gating capabilities, and the ability for daily plan adaptation. These unique advantages hold the potential to improve radiation delivery to patients with intracranial or spine tumors. Clinical trials are currently underway and seek to clarify the role of MRLs in the treatment of CNS malignancies. Future clinical studies are needed to explore the integration of mpMRIs and genomics to develop a biologically adapted radiation therapy paradigm for CNS tumors."} +{"text": "Fungal infections are increasingly associated with critical illness, especially in major burn injury. The risk factors of invasive fungal infections include central venous catheter (CVC) placement, mechanical ventilation, broad-spectrum antibiotics, renal replacement therapy (RRT), and total parental nutrition. Critically ill burn patients have additional risk factors including extensive wounds, impaired immune system, and repeated surgical intervention. Despite significant morbidity and mortality caused by invasive fungal infections, efforts to prevent them with antifungal prophylaxis have not improved outcomes. In patients who develop invasive fungal infection, appropriate empiric antifungal therapy is imperative to reduce morbidity and mortality especially in the setting of delayed culture and sensitivity data. The purpose of this study was to characterize risk factors associated with the development of invasive fungal infection, invasive fungal infection organisms and surgical and pharmacological management.A retrospective chart review was completed of adult patients admitted to the burn ICU found to have an invasive fungal infection . The primary outcome was to identify common fungal organisms. Secondary outcomes included susceptibility pattern of the organism, location of infection, surgical management including debridement and amputation, pharmacological management, median ICU and hospital length of stay, and in hospital mortality.A total of 10 patients of a goal of 100 patients with a median 54% TBSA burns were evaluated at this time. The most common yeast species included candida albicans; mold species included a variety of organisms such as fusarium, zygomycete and paecilomyces. Common risk factors among these patients included CVC access (57%), mechanical ventilation (43%), and RRT (43%). Yeast infections were primarily treated with anidulafungin and fluconazole, while mold infections were managed with systemic amphotericin as backbone in addition to voriconazole or isavuconazole. Patients underwent aggressive surgical debridement for source control. Median ICU stay was 53 days with a median hospital stay of 63 days, and 42% mortality.Fungal infections among critically ill burn patients are associated with the high morbidity and mortality rates. Therefore, mitigation of modifiable risk factors is of utmost importance. This retrospective review of common fungal growth in our unit will inform future empiric antifungal management for patients with concern of invasive fungal infections.Fungal infections present a clinical challenge for burn practitioners, especially in geographically moist areas. Prevention and informed surgical and pharmacological management are key to overcoming this infectious disease threat."} +{"text": "Obesity has become a global health epidemic with profound implications for various medical specialties, including reproductive medicine. This comprehensive review focuses on the anesthetic evaluation and management of obese patients undergoing in vitro fertilization (IVF) procedures. Obesity, as defined by BMI, is associated with infertility and poses unique challenges for anesthetic care. The review also addresses the timing of anesthesia concerning IVF procedures, the impact of obesity on IVF success rates, and the importance of emotional and psychological support for obese patients undergoing IVF. Challenges and future directions in the field are highlighted, focusing on ongoing research, emerging technologies, and the role of multidisciplinary teams in managing these complex cases. In conclusion, this review underscores the critical role of tailored anesthesia and perioperative care in optimizing outcomes for obese patients undergoing IVF. It provides valuable insights for anesthetic providers, reproductive specialists, and healthcare teams, emphasizing the need for a patient-centered approach to address the unique challenges posed by obesity in the context of assisted reproductive technology. Obesity has emerged as a global health epidemic, affecting millions of individuals worldwide and presenting a significant public health challenge. In 2005, approximately 1.6 billion adults globally were overweight BMI: 25-30 kg/m2), and at least 400 million were obese (BMI: >30 kg/m2). By 2015, these numbers had escalated to 2.3 billion and 700 million, respectively [0 kg/m2, Obesity and IVF: an overviewDefinition of Obesity and Its ClassificationObesity is a complex health condition marked by excessive adipose tissue accumulation in the body. BMI is the most commonly used metric for defining and categorizing obesity, as classified by the WHO in Table Prevalence of Obesity and Its Association With InfertilityThe global prevalence of obesity has witnessed a concerning and continuous rise in recent decades, emerging as a significant public health issue. Research indicates that this surge in obesity rates has far-reaching consequences, including its profound impact on reproductive health, both in men and women. The association between obesity and infertility is a growing concern within the medical community, as it sheds light on the intricate interplay between body weight and reproductive function .In womeImportance of IVF as a Fertility Treatment OptionOvercoming ovulatory disorders: Obesity is often intricately linked with ovulatory disorders, such as PCOS, which can hinder natural conception. IVF is particularly advantageous as it effectively bypasses these ovulatory challenges. Through IVF, eggs are directly harvested from the ovaries, ensuring a steady supply of eggs for fertilization, thereby circumventing the irregular ovulation associated with PCOS .ControlAnesthetic evaluation of obese women patientsPreoperative Assessment and Patient HistoryEvaluation of comorbidities: The preoperative assessment of comorbid conditions is paramount, particularly in obese patients undergoing surgical procedures. Obesity is often accompanied by a higher prevalence of medical comorbidities, necessitating a thorough evaluation to manage patient risks comprehensively. Conditions such as diabetes, hypertension, cardiovascular disease, and obstructive sleep apnea (OSA) are frequently encountered in the obese population and can significantly influence anesthesia management. Assessing these comorbidities' nature, severity, and control is critical in determining the patient's perioperative risk profile. This assessment is a foundation for tailoring anesthetic strategies and optimizing patient safety .MedicatPhysical Examination in Obese PatientsAssessment of airway anatomy: Obese patients often present unique challenges related to their airway anatomy. Limited neck mobility, short and thick necks, and excess tissue in the oropharyngeal and supraglottic areas may characterize their airways. These anatomical variations can complicate airway management significantly during anesthesia induction and intubation. Anesthesiologists must carefully consider these factors and employ suitable airway management strategies, such as specialized equipment or alternative airway approaches, to mitigate potential difficulties and ensure safe ventilation .EvaluatLaboratory Tests and InvestigationsComplete blood count (CBC): Rather than delving into the definition of a CBC, it is pertinent to elucidate the changes observed in CBC counts within the obese population. Such insights can prove invaluable for healthcare professionals, especially physicians, as they navigate the challenges presented by obesity. In this context, the CBC becomes an essential tool that scrutinizes various blood components, including RBCs, WBCs, and platelets. Each component within the CBC bears crucial information for anesthesia providers during the preoperative evaluation process. For instance, the RBC count and hemoglobin levels are pivotal in assessing the patient's oxygen-carrying capacity. Low values may indicate anemia, a condition that, if left unaddressed, can adversely impact tissue oxygenation during surgery. WBC counts offer insights into the patient's immune status. Deviations from the normal range may indicate underlying infections or inflammatory conditions, necessitating preemptive action before surgery. Platelet counts, vital for normal blood clotting, help in assessing bleeding risks and guiding decisions regarding blood transfusions or medications such as anticoagulants. By examining these hematological parameters and understanding their variations within the obese population, anesthesia providers can make informed decisions to mitigate bleeding risks, optimize oxygen delivery, and ensure a safer perioperative experience .CoagulaAnesthetic Risk StratificationFollowing the comprehensive preoperative assessment, anesthetic risk stratification should be performed. This involves categorizing patients into risk groups based on their comorbidities, physical status, and the nature of the surgical procedure. Standard classification systems include the American Society of Anesthesiologists (ASA) Physical Status Classification and the Charlson Comorbidity Index . AnestheAnesthetic management strategiesPreoperative OptimizationWeight loss and lifestyle modification: Preoperative weight loss and lifestyle modification are proactive and potentially transformative strategies for obese patients embarking on elective surgery, including IVF procedures. These initiatives are driven by the recognition that obesity can engender complex health concerns and perioperative challenges. Here, we delve deeper into the multifaceted aspects of preoperative weight loss and lifestyle modification, elucidating their manifold benefits .ImproveGlycemic ControlCrucial for surgical success: Elevated blood glucose levels in patients with diabetes can heighten the risk of surgical complications, including impaired wound healing, increased infection susceptibility, and cardiovascular events. Achieving and maintaining optimal glycemic control before surgery can mitigate these risks, promoting a smoother and safer perioperative experience .ImplicaAnesthetic choicesGeneral Anesthesia vs. Regional AnesthesiaTable Sedation OptionsPatient comorbidities: Comorbid conditions like cardiovascular disease or OSA should be carefully considered when choosing sedation options. Some medications used for sedation may have hemodynamic effects or exacerbate respiratory compromise, necessitating a tailored approach that minimizes these risks. Additionally, anesthetic providers must monitor vital signs and promptly address adverse reactions .Airway Equipment considerationsSpecially Designed Operating Room Tables and EquipmentBariatric operating tables: Bariatric operating tables are designed to support the weight and dimensions of obese patients effectively. They offer enhanced stability and durability, which is essential during surgical procedures. These tables are more comprehensive and feature robust mechanisms for adjusting patient positioning. This ensures that patients are adequately supported, minimizing the risk of complications related to positioning, such as pressure ulcers or nerve injuries .More coAirway management challengesAdvanced Airway Management SkillsAnesthesia providers should possess advanced airway management skills, allowing them to adapt to the anatomical nuances of obese patients. This includes expertise in various intubation techniques and strategies for optimizing ventilation. Providers should be prepared to handle scenarios where conventional intubation methods may prove challenging .Video LaryngoscopesVideo laryngoscopes are invaluable tools in managing obese patients with difficult airways. These devices incorporate a camera at the tip of the laryngoscope blade, offering a clear view of the airway and vocal cords. This visual aid enhances the accuracy of intubation attempts, even in cases where direct laryngoscopy may be challenging due to anatomical factors .Supraglottic Airway DevicesSupraglottic airway devices, such as the laryngeal mask airway (LMA), are crucial in securing the airway in obese patients. These devices are inserted above the vocal cords and are particularly useful in scenarios where endotracheal intubation is challenging. LMAs provide a secure airway for positive pressure ventilation and can be a bridge to definitive airway management if needed .Comprehensive TrainingAnesthesia providers should undergo comprehensive training in advanced airway management tools and techniques, especially when caring for obese patients. Regular simulation exercises and ongoing education help maintain proficiency and ensure readiness to address airway challenges effectively .Medication dosing in obese patientsInduction AgentsAdjusting for altered pharmacokinetics: Obesity is associated with significant drug distribution and metabolism changes. In particular, the increased adipose tissue content and expanded volume of distribution can lead to prolonged drug effects. As a result, dosing of induction agents like propofol and etomidate should be cautiously approached in obese patients .Consideration of ideal body weight or lean body mass: To prevent the risk of overdosing and subsequent prolonged sedation or respiratory depression, anesthesia providers often base dosing on ideal body weight or lean body mass rather than total body weight in obese patients. Ideal body weight is calculated based on a healthy BMI, which allows for a more accurate alignment of drug dosing with the patient's physiological characteristics .Maintenance AgentsCareful titration based on patient response: Maintenance agents, including inhalational anesthetics and intravenous infusions, require precise titration based on the patient's response. Continuous monitoring of the depth of anesthesia is essential throughout the procedure. Technologies like bispectral index (BIS) monitoring provide real-time feedback on the patient's level of consciousness, enabling anesthesia providers to adjust maintenance agent dosages as needed .Balancing anesthesia depth: The primary goal is to achieve a balanced anesthetic state that ensures patient comfort while minimizing the risks associated with excessive or inadequate anesthesia depth. Overly deep anesthesia can result in delayed emergence, whereas insufficient depth may lead to intraoperative awareness .Neuromuscular Blocking AgentsHigher dosing requirements: Due to the increased volume of distribution in obese patients, higher initial doses of neuromuscular blocking agents (NMBAs) like rocuronium or vecuronium may be necessary to achieve the desired level of muscle relaxation for surgical procedures. This adjustment is crucial to ensure the effectiveness of NMBA-induced paralysis .Monitoring neuromuscular blockade: Train-of-four (TOF) monitoring is paramount when administering NMBAs to obese patients. TOF monitoring assesses the depth of neuromuscular blockade, aiding anesthesia providers in precise dose titration. This approach ensures that the degree of paralysis aligns with the requirements of the surgical procedure, preventing both inadequate blockade and excessive paralysis. Continuous monitoring continues throughout the surgery to guide the administration of reversal agents when necessary, facilitating a smooth recovery .AnalgesicsWeight-adjusted dosing: Pain management is crucial for obese patients during and after surgery. The dosing of analgesics, whether opioids or non-opioid alternatives, should be adjusted to account for weight-related factors. This adjustment ensures that analgesic effects are adequate to control pain effectively while minimizing the risk of overdose .Multimodal analgesia: In obese patients, a multimodal analgesic approach is often favored to reduce reliance on opioids and mitigate their associated side effects, including respiratory depression and postoperative nausea and vomiting. This approach may encompass non-opioid analgesics, regional anesthesia techniques, and adjunct medications like non-steroidal anti-inflammatory drugs (NSAIDs). By combining multiple analgesic modalities, anesthesia providers can enhance pain control and improve the overall safety profile of pain management in obese patients .Ventilation strategiesRisk of Hypoventilation and Respiratory ComplicationsIncreased vulnerability: Obese patients have unique anatomical and physiological characteristics that make them more susceptible to hypoventilation, oxygen desaturation, and postoperative respiratory complications. These challenges stem from decreased lung compliance, reduced functional residual capacity, and a propensity for upper airway obstruction .Positive end-expiratory pressure (PEEP): PEEP\u00a0is often employed to address these concerns. PEEP helps maintain lung volume by preventing alveolar collapse during expiration. This technique aids in improving oxygenation and mitigating atelectasis, which is a common issue in obese individuals during anesthesia and surgery .Monitoring oxygen saturation: Continuous monitoring of oxygen saturation (SpO2) is essential throughout the surgical procedure to promptly detect any declines in oxygen levels. Obese patients may experience rapid desaturation during periods of hypoventilation, making vigilant monitoring crucial for patient safety .Monitoring end-tidal CO2 (ETCO2): Continuous monitoring of end-tidal carbon dioxide (ETCO2) levels, known as capnography, is a fundamental component of anesthesia for obese patients. ETCO2 monitoring provides real-time feedback on ventilation and allows anesthesia providers to detect hypoventilation early. Rising ETCO2 levels can be an early sign of inadequate ventilation, enabling timely intervention to prevent hypercapnia and associated complications .Elevation of the Head of the BedImproved ventilation: During surgery, elevating the head of the bed in obese patients can help improve ventilation. This adjustment assists in reducing the risk of upper airway obstruction, which is more prevalent when patients are supine. Proper positioning is critical to optimize lung mechanics and maintain effective ventilation .Positioning and Pressure Sore PreventionProper patient positioning is crucial to ensure access to the surgical site and prevent pressure sores, especially in obese patients with limited mobility. Pressure-relieving pads and regular position changes should be employed to minimize the risk of skin complications during prolonged procedures. A thorough understanding of these anesthetic management strategies tailored to obese patients is essential for anesthesia providers and healthcare teams to ensure safe and effective care during IVF procedures .Intraoperative and postoperative considerationsHemodynamic MonitoringContinuous surveillance of hemodynamics is paramount in the care of obese patients undergoing IVF procedures. A higher prevalence of cardiovascular comorbidities, such as hypertension, coronary artery disease, and heart failure, often accompanies obesity. As a result, meticulous attention to hemodynamic parameters is essential to detect and manage potential perioperative cardiovascular issues .Blood Pressure MonitoringClose and continuous blood pressure monitoring, including systolic and diastolic measurements, is crucial. Automated non-invasive blood pressure cuffs should be appropriately sized to ensure accurate readings. This ongoing assessment enables anesthesia providers to detect and respond promptly to changes in blood pressure, whether due to surgical manipulation, anesthesia effects, or underlying cardiovascular conditions .Heart Rate MonitoringContinuous heart rate monitoring is vital to detect any arrhythmias or hemodynamic fluctuations promptly. Anesthesia providers must be prepared to address bradycardia or tachycardia as needed during the surgery, ensuring that the patient remains stable throughout the procedure .Cardiac Output AssessmentIn certain high-risk or complex cases, assessing cardiac output may be necessary. This can be achieved through various techniques, including thermodilution or less invasive methods like pulse contour analysis. Monitoring cardiac output provides valuable insights into the patient's circulatory status and helps guide fluid management and vasopressor/inotropic support when indicated .Temperature managementMaintaining normothermia is of paramount importance in the intraoperative care of obese female patients undergoing IVF. These patients present unique considerations due to their larger body surface area and altered thermoregulation. Such factors elevate their susceptibility to perioperative hypothermia, a condition that can have detrimental consequences, including coagulopathy, heightened vulnerability to surgical site infections, and increased cardiovascular stress .To safeguard the well-being of these patients, it is imperative to employ active warming measures specifically tailored to their needs. One widely utilized method involves the use of forced air warming blankets, which deliver warm air directly to the patient's body, helping to counteract the challenges posed by their altered thermoregulation. Furthermore, warmed intravenous fluids can be employed as an effective means to maintain the core body temperature within the desired range for this patient population. Continuous temperature monitoring throughout the IVF procedure is essential, enabling immediate intervention in case of any deviations from the optimal normothermic range .Fluid managementIn fluid management during surgical procedures, particularly for obese patients, two crucial considerations demand attention. Firstly, obese patients are at a heightened risk of overhydration, which can result in severe complications, including pulmonary edema and cardiovascular strain. Therefore, healthcare providers must exercise caution when administering fluids to this patient population. Implementing individualized fluid management strategies tailored to each patient's unique needs is essential. These strategies should be guided by hemodynamic monitoring, and in some cases, invasive measures might be required to ensure precise fluid balance and prevent overhydration .Secondly, preventing complications like pulmonary edema is paramount when caring for obese surgical patients. To achieve this, it is imperative to avoid excessive fluid administration. Instead, the focus should be on optimizing oxygenation levels. Continuous monitoring of oxygen saturation and end-tidal CO2 and a vigilant assessment for early signs of fluid overload, such as crackles during auscultation, must be integral to the surgical team's protocol. By adhering to these meticulous fluid management and monitoring practices, healthcare providers can minimize the risks associated with overhydration and pulmonary edema, ultimately ensuring safer surgical outcomes for obese patients .Postoperative considerationsPostoperative care for obese patients demands a comprehensive and tailored approach to ensure their safety and well-being during recovery. Firstly, transitioning from the operating room to the recovery room necessitates vigilant monitoring. Healthcare providers must closely observe vital signs, oxygen saturation levels, and consciousness levels and remain alert to any signs of postoperative complications, such as respiratory distress or cardiovascular instability. This heightened level of surveillance is crucial in the immediate postoperative phase to promptly address any issues that may arise .Effective pain management is another critical facet of postoperative care for obese patients. Recognizing that they may require higher doses of analgesics due to altered pharmacokinetics, healthcare teams should adopt multimodal analgesic approaches. These approaches should incorporate non-opioid options to minimize the potential for opioid-related side effects while optimizing pain control and ensuring patient comfort .Early mobilization is a cornerstone of postoperative care for obese individuals. Promptly getting patients up and moving helps mitigate the risk of complications associated with immobility, such as atelectasis (lung collapse) and DVT. Collaboration between physical therapists and nursing staff is vital in facilitating early ambulation and encouraging deep breathing exercises, which can significantly contribute to a smoother recovery .Obese patients are particularly susceptible to postoperative complications, notably atelectasis and DVT. Reduced lung compliance and hypercoagulability make them prone to these issues. Therefore, preventive measures should be integrated into the postoperative care plan. This may include using incentive spirometry to promote lung expansion, early ambulation to improve circulation and lung function, and pharmacological thromboprophylaxis to minimize the risk of DVT formation. By implementing these strategies and maintaining a vigilant postoperative care regimen, healthcare providers can help obese patients recover safely and minimize the potential for complications .Special considerations for IVFTiming of Anesthesia and IVF ProceduresThe timing of anesthesia in conjunction with IVF procedures is a critical and intricately coordinated aspect of patient care. Firstly, anesthesia providers must establish a close and seamless collaboration with the IVF team to ensure that anesthesia induction and surgery are perfectly synchronized with the patient's specific IVF protocol. This synchronization is vital to optimize the timing of crucial IVF procedures, including oocyte retrieval, insemination, and embryo transfer, thereby maximizing the chances of a successful outcome .Oocyte retrieval stands out as a pivotal moment within the IVF process. To ensure patient comfort and minimize discomfort during the transvaginal follicular aspiration, anesthesia should be administered before this procedure. The timing and administration of anesthesia at this stage are critical to ease the patient's experience and allow the IVF team to perform the retrieval smoothly and efficiently .Regarding embryo transfer, the anesthesia approach may differ from oocyte retrieval. In many cases, patients may not require general anesthesia for this procedure. Instead, conscious sedation or regional anesthesia techniques may be more appropriate and well-tolerated by patients. The choice of anesthesia should consider the patient's preferences, comfort, and any specific medical considerations. This personalized approach ensures that the patient remains as relaxed as possible during this crucial step of the IVF process, contributing to a positive overall experience .Implications of Obesity on IVF Success RatesReduced oocyte quality: One of the primary consequences of obesity in the context of IVF is the potential for reduced oocyte (egg) quality in obese women. This decline in oocyte quality can manifest as abnormalities, such as irregular chromosome structure and spindle formation. As a result, obese individuals may experience lower fertilization rates and reduced embryo implantation rates during IVF. These challenges can pose significant obstacles to achieving a successful pregnancy .Altered hormonal profiles: Obesity disrupts hormonal profiles in several ways. Notably, it often leads to increased insulin resistance, a condition in which cells become less responsive to the effects of insulin. Additionally, obesity can alter sex hormone levels, causing elevated estrogen and androgen levels while reducing levels of sex hormone-binding globulin (SHBG). These hormonal imbalances can negatively impact ovarian function, potentially leading to irregular menstrual cycles and suboptimal reproductive outcomes .Increased risk of miscarriage: Obese patients undergoing IVF are at an elevated risk of experiencing miscarriages. This heightened risk emphasizes the importance of preoperative health and weight management optimization. Furthermore, during pregnancy, obese individuals require close monitoring to promptly identify and manage any complications that may arise, given the increased risk associated with their condition .Diminished response to medications: Obesity can result in a diminished response to fertility medications used in IVF, particularly gonadotropins. Due to altered pharmacokinetics, obese patients may require higher doses of these medications to stimulate ovarian follicular development effectively. Tailoring medication dosages to individual patient needs is crucial in optimizing IVF outcomes .Increased risk of complications: Obesity is associated with a heightened risk of complications during IVF procedures. Notably, obese individuals may be at an increased risk of developing ovarian hyperstimulation syndrome (OHSS), characterized by enlarged ovaries and fluid accumulation in the abdomen and chest. Additionally, they may face an elevated risk of thromboembolic events, such as blood clots, during the IVF process. Careful management and monitoring are essential to mitigate these risks and ensure the safety and success of IVF procedures in obese patients .Emotional and Psychological Support for Obese Patients Undergoing IVFPatient counseling: Preoperative counseling tailored to IVF's emotional and psychological aspects is essential for obese patients. It's important to create a safe and non-judgmental space where patients can openly discuss their anxieties, body image concerns, and expectations related to fertility treatment. Addressing these issues early can help patients better cope with the emotional rollercoaster often accompanying IVF .Support groups: Obese patients undergoing IVF can benefit immensely from participating in support groups or counseling sessions for individuals facing similar challenges. These groups provide a supportive environment where patients can share their experiences, express their emotions, and receive advice and encouragement from peers who have undergone similar journeys. Connecting with others who understand their unique struggles can be comforting and empowering .Multidisciplinary approach: A holistic approach involving a team of healthcare professionals is crucial. This multidisciplinary team may include psychologists, social workers, dietitians, and reproductive specialists collaborating to provide comprehensive support. Psychologists and social workers can help patients address the emotional impact of infertility and obesity on their mental health, offering coping strategies and emotional resilience tools .Education: Providing patients with accurate and detailed information about the relationship between obesity, IVF, and fertility outcomes is key. Clear and open communication helps patients make informed decisions and manage their expectations realistically. Educating patients about the specific challenges they may face due to obesity and the potential impact on IVF success can help alleviate anxiety and uncertainty .Challenges and future directionsOngoing Research in the FieldObesity-related factors: Researchers are delving into specific obesity-related factors that can influence fertility and IVF outcomes. This includes studying adipokines (hormones produced by fat tissue), inflammatory markers, and genetic predispositions that may impact reproductive health. Understanding the molecular mechanisms underlying these factors can provide insights into potential interventions to improve fertility and IVF success rates in obese patients .Anesthetic techniques: Research in this area evaluates the safety and efficacy of various anesthetic techniques tailored to obese patients undergoing IVF. This may include investigating the benefits and risks of regional anesthesia options, optimizing sedation strategies, and developing drug dosing protocols that account for the altered pharmacokinetics and pharmacodynamics often seen in obese individuals. Finding the safest anesthesia approach can improve patient comfort and procedural outcomes .IVF protocols: Modified IVF protocols designed to address the unique challenges presented by obesity are a critical area of research. Scientists and clinicians are working on optimizing ovarian stimulation regimens to improve oocyte quality and quantity in obese women. Additionally, researchers aim to develop protocols that reduce the risk of complications like ovarian hyperstimulation syndrome (OHSS) in this patient population, ensuring safer and more successful IVF cycles .Long-term outcomes: Research efforts also extend to studying the long-term outcomes of obese patients and their offspring following IVF. This includes assessing the impact of maternal obesity on maternal and neonatal health and investigating potential epigenetic changes that may occur during IVF procedures. Understanding the lasting effects of IVF in obese patients is crucial for providing comprehensive healthcare and counseling to these individuals and their families .Emerging Technologies and TechniquesPrecision medicine: The application of precision medicine in IVF involves tailoring treatment protocols and anesthesia management to each patient's specific genetic and metabolic characteristics. By analyzing an individual's genetic and metabolic profile, healthcare providers can make more informed decisions regarding fertility medications, dosages, and anesthesia techniques. This personalized approach can optimize treatment outcomes and minimize risks for obese patients, who often exhibit unique physiological variations .RoboticThe Role of Multidisciplinary Teams in Managing Obese Patients Undergoing IVFCollaboration: Effective care for obese patients undergoing IVF requires close collaboration among healthcare specialists. This includes anesthesiologists, reproductive endocrinologists, bariatric specialists, nutritionists, psychologists, and other relevant professionals. These experts work together to develop integrated care plans that address both the medical and psychosocial aspects of obesity and fertility treatment. This collaborative effort ensures that all aspects of a patient's health and well-being are considered .TailoreIn conclusion, the anesthetic evaluation and management of obese patients undergoing IVF procedures is multifaceted and demands precision, empathy, and a multidisciplinary approach. This comprehensive review has underscored the significance of addressing obesity's impact on IVF success rates, the importance of tailored anesthesia and perioperative care, and the need for emotional support throughout the IVF journey. Obesity poses unique medical and psychological challenges, necessitating a holistic approach that bridges the realms of anesthesia, reproductive medicine, and patient well-being. As we move forward, ongoing research, emerging technologies, and collaborative efforts among healthcare providers promise to enhance further the care of obese individuals seeking fertility treatments. By refining our practices and understanding, we can empower these patients to achieve the dream of parenthood while ensuring their safety, comfort, and overall success."} +{"text": "During the COVID-19 pandemic, clinical trials of vaccines received unprecedented publicity; whether this interest might be transferred to vaccine trials generally is unknown. Enrolment in paediatric COVID19 vaccine trials was slower than uptake of adult vaccine trials, and lessons learned are, therefore, of importance for future recruitment and participant experience. Previous studies have investigated motivations for participation in adult vaccine trials , paediatPreviously, we have observed response rates of 2%-4% for similar trials. We therefore hypothesised that prior vaccine trial experience and exposure might modulate the threshold for trial participation, and descriptively studied motivations and barriers to paediatric vaccine trial participation in this context. Ethical approval and feedback from the Oxford Vaccine Centre Public and Patient Involvement (PPI) group was received. Motivations for trial participation were dichotomised by prior trial participation Table ; self-deThis survey has limitations, being an unvalidated survey instrument, the reliance on self-report, and the inability to ascertain motivations among those who declined to participate. Further research including representative sample of the general UK population and better controlling for social desirability bias may shed further light on the nature and magnitude of differences in motivation, providing a basis for targeting adjustments to enrolment\u2014and improve generalisability especially post-pandemic. Parental motivations for enrolling children in clinical trials are understudied and merit detailed exploration to maximise successful recruitment in future trials.Additional file 1: Supplementary Table 1. Baseline characteristics of 81 respondents. P-values are for chi-squared tests."} +{"text": "Catatonia is a complex psychomotor syndrome that often goes unrecognized and, consequently, untreated. Prompt and correct identification of catatonia allows for highly effective treatment and prevention of possible complications. Benzodiazepines and electroconvulsive therapy (ECT) are the most widely studied treatment methods. However, no uniform treatment method has yet been brought forward and no previous attempts to treat catatonia on a patient suffering concomitant major depressive disorder (MDD) with NMDA receptor antagonists have been documented so far.To describe the unknown and novel management of catatonia and MDD with intranasal esketamine, a NMDA receptor antagonist.A 55-year-old woman with a diagnosis of long-standing recurrent major depressive disorder who was admitted to the psychiatric inpatient unit of UniversityHospital Marqu\u00e9s de Valdecilla suffering a complex catatonic, mutative state framed on a severe MDD. Different ineffective therapeutic interventions were deployed during the course of her illness. After failing to improve under conventional pharmacological treatment and ECT, and given the complexity of peripheral venous access on this patient (which disabled the option for iv ketamine use), we decided to initiate compassionate treatment with intranasal esketamine.Intranasal esketamine was effective in the resolution of patient\u2019s complex catatonic state. Clinical response from catatonia was observed after 6 intranasal esketamine administrations (2-week follow-up), reaching full catatonia and MDD remission after 12 sessions in absence of significant adverse eventsEsketamine showed promising effectiveness for the treatment of catatonia in the context of MDD, although further research on this topic is needed.None Declared"} +{"text": "Cardiac fibrosis is a pathological response characterized by excessive deposition of fibrous connective tissue within the heart. It typically occurs following cardiac injuries or diseases. However, the lack of suitable models for disease modeling and high-throughput drug discovery has hindered the establishment of an effective treatments for cardiac fibrosis. The emergence and rapid progress of stem-cell and lineage reprogramming technology offer an unprecedented opportunity to develop an improved humanized and patient-specific model for studying cardiac fibrosis, providing a platform for screening potential drugs and synchronously elucidating the underlying molecular mechanisms. Furthermore, reprogramming cardiac fibroblasts into cardiomyocyte-like cells to reduce scar volume and induce myocardial tissue regeneration is a promising approach in treating cardiac fibrosis. In this review, we summarize the current advancements in stem cell technologies applied to study cardiac fibrosis and provide insights for future investigations into its mechanisms, drug discovery as well as therapy method. Cardiac fibrosis is a prevalent pathological alteration observed in the advanced stages of most cardiovascular diseases (CVDs). This debilitating condition is frequently associated with various cardiac disorders, resulting in impaired heart function and potentially life-threatening complications such as heart failure plays a pivotal role in initiating cardiac fibrogenesis in response to mechanical stress Leask , mitogenFollowing myocardial damage, a plethora of signaling molecules such as chemokines, cytokines and growth factors are released, triggering the activation of cardiac fibroblasts through diverse pathways. The RAAS is activated during the process of cardiac fibrosis and interacts with pathways that contribute to fibrosis , including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), have substantially expanded the availability of human cells for modeling cardiac fibrosis and discovering drugs due to their ability to unlimitedly self-renew and differentiate into types of cells within the body (about 40%) derived from hESCs better mimics the pathological process of cardiac fibrosis . The transplantation of hPSC-CMs holds the potential to directly enhance cardiac function in individuals with reduced fibrosis and increased vascular density. Additionally, hPSC-CMs can enhance cardiac tissue regeneration and repair processes by secreting growth factors, cytokines, and other signaling molecules . This feature illustrates the potential to obtain abundant cardiomyocytes for transplantation\u00a0 in the implantation of hPSC-CMs in a subacute myocardial infarction pig model , mesoderm posterior bHLH transcription factor 1 (MESP1), myocardin (MYOCD), and zinc finger protein, multitype 2 (ZEPM2) to convert human fibroblasts into human induced cardiomyocyte-like cells (hiCMs) from mouse and human fibroblasts, which possess multipotency to differentiate into various types of cardiovascular cells using a transgene-free reprogramming approach involving six small molecules: CHIR99021, A83-01, GSK126, Forskolin (an adenylyl cyclase activator), CTPB (a P300 histone acetyltransferase activator), and AM580 (a RAR\u03b1 activator) (Wang et al. Despite the considerable potential of stem cell therapy in addressing cardiac fibrosis, there are still several obstacles need to be overcome. These challenges encompass the selection of appropriate stem cells sources, concerns regarding biosafety during cell transplantation, and the necessity to improve cell survival and retention rates, among other factors. The advantages and disadvantages of stem cell transplantation and cell reprogramming for cardiac fibrosis therapy are summarized in Table In summary, stem cell therapy for cardiac fibrosis is an advancing field with promising prospects for the future. Ongoing research and technological advancements are propelling these therapeutic approaches towards potential success. However, several challenges persist in current stem cell treatments. Further investigation is required to address issues such as the selection of appropriate stem cell sources, biosafety concerns, and the feasibility to monitor treatment efficacy. Moreover, ensuring the successful engraftment and survival of transplanted stem cells into the heart remains to be tackled. Many transplanted cells do not exhibit long-term viability or fail to differentiate into functional cardiac cells, thereby impeding the overall effectiveness of this therapy. To ensure the safety and efficient implementation of these stem cell-based approaches, rigorous clinical studies and repeated validation are indispensable. Efforts are underway to establish a high-throughput drug screening platform for the development of novel therapies. Striking a balance between complexity and user-friendliness is pivotal for this platform. Through comprehensive research and validation, we can surmount these challenges and unlock the full potential of stem cell therapy for cardiac fibrosis in the future."} +{"text": "Long-term success of peritoneal dialysis as a kidney replacement therapy requires a well-functioning peritoneal dialysis catheter. With ongoing reductions in infectious complications, there is an increased emphasis on the impact of catheter-related and mechanical complications. There is currently a marked variation in the utilization of various types of catheters , methods of catheter insertion , timing of catheter insertion, location of catheter placement and peri-operative practices. Specialized approaches to catheter placement in clinical practice include use of extended catheters and embedded catheters. Marked variations in patient lifestyle preferences and comorbidities, specifically in high acuity patient populations necessitate individualized approaches to catheter placement and care. Current consensus guidelines recommend local procedural expertise, consideration of patient characteristics and appropriate resources to support catheter placement and long-term functioning. This review focuses on an overview of approaches to catheter placement with emphasis on a patient-centered approach. It is reported that approximately 424,000 patients worldwide utilize peritoneal dialysis (PD) as a method of kidney replacement therapy . A well-Knowledge of best practices in catheter insertion can minimize the risk of catheter complications leading to early PD failure. Guideline committees under the sponsorship of the International Society for Peritoneal Dialysis (ISPD) recommend optimal PD catheter implantation be based on individualized patient factors, facility resources and operator expertise . Currentvia trocar and blind insertion via Seldinger technique at the time of catheter placement , 22. EarAnother strategy for timely initiation of PD is the embedded catheter technique, with the external limb of catheter embedded in subcutaneous tissue until the need for dialysis initiation. This allows for early patient commitment to PD, more predictable operating room scheduling, and immediate utilization of the catheter after exteriorization. However, there is a risk of non-usage of catheters, in addition to catheter dysfunction rates secondary to fibrin accumulation \u201328.No specific catheter placement approach has been proven to produce superior outcomes. Comparison of percutaneous placement, open surgical dissection and basic surgical laparoscopy have shown equivalent patient outcomes , 29\u201331. The goals of PD catheter placement involve a balance between pelvic position of catheter tip to facilitate inflow and outflow of dialysate along with an easily visible and accessible exit site. Operator expertise and experience necessitates selection of appropriate available catheter type suited to patient specific conditions. Placement includes the consideration of body habitus, belt-line, skin creases, prior scars, stomas, gastrostomy tubes, recreational habits and occupation. An ideal exit site is either above or below the beltline, with a lateral and inferior directed exit site . In the via a 2- piece extended catheter system, with a long subcutaneous section, while maintaining optimal catheter tip position. Alternatively, single piece catheters with long intercuff segments are also utilized in certain centers necessitate a specialized approach for successfully conducting PD as a dialysis modality. This includes not only optimal exit site and catheter tip position, but utilization of focused interventions to ensure ideal long term function. Patients with obesity require creation of an easily visible upper abdomen/presternal exit site requiring an extended catheter approach. The catheter should be allowed to heal completely for several weeks prior to PD initiation. Ideally, a laparoscopic approach is recommended, utilizing selective omentopexy along with resection of epiploic appendices of sigmoid colon if needed. The upper abdominal and chest exit sites are located in areas with relatively thin subcutaneous layer, minimizing tubing stresses from mobility of the subcutaneous fat layer with postural changes. Data suggests longer time to first exit site infections in patients with extended catheters . MoreovePatients with autosomal dominant polycystic kidney disease (ADPKD) present a unique set of concerns regarding limited peritoneal space, peritonitis risk and hernias. Several studies have reported the feasibility of PD in ADPKD patients \u201340. WithPatients with cirrhosis present their own unique challenges with regards to potential bacterial peritonitis, nutritional challenges, and concerns for leaks \u201349. SeveSafe and effective placement of PD access is critical to the ultimate outcomes of PD as a home dialysis modality. SK and MR were responsible for preparation, writing and editing of this manuscript. Both authors contributed to the article and approved the submitted version."} +{"text": "Furthermore, the SVM model could distinguish MDD patients with different suicidality gradients . In conclusion, we have identified that disrupted brain connections were present in MDD patients with different suicidality gradient. These findings provided useful information about the pathophysiological mechanisms of MDD patients with suicidality.Suicidal behavior is a major concern for patients who suffer from major depressive disorder (MDD). However, dynamic alterations and dysfunction of resting-state networks (RSNs) in MDD patients with suicidality have remained unclear. Thus, we investigated whether subjects with different severity of suicidal ideation and suicidal behavior may have different disturbances in brain RSNs and whether these changes could be used as the diagnostic biomarkers to discriminate MDD with or without suicidal ideation and suicidal behavior. Then a multicenter, cross-sectional study of 528 MDD patients with or without suicidality and 998 healthy controls was performed. We defined the probability of dying by the suicide of the suicidality components as a \u2018suicidality gradient\u2019. We constructed ten RSNs, including default mode (DMN), subcortical (SUB), ventral attention (VAN), and visual network (VIS). The network connections of RSNs were analyzed among MDD patients with different suicidality gradients and healthy controls using ANCOVA, chi-squared tests, and network-based statistical analysis. And support vector machine (SVM) model was designed to distinguish patients with mild-to-severe suicidal ideation, and suicidal behavior. We found the following abnormalities with increasing suicidality gradient in MDD patients: within-network connectivity values initially increased and then decreased, and one-versus-other network values decreased first and then increased. Besides, within- and between-network connectivity values of the various suicidality gradients are mainly negatively correlated with HAMD anxiety and positively correlated with weight. We found that VIS and DMN-VIS values were affected by age ( Major depressive disorder (MDD) is a common psychiatric disorder characterized by an inability to experience pleasure/reward (anhedonia) , affecti. Furthermore, previous studies aver that cortical thickness of ten regions within fronto-temporal-parietal system act as top-ranked classifiers that could differentiate suicide attempts from SI in MDD patients [Neuroimaging and behavioral studies have recently centered on network-based structural and functional alterations of individuals at risk of suicide. Previous studies postulated that fronto-limbic system is the central circuit underlying the suicidal process under depressive conditions \u201315. MDD patients . In addipatients . These fBased on prior studies, we hypothesized that suicidal gradient in MDD patients might arise from disturbances in macroscale brain RSNs and altered brain connections may represent powerful diagnostic biomarkers to discriminate MDD with or without SI and SB. First, the current study mapped the dynamic trajectory of large-scale RSNs roles and their clinical significance with dynamic network-based analysis in MDD patients with suicidality gradient. Second, common and specific network connections associated with different suicidal gradients were identified in MDD patients. Third, the support vector machine (SVM) model was used to explore the role of these abnormal neuroimaging characteristics as objective diagnostic biomarkers in classifying MDD patients with different suicidal gradients. Depression shows gender specificity in which the incidence rate of MDD is approximately twofold higher in women than in men . TherefoAmong the previously mentioned MDD patients, 169 individuals had a medication history; nevertheless, they had refrained from taking medication for a duration of at least three weeks at the time of enrollment. Based on a 17-item HAMD suicide item score, MDD patients were categorized into five categories: a score of 0 was defined as MDD without suicidal ideation (MDDNSI); score of +1 was defined as MDD with mild suicidal ideation (MDDmSI); score of +2 was defined as MDD with moderate suicidal ideation (MDDmoSI); score of +3 was defined as MDD with severe suicidal ideation (MDDSSI); and score of +4 was defined as MDD with SB (MDDSB). HCs were randomly divided into HC and verification groups. Detailed information on all subjects is shown in Table A total of 528 MDD patients and 998 HCs were recruited from the REST-meta-MDD consortium and the All study sites obtained approval from their local institutional review boards and ethics committees. Also, these research protocols were approved by the Ethics Committee of Henan Provincial Mental Hospital Affiliated with Xinxiang Medical University . All participants, their legal guardians, or their legally authorized representatives provided informed consent prior to their involvement in the study.Scan acquisition was completed within 1 week of assessments. Resting-state fMRI and structural T1-weighted MRI brain scans were acquired at each of the 24 participating study sites (see STable These networks comprise the auditory network (AUD), the cingulo-opercular network (CON), the dorsal and ventral attention network (DAN and VAN), the default mode network (DMN), the fronto-parietal network (FPN), the salience network (SAN), the sensorimotor network (SMN), the subcortical network (SUB), and the visual network (VIS). Network connectivity between all pairs of 10 RSNs, as well as between each RSN and all other RSNs were computed.A power atlas was usedp\u2009<\u20090.05 for all tests. In addition, a one-way analysis of variance (ANOVA) test was used to analyze continuous variables, with post hoc least significance difference (LSD) tests for pair-wise comparisons. Chi-squared tests were also used for categorical variables. Notably, each network metric ) was compared across groups using generalized linear model (GLM) analysis adjusted for age, gender, education, and study site as covariables. All p values were adjusted for multiple comparisons using FDR correction.Group comparisons of demographic characteristics and network metrics across MDD subgroups were undertaken using analysis of covariance (ANCOVA) and significance levels were set at p\u2009<\u20090.001.The current study first generated a 226 * 226 connectivity matrix for each subject. Network-based statistical analysis (NBS) method was then used to identify common and differential connections of networks between healthy control (HC) and disease groups, as well as various disease subgroups. Each connection identified by NBS with Bonferroni correction satisfied Due to the potential effects of age and sex in dynamic network analysis, Wilcoxon rank sum tests were used to compare the abnormality of network and clinical variables in sex and age. Specifically, all patients were split into younger (age: 18\u201337) and older (age: 38\u201365) participants or females and males to obtain sex- and age-related alterations in networks and clinical variables, separately.The current study computed Pearson\u2019s correlation between network variables and clinical data.SVM was used in the current study to classify MDD subgroups and HCs in MATLAB based on a library (LIBSVM) . The curAll described analyses were repeated using another set of healthy subjects that included 499 subjects to validate whether network role construction could be replicated and whether selected functional connections could be used for classification.p\u2009<\u20090.001) and subscales scores including anxiety (p\u2009=\u20090.0003), weight (p\u2009<\u20090.0001), retardation (p\u2009<\u20090.0001), and sleep (p\u2009=\u20090.0001), compared with those of MDNSI subjects, indicating that MDD patients R1\u20132 with suicidality had severer depression compared with MDNSI patients. Furthermore, there were no statistically significant differences in additional clinical characteristics upon enrollment, including total disease duration and frequency of episodes among the subgroups of individuals with MDD.Demographic information and characterization of all study subjects are outlined in Table R1\u20133 and pairwise BNC in HC group and suicidality-related MDD patients Fig. . SpecifiTo further map abnormal network connections with significant group differences in within-, between- or one versus other networks of ten RSNs in MDD patients, the current study first established increased and decreased network connections in the suicidality-related MDD patients compared with the HC group as shown in Fig. To understand the clinical significance of abnormal WNC and BNC in MDD subgroups, the current study conducted Pearson\u2019s correlation between FC strength within- and between networks and clinical variables including HAMD total scores and subfactor scores, including HAMD-Anxiety, HAMD-Weight, HAMD-Retardation, and HAMD-Sleep in MDD patients after controlling for covariables of age, gender, education, and study site. Correlation patterns showed group-level associations of WNC and BNC with depressive severity in MDD subgroup patients and established that distinctive network basis was associated with different symptom dimensions in MDD patients with or without suicidality Fig. . These nThe SVM model was used to explore the role of abnormal FC as an objective diagnostic biomarker in MDD patients. Mean FCIs from 31 pairs of network connections were used as input features to the linear support vector classifier (SVC). AUC showed that these FCIs demonstrated a higher capacity to discriminate MDD patients with SB from the HC group (AUC\u2009=\u20090.96). The use of the SVM-trained model as a classifier demonstrated that the SVM-trained model showed better power in separating MDD patients with SI or SB from MDDNSI patients . Furthermore, FCIs also showed greater potential to discriminate suicidality gradient-related MDD patients except for MDDmSI from MDDmoSI patients AUC\u2009=\u20090.73). Detailed information is described in Fig. 3. DetailWilcoxon rank sum tests were used to determine the potential effects of age and sex on large-scale brain networks and clinical variables in females and males, or in younger and older participants, separately. The current study established that age and sex had significantly different impacts on the two variables Fig. . SpecifiThe current study repeated these analyses to validate current findings in independent cohorts that included new 499 HCs and the original 528 MDD patients. More females and lower educational years were found in MDD subgroup patients compared with the new HC group. In addition, large-scale network roles analysis showed similar network dynamics in MDD subgroups compared with the HC validation group . These findings indicate that the use of large-scale network connection approaches to identify more robust diagnostic neuroimaging biomarkers may vary depending on whether the prediction goal pertains to diagnosis. Therefore, the established key features of large-scale network dynamics are crucial for early recognition and timely diagnosis of individuals with suicidality in depression and achieve much greater progress towards understanding and preventing suicide, as well as reducing patients\u2019 risk of morbidity from suicide ideation and attempts and their risks of suicide death. In clinical translational practice, measured imbalanced network links in the current study served as functional endophenotypes to particularly characterize depressive patients who tend to disguise real suicide intent without apparent symptoms. In addition, the current study used this endophenotype to guide informed treatment and monitor if medications target these networks.Several previous studies have established the effects of age and gender on large-scale network dynamics in healthy and depressive disorders \u201362. In mThe current study had some limitations. First, this was a cross-sectional study involving multiple centers. A longitudinal study should be undertaken to validate these findings. Second, the suicidality gradient in depression was assessed using HAMD suicidal factor scores, which may limit findings. Therefore, the use of improved suicidality assessment instruments is necessary to precisely evaluate the severity of suicide in MDD patients in future studies. Third, future studies are needed to establish whether these abnormal networks are long-lasting and how they may interact with environmental and genetic factors.In conclusion, the current study demonstrated that the dynamic trajectory of network roles at a large-scale level was associated with suicidality gradient in MDD patients. Abnormal overlapping network connections were used as neuroimaging biomarkers in the diagnostic identification of subjects who are vulnerable to suicide under depressive conditions. The current study achieved much greater progress towards understanding the pathologic mechanism of suicide and precisely preventing suicidal occurrence via targeting these circuits with effective medical or physical instruments.supplemental material"} +{"text": "In recent few years, high-flow nasal oxygenation (HFNO) has been widely used for management of acute hypoxemic respiratory failure and during postextubation periods, including after endotracheal intubation general anesthesia (ETGA). However, HFNO generates positive pressure in the injured airway following removal of endotracheal tube may cause airway leaks. This is the first case report of severe airway leak syndrome following postextubation use of HFNO in surgical patients.This case report describes a 75-year-old female with critical aortic stenosis who underwent an emergency Bentall procedure. HFNO (flow rate of 45\u2009L/min) was applied after weaning from mechanical ventilation and removal of the endotracheal tube.At 6 hours after HFNO application, subcutaneous emphysema in the neck bilaterally and face was noted, and the emphysema extended into the supraclavicular regions.The HFNO cannula was removed soon after and the patient was re-intubated with an endotracheal tube the following day due to progressive respiratory insufficiency. Unfortunately, the patient general condition deteriorated, as the subcutaneous air collections progressed into deep tissue infections of the neck, mediastinal abscesses, and left-sided empyema. Patient received surgical interventions repeatedly to drain the mediastinal abscess and empiric antimicrobial therapy was given.The patient passed away about 2 months later due to uncontrollable sepsis.Air leaks in the upper airway can occur during the use of post-extubation HFNO use, and the resulting subcutaneous emphysema can progress to severe intrathoracic infections in surgical patients who have a sternotomy wound. Therefore, HFNO-induced subcutaneous emphysema should be treated more aggressively in open thoracic or sternotomy surgeries to prevent the development of intrathoracic sepsis. HFNO is currently used to prevent hypoxic events during anesthesia induction, procedural sedation and as an alternative to respiratory support in critically ill patients.,2 A large-scale multi-center clinical trial further demonstrated that HFNO is not inferior to standard noninvasive mechanical ventilation for preventing reintubation and respiratory failure within 72 hours post endotracheal tube removal in high-risk critically ill adults. Compared with conventional oxygen therapy, HFNO also significantly reduces reintubation rates and rates of respiratory support escalation immediately after endotracheal general anesthesia (ETGA) in adult surgical patients. Therefore, HFNO is recommended over conventional oxygen therapy for the management of acute hypoxemic respiratory failure and for postextubation periods in emergency departments, hospital wards, intermediate or step-down units, and intensive care units. Although clinical studies did not find major complications in postextubation use of HFNO,,6 positive pressure in the upper airway from high gas flow may cause air-leaks into the subcutaneous tissues from the injured airway mucosa.,8 This case report describes a patient who was successfully weaned from invasive mechanical ventilatory support day 1 after a Bentall procedure, but developed extensive subcutaneous emphysema and pneumomediastinum within few hours after switching from endotracheal intubation to HFNO.Specially equipped high-flow nasal oxygenation (HFNO) provides a high flow rates (up to 70\u2009L/min) of warm and humidified mixed oxygen/gas to generate continuous positive pressure in the upper airways, wash-out of dead space in the nasopharyngeal cavity, increase alveolar recruitment and functional residual capacity, reduce work of breathing and respiratory muscle fatigue, enhance airway secretion clearance, and improve hypercapnia post endotracheal tube extubation.A 75-year-old woman with a medical history of chronic hypertension and aortic stenosis developed progressive shortness of breath and orthopnea a few days before surgery. She presented to the emergency department with hypotension and low peripheral oxygen saturation. An echocardiographic study showed calcified and severely stenotic aortic valves with a mean transvalvular pressure gradient of 60\u2009mm Hg and left ventricle dysfunction. The proximal aortic root was dilated to a diameter of 10\u2009cm. Acute cardiac failure was evidenced by elevated serum levels of B-type natriuretic peptide (>500 pg/mL) and pulmonary edema on chest radiography. An urgent Bentall procedure, including graft replacement of the ascending aorta and aortic valves was performed under ETGA and cardiopulmonary bypass. An endotracheal tube was inserted smoothly on the first attempt using a video laryngoscope without complications.The whole surgical procedure was completed within 10 hours. After successfully weaning off cardiopulmonary bypass in the operating room, the patient was transferred to intensive care unit for postoperative care under mechanical ventilatory support. Mechanical ventilation was switched from pressure control and pressure support mode when the patient had regained consciousness and had shown effort of spontaneous respiration the morning after her operation. Following a successful spontaneous breathing trial for an hour, the endotracheal tube was removed and HFNO was applied with 40% fraction of inspired oxygen at a flow rate of 45\u2009L/min via a nasal cannula . The patient settled comfortably with HFNO, and adequate peripheral oxygen saturation was maintained. Six hours later, the patient claimed to have insidious attacks of sharp pain and swelling in the neck and face. Subcutaneous crepitus was detected at the neck bilaterally, extending to the lower jaw and the upper chest. HFNO was discontinued and the patient was put on a non-rebreathing mask for oxygen supplementation. A portable chest radiography taken at bedside confirmed the presence of subcutaneous emphysema in the neck and supraclavicular regions with no signs of pneumothorax or pneumomediastinum who were treated with HFNO after endotracheal tube removal. Two of these patients developed pneumothoraxes and one developed pneumomediastinum at 4 to 5 hours after HFNO use. Air leak problems in these pediatric patients were diagnosed by routine chest radiographies rather the presence of subcutaneous emphysema or hypoxic events. There was another case of an adult female with hemophagocytic lymphohistiocytosis who received endotracheal intubation and mechanical ventilatory support due to acute respiratory failure. HFNO therapy was applied at a flow rate of 40\u2009L/min after weaning from mechanical ventilation. Four days later, the patient developed dyspnea and hypoxemia. A series of radiological studies were performed to investigate and found pneumothorax, subcutaneous emphysema, and massive pneumomediastinum. After HFNO cessation, the patient respiratory conditions improved. Air-leak syndrome during postoperative HFNO use after ETGA in surgical patients have not been reported in the literature.It is generally believed that positive airway pressure generated by HFNO in the upper airway and trachea can squeeze air into subcutaneous tissues via micro-tears in the airway mucosa. However, our case progressed rapidly to intrathoracic sepsis and empyema due to gram negative nosocomial pathogen infections and she eventually expired because of uncontrollable sepsis. We speculated that the sternotomy wound might have precipitated the invasion of nosocomial organisms into the mediastinal subcutaneous air collection. Hence, more aggressive empirical antimicrobial treatment should be considered early stages subcutaneous emphysemas are found in surgical patients with a sternotomy or thoracotomy wound.We reported the first fatal air-leak complication following use of postextubation HFNO in a patient with a sternotomy after cardiac surgery. While most of the other case reports were associated with pneumothorax due to distal airway or lung tissue tears, the leak in our case was most likely located in the upper trachea, as the air-leak was not detected before removal of the cuffed endotracheal tube nor after tracheal re-intubation, and pneumothorax was also not found in our case. The initial clinical signs of air-leak syndrome in our patient were focal pain and detection of subcutaneous emphysema as opposed to being clinically asymptomatic or presence of hypoxia at the late stage in other cases. Therefore, detection of emphysema underneath the neck or facial subcutaneous tissues could be an early sign of upper airway leak when HFNO is applied after tracheal extubation. The outcomes of subcutaneous emphysema due to airway leak is usually self-limiting and requires mainly conservative management.In conclusion, the use of postextubation HFNO is generally safe after ETGA, but air-leak syndrome may still happen in unrecognized airway mucosal injuries, as continuous positive pressure is generated by the HFNO. The presence of subcutaneous emphysema can be an early sign of airway leak following application of HFNO and subcutaneous emphysema should be treated more aggressively in open thoracic or sternotomy surgery to prevent the development of intrathoracic sepsis.Conceptualization: Yu-Yang Liao, Hsuan-Yin Wu, Chen-Fuh Lam, Yi-Ming Wang.Data curation: Yu-Yang Liao, Yi-Ming Wang.Supervision: Chen-Fuh Lam, Yi-Ming Wang.Validation: Hsuan-Yin Wu, Chen-Fuh Lam.Writing \u2013 original draft: Yu-Yang Liao, Hsuan-Yin Wu.Writing \u2013 review & editing: Chen-Fuh Lam, Yi-Ming Wang."} +{"text": "Dear EditorWe thank Lightner and colleagues for their study on surveillance pouchoscopy in ulcerative colitis patients. The authors reported that neoplasia following ileal pouch-anal anastomosis (IPAA) is rare. They recommended pouch surveillance with random biopsies of the anal transition zone (ATZ) for patients with a personal or family history of colorectal neoplasia (CRN)It is unknown whether routine surveillance improves outcomes of pouch neoplasia, since pouch neoplasia is usually diagnosed after symptom development. As such, all patients in this study had a negative surveillance pouchoscopy in the 2\u2009years prior to pouch carcinoma detectionWe question whether random biopsies lead to earlier detection of (pre)cancerous pouch lesions. The authors reported six pouch carcinomas and none were detected in random biopsies. Moreover, six of seven dysplastic lesions identified with random ATZ biopsies were not confirmed in follow-up biopsies and it could be questioned whether the initial lesions contained \u2018true\u2019 dysplasiaFinally, we disagree with the recommendation of pouch surveillance in patients with a family history of CRN. The authors reported a positive family history in only one of 13 patients and previous studies did not identify this as a risk factor for pouch neoplasia.In conclusion, we only advocate pouch surveillance with random ATZ biopsies in high-risk patients with prior CRN. Nevertheless, current data remain scarce and uniform, widely adopted pouch surveillance guidelines are needed to unify practice.Disclosure. The authors declare no conflicts of interest."} +{"text": "The natural amino acid asparagine (Asn) is required by cells to sustain function and proliferation. Healthy cells can synthesize Asn through asparagine synthetase (ASNS) activity, whereas specific cancer and genetically diseased cells are forced to obtain asparagine from the extracellular environment. ASNS catalyzes the ATP-dependent synthesis of Asn from aspartate by consuming glutamine as a nitrogen source. Asparagine Synthetase Deficiency (ASNSD) is a disease that results from biallelic mutations in the ASNS gene and presents with congenital microcephaly, intractable seizures, and progressive brain atrophy. ASNSD often leads to premature death. Although clinical and cellular studies have reported that Asn deprivation contributes to the disease symptoms, the global metabolic effects of Asn deprivation on ASNSD-derived cells have not been studied. We analyzed two previously characterized cell culture models, lymphoblastoids and fibroblasts, each carrying unique ASNS mutations from families with ASNSD. Metabolomics analysis demonstrated that Asn deprivation in ASNS-deficient cells led to disruptions across a wide range of metabolites. Moreover, we observed significant decrements in TCA cycle intermediates and anaplerotic substrates in ASNS-deficient cells challenged with Asn deprivation. We have identified pantothenate, phenylalanine, and aspartate as possible biomarkers of Asn deprivation in normal and ASNSD-derived cells. This work implies the possibility of a novel ASNSD diagnostic via targeted biomarker analysis of a blood draw. ASNS gene occupies 35 kb within chromosome 7q21.3 and is composed of a total of 13 exons glucose to analyze central carbon metabolism, [U-13C]aspartate to assess the specific fate of the ASNS reaction, and [U-13C]glutamine to assess TCA cycle turnover. Additionally, the significant decrements in lactate and central metabolism suggest that in vivo [2H7]glucose metabolic imaging may potentially be utilized to assess the effects of Asn deprivation on brain metabolism [In summary, our findings demonstrate that Asn deprivation leads to a broad-based disruption of the metabolic profiles of patient cells deficient for ASNS. We have identified potential metabolic signatures of Asn deprivation in healthy and ASNSD cells. This observation is of high interest for ASNSD and metabolic research as it warrants future work to establish the relevance of these metabolic signatures and their potential roles as diagnostic and prognostic biomarkers in an in vivo and clinical setting. While our results indicate a certain global metabolic insult caused by Asn deprivation in ASNS deficient cells, further work must be done to discern pathway-specific changes using isotopomer tracer and metabolic flux analysis. The research reported here warrants future studies on ASNSD cell models to assess the utilization of [U-tabolism ."} +{"text": "Conversely, no statistically significant difference in oral microbiota composition was observed, thus further revealing a close relationship between ICI response and gut microbiota diversity in NSCLC patients. Extracellular vesicles (EVs) were broadly classified into three main categories based on their biosynthetic or secretory processes: exosomes, microvesicles/particles/extracellular bodies, and apoptotic vesicles due to their association with both nutritional and inflammatory status. vesicles . With tharcinoma . A modelarcinoma . In addiarcinoma . Gao et Using Multi-Omics to Develop New Strategies for Improving Prognosis and Immunotherapy Outcomes in Cancer\u201d serves as a platform for sharing innovative strategies developed through multi-omics to enhance the effectiveness of immunotherapies and improve patient outcomes. These studies integrate data from various layers, providing valuable insights into the molecular structure of tumors and expanding the scope of cancer biology. Although clinical applications of these techniques are still in the early stages, we believe that several of these new approaches will not only advance our understanding of tumor biology but also significantly shape the future of precision cancer therapies.The Research Topic \u201c"} +{"text": "Escherichia coli bacteremia. Larvae of Strongyloides stercoralis were also observed in stool smears after a centrifugation concentration method. This diagnosis was confirmed by qPCR detection of Strongyloides spp. using the Allplex GI-Helminth (I) Assay (Seegene) (The definitive diagnosis was disseminated strongyloidiasis with concurrent Seegene) in the tS. stercoralis is a soil-transmitted nematode that is endemic in tropical and subtropical countries, especially in areas with inadequate sanitary conditions, and it is recognized as a neglected tropical disease in the gut, resulting in autoinfection. This unique property allows infection to persist for decades (chronic strongyloidiasis) and cause overwhelming infection if people become immunosuppressed later in life, leading to Strongyloides Hyperinfection Syndrome (SHS) or disseminated infection (Strongyloides infection in patients treated with dexamethasone needs to be considered to avoid precipitating SHS and disseminated strongyloidiasis (nfection , 7. Concnfection , so asym"} +{"text": "Plant genotype influences interactions among associated bacteria and fungi;Plant-growth-promoting bacterial communities lead to outcomes exceeding the sum of individual effects; andEnvironmental conditions impact how microbes in communities interact.Soils are home to a wide variety of microorganisms. The collective genome of these organisms is vast, and so individual strains perform some functions that few others can. In addition to the consumption of specific metabolites, many soil microbes excrete unique compounds into their direct environment in soils, at root surfaces, and inside plants as endophytes. The ensuing localized build-up of compounds impacts other organisms by exerting a variety of functions: promoting growth, activating signal transduction, suppressing cellular functions, or changing the physicochemical environment. Microorganisms share soils with plants, whose roots exude cocktails of organic compounds ,2 that fOryza rufipogon wild rice and male parent Oryza sativa cultivated rice had significantly different bacterial and fungal communities than either of the parental lines. Similarly, sorghum lines have different rhizo- and endosphere bacterial communities that contribute to plant performance to different degrees under low nitrogen stress conditions [Plant breeding has focused largely on improved agronomic traits, such as yield and disease resistance, invariably losing some parental traits not selected for. Rhizomicrobiome analysis of modern cultivars versus ancestral accessions has revealed significant differences in the bacterial and fungal communities of rice . The pronditions . Cultivanditions .A unique three-way interaction has been reported among plants, their endophytes, and the associated rhizomicrobial community. Fungal endophytes of Tall Fescue are not only associated with improved biomass yield and stress tolerance, but also with soil fungal community composition and increased diversity . These sStreptomyces [Physicochemical conditions are well known to affect the growth of individual microbial cultures. Invariably, shifts in environmental conditions also impact the fitness of individual species and strains. Farda et al. reviewed the literature on actinomycetes in caves . The scaptomyces . Tarin eptomyces .Various microbial strains isolated from soils have been shown to benefit crop production through mechanisms such as nutrient acquisition or suppression of pathogens. Wang et al. present an analysis of how the consortia of disease-suppressing microorganisms bring about enhanced protection when compared to individual strains . They goThe contributions to this Special Issue all point to the complexity of specific interactions that lead to shifts in microbial communities under specific conditions. Much remains to be done to unravel the specific components of these interactions."} +{"text": "Environmental transmission of bacteria, including multidrug-resistant organisms (MDROs), persists within hospitals despite routine cleaning. In prior work, we identified discordance between 16S profiles of room surfaces and culture of MDROs, suggesting unique environments for MDRO persistence within rooms. To build on this work, we used culture-enriched metagenomic sequencing to identify a broad range of viable taxa on surfaces with strain-level assignment and resistome profiling. Additionally, we evaluated the role of room proximity on sharing bacterial taxa and resistance genes between rooms.We selected three intensive care unit (ICU) rooms at the Hospital of the University of Pennsylvania with varying proximity and sampled 12 surfaces per room divided into three composite samples (Table 1). Sampling was repeated for 3 consecutive days. Samples underwent liquid media enrichment, DNA extraction and shotgun metagenomic sequencing. Strain-level assignment was performed with MetaPhlAn 4.0 and resistance genes assigned via the Comprehensive Antibiotic Resistance Database (CARD).Each composite sample represents approximately 350 square inches of surface areaWe identified 40 strain-level assignments, with 18 shared between rooms. Within individual patient rooms, we identified microenvironments of bacterial strains and resistance genes and an increased probability of detecting cephalosporin resistance genes as distance increased from the patient\u2019s bed and neared bathroom sites . Using mixed effects regression, we found that distance between patient rooms was associated with decreased similarity in microbiomes of the distant in-room sites , while an opposite pattern was observed in the bathroom sites .Rooms that were closer had greater similarity of microbiomes at the distant in-room site. Focused interventions on this microenvironment within patient rooms may be highest yield in reducing room-to-room transmission of bacteria. Shared microbiota at the bathroom site may be linked to plumbing infrastructure, but further research is needed to support this hypothesis.All Authors: No reported disclosures"} +{"text": "Open Biology, titled \u2018Advances in Quantitative Bioimaging\u2019, proposes an overview of the latest advancements in quantitative bioimaging techniques and their wide-ranging applications. The articles cover various topics, including modern imaging methods that enable visualization on a nanoscale, such as super-resolution microscopy and single-particle analysis. These techniques offer unparalleled insights into complex molecular structures and dynamic cellular processes in situ, such as mapping nuclear pore proteins or tracking single histone deposition events throughout the cell cycle. The articles presented in this edition showcase cutting-edge quantitative imaging techniques coupled with advanced computational analysis capable of precisely measuring biological structures and processes. Examples range from correlating calcium release events to underlying protein organization in heart cells to pioneering tools for categorizing changes in microglia morphology under various conditions. This editorial highlights how these advancements are revolutionizing our understanding of living systems, while acknowledging challenges that must be addressed to fully exploit the potential of these emerging technologies, such as improving molecular probes, algorithms and correlation protocols.This special feature of Recent progress in quantitative bioimaging technologies has empowered us to visualize complex molecular architectures, track individual proteins, compare cellular dynamics with nanoscale precision and single-molecule resolution. This leap forward holds significant potential for driving our understanding into uncharted territory by offering fresh mechanistic insights into living systems. In this special feature issue of . 2et al. discusses the power of combining super-resolution microscopy (SRM) with single-particle analysis (SPA). Several primary research articles in this special edition leverage advanced imaging methods to shed light on important cellular processes: Hurley et al. explore the relationship between calcium signalling events and the structural organization of calcium channels in cardiac muscle cells; Lando et al. use single-particle tracking to understand histone CENP-A molecule deposition in fission yeast; Ragaller et al. propose novel smart probes to measure membrane properties, which are crucial for understanding cellular processes. On the computational front, Martinez et al. have developed machine learning-based tools to characterize morphological alterations and behavioural shifts in microglia during neuroinflammation.This special edition features articles highlighting the ground-breaking applications of quantitative bioimaging techniques in various areas of biology. A review by Mendes et al., in their review entitled \u2018Mapping molecular complexes with super-resolution microscopy and single-particle analysis\u2019, discuss the combined power of SRM and SPA [Mendes and SPA . SRM's aMiriam E. Hurley and her colleagues in their paper \u2018Correlative super-resolution analysis of cardiac calcium sparks and their molecular origins in health and disease' have successfully linked calcium release events, referred to as \u2018sparks\u2019, with the nanoscale arrangement of calcium channels known as ryanodine receptors RyR2) in rat heart cells [ in rat hIn vivo assessment of mechanical properties during axolotl development and regeneration using confocal Brillouin microscopy\u2019 by Riquelme-Guzm\u00e1n et al. used confocal Brillouin microscopy to uncover tissue mechanical changes in vivo throughout development and regeneration in the highly regenerative axolotl, with a particular focus on limb and digit cartilage [The article \u2018artilage . Probinget al., the authors used image analysis tools to examine the morphology and phagocytic behaviour of microglia in healthy and pathological conditions in vitro and in brain tissue [In the article titled \u2018Characterization of microglia behaviour in healthy and pathological conditions with image analysis tools\u2019 by Martinez n tissue . The autet al., in their work \u2018Dissecting the mechanisms of environment sensitivity of smart probes for quantitative assessment of membrane properties', present smart probes\u2014Pro12A, NR12S and NR12A\u2014to assess membrane properties [The research presented in this special issue has important implications for various fields. For instance, Ragaller operties . In thei. 3The studies presented here highlight scientific progress made possible by advanced quantitative bioimaging techniques and image analysis. These tools allow us to better understand the intricate layers of cellular functions and expand our perception of how living systems operate across different scales. Over time, these advancements will help bridge the gap between experimental observation and theoretical vision, progressively tackling the formidable complexity intrinsic to biology."} +{"text": "Nitrospirota and Nitrospinota have received significant research attention due to their unique nitrogen metabolisms important to biogeochemical and industrial processes. These phyla are common inhabitants of marine and terrestrial subsurface environments and contain members capable of diverse physiologies in addition to nitrite oxidation and complete ammonia oxidation. Here, we use phylogenomics and gene-based analysis with ancestral state reconstruction and gene-tree\u2013species-tree reconciliation methods to investigate the life histories of these two phyla. We find that basal clades of both phyla primarily inhabit marine and terrestrial subsurface environments. The genomes of basal clades in both phyla appear smaller and more densely coded than the later-branching clades. The extant basal clades of both phyla share many traits inferred to be present in their respective common ancestors, including hydrogen, one-carbon, and sulfur-based metabolisms. Later-branching groups, namely the more frequently studied classes Nitrospiria and Nitrospinia, are both characterized by genome expansions driven by either de novo origination or laterally transferred genes that encode functions expanding their metabolic repertoire. These expansions include gene clusters that perform the unique nitrogen metabolisms that both phyla are most well known for. Our analyses support replicated evolutionary histories of these two bacterial phyla, with modern subsurface environments representing a genomic repository for the coding potential of ancestral metabolic traits.The phyla Bacteria and Archaea are presumed to have retained ancient traits due to the environments being analogous to early-Earth, in some cases isolated from the surface world on geologic timescales . Ge. GeNitroses Fig.\u00a0. Gene clly Figs.\u00a0, 8.Fig. Nitrospirota and Nitrospinota as direct relatives . In. InnxrABota Fig.\u00a0. This susmatales . The verNitrospirota and Nitrospinota are markedly different than the later branching groups that have received much attention due to their ecological prominence, especially in the marine environment, and unique nitrogen-based metabolisms. Despite some differences in particular metabolic functions, the similar evolutionary histories of Nitrospirota and Nitrospinota demonstrate how multiple modes of evolution can shape closely related phyla that occupy similar ecological niches. These data demonstrate that gene loss, de novo origination, or lateral acquisition of new genes is a replicated pattern in later-branching clades of phyla whose extant subsurface-inhabiting members resemble ancestral lineages that initially evolved in a primordial habitat.Here we demonstrate that the ancestral metabolisms of early branching clades for the sister phyla Supplmental Methods and FiguresSupplemental Data 1Supplemental Data 2Supplemental Data 3Supplemental Data 4Supplemental Data 5Supplemental Data 6Supplemental Data 7"} +{"text": "Burgeoning evidence demonstrates that effects of environmental exposures can be transmitted to subsequent generations through the germline without DNA mutations1,2. This phenomenon remains controversial because underlying mechanisms have not been identified. Therefore, understanding how effects of environmental exposures are transmitted to unexposed generations without DNA mutations is a fundamental unanswered question in biology. Here, we used an established murine model of male-specific transgenerational obesity to show that exposure to the obesogen tributyltin (TBT) elicited heritable changes in chromatin interactions (CIs) in primordial germ cells (PGCs). New CIs were formed within theIdegene encoding Insulin Degrading Enzyme in the directly exposed PGCs, then stably maintained in PGCs of the subsequent (unexposed) two generations. Concomitantly,IdemRNA expression was decreased in livers of male descendants from the exposed dams. These males were hyperinsulinemic and hyperglycemic, phenocopyingIde-deficient mice that are predisposed to adult-onset, diet-induced obesity. Creation of new CIs in PGCs, suppression of hepaticIdemRNA, increased fat mass, hyperinsulinemia and hyperglycemia were male-specific. Our results provide a plausible molecular mechanism underlying transmission of the transgenerational predisposition to obesity caused by gestational exposure to an environmental obesogen. They also provide an entry point for future studies aimed at understanding how environmental exposures alter chromatin structure to influence physiology across multiple generations in mammals."} +{"text": "Editorial on the Research TopicRecent advances in the assessment and management of thoracic traumaThoracic trauma presents a significant global public health challenge, comprising approximately 25% of all injuries and contributing to up to 50% of trauma-related fatalities . SurvivoHoepelman et al.). This initiative aimed to delve into the clinical outcomes and quality of life experienced by individuals after surgical rib fixation for flail chest injuries. The findings showed a significant trend, with low complication rates and a favourable one-year quality of life, as assessed with the EQ-5D-5l questionnaire. Nonetheless, it is pertinent to note that substantial variability was observed among patients in this context.The majority of the articles included in this compilation scrutinized outcomes following surgical stabilisation of rib fractures in distinct patient cohorts. A noteworthy endeavour was carried out by the NEXT study group, encompassing a prospective cohort study that spanned six institutions across Switzerland and the Netherlands (Zhang et al. embarked on an evaluation of outcomes following surgical stabilisation of rib fractures in elderly patients. Employing a single-centre, propensity score matching analysis, their investigation identified a nuanced dichotomy. Patients who underwent surgery exhibited a modestly prolonged hospital stay by an average of two days when compared with their counterparts receiving conservative treatment. Nevertheless, the surgical cohort demonstrated markedly improved rates of fracture healing and a shorter duration of analgesic regimens, delineating a balance between hospitalisation duration and therapeutic efficacy.Becker et al. contributed a matched pairs analysis by using data from the German trauma registry. Their study focused on determining the optimal timing for rib fracture surgery. The findings highlighted a distinct advantage for surgical stabilisation within the initial 48\u2005h post-trauma, resulting in significantly shorter durations of intensive care unit and hospital stays compared to fixation performed between three and ten days following the injury.van Veelen et al., a unique perspective emerged as the authors explored outcomes after surgical fixation of chest wall fractures incurred during cardiopulmonary resuscitation efforts. It is worth mentioning that this retrospective, single-centre study included 19 patients, representing the largest reported cohort to undergo fracture fixation due to cardiopulmonary resuscitation. The authors reported a lack of complications associated with rib fixation, with only one infection observed following sternal fixation. Furthermore, the long-term follow-up demonstrated a favourable quality of life, as measured with the EQ-5D-5l questionnaire.Shifting our attention to the study by While the studies included in this Research Topic make substantial contributions to the evidence base, it is essential to acknowledge certain limitations. In the domain of thoracic trauma, the predominant body of research is characterized by retrospective observational studies and non-randomized prospective trials. Moreover, there is a pronounced heterogeneity in surgical techniques and outcome reporting, making comparisons between studies a challenging endeavour . RegardiWhile the studies featured in this Research Topic undeniably advance our understanding of the assessment and management of thoracic trauma, they also reveal a multitude of unanswered questions. Key areas requiring further research include the definition of optimal patient selection criteria for surgical stabilisation of rib fractures. Currently, it remains uncertain whether fixation should be extended to include a broader spectrum of non-flail chest fracture patterns. There is also a pressing need for comparative effectiveness studies examining different surgical techniques. The role of thoracoscopic visualization in fracture management is an interesting topic that also requires more comprehensive evaluation. Moreover, the absence of standardized protocols for perioperative analgesia and rehabilitation is conspicuous. In addition, there is a dearth of research into long-term, patient-centred outcomes, such as persistent disability and return to work. Formal cost-effectiveness analyses comparing surgical stabilisation to non-operative management are also relatively absent. To address these knowledge gaps effectively, it is necessary to conduct high-quality randomised controlled trials with standardised treatment protocols and well-defined outcomes. Multicentre studies can facilitate larger sample sizes, leading to improved generalizability. Overall, continued research is crucial in honing best practices for thoracic trauma care and ultimately enhancing outcomes for these patients. The studies presented in this Research Topic are indeed promising strides forward, but they highlight that a plethora of unanswered questions awaits exploration in future research.Thoracic trauma continues to exact a substantial toll on global health, contributing significantly to morbidity and mortality rates. The research shared in this Topic signifies prominent advancements, yet further investigations are imperative to delineate optimal practices more precisely. Persistent research efforts in this pivotal domain are warranted to mitigate the global public health repercussions of chest injuries and ultimately improve patient outcomes."} +{"text": "Editorial on the Research TopicArtificial intelligence and advanced technologies in neurological surgerySurgical treatment of neurologic disorders has always benefited from technologic advancements in operative techniques and equipment, imaging, predictive analytics, and many others. In recent years, almost all neurosurgical subspecialties have seen a substantial effort to develop, validate, and utilize artificial intelligence and machine learning models in a clinical manner . Unique In this research topic, we explore recent technologic advancements made in neurosurgery, including supervised machine learning models aimed at predicting postoperative survival in glioma patients, customized 3D printing and laser navigation applied to minimally invasive hematoma evacuation, an advanced cerebrospinal fluid (CSF) drainage method for use in posterior fossa tumor resection, and a novel endoscopic approach for treatment of oculomotor nerve palsy, all of which may help to inspire future work in similar topics of interest.Li et al. at an academic institution in China compared the accuracy of traditional statistical models and supervised machine learning models in predicting patient survival following resection for gliomas. Multivariate Cox proportional hazards regression, support vector machine (SVM), random survival forest (RSF), and tree and component gradient boosting (GB) models were evaluated using patient-specific clinical and biomarker variables and were subsequently compared in performance using concordance indexes. Predictably, the traditional Cox proportional hazards regression model performed poorly in both training and testing sets when compared to the supervised machine learning models, of which the GB models produced superior performance in predicting survival. Time-dependent survival performance was additionally assessed between tree GB and component GB models, which displayed good discrimination (area under the curve >0.8) at all evaluated time points. The authors of this study recognized many important patient variables found to influence survival based on these models, including functional status, tumor size, and resection type, which can be utilized to develop patient-specific perioperative plans with the goal of extending survival and limiting morbidity.At the forefront of advancements in neurosurgical outcomes analysis is artificial intelligence and machine learning. A retrospective cohort study conducted by Yuan et al. studied hypertension-induced intracerebral hematoma external drainage techniques based on two new methods in a retrospective analysis: three-dimensional (3D) printing and laser guidance for navigation during puncture and debridement. In the 3D printing method, computed tomography (CT) image reconstructions were utilized to plan endoscope entry and trajectory into hematomas, which were then 3D printed in combination with patient face molds for customized intraoperative guidance. Laser guidance additionally utilized Xper-CT scans and 3D reconstructed images to emit a continuous focus directed towards the hematoma throughout the duration of the procedure. In direct intraoperative and postoperative comparisons, patients treated with 3D printing assistance were found to have significantly shorter operative durations than those treated with laser navigation assistance. However, outcomes including hematoma clearance rate, Glasgow Coma Sale improvement, and hospitalization time were similar between the two groups. The authors noted advantages to both techniques, including real-time navigation feedback and customized care, but may come at increased costs or extended preoperative setup time. Minimally invasive techniques in neurosurgery can be further improved with advancements in imaging and navigation, such as 3D printing and laser guidance.Beyond predictive analytics, developments in imaging technology have been utilized to improve intraoperative techniques. Recent work done by Roethlisberger et al. In their recent work, the authors utilized image-guided ipsilateral trigonal ventriculostomy for cerebellar pressure control during retrosigmoid craniotomy for cerebellopontine angle (CPA) tumor resection, after which outcomes were evaluated in a cohort of 52 patients. Prior to durotomy, the authors performed ventriculostomy of the ipsilateral trigone of the lateral ventricle using CT or magnetic resonance image (MRI) guidance, advancing an external ventricular drain (EVD) to release CSF and decompress the cerebellum. In the prospectively evaluated cohort, cerebellar swelling was avoided in 98% of cases using this technique. However, authors reported an 8% incidence of postoperative intracerebral or intraventricular hemorrhage without clinical complications. Ultimately, the authors recommended consideration of this technique for large posterior fossa tumors but not for small lesions.Developments in image guidance technology have been additionally explored in cerebrospinal fluid (CSF) diversion approaches to reduce cerebellar contusion, such as in the study described by Wang et al. The authors of this work describe detailed anatomic landmarks encountered in their endoscopic approach, focusing on correct identification of the optic strut triangle, consisting of the internal carotid artery, optic nerve, and superior orbital fissure, in preparation for oculomotor nerve decompression. Hollowing of the optic strut by sequential drilling under endoscopic visualization achieved decompression of the optic and oculomotor nerves, resulting in rapid neurologic symptom improvement in 2 presented patient cases. Although still requiring further trials, the techniques described in this study may introduce alternatives to invasive approaches that arise with often extensive complications.New surgical methodologies for conditions previously lacking standardized treatment plans have been developed with the aid of technological advancements including endoscopic approaches. A novel transnasal endoscopic approach for treatment of traumatic oculomotor nerve palsy associated with superior orbital fissure fracture is described in a recent study by Advancements in clinical and intraoperative technology have enabled neurosurgeons to create patient-specific management plans and improve postoperative outcomes for a range of conditions. In this research topic, four original studies were included that demonstrate the breadth of developments made in artificial intelligence-based predictive analytics, intraoperative imaging and navigation technologies, and novel cranial approaches aimed at improving patient outcomes. Further incorporation of machine learning algorithms, reconstructive software, and minimally invasive technology into daily medical practice will allow future generations of surgeons to provide personalized care to patients based on unique comorbidities and anatomic variations.We certainly live in an era of rapid technologic advancement, but this also comes with great responsibility. As physicians and surgeons, it is our duty to question these technologies and understand their limitations before implementing them in our clinical practice. However, it is also our duty to embrace and use them when they can improve our patients\u2019 lives. As our techniques and devices continue to evolve, we look forward to exploring the positive impacts made to neurosurgery and beyond."} +{"text": "The need for high quality evidence is recognized for optimizing practices of parenteral nutrition (PN). The purpose of the present systematic review is to update the available evidence and investigate the effect of standardized PN (SPN) vs. individualized PN (IPN) on protein intake, immediate morbidities, growth, and long-term outcome in preterm infants. A literature search was performed on articles published in the period from 1/2015 to 11/2022 in PubMed and Cochrane database for trials on parenteral nutrition in preterm infants. Three new studies were identified. All new identified trials were nonrandomized observational trials using historical controls. SPN may increase weight and occipital frontal circumference gain and lower the value of maximum weight loss. More recent trials suggest that SPN may easily increase early protein intake. SPN may reduce the sepsis incidence, but overall, no significant effect was found. There was no significant effect of standardization of PN on mortality or stage \u22652 necrotizing enterocolite (NEC) incidence. In conclusion SPN may improve growth through higher nutrient intake and has no effect on sepsis, NEC, mortality, or days of PN. Parenteral Nutrition (PN) is a lifesaving therapy for preterm infants. PN is indicated when oral or enteral nutrition is not possible, insufficient, or contraindicated in order to avoid undernutrition and related adverse consequences. The nutrient stores of very low birth weight and extremely low birth weight preterm infants are low. Bridging PN ensures adequate fluid intake and nutrient supply for weight gain and possibly neurodevelopmental long-term outcome. VLBW infants are vulnerable to postnatal growth failure because the gut is immature, and provision of nutrients is challenging. The evidence showing the beneficial effects of enhanced PN to VLBW infants is accumulating. Providing amino acids and energy immediately after birth with PN is a standard practice to promote positive nitrogen retention . SP. SP18]. However, the currently available commercial SPN solutions may not be the optimum approach. Commercial SPN may need an additional amino acid supply to achieve recommended target intakes and consequently adequate growth defined as intrauterine growth velocity .Beyond improved nutrient intake, the umbrella aim in introduction of SPN is to improve patient safety possibly at the cost of increased PN solution wastage . Due to However, SPN did not significantly prevent hospital associated complications . EspeciaStandard PN Solutions (SPN) Should Generally Be Used over Individualized PN Solutions (IPN) in the Majority of Preterm Infants, Including VLBW Premature Infants .Individually Tailored PN Solution should Generally Be Used When the Nutritional Requirements Cannot Be Met by the Available Range of Standard PN Formulations .It has been estimated that the majority of preterm infants receiving PN via central catheters may actually be treated by SPN, although, the optimum composition is not known ,38. SPN Adequately Powered Randomized Controlled Trials Based on Up-To-Date Parenteral Nutrition Recommendations Are Required to Evaluate the Real Clinical Benefits of SPN vs. IPN .Strengths of the present review are its exhaustive search of the available literature, reproducibility, systematic assessment of evidence and grading of recommendations. However, there are important limitations. Neonatology is rapidly developing and changing. E.g., nutritional recommendations changed several times within the last 20 years. Using historical controls rather than contemporaneous controls carries a high risk of bias and grossly limits the level of evidence. Improvements in nutritional status may rather be a consequence of increased nutritional awareness than a consequence of new developed PN approaches. The observed effects may have been noticed by chance and adequately powered, randomized controlled trials based on up-to-date parenteral nutrition recommendations are urgently required to evaluate the real clinical benefits of SPN bags. Given current parenteral nutrition recommendations a considerable proportion of infants of the reported trials are undernourished. In addition, the composition of SPN and IPN nutritional regimens and consequently the observed nutritional status, varied across and within the different studies, limiting the validity of the results of the meta-analyses. In the clinical experience of the authors, one SPN does not fit all preterm infants. The smaller the infants are, the more often adjustments are required, commercial SPN bags are more expensive than hospital pharmacy produced SPN bags, and finally commercial SPN bags still require pharmacy-based adjustments .We conclude that SPN may improve growth through higher nutrient intake and has no effect on sepsis, NEC, mortality, or days of PN. These observations may have been noticed by chance and adequately powered randomized controlled trials are required to evaluate the real clinical benefits of SPN."} +{"text": "Arachis hypogaea is a segmental allotetraploid in the section Arachis of the genus Arachis along with the Section Rhizomataceae. Section Arachis has several diploid species along with Arachis hypogaea and A. monticola. The section Rhizomataceae comprises polyploid species. Several species in the genus are highly tolerant to biotic and abiotic stresses and provide excellent sets of genotypes for studies on differential gene expression. Though there were several studies in this direction, more studies are needed to identify more and more gene combinations. Next generation RNA-seq based differential gene expression study is a powerful tool to identify the genes and regulatory pathways involved in stress tolerance. Transcriptomic and proteomic study of peanut plants under biotic stresses reveals a number of differentially expressed genes such as R genes , pathogenesis related proteins and defense related genes that are the most consistently expressed genes throughout the studies reported so far. In most of the studies on biotic stress induction, the differentially expressed genes involved in the process with enriched pathways showed plant-pathogen interactions, phenylpropanoid biosynthesis, defense and signal transduction. Differential gene expression studies in response to abiotic stresses, reported the most commonly expressed genes are transcription factors , LEA proteins, chitinase, aquaporins, F-box, cytochrome p450 and ROS scavenging enzymes. These differentially expressed genes are in enriched pathways of transcription regulation, starch and sucrose metabolism, signal transduction and biosynthesis of unsaturated fatty acids. These identified differentially expressed genes provide a better understanding of the resistance/tolerance mechanism, and the genes for manipulating biotic and abiotic stress tolerance in peanut and other crop plants. There are a number of differentially expressed genes during biotic and abiotic stresses were successfully characterized in peanut or model plants (tobacco or Arabidopsis) by genetic manipulation to develop stress tolerance plants, which have been detailed out in this review and more concerted studies are needed to identify more and more gene/gene combinations.Peanut Arachis hypogaea L.) is one of the most important legume crops economically worldwide and its seed a source of high quality edible oil, proteins, minerals and vitamins. It is widely cultivated across developing countries from semi-arid tropics to subtropical regions (st and 2nd respectively based on FAOSTAT data for the year 2020 (Peanut ( regions . China aear 2020 . ProductArabidopsis (135 Mb), rice (430 Mb), Medicago (904 Mb) and soybean (1.1 Gb). Large genome size and polyploidy nature is quite large in size in contry nature hamper cArachis comprises many wild species at different ploidy levels that exhibit resistance/tolerance to several biotic and abiotic stresses, which makes it a rich resource of suitable genes for commercial applications. Some wild species were deployed in the experiments with the aim of transferring the genes for tolerance/resistance to different stresses from the related wild species to the cultivated peanut genotypes in crop improvement programs is well-established and versatile technique with application to detects the enriched sequences in specific tissues at specific time points and used to characterize differential gene expression of plant responses to biotic and abiotic stresses . To inveRalstonia solanacearum , late leaf spot (LLS), rust, aflatoxin contamination and bacterial wilt disease by nacearum Figure\u00a01nacearum . To manaCercospora arachidicola [Hori] and Phaeosariopsis personata [Berk & M. A. Curtis] respectively, are the major foliar fungal diseases in peanut, which cause complete defoliation of leaves leading to significant losses in plant productivity upto 50 to 70% protein, transcription factors , peroxidases and genes related to secondary metabolites in the resistant variety upon pathogen invasion, while there was downregulation of genes including F-box, cytochrome p450, LRR protein kinase and terpene synthase that are associated with several biological processes in the susceptible variety. There is another recent report of DEGs of resistant and susceptible peanut cultivars to early leaf spot infection, which revealed the expression of resistance associated genes like CC-NB-LRR (NLR) type resistance gene, Phytoalexin deficient 4 (PAD 4) and polyphenol oxidase (PPO) that play important roles in mediating early leaf spot resistance and late leaf spot (LLS) diseases also collectively known as \u2018Tikka\u2019 disease caused by 0 to 70% . Early l0 to 70% . Advance0 to 70% . Upon pa0 to 70% . Candidasistance . IdentifPheaosariopsis personata (Cercospora personata) is the most devastating disease in peanut and can lead to yield losses up to 70% under favorable conditions . Furthermore, they identified TDFs (transcript derived fragments) that are associated with defense, signal transduction and metabolism, and further reported several genes for proteins involved in hypersensitive cell death, cell wall fortification and defense mechanism. Differential gene expression analysis in wild type and mutant peanut cultivar against late leaf spot pathogen was also reported by There are several methods available to study differential gene expression during plant-pathogen interactions in peanut, such as Genefishing DEG kit, suppression subtractive hybridization (SSH), cDNA-AFLP and cDNA-microarray techniques . These ansferase . In an e pathway . Kumar aR-genes (381) associated with leaf spot disease was predicted by a RGA-PCR based technique , receptor like proteins (RLPs) and receptor like cytoplasmic kinases (RLCKs), which co-ordinate and initiate protection responses against the invading pathogen , as potential resistance (R) genes play important roles in recognition and activation of disease resistance responses and the identification of putative peanut echnique . Furtherpathogen . Recentlpathogen .Puccinia arachidis that often occurs along with leaf spot disease also because of its rain fed nature, which leads to further yield losses. There are several studies on quantitative trait locus (QTL) in cultivated peanut to identify molecular marker or genetic map for rust resistance technique, which is based on next-generation sequencing (NGS) for genotyping and this resulted in the identification of six candidate genes for rust resistance protein were significantly upregulated in the resistant genotype revealing their important roles in plant defense mechanism. These findings will be helpful in understanding the molecular mechanism of peanut plant defense against the rust pathogen and may assist the breeders in the development of resistant varieties through molecular approaches.Rust is another serious foliar disease of peanut caused by sistance , but thesistance . RecentlAspergillus flavus is an opportunistic saprophytic fungal pathogen that infects a number of seed crops and microarray technology. Furthermore, they identified sixty two genes in the resistant cultivar that were upregulated in response to Aspergillus infection including defense related genes like PR10 protein, defensin, calmodulin, metallothionein like protein, Cu/Zn superoxide dismutase etc. and a large number of hypothetical proteins as the complete genome sequence was not available at that point of time. A similar study has reported the identification of Aspergillus resistance genes in peanut cultivars by comparing transcriptome profiles in resistant and susceptible peanut genotypes using microarray technique and identified hub genes positively associated with resistance to A. flavus in peanut. Their analysis also revealed that upregulation of genes encoding pathogenesis-related protein (PR10), MAPK kinase, 1-aminocyclopropane-1-carboxylate oxidase (ACO1), a serine/threonine kinase, cytochrome P450, pectin esterase, SNARE protein SYP121, pentatricopeptide repeat (PPR) protein and disease resistance response proteins in the esistant peanut cultivar that play major roles in resistance to infection from A. flavus. These studies provide new insights into the molecular mechanism of peanut defense against aflatoxin contamination and further the safety and management of peanut products for human consumption.on etc.) and prodon etc.) . Peanut nditions that cauechnique . Their rchnology . This grRalstonia solanacearum) is the most devastating soil borne disease in peanut (Arachis hypogaea L.) leading to significant yield losses because of reduced plant stand on the field at the seedling stage of the crop. Molecular mechanism of peanut response to R. solanacearum remains unnknown and needs to be studied in detail. In an attempt to explore the molecular mechanism of bacterial wilt resistance in peanut using Genefishing DEG kit, several differentially expressed candidate genes encoding a cyclophilin, ADP-ribosylation factor, antibacterial peptide and disease resistance response proteins were identified by studying the differences in gene expression between inoculated and control peanut seeds into six groups as resistant/susceptible response genes, which included PAMPs induced resistant/susceptible response genes and type III effectors (T3Es) induced resistant/susceptible response genes. Further more, KEGG enrichment pathway analysis of differentially expressed genes showed that MAPK signaling, plant-pathogen interaction, and plant hormone signal transduction pathways were upregulated. WRKY Transcription factors play an important role in plant disease resistance. Differential gene expression analysis of WRKY genes in cultivated peanut displayed different expression patterns in resistant and sensitive peanut cultivars infected with R. solanacearum. The identification of candidate WRKY genes with possible role in peanut resistance to R. solanacearum infection may contribute in the improvement of a resistant peanut variety , pathogenesis related proteins , defense related genes , glutathione S-transferase) and the genes involved in phenylpropanoid pathway are the most commonely expressed ones (Arabidopsis) through genetic manipulation and successfully developed biotic stress resistant plants for functional characterization of genes that integrated into the corresponding genome. There are limited reports on differentially expressed peanut genes for further characterization using genetic engineering to develop stress tolerance plants. The transgenic plants that were developed for functional characterization of diffrentially expressed peanut genes are given in Several peanut genes, which were differentially expressed during biotic stress conditions were further characterized by transgenic approach. Presently, genetic engineering technique such as Cyclophillin (AdCyp) gene that was differentially expressed in wild peanut A. diogoi during late leaf spot infection was incorporated into tobacco genome under a constitutive promoter through the Agrobacterium method and this resulted in enhanced resistance to Ralstonia solanacearum and reduced susceptibility toward Phytophthora parasitica var. nicotianae. Further, the resistance phenomenon was associated with the up-regualtion of various defense related genes genotype enhanced resistance to late leaf spot pathogen and this expression was associated with the co-expression of resistance-related genes, CC-NB-LRR and some protein kinases, while heterologous expression in tobacco enhanced its resistance against Phytophthora parasitica var. nicotianae, Alternaria alternata var. nicotianae and Rhizoctonia solani like cell death and positively regulated defense response genes. Furthermore, ectopic expression of AdVPE in tobacco resulted in enhanced resistance against Phytophthora parasitica var. nicotianae, Alternaria alternata var. nicotianae and Rhizoctonia solani (AdZADH2) was also differentially upregulated in Arachis diogoi, a wild peanut upon challenge with the late leaf spot (LLS) pathogen. Transient over-expression of AdZADH2 under an estradiol inducible promoter (XVE) exhibited hypersensitive response (HR)-like cell death in tobacco leaf and the cell death was associated with the upregulation of antioxidative enzymes such as SOD, CAT and APX and pathogenesis-related (PR) proteins (Vacuolar processing enzymes (VPEs) are cysteine proteases exhibiting caspase-1-like activity, which mediate cell death and upregulated during pathogen infections . AdVPE wa solani . A novelproteins .R gene products, which can directly or indirectly recognize pathogen effector proteins and induce signaling pathways for resistance against the impending pathogen in Nicotiana benthamiana and AhRLK1 overexpression in transgenic tobacco significantly enhanced resistance to R. solanacearum by triggering EDS1 and PAD4 in the R gene signaling pathway that possibly contributed to defense responses against the pathogen protein was found to be upregulated in both approaches . Wang etranensis .Soil salinity is another major abiotic stress factor that affects plant growth and development reducing crop productivity. Peanut is considered to be a moderately salt sensitive species, which makes salinity a liming factor for peanut cultivation. In general, plants respond to salt stress by changing their gene expression, which leads to an increase in the concentrations of several metabolites to protect themselves against high salinity. Transcriptome study has become an important tool for studying the possible mechanism and elucidating signal pathways underlying salt stress tolerance in plants. However, limited information is available about the networks of gene expression regulation related to salt stress in peanut. A microarray study has been carried out in peanut roots under salt stress conditions, which revealed that metabolic pathway, biosynthesis of unsaturated fatty acids and plant-pathogen interaction were upregulated, while photosynthesis and phenylalanine metabolism were downregulated . TranscrTIP3 gene is significantly upregulated in response to salt stress. Furthermore, TIP3 overexpression in Arabidopsis resulted in enhanced seed germination under salt stress corroborating its important role in seed germination under salt stress.A comprehensive study of drought tolerance in cultivated peanut has been performed under salt stress environment and this concurrent stress application has detected several differentially expressed genes and transcription factors (TFs) such as MYB, WRKY, bHLH and AP2/ERF in response to salinity. Moreover, differentially expressed genes related to cell wall growth, antioxidant and peroxidase activity were significantly enriched while DEGs related to metabolic processes, oxidoreductase and catalytic activity were downregulated . AquaporPMP34 that encodes a peroxisomal nicotinamide adenine dinucleotide carrier, and Sodium/H+ antiporters (NHX7 and NHX8), and downregulated expression of proline dehydrogenase 2. This resulted in the accumulation of soluble sugars and proline to maintain the osmotic balance with an additional up-regulation of the aquaporin gene TIP2-1. Moreover, exogenous EBL application upregulated the expression of NHX7 and NHX8 to balance the ion concentrations across membranes with increased peroxidase activity to scavenge reactive oxygen species, and glutathione levels to improve salt tolerance in peanut.Brassinosteroids (BRs) are essential for plant growth and development, and play crucial roles in stress tolerance . HoweverLow temperature is a major environmental factor that limits plant growth, development and yield. Cold stress causes different degrees of damage to the peanut plant at the seedling, flowering, and all other growth stages. A transcriptome or differential gene expression analysis in response to cold or metal stress could provide a deeper insight into the transcriptional mechanism of plants and their protective role against damage. Differentially expressed peanut genes in response to different temperature regimes was carried out using suppression subtractive hybridization (SSH) for cultivated peanut seeds and this study identified genes that are involved in functional categories including metabolism, defense, stress response, signal transduction and transcriptional regulation .2H2, ERF, MYB, NAC and WRKY in response to cold stress, which could be crucial for peanut cold tolerance are non-coding small RNAs that play important roles in various abiotic stresses by modulating gene expression. However, there is no report on the role of miRNAs in cultivated peanuts during cold stress. Very recently, cold-responsive miRNAs and candidate target genes were identified in peanut cold tolerant and sensitive varieties during cold stress using a deep sequencing method. Their analysis revealed several specific cold responsive microRNAs, which appear to mediate cold response. And, several transcription factors including WDRL, GRF and ARF, and genes such as peanuts .EIL (EIN3-like), which reveals a link between ethylene signal transduction and Al resistance related genes in peanut (Aluminum (Al) is the most abundant metal element in the Earth\u2019s crust, and has toxic effects on plant growth in acidic soils . The tarn peanut . An ultrn peanut . The samn peanut .Arachis accessions under drought, salt, cold and metal stress conditions will provide a better understanding of the tolerance mechanism, and will further provide reference for improving abiotic tolerant peanut cultivar through genetic manipulation.Differential gene expression study of peanut plants in response to abiotic stresses, reported by the most of the studies Table\u00a03,Agrobacterium tumefaciens mediated genetic transformation. There are several reports on the characterization of differentially expressed genes in peanut and/or model plants to develop stress resistance plants. The list of transgenic plants deploying differentially expressed peanut genes is provided in Further characterization of differentially expressed genes during various abiotic stresses by genetic manipulation like transgenic approach would aid in developing stress tolerance peanut cultivars, which can help achieve increased crop productivity. Till today, different types of transgenic plants were generated by genetic engineering technique using AhERF019 in Arabidopsis resulted in enhanced tolerance to drought, heat, and salt stresses (LEA) gene was differentially expressed in wild peanut upon infection with late leaf spot pathogen and overexpression of AdLEA in tobacco resulted in enhanced tolerance of plants to dehydration, salinity and oxidative stress. Furthermore, AdLEA overexpressed tobacco plants maintained better photosynthetic efficiency under drought conditions implying that it could be a potential gene for genetic modification in crop plants gene and overexpression of AdGolS3 gene in Arabidopsis resulted in increased raffinose production and tolerance to drought, salt and osmotic stresses plays a significant role in regulating gene expression in plant responses to stresses and was identified from peanut EST sequences available in the NCBI database. Ectopic expression of stresses . Late Emp plants . In silistresses . A CBL-in plants .TIP3 was found differentially upregulated under salt stress condition in cultivated peanut. Furthermore, the ectopic expression of AhTIP3;1 contributed to improved seed germination under salt stress in Arabidopsis was found upregulated during plant-microbe interaction in peanut and further, the overexpression of AhCytb6 gene in tobacco resulted in enhanced seed germination under N2 deficit and salt stress conditions gene was observed to be upregulated was found to be differentially expressed in the wild peanut after late leaf spot infection stress in tobacco are important endogenous non-coding RNAs with an average size of 21 to 23-nt in length that regulate gene expression in plants and animals by regulating mRNA expression post-transcriptionally . RNA polAspergillus flavus under Al stress, root tips of Al-sensitive and Al-tolerant peanut cultivars were analyzed under Al stress condition. Further intergrated analysis of transcriptomics, sRNAs, and degradome data sets revealed differential expression of 89 miRNA-mRNA interactions that might be involved in PCD under Al stress . In respArachis species using differential expression analysis for stress tolerance. However, commercially cultivated transgenic plants were not developed in peanut so far using the identified genes. There could be several reasons for this. Since peanut is a crop of high commercial significance whose produce is of prime importance in human nutrition, it is not easy to get regulatory approvals from the respective Governmental authorities across the world for the deployment of transgenic plants for field- level cultivation. Probably, many major efforts were not made in peanut in this direction because of this reason. With the advent of genome editing technology for various plant systems, the future is very optimistic for developing genome edited crops including peanut for stress tolerance as genome-edited crops might get regulatory approvals more easily compared to transgenic plants.The biological stresses mainly comprise attack from pathogenic fungi, bacteria, viruses, nematode and insects, whereas the abiotic constraints include drought, salinity, cold, metal, waterlogging and temperature changes. To overcome these various stress environments, plants must be capable of tolerating these stress conditions by modulating their metabolism in the right direction. In this direction, the genetically modified crops are considered to be good candidates for sustainable food production. It is to be noted that there were several genes identified in Agrobacterium tumefaciens or Rhizobium rhizogenes mediated genetic transformation technique through either in vitro or in planta methods for improvement. Transgene expression is highly dependent on the promoter selection for gene expression followed by protein synthesis. Several promoters of various origins have been tested for transgene expression besides viral gene promoter CaMV35S in peanut. In the backdrop of this, no meaningful progress of gene editing technique that is gaining enormous attention recently has been made so far in peanut.Genome modifications allow improvements in stress and weed tolerance, plant breeding procedure, productivity, food quality and safety. However, introduction of genetically modified crops may adversely affect the environmental conditions exercising harmful effects on animals and humans and this has been the main concern of the environmentalists . There aThere are several powerful plant-targeted genome editing tools for functional and applied genetic manipulations that include engineered nucleases, such as Zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regulatory interspaced short palindromic repeats (CRISPR) systems .Recently developed prokaryotic immune system based CRISPR technology is a high-throughput genome editing tool that has been found to be very successful in a variety of plant species . The CRIBiotic stress tolerance where crop yield and quality are largely affected by biotic stresses like viral, fungal, bacterial and insects were improved by using CRISPSR/Cas9 system. For instance, wheat and rice have been made tolerant to their respective viral, bacterial and fungal diseases . Tomato,FAD2) gene in peanut. This gene codes for the desaturase that is responsible for the conversion of monounsaturated oleic acid into polyunsaturated linoleic acid. The knock out mutation in FAD2 resulted in high oleic acid content in peanut oil (AhNFR gene through hairy root transformation system and validated the function for nodule formation in peanut. Using the CRISPR/Cas9 system, AhFatB genes Arahy4E7QKU and ArahyL4EP3N were knocked out in peanut, and mutation at Arahy.4E7QKU displayed low palmitic acid and high oleic acid content significantly improving oil quality in peanut (Application of CRISPR/Cas9-based gene editing technique would provide genetic improvement in peanut cultivars against biotic and abiotic stresses. However, application of this breakthrough gene editing technology to peanut is still rare. Till date, there is limited report of CRISPAR/Cas9-based gene editing in peanut. This technique is used for knocking out fatty acid desaturase2 (anut oil . Shu et\u00a0n peanut . PotentiArachis divided into various Sections is a boon to the investigators undertaking differential expression studies using the previously popular techniques like cDNA-AFLP and the highly efficient RNA-Seq studies using the Next Generation Sequencing technologies that became available recently. The goal of these studies is to understand molecular mechanisms during stress conditions and identify the genes responsible for stress tolerance in peanut plants. Depending on the availability of financial resources, the choice of the technology can be made. The primary advantage with the NGS technologies is that they give faster results on gene expression at whole genome level compared to the earlier technologies. The wild Arachis germplasm offers excellent material for the differential expression studies because of the availability of genotypes that are both susceptible and highly resistant to corresponding trait, be it biotic or abiotic stress tolerance. The alloploid species belonging to the Section Rhizomataceae are very highly tolerant to abioic stresses like high temperature and water limited conditions. Hence, the germplasm can be used for identifying tolerance genes within the tolerant genotype itself by comparing sets with and without treatments. Otherwise, a more efficient option would be to compare the resistant and susceptible genotypes at the same ploidy level with and without suitable treatments. Information from such studies could lead to novel genes that would actually decide the trait under consideration. The genes identified can be used in other related legume crop plants. This is particularly because of the possible colinearity of different related genomes in legumes. Hence, the opportunities are enormous when the investigator uses the material judiciously.The wild germplasm belonging to the genus DK: Conceptualization, Writing \u2013 original draft. PBK: Conceptualization, Writing \u2013 review & editing."} +{"text": "Liquid biopsy assays for minimal residual disease (MRD) are used to monitor and inform oncological treatment and predict the risk of relapse in cancer patients. To-date, most MRD assay development has focused on targeting somatic mutations. However, epigenetic changes are more frequent and universal than genetic alterations in cancer and circulating tumor DNA (ctDNA) retains much of these changes. Here, we review the epigenetic signals that can be used to detect MRD, including DNA methylation alterations and fragmentation patterns that differentiate ctDNA from noncancerous circulating cell-free DNA (ccfDNA). We then summarize the current state of MRD monitoring; highlight the advantages of epigenetics over genetics-based approaches; and discuss the emerging paradigm of assaying both genetic and epigenetic targets to monitor treatment response, detect disease recurrence, and inform adjuvant therapy. MRD does not cause clinical symptoms and is not detectable by traditional methods such as imaging or abnormal blood serum protein levels. MRD assays must be sensitive enough to detect as little as 1 cancerous cell in a background of 1 million noncancerous cells. This extreme sensitivity makes MRD assay development complex, but overcoming this barrier imbues MRD assays with the potential for much earlier detection of cancer recurrence than traditional methods, and thus earlier intervention with adjuvant chemotherapy or second and third-line treatments.Detection of MRD indicates the failure of treatment to eliminate all cancerous cells which implies greater probability of future disease recurrence. Monitoring MRD signals during the remission period allows early detection of disease progression . Assayin22.1DNA methylation is a covalent modification of the DNA strand that, in mammals, occurs almost exclusively within the sequence context of cytosine followed by guanosine (CpG) dinucleotides. The genomic acquisition of DNA methylation is an essential developmental process with diverse roles including repressive associations at gene promoters and mobile genetic elements or, conversely, increased transcriptional activity when found within gene bodies [reviewed in Greenberg & Bourc\u2019his ]. GenomeMost DNA methylation-based liquid biopsies target cancer-specific aberrations that separate cancer from its normal tissue counterpart. However, within healthy tissues DNA methylation exhibits highly cell type specific patterns across the genome . This un2.2The term \u201cfragmentomics\u201d describes the study of ccfDNA fragmentation patterns and the use of these patterns to decern biologically relevant information such as nucleosome positioning. Although few assays to-date utilize ccfDNA fragmentation patterns, numerous properties of ctDNA compared to healthy ccfDNA instill fragmentomics with the potential for use in oncological assays ; (ii) shAs for nucleosome positioning, ccfDNA fragmentation patterns downstream of transcription start sites have been shown to reflect differential nucleosome positioning between expressed and unexpressed genes . These cGoing forward, the most sensitive and universal MRD assays will likely combine these epigenomic approaches. Until recently, the combination of DNA methylation and fragmentomics in a single assay was not possible due DNA methylation detection relying on bisulfite conversion . Bisulfi3The marketplace for MRD liquid biopsy assays is new, but several MRD diagnostic tests have now received early regulatory approvals Table\u00a01.While there are only a few somatic mutation-based MRD panels in the marketplace, there are a host currently in development and undergoing clinic trials. For example, Strata Oncology are also exploring a two-staged tumor-informed panel design in their Sentinel trial for cancer recurrence . BurningNotably, genetic mutations are not broadly shared across cancers and the two-stage solutions to this shortcoming are limited by tumor heterogeneity and the volume of a tissue biopsy. That is, because only a subset of a tumor is sequenced there is still a high probability that mutations will be missed. However, a multi-omics approach can augment this shortcoming. The greater frequency and universality of epigenetic changes makes them more sensitive and universal markers for evidence of cancer after curative intent treatment, and somatic mutation testing highlights actionable variants that can inform subsequent treatment. This promise of MRD assays that incorporate epigenetics with somatic mutation testing is being realized. Guardant Health has combined somatic mutations, DNA methylation and fragmentomics into their LUNAR panel, which they have progressed into clinical trials for both primary detection and MRD of early-stage colorectal cancer .Multiple companies are also progressing purely epigenetic-based MRD panel approaches. MethylGene is undertaking a clinical trial on multiple myeloma patients that will utilize DNA methylation sequencing of ctDNA for MRD detection . While GWhile most product development for MRD is concentrated around sequencing large panels of markers, simple DNA methylation-based PCR tests can also be highly efficacious. Colvera, developed by Clinical Genomics, is available as an LDT in the USA and has Medicare coverage for MRD and recurrence monitoring of colorectal cancer. This methylated ctDNA test detected 66.0% of recurrence, significantly higher than the 31.9% sensitivity of carcinoembryonic antigen (CAE), the current standard of care , and alsInterestingly, a simple well-designed PCR test can have adequate diagnostic power when compared to a large NGS panel. This is illustrated when comparing the rates of primary detection of colorectal cancer across the GRAIL-sponsored circulating cell-free genome atlas (CCGA) study T (Trial i4Liquid biopsy is a powerful, multifaceted, and minimally invasive method for MRD detection and hence for monitoring therapeutic response, disease recurrence, or patient resistance to therapy. Although a relatively new field, liquid biopsy assays are showing promising results when compared to current standards of care. Two-staged somatic mutation approaches, where tumor sequencing informs MRD assay targets, allow clinicians to track actionable mutations and monitor for signs of treatment resistance. However, the time required to establish theses assays does not fit well with the patient journey, as clinicians need to know sooner than 5-6 weeks whether a patient is not responding to treatment. Therefore, epigenetic-based MRD assays are preferable at treatment onset, as epigenetic changes are typically more widespread and likely to be shared among a greater number of cancers than somatic mutations. With the recent advent of enzymatic methylation conversion, targeted sequencing approaches combining DNA methylation, fragmentomics and machine learning will likely come to predominate. However, DNA methylation-based PCR tests currently offer the most cost-effective solution within this niche. In fact, a compelling paradigm may be the combination of inexpensive serial testing with a DNA methylation-based assay, then following a positive MRD/recurrence result with a broad NGS-based somatic mutation panel to identify actionable mutations.AJ, JR, CM, KF, and WL wrote and revised this review. All authors contributed to the article and approved the submitted version."} +{"text": "Editorial on the Research TopicRecent advances in hypospadiologyHypospadias is one of the most common genital anomalies in men and displays a wide range of complex phenotypes. Multiple studies have reported a marked global increase in hypospadias cases over the past three decades, although the underlying basis for this remains unclear , 2. WhilBaray et al., developed an automated deep learning-based method for accurate PC measurement using 2D images, which could significantly improve patient assessment by surgeons and researchers alike. The novel pipeline they propose includes three key consecutive steps: penile localization, shaft segmentation, and angle measurement considering only the proximal and distal parts of the penile shaft. This method may overcome current limitations encountered by conventional approaches to measuring arc-type PC.Penile curvature (PC) is a key anatomical component of many hypospadias phenotypes and can have long-lasting effects on patients\u2019 psychosexual health and quality of life. While several prior studies have attempted to establish criteria for evaluating PC, there is still no standardized method for doing so. Despite significant challenges with assessing PC in both clinical practice and research settings, numerous procedures are now being investigated that have potential to resolve longstanding issues. Zhou et al., one-stage correction of severe hypospadias was achieved using a free preputial tube graft in conjunction with urethral plate urethroplasty and a Buck's fascia integral covering (BFIC) to protect the neourethra and minimize fistula risk. Using an alternative approach, Li et al., report their experience with transverse preputial island flap urethroplasty (TPIFU) in a retrospective cohort study. In 136 patient who underwent single-stage TPIFU, re-operation to address postoperative complications was required in 39% of cases, the majority of which were due to urethrocutaneous fistulas .Among the wide spectrum of hypospadias anomalies, proximal cases include a subset of severe phenotypes that can significantly impact treatment protocols and post-operative results. In these instances, choice of surgical approach is heavily influenced by surgeon experience and personal preference in addition to patient anatomy . There is still considerable disagreement about the optimal method for treating proximal hypospadias, but surgeons are increasingly testing new approaches to achieve better patient outcomes. In a study by Tian et al., present the results of a retrospective cohort of 195 patients who underwent hypospadias repair and subsequently developed postoperative fistulas. Patients with recurrent fistulas after initial closure were compared with patients who achieved successful fistula closure, which revealed an association of catheter type used for drainage with local purulent discharge after surgery.Weidler et al., report their results from a multicenter collaboration evaluating the controversy surrounding optimal timing of surgery. In particular, their study focuses on decision making in individuals with differences in sexual development, as well as their caregivers and healthcare providers. Using a semi-structured interview, the authors evaluated potential determinants of successful outcomes in 110 participants. They identify several key themes including; (1) the nature/type of decision being made, (2) person involved in decision making, (3) timing of conversations about surgery, (4) barriers to decision-making surrounding surgery, (5) elements involved in these discussions, and (6) optimal approach to surgical decision-making. Priority was given to children and adolescents with disorders of sexual differentiation to ensure their involvement in all discussions. In summary, while many issues remain unresolved in the field of hypospadiology, novel approaches and improved understanding of surgical and patient-reported outcomes will be crucial to the continuing evolution of this challenging field."} +{"text": "Iatrogenic ST elevation myocardial infarction (STEMI) after aortic valve surgery is a rare complication. Myocardial infarction (MI) due to mediastinal drain tube compression on the native coronary artery is also seen rarely. We present a case of ST elevation inferior myocardial infarction due to post-surgical drain tube placed after aortic valve replacement compressing on the right-sided posterior descending artery (rPDA).A 75-year-old female presented with exertional chest pain and was found to have severe aortic stenosis (AS). After a normal coronary angiogram and proper risk stratification, the patient underwent surgical aortic valve replacement (SAVR). One day after surgery in the post-operative area, the patient was complaining about central chest pain suggestive of anginal pain. Electrocardiogram (ECG) revealed that she has ST elevation myocardial infarction in the inferior wall. Immediately, she was taken to the cardiac catheterization laboratory, which revealed that she has occlusion of the posterior descending artery due to compression by a post-operative mediastinal chest tube. All features of myocardial infarction resolved after simple manipulation of the drain tube.The compression of the epicardial coronary artery after aortic valve surgery is very unusual. There are a few cases of other coronary artery compression due to mediastinal chest tube, but posterior descending artery compression causing ST elevation inferior myocardial compression is unique. Though rare, we need to be vigilant about mediastinal chest tube compression, which can cause ST elevation myocardial infarction after cardiac surgery. The iatrogenic compression of the native epicardial artery is a rare phenomenon. There are a few cases of bypass graft -4 or natA 74-year-old female with no past medical illness presented with exertional chest pain and was found to have severe aortic stenosis (AS). Electrocardiogram (ECG) shows features of left ventricular hypertrophy (LVH). On echocardiography, her mean pressure gradient across the aortic valve was\u00a047 mmHg. As she had symptomatic severe aortic stenosis (AS) without any other significant comorbidities, the plan was made to do surgical aortic valve replacement (SAVR). She underwent preoperative left heart catheterization, which shows normal epicardial coronary arteries.Eventually, the patient underwent a surgical replacement of the stenosed aortic valve with a bioprosthetic valve. The surgery was uneventful, and the patient was sent to the cardiac ICU for monitoring. A mediastinal drain tube was put in to prevent fluid accumulation after cardiac surgery. On post-operative day 1, the patient was complaining of central chest pain with radiation to the arm. ECG was done showing ST elevation in leads II, III, and arteriovenous fistula (aVF) with baseline LVH. It was puzzling as previously, she had no ECG changes suggestive of ischemic heart disease (IHD), and left heart catheterization was also normal. Bedside echocardiogram revealed wall motion abnormality in the middle and distal inferior wall with mildly reduced LV function. STEMI alert was activated, and the patient was taken to the catheterization laboratory emergently.A coronary angiogram revealed that the chest tube is intermittently compressing on the right-sided posterior descending artery (rPDA) limiting blood flow distal to the compression Figure . The draWe present a case of posterior descending artery compression by a mediastinal drain tube placed after SAVR, which is the first reported case. In the past, there were a few reports of native coronary artery or graft compression.Most complications of chest tube placement come from closed pleural chest tube placement, which could be benign to serious complications . There hComplications from open mediastinal tube placement after cardiac surgery are usually benign and underreported. Pneumothorax after removing such tubes or patients suffering from pain due to the tube placement is most encountered by cardiac surgeons . Yet, thAfter surgical aortic valve replacement (SAVR), myocardial ischemia or infarction could be due to supply-demand mismatch as a result of aortic cross-clamping causing ischemia in hypertrophied left ventricle (LV) . STEMI aBeing vigilant about post-surgical drain tubes that may cause compression in the coronary artery can be an easy fix and prevent dreaded complications. Mediastinal chest tubes causing the occlusion of the native coronary arteries are unexpected and easily overlooked."} +{"text": "Objective. To evaluate the impact of setup uncertainty reduction (SUR) and adaptation to geometrical changes (AGC) on normal tissue complication probability (NTCP) when using online adaptive head and neck intensity modulated proton therapy (IMPT). Approach. A cohort of ten retrospective head and neck cancer patients with daily scatter corrected cone-beam CT (CBCT) was studied. For each patient, two IMPT treatment plans were created: one with a 3 mm setup uncertainty robustness setting and one with no explicit setup robustness. Both plans were recalculated on the daily CBCT considering three scenarios: the robust plan without adaptation, the non-robust plan without adaptation and the non-robust plan with daily online adaptation. Online-adaptation was simulated using an in-house developed workflow based on GPU-accelerated Monte Carlo dose calculation and partial spot-intensity re-optimization. Dose distributions associated with each scenario were accumulated on the planning CT, where NTCP models for six toxicities were applied. NTCP values from each scenario were intercompared to quantify the reduction in toxicity risk induced by SUR alone, AGC alone and SUR and AGC combined. Finally, a decision tree was implemented to assess the clinical significance of the toxicity reduction associated with each mechanism. Main results. For most patients, clinically meaningful NTCP reductions were only achieved when SUR and AGC were performed together. In these conditions, total reductions in NTCP of up to 30.48 pp were obtained, with noticeable NTCP reductions for aspiration, dysphagia and xerostomia . While SUR had a generally larger impact than AGC on NTCP reductions, SUR alone did not induce clinically meaningful toxicity reductions in any patient, compared to only one for AGC alone. Significance Online adaptive head and neck proton therapy can only yield clinically significant reductions in the risk of long-term side effects when combining the benefits of SUR and AGC. For this purpose, a retrospective cohort of ten head and neck squamous cell carcinoma patients with daily cone-beam CT (CBCT) was used to compare NTCP for six toxicities using three distinct scenarios. Differences in NTCP between each scenario was evaluated to assess the impact of SUR alone, AGC alone and SUR and AGC combined. Finally, the clinical significance of NTCP reductions associated with each mechanism was established using a decision tree inspired by a model-based patient selection algorithm.Our patient cohort consisted of ten head and neck squamous cell carcinoma patients treated at the Massachusetts General Hospital with volumetric modulated arc therapy, since CBCT imaging was not available for our proton therapy patients at the time of this study. Each patient dataset consisted of a planning CT acquired on a wide bore GE scanner as well as a series of daily CBCT obtained on an Elekta XVI system using a 100 kVp tube voltage and a 220-degree acquisition. The number of CBCTs available for each patient ranged between 30 and 35, for a total of 328 scans analyzed. No patient of this cohort had their treatment interrupted and no offline replanning was deemed necessary during the treatment courses.et alTwo clinical target volumes (CTV) were delineated on each planning CT by a trained radiation oncologist: a high-risk CTV including the primary tumor and high-risk lymph nodes, as well as a low-risk CTV, including bilateral lymph nodes considered at risk for subclinical disease. The constrictor muscles, larynx, oral cavity, spinal cord, brainstem, esophagus and both parotid glands were delineated on the planning CT. The esophagus, constrictor muscles and larynx were contoured following published guidelines for swallowing OARs . The first plan was robustly optimized to both CTVs using the minimax method and adaptation schemes (fast daily OA versus no adaptation). As done in similar studies, our data analysis was focussed on NTCP differences between each scenario rather than absolute NTCP values (Van De Water ar et al . Differeet alFocussing on AGC alone, our results indicate that online adaptive proton therapy can induce NTCP reductions that go beyond what is achieved when applying SUR only. Indeed, total NTCP reductions per patient for xerostomia, dysphagia, aspiration and oral mucositis reported in figure et alet alThe clinical significance of the reductions in NTCP induced by SUR and AGC was assessed using a decision tree inspired by the Dutch model-based selection system (Tambas et alet alet alet alThe fact that clinically meaningful toxicity reductions were observed in five out of ten patients also illustrates the heterogeneous effect of online adaptive proton therapy on toxicity reductions across our patient cohort. This is even more apparent in figure et alet alet alet alet alet alet alet alThis study had some limitations worth mentioning. First, uncertainties in image deformation, contour propagation and residual setup errors beyond treatment adaptation were neglected. NTCP reductions achieved in this work shall therefore be interpreted as the best-case scenario for AGC and might not be fully achievable in a clinical setting. However, it is also worth noting that several strategies have been suggested to mitigate the impact of these uncertainties in the context of online adaptive proton therapy: the integration of structure uncertainties in plan re-optimization (Nenoff et al (et alAnother limitation to consider is the fact that NTCP models were derived from photon patients. Blanchard et al showed tal et al. An evalIn conclusion, this study highlighted for the first time the impact of online adaptive proton therapy on toxicity risks. Combining effects from a reduction of the setup uncertainty setting by 3 mm and the AGC, online adaptive proton therapy based on a limited spot-intensity re-optimization workflow was shown to allow clinically meaningful toxicity reductions in 50% of our patient cohort, with total NTCP reductions up to 30.48 pp for the four main toxicities considered in this work."} +{"text": "POT-PUFF sign has been introduced as a potential alternative for detecting malapposition during coronary bifurcation procedures. Here, we present two clinical cases from a developing country where the POT-PUFF sign was employed to assess the result of proximal optimization therapy after stent implantation. The POT-PUFF sign exhibits potential as an affordable and feasible approach for assessing stent malapposition in settings with limited resources.Acute stent malapposition poses a significant risk for adverse cardiac events following percutaneous coronary intervention. Detection of acute stent malapposition traditionally relies on intracoronary imaging techniques, such as intravascular ultrasound and optical coherence tomography, which may be limited in developing countries due to accessibility issues. A new angiographic sign called the Acute stent malapposition (ASM) refers to post-procedure lack of contact of stent struts with vessel walls. This condition can be detected using intracoronary imaging techniques such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Identifying and addressing malapposition is crucial as it can result in various complications, including impaired stent function, heightened risk of stent thrombosis, and potential adverse cardiac events . RecentlCase oneA 58-year-old man, hypertensive and a weaned smoker, had been suffering from exertional angina for several months. The electrocardiogram showed lateral biphasic T waves. Echocardiography revealed hypokinesia of the anterolateral wall with a moderately impaired ejection fraction of 45%. Coronary angiography revealed significant stenosis at the start of the main marginal artery Figure . After pCase twoOur second case was a 64-year-old hypertensive patient with dyslipidemia on statins. She was admitted for management of chronic coronary syndrome with New York Heart Association class 2 exertional dyspnea. The electrocardiogram was unremarkable. Echocardiography showed left ventricular hypertrophy without segmental contractility abnormalities and a preserved ejection fraction. Stress echocardiography showed ischemia in two segments of the right coronary artery territory. Coronary angiography revealed a long, significant stenosis in the middle segment of the right coronary artery Figure . After pAfter stent implantation, IVUS and OCT can identify remediable irregularities associated with both the stent and the underlying vessel wall. These irregularities include stent under-expansion, geographic plaque miss, strut malapposition, and stent edge dissection, and they have been linked to adverse percutaneous coronary intervention (PCI) outcomes . Strut mThe POT-PUFF sign presents a promising new angiographic indicator for detecting stent malapposition during POT after PCI. While further research is required to validate its effectiveness, the POT-PUFF sign shows great potential in enhancing stent apposition evaluation and improving PCI outcomes in resource-constrained settings."} +{"text": "Glioblastoma (GBM) is an aggressive brain tumor with limited prognosis despite multimodal treatment approaches. Various immunotherapies have been investigated to address the need for novel therapeutic options in GBM with limited success. Recently, alterations in the metabolism of cancer cells which allow for tumor proliferation, but simultaneously alter immune populations leading to an immunosuppressive tumor microenvironment, have been investigated as contributory to therapeutic resistance. This review discusses metabolic alterations in GBM tumor cells which have been investigated as contributory to immunosuppression and resistance to immunotherapies.Glioblastoma (GBM) is the most common primary brain tumor with a poor prognosis with the current standard of care treatment. To address the need for novel therapeutic options in GBM, immunotherapies which target cancer cells through stimulating an anti-tumoral immune response have been investigated in GBM. However, immunotherapies in GBM have not met with anywhere near the level of success they have encountered in other cancers. The immunosuppressive tumor microenvironment in GBM is thought to contribute significantly to resistance to immunotherapy. Metabolic alterations employed by cancer cells to promote their own growth and proliferation have been shown to impact the distribution and function of immune cells in the tumor microenvironment. More recently, the diminished function of anti-tumoral effector immune cells and promotion of immunosuppressive populations resulting from metabolic alterations have been investigated as contributory to therapeutic resistance. The GBM tumor cell metabolism of four nutrients has recently been described as contributory to an immunosuppressive tumor microenvironment and immunotherapy resistance. Understanding metabolic mechanisms of resistance to immunotherapy in GBM can provide insight into future directions targeting the anti-tumor immune response in combination with tumor metabolism. Glioblastoma (GBM) is the most common primary brain tumor with a limited prognosis and a median survival of 15 months despite an aggressive standard of care treatment consisting of maximal safe surgical resection followed by radiation and chemotherapy with temozolomide . DevelopOne novel emerging area of cancer therapeutics is immunotherapies, which target one of the hallmarks of cancer\u2014the ability to evade cellular immunity that would otherwise result in immunological targeting of tumor cells . While iThe tumor microenvironment is affected by unique cancer cell metabolism that not only promotes tumor cell growth but also alters the pH, oxygen, and metabolite contents that affect the survival and function of immune cells in the tumor microenvironment . MetabolGlycolysis is the most prominent metabolic pathway implicated in cancer metabolism as contributory to sustaining the energetic cost of growth and proliferation. During glycolysis, glucose is catabolized to pyruvate which is then converted to lactate to either be secreted or enter the TCA cycle generating ATP and NADH in the process. Glucose metabolism plays a significant role in the brain microenvironment given the high metabolic demand of the brain and lack of glycogen storage within the brain. High blood glucose levels and increased neuronal expression of glucose transporters have been linked to decreased survival in glioblastoma patients . HK2, PKFP, ALDOA, PGAM1, ENO1, ENO2, or PDK1 inhibits GBM tumor growth and prolongs survival in a mouse xenograft model . Gl. Gl13]. Glycolysis requires export of lactate from cells by transporters which co-transport lactate and protons (H+), leading to their accumulation in the tumor microenvironment and resulting in tumor acidosis which impacts the function of immune cells in the tumor microenvironment. Acidosis has been described in other cancers as contributory to immunosuppression . Lactic Strategies that free T cell glycolytic metabolism from the restrictions imposed on these cells by the tumor microenvironment have been evaluated in preclinical models. For example, genetic modification of tumor specific CD4 and CD8 T cells to overexpress phosphoenolpyruvate carboxykinase 1 (PCK1) increased the production of the glycolytic metabolite phosphoenolpyruvate, resulted in increased T cell glycolysis, increased T cell effector function, and restricted tumor growth and prolonged survival in a melanoma mouse model . FurtherLactic acid production has also been suggested to not only reduce anti-tumoral immune cell populations but also promote immunosuppressive populations. Notably, myeloid cells are resistant to lactic acid-induced apoptosis . In factGlycolytic alterations may also specifically impact neutrophils. While less is understood about the metabolic utilization of neutrophils in the tumor microenvironment than leukocytes, neutrophils are generally regarded as highly glycolytic. Neutrophil function has been described to highly depend on glucose availability with lack of glucose abrogating function . suggestInterestingly, the interplay between glycolytic tumor metabolism and immune cell function may be bidirectional with immune cells able to regulate metabolic pathways as well. Zhang et al. show that macrophages produce interleukin-6 which leads to downstream phosphorylation of the glycolytic enzyme phosphoglycerate kinase 1 (PGK1) and facilitates a PGK1-catalyzed reaction towards glycolysis rather than gluconeogenesis through altered substate affinity . PGK1 phENO1, promoted M2 microglia polarization promoting immunosuppression and glioblastoma cell malignancy. Another recent study utilizing differentially expressed genes between high and low glycolytic activity to assign risk scores to classify high and low risk GBM patients found differential infiltration of immune cells and immune checkpoints, suggesting a relationship between glycolytic activity and immunosuppression in patients with GBM [Studies of glycolysis in glioblastoma have paralleled the findings in other cancer types of the significance of increased glycolysis in creating an immunosuppressive tumor microenvironment. The shift to increased aerobic glycolysis from oxidative phosphorylation in glioblastoma is associated with immunosuppression and tumor progression . In GBM,with GBM . Glutamine, an amino acid highly expressed in cancer cells, plays a critical role for cellular function and the generation of energy and metabolic precursors for macromolecule synthesis which help sustain anabolic growth. Glutamine is converted by glutaminase into glutamate which is then converted to \u03b1-ketoglutarate, a critical component of the TCA cycle and in the production of metabolic intermediates utilized in the production of lipids, nucleic acids, and proteins. Upregulated glutamine metabolism in cancer cells promotes tumor growth through supporting macromolecule biosynthesis, altered signaling pathways, and cancer cell proliferation and survival. The metabolism of glutamine provides carbons for the TCA cycle to sustain accelerated anabolism in cancer cells and promotes tumor growth ,40,41.Glutamine is amongst the most prevalent amino acids in the brain as a precursor to the excitatory neurotransmitter glutamate . GlutamaGlutamine metabolic pathways are also upregulated in glioblastoma. Glutamate dehydrogenase (GDH), an enzyme which catalyzes the conversion of L-glutamate into \u03b1-ketoglutarate as part of glutaminolysis, is upregulated in many human cancers and shown to promote tumor growth . An isoeGlutamine metabolism in cancer cells impacts the tumor microenvironment and the immune populations within it in ways similar to glucose metabolism . Cancer Increased uptake of glutamine by tumor cells may result in its depletion in the tumor microenvironment and affect the function of immune cells which utilize glutamine for their own metabolic programs. Activated T cells upregulate glutamine metabolism to generate \u03b1-ketoglutarate to enter the TCA cycle and generate ATP to fulfill the energetic demands of T cell proliferation . GlutamiTargeting glutamine metabolism in a mouse model of colon cancer through a glutamine antagonist 6-Diazo-5-oxo-L-norleucine, which broadly inhibits several glutamine-using enzymes, led to suppression of both oxidative phosphorylation and glycolytic metabolism in cancer cells and decreased tumor-related changes in the microenvironment with decreased hypoxia, acidosis, and nutrient depletion . In contAdditionally, glutamine metabolism by cancer cells leads to the enrichment of various immunosuppressive populations in cancer. Notably, \u03b1-ketoglutarate generated through glutaminolysis restricts anti-tumoral macrophage M1 activation . A separTargeting glutamine metabolism in cancers with known resistance to checkpoint blockade (triple negative breast cancer and lung carcinoma) with a small molecule inhibitor led to the marked inhibition of the generation and recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs) through apoptosis of these MDSCs . AdditioTargeting glutamine metabolism may enhance endogenous anti-tumor immunity through independent mechanisms promoting the metabolic programs of cytotoxic populations while inhibiting immunosuppressive populations. Given the success of combining targeting glutamine metabolism with checkpoint inhibitors in other immunotherapy resistant tumors, it may be worthwhile to explore this combination in GBM. Tryptophan is an essential amino acid utilized for protein biosynthesis and a biochemical precursor to physiologically important compounds such as serotonin and melatonin. The majority of tryptophan which is not incorporated into proteins is broken down into degradation products (kynurenines) via the kynurenine pathway . PhysiolTryptophan catabolism and alterations in kynurenine pathway has been implicated in poor prognosis in several cancer types, including in GBM . The corIDO1- and TDO2- mediated degradation of tryptophan by cancer cells is a driver of immune suppression in the tumor microenvironment through recruitment and activation of myeloid-derived suppressor cells (MDSCs) and induction of anergy of CD8+ T cells . DegradaTryptophan utilization by tumor cells leads to metabolic starvation of T cells which are unable to utilize tryptophan for their own functions and thus promotes immunosuppression in the tumor microenvironment. Inhibition of tryptophan degrading enzymes blocks enzymatic activity and restores cytotoxic T cell activity in vitro and in vivo . T cellsGiven the role of IDO through kynurenine synthesis in generating the tumor microenvironment allowing for immune escape in cancer, IDO inhibition has been explored as an attractive therapeutic option in multiple cancers. Inhibition of IDO was found to effectively normalize plasma kynurenine levels in patients with various tumor types . InteresKynurenine metabolites activate a ligand-activated transcription factor, aryl hydrocarbon receptor (AhR) which results in increased expression of IDO1 and IDO2 in a positive feedback loop. Targeting AhR in vitro led to decreased glioma cell viability . Opitz eTryptophan catabolism and its downstream metabolic pathways are known to contribute to the immunosuppressive tumor microenvironment and contribute to resistance to novel immunotherapies for malignant gliomas. Increased expression of IDO and TDO has been suggested as an acquired resistance mechanism to PD-1 and CTLA blockade in pre-clinical models of multiple cancers, including GBM ,74. The The combination of targeting tryptophan metabolism with immune checkpoint blockade has been also explored in glioblastoma. Combining 1-methyltryptophan, which inhibits IDO, with dual immune checkpoint blockade significantly improved survival in an orthotropic mouse GBM model correlating with increased T-cell survival and synergistic decrease of Treg infiltration . LikewisPotential limitations of IDO1 inhibition that led to failure in this phase 3 trial combining this approach with a PD-1 inhibitor include: insufficient inhibition of IDO1 at the doses being used; the ability of other enzymes involved in tryptophan metabolisms such as TDO2 or pathways downstream of IDO1 inhibition to compensate and still generate immunosuppressive tryptophan metabolites such as kynurenine and its derivatives when IDO1 is inhibited; and lack of patient selection based on IDO1 expression ,78. IDO1Targeting tryptophan metabolism may also have implications for vaccine related cancer therapies which rely on T cell mediated antitumoral responses. IDO expression correlated with lack of specific T cell enrichment at the tumor site and prevented the rejection of tumor cells in mice who have been preimmunized against tumor antigens with a vaccine . This efLipid metabolism physiologically functions to allow for cellular energy storage, synthesis of cellular membranes, and cellular signaling. In cancer, alterations in lipid metabolism help meet high bioenergetic demands by generating energy through beta-oxidation. Utilization of fatty acid oxidation in addition to increased glycolysis allows for bioenergetic flexibility in promoting aggressive tumor growth and metastasis . Glioma cells utilize lipid oxidation and upregulate transport of ketones generated from lipid metabolism to sustain growth . Lipid mAltered lipid metabolism in GBM impacts immune cell function, particularly that of T cells . T cellsWhile less is understood about the metabolic requirements of Treg cells, utilizing fatty acid oxidation over glycolysis may promote Treg survival over the survival of CD4 and CD8 T cells . Lipid sGBM cells are also able to evade the anti-tumor immune response due to altered lipid metabolism impacting the function of antigen presenting cells. Exogenous induction of lipid peroxidation and ferroptosis resulted in release of damage-associated molecular patterns from glioma cells that stimulate dendritic cell activation and maturation and can lead to activation of cytotoxic T lymphocytes by dendritic cells ,95. RecuWhile initially the central nervous system was thought to be an immune-privileged site, current thought points to the presence of immune surveillance in the brain following findings revealing the presence of dedicated lymphatic channels running parallel to dural venous sinuses and allowing for lymphocyte priming from antigen presenting cells in the brain ,100. DesThe most studied immunotherapeutic approaches for GBM are vaccines, immune checkpoint inhibitors, and biologic therapies . The mosImmune checkpoint inhibitors targeting PD-1/PD-L1 and/or CTLA-4 are also being investigated in phase 3 trials in GBM, with initial results suggesting no clinical benefit ,105. WhiBiologic therapies for GBM can be viral or cellular. Oncolytic viruses have overall met with limited success in GBM, and initial anti-tumor T cell immune responses generated by viral infiltration into tumor do not persist without serial treatment . MetabolMetabolic pathways implicated in maintaining immunosuppression in the GBM microenvironment have been well elucidated. However, the potential for targeting these metabolic pathways to condition the tumor microenvironment to become more responsive to immunotherapies remains underexplored in GBM. Preclinical data targeting metabolic pathways in conjunction with immunotherapies largely come from models of more immunogenic cancers. This presents an attractive avenue for further study in GBM, in which modifying a largely immunosuppressive environment may meaningfully alter immunotherapeutic response. While this review discusses the most studied metabolic pathways with respect to immunosuppression in GBM, several other metabolic pathway alterations occur to meet the energetic demands of GBM progression. Arginine metabolism reprogramming in GBM leads to increased intake and decreased degradation of arginine by tumor cells and has been linked to impaired T cell responses due to altered bioavailablity of arginine . TargetiWhile many immunotherapies are being investigated in GBM patients, none have resulted in major improvements in survival outcomes. Negative results from phase II and phase III clinical trials of vaccines and immune checkpoint inhibitors have challenged the potential of these approaches in GBM. Future directions for immune-based strategies for glioblastoma require treatment modalities that can convert a \u2018cold\u2019 tumor with significant local immunosuppression into a \u2018hot\u2019 tumor. The uniquely immunosuppressive environment generated by tumor cellular metabolism in GBM presents an opportunity for augmenting responses to immunotherapy. Combining immunotherapy with agents that target the metabolic alterations resulting in an immunosuppressive microenvironment may have greater success in generating an antitumor immune response. These combinations should be evaluated rigorously preclinically in order to ensure that the most biologically sound combination approaches addressing the antitumor immune response along with tumor metabolism are advanced to clinical trials."} +{"text": "The United States FDA has approved daprodustat (DPD) as the first oral treatment option for anemia due to chronic kidney disease (CKD) in dialysis patients. Clinical trials have demonstrated DPD\u2019s efficacy and safety, showing non-inferiority to darbepoetin and suggesting reduced IV iron usage. DPD also holds potential for treating chronic kidney disease anemia in non-dialysis patients and may have benefits for patients with coexisting renal anemia and heart failure, pending further research and trials. The United States Food and Drug Administration (FDA) has approved daprodustat (DPD) for treating anemia due to chronic kidney disease (CKD) for patients undergoing dialysis for at least 4\u00a0months . This isAnother Randomized, Double-Blind, Phase 3 Study was carried out in Japanese hemodialysis patients with anemia to compare the effects of DPD and darbepoetin. With most participants obtaining and maintaining hemoglobin levels within the target range, the results showed DPD\u2019s non-inferiority to darbepoetin. Also, it was strongly advised to continuously check the hemoglobin response following the start of the DPD treatment. This study also suggested using less IV iron to regulate hemoglobin in individuals receiving DPD . AnotherDPD has not yet been approved for patients with CKD anemia without dialysis, but ASCEND-ND trial has demonstrated safety and efficacy of DPD in treating anemia due to CKD in patients not undergoing dialysis. . DPD wouData from the FDA\u2019s adverse event reporting system (FAERS) may indicate an elevated risk of GI bleeding when HIF-PHIs are used to treat renal anaemia. DPD treatment may also raise the risk of vascular calcification in CKD patients with hyperphosphatemia. Serum copper excess may also be noted in some patients in the treatment.Anemia in Heart Failure is a poor prognostic factor in both acute and chronic heart failure. Although anemia in heart failure is multifactorial, renal anaemia is one of the major causes. Coexisting renal and heart failure is reported to be associated with increased mortality . The StuProvenance and peer review: Not Commissioned, externally peer-reviewed."} +{"text": "Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer related-death in the worldDespite reported benefits, colonoscopy outcomes may differ depending on quality of the endoscopist performing the procedure. Among others, this relates to differences in ability of endoscopists to accurately assess polyp characteristics such as locationOver the last decade, artificial intelligence (AI) in biomedical science has received growing attention. AI can be defined as the simulation of human intelligence by computer systemsWhile evidence is currently scattered, we aimed to write a narrative review to provide a broad overview of current developments within the field of AI and computer science for computer-aided assessment of colorectal polyps. This includes assessment of polyp location, size, morphology and histology, including degree of dysplasia (low grade dysplasia [LGD] versus high grade dysplasia [HGD]) and, in case of suspected malignancy, invasion depth. Since computer-aided polyp detection concerns an already more thoroughly studied and evaluated topicthof July 2022. Key search terms used were \u201ccolorectal,\u201d \u201cpolyp,\u201d \u201cartificial intelligence,\u201d \u201csize,\u201d \u201clocation,\u201d \u201cmorphology,\u201d \u201chistology,\u201d \u201cdysplasia\u201d and \u201cinvasion depth.\u201d Only studies published in English were screened. Reference lists of retrieved studies were manually screened to identify other relevant publications.A comprehensive literature search was performed in the MEDLINE/PubMed, Embase and Cochrane Libraries from the inception of the databases up to and including the 17Accurate determination of polyp location is important to facilitate identification of a polyp or polypectomy site during consecutive colonoscopies and/or surgical procedures. In addition, polyp location can aid in polyp histology predictionTo determine the location of the endoscope tip during colonoscopy procedures, and hence the location of observed polyps, endoscopists often rely on identification of various endoscopic anatomical landmarks and differences in colonic caliber, color tones and vasculature of different colon segmentsSeveral deep learning approaches for orientation in the colon based on analysis ofendoscopic videos and images have been proposed 45464Proposed systems could possibly aid endoscopists in orientation within the colon. However, current studies still concern feasibility studies and accuracy is mostly still limited. Besides, usage of a segment classification that assumes that all colons and segments are of similar length currently limits feasibility of the proposed motion-based localization systemToward the future, the issue of a lack of a solid reference standard could possibly be addressed by using magnetic endoscopic imaging (MEI) devices. These devices can improve accuracy of determination of location within the colon during colonoscopyPolyp size has been shown to be associated with the risk that a polyp harbors advancedhistological featuresIn daily practice, polyp size is based on visual estimation by the endoscopist. However, this strategy is prone to interobserver variabilityWhile most studies showed promising results, some issues should be addressed. Most importantly, similar to polyp location, a robust reference standard is not available for polyp size. This is illustrated by the fact that different reference standards were used in the different studies, limiting robustness and comparison of performance of the different systems. Additionally, several studies used binary polyp size classificationsNext steps for the development of more robust computerized polyp size measurement methods should include prospective evaluation of proposed systems in real-time clinical settings. Simultaneously, the problem concerning the lack of a solid reference standard might possibly be addressed through usage of recently developed endoscope-integrated or -attached polyp measurement toolsPolyp morphology is an important feature for polyp malignancy risk-assessmentColorectal polyps can generally be subdivided into neoplastic and non-neoplastic.Neoplastic lesions concerns both lesions yielding malignant potential and malignant lesions,while non-neoplastic lesions do not yield malignant potential. Hence, removal and analysisof non-neoplastic lesions is often unnecessaryA wide variety of studies describing computer systems trained to differentiateneoplastic and non-neoplastic lesions based on polyp phenotype has been published. For thisreview, we will highlight available prospective clinical trials evaluating the performanceof such systems in real-time clinical settings and using either white light, (magnified)narrow band imaging (NBI) or blue light imaging (BLI) imaging modalities 77787To facilitate implementation of optical diagnosis strategies in daily practice, the Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) initiativeFrom clinical perspective, the fact that different studies managed sessile serrated lesions (SSLs) in different ways should also be addressed. While SSLs are estimated to make up 15\u201330% of CRC casesDespite remaining limitations and need for further optimization of system performances to reach PIVI and SODA thresholds, most CADx systems for differentiation of neoplastic and non-neoplastic lesions showed to be able to meet expert endoscopist performance in real-time clinical settings. In addition, a significant optical diagnosis learning curve for \u2018non-expert\u2019 endoscopists was illustratedTable S1)Several studies assessing the feasibility of deep learning approaches for differentiation of polyps with different degrees of dysplasia (LGD versus HGD) are available innovations in upcoming years will likely aid in improving accuracy of existing CADx systems, while there are also still numerous purposes for which possibilities of computer-aided diagnosis is yet to be explored. In example, besides computer systems that could aid endoscopists in assessment of polyp morphology, systems for purposes such as suggestion of appropriate polyp resection method or assessment of completeness of resection might yield significant clinical potential.The strength of this review is that, to the best of our knowledge, this is the first review to provide such a broad overview of available studies on computer-aided diagnosis of all polyp characteristics essential for clinical decision making. However, in the context of the extensive scope of the aim of this review, we decided to comply to a narrative rather than a systematic review approach. While this might have resulted in accidental miss of relevant publications, this can be considered a limitation.To conclude, with recent breakthroughs in the field of AI and computer science, a major increase in research on the topic of computer-aided colorectal polyp assessment is seen. With commercial availability of CADx systems for differentiation between neoplastic and non-neoplastic polyps, first steps toward improved endoscopy quality with use of CADx systems in daily practice might be ahead. However, optimization of performance is still required to ensure that these CADx systems meet all performance thresholds. Besides, toward the future, further innovation, exploration and clinical validation of computer-aided diagnosis approaches for diagnosis of other polyp characteristics is required for realization of complete computer-aided polyp assessment."} +{"text": "Pleural infection, or pleural empyema, is a severe medical condition associated with high morbidity and mortality rates. Timely and accurate prognostication is crucial for optimizing patient outcomes and resource allocation. Rapid scoring systems have emerged as promising tools in pleural infection prognostication, integrating various clinical and laboratory parameters to assess disease severity and quantitatively predict short-term and long-term outcomes. This review article critically evaluates existing rapid scoring systems, including CURB-65 , A-DROP , dehydration, respiratory failure, orientation disturbance, and low blood pressure), and APACHE II , assessing their predictive accuracy and limitations. Our analysis highlights the potential clinical implications of rapid scoring, including risk stratification, treatment tailoring, and follow-up planning. We discuss practical considerations and challenges in implementing rapid scoring such as data accessibility and potential sources of bias. Furthermore, we emphasize the importance of validation, transparency, and multidisciplinary collaboration to refine and enhance the clinical applicability of these scoring systems. The prospects for rapid scoring in pleural infection management are promising, with ongoing research and data science advances offering improvement opportunities. Ultimately, the successful integration of rapid scoring into clinical practice can potentially improve patient care and outcomes in pleural infection management. Pleural infection, commonly known as pleural empyema, is a serious medical condition characterized by the accumulation of infected fluid in the pleural space, the thin, fluid-filled cavity surrounding the lungs. It can arise as a complication of various respiratory infections, such as pneumonia, and may result from both bacterial and, less frequently, fungal pathogens. Pleural infection poses a significant health burden worldwide, with high morbidity and mortality rates, especially in vulnerable populations such as the elderly, immunocompromised individuals, and those with pre-existing lung diseases -4. ManagPrognostication is pivotal in determining the most appropriate therapeutic approach and predicting patient outcomes in pleural infection. Identifying patients with severe diseases and poor prognoses can aid clinicians in tailoring treatment plans and allocating resources more efficiently. Traditional prognostic indicators such as clinical signs, laboratory parameters, and radiological findings are valuable but may lack the desired accuracy to predict disease progression reliably -10. The Rapid scoring systems have emerged as promising tools in the prognostication of pleural infection. These scoring systems leverage clinical, radiological, and laboratory parameters to generate a quantifiable score, enabling clinicians to quickly evaluate the severity of the disease and predict the likelihood of specific outcomes, such as mortality, treatment response, and length of hospital stay ,15. By sThis review aims to comprehensively evaluate the predictive potential of rapid scoring systems in pleural infection. By critically analyzing the existing literature and summarizing the findings from various studies, we aim to provide an in-depth understanding of the utility and limitations of these scoring systems in clinical practice. We will compare their performance in predicting short-term and long-term outcomes. Additionally, we will explore the factors that may influence the accuracy of these scoring systems, such as patient demographics, microbiological and radiological findings, and the presence of comorbidities.Overview of existing rapid scoring systems for pleural infectionsIn recent years, significant advancements have been made in developing and validating rapid scoring systems tailored for pleural infection prognostication. These scoring systems represent a crucial step toward enhancing clinical decision-making and optimizing patient care in the management of this complex condition. By providing a swift and reliable method to assess disease severity and predict outcomes, these rapid scoring systems offer a valuable tool for healthcare providers . Three pThe CURB-65 ScoreOriginally devised for predicting outcomes in community-acquired pneumonia, the CURB-65 score has been adapted and validated for use in pleural infection scenarios. It is based on five readily available clinical variables: confusion, urea level, respiratory rate, blood pressure, and age \u226565 years. By incorporating these parameters, the scoring system offers a simple yet effective approach to risk stratification and prognostication in pleural infection cases .The A-DROP ScoreOriginally designed for predicting severe pneumonia, the A-DROP score has found relevance in the context of pleural infection prognostication. This scoring system comprises five essential parameters: age, dehydration, respiratory failure, orientation disturbance, and low blood pressure. By encompassing these key variables, the A-DROP score assists in identifying patients at higher risk of adverse outcomes, and guiding appropriate interventions .The APACHE II ScoreWidely employed in intensive care units, the APACHE II score is a comprehensive scoring system that incorporates various physiological parameters to assess disease severity and predict outcomes in critically ill patients, including those with pleural infection. While the APACHE II score may involve more extensive laboratory measurements and clinical evaluations, it offers a more detailed and nuanced assessment of patient status, aiding in precise prognostication .These rapid scoring systems serve as valuable tools for healthcare providers, enabling them to assess disease severity and anticipate patient outcomes rapidly. These scoring systems offer a standardized and objective approach to pleural infection prognostication by integrating key clinical and laboratory parameters. By promptly identifying patients at higher risk of adverse outcomes, clinicians can optimize treatment plans, allocate resources effectively, and potentially improve patient outcomes .Despite their effectiveness, it is essential to recognize that these scoring systems are adjunctive tools and should not replace clinical judgment. The context of each patient's presentation, comorbidities, and response to therapy remains crucial in the overall management of pleural infection. Continued research, validation, and refinement of these rapid scoring systems are vital for maximizing their clinical utility and further improving patient care in pleural infection management. With ongoing efforts and multidisciplinary collaboration, rapid scoring systems promise to positively impact pleural infection management in the future .Comparison of different scoring systemsScoring Criteria and ComponentsScoring criteria and components form the foundation of rapid scoring systems in pleural infection prognostication, as they determine the variables used to generate a numerical score reflecting disease severity. These variables' selection varies among scoring systems based on their intended scope and underlying concepts .Some rapid scoring systems like CURB-65 and A-DROP utilize more straightforward and easily accessible clinical parameters to calculate the score. These criteria typically include age, respiratory rate, blood pressure, and mental status. These variables can be quickly assessed at the bedside and are commonly available in most healthcare settings. By focusing on straightforward clinical indicators, these scoring systems offer a convenient and time-efficient approach to prognostication, particularly in resource-limited environments .On the other hand, the APACHE II score takes a more comprehensive approach by integrating a wide range of physiological and laboratory measurements. These variables encompass arterial pH, oxygenation, serum creatinine levels, and hematocrit. The APACHE II score was originally designed for assessing the severity of critically ill patients in intensive care units and has been adapted for use in various clinical settings, including pleural infection. Including a broader array of physiological parameters enhances the APACHE II score's discriminative ability, allowing for a more detailed evaluation of disease status and patient outcomes .The choice between simpler clinical variables and more complex physiological measurements depends on the scoring system's intended use and clinical context. While rapid scoring systems like CURB-65 and A-DROP offer practicality and ease of use, the APACHE II score provides a more nuanced assessment, especially for critically ill patients. When selecting the most appropriate rapid scoring approach for pleural infection prognostication, healthcare providers must consider the scoring system's applicability to their specific patient population and available resources. These scoring criteria and components are essential for risk stratification and clinical decision-making, contributing to improved patient care and outcomes .Pros and Cons of Each Scoring SystemThe CURB-65 and A-DROP scores offer practical benefits due to their straightforwardness and ease of calculation. These scores utilize easily obtainable clinical parameters, including age, respiratory rate, blood pressure, and mental status, which can be swiftly evaluated at the patient's bedside. Their limited reliance on extensive laboratory tests makes them particularly suitable for settings with limited resources, where access to advanced medical facilities might be constrained. Furthermore, their uncomplicated nature allows for rapid risk assessment, enabling timely interventions in patients with pleural infection. However, the simplicity of the CURB-65 and A-DROP scores might result in some degree of oversimplification in disease evaluation. The sensitivity, specificity, positive predictive value, and negative predictive value of CURB-65 were 71%, 69%, 35%, and 91%, respectively. The best-performing version of the systemic inflammatory response syndrome (SIRS) criteria showed rates of 62%, 73%, 35%, and 89%, respectively, while the standardized early warning scoring system (SEWS) exhibited rates of 52%, 67%, 27%, and 86%, respectively. By concentrating on a restricted set of criteria, these scoring systems may not fully encompass the intricacies and variations present in cases of pleural infection. This limitation could potentially impact their accuracy in predicting outcomes .On the contrary, the APACHE II score provides a more advanced and comprehensive evaluation of a patient's condition, which holds particular significance for those critically ill with pleural infections. The APACHE-II score demonstrated a sensitivity of 89.9% and a specificity of 97.6%. By amalgamating various physiological measurements and laboratory results, the APACHE II score delivers a thorough assessment of the severity of the disease and the dysfunction of organs. This renders it especially pertinent within intensive care units (ICUs) confines. Its capacity to consider multiple variables enables a more subtle and precise classification of risk, thereby assisting healthcare practitioners in customizing treatment strategies for critically ill patients. Nevertheless, the reliance on the APACHE II score on multiple intricate laboratory measurements and complex computations could impede its immediate application within standard clinical practice, particularly in non-ICU environments. In scenarios with limited time and resources, the extensive data collection demanded by the APACHE II score might not always be feasible or pragmatic. Consequently, this could diminish its practicality and clinical influence .Current Challenges in Prognostication Using Rapid ScoringWhile rapid scoring systems hold promise in aiding prognostication for pleural infection, several challenges must be addressed to maximize their clinical utility. Firstly, these scoring systems' validation and external applicability pose significant concerns. Many of these systems are developed and validated in specific patient populations, which may limit their generalizability to diverse cohorts or healthcare settings. To ensure their reliability across various contexts, it is crucial to conduct rigorous validation studies in different patient populations representative of real-world scenarios .Secondly, successfully integrating rapid scoring systems into routine clinical practice requires overcoming practical hurdles. Healthcare providers must receive adequate training and awareness regarding the use and interpretation of scoring results. Seamless incorporation into existing clinical workflows and overcoming potential resistance to change are essential steps in maximizing the impact of these scoring systems on patient care .Another critical challenge is centered around predicting long-term outcomes. While rapid scoring systems often concentrate on short-term outcomes like hospital mortality or length of stay, complexity arises when predicting long-term outcomes, including factors like recurrence rates and functional recovery. These aspects demand a more extensive follow-up period and meticulous data collection. The development of scoring models that can reliably forecast these long-term outcomes holds significant importance, as it can greatly enhance patient management strategies and the support provided post-infection .Addressing these challenges requires continued research and collaboration among healthcare institutions and researchers. External validation across diverse patient populations, transparent reporting of findings, and prospective studies can enhance the reliability and credibility of rapid scoring systems. Additionally, advances in data science and integrating novel biomarkers may offer opportunities to refine these scoring approaches, leading to more accurate and personalized prognostication for pleural infection .By overcoming these challenges and refining existing rapid scoring systems, clinicians can make more informed decisions, tailor treatments, and allocate resources effectively, ultimately leading to improved patient outcomes and enhanced management of pleural infection. With ongoing efforts and future advancements, rapid scoring systems have the potential to revolutionize the way pleural infection is managed, providing valuable tools for healthcare providers and better care for patients .Prognostic value of rapid scoring in pleural infectionEvaluating the Predictive Accuracy of Rapid Scoring SystemsSensitivity and specificity analysis: Sensitivity measures the proportion of true positive cases correctly identified by the scoring system, i.e., the ability to classify patients with adverse outcomes correctly. Specificity, on the other hand, measures the proportion of true negative cases correctly identified, i.e., the ability to classify patients with favorable outcomes correctly. A comprehensive analysis of sensitivity and specificity provides valuable insights into the scoring system's ability to discriminate between patients with different outcomes. High sensitivity and specificity indicate a scoring system's ability to accurately identify positive and negative cases, thereby increasing its reliability in distinguishing patients with better or worse prognoses .Receiver operating characteristic (ROC) curves: ROC curves graphically illustrate the trade-off between sensitivity and specificity at various score thresholds. By plotting sensitivity against (1 - specificity) for different threshold values, the ROC curve visually represents the scoring system's performance in distinguishing between patients with different outcomes. The area under the ROC curve (AUC) quantifies the overall discriminative ability of the scoring system. An AUC value close to 1 indicates excellent discriminative power, meaning the scoring system can effectively differentiate between patients with favorable and adverse outcomes. Conversely, an AUC value close to 0.5 suggests poor discrimination, equivalent to random chance, rendering the scoring system less effective in predicting patient outcomes . ResearcPredictive Potential for Short-Term OutcomesMortality prediction: Mortality prediction is a critical aspect of managing pleural infection, as identifying patients at higher risk of death enables healthcare providers to initiate timely interventions and allocate resources effectively. By integrating clinical and laboratory parameters, rapid scoring systems aim to quantify the mortality risk in infected patients. The scores generated by these systems can serve as an early warning system, alerting clinicians to patients with a higher likelihood of adverse outcomes. Studies that analyze the association between rapid scoring system scores and actual mortality rates are of paramount importance. Evaluating the accuracy and reliability of these scoring systems in predicting mortality is essential for their successful implementation in clinical practice. Validated scoring systems can support evidence-based clinical decision-making, guiding aggressive treatment approaches for high-risk patients and potentially improving overall survival rates in pleural infection cases .Treatment response: Assessing the predictive potential of rapid scoring systems on treatment response is equally significant. Identifying patients less likely to respond to standard therapies is crucial for early intervention and alternative treatment strategies. Rapid scoring systems can assist in predicting treatment response by considering factors such as disease severity, pathogen characteristics, and patient-specific variables. By flagging non-responsive or slow-responding cases, clinicians can promptly modify treatment regimens, thereby preventing disease progression and minimizing complications. This proactive approach to treatment tailoring may improve therapeutic efficacy and enhance patient outcomes. Furthermore, predicting treatment response can aid in the judicious use of healthcare resources, optimize medication utilization, and reduce unnecessary interventions .Length of hospital stay: Prolonged hospital stays in pleural infection cases impact patient well-being and impose a substantial economic burden on healthcare systems. Rapid scoring systems that accurately predict the length of hospitalization can provide valuable insights for resource management and discharge planning. By estimating the expected duration of hospital stay, healthcare providers can allocate resources more efficiently, including hospital beds, staff, and medications. This allows for smoother patient flow and reduces overcrowding in medical facilities. Additionally, accurate predictions of hospital stay duration enable healthcare teams to engage in proactive discharge planning, ensuring that patients receive appropriate care and support after discharge. By minimizing unnecessary hospitalization, rapid scoring systems can contribute to optimizing healthcare resources and improve overall patient care in the context of pleural infection management ,37.Predictive Potential for Long-Term OutcomesRecurrence rates: Pleural infection recurrence is a vexing issue that poses challenges in patient management. Identifying individuals at higher risk of recurrence is crucial for implementing appropriate surveillance and follow-up strategies. Rapid scoring systems, with their ability to provide a quantitative assessment of disease severity, may offer valuable insights into the likelihood of recurrence. Clinicians can tailor long-term treatment planning and preventive measures for high-risk patients by analyzing the correlation between scoring system scores and recurrence rates. A scoring system capable of predicting recurrence can prompt intensified monitoring, early interventions, or targeted therapies to reduce the burden of recurrent pleural infections and improve patient outcomes ,39.Functional outcomes and quality of Life: Beyond short-term outcomes such as mortality and recurrence rates, the impact of pleural infection on functional outcomes and quality of life is paramount. Many survivors of pleural infection experience impaired lung function, reduced exercise capacity, and diminished overall quality of life. Scoring systems that can predict long-term functional outcomes may prove instrumental in optimizing rehabilitation efforts and post-infection support. By identifying patients at risk of poor functional recovery, clinicians can initiate timely interventions such as pulmonary rehabilitation, physical therapy, and psychological support to enhance the patient's overall well-being and quality of life ,41.Understanding the predictive value of rapid scoring systems for both short-term and long-term outcomes is essential for their effective clinical application. The analysis of various studies investigating these aspects provides a comprehensive overview of the potential benefits and limitations of using rapid scoring systems in pleural infection management. Integrating rapid scoring into clinical practice can facilitate risk stratification, personalized treatment planning, and informed decision-making. However, it is crucial to recognize these scoring systems' limitations and potential biases and address them through rigorous validation and future research. By refining and enhancing the accuracy and utility of rapid scoring systems, healthcare providers can optimize patient care and improve outcomes in pleural infection management. Ultimately, the successful integration of rapid scoring into routine clinical practice can positively impact patient well-being and healthcare resource allocation, bringing us closer to more effective and patient-centered pleural infection management strategies ,21.Factors affecting the prognostic accuracy of rapid scoringAccurate prognostication is a critical aspect of managing pleural infection effectively. Rapid scoring systems offer a quantifiable and standardized approach to assessing disease severity and predicting patient outcomes. However, to ensure their reliability and usefulness in clinical practice, it is essential to consider various patient-specific factors that can influence the predictive accuracy of these scoring systems . One sucMicrobiological and radiological findings are another crucial aspect of pleural infection management. The causative microorganisms, their antibiotic sensitivity, and the extent of lung involvement and pleural effusion on imaging can significantly affect disease severity and treatment response. Rapid scoring systems incorporating these findings into their algorithms may offer more accurate prognostic predictions . ComorbiMoreover, interpreting scoring results in the context of the severity of pleural infection is crucial. In mild or moderate cases, scoring systems may have limited discriminatory ability due to the relatively uniform nature of the patient population. However, scoring systems can offer more accurate prognostic insights in severe or complicated infections, guiding clinicians towards more aggressive interventions and monitoring strategies .Impact of Patient DemographicsPatient demographics, specifically age and sex, influence disease progression and outcomes in pleural infection. Age-related factors can significantly impact the clinical course of the infection. As patients age, changes in immune function and physiological reserves may increase infection vulnerability, making elderly individuals more susceptible to severe pleural infection. Additionally, comorbidities commonly accompanying aging can complicate disease management and influence treatment response. Therefore, considering age-related variations in prognostic scoring systems is essential to accurately predict disease severity and outcomes in different age groups .Furthermore, gender-related differences in pleural infection outcomes have been observed in some studies. While the underlying reasons for these disparities are not yet fully understood, it is believed that hormonal and immunological differences between males and females may contribute to varying disease outcomes. For instance, estrogen is known to have immunomodulatory effects that might influence the body's response to infection. Some studies have suggested that female patients with pleural infection may experience milder disease courses and have better treatment responses than males. By incorporating gender as a parameter in prognostic scoring systems, it is possible to account for these gender-specific differences and improve the accuracy of predicting outcomes for both male and female patients .Addressing patient demographics in rapid scoring systems is essential for personalized medicine and individualized patient care. Tailoring treatment strategies based on age and gender considerations can help clinicians optimize therapeutic interventions and improve patient outcomes. However, it is crucial to ensure that any consideration of demographics in scoring systems is evidence-based and supported by rigorous research. Understanding the impact of age and gender on pleural infection outcomes is an ongoing area of investigation, and continued research in this domain will further enhance the accuracy and utility of rapid scoring systems in pleural infection prognostication .Role of Microbiological and Radiological FindingsMicrobiological and radiological findings are integral components in diagnosing and managing pleural infection. Identifying causative microorganisms and their susceptibility to antibiotics is crucial for guiding appropriate antimicrobial therapy, significantly impacting treatment response and overall patient outcomes. Rapid scoring systems that consider microbiological data have the potential to enhance predictive accuracy, particularly in cases where tailored antibiotic treatment is necessary .Microbiological data can reveal valuable information about the type of pathogen causing the infection, its virulence, and its antibiotic resistance. Scoring systems that incorporate microbiological findings can aid clinicians in identifying high-risk patients who may require prompt escalation to targeted and more aggressive therapies. This enables timely adjustments to treatment regimens, potentially preventing treatment failure and the development of complications .Conversely, evaluating disease severity and tissue involvement heavily relies on radiological characteristics. Essential insights regarding pleural effusion, lung parenchymal engagement, and necrosis are provided through imaging techniques like chest X-rays and computed tomography (CT) scans. These radiological attributes mirror both the local and systemic effects of the disease, thereby enhancing clinicians' comprehension of the disease's status and possible complications .Scoring systems integrating radiological parameters offer a more comprehensive and nuanced disease evaluation. Such assessments can assist in risk stratification, allowing healthcare providers to identify patients with more severe infections who may require more intensive management, such as drainage procedures or surgical interventions . By consInfluence of Comorbidities on Scoring SystemsComorbidities significantly shape the clinical course of pleural infection, influencing disease progression, treatment response, and patient outcomes. Conditions such as diabetes, chronic kidney disease, heart failure, and immunosuppressive states can weaken the immune system, impair lung function, and increase the risk of complications. Consequently, patients with comorbidities are often at higher risk of adverse outcomes, including prolonged hospital stays, treatment failure, and increased mortality .Incorporating comorbidities into rapid scoring systems can enhance their prognostic accuracy by providing a more comprehensive assessment of the patient's overall health status. Scoring models considering these additional risk factors can better identify high-risk patients requiring more aggressive interventions or closer monitoring. Tailored treatment plans based on accurate risk stratification can improve clinical outcomes and resource utilization, ensuring that the most vulnerable patients receive the necessary care . HoweverAdditionally, choosing which comorbidities to include in the scoring systems must be carefully considered. Not all comorbidities may impact pleural infection outcomes equally, and some may be more relevant in specific patient populations. Thus, the selection of comorbidities should be based on their clinical significance and the availability of data . MoreoveInterpreting Scoring Results in the Context of Pleural Infection SeverityThe interpretation of scoring results in the context of pleural infection is critical when utilizing rapid scoring systems. It is important to recognize that these scoring systems' accuracy and predictive power may vary depending on the overall severity of the pleural infection in a given patient population . The disDespite their potential usefulness, clinicians need to understand that rapid scoring systems are adjunctive tools and not definitive predictors of outcomes. These systems are designed to aid in risk stratification and decision-making but should not be solely relied upon to make critical clinical decisions. Instead, they should be used with clinical judgment and other diagnostic assessments, such as radiological findings, microbiological data, and the patient's overall clinical status . By inteClinical implications and application of rapid scoringRole of Rapid Scoring in Clinical Decision-MakingRapid scoring systems in pleural infection management have the potential to significantly impact clinical decision-making by providing a quantitative and standardized assessment of disease severity and prognostication. These scoring systems offer valuable information to healthcare providers, aiding in risk stratification, treatment tailoring, and follow-up planning .Risk stratification: Rapid scoring systems excel in identifying patients at higher risk of adverse outcomes, such as mortality or treatment failure. These systems can efficiently classify patients into risk categories by analyzing clinical and laboratory parameters. This enables clinicians to prioritize interventions and allocate resources effectively, especially in resource-constrained settings where optimal utilization of healthcare resources is paramount .Treatment tailoring: One of the key challenges in pleural infection management is selecting the most appropriate treatment strategies for individual patients. Rapid scoring systems play a pivotal role by providing insights into disease severity and potential response to treatment. The scoring results can guide clinicians in choosing the most suitable antimicrobial therapy and drainage procedures and tailoring treatment plans based on the predicted disease severity. This personalized approach enhances therapeutic efficacy, minimizes the risk of treatment failure, and reduces the likelihood of complications .Follow-up planning: Beyond short-term prognostication, rapid scoring systems offer valuable information for long-term follow-up planning. By predicting disease trajectory and long-term outcomes, such as recurrence rates, these systems can inform healthcare providers about the need for post-discharge care and surveillance. Timely detection of potential complications and recurrent infections allows for proactive intervention, leading to better disease management and patient outcomes .Integrating rapid scoring systems into clinical practice empowers healthcare providers with evidence-based decision-making tools, aiding in more informed and precise patient care. The ability to quickly assess disease severity, predict outcomes, and tailor treatments based on individual patient characteristics enhances the overall management of pleural infection, ultimately leading to improved patient outcomes and enhanced healthcare resource utilization. However, ongoing research and validation are essential to continually refine and optimize these scoring systems, ensuring their effectiveness and reliability in real-world clinical settings. By harnessing the full potential of rapid scoring systems, healthcare providers can revolutionize pleural infection management and elevate the standard of care for patients affected by this challenging condition .Integration of Rapid Scoring into Current Management GuidelinesValidation and adaptation: Thorough validation is essential before implementing rapid scoring systems. This involves evaluating the performance of the scoring system in diverse patient populations to ensure its generalizability across different contexts. Validation studies should encompass various demographic profiles, disease severities, and geographic locations. In some cases, adaptation of the scoring system to specific local contexts may be necessary to account for variations in patient characteristics and healthcare practices .Education and training: Effective education and training programs are crucial to familiarize healthcare providers with the rapid scoring system's use and interpretation. Clinicians need to understand the rationale behind the scoring criteria, the significance of specific variables, and how to calculate the scores accurately. Additionally, emphasizing that the scoring system is an adjunctive tool to support clinical judgment can help mitigate any concerns of over-reliance on the scoring results .Standardized documentation: Consistent and standardized documentation of scoring system parameters in patient records is vital for continuity of care. Healthcare providers should diligently record the data used to calculate the score, the actual score itself, and any updates during treatment. Standardized documentation enables clinicians to track disease progression over time and aids in assessing the effectiveness of treatment strategies based on changes in the scoring results .Interdisciplinary collaboration: Pleural infection management involves the collaboration of various medical specialists, each contributing their expertise to patient care. Effective interdisciplinary collaboration is essential for integrating rapid scoring systems seamlessly into the overall management approach. Collaborating with pulmonologists, infectious disease specialists, radiologists, and other relevant disciplines like cardiothoracic\u00a0ensures that all aspects of patient care are considered, and the scoring system's results are interpreted comprehensively .Practical Considerations and Challenges in Implementing Rapid ScoringAccessibility of data: The availability of necessary clinical and laboratory data required for rapid scoring may vary across different healthcare settings. In some facilities, electronic health records (EHRs) might be well-established, allowing easy access to relevant patient data. However, in resource-limited or smaller healthcare facilities, the absence of comprehensive EHR systems could hinder data accessibility. Efforts should be made to streamline data collection and ensure the completeness of data inputs for accurate scoring. This may involve improving data capture and recording practices, and fostering interoperability between healthcare information systems .Scoring system selection: Choosing the most appropriate rapid scoring system for a specific clinical setting requires careful consideration of various factors. Different scoring systems may have been developed and validated in diverse patient populations or healthcare contexts. As such, it is essential to evaluate the applicability and accuracy of each scoring system in the specific patient cohort and resource constraints of the healthcare facility. Factors such as patient demographics, available resources, and the overall clinical context should be considered during the selection process to ensure that the chosen scoring system aligns with the needs and capabilities of the healthcare setting .Time constraints: Rapid scoring systems are designed to provide quick and efficient disease severity and prognosis assessments. However, the practicality of their implementation can be impacted by time constraints, particularly in busy clinical settings where healthcare professionals have limited time to dedicate to scoring calculations. The scoring process should be user-friendly, intuitive, and time-efficient to integrate rapid scoring into routine clinical practice seamlessly. Implementing user-friendly electronic scoring tools or incorporating scoring algorithms into electronic medical record systems can help minimize the time investment required for scoring calculation .Future Directions and Potential Improvements in Rapid Scoring SystemsComprehensive scoring models: To enhance the accuracy of prognostication, future scoring systems could be developed as more comprehensive models. By incorporating additional variables, such as molecular biomarkers or novel radiological parameters, these systems can provide a more nuanced and detailed assessment of disease severity and progression. Integrating biomarkers reflecting the host's immune response or pathogen virulence may offer valuable insights into disease outcomes and treatment responses .Artificial intelligence (AI) integration: Leveraging AI algorithms could revolutionize rapid scoring systems by analyzing vast datasets and identifying patterns that might not be apparent through conventional methods. AI integration can significantly improve the predictive power of these systems. Machine learning algorithms can adapt and refine scoring models based on real-world data, ensuring continuous improvement and adaptability to evolving clinical scenarios .External validation and standardization: It is essential to rigorously validate and standardize rapid scoring systems across diverse patient populations and healthcare settings for widespread clinical adoption. Continued research and collaboration among healthcare institutions and research centers can facilitate the validation process, ensuring the reliability and generalizability of these scoring approaches .Longitudinal predictions: Advancements in scoring methodologies may enable dynamic and longitudinal predictions, offering real-time updates on patient outcomes throughout treatment. Longitudinal assessments can provide insights into disease progression, response to therapies, and potential complications, allowing clinicians to adjust treatment strategies proactively .Top of form critique and limitations of rapid scoring systemsCriticism of Current Scoring ApproachesWhile rapid scoring systems have demonstrated their potential in aiding prognostication for pleural infection, they are not exempt from criticism. Several key criticisms of current scoring approaches warrant consideration:Oversimplification: One significant critique of some rapid scoring systems is their tendency to oversimplify the complexity of pleural infection. By focusing on a limited set of parameters, these scoring systems may not fully capture the multifaceted nature of the disease. The oversimplification could lead to inadequate prognostic accuracy, particularly in cases with diverse clinical presentations and variable disease trajectories .Generalizability: Many rapid scoring systems have been developed and validated in specific patient populations, often based on data from single institutions or regions. Consequently, there may be concerns regarding the applicability of these scoring approaches to more diverse patient cohorts. The lack of external validation across different healthcare settings and populations hinders their generalizability and raises questions about their reliability in real-world clinical scenarios .Lack of longitudinal assessment: Rapid scoring systems typically provide static assessments of disease severity at a particular time point. The absence of dynamic or longitudinal assessments limits their ability to predict changes in disease trajectory over time. In pleural infection, disease progression and response to treatment may evolve over days or weeks, and a single snapshot may not capture the full clinical picture .Limited predictive value for long-term outcomes: While rapid scoring systems have shown promise in predicting short-term outcomes, such as mortality and treatment response, their ability to predict long-term outcomes remains a challenge reliably. Variables influencing long-term recovery, recurrence rates, and functional outcomes are complex and multifactorial, making their inclusion in scoring systems more complex .Limitations of Available Studies and DataSmall sample sizes: Many studies evaluating rapid scoring systems may have limited sample sizes due to the rarity of severe pleural infections or other logistical constraints. Small sample sizes can reduce statistical power, making it challenging to draw definitive conclusions. Moreover, findings from such studies may lack generalizability to larger, more diverse patient populations, potentially limiting the external validity of the scoring systems .Heterogeneity of studies: Studies evaluating rapid scoring systems often utilize varying patient populations, methodologies, and outcome measures. This heterogeneity can complicate direct comparisons between different scoring approaches, hindering the establishment of a consensus on the most effective scoring system for pleural infection prognostication. A standardized approach to study design and outcome measurements would facilitate meaningful comparisons and enhance the reliability of the findings .Retrospective nature: Many studies assessing rapid scoring systems in pleural infection rely on retrospective data, which can introduce inherent biases and limitations. Retrospective data collection may be subject to selection bias, as patient data may not have been originally collected for scoring system evaluation. Additionally, retrospective data might lack completeness, leading to missing or incomplete information that could impact the accuracy and reliability of prognostic evaluations .Missing data and follow-up: Incomplete data and loss to follow-up present significant challenges in prognostic evaluations using rapid scoring systems. Missing data can result from various factors, including patients' refusal to participate in follow-up assessments or incomplete medical records. This missing data can lead to underestimation or overestimation of prognostic accuracy and potentially introduce bias into the results. Ensuring complete and accurate data collection, as well as adequate follow-up, is essential to minimize these potential biases and enhance the validity of prognostic assessments .Addressing Potential Sources of BiasLarge, prospective multicenter studies: Conducting well-designed prospective studies with large and diverse patient populations is essential. By collecting data from multiple healthcare centers, these studies can improve the generalizability of the findings and ensure that the results represent the broader patient population. Prospective studies also allow for standardized data collection, minimizing the risk of data inconsistencies and enhancing the statistical robustness of the scoring system .External validation: External validation of rapid scoring systems is critical to establishing their predictive accuracy in different clinical settings and patient cohorts. Validating the scoring systems in settings beyond their original development ensures that they perform consistently and reliably across diverse healthcare contexts. Such validation strengthens the evidence base supporting the use of these scoring systems and increases confidence in their clinical applicability .Longitudinal assessment: Incorporating longitudinal assessments into rapid scoring systems can provide more accurate predictions of disease trajectories over time. By tracking changes in patient status and outcomes throughout treatment and follow-up, longitudinal assessments can offer insights into the dynamic nature of pleural infection and its response to interventions. This temporal dimension can further enhance the predictive value of the scoring systems, guiding clinicians in making more informed decisions throughout the patient's healthcare journey .Transparent reporting: Transparent reporting of study methods, data collection, and potential sources of bias is crucial for ensuring the credibility and reproducibility of research findings. Comprehensive and clear reporting allows other researchers and healthcare professionals to understand and evaluate the study's methodology and potential limitations. It fosters an environment of scientific rigor and encourages transparency in research, which is vital for building trust in the validity and applicability of rapid scoring systems in pleural infection prognostication .This review article has comprehensively assessed the predictive potential of rapid scoring systems in pleural infection prognostication. Pleural infection is a significant health concern, demanding accurate prognostic tools for effective management. Our analysis of existing scoring systems such as CURB-65, A-DROP, and APACHE II revealed their strengths and limitations in predicting short-term and long-term outcomes. While rapid scoring systems show promise in aiding clinical decision-making and risk stratification, they are not without drawbacks and face challenges related to data limitations and potential biases. However, their integration into clinical practice can potentially improve patient outcomes and optimize resource allocation. Moving forward, rigorous validation, reporting transparency, and data science advances offer promising avenues for refining rapid scoring systems. Multidisciplinary collaboration and prospective studies are critical to unlocking the full potential of rapid scoring in pleural infection management, ultimately contributing to better patient care and outcomes."} +{"text": "Extracellular RNAs are an emerging research topic in fungal-plant interactions. Fungal plant pathogens and symbionts release small RNAs that enter host cells to manipulate plant physiology and immunity. This communication via extracellular RNAs between fungi and plants is bidirectional. On the one hand, plants release RNAs encapsulated inside extracellular vesicles as a defense response as well as for intercellular and inter-organismal communication. On the other hand, recent reports suggest that also full-length mRNAs are transported within fungal EVs into plants, and these fungal mRNAs might get translated inside host cells. In this review article, we summarize the current views and fundamental concepts of extracellular RNAs released by plant-associated fungi, and we discuss new strategies to apply extracellular RNAs in crop protection against fungal pathogens.Extracellular RNAs are an emerging topic in plant-fungal communication.\u2022 Fungi utilize RNAs to manipulate host plants for colonization.\u2022 Extracellular RNAs can be engineered to protect plants against fungal pathogens.\u2022 Fungal-plant interactions can have beneficial, detrimental, or neutral effects on plant hosts. Pathogenic fungi pose serious threats to agronomic yield and ecosystems that is largely conserved between fungi and plants. Key factors of RNAi, namely RNA-dependent RNA polymerase (RDR), Dicer-like (DCL), and Argonaute (AGO) proteins, are highly conserved in both plants and fungi . EVs are nanoparticles encasing cytoplasmic molecules including proteins and RNAs in a lipid bilayer, which are secreted into the extracellular space into the root cortex of its host plant Eucalyptus grandis. Treatment of roots with synthetic Pisolithus milRNAs mimicked regulation of Eucalyptus target genes and strengthened formation of deep Hartig net during root colonization roots in order to establish root nodule symbiosis into the soybean AGO1b to induce cross-kingdom RNAi of nodule-repressive plant genes. Interestingly, both cases of cross-kingdom RNAi help to establish distinct forms of root symbiosis, in which microbial small RNAs seem to act as early stage interaction signals, because RNA delivery into plant cells occurs before the formation of fungal Hartig net and bacterial nodules.The fungal vascular pathogen Zymoseptoria tritici 11 and RH37, which all specifically bind to the EV small RNAs, as well as the two non-specific RBPs annexins (ANN)1 and ANN2 and mRNAs with cognate motifs for targeting them to sites of EV biogenesis. In mammalian systems, multiple RBPs have been implicated in RNA loading into EVs siRNAs into infecting B. cinerea. These A. thaliana small RNAs are suggested to be transported via plant EVs RNAs was found in the plant extracellular fraction . Accordingly, essential field trials in the USA are proceeding to pave the way for final approval. Such development of successful SIGS application keeps high hopes that RNA spray also becomes conceivable for plant protection against fungal pathogens in the near future.Since the discovery of cross-kingdom RNAi and its technological implementation into HIGS application, RNAs have been engineered to confer resistance in plants against diverse pathogenic organisms with significant success and DCLs (RNAi pathway) on cotton (Jain et al. B. cinerea infection in tomato and chickpea under controlled conditions (Nino-Sanchez et al. B. cinerea infection (Qiao et al. Since extracellular RNA stability and delivery have been identified as the major challenges to bring SIGS into a success story against fungal pathogens (Hernandez-Soto and Chacon-Cerdas The SIGS approach stands for a more eco-friendly plant protection strategy that is already in transition into potential field application in first trails (Rank and Koch"} +{"text": "Pancreatic cancer is currently the fourth most common cause of cancer-related deaths and is predicted to be the second leading cause of cancer-related mortality by the year 2030. Most of the malignant neoplasms of the pancreas are ductal adenocarcinomas (PDAC). For several reasons, the prognosis of PDAC is exceedingly poor. Surgical resection is the only curative treatment option, but only about 10\u201320% of patients present with resectable tumors at the time of diagnosis. Moreover, most pancreatic carcinomas are resistant to conventional (radio)chemotherapy. Current clinical standard treatment regimens comprise either mFOLFIRINOX or gemcitabine (with nab-paclitaxel). The selection of either of these regimens is currently based on the patient performance status and comorbidities, while the underlying individual tumor biology is commonly not considered. Although multiple studies aimed at establishing molecular profiles and identification of actionable molecular targets of PDACs, targeted therapies for PDAC patients have not (yet) become an integral part of clinical routine practice. In addition to treatment prediction based on molecular profiling, e.g., in the context of a molecular tumorboard, preclinical culture models that reflect the complex interactions of tumor cells with their microenvironment are promising tools to understand molecular mechanisms of PDAC and to test individual treatment responses. These patient-derived models comprise adherently growing primary cell lines, organoid cultures, organotypic slice cultures and patient-derived xenografts.Garcia et al. recently published a comprehensive review on two-dimensional (2D) cell cultures, 3D organoid cultures, and genetically engineered mouse models (GEMMs) with a special focus on patient derived xenograft (PDX) models . AdherenIn light of the limitations of PDXs as a preclinical model for individual therapy response prediction in personalized medicine, 3D organoid cultures are a highly promising tool. Frappart and Hofmann comprehensively reviewed the methodology and potential use of organoid cultures to improve clinical management of PDAC . EfficieAs mentioned above, most preclinical culture models lack the immune cell compartment. However, multiple suppressive immune cell types including macrophages, myeloid-derived suppressor cells (MDSCs) and regulatory T cells are found in early pancreatic lesions and persist through cancer progression. Holokai et al. described an elegantautologous pancreatic cancer organoid-immune cell co-culture model that may be able to predict the efficacy of targeted therapies . Based oAnother model system that should be mentioned in this context are organotypic slice cultures (OTSCs). We recently established this ex vivo model in our laboratory to explore its potential use for ex vivo response prediction . OTSCs aIn summary, we conclude that to date there is no optimal model system for preclinical response prediction of individual PDAC patients to therapy. Each model system discussed here has its benefits and weaknesses and does not fully reflect the individual patient\u2019s tumor biology in vivo. However, since they complement each other, they may be used in combination rather than singly for reliable response prediction. All of these preclinical patient-derived culture models are certainly highly promising tools in personalized treatment of PDAC; their clinical implementation, though, requires further evaluation and fine tuning."} +{"text": "The clinical use of cellular immunotherapies is gaining momentum and the number of approved indications is steadily increasing. One class of cellular therapies\u2014chimeric antigen receptor (CAR)-modified T cells\u2014has achieved impressive results in distinct blood cancer indications. These existing cellular therapies treating blood cancers face significant relapse rates, and their application beyond hematology has been underwhelming, especially in solid oncology. Major reasons for resistance source largely in the tumor microenvironment (TME). The TME in fact functionally suppresses, restricts, and excludes adoptive immune cells, which limits the efficacy of cellular immunotherapies from the onset. Many promising efforts are ongoing to adapt cellular immunotherapies to address these obstacles, with the aim of reshaping the tumor microenvironment to ameliorate function and to achieve superior efficacy against both hematological and solid malignancies. Cellular immunotherapies, encompassing the use of modified autologous or allogeneic immune cells as treatment against disease, have recently advanced to become part of the standard of care in a few types of relapsed and refractory hematological malignancies. Recent evidence suggests that they might even progress to earlier lines of treatment at least in some indications, highlighting the untapped potential of these approaches.Overall, cellular immunotherapies have so far employed dendritic cell (DC), T cells, or natural killer cells (NK) into patients for treatment of disease. DC vaccines, which utilize mature dendritic cells or monocyte-derived dendritic cells derived from patient blood, harness the natural role of the dendritic cell in antigen presentation and T cell licensing to target cancer. Dendritic cells are pulsed with tumor-associated antigens and neoantigens that would then be presented to T cells in lymph nodes to induce cytotoxic lymphocyte priming and polarization to mount a specific immune response. Various DC vaccines have shown promising safety and efficacy in clinical trials against pediatric solid tumors and other forms of solid tumors \u20133. TheseMeanwhile, TCRs and CARs are receptors genetically engineered into T cells isolated from patient blood and reintroduced into the patient to target cancers. TCRs used are derived from natural sequences that bind the desired antigen and behave similarly to normal TCRs . In contThe tumor microenvironment\u2014comprises malignant cells together with their immediate environment consisting of immune cells, fibroblasts, extracellular matrix (ECM), blood vessels, and secreted factors. The TME can support the survival and proliferation of tumor cells and tumor-associated cell populations and thus contributes a major share to cancer hallmarks Fig.\u00a0. Crucial. Along these lines, the TME profoundly regulates and suppresses immune responses and appears as the aspect to beat to enable cell therapy efficacy.Chemokines released by tumor cells recruit and retain other populations of immunosuppressive cells into the tumor microenvironment Fig.\u00a0. T-regulMany insights have already been gained into improving existing cellular therapy. For instance, application via intratumoral injection leads to increased efficacy of adoptive CAR-T cells in certain tumor indications by physically circumventing the issue of TME exclusion and adoptive cell infiltration , 43. To Chemokines are mediators signaling for directed migration towards the source they originate from . Chemokines orchestrate the localization of cells within the body and accordingly play a crucial role in the trafficking of immunosuppressive cells to the TME , 50. HowChemokine engineering into therapeutic immune cells has been incorporated into cellular therapies with the goal of increasing the migration of both endogenous inflammatory cells and also adoptively transferred cells into the tumor Fig.\u00a0. The cheAnother related strategy to increase immune infiltration is endogenous activation and proliferation, ultimately leading to higher anti-tumor effector cell numbers at the tumor site. In this sense, T cells can be genetically engineered to express immune checkpoint inhibitors, with anti-PD-1 or anti-PD-L1 antibodies being the most utilized avenue \u201361. AntiThe TME is typically rich in cytokines such as IL-1, favoring expansion and polarization of immune suppressive cell populations of myeloid and lymphoid origin . In contThe aforementioned strategies remodeling the cytokine environment in the TME indirectly affect TAMs, MDSCs, and T-regs by antagonizing their suppressiveness or reversing their suppression program. However, other cellular therapy approaches aim to directly target these immunosuppressive populations for elimination or remodeling Fig.\u00a0. For exaSignificant obstacles of cellular immunotherapy in solid tumors do not only arise from immunosuppressive cell populations and a lack of immune cell activation within the TME but are additionally characterized by the establishment of CAF-mediated tumor stroma as a physical barrier, diminishing cellular therapy effectiveness. Along these lines, therapy can be enhanced if either the cellular components creating stroma are depleted or acellular stromal components are digested Fig.\u00a0. FibroblA different strategy to surmount the desmoplastic stroma of the TME and enable superior immune cell infiltration is the direct targeting of fibrous proteins, glycosaminoglycans, and proteoglycans composing the ECM via matrix-degrading components. Heparanase (HPSE) is an enzyme that decomposes heparan sulfate proteoglycans and has been found to be insufficiently expressed in CAR-T cells, thereby limiting their capacity to infiltrate stroma-rich tumors . EquippiVarious strategies have also been developed to address the secondary issue of physical tumor-exclusion\u2014aberrant and dysfunctional vasculature that leads to poor T cell infiltration Fig.\u00a0. One strRecent efforts to remodel the tumor microenvironment with cellular therapies have advanced with the advent of engineering CARs or CAR-like receptors on myeloid lineage cells, notably on macrophages and in some instances dendritic cells Fig.\u00a0. TraditiWhile cellular therapies have come a long way to become an established method of cancer treatment, their future potential for increased efficacy in hematological malignancies and even meaningful efficacy in solid tumor indications largely relies on their ability to address the obstacles posed by the TME. This review highlights the current considerable efforts that have been made to improve various aspects of cellular therapies to reshape the TME to become more permissible for treatment: novel concepts that target immunosuppressive cell populations, inflame an immune-restricted tumor, and address chemotactic signaling and physical barriers excluding immune infiltration. The improvements made on these therapies have been shown to lead to superior anti-tumor efficacy compared to more standard cellular therapies. Moreover, many cellular therapies covered here that target the TME as an entity have been combined with other treatments that primarily target the tumor, forming a dual-pronged targeting approach that in many cases shows synergistic efficacy. Additionally, concepts incorporating combinatorial improvements that address multiple TME obstructions show further enhanced function, demonstrating additionally the promising and synergistic nature of reshaping the tumor microenvironment, and hints at robust effects for combinatorial treatments with existing therapies such as ICB. Promising pre-clinical and clinical results of many of the therapies listed bode well for the application of cellular immunotherapies for the treatment of both hematological and solid tumors in the future."} +{"text": "Introduction: Chediak-Higashi syndrome (CHS) is rare autosomal recessive disorder caused by bi-allelic variants in the Lysosomal Trafficking Regulator (LYST) gene. Diagnosis is established by the detection of pathogenic variants in LYST in combination with clinical evidence of disease. Conventional molecular genetic testing of LYST by genomic DNA (gDNA) Sanger sequencing detects the majority of pathogenic variants, but some remain undetected for several individuals clinically diagnosed with CHS. In this study, cDNA Sanger sequencing was pursued as a complementary method to identify variant alleles that are undetected by gDNA Sanger sequencing and to increase molecular diagnostic yield.Methods: Six unrelated individuals with CHS were clinically evaluated and included in this study. gDNA Sanger sequencing and cDNA Sanger sequencing were performed to identify pathogenic LYST variants.Results: Ten novel LYST alleles were identified, including eight nonsense or frameshift variants and two in-frame deletions. Six of these were identified by conventional gDNA Sanger sequencing; cDNA Sanger sequencing was required to identify the remaining variant alleles.Conclusion: By utilizing cDNA sequencing as a complementary technique to identify LYST variants, a complete molecular diagnosis was obtained for all six CHS patients. In this small CHS cohort, the molecular diagnostic yield was increased, and canonical splice site variants identified from gDNA Sanger sequencing were validated by cDNA sequencing. The identification of novel LYST alleles will aid in diagnosing patients and these molecular diagnoses will also lead to genetic counseling, access to services and treatments and clinical trials in the future. Chediak-Higashi syndrome is a rare autosomal recessive disorder characterized by partial oculocutaneous albinism, bleeding diathesis, recurrent infections, an increased risk of developing the hyperinflammatory condition called hemophagocytic lymphohistiocytosis (HLH), and neurologic impairment . The preCHS has significant clinical overlap with several other genetic disorders, emphasizing the importance of a molecular diagnosis. Other disorders that include gray or silvery hair as observed in CHS include Griscelli syndrome , Elejalde neuroectodermal melanolysosomal syndrome (MIM 256710), and oculocerebral syndrome with hypopigmentation (MIM 257800) . There aLYST) gene is the only known molecular cause of CHS and bi-allelic pathogenic variants in LYST establish a molecular diagnosis detects the majority of pathogenic variants, but for some individuals clinically diagnosed with CHS, pathogenic variants remain undetected, likely due to large-scale indels and deep intronic variants or synonymous exonic variants that lead to aberrant splicing. Uniparental disomy leading to the inheritance of two copies of a pathogenic LYST variant from one parent has also been reported as a molecular mechanism for CHS or the Diagnosis and Treatment of Patients with Inborn Errors of Metabolism or Other Genetic Disorders protocol 76-HG-0238 approved by the National Human Genome Research Institute\u2019s Institutional Review Board. Written informed consent was obtained prior to the study. Clinical evaluation included collecting the medical and family history, physical examination, complete blood count (CBC) blood test. Peripheral blood smear analysis and microscopic hair examination were used to assess the presence of giant inclusions in leukocytes and pigment clumping in hair shafts, pathognomonic features of CHS.Six patients clinically diagnosed with classical or atypical CHS were included in this study. These patients were enrolled over the course of 10\u201320\u00a0years in the Investigation of Chediak-Higashi Syndrome and Related Disorders protocol 00-HG-0153 . Quantitative PCR was performed using TaqMan gene expression assays according to the manufacturer\u2019s specifications. Further details are presented in the Supplementary Data.Total RNA was extracted from cultured primary dermal fibroblasts or melanocytes using the RNeasy Mini Kit (Qiagen). Genomic DNA was removed by on-column DNase I digestion (Qiagen) during total RNA extraction. Reverse transcription was performed using the Omniscript Reverse Transcription Kit (Qiagen) and Oligo (dT)LYST (NM_000081.3) coding sequence (exons 3\u201353), including intron-exon boundaries, were amplified by PCR using the primers listed in Genomic DNA (gDNA) was extracted from peripheral blood or cultured primary dermal fibroblasts using standard procedures. gDNA from cultured primary fibroblasts was used if the gDNA from peripheral blood was no longer available. Regions of the LYST coding sequence (exons 3\u201353) were amplified by PCR using the primers listed in Total RNA was extracted from cultured primary dermal fibroblasts or melanocytes using the RNeasy Mini Kit (Qiagen). cDNA was synthesized by reverse transcription with the High-Capacity RNA-to-cDNA Kit (Applied Biosystems). Regions of the PCR products were cloned into the pCR4-TOPO TA vector using the TOPO TA Cloning Kit (Invitrogen). Single clones were Sanger sequenced to individually analyze the cDNA alleles for which chromatograms obtained from the initial cDNA Sanger sequencing were difficult to interpret.Variant pathogenicity classification was performed according to the standards and guidelines presented by the ACMG-AMP and the ACGS . Furtherp-value of less than 0.05 was considered statistically significant.Statistics were performed using GraphPad Prism 8 version 8.4.3 . A two-tailed Mann-Whitney test was performed for experiments comparing two sets of data. A CHD3 presented with silvery hair, pale skin, and ocular albinism as well as a history of recurrent respiratory and skin infections and nose bleeds. He was clinically diagnosed with classical CHS at the age of 7\u00a0years. Abnormal pigment clumping was observed in his hair shafts . He receStaphylococcus aureus (MRSA). She also had learning difficulties and a mood disorder. Pathognomonic giant inclusions were observed in her leukocytes and abnormal pigment clumping in her hair shafts . These cellular findings substantiate prior cellular findings reported in human CHS and in the beige mouse model (Pathogenic variants have been identified throughout the ication) . Eight oication) ; Table 1ication) . AlthougLYST-expressing cell types, including dermal fibroblasts, melanocytes, NK cells, and lymphoblastoid cell lines, for the preparation of total RNA. Archiving cells from each parent and all available family members would also be useful for variant phasing and segregation studies.cDNA Sanger sequencing in combination with conventional gDNA Sanger sequencing offers several advantages. First, cDNA Sanger sequencing can detect variant alleles that are not readily detectable by conventional gDNA Sanger sequencing. While establishing a clinical diagnosis is valuable, the confirmation of a molecular diagnosis is critical for optimal patient care, genetic counseling for the individual and their family members, and eligibility in future clinical trials. Second, cDNA Sanger sequencing is relatively easy to incorporate into the molecular genetic testing workflow, requiring only routine cell culture and total RNA extraction techniques. An important consideration is patient sample archiving of LYST. Furthermore, only cDNA from each of the six patients was analyzed in this study due to sample availability. While we were unable to assess cDNA from cells derived from family members due to sample availability, cDNA Sanger sequencing could be performed to segregate LYST alleles in a family even if the variant at the level of gDNA is unknown.A key limitation of this study was that we were unable to identify the cause of the full or partial exon skipping at the gDNA level for some alleles. While efforts were made to sequence nearby intronic regions and identify exonic synonymous variants that might lead to the aberrant splicing, proving the consequence of such variants requires further functional validation. With the decreasing costs of genome sequencing and targeted next-generation sequencing, these are becoming viable options for the identification of deep intronic variants leading to splicing changes in LYST gene in CHS. Because of the increasing access to next-generation sequencing and its rapid turnaround time, we recommend the utilization of clinical genome sequencing to include copy number variant analysis for patients in which CHS is suspected. When available, RNA sequencing using lymphoblastoid cell lines and melanocytes could help delineate the resulting splice site abnormalities from intronic variants. For standard clinical practice using exome sequencing and when clinical genome sequencing is not available, targeted gDNA Sanger sequencing and copy number detection is recommended for patients highly suspected to have clinical CHS, followed by RNA sequencing (as above) or cDNA Sanger sequencing if only one or no variants are detected by gDNA Sanger sequencing. It will also be interesting to pursue efforts on long-read sequencing technologies to identify deletions in these large genes and to phase variants in the absence of parental samples in the future. Overall, the identification of disease-causing variants will aid in the future diagnosis and care of individuals with CHS.In this study, the integration of thorough clinical phenotyping and conventional gDNA Sanger sequencing in combination with cDNA Sanger sequencing increased the mutational spectrum of CHS. Based on our experience from this study, we provide the following recommendations for molecular genetic testing of the"} +{"text": "Inhaled medications, including beta-agonists, muscarinic antagonists, and corticosteroids, are the backbone of chronic obstructive pulmonary disease (COPD) treatment, and pharmacotherapy plans are frequently optimized during and following hospitalization. Clinical practice guidelines acknowledge that patients living with COPD may experience medication errors from inadequate inhaler technique or device faults, but inhaled medication errors within COPD pharmacotherapy plans remain unreported. This literature review aimed to collect and present studies describing medication errors occurring with inhaled medications in patients living with COPD during and following hospitalization. The databases searched included Ovid MEDLINE, Embase, and International Pharmaceutical Abstracts. One hundred forty-five unique studies were collected, and 10 studies were included. The rate of inhaled medication errors reported across the 10 studies ranged between 2.5% and 66% of patients living with COPD and who were hospitalized or discharged. The incidence and types of medication errors reported across the studies varied significantly. Standardization in categorizing and reporting inhaled medication errors is necessary for future studies to determine the true incidence of inhaled medication errors occurring in patients living with COPD who are hospitalized or discharged. Patients living with chronic obstructive pulmonary disease (COPD) may take medications to palliate symptoms, improve health status, tolerate exercise, and reduce the risk and severity of exacerbations of COPD (ECOPD) . InhaledHowever, the comprehensive formulary of inhaled medications may be overwhelming for both patients and prescribers and thus there is potential for medication errors. Hospitalization is a critical time wherein inhaled medication errors may occur and between 7% and 33% of patients living with COPD will experience at least one COPD-related hospitalization annually . PatientThe purpose of this review is to collect and present literature describing medication errors occurring with inhaled medications in patients living with COPD during and following hospitalization.Review methodsThis was a literature review utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol . The resAn electronic literature search was performed using Ovid MEDLINE, Embase, and International Pharmaceutical Abstracts on February 14, 2023. Search strings for each database are included in Appendix A and adhered to the PRISMA-S extension for literature search reporting . Study rResults from each database search were exported as a Research Information Systems file and then imported into Covidence . During the initial file upload, Covidence automatically de-duplicated identical records retrieved across databases. Abstracts were independently screened by two authors (KH and MG) and screening conflicts were resolved by a third author (PB). Full texts were independently screened by two authors (KH and MG) and screening conflicts were resolved by a third author (PB). Data abstraction was independently performed by two authors (KH and MG). To minimize heterogeneity across the articles and among authors, extraction was performed using a template in Covidence. Data collected included study location, study design, characteristics of the cohort , characteristics of patients living with COPD , and medication errors. There are many frameworks for reporting medication errors, medication error research, and outcomes attributable to medication errors . BecauseFigure Ten studies were ultimately included and are charted in Table Medication-related problemsIn a pilot study conducted at an academic medical center, pharmacists performing admission and discharge medication reconciliation discovered a medication-related problem (MRP) in 96% of patients during admission and discharge transitions of care, with an average of six MRPs encountered per patient . These MOne Veterans Affairs health care center conducted a pre-post study and found an absolute decrease of greater than 10% in prescribing errors upon discharge in each of the categories of SABA, LABA/LAMA, and ICS upon implementing an order set for ECOPD . DecreasPrescribing errors and omissionsOne retrospective cohort study of older adults hospitalized in Palestine leveraged the Screening Tool of Older Persons\u2019 Prescriptions and Screening Tool to Alert to Right Treatment (STOPP/START) to determine potentially inappropriate prescribing via inappropriate medications and omissions . The autIn one multisite retrospective cohort study conducted in Australia, 93.2% of hospitalized COPD patients received nebulized ipratropium, with 48% of these patients deemed as having received inappropriate nebulized ipratropium because they were ordered (duplicative) inhaled ipratropium concomitantly . At discDiscussionThe rate of inhaled medication errors was heterogeneous across the 10 studies in this review -16. BrowThis literature review is not without limitations. Although the authors utilized a systematic approach to searching, assessing, and presenting the included studies, this literature review did not meet the technical standards of either a systematic or scoping review. Future systematic reviews on the themes and topics raised within this literature review are necessary to answer patient-specific questions. The authors did not perform a bias assessment of each article and doing so would have qualified the methodologic rigor of the included studies; although six studies were retrospective designs ,13,14,16As few as 2.5% or as many as 66% of patients living with COPD who are hospitalized may experience an error in their inhaled medication pharmacotherapy plan. Pharmacologic classes with reported errors include short- and long-acting beta-agonists, muscarinic antagonists, and inhaled corticosteroids. Standardization in categorizing and reporting inhaled medication errors is necessary in subsequent studies; the Pharmacy Quality Alliance Frameworks or Medication Error Reporting and Prevention Index are validated and widely used instruments that may be considered in future studies. Future research should aim to clearly compare and contrast findings across clinical settings and investigations and determine the true incidence of inhaled medication errors."} +{"text": "Maiato and Silva discuss the origin and fate of chromosome segregation errors that satisfy the spindle assembly checkpoint, focusing on anaphase surveillance/correction mechanisms and post-mitotic clearance pathways. Enduring chromosome segregation errors represent potential threats to genomic stability due to eventual chromosome copy number alterations (aneuploidy) and formation of micronuclei\u2014key intermediates of a rapid mutational process known as chromothripsis that is found in cancer and congenital disorders. The spindle assembly checkpoint (SAC) has been viewed as the sole surveillance mechanism that prevents chromosome segregation errors during mitosis and meiosis. However, different types of chromosome segregation errors stemming from incorrect kinetochore\u2013microtubule attachments satisfy the SAC and are more frequent than previously anticipated. Remarkably, recent works have unveiled that most of these errors are corrected during anaphase and only rarely result in aneuploidy or formation of micronuclei. Here, we discuss recent progress in our understanding of the origin and fate of chromosome segregation errors that satisfy the SAC and shed light on the surveillance, correction, and clearance mechanisms that prevent their transmission, to preserve genomic stability. Saccharomyces cerevisiae [300 billion cell divisions must take place every day in the human body to ensure tissue homeostasis and function . In vitrrevisiae ), these Somatic cell aneuploidy is implicated in tumorigenesis, genomic instability, tumor evolution, metastasis, drug resistance, and reduced cancer patient survival, whereas germline aneuploidy directly accounts for infertility, pregnancy loss, and developmental disorders . HoweverCell cycle checkpoints are constitutive feedback control mechanisms that delay cell cycle progression until completion of a critical event, providing time for the correction of potential errors . EliminaRecent high-resolution live-cell studies tracking kinetochore or chromosome behavior through metaphase and anaphase in human somatic cells in culture have revealed that many more chromosomes tend to lag behind in anaphase than previously anticipated . This beThe role of anaphase spindle mechanics was first established through the observation that merotelic kinetochores with uneven microtubules facing the poles experience a significant stretch and elongate under tension, eventually favoring segregation to the correct daughter cell. Only a small fraction (<10%) of the merotelic kinetochores that persist through anaphase show an even microtubule ratio facing the poles and result in long-lasting lagging chromosomes that missegregate . Live imMore recently, it was demonstrated that spindle elongation is directly required for anaphase error correction . The acuAurora B kinase activity at centromeres plays a key role in error correction during early mitosis . HoweverTwo possible models have been proposed to explain how a midzone-based Aurora B activity gradient mediates error correction during anaphase . One is An alternative model favors the idea that midzone Aurora B activity mediates anaphase error correction of merotelic kinetochores by assisting the mechanical transmission of spindle forces to a stable kinetochore\u2013microtubule interface on lagging chromosomes . Live-ceDirect measurements of kinetochore\u2013microtubule half-life during anaphase revealed a low kinetochore\u2013microtubule turnover , which wThe finding of a distinct phosphorylation state on Aurora B substrates at kinetochores of anaphase lagging chromosomes suggestsBut why is the spatiotemporal control of NER important? On one hand, preventing premature NER on incompletely separated chromosomes during normal anaphase protects against polyploidy. Whole-genome duplication is a common evolutionary event that is also frequent in >30% of human tumors early in tumorigenesis and is thought to promote chromosomal instability and metastasis by providing a selective advantage in certain contexts . On the One may argue that a delay of just a few minutes in a process that is normally completed within 5\u201310 min in human somatic cells cannot be explained by a robust checkpoint mediated by Aurora B at the spindle midzone. Instead, midzone microtubules may act independently of Aurora B activity by forming a physical barrier that selectively prevents the recruitment of non-core nuclear envelope proteins , includIn an attempt to separate the role of microtubules from that of Aurora B at the spindle midzone in the spatiotemporal control of NER, high-resolution live-cell microscopy was used to simultaneously monitor Aurora B activity on chromosomes, the recruitment of NPC proteins, and the distribution of spindle midzone microtubules throughout anaphase, upon manipulation of Aurora B midzone localization . These eQuantitative microscopy analyses further revealed that even just a small but significant delay in the completion of NER relative to the main segregating chromosome masses allows most anaphase lagging chromosomes in human cells to gradually correct and move away from the spindle midzone. Moreover, this delay depended on the establishment of a midzone-based Aurora B phosphorylation gradient that prevented formation of micronuclei . TherefoConcerning potential targets involved in the spatiotemporal regulation of NER, Aurora B may regulate Condensin I removal and/or recruitment of HP1 and LBR as chromosomes separate during anaphase or may mAnaphase lagging chromosomes that escape surveillance and correction mechanisms operating in anaphase rarely missegregate to give rise to aneuploidy, but they may lead to the formation of micronuclei . ImportaMicronuclei derived from chromosome segregation errors have four possible outcomes upon mitotic exit: (1) persistence as independent structures; (2) reincorporation into the main nucleus; (3) degradation; or (4) extrusion sensor that mounts a type-I IFN innate immune response through its adaptor protein STING, referred to as the cGAS-STING pathway . The actGiven the possible role of p53 in limiting the proliferation of aneuploid and micronucleated cells, an outstanding question is whether the cGAS-STING pathway somehow crosstalks with p53. Recently, a mutant form of p53 was shown to suppress innate immune signaling through the cGAS-STING pathway, resulting in immune evasion and tumor progression . In thisWhile a lot remains to be known regarding the mechanisms underlying cGAS-STING\u2013mediated immunosurveillance of mitotic errors and their respective implications for tumor evolution, defective micronuclei are now well established as potential hubs for chromothripsis . ChromotWhile the high rates of aneuploidy during female meiosis have been linked to a weakened SAC and intrinsically unstable kinetochore\u2013microtubule attachments , aneuploIn addition to direct missegregation from misaligned chromosomes, late-aligning chromosomes associated with peripheral nuclear positioning during interphase are also more prone to lag behind in anaphase and missegregate at higher frequencies . LikewisOverall, these recent findings instigate future studies to determine the underlying mechanisms that normally prevent aneuploidy during mitosis and meiosis, while continuing to evaluate the contribution of aneuploidy-inducing events of different origin and how cells deal with them in health and disease contexts."} +{"text": "Idiopathic subglottic stenosis (iSGS) is a rare fibrotic disease of the proximal airway affecting adult Caucasian women nearly exclusively. Life-threatening ventilatory obstruction occurs secondary to pernicious subglottic mucosal scar. Disease rarity and wide geographic patient distribution has previously limited substantive mechanistic investigation into iSGS pathogenesis.By harnessing pathogenic mucosa from an international iSGS patient cohort and single-cell RNA sequencing, we unbiasedly characterize the cell subsets in the proximal airway scar and detail their molecular phenotypes. Results show that the airway epithelium in iSGS patients is depleted of basal progenitor cells, and the residual epithelial cells acquire a mesenchymal phenotype. Observed displacement of bacteria beneath the lamina propria provides functional support for the molecular evidence of epithelial dysfunction. Matched tissue microbiomes support displacement of the native microbiome into the lamina propria of iSGS patients rather than disrupted bacterial community structure. However, animal models confirm that bacteria are necessary for pathologic proximal airway fibrosis and suggest an equally essential role for host adaptive immunity. Human samples from iSGS airway scar demonstrate adaptive immune activation in response to the proximal airway microbiome of both matched iSGS patients and healthy controls. Clinical outcome data from iSGS patients suggests surgical extirpation of airway scar and reconstitution with unaffected tracheal mucosa halts the progressive fibrosis.Our data support an iSGS disease model where epithelial alterations facilitate microbiome displacement, dysregulated immune activation, and localized fibrosis. These results refine our understanding of iSGS and implicate shared pathogenic mechanisms with distal airway fibrotic diseases. Idiopathic subglottic stenosis (iSGS) is a rare but devaHistologically, iSGS cases show pronounced fibrosis restricted to the proximal airway mucosa . DiverseIn iSGS the functional alterations underlying airway remodeling remain poorly understood. In this study, we harnessed tissue samples from an international iSGS patient cohort and cutting-edge molecular tools to define the molecular phenotype of the proximal airway mucosa at single-cell resolution. Our results provide an unbiased assessment of the cell types within the normal human subglottis and illuminate the changes accompanying iSGS. The results suggest epithelial barrier dysfunction and immune infiltration are key components of iSGS pathogenesis. Matched superficial and deep tissue microbiomes support displacement of the native microbiome into the lamina propria of iSGS patients rather than disruption of bacterial community structure. However, animal models confirm that bacteria are necessary for pathologic proximal airway fibrosis and suggest an equally essential role for host adaptive immunity in remodeling after mucosal injury. Clinical data support the role of epithelial dysfunction in treatment response. Our data suggests that in iSGS the native microbiome is displaced across a dysfunctional epithelial barrier leading to an adaptive immune response which drives obstructive airway fibrosis. These novel results reshape our understanding of iSGS, implicate shared pathogenic mechanisms with distal airway fibrotic diseases, and open new avenues for therapy.Supplemental Table T1) and performed scRNAseq using the 10x Genomics Chromium platform . The samples were collected and processed at two different sites ; however, both sites collected cases and controls. To maximize our ability to identify rare cell populations, we jointly analyzed data from all samples. We defined inclusion criteria for cells based on observations from the entire dataset, removed low-quality cells accordingly, applied normalization and variance stabilization of the 25,974 recovered cells using Seurat. Initially one small CD8 effector T cell population was grouped together with a larger CD8 T effector population due to observations that cell cycle activity was driving distinct cluster identity. All cell types were identified both in airway scar and healthy mucosa. Notably, we did not observe overt batch effects driven by processing site or sequencing batch in our dimensionality reduction and visualization . Cell types/states were also manually grouped into 4 broad tissue classes based on their identity . Quantification of cell types demonstrated significant differences between iSGS airway scar and matched healthy mucosa controls. Airway scar showed significantly more Immune cells and significantly fewer epithelial cells . When grouping cells into their tissue layer, the epithelium demonstrated significantly more DEG than immune cells . In addi< 0.001) (DEG: P = 0.007) . The dif= 0.007) .Supplemental Figure S4). Gene ontology (GO) pathway analysis supported the Hallmark geneset EMT findings; iSGS airway scar showed enrichment for mitochondrial matrix genes . In parallel, proliferating epithelial cells in iSGS airway scar showed down-regulated glycosylation and junctional protein complexes . Both aerobic respiration and loss of cell-cell adhesion are consistent with EMT.Molecular and functional evidence of epithelial dysfunction in iSGS scar. We further analyzed the epithelial clusters and idenTo provide functional evidence of epithelial barrier dysfunction, we investigated if native bacterial displacement into the deeper lamina propria was a unique feature of iSGS. Employing fluorescence in situ hybridization (FISH) with the pan-bacterial probe, Eub338, we investigated if mucosal biopsies from iSGS and healthy controls evidenced bacteria in the deep layers of the proximal airway mucosa. Representative FISH stains show iSGS mucosa possessed signal for bacteria in the deeper lamina propria while healthy control did not . In a seCharacterization of the mucosal microbiome in iSGS. Given the observed bacterial displacement into the lamina propria of the airway mucosa, we investigated if alterations in microbiome community structure were also observed in iSGS. We first quantified the number of 16S rRNA gene copies in deep tissue biopsies via qPCR . We deteSupplemental Figure S6). The majority of bacterial species present in healthy subglottis were consistent with the established healthy lung microbiome composed of supraglottic predominant taxa . Using ptococcus).Supplemental Fig. 7A) nor between disease severity and alpha diversity or richness .Additional microbial community structure testing using established diversity and richness indices confirmed no detectable differences between iSGS, iLTS and healthy controls. ANOVA testing of alpha diversity and richness .Anatomic location of bacterial species in iSGS mucosal scar. To validate our findings and explore if superficial and deep tissue sampling methods produced unique bacterial communities, we next compared published 16S rRNA sequencing data of superficial swabs of iSGS scar (n = 5) with ourSupplemental Fig. 8). As expected, wild-type mice developed mucosal inflammation and significant thickening of the lamina propria 14 days after injury . Interestingly however, no significant thickening of the lamina propria was observed when using either germ-free mice , or severe combined immunodeficient mice (SCID) lacking ce (SCID) & B.eff cells in scar , along with more CD4 + Treg and more NK cluster 2 cells . In contrast, the NK cluster 1 population was significantly reduced in scar .The native proximal airway microbiome generates an antigen-specific immune response in infiltrating CD4 + and CD8 + T cells. In order to probe the function of the observed immune infiltrate, tissue biopsies acquired during the operative endoscopy of 5 unique iSGS patients were used to create fresh single-cell suspensions as described. Suspensions were rested for 6 hours, then cultured in the presence of a matched iSGS airway microbiome, the microbiome from an unrelated healthy subject, or left untreated.After 24 hours of stimulation, cells were washed and stained for markers of T cell activation (CD154) and analyzed via flow cytometry . For CD4Clinical data suggest that restoring epithelial barrier function is associated with a more durable treatment response. Treatment outcomes of iSGS patients in an ongoing cohort study demonstrIdiopathic subglottic stenosis (iSGS) is a debilitating localized fibrosis of the proximal airway. Affected patients possess tightly conserved clinical demographics, histopathology, and physiologic impairment . Our humThe pseudostratified epithelium lining the human airway comprises several distinct populations of cells with specialized effector functions. Airway epithelium and the overlying mucociliary layer maintain a physical barrier against environmental insults . Many primary respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma, and idiopathic pulmonary fibrosis (IPF), display substantial pathological alterations in the airway epithelium. Evidence suggests that impairment of the epithelial barrier allows bacteria to penetrate the overlying mucociliary layer, intercalate within the epithelium, and activate host immunity. When sustained inappropriately, this inflammation can culminate in fibrotic tissue remodeling and physiologic impairment.in vitro human data and genetic evidence suggest that the airway epithelium plays a central role in disease susceptibility of the residual epithelial cells showed a mechanistic target of rapamycin (mTORC1) pathway activation and enhanced aerobic metabolism. mTOR is a master sensor that integrates environmental factors to regulate cell growth. In general, activation of mTOR stimulates proliferation, mitochondrial biogenesis, and oxidative phosphorylation . The GESAlthough an often-overlooked anatomic subsite, the subglottis is uniquely enriched in antigen-presenting dendritic cells and T lymphocytes . AdditioPrior small case series examining environmental factors contributing to iSGS have implicated disruption of the proximal airway microbiome, one using pathogen-specific molecular approaches, and anoHowever, the displaced microbiome may not be the sole target of the adaptive immune response observed in iSGS mucosal scar. A feed-forward inflammatory loop may become established when peptides from microbial proteins share suffi cient structural similarity with self-peptides and activate autoreactive T cells, termed \u201cmolecular mimicry\u201d. InflammAlthough we acknowledge the limited ability to assign causality in pathologic studies involving human tissue, single-cell transcriptional profiling provides an unbiased assessment of the cell types within the human subglottis and illuminates the epithelial and immune alterations accompanying disease. Histologic localization of pathogens deep in the lamina propria and bacterial community profiling support the functional impact of the observed epithelial dysfunction rather than suggest microbiome disruption is a primary driver of disease. Animal models confirm the importance of both bacteria and host immunity in the pathogenesis of airway fibrosis after epithelial injury and robust clinical data suggests restoring the epithelial barrier with healthy mucosa minimizes disease recurrence.Despite the inherent limits involved in rare disease research, our findings dramatically shift our concept of iSGS disease pathogenesis . UnbiaseDetailed experimental methods are included in the Supplemental Material."} +{"text": "Integrating robotics into orthopedic healthcare represents a transformative paradigm shift driven by technological advancements. This editorial explores the profound impact of robotics on the diagnosis, treatment, and rehabilitation of musculoskeletal conditions. Robotics redefines precision in orthopedic surgery through advanced imaging and real-time feedback, resulting in minimized disruption to tissues and faster recovery. Personalized treatment plans leverage robotics' capabilities to tailor procedures to individual anatomical characteristics, enhancing outcomes and reducing complications. Minimally invasive procedures, facilitated by robotics, mitigate trauma and expedite patient recovery. This collaboration between surgeons and robotic systems enhances precision without supplanting human expertise. Moreover, robotics extends to postoperative rehabilitation, utilizing exoskeletons and motion-capture systems to optimize mobility and strength recovery. While challenges of cost and training exist, proactive collaborations are shaping the future of robotics in orthopedic care. Ethical considerations underline the importance of balancing human intervention with robotic assistance. As robotics evolves, orthopedic healthcare embraces a future where technology and human expertise synergize, ultimately conquering musculoskeletal conditions. In recent years, the realm of healthcare has been undergoing a transformative journey fueled by remarkable technological advancements. Among the most impactful areas experiencing this revolution is orthopedic healthcare, where robotics catalyzes a paradigm shift in approaching the diagnosis, treatment, and rehabilitation of musculoskeletal conditions. As the symbiotic relationship between robotics and orthopedic care continues to evolve, a future brimming with the potential for enhanced precision, swifter recovery times, and overall improved outcomes comes into view.Orthopedic conditions, an extensive array of musculoskeletal disorders, have long posed challenges due to the intricate complexity of human anatomy and the delicate nature of bone and joint structures. Robotics' assimilation into orthopedic care has introduced a new dimension, addressing these challenges with unprecedented precision and efficacy.Robotic systems revolutionizing orthopedicsSeveral robotic systems have emerged as game-changers in orthopedic surgery, each offering unique features and benefits.MAKO Surgical SystemThe MAKO system is renowned for its application in joint replacement surgeries. Advanced imaging and real-time feedback assist surgeons in precise bone preparation and implant positioning, resulting in improved alignment and joint function. Its haptic feedback mechanism aids in accurate bone resection. MAKO utilizes computed tomography (CT) scans to create patient-specific 3D models. Surgeons plan implant placement virtually, ensuring optimal alignment. The robotic arm is guided by the surgical plan in the operating room and provides haptic feedback to prevent excessive bone resection. Surgeons retain control while benefiting from enhanced accuracy.ROSA ROSA is widely utilized in neurosurgery and spine procedures. Its features include real-time intraoperative data, image guidance, and robotic arms for enhanced surgical precision. ROSA facilitates minimally invasive surgeries and assists in complex spinal deformity corrections. ROSA integrates with various imaging modalities\u00a0like CT and X-ray, to create a comprehensive surgical plan. It assists in cranial and spinal surgeries by providing real-time data, enabling precise targeting and trajectory planning. The system's robotic arms are guided by the surgeon's commands, enhancing procedural accuracy.NAVIO Surgical SystemNAVIO offers robotics-assisted procedures in orthopedics, focusing on knee surgeries. It employs intraoperative planning and a handheld robotic-assisted tool for precise bone resurfacing. NAVIO's image-free registration enhances accuracy and outcomes in knee arthroplasty. NAVIO operates without preoperative imaging, utilizing a computer-assisted tool for intraoperative planning. Surgeons use tactile guidance to create a patient-specific plan and execute bone resurfacing accurately. This system enhances implant alignment, potentially improving implant longevity and patient satisfaction.Stryker Mako Total Hip Arthroplasty SystemThe Stryker Mako total hip arthroplasty system (Stryker) is tailored specifically for total hip arthroplasty. It provides a combination of 3D preoperative planning and robotic arm assistance during surgery. Surgeons benefit from real-time feedback, facilitating accurate acetabular cup positioning and leg length restoration. This system combines preoperative planning with intraoperative robotic assistance. Surgeons use a handheld robotic arm to prepare the acetabulum and place the cup precisely. Real-time feedback ensures accurate leg length restoration and hip offset, minimizing complications.RAS (Robotic Arm System) in Spine SurgeryRAS systems are designed to enhance the accuracy of pedicle screw placement in spine surgeries. They utilize advanced imaging and robotic arms to guide surgeons in complex procedures, reducing the risk of nerve injury and revision surgeries. RAS employs advanced imaging and navigation to guide robotic arms for pedicle screw placement. Surgeons create a preoperative plan, and the robotic arm assists in accurate trajectory execution. This reduces radiation exposure, enhances accuracy, and potentially reduces revision surgeries.TM Robotic Guidance SystemMAZOR X Stealth EditionThe MAZOR X Stealth\u2122 Edition robotic guidance system offers both preoperative and intraoperative planning capabilities. With features like customizable implant options, optimal trajectories for implants, and advanced 3D analytics, this planning functionality empowers surgeons to enhance construct optimization and achieve a more predictable surgical procedure. The foundation of robotic precision lies in cutting-edge registration and mechanical stability. The MAZOR X\u2122 platform establishes a closed-loop connection between the robotic arm mounted on the operating table, the securely positioned patient, and a rigid link between the robot and the patient's skeletal structure. This robotic system is table-mounted, optimizing the operating room space while ensuring unparalleled precision. The Stealth\u2122 Navigation technology provides real-time visualization of implant placement within the patient's anatomy, aligning with the pre-operative plan. By seamlessly integrating two guidance technologies into a comprehensive platform, surgeons can confidently execute procedures during surgery, effectively bridging the gap between planning and execution. The navigation feature offers the visibility required to complete the surgical plan. With an accuracy rate of up to 100%, the MAZOR X Stealth\u2122 Edition ensures precise screw placement.Precision redefinedAmong the most compelling contributions of robotics to orthopedics is its capacity to elevate surgical precision. Conventional surgical techniques often hinge on the surgeon's manual dexterity, leaving room for inadvertent errors. Robotic systems, fortified with advanced imaging and real-time feedback mechanisms, empower surgeons to meticulously plan and execute procedures with a degree of accuracy measured in sub-millimeters . This lePersonalized treatment plansIntroducing robotics in orthopedic surgery marks a revolutionary phase in tailored treatment plans. Robotic systems enable surgeons to intricately strategize procedures that cater to each patient's unique anatomical characteristics . This hiMinimally invasive proceduresRobotics has been instrumental in fostering the proliferation of minimally invasive procedures within orthopedics . ConventAdvantages of robotic systems in orthopedicsThe following are the advantages of\u00a0robotic systems in orthopedics.Enhanced precision: Robotic systems offer unmatched precision and accuracy in executing surgical tasks, leading to improved implant alignment and surgical outcomes.Personalized treatment: Robotic platforms allow for the customization of surgical procedures based on each patient's unique anatomy, potentially reducing complications and improving long-term outcomes.Minimized tissue trauma: Robotic-assisted procedures often require smaller incisions and result in less disruption to surrounding tissues, leading to reduced postoperative pain and faster recovery times.Improved implant placement: Robotic systems enable precise implant positioning, potentially increasing implant longevity and patient satisfaction.Real-time feedback: Many robotic platforms provide real-time feedback to surgeons during procedures, allowing for adjustments and ensuring optimal outcomes.Complex maneuvers: Robotic arms can execute complex maneuvers that might be challenging for a human hand, enhancing the surgeon's capabilities.Reduced radiation exposure: In procedures such as spine surgery, robotics can reduce the need for fluoroscopy, leading to lower radiation exposure for both patients and surgical staff.Disadvantages of robotic systems in orthopedicsThe following are the disadvantages of\u00a0robotic systems in orthopedics.High initial costs: Robotic systems require substantial investments in terms of equipment and training, potentially increasing the overall cost of procedures.Learning curve: Surgeons need to undergo specialized training to operate robotic systems effectively, and the learning curve can initially extend procedure times.Limited flexibility: Robotic systems follow preplanned trajectories, which might limit the surgeon's ability to make spontaneous adjustments during the procedure.Dependency on technology: Technical malfunctions or software glitches could interrupt surgeries or lead to suboptimal outcomes, highlighting the system's reliance on technology.Time-consuming setup: Setting up the robotic system and registering patient data can add time to the overall surgical process, especially during the learning phase.Complexity of integration: Integrating robotic systems into existing surgical workflows might be challenging and require adjustments in hospital processes.Ongoing maintenance and costs: Beyond the initial investment, robotic systems require maintenance, software updates, and potential hardware upgrades, leading to ongoing costs.Surgeon-support collaborationA fundamental tenet of understanding robotics in orthopedics is that it augments, rather than supplants, the role of surgeons. Robotic systems are invaluable tools, furnishing real-time insights, haptic feedback, and unparalleled visualization during procedures. Surgeons retain complete control while benefiting from the precision and data-driven guidance offered by the robotic platform . This coPostoperative rehabilitationThe impact of robotics resonates beyond the confines of the operating room, extending to the rehabilitation phase. Robotics-assisted rehabilitation devices, including exoskeletons and motion-capture systems, are revolutionizing how patients regain mobility and strength after orthopedic procedures . These dChallenges and ethical considerationsWhile integrating robotics into orthopedic healthcare holds great promise, it concurrently presents challenges and ethical considerations. The initial expenses associated with procuring and implementing robotic systems can be substantial, engendering concerns about accessibility and healthcare inequities. Furthermore, specialized training to proficiently operate these systems necessitates ongoing education and skill development investments. Ethical dilemmas arise in cases where the equilibrium between human expertise and robotic assistance is at issue. Striking the right balance between surgeon intervention and robotic autonomy necessitates meticulous deliberation. The focus should invariably remain on safeguarding patients\u2019 well-being and ensuring that the benefits of automated technologies outweigh any potential risks.The path aheadAs the realm of robotics in orthopedic healthcare continues its expansion, a proactive and visionary approach is indispensable. Collaborative endeavors involving engineers, medical practitioners, and regulatory authorities are pivotal in refining existing technologies and conceiving novel solutions that cater to the evolving needs of patients. Investments in research and development will be instrumental in fostering innovation, thereby propelling the creation of even more sophisticated robotic systems capable of redefining the boundaries of orthopedic care.Integrating robotics into orthopedic healthcare marks a watershed moment in the medical arena. Its precision, personalization, and minimally invasive approach reshape the landscape of orthopedic procedures, offering patients renewed hope and an enhanced quality of life. As the medical community, policymakers, and technology innovators navigate the challenges and ethical considerations, the collective responsibility lies in shaping a future where robotics and human expertise harmoniously converge, redefining the horizons of orthopedic healthcare. With each surgical procedure and rehabilitation session, robotics propels us closer to a world where musculoskeletal conditions are not merely treated but unequivocally conquered."} +{"text": "To describe clinical features and the course of a case of non-necrotizing herpetic retinitis secondary to Varicella zoster virus (VZV).A single case report documented with multimodal imaging.A 52-year-old female patient with a past medical history of diabetes mellitus who presented with painful red right eye (OD). Ophthalmic examination showed perilimbal conjunctival nodule, granulomatous anterior uveitis, sectoral iris atrophy and increased intraocular pressure. Fundus examination in OD revealed posterior multifocal retinitis. Left eye examination was unremarkable. Polymerase chain reaction (PCR) of aqueous humor sample confirmed the presence of VZV DNA. Systemic antiviral therapy allowed the improvement of intraocular inflammation and disappearance of the retinal non necrotizing retinitis after one year of regular follow-up.Non-necrotizing retinitis is an underdiagnosed form of VZV ocular infection. Herpesviridae are common worldwide. Among the spectrum of viral retinitis, acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN), and Cytomegalovirus (CMV) retinitis are the most severe and sight threatening viral infections [Viral infections due to fections . Besidesfections . The purA 52-year-old female with a past medical history of diabetes mellitus, presented with progressive pain, redness and vision loss of the right eye (OD). Her best corrected visual acuity (BCVA) in OD was 20/200 and 20/20 in the left eye (OS). Anterior segment examination of OD showed a perilimbal nodular conjunctival lesion, granulomatous anterior uveitis with sectoral iris atrophy Fig.\u00a0. IntraocCase reports of NNHR have been described in five patients with positive test results for HSV or VZV in AH who had non-necrotizing retinitis consisting mainly of vasculitis, papillitis, or vitritis . Other cPCR was shown to be a powerful technique that allows detection of small quantities of DNA and RNA in ocular fluids. Various infectious agents can be detected with high specificity and sensitivity, including viruses. Results of PCR analysis of ocular fluids, being available within 24 to 48\u00a0h, have greatly improved the diagnosis of ocular viral infections, particularly those caused by human herpesviruses. AH analysis was contributory in 86.4% of patients with necrotizing viral retinopathies . BodaghiThe viral retinitis described in our patient is different from most cases of atypical viral retinitis reported in the literature, but resembles the cases reported by Hazirolan et al., with retinal lesions that are smaller and focally situated at the posterior pole without progression with antiviral treatment .The underlying reason for the variable clinical manifestations and severity of herpetic posterior uveitis is unknown but could be, in addition to pathogen-related factors, influenced by the variation in patients\u2019 immune capacity. Bodaghi et al. hypothesized that necrotizing herpetic retinitis were due to an intracellular presence of the virus with subsequent cytopathic damage, whereas the NNHR were assumed to be associated with tissue damage based on immunological processes . WensingHazirolan et al. suggested that viral retinopathies might constitute a continuous spectrum of diseases, which clinical presentations depend on the patient\u2019s immune status. Our patient, as well as theirs, with focal posterior non-necrotizing viral retinitis may be located at the starting point of the spectrum of herpetic retinopathies and constitute the mildest form of the disease . HoweverA remission was obtained in all cases after reaching the proper etiological diagnosis and initiating antiviral treatment. Oral acyclovir is mostly used for 6\u00a0weeks , but thiAlbert et al. reported several recurrences after arrest of antiviral treatment, it was the first case of anterior uveitis recurrence after NNHR described in the literature . Long-stFuture studies including a larger number of NNHR patients could reveal characteristics we were unable to identify here. The differential diagnosis of atypical viral retinitis is difficult clinically as it can mimic various other retinal conditions. In agreement with the previous studies, we propose viral analysis of ocular fluids in patients with retinitis, even in the absence of retinal necrosis, before initiation of immunomodulatory therapy and/or in those patients whose symptoms worsen while undergoing immunomodulatory treatments.Varicella zoster virus can cause a wide spectrum of clinical manifestations ranging from severe ARN to slow-progressing necrotizing and non-necrotizing types of inflammation. Non-necrotizing herpetic retinitis are currently underdiagnosed. PCR analysis of ocular fluids along with multimodal imaging could contribute to the confirmation and thus an earlier recognition of the diagnosis and the initiation of appropriate therapy."} +{"text": "A review exploring biological, chemical, and physiological processes that occur between aboveground plant components and belowground (rhizosphere) networks that may be altered due to waterlogged conditions. Above- and belowground linkages are responsible for some of the most important ecosystem processes in unmanaged terrestrial systems including net primary production, decomposition, and carbon sequestration. Global change biology is currently altering above- and belowground interactions, reducing ecosystem services provided by natural systems. Less is known regarding how above- and belowground linkages impact climate resilience, especially in intentionally managed cropping systems. Waterlogged or flooded conditions will continue to increase across the Midwestern USA due to climate change. The objective of this paper is to explore what is currently known regarding above- and belowground linkages and how they impact biological, biochemical, and physiological processes in systems experiencing waterlogged conditions. We also identify key above- and belowground processes that are critical for climate resilience in Midwestern cropping systems by exploring various interactions that occur within unmanaged landscapes. Above- and belowground interactions that support plant growth and development, foster multi-trophic-level interactions, and stimulate balanced nutrient cycling are critical for crops experiencing waterlogged conditions. Moreover, incorporating ecological principles such as increasing plant diversity by incorporating crop rotations and adaptive management via delayed planting dates and adjustments in nutrient management will be critical for fostering climate resilience in row-crop agriculture moving forward. Above- and belowground linkages have long been identified as critical for numerous ecological processes in both natural and managed systems . The mosGlobal change biology influences above- and belowground interactions, altering chemical, biological, and physiological processes and overall plant survival in natural landscapes. Climate stress can drastically alter biogeochemical cycles due to shifts in biomass allocation, whereby plants often allocate more resources belowground . From a 2 of land globally had a greater rate of mycorrhizal colonization, greater alkaline phosphomonoesterase-producing bacteria, and greater overall abundance of bacterivorous nematodes relative to the native species in a mixed polyculture community. This demonstrates that invasives are able to exploit available nutrients by fostering bacteria\u2013nematode interactions more efficiently than their counterpart native species. As climatic extremes such as flooding and drought increase, exploitation of resources and alteration of chemical and biological processes by invasive species will only continue , though the degree of the flooding effect was greater for some taxa than others suggesting variability in their tolerance levels . Successful weed control in corn was determined to need 5\u201310 cm precipitation within 15 d of application to effectively incorporate herbicides and facilitate \u00aduptake by weeds or winter barley (Hordeum vulgare) should be considered. These crops will all be in the ground with living roots during the winter months prior to any extreme precipitation that might impact the growing season. Small-seeded brassica species such as camelina, carinata, and most recently oilseed pennycress may also have utility as a winter annual option. Inclusion of these species into rotations with altered growth habits, nutritional content, and low C:N components may further influence above- and belowground cycling dynamics. Extending crop rotations and including three or more species often enhances soil C accumulation has been developed and marketed as Perennial Kernza\u00ae. Kernza has been shown to drastically reduce nitrate leaching and improve soil health . The goal of perennial grain production is to develop a crop that can compete with annual crops but delivers ecosystem services like perennials found in nature due to deep and extensive root systems. For example, intermediate wheatgrass , though it is unclear ultimately how or when these webs will begin to stabilize and what the ultimate influence will be on the ecosystem. Species shifts in weed populations are anticipated, and existing methods for control may be less effective under extreme weather conditions. Adaptive management in row-crop agriculture, including increased biodiversity and perenniality that bolsters trophic interactions and nutrient balance, will be critical within flooded agroecosystems to mitigate the level of destabilization that is anticipated. Furthermore, we have demonstrated major areas in research especially in regard to rhizosphere processes, including plant\u2013microbe interactions that may foster climate resilience within cropping systems. More research addressing both above- and belowground responses to flooded conditions and how these influences crop productivity and ecosystem function within agroecosystems is needed. Lastly, breeders should consider above- and belowground linkages when identifying key traits for flood-tolerant cultivars."} +{"text": "Nature depicted the genomic differences between late-stage treated metastatic cancers and early-stage untreated primary cancers via a pan-cancer whole-genome sequencing (WGS) analysis.1 This study characterizes unique features of metastatic solid tumors and provides a valuable resource for further investigating tumor evolution and treatment resistance.Recently, a study by Edwin Cuppen\u2019s group published in 2 about 90% of cancer-related death can be attributed to advanced metastatic diseases, and unfortunately, most are incurable by aggressive treatment regimes.3 Therefore, it is important to identify genome differences between metastatic and primary tumors and evaluate their influence on treatment resistance. This may help in understanding and leveraging therapeutic interventions, thus to create more effective therapeutic regimens. The study by Edwin Cuppen and colleagues established a harmonized WGS dataset of 7108 tumor samples from 71 cancer types, including more than 4700 metastatic cancer samples from Hartwig Medical Foundation (Hartwig) dataset and more than 2300 untreated primary cancer samples from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium , including single-base substitutions (SBSs), double-base substitutions (DBSs) and indels (IDs). This result indicates that TMB does not inevitably reflect the status of cancer progression, and the entire mutation spectrums are formed before or during primary cancer progression. Further comparison of mutational process activity revealed the existence of exogenous (such as exposure to platinum or radiation-based treatments) and endogenous (such as increase in APOBEC and SBS1 mutation burden) mutational processes that generate TMB differences. By investigating the divergence of SBS1 mutation burden in detail, the authors revealed a highly cancer type-specific SBS1 mutation burden per age. The majority of tumor types showed a prominent enrichment of SBS1 mutations along with age in both primary and metastatic lesions, however, 4 cancer types only displayed increased SBS1 mutation burdens in metastatic cohorts in an age-independent manner.Compared with TMB, an elevated frequency of structural variants (SVs) was noticed in most tumor types included in metastatic cohorts. The underlying genomic instability signatures linked to this phenomenon are TP53 alterations and genome ploidy, which exhibited significant pan-tumor correlations with duplications and deletions, thus likely to play an essential role in SV increase in metastatic cancers. In addition, the researchers found a modest overall increase of driver gene alterations in patients with metastatic cancers. The majority of genetic drivers enriched by cancer metastasis were tumor-type specific, including some well-known driver genes related to resistance to anticancer treatments, whereas 3 genetic drivers exhibited significant enrichment in metastatic cohorts across various cancer types, suggesting that changes in such genes may promote invasiveness via interfering with tumorigenesis hallmarks of pan-cancer. When comparing therapeutically actionable variants for each type of cancer, the authors found that the metastatic cohort had an overall higher proportion of patients with such variants, although the distribution was highly cancer type specific.The presence of treatment-resistant genetic drivers in advanced cancers led the authors to identify therapeutically enriched drivers (TEDs) that were either treatment enriched or exclusively found in a treatment-specific and cancer type-specific manner. Ultimately, 61 TEDs related to 33 therapeutic groups were identified, and most top hits were well-established resistant drivers to anticancer treatments. Notably, TP53 alterations were found to be frequently relevant with multiple treatment resistances, indicating such variants are potential predictive markers for augmented cancer plasticity and aggressiveness instead of the resistance mechanism for a specific tumor type. Overall, TEDs could be found in 53% of patients in metastatic cohort. After excluding TEDs, the raw difference between primary and metastatic tumors will be reduced by 36% in the number of drivers per sample, suggesting that a significant portion of the metastatic-enriched drivers are very likely linked to anticancer treatment resistance.5 Despite the aforementioned contributions, this study was also limited by the usage of distinct laboratory workups and sequencing procedures for the tumor samples from different datasets and the finite sample sizes of some cancer cohorts. Therefore, it is important to enlarge cancer cohorts and further uniform sample collation and sequencing processes to facilitate and validate the present understanding of cancer development. Moreover, genomic alterations are unable to fully elucidate cancer metastasis and resistance, and using the information from tumor microenvironment and additional cancer omics will also be essential for further anatomizing and better understanding the underlying mechanisms.Taken together, this study confirmed previous findings observed in certain cancer types and provided novel biological insights into the unique characteristics of metastatic cancers and their genomic differences with primary tumors, such as low intratumor heterogeneity, high genomic instability and elevated SVs. Nevertheless, the extent of genetic differences between metastatic and primary cancers varied significantly across cancer types and was affected by anticancer treatment exposure. Among the 23 tumor types, breast, clear cell renal cell, thyroid, prostate and pancreatic neuroendocrine cancers showed strong transformation in genomic landscape in advanced stages. In addition, this study provides a valuable resource for further investigating other aspects of cancer progression, such as the study on genetic immune escape alterations between metastatic and primary cancers conducted also by Edwin Cuppen\u2019s group recently."} +{"text": "Biomaterials offer numerous opportunities to preserve spheroid function and guide spheroid behavior by tailoring the local microenvironment.Spheroids are three-dimensional cell aggregates that mimic fundamental aspects of the native tissue microenvironment better than single cells, making them a promising platform for the study of tissue development and therapeutics. Spheroids have been investigated for decades as models in cancer research, yet we have only just scratched the surface of their potential clinical utility in cell-based therapies. Like many cells, spheroids commonly exhibit a loss of key attributes upon implantation, motivating the need for strategies to regulate their function Systemic or localized injection of cells results in poor survival and inconsistent behavior due to the lack of instructional cues or aberrant signaling from the diseased microenvironment. As an alternative to monodisperse cells, spheroids are three-dimensional cell aggregates that retain key aspects of the cellular microenvironment including cell-cell interactions, engagement with an endogenous cell-secreted extracellular matrix (ECM), and gradients in signaling that result in heterogeneous nutrient distribution that better recapitulate native tissues. Furthermore, spheroids secrete substantially more endogenous trophic factors that promote neovascularization and influence the inflammatory microenvironment Biomaterials have an essential role in the development and application of spheroid-based technologies. Beyond materials-based approaches for spheroid formation, entrapment of spheroids in tunable biomaterials has emerged as a promising strategy to instruct spheroid function and differentiation and regulate cell migration from the spheroid into the surrounding tissues. The synergistic effects of biomaterial properties and spheroid signaling, although not fully understood, directly influence cytokine production, cell spreading and migration, viability, and differentiation. Thus, intelligent selection of a biomaterial is required and should be taken into consideration to instruct spheroid behavior and achieve the desired therapeutic effect.2Our group has predominantly studied spheroids formed of mesenchymal stromal cells (MSCs) to potentiate their secretion of regenerative trophic factors and guide their direct contributions to tissue formation. Spheroids of other cell types are under investigation, and key factors such as cell type and spheroid diameter are intrinsically related to their desired application. Nonetheless, the interplay of additional environmental cues can affect spheroid function and instruct behavior for specific applications. Spheroid function is regulated by the biophysical properties of the spheroid carrier material or entrapment of other components within the spheroid to guide cell function and differentiation.Spheroid function has been widely controlled by encapsulation in engineered hydrogels and controlling biophysical properties such as adhesivity, stiffness, and viscoelasticity. Alginate hydrogels covalently modified with cell-adhesive RGD (Arg-Gly-Asp) peptides are widely used as model systems and vehicles for cell transplantation. RGD-modification regulated cell adhesion, outgrowth, and tissue formation using MSC spheroids e.g., Yes-associated protein, YAP). These findings demonstrate the potential of cell-based materials to increase biomineralization without the need for exogenous osteoinductive cues or growth factors. Recent advances in macromolecular crowding approaches may open the door to improve growth factor retention and influence other relevant ECM properties such as protein content or fiber alignment Instructive materials can also be incorporated within the spheroid itself to guide cell function. As spheroids initially lack an endogenous ECM, our group formed spheroids with an engineered, MSC-secreted ECM to activate integrin signaling In many applications, it may be necessary to leverage biomaterials that provide structure or regulate spatial patterning to achieve desired tissue formation using spheroids. For example, silicon nanowires were applied to promote differentiation of human induced pluripotent stem cell spheroids (hiPSC) into hiPSC-derived cardiomyocytes for cardiac repair 32) that promote angiogenesis, modulate the inflammatory microenvironment, and stimulate wound repair, and MSC spheroids secrete more trophic factors than monodisperse MSCs. MSC spheroids entrapped in fibrin hydrogels with higher elastic moduli (\u223c45\u00a0kPa) secreted significantly more VEGF, while PGE2 secretion was greater for spheroids in softer gels (\u223c5\u00a0kPa) The MSC secretome is a potent collection of bioactive factors that stimulates host cell migration and tissue repair. MSCs secrete endogenous factors such as vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE4Spheroids have enormous promise for use as building blocks for tissue regeneration. Although initial applications injected spheroids into diseased tissues without supportive biomaterials, substantial evidence confirms the capacity for material-driven approaches to potentiate spheroid function. However, we have yet to create materials that accurately model the complex characteristics and behavior exhibited by many human tissues. The use of biomaterials that mimic the biophysical properties of native tissues will increase the therapeutic potential of spheroids in clinical applications.via ultrasound, light, or delivery of fast-reacting small molecules that rapidly stiffen or weaken the biomaterial. Just as spheroids better recapitulate native tissues by increasing complexity from conventional 2D culture systems, we must embrace the same logic of increased complexity and multilayer design when developing biomaterials. This is made more challenging by the need to maintain biocompatibility. Nonetheless, new materials will propel the effective instruction of cell spheroids and establish them as a powerful tool for regenerative medicine, drug discovery, and disease modeling (The development of biomaterials possessing gradients in stiffness, composition, and soluble cues that imitate the heterogeneity of native tissues is a step in the right direction. These attributes can be enabled by chemistries that facilitate non-invasive tunability modeling .Fig. 1BiThe authors declare the following financial interests/personal relationships which may be considered as potential competing interests:J. Kent Leach reports financial support was provided by UC Davis Health System. David H. Ramos Rodriguez reports financial support was provided by UC Davis Health System."} +{"text": "Neuroinflammation is a key secondary event after spinal cord injury (SCI) and can increase barriers to regeneration, leading to various neurological disorders. Infiltrated hematogenous innate immune cells into the injured site are considered the main effector cells of the inflammatory responses after SCI. Glucocorticoids were the standard of care for spinal cord trauma for years due to their anti-inflammatory properties yet were also associated with unwanted side effects. While the administration of glucocorticoids is controversial, immunomodulatory strategies that limit inflammatory responses provide the potential therapeutic approaches to promote functional regeneration following SCI. Herein, we will discuss emerging therapeutic strategies to modulate inflammatory responses to enhance nerve recovery after spinal cord trauma. Traumatic Spinal Cord Injury (SCI) results in an initial primary injury, followed by secondary events including ischemia, anoxia, and excitotoxicity for the first minutes, hours, and days after injury \u20134. As a Various gene therapy-based approaches have been introduced in the last twenty years and continue to be utilized as a powerful therapeutic approach to alter or correct defective genes for the treatment of multiple diseases ,13. WhilNanomedicine employing polymeric nanoparticle (NP) has received significant attention due to its inherent therapeutic potential to modulate immune responses to cure inflammatory responses-mediated disorders including SCI \u201322. PrevStem cells can proliferate and differentiate into any cell type present in the body. Considering their therapeutic potential and abilities of self-renewal and differentiation, stem cells are widely used following SCI ,32. In aImmunotherapeutic approaches for the treatment of SCI have the capacity to indirectly and/or directly enhance functional recovery. Although many preclinical studies have demonstrated therapeutic effects of immunomodulatory factors on SCI, the introduction of these strategies in the clinic faces various limitations for SCI victims. Further investigations will be required to assess how each of the immunomodulatory factors can be employed synergistically to reprogram the immune system to promote functional recovery after SCI while limiting life-threatening side effects."} +{"text": "Background: Overall, ~12% of outpatient visits result in an antibiotic prescription, and 30% of those prescriptions are inappropriate. Behavioral nudges help influence practitioner behavior. We hypothesized that peer comparison combined with a behavioral nudge would influence prescribers to reduce antibiotic prescriptions and improve antimicrobial stewardship in the outpatient setting. We pilot-tested this intervention in outpatient primary care clinics associated with a large Veterans Affairs (VA) medical center. Methods: We conducted a clustered randomized controlled trial of 12 community-based outpatient clinics. All practitioners in the intervention arm received quarterly comparative feedback reports and, when indicated, quarterly patient alert letters. Comparative feedback reports gave personalized feedback about antibiotic prescriptions for upper respiratory tract infections, comparing the recipient\u2019s antibiotic prescriptions to the average for all practitioners at the primary care clinics included in our study. Patient alert letters notified practitioners to patients in their panel with recently detected Clostridioides difficile or resistant organism and their antibiotic exposures. We assessed outpatient visits during the preintervention period (April\u2013September 2020), the intervention period (October 2020\u2013September 2021), and the postintervention period (October 2021\u2013September 2022). A mixed-effects logistic regression model predicting antibiotic prescriptions compared the arms across these periods. Results: The outpatient populations observed in the intervention and control arms were similar during each phase of the study. Prior to the intervention, the average proportion of visits with an antibiotic prescription was lower among clinics in the intervention arm . This difference broadened slightly during the intervention period and the postintervention period . Throughout the study, clinics in the intervention arm typically used more doxycycline and azithromycin and less amoxicillin-clavulanate and sulfamethoxazole-trimethoprim compared to clinics in the control arm. . In the 6-month preintervention period, which coincided with the early phase of the COVID-19 pandemic, antibiotic prescriptions in the intervention compared to control clinics were similar. During the intervention and postintervention periods, the proportion of visits with an antibiotic prescription remained steady for clinics in the intervention arm and increased for those in the control arm. These results suggest that this pilot study using a low-intensity intervention consisting of comparative feedback reports and patient alert letters was successful in influencing the antibiotic prescribing behavior of primary care clinicians practicing in community-based outpatient clinics affiliated with a VA medical center.Financial support: This study was funded by Merck.Disclosures: None"} +{"text": "Cervical cancer is the fourth-leading cause of cancer incidence and death among females according to Global Cancer Statistics 2018.This video demonstrates the fertility-sparing surgery procedure containing radical trachelectomy and pelvic lymphadenectomy with bilateral ascending branches of uterine arteries preservation. The patient was a 34-year-old woman diagnosed with International Federation of Gynecology and Obstetrics stage IB1 moderately differentiated squamous cervical cancer who expressed a strong desire for reproduction. After sufficient consultation, she decided to receive a fertility-sparing treatment protocol. This video highlights the feasibility of sufficiently dissecting paracervical structures and exposing uterine artery branches with complex procedures and no assistance via TU-LESS. We adopted a simplified uterine manipulator, which minimized the squeezing and injury to the cervix, to assist exposure of the surgical field. Resection of the cervix was accomplished transvaginally with a cold knife to ensure sufficient margin. Pathology examination of surgical margin, lymph node specimens, and lymphovascular invasion were negative. The umbilical incision was closed by Zheng\u2019s anchor suturing technique to prevent incisional complications and improve cosmetics.Minimally invasive surgery is safe and effective for fertility-sparing without compromising oncologic outcomes, especially in patients with a tumor size <2\u2009cm."} +{"text": "Bipolar patients (BP) frequently have cognitive deficits, that impact on prognosis and quality of life. Finding biomarkers for this condition is essential to improve patients\u2019 healthcare. Given the association between cognitive dysfunctions and structural brain abnormalities, we used a machine learning approach to identify patients with cognitive deficits.The aim of this study was to assess if structural neuroimaging data could identify patients with cognitive impairments in several domains using a machine learning framework.Diffusion tensor imaging and T1-weighted images of 150 BP were acquired and both grey matter voxel-based morphometry (VBM) and tract-based white matter fractional anisotropy (FA) measures were extracted. Support vector machine (SVM) models were trained through a 10-fold nested cross-validation with subsampling. VBM and FA maps were entered separately and in combination as input features to discriminate BP with and without deficits in six cognitive domains, assessed through the Brief Assessment of Cognition in Schizophrenia.The best classification performance for each cognitive domain is illustrated in Table 1. FA was the most relevant neuroimaging modality for the prediction of verbal memory, verbal fluency, and executive functions deficits, whereas VBM was more predictive for working memory and motor speed domains.Overall, the tested SVM models showed a good predictive performance. Although only partially, our results suggest that different structural neuroimaging data can predict cognitive deficits in BP with accuracy higher than chance level. Unexpectedly, only for the attention and processing speed domain the best model was obtained combining the structural features. Future research may promote data fusion methods to develop better predictive models.None Declared"} +{"text": "Sickle cell disease (SCD) is a prevalent inherited hemoglobin disorder encompassing a cluster of congenital hemolytic anemias, each distinguished by the prevalence of sickle hemoglobin (HbS) . Anemia,Numerous novel agents are currently undergoing clinical development or have been introduced into clinical practice. In addition, the attempts to reduce long-term complications and enhance quality of life continue. This Special Issue aims to delineate both our current understanding and future options in SCD. All articles submitted to this Special Issue underwent a meticulous peer review process. Ultimately, two articles, two brief reports and one review were published. These five manuscripts are discussed below.(i)Forte and colleagues provided important data on the timely issue of COVID-19 and SCD, updating outcomes after two years of the pandemic .(ii)Tsitsikas and colleagues presented the rate of dental extractions in SCD, providing up-to-date knowledge on an understudied complication .(iii)Biswas and colleagues reviewed the role of mitochondria as an emerging consequential in SCD, highlighting pathophysiological and therapeutic challenges .(iv)Kuo and colleagues reported that thromboprophylaxis reduced venous thromboembolism in SCD patients with central venous access devices, studying a large retrospective cohort .(v)Gavriilaki and colleagues studied the immune response of adult SCD patients after their vaccination against COVID-19, providing the experience of a Greek center.Considering the multi-faceted challenges of SCD, we hope that this Special Issue will inspire researchers and clinicians to continue their explorations into novel advances in this field ."} +{"text": "Artificial intelligence (AI) algorithms have been applied in abundant medical tasks with high accuracy and efficiency. Physicians can improve their diagnostic efficiency with the assistance of AI techniques for improving the subsequent personalized treatment and surveillance. AI algorithms fundamentally capture data, identify underlying patterns, achieve preset endpoints, and provide decisions and predictions about real-world events with working principles of machine learning and deep learning. AI algorithms with sufficient graphic processing unit power have been demonstrated to provide timely diagnostic references based on preliminary training of large amounts of clinical and imaging data. The sample size issue is an inevitable challenge for pediatric oncology considering its low morbidity and individual heterogeneity. However, this problem may be solved in the near future considering the exponential advancements of AI algorithms technically to decrease the dependence of AI operation on the amount of data sets and the efficiency of computing power. For instance, it could be a feasible solution by shifting convolutional neural networks (CNNs) from adults and sharing CNN algorithms across multiple institutions besides original data. The present review provides important insights into emerging AI applications for the diagnosis of pediatric oncology by systematically overviewing of up-to-date literature. The exponentially growing knowledge and techniques have explored innovative perspectives for multi-layered diagnoses in pediatric oncology that the expectation of patients and their families have been developed for their specific situation to receive optimized care instantly and comprehensively. Artificial intelligence (AI) strategies can tackle enormous amounts of original data in a short time to solve complex tasks with high accuracy , 2. PhysAI has developed into various computer-assisted theories and is mainly implemented with working principles of machine learning (ML) and deep learning (DL). AI algorithms fundamentally capture data, identify underlying patterns, achieve preset endpoints, and provide decisions and predictions about real-world events. ML, as a main subset of AI, indicates a different flowchart compared with traditional hard-coded software programs which apply algorithms to construct predictive models dynamically by training large amounts of historical data. DL, as a growing aspect of AI, represents benefits in learnable weights and high efficiency with minimal pre-processing based on the structure of convolutional neural networks (CNNs) with multiple inter-connected layers. DL-CNNs composed of multiple stacked CNN layers have advantages in accurate, faster, vendor-independent processing compared with ML algorithms applied previously . NotablyThe application of AI not only makes full use of the various aspects of clinical diversity but also helps to address the current lack of objectivity and universality in expert systems . The appDespite the current AI advancements, the sustainable development of health AI tools relies on the availability of large datasets with strict quality control . SeveralThe prosperous development of AI techniques promotes numerous potential applications in pediatric oncology with two main bottlenecks for successful utilities, including the need for large data entry and a strong graphic processing unit (GPU) with appropriate computer and memory power. AI algorithms provide timely references based on large amounts of clinical and imaging data and sufficient GPU power . MeanwhiClinicians make clinical diagnoses depending on their professional knowledge and clinical experience through signs, symptoms, laboratory, and imaging examinations. It seems hard to guarantee diagnostic accuracy and consistency by dealing with abundant and multidimensional data from the human brain. The AI algorithms have advantages in learning and training vast amounts of data and integrating it into a certain outcome in a very short time, which allows efficiency and effectiveness of computer-aided diagnosis (CAD) in clinical practices. DL algorithms have recently made significant progress in extracting and processing information from medical images, which have been applied in various medical tasks extensively not only in radiology and pathology with satisfactory performance comparable to or even superior to that of human experts. Notably, DL algorithms could identify underlying information from medical images associated with tumor diagnosis . The AI A performance comparison of diagnosis in pediatric hematological malignancies using AI strategies is shown in A performance comparison of diagnosis in pediatric intracranial tumors using AI strategies is shown in versus non-tumor/hemorrhagic and classify subtypes of brain tumors.Attallah , 43 propversus benign diseases [AI techniques have been applied in the diagnosis of pediatric extracranial tumors, mainly including soft-tissue and bone tumors . For bondiseases , 54. TheZhang et al. and FranAI-based principles have been used for the detection and segmentation of pediatric malignant tumors. For example, Wu et al. used a rH3 K27M amplification status in children with midline glioma with significantly greater accuracy ranging from 0.788 to 0.867 than prediction by chance. Giwa et al. [The AI algorithms have represented strengths in detecting tumor patterns by identifying underlying genetic and molecular characteristics associated with specific macroscopic tumor features based on medical images and/or high-throughput data. Zhao et al. reporteda et al. applied The application of AI technology faces some important challenges that must be resolved to ensure its use in pediatric cancer diagnosis . For exaAI techniques have revolutionized the diagnostic field of oncology. Although AI approaches have been widely implemented in adult tumors, specialized applications of AI algorithms in childhood cancer are still limited probably attributed to the insufficient amounts of available data sets. There are limited opportunities to transfer well-trained CNN architectures built on adults into pediatric oncology few CNNs are directly generalizable from adults to children. Therefore, it\u2019s warranted urgently to develop dedicated AI algorithms applied in pediatric oncology. Although the data sets of pediatric oncology are not large enough to perform standardized DL analysis in medical imaging , the int"} +{"text": "The purpose of this report is to provide a comprehensive account of an exceptional case involving the presentation of congenital rubella syndrome (CRS) in a newborn. Furthermore, it aims to document the successful regression of CRS through medical treatment alone. We present the case of a five-day-old infant who was referred to our facility as a CRS case. The patient presented with bilateral white corneal opacity, which was observed shortly after birth. The mother was diagnosed as rubella-positive during pregnancy. Upon the initial examination under anesthesia, both eyes exhibited central white corneal opacity accompanied by large intrastromal cysts. Although a few breaks in Descemet's membrane were observed in both eyes, there were no signs of vascularization or the presence of iridocorneal or lenticular-corneal adhesions. After undergoing medical treatment consisting of topical sodium chloride and steroids, the cysts in both eyes completely regressed. Subsequently, the patient underwent penetrating keratoplasty to further address the dense scar. This case enhances our comprehension of ophthalmological complications associated with CRS and provides valuable insights into alternative therapeutic approaches for corneal stromal cysts. Congenital rubella syndrome (CRS) is a prevalent congenital infection known for its wide range of severe ophthalmic and systemic complications . It typiA five-day-old male infant with a confirmed diagnosis of CRS was referred to our facility for examination due to the presence of white corneal opacification in both eyes. The patient's mother also had a confirmed diagnosis of reactive rubella during pregnancy. Upon the initial examination under anesthesia, both eyes exhibited central white corneal opacity along with large intrastromal cysts. Although a few breaks in the Descemet membrane were identified in both eyes, no signs of neovascularization or iridocorneal or lenticular-corneal adhesions were observed Figure . UltrasoCRS is a prevalent congenital infection characterized by various clinical manifestations, including heart defects, hearing impairments, and ophthalmological abnormalities . The mosIn conclusion, this case study brings attention to the infrequent presentation of corneal stromal cysts in a newborn with CRS, emphasizing the importance of identifying uncommon ophthalmological manifestations associated with CRS. The effective nonsurgical management of corneal stromal cysts demonstrates a noninvasive treatment option. This case contributes to a broader understanding of ophthalmological complications and provides valuable insights into alternative therapeutic approaches for corneal stromal cysts."} +{"text": "The objective was to study clinical cases and understand the link betweencesarean section scar defect with hydrometra and secondary infertility. Aretrospective case series from an assisted reproductive center and infertilitytreatment clinic in the United Arab Emirates. We had five patients withsecondary infertility diagnosed with cesarean section scar defect withpersistent hydrometra based on high resolution transvaginal ultrasoundassessment. The patients underwent surgical repair for the cesarean section scardefect followed by infertility treatment. Transvaginal ultrasound examinationshowed a normal endometrial cavity with triple lining endometrium and absence ofhydrometra; and clinical pregnancy was the main outcome measure. Surgicalcorrection of cesarean section scar defect was successfully performed in thecases presented. The patients had their fertility restored. Clinical studiesrevealed that cesarean section scar defect may lead to abnormal uterinebleeding, dysmenorrhea, pre-/post-menstrual spotting, heavy or prolonged menses,pelvic pain and secondary infertility. Theoretically, an inflammatory response,such as a wound healing process in the uterus due to hydrometra associated withscar defect may impair embryo implantation. The clinical case studies presentedhere are based on the correct diagnosis of the cesarean section scar defect withhydrometra and its successful surgical repair. The patients in our study hadtheir symptoms resolved and attained clinical pregnancy. The number of cesarean sections (C-section) performed is steadily increasing acrossthe world .C-section scar defect can be visualized using transvaginal ultrasound andhysteroscopy . ThisfiThere are only a few studies on the clinical association between secondaryinfertility and C-section scar defect .Repair of C-section scar defect is done by using a minimally invasive surgical methodsuch as hysteroscopy or/and laparoscopy and vaginal procedures ; presented to Al Ain Fertility Centerbetween January 2016 and December 2020. Exclusion criteria:Infertility cases presented with C-section scar defect without hydrometra.Clinical characteristics of patients: all the patients were agedbetween 28 to 41 years who underwent surgical management for cesarean sectionscar defect with hydrometra to treat secondary infertility.Diagnosis: Symptoms related to cesarean section scar defect were reported. Clinical diagnoses were confirmed by transvaginalultrasound imaging. Surgical Treatment: All the surgicalprocedures were performed by hysteroscopy and laparoscopy as per explainedbelow: - Hysteroscopic resection: The uterine cavity isdistended using NaCl solution. Positive pressure is ensured with an automaticpressure infuser. The inferior and superior edges of the defect are resectedusing a cutting loop and coagulation is performed on the thinnest part of thescar approval was obtainedbefore the beginning of the study. The data presented are with completeanonymity of published information and the images used are undernon-identifiable category (ultrasound). In addition, careful case-by-caseassessment was made to ensure that content is fully anonymous and presents norisk to confidentiality of the study participants.invitro fertilization (IVF) treatment under standard antagonistprotocol with preimplantation genetic testing , fluid-filled pouch at the scar site due to impaired woundhealing and thinning of the anterior uterine wall , dysmenorrhea, pelvic pain, postmenstrual spotting, adenomyosis,endometriosis, abscess formation, cesarean scar ectopic pregnancy, and infertility demonstrated that 80% of thepatients diagnosed with a C-section scar defect that had surgical treatments(hysteroscopic and laparoscopic isthmoplasty) became pregnant within 24 months anddelivered before 36 months of treatment. In cases of infertility treatment, thereproductive performance after the scar defect correction surgery shows theeffectiveness of the accurate diagnosis and treatment of patients using efficienttechniques , and when no normalendometrial lining can be visualized. Studies postulated various mechanisms by whichscar defect hydrometra may interfere with embryo implantation ("} +{"text": "As previous studies have shown, indications of drugs adjudicated by these RCTs often get expanded m ensues .A combination of patient-specific factors very often acting wholly significant impact on ability to both adhere to and deal with consequences of rising medication counts in patients with CKD. These often take form of sub-optimal medication adherence, worsening cognitive impairment. The latter is both a factor of declining kidney function itself as well as incident on it due to overall frailty. These factors generally makes it challenging to manage medications in CKD patients.Potentially inappropriate medications maintain a bidirectional relationship with polypharmacy, and both share similar unwanted downstream consequences. Restricting the definitional threshold of polypharmacy in chronic kidney disease patients regardless of underlying primary etiology to only Kidney specific medications is key to reliably identifying patient cohorts for directed interventions. To compliment this, and additionally optimize the management of PIMs and polypharmacy in CKD patients, utility of established structural therapeutic frameworks such as pharmacotherapy optimization and or medication therapy management (MTM) may also prove invaluable long term."} +{"text": "Scher,3 This additional risk is not only due to the association of perinatal inflammation with cerebral haemorrhage and white matter injury,4 but also to the neuronal toxicity of supra-physiological serum concentrations of interleukin-1 beta observed in this situation.5 Even in preterm children without severe neonatal brain injury, perinatal inflammation remains independently associated with decreased motor and social abilities at 30 months of corrected age.3Perinatal inflammation exposure represents an additional risk factor for impaired developmental trajectory in preterm infants.6 This identification is crucial to provide individualised early developmental intervention programmes for these infants. Such programmes have been shown to improve motor and cognitive outcomes in preterm children.7EEG is the primary tool for functional evaluation of brain activity in preterm infants hospitalised within the neonatal unit. Serial longitudinal EEG recordings before term age can accurately assess brain maturation in preterm infants, and identify infants with an unfavourable early developmental trajectory.8 Beyond the estimation of discontinuity and amplitude offered by aEEG evaluation, conventional multi-channel EEG provides key information about other network-based brain activity, such as synchrony, frequency, and reactivity.9 It also delivers crucial information on the dynamics of transient endogenous generators occurring through the complex process of brain maturation.9 The two studies included in our systematic review were limited to aEEG analysis and reported inconsistent findings associated with perinatal inflammation exposure.2 Nevertheless, perinatal inflammation led to a modification of EEG frequencies in most of the preclinical studies assessing its effect on foetal sheep EEG, underlying the importance of the quantitative analysis of conventional EEG in the assessment of early brain maturation.2We agree that amplitude-integrated EEG (aEEG) is currently a useful tool to supervise the brain activity of critically ill preterm infants hospitalised in neonatal units that do not have 24/7 access to conventional EEG. However, aEEG provides a limited assessment compared to conventional EEG, particularly in very preterm neonates who do not demonstrate distinguishable sleep-wake cycling before 29 weeks of gestational age.10Conventional multi-channel EEG is essential to assess brain maturation in preterm infants, especially in those exposed to additional developmental risk factors such as perinatal inflammation. The need for a specialist to apply and interpret conventional multi-channel EEG has often been seen as an impediment to its widespread use within the neonatal unit. However, rather than simplifying the process by utilising fewer channels with less information, we believe that modern engineering solutions will allow the widespread introduction of conventional multi-channel EEG in neonatal units. There have been tremendous recent advances in the development of quantitative analysis and machine learning to develop automated algorithms for conventional multi-channel EEG analysis; such automatisation will soon assist in the further introduction of conventional multi-channel EEG beyond specialist centres."} +{"text": "Aim/ObjectiveWithin the dynamic healthcare technology landscape, this research aims to explore patient inquiries within outpatient clinics, elucidating the interplay between technology and healthcare intricacies. Building upon the initial intelligent guidance robot implementation shortcomings, this investigation seeks to enhance informatic robots with voice recognition technology. The objective is to analyze users' vocal patterns, discern age-associated vocal attributes, and facilitate age differentiation through subtle vocal nuances to enhance the efficacy of human-robot communication within outpatient clinical settings.MethodsThis investigation employs a multi-faceted approach. It leverages voice recognition technology to analyze users' vocal patterns. A diverse dataset of voice samples from various age groups was collected. Acoustic features encompassing pitch, formant frequencies, spectral characteristics, and vocal tract length are extracted from the audio samples. The Mel Filterbank and Mel-Frequency Cepstral Coefficients (MFCCs) are employed for speech and audio processing tasks alongside machine learning algorithms to assess and match vocal patterns to age-related traits.ResultsThe research reveals compelling outcomes. The incorporation of voice recognition technology contributes to a significant improvement in human-robot communication within outpatient clinical settings. Through accurate analysis of vocal patterns and age-related traits, informatic robots can differentiate age through nuanced verbal cues. This augmentation leads to enhanced contextual understanding and tailored responses, significantly advancing the efficiency of patient interactions with the robots.ConclusionIntegrating voice recognition technology into informatic robots presents a noteworthy advancement in outpatient clinic settings. By enabling age differentiation through vocal nuances, this augmentation enhances the precision and relevance of responses. The study contributes to the ongoing discourse on the dynamic evolution of healthcare technology, underscoring the complex synergy between technological progression and the intricate realities within healthcare infrastructure. As healthcare continues to metamorphose, the seamless integration of voice recognition technology marks a pivotal stride in optimizing human-robot communication and elevating patient care within outpatient settings. In recent years, the healthcare sector has witnessed significant advancements in technology integration, exemplified by the deployment of informatic robots across various medical settings. Notably, incorporating mobile intelligent guidance robots (IGRs) within outpatient clinics has emerged as a catalyst for enhancing operational efficiency, optimizing processes, and elevating patient experiences . These aIn 2021, we published a comprehensive assessment in Cureus, critically examining the initial implementation of IGRs within an outpatient clinic setting [To address inefficiencies such as frivolous inquiries and childlike interactions, this study involves augmenting the IGR with voice recognition technology. The primary objective of this augmentation is to analyze users' vocal patterns and discern age-related vocal characteristics, thereby enabling the differentiation of age through subtle vocal nuances. This process entails utilizing advanced voice analysis techniques and machine learning algorithms . This apVoice recognition operates on algorithms that evaluate vocal cadences and establish correlations with age-associated vocal attributes. It's crucial to acknowledge that while voice recognition technology possesses inherent limitations that may affect absolute accuracy, it grants the capability to approximate users' ages. By leveraging the IGR's proficiency in comprehending and analyzing conversational context, the robot can glean generational references and contextual cues, thereby facilitating an estimative boundary of the user's age range.Subsequently, in November 2022, an enhanced IGR equipped with voice recognition technology was deployed at the central lobby of an outpatient setting for 20 days, mirroring the temporal framework of the previous 2019 study. Following data accrual, the collected dataset underwent meticulous analysis, focusing on content accuracy and the frequency of successful human-robot interactions. This investigation relied on quantitative and comparative methodologies, comprehensively assessing user inquiries and data efficiencies post-upgrade. The research attempts to pinpoint areas amenable to refinement and offers strategic insights to guide future enhancements.In this study, 101,672 outpatient visits were documented throughout the designated study duration, resulting in 30,301 human-robot interactions transpiring within 20 days. Notably, within this extensive corpus, 22,423 interactions were classified as successful interactions, a criterion defined by the robot's provision of a relevant response to the inquiry presented. Acknowledging that the IGR could not respond to languages other than Mandarin Chinese and English due to inherent programming constraints is imperative. Furthermore, notable categories such as numerically focused queries, inquiries unrelated to the hospital context, childlike interactions, and nuisance inquiries were substantially minimized or systematically omitted from the recorded dataset.Quantitative data comparing the two distinct study periods is presented in Table Characterized by the continuous enhancement of system applications, Figure Compellingly, health triage-related inquiries and appointment issues emerge as the second and third most frequent themes within the top 10 questions. This observation carries implications that resonate with the existing healthcare framework within China. It mirrors the contemporary state of the healthcare landscape wherein the primary health system remains in a formative phase, accompanied by a noteworthy lack of coordination within the broader healthcare infrastructure. Simultaneously, appointment-related concerns underscore the challenges within the appointment scheduling process, potentially reflecting disparities in resource allocation and logistical intricacies.Drawing a comparative lens to the antecedent year 2019, Figure Nevertheless, amid this trajectory of advancement, latent challenges persist. Foremost among these challenges is the constraint of language selection. In a global healthcare landscape where linguistic diversity prevails, the current scope of our informatic robots remains predominantly confined to Mandarin Chinese and English. The necessity for an expanded linguistic horizon aligns with the multifaceted nature of patient demographics and the imperative of inclusivity within healthcare automation.The incorporation of voice recognition technology marks a significant milestone in the domain of informatic robots deployed in outpatient clinics. This innovative augmentation has yielded notable successes, particularly in improving patient-robot interactions. The capacity of voice recognition technology to analyze users' vocal patterns and identify age-related voice characteristics has effectively addressed a crucial communication challenge, facilitating a more tailored and efficient exchange of information between patients and robots . MoreoveOutpatient clinics consistently serve as crucial windows for patients seeking medical care. However, the introduction of informatic robots, while enhancing efficiency, potentially erodes the essential trust inherent in healthcare interactions . PatientMitigating these apprehensions necessitates comprehensive patient education initiatives . Such inBy equipping patients with relevant knowledge, the significance of the interaction is reinforced, reducing the likelihood of frivolous or childlike interactions . Design Future advancements include the integration of machine learning algorithms, which will support continuous learning from patient interactions, thereby refining responses and adapting to evolving patient needs . CarefulInformatic robots possess the potential to catalyze a transformative shift in outpatient clinics, optimizing efficiency and elevating patient care. However, the intricacies associated with their use require careful consideration . A harmoThe successful integration of voice recognition technology into informatic robots has delivered substantial benefits for patient-robot interactions within outpatient clinics. This technology is a promising step toward optimizing healthcare automation by enabling more accurate age differentiation, fostering personalized engagements, and contributing to a growing knowledge base. As the healthcare landscape evolves, voice recognition technology emerges as a cornerstone in the ongoing quest to refine patient care and enrich the human-robot interaction paradigm.In summary, the narrative surrounding the integration of informatic robots within outpatient clinics embarks on an evolutionary trajectory characterized by dynamic refinement. This narrative underscores the intricate nexus of technology and healthcare services, resonating with repercussions transcending societal and clinical paradigms. As progress is championed, the pursuit of enhancing the precision of patient inquiries resonates with overarching themes of technological amalgamation. Simultaneously, a steadfast commitment to embracing linguistic diversity epitomizes the ethos of inclusivity intrinsically linked to healthcare. Each advancement is an echelon of progress within this narrative, propelling unwavering dedication toward shaping a more nuanced and responsive healthcare future."} +{"text": "Long-acting injectable antipsychotics (LAIAs) are currently the most effective alternative for patients with schizophrenia who exhibit poor adherence. LAIAs can lead the course of treatment with the potential to increase adherence in schizophrenia treatment.Present the results of a network metaanalysis on the comparative efficacy of LAIs in schizophrenia.Included trials of adults with schizophrenia compared the efficacy of LAI vs LAI or placebo through the Positive and Negative Syndrome Scale (PANSS). Efficacy was evaluated through the standarized mean differences (SMD) from baseline to endpoint in the PANSS total scores.Results from 15 studies reported usable results for PANSS score (five antipsychotics compared) are shown in Figure 1. In hierarchical order, haloperidol, aripiprazole, risperidone, and paliperidone reduced the PANSS score significantly more than other drugs.Image:Most LAIAs are equally efficient at reducing overall symptoms, and differences between individual LAIAs are non-significant.None Declared"} +{"text": "New-generation vaccines and novel vaccinal strategies against infectious diseases of livestock, wild and companion animals\u201d highlights advances and innovations in animal vaccines.Vaccination against infectious disease is an invaluable tool to protect humans against severe morbidity and mortality. For this reason, significant advances in human vaccines have propelled the field of vaccinology forward. Emerging and neglected diseases still pose an important challenge ; fortunaTargeted delivery of oral vaccine antigens to aminopeptidase N (APN) protects pigs against pathogenic Escherichia coli challenge infection\u201d describes the complications of oral subunit vaccines and the significant hurdles in overcoming the barriers of the gastrointestinal tract, limiting their development and efficacy. However, by utilizing APN-specific antibody-antigen fusion constructs, researchers have demonstrated the induction of both mucosal and systemic immune responses in a piglet model of bacterial infection, providing a stepping stone toward the realization of an effective and protective oral subunit vaccine targeting APN. The manuscript by Souto et\u00a0al. provides data to support the development of a bivalent vaccine candidate to protect fish from viral hemorrhagic septicemia (VHS) and viral encephalopathy and retinopathy (VER), major threats in aquaculture. By modifying the genome of viral hemorrhagic septicemia virus (VHSV) and introducing an expression cassette encoding the protective antigen domain of nervous necrosis virus (NNV) capsid protein, the authors successfully demonstrated the safety, immunogenicity, and protective efficacy of the recombinant VHSVs (rVHSV) in trout and sole. These findings hold promise for the development of a valuable bivalent live attenuated vaccine for commercially valuable fish species. Anotherstudy assessed the immune responses in calves to vaccines targeting Mycobacterium avium subspecies paratuberculosis (MAP), a cause of chronic enteritis in ruminants. Here, the authors analyzed the immune response induced by truncated MAP antigens as a fusion either on protein particles or as a soluble recombinant MAP (rMAP) fusion protein and compared this to a commercial vaccine. The rMAP fusion protein vaccine displayed the strongest immune response and showed promise in providing protective immunity against MAP infection while avoiding interference with bovine tuberculosis diagnostic tests. In another article, the authors describe a promising vaccination strategy for East Coast fever, a prevalent bovine disease in Africa caused by Theileria parva. In this study, using a recombinant lumpy skin disease virus (LSDV), the authors engineered virus-like particles (VLPs) containing a modified form of the T. parva p67 surface antigen and the bovine leukemia virus (BLV) gag gene. Studies in mice demonstrated the vaccine\u2019s immunogenicity, showing higher antibody titers in the group vaccinated with the recombinant LSDV. This encouraging progress paves the way for further investigations and potential applications of this dual vaccine candidate in cattle. Using recombinant bovine herpesvirus (BHV)-4 expressing nonstructural protein 5 (NSP5) and M fusion protein of porcine reproductive and respiratory syndrome virus (PRRSV), a study suggested that a T cell response induced in recombinant viral vector primed pigs can help in reducing PRRSV-1\u2013associated tissue damage without reducing the viral load. A separate study explored the potential of an adenoviral-vectored Epigraph vaccine as a promising alternative to current Swine Influenza A Virus (IAV-S) vaccines. Their findings demonstrated encouraging results, with the vaccine inducing robust and durable antibody responses in vaccinated pigs, as well as significant protection against viral challenge 6 months after initial vaccination.Within this Research Topic, both original research and review articles are presented. The original article \u201cRecent advances in antigen targeting to antigen-presenting cells in veterinary medicine\u201d outlines the dynamic field of veterinary medicine, where the quest for innovative strategies to combat challenging diseases has gained considerable momentum. Notably, groundbreaking advancements in antigen targeting, with a particular focus on antigen-presenting cells such as dendritic cells, through the use of DC peptides and MHC-II, have emerged as a beacon of hope. Moreover, another review describes the complications of vaccination in wildlife animals. Prion diseases, such as chronic wasting disease (CWD), pose significant challenges due to their unique biology and potential zoonotic risks. Current efforts to manage CWD have been largely ineffective, emphasizing the need for new tools such as vaccines. Despite the hurdles of overcoming immune tolerance and vaccinating wild animals, progress has been made in identifying safe antigens and effective strategies for formulation and delivery, including oral delivery to wild cervids.To complement the original research outlined above, this Research Topic also delves into important questions regarding new vaccine strategies and considerations for future approaches in detailed reviews. \u201cImmune responses in the uterine mucosa: clues for vaccine development in pigs\u201d explores the pursuit of effective strategies, with intrauterine immunization emerging as a promising approach, aiming to elicit localized or systemic immunity that safeguards against potential threats. Finally, Type I interferons (IFNs-\u03b1/\u03b2) are vital components of the innate immune response against viral infections. However, viruses have developed clever strategies to evade the antiviral effects of IFNs, compromising the efficiency of the immune system and vaccines. Understanding these evasion mechanisms can pave the way for the development of innovative vaccines that counteract viral IFN antagonism and induce robust immune responses for enhanced protection against a wide range of pathogens. The review article \u201cReprogramming viral immune evasion for a rational design of next-generation vaccines for RNA viruses\u201d explores advances in developing IFN antagonism-deficient viruses, their immune evasion, and attenuated phenotypes in natural host animal species.The intricate immune system of the upper reproductive tract (URT) serves a remarkable purpose: shielding against sexually transmitted pathogens while simultaneously embracing immune tolerance toward sperm and the developing fetus. The review \u201cThis Research Topic brings a diverse selection of topics outlining advances in the field of veterinary vaccinology. The importance of generating protective vaccines against disease in animals is critical to ensuring their health and wellness, thus favoring production systems and reducing zoonotic disease risk .BP: Writing \u2013 original draft, Writing \u2013 review & editing. RM-R: Writing \u2013 review & editing. ST: Writing \u2013 review & editing. CC: Writing \u2013 review & editing. DA: Writing \u2013 review & editing."} +{"text": "Verticillium wilt (VW), Fusarium wilt (FW) and Root-knot nematode (RKN) are the main diseases affecting cotton production. However, many reported quantitative trait loci (QTLs) for cotton resistance have not been used for agricultural practices because of inconsistencies in the cotton genetic background. The integration of existing cotton genetic resources can facilitate the discovery of important genomic regions and candidate genes involved in disease resistance. Here, an improved and comprehensive meta-QTL analysis was conducted on 487 disease resistant QTLs from 31 studies in the last two decades. A consensus linkage map with genetic overall length of 3006.59\u00a0cM containing 8650 markers was constructed. A total of 28 Meta-QTLs (MQTLs) were discovered, among which nine MQTLs were identified as related to resistance to multiple diseases. Candidate genes were predicted based on public transcriptome data and enriched in pathways related to disease resistance. This study used a method based on the integration of Meta-QTL, known genes and transcriptomics to reveal major genomic regions and putative candidate genes for resistance to multiple diseases, providing a new basis for marker-assisted selection of high disease resistance in cotton breeding. Upland cotton , the most widely cultivated cotton species in the world, has excellent qualities, high yield and is widely adaptable .The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} +{"text": "Large proportion of patients with ADHD experience sleep problems. Well conducted, good quality clinical research could identify non-pharmacological sleep improvement interventions that would benefit patients with ADHD and would inform evidence based guidelines for sleep management in ADHD.To conduct a novel meta-research assessment of available clinical trials in the field of light therapy and non\u2011pharmacological sleep improvement interventions for people with ADHD.Peer-reviewed publications of clinical trials were analysed. An advanced literature search strategy was performed in major medical databases, including EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials and PsycINFO. Available data at WHO-approved clinical trial registries were searched and linked to the published literature. Detailed methodological assessment of results was conducted using the Cochrane Risk of Bias Tool version 2.0 (ROB2), conflict of interest, spin and favourability of findings. Reduction in ADHD symptom severity and improvement of sleep quality served as primary outcomes for the efficacy analysis. Any adverse events were recorded. Statistical analysis of the primary outcomes was conducted by calculating standardised mean difference and transformed as necessary. Publication bias was evaluated with contour enhanced funnel plots and the trim-and-fill procedure, and by summarising unpublished trials.Analysed clinical trials often had a high risk of bias . The primary outcome interpretation and overall trial conclusions frequently favoured the trial intervention. Clinical trials showed an association between primary outcome effect size and interpretation, and risk of bias. Clinical research in this field faces many of the same challenges identified for complex interventions in mental health, such as small sample size, lack of funding and difficulties with blinding.Clinical research regarding light therapy and non\u2011pharmacological sleep improvement interventions for ADHD patients indicates safety and effectiveness but studies often lack methodological rigour.None Declared"} +{"text": "In this critical analysis, we investigate the profound impact of natural disasters and pandemics on the care and adherence to treating diabetic retinopathy, a severe complication of diabetes requiring continuous monitoring and treatment to prevent vision loss. Our study also sheds light on the social and economic context of Puerto Rico, emphasizing recent emergency events that have exacerbated existing public health challenges. Through a comprehensive review of relevant literature from PubMed, Google Scholar, and the George Washington University Himmelfarb Health Sciences Library database, we identified 31 pertinent articles out of 45 evaluated, focusing on the effects of these crises on healthcare delivery, diabetic retinopathy screening, and treatment. The evidence strongly indicates that during such emergencies, barriers to healthcare escalate, leading to significant treatment delays and a reduction in diabetic retinopathy screening and diagnosis, ultimately resulting in deteriorated visual outcomes. Thus, our review underscores the urgent need for the development of effective emergency plans tailored specifically to diabetic retinopathy, particularly in Puerto Rico, where diabetes prevalence and its complications are notably higher. Such plans should not only incorporate established emergency measures but also harness emerging technological advances in the field of ophthalmology to ensure optimal preparedness for future pandemics and natural disasters. Diabetes, characterized by elevated blood glucose levels, poses a global health challenge with both macrovascular and microvascular complications. The incidence of diabetes is rising worldwide, affecting vulnerable populations, especially in disaster-prone regions . The IntThe prevalence of DR is escalating, especially in regions like North America and the Caribbean, with Puerto Rico experiencing a notable burden ,8. This Prior research underscores the exacerbation of diabetes and its complications in disaster settings ,12. DiabDR management revolves around prevention and progression control . While bThis critical analysis aims to elucidate the influence of natural disasters and pandemics on DR care and adherence to treatment. Moreover, it sheds light on Puerto Rico's recent public health challenges, magnified by its susceptibility to disasters . ThroughMaterials & methodsA comprehensive literature review was conducted to identify relevant publications on managing DR during pandemics or natural disasters worldwide. The study also aimed to identify recent public health challenges in Puerto Rico that may have affected the care of DR on the island during and after Hurricane Irma, Hurricane Maria, the 2019-2020 earthquakes, and the COVID-19 pandemic. Additionally, the research sought to assess the presence of diabetes emergency preparation procedures on the island. Furthermore, given the ongoing COVID-19 pandemic, the literature review explored suggested methods and new technological breakthroughs for managing DR.Literature searches were conducted using PubMed, Google Scholar, and the George Washington University Himmelfarb Health Sciences Library database. The search queries focused on terms related to DR, as it is the primary disease of interest in this critical analysis. Similarly, words related to disaster preparedness were included. The search terms used had \"diabetic retinopathy\" (\"retinopatia diab\u00e9tica\"), \"retinopathy\" (\"retinopatia\"), \"retina,\" \"diabetes,\" \"diabetic eye disease,\" \"diabetes mellitus,\" and \"diabetics\" (\"diab\u00e9ticos\"), along with \"disaster preparedness,\" \"emergency preparedness,\" \"natural disasters\" , \"hurricanes\" (\"huracanes\"), \"Hurricane Maria\" (\"Hurac\u00e1n Maria\"), \"Hurricane Irma\" (\"Hurac\u00e1n Irma\"), \"earthquakes\" (\"terremotos\"), \"pandemic\" (\"pandemia\"), \"covid,\" \"covid-19,\" and \"coronavirus.\" Additional terms such as \"prevalence\" , \"Puerto Rico,\" \"intravitreal injections,\" \"anti-vascular endothelial growth factor,\" and \"anti-VEGF\" were used to achieve specific aims.Appendix A provides a list of combinations of the search terms mentioned above. Studies included in the literature review were limited to those written in English or Spanish, available as free full-text, and published from 2017 onwards.ResultsThis study conducted an extensive literature review spanning the period from 2017 to 2022, with the aim of delving into the intricate dynamics between natural disasters, pandemics, and the provision of care for DR. A meticulous analysis of 24 relevant articles provided valuable insights into the challenges faced by DR patients during times of adversity, as depicted in Figure Remarkably, as highlighted in Table\u00a0Intriguingly, the literature appeared to have a significant gap in the specific domain of disaster preparedness strategies tailored to DR during natural disasters\u00a0, a pointThe synthesis of the literature convincingly underscores the susceptibility of DR care to the disruptions posed by natural disasters and pandemics. The aftermath of events like hurricanes and the ongoing COVID-19 pandemic has underscored challenges in timely care provision, leading to delays in vital interventions such as anti-VEGF injections and DR screenings. These delays can potentially worsen the prognosis of DR and heighten the risk of vision loss. Of significant note, the region of Puerto Rico, having endured multiple natural disasters in the past decade alongside the ongoing pandemic, is a vivid example of the disproportionate impact on individuals with chronic illnesses. These crises have laid bare shortcomings in the healthcare system and accentuated the pressing need for robust contingency plans to mitigate considerable health and visual consequences. It is imperative that such plans encompass both established emergency protocols and the integration of emerging technological advancements within the field of ophthalmology.Impact of Pandemics and Natural Disasters on Diabetic Retinopathy: Challenges and Preparedness StrategiesThe ramifications of pandemics and natural disasters on DR care have garnered significant attention within the medical community. This section synthesizes key findings from the literature, shedding light on the barriers encountered by DR patients during these emergency situations and proposing effective preparedness strategies to mitigate their impact.Barriers to care during the COVID-19 pandemic: The COVID-19 pandemic highlighted several barriers that disrupted the continuity of DR\u00a0care. As depicted in Table Impact of recent emergency situations in Puerto Rico: Existing healthcare challenges and socioeconomic factors amplified Puerto Rico's vulnerability to emergencies. Table Proposed pandemic and disaster preparedness plan for DR: To address the challenges highlighted by the impact of emergencies on DR care, a multifaceted preparedness plan is proposed. Table DiscussionThe prevalence of DR, a significant microvascular complication of diabetes mellitus, presents a formidable challenge due to its potential to cause vision impairment and blindness among working-age individuals. This condition is chiefly characterized by diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR), necessitating timely intervention and vigilant monitoring . The conTo mitigate the repercussions of these care disruptions, ophthalmological institutions have outlined recommendations for managing intravitreal anti-VEGF injections during pandemics . These gTelemedicine has proven invaluable when conventional medical access is limited, as witnessed in situations like natural disasters and infectious disease outbreaks. The COVID-19 pandemic has expedited the adoption of telemedicine, enabling remote healthcare delivery through digital platforms. Ophthalmology has particularly benefited from this shift, leveraging advanced hardware, sophisticated software, and high-speed communication technologies to remotely diagnose and manage eye conditions ,28. The Teleophthalmology, mainly via portable devices, has the capacity to bridge accessibility gaps in remote and underserved communities. Research has demonstrated the feasibility of cost-effective DR screening tools utilizing smartphones and telemedicine, resulting in improved DR screening coverage in rural areas . FurtherIn addition to leveraging telemedicine, public health initiatives should prioritize infrastructure enhancements to bolster visual healthcare accessibility. Strengthening hospitals, medical facilities, and primary care clinics, ensuring consistent power supply and backup generators, improving provider communication, expanding the healthcare workforce, enhancing surveillance systems, and refining patient records are imperative. Special attention should be directed toward\u00a0high-risk groups, such as elderly individuals with chronic conditions and immobile patients . ExpandiCommunity pharmacists play a pivotal role in disaster preparedness and response, offering access to medications and healthcare services, thereby mitigating barriers to care . They caNational-level protocols should be established to ensure uninterrupted critical treatment schedules for DR patients. These protocols must recognize the debilitating nature of the disease and prioritize patients at high risk of DR-related blindness, exempting them from lockdown measures and ensuring their protection . SimilarThe COVID-19 pandemic has instigated transformative shifts in care delivery and spurred innovative standards in ophthalmic care. As the global population ages, the prevalence of DR and similar conditions will escalate, further straining healthcare services. In regions like Puerto Rico, where diabetes mellitus is highly prevalent, and healthcare infrastructure and resources might be less stable, swift integration of alternative care methods, such as telemedicine, is crucial to alleviate patient burden while ensuring essential disease management . TelemedFinally, developing an emergency contingency plan for DR management is essential to provide uninterrupted care during crises. Clinicians bear a moral and ethical responsibility to devise strategies to minimize treatment interruptions. Key elements of such a plan include maintaining a comprehensive database of DR patients and their demographics for guided medication distribution and personnel deployment, implementing backup power sources for electricity outages, ensuring access to electronic medical records, and refrigeration for temperature-sensitive medications. Adequate medication and supply reserves ahead of disasters and establishing post-disaster patient communication methods are also vital.It is essential to acknowledge the limitations of this study, including the absence of specific data on the intersection of DR and natural disasters, as well as the lack of tailored recommendations for the unique circumstances in Puerto Rico. However, this critical analysis aims to provide guidance to ophthalmologists in Puerto Rico for effectively managing DR patients during responses to hurricanes, earthquakes, and potential future pandemics like COVID-19. The findings should inspire collaborative efforts among scientists and stakeholders in Puerto Rico to address barriers hindering patient access to teleophthalmology services, especially during times of crisis.In conclusion, given the heightened risks posed by pandemics and natural disasters, developing a robust emergency plan for managing DR is imperative. This urgency is underscored by the heightened vulnerability of regions like Puerto Rico, where the prevalence of diabetes and its complications is substantial. An effective plan should encompass established emergency measures and embrace emerging technological advancements within the field of ophthalmology."} +{"text": "Opioid use for perioperative pain management in burn patients is associated with a high risk of developing chronic opioid use. Ketamine is commonly used as an analgesic adjunct due to its opioid-sparing effects. The purpose of this study is to determine whether analgesia with adjunctive ketamine reduces the risk of developing chronic opioid use in burn patients.Burn patients who underwent burn-related surgeries were identified using relevant ICD-10 Codes. Data were collected using the TriNetX Research Network, a national research database providing de-identified patient medical records.Burn patients undergoing surgical procedures were identified based on their use of opioids alone or in combination with ketamine as adjunctive analgesia. Both groups excluded patients with a prior history of opioid-related and psychiatric disorders to control for potential pre-existing conditions affecting the study outcomes. Outcome analysis included continued opioid use and related psychiatric disorders, including nicotine dependence and anxiety, up to one year after burn injury. Risk ratios for each outcome were then generated using a measure of association analysis through TriNetX.We identified 107,270 patients across 51 health care organizations who underwent burn-related surgeries within one month after burn injury. Excluded from the study were 3,296 (3.07%) patients who had a prior history of opioid-related and psychiatric disorders. The remaining 103,974 patients were sorted into respective groups that received opioids with ketamine and without ketamine . The two cohorts were balanced using (1:1) propensity score matching for age, sex, race, ethnicity, and burn surface area.Patients without ketamine had a higher risk of continuing opioid use , developing nicotine dependence , and developing anxiety disorders at least one year after burn injury.Burn patients whose pain management included adjunctive ketamine ceased opioid use sooner and demonstrated a lesser risk of developing various psychiatric disorders associated with chronic opioid use.This study supports the use of adjunctive ketamine as part of a multimodal approach to pain management in burn patients in order to minimize the risk of chronic opioid use."} +{"text": "Ophiophagus hannah; Cantor, 1836) is distributed in diverse habitats, forming independent populations, which confer differing scale markings, including between hatchlings and adults. Furthermore, king cobra venoms possess unique cytotoxic properties that are used as a defensive trait, but their toxins may also have utility as promising anticancer-agent candidates. However, the impact of geographical distribution and age on these potential venom applications has been typically neglected. In this study, we hypothesised that ontogenetic venom variation accompanies the morphological distinction between hatchlings and adults. We used non-transformed neonatal foreskin (NFF) fibroblasts to examine and compare the variability of venom cytotoxicity between adult captive breeding pairs from Malaysian and Chinese lineages, along with that of their progeny upon hatching. In parallel, we assessed the anticancer potential of these venoms in human-melanoma-patient-derived cells (MM96L). We found that in a geographical distribution and gender-independent manner, venoms from hatchlings were significantly less cytotoxic than those from adults . This is consistent with neonates occupying a semifossorial habitat, while adults inhabit more above-ground habitats and are therefore more conspicuous to potential predators. We also observed that Malaysian venoms exhibited a slightly higher cytotoxicity than those from the Chinese cobra cohorts , which is consistent with Malaysian king cobras being more strongly aposematically marked. These variations are therefore suggestive of differential anti-predator strategies associated with the occupation of distinct niches. However, all cobra venoms were similarly cytotoxic in both melanoma cells and fibroblasts, limiting their potential medical applications in their native forms.Snake venoms constitute a complex, rapidly evolving trait, whose composition varies between and within populations depending on geographical location, age and preys (diets). These factors have determined the adaptive evolution for predatory success and link venom heterogeneity with prey specificity. Moreover, understanding the evolutionary drivers of animal venoms has streamlined the biodiscovery of venom-derived compounds as drug candidates in biomedicine and biotechnology. The king cobra ( Venom is generally defined as a functional trait: a complex secretion produced by a specialised gland tissue that is delivered into the body of another animal via a wound for use in antagonistic interactions . By thisThe scale of mining venoms for drug candidates is immense, as this mixture often contains hundreds of toxins and isoforms that undergo accelerated rates of evolution . This biStudying the natural history and evolution of venomous species provides key insights regarding the biological sources reflecting toxin diversity. Snake venoms function at the ecological and biochemical interface between predator and prey, aiming mainly to facilitate predation . This haOphiophagus hannah; Cantor, 1836) belongs to the Elapidae family and is widely distributed from India to southern China and Southeast Asia in numerous geographically isolated mainland and island populations. These populations form at least four genetically distinct lineages, which are likely separate species prism function. Data were graphed and analysed using GraphPad Prism version 9 for iOS . For the MTT assays, venom cytotoxicity data were normalised to the vehicle-treated cells (100% cell viability) to calculate the percentage of viable cells following venom treatment. Data were then tested for normality using Shapiro\u2013Wilk tests (significance set to"} +{"text": "Perioperative management of estradiol therapy varies considerably among plastic surgeons performing aesthetic surgeries. This study aimed to review available literature regarding perioperative management of estradiol therapy in aesthetic surgery patients, and the risk it poses for developing VTE in the perioperative period.A literature search was performed using online databases to identify studies evaluating VTE in aesthetic surgery patients taking oral contraceptives (OCPs) or hormone replacement therapy (HRT), and transgender patients on feminizing hormone therapy undergoing non-flap feminization surgery . Reported outcomes were extracted from these studies and summarized.A systematic review of the literature yielded 225 studies. Five of these studies met inclusion criteria. One study that was excluded, referenced an article that met inclusion criteria, which was ultimately included in our review for a total of six studies, representing 3,635 patients.Data regarding perioperative management of estrogen therapy is limited in the literature, and standardized guidelines for aesthetic surgery patients have not been elucidated. This has led to inconsistencies in how estrogen is managed for elective, cosmetic procedures. Further research is needed to determine standardized practice guidelines. In the meantime, case-by-case evaluation of surgical appropriateness should continue. Surgeons should also consider risk-mitigating strategies, such as a focus on patient education, more intentional patient questioning regarding estrogen-containing product use, a preoperative coagulability workup for patients with a personal or family history indicative of possible coagulopathy, and specialty-wide efforts to create an aesthetics database and evidence-based guidelines."} +{"text": "BackgroundMeniscal tears are the most common injury of the knee. Surgical treatment has fallen into contention recently and includes arthroscopic meniscectomy and meniscal repair. The primary aim of this study was to quantitatively evaluate patients with isolated meniscal tears and compare their outcomes with patients who have undergone arthroscopic meniscus surgery. The secondary aim of this study was to compare the clinical outcomes of patients who have undergone arthroscopic meniscectomy with patients who have undergone arthroscopic meniscal repair.MethodsThis comparative clinical study screened 334 patients to identify subjects who underwent arthroscopic knee surgery for isolated meniscal tears and compare them to patients with symptomatic isolated meniscal tears awaiting surgery using validated patient-reported outcome measures. These included the Knee Injury and Osteoarthritis Outcome Score, International Knee Documentation Committee Subjective Knee Form, Lysholm score, Tegner score, EuroQol-5 Dimension, and the 12-Item Short Form Health Survey.ResultsA total of 117 patients , Meniscectomy group (n=64), and Meniscal Repair group (n=17)) were included in the final data analysis. Both the Meniscectomy group and the Meniscal Repair group (mean 55-month follow-up) showed significantly better clinical outcomes than patients in the Meniscal Tear group (p<0.05). Overall, the Meniscal Repair group demonstrated superior clinical outcomes when compared to the Meniscectomy group (p<0.05).ConclusionArthroscopic knee surgery showed significant clinical benefit at medium-term follow-up in treating patients with isolated meniscal tears. When feasible, meniscal repair should be performed preferentially over meniscectomy. The menisci are crescentic wedge-shaped structures formed from fibrocartilage located within the medial and lateral compartments of the knee between the corresponding femoral condyle and tibial plateau ,2. MenisTreatment for meniscal tears broadly falls into two categories: conservative vs. surgical, the latter of which includes arthroscopic meniscectomy and arthroscopic meniscal repair. The choice depends on many factors including age, type and severity of tear, the presence of other pathology, and general patient fitness for anesthesia and surgery ,3,4. WheIn general, the treatment for traumatic meniscus tears differs from that of degenerative tears. The latter are less likely to be amenable to repair as by their very definition their blood supply is poor ,2. FurthSurgical management includes arthroscopic meniscectomy and meniscal repair. An arthroscopic partial meniscectomy (APM), in which only the torn section of the meniscus is removed, is now the most frequently performed orthopedic operation in the United States .As compared to meniscectomy, meniscal repair is a more biologically preserving procedure as it retains the native meniscal tissue within the knee joint. Multiple repair techniques have been described in the literature, the most common of which include all-inside, inside-out, and outside-in, with no significant differences in failure rates, complication rates, or clinical outcomes . OutcomeThe decision to proceed with either meniscectomy or meniscal repair involves evaluating both meniscus tear characteristics and patient factors . Meniscal repair has been shown to decrease the incidence of early chondral degeneration and better preserve the knee\u2019s biomechanical properties as compared to meniscectomy . Both prMeniscal repairs are more commonly performed in younger patients and have shown superior outcomes over meniscectomy in patients under 45 years of age . IncreasThere are a limited number of studies directly comparing clinical outcomes between meniscectomy and meniscal repair, with those identified only having short-term follow-up periods, meniscal repairs performed concomitant with anterior cruciate ligament (ACL) reconstruction, and a limited variety of patient-reported outcome measures (PROMs) included in the clinical evaluation.PROMs quantify clinical symptomatology as directly projected by the patients themselves. Varying from general health to disease-specific, PROMs aid clinical decision-making, inform health policy strategies, and develop and refine patient-centered care . GenericThe primary aim of this study is to quantitatively evaluate patients with isolated meniscal tears using validated PROMs and compare their outcomes with patients who have undergone arthroscopic meniscus surgery. The secondary aim of this study is to compare the clinical outcomes of patients who have undergone arthroscopic meniscectomy with patients who have undergone arthroscopic meniscal repair. The primary hypothesis is that arthroscopic surgery improves symptoms of meniscus tears. The secondary hypothesis is that arthroscopic meniscal repair has superior clinical outcomes as compared to arthroscopic meniscectomy.This is a retrospective observational clinical study. All the patients included in this study attended a specialist knee clinic and underwent arthroscopic knee surgery following clinical assessment and radiological investigation. This study was exempt from Institutional Review Board (IRB)/Ethics Committee approval as it was a pragmatic study evaluating the existing clinical practice of the senior author (consultant orthopedic surgeon). This study was registered with the hospital\u2019s Clinical Effectiveness Department (registration number CA9828). This therapeutic research study constituted the first author\u2019s Masters dissertation.This study compared the clinical outcomes of three separate groups. The Pre-Operative group included patients with isolated meniscal tears of the knee joint, the Meniscectomy group included patients who had undergone an arthroscopic meniscectomy, and the Meniscal Repair group included patients who had undergone an arthroscopic meniscal repair.Exclusion criteria consisted of further surgery or further injury to the affected limb, any functionally limiting illness or disease, advanced knee osteoarthritis and concurrent ACL, posterior cruciate ligament (PCL), or lateral collateral ligament (LCL) tears. The presence of any of these factors could confound surgical outcomes reported. Exclusion of these cases ensured any symptoms expressed were attributable only to the original meniscal injury and their surgical treatment. Patients with medial collateral ligament (MCL) tears were not excluded as concurrent MCL tears are relatively common with meniscus tears and the former are predominantly treated conservatively and unlikely to confound the outcome of meniscus surgery.Subjects in the Pre-Operative group constituted a cohort of patients currently on the waiting list for knee surgery who have been clinically and radiologically (magnetic resonance imaging (MRI)) diagnosed with an isolated meniscal tear and whose symptoms were refractory to conservative treatment . The Pre-Operative group allowed for a benchmark from which to compare both surgical treatment options.Surgically treated patients in both the Meniscectomy group and the Meniscal Repair group were identified through the consultant\u2019s surgical logbook and theatre records. All arthroscopic knee surgeries performed from August 2013 to June 2021 were reviewed using the hospital electronic health record system; MediTech version 6 . The Novel Coronavirus (COVID-19) global pandemic had implications for this study as all routine elective surgical procedures (including knee arthroscopies) were canceled for an extended period of time (March 2020 onward), reducing the number of potential participants that could be recruited into this study .o to 90o for six weeks in order to protect the meniscal repair site at the initial healing phase, thereafter the brace was discontinued, and full ROM progressed. All meniscectomies were performed using standard a basket punch followed by a motorized oscillating shaver (Smith & Nephew plc.) whereby only the torn and damaged area of meniscal tissue was resected back to a stable rim . Post-operative physiotherapy rehabilitation included full weight and full ROM without any knee brace or functional restrictions. Patient notes were perused to ascertain the type of arthroscopic knee surgery performed, conformance with the inclusion and exclusion criteria, and documenting intra-operative findings, including meniscus tear laterality , tear configuration, and specific anatomic location .All meniscal repairs included in this study were performed by using an all-inside technique using FAST-FIX 360 for tears located at the posterior horn and middle third (body) of the meniscus. For anterior horn meniscus tears, an outside-in meniscal repair technique was performed using a 1 PDS II (polydioxanone) violet suture . Microfracture around the margin of the intercondylar notch was performed at the same time in order to perforate the subchondral bone and introduce mesenchymal stem cells into the knee joint which in turn optimizes the biological milieu for the meniscal tissue healing process . Post-opData from validated patient-reported outcome measures (PROMs) regarding meniscus-related symptomatology was collected from all three groups. This included the Knee Injury and Osteoarthritis Outcome Score (KOOS) ,17, InteStatistical analysisPlotted histograms with fitted curve lines, box plots, normal Q-Q plots, and the Shapiro-Wilk statistic were used to test the normality of data distribution. Almost all the PROM data (continuous variables) displayed a skewed distribution and therefore the relevant non-parametric statistical tests were used for the data analysis. The Kruskal-Wallis H test accompanied with Dunn\u2019s post-hoc pairwise comparison test was used for the three-way group data analysis. The level of statistical significance was set at p<0.05. Statistical analysis was performed using SPSS for Windows version 26.0 .Figure Baseline demographics for all three groups are summarized in Table Table Figure This study has shown that patients with isolated meniscus tears clinically improved following arthroscopic knee surgery as determined by validated PROM scores. Overall, the clinical outcome of arthroscopic meniscal repair surgery was superior to that of arthroscopic meniscectomy.This study found significantly different outcomes between pre-operative patients with an isolated meniscal tear and those who had undergone either a meniscectomy or meniscal repair surgery. The highest scores across all PROMs were observed in the Meniscal Repair group, with the lowest scores mostly seen in the Pre-Operative group. This study is the first to quantitively evaluate pre-operative patients with isolated meniscal tears using a wide variety of validated PROMs , allowing a standardized benchmark from which to compare surgical interventions and other modalities aimed at treating meniscus pathology. The results from this study demonstrate significant clinical benefit from both meniscectomy and meniscal repair surgery at a mean 55-month follow-up, a finding also shown by a similar study by Engler et al. ,10,22. THistorically, APM has been used in a non-specific manner in patients with knee pain and any form of tear ,22. ThisThe secondary hypothesis of this study was affirmed, finding significantly superior scores in the Meniscal Repair group across almost all PROMs, suggesting Meniscal Repairs have superior outcomes to Meniscectomy for isolated meniscal tears at medium-term follow-up. This finding is corroborated by a meta-analysis by Xu et al. , which sThe superior outcomes observed in this study in the Meniscal Repair cohort could be attributed to preservation of the meniscal tissue and therefore retaining the three key functions they play in the knee. First, they absorb axial loading forces through the joint, by converting them into hoop stresses within the tissue. Second, the menisci stabilize the knee by improving articular congruency between the flat tibial plateaus and concave femoral condyles. Third, they modulate the gliding of the articular surfaces. The removal of the meniscal tissue by meniscectomy impacts its ability to perform such functions and could be attributed to the greater rate of secondary osteoarthritis other studies have observed in this group .The menisci are innervated by the posterior articular branch of the tibial nerve. Similar to the ACL, they too contain mechanoreceptors that contribute to the proprioceptive function of the knee . StudiesA general comparison between the two operations shows that despite meniscal repair having greater day-of-surgery costs , greaterThe main limitation of this study was patient participation and recruitment. This clinical research study was conducted during the novel coronavirus (COVID-19) global pandemic, during which all routine elective surgery had ceased due to nationwide restrictions, resulting in a reduction of individuals eligible to take part. Additionally, due to the nature of postal questionnaires, patients were understandably apprehensive about receiving an envelope that had originated from a hospital during this time, further reducing the compliance rate. This study did not analyze longitudinal patient data of the two surgical groups as pre-operative data was not collected for these patients specifically.\u00a0However, a suitable comparable group of pre-operative patients, refractory to conservative treatment, on a waiting list for meniscal surgery was identified and used as a benchmark from which to assess and compare surgical outcomes. The range of follow-up periods was relatively broad for both groups. However, with a mean follow-up period of 57 and 47 months for the meniscectomy and meniscal repair cohorts, respectively, this study provides a useful perspective on medium-term outcomes following meniscal surgery.Despite limitations forced upon clinical research studies performed during the global pandemic, this analysis is based on comprehensive selection criteria and contributes key interpretation regarding the direct comparison between meniscectomy and meniscal repair in isolated meniscal tears, something only a limited number of papers have done in the past ,35. ThesSuggestions for future research in this field include undertaking a multicenter study that can allow for a larger cohort of patients to be investigated, particularly in the Meniscal Repair group, whilst encompassing various meniscal surgical techniques, to provide more generalizable results. It is likely that specific patient subgroups benefit by varying amounts from each surgical procedure. Larger cohorts would also aid identification of these predictive factors, allowing adequate treatment selection. Implementation of a national database of meniscal operations, similar to the National Joint Registry and the National Hip Fracture Database in the United Kingdom, would also confer these benefits on a larger scale.This study has demonstrated a significant clinical benefit in patients with isolated meniscal tears undergoing arthroscopic knee surgery. The outcomes of meniscal repair\u00a0were superior to that of meniscectomy at medium-term follow-up. Meniscal repair is a more biologically preserving procedure of the knee joint and should be performed preferentially over meniscectomy in isolated meniscal tears when feasible. The findings of this study will greatly benefit both clinicians and patients regarding the management of meniscal tears and better inform public health resource allocation."} +{"text": "Major depressive disorder (MDD) is a highly prevalent mental illness that often first occurs or persists into adulthood and is considered the leading cause of disability and disease burden worldwide. Unfortunately, individuals diagnosed with MDD who seek treatment often experience limited symptom relief and may not achieve long-term remission, which is due in part to our limited understanding of its underlying pathophysiology. Many studies that use task-based functional magnetic resonance imaging (fMRI) have found abnormal activation in brain regions in adults diagnosed with MDD, but those findings are often inconsistent; in addition, previous meta-analyses that quantitatively integrate this large body literature have found conflicting results.This meta-analysis aims to advance our understanding of the neural basis of MDD in adults, as measured by fMRI activation studies, and address inconsistencies and discrepancies in the empirical literature.We employed multilevel kernel density analysis (MKDA) with ensemble thresholding, a well-established method for voxel-wise, whole-brain meta-analyses, to conduct a quantitative comparison of all relevant primary fMRI activation studies of adult patients with MDD compared to age-matched healthy controls.We found that adults with MDD exhibited a reliable pattern of statistically significant hyperactivation and hypoactivation in several brain regions compared to age-matched healthy controls across a variety of experimental tasks.This study supports previous findings that there is reliable neural basis of MDD that can be detected across heterogenous fMRI studies. These results can be used to inform development of promising treatments for MDD, including protocols for personalized interventions. They also provide the opportunity for additional studies to examine the specificity of these effects among various populations-of-interest, including youth vs. adults with depression as well as other related mood and anxiety disorders.None Declared"} +{"text": "To review the pathophysiology of allergic asthma and information on the pharmacology, clinical efficacy, safety profile, and direct drug costs for omalizumab to provide a basis for a defined role of this agent in allergic asthma therapy in managed care organizations.Omalizumab is a monoclonal antibody targeting the high-affinity receptor binding site on human immunoglobulin E (IgE). When bound by omalizumab, IgE does not bind to basophils. As a result, degranulation is attenuated and allergic asthma symptoms are reduced. In asthma trials, omalizumab reduced inhaled corticosteroid and rescue medication requirements and improved asthma control and asthma quality of life in moderate-to-severe allergic asthmatics with disease poorly controlled by inhaled corticosteroids. Omalizumab has generally been well tolerated. However, injection site reactions occur in nearly 1 of every 2 patients, a problem that generally becomes less with continued dose administration. Severe injection site reactions are reported in 12% of patients. Other adverse events commonly reported in clinical trials include viral infections (23%), upper respiratory infections (20%), sinusitis (16%), headache (15%), and pharyngitis (11%). Because the acquisition cost of omalizumab is high , its use is cost-prohibitive in all but the most severe, poorly controlled allergic asthmatic patients who are utilizing large amounts of emergency health care resources to manage exacerbations. Experience with use of this drug beyond 52 weeks is lacking.Although omalizumab has demonstrated efficacy and safety in adults and adolescents with uncontrolled moderate-to-severe allergic asthma, its use should be restricted to a narrowly defined population of allergic asthmatics who utilize large amounts of health care resources. If targeted only toward this population, cost-of-care studies suggest that the high cost of this product in these patients could be offset by savings resulting from the less frequent use of high-intensity medical services for asthma exacerbations. The use of omalizumab beyond 52 weeks needs evaluation."} +{"text": "Mental Illness Stigma is a barrier in access to healthcare. Stigma also influences population health outcomes by worsening, undermining adequate processes. The healthcare professionals show several stigmatising behavirous and cognitions, which may impair the adequate provision of care of this population with mental illness.We aimed to measure mental health stigma in healthcare professionals at a portuguese hospital center.A cross-sectional study of health profissionals was performed using a survey that included socio-economic and job related questions, personal and familiar questions regarding mental health, and Attribution Questionnaire 27 (AQ-27), a translated and validated stigma questionnaire with nine stigma sub-scales .The sample included a total of 388 participants. The majority of the respondants were female . The age ranged from 22 to 69 . According to the job place distribution, we found statistically significant differences in various stigma subscales among several healthcare settings within our center. The inpatient unit professionals showed lesser stigmatising attitudes in anger, coercion, segregation and avoidance domains; and higher stigmatising attitudes in pity and help domains. However, professionals who work at surgery room showed higher stigmatising attitudes in danger and fear, but lesser levels of help domains. We also found differences in five stigma subscales among various health professions. The study didn\u2019t show differences in stigma domains regarding personal or professional contact with mental illness, neither academic studies in mental health.Our findings suggest that workplace environment and profession may impact mental ilness stigma levels in healthcare professionals. We propose that future studies could be done to investigate methods to mitigate mental illness stigma, tailored to address different stigma domains in different workplace settings.None Declared"} +{"text": "Alzheimer's disease (AD) is classified as a tauopathy and is the most common neuropathological correlate of dementia/cognitive impairment. AD is neuropathologically characterized by the presence of beta-amyloid immunoreactive senile plaques and tau positive neurofibrillary tangles. Neuropsychiatric symptoms of AD however continue to be underscored, and therefore, neuropathological correlates of these neuropsychiatric symptoms are not readily studied. Presented here is a case of 60-year-old female who initially presented with anxiety and depression, and continued to be the predominant symptoms although mild cognitive impairment was noted as per the available clinical notes. Postmortem examination of the brain revealed severe Alzheimer's type neuropathological changes, which included significant tau and beta-amyloid pathology in limbic regions, which were thought to represent correlates of the patient's depression and anxiety. This case report illustrates the possible neuropathological correlates of neuropsychiatric symptoms in patients with AD. The author hopes that such a case will promote more in-depth studies into the pathophysiology of neuropsychiatric manifestations in AD. Alzheimer's disease (AD) is regarded as a tauopathy associated with cognitive and functional decline in typically elderly (>65\u2009years) patients although cases of early-onset (before age of 65\u2009years) are possible . NeuropaLimited clinical information was available on the electronic medical chart. As per the information available, this female patient who was 60\u2009years-old at first presentation reported difficulty with short-term memory along with difficulty sleeping. Psychiatric history included depression and anxiety. Neurological examination was notable for mini mental status (MMSE) of 25/30. The patient was clinically diagnosed with mild cognitive impairment based on the MMSE score. Unfortunately, no additional clinical information regarding her cognition could be found. With regards to her depression and anxiety, the patient reported feeling sad about some aspects of her life, and the episodes of sadness were exacerbated by difficulty in her first marriage and from having to switch employment. Clinically, she was diagnosed with major depressive disorder, generalized anxiety disorder, and mild cognitive decline.The patient passed away at hospice facility. After passing, a restricted autopsy limited to postmortem examination of the brain was requested to determine the etiology of her cognitive impairment.The weight of the unfixed brain was recorded at 1330\u2009g. The cerebral hemispheres did not seem to display any significant atrophy. The coronal slices of the cerebral hemispheres did not reveal evidence of atrophy. Ventricular caliber appeared unremarkable. Hippocampus and amygdala did not appear shrunken. Pigment was visible in both the substantia nigra of the midbrain and locus ceruleus of the pons.Histologic examination with immunohistochemical work-up revealed evidence of cerebral amyloid angiopathy in the form of thickened blood vessels in the leptomeninges that were stained by beta amyloid immunohistochemistry. Sampled sections from the cerebral hemispheres showed several beta amyloid positive diffuse plaques and moderate amount of senile plaques throughout neocortex, including cingulate, calcarine, and entorhinal cortices, as well as in the thalamus. There were also scattered tau positive neurofibrillary tangles, neurites, and neuropil threads throughout the cortical gray matter including the superficial and deep layers of the calcarine cortex and entorhinal cortex. Thickened blood vessels that were not stained by beta amyloid immunohistochemistry, and hence consistent with arteriolosclerosis, were noted in the subcortical white matter. Left amygdala showed scattered tau positive neurofibrillary tangles, pretangles, neurites, neuropil threads, and argyrophilic grains. There were also numerous beta-amyloid positive diffuse and senile plaques in the amygdala. Examples of these findings are shown in Midbrain showed some beta amyloid positive diffuse and senile plaques. Although beta amyloid staining was observed in blood vessels of the cerebellar leptomeninges, no definite beta amyloid staining is seen within the cerebellar parenchyma.The final neuropathological diagnosis was reported as Alzheimer's type neuropathological changes ; Braak (neurofibrillary tangle) stage\u2009=\u20096 of 6; CERAD (senile plaque) score\u2009=\u2009C2 (moderate)); cerebral amyloid angiopathy; relatively mild arteriolosclerosis.n\u2009=\u2009906) that psychotic symptoms were more strongly related to the continuum of AD-associated cognitive dysfunction than other neuropsychiatric symptoms. The group also observed a negative correlation between psychotic symptoms and brain volume [n\u2009=\u20091038) that included AD and Lewy body disease pathology. The authors reported higher neurofibrillary tangle (NFT) stages to be associated with depression and agitation and hallucinations associated with higher Lewy body stages [To the author's knowledge, this case is one of the first case examples to demonstrate neuropathological correlation between Alzheimer's type neuropathological changes and clinical history of neuropsychiatric symptoms. Neuropsychiatric symptoms are described in patients with Alzheimer's disease, and animal models have suggested that behavioural and psychological symptoms increase with progressive neuropathology . Depressy stages . These rAPOE-region, respectively. Association analysis excluding the APOE-region identified numerous SNPs corresponding to 40 genes, 9 of which were known LOAD-risk loci primarily in chromosome 11 regions containing the SPI1gene and MS4A genes cluster, and others were novel pleiotropic risk-loci for LOAD conditional with MDD [Interestingly, genetic etiologies shared between AD and depression have been reported. Chiba\u2010Falek et al. performed pleiotropy analysis using genome-wide association studies (GWAS) from publicly accessible websites of AD GWAS and major depressive disorder (MDD) GWAS. The group found moderate enrichment of single nucleotide polymorphism (SNP) associated with late-onset AD (LOAD) across increasingly stringent levels of significance with the MDD GWAS association (LOAD|MDD), of maximum four and eight-folds, including and excluding the Herein, the author has presented neuropathologically severe Alzheimer's type neuropathological changes in a patient whose predominant presentation seems to be neuropsychiatric in the form of anxiety and depression. It is hoped that such a case will encourage further studies of the neuropathological correlates and pathophysiology of neuropsychiatric symptom in AD and other neurodegenerative disorders."} +{"text": "During the COVID-19 pandemic, mental health services often used remote technology to deliver care. However, the rise in remote consultation was largely unplanned. Furthermore, while many patients found remote technology a useful way to access care, others did not. Going forwards, remote technology will continue to play an important role in the delivery of mental healthcare. Research on the most effective ways for mental health services to implement remote technology is thus urgently needed.Electronic health records (EHRs) have been widely adopted in mental healthcare services. EHRs not only support individual patient care, but also open the door to largescale research through the analysis of de-identified clinical data. The South London and Maudsley (SLaM) Biomedical Research Centre (BRC) Case Register is a large EHR dataset comprising structured and unstructured clinical information on patients receiving specialist mental healthcare. In this talk, I will present findings from an analysis of the SLaM BRC Case Register using the Clinical Record Interactive Search tool (CRIS) to evaluate the uptake of remote mental healthcare during the COVID-19 pandemic and its association with medication prescribing. I will discuss the implications of these findings for psychiatrists delivering community mental healthcare and how mental health services can harness remote technology to optimise clinical outcomes.R. Patel Grant / Research support from: NIHR (NIHR301690); MRC (MR/S003118/1); Academy of Medical Sciences (SGL015/1020); Janssen, Consultant of: Induction Healthcare Ltd; Holmusk"} +{"text": "Teaching Point: Subarachnoid hemorrhage is a rare complication of spinal dural arteriovenous fistulas (dAVF) with very characteristic imaging features, knowledge of which is crucial for positive diagnosis and rapid management. We report the case of 45-year-old male without a known history of neurological disease, presenting progressive weakness of lower limbs and tingling-like paresthesia. The evolution of the disease is marked by the onset of thunderclap headache. An endocranial computed tomography (CT) performed in the emergency department showed no particular anomaly. Then, a cerebral magnetic resonance imaging (MRI) was performed showing on axial images hyperintensity in the subarachnoid compatible with a peri mesencephalic subarachnoid hemorrhage space on T2 FLAIR with a normal time of flight (TOF) angiography .Cerebral angiography showed no specific findings.A medullar MRI was then suggested and demonstrated on T2-sagittal MRI intramedAlso, it showed on axial T2 and postPatient was put under surveillance with symptomatic treatment and showed a recovered partial recovery of his motricity and sensitivity.Spinal dural arteriovenous fistulas (dAVF) are the most common spinal vascular malformations (75 to 80%) and more frequently affect male subjects over 50 years that exhibits arteriovenous shunting at the level of the internal leaflet dura mater, corresponding to an abnormal connection between the arterial supply from the medullary dura mater and the medullary venous system and no exact etiology has been fully elucidated .The clinical presentation of sdAVF is often progressive and non-specific mimicking demyelinating or degenerative diseases of the spine, which explains a frequent delay in diagnosis, resulting in an irreversible damage despite an endovascular or surgical intervention.Hemorrhage is very rare but occasionally encountered and may be a source of unexplained subarachnoid hemorrhage.MRI shows an association of centrally located hyperintense signal on T2-weighted images on TSE sequence, corresponding to chronic hypoxic congestive myelopathy attributable to venous hyper pressure hindering venous circulation, dilated peri medullary vessels, hypointense \u2018flow void\u2019 phenomena hypo intense in T2w images, appearing as enlarged and serpiginous veins anteriorly and/or posteriorly to the cord, enhancing after administration of gadolinium The absence of dilated peri medullary vessels do not formally eliminate the diagnosis of Davf. Dynamic MRA (angio-MRI) sequences are more sensitive assets to detect this abnormality.Principal differential diagnosis on imaging includes intramedullary neoplasm, spinal arteriovenous malformation where hemorrhage is common with acute onset, affecting males and females equally.Our case is unique as it depicts the importance of including spinal cord malformations in unexplained cerebral sub arachnoid hemorrhages."} +{"text": "ObjectiveCaregivers support individuals undergoing cancer treatment by assisting with activities, managing care, navigating healthcare systems, and communicating with care teams. We explored the quantity and quality of caregiver participation during recorded clinical appointments in women with metastatic breast cancer.MethodsThis was a convergent parallel mixed methods study. Caregiver participation quality was operationalized using a summative thematic content analysis to identify and sum caregiver roles performed during appointments. Caregiver participation quantity was measured by calculating the proportion of speaking time. Participation quality and quantity were compared to patient activation, assessed using the Patient Activation Measure.ResultsFifty-three clinical encounters were recorded. Identified caregiver roles included: General Support; Management of Treatment or Medication; Treatment History; Decision-Making; Insurance or Money; Pharmacy; Scheduling; Travel Concerns; General Cancer Understanding; Patient Specific Cancer Understanding; Caregiver-Initiated or Emphasis on Symptom Severity; and Caregiver Back-Up of Patient Symptom Description. Caregivers averaged 5 roles (SD 3): 48% of patients had low quality (<\u20095 roles) and 52% had high quality (>\u20096 roles). Regarding quantity, caregivers spoke on average for 4% of the encounter, with 60% of patients having low quantity (<\u20094%) and 40% of patients having high quantity (>\u20094%). Greater quality and quantity of caregiver participation was associated with greater patient activation.ConclusionsCaregivers perform a variety of roles during oncological decision-making visits aiding both patient and provider. Greater participation in terms of quantity and quality by the caregiver was associated with greater patient activism, indicating a need for better integration of the caregiver in clinical decision-making environments."} +{"text": "Populations face a suite of anthropogenic stressors acting simultaneously, which can combine additively or interact to have complex effects on population persistence. Yet we still know relatively little about the mechanisms underlying population-level responses to multifactorial combinations of stressors because multiple stressor impacts across organisms\u2019 life cycles have not been systematically considered in population models. Specifically, different anthropogenic stressors can have variable effects across an organism\u2019s life cycle, resulting in non-intuitive results for long-term population persistence. For example, synergistic or antagonistic interactions might exacerbate or alleviate the effects of stressors on population dynamics, and different life-history stages or vital rates might contribute unequally to long-term population growth rates. Demographic modelling provides a framework to incorporate individual vital rate responses to multiple stressors into estimates of population growth, which will allow us to make more informed predictions about population-level responses to novel combinations of anthropogenic change. Without integrating stressors\u2019 interactive effects across the entire life cycle on population persistence, we may over- or underestimate threats to biodiversity and risk missing conservation management actions that could reduce species\u2019 vulnerability to stress. As humans alter multiple facets of the environment simultaneously, addressing multiple, potentially interacting stressors will be critical for predicting species' responses. Yet the effects of multiple stressors across organisms' life cycle has not been systematically considered in demographic studies. Here, Zettlemoyer proposes a framework to explore the role of multiple stressors on population dynamics in order to make realistic predictions about population viability under different conservation scenarios. Specifically, demographic modelling provides a method to integrate stressors' potential additive and non-additive effects across the entire life cycle, provide mechanistic explanations of species loss and spread under combinations of novel conditions, and improve conservation and management plans. Reviews report that only 136 studies integrate multiple vital rate responses into plant demographic models interactions among anthropogenic stressors and (ii) counteracting effects of stressors on different vital rates might influence population dynamics. Finally, I outline potential experimental designs that integrate multiple stressor effects across the life cycle to predict extinction risk under future environmental conditions.sensuadditive effects, wherein the combined effects of two stressors are equal to the sum of their individual effects (Alliaria petiolata (garlic mustard) interacts additively with deer herbivory to reduce population growth rates of Trillium erectum , only the combination of high levels of interspecific competition and insect herbivory results in population decline and Viola palustris .Eurybia furcata (forked aster), but only when site-level woody encroachment and deer herbivory are high (Cypripedium candidum (white lady\u2019s slipper) under moderate climate change scenarios. However, as drought stress increases, protecting groundwater recharge zones in sites near this hydrologically sensitive species becomes increasingly important (\u03bb as a function of multiple interacting (a)biotic environmental conditions . In order to examine differences in \u03bb between multiple stressors and determine the most relevant vital rate, log-transforming \u03bb will help interpret the impact of vital rates on \u03bb can quantify the sensitivity of \u03bb to changes in each vital rate and/or environmental variable drive differences in \u03bb. For example, invasion and deer herbivory affect multiple vital rates in T. erectum (red trillium), including growth and seedling recruitment, but an LTRE revealed that decreases in fertility largely drive declines in plant fitness , growth and survival show compensatory responses to warming that buffers overall population growth , compensatory responses of ramet growth and clonal reproduction buffer populations from the effects of grazing and harvest , density-dependent mortality due to post-dispersal seed consumption decreases seedling density, resulting in increased fecundity and therefore compensating for low seedling numbers (Pityopsis aspera var. aspera (pineland silkgrass), increasing density decreases \u03bb, but this effect is alleviated by fire . Thus, IPMs, by incorporating environmental covariates in sub-regressions and allowing the use of size-based regression than discrete size classes, can overcome potential pitfalls of underpowered designs or smaller datasets , temperature and precipitation affect fecundity but not growth or survival matrix population models, which use stage- or age-structured state variables and (ii) IPM, which use continuous (often size-dependent) state variables to predict population growth rates as well as (iii) population viability analyses that estimate population size (e.g. count data) from one monitoring event to the next.Vital rates: Rates corresponding to an organism\u2019s individual life stages or progression through development .Additive effects: Type of interaction when the combined impact of two or more stressors on an ecological response is equal to than their algebraic sum; in this case, studies of single stressors can be added to estimate their combined effect.Non-additive interactions: Type of interaction when the combined impact of two or more stressors on an ecological response is not equal to their algebraic sum, such that the intensity of response to one stressor changes with the presence of the other; can be synergistic or antagonistic.Synergistic: Type of non-additive interaction when the combined impact of two or more stressors on an ecological response is greater than their algebraic sum; one stressor can exacerbate the effects of another.Antagonistic: Type of non-additive interaction when the combined impact of two or more stressors on an ecological response is less than their algebraic sum; one stressor can alleviate the effects of another.Perturbation analyses: Demographic analyses exploring how population growth rates respond to changes in vital rates; types of perturbation analysis include (i) prospective analyses (e.g. sensitivity and elasticity) that test how much \u03bb depends on vital rates independent of variability and (ii) retrospective analyses (e.g. LTRE) that decompose variance in \u03bb as a function of variance in vital rates.Demographic compensation: Opposing vital rate responses to stressors wherein the positive effects of one vital rate can negate the negative effects of another.Density-dependent processes: Population-level processes that are sensitive to fluctuations in population density .Kernel: A probability density function that maps the change in the size distribution of individuals at time t to the size distribution after one timestep (t + 1)."} +{"text": "Acne vulgaris is a common skin condition that affects both adolescents and adults worldwide and frequently results in acne scars . AtrophiA 2016 Cochrane study providedData from some of the included RCTs showed that fractional laser, chemical peeling (with and without skin needling), and injectable fillers were more effective than comparator treatments. Many studies that compared other treatment modalities to each other or to placebo concluded no significant difference in either participant-reported or investigator-assessed scar improvement. This review found moP=.0005). Another multicenter, randomized, prospective study [P=.0136). These studies further support the efficacy of injectable fillers for treating acne scars, though additional research with long-term follow-up is warranted to assess the durability of outcomes.Results of clinical trials published subsequent to this review provide"} +{"text": "Angioleiomyoma, a rare variant of leiomyoma, is a benign tumor of mesenchymal origin. Angioleiomyomas of the female urogenital tract are extremely rare, with only six cases of uterine cervical angioleiomyoma previously reported in the literature. In this case study, we report on a 49-year-old female patient who presented with menorrhagia whose initial magnetic resonance imaging (MRI) findings suggested cervical squamous cell carcinoma (SCC). However, following the hysterectomy, histological examination confirmed the lesion to be angioleiomyoma. To the best of our knowledge, there have been no previously reported cases of angioleiomyomas presenting with MRI findings that are suggestive of uterine SCC. Recognizing that angioleiomyomas can mimic uterine malignancies on MRI may prove beneficial for future diagnostic and treatment strategies."} +{"text": "Background: Measles is a highly transmissible respiratory virus that presents with nonspecific prodromal symptoms followed by a characteristic cephalocaudal rash. In the prodromal phase, children with measles can be challenging to differentiate from children with other circulating respiratory viral infections. A measles outbreak in Central Ohio starting in October 2022 coincided with a national surge in children with viral respiratory infections which presented unique challenges in preventing healthcare transmission in the pediatric ambulatory setting. Methods: Following initial identification of presumed community transmission of measles in Central Ohio in November 2022, a multidisciplinary measles response team was convened at Nationwide Children\u2019s Hospital (NCH) to prevent secondary healthcare transmission via rapid-cycle quality improvement. Prevention efforts were focused broadly across NCH ambulatory locations in Central Ohio, including the main campus and offsite emergency departments, regional urgent cares, and primary care network. Preliminary risk factors were identified via chart review of initial cases, which included vaccine status, ZIP code of residence, and known daycare or household exposure. These risk factors were used to guide an intervention bundle comprising enhanced screening at registration and triage, creation of electronic medical record alerts to identify at-risk patients, increased clinician education, and expanded community messaging. As the outbreak evolved, risk factors were updated, and interventions were adjusted to adapt response. Outcome metrics included total patient exposures as well as the relative exposure score. The exposure score was an internal metric derived using the vaccine status of exposed patients and ventilation at the site of exposure to assess likelihood of secondary cases occurring from an exposure. Results: In total, 65 patients with measles were seen at NCH facilities between October 29 and December 8, 2022. The outbreak response was divided into 4 periods: (1) cases identified retrospectively prior to first diagnosis , (2) initial case discovery , (3) implementation of prevention bundle , and (4) updates to the response . Ambulatory healthcare exposures and incidence of secondary cases decreased over the outbreak periods in response to implementation of the prevention bundle . Conclusions: An outbreak of measles occurring simultaneously with peak respiratory viral season presented challenges in early identification of suspected cases and mitigation of healthcare exposure. Transmission was effectively prevented following rapid deployment of a prevention bundle adjusted in real-time through rapid-cycle quality improvement. Ongoing longitudinal vaccination efforts are needed to sufficiently mitigate transmission risk in communities with under-vaccinated populations.Disclosures: None"} +{"text": "Background: A sustainable, continuous supply of alcohol-based hand rub (ABHR) is essential for healthcare workers in health facilities. The WHO provides guidance for production in individual health facilities. In Uganda, using this guidance, an innovative approach was implemented at the district local government level to produce and subsequently distribute ABHR to primary-care health facilities that have limited capacity for local facility-level production. This project was supported by the CDC in collaboration with the Infectious Diseases Institute (IDI) and targeted governmental or district engagement with local partners to ensure sustainability. Methods: District stakeholders were engaged to obtain buy-in and define roles and responsibilities. Overall, 4 staff members in each of 6 supported districts were nominated by District Health Officers for training: 2 staff members were trained to produce ABHR and conduct internal quality control and 2 were trained on external quality control. Districts provided ABHR production-unit facilities and facilitated integration within the government essential supplies delivery system, National Medical Stores in Uganda, which supports last-mile delivery to facilities. An implementing partner purchased initial raw materials necessary for production. The cost of materials for local production was compared to the price of commercial ABHR available in Uganda. Results: Between January and August 2021, 23 staff members were trained, and 380 batches of quality-assured ABHR were produced and distributed to 278 health facilities. Consumption of ABHR in the first distribution was used to benchmark predicted ABHR consumption per targeted facility in subsequent months. Increased demand for ABHR due to the COVID-19 pandemic and the Ebola virus disease outbreak in central Uganda (September 2022) was addressed through emergency requests on a case-by-case basis. ABHR local production costs $3 per liter for materials, less than half of commercial ABHR ($8 per liter). Conclusions: Early results suggest that this approach is potentially sustainable but requires national advocacy as well. Leveraging existing distribution systems while building local capacity for ABHR production and distribution may improve longevity of such innovations in similar resource-limited settings.Disclosure: None"} +{"text": "Mild traumatic brain injury is a complex neurological disorder of significant concern among athletes who play contact sports. Athletes who sustain sport-related concussion typically undergo physical examination and neurocognitive evaluation to determine injury severity and return-to-play status. However, traumatic disruption to neurometabolic processes can occur with minimal detectable anatomic pathology or neurocognitive alteration, increasing the risk that athletes may be cleared for return-to-play during a vulnerable period and receive a repetitive injury. This underscores the need for sensitive functional neuroimaging methods to detect altered cerebral physiology in concussed athletes. The present study compared the efficacy of Immediate Post-concussion Assessment and Cognitive Testing composite scores and whole-brain measures of blood oxygen level\u2013dependent signal variability for classifying concussion status and predicting concussion symptomatology in healthy, concussed and repetitively concussed athletes, assessing blood oxygen level\u2013dependent signal variability as a potential diagnostic tool for characterizing functional alterations to cerebral physiology and assisting in the detection of sport-related concussion. We observed significant differences in regional blood oxygen level\u2013dependent signal variability measures for concussed athletes but did not observe significant differences in Immediate Post-concussion Assessment and Cognitive Testing scores of concussed athletes. We further demonstrate that incorporating measures of functional brain alteration alongside Immediate Post-concussion Assessment and Cognitive Testing scores enhances the sensitivity and specificity of supervised random forest machine learning methods when classifying and predicting concussion status and post-concussion symptoms, suggesting that alterations to cerebrovascular status characterize unique variance that may aid in the detection of sport-related concussion and repetitive mild traumatic brain injury. These results indicate that altered blood oxygen level\u2013dependent variability holds promise as a novel neurobiological marker for detecting alterations in cerebral perfusion and neuronal functioning in sport-related concussion, motivating future research to establish and validate clinical assessment protocols that can incorporate advanced neuroimaging methods to characterize altered cerebral physiology following mild traumatic brain injury. et al. report that blood oxygen level\u2013dependent signal assessed by functional MRI outperforms a standard post-concussion neurocognitive test for classifying concussed athletes and predicting post-concussion symptoms. Blood oxygen level\u2013dependent signal variability may hold promise as a neurobiological marker for alterations in cerebral perfusion and functioning following concussion.Anderson Athletes with minimal physiological and neurocognitive symptoms may therefore be cleared to return-to-play prematurely, which can exacerbate symptoms, increase risk for severe secondary injuries and complicate or prolong recovery.8 Thus, current research aims to discover neurobiological markers that can be used to objectively assess the presence and severity of SRC and to determine when the brain has recovered sufficiently to permit safe return-to-play.Clinicians rely on a variety of assessments to diagnose SRC, including brief neurological examinations, symptom checklists, neurocognitive tests 9 Acute biomechanical injury\u2014sudden stretching of neuronal and axonal membranes\u2014triggers a cascade of neurometabolic changes including the abrupt release of neurotransmitters, ionic fluxes and unregulated extracellular glutamate release, ultimately leading to hyperglycolysis and axonal injury or cell damage.8 This intricate \u2018neurometabolic cascade\u20198 can manifest sequelae including dizziness, nausea, headache, insomnia, amnesia, attentional issues and other physiological and neurocognitive symptoms.11Concussion symptoms reflect a complex series of neurometabolic events that occur during and after the initial impact. Physiological damage from SRC typically occurs in stages, starting with the initial impact or change in velocity and subsequent structural deformation.13 Repetitive TBI in these areas is a particularly serious concern in SRC, as secondary blows that occur during this vulnerable metabolic window can produce catastrophic secondary impairments,14 highlighting the need for accurate diagnostics for safely clearing individuals to return to normal activity following a concussion.Several brain regions, including anterior frontal and temporal areas, medial temporal structures, corpus callosum and subcortical white matter pathways, are particularly vulnerable to bruising and injuries caused by inertial forces.15 researchers have increasingly utilized more advanced functional neuroimaging techniques to elucidate underlying changes in neuropathology post-injury.16 Functional MRI (fMRI) has shown promise for characterizing alterations in neural function post-mTBI across multiple domains. Task-based fMRI studies have demonstrated changes in activation in the parietal cortex, dorsolateral prefrontal cortex and the hippocampus in concussed athletes relative to healthy controls.17 Further, functional connectivity assessed from resting-state fMRI revealed altered connectivity within the default mode, fronto-parietal and motor-striatal networks relative to controls in individuals with mTBI.19 fMRI methods may provide objective biomarkers of neurophysiological injury, affording greater sensitivity and specificity for SRC diagnoses. Recent research suggests that while structural imaging and neurocognitive tests did not accurately discriminate mTBI patients from controls, resting-state functional connectivity measures correctly classified SRC status and predicted long-term cognitive sequealae.20 Functional neuroimaging methods may facilitate SRC evaluation through identification of altered haemodynamics and neurometabolism, detecting impaired neurovascular coupling, cerebral blood flow (CBF) and oxygen metabolism associated with abnormal brain function.21As neurobiological correlates of cognitive and mental health dysfunction from SRC are difficult to detect with standard axial neuroimaging techniques ,23 and that patterns of variability as measured from blood oxygen level\u2013dependent (BOLD) signal are closely linked to neural information processing, cognitive function and brain health.25 Recent studies have demonstrated that BOLD variability can detect vascular pathologies in cerebral small vessel disease,26 Alzheimer\u2019s disease,27 post-traumatic stress disorder28 and stroke29 by capturing underlying differences in cerebrovascular compliance26 that alter haemodynamic function and neurovascular coupling, motivating the investigation of BOLD variability for detecting neurophysiological alterations in mTBI.Neuroscience evidence demonstrates that regional brain activity is inherently variable over time31 increased reactivity of smooth muscle in microvessel walls32 and reduction in the density and diameters of capillaries both proximal and distal to the site of injury.33 Furthermore, altered BOLD variability can indicate sites of neural proliferation and synaptogenesis, indexing post-mTBI neuroplasticity that drives changes in neural signalling and BOLD activation during recovery.15 BOLD variability may therefore serve as a biomarker of changes in individuals\u2019 cerebral vascular status during and following traumatic neurophysiological insult, potentially assisting in the diagnosis of SRC.Mechanisms that may alter BOLD variability following mTBI may include changes in cerebral perfusion,The aim of the present study is to compare regional measures of BOLD variability and cognitive assessment scores for their complementary roles in the evaluation of SRC. Neuroimaging indices of BOLD variability may represent a novel lens for objectively evaluating SRC status by detecting functional disruption, providing information beyond conventional neuropsychological assessment batteries that may improve the detection and management of concussion pathology. While clinically informative, neurocognitive assessments remain limited in their ability to assess the extent of injury or identify neurophysiologically vulnerable individuals. To investigate the potential role of neurocognitive testing and functional neuroimaging in SRC diagnosis, we examined group differences in regional BOLD signal variability and neurocognitive performance on ImPACT in athletes diagnosed with SRC (compared against age-matched control athletes without SRC). We then applied a supervised machine learning algorithm (bagged ensemble random forests) to assess whether whole-brain BOLD variability measures, ImPACT module scores or BOLD and ImPACT composite scores together can discriminate healthy, concussed and repetitive concussion patients. We further applied bagged random forests to assess the extent to which regional BOLD variability measures and ImPACT scores in isolation or combination accurately predict clinical symptom load. Our study therefore assessed BOLD variability in both classification and regression machine learning frameworks for detecting SRC status or post-concussion symptoms from functional neuroimaging data .This study was carried out in accordance with the recommendations and approval of the University of Birmingham Research Ethics Committee. The protocol was also approved by the National Institute of Health Research Centre for Surgical, Reconstruction and Microbiological Research Centre (NIHR SRMRC\u2014Ethics Ref. 11-0429AP28). All subjects gave written informed consent in accordance with the Declaration of Helsinki. Deidentified data from this cohort may be made available by the authors on request.34 Participants included 29 semi-professional rugby athletes diagnosed with SRC and 6 additional rugby athletes diagnosed with repetitive SRC over a 21-day window. Athletes were excluded if they required hospital admission after initial assessment for concussion; presented with intracranial blood, brain tissue injury or non-concussion\u2013related pathologies on initial CT/MR scan; or had history of neurodegenerative pathology or chronic alcohol or drug abuse. In addition, 15 age-matched controls who have not received a concussion in the previous 3 months were enrolled. Other study design features are reported in Yakoub et al.34Study participants were recruited through the Surgical Reconstruction and Microbiology Research Centre (SRMRC), based at Queen Elizabeth Hospital of Birmingham (United Kingdom), as part of the repetitive concussion in sport (RECOS) study.1-weighted magnetization-prepared gradient echo structural image was acquired for each participant .All data were collected on a 3 Tesla Philips Achieva MRI scanner in Birmingham University Imaging Centre (BUIC). A high-resolution multi-echo T35 sensitive to BOLD contrast .The functional neuroimaging data were acquired using an accelerated single-shot gradient echo echoplanar imaging (EPI) sequenceDuring the resting-state fMRI scan, participants were asked to keep their eyes closed. Visual contact could be established at any time to the control room via a coil-mounted reverse mirror. All participants were instructed to lie still, keep their eyes closed and to try and think of nothing.fMRIPrep 20.2.037 and XCP Engine 1.0.39 Pre-processing entailed slice timing correction, motion correction, spatial smoothing [3\u2005mm full width at half maximum (FWHM) kernel], nuisance signal regression, temporal bandpass filtering, linear registration of functional images to structural images and non-linear registration of structural images to a standard-space MNI152 brain template (2\u2005mm isotropic voxel resolution).All MRI data processing was performed using containerized processing pipelines for reproducible analysis of neuroimaging data. Pre-processing steps were performed using 40 All nuisance variables were modelled via a single generalized linear model (GLM), to remove spurious correlations and noise introduced by head motion and variables of no interest. In addition to ICA-AROMA components classified as noise, these included head motion correction parameters, individual volume motion outliers estimated using DVARS41 with outliers flagged above 1.5 standardized DVAR, framewise displacement exceeding 0.5\u2005mm and mean white matter and cerebrospinal fluid signals averaged across all voxels identified from the segmentation of the high-resolution magnetization-prepared rapid gradient echo (MPRAGE). The fully pre-processed resting-state fMRI data were taken as the residuals from this GLM model. The residual image was transformed into normalized MNI152 space and resampled to 4\u2005mm isotropic voxels.Head motion parameters were accounted for using independent component analysis with automatic removal of motion artefacts (ICA-AROMA) analysis.43 BOLD signal variability was computed as the standard deviation of successive differences in the time-series signal extracted for each of the 200 grey matter regions defined by the Schaefer parcellation atlas.44 MSSD mean-centres the amplitude of difference in BOLD signal between frames, providing a more reliable metric of BOLD variability than standard deviation by avoiding inflated estimates of variability. The Schaefer 200 atlas provided sufficient spatial resolution and functional homogeneity within each parcel for examining regional MSSDBOLD signal across the entire cortex.Resting-state mean square successive difference (MSSD)45 The test was designed in the early 1990s specifically to assess concussed players of the National Football League46 and is now a Food and Drug Administration (FDA)\u2013approved neuropsychological testing tool in SRC.47 Inclusion of this particular cognitive test has been demonstrated to increase the sensitivity of post-concussion assessment beyond symptomatic evaluation and physical examination.48Participants completed the 25\u2005min computerized ImPACT assessment under identical administration conditions. ImPACT is a multi-domain online neuropsychological test that has been used as a standard technique documenting baseline cognitive function, characterizing the effects of concussive injury and monitoring the progress of recovery.49 and test\u2013retest reliability.50ImPACT includes a demographic survey, a brief medical history questionnaire and a post-concussion symptom scale consisting of 22 commonly reported symptoms. All participants indicated whether they endorsed each symptom and rated the extent of symptom severity on a seven-point Likert scale (0 = \u2018not experiencing the symptom\u2019 to 6 = \u2018severe\u2019). Scores were summed with higher scores reflecting more post-concussive symptoms. The six neurocognitive ImPACT sub-tests consist of word memory, design memory, X\u2019s and O\u2019s, symbol match, colour match and three letters. Five neurocognitive domain scores are derived from the sub-tests: verbal memory, visual memory, visual\u2013motor processing speed, reaction time and impulse control. Higher scores on the verbal memory, visual memory and visual\u2013motor processing speed composites reflect stronger performance, whereas a higher score on the reaction time composite reflects slower or worse performance. The impulse control composite provides a measure of errors on testing and is used to determine test validity. Test scores were converted to percentile measures and adjusted for age, gender, learning disability and level of education. ImPACT has adequate psychometric properties, including good construct validity34 Measures collected include Digit Span,51 Digit Symbol Coding and Symbol Search,52 a nine-hole peg test of fine motor dexterity53 and balance assessments including a virtual reality system,54 gait analysis56 and the modified balance error scoring system (mBESS),57 facilitating precise concussion diagnosis. Additional assessments, inventories and neuroimaging components collected by the RECOS protocol are reported in Yakoub et al.34As part of the RECOS study protocol, study participants completed additional screening and assessment inventories to examine clinical presentation of SRC.BOLD measures and ImPACT module composite scores, statistical unpaired t-tests were performed and corrected for multiple comparisons using Benjamini\u2013Hochberg control of the false discovery rate (FDR). These comparisons provide for interpretable identification of the specific ImPACT scores and modules most readily associated with SRC status, assessing for group-level effects of SRC and repetitive mTBI that emerge in variables used by our machine learning framework.To identify between-group differences in regional MSSD58 RF machine learning achieves high prediction accuracy when presented with a large number of input variables relative to the sample size,60 as is the case for our neuroimaging data, while still performing well with small numbers of input variables (as is the case for ImPACT scores). This importantly affords the ability to directly compare predictions of concussion status and post-concussion symptoms made by modelling BOLD variability and ImPACT composite scores using the same machine learning approach. Other motivations for selecting RF machine learning for this study include RF\u2019s understood performance, ease of use and resistance to outliers, as well as its capability to consider all BOLD variability regions jointly, avoiding an initial feature selection or engineering step in support of the exploratory nature of this study. Critically, this approach avoids using the results from between-group feature comparisons of BOLD variability to subset regional BOLD variability features that build a smaller and better-performing RF model, as feature engineering BOLD variability metrics is not a goal of the present study.BOLD variability indices and ImPACT composite scores were further assessed for their ability to differentiate healthy, concussion and repetitive concussion subjects and predict clinical symptom load using a random forest (RF) machine learning approach. RF is an ensemble machine learning method that trains an ensemble (i.e. forest) of decision trees to perform either classification or regression.BOLD measures and ImPACT composite scores were used variously as input features (i.e. independent variables), with output features (i.e. dependent variables) being group membership (classification) or post-concussion symptoms (regression). Each RF ensemble was parameterized using leave-one-out crossfold validation, with the minimum leaf size being the only tuned parameter. For ImPACT score models, minimum leaf size was tuned to 5 (preventing overfitting); otherwise, minimum leaf size was tuned to 20. Trees were grown by splitting input variables to maximize reduction in the Gini impurity index,61 repeated iteratively until maximum depth is reached or when all samples belong to a single class. The number of decision trees was increased until mean squared error (MSE) of out-of-bag (OOB) classification or regression predictions stabilized . Forests were grown to 5000 trees total.In our approach, bagged RF regression and classification were performed using built-in functions in MATLAB R2021a. MSSDK from a model fold (i.e. bag) that has been trained with resampling from all other athletes in our data set N, affording a direct test of RF models\u2019 ability to generalize their training data to unseen test set (i.e. OOB) subjects. The overall OOB prediction performance of RF machine learning evaluate three separate sets of input features: (i) ImPACT module composite scores, (ii) whole-brain MSSDBOLD measures and (iii) ImPACT score and MSSDBOLD measures jointly combined. This approach allows us to assess the utility of BOLD variability or ImPACT scores in isolation or combination when predicting SRC status and post-concussion symptoms. One versus all receiver operating characteristic (ROC) curves were calculated for the classification of each group across the three classes of RF models, indicating the true positive rate (i.e. correctly predicting group membership) versus the false positive rate (i.e. incorrectly predicting group membership in the next most likely classification).Individual RF machine learning predictions were generated from an ensemble of OOB decision trees, where the ensemble of decision trees that generate a prediction did not include the test subject\u2019s data in any resampled training data set. Restated, the set of decision trees used to make a prediction for test predicts subject The ROC area under the curve (AUC) was computed for all combinations of group and model to diagnose the overall prediction performance of each class. This AUC is the integral of the ROC curve\u2014i.e. the probability that the conditional probability of a random positive observation is greater than the conditional probability of a random negative observation. Thus, larger probabilities represent greater sensitivity and specificity for the positive label, suggesting greater utility for detecting SRC.For regression models, RF machine learning was instead trained to predict total reported post-concussion symptoms from the same combinations of input BOLD variability and ImPACT score variables (while ignoring group membership). Importantly, control subjects may incidentally report low levels of concussion symptoms in the absence of SRC\u2014further motivating the investigation of functional neuroimaging metrics for detecting SRC status.P value = 0.11). Impulse control is a measure of test validity, used to discard tests with a value above 30. The highest observed impulse control score in our sample was 15 , suggesting all ImPACT scores represent valid administrations and should be included in our analysis.Statistically significant between-group differences were not observed for ImPACT\u2019s composite measures of verbal memory, visual memory, visual\u2013motor processing speed, reaction time and impulse control between healthy control, concussed individuals and repetitive concussion individuals. BOLD measures for concussion or repetitive concussion athletes compared with healthy controls. In contrast with ImPACT score findings, reliable regional differences in MSSDBOLD signal are found in occipital and inferior temporal lobes, premotor areas and the ventral anterior cingulate. We observe that regional MSSDBOLD values are significantly decreased in concussed subjects relative to healthy controls, displaying significantly less fluctuation in BOLD signal amplitude over time. In contrast, all significant regions in repetitive concussion patients show greater MSSDBOLD than in healthy controls, reflecting significantly more pronounced variability in regional BOLD signal relative. This dissociation between BOLD signal decreases in concussion and increases in repetitive concussion suggests that unique pathophysiological mechanisms that implicate functional alterations may underlie the more severe sequelae observed in repetitive SRC.BOLD metrics and ImPACT scores were used to train RF machine learning models. BOLD demonstrated the highest classification accuracy, with ImPACT scores alone producing models with the lowest classification accuracy.Despite evidence for group-level differences in regional BOLD signal variability, no feature selection was performed prior to training RF classifier models, and therefore, all regional MSSDBOLD data. Only the model trained on ImPACT scores alone under-performs this baseline value for classifying concussion subjects . Here, we observe the greatest difference in classification performance between ImPACT scores and MSSDBOLD measures, suggesting BOLD variability is both a more sensitive and specific index of signal associated with repetitive SRC than ImPACT scores.BOLD variability in combination). Ground truth positive labels are reflected along rows, with OOB classification labels in columns . Label confusion suggests this best-performing RF model (correctly classifying 31/50 athletes in our sample) is most sensitive for detecting concussion and repetitive concussion. However, the RF model also displays markedly lower specificity for concussion, misclassifying a majority (11/15) of healthy control subjects as concussed. This suggests that while BOLD variability indeed facilitates detection of SRC and repetitive mTBI, models trained to include BOLD variability measures may require more targeted feature engineering to better distinguish between health controls and subjects with lower SRC severity, as has been shown using functional connectivity data.20 This model\u2019s performance for classifying control subjects (4/15) is also an improvement over the RF model trained using only ImPACT composite scores, which misclassifies all control subjects as concussion subjects (0/15). This performance likely reflects the large label size of concussion athletes and the lack of reliable between-group differences observed with ImPACT scores. These results suggest that MSSDBOLD measures indeed contribute to a classification model with improved prediction accuracy for distinguishing healthy and concussed individuals.BOLD holds promise as a sensitive biomarker for detecting symptomatic abnormalities in cerebrovascular status in athletes with SRC. We briefly review the findings with respect to regional MSSDBOLD and ImPACT modules by examining (i) between-group differences, (ii) their classification accuracy using the categorical RF model and (iii) their regression accuracy using the continuous RF model.The present study demonstrates that MSSD12 Our results identify several cortical areas in those regions that demonstrate significant differences in MSSDBOLD measures in the presence of SRC or repetitive mTBI. Specifically, MSSDBOLD measures in occipital and inferior temporal regions and midline structures (premotor cortex and anterior cingulate) significantly differ between control and concussed athletes. These regions are particularly vulnerable to injury due to inertial forces, either front to back or rotational. We also observed a dissociation in the directionality of BOLD variability changes. Concussed athletes displayed universally decreased BOLD variability across affected brain regions. In addition to reflecting altered neurovascular coupling, patterns of low regional BOLD variability observed for concussion patients may also in part reflect functional hyperconnectivity commonly observed following mTBI,62 such that stronger functional coupling of distal regions entrains BOLD signal amplitude to a more limited band. In contrast, repetitive concussion subjects display uniformly elevated BOLD signal variability in affected regions. As the elapsed duration between most recent SRC and clinical assessment is comparable for concussion and repetitive concussed athletes . In these models, the majority of features ranked as highly important represented BOLD variability measures, not ImPACT scores. Classification based on the categorical RF models demonstrated a higher sensitivity or true positive rate for accurately identifying individuals with repetitive concussions when using BOLD variability (AUC = 0.66) than was observed using ImPACT scores (AUC = 0.25). Overall multi-label classification accuracy was also increased when BOLD variability data were included, with classification error decreasing from 46% to 38% when ImPACT scores and BOLD variability were jointly modelled. This was partially due to increases in classification accuracy for identifying subjects with high overall symptom loads as belonging to concussion or repetitive concussion groups. Classification accuracy of control subjects, while still low, also increased when BOLD variability data were included in the RF models, suggesting that BOLD variability may have greater specificity than ImPACT for detecting SRC. The left middle frontal gyrus, left frontal pole and temporal occipital fusiform gyrus had the largest effects in the RF model classification, which is in line with research suggesting regions in the frontal and temporal lobes are commonly affected in mTBI.BOLD data in a single model produced the best prediction performance with a MSE of 26.9. Feature importance scores indicated that the main variables used to generate predictions for this model were BOLD variability measures, suggesting that variance associated with ImPACT scores is of lower importance than BOLD variability during forest growth and model training. Results from these continuous RF models indicate that MSSDBOLD is a more sensitive predictor of post-concussion symptom totals and that jointly considering functional and neurocognitive data together is a useful approach for machine learning models to improve the accuracy of predictions for total SRC symptom load.Prediction accuracy was highest for RF models trained to predict the total number of post-concussion symptoms using the combination of ImPACT composite scores and BOLD variability variables. The continuous prediction model trained only on ImPACT scores converges during training to a MSE of 30.5 when predicting post-concussion symptoms, showing the largest error and the worst performance. A continuous RF model that trained only on BOLD variability data demonstrated lower MSE (28.7), reflecting improvements to predictive performance. Jointly including ImPACT and MSSDBOLD can be generalized to other populations (i.e. children and adolescents with SRC and non-athletic populations with mTBI). Second, MSSDBOLD cannot currently be used to assess severity of an injury itself, only the extent of the symptom load that it produces, and additional screening methods involving structural neuroimaging techniques will be still required to reveal the extent of injury and changes in pathology during recovery. Third, the analysis approach using MSSDBOLD cannot reveal the actual damage to the vasculature and surrounding neural cells at the site of injury. Fourth, while our study observes high performance for predicting total clinical symptom load in healthy and SRC athletes, our SRC classification models will often mistake healthy controls for concussed subjects. This may be due to our sample\u2019s imbalance between control (N = 15) and concussion (N = 29) subjects or may suggest that more a more precise feature selection step is required to identify MSSDBOLD regions more specific for SRC, possibly requiring higher-resolution cortical parcellation schemes. On the other hand, mismatches in performance may potentially be addressed by methods that do heavily subset BOLD variability as an initial feature selection step, potentially inducing parity in the number of BOLD and ImPACT input variables to afford comparison of prediction accuracy through alternative ML approaches . While random forests appear to be sufficient for our purposes in this manuscript, we do not intend to suggest they are necessary. Fifth, there may be other representations of variability besides MSSDBOLD that better capture the extent of underlying functional alterations in SRC, including representations that jointly consider resting static or dynamic functional correlation or large-scale intrinsic brain network organization. Future research should consider investigating these elements at a fine-grained level to further elucidate neurobiological pathologies in SRC. Sixth, and finally, functional MRI acquisition remains prohibitive in many outpatient clinical settings, though we believe our results at do least motivate further exploration of BOLD variability for monitoring athletes before and after SRC, particularly from a personalized or precision medicine perspective.In this study, we demonstrate that BOLD signal variability holds promise as a diagnostic biomarker for detecting functional neural alterations following SRC. While our approach motivates systematic exploration into BOLD variability\u2019s utility for detecting injury in clinical neuroimaging of concussion, there are several limitations and challenges to this approach. First, given that the concussed group is a highly homogenous athletic population, future studies should examine whether the observed deviations in MSSD73 consistent with the present findings. Executive dysfunction can be a pernicious consequence of TBI,75 implicating alterations to network topology and dynamics in neurological sequela following mTBI.76 Future research may wish to examine brain network alterations for their impact on other cognitive domains or as a potential neurobiological marker of injury and recovery status.These findings emphasize the need for future research to examine how network topology and dynamics are altered by TBI. Recent research has highlighted the importance of global brain network topology for facilitating cognitive abilities,BOLD assessed from resting-state fMRI are sensitive to abnormalities in cerebrovascular status in athletes with SRC. Further, we show that regional MSSDBOLD measures can more sensitively and specifically identify concussed and repetitive concussed individuals within a RF machine learning framework compared with standardized neurocognitive tests. In contrast, ImPACT composite scores do not capture reliable between-group differences in concussion status and cannot be used in isolation to build an RF model that discriminates between concussion, repetitive concussion and healthy athletes. Combining BOLD variability and ImPACT scores leads to the highest prediction performance, supporting the claim that altered BOLD variability provides novel information about altered cerebral vascular status that can aid diagnosis and return-to-play decisions when collected alongside existing assessment protocols for the detection of SRC. Further, we provide evidence that MSSDBOLD contributes to prediction of total post-concussion symptoms, outperforming ImPACT scores across healthy and concussed patients. In conclusion, this paper provides initial evidence that BOLD variability holds promise as a potential clinical marker for SRC, motivating a more systematic exploration of BOLD variability as a candidate biomarker in future work. To investigate the sensitivity and efficacy of MSSDBOLD in diagnosing SRC, future neuroimaging research may wish to deploy MSSDBOLD measures alongside neuropsychological testing protocols and structural neuroimaging methods, providing a more complete assessment of athlete health that includes cerebrovascular alterations and associated cognitive deficits to better facilitate detection of injury in SRC and guide return-to-play decisions.Diagnosis of SRC can be difficult due to the low sensitivity of assessments designed to identify cognitive deficits in athletes with suspected injuries. In addition, clinical evaluation of SRC using structural imaging methods is limited to characterizing anatomic pathology and cannot detect haemodynamic or neurometabolic disruptions. In this work, we provide evidence that functional neuroimaging indices of MSSD"} +{"text": "Sparsity finds applications in diverse areas such as statistics, machine learning, and signal processing. Computations over sparse structures are less complex compared to their dense counterparts and need less storage. This paper proposes a heuristic method for retrieving sparse approximate solutions of optimization problems via minimizing the [[EQUATION]] quasi-norm, where $080% . SimilarHowever, such concepts cannot be directly transferred to FVCA, since preoperative outcome simulation needs to integrate the donor's and patient's facial features at the same time. Subsequently, reliable predictions can only be made once the donor is identified. Automated facial landmark recognition systems such as Emotrics or 3D VECTRA could be used for quick and precise facial measurements , 20. FolThe potential advantages of AI are substantial, particularly for intricate procedures such as FVCA. The degree to which preoperative planning can be detailed and meticulously executed largely predicts the potential success of the outcome.Precision and real-time feedback are essential pillars of contemporary surgical practice. These elements are considerably amplified with the integration of AI into intraoperative image-guidance systems . These aDuring FVCA, the precise fitting of the donor tissue onto the recipient's facial structure is paramount for the success of the procedure , 27. AI Real-time feedback plays a significant role during surgery, a role that might be efficiently fulfilled by AI-integrated intraoperative imaging systems. These systems provide surgeons with real-time data, enabling immediate adjustments to their surgical approach, which can prove invaluable during complex procedures like FVCA . More prDespite distinct advancements in the perioperative patient management including more patient-specific risk profiles, novel biomarkers, and targeted immunosuppressants, allograft rejection persists as a major burden in transplant surgery still affecting more than 15% of solid organ transplant (SOT) patients , 35. MorIn SOT, ML and DNN have been successfully investigated to identify risk patients for transplant rejection. Thongprayoon et al. performed ML consensus cluster analysis for 22,687 Black kidney transplant recipients identifying four distinct clusters. Interestingly, the authors found that the risk for transplant rejection was significantly increased in highly sensitized recipients of deceased donor kidney retransplants and young recipients with hypertension . In liveAcross the different vascularized composite allograft (VCA) surgery subtypes, 85% of VCA patients experience at least one rejection episode one year post transplantation with more than 50% of cases reporting multiple rejection episodes . Such epCancer represents a widely recognized complication of both SOT and VCA, since there is a two to four-fold elevated risk of malignancies following organ transplant. Remarkably, transplant recipients are at a 100-fold higher risk for developing skin cancer . While tAI technology has been shown to provide a versatile and precise screening platform for diverse cancer entities and detect mammographic abnormalities with comparable accuracy to radiologists and reduce radiologist workloads \u201370. Yi eFollowing FVCA, one transplant recipient patient was diagnosed with basal cell carcinoma of the native facial skin six years post-transplant, while another FVCA patient presented with a B cell lymphoma which was treated with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone . DespiteFVCA has emerged as a novel and versatile reconstructive technique to provide adequate therapy for patients with devastating facial wounds and trauma , 87. Whi"} +{"text": "Dystonia syndromes are diverse movement disorders characterized by disabling, painful, and sustained involuntary muscle contraction.Various neurosurgical interventions have been trialled for the treatment of dystonia, including peripheral denervation, intrathecal baclofen infusion, and ablating the basal ganglia or thalamus. However, deep brain stimulation (DBS) primarily targeting the globus pallidus internus (GPi) and the subthalamic nucleus (STN) has evolved as a covetable option with the ability to provide personalized, reversible, and titratable neuromodulation. The available literature has recently been reviewedIn the current edition of the Arquivos de Neuro-Psiquiatria, Listik et al.Similarly, intraoperative target selection has been further refined by studies employing stimulation-outcome mapping in large cohorts. Elias et al.Insights into outcome variation in DBS therapy have also come from the functional magnetic resonance imaging literature. Loh et al. demonstrate that optimal DBS programming engages a functional network resulting in sensorimotor cortex deactivation in 15 cervical dystonia patients with GPi-DBS.There is growing scientific evidence demonstrating the safety and efficacy of DBS for the treatment of medically refractory dystonia, however, optimal patient and surgical target selection remains unclear. Here multiple examples are presented that demonstrate how advances in neuroimaging are contributing to the understanding of DBS therapy in dystonia. These advances may lead to improved patient and target selection and DBS programming."} +{"text": "We present the first documented case of a fistula between the treated zone and the appendix after RFA in a patient with HCC. Contrast-enhanced CT and MRI revealed a subcapsular hepatic nodule with image findings of HCC located adjacent to the ascending colon and cecum. An ultrasound-guided core needle biopsy was subsequently performed to distinguish between hepatic metastasis and HCC. Post-RFA imaging identified a low-attenuating ablated area adjacent to an air-filled appendix. The patient later experienced complications, including increased liver enzymes and an abscess at the ablation site. Imaging revealed a fistulous tract between the RFA zone and the appendix. Over the following months, the patient underwent conservative treatment involving intravenous antibiotics and repeated percutaneous drainage, exhibiting eventual symptom relief and an absence of the fistulous tract upon subsequent imaging. This case highlights the rare complications that can arise during RFA due to peculiar anatomical variations, such as a subhepatic appendix, resulting from midgut malrotation and previous surgery. It is imperative for operators to be cognizant of potential anatomical variations when considering RFA treatment, ensuring comprehensive pre-procedural imaging and post-procedure monitoring. This case also emphasizes the potential viability of nonoperative management in complex scenarios in which surgical interventions pose significant risks."} +{"text": "Rates of late allograft loss have improved slowly in the last decades. Well described traditional risk factors that influence allograft survival include cardiovascular events, rejection, infections and post-transplant neoplasia. Here, we critically evaluate the influence of several non-immunological, non-traditional risk factors and describe their impact on allograft survival and cardiovascular health of kidney transplant recipients. We assessed the following risk factors: arterial stiffness, persistent arteriovenous access, mineral bone disease, immunosuppressive drugs residual levels variability, hypomagnesemia, glomerular pathological alterations not included in Banff criteria, persistent inflammation and metabolic acidosis. Recent high-level evidence confirms the superiority of transplantation in reducing all-cause mortality for most patients with end-stage kidney disease . In the We searched three databases: Medline, EMBASE and Cochrane Library, and included studies from January 2000 to December 2022 with the following terms: \u201ckidney graft survival\u201d, \u201ckidney graft loss\u201d, \u201cfailed kidney transplant\u201d, \u201cchronic allograft nephropathy\u201d, \u201crisk factors\u201d, \u201cchronic kidney disease progression\u201d.Late allograft failure is a heterogenous background picture of several multifactorial pathogenic entities that all contribute to kidney dysfunction in transplant patients. Naesens et al. elegantly described data derived from failing grafts: Importantly, one quarter of biopsies exhibit more than one coexisting disease, and almost one third of patients with lost allograft had no specific diagnosis on the last biopsy performed but highlighted the important prognostic capacity of the extent of chronic damage . ConsequRecent efforts have focused on better characterization of allograft loss and described a more complex picture of the multifactorial pathogenic processes. A study conducted by Mayrdorfer et al. examining 303 death-censored graft losses among 1642 transplant recipients discriminated primary failure causes (responsible for more than 50% persistent estimated glomerular filtration rate decrease) from secondary failure causes (contribution to less than 50% estimated glomerular filtration rate decline) and analyzed data in a time-dependent manner. Late allograft failure was mainly attributed to intercurrent medical events, defined as cardiovascular events or infections conducting to prominent decline in renal function, and representing almost 40% of late graft failures. Moreover, antibody-mediated rejection met increasing frequencies with time as a primary failure cause (48.6% of graft failures at more than 10 years from transplant intervention) while T-cell mediated rejection had a sharp decline with transplant vintage. Interestingly, calcineurin-inhibitors toxicity was isolated in only two cases as a primary cause, but it was described as the most frequent secondary cause responsible for graft loss (64 of 240 late graft failures). The authors once again highlighted the multifactorial etiology of transplant failure .The ability to predict the evolution of the transplanted kidney is of great significance and has been the center of some valuable research. Search of prognostic factors begins even before implantation with evaluation of donor quality. Preimplantation histology may provide important clues but clinical decisions of implanting or discarding the kidney based on this data have shown conflicting results. In a recent large multinational study, discarded kidneys due to biopsy alterations could have been offered to patients with improved survival and quality of life. Data shows 70% of implanted similar grafts matched with the refused grafts due to biopsy were functioning at 10 years .Prediction models can be computed by means of artificial intelligence and deep learning models to predict evolution of estimated glomerular filtration rate after kidney transplantation. Raynaud et al. identified, after performing multinomial regression models, seven significant determinants of progression: donor age, estimated glomerular filtration rate, proteinuria, graft scarring, graft interstitial inflammation and tubulitis, microcirculation inflammation and circulating anti-HLA donor specific antibodies. Resulting computed trajectories were significantly associated with progression to allograft loss .Other techniques proved good forecast capability utilizing sequence-to-sequence modelling in order to create a machine learning algorithm-based prediction model that is based on inputting repeated estimated glomerular filtration rate measurements .Recently, an interesting dynamic prediction tool that incorporates histological, immunological and clinical parameters together with repeated measurements of graft function was validated in multiple cohorts and proved superior prediction performance of allograft survival compared to other similar systems. Individualized parameters that altered survival were estimated glomerular filtration rate, proteinuria, delay between transplant and evaluation, Banff categories , mean fluorescence intensity of anti-HLA donor specific antibodies and repeated measurements of eGFR. The iBox system has proved good prediction ability of graft survival and it has been validated as a valuable endpoint in clinical trials in transplantation ,15.Cardiovascular disease has recently gained well-deserved attention since it represents the main driver of comorbidity and mortality in kidney transplant recipients. Pregnant emphasis was attributed to defining and addressing traditional cardiovascular risk factors in improving survival outcomes in this population. Management of these associated relevant comorbidities have been reviewed elsewhere and they do not meet the purpose of this paper 16,17].,17.16,17The association between increased values of arterial stiffness and eGFR decline has been noted in the general chronic kidney disease (CKD) population and suggests that the resulting hemodynamic stress insults the kidney by means of endothelial dysfunction and microvascular ischemia. Chronic inflammation, oxidative stress and overactivation of the renin\u2013angiotensin systems may represent other possible mechanistic underpinnings . Aortic Continuous functioning arteriovenous fistula after kidney transplantation has the potential to worsen the maladaptive remodeling changes in the cardiovascular system and alter kidney function. A meta-analysis addressing the impact of ligating the arteriovenous fistula showed that patients undergoing access occlusion had better cardiac morphological parameters and better kidney allograft function .Furthermore, patency at 5 years was only 61% and arteriovenous fistula-related complications were frequently reaching about 30% of patients. On the other hand, preservation of the vascular access may provide the advantage of an optimal backup strategy if transition to dialysis is needed. Consequently, decisions should be individualized on several parameters, mainly based on renal and cardiac functions and on selecting complications-prone profile of patients .After kidney transplantation, particularly older patients find themselves at an increased risk for pathological fractures. The fractures appear multifactorial in nature and are associated with unfavorable outcomes, such as subsequent graft loss or mortality. It remains unclear whether only the high end of mineral bone disease spectrum (fractures) is linked to allograft survival decline or if other biologic entities contribute as well .Persistent mineral abnormalities after kidney transplantation mainly include hypercalcemia and hypophosphatemia. Previous severe hyperparathyroidism and high levels of circulating PTH and FGF-23 are established risk factors for altered mineral metabolism post-transplantation. However, impact on outcomes is unclear. As they may not contribute directly to allograft loss and rapid eGFR decline, they are the main drivers of vascular calcifications affecting graft vessels and, interestingly, of tubulointerstitial calcifications on allograft biopsies ,31.Cinacalcet has proven its ability to correct persistent hyperparathyroidism after kidney transplantation and the associated metabolic derangements but without impact on bone mineral density or allograft survival . Data frBiphosphonate therapy in kidney transplant recipients has the clear benefit of improving bone mineral density. Recent studies have proven low rates of adynamic bone disease, strengthening the safety profile of this medication. However, there is no clear data on rates of fractures and there are no benefits or harms related to renal function evolution in kidney transplant recipients .Assessment of pre-transplantation profile of mineral bone disease phenotype may predict survival and high-risk patients. In a cohort of more than 11,000 patients, recipients that exhibited higher levels of pre-transplant serum alkaline phosphatase (>120/U/L) were subject to increased post-transplant mortality. No association was found between circulating PTH or calcium and post-transplant evolution .The negative correlation between graft survival and vitamin D deficiency has been described in an observational manner . InsuffiCurrent therapeutic armamentarium provides means to effectively correct mineral abnormalities in kidney transplant recipients. However, impact of described treatments on graft survival have been insufficiently studied and proved no significant benefits.Excessive immunosuppression contributes to significant complications linked to allograft loss; infections, malignancy and polyoma virus nephropathy account for about one third of graft losses . BecauseInterestingly, another tool available for the evaluation of drug exposure is the time in therapeutic range\u2014addresses the interval of time that a patient is exposed to correct predefined range of values of immunosuppression. Patients with high variability and time in therapeutic range < 40% were at increased risk of de novo donor-specific antibodies and at an estimated four times greater risk of graft loss by 5 years .Hypomagnesemia represents one of the most frequent electrolyte disturbances post-transplantation . SeveralMagnesium deficit exhibits diabetogenic effects and it represents a proven independent risk factor for post-transplant diabetes mellitus ,49. ReceReports on mortality are conflicting and derived from observational retrospective studies. There have been signals of the possible interaction between hypomagnesemia and graft dysfunction . RecentlMagnesium metabolism, however, is important and may have implications in long-term outcomes as it interferes with glycemic alterations, endothelial dysfunction and cardiovascular abnormalities. In addition, correction is cumbersome and magnesium levels may not reflect true stores. No significant trials regarding supplementation and the associated impact on graft function have been conducted .Overall, due to conflicting results and the presence of many confounders, such as the use of CNI, nutritional status, measurement issues, other additional studies addressing this problem will evaluate true impact.The kidney transplant biopsy interpretation is submitted to a well described and standardized score system\u2014Banff classification. Diagnostic entities are established by pathologists after grading several acute and chronic lesions . HoweverDenic et al. conducted a study with repeated biopsies in well-functioning transplant recipients at 5 years post-implantation. Three parameters previously linked to unfavorable graft outcomes were examined: glomerular volume, global glomerulosclerosis and ischemic appearance of glomeruli. All three parameters combine successfully predicted death-censored graft failure at 5 years. Moreover, glomerular ischemia is significantly associated with allograft loss, even after adjustment for Banff scores .Moreover, other recent data highlight the impact of early subclinical inflammation detected on surveillance biopsies on allograft survival. Patients with subclinical inflammation and tubulitis were exposed to a higher hazard of acute rejection and death-censored allograft loss .Implantation of the kidney allograft is often realized in uremic patients exhibiting a state of inflammatory milieu. Moreover, inflammation is enhanced by perioperative events and induced by other stressors. For example, brain death is linked to increased cytokine excretion and ischemia-reperfusion injury can lead to delayed graft function. All forms of rejection are responsible for elevated markers of inflammation, and viral infections could be a source of enhanced cytokine production leading to overreactive innate immunity . AtherosThe persistent inflammatory state is multifactorial and contributes to graft dysfunction by several mechanisms: triggering chronic hypoxia, extracellular matrix deposition and extending graft fibrosis . FurtherMetabolic acidosis identifies as one of the most common complications in kidney transplant recipients. The fall of bicarbonate and pH levels with a decrease in serum partial pressure of carbonic dioxide occurs mainly when the glomerular filtration rate falls under 30 mL/min in patients with chronic kidney disease. This threshold is higher in kidney transplant recipients, showing that metabolic acidosis may occur at higher GFRs in these patients ,64. The Data on allograft survival are pointing to metabolic acidosis as a risk factor for graft dysfunction in the long term. Park et al. conducted a study that showed that low TCO2 concentrations 3 months after transplant are associated with an increased risk of graft loss and death-censored graft failure . FurtherThus, these associations require the application of therapeutic measures to correct acidosis. From this point of view, the data are limited, with most studies focusing on alkali therapy. If supplementation with sodium bicarbonate is effective in patients witch chronic kidney disease, the data in kidney transplant recipients are limited. Schulte at al. evaluated the effect of sodium bicarbonate in kidney transplant recipients with chronic metabolic acidosis. Treatment with sodium bicarbonate was associated with an increased risk of graft failure with no changes in mortality. Authors speculated that the interference with gastric acid pH of oral bicarbonate intake may lead to altered absorption of mycophenolate mofetil. Consequently, patients may be exposed to lower plasma concentrations of mycophenolic acid . The recLong-term survival of kidney allografts is altered mainly by cardiovascular disease, malignancy and infections. However, in order to maximize survival, other relevant pathogenic entities need to be addressed. Care of kidney transplant patients is complex and needs to be centered also on many potential risk factors that can influence long-term survival, consisting of the following: metabolic derangements such as hypomagnesemia, metabolic acidosis and mineral bone disease after transplantation, cardiovascular disease manifesting as arterial stiffness, immunosuppressive drug metabolism and non-adherence, persistent inflammation and glomerular changes not highlighted by Banff criteria. ."} +{"text": "A 72-year-old man presented with painful enlargement of the scrotum and weight loss. Physical examination revealed that the right testicle and epididymis were hardened and tender. Hematology and chest radiography results were normal. Pelvic computed tomography (CT) revealed bilateral hydrocele and an irregular right testicle and epididymis with peripheral contrast enhancement and central necrotic hypodense portions . Radical,Genitourinary tuberculosis is the second most common form of extrapulmonary tuberculosis after lymph node involvement; however, tuberculous orchiepididymitis is rare. Ultrasound may show focal or diffuse areas of hypoechogenicity in the testicle and epididymis, with increased surrounding vascularity on color Doppler imaging, and a hydrocele. CT usually shows irregular testicular masses with heterogeneous or peripheral contrast enhancement, and a hydrocele, with or without calcification"} +{"text": "More than 8 million people contract typhoid annually, resulting in about 100\u2009000 deaths. Despite associated sociopsychological and economic fallouts,,The most frequent co-endemic acute undifferentiated febrile illnesses are flaviviral illnesses, scrub typhus, malaria, leptospirosis and acute viral hepatitis.Several actionable insights emerge from these gaps that are relevant to future diagnostic test development and evaluations. First, investigators must aim to integrate clinical and laboratory results in diagnostic test evaluations. Clinicians are aware that the diagnosis of acute fever requires a combination of several clinical, physiological and contextual parameters. Systematic assessments of the discriminative power of various tests are important to determine the true added value of rapid tests. Second, researchers should use modelling approaches to identify algorithms worth evaluating in trial settings. Models can inform the incremental value and post-test probabilities of rapid diagnostic tests within clinical algorithms based on pretest accuracies of combinations of clinical signs. To improve testing algorithms for multiple pathogens, the global health community needs renewed data mining efforts to inform modelling approaches. Third, implementers should tailor diagnostic test interventions to the needs and preferences of end-users. Guidelines cannot be translated into interventions unless contextualized to specific practice settings. Qualitative studies should therefore be undertaken in high-burden settings to understand drivers of test use and physician-patient preferences to avoid translation failures. Fourth, funders should incentivize diagnostic research. As new infectious challenges emerge, it is important that funding focus does not shift away from this common cause of illness and death.The recent World Health Assembly resolution on strengthening diagnostics capacity"} +{"text": "In this issue of the Journal, Guadamuz et al. considerCancer care delivery research typically aspires to execute intervention studies targeting modifiable clinical and practice-level factors in the care delivery environment , but GuaThe built environment may particularly predict chronic disease , with hoEarlier research indicated that profit and affluence predict for-profit hospitals\u2019 locations, thus intentionally marginalizing Medicaid and uninsured patients ,25. MoreMultilevel policies may beget care access benefitting cancer prevention and survivorship, but enhanced facility proximity and care reimbursement, although necessary, is likely insufficient for optimizing care for patients residing in low area-level socioeconomic status locales. Health-care organizations and their care teams may create and sustain care equity threats. Workforce conditions, such as unfavorable patient to clinician ratios potentiaWe encourage hypothesis testing that considers relationships between the built environment, practice norms , and cancer treatment initiation and survival. How might we design studies to test these relationships? Cancer care delivery espouses advancing beyond traditional randomized clinical trial paradigms to embrace pragmatic trial methods that prioritize external validity and the relevance of community practice . MoreoveGuadamuz et al. reveal a"} +{"text": "On November 7, 2022, dengue virus (DENV), which is not endemic in the continental United States , MCESD, and Arizona Department of Health Services locally acquired mosquitoborne disease response plan, MCDPH and MCESD activated an incident command office on November 10. MCDPH took the following actions: 1) prioritized prospective investigations of health care provider and laboratory reports of DENV and suspected arboviral visits queried from the National Syndromic Surveillance Program's BioSense Platform (BioSense)Aedes aegypti mosquitoes and breeding sites; mosquitoes collected in a professional BG-Sentinel mosquito trapAfter discussions with CDC\u2019s Dengue Branch and Florida Public Health (Coordinated surveillance and response activities identified the first locally acquired human DENV infections in Maricopa County, Arizona. Established partnerships and preexisting plans were essential to mounting a rapid, coordinated response to nonendemic arboviral transmission. MCDPH and MCESD will enhance future surveillance activities to identify and prevent autochthonous DENV transmission, including additional mosquito trap placement around patient residences and public mosquito exposure prevention education."} +{"text": "These on-site sanitation systems, a positivestep toward improved household WASH services, are used by 43% of theglobal population, mainly comprising low- and middle-income countries(LMICs).3 There is an urgent need to expand decentralized(non-sewered system) surveillance as LMICs are currently being overlookedin pandemic prevention as it is currently focused on SARS-CoV-2 wastewaterfrom centralized (sewered) systems.The availabilityand accessibilityof water, sanitation, and hygiene (WASH) services are key in preventingdisease transmission.Wastewater surveillanceof centralized systems presents a vastlydistinct set of challenges compared with fecal sludge surveillance.For example, sewers also contain gray water and sometimes stormwater,and wastewater is commonly sampled as a composite volume over a 24h period, whereas fecal sludge is most commonly grab sampled. Broadeningthe focus of non-sewered sanitation surveillance (NSSS) should accommodatefecal sludge analysis to support globally relevant public health strategies.4 Unfortunately, interest in fecal sludge researchhas been largely limited to a small group of researchers funded bya few core donors. The pandemic has renewed the focus of both scienceand policy. Surveillance of pathogens in fecal sludge may need tobe adapted and could include Vibrio cholerae or poliovirus;however, this should be determined by assessing localized needs. Thepotential of the public health impact in LMICs can be amplified byusing fecal sludge data in addition to clinical data in multipathogendisease surveillance and continuous local monitoring for early warningsof a pandemic.Even before the COVID-19 pandemic, fecal sludge was used as a valuablesource of information for understanding community health.5 but possibly more complex in the Southern Africansanitation field with five decades of human waste research.6 With no formal global network, internationalnonprofit institutions can fill this role by bringing together academicresearch partners and public health officials for interdisciplinaryand collaborative research and increased awareness of NSSS. Such partnershipscan enable these settings to innovatively adapt academic or healthcarelaboratory operations while maintaining high-quality data and alsopromote peer-reviewed literature originating from resource-limitedlaboratory settings.Research partnerships are required to progressfrom individualclinical patient samples to pooled community samples in terms of fecalsludge. The importance of research partnerships is not new,Timelier and better-quality global epidemiologicaldata sets arerequired for better pandemic preparedness in the future. There isa need in LMICs for the different, but unique, value of NSSS comparedto that of wastewater surveillance, built-in capacity at local laboratoriesthat can include fecal sludge as part of continuous multipathogendisease surveillance, and long-term global research collaborationsfocused on creating systems with data-driven approaches. Challengeswill remain, including importation and lengthy delays in suppliesand equipment (such as polymerase chain reaction primers and probesthat are not manufactured in many LMICs), repurposing existing LMIClaboratory spaces for fecal sludge samples, and limited LMIC accessto biosafety level 3 and 4 laboratories for sample processing, therebylimiting pathogen target lists. We recommend that LMICs navigate throughthese barriers to ensure that fecal sludge surveillance benefits publichealth, generates local policy-relevant information for future pandemicprevention and control, and holistically supports global WASH services."} +{"text": "Recently, an empiric Cone-beam Computed Tomography (CBCT)-guided transarterial embolization (TAE) technique has been investigated for lower gastrointestinal bleeding (LGIB). Although this empirical strategy reduced the rate of rebleeding in hemodynamically unstable patients compared to a \u2018wait and see\u2019 strategy, the specified technique is challenging and time-consuming.We present two methods to perform a prompt empiric TAE in LGIB when catheter angiography is negative. Based on the pre-procedural Computed Tomography Angiography bleeding site and using vessel detection and navigation software tools that are integrated in contemporary angiosuites, the culprit bleeding artery could be targeted with only one selective intraprocedural CBCT acquisition.The proposed techniques are promising to reduce procedure time and facilitate the implementation of empiric CBCT-guided TAE in clinical practice when angiography is negative. Empirical transarterial embolization (TAE) is a well-known strategy in interventional radiology (IR). In upper gastrointestinal bleeding, when primary endoscopic hemostasis has failed, endoscopy-directed empiric TAE of the left gastric or gastroduodenal artery is recommended if angiography is negative and vasopressor requirements upon arrival, subsequent inferior mesenteric Digital Subtraction Angiography (DSA) and CBCT angiography failed to demonstrate active bleeding. Because of hemodynamic instability and risk of bleeding recurrence, an empirical TAE (illustrated in Fig.\u00a038y old female patient with history of a lateral pancreatojejunostomy after pancreatic trauma was admitted because of recurrent RBPA and one-time hematemesis. Initial upper gastrointestinal endoscopy and CTA could not identify an active bleeding focus. However, because of progressive hemodynamic instability, the patient was transferred the following day to our tertiary referral hospital. A new CTA now did reveal an active bleeding proximally in the Roux-en Y jejunal loop and the patient was immediately transferred to the angiosuite. Nevertheless, superior mesenteric DSA and CBCT failed to identify a bleeding focus. Regarding inaccessibility for endoscopy, empirical TAE (illustrated in Fig.\u00a0Recent guidelines emphasize the importance of CTA and TAE in the management of active or hemodynamically unstable LGIB (Triantafyllou et al. The use of vessel detection and navigation software could be promising to reduce procedure time and facilitate the implementation of empirical TAE in clinical practice. However, safety and efficacy of this approach should be verified on a larger scale."} +{"text": "Pseudomonas aeruginosa. Fungal infections in MEO are also likely but extremely rare. And conventional microbiology tests is difficult to diagnose.Most of malignant external otitis (MEO) cases reported in the literature are attributed to Aspergillus by metagenomic Next-Generation Sequencing (mNGS) and recovered after comprehensive treatment including operation and voriconazole. The antifungal treatment was delayed due to repeated cultures of secretions being negative and pathological examination showed granulation tissue proliferation with extensive neutrophil infiltration.Two patients were diagnosed with Fungal malignant external otitis (FMEO) due to mNGS might be helpful for patients suspected with FMEO, especially when conventional microbiology tests were negative. Pseudomonas aeruginosa , previously diagnosed otitis externa not responsive to therapy.Aspergillus is also frequently isolated from external auditory canal smears and diagnosis of FMEO should be based on histopathologic confirmation on deep tissue biopsy for the publication of any potentially identifiable images or data included in this article. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.QW: patient management, data collection, and writing original draft. RH and YZ: patient management and data collection. WZ: review and modify the article. HJ: review and modify the article. All authors contributed to the article and approved the submitted version."} +{"text": "Orcinus orca) to quantify patterns of fine-scale foraging movements and their relationships with demography. We reveal striking interpopulation differences in patterns of individual foraging behavior. Females from the endangered Southern Resident (SRKW) population captured less prey and spent less time pursuing prey than SRKW males or Northern Resident (NRKW) females, whereas NRKW females captured more prey than NRKW males. The presence of a calf (\u22643 years) reduced the number of prey captured by adult females from both populations, but disproportionately so for SRKW. SRKW adult males with a living mother captured more prey than those whose mother had died, whereas the opposite was true for NRKW adult males. Across populations, males foraged in deeper areas than females, and SRKW captured prey deeper than NRKW. These population-level differences in patterns of individual foraging behavior challenge the existing paradigm that females are the disproportionate foragers in gregarious resident killer whales, and demonstrate considerable variation in the foraging strategies across populations of an apex marine predator experiencing different environmental stressors.In cooperative species, human-induced rapid environmental change may threaten cost\u2013benefit tradeoffs of group behavioral strategies that evolved in past environments. Capacity for behavioral flexibility can increase population viability in novel environments. Whether the partitioning of individual responsibilities within social groups is fixed or flexible across populations is poorly understood, despite its relevance for predicting responses to global change at the population and species levels and designing successful conservation programs. We leveraged bio-logging data from two populations of fish-eating killer whales ( Rapid environmental change may disrupt cost\u2013benefit tradeoffs of foraging strategies in cooperative species, yet whether populations differ in the partitioning of individual responsibilities within social groups is poorly understood. By combining fine-scale movement and sound data from bio-logging tags and demographic data from long-term population censuses, we reveal opposite patterns of individual foraging behavior between killer whale populations with divergent population trajectories, demonstrating variation in the partitioning of foraging responsibilities in an apex marine predator. Orcinus orca , primarily Chinook (O. tshawytscha) and to a lesser extent chum (O. keta) and coho . We also collected prey remains using fine-meshed dip nets in MATLAB v R2016b to calibrate sound and movement data based on sensor characteristics and tag orientation on the whale and the marmap R package and Fisheries and Oceans Canada (NRKW) to assign demographic variables. These databases contain extensive maternal familial relationships established through field observations and genetic testing in R v.3.6.3 using thFor the model examining the relationship between the presence of a living mother and the number of prey capture dives by adult males model h, , we addiWe were unable to use available salmon abundance indices due to 1) spatial incongruency between the salmon stocks/regions where these abundance data were sampled and the prey consumed by NRKW and SRKW during our study period and location, 2) issues with sporadic coverage and the degree to which effort had been accounted for in some of the existing salmon indices, and 3) reliability issues with applying widely used salmon data from the Albion Test Fishery situated on the Fraser River e.g., , becauseWe analyzed 186.8 h of dive data from 52 Dtag deployments or maximizing energy obtained from foraging (optimizing) . For SRKThe finding that adult SRKW males captured more prey if their mother was alive highlights the opposite patterns of foraging behavior we observed for adult males between the two populations. Males require more energy due to their larger size , and theIt is worth considering an alternative, nonmutually exclusive hypothesis related to the role of group leadership by post-reproductive females to explain the increased prey capture by SRKW males with living mothers. Given that post-reproductive females typically lead groups and thatDifferences in prey abundance and availability between populations could have contributed to the differences in foraging strategies we document here. However, we could not use existing indices of salmon abundance in our analyses because these metrics do not address spatiotemporal uncertainty in the distributions of Chinook salmon returning along one of two paths to the Fraser River. The nuances of migration paths taken are directly related to accurately estimating salmon availability for each population, yet data at this fine-scale spatiotemporal resolution are not currently available. We suggest that future research should elucidate the complex relationships between 1) environmental factors including location, prey distributions, and availability, 2) the behavioral context of the animal at the time of tagging, and 3) differential population-level impacts of anthropogenic pressures, including impacts from tagging and vessel presence, on foraging behavior e.g., , 2021b. This study revealed considerable differences in sex-based and demographic patterns of individual foraging strategies, demonstrating that these strategies are not fixed across two ecologically similar populations of a gregarious marine predator. The total number of prey capture dives and proportion of time capturing prey was female biased in the growing NRKW population, and male biased in the endangered SRKW population. The presence of a calf reduced female foraging activity across populations, but disproportionately so for SRKW females. Adult SRKW males with a living mother exhibited increased foraging behavior, possibly as a compensation strategy to offset their pod\u2019s caloric deficits and/or as an outcome of matriarch-led navigation to areas that promote greater prey capture by their adult sons. Interpopulation differences in individual roles within social groups may have arisen with the loss of key individuals as populations shrink, or may provide small, unbalanced populations experiencing environmental stressors the necessary flexibility to respond to novel and unpredictable environments caused by human-induced rapid environmental change. Indeed, interpopulation variation in individual roles may be an important evolutionary strategy for promoting resilience in the face of change.arad002_suppl_Supplementary_MaterialClick here for additional data file."} +{"text": "To the Editor: Fetal alcohol syndrome (FAS) is characterized by a range of structural birth defects, including facial dysmorphia, central nervous system growth deficits , and prenatal/postnatal growth restriction, which correlate with the magnitude of prenatal alcohol exposure .Due to the development of grossly observable alcohol-induced phenotypes consistent with clinical presentations of FAS, mouse models have become a powerful resource for investigating the development of alcohol-induced dysgenesis . TherefoWe first employed geometric morphometric analyses to contrFurthermore, our analyses revealed that alcohol-induced changes predominantly centered on the lower portions of the face, including the mandible (lower jaw), maxilla (upper jaw), and positioning of the ear . As in cTo validate our observations, we examined offspring for alterations in established measures of alcohol-induced craniofacial defects . ConsistFinally, we conducted a dose-response analysis, contrasting offspring snout-occipital distance and body weight\u2013normalized brain weights with the parental average daily ethanol dose (g/kg). We identified a significant correlation between both measurements and parental alcohol dose for male offspring across the PatExp and DuelExp treatments . In contIn 1981, the US Surgeon General issued a public health advisory warning that alcohol use by women during pregnancy could cause birth defects. Since this time, maternal alcohol use during pregnancy has remained the sole explanation for alcohol-related birth defects. In contrast, paternal drinking and lifestyle choices remain unexamined. Using a physiologically relevant mouse model, our studies are the first to our knowledge to demonstrate that male drinking is a plausible yet completely unexamined factor in the development of alcohol-related craniofacial abnormalities and growth deficiencies. Our study demonstrates the critical need to target both parents in prepregnancy alcohol messaging and to expand epidemiological studies to measure the contributions of paternal alcohol use on children\u2019s health."} +{"text": "Cell-to-cell communication is a critical process that ensures interaction between adjacent and distant cells to maintain cellular homeostasis in normal physiology and pathophysiological conditions. Two adjacent cells communicate to transfer ions and small molecules via Gap junctions, small selective ion channels. Distant cells establish long-range communication via endocrine/paracrine secretions, extracellular vesicles (EVs) and tunneling nanotubes (TNTs) , that membrane-bound exosomes attached to the plasma membrane of brain endothelial cells (BEC), participate in TNT formation between the cells, and facilitate in vitro blood brain barrier (BBB) genesis. Research has also shown that exosomes released by BECs transfer specific cargo to recipient brain cells (Banks et al., Mentor and Fisher suggested TNT-mediated trans-permeability between BEC cells. Recently another study has shown that thrombospondin-1-containing exosomes released from breast cancer cells promote biogenesis of TNTs (Mahadik and Patwardhan, Another issue is the interplay between exosomes and TNTs to harness synergistic effect on intercellular communication. In this context, the work of In conclusion, the synergistic interplay between exosomes and TNTs in long-range intercellular transfer is rapidly evolving as a promising area of cellular communication. Several important questions have been raised by recent advancements in this emerging field of research. What molecular mechanisms govern their on-demand biogenesis in response to cellular toxicities to rescue pathologies? How are exosomes selectively incorporated into TNTs? Do specific pathophysiological conditions enhance or restrict biogenesis of these intercellular conduits and their functionality? Addressing these questions could provide valuable insights into intercellular communications and their complexities, and will open up new avenues for therapeutic intervention.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "Managed care pharmacists utilize clinical guidelines to assist themin identifying acceptable treatment and management of chronic diseases. For thepast several months, an expert panel representing the National Asthma Education andPrevention Program (NAEPP) has discussed updated asthma guidelines, which couldchange future medication management of patients with asthma.To identify new guidelines for asthma control.Taking control of asthma is a foremost objective in managed care, asnew guidelines are debated, and asthma disease management programs identifymore effective models of asthma disease management. Within an effective asthmadisease management program, managed care practitioners, including but not limitedto physicians and pharmacists, must have a thorough understanding of the mostrecent clinical guidelines as well as current knowledge of the current consensusamong opinion leaders regarding asthma treatment and management. This ongoingeducation is critical in order to allow managed care practitioners to perform theirrole and function within their organizations. With the advent of changing asthmapractice guidelines and processes, managed care practitioners need current informationto recognize and apply guidelines-based asthma control.Appropriate asthma treatment requires adherence to currentmanagement guidelines. Approximately one third of asthmatics will not respondto standard asthma treatment and may even worsen while on therapy. Monitoring,close tracking, and regular evaluation of asthma patients at every health careprovider visit is a strategy that can be utilized to generate improved asthma control."} +{"text": "Prosthetic aortic valve dehiscence is an uncommon complication of prosthetic valve endocarditis that may occur in patients who have undergone aortic valve replacement (AVR). The concurrent presence of aortic root pseudoaneurysm may further complicate the clinical presentation through the external compression of coronary arteries. Thus, patients may present with clinical features of coronary ischemia. Echocardiogram and coronary angiography are useful in establishing diagnosis. Treatment involves a multidisciplinary approach involving cardiologists, infectious disease specialists, and cardiothoracic surgeons. The authors of this study discuss a 51-year-old male who presented with anginal chest pain and was found to have a new left bundle branch block, elevated troponins, and left main coronary artery compression complicating aortic root aneurysm. He ended up requiring a re-do AVR, repair of the pseudoaneurysm, and coronary artery bypass graft. Prosthetic aortic valve infection with dehiscence is a major complication in patients with prior valve replacements . This coA 51-year-old male was referred from an outside facility on account of dyspnea, anginal chest discomfort and elevated troponins. His medical history was significant for intravenous (IV) drug use, hepatitis C, and multiple cerebrovascular accidents (CVAs) that necessitated patent foramen ovale closure. His cardiac history was significant for infective endocarditis-related valve dysfunctions status-post bio-prosthetic aortic valve replacement (AVR) and mitral valve repair with an annuloplasty ring.His vital signs included a blood pressure of 130/74 millimeters of Mercury, a pulse rate of 86 beats/minute, and a temperature of 98.6 degrees Fahrenheit. Examination findings were notable for crackles on lung auscultation. Initial lab results showed an elevated high-sensitivity troponin I level of 327 picogram per milliliter (pg/ml) (reference range 3-58 pg/ml). Rapid plasma reagin was negative. Computed tomography (CT) of the lungs suggested pulmonary septic emboli. Electrocardiogram (ECG) showed sinus rhythm and a new left bundle branch block (LBBB) that was not present on an ECG obtained three months earlier. Both ECGs are shown in Figures The cardiology service was consulted. A transthoracic echocardiogram (TTE) was performed and showed an abnormal prosthetic aortic valve function with rocking motion, prosthesis stenosis with peri-valvular regurgitation, pseudo-aneurysm of the aortic root, and ejection fraction of 25%. A transesophageal echocardiogram (TEE) was pursued and showed prosthesis stenosis, high sense of aortic valve more than 180 degrees detached with severe perivalvular regurgitation, and sewing ring dehiscence in the prosthetic aortic valve. It also showed a 4.7 cm by 4.3 cm aortic root pseudoaneurysm communicating with the aortic sinus was subsequently performed and showed external compression of the left main coronary artery (LMCA) and proximal left circumflex artery from the pseudoaneurysm as shown in Figure The aortic root pseudoaneurysm was believed to be the cause of the external pressure on the LMCA as demonstrated in the coronary angiogram; coronary artery bypass graft (CABG) was thus not planned initially. The plan, however, changed during the aneurysmal repair when the patient developed elevated pulmonary artery (PA) pressure and a visibly distended heart. CABG with saphenous vein graft to the left anterior descending artery was therefore performed. PA pressure normalized after the CABG. The dehiscent aortic valve is shown in Figure Unlike an atherosclerotic disease, external compression of the LMCA is a much less common cause of coronary ischemia. Etiologies include pulmonary artery in the setting of primary pulmonary hypertension, perivalvular abscess of the aortic valve, aneurysm of the aortic root, and left ventricular aneurysm -4. PatieProsthetic valve endocarditis (PVE) can result in valve dehiscence and mycotic aortic root aneurysm . The incThe diagnosis is usually made using echocardiography. It is important to remember that a negative TEE does not rule out the presence of vegetation. Large vegetation is a later event and the detection of smaller vegetation by a transesophageal echocardiogram (TEE) can be challenging due to the shadowing effect and reflection of the prosthetic material . MoreoveThe current case faced a distinctive complication involving compression of the left main coronary artery and proximal left circumflex artery by the aortic root pseudoaneurysm. ECG showed LBBB which was concerning for acute coronary syndrome necessitating coronary angiogram. LHC will usually show the area of external compression of the LMCA like in our patient. Surgical treatment of the aneurysms relieves the mechanical compression of the coronary arteries. Surgical management for PVE is not without challenges with some series reporting mortality rates of 20-60% and infection recurrence rate of about 7% . Long-teAortic root aneurysm causing external compression of LCA is an important but unusual cause of myocardial ischemia. Patients may be asymptomatic or present with chest pain and dyspnea. Management requires a multi-disciplinary approach. Since the clinical presentation is varied, clinicians need to be aware of the various presentations and challenge of variation in anatomic structure observed in management of such patients. Therefore, this is an important differential diagnosis to consider in the right clinical scenario: patients with PVE and aneurysmal aortic root, especially those with minimal to no atherosclerotic risk factors."} +{"text": "We also found that youth-reported positive parenting buffered against the association between childhood stress and decreased hippocampal volumes such that youth who experienced high levels of childhood stress and who reported increased levels of positive parenting did not exhibit smaller hippocampal volumes. Our work identifies positive parenting as a resilience factor buffering youth against the deleterious impact of stressful childhood experiences on problem behaviors and brain development. These findings underscore the importance of centering youth perspectives of stress and parenting practices to better understand neurobiology, mechanisms of resilience, and psychological well-being.Childhood stress has a deleterious impact on youth behavior and brain development. Resilience factors such as positive parenting (e.g. expressions of warmth and support) may buffer youth against the negative impacts of stress. We sought to determine whether positive parenting buffers against the negative impact of childhood stress on youth behavior and brain structure and to investigate differences between youth-reported parenting and caregiver-reported parenting. Cross-sectional behavioral and neuroimaging data were analyzed from 482 youth who participated in an ongoing research initiative, the Healthy Brain Network (HBN). Regression models found that youth-reported positive parenting buffered against the association between childhood stress and youth behavioral problems ( Childhood stress (e.g. the death of a loved one or illness) can have a negative impact on mental health and well-being; it is therefore critical to investigate resilience factors that might protect against stress. We consider positive (i.e. warm and supportive) parenting as a buffer against the impacts of childhood stress on youth behavior problems and corticolimbic structure. Youth perceptions of positive parenting moderated the association between childhood stress and (i) youth behavioral problems and (ii) hippocampal volumes. No significant associations emerged from interactions with caregiver-reported positive parenting or amygdala volumes. We conclude that positive parenting may function as a key resilience factor protecting youth from the deleterious impact of stressful experiences and that youth perspectives are critical to understanding how life stress shapes neurodevelopment and behavior.Stress in childhood and adolescence can significantly compromise mental health and well-being . A growiResilience factors such as relationships with caregivers can significantly protect against the many deleterious developmental outcomes associated with childhood stress, with more positive caregiver\u2013child connections being associated with better adjustment and fewer problem behaviors among youth , 13. Varslower amygdala growth over time for youth experiencing high levels of positive parenting and high stress, accelerated amygdala growth for youth experiencing high levels of positive parenting and less stress, and no significant effects of stress and parenting on hippocampal volumes and typically focus on stressful contexts (i.e. socioeconomic disadvantage) and not the actual experience of stress . We were particularly interested in investigating differences between youth versus caregiver perceptions of positive parenting, predicting stronger interactive effects for youth reports of positive parenting compared with caregiver reports.\u03b1 > 0.7, as detailed in our Data from 482 participants between the ages of 10\u201317 years with T1-weighted structural images were analyzed from the ongoing Healthy Brain Network (HBN) research initiative , a checklist measuring family-, community-, and school-based stressors . Due to Youth report and caregiver report of positive parenting were measured using the positive parenting subscale from the Alabama Parenting Questionnaire (APQ) . For eacYouth behavioral functioning was operationalized by the Youth Self-Report (YSR) Total Raw Score. The YSR is a well-validated and widely used 112-item instrument for problem behaviors across the internalizing and externalizing spectrums among children aged 11\u201318 .High-resolution T1-weighted anatomical MRI scans were collected from four sites in the New York City area. We performed standard-processing approaches from FreeSurfer (version 7.1) and excluded participants with low-quality images and high-motion scans . Regression models examined the interactions of stress and parenting in predicting youth behavioral problems and included sex, age, and scanning site as covariates. We fit linear mixed-effects models (LMEMs) for each brain region of interest due to potential variations in research sites and scanners. LMEMs included a random effect of the imaging site and sex, age, and estimated total intracranial volume as covariates. We ran separate models testing interactions between negative life events and a) youth-reported positive parenting and b) caregiver-reported positive parenting for each brain region of interest. For significant interaction terms, we conducted simple slope analyses . Across models, we tested for differences between any significant and nonsignificant interaction terms (see N = 226) anerms see and psycerms see . We ran pproach) .Descriptive statistics are found in Table \u03b2 = 0.14, Praw < 0.001, Pcorrected = 0.017) and a significant main effect of positive parenting . We also found a significant interaction between negative life events and positive parenting . Simple slope analyses indicated that the association between negative life events and behavioral problems was significant at lower and average levels of positive parenting, but not at high levels of positive parenting. There was no relation between stress and behavioral problems when youth were exposed to the highest levels of positive parenting, suggesting a buffering effect. We considered a similar model examining the interaction between stress and positive parenting on behavioral problems using caregivers as the informant of positive parenting. We found no buffering effect of positive parenting against the association between stress and behavioral problems using the caregiver report measure of positive parenting. Models without interaction terms and caregiver report measures of behavioral problems and negative life stress can be found in the We first considered the moderating effect of youth-reported positive parenting on the association between negative life events and youth-reported behavioral problems Fig. . Results\u03b2 = \u22120.07, Praw = 0.029, Pcorrected = 0.042) on the total hippocampal volume. As predicted, there was a significant interaction between youth-reported positive parenting and stress . There was no effect of youth-reported negative life events on hippocampal volumes for participants reporting above-average positive parenting. This finding underscores the stress-buffering role of positive parenting given that reports of negative life events had a negative association with hippocampal volumes only in the presence of below-average and average levels of positive parenting, and not in the presence of above-average positive parenting. Sensitivity analyses testing left and right hippocampal volumes individually can be found in the We next considered the moderating effect of youth-reported positive parenting on the association between negative life events in childhood and hippocampal volumes on total hippocampal volume. We tested differences between interaction terms for our two models on total amygdala volume. There were also no interactive effects between negative life events and youth-reported positive parenting on total amygdala volume .There was not a significant main effect of negative life events (N = 226). In this subsample, adding the presence of a mental health diagnosis was not significantly associated with the total hippocampal volume.We constructed additional models to determine the robustness of our effects see . These aWe ran additional analyses examining associations with several markers of socioeconomic status given connections between socioeconomic status and hippocampal volumes. Results indicated that the potentially comorbid and stressful experience of the socioeconomic environment did not account for observed effects of negative life events and positive parenting on youth behavioral problems and hippocampal volumes see . To accoWe found three major results: (i) negative life events and youth perceptions of positive parenting are associated with behavioral problems, (ii) negative life events are significantly associated with smaller hippocampal volumes, and (iii) positive parenting moderates this association such that youth who reported high levels of positive parenting did not show smaller hippocampal volumes even with increasing levels of stress. Only youth perspectives of positive parenting interacted with childhood stress (measured through negative life events) to predict hippocampal volumes; caregiver report of positive parenting was not related to neurobiology as either a main effect or in an interaction with stress. Such findings underscore the importance of including youth as reporters of their own experiences to better understand consequences for neurodevelopment and behavior . We did Our results underscore well-replicated connections between exposure to childhood stress and smaller volumes in the hippocampus , 32. ThePositive parenting can provide youth with a stable environment to learn social skills, feel supported, and practice cognitive and behavioral regulation. Other work examining interactive effects between childhood stress and parenting on brain volumes has not found evidence of a buffering effect of parenting, instead suggesting that warm and supportive parenting was a compounding positive force in the context of low stress . In contThe protective effect of parenting against the deleterious neurobiological impacts of stress may function through modulating biological and socioemotional processes such as hypothalamic\u2013pituitary\u2013adrenal (HPA) axis responsiveness, cortisol reactivity, and self-regulation. Longitudinal work has found that parenting influences HPA axis and cortisol reactivity, which in turn impacts hippocampal volume during development . In addir = 0.22) between youth and caregiver reports of positive parenting in this sample aligns with previous work establishing small to moderate correlations between youth and caregiver reports of behavioral and emotional functioning , suggesting that the observed interaction between childhood stress and youth-reported positive parenting on hippocampal volumes in our larger sample is not explained by comorbid psychopathology. Similarly, we considered associations with various operationalizations of socioeconomic status considering that socioeconomic disadvantage can be an experience of stress that has been associated with altered corticolimbic structure for consistency in findings (We note several limitations that could serve as important directions for future research. First, we report significant associations that are small in magnitude, with effect size estimates indicating that childhood stress at below-average parenting explains 0.06% of the variance in youth behavioral problems; similarly, childhood stress at below-average parenting explains 0.02% of the variance in total hippocampal volumes. Youth behavioral problems and total hippocampal volumes were also not significantly associated in our supplemental analyses. Of note, we did find a significant association between youth behavioral problems and left hippocampal volumes (detailed in our findings and apprfindings .Our findings have implications for understanding the impact of childhood stress as well as the factors that buffer youth against the noxious consequences of stress. Given the critical role of the hippocampus in memory and goal-directed behavior, alterations in this structure may create vulnerabilities for later negative outcomes. While additional research is needed to clarify complex relations between stress, parenting, and the brain, our data provide insight into how environmental forces may interact to influence neurobiology.pgad145_Supplementary_DataClick here for additional data file."} +{"text": "Spectroscopy imaging machine learning for crop stress.\u201d By exploring these cutting-edge research findings we can gain valuable insights into the application of these technologies to enhance agricultural resilience productivity.Crop stress poses a huge challenge to food security necessitating innovative approaches for early detection monitoring management of stress. In recent years the integration of spectroscopy imaging machine learning techniques has emerged as a promising avenue for detecting various types of crop stress. This editorial work introduces recent publications within the field included in the Research Topic \u201cXiao et\u00a0al. focused on the use of visible and near-infrared spectroscopy combined with deep learning to estimate leaf nitrogen concentration in cotton leaves. The study employed random frog, weighted partial least squares regression and saliency map to select characteristic wavelengths. The models based on convolutional neural network showed excellent performance for both qualitative and quantitative prediction of leaf nitrogen. These findings highlight the potential of deep learning and visible and near-infrared spectroscopy within accurate and real-time assessment of cotton leaf nitrogen content, enabling farmers to make applicable fertilization decisionsWu et\u00a0al. employed an unmanned aerial vehicle (UAV) to obtain multispectral images of a rice canopy and analyzed the response of multispectral reflectance features and physiological parameters including net photosynthetic rate (Pn), plant height (PH), and SPAD to different nitrogen treatments or leakage conditions at various growth stages of the crop. The study extensively analyzed the correlation between vegetation indices (VIs), texture indices (TIs), and Pn based on UAV multispectral images. The techniques and findings presented in this paper provide valuable insights within field-scale photosynthetic monitoring in rice cultivation and improve stress detection and yield prediction.Choudhury et\u00a0al. introduces two innovative algorithms, namely VisStressPredic and HyperStressPropagateNet, to predict the onset and propagation of drought stress in plants using camera-captured image sequences in visible light and hyperspectral modalities. The algorithms analyze visible light sequences at discrete intervals and utilize a deep neural network and hyperspectral images to propagate stress over time, which demonstrate a strong correlation between soil water content and the percentage of stressed plants. These algorithms are evaluated on a dataset of cotton plant image sequences and offer valuable support for studying abiotic stresses in diverse plant species, promoting sustainable agricultural practices.Hu X. et\u00a0al. propose a novel approach called Class-Attention-based Lesion Proposal Convolutional Neural Network (CALP-CNN), utilizing a class response map to locate the main lesion object and identify discriminative lesion details in visual light images. Through a cascade architecture, CALP-CNN effectively handles complex background interference and misclassification of similar diseases. Experimental results on a self-built dataset demonstrate CALP-CNN achieves good classification performance and outperforms the existing fine-grained image recognition methods, highlighting its efficacy in field identification of strawberry diseases.Hu Y. et\u00a0al. presents an enhanced encoder-decoder framework based on DeepLab v3+ analysis of images to accurately identify crops with diverse planting patterns. The network utilizes ShuffleNet v2 as the backbone for feature extraction and incorporates a convolutional block attention mechanism to fuse attention features across channels and spatial dimensions. The enhanced network achieves significant improvements and requires fewer parameters and computational operations compared to other networks. This study demonstrates the effectiveness of Deep-agriNet in identifying crops with different planting scales, making it a valuable tool for crop identification in various regions and countries.The combination of spectroscopy, imaging, and machine learning has a high potential for improving crop stress analysis and management. By utilizing these technologies, we can enhance our understanding of crop stress dynamics, develop precise and targeted stress detection methods, and improve decision-making processes for farmers. Ongoing research, technological advancements, and collaborative efforts are necessary to unlock the full potential of spectroscopy, imaging, and machine learning in mitigating crop stress and ensuring global food security.The\u00a0author\u00a0confirms being the sole contributor of this work and has approved it for publication."} +{"text": "A 60-year-old male patient underwent coronary angiography for acute myocardial infarction. Angiograms revealed significant multivessel disease and an abnormal branch arising from the proximal right coronary artery and extending backwards, likely to the right lung A. Both iIsolated DOPA is a rare vascular malformation that may remain undiagnosed until advanced age, often manifesting with nonspecific symptoms such as recurrent bronchopneumonia, haemoptysis, and dyspnea.,Lack of a connection between the main and affected branch PA, resulting from the involution of the ventral sixth aortic arch, led to the erroneous definition of unilateral pulmonary artery agenesis.\u2022Chest radiograph may provide relevant clues to the diagnosis of DOPA.\u2022CTPA is the method of choice for noninvasive diagnostic confirmation.\u2022Key diagnostic findings are a well-formed but hypoplastic pulmonary artery and a ductal diverticulum on the aortic arch or the base of an epiaortic vessel.Interestingly, DOPA could be suspected by jointly considering the anomalies detected by coronary angiography and chest radiograph. Despite not providing direct visualization of DOPA, these diagnostic modalities could offer subtle but important clues to this rare malformation, ultimately confirmed by CTPA."} +{"text": "Gastrointestinal cancers represent a major challenge to public health. Pancreatic cancer is the most lethal cancer among all gastrointestinal cancers. Most patients cannot meet the criteria of resection at diagnosis, indicating these patients will have dismal prognosis.Neoadjuvant chemotherapy helps some patients regain the opportunity of radical resection. An optimal regimen of chemotherapy is one that maximizes the anti-tumor efficacy while maintaining a relatively manageable safety profile. The development of surgical procedures further improves the outcomes of these patients.Combination therapies in a multidisciplinary manner that involves modified chemotherapy regimen, radical resection, and intestine auto-transplantation may provide the currently best possible care to patients with locally advanced pancreatic cancer. Gastrointestinal cancers account for around 25.8% of newly diagnosed cancers annually. Among them, pancreatic cancer is the most lethal cancer, with a 5-year overall survival rate of only around 12%. There are more than 495,700 new cases of pancreatic cancer each year [Liang and colleagues proposed a modified FOLFIRINOX regimen, consisting of 85% oxaliplatin, 75% irinotecan, and zero fluorouracil bolus . This moThe modified FOLFIRINOX regimen was also applied as a neoadjuvant treatment to borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC) for downstaging and creating surgical opportunity. According to the LAPACT trial that applied gemcitabine plus nab-paclitaxel to LAPC, the neoadjuvant induction therapy achieved a 15% conversion rate of radical resection . The medThe expanded surgical resections after neoadjuvant therapy are critical to the improvement of the radical resection rate in LAPC. For LAPC involving the pancreatic body/tail and the celiac trunk, radical resection can be achieved by the modified Appleby procedure . This group is one of the leading groups that focus on intestine auto-transplantation and liver cancer surgery , 8. As fLiang\u2019s integrated treatment strategy by combining modified FOLFIRINOX with sequential radical resection has established an excellent model of multimodal treatment against pancreatic cancer, and extended criteria of surgical resectability, which would benefit more pancreatic cancer patients at locally advanced stages. The success of this strategy implies that for pancreatic cancer patients, especially those who cannot meet the resectability criteria, the combination of modified chemotherapy and surgical intervention would provide an increased survival benefit. Furthermore, the interim analysis of a prospective phase 3 clinical trial conducted by Liang\u2019s group , compariIn summary, gastrointestinal cancers represent a major challenge to public health. Most patients cannot meet the criteria of resection at diagnosis, indicating these patients will have dismal prognosis. Neoadjuvant chemotherapy helps some patients regain the opportunity of radical resection. The development of surgical procedures further improves the outcomes of these patients. Combination therapies in a multidisciplinary manner that involves modified FOLFIRINOX regimen, radical resection plus intestine auto-transplantation, targeted therapy and immunotherapy may provide the best possible care to patients with LAPC.The modified FOLFIRINOX regimen is currently an optimal treatment option for pancreatic cancer patients. Combination of the modified FOLFIRINOX regimen, radical resection, and intestine auto-transplantation provides the currently best possible survival benefit for those who have otherwise lost the opportunity of surgery. The addition of immunotherapy, targeted therapy, and radiotherapy may further increase the efficacy of the combination therapy."} +{"text": "How adult tissue-specific stem cells with indicated markers contact the adjacent lineage with indicated markers is of significance to be studied. Novel methods bring future findings. Recent advances in lineage tracing, synthetic receptor systems, proximity labeling, and transcriptomics have enabled easier and more accurate cell behavior visualization and qualitative and quantitative analysis of cell-cell interactions than ever before. These technological innovations have prompted researchers to re-evaluate previous experimental results, providing increasingly compelling experimental results for understanding the mechanisms of cell-cell interactions. This review aimed to describe the recent methodological advances of dual enzyme lineage tracing system, the synthetic receptor system, proximity labeling, single-cell RNA sequencing and spatial transcriptomics in the study of adult tissue-specific stem cells interactions. An enhanced understanding of the mechanisms of adult tissue-specific stem cells interaction is important for tissue regeneration and maintenance of homeostasis in organisms.Adult tissue-specific stem cells play a dominant role in tissue homeostasis and regeneration. Various Adult tissue-specific stem cells interactions can be viewed as communication modalities that play a central role in regulating cell behavior and function .In this paper, we first discuss the methods for studying adult tissue-specific stem cells interactions in two directions: bioinformatics analysis and visualization analysis. Specifically, these techniques or methods include lineage tracing, synthetic receptor systems, proximity labeling, and transcriptome analysis. In addition, there are few systematic descriptions of the mechanisms of stem cell interactions. Therefore, this paper also combs the biological understanding of adult tissue-specific stem cells interactions. We do not provide a summary assessment of all relevant literature, and references throughout the text tend to be more illuminating examples. Based on the latest literatures, stems cells referred in this review focus on adult tissue-specific stem cells.in vivo single-cell analysis because of its efficiency and spatiotemporal specificity during long bone formation is clearly illustrated to regenerate the bronchoalveolar junction region after an injury has been demonstrated using dual-recombinase-activated lineage tracing (DeaLT) system, reiterating previous findings . Applyinustrated . It has ustrated . In lungustrated . Updatedustrated .Based on the Cre: Dre dual recombinase reporter system, Lingjuan We also note the contribution of optogenetic genetic engineering to the content of our work, which is widely used to study and control cells and has been previously described . OptogenInspired by the natural cell-signaling paradigm, researchers have implemented artificially designed synthetic receptor systems to manipulate signal translation to control cellular functions, including artificially tunable cellular sensing and subsequent transcriptional responses . The devThe synNotch receptor system, which detects cell-cell contact, was developed during the development of synthetic receptor systems . The synDrosophila model genetically engineered to be expressed in decoy cells to transfer the markers to prey cells . This laThe FucoID protocol installs the glycosyltransferase directly onto the decoy cell without gene expression on the cell membrane . This enProtocols using photocatalysts have greater temporal control and remote manipulation than enzymatic proximity-labeling systems . These pin situ studies of cellular interactions in animal models act as alveolar adult tissue-specific stem cells in response to injury . AT2 celin vivo triggers EphB2 signaling attenuation in adjacent radial neural stem cells (rNSCs) through direct cell contact, leading to rNSC activation and the generation of new neurons . Conversin vitro . TranscrInteractions between immune cells and stem cells have also been reported. The fate of intestinal stem cells (ISC) is regulated by adhesion signals from immune cells . BindingThe paracrine effects of stem cells are also influenced by the cell-cell contact between stem cells and other cells. For example, the immunomodulatory effects of MSCs are enhanced upon contact with pro-inflammatory macrophages . AdditioMoreover, immune cell function is affected by intercellular contact between stem cells and immune cells. This may be due to the secretion of cytokines that affect stem cells . There aStem cells can also regulate immune cell functions through paracrine and intercellular contacts . TGF-\u03b2 Min situ.\u201dIn bone marrow tissue, bone marrow regeneration after radiation clearance is inseparable from the transfer of mitochondria from hematopoietic stem cells to bone marrow mesenchymal stromal cells through intercellular contacts . HematopMechanical signals include both the structure and properties of the ECM and forces generated by the cell through various connections . This inDrosophila, the proliferation and differentiation of all stem cells that ectopically express Piezo are promoted by a mechanism that is inseparable from calcium signaling (Mechanically gated Piezo1 channels are expressed in both neural stem cells and astrocytes and regulate adult neurogenesis . In Drosignaling . Piezo1 ignaling . Furtherignaling . During ignaling . When thignaling . Adult mignaling . The NotWnt and Src-YAP signaling cooperate to drive intestinal regeneration . Additiovice versa in favor of endocrine cell fate (Physical signaling with tunable properties that act immediately and locally is an object of interest to regulate the differentiation of stem cells into specific lineages . The ECMell fate . MSCs arell fate . Smallerell fate . The intell fate . Moreoveell fate . The intell fate .Indeed, numerous researchers have shed a light on how mechanical information affects cell behavior. We are currently studying the mechanisms underlying stem cell interactions to improve the application of stem cells in regenerative medicine. To systematically and precisely elucidate these mechanisms, technologies with higher spatial and temporal resolutions, more realistic simulations of the stem cell microenvironment, and more specific stem cell population differentiation and tracing are required. This demand has led to many powerful technologies that elucidate the mechanisms of stem cell interactions. We discuss how lineage tracing, synthetic receptors, proximity labeling and transcriptome data analysis tools can be applied in the study of CCI. The techniques presented in this paper include but are not limited to using stem cells as research models, and using non-stem cells as research models has complementary and reference significance. In addition, we note some other techniques. For example, SPEAC-seq based on CRISPR-Cas9 with microfluidic microarrays to identify cell signaling pathways . It provThe study of stem cell interactions is in a rapidly evolving stage, especially in the context of rapid iterative updates in biotechnology. Although, the biological understanding of stem cell interactions sorted out in this paper is not sufficient to elaborate a comprehensive picture of stem cell behavior during mammalian development or injury repair, it contributes to a complete description of stem cell interaction mechanisms in the future."} +{"text": "Cerebrovascular injuries resulting from frontobasal head trauma represent a range of imaging and clinical presentations. Severe cerebrovascular injuries such as vessel transection commonly present with profound neurological deficits and are often easily identified with routine imaging. However, small intimal injuries and dissections may be challenging to detect and may be clinically silent or masked by additional injuries in the setting of polytrauma. The onset of symptoms and complications from cerebrovascular injuries may be delayed from the time of initial presentation, and failure to recognize and diagnose these injuries may result in devastating outcomes if management is delayed. In this case report, we present a case of frontobasal craniofacial trauma that resulted in an anterior cranial fossa dural arteriovenous fistula (ACF-dAVF) and supraclinioid segment internal carotid artery (ICA) pseudoaneurysm.\u00a0 Vascular injuries have been identified in 8.5% of skull base fractures in some case series, particularly when the sella turcica-sphenoid sinus complex and the petrous carotid canal are involved ,2. ResulDural arteriovenous fistulas (dAVF) are uncommon vascular lesions with abnormal connections between arteries and leptomeningeal veins or a dural venous sinus\u00a0. They maTraumatic intracranial aneurysms represent fewer than 1% of all intracranial aneurysms . AlthougA 45-year-old male presented with extensive frontobasal and craniofacial injury after an all-terrain vehicle (ATV) rollover. Initial trauma computed tomography (CT) scans depicted bilateral naso-orbito-ethmoid complex fractures with fracture planes extending to the bilateral sphenoid sinus walls. Multi-compartmental intracranial hemorrhage, including subarachnoid hemorrhage and hemorrhagic contusions with basifrontal predominance, were also present. Subsequent CT angiography (CTA) of the neck revealed vessel wall irregularities and non-flow limiting stenosis involving the left supraclinoid ICA, and prominent cortical veins along the right ACF Figures , 2. The Cerebrovascular injury from blunt trauma can be subtle and difficult to detect at initial presentation. It can be stratified using a five-point scale Biffl cerebrovascular arterial injury grading scale\u00a0based on the severity of vessel injury from mild intimal injury (Grade I) to vessel transection (Grade V) Table 11]. Gr. Gr11]. In this case, the patient developed an ACF-dAVF within three days of the initial encounter, which is to our knowledge the first case report of a patient presenting with this condition within one month of the initial injury. In ACF-dAVFs, the cribriform plate is commonly the fistula point, in which afferent arterial supply arises from the distal ophthalmic artery and both anterior and posterior ethmoidal arteries, and venous drainage occurs through frontal cortical veins into the superior frontal sinus or posteriorly into the cavernous sinus or basal vein of Rosenthal ,15. In tTraumatic intracranial aneurysms may be true or false aneurysms. True aneurysms have preserved adventitia and partially disrupted and damaged intima, internal elastic lamina, and media, whereas false aneurysms/pseudoaneurysms result from disruption of all arterial wall layers and are contained by adjacent hematoma and perivascular connective tissues . In partThis report is a description of a rare case of ACF-dAVF and ICA pseudoaneurysm that developed in the days following significant frontobasal craniofacial trauma as an opportunity to discuss the clinical presentation and associated imaging findings of these lesions, and to provide a better understanding of the pathogenesis and management of these and related post-traumatic cerebrovascular injuries and complications."} +{"text": "Scar pregnancy is a rare and potentially life-threatening condition that occurs when an embryo implants and grows within a previous cesarean section scar or other uterine scars. This unique form of ectopic pregnancy poses significant diagnostic and management challenges for healthcare providers. Scar pregnancies are associated with an increased risk of uterine rupture, massive hemorrhage, and other complications, underscoring the importance of early detection and appropriate management strategies . Scar pr"} +{"text": "Discoid lupus erythematosus (DLE) is a chronic variant of cutaneous lupus erythematous developing on sun-exposed areas in multi-morphic forms making diagnosis challenging. Clinical suspicion and prompt treatment are necessary to avoid permanent disfigurement, progression to systemic involvement and poor quality of life. We report a case of delayed DLE diagnosis in a 45-year-old man who presented with a new skin lesion mimicking the early stages of mycosis fungoides that prompted further investigation. Histopathological examination confirmed DLE and appropriate treatment was initiated. However, the atypical clinical presentation led to disseminated DLE and refractory disease control, resulting in scarring and cosmetic disfigurement. Lupus erythematosus (LE) is an autoimmune disease existing on a spectrum of cutaneous and systemic manifestations. Discoid lupus erythematosus (DLE) is the most common variant of chronic cutaneous LE that can present in a variety of morphologies . UnderstA 45-year-old male presented with a new erythematous plaque on the left upper chest after an initial diagnosis of photodermatitis due to the presence of erythematous patches and plaques on the scalp . The newA 4-millimeter punch biopsy from lesional skin showed an orthokeratotic and mildly atrophic epidermis with extensive vacuolar degeneration of the basal layer. There was a dense superficial dermal lichenoid-type of lymphocytic inflammatory infiltrate with scattered melanophages and presence of colloid bodies . Marked Histopathological findings coupled with serological findings were corroborative of DLE and thus the patient was started on short-term oral steroids with prednisolone (20\u00a0mg daily), oral hydroxychloroquine (HCQ) and high-potency topical steroid clobetasol propionate. Treatment included photoprotection recommendations.At a 6-week follow-up, new cutaneous lesions appeared on the back and the Patient\u2019s systemic evaluation was negative to date. The patient is under regular follow-up with dermatology and rheumatology.DLE renders difficulty in clinical suspicion and definitive diagnosis as skin lesions resemble common dermatoses. It can lead to permanent disfigurement with hair loss, dyspigmentation and scarring if not treated early or adequately controlled. The chronic nature of the disease imposes a psychological burden and high morbidity on patients, often requiring psychosocial support , 4. Diag"} +{"text": "Neural oscillatory activity has emerged as a central Research Topic in neuroscience and phase . Despite their conceptually clear-cut operationalization, analyses of these parameters are confronted with an inherent problem: For which frequency range should these parameters be calculated and how should this range be determined? Initially, a priori-defined frequency ranges centered on a prominent power peak were linked to behaviorally relevant functions , has the potential to overcome the above-mentioned limitations. Computation of PF allows definition of recording-specific frequency peaks based on the empirical data, which can be used to compare individuals and/or experimental conditions. Additionally, when paired with novel tools correcting for aperiodic signal components and discrete perception . Correlation analyses revealed no systematic connection between individual alpha PF and the latency of neural markers of visual processing. These findings indicate that individual alpha PF does not systematically shift early sensory processing in time.Two of the four contributions to this Research Topic examine the link between individual alpha PF and visual processing. Strang et al. assessed if individual alpha-band PFs over occipitoparietal and sensorimotor areas are linked to autism spectrum disorders. EEG recordings of neurotypical participants during motor execution and movement observation revealed that individuals with slower sensorimotor PFs exhibited higher autism-spectrum traits. This finding adds important information about potential biomarkers, since research so far largely focused on the classical alpha rhythm. The work by Sponheim et al. recorded individual alpha-band PFs with MEG during rest and visual processing in participants with psychotic psychopathology, their biological siblings, and healthy controls. Alpha PF varied widely across participants and remained temporally stable across multiple months. Moreover, slowed alpha PF was linked to longer visual percept duration in participants with psychopathology, as well as to lower IQ estimates and higher symptom severity. This study shows how fundamental research can inspire a directed functional assessment of neural markers as indicators of clinical symptom severity.Two other contributions studied the link between PFs and trait variables related to neuropsychiatric disorders. The systematic and hypothesis-driven analysis of PF holds the potential to provide exciting and novel roles of neural oscillatory activity. It promises to strengthen the analysis of oscillatory power and phase by providing an empirically-informed frame of reference instead of rigid a priori defined frequency definitions. We hope that this Research Topic has increased the visibility of PF in the neuroscientific audience and motivated future research.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "Cell, Gungabeesoon and colleagues1 demonstrated that a specific subpopulation of neutrophils, characterized by a distinct Sellhi (CD62Lhi) phenotype with an interferon gene signature, acutely accumulates in tumors during successful immunotherapy and is associated with better treatment outcome. These findings enhance our understanding of the neutrophil heterogeneity within the tumor context and highlight their potential in cancer immunotherapy.In a recent study published in Traditionally, neutrophil infiltration of tumor tissue has been primarily associated with tumor progression. However, the remarkable heterogeneity of neutrophils allows them to play multiple roles in this process. In addition to their typical pro-angiogenic and immunosuppressive functions, neutrophils can also have protective roles, such as direct cancer cell killing or stimulation of adaptive immune responses. Importantly, various anti-cancer therapies directly or indirectly (by modulation of tumor microenvironment), impact neutrophil responses and activity. Nevertheless, some immunotherapies fail to induce clinical responses in certain patients, prompting extensive efforts to understand the underlying mechanisms.1 analyzed neutrophil phenotypes expanded after successful immunotherapy. These cells had been previously overlooked in single-cell transcriptomic research due to unintended elimination during standard preparation of the sample. The authors observed that therapy-induced neutrophils expressed high levels of Sell transcripts, encoding the protein Selectin L . These neutrophils exhibited a more immature phenotype (CD101lo), associated with increased cytotoxicity and upregulated expression of genes responsible for regulation of neutrophil degranulation, suggesting their potential immunostimulatory activity. This aligns with prior observations indicating anti-tumoral properties of immature neutrophil populations.2Sellhi neutrophils also exhibited a distinct interferon (IFN) signature, including interferon regulatory factor 1 (IRF1), a crucial driver of their anti-tumor phenotype, and appeared to be essential for the successful therapy , was sustained in tumors after treatment, even as Sellhi neutrophils increased. SiglecFhi neutrophils were previously shown to have pro-tumorigenic properties.5 Here the authors showed that these neutrophils were characterized by multiple gene signatures that support their pro-tumorigenic roles, including expression of genes that promote tumor proliferation, remodeling of extracellular matrix, angiogenesis, suppression of antitumor immunity, and recruitment of myeloid cells, and thus reported to be responsible for metastasizing, sustained in tumors after treatment. Therefore, this study suggests that therapies should aim not only to expand anti-tumor neutrophils, but also to eliminate pro-tumor counterparts. Further human studies will be needed however to understand the dynamics of these populations in a relevant clinical setting following therapy. Human studies should also allow evaluating whether the abundance of these neutrophil populations predict progression and outcome in human cancers.The authors also noted that another population of neutrophils, Single-cell transcriptomics has revolutionized our understanding of neutrophil biology by unraveling the phenotypical and functional diversity of neutrophil subsets across various organs. The pursuit of selective strategies to therapeutically enhance beneficial neutrophil populations while concurrently eliminating tumor-supporting neutrophils remains a compelling approach in immunotherapy. Rather than complete depletion of neutrophils, successful immunotherapy should focus on modulating the tumor microenvironment to favor anti-cancer repolarization of neutrophils. This approach holds the potential to establish an effective strategy for achieving optimal anti-tumor responses and enhancing the outcomes of cancer patients."} +{"text": "Dear colleagues,Pediatric minimally invasive surgery (MIS) epitomizes a dynamic and continuously evolving field that encompasses a broad range of procedures. From fetoscopic interventions in the prenatal population to robotic-assisted bariatric surgeries in overweight adolescents, the spectrum of techniques and patients encountered in pediatric MIS reflects its inherent intricacy and the fascination it inspires.In the context of this particular Special Issue, our primary objective revolved around an extensive exploration of the expansive landscape of pediatric MIS. This comprehensive investigation encompassed a wide range of relevant aspects, including well-established procedures, pioneering and audacious concepts\u2014even those yielding unfavorable outcomes, breakthrough technological advancements, potential hazards and challenges, contentious procedures, and invaluable insights drawn from our counterparts in the realms of general, thoracic, and visceral surgery.Our intention was to transcend a simple retrospective appraisal by eschewing the common narrative of \u201cwhat has been accomplished thus far?\u201d. Instead, our aim was to assemble a compendium of reports from pioneering colleagues from diverse medical disciplines. These individuals have forged innovatively ahead, propelling developments in minimally invasive surgical interventions in order to enhance the welfare of pediatric patients.We are pleased to say that our endeavors have borne fruit, and we believe that we have achieved our objective.To improve the wellbeing of pediatric patients even before their birth, Thomas Kohl delves into the study of fetal surgery, offering insights into both established and emerging minimally invasive approaches. Expanding upon this, Susanne Eva Brunner provides an exhaustive review comparing bimanual techniques and procedures in fetal surgery with single-instrument interventions. Additionally, Lidya-Olgu Durmaz sheds light on the use of minimally invasive techniques in fetal surgery for the treatment of gastroschisis.Regarding infants and congenital malformations, Anne-Sophie Holler describes the endoscopic magnetic-assisted anastomosing technique, specifically designed for the repair of esophageal atresia. Additionally, Julia K\u00fcppers presents an innovative approach termed \u201cendoscopic percutaneous rectal anoplasty\u201d, which has garnered considerable attention from the esteemed Alberto Pena, a prominent authority on anorectal malformation repair, prompting subsequent scholarly discourse. In a closely related context, Ulrike Metzger provides valuable insights into a recently modified approach involving transanal endoscopic-assisted pull-through colectomy targeted toward pediatric patients afflicted by high intestinal aganglionosis. These developments in pediatric surgical interventions offer promising avenues for improved outcomes and enhanced patient care.When it comes to general pediatric surgical procedures, this comprehensive compilation includes many notable contributions. Hanna Noemi Stundner Ladenhauf presents a meticulous evaluation of the minimally invasive approach in managing traumatic pancreatic ruptures, shedding light on its efficacy and potential benefits. Armin-Johannes Michel provides a detailed account of the thoracoscope-guided pericostal suture technique, showcasing its efficacy as a robust fixation method for closing congenital diaphragmatic hernias. The state-of-the-art of advancements in the field of minimally invasive repair of pectus excavatum (MIRPE) is expertly detailed by Frank-Martin Haecker, as he reveals the current developments and techniques employed in this realm. In a similar vein, Christian Tomuschat delves into the boundaries and limitations encountered in laparoscopic partial splenectomy, providing valuable insights into the challenges associated with this minimally invasive procedure.The domain of pediatric surgery encompasses not only general procedures but also extends to minimally invasive urological interventions. In this context, Frank-Martin Haecker contributes valuable insights by reporting on the combined antegrade and retrograde endoscopic injection technique into the bladder neck employed in children with neurogenic bladder disorders. Furthermore, Christian Kruppa presents a fascinating approach to vesicoscopic cross-trigonal ureteral reimplantation, specifically addressing vesicoureteral reflux. This innovative technique offers a compelling avenue for the treatment and resolution of this condition. These advancements in minimally invasive urological procedures within pediatric surgery hold great promise for enhanced patient outcomes and an improved quality of care.Mareike Grosshauser contributes an insightful examination of interdisciplinary knowledge transfer within the study of minimally invasive pediatric surgery. Similarly, Tatjana Tamara K\u00f6nig delves into the topic of telementoring in the context of minimally invasive esophageal atresia repair, shedding light on the potential benefits and implications of this approach. Expanding our understanding, Andrea Schmedding presents a comprehensive nationwide assessment of the current landscape surrounding laparoscopic pediatric inguinal hernia surgery, drawing upon an extensive dataset. Furthermore, Ma\u0142gorzata Sobol offers a unique perspective by focusing on the parental experience of minimally invasive surgery, specifically examining the role of parents\u2019 time perspective as a predictive factor for their child\u2019s postsurgical pain and emergence delirium, and the potential manifestation of post-traumatic stress disorder in parents.The integration of robotic-assisted surgery will be pivotal element in the future landscape of minimally invasive pediatric surgical procedures. Ewan Brownlee and Mark Slack delve into this paradigm-shifting subject, offering an insightful report on the novel Versius surgical robotic system developed by Cambridge Medical (CMR), exploring its potential utility within the pediatric population. In a related investigation, Marit Kayser presents an evaluation of the Versius system for pediatric surgery, employing inanimate models that simulate small infants and, thus, providing valuable insights into its feasibility and effectiveness. Within the pages of this publication, we also encounter a groundbreaking contribution by J\u00fcrgen Holzer, who provide the world\u2019s inaugural account of a pediatric pyeloplasty performed using the Senhance\u00ae robotic system. This pioneering achievement marks a significant milestone in the application of robotic technology in the pediatric surgical domain. Additionally, Elisabeth Ammer explores the phenomenon of \u201crobotic anxiety\u201d and elucidate parents\u2019 perception of robot-assisted pediatric surgery and its impact on their children. This investigation sheds light on the psychological aspects and human factors associated with the adoption of robotic systems in pediatric surgical contexts. Finally, Thomas Krebs offers a comprehensive review encompassing diverse aspects of robotic-assisted pediatric surgery. Our collective insights and synthesis of existing knowledge serve to enrich our understanding and foster advancements in this rapidly evolving field.Nevertheless, the possibilities of minimally invasive pediatric surgery transcend the traditional boundaries of abdominal and thoracic procedures. Within the field of pediatric orthopedics and orthopedic trauma, Karsten Krohn unveils a pioneering technique involving the dual pre-bending of an intramedullary nail to treat diametaphyseal fractures of the distal radius in children. This innovative approach not only renders the procedure and osteosynthesis less invasive but also holds promise for improved patient outcomes. Moreover, the use of resorbable implants presents an intriguing possibility for circumventing the need for subsequent explantation surgeries; this is an area explored by Christoph Roeder. Through a pilot study, he investigates the application of biodegradable intramedullary nailing, specifically for forearm fractures in the pediatric population. His findings shed light on the feasibility and potential benefits of this approach, paving the way for future advancements in pediatric orthopedic interventions. Similarly, Pascal Heye contributes to this line of inquiry by delving into the utilization of resorbable implants for osteosynthesis in pediatric cases. His research further expands our understanding of this evolving field, exploring possibilities for enhanced treatment modalities and improved patient outcomes. Furthermore, Mathis Wegner presents his insights into a minimally invasive orthosis designed to address a fixed equinus deformity following a modified transverse Vulpius procedure. This novel orthosis holds promise in rectifying this deformity while minimizing invasiveness, thus offering potential benefits to pediatric patients.These contributions to the knowledge of minimally invasive pediatric surgery collectively underscore the constant pursuit of innovative techniques and advancements aimed at optimizing patient care and improving long-term outcomes.This remarkable collection merits great attention, as it encompasses 27 pioneering works by surgeons who fearlessly expand the horizons of minimally invasive pediatric surgery.We thank all the contributors, and congratulate them on their excellent work.Best regards from Sankt Gallen, Switzerland and Kiel, Germany.Thomas Franz Krebs and Robert Bergholz."} +{"text": "Injection drug use using nonsterile equipment can lead to transmission of viral, bacterial, and fungal infections. Frontline healthcare workers (HCW) are at high risk for substance use disorder due to unprecedented job stress and access to injectable controlled substances. The Tennessee Department of Health (TDH) developed a collaborative investigative process to determine the risk of bloodborne pathogen (BBP) transmission from licensed HCWs engaging in drug diversion. This program recommends public health action and provides consultation to improve drug diversion programs.In 2019 TDH formed a drug diversion investigation team (DDIT) consisting of pharmacists, epidemiologists and medical directors from the HAI and HIV/STI/Viral Hepatitis programs. The DDIT responds to notification by the Health-Related Boards (HRB) of a licensed HCW under investigation for diversion of injectable products. The DDIT interviews the investigator and meets the facility drug diversion program to review drug diversion policies and processes. Based on the suspected method(s) and, if known, the individual\u2019s Hepatitis B/C and HIV status, recommendations are made regarding the need for patient notification and testing.From 2020\u20132022 the DDIT received notification of 49 licensed HCWs under investigation for diversion of injectable products. Patient notification and testing was recommended in seven facilities for CDC Category A infection control breaches; in two cases, later HCW testing negated the need for further action. Among the 34 facilities queried, only five (14.7%) had existing policies for for-cause BBP testing. Other recommendations to improve diversion programs include infection prevention participation and releasing \u201cnot eligible for rehire\u201d status to other facilities.The TDH DDIT facilitates communication with HRB on reported cases of injectable drug diversion. Joint investigations with facilities raise awareness of the risk of BBP transmission and improve facility diversion programs. Tennessee facilities are adding for-cause BBP testing to their investigation procedures. The TDH DDIT model receives mostly positive responses from facility and health system drug diversion teams and may be considered by other public health jurisdictions.All Authors: No reported disclosures"} +{"text": "Breast cancer is the most common cancer worldwide, and advanced breast cancer with metastases is incurable mainly with currently available therapies. Therefore, it is essential to understand molecular characteristics during the progression of breast carcinogenesis. Here, we report a dataset of whole genomes from the human mammary epithelial cell system derived from a reduction mammoplasty specimen. This system comprises pre-stasis 184D cells, considered normal, and seven cell lines along cancer progression series that are immortalized or additionally acquired anchorage-independent growth. Our analysis of the whole-genome sequencing (WGS) data indicates that those seven cancer progression series cells have somatic mutations whose number ranges from 8,393 to 39,564 compared to 184D cells. These WGS data and our mutation analysis will provide helpful information to identify driver mutations and elucidate molecular mechanisms for breast carcinogenesis. They were clonally selected to yield seven HMEC lines ([Breast cancer is the most common cancer diagnosed among women in the United States (excluding skin cancers). It is the second leading cause of cancer death among women after lung cancer . It is cigenesis to isolate gDNA from HMEC cultures. The quantity of the extracted gDNA was analyzed with an ND-1000 spectrophotometer . For WGS library construction, we used the TruSeq DNA library Prep Kit according to the manufacturer\u2019s instructions. For WGS, paired-end sequencing was performed on the Illumina HiSeq X Ten sequencing instrument, yielding ~150-bp short sequencing reads.Raw sequence reads were aligned to the human reference genome 19 using Burrows Wheelers Aligner , and duphttps://kobic.re.kr/kona) and Sequence Read Archive public database with the accession number PRJKA220370 and PRJNA913438.The whole-genome data are available in the Korean Nucleotide Archive . Then, we performed the driver mutation analysis using the IntOGen cancer mutation browser and obseIn this study, we generated WGS data and analyzed mutation profiles in the HMEC cancer progression series because genetic mutations are one of the most significant factors in determining breast cancer progression and therapeutic management . We hope"} +{"text": "Rhinella marina) that is particularly successful in human-altered landscapes. There have been numerous investigations of the cane toad diet, but most of these studies identified prey items at lower taxonomic resolutions . We used higher resolution for prey identification and multiple dietary measures of prey consumption to assess the ecological role of cane toads in the urban landscape of southwest Florida. Prey taxa commonly considered urban pests dominated the diet of cane toads inhabiting golf course communities, and there were differences in prey consumed during the wet and dry seasons of this region. We provided a better understanding of the potential relationships between cane toads and their prey in the urban environment.Urban ecosystems provide habitat to many species, including invasive species such as the cane toad (Rhinella marina) inhabiting urbanized areas in southwest Florida to provide high taxonomic resolution of prey items, contrast toad diets between sampling seasons and sexes, and assess this invasive species\u2019 ecological role in the urban landscape. A pest control agency collected cane toads from two golf course communities in Naples, Florida, USA during November\u2013December 2018 (early dry season) and June\u2013July 2019 (early wet season), and faunal stomach contents were quantified from a random subsample of 240 adult toads . Yellow-banded millipedes (Anadenobolus monilicornis), big-headed ants (Pheidole spp.), and hunting billbugs (Sphenophorus venatus vestitus) were the most frequently consumed prey items and had the highest total numbers and/or volume with corresponding highest indices of relative importance. There was considerable overlap in the seasonal prey importance values for each golf course community and little if any difference in the importance values between toad sexes in each community. Nonetheless, big-headed ants were the most important prey in both communities during the wet season, while yellow-banded millipedes were the most important dry season prey in one community and hunting billbugs the most important in the other. Despite limited spatiotemporal sampling effort, our results indicated that cane toad was consuming arthropod taxa considered pests in the urban ecosystem. Further studies are needed to investigate the potential effects of human activities and environmental variability on the cane toad diet and to determine whether cane toads act as a biological control for pest populations.We investigated the diet of cane toads ( Rhinella marina) is one such invasive species that has demonstrated an affinity to human habitation [Urban areas are often seen as ecologically inferior to their natural area counterparts; however, in the age of rapid urbanization, these developed areas have nonetheless become complex ecosystems inhabited by many species with their own adaptations to the novel urban conditions ,2. An adbitation ,10,11,12The cane toad is a large, toxic amphibian with a native range from southern Texas, USA and western Mexico, through Central America, and into central Brazil . This NeKnowledge of a species\u2019 diet is crucial to understanding its interactions with other species and, in some cases, function in the urban ecosystems it may inhabit ,25. DextAnaxyrus terrestris). Rossi [There have been three diet studies for cane toads in Florida, all of which were conducted in urban ecosystems. Krakauer characte). Rossi focused The purpose of our study was to examine the dietary composition of cane toads inhabiting residential golf course communities in southwest Florida. The objectives were to provide fine-scale taxonomic resolution of prey items, contrast cane toad diets between sampling seasons and sexes, and assess this invasive species\u2019 ecological role in the urban landscape.Our study was located in Naples, Collier County on the southwest coast of Florida, USA . Herein,A licensed pest control agency was contracted by the golf course communities to remove cane toads from their respective properties. Toads were collected by hand between 22:00 and 01:00 during November\u2013December 2018 (early dry season) and June\u2013July 2019 (early wet season). Captured toads were kept in ventilated buckets and later euthanized via cooling then freezing . We selet-test.For toad sexes, differences in SUL between seasonal collections in the golf course communities were analyzed with Welch\u2019s ANOVA and Games\u2013Howell post hoc tests using the Real Statistics Data Analysis Tools add-in for MicrPercent frequency of occurrence (%F), number (%N), and volume (%V) of cane toad prey taxa were determined byi with equationA percent index of relative importance was calCompound indices such as IRI reduce potential bias associated with the component diet measures ,53. ExamMultivariate analyses were performed on cane toad dietary compositions using PRIMER v6 software . AmbiguoR is an absolute measure of the separation between two or more groups, typically ranging between 0 (no separation of groups) and 1 was used to contrast diet composition between sampling seasons, allowing for differences between toad sexes, and between sexes allowing for differences between seasons. The ANOSIM statistic aration; ). Unlikeificant; ). Two-wap = 0.002) among seasonal sampling events with smaller females collected during the early dry season in golf course Community A , big-headed ants (Pheidole spp.), and hunting billbugs (Sphenophorus venatus vestitus) were the most frequently consumed prey items and had the highest total numbers and/or volume with corresponding highest indices of relative importance (combined IRI of 74%) for all taxonomic categories.A total of 13,961 prey items in 180 taxonomic categories was identified from the stomachs of 239 cane toads . One of Labidura riparia) were also frequently consumed (62% F) during this season, but their lower contributions to prey volume and number resulted in lower relative importance (16% IRI). In contrast, yellow-banded millipedes were the dominant dry season prey in golf course Community B with much lower contributions to the diet measures by hunting billbugs and a corresponding low relative importance (7% IRI). Big-headed ants were the most important early wet season prey in both golf course communities (49% IRI), owing to the high frequency of occurrence and the highest contributions to number of prey items but with relatively low-volume contributions. Yellow-banded millipedes in both communities and lepidopterans, primarily caterpillars, in Community B were also frequently consumed during the wet season and both taxa had the highest prey volume contributions but much lower numbers and corresponding relative importance. Additionally, Cuban May beetles (Phyllophaga bruneri) and scavenger scarab beetles (Hybosorus illigeri) were only consumed during the wet season in both communities.After resolving ambiguous taxonomic categories, there were 109 unique prey taxa , and 14 of these unambiguous taxa had an IRI > 1% for at least one of the seasonal cane toad collections in either of the golf course communities in prey importance value percentages between sampling seasons. The low R value indicated moderate overlap with some separation in prey compositions. The SIMPER routine identified hunting billbugs as contributing the most to the seasonal diet dissimilarity in Community A with a much greater mean importance value percentage for this prey item in the early dry season (Camponotus floridanus) had higher mean percentages during the early wet season. Other distinctive prey items only consumed in the wet season included uneven billbugs and Cuban May beetles. The average similarity value for prey taxa consumed in the early dry season (26.4%) was higher than that of the early wet season (18.9%), but these relatively low similarity values also indicate considerable variability in prey consumed by toads during each season.For golf course Community A, there was a significant difference in prey importance value percentages between toad sexes in golf course Community A; however, the very low R value indicated strongly overlapping importance value compositions with little difference between sexes. Nonetheless, hunting billbugs were identified by the SIMPER routine as contributing the most to the dietary dissimilarity between toad sexes and males exhibited a greater mean Importance value percentage for this prey item in prey importance value percentages between sampling seasons and the low R value indicated moderate overlap with some differences in prey compositions. The SIMPER routine identified yellow-banded millipedes as contributing the most to the seasonal dissimilarity in Community B and this prey item had a substantially greater mean importance value percentage during the early dry season (Asiomorpha coarctata), and shore earwigs also had higher importance value percentages during the early dry season but contributed less to the seasonal dissimilarity. Big-headed ants and lepidopterans had higher mean importance value percentages during the early wet season. Other prey items with distinctive wet season differences included Cuban May beetles, scavenger scarab beetles, darkling beetles (Platydema), and rover ants (Brachymyrmex). Average similarities were higher in the early dry season (23.5%) compared to the early wet season (11.5%), but dietary variability was indicated by the relatively low values.For golf course Community B, there was a significant difference in prey importance value percentages between toad sexes in golf course Community B. The negligible R value indicated dietary compositions were barely separable with little if any differences in prey importance values between sexes. Furthermore, the borderline statistical significance should be interpreted cautiously owing to the relatively high number of replicates/permutations and their influence on significance levels. The SIMPER routine indicated some minor dietary differences by sex . Ideally, dietary investigations should employ at least one metric measuring amount (frequency and number), and one measuring the bulk of food items present in each sample [In addition to prey resolution, the choice of diet metrics may have influenced previous interpretations of cane toad diet. Most studies reported one or two diet metrics for prey taxa, such as frequency and/or number, and only a few measured the bulk (volume or mass) of food items . Only Pah sample . Reportih sample . As demoDespite individual variability and overlapping dietary compositions, cane toads exhibited significant seasonal differences in prey consumption in southwest Florida. Big-headed ants were the most important prey in both golf course communities during the early wet season and contributed the most to the differences for this season in both communities. Florida carpenter ants were also important wet-season prey in Community A. For regions with seasonal patterns of precipitation, cane toads ingested higher numbers of ants during the wet season in a coastal village of the Philippines and withPrey compositions during the early dry season differed significantly from those in the early wet season for both golf course communities, but the importance of dry-season prey types also differed between communities. Hunting billbugs were the most important dry-season prey in Community A, while yellow-banded millipedes were more important in Community B, and both prey items contributed the most to the seasonal differences in the respective communities. The golf course communities in our study were relatively proximal to one another so location does not appear to be a factor; however, different human activities may be affecting arthropod ecology, or our perception as such, within each community . HuntingYellow-banded millipedes, hunting billbug weevils, and bigheaded ants were the most important prey items for cane toads collected from golf course communities in southwest Florida. These arthropods are considered urban pests, but further studies are needed to determine whether cane toads provide any beneficial service with respect to the consumption of these nuisance taxa in the urban ecosystem. Our higher resolution for prey identification provided a better understanding of potential predator\u2013prey relationships and their inferred use of habitats in the anthropogenically altered landscape. Furthermore, using multiple dietary metrics revealed size bias with the prey , and applying compound indices provided a balance for interpretations of prey importance. There were significant seasonal differences in prey importance for cane toads, possibly related to the behavior of toads and the ants consumed during the wet season, and a locational difference in dry season prey importance that could have resulted from pest management practices in the golf course communities or unintentional bias during toad collections. We recognize the limited spatiotemporal scope of sampling effort in the current study and suggest a more rigorous, multiannual sampling design to address the potential effects of human activities and environmental variability on cane toad diet in urban ecosystems."} +{"text": "Wound healing is a complex and coordinated biological process easily influenced by various internal and external factors. Hydrogels have immense practical importance in wound nursing because of their environmental moisturising, pain-relieving, and cooling effects. As photo-crosslinkable biomaterials, gelatine methacryloyl (GelMA) hydrogels exhibit substantial potential for tissue repair and reconstruction because of their tunable and beneficial properties. GelMA hydrogels have been extensively investigated as scaffolds for cell growth and drug release in various biomedical applications. They also hold great significance in wound healing because of their similarity to the components of the extracellular matrix of the skin and their favourable physicochemical properties. These hydrogels can promote wound healing and tissue remodelling by reducing inflammation, facilitating vascularisation, and supporting cell growth. In this study, we reviewed the applications of GelMA hydrogels in wound healing, including skin tissue engineering, wound dressing, and transdermal drug delivery. We aim to inspire further exploration of their potential for wound healing. The skin is a multifunctional barrier organ that protects internal organs from potential environmental hazards . The proGelMA is a synthesised biomacromolecule with excellent biocompatibility and formability; it was first reported to be synthesised by Bulcke et al., in 2000 . Since tin situ photo-crosslinking properties make GelMA hydrogels particularly suitable for application in irregular wounds and hydroxyl (\u2013OH) groups on the side chains of gelatine are substituted by the methylacryloyl group . GelMA-dHAMMA hydrogels were found to promote fibroblast proliferation and \u03b1-smooth muscle actin expression. GelMA-dHAMMA has also been shown to promote wound collagen deposition and angiogenesis and accelerate tissue healing in rabbit full-thickness skin tissue defects are competitive candidates because of their excellent biological characteristics .in vivo vascularisation. In a previous study, epidermal stem cell\u2013derived EVs loaded with VH298 were encapsulated in GelMA hydrogels to enhance the angiogenic ability of diabetic wounds. GelMA hydrogels were shown to be convenient and adaptable delivery carriers for the sustained release of VH298-EVs, effectively promoting wound healing by locally improving blood supply and angiogenesis by increasing the HIF-1a level delivery (Microneedles are one of the transdermal drug delivery techniques that usually release loaded drugs directly into the deep layer of the skin through tiny holes formed by puncture . Hydrogedelivery . The micIn conclusion, GelMA hydrogels have been widely used in many applications, ranging from wound dressings to 3D printing skin tissue engineering. They provide an ideal multistratified anisotropic scaffold for the growth of various cells such as fibroblasts, endothelial cells, and keratinocytes. They can also be used to prepare personalised multifunctional dressings by combining small molecules, metal nanoparticles, and cellular EVs via physical binding or chemical reactions. Therefore, the application prospects of GelMA hydrogels for wound healing are significant. However, the biosafety of GelMA-based hydrogels remains a major obstacle to their clinical applications. The release of unreacted methacryloyl monomers after photo-crosslinking is a potential risk. Furthermore, photo-crosslinking under UV radiation may damage cellular DNA . Additio"} +{"text": "Impairments in cognitive and executive function of presumed cerebral microvascular origin are important and recently recognized neuropathological manifestations of vascular contributions to cognitive impairment and dementia (VCID) , 2. It hStudying WM continues to pose unique methodological and diagnostic challenges for aging research. WM is highly enriched in auto-fluorescent pigments that make rigorous immunohistochemical (IHC) approaches for mechanistic and diagnostic studies extremely challenging. Although astrocytes may degenerate in overt WM infarcts, the vulnerable glial subtypes in diffuse microvascular WM lesions remain essentially unknown. Admittedly, glial lineages are complex and relatively few specific markers are available. Furthermore, the expression of glial markers can change dramatically in regions of WM injury leading to nonspecific false positive staining . In addiTo provide rigorous access to human WM lesions, we recently developed a unique rapid autopsy brain procurement protocol using specimens donated by participants in the Adult Changes in Thought (ACT) study, a prospective, population-based study of aging and incident dementia among men and women in Seattle, Washington . This prA unique opportunity afforded by this rapid autopsy brain procurement protocol is access to fresh tissue samples for direct analysis of human penetrating microvessels. We have developed novel protocols to preserve these vessels for a wide range of physiological and molecular studies performed within 24 hours after procurement. Although cerebral microvascular disease is a common manifestation of aging, prior human and murine vascular and morphological studies were limited mostly to the middle cerebral artery and pial microvessels, and findings were extrapolated to WM penetrating microvessels. Moreover, despite growing interest in WM injury and MRI-defined WM hyperintensities in VCID and AD, vascular studies mostly lacked histopathological, neuroimaging or mechanistic correlation.We established the feasibility to study human penetrating WM arterioles in initial studies of aged human microvascular lesions with low ADNC . We founThe molecular mechanisms that mediate enhanced dysfunction of WM parenchymal arterioles when vascular dysfunction and ADNC coincide remain elusive. Analysis of human WM lesions and WM parenchymal arterioles , 7, as wTaken together WM injury and WM hyperintensities of presumed microvascular origin are of growing interest to aging and VCID researchers. A growing body of evidence supports that microvascular brain injury is accompanied by oxidative stress, astrogliosis, changes in the extracellular matrix , and quantitative MRI-defined abnormalities in prefrontal WM that involve disrupted integrity of axons and myelin. Mechanistic studies are needed to further define contributions of microvascular dysfunction to WM injury, particularly as it relates to the identities of the cell types and molecular signatures that could be harnessed to diagnostically discriminate among VCID, AD or mixed vascular/ADNC."} +{"text": "Cancer is the second most common fatal disease leading to death worldwide. Metastatic growth in distant organs is the main reason for increased cancer mortality . Cancer in vivo mouse models targeting cancer stem cells and their signaling pathways which are effective in treating pancreatic cancer. The article focuses on the mode of action of bioactive plant metabolites from TCM against various signaling pathways such as Wnt and Notch, which regulate cancer stem cells in pancreatic cancer. Zhang et al. explain the inhibition of cancer stem cell signaling pathways involved in epithelial to mesenchymal transition, migration, metastasis and apoptosis of pancreatic cancer cells by the plant metabolites.The exploration of plant derived drugs as potential therapeutic interventions against cancer stem cells and metastasis is an exciting area of research that complement existing cancer therapies and improve patient outcomes. Koklesova et al. describes how nanoparticles specifically designed to target cancer stem cells in tumor, serve as carriers for targeted delivery of plant-based drugs. Several Nano-drugs developed to target and treat the different types of cancer and their subsequent CSCs are discussed. Plant metabolite-based nanoparticles are modified to specifically target cancer stem cells, which helps in reducing the risk of tumor recurrence and the manifestation of metastases. Zhao et al. describe the anti-metastatic effect of thymoquinone in pancreatic cancer and its sensitivity to gemcitabine by regulating collagen. In pancreatic cancer cells, thymoquinone promotes apoptosis, inhibits tumor cell migration, invasion and metastasis, and sensitizes pancreatic cancer cells to gemcitabine. Furthermore, the study shows that thymoquinone stimulates cellular matrix production via TGF\u03b2/Smad pathways.Targeted therapies for the heterogeneous population of cancer tumors and multidrug resistance associated with cancer stem cells are still not effectively established. The review article by Mazurakova et al.). In the systemic review article, Mazurakova et al. detail the effect of flavonoids on breast cancer stem cells to combat therapy resistance and cancer proliferation. The accumulation of breast cancer stem cells (BCSCs) after chemotherapy, prevents further effective treatment of breast cancer patients. Therefore, it is also postulated that eradication of BCSCs in combination with standard cytotoxic drugs and flavonoids specifically targeting CSCs in breast cancer tumor is essential for successful treatment.Studies show that flavonoids have an anticancer effect against various types of cancer. Flavonoids can induce apoptosis and autophagic cell death of breast cancer cells, inhibit cancer proliferation and overcome drug resistance of cancer tumors (This Research Topic provides new data and detailed reviews on plant-derived compounds that target cancer stem cells and inhibit metastasis through various mechanisms of action by modulating self-renewal pathways, suppressing EMT, affecting the tumor microenvironment and disrupting signaling pathways essential for cancer cell migration, invasion and survival. Thus, plant metabolites are promising for developing innovative therapeutic strategies against cancer stem cells and metastasis. Prospective research is inevitable to successfully translate research findings into clinical trials by addressing challenges such as safety, bioavailability, formulation and standardization of herbal medicines. These findings and reviews demonstrate how phytomedicines targeting cancer stem cells significantly reduce metastasis and subsequent mortality. These prospective and innovative findings, if clinically established, are promising and can pave the way to new vistas for cancer therapy."} +{"text": "Advances and Challenges of Non-Invasive Brain Stimulation in Age-Related Neurodegenerative Diseases\u201d, highlighting the significance of aging as a risk factor for neurodegenerative diseases, the limited effectiveness of current treatments and the potential of non-invasive brain stimulation.This editorial summarizes the contributions of the Frontiers Research Topic \u201cAging is a major risk factor for neurodegenerative diseases. Neuronal losses during aging can lead to cognitive decline, particularly when combined with accumulation of toxic proteins. Treatment options for these conditions are limited. Noninvasive brain stimulation (NiBS) techniques, such as transcranial magnetic stimulation (TMS) and transcranial current stimulation (TCS), can modulate brain networks and enhance cognitive functions in both healthy individuals and neurodegenerative patients. The effects of NiBS can persist even after the stimulation ends. However, a comprehensive understanding of its biological mechanisms and clinical applications is still lacking, which poses challenges. This topic aims to explore NiBS as an innovative therapeutic tool, specifically discussing its advances and challenges in treating age-related neurodegeneration.He et al. promoted that spinal cord stimulation (SCS) is a promising treatment for disorders of consciousness (DoC). This study analyzed 66 DoC patients who received SCS treatment to investigate the association between postoperative cerebrospinal fluid (CSF) protein levels and consciousness improvement. Patients with permanent electrodes had higher CSF protein levels than those with temporary percutaneous electrodes. Moreover, elevated CSF protein levels were linked to reduced sagittal diameter and poor outcomes at 3 months. The findings propose that reducing the influence of electrode pads on anatomical changes may improve treatment outcomes. CSF protein levels could serve as potential biomarkers of postoperative outcomes and deserve further exploration.A study conducted by Ni et al.) evaluated the effects of various repetitive TMS (rTMS) stimulation procedures on upper limb function and brain functional network characteristics in stroke patients. The study involved 36 stroke patients who were assigned to either receive 1 Hz stimulation in the contralesional hemisphere and 10 Hz stimulation in the affected hemisphere, or solely 10 Hz stimulation in the affected hemisphere. The results demonstrated that rTMS treatment improved upper limb motor function, enhanced brain network connections, and reduced activation of isolated brain areas. Depending on the specific brain network states, optimal rTMS treatment plans could be suggested for precise rehabilitation.Another study explores the effects of continuous theta burst stimulation (cTBS) on enhancing language abilities in patients with aphasia. The researchers focused on targeting the right posterior superior temporal gyrus (pSTG), a region acknowledged for its critical role in semantic processing. This article presents findings from a randomized controlled trial involving 34 aphasic patients who underwent either cTBS or sham stimulation, followed by speech and language therapy. The study aimed to uncover whether cTBS applied to the right pSTG could promote language recovery and elucidate the underlying brain mechanisms. The results showed promising effects of cTBS, manifesting as improved language performance and modulation of brain activity and connectivity in specific regions. Overall, this research offers valuable insights into potential therapeutic interventions for language rehabilitation in individuals with aphasia.Another study investigates the effects of brain stimulation on two different age groups: middle-aged adults (40\u201360 years) and older adults (65 years and above). The researchers aimed to understand how tDCS impacts behavior and brain function differently in these two groups. Additionally, behavioral assessments and neurophysiological measurements were performed. This research provides valuable insights into age-specific brain stimulation effects and its potential applications for cognitive enhancement.One article explores the potential therapeutic effects of two brain stimulation techniques, median nerve stimulation (MNS) and rTMS, on patients with prolonged disorders of consciousness (pDOC). In a rigorously conducted trial, 75 eligible patients with pDOC were randomly assigned to one of three groups: (1) rTMS + sham-MNS; (2) MNS + sham-rTMS; or (3) MNS + rTMS. The primary outcome was the change in the Coma Recovery Scale-Revised (CRS-R) score after treatment. Findings showed that the combined MNS + rTMS intervention yielded significantly greater improvements in Glasgow Coma Scale (GCS) scores and somatosensory evoked potentials, compared to the other two groups. This research offers valuable insights into the potential benefits of combining brain stimulation modalities to enhance consciousness recovery in patients with pDOC.Another article and elderly adults (65\u201380 years). They aimed to measure the impact of stimulation on motor skills and cortex responsiveness. The study revealed significant age-related differences, indicating that ccPAS enhances action performance and corticomotor excitability more effectively in young adults compared to elderly adults. These findings offer valuable insights into the age-specific effects of brain stimulation and its potential applications for cognitive enhancement. By delving into this research, the researcher can gain deeper understanding of how brain stimulation techniques may differ in their outcomes based on age, contributing to advancements in neurostimulation and its implications for age-related cognitive functions.In a study conducted by Naparstek et al.) presents a comprehensive review of the potential uses of transcutaneous vagus nerve stimulation (tVNS), a non-invasive neuromodulation technique, in the context of cognitive aging. The authors have compiled a thorough review and provided valuable commentary on the existing literature, shedding light on the effectiveness of tVNS in enhancing various cognitive functions in older adults. Through this review, researchers can uncover the promising applications of tVNS for memory, attention, and executive functions in the aging population. This review not only synthesizes the current knowledge on tVNS but also suggests pathways for future research, offering new insights into innovative therapeutic approaches for addressing age-related cognitive decline.Another study (YG: Writing\u2014original draft. WW: Writing\u2014review and editing. JZ: Writing\u2014review and editing."} +{"text": "This cross-sectional study compares clinician and artificial intelligence (AI) chatbot responses to patient vignettes used to identify bias in medical decisions. This study aimed to evaluate AI chatbot responses to clinical questions previously tested in large samples of clinicians to examine established biases in medicine related to gender, race and ethnicity, and socioeconomic status (SES) through published vignettes.Artificial intelligence (AI) chatbots transformed how we access information provided by large language models. However, AI models may carry inherent bias, often mirroring the systematic inequalities present in our society.STROBE) reporting guideline. This study was deemed exempt from the institutional review board at Stanford University. Informed consent was waived because the study did not involve human participants. We selected 19 clinical vignettes in cardiology, emergency medicine, rheumatology, and dermatology. A full list of references can be found in the eReferences in This cross-sectional study followed the Strengthening the Reporting of Observational Studies in Epidemiology (The 4In this cross-sectional study, we observed that AI chatbots provided different recommendations based on a patient\u2019s gender, race and ethnicity, and SES in certain clinical scenarios. We found both overlapping and unique differences in responses among the AI chatbots and between the AI chatbots and physicians. The presence of bias among clinicians and clinical risk algorithms has historically caused disparities in clinical care and led to poorer health outcomes for some marginalized populations. While AI chatbots have shown proficiency in various medical tasks, including passing the United States Medical Licensing Examination, interpreting laboratory tests, and answering patient questions, neither chatbot is approved for medical applications.5 Differences in AI chatbot recommendations have not been fully explored, and their impact is unclear. These differences may be shown to propagate or counter biases that clinicians have, the impact of AI-based tools on health disparities may vary in different clinical situations. However, these tools are being adopted by patients and clinicians, making further research especially urgent.Limitations include a small number of vignettes tested and different assessment scales used per vignette following the original studies\u2019 approaches. Although AI chatbots are promising tools in medicine, our findings underscore the need for careful application of early adoption. Prior studies have suggested that using AI in medicine could contribute to treatment inequities in marginalized racial and ethnic groups."} +{"text": "Endoscopic ultrasound (EUS) has entered its golden age. The benefits of providing refined diagnosis and advanced therapeutic procedures by EUS are numerous and widely appreciated by clinicians worldwide \u20133.Just 20 years ago, EUS diagnosis was based mainly on radial mechanical echoendoscopes with no electronic image enhancement functions . On the Since then, EUS has gone through years of exciting and unrelenting scientific and technologic advancements. The biggest improvements were introduced by image enhancement techniques with ultrasound contrast agents and elastography allowing better detection and characterization of the lesions of interest.Frontiers in Medicine about advancements in the EUS diagnosis of pancreatobiliary diseases, image enhanced EUS for the diagnosis of gallbladder lesions is presented. Differential diagnosis between benign and malignant gallbladder tumors can be challenging in order to select the candidates for surgery. Contrast-enhanced harmonic EUS (CH-EUS) has been previously reported to be useful for the diagnosis of gallbladder tumors and accuracy (90%) . Data inThe usefulness of liquid-based cytology to increase the diagnostic yield of EUS-guided tissue acquisition is also discussed. Several techniques have been used in this regard, including fine needle biopsy with histology needles, rapid onsite cytopathology evaluation, and guidance by CH-EUS. A recent meta-analysis showed a pooled diagnostic sensitivity of 85% with CH-EUS-fine needle aspiration and 75% with standard EUS- fine needle aspiration . HoweverEUS is also a great tool for pancreatic cancer screening in conjunction with magnetic resonance imaging . InteresFinally yet importantly, bibliometric analysis of EUS publications is presented. Compared to previous EUS literature scans , an updaPF wrote the editorial. MT and YY reviewed the manuscript for important intellectual content. All authors contributed to the article and approved the submitted version."} +{"text": "They validated their initial findings by targeted metabolomic analyses in two different cohorts with similarly increased cardiovascular risk, from the United States (n\u2009=\u20092149) and Europe (n\u2009=\u2009833) undergoing cardiac evaluation. This follow-up analysis strengthened their original findings by revealing that the association of erythritol not only remained significant but was independent of age, sex, and other established risk factors. This suggests the additional operation of other than metabolic mechanisms. Indeed both in vitro and in vivo studies in human whole blood and mice revealed an erythritol-elicited increase in platelet adhesion and clot formation (Fig. 1 Their subsequent pilot study showed that a single dose of 30\u2009g erythritol results in prolonged excessive plasma erythritol elevation for over 48\u2009h. The recorded concentrations remained well above the threshold, which increased platelet reactivity and thrombocyte reactivity in vitro,1 suggesting a prolonged thrombotic risk arising from exogenous erythritol.Abnormal vascular function and coagulation represent other central drivers of cardiovascular disease onset and development.3 At present, controlled trials did not detect detrimental effects of erythritol ingestion in healthy humans,5 but specific trials on vascular function and coagulation in healthy and diseased humans are lacking.While these studies support a novel conceptual framework of erythritol-induced promotion of thrombus formation leading to excess cardiovascular risk, several limitations need to be addressed. There is not only a lack of standardization of erythritol measurements but also of the preanalytical conditions. The observed prolonged elevation of erythritol upon dietary intake raises the question of whether simple overnight fasting conditions suffice for the interpretation of baseline concentrations; moreover, the kinetics of erythritol elimination might substantially differ between healthy and metabolically compromised people. Importantly, their in vitro procedures raised the platelet concentrations creating artificial experimental conditions. Also, the mice experiments showing enhanced clot formation upon erythritol injection do not necessarily mirror thrombosis risk in humans. Thus, a direct analysis of platelet activation in humans upon erythritol might better reflect real-life conditions. Further questions arise: to what extent do different conditions affect the relative contributions of exogenous versus endogenous sources to the total circulating erythritol concentration, particularly could people with increased cardiovascular risk produce more erythritol? One might speculate that altered hepatic metabolism in humans with type 2 diabetes, who are at higher risk of fatty liver disease, might at least contribute to the described effects. Of note, epidemiological and cohort studies cannot exclude reverse causality because people with an unfavorable metabolic profile are more prone to consume sugar-free meals to avoid weight gain or hyperglycemia, even before cardiovascular disease diagnosis.Taken together, Witkowski and colleagues shed light on one of the widely-used non-nutritive sweeteners and provide novel evidence for the potentially deleterious effects of erythritol on platelet function. At the same time, these findings raise new questions calling for sufficiently powered double-blind, randomized controlled trials addressing the safety as well as mechanistic studies examining the Janus-head-like features of erythritol. Importantly, the evidence derived from the current study should already suffice for the authorities to re-evaluate their policy statements regarding the cardiovascular and metabolic risks of artificial sweeteners."} +{"text": "Advanced Materials (2023) 10.1002/adma.202306834Owing to the absence of appropriate helical templates, circularly polarized organic ultralong room temperature phosphorescence with a high dissymmetry factor remains a formidable challenge in contemporary research. A team of Qiang Zhao and Yanqing Lu proposes an effective tactic to enable the high dissymmetry factor by employing a circularly polarized phosphorescent system composed of meticulously designed phosphorescent polymers and self-assembled chiral helical superstructures. Specifically, multiple interactions among polymer chains can strictly restrict molecular motions of phosphorescent molecules, thereby inhibiting the non-radiative relaxation pathways and resulting in the emission decay time of 735 ms. The self-organized periodic helical superstructures serve as an ideal medium for enhancing chirality, giving rise to the attained dissymmetry factor of 1.49 and surpassing previous records by two orders of magnitude. The creatively explored system displays remarkable photo-thermal stability and demonstrates the potential applications of photoprogramming photonics. These findings would create a brilliant outlook of the optical multiplexing-based information encryption, and establish the intimate connection between circularly polarized phosphorescent materials and the evolving field of optical information technologies toward the cutting-edge photonic applications and beyond."} +{"text": "Popular press coverage of the Medicare Part D coverage gap is based largely on research conducted using retrospective analyses of administrative claims data. These datasets are incomplete because they lack information about methods of obtaining medication that are commonly used by seniors, including free samples, generic drug discount programs, over-the-counter substitution, and patient assistance programs. As a result, evidence about the effects of 100% cost sharing on seniors is limited and suboptimal. Although the current deficit of information about the coverage gap is not entirely unexpected because the Medicare Part D program is relatively new, reliance on claims-based analyses to inform questions that claims data cannot possibly address accurately has tended to mislead and politicize rather than produce constructive policy guidance. Numerous important health policy questions remain unaddressed. These questions are becoming especially important as optimal approaches to providing health care to seniors are the subject of an increasingly vigorous debate."} +{"text": "Parents frequently purchase and inquire about smartwatch devices to monitor child behaviors and functioning. This pilot study examined the feasibility and accuracy of using smartwatch monitoring for the prediction of disruptive behaviors.N\u2009=\u200910) aged 7\u201310 years hospitalized for the treatment of disruptive behaviors. The study team completed continuous behavioral phenotyping during study participation. The machine learning protocol examined severe behavioral outbursts for preparing the training data. Supervised machine learning methods were trained with cross-validation to predict three behavior states\u2014calm, playful, and disruptive.The study enrolled children (The participants had a 90% adherence rate for per protocol smartwatch use. Decision trees derived conditional dependencies of heart rate, sleep, and motor activity to predict behavior. A cross-validation demonstrated 80.89% accuracy of predicting the child's behavior state using these conditional dependencies.This study demonstrated the feasibility of 7-day continuous smartwatch monitoring for children with severe disruptive behaviors. A machine learning approach characterized predictive biomarkers of impending disruptive behaviors. Future validation studies will examine smartwatch physiological biomarkers to enhance behavioral interventions, increase parental engagement in treatment, and demonstrate target engagement in clinical trials of pharmacological agents for young children. Evidence-based interventions such as parent\u2013child interaction therapy (PCIT) reduce behavioral and emotional symptoms in children by improving parent\u2013child relationships through the implementation of specific rules taught over a multiweek period the effectiveness of PCIT is contingent upon parents making a concerted effort to remember the rules imparted by a provider in engaging with their children and (2) families from rural areas and under-represented populations are less likely to have access to and utilize evidence-based therapies when it is available , there is an opportunity to improve access and effectiveness of behavioral interventions in children and adolescents, including PCIT. Smartwatches measure individual functioning in real time and provide opportunities to identify point-of-care smartwatch biomarkers in young children that can provide prompts for parents of child's impending behavioral outbursts. Accessible digital tools may have the promise of increasing parental engagement for improved outcomes.The growth in children's smartwatch market is largely driven by parental interest to track their child's functioning aged 7\u201310 years were enrolled in this IRB-approved study conducted during May 2020 through December 2020. Registered nurses (RNs) of the Mayo Clinic Child and Adolescent Psychiatry inpatient unit continuously assessed and annotated behavior for 24 hours daily during hospitalization , heart rate (beats per minute), and sleep (including duration and sequence of sleep stages) data through the Garmin Connect mobile application. The smartwatch minute-level data were aggregated and collected through Fitabase. Each participant and family had an abbreviated PCIT training intervention during hospitalization.Calm indicated that the child was sedentary while performing routine activities such as reading, lying down, watching movie, talking/interacting with others, or doing their daily homework. Playful indicated that the child was engaged in a nondisruptive activity of elevated heart rate such as exercising , playing a sport , or playing with other children .Inpatient RNs annotated behavior states as either calm, playful, or disruptive using the behavior code described in Disruptive (behavior codes 9\u201311) indicated that the child showed uncontrolled aggression/behavior warranting intensive behavioral interventions, time-outs, or restraint for safety. For each of the calm, playful, and disruptive phenotypic annotations on a given day, the corresponding average heart rate in the preceding 60 minutes and the durations of sleep stages from the previous night were captured with the smartwatches (see ches see .Decision trees were trained to use heart rate (60-minute average) and sleep data to predict calm, playful, or impending disruptive behaviors across the three behavior phenotypes. The Garmin vivosmart4 smartwatch provides three levels of intensity of motor activity . Notably, when participants were characterized as calm, there was no difference (p\u2009>\u20090.8) between the mean heart rate during the 60-minute calm period and the overall resting heart rate . However, the durations of REM, light, and deep sleep stages were different between participants who exhibited disruptive behavior versus those who did not if the duration of light sleep exceeded 4 hours, and there were no significant associations with the total sleep duration or duration of awake, deep, and REM sleep.The Garmin vivosmart4 watch provides the duration and sequence of sleep stages with an accuracy of 80.89%.Prior research has demonstrated parental acceptance -approved features are becoming ubiquitous across all ages for wellness monitoring and improved health-related outcomes. Cardiology practice has adopted the use of smartwatch devices for monitoring and assessment of remote cardiac monitoring are underway to establish benchmarks and the utility of wearable devices for monitoring, decision support, augmented interventions, and predictive models. Valid and accessible digital biomarkers will have great utility for future pharmacological trials for young children.This study has limitations. First, an inpatient monitoring study did not present specific behavioral triggers in outpatient settings . Biomarker thresholds and accuracies of predicted behavior states may vary between patients based on parents' perception of what constitutes disruptive behavior versus nearly homogeneous annotations of disruptive behavior marked by trained nurses. Second, only one smartwatch brand was used and additional studies with trackers from other vendors are needed. Third, the study used data from hours with complete measurements, hence the impact of time gaps in measurements is yet to be understood.Fourth, it is possible that more computationally intensive algorithms may outperform prediction performance of decision trees with larger sample sizes and duration of observation. Fifth, although the study psychiatrists and medical records did not identify any medication-related side effects in the sample, the potential impact of concurrent psychotropic medications on physiological measures (including sleep disturbances) is unknown as it is highly possible that the threshold of biomarkers varies with time and improves behavior states.Therefore, larger studies with longer duration of observation and treatment modalities are needed to further develop and refine time-series algorithms to predict impending disruptive behavior in children. Finally, digital biomarkers derived in this study need validation in an outpatient setting to guide the development of a technology-enhanced version of behavioral interventions such as PCIT.There is a critical societal need to better understand and leverage scalable remote technologies to foster healthy parenting practices within the framework of traditional evidence-based behavioral therapies such as PCIT. This feasibility study demonstrates the capability to introduce precision target-based technologies using smartwatch-derived biomarkers to improve effectiveness of psychosocial interventions in young children by predicting disruptive behavior in children before manifestation. Such biomarkers when successful could be utilized in delivering precision care to children and families through remote care capabilities\u2014thereby addressing barriers to accessing specialty pediatric behavior clinics."} +{"text": "Acculturation refers to the process of change that occurs when people of different cultural backgrounds are in enduring first-hand contact intersect to impact acculturation experiences in educational settings.While some papers focus on specific demographic groups, there is room for more research that considers Longitudinal studies could provide insights into how acculturation attitudes and experiences evolve over time, especially in relation to educational outcomes.Most of the papers employ cross-sectional designs. Comparative studies could provide insights into how cultural and national contexts influence acculturation processes in education.The papers focus on various geographical contexts. how educational policies impact acculturation processes. Future research could explore the role of policies in facilitating or hindering acculturation in schools.While the papers discuss individual and group experiences, there is a gap in the examination of technology in acculturation within educational settings remains underexplored. Research could focus on how digital platforms and online education impact acculturation experiences.In an increasingly digital world, the role of In summary, while the current Research Topic provides valuable insights into the relationship between acculturation and education, it also opens up multiple avenues for further exploration. These new directions could significantly enrich the academic discourse and have practical implications for educators, policymakers, and researchers alike.EM: Conceptualization, Writing\u2014original draft. NL: Writing\u2014review & editing. CW: Writing\u2014review & editing. DB: Writing\u2014review & editing."} +{"text": "Behavioral and emotional problems were showed to be associated with the prenatal environment. Changes in placental DNA methylation was identified as a relevant potential mechanism of such association.We aimed to explore the associations between placental DNA methylation and child behavior in order to explore pathways that could link prenatal exposures to child behavior.Data including 441 children of 3 years of age from the EDEN mother-child cohort. Child behavior assessed using the Strengths and Difficulties Questionnaire (SDQ). Both hypotheses-driven and exploratory analyses (including epigenome-wide association studies (EWAS) and differentially methylated regions (DMR) analyses) were conducted. The analyses were adjusted for confounding and technical factors and estimated placental cell composition. All the p-values were corrected using a false discovery rate (FDR) procedure for multiple tests.cg26703534 (AHRR), was significantly associated with emotional problems (pFDR = 0.03). In the exploratory analyses, cg09126090 (pFDR = 0.04) and cg10305789 were significantly associated with peer-relationship problems and 33 DMRs were significantly associated with at least one of the SDQ subscales. Placental DNA methylation showed more associations with internalizing than externalizing symptoms, especially among girls. DMRs tented to include highly methylated CpGs.In the hypothesis-driven analysis, This study investigated for the first time the associations between placental DNA methylation and internalizing and externalizing symptoms in preschoolers. Further analyses, such as consortium meta-analyses would be necessary to confirm and extend our results.None Declared"} +{"text": "This could be due to the primary surgical oncologist informed by MD-PALS members being able to better identify key EOL issues surrounding the patient and hence better equipped to conduct a quality GOC discussion during a surgical admission.We established a multidisciplinary palliative surgical intervention (MD-PALS) team comprising healthcare providers of various subspecialties involved in the care of these patients. We then performed a single-centre prospective cohort study recruiting advanced cancer patients who received palliative interventions, comparing the outcomes of those cared for under the newly established MD-PALS team and those who received usual care.6 Future research should delve deeper into investigating and validating the other potential benefits of MD-PALS teams. Robust and rigorous studies will be essential in refining team structures and processes, ensuring the model is optimized to cater to the unique needs of palliative surgical oncology patients.Our study highlights the positive impact of multidisciplinary specialist providers\u2019 involvement in the care of palliative surgical oncology patients, leading to enhanced GOC discussions. MD-PALS teams hold the potential to become the cornerstone of a \u2018Community of Practice\u2019, fostering interdisciplinary collaboration and seamless communication between team members, patients, and their families, ensuring the comprehensive and holistic management of the multifaceted challenges faced by these patients."} +{"text": "This editorial reports from seven international working groups from the US and Europe as follow-up of the Eight Kraepelin Symposium in Munich, LMU, recruiting former and recently recruited ones. It covers basic research investigating the consequences of genetic and environmental factors on psychosis in the translation in preventing psychosis in children of parents with severe mental illness. Secondary prevention aims to avoid further episodes having foci on translation of new mechanisms targeting family communication, patterns of cannabis use or targeting cognitive biases in metacognitive training. Translation in later phases of psychoses refer to translating the knowledge, its evidence and meta-analysis. Novel foci include psychoeducational groups for close relatives of patients with borderline personality disorder and lifestyle behaviors combined with metabolic disturbances in a transdiagnostic psychiatric sample. Recently, metacognitive training gained importance being an important addition to family therapy and cognitive behavioral therapy. Strategies that proved their effectiveness are to be implemented in standard treatment as well as strategies implemented to train professionals in effective crisis and family management.In the nineteenth century, Emil Krapelin pioneereThis special supplement related to the Eighth Kraepelin Symposium\u2014Translation in Psychiatry and Psychotherapy\u2014A Life-long Necessity covers tTranslation from mechanism to mental health practices covers basic research in psychological targets in trauma and its translation in mental health practices . TranslaThe vulnerability\u2013stress-coping model (2\u20133.5) is our conceptual framework guiding psychoeducational and family therapy focusing on the interaction between biological vulnerability, protective personal and environmental factors Garosi et al. and the real world FACE-SZ cohort investigWright et al. investigBighelli et al. investigNovel foci include psychoeducational groups for close relatives of patients with borderline personality (BPD). Pitschel-Walz et al. evaluateIn summary, the vulnerability-stress-coping model provides valuable targets for treatment stressing psychoeducation, family therapy and cognitive behavioral therapy (CBT) and recently MCT proved their effectiveness in meta-analysis. Psychoeducation, communication, and problem-solving skills are the main tools for relapse prevention. Novel trends refer to pioneering psychoeducational groups in borderline personality disorder, cannabis patterns in first episodes and predictive capability for weight gain during treatment in a transdiagnostic sample.Primary intervention is to focus on psychological targets in trauma in children of parents with PHSMI and there should be visiting and complex community programs, residential treatments and online help. Further research, as well as more training for professionals on effective crisis and family management seems necessary."} +{"text": "Case reports are vital components of scientific literature, providing essential insights into rare or unique medical conditions, diagnostic dilemmas, and therapeutic challenges . There hClinical case reports correspond to articles with the lowest level of evidence on the hierarchy of various research study types . HoweverMedical literature is often dominated by observational studies involving larger patient cohorts, leaving rare and unusual cases underrepresented. Case reports fill this gap by presenting detailed accounts of such unique situations that can be useful for other clinicians . Within The diverse range of respiratory diseases often presents diagnostic challenges due to overlapping clinical features. Case reports detailing unique diagnostic dilemmas and the strategies used to resolve them offer valuable learning opportunities for healthcare professionals . By sharCase reports can provide early evidence of the effectiveness of novel therapies or management strategies for different conditions . In instPneumocystis jiroveceii pneumonia, which exhibited a positive response to endobronchial Watanabe spigot and blood coagulation factor XIII supplementation . In the same way, others atipical respiratory infection are exposed in this Research Topic. Sun et al. described a chronic respiratory condition due to Fusobacterium nucleatum in pleural effusion associated with squamous cell carcinoma. Similarly, Yuan et al. presented a case with Actinomyces graevenitzii, Zhang et al. illustrated an abnormal Streptococcus pneumoniae thoracic image presentation, Peng et al. showed a hypervirulent Klebsiella pneumonia, and Liu and Gao described an infection with Chlamydia psittaci in severe pneumonia cases. All these cases had a positive clinical resolution after identification of the pathogen by molecular sequencing. Unfortunately, molecular diagnostics by next-generation sequencing is not a procedure accessible at the most respiratory centers in the world. In this context, these published cases are important to propose management of rare infection cases in respiratory field.For example, in this Research Topic, we present unusual cases that can provide valuable insights for clinicians facing similar challenges in their practice. One of the cases reported highlights a refractory pneumothorax secondary to human immunodeficiency virus -associated Zuccatosta et al.). The absence of cartilaginous support involvement allowed for successful bronchoscopic treatment, resulting in complete and permanent resolution of the stenosis . Other rare conditions are described in the biliobronchial fistula after cholecystectomy surgery case , a Kartagener s\u00edndrome with DNAH9 mutation case , an anomalous systemic arterial supply to the left lower lung lobe , an epithelioid hemangioendothelioma in main bronchus , and tracheal lobular capillary hemangioma . These reports offer important clinical knowledge and potential solutions for managing complex respiratory conditions.Another intriguing cases involved abnormalities in the thoracic anatomy. A post-COVID-19 tracheal stenosis with fibrotic bridges, leading to significant respiratory distress (Finally, this type of evidence serve as powerful teaching tools, especially in medical education . They prDespite representing the lowest level of evidence, clinical case reports continue to be among the most significant sources of knowledge in the biomedical field. They offer valuable insights into unusual disease presentations and the benefits of employing unconventional approaches in treatment . MoreoveRT-C: Writing \u2013 original draft, Writing \u2013 review & editing. ST: Writing \u2013 original draft, Writing \u2013 review & editing."} +{"text": "Pseudomonas aeruginosa PAO1 biofilm cell clusters. These P. aeruginosa cell clusters are in vitro models of the chronic P. aeruginosa infections found in adult cystic fibrosis patients, which display resistance to antibiotic treatments, leading to exacerbated morbidity and mortality. This resistance has been partially attributed to periphery sequestration, where antibiotics are unable to penetrate biofilm cell clusters. The underlying physical phenomena driving this periphery sequestration have not been definitively established. This paper introduces mathematical models to account for two proposed physical phenomena driving periphery sequestration: biofilm matrix attachment and volume-exclusion due to variable biofilm porosity. An antibiotic accumulation model which incorporated these phenomena was able to better fit observed periphery sequestration data compared to previous models.A spatiotemporal model for antibiotic accumulation in bacterial biofilm microcolonies which leverages heterogenous porosity and attachment site profiles replicated the periphery sequestration phenomena reported in prior experimental studies on To solve the time-dependent governing equations for dynamic concentration profiles, the method-of-lines technique was incorporated into the same solver system. Additionally, a variable liquid-interface concentration boundary replaced the constant concentration BC for this dynamic solver due to the observed dynamic BC in the literature data. Relative antibiotic concentrations were inferred from Tseng et al using WebPlotDigitizer (To solve the steady-state form of governing equations used in this paper for equilibrium concentration profiles, a finite-differences solver based on spatial discretization along with the Newton-Raphson technique for the resulting set of non-linear equations was implemented in python in the SPYDER IDE, with code available on Github (igitizer .Supplement 1"} +{"text": "Purpose: Competency assessment standards for Critical Care Ultrasonography (CCUS) for Graduate Medical Education (GME) trainees in pulmonary/critical care medicine (PCCM) fellowship programs are lacking. We sought to answer the following research questions: How are PCCM fellows and teaching faculty assessed for CCUS competency? Which CCUS teaching methods are perceived as most effective by program directors (PDs) and fellows. Methods: Cross-sectional, nationwide, electronic survey of PCCM PDs and fellows in accredited GME training programs. Results: PDs and fellows both reported the highest rates of fellow competence to use CCUS for invasive procedural guidance, but lower rates for assessment of deep vein thrombosis and abdominal organs. 54% and 90% of PDs reported never assessing fellows or teaching faculty for CCUS competency, respectively. PDs and fellows perceived hands-on workshops and directly supervised CCUS exams as more effective learning methods than unsupervised CCUS archival with subsequent review and self-directed learning. Conclusions: There is substantial variation in CCUS competency assessment among PCCM fellows and teaching faculty nationwide. The majority of training programs do not formally assess fellows or teaching faculty for CCUS competence. Guidelines are needed to formulate standardized competency assessment tools for PCCM fellowship programs. Goal-directed critical care ultrasound (CCUS) has become a necessary skill set for clinicians managing critically ill patients. The Accreditation Council for Graduate Medical Education (ACGME) includes CCUS among the core procedural requirements specifically for trainees in anesthesia and emergency medicine residencies Previous surveys of pulmonary and critical care medicine program directors demonstrated a heavy emphasis on informal bedside teaching of ultrasonography skills despite low reported levels of CCUS competency among faculty (i.e. PCCM attendings that routinely work and train fellows in the workplace setting) Better understanding of these gaps will allow for more transparency among pulmonary-critical care fellowship training programs regarding CCUS competency assessment of fellows and faculty, and allow for better standardization among programs nationwide. Our objectives were to investigate perceptions and methods utilized by fellows and teaching faculty in U.S. training programs to achieve and assess competency in CCUS.This study was approved by the New York University Grossman School of Medicine (NYUGSOM) Institutional Review Board (s18-00282). We conducted two cross-sectional surveys on CCUS competency from September to December of 2018: a survey of ACGME-accredited PCCM fellowship program directors or their designees, and a survey of PCCM fellows in ACGME-accredited programs. Surveys were designed through an iterative process of development that incorporated feedback from three groups at our institution: faculty experts in CCUS, PCCM fellowship program key clinical faculty, and senior PCCM fellows. The surveys were distributed via email to 148 PCCM fellowship program directors in the U.S. and Canada by the Association of Pulmonary and Critical Care Medicine Program Directors (APCCMPD). We asked PDs or their designee to complete the online PD survey, and forward a link to a second online survey to their fellows. We sent follow-up emails once a month for two months. The PD survey asked questions regarding methods used to teach CCUS to their fellows and their perceived effectiveness, perceived CCUS competency of their fellows and their teaching faculty that work with their fellows, and methods used to assess CCUS competency of their fellows and teaching faculty (see Appendix A for full PD survey). The Fellows survey asked questions regarding methods used to learn CCUS and their perceived effectiveness, their performance numbers of CCUS examinations, their perceived CCUS competency, and methods of CCUS competency assessment used by their programs (see Appendix B for full Fellows survey). Both surveys captured basic demographic information about respondents and training programs. Survey responses were anonymous and no personally identifiable information was collected. Survey study data was collected and managed using REDCap\u00ae (Research Electronic Data Capture) electronic data capture tools hosted at NYU Grossman School of Medicine Forty program directors completed the PD survey ; the total number of fellows that received survey invitations is unknown and a response rate cannot be definitively calculated but we estimated a response rate of 18%. Program and fellow demographics are described in Table 1. The vast majority were combined PCCM fellowship programs , academic , and moderately sized . Responding fellows represented a spectrum of training years .The majority of PDs thought the vast majority (76-100%) of their faculty were competent to perform US-guided vascular access (62%) and US-guided drainage catheter placement (64%). The majority of PDs (59%) felt that the majority or vast majority (51%-100%) were competent in lung/pleural US. However, only a minority of PDs believed that the majority or vast majority (51%-100%) of their faculty were competent in goal-directed cardiac echo (36% of PDs), abdominal/kidney US (23%), and lower extremity DVT studies (18%).We also performed a sub-analysis to explore if PD\u2019s perception of faculty CCUS competence correlated with their perception of fellow CCUS competence and the strength of that correlation. Spearman\u2019s rank correlation was computed to assess the relationship between PD\u2019s perception of faculty competence and fellow competence for the 5 different CCUS examinations. There was a statistically significant positive correlation for goal-directed echo, r(38) = [0.436], p=0.006; and DVT studies, r(38) = [0.624], p <0.001. It was not statistically significant for US-guided vascular access (p=0.05), US-guided drainage catheter placement (p=0.271), or lung/pleural US (p=0.089).Methods of teaching and learning CCUS and their perceived effectiveness are documented in Table 2. Utilized methods of teaching CCUS (PD survey) and methods of learning CCUS (Fellow survey) were similar for the two surveys--local lecture-based teaching , directly supervised bedside CCUS exams with feedback , local hands-on workshops , and self-directed learning . Slightly lesser use included regional/national courses , case-based didactics , and unsupervised archival of images with subsequent review for teaching . PD and Fellow perceptions of usefulness for these different teaching/learning methods were similar. Percentage of PDs and Fellows that perceived the different teaching/learning methods as \u201cvery\u201d or \u201cextremely useful\u201d on 5-point Likert scale were: hands-on local workshops , directly supervised bedside CCUS exams with feedback , regional/national courses , local lectures , local case-based conferences ; unsupervised CCUS with archival of images and subsequent review and self-directed learning were rated as less useful.Number of each CCUS examination performed by fellows over their fellowship is displayed in Figure 1. Percentage of fellows performing greater than 20 examinations varied by specific CCUS examination type: 90% for US-guided vascular access, 68% for US-guided drainage catheter placement, 69% for goal-directed echocardiography, 66% for lung/pleural US, 33% for abdominal US, and 19% for DVT studies.Program Director and Fellow Surveys: Methods of Assessing Fellow and Faculty CCUS Competency Methods of assessing fellows for CCUS competency are detailed in Table 3. The majority of PDs (54%) report never formally assessing fellows for CCUS competency, and the majority of fellows (67%) also reported never receiving formal competency assessment. Of the programs that do assess their fellows for CCUS competency, the most used method was global assessment by expert faculty . Half of PDs who engage in fellow CCUS assessments reported using formal review of archived real patient images, practical exam on real patients, and use of a standardized assessment tool. However, fellows report all methods other than global assessment by faculty to be used in the minority of their programs. Of the programs that do assess their fellows for CCUS competency, the specific CCUS exams being tested varied: procedural guidance 61% use on PD survey and 46% use on fellow survey; goal-directed Echo 78% and 62% respectively; lung/pleural US 67% and 59%; abdominal/kidney US 33% and 38%, and lower extremity DVT study 50% and 35% respectively.Ninety percent of PDs reported never assessing their teaching faculty for competence in performing CCUS examinations, and 8% did so only pre-employment. Given the very low prevalence of faculty competency assessment in general, data on methods of assessing faculty competence or specific examinations being assessed were deemed too small to draw conclusions and thus not reported.Regarding the documentation of CCUS competency, only 28% of PDs and 7% of fellows reported having a requirement for completion of a designated number of CCUS examinations prior to fellowship graduation, and only a small minority utilize an electronic portfolio to save their clips and images (18% per PDs and 6% per fellows).etails the percentage of fellows at a given fellowship program who attain competency to independently perform basic CCUS examinations by the end of fellowship training, as well as percentage of teaching pulmonary and/or critical care faculty at a given institution currently competent to perform these same CCUS exams. The percentage of PDs that believed the vast majority (76-100%) of their fellows attain competence varied by the specific CCUS examination type\u2014very high perceived percentage of competence for vascular access and drainage catheter placement (97% of PDs for both), moderately perceived percentage of competence for lung/pleural US (71%), and lesser perceived percentage of competence for goal-directed echocardiography (47%), lower extremity DVT study (37%), and abdominal/kidney US (26%). Fellows\u2019 perceptions generally agreed with PD competency perceptions for vascular access and drainage catheter placement, with fellows agreeing or strongly agreeing in their competence , as well as for lung/pleural exam (86% agreement with competence) and lesser perceived competence in DVT studies (50%) and abdominal/kidney US (44%). However, fellows perceived their competence higher for goal-directed echo (77% agree or strongly agree with competence) compared with PD perceptions. Breaking down fellow perceived competency by year of training, all years reported high perceived competency in US-guided vascular access and US-guided drainage catheter placement . A stepwise pattern of increasing perceived competency was seen for goal-directed Echo and lung/pleural US . However, rates of competence by year remained relatively flat/plateaued regardless of year of training for abdominal US and DVT study . CCUS is a complex skill that combines cognitive knowledge along with psychomotor image acquisition skills and affective attitudes, and has become essential in daily practice for intensivists at the bedside Prior surveys of PCCM faculty and trainees have demonstrated heterogeneous institutional practices and methodologies to assess competency Interestingly, these levels of perceived competence were mirrored by fellow-reported experience with the different CCUS examinations, as most fellows reported greater experience with US-guided placement of vascular access devices or drainage catheters , goal-directed echocardiography and lung/pleura assessment but less abdominal and DVT ultrasound experience. About half of fellows reported performing fewer than 10 abdominal or DVT ultrasounds. ACCP/SRLF expert consensus guidelines do not specify the number of each US examination type recommended for CCUS competence A survey of 67 surgical critical care fellowship program directors reported the following exams as \u201cvery important\u201d\u2014FAST exam (75%), central venous access (80%), transthoracic echo (47%), DVT study (3%), and abdominal US for biliary pathology (1.5%) Regarding CCUS competency assessment, we found in this study 54% of PDs and 67% of fellows reported that their programs never conduct formal competency assessments for CCUS. Among the programs that reported conducting formal assessments, a global assessment by expert faculty was the most common method cited by both PDs and fellows. Among those programs that do formally assess their fellows, the majority do not test specifically for competency in DVT studies or abdominal ultrasound. Additionally, there is a lack of use of archival review with feedback as well as development of ultrasound portfolios. Prior studies have documented the issue of poor faculty competence in CCUS as a barrier to training Given the lack of formal assessment of CCUS competency of faculty, it is uncertain what information or data PDs used to answer our survey questions on faculty competence\u2013 institutional delineation of privileges, direct observation, gestalt, or other. Of note, we saw a correlation with PD perception of faculty CCUS competency with their perception of fellow CCUS competency for goal-directed echo (moderate correlation) and DVT studies (strong correlation). This is of uncertain significance, as it could reflect causality , or could represent PD\u2019s inability to differentiate fellow from faculty competence due to lack of tangible metrics for the latter. Future studies to better understand the relationship between fellow and teaching faculty CCUS competency are warranted. PDs and fellows agreed on preferred methodologies for learning CCUS. Both groups reported that regional/national ultrasound courses, hands-on institutional workshops and directly supervised bedside CCUS exams were their most preferred approaches to learning CCUS, reinforcing concepts of learning through active processes. Regional CCUS courses including hands-on workshops with expert faculty have been found to be feasible and efficient in providing much needed hands-on training in CCUS Unsupervised CCUS exams, self-directed learning and lecture-based teaching were the least favored approaches to CCUS education. Brady et al. had determined through their 20-item survey of PCCM program directors that the most common method of learning CCUS was in fact unsupervised, independent bedside learning Our survey has several strengths and limitations. Unlike previous studies, our survey included perceptions of both program directors and fellows and found a general agreement on most topics. Our findings on the perceptions of program directors with respect to the competency of clinical teaching faculty to perform CCUS have not been described previously. The major limitation of our study was the small sample size compared to all PCCM training programs which could introduce selection bias and limit the overall generalizability to all current practices. However, the consistent data from both fellows and faculty does help with overall validity of the themes that emerged from the results, and the heterogeneous distribution of academic and affiliated hospitals improves the generalizability of the findings. However, given the small sample size of this study, we would caution that the results should be viewed as intriguing but ultimately hypothesis-generating and in need of future targeted studies to expand upon this work. Also, as this is a cross-sectional survey, there could be recall biases from the PD or fellow respondents. As stated above, it is uncertain what information PDs used particularly for faculty competence given the overall lack of faculty assessment. We also relied on PDs to forward a survey link to their fellows, introducing another element of potential sampling bias to fellow responses as there was a potential gatekeeper deciding to forward or not the survey to their fellows. Thus the assumption we made is that the responding PDs and fellows likely represent the same training programs, and thus the aggregate data is representative of the same training programs. This assumption is bolstered by the Demographic information detailed in Table 1 which shows very similar PD and Fellow survey demographics . However, as the data collected were anonymous, we expect the fellows to have been truthful and accurate in their responses. Lastly, given the anonymous nature of the data collection, we were able only to carry out analyses in aggregate, but unable to carry out detailed analyses of associations between PD and fellow responses from the same program.Our survey lays a foundation for future directions in the applicability and training of CCUS in clinical practice. Our exploratory analysis suggests that program director and fellow perspectives on CCUS competency overlap substantially; future surveys of PDs only might therefore be sufficient. It is also currently unknown how the COVID-19 pandemic may have impacted CCUS training despite high utilization of CCUS in intensive care units. This may help further improve our teaching practices and develop methodologies using advanced tools such as portable ultrasounds with remote access capabilities in the setting of contact precautions, virtual training and feedback sessions. It is currently unknown if CCUS training methodologies differ between CCM only programs vs PCCM programs and country-wide, survey-based studies are needed to include more CCM only programs.Our study highlights substantial heterogeneity in the CCUS teaching and competency assessment methods among ACGME-accredited PCCM programs in the United States. We found the perceptions of PDs and fellows were in general agreement with high levels of perceived competency to perform CCUS-guided procedures and lung/pleura assessment but deficiencies in the competent performance and interpretation of abdominal and lower extremity diagnostic venous ultrasonography. We also found that the majority and vast majority of programs do not assess their fellows and teaching faculty respectively for competence in CCUS, highlighting a major area of programmatic and curricular need. Our survey also demonstrates that active learning through regional and local hands-on workshops and directly supervised bedside CCUS exams were perceived as extremely useful, whereas, unsupervised CCUS exam, self-directed learning and lecture-based learning were perceived as less useful by both PDs and fellows. These findings suggest that further studies and guidelines are needed to formulate standardized competency assessment tools across all PCCM/CCM fellowship programs. MHA had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. MHA and DP contributed substantially to the study design, data analysis and interpretation. MHA, HD and DP contributed substantially to the writing of the manuscript. The authors have no relevant conflicts of interest to disclose.Appendix AAppendix A"} +{"text": "Biological events occurring in the human brain are elegantly tuned to impart diverse emotions and elaborate behavioral patterns. The role of signaling pathways often changes during the progression of CNS disorders, and there is remarkable spatial heterogeneity in cell types and molecular expression profiles over the brain. Therefore, a full temporal and spatial illustration of the pathological progression of CNS disorders would benefit the development of novel therapeutic strategies. In this Research Topic, 6 articles, including high-quality original research articles and comprehensive reviews, discuss the spatiotemporal regulation patterns of CNS disorders and emerging techniques in this field.Zou et al. explored the cell type-specific modulatory roles of dopamine receptor D1 (D1R)- and D2R-expressing medium spiny neurons in the nucleus accumbens shell in TLE. They found that cell-type-specific inhibition of either D1R-MSN or D2R-MSN alleviated TLE seizures by reducing the number of secondarily generalized seizures and improving seizure stages, without altering the onset time of focal seizures. The data of the aforementioned study along with other studies suggest that different brain areas and cell populations participate in seizure initiation, propagation and termination, thereby highlighting the necessity of demonstrating the spatial heterogeneity of pathological mechanisms of epilepsy.Temporal lobe epilepsy (TLE) is the most prevalent focal seizure, which is highly likely to progress to generalized seizures. Here, Zhou and Zhang. discussed the cell type-specific role of oligodendrocytes in various CNS disorders and delineated the contribution of myelin to neuronal activity. Interestingly, neuronal excitability can also affect myelin functions. The authors overviewed the potential strategies for myelin regeneration through the precise modulation of neuronal activity.Similarly, Yi et al. reviewed the temporal regulation of key biological events that occur during neurodevelopment after experiencing febrile seizures. Febrile seizures are quite common during early childhood (-4%) and receLai et al. examined the molecular mechanisms involved in the treatment of chronic pain using sinomenine, an active ingredient in the natural plant \u2018sinomenium acutum (Thunb.) Rehd. Et Wils\u2019, while focusing on its regulatory roles in distinct immune cell subpopulations. Sinomenine can regulate the interaction among different immune cells, immune cells and neurons and glial cells and neurons to confer immunosuppressive effects.The aforementioned studies dissect pathological mechanisms of CNS disorders from a spatiotemporal perspective. Similar research approaches can also be used to study the pharmacological mechanisms of drugs and other functional compounds. Wong et al. proposed a novel electrochemical localized oxygen scavenging system (eLOS) to induce hypoxia in vitro with spatiotemporal precision. Focal hypoxia is very common in multiple diseases such as ischemic stroke, cardiac arrest and dementia; however, the currently available experimental model of spatially restricted ischemia is limited. Using the eLOS platform, Wong et al. successfully induced axon-restricted hypoxic stress in human cortical neurons and found that localized axonal hypoxic stress induced neuronal death even when the somas remain in the normoxic culturing condition. These findings indicate the potential of the eLOS platform in studying cellular and subcellular changes in white matter after an injury and other hypoxic insults.Studies focusing on the spatiotemporal pathological mechanism of CNS disorders will benefit from the newly developed techniques providing spatiotemporal information. Ya et al. illustrated working principles and provided examples of the application of cutting-edge spatially resolved transcriptomic technologies in studying CNS disorders. The rapid development of these technologies will eventually provide a deeper understanding of the molecular mechanisms underlying CNS disorders.Furthermore, Overall, it has become inevitable to elucidate the pathological progression of CNS in high spatiotemporal resolution. We hope that this Research Topic will help readers understand CNS disorders from a highly spatiotemporally precise perspective."} +{"text": "We thank Drs. Sutt and Fraser for their insightful commentary on our publication. They open an important debate on tracheostomy timing and outcomes of interest.We concur that for decades, research has focused on \u201ctraditional\u201d outcomes such as mortality and length of stay (LOS). Additionally, focus on tracheostomy-specific outcomes including swallowing, and communication may aid efforts to improve recovery after intensive care unit (ICU) discharge.Our analysis of\u2009>\u200917,000 critically ill patients with severe stroke attempted to clarify whether tracheostomy timing is an important piece of the stroke management puzzle .We found that early tracheostomy does not impact neurological outcome (mRS). This was reflected in the SETPOINT2 trial, where 75% of patients in each group experienced poor neurological outcome despite active rehabilitation efforts (~\u200970% of patients were discharged to rehabilitation facilities) [We recognise that, strictly speaking, the timing of tracheostomy should not substantially impact neurological outcome. Studies often inadequately separate early and late groups . The phEvidence on patient-centric outcomes in this population is limited. Our work humbly sought to quell decades of debate on the impact of tracheostomy timing on mortality, neurological outcome (mRS), and LOS, in patients with severe stroke. Given our findings, we commend future efforts to protocolise reporting of additional patient-centred outcomes such as speech , swallowing and psyc"} +{"text": "Editorial on the Research TopicUrothelial carcinoma of renal pelvis and ureter, prognosis and recent advancesUrothelial carcinoma of the renal pelvis and ureter is a prevalent malignancy primarily affecting the elderly population . Its incZhanghuang et al.). The study revealed that non-UTUC deaths accounted for the majority of mortality among patients with localized disease. This highlights the importance of considering non-cancer causes in the management of UTUC survivors. Moreover, UTUC was found to be the leading cause of death in patients with regional and distant stages, emphasizing the need for improved therapeutic strategies targeting advanced disease while considering the increased risk of death from non-cancer causes survivors has provided valuable insights into mortality patterns. By utilizing the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database, a large cohort of UTUC patients was examined and cancer-specific survival (CSS) in renal pelvic urothelial carcinoma (RPUC) patients. Using data from the SEER database, the study compared radical nephroureterectomy (NU) and inadvertent radical nephrectomy (RN). The results underscored the significance of accurate diagnosis and appropriate surgical intervention in RPUC patients. The study concluded that RN could lead to worse oncological outcomes compared to NU, emphasizing the importance of precise surgical planning and execution.Wu et al.).Another study emphasized the importance of distinguishing between radical nephroureterectomy (NU) and inadvertent radical nephrectomy (RN) in patients with renal pelvis urothelial carcinoma (RPUC). A retrospective analysis of data from the SEER database revealed that patients who underwent RN experienced worse overall survival (OS) compared to those who received NU. Furthermore, the study highlighted that the negative impact of RN on OS was more significant in patients with tumors larger than 4.2\u2005cm . While no significant differences were observed in surgical outcomes between the two approaches, the study identified various predictive factors associated with adverse oncological outcomes. Age over 70, positive lymph node metastasis, upper ureter tumor location, and male sex were identified as potential risk factors. Additionally, higher surgical volume showed trends toward favorable outcomes in terms of overall survival and cancer-specific survival.A study utilizing data from the Taiwan nationwide upper urinary tract urothelial carcinoma (UTUC) collaboration database evaluated the outcomes of transperitoneal hand-assisted laparoscopic nephroureterectomy (TP-HALNU) and transperitoneal pure laparoscopic nephroureterectomy (TP-LNU) . The findings indicate that patients who received chemotherapy (CT) combined with NU exhibited improved overall survival (OS) compared to those who received CT alone. This benefit was observed in both nonmetastatic and metastatic UTUC. The study emphasizes the potential advantages of NU in prolonging survival outcomes for patients with advanced-stage UTUC.A multicenter retrospective cohort study addressed the role of nephroureterectomy (NU) in stage IV upper tract urothelial carcinoma (UTUC) was shown to have a negative impact on overall survival (OS), particularly in patients with larger tumors. Furthermore, while the choice between surgical approaches may not significantly influence outcomes, other factors such as patient age, lymph node metastasis, tumor location, and surgical volume should be considered for prognostic evaluation. Finally, the role of nephroureterectomy (NU) in stage IV UTUC demonstrates potential benefits in terms of overall survival (OS) for both nonmetastatic and metastatic cases. These findings underscore the importance of precise diagnosis and treatment among patients with UTUC."} +{"text": "Three years since the onset of COVID-19, pandemic-related trends in child sexual abuse (CSA) remain poorly understood. Common administrative surveillance metrics may have underestimated abuse during the pandemic, given youths\u2019 limited access to mandatory reporters. Research using anonymous service-use data showed increased violence-related online help-seeking but overlooked youth-specific help-seeking for CSA during COVID-19. Understanding pandemic-related trends in CSA can inform abuse detection practices and mental health service provision for youth victims.The purpose of this study was to harness anonymous help-seeking data from the National Sexual Assault Online Hotline (NSAOH) to glean insights about CSA occurrence in the United States during the COVID-19 pandemic.We used an archival sample of victims who contacted NSAOH from 2016 to 2021 . We examined differences in the proportion of youth and adult victims contacting NSAOH during the first COVID-19 year (March 2020 to February 2021) compared to the prior year . Further, we compared key characteristics of hotline interactions among youth victims during the first COVID-19 year to the prior year (n=5913). Using joinpoint regression analysis, we examined linear trends in the number of monthly sampled youth and adult victims (excluding victims of unknown age) from 2016 to 2021 who discussed any victimization event and who discussed recent events .Most youth victims were abused by family members prior to and after the onset of COVID-19. The number of youth victims contacting NSAOH spiked in March 2020 and peaked in November 2020 for all youth and those discussing recent events . We observed a decline in youth victims into spring 2021 for all youth and those discussing recent events . The number of adult victims discussing any victimization event increased steadily from January 2018 through May 2021 and then declined . Trends were stable for adults discussing recent events.This study extends the use of hotline data to understand the implications of the pandemic on CSA. We observed increased youth help-seeking through the NSAOH coinciding with the onset of COVID-19. Trends persisted when limiting analyses to recent victimization events, suggesting increased help-seeking reflected increased CSA during COVID-19. These findings underscore the utility of anonymous online services for youth currently experiencing abuse. Further, the findings support calls for increased youth mental health services and efforts to incorporate online chat into youth-targeted services. As we approach a postpandemic world, understanding trends in child maltreatment during COVID-19 remains vital for informing practices to detect abuse and ameliorate the effects of trauma. Evidence of pandemic-related trends in child maltreatment is conflicting, resulting in part from limitations of traditional surveillance strategies. Apparent declines in child maltreatment reflected in emergency room visits may be aWhile youths\u2019 perspectives are often assessed through self-report survey methodologies, indicators of online help-seeking are potentially valuable. Prior to the pandemic, youth actively sought help for experiences of abuse via online and text-based hotlines ,8, whichRecent work has explored trends in violence-related online help-seeking during the pandemic. Google searches related to child maltreatment increased during the pandemic ,12 but mA study of multinational child helplines lacked cAmid these challenges, research on pandemic-related child maltreatment has largely overlooked child sexual abuse (CSA). However, concerns about victims\u2019 physical and social isolation and accessibility to perpetrators during stay-at-home orders are partWe advance knowledge by addressing limitations of previous work on 3 fronts. First, we examine online help-seeking for sexual violence among youth victims specifically. Second, we incorporate 5 years of observations (2016-2021), providing a broader picture of help-seeking patterns across the pre- and postpandemic onset time periods. Third, we delineate recent events to distinguish violence that occurred during the pandemic.The NSAOH is a US-based online hotline providing 24/7 anonymous crisis intervention services via desktop and mobile internet chat. RAINN , an anti\u2013sexual violence organization in the United States, created and has operated NSAOH since 2006 to serve victims of sexual violence.Data collection via an in-depth online assessment serves an integral role in hotline operations to identify areas for service improvement and staff training. Directly following the first chat session of their shift, staff record session information, such as event characteristics and topics discussed. Because information is not requested for the purpose of completing the assessment, data are often considered unknown . Staff receive instructions for assessment completion both within the assessment and through supplemental training.Data in this study represent a sample of all hotline chats in which the visitor discussed an experience of sexual or other interpersonal violence between January 2016 and December 2021 . Additional information about hotline procedures, the organizational context, and sample inclusion criteria are available in Data used in this study were originally collected as part of ongoing internal program evaluation; thus, informed consent was not required. Analysis of this archival data for the purposes of generating generalizable knowledge of online hotline users and sexual violence experiences was deemed exempt by the Advarra institutional review board under category 4 of the Revised Common Rule.We examined differences in the proportion of youth and adult (aged 18 years and older) victims during the first COVID-19 year (March 2020 through February 2021) compared to the year prior , with victims of unknown age excluded . Among youth (n=5913), we compared perpetrator type (family vs nonfamily), perpetrator living status (currently living with vs not currently living with the victim), event timeframe , and event frequency (repeated abuse vs single occurrence) during the first COVID-19 year compared to the year prior. These analyses used the chi-squared test with pairwise exclusion of missing data; analyses used SPSS .To contextualize trends in youth help-seeking, we used Joinpoint to examine linear trends in the number of monthly sampled victims by age group from 2016 to 2021 among all youth and adult victims . Among youth, we noted statistically significant but small shifts in the proportion of chats that involved family-perpetrated assaults , perpetrators currently living with the victim , recent assaults , and repeated assaults . Inflection points reveal variability in the strength or direction (or both) of trends in the number of victims by age in our sample . Prior tThis study is the first, to our knowledge, to reveal increases in youth help-seeking for sexual violence coinciding with the onset of COVID-19. These increases peaked in November 2020 and were present for all youth victims and for youth victims discussing recent events. Although the number of adult victims increased, this trend was more gradual, preceded the onset of COVID-19, and was not present for those discussing recent events. Our finding that trends were sustained for recent events suggests an increase in youth affected by sexual violence during the pandemic rather than increased help-seeking among all victims for current and past events due to limited alternative support options.While our findings seemingly conflict with declines in abuse-related hospital visits and official reports ,2, evideMost youth who contacted the NSAOH\u2014both prior to and during the pandemic\u2014discussed repeated experiences of violence perpetrated by family members or someone else living with them. During the pandemic, we observed small proportional increases in youths\u2019 chats that featured these characteristics, consistent with elevated violence driven by victims\u2019 increased accessibility to perpetrators in the home amid limited contact with trusted adults . Future work should examine to what extent increased youth help-seeking reflected increased frequency and severity of ongoing violence predating the pandemic or cases of violence that began during the pandemic.The number of chats from youth began to decrease after November 2020. This decline could relate to youth having a greater ability to avoid perpetrators or opportunities to disclose to alternative sources of support as schools reopened in the summer and fall of 2020. However, because reopening policies were variable across the United States, driven by state and local government, this trend should be interpreted with caution.While reported trends were transitory, the effects of sexual abuse are not. Our findings reflect increased help-seeking by youth during the pandemic, an indication of rising demand for mental health services to treat trauma and its sequelae among youth. Given the national shortage of child mental health providers that predates COVID-19 , there iJoinpoint regression analysis allowed us to identify changes in the linear trend of victims\u2019 hotline use from 2016 to 2021. While we interpreted the reason for some of these changes, their causes cannot be definitively ascertained from our analysis. We could not differentiate repeat hotline users from new users, which would help delineate new cases of abuse. Our data collection protocol prioritized the delivery of victim-centered services. We did not solicit information from visitors for assessment purposes, resulting in some missing data and limited demographic information. Future work could incorporate anonymous collection of demographics prior to service provision to enhance the utility of hotline data as a surveillance indicator of child maltreatment. Understanding the interplay of hotline supply and demand will also be useful because changes in staff availability could affect the accessibility and use of services.Our study demonstrates the utility of anonymous online hotline data as a complementary surveillance indicator for child maltreatment that is transferrable to other public health priority areas . Increased help-seeking amid decreased safety at home also speaks to the utility of online support options for youth experiencing abuse. Preparing for future public health emergencies necessitates consideration of additional online communication options that allow youth to privately disclose abuse to trusted adults. Future work should explore how to safely incorporate these communication options into existing services, such as online schooling or telemedicine platforms."} +{"text": "Remyelination biology and the therapeutic potential of restoring myelin sheaths to prevent neurodegeneration and disability in multiple sclerosis (MS) has made considerable gains over the past decade with many regeneration strategies undergoing tested in MS clinical trials. Animal models used to investigate oligodendroglial responses and regeneration of myelin vary considerably in the mechanism of demyelination, involvement of inflammatory cells, neurodegeneration and capacity for remyelination. The investigation of remyelination in the context of aging and an inflammatory environment are of considerable interest for the potential translation to progressive multiple sclerosis. Here we review how remyelination is assessed in mouse models of demyelination, differences and advantages of these models, therapeutic strategies that have emerged and current pro-remyelination clinical trials. Multiple sclerosis (MS) is a chronic demyelinating, inflammatory and neurodegenerative disease of the central nervous system (CNS). Remyelination is a regenerative process by which oligodendrocytes restore myelin sheaths to demyelinated axons. Evidence from animal models indicate that remyelination can restore neuronal conduction , 1981, pRemyelination is robust in many animal models that have been used to study remyelination, which is somewhat discordant with the heterogeneous patterns of oligodendrocyte loss, demyelination and remyelination in human pathology-based studies of MS tissue . The mecThe inflammatory environment can modulate oligodendroglial properties including oligodendroglial survival, migration, differentiation, axon engagement and remyelination . AdvanceIn animal models, aging influences oligodendroglial properties and prog14C has been used to investigate the age of oligodendroglia within MS lesions and this study indicated limited production of new oligodendrocytes within shadow plaques that may have undergone remyelination suggesting that mature surviving oligodendrocytes contribute to subsequent remyelination in human MS lesions (14C) prior to differentiation despite rodent studies indicating that OPCs can directly differentiate into mature oligodendrocytes without cell division is an endogenous lysophospholipid that can be used to generate a focal demyelinating lesion by injection into white matter tracts and demyelination results through disruption of oligodendroglial cell membranes leading In the lysolecithin model, myelin and extrEthidium bromide, a DNA-intercalating agent, injected into white matter tracts creates a focal demyelinating lesion with a larger area of demyelination compared to lysolecithin . EthidiuCombining X-irradiation with ethidium bromide injection has allowed for the investigation of transplanted progenitor cells in a lesion environment devoid of endogenous remyelination potential . NeonataAged animals exhibit slower remyelination after lysolecithin and ethidium bromide injection and agedCuprizone, bis-cyclohexanone-oxaldihydrazone, was first used as an animal model of demyelination in the 1960s . CuprizoMyelin loss occurs after several weeks of cuprizone ingestion and peaks at 4\u20135\u2009weeks . One of Manipulation of astrocyte and microglial responses after cuprizone-mediated demyelination can influence remyelination. Ablation of astrocytes after chronic cuprizone treatment results in improved oligodendrocyte density, remyelination and motor functional outcomes . AstrocyThe role of T cells in cuprizone-mediated demyelination is unclear. T cells are present in cuprizone ingestion and CD8 Toxin models have greatly facilitated the investigation of pathways involved in oligodendroglial proliferation, recruitment, differentiation and remyelination. Promising mechanisms that are under investigation in clinical trials for remyelination in MS that have emerged from investigation of remyelination in focal and systemic toxin models include LINGO-1 antagonism , Nogo-A The major advantages of toxin models are the robust remyelination response with stereotyped kinetics, separation of the demyelinating process from the regenerative process, minimal axonal degeneration, and decline of remyelination with aging that have allowed for discovery of targets that accelerate repair in an aged environment. While focal toxin models have these advantages, the short demyelinating insult and robust remyelination response are limitations. Diffuse CNS demyelination and white matter injury induced by cuprizone ingestion offers the advantage of an environment with prolonged oligodendroglial loss, neuronal stress and subsequent neurodegeneration, which may allow for the investigation of pathways that prevent neuronal degeneration and allow for the ability to assess motor and physExperimental autoimmune encephalomyelitis (EAE) models are one of the most commonly used models to investigate the immunopathogenesis of MS . Immuniz35\u201355 peptide and tranpt-mGFP) ,D. Signipt-mGFP) . Despitept-mGFP) , pharmacpt-mGFP) and K-oppt-mGFP) were abluprizone . Immunizl course . Remyelil course . The relon phase and whet35-55 EAE does not resemble the clinical course of relapsing remitting or progressive MS. The high degree of neurodegeneration and minimal remyelination after the acute EAE phase represent challenges for the utilization of these models in assessing remyelination strategies.Active immunization models have many features that differ from human MS pathobiology and clinical course. The robust inflammatory response and resulting secondary demyelination, early neurodegeneration , sparingEncephalitogenic T cells from CNS antigen immunized mice or myelin-specific T cells isolated from T cell receptor transgenic lines can be used to induce neuroinflammatory disease upon adoptive transfer into naive hosts . A majorAdoptive transfer of myelin-reactive Th17 cells after acute cuprizone ingestion has been used as a model to investigate oligodendroglial responses in the setting of T cell mediated inflammation and has Gfap-tTA) with tetracycline response element (TRE) upstream of IFN-\u03b3 sequence (TRE-IFN-\u03b3) in a double transgenic line allows for temporal regulation of CNS IFN-\u03b3 expression upon removal of doxycycline have been used to investigate demyelination and remyelination. Initial studies of transgenic mice with targeted expression of IFN-\u03b3 from the myelin basic protein (MBP) promotor and gliaycycline . CNS IFNlination . Prolonglination suggestiPlp-CreER\u2122) with a diphtheria toxin subunit A (DTA) floxed stop reporter line (ROSA26-eGFP-DTA) results in oligodendrocyte apoptosis upon exposure to tamoxifen results in oligodendrocyte death, widespread demyelination, microglia and macrophage reactivity, axonal damage and incomplete remyelination (Loss of function of transcription factor myelin gene regulatory factor (MYRF) that induces expression of mature myelin genes in maturlination . Subsequlination . While tChronic encephalomyelitis viral mouse models share pathogenic features similar to MS and may Theiler\u2019s murine encephalomyelitis virus (TMEV) is a single-stranded RNA picornavirus that causes flaccid myelitis in mice and can Mouse hepatitis virus (MHV) is a positive-strand RNA virus with neurotropic strains that can be used to induce a chronic demyelinating disease through intracranial or intranasal inoculation of susceptible mouse strains. An acute encephalomyelitis phase is followed by a secondary phase of demyelination and remyelination . MHV-spein vitro have been used to identify pathways with remyelination potential (High-throughput screens that evaluate the ability of compounds to promote oligodendrocyte differentiation otential . Many paotential .Assessment of remyelination in MS clinical trials has been challenging, with few validated clinical tools to assess remyelination in humans . MeasureAnimal models of MS with demonstrated remyelination capacity vary considerable in their mechanisms of demyelination, inflammatory infiltrates, degree of ongoing inflammatory activity, axonal loss and neurodegeneration and extent of remyelination. Focal toxin models offer the advantage of stereotyped remyelination after a short single demyelinating insult which has allowed for the investigation of factors that promote or inhibit this robust reparative response. A prolonged demyelinating insult predominated by corpus callosum and cortical demyelination and subsequent neurodegeneration and motor decline can be modelled with chronic cuprizone exposure and may share some features of the neurodegenerative process in progressive MS. Both cuprizone and EAE models induce inflammatory subsets of glia that are found in MS tissue and further investigation of how these subsets of glia contribute to ongoing inflammatory activity and promote or inhibit repair may offer insight into potential mechanisms to modulate remyelination in inflammatory settings. While no single animal model recapitulates the pathobiology of MS, considerations of the limitations and advantages of each model should be taken into account when investigating remyelination and translating animal model findings to human MS.DP and EH contributed to writing the manuscript. EF contributed to researching and generating the clinical trial table. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Carotid web (CaW) and carotid free-floating thrombus (CFFT) are rare yet critical causes of ischemic stroke in young adults.A 54-year-old woman presented with a fluctuating right sensory-motor faciobrachial syndrome. A brain MRI scan revealed multiple small recent asynchronous cortico-subcortical ischemic foci in the vascular territory of the left internal carotid artery. A CT angiography identified a CFFT in the left internal carotid artery arising from an underlying CaW. The patient was treated with excellent clinical outcomes with carotid artery stenting and dual antiplatelet therapy.We provide a structured pathophysiological rationale connecting CaW and CFFT and highlight pivotal therapeutic implications. Further studies are needed to investigate this relationship and guide assessment and treatment. Etiological diagnosis of stroke in young adults is a challenging and critical aspect of neurovascular care. Indeed, patients affected by such devastating occurrences have an inherently longer time after the index event and can thus benefit most from adequate secondary prevention strategies . UnfortuCarotid web (CaW) and carotid free-floating thrombus (CFFT) are well-known yet often neglected causes of ischemic stroke in young adults. CaW defines a localized carotid intimal fibromuscular dysplasia presenting as a shelf\u00adlike projection into the lumen of the proximal internal carotid artery , 4. ConvHereby, we describe a case of ischemic stroke due to a CFFT originating from a contiguous CaW. We illustrate the diagnostic and therapeutic implications of these two rare conditions, as well as their possible pathophysiological relationship.A 54-year-old woman presented to the emergency department with a two-day history of fluctuating right sensory-motor faciobrachial syndrome. The patient was an active smoker without further major cardiovascular risk factors. Specifically, she had a normal body mass index and no medical history of hypertension, dyslipidemia, diabetes, neurological or cardiovascular events. Additionally, she was not using estrogen-containing oral contraceptives and her family history was unremarkable for cerebrovascular events. Neurological examination on admission revealed a right inferior facial palsy NIHSS\u2009=\u20092). Brain CT scan and blood tests were normal. A minor stroke was suspected, therefore, the patient initiated dual antiplatelet therapy (DAPT) and was admitted to our Stroke Unit. A brain MRI scan revealed multiple small recent asynchronous cortico-subcortical ischemic foci in the left middle cerebral artery and a subacute/chronic ischemic lesion in the left head of the caudate nucleus, a territory of the recurrent artery of Heubner Fig.\u00a0. Continu. Brain CWe report the case of an otherwise healthy young woman who presented with multi-embolic strokes caused by a CFFT stemming from an underlying CaW. The co-occurrence of these two conditions has been reported anecdotally, and the presence of thrombus superimposition on CaW was suggested to be a contributing factor to stroke recurrence \u201310. HoweRadiological differentials for CaW encompass atherosclerotic plaque with plaque rupture, carotid artery dissection, and fibromuscular dysplasia (FMD). However, the regular morphology of the filling defect, lack of calcium deposits and signs of intramural hemorrhage make atherosclerotic plaque unlikely in our patient. Furthermore, neither CTA nor DSA revealed the presence of an intimal flap, and no other stenotic segments were identified in our imaging studies, reducing the probability of carotid artery dissection and FMD.CTA has shown superior diagnostic accuracy compared to carotid US in diagnosing CaW . It is tAs a secondary prevention, our patient was successfully treated with CAS and transitory DAPT. Evidence of the best management is currently lacking in the literature. Indeed, secondary prevention strategies for CaW and CFFT are based on small case series and expert consensus, as no specific guidelines or clinical trials have been designed to date. Concerning CaW prevention, current strategies aim to avoid long-term complications arising from the high stroke recurrence rates. Although chronic pharmacologic management with anti-platelet agents would fall within current guidelines also antWe described a case of CFFT and CaW co-occurrence focusing on their possible pathophysiological connection as well as diagnostic and therapeutic implications. Meticulous evaluation of non-invasive or invasive vascular imaging tests aiming to detect an underlying CaW in unexplained CFTT should be required. Carotid artery stenting and, eventually, thrombectomy might be a safe and effective secondary prevention strategy to kill two birds with one stone unless underlying thrombophilic conditions requiring anticoagulation therapy are present. Future studies are needed to estimate the frequency and understand the underpinning biologics of the co-occurrence of these two conditions in order to inform assessment and treatment."} +{"text": "Since organizational psychology is a broad and evolving discipline, the topic editors are pleased to announce sixteen articles that highlight new insights into how leadership, collective intelligence, intellectual capital, innovation, job performance, satisfaction advance the tradition, nature, and research methods of organizational psychology. The articles showcase a global perspective of new insights in organizational psychology from Asia, Europe, Middle East, Africa, North America, and Oceania. The authors explored new insights in organizational psychology through conceptual analysis, qualitative and empirical research, a brief research report, and a systematic review.There is a continual focus to expand and provide new insights on leadership theory and research (Lord et al., van Niekerk highlights the importance of psychosocial factors and elevated stress levels that limit a flourishing multi-cultural environment, stakeholder engagement and leader-follower relationships. The author recommends that organizations should promote a multi-cultural team to counteract elevated stress and to better manage psychosocial factors in an organization. Zhao et al. extend the literature on authoritarian leadership by providing a new perspective for authoritarian leadership practice. In comparison to previous research studies, the authors findings indicate authoritarian leadership generates positive employee wellbeing and creativity. Haar and de Jong explored the dark side of leadership personality to provide new insights on how the dark side of leadership could benefit an organization's performance rather than decreasing organizational performance. Latent transition analysis is introduced by Zyberaj et al. for helping organizational psychology researchers to analyze longitudinal data through an applied example utilizing psychological capital and leader-member exchange. The author findings indicates psychological capital is more likely to occur when leader-member exchange is high rather than low. Therefore, high leader-member exchange works hand-in-hand with high psychological capital.Janssens et al. extends the collective intelligence literature and research through a conceptual analysis on the dynamic granular tensions between the needs of the environment with the collective team behaviors over time. The authors explored various methods to help organizational psychology researchers unpack micro-level team behavior. Senawi and Osmadi research study findings reveal that relational capital plays a significant role with intellectual capital for improving property tax reassessment activities. Overall, the attitudes of local government officials must align with relational capital and intellectual capital for successful property tax reassessment performance.Fan et al. research study findings extend self-determination theory to reveal employees' perceptions on organizational support has positive and profound effects on employees' proactive innovative behavior through the satisfaction of basic psychological needs such as autonomy, competence, and relatedness. Liu and Zhang focuses on employees' paradox mindset on innovative performance through role breadth self-efficacy. Employees with a paradox mindset intentionally make innovative things happen through their own actions. Moreover, role breadth self-efficacy and individual ambidexterity play an important role in understanding how employees manage a paradox mindset and innovative performance. Song et al. provide new insights on how employees should manage innovation performance under time pressure. The authors research study findings indicate time pressure significantly improves innovation performance. Therefore, employees operating under time pressures should receive significant leadership support for improving innovative performance.From a new Chinese perspective, Xu et al. investigated the interdependence of psychological capital, social capital and human capital, including the three capital's impact on job performance. The authors study findings discovered new insights on configuration and casual asymmetry from psychological capital, social capital and human capital that affect job performance. Consequently, Xu et al. challenged previous studies' symmetrical regression relationship findings and extended the relationship among psychological capital, social capital and human capital within intelligent career theory. Moreover, high psychological capital plays a key role in high job performance. Sanclemente et al. explored inconsistencies from previous research studies that predict workers' health levels in linear models. The authors research study focused on differences among service sub sectors through linear and non-linear relationships within task complexity, job autonomy, user contacts, time pressure, and psychological and physical symptoms of employees. Overall, Sanclemente et al. research study findings on non-linear relationships indicate medium levels of task complexity from job demands should not exceed greatly to mitigate increased negative impacts to foster service sector employees' physical and psychological well-being in job satisfaction and performance.Levitats et al. provides new insights on unexplored contexts of emotional intelligence in the literature. Specifically, the authors explore the role played by emotionally intelligence in an organization's culture combined with supervisors' emotionally intelligent behaviors. The two-study research findings reveal process links between emotionally intelligent values and practices, and job demands between supervisor emotional intelligence behaviors that affect employee exhaustion and engagement. Chen Y. et al. systematic review provides deeper understanding on the relationship between pay for performance and job performance by highlighting the research studies that examine pay for performance and job performance in real work settings. The results of the systematic review complements the positive effects of pay for performance and job performance in work settings through contextual performance and task performance. In addition, the authors introduce two mediating variables namely, intrinsic motivation and pressure that integrates the positive and negative effects of pay for performance and job performance into one framework.L\u00f3pez-Cabrera et al. research study is to explore potential factors that promote job satisfaction between volunteers and regular paid staff in non-profit organizations. The research study contributes to new understandings of the mechanism that promotes greater satisfaction from volunteer workers vs. regular paid staff through role ambiguity, role conflict and job performance. Chen C. et al. research study provides new insights on positive outcomes of customer incivility that could trigger employees' customer service behavior to challenge and extend the literature stream's focus on negative outcomes and customer incivility. The authors provide a more comprehensive understanding how customer incivility influences employees' behavior and the implications for revenge behavior and customer service behavior and performance in the work environment. Uzum et al. combine crab barrel syndrome and social comparison theory as a new approach for identifying precursors of crab barrel syndrome. The authors' research study findings indicate through social comparison theory that type A personality precedes crab barrel syndrome, especially when the work environment is highly competitive. Consequently, job performance for type A personalities requires strengthening the employee's self-esteem with group support to decrease crab barrel syndrome.The aim of In conclusion, the articles in this Research Topic provide examples of new insights that we find relevant and thought provoking for progressing further research into organizational psychology scholarship from multiple perspectives.MT: Writing\u2014original draft. DT: Writing\u2014review and editing. GG: Writing\u2014review and editing."} +{"text": "Impairments in decision-making processes are believed to play an important role in both substance use disorders and behavioral addictions. Clinical and pre-clinical experimental testing provide complimentary insights on the psychobiological mechanisms of decision-making. The IOWA Gambling Task (IGT) assesses decision-making under ambiguity and risk, in which individuals are faced with four card choices associated with varying monetary reinforcer/loss contingencies. The rat Gambling Task is a pre-clinical version using palatable reinforcers as wins and timeouts mimicking losses. However, studies with interspecies comparisons in these tasks are lacking, but important to facilitate translation of information that may help unravel the complex processes of decision-making and generate clinical advances.This study explores decision-making strategies among humans and rats performing the IGT and rGT.A total of 270 young human adults performed a computerized version of the IGT, and 72 adult outbread male Lister Hooded rats performed the rGT. Performance was assessed and explored by normative scoring approaches and subgroup formations based on individual choices.Results showed that most humans and rats learned to favor the advantageous choices, but the overall level of performance differed considerably. Humans displayed both exploration and learning as the task progressed, while rats showed relatively consistent pronounced preferences for the advantageous choices throughout the task. Nevertheless, variability in individual choice preferences during end performance were evident in both species.Results are discussed in relation to procedural differences impacting performance and potential to study different aspects of decision-making. This is a first attempt to provide formal evaluation of similarities and differences regarding decision-making processes in the IGT and rGT from an explorative perspective.None Declared"} +{"text": "Brain 2022).Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder affecting 1-2% of the population worldwide. Recent large-scale whole-exome sequencing (WES) studies identified hundreds of rare, highly penetrant genetic variations associated with ASD. Many of these genetic variations underlie particular genetic syndromes characterized by a variety of congenital anomalies in addition to the core ASD symptoms. Recently, we reported about certain ultrasonography fetal anomalies (UFAs) associated with later development of ASD who have both fetal ultrasound and WES data. We used an integrative in-house bioinformatics pipeline specifically designated to identify gene-disrupting variants (GDVs) in a panel of >1200 genes associated with ASD according to SFARI gene database. Then, we compared the prevalence of GDVs in these genes between children with and without UFAs. Finally, we applied the Gene Analytics tool to disrupted genes in children with specific fetal anomalies to identify biological pathways associated with both ASD and these fetal anomalies.children with UFAs were more likely to carry GDVs in ASD genes than their counterparts even after adjustment to the sex differences between the groups , and this association was the most prominent with GDVs in the most notable ASD genes . Also, the study shows higher prevalence of children with GDVs in most anatomical systems, with UFAs in fetal size and the head&brain being the most prominent . In addition, children with UFAs had significantly more co-occurring mutations, and the number of mutations in a single fetus was significantly correlated with the number of UFAs .Overall, 115 ASD children were included in this study, of which 49 (42.6%) of them had UFAs in their ultrasound scans . Children with and without UFAs did not differ in their sociodemographic and clinical characteristics except for a significantly lower proportion of males in the UFA group . Notably, Image:Image 2:Our findings suggest distinct genetic mechanisms for ASD subtypes that are characterized by unique UFAs. These findings may form a basis for future prenatal screening approaches for ASD using both ultrasound and genetic testing. Our findings suggest distinct genetic mechanisms for ASD subtypes that arecharacterized by unique UFAs. These findings may form a basis for future prenatal screening approaches for ASD using both ultrasound and genetic testing.None Declared"} +{"text": "Proteome stability is critical for proper cellular functionality and consequently organismal health and it is ensured by an extensive compartment-specific network of machineries known as the proteostasis network (PN) . Key comDeclined proteasome functionality is a hallmark of aging and a major risk factor for the development of many age-related diseases such as neurodegenerative disorders and cardiomyopathies . On the Drosophila experimental in vivo model we previously reported that flies exposed to therapeutic PIs display similar adverse effects with multiple myeloma patients treated with PIs, including both neurotoxicity and cardiac dysfunction [By exploiting the function . Recentlfunction ; these mfunction . Interesfunction ). In supfunction .Taken together, our findings provide mechanistic explanations for the heart-related adverse effects of therapeutic PIs, suggesting that proteasome dysfunction in the heart results in cardiotoxicity and systemic complications due to proteome instability, mitochondria disruption, redox imbalance and metabolic deregulation. Moreover, our therapeutically relevant finding that co-administration of autophagy inducers exert beneficial effects on heart functionality, provide preclinical insights for alleviating PIs-induced cardiac adverse effects and thus preventing anti-tumor therapy discontinuation."} +{"text": "The ATTRv patient underwent heart transplantation because of progressive heart failure. Within the next two years, progressive myopathic symptoms and extracardiac tracer uptake on 99mTc-DPD planar scintigraphy were documented, attributable to ATTR amyloid myopathy. Interstitial amyloid deposits were confirmed by muscle biopsy in both patients, with a particularly high amyloid burden in the adipose tissue. This case report highlights the frequent concomitant presence of cardiac ATTR amyloidosis and ATTR amyloid myopathy. ATTR amyloid myopathy may precede cardiac manifestation in ATTRwt or occur after heart transplantation in ATTRv. Due to the high diagnostic accuracy of 99mTc-DPD scintigraphy for detecting ATTR amyloid myopathy and the emergence of novel therapeutics, it is important to increase the awareness of its presence.We identified two patients with transthyretin (ATTR) amyloid myopathy . Myopathy was the initial manifestation in ATTRwt, whereas it followed neuropathy and cardiomyopathy in ATTRv. The ATTRwt patient showed muscular tracer uptake on This was particularly pronounced in ATTRwt and ATTR-Val122Ile and could be confirmed histologically as ATTR amyloid myopathy in a small subset of patients with Perugini grade 3 on 99mTc-DPD scans.7ATTR amyloid myopathy, which is characterized by intramuscular interstitial amyloid deposits leading to weakness in the upper and/or lower extremities may contribute significantly to morbidity.We herein describe two cases of ATTR amyloidosis (ATTRv and ATTRwt) with clinical, imaging, and histological evidence of ATTR amyloid myopathy, which is probably often underappreciated and underrecognized in routine clinical practice Table .Table 1C99mTc-DPD whole-body planar imaging . There was no family history of amyloidosis. The patient\u2019s medical records were remarkable for bilateral carpal tunnel syndrome ten years and decompression for lumbar vertebral stenosis two years before diagnosis of ATTRv amyloidosis. Neurological examination at the time of diagnosis of ATTRv amyloidosis in 2015 revealed fatigue, paresthesia of the feet, and loss of Achilles tendon reflexes. Dyspnea, bilateral lower leg edema, muscle cramps, mild proximal muscle weakness, upper extremity paresthesia, and numbness in the upper and lower extremities developed over the following 1.5 years. In addition to heart failure treatment, the ATTR tetramer stabilizer tafamidis was started in 2017 when this substance was first available in Austria. Three years after the initial diagnosis, the patient underwent heart transplantation due to progressive heart failure. Tafamidis, which was paused perioperatively, was restarted seven weeks thereafter. On routine follow-up 12 and 19 months after successful heart transplantation, no evidence for recurrent cardiac amyloidosis was found on endomyocardial biopsy and 99mTc-DPD planar scintigraphy showed minor abnormalities with a mixed pattern of mild neurogenic and myogenic changes.Serum creatine kinase (CK) levels were within the normal range.Figure Reticular deposits of homogeneous eosinophilic material, representing amyloid, were mainly observed in the perimysial adipose tissue. Interstitial deposition of amyloid was also found in endomysium of skeletal muscle. Interestingly, the ATTR amyloid load was greater in the surrounding adipose tissue than in skeletal muscle. Immunohistochemistry showed amyloid deposits immunoreactive for transthyretin Figure E-G.99mTc-DPD scintigraphy and cardiac magnetic resonance imaging. No pathogenic mutation could be detected and treatment with tafamidis was initiated in 2019. 99mTc-DPD whole-body planar imaging after diagnosis of ATTRwt amyloidosis showing significant ATTR amyloid deposition initially presented with bilateral lower leg edema, vertigo, numbness in the pretibial area, lower extremity muscle weakness and muscle cramps. The latter had already started 1-2 years before and was initially considered as side effect of statin use. In the absence of monoclonal proteins, diagnosis of cardiac ATTR amyloidosis was obtained by A low-grade sensorimotor axonal polyneuropathy of lower extremities was revealed in 2019. Myopathic changes in the left gluteal muscle could be detected one year later by EMG.CK levels were within the normal range.Figure Hematoxylin and eosin staining showed slight variation of fiber size and increase of endomysial connective tissue. Necrotic fibers were not seen, although few regenerating fibers were present. Single atrophic fibers were vacuolated and contained amorphous sarcoplasmic deposits suspicious of amyloid. These amorphous deposits were clearly identified as green birefringent amyloid deposits on Congo red staining and were immunoreactive for transthyretin Figure A-D.TTR gene have been described to date, characterized by a wide phenotypic heterogeneity.2 The ATTR-Val40Ile variant, which was diagnosed in patient 8 A similar course was seen in patient 99mTc-DPD planar scintigraphy 19 months after heart transplantation revealed pronounced muscular tracer uptake in the shoulder and gluteal regions in the absence of cardiac tracer uptake in the transplanted heart. At the same time the patient complained of progressive muscle weakness and muscle cramps. Biopsy from the deltoid muscle confirmed significant ATTR amyloid deposition. As there was no evidence of progression of the previously diagnosed neuropathy in the follow-up examinations, it seems likely that the patient's complaints were due to increased amyloid deposits in the peripheral muscles after heart transplantation.In ATTRv more than 140 mutations in the 9One possible explanation for the development and clinical presentation of amyloid myopathy could be that ATTRv amyloid binds to pre-existing ATTRv amyloid deposits with high affinity. Therefore, after heart transplantation and release of ATTR amyloid cardiomyopathy, ATTRv amyloid may preferably deposit on pre-existing, formerly subclinical, ATTRv amyloid deposits in skeletal muscle, causing posttransplant amyloid myopathy in our patient. Similarly, it was reported that amyloid cardiomyopathy may develop after liver transplantation in ATTRv patients, due to binding of wild-type transthyretins, produced by the transplanted liver, on pre-existing ATTRv amyloid deposits in the myocardium.7 In this study bone uptake on 99mTc-DPD scintigraphy increased over the 3 h imaging period, whereas cardiac uptake and soft-tissue uptake (mainly muscle) decreased over time. This seems to be contradictory to the Perugini grading system, which is based on the reciprocal and relative decrease in bone uptake on planar imaging. The authors postulated that bone uptake particularly in patients with Perugini grade 3 on 99mTc-DPD scans may be obscured by tracer uptake in overlying skeletal muscles. Extensive soft-tissue uptake may even obscure visualization of cardiac tracer uptake on planar imaging.7 Conversely, it is conceivable that extensive cardiac tracer uptake may obscure visualization of muscular tracer uptake. It must therefore be considered that in our patient amyloid myopathy was already present before heart transplantation but was not noticed due to this phenomenon. However, increasing muscular complaints suggest an increase in amyloid load after heart transplantation.Hutt et al reported that most patients with cardiac ATTR amyloidosis, especially ATTRwt and ATTR-Val122Ile variant showed muscular tracer uptake on bone scintigraphy.Despite clinical improvement of muscular complaints under gene silencing therapy, a scintigraphic follow-up examination in November 2021 (40 months after heart transplantation) still showed a marked increase in muscular tracer uptake in shoulder and gluteal regions. Whether prolonging the duration of therapy will ultimately result in regression of muscular amyloid deposits remains to be seen.6Patient 2 (ATTRwt) complained about lower extremity muscle weakness and muscle cramps, which already started 1-2 years before cardiac manifestation. This was primarily attributed to a side effect of statin therapy. However, it is more likely that these complaints were already due to the subsequently confirmed amyloid myopathy. This is in concurrence with previous reports indicating that amyloid myopathy may precede cardiac manifestation in ATTRwt.It must be noted that ATTR amyloid myopathy is often difficult to distinguish from neuropathy in routine clinical practice. This is particularly because symptoms attributed to amyloid myopathy, such as weakness and cramps, are similar to symptoms of neuropathy, CK levels are mostly within the normal range and changes in EMG are often not very pronounced. This is due to interstitial amyloid localisation, whereas muscle fiber necrosis and muscle fiber alterations, causing changes in CK levels and EMG, are rarely present. Consequently, ATTR amyloid myopathy is likely to be frequently overlooked or mistaken as neuropathy.99mTc-DPD scintigraphy may ultimately be the more important diagnostic screening tool for diagnosis of ATTR amyloid myopathy than biopsy in future, given the current literature.7Histologically remarkable in this case report is the pronounced amyloid deposition in the adipose tissue in both patients, especially in patient 99mTc-labeled-pyrophosphat (99mTc-PYP) was minimal when assessed by qualitative and quantitative metrics. Thus, they conclude that the properties of 99mTc-PYP may be different from 99mTc-DPD in terms of non-cardiac uptake and that 99mTc-PYP cannot be used to image extracardiac ATTR deposition.10In a previous retrospective analysis of 57 patients with cardiac ATTR amyloidosis, Sperry et al noted that skeletal muscle uptake of 99mTc-DPD scintigraphy with high accuracy. As already shown in previous studies, myopathy can precede cardiac manifestation in ATTRwt amyloidosis.6 To date, amyloid myopathy has not been reported in the ATTR-Val40Ile variant and must be recognized as an important contributor to morbidity in these patients. In concurrence with previous reports, our findings from patient 1 (ATTRv) show that neuropathy and cardiomyopathy may precede the initial manifestation of myopathy.6 Whether this also applies to other patients with the ATTR-Val40Ile variant will be subject of future studies.In summary, muscular ATTR deposits can be visualized by 99mTc-DPD scintigraphy enables non-invasive diagnosis of ATTR amyloid myopathy with high accuracy, while invasive muscular biopsy is no longer obligatory. Due to the broad availability of 99mTc-DPD scintigraphy and the emergence of novel therapeutics it is of utmost importance to increase the awareness for the frequent concomitant occurrence of ATTR amyloid cardiomyopathy and myopathy, expanding the clinical spectrum of ATTR amyloidosis.Conclusively, we think that ATTR amyloid myopathy is still underappreciated and underrecognized, because accurate diagnosis in the past seemed difficult to achieve in routine clinical practice. As shown in this case report,"} +{"text": "Emotion regulation is crucial in individuals' cognitive ability to manage and express their emotions effectively. This Research Topic delves into the neural processes and reactions associated with emotion regulation using various neurophysiological techniques, including electroencephalogram (EEG), event-related potentials (ERPs), functional magnetic resonance imaging (fMRI), and transcranial electrical stimulation (tES). Furthermore, it investigates the impact of different stimulus types, aesthetic preferences, and mindfulness practices on emotion regulation. The findings contribute to a comprehensive understanding of emotion regulation strategies and provide insights for potential therapeutic interventions.Yang et al.) has proposed distinct roles for the P100, N170, and P250 neural generators. These generators are involved in encoding comprehensive frames of reference, maintaining structural cohesion, and adapting to internal representations of emotional expressions.Within this context, EEG and event-related potentials are valuable tools for investigating the neural processes and reactions related to emotion regulation. A piece of research component was examined using the mismatch negativity (MMN) in a group of young and middle-aged adults. They employed a modified oddball paradigm to compare responses to standard tones under fearful and neutral facial expressions. The results demonstrated that when exposed to fearful facial expressions, the amplitude of the N1 in response to classic techniques was smaller than in neutral facial expressions.In a study by Additionally, the amplitude was more negative in young adults than middle-aged adults. These findings suggest that the perception of negative emotions visually facilitates the processing of auditory features and enhances acoustic change detection in middle-aged adults. However, this effect cannot compensate for the age-related decline in MMN amplitude.Jamieson et al.).Emotions are interconnected with our social interactions as we navigate the social realm by interpreting and choosing between conflicting emotional cues. The effective face-word Stroop (AFWS) is an experimental method that can help uncover the fundamental neural processes that support crucial social and emotional abilities. Regarding the timing, location, and sequence of control processes involved in responding to emotional conflicts during the AFWS, a study determined that conflict control processes occur within the components of Visually evoked potentials (\u00c5sli and \u00d8vervoll) discovered that the interaction between emotional expressions and model gender influences the magnitude of startle responses. Specifically, greater startle responses were observed when participants viewed angry faces displayed by male models and happy expressions displayed by female models. Another study investigating emotional stimuli in individuals with spinal cord injury proposed an integrated explanation for emotional conflict resolution during response activation tasks. This study emphasized the influence of emotional arousal and primed approach or avoidance motivation. Furthermore, they discussed the role of arousal in individuals with spinal cord lesions, providing insights into the typical mechanisms involved in emotional conflict control. Understanding emotional conflict control is crucial for adaptive behavior and may have implications for therapeutic interventions.On the other hand, the role of other internal variables has also been addressed. A study utilizing electromyography . Moreover, a study conducted with patients suffering from mild traumatic brain injury examined negative frontal alpha asymmetry using EEG data and found greater right-sided frontal activity than healthy controls .Focusing on the clinical population, results from a study suggested that individuals with Authentic pride (AP) demonstrated greater success in down-regulating negative emotions through cognitive reappraisal, both in daily life and experimental settings, compared to individuals with hubristic pride . The amplitudes of the N400 brain wave component were correlated with participants' level of negative affect during the pre-contemplation stage. Another study revealed that post-error adjustments varied depending on the specific task context.Cognitive appraisal and associated emotional processes were also examined in motivational interviewing augmented mindfulness, suggesting that regular physical exercise before meditation can enhance early-stage mindfulness. Neurocognitive research indicates that physical exercise (such as aerobic exercises or yoga) and mindfulness impact similar pathways involved in stress regulation and cognitive control, supporting the idea of synergistic effects between physical exercise and mindfulness. Studies focusing on the psychophysiological impact of physical exercise have shown that it can lead to short-term neurocognitive changes that facilitate cognitive control and the attainment of mindful awareness.Mindfulness is another topic covered in this context. Despite the known benefits of mindfulness for mental health, drop-out rates among mindfulness practitioners can occur due to factors such as chronic stress, cognitive reactivity, and pathology. To address this issue, K\u00fc\u00e7\u00fckta\u015f and St. Jacques, the influence of visual perspective on the emotional aspects of autobiographical memory (AM) retrieval was examined. The review concluded that the impact of visual perspective depends on the emotional nature connected to the event.Lastly, in a review conducted by By investigating the neural correlates and strategies associated with emotion regulation, this research paper aims to advance our understanding of how individuals skillfully handle and display their emotions in various contexts. The multimodal approach provides valuable insights into the underlying processes involved in emotion regulation and informs potential interventions for improving emotional wellbeing and adaptive behavior.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "Background: Nonprescription antibiotic use includes taking an antibiotic without medical guidance . Nonprescription use contributes to antimicrobial resistance, adverse drug reactions, interactions, and superinfections such as Clostridioides difficile colitis. Qualitative studies exploring perspectives regarding nonprescription use among Hispanic patients are lacking. We used the Kilbourne Framework for Advancing Health Disparities Research to identify factors influencing Hispanic patients\u2019 nonprescription use and to organize our findings. Methods: Our study includes Hispanic primary-care clinic patients with different types of health coverage in the Houston metroplex who endorsed nonprescription use in a previous quantitative survey. Semistructured interviews explored the factors promoting nonprescription use in Hispanic adults. Interviews were conducted remotely, in English or Spanish, between May 2020 and October 2021. We used inductive coding and thematic analysis to identify the factors and motives for nonprescription use. Results: Of the 35 Hispanic participants surveyed, 69% were female and between the ages of 27 and 66. All participants had some form of healthcare coverage . Participants reported obtaining antibiotics from their own leftover prescriptions and through trusted persons , buying them under the counter in US markets, and purchasing them without a prescription outside the United States. Thematic analysis revealed the factors contributing to nonprescription use . Themes included beliefs that the \u2018doctor visit was unnecessary,\u2019 \u2018limited direct access to healthcare\u2019 in the United States , \u2018more open indirect access to healthcare\u2019 abroad and under the counter in the United States, and communication difficulties . Figure 2 shows representative quotes across thematic domains. Participants expressed having confidence in medical recommendations from pharmacists and trusted community members in their social networks. Conclusions: Antibiotic stewardship interventions that include pharmacist-driven patient education regarding appropriate antibiotic use may decrease nonprescription antibiotic use in Hispanic communities. Additionally, improving access to care while addressing communication barriers and cultural competency in clinics may improve primary care delivery and reduce potentially unsafe antibiotic use.Disclosure: None"} +{"text": "Multiple myeloma generally occurs in older adults, with the clonal proliferation of plasma cells and accumulation of monoclonal protein resulting in a broad range of clinical manifestations and complications, including hypercalcemia, renal dysfunction, anaemia, and bone destruction (termed CRAB features). A 64-year-old man with no history of malignancy presented with an enlarging precordial lump occurring three years post-sternotomy for uneventful coronary artery bypass grafting surgery. Initial investigations showed anaemia and impaired renal function. Multimodal imaging performed for further evaluation showcases the radio-pathological features which can be encountered in haematological malignancy. Subsequent percutaneous biopsy confirmed an underlying plasma cell neoplasm, and a diagnosis of multiple myeloma was achieved. The prompt resolution of the lesions upon the initiation of treatment highlights the importance of early diagnosis and treatment."} +{"text": "Aedes aegypti\u2013a primary vector of dengue, Zika, and chikungunya viruses. We then validated the use of our approach to generate experimental microcosms colonized by standardized lab- and field-derived bacterial communities. Our results overall reveal minimal effects of cryopreservation on the recovery of both lab- and field-derived bacteria when directly compared with isolation from non-cryopreserved fresh material. Our results also reveal improved reproducibility of bacterial communities in replicate microcosms generated using cryopreserved stocks over fresh material. Communities in replicate microcosms further captured the majority of total bacterial diversity present in both lab- and field-based larval environments, although the relative richness of recovered taxa as compared to non-recovered taxa was substantially lower in microcosms containing field-derived bacteria. Altogether, these results provide a critical next step toward the standardization of mosquito studies to include larval rearing environments colonized by defined microbial communities. They also lay the foundation for long-term studies of mosquito-microbe interactions and the identification and manipulation of taxa with potential to reduce mosquito vectorial capacity.Mosquitoes develop in a wide range of aquatic habitats containing highly diverse and variable bacterial communities that shape both larval and adult traits, including the capacity of adult females of some mosquito species to transmit disease-causing organisms to humans. However, while most mosquito studies control for host genotype and environmental conditions, the impact of microbiota variation on phenotypic outcomes of mosquitoes is often unaccounted for. The inability to conduct reproducible intra- and inter-laboratory studies of mosquito-microbiota interactions has also greatly limited our ability to identify microbial targets for mosquito-borne disease control. Here, we developed an approach to isolate and cryopreserve bacterial communities derived from lab and field-based larval rearing environments of the yellow fever mosquito i) facilitate the study of mosquito traits of interest in the absence of confounding effects of microbiota variation, and (ii) enable reproducible intra- and inter-laboratory studies of mosquito-microbiota interactions to identify microbial targets for disease control. Our results are also of broad interest to researchers in the fields of microbial ecology and host-microbe interactions because they demonstrate how tools commonly used to study microbiota assembly and function in mammals can be leveraged in other systems.Mosquitoes develop in the presence of diverse bacterial communities that shape their ability to transmit disease-causing pathogens. However, our current understanding of mosquito-microbiota interactions is largely based on studies of individuals colonized by low-diversity communities of bacteria that are not commonly associated with mosquitoes in the laboratory or field. In this study, we developed an approach to isolate and cryopreserve microbiota from mosquito larval rearing environments in the lab and field. We then demonstrated the successful use of this approach to produce experimental microcosms colonized by standardized microbial communities. Our results are of critical significance to the field of vector biology because they will directly ( The community of bacteria (hereafter referred to as \u2018microbiota\u2019) present in the aquatic environments where mosquito larvae develop can have profound impacts on mosquito biology by modulating larval growth and development and, consequently, adult survival, reproduction, and the competency of adult female mosquitoes to transmit human pathogens (reviewed in ). HoweveAedes aegypti and Culex quinquefasciatus mosquitoes that serve as primary vectors of arboviral infections and filariasis in humans .We initially sought to develop an approach to isolate and cryopreserve microbiota from conventional larval rearing pans in the laboratory for recapitulation in experimental microcosms. Multiplex sequencing of 16S rRNA gene amplicons for the resulting rearing pan- and microcosm-derived water samples generated a total of 2,669,979 quality-filtered reads with a median sequencing depth of 44,707 reads per sample . An unusi.e., those with a maximum relative abundance \u22641% in rearing pans), with significantly fewer rare ASVs being recovered in experimental microcosms generated using cryopreserved stocks of lower cell densities , even at 5 days post-incubation between any of the microcosms we generated of reads from these samples were assigned to ASVs belonging to one of eight bacterial families within the following phyla/classes: Alphaproteobacteria , Betaproteobacteria (Comamonadaceae), Gammaproteobacteria , and Bacteroidetes . A totalcubation . Howeverenerated .4, 105) . Differences in beta diversity, measured as average Bray-Curtis dissimilarity, were also overall higher between rearing pans and unprocessed controls than between rearing pans and experimental microcosms generated using material from cryopreserved stocks, regardless of cell density . Further= 0.001) , post-ho density .i.e., decreased in abundance) in response to cryopreservation .Finally, we performed ALDEx2 tests to identify rearing pan ASVs that significantly changed in relative abundance in response to cryopreservation and/or re-culturing under conventional mosquito rearing conditions Figs and S4. ion Figs and S4. Next we sought to validate the use of cryopreservation approaches developed above to generate experimental microcosms colonized by microbiota derived from a naturally occurring mosquito larval habitat in the field. Multiplex sequencing of 16S rRNA gene amplicons for the resulting habitat- and microcosm-derived water samples generated a total of 2,111,045 quality-filtered reads with a median sequencing depth of 43,541 reads per sample , with raP = 0.426).As expected, we identified a substantially higher diversity of bacteria (993 ASVs) across the field-derived water samples as compared to those derived from conventional larval rearing pans in the laboratory, with ~42% of reads being assigned to ASVs belonging to the eight bacterial families dominating communities in rearing pans and the remaining ~58% being assigned to ASVs belonging to one of 306 other families within 187 bacterial orders and 34 phyla/classes . A substP > 0.05).ALDEx2 tests identified a total of 110 of the 993 ASVs found in the habitat water samples we sequenced showing significantly different relative abundances in experimental microcosms, but only 12 of these ASVs, representing <6% of all habitat water sequences, were specifically negatively affected in response to cryopreservation Figs and S7. While our isolation and cryopreservation approaches resulted in the loss of some lab- and field-derived bacterial taxa and concurrent changes in the total alpha and beta diversity of microbiota within experimental microcosms as compared to the larval rearing pans and habitat water we originally sampled, we observed little variation among the bacterial communities present within replicate microcosms generated using the same cryopreserved stock, with the only exceptions being those generated using stocks of lower cell densities . On averMosquitoes live in close association with bacteria and other microorganisms that shape their ability to transmit pathogens . Howeveri) decouple the effects of sample processing and the cell density of cryopreserved stocks on the recovery and persistence of bacteria in microcosms from those of larvae, which are known to shape water pH, nutrient levels, and even bacterial metabolism [ii) better reflect natural microbiota exposure and acquisition processes in the field, whereby larvae hatch from eggs laid directly into (or adjacent to) water containing established bacterial communities [Ae. aegypti revealed a bacterial community comprised of ~100 unique bacterial taxa and dominated by members of the Proteobacteria, Bacteroidetes, and Firmicutes, consistent with sequencing studies of other laboratory colonies of mosquitoes [Paenarthrobacter, which were significantly reduced or absent in experimental microcosms and may represent taxa that are not readily amenable to centrifugation and/or cryopreservation using our methodology.In this study, we first developed an approach to isolate and cryopreserve microbiota from conventional larval rearing pans in the laboratory for recapitulation in experimental microcosms. We intentionally conducted our experiments in the absence of any larvae in order to: detected in laboratory rearing pans and commonly detected in field-collected mosquitoes \u201349,60\u201365The cell density of cryopreserved stocks also had a much larger impact on the recovery and persistence of field-derived taxa, with microcosms generated using stocks of lower cell densities exhibiting more variable bacterial communities that were overall lower in complexity that communities in microcosms generated using stocks of higher cell densities. This is consistent with results showing that small sampling volumes from aquatic and other high-complexity environments like soil often fail to adequately capture bacterial diversity \u201377, owine.g., immediately after a rainfall). Defined diets that support mosquito growth and development could also be developed to improve the reproducibility of field bacterial diversity between replicate microcosms, including the maintenance of rare taxa important for community assembly and stability [Overall, experimental microcosms generated using cryopreserved stocks containing lab-derived microbiota exhibited levels of reproducibility that were the same or better than those present under conventional rearing conditions in the laboratory, highlighting the value of our approach for intra-and inter-lab studies of mosquitoes in the presence of standardized microbial communities. Similar levels of reproducibility could also be replicated in microcosms generated using cryopreserved stocks of field-derived microbiota, although reproducibility significantly decreased with decreasing inoculum size\u2013consistent with our previous observation that variability among the bacterial communities present within replicate microcosms was significantly higher in those generated using cryopreserved stocks of lower cell densities. Future studies are warranted to establish best practices for field habitat sampling, though our results at minimum suggest that higher-volume samples are preferable, and that sampling should be avoided in situations where bacterial density is expected to be low . Unmodified bacteria that naturally inhibit pathogen colonization or mosquito fitness could also be disseminated to mosquito populations. The identification of suitable microbial candidates for pathogen or mosquito control will require a comprehensive understanding of the factors that influence the acquisition, maintenance, and transmission of mosquito microbiota and the mechanisms that underlie how individual microbial species and assemblages impact mosquito vectorial capacity. However, the dearth of tools to manipulate mosquito microbiota, including microbiota derived from naturally occurring mosquito habitats in the field, has greatly slowed progress in this area. In this way, the results reported here not only provide a critical first step toward the standardization of microbial inputs in mosquito studies, but also provide a critical first step toward the identification of taxonomic and functional profiles of bacteria associated with phenotypic traits of interest in mosquitoes. For example, a defined microbiota could be universally adopted by the community to conduct vector competence assays in the absence of confounding effects due to microbiota variation. Libraries of cryopreserved microbiota could also be screened to identify bacteria that improve or reduce mosquito fitness and/or pathogen susceptibility, or to predict the success of individual microbial candidates under variable microbial conditions. Similarly, the results reported here strongly support that our methods could immediately be leveraged to expand studies of mosquito-microbiota interactions to include microbial genotypes derived from the field, and thereby conduct lab-based mosquito experiments with field-relevant microbiota.Owing to their ability to impact numerous components of mosquito vectorial capacity, there is a growing interest in exploiting microbes for mosquito-borne disease control. For example, bacteria that naturally colonize the mosquito gut could be genetically modified to produce effector molecules that alter the mosquito\u2019s ability to become infected with and transmit pathogens, or that reduce mosquito fecundity or lifespan (S1 TableAsterisks (*) indicate samples that were removed from the dataset prior to downstream analyses.(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 FigReads from each water library were sampled starting at 1 sequence per step and increased in increments of 100 until the total number of reads per sample was reached. Lines are colored by sample source . Time of sampling of experimental microcosms is designated by line type .(TIF)Click here for additional data file.S2 FigP < 0.05).Proportion of rare (left) and abundant (right) ASVs found in at least one larval rearing pan that were detected in experimental microcosms containing unprocessed water or sterile water plus material from a given cryopreserved stock. An ASV was considered \u201crare\u201d if it had a maximum relative abundance \u22641% across the four larval rearing pans we sampled, while ASVs with a minimum relative abundance >1% were considered \u201cabundant\u201d. Asterisks (*) indicate significant differences between experimental microcosms generated using cryopreserved stocks relative to unprocessed controls as determined by paired Fisher\u2019s exact tests with Bonferroni correction ((TIF)Click here for additional data file.S3 FigEach ASV is presented with its lowest annotated taxonomic rank (to genus level) together with its ASV ID. The ASVs are color-coded according to the phyla they belong to and plotted according to their effect size, calculated as the levels in samples from experimental microcosms relative to levels in samples from larval rearing pans. Dot sizes correspond to the median centered log-ratio (clr) abundance value for each ASV across rearing pan samples. Dots with a bold red outline represent ASVs that were differentially abundant in both experimental microcosms containing unprocessed water and experimental microcosms containing sterile water plus material from cryopreserved stocks see .(TIF)Click here for additional data file.S4 FigEach ASV is presented with its lowest annotated taxonomic rank (to genus level) together with its ASV ID. The ASVs are color-coded according to the phyla they belong to and plotted according to their effect size, calculated as the levels in samples from experimental microcosms relative to levels in samples from larval rearing pans. Dot sizes correspond to the median centered log-ratio (clr) abundance value for each ASV across rearing pan samples. Dots with a bold red outline represent ASVs that were differentially abundant in both experimental microcosms containing sterile water plus material from cryopreserved stocks and experimental microcosms containing unprocessed water see .(TIF)Click here for additional data file.S5 FigReads from each water library were sampled starting at 1 sequence per step and increased in increments of 100 until the total number of reads per sample was reached. Lines are colored by sample source . Time of sampling of experimental microcosms is designated by line type .(TIF)Click here for additional data file.S6 FigEach ASV is presented with its lowest annotated taxonomic rank (to genus level) together with its ASV ID. The ASVs are color-coded according to the phyla they belong to and plotted according to their effect size, calculated as the levels in samples from experimental microcosms relative to levels in habitat water samples. Dot sizes correspond to the median centered log-ratio (clr) abundance value for each ASV across habitat water samples. Dots with a bold red outline represent ASVs that were differentially abundant in both experimental microcosms containing unprocessed habitat water and experimental microcosms containing sterile water plus material from cryopreserved stocks see .(TIF)Click here for additional data file.S7 FigEach ASV is presented with its lowest annotated taxonomic rank (to genus level) together with its ASV ID. The ASVs are color-coded according to the phyla they belong to and plotted according to their effect size, calculated as the levels in samples from experimental microcosms relative to levels in habitat water samples. Dot sizes correspond to the median centered log-ratio (clr) abundance value for each ASV across habitat water samples. Dots with a bold red outline represent ASVs that were differentially abundant in both experimental microcosms containing sterile water plus material from cryopreserved stocks and experimental microcosms containing unprocessed water see .(TIF)Click here for additional data file."} +{"text": "Simulation is a key component of surgical training, enabling trainees to develop their skills in a safe environment. With simulators broadly grouped into physical models and virtual-reality (VR) simulators, it is important to evaluate the comparative effectiveness of the simulator types in terms of validity as well as cost. The review aims to compare the benefits and drawbacks of novel VR and physical simulators within the broader themes of endourology, laparoscopic and robotic operations, and other urological procedures.Key benefits of bench models include their comparatively lower cost, easy access and provision of haptic feedback, whereas VR simulators are generally self-sufficient, reusable and enable skills of haemostasis to be practised. The advent of perfused 3D printed simulators across a range of urological procedures may replace cadavers as the traditional gold-standard simulation modality.Although possessing differing strengths and downsides, VR and physical simulators when used together can have an additive effect due to skill transferability across the platforms. Further comparative studies are required to directly quantify the differences between physical models and VR simulators in terms of performance metrics and cost-effectiveness. There is lack of validated VR simulators for open and reconstructive procedures. Simulation is an integral part of surgical training enabling trainees to hone their technical skills away from actual patients until they achieve a safe level of competency . This isEndourological procedures include ureteroscopy, cystoscopy and transurethral resections of the bladder and prostate. The SIMULATE international prospective trial examined3D model simulators have been recently developed in the field of cystoscopy such as the \u2018FlexBlad\u2019 and \u2018Bla\u25aa\u25aa] examining simulation training in transurethral resection and laser vaporisation procedures of the prostate. The review findings pointed towards VR simulators uniquely possessing data capture and performance evaluation features but that alongside their typically poor haptic feedback, their simulation of bleeding is generally poor for TURP and laser vaporisation. Physical simulators such as bench-top tissue and food-based models also inadequately simulate bleeding for these procedures and carry hygiene risks, but are lower cost and beneficial in that they use real instruments. In the context of laser-based procedures, cadavers demonstrate content validity for holmium laser AEEP training [The European Section of Uro-Technology (ESUT) undertook a systematic review \u25aa\u25aa examintraining with suptraining , VR simutraining \u25aa,16 and PCNL is another endourological procedure for which simulators have been validated. One study used participant ratings and performance data to compare three simulators ; a porciAlthough cadavers are considered the gold-standard simulation modality, artificial perfusion of cadavers is limited by high cost, positive viral profiles and difficulty clearing the vascular tree. One low-cost, nonbiohazardous physical model for robot-assisted partial nephrectomy (RAPN) directlyLive animal models such as porcine models pose ethical challenges not associated with other simulators. One study aimed toVR simulation performance for robot-assisted radical prostatectomy (RARP) has crucially been shown to correlate with live surgical performance in the real operative environment thereby increasing its validity as a training modality. One study of 20 suWith VR, simulation is moving beyond just basic isolated skills training to full procedural simulation. This has been demonstrated for RARP with supFor laparoscopic pyeloplasty, various physical simulators exist with advantages over VR simulators such as significantly lower cost and easy access whilst maintaining anatomical realism. As with aforementioned procedures, 3D printed models for pyeloplasty have been produced demonstrFor the management of urological emergencies such as priapism and testicular torsion, there is an absence of validated VR simulators to develop the skills necessary for the therapeutic interventions these conditions require. There is therefore a reliance on physical simulators to facilitate skill acquisition and these have been incorporated effectively into training curricula. For example, a urological emergency simulation curriculum was devised for military surgeons utilisinFor penile fracture repair, the first validated simulation model was recently created , based oReconstructive urology is another field in which validated VR training is absent. Instead high-fidelity, 3D-printed penile models have been produced for the simulation of plaque incision and graft (PIG) as indicated for the treatment of Peyronie's disease , achieviTo conclude, physical models are generally superior with regard to cost-effectiveness, the provision of haptic feedback and ease of access, while VR simulators are self-sufficient, reusable and avoid the ethical and infection concerns associated with animal models. Although cadavers have long been considered the gold-standard simulation modality, these may soon be superseded by the advent of highly realistic, perfused 3D printed models capable of procedural simulation incorporating anatomical variation and intraoperative complications at a subThe authors received no source of funding and have no conflicts of interest.None.Baldev Chahal, Abdullatif Aydin and Kamran Ahmed have no conflicts of interest or financial ties to disclose."} +{"text": "Watermelon stomach, also known as gastric antral vascular ectasia (GAVE), is a rarely seen cause of acute upper gastrointestinal bleeding or chronic iron deficient anemia, revealed when gastroscopy is performed. GAVE affects predominantly women of advanced aged and is usually associated with certain underlying co-morbidities including liver cirrhosis, autoimmune diseases and chronic kidney disease. Based on the above, we report the case of a 75-year-old woman under hemodialysis for six consecutive years due to end-stage renal disease attributable to hypertensive nephrosclerosis. The patient also suffered from chronic ischemic heart disease, severe peripheral artery disease and an unidentified connective tissue-disease characterized by high levels of anti-nuclear antibodies and clinical symptoms restrained in flares of non-erosive polyarthritis. Six months prior, she developed hyporesponsiveness to recombinant human erythropoietin (rEPO) due to iron deficiency despite the administration of the appropriate dose of intravenous iron as well as the exclusion of other co-existing causes of resistance, namely inadequate hemodialysis, inflammation, malnutrition, severe hyperparathyroidism and underlying hematologic disorders. Surprisingly, the patient experienced a sudden episode of severe upper gastrointestinal bleeding characterized by hemodynamic instability, hemoglobin fall and melena that required blood transfusions. Once hemodynamic stabilization was achieved, an upper endoscopic exam was performed showing the pathognomonic extensive vascular ectasias and patchy erythematosus lesions at the distal antrum. Thus, GAVE should be considered in the differential diagnosis of chronic kidney disease patients who present not only with acute blood loss but also with resistance to rEPO due to inadequate iron stores."} +{"text": "Many cattle and sheep do not produce enough colostrum for their offspring.Prepartum nutrient intake is an accessible strategy for producers to influence colostrum production.Greater prepartum starch intake can influence colostrum composition and increase colostrum yield for beef cattle and ewes.Colostrogenesis is sensitive to fat intake, dependent on the dietary fatty acid composition: greater linoleic acid intake often increases colostrum antibody concentration.Colostral bioactive compounds are frequently altered by a prepartum diet without changes in overall colostrum composition. Prepartum nutrient intake could be strategically used to maximize beneficial compounds for the newborn.IgG), macronutrients, and bioactive compounds that promote physiological maturation and support the immune system or protein (MP) intake, or dietary components such as starch, neutral detergent fiber (NDF), or fat.Most research evaluating how prepartum nutrient intake affects colostrum production has mainly focused on global nutrient under- or over-provision prior to parturition. Imposing mid to late-gestation nutrient restriction reduced first-milking colostrum yield in beef cattle without NE]). This is additionally complicated by using either empirical or mechanistic models to predict energy requirements and dietary sufficiency and which coefficients of energetic efficiency are used for the conversion of ME to NE for pregnancy or maintenance. Thus, utilization of either system can impose a bias on colostrum production responses between studies. Research evaluating carbohydrate consumption prior to parturition is shown in Carbohydrates proportionally contribute the greatest amount of dietary energy in ruminant rations and, as such, relative starch and NDF substitutions have consequences for dietary energy intake that often confound colostrum production responses. Furthermore, studies that manipulate dietary starch and NDF content to achieve specific energy intakes differ in which energy partition they target and MP intake not always being balanced across treatments increased colostrum yield by 80% in Simmental-Angus crossbred beef cattle . These cIn accordance with beef cattle, increasing dietary starch and energy intake in sheep consistently increased colostrum yield . Bancher1 and total IgG concentrations in colostrum ; thus, this factor should be considered when comparing colostral IgG concentrations between studies using different dietary starch sources. Nonetheless, IgG concentration in first-milking colostrum collected within 1 to 12 h after calving has been reduced by greater dietary starch inclusion or ME intake precalving while suppressing the synthesis of de novo FA relative to cows fed a ration that targets 125% or 150% predicted ME requirements prior to calving are substantial but transient and, as such, presumed negligible relative to pregnancy and maintenance requirements. Regardless, numerous studies .Models that evaluate the sufficiency of prepartum shown in have evashown in and 2. Wiso-nitrogenous and iso-energetic rations; Apart from substituting sunflower meal for cottonseed meal as a protein source wherein the authors observed that greater sunflower meal increases first-milking colostrum yield increases colostrum yield . HoweverAs with colostrum yield, colostrum IgG concentration, as measured by radial immunodiffusion or estimThere are limited data regarding how prepartum protein intake affects colostrum macronutrient composition and yield in cattle. That said, from what is available, colostral fat, protein, and lactose concentrations are unaffected , nor areComparatively, colostrum protein concentration has been reported to increase with protein supplementation in some studies with ewes , but notRations typically have 2%DM dietary fat and, generally, dietary fat should not exceed 6% to 7%DM to avoid detrimental impacts on ruminal fermentation. However, greater dietary fat provision can also improve ration palatability, control dust and fines, and alleviate heat stress due to its lesser heat increment respective to proteins and carbohydrates. Increasing prepartum dietary fat intake can concurrently increase energy intake without providing excessive dietary starch. Consequently, prepartum fat intake may have utility for prepartum rations and studies in cattle and ewesLate-gestation fat inclusion rate and source have not been shown to affect first-milking colostrum production in dairy cattle, either when NE concentration was maintained or when \u0251-linolenic) in late-gestation rations could be beneficial for increasing ewe colostrum yield. Currently, it is unclear why this response occurs.First-milking colostrum yield in ewes appears to be more responsive to dietary fat content than cattle, but results across studies remain inconsistent. Some authors have found that specific fat sources can decrease first-milking half-udder colostrum yield collected within an hour and betwInterestingly, colostral IgG concentration, as measured by ELISA or estimated using Brix, appears to be responsive to dietary fat inclusion and source in both dairy and beefAlthough fewer data are available for ewes, their colostral IgG concentration does not appear to respond to fat intake and source as in cattle . Though,Colostral macronutrient concentrations are usually unaltered by dietary fat content and source for cattle . NotablyThe colostral FA profile is the most reported bioactive component among research evaluating prepartum dietary fat intake and source. For both cattle and sheep, colostrum FA composition ubiquitously varies across all reported studies when the dietary fat inclusion rate or source is altered in such a way that coincides with dietary FA intake and maternal plasma FA profile. With respect to other bioactive components and micronutrients, Prepartum nutrient intake has the capacity to influence colostrogenesis in bovine and ovine species and impact colostrum yield and composition. Although ewes are generally more sensitive to ration composition than cattle, there is evidence to suggest that prepartum nutrition can be used strategically to promote colostrum production in both species. Dietary starch and fat content and source appear to exert influence on colostrum IgG concentration, with data indicating that starch:NDF substitutions affects colostrum yield in beef but not dairy cattle. Current data suggest that cattle are irresponsive to dietary protein content, whereas ewe colostrum production responds to dietary protein source and intake. Further work needs to differentiate between carbohydrate, protein, and fat sources, accounting for total IgG and macronutrient yield, to characterize mammogenic capacity under differing nutritional regimens, particularly in relation to the feeding duration and timing of supplementation relative to the onset of colostrogenesis. In addition, there is a need to detail the colostral bioactive profiles, as this constituent often responds to prepartum nutrient intake without changes in the gross composition of colostrum. Colostral bioactive components are inherently important for neonatal development and, as such, prepartum nutrient intake might be used strategically to benefit the offspring."} +{"text": "Psychiatric disorders are complex clinical conditions with large heterogeneity and overlap in symptoms, genetic liability and brain imaging abnormalities. Building on a dimensional conceptualization of mental health, previous studies have reported genetic overlap between psychiatric disorders and population-level mental health, and between psychiatric disorders and brain functional connectivity. Here, in 30,701 participants aged 45\u201382 from the UK Biobank we map the genetic associations between self-reported mental health and resting-state fMRI-based measures of brain network function. Multivariate Omnibus Statistical Test revealed 10 genetic loci associated with population-level mental symptoms. Next, conjunctional FDR identified 23 shared genetic variants between these symptom profiles and fMRI-based brain network measures. Functional annotation implicated genes involved in brain structure and function, in particular related to synaptic processes such as axonal growth (e.g. NGFR and RHOA). These findings provide further genetic evidence of an association between brain function and mental health traits in the population.The online version contains supplementary material available at 10.1186/s12888-023-04905-7. Psychiatric disorders are complex, with a polygenic architecture, and large degree of overlapping symptoms and risk factors. Both imaging and genetics studies have shown numerous but small associations between brain phenotypes, psychiatric disorders, and genetics, such as schizophrenia (SCZ) \u20133, bipolWe have recently deployed a multivariate analysis to study the genetic architecture of brain functional connectivity, revealing genetic variants associated with functional brain connectivity as well as variance in brain activity over time . The resPrevious studies have shown widespread phenotypic and genetic overlap between psychiatric disorders \u201318. In aHere, we aimed to uncover the genetic architecture of mental symptoms and identify shared genetic loci with neurobiological processes related to brain function. Using multivariate analysis , we geneWe utilized data from the UK Biobank with perThe processing pipeline for imaging data used for the multivariate GWAS is described in Roelfs et al. . In shorIn this study we applied MOSTest to the phenotypic data from the ICA decomposition described in Roelfs et al. . MOSTestIn order to quantify the degree of genetic overlap and identify shared genetic loci between the mental health profiles and the imaging features we deployed the pleiotropy-informed conjunctional false discovery rate (conjFDR) through the pleioFDR toolbox . We usedADH1B and ADH5 (chromosome 4) and CRHR1 (chromosome 17).MOSTest revealed 10 significant (P\u2009<\u20095e-8) loci across the 13 previously identified profiles of mental health , bipolarNext, we explored the genetic overlap between the mental health profiles and the psychiatric disorders through the conjunctional false discovery rate (conjFDR) , 36 whicWe then calculated the number of shared genetic loci between the multivariate genome-wide association statistics for mental health profiles and the two multivariate measures of the brain functional connectome using conjFDR. The GWAS summary statistics from our previous study of brain function . In shorIn this study we identified a number of loci associated with multivariate genome-wide association statistics for mental health profiles and found overlapping loci with the measures of brain function and psychiatric disorders. Using MOSTest we were able to leverage the phenotypic overlap between different mental health profiles to identify new loci associated with a multivariate measure of mental health. Genes associated with these loci showed regional expression in different parts of the brain .Our analysis using conjFDR revealed a number of shared loci and genes between the multivariate genome-wide association statistics and the psychiatric disorders. This demonstrates the shared genetics between psychiatric symptoms regardless of clinical diagnosis, emphasizes the utility of using population-level phenotypes to investigate variance in mental health profiles, and highlights the advantage in leveraging pleiotropy between complex phenotypes to boost discovery. We found shared genes with all but two case-control GWAS , which also had the two smallest sample sizes, which may reflect insufficient power to detect an effect , or may We also identified a number of overlapping loci between mental health profiles and fMRI measures of brain function, including 18 shared loci with functional connectivity and 5 shared loci with node variance. The higher number of shared loci for functional connectivity might be partially explained by the number of phenotypes in each composite measure. While the functional connectivity GWAS comprises 210 measures, i.e. partial correlations between 21 brain nodes, the node variance GWAS encompasses only the temporal variance in each node. It is possible that the number of phenotypes included in the multivariate analysis can affect the discovery . Both thThe two conjunctional analyses with fMRI measures and the multivariate genome-wide association statistics for mental health each showed a number of overlapping loci. Not all shared loci were unique, this can be partially explained by the definition of the brain networks in our analyses. The functional connectivity and the node variance measures use the same 21 nodes, and, ultimately, the two measures reflect different properties of the same time series. We found that the number of overlapping loci between the multivariate genome-wide association statistics for mental health and the brain functional connectome was generally larger than findings from our previous study highlighting shared genetic loci between psychiatric disorders and the brain functional connectome. This may partly be due to the larger sample size of the multivariate measure of mental health, but it could also reflect that the multivariate genome-wide association statistics capture genetic variance more generally related to the brain functional connectome. We found little direct overlap between loci of these two GWAS\u2019 separately, which highlights the discovery boost advantage of using conjFDR in phenotypes with generally low heritability.The main implication from our findings is that we can identify shared genetic variants between a multifactorial measure of mental health in an undiagnosed population sample and fMRI-based measures of brain functional connectivity. Several limitations should be considered. First, the data were obtained from a middle-aged and older White British population, which limits the generalizability of the findings. Further, the mental health questionnaires are self-administered, so the data is vulnerable to various response and self-selection biases . We exclIn conclusion, our multivariate GWAS on 13 mental health symptom profiles showed a number of shared genetic loci with two fMRI-measures reflecting brain function and connectivity. This research shows that genetic overlap between mental health symptom profiles and brain functional connectivity can be linked to, among other processes, axonal growth regulation (through NGFR and RHOA) and regulation of MECP2 transcription factors (through MEF2C). This provides further genetic evidence of an association between brain function and mental health traits in the population.Below is the link to the electronic supplementary material.Supplementary Material 1: Supplementary Figures and Tables"} +{"text": "Editorial on the Research TopicMolecular pathogenesis and novel treatments for inherited cardiomyopathiesInherited cardiomyopathies have diverse genetic etiologies, but together are major contributors to cardiac disease that affect patients of all ages, typically with early onset in childhood or adolescence. While inherited cardiomyopathies are currently classified according to functional and morphologic features, finer resolution of these categories has been made possible with the aid of modern genetics. However, despite the identification of many disease-causing variants, effective therapies for the majority of inherited cardiomyopathies remains scarce. In this issue, a collection of original research and review articles unveil and summarize the pathogenic mechanisms and gene expression signatures of various inherited cardiomyopathies as well as novel and extant therapeutic strategies in treating selected subsets of inherited cardiomyopathies.Hilal et al. which discusses in detail how mutations in RAS genes underlie phenotypically diverse cardiomyopathies in addition to distinct systemic syndromology. Notably, one must cautiously distinguish cardiomyocyte-intrinsic from extrinsic effects of RAS hyperactivation. While several in vitro studies demonstrated that ectopic RAS activation results in cardiomyocyte hypertrophy, cardiomyocyte-specific expression of gain-of-function RAS variants did not result in HCM despite cardiomyocyte hypertrophy seen in neonatal mice carrying the same germline mutation in the RAS gene , represents a major co-morbidity of genetic hemochromatosis as well as secondary iron overload. A recent clinical trial demonstrated that amlodipine and chelation combination therapy significantly lowers intracardiomyocyte iron deposition. Mechanistically, amlodipine appears to block the L-type calcium channel, which otherwise provides a major route for iron entry into the cardiomyocyte. Over the past decades, the identification of genes in which pathogenic variants are associated with inherited cardiomyopathies has raised expectations for new therapies. Advances in genomic editing technology hold promise for directly targeting pathogenic variants, and have the potential for shifting the paradigm for treatment in genetic medicine. Other approaches harnessing natural genetic modifying mechanisms that suppress the penetrance of pathogenic variants may also be useful. While the incomplete penetrance of inherited cardiomyopathies often complicates the genetic evaluations of families with cardiomyopathies, the observation that many mutation carriers remain disease free in fact provides paradoxical hope that disease-modifying therapeutics may be achievable. Future omics studies comparing transcriptome and proteome between clinically active and silent mutation carriers may thus uncover novel therapeutic approaches to delaying disease onset. In parallel, development of additional genetic animal models that approximate human cardiomyopathies will enable rigorous mechanistic studies that potentiate development of therapeutic agents."} +{"text": "Structural valve deterioration is commonly defined as an intrinsic permanent change of the bioprosthesis due to leaflet calcification, thickening, pannus formation, tear, or disruption. The resulting deterioration leads to stenosis and/or intra-prosthetic regurgitation. Here we present the case of a 75-year-old patient who underwent aortic valve replacement with a bioprosthetic valve. Predischarge transthoracic echocardiography revealed an aortic prosthesis with normal gradients. Three years later, the patient reported exertional dyspnea. Transthoracic echocardiography was performed and showed a high transvalvular pressure gradient of 80 mmhg with restricted mobility of the leaflet caused by subprosthetic tissue. Redo aortic valve replacement was planned and surgical resection was performed showing pannus ingrowth in both aortic and ventricular side of the bioprosthesis."} +{"text": "We also do not understand how suicide and suicidal ideation changed for different Hispanic immigrant populations since 2015, coinciding with a rise in anti-immigrant political sentiment and policymaking. Without action to either improve public health surveillance or leverage existing data sources with immigration status information to better understand the burden of suicide death and suicide risks among Hispanic immigrants, we may fail to prevent unnecessary loss of life.,,Anti-immigrant attitudes are not a new phenomenon in the U.S.,A key example of these policies was the administration's highly publicized public charge rule changes, which built upon the public charge standard developed through the Illegal Immigration Reform and Immigrant Responsibility Act.,Unfavorable immigration policy has been linked to greater perceived health problems among adults and children.,Despite these risks, deportation fears and the chilling effects of anti-immigrant attitudes and policies likely discouraged enrollment into health insurance programs ,Avoiding care while facing discrimination or psychological trauma can be problematic for suicide prevention. Discrimination is a risk factor for mental health problems among Hispanic persons.In response, public health researchers have an opportunity to increase their understanding of the burden of suicide among Hispanic immigrant populations in relation to the rise of anti-immigrant sentiment. This remains a challenging task when national mental health and suicide statistics do not take immigration status into account, when commonly available data sources restrict access to information about visa status, and when data from the Centers for Disease Control and Prevention do not distinguish between immigrants and U.S.-born Hispanics.Many researchers have attempted to account for immigration status in their studies\u2015cutting across multiple disciplines\u2015although these attempts have been discordant, resulting in different definitions and experiences of unauthorized legal status.Specific actions can be taken while being mindful of stigma-related implementation concerns. First, rather than actively seeking information from Hispanic immigrants, we can prioritize efforts to report deceased immigrants\u2019 citizenship status on either the U.S. Standard Certificate of Death or equivalent state-level forms. Specifically, citizenship status, available by contacting Citizenship and Immigration Services, could feasibly be collected by the medical certifier or funeral director when collecting demographic data required for the death certificate. This information would then be reported into state violent death report systems, which already aggregate deidentified information on country of birth and other sensitive characteristics for suicide decedents.Second, additional initiatives could include collecting citizenship information for immigrants participating in large health surveys. Previous studies suggest that unauthorized immigrants are interested in and willing to discuss legal status in research. To ease the impact of the deportation-related concerns on unauthorized immigrant participation, surveyors should build rapport before presenting legal status questionsThird, the research community can use existing data in creative ways to better understand suicide-related risks experienced by Hispanic immigrants. Data sources collecting citizenship or country of birth information, such as the National Health Interview Survey or Hispanic Community Health/Study of Latinos, respectively, can be used to estimate the relationships between immigration status and important suicide risk factors for Hispanic populations since 2015. Existing data sources can also give us guidance on how to estimate the impact of recent immigration policies on suicide risk factors such as mental health outcomes.We do not fully understand the burden of suicide or recent changes in suicidal ideation among Hispanic immigrant populations in the U.S. However, we hypothesize that increasingly acrimonious immigration attitudes and policies likely worsened suicide-related outcomes for many Hispanic immigrants, authorized and unauthorized. The coronavirus disease 2019 (COVID-19) pandemic is likely intensifying suicide-related risks, given the harmful impacts the pandemic has imposed on Hispanic communities."} +{"text": "The United States Department of Health and Human Services (HHS) pledged $90 million to help reduce health disparities with data-driven solutions. The funds are being distributed to 1400 community health centers, serving over 30 million Americans. Given these developments, our piece examines the reasons behind the delayed adoption of big data for healthcare equity, recent efforts embracing big data tools, and methods to maximize potential without overburdening physicians. We additionally propose a public database for anonymized patient data, introducing diverse metrics and equitable data collection strategies, providing valuable insights for policymakers and health systems to better serve communities. This sum is planned to be distributed to 1400 community health centers (CHCs) serving over 30 million Americans1. Specifically, this pledge will allow health centers to expand analytics and reporting capabilities to enhance healthcare services while supporting patient-level UDS+ data submissions to collect more precise data on health disparities2. We herein propose a national public database featuring voluntarily self-disclosed and deidentified patient data to increase the granularity of health disparities metrics, and propose how this project can incorporate diverse metrics and equitable data collection procedures.In April 2022, Health and Human Services (HHS) pledged 90 million USD to the American Rescue Plan Uniform Data System Patient-Level Submission (ARP-UDS+) funding award in support of new data-driven efforts for Health Resources and Services Administration (HRSA) Health Center Programs to identify and reduce health disparities3. The NHQR is a comprehensive review of American healthcare comparing health outcomes across both state and national levels4. This report revealed that, although communities of color have enjoyed increased healthcare access since 2000, racial inequity persisted in 2021 due to lack of focused interventions addressing disparities3. While CHCs disproportionately serve marginalized populations, their lack of granular data collection is likely leading to underestimations of health disparities in areas requiring the greatest resource support4.Big data has already been proposed to promote health equity at the federal level. For instance, in 2021, the Agency for Healthcare Research and Quality (AHRQ) released the National Healthcare Quality and Disparities Report (NHQR)4. For instance, the Community Health Needs Assessment (CHNA) in the Patient Protection and Affordable Care Act (ACA) requires CHCs to investigate the biggest health-related challenges in their communities and outline solutions5. However, CHNAs often lack subjective data like medical trust and are only collected periodically, producing an unnecessary lag time between when systemic health issues arise and when healthcare providers can identify and respond to them.Big data has impacted patient care for decades by helping health insurance companies incentivize preventative care among patients and physicians, ultimately decreasing the use of costly acute care and improving care equity4. This platform can also be used to monitor medications while empowering CHCs to pinpoint and respond to systemic issues more quickly. Although the database may be skewed towards higher-income individuals with more time to self-report, the resource can help compare assess healthcare quality without overburdening physicians, ultimately improving equity interventions.Given these challenges with current healthcare metrics, the Centers for Medicare and Medicaid Services (CMS) should develop a national database like the CDC\u2019s Vaccine Adverse Event Reporting System (VAERS), which collects self-reported issues with vaccine reactions, to regularly collect self-reported data on symptoms, diseases, adverse reactions, medical trust, and perceptions of health equity through metrics like transportation time or food insecurity6. These metrics were only introduced to eight of these measurements, and that only in 20226. HEDIS also does not stratify metrics by other determinants of health like food insecurity or employment status6. Metrics for further development could also include language access, transportation barriers, and health literacy.Although the data would be self-reported, the requested data should include many new metrics. For instance, the National Committee for Quality Assurance (NCQA) Healthcare Effectiveness Data and Information Set (HEDIS), the basis for many equity measurement systems, HEDIS was inaugurated in 1991 and continued for 31 years without race or ethnicity included in its nearly one hundred performance measures7. CHCs can also assess the readability of patient education materials and track the effectiveness of health literacy interventions like counseling, visual aids, staff training on health literacy communication, and simplified language in educational pamphlets through validated health literacy screening tools like REALM-SF (Rapid Estimate of Adult Literacy in Medicine - Short Form)8. REALM-SF examines abilities to read aloud medical terminology and is available free for download on the National Center for Education Statistics (NCES) website9.Healthcare organizations can better understand language barriers by offering patient surveys after each visit. Depending on the extent of the issue, Community Health Centers (CHCs) can then adopt interpreter services and track its effectiveness through surveys. To address transportation barriers, patients can opt to disclose transportation service use and reasons for missed appointments. CHCs can then partner with transportation providers like Uber WAV (Wheelchair Accessible Vehicles) and Uber Health to improve patient accessibility and cover for deficiencies in available wheelchair-accessible vehicles11.To ensure that the system captures data from marginalized populations, we propose CHCs invest in technology infrastructure and staff training to prepare for more comprehensive data collection by, for instance, leveraging telehealth services to provide care management while streamlining data collection through remote patient monitoring and automated post-checkup surveys. Then, outside partnerships with research organizations can help CHCs analyze this data and devise tailored solutions through partnerships with relevant nonprofits like the National Partnership for Women and Families, which has developed best practices for patient engagement in healthcare, and Leapfrog, which helps analyze data to promote healthcare safety and qualityFurthermore, to promote interoperability with electronic health records, we suggest following the technical standards developed by organizations such as the Office of the National Coordinator for Health Information Technology (ONC) and the Health Level Seven International (HL7) organization. These standards ensure that data can be exchanged seamlessly between different healthcare systems while safeguarding self-reported data. We also recommend consulting with the ONC\u2019s Trusted Exchange Framework and Common Agreement (TEFCA) to help establish policies for securely exchanging health information across organizations.However, marginalized groups must be involved in the design of this database. They could provide input on how to create a user-friendly interface with icons instead of words on buttons to accommodate those with low literacy or limited technological proficiency. The database should also collect data on the widest possible range of demographic factors; provide technical support through online tutorials or help desks staffed by technical support personnel; establish robust privacy policies like strict data access controls, encryption protocols, and other technical safeguards; and implement data quality controls, like automated data validation checks; and seamlessly deliver the data to researchers and policymakers through data dashboards.As big data revolutionizes the world, we must not forget its potential impact on improving health outcomes and disparities. By investing funds into health centers and hospitals for patient-driven reporting and data collection on race and ethnicity and developing minimum standards for health equity metrics collection and reporting across states, public discourse and media then draw on subsequent patient data analyses to bring greater attention to regional and national healthcare inequities, leading lawmakers to prioritize health equity initiatives and healthcare systems to have a clearer picture of the communities they serve.Further information on research design is available in the Reporting Summary"} +{"text": "In recent years, the advancement in biotechnology has enabled much improvement in quality and outcomes of medicine. These innovations have also drawn great attention in dental research fields. Regenerative medicine such as tissue (bone and tooth) engineering has been a hot topic in oral and craniofacial research for a few decades. Cells, signaling molecules and scaffold materials are three key components of tissue engineering approaches. Almost everyday new bioengineering approaches are proposed and tested for various diseases and treatment in dentistry.Liu et al.). EVs secreted by human gingival MSCs (hGMSC-derived EVs) were shown to promote osteogenesis and neovascularization in vitro and in vivo . The roles of stem cell-derived EVs and non-stem cell-derived EVs in bone tissue regeneration are reviewed . Engineering modified EVs may play important roles in future cell free EV-based bone tissue engineering therapies.Stem cells such as mesenchymal stem cells (MSCs) are multipotent and may differentiate into different cell types for tissue repair and regeneration. However technical issues including phenotype consistency, host immune response and potential tumorigenicity are still not completely resolved. Extracellular vesicles (EVs) originate from cellular endosomes and contain bioactive molecules to target cells by paracrine. It is known that these EVs are one of the major mediators of stem cells leading to their biological effects. MSC-derived EVs (MSC-EVs), instead of MSCs, may be potentially used in tissue repair and regeneration. The current status and future therapeutic applications of MCS-EVs in oral and craniofacial tissue regeneration are discussed in a review . Similarly, nanofibrous scaffold material can be modified to provide better coordinated regenerative endodontic treatment when pulp connective-tissue, dentin formation, revascularization and reinnervation need to be well orchestrated . Silk fibroin nanoparticles were coated with genetically engineered cell membrane overexpressing toll-like receptor 4 and loaded with minocycline hydrochloride. These biomimetic nanoparticles demonstrated excellent targeted antibacterial and immunoregulatory effects in vitro and in vivo (ligature-induced periodontitis mouse model) .A new generation of scaffold materials has been developed for tissue engineering. A multifunctional structurally optimized hydrogel scaffold was designed by integrating polyvinyl alcohol, gelatin, and sodium alginate with aspirin and nano-hydroxyapatite (nHAP). The osteogenic of nHAP and anti-inflammatory function of aspirin were successfully synergized . Targeted delivery of antitumor drugs has been recognized as a promising therapeutic modality to improve treatment efficacy, reduce toxic side effects and inhibit tumor recurrence. A controlled-release of an anti-tumor drug (apatinib) from supramolecular nanovalve-modified mesoporous silica was designed for targeted inhibition of osteosarcoma . This in vitro study showed efficient release of antitumor drug and promising results for future osteosarcoma treatment. Enamel white spot lesions do not have effective yet conservative treatment methods. Synergistic remineralization of enamel white spot lesions was achieved by using mesoporous bioactive glasses loaded with amorphous calcium phosphate, which implies great potential for clinical application .Other advancements in oral disease therapies are also made in recent years. Eldecalcitol, a novel active vitamin D3 analog, was shown to be effective on preventing alveolar bone loss in diabetes-associated periodontitis . Understanding the composition and differences between supragingival plaque biofilm microbes on the surface of fixed prostheses and natural crowns can provide patients with targeted guidance to focus on oral hygiene habits, reduce the risk of periodontal diseases and improve the success rate of fixed prostheses.The microbial composition and structural diversity of supragingival plaque on the surface of fixed prostheses were found to differ from that of normal natural crowns, with relatively high levels of periodontally related pathogens and higher microbial metabolism. The microflora on the surface of all-ceramic crowns was more similar to that of natural crowns than to that of porcelain-fused-to-metal crowns . Through the use of AM technology, personalized implant treatment for individual patients can be achieved.In addition to biotechnology, digital technology has also been applied in oral disease treatment, such as implant therapy. Additive manufacturing (AM) can enable the direct fabrication of customized physical objects with complex shapes, based on computer-aided designs. The applications of AM technologies in oral implantology, including implant surgery and restorative products, was reviewed (With the quick advancement of therapeutic approaches, biotechnology, and bioactive materials, it will not be too long before precision and personalized dentistry become reality."} +{"text": "Background: Older people living in residential aged care facilities frequently experience medicines-related harm. Evidence regarding the perception and practices towards reducing these harms may facilitate the development of customised educational programs for pharmacists providing services in RACFs.Objective: To explore Australian pharmacists\u2019 opinions and practices towards reducing the risk of medicines-related harm in aged care residents.Methods: An online survey was developed based on a literature review, expert opinion, and feedback from pharmacists providing services in RACFs. A web link for the survey was shared via professional pharmacy organisations and social media groups with Australian pharmacists providing services in RACFs.Results: A total of 209 pharmacists participated in the survey. Of these, 76% (n = 158) were residential medication management review embedded pharmacists, and 24% (n = 51) were supply pharmacists for RACFs. Most pharmacists believed that medicines-related harm is common in residents , yet few agreed that pharmacists have enough time to participate in medicines-related harm reduction services . There was a high level of agreement regarding the key risk factors and potential strategies for reducing medicines-related harm in residents.Conclusion: Pharmacists agreed that older residents often experience medicines-related harm, but they did not frequently participate in medicines-related harm reduction services. Initiatives to engage pharmacists in team-based harm reduction services and educate aged care staff regarding safe medication management may improve residents\u2019 safety and health outcomes. Medicines play an integral role in disease management, yet can be associated with significant problems, especially in vulnerable older people . Older pPharmacists are recognised as experts in pharmacotherapy and could potentially prevent medicines-related harm in older people . A pharmPrevious studies in Australian RACFs focused on determining pharmacists\u2019 views towards antibiotic prescribing and moniA cross-sectional national survey was conducted between February 2022 and August 2022. Pharmacists across Australia providing clinical or supply services to RACFs were the target population.An initial draft of the survey was generated based on a literature review, expert opinion, and feedback collected from pharmacists providing services to RACFs. The survey comprised questions on demographics, pharmacists\u2019 extent of agreement with statements regarding medicines-related issues and practice considerations, and perceptions towards risk factors for medicines-related harm and potential strategies for reducing medicines-related harm in aged care residents. Question types included Likert scales and free-text boxes. The face and content validity of the draft questionnaire was determined through a pilot sample of 10 registered pharmacists. Based on feedback, the questionnaire was reviewed to ensure it was easy to understand and complete. It was designed to be completed within 15\u00a0min.\u00ae was shared with pharmacists via Australian pharmacy organisations , Pharmacy Daily (an online publication), and social media groups . An information sheet was on the cover page of the survey to provide general information to the potential study participant, including eligibility such as providing any type of services to RACFs. Completion of the survey was deemed as implied consent. We opted for the \u201cOff\u201d setting under multiple responses in SurveyMonkey\u00ae portal, which prevents the survey from being taken multiple times from the same device. Further, we added an additional note \u201cIf you have already taken this survey, then you do not need to submit it again\u201d on the cover page of the survey to prevent multiple responses from the same pharmacist. All participants who completed the survey were entered in a draw to receive one of two AUD$100 gift cards. All returned questionnaires were reviewed for eligibility and completion.In 2020, the total number of RACFs in Australia was 3,300 . An assuU test for non-parametric numerical variables, were used to compare responses between the RMMR/embedded and supply pharmacists. Many supply pharmacists also provide services as RMMR pharmacist after receiving case-related training and accreditation from the Australian Association of Consultant Pharmacists. The purpose of comparing these groups was to assess the differences in their perceptions and practices towards reducing medicines-related harm among aged care residents. A p-value of <0.05 was used as the level of significance in all analyses.Data analysis was carried out using SPSS and Microsoft Office Excel 2019. The mean \u00b1 standard deviation was used to present normally distributed continuous data. Ordinal or skewed data were presented using the median [interquartile range (IQR)], and frequency (percentage) was used to report categorical variables. The study questionnaire was comprised of four main sections: Perception (13 items), Practices (6 items), Risk Factors (11 items) and Strategies (7 items), and a 5-point Likert scale (1 = Strongly disagree to 5 = Strongly agree) was used. Inferential statistics, such as a chi-square test for categorical and Mann-Whitney Approval was obtained from the Tasmanian Human Research Ethics Committee (Reference: H0026755). We followed the reporting guidelines of the STROBE statement for observational studies .From February to August 2022, 209 pharmacists completed the survey. One hundred and forty-six were RMMR pharmacists and twelve were embedded pharmacists within RACFs; we combined these groups as their roles are relatively similar and distinct from supply pharmacists. The demographics of the pharmacists are detailed in n = 174, 83%) and only half believed that safe medication management is usually practiced in RACFs . Almost all pharmacists agreed regarding the risk factors for medicines-related harm in aged care residents, such as polypharmacy, PIMs, dementia, recent drug changes, shortage of aged care staff, transitions of care, renal impairment, and specific drug use . A minority of respondents agreed that antibiotics and antipsychotics are usually prescribed in appropriate circumstances in older residents.n = 199, 95%). Most pharmacists also agreed that RMMRs prevent medicines-related harm , although only 62% of the RMMR/embedded pharmacists believed that their recommendations during RMMRs were typically accepted by general practitioners. Most pharmacists, particularly within the RMMR/embedded pharmacist group, agreed that aged care management personnel consider pharmacists\u2019 suggestions for reducing medicines-related harm in residents , but few agreed that pharmacists have enough time to participate in medicines-related harm reduction services .As with risk factors, the pharmacists displayed high agreement regarding potential strategies for reducing medicines-related harm in aged care residents. Enhancing collaboration between pharmacists and aged care staff was acknowledged by almost all pharmacists as a key strategy to reduce this harm in older residents ; this was lower for supply pharmacists (29%) relative to the RMMR/embedded pharmacists (60%). Also, a significantly lower proportion of the supply pharmacists reported that they were familiar with medication appropriateness tools and routinely utilised these tools. Overall, very few supply pharmacists participated in harm reduction services, reported adverse drug reactions to the Australian Therapeutic Goods Administration, and utilised tools to predict the risk of medicines-related harm. There was a large difference in the proportions of supply and RMMR/embedded pharmacists who agreed that supply pharmacists detect medicines-related harms whilst supplying medicines. Most pharmacists indicated that they routinely recommend deprescribing interventions ; this was lower for supply pharmacists (47%) relative to the RMMR/embedded pharmacists (92%).Only half of the pharmacists indicated that they routinely participate in harm reduction services (The role of pharmacists in aged care is evolving globally and may be critical in reducing the incidence of medicines-related injury in aged care residents . KnowingMost pharmacists agreed that medicines-related harm is highly prevalent in residents. Aged care residents take many medicines for their multiple morbidities, and it is a responsibility of all stakeholders involved in managing older residents to ensure the safe medication management . All staPharmacists believed that older residents frequently experience medicines-related harm due to factors such as polypharmacy, PIMs, anticholinergic drug use and multi-morbidity. They believed increased collaboration between pharmacists and aged care staff would reduce these harms. The 2021 Australian Aged Care Royal Commission report recommended increased communication and collaboration between aged care staff and other healthcare professionals, such as general practitioners and pharmacists providing services in RACFs . In New Relatively few pharmacists in our study agreed that antibiotics and antipsychotics are frequently prescribed in appropriate circumstances in Australian aged care residents. The RedUSe intervention, comprising multidisciplinary case review, provision of education to the staff, and audit and feedback, has recently been introduced in RACFs to reduce inappropriate antipsychotic prescribing . AntibioMost RMMR/embedded pharmacists believed that supply pharmacists do not usually identify medicines-related injury whilst supplying medicines. Many supply pharmacists in our study were not familiar with tools, such as the Beers criteria and anticholinergic drug burden scale, to predict the risk of medicines-related harm in aged care residents. In addition, very few supply pharmacists regularly utilised these tools or routinely engaged in harm reduction services. Similarly, a Malaysian study reported that only 27% of community pharmacists were familiar with Beers criteria and 17% frequently used this tool in practice . Educativia supplying medicines and consultancy, and these roles are executed remotely or in a visiting capacity (In Australia, pharmacists usually provide services in RACFs capacity . There icapacity . Embeddecapacity . In 2023capacity . A recencapacity .This study is the first of its kind that explored the perceptions and practices of Australian pharmacists providing services in RACFs towards reducing the risk of medicines-related injury in residents. One of the key study limitations was that the recommended sample size was not reached, indicating that these findings may not be representative of the entire group of Australian pharmacists providing services for aged care residents.Pharmacists agreed that aged care residents frequently experience medicines-related harm, but their involvement in medicines-related harm reduction services was relatively limited. Initiatives to engage pharmacists in harm reduction services and educate aged care staff regarding safe medication management may improve residents\u2019 health outcomes. Medicines use in aged care residents can be optimised by the presence of embedded pharmacists in a team environment, provision of education to aged care personnel, and collaborative medication reviews with general practitioners. Ideally, supply pharmacists would also play a greater role in accepting responsibility for the risks posed by the medicines they provide to RACFs. Future research is needed to assess the impact of educating aged care staff about safe medication management on residents\u2019 health outcomes."} +{"text": "Elevated peripheral inflammation is common in psychosis. Impairments in general cognition were linked to elevated C-reactive protein (CRP) and other inflammatory markers in patients with psychotic disorders. Whether there is a subgroup of persons with elevated peripheral inflammation demonstrating deficits in specific cognitive domains remains unclear. While molecular underpinnings of altered inflammation in psychosis are hypothesized, genetic contributions to relationships of psychosis, inflammation, and cognition have not been clarified. Thirteen peripheral inflammatory markers and 17 neurobehavioral tasks were quantified in a subset of participants from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Principal component analysis resulted in 5 inflammation factors across inflammatory markers. Three latent cognitive domains were characterized based on the neurobehavioral battery. Hierarchical clustering identified a psychosis subgroup with elevated inflammation and worse cognitive performance. Genetic predispositions to schizophrenia and cognition were explored in relation to inflammation. Among persons with psychosis, higher inflammation indices were associated with impairments of Inhibitory Control and Visual Sensorimotor function. Greater deficits in Inhibitory Control were observed in a high inflammation patient subgroup. Consistent with previous studies, global genetic correlations of schizophrenia, CRP, and cognition were observed. Significant bivariate local genetic correlations of CRP with schizophrenia or cognition across 22 loci with several genes in 1 locus on chromosome 3 suggested pleiotropic mechanisms for inflammatory relationships with cognition and psychosis. Specific neurobehavioral domains may be more sensitive to inflammation dysregulation in psychosis as compared to general cognitive function, particularly performance on tasks requiring ongoing behavioral monitoring and control. These, along with evidence of genetic correlations of CRP, psychosis, and cognition, provide further supporting evidence that inflammation dysregulation is an important underlying mechanistic contributor to the disruption of cognition in psychosis. Targeting this dysregulation may be an avenue for novel therapeutics to improve cognitive outcomes in these patients.None Declared"} +{"text": "Migraine is a primary headache disorder recognized by the World Health Organization as one of the most poorly understood and debilitating neurological conditions impacting global disability. Chronic pain disorders are more frequently diagnosed among cisgender women than men, suggesting that female sex hormones could be responsible for mediating chronic pain, including migraine and/or that androgens can be protective. This review discusses the major gonadal hormones, estrogens, progesterone, and testosterone in the context of molecular mechanisms by which they play a role in migraine pathophysiology. In addition, the literature to date describing roles of minor sex hormones including prolactin, luteinizing hormone, follicular stimulating hormone, and gonadotropin releasing hormone in migraine are presented. Because transgender and gender non-conforming (trans*) individuals are an underserved patient population in which gender-affirming sex hormone replacement therapy (HRT) is often medically necessary to align biological sex with gender identity, results from cisgender patient populations are discussed in the context of these major and minor sex hormones on migraine incidence and management in trans* patients. Migraine headaches are diagnosed based upon attack frequency and aura. When headache symptoms are present for at least three months, episodic migraine is defined as 0\u201314 headache days per month while chronic migraine requires 15 or more headache days . The phy1.2.Cortical spreading depression is defined as the spreading of a slowly propagating wave of cellular depolarization and inhibition within neuronal and glial cells across the cerebral cortex. A large change in the concentration gradient between extracellular potassium and intracellular sodium/calcium ions produces a depression of electrocortical signals that travels anteriorly at a rate of 3\u20136\u2005mm/min , 6. In aPreliminary research on the possible involvement of CGRP in migraine found that patients experienced elevated CGRP levels during the interictal phase when headache symptoms were absent ; furtherGiven that trigeminovascular neurons have intrinsic projections to the cerebrovascular system, cortical hyperexcitability induced within central neurons activates and amplifies the underlying vascular processes that sustain migraine headache. The current neurovascular understanding of migraine suggests that neurological processes are necessary to alter trigeminal activity . Clinica1.3.Migraine is more commonly diagnosed with a higher rate of disability in cisgender women than men , 21. AltResearch on sex differences usually refers to the hormonal differences between female sex hormones and male sex hormones , but the correlation between migraine and menstrual sex hormone fluctuations reveals that the physiological concentration as well as the type of sex hormone is critical for headache pain. The human menstrual cycle typically lasts 28 days and is divided into two stages: the follicular and luteal phase. In the follicular phase, progesterone levels remain low while estradiol steadily increases. Ovulation then triggers a sharp decline in estradiol simultaneous with rising progesterone levels; when progesterone peaks halfway through the luteal phase, estradiol remains slightly elevated until both hormones drop back down to baseline , Figure\u00a0Sex hormones are lipid signaling messengers that can enact long-lasting effects on neurovascular structure and function. To provide more comprehensive treatment for cisgender women/men and to expand the much-needed area of research on chronic conditions within transgender/gender non-conforming (shortened to trans* as a gender-inclusive umbrella term) patients who receive gender-affirming sex hormone replacement therapy (HRT), a comprehensive analysis on the impact of hormonal fluctuations in migraine-related pathological processes and on nociceptive processing is required. This review will first examine pre-existing, chronic pain-related health disparities among trans* patients to determine current healthcare needs regarding pain management and migraine headache. The medical necessity of gender-affirming treatment and current barriers to healthcare access will then be integrated to emphasize that gender affirmation is critical to reestablish important health measures\u2014such as patient self-efficacy and trust in the healthcare system\u2014that will grant trans* patients with the necessary skills needed to improve pain outcomes. Due to the significant knowledge gap between gender-affirming care and physical health disparities, research on sex hormone activity in migraine pathology will be summarized through cisgender patient data as it pertains to ovarian HRT (estrogen/progesterone) and androgen HRT (testosterone). Further gaps in knowledge and future research directions will be identified as needed to improve healthcare practice and to continue gender-affirming healthcare for LGBTQ\u2009+\u2009patients.2.2.1.When explicitly examining sex differences in primary headache, cisgender women report a higher migraine prevalence of 18% compared to 6% among men , whereas2.2.Estrogen is categorized as a \u201cfemale\u201d sex hormone synthesized within the ovaries to induce female sexual maturity; however, this simplification fails to consider the role of estrogen in male physiology as well as on other biological systems in cisgender women. Estrogen incorporates three hormones that have different functions based on the stage of female reproduction: estradiol is the main hormone that is sustained over a woman's lifespan while estrone and estriol are weaker forms that become dominant during menopause and pregnancy, respectively . EstrogeThe high prevalence of disabling migraine features among cisgender women implies that fluctuating levels of estrogen are critical for migraine development, but assumptions based on female physiology and the effects of hormonal signaling currently restrain the understanding of migraine to a system primed for estrogen. The difference in prevalence between migraine with aura during high estrogen and migraine without aura during estrogen withdrawal suggests that in addition to promoting migraine mechanisms, higher levels of estrogen increase CSD susceptibility and encourage significant headache-related disability through neurovascular dysfunction. Headache studies conducted using animal models demonstrated that female mice have intrinsically lower CSD thresholds than male mice , but wheGiven that CSD could be an initiating mechanism of migraine in patients, increased CSD susceptibility from female hormones indicates that estrogen has a critical role in triggering migraine wherein higher hormonal concentrations correlate to worse pain outcomes. However, clinical data from both cisgender and trans* patients differentiate the effectiveness of estrogen on male and female physiology. The introduction of estradiol to male physiology enables rapid CSD and central sensitization induction since low levels of pre-existing estrogen are insufficient to dominate testosterone activity, but for patients with female physiology, the developmental role of estrogen for sexual reproduction could require hormones that exceed healthy estradiol concentrations to propagate migraine mechanisms. During Tanner stage IV which occurs after puberty onset, patients with female physiology report estradiol levels between 15 and 85\u2005pg/ml while male patients report a maximum of 38\u2005pg/ml. In adulthood, female patients experience fluctuating levels of estradiol within the range of 15\u2013350\u2005pg/ml that varies according to the menstrual cycle ; during B receptors from the G-protein-coupled receptor attached to potassium ion channels; this suppression of neuronal hyperpolarization lowers activation thresholds because hyperpolarization is necessary to return neuronal activity back to baseline pathway contains several metabolites vital to regulating excitatory and inhibitory signaling in the central nervous system. Kynurenic acid (KYNA) is a competitive antagonist that binds to the glycine site of the GluN1 subunit of NMDA receptors while other metabolites\u2014such as quinolinic acid (QUINA) and xanthurenic acid (XA)\u2014increase cortical excitability as orthosteric agonists that bind to the GluN2A-D subunit of NMDA receptors. QUINA and XA also activate type-2 metabotropic glutamate receptors . MigrainCentral sensitization consists of two critical components: cortical hyperexcitability facilitated through increased glutamate expression and enhanced synaptic efficiency through long-term potentiation; therefore, revealing the contributions of estrogen signaling on both aspects will improve headache pain relief. Clinical studies on migraine sex differences reported that in addition to elevated CGRP, cisgender women also experience fluctuating CGRP expressions within the central and peripheral nervous systems that correspond to estradiol concentrations across the menstrual cycle . EvidencEstradiol signaling seems to have a minimal role in directly perpetuating cerebral vasodilation since a significant portion of endothelial dysfunction and oxidative stress is proportional to the sensitized strength of trigeminal neurotransmission. However, research on the vascular contributions to migraine with sex hormones is still needed to elucidate the full impact of estrogen. In a study that compared plasma concentrations of nitric oxide among cisgender women with either menstrual migraine, non-menstrual migraine, or non-headache controls, enhanced activation of the nitric oxide pathway during the luteal phase leads to increased nitric oxide synthesis that aligns with reports of oxidative stress markers peaking during the late follicular and early luteal phases . EstrogeEstrogen-mediated disruptions in essential biomolecules bolster the efficiency of trigeminal neurotransmission at the cost of regulatory processes that are necessary to prevent excessive cortical hyperexcitability and cerebral vasodilation; therefore, since migraineurs demonstrate higher levels of serotonin (5-HT) during the ictal phase of headache but lower levels during the interictal phase, estrogen could influence the synthesis of neurotransmitters like serotonin . AlthougIn addition to generating intermediate metabolites that destabilize excitatory and inhibitory cortical signaling, the KYN pathway also reduces serum 5-HT levels in migraineurs by metabolizing the amino acid tryptophan into KYN metabolites at the expense of serotonin synthesis. Michael et al. demonstrAn overview of the current understanding of estrogen signaling on neurovascular migraine mechanisms is summarized in 2.3.Although estrogen hormones are incredibly efficient at accumulating dysfunction within the trigeminovascular system, the role of fluctuating progestin hormones with estradiol signaling could clarify gaps in understanding between migraine headache, hormonal states, and pain symptomology. Progesterone has two receptors: progesterone receptor alpha (PR\u03b1) and progesterone receptor beta (PR\u03b2). Although murine models demonstrate higher expressions of one receptor isoform over the other, human cells contain equivalent amounts of PR\u03b1 and PR\u03b2, which suggests that the PR\u03b1-PR\u03b2 heterodimer is the dominant molecular species for humans . Therefo2.4A receptor activity within neurons of the trigeminal nucleus caudalis gene on chromosome 5 encodes three different isoforms: long (PRL-L), intermediate, and short (PRL-S), but only PRL-L and PRL-S will be considered since unlike humans and rats, mice lack intermediate PRL receptors . PRL-L ae models .Prolactin-induced sensitization imitates estradiol neurogenic inflammation by proliferating CGRP release from sensory neurons via the excessive activation of sensitized TRP channels. Although sensory neurons lack PRL, application of TRP channel activators to cultured female sensory neurons pretreated with prolactin resulted in amplified trigeminal neurotransmission due to enhanced calcium ion influx. Within male physiology, prolactin sensitization might require abnormally high concentrations to further support estrogen-mediated sensitization since males have lower PRL-L and PRL-S expressions in the dorsal root ganglion . PRL-S sWhen prolactin is considered alongside androgen and ovarian hormones, pronociceptive headache states fueled by estrogen can recruit prolactin-induced sensitization to further advance chronic pain since estrogen increases PRL receptor expression. Conversely, testosterone suppresses PRL expression to mitigate central sensitization, but since the molecular pathway defining this androgen-mediated phenomenon has yet to be explored, only coinciding interactions between estrogen and prolactin will be discussed. High concentrations of endogenous estrogen within female migraineurs correlate to an increase in PRL receptor mRNA in dorsal root ganglion neurons; however, because equal expressions of PRL-S and PRL-L were retained in both sexes regardless of estradiol concentrations, estrogen upregulation of PRL expression occurs independently from receptor isoform translation . ApplicaCRE mice to deduce sex differences in migraine. Prior to experimentation, murine models expressed KORCRE neurons in the dorsomedial/ventromedial hypothalamic nuclei and ARC as well as within tyrosine-hydroxylase-positive cells that were quantified as 80% for female and 70% for male mice. In response to RS, enhanced serum prolactin produced allodynia from latent sensitization in both male and female mice, although females experienced an intrinsically greater increase. When the KOR antagonist nor-binaltorphimine dihydrochloride was applied to the right ARC, serum prolactin was reduced likely due to the synchronized TIDA network axis and reduced efficacy of the kappa-opioid receptor (KOR) system to alleviate trigeminal nociception. Previous clinical studies reported that stress activates the hypothalamus of migraineurs to increase cortisol levels, resulting in a positive correlation between stress-induced priming and chronic headache frequency. Since stress increases prolactin and the endogenous KOR agonist dynorphin, central sensitization could decrease the analgesic efficiency of the KOR signaling pathway such that chronic stress would hinder endogenous recovery from headache . Watanab network . Combinehibition , 81. Furhibition . Howeverhibition . Therefohibition . The mec2.6.2.Luteinizing (LH) and follicle-stimulating (FSH) hormones are synthesized from gonadotropin cells in the anterior pituitary to amplify estrogen synthesis during the menstrual cycle . Several2.6.3.Although the majority of gender-affirming healthcare focuses on medical interventions for trans* adults, trans* youth who wish to postpone the puberty of their assigned sex might receive puberty blockers\u2014which are gonadotropin-releasing hormone (GnRH) agonists such as goserelin, leuprolide, and histrelin\u2014to delay the development of secondary sex characteristics and prevent gender dysphoria\u2014which is defined in the DSM-5 as the \u201cpsychological distress that results from an incongruence between one's sex assigned at birth and one's gender identity\u201d , 89. SexGnRH is synthesized within hypothalamic neurons to regulate LH and FSH concentrations throughout the menstrual cycle; the activation of GnRH G-protein-coupled type I receptors on gonadotrophin cells in the anterior pituitary generates GnRH pulse frequencies wherein low pulses stimulate FSH and high pulses promote LH. Although female migraineurs demonstrated normal FSH/LH levels, dysfunction of the hypothalamic-pituitary-adrenal axis could cause abnormal GnRH pulse frequencies. Research demonstrated that persistent GnRH stimulation produces elevated LH:FSH ratios\u2014amplifying the ovarian synthesis of androgen hormones\u2014while minimal stimulation and abnormal GnRH serum levels were associated with hypothalamic amenorrhea . Despite3.Despite the growing number of trans* patients, healthcare practices have yet to move beyond the perspective that this patient population only engages with the healthcare system to receive gender-affirming medical treatment. Research examining pre-existing health disparities among LGBTQ\u2009+\u2009patients has been recognized as a crucial gap in knowledge ; howeverWhile the exact number of trans* individuals with migraine is unknown, there are an estimated 1.4 million transgender adults and 39 million individuals with migraine in the United States . Based oAlthough this risk of headache could be detrimental for the physical and mental wellbeing of an already vulnerable population, transgender men and gender non-conforming individuals who receive androgen HRT might experience some relief from migraine. Yalinay Dikmen et al. investigFrom the available evidence, estrogen HRT is associated with an increased risk for acquired migraine in transgender women while testosterone HRT could potentially provide some pain relief for transgender men with a pre-existing primary headache disorder. Although data from cisgender migraineurs has supported the role of estrogen in promoting migraine mechanisms, gaps in knowledge remain on the minimum physiological concentration of estrogen required to propagate chronic pain states; given that migraine has been observed during states of estrogen withdrawal and elevation , determining physiological hormone concentrations can clarify the association of sex hormones and migraine symptoms. Consenting trans* patients represent the ideal clinical population to investigate this theory as the natural diversity in gender identity and use of gender-affirming hormones allows researchers to clarify the issue of sex hormone functionality without subjecting cisgender patients to potential unwanted side effects. These individuals are also ideal in furthering progress for LGBTQ\u2009+\u2009health outcomes beyond mental health disorders and sexual diseases because current debates regarding the legality of gender-affirming care already establish the immediate need for improved LGBTQ\u2009+\u2009healthcare and better understanding on the long-term effects of HRT. Treatment of headache for cisgender patients can also be improved through trans* data by reframing the consideration of health with gender identity; notably, by replacing binary sex as a health factor with measures of serum sex hormone levels, mechanisms involved in chronic pain pathology can improve the accuracy of disease diagnosis and treatment as well as support pain outcomes hindered by sexist gender stereotypes.4.Despite limited data in trans* individuals with migraine, cisgender data suggests that femininizing estradiol HRT increases the risk for acquired headache and chronic pain while masculinizing testosterone HRT is associated with improved pain relief for patients with a pre-existing headache disorder. Future studies are needed to directly evaluate the risk between gender-affirming HRT and migraine. Ovarian hormones like estrogen and progesterone promote migraine headache via CSD and central sensitization within the trigeminal nociceptive network through reactive species, CGRP, and an imbalance of excitatory/inhibitory neurotransmission while androgens like testosterone attempt to reduce excessive cortical hyperexcitability by bolstering neuroprotective and analgesic qualities. When the effects of sex hormones in cisgender and trans* patients are examined together, rapid sex hormone fluctuations create vulnerabilities through which heightened estrogen induces pronociceptive states and reduced testosterone fails to adequately establish trigeminal neuroprotection. Since many trans* individuals begin HRT when patients are already well into adulthood, pubertal hormones likely establish migraine susceptibility that can be aggravated further by estrogen HRT, thus putting transgender women at the most risk. Susceptibility could be curtailed through pubertal suppression and treatment with puberty blockers, but the same limitations currently impacting adult gender-affirming care also affect trans* youth, maybe even more so due to debates on parental rights to oversee the healthcare decisions of their children. Given the changing landscape of trans* patients seeking gender-affirming healthcare, more investigation into sex hormones on migraine pathology is warranted to determine the impact of gender-affirming HRT and potential chronic pain risk.Research on LGBTQ\u2009+\u2009healthcare has largely focused on educating medical providers about the appropriate terminology to improve interpersonal interactions between patients and providers , 99. How"} +{"text": "Antibiotic resistance stands as one of the most significant public health challenges in recent decades. FEM proteins are responsible for the synthesisof pentaglycine cross-bridge, a primary constituent of bacterial peptidoglycan polymer crosslinking during cell wall biosynthesis. Since they are necessaryfor bacterial survival and antibiotic resistance, they were considered as significant antibacterial targets. We report herein, the virtual screening andselection of FDA-approved drugs and their potent similar molecules as FEM protein inhibitors and analyzed for inhibiting affinity and their ADMET pharmacokineticproperties. This data provide a foundation for the development and optimization of structurally innovative antimicrobial drugs. Staphylococcus aureus causes a wide spectrum of common ailments that can be acquired from the community and in hospitals. Due tolower responsiveness to commercially available drugs, the rise of Methicillin-resistant Staphylococcus aureus (MRSA) clinical isolateshas increased and evolved into various multi-drug resistant strains making the treatment difficult. The foreign expression of altered PBP2a performs the host PBPfunction and governs the strategy of \u03b2-lactam antibiotic resistance in methicillin-resistant S. aureus (MRSA)amino]-3-methylpyridin-2-yl]benzoic acid (PubChem ID: 90080139) against FemX with highest binding energy of -137.66 among all by forming a Pi-sulfur and Pi-alkylinteraction with TYR320, 377 and MET196. The whole complex has involved many hydrogen bonding with several residues listed in active site amino acids of theFemX receptor .In addiinvitro evaluations.For the first time this manuscript reported the FemB inhibitors from FDA approved drug molecules, which can be possibly repurposed.An overview of selected chemical molecules and clinical features with pharmacokinetic properties were analyzed using the pkCSM webserver and labeled ininvitro results. In this work, we virtually examined a library of FDA-authorized drugs from ZINC15 and DrugBank databases againstS. aureus FEM proteins. Three lead molecules were shortlisted based on their docking scores and prioritized based on their minimum bindingenergy and active interactions with the FEM proteins. In this study, we also evaluated the molecules solubility and toxicity properties.The limited therapeutic spectrum against MRSA necessitates an urgent development of antibiotics and medications to enhance the current antibiotic efficacyand drugs to enhance the existing antibiotic efficacy. We report the optimal binding features of structure-based FDA-approved drugs repurposed to treat MRSApathogenic infections. It helps to cross the emergence by following certain time limit management in collaboration with certain existingThe authors declare that they have no known competing interests (or) personal relationships that could have appeared to influence the work reported in thismanuscript. The research leading to these results received funding from the DST-SERB-ECR grant under file no: ECR/2017/003381."} +{"text": "Pain generator-based lumbar spinal decompression surgery is the backbone of modern spine care. In contrast to traditional image-based medical necessity criteria for spinal surgery, assessing the severity of neural element encroachment, instability, and deformity, staged management of common painful degenerative lumbar spine conditions is likely to be more durable and cost-effective. Targeting validated pain generators can be accomplished with simplified decompression procedures associated with lower perioperative complications and long-term revision rates. In this perspective article, the authors summarize the current concepts of successful management of spinal stenosis patients with modern transforaminal endoscopic and translaminar minimally invasive spinal surgery techniques. They represent the consensus statements of 14 international surgeon societies, who have worked in collaborative teams in an open peer-review model based on a systematic review of the existing literature and grading the strength of its clinical evidence. The authors found that personalized clinical care protocols for lumbar spinal stenosis rooted in validated pain generators can successfully treat most patients with sciatica-type back and leg pain including those who fail to meet traditional image-based medical necessity criteria for surgery since nearly half of the surgically treated pain generators are not shown on the preoperative MRI scan. Common pain generators in the lumbar spine include (a) an inflamed disc, (b) an inflamed nerve, (c) a hypervascular scar, (d) a hypertrophied superior articular process (SAP) and ligamentum flavum, (e) a tender capsule, (f) an impacting facet margin, (g) a superior foraminal facet osteophyte and cyst, (h) a superior foraminal ligament impingement, (i) a hidden shoulder osteophyte. The position of the key opinion authors of the perspective article is that further clinical research will continue to validate pain generator-based treatment protocols for lumbar spinal stenosis. The endoscopic technology platform enables spine surgeons to directly visualize pain generators, forming the basis for more simplified targeted surgical pain management therapies. Limitations of this care model are dictated by appropriate patient selection and mastering the learning curve of modern MIS procedures. Decompensated deformity and instability will likely continue to be treated with open corrective surgery. Vertically integrated outpatient spine care programs are the most suitable setting for executing such pain generator-focused programs. Lumbar spinal stenosis (LSS) is defined as a narrowing of the lumbar spinal canal caused by age-related degeneration of the spinal motion segment. It causes encroachment of neural elements and may contribute to back and leg pain. It is a leading cause of disability from lack of mobility due to neurogenic claudication worldwide . Spinal Spondylolisthesis and decoIn this review perspective article, the authors take a fresh, consensus look at the available evidence including their own professional expertise and experiences on using minimally invasive and endoscopic lumbar decompression techniques in a more targeted and personalized care model. 14 professional societies reviewed recent articles on the topic and through their related committees and subcommittees express their professional position. This perspective paper is coordinated by the Interamerican Society For Minimally Invasive Spine Surgery\u2013La Sociedad Interamericana de Cirug\u00eda de Columna M\u00ednimamente Invasiva (SICCMI) and the Spine Subcommittee of the Society For Brain Mapping & Therapeutics (SBMT), and endorsed by the International Society For Minimal Intervention In Spinal Surgery (ISMISS), the Korean Minimally Invasive Spine Society (KOMISS), the Minimally Invasive Surgery Section of the Chinese Orthopaedic Association (COA-MIS SECTION), The Colombian Spine Society, the Bolivian Spine Association, the Iberolatinoamerican Spine Society\u2013La Sociedad Iberolatinoamericana de Columna (SILACO), the Mexican Association of Spinal Surgeons\u2013Associacion Mexicana de Cirujanos de Columna (AMCICO), the Federation of Latinamerican Neurosurgical Societies\u2013Federaci\u00f3n Latino-Americana de Sociedades de Neurocirug\u00eda (FLANC), the Latin American Society of Neurosurgeons of USA & Canada (SLANC), the Brazilian Spine Society\u2013Sociedade Brasiliiera de Columna (SBC), the Brazilian Society For Thoracic Surgery\u2014Sociedade Brasileira de Cirurgia Tor\u00e1cica (SBCT), and the International Intradiscal Therapy Society (IITS).The annual incidence of adult spine disease is estimated at 266 million people globally . The higIn the 2010 Global Burden of Disease (GBD) Study ,23, LBP Most contemporary medical necessity criteria for spinal decompression are based on analyzing advanced imaging studies such as MRI or CT. Using these image-based criteria reserves decompression surgery only for patients with progressive disease ,38,39,40Whoever does not fit these medical necessity criteria is often committed to repetitive cycles of spinal injections, physical therapy, and non-steroidal anti-inflammatory treatments. Those who are so disabled that they cannot even participate in these programs in a meaningful way or have poorly controlled co-morbidities which preclude medical management often cannot get much help. An exemplary summary of traditional Review Clinical Guidelines For Spinal Stenosis affecting coverage decisions is shown in In this perspective paper, SICCMI, in collaboration with 12 other international surgeons\u2019 societies, is confronting the increased scrutiny on the appropriateness of spine care spending by payers, government, and patients in an attempt to deliver on simplified, innovative, less costly, more effective, and more durable treatments for common degenerative and painful spine conditions associated with lower complication and revision rates. Resolution to these problems is needed to meet the increasing demand by the aging baby-boomer population for such simplified treatments.The treatment of the painful degenerative disease process of the spinal motion segment with traditional open spine surgery is dictated by the application of MRI and CT image criteria of spinal stenosis, instability, and deformity. The clinical decision-making for surgery focuses on treating the end-stage of the disease, leaving many patients without timely treatment or no treatment at all. With the backdrop of recent clinical studies describing the limited utility of the lumbar MRI scan and its reporting suffering from relatively low sensitivity and specificity to diagnose the painful spine condition , key opiTraditional open spine surgery in the lumbar spine includes laminectomy. A translaminar decompression is performed by removing the posterior spinal elements, including the spinous process, the lamina, and part of the bilateral facet joints. The benefit of lumbar decompression for symptomatic herniated disc and spinal stenosis has been demonstrated in several prospective randomized clinical trials, including the original study by Weber , the MaiMinimally invasive surgery (MIS) for the treatment of common degenerative conditions of the spine is increasingly practiced. It encompasses a portfolio of surgical techniques that are aimed to alleviate patients\u2019 pain via reduced surgical access resulting in less blood loss and reduced peri- and postoperative problems including pain, nausea, and vomiting. The introduction of tubular retractors and microsurgical dissection techniques simplified the very nature of spine surgery by transforming it through the implementation of less burdensome and more simplified protocols. Over the last 40 years, open spine surgery has established a track record that is interpreted by most patients, employers, and payers as aggressive and too costly due to high out-of-work complications and reoperation rates.Quality of life and cost-effectiveness of minimally invasive surgery (MIS) for spinal stenosis in patients with degenerative lumbar spondylolisthesis (DLS) has been calculated relative to failed medical management and compared to the cost-effectiveness of hip and knee arthroplasty for matched cohorts of patients with osteoarthritis . IncremeSelect pain generators in the lumbar spine are not diagnosed on routine lumbar MRI scan . A recenCommon pain generators in the lumbar spine include (a) an inflamed disc, (b) an inflamed nerve, (c) a hypervascular scar, (d) a hypertrophied superior articular process (SAP) and ligamentum flavum, (e) a tender capsule, (f) an impacting facet margin, (g) a superior foraminal facet osteophyte, (h) a superior foraminal ligament impingement, (i) a hidden shoulder osteophyte, and many others examples, as shown in One example is highlighted by the INTRACEPT prospective, open-label, 1:1 randomized controlled trial. This trial tests the efficacy of basivertebral nerve (BVN) ablation technology compared to a standard care control treatment of vertebrogenic chronic low back pain . ConceptThe authors take the position that direct visualization and treatment of pain generators is the foundation for surgical pain management of the lumbar spine. Spinal endoscopy enables the surgeon to diagnose and treat the painful condition during the same operation ,66,67,68Objective measurements of the foraminal or lateral canal dimensions are rarely given. Surgical stenosis classifications use measurable parameters such as height and width of the posterior disc, lateral recess, or neuroforamen to stratify patients for the most appropriate MIS approach and technique . The lacTreating pain generators involves identifying those structural problems in the lumbar spine that cause the majority of the patient\u2019s symptoms as implicated in the symptoms by history and physical examination or by advanced imaging studies such as MRI or CT scan. Most patients have unilateral or mono-segmental radiculopathy symptoms. When confirmed with diagnostic selective nerve root blocks, these clinical observations highlight that many structural changes in a degenerative spine are multilevel but may not be painful, even if the MRI or CT scan suggests a similar degree of stenosis as within the symptomatic spinal motion segment. For example, exiting and traversing nerve root pain syndromes may or may not exist within the same lumbar motion segment simultaneously. However, when they do, the surgeon can easily be confused with patients whose MRI suggests multilevel disease. Identifying the correct source level of axial facet joint pain in multilevel degeneration may even be more difficult without a radicular component. The staged management concept is the central element of the clinical spine care model. It implies treating validated symptomatic pain generators and ignoring all degenerative changes or injuries that do not hurt.While it is easier to rely on MRI-based criteria of compression, instability, and deformity when deducting a plan of surgical care\u2014certainly within the mainstream of traditionally trained surgeons, and perhaps a coincidence between the radiologist\u2019s confirmation of compressive pathology and the surgical plan of care invites less scrutiny during the health insurance preauthorization process for surgery\u2014identifying the predominant pain generator can be a daunting task. Recommending a targeted surgical treatment plan to a patient in pain is as much of an art as it is a science and relies heavily on judgment and clinical experience. Less aggressive treatment recommendations are often sufficient to substantially reduce pain, all while ignoring traditional decompression and lumbar fusion criteria.What to treat and, more importantly, what to ignore requires attention to detail and utilization of preoperative diagnostic tools of high positive predictive value. For the endoscopic spine surgeon, the plan of care is derived from identifying those pain generators that impair the patient the most. Minimizing the risk-taking and maximizing the benefit, all while managing patients\u2019 expectations about the desired outcome, are the key to achieving high patient satisfaction . The staA new subspecialty is emerging: \u201cSurgical Pain Management.\u201d The term implies a blend of diagnostic and patient management strategies employed by interventional pain physicians comprised of physiatrists, anesthesiologists, and spine surgeons consisting of orthopedic and neurosurgeons. This new emerging subspeciality is a grassroots development driven by enthusiast physicians who invested their careers into a more personalized approach to spine care. Thus, surgical pain management integrates needle-based non-visualized interventions into MIS and endoscopic surgical procedures by tailoring the treatment based on the individual patient\u2019s symptoms and the functional context when the spine care is delivered. Examples of this development include the integration of radiofrequency and laser into endoscopic surgeries. The continued use of rule-based medical necessity criteria for lumbar spine care seems increasingly inappropriate. It invites the delivery of costly, ineffective therapies and treatments which ultimately do not lower the societal burden of spine care. Ignoring individual pain generators stemming from the underlying disease causing cumulative disability does not address the root cause and precludes the patient from definitive care or leads to patient entrapment in repetitive yet ineffective treatment cycles. In the opinion of the KOL authors of this lead perspective article in the JPM special issue \u201cThe Path To Personalized Pain Management,\u201d the staged approach to surgical pain management is poised to lower disability and the direct and indirect costs with all of its hidden unintended consequences of repetitive treatments. Its implementation has the potential for diminishing the burden of failed medical pain management and opioid addiction, delayed returned to work, and disrupted social reintegration. While the authors do not suggest abandoning traditional open spine surgery, we propose integrating staged surgical pain management of directly visualized pain generators early in the disease process into existing spine care programs.The authors of this perspective paper arrived at the consensus statement on the indications for surgical treatment for symptomatic lumbar spinal stenosis based on validated pain generators rather than traditional image-based medical necessity criteria. This approach to treating patients with claudication and sciatica-type low back and leg symptoms represents the authors\u2019 views and their respective surgeon societies. The most published individuals on this team of authors are accomplished and passionate endoscopic spinal surgeons. In experienced hands, approximately 80% of patients with painful degenerative spine conditions may be treated successfully with a targeted outpatient MIS or endoscopic decompression procedure ,82,83. WJudiciously and skillfully executed modern targeted MIS surgeries can provide more cost-effective and less burdensome spine care with shorter treatment cycles as the underlying structural correlate for the patient\u2019s pain is treated causally. Lateral recess and foraminal stenosis are the most common clinically relevant indications for primary surgery and revision surgery after decompression in the lumbar spine. The personalized clinical protocols for treating lumbar spinal stenosis based on validated pain generators are a break with traditional population management protocols that employ image-based medical necessity criteria for intervention since nearly half of the surgically treated pain generators are not shown on the preoperative MRI scan. Common pain generators in the lumbar spine include (a) an inflamed disc, (b) an inflamed nerve, (c) a hypervascular scar, (d) a hypertrophied superior articular process (SAP) and ligamentum flavum, (e) a tender capsule, (f) an impacting facet margin, (g) a superior foraminal facet osteophyte, (h) a superior foraminal ligament impingement, (i) a hidden shoulder osteophyte. It is the authors position, that further clinical research will continue to validate pain generator-based treatment protocols for lumbar spinal stenosis. The endoscopic technology platform enables spine surgeons to directly visualize pain generators, forming the basis for more simplified targeted surgical pain management therapies. Clinical judgment of appropriate patient selection and mastering the learning curve of modern MIS procedures will likely lead to a broadening of the accepted indications for such a pain generator-based approach to patient care. Limitations of this care model are dictated by decompensated deformity and instability, for which open corrective surgery will likely continue to be the treatment of choice. Vertically integrated outpatient spine care programs are probably the most suitable setting for executing such a pain generator focused program since physicians who have complete custody of their patients can minimize protocol breaches by other providers who are not invested in the personalized care model proposed by the authors."} +{"text": "Epidemics in the Pacific Islands noted flu-like symptoms and complications following human ZIKV infection. However, after a severe outbreak in 2015, Latin American studies reported fetal birth defects with maternal infection but reports in other developing countries where outbreaks occurred were not fully characterized. This study aims to review current reports on birth outcomes associated with maternal ZIKV infection .Zika Virus became an emerging health threat in the early 21This narrative review evaluated birth outcomes of Zika positive pregnant women. Research articles were found using Google Scholar, PubMed, and MEDLINE. The inclusion criteria were publication between 2012 to 2022, availability as full text in English, categorization as original research, meta-analyses or case reports. Exclusion criteria were studies that were part of a book chapter or encyclopedia and studies that cited results from developed nations. The articles were studied and 20 methodologically sound studies were selected for review, and the data was classified in themes based on birth outcomes.18 studies reported that infants born to some laboratory-confirmed zika-positive mothers had abnormal birth outcomes after delivery including microcephaly, stillbirth, neurological abnormalities and hearing loss. Maternal ZIKV infection is associated with an increased risk of abnormal birth outcomes in newborns in developing countries. In the countries of studies that did not report abnormal outcomes there may have been a protective factor from previous maternal Dengue Virus (DENV) infection adding protection for their infants.Overall, there appears a difference in birth outcomes of infants born to mothers infected with ZIKV, however more research is needed on environmental factors and prior arboviral infection as additional factors contributing to these outcomes.All Authors: No reported disclosures"} +{"text": "Spinal cord injury (SCI) disrupts the structural and functional connectivity between the higher center and the spinal cord, resulting in severe motor, sensory, and autonomic dysfunction with a variety of complications. The pathophysiology of SCI is complicated and multifaceted, and thus individual treatments acting on a specific aspect or process are inadequate to elicit neuronal regeneration and functional recovery after SCI. Combinatory strategies targeting multiple aspects of SCI pathology have achieved greater beneficial effects than individual therapy alone. Although many problems and challenges remain, the encouraging outcomes that have been achieved in preclinical models offer a promising foothold for the development of novel clinical strategies to treat SCI. In this review, we characterize the mechanisms underlying axon regeneration of adult neurons and summarize recent advances in facilitating functional recovery following SCI at both the acute and chronic stages. In addition, we analyze the current status, remaining problems, and realistic challenges towards clinical translation. Finally, we consider the future of SCI treatment and provide insights into how to narrow the translational gap that currently exists between preclinical studies and clinical practice. Going forward, clinical trials should emphasize multidisciplinary conversation and cooperation to identify optimal combinatorial approaches to maximize therapeutic benefit in humans with SCI. Spinal cord injury (SCI) leads to long-term dysfunction and lifelong disability. There are hundreds of thousands of new patients suffering an SCI each year worldwide, and ninety percent of these SCIs are caused by traumatic events, including traffic accidents, falling, sports injuries, violence, etc. . SCI intThe pathophysiology of SCI involves primary injury and secondary injury. The primary injury is caused by acute mechanical trauma and results in vascular disruption, blood\u2013spinal cord barrier rupture, cell death , and interruption of neural fiber tracts in the spinal cord. The secondary injury references the consecutive pathological events triggered by the primary injury, such as hemorrhage, excitotoxicity, neuroinflammation, demyelination, astrogliosis and extracellular matrix (ECM) remodeling, which aggravate tissue damage, and compromise neuroplasticity . The curIn this review, we provide an overview of recent advances and challenges in SCI research and treatment. We summarize the recent progress regarding interventions after SCI in preclinical rodent and non-human primate models as well as in the clinical settings. We then discuss the current status and challenges with respect to clinical translation, prospect the future of SCI repair, and we highlight combinatory approaches and multidisciplinary cooperation are imperative to optimize clinical outcomes after SCI. This review provides an update of current strategies following SCI and provide researchers with new insights to develop more effective and targeted interventions to facilitate clinically meaningful recovery after SCI.The originally narrow concept of regeneration referred to the regrowth of transected axons across the lesion core to form functional synapses with their original pre-injury targets after SCI. The broad definition of regeneration now encompasses multiple forms of axon growth, including long-distance axon regrowth, compensatory sprouting of injured and spared supraspinal axons as well as propriospinal neurons, synapse remodeling, and circuit reorganization Fig. 1)Fig. 1). Axon outgrowth is driven by the growth cone, a motile structure located at the tip of the growing axon. Growth cone motility and axon growth are determined by the neuronal cytoskeleton, which includes microtubule and actin filament (F-actin) . MicrotuCytoskeletal dynamics and rearrangements are mainly modulated by two intracellular signaling pathways: glycogen synthase kinase 3\u03b2 (GSK3\u03b2) and Rho GTPases. GSK3\u03b2 is downstream of PI3K signaling and is inactivated through serine-9 phosphorylation within its amino-terminal region upon activation of the PI3K pathway. GSK3\u03b2 has been shown to be a crucial negative regulator of microtubule dynamics by phosphorylating multiple microtubule binding proteins (MBPs), such as collapsin response mediator protein 2 (CRMP-2), adenomatous polyposis coli (APC), and microtubule-associated protein-1B (MAP1B) . InhibitEnhancing cytoskeletal dynamics in the growth cone supports axon growth, whereas aberrant cytoskeletal dynamics following injury represents a major obstacle to axon regeneration. Therefore, manipulations targeting cytoskeletal dynamics may be potential strategies to induce axon regeneration of adult neurons following injury.Socs3 in adult retinal ganglion cells magnified JAK/STAT signaling, thereby inducing axon regeneration after optic nerve injury axons in the mouse spinal cord (Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling is involved in regulating axon regeneration and cell survival. JAK is activated by growth factors and cytokines ) and then phosphorylates STATs, which transduce the signals to the nucleus and promote transcription of regeneration-associated genes (RAGs). Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of the JAK/STAT pathway. Ablation of e injury . Activatnal cord .Pten promotes mTOR activation and positively modulates regeneration of facial nerve and CST axons pathway plays a crucial role in regulating fundamental cell processes, including cell growth and metabolism, gene transcription, protein synthesis, and cytoskeletal remodeling . mTOR fuST axons . Activatneration .dlk-1 is sufficient to enhance regrowth capacity of injured axons in C. elegans , a highly conserved mitogen-activated protein kinase kinase kinase (MAP3K), plays a vital role in injury response, apoptosis, axon transport, and regeneration following injury both in the peripheral nervous system (PNS) and in the central nervous system (CNS) . Upon ax elegans . Germina elegans .Klfs), Sox11, Stat3, cAMP-response element binding protein (Creb), and hypoxia inducible factor-1a (Hif-1a) , which initiate pro-regenerative transcriptional programs and enable the reacquisition of regenerative potential. Previous studies have identified multiple pro-regenerative TFs, such as Kr\u00fcppel-like factors ((Hif-1a) . ManipulEpigenetic modifications, which include histone acetylation, DNA demethylation and hydroxymethylation, as well as modification of non-coding RNAs, facilitate access to gene regulatory regions by TFs, thus enabling active transcription of genomic regions and RAG expression. Epigenetic modifications play a key role in embryonic and adult neurogenesis . In receIt is difficult to achieve frank regeneration of injured axons beyond the lesion site in the adult mammalian CNS. Apart from limited intrinsic regenerative competence, multiple extrinsic barriers contribute to the axon regeneration failure. Among these, myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs) represent the major inhibitors to axon regeneration following SCI. Nogo A, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp) are three prototypical myelin-associated inhibitory molecules that exert inhibition on axon regeneration after injury in the adult CNS. These MAIs initiate intracellular Rho and ROCK signaling pathways through multiple receptors and eventually lead to growth cone collapse and prevent neurite extension . CSPGs aSpinal cord injury interrupts the connectivity of the spinal cord and leads to devastating neurological deficits. In addition, concomitant complications, including respiratory and urinary infections, gastrointestinal disorders, muscle atrophy, and chronic pain exacerbate clinical outcomes. Numerous novel approaches have been emerged to ameliorate SCI outcomes that can be divided into two parts: (i) relieving secondary damage via neuroprotection and (ii) fostering neuroplasticity and axon regeneration by triggering intrinsic regenerative mechanisms, ameliorating the extrinsic environment, and applying cell transplantation and neuromodulation technologies . Each ofThe primary mechanical injury to the spinal cord triggers a cascade of complex biological processes, termed the secondary injury, which cause further damage to the spared tissue and exacerbate neurological impairment and regeneration failure. Therefore, interventions that confer neuroprotection during the acute phase are crucial to suppress the spread of the secondary injury and to protect the spinal cord tissue from further damage. Several strategies have been deployed to attenuate the secondary damage. Pharmacological agents like methylprednisolone, minocycline, and cyclosporine A have been used to in patients with SCI to suppress secondary damage . HoweverIn recent years, a large number of novel neuroprotective approaches have emerged designed to counteract the progression of secondary injury. These therapies have demonstrated neuroprotective effects in preclinical studies and provide new perspectives for the treatment of clinical SCI. Oxidative stress following SCI leads to excess release of reactive oxygen species (ROS), which exacerbates secondary injury and results in axon degeneration and permanent neurological dysfunction. Antioxidant enzymes encapsulated in biodegradable nanoparticles have been shown to significantly reduce ROS activity and neuronal cell apoptosis, attenuate mitochondrial dysfunction, and improve locomotor recovery following severe contusive SCI in rats . In a moOveractivation of microglia after SCI exacerbates the inflammatory response and results in loss of neurons, gliosis, and synaptic damage. Inhibition of microglia proliferation by oral administration of the CSF1R inhibitor, GW2580, reduced neuroinflammation and improved locomotor function in mice and non-human primates following lateral spinal cord hemisection . MicroglWhile self-repair spontaneously occurs after injury in the adult mammalian PNS, mature neurons in the CNS fail to regain regenerative competence after SCI. Axon regeneration failure is mostly attributed to the poor intrinsic growth competence of the adult CNS neurons. Axon growth capacity sharply declines with age and is switched off upon maturation. However, over the last few decades, accumulating evidence suggests that axon regeneration and remodeling of neural circuits are possible via pharmacological, molecular, or genetic manipulations in the adult mammalian CNS . SubstanMicrotubule destabilization and actin disassembly following SCI lead to growth cone collapse and retraction bulb formation. The reformation of a growth cone-like structure from severed axon stumps is the first step in axon regeneration. Most manipulations aiming to augment axon regenerative ability eventually converge on cytoskeletal dynamics and remodeling within the growth cone.Rhoa knockdown was shown to enhance axon regeneration and reduce apoptosis, cavity formation, and astrogliosis in a rat compression SCI model , which is mainly produced in the mitochondria. SCI-induced mitochondrial dysfunction and energy deficits exacerbate axon regeneration failure. Syntaphilin (Snph) is a static anchor protein that holds axonal mitochondria stationary on microtubules via its microtubule-binding domain. Enhancing mitochondrial transport by in mice . The mit in mice .Intracellular signaling pathways, such as mTOR, JAK/STAT/SOCS3 and DLK regulate neuronal survival and axon growth. Accumulating evidence suggests that manipulating these pathways could enhance intrinsic growth competence and neuroplasticity after SCI.Socs3 triggered collateral sprouting of intact CST axons to the denervated spinal cord after unilateral pyramidotomy. Moreover, co-deletion of Pten and Socs3 further enhanced CST sprouting with significant restoration of skilled locomotion function, suggesting the reformation of functional circuits mediated by sprouting axons concentration by extruding Cl\u2212 from the cytosol. KCC2 has important roles in synaptic inhibition as well as in neuronal development and plasticity directly modulate transcription of RAGs and initiate the switch from the resting state to the robust regrowth state in damaged neurons. TFs have been shown to be an important determinant controlling axon growth potential in the mature CNS. Over the past decades, researchers have identified several candidate TFs that potentiate the regenerative capacity of injured axons after SCI.Klf6 or Klf7 promoted sprouting and regeneration of CST axons in adult mice promoted histone 3 Lys 9 acetylation (H3K9ac) following peripheral injury, and nal cord . Recent nal cord . These rnal cord . This stIn addition to limited intrinsic growth ability, the hostile microenvironment is another obstacle to axon regeneration after SCI. Indeed, extrinsic growth-inhibitory factors and the deficiency of neurotrophic factors further hamper neuroplasticity and axon regeneration. Therefore, removing inhibitory molecules and augmenting neurotrophic support contribute to render a more permissive environment and promote functional recovery following SCI.The presence of inhibitory factors surrounding the lesion site appears to be the major environmental obstacle to axon growth that prevents the injured axons from real regeneration. Removal of extrinsic inhibitory components by enzymatic degradation, receptor blocking, or antibody neutralization has demonstrated positive effects on axon regeneration and neurological restoration.Chabc gene expression was shown to promote recovery of skilled reaching and ladder walking performance as well as sensory axon conduction following cervical contusion injury in adult rats to specifically modulate PTP\u03c3 released the inhibitory effect of CSPGs on axon growth and markedly fostered functional recovery of sensory, locomotor, and urinary systems after contusive SCI in rats . InhibitAttenuating MAI-mediated inhibition can be achieved by antibody neutralization, receptor antagonists, and genetic inhibition. Anti-Nogo A treatment ameliorated lower urinary tract dysfunction and restored bladder function in rats with severe SCI . The firLotus overexpression has been proved to enhance axon regeneration of the raphespinal tract and reticulospinal tract fibers, suppress axonal dieback of CST fibers, and promote motor recovery in a mouse contusive SCI model into neurons and oligodendrocytes, and transplantation of Lingo-1 shRNA-treated NSPCs facilitated locomotor recovery in mice with contusive SCI are a family of proteins that direct neuronal survival, synaptic function, and axonal growth within the adult nervous system . NFs areBdnf vector into the lesion significantly enhanced sprouting of 5-HT+ axons and increased their synaptic connections with phrenic motor neurons (PhMNs), and contributed to recovery of diaphragm function following cervical SCI is a secreted protein that fosters neuron survival and synaptic plasticity. Delivery of BDNF mRNA with cationic polymers resulted in improved motor function recovery in a mouse model of contusive SCI . Intraspical SCI . Retrogrical SCI . Sustainical SCI . In addiical SCI . Insulin pathway . Igf-1 o in mice . Subcuta in mice . In addi in mice . Vascula in mice . VEGF wa in mice .The substantial loss of neurons and oligodendrocytes following SCI leads to disruption of neural network and signal transduction. Cell transplantation exhibits multitherapeutic capacities, such as replacement of damaged tissue, formation of relay neural circuits, immunomodulation, neuroprotection, and myelin regeneration, thus emerging as a more promising intervention to promote functional improvement following SCI . A varieNeural stem cells/neural progenitor cells (NSCs/NPCs) are self-renewing cells and can differentiate into specific neurons or glial cells to replace damaged spinal cord tissue. Implantation of NPCs/NSCs has shown great therapeutic potential in axon regeneration and functional restoration after SCI in rodents and primates . The obsMSCs are ideal candidate for cell-based therapies. MSCs raise no ethical concerns and can be acquired from diverse tissue sources like bone marrow, placenta, umbilical cord, and adipose tissue. Therefore, MSC transplantation is one of the most promising candidates for SCI repair. The therapeutic effects MSC transplantation after SCI are primarily due to their paracrine activity and trophic support: MSC-secreted factors modulate the immune response and induce neuroprotection, angiogenesis, and fiber regeneration in the injured spinal cord . In the SCs are another potential candidate for transplantation in patients with SCI. SCs have been shown to promote spinal cord repair through multiple mechanisms; they myelinate axons, reduce tissue injury, enhance neuroprotection, and maintain axonal plasticity. SCs are easily acquired from autologous nerve, thus alleviating the risk of immune rejections and avoiding the need for immunosuppression. SCs have demonstrated potential therapeutic effects in rodent SCI models, and their safety and potential efficacy have also been confirmed in clinical trials. A phase I clinical trial in humans with subacute SCI suggested that autologous human Schwann cell (ahSC) transplantation injected into the epicenter of the spinal lesion was safe and feasible. No serious adverse events or neurological complications were detected within in one year after transplantation . AnotherLike ahSCs, iPSCs derived from somatic cells avoid ethical concerns and immune rejection, and they can be reprogrammed to NPCs/NSCs, supporting human iPSC-derived NSC/NPC transplantation as a viable approach to treat SCI. Transplantation of human iPSC-derived NSCs facilitated axon growth and functional neural circuit reconstruction as well as motor function restoration after cervical spinal cord hemisection in rats . SimilarCollectively, the multiple observed therapeutic benefits associated with cell transplantation makes cell-based therapy an attractive approach that could substantially improve outcomes for patients with SCI. However, some remaining issues may limit their clinical practice, including ethical controversy, cell source, intervention time, uncontrolled cell proliferation, and long-term safety. Continued efforts to resolve these issues and concerns could make cell transplantation a feasible clinical option.The descending motor pathways are severely interrupted after SCI. Although the spinal neural circuits below the injury level remain intact, the absence of supraspinal descending commands leads to the circuits functionally dormant and loss of motor function. Neuromodulation is a bioengineering approach that utilizes electrical or magnetic stimulation, pharmacological agents, optogenetics, and chemogenetics to modulate neuronal activity. Neuromodulation has been successfully applied in a variety of neurological diseases. Neuromodulatory technologies applied for SCI aim to reactivate the spinal intrinsic motor circuits below the lesion and ultimately restore the basic motor function and/or voluntary movements. These neuromodulatory inventions primarily include spinal cord stimulation, brain stimulation, and brain\u2013machine interface.Spinal cord stimulation is emerging as a potential therapy to alleviate neurological deficits and promote functional recovery following SCI. Epidural electrical stimulation (EES), transcutaneous spinal cord stimulation (tcSCS) and intraspinal microstimulation (ISMS) are the three forms of spinal cord stimulation that designed to facilitate functional restoration after SCI.Epidural electrical stimulation (EES) applied to the lumbosacral spinal segments has been shown to substantially restore locomotion and motor control after SCI both in preclinical and clinical studies. Paralyzed rats treated with EES were able to perform continuous stepping, walking, and even climbing staircases . Co-deliContinuous EES may abolish proprioceptive information in humans and restrict locomotion recovery. In contrast, spatiotemporal EES enhanced the active control of motor neurons while preserving the interaction between antagonistic muscles to ensure coordination and stability of lower limb movement . SpatiottcSCS is another well-developed form of spinal cord stimulation and has been demonstrated to restore motor, sensory, and autonomic function when used alone or combined with other interventions . tcSCS iPrevious studies have indicated that even clinically complete SCI spares some descending nerve fibers, but they are dormant and insufficient to trigger movement. Brain stimulation has been used to engage the residual motor circuits to restore voluntary limb movement after SCI. The brain stimulation strategies mainly include deep brain stimulation (DBS), transcranial direct current stimulation (tDCS), and transcranial magnetic stimulation (TMS).DBS is a well-established technique that activates neural activity of the target brain region via implanted electrode. Motor cortex electrical stimulation was shown to promote CST axon sprouting, and the combination of motor cortex stimulation and transcutaneous spinal direct stimulation (tsDCS) further augmented CST axon plasticity and restored forelimb motor function after rat spinal cord contusion . This coBrain\u2013machine interface (BMI) has emerged as a novel technique that combines engineering, computer science, and neurophysiology to restore sensorimotor functions in patients with severe neurological disability . BMI recA participant with quadriplegia from cervical SCI regained cortical control of dexterous hand movements using BMI. The participant\u2019s forearm muscles were reactivated and controlled by the intracortically recorded signals, ultimately enabling complete functional movement task like grasping, manipulating, and releasing objects . An indiThe wireless brain\u2013spine interface was employed to directly link the intended motor states decoded from leg motor cortex activity to spatiotemporal EES over the lumbosacral segment to re-establish voluntary control of leg activity. This approach alleviated gait deficits and enabled weight-bearing locomotion on a treadmill and overground in rhesus monkeys with unilateral corticospinal tract lesion during the first week post-injury . As obseNeuromodulation therapies have achieved unexpected efficacy in restoring locomotion and volitional control in both SCI animal models and individuals with SCI. Therefore, these neuromodulatory technologies might be the most promising approach to achieve meaningful functional recovery following SCI.Individual treatments are insufficient to restore meaningful locomotion due to the complex pathological responses after SCI. Therefore, combinatory approaches targeting diverse aspects of SCI pathology are warranted to facilitate functional recovery in humans with SCI. Biomaterials serve as physical and structural supports to guide axon outgrowth and have been widely applied in the treatment of SCI. Meanwhile, biomaterials act as a key component of combinatorial approaches, as they provide temporary storage substrates for the long-term release of drugs, bioactive molecules, and transplanted cells to modulate inflammation, neural plasticity, axon regeneration, and cell survival .Combined delivery of multiple growth factors and chemokines released from hydrogel depots elicited robust propriospinal axon regrowth after complete SCI in both mice and rats. The regenerating propriospinal axons formed synapse-like contacts with neurons below the lesion site and restored electrophysiological conduction across lesions . The supLycium barbarum oligosaccharide (LBO) promoted microglia towards M2 polarization. Combination of LBO, nasal mucosa-derived mesenchymal stem cells, and fibronectin hydrogel synergistically enhanced the M2 polarization of microglia and promoted axon remyelination and recovery of hind limb movement after complete spinal cord transection in rats was shown to promote functional recovery in rodent models of SCI, and its safety and feasibility were confirmed in preliminary phase I/IIa clinical trial. However, the phase 3 clinical trial failed to show significant benefit of G-CSF in the primary end point . A few oAlthough encouraging results have been achieved in SCI animal models, interventions that are effective preclinically demonstrate little efficacy to produce functional improvements when translated into clinical trials. Therefore, the beneficial outcomes from rodent models are not always reproduced in clinical practice. One possible reason is the limitation of rodent models for predicting efficacy in human SCI. The anatomy and size of the spinal cord vary greatly between rodents and primates. For instance, the anatomical characteristics and function of descending pathways involved in motor control demonstrates pronounced interspecies differences between rodents and primates. In rodents, the CST fibers mostly travel in the dorsal columns of the spinal cord, and no direct connections exist between CST fibers and the cervical motoneurons. By contrast, in humans and non-human primates, the CST fibers are mainly located in the lateral columns and have developed direct connections with motoneurons . In addiFuture clinical trials for the treatment of SCI should be designed after considering several factors that may influence outcomes. Accumulating more data and comprehensive preclinical testing is essential before initiating clinical trials to minimize the risk of patients experiencing adverse effects or undergoing futile treatment. Moreover, the lack of reproducibility and robustness in preclinical experiments is another major issue contributing to the failure of clinical translation . Thus, iIndividual therapeutic interventions are inadequate to resolve the multifaceted pathological processes that occur after SCI and to promote spinal cord repair. Multi-targeted, combinatorial approaches are expected to maximize therapeutic effect. However, this becomes more complicated because many aspects must be taken into account when different strategies are combined. For instance, the optimal temporal window of treatment and whether the treatments are safe, tolerable, and feasible in combination must be determined to identify the most effective synergistic strategies. To optimize combinatorial strategies, determine analytical frameworks and achieve clinically relevant recovery in patients with SCI, it is therefore essential to enhance collaboration and communication between basic researchers and clinicians.Spinal cord injury interrupts the descending motor pathways and ascending sensory fibers within the spinal cord, leading to multi-system dysfunction and permanent disability. To alleviate the devastating effects of SCI, researchers have developed a variety of novel therapeutic approaches in recent years, some of which have shown promising therapeutic efficacy in preclinical studies and are progressing to clinical trials. This review summarizes the recent progress of preclinical and clinical strategies in SCI treatment and discusses the challenges and prospects for spinal cord repair.Despite encouraging results in preclinical experiments, many interventions have failed to translate to clinical application. This translational failure is partially due to the complex and multifaceted features of SCI pathology. Hence, a better understanding of the pathological processes following SCI and thorough investigation of intrinsic and extrinsic mechanisms controlling axon growth are urgently warranted to develop novel strategies to achieve greater beneficial outcomes. Notably, most individual therapeutic strategies targeting a single pathophysiological mechanism are insufficient to achieve relevant efficacy, resulting in clinical translation failure. Combinatorial strategies that act on multiple pathological processes of SCI have been shown to be more effective than individual treatments alone. Therefore, combinatorial approaches are more promising to wok synergistically to overcome multiple regeneration barriers and foster neural repair in patients with SCI. Furthermore, multidisciplinary collaboration and conversations are essential to ensure the accuracy of therapeutic design and predictive analysis.Neuronal regeneration or the formation of relay neural circuits after SCI is not necessarily accompanied by associated functional improvement. Rehabilitation training could augment the adaptive plasticity of residual pathways and is expected to trigger reorganization and integration of neural circuitry to promote longer-lasting functional readouts. Together with appropriate rehabilitation, combinatorial strategies might further enhance recovery of neurological function in clinical SCI. Furthermore, it is vital to select appropriate animal models for preclinical studies, and potential strategies should be extensively investigated preclinically in diverse SCI animal models to validate their therapeutic effects. Pronounced species divergence exists between primates and rodents or carnivores, and non-human primate models are particularly relevant for designing interventions and validating their therapeutic potential before translated to clinical application. In the future, further investigation is warranted to identify the neural regenerative mechanisms of functional recovery after SCI, especially in non-human primate models, as they are more similar to those in humans. These studies might be crucial to develop novel therapeutic interventions targeting particular neural circuits to improve function restoration."} +{"text": "Lacrimal gland enlargement can be a feature of thyroid eye disease (TED). Unilateral or asymmetric lacrimal gland enlargement is poorly described and may impede diagnosis. We present the histological and clinical findings of four patients with asymmetric lacrimal gland enlargement.A retrospective case note review was performed for patients over two tertiary orbital clinics presenting with an asymmetrical lacrimal gland enlargement with a background of TED that underwent biopsy to exclude alternate diagnoses. Baseline data was collected for each patient and histopathological images and reports were reviewed.All four patients were hyperthyroid at time of lacrimal gland biopsy. Biopsy demonstrated nonspecific, lymphoid aggregates, typically of B cell type, with no diagnostic findings to support lymphocyte clonality or IgG4-related disease. One biopsy specimen demonstrated evidence of some fibrosis.Asymmetrical lacrimal gland enlargement can occur as part of the TED spectrum but may require biopsy to exclude alternate pathology. Histology demonstrates a non-specific lymphocytic infiltrate. Thyroid eye disease (TED) is the commonest cause of orbital inflammation in adults. It can result in expansion and fibrosis of the extraocular muscles and orbital fat . RadioloThe purpose of this study is to report on the histopathological findings of lacrimal gland biopsies in patients with asymmetric lacrimal gland enlargement.A retrospective review of clinical case notes was performed for all patients presenting to two units between the years 2013 to 2020. Inclusion criteria included patients with known thyroid dysfunction, upper eyelid retraction and/or lid lag in keeping with thyroid eye disease, clinical and/or radiological findings of lacrimal gland enlargement, magnetic resonance imaging (MRI) of the orbits and subsequent lacrimal gland biopsy and serological investigations (eg serum immunoglobulin subclasses) to exclude concurrent disease.Baseline data for each patient was collected including age, sex, ocular comorbidity, laterality, ophthalmic findings, and histopathological findings. Clinical Activity Score (CAS) was obtained for the patient\u2019s initial presentation. The CAS evaluates inflammatory signs and symptoms that are often characteristic of active TED.Ethical approval for this study was not required as per the Human Research Authority (HRA) online decision-making tool. Informed consent was provided by each patient for the procedure and use of clinical information.Four patients were identified through case note review Table . The meaThree of the four patients presented with upper lid retraction. All four patients had inactive disease. Other common presentation features included lid lag and proptosis. MRI had been requested as routine baseline imaging of the orbital contents.All patients were biochemically hyperthyroid and demonstrated asymmetrical lacrimal gland enlargement on MRI (Fig.\u00a0Histopathological analysis of lacrimal gland biopsy specimens showed nonspecific chronic inflammation composed largely of B lymphocytes in all four cases Figs.\u00a0,\u00a03,\u00a04. OLacrimal gland enlargement is a common finding in TED and particularly in the active stage of the disease , 6, 7. ARadiological findings may assist the decision-making regarding biopsy of the lacrimal gland. Epithelial neoplasms predominantly involve the orbital lobe whilst inflammatory and lymphoproliferative lesions tend to involve both the orbital and palpebral lobes . LymphopPreviously reported lacrimal gland histopathological findings in TED have also shown nonspecific inflammatory cell infiltration with and without fibrosis , 13, 14.These nonspecific histological changes, to some extent, diagnoses thyroid eye disease by exclusion, given the lack of a specific histopathological marker, although there remains the possibility of other concurrent, non-specific, diseases such as idiopathic dacryoadenitis that tend to present unilaterally.All four patients in the present study were hyperthyroid which contrasts with previous studies which have shown asymmetric TED clinical presentations predominantly in euthyroid or hypothyroid disease states , 18, 19.There are several limitations to this study. Firstly, the retrospective and non-comparative design limit inferences that can be drawn. Secondly, a standard set of immunohistochemical testing was not undertaken due to the retrospective and multi-centre nature of the study. Finally, we have included a small number of patients, although this may reflect the relatively uncommon nature of TED-related, asymmetric lacrimal gland enlargement.This study confirms that those patients with lacrimal gland enlargement presumed secondary to TED typically show nonspecific chronic inflammatory changes on histopathological analysis. Lacrimal gland biopsy is prudent given concurrent malignant or inflammatory disease is possible with asymmetrical enlargement although radiological imaging modalities of the lacrimal gland show promise in diagnosing active TED."} +{"text": "Brain structural and functional alterations have been consistently proposed to be involved in the neurobiological underpinnings of aging and neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson's disease. Given that pathological perturbations of the central nervous system are often intertwined with brain connectivity alteration, it is becoming increasingly accepted that connectome reorganization plays a key role in determining cognitive or motor disability. The advances in connectome-wide association studies (CWAS) have the potential to allow for the identification of novel neural correlates of neurodegeneration at the whole-brain scale, elucidating how brain-network topology can shape neural responses to neurodegenerative damage.This Research Topic aims to encourage the proposal of state-of-the-art methodologies related to CWAS techniques and their applications to neurodegenerative disorders. A total of five studies collected in this topic mainly cover (1) advanced statistical methods to avoid multiple covariates in analyzing brain connectivity; (2) a data-driven CWAS design to clarify and validate brain network findings associated with aging in a large sample of subjects; (3) a virtual analytical approach to describe brain disconnectome reorganization while avoiding the issue of artifacts that are prone to occur in the presence of white matter hyperintensity; (4) advanced dynamic connectivity measurements as novel brain imaging markers to discriminate AD patients at different stages; and (5) the brain structural covariance network analysis and related novel statistical model to unravel pathological progression of AD. In what follows, we summarized the highlights the methodologies and applications in aging and related neurodegeneration of each article.Smith et al. proposed a subject-level regression model to consider multiple covariates, including parcel-wise geographic/homotopic distance and region or network belongings, to move away from reliance on localization assumptions underlying FC comparisons. The key point is to keep each individual's FC in its own geometry, without morphing to a common template. This could be extraordinarily useful when the extent and location of lesions to brain regions varies across subjects. Additionally, the authors demonstrated high repeatability of this model achieved in individual space with test-retest individual scans.Functional connectivity (FC) comparison across individuals can be challenging in CWAS due to complex covariates in inter-subject variations. Du et al. applied a priori-driven independent component analysis, named NeuroMark, on 6,300 healthy adult with an age range of 49\u201373 years from UK Biobank project. They highlighted multiple significant joint between-network FC changes related to aging occurred in default mode and sub-cortical networks. This spatial diversity of brain network reorganization revealed by CWAS may shed new light on mechanism underlying aging-related brain changes.How aging affects functional networks of the brain in both within-network and between-network connectivity is unclear. To comprehensively explore this effect, Li et al. addressed the focal effect when analyzing brain structural network. To avoid potential confounds of white matter hyperintensity (WMH) in CWAS, the authors proposed a virtual lesion approach to estimate brain connectivity changes in aging. Specifically, WMH frequency maps across age ranges were used to generate virtual lesion masks for each decade as regions of avoidance in white matter tractography. They quantitatively described the spatial disconnectome evolving patterns in cortical and subcortical areas, which might underlie cognitive and sensorimotor deficits seen in aging. The advancement of this virtual lesion approach can further help identify brain disconnectome features contributing to dementia risk.Another study conducted by Penalba-S\u00e1nchez et al. compared multiple FC measurements and evaluated their corresponding network segregation and integration in mild cognitive impairment and AD. The authors unexpectedly observed an increase in late stage AD and a slight decrease of FC in early MCI, and explained the potential underlying cognitive mechanism. Understanding the dynamic and non-linear nature of FC might be crucial for unraveling the unclear neuropathological factors affecting behavior symptoms along the trajectory of AD.Emerging evidence has supported that abnormal brain structural or functional connectivity could have been observed 10\u201320 years prior to the onset of clinical symptoms of AD. Aiming to clarify inconsistent brain FC findings in early stage of AD, the study conducted by Xiao et al. applied SCN analysis using T1-weighted MR images from a longitudinal cohort to examine whether and how earlier brain atrophy patterns impact the progressive changes of gray matter atrophy in AD patients over time. After establishing regular structural connectivity by Pearson correlation and causal structural connectivity by Granger causal analysis, they used a new approach named gray matter based spatial statistics to measure the gray matter volume at the core of the cortical plate, aiming to alleviate partial volume effect and inter-subject variability. High discrimination accuracy based on SCN connectivity features suggests that SCN approach may help identify the unique pathological progression of AD and other types of neurodegeneration.Unlike structural connectivity, which is classically represented by the connection strength of white matter tracts on individual level, brain structural covariance network (SCN) analysis highlights synchronized gray matter atrophy undergoing neurological pathological processes across brain regions on population level. In sum, the collective findings represented in these articles reflect the rapidly expanding development of the CWAS field. One could further expect a rising body of brain network analytical tools and statistical models updated in this emerging area, providing new avenues for identification of brain network markers related to aging and neurodegenerative disorders. However, whether and to what degree the brain network construction procedures affects robustness of findings in neurodegeneration is still in dispute. Therefore, before further translating into clinical applications such as individual auxiliary diagnosis and treatment decision-making, we must be cautious whether the reliability and validity performance of these CWAS approaches has been fully reported and validated in large-sample and multi-center brain imaging data.CY: Writing\u2014original draft. TW: Writing\u2014review & editing. AF: Writing\u2014review & editing."} +{"text": "This review article delves into the intricate and evolving relationship between coronary microvascular dysfunction (CMD) and takotsubo cardiomyopathy (TCM), two intriguing cardiovascular conditions increasingly recognised for their potential interplay. We examine their characteristics, shared pathophysiological mechanisms, diagnostic challenges, and management strategies. Emerging evidence suggests a link between microvascular dysfunction and the development of TCM, leading to a deeper exploration of their connection. Accurate diagnosis of both conditions becomes essential, as microvascular dysfunction may modify TCM outcomes. We underscore the significance of understanding this connection for improved patient care, emphasising the need for tailored interventions when CMD and TCM coexist. Collaborative research and heightened clinical awareness are advocated to advance our comprehension of this relationship. Through interdisciplinary efforts, we aim to refine diagnostic precision, develop targeted therapies, and enhance patient outcomes in cardiovascular medicine. Medical interest has surged toward two distinct yet captivating cardiovascular conditions: coronary microvascular dysfunction (CMD) and takotsubo cardiomyopathy (TCM). While initially perceived as separate entities, recent research hints at a potentially intricate link between these conditions. This article delves into this complex interplay between CMD and TCM, probing their shared pathophysiological mechanisms, clinical presentations, diagnostic challenges, and treatment implications -3.Coronary microvascular dysfunction encompasses a spectrum of disorders characterised by anomalies in the microvasculature's structure and function within the coronary circulation. Unlike traditional coronary artery disease, which affects large epicardial vessels, CMD involves dysfunction in the smaller arterioles and capillaries that regulate myocardial blood flow. Despite the absence of significant obstructive coronary artery disease, CMD leads to angina-like symptoms, myocardial ischemia, and abnormal stress test results. The elusive nature of CMD and its limited diagnostic tools pose challenges in diagnosis, rendering understanding its underlying mechanisms and clinical significance increasingly pivotal ,5.In contrast, TCM, or \"broken heart syndrome,\" manifests as transient left ventricular dysfunction mimicking acute myocardial infarction. Chest pain, electrocardiographic changes, and elevated cardiac biomarkers typify this condition. Often arising from emotional or physical stressors, TCM's hallmark is the unique apical ballooning pattern evident in cardiac imaging. While initially viewed as reversible with a favourable prognosis, recent research illuminates potential severe complications and enduring consequences ,7.The realisation of a possible connection between CMD and TCM carries profound ramifications for both clinical practice and research. Evidence suggests that patients with TCM often exhibit microvascular dysfunction, hinting at an underlying link between these conditions. Understanding this association could offer insights into the triggers and pathogenesis of TCM. Furthermore, discerning the relationship between CMD and TCM stands to shape therapeutic strategies and enhance patient outcomes ,9.This review comprehensively explores the evolving relationship between CMD and TCM. We offer a holistic perspective on their shared pathophysiological mechanisms, clinical manifestations, diagnostic hurdles, and therapeutic implications by delving into the crossroads of these two distinct yet potentially intertwined conditions. Through a critical analysis of existing research, clinical observations, and theoretical models, our synthesis aims to provide healthcare professionals, researchers, and clinicians with an exhaustive resource. This resource illuminates conceivable connections between CMD and TCM, emphasising the importance of recognising and addressing this association in clinical practice. Our in-depth examination of CMD and TCM's complexities strives to advance medical understanding, enhance patient care, and formulate precise strategies for managing these captivating cardiovascular conditions.Coronary microvascular dysfunction (CMD)Definition and Pathophysiology of CMDCoronary microvascular dysfunction encompasses a spectrum of disorders characterised by intricate abnormalities within the smaller coronary vessels, including arterioles and capillaries. In contrast to traditional coronary artery disease, which primarily affects the larger epicardial vessels, CMD homes in on the delicate microcirculation. To comprehensively understand CMD's pathophysiology, it's crucial to explore the underlying mechanisms that have been identified. Endothelial dysfunction stands at the forefront of CMD's pathophysiology, playing a pivotal role in impairing the functionality of the microvasculature. This dysfunction is intricately linked to the imbalance of vasoactive factors and nitric oxide availability, ultimately affecting the vascular tone and endothelium-dependent vasodilation . MoreoveClinical Presentation and Diagnostic ChallengesThe clinical presentation of CMD\u00a0closely mirrors that of obstructive coronary artery disease, making it challenging to distinguish between the two based solely on symptoms. Patients with CMD often report chest pain, dyspnea (shortness of breath), and exercise intolerance, commonly associated with traditional coronary artery disease. This similarity in symptoms can lead to confusion in diagnosis, mainly when relying solely on clinical presentation .One of the critical diagnostic challenges in CMD lies in the limitations of conventional diagnostic tests, such as angiography. Unlike obstructive coronary artery disease, CMD does not involve significant narrowing or stenosis of the larger coronary arteries, typically visualised through angiography. This absence of visually apparent coronary stenosis can lead to underdiagnosis or misdiagnosis, as these tests may not capture the microvascular abnormalities characteristic of CMD .Furthermore, the need for well-defined diagnostic criteria and standardised assessments for CMD exacerbates the difficulty in identifying the condition accurately. The absence of universally accepted guidelines to diagnose CMD makes it challenging for healthcare practitioners to consistently recognise and differentiate it from other cardiac conditions. This lack of standardised criteria also hampers research efforts and makes it difficult to compare findings across studies .The confluence of overlapping symptoms, along with the limited sensitivity of existing diagnostic tests, contributes to a significant underrecognition and underdiagnosis of CMD. This diagnostic shortfall is consequential, potentially resulting in treatment delays and impacting patient outcomes. An appreciable aspect to consider is the percentage of undetected cases due to these challenges. Additionally, it is pertinent to discuss the sensitivity and specificity of the employed diagnostic tests and the symptoms associated with CMD. As the landscape of CMD research evolves, the need becomes apparent to establish standardised diagnostic criteria and innovative diagnostic techniques. By addressing this pressing need, the accurate identification and effective management of this intricate condition can be significantly improved .Underlying Causes and Risk FactorsCoronary microvascular dysfunction is a complex condition influenced by various underlying causes and risk factors extending beyond traditional cardiovascular risk factors. While hypertension, diabetes, and dyslipidemia are recognised as conventional contributors to CMD, a growing body of evidence highlights the significance of non-traditional risk factors in its development .Psychosocial stress emerges as a potent contributor to CMD. Chronic stress triggers the release of stress hormones, leading to endothelial dysfunction and impaired vasomotor responses in the coronary microvasculature. This can result in reduced myocardial blood flow regulation and contribute to the manifestation of CMD symptoms .Hormonal imbalances play a role in CMD pathogenesis, particularly in women. Oestrogen, for instance, exerts protective effects on endothelial function, and its decline during menopause might contribute to microvascular dysfunction. Hormonal fluctuations during the menstrual cycle also influence vasomotor responses, potentially impacting coronary microcirculation .Systemic inflammation is increasingly recognised as a critical player in CMD. Chronic inflammation contributes to endothelial dysfunction, oxidative stress, and impaired nitric oxide bioavailability. Inflammatory cytokines can directly affect coronary microvascular function, altering vasodilation responses and contributing to CMD .Endothelial dysfunction, a hallmark feature of CMD, is a common link between these risk factors. It disrupts the delicate balance between vasodilation and vasoconstriction, impairing coronary blood flow regulation. Endothelial dysfunction contributes to the microvascular abnormalities observed in CMD and lays the groundwork for developing ischemic symptoms ,20.Available Diagnostic Techniques for CMDCoronary flow reserve measurements using Doppler ultrasound: Doppler ultrasound measures blood flow velocities within the coronary arteries during rest and stress. The coronary flow reserve is assessed by calculating the ratio of flow velocities before and after vasodilation. Reduced coronary flow reserve indicates microvascular dysfunction and impaired vasodilatory capacity, which can contribute to myocardial ischemia ,22.Positron emission tomography (PET): Positron emission tomography imaging quantitatively assesses myocardial blood flow at rest and during stress, usually induced by pharmacological agents or exercise. The comparison of these flow measurements provides insights into the functionality of the microvasculature. Positron emission tomography can help identify regions of reduced perfusion and abnormalities in microvascular function, contributing to the diagnosis of CMD ,24.Cardiac MRI: Cardiac MRI offers non-invasive visualisation of the myocardium and surrounding structures. Techniques like myocardial perfusion imaging provide information about blood flow distribution, aiding in identifying microvascular dysfunction. Cardiac MRI can help evaluate myocardial oxygen supply-demand balance and detect ischemic regions without obstructive coronary artery disease ,26.Invasive coronary reactivity testing: Invasive procedures involving the administration of vasoactive agents within the coronary arteries allow for direct assessment of microvascular function. Endothelial-dependent and independent vasodilatory responses are measured, providing insights into microvascular dysfunction. However, the invasiveness of this approach limits its routine clinical use ,28.Despite the availability of these diagnostic techniques, challenges persist in interpreting results and establishing definitive diagnostic criteria. The lack of standardised protocols and reference values makes establishing universally accepted thresholds for diagnosing CMD difficult. Variability in patient populations, equipment, and procedural protocols further complicates result interpretation. Overcoming these challenges requires collaborative efforts among researchers and clinicians to establish consensus guidelines and refine the diagnostic approach for CMD, ultimately enhancing its recognition and management .Current Treatment Strategies for CMDLifestyle modifications: Lifestyle interventions stand as the cornerstone of CMD management. Encouraging patients to adopt a heart-healthy lifestyle is paramount. This includes regular physical exercise tailored to individual capabilities, as exercise has been shown to enhance endothelial function and improve microvascular health. Furthermore, weight management plays a pivotal role, as excess body weight can contribute to metabolic disturbances and exacerbate microvascular dysfunction. Smoking cessation is of utmost importance, given that smoking damages endothelial cells and worsens microvascular health. Additionally, addressing psychosocial stressors through stress reduction techniques, mindfulness, and psychological counselling can contribute to overall well-being and potentially mitigate the impact of stress on microvascular function ,31.Pharmacological interventions: Pharmacotherapy for CMD aims to alleviate symptoms, enhance microvascular function, and target underlying risk factors. Endothelial function-enhancing agents, such as angiotensin-converting enzyme (ACE) inhibitors and statins, promise to improve endothelial health and promote vasodilation. Vasodilators, such as calcium channel blockers and nitric oxide donors, can help alleviate microvascular constriction and enhance coronary blood flow. Additionally, anti-inflammatory agents are being explored due to their potential role in reducing vascular inflammation and improving microvascular function ,33.Patient education and psychosocial support: Patient education is integral to holistic CMD management. Empowering patients with knowledge about their condition, its underlying mechanisms, and the significance of lifestyle modifications fosters active participation in their care. Moreover, addressing psychosocial stressors, including anxiety and depression, is essential, as these factors can exacerbate microvascular dysfunction. Psychological support and counselling can help patients cope with CMD\u2019s emotional and psychological impact, promoting a holistic approach to well-being ,35.Takotsubo cardiomyopathy (TCM)Definition and Characteristic Features of TCMTakotsubo cardiomyopathy, often called \"broken heart syndrome,\" is a unique and transient condition characterised by acute left ventricular dysfunction, typically presenting with symptoms resembling acute myocardial infarction. The hallmark feature of TCM is the distinctive ventricular ballooning observed during cardiac imaging, which resembles a Japanese octopus trap known as \"takotsubo.\" Left ventricular dysfunction typically involves the apex but can also affect other heart segments .Proposed Mechanisms for TCM DevelopmentThe precise mechanisms driving the development of TCM\u00a0remain a subject of continuous investigation and exploration. Multiple hypotheses have emerged, each offering insights into the intricate cascade of events that culminate in this unique cardiac phenomenon. These mechanisms include but are not limited to, surge-induced myocardial stunning, microvascular dysfunction, coronary artery vasospasm, and neurogenic influences .Catecholamine surge-induced myocardial stunning: One of the prominent theories centres around the significant role of the autonomic nervous system's response to stress. A sudden and excessive release of stress hormones, particularly catecholamines such as adrenaline, is thought to trigger a surge-induced myocardial stunning. This stunning effect results in transient myocardial dysfunction, marked by impaired contractility and ventricular ballooning .Microvascular dysfunction: Another hypothesis emphasises the role of microvascular dysfunction in TCM development. Under the influence of stress hormones, there is potential for the small coronary vessels, including arterioles and capillaries, to undergo dysregulation. Microvascular dysfunction disrupts normal blood flow regulation, leading to inadequate myocardial oxygen supply. This compromised perfusion contributes to myocardial stunning and the characteristic ventricular ballooning observed in TCM cases .Coronary artery vasospasm: The involvement of coronary artery vasospasm is also proposed as a mechanism for TCM initiation. Stress-induced alterations in vasomotor tone could trigger transient spasms in the coronary arteries, leading to reduced blood flow to the heart muscle. This diminished blood supply can result in myocardial dysfunction, with the apical region particularly susceptible due to its anatomical characteristics .Neurogenic influences: Neurogenic factors, including the brain-heart connection, have gained attention as potential contributors to TCM development. Emotional stressors can stimulate the autonomic nervous system, leading to altered heart rate variability, sympathetic nervous system activation, and hormonal fluctuations. This complex interplay between the brain and the heart might contribute to the intricate pathophysiology of TCM .Clinical Presentation and Diagnostic Criteria for TCMTakotsubo cardiomyopathy is characterised by a distinctive clinical presentation and diagnostic criteria that differentiate it from other cardiovascular conditions. The hallmark symptom is the sudden onset of chest pain, often accompanied by dyspnea, palpitations, and a feeling of impending doom. This presentation can closely mimic acute coronary syndrome, particularly ST-segment elevation myocardial infarction (STEMI), leading to initial diagnostic challenges .Diagnostic criteria for TCM have evolved to aid in accurate differentiation from other cardiac pathologies. Transient left ventricular dysfunction is a central feature of TCM, with echocardiography and cardiac MRI serving as crucial tools for its visualisation. Coronary angiography reveals the absence of significant coronary artery stenosis or plaque rupture, further supporting the diagnosis. This differentiation is paramount, as TCM is managed differently from acute coronary syndromes .Also, diagnostic criteria exclude other conditions that might mimic TCM's presentation. Pheochromocytoma, a rare tumour causing excess catecholamine release, and myocarditis, inflammation of the heart muscle, should be ruled out due to their potential to induce similar stress-related myocardial dysfunction .Cardiac imaging, particularly echocardiography and cardiac MRI is indispensable in confirming the diagnosis. Echocardiography unveils the hallmark feature of TCM, the unique apical ballooning pattern, which distinguishes it from other cardiac pathologies. Cardiac MRI further enhances diagnostic accuracy by providing detailed insights into myocardial tissue characteristics and perfusion patterns, facilitating the differentiation of TCM from other conditions presenting with similar symptoms .Differentiating TCM from Acute Coronary SyndromeDistinguishing TCM\u00a0from acute coronary syndrome (ACS) is paramount due to their shared clinical presentations, which often include chest pain, dyspnea, and electrocardiographic changes. One crucial distinction is the absence of culprit coronary lesions on angiography in TCM cases. Unlike ACS, where obstructive coronary artery disease is typically evident, TCM patients display normal or near-normal coronary arteries. This disparity emphasises the need for comprehensive angiographic evaluation to exclude coronary artery obstruction and confirm the absence of significant stenosis .Furthermore, TCM patients tend to exhibit less pronounced elevations in cardiac biomarkers, such as troponin levels, when compared to the more typical ACS cases. While troponin elevation is a hallmark of myocardial injury, the extent of elevation in TCM is often milder than observed in ACS, further aiding differentiation. However, it is essential to note that a certain degree of troponin elevation can still be present in TCM cases, underscoring the importance of integrating multiple diagnostic criteria .Cardiac imaging is an invaluable tool in the differentiation process, particularly echocardiography and cardiac MRI. The characteristic apical ballooning pattern observed during imaging is a hallmark of TCM. This distinctive morphology, resembling the shape of a Japanese octopus trap (takotsubo), is a strong differentiator from ACS. Imaging findings directly visualise ventricular dysfunction and shape abnormalities, providing critical insights into the diagnosis .Management and Prognosis of TCMTakotsubo cardiomyopathy management encompasses a multi-faceted approach focused on supportive care to stabilise hemodynamics, address complications, and alleviate symptoms. Given the acute nature of TCM, patients often require vigilant monitoring in a specialised cardiac care setting. Stabilising hemodynamics involves carefully managing fluid balance, blood pressure, and heart rate to ensure optimal cardiac function. Efforts to maintain adequate perfusion and oxygenation are crucial, and interventions like supplemental oxygen and intravenous medications might be employed as necessary .Furthermore, addressing potential complications is of paramount importance in the management of TCM. Patients with TCM are at risk of developing heart failure due to transient left ventricular dysfunction. Standard heart failure therapies, including diuretics and beta-blockers, may be considered to manage volume overload and control heart rate. Arrhythmias, such as atrial fibrillation or ventricular tachycardia, might occur in the acute phase and necessitate appropriate treatment to restore a stable cardiac rhythm. Additionally, systemic embolism, particularly involving the left ventricular clot or thrombus formation, is a potential complication that requires attention to prevent embolic events .Most TCM cases exhibit a favourable prognosis with the spontaneous recovery of left ventricular function within weeks to months. Serial cardiac imaging, such as echocardiography or cardiac MRI, is valuable for monitoring the improvement in ventricular function over time. The heart's remarkable ability to heal and return to normal functioning underscores the transient nature of TCM. However, vigilance remains essential, as some cases might experience a protracted recovery period or recurrent episodes .Lifestyle modifications and addressing psychosocial factors play a crucial role in the long-term prognosis of TCM patients. Encouraging patients to adopt heart-healthy habits, including maintaining a balanced diet, engaging in regular physical activity, and avoiding tobacco and excessive alcohol consumption, contributes to overall cardiovascular well-being. Addressing underlying stressors and providing psychological support is equally important, as emotional triggers often precede TCM episodes. Comprehensive care extends beyond the acute phase to mitigate the potential triggers for recurrent episodes and optimise long-term cardiac health .The interplay between CMD and TCMReview of Studies Suggesting a Connection between CMD and TCMRecent years have witnessed a burgeoning body of research that unveils the captivating prospect of a multifaceted interplay between CMD\u00a0and TCM. This intriguing association has emerged through meticulously scrutinising diverse studies, including case reports and retrospective analyses. These inquiries have illuminated instances where TCM manifested in individuals previously displaying indications of underlying microvascular dysfunction. These preliminary observations have ignited curiosity within the medical community, suggesting a compelling nexus between CMD and TCM's pathogenesis .Numerous case reports have documented instances in which individuals diagnosed with CMD, an ailment marked by coronary microvasculature irregularities, subsequently encountered episodes of TCM. These cases potentially offer insights into a shared physiological connection that warrants closer investigation. Likewise, retrospective patient data analyses have unveiled a suggestive pattern that a subset of TCM cases might be heralded by documented or suspected CMD, implying a temporal relationship deserving thorough exploration .While these revelations prompt inquiries into potential mechanisms and implications, they also underline the need to consider additional research methodologies. Could microvascular dysfunction contribute to or even initiate TCM's development? Could CMD influence the trajectory or prognosis of TCM episodes? Rooted in these clinically observed correlations, these queries beckon a deeper understanding of the shared pathophysiological underpinnings that might underscore this intriguing association .The studies discussed undoubtedly build a compelling case for the connection between CMD and TCM. Nevertheless, they simultaneously serve as a launchpad for broader research endeavours. The implications of such an interrelationship could resonate profoundly, impacting diagnostic precision, risk evaluation, and therapeutic strategies. Hence, the clarion call for further investigation into these intricate dynamics transcends academic curiosity. It promises to advance comprehension of these enigmatic cardiovascular conditions and, by extension, elevate patient care in a substantive and impactful manner -57.Shared Pathophysiological MechanismsEndothelial dysfunction: A central component in both CMD and TCM, endothelial dysfunction refers to the impaired function of the endothelium, the inner lining of blood vessels. In CMD, compromised endothelial function reduces vasodilation and impairs blood flow regulation within the coronary microvasculature. Similarly, endothelial dysfunction could hinder normal coronary blood flow responses in TCM, potentially contributing to the transient myocardial dysfunction observed during TCM episodes .Oxidative stress: Elevated oxidative stress, characterised by an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defences, is a common denominator in CMD and TCM. In CMD, oxidative stress can lead to endothelial dysfunction and structural alterations in the microvasculature, further impairing blood flow regulation. Takotsubo cardiomyopathy episodes, often triggered by stress, can trigger a surge in oxidative stress, which may contribute to myocardial injury and contractile dysfunction .Neurohormonal pathways: Dysregulation of neurohormonal pathways, particularly the autonomic nervous system's response to stress, plays a pivotal role in both conditions. Excessive release of stress hormones, such as adrenaline, can lead to vasoconstriction, increased heart rate, and myocardial oxygen demand. In individuals with pre-existing CMD, this heightened neurohormonal response could trigger the myocardium towards the transient dysfunction observed in TCM .Abnormal microvascular function and autonomic responses: Aberrant microvascular function, a hallmark of CMD, contributes to impaired myocardial perfusion and ischemia. In the context of TCM, microvascular dysfunction could exacerbate the myocardial stunning observed during TCM episodes. Furthermore, abnormal autonomic nervous system responses, including sympathetic overactivity, could influence both conditions, affecting coronary blood flow and myocardial contractility .Potential Role of Microvascular Dysfunction in Triggering TCMMicrovascular dysfunction is a compelling candidate for triggering TCM\u00a0in specific vulnerable individuals. Coronary microvascular dysfunction, marked by compromised vasodilation and impaired myocardial perfusion in the microcirculation, could set the stage for a cascade of events contributing to the initiation of TCM. The intricate link between these conditions is grounded in the notion that microvascular dysfunction might make the myocardium susceptible to the profound physiological responses of stress-induced catecholamine release .In individuals with CMD, the altered microvascular tone and reduced perfusion capacity might weaken the myocardium's resilience against the surge of stress hormones, particularly adrenaline. Stress-induced catecholamines have been implicated in TCM as potential triggers, initiating a sequence of cardiac events that lead to the distinctive features of this condition. The heightened vulnerability created by microvascular dysfunction could predispose the myocardium to stress-induced myocardial stunning, whereby the heart's contractility becomes impaired and its ability to pump blood effectively diminishes. This state of myocardial dysfunction, combined with the surge of catecholamines, could culminate in the hallmark ventricular ballooning pattern observed in TCM, particularly affecting the apex of the heart .Unravelling the intricate connection between microvascular dysfunction and TCM could provide valuable insights into the complex mechanisms governing the onset of TCM. By understanding how microvascular dysfunction amplifies the effects of stress hormones on the heart, researchers and clinicians can develop a more nuanced understanding of the factors contributing to TCM development. This comprehension, in turn, could inform targeted therapeutic approaches that address microvascular dysfunction and stress hormone responses, potentially mitigating the risk of TCM episodes in susceptible individuals .Impact of CMD on the Prognosis and Outcomes of TCMEmerging evidence underscores the potential significance of CMD\u00a0in shaping the clinical course of TCM. Research suggests that pre-existing CMD in individuals experiencing TCM could influence disease severity and subsequent clinical outcomes. This interaction between CMD and TCM holds implications for risk stratification and the development of tailored management strategies .In the context of TCM episodes, individuals with underlying CMD may exhibit more pronounced left ventricular dysfunction. The compromised microvascular function observed in CMD might render the myocardium vulnerable to the stress-induced catecholamine surge that characterises TCM. Consequently, the acute myocardial stunning and contractile impairment associated with TCM might manifest more severely in those with microvascular dysfunction. This could contribute to a heightened likelihood of complications, including heart failure and arrhythmias, impacting the overall prognosis .Recognising CMD as a potential modifier of TCM outcomes is crucial for risk assessment and management decisions. Risk stratification becomes more nuanced when CMD coexists with TCM, as these individuals might warrant closer monitoring and intensive interventions to mitigate the heightened risk of adverse events. Tailored management strategies could involve a more proactive approach to managing cardiac function, optimising fluid balance, and instituting preventative measures against potential complications. Such individualised management aligns with the complex interplay between CMD and TCM, addressing the unique vulnerabilities presented by their coexistence .Incorporating the potential impact of CMD into the risk assessment and management of TCM provides a broader perspective on the factors influencing disease progression and outcomes. As understanding this interaction evolves, healthcare practitioners can better tailor their approach to patient care, ensuring that individuals with CMD and TCM receive a comprehensive evaluation and strategic interventions that optimise their clinical trajectory .Theoretical Models Explaining the Relationship between CMD and TCMExploring the intricate relationship between CMD and TCM has given rise to several theoretical models to unravel the underlying mechanisms that potentially connect these conditions. These models provide valuable insights into the complex interplay between CMD and TCM, shedding light on possible pathways that link these distinct cardiovascular entities .The \"two-hit hypothesis\": This model postulates that CMD is the first \"hit,\" rendering the myocardium more vulnerable to subsequent stressors, such as catecholamine release triggered by emotional or physical stress. In this scenario, microvascular dysfunction could act as a priming factor, altering myocardial responsiveness and making it more susceptible to the detrimental effects of stress hormones. This susceptibility could lead to myocardial stunning and the unique contractile abnormalities observed in TCM. The \"two-hit hypothesis\" suggests that CMD sets the stage for the development of TCM by modifying the myocardium's response to stressors .The \"common substrate hypothesis\": According to this model, CMD and TCM share underlying mechanisms that make them mutually predisposing conditions. These shared mechanisms could include abnormalities in neurohormonal signalling, endothelial dysfunction, and impaired autonomic regulation. Factors that contribute to CMD, such as chronic stress or metabolic disturbances, could also create an environment conducive to the development of TCM under the right circumstances. The common substrate hypothesis underscores the potential interconnectedness of CMD and TCM, proposing that they arise from an everyday pathophysiological basis . ExploriClinical assessment and diagnostic challengesChallenges in Diagnosing CMD and TCM IndividuallyDiagnosing CMD\u00a0and TCM\u00a0as distinct cardiovascular conditions presents significant diagnostic challenges due to their unique complexities .Coronary microvascular dysfunction's subtle presentation and diagnostic complexity: Coronary microvascular dysfunction's inconspicuous and often asymptomatic nature adds to the difficulty of its identification. Unlike typical angina associated with traditional coronary artery disease, CMD often displays vague symptoms or remains entirely asymptomatic. Recognizing CMD becomes particularly challenging as patients may lack characteristic chest pain, leading to delayed diagnosis or overlooking the condition. Moreover, the absence of well-defined diagnostic criteria for CMD further compounds accurate detection .Diverse diagnostic criteria complicate CMD identification: The absence of universally agreed-upon diagnostic criteria for CMD contributes significantly to the diagnostic predicament. Varied definitions and diagnostic approaches across different medical contexts hinder establishing a consistent identification method. This lack of standardized criteria can lead to underdiagnosis or misclassification, impeding the implementation of appropriate management strategies .Takotsubo cardiomyopathy's resemblance to ACS\u00a0and diagnostic confusion: Takotsubo cardiomyopathy's clinical presentation resembles ACS\u00a0with symptoms like chest pain, electrocardiographic changes similar to\u00a0STEMI, and elevated cardiac biomarkers, which can cause diagnostic confusion. The overlap between TCM and ACS can result in healthcare providers selecting ACS treatment strategies without considering the possibility of TCM. Consequently, TCM patients might receive interventions like invasive coronary procedures or antithrombotic therapy that might not suit their condition .Implications of misdiagnosis: Misdiagnosing CMD and TCM can lead to inappropriate treatment plans and interventions. Mistakenly categorizing CMD patients as having non-cardiac causes for their symptoms could delay proper management, potentially exacerbating underlying microvascular dysfunction. Similarly, misidentifying TCM as ACS might expose patients to unnecessary invasive procedures and therapies, subjecting them to undue risks and potential complications .Overlapping Clinical Features and Diagnostic DilemmasThe convergence of clinical features between CMD and TCM\u00a0challenges their accurate diagnosis. Patients with both CMD and TCM may present with overlapping symptoms, including angina-like chest pain, breathlessness, and abnormal results in stress tests. The shared clinical presentation of these conditions accentuates the complexity of discerning one from the other. The diagnostic dilemma arises because these symptoms are common in various cardiac disorders, making it arduous to attribute them to CMD or TCM solely based on clinical presentation .In times of diagnostic uncertainty, the importance of employing precise diagnostic tools becomes evident. These tools must go beyond identifying symptoms and delve into each condition's underlying mechanisms and structural abnormalities. While symptoms might be the initial presentation, accurate differentiation necessitates comprehensive imaging techniques and functional assessments that illuminate the distinct pathophysiological underpinnings of CMD and TCM. This not only aids in pinpointing the correct diagnosis but also forms the foundation for developing targeted management strategies .Appropriate management hinges on accurate diagnosis, especially given the potential impact of shared symptoms on patient outcomes. The pursuit of enhanced diagnostic precision has driven the exploration of advanced imaging modalities such as cardiac MRI, which can delineate the myocardial microstructure and function, aiding in differentiating CMD from TCM. Moreover, non-invasive functional assessments like coronary flow reserve measurements using Doppler ultrasound offer insights into microvascular function and help discern between these conditions. The development and validation of these diagnostic tools are pivotal in overcoming the challenges posed by overlapping clinical features and ensuring optimal patient care .Novel Imaging and Diagnostic Techniques to Assess CMD and TCMThe continuous evolution of imaging and diagnostic technologies has paved the way for innovative methods of assessing CMD and TCM. These advancements offer promising avenues to enhance our understanding and diagnostic capabilities for these conditions .Cardiac MRI with contrast-enhanced perfusion imaging: Cardiac MRI\u00a0has emerged as a powerful tool for evaluating microvascular dysfunction in CMD. Utilising contrast-enhanced perfusion imaging, cardiac MRI allows for a non-invasive assessment of myocardial blood flow and perfusion patterns. This technique helps identify regions of impaired microvascular function and provides valuable insights into the subtler aspects of CMD. Moreover, cardiac MRI's ability to visualise the unique apical ballooning pattern associated with TCM aids in distinguishing it from other conditions with similar clinical presentations .Invasive techniques for microvascular assessment: Invasive techniques, such as coronary reactivity testing and Doppler ultrasound, are increasingly recognised for their potential in assessing microvascular function. Coronary reactivity testing involves administering pharmacological agents to induce controlled vasodilation and measuring the coronary blood flow response. This approach allows for the direct evaluation of microvascular reactivity and provides valuable information about the functional state of the microvasculature. Similarly, Doppler ultrasound offers insights into blood flow velocities within the microcirculation, aiding in identifying abnormalities in blood flow regulation .These novel techniques promise to improve the accuracy and specificity of diagnosing CMD and TCM. By enabling the direct assessment of microvascular function and subtle myocardial changes, these imaging and diagnostic methods enhance our ability to differentiate between these conditions and guide targeted treatment strategies. As these technologies continue to evolve, they are likely to play an increasingly significant role in the clinical management of CMD and TCM, facilitating earlier diagnosis and more personalised patient care .Importance of Accurate Diagnosis for Appropriate ManagementAccurate diagnosis is a cornerstone for effectively managing CMD\u00a0and TCM. The ramifications of misdiagnosis reverberate across patient outcomes, potentially causing profound harm. A misdiagnosed CMD might lead to inappropriate therapeutic interventions that neglect its unique pathophysiology, thereby failing to mitigate underlying microvascular dysfunction. This mismanagement could perpetuate the progression of microvascular impairment, contributing to a cascade of adverse cardiovascular events. Similarly, inaccurately managed TCM could translate into inadequate care for a condition that requires distinct attention. This misalignment in management could impede the natural recovery process and exacerbate the associated symptoms and complications .A comprehensive diagnostic approach is thus paramount to tailoring treatment strategies precisely to the specific condition at hand. Recognising CMD and TCM individually and understanding their potential coexistence inform appropriate therapeutic decisions. Accurate diagnosis empowers healthcare professionals to provide targeted interventions that address the intricate mechanisms driving each condition. Such precision ensures that interventions are aligned with the underlying pathophysiology, optimising the chances of positive patient outcomes. Through an accurate and holistic diagnostic approach, clinicians can circumvent the pitfalls of misdiagnosis, avoid unnecessary interventions, and significantly enhance patient well-being by offering the most fitting and efficacious treatments .Management strategiesConventional Treatment Approaches for CMDManaging CMD entails a comprehensive and multifaceted strategy that focuses on addressing the underlying risk factors contributing to microvascular dysfunction and improving the health and function of the microvasculature itself. This approach aims to alleviate symptoms, improve myocardial perfusion, and enhance cardiovascular health .Lifestyle modifications: A cornerstone of CMD management is empowering patients to adopt healthy lifestyle practices. Encouraging individuals to embrace a heart-healthy diet is crucial, emphasising the consumption of nutrient-rich foods such as fruits, vegetables, whole grains, lean proteins, and healthy fats while minimising processed foods, sugary drinks, and excessive sodium intake. This dietary approach supports blood pressure control, lipid management, and weight maintenance, ultimately promoting better microvascular health .Regular exercise: Physical activity improves endothelial function, enhances microvascular dilation, and increases cardiac fitness. Tailored exercise programmes that combine aerobic activities, strength training, and flexibility exercises can improve blood flow regulation and oxygen delivery to the myocardium. Regular exercise also positively impacts systemic factors such as blood pressure, lipid levels, and glucose metabolism, which are crucial in mitigating microvascular dysfunction .Stress reduction: Stress reduction techniques are pivotal in CMD management. Chronic stress can contribute to endothelial dysfunction and exacerbate microvascular abnormalities. Incorporating relaxation techniques such as deep breathing, meditation, and yoga can help mitigate the effects of stress on the cardiovascular system. Stress reduction also involves addressing psychosocial factors and adopting strategies to manage daily stressors effectively .Smoking cessation: Smoking significantly contributes to endothelial dysfunction and microvascular damage. Encouraging individuals to quit smoking is paramount to improving microvascular health and reducing the risk of cardiovascular events. Smoking cessation interventions, including counselling and pharmacotherapy, can significantly enhance endothelial function .Pharmacological interventions: Pharmacotherapy often addresses associated risk factors and enhances microvascular function. Angiotensin-converting enzyme (ACE) inhibitors manage hypertension and improve endothelial function by reducing vascular resistance. Statins are beneficial for managing dyslipidemia and mitigating inflammation, which can contribute to microvascular dysfunction. Antiplatelet agents, such as aspirin, may be prescribed to reduce the risk of thrombotic events and improve microvascular flow .Current Management Strategies for TCMMonitoring and assessment: Continuous monitoring of hemodynamics, fluid balance, and cardiac biomarkers is paramount to evaluating the extent of ventricular dysfunction, assessing fluid status, and tracking improvements. Regular blood pressure, heart rate, and oxygen saturation assessments help gauge the patient's cardiovascular stability and guide adjustments in medical management .Fluid management: Optimal fluid management is crucial to maintaining an appropriate balance while preventing fluid overload or depletion. Careful monitoring of urine output and central venous pressure aids in tailoring fluid administration, especially in the acute phase. Diuretics may be used judiciously to manage fluid retention and oedema .Complication prevention: Preventing complications is a cornerstone of TCM management. Standard heart failure therapies, including angiotensin-converting enzyme inhibitors, beta-blockers, and diuretics, might be considered in patients with significant ventricular dysfunction. These medications aim to alleviate symptoms, stabilise hemodynamics, and enhance cardiac function .Spontaneous recovery: One of the remarkable aspects of TCM is its tendency towards spontaneous recovery. Most TCM cases exhibit gradual improvement in left ventricular function over time. This recovery is a testament to the transient nature of the condition, although the timeline varies between individuals. Regular echocardiographic assessments are essential to monitor improvements and guide the adjustment of medical therapy .Long-term follow-up and psychological support: Although TCM cases typically show favourable outcomes, long-term follow-up is recommended to ensure sustained recovery and identify any potential recurrence. Psychological support is an integral component of TCM management, as the emotional stress that triggers TCM can leave a lasting impact on patients. Addressing the psychosocial aspects through counselling and support groups can aid emotional healing .Special Considerations When CMD and TCM CoexistWhen confronted with cases where both CMD\u00a0and TCM\u00a0coexist within an individual, an intricate treatment approach is imperative. The convergence of these conditions necessitates a holistic strategy that navigates the complexities of both CMD and TCM, acknowledging their potential interrelation. Central to this approach is recognising the profound impact that microvascular dysfunction, a hallmark of CMD, can exert on the outcomes of TCM .A critical step in managing such cases is meticulously evaluating individual patient characteristics. This evaluation extends beyond the confines of CMD and TCM, encompassing the patient's broader medical history, comorbidities, and risk factors. These factors play a pivotal role in shaping the optimal treatment path. Comprehensive risk assessment guides the selection of therapies, ensuring that interventions are tailored to address the unique nuances of both conditions while considering potential interactions and complications .The personalised approach in this context acknowledges the intricate interplay between CMD and TCM. Rather than viewing these conditions in isolation, healthcare practitioners should perceive them as interconnected components of the patient's cardiovascular landscape. Tailoring interventions to this interplay enhances patient care, yielding a more effective treatment regimen. This personalised strategy may encompass lifestyle modifications, pharmacological interventions, and psychological support, all seamlessly integrated to address both CMD and TCM harmoniously .By adopting this holistic and personalised treatment paradigm, healthcare professionals optimise patient management in cases where CMD and TCM coexist. This approach reflects a nuanced understanding of their potential relationship, emphasising the need to acknowledge the complex interplay between these conditions for the most effective and comprehensive patient care .Potential Future Therapies Targeting Both CMD and TCMImproving microvascular function: Emerging research suggests that interventions designed to enhance microvascular function could hold significant promise for both CMD and TCM. Therapies focused on endothelial health and vasodilation might alleviate the microvascular dysfunction common to both conditions, potentially preventing the cascade of events that lead to TCM. By improving coronary blood flow regulation, these interventions could mitigate the susceptibility of CMD patients to TCM episodes triggered by stressors .Mitigating the effects of stress hormones: Given the role of stress hormones, particularly adrenaline, in triggering TCM, future therapies could aim to modulate the effects of these hormones on the cardiovascular system. Developing agents that buffer the impact of stress-induced catecholamines might prevent or attenuate the myocardial stunning characteristic of TCM. These interventions could safeguard individuals with CMD, who might be at higher risk of developing TCM due to underlying microvascular dysfunction .Modulating neurohormonal pathways: Neurohormonal imbalances are implicated in both CMD and TCM, suggesting that therapies targeting these pathways could benefit both conditions. Agents that influence autonomic nervous system responses, regulate sympathetic activation, and modulate the release of stress hormones could provide a comprehensive approach to managing the intricate relationship between CMD and TCM. By restoring balance to these pathways, such interventions improve microvascular function and reduce susceptibility to TCM .Collaborative efforts between cardiology subfields: The convergence of CMD and TCM highlights the importance of collaboration among various cardiology subfields. Cardiologists specialising in microvascular disorders and those focused on TCM could work synergistically to develop targeted interventions. A collaborative approach could involve integrating expertise in vascular health, heart failure management, and neurohormonal regulation, resulting in therapies that effectively address the shared pathophysiological mechanisms underlying CMD and TCM .Future directions and research implicationsAreas for Further Research into the CMD-TCM RelationshipThe intricate connection between CMD and TCM\u00a0remains an area for further exploration. Research should delve deeper into understanding the underlying mechanisms that link these conditions, such as the role of shared neurohormonal pathways and their impact on microvascular function. Prospective studies could investigate whether CMD predisposes individuals to TCM and how CMD might modify TCM outcomes. Longitudinal studies assessing the prevalence of TCM in patients with documented CMD could help elucidate the temporal relationship between the two conditions.Novel Treatment Avenues Based on Understanding the LinkThe evolving understanding of the potential interplay between CMD and TCM could lead to novel treatment approaches that simultaneously target both conditions. Strategies focusing on improving microvascular function, addressing endothelial dysfunction, and modulating the impact of stress hormones hold promise in preventing or mitigating TCM episodes in susceptible individuals. Exploring the potential synergies between therapies used for CMD and TCM could yield innovative interventions that improve patient outcomes.Importance of Collaborative Research Between Cardiology DisciplinesGiven the potential overlap between CMD and TCM, collaborative research efforts among various cardiology disciplines are paramount. Cardiologists specialising in microvascular disorders and those focused on TCM should work together to uncover shared mechanisms, define diagnostic criteria, and develop comprehensive management strategies. A multidisciplinary approach integrating expertise from diverse fields, including cardiology, endocrinology, and psychology, can offer a more comprehensive understanding of the complex relationship between these conditions.In conclusion, this comprehensive review has illuminated the intricate relationship between\u00a0CMD\u00a0and\u00a0TCM, shedding light on their potential interconnection. Through thoroughly exploring their distinct characteristics, shared pathophysiological mechanisms, diagnostic challenges, and management strategies, we have unveiled the intriguing possibility that microvascular dysfunction may contribute to the development and outcomes of TCM. This understanding has significant implications for patient care, underscoring the importance of accurate diagnosis and tailored interventions, particularly in cases where CMD and TCM coexist. As we navigate the evolving landscape of cardiovascular medicine, we advocate for ongoing collaborative research efforts and heightened clinical awareness to unravel the complexities of this relationship. By doing so, we strive to enhance diagnostic precision, refine therapeutic approaches, and ultimately improve the well-being and outcomes of individuals affected by these fascinating cardiovascular conditions."} +{"text": "Accurate assessment of gender identity and biological sex in dermatology research is crucial since their conflation or poor demarcation undermines patient respect and study accuracy. Clearer guidance is needed for health care researchers, particularly in light of the notable disparities in skin disease rates, skincare practices, literature representation, and the persistent underrepresentation of transgender and nonbinary patients. Although gender identity is a social determinant of health, its assessment in health care research is inadequate. We highlight the intricacy of gender and biological sex in dermatology research, revealing the need for more robust protocols for their assessment. We begin by evaluating the current protocols used to make such assessments, demonstrating lack of consensus. Next, we evaluate the relationships between biological sex and gender identity and how these impact skin health. We then examine the inadequate representation of gender minorities\u2014including those who identify as transgender or gender nonbinary\u2014in academic literature and how this disparity compromises the applicability of evidence-based medicine to all. Finally, we consider the importance of physician communication about gender identity.The articles analyzed in this study emphasize the importance of transparency when delineating differences between biological sex and gender identity. In addition, researchers should be coached on techniques to extinguish investigators\u2019 biases. The models and tools for discerning gender identity and biological sex are shown in Note that the results obtained from the above methods were analyzed in conjunction with other questionnaires to assess correlations between the factors affecting overall population health ,2,4. GenQuestionnairesStanford Gender-Related Variables for Health Research (GVHR) Bem Sex-Role Inventory (BSRI) ,2BSRI: short form ,2GENESIS-PRAXY (Gender and Sex Determinants of Cardiovascular Disease: From Bench to Beyond-Premature Acute Coronary Syndrome) Guidelines and recommendationsSex and Gender Equity in Research (SAGER) guidelines Sex-gender variable: methodological recommendations for increasing scientific value of clinical studies Cisgender (gender identity corresponds to sex assigned at birth) males and females exhibit different rates of various skin diseases . IncreasGender-affirming therapies may induce drastic skin changes. Hormone therapies increase the risk of acne vulgaris, androgenetic alopecia, excessive sebum production, melasma, and hirsutism . DermatoResearchers believe numerous factors contribute to skin differences between gender identities . TransmaGender minority populations also face health care barriers from noninclusive treatment eligibility models. For instance, despite the increased prevalence of acne vulgaris in transgender populations, iPledge medication guidelines for isotretinoin use sex assigned at birth and require contraception to remain eligible .Although increasing female participation in clinical trials is widely supported, data on gender minority participation is nonexistent. Additionally, the risks of some conditions fluctuate depending on the stage of gender-affirming therapies. Although existing data sets may not use inclusive models of gender identity assessment, there is value in their implementation given the prospect of large-scale observational studies and meta-analyses in which these variables could be better assessed. As gender minority populations grow, these inclusive models will help physicians support all patients while ensuring that salient trends and health impacts are captured by research analyses.About 28% of transgender individuals delay seeking preventative care because of mistreatment by health care workers; thus, inclusive language is important to build trust in these communities . MedicalMisgendering patients can have profound effects on patients\u2019 health and safety and can damage the patient-provider relationship . As ideaRobust methodologies exist to eliminate subjectivity and maximize data accuracy and utility. Current approaches to distinguishing gender identity and biological sex are inadequate and threaten the applicability of research findings to many patients. Conflating sex and gender neglects the unique dermatologic health impacts of these attributes and contributes to the underrepresentation of gender minority populations in medical literature. While more research is needed to address these issues, communication training for physicians and other health care providers could be improved. The language used must respect patients\u2019 identities while maintaining objectivity in clinical research."} +{"text": "Major educational goals of Infectious Diseases (ID) are to recruit more trainees into ID and promote good antimicrobial decision-making. National survey research revealed that ID curricula that deemphasize memorization are associated with greater odds of trainees entering the field of ID. As ID electives are not required during medical school, preclinical ID courses could represent the last dedicated opportunity for students to gain exposure to the field and acquire key clinical skills for antimicrobial selection. Yet little is known about how students experience preclinical ID courses. We aimed to explore how students experience and engage with these courses to better understand how best to augment their learning and interest in ID.We conducted individual interviews with a purposeful sample of medical students who took the preclinical ID course during three curricular years (2019-2021). Our semi-structured interviews explored students' challenges in learning ID, as well as the motivations, learning principles, and strategies guiding that learning. We generated a codebook through an iterative, inductive process using Dedoose to code interviews and facilitate analysis. We confirmed and refined major themes over 19 interviews.Establishing Relevance, Organized Study, Relating Ideas, Multi-Modal Learning, Socially Constructed Learning, and Active Engagement with Material) that support student learning, deployed through four main strategies .Students face unique challenges learning ID but are motivated to succeed by both intrinsic and extrinsic factors (Table 1). We identified six core learning principles (Our results build on prior research indicating that students learning ID benefit from incorporation of educational principles and strategies that move beyond rote memorization to encourage active engagement and self-reflection. We found that students preference deep, strategic learning methods propelled by intrinsic motivation, despite external pressures. Our findings have implications for optimizing ID education and ultimately increasing interest in the field.All Authors: No reported disclosures"} +{"text": "A perceived increase in weekly quality control (QC) failures prompted the development of an electronic monitoring system for quality assurance of antibiotic susceptibility testing.Antibiotic susceptibility testing (AST) procedures are sensitive to variations in testing conditions. Our diagnostic laboratory is compliant with recommendations set out in Clinical and Laboratory Standards Institute (CLSI) M100 . The trends in cefepime zone sizes against P. aeruginosa ATCC 27853 also prompted an internal review and these improved when antibiotic disk dispensers were consolidated to improve disk utilization .Persistent recurrent borderline results reflected on the monitoring system sparked the implementation of systematic investigations into QC failures; a replacement program for QC strains; and standardization of incubation timings and desiccant usage. Using new American Type Culture Collection (ATCC) reference strains reduced the percentage of QC antibiotic-organism data which failed or were borderline, and led to greater consistency in testing . Visual presentation of QC data triggered greater reflection. For instance, recurrent failures of ertapenem disks against Systemic monitoring of QC trends is low cost and highlights issues which were previously not apparent. Standardization of practices and a systematic troubleshooting process have improved the quality of our disk diffusion susceptibility testing.All Authors: No reported disclosures"} +{"text": "Coronary vasospasm is a known complication after coronary artery bypass grafting surgery but has rarely been described in non-coronary cardiac operations. We report the case of a 51-year-old male with nonischemic cardiomyopathy and paroxysmal atrial fibrillation. He presented with severe mitral and tricuspid regurgitation and was taken for mitral valve replacement, tricuspid valve repair, and Maze procedure. Postoperative emergent coronary angiography demonstrated diffuse coronary vasospasm. Injection of intracoronary nitroglycerin led to clinical and angiographic improvement. This demonstrates the possibility of coronary vasospasm following mitral valve replacement and effective treatment with intracoronary administration of vasodilating agents. Coronary vasospasm is a known and feared complication following coronary artery bypass grafting surgery that has rarely been described in non-coronary cardiac operations . IatrogeWe describe herein the case of a 51-year-old African American male with hypertension, paroxysmal atrial fibrillation, stage III chronic kidney disease, and nonischemic cardiomyopathy presenting with progressive shortness of breath and bilateral lower extremity edema. Echocardiogram demonstrated severe mitral regurgitation with asymmetric systolic restriction (Carpentier Type IIIc) and moderate-to-severe tricuspid regurgitation Figure . Right hCardiopulmonary bypass (CPB) was initiated with Del Nido cardioplegia. The mitral valve was replaced with 33mm St. Jude Biocor Porcine bioprosthetic, tricuspid valve repair was performed with Edwards MC3 30mm annuloplasty ring, LAA was ligated with AtriCure 50mm AtriClip, and Cox-Maze IV was completed with a cryoprobe. The transesophageal echocardiogram showed a well-seated mitral valve prosthesis with a peak gradient of 5 mmHg, a mean gradient of 2 mmHg, and no paravalvular leak Figure . IntraveCoronary vasospasm is a known and feared complication after coronary artery bypass grafting surgery but has rarely been described in non-coronary cardiac operations. Iatrogenic causes of ST-segment changes, hemodynamic instability, or difficulty weaning from CPB must be considered after valvular surgery and anti-arrhythmia procedures. Left circumflex artery injury or occlusion during mitral valve surgery and right coronary artery injuries during tricuspid valve operations are well described ,3. HowevH\u00a0Shafei et al. reportedUnlike most of the cases above, our patient developed ST segment changes while still in the operating room. The decision to pursue coronary angiography rather than reopening and performing a bypass graft is not trivial, but neither is the exercise of attempting a graft to the obtuse marginal branches. We must also consider the potential injury from cryoablation used during the CMP. Direct ablation of the coronary arteries may lead to significant obstruction or total occlusion. There is also a theoretical risk of indirect injury from cryolesions penetrating too deeply or pericoronary edema following the procedure.\u00a0If technical considerations have been ruled out as a source of coronary injury, systemic administration of vasodilators is an appropriate next step. If this fails to address the issue, then in the appropriate patient, transportation to the coronary catheterization laboratory can provide further information via emergent coronary angiography with the potential to deliver intracoronary vasodilators and perform other advanced interventions. This capability does require a close working relationship between the surgical, anesthesia, and interventional teams within the hospital system. The availability of interventional cardiology allowed us to avoid a bypass graft that likely would have failed in the short term and not addressed the underlying pathology.\u00a0Diffuse coronary vasospasm is a rare and potentially devastating complication following noncoronary cardiac surgery that should be considered in the setting of ECG changes and hemodynamic instability. As demonstrated by this case and the others cited, coronary spasms may present intraoperatively, shortly after the patient arrival to the intensive care unit, or in the first days after noncoronary surgery. Consideration of this pathology in the event of new ECG changes and hemodynamic changes will allow for timely diagnosis and treatment."} +{"text": "Neurotrauma and Repair: from Peripheral to Central Nerve Injury\u201d brought together a diverse group of 58 authors, fostering interdisciplinary collaboration and offering new insights into the multifaceted landscape of neurotrauma research.Neurotrauma, encompassing traumatic brain injury (TBI), peripheral nerve injury (PNI), and spinal cord injury (SCI), continues to be a major global public health concern. The complex pathophysiological mechanisms and lifelong neurological deficits associated with neurotrauma emphasize the urgent need for effective clinical interventions. The Research Topic \u201cThis collaborative effort yielded a body of work that has garnered significant attention within the scientific community, underscoring the importance of the research contributions and the demand for advances in neurotrauma understanding and treatment.Effects of a Neurokinin-1 Receptor Antagonist in the Acute Phase after Thoracic Spinal Cord Injury in a Rat Model\u201d delves into the potential therapeutic effects of neurokinin-1 receptor antagonists on neuroinflammation and edema following SCI . While the study suggests limited impact on reducing edema, it demonstrates a notable reduction in T-lymphocyte invasion and apoptotic cell numbers with the treatment. Additionally, it suggests a trend toward reduced fibrinogen leakage, endothelial and microglial activation, chondroitin sulfate glycosaminoglycan deposition, and astrogliosis. Although general locomotion recovery remained modest, CatWalk gait analysis revealed early improvements in several parameters. This research showcases the intricate and multifaceted nature of SCI and the potential of neurokinin-1 receptor antagonists in mitigating some aspects of neurogenic inflammation.\u201cMuscle-Derived Stem Cell Exosomes with Overexpressed miR-214 Promote the Regeneration and Repair of Rat Sciatic Nerve after Crush Injury,\u201d researchers explore the regenerative potential of muscle-derived stem cell exosomes enriched with miR-214 . The study demonstrates the ability of these exosomes to promote the proliferation and migration of Schwann cells, enhance the expression of neurotrophic factors, and facilitate axon extension in dorsal root ganglion neurons. By targeting PTEN and activating the JAK2/STAT3 pathway, these exosomes hold promise for promoting nerve regeneration in the context of sciatic nerve crush injuries. This research not only contributes to our understanding of neural repair mechanisms but also offers a potential avenue for therapeutic intervention.In \u201cPartially Brain Effects of Injection of Human Umbilical Cord Mesenchymal Stem Cells at Injury Sites in a Mouse Model of Thoracic Spinal Cord Contusion\u201d takes an intriguing angle, investigating the consequences of SCI on the brain . This study explores the potential therapeutic mechanisms of human umbilical cord mesenchymal stem cell injection at the injury site. It highlights the intricate interactions between the spinal cord and the brain, underscoring the interconnectedness of neural systems. This research raises important questions about the broader neurological effects of spinal cord injuries and offers insights into potential therapeutic interventions that could extend beyond the immediate injury site.\u201cA Closed-Body Preclinical Model to Investigate Blast-Induced Spinal Cord Injury\u201d introduces an innovative preclinical model for studying blast-induced spinal cord injuries . These injuries are particularly relevant in military contexts, where exposure to blast overpressure can result in significant spinal trauma. This research enhances our understanding of blast dynamics and their effects on the spinal cord, providing valuable insights into the complexities of these injuries. By investigating markers of traumatic axonal injury and neuroinflammation, this study sets the stage for future research into minimally invasive treatment approaches.\u201cHuntingtin-Associated Protein 1 Ameliorates Neurological Function Rehabilitation by Facilitating Neurite Elongation,\u201d researchers explore the role of Huntingtin-associated protein 1 (HAP1) in promoting neurological function recovery . By activating the TrkA-MAPK signaling pathway, HAP1 demonstrates its potential to enhance neurite elongation and improve outcomes in SCI. This study not only advances our understanding of the molecular mechanisms underlying neural repair but also suggests a promising avenue for therapeutic intervention.In \u201cDifferential Effects on TDP-43, Piezo-2, Tight-Junction Proteins in Various Brain Regions Following Repetitive Low-Intensity Blast Overpressure\u201d delves into the often-overlooked issue of mild traumatic brain injuries caused by repetitive low-intensity blast overpressure . This research highlights the varied effects of such exposures on critical proteins in different brain regions, underscoring the structural and anatomical heterogeneity of the brain. The findings emphasize the need for a comprehensive understanding of neurotrauma's diverse impacts, especially in military and combat-related contexts.\u201cA Cutting-Edge Strategy for Spinal Cord Injury Treatment: Resident Cellular Transdifferentiation,\u201d the authors explore a cutting-edge strategy for SCI treatment\u2014resident cellular transdifferentiation . This innovative approach involves reprogramming mature somatic cells into functional neurons, offering new hope for post-traumatic spinal cord repair and functional improvement. While the mechanisms and induced neuronal subtypes are not yet fully understood, this review provides a comprehensive analysis of the current state of research in this exciting field.In the review article \u201cThese contributions collectively advance our understanding of neurotrauma and offer new insights into potential pathways for treatment. While challenges remain, this collaborative effort signifies progress in the field, underscoring our shared commitment to alleviating the burden of neurotrauma for individuals worldwide. As we reflect on these achievements, we acknowledge the road ahead, filled with challenges and opportunities. Neurotrauma research continues to evolve, driven by a global community of researchers dedicated to translating insights into tangible treatments. Together, we embark on a journey that promises to bring healing and recovery to those affected by neurotrauma, one breakthrough at a time.AY: Writing\u2014original draft."} +{"text": "The mesentery is a broad fan-shaped fold of peritoneum that suspends the loops of small intestine from the posterior abdominal wall. Although primary neoplasms arising in the mesentery are rare, the mesentery is a major avenue for the dissemination of tumours, which can spread through hematogenous, lymphatic, direct or peritoneal seeding. Imaging helps in the diagnosis of these tumours and aids in directing appropriate treatment by assessing their size, extent and relationship with adjacent structures. The aim of this article is to describe the spectrum of imaging findings of the various mesenteric lesions using ultrasound and CT.Evaluation of the mesentery is often neglected during routine ultrasound (US) because of inadequate training and unfamiliarity with the common US features encountered with mesenteric disease. CT plays an essential role in the diagnosis of mesenteric disease. Knowledge of imaging characteristics of various mesenteric lesions helps in timely diagnosis and management. The mesentery is a broad, fan-shaped fold of peritoneum that suspends the loops of small intestine from the posterior abdominal wall. Secondary involvement of the mesentery from tumours elsewhere is much more common than primary mesenteric neoplasms such as desmoid tumour, inflammatory myofibroblastic tumour (IMFT), and others. Most patients with mesenteric lesions present with non-specific symptoms of abdominal pain, tenderness, palpable abdominal swelling, abdominal distension and weight loss. These symptoms are shared by pathologies of other abdominal organs and it is therefore very difficult to identify mesenteric lesions clinically.Some mesenteric diseases present with distinctive imaging findings while others have similar findings, thereby complicating their differential diagnosis. Understanding the characteristic radiological patterns on ultrasound (USG) and CT offers valuable insights for differential diagnoses of mesenteric lesions and their treatment.Primary mesenteric solid neoplasms are rare and the majority of them are benign.1 On USG, this tumour appears as a well-defined or ill-defined mass with heterogenous echotexture and internal vascularity. On CT, it appears as a well-defined or ill-defined mass showing heterogenous enhancement usually in the portal venous phase and it may infiltrate the adjacent organs.2 The MRI appearance of desmoid tumours depends on the relative proportion of cellular, myxoid and fibrous components.The most common soft tissue lesion in the mesentery is a desmoid tumour. It usually occurs in patients with familial adenomatous polyposis (FAP) or Gardner syndrome. Trauma or surgery serves as a predisposing factor for the development of desmoid tumours.3 Inflammatory myofibroblastic tumour appears as a hypo or iso-attenuating mass compared with skeletal muscle depending on the amount of myxoid or collagenous stroma, respectively. Dense central calcification may be noticed. They demonstrate various contrast enhancement patterns including early peripheral enhancement because of vascular tissue , associated soft tissue component and thick irregular septations. Liposarcomas are rare malignant tumours of the mesentery. Liposarcomas are divided into five types histopathologically: well-differentiated, myxoid, pleomorphic, round cell and de-differentiated liposarcoma. Well-differentiated liposarcomas have mixed fatty and soft tissue components while de-differentiated liposarcomas have clearly separated soft tissue and fatty components. Myxoid liposarcomas have fluid density on CT with mixed soft tissue and fatty components. Pleomorphic and round cell liposarcomas have soft tissue components only, with no identifiable fatty component on imaging.5Three patterns of mesenteric involvement have been described for Castleman disease, namely a solitary non-invasive mass (most common), a dominant infiltrative mass with associated lymphadenopathy and matted lymphadenopathy without a dominant mass. These tumours show early, homogenous and intense enhancement . Tumours6 is seen as one or more irregular fibrotic soft tissue mesenteric masses10 They show variable attenuation depending on their contents and may insinuate between the mesenteric vessels on USG and as a unilocular or multilocular cyst with enhancement of the wall or septations on contrast enhanced CT. vessels .11These appear as thin-walled anechoic unilocular cysts with posterior acoustic enhancement on USG and unilocular fluid attenuation lesions with no discernible wall on CT.2 They occur because of entrapment of fluid (secreted by the ovaries during ovulation) between peritoneal adhesions.7 They are seen as a fluid attenuation multilocular cystic lesion, multiple unilocular thin-walled cysts or unilocular cystic mass on CT with enhancing but non-calcified septa, which often surround the ovaries. On USG, they appear as unilocular or multilocular cystic lesions, which may be anechoic or may display contents of variable echogenicity and demonstrate homogeneous enhancement following contrast administration . Other findings observed in cases of abdominal tuberculosis include mesenteric nodularity, fat stranding, peritoneal thickening, localised collections, free fluid, clumping of bowel loops, bowel wall thickening and solid organ involvement in the form of hepatomegaly, splenomegaly, liver and splenic granulomas.Tropheryma whipplei. On imaging, small bowel wall thickening associated with enlarged mesenteric lymph nodes demonstrating hypoattenuating centres because of fat deposition can be seen. Diagnosis is made by small intestinal mucosal biopsy.16It is an infectious condition caused by Gram-positive bacterium, Actinomyces israelii is an anaerobic Gram-positive bacterium and is a normal inhabitant of the oral cavity, gastrointestinal tract and female genital tract. It spreads to involve the mesentery when a mucosal breach is present such as inflammation, surgery, trauma or intrauterine contraceptive device (IUCD) use.17 On imaging, an ill-defined heterogeneously enhancing soft tissue mass infiltrating the mesentery and adjacent organs can be seen. Septic embolism leading to hepatic, renal and splenic abscesses can occur.2 Diagnosis is made based on aggressive imaging features and subtle clinical symptoms in predisposed individuals. Biopsy should be performed in indeterminate imaging findings, which reveal sulphur granules representing bacterial colonies.18These usually occur because of intraperitoneal rupture of liver or splenic hydatid cysts . HydatidMesenteric changes in inflammatory bowel disease include mesenteric fibrofatty proliferation, mesenteric lymphadenopathy, fat stranding , abscess19 (Findings in acute mesenteric ischaemia related to superior mesenteric artery (SMA) thrombosis include dilated bowel loops with paper-thin walls, pneumatosis intestinalis, air within mesenteric vessels, mesenteric fat stranding and free fluid on CECT19 .On USG, tangled serpentine vessels can be seen, which show pulsatile waveforms on spectral doppler while on CECT, tangled serpentine vessels can be seen with early opacification of venous channels in the arterial phase. Direct communication between branches of the SMA and superior mesenteric vein (SMV) can be visualised on volume rendering technique (VRT) images.20 Evaluation of lesions is limited on USG because of operator-dependence, obscuration of the mass in the presence of a gaseous abdomen and obese patients, and inadequate visualisation of the extent of large mesenteric lesions. Contrast enhanced CT is the primary workhorse for evaluation of mesenteric lesions. It helps in determining the origin of the lesions, providing thoughtful differential diagnosis of masses, for selecting the site of biopsy, determining the extent of pathology and accessibility for resectability of lesion. CT, however, has several limitations including poor soft tissue contrast resolution, exposure to ionising radiation and contrast reactions. MRI can be used as the next step in characterising mesenteric lesions. It has higher soft tissue contrast resolution and helps in characterising fluid content of cysts as serous, mucinous, chylous or haemorrhagic and the soft tissue component of solid lesions. Fluoro-deoxyglucose (FDG) positron emission tomography (PET) CT is presently used to detect lymph nodes and distant metastases in mesenteric tumours and also for response assessment to chemotherapy.Ultrasound is the primary imaging modality in the evaluation of mesenteric lesions. It helps in characterising mesenteric lesions as solid or cystic. Ultrasound guided percutaneous biopsy offers real time assessment of the needle tract to avoid vascular injury while performing biopsy.21Management of mesenteric lesions depends on symptoms and imaging findings. Mesenteric lesions detected incidentally on imaging need classification as benign or malignant. Definite diagnosis of a few pathologies such as mesenteric panniculitis, lymphoma, desmoid tumour in patients with FAP and benign cystic lesions can be made on imaging. However, lesions with indeterminate imaging findings need to be biopsied to rule out malignancy. Imaging helps in determining the site for percutaneous biopsy in such tumours. Lesions that are inaccessible to percutaneous biopsy or show indeterminate histopathology findings on percutaneous biopsy require surgical biopsy to confirm the diagnosis.Once confirmed by biopsy, management of the mesenteric lesions depends on the histopathology. Lymphomas and desmoid tumours are managed conservatively with chemotherapy and hormonal therapy or imatinib, respectively. Well-circumscribed lesions located in the periphery of the mesentery can be resected completely, without sacrificing significant bowel length or major mesenteric vessels. Infiltrative mesenteric lesions, located in the root of mesentery are usually managed conservatively because of involvement of major vessels and the need for sacrificing a major portion of bowel, which may lead to small bowel syndrome. Well-defined malignant tumours and symptomatic benign tumours are treated surgically. The goal of surgery is R0 resection , while R1 resection followed by adjuvant chemoradiotherapy can also be performed. Well-defined asymptomatic benign lesions can be followed up and resection is performed when they become large or cause symptoms. Symptomatic infiltrative benign or malignant lesions can be managed by debulking surgery to reduce tumour load and prevent complications such as bowel obstruction or mesenteric ischemia.Although histopathology is the gold standard for diagnosis of mesenteric lesions, imaging plays an important role in diagnosis of mesenteric neoplasms, detection of complications and in deciding appropriate treatment options. Ultrasound is inadequate for optimal visualisation of mesenteric neoplasms and in detecting their relation with other structures because of shadowing from bowel gas, calcification or inadequate penetration of sound beams in obese patients. CT is an excellent imaging modality in the characterisation of mesenteric lesions, detecting their extent and relations with surrounding structures, which is useful for surgical planning. However, CT too has several limitations and other imaging modalities such as MRI and FDG-PET can be helpful in further characterisation of mesenteric lesions."} +{"text": "This report aimed to present a case of wrist-tendon rupture and to discuss a rare complication after corticosteroid injection. A 67-year-old woman had difficulty extending her left-thumb interphalangeal joint several weeks after a palpation-guided local corticosteroid injection. Passive motions remained intact without sensory abnormalities. Ultrasound examination showed hyperechoic tissues at the site of the extensor pollicis longus (EPL) tendon at the wrist level and an atrophic EPL muscle stump at the forearm level. Dynamic imaging demonstrated no motion in the EPL muscle during passive thumb flexion/extension. The diagnosis of complete EPL rupture, possibly due to inadvertent intratendinous corticosteroid injection, was therefore confirmed. This report aimed to present a case of wrist-tendon rupture and to discuss a rare complication after corticosteroid injection. A 67-year-old female complained of difficulty in extending the left thumb for several months. The medical history comprised radial wrist pain after a contusion injury one year ago, for which corticosteroid injection under palpation guidance had also been performed, with gradual symptom relief. The physical examination revealed loss of the active extension of the left-thumb interphalangeal joint with normal passive motions . Other fThe posterior interosseous nerve (PIN) remained bilaterally intact based on dynamic tracking from the level of the supinator tunnel to the dorsal wrist . Moving Finger drop can ensue due to neurological and orthopedic causes . In caseStatic ultrasound examination can serve as a helpful tool for scrutinizing tendon injury, whereas dynamic imaging can be employed to validate motion problems. The most common sonographic finding of tendon rupture is loss of fiber continuity with the formation of a retracted stump. The absence of normal tendon gliding during passive motion further confirms the diagnosis . In chroOne of the important etiologies of spontaneous EPL tendon rupture is intratendinous corticosteroid injection. Other causes include distal radial fracture, repetitive friction against metal implants, and contusions . Local cNeedless to say, ultrasound is a preferred tool for guiding the needle, in order to avoid unwanted intratendinous corticosteroid injection ,17. Peri"} +{"text": "This case highlights the importance of having constrictive pericarditis (CP) as a differential diagnosis in unexplained sign and symptoms of right-sided heart failure. This case portrays challenges in diagnosing CP caused by certain rheumatologic diseases despite advances in diagnostic modalities, clinical suspicion remains the most important tool for this diagnosis. Constrictive pericarditis (CP) is a rare condition that often presents with non-specific symptoms and is often misdiagnosed. CP is characterized by a rigid pericardium that restricts the heart, resulting in signs and symptoms of diastolic heart failure. It occurs as a late sequela of pericardial inflammation caused by prior infection or radiation, inflammatory diseases and rarely, connective tissue disorders. We present a case of new-onset right-sided heart failure caused by constrictive pericarditis in a patient with diffuse systemic sclerosis (SSc). This case highlights the importance of having CP in our differential diagnosis in patients with unexplained sign and symptoms of right-sided heart failure and increased systemic venous pressure. This is crucial since CP secondary to SSc is largely curable and failure to diagnosis has devastating consequences. This case portrays the challenges in diagnosing pericardial diseases caused by certain rheumatologic diseases and that despite advances in diagnostic modalities, clinical suspicion remains the most important tool for this diagnosis.A 27-year-old female with a seven-year history of diffuse systemic scleroderma complicated by recurrent pericarditis and severe Raynaud\u2019s disease resulting in gangrene and amputation of the upper and lower extremity digits presented to the hospital with two weeks of progressive shortness of breath, early satiety, fatigue, abdominal distention, and lower extremity pain and edema. The physical examination was notable for the presence of jugular vein distention with positive hepatojugular reflux, right upper quadrant tenderness, ascites and 3+ lower extremity edema to the thighs. Her heart rate was 108 beats per minute; other vital signs were within normal limits. EKG showed sinus tachycardia with nonspecific ST-T wave changes. Chest x-ray showed a moderate right-sided pleural effusion with right basilar airspace opacity and a cardio mediastinal silhouette. Transthoracic echocardiogram demonstrated a normal left ventricular ejection fraction, mildly reduced right ventricular function, mild pulmonary hypertension with an estimated mean pulmonary artery pressure of 40 mmHg, and no significant valvular abnormalities. Abdominal ultrasound redemonstrated ascites and was also notable for hepatomegaly and a hyperechoic pancreatic mass.Initially the patient\u2019s ascites was attributed to intrinsic hepatic disease and she was started on diuretics. However, her renal function deteriorated, halting diuresis while further diagnostic evaluation was pursued. The patient continued to have abdominal distension and shortness of breath which prompted a cardiovascular evaluation with a right heart catheterization. Mild pulmonary arterial hypertension was noted with elevated mean pulmonary arterial pressure (mPAP) of 28 mmHg. Due to the discrepancy between the mildly elevated cardiac filling pressures and significant anasarca on physical examination, a repeat hemodynamic assessment was pursued. The patient underwent right and left heart catheterization which discovered near equalization of the diastolic filling pressures, raising suspicion for pericardial tamponade constrictive physiology . In addiAs most diagnostic imaging studies were contraindicated due to the patient\u2019s impaired renal function, a cardiac MRI without contrast was obtained to evaluate for possible pericardial disease. Cardiac MRI showed an abnormally thick pericardium (4\u20135 mm) and evidence of significant pericardial adhesion with a small dependent pericardial effusion. The ventricles were cone shaped and a septal bounce was seen during diastole. In addition, free breathing CINE imaging demonstrated ventricular interdependence. These findings were consistent with pericardial constriction.After extensive discussion between cardiology, rheumatology, nephrology and cardiothoracic surgery, the primary team agreed that surgical intervention was the best option to improve this patient\u2019s quality of life and disease prognosis. Subsequently, she underwent successful pericardiectomy with complete resolution of her symptoms. The pathology report revealed extensive dense fibrosis in the pericardium that was likely secondary to patient\u2019s known collagen vascular disease.Cardiac involvement in both limited and diffuse SSc has been recognized over the years as one of the most rare and feared complications due to poor prognosis . CardiacThe noteworthy pathophysiology involved in presentation of this condition is unique in that there is recurrent coronary microvascular ischemia and myocardial inflammation which leads to ischemic necrosis, reperfusion damage, and myocardial fibrosis . This adHowever, constrictive physiology can complicate virtually any condition associated with pericardial effusion . The nonCertain serologic tests for patients with systemic sclerosis can provide useful information about specific organ involvement, including cardiac manifestations. Studies have shown that patients with SSc with myocarditis had cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) and antiproteinase 3 (PR3) antibody positivity . FurtherOverall, due to the high prevalence of cardiac involvement in patients with SSc, it becomes imperative to do a thorough history taking and examination of this population. Prompt recognition and management of constrictive pericarditis can alleviate symptoms such as volume overload, drastically transform these patients\u2019 quality of life, improve prognosis, and decrease mortality.This case portrays the challenges in diagnosing pericardial diseases caused by certain rheumatologic diseases and that despite advances in diagnostic modalities, clinical suspicion remains the most important tool for this diagnosis.To be able to recognize rare but very specific findings of a constrictive pericarditis physiology.To understand the role of Multidisciplinary approach to benefit the patient\u2019s quality of life.A patient presenting with an odd case of Constrictive Pericarditis due to Systemic Sclerosis."} +{"text": "A hallmark of retroviral replication is stable integration of the viral genome in the host cell DNA. This characteristic makes retroviral-derived vector particles attractive vehicles for gene therapy. However, retroviral integration is not a random process. Lentiviruses preferentially integrate in the body of active transcription units, while gammaretroviruses, including Moloney Murine Leukemia Virus (MLV), favour transcription start sites and CpG islands. In clinical trials using gammaretroviral vectors for gene therapy, leukemogenesis has been associated with integration of vectors near oncogene transcription start sites. We found that the bromodomain and extra-terminal (BET) proteins interact with MLV integrase and direct integration towards transcription start regions. BET proteins specifically bind and co-localize with the gammaretrovirus integrase protein in the nucleus of the cell. The interaction is gammaretroviral-specific and mediated by the integrase C-terminal domain and the BET extraterminal (ET) domain as determined by co-immunoprecipitation assays and in an Alphascreen assay using recombinant proteins. Interfering with chromatin interaction of BET proteins via specific bromodomain inhibitors JQ1 and l-BET decreases MLV virus replication and MLV vector transduction 5-to 10-fold, while HIV vector transduction is not affected. Analysis of viral DNA intermediates by quantitative PCR revealed a block at the integration step. In addition, bromodomain inhibitors do not have an effect on the late steps of viral replication. MLV integration site distribution analysis revealed a strong correlation with the BET protein chromatin binding profile. Finally, expression of an artificial fusion protein that merges the BET integrase binding domain with the chromatin interaction domain of the lentiviral targeting factor LEDGF/p75, retargets MLV integration into the body of actively transcribed genes, paralleling the Human Immunodeficiency Virus (HIV) integration pattern. Our results explain the molecular mechanism behind gammaretroviral integration site targeting and suggest methods for engineering gammaretroviral vectors with a safer integration site profile."} +{"text": "Next-generation DNA sequencing has dramatically affected cancer genomics efforts in several important ways. Although whole genome sequencing remains an analytical challenge, such efforts are yielding data that elucidate the myriad ways in which a genome can be influenced by single point mutations, focused insertions or deletions, and large structural alterations. In addition to cataloguing somatic alterations, various correlation analyses are indicating the genes whose alterations most profoundly determine patient outcomes, patient responses to therapeutics and other important aspects of disease biology. We have recently begun exploring how the digital nature of next-generation sequencing reads allows important information about tumor cell genomic heterogeneity to be inferred, revealing the earliest mutations and how the composition of the tumor cell mass changes over time under the influence of stressors such as chemotherapy."} +{"text": "To study the role of hypotension and associated injuries in increasing the chances of secondary amputation in lower limb with vascular injuries.This study was conducted in the Department of cardiovascular and thoracic surgery( CVTS ), Sher-i- Kashmir Institute of Medical Sciences, ( SKIMS ) Srinagar Kashmir India and comprised all patients sustaining vascular injury due to different causes like road traffic accident, fire arm and blast injuries or falling from height during the last five years. Following admission to our Department, the patients were divided into two groups. The first group with associated injuries was hemodynamically unstable during vascular repair or in post-operative period and the second group had no associated injuries and was hemodynamically stable during vascular repair and in post-operative period.During the past five years, 95 patients were operated for lower limb vascular injury in our department. Of these 25 patients had associated multi-organ injuries and were hemodynamically unstable and needed intensive care monitoring after surgical intervention. Additionally, 10 patients died due to associated multiple organ injuries, 10 needed amputation due to recurrent thrombosis of their anastomosis, and in five patients limb salvage was achieved. Seventy patients who had isolated limb vascular injuries with no associated injuries or hypotension were hemodynamically stable and were kept in low dependency unit after vascular repair. Only Four patients from this group needed amputation for thrombosis of the anastomosis.Patients with shock and related injuries face significant rate of amputation. These patients whether with multi-organ injuries or isolated vascular injuries need judicious treatment for hypovolumic shock during surgical intervention and in post-operative period. Injury to the popliteal vessels has been recognized as one of the most limb-threatening peripheral vascular injuries so far as vascular trauma has been studied. The popliteal artery is a true end artery with a tenuous collateral supply. The popliteal vein provides the bulk of lower limb and foot drainage. This explains why injury to these vessels is so dangerous. Management of these multiply injured patients can be very challenging and restoring perfusion to an ischemic extremity needs to be accomplished within 6\u20138 hours, if limb is to be salvaged. Clean and sharp cut in the artery closed by primary repair behave differently than an arterial repair with RSV(Reverse saphenous vein graft) graft which needs multiple Fogarty catheterization for retrieval of thrombus. Extensive tissue damage increases chances of compartment syndrome (CS). Post\u2013operative infection and CS are most important causes for amputation. Conventionally there are hard and soft signs of vascular injury. Hard signs which warrant immediate intervention include i) external arterial bleeding, ii) rapidly expanding hematoma, iii) palpable thrill, and audible bruit, iv) signs of acute limb ischemia. Soft signs of vascular injury warrant urgent evaluation in the form color Doppler/angiography. The successful management of vascular injury includes two goals: i) treating the life-threatening problems by fluid resuscitation, control of bleeding and ensuring adequate oxygenation; ii) repairing the injured vessel and save the limb. Arterial repairs include: reverse saphenous vein graft, primary repair, PTFE( polytetrafluroethylene) graft, ligation, and vein patch. CS leads to tissue necrosis, permanent functional impairment, or severe renal failure and death. The general consensus is that intra-compartmental pressures (ICPs) greater than 30mm Hg require intervention. During the first and second world wars, important knowledge had been gained both in diagnosis and treatment of vascular injuries, but vascular reconstructive methods were mainly introduced during the Korean and Vietnam wars with tremendous progress , 2.The studied population included patients with sustained vascular injury due to different causes like road traffic accident, fire arm and blast injuries or falling from height and admitted to our center during the past five years. The patients were divided into two groups of hemodynamically unstable and stable patients during vascular rep air or in post-operative period and notes were taken of their other associated injuries. Severity of injury was assessed by MESS (mangled extremity severity score). All hemodynamically unstable patients during and after surgery, had multiple organ injury and needed intensive care monitoring. However, hemodynamically stable patients were managed in a low dependency unit after vascular repair, and had predominantly isolated lower extremity injury or associated minor injuries. All patients operated for lower limb vascular injury were followed for post-operative outcome with respect to patency of the anastomosis and adequate blood flow for viability of the limb. Distal blood flow was assessed by clinical examination followed by Doppler study to confirm doubtful clinical examination. All patients who needed primary or secondary amputation with MESS score equal to or greater than 7 were excluded from the study. The study included only patients with MESS score of <6 and confirmed to have good vascularity on table by clinical as well as by vascular Doppler examination. Hemodynamic parameters and blood gas analysis were checked during and after operation. Post-operative blood gases and electrolytes were determined four hourly in patients who needed intensive care monitoring. Other associated injuries were taken care of by respective departments including general surgery, plastic surgery, neurosurgery and by critical care specialists.0 double arm prolene. As for associated injuries, the patients referred to other specialties. Hemodynamic parameters, blood gas and electrolytes were checked during the operation.After initial resuscitation and assessment, patients with confirmed arterial injury were operated under general anesthesia immediately following basic work-up. Patients with multi-organ injury were directly shifted to the tertiary care hospital from the spot of injury. Forty patients with isolated limb injury were referred after skeletal fixation by an orthopedist. Exposure was made through an incision in the aspect of knee, approximately central to site of injury. After controlling the affected arterial segment, medial proximal and distal embolectomy was performed, and backflow and inflow were assessed. Arterial repair was done either by primary end-to-end anastomosis or by reverse sephanous vein (RSV) graft. RSV was always taken from contralateral large saphenous vein. Suture material used for anastomosis was always 6During five past years, 95 patients, 87 males and 8 females, aged from 18 to 45 years were operated in our department, for lower limb vascular injury. Younger patients sustained vascular injuries mostly due to motorcycle and fire arm accidents, while older patients received vascular injuries either due to blast injury or fall from height. Following surgical intervention, 25 patients with associated multi-organ injuries needed intensive care monitoring. Of these, 10 patients died due to associated multiple organ injuries, and 10 had amputation due to recurrent thrombosis of their anastomosis, and in five patients limb salvage was achieved, but their functional outcome was not as good as those who never had hypotension during surgical intervention or in post-operative period. After vascular repair, 70 patients with isolated limb vascular damage and no associated injuries were kept in low dependency unit. Patients with isolated limb vascular injury and managed in low dependency unit after surgical intervention never had prolonged hypotension, either during vascular repair or in post-operative period and four patients from this group needed amputation for thrombosis of the anastomosis. One of these patients died due to infectious complications followed by DIC even after amputation. In remaining three, one patient had atherosclerosis, one had hypercoagulabe state for protein C deficiency, and the third patient had no apparent sign of thrombosis of anastomosis.Advances in hemorrhage control, wound care, orthopedic and vascular surgery during Iraq and Afghanistan war have allowed greater attention to shift toward limb salvage efforts. They also suggest that hypotension may result in muscle damage at even lower compartment pressures . PatientPatients with vascular and multi organ injuries ,active hemorrhage and shock have a poor prognosis and demand more urgent management than do patients with isolated limb injuries in which perfusion and blood pressure remains optimal. Shock is associated with a significant rate of amputation. These patients, whether with multi-organ or isolated vascular injuries, need judicious treatment for hypovolumic shock during surgical intervention and post-operative period."} +{"text": "The question whether neural activity follows a rate code or a temporal code is still an unsolved issue in neuroscience. Recent theoretical works have suggested that realistic models of spike-timing-dependent-plasticity (STDP) in recurrent networks could resolve this issue because they observed a seemingly unique relation between the neural code and the resulting pattern of synaptic connections . In partWe have disproved both assumptions. In particular, here we show that already simple STDP models can easily grow bidirectional connections for a temporal code based on spike synchronization unless synchronization is extremely precise (see for dispThus, both rate coding and temporal coding based on coarse synaptic synchronization can account for the bidirectional connectivity observed, for example, in visual cortex . However"} +{"text": "Prostatic stromal hyperplasia with atypia (PSHA) is a rare histologic finding diagnosed incidentally on prostate biopsies, transurethral resection specimens, and radical prostatectomy specimens. PSHA has a bizarre histologic appearance and these lesions often raise concern for sarcoma; however, their clinical course is indolent and does not include extraprostatic progression. We discuss a case of PHSA discovered on prostate biopsy performed for an abnormal digital rectal examination and review the literature on this rare pathologic finding. Prostatic stromal hyperplasia with atypia (PSHA) is a rare histologic finding diagnosed incidentally in specimens from transrectal ultrasound (TRUS-) guided needle biopsy of the prostate, transurethral resection of prostate (TURP), radical prostatectomy, and simple prostatectomy . BecauseA 55-year-old man underwent a 10-core TRUS biopsy for a grossly abnormal digital rectal exam. Histologic examination revealed PSHA is characterized by one or more ill-defined, uncircumscribed, and hyperplastic stromal nodules infiltrating around benign acini . ImmunohPSHA does not generally present as a symptomatic lesion in and of itself, though symptomatic cases have been reported . In all This finding has been referred to by a variety of names including: atypical stromal hyperplasia, symplastic leiomyoma, and pseudoneoplastic lesion of the prostate gland. PSHA was previously grouped with low malignant potential findings such as phyllodes tumor and low-grade sarcoma as stromal tumors of unknown malignant potential (STUMP); however, given the univerally benign course of PSHA, this may constitute a misnomer. The current nomenclature emphasizes the expected indolent clinical course with treatment focused on the original disease of interest ."} +{"text": "To understand the impact of integrative medicine (IM) therapies on patients receiving care at BraveNet practice-based research network (PBRN) via longitudinal collection of patient-reported outcomes. Previously, the BraveNet PBRN conducted a cross-sectional study including over 4,000 patients receiving clinical care at the 9 IM clinics, which comprise the Bravewell Clinical Network and BraveNet PBRN. This effort provided important information about patients receiving care at these IM clinics as well as the type of medical condition and IM treatments patients were receiving.The current pilot study extends the prior study by collecting patient-reported outcomes every 6 weeks for 6 months from patients receiving various types of IM services . Patients are asked to complete demographics, substance use, exercise habits, Perceived Stress Scale, Arizona Integrated Health Outcomes, and Patient Related Outcomes Measurement Information System-29 measures. Questions examining the patients\u2019 prior IM history, perceived benefits of IM treatments, and satisfaction with IM clinic are also included. Medical records are reviewed to obtain billing and healthcare utilization information. While electronic questionnaires are completed using the REDCap (Research Electronic Data Capture) system, patients may also complete the questionnaires via paper format.The Penny George Institute for Health and Healing has been successfully piloting this project and 200 participants are enrolled to date. Additional BraveNet PBRN sites are joining the pilot study and expanded results of the entire pilot study will be presented.Practice-based research and patient-reported outcome measures will be key factors in demonstrating the effectiveness of IM interventions in the treatment of many clinical conditions. Multicenter participation provides increased enrollment and allows for generalizability of results from which future randomized controlled trials may be developed."} +{"text": "Gene expression profiling has been widely used to study molecular signatures of many diseases and to develop molecular diagnostics for disease prediction. Gene selection, as an important step for improved diagnostics, screens tens of thousands of genes and identifies a small subset that discriminates between disease types. A two-step gene selection method is proposed to identify informative gene subsets for accurate classification of multiclass phenotypes. In the first step, individually discriminatory genes (IDGs) are identified by using one-dimensional weighted Fisher criterion (wFC). In the second step, jointly discriminatory genes (JDGs) are selected by sequential search methods, based on their joint class separability measured by multidimensional weighted Fisher criterion (wFC). The performance of the selected gene subsets for multiclass prediction is evaluated by artificial neural networks (ANNs) and/or support vector machines (SVMs). By applying the proposed IDG/JDG approach to two microarray studies, that is, small round blue cell tumors (SRBCTs) and muscular dystrophies (MDs), we successfully identified a much smaller yet efficient set of JDGs for diagnosing SRBCTs and MDs with high prediction accuracies . These experimental results demonstrated that the two-step gene selection method is able to identify a subset of highly discriminative genes for improved multiclass prediction."} +{"text": "Pain responses can be suppressed by heterotopic continuous noxious conditioning, e.g. continuous noxious cold stimulation.These diffuse noxious inhibitory controls (DNIC) may be abnormal in migraine . DNIC eWe examined in healthy volunteers blood oxygenation level dependent (BOLD) responses in prefrontal cortex to repeated continuous noxious cold stimulation. The relationships between those responses and degree of inhibition of laser-induced pain during heterotopic cold stimulation were analyzed.Our results show that cold-induced BOLD response in anterior cingulate, orbitofrontal and lateral prefrontal cortices predict cold-induced heterotopic analgesia and attenuation of cerebral BOLD responses to laser stimulation. Prefrontal responses to the onset of cold stimulation were strongly related to the subsequent DNIC effect.We conclude that early responses to noxious conditioning are important for prediction of the analgesic DNIC effect. We hypothesize that this predictive effect of frontal cortices may be abnormal in chronic migraine."} +{"text": "Rapid and efficient selection of emotionally salient or goal-relevant environmental stimuli is crucial for flexible and adaptive behaviors. Emotional events rapidly and automatically capture attention by activating subcortical neural structures Ohman, . BehavioWith regard to the interaction of emotion and attention, there are unsolved and controversial issues. For example, to what extent does emotional stimulus processing depend on attentional resource availability? Previous studies have shown conflicting results, probably due to several factors, including attentional load allocated to competing tasks. Some studies have demonstrated that emotional faces evoke amygdalar responses even when attention is diverted to other stimuli, suggesting that some types of emotional perception occur outside of top-down directed attention and two ignore-faces conditions (easy and difficult digit/letter-matching tasks). The behavioral data suggested that the experimental design successfully controlled the attentional load and perceptual properties of emotional stimuli presented foveally or peripherally in the visual field. Their study resulted in two main findings. First, amygdalar activity was strongly suppressed during high attentional loads, which suggests that emotional information processing might be suspended when attention-demanding cognitive tasks are performed simultaneously. Although this finding is not new (Pessoa, Morawetz et al. directly Pessoa, , this waIn summary, Morawetz et al. provided"} +{"text": "Examining process rates alone may obscure the microbial physiological mechanisms that underlie climate-induced changes in soil C cycling, leading to contradictory patterns among different studies. For instance, in a large-scale survey of soil protease activities from climate manipulations, drier and warmer conditions resulted in lower extracellular enzyme activities (EEA) compared to ambient conditions (Brzostek et al., In this issue, Steinweg et al. examine These findings challenge our existing knowledge about the mechanisms driving EEA in soils. In the laboratory, EEA increases linearly with temperature over the narrow temperature range observed here (German et al., The work of Steinweg and colleagues is an example of how shifts in gross process rates emerge from multiple interacting microbial mechanisms. However, these physiological feedbacks are often not incorporated into biogeochemical models. For instance, despite ample evidence that soil microbes shift allocation to enzyme production depending upon resource availability, EEA is often modeled simply as a function of the microbial biomass pool size. This approach may be valid in some ecosystems under steady state conditions or during the growing season (Kivlin and Treseder, Shifts in intracellular C allocation may also affect element cycling at the ecosystem scale if the stoichiometric requirements of the microbial biomass are altered. Steinweg and colleagues found that enzyme ratios varied with season, indicating higher microbial C vs. N demand in the winter. They suggest that changes in enzyme stoichiometry may reflect increased microbial maintenance cost during freeze-thaw cycles, which impose a high C cost on the microbial biomass. Shifts in biomass C:N have also been observed in response to altered substrate stoichiometry (Fanin et al., Based on the findings of Steinweg et al. many of While Steinweg et al. focus onMultiple processes will have large consequences for soil C storage in future climates, including climate controls on enzyme production and turnover, and tradeoffs in microbial allocation to growth, respiration, and resource acquisition. Yet, because all of these processes interact, the effects of climate change on soil C pools and fluxes can be extremely variable. As Steinweg and colleagues demonstrate, measuring mass-specific microbial responses is the first step toward improving our understanding of microbial physiological responses to altered climate regimes. However, studies that simultaneously examine the links among these mechanisms will be necessary to predict when tradeoffs in microbial C allocation occur and their long-term effects on soil C storage. By viewing ecosystem responses to temperature and precipitation through the lens of microbial physiology, we may arrive at a more mechanistic understanding of soil feedbacks on climate change."} +{"text": "Globally, forests store ~45% of carbon sequestered terrestrially, contribute more to the terrestrial sink per area than any other land cover type, and assimilate an important portion of anthropogenic emissions Bonan, . ForestsThe justification for physiological research on drought-induced tree mortality is often stated as a need to improve the predictive capability of vegetation models through incorporation of mortality mechanisms must be simulated across the Earth. Dynamic global vegetation models (DGVMs) coupled with general circulation models are a common tool for simulating vegetation response to climate change , derived from tree-ring records and predictable from regional climate, is highly correlated with forest mortality in the southwest USA improved experimentation to distinguish physiological causes from symptoms, (2) continued model development based on existing knowledge and emerging discovery, (3) improved model validation against both experimental results and regional-scale mortality observations, and (4) high-resolution measurement of forest composition at large scales. While ecologists studying tree mortality have favored investigating physiological mechanism, measuring species composition and mortality at high resolution across regions is crucial for providing baseline observations to constrain model predictions. Without improved input on current forest conditions, even accurate models of forest mortality cannot generate useful predictions of change."} +{"text": "Age-related macular degeneration (AMD) is the most common cause of legal blindness among the elderly in developed countries. The prevalence of advanced forms of AMD is increasing; it is expected to rise by 50% by the year 2020 in the United States. Early identification of AMD susceptibility and implementation of preventive measures are important management strategies. Antibodies against vascular endothelial growth factor (VEGF) have become the treatment of choice in patients with choroidal neovascularization (CNV); however, substantial improvement of vision occurs only in approximately one-third of patients. Early diagnosis and treatment of CNV may increase the success rate of treatment.Standard diagnostic modalities including fundus angiography and optical coherence tomography can detect CNV in clinical stages when vision is affected. In a novel approach, Takeda and coworkers evaluated the role of an eosinophil/mast cell chemokine receptor, CCR3, in CNV. They studied CCR3 expression among patients with AMD and previously untreated surgically excised CNV membranes, donor eyes of age-matched non-AMD controls, atrophic AMD, uveal melanoma, and surgically excised epiretinal membranes. Additionally, in vivo CCR3 bioimaging was performed in transgenic mice with spontaneous CNV using intravenous quantum-dot labeled CCR3 antibody fragments followed by fundus fluorescent imaging which demonstrated hyperfluorescent signals in regions of the fundus that were silent on standard fluorescein angiography. These hyperfluorescent dots were subsequently confirmed to be CNVs using histologic examination. The investigators showed that CCR3 was specifically expressed in the endothelial cells of all human CNV membranes but not in other conditions. Interestingly, they found that CCR3 neutralization was superior to VEGF blockade in suppressing laser-induced CNV in mice. Considering emerging safety concerns about continual blockade of VEGF, which is constitutively expressed in the normal adult human retina and needed for retinal health, a treatment strategy based on more specific targeting of CNV would be desirable.These findings suggest that CCR3 targeting may be a viable strategy for early detection and treatment of CNV, and might be superior to the current standard of care. CCR3 bioimaging would probably be most useful in eyes at high risk for CNV such as multiple large drusen or sound fellow eyes of patients with clinically evident CNV; it can also serve as a useful tool for differentiating lesions mimicking CNV."} +{"text": "Background. Aberrant right hepatic duct (ARHD) draining intocystic duct (CD) is relatively rare but clinically importantbecause of its susceptibility to injuries during cholecystectomy. These injuries are often-times missed or diagnosed late and as aresult can develop serious complications. Methods. Fourconsecutive patients diagnosed with ARHD draining into CD wereidentified for inclusion. Results. The mean age of patients was42.5 years. The diagnosis in one of the patient was incidentalduring a routine endoscopic retrograde cholangiopancreatography(ERCP). Other three patients were diagnosed post-cholecystectomy-one presented with suspected intra-operative biliary injury, onewith persistent bile leak and another with recurrent cholangitis. Inadequate filling of the segment of liver on ERCP with dilationof intrahepatic ducts in the corresponding segment on imaging waspresent in two patients with complete obstruction of ARHD whichwas managed surgically. In another patient, the partiallyobstructed ARHD was managed by endoscopic therapy. Conclusion. ARHD draining into the CD can have varied clinical manifestations. In appropriate clinical settings, it should be suspected inpatients with persistence of bile leak early aftercholecystectomy, segmental dilation of intrahepatic-bile ducts onimaging and paucity of intrahepatic filling in a segment of liveron ERCP. Bile duct injury is an uncommon complication following cholecystectomy. With the increasing use of laparoscopic cholecystectomy (LC), there has been an associated increase in the incidence of bile duct injuries . Early s Therefore, the knowledge of various biliary anomalies and their early identification may further assist in decreasing the rate of biliary tract injuries. Here we present a case-series on various presentations and management of a rare anomaly of biliary tree.A 55-year-old woman presented 3 days postcholecystectomy (LC) with upper abdominal pain. HIDA scan revealed a bile leak. ERCP with minimal contrast injection revealed a leak from cystic stump; therefore a 10 F biliary stent was placed. Six weeks later a repeat ERCP revealed no leak from the cystic duct stump. However, large branch of the right intrahepatic duct was filled through the cystic duct stump . MinimalA 38-year-old Caucasian woman was referred to our hospital for recurrent episodes of gram-negative bacteremia. On presentation she was asymptomatic. Her past surgical history was significant for complicated cholecystectomy requiring conversion from laparoscopic to open technique six years earlier when she was 28 weeks pregnant. The surgical report described normal common and cystic ducts and described bile staining within the hilum where a drain was placed. After a few days drainage stopped and drain was removed. She was found to have minimally abnormal LFT's during a routine blood workup, a year after the surgery. Ultrasound at that time demonstrated dilated biliary tree in a segment of the right lobe of the liver and an ERCP revealed a questionable cystic dilation of distal common bile duct (CBD), for which sphincterotomy was performed. She had recurrent episodes of fever in the subsequent years and blood cultures persistently grew Klebsiella species. Computerized tomography (CT) scan and MRCPA 27-year-old healthy young woman with history of generalized fatigue presented for further evaluation of abnormal liver biochemistries. Her alkaline phosphatase levels had nearly increased 3 times the upper limits of normal. The most recent LFT revealed elevation of aspartate aminotransferases (AST) (104\u2009U/L) and alanine aminotransferases (ALT) (234\u2009U/L), which were reported as normal two years ago. An abdominal ultrasound showed no focal lesions. MRCP was performed which did not reveal any abnormal findings. Clinical examination was normal. In view of strong clinical suspicion of sclerosing cholangitis, ERCP was performed which revealed diffuse multifocal strictures with beading of intrahepatic ducts bilaterally, suspicious for primary sclerosing cholangitis. An aberrant branch of right hepatic duct draining into CBD with cystic duct originating from the aberrant branch was noted on ERCP .A 50-year-old woman presented with symptomatic cholelithiasis. Elective LC was attempted at an outside facility. Intraoperative cholangiogram (IOC) was interpreted as-right intrahepatic ducts filling without opacification of mid-CBD and CHD. Surgery was aborted in view of suspicion of bile duct injury. Two JP (Jackson-Pratt) drains were placed and she was referred to our center. ERCP performed at our center revealed cystic duct remnant leak and staples were noted close to CBD. There was inadequate filling of intrahepatic ducts in a segment of right hepatic lobe . SphinctAberrant right hepatic duct (ARHD) is branch providing biliary drainage to variable portion of right hepatic lobe and drains directly into the extrahepatic biliary tree. ARHD is a common bile tract anomaly with the incidence of 4.6%\u20138.4% and it frequently drains into common hepatic duct, CBD or even left hepatic duct . HoweverIOC during LC has been utilized to identify anatomic variants of biliary tract, even though it's routine use is debatable . While sPersistent bile leak may be an initial presentation of injury to the ARHD during cholecystectomy . These pLess frequently, patients with ARHD injury can present in the postoperative period weeks to months later, with cholestatic pattern of abnormality on LFT's, if the aberrant duct is blocked. In addition, these patients can also present with episodes of cholangitis in the obstructed segment of biliary tree as was the case with our second case. A high index of suspicion is required to look for these complications. Segmental dilation of intrahepatic ducts may be revealed on a CT-scan. These patients will require cholangiography (PTC or ERCP) to define the anatomy of biliary tree. Scantiness of intrahepatic filling on ERCP with dilation of intrahepatic branches in the same sector on radiologic imaging should be a useful clue to the diagnosis of obstruction of aberrant branch of bile duct. PTC can be performed when intrahepatic ducts are dilated; sometimes both the procedures may be required to obtain the diagnosis as was tUsually, the initial management of patients presenting with a bile leak after LC is decompression of biliary tree by placing a stent with or without sphincterotomy or placement of naso-biliary drain or percutaneous drain . If an aThe diagnosis of aberrant right hepatic duct draining into cystic duct can be incidental during ERCP or MRCP if performed before surgery, as in our third patient. In these situations, the knowledge of aberrant anatomy of biliary track would be important for a surgeon to avoid any inadvertent complications if they undergo cholecystectomy or any other biliary surgery. In addition, the safe approach to avoid injury to aberrant bile-ducts during cholecystectomy is adhering to the gallbladder itself, identifying the triangle of Calot and using the \u201ccritical view of safety (CVS)\u201d, as described by Strasberg, before dividing the cystic structures. CVS involves 3 steps: (i) clearing triangle of Callot of fat and fibrous tissue, (ii) separation of lowest part of GB from liver bed, (iii) only 2 structures (cystic artery and cystic duct) should be seen entering GB . In summary, we present a varied clinical presentation and management of a relatively rare but clinically significant anatomic variation of bile duct anatomy. Aberrant bile-duct injury is often missed as subtle signs of injury remain unrecognized both by surgeons as well as by gastroenterologists. Aberrant bile duct injury after cholecystectomy should be strongly suspected in following situations: (i) paucity of intrahepatic filling in a segment of liver on ERCP; (ii) abnormal LFTs with segmental dilation of intrahepatic-bile ducts on abdominal CT-scan or ultrasound."} +{"text": "They provide a broad overview of the important advances that such mechanistic studies in Drosophila have made to our understanding of the age-related decline in muscle mass and strength, immune response, stress resistance, sexual behavior, and cognitive function. Walton and Pizzitelli (Caenorhabditis elegans. The authors dissect molecular and cellular mechanisms through which the spatiotemporal dynamics of unsaturated fatty acids regulates longevity by modulating the Nuclear Hormone Receptor signaling and maintaining the integrity of various organellar membranes. They also explore the mechanistic links between hydrolysis of neutral lipids and several longevity-defining processes, discuss how lipid-derived signaling molecules impact signaling networks central to longevity assurance, and outline the essential roles of mitochondrial membrane lipids in longevity regulation via multiple cellular pathways. Postnikoff and Harkness (Aging of multicellular and unicellular eukaryotic organisms is a highly complex biological phenomenon that affects a plethora of processes within cells. This wide array of longevity-defining cellular processes\u2014which are governed by an evolutionarily conserved signaling network\u2014includes oxidative metabolism and protein synthesis in mitochondria, lipid, and carbohydrate metabolism, NADzzitelli demonstrzzitelli explore zzitelli provide Harkness offer usHarkness outline Harkness provide Harkness summarizHarkness provide"} +{"text": "Luminescent colloidal quantum dots (QDs) possess numerous advantages as fluorophores in biological applications. However, a principal challenge is how to retain the desirable optical properties of quantum dots in aqueous media while maintaining biocompatibility. Because QD photophysical properties are directly related to surface states, it is critical to control the surface chemistry that renders QDs biocompatible while maintaining electronic passivation. For more than a decade, investigators have used diverse strategies for altering the QD surface. This review summarizes the most successful approaches for preparing biocompatible QDs using various chemical ligands. These applications require an appropriate fluorescent probe having specific chemical and optical properties. Organic and genetically-encoded fluorophores generally have narrow absorption, broad emission, and are vulnerable to continuous irradiation by the excitation source which limits their usefulness in some applications such as multiplexed measurements, long-term imaging, and single molecule imaging, among others ..83].4.2.n-alcanoic acids (PE-PEG) was the attached to SiO2-OTMS-coated QDs through hydrophobic interactions [2 and PE-PEG showed similar brightness over pH 1\u201314. They also evaluated the cellular toxicity of these nanoparticles with and without embedded QDs and found that the toxicity is purely due to the exposure of bare nanoparticles, indicating QDs were adequately protected within the silica spheres with no appreciable leaching of heavy metals [Gao\u2019s group found thractions . As Figuy metals .5.To enable the use of QDs in a wider range of biological applications, all of the preceding methods require a route for attaching biomolecules stably onto the QD surface. A suitable ligand candidate should allow attachment of a diversity of biomolecules including nucleic acids, proteins , polysaccharides, and peptides. Biomolecules are commonly conjugated to the QD surface through the following approaches : (1) cov6.in vivo diagnostics and treatments.Biocompatible QDs are typically generated through either an organic synthetic route requiring subsequent ligand exchange or encapsulation, or a more direct aqueous synthetic route where the nanocrystals are inherently water-soluble. There are nearly countless variations of these methods reported in the literature where each protocol carries its own inherent advantages and disadvantages and must be considered in light of the eventual application. A ligand exchange procedure that uses small charged molecules can maintain minimal hydrodynamic diameters, but they are usually more susceptible to aggregation in biological buffers or solutions of high ionic strength. These compact capping ligands often fail to maintain suitably high luminescence without additional processing. Methods that improve the density of ligands on the QD surface while ensuring a strong binding interaction appear to have the most promise. Polymer and silica coatings are better able to isolate QDs from solution which results in improved colloidal stability, limited non-specific binding, and high QY. However, these characteristics are often achieved at the expense of compact size which can impede cellular mobility and limi"} +{"text": "In trial design, decisions are made about which intervention components/processes to standardise and which remain flexible to maximise utility and/or effectiveness. The intervention-context-system fit for complex interventions impacts on trial recruitment, delivery and outcomes. Survey vignettes and discrete choice experiments are quantitative researcher led approaches which focus on a few measurable attributes. Our aim was to explore the utility of qualitative vignettes as a methodological tool allowing service users/providers to contribute to intervention design.A case series of four acceptability and feasibility studies with service users and providers. Data were collected at different pre-trial stages: i) vignettes of studies in a systematic review of incentives for breastfeeding and smoking cessation in pregnancy, subsequently modified following emergent qualitative analysis; ii) emergent vignettes in the last of up to 8 serial qualitative interviews investigating infant feeding behaviour, following a systematic review showing poor generalizability of effective interventions in the UK context; iii) intervention vignettes of an effective intervention (groups for weight management) to refine the design for a new population (women treated for breast cancer) and iv) emergent intervention vignettes explored at a second interview with obese older adults.Illustrations of how qualitative vignettes can complement quantitative design tools will be presented.Carefully constructed qualitative vignettes combining known effective and emergent promising intervention aspects can optimise trial design. When talking service users and providers through a potential intervention, different perspectives emerge compared with responses to closed or more abstract questions."} +{"text": "Eating disorders (ED) are chronic, deadly illnesses and especially for adults with anorexia nervosa, existing treatments have limited proven efficacy. Growing knowledge about the neural underpinnings to ED provides an avenue for more targeted, brain directed interventions. Brain stimulation techniques, such as Transcranial Magnetic Stimulation (TMS), transcranial Direct Current Stimulation (tDCS), Vagus Nerve Stimulation (VNS) and Deep Brain Stimulation (DBS) have the ability to directly alter neural activity within the brain. Such methods are being used extensively within both research and clinical settings to treat movement disorders such as Parkinson's and a range of psychiatric illnesses including depression. Findings within such disorders, relevant animal models and more recent research within ED populations have led to a strong rationale for the use of brain stimulation in ED. This paper systematically reviews this literature, identifying deficits in the current knowledge in an attempt to help guide future research and clinical practice within the imminent field of brain directed interventions for ED.Understanding and Treating Eating Pathology stream of the 2013 ANZAED Conference.This abstract was presented in the"} +{"text": "Biomedical imaging is a rapidly growing field to provide a state-of-the-art tool for preclinical biomedical research and clinical applications, in view of its ability to noninvasively reveal subtle structural variations of biological tissues and visualize in vivo physiological and pathological processes at the cellular and molecular levels. Mathematical methods are involved with imaging theories, models, and reconstruction algorithms in biomedical imaging. X-ray computed tomography (CT) was a successful application of mathematical method in medical imaging. The CT mathematical model can be reduced to a Radon transform. The inverse transform of Radon transform is invented by Radon in 1917. Magnetic resonance imaging (MRI) is a versatile medical imaging modality. MRI can provide more diagnostic information than any of the existing imaging techniques. It does not involve the use of ionizing radiation, hence free from associated harmful effects. Inverse Fast Fourier Transform (IFFT) is a standard method of image reconstruction in MRI from uniformly sampled K-space data. From nonuniform K-space data, iterative algorithms can improve image quality of image reconstruction for MRI. In the optical molecular imaging, the radiative transport equation (RTE) is the fundamental equation to describe photon propagation in biological tissues. The forward solution predicts photon propagation in the optical molecular imaging. The inverse solution can reconstruct molecular probe distribution in a small animal for providing unique insights into disease pathogenesis, drug development, and responses of therapy. The solutions for RTE usually involve analytical methods, Monte Carlo (MC) method, diffusion approximation (DA) method, simplified spherical harmonics method, and some numerical methods.In this special issue, each paper was reviewed by at least two reviewers and revised according to review comments. This special issue covered most of common biomedical imaging models and various image processing methods, such as registration, segmentation, and so forth, were involved. For Positron Emission Tomography (PET) imaging model, two attenuation correction methods based on X-rays CT (CTAC method) and segmentation of emission images (SE-AC method) were simulated with Monte Carlo method and compared. For synchrotron Micro-CT imaging model, a semiautomatic segmentation algorithm for extracting the complete structure of acini has been proposed. For ultrasound imaging model, a common carotid artery segmentation scheme based on active shape model can get better result and promote the translation of carotid 3D US to clinical care for the monitoring of the atherosclerotic disease progression and regression. For MRI model, a mesh-deformation constraints based image registration algorithm was carefully investigated. Also the development of image segmentation for intracranial aneurysms and rotation covariant image processing method for biomedical applications are summarized. Furthermore, in order to accelerate the parallel imaging, a sparse constrained reconstruction approach with variable splitting methods was proposed and verified: total variation (TV)-minimization interior tomography algorithm, dynamic and robust blind watermarking scheme to resist against common distortions, modified global and modified linear contrast stretching techniques for identification of various stages and species of malaria, a 3D surface-based deformable model as guidance for nonrigid 3D medical image registration and fusion, mathematical or computational modeling for oncogene inactivation, a group factor analysis model for neuroimaging applications by assigning separate factor patterns to control and patient groups yielding more reasonable factor scores and patterns, different MISO Volterra methods to model simulated ultrasound contrast agents signals, an automated process that determines whether an aortic object in a slice is a candidate for aortic dissection or PAU based on contrast enhanced CT data, image-based computational techniques to quantify the severity and directionality of individual scratches and scrapes, combination of genetic algorithm and closed loop to obtain optimal ternary command which maximized the contrast to tissue ratio, and magnetoacoustic tomography with magnetic induction (MAT-MI) for generating electrical conductivity images of biological tissues with high spatial resolution. An acceleration strategy for fluorescence molecular tomography (FMT) with early photons is proposed using graphics processing units (GPUs). The fluorescence molecular tomography (FMT) with early photons can efficiently improve the spatial resolution and fidelity of the reconstructed results. An efficient compressed sensing-based algorithm is proposed for CT image reconstruction from few-view data to suppress the streak artifact. The compressed sensing (CS) algorithm shows the potential to accurately recover images from highly undersampled data. The discriminant analysis techniques are discussed using MRI to identify the correlative pattern of brain changes for differentiating parkinsonian syndromes. A hybrid multiscale and multilevel image fusion algorithm for green fluorescent protein (GFP) image and phase contrast image of Arabidopsis cell is proposed. This algorithm uses different fusion strategies for different detailed subbands, which include neighborhood consistency measurement (NCM) that can adaptively find balance between color background and gray structure. A detrended fluctuation analysis (DFA) method is applied to image analysis to investigate the characteristic of different type of simulated and lymphoma image. A method is presented to estimate the tilt and decentration of intraocular lens (IOL) more accurately. The Bayesian hierarchical model for the analysis of categorical longitudinal data is investigated from sedation measurement for MRI and CT. In vivo MRI of local drug delivery is discussed to visualize and quantify the time resolved distribution of MRI contrast agents.These papers represent an insightful observation into the state of the art, as well as future topics in this biomedical imaging field. We hope that this special issue would attract a wide attention of the peers.Wenxiang CongKumar DurairajPeng Feng"} +{"text": "Although the advent of MRI impacted significantly our presurgical investigation, ictal semiology with interictal and ictal EEG has clearly retained its roles in localizing epileptogenesis. MRI-identified lesions considered epileptogenic on semiological and electroencephalographic grounds have increased the likelihood of resective surgery effectiveness whereas a nonlesional MRI would diminish this probability. Ictal propagation and the interplay between its source and destination have emerged as a significant component of seizure evaluation over the past 30 years. Epilepsy and Functional Anatomy of the Human Brain [Ictal semiology and EEG dominated our localization of intractable epileptogenesis prior to the introduction of MRI. Dr. John Girvin and I each attempted to outdo the other in obtaining patient and observer descriptions of the patients' seizures, guided by the most comprehensive observations and perceptions documented by Wilder Penfield and Herbert Jasper in an Brain . SeizureIn addition to Penfield's identification for a semiological pattern as representing temporal lobe epilepsy and subsequent description of mesial temporal ictal semiology , subsequThe works of International League against Epilepsy Commissions on Epileptic Seizure Classification and Terminology have, in sequential fashion, clarified our clinical analyses. The 1981 ILAE Commission classified partial seizures into simple partial (consciousness preserved) and complex partial (consciousness impaired). This division has encountered clinical and heuristic limitations as it depends upon evaluating an entity\u2014consciousness\u2014that can neither be defined nor assessed. Gloor discusseCombined with ictal semiology, ictal and interictal EEG were the principal tools before the mid-1980s to localize epileptogenesis in virtually all patients whose intractable focal epilepsies required resective surgery for alleviation. Focal temporal interictal spikes, if predominant over one temporal lobe, lateralised temporal lobe seizure origin in over 90% of patients [For many years, nasopharyngeal or sphenoidal EEG leads supplemented the Ten Twenty EEG electrode system to better record anterior-mesial temporal EEG activity, especially spikes. As illustrated by F. A. Gibbs and E. L. Gibbs , the antOur group at Western/University Hospital was the first to formally study and describe the morphology of scalp-recorded focal seizures-temporal and extratemporal . Recognisubdural electrodes. Inserted as imbedded in silicon strips through burr holes to avoid a craniotomy during the patient's evaluation, these electrodes record directly from the cortical surface. Moreover, they may extend to mesial and inferior cortical surfaces, areas remote from scalp electrodes. For patients with temporal lobe epilepsy, SDE provides more precise and sensitive ictal and interictal recording from the mesial temporal regions. In 1979, Dr. John Girvin and Mr. Dan Jones, EEG technologist, designed Commercially manufactured subdural electrodes were not available in the early 1980s, resulting in some other epilepsy centres purchasing our in-house-manufactured electrodes. Design and manufacture of SDE at UH without any complication continued by Dan Jones and Frank Bihari for over 20 years. Figures However, in 2004 London Health Sciences Centre chose to make use of commercially produced electrodes, though at a significantly greater cost. Our centre was the first to routinely employ subdural electrodes (SDE), and they continue today as a major part of evaluation of about 50% of our patients ultimately operated upon. We studied 27 consecutive patients whose temporal lobe epilepsy clinically implicated both temporal lobes from ictal semiology, scalp EEG, and imaging features. We found that the side of SDE-recorded seizures correlated with that containing most scalp spikes and most scalp-recorded seizures in most but not all patients, confirming the value of both EEG and SDE .Although unable to detect small cortical epileptogenic lesions, plain skull X-rays had disclosed several cranial and intracranial abnormalities of lateralising value. Cranial erosion on skull roentgenography could have resulted from a previous wide fracture or from a subdural or subarachnoid cyst; one or more asymmetrical cranial features may have indicated cerebral hemiatrophy, compatible with accompanying epileptogenesis; intracerebral calcification may have represented tumours or congenital lesions. Pneumoencephalography disclosed displaced or deformed ventricles from tumours, abscesses, hematoma, and other lesions. Cerebral arteriography helped localize expanding lesions but proved less helpful in the study of atrophic lesions . A major advance in evaluating patients for temporal lobe surgery was the advent of MRI. Imaging afforded by MRI discloses focal structural abnormalities underlying intractable epilepsy that may remain undetected by earlier neuroimaging methods . SubsequThree common epileptogenic lesions are particularly well displayed by MRI: mesial temporal sclerosis, cortical dysplasia (CD), and benign tumours such as dysembryoplastic neuroepithelial tumours (DNETs) and gangliogliomas (GGL). Rhythmic epileptiform discharges (REDs) may characterize the scalp EEGs of those with focal CD ; abundanThe presence or absence of mesial temporal sclerosis (MTS) became far better displayed by MRI than any previous imaging modality. This greatly facilitated, with EEG, an assessment as to whether one or both temporal lobes are epileptogenic. In the latter instance, assessment of their relative epileptogenicities may influence a surgical decision. In some patients, MRI and EEG (via REDs) have demonstrated both MTS and CD with comparable epileptogenicity in each, termed \u201cdual pathology\u201d , 19. OriThe appearance of dual pathology in some patients augmented our awareness of seizure propagation and its influence on semiology. Thus, ictal symptoms and signs may signify the site of seizure spread rather than origin. Both normal cerebral connectivity and neuronal pathways developed in the process of epileptogenesis likely participate in seizure spread. For example, occipital seizures may propagate to the mesial temporal region via the \u201cventral stream,\u201d a multisynaptic pathway that terminates primarily in the amygdala but also in the parahippocampal area . Munari personal communication). However, often a full temporal lobectomy has been performed . Surgical approach and technique have not measurably changed over the years.Three approaches to the mesial temporal region have been described: sylvian fissure, middle temporal gyrus, and inferior temporal pole . Our surThat a substantial left temporal lobectomy will significantly impair verbal memory has become increasingly realized over the past decades creating a distinction between left and right temporal epilepsy in terms of surgical candidature , 25. Con"} +{"text": "This study is the first to use quantitative perfusion CMR to evaluate regional differences in myocardial blood flow (MBF) in patients with left bundle branch block (LBBB).LBBB is often associated with underlying CAD but its presence can limit the diagnostic accuracy of non-invasive imaging tests. In particular, there is a high incidence of false-positive results with exercise SPECT due to apparent septal perfusion defects. The use of vasodilator stress has reduced but not eliminated this problem. Several hypotheses have been postulated to explain the cause of such perfusion defects, and these include early activation of the septum, leading to shortened diastole and reduced blood flow; partial volume effects caused by impaired septal thickening; and increased septal intra-myocardial pressure during diastole, resulting in reduced flow reserve. A number of small studies using PET or early quantitative SPECT techniques have evaluated regional differences in MBF in patients with LBBB, but the results have been conflicting and have shown either no regional differences or a relative but not absolute reduction in septal perfusion. This study re-evaluates the unresolved question of septal perfusion in LBBB using quantitative perfusion CMR.9 patients with LBBB and no significant CAD underwent adenosine stress/rest perfusion CMR at 1.5T and X-ray coronary angiography. Absence of CAD was defined as luminal stenosis <40% on quantitative coronary angiography in all major vessels. Mid-ventricular perfusion data were segmented into 3 regions for each patient: septal, adjacent (anterior-inferior) and lateral. MBF and myocardial perfusion reserve (MPR) were then determined for the septal and lateral regions by Fermi function deconvolution.Resting MBF was similar in both septal and lateral regions in all patients ."} +{"text": "Coincident expression of otherwise unrelated inborn errors of metabolism may occur as a result of large deletions of multiple gene, referred to as the contiguous gene deletion syndrome. We describe two male infants who presented with failure to thrive and raised urinary glycerol levels, leading diagnosis of glycerol kinase deficiency, congenital adrenal hypoplasia and myopathy.These clinical diagnoses, suggest Xp21 contiguous gene deletion syndrome.The two male infants currently 48 months and 3 months old, presented with failure to thrive at 10 months and 1 month of age respectively. On evaluation for metabolic causes of poor weight gain, urine organic acids showed high levels of glycerol. Further results revealed pseudo-hypertriglyceridemia which raised the suspicion of glycerol kinase deficiency. Both infants were persistently hyponatremic and hyperkalemic, and the synacthen test showed a suboptimal cortisol peaks. Plasma renin was high with low aldosterone indicating mineralocorticoid defiency.The older male infant who presented at 10 months of age also had significant developmental delay with muscular weakness and markedly raised creatinine kinase.He was confirmed to have Duchene Muscular Dystrophy.Both the infants were started on steroid and salt replacement and monogen feeds containing medium chain triglycerides. Their weight improved with normalization of sodium & potassium levels. The above spectrum of clinical & biochemical features is consistent with a diagnosis of Xp21 contiguous gene deletion syndrome. Although rare, raised urinary glycerol and serum triglycerides leads to suspicion and allows early recognition of this condition, where prompt treatment can prevent life-threatening adrenal crises."} +{"text": "Dilated cardiomyopathy (DCM) occurring due to an unknown etiology or genetic predisposition is termed as idiopathic dilated cardiomyopathy (iDCM), although iDCM may also result from viral exposure. However, the incidence of myocardial inflammation and its relation to left ventricular (LV) function in iDCM remains unknown.Cardiovascular magnetic resonance (CMR) imaging allows for the visualization of myocardial inflammation using early Gadolinium enhancement (EGE). We applied EGE imaging in the setting of clinically suspected iDCM to determine both the incidence and relation of myocardial inflammation to LV function.26 patients were referred to us for the assessment of iDCM following a clinical suspicion of iDCM, based upon the following criteria: ejection fraction below 45%; invasive exclusion of significant coronary artery disease using a cutoff of 50% stenosis; stable clinical course for at least 3-months prior to the CMR study; exclusion of myocarditis within the past 12 months; as well as exclusion of comorbidities which may otherwise account for patient presentation including valvular heart disease.Standard CMR imaging procedures for the assessment of LV function and EGE were utilized. EGE images were acquired before and early after (over 4 minutes) Gd-DTPA 0.1ml/kgBW contrast injection using T1-weighted images.LV function was assessed by manually tracing endo- and epicardial contours. Myocardial signal intensity was normalized to skeletal muscle, generating a ratio that had to be greater than or equal to 4 to be considered positive for EGE.Eighteen patients (69%) presented with EGE and a significantly increased EGE ratio . The ratio of EGE correlated with LVEDVI and LVESVI , LVSVI , and LVEF . Patients with elevated EGE had significantly dilated left ventricles and globally reduced ventricular function: LVEDVI and LVESVI were increased, while LVSVI and LVEF were reduced (Figure Using CMR-based EGE as a surrogate marker of myocardial inflammation, we provide first evidence for a high incidence of inflammation in patients with clinically suspected iDCM. The extent of myocardial enhancement was directly related to reduced ventricular function. CMR-based assessment of myocardial inflammation may be utilized as a biomarker for patient prognosis and guide medical therapy to target those patients in whom there is active myocardial inflammation."} +{"text": "This case report illustrates two unusual cases of parapharyngeal schwannomas mimicking carotid body tumors in terms of characteristic vascular displacement. Carotid body tumors classically cause splaying of internal and external carotid arteries demonstrating the Lyre sign on imaging. Also interestingly, both of these cases were seen in younger ages and include cervical sympathetic chain schwannoma and vagal schwannoma. However, these schwannomas revealed hypovascularity on imaging studies allowing differentiation from hypervascular carotid body tumors. Preoperative distinction between carotid body tumors and schwannomas is very important. Carotid body tumors, cervical sympathetic chain schwannomas, and vagal schwannomas have common location in neck that is the retrostyloid compartment of parapharyngeal space \u20133. AmongAn 18-year-old female was referred to the otolaryngology department with a swelling on the left side of the neck since 4 months. On examination, nonpulsatile mass near angle of the left mandible was seen. Cranial nerve examination was normal. Doppler ultrasonography revealed hypoechoic mass in the left carotid space showing mild peripheral vascularity . ComputeA 17-year-old female came with history of painless swelling on the left side of the neck and change in voice since 2 months. On examination, there was nontender swelling noted posterior to the angle of the left mandible. USG neck revealed hypoechoic mass on the left parapharyngeal space showing mild vascularity on the Doppler study . On CT sVagal schwannomas, carotid body tumours and cervical sympathetic chain schwannomas are the most common tumours of the retrostyloid parapharyngeal space , 2. CaroSchwannomas or neurilemomas, are derived from schwann cells. They are common in middle age with female preponderance \u20133. In thPreoperative diagnosis is very important in these retrostyloid parapharyngeal masses as management of carotid body tumors varies from surgery to radiation to observation, while complete surgical excision is the therapy of choice in vagal and cervical sympathetic schwannomas . Also, rBoth of the described tumors displayed splaying of external and internal carotid arteries on CT contrast study, MRI, and DSA which was also confirmed at surgery. However both of these tumors demonstrated mild vascularity on the Doppler USG, CT, and DSA.Although characteristic vascular displacement, that is, splaying of carotid bifurcation helps to distinguish carotid body tumor from other retrostyloid parapharyngeal masses, similar vascular displacement can be seen in vagal and cervical sympathetic chain schwannomas. So, this imaging pitfall should be taken into account while considering differential diagnosis of retrostyloid parapharyngeal tumors.Both of these tumors showed hypovascularity, hence favor schwannomas rather than carotid body tumors. Internal vascularity and enhancement characteristics of the tumor should be given more importance while differentiating schwannomas from carotid body tumors. Hence enhancement pattern is the imaging pearl in differentiating carotid body tumors from schwannomas."} +{"text": "Drug addiction is a serious public health problem that consists of a compulsive drive to take drugs despite repeated severe adverse consequences . FactorsThe accumulated evidence supports the view that a large number of substance users suffer from significant neuropsychological impairments . NeuroimBefore elaborating the idea of drug-induced cognitive changes in patients addicted to illicit drugs, it is important to briefly discuss the influence of potential premorbid deficits on the cognitive performance of some drugs abusers . For exaThe prefrontal cortex (PFC) and the striatum participate in integrated functions that are modulated by glutamate and dopaPathological changes in the orbitofrontal cortex (OFC) might also be involved in the manifestation of addiction-related behaviors because it is relevant to outcomes related to primary reinforcers . OFC neuImpaired self-control plays a fundamental role in drug-taking behaviors in addictive states . ImpulsiThe available evidence does support the thesis that impulsivity is a vulnerability marker for substance abuse , 12. SevInterestingly, abnormalities have been identified in frontal networks that subsume poor self-regulation and impulse control in cocaine dependency. Specifically, cocaine users were reported to show stronger connectivity within the perigenual anterior cingulate cortex (ACC) social processing/\u201cmentalizing\u201d network . This stAttention represents a number of intimate mechanisms that facilitate the filtering, selection, and processing of information . In subsPoor cognitive performance in areas of risk-taking and decision making may influence the degree to which illicit drug users engage in risky behaviors with consequent negative health consequences. Deficits in tests of decision making have been found in patients who suffer from marijuana , 50, cocIn summary, drug addiction is marked by mild, yet pervasive, cognitive disruptions that may cause the negative progression of the clinical course, threaten sustained abstinence , or incr"} +{"text": "The letter by Mullier8C intervals,The inhibition of pre-hepatic/hepatic CYP3A4 metabolism of amiodarone alters both plasma and cardiac substrate:metabolite ratios. It therefore reduces alterations of PR and QTC by inhibiting the rapid component of delayed rectifier K+ current (Ikr), leading to significant QT prolongation in healthy subjects and in patients with dilated or hypertensive cardiomyopathy,The interaction of grapefruit juice with amiodarone is more complicated than previously thought. Naringenin, the naringin (the predominant flavonoid in grapefruit juice) aglycone, has recently been reported to prolong QTEven though cases of QT prolongation and torsades de pointes with amiodarone are rare, a case has been reported of a female patient who presented with marked QT prolongation associated with ventricular arrhythmias including torsades de pointes, requiring electrical cardioversion after amiodarone administration, after she had been drinking large quantities of among others grapefruit juice."} +{"text": "Chronic heart failure (CHF) is the leading cause of hospitalization and death in industrialized countries. CHF is frequently associated with humoral and metabolic disturbances, including reduced bioavailability of the important signalling molecule nitric oxide (NO), which has vasodilating properties. Several studies reported high plasma levels of asymmetrical NG, NG-dimethyl-L-arginine (ADMA), an endogenous inhibitor of NO production, in CHF, contributing to endothelial dysfunction. The Dynamic Vessel Analyzer (DVA) enables dynamic analyses of retinal vessels. NO is a mediator of retinal vasodilator response to flicker light. Reduced response of retinal arterioles to flicker light may be an attractive technique to non-invasively assess endothelial dysfunction. The aim of the study was to test the hypothesis that retinal vessel response to flicker light is reduced in patients with CHF and correlates inversely with serum ADMA levels.16 patients with non-ischemic cardiomyopathy and 22 healthy volunteers were included. Retinal arteriolar flicker response as percent change from baseline and serum ADMA level were measured.Retinal arteriolar flicker response was significantly reduced in CHF patients compared to the healthy control group . ADMA levels tended to be higher in CHF patients . Noteworthy, we observed a highly significant inverse correlation between retinal arteriolar flicker response and ADMA levels .Our findings suggest that analysis of retinal vessels could be an attractive non-invasive method to quantify endothelial dysfunction in CHF."} +{"text": "Candida is the most common human fungal pathogen and the cause of invasive candidiasis, the fourth leading cause of nosocomial bloodstream infection in the United States with an estimated annual cost of \u223cUS$2 billion and mortality that exceeds 40% despite administration of antifungal therapy in modern intensive care unit facilities Candida yeast cells intravenously and mimics skin-derived bloodstream human candidiasis, has been successfully employed to study fungal and host factors that regulate susceptibility to the infection Candida expresses a variety of virulence factors that contribute to its pathogenesis and could be exploited for development of vaccines and targeted therapeutic strategies. Firstly, Candida albicans filaments' virulence factors, including secreted aspartyl proteases and phospholipases, are thought to be important for Candida invasion in infected organs and, probably, for mediating fungus-induced tissue immunopathology Candida is able to efficiently adhere to and invade epithelial and endothelial cells via induced endocytosis and active penetration; both adhesion and invasion facilitate Candida dissemination Candida to form biofilms on implanted medical devices such as central venous catheters, which are a frequent portal of entry for invasive infection in humans Candida factors that promote its adhesion and invasion, the agglutinin-like sequence (Als) family has attracted significant attention; Als3 in particular, a C. albicans\u2013specific virulence factor, was recently shown to mediate brain-specific Candida endothelial invasion and tissue penetration vps51\u0394/\u0394 C. albicans mutant was shown to be responsible for its increased ability to invade brain endothelial cells in vitro and traffic to the brain in vivo via binding to the gp96 heat shock protein, which is expressed specifically on brain endothelium Candida tissue burden C. albicans virulence factor is its ability to transition between unicellular yeast cells and filamentous growth during infection; in fact, it is the interchange between these morphotypes that is critical for pathogenesis, as strains locked either in the yeast or the filamentous forms have attenuated virulence in vivo albicans Candida species such as Candida glabrata, which is an important cause of invasive candidiasis in humans even though it does not form hyphae. Strikingly, the ability of C. albicans to form filaments in vivo is tissue-specific Candida growth in mice such as the liver and spleen prevent Candida filamentation, whereas hyphal formation is abundant in the kidney, the target organ of murine disseminated candidiasis, where Candida proliferation is inexorable Candida filamentation could lead to the discovery of novel therapeutic interventions.Moreover, a fundamental Candida immune response is fungal recognition by the innate immune system. Over the past decade there has been an explosion in our understanding of how soluble and membrane-bound pattern recognition receptors (PRRs) recognize various pathogen-associated molecular patterns (PAMPs) of Candida yeast and filamentous forms in modulating downstream anti-Candida immune responses. In addition, more studies are needed to understand how Candida influences its recognition in vivo by employing immune evasion strategies; for example, \u03b2-glucan exposure on the Candida surface occurs in infected mouse tissues only late after infection The challenge for future research will be to define how Candida experimental strains impedes on drawing definite conclusions about the in vivo role of certain PRRs, as apparently discrepant results have been reported for some TLRs and CLRs with different fungal strains Candida strains in mammals could potentially be ameliorated by employing non-vertebrate and/or mini-vertebrate model hosts that have evolutionarily conserved innate immune pathways , and could allow for facile and inexpensive high-throughput screening of greater numbers of Candida strains C. albicans is the most common agent of human invasive candidiasis, research performed until now has predominantly focused on the recognition of this species, and much less is known about the interaction of other Candida species with the immune system. It is expected that research aiming to gain more insight on the recognition of emerging non-albicans Candida species will represent an important area of research in the coming years.In addition, the notable diversity in PAMP structure among various Candida killing Candida ingestion is followed by assembly of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex at the phagosomal membrane and oxidative burst, which leads to generation of candidacidal reactive oxygen species and K+-influx\u2013induced activation of neutrophil candidacidal granular proteases Candida yeast-to-hyphae conversion, a process dependent on the oxidative burst Candida yeasts and hyphae and appear important for anti-Candida host defense in vivo Neutrophils are indispensable for host defense against invasive candidiasis, and neutropenia is a well-recognized risk factor for development of and adverse outcome after infection in humans Nonetheless, neutrophils have differential effects in invasive candidiasis in vivo depending on the phase of the infection in mice. Specifically, early neutrophil presence after infection is protective, whereas neutrophil presence late after infection is pathogenic Candida phagocytosis and secretion of a variety of pro-inflammatory cytokines and chemokines that orchestrate the antifungal innate immune response Candida compared to neutrophils; the lack of macrophage myeloperoxidase and extracellular trap formation may, at least in part, account for this deficit Candida effects in mice; yet, the importance of Candida-induced nitric oxide formation in human phagocytes is unclear Candida infection. In addition, future studies should aim to shed light on the relative role of recruited versus resident monocytes/macrophages in host defense against invasive candidiasis.Besides neutrophils, monocytes/macrophages are key phagocytic cells for protection against invasive candidiasis, as their depletion in mice leads to increased mortality Candida challenge, monocytes were recently shown to also confer protection following systemic Candida re-infection via functional reprogramming that involves the dectin-1/Raf-1 non-canonical signaling pathway and results in enhanced cytokine production Intriguingly, besides the protective role of monocytes/macrophages in host defense against primary Candida yeast and hyphal forms and respond differentially to the Candida morphotypes by priming the production of distinct cytokines + dendritic cells were recently shown to activate invariant natural killer T cells to mediate innate immune responses against fungi (including Candida) via dectin-1- and MyD88-dependent mechanisms without apparent requirement for fungal lipid antigen presentation Candida effects after systemic infection Candida-specific CD4+ T cells after systemic infection of mice vaccinated with the Als-derived peptide pALS Candida immunity could lead to the design of effective vaccination and immunomodulatory strategies against invasive and mucosal candidiasis in patients.The role of other hematopoietic cells in host defense against invasive candidiasis merits further investigation. For example, dendritic cells are able to phagocytize Candida killing capacity of human myeloperoxidase-deficient phagocytes, invasive candidiasis occurs in patients with myeloperoxidase deficiency, the most common inherited phagocytic disorder In agreement with the requirement of innate immunity for effective host defense in the mouse model of invasive candidiasis, certain innate immune factors have been associated with protection against the infection in humans Candida immunity in humans \u2212/\u2212Card9 and \u2212/\u2212dectin-1 mice are both susceptible to invasive candidiasis Click here for additional data file."} +{"text": "Unfortunately, at present, degenerative retinal diseases such as retinitis pigmentosa remains untreatable. Patients with these conditions suffer progressive visual decline resulting from continuing loss of photoreceptor cells and outer nuclear layers. However, stem cell therapy is a promising approach to restore visual function in eyes with degenerative retinal diseases such as retinitis pigmentosa. Animal studies have established that pluripotent stem cells when placed in the mouse retinitis pigmentosa models have the potential not only to survive, but also to differentiate, organize into and function as photoreceptor cells. Furthermore, there is early evidence that these transplanted cells provide improved visual function. These groundbreaking studies provide proof of concept that stem cell therapy is a viable method of visual rehabilitation among eyes with retinitis pigmentosa. Further studies are required to optimize these techniques in human application. This review focuses on stem cell therapy as a new approach for vision restitution in retinitis pigmentosa. At present, degenerative retinal diseases such as retinitis pigmentosa (RP) and dry type age related macular degeneration (AMD) remain untreatable. Patients with these conditions suffer progressive visual decline resulting from continuing loss of photoreceptor cells and outer nuclear layers. Both disorders are characterized by the progressive dysfunction and death of the light sensing photoreceptors of the retina and other supportive cells. Because of the limited regenerative capacity of the mammalian retina, retinal progenitor cell are being developed to serve as \u201cspare parts\u201d for lost photoreceptor cells. Advances in molecular biology have identified innovative approaches that, for the first time, provide hope for permanent visual rehabilitation. Stem cell therapy can potentially replace lost photoreceptor and retinal pigment epithelial cell and subsequently restore visual function in eyes with degenerative retinal disorders .A potential target disease for stem cell therapy is retinitis pigmentosa (RP). RP is the most commonly inheritable eye disease that causes progressive loss of photoreceptor cells resulting in gradual visual decline. While the onset of RP may occur during infancy, the first symptoms are usually observed in early adulthood, beginning with nyctalopia or night blindness followed by loss of peripheral vision and eventually, as the central photoreceptors in the macula are damaged, loss of fine central vision. Morphologically, these retinas are characterized by centripetal proliferation of bone spicule-like pigmentation, attenuation of retinal blood vessels and optic nerve pallor . At leasTransplantation of progenitor stem cells that can be stimulated to become replacement photoreceptors and supportive outer retina cells can theoretically lead to treatments that restore visual function . RecentlTwo types of stem cells may be utilized to produce retinal progenitor cells. Firstly, Embryonic stem (ESC) and secondly, induced pluripotent stem (IPS) cells. Both types of cells are pluripotent and capable of becoming any cell type. ESC\u2019s are derived from embryos while IPS cells are obtained from a variety of adult tissues such as skin, bone marrow, teeth. IPS cells, if successfully implanted and optimized, can potentially provide an unlimited supply of stem cells for transplantation. Cell replacement is one approach for restoration of vision in RP. Because visual loss usually occurs when the outer retinal photoreceptor layer is lost, therapeutic timing should be at this stage of disease. Singh and colleagues have demonstrated using a murine model of severe human retinitis pigmentosa, that at a stage when no host rod cells are remaining, transplanted rod precursors can reestablish an anatomically distinct and appropriately polarized outer nuclear layer. In their study, restoration of a trilaminar retinal organization was restored to RD1 hosts with only two retinal layers before treatment. The introduced rod precursors continued to develop in the host niche to become mature rods complete with light-sensitive outer segments and connections to host neurons downstream. Visual function was also restored. These findings indicated that stem cell therapy may reinstate a light-sensitive cell layer de novo and restore structurally damaged visual circuits. In this model, total photoreceptor layer reconstruction is one approach to further develop cell-based strategies for retinal repair .ESC\u2019s have been shown to generate functional photoreceptor cells restoring light response of photoreceptor-deficient mice, but there is concern over the risk for tumor formation using ESC. Li and colleagues successfully cultured Nestin(+)Sox2(+)Pax6(+) multipotent retinal stem cells (RSCs) from the adult mouse retina. These ESC\u2019s are capable of producing functional photoreceptor cells that restore light response of photoreceptor-deficient RD1 mutant mice. After several cycles of expansion using growth factors, cultured RSCs still maintained proliferation and differentiation potential .Under optimized differentiation conditions, ESC\u2019s can differentiate into all the major retinal cell types found in the adult retina such as photoreceptor cells under optimized differentiation conditions. Following transplantation into the subretinal space of slowly degenerating RD7 mutant eyes, RSC-derived photoreceptor cells were shown to integrate into the retina, and develop into cells morphologically resembling endogenous photoreceptors and forming synapses with resident retinal neurons. When transplanted into eyes of photoreceptor-deficient RD1 mutant mice, an RP model, RSC-derived photoreceptors can partially restore light response, indicating functionality. In animal studies, no evidence for tumor development was found . Along similar lines, autologous IPS cells are being developed for stem cell transplantation. This lack of immunogenicity confers an important advantage. Because IPS cells are autologous or derived from the same organism, they do not incite immunological reaction nor require use of immunosuppressive medication . Li and colleagues recently transplanted human IPS cell-derived retinal pigment epithelium (RPE) cells into the subretinal spaces of mouse models with the Rpe65rd12 /Rpe65rd12 form of RP. A healthy adult provided skin fibroblasts cultured with lentivirus-delivered genes encoding transcription factors OCT4, SOX2, KLF4, and MYC. Antibody staining of markers and a teratoma assay demonstrated pluripotency of the hiPS cells. Culturing in differentiation medium guided their fate to RPE. By 12 weeks, from 30% to 50% of the surfaces of 12-well dishes were coated with RPE with characteristic hexagonal shapes, perinuclear melanin granules, and microvilli [The target mice had albinism, which provided a white contrast against which the transplanted pigmented cells would be visible. The mice also had severe combined immune deficiency to prevent graft-vs-host disease. An injection of 1000 hiPS-derived RPE cells was administered into the subretinal space in the right eyes of 34 mice at two days following birth. The mice were sacrificed at six months, shortly before they would have died from severe combined immune deficiency .Successful development into RPE cells was indicated by: 1) microscopic confirmation of pigmented hiPS-derived RPE admixed into the native, albino RPE; 2) quantitative polymerase chain reaction detection of markers of human fetal RPE and IPS-derived RPE; 3) positive staining for rhodopsin indicating that the hiPS-derived RPE cells phagocytosed photoreceptors. Furthermore, in some mice, electroretinogram (ERG) response to measure neuronal function, demonstrated a small but significant improvement of mean \u03b2-wave peak difference between treated and control eyes of 13.7 \u03bcV P = 0.0246). Furthermore, no tumor growth was observed [. FurtherThe use of retinal progenitor sheet transplantation is another promising approach. Seller and Aramant demonstrated that when freshly dissected sheets of fetal-derived retinal progenitor cells are mixed with RPE and transplanted subretinally, improvements of visual acuity are observed among animals and humans. Visual improvement in this model is attributed to restoration of synaptic connections between transplant and host when transplant processes proliferate into the inner plexiform layer of the host retina and presumably form synapses. One drawback of widespread use of this method is limited supply of fetal donor tissue .Future areas for stem cell development include methods for optimizing stem cell production and delivery. The use of specific extracellular matrix can stimulate the development of human pluripotent stem cells into transient organized neuroepithelum with rapid differentiation into retinal progenitor cells . Garit-HPreviously, RP was considered a devastating and untreatable condition. These pioneering animal studies provide hopeful evidence for the hypothesis that stem cell therapy is a viable means for visual rehabilitation of RP patients. What is now known is that stem cell therapy can potentially replace degenerate photoreceptors and outer retinal cells. When placed in the appropriate tissue niche, these stem cells not only survive but differentiate into critical retinal cells, develop a retina-like organizational structure and exhibit functional characteristics of full-fledged photoreceptors and outer retinal cells. Further studies are needed to optimize techniques and validate these findings before proceeding to human trials. Conflicts of Interest: None declared."} +{"text": "Bone plays metabolic roles through osteocalcin(OC) when it is released into the systemic circulation in uncarboxylated form. Identified novel metabolic roles of OC include increasing insulin secretion and sensitivity, energy expenditure, reduction of fat mass and mitochondrial proliferation and functional enhancement. The onset of puberty can be influenced metabolic factors. This study was aimed to determine serum OC levels in girls with central precocious puberty(CPP) and to investigate the effects of OC on the onset of puberty.Serum OC levels of girls CPP (n=30) and their age-matched controls (n=30) were measured. GnRH stimulation test was performed in CPP group. Bone age was determined in all subjects.Serum OC levels were significantly higher in CPP group compared with control group . Serum OC levels were correlated with peak LH levels during GnRH stimulation test , bone age and bone age advance , but not related to age, height, weight and BMI.Serum OC seems to be associated with the onset of puberty leaving casual relations unresolved."} +{"text": "To report a case of central serous chorioretinopathy after solar eclipse viewing.A middle-age man developed a sudden-onset unilateral scotoma after viewing a partial solar eclipse in Hong Kong. Fundus examination, fluorescein angiography, and optical coherence tomography showed features compatible with central serous chorioretinopathy. The patient was managed conservatively and reevaluated periodically. Serial optical coherence tomographic evaluations demonstrated an initial increase in the amount of subretinal fluid which spontaneously resolved 10 weeks after the onset of symptoms.This case demonstrates the possibility of development of central serous chorioretinopathy following solar eclipse viewing. Retinopathy following viewing of a solar eclipse without the use of safe eyewear has been well-documented in the literature. The usual lesion consists of mild foveal changes due to photochemical damage to the retina. Patients usually present with reduced visual acuity and a central scotoma. Classical findings on fundus examination include a yellow-white spot in the fovea surrounded by granular changes in the retinal pigment epithelium (RPE). Fundus fluorescein angiography (FA) may reveal a small central foveal window defect. Optical coherence tomography (OCT) may also demonstrate hypo- or hyperreflective lesions in the outer retina and RPE.4Central serous chorioretinopathy (CSCR) is an entity characterized by neurosensory retinal detachment with or without RPE detachment. Previous studies have reported the association of CSCR with various risk factors such as psychological stress, type A personality, pregnancy, untreated hypertension, use of corticosteroids, and psychopharmacologic medications.7Herein, we describe a rare case of CSCR after viewing a solar eclipse. To our knowledge, the association between CSCR and solar eclipse viewing has not been reported in the literature.A 44-year-old Caucasian man with good past health and unremarkable ophthalmic history presented with an acute-onset relative scotoma in his left eye after viewing a partial solar eclipse in Hong Kong on July 22, 2009.The patient was reassessed six weeks later and he still complained of a persistent central scotoma. Nonetheless, visual acuity remained stable. Fundus examination of the left eye showed an increase in subretinal fluid. OCT demonstrated an increase in the serous neurosensory retinal detachment . Ten weeTo the best of our knowledge, this is the first report describing acute CSCR after direct solar eclipse gazing. Unprotected sun-gazing, particularly during an episode of solar eclipse, is a well-known cause of solar retinopathy.Clinical features of CSCR include accumulation of subretinal fluid, neurosensory retinal and RPE detachment, and leakage with angiographic evidence of RPE hyperpermeability.The exact pathogenetic mechanism of CSCR in our case remains unclear. We hypothesize that intense sunlight was preferentially absorbed by melanosomes in the RPE, causing localized RPE damage and thus resulting in CSCR."} +{"text": "In addition, no change in intracerebral incubation period was observed following active rumen digestion of unbound hamster HY TME prions and HY TME prions bound to a silty clay loam soil. These results demonstrate that both unbound and soil-bound prions readily survive rumen digestion without a reduction in infectivity, further supporting the potential for soil-mediated transmission of chronic wasting disease (CWD) and scrapie in the environment.Before prion uptake and infection can occur in the lower gastrointestinal system, ingested prions are subjected to anaerobic digestion in the rumen of cervids and bovids. The susceptibility of soil-bound prions to rumen digestion has not been evaluated previously. In this study, prions from infectious brain homogenates as well as prions bound to a range of soils and soil minerals were subjected to in vitro rumen digestion, and changes in PrP levels were measured via western blot. Binding to clay appeared to protect noninfectious hamster PrP Sc, a misfolded isoform of a normal cellular prion protein (PrPc) found in all susceptible species Sc exhibits resistance to proteolysis and inactivation, increased hydrophobicity, and a propensity for aggregation Sc can seed conversion of PrPc to PrPSc (\u2018replicate\u2019) and thereby initiate prion propagation and, presumably, disease infection Prion diseases, or transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases that afflict ruminants, including cattle , sheep and goats (scrapie), and deer, elk, and moose (chronic wasting disease or CWD), as well as humans (Creutzfeld-Jakob disease or CJD) Natural transmission of CWD and scrapie occurs primarily or exclusively through ingestion or inhalation of prion-contaminated material shed from infected hosts or present in mortalities Sc survives the digestive processes in the rumen and lower gastrointestinal system. Results from previous in vitro studies of PrPSc fate in rumen digestion have been varied. Scherbel and colleagues observed a near-complete loss of 263 K hamster PrPSc, as detected by western blot, following rumen digestion Sc in scrapie-infected sheep brain homogenates following exposure to rumen and other alimentary fluids Sc was detected post-digestion when precipitation and proteinase-K digestion were used prior to western blotting. An additional limited study found no evidence of scrapie PrPSc digestion in rumen fluids Sc.Prions are orally infectious Sc (both CWD-elk and hamster) has been shown previously Ingestion of prion-contaminated soil has been implicated as a likely mechanism of natural CWD and scrapie transmission Sc levels were measured by western blotting. Intracerebral hamster bioassay was also employed to measure changes in infectious titer. The results demonstrate the strong resistance of both unbound and soil-bound prions to rumen digestion, which further supports the efficacy of soil-bound prion ingestion as a natural route of disease transmission in ruminants.Adsorption of prions to soil may alter prion resistance to host degradation, thus potentially altering their oral infectivity and transmissibility. The objective of this research was to evaluate and compare the ability of rumen digestion to degrade unbound prions as well as prions bound to a range of soils and soil minerals. In vitro anaerobic digestion assays seeded by bovine rumen fluid were conducted, and the resultant PrPAll procedures involved in animal bioassay were approved by the Creighton University Institutional Animal Care and Use Committee and complied with the Guide for the Care and Use of Laboratory Animals. Collection procedures for rumen fluid from cannulated dairy cows was approved by the University of Nebraska-Lincoln Institutional Animal Care and Use Committee.++ or Mg++ using strain-dedicated Tenbroeck tissue grinders .Prion-infected brain tissue was collected without prior buffer profusion from golden Syrian hamsters infected with the hyper (HY) strain of transmissible mink encephalopathy (TME) as previously described Sc/PrPc and uninfected PrPc from brain homogenates were sorbed to a range of soils as described previously 2, Sigma Aldrich, St. Louis, MO) were used and have been described previously HY TME PrP2, 10% H2, and 5% CO2. Rumen fluid was diluted 1\u223610 or 1\u22365 in McDougall's buffer with soluble carbohydrates . There was no difference in immunoblot results between 1\u223610 and 1\u22365 rumen\u2236buffer dilutions (data not shown).Standard in vitro rumen digestion assay methods were followed Resazurin dye was used as an indicator of redox state and does not affect in vitro digestion Sc in digested and undigested samples was accomplished using SDS-PAGE/Western blotting as described previously without modification Detection of PrPIntracerebral inoculations of male golden Syrian hamsters were conducted as described previously Two-tailed student's T-tests assuming unequal variances were performed using Microsoft Excel to determine statistical significance as noted. P values less than 0.05 were considered statistically significant.An in vitro digestion assay was employed to simulate rumen digestion of prion-contaminated material. Standard methods, including standard rumen fluid sampling procedures and substrate and buffer compositions, were used Sc from brain homogenate was not significantly reduced in actively digested samples compared to inactive and buffer controls .Unbound HY TME PrPSc following in vitro rumen digestion, but somewhat inconsistent with Scherbel et al. Sc degradation during active digestion in the absence of detergents. Methodological differences such as rumen fluid seed or western blotting techniques may be responsible for the observed differences. For instance, we collected rumen fluid from a live, cannulated dairy cow while Scherbel et al. collected fluid from a slaughtered beef bull.These results are consistent with the result of Nicholson and colleagues Sc was sorbed to a range of soils and soil minerals and exposed to in vitro rumen digestion. Consistent with the unbound results, HY PrPSc bound to silty clay loam (SCL) soil was not reduced following active rumen digestion (Sc bound to SCL soil demonstrated similar resistance to digestion (data not shown). Increased detection of PrPSc bound to bentonite clay (2) and not a direct effect on PrPSc.To determine the effect of soil on the susceptibility of prions to rumen digestion, PrPabnormal , the lowSc was not detected on sand samples actively digested .HY TME bound to sandy loam (SL) soil and sand was susceptible to rumen digestion , and PrPdigested , lane 4.c from uninfected hamster brain homogenate (data not shown). Since there is a well-established relationship between HY TME infectious titer and incubation period Sc levels before and after digestion in unbound and SCL soil-bound PrPSc (Hamsters were inoculated with unbound and SCL-bound HY TME prions subjected to either active or inactive (pre-autoclaved) in vitro rumen digestion. The incubation periods of hamsters inoculated with inactive or active samples were equal . The incnd PrPSc .Sc replication efficiency Also consistent with previous results, the mean incubation time of SCL soil-bound HY TME was significantly longer (13 d) than unbound HY TME [27]. ThSc resistance to in vitro rumen digestion Sc abundance To initiate infection via absorption across the lower gastrointestinal epithelium, orally ingested prions must survive passage through the rumen bundance , and conbundance . MoreoveSc resistance to digestion with respect to soil type, where, in contrast to the other soils and minerals, PrPSc levels bound to sand and sandy loam soil were reduced following digestion (2 is not significantly different than unbound prions (data not shown). Based on the established relationship between PMCA replication efficiency and infectious titer We did observe variance in PrPigestion . VariancA number of factors must be considered in extending the present results. First, the results were obtained using in vitro digestion, which is a simulation of in vivo processes with limitations Sc, it may alter PrPSc uptake efficiency, which would not be detected by immunoblot or intracerebral bioassay. Thus, study of soil-bound prions in, for example, the gut-loop system employed by Dagleish and Jeffery Finally, unbound and soil-bound prions surviving rumen passage will be exposed to stomach and intestinal digestion before uptake. These two processes are less complex than rumen digestion, and previous results indicate unbound prions are resistant to both Figure S1Sc without proteinase-K treatment.Rumen digestion of unbound HYTME PrP(DOCX)Click here for additional data file.Table S1PrP Adsorption to Soil and Soil Minerals.(DOCX)Click here for additional data file."} +{"text": "Escherichia coli sepsis in baboons strongly induces procoagulant responses and affects the integrity of the lung. These effects are diminished by the treatment with compstatin, a C3 convertase complement inhibitor [Pulmonary fibrosis is a major and common medical condition, characterized by progressive scaring and decline in lung function. Persistent inflammation and acute lung injury in response to sepsis are potential triggers of the fibrotic response. Recently, we have reported that nhibitor .E. coli sepsis triggered metabolic and signaling pathways related to lung remodeling and fibrosis, and whether complement inhibition could attenuate these pathways.Here we used the baboon model described in conjuE. coli challenge. Immunochemical and biochemical analysis reveals enhanced collagen synthesis, induction of profibrotic factors and increased cell recruitment and proliferation. Compstatin treatment decreases sepsis-induced expression of extracellular matrix genes, including eight collagen genes. Sirius Red and immunofluorescence staining for procollagens 1 and 3 confirms the collagen deposition in the lung. Ingenuity\u00ae pathway analysis of transcriptomics data shows that compstatin treatment reduces sepsis-induced expression of genes involved in fibroblast transformation and connective tissue production, cell chemotaxis, migration and proliferation (see Table Microarray gene expression analysis shows that sepsis augments several fibrotic gene clusters in the lung as early as 24 hours post Our data demonstrate that bacterial sepsis initiates pulmonary collagen deposition, and complement inhibition effectively attenuates the fibrotic response. This suggests that complement inhibitors could be used for prevention of sepsis-induced pulmonary fibrosis."} +{"text": "Endogenous retroviruses (ERVs) have much lower mutation rates than exogenous retroviruses (XRVs), therefore they are an important tool in analysing the long-term evolutionary history of retroviruses. Their transmission patterns also act as useful markers when studying host phylogenetics.[Oryctolagus cuniculus) [Lepus europeaus) [Microcebus murinus) [Cheirogaelus medius) [gamma- and beta- retroviruses, which are present in many vertebrate species The aim of this project is to look for and characterise further examples of primate ERVs and therefore gain insight into the evolutionary history of retroviruses and their primate hosts. This will involve data mining of primate genomes for previously unknown ERVs as well as PCR based screening of genera for which genome sequences are not available. Preliminary work suggests that prosimian primate genomes contain previously unclassified endogenous lentiviruses, so PCR-based screening will be used with DNA samples from lemurs, bushbabies and lorises to sequence and characterise these viruses.Recently, the first examples of endogenous lentivirus were characterised. The earliest was rabbit endogenous lentivirus type K in the European rabbit pol), group-specific antigen (gag) and envelope (env) genes of representative XRVs from all known retroviral genera were used to identify regions of the host genome which are highly similar to retroviral genes. We have validated this method by successfully searching the human genome for known ERV insertions. Regions of interest are then extracted and analysed in detail.The bioinformatics analysis component of this project used Exonerate to perfopol gene on sampM. murinus genome sequence identified 3542 ERV-like regions. This included 256 regions of less than 10,000 base pairs which incorporated gag, pol and env-like sequences in the correct orientation. The subset of pol genes which were within these 256 proviruses appear to be closely related to known gamma- and beta-retroviruses from other species.Bioinformatics analysis of the low-coverage Varecia variegata, Eulemur rufus and Mirza coquereli; the loris Perodictus potto and the bushbaby Galago moholi, although these insertions are yet to be further characterised.Preliminary laboratory work has shown previously uncharacterised lentiviral insertions in several species of lemur - murinus genome. Preliminary laboratory results suggest that there are undescribed endogenous lentiviruses in further prosimian primate species. Methodology has been established which can be used to screen further species for proviral insertions and to explore these in detail.Multiple potential ERV sequences have been found in the M."} +{"text": "Entropy is an elusive and somehow non-intuitive concept. Nevertheless, entropy governs spontaneous thermodynamic processes as important contribution to Gibbs Free Energy. Information theory defines Shannon entropy as a measure for uncertainty. In the context of protein binding the inherent link between flexibility, thus conformational entropy, and substrate specificity is discussed. Substrate promiscuity of proteases is quantified as cleavage entropy correlating local binding site flexibility directly with substrate readout. Caspases are examined as example protease family, where active site dynamics play a major role in mediating substrate specificity. Direct comparison of entropy in substrate data allows highlighting previously unexpected similarities in substrate recognition in proteases. Promiscuous binding to several protease targets demonstrates the emerging importance of quantitative studies on binding specificity. Shannon entropy applied to probability densities is used to rationalize ordering or disordering by binding processes. We have developed a data-driven method to reconstruct probability densities from discrete sampling by computer simulations. Application to solvent degrees of freedom leads to excellent correlation with experimental data."} +{"text": "Bisphenol A (BPA) is a chemical widely used to make polycarbonate plastics and epoxy resins lining food and beverage containers. A number of in vitro and in vivo studies have demonstrated that BPA has an estrogenic effect by binding to the nuclear estrogen receptor, and early BPA exposure could in induce early puberty. However, effects of human exposure to BPA on pubertal onset and the association of gonadotropin levels have not been fully evaluated. We aimed to study whether serum bisphenol A levels are associated with central precocious puberty (CPP) in Korean children.A total of 103 girls were enrolled. Pubertal staging, anthropometry, bone maturation were assessed. Gonadotropin releasing hormone-stimulation test were conducted to determine the basal and peak levels of luteinizing hormone (LH). Serum bisphenol A levels were analysed by gas chromatography/mass spectrometry method. Geometric mean serum BPA levels were higher in CPP girls than in controls . In partial correlation analysis controlling for age and body mass index, serum BPA level showed significant positive correlation with bone age , fat mass , waist circumference , basal LH levels , and peak LH levels . Bone age, height, basal/peak LH levels and prevalence of CPP increased significantly with increasing tertile of serum BPA. Increased risk of CPP [Odds ratio] was observed across increasing serum BPA tertile after adjusting for age and BMI.Serum BPA level was higher in CPP girls compared with controls, and higher serum BPA level was associated with increased risk of CPP. Prospective studies are needed to determine potential causal links between BPA exposure and CPP."} +{"text": "We present a case of myocardial infarction in a 19 year old female with cystic fibrosis who had a heart and lung transplant performed at the age of four years old. She presented atypically with a one day history of severe, intermittent, central, sharp chest pain, radiating to her back and down her left arm. A coronary angiogram showed proximal stenosis of the left anterior descending artery and right coronary artery. She was treated with percutaneous coronary intervention, involving drug eluting stents to the left anterior descending artery (LAD) and the right coronary artery (RCA). In this study we discuss the pathophysiology, investigations and treatment of cardiac transplant vasculopathy. Although complete reversal of LAD and RCA stenosis was achieved, routine follow-up with coronary angiography and careful control of cardiac risk factors will be important to identify and reduce future restenosis and adverse cardiac events. Heart and lung transplantation in children with cystic fibrosis (CF) and end-stage lung disease are now rarely performed, with bilateral sequential lung transplantation (BSLT) being the preferred procedure . AlthougA 19 year old female with CF who had a heart and lung transplantation in 1997 presented to the Emergency Department (ED) with a one day history of severe, intermittent, central, sharp chest pain, radiating to her back and down her left arm. This was associated with intermittent paraesthesia, pallor and coldness in her left hand. The chest pain was worse on deep inspiration but was not positional or exacerbated by movement. Over the previous four weeks she had been having a productive cough with a reduced exercise tolerance but no chest pain.9/L), creatinine (138 \u03bcmol/L) and urea (12.8 \u03bcmol/L).On examination there was no swelling, pallor or erythema of her left arm/hand and no chest wall tenderness. She was well perfused with a regular pulse and a stable blood pressure. No murmur or added heart sound was present and vesicular breath sounds were heard on auscultation. A chest radiograph showed no acute changes and an initial electrocardiogram (ECG) taken in the ED showed a sinus tachycardia with no ST or T wave changes. Initial blood tests were normal apart from an elevated white cell count was 10,801. A computed tomography pulmonary angiogram (CTPA) the following day showed no pulmonary embolus (PE) and no vascular abnormalities. A coronary multi-slice computed tomography (MSCT) was not performed as it is not used as an investigation of acute MI in inpatients at St James\u2019s University Hospital.Later that day the patient was reviewed by a cardiology registrar who performed a bedside echocardiogram. This demonstrated moderate left ventricular impairment due to extensive apical akinesis and anterior/antero-septal hypokinesis with an ejection fraction of 42%. No valvular dysfunction was identified. That evening the patient received percutaneous coronary intervention (PCI) which illustrated a 95% proximal stenosis of the left anterior descending artery (LAD), normal left circumflex artery (LCx) and 80-95% proximal stenosis of the right coronary artery (RCA) Figure\u00a0. Drug elCardiac transplant vasculopathy (CTV) is a rapidly progressive form of atherosclerosis involving thickening of the intima, leading to stenosis of coronary artery grafts and subsequent myocardial ischaemia . It is gThe development of CTV is thought to be due to a combination of an immune-mediated process and non-immunologic risk factors resulting in endothelial injury and subsequent fibroelastic proliferation of the intima . Risk faThe diagnosis of CTV is particularly challenging as it rarely presents with typical angina, despite 10-30% of patients with heart transplants having partial reinnervation . HoweverIn many transplant centres, patients with heart transplants receive annual coronary angiography. However, due to the diffuse nature of CTV, angiography may underestimate the severity of disease or miss it completely . The patThe gold standard investigation of CTV is intravascular ultrasound (IVUS) which has the ability to assess the amount of intimal thickness and identify vessel wall morphology . A studyA number of non-invasive radiological modalities (e.g. dobutamine stress echocardiography (DSE), myocardial perfusion imaging (MPI) and multislice computed tomography (CT) coronary angiography) have also been utilized to assist in the diagnosis of CTV, with variable degrees of sensitivity and specificity . A pilotThe most effective treatment of CTV is prevention and modification of risk factors using antihypertensive agents , statins (e.g. pravastatin) and strict diabetic control. Coronary artery bypass grafting is rarely an option in CTV due to the diffuse nature of the disease process and the limited availability of donor hearts makes re-transplantation unlikely. In patients with heart transplants presenting with chest pain or features of congestive heart failure, if the ECG or echocardiogram show ischaemic changes or wall motion abnormalities, acute coronary syndrome should be suspected and patients should be treated accordingly with antiplatelet agents and PCI .A systematic review of six small, retrospective, nonrandomised studies comparing the use of bare-metal stents (BMS) with drug-eluting stents (DES) in the treatment of CTV (328 lesions treated with BMS and 287 lesions treated with DES) showed that DES were associated with a lower restenosis rate at 6\u201312 months, but in only half of the six studies were the differences statistically significant . There wA recent retrospective nonrandomised study involving 34 patients receiving a total of 46 stents (27 DES vs 19 BMS) is the first to suggest a clinical benefit with DES compared to BMS in the treatment of CTV . RandomiMaintenance immunosuppression following heart transplantation usually consists of a triple therapy of corticosteroids , a calcineurin inhibitor (CNI) (cyclosporine or tacrolimus) and an antiproliferative agent . AzathioTacrolimus and cyclosporine have failed to demonstrate prevention of CTV after heart transplantation and there appears to be little difference between these CNIs in terms of long-term development of CTV . HoweverIn terms of CTV prevention, the optimum maintenance immunosupression regime is unclear and a long-term randomised trial is required to determine this. The maintenance immunosupression regime following heart and lung transplantation for the patient in this case consisted of tacrolimus and prednisolone without the use of an antiproliferative agent. There was no change in the maintenance immunosupression regime post MI.MI must be considered in young patients with CF and a heart and lung transplant with atypical chest pain. Although complete reversal of LAD and RCA stenosis was achieved in this case with the use of PCI and DES, routine follow-up with coronary angiography and careful control of cardiac risk factors will be important to identify and reduce future restenosis and adverse cardiac events.Written informed consent was obtained from the patient for publication of this case report and any accompanying images.BMS: Bare-metal stents; BSLT: Bilateral sequential lung transplantation; CF: Cystic fibrosis; CFRD: Cystic fibrosis related diabetes; CMV: Cytomegalovirus; CNI: Calcineurin inhibitor; CTV: Cardiac transplant vasculopathy; DES: Drug eluting stents; DSE: Dobutamine stress echocardiography; ECG: Electrocardiogram; ED: Emergency Department; CTPA: Computed tomography pulmonary angiogram; IVUS: Intravascular ultrasound; LAD: Left anterior descending artery; LCx: Left circumflex artery; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; PE: Pulmonary embolus; RCA: Right coronary artery; MPI: Myocardial perfusion imaging; CT: Computed tomography.The authors declare that they have no competing interests.JE and DP were both involved in the management of the case. JE wrote the case report with assistance from DP. Both authors read and approved the final manuscript."} +{"text": "The patient with a history of bone pain and muscle weakness, was thought to have oncogenic osteomalacia as a result of biochemical investigations and directed to Nuclear Medicine Department for a whole-body bone scintigraphy and 111In-octreotide scintigraphy. There was no focal pathologic tracer uptake, but generalized marked increase in skeletal uptake on bone scintigraphy. Octreotide scintigraphy showed accumulation of octreotide in the region of the left lobe of the thyroid gland in the neck. Thereafter, parathyroid scintigraphy was performed with technetium-99m labeled metroxy-isobutyl-isonitryl (99mTc-MIB) and MIBI scan demonstrated radiotracer uptake at the same location with octreotide scintigraphy. The patient underwent left inferior parathyroidectomy and histopathology confirmed a parathyroid adenoma. Somatostatin receptor positive parathyroid adenoma may show octreotide uptake. Octreotide scintigraphy may be promising and indicate a possibility of using somatostatin analogues for the medical treatment of somatostatin receptor positiveConflict of interest:None declared. HowevA 48-year-old woman was presented to our department with history of bone pain, muscle weakness. Biochemical investigations showed hypophosphatemia ; increased alkaline phosphatase ; normocalcaemia supporting hypocalcaemic onkogenic osteomalacia.Whole body bone scintigraphy was performed after intravenous administration of 20 mCi (740 MBq) of methyleno-diphosphonate labeled with technetium-99m (Tc- 99m MDP). Bone scan showed metabolic bone disorder featured by the following characteristics: Prominent tracer uptake in the calvarium, mandible, spine, rib, and bilateral femora; intense uptake at the costochondral junctures and faint kidney visualization . BesidesParathyroid adenoma is part of a spectrum of parathyroid proliferative disorder that includes parathyroid hyperplasia, parathyroid adenoma and parathyroid carcinoma . Eighty Patients with primary hyperparathyroidism may present clinical evidence of elevated serum calcium levels which include non-specific symptoms such as fatigue, pain and weakness as well as polydipsia, polyuria, and nephrolithiasis . SonograSome studies also have suggested a role for somatostatin analogues in the medical treatment of hyperparathyroidism ,12,13. FIn conclusion, when a focal uptake was observed in the region of the thyroid gland on octreotide scintigraphy, the presence of parathyroid adenoma should also be considered. Parathyroid tumors expressing somatostatin receptors may show octreotide uptake and octreotide scan may be promising and indicate a possibility of using somatostatin analogues for medical treatment of somatostatin receptor positive parathyroid tumors in some situations which surgery is not possible and parathyroid tumor recurrence."} +{"text": "Dear Editor,Atrial fibrillation (AF) is one of the most frequent complications after cardiac surgery. It occurs in approximately 20% to 35% of patients after coronary artery bypass graft (CABG) surgery and in more than 50% of patients after valve surgery . AF afteAlthough many of potential risk factors for development of post-operative AF have previously been demonstrated in cardiac surgery patients ; the resRegarding the relatively high prevalence of opium abuse among patients undergoing cardiac surgery and considering its potential role in prediction of AF after cardiac surgery, anesthesiologists and cardiac surgeons should provide better preventive measures when planning surgery in opium addict patients. Since most of the studies performed in this field were retrospective, with inherent limitations, future prospective studies are needed to confirm this association."} +{"text": "In the traditional view on brain activity dynamics, the cognitive flow of information wanders through multiple stable states driven by task-dependent inputs -3. This It has been recently proposed that such transient states are basically shaped by anatomical connectivity and transitions between them occur even in the absence of external stimuli : Noise eA different metaphor of transient brain dynamics was proposed by Rabinovich and colleagues . In suchIn this work we develop an empirical criterion to discern whether observable neural ensemble activity can be originated by non-autonomous yet deterministic dynamical systems or rather by stochastic fluctuations between temporally attracting states. Towards this goal, we used in vivo multiple single-unit recording in rodent frontal cortex during a decision making task. Effective dynamics of neural activity is first empirically reconstructed in nonlinear state spaces . Then, tUnderlying dynamics of recorded ensemble activity is probably driven by a slowly drifting, non-autonomous dynamical system containing low-order nonlinear interactions."} +{"text": "Colorectal cancers are the third most common type of cancers globally, affecting both sexes . As of nNine normal and 25 tumoral colon tissue sections (3mm diameter x 10 \u00b5m thick) embedded in the form of paraffinized tissue microarray, stabilized in an agarose matrix were analyzed directly by IR imaging. To avoid chemical deparaffinization, a modified Extended Multiplicative Signal Correction (EMSC) method[EMSC permitted mathematical correction of the spectral interferences originating from paraffin and agarose. K-means classification allowed to identify and to distinguish important histological features of the colonic tissues such as crypts, lamina propria, tumor, etc. When compared to HPS stained images, after whole slide image analyzed with crop and score Calopix module from TRIBVN or through pathologist control, color-coded spectral images not only reveal features representative of the biochemical make up of the tissues, but also highlight additional features like intra-tumoral heterogeneity and tumor-associated stroma, which are difficult to discern by conventional histopathology. The LDA prediction model was promising since an average sensitivity of 91 % was achieved in the identification and prediction of tumoral tissues.IR imaging allowed differentiating and detecting normal and tumoral colon tissue features based on their intrinsic biochemical information. This chemical-free approach on paraffinized tissue biopsies combined with multivariate statistical image analysis opens a new avenue for numerical spectral histopathology and appears as a promising tool for colon cancer diagnosis. Further work to improve the model and to predict tumors in blind samples is ongoing."} +{"text": "The regulation of gene expression plays a pivotal role in complex phenotypes, and epigenetic mechanisms such as DNA methylation are essential to this process. The availability of next-generation sequencing technologies allows us to study epigenetic variation at an unprecedented level of resolution. Even so, our understanding of the underlying sources of epigenetic variability remains limited. Twin studies have played an essential role in estimating phenotypic heritability, and these now offer an opportunity to study epigenetic variation as a dynamic quantitative trait. High monozygotic twin discordance rates for common diseases suggest that unexplained environmental or epigenetic factors could be involved. Recent genome-wide epigenetic studies in disease-discordant monozygotic twins emphasize the power of this design to successfully identify epigenetic changes associated with complex traits. We describe how large-scale epigenetic studies of twins can improve our understanding of how genetic, environmental and stochastic factors impact upon epigenetics, and how such studies can provide a comprehensive understanding of how epigenetic variation affects complex traits. The term epigenetics was originally introduced to describe how interactions between genetics and environment can give rise to phenotypes during development de novo methylation and the maintenance of methylation patterns during replication Epigenetic mechanisms are present in many taxa, but DNA methylation has been most extensively studied in mammals where it appears to be restricted to the cytosine base, and especially in the context of CpG dinucleotides. CpG dinucleotides are cytosine\u2013phosphate\u2013guanine sequences that typically cluster in genomic regions referred to as CpG islands (CGI), which are often located in gene promoters and exhibit low levels of DNA methylation. However, DNA methylation in mammals can also occur outside the CpG context, and this has been reported for example in embryonic stem cells H19 locus control imprinting and gene expression at the maternally imprinted and transcriptionally-silenced insulin-like growth factor II (IGF2) locus and at the paternally imprinted and silenced H19 region de novo DNA methylation has also been suggested twins are traditionally regarded as genetically identical, therefore any phenotypic differences within MZ twin pairs are classically attributed to environmental factors. However, epigenetic variants can also associate with phenotypic differences, and the identification and interpretation of such associations is currently an important area of research. Epigenetic studies of disease-discordant MZ twins, who are completely matched for genetics, age, sex, cohort effects, maternal influences and common environment, and are closely matched for other environmental factors, should be considerably more powerful in detecting disease-related epigenetic differences than epigenetic studies of unrelated disease cases and controls with different life-histories. In the following sections we consider the value of twin studies in epigenetics and discuss recent findings highlighting the possibility that epigenetic variation can be transmitted through generations and impact upon common diseases.Heritability is the proportion of the phenotypic variance in the population that is attributed to genetic variation. Heritability estimates are traditionally obtained by comparing the extent of similarity between relatives in classical twin studies, twin-adoption studies, sib/half-sib studies, and transgenerational family studies. Each has weaknesses, but for most traits twin studies are generally regarded as the most reliable because they are unbiased by age effects and offer the ability to separate common environment from genetic effects post hoc in twins who differed most in lifestyle. However, the study was cross-sectional instead of longitudinal, potentially obscuring comparison of individual variability; furthermore, comparing epigenetic patterns in fast-growing children and adults might not be generalizable to the aging process. To this end, a recent longitudinal study of twin epigenetic heritability assayed DNA methylation patterns in the promoters of three genes in 46 MZ and 45 DZ twin pairs sampled at 5 and 10 years of age Several studies have examined DNA methylation patterns in twins. Early work focused on X-chromosome inactivation patterns in females \u2013 where one X chromosome is inactivated at random and the silent state of the inactive X-chromosome is maintained by DNA methylation IGF2) gene and the paternally imprinted H19 region, estimating high epigenetic heritability in those regions using multiple tissues from 182 newborn MZ and DZ twins Substantive evidence for epigenetic heritability has been obtained from further studies of age-matched twins using larger samples Overall, these findings confirm that DNA methylation is a heritable trait on a genome-wide basis, but also highlight the importance of taking age into account when studying epigenetic processes. Furthermore, the results are consistent with recent population-based findings of quantitative trait loci (QTL) for DNA methylation DNA methylation patterns can be affected by genetic variation, environmental changes, heritable and non-heritable changes in other epigenetic processes , and stochastic changes over time. All these factors can contribute to DNA methylation heritability estimates, which are therefore time-, tissue-, locus- and population-specific. There are three further important aspects of epigenetic heritability. First, does twin epigenetic heritability reflect stability in methylation transmission during mitosis and meiosis? Second, does epigenetic variation contribute to phenotype heritability? Finally, how do epigenetic heritability findings relate to time-dependent methylation changes?In mammals, maintenance DNA methyltransferases and histone methyltransferases ensure propagation of epigenetic marks through mitotic cell divisions with high fidelity in two discordant or concordant pairs of schizophrenic twins; this study found greater methylation differences between discordant MZ twins than in unrelated cases Recently, several epigenetic studies of MZ discordant twins have examined differences in DNA methylation profiles, aiming to identify differentially methylated regions (DMRs) in human disease The power of discordant MZ twin studies to detect DMRs will depend on a number of factors, including the effect size of the epigenetic change on the phenotype, the similarity of methylation profiles between MZ twins, sample size, and the sensitivity and coverage of the methylation assay. An estimate of the power of the discordant MZ twin design for a specific microarray methylation assay There are several aspects of epigenetic studies where twins present novel opportunities to understand the biology and the mechanisms underlying complex traits. We suggest a few examples.http://www.muther.ac.uk/), which aims to assay gene expression variation in multiple tissues in twins and to identify regulatory genetic variants, can be linked with epigenetic data to explore the tissue specificity and functional consequences of epigenetic variation in twins. This project is being extended to RNA sequencing (via the EUroBATS project), and this will also allow differential allelic expression to be explored. Allele-specific expression (ASE) patterns are relatively common and are under strict genetic control Twin resources such as the MuTHER (multiple tissue human expression resource) project affect epigenetics. ARTs include IVF and related technologies http://www.twinsuk.ac.uk/) aims to discover methylated genes responsible for discordance of ten common traits and diseases. The study is using MeDIP-seq on blood samples to assay epigenomic differences in 5000 adult UK twins aged 16\u201385, discordant and concordant for a wide variety of diseases and environments. Next-generation sequencing, although currently at significant cost, has the potential to prove powerful in detecting disease-related methylation differences at a high level of resolution in a sample of this size. Another ongoing large-scale prospective study consists of a cohort of Australian newborn twins http://www.euengage.org/), where MeCAP-seq is being performed by sample pooling across multiple traits in discordant twins.A recent large-scale study (EpiTwin \u2013 Two further areas that can benefit from the epigenetic differences observed in MZ twins are forensic science and medical transplantation. Although twins are no more likely to be criminals than the general population, one in 250 people are MZ twins and legal cases involving MZ twins are high-profile. For example, the genetic identity of MZ twins can allow twins to provide each other with alibis in criminal cases. Differences in epigenetic profiles between MZ twins, if consistently replicated, could in future lead to closing this loophole. In transplantation there are reports of occasional graft failures in identical twins. Studying subtle differences in twin epigenetic profiles could improve transplantation outcomes, where small epigenetic changes of immune-related genes in the host or in transplanted organs could affect transplant success The study of epigenetic profiles in twins offers an excellent opportunity to understand the causes and consequences of epigenetic variation. Twin epigenetic heritability estimates tell us about the genetic control of DNA methylation variability and the stability of methylation patterns during cell division. The contribution of epigenetic variants to complex phenotypes can be assessed using disease-discordant MZ twins who are otherwise matched for genetics, age, sex, cohort effects, maternal effects and a common environment. These twin designs are considerably more powerful discovery tools than studies on singletons. In the near future, large-scale epigenetic studies in twins across different ages, tissues, and diseases will improve our understanding of the etiology and mechanisms of a wide range of common complex traits and diseases."} +{"text": "Vaccination strategies capable of eliciting neutralizing antibody responses to HIV remain elusive despite extensive efforts. Alternative antibody functions offer opportunities for protection without necessarily achieving broad neutralization breadth. Viral immune exclusion through aggregation has been proposed as an alternative protection pathway, but mechanisms for studying this phenomenon at the scale necessary for clinical trials have not been explored.Concentrated fluorescent virions of two colors, suspended in hydroxyethylcellulose (HEC) gel, which has been formulated to simulate the diffusion characteristics of cervical mucus, are imaged over time. Mean squared displacement and incidence of colocalized viral particles are determined. The addition of monoclonal antibodies of various specificities and isotypes affects these parameters is explored. Immunoglobulin isolated from HIV-1 positive individuals was examined as well. Correlative scanning electron micrographs of the same preparations were performed to confirm the nature of suspected aggregates.Multimeric antibodies, rather than monomeric isoforms, selectively hinder the diffusion characteristics of colocalized virions, more so than non-aggregated virions. The incidence of colocalized virions is also increased in a concentration dependent manner. Excessive antibody or virus concentration is seen to obviate aggregate formation. These results are seen in both monoclonal antibody experiments alongside polyclonal patient IgA isolated from breast milk and IgM from serum.Virus aggregation has been demonstrated as a feasible effector function of HIV-1 specific antibody preparations. This assay platform is amenable to adaptation for medium to high throughput sample screening and low sample size. Monoclonal antibodies as well as patient samples are able to induce similar behaviors. Measurement of viral aggregation as a corollary of vaccine efficacy is deserving of further exploration in a clinical setting."} +{"text": "The resulting adducts were fully characterized by spectroscopic and analytical methods; they constitute interesting substrates for further organic transformations.The chemical behaviour of various alkyl-substituted, acyclic conjugated bisallenes in reactions involving polar intermediates and/or transition states has been investigated on a broad scale for the first time. The reactions studied include lithiation, reaction of the thus formed organolithium salts with various electrophiles , oxidation to cyclopentenones and epoxides, hydrohalogenation , halogenation (Br"} +{"text": "X-linked hypohidrotic ectodermal dyplasia (XLHED) is the most common form of ectodermal dysplasia. It often presents with ocular symptoms, already in early childhood. Multiple ophthalmological tests are available, but in early childhood only tests of lower invasiveness can be applied. We have evaluated tear film tests and ocular surface staining as screening methods in pediatric patients with signs of ectodermal dysplasia. These tests may also be used in adults with confirmed XLHED to determine the severity of ocular surface disease.Twelve children and 14 adults with XLHED were subjected to a panel of tests including the ocular surface disease index (OSDI), non-invasive measurement of tear film break-up time (NIBUT), osmolarity, Schirmer test, lissamine green staining, fluorescein staining, meibography and infrared thermography. Sensitivity and specificity were determined for single tests and selected test combinations. For adults with XLHED, OSDI, NIBUT and osmolarity were the best single routine tests . Their combination increased the sensitivity to 92.8%. Meibography yielded optimal results (100% sensitivity and specificity). Infrared thermography revealed a typical pattern for XLHED. In children with XLHED, NIBUT or OSDI were the most convincing single tests , combination of which increased the sensitivity to 100%. More invasive tests such as meibography and infrared thermography led to good results if they were tolerated.Tear film tests can help to establish an early diagnosis in individuals with suspected XLHED, even before genetic test results are available. Meibomian gland disorder and resulting hyperevaporative dry eye are typical features of XLHED. Once the diagnosis is made, tear film tests are an important instrument to establish an effective therapy of dry eye disease."} +{"text": "Spinal cord injury (SCI) causes chronic peripheral sensitization of nociceptors and persistent generation of spontaneous action potentials (SA) in peripheral branches and the somata of hyperexcitable nociceptors within dorsal root ganglia (DRG). Here it is proposed that SCI triggers in numerous nociceptors a persistent hyperfunctional state that originally evolved as an adaptive response to compensate for loss of sensory terminals after severe but survivable peripheral injury. In this hypothesis, nociceptor somata monitor the status of their own receptive field and the rest of the body by integrating signals received by their peripheral and central branches and the soma itself. A nociceptor switches into a potentially permanent hyperfunctional state when central neural, glial, and inflammatory signal combinations are detected that indicate extensive peripheral injury. Similar signal combinations are produced by SCI and disseminated widely to uninjured as well as injured nociceptors. This paper focuses on the uninjured nociceptors that are altered by SCI. Enhanced activity generated in below-level nociceptors promotes below-level central sensitization, somatic and autonomic hyperreflexia, and visceral dysfunction. If sufficient ascending fibers survive, enhanced activity in below-level nociceptors contributes to below-level pain. Nociceptor activity generated above the injury level contributes to at- and above-level sensitization and pain (evoked and spontaneous). Thus, SCI triggers a potent nociceptor state that may have been adaptive (from an evolutionary perspective) after severe peripheral injury but is maladaptive after SCI. Evidence that hyperfunctional nociceptors make large contributions to behavioral hypersensitivity after SCI suggests that nociceptor-specific ion channels required for nociceptor SA and hypersensitivity offer promising targets for treating chronic pain and hyperreflexia after SCI. My focus is on the many uninjured nociceptors that are chronically altered by SCI and positioned to help drive below-level and at-level pain.Neuropathic pain in general and spinal cord injury (SCI) pain in particular are usually viewed as maladaptive consequences of neural injury , sprout new branches within the dorsal horn after SCI, which potentially could lead to more extensive nociceptive input to dorsal horn neurons 3 days to 8 months after SCI compared to what has been reported (0\u201320%) for dissociated small DRG neurons sampled from rats with peripheral neuropathy under these quite different conditions can be triggered in nociceptors by a combination of events after SCI that mimic patterns of signals used by nociceptors to recognize particularly severe e Figure . I then Long-lasting changes in intrinsic functional properties of primary sensory neurons are likely to depend upon changes in gene expression in these neurons to the nociceptor's own branches. This includes immediate injury discharge and both positive injury signals , and negative injury signals transported from damaged axons to the nucleus , which are unlikely to have axons projecting close enough to the lesion to experience axotomy or other forms of direct damage are conveyed directly to cells within the DRG after peripheral injury/inflammation and after SCI Figure . Periphe2) that avoids apparent tissue inflammation produce behavioral hypersensitivity for at least 1 month afterwards, which is accompanied by Nav1.8 upregulation and is dependent upon Nav1.8 expression, suggesting a key role for intrinsically altered nociceptors continuing release of extrinsic signals, such as inflammatory mediators, that continuously refresh the hyperfunctional state, (2) positive feedback loops between nociceptor activity and inflammatory and retrograde synaptic effects, and (3) switching of the nociceptor into a potentially permanent intrinsic hyperfunctional state that remains after the extrinsic induction signals fade (\u201cnociceptor memory\u201d). First, widespread inflammation may persist chronically after SCI . Somata of nociceptors identified thus far in vertebrates, molluscs, and annelids are often located centrally, distant from their peripheral receptive fields, which ensures that these cells can survive sublethal injury that destroys their peripheral branches. In the mollusc, Why haven't chronic, somally expressed HSA states in nociceptors been reported previously in mammalian models of long-lasting pain? Few chronic studies have tested somal excitability in nociceptors, or recorded under conditions where nociceptor SA generated in the DRG could be distinguished from SA generated peripherally. Moreover, most studies of dissociated nociceptors have examined ionic currents under voltage clamp, without testing for somal hyperexcitability or SA. In addition, common models of long-lasting pain, including models based on cutaneous injection of inflammogens, surgical incision models (which produce relatively little inflammation or nerve damage), and various nerve injury models may not mimic adequately severe peripheral injuries that involve extensive amounts of tissue destruction combined with prolonged inflammation\u2014i.e., the traumatic conditions most likely to result in chronic pain in humans. Thus, while standard pain models produce many sensitizing effects on nociceptors and other hyperfunctional alterations in nociceptors contribute significantly to human at- and below level pain, as well as to hyperreflexia and visceral problems after SCI, pharmacological agents that selectively target nociceptor hyperexcitability should be clinically useful. A number of genes important for excitability are preferentially expressed in nociceptors, raising the possibility that blocking their function could ameliorate some of the suffering caused by SCI while producing minimal side effects. Indeed, preliminary results show that SA in dissociated nociceptors depends upon nociceptor-specific Nav1.8 channels, and indicate that knocking down the expression of these channels can attenuate behavioral hypersensitivity after SCI (Yang et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Daphnia magna) \u2013 bacterium (Pasteuria ramosa) system typifies such specificity and high virulence. We studied the North American host Daphnia dentifera and its natural parasite Pasteuria ramosa, and also found strong genetic specificity for infection success and high virulence. These results suggest that Pasteuria could promote Red Queen dynamics with D. dentifera populations as well. However, the Red Queen might be undermined in this system by selection from a more common yeast parasite (Metschnikowia bicuspidata). Resistance to the yeast did not correlate with resistance to Pasteuria among host genotypes, suggesting that selection by Metschnikowia should proceed relatively independently of selection by Pasteuria.The Red Queen hypothesis can explain the maintenance of host and parasite diversity. However, the Red Queen requires genetic specificity for infection risk and strongly virulent effects of infection on host fitness. A European crustacean ( R0 when all else is equal, Genetic specificity between hosts and their parasites shapes the ecology and evolution of infectious disease Daphnia magna and its sterilizing bacterial parasite Pasteuria ramosa exemplify genetic specificity Pasteuria \u2013 the physical attachment of spores to the host oesophageal wall Pasteuria inflicts high virulence on infected hosts through sterilization Pasteuria epidemics can become large D. magna-Pasteuria system The European freshwater crustacean Pasteuria could maintain genetic diversity in other susceptible host species. Therefore, Pasteuria could act as a general catalyst of Red Queen-driven coevolution in freshwater systems. To test this possibility, we looked for genetic specificity for infection with Pasteuria in a natural North American host, Daphnia dentifera, using an established experimental design Pasteuria castrates its European D. magna hosts: Pasteuria's specificity and virulence effects are general, the European Daphnia \u2013 Pasteuria story may apply more broadly.These results suggest that D. dentifera populations, epidemics of the yeast Metschnikowia bicuspidata are usually larger and more frequent than Pasteuria epidemics Metschnikowia does not, however, exhibit genetic specificity with D. dentiferaPasteuria may not necessarily resist Metschnikowia. Such parasite-specific resistance and five Pasteuria isolates all originated from Midland Lake, Greene County, Indiana, USA. The five Pasteuria isolates were taken from five different infected hosts in 2010 and were propagated by feeding homogenized, infected hosts to a single host genotype (H119). These isolates likely consist of a mix of Pasteuria clones and represent ecologically relevant sub-populations of Pasteuria . We used only this lab-based culture because Metschnikowia isolated from different lakes and in different years show no genetic variation in infectivity or virulence on D. dentiferaD. dentifera (which is not a protected or endangered species), but permission was obtained for access to lakes.The experiments used host and parasite cultures and previously established laboratory protocols. The six clonal genotypes of Pasteuria isolates, one Metschnikowia isolate, and a sham-exposure control), replicated 15 times, for a total of 630 experimental units. Four of the Pasteuria replicates were lost due to accidental death after treatment exposure. Maternal lines consisted of individual Daphnia kept under favourable conditions (20\u00b0C and 16\u22368 hour light/dark) in 40 mL of medium . Experimental animals consisted of second clutch offspring of third-generation maternal lines and were also kept in 40 mL of medium and fed ample food. In the parasite exposure treatments, each neonate (<24 hour old) received a high dose of spores produced by gently crushing and diluting infected hosts. These doses aimed to yield similar infection levels among parasite species (based on pilot data). Sham controls received 100 \u03bcL of a Daphnia solution (50 uninfected hosts ground in 10 ml nanopure water). Replicates were fed lower food during exposure to increase spore uptake by hosts 6Ankistrodesmus algal cells) again. Hosts were checked daily for reproduction and mortality for 25 days. Medium was refreshed every 2\u20133 days.The experimental design involved a factorial manipulation of these hosts and parasites. We crossed the six host genotypes with seven parasite treatments (five http://www.r-project.org). We analysed infection risk by testing the fixed effects of host genotype and parasite species using data from only parasite-exposed hosts (not sham-exposed hosts). We tested for genetic specificity of Pasteuria infection using the fixed effects of host genotype and parasite isolate. Both Generalized Linear Models (GLM) were estimated with a binomial error distribution, and significance of each treatment was evaluated with deviance tests . However, in previous Daphnia-parasite studies, genotype is fitted as a fixed effect, a random effect or both (e.g. Metschnikowia and Pasteuria (averaged over the five isolates) for each host genotype using a Spearman rank correlation.All analyses were performed using the statistical package R . Fecundity was analysed by testing the fixed effects of infection status (infected or not), host genotype, and parasite species. Both host survival and r were analysed by testing the fixed effects of host infection status (infected or not) and parasite species. All of these tests used data from parasite-exposed hosts only; for r, the means of data from each infection category and parasite species for each host genotype were used.We examined the fitness consequences of infection by the two parasites using three metrics: production of host offspring (fecundity), host survival, and the instantaneous rate of host population growth, Metschnikowia's capacity to disrupt Red Queen dynamics between D. dentifera and Pasteuria should be reduced if the host pays an activation cost of resistance to Metschnikowia We looked for evidence of an activation cost of resistance to Metschnikowia by comparing host fecundity, survival, and r in controls (sham-exposures) with hosts that were exposed to parasites but did not suffer infection .Fecundity across treatments was examined using a GLM fit with a quasipoisson error distribution (used due to over-dispersion of the fecundity data), and survival analyses used Cox's proportional hazards. Measures of Pasteuria) and between parasite species. Infection risk from Pasteuria depended on the specific combination of host and parasite genotypes . As expected based on prior studies, host genotype strongly influenced infection risk from Metschnikowia . There was, however, no correlation between a genotype's risk of infection by Metschnikowia and its overall risk of infection by Pasteuria depended on both infection status and parasite species: infection with either parasite reduced r, but Pasteuria infections reduced r more than Metschnikowia infections. Thus, Pasteuria was more virulent . Thus, there was no evidence for a fitness cost of mobilising resistance mechanisms against Metschnikowia to a lesser extent than Pasteuria should reduce host population densities, even during small epidemics Due to differences in specificity and virulence, these two parasites may exert different ecological impacts on host populations. Theory suggests that specificity can reduce invasion success of parasites; i.e., they will have a lower reproductive ratio Pasteuria and Metschnikowia could either amplify or dampen Red Queen oscillations. A negative correlation would indicate antagonistic pleiotropy, where resistance to Pasteuria would come at a cost to resistance to MetschnikowiaMetschnikowia and Pasteuria suggests evolution of D. dentifera in response to the two parasites should proceed relatively independently. Thus, we do not expect Metschnikowia epidemics to amplify or dampen Red Queen dynamics between D. dentifera and Pasteuria.Correlations between host resistance to Pasteuria could promote genetic diversity in multiple host species through host-parasite coevolution. Pasteuria exhibits strong genetic specificity and high virulence with its North American host, D. dentifera, just as it does with its European host, D. magna. Can Pasteuria then promote host diversity in North American lakes? We cannot yet fully answer that question with these or other data, but the D. dentifera-Pasteuria system in isolation certainly contains several of the essential ingredients of the Red Queen. Still, it seems likely that the larger epidemics of the more common Metschnikowia yeast may mean that parasite-mediated selection in D. dentifera is driven primarily by Metschnikowia, making Red Queen dynamics relatively rare. This possibility further highlights the need to consider other co-occurring parasites when exploring host-parasite coevolution.In conclusion,"} +{"text": "Cardiogenic shock is very uncommon in healthy people. The differential diagnosis for patients with acute heart failure in previously healthy hearts includes acute myocardial infarction and myocarditis. However, many drugs can also depress myocardial function. Propofol and fentanyl are frequently used during different medical procedures. The cardiovascular depressive effect of both drugs has been well established, but the development of cardiogenic shock is very rare when these agents are used.After a minor surgical intervention, a 32-year-old Caucasian woman with no significant medical history went into sudden hemodynamic deterioration due to acute heart failure. An urgent echocardiogram showed severe biventricular dysfunction and an estimated left ventricular ejection fraction of 20%. Extracorporeal life support and mechanical ventilation were required. Five days later her ventricular function had fully recovered, which allowed the progressive withdrawal of medical treatment. Prior to her hospital discharge, cardiac MRI showed neither edema nor pathological deposits on the delayed contrast enhancement sequences. At her six-month follow-up examination, the patient was asymptomatic and did not require treatment.Although there are many causes of cardiogenic shock, the presence of abrupt hemodynamic deterioration and the absence of a clear cause could be related to the use of propofol and fentanyl. Cardiogenic shock is the most serious form of presentation of heart failure (HF). The anticipation of hemodynamic deterioration and multiple organ failure in these patients is very important in terms of survival. The outcome for patients with refractory acute cardiogenic shock remains disproportionately poor. Technological advances in recent years have enabled the development of new treatments, such as extracorporeal life support (ELS). ELS is a variation of cardiopulmonary bypass which could improve the outcomes of patients in cardiogenic shock . AlthougWe report the case of a 32-year-old Caucasian woman who experienced sudden, severe hemodynamic deterioration after undergoing a minor surgical procedure. Her medical history was unremarkable except for a vaginal delivery two years before. She underwent surgery to remove a Bartholin cyst, and no infection in the gland was found. The operation was performed while the patient was under sedation and being given an analgesic. Spontaneous breathing was maintained by infusing a propofol bolus 1 mg/kg) and fentanyl 100 \u03bcg intravenously. During surgery, the patient remained hemodynamically stable. She has nausea and vomiting in the early post-operative period, which were treated with intravenous ondansetron 4 mg). A few minutes later the patient went into sudden hemodynamic deterioration, with sinus tachycardia (113 regular beats/minute) and hypotension (50/30 mmHg). Pulse oximetry showed that her oxygen saturation level had decreased to 80% despite oxygen supplementation through a face mask (fraction of inspired oxygen 40%). In this clinical situation, we treated her with intravenous dopamine and dobutamine, as well as with mechanical ventilation because of global respiratory failure . The electrocardiogram showed sinus tachycardia. Signs of HF were found on her chest X-ray, and urgent transthoracic echocardiography (TTE) revealed severe biventricular dysfunction with global hypokinesia and a LVEF estimated to be 35%. Coronary angiography showed no coronary lesions, and an intra-aortic balloon pump was inserted for counterpulsation. Repeat TTE revealed a LVEF of 20% with a dilated left ventricle showing severe left ventricular dysfunction during the acute phase.Click here for fileShort-axis view showing severe left ventricular dysfunction. Transthoracic echocardiography showing severe left ventricular dysfunction during the acute phase.Click here for fileApical four-chamber view after total recovery of left ventricular function. Transthoracic echocardiography showing total recovery of left ventricular function before discharge.Click here for fileShort-axis view after total recovery of left ventricular function. Transthoracic echocardiography showing total recovery of left ventricular function before discharge.Click here for file"} +{"text": "Cellular and molecular regulation of the immune system is exquisitely controlled in the brain and is disrupted in neoplasia. Despite accumulation of immune cells in the tumor microenvironment, glioblastoma (GBM) growth persists while the mechanisms suppressing immune function remain largely unknown. Myeloid derived suppressor cells (MDSCs) are a heterogeneous class of immune cells responsible for immunomodulation through the suppression of cytotoxic T-cells. These populations are elevated in the peripheral blood of GBM patients, but their roles within the GBM microenvironment are uncharacterized. Through immunofluorescence analysis, we identified MDSCs within human GBM specimens, suggesting an immunosuppressive phenotype marked by arginase 1 (Arg1) staining. We have also observed co-localization between MDSCs and GBM cancer stem cells (CSCs) in both human tissues and mouse xenografts, leading to the hypothesis that CSCs recruit MDSCs to the tumor microenvironment, promote their survival, and that MDSCs are responsible for the immune-evasive properties of CSCs Fig. . Intracr"} +{"text": "Hypertrophic cardiomyopathy (HCM) is most common in patients under 40 years and is associated with early sudden death, but HCM is increasingly recognized in elderly patients. We sought to characterize and identify features unique to elderly HCM patients when compared with youthful patients using CMR.Cine CMR and late gadolinium enhancement (LGE) imaging were performed in 902 HCM patients, including 202 young , and 143 elderly patients .Elderly HCM patients had a lower proportion of males . They had significantly lower left ventricular (LV) mass and lower maximal LV wall thickness . The most common maximal thickness segment in the elderly patients was in the basal anterior septum . Elderly patients were also more likely to have the thickest segment located within the septum . Elderly patients were far less likely to have massive hypertrophy .Elderly HCM patients had a smaller LV cavity size, with lower LV end-diastolic volume and smaller LV end-diastolic dimension . The elderly patients had similar LV ejection fraction (LVEF) and similar rates of depressed (<60%) LVEF .The prevalence of LGE (a marker of fibrosis) was similar in both groups . When present, both LGE mass and percentage of LV with LGE were similar.Substantial amounts of late gadolinium enhancement are compatible with normal longevity in many patients with hypertrophic cardiomyopathy. Presence of LGE may thus have different prognostic significance across the vast spectrum of HCM. This has potential implications for using LGE as a risk stratification tool for sudden death in HCM.Nil."} +{"text": "Successful scientific investigations at CAM institutions are often hampered by limited research infrastructure. Enhancing the clinical trial capabilities of our chiropractic research center was one goal of 2 NIH/NCCAM developmental center grants.Web applications were enhanced and customized based on individual project needs and trial team requests. Templates were built to support quick development and standard functionality of project web applications. We also developed standardized processes to effectively provide project-specific participant management, data collection, staff training, and quality control.Web applications included: the Centralized Participant Database System and Project/Users Permissions System to securely capture participant contact information and control personnel access to web modules; a real-time participant tracking report to monitor recruitment and participant flow; a role-specific Reminder System to track outstanding activities requiring personnel follow-up; and double key-entry verification on web data used for an adaptive treatment allocation algorithm. Templates of these tools can be incorporated into any new trial\u2019s web application. Study protocol templates facilitate timely, accurate translation of research proposals into detailed protocols for IRB applications, DSMC review and training. A revised training plan included role-specific training logs for tracking training objective completion and a thorough certification process for key protocols to ensure accurate and consistent performance. Quality control templates support the informed consent process and fidelity of trial interventions and outcomes assessment. We implemented these enhanced resources in 5 clinical trials. To date, our team has completed 3378 phone screens, conducted 1439 first and 473 second in-person screening visits, enrolled 394 participants, and followed 315 through trial end. The study protocol templates have been used in two additional clinical trials currently undergoing IRB review.We expanded our capacity to support multiple, diverse trials with complex methodologies. This is a successful example of a CAM institution successfully leveraging research grant funding to enhance research infrastructure."} +{"text": "Synapses in neuron networks filter incoming spikes with a wide variety of time constants, affecting the stability of various collective dynamics , the selHere, we addressed this issue working out a unified framework in which from small to large synaptic time scales the same approximated theoretical description holds for the firing rate dynamics of spiking neuron networks. Starting from single-neuron stochastic dynamics, we derived a set of ordinary differential equations for the population emission rate relying on the spectral expansion of the associated Fokker-Planck equation, eventually extending to the colored noise case a previous derivation obtained under white noise hypothesis . The resMoreover, such perturbative approach allowed to avoid the analytical difficulties of dealing with multi-dimensional Fokker-Planck equations with discontinuous boundary conditions. A simplification which helped in highlighting as main result that networks of neurons with non-instantaneous synapses can, under fairly broad assumptions, be described by equivalent networks with suitable distributions of transmission delays. A formal analogy valid from simple VIF models to more realistic point-like simplifications like LIF or EIF neurons."} +{"text": "Late gadolinium enhancement (LGE) is excellent for identifying focal lesions in the myocardium , but diffuse homogeneous abnormalities are not readily detectable. Quantitative measurement of the myocardial extracellular volume (ECV) fraction using MRI has recently been validated histologically, and implemented for parametric imaging in patients. We hypothesized that quantification of ECV using ECV imaging could detect focal lesions detected by LGE, and diffuse homogenous disturbances in the myocardial extracellular volume fraction which are not detectable by LGE. The objective of the study was to examine the diagnostic utility of ECV MRI for detecting myocardial tissue abnormalities compared to LGE.Consecutive patients referred for clinical cardiac MRI evaluation of known or suspected heart disease were prospectively enrolled . MRI was undertaken at 1.5T using a Modified Look-Locker Inversion recovery (MOLLI) sequence before and 15 minutes after an intravenous bolus of a gadolinium-based extracellular contrast agent . Maps of the extracellular volume fraction (ECV images) were generated using MOLLI-derived T1-mapping before and after contrast, calibrated to hematocrit from a venous blood sample. Motion correction and co-registration was performed offline using an automated dedicated algorithm. ECV images were interpreted quantitatively and the results were compared to clinical assessment of LGE images. Increased myocardial ECV was determined by quantitative comparison to established normal values where the 95% confidence limits are 20-32%.Out of 32 patients, 10 had focal lesions . All lesions identified by increased ECV were also identified by blinded clinical read of LGE images (100% agreement). Among patients with normal LGE findings (n=22), two patients (9%) had diffusely increased myocardial ECV . The figure shows examples of LGE and ECV images in a normal finding, a focal lesion and a case with diffusely increased ECV.Our initial findings suggest that ECV and LGE imaging have excellent diagnostic agreement for identifying focal myocardial findings such as those seen in myocardial infarction and non-ischemic heart disease. The ability of ECV imaging to quantify and detect diffuse abnormalities in myocardial ECV increased the number of diagnostic findings compared to LGE in 9% of cases with otherwise normal LGE. Further studies in larger populations are warranted to explore the diagnostic and prognostic benefits of ECV imaging in assessment of diffuse pathologies of the myocardial extracellular space.The study has been funded in part by a grant (PI: Dr. Ugander) from the Swedish Society for Medical Research."} +{"text": "Central statistical monitoring (CSM) can identify trial misconduct, and help to prioritise on-site visits and additional training. Key risk indicators (KRIs) focus CSM on variables most likely to affect study reliability or patient safety. We developed the use of robust minimum covariance determinant (MCD) distances to detect outlying centres in the context of KRI analyses.Initially, a summary statistic (e.g. mean) describing the KRI is calculated for each centre and robust MCD-based distances are calculated by the FAST-MCD algorithm . For each KRI, robust estimates of the multivariate location Robust MCD distances offer a flexible approach for analysing both univariate and multivariate KRIs and can be implemented in standard statistical software."} +{"text": "Major trauma is the leading causing of death in young adults across the globe. Themortality from traumatic cardiac arrest remains high but survival with good neurologicaloutcome from cardiopulmonary arrest following major trauma has now been reported. Rapid,effective intervention is required to address potential reversible causes of traumaticcardiac arrest if the victim is to survive. There is no standard treatment algorithm fortraumatic cardiac arrest. We present a simple algorithm to manage the major traumapatient in actual or near cardiac arrest.We reviewed current pre-hospital clinical practice and the published literature on majortrauma management. An algorithm was developed and used regularly by London\u2019s AirAmbulance pre-hospital physician/paramedic trauma team.The algorithm addresses the need treat potential reversible causes of traumatic cardiacarrest. This includes immediate resuscitative thoracotomy in cases of penetrating chestor abdominal trauma resulting in cardiac arrest, airway management, optimisingoxygenation, reversal of hypovolaemia using intravenous/intraosseous fluid replacementand chest decompression to exclude tension pneumothorax.A standard approach to traumatic cardiac arrest is feasible. Use of a treatmentalgorithm can rapidly, simultaneously address reversible causes of traumatic cardiacarrest and has the potential to save lives."} +{"text": "MDLcompress. We apply this tool to explore the relationship between miRNAs, single nucleotide polymorphisms (SNPs), and breast cancer. Our new algorithm outperforms other grammar-based coding methods, such as DNA Sequitur, while retaining a two-part code that highlights biologically significant phrases. The deep recursion of MDLcompress, together with its explicit two-part coding, enables it to identify biologically meaningful sequence without needlessly restrictive priors. The ability to quantify cost in bits for phrases in the MDL model allows prediction of regions where SNPs may have the most impact on biological activity. MDLcompress improves on our previous algorithm in execution time through an innovative data structure, and in specificity of motif detection (compression) through improved heuristics. An MDLcompress analysis of 144 over expressed genes from the breast cancer cell line BT474 has identified novel motifs, including potential microRNA (miRNA) binding sites that are candidates for experimental validation.We describe initial results of miRNA sequence analysis with the optimal symbol compression ratio (OSCR) algorithm and recast this grammar inference algorithm as an improved minimum description length (MDL) learning tool:"} +{"text": "Optical coherence tomography (OCT) has enhanced our understanding of changes in different ocular layers when axial myopia progresses and the globe is stretched. These findings consist of dehiscence of retinal layers known as retinoschisis, paravascular inner retinal cleavage, cysts and lamellar holes, peripapillary intrachoroidal cavitation, tractional internal limiting membrane detachment, macular holes (lamellar and full thickness), posterior retinal detachment, and choroidal neovascular membranes. In this review, recent observations regarding retinal changes in highly myopic eyes explored by OCT are described to highlight structural findings that cannot be diagnosed by simple ophthalmoscopy. Pathologic or high myopia is defined as a refractive error of \u22126.00 diopters (D) or greater and an axial length exceeding 26 mm.2Optical coherence tomography (OCT) has recently made it possible to explore changes in ocular layers as axial myopia progresses and the globe is stretched. These findings consist of dehiscence of retinal layers known as retinoschisis, paravascular inner retinal cysts and lamellar holes, peripapillary intrachoroidal cavitation , tractional internal limiting membrane detachment, macular holes (lamellar and full thickness), posterior retinal detachment and choroidal neovascular membranes.In this review, we describe retinal changes in highly myopic eyes according to findings observed by OCT.The early stages of myopic retinal changes can easily be underestimated by biomicroscopy, angiography or ultrasonography, and therefore remain undiagnosed. Recently, OCT with its fine cross-sectional imagery of retinal structures has greatly facilitated the evaluation of posterior vitreoretinal anatomy in eyes with high myopia. It can also reveal otherwise undetectable retinal changes in asymptomatic patients. The OCT ophthalmoscope produces longitudinal retinal B-scans and coronal C-scans.B-scan produces cross-sectional images of retinal morphology which bears strong resemblance to histology. OCT C-scans are represented as 2-dimensional transverse slices at any given depth through the retina, thereby enabling visualization of the lateral extent of different structures. OCT C-scans are associated pixel-to-pixel points with simultaneously confocal images used to identify the exact position of lesions on the posterior pole. With en face OCT, localization and relation of retinal lesions can be precisely defined, especially in myopic eyes. En face OCT provides accurate imaging of retinal abnormalities in high myopia and allows width measurement and point-to-point localization of changes.Myopic posterior staphyloma, with its outward globe bulge, results in a deep concave B-scan OCT and distorted retinal structures. Because of the smaller base curvature of the horizontal section and larger base curvature of vertical section, macular structures can be defined more easily by vertical sections . Remarkably, the incidence of internal limiting membrane (ILM) detachment and macular retinoschisis was significantly higher in eyes with paravascular lamellar holes than those with other paravascular abnormalities. Paravascular lamellar holes were associated with ILM detachment in 44% and with macular retinoschisis in 20% of eyes. More than 80% of eyes with macular retinoschisis had paravascular lamellar holes.Tractional ILM detachment was reported in 2.4%\u20136% of highly myopic persons.In a study by Bando et alThe prevalence of myopic foveoschisis (MFS) ranges from 9% to 34% in highly myopic eyes with posterior staphylomas.23MFS tends to occur in eyes with severe myopic retinopathy.25Half of patients with MFS have been reported to develop retinal detachment or macular holes within two or more years of follow-up.26Choroidal neovascular membrane (CNV) is considered to be the most important sight-threatening complication of high myopia. Myopic CNV has been classified into active, scar and atrophic stages.In the scar stage, only the surface of the neovascular tuft shows high reflectivity and the tissue underneath is markedly attenuated. Overlying retinal layers are not disarranged or disorganized, cystic changes are also absent.In the atrophic stage, the CNV becomes flat and chorioretinal atrophy around the regressed CNV is highly reflective.29Macular holes always exist at the edge of a pigmented lesion suggestive of an old CNV. Therefore periodic OCT examinations for evaluation of macular holes or macular retinoschisis, even in patients in atrophic stages, are recommended. The retina in the area of chorioretinal atrophy around the CNV is very thin regardless of coexisting macular retinoschisis, but the retina at the edge of CNV in myopic eyes with large chorioretinal atrophy (larger than 1 disc diameter) has been reported to be significantly thinner in eyes with chorioretinal atrophy smaller than 1 disc diameter around the CNV.28Posterior retinal detachment is another consequence of ocular expansion and posterior staphyloma in high myopic eyes. Full thickness macular hole and tractional maculopathy may accompany this finding and may be its contributor .Macular hole formation in myopic eyes has multiple etiologies. Expansion of the globe, tractional components and growth of neovascular membranes through clefts in the posterior pole may create partial thickness and/ or full-thickness macular holes. In asymptomatic myopic persons, macular holes were detected in 6.26% of cases.Pathologic myopia is accompanied by thinning and stretching of the globe. With increasing age and myopia, these changes further progress.Individuals with high myopia are subject to various retinal pathologies including posterior pole and peripapillary lesions. Because of extreme retinal thinning and chorioretinal changes in these persons, simple fundus examination may miss subtle retinal pathologies. OCT is an accurate tool which can localize such anatomical changes. It seems to be the paraclinical test of choice for highly myopic eyes."} +{"text": "Cancer cells have altered metabolism, with an increased rate of glucose uptake, increased glycolysis, and due to the Warburg phenomenon, increased production of biomass (amino acids and nucleic acids) as metabolic byproducts. Association of these metabolic changes with breast cancer subtype and tumor gene expression has not been evaluated, nor is it well understood what biological processes and characteristics are most important in driving altered metabolic state in breast cancer.Thirty-four breast tumors and six samples of cancer-adjacent normal tissue were analyzed by liquid and gas chromatography (LC/GC) mass spectrometry (MS) to determine the expression of 379 metabolites. The same tissues were also used to perform gene expression microarrays and the resulting gene expression profiles were used to identify tumor subtype. These data combined with clinical tumor characteristics were evaluated in association with metabolic phenotype. To complement these analyses of human tissues, in vitro assays using human breast cancer cells alone and in coculture with cancer-associated fibroblasts (CAFs) were performed to study glucose uptake and utilization.Unsupervised cluster analysis on all metabolites resulted in two main clusters, with differences in the prevalence of aggressive tumor subtypes in each cluster. Characteristic of the Warburg phenomenon, four groups of metabolites showed differential levels between the two tumor clusters: amino acids, sugars, nucleic acids, and citric acid (TCA) cycle metabolites. Normal breast tissue samples were similar to less aggressive tumors with low biomass production and decreased levels of glycolysis/TCA byproducts. Parallel to these results in human tissues, glucose uptake was increased in basal-like breast cancer cells when they were cocultured with fibroblasts, but less aggressive luminal-fibroblast cultures did not show increased glucose uptake. Rather, in luminal cocultures, the fibroblasts appeared to suppress glucose uptake. Glucose utilization (oxidation and glycogen synthesis) was also higher in basal-like mono- and cocultures compared to luminal cultures. Consistent with these findings that the stroma influences metabolic phenotype, tumors that had active wound response gene expression had the more aggressive, Warburg-like metabolic profile.We observed distinct metabolic profiles associated with more aggressive breast cancer tumors. Based both on the observed patterns of glucose uptake and utilization in cocultures, and on the association between wound response activation and metabolic profile, these metabolic signatures appear to be influenced by multiple factors, including the stroma. These data suggest that integration of genomic and metabolic data provide insights for better understanding a Warburg effect in human breast cancer that may be regulated by the stroma."} +{"text": "Visual hallucinations (VH) represent one of the core features in discriminating dementia with Lewy bodies (DLB) from Alzheimer\u2019s Disease (AD). Previous studies reported that in DLB patients functional alterations of the parieto-occipital regions were correlated with the presence of VH. The aim of our study was to assess whether morphological changes in specific cortical regions of DLB could be related to the presence and severity of VH. We performed a cortical thickness analysis on magnetic resonance imaging data in a cohort including 18 DLB patients, 15 AD patients and 14 healthy control subjects. Relatively to DLB group, correlation analysis between the cortical thickness and the Neuropsychiatric Inventory (NPI) hallucination item scores was also performed. Cortical thickness was reduced bilaterally in DLB compared to controls in the pericalcarine and lingual gyri, cuneus, precuneus, superior parietal gyrus. Cortical thinning was found bilaterally in AD compared to controls in temporal cortex including the superior and middle temporal gyrus, part of inferior temporal cortex, temporal pole and insula. Inferior parietal and supramarginal gyri were also affected bilaterally in AD as compared to controls. The comparison between DLB and AD evidenced cortical thinning in DLB group in the right posterior regions including superior parietal gyrus, precuneus, cuneus, pericalcarine and lingual gyri. Furthermore, the correlation analysis between cortical thickness and NPI hallucination item scores showed that the structural alteration in the dorsal visual regions including superior parietal gyrus and precuneus closely correlated with the occurrence and severity of VH. We suggest that structural changes in key regions of the dorsal visual network may play a crucial role in the physiopathology of VH in DLB patients. Dementia with Lewy bodies (DLB) is the second most common form of dementia in the elderly after Alzheimer\u2019s Disease (AD). Despite the precise nosological relationship between DLB and AD remains uncertain, persistent visual hallucinations (VH) along with fluctuations in cognitive function and parkinsonism represent the core feature in discriminating DLB from AD and other dementias The physiopathology underlying VH in DLB is not well understood. Causative models for complex VH have suggested that the origin of this deficit may be related to a range of pathological alterations affecting both the dorsal visual stream, specialized for visuo-spatial attention and location, and the ventral visual stream, designated to object recognition In this context, structural Magnetic Resonance Imaging (MRI) could be a powerful tool to investigate the aetiology of core symptoms in DLB. To date, several studies by using voxel-based morphometry (VBM) found widespread cortical sites of grey matter atrophy in DLB patients compared to healthy controls Cortical thickness approach allows to perform cortical parcellation and to measure with great reliability the pathological thinning of the cortical grey matter. By measuring a real physical quantity that is much easier to interpret and to localize in comparison to the three-dimensional VBM, cortical thickness methods provide a better localization of structural changes because the smoothing procedure is performed on a two-dimensional manifold which reduces morphological artefacts due to ageing and pathological processes Despite the potential advantage of cortical thickness analysis, to date this approach has not been applied to DLB patients.In the present study, we performed cortical thickness analysis to verify the presence of cortical grey matter damage related to VH in DLB patients. To this aim, firstly, we compared DLB patients respect to healthy controls. Subsequently, we included a comparison against AD groups to exclude possible pathologic alterations arising as a result of a dementia process per se and not specific to DLB pathology. Finally, relatively to DLB group, we performed a correlation analysis between the cortical thickness and the Neuropsychiatric Inventory (NPI) hallucination item scores to highlight the cortical regions which were effectively related to the occurrence and severity of VH.The study was approved by the Institutional and Ethics Committee of the University \u201cG. d\u2019Annunzio\u201d Chieti-Pescara (ID#157801). All procedures were conducted according to the Declaration of Helsinki and subsequent revisions All patients underwent MRI scan within six months before the inclusion in the study and dopaminergic presynaptic ligand ioflupane SPECT (DAT scan).Global tests of cognition included Clinical Dementia Rating (CDR), Mini Mental State Examination (MMSE), Dementia Rating scale-2 (DRS-2) Exclusion criteria were uncontrolled hypertension, myocardial ischemia, peripheral vascular disease and chronic kidney.1-Weighted Turbo Field-Echo sequence was carried out. Participants with images characterized by motion artefacts were excluded from the analysis.All acquisitions were carried out with a Philips Achieva 3 T scanner equipped with 8-channel receiver coil. After scout and reference sequences, a 3-dimensional T1-weighted image was estimated at each vertex across the brain surface using Freesurfer software package (http://surfer.nmr.mgh.harvard.edu). This method has been previously described in detail by Fischl and Dale Cortical thickness on TCortical brain regions affected by cortical thinning were classified by using the Desikan-Killiany Atlas integrated in FreeSurfer.SPSS version 14.0 was used for statistical analysis. Analysis of variance (ANOVA) among groups and Tukey\u2019s HSD post-hoc test was performed on demographic and clinical data. Chi-squared test was carried out for gender.For each hemisphere, comparison among groups was performed by using general linear model (GLM), including cortical thickness as dependent factor and group as independent factor. MMSE, CAF and UPDRS scores were included as covariates.https://surfer.nmr.mgh.harvard.edu/fswiki/FsgdFormat).FreeSurfer processing stream was used to assess the pairwise differences among groups was used to individuate statistically significant regions where NPI hallucination item scores and thickness were correlated. MMSE, CAF, UPDRS scores were included as nuisance factors.In DLB group, QDEC . Next, SPSS version 14.0 was used for statistical computation and MMSE, CAF and UPDRS scores were included as nuisance factors.To perform partial correlations between NPI hallucination item scores and mean cortical thickness values in the posterior regions which were affected significantly in DLB in comparison with AD, the mean cortical thickness values were extracted from each region of interest (defined by Desikan-Killiany Atlas) by using \u201caparcstats2table\u201d command line, in cortical thickness between DLB and age-matched healthy controls. Cortical thickness was reduced in the posterior regions of DLB. Specifically, pericalcarine, lingual gyri, cuneus precuneus and superior parietal gyrus were affected bilaterally. panel B shows regional differences (corrected p<0.05) in cortical thickness between DLB and AD. Cortical thickness was reduced in DLB compared to AD in the right posterior regions including superior parietal gyrus, precuneus, cuneus, pericalcarine and lingual gyri.With the present MRI study, we have evidenced that DLB patients are characterized by marked cortical thinning in posterior regions when compared with AD and age-matched healthy controls.Posterior cortical regions play a critical role in the visual information processing, and their damage was related to recurrent VH in DLB patients Consistently with neuroimaging Although previous studies reported abnormalities related to VH in DLB or Parkinson\u2019s Disease (PD) patients compared to control groups Additionally, despite both the dorsal and ventral attention networks were affected in DLB as compared to controls and AD, the correlation analysis between cortical thickness and NPI hallucination item scores, suggested a greater involvement of the dorsal attention regions including superior parietal gyrus and precuneus in the occurrence and severity of VH in DLB.The superior parietal region is implicated in visuo-spatial working memory Precuneus acts in concert with the parietal regions, elaborating information about motor imagery and more abstract mental imagery tasks Despite impairment of dorsal stream is well defined in DLB patients, the ventral stream resulted to be affected in both AD and DLB as compared to controls. However a different distribution of grey matter loss along the ventral pathway was found in DLB and AD. Specifically, cortical thinning in lingual and pericalcarine giri was observed in DLB, whereas a marked and diffuse cortical thinning was found in the mesial temporal cortex in AD. This latter structural alteration could be linked to greater memory impairment affecting AD patients and it is in accordance with previous morphometric studies According to previous reports from our group Different models have suggested a central role of posterior regions in manifestation of VH"} +{"text": "Client-owned pet dogs represent exceptional translational models for advancement of Cancer Research, as they reflects the complex heterogeneity observed in human cancer. We have recently shown that a genetic vaccine targeting dog telomerase (dTERT) and based on Ad/DNA-EGT technology can induce strong cell-mediated immune responses against this tumor antigen and increase overall survival of dogs affected by B-cell lymphosarcoma (LSA) in comparison with historical controls when combined with COP chemotherapy regimen. Here, we have conducted a double arm clinical trial with an extended number of LSA patients, measured the antigen-specific immune response and evaluated potential toxic effects of the immunotherapy along with a follow up of patients survival for three years and half. The immune response was measured by ELISPOT. The expression of dTERT was quantified by quantitative PCR. Changes in hematological parameters, local/systemic toxicity or organic dysfunction and fever were monitored over time during the treatment. dTERT-specific cell mediated immune responses were induced in almost all treated animals. No adverse effects were observed in any dog patient that underwent treatment. The overall survival time of vaccine/COP treated dogs was significantly increased over the COP-only treated cohort . There was a significant association between dTERT expression levels in LSA cells and overall survival (OS) among vaccinated patients. In conclusion, Ad/DNA-EGT-based cancer vaccine against dTERT in combination with COP chemotherapy is safe and significantly prolongs the survival of LSA canine patients. These data confirm the therapeutic efficacy of dTERT vaccine and support the evaluation of this approach for other cancer types as well as the translation of this approach to human clinical trials."} +{"text": "Optimizing productivity and growth of recombinant Chinese hamster ovary (CHO) cells requires insight and intervention in regulatory processes. This is to some extent accomplished by several 'omics' approaches. However, many questions remain unanswered and bioprocess development is therefore still partially empirical. In this regard, the analysis of DNA methylation as one of the earliest cellular regulatory levels is increasingly gaining importance. This epigenetic process is known to influence transcriptional events when it occurs at specific genomic regions with high CpG frequencies, called CpG islands (CGIs). Being methylated, CGIs attract proteins with methyl-DNA binding domains (MBD proteins) that in turn can interact with chromatin modifying complexes, thereby leading to a transcriptionally inactive state of the associated gene . In CHO Based on the genomic and transcriptomic information available for CHO cells ,5, 21,992+, MAPK and Wnt signalling systems were comprised within the latter group and showed a large coverage by differentially methylated components. 48 hours upon butyrate addition the number of differential methylations decreased by about 90 %. COBRA analysis of the Wnt responsive myc proto-oncogene protein-like gene showed clearly detectable cleavage products 24 hours upon butyrate addition, that completely vanished another 24 hours later (Figure Butyrate treated CHO DP-12 cultures stopped proliferating and decreasing viabilities could be detected 24 hours upon addition of the SCFA Figure . Simultar Figure , confirmOur first genome-wide screening for differential DNA methylation in CHO cells shows that the epigenetic response upon butyrate treatment seems to be highly dynamic and reversible. This was confirmed by applying the bisulfite-based single-gene method COBRA to analyze a region of the myc proto-oncogene protein-like gene. Furthermore, detection of differential methylation before butyrate addition indicates that heterogeneity in DNA methylation occurs even if cells originated from the same preculture and were treated identically. This occurrence of differentially methylated genes in parallel cultivations strongly fosters the hypothesis that the culture history influences final process outcomes . It unde"} +{"text": "Sensory cortex often undergoes population activity fluctuations due to attentional modulations and arousal changes, but activity fluctuations can also be generated intrinsically. The mechanisms that underlie these spontaneous activity fluctuations are unknown, in particular whether they arise from common inputs or more active neuronal processes. We measured the activity of tens of V1 neurons simultaneously in monkeys stimulated with oriented visual stimuli, and found that the tuning curves (TCs) of orientation selective neurons spontaneously underwent shifts and multiplicative scalings proportional to population activity while their widths remained constant Based on this observed TC activity dependence, we constructed a precise statistical model featuring Poisson-like firing, shifts and gain modulation. The model not only accounted for neuronal co-variability but also approached the performance of state-of-art decoding methods. Surprisingly, we found that decoding performance on sensory stimuli increased with population activity, despite the fact that the stimulus was identical. Therefore, spontaneous population activity fluctuations display highly non-random features, boosting TCs by shifts and multiplicative factors that gate information processing.We found that TCs are shifted and scaled by a multiplicative factor proportional to mean population activity Figure . The amoThe observed boosting properties of TCs motivated us to build a statistical model with Poisson-like neurons that includes a multiplicative scaling factor (PS). We observed that the effect of population activity on TCs is not purely multiplicative, and we introduced therefore a shift (PSS). Our models approached the performance of state-of-art decoding techniques and provided higher accuracy than other tested decoders based on population vector and independent Poisson neurons. Experimental methods are as in ."} +{"text": "Diverse therapeutic strategies for food allergy are under investigation including food allergen-specific and non-specific approaches. Allergen-specific approaches include immunotherapy with native food allergens, immunotherapy with mutated recombinant allergens, and diets containing extensively heated milk or egg. Native allergen immunotherapy can be administered via oral, sublingual, subcutaneous, or epicutaneous route. Oral immunotherapy trials with native food allergens such as milk, peanut, or egg reported that approximately 50-75% of the treated subjects reached and tolerated the maintenance dose. Failure of desensitization occurred in about 10-20% of the treated subjects and might be associated with the most severe and likely permanent food allergy phenotype, as opposed to the successful desensitization and tolerance that might be associated with a transient clinical phenotype and higher chances of spontaneous resolution of food allergy. Food allergens can be altered to decrease their allergenicity and lower the risk of acute adverse reactions. Immunotherapy with mutated recombinant peanut proteins, which have decreased IgE-binding activity, co-administered within heat-killed E.coli to generate maximum immune response had a strong protective effect in the mouse model of peanut anaphylaxis. This vaccine is being currently evaluated in the phase I clinical trials in adults with peanut allergy. Heating and processing changes food protein conformation and affects how food proteins are digested and transported via the gut barrier. Extensively heated (baked) milk and egg are tolerated by approximately 70% of the milk or egg allergic children. Diets containing extensively heated (baked) milk and egg represent an alternative approach to food oral immunotherapy and are already changing the paradigm of strict dietary avoidance for food-allergic patients."} +{"text": "We construct a state-and-transition model for mammals in tropical savannas in northern Australia to synthesize ecological knowledge and understand mammalian declines. We aimed to validate the existence of alternative mammal assemblage states similar to those in arid Australian grasslands, and to speculate on transition triggers. Based on the arid grassland model, we hypothesized that assemblages are partitioned across rainfall gradients and between substrates. We also predicted that assemblages typical of arid regions in boom periods would be prevalent in savannas with higher and more regular rainfall. Data from eight mammal surveys from the Kimberley region, Western Australia (1994 to 2011) were collated. Survey sites were partitioned across rainfall zones and habitats. Data allowed us to identify three assemblage states: State 0:- low numbers of mammals, State II:- dominated by omnivorous rodents and State III:- dominated by rodents and larger marsupials. Unlike arid grasslands, assemblage dominance by insectivorous dasyurids (State I) did not occur in savannas. Mammal assemblages were partitioned across rainfall zones and between substrates as predicted, but\u2014unlike arid regions\u2014were not related strongly to yearly rainfall. Mammal assemblage composition showed high regional stability, probably related to high annual rainfall and predictable wet season resource pulses. As a consequence, we speculate that perpetually booming assemblages in savannas allow top-down control of the ecosystem, with suppression of introduced cats by the dingo, the region's top predator. Under conditions of low or erratic productivity, imposed increasingly by intense fire regimes and introduced herbivore grazing, dingoes may not limit impacts of cats on native mammals. These interacting factors may explain contemporary declines of savanna mammals as well as historical declines in arid Australia. The cat-ecosystem productivity hypothesis raised here differs from the already-articulated cat-habitat structure hypothesis for mammal declines, and we suggest approaches for explicit testing of transition triggers for competing hypotheses. The processes that drive fluctuations in population size and community composition have long been a source of fascination for ecologists, and gaining a general understanding of their identity and effects remains an enduring goal. Although some emphasis has been placed on the influence of intrinsic factors, such as social interactions, in driving species' dynamics In many systems, the interplay between bottom-up and top-down forces can lead to the existence of alternative states that are characterized by different dominant species or species-groups State-and-transition models were initially developed to assist in managing non-equilibrial rangeland systems Here, we apply state-and-transition modelling to synthesize knowledge about native mammal assemblages in the Kimberley region of northern Australia and explore factors that might drive them. This region is of considerable conservation concern: populations of many mammal species are declining across the northern Australian savannas, conceivably towards irreversible regional or total extinctions. Worldwide, about a quarter of all mammal species are threatened with extinction; about 38% of land mammals suffer from habitat loss associated with diversion of natural resources to benefit humans, and 16% are at risk from hunting or harvesting Although mammal declines elsewhere in Australia have received considerable attention Sminthopsis macroura, Pseudomys desertor, Rattus villosissimus, Mus musculus) and functional groups (particularly insectivorous dasyurids and omnivorous rodents).We use a recently described model from central Australia There are two key differences between central Australian arid grassland assemblages and those of the Kimberley's tropical savannas: (1) The former are now largely devoid of medium-sized mammals (e.g. peramelids) whereas all medium-sized mammals persist in the tropical savannas, albeit in most cases, with greatly reduced ranges It is important that state-and-transition models be testable annual rainfall,rocky versus non-rocky savannas, andthe abundance and representation of particular species and taxonomic or functional groups.Because of the importance of antecedent rainfall in driving patterns of mammalian abundance and composition through time, we predicted also that inter-annual differences in rainfall would lead to shifts between states. Rainfall, and thus productivity, is predictable in the Kimberley but not in central Australia, where erratic rainfall drives ephemeral pulses of productivity. In consequence, we predicted further that Kimberley mammal assemblages would be more stable and exist in higher states than those in central Australia. We use our results to generate hypotheses about the key factors that prompt shifts between assemblage states and hence further our understanding of the threats to the Kimberley mammal faunas. These hypotheses also can be extended to, and tested in, other tropical savanna areas.4 grasses dominating the ground layer The Kimberley region is in the far north west of Australia and represents the Western Australian component of Torresian habitats. It has a tropical monsoonal climate with rain falling mostly during the summer from November to April. Annual rainfall ranges from 1400 mm on the far north coast to <400 mm along the semi-arid southern boundary . AlthougTo classify mammal assemblage states, we collated data from 229 survey sites in savanna across all the major Kimberley bioregions All survey data presented here consist of one-off site surveys. Where repeat site surveys occurred, we maintained temporal independence by choosing just one survey at random to represent that site. As different rainfall regions and savanna habitats provide the potential conditions needed to drive different states and transitions, we considered this space-for-time approach to be appropriate.This study makes use of data from eight separate mammal fauna surveys with differing methodologies and trap effort per site . DespiteAnalyses were performed on individual species and also on pre-defined functional groups , terrestrial omnivorous rodents (Muridae), arboreal rodents, large marsupials (>150 g) including dasyurid predators, bandicoots (peramelids), possums , and small macropods (macropodids <2000 g)). We compared species and taxonomic/functional groups in terms of their abundance, measured here as percentage trap success for each survey. We tested for potential under-estimation of small dasyurids among surveys by separately analyzing trap records from pitfall traps based on the rationale that pitfall traps are the most effective method for estimating the abundance of small dasyurids in arid grassland surveys The hypothesis that species and mammal groups differ in abundance among rainfall zones and between rocky and non-rocky savannas was tested using Kruskal-Wallis tests. This non-parametric test was chosen due to inequality of sample sizes and non-normality of the survey data, which had many zero values. The effect of fluctuations in annual rainfall within rainfall zones/savanna types was tested using regressions of trap success over previous wet season rainfall. Differences among mammal assemblages across rainfall zones and savanna habitats were explored using Bray Curtis ordinations, with the Sorensen dissimilarity distance used to calculate separation between surveys. A non-parametric multi-response permutation procedure (MRPP) was used to test for differences among predefined rainfall zone and savanna habitat (rocky and non-rocky) groups. We used PC-ORD 4 for ordinations and MINITAB 14 for all statistical analyses.Zyzomys argurus, Pseudomys nanus, Rattus tunneyi and P. delicatulus. The next most prominent group comprised large dasyurid predators , with 0.95% trap success. Small insectivorous dasyurids were relatively rare and yielded a total trap success of only 0.09%. Other groups represented in the surveys included bandicoots (0.58%) and arboreal rodents (0.43%). The low trap success rate for macropods and possums (<0.2%) probably reflects ineffective sampling rather than low numbers as these animals are not often trapped even where locally numerous.After removal of data from sites sampled more than once, we recorded a total of 5138 mammals from 71,016 trap nights (mean trap success 7.24%) . The larCanis lupus dingo and feral cats Felis catus were abundant. Dingoes were frequently observed and recorded in the high and medium rainfall zones during surveys . Similarly, cats are present throughout the Kimberley Although not recorded by trapping, dingoes P. delicatulus, P. nanus) were more numerous in low rainfall zones and non-rocky savannas, while others were most abundant in high rainfall rocky savannas showed variable responses to rainfall and habitat. Some rodent species , the bandicoot Isoodon auratus and arboreal rodents occurred only in surveys in the high rainfall zone , including rodents and small dasyurids, were captured using pitfall traps irrespective of rainfall zone . RodentsIn individual surveys, 17% of sites had no mammals (State 0), 2% were dominated by insectivorous dasyurids (State I), 37% were dominated by omnivorous rodents (State II) and 44% had a significant component of large mammals in addition to omnivorous rodents (State III). Surveys yielding zero mammals (State 0) were unusual in high (8% of surveys) and medium (0%) rainfall rocky savannas but more common in non-rocky savannas and in low rainfall rocky savannas (32%). Small dasyurids (State I) dominated assemblages in 1% of high rainfall rocky savannas, and in 5% and 10% of rocky and non-rocky sites in the low rainfall zone. Rodents dominated assemblages (State II) in medium rainfall non-rocky (73%), low rainfall rocky (63%) and low rainfall non-rocky (71%) savannas. State II assemblages were also common in medium rainfall rocky (25%) and high rainfall non-rocky savannas (38%), but less so (6%) in high rainfall rocky savannas. State III assemblages with large CWR mammals (>150 g) were restricted to high rainfall or rocky savannas, with 84% and 75% of surveys yielding these assemblages in high and medium rainfall rocky savannas, and 40% in high rainfall non-rocky savannas.Z. argurus and P. desertor and on non-rocky substrates (sand plains and open non-rocky savannas) by P. nanus, P. delicatulus and R. tunneyi. These species differ from their arid zone counterparts where State II assemblages are dominated by Notomys alexis and Pseudomys hermannsburgensis (Letnic and Dickman 2010). Finally, surveys in the high rainfall zone conformed to State III arid zone assemblages, with rodents and marsupial groups including predatory dasyurids dominating. State III assemblages were dominated by rodents and the large dasyurid predator Dasyurus hallucatus on rocky substrates. State III assemblages also included bandicoots (Isoodon macrourus and I. auratus), arboreal rodents (Mesembriomys macrurus and Conilurus penicillatus) and infrequently trapped possums (e.g. Wyulda squamicaudata) and small macropods . The latter groups, comprising CWR mammals, have become extinct since European settlement in central Australian grasslands This study confirms the existence of alternative assemblage states for mammals in tropical savannas of the Kimberley region. A proposed model depicting these states is shown in Sminthopsis macroura, S. virginiae, Planigale ingrami, P. maculata and Pseudantechinus ningbing occurred throughout Kimberley. However, they never occurred at high abundance, nor were they ever more common than other mammal groups. In contrast, arid assemblages are often dominated by small dasyurids (i.e. State I) A key difference between the arid zone assemblages described by Letnic and Dickman D. hallucatus, P. tapoafata), bandicoots and arboreal rodents have generally been restricted to high rainfall savannas in the Kimberley and Top End regions since the 1980s The assemblages described here correspond closely with previous reports on mammals in the Kimberley savannas Key transition triggers for changes in mammal assemblage state in central Australian grasslands are rainfall events that drive ephemeral pulses of primary production, and wildfires, drought, grazing by introduced herbivores and predation by introduced predators (cats and foxes) D. hallucatus) Despite the predictability of these patterns, assemblage states were not fixed; for example, State II assemblages sometimes occurred in the high rainfall zone and State III assemblages in the medium rainfall zone. Several other studies have also documented changes in assemblage states at particular sites over time High regional stability among assemblages of Kimberley savanna mammals in response to inter-annual differences in rainfall suggests that transitions there are governed differently from those in central Australian grasslands. Because savanna productivity is generally relatively high due to higher rainfall than in more arid regions, factors that effect downward state transitions may assume more importance in driving assemblage changes. Such factors operating in the savannas may also explain the relatively low abundance of mammals in most Kimberley assemblages relative to those in the arid grasslands during periods of population irruption Predation by introduced cats and foxes drives mammal assemblages towards lower states in arid regions Of the predators in the Kimberley savannas, dingoes are most likely to have a top-predator role and to influence mammal assemblage states. Ecological theory and many empirical observations show that where resource pulses are regular, as in the Kimberley relative to the arid zone, predators often maintain higher and more stable populations and can then exert strong regulatory effects on prey If dingoes act as \u2018biodiversity regulators\u2019 As in the conceptual model for arid Australian assemblages, fire regimes and introduced herbivores have major influences on assemblages of savanna mammals Arid zone mammals typically occur as State 0 or State I assemblages for long periods until shifted up by large but infrequent flooding rains The cat-ecosystem productivity hypothesis posited here, and depicted in"} +{"text": "It has been previously shown that loss of consciousness is associated with a breakdown of dominating fronto-parietal feedback connectivity as assessed by electroencephalogram (EEG) recordings. Structure and strength of network connectivity may change over time. Aim of the current study is to investigate cortico-cortical connectivity at different time intervals during consciousness and unconsciousness. For this purpose, EEG symbolic transfer entropy (STEn) was calculated to indicate cortico-cortical information transfer at different transfer times.The study was performed in 15 male volunteers. 29-channel EEG was recorded during consciousness and propofol-induced unconsciousness. EEG data were analyzed by STEn, which quantifies intensity and directionality of the mutual information flow between two EEG channels. STEn was computed over fronto-parietal channel pair combinations to analyze changes of intercortical directional connectivity. Feedback and feedforward connectivity was calculated for transfer times from 25 ms to 250 ms in 5 ms steps. Transfer times leading to maximum directed interaction were identified to detect changes of cortical information transfer induced by unconsciousness (p<0.05).The current analyses show that fronto-parietal connectivity is a non-static phenomenon. Maximum detected interaction occurs at decreased transfer times during propofol-induced unconsciousness . Strength of maximum feedback interaction decreases during unconsciousness (p\u200a=\u200a0.026), while no effect of propofol was observed on feedforward interaction. During both consciousness and unconsciousness, intensity of fronto-parietal interaction fluctuates with increasing transfer times.Non-stationarity of directional connectivity may play a functional role for cortical network communication as it shows characteristic changes during propofol-induced unconsciousness. Altered states of consciousness are associated with changes in directional (effective) and functional connectivity within a fronto-parietal network. This is observed as a common phenomenon during anesthesia, vegetative states and sleep Recent studies show that functional connectivity of cerebral areas is not a static phenomenon, but shows spontaneous fluctuations over time However, so far, fluctuations of neuronal network connectivity have been shown for functional connectivity as measured by functional magnetic resonance imaging (fMRI). The current study evaluates whether directional cortical connectivity as measured by electroencephalogram (EEG) may also show fluctuations, but in the range of milliseconds Fifteen healthy male volunteers participated after approval by the university's ethics committee and informed written consent. The study was conducted in the department of anesthesiology of the Technische Universit\u00e4t M\u00fcnchen, Germany. Standard monitoring parameters and 29-channel EEG were continuously recorded with a sampling rate of 5 kHz using BrainAmp electroencephalographic amplifier and BrainVision Recorder data acquisition software. Propofol was administered by a target controlled infusion pump . Subjects received propofol in stepwise increasing concentrations until loss of consciousness occurred, which was defined clinically when subjects stopped following the investigator's instruction to squeeze his hand. TCI concentration at this point was maintained for 10 minutes to allow equilibration. EEG was recorded without drug application and during propofol-induced unconsciousness (10 minutes). Basic artifact detection and average reference were performed on EEG recordings.In existing EEG data of propofol-induced unconsciousness we applied EEG analysis within the framework of an information-theoretic approach allowing a model-free exploration of directed interactions between frontal (process X) and parietal (process Y) electrodes. For this purpose, EEG symbolic transfer entropy (STEn) was calculated For calculation, STEn analyzes consecutive sequences For frontal (x) and parietal (y) EEG this indicates feedforward parietal \u2192 frontal projections between parietal and frontal electrodes . STEn was computed over fronto-parietal channel pair combinations at consciousness and propofol-induced unconsciousness using one artifact free EEG signal of 10 s length for each subject . Acording to the signal length criterion Values of STEn may indicate spurious interdependencies in the EEG caused by spectral changes. To address this question, surrogates from the electroencephalographic signals were derived by maintaining the spectral amplitudes and randomising the phase non-parametric STEn showed consistent results even in different setups, e.g. embedding parameters, electrode montage Further studies with different anesthetics and altered states of consciousness are required to clarify some open points. Unconsciousness was induced by propofol. Therefore, it remains an open question, whether the detected results are a propofol-specific phenomenon or reflect characteristics of unconsciousness in general. The small number of subjects and low spatial resolution of the fronto-parietal network analyzed in EEG represent further limitations. Method inherent issues can not be fully excluded. Estimation of transfer times as performed in the present analysis may also include intrinsic prediction within one area In conclusion, our results indicate that cortical information transfer is not a static process but fluctuates periodically. Fluctuations of directional connectivity seem to reflect an intrinsic phenomenon of the brain to energetically optimize cortical communication. Characteristically, fluctuations are changed during propofol-induced unconsciousness towards faster information transfer. At the same time, the amount of parieto-frontal feedforward projections is not reduced during unconsciousness, while fronto-parietal feedback interactions are reduced. Both the inhibition of feedback connectivity and the altered fluctuation of information transfer during propofol administration are proposed as functional correlates of loss of consciousness."} +{"text": "Quality of Life (QoL) data from oncology trials may have missing data which cannot be assumed to be missing completely at random (MCAR) . IgnorinWe searched MEDLINE (2002-2012) to identify oncology trials reporting longitudinal analysis of QOL data. The appropriateness of the analysis was reviewed and trials reporting QOL as primary/secondary endpoint were assessed for reporting quality using the CONSORT extension for PROs .69 RCTs reporting longitudinal QOL analyses were identified. 29 (42%) use an analysis to account for the nature of the missing data. Methods varied widely, eg pattern-mixture models, conditional linear models, QTWiST, joint longitudinal models, generalised estimating equations, selection models and Markov models. Fourteen papers used more than one method check the robustness of their results.In order for QOL data to adequately inform clinical decision-making the correct analysis needs to be performed. Statistical methods ignoring the missing data were found to over-estimate QOL but it was rare for the significance of QOL differences between treatments to change. A strategy for appropriate analysis of QOL data will be presented using case studies to highlight where ignoring informative missing data could alter the conclusions regarding treatment differences."} +{"text": "Progressive increase of temperatures as well as longer seasonal drought periods revealed by climate studies correspond to fast environmental changes that forest species face with their actual genetic background. Natural selective processes cannot develop an adaptive response within this time frame. Thus the capability of forest tree species to adapt to the new environments will depend on their genetic background, but also rely on their phenotypic plasticity. Several reports have shown the involvement of epigenetic modifiers as the basis of the phenotypic plasticity, and in particular to the adaptation to abiotic stresses. DNA methylation (methylation of cytosine residues)is one the most important epigenetic modification in eukaryotes. Itis involved in specific biological processes such as gene transcription regulation, gene silencing, mobile element control or genome imprinting.Therefore, there is a great interest in analyzing cytosine methylation levels and distribution within the genome.HpaII and MspI are isoschizomers that are frequently used to detect cytosine methylation. HpaII cannot cleave if one or both cytosines are fully methylated (in both strands), whereas MspI cleaves C5mCGG but not 5mCCGG sequences). For each sample, MSAP analysis is performed using both EcoRI/HpaII and EcoRI/MspI digested samples. Comparative analysis between EcoRI/HpaII and EcoRI/MspI fragment patterns allows the identification of two types of polymorphisms: (1) \u201cMethylation-insensitive polymorphisms\u201d that are associated with genetic variability and will show common EcoRI/HpaII and EcoRI/MspI profiles among samples; and (2) \u201cMethylation-sensitive polymorphisms\u201d that are associated with epigenetic variability and detected as amplified fragments differing in their presence or absence or in their intensity between EcoRI/HpaII and EcoRI/MspI patterns of the same sample. Thus, full methylation of the internal cytosine at the assayed CCGG sites will be associated with fragments detected in EcoRI/MspI pattern which are absent or less intense in EcoRI/HpaII profile. Hemi-methylation of the external cytosine will be associated with fragments observed in EcoRI/HpaII pattern which are absent in EcoRI/MspI profile.In order to analyze methylation-sensitive anonymous CCGG restriction sites we used MSAP technique (Methylation-Sensitive Amplified Polymorphism), an AFLP-based technique for the analysis of cytosine methylation. The technique is based on the use of isoschizomers that show differential cleavage sensitivity to cytosine methylation. Fagus sp.) and gymnosperm (Pinus sp.) species.We have optimized DNA methylation analysis for two forest tree species, including both angiosperm (Pinus pinea L. a specie which is characterized by a low genetic variability and high level of phenotypic plasticity. Representative populations spanning the whole distribution of this specie within Spanish geography were chosen for this study, including coastal and interior populations. MSAP patterns from vegetative propagated trees were compared among and within populations. Percentage of methylation-sensitive polymorphisms was calculated and selective markers were identified.The set-up of the MSAP technology has allowed study intra-specific variability of DNA methylation in Fagus sylvatica L. in response to water deficit we analyzed two populations of beech from Spain and Sweden which differ in the response to water stress. Patterns of DNA methylation clearly differed between populations. Although the rate of DNA methylation was similar between irrigated and non-irrigated trees in each polpulation after AMOVA, some specific MSAPs associated with water stress response were identified.To test a possible role of DNA methylation in the plasticity of"} +{"text": "DNase I hypersensitivity (DHS) combined with next generation sequencing (DNase-seq) is an efficient way of observing, in a single experiment, the genome-wide chromatin effects associated with the binding of multiple transcription factors. Using quantitative contrasts of DHS before and after estrogen and androgen stimulation in breast and prostate cancer cell lines, we have shown that differential DHS can accurately predict hormone induced transcription factor binding. Despite its effectiveness, the DHS assay can vary significantly depending on the experimental parameters. To increase the robustness of this assay, we have systematically evaluated two major parameters, digestion level and fragment size. We found that while there is a broad range of suitable digestion level, over-digestion dramatically decreases the efficiency of detecting DHS regions. More interestingly, we found that different fragment sizes capture distinct chromatin elements, and thus represent different chromatin structures. We were able to classify different combinations of estrogen receptor coregulators that resulted in different local chromatin structures."} +{"text": "Aging is worldwide recognized as a dominant risk factor for most forms of cardiovascular disease -3. HowevIn adult and elderly humans, high levels of physical activity preserve the protective role of preinfarction angina against in-hospital mortality and cardiogenic shock after myocardial infarction. More recent data indicate that higher levels of physical activity performed before primary coronary angioplasty may independently predict the reduction of early and late cardiac mortality in older infarcted patients . Accordi"} +{"text": "Mitotic chromosome motions have recently been correlated with electrostatic forces, but a lingering \"molecular cell biology\" paradigm persists, proposing binding and release proteins or molecular geometries for force generation.Pole-facing kinetochore plates manifest positive charges and interact with negatively charged microtubule ends providing the motive force for poleward chromosome motions by classical electrostatics. This conceptual scheme explains dynamic tracking/coupling of kinetochores to microtubules and the simultaneous depolymerization of kinetochore microtubules as poleward force is generated.We question here why cells would prefer complex molecular mechanisms to move chromosomes when direct electrostatic interactions between known bound charge distributions can accomplish the same task much more simply. Molecular mechanisms underlying mitosis, particularly those associated with directed chromosome movement during the cell cycle, have been pursued intensely over the past two decades with no clear picture emerging--or is there? Recent experiments identify positively charged kinetochore-associated molecules that likely interact with negatively charged microtubule ends to generate electrostatic-dependent poleward forces that drive chromosome motion . This coIndeed, current thought on mitotic motions is shifting from a molecular to a more electrostatics-based framework -3, and psic] attempted to explain chromosome motions by nanoscale electrostatics and unnecessary sophistry...\" [Perhaps the most surprising part of this story is the untimely resistance to classical electrostatics by the cell biology community. For example, critiques including \"...groundless speculations in which the authors [stry...\" , and reqstry...\" suggest stry...\" ,2, and istry...\" and redustry...\" .To gain perspective on this subject, it may be instructive to consider the problem of cell division in an evolutionary context, and more specifically in an ancestral cell that lacked \"modern\" molecular machinery. Clearly, cells have been dividing since the origin of life, and the mechanisms underlying this fundamental process in modern cells are likely derived from some ancestral state--just like other cellular processes were likely derived from ancestral, catalytic RNAs that were later supplemented with supporting proteins. In a simple cell, all chromosome movements during mitosis are readily explained by electrostatic interactions between core components of the system , without the requirement for supplemental protein machinery -6. Why tOur current bottleneck in understanding mitotic chromosome movements seems reminiscent of another challenging question in our imperfect scientific history, namely the self-imposed constraints of ancient Greek astronomers in trying to explain geocentric planetary motions with perfect circles. Indeed, layers of epicycles were incorporated into an increasingly complex scheme of integrated circles that was \"understood\" by only the best natural philosophers of the time. It took ~2,000 years of scientific work by Brahe, Galileo, Kepler and Newton to achieve the simplicity of a modern theory based on a different conceptual scheme, i.e., elliptical orbits in a heliocentric solar system.Twenty years ago, Guenter Albrecht-Buehler lamented the view of many cell biologists that \"molecular analysis of cellular functions\" is the only acceptable approach to cell biology , yet thiThe authors declare that they have no competing interests.DHS made intellectual contributions and drafted the manuscript. LJG conceived the study. All authors read and approved the final manuscript."} +{"text": "We conducted a qualitative study to gain insight into the high retention rate and variable outcomes achieved in the 3-year PODOSA (Prevention of Diabetes and Obesity in South Asians) family-based cluster randomised controlled trial of a dietitian-delivered lifestyle modification intervention.We interviewed 21 trial participants and family volunteers following trial completion. Purposive sampling ensured representation of the diversity within the trial population. Data were thematically analysed. Findings were shared with trial dietiticans once the trial had closed.Many participants were aware of their family history of diabetes and attracted by the availability of information and monitoring. Offering home or clinic-based interventions, communication in the participant's chosen language(s) and excellent relationships between participants and dieticians contributed to retention. Adaptations in food choices were accommodated by participants, although community and faith based considerations made consistent adherence challenging. Participants found increasing their level of physical activity difficult given other demands, including long working hours, physically demanding employment and domestic commitments.Undertaking qualitative research allowed in-depth insight into participation, retention and adherence in the PODOSA trial. The main benefit participants sought was information regarding diabetes. Home-based interventions and continuity in dieticians were included in trial design, but it was not anticipated that these relationships would contribute so greatly to retention. Adaptations in food choices were not felt to be an extra burden upon participants but were made more difficult due to cultural considerations. Increasing levels of physical activity were felt to be an additional burden, again augmented by cultural considerations."} +{"text": "Rodent models of heterotopic cardiac transplantation are important for gaining a better understanding of heart allograft rejection. This study compared a working heart (WkHt) transplant model, which have developed by our laboratory, with the traditional non-working heart (Non-WkHt) model using cardiac MRI (CMRI) and pathological evaluation. Our results indicate that the physiological hemodynamic loading significantly impacts graft immune cell infiltration and myocardial function. Our WkHt transplant model with intact pulmonary circulation, retains hemodynamic loading close to that of native heart, and is thus more appropriate for both functional and immunological studies, especially for developing the clinically relevant CMRI techniques for comprehensive evaluation of the heart graft.The traditional heterotopic heart transplantation rodent model ,2 lacks WkHt model: En bloc of graft heart and lung was transplanted into the recipient abdomen. Graft aorta and superior vena cava (SVC) were anastomosed with recipient abdominal aorta and inferior vena cava (IVC), respectively.,4 Non-WkAlthough isograft hearts from both models had strong heart beats and normal ECG, they exhibited very different cardiac functions revealed by CMRI Fig.. The WkHOur results indicate that hemodymamic loading significantly impacts the graft status. The WkHt transplant model, with intact pulmonary circulation, retains physiological conditions close to that of the native heart, and therefore is more appropriate for functional and immunological studies, especially for developing the clinically relevant CMRI techniques for comprehensive evaluation of the heart graft.This study is supported by grants from the National Institutes of Health (P41EB001977 and R01HL-081349)."} +{"text": "Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (FOLFOX) is a common chemotherapeutic regimen for advanced colorectal cancer. Here, we present a case of interstitial lung disease associated with FOLFOX therapy.A 74-year-old man with a history of metastatic colorectal cancer was admitted with a four week history of progressive dyspnoea and evidence of severe respiratory failure. He had recently completed six cycles of FOLFOX chemotherapy in the months prior to presentation. Investigations did not reveal convincing evidence of infection or pulmonary embolism. CT chest demonstrated widespread pulmonary infiltrates and interlobular septal thickening. The patient was commenced on both broad spectrum antibiotic therapy and high dose corticosteroid treatment however his respiratory failure continued to progress. The patient died four days after admission due to progressive respiratory failure. Subsequent post-mortem examination demonstrated evidence of diffuse alveolar damage without evidence of tumour infiltration, infection or pulmonary embolism.Although infrequent, pulmonary toxicity can occur in association with FOLFOX therapy. Cessation of therapy and prompt initiation of corticosteroids may improve outcomes. Oxaliplatin in combination with 5-fluorouracil (5-FU) and leucovorin (FOLFOX) is an effective chemotherapeutic regimen for advanced colorectal cancer, improving survival with acceptable tolerability and side effect profile.A 74-year-old man with a history of metastatic colorectal cancer was admitted with a four week history of progressive dyspnoea and haemoptysis. He had undergone a right hemicolectomy three and a half years previously for a Duke\u2019s A colorectal cancer. Three years post resection, a large single liver metastasis was identified with no other evidence of metastatic disease on PET scanning. CT examination of the chest at the time demonstrated only mild emphysematous changes .The patient was commenced on FOLFOX chemotherapy and underwent six cycles from October to December 2008. A re-staging CT scan in January 2009 demonstrated progressive malignant disease with multiple new metastases within the liver. Chest imaging at this time revealed bilateral peripheral subpleural reticular changes and interlobular septal thickening without evidence of overt lung metastases . No chanThe patient subsequently presented in early February 2009 with four weeks of worsening dyspnoea and haemoptysis. His Creactive protein level was moderately elevated although white cell count and differential were normal. Arterial blood gases demonstrated severe type I respiratory failure. CT pulmonary angiogram excluded pulmonary embolism but demonstrated new patchy infiltrates with interlobular septal thickening . Sputum He was commenced on empirical broad spectrum antibiotics and high dose intravenous corticosteroid therapy. His respiratory failure worsened and after discussion with both the patient and his family, mechanical ventilation was not administered. The patient died four days after admission from progressive respiratory failure.Post-mortem examination did not demonstrate evidence of an infective aetiology on staining and culture of fresh specimens. There was also no evidence of emboli, thrombus or malignant infiltration within the lungs. Histological examination demonstrated widespread generalised changes within both lungs, with oedema, intra-alveolar haemorrhage and fibrin deposition along with interstitial and intraluminal fibroblastic proliferation without mature fibrosis. These findings were consistent with diffuse alveolar damage.Diffuse alveolar damage (DAD) is a common histopathological finding in patients with ARDS and is commonly associated with infections (both respiratory and systemic). It is more frequently seen in immunocompromised patients. Although drug reactions are a relatively uncommon cause of DAD, chemotherapeutic agents are overrepresented as potential precipitants. Mortality following histologically proven DAD obtained from surgical lung biopsy has been reported to be greater than 50%.7et al. demonstrated improved response rate, median time to progression and overall survival in patients with advanced colorectal cancer treated with FOLFOX in comparison to a regimen utilising Irinotecan instead of Oxaliplatin.17Oxaliplatin, in combination with 5-fluorouracil and leucovorin (FOLFOX) has been shown to be an effective regimen for the treatment of advanced colorectal cancer.Although pulmonary toxicity from FOLFOX appears to be an uncommon and apparently idiosyncratic effect of therapy, this case highlights the importance of clinicians being aware of this potentially fatal complication and the importance of regular follow-up.Given the temporal relationship between the use of FOLFOX and the onset of radiological changes and clinical symptoms, we believe that FOLFOX is the likely precipitant in this case. Whilst this appears to be an uncommon adverse effect, early recognition may allow prompt cessation of FOLFOX therapy and initiation of systemic corticosteroids, and this has the potential to improve outcomes for such patients."} +{"text": "Batrachochytrium dendrobatidis - Bd) are major drivers of amphibian declines worldwide. Habitat loss regulates host-pathogen interactions by altering biotic and abiotic factors directly linked to both host and pathogen fitness. Therefore, studies investigating the links between natural vegetation and chytridiomycosis require integrative approaches to control for the multitude of possible interactions of biological and environmental variables in spatial epidemiology. In this study, we quantified Bd infection dynamics across a gradient of natural vegetation and microclimates, looking for causal associations between vegetation cover, multiple microclimatic variables, and pathogen prevalence and infection intensity. To minimize the effects of host diversity in our analyses, we sampled amphibian populations in the Adirondack Mountains of New York State, a region with relatively high single-host dominance. We sampled permanent ponds for anurans, focusing on populations of the habitat generalist frog Lithobates clamitans, and recorded various biotic and abiotic factors that potentially affect host-pathogen interactions: natural vegetation, canopy density, water temperature, and host population and community attributes. We screened for important explanatory variables of Bd infections and used path analyses to statistically test for the strength of cascading effects linking vegetation cover, microclimate, and Bd parameters. We found that canopy density, natural vegetation, and daily average water temperature were the best predictors of Bd. High canopy density resulted in lower water temperature, which in turn predicted higher Bd prevalence and infection intensity. Our results confirm that microclimatic shifts arising from changes in natural vegetation play an important role in Bd spatial epidemiology, with areas of closed canopy favoring Bd. Given increasing rates of anthropogenic habitat modification and the resulting declines in temperate and tropical frogs, understanding how vegetation cover and disease interact is critical for predicting Bd spread and developing appropriate management tools for wild populations.Habitat loss and chytridiomycosis (a disease caused by the chytrid fungus Anthropogenically driven habitat change has important implications for host-pathogen interactions, because even slight changes in environmental conditions can modify numerous biotic and abiotic factors that influence these interactions Batrachochytrium dendrobatidis (Bd), for instance, is more prevalent and occurs at higher infection intensities in pristine tropical forests compared to disturbed habitats Bd-induced amphibian declines Shifts in microclimate and changes in host community structure across gradients of habitat alteration play important roles in amphibian epidemiology Bd, thus limiting pathogen growth and persistence Bd persistence in these environments From the host's perspective, immune responses usually decrease as a result of the multiple effects of habitat alteration Bd in populations of the common Green Frog (Lithobates clamitans) across a gradient of natural vegetation and microclimate. We sampled frogs in the southern Adirondack Park, New York State, a region with relatively low amphibian diversity and high dominance of this habitat generalist host Bd in amphibians and (ii) test for causal associations linking vegetation cover and microclimate with both Bd prevalence and infection intensity. Combined, these goals may elucidate whether vegetation and microclimate modulate disease risk in temperate amphibian populations affected by anthropogenic habitat change.Here, we examined the infection dynamics of Bd is enzootic and widespread in the northeastern U.S. Bd growth in this region Lithobates clamitans, Ranidae), the locally dominant amphibian host species. Green Frogs breed in permanent ponds during the boreal spring and summer, and typically spend most of the time at the shallow banks of water bodies \u22121. We recorded body weight (g) for each captured individual and screened post-metamorphic frogs with sterile swabs to quantify Bd prevalence and infection intensity (average of 16.6 L. clamitans per site). We tested samples for Bd in singlicate using Taqman qPCR Bd in each sample. This protocol maximizes amplification efficiencies by diluting extracts to reduce inhibition in environmental samples. For calculations of Bd prevalence, we categorized individuals as Bd-positive when their qPCR showed an infection load of greater than or equal to one g.e. Bd prevalence as the percentage of infected individuals and Bd infection intensity as average number of g.e. per population.We sampled anuran populations in the Adirondack Park of the State of New York . This region is heavily forested with elements representative of temperate and boreal forests \u22121) as a proxy for host population density. We specifically chose this study system because of its relatively low species diversity and high single host species dominance. These community attributes allow us to test hypothesis about the roles of microclimate in disease dynamics without the potential effects of complex host community structure. Nonetheless, we recorded host community diversity , and we reported the model with the highest goodness-of-fit for each run. We also used CAR to test for associations of natural vegetation with host population and community attributes .To control for the effects of spatial autocorrelation among ponds, we analyzed our data using conditional autoregressions (CAR). We used CAR to test the relationship of each explanatory variable with Bd infection parameters. Because canopy density may be a better proxy for microclimate than our actual temperature records from a single data logger per pond, we tested an alternative path diagram in which canopy density directly affected Bd infection parameters. We compared goodness-of-fit among models using Expected Cross-validation Index (ECVI), an AIC-based index. We conducted CAR using Spatial Analysis in Macroecology v4.0 We used path analyses to statistically test for the strength of unidirectional cascading effects linking natural vegetation, canopy density, water temperature, and Bd at all study sites with mean prevalence of 24.25%\u00b116.41 SD and mean infection intensities of 29.36\u00b1151.60 SD, reaching a maximum load of 1063.23 g.e. in our focal species without observed mortalities. Canopy density was the best predictor of Bd prevalence in L. clamitans , maximum daily average temp. , minimum daily average temp. ], and natural vegetation . We found no significant relationships between Bd prevalence and average body weight, capture rate, elevation, host community diversity, or overall host community biomass.We detected Bd infection intensity. Canopy density best predicted Bd infection intensities , maximum daily average temp. , minimum daily average temp. ], natural vegetation , average body weight , and capture rate were also significant predictors of Bd infection intensity in L. clamitans. Similar to prevalence, we found no direct associations of Bd infection intensity with elevation, host community diversity, or overall host community biomass.We found similar results for Bd prevalence and infection intensity, our model selection identified three key environmental factors: canopy density, natural vegetation, and daily average water temperature and infection intensity underscores the dominance of the focal species across this landscape . The amount of natural vegetation surrounding our sampling ponds did not significantly predict host population and community attributes; namely host average body weight , host capture rate , overall host community biomass , species richness , and host diversity .The high evenness and low diversity among our sampling ponds . Although these species may help maintain Bd throughout the cold months, it is unlikely that they have a strong effect on disease dynamics later in the season, because they spend long periods of time away from water bodies Bd growth Bd infections in the wild Bd prevalence and infection intensity in temperate amphibian populations by modulating shade and associated microclimatic patterns, and that host community structure plays at most a minor role in our study system.The effects of habitat loss and forest fragmentation on host-pathogen interactions are varied Bd prevalence and infection intensity were environmental variables associated with vegetation cover and microclimate in Pennsylvania showed that the proportion of leaf-litter and vegetation in the pond substrate correlated positively with Bd prevalence and infection intensity Bd transmission by providing substrates for Bd growth. Alternatively, leaf-litter may be an indicator of canopy cover and total degree of shade, which are potentially the true drivers of higher Bd levels in natural forest habitats. Similarly, in Costa Rica and Australia, localities with little to no canopy cover may provide amphibians with a refuge from Bd-induced extinction Bd year round (above 69%) Bd infections by environmental factors is a general phenomenon, and that these environmental controls linking natural vegetation to Bd dynamics are similar in tropical and temperate amphibian communities.The best predictors of mate see . The amontensity . A studyBd growth and persistence in both host and the environment, and (ii) by changing host's ability to fight and clear Bd through thermoregulation. The growth rate of Bd in the laboratory is strongly temperature-dependent, with an optimum climatic envelope ranging between 17\u201325\u00b0C and reduced persistence at temperatures above 28\u00b0C Bd growth may have been limited during some periods in our highest-temperature ponds. In fact, in four of our ponds 40.85\u00b114.42% SD of water temperature records were above 25\u00b0C during the study period. Our data closely match the association between Bd infections and temperature found by Raffel et al. Bd infection intensities and prevalence at sites with average water temperatures above 23\u00b0C. In the State of Maine, USA, Bd infections were lower during the peak of the summer than in spring and fall, presumably because water temperatures often exceeded the optimal temperature range for Bd growth Bd-infected frogs were largely absent from sites where spring water exceeded 25\u00b0C Bd strain showed that pathogen growth in vitro is hampered by short exposures to high temperatures that would typically be available to frogs at basking sites Bd infections Bd infection and transmission in open habitats Bd loads Bd infection intensity and frog survival were unrelated to water temperature Microclimate can affect amphibian disease risk in two ways by (i) regulating Bd system are larger than the effects imposed by density-dependent forces that typically predict prevalence and infection intensity in other temperate amphibians Bd infection intensity, potentially indicating density-dependent controls; however, this effect was marginal and capture rate was not a significant predictor of Bd when considered together with environmental factors in model selection. The potential effect of density on Bd was not linked to forest cover because we did not detect a significant effect of natural vegetation on host capture rate. Pathogen build-up to lethal infection intensities is more likely to occur in dense populations, under conditions that promote continuous reinfection of the hosts Our results indicate that the small-scale effects of vegetation and microclimate on our host-Bd susceptibility Bd prevalence and infection intensities. One potential explanation is that disease risk drops with age in response to host-acquired immunity, as repeated exposure to a given pathogen increases host resistance Bd infection intensity when considered independently, this parameter became a weak predictor when considering other environmental variables in the analysis. This weak effect of host body weight on Bd infection coupled with the fact that vegetation cover had no influence on host capture rate is an indication that, in our study system, habitat change has a larger influence on pathogen fitness than on host fitness. This result suggests that our focal species is highly resistant to Bd regardless of microclimate and vegetation. In fact, L. clamitans persists with a local Bd strain in the laboratory within optimal Bd grow temperatures Earlier studies in both tropical and temperate zones have found ontogenetic differences in Bd infections in both temperate and tropical systems Bd epidemics Bd resistance or tolerance could be a useful tool for assisted reintroductions in the wild Bd is most prevalent. With the high rate of anthropogenic modification to temperate and tropical forests, understanding how vegetation cover and disease interact is critical for predicting Bd spread and developing appropriate management tools for wild populations. Our results indicate that species-specific in situ management strategies will need to consider fine-scale microclimatic factors to safeguard Bd-susceptible species with narrow geographic distributions We have shown that disturbances to natural forest habitats reduce Table S1Model selection for environmental and biological variables influencing Batrachochytrium dendrobatidis (Bd) prevalence and infection intensity in populations of Lithobates clamitans in the Adirondack region, New York, USA.(DOCX)Click here for additional data file."} +{"text": "This study intends to develop a physiologic thumbprint for nonconvulsive seizures (NCSz) after acute brain injury. Abnormal electrographic brain activity including NCSz is common after acute brain injury and is associated with poor outcome. Mechanisms underlying this phenomenon are poorly understood but in animals periods of inadequate perfusion during seizures have been documented. In the present study we hope to gain better understanding of the relationship between abnormal electrographic patterns and brain homeostasis in patients with subarachnoid hemorrhage (SAH).2), regional cerebral blood flow (rCBF), and intracranial pressure monitoring; 69% (n = 36) also with intracortical EEG . Each minute of EEG was categorized separately into non-ictal, on the ictal-interictal continuum (including periodic discharges at 2 Hz or faster), or seizures. We identified seizure onsets on ICE recordings and extracted the physiologic monitoring data 30 minutes pre and post seizure onset. Physiologic profiles based on standard error of the means plots were generated using high-frequency time series physiologic measurements and interpreted by visual analysis.Between June 2006 and June 2010, 51 poor-grade SAH patients underwent multimodality monitoring with microdialysis, brain oxygen tension of patients with ICE recordings . NCSz were preceded by an increase in rCBF starting 15 minutes prior to onset of depth NCSz that stayed elevated throughout the observation period. Heart rate, mean arterial, intracranial, and cerebral perfusion pressures were elevated surrounding NCSZ. There was a small transient drop in PbtOThese findings confirm in comatose human beings that NCSz detected by ICE are associated with hyperemia, increased metabolism, and possibly brain tissue hypoxia, which serve as surrogates for secondary brain injury. Future research should implement novel approaches for ICU time-series data analysis, evaluate surface seizures, and utilize other surrogates of brain metabolism such as microdialysis."} +{"text": "Groin infections resulting in arterial bleeding due to bacterial vessel destruction are a severe challenge in vascular surgery. Patients with them most often present as emergencies and therefore need individualized reconstruction solutions.Case 1 is a 67-year-old man with infectious bleeding after an autologous reconstruction of the femoral bifurcation with greater saphenous vein due to infection of a bovine pericard patch after thrombendarterectomy. Case 2 is a 35-year-old male drug addict and had severe femoral bleeding and infection after repeated intravenous and intra-arterial substance abuse. Both patients were treated with an autologous obturator bypass of the superficial femoral vein. We review the current literature and highlight our therapeutic concept of this clinical entity.Treatment should include systemic antibiotic medication, surgical control of the infectious site, revascularization and soft tissue repair. An extra-anatomical obturator bypass with autologous superficial femoral vein should be considered as the safest revascularization procedure in infections caused by highly pathogenic bacteria. Severe groin infections with inguinal blood vessel destruction may be caused by intravenous substance abuse, radiation scars, transfemoral interventions and, most commonly, infection of prosthetic vascular implants (incidence 2% to 18%). ComplicStaphylococcus aureus (MRSA) superinfection of an inguinal lymphatic fistula. For surgical control of bleeding, orthotopic revascularization with iliacofemoral and iliacoprofundal greater saphenous vein interposition and resection of the xenogenic patch material was performed, accompanied by systemic MRSA-specific antibiotic treatment. Three weeks later rebleeding occurred due to an infectious arterial pseudoaneurysm. Intra-operative findings revealed complete erosion of the profundal venous graft anastomosis or severe claudication-7. Witho% or seveThe obturator bypass, with primary patency rates of up to 76% after 2 years, has proven to be feasible in a few small clinical series with a considerable risk of late prosthetic graft infection remaining,3,4,9-11Streptococcus in this report. With proven susceptibility of several native and prosthetic materials to MRSA and rising clinical incidence, femoral vein obturator bypass is the safest revascularization procedure with the best long-term results[To the best of our best knowledge, investigators of only one clinical series have reported the use of obturator bypass fashioned from autologous superficial femoral vein at infection sites. We ther results.Pseudomonas aeruginosa and Group B Streptococcus. It should be considered the primary treatment option by vascular surgeons confronted with this problem, especially in young patients.The extra-anatomic obturator bypass with femoral vein is a safe and feasible revascularization procedure in patients with severe groin infections and highly pathogenic bacteria such as MRSA, Written informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests and did not receive any payment from industrial partners.RK, CB, CT and AB performed surgery on the patients and were responsible for postoperative intensive medicine care. UL performed vascular graft infection studies in mice and was a major contributor in writing the manuscript. All authors read and approved the final manuscript."} +{"text": "This case study followed one adolescent patient who underwent bilateral deep brain stimulation of the centromedian parafascicular complex (CM-Pf) for debilitating, treatment refractory Tourette's syndrome for a period of 1.5 years. Neurocognitive testing showed no significant changes between baseline and follow-up assessments. Psychiatric assessment revealed positive outcomes in overall adaptive functioning and reduction in psychotropic medication load in this patient. Furthermore, despite significant baseline psychiatric comorbidity, this patient reported no suicidal ideation following electrode implantation. Deep brain stimulation is increasingly being used in children and adolescents. This case reports on the positive neurologic and neuropsychiatric outcome of an adolescent male with bilateral CM-Pf stimulation. Tourette syndrome (TS) is a chronic, childhood onset neuropsychiatric disorder, which occurs in approximately one percent of the general population, consists of motor tics and at least one vocal tic lasting longer than one year . Tic symHigh-frequency (above 100\u2009Hz) deep brain stimulation (DBS) is being increasingly used as an efficacious treatment modality in patients with severe TS complicated by behavioral and psychiatric comorbidity that is refractory to first and second line treatment . Here, wA 17-year-old left-handed male with severe Tourette's syndrome, attention deficit hyperactivity disorder (ADHD), and obsessive compulsive disorder (OCD) was evaluated by pediatric neuropsychology and child psychiatry prior to the date of electrode implantation for DBS for treatment of refractory tic symptoms. The patient was treated with bilateral centromedian parafascicular complex (CM-Pf) stimulation and was followed for 1.5 years. Preoperative neuropsychometric testing was noteworthy for borderline general intellectual functioning and commensurate academic achievement . CognitiPreoperative psychiatric evaluation demonstrated severe psychosocial impairment related to treatment refractory Tourette's syndrome. Social impairment was associated with significant amounts of missed school and anxiety related to tics. Attempts to garner employment were hampered with being overwhelmed by his neurologic symptoms. Past psychiatric history was significant for three prior psychiatric hospitalizations, all occurring within the context of managing a complicated psychotropic medication regimen, and treatment approach for comorbid psychiatric conditions . InpatiePostoperative neuropsychometric testing revealed general cognitive functioning that had remained stable across time . The patPostoperative psychiatric evaluation was noteworthy for significant functional and psychosocial gains. No concerns for suicidal or self-injurious thoughts or actions were noted. The patient's psychotropic medication load was also significantly reduced . ImproveThis case report focused on the neurocognitive and psychosocial outcomes in an adolescent male who had received DBS for severe refractory Tourette's syndrome followed for 1.5 years. This patient demonstrated no significant changes in his follow-up psychometric testing and reported significant improvement in psychosocial functioning postoperatively. He was able to decrease his psychotropic medication load during follow-up psychiatric assessments and did not report any suicidal ideation throughout the course of treatment. DBS is being increasingly used for treatment-refractory TS in adults and is an important emerging treatment modality of treatment-refractory TS within the pediatric population . Thus faCase reports documenting long-term treatment outcomes in both adults and adolescents with severe refractory TS using DBS have yielded mixed results with regards to improved psychosocial functioning and overall quality of life. Stimulation of the globus pallidus internus (GPi) was shown to be beneficial in one adolescent boy with severe TS and comorbid OCD and anxiety but had little therapeutic benefit in another patient with similar tic severity, but lacking comorbid psychiatric conditions , 7. AckeIn a larger prospective cohort study, Porta and colleagues documented improvement in tic symptoms, as well as improvement in neuropsychiatric symptoms without cognitive decline in a 24-month followup of 15/18 patients who underwent bilateral thalamic stimulation [Given the ongoing need for awareness of cognitive and psychiatric outcomes in adolescent patients who have undergone DBS treatment, we specifically focused on the neurocognitive and psychosocial outcomes in an adolescent male who had received DBS for severe refractory TS . This ca"} +{"text": "Acute variceal bleeding continues to be associated with significant mortality. Current standard of care combines hemodynamic stabilization, antibiotic prophylaxis, pharmacological agents, and endoscopic treatment. Rescue therapies using balloon tamponade or transjugular intrahepatic portosystemic shunt are implemented when first-line therapy fails. Rescue therapies have many limitations and are contraindicated in some cases. Placement of fully covered self-expandable metallic stent is a promising therapeutic technique that can be used to control bleeding in cases of refractory esophageal bleeding as an alternative to balloon tamponade. These stents can be left in place for as long as two weeks, allowing for improvement in liver function and institution of a more definitive treatment. Acute variceal bleeding continues to be associated with significant mortality. Recently published randomized controlled trials have shown that mortality from acute variceal bleeding has decreased over the past two decades from 42% to 15%, but this figure is still remarkably high [Balloon tamponade (BT) using Sengstaken-Blakemore tube used to be the primary therapy prior to the availability of endoscopic methods. Sengstaken-Blakemore tube, was first described in 1950 , is a muSurgical management for bleeding esophageal varices falls into two categories: shunt and nonshunt procedures. Nonshunt procedures include esophageal transection and gastroesophageal devascularization. Shunt procedure is classified into selective shunts such as splenorenal shunts, partial shunts such as calibrated small-diameter portacaval shunts, and nonselective shunts such as portacaval shunts. Surgical procedures are used less frequently in the era of advanced endoscopic therapy, TIPS, and liver transplant. However, surgical intervention remains an important and effective treatment modality in selected patients . Distal TIPS is an intrahepatic shunt that is placed using a percutaneous approach. It connects the hepatic vein and intrahepatic branch of portal vein using an expandable metallic stent with a diameter of 8 to 12\u2009mm. TIPS was introduced as an alternative to surgery in the 1990s and has replaced surgical shunts in most centers . CurrentThe previously listed limitations of the current rescue therapies have led to the continued search for other methods as rescue therapy for refractory esophageal variceal bleeding.Self-expandable metal stents (SEMSs) are increasingly used in treatment of esophageal obstruction, stricture, leak, perforation, and tracheoesophageal fistula . AnecdotThe initial pilot study by Hubmann et al. in 2006 reported the use of SEMS in 20 patients with massive ongoing esophageal variceal bleeding . All patHubmann et al. published their extended series of 39 patients with massive ongoing esophageal variceal bleeding despite prior use of endoscopic or pharmacological therapy . ResultsWright et al. reported their experience using the SX-Ella Danis stent in ten patients with variceal bleeding and contraindications to TIPS insertion or balloon tamponade . The patDech\u00eane et al. recently reported their experience using SEMS in 8 patients with refractory esophageal variceal bleeding events . One patStandard fully covered SEMSs have also been used successfully for the management of esophageal tears caused by Sengstaken-Blakemore tube or banding. These applications further confirm the important role of SEMS in the successful management of iatrogenic esophageal injuries , 26, 27.Limited data suggests that specially designed SEMS (SX-Ella Danis stent) can effectively stop refractory bleeding from esophageal varices . This stStent placement requires appropriate training and expertise. Gastric varices will not be adequately compressed by the stent and persistent variceal bleeding after stent placement should raise the suspicion for presence of bleeding gastric varices. Appropriate precautions to prevent aspiration are needed since the stent is positioned at the gastroesophageal junction. Distal stent migration into the stomach was observed frequently but was not associated with apparent complications. Stent-related compression of the left main bronchus was reported in one patient and was treated successfully with stent removal , 28. No Current rescue therapies for bleeding esophageal varices are effective in stopping the bleeding in the majority of patients . In some"} +{"text": "Pragmatic trials of treatment pathways can require patient awareness of treatment allocation in order to better represent clinical reality, for example when concordance with a treatment has an important effect on outcome. Conversely, masking of treating clinicians to allocation group can be impossible when full clinical assessment requires knowledge of the current treatments, resources do not permit separate teams for treatment and assessment or when such duplication of clinician contact might affect an outcome such as patient experience.The LiGHT trial is a 718 subject multi-centre 6-year NIHR-funded study of two treatment pathways for glaucoma with outcome measures of health related quality of life and cost effectiveness. We aimed to minimise variation in aspects of clinical behaviour that might introduce bias by affecting either of these outcomes.Custom-written decision support software permits real-time decision-making using analysis of multiple clinical measures made by masked observers: optic disc analysis, visual field assessment and intra-ocular pressure measurements. Treatment targets are objectively defined according to disease severity criteria. Target attainment accounts for known measurement uncertainties.A treatment algorithm based on robust, published criteria determines clinical decisions that influence cost or patient experience .Where objective criteria for clinical decisions exist, it is possible to balance the competing demands of reducing bias with protocol-driven escalation criteria with a pragmatic \u2018real-world\u2019 approach to therapeutic choices permitting variation in clinical practice, in a manner acceptable to clinicians recruiting into an unmasked pragmatic trial."} +{"text": "Picea rubens) populations at high elevation sites in Southern Appalachians to anthropogenic sulfate depositions. Red spruce seedlings are more sensitive to drought and cold stresses elicited by exposure to anthropogenic sulphate air pollution, than old trees. Genetic variation in seedlings and young trees was significantly reduced in heavily polluted stands. Several candidate genes involved in cold acclimation and calcium metabolism demonstrated signatures of selection corresponding with sulfate pollution levels. SNP allele frequencies at one gene involved in calcium metabolism demonstrated directional selection in response to anthropogenic sulfate deposition in red spruce growing at severely polluted high elevation sites, which corresponds well with the putative role of this gene in adaptation to acidification stress. Unlike range-wide experimental designs (e.g. the popular FST outlier test) and nucleotide diversity-based association studies, our within-population testing approach disentangled the confounding effects of geographic variation and demography from the genetic effects of recent selection.Rapid environmental changes, such as anthropogenic air pollution, can create significant evolutionary pressures on populations, species and ecosystems. Evolutionary processes occurring in natural populations at very short time scales, especially in response to human-induced environmental changes, are not well understood. Confounding effects of geographic variation and demography cannot be easily separated from signatures of recent selection in natural populations. We investigated the genetic response of declining red spruce ("} +{"text": "The goal of enhanced nutrition in critically ill patients is to improve outcome by reducing lean tissue wasting. However, such effect has not been proven. This study aimed to assess the effect of early administration of parenteral nutrition (PN) on muscle volume and composition by repeated quantitative computer tomography (qCT).We performed a preplanned substudy of a randomized controlled trial (EPaNIC) that compared early initiation of PN when enteral nutrition was insufficient (early PN) with tolerating a pronounced nutritional deficit for 1 week in the ICU (late PN) [Critical illness evoked substantial loss of femoral muscle volume in 1 week, irrespective of the nutritional regimen. Early PN reduced the quality of the muscle tissue, as reflected by the attenuation, revealing increased intramuscular water/lipid content. Early PN also increased the volume of adipose tissue islets within the femoral muscle compartment. These changes in skeletal muscle integrity correlated with caloric intake. In the abdominal muscle compartments, changes were similar, albeit smaller. Femoral and abdominal subcutaneous adipose tissue compartments were unaffected by disease and nutritional strategy.Early PN did not prevent the pronounced wasting of skeletal muscle observed over the first week of critical illness. Moreover, early PN increased the amount of adipose tissue within the muscle compartments."} +{"text": "Varanus komodoensis). The growth of 400 individual Komodo dragons was measured in a capture-mark-recapture study at ten sites on four islands in eastern Indonesia, from 2002 to 2010. Generalized Additive Mixed Models (GAMMs) and information-theoretic methods were used to examine how growth rates varied with size, age and sex, and across and within islands in relation to site-specific prey availability, lizard population density and inbreeding coefficients. Growth trajectories differed significantly with size and between sexes, indicating different energy allocation tactics and overall costs associated with reproduction. This leads to disparities in maximum body sizes and longevity. Spatial variation in growth was strongly supported by a curvilinear density-dependent growth model with highest growth rates occurring at intermediate population densities. Sex-specific trade-offs in growth underpin key differences in Komodo dragon life-history including evidence for high costs of reproduction in females. Further, inverse density-dependent growth may have profound effects on individual and population level processes that influence the demography of this species.Somatic growth patterns represent a major component of organismal fitness and may vary among sexes and populations due to genetic and environmental processes leading to profound differences in life-history and demography. This study considered the ontogenic, sex-specific and spatial dynamics of somatic growth patterns in ten populations of the world\u2019s largest lizard the Komodo dragon ( Somatic growth patterns represent a major component of an organism\u2019s life-history Sex-specific growth variation must occur to result in sexual size dimorphism (SSD), reflecting different tactics and requirements for energy acquisition and investment between maximum female and male body size Across a species distribution growth rates influencing life history and demography can vary considerably due to an interaction between genetic and environmental regulation Several issues have hindered understanding of the causes of individual growth rate variation in animals, and particularly ectotherms that experience indeterminant growth. First, most growth rate models do not accommodate potential polyphasic growth Varanus komodoensis; 300 cm snout-vent-length and 87 kg body mass). Data were collected from marked individuals from 2002\u20132010, with the aim to evaluate individual, sex-specific and spatial patterns in somatic growth. It was assumed that several energy allocation trade-offs may alter investment in growth in Komodo dragons during life-history changes including distinct transitions in habitat use, sex related growth differences pre- and post-maturation, and aging, that may occur in long-lived apex predators such as this, which have very low mortality due to predation . Each of these phenomena could result in polyphasic growth trajectories involving growth \u201clags\u201d and \u201cspurts\u201d across ontogeny. As this sort of pattern may not be possible to model with the use of standard growth models such as the von Bertalanffy growth function in this species was addressed. Such pronounced SSD must entail different tactics and requirements for energy acquisition and investment The final aim considered spatial variation; looking at differences in ecological, demographic and genetic factors on the islands that may account for differences in growth patterns among sites. Dragon body size varies dramatically between islands, with the presence of dwarf and giant forms in part suggesting spatial variation in growth. For Komodo dragons potential variation in growth could be mediated by differences in prey availability Rusa timorensis), feral pig (Sus scrofa) and water buffalo The Komodo dragon is endemic to five islands in eastern Indonesia, with four island populations in Komodo National Park and several fragmented populations on Flores 2 Komodo Island); Loh Baru (Lba), Loh Buaya (Lbu), Loh Dasami (Lda) and Loh Tongker (Lto) ; and one site on each of the islands of Gili Motang and Nusa Kode . Only two of 1062 marked Komodo dragons moved between any of the sites during the course of the study and hence the ten sites are considered discrete closed populations.To evaluate growth patterns in Komodo dragons, a capture-mark-recapture (CMR) study was undertaken at ten sites on four islands in Komodo National Park , eastern Indonesia , during Dragons were captured in a trapping grid at each site using aluminium box traps and noose poles, and were uniquely marked with passive integrated transponder (PIT) tags . Further details of the capture program are outlined elsewhere Absolute growth rates were calculated from growth records for each individual sampled using snout-vent-length as the dependent variable, and included negative and zero growth rates because animals can shrink in size due to senescence or in response to extreme resource limitation A two-stage statistical modelling approach was used to model somatic growth Size-specific growth rates were modelled as a function of snout-vent-length using a GAMM t- and F-ratio tests The mgcv package Size frequency distributions were constructed for all male and female lizards using the SVL obtained at the first capture event. Using sex-specific age-at-size equations we predicted the mean age for each individual at first capture. To evaluate if male and female size and predicted age distributions differed significantly we performed Kolmogorov-Smirnov tests in program R is) (see methods below for determination of site estimates for each covariate). The four candidate models, including a null model, were fitted again using a GAMM approach in the mgcv package w), considering the strength of evidence that the candidate model is the best model for the data Four competing models were conceived involving three putative covariates; population density, prey availability, and level of inbreeding Faecal counts were conducted annually from 2003\u20132010 (i.e. late dry season) at each site, with faeces of Timor deer and water buffalo counted within circular plots on 150 m transects in each site. Hand-held GPS units were used to locate transect line starting points, and ungulate faeces were counted within 30 sample plots placed at 5 m intervals along each transect. Between 20 and 41 transects were randomly positioned and orientated at each site, providing a total of 308 transects with a total length of 45.50 km. Faecal counts of both species show positive relationships with actual density estimates derived from distance sampling V. komodoensis genetic microsatellite data sampled from eight sites is) were calculated using Genetix 4.01 is values to a frequency distribution of fixation indices obtained after 10,000 permutations of alleles.Estimates of site-specific inbreeding coefficients were obtained predominantly from previously analysed This Research was authorized under successive collaborative research memorandums of understanding (MOU), first (2002\u20132007) between Zoological Society of San Diego, The Nature Conservancy and the Indonesian Department of Forest Protection and Nature Conservation (PHKA), and second (2008\u20132015) under MOUs between the Komodo Survival Program and PHKA. Animal experimental ethics committee approval was obtained from the University of Melbourne (under Permit 0911162.1).Growth measurements were obtained from 400 individually marked Komodo dragons refer to capturedThe estimated size-specific growth function for Komodo dragons was polyphasic with highest growth rate at the juvenile stage , and incComparing the estimated size-specific growth curves of both sexes however,The estimated size-at-age growth curves indicate that males and females are of similar size until \u223c7 years , after wThe estimated age-specific growth function indicateMale and female lizards exhibited significantly different frequency distributions in body size with males exhibiting substantially larger body sizes than females exhibited: distinct sex-based differences in growth trajectories, suggesting altered energy allocation tactics with different life-stages; and spatial variability in growth rates, due to population density-dependent processes.Somatic growth dynamics of individuals and populations can have profound consequences for fitness, life-history and demography In species with indeterminate growth, where females have higher energy costs for reproduction, they must allocate nearly all energy investment from growth to reproduction after maturity ; whereas males may typically invest considerably less to ensure reproductive success increases with body size The largest females tend to be in poor body condition due to extended periods of fasting whilst nest-guarding. Males in comparison appear to live longer presumably aided by lower reproductive costs and an absence of predation conferring higher male survival. A consequence of these sex related differences appears to be large differences in the age of maturity and also maximum longevity estimates . Female Significant variation in mean growth rates was evident among sites and islands . SupportWith size-specific growth variation among sites and islands, it would be worthwhile to detect specific habitats with distinct environmental or genetic differences in dragon growth trajectories that underpin life-history traits such as maximum body size, longevity and vital rates. Vast geographic variation in phenotypic traits are recognised in various intra- and inter-specific studies of sea turtles Our study shows that across ontogeny somatic growth of Komodo dragons is polyphasic in males, yet not in females, as a consequence of differences in energy allocation tactics regarding the onset of reproduction, which also result in an extreme contrast in longevity between sexes. This vast difference in life-span likely has a significant effect on population sex ratios, which in turn could be increasing sexual size dimorphism (SSD) within this species. In future it would be interesting to compare how SSD may vary between populations in regards to demographics and environmental quality Figure S1Mean growth year index as a predictor for growth rate in Komodo dragons. Year index was one covariate in the fitted generalized additive mixed model (GAMM). Dotted lines represent the 95% confidence interval for the fitted values.(TIF)Click here for additional data file.Figure S2Spatial variation in growth rates in Komodo dragons. Mean growth rates (cm SVL/yr) for each site indicate spatial variation in growth among sites and islands. Error bars are standard errors of site mean growth rates.(TIF)Click here for additional data file.Methods S1(DOCX)Click here for additional data file.Methods S2Methods & Results.(DOCX)Click here for additional data file.Table S1(DOCX)Click here for additional data file.Table S2(DOCX)Click here for additional data file."} +{"text": "Dear Editor,The study named \u201cThe role of myocardial perfusion gated SPECT study in women with coronary artery disease\u201d reveals some current and important issues in diagnosing myocardial ischemia in women . BecauseOn the other hand the evaluation criterion for diagnosing ischemia seems controversial in the study. The question is that: \u201cDo the left ventricular (LV) wall motion abnormality and decreased systolic thickening at the segment with reduced perfusion in gated SPECT study necessarily show true ischemia as it is expressed in the study?This approach considers that wall motion abnormality and perfusion defects occur exactly at the same time in CAD stages, but as it is known, wall motion abnormalities follow quite a bit later after the perfusion defects appear. Myocardial hypoperfusion is first seen in ischemic cascade, and followed by decrease in metabolic activity, relaxation impairment (diastolic dysfunction), reduction in contractility (systolic dysfunction), global LV dysfunction, ECG changes and angina pectoris, respectively . So, theMore importantly, because the imaging begins 30-60 minutes after the radiopharmaceutical injection, stress\u2013gated images with Tc-99m MIBI show stress perfusion at the time of injection, but LV function at the time of acquisition. Snapper et al. demonstrated that the combination of a perfusion defect with normal wall motion and thickening in the same segment on stress-gated MIBI images was associated with a high positive predictive value (96%) for detecting ischemia. They concluded that the diagnosis of ischemia could be made confidently in patients with normal wall thickening in a segment with perfusion defect. The lack of wall thickening was found less specific, because only 40% of the cases with perfusion defects and wall motion abnormalities showed reversibility on rest perfusion imaging . Thus, tFinally, the criterion mentioned in the study could be entirely true and supporting if all the subjects had been shown to have reversible defect (ischemia), but some patients are reported to have myocardial infarction. So the criterion might include myocardial scar in patients with fix defect (particularly when the presence of metabolic activation on the defect related with hibernation was excluded). In the routine evaluation of gated SPECT studies, wall motion abnormality and/or systolic thickening at the same segment with fixed defect primarily indicates myocardial scar. So, the inclusion criterion that the authors used in the study constitutes a great limitation for drawing true conclusions about ischemia and/or infarct without making some comparisons between post-stress and rest end-systolic and end-diastolic volumes or measuring LVEF differences together with the wall motion abnormalities.The evaluation criteria to differentiate ischemia, infarct and soft tissue attenuation artifacts in stress-rest gated SPECT imaging may be simply summarized as below:1. Normal perfusion with no wall motion abnormality or TID: Normal2. Normal perfusion with wall motion abnormality or TID: Stunning (and/or multivessel disease?).3. Reversible ischemia with no wall motion abnormality, TID or reduced LVEF in stress-gated images: Ischemia.4. Reversible ischemia with wall motion abnormality, TID or reduced LVEF in stress-gated images: Severe ischemia with increased cardiac event rate.5. Fixed defect with normal wall motion or wall thickening: Soft tissue attenuation artifact.6. Fixed defect with wall motion or wall thickening abnormality: Myocardial scar."} +{"text": "Cryopreservation and transplantation of ovarian tissue is one option for re-establishing ovarian function, but optimal conditions for graft sustainment and follicular survival are still considered experimental. The present study aims to analyze the effect of FSH treatment on the resting follicle pool in fresh and cryopreserved primate ovarian tissues following xenografting.Ovarian tissues from adult marmosets were grafted freshly or following cryopreservation to ovarectomized nude mice treated with FSH 25 IU twice daily post transplantation or left untreated as controls. Grafts were retrieved 2 or 4 weeks after transplantation to evaluate the number and morphological appearance of follicles.Early start of FSH treatment within 1 week following transplantation partly prevents primordial follicle loss in fresh and frozen-thawed tissues, whereas after a 3 weeks time interval this effect is present only in fresh tissues. A similar positive effect of early, but not later FSH treatment on primary follicles is seen in fresh tissues compared to only marginal effects in frozen-thawed tissues. The percentage of morphologically normal follicles is generally increased in FSH treated tissues, whereas the percentage of primary follicles over all primordial and primary follicles is increased by FSH only in freshly-grafted tissues.FSH treatment alleviates depletion of the resting follicle pool and promotes normal follicular morphology both in freshly and frozen-thawed grafted tissues. In previously cryopreserved tissues, applying to most of the tissues intended for clinical use in fertility preservation attempts, its positive effect on primordial follicle numbers and potential graft sustainment is dependent on an early start of treatment within one week of transplantation. Increasing cancer survival rates and awareness of fertility as a quality of life issue in long-term cancer survivors have fuelled the growing demand for fertility preservation in recent years . In femain vitro study has confirmed equal effectiveness of human recombinant FSH compared to marmoset FSH on the marmoset FSH receptor . Grafting duration has no influence on mean primordial follicle numbers compared to untreated tissues but not at 4 weeks and frozen-thawed (29.9+/\u22122.9%) ovarian tissues. In freshly grafted tissues, these proportions decrease significantly after transplantation and then remain stable over time , but not FSH-treated tissues (p=0.411; Figure\u2009The size of the resting follicle pool determines the ovarian reserve of an individual and correlates with graft sustainment after restoration of fertility by ovarian tissue cryopreservation and transplantation. Assessment of ovarian reserve following ovarian tissue transplantation is challenging when using established markers and indicates high variability between patients . Besidesnd week of transplantation. In freshly but not in frozen-thawed grafted tissues, a positive effect of FSH treatment on primordial follicle number was also observed if the start of treatment was postponed to 3 weeks post transplantation. As we have previously documented in the marmoset [in vitro co-culture system had previously been described for other non-human primates [Enhanced follicular depletion through FSH effects during ovarian stimulation has anecdotally been reported in the human , but conmarmoset , and othmarmoset ,33,34, cprimates . In humaprimates , thus enprimates , and forprimates , suggestWhen started after a prolonged grafting period of frozen tissues, FSH negatively influences primordial follicle numbers that are already low and most likely at this point reflect manifestation of preceding tissue damages due to cryopreservation. Since primary follicle numbers are increased in these tissues, the reduction in the primordial follicle pool may additionally mirror the beginning of follicular recruitment becoming apparent in already low primordial follicle numbers. However in fresh tissues, baseline values of follicle numbers are higher also after a prolonged grafting period, and FSH treatment following early or at a later point in time after transplantation prevents primordial follicle loss. This is in agreement with viability studies on fresh and frozen ovarian tissue resulting in significantly reduced viability when applying a slow-freezing protocol .per se on follicle pool dynamics and primary follicle activation in adult and prepubertal ovarian tissues [Proportional analysis of primary and primordial follicle number can indicate initiation of follicular growth, and for xenografted human ovarian tissue the influence of cryopreservation and timi tissues . This co tissues . As the FSH treatment alleviates depletion of the resting follicle pool and promotes normal follicular morphology both in freshly and frozen-thawed grafted tissues. In previously cryopreserved tissues, applying to most of the tissues intended for clinical use in fertility preservation attempts, its positive effect on primordial follicle numbers and potential graft sustainment is dependent on an early start of treatment within one week of transplantation. Whereas in fresh tissues FSH treatment following xenografting results in a higher percentage of primary over all un-advanced follicles, this appears to be largely independent of FSH in frozen-thawed tissues.All authors declare that they have no competing interests.VVS and BS designed the study, analyzed and interpreted the results and drafted the manuscript. RC performed the experiments and analyzed the results. EN and LK participated in the study design, helped in the acquisition of funding and critically reviewed the manuscript. RO helped to perform statistical analysis and with the drafting of the manuscript. All authors read and approved the final manuscript."} +{"text": "Duchenne muscular dystrophy (DMD) is a severe, progressive muscle-wasting disorder, while Becker muscular dystrophy (BMD) is milder muscle disease . Both arThe exon skipping approach uses antisense oligonucleotides (AONs) to induce skipping of targeted exons during pre-mRNA splicing, with the aim of reading frame restoration, converting of the severe DMD into the milder BMD phenotype . This apAfter promising results in cultured cells and animal models where AON treatment allowed in dystrophin restoration (reviewed in ), a firsTowards systemic application, studies in animal models revealed that dystrophic muscles facilitated uptake of 2OMePS AONs and that subcutaneous delivery was feasible . In a suIn parallel, preclinical studies to further optimise treatment regimens are in progress as well as clinical trials for additional exons for exon 44 skipping . Trials are planned for exon 45 and 53 skipping .The mutation specificity of the approach poses challenges to drug development regulations. A concerted effort of academic researchers, industry, regulators and patients is needed to adapt regulations to enable application of these personalised medicine approaches to rare diseases."} +{"text": "Olfactory dysfunction develops in many neurodegenerative diseases, and is an early feature of the most common neurodegenerative disorder, Alzheimer's disease (AD).Here we compared olfactory function prospectively in cohorts of patents with PCA and typical AD (tAD). Neuroanatomical associations of odour identification were assessed using voxel-based morphometry (VBM). We hypothesised that PCA would be associated with olfactory impairment qualitatively similar to tAD, but less severe ; and that deficits of odour identification in both syndromes correlate with grey matter loss in anteromedial temporal and inferior frontal lobes.6\u201310Fifteen patients fulfilling consensus criteria for PCA,supplementary table S1). Further details about the behavioural assessments are in online supplementary material.All subjects had a comprehensive general neuropsychological assessment which corroborated the clinical impression in both disease groups (see online supplementary table S2) before identifying it; and target-foil choices were name-picture combinations rather than odour names alone, to maximise available response cues. Group differences were assessed using analysis of variance (ANOVA) or \u03c72 tests (Stata V.12.1), adjusting for cognitive severity, verbal processing measures, age and gender.Olfactory processing was assessed using the 40-item, four-alternative-forced-choice University of Pennsylvania Smell Identification Test (UPSIT: British version).http://www.fil.ion.ucl.ac.uk/spm) following previously described procedures . Linear regression was used to examine voxel-wise associations between regional grey matter volume and odour identification performance (age-normed and gender-normed percentile score) across the combined patient cohort, within the PCA subgroup, and between syndromic subgroups, incorporating syndromic group, mini-mental state examination (MMSE) score and total intracranial volume as covariates. Statistical parametric maps were assessed thresholded over the whole brain volume and after multiple-comparisons correction over small volumes of interest specified in our prior anatomical hypotheses.Twelve patients with PCA and eight patients with tAD had T1-weighted volumetric magnetic resonance (MR) brain images acquired on a 3.0T Siemens Trio scanner. VBM was performed using SPM8 . Based on published UPSIT norms,supplementary table S1). An error analysis of individual odour items in the identification test revealed a qualitatively similar profile of errors across all groups (see online supplementary figure S2).For both patient groups, mean odour categorisation and identification raw scores were significantly lower than the HC group . Across the combined patient cohort, performance on the odour identification task was positively associated with regional grey matter volume in right entorhinal cortex and parahippocampal gyrus . At a more lenient threshold (p<0.001 uncorrected over the whole brain volume), additional associations were present in more distributed, predominantly right-sided cerebral areas, including hippocampus, posterior inferior temporal gyrus/sulcus, temporo-parieto-occipital junction and premotor cortex (see online supplementary table S3). Similar grey matter associations of odour identification performance were identified for the PCA subgroup alone . Direct comparison between the PCA and tAD subgroups revealed no significant between-group differences in regional grey matter correlations of olfactory performance.Statistical parametric maps of significant regional grey matter associations of odour identification performance are displayed in Here we have demonstrated deficits of odour identification and categorisation in patients with PCA relative to HCs. A similar proportion around 30%) of patients with PCA and tAD in this study had an absolute deficit of odour identification referenced to published age and gender norms and taking account of associated cognitive impairment. Olfactory impairment was similar quantitatively and qualitatively in the PCA and tAD groups. To the extent that PCA manifests underlying AD, the findings imply that olfactory impairment is a hallmark of AD pathology. It is noteworthy that only a minority of patients in both phenotypical groups here reported olfactory symptoms, suggesting that in many cases olfactory impairment is \u2018subclinical\u2019. Mean corrected odour identification scores were higher than categorisation scores in the HC and PCA groups: this unexpected finding might hold clues to the cognitive organisation of olfactory knowledge or the cognitive strategies engaged by these tests, and would warrant further study in larger populations. Odour identification tasks tend to be cognitively demanding and therefore potentially susceptible to executive and attentional deficits that accompany AD.0% of pat13The deficit of odour identification identified here was associated with regional grey matter volume in a cerebral network focussed on the right anteromedial temporal lobe. The most robust neuroanatomical associations occurred in parahippocampal gyrus and entorhinal cortex: areas linked to odour identification in healthy human subjects.This study has several limitations that suggest directions for future work. We did not assess perceptual encoding of odours: it will be important to compare associative and perceptual olfactory functions directly, to assess the extent to which these different factors contribute to olfactory impairment in AD. The patient groups studied here were relatively small: there is a need to extend the work to larger patient cohorts spanning other AD phenotypes and in direct comparison with other neurodegenerative pathologies."} +{"text": "After publication of our work , we notiThe authors declare no competing interests.JL and DM designed research; JL carried out phylogenetic analyses, and JL and DM wrote the manuscript. Both authors read and approved the final version."} +{"text": "Microscopic Colitis (MC) is characterized by chronic watery diarrhea, grossly normal appearing colonic mucosa during conventional white light endoscopy, and biopsy showing microscopic inflammation. We report a case of collagenous colitis with gross endoscopic findings. A 71-year-old female with past medical history of coronary artery disease, carotid artery disease, hypertension, and diabetes mellitus type 2 was being evaluated for recurrent intermittent diarrhea. Patient denied any abdominal pain, weight loss, or any blood in stool. Patient was not on any medications and lab work was within normal limits. Colonoscopy was required to further evaluate patient's diarrhea. Colonoscopy revealed multiple scattered segments throughout the colon with increased nodularity and loss of vascular markings in the hepatic flexure, descending colon and cecum Figures . These fMicroscopic examination showed lymphocytic colitis with marked thickening of the superficial collagen table consistent with collagenous colitis. The submucosal collagen was dense and paucicellular with several entrapped lymphocytes and capillaries (red arrow). The lamina propria displays an increase in eosinophils, plasma cells, and lymphocytes (black arrow) .Microscopic Colitis (MC) is characterized by chronic watery diarrhea, grossly normal appearing colonic mucosa during conventional white light endoscopy, and biopsy showing microscopic inflammation. It accounts for 4%\u201313% of patients evaluated for chronic diarrhea and divided into lymphocytic and collagenous colitis . CertainAlthough identical clinically, both types of colitis have distinct microscopic findings. Lymphocytic colitis is characterized by intraepithelial lymphocytosis while collagenous colitis is diagnosed by thickening of subepithelial collagen layer of more than 10 micrometer [By definition colonic mucosa has a normal appearance in MC. Yet distinct endoscopic findings, particularly for collagenous colitis, have been described in the literature. These findings include alteration of mucosal vascular pattern, mucosal abnormalities such as red spots, increased mucosal nodularity, or textural alteration, and pseudomembranes . Recent advance in endoscopy may enhance the ability to detect MC. A newly developed post processing light filters such as i-Scan helps to enhance the visualization of mucosal pattern and vascular architecture. Chromoendoscopy using indigocarmine dye sprays may show a mosaic pattern of mucosa in lymphocytic colitis and a nodular, grooved pattern in collagenous colitis . These nMicroscopic Colitis is traditionally known to have normal colonic mucosa on endoscopy. Recent advance in endoscopic techniques has shown that various mucosal abnormalities such as alteration of mucosal vascular pattern and increased mucosal nodularity are associated with MC. These newer techniques will allow us to get targeted biopsy, which will increase the yield of endoscopic diagnosis of MC."} +{"text": "Borrelia burgdorferi infection. Little has been published in the medical literature about patients with chronic Lyme disease or their relationships with healthcare providers. The objective of this study was to gain insights into the health beliefs and experiences of patients with chronic Lyme disease.Chronic Lyme disease is a term that describes a constellation of persistent symptoms in patients who may or may not have serologic evidence of This was a qualitative, descriptive study in which face-to-face in-depth interviews were conducted with patients who were diagnosed with or self-identify as having chronic Lyme disease. Patients were recruited through Connecticut-based Lyme disease mailing lists and support groups. A coding structure was developed using an iterative process. Transcribed interviews were coded using Atlas.ti software and analyzed for emergent topics and themes. Interviews were conducted until thematic saturation was achieved.A total of 12 interviews were conducted. Four major themes emerged. Patients reported: (1) diminished health status associated with chronic Lyme disease; (2) concerns about persistence of symptoms ; (3) two divergent types of physician-patient relationships ; and (4) seeking and receiving unconventional care .Our findings show that patients report a marked decrease in health status associated with chronic Lyme disease and are often unsatisfied with care in conventional settings. Negative experiences with providers were associated with reports of dismissive, patronizing, or condescending attitudes. Positive experiences were associated with providers reported to be attentive, optimistic, and supportive. Patient-centered approaches that acknowledge suffering and focus on continuity of care and symptomatic relief may result in increased patient satisfaction."} +{"text": "Increasing the use of pharmacotherapies for alcohol dependence has the potential to improve patient outcomes and reduce health-care costs by reducing hospital admissions. This randomized controlled trial (RCT) evaluated the cost-effectiveness of tailored mailed feedback on general practitioner (GP) prescribing for alcohol dependence and alcohol-related hospital admissions. General practitioners (N = 115) in 10 communities randomized to the experimental arm of the Alcohol Action in Rural Communities (AARC) project received tailored mailed feedback on their prescribing of acamprosate and naltrexone. Segmented regression analysis examined the impact of the intervention relative to GPs\u2019 prescribing and inpatient hospital admissions for alcohol dependence in those communities. Incremental cost-effectiveness ratios were estimated to compare costs per additional prescription written and costs per inpatient admission averted. Trend analysis showed GPs significantly increased their prescribing of acamprosate and significantly decreased their prescribing of naltrexone . Rates of alcohol-related inpatient admissions for alcohol dependence decreased significantly in the experimental group compared with the control group . Similar to evidence showing SBI can improve patient outcomes, this study showed mailed tailored feedback to GPs achieved cost-effective increases in their prescribing of acamprosate, with a subsequent and plausibly causal reduction in inpatient hospital admissions for alcohol dependence. Demonstrating the capacity of brief intervention in primary-care settings to reduce demand for tertiary care services appears to be a promising direction for the SBI field. A large-scale RCT of the cost benefit of tailored feedback to GPs appears warranted."} +{"text": "We used ecologic niche modeling of outbreaks and sporadic cases of filovirus-associated hemorrhagic fever (HF) to provide a large-scale perspective on the geographic and ecologic distributions of Ebola and Marburg viruses. We predicted that filovirus would occur across the Afrotropics: Ebola HF in the humid rain forests of central and western Africa, and Marburg HF in the drier and more open areas of central and eastern Africa. Most of the predicted geographic extent of Ebola HF has been observed; Marburg HF has the potential to occur farther south and east. Ecologic conditions appropriate for Ebola HF are also present in Southeast Asia and the Philippines, where Ebola Reston is hypothesized to be distributed. This first large-scale ecologic analysis provides a framework for a more informed search for taxa that could constitute the natural reservoir for this virus family. Mononegavirales, family Filoviridae) are unknown potential reservoirs, including bats, rodents, arthropods, and plants to the nearest 0.001\u00b0. Although assigned geographic coordinates may not fix the exposure point precisely, they represent our best guess as to its position and are likely to be representative of the coarse-scale ecologic conditions. Distributional data for filovirus-associated HF occurrences in hominids were accumulated from the literature . Occurrehttp://www.lifemapper.org/desktopgarp/). In general, GARP focuses on modeling ecologic niches (the conjunction of ecologic conditions wherein a species can maintain populations without immigration) Ecologic niches and potential geographic distributions were modeled by using the Genetic Algorithm for Rule-set Prediction (GARP) (Occurrence points are divided evenly into training (for model building) and test datasets. GARP works in an iterative process of rule selection, evaluation, testing, and incorporation or rejection: a method is chosen from a set of possibilities and applied to the training data to develop or evolve a rule. Predictive accuracy is evaluated on the basis of the test data. Rules may evolve in ways that mimic DNA evolution . Change in predictive accuracy between iterations is used to evaluate whether particular rules should be incorporated into the model; the algorithm runs 1,000 iterations or until convergence. Model quality was evaluated through independent test dataset reserved prior to modeling; a chi-square test was used to compare observed success in predicting the distribution of test points with that expected under a random model .http://edcdaac.usgs.gov/gtopo30/hydro/), and climate characteristics, including daily temperature range; mean annual precipitation; maximum, minimum, and mean annual temperatures; solar radiation; frost days; wet days; and vapor pressure . These coverages are worldwide and provide a consistent view of ecologic variation across regions studied. GARP\u2019s predictive ability has been tested under diverse circumstances . The resulting dataset represents unique combinations of environments and predictions; its attributes table provides the model prediction for all environmental combinations to permit visualization of ecologic variation. We also compared ecologic conditions inside and outside of the modeled Ebola HF distribution within 11 regularly spaced circular windows (radius 50 km); comparisons were summarized through Mann-Whitney U-statistics, permitting a nonparametric visualization of the strength of association of each ecologic dimension with the range limit.-7). Although subsequent modeling was done without subsetting to maximize occurrence data, these preliminary results nonetheless indicated excellent predictivity of our distributional hypoptheses. The geographic distribution of filovirus disease spreads generally across the humid Afrotropics A. OutlieFiloviridae in general , a complementary distributional area was predicted D. Marbur Sequential omission of Ebola virus species from analyses provided a view of ecologic similarity of species Inspection of niche models of Ebola HF occurrences (Marburg HF excluded) in ecologic space provided Distributional limits are complex results of multiple causal agents. A species is seldom limited on all sides by a single factor; rather, distributional limits are the combined result of many such factors. Inspection of the ecologic dimensions coincident with modeled geographic limits of Ebola HF occurrences showed s Given the mysterious origin of Ebola Reston virus A. ProjecThe ecologic niche characteristics reconstructed for filovirus species disease outbreaks coincided closely with phylogenetic patterns in the group , GARP predictions will be overly large. Jackknife manipulations (systematic omission of ecologic dimensions to assess sensitivity to coverage density) can, to some degree, help in assessing sensitivity to coverage completeness Detailed understanding of the geography and ecology of filovirus HF outbreaks represents an underexplored avenue of investigation regarding natural transmission cycles of filoviruses. We assembled available information regarding filovirus HF outbreaks and used various analytical tools to arrive at a detailed understanding of geography and ecology of filovirus disease occurrences. Consequently, we can now assemble criteria by which potential reservoir taxa might be judged. If one assumes a fair degree of host specificity in this host-parasite system, patterns of codistribution and cophylogeny can be expected. Hence, criteria include the following: 1) African Ebola virus reservoirs would be distributed principally in evergreen broadleaf forest; 2) the main focus of the geographic distribution of the reservoir(s) would be in the Congo Basin; 3) a disjunct distributional area would be present in West Africa; 4) a related taxon in eastern Africa would range in more arid habitats; 5) the reservoir would belong to a clade more broadly distributed across Africa and Southeast Asia. Assessment of potential reservoir taxa by using these criteria has begun , with the idea of eventually testing hypotheses of host associations through ecologic niche comparison methods"} +{"text": "Most pathogenesis studies focus on pathogen virulence attributes that mediate host colonization, toxicity, or immune evasion. Some studies focus on how pathogens employ active mechanisms to acquire essential nutrients such as iron and vitamins from the host by producing siderophores or avidins. In order to prevent pathogen nutrient acquisition, host cells employ a process called nutritional immunity to sequester these nutrients, particularly iron, from invading pathogens How and where do intracellular pathogens obtain sufficient amounts of energy and nutrients to support their replication? Pathogens may either parasitize existing energy stores or manipulate the host cell to create usable energy and anabolic precursor metabolites. Several recent studies have identified the host AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) kinases as two important regulators of cellular metabolism whose activities are often altered during infection. However, the AMPK/mTOR pathway also regulates autophagy, which can destroy cytosolic pathogens. While the evasion of autophagy by pathogens is well appreciated, recent work suggests that both the AMPK/mTOR pathway and autophagy itself can provide intracellular metabolites that support intracellular pathogen replication.During times of limited nutrient availability, intracellular ATP levels fall, with a corresponding increase in AMP levels. Within eukaryotic cells the increased AMP\u2236ATP ratio induces AMPK activity, which in turn initiates a series of signaling events that stimulate energy and nutrient acquisition In order to achieve optimal levels of proliferation, many pathogens must manipulate activity of AMPK and mTOR. Interestingly, several viral pathogens have evolved strategies that allow for the induction of both AMPK and mTOR activity. For example, infection with human cytomegalovirus (HCMV) increases both AMPK and mTOR activity Simian virus 40 (SV40) infection also stimulates both AMPK and mTOR activity. SV40 small T antigen is both necessary and sufficient for AMPK activation Mycobacterium tuberculosis and Chlamydia trachomatis utilize fatty acids derived from lipid droplets Enveloped viruses require host lipids to generate the virion membrane. Activated mTOR stimulates fatty acid and lipid synthesis, and therefore could prove beneficial for virus assembly. In fact, host lipid metabolism is essential for the hepatitis C virus (HCV) life cycle and is highly regulated during infection AMPK activation also inhibits the replication of several arboviruses, including Rift Valley fever virus (RVFV) Leishmania donovani amastigotes (the parasitic form that grows inside macrophages) preferentially generate energy through fatty acid oxidation and amino acid catabolism L. donovani acquires fatty acids and amino acids from the infected host cell. Consistent with this finding, transcriptomic analysis of macrophages infected with the related parasite Leishmania major suggests that infected cells increase glucose transport, glycolysis, and starch degradation Leishmania alters host metabolic processes, a reasonable hypothesis is that intracellular Leishmania activates AMPK to benefit parasite replication. Activated AMPK could stimulate increased glucose utilization and autophagy, thus creating elevated levels of anabolic precursor pools for parasite growth. Parasite replication requires the Leishmania protein GP63, which cleaves and inactivates mTOR to reduce type I interferon production, thus AMPK activation could further benefit parasite replication by inhibiting mTOR It takes a lot of energy to make hundreds, thousands, or potentially millions of new parasites, bacteria, or viruses. It seems logical that intracellular pathogens that undergo significant intracellular growth would activate AMPK due to the energetic demands placed on the infected cell. Activation of AMPK could provide several benefits for intracellular pathogens. The increased glucose uptake, glycolysis, and fatty acid breakdown would increase available intracellular energy and nutrient pools needed for pathogen replication. For example, Francisella tularensis growth is impaired in autophagy-deficient host cells. Bacterial growth was restored in autophagy-deficient cells by supplying the infected cells with excess pyruvate or amino acids. Since F. tularensis replicates within the cytosol of host cells, our results suggest that intracellular F. tularensis uses autophagy to increase cytosolic nutrient pools that support bacterial growth F. tularensis avoids engulfment by classical autophagosomes Autophagy is an essential cellular process that recycles cellular constituents from macromolecular complexes under conditions of nutrient stress. As discussed above, autophagy is positively regulated by AMPK and negatively regulated by mTOR. However, autophagy also functions as a host defense mechanism that destroys intracellular pathogens through a process termed xenophagy. While generally viewed as detrimental for intracellular pathogens, some bacteria and viruses use autophagosomes as a replicative niche AMPK and mTOR are critical regulators of host cell metabolism making them logical targets for manipulation by invading pathogens. The energetic burden of the host cell to create hundreds or more pathogens should deplete cellular ATP levels, thus activating AMPK. AMPK induction stimulates host processes to produce energy and nutrients that the pathogen could then steal from the host. This idea suggests AMPK activation may be a common theme among infection by successful intracellular pathogens. On the other hand, mTOR signaling stimulates protein and lipid synthesis, which could be beneficial for many viral pathogens; whereas mTOR modulation is likely less important for free-living bacteria pathogens and parasites that supply their own biosynthetic and translation machinery. Identifying what nutrient sources are required for intracellular growth and how host metabolic signaling is manipulated by infection is being investigated in viral pathogenesis, yet remains poorly understood in bacterial and parasitic pathogenesis.Manipulating host metabolism is an attractive approach to controlling infection as targeting the host rather than the pathogen should considerably reduce the ability of pathogens to develop drug resistance. Several drugs already in clinical use target the AMPK or mTOR kinases to treat diseases such as cancer and diabetes. The studies described above suggest that these drugs may have additional uses in treating infections with intracellular pathogens. As our understanding of pathogen manipulation of host metabolism grows, it may also be possible to develop inhibitors of specific host metabolic pathways hijacked by intracellular pathogens. Identifying the essential nutrients required for intracellular pathogen proliferation and the host pathways manipulated to acquire these nutrients will be a significant step in understanding the requirements for viral, bacterial, and parasitic pathogenesis and identifying new targets for novel therapeutics."} +{"text": "Poecilia parae, a colour polymorphic fish, exhibit five distinct phenotypes: drab-coloured (immaculata), striped (parae), structural-coloured (blue) and carotenoid-based red and yellow morphs. Previous work indicates that immaculata males employ a sneaker strategy, whereas the red and yellow morphs exploit female preferences for carotenoid-based colours. Mating strategies favouring the maintenance of the other morphs remain to be determined. Here, we report the role of agonistic male-male interactions in influencing female mating preferences and male mating success, and in facilitating the evolution of AMSs.Intense competition for access to females can lead to males exploiting different components of sexual selection, and result in the evolution of alternative mating strategies (AMSs). Males of P. parae morphs during indirect and direct interactions with sexually receptive females. Two morphs, parae and yellow, use aggression to enhance their mating success by 1) directly monopolizing access to females, and 2) modifying female preferences after winning agonistic encounters. Conversely, we found that the success of the drab-coloured immaculata morph, which specializes in a sneak copulation strategy, relies in its ability to circumvent both male aggression and female choice when facing all but yellow males.Our study reveals variation in aggressiveness among Strong directional selection is expected to deplete genetic variation, yet many species show striking genetically-based polymorphisms. Most studies evoke frequency dependent selection to explain the persistence of such variation. Consistent with a growing body of evidence, our findings suggest that a complex form of balancing selection may alternatively explain the evolution and maintenance of AMSs in a colour polymorphic fish. In particular, this study demonstrates that intrasexual competition results in phenotypically distinct males exhibiting clear differences in their levels of aggression to exclude potential sexual rivals. By being dominant, the more aggressive males are able to circumvent female mating preferences for attractive males, whereas another male type incorporates subordinate behaviours that allow them to circumvent male aggression and female mating preferences. Together, these and previous results indicate that exploiting different aspects of social interactions may allow males to evolve distinct mating strategies and thus the long term maintenance of polymorphisms within populations. Intense sexual selection can lead to competing males evolving alternative ways to obtain fertilizations, thereby enhancing their reproductive success . In geneUta stansburiana), males have evolved AMSs and the relative fitness of each strategy fluctuates depending on the frequency of the competing strategies from one generation to the next )A and MB representing total proportion of time spent with male A or B, respectively, positive values of this index (MA - MB) would indicate a preference for male A and negative values a preference for male B. To determine whether there was a switch in female mating preferences after observing male-male interactions, we subtracted the post-male competition preference score from the pre-male competition preference score . We determined if females switched or enhanced their mate preferences between trials using a paired t-test. Preference scores were arcsine transformed to meet the assumptions of parametric tests into two categories: aggressions received and initiated. Both categories (aggressions received and initiated) were analysed using Kruskal-Wallis non-parametric ANOVAs. To determine which morphs were attacked less and attacked more, we ran multiple comparisons of mean ranks. We also performed Kruskal-Wallis non-parametric ANOVAs and multiple comparisons of mean ranks to analyse aggressions received and initiated during the open aquarium experiments. To compare whether there were differences in the number of attacks performed by males during direct and indirect interactions with females, we used a Mann-Whitney test. Finally, the difference in number of gained or lost copulations to the competitors was analysed with Wilcoxon matched pair tests. All data sets were tested for normality and analysed with STATISTICAJLHG conceived the study, carried out the experiments, analysed the results and drafted the manuscript in partial fulfilment of a doctoral degree at Syracuse University, New York (USA). JACU contributed to the study design, supervised the study, edited and revised the manuscript critically. Both authors have read and approved the final manuscript.This file includes: Table A1 with additional information of the standard body lengths (mm) of males used during the experiments. Table A2 presents a brief description of aggressive behaviours commonly displayed by males of Poecilia parae. Figure A1 presents a simplified view of the experimental settings.Click here for file"} +{"text": "In this article, we review studies of astrocytic-neuronal interactions and their effects on the activity of oxytocin (OXT) neurons within the magnocellular hypothalamo-neurohypophysial system. Previous work over several decades has shown that withdrawal of astrocyte processes increases OXT neuron excitability in the hypothalamic supraoptic nucleus (SON) during lactation. However, chronically disabling astrocyte withdrawal does not significantly affect the functioning of OXT neurons during suckling. Nevertheless, acute changes in a cytoskeletal element of astrocytes, glial fibrillary acidic protein (GFAP), occur in concert with changes in OXT neuronal activity during suckling. Here, we compare these changes in GFAP and related proteins with chronic changes that persist throughout lactation. During lactation, a decrease in GFAP levels accompanies retraction of astrocyte processes surrounding OXT neurons in the SON, resulting from high extracellular levels of OXT. During the initial stage of suckling, acute increases in OXT levels further strengthen this GFAP reduction and facilitate the retraction of astrocyte processes. This change, in turn, facilitates burst discharges of OXT neurons and leads to a transient increase in excitatory neurochemicals. This transient neurochemical surge acts to reverse GFAP expression and results in postburst inhibition of OXT neurons. The acute changes in astrocyte GFAP levels seen during suckling likely recur periodically, accompanied by rhythmic changes in glutamate metabolism, water transport, gliotransmitter release, and spatial relationships between astrocytes and OXT neurons. In the neurohypophysis, astrocyte retraction and reversal with accompanying GFAP plasticity also likely occur during lactation and suckling, which facilitates OXT release coordinated with its action in the SON. These studies of the dynamic interactions that occur between astrocytes and OXT neurons mediated by GFAP extend our understanding of astrocyte functions within the central nervous system."} +{"text": "The emergence of spontaneous bursting events in developing neuronal networks likely depends on the evolving network connectivity. Theoretical models have shown that hierarchical network structures embedding clusters of strongly inter-connected neurons are optimal for initiating and sustaining spontaneous activity . It is cTo test this we chronically manipulated activity-dependent structural plasticity by inhibition of protein kinase C (PKC) in developing networks of cortical neurons in vitro. Previous studies showed that PKC inhibition in developing cerebellum promotes dendritic outgrowth and arborization of Purkinje cells and impairs pruning of climbing fibers. We found that developmental inhibition of PKC in cortical cell cultures increased dendritic outgrowth, impaired neurite fasciculation and clustering and abolished network pruning. This resulted in more homogeneous and potentially better connected networks fig. . As a re"} +{"text": "This study investigated procedural errors made during root canal preparation using stainless steel and nickel-titanium (NiTi) instruments by undergraduate students, using two diagnostic imaging methods.n=20; group 1: K-Flexofile, group 2: K3, and group 3: BioRace). The root canals were filled with gutta-percha and AH Plus. Periapical radiographs and cone beam computed tomography (CBCT) images were obtained to detect procedural errors made by undergraduate students during root canal preparation. Two examiners evaluated the presence or absence of fractured instruments, perforations and canal transportations. The agreement between observers was assessed using the kappa coefficient. The Kolmogorov-Smirnov, Fisher exact, ANOVA and Tukey tests were used for statistical analysis. The level of significance was set at 5%.Sixty human molars were divided into three groups (There were no significant differences in detecting procedural errors between two- and three-dimensional diagnostic imaging methods. There were no significant differences in procedural errors between stainless steel and NiTi instruments. Mean preparation time was recorded in minutes, and results were significantly different between the three groups. NiTi instruments had the lowest mean preparation time.Both periapical radiographs and CBCT identified procedural errors, however, three-dimensional images offered more diagnostic resources. The frequency of procedural errors was low for any of the endodontic instruments despite being used by inexperienced operators. Centralizing ability and apical transportation were not influenced by mechanical motion or type of instrument used. Hartmann et al. . Further research should investigate new concepts and technologies that raise opportunities for discussion, reflection and changes in the scientific world.The frequency of procedural errors during the preparation of canals of maxillary and mandibular molars using stainless steel and NiTi instruments was low regardless of diagnostic imaging method when used by inexperienced operators."} +{"text": "Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by short-limbed skeletal dysplasia. Some patients also develop defects in cell-mediated immunity and antibody production. Granulomatous inflammation has been described in patients with various forms of primary immunodeficiencies but, to date, has not been reported in patients with Cartilage-hair hypoplasia.To describe granulomatous inflammation as a novel feature in patients with CHH, assess associated immunodeficiency and evaluate treatment options.In a retrospective, observational study, we collected clinical data on 21 patients with CHH in order to identify and further characterize individuals with granulomatous inflammation.Four unrelated patients with CHH (with variable degrees of combined immunodeficiency) developed epithelioid cell granulomatous inflammation in the skin and visceral organs. Anti Tumor necrosis factor alpha monoclonal antibody therapy in 3 of these patients led to significant regression of granulomas. However, one treated patient developed fatal progressive multifocal leukoencephalopathy due to the JC polyomavirus. In two patients, immune reconstitution after allogeneic hematopoietic stem cell transplantation led to the complete disappearance of granulomas.To the best of our knowledge, this is the first report of granulomatous inflammation in patients with CHH. Although Tumor necrosis factor alpha antagonists may effectively suppress granulomas, the risk of severe infectious complications limits their use in immunodeficient patients."} +{"text": "DNA methylation may play a role in the etiology of neuropsychiatric disorders through abnormal genomic methylation patterns regulating genes involved in brain development or physiology. In this study we explored the DNA methylation profile of depression in the prefrontal cortex because converging evidence from brain imaging and postmortem studies has implicated this region in depression neuropathology.et al., doi: 10.4161/epi.6.11.17876). Overall, these data represent relatively unbiased coverage of the genome, including CpG-rich domains such as CpG islands and repetitive elements.In order to better understand both the wild type genomic DNA methylation patterns and aberrant methylation events occurring in disease states we profiled DNA methylation patterns in human postmortem brains of 12 depressed and non-psychiatric controls using the methylation mapping and paired-end sequencing (Methyl-MAPS) method. Methyl-MAPS is an enzymatic-base method that can delineate the methylation status of greater than 80% of CpG sites genome-wide across all RefSeq annotated genes, but significant variations were detected proximal to the TSS (referred to as \u201cCpG island shores\u201d). We observed statistically significant methylation loss in CpG island shores in depressed cases compared to controls. These findings were replicated in purified neuronal cell populations. Using an independent sample of depressed cases and matched non-psychiatric controls, we isolated neuronal nuclei from the dorsal prefrontal cortex of 11 depressed cases and 11 controls. Due to limited quantities of neuronal DNA typically obtained from isolation of nuclei using fluorescence-activated cell sorting, we used the Illumina HumanMethylation450 BeadChip. DNA methylation differences in CpG island shores revealed that, of the CpG dinucleotides with significant methylation differences, >95% showed loss of methylation in depressed brains. The underlying mechanism involved in the loss of methylation in depression psychopathology is unclear. However, the global 5-hydroxymethylcytosine levels in neuronal DNA from the same sample specimens also showed a loss of hydroxymethylation in depressed brains compared to controls. Although these data were not statistically significant, they revealed an important trend in loss of hydroxymethylation and the possible mechanism for DNA demethylation in brains of depressed patients. Gene ontology analysis of genes with significant methylation differences (primarily loss of methylation) in depressed vs. controls identified a number of cellular functions. Of note, the fourth most significant gene set identified was involved in programmed cell death and 74% of the genes in this set were associated with neuronal cell death. These changes in methylation dynamics suggest a possible mechanism linking neuronal cell death associated with oxidative stress and inflammation in the depressed brain."} +{"text": "This review will focus on the often overlooked roles of PARylation in chromatin remodeling, epigenetics, and transcription to explain why some cancers may be unresponsive to Parp inhibition. We predict that understanding the impact of PARylation on gene expression will lead to alternative approaches to manipulate the Parp pathway for therapeutic benefit.Poly(ADP-ribose) polymerase (Parp) is an enzyme responsible for catalyzing post-translational modifications through the addition of poly(ADP-ribose) chains (known as PARylation). Modification by PARylation modulates numerous cellular processes including transcription, chromatin remodeling, apoptosis, and DNA damage repair. In particular, the role of Parp activation in response to DNA damage has been intensely studied. Tumors bearing mutations of the breast cancer susceptibility genes, Brca1/2, are prone to DNA breakages whose restoration into functional double-strand DNA is Parp dependent. This concept has been exploited therapeutically in Brca mutated breast and ovarian tumors, where acute sensitivity to Parp inhibitors is observed. Based on Breast cancer is an epidemic afflicting approximately one out of every nine women and gemcitabine showed improved overall survival of varying degrees of homology , all of whom use NAD+ as a substrate to catalyze the addition of ADP-ribose moieties onto target proteins locus glycohydrolase (known as Parg). Parg catabolizes ADP-ribose polymers synthesized by Parp-1. This enzymatic activity has been demonstrated to impair Parp-mediated chromatin remodeling In addition to histone H1 removal, Parp-1 configures chromatin through modification of proteins involved in remodeling and organizing chromatin structure. PARylation generally results in protein activation, but can also result in functional suppression of chromatin remodelers. For example, PARylation is inhibitory to the function of the repressive remodeling complex Iswi , together with histone deacetylases (Hdacs), results in a repressive complex, inactivating the transcription of genes involved in cardiomyocyte differentiation through deacetylation of histones .Finally, we propose that Parg represents an attractive therapeutic target Figure . The undParp-1 is an important activator of transcription and probably plays an important role in promoting transcription of tumor suppress genes. Therefore, we postulate Parp inhibitors may actually have pro-oncogenic effects on some cell populations. But, what is the impact of inhibiting Parg on these same processes? While the overall impact of Parg on gene regulation remains unclear at this time, it has been shown that Parg can block Parp-1 mediated chromatin remodeling and transcriptional activation in specific circumstances. Therefore, we speculate Parg inhibition might heighten the effects of PARylation, thus promoting the transcription of tumor suppressor genes. Further, in cancer cells having defects in the PARylation pathway such as aberrantly dePARylated Ctcf, Parg inhibition might serve to correct these deficiencies.in vivo (Marienfeld et al., in vitro data showing growth inhibitory activity of Parg inhibition or knockdown in multiple types of cancer (Fauzee et al., Supporting these rationale for Parg inhibition being a novel approach for anti-cancer therapy are several reports indicating Parg inhibition has potent anti-tumor effects against cholangiocarinoma The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Acute liver failure related to hepatitis B infection may occur after acute HBV infection or during an exacerbation (flare) of a chronic HBV infection. The condition is associated with a very high morbidity and mortality rate.We present the diagnosis and management difficulties of a four-case series admitted to our clinic during the last year, with severe acute liver failure, with encephalopathy that required medical management, intensive care and organ support, including artificial extracorporeal liver support.In the presence of acute liver failure and serological evidence of hepatitis B viral infection, differentiating between acute infection and exacerbation (flare) of chronic infections remains a challenge. Mortality rates remain high inspite of recent medical advance."} +{"text": "NATbox: Network Analysis Toolbox in the language R that houses a battery of BSL algorithms in conjunction with suitable statistical tools for modelling FRs in the form of acyclic networks from gene expression profiles and their subsequent analysis.There has been recent interest in capturing the functional relationships (FRs) from high-throughput assays using suitable computational techniques. FRs elucidate the working of genes in concert as a system as opposed to independent entities hence may provide preliminary insights into biological pathways and signalling mechanisms. Bayesian structure learning (BSL) techniques and its extensions have been used successfully for modelling FRs from expression profiles. Such techniques are especially useful in discovering undocumented FRs, investigating non-canonical signalling mechanisms and cross-talk between pathways. The objective of the present study is to develop a graphical user interface (GUI), i) impute missing observations in the given data (ii) model FRs and network structure from gene expression profiles using a battery of BSL algorithms and identify robust dependencies using a bootstrap procedure, (iii) present the FRs in the form of acyclic graphs for visualization and investigate its topological properties using network analysis metrics, (iv) retrieve FRs of interest from published literature. Subsequently, use these FRs as structural priors in BSL (v) enhance scalability of BSL across high-dimensional data by parallelizing the bootstrap routines.NATbox is a menu-driven open-source GUI implemented in the R statistical language for modelling and analysis of FRs from gene expression profiles. It provides options to (http://bioinformatics.ualr.edu/natboxWiki/index.php/Main_Page.NATbox provides a menu-driven GUI for modelling and analysis of FRs from gene expression profiles. By incorporating readily available functions from existing R-packages, it minimizes redundancy and improves reproducibility, transparency and sustainability, characteristic of open-source environments. NATbox is especially suited for interdisciplinary researchers and biologists with minimal programming experience and would like to use systems biology approaches without delving into the algorithmic aspects. The GUI provides appropriate parameter recommendations for the various menu options including default parameter choices for the user. NATbox can also prove to be a useful demonstration and teaching tool in graduate and undergraduate course in systems biology. It has been tested successfully under Windows and Linux operating systems. The source code along with installation instructions and accompanying tutorial can be found at Classical biological experiments have focused on understanding changes in the expression of single genes across distinct biological states. Such differential gene expression analyses while useful may not provide sufficient insight into their interactions or functional relationships (FRs). Understanding FRs is crucial as genes work in concert as a system as opposed to independent entities. On a related note, phenotype formation is mediated by pathways comprising of complex interactions between several genes as opposed to a single gene. Recent development of high-throughput assays in conjunction with sophisticated computational tools has enabled modelling such interactions and gain system-level understanding.Several commercial and non-commercial software packages have been developed in the past for modelling gene interactions. Ontology-based packages ,2 that rBayesian structure learning (BSL) techniques have beehttp://bioinformatics.ualr.edu/natboxWiki/index.php/Main_Page.Several open-source packages are available for BSL and can be used to model gene networks -13. Howei) determine missing values in a given data using the functions LLSimpute, also implemented in the R-package pcamethods [ii) Learn acyclic network structure using BSL routines from the R-package deal [dynamicGraph [iii) identify what the author term as 1st order network structure using a resampling procedure and (iv) reconstruct coherent sub-regulatory networks using an extended version of the algorithm CODENSE [Prior to a detailed description of NATbox functionalities, we briefly review those of a closely related package BNArray which waamethods (ii) Leaage deal . SubsequmicGraph (iii) id CODENSE . In the The comparisons are also enclosed under Table i. GUI: NATbox provides a convenient menu-driven graphical user interface (GUI) developed using Tcl/Tk for modelling and analysis of gene expression networks. This has to be contrasted with BNArray [ BNArray , which iii. Input/output: The input data in NATbox is assumed to be in tab-delimited text format, similar to that of BNArray. In NATbox, the rows of the input file represent independent experiments whereas the columns represent the names of the genes. However, in BNArray the rows represent the genes of interest and the columns represent their expression across experiments. Unlike NATbox, BNArray does not specify whether the experiments need to be independent or dependent.iii. Missing values: Gene expression profiles often have missing values. For instance, in microarray data such missing values are common and may be attributed to experimental artefact, improper hybridization and non-specific binding of the probes. It is prudent to use suitable statistical techniques to accommodate such data sets rather than discard them. NATbox provides an option to determine missing values using nearest-neighbour averaging approach (menu: File), impute.knn (R-package impute) which has been found to perform well for high-dimensional data sets [LLSImpute) [pcamethods).ata sets . BNArraySImpute) algorithiv. Functional relationships: NATbox provides the option to model functional relationships using a battery of Bayesian structure learning techniques from the R-package (bnlearn) [menu: Bayesian Networks). It is important to note that they model the network structure solely from the joint probability distribution in the absence of explicit temporal information. The tab-delimited input data should be in the form of a matrix where the columns represents the number of genes, and rows the number of repeated (independent) experiments. Each element in the matrix represents the expression value of that gene in a given experiment.bnlearn) : GS is b\u2022 Incremental Association Markov Blanket Algorithm (IAMB) : IAMB is\u2022 Fast Incremental Association Markov Blanket Algorithm (Fast-IAMB) : Fast-IA\u2022 Interleaved Incremental Association Markov Blanket Algorithm (Inter-IAMB) : Inter-I\u2022 Max-Min Parents Children Algorithm (MMPC) : MMPC ismutual information, mutual information for Gaussian distributed data, fast mutual information, Pearson's \u03c72, Akaike information criterion) as well as numerical/continuous distributions are provided. NATbox also provides an interface to the search and score algorithm from bnlearn. HC searches the model space and retrieves the best model using a scoring criterion which is also provided. Several choices of scoring criterion are provided for categorical/discrete and numerical/continuous distributions (Gaussian posterior density). Each BSL technique works under implicit assumptions and may result in spurious conclusions when these assumptions are violated. NATbox provides a battery of BSL techniques to alleviate such concerns. For instance, constraint-based techniques can be affected by sample sizes and are sensitive to initial results of the conditional independence tests. Search and score algorithms can result in local optima, hence may benefit from multiple random restarts unlike constraint-based approaches.Several choices of conditional independence tests for categorical/discrete are deemed robust. Bootstrap procedures can be computationally demanding for high-dimensional data sets. Search and score techniques such as hill-climbing implicitly require several random restarts during the confidence estimation. NATbox provides an option to parallelize bootstrapping across multiprocessor or multi-core processor by invoking the appropriate routines from the R-package SNOW (Simple Network Of Workstations) [nfidence of an edtations) . Such patations) is shown\u03b8 > 0.8) on the acyclic graph learned from the given data, Fig. dynamicGraph [The results of the bootstrap are written onto a tab-delimited file. An option is also provided for highlighting the robust FRs (micGraph for visuwhitelisting (include) and blacklisting (exclude) FRs. Such priors impose constraints on the network structure which implicitly rely on prior knowledge and needs to be chosen prudently in order to avoid bias during learning. However, a proper choice can alleviate uncertainty and improve accuracy of the conclusions. A text retrieval interface is provided for identifying structural priors and can be useful for investigating well-established signalling mechanisms.In addition, NATbox GUI also provides options for incorporating structural priors in BSL by vi. Network analysis metrics: BSL techniques are useful in inferring the cause-effect relationships and network structure from the gene expression profiles. However, they provide no insight into the network's topological properties. NATbox incorporates social network analysis metrics and motif finder from the package (igraph) [menu: Network Analysis Metrics) for investigating the topological properties of the networks generated using BSL techniques. Such metrics can be especially useful in investigating large networks. The input is assumed to be a binary adjacency matrix of the network constructed using BSL with ones and zeros representing the presence/absence of an edge respectively. Since BSL results in directed acyclic graphs, the corresponding binary adjacency matrix need not be symmetric. The centrality measures along with their respective parameter options are provided for the user. A detailed discussion of these centrality measures are deferred to [igraph [igraph package incorporated into NATBox also provides option to save the acyclic network in formats compatible with Cytoscape [(igraph) under . The user has the option to input the (a) pairs of gene names (co-occurrence) of interest through the GUI or (b) upload a two-column matrix of FRs of interest or those identified as robust by the bootstrap procedure. For well-documented studies, an integrated approach that incorporates the results from the Text Retrieval in justifying the choice of whitelisted (include) and/or blacklisted (edges) in BSL. The Text Retrieval results are in html format, with a list of PUBMED identifiers hyper-linking to the respective abstracts/articles in PUBMED. The results of text retrieval on gene expression data from [ata from is showni) expand the choice of structure learning algorithms including dynamic bayesian networks (ii) improve statistical inference of the network features (ii) parallelization of the implemented routines across multi-core and multi-processor machines of BSL functions as well as bootstrapping (iii) provide a web-interface so as to obviate the need for local installation of the toolbox (iv) enhance text retrieval so as to accommodate advanced text mining approaches.Modelling and analysis of gene expression networks is an area of active research. Several tools have been proposed in the literature for the same. Recently, Bayesian structure learning (BSL) techniques in conjunction with high throughput assays were used successfully to capture functional relationships. Existing packages may demand the user to have considerable programming expertise. NATbox provides a convenient menu-driven GUI along with appropriate parameter recommendations including default parameter choices for modelling and analysis of gene expression networks. It incorporates diverse functionalities from existing R-packages. This in turn encourages transparency and reproducibility, characteristic of open-source environment. NATbox can also be used as a teaching and demonstration tool for graduate courses in systems biology. Immediate future enhancements to the toolbox include (The authors declare that they have no competing interests.bnlearn package and was involved in trouble shooting the Bayesian structure learning routines. RN wrote the manuscript.SSC and MAB implemented the toolbox under RN's guidance. MS developed the"} +{"text": "Patients after fractures become more and more immobile. Necessary stimuli decrease further. It comes to progressive deconditioning, whereby the vicious circle is complete, because it results in decreasing muscle cross-sectional area as well as bone strength. Accordingly, therapy concepts have to focus on maintenance and increasing muscle force and power. An established method is intensive resistance exercise training aimed to hypertrophy. Also the training program must ensure that forces reach the minimal effective strain and leads to bone remodelling. High-load resistance exercises effectively increase muscle and bone at the same time.Bone and muscle are dynamic tissues. Muscle adapts to stimuli above thresholds (energetic emptying > exhaustion). Wolff\u2019s law states that structural bone adaptation is driven by the experienced bone strains. Osteocytes within our bones regulate bone formation and degradation in response to mechanical stimuli. The largest strains emerge from muscle contractions. A lot of diseases are associated with secondary muscle weakness (sarcopenia) and reduced bone density (osteoporosis). Both deficits cause an increase in fall incidence. About every 4"} +{"text": "Yersinia pestis, are highly variable in their response to plague ranging from near deterministic extinction to a low probability of extinction despite persistent infection . Much of the work to understand this variability has focused on specific host characteristics, such as population size and resistance, and their role in determining plague dynamics. Here, however, we advance the idea that the relative importance of alternative transmission routes may vary causing shifts from epizootic to enzootic dynamics. We present a model that incorporates host and flea ecology with multiple transmission hypotheses to study how transmission shifts determine population responses to plague. Our results suggest enzootic persistence relies on infection of an off-host flea reservoir and epizootics rely on transiently maintained flea infection loads through repeated infectious feeds by fleas. In either case, early-phase transmission by fleas has been observed in laboratory studies, and we show that it is capable of driving plague dynamics at the population level. Sensitivity analysis of model parameters revealed that host characteristics vary in importance depending on transmission dynamics, suggesting that host ecology may scale differently through different transmission routes enabling prediction of population responses in a more robust way than using either host characteristics or transmission shifts alone.Host populations for the plague bacterium, Yersinia pestis, remains a public health concern because of its high virulence in multiple mammal species, including humans, and its role in past pandemics in humans. Despite its historical importance and the continued threat of human cases, plague is primarily a disease of rodents and their fleas. Consequently, humans are at greatest risk of exposure to Y. pestis during plague epizootics when rodent hosts die in large numbers increasing potential exposures to sick or dead animals and infectious fleas Plague, caused by the bacterium However, rodent species show high variability in their population-level response to plague infection, and the mechanisms that determine outbreak conditions are not fully understood. The variability in host response can be compartmentalized into two classes: either enzootic or epizootic . This classification enables predictions that can be based on observable intra-population dynamics rather than invoking landscape-level maintenance mechanisms involving the interaction of plague dynamics in multiple species Rhombomys opimus) in Kazakhstan, show high levels of prolonged resistance , rarely survive plague infection Previous research on plague dynamics depended on observation of host characteristics to differentiate between epizootic and enzootic populations. For example, enzootic hosts, such as great gerbils allows for the maintenance of infection levels in fleas and increases infectious duration for early-phase transmission Y. pestis has survived in carcasses and soil for several days under both field and laboratory conditions Experimentally studying transmission routes in natural systems is nearly impossible, but laboratory experiments have identified effective transmission routes that could also affect population responses to plague infection. In particular, early-phase transmission by un-blocked fleas has been shown to be a viable alternative to blocked-flea transmission in several flea species under laboratory conditions Y. pestis dynamics that incorporates three routes of plague transmission: 1) the booster-feed infection cycle; 2) the build-up of infectious, questing fleas; and 3) contact with carcass-derived material. We parameterize the model for an epizootic host, the black-tailed prairie dog, and for an enzootic host, the California ground squirrel (Spermophilus beecheyi). We sequentially remove or reduce each transmission route to understand how the influence of each route may vary between characteristic epizootic and enzootic hosts. We also use sensitivity analysis of model parameters to quantify the importance of transmission routes across a broader range of species and to explore how previously identified host characteristics interact with transmission to improve prediction of plague dynamics.In order to simultaneously consider how multiple transmission routes interact to determine plague dynamics, we present a general model of We developed an ordinary differential equation (ODE) model consisting of both host and flea submodels causing fleas to transition to EP stage 2 , while the infectious, questing flea reservoir increases almost throughout . InfectiSystematic removal of transmission routes helped provide a clearer picture of each in plague dynamics, especially for epizootic behavior . For thea, was positively correlated with enzootic probability but had little effect on extinction probability. Increasing transmission efficiency from EP2, L\u03b2, increased extinction probability as did an increase in the transition rate between EP1 and EP2 for fleas taking non-infectious blood meals, E\u03b8.Our multi-parameter sensitivity analysis was consistent with the relative importance of transmission routes described above and revealed that model results were sensitive to parameters influential to both the booster-feed infection cycle and the infectious, questing flea reservoir ; Fig. 3.\u03d5, and shorter host exposure periods . However, increased host resistance, p, and increased host carry capacity, K, served to decrease epizootic behavior. In contrast, enzootic probability was increased by increasing host carrying capacity and declined with higher rates of resistance loss, shorter host exposure periods, and decreasing host connectance . Sensitivities that are not reported were not significant.Population responses to plague infection were also sensitive to several host parameters in the model . Among tOur model produced characteristic enzootic and epizootic behaviors, and model behaviors for our specific parameterizations were consistent with empirical observations of plague activity in the hosts they were based on, black-tailed prairie dogs and California ground squirrels. The agreement with natural systems highlights our ability to reliably compare the shifting roles of transmission routes in creating each dynamic. In particular, the booster-feed infection cycle is primarily responsible for epizootic behavior. While laboratory experiments have demonstrated that the booster feed infection cycle results in the maintenance of infection levels in fleas B; Our sensitivity analysis supports the role of shifting transmission dynamics in determining plague dynamics in the host population. We found that epizootic behavior was strongly affected by flea characteristics that determine both the strength and turnover rate of the booster-feed infection cycle, while enzootic potential was strongly influenced by flea questing efficiency adding support to the involvement of a flea reservoir in the maintenance of plague at the population level While the flea reservoir may be important in connecting spatially distinct groups of hosts, we also hypothesize that questing fleas may act as a bridge in enzootics, connecting temporally separated pools of susceptible hosts generated from a resistant refuge. This endogenously derived temporal bridge contrasts with more traditionally hypothesized exogenous sources of re-infection. Bat rabies virus may display a similar endogenous bridging mechanism by entering a quiescent state during host hibernation, thus creating a bridge between birth pulses that refresh the susceptible pool Most of the previous research on the variability in population responses to plague infection has focused on host traits, and our sensitivity analysis confirmed some of these observations, particularly the importance of host resistance and population size as observed in Asian great gerbils However, while our analysis confirms previous observations on the role of host characteristics in determining disease dynamics, it is important to note that these traits do not act independently of transmission routes to determine population response and thus, the effects of host traits may depend on the specific transmission routes operating. For example, we found that increasing host carrying capacity generally increased enzootic potential in our sensitivity analysis. However, our specific results for prairie dogs and California ground squirrels exhibited the opposite of the expected responses with black-tailed prairie dogs having larger population sizes but higher probabilities of extinction. Here, knowledge of transmission shifts may be more informative. Specifically, the importance of booster-feeds in epizootics, a transmission route that relies on continued contact between hosts and fleas, may create a situation where increasing host abundance leads to large epizootic potential that cannot be maintained. This is in contrast to enzootic hosts where an endogenous bridging mechanism like infectious, questing fleas overcomes issues of host limitation. The maintenance of infection potential in a flea reservoir may also alter the traditionally hypothesized role of resistance in promoting enzootics. In this case, resistance may primarily be important in avoiding epizootics and becomes important in promoting enzootics only when infectious, questing fleas dominate transmission. Thus, host and flea characteristics may scale up through transmission routes allowing for more robust predictions than when considering either host or flea characteristics alone.Figure S1Flow chart for the host sub model. The three transmission routes included in the model are highlighted: booster-feed infection cycle (blue), infectious, questing flea reservoir (green), and infectious carcasses (orange).(TIF)Click here for additional data file.Figure S2Flow chart for the flea submodel. The relationship between the booster-feed infection cycle (blue) and infectious flea reservoir (green) is highlighted.(TIF)Click here for additional data file.Table S1Alternate flea parameter values. Parameter values for the prairie dog flea O. tuberculata cynomuris. Other flea species are provided for comparison.(DOC)Click here for additional data file.Text S1Alternate flea submodel which prevents the buildup of infectious, questing fleas.(DOC)Click here for additional data file.Text S2Parameter fitting and estimation.(DOC)Click here for additional data file.Text S3Detailed prairie dog and California ground squirrel model outputs.(DOC)Click here for additional data file."} +{"text": "Urobatis halleri, as a model species. First, we examined the effects of temperature on vertebral elemental incorporation . Second, we tested the relationship between water and subsequent vertebral elemental composition by manipulating dissolved barium concentrations . We also evaluated the influence of natural variation in growth rate on elemental incorporation for both experiments. Finally, we examined the accuracy of classifying individuals to known environmental histories (temperature and barium treatments) using vertebral elemental composition. Temperature had strong, negative effects on the uptake of magnesium (DMg) and barium (DBa) and positively influenced manganese (DMn) incorporation. Temperature-dependent responses were not observed for lithium and strontium. Vertebral Ba/Ca was positively correlated with ambient Ba/Ca. Partition coefficients (DBa) revealed increased discrimination of barium in response to increased dissolved barium concentrations. There were no significant relationships between elemental incorporation and somatic growth or vertebral precipitation rates for any elements except Zn. Relationships between somatic growth rate and DZn were, however, inconsistent and inconclusive. Variation in the vertebral elemental signatures of U. halleri reliably distinguished individual rays from each treatment based on temperature (85%) and Ba exposure (96%) history. These results support the assumption that vertebral elemental composition reflects the environmental conditions during deposition and validates the use of vertebral elemental signatures as natural markers in an elasmobranch. Vertebral elemental analysis is a promising tool for the study of elasmobranch population structure, movement, and habitat use.Differences in the chemical composition of calcified skeletal structures have proven useful for reconstructing the environmental history of many marine species. However, the extent to which ambient environmental conditions can be inferred from the elemental signatures within the vertebrae of elasmobranchs has not been evaluated. To assess the relationship between water and vertebral elemental composition, we conducted two laboratory studies using round stingrays, The trace and minor elemental composition of biomineralized structures can provide insight into the environmental conditions in which the elements were deposited. Elemental assays of coral skeletons and foraminifera tests, for example, have been commonly applied as surrogates of past climatic or oceanographic conditions \u20133. RecenThe most widespread and expanding application of elemental markers in biomineralized structures has occurred using the otoliths of fishes ,5. OtoliThe elemental composition of biogenic calcified structures is not a simple reflection of environmental conditions. A variety of physiological barriers and processes are encountered as elements are taken up from the water through the gills or intestine, transferred through the blood plasma, and eventually incorporated into biomineralized structures . PhysiolSharks, skates, and rays (elasmobranchs) are cartilaginous fishes that lack otoliths. Elasmobranch skeletons are composed of mineralized cartilage, an impure (non-stochiometric) form of carbonated calcium phosphate (hydroxyapatite) . Like thChemical analyses of elasmobranch vertebrae to date have been predominately directed toward age validation ,27 and dUrobatis halleri, as a model species. We manipulated environmental concentrations of barium (Ba) to determine the extent to which vertebral elemental ratios reflect the ambient environment. Finally, we evaluated the utility of these elemental markers to distinguish the environmental history experienced by individual rays using multivariate classification models. These experiments allowed us to test the following hypotheses: (i) elemental incorporation in vertebrae is mediated by water temperature; (ii) vertebral Ba to calcium ratios (Ba/Ca) reflects water Ba/Ca; (iii) growth rate does not significantly influence vertebral elemental composition; and (iv) vertebral elemental markers can distinguish individuals based on differences in environmental history. This investigation represents the first attempt to evaluate the utility of vertebral chemistry as potential records of environmental history in elasmobranchs.Key assumptions regarding vertebral elemental incorporation in relation to the physical and chemical environment must be evaluated before broader ecological questions and hypotheses can be addressed using naturally occurring elemental markers in elasmobranchs. We quantified the effects of temperature and growth rate on vertebral elemental incorporation through controlled laboratory studies using the round stingray, This investigation was conducted with a permit from the California Department of Fish and Game (803099-01) and in strict accordance with guidelines established by the American Fisheries Society and National Institutes of Health for the use of fishes in research. Experimental protocol was approved by Oregon State University\u2019s Institutional Animal Care and Use Committee (3783).Urobatis halleri, is a benthic, live-bearing elasmobranch that occurs in estuaries and nearshore coastal soft bottom habitats from Panama to Eureka, California, USA ) experiment.Correlations (r) between partition coefficients (DThe number (n) of round rays included in growth rate estimates, observed range of individual somatic growth rates (mm disc width month-1), and vertebral precipitation rates (\u03bcm radius month-1) are reported for each treatment. Significant p-values are indicated by bold font.(PDF)Click here for additional data file."} +{"text": "Vascular injury represents less than 1% of all injuries, but deserves special attention because of its severe complications. Amputation or retention of a painful functionless limb is the most untoward result of severe vascular injury or inadequate treatmet. Thus, vascular injury needs a judicious and multidimensional approach.This retrospective study was done to asess the outcome of minor modifications of the methodology of extremity fasciotomy by making it liberal with respect to incision and definition.Out of 55 patients in 2008, 45 patients (Group A) had either no fasciotomy or limited primary fasciotomy, 10 patients (Group B) had primary liberal fasciotomy. Another group from 2008 onwards had undergone primary liberal fasciotomy in all the 45 patients (Group C).In group A, we had 5 amputations and one death. In group B, there were no amputations or deaths and from group C, we had one amputation and no deaths.Blunt and distal traumatic vascular injury of the extremities and its repair should always combined with primary liberal fasciotomy, which although increases manageable morbidity, avoids disability . Vascular injury represents less than 1% of all injuries, but deserves special attention because of their severe complications. Amputation or retention of a painful functionless limb is the most untoward result of severe vascular injury or inadequate treatment, so vascular injury needs a judicious and multidimensional approach. Patients with pain out of proportion to injury, pain upon passive stretching, sensory changes, weakness or parasthesia after vascular repair indicate vascular compromise due to compartment syndrome and need immediate fasciotomy. Popliteal artery injuries continue to result in maximum limb loss, possibility due to use of limited fasciotomy.This study was done to assess the outcome of minor modifications of the methodology of extremity fasciotomy by making it liberal with respect to incision and definition.We studied 55 patients in 2008 with firearm or splinter vascular injuries of extremities; 45 patients (Group A) underwent different methods of vascular repair either without primary fasciotomy or with limited fasciotomy. Only 10 patients (Group B) had liberal primary fasciotomy. After 2008 to date, we treated 45 patients (Group C) with different types of vascular injuries, by different reparatory methods all of which received primary liberal fasciotomy.Assessment included emergency work-up: clinical examination, CBC, KFT, ECG, chest x-ray, USG abdomen, color flow Doppler, blood grouping and cross-matching; only 6 patients were subjected to pre-operative angiography.Vascular repair was done by primary end-to-end anastomosis or reverse sephanous vein graft either without fasciotomy or with varied limits of fasciotomy.Limited fasciotomy included superficial incision with inadequately cut deep fascia, isolated compartment fasciotomy, inadequate length of fasciotomy not passing across proximal and distal joints. Liberal fasciotomy included cutting through skin, deep fascia as well as outer covering of underlying exposed muscles (epimysium), till muscle pouts out. Oozing blood from muscle indicates adequate blood flow through the repaired vessel as well as adequacy of fasciotomy, thus it has therapeutic as well as diagnostic importance. Checking muscle viability with low voltage electric cautery stimulation. Confirming muscle viability helps in adequate debridement to prevent infective complications of dead tissue.We use S-shaped incision both at elbow and popliteal fossa, closure of this incision does not cause any constricting effect, while in case of liberal primary fasciotomy, the same incision is extended. The repaired vessel is loosely covered either by surrounding fat or muscle to prevent desiccation of the vessel. Curved fasciotomy incisions decompress the maximum area of the extremity and avoids superficial venous injury.Ensure muscle pouting along fasciotomy wound. All-compartmental fasciotomy is better than isolated-compartment fasciotomy. Dressings should not be tight. Avoid entrapment of adventitia in the anastomotic suture line.Passing a Fogarty catheter damages endothelium and increases tendency of thrombosis, thus anticoagulation is recommended.From group A, we had 5 amputations and one death (death due to infective complications of gangrene followed by DIC - despite that the limb was amputated); from group B we had no complications and from group C one amputation and no deaths were recorded; 12 patients from group A needed either extension of fasciotomy or secondary fasciotomy.Most of the patients with liberal primary fasciotomy need care by a plastic surgeon. But 25% patients were discharged and referred to their respective primary health care centers for regular dressings and admitted subsequently for split-thickness skin grafting with favorable results.All those patients with primary liberal fasciotomy even with borderline muscle viability at the time of primary vascular repair had the least amputation rate. There was no significant increase in infection rate. Soaked dressings were changed regularly. One significant complication with primary liberal fasciotomy was pain which needed short interval analgesics. Also changing dressings in these patients was time consuming and significantly painful which demanded extra patience by patient as well as attending resident. These patients have long lasting paresthesia at graft site with varied presentation. Patients in high dependency units with no or limited fasciotomy obscured signs of compartment syndrome due to liberal use of analgesics. Delayed or revised fasciotomy in these patients helped to a very limited extent, and in the long run gave a functionally disabled limb with chronic pain in saved limbs.Delayed fasciotomy, revision fasciotomy and disability due to amputation/vegetative limb or chronic limb parasthesia all have a very strong psychological impact in contrast to less morbidity associated with primary liberal fasciotomy.In patients with primary liberal fasiotomy crossing knee and ankle in lower limb, elbow and wrist in upper limb with cutting some fibers of reticulum at ankle or wrist appreciably improved blood flow. Any vascular injury associated with blunt trauma limb, fracture, venous injury, longer duration of ischemia; below knee/elbow vascular repair needed primary liberal fasciotomy whether the patient had a tense compartment at the time of vascular repair or not.Extensive soakage from fasciotomy wound needs frequent change of dressings, which is painful and cumbersome for patient. Frequent analgesics make patients apprehensive. Painful postural changes and difficulty in assuming comfortable postures effects sleep. Longer hospital stay is uncomfortable.Compartment syndrome is a surgical emergency characterized by raised pressure in an unyielding osteofascial compartment caused by trauma, revascularization, myocyte edema after ischemia-reperfusion injury, or resuscitation -4. The cBlunt and distal traumatic vascular injury of extremities and its repair should be combined with primary liberal fasciotomy, which may although increase manageable morbidity, will avoid lifelong disability. No fasciotomy can be acceptable when chances of compartment syndrome are absolutely nil; however, limited fasciotomy is absolutely discouraged in favor of primary liberal fasciotomy."} +{"text": "The autonomic nervous system (ANS) and innate immunity are intimately linked. Heart rate variability (HRV) analysis is a widely employed method to assess cardiac ANS activity, and changes in HRV indices may correlate with inflammatory markers. Here, we investigated whether baseline HRV predicts the innate immune response. Second, we investigated whether the magnitude of the inflammatory response correlated with HRV alterations.Escherichia coli O:113). Of these, 12 healthy volunteers were administered LPS again 2 weeks later. HRV was determined at baseline (just prior to LPS administration) and hourly thereafter until 8 hours post LPS. Plasma cytokine levels were determined at various time points.Forty healthy volunteers received a single intravenous bolus of 2 ng/kg endotoxin (lipopolysaccharide (LPS), derived from Baseline HRV indices did not correlate with the magnitude of the LPS-induced inflammatory response. Despite large alterations in HRV following LPS administration, the extent of the inflammatory response did not correlate with the magnitude of HRV changes. In subjects that were administered LPS twice, inflammatory cytokines were markedly attenuated following the second LPS administration, while LPS-induced HRV alterations were similar. See Figure HRV indices do not predict the innate immune response in a standardized model of systemic inflammation. The innate immune response results in HRV changes; however, no correlations with inflammatory cytokines were observed. These findings suggest that cardiac ANS activity may not reflect ANS outflow to other organs involved in the innate immune response. Furthermore, the magnitude of endotoxemia-related HRV changes does not reflect the extent of the inflammatory response."} +{"text": "An asymptomatic issueless young staff nurse underwent pre-employment health screening and USG abdomen showed multiple hypodense lesions in liver. Further screening with whole body positron emission tomography-computed tomography (PET-CT) scan showed significantly FDG avid mass involving most of the right lobe of liver with multiple large FDG avid lymph nodal metastases. Unsuspected focal abnormal, FDG avid, hyperdense mural nodule was seen in uterus, which is the site of primary. With the advent of sophisticated medical instrumentation in the diagnostic workup for malignancies, detailed investigations fail to reveal the primary site of origin for a subset of patients with metastatic carcinoma. This is often referred to as Carcinoma of Unknown Primary (CUP) or occult primary malignancy.The exact incidence of CUP in the United States is not precisely known, but it is definitely underreported. Its actual incidence is most probably between 2 and 6%. In 15\u201325Clinical presentation of cancer of unknown primary origin is extremely variable and depends on the extent and type of organ involvement. Investigations are usually guided by any positive findings on initial evaluation. Patients have early dissemination of their cancer without symptoms at the primary site. The symptoms often depend on the site of metastases, like ascites may be the initial presentation in a patient with a GI or an ovarian malignancy, etc.The patient was an issueless, 32-year-old staff nurse undergoing pre-employment health checkup. USG abdomen showed a large heterogenous lobulated mass with predominant hypoechogenicity suggestive of possible atypical hemangioma or possible evolving abscess. Magnetic resonance imaging (MRI) of abdomen showed a large heterogenous enhancing hypodense lesion with altered signal intensity with a large exophytic component in the right lobe of liver suggestive of possible hepatic adenoma/atypical hemangioma/possible neoplasm. Fine needle aspiration cytology (FNAC) followed by trucut biopsy was suggestive of possible metastatic rhabdomyosarcoma.18F FDG (Fluoro Deoxyglucose) intravenously in euglycemic status. After 1 hour, the patient was imaged. Images showed large hypodense, significantly FDG avid, non-enhancing mass involving most of the right lobe of liver [Standard Uptake Value (SUV) max 30 g/ml]. Multiple large FDG avid, left axillary, porta hepatic, celiac and retropancreatic lymph nodal metastases were also present. Portal vein was seen encased by the tumor at porta hepatis. Inferior venacava was obstructed below the liver and collateralized via azygos and hemiazygous system. [Whole body positron emission tomography-computed tomography (PET-CT) scan was done using 8 mCi on system. . Inferio system. .The patient underwent further pelvic USG and was biopsy proven. The patient was started on chemotherapy and is doing well for the past 6 months. Follow-up CT of abdomen showed recession in size of liver metastases.Rhabdomyosarcoma is primarily a disease affecting children; it rarely affects adults. Common sites of involvement are the head and neck 28%), extremities 24%), and genitourinary tract (18%).8%, extre Uterine %, and geMost uterine sarcomas fall into the category of leiomyosarcoma, endometrial stromal sarcoma, or undifferentiated sarcoma.5 MetastaRhabdomyosarcoma is subdivided into three general types histologically as follows.Embryonal rhabdomyosarcoma: This usually occurs in head and neck locations with small round or oval tumor cells and a finely granular eosinophilic cytoplasm. Well-differentiated tumors demonstrate elongated, strap-shaped or tadpole-shaped rhabdomyoblasts.Alveolar rhabdomyosarcoma is the next variety comprising relatively small, poorly differentiated round and oval cells aggregated into irregular clusters or nests separated by fibrous septa. An occasional variant, referred to as the botryoid type, shows a diffuse myxoid or mucoid matrix with thinly scattered primitive mesenchymal cells. The characteristic feature of this type is a peripheral zone of increased cellularity, sometimes known as the \u201ccambium layer.\u201dPleomorphic rhabdomyosarcoma shows randomly arranged eosinophilic cells with considerable variation in cell size and shape, as well as variation in nuclear size and shape. The pleomorphic cells are often admixed with small, primitive mesenchymal cells. This tumor is often so undifferentiated that the identification of the cell of origin is difficult or impossible. Positive immunostains for desmin and myoglobin are helpful as in our case.Regardless of the histologic subtype, special stains are often quite useful for differentiating rhabdomyosarcoma from other neoplasms. The trichrome stain is especially useful because it colors rhabdomyoblasts bright red while myofilaments and cross-striations have fuchsinophilic properties, also highlighted by PTAH (deep purple color). Myxoid stroma may be positive for hyaluronidase with acid mucopolysaccharide staining, although many other tumors also have positive stroma with these stains. The most418F FDG PET-CT is an important screening tool for the evaluation of unknown primaries as well as for staging and follow-up of several malignancies.[In patients with metastatic disease, prognosis is poor with a 5-year event-free survival rate of less than 30%. 18F FDG gnancies.8 FDG PETOur patient was unique, as she was a young asymptomatic lady presenting with multiple large liver and nodal secondaries, which is relatively an uncommon site for metastases. The patient had no previous history of menorrhagia or metrorrhagia as usually expected in uterine rhabdomyosarcomas. Incidentally detected mural nodule in uterus helped in finding the site of hidden primary malignancy."} +{"text": "We compared the difference in left atrial tissue remodeling (LATR) pre-ablation and post-ablation lesion characteristics between three methods for electrical isolation of pulmonary veins routinely done to treat paroxysmal atrial fibrillation (PAF).Patients presenting with PAF who qualified for a cryo, PVAC or SRF ablation were prospectively followed. DE-MRI of the left atrium (LA) was performed prior to and three months post procedure. The degree of LATR is reported as a percentage of the total LA area.37 patients were included in this study. Six patients underwent an ablation using PVAC catheter, SRF catheter was used in 14 patients, and 17 patients underwent a cryoballoon ablation. Pre-ablation LATR was comparable in all three cohorts (Figure From our preliminary results, PVAC ablation appears to result in lesser scar formation as compared to Cryo and SRF ablation. The greater recurrence in patients with low scar post-ablation suggests the need to implement an adequate ablation strategy that results in greater scar to maximize successful outcomes. DE-MRI is an appropriate method to compare lesion formation induced by different ablations strategies.None."} +{"text": "Two variants with evidence of association with higher endometrial cancer grade (p-trend<10\u20136) have been selected for validation in independent sample sets. These SNPs are located in or near genes not previously reported to be involved in cancer aetiology or prognosis and, if confirmed, would represent novel gene targets. Neither of these SNPs fall into the top 1500 SNPs prioritised for validation of association with risk. Results to date suggest that genetic alleles associated with prognostic features, such as cancer grade, may be distinct from those associated with predisposition. GWAS analysis of tumour prognostic features is thus likely to improve understanding of biological pathways influencing outcome for endometrial cancer patients.Endometrial cancer is the most commonly diagnosed gynaecological cancer. Although endometrioid endometrial cancer (80% of cases) generally carries a good prognosis, some patients with this tumour subtype relapse within two years. Identifying genetic variants associated with prognosis could inform clinical decision-making for management at diagnosis, and inform development of chemotherapeutic agents targeting aggressive disease. Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in cancer susceptibility. Presently there are limited published studies using GWAS data to identify single nucleotide polymorphisms (SNPs) associated with tumour prognostic indicators, such as grade. We used case data from an endometrial cancer case-control GWAS to assess association of SNPs with endometrial cancer grade. Genome-wide genotyping of 1285 Australian and British women with endometrioid endometrial cancer and reporting Caucasian ethnicity was performed using the Illumina 610K BeadChip. After applying quality control measures, data on 583,366 SNPs for 1220 cases with grade information were used in the analysis. PLINK software was used to assess SNP association with grade , adjusting for study group . Fifty-seven SNPs were found to be significant at <10"} +{"text": "Reduced muscle strength- commonly characterized by decreased handgrip strength compared to population norms- is associated with numerous untoward outcomes. Preoperative handgrip strength is a potentially attractive real-time, non-invasive, cheap and easy-to-perform \"bedside\" assessment tool. Using systematic review procedure, we investigated whether preoperative handgrip strength was associated with postoperative outcomes in adults undergoing surgery.PRISMA and MOOSE consensus guidelines for reporting systematic reviews were followed. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials (1980-2010) were systematically searched by two independent reviewers. The selection criteria were limited to include studies of preoperative handgrip strength in human adults undergoing non-emergency, cardiac and non-cardiac surgery. Study procedural quality was analysed using the Newcastle-Ottawa Quality Assessment score. The outcomes assessed were postoperative morbidity, mortality and hospital stay.Nineteen clinical studies comprising 2194 patients were identified between1980-2010. Impaired handgrip strength and postoperative morbidity were defined inconsistently between studies. Only 2 studies explicitly ensured investigators collecting postoperative outcomes data were blinded to preoperative handgrip strength test results. The heterogeneity of study design used and the diversity of surgical procedures precluded formal meta-analysis. Despite the moderate quality of these observational studies, lower handgrip strength was associated with increased morbidity (n = 10 studies), mortality (n = 2/5 studies) and length of hospital stay (n = 3/7 studies).Impaired preoperative handgrip strength may be associated with poorer postoperative outcomes, but further work exploring its predictive power is warranted using prospectively acquired, objectively defined measures of postoperative morbidity. A substantial minority of patients sustain an excess of postoperative complications and acceThe systematic review was undertaken in accordance with the PRISMA Preferr.Two of the authors (P.S. and M.A.H.) searched the electronic databases MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials independently using the following population search terms: 'postoperative complications' OR 'perioperative complications' OR 'surgical complications' OR 'surgical outcome'. These search results were combined with 'handgrip dynamometry' OR 'hand grip dynamometry' OR 'hand grip strength' OR 'handgrip strength' OR 'maximal voluntary contraction' in the title or abstract text using the Boolean search operator 'AND'. . The references of retrieved articles were hand searched for any relevant articles not identified in the original search. The study selection criteria were limited to include only studies reported in the English language and those involving human adults undergoing surgery (including cardiac and transplant surgery). Each abstract was screened to identify studies that had assessed handgrip strength prior to surgery. Studies were excluded if postoperative outcomes focussed on upper limb neuromuscular functional outcomes alone.The data were extracted on to a standardized data entry form by each reviewer. Differences between the reviewers were resolved by re-examination of the original manuscript until consensus was obtained. Data extracted for comparison included year of publication, primary author, total number of subjects, mean patient age, proportion of male subjects and co-morbidity (where reported). The method of quantifying or qualifying handgrip strength was recorded.The specific outcomes sought in each article were: (i) mortality, (ii) postoperative morbidity, categorized according to the Post Operative Morbidity Survey, (iii) length of hospital stay . PrimaryThe procedural quality of each trial was assessed using several criteria, although no studies were excluded on the basis of these assessments. The quality of studies was scored according to the Newcastle-Ottawa Quality Assessment Scale Additio, on a scNineteen studies were identified that compared postoperative outcomes in relation to handgrip strength Table , comprisThe majority of studies measured handgrip strength pre-operatively Table . Eleven Variable definitions for impaired handgrip strength have been used across studies Table . StudiesTable Tables Table Contrary to large population studies, our systematic review of the relationship between preoperative handgrip strength and postoperative outcome did not find compelling data to support the hypothesis that the results of studies in the general population translate to perioperative medicine. The majority of studies were considered to be of reasonable quality. Despite these quality scores, many studies contained important potential confounding factors which varied markedly between studies. A range of different instruments have been employed to measure grip strength, with other corroborative assessments of strength being frequently absent. Due to the substantial variation in the way in which each specified outcome had been defined between studies, plus the lack of analyses testing any one particular association, it was not possible to perform meta-analyses of results or formally test the heterogeneity (consistency) between studies. This marked heterogeneity between studies limits any definitive conclusions for the perioperative environment and renders this preoperative assessment largely unexplored. Nevertheless, several of these studies - albeit with the limitations as discussed above - suggest the role for preoperative handgrip strength assessment should be explored further.Large epidemiological studies have shown that perioperative morbidity is associated with dramatic differences in post-discharge life expectancy across different operations and health systems . The cosThere are also compelling basic biological reasons for establishing the role of handgrip strength in preoperative assessment. Cardiopulmonary reserve is a long-established predictor of cardiovascular and all-cause mortality, in both asymptomatic individuals and patients with cardiovascular disease . CardiacOne limitation of this systematic review is that no original study data were retrieved, although given the heterogeneity of both study design and the surgical populations in question this would have been unlikely to alter the main conclusions. Because only published reports were examined , a formal assessment of publication bias was not undertaken. It remains possible that not all relevant studies may have been identified since unpublished studies were not sought. There is very little perioperative demographic data provided in these studies, including cardiovascular risk and the identification of higher risk patients. Standards of postoperative care were not reported or apparently standardized. Since no interventions were conducted based on preoperative handgrip strength assessment, the studies only provide associative conclusions.This systematic review has generated two significant clinical implications. Firstly, given the compelling general population data that predicts longevity, there is clearly a need for the further prospective assessment of whether preoperative handgrip strength can help stratify risk of adverse postoperative outcomes. Second, these studies demonstrate that handgrip strength is a feasible, pragmatic, real-time bedside tool that may enhance preoperative risk stratification.Impaired preoperative handgrip strength may be associated with increased postoperative morbidity, mortality and prolonged hospital stay following surgery. Given the robust predictive power of this inexpensive, objective bedside test beyond the perioperative population, further studies of its' role in predicting postoperative outcomes appear to be warranted provided prospective, objectively defined measures of morbidity are employed.The authors declare that they have no competing interests.All authors contributed to Study design, Conduct of study, Data analysis and Manuscript preparation.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2253/12/1/prepubChecklist of items demonstrating adherence to PRIMSA systematic review guidelines.Click here for fileNewcastle Ottowa Scale.Click here for file"} +{"text": "Petromyzon marinus). This dataset allows the exploration of early vertebrate evolution because the lamprey lineage split from that of other vertebrates before the emergence of hinged jaws, the defining feature of jawed vertebrates . Additionally, lamprey axons are not ensheathed by myelin is particularly relevant because MBP is an abundant structural myelin constituent essential for myelination in the central nervous system (CNS). The fact that MBP had not been traced in species more ancient than gnathostomata Figure . The fun) Figure . MBP andOther presumed myelin proteins traced in the lamprey genome are not functionally related to myelin at all, despite an equivalent gene ontology (GO) term. For example, MYT1L (myelin transcription factor-1-like), a neuronal transcription factor , PMP22 , MAL (myelin and lymphocyte protein), and PLP (proteolipid protein) were previously noted to be evolutionarily older than vertebrates (Mazumder et al., Taken together, the lamprey genome does not provide reason to consider that myelin may have evolved in non-jawed vertebrates. More generally, conclusions from genomic datasets on cellular structures come with the danger of misinterpretations if not carefully considered in conjunction with morphological analyses (Bullock et al.,"} +{"text": "Transplantation therapy for diabetes is limited by unavailability of donor organs and outcomes complicated by immunosuppressive drug toxicity. Xenotransplantation is a strategy to overcome supply problems. Implantation of tissue obtained early during embryogenesis is a way to reduce transplant immunogenicity. Insulin-producing cells originating from embryonic pig pancreas obtained very early following pancreatic primordium formation (embryonic day 28 (E28)) engraft long-term in non-immune, suppressed diabetic rats or rhesus macaques. Morphologically, similar cells originating from adult porcine islets of Langerhans (islets) engraft in non-immune-suppressed rats or rhesus macaques previously transplanted with E28 pig pancreatic primordia. Our data are consistent with induction of tolerance to an endocrine cell component of porcine islets induced by previous transplantation of embryonic pig pancreas, a novel finding we designate organogenetic tolerance. The potential exists for its use to enable the use of pigs as islet cell donors for humans with no immune suppression requirement. J. Transplantation, why transplantation of embryonic pancreatic primordia to replace endocrine pancreas function is advantageous relative to transplantation of either pluripotent embryonic stem (ES) cells, or of terminally differentiated (adult) organs [We have reviewed previously, for ) organs : (1) unlTransplantation of human embryonic pancreas in human hosts has been contemplated . HoweverCells originating from E28 pig pancreatic primordia transplanted in mesentery engraft similarly in non-immune-suppressed STZ-diabetic rhesus macaques , 8. GlucIn lieu of increasing the numbers of transplanted primordia or transplant surgeries in diabetic rhesus macaques, we embarked on a series of experiments to determine whether porcine islets, a more easily obtainable and possibly more robust source of insulin-producing cells, could be substituted for animals in which embryonic pig pancreas already had been engrafted. To this end, we implanted adult porcine islets beneath the capsule of one kidney of rats or macaques, that several weeks earlier had been transplanted with E28 pig pancreatic primordia in mesentery. We employed the renal subcapsular site for islet implantation so that we could differentiate engrafted porcine tissue originating from the islets from tissue originating from prior mesenteric E28 pig pancreatic transplants, that never engraft in host kidney , 8. In t Figures Neither cells that stain for insulin nor cells to which the probe for porcine proinsulin mRNA binds are present in contralateral (nonimplanted) kidneys of STZ diabetic rats or macaqTo provide additional evidence that cells in the kidneys of islet-implanted rats or macaques previously transplanted with E28 pig pancreatic primordia in mesentery are of porcine origin, we demonstrated using fluorescent in situ hybridization, that the cells contain pig X chromosomes , 8. ShowMultiple organs were excised from a STZ-diabetic macaque transplanted with E28 pig pancreatic primordia in mesentery and subsequently with porcine islets in the renal subcapsular space of one kidney. Tissues were homogenized individually and total RNA was purified. RT-PCR was performed using primers specific for pig or monkey proinsulin mRNA. Products were separated by electrophoresis on 3% agarose gels and their identities confirmed by sequencing in the Washington University Core Protein and Nucleic Acid Chemistry Laboratory [To ascertain whether cells originating from kidney-implanted porcine islets function in rats or rhesus macaques, we determined whether the glucose tolerance of STZ-diabetic animals normalized partially by prior transplantation of E28 pig pancreatic primordia in mesentery was rendered normal by subsequent islet implantation, and measured glucose-stimulated insulin release from islet-implanted kidneys in vitro. Rats were rendered fully glucose tolerant by subsequent implantation of porcine islets in one kidney . The gluAs illustrated in a representative of 3 experiments using weight-matched tissue, no insulin could be detected at time 0 in supernatants from the implanted macaque kidney . HoweverCells containing endocrine granules in an expanded renal subcapsular space were identified in electron micrographs of kidneys from rats implanted with porcine islets following transplantation of E28 pig pancreatic primordia in mesentery . FigureThe shortage of human pancreas donor organs imposes severe restrictions on the use of allotransplantation to treat diabetes mellitus \u201322. WhenThe severity of humoral rejection effectively precludes the use of pigs as whole pancreas organ donors for humans. However, because they are vascularized by the host posttransplantation, islets like other cell transplants are not subject to humoral rejection. Porcine islets are rejected within two weeks of transplantation in non-immune suppressed non-human primates , 16\u201318. Xenotransplantation of embryonic pig pancreatic primordia in lieu of mature pig organs or porcine islets couples the wide availability of pig organs with the immunological advantages inherent in transplanting cellular embryonic tissue, circumventing humoral rejection and obviating the need for host immune suppression . HoweverCells from porcine islets do not survive afterimplantation in rat or macaque kidneys without prior transplantation of E28 pig pancreatic primordia transplantation in mesentery , 8. WholSchroeder et al. define tEngraftment of pancreatic progenitors transplanted across a xenogeneic barrier to non-immune-suppressed immune-sufficient hosts has been reported twice previously. Eloy et al. described normalization of glucose posttransplantation of E15, but not E18 embryonic chick pancreas into liver of non-immune-suppressed STZ-diabetic rats . AbrahamHost immune suppression is required for successful engraftment of embryonic pig pancreas in rodents or non-hInterestingly, GALT may have served similarly to prevent an immune response to insulin-producing cells scattered originally in the gut epithelium of primitive vertebrates , 32 and Harada et al. have proposed a similar coopting of oral tolerance to explain the muted immune response in vivo and by cells from mesenteric lymph nodes in vitro to a colon carcinoma of BALB/c origin or a human CD80-transfected DBA/2 mastocytoma injected into the subserosal space of cecum in BALB/c mice relative to tumors injected subcutaneously . One way to confirm a causative link between gut immunity and our ability to transplant E28 pig pancreatic primordia and porcine islets in non-immune-suppressed hosts would be to \u201cbreak\u201d the established oral tolerance , using gIn any case, we have demonstrated in two species , 8, a no"} +{"text": "Natural Killer (NK) cells contribute to the control of cancer through immunosurveillance and may influence phenotypic sculpting of cancer through immunoediting. NK cells may also contribute to the control of hematological malignancies such as acute myeloid leukemia (AML) following allogeneic stem cell transplantation. However, no studies have shown direct clinical evidence that supports immunoediting by NK cells in AML at presentation, or whether activating ligand expression at diagnosis serves as a prognostic indicator of survival. We now show that at diagnosis, expression of NK cell ligands on AML blast populations is heterogeneous. Furthermore, expression of multiple activating ligands is associated with favorable cytogenetics and improved leukemia-free survival. In analyses of paired diagnostic and relapse samples, AML blasts exhibiting lower expression of activating ligands were selectively increased at relapse, indicating that NK cell-mediated blast immunoediting occurred prior to AML escape. Therapeutically, NK cell activating ligands could be upregulated on AML by in vitro treatment with bortezomib that enhanced NK cell-mediated cytotoxicity. Thus, diagnostic analyses of the expression of NK cell activating ligands in AML could be used to design therapeutic approaches for specific patients, and agents that stimulate NK cell function by restoring NK cell ligand expression may be appropriate to eliminate minimal residual disease and reduce risk of relapse."} +{"text": "Disseminated metastatic breast cancer needs aggressive treatment due to its reduced response to anticancer treatment and hence low survival and quality of life. Although in theory a combination drug therapy has advantages over single-agent therapy, no appreciable survival enhancement is generally reported whereas increased toxicity is frequently seen in combination treatment especially in chemotherapy. Currently used combination treatments in metastatic breast cancer will be discussed with their challenges leading to the introduction of novel combination anticancer drug delivery systems that aim to overcome these challenges. Widely studied drug delivery systems such as liposomes, dendrimers, polymeric nanoparticles, and water-soluble polymers can concurrently carry multiple anticancer drugs in one platform. These carriers can provide improved target specificity achieved by passive and/or active targeting mechanisms. Breast cancer is the most common cancer in females and the second most common cause of death in women in the United States . MetastaFor better therapeutic effectiveness combination anticancer treatment has long been adopted in clinics. The general rationale for employing combination therapy is twofold. First, when multiple drugs with different molecular targets are applied, the cancer adaptation process such as cancer cell mutations can be delayed. Second, when multiple drugs target the same cellular pathway they could function synergistically for higher therapeutic efficacy and higher target selectivity. Currently available combination regimens for metastatic breast cancer in clinics are limited to administrating a physical mixture of two or more anticancer agents. The clinically used combination regimens in the US can be broadly classified based on their mechanisms of action Figures includinSmall molecule chemotherapeutic agents can be given singly or in combination . ToxicitStreptomyces bacteria, are a class of drugs widely used and studied in cancer chemotherapy. Mechanisms of action of anthracyclines are (1) to inhibit DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells, (2) to inhibit topoisomerase II, preventing the relaxing of supercoiled DNA, and thus blocking DNA transcription and replication, and (3) to create iron-mediated free oxygen radicals that damage the DNA and cell membranes. Anthracyclines-based combination chemotherapy has shown improved anticancer activity than anthracyclines alone. For example, doxorubicin has achieved response rate of 40\u201350% as single agent while 60\u201370% in combination [With response rates of up to 60% in previously untreated patients with metastatic breast cancer anthracycline-based regimens are one of the most widely used first-line chemotherapies. Because of this advantage patients relapsing more than 12 months after anthracycline-based treatment may be reinduced with anthracycline-based combination chemotherapy . Anthracbination . These rbination . The combination . These rbination , 24. JoeTaxanes are another class of chemotherapy agents originally derived from natural sources then synthetically derivatized including paclitaxel (Taxol) and docetaxel (Taxotere). The mechanism of action of taxanes is to disrupt microtubule function. Microtubules are essential to cell division, and taxanes stabilize GDP-bound tubulin in the microtubule, thereby inhibiting the process of cell division. Therefore taxanes also can be classified as mitotic inhibitors. However due to their poor water-solubility, taxanes encounter difficulties in pharmaceutical formulation and this often results in reduced bioavailability.Different mechanisms of action of anthracyclines and taxanes provide the rationale of combination therapy of these two classes of drugs. Taxanes and anthracyclines typically do not produce overlapping toxicities with existing therapies. Bria et al. reported improved time to progression and overall survival from doxorubicin with paclitaxel (or docetaxel) therapy compared to anthracycline-based combination therapy (FAC or AC). Although greater hematologic toxicity (such as neutropenia) occurs from taxane containing regimen (74%) than the anthracycline regimen (63%) the overTaxane with nonanthracycline combinations is another highly effective regimen and is particularly useful in patients with rapidly progressive visceral metastases, who were previously treated with an anthracycline. In this regimen, capecitabine and gemcitabine are drugs of choices as nonanthracycline drugs for combination with taxanes (docetaxel or paclitaxel). Albain et al. reported the combination of gemcitabine and paclitaxel regimen to be superior to paclitaxel alone with longer time to progression (6 versus 4 months) and better response rate (41% versus 26%). However toxicity of this combination was higher with increased neutropenia (61% versus 22%), fatigue (19% versus 13%), and neuropathy (24% versus 22%) .Increased use of anthracyclines and taxanes in adjuvant (given in addition to main treatment) and neoadjuvant (given before the main treatment) settings limits the treatment options for patients upon relapse. Multidrug resistance (MDR) is a major limitation of conventional chemotherapy . This isAs discussed above most combination therapies with small molecule chemotherapeutic agents present improved clinical benefits including enhanced response rate and prolonged overall survival, progression-free survival, relapse-free survival, and/or time to progression. However, with additive efficacy the adverse effects from each agent are compounded resulting in patients' suffering from more treatment-related toxicity. The nonspecific nature of small molecule chemotherapeutics accounts for much of the toxicity due to nonselective biodistribution in healthy tissues concurrently with tumor accumulation. Additionally exposure to multiple conventional chemotherapeutic agents reduces response rate due to increased efflux of these drugs out of the cells mediated by the overexpression of MDR related efflux pumps or transporters . TherefoSmall molecule chemotherapeutic agents lack cancer cell-specific targeting ability and also affect the fast-dividing normal cells of the body . Therefore, the major adverse effects from these chemotherapeutic agents are nonspecific toxicities including anemia, nausea, vomiting, and hair loss. Biologic agents are advantageous to chemotherapy in their ability to actively target-specific receptors. Conventional chemotherapy does not discriminate effectively between tumor cells and rapidly dividing normal cells thus leading to nonspecific adverse effects. In contrast, target-specific anticancer therapies interfere with molecular targets that have an important role in tumor growth or progression distinct from normal cells. Also some of these agents act as inhibitors to MDR-related proteins thereby increasing the response rate . OverallMonoclonal antibodies are monospecific antibodies made by identical immune cells as clones of a unique parent cell. Due to their nature monoclonal antibodies can be designed to bind to specific substances hence they are widely used for target specific detection or purification . ApproxiBevacizumab, a monoclonal antibody against VEGFR, acts as an inhibitor of angiogenesis. VEGF is an important signaling protein involved in both vasculogenesis (the formation of the circulatory system) and angiogenesis (the growth of blood vessels from preexisting vasculature). Since angiogenesis is the essential way of providing nutrition to tumors and a fundamental step in the transition of tumors from a dormant state to a malignant one, it serves as important target for anticancer therapy. As monotherapy in metastatic breast cancer, it has only modest activity (response rate of 9%) . HoweverCetuximab is a monoclonal antibody that targets overexpressed EGFR in various cancers . EGFR isMonoclonal antibodies as biologic anticancer agents have shown reduced toxicity while having modest activities. The low response rates due to drug resistance can explain such modest activities. TRZ resistance is developed in about 70% of TRZ-treated breast cancer patients in early treatment period and onlyLapatinib is a small molecule dual tyrosine kinase receptor inhibitor of EGFR and HER2 that, like TRZ, has demonstrated a significant improvement in overall survival when added to the treatment of HER2-positive metastatic breast cancer . The benAnother strategy for targeting VEGF and tumor angiogenesis is the use of small molecule tyrosine kinase receptor inhibitors that target the VEGF receptor (VEGFR), including sunitinib, sorafenib, axitinib, and pazopanib. Gianni et al. reported improved response rate of 72% with the docetaxel plus sunitinib combination compared to 11% with sunitinib monotherapy. Most common side effects of sunitinib are anorexia, fatigue, mucositis, diarrhea, and nausea. However, the combination was well tolerated and did not significantly worsen the toxicity associated with the chemotherapy alone . Although these agents, alone or in combination with chemotherapy and/or other biologics, hold great promise, to date they have failed to demonstrate significant activity in metastatic breast cancer , 55. MosP = 0.02) of patients receiving olaparib, gemcitabine, and carboplatin compared to that of placebo and chemotherapy groups [Poly(adenosine diphosphate-ribose) polymerase (PARP) is a DNA-binding protein involved in detection and repair of DNA strand breaks . PARP iny groups .Although not many of the regimens are clinically approved, the concept of combination of two or more target-specific biologic agents is promising . The ratCmax\u2061 were not significantly different in comparing the combination with lapatinib alone. AUC24 and Cmax of TRZ were not significantly different when comparing the combination to trastuzumab alone [Beneficial therapeutic effectiveness from combination treatment is promising when considering theoretically nonoverlapping mechanisms of action of each anticancer agent. However, current combination treatments in metastatic breast cancer are far from perfect with moderate enhanced efficacy but additive toxicity as described above. Commonly these anticancer agents are administered together as a physical mixture of each agent without pharmacokinetic modification. These agents (free drugs) therefore distribute are eliminated independently of each other. As a result the additive effects are seen not only in anticancer activity but concurrently in adverse effects. Combining molecularly targeted agents is an improved strategy, but brings added complications including patient compliance issue. For example, in HER2 targeted combination therapy with TRZ and lapatinib, these two agents have two different routes of administration. TRZ is given intravenously weekly while lapatinib is administered daily as an oral formulation. Due to two different ways of administration with different schedules it is challenging to manage proper pharmacokinetic and pharmacodynamic profiles and virtually impossible to achieve uniform temporal and spatial codelivery. Storniolo et al. reported the results of a pharmacokinetic study of coadministration of TRZ and lapatinib to 27 patients. Serial blood samples were collected over a 24-hour period after ingestion of the lapatinib dose and/or the initiation of the 0.5-hour TRZ infusion. They reported that lapatinib area under the plasma drug concentration versus time curve within a 24-hour period after dosing and ab alone . HoweverThe challenges discussed above have driven researchers to investigate novel approaches by incorporating nanotechnology with combination anticancer treatment. The promising hypothesis is that by delivering two of more drugs simultaneously using a carrier-mediated drug delivery system the combination system can generate synergistic anticancer effects and reduce individual drug related toxicity. However this area of delivering multiple drugs with a single vehicle remains largely unexplored while most research efforts focus on single agent delivery systems. Therefore, here we will review carrier-mediated drug delivery systems containing multiple anticancer agents for cancer treatment in general not limited to metastatic breast cancer. Carrier-mediated drug delivery systems can offer many advantages over delivery of physical mixture of multiple drugs. The advantages include (1) prolonged drug circulation half-life mediated by the carrier, (2) reduced nonspecific uptake, (3) increased accumulation at the tumor site through passive enhanced permeation and retention (EPR) effect and/or active targeting by incorporation of targeting ligands , (4) preLiposomes are spherical vesicles composed of one or more lipid bilayers with a drug containing aqueous core . LiposomAnother unique liposomal system is a polymer-caged nanobin PCN, developeAttaching targeting ligands such as antibodies and peptides to a drug carrier is a widely applied strategy drastically increasing carrier accumulation in the desired cells, tissues, and organs. Several such targeted liposomes have been developed for combination drug delivery applications . Wu et aAs with any carrier-mediated codelivery system, determination of the optimal dose as the relative ratio of multiple drugs is a complex aspect in liposome-based combination drug delivery system. Mayer et al. reported precise control over combinatorial drug dosing in liposomes . The comDendrimers are well-established three-dimensional, branched polymers that have been thoroughly investigated as controlled and targeted drug delivery systems. The structure of dendrimers can be defined by an initiator core and layers of branched repeating units with functional end groups on the outmost layer . DendrimPolymeric nanoparticles are submicron-sized aggregate structures (3\u2013200\u2009nm) that are prepared using random or block copolymers. Polymeric nanoparticles are widely used as drug delivery carriers where the active drug may be physically encapsulated or covalently bound to the polymer matrix depending upon the method of preparation. Several polymeric nanoparticle systems have been explored specifically for combination drug delivery in cancer using both passive and active targeting strategies . For exaIn general it has been shown that polymeric nanoparticles, compared to liposomes, have greater stability, controlled size distribution, more tunable physicochemical properties, sustained and more controllable drug-release profiles, and higher loading capacity for poorly water-soluble drugs. While majority of the nanoparticle systems described above have demonstrated synergistic therapeutic efficacy in both in vitro and in vivo models some of these studies specifically illustrate that synergistic therapeutic effect is primarily due to the ability to administer two drugs in a tunable mass ratio with predictable spatial and temporal drug release profiles. For example Sengupta et al. developed a hybrid polymeric micelle comprisiPolymer-drug conjugates are drug delivery systems in which a drug is covalently bound to a water-soluble polymeric carrier, normally via a biodegradable linker. Such nanoconstructs were first proposed in the 1970s , develop N-(2-hydroxypropyl)methacrylamide (HPMA) is one example of biocompatible, non-immunogenic, non-toxic water-soluble copolymers that can be tailor-made for specific combination drug delivery needs . The uniOthers have explored modifications of the PEG backbone to conjugate a combination of chemotherapeutic agents. While unmodified PEG can only conjugate two drug molecules per chain (one on each end), Pasut et al. developed a PEG with a dendritic structure on one end that allowed coupling of upto 8 nitric oxide (NO) and one epirubicin (EPI) molecule per chain , 100. InOur research group has recently proposed a novel carrier-mediated combination drug delivery system for HER2 overexpressing metastatic breast cancer . We synthttp://www.celator.ca/) has developed a methodical approach to assess different drug ratios within their liposomal technology resulting in the development of different liposomal formulations that are now being assessed in phase II clinical trials, namely, CPX-1 (irinotecan: floxuridine) and CPX-351 (cytarabine: daunorubicin). Such an approach needs to be extended to other combination delivery systems such as dendrimers or polymer-drug conjugates. Determination of the kinetics of release of each drug in a multidrug combination system will be also necessary to determine the optimum ratio as one drug may affect the release profile of the other drug and thereby affect activity. Finally clinical development of these combination products is extremely challenging, due to developmental costs of designing such complex systems. However, these combination drug delivery system-based therapeutics are likely to be perceived by pharmaceutical companies as novel opportunities to extend the patent lives compared to current blockbuster drugs.The presence of two or more therapeutic agents on a single carrier platform offers new therapeutic possibilities but at the same time poses many new challenges. In order to identify an appropriate drug combination, it is necessary to perform thorough biological evaluation which must be supported by a profound understanding of the molecular mechanisms involved. Another critical aspect is the determination of the optimal mass ratio of each component within a combination drug delivery system. This requires systematic research investigating the impact of different drug ratios on the biological activity of the combination delivery systems. Recently a Canadian pharmaceutical company Celator ("} +{"text": "Tension-type headache (TTH) is the most prevalent headache among adults and is associated with impaired functional and psychosocial quality of life. Further analysis of eventual pathophysiology and comorbidities is needed. Temporomandibular Disorders (TMD) and TTH are frequently coexisting disorders and both characterized by increased pericranial tenderness. In a specialised tertiary headache centre more than half of the patients were also diagnosed with TMD but their eventual causality is yet unknown. Likewise is the relationship between tenderness, sleep quality and oral health in TTH patients also unknown. Our aim was to characterize the relationship between pericranial tenderness, sleep quality and oral health in TTH patients in comparison with healthy controls.The survey included 58 consecutive patients with frequent, episodic TTH or chronic TTH from a tertiary Headache Center and 58 healthy controls. Questionnaires regarding The Research Diagnostic Criteria for Temporomandibular Disorders (RDC), Oral Health Impact profile and Sleep/tiredness/snoring were completed.TTH-patients were significantly more affected in the RDC-Screening by increased characteristic pain intensity (CPI) regarding self reported temporomandibular pain (TMP) (p<0.001), decreased quality of life , and the total sleep score (p<0.001) compared to healthy controls).TTH patients are severely affected by TMP; demonstrate impaired sleep quality and oral health function and may reflect common underlying pathophysiological mechanisms."} +{"text": "Complex patients present with numerous risk factors and disease states. Clinical uses of biomarkers include diagnosis , risk stratification (assessing future risk of adverse outcomes or monitoring risk of adverse events), screening, and guiding therapy. Plasma natriuretic peptide are released from the heart in response to volume overload, as well as serving as markers of elevated filling pressures, a finding that in many cases would otherwise only be detectable with invasive testing. Therefore, the use of natriuretic peptides is an important adjunct to echocardiography in many circumstances. Just as BNP levels can be considered the arbitrator of CHF, cardiac troponins (TnI/TnT) are decisive for myocardial necrosis. The introduction of novel assays with even higher clinical sensitivity, detecting troponin levels at nanogram quantities, suggest even earlier diagnosis of acute myocardial infarction and identification of patients at substantial risk post-infarction. NGAL is one of the earliest and most robustly induced genes and proteins in the kidney after ischemic or nephrotoxic injury. Elevations are detectable within hours of acute kidney injury (AKI); whereas corresponding creatinine elevations lag 1 to 3 days behind."} +{"text": "This manuscript describes the NIH Human Microbiome Project, including a brief review of human microbiome research, a history of the project, and a comprehensive overview of the consortium's recent collection of publications analyzing the human microbiome. The Human Microbiome Project (HMP) Pioneering medical microbiologists applied these approaches, finding far more microbial diversity than expected even in well-studied body site habitats http://commonfund.nih.gov/hmp/) To coordinate these efforts relating the microbiome to human health, the NIH Common Fund launched the HMP as a community resource program unique to the study of the microbiome Any study of human populations must put both subject protection and study design first, and the HMP was no exception. Power calculations for microbiome studies in human cohorts are particularly challenging, as they must simultaneously address assay types , depth of sequencing, taxon detection, and fold abundance changes in clades, genes, or pathways of interest http://hmpdacc.org) hosts all available HMP data and many tools, focusing the tremendous quantity of raw data through lenses such as SitePainter Finally, quality data generation from appropriately designed microbiome studies enables a variety of subsequent computational analyses . While wThe HMP was designed in part to address a key question about our microbial selves: do all humans have an identifiable \u201ccore\" microbiome of shared components comparable to our shared genome A potentially more universal \u201ccore\" human microbiome emerged during the consideration of microbial genes and pathways carried throughout communities' metagenomes. While microbial organisms varied among subjects as described above, metabolic pathways necessary for human-associated microbial life were consistently present, forming a functional \u201ccore\" to the microbiome at all body sites Data from individuals without overt signs of disease serve as an excellent reference for disease-associated microbiome studies, while also providing a comprehensive baseline for comparison of Western populations with disparate geographic, ethnic, and genetic cohorts The HMP has thus greatly advanced our knowledge of the microbes in a healthy adult reference population, and provided much-needed infrastructure in terms of reference genomes, laboratory protocols, computational methods, and ELSI considerations"} +{"text": "Although very late stent thrombosis (VLST) after drug-eluting stent (DES) implantation remains a major concern, the precise mechanisms have not been clarified. An association between late acquired incomplete stent apposition (ISA) and VLST of DES has been suggested by several intravascular ultrasound studies demonstrating very high prevalence of ISA in the setting of VLST. To clarify the pathological mechanisms of VLST, we investigated vascular responses of coronary arteries of VLST cases after DES implantation. Drug-eluting stents (DESs) have dramatically reduced angiographic restenosis and clinical need for repeat revascularization procedures , 2. Howe The pathological findings from patients who died of late DES thrombosis have demonstrated that delayed arterial healing characterized by incomplete reendothelialization is an important underlying factor . The patAlthough a correlation has been observed between uncovered DES struts and LST, in our pathological studies of Japanese patients, considerable number of cases showed neointimal coverage with reendothelialization of a great deal of the DES struts, especially in simple lesions beyond 1 year . Thus, e Late ISA has been observed on follow-up intravascular ultrasound (IVUS) in patients who received sirolimus-eluting stents (SESs) . Althoug Thus, late ISA by focal positive vessel remodeling caused by medial necrosis may be responsible for LST and/or VLST after DES implantation. Peri-stent contrast staining (PSS) was defined as contrast staining outside the stent contour extending to \u226520% of stent diameter measured by quantitative coronary angiography. PSS found within 12 months after SES implantation appeared to be associated with subsequent VLST . PSS couRecent studies have identified immune cells and mediators at work in atheroma, implicating inflammatory mechanisms in disease development . As prevThus, DES can induce atherosclerotic and thrombogenic lesions with a significantly higher incidence and earlier than with BMS. LST may be more frequently related to incomplete healing and/or inadequate neointimal coverage with poor re-endothelialization. However, in the cases of VLST, several pathological studies have suggested a causal relationship between the inflammatory responses to the durable polymer and VLST, provoking late ISA and accelerated atherosclerosis followed by neointimal disruption. Histopathologic differences among DES platforms have been observed; this may reflect unique responses to the specific polymer/drug. Thus, until novel DES using superbly biocompatible and/or biodegradable polymers becomes available, we still need to be cautious and carefully keep surveying these devices."} +{"text": "Isolated granulomatous noncaseating pancreatitis is a rare condition exceptionally described in human population. We demonstrate a case of the a 71-years-old female patient suffering from recent diabetes mellitus, generalized atherosclerosis and hypertension who died due to pulmonary embolism and terminal bronchopneumonia. Lipomatosis of pancreatic tissue was observed during the postmortem examination. Histological examination of pancreatic tissue discovered multiple small noncaseating epithelioid cell and giant cell granulomas, partly replacing the islets of Langerhans. To our knowledge, our case represents the first description of noninfectious granulomatous pancreatitis associated with acute manifested insulin-dependent diabetes mellitus. Noncaseating granulomatous inflammation confined to the pancreas has been only exceptionally described in human patients. Infections like tuberculosis and syphilis, exogenous noxes, autoimmunity, and systemic granulomatous diseases are the most frequent causes of granuloma formation within the pancreatic tissue . AbdominA 71-year-old obese woman was admitted with the recent onset of diabetes mellitus manifested as hyperglycaemic ketoacidotic precoma. The past medical history was unremarkable. Recently, arterial hypertension was discovered. Her body weight was 110\u2009kg, BMI 38. The plasma glucose level ranged from 3.1 to 15.1\u2009mmol/L. The patient was treated with intensified insulin regime. The status of the patient was complicated by intermittent fever and several antibiotics were repeatedly administered. Terminally, clinical signs of septic shock and multiorgan failure appeared and the patient died. Postmortem examination performed 11 hours after death discovered signs of septic shock with activation of spleen pulp and terminal bronchopneumonia. Thromboemboli were found in several peripheral branches of the pulmonary artery. Hypertrophy of the heart (545\u2009g), predominantly of the left ventricle, was also observed. The pancreas showed a macroscopically lobular arrangement and lipomatosis; other macroscopic changes were not visible. Lungs, thoracic lymph nodes, and other organs did not show any changes corresponding with tuberculous process or sarcoidosis.\u03bcm-thick sections were stained with haematoxylin and eosin and by immunohistochemical methods using N-Histofine Immunohistochemical staining reagent and 3-3\u2032diaminobenzidine as a chromogen to visualize the reaction. The list of antibodies, including manufacturers and the dilutions used, is introduced in Five representative tissue samples of pancreatic tissue taken from head, body, and tail were fixed with 10% formalin and routinely embedded in paraffin. Five-Microscopic examination of pancreatic tissue discovered an increased amount of lipomatous tissue within the pancreatic lobules. Irregular inflammatory infiltrates of a variable density composed predominantly of small lymphocytes and sparse neutrophilic and eosinophilic granulocytes were also observed (\u03bcm) noncaseating epithelioid granulomas with giant cells, without Schaumann bodies, were present within the pancreatic lobules and pancreatic hormones verified the original microscopic finding of absence of islets of Langerhans . The majority of patients were presented by the obstructive jaundice, weight loss, and abdominal pain. Other autoimmune disorders, like sclerosing cholangitis or interstitial pneumonia, can appear in patients with AP. Histologically, AP is characterized by dense lymphoplasmacytic infiltrates and secondary fibrosis within the pancreatic tissue. Inflammation frequently displays a patchy collar arrangement around both small and large interlobular ducts and periphlebitis and obliterative phlebitis is invariably observed . It seemDiabetes mellitus in adults is predominantly of type 2. Much less frequently, type 1 diabetes and latent autoimmune diabetes (LADA) can appear in adult patients . DiabeteOur recent finding suggests that granulomatous pancreatitis is a possible underlying cause of diabetes mellitus and urges the microscopic examination of pancreatic tissue obtained during the post mortem examination of patients who died with signs and symptoms of recently manifested diabetes mellitus."} +{"text": "Burden of obesity has increased significantly in the United States over last few decades. Association of obesity with insulin resistance and related cardiometabolic problems is well established. Traditionally, adipose tissue in visceral fat depot has been considered a major culprit in development of insulin resistance. However, growing body of the literature has suggested that adipose tissue in subcutaneous fat depot, not only due to larger volume but also due to inherent functional characteristics, can have significant impact on development of insulin resistance. There are significant differences in functional characteristics of subcutaneous abdominal/truncal versus gluteofemoral depots. Decreased capacity for adipocyte differentiation and angiogenesis along with adipocyte hypertrophy can trigger vicious cycle of inflammation in subcutaneous adipose tissue and subsequent ectopic fat deposition. It is important to shift focus from fat content to functional heterogeneity in adipose tissue depots to better understand the relative role of subcutaneous adipose tissue in metabolic complications of obesity. Therapeutic lifestyle change continues to be the most important intervention in clinical practice at any level of increased adiposity. Future pharmaceutical interventions aimed at improving adipose tissue function in various subcutaneous depots have potential to help maintain adequate insulin sensitivity and reduce risk for development of insulin resistance complications. Prevalence of obesity has been increasing in the US. In 1960s, prevalence of obesity was approximately 13% , 3. ObesHowever, we have to consider clinical paradoxes along the spectrum of obesity, insulin resistance and metabolic complications. Metabolically healthy but obese (MHO) phenotype exhibits higher insulin sensitivity, absence of hypertension, and favorable lipid, inflammation, hormonal and liver enzyme profile. On the basis of epidemiological and clinical studies, prevalence of MHO phenotype varies from 10%\u201340% . The extExcessive insulin resistance and related metabolic abnormalities can be due to differential distribution of adipose tissue and/or adipose tissue dysfunction. Anatomically adipose tissues can be divided into truncal region or peripheral region. Truncal adipose tissue includes subcutaneous fat in thoracic and abdominal region and also intrathoracic and intraabdominal fat depots . PeripheVague in 1947 described two patterns of adipose tissue distribution\u2014android (upper body) and gynoid (lower body)\u2014and suggested that android obesity was associated with diabetes, coronary artery disease, gout, and uric acid renal stones . Later oVisceral fat has increased metabolic activity, both lipogenesis and lipolysis, compared to other fat depots. Free fatty acids, product of lipolysis, can directly enter liver via portal circulation and lead to increased lipid synthesis, gluconeogenesis, and insulin resistance resulting in hyperlipidemia, glucose intolerance, hypertension, and ultimately atherosclerosis . Excess We have examined the relationships between generalized and regional adiposity and insulin sensitivity in a group of nondiabetic men with varying degree of obesity . We concSimple explanation for stronger relationship between subcutaneous adipose tissue and insulin sensitivity comes from larger volume of subcutaneous adipose tissue mass. The subcutaneous abdominal fat mass is approximately twice more than intraperitoneal fat mass and total subcutaneous truncal fat mass can be 4-5 times larger than intraperitoneal fat mass , 23, 26.\u03baB stress pathway were upregulated suggesting stimulation of inflammatory mediators. Lundgren et al. [Inflammation in adipose tissue has been identified as a mediator of systemic insulin resistance. This has been suggested by presence of macrophage in the form of crown-like structures (CLSs) in adipose tissue. Apovian et al. examinedn et al. examinedn et al. . This isn et al. reportedn et al. , 35. Recent work on angiogenesis in adipose tissue has provided important insights into potential mechanisms of heterogeneity in the systemic metabolic impact of specific adipose tissue compartments. Gealekman et al. reportedIn contrast to abdominal subcutaneous adipose tissue, larger subcutaneous thigh fat mass has a protective effect. The Health, Aging, and Body Composition Study reported\u03baB pathway. The resultant effects are downregulation of cellular insulin signaling, recruitment of additional macrophages through monocyte chemoattractant protein 1, propagation of inflammation by interleukins and tumor necrosis factor alpha, and tissue matrix remodeling through matrix metalloproteinase-9 [Finally, it is worth putting truncal/abdominal subcutaneous adipose tissue characteristics all together to explain their emerging role in insulin resistance . Increaseinase-9 . These iConclusion. There is enough evidence in the literature for association between obesity and insulin resistance. Many investigators have proposed that visceral adipose tissue is a major contributor to insulin resistance. Our previous studies, in concordance with those of other investigators, suggest that subcutaneous truncal adipose tissue has significant impact on development of insulin resistance. Thus, adipose tissue distribution and function in different body compartments can be heterogeneous and can differentially contribute to insulin resistance. Changing focus from visceral adipose tissue mass as a sole contributor to insulin resistance to functional heterogeneity in adipose tissue depots can help better understand relationship of adiposity and insulin resistance. Therapeutic lifestyle change, including physical activity and weight loss, continues to be the most important intervention at any level of adiposity. One can envision that better understanding of adipose tissue function in various depots will help identify much needed additional and more effective therapeutic modalities to improve adipose tissue function and maintain adequate systemic glucose and lipid metabolism to reduce risk for morbidity and mortality associated with insulin resistance."} +{"text": "Since the introduction of recombinant human growth hormone (GH) in in the mid-1980s, supplies are almost limitless and predictably GH usage has escalated dramatically. There have been more than 150,000 children treated with GH worldwide with a wide variety of growth disorders.Adverse events (AE) with all forms of drug therapy are markedly under-reported, considerably underestimating the incidence of the AE. This under-reporting occurs even when the AE is serious and has a possible or probable association with GH therapy. Careful audit of the frequency of reporting of severe AE to other drugs with a possible or probable association with treatment is only 14%. Furthermore missing data is very common and adds to the difficulty in interpreting AE.Important conditions (adverse events) possibly linked to GH treatment are fortunately rare. There are several major limitations to accurately assessing the prevalence and risk of rare adverse events. Firstly, extremely large datasets are required found in large databases such KIGS and NCGS each with >50,000 enrolled patients. Secondly, accurate risk assessment of the possible adverse event in an untreated population that matches the GH treated population has rarely been determined.Important potential adverse events that have received considerable attention will be addressed. These include; tumour recurrence, new malignancies including leukaemia, diabetes mellitus, benign intracranial hypertension and slipped upper femoral epiphyses. The physiological rationale and the risk of these conditions during GH treatment will be addressed.Serum IGF-I monitoring to prevent elevated levels that may further increase the risk of adverse events is recommended. The potential adverse consequences of sustained elevated serum IGF-I levels will be discussed. In addition, monitoring IGF-I helps to monitor compliance of GH therapy in children with GH deficiency."} +{"text": "Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited genetic disease characterized by compensatory pathological left ventricle (LV) hypertrophy due to sarcomere dysfunction. In an important proportion of patients with HCM, the site and extent of cardiac hypertrophy results in severe obstruction to LV outflow tract (LVOT), contributing to disabling symptoms and increasing the risk of sudden cardiac death (SCD). In patients with progressive and/or refractory symptoms despite optimal pharmacological treatment, invasive therapies that diminish or abolish LVOT obstruction relieve heart failure-related symptoms, improve quality of life and could be associated with long-term survival similar to that observed in the general population. The gold standard in this respect is surgical septal myectomy, which might be supplementary associated with a reduction in SCD. Percutaneous techniques, particularly alcohol septal ablation (ASA) and more recently radiofrequency (RF) septal ablation, can achieve LVOT gradient reduction and symptomatic benefit in a large proportion of HOCM patients at the cost of a supposedly limited septal myocardial necrosis and a 10-20% risk of chronic atrioventricular block. After an initial period of enthusiasm, standard DDD pacing failed to show in randomized trials significant LVOT gradient reductions and objective improvement in exercise capacity. However, case reports and recent small pilot studies suggested that atrial synchronous LV or biventricular (biV) pacing significantly reduce LVOT obstruction and improve symptoms (acutely as well as long-term) in a large proportion of severely symptomatic HOCM patients not suitable to other gradient reduction therapies. Moreover, biV/LV pacing in HOCM seems to be associated with significant LV reverse remodelling. Hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited genetic disease characterized by compensatory LV hypertrophy mainly due to sarcomere dysfunction. Prevalence of the disorder in the general population is estimated to be 0.2% . A subseMedical therapy is at least partially effective in the majority of HOCM patients and consIn severely symptomatic HOCM patients despite optimal medical treatment and with significant resting or provocable LVOT obstruction (with gradient \u226530 mm Hg at rest or \u226550 mm Hg during exercise) non-pharmacologic treatment is indicated even in less symptomatic HOCM patients , with a even in In the overwhelming majority of HOCM patients LV/biV pacing is acutely more effective for gradient reduction than standard RVA pacing: eight out of nine in one study and all In contrast to studies with DDD RVA pacing, LV/biV pacing showed that the reduction in LVOT gradient induced a progressive and significant reduction in LV mass (reverse remodelling) . The thiDuring long term LV/biV pacing in HOCM there was no SCD/syncope in patients with CRT-P ,38. In tThe small number of patients included in studies with LV/biV pacing in HOCM as well as the fact that all of them are observational and uncontrolled requires caution in interpreting the results. However, the differences observed in comparison with standard DDD RVA pacing warrants further research. Considering the relatively large number of HOCM patients submitted to cardioverter-defibrillator implantation for primary or secondary prevention, data for such analysis should be readily available.In selected patients with HOCM, LV/biV pacing is feasible and usually the best configuration for gradient reduction. Overall, LV/biV pacing in patients with HOCM significantly and progressively improves functional capacity and quality of life. It may also induce LV reverse remodelling."} +{"text": "Microbial cells are highly complex and heterogeneous systems. In general, cell populations contain subgroups of cells which exhibit differences in growth rate as well as resistance to stress and drug treatment In the past 20 years a new form of microscopy, atomic force microscopy (AFM), has revolutionized the way researchers probe the microbial cell surface. Instead of using an incident beam, AFM measures the minute forces acting between a sharp tip and the sample AFM is much more than a surface-imaging tool in that it also measures the localization and mechanical properties of the individual cell surface molecules. In this modality, known as single-molecule force spectroscopy, the cantilever deflection is recorded as a function of the vertical displacement of the scanner (as the sample is pushed towards the tip and it retracts) Lactobacillus rhamnosus GG, Lactococcus lactis, and Lactobacillus plantarumL. rhamnosus GG had a rough surface morphology decorated with 15 nanometer\u2013high wave-like structures, attributed to the production of extracellular polysaccharides involved in host adhesion L. lactis showed 25 nanometer\u2013wide striations documenting peptidoglycan cables running parallel to the short cell axis, thus supporting the classical model for peptidoglycan organization Bacillus subtilisL. plantarum documented a highly polarized surface morphology that was correlated with a heterogeneous distribution of teichoic acids There has been rapid progress in recent years using AFM for imaging microbial surfaces under physiological conditions. In structural biology, AFM has provided fascinating insights into the supramolecular architecture of membrane proteins, thereby complementing data obtained by electron and X-ray crystallography Bacillus thuringiensis flagella involved in cell motility Aspergillus fumigatusCorynebacterium glutamicumStaphylococcus aureus was observed during growth, revealing ring-like and honeycomb structures at 20 nanometers resolution Bacillus atrophaeus spores revealed germination-induced alterations in spore coat architecture and disassembly of rodlet structures Candida albicans and macrophages Remarkably, high-resolution imaging has allowed researchers to observe cell surface structures to a resolution of a few nanometers. Observed structures include Escherichia coli cells AFM imaging thus opens up unprecedented possibilities for studying the structural details of the surface of microbial pathogens without drying, staining, or fixation. As conventional AFM imaging is limited by a rather poor temporal resolution, an important challenge is to increase the speed of AFM to study fast dynamic biological processes Shewanella oneidensis bacteria C. albicans with AFM tips terminated with specific antibodies triggered the formation and propagation of adhesion nanodomains on the cell surface While AFM imaging lacks biochemical specificity, single-molecule force spectroscopy with functionalized AFM tips makes it possible to map the distribution of specific molecules on living cells. The method involves scanning the cell surface with a tip bearing cognate ligands while measuring specific receptor-ligand forces E. coli fimbrial adhesive protein FimH which strengthen under external mechanical force C. albicans revealed sawtooth patterns with multiple force peaks, corresponding to the force-induced unfolding of hydrophobic tandem repeats engaged in cell adhesion and respond to force . Knowing these molecular properties is critical to our understanding of cell surface functions.Many challenges remain to be addressed. As we have already discussed, further developments in high-speed AFMs"} +{"text": "There is no consensus on optimal use of radiotherapy following radical prostatectomy. The purpose of this study was to describe opinions of urologists and radiation oncologists regarding adjuvant and salvage radiotherapy following radical prostatectomy.Urologists and genitourinary radiation oncologists were solicited to participate in an online survey. Respondent characteristics included demographics, training, practice setting, patient volume/experience, and access to radiotherapy. Participant practice patterns and attitudes towards use of adjuvant and salvage radiotherapy in standardized clinical scenarios were assessed.One hundred and forty-six staff physicians participated in the survey (104 urologists and 42 genitourinary radiation oncologists). Overall, high Gleason score , positive surgical margin , and extraprostatic tumour extension conferred an increased probability of recommending adjuvant radiotherapy. Radiation oncologists were more likely to recommend adjuvant radiotherapy across all clinical scenarios . Major differences were found for patients with Gleason 6 and isolated positive surgical margin (radiotherapy selected by 21% of urologists vs. 70% of radiation oncologists), and patients with extraprostatic extension and negative surgical margins (radiotherapy selected by 18% of urologist vs. 57% of radiation oncologists).Urologists and radiation oncologists frequently disagree about recommendation for post-prostatectomy adjuvant radiotherapy. Since clinical equipoise exists between adjuvant versus early salvage post-operative radiotherapy, support of clinical trials comparing these approaches is strongly encouraged. Approximately 40% of patients diagnosed with prostate cancer will be treated with radical prostatectomy and approximately 15-35% will develop a detectible serum prostate-specific antigen (PSA) following surgery . A positTraditionally, clinicians may have been more likely to treat patients with androgen deprivation if clinicopathologic features were associated with high risk of systemic disease and more likely to treat patients with adjuvant or salvage radiotherapy if features were associated with high risk of isolated localized disease . HoweverWhile indications for pelvic radiotherapy may have changed, questions remain about the timing of treatment. Adjuvant radiotherapy is offered to patients prior to PSA recurrence while salvage radiotherapy reserves treatment, and its associated side effects, for men with proven biochemical recurrence. Randomized trials of adjuvant radiotherapy versus observation reveal a reduction in biochemical recurrence and prolonged survival (SWOG 8794) while observational studies suggest salvage radiotherapy versus observation reduces progression and prolongs survival ,20. The th, 2011. Institutional ethics approval was obtained for this survey from the Ottawa Hospital Research Ethics Board prior to study commencement.In October 2011, Canadian Urological Association (CUA) members and genitourinary radiation oncologists from the Canadian Association of Radiation Oncology (CARO) were invited to participate in an online survey. CUA members were contacted through the CUA listserv and radiation oncologist emails were available through the CARO member directory. A second request was made one month following the original invitation. E-mail recipients were provided with a hyperlink to an online survey that populated a secure database. The survey was closed on November 7Participants were asked to provide demographic information including age, geographic location of practice, specialty (urology or radiation oncology), practice type (academic or community), years in practice, sub-specialty training, number of prostate cancer patients assessed per year, and access to radiotherapy.Respondents were asked to rate how various clinical and pathologic variables independently influenced their recommendation for adjuvant and salvage radiotherapy via Likert items. Clinical variables included patient age, urinary continence, and erectile function. Pathologic variables included extraprostatic tumour extension, seminal vesicle tumour invasion, lymph node metastases, pre- and post-operative PSA concentrations, Gleason score, pathologic stage, and surgical margin status. Respondents were provided with a standardized case scenario of a healthy 60 year old male 3-months post radical prostatectomy with an undetectable PSA. They were asked to recommend for or against adjuvant radiotherapy for this patient given varied Gleason score, pathologic stage, and surgical margin status.adjuvant radiotherapy after radical prostatectomy in the provided clinical scenario. A-priori independent variables for the clinical scenario model were Gleason grade, tumour stage, surgical margin status, and medical specialty. P-values < 0.05 were considered statistically significant.Survey responses were summarized with frequencies and percentages. Associations between clinician/patient characteristics and choice of adjuvant radiotherapy were calculated using logistic regression. Log binomial regression was used to calculate relative risks (RR) using the proc genmod procedure in SAS. RR are presented with 95% confidence intervals (CI). Candidate predictor variables included clinician characteristics and pathologic factors . Each predictor variable was assessed as a categorical variable. The primary outcome was the respondent\u2019s decision to recommend From 586 listed emails, 146 (25%) staff physicians participated in the survey and were included in the analysis. 104 (22%) of solicited urologists and 42 (40%) of solicited genitourinary radiation oncologists completed the survey. The majority of radiation oncologists and approximately half of urologists indicated they practiced in an academic institution. Sub-specialty training in genitourinary oncology was reported in 51 (35%) respondents. The mean number of years in practice was 14 years (SD 10.3). Full demographic characteristics are presented in A majority of urologists and radiation oncologists reported that recent randomized trials have changed the way they manage patients after radical prostatectomy. When asked their opinion regarding the value of adding androgen deprivation therapy (ADT) to adjuvant or salvage radiotherapy, 29 (35%) urologists and 13 (32%) radiation oncologists reported believing it is likely beneficial and 44 (52%) urologists and 22 (55%) radiation oncologist would recommend it to high risk patients. A large proportion of urologists and radiation oncologists believed more research is required to evaluate the benefit and harm of ADT when used in conjunction with radiotherapy following prostatectomy. The influence of clinical and pathologic factors on the recommendation for adjuvant or salvage radiotherapy is presented in Large differences were identified in the opinions of radiation oncologists and urologists regarding recommendations for adjuvant radiotherapy when pathologic variables were placed in the context of a standardized clinical scenario . SeventyOverall, radiation oncologists were 48% more likely to recommend adjuvant radiotherapy compared to urologists . Of the remaining clinical factors evaluated, only physician age had a significant impact on the recommendation for adjuvant radiotherapy with older physicians being less likely to recommend radiotherapy . Practice setting, access to radiotherapy, and genitourinary oncology fellowship training did not strongly influence the probability of recommending radiotherapy .Pathologic variables were associated with the recommendation for adjuvant radiotherapy . A GleasTo adjust for potential confounders, multivariable analysis was performed to determine the independent associations between each predictor variable and the recommendation for adjuvant radiotherapy . PatholoThis survey explored the practice patterns and opinions of two different specialty groups involved in the management of patients with prostate cancer, urologists and radiation oncologists, and identified factors that influence recommendations for post-operative radiotherapy. For every pathological variable examined, radiation oncologists were more likely to recommend adjuvant radiotherapy than were urologists with a mean absolute difference of 27% and relative difference of 48%. There were clinical scenarios where urologists and radiation oncologists agreed; specifically, both commonly recommended adjuvant radiotherapy in patients with extraprostatic tumour extension and a positive surgical margin, high Gleason score and a positive surgical margin, or seminal vesicle invasion. Conversely, there was lack of consensus for patients with low Gleason score and an isolated positive surgical margin, and for patients with extraprostatic extension and negative surgical margin. The influence of medical specialty on treatment recommendations was striking and is a trend that has been previously observed amongst urologists and radiation oncologists when selecting primary treatment of prostate cancer .Standardized scenarios in the survey represented patients that would have met inclusion criteria for entry into SWOG 8794 . The SWOExamining each variable independently, a large proportion of physicians surveyed were more likely to recommend adjuvant post-operative radiotherapy in patients with extraprostatic disease, high Gleason score, seminal vesicle invasion, and positive surgical margins. It is interesting to note that surgical margin status appeared to influence urologists much more than radiation oncologists (RR 1.6 vs. 1.08). Taken as a whole, these results indicate a departure from the dogmatic approach of avoiding radiotherapy in patients with high risk of metastases . FactorsAmong post-operative patients who develop a detectable serum PSA, the survey identified several factors that influence the likelihood of physicians recommending salvage radiotherapy. In addition to the pathological and clinical characteristics identified for adjuvant radiotherapy, post-operative PSA kinetics strongly influenced physician opinion. Physicians were more likely to recommend radiotherapy when there was a prolonged duration between prostatectomy and detection of post-operative PSA and when the PSA doubling time was long. This finding is somewhat surprising and illustrates a misconception amongst physicians surveyed regarding the value of salvage radiotherapy for long and short PSA doubling times (PSADT). Although observational studies have reported a better prognosis for men with PSADT > 10 months, the absolute benefit of salvage radiotherapy is in fact greater in men with rapid PSADT ,20. TherA limitation of the current literature is a lack of randomized comparison of adjuvant and salvage radiotherapy. Adjuvant radiotherapy (prior to PSA recurrence) may be better than salvage radiotherapy (when PSA becomes detectible) for several reasons. Firstly, recurrences are predominantly local in the absence of seminal vesicle invasion or lymph node metastases, therefore early local treatment may prevent metastases . FurtherIdentification of patients likely to benefit from post-operative radiotherapy is important since this intervention is associated with harm . ComplicThis survey has limitations. We are unable to determine the true response rate since email lists were used and the activity of the email accounts could not be determined. While a wide distribution of clinician age, practice setting, and sub-specialty training was observed in the respondents, information about non-respondents was not available to assess potential biases. This survey included primarily Canadian physicians, and practice patterns may be different in other health care settings. Finally, this survey draws data from responses to realistic but fictional patient scenarios and thus cannot control for variations in respondent interpretation.The results of this survey reveal some consensus and some salient differences in the opinions of physicians regarding post-radical prostatectomy radiotherapy. Most notably, there was a large difference in the proportion of urologists and radiation oncologists who recommended radiotherapy for patients with low Gleason scores and isolated positive margins or extraprostatic extension. Since clinical equipoise exists between adjuvant and early salvage post-operative radiotherapy, support of clinical trials comparing these two approaches is strongly encouraged."} +{"text": "Cuculus canorus) is a generalist brood parasite that lays its eggs in the nest of many different passerine birds, but each female tends to specialize on one particular host species giving rise to highly specialized host races. The different host species show large variation in their ability to invest in the parasitic offspring, presenting an opportunity for female cuckoos to bias offspring sex ratio in relation to host species quality. Here, we investigate host-race specific sex allocation controlling for maternal identity in the common cuckoo. We found no evidence of any significant relationship between host race and sex ratio in one sympatric population harbouring three different host races, or in a total of five geographically separated populations. There was also no significant association between host quality, as determined by species-specific female host body mass, and cuckoo sex ratio. Finally, we found no significant relationship between individual cuckoo maternal quality, as determined by her egg volume, and sex ratio within each host race. We conclude that the generalist brood-parasitic common cuckoo show no significant sex-ratio bias in relation to host race and discuss this finding in light of gene flow and host adaptations.Sex allocation theory and empirical evidence both suggest that natural selection should favour maternal control of offspring sex ratio in relation to their ability to invest in the offspring. Generalist parasites constitute a particularly interesting group to test this theory as different females commonly utilize different host species showing large variation in provisioning ability. The common cuckoo ( Fisher In birds, females are the heterogametic sex and the sex determining division in avian meiosis occurs prior to ovulation and fertilization, providing the females with an unusual direct opportunity to modify offspring sex ratio Cuculus canorus) therefore constitutes a particular interesting species for investigating sex allocation. The common cuckoo is highly polygynous with ca. half of all males siring offspring with more than one female and is sexually size dimorphic The avian brood-parasitic common cuckoo (Molothrus ater) A few previous studies have not revealed any significant relationship between host species and sex ratio in the common cuckoo or the brood-parasitic brown-headed cowbird was drawn by puncturing either the brachical or femoral vein. Permits for working with cuckoos and their hosts and collect DNA samples was received in each country; permits were issued by the Ministry of Environment and Water in Bulgaria; the Municipal Office in Hodonin (3C2KA/2003) in the Czech Republic; the Southeast Finland Regional Environment Centre in Finland; the Middle-Danube-Valley Inspectorate for Environmental Protection (31873), Nature Conservation and Water in Hungary; and the Regional Ethical Committee in Wroc\u0142aw and the Faculty of Biology (KWB.0118.1-2003), University of Wroc\u0142aw in Poland.Milaria calandra), great reed warblers and marsh warblers was collected in the surroundings of Zlatia, north-western Bulgaria A. scirpaceus) in Luzice, Czech Republic where also great reed warblers, marsh warblers and sedge warblers (A. schoenobaenus) are parsitized Phoenicurus phoenicurus) Data on three sympatrically breeding cuckoo host races parasitizing corn buntings . All loci were amplified by polymerase chain reaction (PCR) on a GeneAmp PCR System 9700 and run on a 3130XL Genetic Analyser . The sex marker and microsatellites were scored in Genemapper v. 3.7 , and the mitochondrial sequence data were assembled and manually checked in Geneious v. 4.7.6 We used the CHD1-M5 primer in combination with P8 for molecular sex determination Many cuckoo nestlings were collected within the same geographic area and could be either full- or halfsiblings, and hence potentially represent a problem of pseudoreplication. We therefore analysed a genetic dataset on 13 microsatellite markers . Furthermore, there were no significant differences in sex ratio between any pair of the five host races pooled across the different geographic localities , or between sympatric and allopatric populations, including host species as a random effect to control for host race identity .In order to analyze the effect of host species quality we included species-specific host female body mass In this study, we investigated host-specific sex ratio in the generalist brood-parasitic common cuckoo. We hypothesized that sex ratio of cuckoo offspring should vary in relation to host species quality in accordance with predictions from sex allocation theory. However, we found no evidence of any significant relationship between host race and sex ratio in one sympatric population harbouring three different host races, or in a total of five different geographically separated populations. Hence, our results corroborate the few previous studies on avian brood parasites According to theory, female cuckoos have both the ability and opportunity to increase their own fitness by selectively producing the rarer sex. Firstly, avian females have an unusual direct opportunity to modify offspring sex ratio because the sex determining division in avian meiosis occurs prior to ovulation and fertilization The traditional Trivers-Willard hypothesis rests on three assumptions. Firstly, parental condition must be associated with offspring condition; secondly, any difference in offspring condition must persist into adulthood; and thirdly, condition must differentially affect the mating success of one sex more than the other sensu Trivers and Willard The occurrence of genetic differentiation and assortative mating may explain why females show no evidence of sex ratio bias in relation to host quality. If males commonly mate within their own host race, males from large host races will not compete directly with males from smaller host races, and therefore not achieve a higher reproductive success than their sisters. Hence, natural selection will not select for a male-biased sex ratio sensu Trivers-Willard may be counteracted by the selection for smaller females in cuckoos. This could also explain the lack of any relationship between sex ratio and female quality, as determined by cuckoo egg volume, within each host race. It is also possible that egg volume does not capture maternal quality in the way we expect, and that other measures like investment in hormones and anti-oxidants in the oocyte would be more suitable A comparative study on the family Cuculidae suggests that sexual size dimorphism has more likely evolved via coevolution than sexual selection in this taxa We conclude that the generalist brood-parasitic common cuckoo show no evidence of sex-ratio bias in relation to host race, host race quality or individual maternal quality."} +{"text": "Aging is accompanied by substantial changes in brain function, including functional reorganization of large-scale brain networks. Such differences in network architecture have been reported both at rest and during cognitive task performance, but an open question is whether these age-related differences show task-dependent effects or represent only task-independent changes attributable to a common factor . To address this question, we used graph theoretic analysis to construct weighted cortical functional networks from hemodynamic responses in 12 younger and 12 older adults during a speech perception task performed in both quiet and noisy listening conditions. Functional networks were constructed for each subject and listening condition based on inter-regional correlations of the fMRI signal among 66 cortical regions, and network measures of global and local efficiency were computed. Across listening conditions, older adult networks showed significantly decreased global efficiency relative to younger adults after normalizing measures to surrogate random networks. Although listening condition produced no main effects on whole-cortex network organization, a significant age group x listening condition interaction was observed. Additionally, an exploratory analysis of regional effects uncovered age-related declines in both global and local efficiency concentrated exclusively in auditory areas , further suggestive of specificity to the speech perception tasks. Global efficiency also correlated positively with mean cortical thickness across all subjects, establishing gross cortical atrophy as a task-independent contributor to age-related differences in functional organization. Together, our findings provide evidence of age-related disruptions in cortical functional network organization during speech perception tasks, and suggest that although task-independent effects such as cortical atrophy clearly underlie age-related changes in cortical functional organization, age-related differences also demonstrate sensitivity to task domains. Aging is characterized by marked declines in sensory and cognitive functions In recent years, graph theoretic analysis has offered a powerful data-driven framework to explore the topological organization of brain networks These functional differences are underlain by neuroanatomical changes across the lifespan. Such changes include widespread atrophy of both subcortical and cortical grey matter structures Given these pervasive, co-occurring functional and neuroanatomial changes, the question also arises whether age-related effects on brain functional organization are independent of cognitive domains , or show task specificity. Recently, Wang et al. examined changes in functional networks of younger and older adults obtained via fMRI during memory encoding and retrieval tasks involving visually presented words and pictures To address these questions, we employed functional MRI to investigate age-related differences in large-scale cortical networks associated with speech perception tasks. In the scanner experiment, we tested 12 younger and 12 older adults' abilities to recognize spoken word stimuli and match them to objects on a screen in both a quiet listening condition and in loud multi-talker background noise regional measures) and also averaged across all nodes in each network to describe the overall network topology. We compared both regional and whole-cortex measures across age groups and task conditions, after normalizing the graph measures to values in surrogate random networks. Additionally, to test for a relationship between age-related changes in functional network properties and neuroanatomical characteristics, we examined the relationship between whole-cortex network measures and mean cortical thickness.In the present analysis, we applied graph theoretic analysis to construct weighted cortical functional networks for each subject and listening condition based upon interregional correlations of the fMRI signal among 66 cortical regions. Graph measures describing the efficiency of global and local information transfer were computed within each individual network node of older adults coupled with age-related increases in cognitive areas in prefrontal and posterior parietal cortex, changes believed to underlie a compensatory mechanism for reduced sensory abilities in aging To foreshadow the results, we found significant age-related decreases in global network efficiency, agreeing with previous studies of age effects on large-scale brain networks globE) and local (locE) efficiency were computed and averaged across all cortical regions to quantify the efficiency of global and local information transfer within the networks. by assigning connections based on the inter-regional correlation of fMRI responses between 66 cortical regions specified in the Desikan-Killiany atlas . Both younger and older adults possessed small-world network topologies characterized by es e.g., . RelativTo test these differences statistically, summary measures of osts see . HencefoConceivably, observed differences in brain functional connectivity could be related to head motion in the scanner Next, we tested for effects of subject group and listening condition on network measures within individual cortical regions. We applied a single p-value cutoff of 0.05 (uncorrected for multiple comparisons) to establish significance for regional effects; thus, our results at the regional level must be regarded as exploratory. Additionally, we found several areas that showed main effects of listening condition on the network measures see . The noiWe also observed regions showing an interaction effect between subject group and task condition see . For , ssubjects .As anticipated, older adults had significantly reduced mean cortical thickness relative to younger adults despite normal peripheral hearing abilities Interestingly, we observed a different pattern of results in these residual data relative to the original results see , S2. ForThe performance effect analysis also revealed a different pattern of results for the regional network measures . As in tyrus see . ListeniIn this study, we applied a weighted graph theoretic analysis to assess cortical functional organization in younger and older adults during performance of a speech perception task in both quiet and noisy listening conditions. We found that older adult cortical networks possessed significantly reduced global efficiency relative to younger adults after normalizing graph measures to values in randomized networks. Most importantly, a significant group x listening condition interaction effect for This report adds to a body of research linking cognitive aging to disrupted organization of communication pathways encompassing the entire cerebral cortex Importantly, the age-related disruptions observed for whole-cortex network properties were underlain by regional changes concentrated in auditory areas of the lateral temporal cortex. Older adults possessed decreased global and local efficiency within bilateral superior and middle temporal cortex. The superior temporal cortices constitute key auditory regions responsible for low-level acoustic analysis; thus, declines in efficient information transfer involving these regions could affect mapping of inputs from the peripheral auditory system onto acoustical representations Additionally, we observed regions that exhibited main effects of listening condition (quiet vs. noisy) on either global or local efficiency. Several of these regions overlapped the default-mode network, including bilateral posterior parietal and right parahippocampal cortex We also found several cortical areas showing significant group x listening condition interaction effects on the regional network measures. Group x condition interaction effects were observed in left primary auditory cortex, right middle temporal cortex, and in default-mode areas within posterior parietal cortex. Thus, in addition to task-dependent age-related differences on whole-cortex network structure, the two listening conditions evoked differential effects on network organization between younger and older adults at the regional level.In addition, group x condition interaction effects on Based on findings of consistent age-related differences in activation patterns and functional network topology across memory encoding and recognition tasks, Grady et al. and Wang et al. argued that age-related changes in brain network organization derive from a common, domain-general factor Declining cognitive performance is a central aspect of aging. Even though the older participants in our study possessed normal peripheral hearing abilities, their speech perception performance was significantly worse than that of younger adults under the increased sensory/cognitive demands of the noisy listening environment Ultimately, the effects of reduced cognitive performance on cortical functional organization in aging remains an area for further investigation. However, the significant age-related effects at both the whole-cortex and regional levels in this residual analysis suggest that task performance is not the only important factor driving the results observed in this study. These types of complementary analyses may prove useful in future studies to help disentangle the various behavioral, anatomical, and physiological factors influencing functional organization of the cortex in both aging research and comparative neuroimaging studies in general.Looking across all subjects, we found a significant positive correlation between mean cortical thickness and It is also worth noting some important limitations of our study. First, similar to previous studies This study provides evidence of age-related disruptions in large-scale cortical functional organization during performance of a speech perception task. Although the observed age-related differences in whole-cortex network topology partly corroborated previous studies of resting-state connectivity All subjects in this experiment gave informed written consent prior to inclusion in the study and were compensated monetarily for their participation. All research was conducted under the approval of the Northwestern University Institutional Review Board, and thus adhered to the ethical standards outlined in the 1964 Declaration of Helsinki.In this study, we employed functional magnetic resonance imaging (fMRI) to examine characteristics of cortical functional networks related to speech perception in noise (SPIN) performance in younger (19\u201327 years) and older (63\u201375 years) adults We recruited twelve younger ; 8 females) and twelve older ; 6 females) adults with no reported neurological deficits for participation in the study.Speech stimuli consisted of a set of twenty target words obtained from In the scanner experiment, subjects were presented with one-word speech stimuli via headphones . During each stimulus presentation, subjects were shown three images on a screen, including an image matching the target word and two distracters, and used a response box to select the image corresponding to the target word. For instance, in one trial, subjects heard the word \u201cwitch\u201d in the presence of background noise, and had to select between images of a witch and two other objects from the list of stimuli. Stimuli were presented in 12-second blocks consisting of three individual stimuli (each corresponding to the same listening condition), limiting response times to four seconds per stimulus. In total, the fMRI experiment consisted of 60 stimulus blocks per condition as well as 30 null blocks during which no stimuli were presented, with all blocks presented in pseudorandomized order.*-weighted functional images were acquired using a susceptibility-weighted EPI pulse sequence , with 24 slices acquired per scan in an interleaved measurement . Functional image acquisition occurred directly after each 12-second stimulus block and lasted two seconds in duration, resulting in a 14-second repetition time (TR). The sparse functional image acquisition (long TR) ensured there was no scanner noise during stimulus presentation MR imaging data were acquired on a Siemens 3T Trio machine at the Center for Advanced MRI at Northwestern University. T1-weighted, high-resolution anatomical images were acquired axially . During the speech perception experiment, T2We pre-processed MRI data using AFNI V) were extracted containing the functional data from the stimulus blocks corresponding to the listening condition of interest, and pair-wise, zero time-lag Pearson's correlations were calculated between nodes such thati and j, where R) containing the pair-wise correlations of the fMRI responses between each pair of cortical regions for each listening condition.Next, using FreeSurfer's automated cortical parcellation G by assigning undirected, weighted connections (edges) between nodes whose absolute pair-wise correlation exceeded a pre-specified cost threshold, cr. This resulted in a weighted adjacency matrix (W), such that ij\u200a=\u200aW|ijR| if ij|\u2265rc|R or ij\u200a=\u200a0W if ij|60% and sufficient right ventricular function. Ten days later she was discharged to rehabilitation in a stable condition.The patient had signs of FM on histological findings with foci myocyte necrosis and lymphocytic infiltration with interstitial oedema. In spite of serologic studies and viral genome research on myocardial biopsies, including in situ hybridization and polymerase chain reaction, pathogenic agents were not identified.FM is clinically characterized by distinct onset of cardiac symptoms in otherwise healthy patients after nonspecific flu-like symptoms rapidly resulting in severe ventricular dysfunction and cardiogenic shock. Most of these patients with acute fulminant myocarditis are stabilized with heart failure management and recover within a few weeks . HoweverFor our case percutaneous cannulation and emergency implementation of ECMO was initially the therapy of choice due to her life-threatening condition, maybe as a bridge to decision. With cardiac nonrecovery evident and progressive endorgan dysfunction, support was escalated to biventricular nonpulsatile CentriMag assist device implantation. Arguments in favour of BVAD shortterm support are better unloading of both ventricles, a primary condition for recovery from fulminant myocarditis, and avoidance of significant morbidities associated with prolonged ECMO support . Successful treatment of fulminant myocarditis with severe hemodynamic compromise and end organ failure is possible with early CentriMag biventricular assist device implantation. In most cases it facilitates completely cardiac recovery."} +{"text": "Hundreds of diverse genetic loci have been linked to autism spectrum disorders (ASDs), making large-scale analysis essential for understanding the molecular events underlying the pathogenesis of these disorders. Our laboratory first released the autism database AutDB in 2007 as a bioinformatics tool for systematic curation of all known ASD candidate genes -3. AutDBTo curate the PIN module, our researchers utilize a multi-level annotation model to systematically search, collect and extract information entirely from published, peer-reviewed scientific literature. Although we initially consult public molecular interaction databases (HPRD and BioGRID) and commercial molecular interaction software , every interaction is manually extracted and verified by evaluating the primary reference articles from PubMed. Our manual curation has proved critical for accurate annotation, because these references were the second largest source of references for the initial PIN dataset, providing more interactions than both HPRD and Pathway Studio. Each ASD gene entry within the PIN module is presented as a multi-level display, with interactive graphical and tabular views of its corresponding interactome.The initial PIN dataset includes interactomes for 86 ASD candidate genes, with a total of 1,311 direct protein interactions garnered from 533 unique primary references. These interactomes are composed of 6 interaction types and 13 species, documented by 402 distinct pieces of evidence. Our researchers will expand and maintain the data content of the PIN module with systematic updates.We have created an integrated bioinformatics tool that can be used for the large-scale analysis of the biological relationships among ASD candidate genes. Such network analysis is envisioned to provide a framework for identifying the key molecular pathways underlying ASD pathogenesis, potentially leading to the development of novel drug therapies."} +{"text": "We investigated the occurrence of goal-directed motivational change in the form of apathy in patients with frontotemporal dementia (FTD), particularly those with behavioral variant social and executive deficits (bvFTD). Standardized behavioral inventory was employed to survey and compare apathy ratings from patients and caregivers. In cases of bvFTD, apathy ratings were further related to measures of social cognition, executive function, and atrophy on brain MRI. Results indicated that caregivers rated bvFTD patients as having significantly elevated apathy scores though patient self-ratings were normal. Caregiver and self-ratings of FTD samples with progressive nonfluent aphasia and semantic dementia did not differ from healthy controls and their informants. In the bvFTD sample, caregiver apathy scores were not correlated with general cognitive screening or depression scores, but were significantly correlated with social cognition and executive function measures. Voxel-based morphometry revealed that apathy ratings in bvFTD were related to prominent atrophy in the right caudate , the right temporo-parietal junction, right posterior inferior and middle temporal gyri, and left frontal operculum- anterior insula region. Findings suggest that bvFTD is associated with a significant breakdown in goal-directed motivated behavior involving disruption of cortical-basal ganglia circuits that is also related to social and executive function deficits."} +{"text": "Lesion-symptom mapping studies are based upon the assumption that behavioral impairments are directly related to structural brain damage. Given what is known about the relationship between perfusion deficits and impairment in acute stroke, attributing specific behavioral impairments to localized brain damage leaves much room for speculation, as impairments could also reflect abnormal neurovascular function in brain regions that appear structurally intact on traditional CT and MRI scans. Compared to acute stroke, the understanding of cerebral perfusion in chronic stroke is far less clear. Utilizing arterial spin labeling (ASL) MRI, we examined perfusion in 17 patients with chronic left hemisphere stroke. The results revealed a decrease in left hemisphere perfusion, primarily in peri-infarct tissue. There was also a strong relationship between increased infarct size and decreased perfusion. These findings have implications for lesion-symptom mapping studies as well as research that relies on functional MRI to study chronic stroke."} +{"text": "Chimera states are spatio-temporal patterns of synchrony and disorder observed in homogeneous oscillatory media with nonlocal coupling. They are characterized by coexistence of distinct spatial regions with regular synchronized and irregular incoherent motion. Initially discovered for phase oscillators, chimera states have been also found in systems of nonlocally coupled discrete maps , time-coWe demonstrate the existence of chimera states for neural oscillators . In detaSurprisingly, we find that for increasing coupling strength classical chimera states undergo transitions from one to multiple domains of incoherence. Then patches of synchronized dynamics appear within the incoherent domain giving rise to a multi-chimera state. We find that, depending on the coupling strength and range, different multi-chimeras arise in a transition from classical chimera states. The additional spatial modulation is due to strong coupling interaction and thus cannot be observed in simple phase-oscillator models."} +{"text": "Even if better clinical outcomes have been achieved with the implantation of newer generation continuous-flow left ventricular assist devices (LVADs), infection complications are still a major risk for these patients in long-term follow-up.We present a case of a 56-year-old male with dilated cardiomyopathy who was urgently implanted with left ventricular assist device HeartMate II. During the entire postoperative period, we observed repeated life-threatening septic complications. Clinical signs of infection disappeared after prolonged treatment with broad-spectrum antibiotics and patient was discharged to outpatient monitoring. During the entire duration of circulatory support, no LVAD suction events were detected, pump power consumption remained in the normal range and the patient was listed for heart transplantation. Patient was two month rehospitalized due to worsening of his status. Hemoglobinuria, an increase of inflammatory markers, and alteration in hepatic and renal function were detected. TEE imaging showed no obstructive formation in inflow or outflow cannulas; only velocities were decreased. The LV was severely dilated and the aortic valve was opening at each contraction. Patient was initially considered for systemic thrombolysis, but this urgent status was finally solved with explantation of the LVAD and subsequent heart transplantation. Massive obstruction with thrombus-like formation was found in the outflow cannula. Histopathologic examination and microbiologic culturing of the mass showed extensive fungal growth (Aspergillus species). During the postoperative period, patient was aggressively treated with antifungal therapy. He was discharged 8 weeks after the transplantation.We believe that clinical decision-making in patients with signs of ongoing sepsis and end-organ dysfunction together with any signs of LVAD malfunction should be very straightforward in terms of device exchange or explantation."} +{"text": "Congenital muscular torticollis (CMT), also known as fibromatosis colli, is recognized as unilateral contracture and shortening of the sternocleidomastoid (SCM) muscle due to muscle atrophy and interstitial fibrosis, causing ipsilateral head tilt and turn Do, . Its freThis 31-year-old woman exhibited a fixed left head tilt and turn with minor limitation of cervical range of motion since childhood. Her forceps-assisted birth by vaginal delivery was not associated with perinatal injuries. During childhood, she reported persistent head tilt to the left. She had headaches and back pain presumably from compensatory efforts at straightening her neck posture. There was no sensory trick or abnormal posturing of other body segments. Palpation of her neck musculature revealed a non-tender, taut fiber within the left SCM. She had limitation of right head tilt into the affected SCM but experienced substantial relief of their torticollis and associated pain following partial myectomy of the anterior belly of the SCM muscle. Biopsy in both cases demonstrated fibrous transformation of skeletal muscle fibers Figures , pathognCMT is a rare cause of pseudodystonia expressed as torticollis, whose recognition is important in order to avoid ineffective and potentially harmful antidystonic treatments. CMT is usually recognized in neonates as a circumscribed palpable mass confined to the SCM, affected unilaterally, which may gradually disappear between 4 and 8 months of age or be associated with other orthopedic abnormalities such as hip dysplasia or lower extremity abnormalities (Morrison and MacEwen, Although isolated successes have been reported with chemodenervation (Bouchard et al., Besides CMT, other causes of pseudodystonic torticollis include focal myopathies, rotational atlantoaxial subluxation, posterior fossa tumors, congenital Klippel\u2013Feil anomaly, syringomyelia, trochlear nerve palsy, and vestibular torticollis."} +{"text": "Objective: The aim of this work was to review de literature about the role of mesenchymal stem cells in bone regenerative procedures in oral implantology, specifically, in the time require to promote bone regeneration.Study Design: A bibliographic search was carried out in PUBMED with a combination of different key words. Animal and human studies that assessed histomorphometrically the influence of mesenchymal stem cells on bone regeneration procedures in oral implantology surgeries were examined.Reults:- Alveolar regeneration: Different controlled histomorphometric animal studies showed that bone regeneration is faster using stem cells seeded in scaffolds than using scaffolds or platelet rich plasma alone. Human studies revealed that stem cells increase bone regeneration.- Maxillary sinus lift: Controlled studies in animals and in humans showed higher bone regeneration applying stem cells compared with controls.- Periimplantary bone regeneration and alveolar distraction: Studies in animals showed higher regeneration when stem cells are used. In humans, no evidence of applying mesenchymal stem cells in these regeneration procedures was found.Conclusion: Stem cells may promote bone regeneration and be useful in bone regenerative procedures in oral implantology, but no firm conclusions can be drawn from the rather limited clinical studies so far performed. Key words:Mesenchymal stem cells, bone regeneration, dental implants, oral surgery, tissue engineering. Embryonic stem cells are derived from blastocysts and are Surgical bone regeneration procedures such as guided bone regeneration or maxillary sinus augmentation, are well established , but metThe aim of this work was to review de literature about the role on MSC in bone regenerative procedures in oral implantology, specifically, in the time require to promote bone regeneration.A bibliographic search in PUBMED with a combination of different key words: mesenchymal stem cells, bone regeneration, dental implants, tissue engineering, dental pulp stem cells, periodontal ligament stem cells, apical papilla stem cells, deciduous teeth stem cells, oral implantology, oral surgery. Moreover, the references of the articles were also assessed. English articles published until 2011 were evaluated. Animal and human studies that assessed the influence of MSC on bone regeneration procedures in oral implantology surgeries were examined. Studies about alveolar bone regeneration, maxillary sinus lift, periimplantary bone regeneration and alveolar distraction were identified.-Inclusion criteriaDue to the number of studies performed no strict inclusion criteria could be performed. Only studies that used MSC to performed bone regeneration where histologic or histomorfometric analysis was performed were included. The studies should specify the moment where the analysis was carried out.\u2022Clinical Human studies: Clinical trials, case-controls and case series were included. Case reports were excluded.\u2022 Animal studies: Controlled studies were included. Non-controlled studies were excluded.When we applied these inclusion criteria, 26 articles were specifically analyzed. Data about study design, bone regeneration surgery performed and time of histologic -histomorfometric study was carefully taken in account. Different MSC sources, scaffolds and growth factors were used in the reviewed articles so no differences between studies could be performed in this sense.Tissue engineering is an emerging interdisciplinary field, which applies principles of life sciences and engineering towards the development of biological substitutes that restore, maintain and improve the function of damaged and/or lost tissues . In tiss-Alveolar bone regeneration\u2022Animal studiesDifferent studies have compared bone regeneration using MSC and PRP. Yamada et al. in 10 mmMylonas et al. applied Other studies exposed that MSC can also accelerate bone formation in alveolar shockets ,27, in 1Clinical human studiesMeijer et al. implante-Maxillary sinus lift \u2022Animal studiesControlled studies in animals using MSC to increase bone regeneration in maxillary sinus lifts have been performed. Pieri et al. in a spl\u2022Clinical human studiesClinical case series studies using MSC with different biomaterials have been performed. Shayesteh et al. performeGronshor et al. in a conVery recently the first controlled clinical trial using engineered bone stem cells in maxillary sinus elevation has been performed. Rickert et al. executed-Periimplantary bone regeneration\u2022Animal studiesAnimal studies have evaluated MSC combined with PRP in order to enhance periimplantary bone regeneration. Yamada et al. regeneraDifferent studies have evaluated the regeneration potential of stem cells harvested from different sources. Ito et al. compared-Alveolar distraction\u2022Animal studiesQi et al. evaluateControlled animal studies reveal that stem cells combined with PRP accelerate bone regeneration in oral implantology surgeries. This combination has shown higher capacity than PRP alone to promote bone regeneration. Controlled, long-term follow up clinical human studies have not been performed, but so far, no serious complications related to stem cells grafting (like systemic inflammatory response) have been reported. There is only one very recently clinical trial performing maxillary sinus lift using stem cells seeded on a xenograft showing similar morphometric results than autografts with xenograft. The interesting results of this clinical work as well as those of previous animal studies, indicate that stem cells may promote bone regeneration and be useful in human oral implantology. Many different scaffolds are used; for this reason and the heterogeneity between studies, no big conclusions can be performed yet. More clinical controlled studies applying stem cells are necessary to validate in humans, the favorable results observed in animals."} +{"text": "Cu+ is significantly more bactericidal than Cu2+ due to its ability to freely penetrate bacterial membranes and inactivate intracellular iron-sulfur clusters. Copper ions can also catalyze reactive oxygen species (ROS) generation, which may further contribute to their toxicity. Transporters, chaperones, redox proteins, receptors and transcription factors and even siderophores affect copper accumulation and distribution in both pathogenic microbes and their human hosts. This review will briefly cover evidence for copper as a mammalian antibacterial effector, the possible reasons for this toxicity, and pathogenic resistance mechanisms directed against it.Recent findings suggest that both host and pathogen manipulate copper content in infected host niches during infections. In this review, we summarize recent developments that implicate copper resistance as an important determinant of bacterial fitness at the host-pathogen interface. An essential mammalian nutrient, copper cycles between copper (I) (Cu Copper is both an essential mammalian micronutrient and a potent antibacterial agent. The Smith Papyrus, an ancient Egyptian medical text dated at 2400 BC, is the earliest medicinal archive to recommend copper sulfate to sterilize water and treat infections ] Liochev, .\u22129 s before reacting with organic molecules in vivo ]:Hydroxyl radicals are extremely reactive, cannot be scavenged by enzymatic reaction, and have a diffusion controlled half-life of ~10Hydrogen peroxide can in turn participate in reaction 1 and may further propagate radical formation.Escherichia coli mutant with multiple copper efflux deficiencies to hydrogen peroxide oxidation by macrophage-like THP-1 cells was found to be ATP7A-dependent, suggesting metal catalyzed oxidation by secreted copper ions .Phagosomal copper may add to, and perhaps synergize with, the diverse cellular microbial killing strategies described since Elie Metchnikoff's pioneering work on phagocytosis Gordon, . These sM. tuberculosis upregulates genes encoding copper efflux-associated P1B-type ATPases during macrophage infection exhibit higher growth than concomitant rectal isolates in a medium containing an inhibitory concentration of copper may reduce the outer membrane's copper permeability , copper sequestration (CusF and siderophores), and copper oxidation (mixed copper oxidases and superoxide dismutase mimics). For the sake of brevity, the following sections primarily discuss Cu2+ detection and resistance proteins that have been described in E. coli transcriptionally activates both plasmid- and chromosomally-encoded copper homeostatic systems in response to intracellular Cu+ sensing through CueR, a MerR-family metalloregulatory transcriptional activator located at the dimer interface system confers copper-tolerance under moderate to high copper levels in oxic conditions proton antiporter family, CusB belongs to the membrane fusion protein family which anchor into the cytoplasmic membrane with a long periplasm-spanning domain, and CusC is an outermembrane protein with homology to the TolC-stress response protein studies of the closely related E. coli, the periplasmic chaperone CusF binds copper, ultimately delivering it to CusCBA for export such as methanobactin and phytochelatin from copper toxicity, suggesting that yersiniabactin's iron uptake function does not contribute to this phenotype. Copper oxidation state selectivity among microbial small molecules is also observed in pyoverdin and pyochelin, two major siderophore types expressed by P. aeruginosa . Cu+ is more toxic than Cu2+ when applied under anoxic conditions, as demonstrated by Macomber and Imlay . CueO is structurally similar to the large, cross-Kingdom family of MCOs [including ascorbate oxidase and the ferroxidases Fet3 and ceruloplasmin pathway with copper-bound active sites and (7)]:+ concentrations while increasing oxidized\u2014and less toxic\u2014Cu2+ ion concentrations. Periplasmic Cu,Zn-SOD may similarly protect against copper stress, although there are distinctive pathogenic advantages to deploying a non-protein catalyst such as copper-yersiniabactin in the phagosomal microenvironment that help resist copper toxicity. SOD activity may promote bacterial survival in several pathologically important host niches and its connection with copper suggests new insights into host defense mechanisms that are critical to infection pathogenesis.Copper-yersiniabactin confined within the phagolysosome may thus greatly diminish concentrations of superoxide (a reductant), while maintaining or increasing production of hydrogen peroxide (an oxidant). This may have the effect of minimizing reduced CuMuch remains to be understood about the mechanisms by which mammalian hosts deploy copper to resist infection, and how pathogenic bacteria respond to these strategies. ATP7A's emerging role in direct antibacterial immunity warrants its detailed study in mammalian cells that encounter bacterial pathogens. Cell type, pathogen, and regulatory activity may result in unforeseen interactions between copper and other innate immune effector molecules. Possible cooperation with mammalian copper absorption and trafficking may suggest routes by which copper-based immunity could be therapeutically supported. Both basic and translational research efforts will be necessary to understand these details.E. coli binds copper during humans infections (Grass et al., in vivo and in environmental settings will be necessary to optimize antimicrobial uses of copper.Copper's inherent toxicity has renewed interest in its use as an antimicrobial. Three hundred different copper and copper alloy surfaces are registered with the U.S. Environmental Protection Agency as antimicrobials and trials are underway to determine whether copper treated surfaces can significantly reduce nosocomial infections (The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Next generation sequencing platforms and high-throughput genotyping assays have remarkably expedited the pace of development of genomic tools and resources for several crops. Complementing the technological developments, conceptual shifts have also been witnessed in designing experimental populations. Availability of second generation mapping populations encompassing multiple alleles, multiple traits, and extensive recombination events is radically changing the phenomenon of classical QTL mapping. Additionally, the rising molecular breeding approaches like marker assisted recurrent selection (MARS) that are able to harness several QTLs are of particular importance in obtaining a \u201cdesigned\u201d genotype carrying the most desirable combinations of favourable alleles. Furthermore, rapid generation of genome-wide marker data coupled with easy access to precise and accurate phenotypic screens enable large-scale exploitation of LD not only to discover novel QTLs via whole genome association scans but also to practise genomic estimated breeding value (GEBV)-based selection of genotypes. Given refinements being experienced in analytical methods and software tools, the multiparent populations will be the resource of choice to undertake genome wide association studies (GWAS), multiparent MARS, and genomic selection (GS). With this, it is envisioned that these high-throughput and high-power molecular breeding methods would greatly assist in exploiting the enormous potential underlying breeding by design approach to facilitate accelerated crop improvement. IntUnlike regular breeding programmes, the major objective of phenotyping in GS is to predict GEBVs rather than selection of genotypes , 107. PrBy its nature, GS focuses on genetic improvement of QTs rather than understanding their genetic basis , 115. Inin silico and Peleman and van der Voort [Ideotypes or ideal plant types are known to plant breeder, since 1968 when Donald defined er Voort describein silico designing of a superior genotype through combining desirable loci (https://www.integratedbreeding.net/ib-tools/breeding-decision). The concept of breeding by design includes (i) locating genes/QTLs associated with important traits (ii) exploring the allelic variation at these loci and the estimation of phenotypic effects of these allelic variants (iii) choosing desirable recombinants by targeting marker/haplotype-defined genomic fragments , 118. ReAvailability of highly saturated genetic maps and populations like ILs has facilitated fine mapping of various QTLs . FurtherOnce genetic loci influencing the expression of the trait have been mapped precisely, allelic variants at all these loci can be mined along with their relative contribution to complex traits, and highly resolved marker haplotypes could be recovered for several agriculturally important traits . With thMoreover, precise phenotyping or phenomics is one of the major bottlenecks in capitalizing the full potential of breeding by design concept . TherefoRapidly decreasing genotyping and sequencing costs are dramatically changing the scenario of genomics-assisted breeding. For instance, a shift has been seen from biparental to multiparental populations, and, with the help of various NGS-based sequencing platforms, a detailed genetic analysis of these complex mapping resources would likely to be feasible. Moreover, extensive recombination and multiallelic nature of these lines make them an excellent platform for practising multiparent MARS and GS. More importantly, the development of such public resources like MAGIC and NAM would strengthen the community-based research approach . Additionally, by virtue of eliminating need for any prior QTL information, MARS and GS schemes would save time, money, and energy that is required for finding significant gene-trait relationships. Still, realization of immense potential of all these approaches would greatly rely on throughput, precision, and cost effectiveness of phenotyping techniques. Though, precise phenotyping has always been a potent limiting factor in genetic analysis of QTs, efforts are underway to meet the growing demands for accurate and HTP screening against various biotic/abiotic stresses. It is envisaged that parallel developments in the next-generation phenotyping systems would help in making GS a practical reality in case of plant species as well. Therefore, rising molecular breeding methods like MARS or GS would enable harnessing unexplored genetic variation to a greater extent, thereby facilitating speedy development of superior cultivars."} +{"text": "Alcohol use and tobacco smoke exposure are frequently correlated, with many individuals smoking and/or experiencing secondhand smoke (SHS) exposure while drinking . Unfortunately, most medical school curricula do not adequately address the topic of screening and brief intervention (SBI) for tobacco use, SHS exposure, and/or problematic drinking. The aim of this study was to assess the effectiveness of a three-part educational intervention for health-professions schools to address the consequences of SHS exposure and develop SBI skills in medical students. Because information regarding the effects of smoking and SHS can be effectively communicated via self-directed online lectures, we developed an online training module including a videotaped lecture series with accompanying PowerPoint slides. To help students develop diagnostic skills related to SHS and other substance exposure, 10 standardized patient cases were included for instruction and testing. Finally, a clinical-instruction DVD provided examples of how practitioners can implement motivational-interviewing strategies in behavior change counseling related to tobacco use, with or without co-occurring alcohol use. Participants in the educational intervention, compared with controls (no intervention), scored significantly higher on the SHS Competency Exam. In addition, 100% of students who received the intervention reported plans to screen for SHS exposure. This educational intervention may be a valuable addition to medical and health professional school curricula while requiring minimal faculty time and effort."} +{"text": "Literary data suggest apparently ambiguous interaction between menopausal status and obesity-associated breast cancer risk based on the principle of the carcinogenic capacity of estrogen. Before menopause, breast cancer incidence is relatively low and adiposity is erroneously regarded as a protective factor against this tumor conferred by the obesity associated defective estrogen-synthesis. By contrast, in postmenopausal cases, obesity presents a strong risk factor for breast cancer being mistakenly attributed to the presumed excessive estrogen-production of their adipose-tissue mass. Obesity is associated with dysmetabolism and endangers the healthy equilibrium of sexual hormone-production and regular menstrual cycles in women, which are the prerequisites not only for reproductive capacity but also for somatic health. At the same time, literary data support that anovulatory infertility is a very strong risk for breast cancer in young women either with or without obesity. In the majority of premenopausal women, obesity associated insulin resistance is moderate and may be counteracted by their preserved circulatory estrogen level. Consequently, it is not obesity but rather the still sufficient estrogen-level, which may be protective against breast cancer in young adult females. In obese older women, never using hormone replacement therapy (HRT) the breast cancer risk is high, which is associated with their continuous estrogen loss and increasing insulin-resistance. By contrast, obese postmenopausal women using HRT, have a decreased risk for breast cancer as the protective effect of estrogen-substitution may counteract to their obesity associated systemic alterations. The revealed inverse correlation between circulatory estrogen-level and breast cancer risk in obese women should advance our understanding of breast cancer etiology and promotes primary prevention measures. New patents recommend various methods for the prevention and treatment of obesity-related systemic disorders and the associated breast cancer. Many studies support an apparently Janus-faced ambiguous interaction between obesity and breast cancer risk depending on the menopausal status of patients -3. In yoNevertheless, several authors could find confusing and disturbing associations between obesity and breast cancer risk in postmenopausal women. Obese postmenopausal women, who had never used hormone replacement therapy (HRT) exhibited fairly high breast cancer risk . By contIn premenopausal cases, the results of clinical studies justify that obesity induces mild or moderate decrease in circulating estrogen levels reflected by their inclination to anovulatory infertility and long or irregular menstrual cycles . Based oEven larger studies, which equivocally strengthen the protective effect of obesity for premenopausal breast cancer risk, confess that the responsible mechanisms are completely obscure. Evidences, provided by clinical endocrinological studies regarding correlations between defective hormonal status of obese women and decreased breast cancer incidence, are inconsistent or fairly contradictory . ConsideObesity is a well-known cancer risk factor associated with different grades of insulin resistance and a disturbance of male to female circulating sexual steroid levels , 20. HypThe aim of the present study is to clarify the realistic correlations between breast cancer risk and obesity-associated hormonal alterations during the whole life of women. Moreover, this study tries to reveal the sources of the misleading clinical and epidemiologic results suggesting the breast cancer protective effect of obesity in the young. These associations are examined in an analytical review based on the results of prospective, case-control and meta-analytic studies.1). The main stream of obesity related alterations is a self-generating, progressive insulin resistance in thorough interplay with the dysmetabolism and inflammation of adipose tissue mass and with an imbalance of sexual steroid production in the endocrine organs.Clinical and experimental evidences prove that obesity, particularly visceral fatty tissue deposition leads to insulin resistance, associated with diverse immunologic, metabolic and hormonal alterations mediating breast cancer risk is a defect of insulin-mediated cellular glucose uptake, which may elicit many disorders in the gene regulation of cellular metabolism, growth, differentiation and mitotic activity. The progression of this disorder predisposes patients to a variety of diseases, such as metabolic syndrome, type-2 diabetes, cardiovascular lesions and malignancies at different sites .in the first, compensated phase of insulin resistance maintains serum glucose level within the normal range by means of an increased secretory capacity of insular \u03b2-cells . Insulindevelops in the second, partially uncompensated phase of insulin resistance when the enhanced insulin synthesis of pancreatic islet cells is not enough to maintain euglycemia. This is a quartet of elevated fasting glucose, high serum triglyceride, low HDL cholesterol level and hypertension, being characteristic of viscerally obese patients . Each ofHyperglycemia is advantageous for the unrestrained DNA synthesis of tumor cells. It provokes deliberation of free radicals causing derangements in both DNA and enzymes having important role in repair mechanisms [chanisms , 33. Higchanisms . A prospchanisms .Dyslipidemia is a complex disturbance of the lipid metabolism associated with insulin resistance and hyperinsulinemia [ulinemia . Serum lulinemia , 38. Resulinemia .Hypertension usually shows close positive correlation with obesity, insulin resistance and hyperinsulinemia [ulinemia , 41. Eleulinemia , 42. Theulinemia . In postulinemia .Metabolic syndrome is associated with both increased breast cancer risk and high mortality rates in postmenopausal cases , 46. Timis the uncompensated phase of insulin resistance when the secretory capacity of insular \u03b2-cells becomes exhausted and the decreased serum insulin level results in hyperglycemia. The disrupted glucose homeostasis, the excessive formation of free radicals and the protein glycation depress the activities of the antioxidant scavengers and enzymes. These noxious processes cause serious damages in all biological structures even at a molecular level , 48. Thehyperandrogenism and anovulatory infertility through several pathways as insulin is a potent regulator of sexual steroid production in the endocrine organs [ovarian androgen production at the expense of reduced estrogen synthesis [Obesity related insulin resistance and excessive insulin synthesis in women may contribute to e organs . Hyperinynthesis . High inynthesis . Therapeynthesis , 59. A rynthesis .adrenal androgen synthesis as well by means of increased adrenal sensitivity to adrenocorticotropin. At the same time, high insulin level may favor the luteinizing hormone(LH) secretion of pituitary. Increased LH level also stimulates androgen biosynthesis by the activation of adrenal gland and ovarian theca cells [Hyperinsulinemia promotes ca cells , 62. Accca cells . In centca cells , 65.Insulin resistance, hyperinsulinemia and excessive IGF-I activity mediate defective estrogen synthesis by counteraction to aromatase enzyme gene expression at cellular level. The aromatase enzyme complex catalyzes the conversion of androgens to estrogens in a wide variety of tissues. In premenopausal women, the ovaries are the principle sources of estradiol; by contrast, in postmenopausal women when the ovaries cease to produce estrogen, it is synthesized in a number of extragonadal sites . These sIn premenopausal insulin resistant women with type-2 diabetes, the ovaries exhibit decreased capacity to convert androgen to estrogen, probably due to a reduction of ovarian aromatase activity . ConversEstrogens decrease low grade inflammatory reactions and may in parallel reduce the glucocorticoid responses. Low estrogen levels after menopause allow the predominance of glucocorticoids and the manifestation of the metabolic syndrome. These observations suggest that the disturbed equilibrium between sex hormones and glucocorticoids may be a critical element in the manifestation of metabolic syndrome-related pathologies .Visceral adipose tissue has important functions in energy homeostasis, metabolic equilibrium, immune responses and in the regulation of cell proliferation. Secretion of signaling molecules; adipokines regulates the cellular microenvironment both locally and systemically -73.The chronic low grade inflammation associated with obesity is an important player in tumor development and progression. Increased IGF-I level may mediate the inflammation of adipose tissue via its effects on immunologically active cells including macrophages and T cells . IGF-I madipocytokines; such as leptin, adiponectin resistin, ghrelin etc. [Adipokines include unique products of fatty tissue known as lin etc. . Leptin lin etc. . High lelin etc. . Converslin etc. . The ballin etc. .Proinflammatory cytokines produced in excessive adipose tissue mass increase nitric oxide (NO) production, a substrate for reactive oxygen species (ROS). Accumulation of cytokines and ROS further contribute to insulin resistance resulting in elevated circulating glucose and free fatty acid levels. All signaling molecules of fatty tissue including cytokines, hormones and growth factors are involved in the regulation of the proliferation, invasion and metastatic spread of tumor cells . ProinflOut of several hormones affecting body mass and adipose tissue deposition, estrogens promote, maintain and control the ideal distribution of body fat . These sEstrogen regulates the metabolism, differentiation, growth and cell kinetic mechanisms of adipocytes. In healthy premenopausal women central adipocytes show higher insulin sensitivity and exhibit a higher turnover rate despite similar fat content as compared with male cases . ConversObesity and overweight are important concomitants of insulin resistance and they are strongly associated with disturbed equilibrium of male to female sexual hormone concentrations in women . HealthyHealthy premenopausal women are typically protected from cardiovascular diseases and hypertension as compared with men and this has been hypothesized to be because of the protective effects of estrogens. Conversely, obese, diabetic young women, and postmenopausal cases may lose this protected state as their bioavailable estradiol levels are strongly reduced .Estrogen may have crucial role in the maintenance of normal serum lipid levels. Postmenopausal women have higher total cholesterol, LDL cholesterol and triglyceride levels, whereas lower HDL cholesterol levels as compared with premenopausal cases. These changes may be regarded as a shift toward a more atherogenic lipid profile in estrogen deficient milieu . PostmenEstradiol has cardiovascular protective impact by its anti-hypertensive activity as well. Estrogens can downregulate components of the renin-angiotensin system (RAS) and reduce the expression and activity of angiotensin I-converting enzyme , 95. EstClinical and experimental studies support that estradiol has also antioxidant activities , 99 thatpancreatic islet cells [Estrogens have beneficial effects on the energy metabolism and glucose homeostasis by means of several pathways . Estrogeet cells . Estrogeet cells . EstrogeIn the liver, estrogen regulates insulin sensitivity by the balanced activation of glycogen synthase and glycolytic enzymes to maintain the equilibrium of glycogen synthesis and glycogenolysis. In ER-\u03b1 knockout mice, hepatic insulin resistance was associated with decreased glucose uptake in skeletal muscles [ muscles .In the peripheral tissues, ERs advantageously modulate the insulin stimulated glucose uptake through regulation of the phosphorylation of insulin receptor protein. In hyperinsulinemia, high concentrations of estradiol can inhibit the excessive insulin signaling in adipocytes [ipocytes , which mERs have crucial roles in cellular glucose uptake by regulation of intracellular glucose transporters (GLUTs) and enhancing both GLUT4 expression and translocation . In humaEstrogens and ER signals have pivotal role in the regulation of growth hormone (GH) activity by means of modulation of its secretion and cellular GH receptor function. Estrogens play a major and positive role in the regulation of GH-IGF-I axis in both genders , which mPostmenopausal hormone replacement therapy (HRT) reduced abdominal obesity, insulin resistance, new-onset diabetes, hyperlipidemia, blood pressure, adhesion molecules and procoagulant factors in women without diabetes and reduced insulin resistance and fasting glucose in women with diabetes .Low grade systemic inflammation may be associated with estrogen deficient states, namely menopause and ovariectomy. At early stages of estrogen deficiency estrogen administration decreased the inflammation associated risk of developing cardiovascular disease . NeverthPhytoestrogens may advantageously influence the level of adipokines in insulin resistant women. In postmenopausal cases, diet, physical exercise and daily oral intake of soy isoflavones had a beneficial lowering effect on serum leptin, and TNF-\u03b1 levels and showed a significant increase in mean serum levels of adiponectin . EpidemiEstrogen advantageously regulates serum levels of available growth factors. In clinical studies estradiol lowered, whereas testosteron increased total IGF-I level and estradiol specifically suppressed unbound, free IGF-I level . CrosstaThe presumed synergistic contribution of ERs and GFRs to cancer development and progression would be a permanent danger without contraregulatory impact. Inhibition of growth factor signaling in apparently ER-negative breast cancer cells successfully restored ER expression suggesting a dynamic, inverse relationship between the two receptor systems . Moreoveobese premenopausal women, peripheral, subcutaneous adiposity is typical and there is a lower incidence of obesity associated dysmetabolism. By contrast, in obesepostmenopausal cases, circulating levels of estrogen are dramatically decreased and adipose tissue distribution becomes more male-like. Predominance of visceral adiposity and the associated metabolic and hormonal disorders mean high risk for obesity related diseases, included breast cancer [Fat deposition is thoroughly affected by male to female sexual steroid level . Circulat cancer .The most important data characterizing the grade of obesity are body mass index (BMI) and weight in kilogram , 5, 118 Some authors reported on the value of WC, HC and WHC ratio in the prediction of premenopausal breast cancer occurrence , 122. CoMagnetic resonance imaging (MRI) was used to quantify separately the mass of visceral and subcutaneous abdominal fat depositions in obese adolescent girls . Mass ofIn conclusion, neither BMI nor circumference measurement may exactly separate the metabolically indifferent, subcutaneous fat and the dangerous visceral fat, which may partially explain the controversial correlations between obesity grade and breast cancer risk.Circulating female sexual steroid levels and fertility continuously decrease during the life of women. The ability to conceive is at its peak in young women under 30 years of age with a continuous decline from the fourth decade, which suggests decreasing fertility even in the premenopausal phase . Menopau1).In premenopausal women, the good equilibrium of sex steroid synthesis defines health and reproductive capacity, whereas good, symptom-free adaptation to the estrogen deficient environment is a prerequisite of postmenopausal health. Changes in the hormonal equilibrium during women\u2019s lives strongly influence the obesity associated breast cancer risk the coexistence of anovulatory infertility and insulin resistance represents common risk for the cancers of highly hormone dependent breast, endometrium and ovary , 148. MoHyperprolactinemia is also associated with cycle disorders, reproductive dysfunction and hyperandrogenism in women, however, it may be sharply discerned from PCOS and other disorders related to androgen excess. An increased overall cancer risk was found in hyperprolactinemia patients but further investigations are necessary to confirm these results . Data ofHow can we explain the increased prevalence of breast, endometrial and ovarian cancers in women with fertility disorders, even without obesity? In premenopausal cases, slight or moderate decrease in circulating female sexual steroid levels may be enough to block the delicate mechanism of ovulation. At the same time, a slightly estrogen deficient milieu confers preferential cancer risk for the female organ triad having high estrogen demand , 136.In women, multiparity and risk for malignancies at several sites exhibit an inverse relationship -157. HigNulliparity may be associated with ovulatory disorders in the majority of cases and there are studies, which equivocally exhibited increased prevalence of breast cancer in nulliparous women , 162. Fuin vitro fertilization (IVF) in anovulatory cases [Possible role of fertility medications in the increased risk of breast cancer has been hypothesized. However, large studies were not able to find any associated risk of breast cancer after ovulation provocation and ry cases . Moreovery cases . Recentlry cases . Howeverry cases . These rIn postmenopausal estrogen deficient, obese cases the regional distribution of fat deposition near uniformly affects the visceral region in close correlation with their high breast cancer risk .Obese postmenopausal women never using HRT are obviously insulin resistant. Moreover, ageing after menopause is a further factor increasing the cancer risk as it is associated with a continuous estrogen loss and parallel advancing insulin resistance [sistance . In old obese HRT user postmenopausal women, the incidence of breast cancer is equivocally reduced [In reduced . The pro reduced . In HRT reduced yields f reduced and by i reduced . All theA great challenge is to explain the beneficial anticancer impact of HRT in obese postmenopausal women based on the misbelief that they have excessive circulatory estrogen level. To solve this contradiction, some authors assumed that mediators other than estrogen, such as insulin and insulin-like growth factors might confer the obesity associated breast cancer risk after menopause . Oral contraceptive (OC) use replaces the natural menstrual cycle with relatively steady levels and fluctuations of artificial sex hormones.Recent epidemiological studies have confirmed that combined oral contraceptives provide substantial protection against endometrial and ovarian cancer in the endangered anovulatory women , 169. EfIn PCOS cases, treated with OCs, the volume of cystic ovaries is reduced, ovarian testosterone secretion is decreased and there are favorable effects on carbohydrate and lipid metabolism as well . A recenUse of HRT has highly controversial associations with breast cancer risk. Till now, the carcinogenic capacity of postmenopausal estrogen therapy was a prevailing concept [ concept . By cont concept , 172. ReIn 2011, the WHI Randomized Controlled Trial strengthened that the estrogen treatment in women with prior hysterectomy resulted in a significantly lower risk for breast cancer than in untreated controls . Breast Today, increasing numbers of evidence from the clinical trials suggest that unopposed estrogen as hormone treatment does not increase the risk of breast cancer, and may even reduce it. The earlier concepts regarding the breast cancer risk of hormone replacement therapy are completely changing -178.HRT decreases the accumulation of central fatty tissue in obese postmenopausal women and provides them long term metabolic and health benefits , 167. HR environmental estrogens (xenoestrogens) occurs through diet, household products and cosmetics, but concentrations of single compounds in breast tissue are generally lower than needed for assayable estrogenic responses [Exposure to esponses . ExposurEndocrine disruptors (EDs) are environmental chemicals that are able to bind hormonal receptors. These compounds may disrupt the endocrine regulation of reproduction and adaptive mechanisms and promote the development of endocrine disorders. Since several EDs have a structure similar to that of endogenous steroid hormones such as estrogens, they have an affinity for steroid hormone receptors and may alter the normal hormone-mediated reactions [eactions . EnvironPoor natural light exposure mediates deleterious metabolic and hormonal alterations by excessive melatonin secretion; such as insulin resistance, deficiencies of estrogen, thyroxin and vitamin D [itamin D . Long teBefore the introduction of antiestrogens, high dose estrogen was successfully administered as endocrine therapy for postmenopausal women with advanced breast cancer. Nowadays, the ambiguous, unreliable therapeutic effects and high toxicity of antiestrogens suggest the necessity of finding new strategies for breast cancer treatment . RecentlPhytoestrogen containing health supplement compositions are recommended by some patents for the prevention or treatment of postmenopausal breast cancer and for the alleviation of menopausal symptoms [symptoms . Soybeansymptoms . A recensymptoms .Obesity-associated hormonal disorders confer breast cancer risk during the whole life of women without any ambiguous interaction between obesity and menopausal status. Erroneous results regarding the breast cancer protective effect of obesity in young women derive mainly from the deceivingly lower tumor incidence among them. Further misleading factor may be that hormonal disorders related to anovulatory infertility are strong cancer risk factors for the breast both in obese and non-obese young women. Low incidence rate of breast cancer in young obese women may be a very important misleading finding. In the majority of premenopausal obese cases a predominantly subcutaneous adipose tissue deposition results in milder insulin resistance being counteracted by their preserved hormonal cycle. Consequently, in obese premenopausal women their circulatory estrogen level confers protective effect against breast cancer rather than obesity.Tumor cell kinetics may also provide an explanation for the low breast cancer incidence rate in obese premenopausal cases. A long term exposition to harmful environmental and systemic factors is necessary for cancer initiation; moreover the tumor growth from the initiation to clinically diagnosable size takes further several years. This double delay of clinical appearance of breast cancers may frequently result in a postmenopausal tumor, though it was initiated in the premenopausal period. Anovulatory infertility and the associated hormonal defects seem to be stronger breast cancer risk factors than adiposity alone and these alterations are not rare even among control cases with normal weight. Studies on obesity-related breast cancer risk disregarded the random occurrence of these hormonal alterations both among obese cases and lean controls. Moreover, oral contraceptive use is fairly widespread among premenopausal women, which may reverse the mild hormonal defects and attenuates their cancer risk either in obese or in lean cases. Strict selection of healthy, lean control women for obesity associated breast cancer studies and taking into account the OC use among obese cases and controls will justify the health advantage of normal body weight over obesity.Recognition of the inverse correlation between circulatory estrogen-level and breast cancer risk in obese women should advance our understanding of breast cancer etiology. Moreover, it would promote primary cancer prevention measures and the introduction of causal cancer therapy.2 and 3). Circulatory endogenous estrogen was blamed to provoke cancer initiation and promotion in the highly hormone responsive female organs, however, this misbelief yielded fairly controversial results in the clinical and experimental fields of medicine. Nowadays, overwhelming literary data suggest that estrogens have advantageous impact on dysmetabolism and hyperandrogenism, which are essential sources of tumor development.Changing concepts concerning breast cancer etiology provide completely new strategies against mammary tumors (Tables Recent patents disclose oral contraceptive and metformin derivative treatment possibilities for breast cancer prevention and therapy. Moreover, a new invention provides special estrogen derivatives being metabolically more advantageous for the treatment of PCOS than oral contraceptives. As anovulatory disorders in young women are strong risk factors for breast cancer, insulin resistance screening of asymptomatic occult cases in the population and their hormone treatment would be effective primary breast cancer prevention.In postmenopausal cases, obesity, metabolic syndrome, type-2 diabetes and hysterectomy are strong risk factors for mammary malignancies. Hormone replacement therapy in these endangered cases would be advantageous preventive measure.The present practices of breast cancer therapy have fairly controversial results. Worldwide administration of antiestrogen compounds for breast cancer treatment yielded thorough disappointment. Antiestrogens are cytostatic agents blocking the most important regulatory mechanisms associated with estrogen receptors. They do not have only toxic effects but also strong carcinogenic capacity. Recently, scientists in some centers confess, that one armed estrogen treatment is rather cancer protective than carcinogenic. Certain patents disclose the beneficial effects of phytoestrogens in breast cancer prevention and therapy. Moreover, publications on the high dose estrogen treatment of advanced breast cancer cases are regularly returning and the results are fairly encouraging. Today, we are on the route to regard estrogens as beneficial anti-cancer drugs rather than carcinogenic agents."} +{"text": "To describe uncommon association between central retinal artery obstruction and dominant macular drusen in two young female patients. First patient, a 22-year-old female was presented with right central artery obstruction associated with bilateral dominant macular drusen. Systemic evaluation disclosed the presence of mitral valve regurge. Second patient, a 34-year-old female with a previous history of right central retinal artery obstruction diagnosed elsewhere. Fundus exam showed bilateral dominant macular drusen and her systemic evaluation revealed severe rheumatic valve stenosis, moderate aortic regurge with moderate to severe tricuspid regurge and she underwent mitral valve replacement. To the best of our knowledge, the association between central retinal artery obstruction and dominant macular drusen was not previously reported. Occlusive disorders of the retinal circulation are among the most dramatic problems encountered by the ophthalmologists because of their rapid onset, their potentially profound effects on vision, and their strong association with life-threatening systemic diseases.The causes of retinal arterial occlusion in young adult patients often differ from those found in older adults.8We report herein, two cases of right central retinal artery occlusion associated with bilateral dominant macular drusen in young adult females with cardiac valve diseases.A 22-year-old female presented with sudden loss of vision in her right eye for 10 hours duration with past ocular history of intermittent visual obscurations in both eyes for the last 3 years. Details of ocular examination can be seen in Diagnosis: right central retinal artery occlusion; Management: immediate paracentesis, ocular massage in conjunctions with Carbogen and Diamox.Investigation: The following were within normal limits:Physical examinations, CBC, ESR, Electrolytes, Hgb electrophoresis, PT, PTT, protein electrophoresis, central plasma viscosity, lipid profile, plasma homocysteine, blood sugar, C proteins, antiphospholipid antibodies, plasma fibrinogen, lipoprotein A, abnormal factor V leiden, antithrombin III deficiency, protein S and C deficiency. revealed a delay in retinal arterial filling with prolong arteriovenous transit time with ground glass appearance in the right eye and sharply demarcated hyper fluorescent spots in the temporal aspect of macular in both eyes.Intravenous fluorescein angiography Cardiac evaluation was performed by a cardiologist and her carotid doppler was within normal and echocardiography showed mild mitral regurge. The patient was treated with Aspirin.A 34-year-old female referred with diagnosis of right retinal arterial occlusion presented with history of decreased vision in her right eye for 1 year after an attack of cerebrovascular accident with left side weakness. Surgical and medical history revealed diagnosis of heart valvular disease and she underwent mitral valve replacement three years ago and using warfarin and digoxin. Details of ocular examination can be seen in Diagnosis: old recanalized right central artery occlusions with bilateral macular drusen.Investigation: Systemic evaluation by her Cardiologist showed rheumatic mitral valve stenosis, moderate aortic regurgitations with moderate to severe tricuspid regurge status post mitral valve replacement. revealed to some extent a delay in arterial filling with prolong arteriovenous transit time in right eye and hyper fluorescent spots macular area of both eyes.Intravenous fluorescein angiography Dominant macular drusen (Doyne honey comb dystrophy) is an autosomal dominant disorder, which mimics drusen seen in age-related macular degeneration. This disorder occurs in younger patients at 20 to 30 years of age and the extent of the drusen is variable, with most cases limited to the posterior pole. Affected patients may later develop choroidal neovascularization. It may be relevant that drusen like deposits can be seen in some renal disorders that involve basement membrane abnormalities, such as Alport's syndrome and membranoproliferative glumerulonephritis Type II.910Further literature review showed no reports of association of dominant macular drusen with other systemic disorders, particularly cardiac valvular disorders. Our cases revealed a trait of young adult females with bilateral dominat macular drusen, each of them presented with right central artery occlusion secondary to cardiac valvular disease. This association is based on observations which could be coincidental findings. And to the best of our knowledge these associations have not been reported previously."} +{"text": "Unexpected drug efficacy or resistance is poorly understood in cancers because of the lack of systematic analyses of drug response profiles in cancer tissues of various genotypic backgrounds. The recent development of high-throughput technologies has allowed massive screening of chemicals and drugs against panels of heterogeneous cancer cell lines. In parallel, multi-level omics datasets, including genome-wide genetic alterations, gene expression and protein regulation, have been generated from diverse sets of cancer cell lines, thus providing a surrogate system, known as cancer cell line modeling, that can represent cancer diversity. Taken together, recent efforts with cancer cell line modeling have enabled a systematic understanding of the causal factors of varied drug responses in cancers. These large-scale association studies could potentially predict and optimize target windows for drug treatment in cancer patients. The present review provides an overview of the major types of cell line-based large datasets and their applications in cancer studies. Moreover, this review discusses recent integrated approaches that use multi-level datasets to discover synergistic drug combination or repositioning for cancer treatment. IntroductionLarge-scale datasets from cell line panelsSystematic analysis of multi-level omics and chemical screening dataPerspectives1.in vivo anticancer drug responses or optimize target treatment windows in clinical trials.Cancer cells exhibit varied responses to anticancer agents . Fast hiin vitro cell line modeling in translational cancer studies.The goals of this review are to survey the major types of cell line-based high-throughput datasets and highlight their applications in the systematic modeling of selective drug responses in cancer samples. This review focuses on several representative types of large datasets, including genotyping, gene and protein regulation, and chemical screening from well-defined cancer cell line panels. The major analytical efforts conducted with these representative datasets will be described, together with systematic approaches to integrate the multi-level omics and drug data. We expect that the present review will provide clear insights into the future impact of 2.Several cancer cell line panels have been organized to perform large-scale chemical screening and multi-level omics data profiling. For example, the National Cancer Institute (NCI) developed a panel of 60 well-characterized cancer cell lines from diverse tumor types for the purpose of chemical screening against heterogeneous cancer subtypes . This paMore recently, the sizes of cell line panels for chemical screening and omics data generation have greatly increased. For example, GlaxoSmithKline (GSK) released various genomic profiling datasets from a panel of >300 cancer cell lines that comprised 24 different cancer lineages 7). In . In 7). Genotypic variation among cancer cells is the major cause of inconsistency in anticancer drug responses. The prospect of targeted cancer therapies relies mainly on extensive information on the genetic variations observed in diverse cancer types. Recent efforts based on high-throughput PCR and sequencing technologies have generated reliable annotations of genome-wide genetic alterations in large cancer cell line and tissue sample collections ,9. For eIn addition to somatic mutations in coding regions, SNPs and copy number alterations in cancer cells have been proven to be of significant importance for understanding of cancer progression and therapies. For example, cancer subtype-specific SNP markers or CNA exhibited powerful predictions regarding drug responses, clinical prognostics and oncogenic factor identification ,12. In 2Gene expression analysis in cancers has provided considerable information on diagnostic or prognostic marker signatures and potential drug targets. DNA microarray experiments have generated substantial transcriptome-wide gene expression profile information in various cancer samples. A DNA microarray dataset of the NCI60 cell lines was initially generated to explore the expression of approximately 8,000 unique genes 18). Th. Th18). Cancer transcriptome expression profiles were also generated for the GSK and CCLE cell lines. The GSK dataset includes gene expression data for >300 cell lines, each in triplicate, thus providing a robust statistical analysis Table I. This daAlthough large-scale gene expression studies have yielded useful information for cancer biomarker identification and targeted cancer therapy development, high-throughput protein expression and activation level screening are required in order to better understand cellular signaling in the contexts of tumorigenesis and drug response. Reverse-phase protein array (RPPA) technologies, which are based on sample spot arrays for specific antibody reactions, allow fast, quantitative measurements of protein expression or phosphorylation in a large cancer sample panel . More thhttp://dtp.nci.nih.gov/index.html). This is the largest dataset for studies of structure-activity relationships between anticancer agents and diverse cancer subtypes. The COMPARE program is a useful tool with which to search for compounds with similar patterns of cellular sensitivity in the NCI60 panel is another exciting project that has extended ideas about cell line modeling to human cancer tissue samples. An increasingly large collection of clinical cancer samples are directly used to generate multi-level omics data, thus revealing a comprehensive landscape of genetic alterations and transcriptional regulation in each cancer subtype . A recendatasets . TogetheTogether with systematic cell line modeling using large omics datasets, RNAi screening data were recently generated to identify the target genes associated with changes in cancer phenotypes. For example, a kinome-based shRNA screening study was performed to determine the mechanism of resistance against BRAF inhibitors in colon cancers that harbored an activating mutation in the BRAF oncogene . Feedbac"} +{"text": "Detection of a novel Gammaretrovirus, Xenotropic Murine leukaemia virus-Related Virus (XMRV) has been reported in peripheral blood mononuclear cells of patients with chronic fatigue syndrome, and in prostate cancer tissue. As Multiple Sclerosis (MS) is a disease with retroviral association (human endogenous retroviruses (HERVs)), we investigated whether XMRV could be contributing to MS aetiology by testing a well defined cohort of Danish MS patients for the presence of XMRV sequences.We have analysed DNA samples isolated from peripheral blood mononuclear cells (PBMCs) from 50 Danish patients with clinically well-characterized MS for evidence of the presence of XMRV gag or env sequences by PCR, using concomitant amplification of the cellular GAPDH gene as control.In this study, which included relevant positive and negative isolation controls and PCR controls, we failed to detect XMRV sequences in PBMCs from Danish MS patients.There is no apparent association between XMRV infection and MS in Denmark."} +{"text": "Septic shock is one of the major causes of death in children and is characterized by a massive inflammatory response. To present date, no studies have been performed to assess the impact of such an \u2018inflammatory hit\u2019 on aortic wall structure and myocardial performance.This study shows that despite adequately preserved systolic biventricular function, frequently reduced aortic elasticity may indicate aortic wall pathology, being associated with biventricular hypertrophy and concomitant delayed biventricular relaxation in pediatric patients after septic shock.Septic shock is one of the major causes of death in children and is characterized by a massive inflammatory response. To present date, no studies have been performed to assess the impact of such an \u2018inflammatory hit\u2019 on aortic wall structure and myocardial performance. The objectives of the current study were therefore to prospectively assess aortic elasticity and biventricular systolic and diastolic function in a group of pediatric patients after meningococcal septic shock by using MRI.Eighteen pediatric meningococcal septic shock survivors treated with at least 2 inotropic and vasoconstrictive agents for 48 hours or longer and 18 for age and gender matched controls were prospectively studied. Routine MRI was used to assess aortic pulse wave velocity (PWV) and systolic and diastolic biventricular function. Independent-samples-t-test and Pearson-correlation-coefficient were used for statistical analysis.Sepsis patients showed reduced aortic elasticity vs. controls . Systolic biventricular function was preserved , whereas biventricular mass was increased . Also, delayed biventricular relaxation was found after sepsis: peak filling rates corrected for end-diastolic-volume (PFREDV) across the mitral and tricuspid valve were significantly reduced . Increased PWV in aortic arch and descending aorta were associated with increased LV mass and delayed LV relaxation parameters.Despite adequately preserved systolic biventricular function, reduced aortic elasticity in pediatric patients after septic shock may indicate aortic wall pathology, being associated with biventricular hypertrophy and concomitant delayed biventricular relaxation. Long-term prognosis after septic shock may therefore be adversely affected considering the cumulative effects of cardiovascular disease during a lifetime.No disclosures."} +{"text": "While monkeys perform a task alternating between behavioral adaptation --relying on feedback monitoring and memory of previous choices-- and repetition of previous actions, firing rates in dorsal Anterior Cingulate Cortex (dACC) modulate with cognitive control levels . FurtherWe used spike-train metrics to decodWe found that timing sensitivity could improve behavioral adaptation vs. repetition classification of single unit spike trains. Optimal decoding occurred when accounting for spike times at a resolution <= 200 ms. Furthermore, spike-train metrics decoding of unitary discharges was related to the monkeys' response time. A downstream neural decoder could exploit this temporal information through coincidence detection determined by synaptic and membrane time constants. In addition, when decoding two units jointly, we found that each pair had a specific optimal distinction degree between spikes coming from the two different neurons. In a realistic neural decoder, the tuning of this distinction degree might occur through non-linear dendritic integration.To further investigate the computational properties of temporal decoding in the context of decision-making, we are implementing a recurrent spiking neural network with connectivity leading to attractor dynamics. In this framework, each decision is mapped to a state in which a corresponding neural subpopulation shows elevated activity, as observed experimentally in dlPFC . In addiThe spatiotemporal structure of spike trains appears to be relevant in this cognitive task. This opens the possibility for pattern matching-based decoding of dACC activity, potentially leading to adapted behavioral response."} +{"text": "Tightly controlled extracellular matrix (ECM) homeostasis and remodeling is critical for normal organ homeostasis, wound healing and tissue repair. However, excessive or uncontrolled ECM deposition contributes to aberrant homeostasis of tissue microenvironment in various inflammatory diseases and tumors. Matricellular proteins are a set of structurally unrelated ECM proteins that do not exert a primary role in tissue architecture but have regulatory roles in embryonic development, tissue injury, inflammation and tumor progression. Two recent studies demonstrated that matricellular proteins in the ECM surrounding dormant tumor cells may determine the fate of tumor cells to remain quiescent or undergo metastatic outgrowth. The identification of matricellular proteins in regulating ECM homeostasis and remodeling specific organ niches during tumor dormancy may provide potential novel extracellular targets for the development of therapeutic interventions against tumor dormancy.Many cancer patients who have undergone surgical resection of their primary tumors suffer from metastatic relapse several months, years or even decades later. Current evidence supports the idea that tumor cells can be disseminated at an early stage of tumor progression. The disseminated tumor cells (DTCs) exist in a quiescent state at a hostile site, but may switch from quiescence to proliferative metastatic growth in a permissive and supportive microenvironment. Increasing data suggest that tumor dormancy can be regarded as a protracted asymptomatic stage during which tumor cells either remain in a quiescent state or their proliferation is balanced by cell death due to immunosurveillance or insufficient angiogenesis and periostin (POSTN), play crucial roles in regulating DTC dormancy. TSP-1 is enriched in the basement membrane of mature microvessel stalks and maintains DTCs in a dormant state; however, TSP-1 levels are markedly decreased at the sprouting neovascular tips of newly forming vessels. Interestingly, they also found an increased distribution of matricellular proteins, such as POSTN, tenascin-C and SPARC, together with fibronectin and TGF-\u03b21, around these growing tips. The authors further provided evidence that high POSTN and active TGF-\u03b21 expression surrounding neovascular tip cells enables DTCs to exit from dormancy and triggers metastatic relapse proteins, mainly including thrombospondins (TSPs), OPN, tenascins, SPARC, POSTN and CCNs, which do not exert a primary role in tissue architecture but regulate similar biological functions in response to external stimuli during embryonic development, tissue injury, inflammation and tumor progression to maintain quiescence, whereas the perivascular niche accommodates more activated HSCs. Quiescent HSCs reside preferentially at the endosteal region where bone-lining osteoblasts and their secreted proteins are critical components of HSC niches. Interestingly, bone marrow microenvironment is also a critical reservoir for DTCs. When metastasizing to the bone, DTCs take shelter in HSC niches in bone marrow and adopt similar mechanisms to those used by HSCs for homing to bone marrow. That is to say, DTCs may occupy and remodel preexisting physiological HSC niches to help them survive and subsequently grow and metastasize (Wan et al., How do matricellular proteins maintain dormant tumor cells in a quiescent state or reactivate them to metastatic outgrowth? As a class of structurally unrelated ECM proteins, matricellular proteins serve as links between the ECM and cells to regulate cell-cell and cell-matrix interactions, and their functions are highly dependent upon the cues from local microenvironment. These matricellular proteins are often needed for ECM remodeling during embryonic development and their expressions are highly induced at sites of injury, inflammation or tumors within the adult organism. An excessive or uncontrolled matricellular proteins\u2019 function contributes to aberrant remodeling and homeostasis of tissue microenvironment in various inflammatory diseases and tumors. Matricellular protein knockout mice are often viable, but typically exhibit abnormal responses to mechanical stress, wound healing, inflammation and tumor metastasis. POSTN, for example, can directly interact with collagen I, fibronectin and Notch1 via its EMI domain and interact with tenascin-C and BMP-1 via its FAS1 domains (Norris et al., The work by Ghajar et al. and Boyerinas et al. greatly expanded our understanding of the roles of tissue microenvironmental cues in regulating tumor dormancy and subsequent metastatic growth. The identification of matricellular proteins in regulating ECM homeostasis and remodeling specific organ niches during tumor dormancy provides useful extracellular targets for the development of therapeutic interventions to induce or maintain DTCs in a dormant state, or alternatively to activate and then eradicate dormant DTCs."} +{"text": "The majority of neural encoding models employed today consist of a linear feature-selection stage followed by a static memoryless nonlinearity generating the neuronal rate of response. Although such linear-nonlinear (LN) models have been proven useful in characterizing computation in many neurons (see and refeHere we investigate nonlinear-nonlinear neuron models that combine both biophysics and dendritic computation. Specifically, we consider models in which the nonlinear dendritic processing of input stimuli is described by a Volterra series and the"} +{"text": "To the Editor: Factor et al. recently reported the results of a population-based, case-control study regarding risk factors for pediatric invasive group A streptococcal (GAS) infection were unlikely to have received NSAIDs in the 2 weeks before their interview should be surprising. A more informative case-control study would have matched case-patients with similar-aged children who had febrile infections not caused by GAS infection; both groups of children would have been equally likely to have received analgesic and antipyretic medications. Furthermore, population-based data suggest that most patients with invasive GAS infection are hospitalized (Prospective studies have failed to define a causal link between NSAIDs and invasive GAS infections (Although NSAIDs may neither alter the risk of developing an invasive GAS infection nor accelerate an established infection, these drugs can mollify the signs and symptoms of streptococcal infection, possibly delaying appropriate management and treatment ("} +{"text": "Sir,A 60-years-old male presented to us with complaint of fever and cough with expectoration for last one month and pus discharging sinus on anterolateral aspect of right side chest wall for last one week. There was no history of hemoptysis, chest pain, dyspnoea or any previous swelling on chest wall at the site of discharging sinus. There was no previous history of tuberculosis or any anti-tubercular drugs (ATT) intake. Also there was no past history of intercostal tube drain (ICD) insertion or any history suggestive of pleural effusion. On respiratory system examination, crepts were present in bilateral lung fields. Examination of cardiovascular system and gastrointestinal system was absolutely normal.In laboratory investigation, ESR was raised while complete blood count (CBC), renal function test, liver function test were within normal limit. Smear and culture of sputum was positive for acid fast bacilli. Pus from discharging sinus failed to reveal any growth of pyogenic or fungal organism on staining as well as culture. CECT of -thorax was performed after injecting dye in the discharging sinus which revealed the presence of bronchopleurocutaneous fistula. Frontal CT scout view demonstrates extensive fibrocavitatory changes in both lungs more on right side with right sided mediastinal shift. It also revealed volume loss of right lung associated with extensive pleural thickening and blunting of CPA. Infant feeding tube was used for injecting dye in fistula. Axial chest CT demonstrates movement of dye injected in subcutaneous fistula along posterior pleural space into cavity in posterior segment of right upper lobe. From the cavity dye entered in draining segmental bronchus, thus confirming the presence of bronchopleurocutaneous fistula . There wPatient was diagnosed as a case of pulmonary tuberculosis with bronchopleurocutaneous fistula. Patient was put on antitubercular drugs. Patient responded well and the fistula healed.Bronchopleurocutaneous fistula is a pathological communication between bronchus, pleural space and skin. It usually develops due to pulmonary operations, perforating chest trauma, empyema, lung abscess, pneumonia or massive pulmonary infarction.\u20133 Occasi4"} +{"text": "Implementation of an evidence-based care bundle in critically ill patients has been shown to improve outcome. Use of care bundles to reduce ventilator-associated pneumonia and other ICU complications has been increasing in critical care practice.We conducted a prospective audit on implementation of a care bundle after audit approval. We collected data for 101 patient days from all patients admitted to Hull Royal Infirmary ICU during the month of November 2011. We collected information regarding stress ulcer prophylaxis, deep vein thrombosis (DVT) prophylaxis, ventilator care bundle, blood glucose control, daily assessment of need for a central line, sedation score assessment and delirium score assessment at least twice a day.All patients received stress ulcer prophylaxis. At least 95% of patients received DVT prophylaxis, adequate blood glucose control and appropriate sedation need assessment. There was further scope for improvement in areas of sedation hold practice and assessing daily need for a central line. Poor clinical practice was identified in delirium score assessment and head elevation to reduce VAP. See Table It is very challenging to implement care bundles despite evidence showing that they improve outcome. A recent study suggests that doing a daily quality rounds checklist (QRC) will improve long-term compliance, thereby reducing potential complications for intensive care patients . We have"} +{"text": "Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that carries a high burden of morbidity and mortality. Immune system dysfunction has been undisputedly demonstrated to underlie SSc pathogenesis. In particular, pDCs not only circulate in very high number in SSc patients but also secrete high concentrations of specific chemokines that directly drive various features of SSc, including endothelial dysfunction and fibroblast activation.Plasmacytoid dendritic cells (pDCs) were isolated from whole blood of early diffuse SSc, late diffuse SSc, limited SSc patients or healthy controls. The genome-wide profiling of microRNAs (miRNA) was performed on pDC total RNA by using the Illumina miRNA Profiling Array. Genes targeted by differentially expressed miRNAs were identified thanks to a combination of Miranda, Mirtar and MirPath prediction algorithms.On the quest to decipher why pDCs appear so abundantly in SSc and their activity is deregulated, miRNA profiling was performed. miRNA screening demonstrated that seven miRNAs were significantly over- and two were under-expressed in pDCs from patients with early diffuse SSc compared to late diffuse disease, limited SSc or healthy controls and this profile perfectly correlated with pDC abundance in the different disease stages. According to Miranda, Mirtar and MirPath prediction algorithms, this set of 9 miRNAs is predicted to influence a vast number of target genes, mostly involved in three molecular pathways: 1) leukocyte apoptosis, 2) epidermal growth factor EGFR (ErbB) signaling and 3) WNT signaling. Interestingly, the emergence of the leukocyte apoptosis pathway might provide a preliminary hint on why pDCs are expanded early in SSc. On the other side, ErbB and WNT signaling are ultimately involved in immune response regulation and often linked to the malfunctioning of the immune system in SSc.Altogether these unique observations suggest that SSc-associated miRNAs could strongly impact on cellular pathways involved in SSc pathology, and therefore they would provide an important target for disease prediction and therapeutic approaches."} +{"text": "Local populations of sensory cortical cells exhibit a diverse range of activity patterns. However, classical approaches have neither fully accounted for nor characterized this heterogeneity, especially in response to natural stimuli. First, classical single cell recordings suffered from sampling bias and favored highly responsive cells . Second,We analyzed data sets from two recording sessions in anaesthetized cats viewing natural movies. To quantitatively measure the difference between model predictions and the recording, we used the earth mover's distance to quant"} +{"text": "Chemical inducers such as 5-azacytidine (AzaC) and 5'-iodo-2'deoxyuridine (lUdR) have been used to discover and characterize endogenous retroviruses from rodent and avian speciecs, for example KBALB mouse cells. We found that induction conditions that have been optimized for mouse cells were not successful in inducing retrovirus from cell lines of other species, including nonhuman primates. Therefore, we developed a step-wise strategy based upon identification of critical parameters for endogenous retrovirus induction in mouse cells for optimizing induction conditions for non-murine cells. Using this approach, we have determined optimum conditions for investigating inducible endogenous retroviruses from Vero cells, which are of African green monkey (AGM) origin, a species that has never been reported to produce endogenous retroviruses .Based upon a step-wise induction strategy , Vero cegag, pol, and env regions related to endogenous SERV and BaEV sequences previously reported in the AGM DNA. Biological studies showed no evidence of replication-competent particles using several target cell lines. Similarly, an RT activity could be induced from a dog cell line, which is another species with no evidence of retrovirus isolation. This is currently under investigation for further characterization.The results demonstrated that endogenous retrovirus particles could be induced from Vero cells under optimized cell growth and drug treatment conditions. Molecular analysis indicated that the particles contained The induction of retrovirus particles from Vero cells was low and detected in cell-free supernatant only by using a highly sensitive PCR-based RT assay and virus-specific PCR assays. Further investigations of various emerging virus detection technologies used for novel virus discovery has demonstrated that induced viral RNAs could be detected in drug-treated cells using high throughput 454-massively parallel or deep sequencing: investigations with virus microarrays and long range PCR with mass spectrometry are ongoing. The results support that the combination of chemical induction strategy with sensitive broad virus detection technologies may be used for the discovery of novel endogenous retroviruses."} +{"text": "Vision loss degrades the quality of life of aged individuals. The major cause in industrialized countries is age-related macular degeneration (AMD), a blinding eye disease due to death of photoreceptors in the macula, a specialized retinal region responsible for high acuity vision. Photoreceptor death in AMD is thought to follow damage to the retinal pigment epithelium (RPE) , a monolRobust mTOR activation in the context of OXPHOS deficiency is counterintuitive because mTOR integrates trophic factor and nutrient availability signals to regulate cell growth and proliferation , and poiOXPHOS deficiency leads eventually to RPE atrophy, which is seen more commonly in AMD than RPE hypertrophy. Our findings suggest that RPE hypertrophy may be present at earlier stages of AMD. Indeed, ocular coherence tomography imaging demonstrated thickened macular RPE more frequently in early AMD eyes than in advanced AMD or control eyes . RPE hypertrophy may be less prominent in advanced AMD because drusen and diminished transport through aged Bruch's basement membrane may restIntriguingly, pharmacological inhibition of mTORC1 with rapamycin blunted RPE dedifferentiation and hypertrophy and preserved photoreceptor numbers and function for both the metabolic and oxidative stress models . Rapamyc"} +{"text": "In order to generate more accurate consensus sequences from ESTs, tools are needed to reduce or eliminate errors from de novo assemblies.Expressed Sequence Tags (ESTs) have played significant roles in gene discovery and gene functional analysis, especially for non-model organisms. For organisms with no full genome sequences available, ESTs are normally assembled into longer consensus sequences for further downstream analysis. However current We present iAssembler, a pipeline that can assemble large-scale ESTs into consensus sequences with significantly higher accuracy than current existing assemblers. iAssembler employs MIRA and CAP3 assemblers to generate initial assemblies, followed by identifying and correcting two common types of transcriptome assembly errors: 1) ESTs from different transcripts are incorrectly assembled into same contigs; and 2) ESTs from same transcripts fail to be assembled together. iAssembler can be used to assemble ESTs generated using the traditional Sanger method and/or the Roche-454 massive parallel pyrosequencing technology.de novo EST assembly programs using both Roche-454 and Sanger EST datasets. It demonstrated that iAssembler generated significantly more accurate consensus sequences than other assembly programs.We compared performances of iAssembler and several other We demonstrate the utility and performance of this program by performing assemblies on different EST datasets with different sets of parameters.iAssembler is implemented in Perl and can be executed under either 32-bit or 64-bit Linux systems with Bioperl installede novo assemblies of EST sequences. As shown in Figure iAssembler employs an iterative assembly strategy and automated assembly error corrections to deliver highly accurate The unique feature of iAssembler is its ability to detect and automatically correct all possible assembly errors. Following initial assemblies by MIRA and CAP3, all-versus-all pairwise sequence alignments of resulting unigenes are performed using the NCBI megablast program. Unigenes whose overlapped sequence length and identity, and overhang length meet user-defined cutoffs are identified as type II assembly errors, i.e., sequences from same transcripts fail to be assembled together. The megablast assembler then utilizes the pairwise sequence alignment information to join the unigenes into new contigs. Next, the type I error corrector module maps individual EST members to their corresponding contigs using megablast. ESTs that have sequence similarities to their corresponding contigs less than and/or overhang lengths larger than the corresponding user-defined cutoffs are identified as type I assembly errors, i.e., two different transcripts are incorrectly assembled together. These misassembled ESTs are then extracted by the type I error corrector and together with unigenes derived from the current round of assembly and error correction, are used as the input sequences in the next round of assembly and error correction Figure .The iterative assembly strategy employed by iAssembler can result in loss of accuracy in final unigene base calling since later assemblies are performed on unigenes generated from previous assemblies, instead of ESTs; thus during assemblies by CAP3 and megablast assemblers, the information of depth of coverage by individual EST members at each unigene position will be lost and thus not used in base calling of assembled sequences. This will cause significant number of wrongly called bases in unigenes. iAssembler provides a unigene base error correction module Figure which reFollowing corrections of type I and II assembly and unigene base calling errors, iAssembler reevaluates the resulting unigenes and identifies and corrects new assembly and base calling errors. The error identification and correction steps will be iterated until no new errors can be identified or corrected.It is worth noting that not all identified assembly errors can be corrected by iAssembler. A simple such example is illustrated in Figure iAssembler is designed to generate highly accurate assemblies of EST sequences by performing iterative assembly strategy and automated error detection and correction. The three assemblers in iAssembler, MIRA, CAP3 and megablast assemblers, are all base on the overlap-layout-consensus strategy thus iAssembler is applicable for ESTs with relative long sequences, such as those generated using Sanger and/or Roche-454 platforms.The workflow of iAssembler is shown in Figure Cleaned EST sequences are first supplied to iAssembler with appropriate user-defined parameters. iAssembler first employs MIRA to assemble EST sequences, followed by assembling the resulting MIRA unigenes using CAP3. These two open source assemblers were chosen because we have observed that MIRA is efficient in handling large-scale and relatively short Roche-454 reads while CAP3 can complement MIRA by correcting certain type II assembly errors. Following initial assemblies by MIRA and CAP3, type II assembly errors (unigenes belonging to same transcripts) are then identified by performing all-versus-all pairwise sequence alignments of the resulting unigenes using the NCBI megablast program. iAssembler then utilizes the pair-wise alignment information to assemble these unigenes into new contigs using the megablast assembler module. Next, iAssembler identifies type I assembly errors by aligning individual EST members to their corresponding unigenes. The misassembled ESTs, whose alignments to their corresponding unigenes do not satisfy cutoffs of user-specified parameters such as minimum percent identity or maximum overhang, were then extracted and used in the next round of assembly and error correction. Finally, unigene base calling errors are corrected based on alignment information of individual ESTs to their corresponding unigenes contained in the SAM output file. iAssembler iterates through error identification and correction steps until no new errors can be identified or corrected.The main output of iAssembler includes 1) the final assembled unigene sequence file in FASTA format, 2) a text file summarizing the statistics of alignments of ESTs against their corresponding unigenes, which provides necessary information to assess the quality of the assembly, and 3) a file containing detailed alignment information of individual EST sequences against their corresponding unigenes in SAM format. SAM format is a generic alignment format for storing read alignments against reference sequences and has E. coli genome sequences, which resulted in a total of 246,993 olive ESTs with an average length of 196 bp and 362,445 tomato ESTs with an average length of 579 bp. EST assemblies were performed using a single CPU on a server with six Quad-core 2.93 GHz Intel Xeon processor and 64 GB of RAM. The following parameters were used for all the tested assembly programs, if applicable: minimum overlap length of 40 bp, minimum overlap percent identity of 97%, and maximum overhang length of 30 bp. Detailed commands and parameters used for these assemblers are listed in Table We compared the performance of iAssembler to that of several commonly used EST assembly programs including MIRA, CAP3, TGICL, Phrap, and Newbler. An olive EST dataset generated using the Roche-454 platform as described in Alagna et al. and a toAs shown in Table We then tested performances of these assemblers using another set of parameters: minimum overlap length of 50 bp, minimum overlap percent identity of 95%, and maximum overhang length of 20 bp. The results also indicated that iAssembler generated much higher quality of assemblies than other assembly programs we investigated using the megablast program with a minimum percent identity of 99 and a word size of 20. Only ESTs aligned to Arabidopsis cDNAs in their entire length were kept and the final collection contained 394,298 ESTs. These ESTs were assembled de novo using the six assemblers with the following parameters: minimum overlap length of 40 bp, minimum overlap percent identity of 97%, and maximum overhang length of 10 bp : LinuxProgramming language: PerlOther requirements: Bioperl version 1.006 or higherThird-party tools: BLAST, CAP3 and MIRA. These tools are already integrated into the iAssembler package.License: NoneAny restrictions to use by non-academics: noneZF conceived the general idea of this project and provided the guidance on the whole study. YZ developed the software and performed comparison with other assemblers. JG and LZ helped with design and evaluation of the software. ZF, YZ, and JG wrote the manuscript. All authors have read and approved the manuscript.Examples of common EST assembly errors. The file provides several examples of common EST assembly errors.Click here for filePerformances of EST assembly programs. The file provides evaluation results on performances of several EST assembly programs.Click here for file"} +{"text": "Tropheus sp., a Lake Tanganyika endemic with rich geographical colour pattern variation, in which the strength of sexual isolation varies between populations. We conducted two-way mate choice experiments to compare behaviour of males of a red-bodied morph (population Moliro) towards females from their own population with behaviour towards females from four allopatric populations at different stages of phylogenetic and phenotypic divergence. Males courted same-population females significantly more intensely than females of other populations, and reduced their heteromorphic courtship efforts both with increasing genetic and increasing phenotypic distinctness of the females. In particular, females of a closely related red-bodied population received significantly more courtship than either genetically distinct, similarly coloured females (\u2018Kirschfleck\u2019 morph) or genetically related, differently coloured females (\u2018yellow-blotch\u2019 morph), both of which were courted similarly. Genetically and phenotypically distinct females (Tropheus polli) were not courted at all. Consistent with previous female-choice experiments, female courtship activity also decreased with increasing genetic distance from the males\u2019 population. Given successful experimental and natural introgression between colour morphs and the pervasive allopatry of related variants, we consider it unlikely that assortative preferences of both sexes were driven by direct selection during periods of secondary contact or, in turn, drove colour pattern differentiation in allopatry. Rather, we suggest that sexual isolation evolved as by-product of allopatric divergence.Whether premating isolation is achieved by male-specific, female-specific or sex-independent assortative preferences often depends on the underlying evolutionary processes. Here we test mate preferences of males presented with females of different allopatric colour variants of the cichlid fish Assortative and conspecific mate preferences play an important role in maintaining reproductive isolation between species or among morphs within a species . It has Tropheus comprises another cichlid species complex with rich allopatric colour pattern variation dates back to approximately 1.5 million years ago on the extent of phenotypic and genetic differentiation , 2012. WIn the previous mate choice experiments, females were offered a two-way choice between a homomorphic and a heteromorphic male, and interactions of females with the males were scored in categories representing aggression and mate preference. Although designed as female choice experiments, both male and female preferences could have contributed to the observed patterns, for instance because the intensity of male courtship apparently influences female preferences in within-population interactions (Tropheus sp. \u2018red\u2019 (Tropheus moorii (T. moorii), a genetically distinct population with a red \u2018Kirschfleck\u2019 (cherry-blotch) colour pattern equipped with internal box filters, heaters and hollow bricks and illuminated with overhead white light in a 12:12 h light:dark cycle.Tropheus by Experimental setup was analogous to the female-choice design developed for n = 15 males) were given a choice of one female from the Moliro population and one female from one of the four other populations , resulting in four experiments with the four different heteromorphic populations. Heteromorphic stimulus females were from Ndole , Chiseketi , a location north of Mabilibili and a location south of Isonga . Logistic constraints limited the numbers of stimulus females that could be used in the experiments. Males of the Moliro population with package glmmADMB.To account for the repeated use of individual males and females, we employed generalized linear mixed models (GLMM) with male and female identities as crossed random factors. As male behaviour towards homomorphic females did not differ between experiments (see Results), data from all four experiments were combined to build models testing for morph-dependent differences in male and female behaviour. As the response variables were tallies of events, models were fitted with negative binomial error distributions and log link functions, and included total observation time as offset. Analyses were conducted in R v. 2.15.0 aggressive and courtship behaviour of males towards homomorphic females was independent of the morph of the alternative stimulus female, (ii) males behaved differently towards homomorphic and heteromorphic females in the contexts of both courtship and aggression, and addressed significantly more courtship and significantly less aggression to homomorphic females, and (iii) the intensity of male heteromorphic courtship, but not of aggression, depended on the females\u2019 population, as genetically and phenotypically similar females received significantly more courtship than females of genetically and/or phenotypically distant populations. Females from genetically distant populations also showed reduced courtship activity towards Moliro males, but an opposite trend in the allocation of aggression, which they only displayed in homomorphic encounters. Aggression between males and females reflects competition for feeding territories , and mayTropheus, which demonstrated that discrimination against foreign populations is not universal and amongst other possible factors dependent on the similarity between the involved morphs and previously , genetically related females with distinct colour pattern (Chiseketi) and genetically distinct but similarly coloured females (\u2018Kirschfleck\u2019). Males did not differentiate in their courtship rates between the latter two heteromorphic populations (Chiseketi and \u2018Kirschfleck\u2019), whereas they displayed significantly more courtship quivers to the genetically and phenotypically similar population (Ndole), and significantly less courtship towards the genetically and phenotypically distinct T. polli. Apparently, male discrimination was influenced not only by colour pattern differences but also by divergence in other, for example olfactory or acoustic, cues , which did not discriminate between homo- and heteromorphic males in laboratory two-way female choice tests against a bluish morph , and hence the maximum divergence between populations, dates to approximately 1.5 Ma , the time span within which sexual isolation evolved among Tropheus populations fits well with the haplochromine model.Overall, mate choice data of la flies and haplTropheus populations at their various stages of phylogenetic and phenotypic divergence has the potential to improve our general understanding of how allopatric populations evolve premating isolation on their way to speciation.In conclusion, males of the Moliro population discriminate between females of different populations, and even vary their courtship behaviour between females of the same population and a phenotypically and genetically similar population. Discrimination among populations appears to increase with both, genetic distance and colour pattern dissimilarity. On the basis of current evidence, we consider it likely that assortative mate preferences evolved in both sexes as a by-product of allopatric divergence under natural or social selection. Experiments testing the effects of learning and sensory environments on mate choice are warranted to address the mechanisms underlying sexual isolation within this species complex. Understanding assortative mate preferences among"} +{"text": "Rubiaceae (coffee), Violaceae (violet), Cucurbitaceae (cucurbit), Fabaceae (bean) and recently Solanaceae (potato family), but it is very likely that cyclotides are more widely distributed since their predicted number in Rubiaceae alone is ~50.000. Additionally, the pharmacological validation of plants used in traditional medicines may trigger the discovery of novel uterotonic compounds [Drug discovery from natural products is still one of the biggest sources of novel lead compounds. In particular, plant cyclotides, disulfide-rich peptides comprising three conserved disulfide bonds in a knotted arrangement, known as cyclic cystine knot motif, and a head-to-tail cyclization, have been extensively investigated over the last four decades for their use as scaffolds in drug development. However, their distribution among flowering plants still remains limited to few species of the families of ompounds .de novo sequencing and automated database identification. The aqueous extracts and semipure peptide fractions have been tested further in a collagen gel contractility assay model and showed varying ability to induce contractions in human myometrial smooth muscle cells.Based on the use of plants in traditional Nigerian medicine during pregnancy and childbirth, we analyzed several plants from different families to evaluate their uterotonic properties at cellular level and to identify cyclotides as active molecules. Using a MALDI-TOF/TOF-based screening protocol we were able to identify many novel cyclotide-containing species which was confirmed by manual In conclusion, our results underpin earlier suggestions that cyclotides are one of the largest peptide classes within plants, covering a large chemical space based on their high sequence diversity. The evaluation of contractile properties of plants used in traditional medicines offers new starting points for the discovery and development of peptide-based uterotonic drug leads."} +{"text": "Arterial embolism with lower limb ischemia is a rare manifestation of paraneoplastic hypercoagulability in cancer patients. We report a unique case of fatal thromboembolism involving both circulations associated with a poorly differentiated neuroendocrine tumor of the lung with rapid progress despite high doses of unfractioned heparin and review the current literature on anticoagulative regimen in tumour patients. Limb ischemia due to arterial embolism in cancer patients has been reported for phaeochromocytoma, malignant melanoma, angiosarcoma, or cardiac tumour patients \u20133. SinglVascular tumour invasion, metastatic spread, and fragmentation of cardiac masses need to be distinguished from paraneoplastic effects like catecholamine associated vasospasm, protein precipitation, and hypercoagulability . The latEmbolism suggestive of Trousseau syndrome may occur as initial symptom resulting in tumour diagnosis, as complication alongside disease progression or may be triggered by specific chemotherapy agents , 12. ThrHere we report the unique case of a patient diagnosed with a multilocular metastasized neuroendocrine tumour (NET) of the lung suffering from progressive arterial embolisms in both circulations leading to bilateral lower limb ischemia, pulmonary embolism, stroke, and finally death five weeks after the initial bout of chemotherapy despite high doses of unfractioned heparin.A 58-year-old Caucasian male was admitted to the Oncology Department with polyuria and weight loss of seven kilos in the last two weeks. Risk factors were arterial hypertension and cigarette smoking. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) with hyponatremia was noticed and tumour search detected metastatic liver disease and enlarged hilar lymph nodes. Blood analysis revealed elevated levels for neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), cytokeratin-fragment (Cyfra), and liver biopsy specified metastases of a small cellular, poorly differentiated neuroendocrine tumour (NET). Further staging via FDG PET disclosed the primary tumour near the left lung hilus with positive mediastinal and hilar lymph nodes, diffuse osseous filiarisation, and a sole metastasis in the right adrenal gland. Oncology board consensus decision was made for palliative chemotherapy with cisplatin and etoposid as common for dedifferentiated NET.Two weeks after the initial bout of chemotherapy the patient presented in the Surgical Department with incomplete ischemia of the left lower limb. Immediate interventional recanalization failed and open embolectomy of the tibiofibular trunk with consecutive venous patch plasty was performed. Histological examination of the embolus showed no malignancy. Three days later reischemia of the same leg occurred and the operative procedure was repeated. Search for embolic origin by CT-scan disclosed clinically inapparent pulmonary embolism in three lobes. Mural thrombus of the infrarenal aorta with perifocal aortic wall calcifications appeared identical to the initial staging CT . All tumAgain four days later, transfemoral and pedal embolectomy with multilocular patch plasties of all native crural arteries as ultima ratio due to complete ischemia had to be performed. Decision was made for major amputation as symptoms recurred again two days later. After clinical signs of ischemia of the contralateral limb and respiratory impairment, all parties agreed upon the best supportive care concept. The patient died three days later after an additional stroke with left-sided hemiplegia. Autopsy revealed right-sided heart failure due to new severe pulmonary embolism as cause of death, as well as heavy thrombotic alterations of all major arterial vessels .To our best knowledge this is the first case with fulminant arterial embolisms involving the lung, brain, and both legs within a two-week period despite high doses of unfractioned heparins as paraneoplastic symptoms of a multilocular metastasized NET.Initially, calcifications of the infrarenal aorta with intraluminal thrombus were suggested as origin of embolism and protective stenting was discussed but not conducted due to the rapid chain of events Figures and 2. RConclusively, paraneoplastic or chemotherapy-triggered hypercoagulability remains as possible explanations for generalized thromboembolic disease.Paraneoplastic syndromes occur in about 10% of malignant diseases and are defined as symptom complexes that cannot be readily explained by either the local or distant spread of cancer cells or specific secretory products . ConstitCisplatin, as part of the chemotherapeutic regimen among other substances such as thalidomide, is known to trigger thromboembolism in cancer patients with different nonrelated tumour entities \u201321. The 9/litre as the patient worsened rapidly.Some authors have reported secondary heparin-induced thrombocytopenia (HIT) of type II in cancer patients suggesting a higher incidence due to bone marrow infiltration , 25. HITIn terms of which anticoagulant drug to administer in paraneoplastic embolism, low-molecular-weight heparin (LMWH) seems to be superior compared to unfractioned heparin (UFH) and vitamin K antagonists. This assumption is mainly supported by studies with patients suffering from deep vein thrombosis , 28. RegLower limb ischemia in tumour patients is a severe paraneoplastic complication and might be the first clinical sign in a fast chain of overwhelming thromboembolic events. Tumours of neural crest origin seem to bear a high risk of hypercoagulation. Adequate surgical intervention and sufficient anticoagulation are the only treatment options and may be still too late. Further substantial research on anticoagulative treatment in tumour patients suffering from severe thromboembolic complications is needed."} +{"text": "Effort thrombosis refers to axillary-subclavian vein thrombosis associated with strenuous and repetitive activity of the upper extremities. Spontaneous thrombosis of upper extremity veins, subsequently termed the Paget-Schroetter syndrome, is relatively rare.A 26 -year-old woman presented with progressive left arm swelling that had started one week before admission. Her past medical history was unremarkable for trauma to the shoulder or arm, venous catheter insertion or intravenous drug usage. She was otherwise healthy and did not report any personal or family history of hematological disorders and denied using oral contraceptives. On further questioning, the patient gave a history of knitting daily, at continuous stretches of 4\u20136 hours. Physical examination revealed nonpitting edema involving the entire left upper extremity. The left upper limb showed normal arterial pulses and there was no neurological deficit or bony injury. A color Doppler and duplex ultrasound scan of the left upper limb showed acute deep vein thrombosis involving the left axillary and subclavian veins.Blood was taken for factor V Leiden-factor II (G20210A) mutations and antinuclear antibody concentrations, all of which were normal. The coagulation profile revealed activated partial thromboplastin time and prothrombin time within normal range. Anticoagulation was then started with heparin and continued with warfarin. As an outpatient, she completed 8 weeks of anticoagulation therapy. A repeat ultrasound examination showed that the thrombus had resolved completely and the left subclavian vein appeared intact. After having excluded other possible predisposing factors for upper limb deep vein thrombosis, we concluded that our patient`s thrombosis was primarily prolonged knitting induced.The upper limb is an uncommon site for deep vein thrombosis. Primary axillary-subclavian vein thrombosis is, however, well described and is also called Paget-Schroetter syndrome.6In 1894, von Schroetter was the first to identify vascular trauma from muscle strain as a potential etiologic factor. It is believed that retroversion, hyperabduction and extension of the arm involved with these activities impose undue strain on the subclavian vein leading to microtrauma of the endothelium and activation of the coagulation cascade. Substantial evidence now supports the role of anatomical abnormalities involving the thoracic outlet in the pathogenesis of effort thrombosis.7Effort thrombosis of the upper extremity has been described in athletes involved in a wide variety of sports, including ball games, combatant sport and heavy athletics, games with rackets or clubs, push-up exercise and aquatic sports.Hand knitting might be a potential risk for upper limb thrombosis. Effort thrombosis should be suspected in women who perform repeated hand knitting and present with symptoms characteristic of effort thrombosis."} +{"text": "Leptospira infection or icterohemorrhagic disease (LIR) are not rare entities. Our study introduces a patient infected with LIR following repeated professional underwater dives.Because of disturbances in visual acuity, the patient initially turned to the services of the Timi\u015foara Ophthalmological Clinic in 2011, and was later sent to the Infectious Diseases Clinic of Timi\u015foara, showing low grade fever, moderate hepatosplenomegaly, discreet subicteric sclera and a severely increasing deterioration of visual acuity.Direct ophthalmoscopy revealed disseminated bilateral chorioretinitis foci. The Infectious Diseases Clinic Laboratory confirmed hematological and serological diagnosis of LIR.The ocular chorioretinal determination of LIR is not frequent. In such situations, inoculation particularities along with evolving clinical and biological characteristics invite the clinician to extend the area of investigation."} +{"text": "Genome-wide association studies (GWAS) have achieved great success in identifying common genetics variants associated with increased risk for developing breast cancer. More recently, advances in next-generation sequencing (NGS) have made possible identification of mutations associated with breast cancer. However, to date, the information generated by GWAS and NGS has not been maximally leveraged and integrated with gene expression data to identify biomarkers associated with the most aggressive subset of breast cancer: the triple-negative breast cancer (TNBC). Here we present results from an integrative genomics approach that combines GWAS and sequence information with gene expression data to identify functionally related genes and biological pathways enriched for expression-associated genetic loci and mutations associated with TNBC using publicly available data.We used publicly available data derived from 60 GWAS involving over 400,000 cases and over 400,000 cancer-free controls to identify SNPs and associated genes with increased risk of developing breast cancer. Specifically, we first identified SNPs in population-based human cohorts that are associated with the expression of genes in TNBC. Mutations and associated genes were identified by mining publicly available RNA-Seq and whole exome/ genome sequencing data derived from 104 TNBC patients. Gene expression data were from 124 TNBC tumors and 142 cancer-free controls. We performed supervised and unsupervised analysis on gene expression data from genes containing genetic variants and mutations to identify functionally related genes. Additionally, we performed pathway prediction and network modeling using Ingenuity. For each predicted pathway and network, we counted the number of SNPs and mutation events by direct enumeration.We identified 600 SNPs mapped to 205 genes, and 250 genes with mutations that included inserts, deletions (Indels) and copy number variants. Hierarchical clustering revealed functional relationships and similarity in patterns of expression profiles between SNP-containing genes and genes containing mutations. We identified multi-gene biological pathways enriched for SNPs and mutations. Many of the pathways identified have been proposed as important candidate pathways for TNBC, including the p53, NFkB, apoptosis, BRCA, DNA repair and DNA mismatch repair pathways.The results provide convincing evidence that integrating GWAS and sequence information with gene expression data provides a unified and powerful approach for biomarker discovery in TNBC. Furthermore, the results provide insights about the broader context in which genetic variants and mutations operate in TNBC."} +{"text": "A new study provides information on another possible mechanistic pathway by revealing that cadmium impairs NAT-dependent carcinogen metabolism as demonstrated by altered biotransformation of environmental aromatic amines (AAs) N-acetyltransferases, are metabolic enzymes known to play a major role in the biotransformation of exogenous chemicals including AAs, many of which are known or suspected human carcinogens.Cadmium accumulates in body tissues and causes disease of the lungs, kidneys, liver, testes, prostate, and bladder. It also is thought to potentiate the carcinogenicity of many common workplace chemicals. NATs, or arylamine In the current study the authors exposed purified NAT enzymes to cadmium and found the exposure led to rapid and irreversible functional impairment\u2014removing the cadmium could not restore enzyme activities. They also exposed lung epithelial cells and laboratory mice to cadmium, then assessed NAT acetylation activity in the cells and mouse tissue samples. Biologically relevant concentrations of cadmium similar to those found in the lung tissue of heavy smokers impaired the NAT-dependent acetylation of carcinogenic AAs in lung epithelial cells, and NAT activity was strongly impaired in multiple tissues of mice exposed to cadmium.These findings indicate acute cadmium exposure can alter the metabolism of carcinogenic AAs through impairment of the NAT-dependent pathway, with potentially important toxicologic effects\u2014especially considering AAs are commonly found in cigarette smoke along with cadmium. The authors recommend further studies to address whether chronic cadmium exposure leads to similar effects."} +{"text": "The disruption of mother-infant interactions can have life-long detrimental consequences for offspring and mothers. Recently, science has begun to emphasize translational research including preclinical and neurobiological research that may have direct implications for clinical populations and issues (see Figure"} +{"text": "Nowadays, the use of cardiopulmonary bypass (CPB) followed by systemic hypothermia is common in cardiac surgery procedures. CPB causes a systemic inflammatory response syndrome (SIRS) that is markedly expressed in congenital caridiosurgical surgery programe resulting with deleterious consequences. Those effects are mediated through cytokines and others mediators of acute inflammatory response in circulation, which may lead to low cardiac output syndrome, multiorgan failure and lethal outcome after surgical total correction of congenital heart disease. The best method for SIRS prevention remains unclear, although some authors suggest perioperative use of corticosteroids. The study sough to evaluate the impact of perioperative corticosteroids on SIRS extent as well as clinical outcomes following total correction of congenital heart disease.The study was conducted as prospective randomized controlled trial. We enrolled 60 patients who were scheduled for total correction of congenital heart disease.In this study we examine the effects of corticosteroids in different doses and different time. Patients were divided into three groups with respect to perioperative corticosteroids administration regime.More favorable clinical outcomes as well as laboratory findings were obtained in group of patients receiving high doses of corticosteroids. The best clinical outcome was observed in group receiving (30mg/kg metilprednisolon after induction in anesthesia), where we found the shortest ICU stay , the lowest requirements for inotropic support , the shortest ventilation time .Our study presumably described that perioperative corticosteroids provide more favorable outcomes in group of patients who undergo total correction of congenital disease. However, further prospective multicentric randomized trials are required with aim to elucidate optimal timing and dosing regimens of perioperative corticosteroids."} +{"text": "Astatotilapia latifasciata (Figure Haplochromis obliquidens. This species was described as Haplochromis latifasciatus [Astatotilapia [Haplochromis \"zebra obliquidens\" in the aquarium trade. Astatotilapia latifasciata has been reported to occur in Lake Nawampasa a small satellite lake of the much larger Lake Kyoga, and in Lake Kyoga located north of Lake Victoria in Uganda [After the publication of our work , we detea Figure , was errasciatus and lateotilapia . Our misn Uganda ."} +{"text": "Vancomycin-resistant Enterococci (VRE) is one of the most important hospital pathogens.The aim of the study was to evaluate the VRE colonization in patients hospitalized at the Hematology Intensive Care Unit and associated risk factors.Enterococci were isolated by standard microbiological methods. Isolate sensitivity was tested by disk-diffusion test using the 30\u03bcg/ml (BBL) Vancomycin plates according to CLSI standard.Prospective cohort study involved 70 patients hospitalized at the Intensive Care Unit (ICU), Clinic for Hematology, during three months. Demographic data and data risk factors for VRE colonization during present and previous hospitalization (within 6 months) were recorded for each patient using the questionnaire. Feces or rectal swab was collected for culture from patients on admission and at discharge in case when VRE was not isolated on admission. The Upon admission, 7% of patients were already colonized with VRE. The rate of VRE colonization during present hospitalization was 41.5%. Univariate logistic regression demonstrated statistical significant differences of acute myeloid leukemia (AML) diagnosis , length of present stay , use of aminoglycosides , and pip/tazobactam in present hospitalization, duration of use of carbapenem and pip/tazobactam in present hospitalization between the VRE-colonized and non-colonized patients. AML, use of carbapenem in previous hospitalization and duration of use of piperacillin/tazobactam in present hospitalization were independent risk factors of VRE-colonized patients according to multivariate logistic regression.VRE colonization rate was high among patients admitted to hematology ICU. Rational use of antibiotics and an active surveillance may be helpful preventive measures for development of bacterial resistance to antimicrobial agents.None declared"} +{"text": "Dendroctonus ponderasae Hopkins) and its associated pathogenic fungi in western North America has resulted in the loss of more than 13 million hectares of pines since 1999 in British Columbia alone [Pinus contorta Dougl. ex Loud. var. latifolia) in British Columbia. However, since 2006 MPB has spread into northern Alberta, where lodgepole pine hybridizes with jack pine (Pinus banksiana Lamb.) [G. clavigera differ, and that water deficit affects these responses.The ongoing outbreak of mountain pine beetle two year old lodgepole and jack pine seedlings in growth rooms, and (2) ca. sixty year old lodgepole x jack pine hybrids in naturally regenerated, thinned stands. Soil relative water content was monitored using time-domain reflectometry. Seedlings were subjected to watering or water deficit for one week prior to wounding or wounding plus Tree physiological status was evaluated by measuring gas exchange and stomatal conductance using a LiCor 6400, stem hydraulic conductivity using a low-pressure flow meter and safranin dye xylem perfusion, and HPLC. Defense responses were assessed by lesion measurements histochemistry, and qRT-PCR.Stomatal conductance and photosynthesis significantly decreased under water deficit for both lodgepole and jack pine seedlings, but seedling hydraulic conductivity was not affected. The mild water deficit applied to the mature trees reduced stomatal conductance and photosynthesis, but not significantly.G. clavigera-induced lesions developed more slowly in jack pine than lodgepole pine seedlings. Stem hydraulic conductivity decreased in inoculated lodgepole but not jack pine seedlings, likely because of greater tracheid occlusion caused by increased fungal growth and/or resin production in lodgepole pine [G. clavigera in the co-evolved lodgepole pine host than in the new jack pine host, and (2) defense responses are slowed by water limitation.Stem lesions are a means of killing and compartmentalizing invading organisms . G. clavole pine . Water dole pine , with loole pine . Accordiaquaporin and five DREB genes, families associated with water stress responses. Although the mild water deficit did not significantly alter expression of these genes, expression of one aquaporin and one DREB decreased in response to G. clavigera inoculation. We then profiled five chitinase and four terpene synthase defense-associated genes. Expression of two chitinases was significantly induced by water deficit but not G. clavigera. Expression of other chitinases significantly increased in response to fungalinoculation, but the response was attenuated by water deficit. Expression of one terpene synthase significantly increased with fungal inoculation, but this response was also attenuated under water deficit. In contrast, water deficit increased constitutive expression of another terpene synthase. Higher constitutive expression of the monoterpene synthase under mild water stress suggests a pre-emptive defense via higher biosynthesis of volatile monoterpenes. Microarray and qRT-PCR analyses of the lodgepole and jack pine seedling experiment are underway.We then examined the effect of water deficit on transcript abundance corresponding to genes classically associated with drought and defense responses. We conducted qRT-PCR transcript abundance profiling of secondary phloem from mature lodgepole x jack pine hybrids. We first profiled four Our analyses suggest that defense responses of jack pine differ from those of lodgepole pine. Molecular analyses are underway to further characterize these differences. Both constitutive and induced defense responses are modulated in pines by water deficit, and this response appears to be gene-specific. This study shows evidence of cross talk between the water stress and defense responses of pine trees."} +{"text": "Brain stem arteriovenous malformations (AVMs) are rare and their clinical management is controversial. A location in highly eloquent areas and a greater risk of radionecrosis are both serious issues for radiosurgery of this entity. We report a case of a pontine AVM treated successfully with gamma knife therapy. At 3 years angiographic follow-up, imaging demonstrated complete thrombosis and there were no new neurological deficits, and at 7 years clinical follow-up, the patient continued to be neurologically stable. Although all treatments carry risk of neurological compromise, gamma knife therapy may offer the best treatment option for brain stem AVMs as seen in the case presented herein. This case illustrates a rare case of holo-pontine AVM tolerating gamma radiation with complete angiographical response and minimal neurological sequalae. Arteriovenous malformations (AVM) are congenital vascular malformations with direct arterial to venous connections without an intervening capillary network Doppman . The abrThe main diagnostic tools for these pathologic entities are magnetic resonance imaging (MRI), CT angiogram, and angiography , where single treatment of a pontine AVM with overlapping isodoses led to complete obliteration without any new neurological deficit.Any treatment of brain stem AVMs offers considerable risk for neurological compromise. Radiosurgery in highly selected cases may offer a treatment option with reasonable risks."} +{"text": "Overproduction of insulin and associated hypoglycemia are hallmark features of this disease. Diagnosis can be made through demonstration of hypoglycemia and elevated plasma levels of insulin or C-Peptide. Metastatic disease can be detected through computerized tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET)/CT. Somatostatin receptor scintigraphy can be used not only to document metastatic disease but also as a predictive marker of the benefit from therapy with radiolabeled somatostatin analog. Unresectable metastatic insulinomas may present as a major therapeutic challenge for the treating physician. When feasible, resection is the mainstay of treatment. Prevention of hypoglycemia is a crucial goal of therapy for unresectable/metastatic tumors. Diazoxide, hydrochlorothiazide, glucagon, and intravenous glucose infusions have been used for glycemic control yielding temporary and inconsistent results. Sandostatin and its long-acting depot forms have occasionally been used in the treatment of Octreoscan-positive insulinomas. Herein, we report a case of metastatic insulinoma with very difficult glycemic control successfully treated with the radiolabeled somatostatin analog lutetium ( Insulinoma is a rare pancreatic neuroendocrine tumor . OverproThe treatment of unresectable metastatic insulinoma is associated with prolonged hospitalization for intravenous glucose infusion. The management of recurrent hypoglycemia also encompasses the administration of diazoxide, hydrochlorothiazide, and glucagon.Sandostatin and its long-acting depot form (Sandostatin LAR) are an adjunct therapy to neuroendocrine tumors. There are a few reports of glycemic control in patients with insulinoma treated with radio labeled somatostatin analogs , 5.The m-TOR inhibitor everolimus has been used to control hypoglycemia in this group of patients \u20137. Moreo177LU).Herein, we report a case of metastatic insulinoma successfully treated with the radiolabeled somatostatin analog lutetium . Computerized tomography (CT) scan of the abdomen was performed confirming the sonographic findings. The patient underwent a liver biopsy. Histopathology and immunohistochemistry results were consistent with low-grade neuroendocrine neoplasia (positive stain for chromogranin A) . InsulinThe patient received continuous intravenous glucose because of recurrent episodes of hypoglycemia throughout the hospital stay . GlucagoOctreoscan was performed showing a high uptake in focal areas of the liver, left lower quadrant of the abdomen, and cervicothoracic area .177LU) 8 weeks apart beginning on hospital day 56. By the second administration of the radiopharmaceutical, Octreoscan SPECT/CT had already shown objective metabolic and radiologic response to treatment has been successfully tested in the treatment of gastroenteropancreatic neuroendocrine tumors [Radiolabeled somatostatin analog lutetium did show clear evidence of objective response in line with other reports.After results of Octreoscan became available, we decided to use radiolabeled somatostatin analog because of previous reports of glycemic control and objective responses. Glucose levels steadily improved, as shown in 177LU) may represent an option for glycemic and systemic disease control, as shown in the case presented here.In summary, unresectable metastatic insulinomas may present as a major therapeutic challenge for the treating physician. For Octreoscan-positive tumors, radiolabeled somatostatin analog lutetium ("} +{"text": "Pulse wave velocity (PWV) is an indirect measure of vascular stiffness. Higher PWV is a recognised cardiovascular risk marker. Magnetic resonance imaging (MRI) is a non-invasive method of assessing PWV. Assessing maternal influences on offspring PWV is important as reduced fetal nutrient supply and impaired early development are linked with an increased risk of cardiovascular disease in adulthood. In multiparous women, changes in the uterine spiral arteries arising during previous pregnancies result in increased fetal nutrient supply. Rat studies have shown that changes in maternal fatty acid intake in pregnancy are associated with increased offspring arterial stiffness. Some studies of human adults suggest omega-3 fish oils reduce arterial stiffness. The objective of the study was to measure vascular stiffness using MRI, and examine maternal influences on vascular structure in children aged 9 years.Aortic PWV was assessed in 125 children aged 9 years using velocity-encoded MRI as part of a study of developmental influences on cardiovascular structure and function. Maternal diet had been assessed in early and late pregnancy, and the child's diet at age 9 years, using administered food frequency questionnaires.PWV values fell within previously reported childhood ranges. Childhood aortic PWV was lower in offspring of multiparous mothers . Higher maternal oily fish intake in pregnancy was associated with lower childhood aortic PWV , but there was no association with the child\u2019s current fish intake.MRI measurements of childhood aortic PWV indicate that the mother\u2019s parity, and normal variations in maternal oily fish intake in pregnancy, may alter vascular development in utero - changing arterial structure and function with long-term consequences for cardiovascular risk in later life.This work was supported by funding from the British Heart Foundation and the National Institute for Health Research ."} +{"text": "Introduction. The mechanisms underlying the association between insulin resistance and intrahepatic lipid (IHL) accumulation are not completely understood. We sought to determine whether this association was explained by differences in fasting non-esterified fatty acid (NEFA) levels and/or NEFA suppression after oral glucose loading. Materials and Methods. We performed a cross-sectional analysis of 70 healthy participants in the Hertfordshire Physical Activity Trial who underwent oral glucose tolerance testing with glucose, insulin, and NEFA levels measured over two hours. IHL was quantified with magnetic resonance spectroscopy. Insulin sensitivity was measured with the oral glucose insulin sensitivity (OGIS) model, the leptin: adiponectin ratio (LAR), and the homeostasis model assessment (HOMA). Results. Measures of insulin sensitivity were not associated with fasting NEFA levels, but OGIS was strongly associated with NEFA suppression at 30 minutes and strongly inversely associated with IHL. Moreover, LAR was strongly inversely associated with NEFA suppression and strongly associated with IHL. This latter association was explained by reduced NEFA suppression (P = 0.24 after adjustment). Conclusions. Impaired postprandial NEFA suppression, but not fasting NEFA, contributes to the strong and well-established association between whole body insulin resistance and liver fat accumulation. Excess intrahepatic lipid (IHL) accumulation is an important component of the spectrum of metabolic derangements associated with central obesity and insulin resistance . StudiesNEFA suppression is impaired in type 2 diabetes and NAFLThe rationale and design for the Hertfordshire Physical Activity Trial ISRCTN 60986572) have been described previously 8], and o"} +{"text": "The spiking state is thought to be maintained by a positive feedback loop between a nonspecific, calcium-sensitive cationic current (ICAN) carried by canonical transient receptor potential (TRPC) channels and heightened intracellular calcium levels sustained during sufficiently fast spiking. Bistable persistent spiking (PSB) has been observed across layers and cell types in mEC and has been implicated in working memory and grid cell function, so cholinergic modulation of TRPC channels represents a potentially fundamental mechanism shaping the spiking output of mEC neurons. However, spiking of mEC neurons during navigation and goal directed behavior in vivo is strongly theta modulated (4-12 Hz), and it is not known how the PSB mechanism may interact with theta oscillations. In the present study we evaluated the effect of muscarinic modulation on input-output processing of mEC neurons to tonic, slowly varying, and oscillatory inputs. First, we investigated the frequency to injected current (FI) relationship using step and ramp current injection protocols in the presence of the muscarinic agonist carbachol (CCh). FI measures made following suprathreshold pre-pulse current injections exhibited higher spike frequencies than when measured following subthreshold pre-pulses, illustrating a spike-history dependence of the FI relationship. The instantaneous spike frequency measured during a range of current steps showed a positive slope for most PSB neurons, indicating that ICAN acts as a reverse spike frequency adaptation mechanism. In response to linearly increasing ramp current stimuli, mEC neurons showed a steep acceleration followed by a plateau of spike frequency. Spike frequency hysteresis during decreasing ramp stimuli demonstrated significant adaptation for higher input levels, but spiking was often maintained at lower levels of injected current. Next, using different combinations of theta frequency sinewave current injections and DC holding currents, we were able to generate a range of spiking patterns where spikes were elicited on different proportions of theta cycles and at different phases of the theta input. With muscarinic activation, spiking was elicited on a higher proportion of theta cycles and at earlier phases of the oscillatory input for lower levels of tonic current input. A subset of recorded neurons exhibitted repeated sequences of intrinsic phase precessing spiking behavior. Similar to the plateau in spike rate observed with ramp stimuli, in response to stimuli composed of sinewaves superimposed on ramps, spiking phase rapidly advanced and maintained an 'early-phase plateau' as DC current continued to increase. Taken together, we demonstrate that muscarinic modulation of TRPC channels determines the gain of the frequency to injected current relationship of mEC neurons, interacts with adaptation mechanisms to generate spike history dependencies of spike rate including hysteresis, and shapes the distribution of spiking phases relative to oscillatory input. We propose that increasing activation of ICAN by spike-triggered calcium influx as an animal enters a firing field may provide a cellular mechanism contributing to theta phase precession of mEC grid cells.In the presence of muscarinic cholinergic modulation"} +{"text": "To the Editor: Rift Valley fever (RVF) virus causes severe disease, abortion, and death in domestic animals in Africa and the Arabian Peninsula. Humans are infected by mosquitoes, which maintain epizootic transmission, or through exposure to infected animal tissue. Although human disease may be mild, sometimes severe retinitis, meningoencephalitis, or hemorrhagic fever syndromes may develop in patients. In Africa, epizootics and associated human epidemics usually follow heavy rainfall and Kenya (1997), which suggests that the virus was imported through infected mosquitoes or livestock from East Africa and the Department of Defense Global Emerging Infections Surveillance and Response System (DoD-GEIS) monitor the satellite-derived normalized difference vegetation index (NDVI), which reflects recent rainfall and other ecologic and climatic factors \u2013 panel A Satellite-derived rainfall estimates show that widespread rainfall occurred over most of western Saudi Arabia and Yemen from mid-April to mid-June 2005 (No human cases of RVF have been reported in Saudi Arabia and Yemen since the 2000 outbreak, but in September 2004 the Saudi Ministry of Agriculture reported that 5 RVF-seropositive sheep had been identified during routine surveillance in Jizan where most infected persons were exposed during the outbreak in 2000 (Since RVF virus can be maintained in mosquito eggs for extended periods and transmitted under favorable conditions ("} +{"text": "Zosterisessor ophiocephalus), thornback ray (Raja clavata), and scorpionfish (Scorpaena scrofa) were studied. At least four caseinolytic proteases bands were observed in zymogram of each enzyme preparation. These proteolytic preparations were successfully used in the deproteinization of shrimp wastes for chitin extraction. Furthermore, a trypsin was purified from the pyloric ceca of Pacific cod using chromatographic methods. The cod trypsin was successfully applied to catalyze dipeptide synthesis using series of \u201cinverse substrates.\u201d A Mackerel trypsin was also purified from defatted viscera by supercritical carbon dioxide, and its biochemical properties were studied.Sea products are valuable resources of natural substances such as lipids, polysaccharides, enzymes, vitamins, and proteins. In this issue, a variety of fish proteases have been characterized and sometimes purified. Many of these enzymes display potentially interesting new biochemical properties for industrial applications. Their potential adequacy for biotechnological applications such as chitin extraction was demonstrated. Biochemical characteristics of crude alkaline protease extracts from the viscera of goby . Sea products proteins digestion using bacterial proteases generated protein hydrolysates displaying interesting biochemical properties and antioxidant activity. Antioxidative activities and biochemical properties of protein hydrolysates with different hydrolysis degrees, prepared from cuttlefish using an Alcalase and This issue highlights the potential of sea products as valuable resources of bioactive peptides and proteins such as hydrolytic enzymes, lectins, and antioxidants. These resources might be of great interest for industrial biotechnological processes using safe and natural materials such as peptides or enzymes. Dicer is an RNase III enzyme with two catalytic subunits, which catalyzes the cleavage of double-stranded RNA to small interfering RNAs and micro-RNAs, which are mainly involved in invasive nucleic acid defense and endogenous genes regulation. In addition, Dicer is thought to be involved in defense mechanism against foreign nucleic acids such as viruses. A paper focused on the recent progress of Dicer-related research and discussed potential RNA interference pathways in aquatic species. Dicer is abundantly expressed in embryos, indicating the importance of the protein in early embryonic development. Nabil MiledNabil MiledMoncef NasriMoncef NasriHideki KishimuraHideki KishimuraFaouzi Ben RebahFaouzi Ben Rebah"} +{"text": "University course processes have recently changed with student enrolments increasing, ultimately placing new demands on student placements within the healthcare setting. In response to the changing university curriculum and in line with the Victorian Department of Health, Clinical Placement Networks and Health Workforce Australia, Northern Health (NH) Podiatry department identified a unique opportunity in provision of clinical placement education.NH developed an innovative and exciting approach to the management and delivery of podiatry student clinical placements in order to increase capacity. Recruitment to a new Podiatry Clinical Educator (CE) position allowed implementation of strategies to significantly increase capacity, ensure provision of high quality, evidenced based and safe clinical education whilst supporting podiatrists and students.To increase student capacity with limited resources, NH created a Podiatry CE position. This facilitated developments including; 2:1 Model of Supervision with peer learning and incorporating a focus on student feedback and reflection, integrating simulation into traditional clinical education, evidenced based tutorials and support to podiatrists and students.Preliminary evaluation findings show significant increase in capacity with high student and podiatrist satisfaction. Results of student placement evaluations will be presented including perspectives on simulation, peer learning and specific podiatrist professional experiences.With a Podiatry CE position and great team functioning; strategies implemented allow consistent provision of efficient, high quality, evidence based podiatry student clinical placements enabling increased capacity."} +{"text": "Prosthodontists can serve as productive members of the craniofacial team and can help coordinate multidisciplinary treatment of patients with congenital anomalies. Often there are few, if any, evidence-based criteria to assist them in developing \u201ccorrect\u201d clinical protocols. When syndromes involve hypodontia, oligodontia, or anodontia, coordinating prosthetic treatment through phases of three-dimensional growth and development can be daunting.Early implant intervention with anodontia patients is acceptable in some treatment centers. Correcting previously untreated adolescent oligodontia can be extremely challenging and removal of strategic teeth with immediate implant placement is surely controversial. Understanding the morbidity of grafting in these patients and the questionable long-term survival of overdenture abutment teeth will lend to an active discussion of the advocated aggressive therapeutic approach."} +{"text": "Neuronal death and subsequent denervation of target areas is a major feature of several neurological conditions such as brain trauma, ischemia or neurodegeneration. The denervation-induced axonal loss results in reorganization of the dendritic tree of denervated neurons. Dendritic reorganization of denervated neurons has been previously studied using entorhinal cortex lesion (ECL).ECL leads to shortening and loss of dendritic segments in the denervated outer molecular layer of the dentate gyrus . HoweverTo perform comparative electrotonic analysis we used computer simulations in anatomically and biophysically realistic compartmental models of 3D-reconstructed healthy and denervated granule cells. Our results show that somatofugal and somatopetal voltage attenuation due to passive cable properties was strongly reduced in denervated granule cells. In line with these predictions, the attenuation of simulated backpropagating action potentials and forward propagating EPSPs was significantly reduced in dendrites of denervated neurons. In addition, simulations of somatic and dendritic frequency-current (f-I) curves revealed increased excitability in deafferentated granule cells.Taken together, our results indicate that unless counterbalanced by a compensatory adjustment of passive and/or active membrane properties, the plastic remodeling of dendrites following lesion of entorhinal cortex inputs to granule cells will boost their electrotonic compactness and excitability."} +{"text": "Mammalian gene regulation is often mediated by distal enhancer elements. Despite this, mechanistic investigations of correlated expression have thus far been focused on proximal promoter regions, mainly because distal enhancers are not known for a vast majority of genes. However, distal enhancers of co-regulated genes are likely to have correlated activity.cis) and from different chromosomes, after accounting for HS autocorrelation affecting cis-pairs. Using non-parametric tests and controlling for dependencies, highly correlated pairs are compared with background pairs for: enrichment of co-occurring binding motifs; for correlated gene expression across the 15 cell samples sourced for HS data; for shared gene function; for evidence of interactions between shared enhancer-binding transcription factors (TFs) and chromatin-modifying enzymes; and for Hi-C evidence of pair co-localization. The relationship between correlated enhancers now established, we conclude by scaling this pairs perspective to the building and validating of an enhancer network.Using P300-bound regions as putative enhancers and usinWe find that correlated enhancers tend to share common TF-binding motifs, and that several chromatin modification enzymes preferentially interact with these TFs. We show that we can predict correlated enhancers with 73% accuracy based only on the presence of shared motifs for specific TFs. Also, genes near correlated enhancers have correlated expression and share common function. Correlated enhancers coincide with spatially proximal genomic regions assayed by Hi-C in two different cell types. Finally we construct an enhancer network based on shared motifs and correlated activity, and show its high overlap with biological processes and pathways.Overall, our analysis suggests that functionally linked genes may be co-regulated by distal enhancers whose activities are regulated by common sets of TFs and mediated by both 3D chromatin structure as well as chromatin modification enzymes. Our work represents the first investigation of enhancer networks based on correlated activity across multiple cell types."} +{"text": "Nocardia infections; ganciclovir, valganciclovir, or acyclovir for cytomegalovirus related complications in at-risk recipients; and lamivudine for prevention of progressive liver disease in HBsAg positive recipients. Viral load monitoring and pre-emptive treatment is used for BK virus infection. Infection with new organisms has recently been reported, mostly due to inadvertent transmission via the donor organ.Infections are the leading cause of hospitalization in transplant recipients. The increased risk of new onset diabetes after transplantation, cardiovascular disease, post-transplant lymphoproliferative disorders adversely affects allograft outcomes. Risk is determined by epidemiologic exposure, immunosuppressive therapy and prophylaxis. The predictable sequence of appearance of infections helps in making management decisions. High likelihood of infections with unusual and multiple organisms necessitates aggressive use of imaging techniques and invasive procedures. Serologic tests depend upon antibody response and are unreliable. Nucleic acid based assays are sensitive, rapid, and allow detection of subclinical infection and assessment of response to therapy. Preventive steps include screening of donors and recipients and vaccination. All indicated vaccines should be administered before transplantation. Inactivated vaccines can be administered after transplantation but produce weak and transient antibody response. Boosters may be required once antibody titers wane. Post-transplant chemoprophylaxis includes cotrimoxazole for preventing urinary tract infections, pneumocystis and Optimal use of immunosuppressive drugs in a renal transplant recipient (RTR) requires a careful balancing act. Availability of potent and specific immunosuppressive agents has reduced the incidence of acute rejection to about 10\u201315% in most centers. However, despite refinements in diagnostic techniques and discovery of new anti-microbial drugs, the risk of infection amongst transplant recipients has not come down. showed iInfection risk is even greater in the pediatric transplant population. Data from the North American Pediatric Renal Transplant Cooperative study show that 38\u201342% patients transplanted between 1987 and 2002 required hospitalization for infections. Infection was the primary cause of hospitalization in the first 2 years after transplantation, exceeding that for rejection. Cl55 Cl5455In conclusion, infections remain a major problem in the transplant population. They are a main cause of death with functioning graft, and cause a number of other complications that increase morbidity. Molecular diagnostic techniques have allowed earlier identification and better monitoring of infections. Prophylactic strategies include vaccination and targeted post-transplant chemoprophylaxis. Use of drugs carries the risk of late and resistant infections. A high index of suspicion and early and aggressive use of diagnostic techniques are essential for accurate diagnosis and improved outcomes."} +{"text": "WebGimm is a free cluster analysis web-service, and an open source general purpose clustering web-server infrastructure designed to facilitate easy deployment of integrated cluster analysis servers based on clustering and functional annotation algorithms implemented in R. Integrated functional analyses and interactive browsing of both, clustering structure and functional annotations provides a complete analytical environment for cluster analysis and interpretation of results. The Java Web Start client-based interface is modeled after the familiar cluster/treeview packages making its use intuitive to a wide array of biomedical researchers. For biomedical researchers, WebGimm provides an avenue to access state of the art clustering procedures. For Bioinformatics methods developers, WebGimm offers a convenient avenue to deploy their newly developed clustering methods. WebGimm server, software and manuals can be freely accessed at Identifying groups of co-expressed genes through cluster analysis has been successfully used to elucidate affected biological pathways and postulate transcriptional regulatory mechanisms. Methods for co-expression analysis of gene expression data have been extensively researched, and numerous clustering algorithms have been developed. New clustering algorithms often have been implemented as stand-alone computer programs, R packages, or both . NumerouThe rationale for developing WebGimm is two-fold. First, sophisticated and better performing clustering methods are likely to be used more often if they are accessible through a streamlined and familiar interface requiring only minimal computational resources and no local installation. Second, an integrated web-based cluster/treeview-like platform that also incorporates functional enrichment analysis will further improve the utility of even simple hierarchical clustering procedures. We aimed to combine the \"wrapper\" model to facilitate access to clustering algorithms implemented in R, with the web-server model of deployment that obviates any local software installation.cluster/treeview package. The version of the software deployed on our server implements multiple infinite mixture model based clustering procedures [k-means clustering). In addition, functional analysis using the CLEAN framework and FTreeView browser [To achieve these goals, we developed WebGimm, an open source general purpose clustering web-server infrastructure designed to facilitate the easy deployment of integrated cluster analysis servers based on clustering algorithms implemented in R. The design of our Java Web Start (JWS) client was modeled after the familiar ocedures ,8-11 as browser are inteWebGimm is an open source general purpose clustering web-server infrastructure designed to facilitate the easy deployment of integrated cluster analysis servers based on clustering algorithms implemented in R. The system consists of a Java GUI client deployed using the Java Web Start (JWS), and the server-side infrastructure designed around Java-based WebGimm server and multiple computing R servers. The server architecture is shown in Figure Rserve infrastructure http://www.rforge.net/Rserve/. R servers perform all computational tasks associated with cluster analysis and functional enrichment analysis by executing an R script with parameters supplied by the WebGimm server. R servers provide clients with feedback about the progress being made and also send a notification once the computation completes. Jobs are assigned to the servers in a round-robin fashion to evenly distribute the load among a \"farm\" of R servers.The design of the Java client is modeled after the familiar cluster/treeview package. The client's function is to pass user-specified analysis parameters and data to the server for analysis, and to facilitate viewing and downloading of analysis results. The server facilitates simple data centering and scaling, executing various clustering algorithms, performing functional enrichment analysis using CLEAN and viewing results of functionally annotated clustering results using Functional TreeView (FTreeView) . The Webk-means clustering). In addition to providing a convenient tool for using GIMM, the integrated functional analysis and FTreeView browser provide a strong incentive to use the tool even when applying simple clustering procedures. The simplicity of deployment and the interface allows anybody with only conceptual understanding of cluster analysis to start using it with little effort.WebGimm serves as an integrated platform for cluster analysis, functional annotation of clustering results, and for exploring analytical results using the (FTreeView). The version of the software deployed on our server implements Gaussian Infinite Mixture Model (GIMM) based clustering procedures ,8-10 as Figure The WebGimm infrastructure also provides a convenient way to implement and distribute newly developed clustering procedures. The complete code for client and server-side software, as well as instructions for deploying the server, can be downloaded from the support web site. By making simple modifications to the client GUI and the backend R scripts, Bioinformatics developers can deploy their own methods on their own servers in a way that is accessible to users without technical Bioinformatics expertise. Such deployment will likely increase the impact of their procedures, while allowing biomedical researchers to easily test state of the art analytical procedures and choose the one producing most meaningful results for their dataset at hand. Furthermore, separating the computational infrastructure from the user interface allows for a straightforward adoption of advanced computational paradigms. For example, the recent implementation of the hierarchical clustering using CUDA general purpose programming tools for NVIDIA Graphical Processing Units achieved 48-fold speed-up over typical desktop CPU using traditional sequential algorithm . ImplemeProject name: WebGimmhttp://ClusterAnalysis.orgProject home page: Operating system: platform independent client , Linux-based web-server, platform-independent R packagesProgramming language: Java, C++, MySQL, ROther requirements: NoneLicense: The tool is available online free of charge, and code is available based on GNU GPL.Any restrictions to use by non-academics: NoneCLEAN: Clustering Enrichment Analysis; DAVID: Database for Annotation, Visualization and Integrated Discovery; GIMM: Gaussian Infinite Mixture Model; JWS: Java Web Start.'The authors declare that they have no competing interests.VJ developed the complete server infrastructure and the JWS client. MM conceived and led the development of the software and the web-server. JF developed the server-side R scripts for performing cluster analysis and functional analysis. ZH develops and maintains the c++ GIMM code, VJ and MM wrote the paper. All authors read and approved the final manuscript."} +{"text": "Female genital tuberculosis remains as a major cause of tubal obstruction leadingto infertility, especially in developing countries. The global prevalence of genital tuberculosis has increased during the past two decades due to increasing acquired immunodeficiencysyndrome. Genital tuberculosis (TB) is commonly asymptomatic and it is diagnosed duringinfertility investigations. Despite of recent advances in imaging tools such as computed tomography (CT) scan, magnetic resonance imaging (MRI) and ultrasongraphy, hysterosalpinography has been considered as the standard screening test for evaluation of tubal infertilityand as a valuable tool for diagnosis of female genital tuberculosis. Tuberculosis gives rise tovarious appearances on hysterosalpingography (HSG) from non-specific changes to specificfindings. The present pictorial review illustrates and describes specific and non-specific radiographic features of female genital tuberculosis in two parts. Part I presents specific findings oftuberculosis related to tubes such as \"beaded tube\", \"golf club tube\", \"pipestem tube\", \"cobblestone tube\" and the \"leopard skin tube\". Part II will describe adverse effects of tuberculosison structure of endometrium and radiological specific findings, such as \"T-shaped\" tuberculosis uterus, \"pseudo-unicornuate \"uterus, \"collar-stud abscess\" and \"dwarfed\" uterus withlymphatic intravasation and occluded tubes which have not been encountered in the majorityof non-tuberculosis cases. Female genital tuberculosis (FGTB) is one formof extrapulmonary manifestations of tuberculosisand includes 5% of all female pelvic infections, 2. It iThe reported prevalence of genital tuberculosis hasshown a descending trend in developed countries, butrecently, its rate has started to increase again due toco-infection with human immunodeficiency virus(HIV) and the development of drug resistants trains ofMycobacterium tuberculosis -6. PrimaDiagnosis of genital TB may be difficult becausemajority of cases are asymptomatic; furthermore, inhigh prevalence-countries, culture facilities for mycobacterium and histopathologic diagnosisare limited-11. In tThis part of pictorial review illustrates and describes endometrial changes following genital tuberculosis detected by HSG. Tubal tuberculosis is disseminated to the endometrium in approximately 50% of cases and persThe pathognomonic findings for tuberculosisinclude specific and non-specific features. Specificradiographic features are \"collar-stud abscess\",\"T-shaped\" uterus and unicornuate uterus-likeappearance (the \"pseudounicornuate\" uterus). Otheruterine changes due to tuberculosis known as nonspecific features include endometritis, synechiae,distortion of uterine contour, and venous and lymphatic intravasations , 15.Uterine manifestations in tuberculosis may varyfrom mild endometritis to severe scarring and deformity leading to total obliteration of the uterinecavity 16). In. In16). Later with progression of TB, caseation and ulceration of endometrium occur, and intrauterine scarring may result in synechiae and intrauterineadhesions. In this stage, the uterine cavity is usually normal in size, but irregularity of uterine contour, filling defects, lack of uterine contractilityand tubal patency may be seen .With progression of disease, irregularity ofuterine contour and filling defects may resultin a denticulate cavity 18, 19), 1918, 1A dwarfed uterus which is characterized witha small and shrived uterus with irregularity anddisproportion between uterine cavity and cervix,while trifoliate shaped uterus are other presentations of uterine tuberculosis (17).After long duration of infection, extensive destruction of endometrium and myometriumfollowed by fibrosis and complete obliteration of the uterine cavity may occur as the\"Netter syndrome\" (21). Hysterosalpingographic characteristic of Netters syndrome iscalled \"glove\u2019s finger\" consisted of a cervical canal and a small part of the uterus (21). Other radiographic findings of tubercular affection of the uterus include theformation of a \"collar-stud abscess\", whichis pathognomonic for tuberculosis (14).This feature should be differentiated fromintracavitary changes due to necrosis in anadjacent uterine leiomyoma. A collar-studabscess classically has a narrow neck with abroader base which is away from the endometrial cavity.The venous and lymphatic intravasation inuterine and adnexal vessels is acomplicateddisorder which occurs due to progressive destruction and ulceration of endometrium.Themost important cause of intravasation is the entry of contrast medium to the venous andlymphatic canals through unprotected ves-sels. Although this feature is not specific fortuberculosis, it can be detected by HSGs performed early in the menstrual cycle, shortlyafter endometrial instrumentation or pathological deficiency of endometrium . It isaIn hysterosalpingography filling of multiple,parallel beaded channels are seen.Contrast in thin delicate lymphatics are differentiated from blood vessels by their narrower caliber and reduced draining of contrast. Cervical tuberculosis is rare due to the nature of stratified squamous epithelium of theectocervix which causes to be resistance tobacterial penetration - 26. TheIn the cervix, the tuberculous lesion can beulcerative or proliferative. In the ulcerativeform, the ulcers have wavy borders, clean cutedges and a yellow base. The proliferative lesion has papillary formations which may bepedunculated or sessile.On HSG, caseous ulceration of the mucosaproduces ragged irregular contours and diverticular outpouching with a feathery appearance . The other various featuressuch as adhesions, distortion and a serratedendocervical canal have also seen in somecases.There are useful differential diagnostic criteria suggested by Klein et al. for diag Calcified lymph nodes or smaller irregularcalcifications in the adnexal area.Obstruction of the fallopian tube in the zoneof transition between the isthmus and the ampulla.Multiple constrictions along the course ofthe fallopian tube.Endometrial adhesion and/or deformity orobliteration of the endometrial cavity in theabsence of curettage or of surgical terminationof pregnancy.Uterine tuberculosis may show a range of mildto severe endometritis, restricted to superficiallayers of endometrium or endometrial ulcer leading to progressive destruction, obliteration anddeformity of the uterus in the late stages.Some of the hysterosalpingographic findings ofuterine tuberculosis, such as \"T-shaped\" tuberculosis uterus, \"pseudounicornuate\" uterus, \"collarstud abscess\" and \"dwarfed\" uterus with lymphatic intravasation and occluded tubes, are specificfor female genital tuberculosis and have not beenencountered in the majority of non-tuberculosiscases. Diagnosis of these radiographic characteristics is reliable evidence of genital tuberculosisand iscrucial in the infertility workup in order tomake a proper decision."} +{"text": "Platelet-derived growth factor (PDGF) has ample evidence to support its importance in pulmonary fibrosis. Expression of PDGF in the lungs of IPF patients as well as in BAL samples from animal models of lung fibrosis support its involvement during disease development. Vascular endothelial growth factor (VEGF) being a key regulator of angiogenesis and its receptors have been shown to be involved in the pathogenesis of pulmonary sarcoidosis and fibrosis. The hypothesis under investigation is that receptor tyrosine kinase inhibitors (e.g. Sutent) will slow both the fibrotic processes associated with PDGF signaling and the angiogenic processes regulated by VEGF. We tested two RTKi compounds from Pfizer\u2019s internal portfolio (SU-11248 (Sutent), SU-14813) in the bleomycin-induced pulmonary fibrosis mouse model. Prophylactic as well as therapeutic dosing protocols were conducted. Endpoints included histology, body weights, wet lung weights, lung HO-Pro levels and tissue and serum samples for biomarker and lung exposure analyses. Statistically significant reductions in histological changes were demonstrated in lungs treated with both RTK inhibitors in both percentage of total collagen and inflammatory collagen present. RTK inhibitors demonstrated a statistically significant reduction in both wet lung weight and lung HO-Pro content when dosed prophylactically and therapeutically compared to controls. We have demonstrated that broad-spectrum RTK inhibition is efficacious in inhibiting established pulmonary fibrosis in the bleomycin-induced mouse model. Sutent and other broad spectrum RTKis may provide therapeutic benefit to IPF patients by slowing both the fibrotic and angiogenic processes regulated by tyrosine kinases."} +{"text": "The National Cancer Institute (NCI) supports a Cancer Centers Program (CCP) including 66 NCI-designated cancer centers. Several CCPs have associations with Integrative Medicine Programs (IMPs). However, limited information is available regarding cancer-CAM research and collaborations between them. An inventory by NCI\u2019s Office of Cancer Complementary and Alternative Medicine (OCCAM) was conducted to learn about CAM related services and resources at NCI\u2019s CCPs and IMPs, including members of the Consortium of Academic Health Centers for Integrative Medicine (CAHCIM).Sixty-six NCI-designated cancer centers of the CCP and 41 IMPs were eligible to participate in a brief inventory about clinical services, education, and research. This project examines the CCP-IMP cancer research results of this inventory.Most CCPs and IMPs indicated collaborating with each other and also working independently. CCPs conducted more independent research (38%) than IMPs (28%). Types of research collaborations included mainly clinical research . International collaborations were higher among CCPs (27%) compared to IMPs (11%). Both CCPs and IMPs reported NIH as their major source of funding . About 70% of CCPs and IMPs reported having CAM research experts in their centers. When asked if their institutions would find an NCI training on cancer CAM research grants beneficial, both CCP (85%) and IMP (94%) respondents were interested in such training and considered it to be beneficial.This inventory shows that research collaborations between CCPs and IMPs are ongoing. However, additional in depth details are needed. Research training on cancer CAM grants can be beneficial in fostering research collaborations and in advancing cancer CAM research among CCPs and IMPs."} +{"text": "Diabetic peripheral neuropathy (DPN) affects the sensory, motor, and autonomic nervous system. The biomechanical changes resulting from DPN may translate to increased plantar pressures in the foot, which contributes to the pathogenesis and development of foot ulcers. This review aims to investigate the existing biomechanical literature associated with gait, dynamic electromyography and plantar pressure of patients with DPN.Electronic databases were searched for papers reporting observational studies on patients with DPN in gait, dynamic electromyography or plantar pressure. Exclusion criteria were papers investigating children, interventional studies or studies published prior to 2000.Twenty-five papers met the inclusion criteria and were reviewed. Overall there were disparities between studies due to methodological differences in reporting such as the disease duration and degree of neuropathy of participants. DPN subjects walked slower, with smaller stride length and reduced knee extension and active ankle plantar/dorsiflexion compared to healthy and diabetes controls. Dynamic electromyography studies suggested an early activation of lateral gastrocnemius, whilst findings in the tibialis anterior and vastus lateralis muscles were inconsistent. Markedly elevated forefoot peak plantar pressures (PPP) were observed in those with a history of ulceration.This review suggests marked biomechanical variation in DPN patients compared to controls. Studies investigating kinematic (description of movement) variables of the foot are lacking and further studies are needed. It is recommended that future DPN biomechanical studies should document the duration and degree of DPN."} +{"text": "Ostracism\u2014being ignored and excluded\u2014causes distress and threatens psychological needs ? We will review the emerging research on vicarious ostracism, highlighting the neural correlates of this phenomenon. Finally, we posit future research questions to strengthen the theoretical understanding of vicarious ostracism from social cognitive and evolutionary psychological perspectives.Empathy research suggests that individuals vicariously experience others' pain. Most of this research has focused on vicarious physical pain, but might observers also experience vicarious We are aware of nine experimental studies demonstrating vicarious ostracism. These studies find that observers recognize an ostracized individual's distress and also feel ostracized themselves and anterior insula (AI), two brain regions activated by directly experiencing ostracism popular? When participants are eliminated, they are openly rejected . Schadenfreude research has found feelings of dislike, anger, or resentment can lead to perceived deservingness and pleasure at another's misfortune, both in self-reports and neurological measures (Weiner, Williams argues a Weiner, . If ostr"} +{"text": "The aim of this study was to assess the clinical implications of reversed ophthalmic artery flow (ROAF) for stroke risk and outcomes in subjects with unilateral severe cervical carotid stenosis/occlusion.We investigated 128 subjects (101 with acute stroke and 27 without), selected from a large hospital patients base , identified with unilateral high-grade cervical carotid stenosis/occlusion by using duplex ultrasonography and brain magnetic resonance imaging. All clinical characteristics were compared for stroke risk between acute stroke and nonstroke groups. Patients with acute stroke were divided into 4 subgroups according to ophthalmic artery flow direction and intracranial stenosis severity, and stroke outcomes were evaluated.The acute stroke group had significantly higher percentages of ROAF , carotid occlusion , and severe intracranial stenosis . However, multivariate analysis demonstrated that intracranial stenosis was the only significant risk factor . Analysis of functional outcomes among the 4 subgroups of patients with stroke showed significant trends (p \u200a=\u200a 0.018 to 0.001) for better stroke outcomes from ROAF and mild or no intracranial stenosis. ROAF improved 10\u201320% stroke outcomes, as compared to forward ophthalmic artery flow, among the patients with stroke and the same degree of severities of intracranial stenosis.Patients with acute stroke and severe unilateral cervical carotid stenosis/occlusion significantly have high incidence of intracranial stenosis and ROAF. Intracranial stenosis is a major stroke risk indicator as well as a predictor for worse stroke outcomes, and ROAF may provide partial compensation for improving stroke outcomes. Extracranial severe carotid stenosis or occlusion is a well-known pathogenic factor for ischemic stroke. The risk of stroke increases in patients with concurrent severe stenosis of extra- and intracranial vessels To address this question, we selected patients with acute ischemic stroke and unilateral high-grade cervical carotid stenosis/occlusion and evaluated clinical functional outcomes in the presence of ROAF and intracranial stenosis. We hypothesized that intracranial stenosis would be a predictor for stroke risk and poor stroke outcomes and that the presence of ROAF would provide compensation for improving stroke outcomes in patients with ischemic stroke and severe unilateral cervical carotid stenosis/occlusion.This retrospective cohort study was carried out within the certificated Neurovascular Ultrasound Laboratory in Tri-Service General Hospital, Taipei, Taiwan. Written consent was given by every subject before the examination. The study was approved by the hospital's Institutional Review Board for Human Studies. Between January 1, 2005 and July 31, 2012, 3 certified sonographers screened 14,701 consecutive subjects for carotid stenosis or occlusion (100%) of the cervical segment of the ICA. They underwent a detailed neurological examination and provided clinical history based on a structured checklist Head MRI was performed to differentiate stroke type when clinically indicated. The 128 selected patients underwent cranial MRI with multiple modalities, including fluid-attenuated inversion recovery, diffusion-weighted imaging, and three-dimensional time-of-flight magnetic resonance angiography, to differentiate stroke pattern and type if appropriate. The grade of intracranial vascular stenosis was classified into 2 groups: normal to mild stenosis (\u226450%) or moderate stenosis to occlusion (>50%), as described in previous reports Continuous variables were calculated as mean \u00b1 standard deviation. Categorical variables were expressed as numbers and percentages. Categorical or continuous variables were patient age, gender, vascular risk factors, ROAF, and cervical and intracranial stenosis. Odds ratios (ORs) were used to estimate multivariate relative risks, and 95% confidence intervals (CIs) were evaluated with age-adjusted logistic regression analyses. The multivariate logistic regression with a forward selection model was performed to identify significantly independent contribution factors for acute stroke. Attributable risk difference was calculated between the acute stroke and non-stroke groups for investigating the risk of ROAF in patients with acute stroke and severe intracranial stenosis. Fisher's exact tests for categorical variables and Mantel\u2013Haenszel extension tests for trend analyses were conducted for stroke outcome evaluation to assess the compensation effect of ROAF on intracranial stenosis severity. Statistical analyses were performed with SPSS version 19 . Values were considered statistically significant at p<0.05.Out of 14,701 consecutive subjects, only 128 met the study criteria. Among them, 27 subjects had not experienced strokes and had no evidence of stroke as assessed clinically and with brain MRI, and these subjects were considered as the non-stroke group. The remaining 101 subjects had experienced acute ischemic strokes, including 58 with first-ever onset and 43 with recurrent strokes. There were no statistically significant differences in clinical characteristics after age-adjusted univariate analysis between the 2 subgroups, and they were hence collectively considered as the acute stroke group. Statistical analysis revealed that acute stroke group was younger than the non-stroke group. The reason may be that the lack of symptoms in the non-stroke group delayed their decision to screen for the risk of carotid stenosis. To further determine acute stroke risk factors in patients with unilateral high-grade cervical carotid stenosis/occlusion, we compared clinical characteristics between the non-stroke and acute stroke groups with age-adjusted univariate logistic analysis. Among the 81 patients with intracranial stenosis , 80 had ipsilateral severe intracranial stenosis/occlusion in the anterior circulation, and 33 patients had other concomitant critical lesions in the contralateral anterior or posterior circulation. However, no difference of ROAF occurrence was observed between patients with ipsilateral severe intracranial stenosis/occlusion in the anterior circulation and those with multiple severe intracranial stenoses at other locations.To evaluate the roles of individual risk factors in predisposition to acute stroke in patients with unilateral high-grade cervical carotid stenosis/occlusion, we performed multivariate analyses with a forward selection model . The comWe employed logistical regression analysis to explore the role of severe intracranial stenosis in ROAF occurrence. To evaluate the relationship between OA flow direction and intracranial stenosis severity in the context of stroke outcomes, 4 acute stroke subgroups were analyzed by Fisher's exact tests for categorical variables and Mantel\u2013Haenszel extension tests for trend analyses. However, regardless of blood flow direction of OA, the patients with intracranial stenosis had worse stroke outcomes than those without. This study demonstrated that intracranial stenosis was the major risk factor for the development of acute stroke in patients with severe unilateral cervical carotid stenosis/occlusion. Patients with acute ischemic stroke and concurrent severe cervical carotid stenosis/occlusion and intracranial stenosis had a higher rate of ROAF and worse stroke outcomes compared to those with extracranial severe carotid stenosis alone. However, ROAF partially compensated for cerebral insufficiency and was associated with improved stroke outcome.Angiographic and pathologic evidence has previously demonstrated racial differences in the distribution of cervicocerebral atherosclerosis In The strengths of this study are that the included patients were strictly selected using CCDU and brain MR angiography data from a large patient pool , and the patients with ischemic stroke all had the large artery atherosclerosis stroke type. However, the novel findings and potential implications of ROAF are limited by the lack of conventional digital subtraction angiography, which is the gold standard for confirming the diagnosis of extra- and intracranial stenosis and for imaging the cerebral collateral vessels. In addition, some medications in patients with ischemic stroke have been linked to better collateral circulation Our study found that patients with acute ischemic stroke and unilateral severe cervical carotid stenosis/occlusion had a significantly higher occurrence of severe intracranial stenosis and ROAF. Regardless of blood flow direction of OA, the patients with severe intracranial stenosis have worse stroke outcomes as compared to those without. ROAF may act as a secondary collateral when brain tissues receive insufficient blood supply from the primary collaterals, thereby providing patients a valuable, but limited, compensation for partial improvement of stroke outcomes. The results of this study revealed an important implication for clinical practice. It suggested that patients with ischemic stroke should undergo advanced brain imagining and cerebral hemodynamic evaluation when they were detected with unilateral severe cervical carotid stenosis/occlusion and ROAF by CCDU. Early identification of the intracranial pathological vascular lesions and hemodynamic compromise are essential for determining optimal therapeutic strategies for improving stroke outcomes."} +{"text": "Mitochondria is known as powerhouse of cell because they generate most of the cell's supply of adenosine triphosphate (ATP), used as a source of chemical energy. In addition to supplying cellular energy, mitochondria are involved in a range of other processes, such as signaling, cellular differentiation, cell growth, and cell death. Transcription and replication of mitochondrial DNA (mtDNA) are important steps in mitochondrial biogenesis and mitochondrial transcription factor A (Tfam) is essential for mtDNA transcription and replication. However, the functional significance of mitochondria has not been established in osteoclastic bone resorption.There is accumulating evidence that osteoclasts, the primary cells responsible for bone resorption, are involved in bone and joint destruction in rheumatoid arthritis. Bone resorption is highly regulated by mature osteoclast function as well as osteoclastogenesis. The life span of mature osteoclasts is relatively short both fl/fl mice with cathepsin K-Cre transgenic mice, in which the Cre recombinase gene is knocked into the cathepsin K locus and specifically expressed in mature osteoclasts. The in vivo effects of Tfam deficiency on bone metabolism were examined by histological and histomorphometric analysis. The survival and bone-resorbing activity of Tfam cKO osteoclasts were determined by in vitro survival assay and pit formation assay, respectively.To address this question, we generated osteoclast-specific Tfam conditional knock-out (cKO) mice by mating TfamThe expression level of Tfam, mtDNA copy number, and cellular ATP level were markedly reduced in osteoclasts derived from Tfam cKO mice. The body size of Tfam cKO mice was smaller than that of the control mice, although trabecular bone volume remained unchanged by Tfam deficiency. However, histological sections of proximal tibia and lumbar spine of Tfam cKO mice showed significantly decreased osteoclast number. Interestingly, Tfam cKO osteoclasts exhibited increased bone-resorbing activity in spite of their pro-apoptotic tendency.This study demonstrates that Tfam cKO osteoclasts exhibited increased bone resorption with accelerated apoptosis, indicating that there may be an inverse correlation between osteoclast survival vs bone resorption. Further investigation of mitochondria in bone-resorbing osteoclasts will give us new insights into the molecular mechanism regulating bone homeostasis."} +{"text": "In this study, we used high-dimensional pattern regression methods based on structural and functional brain data to identify cross-sectional imaging biomarkers of cognitive performance in cognitively normal older adults from the Baltimore Longitudinal Study of Aging (BLSA). We focused on specific components of executive and memory domains known to decline with aging, including manipulation, semantic retrieval, long-term memory (LTM), and short-term memory (STM). For each imaging modality, brain regions associated with each cognitive domain were generated by adaptive regional clustering. A relevance vector machine was adopted to model the nonlinear continuous relationship between brain regions and cognitive performance, with cross-validation to select the most informative brain regions (using recursive feature elimination) as imaging biomarkers and optimize model parameters. Predicted cognitive scores using our regression algorithm based on the resulting brain regions correlated well with actual performance. Also, regression models obtained using combined GM, WM, and PET imaging modalities outperformed models based on single modalities. Imaging biomarkers related to memory performance included the orbito-frontal and medial temporal cortical regions with LTM showing stronger correlation with the temporal lobe than STM. Brain regions predicting executive performance included orbito-frontal, and occipito-temporal areas. The PET modality had higher contribution to most cognitive domains except manipulation, which had higher WM contribution from the superior longitudinal fasciculus and the genu of the corpus callosum. These findings based on machine-learning methods demonstrate the importance of combining structural and functional imaging data in understanding complex cognitive mechanisms and also their potential usage as biomarkers that predict cognitive status. Aging is associated with declines in neurocognitive functions often characterized by degeneration of brain tissue, changes in brain function, and accelerated cognitive decline, particularly in clinical cases such as Alzheimer's disease (AD). However, despite the connection with neural changes, diagnosis of clinical cognitive impairment to date still primarily depends on cognitive changes measured by neuropsychological assessments. Neuroimaging studies have shown that structural and functional brain changes often precede clinical symptoms of cognitive impairment , which ra priori. As such, characterizations of brain changes in normal or clinical aging have had specific and limited scopes within each study and have been relatively unwieldy in the context of the multi-faceted nature of the issue.Finding specific brain regions involved in a cognitive process has been a recurrent goal in functional neuroimaging in the last two decades -5. In thTo overcome the limitations of univariate and ROI-based approaches, machine learning-based pattern analysis methods have been widely adopted to automatically derive distinctive brain regions related to a hypothesis or a given study objective . The maja priori hypotheses water. The images were obtained on a GE 4096 scanner, during a resting state scan with eyes open [Details of our image acquisition parameters have been described in . Brieflyyes open . After tAll MR images used in this study were pre-processed using a mass-preserving shape transformation method . Gray ma15O] PET-CBF image pre-processing included normalization for global activity, removal of extraneous signal scatter by thresholding the image intensity at 80% of the gray matter mean, and removal of activity in the skull, nasal sinuses, and cerebellum. PET-CBF images were rigidly registered to the corresponding participants\u2019 MR image then deformed to the same template space based on the spatial normalization transformation parameters determined from the MRI. After registration, PET-CBF images were smoothed using a 12mm Gaussian filter. PET-CBF alone, and one using both MRI and PET. To evaluate model performances, we examined the MSEs and correlation coefficients indexing the strength of agreement between the actual cognitive scores and scores predicted by the models. Since MSEs and correlation coefficients are not normally distributed, differences in cognitive score predictions between models were statistically compared using non-parametric random permutation testing [For step 3 of each cognitive domain, a summary map of brain region contributions to cognitive score prediction was obtained by averaging the spatial difference maps from all leave-k-out cases. To facilitate comparison of contribution maps across the optimized models using single or combined imaging modalities, we then normalized the contribution levels to a range from 0 to 1, indexing lowest to highest predictive contributions respectively. The predicted cognitive scores were also based on averaged optimal predicted scores across all leave-k-out cases for each cognitive domain. Overall, we performed three RVR computations for each of the four cognitive domains: one RVR using MRI (white and gray matter structure) alone, one using [ testing , which wThe study was approved by the local Institutional Review Board of the University of Pennsylvania and the National Institute on Aging. Written informed consent was obtained from all participants at each visit. MSEs were used to describe the performance of machine learning-based regression models top. As For visualization, We additionally evaluated whether the detected imaging biomarkers were more effective predictors of cognitive performance than another important factor related to cognitive decline, age. For comparison, The top panels of As shown in Several brain regions predicting LTM were also involved in STM . SpecifiFor semantic retrieval, predictive brain regions included left occipital-temporal, bilateral inferior frontal, insula, medial and lateral orbitofrontal areas, as well as right superior longitudinal fasciculus and periventricular areas . MaximumFor manipulation, predictive contributions were observed in the right inferior frontal, and insula regions, left precentral and middle frontal regions, bilateral anterior cingulate and temporal areas, as well as the left uncinate fasciculus and genu of the corpus callosum . MaximumTo validate the performance of our multi-modality pattern regression method, we also applied conventional GLM analysis with the same cognitive components. The GLM analyses revealed positive correlations between GM/WM/PET and cognitive performance, as shown in The GLM analysis also showed that manipulation was significantly associated with WM volumes across several regions. Similarly, the majority of brain regions detected by multi-modality pattern regression were from structural MRI, especially WM, which had the highest contribution to manipulation performance . HoweverWe highlight that GLM maps indicate the directions of associations separately between each imaging modality and each cognitive domain. By contrast, the contribution maps obtained from pattern regression shows the combined power of multi-modality imaging with no sign of association. Thus, the combined associations are less restricted and show simultaneous contributions across imaging modalities that could be due to a positive brain-behavior association in one modality but a negative association in another. In addition, direct comparison of the contributions across modalities is not meaningful with the GLM maps but relatively straightforward with the contribution indices used in our pattern regression method.This study applied a multi-modality pattern regression method to investigate the brain imaging biomarkers related to memory and executive functions. Combined regression models for LTM, STM and semantic retrieval had similar prediction power, with regression rates of 0.41, 0.45 and 0.46 respectively . AlthougOur finding that LTM and STM involved middle and medial frontal regions, along with temporal regions and the hippocampus and amygdala (for LTM) is consistent with the existing literature on brain regions involved in episodic memory. Episodic memory tasks generally involve accessing the representations of the test items including contextual information about when and where the items were encountered. Many studies have shown that the hippocampus is an important region that forms and stores such item-context associations , superior longitudinal fasciculus and genu were associated with semantic retrieval and manipulation performance, with the maximum contribution from white-matter images. Other studies have similarly found that these white-matter regions show structural declines with age that are associated with poorer performance in tests of executive function and working memory -57. ThesThis present study focused on modeling the continuous cross-sectional distribution of cognitive performance across individuals instead of individual longitudinal performance changes over time. It is plausible that longitudinal data may capture distinct important regional contributions toward cognitive performance ,58. We nWe investigated the utility of multi-modality high-dimensional pattern regression for detecting imaging-based biomarkers of cognitive ability in a cohort of cognitively normal older adults. Our findings show that this machine learning-based pattern regression method is able to detect specific brain regions associated with different cognitive processes, while simultaneously assessing the contribution of different imaging modalities. Moreover, the combination of PET and MRI was better than each modality alone. Critically, our results suggest that functional imaging provided slightly better predictive ability than structural MRIs for memory functions, but WM modality outperformed PET when predicting executive functions. The predicted cognitive scores using our methodology could be used to identify individuals with risk of future cognitive decline from baseline images, such as in the case of when the predicted score deviate from the normal range. Future studies will evaluate imaging biomarkers of additional aspects of memory and executive function as well as the predictive ability with respect to longitudinal performance."} +{"text": "Heterotopic transplantation of pluripotent stem cells (PSCs) produces growths known as teratomas (Greek word for monstrous), which consist of a heterogeneous amalgamation of fetal-like tissues. Engraftment of even a few undifferentiated cells is potentially sufficient for teratoma formation. Such an event would have far reaching consequences for the future of this field. Current differentiation protocols produce cultures with unknown degrees of purity and are therefore potentially hazardous. We provide here a succinct overview of current methods and outline challenges for the removal of residual teratoma-initiating cells.OCT4 promoter controls HSV1 thymidine kinase expression, allowing for selective ablation of undifferentiated PSCs upon treatment with of Ganciclovir [Retrospective and prospective approaches for teratoma depletion have been the subject of significant investigation. Retrospective removal includes standard oncologic treatments of formed tumors via radiation, chemotherapy, and surgery . To avoiciclovir . UnfortuProspective depletion of teratoma-initiating cells is advantageous to retrospective removal as such methods prevent initial tumor formation. Two main strategies of prospective removal include treatment with agents specifically cytotoxic to undifferentiated cells and mechanical separation. The first was extensively developed by the lab of Dr. Andre Choo, who produced the cytotoxic antibody mAb 84 which targets PODXL, a protein abundantly expressed by PSCs .Non-cytotoxic cell separation has emerged as a central approach for depletion of teratoma-initiating cells. This method relies on tagging undifferentiated cells either by inducing reporter gene expression or through reversible labeling of surface antigens. Labeled cells are then removed through fluorescence- or magnetic-activated cell sorting (FACS or MACS). Although tagging PSC-specific surface antigens is considered safer than introducing gene reporters , this goA major advantage to utilizing surface markers for prospective separation is that this method relies on the intrinsic properties of the cells and therefore can be applied to all PSC lines and differentiation conditions. A typical protocol may entail removing cells expressing a tailored combination of surface markers such as SSEA-5 and/or CD9 and/or CD90 . Such a In summary, we propose that prospective removal is superior to retrospective approaches since the latter may result in anatomical damage and also risks malignant and/or metastastic transformation. As such, retrospective removal should always be considered a backup rather than first line. We also believe that clinical utilization of PSC derivatives should rely on combination of prospective approaches to provide the highest level of safety. One example is to utilize PSC-specific antibodies for cell separation followed by a subsequent cytotoxic antibody incubation step . Ultimat"} +{"text": "Dear editor,Aortocaval Fistula (ACF) is a rare condition of an Abdominal Aorta Aneurysm (AAA). ACF caused by perforation of atherosclerotic infrarenal aortic aneurysm into the adjacent IVC, iliac vein, or left renal vein. Its inciA 63-year-old man presented to Emergency Department with sudden left flank pain.Abdominal physical examination revealed palpable mass, tenderness and self-guarding in left flank area without rebound tenderness. All peripheral pulses were present.Sonography of abdomen displayed infrarenal AAA with 63mm diameter. CT-images demonstrated infrarenal aortic aneurysm with fistula to IVC arising from aneurysm lumen that penetrated to retroaortic renal vein situated beneath the aneurysm .At laparotomy No hematoma or active bleeding existed in peritoneal space. Followed by controlling blood flow of aneurysm neck, distal common iliac arteries were clamped. Therefore, renal veins became noticeable posterior the aorta. IVC was dilated excessively 4 cm and trill was palpable on aneurysmal site. Further investigations revealed that exact site of fistula at the entrance of left renal vein to IVC.IVC was repaired and renal vein was ligated and aneurysm repaired using 20 tubular Dacron graft. There are several causes for ACF including spontaneous rupture of atherosclerotic aneurysm directly into adjacent IVC, penetratEarly diagnosis of ACF prior to surgery is vital and also difficult due to rarity of complication and non-specificity of the signs and symptoms. Standard signs of ACF as a result of aneurysmal disease, include acute abdominal pain, hypotension, and pulsatile abdominal mass. However Specific treatment for ACF is operative transaortic closure of fistula and placement of prosthetic graft or endovascular repair of fistula."} +{"text": "Dear Editor,We enjoyed reading the excellent article by Yilmaz and colleagues on noninvasive assessment of liver fibrosis using aspartate transaminase to platelet ratio index (APRI) in adult patients with chronic liver disease (CLD) . They peA drawback for using APRI is that its performance is not reliable in women, younger patients and in those with non-vertically-transmitted hepatitis C virus infection . Alterna"} +{"text": "With the recognition of early trauma coagulopathy, trauma resuscitation has recently shifted towards early and aggressive transfusion of platelets (PLTs). However, the clinical benefits of this strategy remain controversial. This systematic review examined the impact of an aggressive approach (higher PLT:RBC ratios) compared to restrictive PLT transfusions (lower PLT:RBC ratios) in the acute phase of trauma resuscitation.We systematically searched Medline, Embase, Web of Science, Biosis, Cochrane Central and Scopus to identify relevant randomized controlled trials (RCTs) and observational studies comparing the effect of two or more different PLT:RBC ratios in trauma resuscitation. We excluded studies using whole blood or systematically addressing the use of hemostatic products. Two independent reviewers selected the studies, extracted data using a standardized form, and assessed the risk of bias using the Newcastle-Ottawa scale and a checklist of key methodological elements . Disagreements were solved by consensus or a third party. The primary outcome was mortality. Secondary outcomes were multiple organ failure (MOF), lung injury and sepsis. A meta-analysis using random effects models was planned.n = 4,230 patients). No RCT was identified. All studies were considered to be at low risk of bias and addressed confoundings through multivariate regression or propensity scores. Four studies reported a decrease in mortality with higher PLT:RBC ratios in patients requiring massive transfusion and one study observed no mortality difference in nonmassively transfused patients. Two studies reported on the implementation of a massive transfusion protocol with higher PLT:RBC ratios; only one revealed a survival benefit (n = 211). Of the three studies accounting for survival bias, two demonstrated a survival benefit . Among two studies reporting on the secondary outcomes (n = 854), one observed an increase in MOF with higher PLT:RBC ratios. Clinical heterogeneity between studies and methodological limitations precluded the use of a meta-analysis.From 6,123 citations, seven observational studies were included (There is insufficient evidence to strongly support the use of a specific PLT:RBC ratio for acute trauma resuscitation, especially considering survival bias and nonmassively transfused patients. RCTs examining both safety and efficacy of liberal PLT transfusions are warranted."} +{"text": "To describe a consensus-based case review development process that applies eligibility and diagnostic criteria for diverse clinical trials of chiropractic care for chronic pain conditions.A multidisciplinary team of investigators and clinical research staff provide iterative feedback to develop case review processes for application across complex clinical trials involving biomechanical testing and/or spinal manipulation. Investigative team members design eligibility criteria and operational definitions consistent with the specific aims of the trial. These parameters are codified in study protocols and programmed into secure, web-based data collection systems that record eligibility decisions. The clinical team develops study-specific procedures, documentation templates, and flow-charts for conducting meetings. Research records are uploaded onto a web server for panel members to view during the meeting.Our case review panel consists of research clinicians, project managers, study coordinators and the senior clinician who convene twice weekly to discuss participants who remain eligible following completion of baseline visits. The research clinician who performed the eligibility examination begins case review with an oral presentation of the case and leads the case review panel through a discussion of safety and compliance issues, eligibility concerns, diagnosis determination, and clinical precautions. Panel members provide clinical recommendations and determine final eligibility status by consensus vote. The senior clinician determines eligibility only in cases where consensus (80%) is not reached. Through this process, our research clinic presented 534 cases, excluded 174 participants, and allocated 291 into two phase II clinical trials and six feasibility studies over a three year period.Our case review process utilizes the combined scientific and clinical experience of panel members for consistent eligibility determination, thereby reducing selection bias and ensuring that participants are appropriate candidates for study procedures. The consensus building process creates a collegial environment that enhances clinical trial management and fosters rigorous clinical research."} +{"text": "Avian malaria is an important cause of the decline of endemic Hawaiian honeycreepers. Because of the complexity of this disease system we used a computer model of avian malaria in forest birds to evaluate how two proposed conservation strategies: 1) reduction of habitat for mosquito larvae and 2) establishment of a low-elevation, malaria-tolerant honeycreeper (Hawaii Amakihi) to mid-elevation forests would affect native Hawaiian honeycreeper populations. We evaluated these approaches in mid-elevation forests, where malaria transmission is seasonal and control strategies are more likely to work. Our model suggests the potential benefit of larval habitat reduction depends on the level of malaria transmission, abundance of larval cavities, and the ability to substantially reduce these cavities. Permanent reduction in larval habitat of >80% may be needed to control abundance of infectious mosquitoes and benefit bird populations. Establishment of malaria-tolerant Amakihi in mid-elevation forests increases Amakihi abundance, creates a larger disease reservoir, and increases the abundance of infectious mosquitoes which may negatively impact other honeycreepers. For mid-elevation sites where bird populations are severely affected by avian malaria, malaria-tolerant Amakihi had little impact on other honeycreepers. Both management strategies may benefit native Hawaiian honeycreepers, but benefits depend on specific forest characteristics, the amount of reduction in larval habitat that can be achieved, and how malaria transmission is affected by temperature. Plasmodium relictum) and its vector, the Southern House Mosquito (Culex quinquefasciatus), are considered primary contributors to population declines of native Hawaiian forest birds More than one-third of all U.S. listed bird species occur in Hawaii, and 71 Hawaiian birds have gone extinct since humans colonized the islands Temporal and spatial dynamics of malaria in Hawaii are driven by seasonal, annual, and elevational weather patterns To reduce future population impacts and potential species extinctions, conservation strategies that reduce the impact of avian malaria on Hawaiian honeycreepers are essential. However, conservation strategies to preserve future populations of Hawaiian birds can be controversial if focused strictly on habitat improvement Sus scrofa) feed on native tree ferns (Cibotium glacum) creating cavities that fill with rainwater. These cavities are an important and ideal habitat for mosquito larvae, especially in mid-elevation forests Common methods for reducing mosquito abundance include reduction of larval habitat, insecticides that increase larval or adult mortality rates, and the introduction of predators on mosquitoes Hemignathus virens) found in low-elevation forests may have developed malaria-tolerance compared to conspecific birds at mid- and high- elevations Although most of the native Hawaiian forest birds are highly susceptible to avian malaria Ecological models can provide an indispensable tool for exploring the consequences of alternative management strategies All necessary access and collection permits for this study were obtained from the State of Hawaii, Department of Land and Natural Resources and Hawaii Volcanoes National Park.2 study sites with mosquito larval habitat larval mosquito habitat and associated larval mosquitoes were in Himatione sanguinea sanguinea), and Iiwi (Vestiaria coccinea). The model also includes the Japanese White-eye (Zosterops japonicus) to represent introduced species, which typically have lower prevalence and intensity of infection with malaria Our simulation model Mosquitoes and all bird species are divided into immature and adult stages. Adult mosquitoes are subdivided into susceptible, latent, and infectious disease stages. Native juvenile (susceptible when hatched) and adult birds are subdivided into susceptible, acutely infected, and recovered stages. Acutely infected birds have a high parasitemia Mosquito dynamics are driven by rainfall and temperature 2, and no mosquito larvae. Simulations were then conducted for a 24 year period (1980\u20132003) using historical weather conditions (see above). Mosquito dynamics typically became stable within a few years regardless of the initial densities or elevation We modeled the potential impact of reducing larval habitat for two study sites where pig-created cavities provide an important habitat for mosquitoes (Cooper and Waiakea). We modeled the potential impact of Amakihi establishment at all four study sites. Initial conditions for our simulations used predicted bird densities in the absence of malaria To assess the potential effects of different weather patterns caused by variation in elevation and topography across the Hawaiian landscape, we modeled both conservation strategies under five climate scenarios derived from our baseline climate (1980\u20132003) data at study site Cooper . Three dIn mid-elevation forests with feral pigs, our model predicts that density of adult and infectious mosquitoes change in proportion to the carrying capacity for larval mosquitoes and in response to climate . For bas2. Once this threshold was reached, further reductions produced dramatic increases in honeycreeper populations. These simulated population increases were accompanied by large increases in the percentage of susceptible and large decreases in the percentage of chronically-infected individuals is an important driver of mosquito dynamics, but density of infectious mosquitoes is the primary driver of malaria transmission to susceptible Hawaiian birds.Weather patterns interact with the larval habitat reduction needed to enhance bird populations . Effecti2 after establishment of malaria-tolerant Amakihi. Presence of malaria-tolerant Amakihi in mid-elevation forests increased the predicted density of Amakihi by >900 birds/km2 at Cooper and Waiakea, while Apapane and Iiwi were not additionally affected in mid-elevation forests, but the density of infectious mosquitoes increased by 25% at Cooper, 26% at Waiakea, and 303% at Crater. At Pu'u, the density of infectious mosquitoes was <1/kmaffected because affected . At Pu'uaffected . The pre2 threshold, indicating that less tolerant Amakihi populations at these sites were limited by malaria. In these simulations the proportion of chronically-infected Amakihi exceeded 85\u201389%, indicating high rates of disease transmission.Predicted changes in malaria-tolerant Amakihi depended on the density of infectious mosquitoes . ClimatePredicted Apapane and Iiwi population responses to malaria-tolerant Amakihi depended on the density of infectious mosquitoes. Apapane and Iiwi densities were generally unaffected in forests where malaria transmission was either very low (Pu'u) or high (Waiakea and Cooper). At high transmission sites, malaria infection had already reached a high level so further increasing the reservoir of chronically-infected birds had little effect. At low transmission sites, predicted Amakihi density was not affected because there was little malaria impact and bird communities in these forests were unaffected. Apapane and Iiwi populations declined in forests where the density of infectious mosquitoes was below the threshold needed to enhance native bird populations . In these forests small increases in density of infectious mosquitoes increased rates of disease transmission which benefited malaria-tolerant Amakihi, but were detrimental to susceptible Apapane and Iiwi.Avian malaria has a significant population impact on susceptible Hawaiian honeycreepers and disease transmission by mosquito vectors is likely a primary factor contributing to the decline and restricted distribution of native Hawaiian forest birds 2) before mosquito control benefits mid-elevation honeycreepers. For infectious mosquito densities above this threshold, most surviving birds are predicted to be chronically-infected with malaria, and therefore a disease reservoir for susceptible birds. Although both rainfall and temperature affect the relationship between larval habitat and malaria transmission, model results indicate that the density of infectious mosquitoes was the key factor influencing transmission and bird abundance . Above this threshold, an increase in the density of infectious mosquitoes from malaria-tolerant Amakihi does not significantly increase the impact of avian malaria on bird populations (Our model indicates malaria-tolerant Amakihi could increase the abundance of infectious mosquitoes in some mid-elevation forests and therefore decrease densities of more susceptible honeycreepers. The negative impact of malaria-tolerant Amakihi on other honeycreepers should be highest at sites where density of infectious mosquitoes is below a predicted threshold of 300/kmulations . OverallWhether translocation of Amakihi would succeed depends on many factors In Hawaii, malaria infection patterns are driven by the effects of temperature and rainfall on mosquito dynamics across an elevational gradient, seasonal weather patterns, and availability of larval habitat Even low densities of infectious mosquitoes appear sufficient to produce high rates of malaria infection in native Hawaiian birds. In part, these high rates of malaria transmission likely result from favorable climatic conditions, abundant larval mosquito habitat, and efficient transmission of the malaria parasite between mosquito vectors and avian hosts. Native birds that survive malaria infection acquire immunity, but also become an effective reservoir for malaria transmission to mosquitoes and then to susceptible Hawaiian birds. Reducing the amount of larval habitat for mosquitoes by feral pig management or other alternatives provides one potential strategy to help control malaria impacts and would likely be most beneficial in mid-elevation forests. Establishment of malaria-tolerant Amakihi to mid-elevation forests benefits Amakihi populations, but could negatively impact other honeycreepers depending on the larval habitat and malaria transmission. Our evaluation uses an ecological model that provides a simplified representation of the Hawaiian forest bird malaria system which appears to provide realistic, but somewhat uncertain predictions of mosquito, bird, and malaria patterns in Hawaii"} +{"text": "The eyedrop form of rebamipide was approved in Japan for use in the treatment of dry eye diseases, because it up-regulates mucin secretion and production. Others reported that rebamipide, a gastroprotective drug, could not only increase gastric mucus production but also suppressed gastric mucosal inflammation and that it was dominantly distributed in mucosal tissues. In this study we investigated whether rebamipide has anti- inflammatory effects in the ocular surface.We used ELISA and quantitative RT-PCR assay to examine the effects of rebamipide on polyI:C-induced cytokine expression by primary human conjunctival epithelial cells. We studied the effects of rebamipide on ocular surface inflammation in our murine experimental allergic conjunctivitis (EAC) model. Moreover, we also observed their condition of allergic conjunctivitis when we treated the dry eye patients accompanied with allergic conjunctivitis using rebamipide.Rebamipide could suppress polyI:C-induced cytokine mRNA expression and the production of CXCL10, CXCL11, RANTES, MCP-1, and IL-6 in human conjunctival epithelial cells. The topical administration of rebamipide suppressed conjunctival allergic eosinophil infiltration in our EAC model. Furthermore, the allergic conjunctivitis which accompanied by dry eye patients treated with rebamipide tended to be better.The topical application of rebamipide on the ocular surface might suppress ocular surface inflammation by suppressing the production of cytokines by ocular surface epithelial cells."} +{"text": "Long-lasting insecticidal nets (LLINs) and indoor residual sprays (IRS) have decimated malaria transmission by killing indoor-feeding mosquitoes. However, complete elimination of malaria transmission with these proven methods is confounded by vectors that evade pesticide contact by feeding outdoors.For any assumed level of indoor coverage and personal protective efficacy with insecticidal products, process-explicit malaria transmission models suggest that insecticides that repel mosquitoes will achieve less impact upon transmission than those that kill them outright. Here such models are extended to explore how outdoor use of products containing either contact toxins or spatial repellents might augment or attenuate impact of high indoor coverage of LLINs relying primarily upon contact toxicity.LLIN impact could be dramatically enhanced by high coverage with spatial repellents conferring near-complete personal protection, but only if combined indoor use of both measures can be avoided where vectors persist that prefer feeding indoors upon humans. While very high levels of coverage and efficacy will be required for spatial repellents to substantially augment the impact of LLINs or IRS, these ambitious targets may well be at least as practically achievable as the lower requirements for equivalent impact using contact insecticides.Vapour-phase repellents may be more acceptable, practical and effective than contact insecticides for preventing outdoor malaria transmission because they need not be applied to skin or clothing and may protect multiple occupants of spaces outside of treatable structures such as nets or houses. Long-lasting insecticidal nets (LLINs) and indoor residual spraying (IRS) have dramatically reduced malaria transmission by indoor-feeding (endophagic) mosquito populations in recent years -4. HowevWhile mosquitocidal vaccines and drugHowever, it is crucial to clearly distinguish between alternative modes of action of vector control products and assess their potential comparative value for preventing malaria. Pesticide products either deter insects away from protected houses, sleeping spaces and humans, or they kill those that make physical contact with them . While rh,\u03a9) compared with that predicted under baseline conditions where neither measure was in place:Existing models of the interaction between contrasting deterrent and toxic properties ,18 assumh,0,\u03a9) or as a community-wide average, reflecting the coverage-weighted mean of such non-users and users of one or both measures [This term was calculated for unprotected individuals lacking either of these measures . For simAnopheles gambiae, which rarely uses cattle as alternative non-human hosts, and zoophagic Anopheles arabiensis, which does where they are available. These relative exposure outcomes (\u03c8) were predicted as a function of the mean proportion of malaria transmission exposure of a non-user of any measure which occurs indoors (\u03c0i) [\u0394) or pre-feed mortality of mosquitoes attacking users of the product [In all cases, coverage levels of 80% were assumed for both the indoor and outdoor protection measures, consistent with current global targets for LLINs and IRS , and twoors (\u03c0i) ,25,26 an product . By comp product . TherefoLLINs depend upon high proportions of human exposure occurring indoors to achieve maximum impact upon malaria transmission Figure . Note thi), spatial repellents applied outdoors consistently supplement the impact of indoor toxins because mosquitoes diverted from outdoor repellent users may subsequently attack those protected indoors by lethal LLINs and vectors rarely feed upon non-human blood sources , Syngenta (SJM), Pinnacle Development (SJM) and SC Johnson (SJM).Both authors formulated the research questions and developed the conceptual basis of the model. GFK drafted the model formulation and manuscript, which was then critiqued and edited by SJM. All authors have read and approved the final version of the manuscript.Figure S1. Purely community-level impact of products for outdoor malaria prevention expressed in terms of the mean relative risk of exposure experienced by non-users of any protective measure.Click here for fileFigure S2. Additional incremental community-level impact of outdoor contact toxins or repellents that are exclusively used outdoors or used both indoors and outdoors when combined with indoor LLINs with contact toxins, compared with their direct impact as stand-alone intervention strategies.Click here for fileFigure S3. Progressive community-level impact upon a completely outdoor transmission system of products with increasing efficacy of personal protection achieved by either repelling or killing attacking mosquitoes before they feed upon human users.Click here for fileSupplemental methods S4. Detailed model description.Click here for file"} +{"text": "To identify whether axillary US is less accurate in invasive lobular breast cancer than in ductal breast cancer.Randomised cohorts of screening and symptomatic patients were retrospectively identified from histology records of 2010/11. Axillary US of 65 patients with primary breast cancers (BC) from each group of invasive lobular cancer (ILC) and invasive ductal cancer (IDC) were reviewed. Preoperative US-guided needle biopsy sampling was performed on abnormal lymph nodes (LN).See Tables The previous literature on this topic is inconclusive. Some authors have suggested axillary ultrasound in ILC may be less accurate than in IDC, with a higher false-negative axillary assessment rate. Another study concluded that axillary US accuracy rates in ILC were comparable with previous published studies of IDC, used FNA in all cases. We specifically compared accuracy rates of preoperative axillary staging between ILC and IDC in own institution, with 14G needle biopsy as the procedure of choice to sample abnormal nodes. We found that there is no statistical difference in accuracy in US axillary staging between ILC and IDC."} +{"text": "P301S) mice develop tau filamentous inclusions and axonopathy in retinal ganglion neurons (RGCs), in the absence of neuronal loss or alterations in the outer retina. Moreover, we showed that tauP301S transgenic retinal explants do not respond to neurotrophic stimuli in vitro. Here, we investigated the impact of tau pathology on RGC physiology in living animals and neurotrophin signaling pathways in vivo. In anesthetized 5-month old wild type (WT) and tauP301S mice, we measured RGCs activity using pattern electroretinogram (pERG), which selectively detects RGC response upon pattern light stimuli exposure. In transgenic tauP301S mice the amplitude of both P1 positive and N2 negative components of pERG at saturating contrast and spatial frequency was significantly smaller than WT values. Furthermore, retinal acuity was significantly reduced in tauP301S mice. Using uniform flickers of light (flash ERG), we measured the activity of the outer retina and found that outer retina response was preserved in tauP301S mice. Neurotrophins, and especially brain-derived neurotrophic factor (BDNF), are important modulators of neuronal survival and function in the brain and in the visual system. We therefore investigated the BDNF signaling pathway and found that BDNF signalling was altered in tauP301S transgenic retinas. Our results indicate that, in the tauP301S mouse, tau pathology specifically impairs the activity of RGCs, without affecting the outer retina function and is associated with BDNF signalling alterations. Given the role of BDNF in synaptic plasticity, these data suggest that mild levels of tau pathology are sufficient to trigger significant neuronal dysfunction possibly through alteration of neurotrophic signalling. Funded by a grant of Compagnia di San Paolo awarded to LG.Intracellular inclusions made of microtubule-associated tau protein are a defining pathological hallmark of tauopathies, which include Alzheimer disease and familial frontotemporal dementia and parkinsonism linked to chromosome 17. Altered levels of tau protein have been detected in the retina and optic nerve of patients with glaucoma, suggesting that retina degeneration and tauopathies share similar pathogenic mechanisms. We have recently demonstrated that P301S mutant human tau (tau"} +{"text": "The insect olfactory system is capable of classifying odorants by encoding and processing the neural representations of chemical stimuli. Odors are transformed into a neuronal representation by a number of receptor classes, each of which encodes a certain combination of chemical features. Those representations resemble a multivariate representation of the stimulus space . The inschannel correlation). In previous work, we demonstrated how lateral inhibition in an olfaction-inspired network reduced channel correlation [Olfactory receptors typically have broad receptive fields, and the odor spectra of individual receptor classes overlap. From the viewpoint of multivariate data processing, overlapping receptive fields cause correlation between input variables ,5. After"} +{"text": "Intrinsic foot muscle weakness has been implicated in a range of foot deformities and disorders. However, to establish a relationship between intrinsic muscle weakness and foot pathology, an objective measure of intrinsic muscle strength is needed. The aim of this review was to provide an overview of the anatomy and role of intrinsic foot muscles, implications of intrinsic weakness and evaluate the different methods used to measure intrinsic foot muscle strength.Literature was sourced from database searches of MEDLINE, PubMed, SCOPUS, Cochrane Library, PEDro and CINAHL up to June 2012.There is no widely accepted method of measuring intrinsic foot muscle strength. Methods to estimate toe flexor muscle strength include the paper grip test, plantar pressure, toe dynamometry, and the intrinsic positive test. Hand-held dynamometry has excellent interrater and intrarater reliability and limits toe curling, which is an action hypothesised to activate extrinsic toe flexor muscles. However, it is unclear whether any method can actually isolate intrinsic muscle strength. Also most methods measure only toe flexor strength and other actions such as toe extension and abduction have not been adequately assessed. Indirect methods to investigate intrinsic muscle structure and performance include CT, ultrasonography, MRI, EMG, and muscle biopsy. Indirect methods often discriminate between intrinsic and extrinsic muscles, but lack the ability to measure muscle force.There are many challenges to accurately measure intrinsic muscle strength in isolation. Most studies have measured toe flexor strength as a surrogate measure of intrinsic muscle strength. Hand-held dynamometry appears to be a promising method of estimating intrinsic muscle strength. However, the contribution of extrinsic muscles cannot be excluded from toe flexor strength measurement. Future research should clarify the relative contribution of intrinsic and extrinsic muscles during intrinsic foot muscle strength testing. Intrinsic foot muscles contribute to the support of the medial longitudinal arch,2 and arThe electronic databases MEDLINE, PubMed, SCOPUS, Cochrane Library and CINAHL were searched between 21 May and 21 June 2012 to locate scientific articles on intrinsic foot muscles and muscle strength measurement. The main search terms and number of articles retrieved are listed in Table\u2009Fifty three research articles were identified that related to intrinsic foot muscles and strength measurement. Articles had to meet certain criteria for inclusion. The inclusion criteria were as follows.(i) Research related to the role of intrinsic foot muscles(ii) Research related to the anatomy of intrinsic foot muscles(iii) Research describing the measurement of intrinsic muscles and toe muscle strength or weakness. Papers relating to the intrinsic foot muscle strength were considered initially, but it became apparent that few papers existed. Therefore the search was broadened to include articles relating to the measurement of toe muscles(iv) Publication in peer-reviewed journals(v) Full-text English language articlesplantar aponeurosis and includes the abductor hallucis, flexor digitorum brevis, and the abductor digiti minimi[quadratus plantae and the lumbricals. The third layer consists of adductor hallucis transverse, adductor hallucis oblique, flexor hallucis brevis and flexor digiti minimi brevis. The deepest layer consists of the three plantar interossei. All the plantar intrinsic muscles are innervated by the medial and lateral plantar branches of the tibial nerve[The plantar and dorsal intrinsic muscles of the foot have both their origin and insertion within the foot,27. Intrti minimi. The secextensor hallucis brevis and extensor digitorum brevis. The deep layer consists of the dorsal interossei muscles. The extensor hallucis brevis and extensor digitorum brevis is innervated by the deep fibular nerve while the dorsal interossei are innervated by the lateral plantar nerve with the first and second dorsal interossei also receiving part of their innervation from the deep fibular nerve[extensor hallucis brevis and extensor digitorum brevis during walking varied significantly between participants, with some participants demonstrating no activation of extensor digitorum brevis during gait[. The extensor hallucis brevis and extensor digitorum brevis muscles are now widely used in tissue grafts, such as the island flap to cover soft tissue defects in the distal leg and ankle regions[The dorsal intrinsic muscles of the foot can be divided into two layers. The mosar nerve. The dorar nerve. Early Eing gait. The ext regions. Therefoquadratus plantae disproves this hypothesis. The medial and lateral attachment sites of the quadratus plantae muscle into the calcaneus is unique to humans[quadratus plantae is unique to the foot as there is no analogous muscle in the hand[. Since the flexor digitorum longus tendon enters the foot from the medial side and pulls the toes medially[quadratus plantae allows the toes to flex in the sagittal plane by redirecting the pull of the flexor digitorum longus. This is a necessary development for bipedal ambulation[It has been hypothesised that during human evolution, toe flexor force and function are gradually diminishing and therefore plantar intrinsic muscles are becoming largely redundant in the foot. In simio humans and quadthe hand. Since tmedially, one thebulation. Therefoabductor digiti minimi, abductor hallucis, flexor digitorum brevis, dorsal interossei and lumbrical muscles were all active during the stance phase of gait and continued until toe off[flexor hallucis brevis and flexor digitorum brevis muscles are able to exert forces approximately 36% and 13% of body weight during the propulsive phase of walking[et al.[A number of studies reveal that intrinsic foot muscles are active as a group during walking,4,36. A walking. However walking or have walking. Mann ang[et al. and Goldg[et al. postulatg[et al.,40. Therabductor hallucis, flexor digitorum brevis and the quadratus plantae muscles during relaxed standing with a significant increase in activity with increased postural demands[et al.[The role of intrinsic muscles in the support of the medial longitudinal arch has been investigated in both standing-5 and wa demands. Reeser s[et al. suggestes[et al.. The lacs[et al.. TherefoThe next section will review the influence of intrinsic muscle weakness in the development of pes cavus in Charcot-Marie-Tooth disease, lesser toe deformities, hallux valgus and heel pain.Charcot-Marie-Tooth disease (CMT) is a peripheral neuropathy, where anatomically distal muscles including the intrinsic muscles are preferentially affected. WeaknesMuscle imbalances between the intrinsic and extrinsic foot muscles have been proposed as the possible cause for lesser toe deformity,11,46. Cextensor digitorum longus and brevis are balanced by the flexors forces produced by long and short toe flexors[et al.[et al.[In an unaffected foot, the strong extension forces at the MTP joint by the flexors. However flexors. The fins[et al. support s[et al.,46, rupts[et al.. These as[et al. in partil.[et al. reportedbunion, describes a foot deformity characterised by lateral deviation of the great toe at the MTP joint away from the midline of the body[abductor hallucis compared to the adductor hallucis transverse and adductor hallucis oblique[abductor hallucis muscle in patients with symptomatic hallux valgus deformity[Hallux valgus, or the body. One pros oblique,13. Whens oblique. This thet al.[The role of the intrinsic muscle weakness in the development of plantar heel pain, or plantar fasciitis, is unclear. One theory proposed by Allen and Gross describeet al. of partiet al.. The atret al.. Hence, The next section will review the \u2018direct\u2019 and \u2018indirect\u2019 methods of measuring intrinsic muscle strength. The subheading \u2018direct methods of assessing intrinsic/extrinsic muscle strength\u2019 reviews the methods that can directly measure a unit of force or power. However, these \u2018direct\u2019 methods actually measure toe flexion strength which is a combination of intrinsic and extrinsic muscle strength. The subheading \u2018indirect methods of assessing intrinsic muscle strength\u2019 reviews methods that are unable to directly measure force but provide information regarding intrinsic muscle structure and activity.The direct methods reported in the literature include a variety of clinical tests,19,49,50Toe dynamometry is an objective tool used to measure toe flexor strength. Different methods of using toe dynamometry have been reported including hand-held dynamometry, fixed dThe different types of toe dynamometers allow testing of different actions of the toes. The procedure used to measure toe flexor strength with hand-held dynamometry involves the dynamometer being positioned beneath the interphalangeal joint of the hallux to measure either greater toe strength or interphalangeal joints two to five, for lesser toe strength. As suchinterossei and lumbrical muscles, Garth and Miller[interossei and lumbrical muscles can be electrically stimulated to produce flexion at the MTP joint and extension at the interphalangeal joint[interossei and lumbrical in the hand and foot, flexion at the MTP joint and extension interphalangeal joint are likely actions of intrinsic foot muscles. Therefore, hand-held dynamometry might activate intrinsic muscles more effectively than other types of toe dynamometry because it promotes flexion at the MTP joint and extension at the interphalangeal joint.The different types of toe dynamometry may activate intrinsic muscles to varying degrees because each model promotes different actions of the toes. Cuff-based fixed dynamometry, the modified hand grip tester and fixed dynamometry all allow flexion at the MTP joint, but do not provide a way to limit excessive flexion at the interphalangeal joints. A toe curling action can occur during toe flexor testing, an action which is hypothesised to activate the long (extrinsic) toe flexors. Based od Miller postulatd Miller. Studiesal joint. Based oAnother important consideration when measuring intrinsic muscle strength is the position of the ankle. Spink and co-workers hypothesThe Paper Grip Test involves the participant attempting to hold a standard piece of paper, like a business card, underneath the hallux or lesser toes while the examiner attempts to pull the card away,15. The et al.[There are a limited number of validation studies of the Paper Grip test as a measure of intrinsic muscle strength. De Win et al. conducteet al.. Furtheret al.. TherefoPlantar pressure sensors can assess the force beneath the toes. Plantar pressure measurement is generally available in two different forms: (1) in-shoe systems such as Novel Pedar\u00ae, TekScan F-Scan\u00ae, RS-Scan Insole\u00ae, IVB Biofoot \u00ae and; (2)The validity of using plantar pressures to determine intrinsic muscle strength is questionable because the contribution of the extrinsic muscles during the pressure measurement is unknown. Electromyography performed during Paper Grip Test has revealed that some extrinsic toe flexor muscles, particularly the long toe flexors muscles and ankle plantar flexor muscles were active. TherefoThe Intrinsic Positive Test is a qualitative test designed to assess intrinsic muscle function of the lesser toes. The tesThe indirect methods that will be reviewed are: Magnetic resonance imaging (MRI); computerised tomography (CT); ultrasonography; electromyography (EMG) and muscle biopsy. Indirect methods are generally used to estimate muscle structure -24,55-57Magnetic resonance imaging (MRI) is the method of choice for detecting soft tissue structure and abnormalities,59. It het al.[MRI has been used in three main ways to assess intrinsic muscle atrophy: (1) qualitative observation of muscle atrophy,7; (2) fet al. has alsoThe significant limitation of qualitative observations of muscle atrophy and using the five point scale to assess intrinsic muscle atrophy is that conclusions are based on a selected image, which may not be representative of the entire muscle. The MR images of intrinsic foot muscles can be taken in the coronal,7, transThe total volume of intrinsic foot muscles can be calculated by multiplying the total cross sectional area of the muscle, determined from MRI, by the distance between the sections, which is the gap between each MRI slice,57,60. Tet al.[MRI can also be used to estimate physiological cross-sectional area (PCSA) of intrinsic muscles. PCSA haet al. has showet al. and suggAn important advance in MRI is the fast-cine phase contrast (or dynamic MRI), which allows images to be acquired while the participant performs an action. Dynamicet al.[et al.[Computerised tomography (CT) is an imaging technique that uses ionising radiation to generate three dimensional images of musculoskeletal structures. CT scanet al. and Muell.[et al. performel.[et al.. Furtherl.[et al..dorsal interosseus muscle, adductor hallucis muscle, and the first lumbrical muscle[abductor hallucis[abductor digiti minimi[flexor hallucis brevis[quadratus plantae[extensor digitorum brevis[et al.[abductor hallucis muscles.Ultrasonography is a technique that uses mechanically produced longitudinal sound waves to create an image. Ultrasol muscle. More re hallucis,61,69, aum brevis. StudiesUltrasonography has two main limitations; low spatial resolution of the image, and theet al.[Electromyography (EMG) has been assessed by non-invasive surface electrodes and invasive intramuscular electrodes. Surfaceet al. recordedet al.. Therefoabductor hallucis, flexor digitorum brevis, dorsal interossei and quadratus plantae during standing task with increasing postural difficulty. The study revealed increased EMG signal amplitude in all muscles with increasing postural demands of the task, as assessed by deviation of the centre of pressure[Intramuscular EMG involves needle electrodes placed directly in the muscle. Most intramuscular EMG studies of intrinsic foot muscles insert needle electrodes into individual muscle bellies-5,28. Hopressure. The limpressure. Therefoet al.[abductor hallucis muscles in participants with symptomatic hallux valgus and reported histological abnormalities including muscle fibres atrophy, lipid laden fibres and ultrastructural changes in the mitochondria. However, the limitation of muscle biopsies is that findings may not be representative of the whole muscle belly[Muscle biopsy can be used to detect changes in muscle histology and ultrastructure. Biopsy et al. performele belly. TherefoThere is no gold standard method to measure intrinsic muscle strength in the foot. At present methods of measuring intrinsic muscle strength can be categorised as direct and indirect methods. Direct methods are able to quantify,15-19,50However, hand-held dynamometry has some barriers to accurately measure intrinsic muscle strength. First, it is currently unknown which intrinsic muscles are active during the hand-held dynamometry test. Second, it is unclear what action should be performed by the toes to best activate the individual intrinsic muscles during the dynamometry test. Garth and Miller hypothesIndirect methods such as imaging modalities-24,55-57This review suggests that at present, there is no adequately validated method of measuring intrinsic muscle strength. The main challenges are that no direct method can isolate intrinsic muscle strength from extrinsic muscle strength, and indirect methods cannot quantify muscle force. Future research in this field would benefit from using a combination of indirect and direct methods to measure intrinsic muscle force, because both measures have their strengths and limitations. For instance, a study comparing muscle architectural information from MRI, muscle modelling estimates of muscle force and muscle activation data from EMG, with the findings of direct methods such as hand held dynamometry would disentangle each method\u2019s limitation. Also indwelling EMG during hand-held dynamometry would enable both intrinsic and extrinsic muscle activity patterns to be compared, although this approach has numerous practical and analytical considerations to overcome. Nevertheless, a strong correlation would validate the findings of direct methods used to measure intrinsic muscle strength.An accurate and reliable measure of intrinsic muscle strength will enable prospective studies to address the causal relationship questions between intrinsic muscle weakness and foot/toe deformity in conditions like Charcot-Marie-Tooth disease,7, diabeIn conclusion, measuring intrinsic muscle strength poses many challenges. Most studies have focussed on toe flexor strength as a surrogate measure of intrinsic muscle strength, while other actions of toe muscles have not been assessed. Hand-held dynamometry represents a promising method of estimating intrinsic muscle strength. However, the contribution of extrinsic muscles cannot be excluded from toe flexor strength measurement. Future research should clarify the relative contribution of intrinsic and extrinsic muscles during intrinsic foot muscle strength testing.The authors declare that they have no competing interests.AS searched the literature, analysed the articles and drafted the review. JB, CH and KR conceptualised and edited the review. All authors read and approved the final manuscript."} +{"text": "Mesorhizobium metallidurans STM 2683T and Mesorhizobium sp. strain STM 4661 were isolated from nodules of the metallicolous legume Anthyllis vulneraria from distant mining spoils. They tolerate unusually high Zinc and Cadmium concentrations as compared to other mesorhizobia. This work aims to study the gene expression profiles associated with Zinc or Cadmium exposure and to identify genes involved in metal tolerance in these two metallicolous Mesorhizobium strains of interest for mine phytostabilization purposes.Mezorhizobium strains were sequenced and used to map RNAseq data obtained after Zinc or Cadmium stresses. Comparative genomics and transcriptomics allowed the rapid discovery of metal-specific or/and strain-specific genes. Respectively 1.05% and 0.97% predicted Coding DNA Sequences (CDS) for STM 2683 and STM 4661 were significantly differentially expressed upon metal exposure. Among these, a significant number of CDS involved in transport and sequestration were identified. Thirteen CDS presented homologs in both strains and were differentially regulated by Zinc and/or Cadmium. For instance, several PIB-type ATPases and genes likely to participate in metal sequestration were identified. Among the conserved CDS that showed differential regulation in the two isolates, we also found znuABC homologs encoding for a high affinity ABC-type Zinc import system probably involved in Zinc homeostasis. Additionally, global analyses suggested that both metals also repressed significantly the translational machinery.The draft genomes of the two Mesorhizobium strains. Very few of them were involved in the non-specific metal response, indicating that the approach was well suited for identifying genes that specifically respond to Zinc and Cadmium. Among significantly up-regulated genes, several encode metal efflux and sequestration systems which can be considered as the most widely represented mechanisms of rhizobial metal tolerance. Downstream functional studies will increase successful phytostabilization strategies by selecting appropriate metallicolous rhizobial partners.The comparative RNAseq-based approach revealed a relatively low number of genes significantly regulated in the two Such a phytostabilization approach is nevertheless challenging since it requires metallicolous plants able to grow in soils where nutrients are most often dramatically scarce. Legume/rhizobia symbioses which transform atmospheric dinitrogen into organic nitrogen is of ecological interest here as it can improve natural soil fertility and thereby allow the colonization of other plant species and the installation of a plant cover ..Strains,Click here for filePrimers used for quantitative PCR assays.Click here for file"} +{"text": "Propionic acidaemia (PA) results from deficiency of Propionyl CoA carboxylase, the commonest form presenting in the neonatal period. Despite best current management, PA is associated with severe neurological sequelae, in particular movement disorders resulting from basal ganglia infarction, although the pathogenesis remains poorly understood. The role of liver transplantation remains controversial but may confer some neuro-protection. The present study utilises quantitative magnetic resonance spectroscopy (MRS) to investigate brain metabolite alterations in propionic acidaemia during metabolic stability and acute encephalopathic episodes.Quantitative MRS was used to evaluate brain metabolites in eight children with neonatal onset propionic acidaemia, with six elective studies acquired during metabolic stability and five studies during acute encephalopathic episodes. MRS studies were acquired concurrently with clinically indicated MR imaging studies at 1.5 Tesla. LCModel software was used to provide metabolite quantification. Comparison was made with a dataset of MRS metabolite concentrations from a cohort of children with normal appearing MR imaging.MRI findings confirm the vulnerability of basal ganglia to infarction during acute encephalopathy. We identified statistically significant decreases in basal ganglia glutamate+glutamine and N-Acetylaspartate, and increase in lactate, during encephalopathic episodes. In white matter lactate was significantly elevated but other metabolites not significantly altered. Metabolite data from two children who had received liver transplantation were not significantly different from the comparator group.The metabolite alterations seen in propionic acidaemia in the basal ganglia during acute encephalopathy reflect loss of viable neurons, and a switch to anaerobic respiration. The decrease in glutamine + glutamate supports the hypothesis that they are consumed to replenish a compromised Krebs cycle and that this is a marker of compromised aerobic respiration within brain tissue. Thus there is a need for improved brain protective strategies during acute metabolic decompensations. MRS provides a non-invasive tool for which could be employed to evaluate novel treatments aimed at restoring basal ganglia homeostasis. The results from the liver transplantation sub-group supports the hypothesis that liver transplantation provides systemic metabolic stability by providing a hepatic pool of functional propionyl CoA carboxylase, thus preventing further acute decompensations which are associated with the risk of brain infarction. Propionic acidaemia results from deficiency of the biotin-dependent mitochondrial enzyme propionyl CoA carboxylase. The commonest and most severe form of PA presents in the neonatal period with acute metabolic acidosis, hyperammonaemia and progressive encephalopathy. Despite optimal management, later neurologic sequelae are a major cause of morbidity, and include neurodevelopmental delay, episodic acute encephalopathy, and movement disorders due to a propensity to basal ganglia infarction . The maiThe pathogenesis of the neurological insult remains poorly understood. Neurological damage may occur secondary to hyperammonaemia; alternatively inhibition of the mitochondrial Krebs cycle and electron transfer chain by accumulating metabolites may lead to a \"bioenergetic stroke\" . Based oin vivo changes in regional metabolites within the brain, and could be specifically employed to monitor directly alterations in brain energy metabolites including glutamine, glutamate and lactate. Previous MRS reports have demonstrated elevated glutamine+glutamate (Glx) in the basal ganglia of metabolically stable PA patients [Magnetic resonance spectroscopy (MRS) is a non-invasive technique capable of probing patients , while lpatients .The present study utilises quantitative MRS to investigate brain metabolite alterations both during metabolic stability and acute encephalopathic episodes, confirming the basal ganglia as a particular target and demonstrating novel insights in to alterations in neurotransmitter metabolites in particular glutamine and glutamate.Eight children with propionic acidaemia were studied (median age (range) at first MRS, 36 7-190) months) . During these episodes all children required ventilatory support and continuous veno-venous haemofiltration (CVVH), and only one episode was associated with significant persistent hyperammonaemia. During these episodes three children received intravenous sodium benzoate and two received sodium phenylbutyrate.MRS studies were performed concurrently with clinically indicated MRI scans at 1.5 Tesla facilitated by general anaesthesia as needed. Five studies from three children were acquired during severe acute episodes requiring intensive care support. Six studies from six children were acquired with elective outpatient MRI studies undertaken during metabolic stability and before any severe acute episode had occurred.MRS was acquired using point resolved spectroscopy (PRESS) technique with 2 cm-sided voxels located in the left basal ganglia and right parieto-occipital white matter. Voxels were placed in standard positions guided by T1 and T2 weighted image sequences in coronal, sagittal and axial planes. Spectra were quality-assessed to ensure appropriate voxel localisation, shimming and water suppression. Raw data were processed using LCModel [Comparison was made with MRS metabolite data from a cohort of children with normal appearing MRI and similar age profile who had undergone MRI/MRS for investigation of various suspected neurodegenerative and neurocognitive conditions age 4.7(0.5-16.7) years; basal ganglia n = 63, 4.1(0.5-16.7) years).Mean spectra were generated for each cohort for basal ganglia and white matter from LCModel fitted spectra after baseline subtraction. Spectra were compared by qualitative visual inspection.Metabolite concentrations for each region were compared between groups by Mann Whitney nonparametric U test (SPSS Statistics 17.0), with the p-value determined by the exact 2-tailed significance, with significance level set at p < 0.05.The basal ganglia appeared normal in all children (n = 6) prior to any severe acute episode beyond the neonatal period. MRI obtained during severe acute episodes demonstrated abnormal signal in the basal ganglia variably including the caudate heads, putamen and globus pallidi and in some cases there was also evidence of acute changes in the dentate nuclei and cerebral cortex. One child demonstrated evidence of previous basal ganglia infarction relating to a previous acute encephalopathic episode, with cystic degeneration of caudate, putamen and globus pallidus. Interestingly the hippocampi appeared atrophic in seven cases. Cerebral volume loss was most marked in children with preceding severe acute episodes. The two children who had liver transplantation had normal appearing basal ganglia, cortex and white matter on MRI undertaken more than 10 years post-transplant, with one showing probable temporal mesial sclerosis.Analysis of mean spectra figure and meanMRS studies undertaken during metabolic stability before any severe acute episodes beyond the neonatal period demonstrated decreased Glx in basal ganglia compared to the normal MRI comparator group but a trend to increase in white matter. Glutamine alone was significantly decreased in basal ganglia during metabolic stability. Mean lactate was not elevated, although two cases had reliably detected lactate in basal ganglia. There was no significant decrease in the total N-acetylaspartate and N-acetylaspartylglutamate (tNAA) in this group.myo-inositol, and no propionic acid was detected in the propionic acidaemia cohort.MRS studies acquired during severe acute episodes demonstrated significantly decreased tNAA, Glx and creatine, and significantly elevated lactate, in the basal ganglia compared to both the normal MRI comparator group and to the metabolically stable propionic acidaemia cohort. In white matter lactate was significantly elevated but other metabolites were not significantly altered. . There were no significant differences between groups in brain Separate analysis of brain metabolites from the two children post-liver transplant demonstrated normal basal ganglia tNAA and slightly decreased Glx. tNAA was elevated in white matter and total choline decreased.The data presented represent the largest series of children with the severe neonatal form of propionic acidaemia to be investigated with MRS, and is to our knowledge the first to study children during severe acute encephalopathic episodes. The selective vulnerability of the basal ganglia in PA is well established, and our data provide further insight in to processes occurring within the basal ganglia. MRI results found that basal ganglia appeared normal in children who had not had a severe acute encephalopathic episode beyond the neonatal period, as similarly reported in glutaric aciduria , but werDecreased tNAA is seen in many pathologies, and is thought to reflect loss of viable neurons includinThe alterations seen in glutamine and glutamate in basal ganglia are of particular note. Glx was significantly decreased during severe acute episodes, with a smaller (non-significant) decrease noted in basal ganglia in studies acquired during metabolic stability. The ratio of Glx/tNAA was lower in the propionic acidaemia cohort than in cohorts of children with other defined inherited metabolic disorders including a cohort with confirmed respiratory chain disorders, while the Glx/NAA ratio was elevated in a cohort with the urea cycle disorder argininosuccinic aciduria . This suggests that the alterations seen in Glx here were not simply a reflection of neuronal loss represented by lower tNAA.Although the spectral signals from glutamine and glutamate overlap, there is increasing evidence that they can be differentiated in the analysis of cohorts even at 1.5Tesla using software such as LCModel. Such evidence includes Montecarlo simulations of normal brain spectra fitted with LCModel , compariA previous MRS study reported elevated basal ganglia Glx in three metabolically stable propionic acidaemia patients who had normal ammonia and near-normal glutamine and glutamate in plasma and cerebrospinal fluid leading the authors to suggest differential mechanisms regulating brain parenchymal metabolism . HoweverThe administration of the alternative pathway drugs used to control hyperammonaemia depletes plasma glutamine and glycine and may contribute to the decreased brain Glx seen. Furthermore, all children were haemofiltered during severe acute episodes which may further deplete glutamine due to its high sieving coefficient . HoweverThe acute decrease seen in Glx supports the hypothesis that they are consumed to replenish a depleted Krebs cycle , and thaThere is a need for brain protective strategies during acute metabolic decompensations, with potential methods including brain cooling, adequate energy provision, and anaplerotic therapies. MRS could provide a tool to monitor the effect of dietary supplements aimed at increasing glutamine levels, specifically monitoring metabolite levels within the target-organ of interest, namely the brain.The two children who had liver transplant have had no severe acute encephalopathic episodes beyond the neonatal period, and have normal appearing basal ganglia on MRI. MRS demonstrated normal/high tNAA reflecting the absence of major neuronal loss and correlating with their good neurocognitive status, and no reliably detected lactate. The small numbers preclude statistical significance, but Glx was slightly increased in white matter but decreased in basal ganglia compared to the comparator group. These results support the hypothesis that liver transplantation provides systemic metabolic stability by providing a hepatic pool of functional propionyl CoA carboxylase, thus preventing further acute metabolic decompensations which are associated with the risk of brain infarction.The data presented here have yielded some interesting observations, however further prospective data collection and analysis could overcome some of the specific limitations of the present work. In particular, use of higher field strength MRI scanners (3Tesla and above) would provide more robust differentiation of the metabolites of interest, notably glutamine and glutamate. Serial data collection in specific patients could also confirm the alterations in brain metabolites seen before, during and after metabolic decompensations. Finally analysis of a larger cohort of post-liver transplant patients as well as longer follow up with serial studies will provide stronger evidence for the therapeutic value of liver transplantation in PA.in vivo brain metabolic derangements, and can feasibly be employed in children with acute encephalopathy. In propionic acidaemia the use of MRS in conjunction with MRI has confirmed the basal ganglia as a particularly vulnerable target and has demonstrated novel insights in to alterations in neurotransmitter metabolites. Evaluation of patients in long-term follow up after liver transplantation demonstrates the potential for good neurological outcome and near-normal brain metabolism. MRS provides a tool to directly evaluate the tissue-level effects of novel treatment strategies including anaplerotic therapies.We have demonstrated that quantitative MRS is able to offer insight in to The authors declare that they have no competing interests.JED carried out data analysis and collated clinical data and drafted the manuscript.NPD, MW, YS assisted with data processing including software development.AC, PJM and JHW provided clinical management for subjects, assisted with patient recruitment and critically appraised the manuscript.PG and ACP conceived of the study and participated in its design.All authors read and approved the final manuscript."} +{"text": "Implementation of alcohol screening and brief intervention (SBI) is a prevention priority. The Veterans Affairs (VA) Healthcare System uses a clinical reminder (CR) in the electronic medical record to prompt and document results of screening and trigger a subsequent CR for BI when screening is positive. Although screening rates are over 90%, marked variability in screening quality has been documented. Four researchers observed clinician interactions with CRs during alcohol screening at nine primary care clinics in the northwest US to identify barriers and facilitators to using CRs to implement quality screening. Observers took handwritten notes, which were transcribed and analyzed qualitatively using an a priori coding template adapted during analyses. We observed 58 support staff caring for 166 patients. Alcohol screening prompted by the CR was often uncomfortable and of low quality. Clinicians often offered disclaimers prior to screening or made adjustments to how questions were presented, with some citing the sensitive nature of the questions. Verbal screening typically did not include asking questions verbatim. There was substantial variability in methods of conducting screening across clinics, with some using the CR to facilitate in-person screening by interview and others entering patient responses into the CR after completion of a paper-based screen. Although the CR was designed to trigger a subsequent CR for BI when positive, some clinics used paper encounter forms for this. Findings suggest that VA CRs have important limitations as a method of facilitating effective, high-quality alcohol screening. Barriers observed reflect a combination of limitations of CR technology , ways the CR was implemented, clinical workflow, complexity of patient needs, and alcohol-related stigma. Future research should address these barriers to effectively implement recommended care."} +{"text": "The pressure flow model of phloem transport envisaged by M\u00fcnch has gain The pressure flow model of phloem transport M\u00fcnch, has gainP) for a given viscosity (\u03b7), predicts that variation in flow path geometries of STs , will alter their hydraulic conductances (Lo and see Equation 2) and hence impact axial volume flow rates (Rv) through them.Experimental observations provide persuasive support for phloem sap moving through STs by bulk flow by variations in sieve pore radii provided by plasmodesmata interconnecting these cells.Phloem unloading rates are regulated by hydraulic conductances (Equation 2) of the unloading pathway rather than the axial hydrostatic pressure differential Equation 1). In this context, the latter is comparable between a source and an array of sinks irrespective of their rates of phloem unloading of symplasmic unloading pathways linking SEs with phloem parenchyma cells in the release phloem Figure .Key elements of the high-pressure manifold model of phloem transport articulated by Fisher and captOur analysis of the high-pressure manifold model of phloem transport primarily rests on evaluating the extent to which the model is consistent with known properties of resource flow through the phloem. Of necessity much of this analysis will focus on phloem transport in herbaceous plants where most experimental studies have been undertaken. However, with appropriate caveats, the analysis is extended to phloem transport in trees.Bulk flow in the M\u00fcnch model is conceived to be restricted to STs alone in which substantial hydrostatic pressure gradients develop from their source to sink ends. In contrast, the high-pressure manifold model trees during the photoperiod and stem (transport) lengths that accounts for phloem translocation by M\u00fcnch pressure flow in plant heights spanning several orders of magnitude exceed the potential capacity of phloem loading, phloem sap concentrations of sugars, accompanied by ST hydrostatic pressures, decline until a new equilibrium between loading and unloading rates are reached. This condition could cause a pronounced axial gradient in ST hydrostatic pressure from source to sink to develop. The corollary is sink limitation whereby the potential capacity for phloem loading of sugars exceeds that of phloem unloading. For this condition, any increase in rates of phloem unloading is met by a commensurate increase in phloem loading. This condition would sustain high phloem sap sugar concentrations and hence ST hydrostatic pressures throughout the system.There are no direct measures of rates of phloem loading and unloading. However, there is considerable indirect evidence suggesting that potential capacities of leaf photosynthesis arranged in series with phloem loading exceed those of phloem unloading into expanding and storage sinks. For instance, under optimal environmental conditions for leaf photosynthesis, increasing sink/source ratios by experimentally attenuating sugar export from a portion of leaves results in elevated rates of sugar export from the untreated leaves of trees expressed on a cross-sectional area basis i.e., \u03c0r2) would vary directly with sieve pore radius raised to the second power. However, across a cohort of test species, estimates of phloem transport velocities were found to exhibit an inverse rather than the predicted direct relationship with their estimated ST hydraulic conductivities in STs plants whose STs do not seal upon severance, allowing phloem transport to continue. Hence rates of phloem transport can be estimated by measuring quantities of phloem sap exuded from cut surfaces across specified times. The estimated transport rates can be expressed as ST fluxes based on measures of their cross-sectional areas through which axial transport takes place surgical removal of phloem cross-sectional area in stems was found to exert little influence over axial flow rates in both woody plants or storage organs. In particular, under high source/sink ratios, net resource flows occur from transport phloem of petioles, stems and roots into storage pools of their ground tissues in which transport phloem is embedded. A striking example of this phenomenon is accumulation of sucrose in storage parenchyma cells of sugarcane stems to concentrations that match those of the phloem sap Patrick, . Thus, cPhloem unloading may be arbitrarily divided into SE unloading and post-SE unloading which extends from phloem parenchyma cells to cellular sites of resource utilization or storage in non-vascular cells. For the purposes of evaluating the high-pressure manifold model of phloem transport, the primary focus is on SE unloading wherein resources reach the phloem parenchyma cells. However, some consideration, where relevant, will be given to post-SE unloading.A central tenant of the high-pressure manifold model is that hydraulic conductances of the symplasmic unloading pathways, from SEs of release phloem, impose a major constraint over bulk flow of resources through the source-path-sink system Figure . This diThe most definitive experimental approach to mapping phloem-unloading pathways has been through the use of membrane-impermeant fluorochromes introduced into phloem sap as membrane-permeant esters or as tags linked to transgenically-expressed foreign molecules under the control of companion cell specific promoters.Axial delivery pathways into apical meristems comprise protophloem SEs giving way to strands of provascular cells more proximal to the apical dome. Distribution of membrane-impermeant fluorochromes, imported through the phloem, have identified putative symplasmic unloading pathways extending from terminal ends of protophloem SEs through provascular stands to reach meristematic cells in root apices of monocots predicts that any symplasmic bulk flow of phloem sap exiting from SE/CC complexes will encounter considerable hydraulic resistances and hence a proportionate reduction in hydrostatic pressure upon entering recipient cells. These predictions are consistent with the presence of large (1.0 MPa) differences in hydrostatic pressures between release phloem SEs and cortical/epidermal cells of root tips measured directly using aphid stylet micromanometry and pressure probe respectively Table . Similar\u22121 into a developing wheat grain across a set of microchannel radii (see Table Rv \u2013 Equation 1) from which microchannel numbers supporting the observed volume flow rate were derived. From these data, microchannel numbers per plasmodesmata were estimated assuming that a single row of microchannels occupy 50% of the sleeve cross-section. Microchannel numbers per plasmodesma then allow determination of plasmodesmatal numbers required to support the observed volume flow rate of a solute i are described by Fick's First Law of diffusion as:D is the diffusion coefficient of solute i; A is the cross-sectional area (r = \u03c0r2) of the diffusional pathway; \u0394C is the concentration difference of solute i between either end of the diffusive pathway; \u0394x is the length of the diffusive pathway.Since SE/CC complexes and vascular parenchyma cells share identical apoplasmic water potentials, turgor differentials arise from intracellular osmotic differentials and, as a result, concentration differences of phloem sap constituents. Hence diffusion must be a component of phloem unloading and the issue of the relative contributions of symplasmic phloem unloading by diffusion and bulk flow becomes one of degree. Diffusion rates and bulk flow (Equation 1) in SE unloading, published sucrose concentrations in SEs with that of 14C-sucrose along elongating pea epicotyls, independent of their differing symplasmic concentration gradients, suggests symplasmic unloading of these disparate solutes is primarily by bulk flow rather than diffusion and Ficks First Law of diffusion Equation 3). That is, rates of these two processes are proportional to the radius of the conducting pipe raised to the fourth and second powers respectively. Thus, control of pipe radius can exert a four-fold greater control over rates of bulk flow compared to diffusion. This translates into an operational system whereby modest changes in microchannel dimensions can elicit substantial impacts on bulk flow rates of solute unloading from release phloem as illustrated in Tables . That isIn addition to optimizing control over phloem unloading (see above), bulk flow also avoids a dependence upon a very high level of co-ordination of unloading between individual solute species to avoid compromising phloem transport as outlined in the following scenario. If symplasmic unloading were to occur primarily by diffusion, then a mechanism must be present to ensure exit rates of each solute species and water from release phloem SEs match their rates of replenishment by axial transport. This is not a trivial requirement as diffusion rate of each solute moving through the same unloading pathway geometry depends not only on their concentration differences between SEs and vascular parenchyma cells but also on their individual diffusion coefficients (see Equation 3). Moreover phloem-imported water will diffuse at rates dictated by water potential differences between SE-CCs and vascular parenchyma cells. In these circumstances it would be very problematic for axial rates of each solute and water transported into, to match those of their diffusional exit from, release phloem SEs. As a consequence, regulation of ST hydrostatic pressures of release phloem could be compromised. This problem does not apply if SE unloading were to occur by bulk flow since solutes and solvent are transported at identical fluxes .Rv and see Equation 1) and cortical cell turgor points to hydraulic conductances of plasmodesmata, located along the symplasmic unloading pathway, exerting a major regulatory influence over radial fluxes of water and hence solutes travelling from SEs to cortical cells. This explanation also accounts for transport behaviors in developing seeds whereby coat cell turgors were found to be invariant across a three-fold range of seed growth rates exhibited between French bean cultivars and densities, formed during their development at various cellular interfaces located along phloem unloading pathways set upper limits for symplasmic hydraulic conductances. For example, inferred from Stoke's radii of the permeating molecules, these data yield conservative estimates of plasmodesmal microchannel radii for phloem and non-phloem domains that extend over a two-fold range (see Section Is Symplasmic Sieve Element Unloading Dominated by Bulk Flow?). In relative terms, these radii translate into a 16-fold range of hydraulic conductances. Second, plasmodesmal gating (open versus closed), mediated by callose deposition/hydrolysis around plasmodesmal neck regions, has been demonstrated to play a key role in regulating transmission of macromolecular signals orchestrating cell development (Burch-Smith and Zambryski, Conductance for symplasmic movement between two adjacent cells is a function of their averaged conductance of plasmodesmata summed over the density of plasmodesmata located in their shared wall. Plasmodesmal densities are under both positional and developmental control (Burch-Smith and Zambryski, Within meristematic sinks, plant hormones regulate rates of cell division and hence sink demand. This hormone function is linked with their ability to directly act on transport processes delivering resources to hormone-enriched sites Patrick, . Fully-eFor expansion/storage sinks, some insights into the regulatory mechanisms integrating sink demand with plasmodesmal control of resource flow along phloem unloading pathways has been obtained from observations of developing seeds. Phloem unloading pathways in developing seeds universally contain a symplasmic discontinuity at, or proximal to, their maternal and filial interfaces at which phloem-imported resources are released to, and retrieved from, the seed apoplasmic space (Zhang et al., Crop biomass yield potential is the harvested yield per plant of any cultivar raised under optimal environmental conditions for its development in the absence of any limitation imposed by abiotic or biotic stresses (Evans and Fischer, The elements carbon, hydrogen and oxygen account for ca 90% of crop biomass yield. These elements reach the harvested units as phloem-imported sugars that form the major osmotica generating ST hydrostatic pressures propelling bulk flow from source to sink. The preceding analysis of the high-pressure manifold model of phloem transport identified hydraulic conductances of plasmodesmata, located at the sink-end of phloem pathways, as key regulators of bulk flow rates from source to sink and for partitioning of flow rates between competing sinks Figure . This shZea mays ADP-glucosepyrophosphorylase, under control of an endosperm-specific promoter, in pre-storage grains of wheat (Smidansky et al., The pre-storage phase of harvestable organ development is photoassimilate limited as demonstrated by positive responses of harvestable organ numbers to elevated source/sink ratios (Ruan et al., The storage phase filling rates are characteristically sink-limited (Borr\u00e1s et al., Overall, the above circumstantial evidence indicates that opportunities may well exist to improve crop biomass yield through manipulating resource transport informed by the high-pressure manifold model of phloem transport.Reviewing current knowledge of phloem transport leads to a strong circumstantial case being made for the high-pressure manifold model of phloem transport. This is considered sufficient to warrant further study of the model. Initially, most effort could be directed to increasing knowledge of the plasmodesmal sub-structures and how these influence resource flow through their plasmodesmal microchannels. In particular, it is crucial to obtain direct evidence that hydraulic conductances of plasmodesmata, linking SEs with surrounding phloem parenchyma cells, support SE unloading of phloem sap by bulk flow. This enterprise could be informed by the exciting findings emerging from investigations of water flows through nanotubes showing that, with radii of several nm, flow velocities exceed those predicted by the Hagen-Poiseuille law by four to five orders of magnitude (Majumber et al., This paper is dedicated to the memory of Donald Fisher, a modest, but passionate, plant scientist. Don's contributions to advancing our conceptual knowledge of phloem transport biology were substantial, unyielding in their rigor and trail blazing in their impact on the field.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The present investigation compared parenting practices in a sample of preschoolers whose mothers reported smoking during pregnancy versus those who did not.A sample of n = 216, 3.0- to 5.11-year-old children, participants in an ongoing longitudinal study, was separated into those reportedly exposed to smoking in utero and those who were not. Parenting practices were compared between the two groups, using T-tests and exact logistic regressions. Multiple linear regressions and multivariate logistic regressions were used to examine the association between smoking status and parenting, controlling for variables also known to be associated with parenting practices.Current study findings suggest that smoking during pregnancy is associated with harsh parenting practices.Study results highlight the possible role of parenting in disruptive outcomes well-known in toddlers exposed to nicotine in utero and have implications for targeting early interventions in these populations. An association between prenatal cigarette exposure and disruptive behavior in childhood has been reported in the empirical literature from multiple independent investigations . HoweverNumerous individual and psychosocial differences have been found between mothers that smoke during pregnancy and mothers that do not. Such differences have included the findings of more antisocial character traits in smoking mothers and a higher likelihood of selecting mates with these traits . MothersThe above mentioned personal and psychosocial features of pregnancy smokers may themselves contribute to poor parenting skills. To further complicate the challenges of parenting in this population, the child of a pregnancy smoker may also be more difficult to parent than the child of a non-smoker on the basis of biological risk factors. For example, while the mechanism remains unclear, smoking while pregnant has been associated with increased negativity in toddlers measured as rebelliousness, risk taking, and impulsivity, behaviors often found in children with disruptive disorders . Brook eTo better understand the relationship between smoking in pregnancy and early child behavioral problems, further examination of parenting among pregnancy smokers compared to non-smokers is now warranted. There is a dearth of published studies that specifically inform this issue. While most prior investigations have focused on prenatal smoking and risk for disruptive behavior outcomes in the child, parenting constructs were also examined in some of these studies. These available study findings have suggested that mothers who smoked showed less parental nurturing, as well as poor behavioral management and dyadic communication skills , 23, 24.Additional studies have examined parenting among pregnancy smokers at multiple stages of development, from neonates to adolePreschool age children (n = 306) between the ages of 3.0 and 5.11 and their caregivers were recruited from pediatricians\u2019 offices, daycares, and preschools in the St. Louis metropolitan area using the Preschool Feelings Checklist (PFC) , a briefThe PAPA is an interviewer-based diagnostic assessment with established test-retest reliability designed for use in children ages 3 to 6 . The PAPThe CAPA is an interviewer-based, structured psychiatric interview for children with collection of data on symptom onset, frequency, intensity and duration according to DSM-IV, III-R or ICD-10 criteria. Modules such as substance use (tobacco), can be used separately, and test-retest reliability for diagnoses range from k = 0.55 (conduct disorder) to k = 1.0 (substance abuse) . MothersThe HBQ-P is a 140-item reliable and valid parent informant measure that produces dimensional ratings of 4- to 8-year-old children\u2019s functioning in the domains of emotional and behavioral symptomotology, impairment, adaptive social functioning, and physical health using a 3-point Likert scale with a 20-minute completion time .Parenting practices based on self-report were examined in mothers who smoked versus those who did not smoke cigarettes during pregnancy in a sample of n = 306 children enrolled in an ongoing longitudinal investigation of preschoolers. T-tests and exact logistic regressions were used to compare the differences for parenting variables between mothers who smoked and those who did not. Mann-Whitney U tests were used to compare two smoking categories. Multiple linear regressions and multivariate logistic regressions were used to examine the association between smoking status and parenting variables (frequency or intensity) controlling for confounding variables.Of the n = 306 preschoolers from the longitudinal investigation, n = 216 participants had data available on both parenting and smoking exposure. Demographic characteristics of study participants included in this analysis are shown in T-tests and exact logistic regressions revealed that mothers who did not smoke during pregnancy were significantly less likely than mothers who smoked to: (1) give verbal dispraises ; (2) ever leave bruises ; (3) verbally reject .A multiple linear regression controlling for demographic differences including total family income, baseline education of the biological mother, ethnicity, and several variables known to impact parenting including alcohol during pregnancy and HBQ-P externalizing scores were controlled and included as covariates shown below. In this analysis, as depicted in Smoking during pregnancy was also significantly associated with leaving marks or bruises (intensity) . SmokingThe current study findings suggest specific parenting differences in those mothers that smoked during pregnancy compared to those who did not. Pregnancy smokers demonstrated harsher parenting in several specific domains than parents who did not smoke during pregnancy. These differences remained significant even after other factors known to be associated with poor parenting such as low SES, alcohol use, and child\u2019s externalizing behavior scores were accounted for in the analysis. Parenting behaviors among pregnancy smokers remain under-investigated. Current findings suggesting increased levels of harsh parenting in pregnancy smokers extend the extant literature associating pregnancy smoking exposure to child disruptive outcomes. These findings point to modifiable risk factors in pregnancy smokers to ameliorate child disruptive outcomes. While further studies are warranted to elaborate on the mechanisms that drive this association, study results suggest that parenting should be an important target for dyads exposed prenatally to cigarettes. Other studies have suggested treatment intervention to be less effective in children prenatally exposed to cigarettes, warranting further understanding and need for targeted treatment . RegardlStudy limitations include a relatively small sample size of pregnancy smokers that were from a longitudinal investigation on depression. Other potential limitations were no bioassay confirmation of smoking measurements and no maternal personality assessment. Additionally, current study findings show less Caucasian and more African American mothers in the group of pregnancy smokers versus non-smokers, making the findings less generalizable to the population. This is also important as multiple smoking investigations find Caucasians to be the ethnic group making up the large majority of pregnancy smokers. Further investigations of such ethnic differences are warranted.Finally, our reliance on self-reported parenting in the absence of observational parenting measures is a limitation due to the possibility of bias towards appropriate, socially acceptable responses and shared method variance with the same reporter providing information on both predictor and outcome . HoweverThe present investigation compared parenting practices in preschoolers whose mothers reported smoking during pregnancy versus those who did not. Current study findings suggest that smoking during pregnancy is associated with harsh parenting practices. While the current investigation is preliminary and limited by a small sample size, study findings inform the need for larger investigations that specifically examine parenting of younger children among pregnancy smokers, taking into account key variables such as maternal personality characteristics and other related substance use. Future investigations could inform how to improve parenting skills to minimize disruptive behaviors in young children of pregnancy smokers at greatest risk for harsh parenting. Such studies would help identify those most likely to benefit from targeted parenting interventions to optimize public health resources."} +{"text": "Direct implantation of isolated myoblasts, cardiomyocytes, and bone-marrow-derived cells has shown prospect for improved cardiac performance in several animal models and patients suffering from heart failure. However, direct implantation of cultured cells can lead to major cell loss by leakage and cell death, inappropriate integration and proliferation, and cardiac arrhythmia. To resolve these problems an approach using 3-dimensional tissue-engineered cell constructs has been investigated. Cell engineering technology has enabled scaffold-free sheet development including generation of communication between cell graft and host tissue, creation of organized microvascular network, and relatively long-term survival after Cardiac repair by cell therapy offers hope to improve performance of diseased heart by reconstituting or maintaining cardiac specific tissue . First sNevertheless, the hypothesis that cardiac function in heart failure can benefit from cell therapy has gained extensive attention and preliminary clinical trials have been launched \u201314. MiyaOne of the crucial issues in cell therapy for heart failure has been the cell delivery route. Injection of the cells has been the most typical method in clinical feasibility studies . The celIn addition, arrhythmogenicity of intramyocardial myoblast transplantation has aroused debate. Episodes of ventricular tachycardia and fibrillation have been noted after several feasibility studies. Due to small number of patients in nonrandomized series and the arrhythmogenic nature of the heart disease itself, direct causality is difficult to conclude. In an early study of Menasch\u00e9 et al., 4 out of 10 patients experienced sustained ventricular tachycardia , and in Another approach for cell delivery as opposed to injection involves tissue-engineered constructs. The main advantage of this technology over standard cell implantation lies on the preservation of microcellular communication and matrix, which is lost upon trypsin treatment in the typical procedure of cell preparation. Epicardial deposition of cell sheets might be a solution to prevent significant cell loss and arrhythmia after cell transplantation . Memon eCurrent tissue engineering methods allow us to reconstruct myocardial tissue grafts for clinical applications, though human fetal and neonatal cardiomyocytes are difficult to obtain. Therefore, several classes of stem cells are being investigated as a potential cell source. Despite their attractive potential to differentiate into various cell types, several issues remain, including difficulties in obtaining and amplifying the cells and the lack of understanding of the mechanisms for differentiation and proliferation. Consequently, the clinical cell sheet transplantation has mainly focused on utilization of myoblasts.bcl2 was shown to enhance the efficacy of sheet transplantation therapy in acute myocardial infarction [bcl2 improved myoblast sheet transplantation therapy also in chronic myocardial infarction model [Memon et al., reportedfarction . Moreoveon model .Dilated cardiomyopathy (DCM) is characterized by global myocardial remodeling, which mainly consists of myocardial fibrosis associated with changes in the cytoskeletal and sarcolemmal proteins in cardiomyocytes, leading to a reduction in the number and function of these cells . ConsequHoashi et al., showed tPreclinical studies in impaired porcine heart using single monolayer skeletal muscle cell sheet demonstrated improved cardiac performance accompanied with increased myocardial perfusion and viable myocardial tissue .Further, Miyahara et al., used mesenchymal stem cells (MSCs) derived from adipose tissue in a rat myocardial infarction model . MSC sheDifficulties still exist in the outcome of cell therapy, as it is challenging to control the cell growth and localization of the grafted cells and to deliver a cell sheet patch that significantly aids the function of the damaged myocardium. To overcome these problems research has begun on fabricating three-dimensional cardiac grafts composed of multilayered cell sheets. Several methods have been studied with reconstructed tissues based on biodegradable scaffolds, such as poly(lactic-co-glycolic acid) and gelatin or extracellular matrix components , 49.In native cardiac tissue the cell density is considerably high, cells being tightly interconnected with gap junctions facilitating electrical communication. The use of scaffolds can lead to abnormal tissue development, electrical communication caused by insufficient cell-to-cell connections, inflammatory responses, and fibrous tissue formation. Alternatively, fabrication of scaffold-free cell sheets requires means of cell detachment from the culture surface that will preserve cell morphology, orientation within the scaffold, and adhesion to surrounding cells and the extracellular matrix. One way to achieve such detachment is to covalently employ a temperature-responsive polymer on cell culture surface. Poly(N-isopropylacrylamide) (PIPAAm) is a hydrophobic polymer at temperatures above 32\u00b0C which\u2014after grafting to cell culture dishes\u2014allows cell adhesion and proliferation . At temp\u03bcm. These sheets, however, were subject to necrosis due to limited oxygen supply. The same method was then used to create prevascularized sheets composed of cardiomyocytes, endothelial cells, and fibroblasts. These sheets effectively integrated with the coronary circulation after implantation and evaded necrosis. Furthermore, Itabashi et al., fabricated cardiomyocyte sheets using polymerized fibrin-coated culture dishes [Stevens et al., and Itabashi et al., described other methods for creating scaffold-free sheets. Stevens et al., created embryonic stem cell-derived cardiomyocyte sheets utilizing Teflon-coated low-attachment tissue culture dishes combined with rotating orbital shaker . The diae dishes . This meIn addition to cell-to-cell communication, the layers need to establish a connection with each other and with the host tissue. Using a multielectrode extracellular recording system, Haraguchi et al., demonstrated that the electrical coupling between 2 sheets starts approximately 34 minutes after initial layering and is completed by about 46 minutes. They also showed small molecule exchange through gap junctions and presence of connexin-43 within 30 minutes of layering .When Shimizu et al., implanted a 4-layered neonatal rat cardiomyocyte sheet into the subcutaneous space of nude rats, synchronous beating and survMiyagawa and colleagues showed that neonatal cardiomyocyte sheets fabricated on temperature-responsive culture dishes attached to the infarcted myocardium and led to an improvement in cardiac performance and improved vascular density . The impAnother study demonstrated a similar electrical integration between a neonatal myocyte sheet and the host myocardium without serious arrhythmia . Furtherin vitro rely on diffusion. In order to reconstruct thicker and metabolically active tissue grafts sufficient blood supply network has to be created.Heart is a metabolically active organ that requires virtually constant oxygen supply in order to function in a normal fashion. The major limitation of the multilayered cell grafts is insufficient circulation causing hypoxia, nutrient insufficiency, and accumulation of waste products. Cells in living tissues receive oxygen supply through a capillary network, whereas the cultured cell aggregates in vitro in tissue-engineered constructs before transplantation. Levenberg et al., demonstrated the induction of endothelial vessel networks in engineered skeletal muscle tissue constructs using a 3D culture system consisting of myoblasts, embryonic fibroblasts, and endothelial cells coseeded on porous, biodegradable polymer scaffolds [in vitro bone coculture model with human MSCs, human umbilical vein endothelial cells (HUVECs) [One strategy could be to generate capillary-like networks caffolds . Similar(HUVECs) , 62, and(HUVECs) . As the Sasagawa et al., developed a novel cell sheet stacking manipulation technique to create multilayered cell sheets from human skeletal muscle myoblasts . They pl\u03bcm thick [\u03bcm thick. In order to progress the human cell sheet applications the greater thickness of the construct would be of great advantage. Sekiya et al., investigated the relationship between the number of transplanted cell layers and cardiac function. They found a significant improvement of cardiac function, induction of angiogenesis, more elastic fibers, and less fibrosis with implantation of 3- and 5- layered myoblast sheets compared to single layer [A single myoblast layer is about 45\u2009\u03bcm thick . Accordile layer .Shimizu et al., showed that the 1-, 2-, and 3-layer constructs transplanted into the dorsal subcutaneous tissue of nude rats thoroughly survived without necrosis . Howeverin vitro and increased blood perfusion in vivo by using a coculture of fibroblasts and human smooth muscle cells [One way to enhance the cell sheet graft survival is to promote angiogenesis. Enhanced angiogenesis and functional improvement were achieved by using cocultured cell sheets with fibroblasts and endothelial progenitor cells . Anotherle cells . In addile cells . Stimulation of angiogenesis has also been shown in single cell-type cell sheets. Miyagawa et al., demonstrated that human HGF gene transfection enhanced the cellular cardiomyoplasty likely by stimulating angiogenesis, restoring the impaired extracellular matrix, and promoting the integration of the dissociated grafted myocytes . Zakharoin vitro and in vivo models and demonstrated that cardiac cell sheets express VEGF, Cox-2, and Tie-2 and exhibit endothelial cell organisation and microvessel formation [in vivo. Expression of these proangiogenic genes was further induced by preventing graft apoptosis with antiapoptotic gene therapy [To understand the molecular mechanisms of cell sheet angiogenesis Sekiya et al., studied both ormation . Kitabay therapy . Moreove therapy . Memon e therapy . Finally therapy . In thisDifficulties in reproducibility in cell injection therapy, including low survival and function of the cells, have led to search for more robust methods. Engineering of 3D cell constructs has currently been under extensive investigation. Preassembled cell constructs might provide effective tools for the future cell therapy research. Establishment of programmable materials used in the cell engineering technology has enabled the creation of scaffold-free cell sheets in a rather simple and inexpensive method. The main aspects of cell sheet construction that must be met for successful regenerative therapy are dynamic, electrical, and histological integration. Increased cell-to-cell communication and survival in cell sheets warrant further attention. The reviewed studies demonstrate the existing potential to produce viable, functional myocardial tissue implantable constructs well beyond the current diffusion-limited thickness regime."} +{"text": "Thus, targeting IAP proteins represents a promising molecular targeted strategy to overcome apoptosis resistance in childhood leukemia, which warrants further exploitation.Inhibitor of Apoptosis (IAP) proteins are a family of proteins with antiapoptotic functions that contribute to the evasion of apoptosis, a form of programed cell death. IAP proteins are expressed at high levels in a variety of human cancers including childhood acute leukemia. This elevated expression has been associated with unfavorable prognosis and poor outcome. Therefore, IAP proteins are currently exploited as therapeutic targets for cancer drug discovery. Consequently, small-molecule inhibitors or antisense oligonucleotides directed against IAP proteins have been developed over the last years. Indeed, IAP antagonists proved to exhibit Cancer cells have typically acquired the ability to evade apoptosis, a form of programed cell death . In addic and second mitochondria-derived activator of caspases (Smac) pathway and the mitochondrial (intrinsic) pathway . Signal s (Smac) . Smac fas (Smac) . By comptivation .The family of IAP proteins comprises eight human analogs . Among tExpression levels of IAP proteins are elevated in a variety of human malignancies including pediatric leukemia, which may be caused by genetic events as well as by transcriptional or posttranscriptional mechanisms. It is important to note that aberrant expression of IAP proteins was described to correlate with adverse patients\u2019 outcome, suggesting that IAP proteins bear a prognostic impact.The prognostic significance of XIAP has been studied in childhood acute myeloid leukemia (AML). XIAP has been associated with adverse prognosis in pediatric leukemia by independent studies showing a correlation of high mRNA and protein expression levels of XIAP and several unfavorable prognostic parameters including high-risk groups for cytogenetics, immature morphology, poor treatment response to induction chemotherapy, and reduced relapse-free survival , 9. ThesIn childhood ALL, a large study comprising the analysis of 222 patients showed that high expression levels of ML-IAP mRNA correlated with a favorable rather than an unfavorable prognosis . In addide novo AML or a locked antisense oligonucleotide was reported to induce apoptosis in leukemia cell lines and also potentiated the chemotherapeutic antileukemic effects \u201327. In aIAP proteins are promising novel targets for molecular targeted therapy in childhood leukemia. Agents antagonizing IAP proteins, including small-molecule inhibitors and antisense oligonucleotides, have been shown to trigger apoptotic and non-apoptotic cell death alone or in combination in preclinical studies in pediatric leukemia. Currently, IAP antagonists are under evaluation in early clinical trials in adult leukemia. Thus, IAP-targeting treatment strategies warrant further clinical investigation in childhood leukemia.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The authors present the endoscopic intranasal orbital decompression, one of the surgical techniques used for orbital decompression. It can be applied for various indications. The most common indications are: maxillo-facial trauma, orbital haemorrhage, subperiorbital abscess as the complication of sinusitis, optic neuropathy, thyroid-associated orbitopathy (Graves\u2019 orbitopathy). The authors conclude that the endoscopic transnasal orbital decompression is a valuable and safe operational technique for patients requiring orbital decompression."} +{"text": "Physiologic (flexible) pes planus (flatfoot) is a descriptive term for feet that have a visually lowered medial longitudinal arch often in association with rearfoot eversion . ReporteA systematic review of randomised, quasi-randomised or controlled clinical trials comparing rigid or semi-rigid functional foot orthoses with: no orthoses or any other approach to managing symptomatic flexible pes planus in the adult. Relevant data bases were searched from inception to October 2011 with studies meeting the predetermined inclusion criteria retrieved and screened by two independent reviewers. No restrictions were placed on type of foot orthoses or alternative interventions. Included studies were independently assessed by two reviewers with risk of bias determined by the Cochrane criteria. Where feasible, meta-analysis will be undertaken.A narrative summary will be presented of the results with outcome measures to include: pain, gait changes , dynamic foot function or static foot posture changes.A determination of the current level/s of evidence for the use of foot orthoses in the adult with symptomatic pes planus."} +{"text": "Tau inclusions composed of tau fibrils are one of the key hallmarks of Alzheimer\u2019s disease and other tauopathies. Studies from transgenic animal models and human AD pathological cases suggest that tau inclusions spread from the transentorhinal cortex to mono and transynaptically connected regions of the hippocampus and neocortical regions. This study examines cell-to-cell propagation of pathological tau in cell culture and in vivo animal models.To study transfer between donor and recipient cells, donor primary neurons isolated from human tau expressing mice (line rTg4510) were co-cultured in microfluidic(MF) chambers with recipients that were either GFP expressing tau knockout, or wildtype neurons (model one). In another model (model two) in which more aggregates were formed, fluorescently tagged pro-aggregating domains of tau (RD) were expressed in neurons using lentivirus; mCherry was used to label the recipient cell population. Immunofluorescence (IF) and live imaging were performed to examine transfer of tau between donor and recipient neurons. To further increase tau aggregate formation (model three), brain-derived tau filaments or full length recombinant tau were used as seeds to induce endogenous tau templating, and the effect on propagation was monitored. To gain insight into possible mechanism of tau transfer between entorhinal cortex (EC) and mono-synaptically connected hippocampal cells, immuno-electron microscopy (IEM) was used to examine tau distribution in donor and recipient cells.1. In both models one and two, endogenously produced tau transferred from donor to recipient cells. Live imaging and IF revealed that donor tau was localized, and accumulated into synapses derived from recipient cells.2. In model three, exogenous aggregated tau was taken up and induced templating of endogenous full-length tau or RD. These tau aggregates transferred from donor to recipient cells in MFs.3. Tissue IEM showed human tau in pre-synaptic terminals derived from EC neurons that express tau transgene, and in post-synaptic compartments derived from recipient granule cell dendrites in the hippocampus.in vitro and in vivo models. Future studies will elucidate the relevance of synaptic accumulation and the mechanism by which propagation occurs.Our data demonstrates that endogenous produced, physiologically relevant tau, aggregates derived from tau fragments and tau generated by templating transferred between neurons in culture. Current data implicates synapses as a point of accumulation for tau during propagation"} +{"text": "Effective improvement in sorghum crop development necessitates a genomics-based approach to identify functional genes and QTLs. Sequenced in 2009, a comprehensive annotation of the sorghum genome and the development of functional genomics resources is key to enable the discovery and deployment of regulatory and metabolic genes and gene networks for crop improvement.Sorghum bicolor exons and UTRs. The genechip contains 1,026,373 probes covering 149,182 exons across the Sorghum bicolor nuclear, chloroplast, and mitochondrial genomes. Specific probesets were also included for putative non-coding RNAs that may play a role in gene regulation , and confirmed functional small RNAs in related species (maize and sugarcane) were also included in our array design. We generated expression data for 78 samples with a combination of four different tissue types , two dissected stem tissues (pith and rind) and six diverse genotypes, which included 6 public sorghum lines representing grain, sweet, forage, and high biomass ideotypes.This study utilizes the first commercially available whole-transcriptome sorghum microarray (Sorgh-WTa520972F) to identify tissue and genotype-specific expression patterns for all identified Here we present a summary of the microarray dataset, including analysis of tissue-specific gene expression profiles and associated expression profiles of relevant metabolic pathways. With an aim to enable identification and functional characterization of genes in sorghum, this expression atlas presents a new and valuable resource to the research community. Its unique and advanced ability to grow in regions of low and variable rainfall highlight its potential to impact agricultural productivity in widespread water-limited environments [\u0394]Ct) [\u0394]Ct) . Gene exhttp://affymetrix.com).The transcriptome dataset supporting the results of this article is available through NCBI's Gene Expression Omnibus (GEO) under accession number GSE49879, and the Sorghum Genome Array is available through Affymetrix . Common: genes expressed in all 78 tissue types .Click here for fileGene Ontology classifications in the biological processes category identified using the AgriGO Singular Enrichment Analysis (SEA).Click here for fileIdentification of stably expressed genes.Click here for fileList of small RNAs included in microarray design.Click here for fileNumber of tissue-specific small RNAs across sorghum ideotypes. AR2400: biomass sorghum; Fremont: sweet sorghum; PI152611: forage sorghum; Common: number of genes in common among all three ideotypes.Click here for fileExpression of select sucrose metabolizing enzyme/transporter genes.Click here for fileExpression of select phenylpropanoid-monolignol biosynthesis pathway genes.Click here for file"} +{"text": "Approximately one third of patients treated with cardiac resynchronization therapy do not derive any detectable benefit. In these patients, acute invasive hemodynamic evaluation can be used for therapy optimization. This report describes the use of systematic invasive hemodynamic measurements for clinical decision making in a patient who experienced severe ventricular arrhythmias and clinical deterioration following a biventricular upgrade. Cardiac resynchronization therapy (CRT) has been established as an effective treatment for heart failure patients with severe left ventricular (LV) systolic impairment and electrical dyssynchrony . UnfortuA 65-year-old male patient with non-ischemic dilated cardiomyopathy, left ventricular ejection fraction of 20%, intra-ventricular conduction delay with a QRS duration of 148 ms, and NYHA class 3 was scheduled for upgrade of an implantable cardioverter defibrillator (ICD) to a cardiac resynchronization therapy - defibrillation (CRT-D) system. The ICD had previously been implanted for primary prevention. Echocardiography prior to the BiV upgrade demonstrated myocardial scarring of the LV lateral wall and showed no evidence of mechanical dyssynchrony. Unfavorable coronary venous anatomy required epicardial LV lead placement in the lateral position via minimal lateral thoracotomy. Four weeks later, the patient was admitted with multiple ICD discharges due to incessant ventricular tachycardia (VT) . He was An invasive hemodynamic pacing study was performed to evaluate the hemodynamic effect of conventional BiV pacing and to explore whether LV endocardial pacing could effectuate hemodynamic improvement. For this purpose, a temporary pacing electrode and a RADI pressure wire were positioned within the LV cavity, another temporary pacing electrode was placed in the right atrium . The RADNeither LV, RV or BiV pacing with the implanted system nor LV endocardial pacing at different sites improved LVdP/dtmax as compared to baseline . FurtherPatient selection plays an important role in CRT response. According to the ESC heart failure guidelines available at the time of device implantation, our patient had a class I indication for CRT . HoweverThe presence of myocardial scar at the area targeted by the LV lead is an important determinant of CRT response . Lead poIn a small percentage of patients, CRT may potentiate ventricular tachyarrhythmias. The exact mechanisms of proarrhythmia remain largely unclear but our findings suggest that pacing in the region of myocardial scar may facilitate its development. This conception is supported by the morphology of the VT which suggested a lateral exit site close to the LV epicardial pacing lead. A suggested underlying mechanism is a potential increase in local myocardial oxygen demand by pacing, precipitating ischemia in the peri-infarct zone and making it vulnerable to re-entry ,9. The cThis case report illustrates the potential contribution of acute invasive hemodynamic evaluation to clinical decision making in CRT. Acute hemodynamic testing may also be considered as a step-up approach to justify implantation of a LV endocardial lead and to guide lead positioning optimization. Finally, this case underlines the importance of considering the possibility of CRT related proarrhythmia, whenever CRT treated patients develop new ventricular tachyarrhythmia's."} +{"text": "Nitric oxide (NO) is a potent biological mediator and plays an important role in cardiovascular homeostasis. Here it activates the soluble guanylyl cyclase (sGC) that synthesizes cGMP. The intracellular second messenger cGMP regulates vascular tone, vascular permeability, modulates inflammation and platelet reactivity. In platelets cGMP activates platelet inhibitory pathways via PKG and thereby inhibits platelet activation. Many cardiovascular diseases e.g. pulmonary arterial hypertension (PAH), are associated to a defective NO signalling. Therefore agents that stimulate the sGC are interesting therapeutic tools for the treatment of several cardiovascular diseases.Riociguat (Bay 63-2561) stimulates the sGC NO-independently without the risk of nitrate tolerance. Clinical Phase II and III studies determined the efficacy and tolerability in pulmonary hypertension patients. Riociguat was well tolerated and also significantly improved exercise capacity and hemodynamic parameters. To further analyse the effects of riociguat on platelet activation we tested the inhibitory effects on functions in isolated platelets and whole blood to elucidate additional applications of riociguat and to estimate adverse effects such as increased bleeding tendencies.In order to study the effects of riociguat on platelet sGC activity we monitored the VASP phosphorylation and cyclic nucleotides in washed platelets. Already low therapeutically relevant doses of 0.1 \u00b5M riociguat increased cGMP levels and VASP phosphorylation significantly. Consistent to these findings ADP induced platelet activation in washed platelets, as shown by platelet shape change, aggregation and integrin activation, was significantly impaired using low doses of riociguat. Additionally adhesion on collagen under shear conditions is significantly reduced in platelet riched plasma. In contrast to that one hundred times higher concentrations of riociguat were needed to obtain a significant increase of VASP phosphorylation as well as a significant inhibition of ADP induced aggregation in whole blood.Our results indicate that riociguat treatment will not lead to an increased bleeding tendency in pulmonary hypertension patients. Additional possible applications of riociguat, where targeting platelet function is beneficial, might be achieved using higher doses of riociguat."} +{"text": "People who have extremely high-arched feet or pes cavus often suffer from substantial foot pain. Custom-made foot orthoses have been shown to be an effective treatment option, but their specificity is unclear. It is generally thought that one of the primary functions of custom foot orthoses is redistribution of abnormal plantar pressures. This study sought to identify variables associated with pain relief after custom foot orthoses intervention.\u00ae in-shoe plantar pressure data from a randomised controlled trial of 154 participants with painful pes cavus were retrospectively re-analysed at baseline and three month post orthoses intervention. The participants were randomised to a treatment group prescribed custom-made foot orthoses or a control group given sham orthoses.Demographic, physical characteristics and Pedarp=0.03). Our final model predicted 73% of the variance in pain relief from custom foot orthoses and consisted of initial pain level, BMI, foot alignment, and changes in both Dynamic Plantar Loading Index and pressure-time integral. Results indicate that a primary function of effective orthotic therapy is redistribution of abnormal plantar pressures.No relationship between change in pressure magnitude and change in symptoms was found in either group. While redistribution of plantar pressure, measured with the Dynamic Plantar Loading Index, had a significant effect on pain relief (This study provides the mechanism by which custom-made foot orthoses reduce pain and disability in patients with painful pes cavus. The proposed model may assist in better designing and assessing orthotic therapy for pain relief in patients with a variety of painful foot disorders."} +{"text": "Environmental Health Perspectives (EHP) established the Paper of the Year in 2008 mouse as an epigenetic biosensor to demonstrate that genistein, the major phytoestrogen in soy, increases DNA methylation of the Agouti gene, resulting in population-level decreased incidence of adult-onset obesity, diabetes, and cancer. At the inception of this study, epidemiological data suggested that increased dietary genistein plays a role in decreased incidence of cancer in Asians compared with Westerners. Thus, they hypothesized that early dietary exposures, including genistein, might be linked to adult health status via epigenetic mechanisms. These authors demonstrated that maternal dietary genistein supplementation of mice during gestation at levels comparable to humans consuming high soy diets shifted the coat color of heterozygous viable yellow agouti (Avy/a) offspring toward pseudoagouti. This phenotypic change was significantly associated with increased methylation of six cytosine\u2013guanine sites in a retrotransposon upstream of the transcription start site of the Agouti gene. A significant finding was that genistein-induced hypermethylation persisted into adulthood, decreasing ectopic Agouti expression and protecting offspring from adult-onset obesity.in utero dietary genistein affects gene expression and alters susceptibility to obesity in adulthood by permanently altering the epigenome. They also established the framework for future studies by showing that both genistein and methyl donors, such as folic acid, betaine, and choline, counteract DNA hypomethylation caused by bisphenol A, an endocrine-active agent used to make polycarbonate plastic. Their results showed that simple dietary changes can protect against the deleterious effects of environmental toxicants on the fetal epigenome (pigenome .EHP congratulates Dolinoy and colleagues for their contribution to the environmental health science literature. In addition to demonstrating that single-nucleotide polymorphisms can affect environmentally responsive genes, they demonstrated that early nutritionally and environmentally induced epigenetic modifications may be an alternative mechanism underlying individual susceptibilities to environmental agents."} +{"text": "Insecticide Treated Nets (ITNs) remain an important tool for sustained malaria control and play an integral part in malaria elimination strategies. As malaria incidence decreases in holodemic areas, however, proactive and regular use of ITNs may simultaneously decline if risk perception diminishes.In Summer 2012, we conducted a cross-sectional survey of three communities in Vanuatu: i) where malaria has been locally eliminated (Aneityum), ii) where malaria remains present but with rapidly declining incidence (Ambae), and iii) an urban area where malaria transmission may or may not occur (Efate). Respondents were asked a battery of questions regarding knowledge of malaria, ITN possession and use, and compliance with other anti-malaria interventions. Information on basic demographics, education levels, dietary habits and household economic activities were also recorded.Residents of Aneityum reported near universal use of ITNs, but uneven knowledge of malaria, particularly in younger individuals born around the time of malaria elimination. Residents in the other communities reported less consistent, though high levels of ITN use despite past individual malaria diagnoses.Results indicate that achieving sustained high levels of ITN use in near- and post-elimination contexts is possible, but that maintaining awareness could present a long-term challenge to prevent reintroduction and recrudensence. Sustained local community cooperation will be essential to maintaining elimination efforts worldwide."} +{"text": "Implantable cardioverter defibrillator (ICD) is the currently accepted treatment for prevention of sudden cardiac death (SCD). Left ventricular ejection fraction is the only useful tool currently available to risk stratify patients at risk of SCD. Several other parameters have been studied for further risk stratification of SCD. Selection of appropriate subjects will improve the efficacy of treatment and also avoid unwanted ICD implantations in low risk patients. Role of QRS duration, QT dispersion, signal-averaged ECG, heart rate variability, ambulatory ECG monitoring, heart rate turbulence, T wave alternans, baroreceptor sensitivity and heart rate recovery have been investigated to identify patients at higher risk of arrhythmia and sudden cardiac death. However, none of these non-invasive tests could reliably stratify patients at risk of sudden cardiac death .Fragmented QRS complex (fQRS) has been identified as one of the non-invasive markers of mortality and sudden cardiac death . fQRS haIn this issue of the journal Apiyasawat et al have repThus based on the available data in the literature, fQRS cannot be reliably used for risk stratification of SCD currently. More understanding is needed on the relation between fQRS, scar burden and arrhythmia inducibility before i"} +{"text": "Myocardial PVM may be used to assess peak velocities and the times to those peaks (TTP) in order to characterise healthy and pathological regional heart motion . HoweverAn efficient navigator-gated spiral trajectory PVM sequence was used to scan basal, mid-ventricular and apical short-axis slices in ten healthy volunteers on two separate occasions. Retrospective cardiac gating was implemented, allowing analysis of all major velocity peaks throughout the cardiac cycle, including atrial systole. The reproducibility of peak velocities and their TTP values was assessed by Bland Altman analysis. Analysis of TTP vales was repeated after normalisation to a fixed systolic and diastolic length.Reproducibility data are shown in Table High temporal resolution myocardial PVM with retrospective cardiac gating is a highly reproducible technique for measuring all peak velocities in the cardiac cycle, including those in atrial systole. Absolute and normalised systolic TTP values have comparable reproducibility. However the reproducibility of diastolic TTP values is improved following normalisation to a fixed systolic and diastolic length. This is particularly apparent for the late diastolic peak representing atrial systole.The authors acknowledge the support of Heart Research UK, Imperial College London and NIHR Royal Brompton Cardiovascular Biomedical Research Unit."} +{"text": "Many drugs are characterized by polypharmacological mechanisms of action. Thus, prospective drug discovery studies often start by testing large compound libraries in multiple and diverse High-Throughput Screening (HTS) assays. These large heterogeneous data collections pose numerous computational challenges concerning processing, curation, and analysis of untreated output files generated by plate readers. We have developed the freely-accessible HTS Navigator software to enable and facilitate the processing and analysis of polypharmacological HTS data. We report on the capabilities of Navigator and present several case studies where we employed cheminformatics approaches embedded within the Navigator to curate and analyze large datasets of compounds tested toward different panels of targets. Examples include libraries of compounds tested for their inhibition potencies across several CYP450; or for their inhibition of multiple protein kinases; or their binding profiles against multiple GPCRs. We show how to quickly identify and highlight compounds with unique mono- and dual- selectivity for certain targets in the curated HTS matrix. We discuss the problem of experimental variability in HTS data and its consequences for molecular modeling and emphasize the synergistic potential of different cheminformatics approaches to detect both false-positive and false-negative compounds using neighborhood analysis and target baseline correction factors. Finally, we describe the Chemical\u2212Biological Read-Across (CBRA) approach also imp"} +{"text": "Migraine attacks originate in the meninges which are densely innervated by trigeminal nerve fibers. Stimulated endothelial cells of dural blood vessels secrete nitric oxide, where neuropeptides are released from trigeminal nerve fibers. This, in turn, leads to meningeal Plasma Protein Extravasation (PPE), serving as an established indicator for migraine attacks in animal models. In our mouse migraine model, we sensitized mice against the 5-HT2B receptor agonist meta-chlorphenylpiperazine (mCPP). Mice kept under hypoxic conditions for four weeks displayed significantly elevated PPEs in the dura mater upon mCPP injection. Tissue accumulation of the tracer Evans Blue was measured to quantify the extent of the PPE. In this study, several histological tracers were employed to identify the part of the vasculature where PPE occurs and the cellular mechanism associated with it. Injections of BSA-FITC verified the mCPP induced PPE in the dura mater. After leaving the blood vessels, the tracer was incorporated into perivascular, CD68-positive macrophages. With electron microscopic studies using the tracer HRP (horse radish peroxidase) we demonstrated that the PPE is associated with increased transcytotic transport. After 5-HT2B receptor activation, HRP escapes from capillaries and venules of hypoxic mice via an increased transcytotic transport in the endothelium. The hypoxic treatment itself increases transcytosis in arterioles, which may be indicative of a proinflammatory state of the endothelium. HRP was also detectable in intercellular clefts, but was always retained at tight junctions In summary, we demonstrated that in mice hypoxic treatment induces dural PPE via increased transcytotis at arterioles and that this is elevated to capillaries and venules after mCPP-injection."} +{"text": "Paradoxical embolus through a patent foramen ovale is a well-reported phenomenon. Clinical consequences include stroke, intestinal infarction, lower limb ischaemia, and even acute myocardial infarction (MI), via embolisation to the coronary arteries. We present a case of acute MI, cardiogenic shock, and cardiac arrest caused not by this mechanism, but by embolisation of thrombotic material to the aortic root with transient complete occlusion of the left main stem (LMS) coronary artery. During percutaneous coronary intervention to treat this occlusion the thrombus became lodged at the aortic bifurcation causing lower limb ischaemia. Despite successful treatment of this via bilateral groin exploration and thromboembolectomy the patient became increasingly acidotic and an abdominal and pelvic CT scan was performed. This revealed the source of the thrombus to be the patient's congested and compressed pelvic veins which were the result of a large, previously undiagnosed ovarian malignancy with metastatic spread. Although very unusual we feel this case highlights an important differential in the diagnosis of anterolateral MI and images similar to those presented here are previously unreported in the literature. Paradoxical embolus through a patent foramen ovale is a well-reported phenomenon. Clinical consequences include stroke, intestinal infarction, lower limb ischaemia, and even acute myocardial infarction (MI), via embolisation to the coronary arteries. We present a case of acute MI, cardiogenic shock, and cardiac arrest caused not by this mechanism, but by embolisation of thrombotic material to the aortic root with transient complete occlusion of the left main stem (LMS) coronary artery.A 57-year-old woman presented acutely to the primary percutaneous coronary intervention (PCI) service at our institution with a history of indigestion-type symptoms for several hours followed by acute shortness of breath, back, and chest pain. She was previously fit and well with no personal or family history of cardiac disease. Her electrocardiogram (ECG) showed typical changes of anterolateral ST elevation myocardial infarction (STEMI) and she was transferred immediately to the catheterisation lab. The patient was haemodynamically unstable with signs of cardiogenic shock; femoral arterial and venous sheaths were inserted on arrival. Initial coronary angiography revealed a large irregular mass in the aortic root causing 1) branch consistent with microembolisation. These findings were confirmed on transoesophageal echo (TOE) which also demonstrated anterior wall akinesis (as expected) and a patent foramen ovale with a small left-to-right shunt. However, an angiogram of the distal aorta revealed occlusion of the left common iliac artery with compromised lower limb circulation evident both angiographically , aortic root thrombus, or possible dissection. On return of cardiac output (within minutes) a repeat aortogram via the coronary guide-catheter was performed . Surprisphically and clinAt this stage a vascular surgery opinion was sought and the decision made to perform urgent open groin exploration with thromboembolectomies bilaterally in the cardiac cath-lab. The patient remained critically unwell and required an intra-aortic balloon pump as well as increasing inotropic support to augment cardiac output. Successful catheter trawl proximally and distally restored lower limb perfusion and embolic material was sent for emergent histology, whilst four-compartment calf fasciotomies were performed to prevent the development of subsequent compartment syndrome. Despite this acute management the patient's clinical state continued to deteriorate with worsening metabolic acidosis, rising lactate levels, and falling blood glucose.An urgent CT scan was undertaken to exclude significant mesenteric ischaemia, however, this revealed the presence of a huge ovarian tumour with pelvic venous congestion, thrombus, and evidence of widespread metastatic spread or \u201comental cake\u201d. There was no evidence of bowel, renal or liver ischaemia however the patient continued to deteriorate and ITU support was sadly withdrawn after consultation with the patients' family and clinical team. Blood tests taken prior to deterioration did not reveal any evidence of thrombophilia although routine clotting parameters were deranged due to the patient's poor clinical state. A postmortem examination reinforced the clinical and radiological findings Figures and 5 anAlthough a sad and thankfully rare case, we feel this paper illustrates an important differential in the cause of acute myocardial infarction. Paradoxical embolus through a patent foramen ovale is a well-reported phenomenon. Clinical consequences include stroke, intestinal, or renal infarction, and lower limb ischaemia. Paradoxical embolism to the coronary arteries has been previously proposed as a cause of MI and bothTo our knowledge this is the first report of a venous thromboembolism causing complete coronary artery occlusion and subsequent iliac obstruction after entering the arterial circulation via PFO. As such this is a novel condition which highlights many learning points in terms of diagnosis and management, not least the importance of multidisciplinary team working between surgical, radiological, cardiological, and anaesthetic colleagues."} +{"text": "Macropus and Wallabia) exhibit more expansive areas of high radiodensity in the distal tibia than arboreal or terrestrial quadrupeds , which may reflect the former carrying body weight only through the hind limbs. Arboreal quadrupeds exhibit smallest areas of high radiodensity, though they differ non-significantly from terrestrial quadrupeds. This could indicate slightly more compliant gaits by arboreal quadrupeds compared to terrestrial quadrupeds. The observed radiodensity patterns in marsupial tibiae, though their statistical differences disappear when controlling for phylogeny, corroborate previously documented patterns in primates and xenarthrans, potentially reflecting inferred limb use during habitual activities such as locomotion. Despite the complex nature of factors contributing to joint loads, broad observance of these patterns across joints and across a variety of taxa suggests that subchondral radiodensity can be used as a unifying form-function principle within Mammalia.Joint surfaces of limb bones are loaded in compression by reaction forces generated from body weight and musculotendon complexes bridging them. In general, joints of eutherian mammals have regions of high radiodensity subchondral bone that are better at resisting compressive forces than low radiodensity subchondral bone. Identifying similar form-function relationships between subchondral radiodensity distribution and joint load distribution within the marsupial postcranium, in addition to providing a richer understanding of marsupial functional morphology, can serve as a phylogenetic control in evaluating analogous relationships within eutherian mammals. Where commonalities are established across phylogenetic borders, unifying principles in mammalian physiology, morphology, and behavior can be identified. Here, we assess subchondral radiodensity patterns in distal tibiae of several marsupial taxa characterized by different habitual activities . Computed tomography scanning, maximum intensity projection maps, and pixel counting were used to quantify radiodensity in 41 distal tibiae of bipedal (5 species), arboreal quadrupedal (4 species), and terrestrial quadrupedal (5 species) marsupials. Bipeds ( Dendrolagus; Dendrolagus), in that the former are able to decouple speed and cost of transport Eutherian and metatherian lineages diverged approximately 160 million years ago Eutherian mammals and marsupials Compressive strength of subchondral bone is determined by mineral content and porosity Primates and xenarthrans exhibit subchondral radiodensity patterns that corroborate theoretical expectations of limb loading according to their habitual activity patterns . Human distal radii exhibit lower weight-bearing (compressive) loads compared to suspensory and quadrupedal primates, as would be expected since human forelimbs no longer have an active weight-bearing role in locomotion Mammalia. In order to achieve these aims, we test two predictions. First, bipedal marsupials should exhibit significantly more expansive high radiodensity area in the distal tibia compared to quadrupedal marsupials because of the unique mechanics of their hopping gait, and because they carry body weight only through the hind limbs rather than all four limbs . Second, high radiodensity area in distal tibiae of terrestrial quadrupedal marsupials should exceed high radiodensity area in distal tibiae of arboreal quadrupedal marsupials because the latter may systematically adopt a more compliant gait, and/or systematically use more compliant arboreal substrates . If observed relationships between high radiodensity patterns and limb use in marsupials are consistent with previously documented relationships in eutherian mammals , it would be reasonable to elevate these relationships to unifying form-function principles throughout Mammalia.The goals of this study are two-fold. First, we aim to document whether a form-function relationship exists in radiodensity patterns in subchondral bone of marsupial distal tibiae. Second, we evaluate whether radiodensity patterns of subchondral bone exhibit a unifying form-function principle within The study sample consists of data derived from 41 marsupial tibiae housed in collections curated at the: Australian Museum (AM), Australian National Wildlife Collection (ANWC), Queensland Museum (QM), and Tasmanian Museum (TM) maps from the standard reconstructions and fitted them to 3D renderings of distal tibiae generated from the bone reconstructions Following field observations and locomotor descriptions Ratio distributions for gait groups did not differ significantly from normal distributions according to a series of Kolmogorov-Smirnov Tests (p>0.05). Thus, we applied a series of one-way ANOVAs in order to statistically evaluate observed differences between gait group means . Gait grphytools package In our sample, some marsupial taxa representing gait groups are also closely related . In order to tease apart the extent to which observed gait group differences may have reflected phylogeny and function, we performed a second set of ANOVAs in which we accounted for phylogenetic effects (pANOVAs). We constructed a phylogenetic tree with known divergence dates for taxaDendrolagus) has a comparatively low mean ratio of 0.017 (n\u200a=\u200a2). When accounting for phylogeny, the comparison of species means eliminates statistical significance again has a comparatively low mean ratio of 0.300 (n\u200a=\u200a2) compared to other macropods. When accounting for phylogeny, the comparison of species means eliminates statistical significance , the ankle was observed to be the greatest contributor to whole limb work and power over a range of accelerations and decelerations The distinctiveness of distal tibiae of bipedal marsupials corroborates findings of others who have noted distinctiveness of the calcaneus of bipedal marsupials It was unexpected that mean radiodensity ratios of arboreal and terrestrial quadruped marsupials did not differ significantly. Arboreal quadrupedal primates exhibit gait compliancy compared to terrestrial quadrupedal primates, and thus limbs of the former experience lower peak vertical components of SRFs A second potential explanation for the unexpected non-significant difference between arboreal and terrestrial marsupial quadrupeds could be related to the application of such rigid gait and substrate use categories in the first place. There are a wealth of primate observational data on locomotor activities and substrate use Vombatus and Lasiorhinus) and non-fossorial terrestrial quadrupeds would facilitate another potentially interesting comparison within marsupials. Wombats are described as emphasizing forelimbs during digging, while their hind limbs are primarily relegated to clearing accumulated sediment Expanding samples of fossorial , the observed trend exhibited by bipedal and quadrupedal marsupials adds to the accumulating evidence suggesting that the relationship between relative area of maximum radiodensity and joint compressive loads in limbs may be a unifying form-function principle amongst eutherian and metatherian mammals. By demonstrating how behavior influences morphology in a variety of mammals, these unifying principles support the existence of form-function signals in skeletal tissues that often elude comparative functional anatomists.Table S1Specimen information and raw data used in analyses.(XLS)Click here for additional data file.Table S2Nexus tree file used in the pANOVA. The phylogenetic tree with known divergence dates for taxa in the sample is based on recent molecular studies of marsupials (NEX)Click here for additional data file."} +{"text": "Osteonecrosis after craniofacial radiation (ORN), osteomyelitis and bisphosphonates related necrosis of the jaw (BRONJ) are the predominant bone diseases in Cranio- and Maxillofacial surgery. Although various hypothesis for the pathophysiological mechanisms including infection, altered vascularisation or remodelling exist, the treatment is still a challenge for clinicians. As the classical pharmacological or surgical treatment protocols have only limited success, stem cells might be a promising treatment option, indicated by recently published data. In maxillofacial surgery clinicians face three diseases of the jaws predominantly: osteonecrosis after craniofacial radiation (ORN), osteomyelitis and bisphosphonates related necrosis of the jaw (BRONJ). Numerous reports exist suggesting various pathological mechanisms and treatment modalities for these diseases ,2. Altho"} +{"text": "Transcranial direct current stimulation (tDCS) is a promising tool for cognitive enhancement and neurorehabilitation in clinical disorders in both cognitive and clinical domains . Here we suggest the potential role of tDCS in modulating cortical excitation/inhibition (E/I) balance and thereby inducing improvements. We suggest that part of the mechanism of action of tDCS can be explained by non-invasive modulations of the E/I balance. Cognitive enhancement is a popular topic in the neuroscience community. Non-invasive neuromodulation methods, such as transcranial direct current stimulation (tDCS) can either increase or decrease cortical excitability studies have shown that anodal tDCS reduces local concentrations of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), whereas cathodal tDCS reduces excitatory glutamate levels receptors and brain-derived neurotrophic factor (BDNF) in the synaptic potentiation of the motor cortex after anodal tDCS balance, measured by ratios of glutamate/GABA, may provide more meaningful interpretations of individual cognitive performance and deficits than glutamate or GABA alone. GABA and glutamate contribute in a complementary fashion to high-level prefrontal cognitive performance in healthy adults and transcranial alternating current stimulation (tACS) is currently unknown and requires further exploration.Roi Cohen Kadosh filed a patent for an apparatus for improving and/or maintaining numerical ability."} +{"text": "RPE65) gene. Tremendous challenges still lie ahead to extrapolate these studies to other retinal disease-causing genes, as human gene augmentation studies require testing in animal models for each individual gene and sufficiently large patient cohorts for clinical trials remain to be identified through cost-effective mutation screening protocols.Retinal dystrophies cause severe visual impairment due to the death of photoreceptor and retinal pigment epithelium cells. These diseases until recently have been considered to be incurable. In the last two decades genetic studies have shed light on the molecular causes of several of these diseases, which has opened new avenues to develop therapeutic approaches. The mammalian eye has been at the forefront of therapeutic trials based on gene augmentation in humans with Leber congenital amaurosis, an early-onset recessive retinal dystrophy, due to mutations in the retinal pigment epithelium-specific protein 65 kDa (Pharmacological approaches to antagonize retinal degeneration are also under development, including modulation of the immune system."} +{"text": "While the effects of hypoxia on stem cells have been examined under in vivo hypoxia on a recently characterized population of pluripotent stem cells known as very small embryonic-like stem cells (VSELs) by whole-genome expression profiling and measuring peripheral blood stem cell chemokine levels.We investigated the effects of We found that exposure to hypoxia in mice mobilized VSELs from the bone marrow to peripheral blood, and induced a distinct genome-wide transcriptional signature. Applying a computationally-intensive methodology, we identified a hypoxia-induced gene interaction network that was functionally enriched in a diverse array of programs including organ-specific development, stress response, and wound repair. Topographic analysis of the network highlighted a number of densely connected hubs that may represent key controllers of stem cell response during hypoxia and, therefore, serve as putative targets for altering the pathophysiologic consequences of hypoxic burden.A brief exposure to hypoxia recruits pluripotent stem cells to the peripheral circulation and actives diverse transcriptional programs that are orchestrated by a selective number of key genes. Hypoxia is a pathophysiologic condition commonly seen in lung diseases and in many other disorders such as tissue ischemia and cancer . In the et al isolated a homogenous population of rare, small stem cells from adult murine BM mononuclear cells that expressed embryonic lineage markers, and were thus named very small embryonic-like stem cells (VSELs) .Click here for fileGene product interaction network of differentially expressed genes in VSELs. This file contains two figures depicting a gene product interaction network of differentially expressed genes in VSELs after in vivo exposure to hypoxia. Panel (A) highlights up and downregulated genes (red and green respectively). This network has 424 genes (nodes) and 604 connections (edges). Note that each connection represents a known direct interaction between two gene products. Panel (B) demonstrates that the topology of this network is scale-free because it follows a power law distribution. Nk, degree distribution; k, nodal connectivity.Click here for file"} +{"text": "The great importance of cytological examination in diagnostic procedures of thyroid gland pathological lesions is widely known. Unfortunately, cytology as a diagnostic method presents many limitations due to possible presence of elements abnormal for thyroid gland physiology and histology. Especially difficult in cytological diagnosis appear: among non-neoplastic lesions - dyshormonogenetic and amyloid goiter and Riedel disease and among neoplastic lesions - rare microscopic variants of tumours, neoplasms arising from ectopic tissues and nonepithelial tumours."} +{"text": "Human monoclonal antibodies have been characterized recently that potently neutralize HIV-1 isolates across all clades. These exciting new antibodies (PGT series) were derived from direct functional screening of B cells from IAVI protocol G donors (Theraclone/Monogram) and are unusually potent with binding predicted to be to novel glycan-dependent epitopes on Env.Structures of these new PGT antibodies are being determined by x-ray crystallography and electron microscopy with further characterization using binding and mutagenesis assays.The crystal and EM structures so far have been elucidated for many of these antibodies. Work on the others are in progress, focusing on Fab complexes with glycans, gp120 core and fragment constructs, as well as Env trimers.Structural characterization and biochemical analysis of these antibodies have uncovered novel specificities to new glycan-dependent epitopes and reveal further mechanisms for viral neutralization. These new epitopes provide additional insights for neutralization of HIV-1 and how antibodies can bind and penetrate the glycan shield, a novel framework for structure-assisted vaccine design.This study was supported by the International AIDS Vaccine Initiative (IAVI), Ragon Institute of MGH, MIT and Harvard, and NIH AI84817."} +{"text": "Self-organized criticality refers to the spontaneous emergence of self-similar dynamics in complex systems poised between order and randomness. The presence of self-organized critical dynamics in the brain is theoretically appealing and is supported by recent neurophysiological studies. Despite this, the neurobiological determinants of these dynamics have not been previously sought. Here, we systematically examined the influence of such determinants in hierarchically modular networks of leaky integrate-and-fire neurons with spike-timing-dependent synaptic plasticity and axonal conduction delays. We characterized emergent dynamics in our networks by distributions of active neuronal ensemble modules and rigorously assessed these distributions for power-law scaling. We found that spike-timing-dependent synaptic plasticity enabled a rapid phase transition from random subcritical dynamics to ordered supercritical dynamics. Importantly, modular connectivity and low wiring cost broadened this transition, and enabled a regime indicative of self-organized criticality. The regime only occurred when modular connectivity, low wiring cost and synaptic plasticity were simultaneously present, and the regime was most evident when between-module connection density scaled as a power-law. The regime was robust to variations in other neurobiologically relevant parameters and favored systems with low external drive and strong internal interactions. Increases in system size and connectivity facilitated internal interactions, permitting reductions in external drive and facilitating convergence of postsynaptic-response magnitude and synaptic-plasticity learning rate parameter values towards neurobiologically realistic levels. We hence infer a novel association between self-organized critical neuronal dynamics and several neurobiologically realistic features of structural connectivity. The central role of these features in our model may reflect their importance for neuronal information processing. The intricate relationship between structural brain connectivity and functional brain activity is an important and intriguing research area. Brain structure is thought to strongly influence and constrain brain function . Concurrently, brain function is thought to gradually reshape brain structure, through processes such as activity-dependent plasticity . In this study, we examined the relationship between brain structure and function in a biologically realistic mathematical model. More specifically, we considered the relationship between realistic features of brain structure, such as self-similar organization of specialized brain regions at multiple spatial scales and realistic features of brain activity, such as self-similar complex dynamics poised between order and randomness . We found a direct association between these structural and functional features in our model. This association only occurred in the presence of activity-dependent plasticity, and may reflect the importance of the corresponding structural and functional features in neuronal information processing. The temporal and spatial statistics of EEG, ECoG, MEG and fMRI signals likewise show power-law scaling Self-organized criticality is increasingly postulated to underlie the organization of brain activity Brain dynamics are thought to be strongly influenced by neuroanatomical connectivity The presence of an intuitive association between self-similar brain structure and self-similar brain dynamics , has not been previously examined. The relationship between brain structure and dynamics is reciprocal: while the structure strongly constrains the dynamics, the dynamics continuously modify the structure through mechanisms such as activity-dependent synaptic depression A number of modeling studies recently reported self-organized critical avalanche dynamics in neuronal networks with nontrivial topology and activity-dependent plasticity The fundamental organizational unit of our network model is a densely connected 100-neuron module The studied leaky integrate-and-fire neuron evolves according toormation .For a postsynaptic neuron Synaptic weights changed at every spike of a neuron incident to the synapse, according to a spike-timing-dependent plasticity (STDP) rule . The STDibutions . The uniParameter values of the model were adapted from the Thivierge and Cisek Each network comprised l levels . The denff rates . SynapseThe wiring cost associated with each scaling function was computed by estimating the number of synapses in each hierarchical level for that function, equating the cost of each synapse with the number of its hierarchical level to other meaningful changes in neurobiologically relevant parameters, such as changes in external current, changes in conduction delays, changes in the postsynaptic response, presence of neuronal inhibition, changes in the STDP rule and changes in network size . Theoretvity see , but begweakened , top, buweakened , bottom.in vivo each neuron is thought to have thousands of synapses. We compensated for the small number of connections in our model by setting the postsynaptic-response magnitude of each neuron to a value which could theoretically exceed the neuron spike threshold and by using an instantaneous STDP learning rate that substantially exceeds empirically observed values and self-similarity of dynamics . We now discuss the mechanisms behind this association, and the implication of our findings for empirical research.We found that despite seemingly stable neuronal activity, spike-timing-dependent plasticity enabled coherent within- and between-module neuronal activity. Furthermore, we showed that two variations of the STDP rule produced distinct weight distributions, but enabled a broad critical regime on conducive network topologies. In contrast, fixed or randomly altered synaptic weights were associated with subcritical dynamics and negligible module spike rates. STDP may facilitate coherent within-module activity by intermittently potentiating and depressing synapses between reciprocally connected neurons. In small networks, simulations showed that intermittent synaptic potentiation and depression was associated with pairwise neuronal synchrony, fluctuations of synaptic weights and continuous reversal of phase differences between reciprocally connected pairs of neurons (results not shown). In our networks, within-module weights were potentiated during module spikes, and depressed between module spikes . These aRecent studies have shown the importance of short-term synaptic depression in self-organized critical dynamics in networks of spiking neurons, but have not concurrently considered the effects of STDP Modular networks with low wiring cost showed a broad critical regime. Modular networks with high wiring cost showed a narrow critical regime, possibly due to high numbers of costly long-range connections, which enabled a rapid onset of globally synchronous, supercritical dynamics. Lattice networks with low wiring cost showed a narrowed critical regime due to uncoordinated inhibition and a consequent loss of coherent ensemble dynamics. Modularity and low wiring cost were hence simultaneously required for self-organized criticality to emerge. This simultaneous requirement is notable, as both properties are thought to be ubiquitously present in neuroanatomical organization.In an early comprehensive exposition, Jensen We found that inhibitory neurons in our model did not explicitly enable a broad critical regime. In contrast, recent network simulations of simple stochastic neurons by Benayoun et al. Our findings may be used to generate empirically testable hypotheses of the relationship between anatomical connectivity and emergent network dynamics. For instance, we hypothesize that self-organized critical dynamics in dissociated neuronal cultures emerge on a low-cost modular neuroanatomical connectivity. Recent studies show that dissociated neuronal cultures self-organize towards a critical state, via subcritical and supercritical states Our findings may hence be used to explicitly compare structure and dynamics of dissociated neuronal cultures, throughout this period of self-organization. A recent study found that functional activity patterns of dissociated neuronal cultures constitute a small-world network A clear limitation of our study is the oversimplified symmetric hierarchical organization and the relatively small size of our model. Substantial increases in the number of modules, and in the number of neurons within modules, are required to make realistic inferences about neuronal dynamics at larger scales. The study hence sets the groundwork for simulations of large networks of spiking neurons and for characterization of spatiotemporal activity patterns emergent on these networks. Such simulations may be conducted on increasingly detailed maps of large-scale anatomical connectivity in healthy subjects Studies of neuronal dynamics often employ numerical integration schemes (such as the Euler method), and manually store all previous spike times to compute synaptic currents. An advantage of the integrate-and-fire neuron model is the ability to integrate subthreshold activity exactly and incorporate effects of all previous spikes without the need for explicit summation at each step Despite growing empirical evidence for self-organized criticality, several important studies argue against this evidence, by either noting the potential for spurious reports of power-law scaling, or by attributing such scaling to simpler mechanisms, such as diffusive processes In conclusion, we show an association between modularity, low cost of wiring, synaptic plasticity and self-organized criticality in a neurobiologically realistic model of neuronal activity. Our findings theoretically reinforce the reciprocal relationship between connectivity and dynamics on multiple spatial scales.Text S1Supporting information code.(PDF)Click here for additional data file.Text S2Supporting information code.(TXT)Click here for additional data file.Text S3Supporting information code.(TXT)Click here for additional data file.Text S4Supporting information code.(TXT)Click here for additional data file.Text S5Supporting information code.(TXT)Click here for additional data file.Text S6Supporting information code.(TXT)Click here for additional data file.Text S7Supporting information code.(TXT)Click here for additional data file.Text S8Supporting information code.(TXT)Click here for additional data file.Text S9Supporting information code.(TXT)Click here for additional data file.Text S10Supporting information code.(TXT)Click here for additional data file.Text S11Supporting information code.(TXT)Click here for additional data file.Text S12Supporting information code.(TXT)Click here for additional data file.Text S13Supporting information code.(TXT)Click here for additional data file.Text S14Supporting information code.(TXT)Click here for additional data file.Text S15Supporting information code.(TXT)Click here for additional data file.Text S16Supporting information code.(TXT)Click here for additional data file.Text S17Supporting information code.(TXT)Click here for additional data file."} +{"text": "The role of cortical feedback in thalamo-cortical processing loop have been extensively investigated over the last decades. In general, these studies focused on cortical feedback exerted over lateral geniculate nucleus (LGN) principal cells, only in several cases the effects of cortical inactivation were investigated simultaneously in both thalamic relay cells and perigeniculate nucleus (PGN) inhibitory neurons. In the previous study we showeTo identify network mechanisms underlying such functional changes we conducted a modelling study in NEURON on several networks of point neurons with varied model parameters, such as membrane properties, synaptic weights and axonal delays. We considered five network topologies of the retino-geniculo-cortical pathway -6.All models were robust against changes of axonal delays except for delay between LGN feed-forward interneuron and principal cell when this connection was present. In all such cases the models were found to be very sensitive to this delay. To reproduce the experimental results the mode"} +{"text": "Pulmonary tumor thrombotic microangiopathy is a rare complication of malignant diseases. The diagnosis is extremely difficult and is most often performed after death. Invariably, patients develop acute pulmonary hypertension causing right heart failure, shortness of breath and death in a few days. We describe the clinical and radiological findings of a patient who presented with this complication.A 28-year-old Caucasian woman with a previous history of pelvic tumor resection two months previously, suggestive of metastatic adenocarcinoma, presented with intense shortness of breath. A computed tomography scan showed signs of acute cor pulmonale and diffuse nodular opacities associated with a tree-in-bud pattern disseminated through her lungs, suggestive of bronchiolitis. Our patient's condition worsened and she underwent a surgical biopsy. Pathologic analysis of the biopsied specimens revealed pulmonary tumor thrombotic microangiopathy. Our patient's tumor evolved from a gastric origin (Krukenberg tumor). She underwent progressive clinical deterioration and died less than 24 hours after the biopsy. None of the cases described previously in the literature had diffuse centrilobular nodular opacities associated with a tree-in-bud pattern disseminated through the lungs, as in our case.Pulmonary tumor thrombotic microangiopathy should be considered in cancer patients with rapidly progressing dyspnea, chest computed tomography findings compatible with pulmonary hypertension and typical findings of inflammatory bronchiolitis. Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare complication of malignant diseases. The diagnosis is extremely difficult and is most often performed after death . InvariaA 28-year-old Caucasian woman presented to our hospital with a previous history of abnormal vaginal bleeding and abdominal pain that had begun four months prior to her initial presentation. A transvaginal ultrasound was performed at that time and demonstrated solid lesions in her left adnexal region, confirmed two weeks later with magnetic resonance imaging. She then underwent an exploratory laparotomy with a bilateral anexectomia. A pathological examination diagnosed a solid poorly differentiated adenocarcinoma, with signet ring cells diffusely infiltrating the ovaries and fallopian tubes bilaterally, compatible with a metastatic pelvic tumor of probable gastric origin, traditionally known as a Krukenberg tumor. After surgery, during the staging and treatment planning, our patient presented to our Emergency Room complaining of dry cough and shortness of breath of recent onset, with intense and progressive worsening. She had no other complaints and no fever. On examination, she was in generally poor condition, malnourished, dehydrated, with tachycardia and dyspnea; pulmonary auscultation revealed decreased breath sounds and mild wheezing in both lungs. Her leukocyte count showed no signs of infection; a blood test revealed the presence of mild anemia and a chest X-ray showed no abnormalities. Due to clinical suspicion of a pulmonary thromboembolism, our patient underwent a computed tomography (CT) scan of her chest, pelvis and thighs. Although the angiographic phase did not present any signs of pulmonary thromboembolism, the CT scan showed signs of acute cor pulmonale characterized by increased right heart chamber dimensions, slight interventricular septum deviation and a right ventricular to left ventricular ratio greater than 1.5 Figures , 4 and 5Laboratory investigations were remarkable for microcytic anemia and a strongly positive D dimer (1100 ng/mL). Her arterial blood gas examination breathing room air showed hypoxia with respiratory alkalosis . Our patient was admitted with a presumptive diagnosis of pulmonary thromboembolic disease.PTTM is a rare complication of malignancies commonly detected after death. It was first described by von Herbay and colleagues as a diffuse intimal myofibroblast proliferation that causes pulmonary hypertension, leading to cardiopulmonary failure and death . This diDistinguishing between the clinical presentation of lymphatic and microvascular disease can be challenging, and many authors do not distinguish between these two. Soares and colleagues evaluated a series of 222 patients who had undergone autopsy, including 19 with microvascular pulmonary arterial embolism and 44 with lymphangitic carcinomatosis . AlthougOn histopathological investigation, pulmonary tumor thrombotic microangiopathy is characterized by widespread fibrocellular intimal hyperplasia of small pulmonary arteries, also called carcinomatous endarteritis induced by tumor microemboli . DiffuseNone of the cases described previously in the literature had diffuse centrilobular nodular opacities associated with a tree-in-bud pattern disseminated through the lungs, as in our case.PTTM should be considered in cancer patients with a rapidly progressing dyspnea, chest CT compatible with pulmonary hypertension and typical findings of inflammatory bronchiolitis.Written informed consent was obtained from our patient's next of kin for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.All the authors contributed to the writing of the paper. The original manuscript was written by MFA and AB, and the final version by MDG. RC and JLG contributed the CT images and additional references. All authors read and approved the final manuscript"} +{"text": "Ungulates exert a strong influence on the composition and diversity of vegetation communities. However, little is known about how ungulate browsing pressure interacts with episodic disturbances such as fire and stand thinning. We assessed shrub responses to variable browsing pressure by cattle and elk in fuels treated and non-fuels treated forest sites in northeastern Oregon, US. Seven treatment paddocks were established at each site; three with cattle exclusion and low, moderate and high elk browsing pressure, three with elk exclusion and low, moderate and high cattle browsing pressure, and one with both cattle and elk exclusion. The height, cover and number of stems of each shrub species were recorded at multiple plots within each paddock at the time of establishment and six years later. Changes in shrub species composition over the six year period were explored using multivariate analyses. Generalized Linear Mixed Models were used to determine the effect of browsing pressure on the change in shrub diversity and evenness. Vegetation composition in un-browsed paddocks changed more strongly and in different trajectories than in browsed paddocks at sites that were not fuels treated. In fuels treated sites, changes in composition were minimal for un-browsed paddocks. Shrub diversity and evenness decreased strongly in un-browsed paddocks relative to paddocks with low, moderate and high browsing pressure at non-fuels treated sites, but not at fuels treated sites. These results suggest that in the combined absence of fire, mechanical thinning and ungulate browsing, shrub diversity is reduced due to increased dominance by certain shrub species which are otherwise suppressed by ungulates and/or fuels removal. Accordingly, ungulate browsing, even at low intensities, can be used to suppress dominant shrub species and maintain diversity in the absence of episodic disturbance events. Both livestock and wild ungulates commonly occupy high elevation pastures during the summer months in many parts of the globe. In the western United States, most ranchers bring their livestock to high elevation summer pastures that are located within public forest lands Considerable research has been conducted on the separate impacts of fires Odocoileus virginianus) led to loss of preferred woody species which in turn resulted in increased abundance of less palatable understory plants such as sedges Both episodic disturbances The response of vegetation diversity to ungulates can also vary depending on browsing frequency and intensity We measured the compositional and diversity responses of native forest shrubs to variable browsing pressure over several years from dominant ungulate herbivores, cattle and elk, at sites where fuel loads were mechanically removed and followed by prescribed fire, and at sites with no history of fire or fuels removal for 40 years (referred to fuels treated and non-fuels treated respectively from here on). We hypothesized that vegetation responses to browsing would vary between fuels treated and non-fuels treated sites, and that the greatest level of diversity would be achieved at moderate levels of browsing pressure, particularly at non-fuels treated sites where shrub cover and dominance is high.Research was conducted under approval and guidance by an Institutional Animal Care and Use Committee (IACUC 92-F-0004), as required by the United States Animal Welfare Act of 1985, following the IACUC protocol for conducting cattle, elk, and mule deer research in our study area. Permission to perform the study was given by the USDA Forest Service Pacific Northwest Research Station.Our study was carried out within the Starkey Experimental Forest and Range (SEFR) in the Blue Mountains Ecological Province of northeast Oregon , approxiPseudotsuga menziesii) and grand fir (Abies grandis) Conditions at SEFR are typical of montane forest types of interior western North America Pinus ponderosa), western larch , lodgepole pine (Pinus contorta), and Englemann spruce (Picea engelmannii). Common understory grass and grass-like species include Idaho fescue (Festuca idahoensis), elk sedge (Carex geyeri), pinegrass , western fescue , Kentucky bluegrass (Poa pratensis), and annual bromes (Bromus spp.). Common forbs include lupine (Lupinus spp.), strawberry (Fragaria spp.), tall annual willowherb (Epilobium paniculatum), and western yarrow (Achillea millefolium). Common shrub species include bearberry (Arctostaphylos uva-ursi), big huckleberry (Vaccinium membranaceum), grouse huckleberry (Vaccinium scoparium), rose (Rosa spp), snowberry , shinyleaf spiraea (Spiraea betulifolia lucida), twinflower , sticky currant (Ribes viscosissimum), prickly currant (Ribes lacustre), raspberry (Rubus spp.), Saskatoon serviceberry , black hawthorn (Crataegus douglasii), snowbrush (Ceanothus velutinus), willow , oceanspray (Holodiscus discolor), wax currant (Ribes cereum var. cereum), orange honeysuckle (Lonicera ciliosa), Scouler's willow , elderberry (Sambucus spp.), mountain ash (Sorbus scopulina), black cottonwood , and boxleaf myrtle (Paxistima myrsinites).In addition to Douglas-fir and grand fir, other canopy tree species present in these stands include ponderosa pine (Fuels reduction treatments were applied to grand fir and Douglas-fir stands (between 10 and 50 ha in size) in SEFR between 2000\u20132003 Stands were mechanically thinned with a feller-buncher to reduce fuel loadings to <35 tons/ha, compatible with fuel loads considered unlikely to carry stand-replacement fires Following fuels reduction treatment, exclosures ranging in size from five to seven hectares were established at five mixed Douglas-fir and grand-fir forest sites in the SEFR: Half Moon (HM), Louis Spring (LS), Bally Camp (BC), Doug Prairie (DP), and Bee Dee (BD) . Three . The othThe exclosures were established at each site by constructing a fence eight feet in height that excluded all ungulates , but allowed for other wildlife to pass under, over, or through. The exclosures were constructed in the year following the fuels treatments. The size and shape of each exclosure varied with site conditions, including topography, slope, forest structure, and the shape of the forest patch to minimize site variation within and among exclosures. The ungulate exclosures were divided into seven, roughly equal-sized paddocks in which seven different levels of cattle and elk herbivory treatments were randomly assigned and implemented . The levBrowsing intensity for each treatment level was defined in terms of the number of days per ha that elk and cattle use Douglas-fir and grand fir habitat types in the interior northwestern United States, broken down into three levels of forage utilization: high\u201445% utilization; moderate\u201430% utilization; and low\u201415% utilization. These levels typify the range of grazing and browsing use established for cattle on summer ranges in Douglas-fir and grand fir habitat types on public lands like those at SEFR Stocking density for each type of ungulate was then calculated using standard forage allocation procedures The calculated stocking densities were then refined so that the final number of cattle days per ha and elk days per ha for each treatment level corresponded to what was logistically feasible to implement with the tractable animals. Moreover, the number of animals must be compatible with each ungulate's group behavior for foraging and the need to complete the trials in as few days as possible to minimize changes in forage availability and phenology. Consequently, we used 4 elk and 6\u20138 cattle per trial to most efficiently approximate the calculated stocking densities. The diets of elk and cattle tend to converge during late summer in grand fir and Douglas-fir forests 2 plots (4\u00d710 m) were systematically established in each paddock. Due to differences in paddock size and layout, the number of plots per paddock varied (from 12\u201318), though the percent of each paddock sampled remains similar (7\u20139%). Plot locations were determined using real-time differential global positioning system placed in a geographic information system (GIS). Plots were located 15 m apart along transect lines, with each transect line spaced 15 m apart from one another within each paddock. Edges of paddocks were excluded from sampling with a 5 m buffer, and a random starting point was used to determine the starting point of each transect (ranged from 5\u201310 m from the outer edge of exclosure).Permanent 40 mdiversity function in the vegan package The absolute and relative cover of shrub species were estimated using the line-intercept method, with transects running along the center of each 4\u00d710 m plot. Within each 4\u00d710 m plot, all shrub stems \u22651 m in height were identified, counted, and their height measured to the nearest cm. Due to their high abundances, stems <1 m in height were identified, enumerated, and their height and cover measured in a smaller 2\u00d710 m plot through the center of each permanent 4\u00d710 m plot. Shrub abundances were adjusted by dividing the number of stems by the area of the sampling plot area prior to analyses. Sampling occurred in July just before implementation of the browsing treatments, and again in July, after six years of the browsing treatment. Shrub diversity and evenness were calculated for each plot using all species with Simpson index using the The overstory has a strong influence on understory vegetation dynamics in western coniferous forests metaMDS function in the R package vegan Multivariate analyses were carried out to compare the relative changes in shrub species composition across un-browsed paddocks and paddocks under differing levels of browsing pressure by elk and cattle separately. A Non-metric Multidimensional Scaling was conducted using the glmmPQL function of the MASS package plot function in R Because of the nested structure of our sampling design, ungulate treatment effects on vegetation structure were assessed with Generalized Linear Mixed Models GLMM; with theInitial mean shrub cover and height were higher at paddocks within non-fuels treated sites than paddocks within fuels treated sites . Mean shAt non-fuels treated sites, the change in shrub composition was much greater at un-browsed paddocks compared to browsed paddocks, regardless of browsing intensity or ungulate type . The comIn contrast, un-browsed paddocks showed minimal change in shrub composition at fuels treated sites . The amoShrub species diversity and evenness were strongly affected by the interaction between fuels treatment and browsing at all three levels indicatiIn non-fuels treated sites, shrub species diversity and evenness generally did not change over the study period in browsed paddocks regardless of ungulate type or browsing pressure . HoweverOur results demonstrate that ungulates have an important role in maintaining plant diversity in western forest ecosystems in the absence of episodic disturbance events such as fire and/or mechanical fuels removal. This finding agrees with Rambo and Faeth Episodic disturbances provide new growth that is often highly preferred by ungulates While we hypothesized that diversity would be highest at moderately browsed paddocks, shrub diversity was consistently higher at all three levels of browsing pressure compared to ungulate exclusion, and no differences were observed among paddocks under different levels of browsing pressure. This suggests that relatively little browsing, 8 and 10 days per hectare annually for elk and cattle respectively, is needed to suppress dominant shrub species and maintain shrub diversity in this ecosystem. Furthermore, diversity is not reduced under higher levels of browsing pressure, of up to 32 and 30 days per hectare annually for elk and cattle respectively. It has been suggested that reduced diversity occurs once browse-tolerant species become dominant Furthermore, because we conducted our browsing treatments towards the end of the summer when the diet of elk and cattle converge, we cannot conclude from our findings that perennial understory vegetation in western conifer forest is insensitive to browsing pressure or ungulate type. Cattle and elk may have different effects on shrub dominance and diversity patterns at the beginning of the growing season, particularly with high browsing pressure. Accordingly, browsing effects at different times of the year need to be determined to assess how much browsing pressure is required to maintain diversity when herbivory occurs during the spring, early summer, late summer/fall, or a combination of the three with some browsing in each season. The latest scenario is the most realistic since elk and other wild ungulates are likely to visit these sites several times over the growing season.Our findings have important implications for both livestock and wild ungulate management in dry forests of the western United States. First, management decisions to modify ungulate densities on the landscape will result in changes in abundance of different shrub species that could be based on a priori designs to meet vegetation management objectives for other resources, such as the desire to increase abundance of certain shrubs as habitat for wildlife. Second, while specific shrub responses may vary by type of ungulate and by the background site conditions in which herbivory occurs, either cattle or elk can be used to maintain shrub diversity in the absence of episodic disturbances. Consequently, management decisions that alter ungulate browsing patterns should take into consideration other current forest management activities and disturbances that may alter inter-specific interactions, such as prescribed burning and fuels removal. These considerations are particularly important to sustaining biodiversity in seasonally arid and fire-prone forest ecosystems of the Western United States where natural and human-induced disturbances exert strong control on vegetation."} +{"text": "Stroke after internal jugular venous cannulation typically leads to acute carotid or vertebral arteries injury and cerebral ischemia. We report the first case of delayed posterior cerebral infarction following loss of guide wire after left internal jugular venous cannulation in a 46-year-old woman with a history of inflammatory bowel disease. Our observation highlights that loss of an intravascular guide wire can be a cause of ischemic stroke in patients undergoing central venous catheterization. Inadequate placement of a jugular venous catheter is a well-known complication, with serious and immediate secondary complications including stroke. Acute complications are usually associated with injury to contiguous structures , leading0) to segment V3 with no signs of arterial dissection (A 46-year-old woman with a history of inflammatory bowel disease was admitted for recurrence of severe active colitis and treated by intravenous corticosteroids. Left internal jugular venous cannulation was performed for total parenteral nutrition using the Seldinger technique. During catheterization, the patient suddenly experienced transient dizziness and blurred vision. No further problems were observed after withdrawing the catheter. The anaesthetist did not report any inattention during the procedure. Five days after hospital discharge, the patient presented sudden onset of difficult swallowing. Neurological examination revealed left hemiataxia with hypermetria, left Horner's sign, right deviation of the uvula indicating left palatal palsy, and hypoesthesia of the left hemiface. General examination revealed left cervical subcutaneous hematoma with no hemodynamic impairment . Brain mssection . A lost ssection . Cervicassection , and totssection . The guiCases of acute stroke caused by vertebral intimal damage with thrombosis leading to posterior cerebral infarction during internal jugular venous cannulation have been previously reported \u20139, althoIn conclusion, our observation highlights that stroke after catheter placement is scarce but constitutes a major and potentially fatal complication of a benign condition."} +{"text": "Three techniques for the treatment of intractable pancreatic fistula: percutaneous transfistulous pancreatic duct drainage (PTPD), percutaneous transfistulous pancreatojejunostomy (PTPJ), and percutaneous transfistulous pancreatic duct embolization (PTPE) are presented as treatment options for intractable pancreatic fistula. PTPD is effective for most cases of intractable fistula that communicate with the main pancreatic duct. However, PTPD itself is not enough in some specific cases. PTPJ and PTPE are applicable in such cases. Pancreatic fistula (PF) remains a significant problem in the management of pancreatectomy. Despite decreased morbidity and mortality rates after pancreatic resection, PF remains a common and potentially lethal complication after pancreatectomy. Its reported incidence varies from 6 to 38% \u20137. If PFPF also sometimes becomes a significant problem in severe acute pancreatitis. Pseudocysts and postnecrotic collections of the pancreas are treated by percutaneous drainage if they are large and likely to aggravate the patients' condition. Approximately 65\u201390% of patients recover from this disease by percutaneous drainage alone . HoweverTechniques of percutaneous transfistulous drainage of the main pancreatic duct (percutaneous transfistulous pancreatic duct drainage: PTPD) for intractable PF cases are presented. Furthermore, percutaneous transfistulous pancreatojejunostomy (PTPJ) and percutaneous transfistulous pancreatic duct embolization (PTPE) are also presented as advanced techniques of PTPD.This technique is useful for major PF in which the main pancreatic duct is visualized in fistulography , 14. AnyWhen intractable PF is developed after pancreatoduodenectomy, abscess around the pancreatojejunostomy is drained percutaneously at first. Then, drainage catheters are inserted into the pancreatic duct (PTPD procedure) and jejunum, respectively. A guidewire is inserted into the jejunum via percutaneous transfistulous route through the drainage tube. The guidewire, grasped by a basket catheter inserted from the percutaneous transhepatic biliary drainage (PTBD) route under fluoroscopy, is led externally via the PTBD outlet Figures . FinallyLarge postnecrotic collection can be formed owing to disruption of the main pancreatic duct in some severe necrotizing acute pancreatitis Figures . In suchPF represents clinically relevant complications with life-threatening consequences after pancreatic resection and in acute necrotizing pancreatitis. PTPD, PTPJ, and PTPE are presented as treatment options for intractable PF. Visualization of the main pancreatic duct during fistulography indicates that the PF is intractable.The conventional treatment strategy for PF consists of establishing adequate external drainage, treating infection, providing nutritional support, and reducing pancreatic juice secretion by parenteral nutrition or octreotide. With effective drainage, most of the PF can be cured by conservative treatment. However, the management of intractable PF cases has not been standardized and remains challenging. The management of intractable PF is individualized. Several procedures have been reported, including endoscopic drainage, percutaneous intervention , and surTranspapillary stents can bypass the high resistance of the sphincter of Oddi, ductal strictures, and calculi, thereby reducing the intraductal pressure that is the driving force behind the fistula. Endoscopic pancreatic sphincterotomy is also recommended for the treatment of PF after DP . HoweverIn necrotizing pancreatitis, disruption of main pancreatic duct appears to be associated with the most severe form of necrosis , 20. Uom"} +{"text": "Pancreatic cancer shows a characteristic tissue structure called desmoplasia, which consists of dense fibrotic stroma surrounding cancer cells. Interactions between pancreatic cancer cells and stromal cells promote invasive growth of cancer cells and establish a specific microenvironment such as hypoxia which further aggravates the malignant behavior of cancer cells. Pancreatic stellate cells (PSCs) play a pivotal role in the development of fibrosis within the pancreatic cancer tissue, and also affect cancer cell function. PSCs induce epithelial-mesenchymal transition and cancer stem cell (CSC)-related phenotypes in pancreatic cancer cells by activating multiple signaling pathways. In addition, pancreatic cancer cells and PSCs recruit myeloid-derived suppressor cells which attenuate the immune reaction against pancreatic cancer cells. As a result, pancreatic cancer cells become refractory against conventional therapies. The formation of the CSC-niche by stromal cells facilitates postoperative recurrence, re-growth of therapy-resistant tumors and distant metastasis. Conventional therapies targeting cancer cells alone have failed to conquer pancreatic cancer, but targeting the stromal cells and immune cells in animal experiments has provided evidence of improved therapeutic responses. A combination of novel strategies altering stromal cell functions could contribute to improving the pancreatic cancer prognosis. The prognosis of pancreatic cancer remains poor despite diagnostic and therapeutic improvements. A sensitive early detection screening method has not yet become available, and clinical symptoms such as obstructive jaundice or back pain are signs of advanced disease. Most patients are not eligible for curative surgery, due to the local invasion and distant metastasis Hidalgo, . ChemothKras, inactivating mutations of tumor suppressor p16, p53, and Smad4 reside within pancreatic parenchyma and remain in a quiescent state in normal pancreas. Quiescent PSCs contain vitamin A droplets in the cytoplasm than CD10\u2212 PSCs, whose siRNA-based knockdown attenuated the invasive capacity of the pancreatic cancer cells . EMT is characterized by the loss of epithelial phenotypes and gain of mesenchymal phenotypes, increased cellular migration and invasion, which is an indispensable process for the initiation of metastasis are the counterpart of the normal stem cells was correlated with the presence of a fibrotic focus in pancreatic cancer tissue, suggesting desmoplasia provides a hypoxic condition within the tumor or granulocytic MDSC (CD11b+CD15+)] have been reported and mutant p53 (inactivating mutation R172H) in the pancreas, recapitulating human pancreatic cancer including prominent desmoplasia in pancreas (Chang et al., PSCs interact with another type of immune cells, which also promote the growth of pancreatic cancer. Mast cells trigger type I hypersensitivity in various diseases such as bronchial asthma and urticaria (Beunk et al., As summarized in this review, tumor-stromal interaction has pivotal role in pancreatic cancer progression. Interventions directed to the desmoplasia-inducing signaling pathways revealed favorable effects, such as the inhibition of Shh pathway or CTGF pathway in mouse model (Olive et al., Targeting immune cells could be an alternative approach to modify the tumor microenvironment. Restoring the immune reaction could be performed by several agents, such as ATRA or IL-12 in mouse model, which exhibited therapeutic effects (Kerkar et al., Pancreatic cancer is a deadly disease and its establishment proceeds silently. Stromal reaction and escape from immune surveillance are perpetuating systemic changes. The involvement of stromal cell activation and immunosuppression enable cancer cells to remain in a favorable niche, leading to distant metastasis and therapy resistance. A schematic view of the cancer cell-stromal cell interaction is shown in Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "TP63, TERT-CLPTMIL and 8q24.21, to be highly associated with disease risk. Whole transcriptome sequencing (RNA-Seq) is a revolutionary tool for generating a large amount of qualitative and quantitative information, thus helping to explore known and novel transcripts, splicing forms and fusion genes.Bladder cancer is the 9th most common cancer worldwide and the 13th most common cancer-related cause of death. Bladder cancer frequently recurs after the removal of primary carcinomas. This recurrence leads to repeated surgeries and long-term treatment and surveillance, making it the most expensive type of cancer to treat. Genetic factors and environmental factors such as cigarette smoking and occupational exposure to aromatic amines are linked to bladder cancer risk. Genome-wide association studies (GWAS) for bladder cancer have identified multiple genetic variants within genes and regions, including To understand the genetic and genomic landscape of the GWAS susceptibility regions, we investigated and characterized the entire transcriptome of normal and tumor bladder tissue samples by using powerful massively parallel RNA sequencing. We used an Illumina HiSeq 2000 instrument to sequence six paired samples of normal and tumor bladder tissues. For each of the samples, we generated 50 Gb of 100-bp reads to represent the whole transcriptome.Using the Bowtie/TopHat and Samtools packages, we successfully aligned approximately 80% of the total sequence reads against the human genome reference sequence (build 19). Our analysis sought to identify alternative splicing forms, novel exons, non-coding transcripts and chimeric fusion events. Total levels of mRNA in normal and tumor samples were evaluated by Cufflinks analysis based on the Ensembl transcripts database. Multiple splicing isoforms were identified for some of the GWAS susceptibility genes, and some of these isoforms were differentially expressed between the tumor and normal samples. We found that novel transcripts and non-coding RNAs corresponding to gene desert regions such as 8q24 were abundantly expressed. Our next step will focus on validation of these differentially expressed genes and novel transcripts by using quantitative RT-PCR on independent samples.Using RNA-Seq, we explored transcripts corresponding to candidate regions identified by bladder cancer GWAS. Some of these transcripts demonstrated splicing variability and differential levels of expression between normal and tumor tissue samples, which might be of importance for bladder cancer."} +{"text": "Pseudomonas, type III secretion systems (T3SS) and T3 effectors do not appear central to pathogenesis of pectobacteria. Indeed, recent genomic analysis of several Pectobacterium species including the emerging pathogen Pectobacterium wasabiae has shown that many strains lack the entire T3SS as well as the T3 effectors. Instead, this analysis has indicated the presence of novel virulence determinants. Resistance to broad host range pectobacteria is complex and does not appear to involve single resistance genes. Instead, activation of plant innate immunity systems including both SA and JA (jasmonic acid)/ET (ethylene)-mediated defenses appears to play a central role in attenuation of Pectobacterium virulence. These defenses are triggered by detection of pathogen-associated molecular patterns (PAMPs) or recognition of modified-self such as damage-associated molecular patterns (DAMPs) and result in enhancement of basal immunity . In particular plant cell wall fragments released by the action of the degradative enzymes secreted by pectobacteria are major players in enhanced immunity toward these pathogens. Most notably bacterial pectin-degrading enzymes release oligogalacturonide (OG) fragments recognized as DAMPs activating innate immune responses. Recent progress in understanding OG recognition and signaling allows novel genetic screens for OG-insensitive mutants and will provide new insights into plant defense strategies against necrotrophs such as pectobacteria.Soft rot pectobacteria are broad host range enterobacterial pathogens that cause disease on a variety of plant species including the major crop potato. Pectobacteria are aggressive necrotrophs that harbor a large arsenal of plant cell wall-degrading enzymes as their primary virulence determinants. These enzymes together with additional virulence factors are employed to macerate the host tissue and promote host cell death to provide nutrients for the pathogens. In contrast to (hemi)biotrophs such as Pseudomonas syringae and Xanthomonas spp. that rely on living plant cells for nutrient acquisition at least until later stages of infection. Their lifestyle is largely dependent on their ability to avoid and suppress plant defense responses most notably by secretion of effector proteins enabling them to obtain nutrients and multiply within living plant tissue , conserved structures such as the bacterial flagellin essential for the microbial lifestyle . The resPectobacterium and Dickeya are classical and well-studied examples of necrotrophic plant pathogenic bacteria. Their taxonomical classification has been revised several times in recent years. They were first characterized in the early 20th century , i.e., wasabi , P. wasabiae WPP163 (accession: CP001790.1), P. wasabiae SCC3193 and a polyketide phytotoxin to virulence of the bacterium. T4SS machineries translocate DNA and/or proteins across the bacterial cell wall into bacterial or eukaryotic cells but absent from genomes of other Pectobacterium species. These islands contain uncharacterized genes but also genes encoding for example a second type VI secretion (T6SS) machinery and a bacterial microcompartment of unknown function. T6SS is a common protein secretion system in Gram-negative bacteria and it has been reported to function in interactions with animals, plants and other bacteria and EF-Tu receptor (EFR), that recognizes one of the most abundant and conserved proteins of bacteria, Ef-Tu (Pseudomonas and necrotrophic Pectobacterium trigger PTI responses through the recognition of flagellin (Inducible plant innate immunity responses are comprised of two separate lines of defense that are distinguished by the type of pathogen-derived molecules (elicitors) recognized. The first has an equivalent in animals and is triggered after the perception of a group of conserved, or general, pathogen-derived molecules, called PAMPs/MAMPs that can be present in both pathogenic and non-pathogenic microorganisms . Well-cha, Ef-Tu . Recognilagellin . Furtherlagellin .Pseudomonas syringae usually express 15\u201330 effectors depending on the strain , that controls several ABA- and JA-regulated genes resulted in decreased tolerance to necrotrophic pathogens but also to water deficit and salt stress overlapping at least partly with those induced by PAMPs including oxidative burst, cell wall strengthening, production of phytoalexins and proteinase inhibitors as well as hormone biosynthesis are involved in OG sensing. WAK1 and WAK2 have been shown to bind to pectin in vitro and WAK1in vitro . The in x dimers . The eggx dimers . Even shWAK1 is up-regulated by OGs OGs and also compared the expression changes between OG-PTI and Flg22-PTI . Furthermore, NO was found to contribute to OG-induced immunity against B. cinerea. Whether this applies to Pectobacterium remains to be demonstrated.Interestingly, recent studies indicate participation of NO in OG-PTI . It was Figure 1, PTI appears central to plant defense against broad host range bacterial necrotrophs like Pectobacterium. ETI, which is highly efficient against (hemi)biotrophs such as Pseudomonas is not an effective strategy to combat necrotroph infection, as ETI relies on localized cell death to trigger the downstream defense responses. Necrotrophs like Pectobacterium employ induction of cell death as part of their virulence strategy, thus ETI would rather enhance than prevent the infection. Indeed Pectobacterium species have a very limited arsenal of T3 effectors and those few that have been studied appear to promote infection by causing cell death. Consequently, plant immune responses are triggered by recognition of conserved pathogen-associated molecular patterns (PAMPs) such as flagella or damage-associated molecular patterns (DAMPs) such as OGs released by the action of PCWDEs by respective pattern recognition receptors. While the PTI induced by PAMP recognition is a common response to both biotrophs and necrotrophs, DAMPs are more typical to necrotrophic interactions. Consequently, Pectobacterium strives to attenuate PTI particularly in the early phase of infection by tight control of PCWDE production minimizing DAMP generation. PAMP and DAMP recognition events trigger partly overlapping defense responses including induction of defense gene expression and synthesis of various defensive compounds such as phytoalexins, defensins, and PR-proteins \u2013 resulting in PTI. Indeed prior induction of either response will enhance plant resistance to Pectobacterium. Elucidating the molecular details of these two partially redundant signal networks is essential for our understanding of the plant-necrotroph interactions and can take advantage of the rapidly developing genomic techniques including transcriptional profiling and RNA sequencing combined with the powerful genetic screens available in Arabidopsis for mutants altered in their PTI responses. In particular elucidation of the less well-characterized OG-induced PTI deserves further studies including correlation of the chain length of the OG elicitor to a particular response at specific stages of infection and defining the downstream components that are most significant for bacterial resistance. Such studies would be crucial for providing new insights into plant defense strategies against necrotrophs. Further genome level analysis would also help to elucidate the interactions of Pectobacterium with other plant associated microbes, as well as their insect vectors.In summary, see The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Inhibiting transport of virions within the female reproductive tract is an attractive mechanism for transmission prevention. The mucosal environment varies with menstrual cycle and concurrent bacterial vaginosis (BV). Previous studies of transport within mucosal samples have focused on cervico-vaginal samples in exclusion. Severe BV corresponds to increased incidence of female-to-male HIV-1 transmission although the mechanism remains unclear.We have established a cohort of HIV +ve and \u2013ve women to be longitudinally studied for correlates of inhibited transport phenotypes. Cervical and cervico-vaginal mucus samples are collected, along with mucosal antibodies, vaginal smears, hormone levels, viral load, T cell monitoring panels as well as medical and behavioral history. Viral transport assays employ a diverse panel of viral isolates, testing clade specific effects. As of this interim analysis, over 60 study subjects have been recruited and repeat sampling is beginning.The hormone profile demarcating menstrual cycle phase correlates strongly with particle movement. In CVM, the nature of viral interactions with their environment changes; lowest progesterone to estradiol ratio corresponds with hindered diffusion. Non-reactive similarly sized PEGylated beads have freely diffusive behavior throughout the menstrual cycle. Cycle classification into follicular, mid-cycle and luteal periods demonstrates that CVM in the luteal phase is, unexpectedly, most permissive to viral transport. Severe BV has modest effects on pH of CVM and no effect on CM. This is reflected in viral transport characteristics whereby the magnitude and nature of movement is invariant during severe BV relative to healthy flora.It is unlikely that the mechanisms of increased transmission with BV are related to virus diffusing more freely within mucus. Correlates of hindered diffusion are not restricted to adaptive immune responses. This study begins to reveal the significance of immune correlates and hormone profiles on HIV-1 transmission mechanisms and transport in the female reproductive tract."} +{"text": "Ovis aries) to construct a linkage map for bighorn sheep, Ovis canadensis. We then assessed variability in genomic structure and recombination rates between bighorn sheep populations and sheep species.The construction of genetic linkage maps in free-living populations is a promising tool for the study of evolution. However, such maps are rare because it is difficult to develop both wild pedigrees and corresponding sets of molecular markers that are sufficiently large. We took advantage of two long-term field studies of pedigreed individuals and genomic resources originally developed for domestic sheep , resulting in an autosomal female map of 3166 cM and an autosomal male map of 2831 cM. Despite differing genome-wide patterns of heterochiasmy between the sheep species, sexual dimorphism in recombination rates was correlated between orthologous intervals.Ovis species. However, domestication may have played a role in altering patterns of heterochiasmy. Finally, we found that interval-specific patterns of sexual dimorphism were preserved among closely related Ovis species, possibly due to the conserved position of these intervals relative to the centromeres and telomeres. This study exemplifies how transferring genomic resources from domesticated species to close wild relative can benefit evolutionary ecologists while providing insights into the evolution of genomic structure and recombination rates of domesticated species.We have developed a first-generation bighorn sheep linkage map that will facilitate future studies of the genetic architecture of trait variation in this species. While domestication has been hypothesized to be responsible for the elevated mean recombination rate observed in domestic sheep, our results suggest that it is a characteristic of The construction of genetic linkage maps in model organisms and domesticated species enables studies of the genetic architecture of trait variation and genome evolution. However, such resources for free-living populations of non-model species are still rare because it is difficult to acquire large enough pedigrees and associated sets of molecular markers ,2. The uOvis canadensis), a mountain ungulate inhabiting western North America )We constructed a first-generation bighorn sheep linkage map using DNA from two wild pedigreed population and genomic resources originally developed for domestic sheep. Since bighorn sheep and domestic sheep genomes are very similar, future efforts to increase marker density in specific chromosomal regions should be relatively straightforward. This could be achieved using bighorn sheep single nucleotide polymorphism (SNP) markers recently discovered using the OvineSNP50 Beadchip , additioThe main reason for developing genomic resources in bighorn sheep is to allow studies of complex trait genetic architecture and evolution under natural settings. In the NBR population, genomic resources will enable investigations into the genetic basis of fitness, inbreeding depression and genetic rescue . In RM, Ovis species while the unusual male-biased heterochiasmy might have been a consequence of domestication. Finally, we have demonstrated that interval-specific patterns of sexual dimorphism could be conserved among closely related species, possibly due to the position of these intervals relative to centromeres and telomeres.While resources developed for domestic sheep are obviously highly useful to bighorn sheep research, genomic research in bighorn sheep can also yield valuable information through comparisons with domestic sheep in return. For example, we have demonstrated how linkage mapping in bighorn sheep can be used to infer ancestral marker order in domestic sheep. Also, by comparing the domestic sheep map with the map of a close wild relative, we were able to determine that the elevated recombination rates observed in domestic sheep were likely a characteristic of The NBR population was established by transplanting four rams and eight potentially pregnant ewes from Banff National Park in 1922 . The popThe RM population is native to a small isolated mountain range located about 50 km east of the Canadian Rockies in Alberta, Canada . ImmigraIn both populations, parentage was originally determined with ~30 microsatellite loci using the 95% confidence threshold in Cervus . For theIn addition to markers used for the initial pedigree reconstruction, microsatellites putatively distributed throughout the genome of our focal species were identified using the domestic sheep IMF map version 4.7 ,51. MarkWe constructed population-specific linkage maps as well as an integrated map where populations were treated as independent families using CRI-MAP . The sam10 likelihoods. The relative sex-averaged length of different maps was compared by summing the length of intervals that were present in both maps of Lovich and Gibbons . This inSince the length of an interval partly depends on the subset of markers included in a linkage analysis, we assessed the validity of comparing intervals between maps constructed using different number of markers (the domestic sheep IMF map 4.7 contains about 1400 markers). To accomplish this, we repeated cross-species analyses using information derived from additional linkage maps based solely on markers mapped in both species. Results and conclusions were essentially the same as for previous analyses and are therefore not presented. These maps are available in Additional file All research protocols were approved by the University of Alberta Animal Use and Care Committee, affiliated with the Canadian Council for Animal Care (Certificate 610901).JP designed the study, conducted laboratory work, performed data analysis and wrote the manuscript. JTH designed and supervised fieldwork at NBR and performed paternity analyses. CSD implemented laboratory methods and performed laboratory work. JMM participated in laboratory work and data analysis. JFM provided marker information and constructed a domestic sheep linkage map composed solely of markers mapped in bighorn sheep. DWC planned and supervised the study. All co-authors read and commented on draft versions of the manuscript. All authors read and approved the final manuscript.List of markers, map position and variability. Excel document displaying List of markers, map position and variability.Click here for fileComparison of bighorn sheep population-specific maps. PDF displaying comparison of bighorn sheep population-specific maps.Click here for fileComparison of intervals present in both population-specific bighorn sheep maps. XLS file displaying comparison of intervals present in both population-specific bighorn sheep maps.Click here for fileComparison of intervals present in bighorn sheep and domestic sheep maps. XLS file displaying comparison of intervals present in bighorn sheep and domestic sheep maps.Click here for fileBighorn sheep mapping pedigrees. PDF file displaying bighorn sheep mapping pedigreesClick here for fileBighorn sheep and domestic sheep linkage maps based on shared markers only. XLS bighorn sheep and domestic sheep linkage maps based on shared markers onlyClick here for file"} +{"text": "Implantation of pacemakers can be challenging in the context of dilated cardiac chambers and valvular regurgitation. We report a difficult case of single chamber pacemaker implantation in a patient with restrictrive cardiomyopathy resulting in grossly enlarged atria and severe tricuspid regurgitation. In this situation, use of a slittable guiding sheath, more typically used for coronary sinus lead implantation, greatly facilitated rapid and stable deployment of the right ventricular lead. An initial attempt at single chamber pacing using a screw-in right ventricular lead was difficult due to lead instability and took 3 hours , Panel AGuiding sheaths are commonly used to facilitate coronary sinus lead implants and paciOther strategies that could be considered in difficult pacing cases are alternative lead placement strategies by using either pre-shaped stylets or self-shaped stylets. If apical positioning is difficult, then placement of the lead into the right ventricular outflow tract septum can be facilitated by shaping a stylet with a generous distal curve with a swan neck deformity (angulated posteriorly). The whole lead, with the stylet either fully inserted, or pulled back from the tip, is then inserted into the pulmonary artery initially, before being pulled down into a stable right ventricular outflow tract septal position . The usOther strategies that might be considered include left ventricular lead placement through the coronary sinus , or use During acute implantation, the presence of a stable R wave suggests a good pacing site. Recent studies have shown that the current of injury is better than R wave, slew rate and impedance measurements at predicting acute stability during active fixation lead implants ,8. In chAlternative lead placement strategies, including the use of appropriately-selected tools may greatly facilitate difficult cases, even when these tools are not part of conventional equipment typically used for single chamber pacemaker implantation."} +{"text": "While increased pulmonary arterial expression of sGC has been reported in this mouse model of pulmonary hypertension, chronic hypoxia had minimal effects on relaxation to an NO donor. Catalase markedly restored contraction to phenylephrine and the aortic relaxation to hypoxia. Chronic treatment of mice with cobalt protoporphyrin IX, which induces heme oxygenase and ecSOD, attenuated the development of pulmonary hypertension without restoring relaxation to ACh. In addition, chronic treatment of mice with delta-aminolevulinic acid, a precursor to the sGC activator protoporphyrin IX and heme needed for sGC activation and heme oxygenase activity, also attenuated pulmonary hypertension development without restoring responses to ACh. Thus, redox mechanisms regulating PKG seem to be important contributors to vascular oxygen sensing mechanisms. In addition, increased ecSOD expression and PKG-mediated vasodilation to endogenously generated peroxide and other sGC activators may function as a protective mechanism against the development of hypoxia-induced pulmonary hypertension.There is much controversy in mechanisms controlling the pulmonary arterial response to acute and chronic hypoxia. Our previous work suggests bovine pulmonary arteries (BPA) contract to hypoxia via removal of a relaxation mediated by hydrogen peroxide derived from superoxide generated by Nox4 . In cont"} +{"text": "Abiotic stress conditions adversely affect plant growth, resulting in significant decline in crop productivity. To mitigate and recover from the damaging effects of such adverse environmental conditions, plants have evolved various adaptive strategies at cellular and metabolic levels. Most of these strategies involve dynamic changes in protein abundance that can be best explored through proteomics. This review summarizes comparative proteomic studies conducted with roots of various plant species subjected to different abiotic stresses especially drought, salinity, flood, and cold. The main purpose of this article is to highlight and classify the protein level changes in abiotic stress response pathways specifically in plant roots. Shared as well as stressor-specific proteome signatures and adaptive mechanism(s) are simultaneously described. Such a comprehensive account will facilitate the design of genetic engineering strategies that enable the development of broad-spectrum abiotic stress-tolerant crops. Abiotic stresses such as drought, salinity, flood, and cold vastly affect plant growth and metabolism that ultimately disturbs plant life \u2014acetone precipitation and phenol extraction method helped to overcome the above challenges to certain extent . Firstly, breakthroughs in soft ionization methods such as matrix assisted laser desorption ionization (MALDI) are also involved in the response of roots to drought stress.Evidence from several proteomic studies showed that roots respond to drought stress using mechanisms similar to those occurring in damaging cells. For instance, enhanced levels of proteosomal factors were detected in drought-tolerant varieties of rapeseed seedlings in soil. Root is the primary organ of exposure and hence responds rapidly. Several proteomic-based investigations have provided new insight into root responses and adaptation against high salinity.++ signaling protein or Ca++ binding protein, (4) phosphoproteins involving activation of kinase cascade, and (5) ethylene receptors. Receptor protein kinases (RPKs) in rice roots and calreticulin (CRT) alteration in carbohydrate and energy metabolism, (2) changes in ion homeostasis and membrane trafficking, (3) ROS scavenging, and (4) dynamic reorganization of cytoskeleton and redistribution of cell wall components.Alteration in carbohydrates and energy metabolism under salinity can be addressed by the high abundance of enzymes involved in glycolysis, TCA cycle, electron transport chain (ETC), and ATP synthesis was produced , amino acids (aspartate aminotransferase), and lipids (lipoxygenase) were induced as early flood responsive proteins or freezing (<0\u00b0C) temperatures can induce ice formation in plant tissues, leading to cellular dehydration were found to be higher in abundance as a chilling stress response in roots of rice (Cui et al., Several other proteome signatures provided insights on plants' preparation for recovery once the stress is being released. For example proteins involved in cellulose synthesis, such as UDP-glucose pyrophosphorylase were highly abundant in rice roots upon 48 h chilling stress (Amor et al., Proteomic analyses on plant roots under various abiotic stress conditions revealed important information on proteins involved in the abiotic stress response. This leads to the identification of molecular and cellular mechanisms that are specific to certain abiotic stress or shared between two or more abiotic stress conditions Figure . For insde novo protein synthesis, growth-related signaling, and secondary metabolism were enhanced during recovery from flood stress as a replenishment of the stress-induced effects. Together, these changes suggested a compensatory mechanism by which the stress-induced effects could significantly be recovered.At the recovery phase, increased lignin biosynthesis was found following cold and drought stress. This molecular mechanism results in enhanced mechanical strength of roots by hardening cell wall at the root tip. Changes in abundance for cytoskeleton associated proteins were also observed, that can be looked upon as compensation against reduced cell size as well as repairing injuries caused by drought, salinity, and flood stress. Moreover, the levels of proteins related to As mentioned in this review, majority of literature reported proteomic analyses of the root response at least after 24 h of exposure to cold, drought, high salinity, or flooding stress. Therefore, early proteomic changes associated with individual abiotic stress remain to be elucidated, which will allow the identification of distinct sets of effectors for stress signaling. The function of these early effectors may be masked by secondary processes at a later stage. Technically, most of these proteomic studies have utilized the gel based separation approaches Table that resThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Strix occidentalis, the northern goshawk, Accipiter gentilis, and the Pacific fisher, Martes pennanti. Whether protection of these upper-trophic level species confers adequate conservation of avian forest diversity is unknown.As a result of past practices, many of the dry coniferous forests of the western United States contain dense, even-aged stands with uncharacteristically high levels of litter and downed woody debris. These changes to the forest have received considerable attention as they elevate concerns regarding the outcome of wildland fire. However, attempts to reduce biomass through fuel reduction are often opposed by public interest groups whose objectives include maintaining habitat for species of concern such as the spotted owl, 2 area in the Sierra Nevada. Our approach, which accounts for variations in detectability of species, estimates occurrence probabilities of all species in a community by linking species occurrence models into one hierarchical community model, thus improving inferences on all species, especially those that are rare or observed infrequently. We address how the avian community is influenced by covariates related to canopy cover, tree size and shrub cover while accounting for the impacts of abiotic variables known to affect species distributions.We use a multi-species occurrence model to estimate the habitat associations of 47 avian species detected at 742 sampling locations within an 880-kmEnvironmental parameters estimated through our approach emphasize the importance of within and between stand-level heterogeneity in meeting biodiversity objectives and suggests that many avian species would increase under more open canopy habitat conditions than those favored by umbrella species of high conservation concern. Our results suggest that a more integrated approach that emphasizes maintaining a diversity of habitats across environmental gradients and minimizing urbanization may have a greater benefit to ecosystem functioning then a single-species management focus. Biodiversity is integral to ecosystem functioning Forested ecosystems support over 80% of terrestrial biodiversity worldwide and have high species diversity for many taxonomic groups, including birds Strix occidentalisMartes pennantiAccipiter gentilisStrix occidentalis occidentalis, and Pacific fisher are typically associated with denser, closed-canopy, multi-storied stands. Modification of these habitats to reduce the threat of fire is perceived to decrease habitat suitability for these old-growth forest associated species and fuel treatments in the Sierra Nevada are required to make special considerations for them. For instance, stands within spotted owl protected activity centers around known nests are required to be managed to maintain a minimum of 70 percent tree canopy cover and to retain dominant and co-dominant trees that are at least an average of 61 cm in diameter at breast height (DBH) Fuel reduction treatments are increasingly being applied in an attempt to reduce the risk of high-severity fire and increase forest resiliency Conservation of upper-trophic level species, such as the spotted owl, is thought to provide an umbrella of protection to other species that have similar habitat associations but have smaller area requirements 2 conservation area, the Lake Tahoe Basin, located in the central Sierra Nevada Mountains , white fir (Abies concolor), red fir (A. magnifica), incense-cedar , lodgepole pine (P. contorta), and sugar pine (P. lambertiana).The Lake Tahoe Basin is located on the eastern crest of the Sierra Nevada straddling the states of California and Nevada . ElevatiAvian point counts were conducted at 742 locations in the upland forested areas of the Lake Tahoe Basin Management Unit during the course of the breeding season (mid-May to early July) of 2002 to 2005 Sample locations were selected using a combination of systematic/grid sampling and stratified random sampling. Four points were randomly selected from within a hexagonal grid laid across the Lake Tahoe Basin using spacing parameters of the Forest Inventory and Analysis program (N\u200a=\u200a98). An additional 74 locations were randomly selected across a range of urban development classes. At each of these primary sampling locations, a cluster of additional sampling points was conducted 200 m from each primary point count station. Sampling locations for each year of the study were selected randomly. Combined, these sampling designs ensured that data points were distributed across the basin and adequately addressed the influence of urbanization. There was a minimum distance of 200 m between all sampling points.We characterized habitat using several explanatory variables with Geographic Information Systems (GIS) for the area within a 150-m radius of the survey locations. Although birds were recorded only when detected within 100 m of a sample point, we selected a 150-m radius to define our habitat variables as birds on the edge of the sampling radius are likely responding to surrounding forest conditions. Habitat parameters were derived from a GIS vegetation layer (30-m\u00d730-m raster cell) based on IKONOS satellite imagery collected in 2002 i, iz, is a Bernoulli process where the probability that species i is present at location j : We analyzed the data using a hierarchical multi-species modeling approach developed in Dorazio and Royle i at location j during sampling occasion k, denoted i at location j during sampling occasion k given that the species was present. We similarly modeled species detection probabilities using the logit link function:i species implemented in the programs R and WinBUGS with flat priors for each of the community-level parameters. We ran three chains of the model for 15000 iterations after a burn-in of 10000 iterations and saved every fifth estimate . We assessed that the model had convergence using the R-hat statistic Calypte anna, blue-gray gnatcatcher Polioptila caerulea, bushtit Psaltriparus minimus, lazuli bunting Passerina amoena, and orange-crowned warbler Oreothlypis celata) and were considered vagrants or non-breeding periodics . The house finch Carpodacus mexicanus and mourning dove Zenaida macroura were also excluded from our analyses as their presence in forests is dependent upon urban development (i.e. they are not expected in forests lacking urbanization). These species were excluded from the model because they would not be representative of the community. Seven additional species considered very rare, Calliope hummingbird Stellula calliope, Hammond\u2019s flycatcher Empidonax hammondii, lesser goldfinch Spinus psaltria, Pacific-slope flycatcher Empidonax difficilis, purple finch Carpodacus purpureus, ruby-crowned kinglet Regulus calendula, and yellow warbler Dendroica petechia), were observed fewer than 20 times, and they were included in our hierarchical model but not in our presentation of covariate estimates for individual species because their covariate estimates could be misleading. The mean and standard deviation of the occurrence and detection probabilities for all species included in the model are presented in We recorded 61 species of birds during 2021 visits to 742 point count stations. Of these 61 species detected, we excluded five species from our models as they typically breed at lower elevations is likely to decrease the occurrence probabilities for old-forest associates. Further, our results also underscore the consistently negative impact of urban development on many avian species in the Lake Tahoe Basin and suggest that actively managing the extent and placement of urban development to minimize biodiversity impacts is as important as considerations of forest structure.Forest thinning projects have frequently been opposed by those concerned with maintaining suitable habitat for old-forest associated species of concern, such as the spotted owl, which require old forest conditions, namely high canopy cover and large trees Spizella passerina, that specialize on forest edge habitats and require both highly forested areas and shrub fields to meet their life history requirements. The results of our model indicate that past practices and management approaches that lead to increased homogenization of the forest will have negative impacts on avian diversity. Management approaches, such as fuel reduction treatments, or the use of prescribed or managed wildland fire, may be designed to restore at least some of the variability within and among stands that existed during an active fire regime, thereby enhancing habitat conditions for conserving avian biodiversity.Parameters estimated through our multi-species model emphasize the importance of within and between stand-level heterogeneity in meeting biodiversity objectives. At the stand level, some species responded positively to higher variance in tree size and canopy cover; thus, increasing forest heterogeneity in forest stands would improve habitat suitability for these species see . SpeciesThe link between habitat heterogeneity and biodiversity has been well-established (reviewed in Appendix S1Upland forest bird frequency status (ranging from very common to very rare) and mean detection and occupancy probabilities with one standard deviation.(DOCX)Click here for additional data file.Appendix S2Mean parameter estimates for upland bird species included in our analysis. Values indicate the change in occurrence predicted for each change in one standard deviation in the response variable. Bold indicates that the posterior interval did not overlap zero. The following seven species were excluded from this table because they were observed fewer than 20 times: Calliope hummingbird Stellula calliope, Hammond\u2019s flycatcher Empidonax hammondii, lesser goldfinch Spinus psaltria, Pacific-slope flycatcher Empidonax difficilis, purple finch Carpodacus purpureus, ruby-crowned kinglet Regulus calendula, and yellow warbler Dendroica petechia).(DOCX)Click here for additional data file."} +{"text": "Personalized medicine in the days of genetic research is seen as molecular biologic specification in individuals, not as individualized care oriented to patients needs in the sense of person-centered medicine. Yet the question can be raised whether this focus can ameliorate health care needs in view of the invested resources. Studies suggest that patients often miss authentically patient-centred care and individual physician-patient interaction and therefore decide to choose complementary and alternative medicine (CAM). By means of a meta-ethnography this project explored patients\u2019 views about individualized medicine and described the patients\u2019 perspectives of integrative and person-centred services.The procedure included first an electronic databases search for \u2018qualitative research\u2019 AND \u2018CAM\u2019 AND \u2018patient expectations\u2019 subject headings, supplemented with citation searches and hand searching. Second, studies were assessed using an inclusion/exclusion checklist and a quality score according to an adjusted checklist of Behrens and Langer. The third step was meta-ethnography according to Noblit and Hare's method to synthesize and interpret key concepts of individualized medicine using a line of argument synthesis.A set of 67 electronic databases including CAM, nursing, nutrition, psychological, social, medical databases, the Cochrane Library and DIMDI were searched. Nine thousand five hundred seventy-eight citations were screened, 63 full text publications reviewed, 38 appraised and 30 articles were included. The third-order constructs emerging through the synthesis and interpretation conducted by the multidisciplinary research team were: \"Personal development\", \"holism\", \"alliance\", \"room for connecting different models\", \"self activation\", \"dimensions of well-being\".The perspective of patients choosing alternative and complementary medicine regarding individualized care clearly differs from the current idea of personalized genetic medicine. Individualized medicine has therefore concurrently to bear in mind the humanistic approach of holistic, transformative, integrative and self-activation needs of patients. The allocation of resources should consider patients needs to enhance a high-quality biomedical or scientific health care system."} +{"text": "Reaxys is an authoritative web-based workflow solution designed for chemistry researchers in drug discovery, chemicals and academic research . Reaxys With historical coverage dating right back to 1771 and continuing through todays cutting-edge research, Reaxys covers the most important chemistry-related literature and patent sources and provides unparalleled depth of information on reactions, substances and related property data.To make the most effective use of this information Reaxys offers two new entry points into the data:\u2022 Chemical space analysis, analogue sourcing, fuelling hit-to-lead programs and IP prior-art searching are possible through the Reaxys Structure Flat File.\u2022 Programmatic interaction with the database by custom clients, downloading bulk data from Reaxys using scripts, executing batch queries and integrating Reaxys into server-based data-intensive pipelining or workflow applications are possible through the Reaxys APIs.The Reaxys Structure Flat File and the Reaxys APIs will facilitate chemoinformaticians and information managers to integrate Reaxys into chemical information processing environments. In our poster, we present common use cases and possible applications. In addition, we describe successful implementations, illustrating how additional insights and efficiency can be gained."} +{"text": "Astatotilapia latifasciata (Figure Haplochromis obliquidens. This species was described as Haplochromis latifasciatus [Astatotilapia [Haplochromis \"zebra obliquidens\" in the aquarium trade. Astatotilapia latifasciata has been reported to occur in Lake Nawampasa a small satellite lake of the much larger Lake Kyoga, and in Lake Kyoga located north of Lake Victoria in Uganda [After the publication of our work , we detea Figure , was errasciatus and lateotilapia . Our misn Uganda ."} +{"text": "The 2011 EMBO Conference Series on the Assembly and Function of Neuronal Circuits was held from 25 to 30 September 2011 at Monte Verit\u00e0 in Ascona, Switzerland. Approximately 100 participants explored current challenges and approaches to studying neural circuit function and organization. The 2011 EMBO Conference Series on the Assembly and Function of Neuronal Circuits was held from 25 to 30 September 2011 at Monte Verit\u00e0 in Ascona, Switzerland. Approximately 100 participants explored current challenges and approaches to studying neural circuit function and organization. The conference was organized into two sessions of oral presentations per day followed by an evening lecture and a nightly poster session at the Centro Stefano Franscini. The generously timed meals and coffee breaks offered additional opportunities for more informal and intimate discussions throughout the meeting.Caenorhabditis elegans, Drosophila, zebrafish, songbirds, rodents and macaques to electric fish, turtles and Egyptian fruit bats. In addition to experimental approaches, a few computational studies were presented that provide models to describe circuit dynamics, such as the influence of cortical inhibition.The topics spanned themes such as the importance of inhibition and its interplay with excitation in shaping circuit activity, the effects of neuromodulators on neurons and behavior, the genetic underpinnings of behavior and how specific neuron types wire and communicate. There was a notable trend toward the use of combinations of genetic, optical, electrophysiological and behavioral methods. We noticed a surge in the use of optogenetics for fine manipulation of genetically defined neurons, as well as many studies in awake, behaving animals, with the use of imaging or electrophysiology. A wide range of model organisms was used, from the traditionally popular Herein we sample a few highlights from the meeting that showcase the breadth of current research in neuronal circuits. Owing to space limitation, we apologize that we cannot comment on all of the presentations.Massimo Scanziani presented work on the mouse primary visual cortex (V1) and lateral geniculate nucleus (LGN). He expressed light-activated opsins, Channelrhodopsin-2 (ChR2) and archaerhodopsin (Arch) in layer VI (L6) pyramidal neurons and found that L6 excitation decreases firing rates in more superficial layers (presumably via interneurons) and in LGN . Sonja Hofer, who received a prize for the best short oral presentation, used a combination of two-photon microscopy and patch-clamp recordings to study the connectivity and tuning preferences of different cell types in mouse V1. She found that whereas excitatory pyramidal neurons receive sparse input from neurons with similar tuning preferences, parvalbumin (PV)-positive GABAergic interneurons receive input with high probability from neurons with diverse stimulus preferences. Yang Dan expressed ChR2 in subsets of interneurons and Arch in pyramidal neurons in mouse V1. Exciting PV neurons sharpened orientation tuning and enhanced direction selectivity . Exciting somatostatin neurons enhanced direction selectivity but did not change orientation tuning. Kevin Franks examined how recurrent connectivity in the piriform cortex (PCx) gates sensory information from the olfactory bulb. He found that a distributed and excitatory recurrent network in PCx activates strong feedback inhibition such that, if recurrent activity precedes sensory input, feedback inhibition will arise to suppress bulb-evoked spiking.Drosophila brain learn to select for sexually receptive females. He found that courtship learning depends on the activation of a specific class of dopaminergic neurons in the protocerebrum which project to neurons with a subtype of dopamine receptors in the mushroom body. David Anderson presented new techniques for the study of the role of dopaminergic neurons involved in hunger in Drosophila.Barry Dickson presented his work on how neural circuits in the male C. elegans to decide whether to exploit a food patch or to abandon it and explore other options. She found that this decision depends on the expression of the catecholamine receptor tyra-3, a homolog of the vertebrate adrenergic receptor. Alex Shier described the importance of hypocretin in sleep regulation in larval zebrafish and showed a promising technique for identifying drug targets using high-throughput behavioral screening.Cori Bargmann probed the genetic mechanisms that allow N-methyl-D-aspartate receptors at cortical dendrites. Bartlett Mel described theoretical approaches to understanding excitatory and inhibitory synaptic input to dendrites and stressed that dendrites must be considered processing units in their own right. Michael Ha\u00fcsser showed in vivo patch recordings from orientation-tuned mouse V1 dendrites. Erin Schuman showed the existence of many mRNAs at dendrites, suggesting a place to look for a molecular basis for dendritic computation.Dendritic computation was featured in several studies. Jackie Schiller demonstrated supralinear summation between thalamocortical and corticocortical synapses via Drosophila olfactory system wires, and Oscar Mar\u00edn showed how Cajal-Retzius cells in layer I in cortex are distributed across the future cortical surface. Tania Rinaldi Barkat showed that the auditory critical period for thalamocortical modification depends on telencephalin, a membrane adhesion protein, and that its loss induces precocious spine maturation on pyramidal cells in layer IV of the primary auditory cortex.A few talks addressed how neurons find their targets during development. Andrew Huberman described work addressing the problem of how retinal ganglion cells find their targets in the brain. Liqun Luo showed how the Nirao Shah showed that a sexually dimorphic gene with higher expression in the male mouse bed nucleus of the stria terminalis and medial amygdala may play a role in sexual behavior. Allison Doupe and Bence \u00d6lveczky presented recordings from nuclei in songbirds to demonstrate the role of variability in producing learned motor patterns. Peer Wulff presented a study on how the selective ablation of PV neurons in the medial prefrontal cortex of mice impairs spatial working memory and cognitive flexibility. Daniel Salzman showed that neurons in the monkey basolateral amygdala (BLA) may contribute to selective attention via their projections to extrastriate cortex. Single BLA neurons showed sustained excitation or inhibition from stimuli that indicate high- or low value rewards. Adi Mizrahi showed that, by patching neurons in primary auditory cortex, pup odors modulate responses to ultrasonic pup vocalizations in lactating mothers, but not in na\u00efve virgins. Alla Karpova observed abrupt and synchronous firing of neuronal ensembles in medial prefrontal cortex during transitions in behavioral strategies of rats performing two-alternative choice tasks. Nachum Ulanovsky demonstrated a large-scale cognitive map in bats and presented recordings from place cells in the hippocampus. He showed three-dimensional representations of space in the hippocampus as bats flew in the laboratory.Jeff Lichtman showed how axons at the neuromuscular junction connect to the muscle and showed preliminary efforts to image the mouse cortical connectome via large-scale serial electron microscopic reconstruction. Hongkui Zheng, from the Allen Institute for Brain Science, presented new initiatives to provide a whole-brain, three-dimensional map of axonal projections using cell-type specific creatinine (Cre) lines and Cre-dependent viral tracers.Amid talks about the remarkable wiring specificity of particular circuits, Haim Sompolinsky gave a thought-provoking lecture on how random connectivity may be an efficient strategy for encoding of sensory stimuli. He reviewed new developments in the field of compressed sensing and offered a glimpse of its potential use in neuroscience.The diversity of topics covered at this year's conference reflects the wide range of approaches neuroscientists currently use to study neuronal circuits. From examining the molecules and genes of specific cell-types to developing models of how networks of randomly connected neurons behave, the study of neuronal circuits is rapidly expanding, and we predict that it will continue to grow in the future.Arch: archaerhodopsin; BLA: basolateral amygdala; ChR2: channelrhodopsin-2; LGN: lateral geniculate nucleus; PCx: piriform cortex; PV: parvalbumin; V1: primary visual cortex.The authors declare that they have no competing interests.AYW and JYC wrote the meeting report, and both authors approved the final manuscript."} +{"text": "In eukaryotic organisms, DNA is packaged into chromatin structure, where most of DNA is wrapped into nucleosomes. DNA compaction and nucleosome positioning have clear functional implications, since they modulate the accessibility of genomic regions to regulatory proteins. Despite the intensive research effort focused in this area, the rules defining nucleosome positioning and the location of DNA regulatory regions still remain elusive.Ab initio physical descriptors derived from molecular dynamics were used to develop a computational method that accurately predicts nucleosome enriched and depleted regions.Naked (histone-free) and nucleosomal DNA from yeast were digested by microccocal nuclease (MNase) and sequenced genome-wide. MNase cutting preferences were determined for both naked and nucleosomal DNAs. Integration of their sequencing profiles with DNA conformational descriptors derived from atomistic molecular dynamic simulations enabled us to extract the physical properties of DNA on a genomic scale and to correlate them with chromatin structure and gene regulation. The local structure of DNA around regulatory regions was found to be unusually flexible and to display a unique pattern of nucleosome positioning. Our experimental and computational analyses jointly demonstrate a clear correlation between sequence-dependent physical properties of naked DNA and regulatory signals in the chromatin structure. These results demonstrate that nucleosome positioning around TSS (Transcription Start Site) and TTS (Transcription Termination Site) (at least in yeast) is strongly dependent on DNA physical properties, which can define a basal regulatory mechanism of gene expression. Further4 -9.in vivo is really dictated by the DNA sequence is still an issue of strong discussion [DNA underlying sequence has long been considered to be an important contributor to nucleosome assembly -13. Crysscussion -27.ab initio physical descriptors derived from molecular dynamics (MD) simulations of short DNA oligonucleotides [Our group and others have provided indirect evidence highlighting the connection between DNA physical properties and chromatin organization -30. In pleotides -35. Thisleotides ,37. VeryYeast DNA fragments were prepared and sequenced following the experimental approach described in Figure -8), while the same tetramer was rarely present at primary cutting sites unveiled that LRs are located in regions with large variations in flexibility, where an extremely flexible site is surrounded by stiff motifs ,The MNase tetramer preferences Tables and 2 arAs previously suggested by other groups ,11,43-50-503. WheThe analysis of MD-derived descriptors of naked DNA showed that key genomic regions, such as at TSSs and TTSs, were marked by unusual flexibility properties intrinsic physical properties of naked DNA determine major nucleosome location signals in yeast, especially those at TSS and TTS. This hypothesis is indirectly supported by very recent studies , where nEssential regions for gene regulation like TSSs and TTSs are characterized by unusual physical properties that disfavor positioning of nucleosomes and therefore expose DNA to interaction with regulatory proteins. This property of regulatory regions is quite general across the genome. The genes with well-defined CLRs at regulatory regions did not differ from those with more diffuse signals in terms of Gene Ontology analysis , promoteDrosophila melongaster genome with the high-resolution genomic nucleosome map available [All conclusions drawn here have been derived from the analysis of yeast genome and thus concerns exist whether they can be validated for higher eukaryotes with a different sequence composition at regulatory regions. Therefore, we compared the sequence-dependent physical properties of the vailable . The comvailable . Extensivailable . All theSaccharomyces cerevisiae BY4741 strain, DNA were isolated from Cleaved DNA samples were sequenced on the Illumina/Solexa Genome Analyzer (GA) IIx to generate reads of 54 bp length. Data were processed with standard GA base calling pipeline to convert initial raw images into sequences. All sequencing experiments were done in duplicates. Pooled data highly converged, as the reproducibility of individual experiments was very large in all cases . Correction of nucleosomal digestion profiles was done by using the degradation profiles obtained for naked DNA as background account for regions were MNase degradation has been especially extensive. Low coverage regions (LRs) were detected in both nucleosomal and naked DNA as genomic segments with non-zero coverage below certain thresholds , considering the equilibrium conformation as the origin of energies following the approach suggested by Lankas and others [tilt, kroll, kshift, ktilt, krise and kslide) are taken from the diagonal of the matrix. Ktotal is obtained as the product of the six pure stiffness constants and gives a rough global estimate of the flexibility of each base pair step in solvent water by using a newly developed force-field . Base pad others ,32,42,41T \u0398 X; where \u0398 is the stiffness matrix derived from MD simulations; X (or XT) is the deformation vector (or its transposed), given by translating a relaxed DNA fiber into the coiled nucleosome core DNA conformation as described for averaging and smoothing of X-ray structures declare that they have no competing interestsThe authors have made the following declarations about their contributions: MO had the idea and make the general planning of the study. Conceived and designed the experiments: OD MS MO. Performed the experiments: OD. Analyzed the data: OF FB AP MO. All authors contributed to the writing of the manuscript. All authors read and approved the final manuscript.Additional Methods, Additional Figures and Additional Tables. PDF document with detailed methods and additional results.Click here for file"} +{"text": "Understanding population-level responses to human-induced changes to habitats can elucidate the evolutionary consequences of rapid habitat alteration. Reservoirs constructed on streams expose stream fishes to novel selective pressures in these habitats. Assessing the drivers of trait divergence facilitated by these habitats will help identify evolutionary and ecological consequences of reservoir habitats. We tested for morphological divergence in a stream fish that occupies both stream and reservoir habitats. To assess contributions of genetic-level differences and phenotypic plasticity induced by flow variation, we spawned and reared individuals from both habitats types in flow and no flow conditions. Body shape significantly and consistently diverged in reservoir habitats compared with streams; individuals from reservoirs were shallower bodied with smaller heads compared with individuals from streams. Significant population-level differences in morphology persisted in offspring but morphological variation compared with field-collected individuals was limited to the head region. Populations demonstrated dissimilar flow-induced phenotypic plasticity when reared under flow, but phenotypic plasticity in response to flow variation was an unlikely explanation for observed phenotypic divergence in the field. Our results, together with previous investigations, suggest the environmental conditions currently thought to drive morphological change in reservoirs may not be the sole drivers of phenotypic change. Understanding how populations respond to widespread and rapid environmental change will be a first step in elucidating the evolutionary consequences of disturbed habitats. Habitats altered by humans may destine populations to extirpation . We also predicted C. venusta offspring reared in flowing water would have more fusiform body shapes compared with fish reared in lentic conditions and would parallel shape variation observed in reservoir and stream habitats.Here, we tested for phenotypic divergence of ats Fig. . Althougats Fig. had prevC. venusta from three reservoirs in the Hilly Gulf Coastal Plains in northwest Mississippi, USA were combined from each population were split evenly and stocked into one of four experimental stream units located at the Lake Thoreau Environmental Center near Hattiesburg, MS that transferred water from the outflow end of units to the upstream riffle of groundwater. Thus, we had a 2 \u00d7 2 factorial design with population crossed with flow and nonflow treatments. Adult C. venusta were allowed to spawn and then removed once juvenile fish were observed. All adults were removed by 3 July 2012. Experimental stream units were then monitored, and juveniles were culled to keep densities approximately equal among the four units. Spawned C. venusta were removed on 10 September 2012 and then 1 December 2012, euthanized by overdose of MS-222 and preserved in 10% formalin. We only used individuals that had reached adult size in analyses.We assessed potential genotypic differences and flow-induced phenotypic plasticity in morphology between reservoir and stream populations by spawning http://life.bio.sunysb.edu/morph/) and R (R Development Core Team n = 18) but because some shape variables often do not explain an appreciable amount of variation . All mancova models assume multivariate normality, homogeneity of covariance matrices, independence of observations, linear relationships between covariates and dependent variables, and homogeneity of slopes among groups (Rencher mancova model included 8 shape variables (explaining 89.9% of the variation in shape) as dependent variables, standard length (SL) as a covariate , habitat type (to test for effects of stream or reservoir habitats), basin (to test for basin-level effects) as fixed factors. Heterogeneity of slopes was tested among basins, and between habitat types by including SL in the respective interaction terms. All nonsignificant interaction terms were removed from the final model, and F-values were approximated using Wilk's lambda. Because of the statistical power associated with mancova of shape data, we focused our interpretation of model results on effect strengths by use of partial eta squared by the shape variables matrix to yield habitat divergence vector scores for each individual. This divergence vector summarizes the shape variation that was elicited in fish from reservoir and stream habitats. The nature of this shape change was visualized using thin-plate spline transformation grids.To assess the nature of morphological divergence in reservoir habitats, we calculated a morphological divergence vector as defined by Langerhans between mancova to test for population-level differences and flow-induced phenotypic plasticity on body shape variation within mesocosm-reared C. venusta. The mancova model included 8 shape variables as dependent variables (explaining 89.0% of the variation in shape), Population (stream or reservoir) and treatment (flow or no flow) were included as fixed factors, and SL as a covariate. Heterogeneity of slopes was tested between populations and treatment by inclusion of SL in each respective interaction term. Nonsignificant interaction terms were omitted from the final model. To quantify the nature of population-level and flow-induced plasticity of body shape variation of mesocosm-reared individuals, divergence vectors for population and treatment were calculated from the final model (similar to above). We visualized shape deformations along each population and treatment divergence vector using thin-plate spline transformation grids. All analyses were conducted in R unless otherwise stated . We predict these species-specific responses are more likely due to underlying genetic variation and ecologies between the species that are interacting with similar environmental conditions in reservoirs.Repeated morphological divergence in replicate reservoirs suggests these habitats are facilitating phenotypic changes in populations of Franssen demonstrC. venusta and C. lutrensis may explain their disparate responses to reservoir habitats, although data on their ecologies are limited. A better understanding the ecologies of these species or differences in their underlying genetic architecture may help elucidate mechanisms behind their disparate morphological changes in reservoir habitats.Morphological diversification in fishes has been linked to dissolved oxygen concentrations and light availability . This reversal of caudal regions of the two populations in mesocosms compared with field-collected fish likely indicates fish in the field are exposed to plasticity-inducing factors that were absent in mesocosms. In fishes, there is a general propensity for species inhabiting moving water to be more streamlined than fishes in lentic habitats . While continued exposure to environmental cues that elicit plasticity of traits can result in canalization . Nonetheless, the mancova of body shape variation of field-collected individuals indicated Basin and the Basin \u00d7 Habitat interaction had significant effects on body shape variation, indicating fish body shape varied among basins and had dissimilar responses to reservoir habitats among basins. However, both of these effects explained less variation than the habitat term, suggesting variation between habitat types had a stronger influence on body shape variation than variation due to genetic variation among basins. While the lack of basin-level replication in the mesocosm experiment was not ideal, we think it is unlikely and have no evidence that would suggest nonadaptive evolutionary processes shaped the genetic structure of C. venusta in the Grenada basin.Lack of basin-level replication in the mesocosm experiment may limit our ability to extrapolate our results and interpretations to other reservoir systems. This would be especially true if drift, mutation, or recombination had stronger effects than selection on the genetic structure of C. venusta in reservoir habitats (compared with C. lutrensis) indicates selective pressures may vary among reservoirs or that different species respond to similar selective pressures in different fashions. Together, investigations of morphological changes of fishes in reservoir habitats may suggest that the reduction in factors that can contribute to morphological variation to one or two variables may be an over-simplification when comparing phenotypic variation in different habitats. Indeed, a multitude of environmental conditions likely covary between these different habitats. A better understanding of the spatial and temporal variation in other potential environmental selective pressures and how these conditions interact with genetic variation to produce phenotypic variation will be needed to understand how reservoirs can alter the evolutionary trajectories of resident populations.The inability to elicit similar phenotypic variation in individuals reared in flow variation (this paper) and in the presence of predators Franssen to morphMost organisms live in environments that have been altered at least to some extent by humans Palumbi . It will"} +{"text": "Patients with Turner's syndrome have increased cardiovascular (CV) morbidity and mortality, potentially over and above that explained by the higher rate of both congenital heart disease and associated endocrine disorders and hypertension. GH administration to maximise adult height is a well-established treatment form but may affect cardiovascular status, ventricular mechanics and myocardial function. Furthermore, given the adverse CV effects of supra-physiological GH levels associated with acromegaly and in the field of sports doping, concern has been voiced about potential risks associated with this form of treatment.CMR based strain derivatives offer advanced analysis of myocardial deformation and function. Such technologies are thought to increase sensitivity and may allow detection of \"pre-clinical\" disease not apparent by assessment of conventional parameters such as ventricular volumes and ejection fraction (EF).52 patients with Turner syndrome underwent a comprehensive CV CMR study. Patients with structural heart disease such as aortic coarctation, haemodynamically important valve disease, previous myocardial infarction or cardiac surgery were excluded. Of the remaining 35 adult patients 14 had a history of previous exposure to GH (GH +ve), 21 had no history of GH treatment (GH -ve).Assessment of ventricular mass, volumes and derived EF was performed by means of signal intensity thresholding based detailed endocardial contouring using commercial software . LV/RV longitudinal and LV circumferential strain was analysed using an endocardial feature tracking software package .The demographic and haemodynamic data of both groups is summarised in Table Childhood GH exposure appears to have no detectable detrimental late effects on LV/RV ventricular performance. This study therefore provides further reassurance regarding the long term safety of childhood GH administration in patients with Turner's syndrome.None."} +{"text": "To assess our preoperative pickup of malignant axillary lymph nodes by ultrasound and FNA compared with one-stop nucleic acid amplification (OSNA) and final histology.At our unit all patients with invasive breast cancer undergo axillary ultrasound, and those with suspicious or equivocal findings undergo axillary FNA. If FNA is positive we proceed to axillary node clearance (ANC). If axillary assessment is normal we perform sentinel node biopsy (SNB) with intraoperative OSNA, unless planned for neoadjuvant chemotherapy or primary medical therapy. In patients with positive OSNA, further surgery is performed as per hospital protocol. Retrospective correlation of preoperative axillary ultrasound and FNA findings with intraoperative OSNA in the SNB group and final histology in the ANC group was performed, with patients diagnosed with invasive breast carcinoma between September 2010 and September 2011.n = 27: 22 imaging normal, three equivocal, two abnormal).See Figure This is the first study correlating preoperative imaging with OSNA. Our high rate of preoperative diagnosis is encouraging, but suggestions for improvement are discussed."} +{"text": "In clinical practice, the risk of cerebrovascular events originating from carotid atherosclerotic plaques is correlated to the degree of luminal narrowing, commonly designated the degree of stenosis. Though the degree of stenosis is a proven marker of plaque vulnerability, it is widely recognized that better risk markers for cerebrovascular events are needed. Known morphological features of plaque vulnerability are large lipid-rich necrotic cores (LR-NC) with thin fibrous caps that generate localized elevated mechanical stresses within the fibrous cap separating arterial lumen from LR-NC. Thus, determination of local biomechanics using computational simulations may have clinical implications.Biomechanical stress levels could be indicative of plaque rupture risk. Thus, we wished to determine whether different plaque morphologies in a longitudinal section affects the level of local mechanical forces.Two patients scheduled for carotid endarterectomy were scanned using MRI and idealized anatomical 2D models of individual carotid bifurcations were created figure . KeepingSignificant differences were apparent comparing the two different patient morphologies using surface plots of degree of stenosis, peak principal mechanical stresses, and fibrous cap thickness figure . In partIdentical plaque morphologies may yield significantly different mechanical stress levels depending on vessel geometry. Further studies are needed to determine if the varying stress levels are indicative of differing risks of plaque rupture."} +{"text": "The ability to accurately identify bird species is crucial for wildlife law enforcement and bird-strike investigations. However, such identifications may be challenging when only partial or damaged feathers are available for analysis.Meleagris gallopavo), Canada goose (Branta canadensis), blue heron (Ardea herodias) and pygmy owl . The mtDNA was successfully obtained from 'fresh' feathers, historic museum specimens and archaeological samples, demonstrating the sensitivity and versatility of this technique.By applying vigorous contamination controls and sensitive PCR amplification protocols, we found that it was feasible to obtain accurate mitochondrial (mt)DNA-based species identification with as few as two feather barbs. This minimally destructive DNA approach was successfully used and tested on a variety of bird species, including North American wild turkey (By applying appropriate contamination controls, sufficient quantities of mtDNA can be reliably recovered and analyzed from feather barbs. This previously overlooked substrate provides new opportunities for accurate DNA species identification when minimal feather samples are available for forensic analysis. Accurate identification of bird species is crucial for wildlife law enforcement and other aspects of wildlife forensics. Currently, many birds and bird products (such as feathers) are protected under the US Migratory Bird Treaty (MBTA), the US Endangered Species Act (ESA) and the Convention on International Trade in Endangered Species (CITES). Identification of these protected species by law enforcement personnel may be challenging when only partial or damaged feathers are available for examination. Additionally, other criminal investigations, such as bird larceny, may also be contingent upon accurate species identification of bird feathers . Althouget al. [GenBank: BLAST: Basic Local Alignment Search Tool; EDTA: ethylene diamine tetraacetic acid; PCR: polymerase chain reaction; MSSC: modified silica-spin column; QDIK: Qiagen's DNA Investigator Kit; SFU: Simon Fraser University.The authors declare that they have no competing interests.CFS participated in the design of the study, performed DNA extractions and PCR amplifications, conducted sequence alignments and species identifications, and drafted the manuscript. GPN conceived of the study, participated in its design and helped to draft the manuscript. DYY participated in the design and coordination of the study, performed DNA extractions and amplifications, and helped to draft the manuscript. All authors read and approved the final manuscript."} +{"text": "International policy is placing increasing emphasis on adaptation to climate change, including the allocation of new funds to assist adaptation efforts. Climate change adaptation funding may be most effective where it meets integrated goals, but global geographic priorities based on multiple development and ecological criteria are not well characterized. Here we show that human and natural adaptation needs related to maintaining agricultural productivity and ecosystem integrity intersect in ten major areas globally, providing a coherent set of international priorities for adaptation funding. An additional seven regional areas are identified as worthy of additional study. The priority areas are locations where changes in crop suitability affecting impoverished farmers intersect with changes in ranges of restricted-range species. Agreement among multiple climate models and emissions scenarios suggests that these priorities are robust. Adaptation funding directed to these areas could simultaneously address multiple international policy goals, including poverty reduction, protecting agricultural production and safeguarding ecosystem services. The need for adaptation to climate change is an emerging focus of international policy . The impEcosystem-based Adaptation is the use of ecosystem services to help people adapt to climate change. Intact ecosystems provide clean water, shoreline protection, and other services in the face of climate change, providing adaptation options that are often cheaper and more enduring than technical or engineering solutions . MaintaiPriorities linking ecosystems and food production are particularly important because human and natural responses to climate change are interwoven \u20138. ImpovAdaptation action in these areas could simultaneously enhance food security and maintain ecosystem function. This has policy relevance on multiple levels, as food security and ecosystem integrity are two of the three major benchmarks for climate change response established in the United Nations Framework Convention on Climate Change (UNFCCC), and make substantial contribution towards sustainable development, thus helping meet all three UNFCCC criteria . However2) which are indicative of highly complex and biodiverse ecosystems pre pre43] pUncertainty associated with species and agricultural modeling is more difficult to constrain. In the tropics, species ranges may not sample all climatic conditions that are physiologically tolerable, resulting in over-estimation of range loss. Adaptation priorities for non-avian restricted-range species may not match those for birds, due to different taxonomic climatic tolerances. SDM are fitted to empirical data using current climatic conditions and may not simulate future range changes well when future climatic conditions are outside the range of current climate. Adaptation in agriculture may moderate crop losses, resulting in over-estimation of crop impacts. For instance, consumption may switch to crops which may be grown in a region but are not culturally favored, once suitability for preferred crops declines. For these reasons, regional analyses incorporating social factors, taxa other than birds, and analyses of adaptation capacity are essential complements to this global analysis.The priorities identified here reinforce and expand on the findings of other research into agricultural and biodiversity responses to climate change. Areas of agricultural vulnerability identified in this study overlap with those defined in other global assessments of agricultural impacts of climate change \u201346. For Possible adaptation responses in these priority areas might include actions that integrate adaptation for agriculture and ecosystems. For instance, agroforestry can help reduce soil temperatures and maintain soil moisture as air temperatures increase, and, with the appropriate choice of tree species, can help provide habitat for restricted-range birds and other wildlife. Protecting upland forests that provide fog interception or provide watershed protection for dams may be critical for agriculture in areas of declining precipitation, at the same time providing habitats that will permit range migrations in forest birds responding to climate change. Many of these solutions require planning on scales broader than individual farms or protected areas, which is why we have aggregated our results at spatial scales roughly coincident with scales of ecosystem and regional planning (one degree).It is likely that finer-grained analyses will confirm some or all of the regional priority areas identified will be required. Both approaches can be effective , so wiseAdaptation practice is currently being pioneered in first-generation projects around the world. These efforts are addressing the adaptation needs of communities and ecosystems, increasingly recognizing deep interdependencies between the two. Meeting short-term development needs while establishing long-term sustainability of ecosystem services is a fundamental challenge. Among the best places to build experience in melding human and ecosystem responses will be regions experiencing substantial change in both. Innovative solutions and lessons from these areas can inform second-generation adaptation responses worldwide. Investment in the priority regions identified here is therefore a first step in developing a lasting, multi-sector approach to adaptation.Table S1Species and parameters used for EcoCrop modeling.Some crop species contained different species and varieties, so the model adapted the widest range of environmental requirement among species/varieties. The list of species used in the model appears below the table. Minimum and maximum temperature/precipitation requirements represent the environmental range where crop growth is possible and optimal minimum and maximum temperature/precipitation requirements are the environmental range of optimal growth.(DOCX)Click here for additional data file.Figure S1Performance of each SDM tested by overall accuracy, Kappa, TSS, MCC, specificity and sensitivity.Maxent scored highest performance except sensitivity that RF scored the highest performance.(TIF)Click here for additional data file.Figure S2Global map of crop suitability and suitability for range restricted birds change in 2050 under A2 emission scenario.Areas in which overall decreases are anticipated in crop suitability are shown in green, with increasing color intensity indicating multiple GCM agreement. Areas of declining climatic suitability for restricted range birds are shown in blue, with increasing color intensity indicating multiple GCM agreement. Overlap of declining crop suitability and declining restricted range bird climatic suitability is shown in shades of yellow (lowest GCM agreement) to red (highest GCM agreement).(TIF)Click here for additional data file.Figure S3Global map of crop suitability and suitability for range restricted birds change in 2050/2090 under B1 emission scenario.Areas in which overall decreases are anticipated in crop suitability are shown in green, with increasing color intensity indicating multiple GCM agreement. Areas of declining climatic suitability for restricted range birds are shown in blue, with increasing color intensity indicating multiple GCM agreement. Overlap of declining crop suitability and declining restricted range bird climatic suitability is shown in shades of yellow (lowest GCM agreement) to red (highest GCM agreement).(TIF)Click here for additional data file.Figure S4Global map of crop suitability and suitability for range restricted birds change in 2050/2090 under A2 emission scenario using the ensemble mean of 5 GCMs.Areas in which overall decreases are anticipated in crop suitability are shown in green. Areas of declining climatic suitability for restricted range birds are shown in blue. Overlap of declining crop suitability and declining restricted range bird climatic suitability is shown in red.(TIF)Click here for additional data file.Figure S5Global map of crop suitability and suitability for range restricted birds change in 2050/2090 under B1 emission scenario using mean of 5 GCMs.Areas in which overall decreases are anticipated in crop suitability are shown in green. Areas of declining climatic suitability for restricted range birds are shown in blue. Overlap of declining crop suitability and declining restricted range bird climatic suitability is shown in red.(TIF)Click here for additional data file.Figure S6Global map of crop suitability and suitability for range restricted birds change in 2090 under A2 emission scenario using 6 Species Distribution Model results.Areas in which overall decreases are anticipated in crop suitability are shown in green, with increasing color intensity indicating multiple GCM agreement. Areas of declining climatic suitability for restricted range birds are shown in blue, with increasing color intensity indicating multiple GCM agreement. Overlap of declining crop suitability and declining restricted range bird climatic suitability is shown in shades of yellow (lowest GCM agreement) to red (highest GCM agreement).(TIF)Click here for additional data file."} +{"text": "Stress myocardial perfusion MRI allows for accurate detection of flow-limiting stenosis in the coronary artery. However, reduced diagnostic accuracy of stress myocardial perfusion MRI was reported in patients with coronary artery bypass grafts (CABG). Flow measurement in CABG is another MR approach that permits functional assessment of graft stenosis. The purpose of this study was to evaluate the value of MR study that combines MR flow measurement of CABG and stress myocardial perfusion MRI in detecting graft stenosis.Thirty-two consecutive patients with previous CABG surgery who had recurrent chest pain were studied. All patients gave informed consent and underwent both coronary angiography and cardiac MRI. After obtaining cine MRI, stress-rest myocardial perfusion MRI and late gadolinium enhanced (LGE) MRI, blood flow volume in the resting state was quantified in 61 graft conduits by using phase contrast cine MRI. The presence or absence of myocardial ischemia was visually determined by identifying stress-induced hypoenhancement in the absence of LGE or hypoenhancement larger than LGE. Stenoses \u226570% in grafts or grafted native vessels were considered significant on coronary angiography.Coronary angiography revealed significant stenoses in the grafts or grafted native vessels in 19 (31%) of the 61 CABG conduits. Stress-rest perfusion CMR alone yielded the sensitivity and specificity of 73% and 81%, respectively. Receiver operating characteristic analysis demonstrated that the optimal cutoff values of MR blood flow volume was 28mL/min for predicting significant stenosis on angiography . By combining MR blood flow measurement and stress-rest perfusion MRI, the sensitivity and specificity of MR study were improved to 95% and 81%.MR flow measurement of CABG combined with stress-rest perfusion MRI can provide excellent diagnostic accuracy for predicting significant stenoses in the grafts or grafted native vessels in patients with previous CABG.Departmental reseach funding."} +{"text": "Previously proposed panels of liver fibrosis usually include 2 to 7 blood markers. The majority of publications were concerned with liver fibrosis among patients with chronic hepatitis C (CHC). However, few studies have assessed drug-mediated liver fibrogenesis, non-alcoholic fatty liver disease (NAFLD), Schistosoma mansoni-induced liver fibrosis, and hepatitis B virus-related liver fibrosis. In the work entitled \"Noninvasive assessment of liver fibrosis with the aspartate transaminase to platelet ratio index (APRI): Usefulness in patients with chronic liver disease,\" authors The authors came to the conclusion that APRI was significantly associated with fibrosis score in patients with CHC and NAFLD, but not in patients with CHB. However, some reports showed a significant correlation between fibrosis scores and APRI in Chinese and KoreConsequently, studies that investigate populations with etiologically different liver fibrosis may require the use of indices that involve direct fibrogenesis and/or oxidative stress markers, in addition to liver specific markers. The limited number of variables in APRI may minimize its potential in monitoring the basic events in scar formation, which is the common scenario in etiologically different fibrosis. However, the contradictory outcomes of different studies in the last few years may raise the question: Do we need a common liver fibrosis index or etiology-related indices?"} +{"text": "This study is to evaluate the early results treatment of patients with total occlusion of the left main coronary artery. Total occlusion of the left main coronary artery is a very rare finding in patients with acute coronary syndrome. In these cases, patients present various clinical symptoms, however the symptoms and the survival of these patients depend on the development of collaterals and adequate medical intervention.Between January 2002 till May 2013, four patients with acute coronary syndrome caused by total occlusion of the left main coronary artery underwent emergent coronary artery bypass grafting(CABG). All patients presented chest pain, signs of cardiogenic shock with CK-MB level above100 ng/ml on admission. IABP was inserted and emergent PCI and consecutive surgery within 24 hrs were performed. One patient out of the four underwent on-pump beating heart CABG, the rest of the patients underwent classical CABG with induced cardiac arrest using blood cardioplegia with maintained normothermia. Early postoperativeevaluation was performed in terms of: ejection fraction, bleedings, CK-MB level and deaths.Three patients, who underwent classical CABG with induced cardiac arrest using blood cardioplegia with maintained normothermia, survived, whereas patient who underwent on-pump beating heart CABG died in the post-operative period due to hemodynamic failure with an ineffective response to reanimation.It is very difficult to treat such patients with acute coronary syndrome complicated with cardiogenic shock caused by total occlusion of left main coronary artery. Such patients could develop massive myocardial infarction and should be treated immediately with emergent PCI, IABP and emergent CABG within 24 hours.On-pump beating heart CABG is possible in these patients, however we recommend treating such highly risky patients by CABG with induced cardiac arrest using blood cardioplegia with maintained normothermia."} +{"text": "Lupus nephritis belongs to the most serious organ involvements in juvenile systemic lupus erythematosus (SLE) and its adequate treatment is crucial for the prognosis of the disease. The intensity of the treatment should be determined by the kidney biopsy findings scored by the WHO or ISN/RPS classifications. Considering the benefits and risks of the kidney biopsy, some authors have suggested indications for its performance in lupus nephritis based on clinical manifestations comprising significant proteinuria, haematuria with proteinuria, presence of cellular casts and elevated serum creatinine. However, many studies have revealed notable discrepancies between the clinical signs and biopsy findings. Thus, performing kidney biopsy especially in a juvenile SLE patient with no clinical signs of renal disease remains controversial.To emphasize the role of renal biopsy in patients with juvenile SLE with normal clinical kidney manifestations.A case report of a patient diagnosed and treated in a pediatric rheumatology centre in multidisciplinary collaboration.A thirteen-year-old boy presented with arthritis and pleural effusion. His laboratory tests showed elevated ESR, anemia, leukopenia, decreased C3 and C4, positive ANA and anti-dsDNA. Despite normal urine sediment, creatinine clearence and no proteinuria, kidney biopsy was performed and revealed diffuse proliferative lupus glomerulonephritis class IV-S(A) according to the ISN/RPS 2003 classification. In the next course Libman-Sacks endocarditis occurred. With diagnose of juvenile SLE with severe kidney involvement the patient was treated with corticosteroids and intravenous cyclophosphamide followed by azathioprine, which was later switched to cyclosporine A, subsequently in combination with mycophenolate mofetil. Despite the serious course of the disease urine analysis and creatinine clearence remained normal for the whole period.Based on our experience with a patient with juvenile SLE with severe lupus nephritis despite their normal urine analysis and creatinine level, in accordance with some other authors, we recommend performing kidney biopsy in newly diagnosed juvenile SLE patients unless the risk to benefit ratio of the procedure is very high."} +{"text": "This case report highlights an unusual case of sudden sensorineural hearing loss related to superficial siderosis (SS). Our patient had a craniotomy for medulloblastoma 23 years earlier, and this may represent a delayed complication related to this procedure. Magnetic resonance imaging (MRI) remains the key diagnostic investigation to illustrate the imaging features of superficial siderosis and exclude other pathologies. Increased awareness of progressive and sudden hearing complications caused by SS is important in the otolaryngologic community to expedite management and better counsel patients during the consent process. Superficial siderosis (SS) classically affects the leptomeninges, brain, brainstem, cerebellum, cranial nerves and spinal cord secondary to hemorrhage and hemosiderin deposition . Hemosid It is an uncommon condition with only approximately 100 cases reported . Early c This case report provides an account of a young male who presented with sudden sensorineural hearing loss. A 30-year-old Caucasian male patient presented to our clinic with sudden-onset left-sided sensorineural hearing loss and nonpulsatile tinnitus. His medical background was remarkable for a medulloblastoma treated with a suboccipital craniotomy and tumour resection with adjuvant radiotherapy at the age of seven. The patient had no postoperative complications or evidence of tumour recurrence on long-term followup. Examination revealed bilateral sensorineural hearing loss on tuning fork testing with normal otoscopic findings. Dysdiadochokinesia, past pointing, and intention tremor were also noted affecting the patient's left upper limb. Audiometry showed bilateral down-sloping moderate-severe sensorineural hearing loss, which was slightly worse on the left side. No prior audiometry was available for comparison. The pathogenesis of SS results from chronic hemorrhage into the subpial layers with a predilection for the superior vermis, crests of the cerebellar folia, basal frontal lobe, temporal cortex, brainstem, spinal cord, nerve roots, and cranial nerves one and eight. The sources of hemorrhage are cerebrospinal fluid (CSF) cavity lesions, tumors, and vascular abnormalities . The exhaustion of ferritin biosynthesis by the microglial cells as a result of iron overload subsequently causes neuronal injury . Cerebel The patient's history of previous intradural cranial surgery for medulloblastoma is a risk factor for later development of SS and may T2-weighted fast imaging employing steady-state acquisition (FIESTA) magnetic resonance imaging (MRI) revealed hypointense thickened bands along the vestibulocochlear nerves bilaterally which represent classic diagnostic features of SS . FIESTA SS is a well-described delayed complication following craniotomy. Patients and their carers must be counseled regarding its association with sensorineural hearing loss, both sudden and progressive, during the consent process. Increased awareness of SS amongst the otolaryngologic community is important so that appropriate audiometric testing, imaging, and management may be expedited."} +{"text": "Weight suppression has been found to negatively predict treatment completion of cognitive behavioural therapy (CBT). However, subsequent attempts to replicate these findings have failed. In light of this, the current study revisits the relationship between weight suppression and treatment outcomes in bulimia nervosa. We propose that moderator effects may assist in interpreting previous inconsistency. Moderators tested were parent history of overweight, chubby/overweight childhood body shape, higher pre-treatment body mass index, and highest ever adult weight discrepancy. Participants were 117 female outpatients aged 16-54 years with bulimic disorders treated with enhanced cognitive behavioural therapy at a specialist community clinic. Logistic regression indicated that pre-treatment weight suppression did not predict drop-out or poor treatment outcome. No moderator effects were observed when hypothesised moderator features were included in treatment completion or treatment outcome models. The current study calls into question the association between weight suppression and treatment outcome. Future research into moderator models, using a larger sample, could assist us to refine conceptualizations of why some patients who have a weight suppression history are vulnerable to poor treatment adherence and outcome and to establish clinical interventions that enhance prognosis.Adult Treatment and Services stream of the 2013 ANZAED Conference.This abstract was presented in the"} +{"text": "Lobular capillary hemangioma (LCH) is a benign lesion of vascular origin. It rarely involves nasal cavity which most commonly manifests as progressive nasal obstruction and epistaxis. In this report we present a case of LCH of the nasal cavity which occurred approximately one month after delivery. There was no recurrence after complete endoscopic resection during one year follow up. Lobular capillary hemangioma (LCH) is a benign lesion of vascular origin. The most common sites of lesion are the skin and oral mucosa. LCH rarely involves nasal cavity which most commonly manifests as progressive nasal obstruction and epistaxis. Trauma and hormonal changes are presumed as two major predisposing factors -4. In thA 32-year-old woman came to hospital clinic with complaint of progressive right-sided nasal obstruction associated with intermittent mild epistaxis, muco-purulant rhinorrhea and post nasal drip since 10 months ago began one month after her uncomplicated delivery of a normal baby. She was completely asymptomatic during her pregnancy.. She didn\u2019t mention any history of nasal trauma or nasal intubation but she has had history of multiple nasal packing during recent months. Endoscopic examination of nasal cavity revealed a red large polypoid mass which bled easily and originated from posterior part of middle turbinate.A CT scan of the paranasal sinuses also revealed a right nasal cavity soft tissue mass without any evidence of bony destruction or extension of the mass into the adjacent paranasal sinuses .The patient was taken to the operating room where the soft tissue mass was completely excised using endoscopic techniques. The surgery involved partial resection of the middle turbinate .Histologic finding showed proliferation of small capillaries lined by plump endothelial cells in a loboular pattern .There was no recurrence during the one-year follow-up period.Hemangiomas are vascular neoplasms that morphologically classified in to capillary, cavernous, arteriovenouse and epitheliod type . LCH, whThe etiology of LCH remains unknown but trauma and hormonal changes, such as those that occur in pregnancy, are thought to be major etiologic factors. Viral oncogenes, microscopic arteriovenous malformations, cytogenetic abnormalities and production of angiogenic factors are also associated with LCH . In fourA giant pyogenic granuloma of the posterior part of the nasal septum that occurred after prolonged use (30 days) of a nasogastric feeding tube has also been recorded . In a st Clinical symptoms include nasal obstruction, Epistaxis, Epiphora, purulant or mucous rhinorrhea and nasal deformity . In a stThe treatment of choice for these lesions is complete excision using endoscopic approach even for large lesions. In our case, there was no recurrence after complete endoscopic resection during one year follow up."} +{"text": "Grass pollen allergens are a major cause of allergic respiratory disease but traditionally prescribing practice for grass pollen allergen-specific immunotherapy has favoured pollen extracts of temperate grasses. Here we aim to compare allergy to subtropical and temperate grass pollens in patients with allergic rhinitis from a subtropical region of Australia.Paspalum notatum), Johnson grass and Bermuda grass (Cynodon dactylon) as well as the temperate Ryegrass (Lolium perenne) were measured by skin prick in 233 subjects from Brisbane. Grass pollen-specific IgE reactivity was tested by ELISA and cross-inhibition ELISA.Sensitization to pollen extracts of the subtropical Bahia grass (Patients with grass pollen allergy from a subtropical region showed higher skin prick diameters with subtropical Bahia grass and Bermuda grass pollens than with Johnson grass and Ryegrass pollens. IgE reactivity was higher with pollen of Bahia grass than Bermuda grass, Johnson grass and Ryegrass. Patients showed asymmetric cross-inhibition of IgE reactivity with subtropical grass pollens that was not blocked by temperate grass pollen allergens indicating the presence of species-specific IgE binding sites of subtropical grass pollen allergens that are not represented in temperate grass pollens.Subtropical grass pollens are more important allergen sources than temperate grass pollens for patients from a subtropical region. Targeting allergen-specific immunotherapy to subtropical grass pollen allergens in patients with allergic rhinitis in subtropical regions could improve treatment efficacy thereby reducing the burden of allergic rhinitis and asthma. Grass pollens are amongst the most frequently recognised aeroallergens worldwide ,2. AllerLolium perenne) which is the major clinically relevant allergenic grass pollen in temperate regions of Australia [Paspalum notatum), Johnson grass and Bermuda grass (Cynodon dactylon) were among the most abundantly observed grasses [Despite the clinical importance of grass pollen allergy in allergic respiratory diseases, it has not been established which of the grass pollens are most relevant to Australian environments, with the exception of Ryegrass grass pollen extracts, house dust mites , cat hair , moulds , and Ragweed pollen .Skin prick testing were performed according to the guidelines of the Australian Society for Clinical Immunology and Allergy . BrieflyArachis hypogaea extract) was prepared as a control allergen [Proteins from non-defatted pollen grains of Ryegrass, Bahia, Timothy, Johnson and Bermuda grasses were extracted in phosphate buffered saline with complete protease inhibitor cocktail for three hours on a rotating wheel at 4\u00b0C and clarified as previously described . Raw peaallergen .Plasma samples diluted 1/10 were tested by ELISA with microtiter plate wells coated with 5 \u03bcg/ml of whole grass pollen extract as described previously . InhibitData was assessed for normality by Kolmogorov-Smirnov test and assessed for differences by Friedman's ANOVA with Dunn's multiple comparison tests. P values less than 0.05 (*), < 0.01 (**), or < 0.001 (***) were considered significant. Correlations of SPT and IgE reactivity between different grass pollens were determined by Spearman's rank test for paired data.Participants were recruited from amongst patients presenting to an Immunology or Respiratory clinic at a major public hospital in Brisbane, as well as amongst healthcare and laboratory workers. Seventy seven participants were skin prick test (SPT) negative to all aeroallergens tested. Eighty subjects were SPT positive to allergens other than grass pollens with house dust mite being the most frequently recognized allergen. Seventy six of the 233 participants assessed by skin prick tests showed positive reactions to at least one grass pollen extract . There were 48 grass pollen-allergic subjects for whom SPT data was available for each of Ryegrass, Bahia, Johnson and Bermuda grass pollens. Of these 48 subjects there were eight (16%) who only showed positive SPT to subtropical grasses, whereas three (6%) showed a positive SPT to Ryegrass pollen only.SPT wheals were significantly larger with Bahia and Bermuda grass pollens than with Ryegrass pollen Figure . InteresThere were significant correlations in allergic sensitivity between each of the grass pollens Table . The strIgE reactivity with each of the grass pollens was tested by ELISA in 175 subjects for whom plasma was available. The IgE reactivity of the 70 SPT-negative, non-atopic donors was used to define the normal range. Concentrations greater than three standard deviations above the mean IgE reactivity of normal subjects were considered positive; these cut off values were as follows - Bahia grass , Bermuda grass (0.129 OD) and Ryegrass (0.187 OD). Using this definition, of 50 subjects with allergies other than grass pollen, there were one, two, two and four subjects who tested positive for IgE reactivity with Bermuda, Johnson, Bahia and Ryegrass pollen, respectively. Forty five of 55 (81%) of grass pollen-allergic subjects with positive SPT to any grass pollen showed IgE reactivity with at least one of the four grass pollens by ELISA. There were ten subjects (18%) who only showed IgE reactivity with subtropical grass pollens whereas only four (7%) subjects showed IgE reactivity with Ryegrass pollen only. Mostly, subjects showed IgE reactivity with more than one grass pollen but there were differences in the levels of IgE reactivity.The IgE reactivity of the grass pollen-allergic donors was higher with Bahia grass pollens than with Johnson and Ryegrass pollens Figure . IgE reaPlasma IgE reactivity with each of the grass pollens were well correlated amongst the grass pollens Table . HoweverReciprocal cross-inhibition assays were performed in a subset of subjects known to have grown up in the Brisbane area and who would represent patients primarily exposed to subtropical grass pollens, in order to compare the strength of IgE reactivity with subtropical versus temperate grass pollen allergens Figure . The relHitherto grass pollen allergy has been primarily studied in subjects living in regions with temperate climates such as parts of Europe and North America where Timothy grass pollen is the predominant clinically important grass pollen. Ryegrass pollen has been considered to be the most clinically important grass pollen allergen in Australia ,13. HoweHere we show marked differences in the relative avidity of IgE binding between different grass pollens in dose responsive four-way reciprocal cross-inhibition experiments. Other studies of patients from temperate regions focused on inhibition of IgE reactivity with Timothy grass pollen extract or its allergenic components with an excess of pollen inhibitor and reported maximal inhibition capacity but not relative avidity as revealed by decreasing doses of pollen inhibitor ,27. PoolThere were differences in the degree of correlation of SPT sensitivity Table and plasThere are known to be differences in allergen composition amongst grass pollens. Pollens of different species of temperate grasses all contain several major allergen families including group 1, 2, 4 and 5 whereas the subtropical grass pollens lack the group 2 and 5 allergen families . There aThe difference in allergic sensitivity and allergen recognition depends not only on biological differences between the pollens but also upon the origin of the patients investigated. Our observations with patients from a subtropical region is in contrast to IgE reactivity of patients from the temperate region city of Melbourne, who showed substantially higher IgE reactivity with pollens of Ryegrass compared with Bahia and Bermuda grasses . SimilarWe also sought to compare the allergic sensitivity and IgE reactivity amongst subtropical grass pollens. The same heterogeneity evident within temperate grass pollen allergens discussed earlier might be expected for pollen allergens of the subfamilies of subtropical grasses. Indeed we observed Johnson grass pollen elicited lower SPT and plasma IgE reactivity than Bahia grass pollen as well as lower capacity to inhibit serum IgE reactivity with other grass pollens, including Bahia grass pollen suggesting that there may be allergenic differences between these Panicoideae grass pollens. It is worth considering that although both these grasses belong to the one subfamily they align to different subtribes, Paniceae for Bahia grass and Andropogoneae for Johnson grass, which may explain why these grass pollens were not interchangeable. A difference between Bahia and Bermuda grass pollens was not evident by SPT but Bahia grass pollen showed higher levels of IgE reactivity than Bermuda grass pollen. We noted that Bermuda grass pollen appeared to be more allergenically distinct from Ryegrass than Bahia grass pollen since in three of five donors IgE reactivity with Bermuda was only substantially inhibited by itself and it had only limited capacity to block IgE reactivity with Ryegrass, Johnson or Bahia in some subjects. Also, SPT and plasma IgE reactivity with Bermuda showed the least correlation with Ryegrass suggesting greater allergenic differences between Bermuda and Ryegrass pollens than between Bahia and Ryegrass. However, further studies are warranted to confirm this observation with a wider representation of patients from subtropical regions.The outcomes of this study are likely to impact upon the clinical efficacy of grass pollen allergen-specific immunotherapy in patients from a subtropical region. Whilst for many treatment for allergic rhinitis can be managed by allergen avoidance and pharmacotherapy, for others with more severe disease, specific immunotherapy is indicated . Grass pHere we demonstrate higher SPT and IgE reactivity with subtropical grass pollens than Ryegrass in patients from a subtropical region. We also observed incomplete and asymmetric cross-inhibition of serum IgE between subtropical grass pollens and the Ryegrass pollen allergen in patients with grass pollen allergy in Brisbane. Further studies are warranted to assess difference in allergic sensitization in other parts of Australia, including arid and wet tropical regions where there are hotter climates and subtropical grass pollens are likely to contribute to grass pollen sensitization. It will be necessary in the longer term to investigate whether differences observed here in IgE recognition of subtropical and temperate grass pollen affect the efficacy of immunotherapy for patients primarily sensitized to subtropical grass pollen allergens in Australia and other regions with similar climatesELISA: Enzyme-linked immunosorbant assay; IC50: Inhibitor concentration giving 50% inhibition; IgE: Immunoglobulin E; OD: Optical density units; SPT: Skin prick test.JMD has received grants from the Asthma Foundation of Australia, Australian Society for Clinical Immunology and Allergy, The University of Queensland and the National Health and Medical Research Council of Australia, has collaborations with Sullivan Nicolaides Pathology (Queensland) and Phadia Pty Ltd , and is an inventor on an Australian and US patent on \"Novel immunogenic molecules and uses thereof (Bahia grass)\". JMD has also received consulting fees from Stallergenes Pty Ltd and has a collaborative research agreement with this company. MT has received Honoraria from Novartis for asthma nurse education presentations. JWU has been paid Honoraria from Astra Zeneca to present updates on asthma at approved medical education events.JD was the senior author of this manuscript. JD designed the study, analysed data, prepared and edited the manuscript. HZL performed the ELISA experiments. MG and MT assisted with patient recruitment and skin prick testing. JWU was involved with subject recruitment and provided intellectual input to the study. All authors read and approved the final manuscript."} +{"text": "Monilethrix is an autosomal dominant hair shaft disorder characterized by intermittent constrictions result in short and fragility hair. We present here two afghan siblings girl, 5 and 3 years, born of consanguineous marriage, come to our department of dermatology with complains of hair loss and inability to growth long hair of the scalp since birth. When the hairs reached a certain length, they were broking. There was no relevant familial history. On examination, we found diffuse thinning of scalp hair with broken, short and spars hairs. The length of hairs was less than 2 centimeter. Multiple keratotic papules were present on entire the scalp. Hairs in eyebrows also were involved. Diffuse hair loss seen in trunk and extremity. Nails and dental were normal appearance. Other systemic examination of hair showed beaded appearance with certain interval. Histopathologic examination of scalp showed misdirection with abnormal and tortuous appearance and bulb shaped shaft in some foci considering for monilethrix. Its differential diagnosis include monilethrix-like congenital hypothericosis, alopecia areata with variable activity in the course of disease, primary cicatricial alopecia (border of fibrotic area), chemotherapy induced alopecia, monilethrix-like effect from hair styling gel and pseudo-monilethrix. There is no specific treatment of monilethrix. Improvement by hormonal treatment reported in one study that hair growths increased after first menstrual period, so it suggested hormonal influence may improve hair growths. In literatures many different options for treatment of monilethrix proposed such as oral retinoid Griseofulvin and recently topical minoxidil 2%. One study showed improvement molinethrix after treatment by iron supplementation in iron deficiency anemia."} +{"text": "Eliciting effective antibody responses are key to the design of HIV vaccines. While the HIV envelope protein is highly immunogenic and provokes a high-titer antibody response during viral infection and experimental immunization, affinity-matured antibodies capable of neutralizing diverse HIV isolates are rarely elicited. While recent vaccine regimens have focused on DNA, viral vector, VLP, or attenuated virus vaccines, of increasing interest are improved recombinant envelope protein immunogens. Immunizations with trimeric gp140 proteins induce higher-titer neutralizing antibody responses and have structural benefits over monomeric gp120 immunizations. Novel approaches being taken for recombinant trimeric gp140 immunogens include the use of consensus and multi-clade gp140 trimers. A consideration for these synthetic proteins that is key to vaccine efficacy: do these proteins structurally represent a native trimeric envelope?To address potential differences in the functional conformation of gp140 trimers, we evaluated the conformational characteristics of trimeric gp140 proteins from varying HIV-1 strains as well as engineered consensus gp140s via binding studies using surface plasmon resonance with a panel of well-characterized monoclonal antibodies (MAbs).Consensus trimers were recognized by more monoclonal antibodies than the primary strain gp140s, suggestive of the benefits of engineered trimers. However, analysis revealed a low trimer concentration that is competent to bind the quaternary-recognizing MAb PG9. Considering the binding to other conformational MAbs, this suggests that while the consensus gp140s contain appropriately conformational monomers and are trimeric, the vast majority of the protein is not in a proper quaternary structure.These data suggest that it is important to fully assess structural differences of immunogens even though obvious phenotypic differences may not be present. Taken together, these observations demonstrate the need to evaluate immunogens in a manner that allows the measurement of functional epitope exposure and solution conformation to assess the potential to elicit a potent, broadly-neutralizing antibody response."} +{"text": "FUS is a DNA/RNA binding protein found to be mutated in some cases of both sporadic and familial forms of ALS. It is still not clear how ALS-causing mutations in FUS leads to motor neuron degeneration. Here, we exploited a Drosophila model and mammalian neuronal cell lines to elucidate the role of the RNA-binding ability of FUS in regulating FUS-mediated toxicity. To determine the role of the RNA binding ability of FUS in ALS, we mutated FUS RNA binding sites to leucines and generated RNA binding-incompetent mutants (4F-L) with and without ALS causing mutations R518K or R521C. We found that mutating 4F to L residues makes FUS RNA binding-incompetent. We observed that ectopic expression of RNA binding-incompetent FUS in fly brain, eyes and motor neurons strongly blocks neurodegenerative phenotypes as compared to RNA-binding-competent FUS carrying ALS causing mutations. Interestingly, RNA-binding deficient FUS strongly localized to the nucleus of Drosophila motor neurons and mammalian neuronal cells whereas FUS carrying ALS linked mutations was distributed to the nucleus and cytoplasm.in vivo unbiased genetic screen that led to the discovery of several dominant modifiers of mutant FUS toxicity including proteins involved in regulating SG dynamics, mitochondrial functions and RNA splicing. These genetic modifiers would help in identifying potential therapeutic targets for ALS.Importantly, we found that incorporation of mutant FUS into stress granules is dependent on the RNA-binding ability of FUS. SGs are dynamic aggregates composed of proteins and RNA that are formed when cells are under a variety of stresses. We observed that normally cytoplasmic SGs rapidly disassemble when stress conditions end, whereas cytoplasmic SGs formed in ALS patient cells having a FUS mutation fail to disassemble. This suggests that mutant FUS sequesters proteins and RNAs important for cellular homeostasis and the defect in disassembly of cytoplasmic SGs contributes to ALS. Finally, following up these observations we performed an"} +{"text": "Pompe disease (glycogen storage disease type II) is an autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme acid alpha-glucosidase. Enzyme replacement therapy (ERT) with alglucosidase alfa has resulted in a clinical benefit in a subset of patients. Cross-reactive Immunological Material (CRIM)-negative status is associated with poor prognosis. Patients with CRIM-negative infantile Pompe disease mount a strong immune response against alglucosidase alfa ERT, resulting in a clinical decline and death despite therapy. Most develop high sustained antibody titers. Based on our clinical and laboratory experience, about 40 percent of patients with infantile Pompe disease develop HSAT. Early identification of patients at risk is needed to allow for treatment intervention with immune tolerance induction (ITI) protocols. These protocols have included the use of agents such as rituximab, methotrexate, IVIG, and agents that target the plasma cells. Different treatment approaches are needed for patients with Pompe disease treated with ITI in the na\u00efve setting as compared to patients with high sustained antibody titers. Without ITI, the CRIM-negative patients do poorly on ERT alone. We will present a successful global experience in 15 cases and discuss the safety, efficacy and feasibility of a clinical algorithm developed at our institution to identify CRIM-negative status and allow timely initiation of ERT and ITI in this vulnerable population. Our data show that the clinical algorithm of rapidly diagnosing and initiating ITI coincident with the start of ERT in CRIM-negative patients is feasible and can be achieved in a timely manner."} +{"text": "Xenograft mouse models represent helpful tools for preclinical studies on human tumors. For modeling the complexity of the human disease, primary tumor cells are by far superior to established cell lines. As qualified exemplary model, patients\u2019 acute lymphoblastic leukemia cells reliably engraft in mice inducing orthotopic disseminated leukemia closely resembling the disease in men. Unfortunately, disease monitoring of acute lymphoblastic leukemia in mice is hampered by lack of a suitable readout parameter.Patients\u2019 acute lymphoblastic leukemia cells were lentivirally transduced to express the membrane-bound form of Gaussia luciferase. In vivo imaging was established in individual patients\u2019 leukemias and extensively validated.Bioluminescence in vivo imaging enabled reliable and continuous follow-up of individual mice. Light emission strictly correlated to post mortem quantification of leukemic burden and revealed a logarithmic, time and cell number dependent growth pattern. Imaging conveniently quantified frequencies of leukemia initiating cells in limiting dilution transplantation assays. Upon detecting a single leukemia cell within more than 10,000 bone marrow cells, imaging enabled monitoring minimal residual disease, time to tumor re-growth and relapse. Imaging quantified therapy effects precisely and with low variances, discriminating treatment failure from partial and complete responses.For the first time, we characterized in detail how in vivo imaging reforms preclinical studies on patient-derived tumors upon increasing monitoring resolution. In the future, in vivo imaging will enable performing precise preclinical studies on a broad range of highly demanding clinical challenges, such as treatment failure, resistance in leukemia initiating cells, minimal residual disease and relapse. Preclinical mouse models are helpful tools for studying biology and therapy of diseases. Novel therapeutic approaches undergo detailed preclinical evaluation before translation into clinical trials In cancer research, a variety of different mouse models exist including xenotransplantation models and syngeneic models At best, xenotransplanted tumor cells generate a disease in mice which highly resembles the disease in men Nevertheless, sensitive follow up of leukemia progression in mice remains a limitation of the model. Invasive bone marrow aspirations in mice require prolonged periods of recuperation; blood sampling is hampered by late and heterogeneous presence of tumor cells into the peripheral blood In vivo imaging based on molecular cell marking represents a sensitive readout parameter to monitor xenotransplanted tumors in mice, e.g., using bioluminescence Here, we established the molecular labeling of patient-derived ALL cells and characterized in detail, how bioluminescence in vivo imaging enables a novel level of precision for future preclinical studies. In vivo imaging enabled quantification of treatment effects and monitoring of minimal residual disease in mice. The improved mouse model will allow performing decisive and complex preclinical studies on individual leukemias in the future.Ethikkommission@med.uni-muenchen.de, April 15/2008, number 068-08) and with the Helsinki Declaration of 1975, as revised in 2000.Written informed consent was obtained from all patients and from parents/carers in the cases where patients were minors. The study was performed in accordance with the ethical standards of the responsible committee on human experimentation .All animal trials were performed in accordance with the current ethical standards of the official committee on animal experimentation , 1 mM sodium pyruvate and 50 \u00b5M 1-thioglycerole in the absence of further cytokines as described The IVIS Lumina II Imaging System was used . Mice were anesthetized using isoflurane, placed into the imaging chamber in a supine position and fixed at the lower limbs and by the inhalation tube. Coelenterazine was dissolved in acidified methanol (HPLC grade) at concentration 10 mg/ml and diluted shortly before injection in sterile HBG buffer . Immediately after intravenous tail vein injection of 100 \u00b5g of native Coelenterazine, mice were imaged for 15 seconds using a field of view of 12,5 cm with binning 8, f/stop 1 and open filter setting. To monitor tumor growth, mice were imaged once weekly; after therapy, mice were imaged every other day.4 photons per second per cm2 per solid angle of one steradian (sr). Different regions of interest (ROI) were defined and signals were considered positive, when light emission exceeded background in each ROI; background was measured in 15 mice harboring GLuc negative leukemias; a ROI covering the entire animal was used (background 4\u00d7106 photons per second); as an exception and to determine early engraftment\u200a=\u200aminimal disease, a small ROI was set at femurs at the location, where and when first light emission became visible; depending on the expression level of the transgenes, overt leukemia was considered above 109\u20131010 photons per second using the ROI covering the entire animal; overt leukemia served as criterion for ending experiments, as it shortly preceded onset of clinical signs of disease in mice.The Living Image software 4.x was used for data acquisition and quantification of light emission using a scale with a minimum of 1,8\u00d710Control animals received physiological salt solution intraperitoneally; treatment group mice were injected i.p. with a single dose of either Etoposid or Cyclophosphamide diluted in 0.9% NaCl.http://bioinf.wehi.edu.au/software/elda).Mean and standard error of the mean (SEM) were calculated using the Microsoft Excel 2010 software . To determine significance of treatment effects in vivo, Mann-Whitney Rank Sum Test and the Sigma Plot 12 software was used. CSC frequencies were calculated according to Poisson statistics using the ELDA software application was chosen in its membrane-bound form Leukemia cells are notoriously difficult to transfect and patient-derived leukemia cells do not allow antibiotics-based selection in vitro. Therefore, lentiviral transduction was chosen, although transgene integration into unsuitable genomic sites might alter cell function. GLuc was cloned into a lentiviral vector harboring additionally copepod green fluorescence protein (GFP) . PrimaryAll 9 samples from children with ALL were successfully transduced, although transduction efficiencies and levels of transgene expression varied widely between samples . While hFor imaging, the convenient IVIS Lumina II Imaging System was used together with an optimized protocol (for details see suppl. Results). Kinetics of GLuc-emitted light from leukemia cells was similar to published kinetics on GLuc-expressing T-cells Bioluminescence in vivo imaging using GLuc visualized engraftment of patient-derived ALL cells in mice first in the lower extremities where bones and bone marrow are located directly under the fur . Over tiLikewise, light emission strongly depended on the number of cells injected, indicating that both kinetic and dose response were clearly represented by in vivo imaging in this model . The groTo reassure that imaging reliably visualized the leukemic disease, in vivo imaging data were correlated to conventional post mortem readouts. Single mice engrafted with sample ALL-50 were sacrificed weekly and bone marrow and spleen were analyzed by flow cytometry and immunohistochemistry to quantify leukemic cells. Imaging was more sensitive in detecting leukemic infiltration in bone marrow than in spleen arguing towards the highest sensitivity of imaging in visualizing ALL in bone marrow located directly under the fur , but wasTo quantify light emission, regions of interest were defined and analyzed using the Living Image software 4.0 . In close correlation to the visual impression, quantification revealed first engraftment in a region covering the lower extremities, while inner organs became visible at late time points followed by extremely rapid signal increase . For furQuantification of light emission revealed a strictly logarithmic growth of patient-derived leukemia cells in mice covering up to 4 orders of magnitude . SimilarIndividual leukemias were obtained from patients with very different clinical parameters, including primary disease and relapse, and contained completely different cytogenetic and molecular alterations . Light emission quantification of ALL samples showed that all samples grew in a logarithmic pattern in mice . Thus, logarithmic growth appears as general principle how human leukemia cells behave in mice. Nevertheless and according to published data To control quality parameters of the model, assay variances were estimated. Imaging showed a highly reproducible growth of leukemia in mice with surprisingly low intra- and inter-assay variances considering that an in vivo model was studied represents a major clinical threat as MRD is difficult to treat and often followed by relapse. Appropriate preclinical models to study MRD are required 4 photons per second using defined criteria, see Methods for details), most mice were sacrificed and bone marrow and peripheral blood analyzed by flow cytometry, quantitative real time PCR and immunohistochemistry. All remaining mice showed constant light increase similar to the kinetic shown in To test, whether GLuc-based in vivo imaging could visualize MRD, its sensitivity was measured. Groups of mice were engrafted with equal cell numbers of the same sample and were imaged three times weekly. Upon crossing a clearly defined detection threshold are able to maintain tumor growth and therefore represent the most important targets for anti-cancer therapy Bioluminescence in vivo imaging allowed observing each group of mice within the LDTA repetitively over time . TherebyTNF-related, apoptosis-inducing ligand) prior to transplantation significantly reduced engraftment of cells in mice . Imaging allowed starting treatment in mice with equal tumor burdens, although rarely mice had to be excluded, as leukemia grew highly homogenously in mice . Mice were treated with conventional cytotoxic drugs by systemic bolus injections in concentrations modeling drug doses typically applied in patients Individual leukemias were grown until advanced disease . Treatment nearly eliminated tumor cells from peripheral blood, while imaging visualized the remaining tumor burden post treatment . Due to limited sensitivity, conventional measurement in peripheral blood appears overestimating therapeutic effects, although this readout was most frequently used for disease monitoring until today.In our model, each mouse harbors the leukemia of an individual patient. Imaging-guided preclinical treatment trials in mice revealed that individual ALL samples retained individual sensitivities towards conventional cytotoxic drugs. While the T-ALL sample ALL-4S was sensitive towards treatment with Cyclophosphamide, it was resistant towards Etoposid; in contrast, the B-ALL sample ALL-199 was resistant towards Cyclophosphamide, but sensitive towards Etoposid . AccordiMost importantly, imaging was able to quantify therapeutic responses and to visualize tumor regrowth. Due to low assay variances, imaging allowed distinguishing treatment failure/drug resistance/progressive disease from partial or complete response . As addiTaken together, in vivo imaging allowed the rapid, precise and individual quantification of treatment responses.The sensitivity of tumor cells towards treatment depends on the disease stage at which the drug is given After treatment, imaging reliably quantified residual disease. Short-interval imaging revealed short \u201clag phase\u201d of no-growth after a single application for certain, but not all drugs and samples . In the Taken together, we have introduced and validated in detail GLuc-based bioluminescence in vivo imaging in the xenograft mouse model of individual patient\u2019s ALL. Imaging was easy to perform and gave rise to highly sensitive and reliable results which enable the non-invasive accurate and detailed monitoring of disease progression and treatment responses.GLuc-based bioluminescence in vivo imaging was introduced and intensively validated as novel readout parameter for the preclinical model of patient-derived ALL growing in mice. In vivo imaging allowed performing preclinical trials on a novel level of accuracy and precision including stage-specific therapy and quantification of treatment responses. In the future, improvement of the individualized ALL mouse model by in vivo imaging will allow performing preclinical trials more exactly and in more detail.Imaging allowed modeling disease stages in mice which represent current challenges in the clinics such as minimal residual disease and tumor regrowth. Imaging was highly sensitive and continuous and correlated well with post mortem results regarding tumor distribution. Assay variances were minimal which will reduce the number of animals required per experiment. In addition, tumor growth was orthotopic and homogenous and tumor cells were derived from individual patients with genetically defined tumors; limiting dilution assays were easily visualized to study drug sensitivity of leukemia initiating cells. Taken together, GLuc-based imaging will allow performing high quality and convenient preclinical treatment trials in the individual mouse model of ALL in the future.The most important challenges in cancer treatment represent treatment failure and relapse. Using in vivo imaging, treatment failure is easily detectable in the first days after treatment as light emission continues increasing despite of therapy; short-period treatment quantification will allow speeding up preclinical treatment trials. Tumor regrowth is visualized by quantification of post-therapeutic residual disease followed by monitoring increase in light emission. Thus, our model is able to exactly map both important clinical challenges for preclinical trials.In addition to bioluminescence imaging, fluorescence imaging represents an interesting alternative with a better anatomical resolution, especially using near- infrared fluorochromes Recently, two groups published the use of firefly luciferase for in vivo imaging of transplanted individual ALLs The major advantage of using GLuc instead of firefly luciferase for in vivo imaging is the markedly increased light emission from superficial organs such as bone marrow in the lower extremities of mice Leukemic disease serves as a suitable model disease for cancer in general since leukemia cells are easier in handling compared to solid tumor cells. Many important research discoveries in cancer biology were first described in leukemia; for example, oncogenic mutations are best characterized in acute myeloid leukemia Taken together, GLuc-based in vivo imaging in the individualized preclinical model of ALL enables performing treatment trials on a novel level of accuracy and precision. It enables quantifying therapy effects and remaining disease burdens as well as exact modeling of distinct disease stages. The model facilitates the detailed preclinical analysis of novel therapies for preparing their translation into the clinics. The model allows preclinical trials addressing the most demanding current clinical challenges, such as treatment failure, resistance in leukemia initiating cells, minimal residual disease and relapse.Supporting Information S1(PDF)Click here for additional data file."} +{"text": "The link between high maternal blood pressure and poor pregnancy outcome is well established. Similarly the causal relationship between acute maternal hypotension and acute fetal distress is well recognised. The link between poor pregnancy outcome and persistent maternal hypotension is less well known.McClure Brown was the It is problematic that previously reported studies have defined maternal hypotension differently. However, Warland attempteIn summary, there is a small body of research which has consistently demonstrated the negative effect of persistent maternal hypotension on poor pregnancy outcome including stillbirth. These studies have been conducted using a range of approaches including prospective cohort, retrospective case-control and population based data bank analysis. Many questions remain unanswered, including the definition of hypotension, the level at which hypotension becomes problematic, and how best to manage maternal hypotension in pregnancy."} +{"text": "BCR-ABL translates into an abnormal tyrosine kinase that accelerates development of chronic myelogenous leukemia [Gene fusions are hybrid genes formed when two discrete genes are incorrectly joined together. Gene fusions are found to play roles in tumorigenesis. For example, the fusion gene leukemia . A netwoleukemia performeWe mined three public databases for cancer-related gene fusion sequences, and one database for fusions records from cancer studies, transcriptome analysis, and genetic disorders. Specifically, we processed each dataset by removing incomplete entries and then extracted gene-fusion pairs. Genes serve as the nodes in the network and each fusion pair is joined by an edge. Repeating pairs were represented once. We used Cytoscape to build five networks: one for each dataset and the fifth that encompasses all datasets. We graphed the occurrence of degree in each single dataset network to determine an empirical definition for hub genes.MLL and MALAT1, both of which have roles in tumorigenesis. The network also highlights genes such as WDR74 and COL1A1, which are not much studied.The comprehensive network includes 9852 genes, displays 12,791 relationships, and highlights 1248 hub genes. The network highlights genes such as This preliminary network analysis provides interesting features of tumorigenesis-related fusions. Further systematic analysis of gene fusion networks may aid researchers to better understand cancer gene fusions and test novel fusions in specific types of cancer."} +{"text": "Thirty-four countries worldwide have abnormally high sex ratios (>102 men per 100 women), resulting in over 100 million missing women. Widespread sex selective abortion, neglect of young girls leading to premature mortality, and gendered migration have contributed to these persistent and increasing distortions. Abnormally high adult sex ratios in communities may drive sexually transmitted disease (STD) spread where women are missing and men cannot find stable partners. We systematically reviewed evidence on the association between high community sex ratios and individual sexual behaviors.Seven databases were searched without restrictions on time or location. We followed PRISMA guidelines and evaluated quality according to STROBE criteria. 1093 citations were identified and six studies describing 57,054 individuals were included for review. All six studies showed an association between high community sex ratios and individual sexual risk behaviors. In high sex ratio communities, women were more likely to have multiple sex partners and men were more likely to delay first sexual intercourse and purchase sex. Only two studies included STD outcomes.High community sex ratios were associated with increased individual sexual risk behavior among both men and women. However, none of the studies examined unprotected sex or appropriately adjusted for gendered migration. Further studies are needed to understand the effect of community sex ratios on sexual health and to inform comprehensive STD control interventions. Sex selective abortions have become so widespread that the global sex ratio at birth has increased from 105 to 107 High sex ratios establish communities where surplus men cannot form stable partnerships with women, potentially driving risky sexual behaviors that accelerate transmission of sexually transmitted diseases (STDs). Increased STD burden in high sex ratio communities may be due to increased unsafe commercial sex The potential for high adult sex ratios to drive STD transmission has been previously hypothesized surplus men, forced bachelor, sex ratio, male-female ratio, or gender ratio, and HIV/AIDS, std, sexual behavior, sexually transmitted disease, risk behavior, sex workers, or commercial sex. Our PubMed search terms are available in We conducted a literature search through 30 August 2012 of articles that addressed the association between adult community sex ratios and individual sexual risk behaviors and STD biomarkers. We searched abstracts using combinations of the key words Abstracts were checked for potential relevance, and had to meet the following criteria: only quantitative, English-language population-based research studies; sex ratios measured across multiple partner markets (a community unit defined by each study); and reported individual sexual risk outcomes (behaviors or biomarkers). In order to conduct a comprehensive global systematic review, no limits were placed on study date, location, race or ethnicity of study participants, or the definition of sex ratio. Partner markets were defined as discrete geographic units in which individuals were more likely to find a stable partner. Behavioral outcomes included in the study were multiple sex partners, sex with commercial sex workers, forced sex, premarital sex, recent sex, and self-reported sexually transmitted disease. Biomarker outcomes included a positive test for any sexually transmitted disease. We excluded studies conducted in settings with primarily low sex ratios and studies that were not population-based. Outcomes related to health seeking behaviors, mental health, or unrelated to sexual behavior were excluded. Case studies, qualitative studies, and ecological studies were excluded.We used PRISMA guidelines to identify and exclude studies (Text S2). Two independent reviewers (CB and JT) analyzed full-text articles for inclusion in the review. The reference sections of the remaining articles were then searched to identify other studies that met our inclusion criteria. Source data were reviewed (by JT and CY) and data were abstracted into tables. We contacted study authors to retrieve missing study data. Effect size was measured according to parent data, as either the coefficient or odds ratio. In some cases, statistical significance was converted to a p-value. We used adjusted odds ratios in studies with both crude and adjusted data.We graded the quality of each study using the STROBE reporting criteria for cross-sectional studies [30]. WeOur search yielded a total of 1093 studies . Most inSix studies were included in this review describing 57,054 individuals. Three studies were conducted in high-income countries Definitions of adult sex ratios, migration, and partner markets substantially differed between studies. Although the adult sex ratio is typically reported as the number of men per 100 women of a certain age, two studies reported the number of women per 100 men. These measures were not converted into standard measures of sex ratios in order to preserve apparent effect sizes from the studies. None of the studies included individual-level data for migration, although two of the studies included migrants in community-level census data but excluded migrants in the study sample All six studies found an association between high sex ratios and increased sexual risk outcomes . Among tTwo studies found a concurrent decrease in some sexual risk outcomes and increase in other sexual risk outcomes Few of these studies examined mechanisms linking the connection between high community sex ratio and individual behavior. Two studies examined purchasing of sex among men High adult sex ratios are increasingly common in many parts of the world, but the impact of these global demographic changes on individual sexual behaviors is poorly understood. The proportion of men older than 25 years old who fail to marry in China will nearly triple in the next twenty years, even if sex ratio trends reverse now Our review found limited evidence that high sex ratios were associated with increased sexual risk behavior among women. One study in China Our review suggests increased sexual risk behaviors among men in high sex ratio communities as well. Two studies found that men in high sex ratio communities delay first sexual intercourse, but have an increased risk of purchasing sex, compared to men in normal sex ratio communities Understanding the mechanisms that link community sex ratios and individual risk can guide risk-reduction strategies, from community-level to individual-level interventions. However, we found little evidence that linked the impact of community sex ratios and individual sexual risk behaviors . The onlMigration of surplus men away from high sex ratios is a critical issue because it may inadvertently increase sex ratios in destination communities. However, none of the studies examined gendered migration as either a potential driver of increased sex ratios or a potential cause of individual risk behavior. One study of migrant communities in North Carolina with high sex ratios found an increase in commercial sex use among in communities with fewer women Despite our comprehensive search strategy, our review highlights the relatively limited literature on community sex ratios and sexual health. The reporting quality of some of the studies was poor. One study presented only data that did not differentiate male and female sexual behaviors Our review has several limitations. First, meta-analysis was not possible due to substantial variation in study methodology. Although sex ratios are commonly reported as number of males per 100 females, two studies reported sex ratios as the number of females per 100 males. Variations in study definition of sex ratio and outcomes measures did not permit comparisons of effect size. In order to broaden the scope of the review, we did not place any restrictions on time or location of included studies. Nevertheless, our study included data from only four countries, introducing the possibility of publication and location bias. Three of the included studies were conducted in countries with high sex ratios, but other nations, particularly those in Asia, also have abnormally high sex ratios. Future studies in these settings are warranted. Increased understanding of the mechanisms that drive sexual risk behavior in high sex ratio communities will strengthen comparability between study settings. We did not include studies where sex ratios are predominately low, a demographic phenomenon noted in African-American communities, communities that experience net out-migration, and nations in Eastern Europe Profound demographic changes will fundamentally shift population structures across the globe. Sex ratios will continue to rise in many regions of the world, but their effect on human health, particularly sexual health, remains poorly described. Our review found evidence that high community sex ratios may be associated with increased sexual risk behaviors among both men and women. More epidemiology research, especially among men, is needed to understand the mechanisms driving this association. In addition, prospective studies that include individual STD and migration data are warranted to further assess the findings in this review. Understanding the impact of community sex ratios on sexual health will inform structural STD control interventions, which can better target populations at increased STD risk.Table S1STROBE reporting criteria for cross-sectional studies (full-text).(DOCX)Click here for additional data file.Text S1PubMed Search Strategy.(DOCX)Click here for additional data file.Checklist S1PRISMA Checklist.(DOC)Click here for additional data file."} +{"text": "Arabidopsis veins provide an experimental system to identify such switches. The extent of ingrowth deposition responds to various abiotic and applied stresses, enabling bioinformatics to identify candidate regulatory genes. Furthermore, simple fluorescence staining of PP TCs in leaves enables phenotypic analysis of relevant mutants. Combining these approaches resulted in the identification of GIGANTEA as a regulatory component in the pathway controlling wall ingrowth development in PP TCs. Further utilization of this approach has identified two NAC -domain and two MYB-related genes as putative transcriptional switches regulating wall ingrowth deposition in these cells.In species performing apoplasmic loading, phloem cells adjacent to sieve elements often develop into transfer cells (TCs) with wall ingrowths. The highly invaginated wall ingrowths serve to amplify plasma membrane surface area to achieve increased rates of apoplasmic transport, and may also serve as physical barriers to deter pathogen invasion. Wall ingrowth formation in TCs therefore plays an important role in phloem biology, however, the transcriptional switches regulating the deposition of this unique example of highly localized wall building remain unknown. Phloem parenchyma (PP) TCs in These cells inuities . The incArabidopsis often develop extensive wall ingrowths. Well-known examples include companion cells (CCs) in pea , phloem bidopsis , and botvulgaris . In pea,vulgaris , and in e PP TCs . TCs aree PP TCs , particue PP TCs . Wall inVicia faba cotyledons have established that auxin (V. faba cotyledons (Arabidopsis that enabled a combined bioinformatics and reverse genetics approach to be undertaken to discover that GIGANTEA (GI)is a component of a pathway regulating wall ingrowth deposition in PP TCs. Further, we describe preliminary results using this approach to identify previously uncharacterized members of the NAC -domain and MYB-related gene families as putative transcriptional regulators of wall ingrowth deposition in PP TCs.Transfer cell development occurs across normal developmental windows but also in response to biotic and abiotic stress . Recent at auxin , ethylenat auxin , and reaat auxin functiontyledons and endotyledons , 2012 inArabidopsis are known to occur in PP of the minor vein network in both leaves . Higher magnification views revealed that the Calcofluor White staining showed a distinctive mottled appearance, a characteristic consistent with staining the patchy and tangled wall ingrowths seen in leaf PP TCs by scanning electron microscopy . Double labeling experiments have shown that Aniline Blue gives the same mottled patterns of staining for PP TCs as does Calcofluor White . The levels of reduced abundance in each line, while significant, were not comparable to that seen for the gi-2 mutant (Table 1), indicating the possibility that these transcription factors may be acting redundantly with unidentified orthologs in controlling wall ingrowth deposition. In silico expression data (eFP and Genevestigator) shows that all four genes are expressed at very low levels in leaves, and qPCR confirmed this observation directly for both expanding and fully expanded leaves . Low expression might be expected for genes operating as putative regulators of wall ingrowth deposition specifically in PP TCs, since the number of PP TCs relative to most other cell types in the leaf is exceedingly low (AtSWEET11 promoter) over-expression to test the role of these transcription factors as regulators of wall ingrowth deposition in Arabidopsis.Based on the successful approach used by ngly low , and manngly low . Given ttrans-differentiation of non-vascular cells into metaxylem- and protoxylem-like vessel elements, respectively or VND7, both NAC-domain transcription factors, causes ectively , a proceectively and AtMYectively also cauectively . Buildinectively , thus ouectively , 2009.Arabidopsis has proven useful to identify candidate genes operating as putative transcriptional regulators of wall ingrowth deposition in TCs. The discovery of GI as a component in the pathway regulating wall ingrowth deposition, and identification of NAC-domain and MYB-related genes as putative \u201cmaster switches\u201d involved in controlling this process, provides new lines of investigation to understand the genetic control of TC development and the cell biology of localized wall ingrowth deposition. Ultimately, identifying master switches which respond to various inductive signals to coordinate wall ingrowth deposition in TCs may provide new opportunities for improving crop yield by manipulating this process.The formation of wall ingrowths in TCs impacts on phloem loading and post-phloem unloading processes in many species, with corresponding impacts on plant development and reproduction. Development of an experimental system to investigate PP TCs in The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Ciliopathies is an emerging class of genetic disorders due to altered cilia assembly, maintenance or function. Syndromic ciliopathies affecting bone development have been classified as skeletal ciliopathies. Mutations in genes encoding components of the intraflagellar transport (IFT) complex A, that drives retrograde ciliary transport, are a major cause of skeletal ciliopathies. Mainzer-Saldino syndrome (MSS) is a rare disorder characterized by phalangeal cone-shaped epiphyses, chronic renal failure and early-onset severe retinal dystrophy.IFT140 mutations in seven MSS families. The effect of the mutations on IFT140 localization was assessed using flagged-IFT140 mutant proteins which showed a partial to nearly complete loss of basal body localization associated with an increase of cytoplasm staining while the wild-type Flagged-IFT140 protein predominantly localized to the basal bodies in RPE1 cells. To assess the impact of IFT140 mutations on ciliogenesis, abundance and morphology of primary cilia were studied in cultured fibroblasts of patients and detected absent cilia in a high proportion of patient cells compared to controls. Ciliary localization of anterograde IFTs were altered in MSS patient fibroblasts supporting the pivotal role of IFT140 in proper development and function of ciliated cells.We collected 16 families presenting three diagnostic criteria of MSS. Through ciliome re-sequencing combined to Sanger sequencing, we identified IFT140 mutations in seven MSS families. After Sensenbrenner and Jeune syndromes, MSS is the ultimate skeletal ciliopathy ascribed to IFT disorganization.Here we report on compound heterozygosity or homozygosity for"} +{"text": "Obsessive-compulsive disorder (OCD) is characterized by an excessive focus on upsetting or disturbing thoughts, feelings, and images that are internally-generated. Internally-focused thought processes are subserved by the \u201cdefault mode network\" (DMN), which has been found to be hyperactive in OCD during cognitive tasks. In healthy individuals, disengagement from internally-focused thought processes may rely on interactions between DMN and a fronto-parietal network (FPN) associated with external attention and task execution. Altered connectivity between FPN and DMN may contribute to the dysfunctional behavior and brain activity found in OCD.The current study examined interactions between FPN and DMN during rest in 30 patients with OCD (17 unmedicated) and 32 control subjects (17 unmedicated). Timecourses from seven fronto-parietal seeds were correlated across the whole brain and compared between groups.OCD patients exhibited altered connectivity between FPN seeds (primarily anterior insula) and several regions of DMN including posterior cingulate cortex, medial frontal cortex, posterior inferior parietal lobule, and parahippocampus. These differences were driven largely by a reduction of negative correlations among patients compared to controls. Patients also showed greater positive connectivity between FPN and regions outside DMN, including thalamus, lateral frontal cortex, and somatosensory/motor regions.OCD is associated with abnormal intrinsic functional connectivity between large-scale brain networks. Alteration of interactions between FPN and DMN at rest may contribute to aspects of the OCD phenotype, such as patients' inability to disengage from internally-generated scenarios and thoughts when performing everyday tasks requiring external attention. Obsessive-compulsive disorder (OCD) is characterized by intrusive thoughts, feelings, or images (obsessions) and repetitive behaviors (compulsions) aimed at reducing anxiety associated with obsessions. Neuroimaging studies examining brain activation in OCD at rest, during symptom provocation, and in response to cognitive tasks have made critical advances in elucidating the neurobiological substrates of the disorder, pointing to dysfunction in several cortical and subcortical regions. While dysfunction in orbital, medial frontal, and striatal areas composing fronto-striatal circuits A growing body of literature in neuroscience has begun to emphasize the importance of interactions between brain regions, due to the realization that a typical brain area is likely to support multiple cognitive functions and that unique functionality is most likely to emerge through inter-regional connectivity Recent investigations of rs-fcMRI in OCD focusing on the striatum The investigation of competitive interactions between FPN and DMN at rest is particularly relevant for the study of OCD. Not only are nodes of these networks found to be abnormal during task-based studies of OCD, but the phenomenology of the disorder is consistent with the idea of a disrupted relationship between ongoing internal thought and external information, in that patients often excessively focus on internally-generated fears that are inconsistent with evidence present in the external environment This research was approved by the Institutional Review Board of the University of Michigan Medical School, following the principles set forth by the Declaration of Helsinki. All subjects provided written informed consent. Resting-state functional connectivity data were acquired for a total of 69 subjects. Seven subjects were excluded due to technical problems , leaving a total of 62 participants including 30 OCD patients and 32 control subjects for further analysis. Seventeen OCD patients were unmedicated for a minimum of 6 months prior to study participation (uOCD) and 13 were medicated (mOCD), primarily with serotonin-reuptake inhibitors without psychiatric diagnoses and 15 medicated patient controls (mPC). Subjects with any history of OCD were excluded from both control groups. Subjects in the mPC group were patients with remitted major depression who were on SRI medication and had Subjects were evaluated by a trained clinician using the Structured Clinical Interview for DSM-IV . A T1-weighted image was acquired in the same prescription as functional images to facilitate co-registration. Functional images were acquired with a T2*-weighted, reverse spiral acquisition sequence sensitive to signal in ventral frontal regions 3, normalized to the template MNI152 brain , and smoothed with a 5 mm isotropic Gaussian smoothing kernel using the Statistical Parametric Mapping (SPM) 2 package .Physiologic signals (heart rate and respiration) were removed from the data using RETROICOR www.nitrc.org/projects/conn, see ref. Analysis of functional connectivity of LFBFs was carried out with the \u201cconn\" toolbox controlled for correlations due to movement. Data were filtered between .01 and .10 Hz. We examined connectivity patterns separately for seven different seed regions-of-interest (ROIs) located in FPN. Given abundant evidence of positive correlations among FPN nodes, the timecourses for these separate seeds are not likely to be completely orthogonal; thus we cannot make strong claims about distinct patterns of connectivity between the different seeds. Nevertheless, given recent evidence identifying dissociable cingulo-opercular and dorsolateral prefrontal and parietal systems within FPN Coordinates (in MNI format) for these seeds were taken from prior studies, which have identified a \u201ccore\" task-set network that includes bilateral dorsal anterior insula and posterior medial frontal cortex Although not our main focus of analysis, we also sought to investigate within-DMN patterns of connectivity, due to two prior reports of reduced connectivity in OCD Relationships with symptom severity were examined by extracting connectivity values from regions showing group differences and correlating these with Y-BOCS scores in the OCD group.Several post-hoc analyses were performed to examine the impact of other variables on results and adjacent regions of posterior temporal cortex, and dorsomedial prefrontal cortex (DMPFC) . PatientHyper-connectivity in OCD was also found with dorsolateral and anterior inferior parietal seeds of FPN, although differences with DMN were less robust than with anterior insula seeds. For the left dorsolateral prefrontal (DLPFC) seed, patients had greater connectivity with right anterior insula/frontal operculum \u2013 also a part of FPN \u2013 as well as ventral occipital lobe/cerebellum. For the right DLPFC seed, patients not only had greater connectivity with the posterior cingulate cortex in the DMN, but also showed increased coupling with right lateral frontal regions of FPN.Fewer group differences emerged for connectivity with anterior inferior parietal seeds, with the left hemisphere exhibiting more connectivity with left pre-postcentral gyrus and the right hemisphere exhibiting more connectivity with PCC/precuneus for OCD patients as compared to controls.There were no regions within DMN that exhibited group differences in connectivity with anterior medial frontal (aMFC) or PCC seeds at the current threshold, which was corrected for multiple comparisons. However, as two prior studies have reported altered resting-state connectivity within DMN in OCD Connectivity between the right anterior insula seed and right thalamus was significantly related to Y-BOCS scores, with greater severity of symptoms associated with reduced connectivity . No other connectivity values were related to OC symptom severity.As is shown in the Supporting information , group dwithin DMN itself, although these effects only emerged at lower levels of significance. Negative connectivity among controls was evident despite the fact that global normalization was not used in the analysis Primary results from the current study revealed reduced negative connectivity between the fronto-parietal network and default mode network in OCD. Patients also showed more positive connectivity between fronto-parietal seeds and several areas outside DMN, including somato-motor areas and other FPN regions . However, not all group differences reflected increased connectivity in OCD, as patients showed less positive connectivity than control subjects Research on DMN has garnered much interest since the initial observation of reduced blood flow within several anatomically-widespread brain regions during cognitive tasks versus passive viewing Recent evidence has identified dissociable sub-networks within FPN, with dorsal regions of anterior insula and medial frontal cortex forming a \u201ccore\" network involved in implementing and maintaining attention to external task demands and detecting salient events Connectivity differences with FPN occurred across a number of DMN regions, including PCC, pIPL, DMPFC/aMFC, and parahippocampus. Despite the consistent activation of these brain regions across several different tasks involving internally-directed cognition OCD patients also showed greater positive interactions between FPN seeds and several areas outside of DMN, including pre-postcentral gyrus and posterior insula, which are part of a somatosensory/interoceptive and motor network Although the general absence of correlations with Y-BOCS scores might seem surprising, this may indicate that group differences reflect stable biomarkers of OCD not sensitive to symptom severity differences, similar to the mechanism suggested for the error-related negativity Unlike group differences found with FPN seeds, OCD patients showed less positive connectivity than controls subjects within DMN, a finding that was not due to differential motion. Although this effect was found only at a lowered threshold, it is consistent with two prior reports To our knowledge, this is the first report of altered intrinsic connectivity between distributed regions of fronto-parietal and default mode networks in OCD. However, there are several limitations of the current study, many of which could be addressed by future research. Given that results were not corrected for multiple seed comparisons, replications using a larger sample size are necessary. In addition, OCD and controls groups were not matched on generalized depression/anxiety and education levels. Although post-hoc inclusion of these factors in multiple regressions indicated that these effects were not driving the reported group differences in connectivity, future studies would benefit from investigating the effects of these variables on brain connectivity. Of particular interest for the study of psychopathology, hyperactivity in DMN has been identified in other psychiatric disorders Click here for additional data file.Table S1Medications taken by OCD patients (mOCD) and medicated control subjects (mPC). SSRIs\u200a=\u200aselective-serotonin reuptake inhibitors; SNRIs\u200a=\u200aserotonin-norepinephrine reuptake inhibitors; TCAs\u200a=\u200atricycle antidepressants. All subjects except 1 mOCD patient were taking a serotonin reuptake inhibitor (SSRI or SNRI). Two mOCD and 3 mPC subjects were taking more than one medication .(DOCX)Click here for additional data file.Table S2Significance of diagnosis in predicting connectivity separately for unmedicated and medicated participants. Results obtained from multiple regressions also including generalized anxiety/depression and education as predictors. PCC\u200a=\u200aposterior cingulate cortex; pIPL\u200a=\u200aposterior inferior parietal lobule; DMPFC\u200a=\u200adorsomedial prefrontal cortex; aMFC\u200a=\u200aanterior medial frontal cortex; aI/fO\u200a=\u200aanterior insula/frontal operculum.(DOCX)Click here for additional data file."} +{"text": "In children compliance with breath-hold instructions and motion control can be significantly reduced and there is limited data on CMR reproducibility.In adults CMR is the gold standard technique for evaluation of LV function, with reportedly excellent interstudy reproducibilityTo determine the interstudy reproducibility of cardiovascular magnetic resonance (CMR) measurements of left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), cardiac output (CO), end-systolic mass (ESM) and end-diastolic mass (EDM) in children and examine the influence of analysis technique.CMR was performed in 10 healthy children aged 9 years as part of a study of developmental influences on cardiovascular structure and function. Contiguous short axis steady state free precession LV cine images were acquired. Scans were repeated following a short interval. Interstudy variability was assessed on datasets analysed using a manual post processing technique (Osirix). Each dataset was analysed with the papillary muscles and trabeculae included or excluded from the blood pool. Intra- and interobserver reproducibility was assessed on 10 datasets using both techniques.Inter-study coefficients of variation (CVs) were similar for measurements including or excluding the papillary muscles and trabeculae, though marginally smaller for the latter. CVs for measurements excluding the papillary muscles and trabeculae were generally higher than those reported from studies of adults . Nonetheless, for all parameters the variability between subjects was greater than the interstudy and interobserver variability combined (e.g. for CO standard deviations were 1.83 for between subject variability and 0.42 for interstudy variability respectively).CMR measurements of cardiac structure tend to be less reproducible in children than in adults, probably due to difficulty in following breath hold instructions. Nonetheless, between subjects variability is greater than interstudy and interobserver variability, indicating that useful measurements can be obtained for research studies."} +{"text": "Although social workers encounter many clients with substance use problems, curricula rarely require education on addictions. The screening, brief intervention, and referral to treatment (SBIRT) model was initially directed to practicing physicians. Recently, training has evolved to include medical students. This study describes the first known application of SBIRT training to social work students. The goal was to assess students\u2019 knowledge of and attitudes toward alcohol misuse before and after SBIRT training. Students were given a questionnaire assessing attitudes, knowledge and perceived skills with regard to substance misuse. A computerized training session focused on symptoms of at-risk drinking and implementing SBIRT. Descriptive statistics explained overall knowledge, attitudes, and perceived screening and intervention skills. T-tests compared changes pre- and post-test. Seventy-four social work students (33 undergraduate and 41 graduate) completed the training modules and pre- and post-tests. Significant differences were found in seven of the 13 questions. Students reported more confidence in their ability to assess for alcohol misuse and successfully intervene with clients who have substance use behaviors. They reported feeling more strongly that routine screening and brief intervention were crucial to clinical practice. Incorporating alcohol screening and brief intervention techniques into social work practice is an important aspect of effective treatment. Training students to screen and intervene is critical to improving treatment skills. Teaching SBIRT is a simple and effective way to implement addictions education into social work curricula. Such training appears to increase students\u2019 perceptions of their ability to change client behaviors and reduce client alcohol misuse."} +{"text": "This survey determined the extent to which the herb Moringa oleifera commonly used for medicinal and nutritional purposes is being consumed among HIV positive patients.The study was a cross-sectional survey carried out at Parirenyatwa Hospital Opportunistic Infections Clinic. A convenience sample of 263 HIV-infected adults was taken from the Zimbabwe National Antiretroviral Roll-out Program. Using a previously piloted researcher administered questionnaire; patients who reported to the clinic over six months were interviewed about their use of herbal medicines. The focus was on Moringa oleifera use, and included plant part, dosage, prescribers and the associated medical conditions.Sixty-eight percent (68%) of the study participants consumed Moringa oleifera. Of these, 81% had already commenced antiretroviral drugs. Friends or relatives were the most common source of a recommendation for use of the herb (69%). Most (80%) consumed Moringa oleifera to boost the immune system. The leaf powder was mainly used, either alone (41%) or in combination with the root and/or bark (37%).Moringa oleifera supplementation is common among HIV positive people. Because it is frequently prescribed by non-professionals and taken concomitantly with conventional medicine, it poses a potential risk for herb-drug interactions. Patient medication history taking should probe for herbal supplementation and appropriate counselling done. Further experimental investigations into its effect on drug metabolism and transport would be useful in improving the clinical outcome of HIV positive patients on HAART."} +{"text": "Stroke trial outcomes are usually classified in ordered functional categories, e.g. the modified Rankin Scale (mRS). Using a single cut-off to distinguish \"good\" and \"poor\" outcome is statistically inefficient and could miss effects in subgroups where few patients can be expected to achieve good outcome. \"Ordinal shift analysis\", using ordinal logistic regression to estimate a common odds ratio for all possible outcome category thresholds, is more efficient but could still obscure clinically important differences in response among prognostic subgroups. An alternative \"prognosis based outcome\" (PBO) approach defines separate, clinically meaningful good and poor outcome thresholds (GOTs and POTs) within each prognostic stratum. The strata are then combined in an overall trichotomous comparison of \"good\"/\"intermediate\"/\"poor\" outcomes.We defined prognostic categories, based on initial neurological scores, and derived suitable GOTs and POTs for the mRS, using data from a hospital stroke register. We then validated these thresholds using baseline and outcome data from the Scandinavian Candesartan Acute Stroke Trial (SCAST). Finally we performed trichotomous PBO analysis on the SCAST data.PBO analysis confirmed the overall neutral results of SCAST but did identify a notable negative treatment effect within the good prognosis group.This subgroup effect was not predicted, so requires independent confirmation. The PBO approach is clinically intuitive, can be used to analyse treatment response within different prognostic groups (as in cancer staging systems), and is statistically efficient. Also, it does not require multivariable modelling, making it easier to combine data from different studies in individual patient data meta-analysis."} +{"text": "Spinal lesions substantially impair ambulation, occur generally in young and otherwise healthy individuals, and result in devastating effects on quality of life. Restoration of locomotion after damage to the spinal cord is challenging because axons of the damaged neurons do not regenerate spontaneously. Body-weight-supported treadmill training (BWSTT) is a therapeutic approach in which a person with a spinal cord injury (SCI) steps on a motorized treadmill while some body weight is removed through an upper body harness. BWSTT improves temporal gait parameters, muscle activation patterns, and clinical outcome measures in persons with SCI. These changes are likely the result of reorganization that occurs simultaneously in supraspinal and spinal cord neural circuits. This paper will focus on the cortical control of human locomotion and motor output, spinal reflex circuits, and spinal interneuronal circuits and how corticospinal control is reorganized after locomotor training in people with SCI. Based on neurophysiological studies, it is apparent that corticospinal plasticity is involved in restoration of locomotion after training. However, the neural mechanisms underlying restoration of lost voluntary motor function are not well understood and translational neuroscience research is needed so patient-orientated rehabilitation protocols to be developed. Spinal cord injuries (SCIs) cause substantial social, economic, and health burdens. In the majority of cases, the spinal cord is not completely severed and thus some fiber tracts and segmental spinal cord circuits remain intact , which dIn addition to spontaneous reorganization of the brain after SCI, spinal cord circuitries have the capacity to alter their structure and function with motor training , as suppIn humans, BWSTT improves lower extremity motor scores, increases the amplitude of muscle activity in the ankle extensors during the stance phase of walking, and improves walking ability and clinical outcome measures \u201331. A reBased on the aforementioned findings, it is apparent that BWSTT contributes to restoration of locomotion. Because remodeling of neuronal circuits as a result of plasticity occurs at multiple sites of the central nervous system , 32 restThe corticospinal tract is the most direct pathway between the cerebral cortex and spinal cord with corticospinal axons monosynaptically synapsing onto spinal motor neurons. Even though neurons of the motor cortex are not required for simple locomotion, they exhibit a profound step-related frequency modulation in the cat \u201335. ThisThe involvement of supraspinal neural control in human walking can be assessed by a variety of techniques utilized in isolation or in combination, including electroencephalography (EEG), electromyography (EMG), transcranial magnetic and electric stimulation (TMS and TES), and neuroimaging , 46. SinA single stimulus of TMS produces a synchronized discharge of cortical interneurons and pyramidal neurons that travel down the corticospinal tract. Epidural electrodes in the spinal cord detect several waves following TMS, termed direct (D) and indirect (I) waves. I waves originate in the motor cortex most likely through activation of corticocortical projections onto corticospinal neurons , while D\u03b1-motor neurons and interneurons [However, the MEP amplitude is not a reliable measure of corticospinal excitability. This is because TMS-induced action potentials in cortical axons spread transynaptically to many other neurons that actrneurons .The aforementioned limitations can be counteracted by reducing the TMS intensity below the MEP threshold. Direct recordings in awake human subjects have shown that TMS at subthreshold MEP intensities, which does not evoke any descending corticospinal volleys, depresses the MEP evoked by a subsequent suprathreshold TMS and the Various training protocols in uninjured subjects induce reorganization of corticospinal actions on lumbosacral motor neurons. For example, balance training decreased the TA and soleus MEP amplitudes , while 3In motor incomplete SCI subjects at rest, MEPs are either absent or very small in amplitude with prolonged latencies, which are considered signs of impaired transmission of the fastest conducting corticospinal neurons \u201377. FurtfMRI showed a greater activation in sensorimotor cortical and cerebellar regions following 36 BWSTT sessions [Reorganization of corticospinal actions with training in neurological disorders has been shown in few studies. In 4 male SCI subjects with tetraparesis, sessions consistesessions . Three-tsessions . Furthersessions . The lowsessions .One person with an American Spinal Injury Association (ASIA) Impairment Scale (AIS) D at Thoracic 5\u20137 received 60 BWSTT sessions with a robotic exoskeleton device (Lokomat). Before training, the patient stepped at 0.5\u2009m/s with 50% body\u2009weight\u2009support (BWS), and after training the patient stepped at 0.89\u2009m/s with 20% BWS. Electrophysiological tests, illustrated as a schema in The TA MEPs evoked at 1.3 TA MEP threshold during assisted stepping before and after training are shown in The spinal cord constitutes the final common pathway for segmental and supraspinal pathways underlying motor behavior. Electrical stimulation of a mixed peripheral nerve at low intensities activates primary (Ia) afferent axons which synapse in the spinal cord. Alpha motor neurons activated monosynaptically by Ia afferent volleys induce a synchronized reflex response known as the Hoffmann-(H-) reflex , which iCortical control of spinal reflex circuits has been extensively investigated in awake humans by means of TMS. Subthreshold TMS produces a short-latency inhibition on the soleus H-reflex followed by a period of facilitation , 87\u201389 wIn addition to the H-reflex, the TA long-latency (or M3) ankle stretch reflex was facilitated when the MEP arrived in the spinal cord at the same time . HoweverPersistent changes in H- or stretch reflex amplitudes may be regarded as signs of learning and plasticity as a result of training, which have been shown after various training protocols. For example, 30\u2009min ankle cocontraction training decreased the ratio of maximal H-reflex versus maximal M wave (Hmax/Mmax) and improved motor performance defined as the difference between the maximum and minimum torque displacements within 1\u2009min . The solNonetheless, the aforementioned changes in H-reflex amplitude can result from modifications of interneuronal circuits interposed in the spinal pathway or by changes on the strength of descending pathways, since the latter is potent regulator of spinal reflex circuits behavior \u2013107. ThiLimited evidence exists on plastic changes of the cortical control of spinal reflexes after locomotor training in neurological disorders. Forty BWSTT sessions in 29 patients with incomplete SCI reestablished the TMS-induced long-latency soleus H-reflex facilitation with subjects at rest . It shouIn One of the spinal interneuronal circuits with paramount contribution to the neural control of movement is that of disynaptic reciprocal Ia inhibition. Reciprocal inhibition refers to an automatic antagonist motor neuron inhibition when an agonist muscle contracts. Following an SCI, the reciprocal inhibition is either reduced or replaced by reciprocal facilitation \u2013124 leadRegulation of locomotion by reflexly mediated spinal circuits that integrate sensory inputs is well established. The contribution of muscle afferents mediating information about the amplitude and rate of muscle stretch is easily recognized by the phase-dependent modulation of short-latency spinal reflexes during walking. The short-latency soleus and quadriceps extensor reflexes in humans are modulated in a way that promotes bipedal gait. The ankle stretch and soleus H-reflexes increase progressively from mid- to late stance in parallel with the soleus EMG activity and are significantly depressed or abolished during the swing phase of gait \u2013115, 125\u03b1 motor neurons coincided with activity of Ia inhibitory interneurons [The soleus H-reflex depression during the swing phase in humans has been partly ascribed to reciprocal Ia inhibition exerted from common peroneal nerve group I afferents on soleus motor neurons, which is regulated in a similar manner to that reported in animals and corresponds largely to absent reciprocal inhibition in the stance phase and maximal in the swing phase , 128. Durneurons , 130. Iarneurons .Animal studies through intracellular recordings provided a detailed knowledge of the pathway and integration of segmental and supraspinal convergence at the interneuronal level \u2013135 withDescending control of reciprocal inhibition has clearly been postulated in humans. In particular, the reciprocal inhibition exerted from common peroneal nerve group I afferents on soleus motor neurons was observed 50\u2009ms before the onset of TA EMG activity . FurtherFindings on the reorganization of reciprocal inhibition as a result of motor training in health and disease are limited. Stimulation of the common peroneal nerve with a train of 10 pulses at 100\u2009Hz with and without motor cortex stimulation potentiated reciprocal inhibition in control subjects . ReciproIn D-C)-(B-A) whereas A is the test soleus H-reflex (baseline soleus H-reflex modulation pattern during stepping), B is the soleus H-reflex conditioned by subthreshold TMS, C is the soleus H-reflex conditioned by common peroneal nerve stimulation , and D is the reciprocal inhibition conditioned by subthreshold TMS. Positive values indicate potentiation of reciprocal inhibition and negative values indicate attenuation of reciprocal inhibition. Locomotor training contributed significantly to attenuation of reciprocal inhibition exerted from ankle flexor afferents to extensor motor neurons during the stance phase. Most importantly, potentiation of reciprocal inhibition at swing phase initiation (i.e., bin 9 in The net effects of subthreshold TMS on the reciprocal inhibition during BWS-assisted stepping before and after 60 BWSTT sessions are indicated in SCI changes the human body homeostasis leading to myriad changes of multiple systems. In most cases, the spinal cord is not completely severed and thus some fiber tracts and segmental spinal cord circuits remain intact. Based on the plastic capabilities of the central nervous system, it is apparent that the adult lesioned motor system reorganization occurs spontaneously after an injury and after training. Electrophysiological studies have shown that BWSTT increases the MEP amplitude, changes the common drive of antagonist muscles from corticospinal inputs with subjects seated, and alters the TA MEP modulation pattern during BWS assisted stepping. Further, BWSTT reestablished the TMS-induced long-latency soleus H-reflex facilitation and potentiated the short-latency soleus H-reflex depression following subthreshold TMS with subjects at rest, while cortical modulation of the soleus H-reflex during stepping changed significantly. Lastly, BWSTT changed the cortical control of reciprocal inhibition during BWS assisted stepping in a manner that promotes bipedal gait. These findings support the notion that improvements in locomotor function from treadmill training are mediated, in part, by changes in the corticospinal drive of spinal reflex circuits, spinal interneuronal circuits, and output of leg muscles during walking.Plasticity in the brain and spinal cord underlying restoration of lost function can be driven by appropriately designed interventions , 151. De"} +{"text": "These DNA modifications occur only during nuclear development and programmed genome rearrangement. We describe these modifications in three classes of eliminated DNA: germline-limited transposons and satellite repeats, aberrant DNA rearrangements, and DNA from the parental genome undergoing degradation. Methylation and hydroxymethylation generally occur on the same sequence elements, modifying cytosines in all sequence contexts. We show that the DNA methyltransferase-inhibiting drugs azacitidine and decitabine induce demethylation of both somatic and germline sequence elements during genome rearrangements, with consequent elevated levels of germline-limited repetitive elements in exconjugant cells. These data strongly support a functional link between cytosine DNA methylation/hydroxymethylation and genome stability, highlighting the ability of the cells to distinguish and specifically methylate aberrant chromosomes but not their properly structured isoforms. In addition, we identify a motif strongly enriched in some methylated/hydroxymethylated regions of parental MAC chromosomes, and we propose that this motif recruits DNA methylation machinery to specific chromosomal regions in the parental macronucleus. No recognizable methyltransferase enzyme has yet been described in O. trifallax, raising the possibility that it might employ a novel cytosine methylation machinery to mark DNA sequences for elimination during genome rearrangements.Cytosine methylation of DNA is conserved across eukaryotes and plays important functional roles regulating gene expression during differentiation and development in animals, plants and fungi. Hydroxymethylation was recently identified as another epi-genetic modification marking genes important for pluripotency in embryonic stem cells. Here we describe"} +{"text": "Cerebral small vessel disease leads to dementia and stroke-like symptoms. Lacunes, white matter lesions (WML) and microbleeds are the main pathological correlates depicted in in-vivo imaging diagnostics. Early studies described segmental arterial wall disorganizations of small penetrating cerebral arteries as the most pronounced underlying histopathology of lacunes. Luminal narrowing caused by arteriolosclerosis was supposed to result in hypoperfusion with WML and infarcts.We have used the model of spontaneously hypertensive stroke-prone rats (SHRSP) for a longitudinal study to elucidate early histological changes in small cerebral vessels. We suggest that endothelial injuries lead to multiple sites with blood brain barrier (BBB) leakage which cause an ongoing damage of the vessel wall and finally resulting in vessel ruptures and microbleeds. These microbleeds together with reactive small vessel occlusions induce overt cystic infarcts of the surrounding parenchyma. Thus, multiple endothelial leakage sites seem to be the starting point of cerebral microangiopathy. The vascular system reacts with an activated coagulatory state to these early endothelial injuries and by this induces the formation of stases, accumulations of erythrocytes, which represent the earliest detectable histological peculiarity of small vessel disease in SHRSP.In this review we focus on the meaning of the BBB breakdown in CSVD and finally discuss possible consequences for clinicians. The clinical picture of cerebral small vessel disease (CSVD) is complex since the disease develops insidiously and its etiology is only partly understood. Limited correlations between neurological symptoms, imaging diagnostic and pathological findings impede an early enough diagnostic and therefore therapy. It\u2019s obvious, however, that an illness of rather small blood vessels leads to subtle development of dementia and / or episodes of stroke-like symptoms if neurological sensitive areas are affected by so called strategic infarcts. Lacunes, diffuse white matter lesions and microbleeds are the pathognomonic pathological correlates detectable with modern imaging diagnostic.Lacunes, found in 6% to 11% of autopsied brains, are defined as scars or remnants of small infarcts with a diameter ranging from 3 to 20\u00a0mm predominantly found in the basal ganglia, thalamus, pons, subcortical and cerebellar white matter areas[More than 40\u00a0years ago Fisher described the \u201csegmental arterial wall disorganization\u201d of small penetrating cerebral arteries defined by vessel enlargement due to wall remodeling with \u201closs of meshwork\u201d, \u201chemorraghic extravasation\u201d and deposits of fibrinoid material as one uFrom the current point of view the chronic small vessel wall alterations found in CSVD comprise three subtypes including lipohyalinosis, arteriolosclerosis and cerebral amyloid angiopathy (CAA). EspeciaMoreover, common acute lesions found in CSVD are cerebral microbleeds and primary intracerebral hemorrhages, discussed as consequence of small vessel wall fragility converging with acute hemodynamic changes possibly caused by fluctuations of the blood pressure,8. MicroOcclusions of degenerative altered small vessels, typically found in cerebral macroangiopathy associated with thrombotic or embolic stroke, might be a reasonable explanation for lacunar infarcts, but those occlusions are a rather rare event in brain autopsy of patients with CSVD. Thus, WWe have recently collected data in the model of spontaneously hypertensive stroke-prone rats (SHRSP) that strikingly support the importance of an early BBB dysfunction for the development of CSVD, which will be discussed in this review.Only few animal models have been recognized to be suitable for describing CSVD,10. AlthSHRSP were obtained by selective breeding from spontaneously hypertensive rats (SHR) for the development of spontaneous infarcts-13 and e3, larger non-territorial infarcts anyhow commonly distributed in specific territories of the large cerebral arteries, rarely covering multiple vascular territories or seen in the border zones of the large cerebral arteries as well as territorial infarcts in some cases affecting the whole hemisphere[SHRSP develop small lacunar-like lesions with a volume ranging from 2 to 57\u00a0mmmisphere,19,20. Tmisphere. Howevermisphere.Ischemic lesions are predominately found in cortical areas and In contrast, the exact localization and extent of WML have been rarely investigated in SHRSP and therefore the respective existing data is quite incomplete. Myelin stainings show a rarefication of white matter substance accompanied by a general volume expansion in SHRSP with BBB leakage. For theBy genetic factors SHRSP develop a vascular risk profile, which comprises arterial hypertension, insulin resistance and hyperinsulinemia, mixed hyperlipidemia and elevated levels of free fatty acids. This geStarting a longitudinal study with around 130 SHRSP we were able to define some kind of pathological cascade which is described in the following: The small vasculature of rather juvenile SHRSP is not distinguishable from age matched Wistar controls. However starting from an age of 12\u00a0weeks, in SHRSP we occasionally found in capillaries of the basal ganglia, the hippocampus and cortical areas intraluminal accumulations of erythrocytes within their walls and within the adjacent perivascular parenchyma indicating associated BBB damage at already young ages FigureI would tDisturbances of autoregulation of small vessel tonus represent another possible reason that at least promotes the formation of stases. This is reflected in constrictions and dilatations of the vessel wall we occasionally found in arteriolar segments with stases SHR (SHRSR), an animal model with polygenetic and multifactorial inheritance of chronic arterial hypertension, including renal factors, prostaglandin-adrenergic interactions and abnormalities of the pituitary gland, developConcluding, SHRSP exhibit a complex cascade of CSVD and until now it is unclear, whether SHR develop a comparable natural course of microvascular dysfunction accompanied by histopathological phenomena exceeding their described BBB leakage.Thus, coming back to the headline of this review we can state that the SHRSP develops overt infarcts that mainly originate from breakdown of the BBB and not from occluded vessels. Thrombotic occlusions of small penetrating vessels occur only at the end of a pathological cascade originated by endothelial damage. This may have important clinical consequences. Patients with stroke-like symptoms caused by thrombotic or embolic occlusions of large vessels generally benefit from an anti-thrombotic treatment. But the effect of such a treatment could be even detrimental if stroke patients suffer from multiple small vessel lesions originally caused by BBB leakage.Moreover, one has to ask what is the main difference between SHRSP and controls? Do control rats develop the pathology of CSVD cascade only later on or in other words: Are the vascular risk factors in SHRSP some kind of accelerator for a pathology caused in controls simply by aging? We also found an increasing number of stases in older control rats correlating with vascular changes in the kidney comparable to the findings in SHRSP. Control rats exhibit limited mini- and microbleeds and so far no one exemplar developed overt ischemic lesions. Thus, it is obvious that the vascular system also in control rats undergoes an age-dependent impairment. But probably only a very little fraction of them will develop the typical pathological cascade of CSVD we have found in SHRSP.The genetically most related population to SHRSP is the SHRSR. The risk profile also includes chronic arterial hypertension with disturbances of renal factors. HoweverThus, besides aging and vascular risk factors we suppose that CSVD pathology needs a certain combination of genetic risk factors and is in its development positively or negatively influenced by lifestyle. In this regard it is very important to mention that the incidence and development of overt infarcts in SHRSP can be heavily promoted by a high salt diet. Moreover, an application of a salt-loaded diet induces an abrupt malign increase of the arterial blood pressure, associated with forced vessel wall ruptures leading to an extended breakdown of the BBB with associated cerebral edema and large primary intracerebral hemorrhages,19,20,38Concluding, the conglomerate of vascular and genetic risk factors in SHRSP obviously favors an initially small and insidious age-dependent developing of endothelial injuries leading to an increasing BBB leakage. The vascular system seems to react with a restricted coagulation which causes stases of erythrocytes as a rather byproduct.It is a challenge for modern imaging diagnostics to detect these early vascular changes to selectively recognize patients with an elevated vascular risk profile. One approach could be the development of new, especially renal biomarkers in blood and urine. Therefore, in SHRSP we have just started to investigate urine concentrations of the kidney-injury-molecule-1 (KIM-1), marking a renal tubular damage. We are Meanwhile our probably best weapon against small cerebral vascular diseases is the promotion of healthy campaigns persuading people to prevent the age driven progress of CSVD under the slogan:More physical activity, less salt, no smoking!A\u03b2: Amyloid-\u03b2; BBB, Blood brain barrier; CAA: Cerebral amyloid angiopathy; CE-\u03bcMRA: Contrast-enhanced magnetic resonance microangiography; CSVD: Cerebral small vessel disease; HE: Hematoxylin Eosin; IgG: Immunoglobulin G; KIM-1: Kidney-injury-molecule-1; MCA: Middle cerebral artery; MRI: Magnetic resonance imaging; MRA: Magnetic resonance angiography; SHR: Spontaneously hypertensive rats; SHRSP: Spontaneously hypertensive stroke-prone rats; SHRSR: Spontaneously hypertensive stroke-resistant rats; SPECT: Single photon emission compute tomography; STL: Solanum tuberosum lectin; vWF: Von-Willebrand factor; WML: White matter lesions.The authors declare that they have no competing interests.SS, CB, CC and HB wrote the manuscript. All authors read and approved the final manuscript."} +{"text": "Hyperglycemia and hypoglycemia have been linked to worse outcomes in critically ill patients. While there is controversy as to the optimal tightness of glucose control in critically ill patients, there is agreement that an upper limit to safe glucose levels exists and that avoiding hypoglycemic episodes should be prioritized. Our algorithm can assist clinicians in maintaining blood glucose ([Gbl]) within a desired target range while avoiding hypoglycemia.Our model predictive control (MPC) algorithm uses insulin and glucose as control inputs and a linearized model of glucose-insulin-fatty acid interactions. To allow the controller model to learn from data, a moving horizon estimation (MHE) technique tailored the tissue sensitivity to insulin to individual responses. Patient data were from the HIDENIC database at the University of Pittsburgh Medical Center. [Gbl] measurements, typically hourly, were interpolated to impute a measurement every 5 minutes. The model captured patient [Gbl] via nonlinear least squares by adjusting insulin sensitivity (SI) and endogenous glucose production (EGP0). The resulting virtual patient (VP) is used to evaluate the performance of the MPC-MHE algorithm.MPC controller performance on one VP is shown in Figure The MPC-MHE algorithm achieves targeted glucose control in response to changing patient dynamics and multiple measured disturbances for a pilot population of 10 VPs. Furthermore, the MHE scheme updates patient parameters in real time in response to changing patient dynamics."} +{"text": "Female genital tuberculosis (TB) remains as a major cause of tubal obstruction leading to infertility, especially in developing countries. The global prevalence of genital tuberculosis has increased during the past two decades due to increasing acquiredimmunodeficiency syndrome (AIDS). Genital TB is commonly asymptomatic, andit is diagnosed during infertility investigations. Despite of recent advances in imaging tools, such as computerized tomography (CT) scan, magnetic resonance imaging (MRI) and ultrasongraphy, hysterosalpingography is still the standard screeningtest for evaluation of tubal infertility and a valuable tool for diagnosis of femalegenital tuberculosis. Tuberculosis gives rise to various appearances on hysterosalpingography (HSG) from non-specific changes to specific findings. The present pictorialreview illustrates and describes specific and non-specific radiographic features of femalegenital tuberculosis in two parts. Part I presents specific findings of tuberculosis relatedto tubes such as \"beaded tube\", \"golf club tube\", \"pipestem tube\", \"cobble stone tube\"and \"leopard skin tube\". Part II describes adverse effects of tuberculosis on structure ofendometrium and radiological specific findings such as \"dwarfed\" uterus with lymphaticintravasation and occluded tubes, \"T-shaped\" tuberculosis uterus, \"pseudounicornuate\"uterus and \"Collar-stud abscess\", which have not been encountered in the majority ofnon-tuberculosis cases. Female genital tuberculosis (FGTB) is one formof extrapulmonary manifestations of tuberculosis,while it includes 5% of all female pelvic infectionsand 10% of pulmonary tuberculosis cases . Itis mThe reported prevalence of genital tuberculosishas shown a descending trend in developed countries,but recently, its rate has started to increaseagain due to co-infection with human immunodeficiencyvirus (HIV) and the development of drug-resistantstrains of Mycobacterium tuberculosis -6.Primary infection of the female genital organs isvery rare , and is Diagnosis of genital TB may be difficult becausemajority of cases are asymptomatic; in addition,facilities for mycobacterium culture and histopathologyare limited in high-prevalence countries-11. In tThis pictorial review describes specific and nonspecificradiographic features of tubes caused bytuberculosis as seen on HSG.Mycobacterium tuberculosis is responsible fordisease in approximately 90-95% of cases and producesgranulomatous salpingitis and endometritisleading irregular menstrual bleeding and infertility.In 5-10% of patients, the infection results from Mycobacteriumbovis, especially when the source ofinfection is acquired from the gastrointestinal cases, 18.Genital tuberculosis usually spread to genitalsite from three routes, including hematogenous,lymphatic or adjacent viscera , while iPrimary infection of genital TB is rare, and mayresult from direct introduction of TB bacilli atsexual intercourse with a male partner with genitourinaryTB. Ascending spread of infection fromthe vagina, cervix and the vulva has been reported.Tha fallopian tubes are the initial focus of femalegenital tuberculosis, and usually involved bilaterallynot symmetrically . The patThe transitional region between the isthmusand ampulla is the most frequent site of tubalobstruction. Sometimes, hydrosalpinx or pyosalpinxwith thick fibrotic wall is formed at thedistally blocked fallopian tube.The ovaries areoften seen in normal appearance and the diagnosisis established only on histopathologicalstudies .In some cases, ovarian tubercle, adhesion, capsularthickening and ovarian or pelvic abscess areformed .Most of the cases involved in genital TB have been detected in reproductive age; a range of 20-45 year-old . GenitalTuberculous lesions of the cervix present withpostcoital bleeding, abnormal discharge and,on examination, have appearances similar tocancer of the cervix . InvolveHysterosalpingographic presentation of tubalTB vary from non-specific changes such as hydrosalpinxto specific pattern such as \"beadedtube\", \"golf club tube\", \"pipestem tube\", \"cobblestone tube\" and the \"leopard skin tube\". Of courThe presence calcified lymph nodes in thepelvis or in the course of fallopian tubes mayenable the diagnosis of the TB. Plain films ofthe pelvis may show such calcifications whichmust be differentiated from other causes of calcificationssuch as calcified pelvic nodes, calcifieduterine myomas, urinary calculi, pelvicphleboliths and calcification in an ovarian dermoid. The calCaseous ulceration of tubal mucosa createsan irregular, ragged or divertucular appearanceon the contour of the tubal lumen on HSG. Divierticularcavities surrounding of the ampullarportion may give it a \"tufted\" like appearance. Isthmic diverticula may resemblesalphingitis isthmica nodosa, \"TB-SIN\" likeappearances can be differentiated from classicSIN . In \"TB-SIN diverticular outpouchingare larger, asymmetric, with a morebizarre pattern (in size and number) and arenot usually restricted to the isthmic portionof the tube as compared with those of SIN ,16. TheTubal occlusion in tuberculosis is consideredthe most common finding seen on HSG and occursmost commonly at the junction between theisthmus and ampulla. in the region of isthmus andampulla. Although cornual occlusion followingampullar obstruction is the most common site oftubal occlusion caused with any factor, it is not socommon in tuberculosis.Multiple constrictions along the course of fallopiantube may form due to scarring and present as\"beaded\" appearance . While tOcclusion of the isthmus or fimbrial end of thetube filled with serous or clear fluid produce aretort-shaped dilation of the tube (large-sausageshaped)which initially is a pyosalpinx that changeto hydrosalpinx. Hydrosalpinx is usually moderateor slight with a \"golf club like appearance\" to theampulla 16)..16).Twisting of the hydrosalpinx may result in afloral pattern- \"the floral hydrosalpinx\" .ThickenIntraluminal scarring can give rise to a cobblestonepattern which is an effective radiographic sign of intraluminaladhesions in hydrosalpinges and associatedwith concern of infertility 34). A . A 34). In chronic tuberculosis, following repeatedepisodes of acute exacerbation, a dense peritubalconnective tissue scarring occurs in andaround the tubes, leading to peritubal adhesions.The tubes become vertically or horizontallyfixed, interfering with access of fallopiantubes to the ovary at ovulation and transport ofthe ovum.In this non-specific finding, the contrastspill from a vertically fixed tube appears to bebounded laterally by adhesions, which givesrise to straight spill appearance . ThefalDense adhesions may resemble lead to visualizationof septations and bizarre \"criss-crossspill\" pattern. Sometimes, peritoneal granulomasformation produces small rounded fillingdefects seen additionally to these septations.Everted fimbria with a patent orifice impartingcharacteristic \"tobacco pouch\" appearance.HSG is considered as an important diagnostic tool inthe investigation of internal architecture of female genitaltract and helpful procedure in diagnosis of femalegenital tuberculosis. Tubal and uterine lesion scarringremained of genital TB, are presented as specific andnon-specific radiographic features which should bediffered from other pathological conditions. Since theincidence of genital tuberculosis has been increasedduring the past two decades, the clinicians increasinglyfaced with cases of genital TB and its consequencessuch as infertility, so reviewing of these features areconsidered in differential diagnosis of the causes of infertilityand timing intervention and treatment."} +{"text": "Recent findings from electrophysiology and multimodal neuroimaging have elucidated the relationship between patterns of cortical oscillations evident in EEG/MEG and the functional brain networks evident in the BOLD signal. Much of the existing literature emphasized how high-frequency cortical oscillations are thought to coordinate neural activity locally, while low-frequency oscillations play a role in coordinating activity between more distant brain regions. However, the assignment of different frequencies to different spatial scales is an oversimplification. A more informative approach is to explore the arrangements by which these low- and high-frequency oscillations work in concert, coordinating neural activity into whole-brain functional networks. When relating such networks to the BOLD signal, we must consider how the patterns of cortical oscillations change at the same speed as cognitive states, which often last less than a second. Consequently, the slower BOLD signal may often reflect the summed neural activity of several transient network configurations. This temporal mismatch can be circumvented if we use spatial maps to assess correspondence between oscillatory networks and BOLD networks. It is understood that whereas functional MRI (fMRI) can effectively describe the spatial activation patterns of whole-brain networks, it is limited to measuring the delayed hemodynamic response observed in the blood oxygen level dependent (BOLD) signal. This delay limits its ability to describe rapid changes in neural activity underlying the sequential processing stages inherent to any cognitive task. We can obtain much higher temporal resolution from electroencephalography (EEG), magnetoencephalography (MEG), or electrocorticography (ECoG) data. However, due to limitations on the number and location of feasible electrode placements and to difficulties in measuring signals from sub-cortical regions, these methods do not provide complete whole-brain neural activity measures with a spatial precision equivalent to that of fMRI. The above temporal and spatial limitations can be addressed through studies combining fMRI data with simultaneously recorded EEG data, or with co-registered MEG or ECoG data recorded in separate sessions. To best interpret the results of such multimodal studies, one must understand the relationship between the BOLD signal, neuronal activity at a local level, oscillations in neuronal assemblies, and the large-scale rapid oscillatory networks measurable with EEG, MEG, and ECoG. Here, we describe how cortical oscillations organize post-synaptic potentials and neuronal firing, functionally connecting activity in disparate regions to form the widespread cortical networks observed in the BOLD signal.At the local level, several studies have used invasive techniques to simultaneously record action potentials (APs), BOLD signal strength, and cortical oscillations. It should be noted that the BOLD signal might be expected to correspond less closely to APs measured via single-cell and multi-unit recordings than to local field potentials (LFPs), which reflect post-synaptic potentials summed across large numbers of neurons, because a single fMRI voxel typically contains more than a million neurons and slow (30\u201350\u2009Hz) gamma ranges may organize activity at a local level by integrating some signals while segregating others, and simultaneously coordinate multiple organized local patterns across much greater distances. These multi-frequency patterns provide an optimal explanation for the mechanisms of cognitive processing because they dynamically change at the same pace as cognition.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Rapamycin binds with FK- binding protein 12 to inhibit the mechanistic Target of Rapamycin (mTOR) protein [Rapamycin is a macrocyclic antibiotic produced by the bacteria in vitro is less pronounced than the Warburg effect in cancer, identifying the cellular metabolism behind fibrosis suggests at potential therapies directed at fibroplasia. Our investigations into fibroblast metabolism and rapamycin's inhibitory effect suggests at a critical link between cellular metabolism and unregulated fibroblast proliferation that could elucidate rational druggable targets to mitigate LTS and fibrosis in general.Fibrosis is the terminal pathological outcome of myriad chronic inflammatory diseases. The process is defined by the excessive accumulation of fibrous connective tissue components of the extracellular matrix in inflamed tissue . The excmTOR's regulatory role makes the protein a critical node between metabolism and cell proliferation. Environmental factors such as stress and energy influence mTOR, which in turn regulates protein, lipid, and nucleotide biosynthesis, mitochondrial proliferation and function, cell growth and development amongst other cell functions. In fibroblasts mTOR regulates cell kinetics and collagen and other extracellular matrix molecule production. Inhibition of mTOR has been explored in cancer, cardiovascular disease, autoimmunity, and metabolic disorders. In immune cells including T-lymphocytes and macrophages, mTOR subunit inhibition results in reduced metabolism which in turn impacts immune cell activation and function . Based oAlternatively myofibroblasts have been the focus of extensive research in fibrosis, given their role in secreting ECM and collagen along with their fundamental contribution to wound contracture. Epithelial-mesenchymal transition (EMT), a process whereby fully differentiated epithelial cells undergo transition to a mesenchymal phenotype giving rise to myofibroblasts. EMT is increasingly recognized as a contributing factor to tissue fibrosis following epithelial injury and a fundamental process involved in carcinogenesis and metastasis. Inhibition of mTOR signaling through rapamycin has been shown to attenuate the process of EMT. This offers additional mechanistic rationale for mTOR inhibition as a therapeutic strategy in human fibrosis.Strong preclinical and human evidence also offers support for the use of rapalogs beyond its effects modulating the end-effectors of fibrinogenesis (fibroblasts & myofibroblasts). In preclinical models, immunocompromised mice exhibit decreased fibrosis during wound repair . T-cell Rapamycin is a Food and Drug Administration (FDA)-approved drug that promotes long term tolerance in organ transplant patients, and is incorporated within coronary stents to reduce restenosis and accelerated arteriopathy. Rapamycin and rapalogs mechanism of action is to bind to FKBP12 to inhibit a subunit protein of mTOR, mTORC1 , 7. FiguOutstanding questions to be addressed include the specific signaling pathway by which rapamycin inhibits fibroplasia, and if more specific targeting of these cellular mechanisms would be effective in treating the disease in the trachea as well as other organs. Future studies will also address therapeutic delivery with sustained topical application ideal to address organ specific fibrosis and avoid side effects associated with systemic administration. Specific to LTS, a rapamycin-eluting stent could assist in suppressing the inflammatory response, fibroblast proliferation, and collagen synthesis seen in LTS while providing structural support of the tracheal wall."} +{"text": "Healthy animals perform better than those that are diseased; therefore there are significant benefits from preventing disease on farm by investigating new vaccine delivery systems. Recently, viral vectors have risen to prominence as candidates for generating immune responses. Of these viral candidates, lentiviruses are attractive as they have the ability to transduce non-dividing antigen presenting cells. For example, lentiviral vectors have been shown to produce an antigen-mediated immune response in mice, providing long term, sterile protection against Malaria.Transformed human embryonic kidney 293T) cells were transfected with four plasmids which encode the various vector components for the production of lentiviral vectors. Vectors produced so far contain an eGFP reporter cassette to facilitate measurement of infectivity by flow cytometry. Self-inactivating (SIN) vectors have been produced to decrease the probability of the generation of replication-competent virus[93T cellsin vitro. Integration deficient vectors appear to have to correct phenotype as eGFP-positive cells decreased over time in dividing cells.Stable expression of antigens is important to a successful vaccine, therefore the stability of ovine lentiviral transduction was evaluated over a 4 week period with eGFP-positive cells measured periodically. 50% of cells remained eGFP-positive after 4 weeks in rapidly dividing cells suggesting a sustained, stable transduction. Ovine lentivirus vectors have the ability to infect a wide range of cell types from different species with similar efficiency to the well characterised murine leukaemia virus (MLV) vector. Self-inactivating vectors with non-active LTRs retain the ability to express transgenes in vitro. Future studies will investigate ovine lentiviral vectors mechanisms of immune response in vitro and study their efficiency to deliver appropriate immunity in vivo.We have created a novel, self-inactivating, integration deficient ovine lentiviral vector which retains the ability to express transgenes"} +{"text": "Pulmonary vein stenosis (PVS) is a known complication after catheter ablation of arrhythmias. Surprisingly, little information is available on its manifestations in the lung. We describe the case of a 39-year-old woman who presented from an outside hospital with worsening shortness of breath after catheter ablation of pulmonary veins for atrial fibrillation. After an initial diagnosis of pneumonia and its nonimprovement with antibiotics, a surgical lung biopsy was done and interpreted as nonspecific interstitial pneumonia (NSIP) with vascular changes consistent with pulmonary arterial hypertension. Later, she was admitted to our institution where a transthoracic echocardiogram (TTE) and subsequent computed tomography (CT) angiogram of the heart showed severe stenosis of all four pulmonary veins. The previous lung biopsy was rereviewed and reinterpreted as severe parenchymal congestion mimicking NSIP. Our case demonstrates that PVS is an underrecognized complication of catheter ablation, and increased awareness among both clinicians and pathologists is necessary to avoid misdiagnosis. A 39-year-old woman with no history of smoking presented with a nine-month history of progressive dyspnea on exertion and dry cough. One month before the onset of symptoms, she underwent a successful cardiac ablation of pulmonary veins for refractory atrial fibrillation. Computed tomography (CT) of the chest was done eight weeks prior to presentation and revealed bilateral scattered ground-glass opacities, diffuse septal thickening, and patchy consolidations in left lung Figures . After fAt admission, she was comfortable at rest, saturating at 92% with clear lungs on auscultation. Repeat imaging showed continued presence of diffuse septal thickening and ground-glass opacities Figures . BecauseSubsequently, her steroids were tapered, and, after we discussed the case with cardiologists at our institution, the patient underwent balloon angioplasty with pulmonary vein stenting . Six weeThe incidence of PVS after catheter ablation for atrial fibrillation ranges from 1% to 3% . Lung paIn conclusion, postablative patients with any pulmonary symptoms should have a high suspicion for PVS. It not only mimics other disease entities clinically and radiographically, but also can mimic other etiologies histologically, as seen with our case. Such delay and misdiagnoses subject patients to erroneous treatment and can cause irreversible secondary pulmonary parenchymal and vasculature changes with poorer outcomes ."} +{"text": "Although motivational disturbances are common in schizophrenia, their neurophysiological and psychological basis is poorly understood. This electroencephalography (EEG) study examined the well-established motivational direction model of asymmetric frontal brain activity in schizophrenia. According to this model, relative left frontal activity in the resting EEG reflects enhanced approach motivation tendencies, whereas relative right frontal activity reflects enhanced withdrawal motivation tendencies. Twenty-five schizophrenia outpatients and 25 healthy controls completed resting EEG assessments of frontal asymmetry in the alpha frequency band (8\u201312 Hz), as well as a self-report measure of behavioral activation and inhibition system (BIS/BAS) sensitivity. Patients showed an atypical pattern of differences from controls. On the EEG measure patients failed to show the left lateralized activity that was present in controls, suggesting diminished approach motivation. On the self-report measure, patients reported higher BIS sensitivity than controls, which is typically interpreted as heightened withdrawal motivation. EEG asymmetry scores did not significantly correlate with BIS/BAS scores or with clinical symptom ratings among patients. The overall pattern suggests a motivational disturbance in schizophrenia characterized by elements of both diminished approach and elevated withdrawal tendencies. Motivational impairment has been linked to schizophrenia since Kraepelin\u2019s inversely related to regional activity. Left frontal activity is believed to reflect approach motivation, whereas right frontal activity is associated with withdrawal motivation. These asymmetrical frontal EEG findings are supported by lesion studies, though hemodynamic studies have been less consistent Considerable evidence supports the motivational direction model of asymmetric frontal brain activity Frontal asymmetries assessed in the resting EEG are believed to relate to stable dispositional motivational tendencies. Consistent with this notion, several studies demonstrate associations between degree of lateralization of activation and scores on conceptually related self-report motivational trait measures. For example, in studies using the BIS/BAS scales Frontal asymmetry and motivational tendencies have been examined explicitly in schizophrenia in only two prior studies. One found that recent-onset patients showed more right frontal lateralization than healthy controls during a two-minute recording with eyes closed The current study assessed both resting frontal EEG asymmetries and self-reported approach/withdrawal tendencies in schizophrenia. The prior literature, though very limited, led to the prediction that patients would show relatively more right frontal lateralization and higher BIS scores than matched healthy controls. We also explored whether frontal asymmetries relate to individual differences on the BIS/BAS and to symptom levels among patients.Twenty-five outpatients with schizophrenia and 25 healthy control subjects participated in this research. Schizophrenia patients were recruited from outpatient treatment clinics at the Veterans Affairs (VA) Greater Los Angeles Healthcare System and through presentations in the community. Patients met criteria for schizophrenia based on the Structured Clinical Interview for DSM-IV Axis I Disorders SCID . None ofHealthy controls were recruited through flyers posted in local newspapers, websites, and posted advertisements. An initial screening interview excluded potential control participants with identifiable neurological disorder or head injury, had schizophrenia or other psychotic disorder in a first-degree relative, or were not sufficiently fluent in English. Potential controls were screened with the SCID and excluded for history of schizophrenia or other psychotic disorder, bipolar disorder, recurrent depression, lifetime history of substance dependence, or any substance abuse in the last 6 months. Potential controls were also administered portions of the Structured Clinical Interview for DSM-IV Axis II Disorders SCID-II and exclAll SCID interviewers were trained through the Treatment Unit of the Department of Veterans Affairs VISN 22 Mental Illness Research, Education, and Clinical Center (MIRECC) to a minimum kappa of 0.75 for key psychotic and mood items For all patients, psychiatric symptoms during the previous month were rated using the expanded 24-item UCLA version of the Brief Psychiatric Rating Scale BPRS by a traAll participants completed the BIS/BAS The research design and methods reflect standard procedures for studies of frontal EEG asymmetry Off-line analysis was performed using Brain Vision Analyzer software . All EEG data were re-referenced to the average of the mastoids t-tests and for categorical variables with chi-square tests; descriptive data for clinical symptom ratings in the patient group are also presented. For the main data analyses, group differences in alpha asymmetry scores and self-reported BIS/BAS scores were evaluated with independent samples t-tests. Finally, we evaluated whether asymmetry scores were associated with BIS/BAS scores and symptoms (patients only) using Pearson correlation coefficients within each group.For demographic data, group differences for continuous variables were evaluated with Demographic information for both groups and clinical data for the schizophrenia group are presented in The schizophrenia group had a typical age of onset and was chronically ill. They showed mild to moderate levels of clinical symptoms at the time of testing that are comparable to prior studies of stabilized outpatients Descriptive statistics and results of between-group comparisons are summarized in Although patients had numerically lower mean scores on the secondary index (F8\u2013F7) than controls, the groups did not significantly differ. Finally, for the analysis of the P4\u2013P3 electrodes, there was no significant group difference in parietal asymmetry scores.As shown in Among patients the F4\u2013F3 asymmetry index was not significantly correlated with BIS, BAS, or any of the three BAS subscales . Similarly, for controls, the F3\u2013F4 asymmetry index was not significantly correlated with BIS, BAS, or BAS subscale scores . There were no significant correlations between asymmetry and total symptoms or symptom subscale scores on the BPRS . Results for the correlation analyses were essentially identical using Spearman correlation coefficients.In this first study to evaluate approach and withdrawal motivation in schizophrenia using both self-report and EEG measures, patients showed an atypical pattern of differences from controls. On the resting EEG measure patients failed to show the left lateralized activity that was present in controls, suggesting diminished approach motivation in the schizophrenia group. On the self-report measure, patients reported higher BIS sensitivity than controls, which is typically interpreted as heightened withdrawal motivation. EEG asymmetry scores however, were not significantly correlated with self-reported motivational traits in either group. The overall pattern of group differences converges to suggest a motivational disturbance in schizophrenia characterized by elements of both diminished approach tendencies and elevated withdrawal tendencies.The current between-group motivational differences confirm and extend the few prior studies using either EEG or self-report measure alone. Regarding EEG, the two groups showed opposite asymmetry patterns at mid-frontal sites, the most commonly examined sites in the frontal asymmetry literature The patients\u2019 elevated self-reported scores on the BIS scale, but normal scores on the BAS scales, also converge with the few prior relevant studies in schizophrenia Overall, the current findings suggest that when it comes to understanding motivational factors that hold people with schizophrenia back from pursuing personally relevant goals, it is important to consider multiple processes. Diminished initiation and persistence in goal-directed activities may stem from a lack of desire to pursue potentially rewarding outcomes and/or a strong drive to avoid potentially unpleasant emotions and cognitions associated with efforts to pursue desired outcomes.Results from the current study are not fully consistent with prior studies, in that frontal asymmetry scores did not significantly correlate with symptom levels or with BIS/BAS scores. Regarding symptoms, Jetha et al. We also did not find significant correlations between frontal asymmetry and scores on the BIS/BAS scales in either patients or controls. Such correlations have been reported in some studies in clinical and healthy samples, though a number of studies have failed to find significant correlations, particularly for the BIS scale The current finding of increased withdrawal motivational tendencies in schizophrenia should be interpreted in the context of some limitations. First, this cross-sectional study of chronically ill patients cannot address the question of whether this pattern precedes the onset of schizophrenia or is the consequences of living with a severe mental illness. Although prior research demonstrating the same asymmetry pattern is present in recent-onset patients and that asymmetry scores show good longitudinal stability in schizophrenia is consistent with the notion that elevated right frontal lateralization reflects an enduring trait that is present from at least the early post-onset period Although the approach and withdrawal motivational framework has been extensively studied in internalizing and externalizing disorders, the current findings suggest it may be informative for understanding motivational disturbances in the psychosis dimension of psychopathology as well. The framework has treatment implications for schizophrenia patients with elevated withdrawal motivation. For example, CBT, emotion regulation, and mindfulness interventions that target symptoms such as anxiety and hyper-arousal may be useful for these individuals, and frontal asymmetries have been found to provide an informative biomarker in the context of these types of treatment studies Data S1(SAV)Click here for additional data file."} +{"text": "Hypertrophic cardiomyopathy (HCM) with midventricular hypertrophy is an uncommon phenotypic variant of the disease. Midventricular hypertrophy predisposes to intracavitary obstruction and downstream hemodynamic sequelae.We present a case of HCM with midventricular hypertrophy and obstruction diagnosed after a CT scan of the abdomen incidentally revealed a filling defect in the left ventricular apex. Transthoracic echocardiography demonstrated mid left ventricular hypertrophy and obstruction, as well as an aneurysmal apex containing a large thrombus. Cardiovascular MRI showed a spade-shaped left ventricle with midcavitary obliteration, an infarcted apex and regions of myocardial fibrosis. Due to the risk of embolization and a relative contraindication to anticoagulation, the patient underwent surgery including thrombectomy, septal myectomy and aneurysmal ligation.Hypertrophic cardiomyopathy with midventricular hypertrophy leads to cavity obstruction, increased apical wall tension, ischemia and ultimately fibrosis. Over time, patchy apical fibrosis can develop into a confluent scar resembling a transmural myocardial infarction in the left anterior descending coronary artery distribution. Aneurysmal remodeling of the left ventricular apex potentiates thrombus formation and risk of cardioembolism. For these reasons, hypertrophic cardiomyopathy with midventricular obstruction portends a particularly poor prognosis and should be recognized early in the disease process. Hypertrophic cardiomyopathy is defined as a myocardial disease characterized by unexplained left ventricular hypertrophy in association with non-dilated ventricular chambers . The dis2) status-post gastric bypass surgery over ten years prior to presentation was admitted for evaluation of an upper gastrointestinal bleed. Postoperatively following gastric bypass surgery, the patient became hemodynamically unstable and developed acute kidney injury. Although her renal function improved, the underlying etiology of her postoperative complications remained unknown. An abnormal electrocardiogram noted several years later suggested a prior myocardial infarction, retrospectively hypothesized incurred perioperatively. The abnormal electrocardiogram prompted invasive coronary angiography which showed no evidence of obstructive coronary artery disease. During the current admission for upper gastrointestinal bleeding, an abdominal CT scan with intravenous contrast serendipitously revealed a filling defect in the left ventricular apex. Transthoracic echocardiography confirmed the presence of a large, heterogeneous apical mass and additionally showed midventricular hypertrophy measuring 20 mm in the interventricular septum, resulting in systolic apposition of the midventricular segments with midcavity hypertrophy , a measured ejection fraction of 65% and an aneurysmal apex , oxygen supply-demand mismatch, ischemia and ultimately infarction and fibrosis. Patients with HCM also have abnormally thickened intramural arteries with decreased luminal size . CoupledThe increasingly utilized CMR technique of native T1 mapping characterizes myocardium based on quantitative T1 relaxation times, altered by the presence of fibrosis, without the need for intravenous gadolinium contrast agent. Increased T1 relaxation times in hypertrophic cardiomyopathy correlate with abnormalities in left ventricular systolic function even in the absence of late gadolinium enhancement . In the Patients with HCM and midventricular obstruction may exhibit a characteristic echocardiographic Doppler pattern of blood flow in the left ventricle . Due to This morphological variant of HCM deserves clinical recognition. In a Japanese study of 490 cMaron et al. have queHypertrophic cardiomyopathy with midventricular hypertrophy and obstruction is a relatively uncommon variant of HCM that may lead to an infarcted apex and aneurysm formation. Mid ventricular obstruction with apical aneurysm formation predisposes to thrombus formation and portends a poor prognosis. Repercussions of aneurysm formation included ventricular arrhythmias, thromboembolism, predisposition to end stage disease and death. Physicians should be aware of this variant and consider these patients to be at higher risk when making management decisions."} +{"text": "Iron oxide nanoparticles (IONPs) are frequently used for biomedical applications including magnetic resonance imaging, drug delivery or tumor treatment by hyperthermia. Since IONPs can reach the brain from periphery or are directly applied into the brain, the investigation of potential adverse effects of IONPs on properties and functions of the different types of brain cells is an important task. In order to directly compare different types of brain cells concerning the uptake and toxicity of IONPs, we synthesized fluorescent IONPs and characterized these BODIPY-labeled particles regarding their physicochemical properties. In the medium used for the cell studies, these particles had a hydrodynamic diameter of around 158 \u00b1 28 nm and a negative surface charge with a zeta-potential of -10 \u00b1 2 mV. Exposure of primary cultures of rat astrocytes, neurons and microglial cells revealed that among these cell types, microglial cells accumulated IONPs most rapidly. However, microglial cells were also most vulnerable towards acute IONP-induced stress while astrocytes and neurons were not acutely damaged by IONPs. In microglial cells, but not in astrocytes or neurons, IONPs were found to be localized in lysosomes and large amounts of reactive oxygen species (ROS) were observed after IONP-exposure. The IONP-induced toxicity in microglial cells was prevented by neutralizing lysosomes or by chelation of intracellular ferrous iron ions, suggesting that the toxic potential of IONPs in microglia involves rapid particle uptake, liberation of ferrous iron from the internalized IONPs in the acidic lysosomal compartment and iron-catalyzed ROS formation. These data suggest that also in brain IONPs may harm microglial cells and compromise microglial functions."} +{"text": "Abnormal accumulation of cytosolic aggregates or inclusion bodies is a hallmark of several neurodegenerative diseases. Many common or specific molecular components such as ubiquitin, \u03b1-synuclein, TDP-43, or tau in neuronal cytosolic inclusion bodies have been identified as being associated with cellular pathogenic mechanisms of disease. Recently, stress granule (SG) marker proteins such as PABP and G3BP were found in cytosolic inclusion bodies of patients with frontotemporal lobar dementia (FTLD), alzheimer's disease (AD), or amyotrophic lateral sclerosis (ALS), suggesting that inappropriate SG dynamics contribute to pathogenic mechanisms . MoreoveFUS mutations [atg7 siRNA increased the number of SGs, whereas activation of autophagy reduced SG accumulation. Further analysis showed that mutant FUS-positive SGs were regulated by autophagy regulation in post-mitotic neurons. Most importantly, autophagy activation reduced mutant FUS-positive SG accumulation as well as mutant FUS-mediated neurite fragmentation and cell death in response to oxidative stress in disease-associated cultured neurons, suggesting a role for persistent SGs in neurodegeneration as well as involvement of autophagy in ALS-linked SG regulation. However, this finding needs to be confirmed in transgenic animal models and patients with specific iPSC-derived neurons associated with persistent SGs and SG aggregates [To address these questions, our study investigated the role of autophagy, which controls the quality of proteins or organelles, in the regulation of ALS-linked SGs and neurodegeneration in disease-associated cultured neurons . Fused iutations . Interesgregates .Our study provides important insights into the roles of autophagy and disease-associated SGs in neurodegeneration. SGs are generally considered as a defense mechanism in neurons under stress conditions. However, persistent SGs in neurons might actually inhibit protein translation by sequestering mRNA and RNA-binding proteins, which are normally involved in transcriptional regulation in the nucleus or transport of mRNAs into dendrites/axons. Therefore, persistent SGs can lead to accumulation of toxic components/loss of essential components even after stress. According to our unpublished data, mutant FUS sequesters mRNAs that are involved in neuronal integrity into persistent SGs, which induces neurite fragmentation/shrinkage caused by oxidative stress in cortical neurons.atg5\u2212/\u2212 MEFs causes SG formation/accumulation without any stress, suggesting that cellular homeostasis of SGs is tightly associated with autophagy. During normal aging or disease progression in the brain, dysregulated or insufficient autophagy combined with environmental factors such as acute or chronic stresses may accelerate SG formation and development of persistent SGs into larger cytosolic inclusions, leading to increased stress vulnerability in neurons as well as neurodegeneration.Moreover, our studies have shown that autophagy deficiency in However, the following questions remain to be answered in the context of autophagic regulation of SGs in physiology and pathology: How do cells regulate and harmonize formation/disassembly/autophagic degradation of SGs in response to different stresses in physiology and pathology? Which signals induce autophagic clearance of physiological or pathological SGs as opposed to disassembly of SGs or fusion with P-bodies? How are transient or persistent SGs recognized by autophagy machineries? What is the specific role of autophagy in regulation of SGs in relation to neuronal RNA granules such as P-bodies or transporting RNA granules in polarized neurons? More detailed studies are needed to elucidate autophagic regulation of SGs. Therefore, future efforts will provide novel opportunities for therapeutic intervention by targeting regulation of SGs via manipulation of the autophagic pathway in several neurodegenerative diseases associated with SGs such as ALS ."} +{"text": "Odorant Receptor genes). To identify whether shifts in pheromone composition among related lineages of orchid bees are associated with divergence in chemosensory genes of the olfactory periphery, we searched for patterns of divergent selection across the antennal transcriptomes of two recently diverged sibling species Euglossa dilemma and E. viridissima.Insects rely more on chemical signals than on any other sensory modality to find, identify, and choose mates. In most insects, pheromone production is typically regulated through biosynthetic pathways, whereas pheromone sensory detection is controlled by the olfactory system. Orchid bees are exceptional in that their semiochemicals are not produced metabolically, but instead male bees collect odoriferous compounds (perfumes) from the environment and store them in specialized hind-leg pockets to subsequently expose during courtship display. Thus, the olfactory sensory system of orchid bees simultaneously controls male perfume traits (sender components) and female preferences (receiver components). This functional linkage increases the opportunities for parallel evolution of male traits and female preferences, particularly in response to genetic changes of chemosensory detection .We identified 3185 orthologous genes including 94 chemosensory loci from five different gene families . Our results revealed that orthologs with signatures of divergent selection between Our results suggest that rapid changes in the chemosensory gene family occurred among closely related species of orchid bees. These findings are consistent with the hypothesis that strong divergent selection acting on chemosensory receptor genes plays an important role in the evolution and diversification of insect pheromone systems.The online version of this article (doi:10.1186/s12862-015-0451-9) contains supplementary material, which is available to authorized users. Olfaction allows animals to perceive volatile chemicals from the environment and is therefore essential for the detection and discrimination of food resources, predators, and conspecifics in a diverse array of taxa , 2. In iOstrinia nubilalis, has shown that divergence in pheromone recognition might be best explained by nucleotide substitutions in pheromone receptor genes ."} +{"text": "Historically, the catheter peak-to-peak pressure gradient (PPG) has been used as the diagnostic gold standard to evaluate the degree of pulmonary outflow tract obstruction in congenital heart disease (CHD) and was employed to decide when to intervene. Today, estimated maximal Doppler gradients are generally decisive. Cardiovascular phase contrast magnetic resonance (PCMR) measurements are frequently performed during routine follow-up. However, it remains unclear how to deal with PCMR flow velocities that can also serve for the estimation of pressure gradients.In 75 patients with pulmonary outflow tract obstruction maximal and mean PCMR gradients were compared to maximal and mean Doppler gradients. Additionally, in a subgroup of 31 patients maximal and mean PCMR and Doppler pressure gradients were compared to catheter PPG.Maximal and mean PCMR gradients underestimated pulmonary outflow tract obstruction as compared to Doppler . However, in comparison to catheter PPG, maximal PCMR gradients and mean Doppler gradients revealed best agreement . Mean PCMR gradients underestimated, while maximal Doppler gradients systematically overestimated catheter PPG .Estimated maximal PCMR pressure gradients and mean Doppler gradients from routine CHD follow-up agree well with invasively assessed PPG. There is evidence to either apply maximal PCMR gradients or mean Doppler gradients to evaluate the severity of pulmonary outflow tract obstruction during follow-up of CHD.N/A."} +{"text": "Gradually increasing prosthetic ankle stiffness influenced the shape of the prosthetic ankle plantarflexion moment, more closely mirroring the intact ankle moment. Increasing ankle stiffness also corresponded to increased prosthetic ankle power generation and increased braking ground reaction forces of the amputated leg. These findings further our understanding of how to deliver assistance with powered knee-ankle prostheses and the compensations that occur when specific aspects of assistance are added/removed.Powered knee-ankle prostheses are capable of providing net-positive mechanical energy to amputees. Yet, there are limitless ways to deliver this energy throughout the gait cycle. It remains largely unknown how different combinations of active knee and ankle assistance affect the walking mechanics of transfemoral amputees. This study assessed the relative contributions of stance phase knee swing initiation, increasing ankle stiffness and powered plantarflexion as three unilateral transfemoral amputees walked overground at their self-selected walking speed. Five combinations of knee and ankle conditions were evaluated regarding the kinematics and kinetics of the amputated and intact legs using repeated measures analyses of variance. We found eliminating active knee swing initiation or powered plantarflexion was linked to increased compensations of the ipsilateral hip joint during the subsequent swing phase. The elimination of knee swing initiation or powered plantarflexion also led to reduced braking ground reaction forces of the amputated The number of individuals with lower-limb amputations living in the U.S. is projected to grow dramatically , and comand ankle joints affect the walking mechanics of amputees. This is especially true when examining outcomes in transfemoral amputees and during overground walking. Interesting prior studies have sought to emulate autonomous prosthetic systems with externally-powered devices and treadmill-based test beds to answer some of these questions regarding the plantarflexive assistance occurring during the mid- to late stance phase of walking are comg . While and ankle assistance influence the walking mechanics of transfemoral amputees. With the rapid advances in powered prosthetic hardware and the encouraging prior studies that demonstrate the potential benefits of these devices [Little is known about how combinations of knee devices , 27, theThree male subjects with unilateral amputations at or above the knee . Repeated trials were conducted until five clean force plate contacts were captured for both amputated and intact legs. Ground reaction force (GRF) and kinematic data were collected using an eight-camera motion capture system . For each subject, reflective markers were placed on the posterior sacrum and bilaterally on the posterior superior iliac spine (PSIS), anterior superior iliac spine (ASIS), greater trochanter, lateral and medial femoral epicondyle, lateral and medial malleolus, posterior heel, dorsal foot, and fifth metatarsal head. Clusters of three markers affixed to thermoplastic shells were wrapped bilaterally to the thigh and shank.\u03c4, at the knee and ankle joints as a function of three impedance parameters: joint stiffness, k, equilibrium angle, \u03b8e, and damping coefficient, b, according to i corresponded to the knee or ankle joint, \u03b8 was the joint angle and Subjects wore a powered knee and ankle prosthesis featuring on-board mechanical sensors, including sensors to measure knee and ankle position and velocity, as well as axial load applied through the shank . Sensor xtension . TransitTo provide knee swing initiation, the prosthesis knee equilibrium angle was increased from 0\u00b0 to 60\u201375\u00b0 flexion (ranged across subjects) during terminal stance as a linear function of decreasing prosthesis vertical load ; the stiSpatiotemporal, kinematic and kinetic data were analyzed using Visual3D and Matlab . Kinematics were segmented from heel contact to heel contact; kinetic data were segmented from heel contact to toe-off (stance phase) and toe-off to heel contact (swing phase), and normalized to body mass (kg). All data were low-pass filtered and averaged across strides. Average peak values were calculated for joint kinematics. Average positive and negative values were calculated for GRF and joint kinetics during stance, and also calculated for joint kinetics during swing. To provide objective comparisons of these metrics across all conditions, across-subject statistics were performed . For each quantity, two analyses of variance with repeated measures (ANOVAs) were evaluated (\u03b1 = 0.05). One two-way ANOVA tested the effects of powered plantarflexion and increasing ankle stiffness. The second tested the effect of swing initiation. Post-hoc tests using a Bonferroni correction factor were used to identify differences between conditions.Increasing ankle stiffness had a significant effect on stance time of the intact leg (p = 0.02), with a trend toward reduced stance time. There were no differences in step length, step time, swing time, overall cycle time, walking speed, stride length, or stride width for either amputated or intact legs .amputated leg was affected by increasing ankle stiffness (p = 0.023) and powered plantarflexion of the Powered plantarflexion had a significant effect on the peak stance phase knee flexion angle of the intact leg (p = 0.002), with a trend toward less knee flexion with powered plantarflexion. Knee swing initiation increased peak knee flexion of the amputated leg in swing , and powered plantarflexion and increasing ankle stiffness had a significant interaction effect on average positive hip power , knee flexion moment (p = 0.043), and ankle plantarflexion moment , were decreased and others increased. We found in the absence of knee swing initiation, these transfemoral amputees compensated by reducing the braking ground reaction force of the intact leg . This fien shown . In thisintact leg also occurred with a lack of powered plantarflexion in the presence of knee swing initiation the knee extension moment in early stance, irrespective of ankle stiffness . While many studies have been focused on reducing the metabolic cost of amputee walking by providing assistance at the ankle joint exclusively, this investigation reveals that the synchronization of ankle and knee power in late stance and monitoring how these changes influence kinetics of proximal joints and joints of the intact leg may be especially important to resolve the increased metabolic cost of amputee walking. Finally, based on the biomechanical outcomes evaluated in this study, when fitting elderly patients or other patients at risk of exhibiting gait instability or sustaining fall-related injuries with active knee-ankle prostheses, control strategies that deliver both active knee and ankle assistance may prove to be detrimental. Powered plantarflexion and knee swing initiation were shown to increase braking ground reaction forces relative to conditions that did not provide these functions, which would likely influence stability in the sagittal plane. Thus, hybrid solutions which selectively deliver active knee or ankle assistance could be beneficial. These implications are subjective, and we also understand that individual patient needs could be coupled and be presented simultaneously. Thus, as mechanically-active devices become more commonplace, studies which comprehensively identify how specific aspects of active knee and ankle control influence the biomechanics of locomotion are likely to become increasingly important."} +{"text": "Mucormycosis is an invasive mycotic disease caused by fungi in the zygomycetes class. Although ubiquitous in the environment, zygomycetes are rarely known to cause invasive disease in immunocompromised hosts with a high mortality even under aggressive antifungal and surgical therapy. Clinically, mucormycosis frequently affects the sinus occasionally showing pulmonary or cerebral involvement. However skeletal manifestation with Rhizopus microsporus (RM) osteomyelitis leading to emergency surgical proximal femoral resection with fatal outcome has not been described yet.We report the case of a 73-year-old male suffering from myelodysplastic syndrome with precedent bone marrow transplantation. Six months after transplantation he consulted our internal medicine department in a septic condition with a four week history of painful swelling of the right hip. Radiography, computed tomography and magnetic resonance imaging revealed multiple bone infarcts in both femurs. In the right femoral head, neck and trochanteric region a recent infarct showed massive secondary osteomyelitis, breaking through the medial cortex. Emergency surgical proximal femoral resection was performed due to extensive bone and soft tissue destruction. Microbiological and basic local alignment search tool (BLAST) analysis revealed RM. Amphotericin B and posaconazole treatment with septic revision surgery was performed. However the disease ran a rapid course and was fatal two months after hospital admission.This alarming result with extensive RM osteomyelitis in the proximal femur of an immunocompromised patient may hopefully warn medical staff to perform early imaging and aggressive surgical supported multimodal treatment in similar cases.The online version of this article (doi:10.1186/1471-2334-14-488) contains supplementary material, which is available to authorized users. Zygomycetes are environmental nonseptate molds widely distributed in soil, plants, and decaying material , 2. The Previously reported risk factors for mucormycosis are prolonged neutropenia, immunosuppression, iron overload and prolonged hyperglycemia or manifest diabetes. Patients treated with allogeneic hematopoietic stem cell transplantation often suffer from a combination of these risk factors . The proHere we describe the unique case of fatal invasive osteomyelitis in an allo-HSCT recipient caused by RM. Extensive diagnostic evaluation revealed multiple old bone infarcts complicated with invasive fungal disease. Although systemic antifungal treatment and repetitive radical surgery was started immediately cure could not be provided.We report on a 73-year-old male with recently diagnosed myelodysplastic syndrome RAEB I showing complex karyotype. A routine-checkup revealed a tricytopenia in the blood count as well as a mild splenomegaly, further examinations including bone marrow biopsy confirmed the diagnosis. Facing the high-risk constellation of this disease and theEleven months later allogeneic matched unrelated donor stem cell transplantation after conditioning chemotherapy with fludarabine, treosulfane as well as antithymocyte globuline and prophylactic immunosuppressive medication containing of cyclosporine and mycophenolatmofetile was performed successfully. No relevant complications occurred during the first weeks of follow-up besides moderate acute graft versus host disease of the skin which was immediately responsive to steroid treatment. Bone marrow examinations one month after transplantation showed complete cytogenetic remission of the disease as well as complete donor chimerism. With no further signs of graft versus host disease and a good clinical condition of the patient the immunosuppressive treatment could be constantly tapered during the following months. Continuous prophylactic antiinfectious medication with acyclovir, co-trimoxazole and posaconazole was administered.Six months after transplantation without remaining medication the patient was presented to our internal emergency department with a critical septic condition showing fever (body temperature above 40\u00b0C) and dyspnea, and was immediately transferred to the intensive care unit (ICU). Intubation and mechanical ventilation had to be initiated due to respiratory failure. Computed tomography (CT) scan revealed bilateral infiltrations referring to atypical pneumonia and regional osteopaenia with mild focal bone lysis at the level of the lumbar spine. Lumbar spondylodiscitis was ruled out by magnetic resonance tomography imaging (MRI).No relevant bacterial, viral or fungal cause could be identified by bronchoalveolar lavage and multiple blood culture collections during the stay on the ICU. Cardiac echocardiography was performed and culture-negative endocarditis could be ruled out. The patient constantly improved under combinatory empiric antibiotic, antiviral and antifungal (azole) medication, extubation could be performed 7\u00a0days after intubation. While the respiratory situation completely stabilized, the clinical condition of the patient constantly deteriorated in the following days. For the first time the patient reported right hip pain.In consequence ultrasound, CT and MRI of the right hip and thigh were performed in order to identify and localize a potential inflammatory focus. The imaging revealed multiple old bone infarcts in both femurs as well as a new infarct with massive secondary osteomyelitis in the right femoral head, neck and trochanteric region, breaking through the medial cortex into the surrounding soft tissue Figure\u00a0. With emInvasive disseminated Rhizopus-infections develop in fewer than \u00bc of localized forms and have an estimated mortality rate of 78\u2013100% in allo-HSCT recipients [Immunocompromised patients, particularly suffering from hematological diseases treated by allo-HSCT face a high risk of invasive fungal infections . InvasivCompared to focal RM fungal infections disseminated infections are even more seldom , 13, 14.Mucormycosis spreads from isolated infection hematogenously to other organs. The most common sites of origin are sinuses (39%), lungs 24%), and skin (19%) 4%, and s. DissemiFurthermore establishing the diagnosis of invasive fungal infections, primarily based on standard culture-based mycological methods is often difficult, especially in early stages . AccordiTherapy for mucormycosis infections includes systemic antifungal drugs and local surgical debridement . RegardiThis dramatic case of rapidly progressive and ultimately fatal RM infection of the bone illustrates the diagnostic and therapeutic challenges of mucormycosis in immunocompromised hosts. Amongst others, abscess formations should always be suspicious of invasive fungal infection under these circumstances. Rapid and exact diagnosis by both morphology and molecular techniques is crucial for starting early treatment of fungal infection. Amphotericine B should be used as soon as mucormycosis is suspected. If the patient\u2019s condition is not improving, addition of posaconazole should be considered. At the same time, early and aggressive surgical debridement has to be performed first to detect the pathogen and second to establish local control. Comprehensive multimodal therapy for mucormycosis may create more opportunities to improve patient\u2019s outcome despite the very low overall survival rate in disseminated cases.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor of this journal."} +{"text": "A rat model of antineutrophil cytoplasmic antibody (ANCA) associated vasculitides reveals crescentic glomerulonephritis as seen in human renal biopsies and diffuse lung hemorrhage that is not well documented in human lung biopsies. A 64-year-old male, with shortness of breath and mild elevation of serum creatinine, was found to have a positive serum test for ANCA, but negative antiglomerular basement membrane antibody. A renal biopsy showed pauci-immune type of crescentic glomerulonephritis and focal arteritis. The prior lung wedge biopsy was retrospectively reviewed to show diffuse hemorrhage and hemosiderosis with focal giant cells. In addition, small arteries revealed subtle neutrophil aggregation, and margination along vascular endothelium, but no definitive vasculitis. The pathology of ANCA associated vasculitides results from activated neutrophils by ANCA and subsequent activation of the alternative complement cascade with endothelial injury, neutrophil aggregation and margination. Our findings, after the correlation between lung biopsy and renal biopsy, imply that the top differential diagnosis in the lung biopsy should be microscopic polyangiitis when diffuse pulmonary hemorrhage and hemosiderosis are present in this ANCA-positive patient. In humans, ANCA associated systemic vasculitides clinically range from microscopic polyangiitis to granulomatosis with polyangiitis to eosinophilic granulomatosis with polyangiitis . The systemic vasculitides mainly involve small vessels of the lungs and kidneys, causing compromised lung function and rapid progressive renal failure \u20134. ConveA 64-year-old male had progressive dyspnea over six-month duration. The patient had a history of asthma but never smoked. A recent cardiac evaluation included normal echocardiogram and stress test. Computerized tomography (CT) chest imaging without contrast revealed bilateral mild ground-glass opacities in the lungs, slightly greater within the middle and lower lobes on the right side, suggestive of mild interstitial lung disease. He was found to have positive serum p-ANCA at titer of 1\u2009:\u2009640 while the antiglomerular basement membrane antibody was negative. His serum test for myeloperoxidase was positive at greater than 8 units while his serum level of proteinase-3 was negative. Wedge lung biopsies from the right upper, middle, and lower lobes were performed to reveal red to purple color from pleural surface and red color on the cross sections grossly. Microscopically, the biopsies mainly revealed diffuse hemorrhage and hemosiderosis Figures , but no The patient's renal biopsy showed cellular crescents in 3 of 12 glomeruli and focal fibrinoid vasculitides in a small artery Figures with milPulmonary hemosiderosis indicates chronic hemorrhage, as iron positivity is identified in hemosiderin-laden macrophages. Traditionally, the differential diagnosis for diffuse pulmonary hemosiderosis includes idiopathic pulmonary hemosiderosis versus Goodpasture's syndrome, which is supported by a positive test for antibasement membrane antibody , 16. GooUnlike Goodpasture's syndrome with one positive antibody and one main finding of pulmonary hemorrhage and hemosiderosis, ANCA associated vasculitis can range from microscopic polyangiitis to granulomatosis with angiitis and eosinophilic granulomatosis with polyangiitis in lung biopsies. Pathologic morphology of ANCA associated microscopic polyangiitis in lung biopsies is not well established , 9, but In summary, a positive ANCA test is an additional serology biomarker suggestive of systemic vasculitis. The criteria for ANCA associated variants of pulmonary vasculitis should be further investigated beyond traditional morphologic findings, which were established many years before ANCA test was discovered. The animal model of ANCA associated systemic vasculitides appears coupled with our findings after the current correlation between the lung biopsy and renal biopsy, implying that microscopic polyangiitis should be on the top differential diagnosis when diffuse pulmonary hemorrhage and hemosiderosis are the main findings in ANCA-positive patients."} +{"text": "About 90% of mortality associated with cancer is attributable to metastatic disease. Thus, our ability to treat cancer is largely dependent on the capacity to prevent metastasis. Metabolic reprogramming is recognized to support cellular transformation and tumor initiation; however, whether or how metabolism supports metastasis remains an open question. This study seeks to identify metabolic predictors of metastasis, with the rationale that understanding metabolic changes will lead to novel insights into metastasis and perhaps new therapies to treat metastatic disease.A patient-derived xenograft model was used in which metastasis in mice strongly correlates with metastatic history of patient donors. Tumor cells were originally obtained from melanoma patients and passaged exclusively in highly immunocompromised mice . In thisUnsupervised hierarchical clustering revealed that in every case, a given tumor biopsy was most closely related to all other biopsies descended from the same parental tumor. In addition, as a frequent mutation in melanoma, BRAF-mutant tumors were easily distinguished from BRAF-wild type tumors by their metabolomic signatures. More importantly, several metabolic pathways were found altered significantly when metabolomics profiles between melanoma lines with high or low metastatic potentials were compared.The MS-based metabolomic analysis of patient-derived melanoma xenografts demonstrates that tumors contain individual metabolomic identities that can be tracked. It may be possible to identify metabolomic features from primary tumors that predict various aspects of tumor biology, including the propensity to metastasize. The altered metabolic pathways in highly metastatic melanomas are potential therapeutic targets."} +{"text": "Depression and anxiety disorders are characterized by complex and idiopathic etiologies. One prominent hypothesis, termed \u201cthe neurogenesis hypothesis,\u201d posits that stress-induced decreases in hippocampal neurogenesis underlie depressive episodes , the other brain structure that integrates new neurons in the adult mammalian brain, remains unspecified. Subventricular zone (SVZ) neuroblasts migrate to the OB along the rostral migratory stream (RMS). Chronic stress affects this migration within the olfactory epithelium or OB sensory afferentation (OMP+ cells), suggesting deficits in odor processing rather than detection. Corticosterone administration decreased cell proliferation in the dentate gyrus (DG), but did not affect cell proliferation in the SVZ. These data suggest a different mechanism by which corticosterone affects neuroblasts destined for the OB. To investigate this, survival of newly born neurons maturing in the DG and OB was examined. Glucocorticoids decreased cell survival in both regions; this effect was prevented by co-administration of FLX. Additionally, dendritic complexity of newly integrated neurons increased following FLX administration, potentially contributing to the partially rescued phenotype. Taken together, these results link major depressive disorder and neurogenesis-dependent olfactory deficits within the DG and OB. Understanding the implications of impaired olfactory function and neurogenesis in depressed humans warrants further investigation; additional mechanisms by which glucocorticoids modulate neurogenesis and functional synapse formation should be examined.A new study Siopi et al. provides+) in the SVZ and OB relative to psychiatrically healthy people (Maheu et al., + cells in the SVZ was reduced without simultaneous reductions in the OB. These data suggest that impaired migration and ectopic differentiation leads to neuroblast accumulation in the OB of unmedicated depressed individuals. Antidepressant treatment facilitates neuroblast migration out of the SVZ, but cells that differentiated ectopically prior to treatment persist (Maheu et al., The translational significance of these new data is worth considering in the context of vast species differences in rates of olfactory neurogenesis and reliance on olfaction. Rodents rely more heavily on olfaction than humans, and neurogenic rates in the OB are minimal in adult humans (Kam et al., Although stress-induced increases in glucocorticoids directly regulate neurogenesis, immune cells are also responsible for maintenance of the neurogenic niche (Ziv et al., In sum, Siopi and colleagues suggest that chronic elevated glucocorticoids reduce hippocampal and olfactory neurogenesis, leading to depressive-like states and impaired olfactory function Figure . FluoxetAll authors contributed equally to the writing and review of this manuscript.JB is supported by an OSU Presidential and Pelotonia pre-doctoral fellowship. YC was supported by National Institute of Dental and Craniofacial Research Grant T32DE014320.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Dear Editor,Recently, we conducted a preclinical investigation to find the ameliorative properties of metformin on renal biochemical and histologic alterations of gentamicin-induced kidney damage in male Wistar rats . In this"} +{"text": "Voriconazole is an established first-line agent for treatment of invasive fungal infections in patients undergoing allogeneic stem cell transplantation (ASCT). It is associated with the uncommon complication of periostitis. We report this complication in a 58-year-old female undergoing HSCT. She was treated with corticosteroids with minimal improvement. The symptoms related to periostitis can mimic chronic graft-versus-host disease in patients undergoing HSCT and clinicians should differentiate this from other diagnoses and promptly discontinue therapy. Invasive fungal infections lead to significant morbidity and mortality in patients who are undergoing allogeneic stem cell transplantation (ASCT) \u20133. TreatA 58-year-old woman with intermediate risk acute myeloid leukemia in first complete remission underwent ASCT from an HLA-matched sibling. Her initial induction was complicated by hypoxia, pulmonary infiltrates, and fevers despite broad-spectrum antibiotics. She was treated with voriconazole with clinical improvement and was presumed to have invasive fungal infection. Voriconazole was continued throughout her transplant course given persistent chest CT abnormalities.At day 79 after ASCT, the patient complained of swelling in her left middle finger. Physical examination revealed discrete tender swelling of the middle phalanx on the third finger. This continued to worsen and one month later she was complaining of further swelling involving the fourth finger . In addiVoriconazole is a triazole antifungal that is indicated for the treatment of invasive aspergillosis. Common adverse effects include visual disturbances, hallucinations, QT prolongation, and hepatotoxicity. With prolonged use however, newly described adverse effects, including periostitis, alopecia, and development of skin cancers, have been noted . PainfulMost cases of voriconazole-induced periostitis have been reported in patients who have undergone solid organ transplantation \u20137. Few cThe clinical presentation and radiologic findings of patients who develop voriconazole-induced periostitis are nonspecific and insidious and may be confused with rheumatologic or endocrinologic disorders. In the setting of ASCT, symptoms may mimic cGVHD. Prior cases reported in the ASCT setting were also treated with corticosteroids for cGVHD, resulting in temporary symptom relief and a delay in discontinuing voriconazole \u201311. In oGiven that long-term voriconazole therapy is increasingly common, clinicians managing ASCT patients should be aware of this complication. We recommend periodic measurement of ALP and fluoride levels in patients on prolonged voriconazole therapy. In patients on voriconazole who report nonspecific musculoskeletal complaints following ASCT, drug-induced periostitis should be included in the differential diagnosis along with cGVHD."} +{"text": "Arthroscopic treatment of these disordersproduces more favourable results than open procedures.We report two patients who were not responding toconservative management and were treated with directarthroscopic distal clavicle excision and subacromialdecompression in single setting. Both patients gained goodpostoperative outcome in terms of pain score, function andstrength improvement assessed objectively with visualanalogue score (VAS) and University of California LosAngeles Score (UCLA).Shoulder impingement syndrome and acromioclavicularjoint osteoarthritis often occur simultaneously andeasily missed. Kay et al. reported excellent results withcombined arthroscopic subacromial decompression andresection of the distal end of the clavicle in patients withboth disordersAcromioclavicular joint arthritis, distal clavicle excision,Arthroscopy, Mumford operation. Resection of the distal clavicle, as described byMumford 2, is a reliable surgical option in acromioclavicularjoint (ACJ) osteoarthritis and shoulder impingementsyndrome. Symptom improvement has been satisfactory inmost reported series. Historically, distal clavicle resectionhas been performed using an open incision over the ACJ withdetachment of the deltoid and trapezius muscles. Significant morbidity may follow with these open procedures. Woundinfection, residual acromioclavicular joint instability,cosmetically unacceptable scar, postoperative shoulderweakness and stiffness are among the common complicationsreported from these open procedures 3.Symptomatic acromioclavicular osteoarthritis and distalclavicle osteolysis can be treated effectively with both nonoperativeand operative means. Non-operative treatmentsincluding physiotherapy, non-steroidal anti-inflammatorydrugs (NSAIDS) and corticosteroid injection may help torelieve the symptoms. However, surgical Patient OneAn active 64 year old lady with no previous history of traumawas referred for evaluation of persistent anterosuperiorleft shoulder pain for one year. The pain worsened whenshe tried to reach across the body or behind the back. Shealso experienced discomfort with rotational and overheadmovements of the left shoulder. Physical examinationrevealed tenderness over the left acromioclavicularjoint. Cross body adduction and active compression testsreproduced the symptoms at the acromioclavicular joint.Neer and Jobe impingement tests were positive. Plainradiographs revealed osteoarthritis of acromioclavicularjoint with narrowing of joint space The patient was put on beach chair position. Through astandard posterior portal, the arthroscope was insertedto screen for underlying pathology. Meanwhile, anotheranterior portal was made via outside in technique withspinal needle, in line with the AC joint (to facilitate the AC joint resection later). Osteophytes were shaved throughthe anterior portal first, and then switched to posteriorportal for bursectomy as this facilitated subacromialspace viewing and subacromial decompression. Lateralportal was created with spinal needle, 3cm to the lateral of acromion edge. By viewing the scope from the lateralportal, resection of inferior part of AC joint was performeddirectly from the anterior portal. Further resection of ACjoint, especially at the superior edge was achieved withthe 70-degree scope to shave from anterior portal. Using the 70-degree scope from the standard lateral portal andalso posterior portal, the entire AC joint could be viewedin detail which helped preserving the superior capsule andligament. Finally, we switched the scope to the anteriorportal for final checking for remnants of osteophytes anddistal clavicle.Postoperative, patient went through standard rehabilitationprotocol, with early range of movement exercises from dayone postoperatively. The shoulder was protected with armsling for 7 to10 days. The patient returned to her normalactivities at six weeks following surgery. Both VAS andUCLA scores showed improvements compared withpreoperative findings. During follow up at six months, sheremained pain free and achieved full range of movementsof the shoulder without impingement signs Patient TwoA 54 year old male presented with a 4 year historyof gradually worsening right anterosuperior shoulderpain. He had a history of a motor vehicle accident in2009, sustaining direct trauma to his right shoulder.Arthroscopic debridement had been carried out in 2010but the pain was only partially relieved. The patient hadsought to relieve his pain with anti-inflammatory drugs,corticosteroid injection and physiotherapy but to littleavail. Patient had limited range of movement of the rightshoulder especially adduction. He experienced difficultyreaching for his wallet and tucking his shirt behind his back. Physical examination revealed healed previousarthroscopic portals. Positive tests included cross-bodyadduction and active compression, with pain locatedspecifically at the acromioclavicular joint. There was noevidence of impingement signs or glenohumeral instability.Standard radiographs demonstrated maintenance of theacromioclavicular joint space, but marked hypertrophicdegenerative changes Postoperative radiographs demonstrated adequate boneresection and no obvious translation of the clavicle relativeto the acromion 4.Arthroscopic resection of the distal clavicle andsubacromial decompression can avoid complicationsarising from the open method. Preserving the posteriorand superior aspects of the acromioclavicular capsuleavoids creating iatrogenic distal clavicular anteroposteriorinstability. Moreover, arthroscopic excision provides theadvantage of evaluating glenohumeral joint at the time ofsurgery. Other shoulder joint pathology such as rotator cuffdisease, loose bodies, labral tears and chondral injurieswill not be missed. Hence, there will be only a singleprocedure needed to solve the patient\u2019s shoulder problems.Arthroscopic subacromial decompression and arthroscopicresection of the acromioclavicular joint as separateprocedures have been well documented. However, there islittle documentation on the success rate of resection withconcomitant subacromial decompression. In our case, wefound excellent results with arthroscopic resection of theacromioclavicular joint and subacromial decompressionin a single setting. Maintaining the integrity of the capsular attachments minimizes the amount of bleedingand trauma into the subacromial space, thereby decreasingpostoperative pain while avoiding creating iatrogenic distalclavicular horizontal instability. When this procedure is performed on properly selected patients, there are fewerpostoperative complications. Patients return to activitiesearlier while achieving similar long-term outcomes asthe open procedure"} +{"text": "Most healthcare professional training programs lack sufficient curricula on substance use-3, and eIn year two of the project, students training began integrating SBIRT into their clinical experiences. Implementation packets were distributed to students with resources and instructions tailored to fit the varied needs of the programs and clinical sites. Clinical practice was supervised by SBIRT-trained clinical preceptors when possible or self-evaluated by students using the Brief Intervention Observation Sheet fidelity scale. Qualitative feedback was collected from faculty, clinical preceptors, and students to identify facilitators and barriers to integration of SBIRT into clinical experience.Preliminary data showed that 56 students practiced SBIRT at their clinical site during the first semester of implementation, with 9% completing screening only (no BI indicated) and 91% completing screening and BI. Fidelity ratings revealed strong completion of BI steps with no significant difference between the groups , although BSN students demonstrated stronger motivational style . Qualitative data revealed institutional barriers to integrating SBIRT into some nursing clinical sites, while MSW clinical sites generally facilitated student practice and some adopted SBIRT agency-wide.Students need opportunities to integrate SBIRT practice into clinical experience and receive supervised feedback to achieve competency. Plans must be tailored to meet the institutional needs of clinical sites, which can vary for BSN and MSW students."} +{"text": "Nephronophthisis is an autosomal recessive renal ciliopathy that constitutes the leading monogenic cause of end-stage renal disease in children. The KOUNCIL consortium is a collaboration between the UMC Utrecht, the Radboud UMC Nijmegen and UC London aimed at elucidating the genetic etiology and pathophysiological mechanisms underlying nephronophthisis and identifying drugs that prevent or delay renal insufficiency. Our goal is to improve genome diagnostics, genetic counselling and therapeutic options for nephronophthisis patients.in vitro and in vivo models. Genotypic and phenotypic patient characteristics are registered in a nephronophthisis database, facilitating correlation analyses and identification of early phenotypic markers. Newly identified nephronophthisis-genes are incorporated into diagnostic next-generation sequencing panels of ciliary genes. We use a systems-biology approach to identify and functionally characterize nephronophthisis-associated protein modules. Finally, we use high-throughput repurposing screens in zebrafish embryos to identify FDA-approved drugs that halt renal failure.We employ next-generation sequencing to identify novel disease genes in 100 nephronophthisis patients included within the AGORA biobank project. The functional effect of novel mutations is assessed using IFT172, WDR34 and WDR60) for nephronophthisis-related disorders. Clinical guidelines and new diagnostic tools for nephronophthisis are developed and implemented in diagnostics. We expect to identify drugs that can lead to novel therapies for nephronophthisis.With this approach, we expect to uncover the causal mutation in 60-90% of nephronophthisis patients. KOUNCIL members were involved in the recent identification of three novel genes (The KOUNCIL study is designed to advance understanding of renal ciliopathies and improve clinical care for nephronophthisis patients."} +{"text": "This survey sought to evaluate differences in the understanding and management of shunt-dependent hydrocephalus among the senior North American Pediatric Neurosurgery membership.Surveys were sent to all active American Society of Pediatric Neurosurgeons (ASPN) members from September to November 2014. A total of 204 surveys were sent from which 130 responses were recorded, representing 64% of active ASPN membership. Respondents were asked 13 multiple choice and free response questions focusing on four problems encountered in shunted hydrocephalus management: Shunt malfunction, cerebrospinal fluid (CSF) overdrainage, chronic headaches and slit ventricle syndrome (SVS). Qualtrics\u00ae online survey software was used to distribute and collect response data.ASPN surgeons prefer three varieties of shunt valves: 41% differential pressure, 29% differential with anti-siphon device (ASD), and 27% programmable. Respondents agree shunt obstruction occurs most often at the ventricular catheter due to either in-growth of the choroid plexus (67%), CSF debris (18%), ventricular collapse (8%), or other reasons (9%). Underlying causes of obstruction were attributed to small ventricular size, catheter position, choroid plexus migration, build-up of cellular debris, inflammatory processes, or CSF overdrainage. The majority of respondents (>85%) consider chronic overdrainage a rare complication. These cases are most often managed with ASDs or programmable valves. Chronic headaches are most often attributed to medical reasons and managed with patient reassurance. The most popular treatments for SVS include shunt revision (88%), cranial expansion (57%) and placement of an ASD (53%). SVS etiology was most often linked to early onset of shunting, chronic overdrainage and/or loss of brain compliance.This survey shows discrepancies in shunt-dependent hydrocephalus understanding and management style among a representative group of experienced North American pediatric neurosurgeons. In particular, there are differing opinions regarding the primary cause of ventricular shunt obstructions and the origins of SVS. However, there appears to be general consensus in approach and management of overdrainage and chronic headaches. These results provide impetus for better studies evaluating the pathophysiology and prevention of shunt obstruction and SVS."} +{"text": "The insular cortex (IC) is considered a rich hub for context-sensitive emotions/social cognition. Patients with focal IC stroke provide unique opportunities to study socio-emotional processes. Nevertheless, Couto et al. have rec The insular cortex (IC), a brain region localized deep in the lateral sulcus, has been recently considered an interoceptive region , the right IC (whose lesion did not impair disgust recognition in Straube\u2019s) is supposed to index negative emotions and disgust, as reported in several other studies of the IC renders focal damage extremely infrequent in clinical practice , we assessed interoceptive sensitivity in the same two patients and found that interoceptive-related behavior was differentially impaired in each case: the insular lesion affected cardiac interoceptive measures whereas the subcortical lesion yielded preserved performance. Thus, the subcortical patient\u2019s impairments in social cognition and negative emotion cannot be explained by canonical interoceptive signals running through autonomous pathways. These factors notwithstanding, further studies would elucidate the relationship between interoceptive sensitivity and social cognition in subcortical lesions.The neuroanatomical and behavioral evidence offered by Couto et al. also sugThe predictive coding approach is gaining acceptance within the neuroscience community Friston, . PredictPredictive coding principles apply not only to basic brain function but also to social cognition by subcortical areas (lower in the hierarchy). PE-signals affecting the insular region would modulate connections, whereas PE-signals targeting more frontal areas would reach minimization.The above hypothesis suggests a two-sided explanation of the behavioral effects reported by Couto et al. On the one hand, PEs and response times are strongly correlated suggest high variability in the patients\u2019 performance. This variability can be interpreted in terms of preserved/affected hubs connecting the lesion sites with other ipsilateral regions and with their contralateral regions. Here, we have proposed that effective connectivity analysis constitutes a novel approach to examine functional connectivity and explain why only some stroke patients are impaired in these domains. Specifically, effective connectivity studies allow us to assess compensatory, contralateral, and subsidiary networks. Moreover, given the existence of transitory post-stroke deficits in empathy and other social cognition domains, this approach may be used to test the functional-remapping hypothesis in cases of IC damage and similar hypotheses in patients with lesions to other brain regions. Dynamic causal models of effective connectivity may provide an opportunity to achieve \u201ceffective\u201d cross-talk between clinicians and basic neuroscientists (Kahan and Foltynie, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The purpose of this case is to describe the complex perioperative management of a 30-year-old woman with congenital heart disease and multiple resternotomies presenting with pulmonary homograft dysfunction and evaluation for percutaneous pulmonary valve replacement. Transvenous, transcatheter Melody valve placement caused left main coronary artery occlusion and cardiogenic shock. An Impella ventricular assist device (VAD) provided rescue therapy during operating room transport for valve removal and pulmonary homograft replacement. ECMO support was required following surgery. Several days later during an attempted ECMO wean, her hemodynamics deteriorated abruptly. Transesophageal and epicardial echocardiography identified pulmonary graft obstruction, requiring homograft revision due to large thrombosis. This case illustrates a role for Impella VAD as bridge to definitive procedure after left coronary occlusion and describes management of complex perioperative ECMO support challenges. Venoarterial ECMO was then instituted via femoral vessels and she was transported to the ICU in critical condition. On the fourth day of ECMO support, she developed a large hemothorax requiring chest tube decompression, six units of RBCs, and two units of platelets. The heparin infusion was subsequently held and bleeding resolved over several hours. The following day, the patient was requiring minimal inotropic support and the decision was made to go to the operating room and attempt to wean ECMO. Unexpectedly, when ECMO was stopped her blood pressure suddenly dropped to 43/35 and the end tidal CO2 was lost (<10\u2009mm\u2009Hg) despite adequate ventilation. Transesophageal echocardiography was urgently performed demonstrating probable RVOT graft obstruction ) in the catheterization laboratory. After initial balloon inflation, there was visible homograft enlargement, and simultaneous aortic root angiogram was performed demonstrating patent right and left coronary arteries (LCA). The right ventricular outflow tract was then prepared with successful placement of two Palmaz stents. Repeat coronary angiography demonstrated patent LCA prior to Melody valve deployment. The Melody valve was then deployed and the patient developed progressive, severe hypotension, bradycardia, and cardiogenic shock. Transthoracic echocardiogram (TTE) demonstrated akinesis of the lateral and anterior walls of the left ventricle (LV) and severe acute mitral valve regurgitation. She instantly developed severe pulmonary edema with fluid filling the endotracheal tube and anesthesia circuit . A repeatruction with esttruction . Epicardtruction . The obsThis case illustrates the known potential complication from Melody valve implantation with left coronary artery compression \u20134 despit"} +{"text": "Candida spp. sepsis. This is the first observational study describing the altered immune response of patients with candidemia. The authors included non-neutropenic critically ill patients with candidemia and non-septic controls, and excluded patients with human immunodeficiency virus infection, who had undergone solid or bone marrow transplantation or with other known causes of impaired immune response. The authors hypothesized that their findings may help explain why patients with fungal sepsis show a high mortality despite appropriate antifungal therapy.We read with great interest the article by Spec et al. investigIn our opinion, the observed T-cell exhaustion associated with candidemia may also contribute to explain the paradox of the evidence published recently about invasive fungal infection (IFI) prevention . From ouImplications for future research may include potential additional mechanisms of impaired immunological function to fill the gap between bedside data and pre-clinical findings.IFI, invasive fungal infection"} +{"text": "Improving Handover of Patients in Critical Care following Cardiac Surgery: an audit and successful implementation of an electronic quality improvement toolFollowing cardiac surgery, professional responsibility and accountability for patients is transferred from the operating theatre to critical care. Optimising 'handover' is imperative and we sought to improve safety, quality and effectiveness of this within our unit.A closed loop audit for all post-operative patients (Aug 2014 - Nov 2014) was performed to assess the handover process including personnel, environment and documentation on the electronic patient record (Metavision).Prior to the first cycle, relevant stakeholders were consulted - anaesthetists, cardiac surgeons and nurses. A subsequent survey determined 'gold standard criteria' for handover before undertaking the second cycle.A new electronic tool was created on Metavision to implement a change where specific anaesthetic and surgical representatives could document their plans including parameters and post-operative instructions.Our audit showed objective improvement in presence of team members, especially surgeons; more frequent 'sterile cockpit' environment; significantly better documentation to guide the critical care MDT.We demonstrated improvements in handover by following a system that utilizes the F1 racing model in the critical care setting. Moreover, a novel electronic tab dedicated for patient handover has significantly improved documentation. With ongoing challenges of maintaining continuity of care, we suggest other units adopt our strategy."} +{"text": "The ability to estimate societal cost-savings given a change in population lifestyles is of interest to health promotion specialists and decision makers. A population-based model named Risk factors, Health and Societal Costs (RHS) was developed to simulate changes in incidence and related societal costs of several chronic diseases after five to ten years, following assumed changes in four common risk factors for disease: obesity (BMI>30), daily tobacco smoking, lack of physical activity and risky consumption of alcohol.The RHS model is based on relative risks (RR) and potential impact fractions (IF) that simulate the changes in disease incidence of reducing the exposure to risk factors . RelativThe scenarios, which assume a certain reduction in population risk factor prevalence, show that considerable health gains and savings in societal costs can arise from modest changes in population lifestyle habits. As an example, a 1% reduction in prevalence in daily smoking under five years among Stockholm county population is estimated to lead to health gain of 64 QALYs and societal savings of 13 million Swedish krona (1.2 million GBP).The RHS model estimates future cases of illness and related societal costs due to lifestyle risk factors in the population. By creating scenarios with assumed changes in risk factors, the model can estimate potential health gains and societal costs savings, which can be used as relevant arguments in discussions with decision-makers for a more health-promoting health care system."} +{"text": "Gluten related disorders a range of inflammatory disorders of the small intestine characterized by malabsorption after ingestion of gluten in individuals with a certain genetic background. Clinical presentation can vary from full-blown malabsorption to subtle and atypical symptoms. Diagnosis currently relies on clinicopathologic studies including mucosal biopsy, serologic tests, and the effects of a diet free of gluten on the symptoms. Mucosal pathologic features are also variable, ranging from mild abnormalities, including intraepithelial lymphocytosis, to completely flat mucosa . Since tCeliac diseaseNon Celiac Gluten Sensitivity"} +{"text": "Movement disorders in idiopathic normal pressure hydrocephalus (iNPH) are represented by gait disturbance . However, upper extremity bradykinesia was frequently found among iNPH patients. We assessed their upper extremity function by quantitative finger tapping test and checked the correlation with other demographic factors.We evaluated the 10-second finger tapping movements of 8 patients using magnetic-sensor coil system. Clinical symptoms were evaluated by the iNPH grading scale, mini-mental state examination and frontal assessment battery (FAB). The correlation of tapping parameters with clinical indicators was estimated.The patient's age correlated significantly with 6 of 21 finger-tapping parameters, including total tapping distance , coefficient of variation of maximum amplitude , energy balance , average maximum opening acceleration , tapping frequency , and average finger tapping interval . The severity of illness represented by iNPH grading scale correlated with other 2 parameters, including average maximum closing velocity and coefficient of variation of maximum closing velocity .Our data support the diagnostic value of quantitative finger tapping test for estimating the severity of bradykinesia underlying the iNPH symptomatology. Though preliminary, different patterns of correlations found in this study could potentially indicate the fundamental processes discriminating aging and disease progression."} +{"text": "Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly that usually manifests as severe left-sided heart failure and mitral valve insufficiency during the first one to two months of life. The majority of these cases die in infancy if not corrected early upon presentation. Adulthood presentation is rare and most of the untreated patients who reach adulthood present with left ventricular dysfunction, severe mitral regurgitation, and sometimes myocardial infarction. Here we report a case of a 20-year-old woman with a history of exercise intolerance since childhood that was misinterpreted as asthma until a 2D-Echo revealed ALCAPA with RCA collaterals to the left anterior descending artery, preserved LV ejection fraction, and absence of apparent mitral valve abnormality. One month after the ALCAPA diagnosis, she successfully underwent surgical reconstruction of left main and pulmonary artery without any major complications. She had normal left ventricular function without apparent ischemic cardiac symptoms eighteen months after procedure. Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital anomaly occurring in 1 of 300,000 live births and accoThe ALCAPA anomaly may result from abnormal septation of the conotruncus into the aorta and pulmonary artery, or from persistence of the pulmonary buds together with involution of the aortic buds that eventually form the coronary arteries. ALCAPA is usually an isolated cardiac anomaly that does not present prenatally because of the favorable fetal physiology that includes equivalent pressures in the main pulmonary artery and aorta secondary to a nonrestrictive patent ductus arteriosus, and the relatively equivalent oxygen concentrations due to parallel circulations. This results in normal myocardial perfusion and, therefore, no stimulus for collateral vessel formation between the right and left coronary artery systems is present. Shortly after birth, as the circulation becomes one in series, pulmonary artery pressure and resistance decrease, as does oxygen content of pulmonary blood flow. This causes a drop in antegrade flow and oxygen content of the anomalous left coronary artery, leading to myocardial ischemia. Furthermore, collateral circulation between the right and left coronary systems ensues and the left coronary artery flow reverses and enters the pulmonary trunk due to the low pulmonary arterial pressure, causing coronary steal phenomena. Consequently, fixed ischemia or myocardial infarction occurs. Eighty-five percent of all cases of ALCAPA present within the first two months of life. The typical clinical course involves severe left-sided heart failure and significant mitral valve insufficiency secondary to papillary muscle ischemia, permanent fibrosis, or left ventricular dilatation. The late presentation is extremely rare and usually with significant cardiac function compromise.A 20-year-old woman presents with chronic dyspnea on exertion and exercise intolerance that was attributed to and treated as presumed exercise-induced asthma since childhood. She experienced worsening left-sided chest heaviness and was subsequently referred to our institute. She has no coronary risk factors and no family history of premature coronary artery disease or congenital heart condition. Physical examination was normal except a subtle continuous murmur at apex and lower right sternal border. ECG showed sinus rhythm without ST or T wave changes . Chest X-ray showed no cardiomegaly . Serial cardiac enzymes were negative. In the light of cardiac murmur, an echocardiogram was obtained and revealed anomalous coronary arteries with a large left coronary artery to main pulmonary artery fistula. There was mild left ventricular enlargement with preserved left ventricular contractile function and an ejection fraction of 65%. The appearance of the left ventricle and left atrium was consistent with a systemic to pulmonary vascular shunt with increased stroke volumes in the left heart. There were no structural abnormalities of the aortic, mitral, tricuspid, or pulmonic valves, and there was very mild mitral regurgitation by Doppler. A subsequent cardiac catheterization confirmed the diagnosis of ALCAPA with retrograde filling through collaterals arising from an enlarged right coronary artery (12\u2009mm) (As a rare congenital heart condition, ALCAPA even more rarely has a late presentation in adulthood as few of these patients survive past childhood without surgical repair . Among tIn infants, most of the patients with surgically corrected ALCAPA show normalization of both ventricular function and mitral valve insufficiency , 12. EstIn conclusion, even as a rare scenario of a rare disorder, diagnosis of adulthood ALCAPA should be considered not only in adult patients presenting with clear evidence of ischemic heart disease, left ventricular dysfunction, or arrhythmias, but also more importantly in patients with minor symptoms of exercise intolerance or dyspnea that could be easily misinterpreted or missed without high clinical suspicion and detailed physical and diagnostic evaluation, as early diagnosis and timely surgical treatment usually results in an excellent prognosis.Supplemental Figure 1: 12-lead ECG showed normal sinus rhythm with no specific ST and T changes.Supplemental Figure 2: Chest x-ray showed no cardiopulmonary pathology.Click here for additional data file."} +{"text": "Although intravascular injection of contrast media is very important in diagnostic radiology but may lead to acute renal failure and hospitalization. It seems that, pathogenesis of contrast media nephrotoxicity acts through renal vasoconstriction, medullary ischemia, tubular cell death and production of reactive oxygen species. Pretreatment with antioxidants attenuated renal side effects of contrast media in patients and laboratory animals.et al. used green tea (Camellia sinensis) extract in combat with contrast media nephrotoxicity in rats for the first time have been completely observed by the author.None declared."} +{"text": "Spontaneous intracerebral hemorrhage (ICH) is a particularly severe type of stroke for which no specific treatment has been established yet. Although preclinical models of ICH have substantial methodological limitations, important insight into the pathophysiology has been gained. Mounting evidence suggests an important contribution of inflammatory mechanisms to brain damage and potential repair. Neuroinflammation evoked by intracerebral blood involves the activation of resident microglia, the infiltration of systemic immune cells and the production of cytokines, chemokines, extracellular proteases and reactive oxygen species (ROS). Previous studies focused on innate immunity including microglia, monocytes and granulocytes. More recently, the role of adaptive immune cells has received increasing attention. Little is currently known about the interactions among different immune cell populations in the setting of ICH. Nevertheless, immunomodulatory strategies are already being explored in ICH. To improve the chances of translation from preclinical models to patients, a better characterization of the neuroinflammation in patients is desirable. Intracerebral hemorrhages (ICH) account for 10\u201315% of all strokes into neurotoxic components such as heme and iron which are major contributors to secondary brain injury to various stimuli. Neuroinflammation after ICH involves the early activation of resident microglia, release of proinflammatory mediators and the influx of peripheral leukocytes and has major role in the pathophysiology of secondary brain damage and mitogen-activated protein kinase signaling pathways serum reduced BBB breakdown, axonal injury and neurological deficit days. As cellular parts of the adaptive immune system, B cells participate in humoral immune responses, while T cells are involved in cellular immunity. T cells express either the CD4 or the CD8 cell surface marker determining their function: modulating immune responses or eliciting cytotoxicity.Increasing evidence suggests an important role of adaptive immunity and particularly T lymphocytes in secondary brain damage after ischemia where it decreased peri-hematomal edema and reduced neurological impairment compared with control individuals is one of the main effector molecule of T lymphocytes is upregulated and 64Cu-labeled nanoparticles conjugated with anti-ICAM-1 antibody for PET imaging have been developed (Wunder et al., In vivo labelling is performed using MRI agents including iron-oxide nanoparticles (Stuber et al., To investigate the mechanisms underlying the trafficking of systemic immune cells into the brain, contrast media targeting endothelial selectin, ICAM and VCAM have been developed. These include in vivo neuroimaging has been barely used to investigate the ICH-induced inflammatory processes. In collagenase-induced ICH, enhanced MRI with microparticles of iron oxide targeted to VCAM-1 revealed the maximal VCAM-1 expression 24 h after ICH which returned to baseline 5 days following hemorrhage induction (Gauberti et al., The above detailed labeling methods are increasingly used in clinical and experimental studies to characterize inflammatory processes in neurologic disorders including cerebral ischemia, multiple sclerosis, Alzheimer\u2019s and Parkinson\u2019s disease (Jacobs and Tavitian, Inflammatory processes are increasingly recognized as important players in the pathophysiology of secondary brain damage after ICH. There is now solid information on the infiltration pattern of leukocytes in experimental ICH. The pathophysiological role of specific leukocyte populations is beginning to be better understood but little is known about the interactions among these immune cells. Because of the delayed nature of brain damage after ICH, adaptive immune cells may play an important role in the subacute and the regenerative phases after ICH. Translation of preclinical findings into the clinical setting is challenging because of limitations of current animal models of ICH. Moreover, the local and systemic neuroinflammatory response in ICH patients remains to be better characterized.All authors were involved in writing the review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Suppression of lipid signal is a basic requirement in coronary magnetic resonance angiography (CMRA) because coronary arteries are embedded in epicardial fat and signal from fat can decrease coronary vessel conspicuity. Most CMRA scans are currently performed with fat suppression techniques such as Spectral Presaturation with Inversion Recovery (SPIR). However, methods based on spectrally-selective fat saturation are sensitive to B0 and B1 field inhomogeneities. Recent improvements in chemical shift based water fat separation methods such as Dixonprovides This work was performed on a 3T scanner equipped with a 32-element cardiac receiver coil. Data were acquired in eight healthy volunteers and eight patients with suspected coronary artery disease . Two different scans were performed in each of them: 1) Conventional whole heart CMRA with SPIR fat suppression and 2) two-point Dixon CMRA. Two experts readers, blinded to the methods used, scored the image quality for each dataset. In addition, signal-to-noise ratio of blood, fat and myocardium, contrast-to-noise ratio (CNR) between blood, fat and myocardium, and right coronary artery sharpness and length were measured to compare these two techniques quantitatively. A Wilcoxon Signed-Rank was used for statistical analysis for comparison between images acquired with Dixon and SPIR.All scans were successfully performed and produced good quality images in all volunteers. Figure These findings demonstrate that Dixon water-fat separation leads to higher SNR of coronary blood and myocardium and improved image quality scores for coronary artery visualization at high field strengths. Furthermore, the additional fat data that is available with Dixon protocols may be an important biomarker and improve the diagnostic value of CMRA.Wellcome Trust and ESPRC Medical Engineering Centre."} +{"text": "Eutrophication increases the phytoplankton biomass that can be supported during a bloom, and the resultant uptake of dissolved inorganic carbon during photosynthesis increases water-column pH (bloom-induced basification). This increased pH can adversely affect plankton growth. With OA, basification commences at a lower pH. Using experimental analyses of the growth of three contrasting phytoplankton under different pH scenarios, coupled with mathematical models describing growth and death as functions of pH and nutrient status, we show how different conditions of pH modify the scope for competitive interactions between phytoplankton species. We then use the models previously configured against experimental data to explore how the commencement of bloom-induced basification at lower pH with OA, and operating against a background of changing patterns in nutrient loads, may modify phytoplankton growth and competition. We conclude that OA and changed nutrient supply into shelf seas with eutrophication or de-eutrophication (the latter owing to pollution control) has clear scope to alter phytoplankton succession, thus affecting future trophic dynamics and impacting both biogeochemical cycling and fisheries.Human activity causes ocean acidification (OA) though the dissolution of anthropogenically generated CO Taken together with other climate change events, notably changes in temperature and water-column stability, OA has the potential for various impacts upon marine plankton communities and production ,34. Studher [H+] , it is u sources ,37, to b"} +{"text": "Intracranial infection of the neurotropic JHM strain of mouse hepatitis virus (JHMV) into the central nervous system (CNS) of susceptible strains of mice results in an acute encephalomyelitis, accompanied by viral replication in glial cells and robust infiltration of virus-specific T cells that contribute to host defense through cytokine secretion and cytolytic activity. Mice surviving the acute stage of disease develop an immune-mediated demyelinating disease, characterized by viral persistence in white matter tracts and a chronic neuroinflammatory response dominated by T cells and macrophages. Chemokines and their corresponding chemokine receptors are dynamically expressed throughout viral infection of the CNS, influencing neuroinflammation by regulating immune cell infltration and glial biology. This review is focused upon the pleiotropic chemokine receptor CXCR2 and its effects upon neutrophils and oligodendrocytes during JHMV infection and a number of other models of CNS inflammation. Intracranial infection of susceptible mice with the JHM strain of mouse hepatitis virus (JHMV) causes an acute encephalomyelitis followed by a chronic demyelinating disease. JHMV, after initially infecting ependymal cells lining the ventricles, rapidly disseminates to astrocytes, oligodendroglia, and microglia throughout the brain and spinal cord chemokine family CXCL1 and CXCL2. CXCL1 and CXCL2 are potent chemoattractants for peripheral mononuclear cells (PMNs), binding and signaling through their receptor CXCR2 . Neutralization of CXCR2 almost completely abrogated neutrophil infiltration into the CNS Figures . Without+ T cells are all capable of direct permeabilization induction, and their presence precedes axonal damage, demyelination, and clinical disease chemokine signaling on oligodendroglia during JHMV-induced neuroinflammation. It will be important to analyze the effects of selectively ablating CXCR2 on oligodendroglia during JHMV-induced demyelination, while simultaneously manipulating the cellular sources of ELR-positive chemokines in the CNS that may promote neuroprotection during chronic JHMV-induced disease.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "To meet these challenging demands, we and others developed physiologically relevant mouse models and characterized their hearts with planar AP mapping. Here, we summarize the progress toward panoramic fluorescence imaging and its prospects for the mouse heart. In general, several high-resolution cameras are synchronized and geometrically arranged for panoramic voltage mapping and the surface and blood vessel anatomy documented through image segmentation and heart surface reconstruction. We expect that panoramic voltage imaging will lead to novel insights about molecular arrhythmia mechanisms through quantitative strategies and organ-representative analysis of intact mouse hearts.To investigate the dynamics and propensity for arrhythmias in intact transgenic hearts comprehensively, optical strategies for panoramic fluorescence imaging of action potential (AP) propagation are essential. In particular, mechanism-oriented molecular studies usually depend on transgenic mouse hearts of only a few millimeters in size. Furthermore, the temporal scales of the mouse heart remain a challenge for panoramic fluorescence imaging with heart rates ranging from 200 min In addition, AP duration (APD) and the stability of cardiac repolarization are regulated by distinct K+ channel types, e.g., during ischemia activation of ATP-sensitive K+ channels (KATP) leads to APD shortening thereby preventing potentially detrimental intracellular Ca2+ overload. While each principle contributes to impulse generation, propagation and/or modulation in heart tissue, the molecular mechanisms of AP modulation and disease changes are exceedingly complex and depend on thorough analysis in intact heart tissue based on non-invasive imaging methods.Molecular physiology and genetic engineering studies have established complex genetic and cellular determinants of impulse propagation in mouse models. Four distinct molecular principles were identified: connexin channels at gap junctions control solute flux between myocytes and electrical current flow throughout the myocardial syncytium Figure ; cardiac2+ dye) have become a central strategy to study impulse propagation in transgenic mouse hearts in which EC coupling cycles occur an order of magnitude faster than human heart. High VSDI based resolution has allowed the functional characterization of anisotropic impulse propagation in mouse hearts. This has revealed the physiological relevance of select Nav1.5 channel membrane targeting mechanisms and led to the concept of distinct, locally confined pools of Nav1.5 channels at the intercalated disc (ICD) vs. the lateral cell membrane or multiparametric imaging and a planar resolution of 50\u2013100 \u03bcm are achieved. Each sensor pixel records the fluorescent signal average of multiple cells. The tissue-specific propagation of epicardial AP wave fronts can be analyzed during sinus rhythm Figure or durinFurthermore, both physiological and pathological changes of cardiac repolarization can be analyzed. Abnormal AP formation as mechanism of triggered arrhythmias, abnormal AP propagation , and reentry contribute to arrhythmia initiation and/or propagation. Optical signals recorded by individual pixels can be analyzed to determine local APD, e.g., repolarization at 80% of the signal amplitude Figure . Similar2+ transients) cannot be analyzed continuously throughout the whole surface of the mouse heart, especially the spatially complex 3D impulse spread during fast arrhythmias. In addition, the high curvature-to-volume ratio of mouse hearts distorts fluorescent signals originating from shallow angles of peripheral boundaries, limiting the effective ROI of single camera approaches , while ex vivo imaging additionally facilitates detailed analysis about the time and location of residual chaotic activity in the heart. Finally, detailed experimental knowledge about the electrical activity on the cardiac surface together with internal tissue structures can be combined through 3D computational methods to reconstruct the hidden spatiotemporal dynamics of arrhythmias and therapeutic interventions inside the heart tissue in a non-invasive manner.External and internal cardioverter defibrillators (ICDs) are routinely used in clinical medicine, but electrical shocks can cause significant side effects including tissue damage and traumatic pain. Recently, a new strategy for arrhythmia control using low-energy antifibrillation pacing (LEAP) was developed. LEAP uses a series of five low-energy pulses to terminate atrial fibrillation 2+ transients. Recent data from transgenic mouse hearts identified novel molecular determinants of ion channel expression and targeting in cardiac myocytes with marked effects on the conduction properties of the ventricles. This led to the realization that complex molecular mechanisms underlie the anisotropic activation pattern of the intact hearts, namely ion channel complexes at gap junctions, lateral membranes, and T-tubules, and all with specific effects on conduction properties. In general, acquired or genetic changes result in decreased spatiotemporal AP propagation and conduction delay, which may contribute to arrhythmogenesis. Panoramic imaging of mouse and larger hearts will contribute to better understanding of arrhythmia propensity and onset, as well as support clinical translation of important new therapeutic concepts, in particular 3D-MIMS and LEAP.In summary, panoramic imaging of rabbit and larger mammalian hearts has been successfully developed whereas panoramic imaging of smaller, particularly transgenic mouse hearts will most likely be realized in the near future based on the success of VSDI and multiparametric readouts such as combined CaThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Middle East respiratory syndrome (MERS) cases continue to be reported from the Middle East. Evaluation and testing of patients under investigation (PUIs) for MERS are recommended. In 2013\u20132014, two imported cases were detected among 490 US PUIs. Continued awareness is needed for early case detection and implementation of infection control measures. Middle East respiratory syndrome coronavirus (MERS-CoV) infection was first reported in September 2012 in a patient with fatal pneumonia in Saudi Arabia (http://www.cdc.gov/coronavirus/mers/index.html). The PUI guidance was created to assist health care providers determine which patients should be considered for MERS-CoV evaluation and testing. To inform state and local health departments of the basic demographic and clinical characteristics of PUIs and on assay use, we summarized the descriptive analysis of PUIs in the United States.Using World Health Organization guidelines and definitions assays for detection of MERS-CoV , other pathogen testing was not performed or detected pathogens were not reported . Timely >2 weeks before specimen collection, testing using the CDC MERS-CoV serologic assay on a single serum specimen is recommended. CDC also recommends testing for common respiratory pathogens , but identification of a respiratory pathogen should not preclude MERS-CoV testing (Currently in the United States, the preferred method for detecting MERS in PUIs with recent symptom onset is to test lower respiratory, naso-oropharyngeal, and serum specimens by using the CDC rRT-PCR assay. For PUIs in whom symptom onset occurred The 2 US cases of imported MERS were detected in health care providers from Saudi Arabia. These cases prompted a CDC guidance update recommending evaluation and testing of persons with less severe respiratory illness who had strong epidemiologic risk factors, particularly heath care exposure, for MERS-CoV infection. Occupation, recent travel history, recent visit to a health care facility, and contact will ill persons should be determined when evaluating persons with respiratory illness. As testing increases, especially serologic testing, additional MERS cases, including mildly symptomatic cases and cases among younger persons are being identified. These cases highlight the range of severity of MERS-CoV infection and the need to consider testing persons with a compatible travel history who may not match the clinical profile of the initially described case-patients. CDC plans to revise MERS-CoV guidance as needed."} +{"text": "Headache is one of the most common causes of access to Emergency Departments (ED). Primary headaches and headaches secondary to benign conditions (e.g headache attributed to acute sinusitis) represent the majority of cases, while secondary life-threatening headaches are less frequent. The primary objective in the ED setting is to decide whether the headache is primary or secondary and recognize serious life-threatening conditions presenting with headache and requiring prompt medical diagnosis and care, such as subarachnoid hemorrhage (SAH), intracerebral hemorrhage, cerebral venous sinus thrombosis (CVST), cervical artery dissection (CAD), brain tumors, pituitary apoplexy, spontaneous intracranial hypotension, or intracranial infections. Careful history taking and physical examination remain the most important part of the assessment of the headache patient. A thoro"} +{"text": "Dictyostelium discoideum is triggered by starvation. When placed on a solid substrate, the starving solitary amoebae cease growth, communicate via extracellular cAMP, aggregate by tens of thousands and develop into multicellular organisms. Early phases of the developmental program are often studied in cells starved in suspension while cAMP is provided exogenously. Previous studies revealed massive shifts in the transcriptome under both developmental conditions and a close relationship between gene expression and morphogenesis, but were limited by the sampling frequency and the resolution of the methods.Development of the soil amoeba Here, we combine the superior depth and specificity of RNA-seq-based analysis of mRNA abundance with high frequency sampling during filter development and cAMP pulsing in suspension. We found that the developmental transcriptome exhibits mostly gradual changes interspersed by a few instances of large shifts. For each time point we treated the entire transcriptome as single phenotype, and were able to characterize development as groups of similar time points separated by gaps. The grouped time points represented gradual changes in mRNA abundance, or molecular phenotype, and the gaps represented times during which many genes are differentially expressed rapidly, and thus the phenotype changes dramatically. Comparing developmental experiments revealed that gene expression in filter developed cells lagged behind those treated with exogenous cAMP in suspension. The high sampling frequency revealed many genes whose regulation is reproducibly more complex than indicated by previous studies. Gene Ontology enrichment analysis suggested that the transition to multicellularity coincided with rapid accumulation of transcripts associated with DNA processes and mitosis. Later development included the up-regulation of organic signaling molecules and co-factor biosynthesis. Our analysis also demonstrated a high level of synchrony among the developing structures throughout development.D. discoideum development as a series of coordinated cellular and multicellular activities. Coordination occurred within fields of aggregating cells and among multicellular bodies, such as mounds or migratory slugs that experience both cell-cell contact and various soluble signaling regimes. These time courses, sampled at the highest temporal resolution to date in this system, provide a comprehensive resource for studies of developmental gene expression.Our data describe The online version of this article (doi:10.1186/s12864-015-1491-7) contains supplementary material, which is available to authorized users. D. discoideum exhibits a developmental program unique among model organisms , and the complete time series data sets are accessioned at the NCBI Gene Expression Omnibus .Further analyses of these data may focus on identifying additional co-regulated transcriptional regulators and target genes. The enhanced temporal resolution of these data provides more informative transcription profiles than previous studies. Perhaps clustering of genes by expression pattern will yield improved hypotheses regarding shared regulation and function. As future studies examine the phenotypic consequences of transcription factor knockout mutations, as well as the binding specificity of important transcriptional regulators, these data will serve as a critical reference point for inferring regulatory interactions. To facilitate exploration by the larger community, user-friendly analysis tools for these data are available at dictyExpress . These data may also be viewed and analyzed using the dictyExpress toolkit [www.dictyExpress.org].The additional material includes the Additional file"} +{"text": "Visual category perception is thought to depend on brain areas that respond specifically when certain categories are viewed. These category-sensitive areas are often assumed to be \u201cmodules\u201d (with some degree of processing autonomy) and to act predominantly on feedforward visual input. This modular view can be complemented by a view that treats brain areas as elements within more complex networks and as influenced by network properties. This network-oriented viewpoint is emerging from studies using either diffusion tensor imaging to map structural connections or effective connectivity analyses to measure how their functional responses influence each other. This literature motivates several hypotheses that predict category-sensitive activity based on network properties. Large, long-range fiber bundles such as inferior fronto-occipital, arcuate and inferior longitudinal fasciculi are associated with behavioral recognition and could play crucial roles in conveying backward influences on visual cortex from anterior temporal and frontal areas. Such backward influences could support top-down functions such as visual search and emotion-based visual modulation. Within visual cortex itself, areas sensitive to different categories appear well-connected and their responses can be predicted by backward modulation. Evidence supporting these propositions remains incomplete and underscores the need for better integration of DTI and functional imaging. A current challenge for visual neuroscience is to explain how perception of complex and meaningful objects is achieved. High-level vision is associated with anatomically-focal, functionally-defined brain areas in human occipitotemporal cortex, usually localized using functional magnetic resonance imaging (fMRI). These \u201ccategory-sensitive\u201d areas are typically inferred to be specialized for processing their preferred visual categories or estimate their effective connectivity using functional brain imaging methods including fMRI, electroencephalography (EEG) or magnetoencephalography (MEG). However, few studies to date have combined DTI and effective connectivity techniques. DTI maps structural connections composed of axonal fiber tracts. In contrast, effective connectivity measures how functional responses influence (or \u201ccause\u201d) each other. However, they share the similar goal of inferring functional integration, with DTI showing which areas are connected and effective connectivity showing the experimental conditions under which these structural connections might enact their influence. Studies using these methods have not provided a comprehensive picture of human structural connections or the effective interactions supported by these structures. Nevertheless, the findings reviewed here suggest specific structural and effective network properties that are relevant to visual analysis of complex stimuli. These network properties include influences of major, long-range fiber bundles, backward connections from higher to lower-level areas and interactions between areas with dissimilar category preferences. These network properties can potentially explain diverse phenomena, including top-down, attentional and emotional modulation of visual cortex, oscillatory power changes and repetition-related response modulations. This review covers these findings, discusses the deficiencies of existing theories and describes how a functional integration approach is well-suited to advance understanding of visual processing in human occipitotemporal cortex. in vivo in humans.Responses in category-sensitive brain areas are likely to be influenced by the different types of connections associated with hierarchical networks. Hierarchical structures , which would then guide visual object processing via backward connections Bar, . SimilarVisual cortex appears to contain a hierarchical apparatus and therefore response specificity in visual cortex likely depends on distinguishable forward and backward influences. Moreover, mainstream computational models make important assumptions about the influences of forward and backward influences. While many models rely solely on forward influences, models such as predictive coding posit specific roles for backward connections. While the DTI and effective connectivity studies performed to date and reviewed herein do not yet support any particular computational theory in detail, they provide evidence for a role of backward influences during perception of high-level visual stimuli.Multiple areas that are sensitive to the same category have been described as hierarchies. At the most general level in visual cortex, all areas may be associated with the dorsal or ventral hierarchical streams . Effective and structural connectivity measures are complementary, even though their relationship is not fully understood , mostly oriented along a posterior-anterior axis. These bundles have been observed using human post-mortem dissection and can be imaged using DTI , arcuate/superior longitudinal (AF/SLF) and inferior occipitofrontal (IFOF) fasciculi. ILF projects down the length of the temporal lobe, with fibers terminating posteriorly in inferior occipital cortex (near OFA) and fusiform gyrus (near FFA) and anteriorly in the temporal pole, amygdala and hippocampus and superior longitudinal (SLF) fasciculi share overlapping anatomical courses and are often considered together . The OFC/VMFC could influence visual areas directly, via IFOF, or indirectly, via the uncinate fasciculus, which connects OFC/VMFC to the anterior temporal lobe and the amygdala in different fiber bundles. To date, the details of these dissociations are still not clear, as they are different in each study, with mixed evidence for a selective role of the ILF for face recognition. Although no major fiber bundle is likely to contribute to recognition of any single category (such as face or scene perception), the function of a given fiber bundle might contribute more to recognition of some categories than others. Thus, linking behavioral recognition performance to fiber bundle properties is a promising research method. Research linking fiber bundles with behavior has also been well-served by combining DTI with fMRI functional localization . These studies therefore only considered reciprocal models OFC/VMFC via IFOF; (2) OFC/VMFC via the uncinate fasciculus and ILF; and (3) inferior frontal cortex via AF/SLF. Frontal influences on visual cortex have been tested in a number of effective connectivity studies, and these studies suggest that frontal areas can sensitize occipitotemporal visual areas to detect expected stimuli, particularly during visual search.The more prevalent evidence for this top-down modulation involves OFC or VMPFC faces, chairs or houses during fMRI scanning, significant category-specific bilinear parameters were observed on connections from prefrontal cortex to face-, chair- and house-sensitive ventral temporal areas Effective connectivity analyses should be combined with DTI to investigate the functional specialization of the major fiber bundles . (2) These fiber bundles may support fast feedforward shortcut pathways that trigger early influences of backward connections may be useful for understanding computations outside the visual system. Oscillations are another widespread phenomenon which can be investigated using connectivity-based methods and have been proposed to be a fundamental mechanism for brain communication . Effective connectivity analysis cannot determine whether a connection between two areas is direct or indirect. Methods such as DTI, effective connectivity and conventional functional imaging methods based on the general linear model can overcome their weaknesses when used in conjunction.Effective connectivity analysis applied to fMRI data can also be problematic, due to the uninformative temporal resolution of the blood-deoxygenation response signal. This problem is acute for methods such as Granger Causality and structural equation modeling, which depend on exact timing of fMRI response signals to draw inferences about connectivity between underlying neuronal sources computationally tractable; (2) includes all plausible models; and (3) can be adequately compared to model spaces used in similar studies. The present review presents the outcomes of model comparisons, even though the model spaces used by each study vary widely, often omit plausible models that are of theoretical interest or estimate the parameters of only one model. Newer methods such as post hoc model comparison (Rosa et al., A particularly vexing challenge in applyingThis article reviews recent work examining structural and effective connectivity associated with category-sensitive areas in high-level visual cortex in the human. These studies add to our knowledge of the functions of forward and backward interactions between visual areas and top-down influences from frontal areas and the amygdala. More work is needed to develop theory that moves beyond a focus on the modular nature of individual areas with only feedforward interactions. Structural and effective connectivity studies have not yet given us a complete picture of network interactions and, like any method, possess both strengths and limitations. Nevertheless, they allow direct testing of connectivity in ways that complement more conventional uses of brain imaging and therefore hold promise for answering numerous future research questions.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Advances in target-based drug discovery strategies have enabled drug discovery groups in academia and industry to become very effective at generating molecules that are potent and selective against single targets. However, it has become apparent from disappointing results in recent clinical trials that a major challenge to the development of successful targeted therapies for treating complex multifactorial diseases is overcoming heterogeneity in target mechanism among patients and inherent or acquired drug resistance. Consequently, reductionist target directed drug-discovery approaches are not appropriately tailored toward identifying and optimizing multi-targeted therapeutics or rational drug combinations for complex disease. In this article, we describe the application of emerging high-content phenotypic profiling and analysis tools to support robust evaluation of drug combination performance following dose-ratio matrix screening. We further describe how the incorporation of high-throughput reverse phase protein microarrays with phenotypic screening can provide rational drug combination hypotheses but also confirm the mechanism-of-action of novel drug combinations, to facilitate future preclinical and clinical development strategies. The evolution of many complex human diseases has generated multiple biological redundancies in the genetics, pathway signaling networks and pathophysiology of disease thus counteracting the efficacy of new therapeutics. In such complex diseases exemplified by cancer, neurodegeneration, cardiovascular, bacterial, and viral infections, combination therapies represent the standard of care strategies provides a new opportunity to discover and prioritize drug combination and polypharmacology strategies objectively while appropriately tailoring their use to complex disease during early stage drug discovery platform and Compound Synergy Extension (Genedata Screener\u00ae). Such tools enable rapid drug combination screening across phenotypic assays at scale to enable a more transparent review of drug combination data placed into context of multiple drug combination sets to aid benchmarking and prioritization. Incorporation of genomically annotated patient derived cell panels into high capacity drug combination screening activity further supports pharmacogenomics and personalized healthcare approaches to drug combination strategies. High-content single cell analysis of specific phenotypic events over both dose and time enable a significantly more robust evaluation of the quality of drug combination data. Such considerations support the interpretation of whether synergistic and additive drug combination data occur at physiologically relevant doses.A limitation of screening large compound libraries in complex cell based assays compared with more traditional biochemical drug screening is throughput and cost. Both throughput and cost are particularly limiting when considering the evaluation of multiple drug combinations across a factorial dose-ratio matrix where the number of individual combination dose ratios increases quadratically with the number of agents under study. For practical reasons, medium to high-throughput phenotypic screening across cancer cell lines have traditionally employed simple single endpoint analysis of tumor cell viability or cell proliferation in 2D mono-culture circumvents many of the challenges associated with co-dosing distinct components in vivo. Thus, application of more systematic approaches to evaluate the kinetics and sensitivity of drug combinations across broad dose ranges and multiple phenotypic parameters promise to enhance the quality and robustness of preclinical drug combination data and support more informed prioritization of the most appropriate combination strategies to move forward into in vivo and clinical settings.A significant challenge to translating effective drug combinations identified from in vitro or in vivo models ; the Human Antibody Initiative ; and the Human Protein Atlas Project (www.proteinatlas.org/) to derive high quality mono-specific antibodies are poised to further advance antibody-based proteomics into broader areas of human pathway biology. Correlation of basal RPPA post-translational dataset with compound EC50 values from phenotypic assays performed across cell panels has identified protein level markers of drug sensitivity and resistance models is correlation of phenotypic response with genomic biomarkers. Such pharmacogenomic studies support biomarker discovery and patient stratification hypothesis. However, as described in this review article, adaptive resistance mechanisms that guide combination response are often operating only at the post-translational level. Thus, RPPA analysis applied to related monotherapy and drug combination arms can be correlated with additive, synergistic, or antagonist phenotypic response across a dose matrix study to identify pharmacodynamic biomarkers that confirm the mechanism-of-action of the drug combination effect and provide biomarkers to guide future clinical development.In 2010, the US FDA issued an updated draft guidance to support the further development of novel drug-combination therapies. Previous guidance recommended demonstrative evidence of a positive efficacy and safety response across all monotherapy and combination arms. The updated guidance now supports the proposal of clinical trial designs where single or multiple monotherapy arms can be left out on the grounds that no efficacy benefit would be expected. This new update now provides an opportunity to exploit synthetic lethality and multi-drug cocktails. Phenotypic screening campaigns are particularly suited to discovery of synthetic lethality by performing screens on matched pairs of cell models, representing suspected natural or engineered genetic vulnerabilities or distinct sensitivities to known agents. The latest advances in phenotypic screening technologies combined with high-throughput pathway profiling are now well placed to provide high quality preclinical data that provide for a more robust, transparent and objective prioritization of drug combinations.Both authors contributed to the conception of this review article, drafted the paper, and approved the version for submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "PRKCSH and SEC63) or ADPKD (PKD1 and PKD2) confirm the clinical diagnosis. Genetic studies showed that accumulation of somatic hits in cyst epithelium determine the rate-limiting step for cyst formation. Management of adult PLD is based on liver phenotype, severity of clinical features and quality of life. Conservative treatment is recommended for the majority of PLD patients. The primary aim is to halt cyst growth to allow abdominal decompression and ameliorate symptoms. Invasive procedures are required in a selective patient group with advanced PCLD, ADPKD or liver failure. Pharmacological therapy by somatostatin analogues lead to beneficial outcome of PLD in terms of symptom relief and liver volume reduction.Polycystic liver disease (PLD) is the result of embryonic ductal plate malformation of the intrahepatic biliary tree. The phenotype consists of numerous cysts spread throughout the liver parenchyma. Cystic bile duct malformations originating from the peripheral biliary tree are called Von Meyenburg complexes (VMC). In these patients embryonic remnants develop into small hepatic cysts and usually remain silent during life. Symptomatic PLD occurs mainly in the context of isolated polycystic liver disease (PCLD) and autosomal dominant polycystic kidney disease (ADPKD). In advanced stages, PCLD and ADPKD patients have massively enlarged livers which cause a spectrum of clinical features and complications. Major complaints include abdominal pain, abdominal distension and atypical symptoms because of voluminous cysts resulting in compression of adjacent tissue or failure of the affected organ. Renal failure due to polycystic kidneys and non-renal extra-hepatic features are common in ADPKD in contrast to VMC and PCLD. In general, liver function remains prolonged preserved in PLD. Ultrasonography is the first instrument to assess liver phenotype. Indeed, PCLD and ADPKD diagnostic criteria rely on detection of hepatorenal cystogenesis, and secondly a positive family history compatible with an autosomal dominant inheritance pattern. Ambiguous imaging or screening may be assisted by genetic counseling and molecular diagnostics. Screening mutations of the genes causing PCLD ( Polycystic liver disease (PLD) is a collection of rare human disorders that result from structural changes in the biliary tree development ,2. GenetThree PLD entities are recognized in adults. Von Meyenburg complexes with characteristic small, non-hereditary nodular cystic lesions [ORPHA386] ,5. IsolaThis paper reviews the pathological and clinical features of these 3 adult cystic disorders that share presence of numerous hepatic cysts with an intact biliary tree architecture.PLD is a rare inherited Mendelian disorder that is characterized by development of multiple hepatic cysts. The classification of PLD follows the histological changes that are due to ductal plate malformation (DPM) during fetal development ,7. Definth week of gestation by formation of single layered hepatoblasts surrounding the portal vein . Duplication of ductal plate cells forms a double layer that finally dilate to a tubular structure, the primitive bile duct. Hepatoblast differentiation to a biliary phenotype and tubulogenesis is stimulated by the Notch, TGF-\u03b2 and canonical Wnt signaling pathways and SEC63 [OMIM*608648] may confirm the clinical diagnosis and differentiate it from other PLD and Caroli syndrome (CS). PLD is characterized by intrahepatic disease, a more late onset of disease in adulthood and absence of congenital hepatic fibrosis (CHF).Young and adult ADPKD patients are difficult to distinguish with other hepatorenal fibrocystic diseases such as ARPKD and other ciliopathies . ARPKD hCD is characterized by saccular, cystic dilations of the more larger intrahepatic biliary system. In CS large and small intrahepatic bile duct ecstasies are accompanied with CHF. CS has been typically associated with renal disease as in ARPKD . The incBoth PCLD and ADPKD have an autosomal dominant inheritance pattern and the recurrence risk is 50%. Genetic studies indicate an evident inter-familial clinical heterogeneity in PLD disease course among similar-aged patients. Secondly, intra-familial studies suggested a considerable phenotypic variability of hepatic cysts Figure\u00a0. ClinicaThese considerations raise the question whether it is appropriate to screen members or children at-risk. Counseling should include discussion about insurance, employment and psychological factors. Genetic counseling is recommended in severely affected PLD and may afford differentiation between ADPKD and PCLD ,12.Molecular diagnostics may assist the counseling process to establish a firm diagnosis in symptomatic patients and families. In particular ADPKD, determination of the responsible gene is useful for those who are at-risk in order to develop a strategy to prevent severe progressive disease events or complications . If the VMC is an asymptomatic condition without long-term consequences and treatment is not warranted. The primary aim of PLD therapy is to reduce symptoms by curtailing hepatic cyst development. The treatment of choice is driven by individual complaints . AlthougThe first advice in PCLD and ADPKD is to stop oral anticonceptives ,78. AlthThe different invasive approaches with possible beneficial outcomes in independent studies include aspiration sclerotherapy, laparoscopic cyst deroofing or liver transplantation ,40,84. CTreatment of portal hypertension and ascites are not different from that in patients with other causes. In a selected patient group were invasive procedures such as a vascular or bile duct stent placement optional for decompression of the portal vein, inferior vena cava or bile duct, or in HVOO treatment ,85. In gRecent development of pharmacological options opened up new treatment strategies for severe PLD patients. Long-term follow-up studies with somatostatin analogues demonstrated that these agents consistently lower total liver volume in PLD patients ,87. A rePLD compromises a clinically heterogeneous liver phenotype identified in VMC, ADPKD and PCLD patients. Massively enlarged livers are present in a subset of ADPKD and PCLD. Genetics and environmental factors such as exogenous estrogen intake and number of pregnancies contribute to disease progression. A considerable intra-familial variability in liver phenotype and extra-hepatic features makes screening modalities uncertain in PCLD. Evaluation of PLD-related symptoms and quality of life are necessary to decide beneficial management.th September 2013; http://www.biobase-international.com/product/hgmd.Human Gene Mutation Database for Human Genetics Research; HGMD\u00ae Professional 2013.3 - 27AAA: Abdominal aorta aneurysm; ADPKD: Autosomal dominant polycystic kidney disease; ARPKD: Autosomal recessive polycystic kidney disease; CD: Caroli disease; CS: Caroli syndrome; CT: Computer tomography; CHF: congenital hepatic fibrosis; DPM: Ductal plate malformation; ER: Endoplasmic reticulum; HVOO: Hepatic venous outflow obstruction; ICA: Intracranial aneurysm; IVC: Inferior vena cava; LVH: Left ventricle hypertrophy; MELD: Model for end-stage liver disease; MRI: Magnetic resonance imaging; PC1: PC2 polycystin-1, -2; PCLD: Isolated polycystic liver disease ; PKD1: PKD2 polycystic kidney disease-1, -2; PLD: Polycystic liver disease; PRKCSH: Protein kinase C substrate 80\u00a0K-H ; SEC63: Saccharomyces cerevisiae homolog 63; VMC: Von Meyenburg complexes.Authors declare that they have no competing interests.WC researched the data and drafted the manuscript. WC and JD contributed to the content and wrote the article. JD is responsible for critical revision of the content. Both authors read and approved the final manuscript."} +{"text": "Cortical dysplasia is associated with intractable epilepsy and developmental delay in young children. Recent work with the rat freeze-induced focal cortical dysplasia (FCD) model has demonstrated that hyperexcitability in the dysplastic cortex is due in part to higher levels of extracellular glutamate. Astrocyte glutamate transporters play a pivotal role in cortical maintaining extracellular glutamate concentrations. Here we examined the function of astrocytic glutamate transporters in a FCD model in rats. Neocortical freeze lesions were made in postnatal day (PN) 1 rat pups and whole cell electrophysiological recordings and biochemical studies were performed at PN 21\u201328. Synaptically evoked glutamate transporter currents in astrocytes showed a near 10-fold reduction in amplitude compared to sham operated controls. Astrocyte glutamate transporter currents from lesioned animals were also significantly reduced when challenged exogenously applied glutamate. Reduced astrocytic glutamate transport clearance contributed to increased NMDA receptor-mediated current decay kinetics in lesioned animals. The electrophysiological profile of astrocytes in the lesion group was also markedly changed compared to sham operated animals. Control astrocytes demonstrate large-amplitude linear leak currents in response to voltage-steps whereas astrocytes in lesioned animals demonstrated significantly smaller voltage-activated inward and outward currents. Significant decreases in astrocyte resting membrane potential and increases in input resistance were observed in lesioned animals. However, Western blotting, immunohistochemistry and quantitative PCR demonstrated no differences in the expression of the astrocytic glutamate transporter GLT-1 in lesioned animals relative to controls. These data suggest that, in the absence of changes in protein or mRNA expression levels, functional changes in astrocytic glutamate transporters contribute to neuronal hyperexcitability in the FCD model. Development of seizures in children is often associated with focal cortical dysplasia arise in part from deficits in astrocytic glutamate uptake.Many of the anatomical and electrophysiological characteristics of human FCD are reproduced following transcortical freeze-lesions in the newborn rat to avoid receptor desensitization or excitotoxicity . Under physiological conditions, experimental evidence indicates it is difficult to overwhelm astrocytic glutamate transporters. High frequency stimulation for prolonged periods does not affect glutamate clearance from the ECS; Diamond and Jahr, in vivo, can effectively reduce glutamate to ambient levels when challenged repeatedly with 100-fold glutamate increases over physiological [Glu\u2212]out levels following neuronal activity and maintaining out and [Glu\u2212]in. This is achieved by coupling glutamate transport to Na+ and K+ transport down their respective concentration gradients and the hyperpolarized astrocyte membrane potential (Anderson and Swanson, Glutamate uptake is achieved against a ~1000-fold concentration gradient between [GluOur data clearly indicate significant alterations in glutamate transporter function. We observed a near 10-fold reduction in TBOA sensitive transporter function. Furthermore, application of DHK, a GLT-1 specific non transportable inhibitor, suggests ~90% of the currents in both sham-operated and lesioned astrocytes are mediated by GLT-1. Application of the same concentration of glutamate in puffing experiments ruled out the possibility that the reduced glutamate transporter responses in the lesioned astrocytes were the result of less glutamate release following stimulation in lesioned animals. Inefficient clearance of glutamate by astrocytic glutamate transports following electrical stimulation contributed to an enhanced hyperexcitability in the dysplastic cortex, which can be explained in part by altered kinetics of the NDMA receptor-mediated currents.+ has been used to study reverse glutamate transport (Szatkowski et al., +, coupled with our reported depolarized membrane potential in glia cells would create the perfect environment for transporters to function in reverse (Brew and Attwell, + which plays a significant role in neuronal excitability.We postulated that the loss in GLT-1 transporter function would be paralleled by decreased protein and mRNA expression. To our surprise, this is not what we observed. Given our data, it seems likely that a change in transporter effectiveness may underlie the observed decreases in evoked transporter currents. The activity of glutamate transporters is affected by a variety of neuromodulators and second messenger systems. Decreases in transporter activity are induced by caffeine (Shin et al., in utero MAM cortical dysplasia model (Harrington et al., Elevated levels of extracellular glutamate have been reported in patients with epilepsy (During and Spencer, Susan L. Campbell performed whole cell voltage clamp electrophysiology in neurons and astrocytes, immunohistochemistry and contributed to the writing of the manuscript. John J. Hablitz oversaw aspects of experimental design, implementation and writing of the manuscript. Michelle L. Olsen performed whole cell voltage clamp electrophysiology in astrocytes, neurons, Western blots, qPCR, immunohistochemistry and writing the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Coronary perfusion pressure is a combination of proximal perfusion pressure and distal coronary artery pressure resulting from contraction and relaxation of the myocardium and the consequences on the microcirculation. Wave intensity analysis (WIA) defines dominant waves causing coronary filling during the cardiac cycle and allows separation of proximally and distally originating waves.Reduced myocardial perfusion has been shown to predict mortality in hypertrophic cardiomyopathy (HCM), however no study has assessed the relationship between coronary filling patterns and downstream absolute myocardial perfusion.To obtain data for WIA, simultaneous pressure and coronary flow velocity in the proximal coronary arteries was obtained in 20 patients with HCM at rest and with adenosine. Patients then underwent cardiovascular magnetic resonance (CMR) perfusion imaging at rest and with adenosine. Myocardial blood flow (MBF) was quantified from CMR perfusion images using a pixel-wise model-constrained deconvolution algorithm.All patients completed the study successfully. No patients had significant epicardial coronary artery disease. On WIA, distally originating waves predominated compared to proximally occurring waves. The backward expansion wave, which occurs due to myocardial relaxation, correlated with MBFat rest . On CMR, myocardial perfusion reserve was reduced (mean 1.52\u00b10.42) withan endocardial to epicardial ratio that worsened with adenosine .Patients with HCM had predominantly distal waves governing coronary filling, emphasisingthe importance of the microcirculation in this disease. There was an increased backward compression wave during systole in keeping with compression of the microcirculation with a relative reduction in the size of the backward expansion wave. CMR demonstrated the downstream effects of these abnormalities, with reduced myocardial perfusion and an abnormal endocardial to epicardial ratio. Patients with a smaller backward expansion wave had a lower MBF, suggesting that impaired myocardial relaxation results in poorer myocardial perfusion.This work was funded by the British Heart Foundation and the NIHR Cardiovascular BRU."} +{"text": "Since INR was developed only to monitor long-term treatment of vitamin K antagonists (VKA), effects of other coagulation conditions, i.e., antiplatelet treatment, thrombocytopenia, hyperfibrinolysis or inherited platelet disorders can not be detected by INR measurements. A possible application for POC coagulometers in the prehospital setting is to assess INR in emergency patients treated with VKA. However, this issue was extensively studied in large (non-emergency) cohorts involving appropriate sample sizes and valid study designs [With great interest we read the recent article of Beynon et al. . The aut designs , 4.In the past decades, VKA accounted for the most prescribed anticoagulants worldwide in patients with atrial fibrillation and deep vein thrombosis. This practice is now under considerable change since non-vitamin K antagonist oral anticoagulants (NOAC) are available . The dimWe agree with the authors that the implementation of POC coagulometers might be feasible in pre-hospital emergency settings but the search for an easily available parameter enlightening the complexities of the entire coagulation system continues."} +{"text": "Past and recent findings on tumor heterogeneity have led clinicians and researchers to broadly define cancer development as an evolving process. This evolutionary model of tumorigenesis has largely been shaped by seminal reports of fitness-promoting mutations conferring a malignant cellular phenotype. Despite the major clinical and intellectual advances that have resulted from studying heritable heterogeneity, it has long been overlooked that compositional tumor heterogeneity and tumor microenvironment (TME)-induced selection pressures drive tumor evolution, significantly contributing to tumor development and outcomes of clinical cancer treatment. In this review, we seek to summarize major milestones in tumor evolution, identify key aspects of tumor heterogeneity in a TME-dependent evolutionary context, and provide insights on the clinical challenges facing researchers and clinicians alike. Cancer has been traditionally typified by a stepwise accumulation of mutations in key oncogenes and tumor suppressors . For decMeanwhile, tumors are often described as heterogeneous, owing to the intricate genetic diversity and assorted morphological phenotypes they embody . IntratuAdvances in next-generation sequencing techniques and the inception of The Cancer Genome Atlas (TCGA) have revealed extensive heterogeneity at the molecular level . HoweverIn this review, we will revisit the key milestones in tumor evolution, highlight the evolving concepts of tumor heterogeneity, and provide insight on the clinical challenges facing researchers and clinicians alike.Three hundred years after the invention of the microscope, concurrent with the dawn of Darwinian evolution, German physiologist Johannes Muller and his assistants applied microscopy to human tumor samples in 1833. Until this point, all recorded knowledge of tumors was collected with the naked eye, leaving layers of critical information untapped. Applying methods used by botanists and plant physiologists, Muller transformed pathology and modern medicine with his monograph on cancer. This led to his conjecture that tumors are composed of new cells within a diseased organ. Muller and colleagues morphologically distinguished carcinoma subtypes within a single tumor and noted variation among tumor-adjacent connective tissues, detailing the vast heterogeneity observed. It was Muller\u2019s student, famed pathologist Rudolf Virchow, who later determined that all tumors derive from normal cells. Muller and Virchow transformed modern medicine not just by inventing the field of pathology, but also by recording some of the earliest evidence that tumors are heterogeneous , 10.All tumors possess some form of somatic mutation, and our current understanding of tumor heterogeneity is built upon the principle that acquired mutations are heritable . EssentiGenetic heterogeneity of tumors is rooted in one of the key hallmarks of cancer: genetic instability . Severalet al. challenged this with stochastic simulation of tumor evolution and reasoned that, though individually weak, the cooperative burden of small-scale accumulated passenger mutations has a present role in tumor progression, and may be the cause for complex oncological events that remain unanswered by the driver-centric model [Tumor cells undergo a series of genetic events that contribute to genomic instability throughout tumor progression Figure\u00a0A. Howeveic model .Figure 2C. albicans suggest aneuploidy promotes fitness throughout drug resistance evolution, similar to cancer, contrasting S. cerevisiae, which displays growth deficits as a result of aneuploidy [S. cerevisiae diploids exhibit an increased number aneuploidy events under strong selection pressure [Genomic analyses have provided evidence that drastic rearrangement events such as aneuploidy, a defining feature of genetic instability and cancer, and chromothripsis drive cancer progression . Despiteeuploidy . Others pressure . ComparaIn the past 10\u00a0years, genetic sequencing data from independent laboratories and collective efforts from The Cancer Genome Atlas (TCGA) and ICGC produced global genetic profiles of different types of cancer \u201336. As dThe epigenome is defined as the whole suite of epigenetic factors that regulate expression of the genome and includes both heritable and non-heritable cellular changes that have been shown to contribute to tumor development and progression . Temporaet al. found that epigenetic alterations can be influenced by adjacent genes [et al. applied ChIP-seq to show epigenetic enabling of the von Hippel-Lindau (VHL) tumor suppressor activation of hypoxia inducible factors (HIFs) for metastasis [et al. recently reported an increased variance of putative CpG sites in tumor cells compared to normal cells across several types of cancer [Next generation sequencing techniques have advanced the current understanding of the epigenome and further complicated the current concept of tumor heterogeneity. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) offers single nucleotide resolution, an unlimited dynamic range, and the capacity to multiplex samples . Recentlnt genes . Anothertastasis . More ovf cancer . Signifif cancer .Cancer evolution and heterogeneity is a long debated subject that questions the tumor origin. Borrowing principles of evolution and biodiversity, scientists have reasoned that tumors originate in stem cell populations, as the innate longevity of stem cells increases the chance of acquiring harmful mutations . Increasin vitro assays are not a true assessment of self-renewal capacity [et al. isolated the reputed CSC population using classical stem cell markers from patient peripheral blood and demonstrated that a subpopulation of progenitor cells could recapitulate AML in SCID mice and displayed potential for self-renewal. These findings formed the basis for the modern CSC hypothesis and led to the further identification of cancer stem-like cells tumor initiating cells in breast cancer and brain tumors [Early clonogenic and tumor sphere forming assays showed evidence of stem like cells in heterogeneous tumors; however, these capacity . Furthercapacity . Moreovecapacity . Lapidotn tumors .The traditional CSC hypothesis implies that cellular hierarchies exist in tissues with stem cells or CSC (in tumors) at their respective apices . Chafferet al. compiled an extensive molecular taxonomy report across several different cancer types where tissue of origin provided the strongest identification signal [et al. provides direct evidence that the tumor stroma harbors a deregulated ECM that promotes malignancy and intratumoral heterogeneity in mammary gland models [It is abundantly clear that the evolutionary selection of fit clones is a system-wide process that occurs in a dynamic tissue milieu termed the tumor microenvironment (TME) . Bisselln signal . This ked models . Michor d models . These ret al. used 3D cell culture to demonstrate that hypoxia inhibits differentiation of colon cancer cells and maintains a stem-like phenotype [et al. demonstrated that myofibroblasts secrete factors that maintain the CSC population in colon cancer cell culture models [et al. reported basal breast cancers cells retain the ZEB1 promoter in a configuration allowing ample response to environmental signals [Stem cell self-renewal and differentiation is dictated by the microenvironment, or stem cell niche. Normal stem cell niches are generally located in hypoxic tissue niches that promote the stem cell phenotype. Poorly vascularized tumors contain hypoxic regions with undifferentiated \u2018stem-like\u2019 tumor cells that survive under control of HIFs . Yeung ehenotype . In addie models . They sh signals . These ret al. recently demonstrated that, in the context of chronic liver inflammation, depletion of a p53-dependent senescence program in tumor cells results in increased cirrhosis and fibrosis that promotes adjacent epithelial malignant transformation and transient intratumoral heterogeneity [Studies on deregulation of the tumor secretome provide compelling evidence for the TME as a major contributor to compositional tumor heterogeneity. Substantial evidence supporting a role for inflammation in cancer progression has been reported in the last decade and is commonly accepted as a hallmark characteristic of the TME . One of ogeneity .The collective interplay between the CSCs and the TME results in compositional intratumor heterogeneity Figure\u00a0B. HoweveThe dawning of the age of \u2018omics\u2019 brought with it great hope for discovery and validation of novel biomarkers, relevant drug targets, and disease-specific signatures . Powerfuet al. recently generated a computer model to further study multifocal prostate cancer based on data obtained from 152 human prostatectomy specimens evaluated by DNA microarray analysis, where they demonstrated heterogeneous individual foci with a common clonal precursor [et al. reported another mathematical model of personalized treatment that integrates dynamics of evolutionary genetics into analysis and treatment design. Their analyses of hypothetical cases as well as a simulated clinical trial of over 3 million qualified \u2018patients\u2019 showed that augmented and, occasionally counterintuitive, nonstandard treatment strategies may lead to improved patient survival compared with the current model of personalized medicine [Careful consideration of the complete tumor context is essential to understanding and developing more effective personalized treatments that address tumor heterogeneity. The first challenge is whether genetic and compositional profiling of multifocal tumors of monoclonal origin displaying intrafocal heterogeneity can be effectively manage . Multiforecursor . Beckmanmedicine .et al. showed evidence of two genetically distinct tumor cell subclones in communication to maintain the tumor population [et al. employed advanced genomics techniques to further understand the underlying mechanisms driving pancreatic cancer progression and metastasis. Despite showing vast genetic diversity, the authors were able to elucidate a distinct pattern of genomic instability [et al. recently used integrated genomics to characterize the functional role of key genetic driver mutations in luminal breast cancer and correlated specific genetic signatures with poor prognosis [A number of new concepts have emerged in recent years. The concept of intratumoral cell competition among heterogeneous clones reshaped our classic hierarchical view of heterogeneity and potentially can be exploited as therapeutic entry points in eradicating multifocal cancers . Cleary pulation . This letability . Moreoverognosis . Althouget al. used Pathway Recognition Algorithm using Data Integration on Genomic Models (PARADIGM) analyses based on copy number alterations (CNAs) and mRNA expression of data from the MicroMetastases Project (MicMa) cohort to show that integrated analysis of DNA copy number alteration and mRNA expression leads to improved prognostic discrimination of patients compared to separate analysis of any other molecular levels [With massive omics data generated from The Cancer Genome Atlas (TCGA), various algorithms and tools for recognition of activated and altered pathways exist for integrative analysis of two or more types of omics data and are rapidly proving worthwhile . Notablyr levels . Five dir levels . Similarr levels . Among tr levels .Taken together, future integrated omics analyses with consideration of compositional heterogeneity inferred by interplay between intratumoral subclones and TME will allow us to identify more robust biomarkers and devise therapeutic strategies for cancer treatment, such as staggering targeted therapies to keep selection pressures minimal . Mapping"} +{"text": "IbGGPS, was isolated from sweetpotato storage roots. Green fluorescent protein (GFP) was fused to the C-terminus of IbGGPS to obtain an IbGGPS-GFP fusion protein that was transiently expressed in both epidermal cells of onion and leaves of tobacco. Confocal microscopic analysis determined that the IbGGPS-GFP protein was localized to specific areas of the plasma membrane of onion and chloroplasts in tobacco leaves. The coding region of IbGGPS was cloned into a binary vector under the control of 35S promoter and then transformed into Arabidopsis thaliana to obtain transgenic plants. High performance liquid chromatography (HPLC) analysis showed a significant increase of total carotenoids in transgenic plants. The seeds of transgenic and wild-type plants were germinated on an agar medium supplemented with polyethylene glycol (PEG). Transgenic seedlings grew significantly longer roots than wild-type ones did. Further enzymatic analysis showed an increased activity of superoxide dismutase (SOD) in transgenic seedlings. In addition, the level of malondialdehyde (MDA) was reduced in transgenics. qRT-PCR analysis showed altered expressions of several genes involved in the carotenoid biosynthesis in transgenic plants. These data results indicate that IbGGPS is involved in the biosynthesis of carotenoids in sweetpotato storage roots and likely associated with tolerance to osmotic stress.Sweetpotato highly produces carotenoids in storage roots. In this study, a cDNA encoding geranylgeranyl phyrophosphate synthase (GGPS), named Carotenoids are widely produced in many plants and provide potent nutritional benefits to human and animal health. The biosynthetic pathway of carotenoids has gained relatively intensive investigations in different plants , 2. CaroGGPS cDNAs have been cloned from multiple plant species. A gene expression study using sunflower seedlings showed that the HaGGPS was expressed after 2 days of seed imbibition , 39ArabiIbGGPS gene was cloned from storage roots of sweetpotato. Subcellular localization, transgenic approach and metabolite analysis demonstrated its involvement in the biosynthesis of carotenoids. Transgenic plants showed its expression associated with an osmotic stress tolerance. These data will be instructional to future sweetpotato breeding for high production of carotenoids and stress-tolerant varieties.In conclusion, an"} +{"text": "Antiphosphospholipid syndrome (APS) secundary to systemic lupus erythematosus (SLE) can be recognised in children with arterial or venous thrombosis. Amaurosis due to thrombosis of central retinal vene is rarely presenting manifestation of SLE with secondary APS.To present APS secundary to SLE with aggresive ophtalmological onset in 17 years old female.We report a patient with unilateral amaurosis due to thrombosis of central retinal vene. Amaurosis was a reason for her urgent admission at Ophtalmology. She was transferred to Pediatric rheumatology department as suspected SLE. The patient had rapidly developing disease. Eleven days after the attack of retinal vene thrombosis, she became febrile with malar rash, facial ulcer, neurological symptoms (right Mingazzini positive), arterial hypertension, haemathological abnormalities, proteinuria and immonological disorders. Head MRI-MRA was performed and suboclusion of left medial cerebral artery was found. The diagnosis of APS secundary to SLE was established.The patient significantly improved with aggresive immunosupresive and prompt anticoagulant therapy but ohtalmological complication have been improved slowly with uncertain prognosis.The patients with SLE related symptoms have to be reffered to rheumatologist immediately because APS secundary to SLE may have aggressive thrombotic onset and cause serious organs damages.None declared."} +{"text": "New extensive use of thoracic ultrasound (TUS) takes information also from physical acoustic phenomena that are not directly convertible into images of the human body.This tenNo evaluation on technical issues feasibly , no comparison of the results of TUS and those of a reference standard (i.e. CXR);Diagnostic access bias , bias from reader/training experience on CXR (no paediatric radiologists);Imaging analysis bias i.e. absence of preliminary definition of the methods for imaging (CXR) interpretation, selection bias (patients from birth to adult undergoing chest radiography for suspected community acquired pneumonia)."} +{"text": "Optical mapping provides long-range information of the genome and can more easily identify large structural variations. The ability of optical mapping to assay long single DNA molecules nicely complements short-read sequencing which is more suitable for the identification of small and short-range variants. Direct use of optical mapping to study population-level genetic diversity is currently limited to microbial strain typing and human diversity studies. Nonetheless, optical mapping shows great promise in the study of plant trait development, domestication and polyploid evolution. Here we review the current applications and future prospects of optical mapping in the field of plant comparative genomics.Optical mapping has been widely used to improve Optical mapping is a molecular technique that produces fingerprints of DNA sequences in order to construct genome-wide maps . The seqde novo genome assembly and identification of relatively large structural variants in genetic diversity studies. While optical mapping is readily available across a wide range of organisms including bacterial, fungi, plant and mammalian genomes [Optical mapping offers several unique advantages over traditional mapping approaches, including single molecule analysis and the ability to assay long DNA molecules data support each other, but are both inconsistent with linkage maps, especially in heterochromatic regions where recombination is scarce [Similar to optical maps, genetic maps could be a useful guide in anchoring scaffolds and identifying assembly issues ,19. Howes scarce . Similars scarce . Genome s scarce ,20.Genome \u2018upgrades\u2019\u2009, or improvement of genome assemblies are possible through the incorporation of the optical mapping information into existing sequences. For example, optical mapping was essential in upgrading the rice Nipponbare reference genome in several important ways ,18. FirsSimilar to rice, optical maps have been extensively used to improve the Medicago genome assembly starting with release version Mt3.5, and were helpful both during the chromosomal anchoring and to correct errors in the linkage maps ,22. To bOptical mapping can be very useful in assisting the assembly of polyploid and highly heterozygous plant genomes, which are notoriously difficult to assemble . Many plDespite recent progress in genome assembly methodologies, a significant portion of many genomes remains inaccessible to assembly by short sequencing reads . A comprde novo assembly is still challenging and large amounts of true SVs may be lost during the assembly process. For most organisms, the \u2018reference\u2019 genome only represents a single individual and requires substantial amount of investment for the initial genome assembly and subsequent finishing. Most assemblies can only reach \u2018draft\u2019 status, often containing a large number of sequence gaps and assembly errors that could easily show up as false SVs during sequence comparisons.Pairwise sequence alignments between assembled genomes remains one of the most powerful tools for plant comparative genomics, and could identify SVs with the best accuracy if the assemblies themselves were correctly reconstructed. However, Split reads at the same position could indicate genomic breakpoints derived from inversions, deletions and insertions. Discordant pairs reveal spacing difference due to deletions or insertions, or presence-absence variations (PAVs). Read depth variations can be used to identify copy number variations (CNVs) that are likely derived from tandem or segmental duplications retrotransposon-mediated gene duplication [Some important agronomic traits are directly caused by structural variations which could be studied with a whole genome association framework across varieties or diversity panels. For example, the lication . Currentet al. uncovered large structural variants that are associated with selective sweeps in Arabidopsis lines from Sweden, based on a suite of methods from \u2018manual\u2019 detection of breakpoints to de novo assembly. They acknowledged that many polymorphisms may be complex and difficult to resolve using short-read sequencing data [In addition to agronomic traits, a wide range of studies in plants, including domestication, polyploidy, population history and natural selection could benefit from optical mapping. Long ing data . Re-sequing data , althougBrassica napus genome, an allotetraploid merged from two diploid Brassica genomes [The application of optical mapping could reveal structural changes following polyploidy events in plants that might be difficult to study using other techniques. Studies show that homeologous exchanges (HEs) occur frequently between subgenomes inside polyploid genomes and often involve large chromosomal segments. This was studied in the genomes . Each HE genomes . While r genomes . The dirOptical mapping is an important technique that can provide long genomic linkage information in a high-throughput manner, which has substantially improved the assemblies of several important model plant genomes sequenced to date. Direct comparisons of genome structures have so far been lacking in plants, but optical mapping shows great promises at revealing genomic regions that are not easily accessible through conventional sequencing methods. Optical mapping could become an integral part of the mapping tools in the study of plant domestication, polyploid evolution, and trait development."} +{"text": "Here we used a well-characterized panel of lung cancer cell lines to develop the most comprehensive view of cancer cell metabolism to date.Cancer cells display oncogene-driven rewiring of metabolism to produce energy and macromolecules for growth. Inhibition of growth-promoting metabolic pathways may prove to be a useful therapeutic strategy in cancer. We previously identified distinct metabolic platforms that enabled cancer cells to produce macromolecular precursors from glucose and glutamine, the two most abundant nutrients. However, neither the full breadth of cancer cell metabolic diversity, nor the complement of mechanisms by which tumor mutations elicit metabolic reprogramming, are known. Because metabolic flux can be analyzed in vivo.81 non-small cell lung cancer cell lines were analyzed for a set of well-defined metabolic parameters. These cell lines were also subjected to extensive genomic, epigenetic, and gene expression analysis, and tested for sensitivity to chemotherapeutic agents and genome-wide siRNA screens. These rich data sets will streamline the establishment of novel correlations between metabolism and molecular/cell biological features. All cell lines were characterized for nutrient utilization, nutrient addiction, and focused flux assays to trace the metabolism of isotope-labeled glucose and glutamine in identical culture condition. Ongoing experiments are assessing metabolism of the same cells grown The 81 cell lines displayed surprising metabolic heterogeneity. Although all cells used glucose and glutamine to produce biosynthetic precursors, contributions of these two nutrients varied considerably, as did the pathways used. For individual isotopic labeling patterns, differences of >30-fold were observed across the panel. Unsupervised clustering produced two metabolic superfamilies differentiated by relatively glucose carbon contribution into precursor pools, as well as numerous subfamilies which may correlate to different metabolic pathways. Although KRAS-mutant cells were distributed across panel, the LKB1/KRAS co-mutation cells aggregated into the low-glucose m0 superfamily. Ongoing work will examine the ability of metabolic phenotyping to predict combinatorial mutations and vulnerabilities to drugs and siRNAs.Focused metabolic assays can produce a highly informative view of the metabolic phenotyping among large panels of cell lines. It describes an unparalleled view of the connections between genetics, drug sensitivity and cell-autonomous metabolism in NSCLC."} +{"text": "Using our experience of over 500 patients who have undergone pre-biopsy mpMRI and subsequent transperineal saturation prostate biopsy, we aim to:\u2022 Illustrate the commonly overlooked areas in diagnosing prostate cancer with mpMRI.\u2022 Emphasise technical factors that can contribute to suboptimal image interpretation.\u2022 Highlight normal anatomical structures and non-cancerous abnormalities that mimic tumour.\u2022 Demonstrate the use of mpMRI to direct further management.mpMRI may be used in the pre-biopsy setting to determine type of biopsy , and predict biopsy outcome to the extent that biopsies may be avoided altogether. Tumour localisation within the prostate gland aids targeted biopsy and influences treatment . Tumours with unusual appearances and those in uncommon sites hinder MRI interpretation, potentially leading to false-negative or \u2013positive findings. These areas of pitfall can be divided into normal anatomical structures in the peripheral or transitional zones or non-cancerous abnormalities that mimic tumours (e.g. granulomatous prostatitis).It is also important to acknowledge that mpMRI itself has limitations. Technical challenges in relation to DWI may lower tumour sensitivity due to anatomical distortion, inadequate suppression of benign prostate tissue and suboptimal ADC map windowing.It is paramount that radiologists are aware of the commonly missed locations of prostate cancer, tumour mimics and the limitations of mpMRI, particularly in the context of a multidisciplinary team setting. This would serve to improve diagnostic accuracy, target areas for biopsy more precisely and correctly influence management."} +{"text": "Most researchers leverage bottom-up suppression to unlock the underlying mechanisms of unconscious processing. However, a top-down approach \u2013 for example via hypnotic suggestion \u2013 paves the road to experimental innovation and complementary data that afford new scientific insights concerning attention and the unconscious. Drawing from a reliable taxonomy that differentiates subliminal and preconscious processing, we outline how an experimental trajectory that champions top-down suppression techniques, such as those practiced in hypnosis, is uniquely poised to further contextualize and refine our scientific understanding of unconscious processing. Examining subliminal and preconscious methods, we demonstrate how instrumental hypnosis provides a reliable adjunct that supplements contemporary approaches. Specifically, we provide an integrative synthesis of the advantages and shortcomings that accompany a top-down approach to probe the unconscious mind. Our account provides a larger framework for complementing the results from core studies involving prevailing subliminal and preconscious techniques. The unconscious mind fascinates and challenges human thinking . PervasiRecovering from a volatile history plagued by quackery and charlatanism, hypnosis has become a viable venue of cognitive science . At leasUsing hypnosis in the study of the unconscious mind dates back to early psychodynamic conceptions when analysts leveraged hypnotism to probe unconscious thoughts and feelings of analysands . RevisitWe review contemporary suppression and inattention techniques to assess their relative merits and drawbacks. Thereafter, we contrast the strengths and weaknesses of contemporary approaches \u2013 i.e., subliminal and preconscious methods \u2013 with those of instrumental hypnosis. Showcasing findings using hypnosis, we sketch out how this top-down approach provides the experimental means to foster new perspectives to study the unconscious mind.Subliminal and preconscious approaches represent active areas of research within the domain of unconscious cognition . Guided Figure 1; The global workspace model entails that unconscious processing of sensory events occurs in two ways: conscious suppression of sensory signals, corresponding to perceptual failures, and preconscious processing of sensory events reflecting attentional failures . In this procedure, both stimuli compete to access consciousness, resulting in the temporary conscious suppression of the ineffective stimulus , which elicits longer and deeper suppression compared to BR (Frontiers in Psychology research topic on conscious suppression). Importantly, interocular suppression techniques yield competition at the sensory level and at the representational level . Bistable representations reflect the inherent ambiguity conveyed by these images as our brain processes resolve these competing interpretations , these failures to detect prominent task-irrelevant stimuli occur when individuals engage in a demanding cognitive task and CB mainly reflect lapses of attention, wherein unattended signals lack the necessary energy and sustainability to reach conscious perception . Both exUnattended events during IB and CB induce preconscious processing, yielding priming effects e.g., , impliciIn a stream of rapidly presented visual stimuli, attending to a task-related stimulus impairs attentional processing of subsequent stimuli at short latencies . This atFigure 1; Subliminal approaches exploit the limits of perception to suppress awareness of sensory events . These tThe broad range of mechanisms selectively engaged by each of the abovementioned methods challenges our capacity to generalize findings across different tasks. As we explained, these techniques yield important findings about the scope and depth of subliminal and preconscious processing. Notably, bottom-up approaches afford researchers with plentiful experimental control, yet offer limited ecological validity. Conversely, top-down approaches, such as IB and CB, propose an ecological tactic to investigate unconscious processing , but remFigure 3), we follow the criteria put forth in the literature (To assess the aforementioned techniques (see terature . This se(i)Generality: whether the technique applies to a broad range of stimuli or only to a select few.(ii)Stimulus location: whether the stimulus has to be presented at the center or the periphery of the visual field.(iii)Temporal constraint: whether the technique imposes a temporal constraint relative to the duration of the stimulus presentation.(iv)Robustness: whether this technique completely abolishes awareness.(v)Invariant stimulation: whether conscious suppression requires significant modifications of sensory events to make a stimulus invisible \u2013 e.g., adding a mask to induce conscious suppression during backward masking.Hypnosis represents an increasingly popular area of research in cognitive science, including notable ventures in the domains of perception, attention, memory, and motor control . For exaTheoretical frameworks for hypnosis largely cluster around the appellations of state and non-state models. State theories posit that hypnosis implies a particular psychological state \u2013 e.g., an altered state of consciousness \u2013 whereas non-state theories typically argue that hypnosis essentially reduces to sociocognitive factors such as motivation and compliance . In spitTop-down regulatory processes \u2013 e.g., attention, cognitive control and monitoring \u2013 play a central role in mediating responses to hypnotic suggestions . SpecifiEmphasizing the importance of individual variability, compliant participants frequently report using different cognitive strategies to successfully respond to the very same suggestion . This inFigure 4; Figure 5), a significant experimental benefit to better isolate the NCC. The content of hypnotic suggestions selectively targets specific mental functions and behaviors. Thus, we will demonstrate how hypnosis encompasses a wide variety of experimental possibilities to investigate unconscious processes . Here we discuss several avenues based on such research developments.Hypnotic suggestions divide as a function of type and content .Hypnosis also modulates phenomenological aspects of conscious experience, such as pain perception . Called Posthypnotic amnesia (PHA) represents memory lapses of events that took place under hypnosis, after termination of hypnotic induction . AffordiPast research shows that temporarily irretrievable material influences behavior nonetheless . For exaContrary to PHA, few studies looked at the effects of hypnotic agnosia \u2013 i.e., the functional inability to access semantic knowledge . This reHypnosis can decouple volitions and actions . HypnotiIntrusive cognitions and emotions often accompany psychopathology . In ordeIn experimental psychopathology, hypnotic suggestions target specific functions and dramatically influence cognitions and behaviors . For exaThe fields of neuropsychology and behavioral neurology often feature deficits that are amenable to top-down influences at diffeWhether hypnosis acts through suppressive means or influences attention to impede conscious access, this top-down methodological approach possesses formidable potential to study the unconscious mind. Two general features make hypnosis a unique approach. First, hypnotic suggestions afford researchers with a wide spectrum of experimental possibilities. Second, whereas the prevailing approaches either take advantage of perceptual limitations or interfere with top-down amplification processes, hypnosis harness top-down processes to investigate both subliminal and preconscious phenomena. Indeed, due to the variety of hypnotic suggestions, hypnosis can prompt perceptual and attentional failures. Also, the accuracy of hypnosis allows rFigure 1). During hypnotically induced subliminal and preconscious processing, hypnotic responses recruit frontal networks implicated in top-down attentional regulation, control and monitoring processes : this approach applies to a broad range of visual and non-visual stimuli; works equally well for stimuli presented centrally or peripherally; hardly necessitates temporal constraint relative to the presentation of the stimulus or variation in sensory events. Finally, various experiments imply the robustness of unconscious hypnotic phenomena, even if the phenomenological dimensions of hypnosis remain roughly defined (Overall, the use of hypnosis to investigate the cognitive unconscious compares favorably to contemporary methodologies (see defined . This ap defined . In compDespite these benefits, certain obstacles to the use of hypnosis in the context of the suppression of consciousness might arise. Here we address some of these concerns. First, HHSs are often carefully selected in hypnosis experiments to demonstrate the full potential of hypnotic suggestions , despiteA final concern pertains to the objective control of subjects\u2019 awareness, a central issue that transcends research on conscious and unconscious processes . AlongsiHere we herald instrumental hypnosis as a new experimental vehicle to probe the structure and functioning of the cognitive unconscious. Whereas most current techniques investigate the unconscious mind via subliminal approaches that challenge our perceptual limitations and preconscious approaches that rest on inattention, the hypnosis lens facilitates both suppression and inattention via top-down mechanisms. Beyond the empirical potential to explore novel ideas and hypotheses, top-down control provides scientists with increased experimental flexibility by allowing target processing of specific sensory events. Moreover, hypnotic hallucinations provide an efficient means to capture the NCC using a full two-by-two balanced design allowing for a direct comparison of conscious and unconscious conditions. Thus, scholars stand to benefit from the use of hypnosis in their quest to better understand the underpinnings of the unconscious mind . IncorpoThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The cerebellum plays an important role in motor control. The cerebellar key players include Purkinje cells (PCs), mossy fibers, climbing fibers, and parallel fibers. Each PC receives inputs from many parallel fibers and from a single climbing fiber. Cerebellar outputs originate from the deep cerebellar and vestibular nuclei. Cerebellar nuclei (CN) neurons receive inhibitory inputs from PCs and excitatory inputs from mossy fiber and climbing fiber collaterals. In this work, we studied how regular and irregular, as well as synchronous and asynchronous, PC firing frequencies affect the eye movements in mice and CN neuron model behavior. Floccular PCs on one side of the head were optogenetically stimulated . We use"} +{"text": "Mental health care services play an important role following disasters program over a 2-year period following two major Australian bushfire and flood/cyclone disasters. Predictor variables examined in negative binomial regression analysis included consumer and event characteristics (disaster type).The bushfire disaster resulted in significantly greater service volume, with more than twice the number of referrals and nearly three times the number of sessions. Service delivery for both disasters peaked in the third quarter. Consumers affected by bushfires, diagnosed with depression, anxiety, or both of these disorders utilized sessions at significantly higher rates.The substantial demand for primary mental health services following disaster can vary with disaster type. Disaster type and need-based variables as key drivers of service use intensity indicate an equitable level of service use. Established usage patterns assist with estimating future service capacity requirements. Flexible referral pathways can enhance access to disaster mental health care. Future research should examine the impact of program- and agency-level factors on mental health service use and factors underpinning treatment non-adherence following disaster."} +{"text": "The ideal cancer therapy not only induces the death of all localized tumor cells, but also activates a systemic antitumor immunity. High intensity focused ultrasound (HIFU) has the potential to be such a treatment, as it can non-invasively ablate a targeted tumor below the skin surface, and may subsequently augment host antitumor immunity.This talk is to introduce increasing animal and clinical evidences linking antitumor immune response to HIFU ablation, review the potential mechanisms, and discuss challenges and opportunities involved in HIFU-enhanced host antitumor immunity.It is concluded that HIFU immunotherapy may play an important role in preventing local recurrence and metastasis of cancer after HIFU treatment."} +{"text": "The last decade has witnessed an exponential increase in the researches being carried out to combat aging using drug therapy. Few specific drugs like Metformin, Rapamycin and Resveratrol have displayed promising results in anti-aging research of mice, fruit fly and worm. Basically these drugs interfere genetically with the important aging pathways such as IIS, TOR, and NAD+ dependent pathway, and results in lifespan extension in a number of species ranging from worm to mammals .Drosophila resulting in lifespan extension along with increased stress resistance, reduced fecundity and increased lipid levels. Also rapamycin treatment has shown to further extend the lifespan of some long lived IIS mutants, and dietary restricted flies, indicating additional mechanisms of lifespan extension [Rapamycin which was originally an immuno-suppressive drug used for kidney transplant patients for years, is an inhibitor of protein kinase target of rapamycin (TOR). Rapamycin inhibits the TOR by forming a complex with FKBP12, which goes on to bind with TOR complex1. The mechanism of rapamycin mediated lifespan extension has largely remained conserved in different model species, for example the genetic mutations/deletions of S6K and 4E-BP in mice and its homologues in worms have resulted in extended lifespan. Rapamycin treatment has led to reduced phosphorylation of S6K in Drosophila. In flies the midgut stability is maintained by multipotent intestinal stem cells (ISCs) in hindgut proliferation zone (HPZ) and controlled by locally emanating Wingless and Hh signals. Under the stress conditions such as aging, pathogen exposure, genotoxins or ROS inducing compounds, the ISC proliferation increases strongly in order to restore the large parts of intestinal epithelium. The epithelial integrity is disrupted by this regenerative event leading to accumulation of mis-differentiated cells and resulting in a dysplastic pheno-type [Gut has been considered as an unique important target organ in mediating the lifespan extension at the organismal level because of its immunity and nutrition intake . Also theno-type . Intereseno-type .Drosophila as a model system to carry out such study [Drosophila intestinal epithelium. We have proposed that, along with inhibiting mTOR, rapamycin can also significantly delay the microbial expansion by upregulating the negative regulators of IMD/Rel pathway in the aging guts , is significantly up regulated in rapamycin treated flies suggesting that rapamycin can improve the intestinal capacity for antioxidants. The autophagy genes atg1, atg5 and atg8b displayed increased mRNA expression level in intestinal tissues, indicating that rapamycin can induce autophagy and increase the lifespan. The anti-microbial peptide (AMP) gene dpt and the dual oxidase gene (duox), which is associated with reactive oxygen species (ROS) levels, were significantly decreased in rapamycin treated aged guts, indicating that rapamycin may reduce the intestinal ROS accumulation in aging flies . Thus raThese findings clearly show that rapamycin treatment maintains the gut stability during aging in Drosophila, leading to healthspan and lifespan extension. It should be noted that due to the high evolutionary conservation of mTOR pathway in different species, the same mechanism underlying rapamycin treatment could apply in other species as well. Thus rapamycin holds great future potential in various gastrointestinal disorders and cancers along with lifespan extension."} +{"text": "Paraneoplastic neurological syndromes (PNS) are neurologic deficits triggered by an underlying remote tumor. PNS can antedate clinical manifestation of ovarian malignancy and enable its diagnosis at an early stage. Interestingly, neoplasms associated with PNS are less advanced and metastasize less commonly than those without PNS. This suggests that PNS may be associated with a naturally occurring antitumor response.N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. An approach to the diagnostic workup of underlying tumors is discussed.We review the literature on the diagnosis, pathogenesis and management of PNS associated with ovarian tumors: paraneoplastic cerebellar degeneration (PCD) and anti-PCD can precede the manifestation of ovarian carcinoma. Anti-NMDAR encephalitis in young women appears often as a result of ovarian teratoma. Since ovarian tumors and nervous tissue share common antigens , autoimmune etiology is a probable mechanism of these neurologic disorders. The concept of cross-presentation, however, seems insufficient to explain entirely the emergence of PNS. Early resection of ovarian tumors is a significant part of PNS management and improves the outcome.The diagnosis of PNS potentially associated with ovarian tumor indicates a need for a thorough diagnostic procedure in search of the neoplasm. In some patients, explorative laparoscopy/laparotomy can be considered. PNS precede clinical manifestation of ovarian tumors and enable their diagnosis at an early stage.Paraneoplastic cerebellar degeneration (PCD) can coexist with ovarian carcinoma.Anti-NMDAR antibodies detected in patient affected with encephalitis are highly suggestive of ovarian teratoma.Ovarian tumors and nervous tissue share common antigens in PNS \u2014the concept of cross-presentation, however, may not be sufficient to explain an emergence of PNS.Cell-mediated immune response plays a role in the pathogenesis of PNS.Antibody-mediated immune response is a major mechanism of anti-NMDAR encephalitis and other NSAS.In patients with PNS associated potentially with ovarian tumors, transvaginal ultrasound examination and pelvic CT scan are indicated\u2014if negative, PET imaging is required.If imaging studies remain normal, explorative laparoscopy/laparotomy should be considered.An early resection of ovarian tumors is a significant part of PNS management and improves the outcome.Paraneoplastic neurological syndromes (PNS) are defined as the pathologic involvement of the nervous system in the course of malignancy. This entity does not include tumor infiltration, compression or metastasis of the nervous system , balance and gait disturbances, speech disorder (dysarthria) and altered ocular movements may display pleocytosis (with a high fraction of lymphocytes), elevated protein or oligoclonal bands in PCD can reveal cerebellar atrophy strongly indicates the presence of ovarian tumor in patients with neurological deficit. If the tumor is not identified, an obligation for systematic screening exists. Surgery and immunomodulatory treatment are considered as the most important management among such a group of patients."} +{"text": "In this guest editorial, Andrew Beck discusses the importance of open access to big data for translating knowledge of cancer heterogeneity into better outcomes for cancer patients. Cancer is a heterogeneous disease, which is comprised of a collection of diseases traditionally categorized by tissue type of origin. A distinct set of etiologic causes, treatments, and prognoses are associated with different cancers, and even within a given tissue type, cancer shows significant variability in molecular and clinical features across patients. This interpatient heterogeneity is a major rationale for large-scale research efforts to comprehensively profile the molecular landscape of patient cancer samples across all major cancers ,2. ThesePLOS Medicine show the potential clinical utility of measuring intratumoral genetic heterogeneity in clinical cancer samples.A major challenge in cancer therapy is the development of resistance to molecularly targeted therapies. Although targeted therapies may show initial benefit in the subset of patients carrying a targeted molecular alteration, most patients will nevertheless go on to develop resistance for most advanced solid cancers. Identifying and overcoming drug resistance represents one of the most significant challenges facing cancer researchers today . It is iIn one, James Brenton, Florian Markowetz, and colleagues applied the Minimum Event Distance for Intra-tumour Copy-number Comparisons (MEDICC) algorithm they recently developed for phylogenetic quantification of intratumoral genetic heterogeneity from multiregion DNA copy number profiling data to prediThe second study comes from James Rocco and colleagues . PreviouThe continuing generation of high-quality, open-access Omics data sets from large populations of cancer patients will be critically important to enable the development of computational methods to translate knowledge of cancer heterogeneity into new diagnostics and improved clinical outcomes for cancer patients. As one step towards this goal, the DREAM consortium will use open innovation crowd sourcing to identify top-performing computational methods for inferring genetic heterogeneity from next-generation sequencing data provided by a large multi-institutional community of cancer genomics projects, including the ICGC and TCGA . If succIn parallel with these advances in computational methods for inferring intratumoral heterogeneity from genomics data, genomics technologies for measuring intratumoral heterogeneity at increasingly fine levels of granularity continue to improve. For example, recent advances in single-cell sequencing of DNA have provided detailed portraits of intratumoral genetic heterogeneity and clonal evolution in cancer ,21, and Establishing the clinical utility of these new approaches for measuring intratumoral molecular heterogeneity will require applying these methods to large sets of archival tumor samples from randomized trials of cancer therapeutics and high"} +{"text": "High density microelectrode arrays (MEAs) provide extracellular recordings from thousands of closely spaced electrodes and with sub-millisecond resolution. These devices offer thus novel capabilities to investigate the interplay between ongoing and evoked electrophysiological signaling within networks in-vitro. However, to effectively take advantage from the spatiotemporal resolution of these MEAs, adapted analysis tools are needed. Here we report on our recent advancements toward this goal. A novel high density MEA with on-chip stimulating electrodes was used to record from 4096 electrodes and electrical stimulation was delivered alternatively through one of the 16 equally spaced electrodes on hippocampal primary cultures derived from mouse. The evoked activities propagated reliably across the network and were specific to the stimulating electrode ). Here,"} +{"text": "In routine cardiac MRI (CMRI) practice, radiological technologists are expected to optimize and utilize EKGs in gating and physiological monitoring. Many cardiac sequences are critically dependent on heart rate and rhythm and EKG gating problems lead to poor or non-diagnostic images. The technologist's syllabus does not routinely include formal EKG recognition or CMRI trouble-shooting techniques.In this educational exhibit, we describe common EKG rhythms and discuss imaging parameter options for overcoming magneto-hemodynamic effects, dealing with high or low heart rates and abnormal rhythms.An image sequence/EKG rhythm quick algorithm is included for reference and will be the basis of the exhibit.Basic EKG rhythm recognition and imaging optimization tips are the building blocks of good cardiac MRI - something every good CMRI technologist should know but are rarely formally taught.None."} +{"text": "The adult liver has unique regenerative capabilities. Adult livers generally regenerate fully functional liver cells when injured, unlike other vital adult organs which typically respond to cell loss by forming scar tissue. The mechanisms underlying these differences are not well understood, particularly since adult livers are perfectly capable of scarring. In fact, transient scar formation normally occurs in situations that lead to efficient and complete recovery of functional liver mass, such as 70% partial hepatectomy (PH). Scarring also occurs to some extent during many types of chronic liver injury, although progressive scarring (dubbed cirrhosis) occurs in only a minority of individuals with chronic liver injury. Even in cirrhotic livers, however, scarring has been shown to regress gradually once factors driving chronic injury are alleviated. The aggregate data suggested to us that the unique regenerative capabilities of adult livers are linked to its ability to control the formation and regression of scar. Our research has focused on delineating the mechanisms that control scarring. The results will help to clarify why injured livers typically regenerate healthy parenchyma, as well as why other organs replace wounded tissue with scar.The wound healing process necessitates some degree of scarring. Scarring is characterized by excessive extracellular matrix deposition, but also involves inflammation, vascular remodeling, and accumulation of cell types that are relatively inconspicuous in healthy tissues, such as progenitors and myofibroblasts (MF). In adult livers, each of these scarring-related responses is regulated by Hedgehog (Hh), a fetal morphogenic signaling pathway that reactivates during adult liver injury . Hh pathRecently, we proved that canonical Hh signaling controls the fate of liver MF . MF accuRecently, we have begun to evaluate a related novel hypothesis, namely, that Hedgehog controls liver regeneration after PH by modulating the differentiation of these multi-potent myofibroblastic progenitor cells. Transgenic mice were generated to permit conditional deletion of either floxed-Smoothened or floxed-YFP alleles in aSMA-expressing cells. By studying the Smoothened-deleted mice, we were able to determine how selectively abrogating Hh signaling in aSMA(+) cells (and their progeny) influenced regenerative responses to PH. By studying the YFP-marked mice, we were able to track the fate of cells that expressed aSMA after PH. The results demonstrate that Hh signaling in aSMA(+) cells orchestrates both scarring and regeneration after PH; prove that these processes are required for the liver to regenerate normally after PH; and show that post-PH regeneration involves differentiation of myofibroblastic progenitors into hepatocytic and ductular cells .Regeneration of adult livers requires Hh-dependent modulation of epithelial-mesenchymal transitions in multipotent progenitors. Data generated by studying models of acute and chronic liver injury reveal that robust epithelial to mesenchymal transitions (EMT) normally occur in injured livers, and show that conditionally abrogating canonical Hedgehog signaling in multi-potent aSMA-expressing cells blocks these EMT, instead triggering a cascade of mesenchymal-to-epithelial transitions (MET). This has global consequences for liver wound healing. Regeneration of different types of liver cells becomes unbalanced, leading to excessive accumulation of quiescent HSC but reduced outgrowth of hepatocytic and ductular progenitors and their progeny, as well as depletion of MF populations. Thus, de-regulating Hh-sensitive EMT/MET responses disrupts both scarring and regeneration of injured livers. These findings, in turn, suggest that the liver is uniquely suited for regeneration because it harbors large populations of multi-potent progenitors and is generally able to constrain signals, such as Hedgehog, that modulate the differentiation of these cells towards less epithelial phenotypes."} +{"text": "The human genome contains nearly 400,000 sequences related to retroviruses that have accumulated due to ancient infections of the germ line and subsequent fixation during evolution. Most of these endogenous retroviral sequences (ERVs) currently exist as solitary long terminal repeats (LTRs), the product of recombination between LTRs of the integrated proviral form. Since retroviral LTRs naturally contain transcriptional promoters and enhancers, these sequences have great potential to impact regulation of individual genes and gene regulatory networks. Numerous cases of LTRs serving as promoters for human genes have been described by our group and others, and some examples will be presented. While such co-option of LTRs as regulatory gene modules indeed occurs in normal cells, particularly in placenta or in early development, transcriptional activity of most endogenous LTRs is epigenetically suppressed in somatic tissues, likely as a host defense against unregulated transcription. Cancer cells represent an abnormal epigenetic environment where LTRs and other classes of transposable elements (TEs) are often hypomethylated, leading to their transcriptional activation. This activation could result in abnormal, cancer-specific expression of nearby genes. To study this phenomenon, we are analyzing whole transcriptome data of cancers specifically to identify gene deregulation due to transcriptional activity of LTRs or other TEs. Our results suggest that the regulatory potential of these sequences is often used by cancer cells, providing one avenue to up-regulate genes. Thus, while some LTRs/TEs have been co-opted to serve in normal gene expression, the same regulatory qualities can be exploited in carcinogenesis."} +{"text": "Introduction. Chronic pancreatitis (CP) is considered an inflammatory disease that may cause varying degrees of pancreatic dysfunction. Conservative and surgical treatment options are available depending on dysfunction severity. Presentation of Case. A 36-year-old male with history of heavy alcohol consumption and diagnosed CP underwent a duodenal-preserving pancreatic head resection (DPPHR or Beger procedure) after conservative treatment failure. Refractory pain was reported on follow-up three months after surgery and postoperative imaging uncoveredstones within the main pancreatic duct and intestinal dilation. The patient was subsequently subjected to another surgical procedure and intraoperative findings included protein plugs within the main pancreatic duct and pancreaticojejunal anastomosis stricture. A V-shaped enlargement and main pancreatic duct dilation in addition to the reconstruction of the previous pancreaticojejunal anastomosis were performed. The patient recovered with no further postoperative complications in the follow-up at an outpatient clinic. Discussion. Main duct and pancreaticojejunal strictures are an unusual complication of the Beger procedure but were identified intraoperatively as the cause of patient's refractory pain and explained intraductal protein plugs accumulation. Conclusion. Patients that undergo Beger procedures should receive close outpatient clinical follow-up in order to guarantee postoperative conservative treatment success and therefore guarantee an early detection of postoperative complications. Chronic pancreatitis (CP) is a progressive inflammatory disease that may lead to exocrine and endocrine organ dysfunction . An overA 36-year-old male was referred to an outpatient clinic due to constant chronic abdominal pain. The subject had a history of heavy alcohol intake and was diagnosed with CP. Initial conservative treatment included Omeprazole, Pancreatin, nonsteroidal analgesics, and lifestyle modifications that consisted in a fractionated diet and alcohol intake cessation. Despite conservative treatment, symptoms persisted with progressive weight loss and mild steatorrhea was reported. Initial CT scan showed small calcification areas on pancreatic head and sparse calcifications in pancreatic body and tail. Mild enlargement of the pancreatic head and fibrosis without defined focal lesions was also present. Main pancreatic duct (maximum diameter of 1.0\u2009cm) and common bile duct dilation were evidenced (maximum diameter of 1.4\u2009cm). Following a 3-year conservative treatment failure, the patient underwent Beger procedure in January 2014 with no intraoperative complications and consisted in pancreatic head resection with main pancreatic duct stenotic portion responsible for main pancreatic duct dilation. Also, no further signs of intrinsic obstruction were found. The subject developed a biliodigestive anastomosis fistula as a postoperative complication that was conservatively treated and was discharged from the hospital. Three months after the Beger procedure, subject reported new onset epigastric and bilateral hypochondrial abdominal pain but no fever, vomiting, weight loss, or any signs of obstruction . Subsequent laboratory findings excluded the possibility of biliary tract obstruction. A CT scan revealed diffuse thickening of small intestine and suggested inflammation near the residual pancreatic parenchyma. A subsequent MRI evidenceThree surgical approaches have been described so far for chronic pancreatitis: decompression, pancreatic resection, and denervation. Some surgical procedures employ a combination of these approaches. Decompression therapies consist of duodenal-preserving pancreatic head resection (DPPHR) and local resection of the pancreatic head with extended longitudinal pancreaticojejunostomy (LR-LPJ), known as Beger and Frey procedures, respectively. Trials comparing Beger and Frey procedures have shown no statistical difference concerning morbidity, mortality, and pancreatic function, as both ensure gastrointestinal continuity. Frey procedure preserves the posterior capsule of the pancreas and requires pancreaticojejunal anastomosis, while DPPHR requires a pancreaticojejunal and a biliodigestive anastomosis. Therefore, surgical experience should be taken into consideration when electing which technique to perform . ExocrinDuring clinical investigations of refractory pain after Beger procedure, imaging may reveal worsened pancreas parenchymal abnormalities and protein plugs due to defective drainage of a narrowed main pancreatic duct or pancreaticojejunal anastomosis stricture. This case demonstrates an uncommon complication of Beger procedure. Therefore, patients that undergo surgical treatment have to be closely monitored in an outpatient clinic in order to guarantee postoperative conservative treatment and early detection of possible complications related to the initial surgical procedure."} +{"text": "Vestibular migraine (VM) has been increasingly recognized as a possible cause of episodic vertigo, but its pathophysiology is still unclear.We used advanced non-invasive neuroimaging to examine the functional response of neural pathways associated with vestibular stimulation in patients with VM.Twelve patients with VM underwent whole-brain blood oxygen level-dependent (BOLD) fMRI during ear irrigation with cold water. The functional response of neural pathways to this stimulation in patients with VM was compared to age- and gender-matched patients with migraine without aura (MwoA) and healthy controls (HC). Secondary analyses explored associations between BOLD signal change and clinical features of migraine in patients.We observed a robust cortical and subcortical pattern of BOLD signal change in response to ear irrigation across all participants. Patients with VM showed significantly increased thalamic activation in comparison with both patients with MwoA and HC. The magnitude of thalamic activation was positively correlated with the frequency of migraine attacks in patients with VM.We provide novel evidence for abnormal thalamic functional response to vestibular stimulation in patients with VM. These functional abnormalities in central vestibular processing may contribute to VM pathophysiology.No conflict of interest."} +{"text": "Periodontitis is an established common chronic disease, yet its burden on health care costs remains largely neglected. The aim of this study was to estimate the cost of periodontal procedures in dental specialist clinics in the Malaysian public sector.Five periodontal specialist clinics in the Ministry of Health were randomly selected. A list of periodontal procedures was identified by an expert group. Procedures were classified as diagnostics, non-surgical periodontics and periodontal surgeries. Costing for each procedure was primarily activity-based to measure cost of dental equipment, consumables and labour cost (average treatment time). Expenditures for administration, utilities and maintenance at clinics used unit cost calculations employed from step-down approach. A total of 165 patients newly diagnosed with periodontitis were followed up for one year to determine the cost of managing these patients during the said period.A total examination package costed USD38, but separate diagnostics procedures such as full-mouth periodontal assessment, electric pulp test, intraoral and panoramic radiographs costed an average of USD23. For nonsurgical procedures, full-mouth supragingival scaling costed USD68 and full-mouth subgingival debridement costed USD135, higher if with systemic/ local delivery antibiotics. Costs for desensitisation, occlusal adjustments (with selective grinding) and splinting were USD41, USD42 and USD50, respectively. Surgical procedures cost an average of USD294 for resective surgeries and USD613 for regenerative surgeries. The total provider costs for managing periodontitis patients for one year was estimated to be USD805. The costs borne for patients requiring surgeries was about three-fold compared to those who required only nonsurgical periodontal treatment (USD540).Specialist dental treatment for periodontitis patients in the public sector is costly. Cost estimates obtained from this study are useful for estimating economic burden of specialist periodontitis management at the national level, as well as providing the basis for economic evaluation of the specialist periodontal care programme."} +{"text": "WGS) and Next Generation Sequencing (here: NGS-CA) approaches were witnessed in the past few years, since cataloging or landscaping all possible cancer aberrations appears to be both scientifically relevant and useful for therapeutic strategies. This search has been performed through Medline using NGS with appropriate cancer types/subtypes definitions and paying particular attention to the major overviews from groups on both sides of the Atlantic . The scope here is to overview general pitfalls and perspectives in the whole area of NGS-CA studies and to suggest probable trends and prudent recommendations.Great increase in Whole Genome Sequencing (elstein: and 2]))WGS) andWGS-NGS studies have been published so far on neuroblastoma or other pediatric tumors is stCAN-GEN approach ) demo) demoint pursued ."} +{"text": "A 73-year-old lady sustained mutliple injuries including pelvic fractures and extensive soft tissue injuries to her left groin and thigh after being run over by a car and trailer. Closed internal degloving injury of the left thigh was diagnosed and required surgical management.How should this patient be managed initially?What is a Morel-Lavallee lesion?Describe the pathophysiology of this injury?How is this injury managed surgically?The patient was transferred to a major trauma hospital with injuries to her left arm, trunk, groin, and leg for assessment and management. Initial management followed the Advanced Trauma Life Support principles. On arrival to the emergency department, her airway was patent, breathing spontaneously, with a heart rate of 70, blood pressure of 100/60, and Glasgow Coma Scale of 15. Examination revealed multiple soft tissue and skeletal injuries. Initial investigations showed Hb 90, unremarkable chest X-ray with plain trauma films demonstrating comminuted left superior and inferior pubic rami fractures and left wrist fractures. Computed tomographic scan showed the pelvic fractures and subcutaneous emphysema involving the left anterior thigh and anterior abdominal wall due to extensive thigh degloving injury.The lady sustained significant soft tissue injury and pelvic trauma from a low-velocity motor vehicle accident. On examination, she had extensive contusions and abrasions to the left proximal thigh extending to groin and posteriorly to the buttock, as well as a perineal hematoma. Closed internal degloving injury is caused by blunt injury producing significant soft tissue injury that is associated with pelvic trauma. A Morel-Lavallee lesion is a closed internal degloving injury overlying the greater trochanter.1The injury occurs when the subcutaneous tissue is sheared from the underlying fascia with avulsion of the perforating vessels. The cavity is filled with hematoma and liquefied adipose tissue. The force exerted on the superficial soft tissue also disrupts the vascular supply to the skin. This can also cause abrasions or friction burns.The patient underwent exploration and washout in theater with 1.7 L of haemoserous fluid drained initially from the cavity. Thorough debridement of devascularized tissue is the mainstay of surgical management of internal degloving injuries. Often multiple debridement procedures are required to excise nonviable tissue, with vacuum-assisted closure useful for temporary coverage. (3) In some instances, the patient's condition may dictate a delay to complete debridement. Similarly, extensive open avulsion type soft tissue injuries require staged debridement. (2) Expanding hematoma in the zone of injury may further jeopardize the overlying tissue and requires immediate drainage, either percutaneously or open. (4) Delayed closure of skin flaps and/or split-thickness skin graft are used to repair the defect after adequate debridement. Undamaged but avascular skin can be reapplied to the debrided surface as a full-thickness skin graft after excising the subcutaneous fat. (2) The patient was stabilized in intensive care unit, and the left thigh skin was allowed to demarcate and then debridement and application of negative pressure dressing (vacuum-assisted closure) was performed. She required multiple procedures for further washouts and change of dressings. The defect was reconstructed with split-thickness skin graft and skin flap repair with sutures and autologous platelet enriched/bovine thrombin glue.Closed internal degloving injuries require prompt surgical assessment. Patient factors including severity of skeletal injuries direct the surgical management of the associated soft tissue injury but debridement and delayed repair remains the mainstay of treatment."} +{"text": "Ranitomeya variabilis. This species deposits its tadpoles and egg clutches in phytotelmata and chemically recognizes and avoids sites with both predatory conspecific and non-predatory heterospecific tadpoles . Combining chemical analyses with in-situ bioassays, we identified the molecular formulas of the chemical compounds triggering this behavior. We found that both species produce distinct chemical compound combinations, suggesting two separate communication systems. Bringing these results into an ecological context, we classify the conspecific R. variabilis compounds as chemical cues, advantageous only to the receivers (the adult frogs), not the emitters (the tadpoles). The heterospecific compounds, however, are suggested to be chemical signals , being advantageous to the emitters (the heterospecific tadpoles) and likely also to the receivers (the adult frogs). Due to these assumed receiver benefits, the heterospecific compounds are possibly synomones which are advantageous to both emitter and receiver \u2012 a very rare communication system between animal species, especially vertebrates.The evolution of chemical communication and the discrimination between evolved functions and unintentional releases (cues) are among the most challenging issues in chemical ecology. The accurate classification of inter- or intraspecific chemical communication is often puzzling. Here we report on two different communication systems triggering the same parental care behavior in the poison frog Communication in the biological sense is defined by Wilson as the aRanitomeya variabilis )S1 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file."} +{"text": "One of the most critical shifts must be away from top-down mercury policy toward active engagement with ASGM communities to effectively address the underlying social and economic reasons why mercury is used. Notably, Annex C of the Convention requiresStrategies should reflect lessons learned in past programs about the mining policies required for mercury reduction solutions to take hold in ASGM communities. The United Nations Industrial Development Organization (UNIDO) conducted mercury abatement programs in ASGM that yielded some positive results , includiTo convey messages about mercury risks and mercury-free alternatives, community-based approaches can be more effective than conventional technical strategies that have dominated mercury-reduction initiatives. In Zimbabwe, UNIDO mercury abatement campaigns had some promising results in promoting cleaner technologies using such alternative approaches . In KadoFinally, public health officials and others should ensure that ambitious mercury reduction targets are not used as a rationale for harshly policing impoverished mining communities. The government of Zimbabwe implemented heavy-handed police crackdowns on ASGM between 2006 and 2009, which had negative environmental and social repercussions, weakening trust between regulators and low-income mining communities . More thThe challenges of reducing mercury use in ASGM have long been documented, as noted previously . We stro"} +{"text": "Controversy exists regarding the structural and functional causes of hallux limitus including metatarsus primus elevatus, long first metatarsal, first ray hypermobility, shape of the first metatarsal head and the presence of hallux interphalangeus. Papers have reported on the radiographic evaluation of these measurements in feet affected by hallux limitus, however no study to date has made direct comparisons between the affected and unaffected foot in a group of patients with unilateral hallux limitus. This case-control pilot study aimed to establish if any such differences existed.Dorsoplantar and lateral weightbearing x-rays of both feet in 30 patients with unilateral hallux limitus were assessed for grade of disease, lateral intermetatarsal angle, metatarsal protrusion distance, plantar gapping at the first metatarso-cuneiform joint, metatarsal head shape and hallux abductus interphalangeus angle. Data analysis was performed using SPSS version 22.0.0.0 .Mean radiographic measurements for both affected and unaffected feet demonstrated that metatarsus primus elevatus, a short first metatarsal, first ray hypermobility, a flat metatarsal head shape and hallux interphalangeus were prevalent in both feet. There was no statistically significant difference found between feet for any of the radiographic parameters measured .No significant differences exist in the presence of structural risk factors examined between the affected and unaffected foot in patients with unilateral hallux limitus. The influence of other intrinsic factors including footedness and family history should be investigated further."} +{"text": "Hypertrophic cardiomyopathy is a common cardiovascular genetic disease characterized by sarcomeric gene mutations which lead to findings of cardiac hypertrophy, myocyte disarray, and fibrosis. While late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) detects focal, macroscopic regions of replacement fibrosis non-invasively, novel T1 CMR measurement techniques including extracellular volume fraction (ECV) diffuse interstitial fibrosis throughout the myocardium. Plasma B-type natriuretic peptide levels are often elevated in situations of increased wall tension and volume overload. Given that such states may be associated with myocardial fibrosis, and because BNP levels provide independent prognostic insight in HCM, we sought to determine the association between BNP and ECV measurement by CMR.We recruited 50 consecutive patients referred to the UPMC Hypertrophic Cardiomyopathy Center and UPMC Cardiovascular Magnetic Resonance Center for clinical evaluation to participate in a prospective cohort formed to describe the association between CMR data and outcomes. Contemporaneous echocardiography, treadmill stress echocardiography, and clinical evaluation data were recorded. BNP levels were obtained as part of routine clinical care or drawn the same day as CMR study using research funding. We computed ECV from measures of pre and post contrast T1 of mid-myocardium and blood (short axis prescriptions at the base and mid ventricle) using modified Look-Locker inversion recovery (MOLLI) pulse sequences. BNP levels were natural log transformed given their skewed distribution. Univariable and multivariable regression models tested for associations between markers of cardiac remodeling as well as other predictors of BNP , left ventricular outflow obstruction, body mass index(BMI), findings of late gadolinium enhancement, ECV). Models were constrained to 4 independent variables to avoid overfitting.There was a moderate correlation between lnBNP and ECV (Figure We found a novel association between lnBNP and ECV by CMR, after adjustment for confounding variables. The relationship persisted even after including LGE in regression models and stratifying by its presence. BNP and ECV are both strong predictors of adverse events. Detection of diffuse interstitial fibrosis by ECV may be a meaningful imaging biomarker to characterize HCM status, progression, and outcomes and warrants further study.American Heart Association, Pittsburgh Foundation."} +{"text": "Saccadic eye movements are made about twice a second to shift our gaze either consciously or unconsciously. Brainstem burst neurons trigger each saccade with a bursting activity closely related to saccadic velocity that must be transformed into persistent firing activity to maintain post-saccadic eye position. A conceptual neural mechanism achieving this velocity to position integration is the oculomotor neural integrator (NI). Neurons in the nucleus of prepositus hypoglossi (NPH) in mammals and equivalently Area I (AI) in goldfish have been demonstrated to exhibit persistent activity relating to eye position. Ipsilateral positive feedback found in NPH and AI , and comThe model consists of an excitatory burst neuron (EBN), an inhibitory burst neuron (IBN), a tonic neuron (TN), and a bilateral NI network in which 15 integrator neurons (INs) are included unilaterally. Each IN receives input from TN, EBN, and IBN, and also has positive recurrent feedback connections from all ipsilateral INs including commissural inhibitory connections from all contralateral INs. The output of EBN, IBN, and each NI are weighted-summed at a motor neuron whose output is sent to an eye plant model to simulate eye movements. These neuron models are described as conductance-based spiking neurons. Synaptic weights in the model were carefully tuned to reproduce saccades and post-saccadic stable eye positions. Following individual modification of either the synaptic weights of ipsilateral feedback connection or those of commissural inhibition we measured post-saccadic eye position drift.Simulation results showed that persistent firing activity of INs is maintained principally by the ipsilateral positive feedback. By contrast, commissural inhibition contributed mainly to null eye position which is the asymptote from which the NI becomes leaky. These findings are the first demonstration by a NI neuronal network model assigning specific and different roles to the ipsilateral positive feedback and the commissural inhibition. In future work, we will use this model to evaluate the elective eye holding properties within the two hemi-field NIs."} +{"text": "Parkinson\u2019s disease (PD) is one of the most common movement disorders in adults, often cannot be adequately controlled with medical treatment, and thereby treated with the neurosurgical procedures. Unilateral pallidotomy, making a lesion in the globus pallidus pars interna (GPi), was the predominant surgical technique until early 1900s. Thereafter, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a mainstream surgical technique for managing not only the cardinal dopaminergic features of PD, but also levodopa-induced motor fluctuations and dyskinesia.Recent review studies, however, reported that unilateral pallidotomy also has long-term effect on both cardinal symptoms and motor complications . Currently, transcranial magnetic resonance guided focused ultrasound (MRgFUS), without necessity of opening the cranium, has been developed as a minimal invasive surgical technique, generating precise and focal thermal lesion in the brain compared to previous radiofrequency thermal lesion.The authors underwent world first MRgFUS pallidotomy to confirm its efficacy as well as potential side effects. We hereby demonstrated the beneficial effects of MRgFUS pallidotomy in PD patient for improving levodopa induced dyskinesia as well as motor symptoms."} +{"text": "Volition is generally considered as a defining human faculty; but the outcome of a voluntary decision can be predicted by brain activity even before subject\u2019s conscious awareness , and simGymnotus sp. revealed a bimodal distribution of electric organ discharge rate (EODR) demonstrating Down- and Up-states of sensory sampling and neural activity; movements only occurred during Up-states and Up-states were initiated before movement-onset. EODR during voluntary swimming initiation exhibited greater trial-to-trial variability than the sound-evoked increases in EODR. The sensory sampling variability increased before, and declined after voluntary movement onset as previously observed for the neural variability associated with decision-making in primates [Cortical activity precedes self-initiated movements by several seconds in mammals; this observation has led into inquiries on the nature of volition . Preparaprimates . In contprimates . SpontanUsing statistical analyses of spontaneous exploratory behaviors and associated preparatory sensory sampling increase, we conclude that electric fish exhibit all the established hallmarks of volition, and that voluntary behaviors in vertebrates may generally be preceded by increased sensory sampling. The dorsal telencephalon is required for spatial learning in teleosts and might initiate movement via its projections to the tectum . Our res"} +{"text": "Subarachnoid hemorrhage may be complicated by neurogenic stunned myocardium, a catecholamine-induced transient cardiomyopathy that displays a wide clinical spectrum of cardiac abnormalities, including electrocardiographic changes, arrhythmias, myocardial necrosis, and left ventricular systolic and diastolic dysfunction. However, less is known about the cardiac metabolic consequences of acute subarachnoid hemorrhage. Prunet and coworkers\u2019 recent study provides scintigraphic evidence suggesting that glucose metabolism and sympathetic cardiac innervation are severely and globally depressed during the acute phase of the disease. Metabolic and innervation abnormalities are largely overlapped and are probably not causally related to myocardial ischemia, suggesting that impaired glucose metabolism is probably neurogenic in nature. The scintigraphic defects seem to reverse slowly, within months of the onset of cerebral bleeding. Interestingly, scintigraphic evidence of metabolic myocardial alterations may exist even in the absence of clinical features of cardiac disease, possibly representing a subclinical type of neurogenic stunned myocardium. Critical Care deals with this poorly studied area [Subarachnoid hemorrhage (SAH) may cause transient cardiac dysfunction, possibly attributed to massive release of catecholamines. The influence of catecholamine oversecretion on cardiac metabolism has been extensively studied in Takotsubo cardiomyopathy (TTC), which is also considered catecholamine induced in nature. However, data regarding acute myocardial metabolic alterations in SAH are sparse. The recent article by Prunet and colleagues in ied area .18\u2009F-fluorodesoxyglucose positron emission tomography) and sympathetic innervation (studied by 123I-meta-iodobenzylguanidine scintigraphy) in 83.3% (25/30) and 90% (27/30), respectively, of 30 patients with acute SAH. Despite extensive changes in glucose metabolism and innervation, coronary perfusion was not affected. The topography and extent of metabolic and innervation scintigraphic defects were largely overlapped, supporting the hypothesis that metabolic shifts occurred secondarily to neurocardiogenic injury rather than cardiac ischemia [123I-meta-iodobenzylguanidine scintigraphy 6\u00a0months later [In their recent article, Prunet and coworkers assessed myocardial glucose metabolism and sympathetic innervation in SAH by means of scintigraphy, and investigated the possible associations with left ventricular (LV) systolic and diastolic dysfunction, troponin elevation and SAH outcomes . The autSAH-induced neurocardiogenic injury demonstrates comparable scintigraphic features ,5 with TAlthough increased adrenergic tone has been accounted for in both SAH and TTC , there mWhat is remarkable in the study by Prunet and colleagues is not the detection of neurometabolic myocardial alterations in SAH \u2013 such changes might probably be expected, since similar findings have been described in TTC. No, what is remarkable is that regional scintigraphic defects may widely exist within myocardium of SAH patients without clinical, echocardiographic or laboratory evidence of neurogenic stunned myocardium (NSM). The term NSM has been introduced to describe myocardial injury and dysfunction occurring after diverse types of acute brain injury (including SAH) as a result of imbalance of the autonomic nervous system . The diaOne should point out that the presence of neurometabolic cardiac abnormalities showed no association with clinical outcomes in Prunet and colleagues\u2019 study . HoweverIn conclusion, the study by Prunet and colleagues underlines two different aspects in SAH. First, alterations in glucose metabolism, possibly neurogenic in origin, may affect widely the myocardium during the acute phase of SAH. Second, and more important, the study emphasizes that prolonged and slowly reversible neurometabolic abnormalities may globally occur in SAH even when conventional cardiac evaluation is negative for NSM. The clinical impact of such neurometabolic shifts may be greatly underestimated, as they are difficult to diagnose in the clinical practice. Additional research, including also hemodynamically unstable patients with depressed LV function, is necessary to clarify further the role of neurometabolic cardiac alterations in acute SAH."} +{"text": "Diagnostic assays that leverage bloodborne neuron-derived nanoscale extracellular vesicles (nsEVs) as \u201cwindows into the brain\u201d can predict incidence of Alzheimer's Disease (AD) many years prior to onset. Beyond diagnostics, bloodborne neuronal nsEVs analysis may have substantial translational impact by revealing mechanisms of AD pathology; such knowledge could enlighten new drug targets and lead to new therapeutic approaches. The potential to establish three-dimensional nsEV analysis methods that characterize highly purified bloodborne nsEV populations in method of enrichment, cell type origin, and protein or RNA abundance dimensions could bring this promise to bear by yielding nsEV \u201comics\u201d datasets that uncover new AD biomarkers and enable AD therapeutic development. In this review we provide a survey of both the current status of and new developments on the horizon in the field of neuronal nsEV analysis. This survey is supplemented by a discussion of the potential to translate such neuronal nsEV analyses to AD clinical diagnostic applications and drug development. Bloodborne neuron-derived nanoscale extracellular vesicles (nsEVs) have shown substantial potential as \u201cwindows into the brain\u201d that enlighten central nervous system (CNS) disorder-associated changes in brain biochemistry and intercellular communication \u20137. This There are no universally accepted criteria for classifying nsEVs. This lack of standard taxonomy creates ambiguity in interpreting and communicating the results of nsEV-related experiments. Our simple classification system defines nsEVs as cell-derived vesicles with submicron diameters and groups them into two categories: exosomes and ectosomes.Exosomes are manufactured within multivesicular bodies (MVBs), cytoplasmic vesicles that have diameters in the 250\u20131,000\u2009nm range , 9, and Others have categorized ectosomes into a number of somewhat ambiguous subclasses: shedding vesicles, microvesicles, exosome-like vesicles, nanoparticles, microparticles, and oncosomes . AlthougnsEVs with diameters between 100\u2009nm and 200\u2009nm can be either exosomes or ectosomes; the vesicle category into which a given nsEV would be classified would be determined by whether the nsEV is formed within a MVB or budded off from the cell plasma membrane. The preceding sentence is framed in a hypothetical sense because, as suggested by the above remarks regarding tetraspanins being common to both exosomes and ectosomes, there are no existing analytical methods that allow one to determine whether a given nsEV isolated from blood was formed inside of a MVB or is instead the product of budding from the plasma membrane.nsEVs encapsulate nucleic acids, primarily microRNAs (miRNAs) and messenger RNAs (mRNAs). nsEVs also feature integral membrane proteins, proteins covalently bound to nsEV membranes, proteins noncovalently associated with nsEV membranes, and proteins that occupy nsEV interior volumes. nsEVs' principal function is transferring signals from sender to recipient cells. nsEVs originating from sender cells can fuse with membranes of and release their contents into the cytoplasm of recipient cells or have Given the desire to leverage bloodborne nsEV analysis in enlightening AD-associated changes and brain biochemistry and intercellular signaling processes, we note here that neuronal nsEVs have been observed to migrate from the CNS into the bloodstream in animal experiments . The exiThe predictive ability of bloodborne neuronal nsEV analysis illustrated by the biomarker validation studies of Goetzl and coworkers, which accurately forecasted AD onset up to ten years prior to clinical diagnosis \u20134, has gThe first step in Goetzl's nsEV AD biomarker quantification process was chemical precipitation (CP) to isolate nsEVs from plasma. After nsEV precipitation, neuronal nsEVs were enriched from the bulk nsEV population using streptavidin-coated agarose beads loaded with biotinylated anti-neuronal marker protein (CD171) Abs. Finally, nsEVs were exposed to lysing conditions and biomarker proteins in nsEV lysates were quantified by ELISA. The Cartesian coordinate system of As illustrated in The third nsEV analysis dimension, biomarker abundance, differs from the other two dimensions in that biomarker abundance, and thus position on the biomarker abundance axis, is dictated by nsEV composition. The researcher chooses which biomarker(s) to quantify and thus defines biomarker abundance axis label(s). As discussed in The underexplored opportunity in the area of leveraging bloodborne neuronal nsEV omics profiling in AD biomarker discovery for drug molecule and therapeutic modality development is well framed by discussing existing neuronal nsEV AD biomarker validation and discovery-related literature; the latter is particularly relevant to utilizing neuronal nsEV analysis in identification of novel drug targets and establishment of new treatment paradigms. In this discussion we define nsEV biomarkers as protein or nucleic acid nsEV constituents with abundances that differ in diseased relative to normal subjects. This definition encompasses nsEV-associated molecules with relative abundances that change prior to clinical manifestation of disease symptoms and thus can be predictive of disease onset as well as molecules with abundances that change as functions of disease progression or reversion due to positive treatment responses.\u03b242) experiments featuring nanogold-conjugated Ab labeling of respeThere are several technical considerations that are important for generating nsEV omics datasets that would enable 3D nsEV analysis such as depicted in Obtaining neuronal nsEV omics datasets using methods described above will provide omics analyses with even greater translational potential. Next generation analyses could be enabled by advances in two emerging areas: microfluidic devices that sort bloodborne neuronal nsEV subpopulations directly from plasma based on abundances of multiple nsEV surface markers and engineered Abs or aptamers that bind epitopes exclusive to AD neuronal nsEV exteriors.6-fold lower than cell volumes, to flow cytometric sorting of individual nsEVs. First, nsEV flow rate must be rigorously controlled to prevent \u201cswarming,\u201d a phenomenon causing groups of nsEVs to be detected as single fluorescence events and leading to encapsulation of multiple nsEVs within sorted fluid droplets [There are two primary obstacles, which arise from nsEV volumes being 10droplets . Second,droplets . The utiFurther development of existing nonstandard flow cytometers could allow swarming and autofluorescence issues to be overcome. Regarding swarming, Pulse Laser Activated Cell Sorter (PLACS) microfluidics devices achieve Proteins with posttranslational modifications such as glycation, glycosylation, and nitration \u201337 can gAntigen-loaded Dynabeads are routinely used for probe library screening . As suchMulticolor nsEV cytometry with various combinations of AD nsEV-specific probes and/or commercial Abs against AD nsEV biomarker surface proteins identified by proteomic profiling can address the important question of whether the overall bloodborne neuronal nsEV population is comprised of distinct subpopulations featuring different combinations of AD-specific surface proteins and/or epitopes. Sorting nsEV subpopulations would facilitate downstream omics and/or individual AD biomarker analyses that may enlighten both cell-to-cell heterogeneity of AD-associated changes in neuronal molecular composition and the existence of neuronal nsEVs that carry distinct groups of signaling molecules. Knowledge of such heterogeneity and distinct modes of intercellular communication could enlighten the interplay among different mechanisms of AD pathology and thus be a valuable facilitator of AD drug target identification and therapeutic development.With respect to forthcoming developments in the area of neuronal nsEV diagnostics hardware for clinical applications, recent progress in miniaturizing complex laboratory operations suggests that the future may prove to hold substantial advances in terms of constructing portable devices for point-of-care quantification of neuronal nsEV biomarkers. Regarding the specifics of this recent progress, protein microarray-based multiplex fluorescent ELISA assays and accuAdvances in neuronal nsEV isolation and analysis methods that leverage neuronal nsEVs could provide \u201cwindows into the brain\u201d using noninvasive diagnostic assays, requiring only microliters of blood obtained during routine doctor's office visits, which quantify Alzheimer's Disease (AD) biomarker proteins in nsEVs. Such assays could enable rapid diagnosis for CNS disorders and facilitate the development of personalized treatment programs. Continued increases in public and private funding for nsEV-focused research should enable realization of this goal in a timely manner and hasten the development of next generation nsEV analyses that provide a more accurate analysis of AD biomarkers in plasma. Although it will take time, as has been the case for the human genome sequence, to translate omics-derived AD biomarker discoveries from bench-to-bedside, it is clear that the ever-increasing convergence of biomedical research will augment the relative rate of translation. As such, it is anticipated that we are only years, rather than decades, away from seeing drugs and/or therapeutic modalities inspired by 3D bloodborne neuronal nsEV analyses have a clinical impact in treating this devastating disease."} +{"text": "ReGeneraTing Agents (RGTAs) are a family of polymers bioengineered to stabilise heparin-binding growth factors by mimicking HeparanSulphate (HS) thereby protecting them and promoting tissue repair and regeneration. In inflammation, destruction of HS exposes the ExtraCellularMatrix \u2013 ECM to the actions of proteases and glycanases which break them down and also act on cytokines and growth factors to prevent adequate repair. In injured tissue, RGTAs would replace destroyed HS by binding to the structural proteins and reconstruct the ECM scaffold. Growth factors will also bind to RGTA and resume position and organization resembling that of non-injured tissue. Hence RGTAs showed they induce a regeneration process by restoring -the proper cellular micro-environment. More recently a RGTA named CACIPLIQ20 was adapted to skin lesions and has shown efficacy in various trials of non-healing leg ulcers.In this pilot prospective study, we applied the same RGTA with meticulous wound care techniques practiced on 10 patients with wounds of varying sizes (average of 13cm\u00b2) and depth but with the same underlying theme of poor vascularity and using the recommended sterile application technique twice a week until the wounds healed or over-granulation occurred.All wounds eventually healed, even chronic ones. We found that granulation tissue grew again where there was dead skin and no visible underlying blood supply which in usual circumstances would have resulted in loss of limb length,dry gangrene or at best healing by severe scarring. Exposed tendons were also covered with granulation tissue, but instead of a scarred non-mobile digit, simultaneous therapy resulted in a fair range of motion. Full thickness palmar and dorsal wounds also granulated and the dorsal wound healed beautifully reproducing a flexible movable dorsal surface not seen in granulating, scarred healing.The revascularisation, development of non-adherent coverage reproducing normal skin features and mobility preserved overlying tendons all suggest that RGTA is a promising alternative treatment."} +{"text": "Only scarce data is available on early infection by human T-lymphotropic virus (HTLV). In particular, the modes of clonal selection during primary infection cannot be analyzed due to the paucity of available samples. Therefore, we addressed this question in a closely related animal model, bovine leukemia virus (BLV). As HTLV, BLV persist indefinitely into its host and is generally asymptomatic but can also lead to lymphoma or leukemia. Both viruses replicate by colonizing new lymphocytes or via clonal proliferation of infected cells. However, the modes of replication occurring soon after infection of new hosts are currently unknown. We used high-throughput sequencing to map and quantify the insertion sites of the provirus in order to monitor the clonality of the BLV-infected B-cell population (i.e. the number of distinct clones and abundance of each clone). We found that BLV propagation shifts from cell neoinfection to clonal proliferation in less than 3 months post-inoculation. Initially, BLV proviral integration significantly favors transcribed regions of the genome. Negative selection then eliminates more than 96% of the clones detected at seroconversion and disfavoring BLV-infected B-cells carrying a provirus located close to a promoter or a gene. This selection is more stringent in animals where proviral load set point is low. Among the surviving proviruses, clone abundance nevertheless positively correlates with proximity to a transcribed unit or a CpG island. We conclude that massive clone selection occurs during primary infection disfavoring proviruses located nearby genes and this selection is stronger in low proviral load animals."} +{"text": "A 49-year-old man with intermittent headaches and right sided parietal lump was found to have an intraosseous right parietal lesion on computed tomography (CT) and magnetic resonance imaging (MRI). A stereotactic craniectomy and excision of the lesion were performed with histopathology confirming features consistent with primary lipomatous meningioma with intraosseous extension. Lipomatous meningiomas are very uncommon subtype of meningiomas, with ongoing discussions as to their true pathogenesis. To our knowledge this case represents the first reported case of a lipomatous meningioma with predominant intraosseous extension. A 49-year-old Caucasian male who works as a joiner presented with intermittent headaches and a progressively increasing right sided parietal lump. He denied any history of trauma or infective process and past medical history was unremarkable. The physical examination was normal apart from a palpable nonfluctuating, nontender mass overlying the right parietal region.Skull X-ray, CT brain, and MRI brain revealed a single solitary lytic lesion within the right parietal bone with immense thinning of the outer table and erosion through the inner table without intracranial extension , althougThe patient underwent a stereotactic craniectomy of the right parietal lesion. A wide craniotomy was performed and upon elevation of the bone flap a small defect in the dura was present with what appeared to be an arachnoid granulation, consistent with the observations on the MRI. A pale white, well-delineated tumour could be seen eroding through the bone. A dural resection was performed around a small attached tan coloured tumour and the brain was inspected with no evidence of tumour involvement. Ensuring clear margins, duraplasty and cranioplasty were performed.Histology of the skull flap revealed cyst-like spaces surrounded by meningioma with foci showing typical meningothelial morphology interspersed with areas composed of cells showing variable vacuolation Figures . Area ofLipomatous meningiomas are rare subtypes of meningiomas. First described by Bailey and Bucy in 1931 . The WHOMetaplastic lipomatous meningiomas can be defined as meningiomas with striking focal or widespread mesenchymal areas, including osseous, cartilaginous, lipomatous, myxoid, or xanthomatous tissue components . LipomatThroughout the English literature 41 cases of lipomatous meningiomas have been described , one ass"} +{"text": "This clinical trial is testing whether drugs that inhibit pain processing pathways in the brain can help with pain in the hand caused by osteoarthritis. Other clinical studies include the \u2018Pain Perception in Osteoarthritis\u2019, or PAPO study, investigating tissue damage and pain in people undergoing knee replacement surgery for osteoarthritis. Both studies are on the UK NIHR portfolio of network-adopted studies.The Sofat laboratory currently investigates the mechanisms responsible for pain and tissue damage in arthritis. Clinical studies include \u2018Pain management in osteoarthritis using centrally acting analgesics\u2019 to decipher regions of damage in affected joints and evaluating which brain regions are activated by arthritis pain. We also use non-invasive quantitative sensory testing (QST) methods to identify pain pathways. QST identifies sensation and pain thresholds by stimulating the skin.Our laboratory research uses a basic science mechanistic approach to investigate the influence of endogenous damage-associated molecular patterns (DAMPs) in driving chronic inflammation in joints. Molecules of interest include interaction of the DAMPs tenascin-C and fibronectin with oral pathogens."} +{"text": "Chest compression during cardiopulmonary resuscitation (CPR) could bring out unintended complications which are mainly composed of chest injuries. The aim of this study was to assess whether there was a significant difference in the complications of CPR between out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) survivors using multidetector computed tomography (MDCT).We performed a retrospective cohort study in the emergency departments of two academic tertiary care centres from January 2009 to May 2014. We enrolled both OHCA and IHCA patients who underwent successful CPR. The enrolled patients had undergone a chest CT within 48 hours after ROSC. We evaluated the MDCT findings of the CPR-related chest injuries and compared complications between OHCA and IHCA patients.[AQ1]A total of 148 patients were finally enrolled in this study, OHCA were 89 (60.1%) and IHCA were 59 (39.8%). The mean CPR time, both in-hospital and total, was longer in OHCA survivors. Rib fractures were detected more in OHCA survivors. Frequency of multiple rib fractures was higher in OHCA survivors. Frequency of sternum fractures was higher in OHCA survivors, showing no significant difference. In lung injuries, lung contusion and pneumothorax account for the large part, and OHCA survivors had higher incidence in both complications but statistically insignificant. Major complications occurred in eight cases in OHCA survivors and three cases in IHCA survivors during the study period. After adjusting for the time factor in multiple logistic regression analysis, rib fractures and multiple rib fractures became statistically significant in OHCA survivors. See Figures Frequency of rib fractures and multiple rib fractures were higher in OHCA survivors. Further investigation is needed into the relation between the location of CPR and the CPR-related injuries, efforts to reduce the complications after CPR."} +{"text": "Boechera stricta (rockcress), a close perennial relative of model plant Arabidopsis. First, using Bayesian kriging, we mapped the topography and environmental gradients and explored the spatial distribution of naturally occurring rockcress plants and two neighbors, Taraxacum officinale (dandelion) and Solidago missouriensis (goldenrod) found in close proximity within a typical diverse meadow community across topographic and environmental gradients. We then evaluated direct and indirect relationships among variables using Mantel path analysis and developed a network displaying abiotic and biotic interactions in this community. We found significant spatial autocorrelation among rockcress individuals, either because of common microhabitats as displayed by high density of individuals at lower elevation and high soil moisture area, or limited dispersal as shown by significant spatial autocorrelation of naturally occurring inbred lines, or a combination of both. Goldenrod and dandelion density around rockcress does not show any direct relationship with rockcress fecundity, possibly due to spatial segregation of resources. However, dandelion density around rockcress shows an indirect negative influence on rockcress fecundity via herbivory, indicating interspecific competition. Overall, we suggest that common microhabitat preference and limited dispersal are the main drivers for spatial distribution. However, intra-specific interactions and insect herbivory are the main drivers of rockcress performance in the meadow community.This study investigates the relative influence of biotic and abiotic factors on community dynamics using an integrated approach and highlights the influence of space on genotypic and phenotypic traits in plant community structure. We examined the relative influence of topography, environment, spatial distance, and intra- and interspecific interactions on spatial distribution and performance of Boechera stricta (rockcress), an emerging ecological model plant species . Second, we determined the spatial structure of environmental and intra- and interspecific variables (see Methods for detailed description of these variables) using piecewise Mantel correlograms , aspen (Populus tremuloides), birch (Betula spp.), and burr oak (Quercus macrocarpa). Other common plant species that inhabited the meadow were goldenrod (Solidago missouriensis), dandelion , mouse-ear chickweed (Cerastium vulgatum), snowberry , and sedge (Carex spp.). The relief between the highest and the lowest measured point across the study area was 9.55 m.We studied spatial distribution and performance of rockcress grid. Please refer to Appendix for exact intervals for individual parameters. Flat priors and reproduction , and line] of rockcress, density of neighboring plants (goldenrod density and dandelion density), and herbivory on rockcress leaves . Data were standardized before calculating Euclidean distances of the individual bins of lag distance at every 2.5 m in the correlograms. A pairwise correlation between all the variables was determined using simple Mantel test that guided the path analysis.A correlogram in this context is a plot of the spatial autocorrelation with lag distance, and the Mantel test can be used to test the significance of the correlations. A simple Mantel test Mantel, was perfa priori hypothesis that A effects B and B effects C, the partial Mantel test can be used to test if C effects A in the absence of B, C~ A|B. If A and/or C displayed significant spatial autocorrelation then space was added as an additional partial, C~A|Space + B, in the partial Mantel test on underlying ecological processes by looking at the relationship between two variables and keeping all other variables constant. For example, given the P = 0.05, Figure P \u2264 0.05) spatial autocorrelation among rockcress individuals as well as a positive relationship between soil moisture and rockcress Figure . The rel) Figure . Vapor p) Figure and no i) Figure but thisrosette diameter), reproduction , and line were significantly spatially autocorrelated to 20.8 m (rosette diameter). Genetically similar individuals were found in close proximity of one another spatial autocorrelation around rockcress was positively correlated with rosette herbivory was negatively correlated with fruit production (fruit number) spatial autocorrelation in neighboring densities of goldenrod (range = 12.6 m) and dandelion (range = 12.6 m) was the lowest among intra-specific traits that indicates greater intra-specific diversity of rockcress plants within short distances. Inter-specific interactions showed some indirect influence on rockcress distribution mediated through increased herbivory than did performance or fitness measures (8\u201320 m) and landscape attributes , indicating that clustering of similar sized plants had both genetic and micro-environmental influences. To date, local adaptation in rockcress for defensive traits has been documented on a broad geographic scale of rockcress is usually found in other mountain ranges (about 2500 m) . Probably as a consequence of lower and drier habitats in the Black Hills, we find rockcress on N-facing slopes and in shaded areas. Recent genotyping studies indicate that rockcress in the Black Hills probably originated from lower latitudes in the southern Rockies are much lower than elevations where this species that flea beetles tend to attract one another. It should be noted that we did not detect a significant correlation between line and herbivory, despite the detection of significant genetic variation from common garden experiments among these lines in resistance and glucosinolate toxin production in previous studies and dense enhanced our understanding of the underlying ecological processes of complex spatial interactions and allowed us to dissect direct and indirect effects of biotic and abiotic factors on distribution and performance of a rockcress population. Our attention to spatial distributions and associations expands the possible causations underlying community assembly associations over non-spatial analyses and our results help generate hypotheses for future experimental studies in ecological and evolutionary genomics.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Determining the exact genetic causes for a patient and providing definite molecular diagnoses are core elements of precision medicine. Individualized patient care is often limited by our current knowledge of disease etiologies and commonly used phenotypic-based diagnostic approach. The broad and incompletely understood phenotypic spectrum of a disease and various underlying genetic heterogeneity also present extra challenges to our clinical practice. With the rapid adaptation of new sequence technology in clinical setting for diagnostic purpose, phenotypic expansions of disease spectrum are becoming increasingly common. Understanding the underlying molecular mechanisms will help us to integrate genomic information into the workup of individualized patient care and make better clinical decisions. Medical textbooks usually provide characteristic descriptions of a disease and its progression. In reality, it can be challenging to recognize clinical presentations in an individual patient due to disease variations. Besides a few cases with classical presentations, many patients have atypical or overlapping manifestations. Understanding the similarities and differences between phenotypic abnormalities of human disease remains a major task for clinicians throughout their long medical training and practice. Meanwhile, precise and individualized diagnosis is often limited by current knowledge of disease etiologies. The large number of diseases, broad and incompletely understood phenotypic spectrums, and various genetic heterogeneity are all the contributing factors that hamper the diagnostic yield. A report from a clinical laboratory specializing in diagnostic exome sequencing discovered that about 5% of individuals in their patient cohort had two definitive genetic disorders . Such oc CFTR gene. Unlike this well-studied disorder, patients with defects in other single genes are often found to have broad clinical presentations without well-defined genotype-phenotype correlations. For example, DNA polymerase gamma (POLG) deficiency can lead to multiple categories of diseases, such as progressive external ophthalmoplegia, Alpers' syndrome, Parkinsonism, and juvenile spinocerebellar ataxia-epilepsy syndrome [ POLG related diseases is generally recessive, while autosomal dominant POLG mutations also exist. The clinical heterogeneity often makes diagnosis considerably difficult and contributes to diagnosis dilemmas. The clinical presentations of mitochondrial DNA (mtDNA) related disorders also show a wide spectrum of clinical variations. Despite relatively high prevalence of mitochondrial disorders, it is widely acknowledged that they are complex diseases to make a definite clinical diagnosis if based on clinical presentations exclusively [ SURF1 gene was found segregating with the disease; therefore, the diagnosis was revised to be Leigh syndrome [ VLDLR-associated congenital cerebellar ataxia with intellectual disability syndrome. However, the original clinical diagnosis is pontocerebellar hypoplasia since the clinical features were different from symptoms described for VLDLR-associated disease.Cystic fibrosis is a well-recognized single-gene disorder, and its disease severity can be roughly correlated to mutations observed in thesyndrome . The inhlusively . Presencsyndrome . In anot EBP gene encoding emopamil-binding protein [ EBP gene.Recently, a novel clinical syndrome was described for male patients with digital abnormalities, intellectual disability, and short stature in a multigeneration family . Extensi protein . As defe MAB21L2 gene were recently identified as a new cause of eye malformations. Interestingly, both dominant and recessive inheritance patterns were observed. The patients with the monoallelic mutations showed much more severe eye abnormalities as well as defects in other systems such as skeletal dysplasia, macrocephaly, and learning disability, while others with a biallelic mutation had only a mild eye phenotype and subtle dysmorphic facial features. This evidence indicated that the zygosity of a genetic defect can contribute to different pathogenic mechanisms [The type of genetic abnormalities can contribute to phenotype variations of a disease. A relatively large size of genomic aberration in terms of copy number variations (CNVs) is commonly seen in autosomal dominant or X-linked diseases. Point mutations are often observed in single-gene related autosomal recessive disorders. When types of point mutations range from nonsense, missense to splice site mutation, the corresponding clinical presentation can also differ considerably. Patients with nonsense mutation in alpha-1 type I collagen can have milder skeletal manifestation than these with missense mutation . Missenschanisms .Currently, clinicians need to know a variety of methodologies in order to request testing for a complete molecular profile of a gene. Patients can only afford a limited number of tests due to financial burden and thus do not have the necessary genetic workup. It is now possible to obtain a relatively comprehensive genetic workup within one assay to detect both point mutation and copy number variation for a set of different genes , 10. As TBX6 gene [ TBX6 haplotype in this disease. After extensive linkage and genotyping analysis, it was revealed that copresence of a TBX6 null allele and a common haplotype containing three common single-nucleotide polymorphisms (SNPs) can lead to congenital scoliosis in patient. Thus, this common TBX6 haplotype acts as a hypomorphic genetic modifier to modulate the penetrance of the disease presentation in carriers of TBX6 null mutations.The penetrance of a disease phenotype can be influenced by combinatory effect of two alleles. Most recently, sequencing a cohort of patients with sporadic congenital scoliosis identified multiple heterozygous null mutations inBX6 gene . The disGenetic heterogeneity is one of the important factors to consider during genetic workup for disorders with overlapping clinical presentations. For disorders with relatively defined clinical phenotypes, such as glycogen storage disorder, both clinical evaluation and routine laboratory testing may provide initial clues leading to a correct clinical diagnosis. Regarding disorders with nearly indistinguishable clinical phenotypes, such as congenital defects of glycosylation, the result from biochemical testing may not be sufficient to narrow down a possible underlying genetic cause. As to disorders with a broad spectrum of clinical presentations, the large number of genes associated with these phenotypes makes it difficult or impossible to pinpoint an exact gene if molecular testing is not requested. Disease-targeted multigene panels and whole-exome sequencing allow precise molecular diagnosis made for patients with previously unrealized genetic defects , 14. MorEpistatic interactions have been recognized to play important roles in pathogenesis and phenotype variability . When moThe rapid progress of high-throughput genomic sequencing and corresponding analysis tools in molecular diagnosis have revolutionized the practice of clinical diagnosis . ComprehEnding the diagnostic odyssey, the FORGE (Finding of Rare Disease Genes) Canada Consortium identified genetic causes for 146 disorders over a 2-year period through a nation-wide collaboration effort among clinicians and scientists . Precisi"} +{"text": "July is National Cleft and Craniofacial Awareness and Prevention Month, an observance intended to raise awareness and improve understanding of birth defects of the head and face. Common craniofacial birth defects include orofacial clefts , craniosynostosis (when the skull sutures join together prematurely), and anotia/microtia .This year, CDC highlights research on the association between smoking during early pregnancy and orofacial clefts. Although the causes of most orofacial clefts are unknown, the 2014 Surgeon General\u2019s report confirmed that maternal smoking during early pregnancy can cause orofacial clefts in babies (http://www.nccapm.org/about.html.Orofacial clefts occur very early in pregnancy. Health-care providers should encourage women who are thinking about becoming pregnant to quit smoking before pregnancy or as soon as they find out that they are pregnant. Additional information regarding National Cleft and Craniofacial Awareness and Prevention Month is available at"} +{"text": "We present the case of a 63-year-old woman with limited metastatic colorectal cancer to the lungs and liver treated with FOLFIRI-bevacizumab, followed by consolidative hypofractionated radiotherapy to right paratracheal metastatic lymphadenopathy. We treated the right paratracheal site with 60 Gy in 15 fractions . The patient tolerated the treatment well, and six months later started a five-month course of FOLFIRI-bevacizumab for new metastatic disease. She presented to our clinic six months after completing this, complaining of productive cough with scant hemoptysis, and was found to have localized tracheal wall breakdown and diverticulum in the region of prior high-dose radiation therapy, threatening to progress to catastrophic tracheovascular fistula. This was successfully repaired surgically after a lack of response to conservative measures. We urge caution in treating patients with vascular endothelial growth factor (VEGF) inhibitors in the setting of hypofractionated radiotherapy involving the mucosa of tubular organs, even when these treatments are separated by months. Though data is limited as to the impact of sequence, this may be particularly an issue when VEGF inhibitors follow prior radiotherapy. Bevacizumab is a monoclonal antibody that antagonizes the pro-angiogenic vascular endothelial growth factor (VEGF), and can be a highly effective agent for treating metastatic cancer; it inhibits tumor growth by limiting its blood supply. Bevacizumab has also been shown to be effective when given concurrently and adjuvantly with radiotherapy in the treatment of glioblastoma multiforme . HoweverWe report a case of a patient with oligometastatic colorectal cancer who was treated with FOLFIRI-bevacizumab followed two months later by hypofractionated radiotherapy, and six months later treated with\u00a0FOLFIRI-bevacizumab again. This patient unfortunately experienced a tracheal diverticulum 17 months after radiotherapy and six months after her second course of FOLFIRI-bevacizumab imaging. Her most recent bronchoscopy, 15 months postsurgery, shows continued resolution of the tracheal diverticulum Figure . In thisCombination bevacizumab and radiotherapy has been shown to be effective for glioblastoma multiforme, but may be associated with significant adverse effects for treatment of other sites. This risk may be highest when treating mucosal sites. Stephens et al. showed increased rates of tracheoesophageal fistula within the radiation field in patients treated with VEGF inhibitors after hypofractionated radiotherapy adjacent to the esophagus . GoodgamIn this case, we administered highly conformal hypofractionated radiation therapy with definitive intent to an ultra-central right paratracheal nodal metastasis with the high dose region including a portion of the tracheal wall contralateral to the esophagus. Rather than tracheoesophageal fistula, we observed localized tracheal wall breakdown and diverticulum into the mediastinal fat after bevacizumab-containing systemic therapy was administered with a substantial time gap after the completion of radiation therapy. Because of concern of progression to potentially catastrophic fistula between the trachea and superior vena cava, a serratus muscle flap repair was performed with good success.The hypofractionated radiation therapy regimen we used, 60 Gy in 15 fractions, was intensive because of definitive intent. By conventional linear-quadratic modeling, the equivalent dose in 2 Gy fractions would be 70 Gy for early/tumor effects and 84 Gy for late effects . Even so, this falls within the range of what has been used safely in dose escalation studies of conventionally fractionated radiation therapy alone and chemoradiation for locally advanced lung cancer involving mediastinal nodes, and substantially less than stereotactic ablative radiotherapy regimens used safely for central and ultra-central tumors such as 50 Gy in 4 fractions or 60 Gy in 8 fractions . We haveIt is unclear, however, when or if there is a safe way to combine bevacizumab with dose-intensive hypofractionated radiotherapy overlapping mucosal sites. Mucosal irradiation may preclude future administration of bevacizumab due to risk of toxicity, as bevacizumab may inhibit wound-healing after radiotherapy by diminishing angiogenesis to radiation-damaged tissue, which increases risk of treatment-related toxicity. We urge caution when considering dose-intensive radiotherapy to mucosal locations in association with VEGF inhibitors, and recommend close communication with medical oncologists to continue holding VEGF inhibitors after radiotherapy has been completed.We present a case of tracheal diverticulum following bevacizumab and paratracheal radiotherapy. We urge caution in treating patients with vascular endothelial growth factor (VEGF) inhibitors in the setting of hypofractionated radiotherapy involving the mucosa of tubular organs, even when these treatments are separated by months. Though data is limited as to the impact of sequence, this may be particularly an issue when VEGF inhibitors follow prior radiotherapy."} +{"text": "Diagnostic ultrasound (DUS) pressures have the ability to induce inertial cavitation (IC) of systemically administered microbubbles; this bioeffect has many diagnostic and therapeutic implications in cardiovascular care. Diagnostically, commercially available lipid-encapsulated perfluorocarbons (LEP) can be utilized to improve endocardial and vascular border delineation as well as assess myocardial perfusion. Therapeutically, the liquid jets induced by IC can alter endothelial function and dissolve thrombi within the immediate vicinity of the cavitating microbubbles. The cavitating LEP can also result in the localized release of any bound therapeutic substance at the site of insonation. DUS-induced IC has been tested in pre-clinical studies to determine what effect it has on acute vascular and microvascular thrombosis as well as nitric oxide (NO) release. These pre-clinical studies have consistently shown that DUS-induced IC of LEP is effective in restoring coronary vascular and microvascular flow in acute ST segment elevation myocardial infarction (STEMI), with microvascular flow improving even if upstream large vessel flow has not been achieved. The initial clinical trials examining the efficacy of short pulse duration DUS high mechanical index impulses in patients with STEMI are underway, and preliminary studies have suggested that earlier epicardial vessel recanalization can be achieved prior to arriving in the cardiac catheterization laboratory. DUS high mechanical index impulses have also been effective in pre-clinical studies for targeting DNA delivery that has restored islet cell function in type I diabetes and restored vascular flow in the extremities downstream from a peripheral vascular occlusion. Improvements in this technique will come from three dimensional arrays for therapeutic applications, more automated delivery techniques that can be applied in the field, and use of submicron-sized acoustically activated LEP droplets that may better permeate the clot prior to DUS activation and cavitation. This article will focus on these newer developments for DUS therapeutic applications.The online version of this article (doi:10.1186/s40349-016-0062-y) contains supplementary material, which is available to authorized users. Although diagnostic ultrasound (DUS) systems and lipid-encapsulated perfluorocarbons (LEP) like Definity or Sonazoid have been approved only for imaging applications; these two products have significant therapeutic potential for non-invasive targeted thrombolysis and drug delivery. Ultrasound and microbubbles alone as a method of dissolving thrombi was first introduced in 1997 . SubsequThe potential for intermittent high MI impulses from a DUS transducer was first examined in a canine model of arteriovenous graft thrombosis, where intermittent high MI impulses all <1.9 MI) were applied when low MI imaging detected microbubbles within the risk area . These h.9 MI werThis study prompted subsequent investigations which examined the efficacy of DUS high MI impulses in restoring microvascular and epicardial blood flow in porcine models of acute ST segment elevation myocardial infarction, or STEMI \u201312. ThesSlight prolongations in pulse duration on a DUS transducer may improve the amount of thrombus dissolution. By increasing pulse duration from <5 to 20\u00a0\u03bcs on a DUS transducer, a higher epicardial recanalization rate was achieved with DUS-guided therapy added to \u00bd dose tissue plasminogen activator. Despite the higher epicardial recanalization rate, both short and longer pulse duration high MI impulses were equally effective in ST segment resolution and improvement in wall thickening within the risk area . The guiIn an ischemic stroke, transcranial DUS and intravenous LEP microbubbles, even in the absence of tissue plasminogen activator, have recanalized intravascular and microvascular thrombi in a large porcine animal model . In thisA considerable number of small animal studies have demonstrated the ability of DUS-guided cavitation of LEP to target the delivery of DNA or RNA \u201322; Tabl2; Tabl2.The use of a commercially available LEP and DUS for targeted thrombolysis is now being tested in the first clinical trials , with prOne problem with microbubbles is that they are confined to intravascular spaces, and inertial cavitation can only increase subendothelial delivery. The LEP can also be formulated into droplets, even for the lower molecular weight fluorocarbons like octafluoropropane . Since tDUS, diagnostic ultrasound; IC, inertial cavitation; LEP, lipid-encapsulated perfluorocarbons; MI, mechanical index; NO, nitric oxide; PWD, pulsed wave Doppler; STEMI, ST segment elevation myocardial infarction"} +{"text": "The mere sight of foods may activate the brain\u2019s reward circuitry, and humans often experience difficulties in inhibiting urges to eat upon encountering visual food signals. Imbalance between the reward circuit and those supporting inhibitory control may underlie obesity, yet brain circuits supporting volitional control of appetite and their possible dysfunction that can lead to obesity remain poorly specified. Here we delineated the brain basis of volitional appetite control in healthy and obese individuals with functional magnetic resonance imaging (fMRI). Twenty-seven morbidly obese women (mean BMI = 41.4) and fourteen age-matched normal-weight women (mean BMI = 22.6) were scanned with 1.5 Tesla fMRI while viewing food pictures. They were instructed to inhibit their urge to eat the foods, view the stimuli passively or imagine eating the foods. Across all subjects, a frontal cortical control circuit was activated during appetite inhibition versus passive viewing of the foods. Inhibition minus imagined eating (appetite control) activated bilateral precunei and parietal cortices and frontal regions spanning anterior cingulate and superior medial frontal cortices. During appetite control, obese subjects had lower responses in the medial frontal, middle cingulate and dorsal caudate nuclei. Functional connectivity of the control circuit was increased in morbidly obese versus control subjects during appetite control, which might reflect impaired integrative and executive function in obesity. In our modern society humans are surrounded by food advertisement and palatable visual food cues are readily available and on display in supermarkets and restaurants. Despite complex homeostatic mechanisms that govern eating and appetite , the merThe sight of food cues engages the brain\u2019s reward circuit and it shows greater activation encountering palatable versus bland foods , especiafunctional connectivity of the cognitive control networks and the reward circuit has remained elusive. It is indeed possible that the previously reported elevated reward circuit responses to palatable foods in obese individuals [The evidence of the influence of obesity on the functioning of the fronto cortical appetite control systems remains mixed, nevertheless. Some studies have reported no effects of Body Mass Index (BMI) on cortical inhibitory circuits , while sividuals \u20136 could Here, we used functional magnetic resonance imaging (fMRI) to study brain circuits supporting cognitive appetite control in normal-weight and morbidly obese individuals. Participants viewed pictures of foods, while their task was to either inhibit their urges to eat, imagine eating the foods or watch the foods passively. We hypothesized that volitional control of appetite would engage the fronto-cortical circuits, and that obese individuals would have lower frontal activations reflecting failure to volitionally inhibit their urges to eat. In line with this, we also predicted that functional connectivity of the control circuit would be lowered in obese individuals.http://www.clinicaltrials.gov). All participants signed an ethical committee-approved, informed consent form prior to scans.The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethical Committee of the Hospital District of South-Western Finland were recruited for the study were recruited as a control group to assess the nutritional state .inhibition condition, they had to inhibit urges to eat the food, during passive viewing condition they had to view the foods passively, and during imaginary eating condition they had to imagine eating the foods. The blocks were presented in a fixed, pseudo-randomized order, which was counterbalanced across participants. Altogether there were twenty blocks of each condition, and total scanning time was approximately 19 minutes. Participants were given written and spoken instructions before entering the scanner, and they practiced the task in the scanner before the experiment began. The participants were also interviewed after the experiment to assure that they had finished the task as instructed.Stimuli and design are summarized in The stimulus presentation and behavioral data collection were controlled with Presentation software . Stimuli were projected from an LCD projector onto a non-magnetic screen mounted at the foot of the bore, and an angled mirror reflected images onto the screen into the participants\u2019 field of vision.3 resolution) were acquired using a T1-weighted sequence .Altogether 380 functional volumes were acquired. Furthermore, four \u2018dummy\u2019 volumes were acquired and discarded at the beginning to allow for equilibration effects. The dummy volumes were not included in the analysis. Data were pre-processed and analyzed using SPM8 software (http://www.fil.ion.ucl.ac.uk/spm/) running on Matlab 2011b. The EPI images were realigned to the first scan image by rigid body transformations to correct for head movements. Echoplanar and structural images were co-registered and normalized to the T1 standard template in MNI space using linear and non-linear transformations, and smoothed with a Gaussian kernel of 8 mm full width at half maximum\u2014FWHM 8 mm.MR imaging was performed with Philips Gyroscan Intera 1.5 T CV Nova Dual scanner at Turku PET centre. Whole-brain functional data were acquired with T2* weighted echo-planar imaging (EPI) sequence, sensitive to the blood-oxygen-level-dependent (BOLD) signal contrast . High-resolution anatomical images corrected at the cluster level.A whole-brain random effects model was used. This two-stage process (first and second level) assesses effects on the basis of inter-subject variance and thus allows inferences about the population that the participants are drawn from. For each participant, we used a general linear model (GLM) to assess regional effects of task parameters on brain activation. The first level model included all three experimental conditions as well as the six realignment parameters as effects of no interest. Low-frequency signal drift was removed using a high-pass filter (cut-off 128 s) and we applied autoregressive AR(1) modeling of temporal autocorrelations. The individual contrast images were generated using the t-contrasts i) inhibition minus viewing, ii) imaginary eating minus viewing, and iii) inhibition minus imaginary eating, as well as the opposite contrasts. The contrast images of the voxel-wise difference in beta estimates for the contrasts of interest. The second-level analysis used these contrast images in a new GLM from which generated statistical images, that is, SPM t-maps across all subjects and between subject groups. When the second-level analysis has balanced designs at first level with similar numbers of similar events for each subject it closely approximates a true mixed-effects design, exhibiting within- and between-subject variance. In addition, second-level analysis in SPM is considered to be robust against unequal group sizes, when unequal variances are assumed. The inhibition minus passive viewing and imaginary eating versus passive viewing contrasts were used to delineate the brain regions involved in cognitive control of appetite and mental processing of the hedonic value of the foods. The appetite control contrast (inhibition minus imaginary eating) was considered the main contrast of interest for revealing the neural basis of appetite control, as this enabled contrasting the two active food-related tasks directly against each other, thus accounting for effects of increasing task complexity in the active versus passive viewing conditions . Data weThe connectivity between brain regions can vary as a function of the psychological context . This isSource regions for the brain\u2019s inhibition network were selected from a previous meta-analysis on inhibitory processing in Go/No-Go tasks , 11 and Contrasting the inhibition condition with passive viewing revealed widespread activation in fronto-cortical regions , Table 3In inhibition minus imaginary eating comparison, normal-weight subjects showed stronger activations than obese subjects in bilateral dorsal caudate nuclei and anterior cingulate cortex , Table 5Across all subjects, the right caudate nucleus showed increased task-driven (inhibition versus passive viewing) connectivity with bilateral precunei and cunei and parietal cortices . InferioBetween-group comparisons revealed that obese subjects had stronger functional connectivity between middle frontal cortex and bilateral supplemental motor area (SMA), right putamen and right middle temporal gyrus , Table 6Hunger ratings did not Here we show that volitional appetite control while viewing visual food cues activates a network of prefrontal, frontal and parietal and inferior cerebellar cortical regions. This confirms that the fronto cortical control system \u2013 well known for inhibition and error monitoring ,9 is alsEating and appetite are controlled by complex homeostatic mechanisms . In realThese findings from the task-evoked BOLD responses to cognitive appetite control accord with those made by Yokum et al. They compared the neural responses of three cognitive reappraisal strategies when adolescent subjects viewed visual food cues and thought of the long-term costs or benefits of not eating the food and suppressing cravings for the food. They found increased activation in inhibitory prefrontal and superior frontal regions during these mental tasks, yet in that study participants\u2019 BMI did not modulate the intensity of brain activation . FurtherDuring the inhibition versus imaginary eating condition, normal-weight individuals showed stronger responses than obese individuals in medial frontal and orbitofrontal cortices, as well as in dorsal caudate nucleus . With moenhanced rather than diminished connectivity of the appetite control network in obese versus normal-weight individuals (Against our predictions, functional connectivity analysis revealed ividuals . Obese iAltogether these findings imply that modulating the brain activity of the whole inhibitory circuitry may prove effective to combat our urges to eat excessively. Indeed, most of the currently available anti-obesity pharmaceuticals modulate widespread neurotransmitter systems . InteresWe did not measure blood glucose or insulin levels, which are shown to influence fMRI responses to food pictures . HoweverWe conclude that premotor areas, superior frontal cortices and the precuneus support cognitive control of appetite upon encountering visual food cues. Although these areas seem to function similarly in obese and normal-weight individuals, dorsal striatal responses during volitional appetite control are reduced in obese individuals. This suggests that even though frontal inhibitory function seems to be largely preserved in obesity, altered reward and homeostatic signaling together with heightened functional connectivity within the cognitive control circuit likely play an important role in the pathophysiology of obesity, and drive excessive eating and contribute to development and maintenance of obesity."} +{"text": "Inflammation is the first biological response of the immune system against infection or irritation. However, accumulating epidemiological and clinical study indicates that zealous acute inflammation or chronic inflammatory reaction is a significant risk factor to develop various human diseases. Controlling or modulating inflammation is therefore important to prevent or ameliorate certain diseases, such as organ transplantations, allergic diseases, and autoimmune diseases. T. wilfordii extract in patients with rheumatoid arthritis , cyclosporin A (CsA), rapamycin, tacrolimus (FK506), and fingolimod FTY720) (summarized in review ). In add0 (summarThis special issue will introduce you to the valuable research reports on anti-inflammatory natural products, ranging from basic researches to exploring roles of natural products against inflammatory diseases. We hope this timely special issue will encourage the research and development of valuable natural products and finally lead to the development of novel therapeutic agents to provide better care to patients.Yifu YangYifu YangLifei HouLifei HouAbdelfattah El OuaamariAbdelfattah El OuaamariLijun XinLijun Xin"} +{"text": "The primary complication of any available anticoagulant therapy is the risk of bleeding. Rapid reversal of anticoagulation may be necessary in patients requiring emergency treatment due to uncontrolled bleeding. Prothrombin complex concentrates (PCC) are frequently used to reverse the effect of vitamin K antagonists such as warfarin and have also been suggested to be potentially effective in reversing the effects of the new oral anticoagulants. The present study was therefore designed to determine whether the four-factor PCC Beriplex\u00ae (25 to 75 IU/kg). Bleeding was assessed based on the time to hemostasis and the total blood loss after induction of a standardized kidney injury. In parallel, the following biomarkers of hemostasis were determined: factor Xa inhibition, prothrombin time (PT), activated partial thromboplastin time (aPTT), whole blood clotting time (WBCT), and thrombin generation (TGA).Rabbits were treated with a high intravenous bolus dose of edoxaban followed by the administration of Beriplex\u00ae resulted in a dose-dependent reversal of edoxaban-induced bleeding as indicated by reduced time to hemostasis and total blood loss. Both parameters achieved statistical significance compared with placebo at the Beriplex\u00ae dose of 50 IU/kg under fully blinded study conditions. The biomarkers correlating best with Beriplex\u00ae-mediated edoxaban anticoagulation reversal included PT, WBCT and endogenous thrombin potential.The results confirmed increased and prolonged bleeding of edoxaban-treated animals following standardized kidney injury compared with vehicle administration. Parallel monitoring of biomarkers of hemostasis showed a prolongation of PT, aPTT, WBCT, and changes in thrombin generation parameters. Subsequent administration of Beriplex\u00ae treatment effectively reversed edoxaban-induced anticoagulation in an animal model of acute bleeding at clinically relevant dose levels.In summary, Beriplex"} +{"text": "Post-stroke care after hospital discharge suffers from lack of intersectoral collaboration within the public health sectors. Hence, primary care remains the only option in managing stroke patients in underserved areas in Malaysia. This study aimed to identify the areas, which can be better coordinated to deliver optimal post-stroke care in community setting. A seamless transfer of care model known as integrated Care Pathway for Post Stroke patients (iCaPPS) was designed to address this issue.Expert panel discussions comprising of family physicians, neurologists, rehabilitation physicians and therapists, and nurse managers from both Ministry of Health and the academia were conducted. Modified Delphi technique was employed to resolve practice variations through additional literature support. Care algorithms were designed around existing work schedules and available resources at public health centres.Identified areas for coordinated transfer of care include: identification of patient criteria suitable for long-term stroke management at primary care facilities, information required at transfer of care, stroke risk factors treatment targets, screening for stroke complications and rehabilitation guide for primary care team. Care algorithm including appropriate tools were summarised to identify patients requiring further multidisciplinary rehabilitation interventions i.e. assessment for those uninitiated or missed out on rehabilitation and leisure intervention for those indicated, screening for swallowing disorders as well as mental health disorders (i.e. depression and dementia).The iCaPPS would facilitate coordinated primary care-led post-stroke management for patients residing at home in the community, hence promoting better collaboration within public health sectors. Clinical outcomes and cost effectiveness of iCaPPS can be evaluated for benefit of stakeholders and stroke survivors."} +{"text": "Chronic migraine is a debilitating disease particularly in women and underlying pathophysiology remains unclear. Clinically relevant migraine models are missing.The aim of this study is to mimic chronic migraine model in rats and to test migraine drugs.Study was approved the Institutional Animal Care and Use Committee and care and handling of animals were in accord with National Institute of Health guidelines. Nasociliary nerve (NCN), which is the rat correlate of opthalmic branch of trigeminal nerve is ligated to mimic chronic headache. Glyceroltrinitrate (GTN) was administered to induce acute migraine attack. Sumatriptane and CGRP receptor antagonist were administered. Pain, anxiety related behavior were recorded. Mechanical allodynia, thermal hyperalgesia was tested by VF/ EVF and acetone; anxiety by elevated plus maze (EPM). Activated areas were investigated by c-fos immunoreactivity and plasma extravasation was studied by horse radish peroxidase.NCN ligation, GTN administration model demonstrated mechanical allodynia, thermal hyperalgesia. Anxiety accompanying pain was confirmed by EPM. Extravasation in dura mater was shown by Horse radish peroxidase. Significantly c-fos immunoreactivity was increased in ipsilateral brainstem TNC compared to contralateral and also in cortical structures constituting pain matrix. CGRP antagonists decreased pain related behavior and c-fos positive cells.Mechanical allodynia, thermal hyperalgesia, c-fos staining confirming central and peripheral sensitization is exhibited in NCN ligated rats and pain related anxiety is confirmed. CGRP receptor antagonists are effective for chronic headache treatment. This chronic migraine model is relevant to human migraine and eligible for further drug investigations.No conflict of interest."} +{"text": "Infectious diseases are a major health problem worldwide, causing many serious complications, including autoimmune disorders in unvaccinated populations. The vaccinations represent the most effective method of preventing infectious diseases and cost benefit analysis of vaccination programmes demonstrated their utility. On the basis of Orphanet database, in Italy rare diseases affect almost 2 million people, and 70% of them are children. Among neurodegenerative disorders, children with spinal muscolar atrophy should receive routine immunizations, including influenza and pneumococcal vaccines; for pediatric patients affected by Becker's Muscular Dystrophy influenza and pneumococcal vaccines are indicated in case of severe weakness of respiratory muscles . Immunoc"} +{"text": "Plasmodium sporozoites may function as protective immune responses. They cover immune induction quite extensively but discuss virtually nothing on effector mechanisms of antibody responses against sporozoites. Because their review should be balanced by reference to studies describing effector mechanisms, this commentary will confine itself to recounting some of these.Dups et al. assess hIn vitro exposure to serum from immunized mice results in an antibody-mediated precipitant projecting from sporozoites (In vitro inhibition of sporozoite motility by serum from immune animals subsequently suggested that anti-sporozoite antibodies can function by blocking sporozoite motility (in vitro studies showed that monoclonal antibodies against the CS antigen blocked in vitro invasion by sporozoites into target cells (in vivo inhibition of sporozoite motility and inhibition of sporozoite invasion of dermal blood vessels by antibodies (rozoites . Becausemotility . Furtheret cells , 5. Substibodies . And an tibodies .Plasmodium berghei sporozoites injected by mosquitoes into sporozoite-immunized vs. non-immunized mice showed significantly fewer sporozoites were deposited in immune mice (in vitro (in vitro and in vivo (Anti-sporozoite antibodies act even earlier during challenge by mosquito bite, by inhibiting release of sporozoites from the mosquito proboscis into skin . This apune mice . CS protin vitro and intoin vitro , 11. Thu in vivo .Some sporozoites injected by mosquitoes into immunized hosts may successfully escape into the blood. Indeed, sporozoites that bypass skin by being injected intravenously by syringe into mice passively immunized with immune serum are cleared effectively from the circulation , indicatIn vitro studies have documented that opsonized sporozoites are prone to phagocytosis (in vivo. Furthermore, antibodies also inhibit invasion and traversal through hepatocytes, events that rely on sporozoite motility (Conceivably, antibody-coated sporozoites may be blocked during attempted passage through Kupffer cells prior to hepatocyte invasion , 14. In ocytosis \u201317, suggmotility .Thus, anti-sporozoite antibodies can act sequentially against sporozoites at different stages of sporozoite invasion from the skin to invasion of dermal blood vessels, to passage from Kupffer cells into hepatocytes, and subsequent traversal of sporozoites through a series of hepatocytes.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Recruiting patients to research and collecting study data in a primary care setting, combined with maximising retention rates from a primary care population can be challenging and requires recruitment and retention methods which are innovative, efficient and transferrable.To apply low resource intensive and rapidly implemented recruitment and retention innovations for use in primary care settings that ensure patient recruitment and follow-up targets are achieved.A range of innovative recruitment and retention strategies are utilised by Keele CTU including; electronic aide-memoires linked to Read codes; physical aide-memoire prompts in consulting rooms; automated referral methods; postcard, repeat, email, SMS and minimum data collection reminder mailings; death and departure auditing.Methods used; sustain routine care whilst simultaneously screening for research data and participants; provide flexible instruments compatible with all general practice infrastructures; increase clinical precision in identifying suitable participants; automates recording of study data collection; ensures minimal impact on consultation time; contribute towards the delivery of excellent retention rates.Recruitment aide-memoires, automated innovations and retention strategies can all be embedded easily into a primary care setting. These tools, without over burdening the busy primary care practitioner, result in simple and effective methods of prompting patient recruitment and retention. Excellent recruitment and retention rates are possible, despite encountering differences in primary care infrastructure. Such methods should be utilised more widely to facilitate primary care research, if this is where many conditions are diagnosed and managed."} +{"text": "Coregonus sardinella) is a bellwether for Arctic lakes as an important consumer and prey resource. To explore the consequences of climate warming, we used a bioenergetics model to simulate changes in Least Cisco production under future climate scenarios for lakes on the Arctic Coastal Plain. First, we used current temperatures to fit Least Cisco consumption to observed annual growth. We then estimated growth, holding food availability, and then feeding rate constant, for future projections of temperature. Projected warmer water temperatures resulted in reduced Least Cisco production, especially for larger size classes, when food availability was held constant. While holding feeding rate constant, production of Least Cisco increased under all future scenarios with progressively more growth in warmer temperatures. Higher variability occurred with longer projections of time mirroring the expanding uncertainty in climate predictions further into the future. In addition to direct temperature effects on Least Cisco growth, we also considered changes in lake ice phenology and prey resources for Least Cisco. A shorter period of ice cover resulted in increased production, similar to warming temperatures. Altering prey quality had a larger effect on fish production in summer than winter and increased relative growth of younger rather than older age classes of Least Cisco. Overall, we predicted increased production of Least Cisco due to climate warming in lakes of Arctic Alaska. Understanding the implications of increased production of Least Cisco to the entire food web will be necessary to predict ecosystem responses in lakes of the Arctic.Lake ecosystems in the Arctic are changing rapidly due to climate warming. Lakes are sensitive integrators of climate-induced changes and prominent features across the Arctic landscape, especially in lowland permafrost regions such as the Arctic Coastal Plain of Alaska. Despite many studies on the implications of climate warming, how fish populations will respond to lake changes is uncertain for Arctic ecosystems. Least Cisco ( Lakes are prominent features across the Arctic landscape, especially in lowland permafrost regions where the landscape comprises thousands of lakes and the lake area fraction (lake area/land area) can exceed 40%, such as on the Arctic Coastal Plain of Alaska and loons (Gavia spp.). Therefore, changes in growth rates and size structure of Least Cisco could have implications throughout the food web. Least Cisco will likely have strong responses to climate warming as temperatures exceed the optimum temperature of 16.8\u00b0C for coregonids and Alaska blackfish , whereas widely distributed, but found more often in highly connected systems, are Least Cisco, Broad whitefish (Coregonus nasus), and Arctic grayling . Similar to nearby systems in the Brooks Range , Dolly varden , rainbow smelt (Osmerus mordax), Humpback whitefish (Coregonus oidschian), and the top predators Northern pike (Esox lucius) and burbot ]; Seigle To parameterize the Least Cisco model to lakes on the Arctic Coastal Plain, we assumed Least Cisco feed primarily in the water column and their diet remains constant throughout the year. In the model, diets were evenly divided among expected prey groups of bosmina (1674 J/g wet mass), copepods (2792 J/g wet mass), other cladocerans (2514 J/g wet mass), diptera (1763 J/g wet mass), and leptodora (867 J/g wet mass) using previously published values for prey energy density for different climate scenarios by holding annual ration and pCmax constant at the level determined for current conditions. By holding annual ration and pCmax constant, we can predict growth for future temperature scenarios. Holding feeding rate and food availability constant has been useful in projecting growth differences with climate change predictions in other systems of Least Cisco indicates growth only occurs during the summer under current temperatures for all age classes estimated for growth under current temperatures ranged from 0.33 to 0.59 across age classes of Least Cisco and accumulated biomass (g) of Least Cisco increased under all future scenarios of warmer temperatures with a constant pCmax Figs. , 6A. MorAge classes of Least Cisco responded differently to increasing temperatures. Relative growth shows an exponential decrease from younger to older age classes for all the climate scenarios produced by the SNAP projections Fig. . YoungerThe annual ration estimated for growth under the current temperatures ranged from 5.61% to 3.18% in Lake Michigan and Cisco (Coregonus artedii), by reducing suitable habitat with warmer temperatures in headwater streams of southern British Columbia, Canada in which their growth rates were more sensitive to prey quality than temperature in Lake Michigan (Madenjian et al. Using the generalized coregonid model for comparing differences in Least Cisco growth on the Arctic Coastal Plain provides relative comparisons of future climate projections and identifies knowledge gaps. We used a value for the respiration parameter (Wohlschag The empirical data available on the physical and biological components of Arctic freshwater systems are increasing; however, our only option was to compile data from a variety of sources and regions. With a spatially focused assessment of Least Cisco, a more robust model could be built as large differences occur across the landscape. For example, climate warming in the winter is expected to affect coastal areas more than inland areas due to the influence of a longer marine ice-free period. In contrast, during the summer, the projected temperature increases are of a lesser magnitude on the coast and more pronounced in inland areas. Within a region, systematic differences in lake size and morphometry can generate differences in both ice phenology and summer water temperatures despite common climate conditions (Shuter et al."} +{"text": "Gender-based differences in the cardiac morphology and function in patients with volume-overload cardiac pathologies has been widely examined. However the relationship between gender and contractility is not well defined.Therefore we evaluate the gender influence on contractile capacity in patients with volume overload, present with severe mitral valve regurgitation and preserved left ventricular function.Right auricle samples from 40 patients with severe mitral regurgitation, scheduled for elective mitral valve surgery, were obtained before extracorporal circulation (ECC). The fibers were prepared and skinned to remove membrane-dependent properties and exposed to gradual increase of calcium concentration.Female fibers achieve higher force values than male patients at the highest step of calcium concentration . Male and female fibers show an anticyclical course when exposed to increasing steps of calcium concentrations: starting with lower force values at lower calcium concentrations in males, the steepness of pCa-force-curve is flatter compared to female counterparts . At higher force values females achieve higher maximal forces and lower force values for males .Calcium sensitivity, given as half maximal concentration, is achieved at pCa 5.0 in females and between 6 and 5.5 for males (p 0.04).Male and female fibers from patients with severe mitral regurgitation show adverse calcium induced force properties. Male fibers achieve lower maximal force values, starting at higher base values in low calcium concentration condition and might therefore have higher sensitivity to calcium."} +{"text": "Auditing is an integral part of quality assurance in trials. The introduction of risk-based monitoring in industry coupled with reduced funding for academic trials indicates a need to enhance the comprehensive oversight of trials. Generating an internal audit system streamlines quality management across the clinical trials unit. We aimed to pilot a robust in-house process that prioritises patient safety and monitors trial delivery.Ten healthcare professionals within our team voluntarily formed an internal audit group and received appropriate training. Sub-teams were assigned individual trials to audit over a three month period. Quality and SOP compliance data was collated in a comprehensive audit spreadsheet and processes covered included examination of Site Files, Case Report Forms, Serious Adverse Events (SAE), and source data verification (SDV). Findings were amalgamated into a Corrective Action Preventative Action (CAPA) Plan and fed back to the wider team. Team actions were subsequently reviewed after six weeks as a follow-up measure.Preliminary findings of five internal audits highlighted areas for improvement within data and procedural systems including; informed consent, SAE reporting, and SDV. Additionally, the Audit Group proved a useful measure in developing overall quality standards of the team, highlighted by staff learning, improved knowledge and adherence to regulatory standards.In line with upcoming EU legislation and ICH GCP, maintaining rigorous auditing processes and adherence to quality standards is of utmost importance. The ongoing quarterly internal audit cycle will be continuously reviewed, feeding into an evolving quality management system ensuring best practice across the unit."} +{"text": "Plant immunity relies on a complex network of hormone signaling pathways in which jasmonic acid (JA) plays a central role. Successful microbial pathogens or symbionts have developed strategies to manipulate plant hormone signaling pathways to cause hormonal imbalances for their own benefit. These strategies include the production of plant hormones, phytohormone mimics, or effector proteins that target host components to disrupt hormonal signaling pathways and enhance virulence. Here, we describe the molecular details of the most recent and best-characterized examples of specific JA hormonal manipulation by microbes, which exemplify the ingenious ways by which pathogens can take control over the plant\u2019s hormone signaling network to suppress host immunity. Agricultural productivity depends on the capacity of plants to adapt to changing environmental conditions. In nature, plants live in complex environments in which they intimately interact with a broad range of microbial pathogens with different infection strategies. To defend themselves, plants have evolved sophisticated strategies to perceive their attacker during the infection process and to translate this perception into an effective immune response. Recognition of highly conserved microbe-associated molecular patterns (MAMPs) by host cell transmembrane pattern recognition receptors (PRRs) leads to MAMP-triggered immunity (MTI) that restricts pathogen growth . To overBotrytis cinerea, whereas the SA pathway is primarily induced by and effective in mediating resistance against biotrophic and hemi-biotrophic pathogens such as Pseudomonas syringae . . P. syrit manner . Of noteelopment . In combd by COR .P. syringae mutants unable to produce COR show reduced virulence . In. InB. cidefenses . SSITL rdefenses . FurtherLaccaria bicolor, support host growth by providing growth-limiting nutrients to their plant host through a mutualistic symbiotic relationship within the plant roots [L. bicolor. MiSSP7 is an effector protein indispensable for the establishment of mutualism with their host plants [in planta or through transgenic overexpression of the PtJAZ6 gene [Beneficial microbes establish long-term relationships with their host plants to fulfill their life cycles . Ectomycnt roots . In ordet plants . Upon pet plants ,80. In tAZ6 gene . This inThe importance of signaling molecules in plant immunity is a well-established notion in plant biology and the molecular mechanisms regulating the phytohormone-mediated defenses have been extensively studied in the last decades. In this context, the role of hormones in plant immunity is further highlighted by the increasing number of pathogens producing phytohormones or phytohormone mimics and by the identification of a plethora of microbial effectors targeting hormonal pathways to promote disease or establish beneficial interactions. Of note, virulence activities of effectors on specific hormonal components can lead to the identification of novel mechanisms of host hormonal regulation unknown to date. In addition, an improved mechanistic understanding of how pathogenic toxins and effectors manipulate host hormonal components will be instrumental in identifying new defensive hubs and to develop new plant varieties with improved resistance to pathogens."} +{"text": "Pulseless electrical activity cardiac arrest is associated with poor outcomes and the identification of potentially reversible reasons for cardiac arrest is fundamental.We describe the case of a 46-year-old male with the rare coincidental finding of supravalvular aortic stenosis and coronary vasospasm leading to recurrent pulseless electrical activity cardiac arrest. Extracorporeal life support was successfully applied for hemodynamic stabilization. Supravalvular aorticstenosis underwent surgical repair. The patient survived five time resuscitation and was discharged after full neurological recovery.Coronary vasospasm and supravalvular aortic stenosis are rare but potentially reversible causes of pulseless electrical activity cardiac arrest. Extracorporeal life support allows accurate diagnostic and possibly therapy even of uncommon reasons for cardiac arrest.The online version of this article (doi:10.1186/s12872-016-0284-5) contains supplementary material, which is available to authorized users. Cardiac arrest due to pulseless electrical activity (PEA) is associated with poor survival and neurological outcome when compared to a shockable rhythm , 2. To pWe describe here for the first time the case of a patient with the rare coincident finding of coronary vasospasm and supravalvular aortic stenosis leading to recurrent pulseless electrical activity cardiac arrests.A 46-year-old male was successfully resuscitated for out-of-hospital cardiac arrest due to ventricular fibrillation Fig.\u00a0. CoronarBecause of the development of a severe acute respiratory distress syndrome five days after admission our ECMO team established a veno-venous extra-corporeal membrane oxygenation (vvECMO) system using a 31 Fr bi-caval cannula and transferred the patient to our center that was confirmed by CT (Fig.The patient has no family history of cardiac death. He underwent patch-repair for supravalvular aortic stenosis during childhood. On day 6 transthoracic and transesophageal echocardiography revealed a remaining supravalvular aortic stenosis (Vy CT Fig..The patient had full neurological recovery and was discharged to follow-up treatment. A cardiac defibrillator was implanted for secondary prevention of the initial VF.We report a case of recurrent cardiac arrests due to coronary vasospasm and supravalvular aortic stenosis.The patient survived five episodes of cardiac arrest, four of them with PEA which is an uncommon complication of vasospastic angina. Patients with vasospastic angina pectoris are at higher risk of sudden cardiac death and most often cardiac arrest occurs due to tachycardic ventricular arrhythmia . NeverthVeno-arterial ECMO is considered as the preferred method for extracorporeal life support to allow further diagnosis and therapeutic measures when standard life support fails to achieve ROSC . PercutaIn conclusion, the coincidence of coronary vasospasm and supravalvular aortic stenosis lead to recurrent pulseless electrical activity cardiac arrest in this case. Unusual causes for refractory cardiac arrest should be considered during and after resuscitation. Extracorporeal life support provides the opportunity for accurate diagnostic and therapy when routine diagnostic measures are not sufficient.CT, computer-assisted tomography; ECLS, extracorporeal life support; ECMO, extracorporeal membrane oxygenation; PEA, pulseless electrical activity; ROSC, return of spontaneous circulation."} +{"text": "It seems that renal tubular damages in acute renal failure involved in gentamicin nephrotoxicity or ischemia/reperfusion mainly induced by increasing of reactive oxygen species (oxidative stress). According to this attitude, many researchers have been used different antioxidant agents in combat with gentamicin nephrotoxicity. Treatment of animal with metformin against gentamicin revealed that gentamicin might be induced renal tubular damages via energy depletion in renal tubular cells besides inducing of oxidative stress. More studies are needed to clarify renal protective effect of adenosine monophosphate-activated protein kinase (AMPK) activator such as metformin in combat with gentamicin nephrotoxicity.In spite of undesirable gentamicin nephrotoxicity,\u200f this antibiotic is commonly used versus Gram-negative bacteria and still constitutes the only effective therapeutic alternative against microorganisms-pseudomonas, proteus and serratia \u2013 that are insensitive to other antibiotics . MoreoveThe pathological mechanisms involved in gentamicin induced nephrotoxicity include induction of oxidative stress, apoptosis, necrosis, up regulation of transforming growth factor B, elevation of endothelin I , increase of monocyte/macrophages infiltration , phospholipidosis an increase of intracellular sodium ions ,3. GentaGentamicin nephrotoxicity is characterized functionally by an increase of serum creatinine, blood urea nitrogen, and decrease in glomerular filtration rate , which mMore investigations showed that antioxidant agents inhibited or attenuated gentamicinnephrotoxicity in rats. Usage of antioxidants improved histological injuries such as tubular necrosis, tubular cell edema and apoptosis in gentamicin-injected rats -8.Metformin that used by diabetic patients showed oxidative stress inhibitor activity and adenosine monophosphate-activated protein kinase (AMPK) activator. Some researchers evaluated effects of metformin against gentamicin nephrotoxicity. They reported beneficial effect of metformin in combat with renal histopathological changes induced by gentamicin -10.Alterations in epithelial cell polarity and in the subcellular distributions of epithelial ion transport proteins are key molecular consequences of acute kidney injury and intracellular energy depletion. AMPK, a cellular energy sensor, is rapidly activated in response to renal ischemia, and renal epithelial cells subjected to energy depletion .In the study of Baradaran and colleague for the first time combination effect of metformin and garlic extract evaluated against gentamicin nephrotoxicity. They showed that this treatment attenuated renal histopathological injuries including epithelial cell vacuolization, degeneration, tubular cell flattening, hyaline cast, tubular dilatation, and debris materials in tubular lumen- induced by gentamicin . TreatmeThe author wants to thank from the personals of Department of Anatomy, Lorestan University of Medical Sciences.MT is the single author of the manuscript.The author declared no competing interests.Ethical issues have been completely observed by the author.None declared."} +{"text": "Objective: The purpose of this study was to assess central (aortic) vascular dysfunction in post renal transplant patients by high-resolution cardiovascular magnetic resonance imaging (CMR). Background: Renal transplant recipients are at increased risk of cardiovascular (CV) disease. The cardiac phenotype in post-transplant recipients is not well defined. A recent study suggested myocardial perfusion is impaired in renal transplant patients irrespective of the degree of left ventricular hypertrophy.We hypotMethods: Twenty-five asymptomatic renal transplant patients (RT) and 17 hypertensive controls (HT) underwent CMR scanning at 1.5 T. Myocardial function, late enhancement, aortic pulse wave velocity and first-pass perfusion at rest and stress was performed. Myocardial Perfusion Reserve Index (MPRI) was calculated as the ratio of hyperemic to resting myocardial blood flow by dividing the myocardial perfusion at stress by rest perfusion (corrected to rate pressure product). Pulse wave velocity (PWV) was calculated as the ratio between the distance and time from ascending aorta to descending aorta at the level of main pulmonary artery. Statistical analyses were performed using mixed effects modelling for MPRI and linear regression for relationship between MPRI and PWV.Results: Baseline clinical characteristics were similar for RT and HT control groups. Mean inter-ventricular septal thickness and LV mass indexed to body surface area were similar in both RT cases and HT controls. MPRI was significantly lower in the RT group compared to the HT group , globally and in all three coronary artery territories[Conclusions: In our cohort population, there is no evidence of increased aortic stiffness in post renal transplant patients compared to hypertensive patients. Although these patients demonstrate impaired myocardial perfusion reserve, this is not correlated with increased aortic stiffness.None."} +{"text": "Rapidly destructive coxarthrosis (RDC) is a rare syndrome that involves aggressive hip joint destruction within 6\u201312 months of symptom onset with no single diagnostic laboratory, pathological, or radiographic finding. We report an original case of RDC as an initial presentation of seronegative rheumatoid arthritis (RA) in a 57-year-old Caucasian woman presenting with 6 months of progressive right groin pain and no preceding trauma or chronic steroid use. Over 5 months, she was unable to ambulate and plain films showed complete resorption of the right femoral head and erosion of the acetabulum. There were inflammatory features seen on computed tomography (CT) and magnetic resonance imaging (MRI). She required a right total hip arthroplasty, but arthritis in other joints showed improvement with triple disease modifying antirheumatic drugs (DMARD) therapy and almost complete remission with the addition of adalimumab. We contrast our case of RDC as an initial presentation of RA to 8 RDC case reports of patients with established RA. Furthermore, this case highlights the importance of obtaining serial imaging to evaluate a patient with persistent hip symptoms and rapid functional deterioration. Rapidly destructive coxarthrosis (RDC) of the hip joint was initially coined in 1970 . The joiA 57-year-old Caucasian woman was referred to our rheumatology outpatient center from the orthopedics service for assessment of a possible inflammatory etiology for her rapidly destructive arthritis. Initial diagnostic work-up was significant for elevated inflammatory markers, weakly positive antinuclear antibody (ANA) and otherwise negative autoimmune markers including both rheumatoid factor (RF) and anticitrullinated peptide (anti-CCP) . All culInitial plain films of her right hip and pelvis showed femoral head lucencies compatible with subchondral cysts (but no definite fracture) and moderate diffuse articular joint space loss with flattening of the femoral head . Over a Three right hip aspirations were attempted with sufficient sample in only one attempt, which showed bloody fluid, 0.6 nucleated cells (17% neutrophils), and presence of only extracellular but not intracellular calcium pyrophosphate dehydrate (CPPD) crystals. Synovial biopsy did not reveal any crystals. Historically, CPPD crystal deposition disease can cause such acutely destructive disease on imaging and pathology , but theThe major differential diagnosis of this atypical case of destructive arthritis is outlined in In order to definitively differentiate between chronic sepsis, malignancy, and a chronic inflammatory process, an open biopsy of the hip was performed by the orthopaedic service, which showed overall morphology with features of chronic inflammation, fibrosis, multinucleated giant cell reaction with dystrophic calcification, and reactive synovial proliferation . CultureAn inflammatory etiology was most likely given multiple swollen joints, elevated inflammatory markers, constitutional symptoms, evidence of inflammatory features on imaging, and other causes excluded. Hence, a diagnosis of seronegative rheumatoid arthritis (RA) was ultimately made, fulfilling 4/7 of the 1987 RA American College of Rheumatology (ACR) classification criteria and scorInflammatory arthritis is a rare cause of RDC with only 8 case reports of patients with preexisting RA , 9\u201311. LAnother atypical feature of this patient's presentation was an associated benign soft tissue mass with enhancement involving the articular region, acetabulum, sacroiliac region, and anterior pelvis . A previTotal hip arthroplasties have been used as a treatment modality for severe RDC with good response in a retrospective review of total hip arthroplasties performed on patients with RDC . HoweverTo conclude, rheumatoid arthritis is a rare cause of rapidly destructive coxarthrosis (RDC). We present the first case report of RDC as the initial presentation of seronegative rheumatoid arthritis in a 57-year-old woman who required right total hip arthroplasty, but whose other active joints had a good response to DMARD and biologic therapy. This case also highlights the importance of obtaining serial imaging to evaluate a patient with persistent hip symptoms and rapid functional deterioration."} +{"text": "Laparoscopic appendectomy is increasingly accepted as the preferred surgical treatment for acute appendicitis and represents one of the most common emergency operations performed in both adult and paediatric populations. However, in patients with perforated appendicitis laparoscopy is associated with an increased incidence of postoperative intraabdominal infections compared to open appendectomy. Nowadays urgent imaging is commonly requested by surgeons when postoperative complications are suspected. Due to the widespread use of laparoscopy, in hospitals with active surgical practices clinicians and radiologists are increasingly faced with suspected postappendectomy complications. This pictorial essay illustrates the normal cross-sectional imaging findings observed shortly after laparoscopic appendectomy and the spectrum of appearances of iatrogenic intraabdominal infections observed in adults and adolescents, aiming to provide radiologists with an increased familiarity with early postoperative imaging. Emphasis is placed on the role of multidetector CT, which according to the most recent World Society of Emergency Surgery (WSES) guidelines is the preferred and most accurate modality to promptly investigate suspected intraabdominal infections and highly helpful for correct therapeutic choice, particularly to identify those occurrences that require in-hospital treatment, drainage or surgical reintervention. In teenagers and young adults MRI represents an attractive alternative modality to detect or exclude iatrogenic abscesses without ionising radiation.Teaching pointsLaparoscopic appendectomy is the preferred surgical treatment for uncomplicated acute appendicitis\u2022 In perforated appendicitis laparoscopy results in increased incidence of intraabdominal infections\u2022 Multidetector CT promptly assesses suspected iatrogenic intraabdominal infections\u2022 Interpretation of early postoperative CT requires knowledge of normal postsurgical imaging findings\u2022 Postsurgical infections include right-sided peritonitis, intraabdominal, pelvic or liver abscesses\u2022 Acute appendicitis (AA) represents one of the most common surgical emergencies worldwide and often occurs in young people, adolescents and children. Nowadays laparoscopic appendectomy (LA) has become increasingly accepted as the preferred surgical procedure in adult patients with suspected or documented AA \u20134.However, despite several published studies it is still unclear whether the classical open appendectomy (OA) remains superior to LA in terms of efficacy and safety. Although with similar overall short-term morbidity and mortality compared to OA, in adults LA is associated with lower incidence of wound infection, postoperative ileus and analgesics use, an earlier resumption of normal diet, shorter hospitalisation and more rapid recovery to normal activities , 5, 6. PSimilarly, in paediatric populations LA currently represents the preferred surgical procedure for most cases of AA and is associated with shorter hospitalisation, earlier resumption of normal diet and activities, and a reduced morbidity including lower incidence of wound infections and postoperative ileus , 10. How2 pneumoperitoneum and a local thermal effect from surgical instrumentation , 2221, 2Exceptionally, intraabdominal infections may seed via a patent processus vaginalis leading to the formation of a scrotal abscess .Furthermore, as with other abdominal surgeries, the portal venous system should be carefully scrutinised for signs of dilatation and filling defects. Following appendectomy pylephlebitis has been occasionally reported to involve the superior mesenteric vein, particularly in patients with underlying coagulopathy or when the operation is performed in advanced stages of the disease with peritonitis .Appendectomy remains one of the most common emergency surgical procedures and is increasingly performed using laparoscopy. Partly due to fear of litigation, urgent diagnostic imaging is increasingly requested by surgeons when postoperative complications are suspected after laparoscopic procedures. Prompt cross-sectional imaging investigation with MDCT and familiarity with the normal postoperative findings and the imaging appearances of IAA are helpful for accurate diagnosis and correct therapeutic choice, particularly to identify those occurrences that require prolonged in-hospital treatment, drainage or surgical reintervention. When available, MRI represents a valuable alternative modality that allows avoiding ionising radiation in young patients and adolescents in good clinical condition , 15."} +{"text": "The incorporation of tidal inundation information and detailed data on landscape features, such as the structure of saltmarsh vegetation at mangrove boundaries, should improve the accuracy of models that are being developed to forecast mangrove distributional shifts in response to sea-level rise.Few studies have empirically examined the suite of mechanisms that underlie the distributional shifts displayed by organisms in response to changing climatic condition. Mangrove forests are expected to move inland as sea-level rises, encroaching on saltmarsh plants inhabiting higher elevations. Mangrove propagules are transported by tidal waters and propagule dispersal is likely modified upon encountering the mangrove-saltmarsh ecotone, the implications of which are poorly known. Here, using an experimental approach, we record landward and seaward dispersal and subsequent establishment of mangrove propagules that encounter biotic boundaries composed of two types of saltmarsh taxa: succulents and grasses. Our findings revealed that propagules emplaced within saltmarsh vegetation immediately landward of the extant mangrove fringe boundary frequently dispersed in the seaward direction. However, propagules moved seaward less frequently and over shorter distances upon encountering boundaries composed of saltmarsh grasses versus succulents. We uniquely confirmed that the small subset of propagules dispersing landward displayed proportionately higher establishment success than those transported seaward. Although impacts of ecotones on plant dispersal have rarely been investigated Impacts of climate change may be displayed by a variety of responses at the individual population, species, community, or ecosystem level. Populations are predicted to track their niche and shift predictably towards suitable areas , 2, but Although directional dispersal of individuals towards those areas suitable for sustaining populations has often been discussed , 8 and msensu boundary permeability within the buffer. Conversely, propagules from succulent-grass plots rooted a mean (\u00b1 se) distance of 6.7 (\u00b1 5.1) cm seaward of the starting position. On the last sampling date, we also observed a trend towards greater leaf production by A. germinans seedlings (71% produced leaves) from the grass monoculture treatment compared to leaf production by seedlings (52%) that were emplaced into the succulent-grass ecotone treatment. Finally, A. germinans propagules that had been emplaced into grass monoculture plots produced a slightly higher number of leaves than that recorded for individuals emplaced into succulent-grass plots .The composition of the experimental saltmarsh boundaries into which propagules were emplaced also influenced spatial patterns of mangrove establishment. By 6 weeks, 50.8% of all propagules had successfully rooted . Of the ositions . AdditioFactors influencing an inland niche shift of the black mangrove emerge from our quantification of landward movement of mangrove propagules upon encountering saltmarsh boundaries. Our study demonstrates that biotic boundaries erected by saltmarsh plants play a key role in directing the initial sequence of landward migration of mangroves expected under conditions of increasing sea-level. More specifically, hydrochorous transport vectors and structural features of saltmarsh plants combine to determine permeability of inland boundaries to dispersing mangrove propagules. By recording both propagule retention and seedling establishment at landward mangrove margins we newly identified processes that contribute to successful mangrove persistence during inland migration. Our work provides empirical assessment of responses by early life-history stages of the black mangrove to the spatial arrangement of co-occurring coastal taxa thereby adding insight into the adaptive capacity for mangroves to respond to challenges from climate change.in situ work on mangrove dispersal [In agreement with ispersal , mangrovispersal , 20. Theispersal . This fiSporobolus virginicus, because both frequency and distance of seaward dispersal of propagules was reduced compared to the boundary containing succulent plants. Where succulents were present, comparatively higher proportions of propagules transported seaward led to a reduced abundance of potential colonizers remaining at the leading edge of mangrove migration. Propagule dispersal through saltmarsh plants was likely influenced by the physical characteristics of the saltmarsh taxa, such as structural complexity [Although propagules emplaced into either boundary condition, i.e., grass monoculture or succulent-grass, generally moved seaward, the influence of saltmarsh taxa on the inland movement of the remaining propagules varied in a consistent way. Notably, propagule retention was improved at the saltmarsh boundary composed of monocultures of the saltmarsh grass, mplexity , height Rhizophora mangle propagules, which are considerably larger and distinctly different in shape than A. germinans [A. germinans propagules through succulent saltmarsh vegetation at our study site.Various types of saltmarsh-mangrove boundaries occur throughout the Caribbean and Gulf of Mexico , 28, 30.erminans , may becerminans ; whereaspersonal observations), suggest that some propagules transported landward are able to survive and ultimately achieve reproductive success. As appears to be true for mangroves, studies of migration by terrestrial plants challenged by climate drivers have also reported examples of directional dispersal running counter to the predicted direction of a niche shift [Aglaia aff. flavida were preferentially deposited uphill by Casuarius bennetti while, in contrast, most undispersed seeds moved downhill. Thus spatial shifts of both this montane plant and black mangrove appear to depend upon a comparatively small subset of propagules that are transported to, and successfully establish in, suitable sites.Landward transport of mangrove propagules at the saltmarsh boundary occurred within days; yet a pattern demonstrating inland recruitment persisted for at least 6 weeks, after which time most propagules became established seedlings. Moreover, a proportional increase in seedling establishment and leaf production was recorded for propagules that dispersed landward relative to seaward. These observations are aligned with Rabinowitz who docuhe shift , 15, 16.he shift , 14, 43 he shift . Directihe shift . Mack [4Previously unavailable information on the direction of mangrove propagule dispersal across saltmarsh boundaries and spatial patterns of seedling establishment in the context of landscape features emerged from our experiments. Building on these findings, conditions under which boundary permeability to tidally-dispersed mangrove propagules and subsequent recruitment patterns might be altered can be identified. For instance, the potential for mangroves to be transported landward and establish at comparatively higher tidal elevations should vary if dispersal vectors or saltmarsh community composition are modified because of associated impacts to boundary function , 36, 39.Climate change is expected to increase the frequency/intensity of storms , which mAdditionally, propagule dispersal may be altered if the ecotone between saltmarsh succulents and grasses itself responds dynamically to climate drivers by shifting landward . As struFurthermore, complex biotic interactions between mangroves and saltmarsh taxa may operate not only during mangrove dispersal and recruitment, as shown here, but also during later life stages . In thisIn summary, our results suggest that interplay between tidal transport and physical attributes of saltmarsh vegetation assumes a critical role in directing the initial phase of shifting mangrove distributions and thus the capacity of black mangroves to respond to rising sea-level. These combined findings imply that any modification of tidal conditions or changes in plant composition of intertidal/supratidal landscapes through which propagules must disperse should impact the rate of successful mangrove migration as a consequence of altered mangrove dispersal and boundary permeability. The next challenge is to evaluate the capacity of mangroves to migrate inland as the coastal landscape is rearranged not only by rising sea-level but also other climate drivers.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file."} +{"text": "The accurate definition of organs at risk (OARs) is required to fully exploit the benefits of intensity-modulated radiotherapy (IMRT) for head and neck cancer. However, manual delineation is time-consuming and there is considerable inter-observer variability. This is pertinent as function-sparing and adaptive IMRT have increased the number and frequency of delineation of OARs. We evaluated accuracy and potential time-saving of Smart Probabilistic Image Contouring Engine (SPICE) automatic segmentation to define OARs for salivary-, swallowing- and cochlea-sparing IMRT.Five clinicians recorded the time to delineate five organs at risk for each of 10 CT scans. SPICE was then used to define these structures. The acceptability of SPICE contours was initially determined by visual inspection and the total time to modify them recorded per scan. The Simultaneous Truth and Performance Level Estimation (STAPLE) algorithm created a reference standard from all clinician contours. Clinician, SPICE and modified contours were compared against STAPLE by the Dice similarity coefficient (DSC) and mean/maximum distance to agreement (DTA).For all investigated structures, SPICE contours were less accurate than manual contours. However, for parotid/submandibular glands they were acceptable . Modified SPICE contours were also less accurate than manual contours. The utilisation of SPICE did not result in time-saving/improve efficiency.Improvements in accuracy of automatic segmentation for head and neck OARs would be worthwhile and are required before its routine clinical implementation. The accurate definition of organs at risk (OARs) is required to fully exploit the benefits of intensity-modulated radiotherapy (IMRT) for head and neck cancer. HoweverFollowing head and neck radiotherapy, adverse late effects are highly prevalent and these impact on both organ function and more general domains of well-being, such as physical, mental and social health. RadiatiSwallowing dysfunction is seen in up to half of patients treated with definitive synchronous chemo-radiotherapy and is the most common late grade \u22653 toxicity; the incidence has increased with intensification of treatment including addition of chemotherapy or altered fractionation-16. ThisPermanent and predominantly high frequency sensori-neural hearing loss may occur in 40-60% of patients who receive radiotherapy to areas such as the nasopharynx, para-nasal sinuses and parotid bed-31. ThisSignificant anatomic changes and alteration in dose to target volumes and OARs may occur during a course of head and neck radiotherapy-37. A stSmart Probabilistic Image Contouring Engine (SPICE) is an automated commercially available algorithm, which combines an atlas-based and model-based approach to segmentation of head and neck lymph node levels and OARs. The atlThis study aims to evaluate accuracy and time-saving of SPICE to define OARs for salivary-, swallowing- and cochlea-sparing IMRT.utilisation of SPICE in clinical practice (clinician review and modification). These also demonstrate introduction of bias by automatic segmentation .Ten radiotherapy planning CT scans were selected where the OARs of interest were not distorted by tumour or artefact . Five clinicians (four Consultants/Attending Physicians and one Fellow) recorded for each scan the time to manually delineate the parotid and submandibular glands, larynx (supraglottic and glottic larynx defined as one structure), pharyngeal constrictor muscles and cochleae according to a locally agreed protocol based on published guidelines ,48,49. SThe Simultaneous Truth and Performance Level Estimation (STAPLE) algorithm employs a probability map to create a \u2018best fit\u2019 from a collection of contours Figure\u00a050]. Th. Th50]. t-test (to determine efficiency in the utilisation of SPICE). Significance was assessed at the p\u2009<\u20090.05 level.Statistical comparisons using multiple linear regression analysis were made between mean values of all matrices for: SPICE against STAPLE versus manual against STAPLE (to determine the accuracy of SPICE); and modified SPICE against STAPLE versus manual against STAPLE . As a further measure of accuracy, SPICE was compared with the most discordant clinician contours (determined against STAPLE and by ranking of clinicians) for each structure measured by DSC and DTA, using the Wilcoxon signed rank test. The total times to manual versus modify SPICE contours for all structures and clinicians were compared using Student\u2019s paired SPICE submandibular gland \u20181\u2019 and parotid gland \u20182\u2019 contours demonstrated best concordance with STAPLE Table\u00a0 and4. SThe total proportions of SPICE contours determined by visual inspection not to require alteration were: parotid glands 17%), submandibular glands (41%), larynx (8%), pharyngeal constrictor muscles (4%), and cochleae (28%). The mean DSCs were significantly reduced for modified SPICE contours compared with manual for all structures Figure\u00a0. However%, submanThe respective per scan overall mean times for manual and modified SPICE contours were 14.0 and 16.2\u00a0minutes Figure\u00a0. Only onThis study showed that for head and neck OARs: (i) SPICE contours were less accurate than manual contours, but acceptable for the definition of parotid and submandibular glands; (ii) modified SPICE contours remained inferior to manual contours; and (iii) the utilisation of SPICE compared with manual delineation did not result in time-saving/improve efficiency.et al compared for two CT scans and eight clinicians, manual and automatic modified contours for delineation of the clinical target volume as well as parotid glands, spinal cord, brainstem and (for one scan) the optic apparatus[ISOgray atlas-based auto-segmentation algorithm was evaluated for definition of the brainstem, parotid glands and mandible[Automatic segmentation to define selected head and neck OARs may reduce inter-observer variability,55. Chaopparatus. For theBrainlab automated segmentation algorithm, which employs atlas-based and deformable registration, was assessed for accuracy of definition of neck nodal regions and selected head and neck OARs[The updated eck OARs. In 10 \u2018Clinical validation of a multiple-subject atlas-based autosegmentation tool was performed by measuring the DSC and mean DTA for manual contours (outlined by one of 10 clinicians and agreed by an expert panel) and modified contours (outlined by one of two clinicians) for neck levels, parotid and submandibular glands in 12 patients. For manWe found that SPICE automatic contours were less accurate/inferior to manual contours for all investigated structures, but acceptable for the parotid and submandibular glands. For the parotid and submandibular glands, the DSCs were satisfactory;,52 for pWhether differences between manual, automatic or modified contours result in clinically relevant alterations in measured doses to OARs is uncertain. This will partly depend on proximity of normal structures to the treatment volume and the dose gradient. In this study, the target volumes were not defined. This may have influenced the low percentage of OARs determined by visual inspection not to require alteration i.e., clinicians only considered the conformity of automatic contours to normal structures rather than clinical relevance or requirement for this.This study represents an independent clinical evaluation of automatic segmentation using SPICE and its utilisation for head and neck OARs. It determined the accuracy of SPICE by comparison against a reference standard created using STAPLE, for five head and neck OARs important in function-sparing IMRT. Future work should evaluate automatic segmentation in the presence of distortion by tumour or artefact e.g., dental amalgam; and determine the variation in measured dose to OARs between manual, automatic and modified contours.For the investigated head and neck OARs, SPICE automatic segmentations were less accurate than manual contours. However, these were acceptable for the definition of parotid and submandibular glands. The modification of SPICE contours improved accuracy, but these remained inferior to manual contours and the process did not result in time-saving. Improvements in automatic segmentation of head and neck OARs would be worthwhile and are required before routine clinical implementation.OARs: Organs at risk; IMRT: Intensity-modulated radiotherapy; SPICE: Smart Probabilistic Image Contouring Engine; STAPLE: Simultaneous Truth and Performance Level Estimation; DSC: Dice Similarity Coefficient; DTA: Distance to agreement; PARSPORT: Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer; Gy: Gray; kV: kilovoltage; CT: Computed tomography.The authors declare that they have no competing interests.DT designed and coordinated the study, participated in contouring, analysed part of the data, interpreted data, drafted the manuscript. CB performed STAPLE and volume overlap measurements. TL analysed the data. AA provided the DTA algorithm and helped with volume overlap measurements. LL, BY, AJS, NJS participated in contouring. CR/NJS conceived the study, participated in its design and coordination and helped draft the manuscript. All authors read and approved the final manuscript."} +{"text": "To assess medical and nursing students\u2019 intentions to migrate abroad or practice in rural areas.We surveyed 3199 first- and final-year medical and nursing students at 16 premier government institutions in Bangladesh, Ethiopia, India, Kenya, Malawi, Nepal, the United Republic of Tanzania and Zambia. The survey contained questions to identify factors that could predict students\u2019 intentions to migrate. Primary outcomes were the likelihoods of migrating to work abroad or working in rural areas in the country of training within five\u00a0years post-training. We assessed predictors of migration intentions using multivariable proportional odds models.Among respondents, 28% (870/3156) expected to migrate abroad, while only 18% (575/3158) anticipated a rural career. More nursing than medical students desired professions abroad . Career desires before matriculation correlated with current intentions for international and rural careers. Time spent in rural areas before matriculation predicted the preference for a rural career and against work abroad .A significant proportion of students surveyed still intend to work abroad or in cities after training. These intentions could be identified even before matriculation. Admissions standards that account for years spent in rural areas could promote greater graduate retention in the country of training and in rural areas. We know very little regarding the characteristics of students inclined to work in rural areas or remain in the country in which they train.\u2013http://biostat.mc.vanderbilt.edu/StudentMigration).Previous studies on health worker retention are mainly from high-income countries,\u2013We considered countries in sub-Saharan Africa and south-east Asia that were classified by WHO as having a critical shortage of health service providers .,To enhance similarity between study institution governance structure and founding principles, we excluded countries without both a government medical and nursing school, or in which either school was established after 1993. This date corresponds to a period of increased attention to health sector reform in developing countries that may have affected guiding missions of health training institutions established thereafter.The 16 study sites selected are listed in We conducted the study from September 2011 to April 2012. Students eligible for our study were first- or final-year students enrolled in medical or nursing (Bachelor of Science) degree programmes. At each institution, a self-administered questionnaire was given to all eligible students attending a mandatory class lecture. Written informed consent was obtained before survey administration. Survey items assessed student background characteristics such as socioeconomic status and place of origin, attitudes towards rural and international careers and student career intentions (Appendix). Questions, derived from literature review (Appendix), consisted largely of multiple-choice items and five-point Likert scales. Surveys were in English. To minimize potential bias from variable English proficiency, official language translations were provided as an aide alongside the English questions in five countries where English is not an official language. Translations were validated using independent back-translation. Field testing was performed in each country and country-specific modifications were made to ensure relevant terminology. The two primary outcomes were self-reported likelihood of choosing to work outside the country or in a rural setting inside the country within five years post-training.Questionnaire results were entered electronically and data entry audited by randomly selecting 22 electronic questionnaires from each country for comparison with hard copies. Audit sample size was calculated to ensure an estimated data entry error rate less than\u20095% with 95% confidence interval (CI). Questionnaires with more than\u200925% of responses missing were excluded from analysis.http://www.r-project.org) for data analyses.For each country, we used summary statistics to describe respondent characteristics and multivariable proportional odds models to estimate the independent relationship between 14 selected characteristics and the likelihood to work internationally or in rural areas. The number of characteristics selected was computed using the smallest country sample size.At the 16 institutions studied, 3822 students were enrolled in first- or final-year medical or nursing degree classes . Of thesTen schools in sub-Saharan Africa comprised 66% (2118/3199) of the study population, while six South Asian schools encompassed 34% (1081/3199) . MedicalOf all students, 28% (870/3156) reported being very likely to choose work abroad within five years of completing training . InternaMultivariable analysis showed that nursing students were more likely than medical students to intend careers abroad . Final-year students were less likely to plan international careers than first-year counterparts of all students reported high likelihood of choosing a rural career within five years of training, including 16% (360/2257) of medical and 24% (215/901) of nursing students . In sub-As with international migration intentions, individuals who upon school entry had desired a rural career were now nearly five times more likely to plan one . Our aggregate class response rate is high (84%). Our study is systematic, employing rigid yet relevant selection criteria to identify study sites. All participating nations face significant health worker shortages and ongoing emigration, but possess stable environments where retention policies are not superseded by larger systemic sociopolitical motivators of migration. We independently analysed 14 student characteristics to identify predictors for a career in the country or in rural areas. Our results have implications for education and health-care policy-makers in LMIC and donor nations.Our sample cannot be generalized to areas where internal conflict or political turmoil may drive migration regardless of student characteristics, nor can it be extrapolated to non-Anglophone countries. Sub-Saharan African countries have comparable physician emigration rates regardless of national language,,,,,Our data suggest that students\u2019 career desires before matriculating may persist into the last year of training. Although our study design cannot exclude recall bias, the direction of recall error is unclear and should be further investigated through longitudinal assessment. Similarly, under-reporting of true migration intentions due to perceived values of the school professionals might create a social bias. However, if such bias is present it would strengthen our results, since the true number of students intending to migrate may be higher and those planning to work in rural areas even lower than we report. Social bias was mitigated by survey anonymity and is unlikely to have affected class years differently. Our cross-sectional questionnaire of students\u2019 intentions is not validated for predicting actual migration behaviour. Nonetheless, the similarity of our results to existing migration statistics suggests that students\u2019 intentions may resemble such behaviour.,Further research is needed to understand the migration intentions of students. Our study focused on students at premier public schools, where institutional missions focus on producing practitioners for domestic service and health-care leadership, and where public funds offset educational expenses. Migration ambitions may differ at private or newly-established public institutions with varying school resources, values and admissions standards. Also, longitudinal analysis is needed to discern whether differences in career plans between first- and final-year classes represent an evolution of students\u2019 preferences during the schooling period or a change in class composition resulting from recent enrolment expansions at many institutions studied. Finally, additional migration routes of health professionals in LMIC remain to be studied: from public to private sector and from clinical to administrative sector. This is important research since health professionals\u2019 movements from clinical public-sector work threaten already fragile public-health systems.\u2013,,,Increased demand for health professionals in developed countries is projected to attract even more LMIC graduates,With nearly 64% of people in sub-Saharan Africa and 69% in South Asia residing in rural areas,"} +{"text": "Addiction services organizations have been slow to adopt and implement evidence-based practices (EBPs) for substance abuse and dependence. This is due in part to poor worker morale and organizational climates that are not conducive to successful learning and integration of these practices . Person-Direct service providers (N = 120) from four addiction services organizations in a large Midwestern city responded to a survey assessing provider morale, organizational learning climate, agency expectations for EBP use, agency resources for EBP use, and provider attitudes towards EBP use. Difference scores between provider- and agency-level factors were computed to model provider-agency fit. Linear regression models were accounted for in all analyses, but were determined to be insufficiently sensitive in modeling the curvilinear (inverted U-shaped) relationships expected in this study. Therefore, quadratic regression analyses were conducted to more adequately model the level of the dependent variables across the entire \u201cfit continuum.\u201dMisfit between agency expectations and provider attitudes and between agency resources and provider attitudes were associated with poorer provider morale and weaker organizational learning climate. For all hypotheses, the curvilinear model of provider-agency misfit significantly predicted provider morale and organizational learning climate Figures and 2. MThis research benefits from a strong theoretical framework, consistent findings, and significant practical implications for substance abuse treatment agencies. Provider morale and organizational learning climate are important indicators of successful EBP implementation. Comprehensive attempts to strengthen these outcomes must consider both provider- and agency-level characteristics regarding EBP use. Managers and supervisors should consider conducting periodical self-assessments of their agency\u2019s cultural predispositions toward EBP implementation and addiction service providers\u2019 openness, abilities, and general attitudes towards using EBPs. Organizational efforts to more closely align provider attitudes and agency priorities will likely constitute a key strategy in fostering the implementation of EBPs in addiction services organizations."} +{"text": "In MOF the competition for the amino acid arginine between the microcirculation and the inflammatory response is important. The endothelial nitric-oxide synthase (eNOS) uses arginine to produce nitric oxide (NO), which results in microcirculatory vasodilatation, whereas arginase and the inflammatory nitric-oxide synthase (iNOS) use arginine in the inflammatory response to produce acute phase proteins and to stimulate the host response. Enhanced arginine consumption combined with decreased arginine To investigate the role of the NOS enzymes during endotoxemia and the effect of citrulline supplementation on the arginine-NO synthesis and microcirculation.-/-; n= 39), deficient eNOS mice and double knock-out (KO) mice received a continuous LPS infusion for 18 hrs alone or combined with citrulline (37.5mg) for the last 6 hrs. SDF-imaging was used to evaluate the microcirculation in jejunal villi and the NO production in jejunal tissue was determined by in vivo NO spin trapping and quantified by electron spin-resonance spectrometry. After the microcirculatory measurements or in vivo NO spin trapping, mice were sacrificed, blood and tissues were sampled. Amino-acid concentrations in blood and tissue were measured by High Performance Liquid Chromotography.Wildtype (n= 39), deficient iNOS mice, (iNOS-/- or eNOS-/- mice this was not accompanied by a decreased intracellular arginine availability. Jejunal NO production was significantly decreased in all mouse strains during endotoxemia, except for eNOS-/- mice. LPS infusion resulted in a significantly decrease in jejunal microcirculation in wildtype and iNOS-/- mice. However, mice lacking a functional eNOS enzyme, as present in eNOS-/- and double KO mice, perfusion in jejunal tissue did not decrease during LPS infusion. Also the beneficial effects of citrulline supplementation during LPS infusion on the microcirculation were not present in eNOS-/- or double KO mice, although citrulline significantly enhanced the plasma arginine availability in all mouse strains. In addition, tissue arginine availability did not increase in citrulline supplemented NOS deficient mice.LPS infusion significantly decreased plasma arginine availability in all mouse strains. However, in the jejunal tissue of iNOSde novo synthesis during sepsis, however to enhance the microcirculation during sepsis, citrulline requires a functional eNOS enzyme. Therefore, future research needs to focus both on improvement of the arginine de novo synthesis and maintenance of a functional eNOS enzyme during sepsis.Citrulline improves the arginine"} +{"text": "There is increasing integration of qualitative research within randomised controlled trials (RCTs). However, how these methods are applied at the pre-trial stage to inform trial design and conduct is less well explored. Here we describe how qualitative methods were used in a feasibility study to inform the design of a pilot RCT.Semi-structured interviews with purposely sampled clinicians (n=61) and patients (n=32) explored current clinical practice and views about the proposed trial interventions and protocol. Analysis used constant comparative approaches. Emerging findings were disseminated through focused reports/presentations to the study management group and steering committee as research progressed.Qualitative findings informed changes to fundamental aspects of trial design and proposed outcome measures. Clinicians' interpretations of the original interventions were variable, and descriptions of current practice/terminology consistently differed with assumptions made in the grant proposal and commissioned call for research. New outcomes were recognised, prompted by clinicians'/patients' priorities. Measuring and reporting these outcomes was deemed crucial for a full trial's potential to impact future practice. Interviews with clinicians also prompted new \u2018in trial\u2019 data collection requirements, as clinicians anticipated potential changes to their clinical practice to accommodate the trial interventions. These changes had potential to impact the primary outcomes, prompting recommendations to measure/record these practices during trial conduct.Qualitative research at the pre-trial stage can transform fundamental aspects of trial design/delivery. Presenting emergent findings as the research progresses is one approach to enhancing impact, facilitated by participation of qualitative researchers as core members of investigator teams."} +{"text": "In contrast, remarkable advances in its basic genomics have not been sufficiently translated into the molecular epidemiology of diphtheria. A recent report by Zasada . More recently, a multilocus sequence typing (MLST) scheme for C. diphtheriae was developed . The second approach is locus oriented and makes use of the repetitive DNA sequences, namely, variable number tandem repeats (VNTR) and clustered, regularly interspaced short palindromic repeats (CRISPR) loci.Two in silico\u2013inspired approaches have recently been pursued toward more precise molecular genetics and epidemiology of diphtheria. The first approach is based on whole-genome sequencing (WGS). After years of stagnation, the number of complete C. diphtheriae analysis might offer a broader range of possible general solutions from global tracing of large clonal clusters (current threshold) toward fine-tuned strain discrimination. At the same time, a multicenter evaluation of recently developed inexpensive and discriminatory VNTR and CRISPR methods is warranted to see if and how they could complement regional surveillance."} +{"text": "The brainstem is the major site of trigeminal pain processing and modulation and plays a key role in the pathophysiology of various headache disorders. However, comprehensive human imaging studies on function and activity of brainstem areas following trigeminal nociceptive stimulation are scarce.To develope a viable protocol for brainstem fMRI of standardized trigeminal nociceptive stimulation.21 healthy participants were scanned on a 3T scanner with a standardized trigeminal nociceptive stimulation protocol for event-related fMRI using a specifically designed sequence for high resolution brainstem echo planar imaging as well as a brainstem specific noise correction technique and brainstem template.We observed significant BOLD responses in areas typically involved in trigeminal nociceptive processing such as the spinal trigeminal nuclei (sTN), thalamus, SII, insular cortex and cerebellum as well as in a pain modulating network including the dorsal raphe nuclei (DRN), periaqueductal grey area (PAG), hypothalamus (HT) and nucleus cuneiformis (CN) . Using PPI analyses, we found enhanced connectivity of the sTN with the HT and the CN.Our results are in line with previous animal and human imaging studies on brainstem processing of nociceptive stimuli. However, using the proposed high resolution imaging technique, we achieved a more detailed insight into brainstem pain processing as compared to whole brain fMRI. High resolution brainstem fMRI of trigeminal nociceptive stimulation offers a unique opportunity to better understand headache pathophysiology.No conflict of interest."} +{"text": "The mechanism by which this activity regime is generated is well-known [While the physics of local field potential (LFP) generation are well-established, the complexity of neural network dynamics means that interpreting LFP measurements in terms of the underlying neural activity is very difficult . Recent ll-known , and manWe describe three key results from our simulations. Firstly, we found that perisomatic synaptic currents on pyramidal neurons resulting from basket interneuron firing dominate the LFP during gamma oscillations, in agreement with recent experimental results ,4. We pr"} +{"text": "Peripheral neuropathy is a common complication of arsenic toxicity. Symptoms are usually mild and reversible following discontinuation of treatment. A more severe chronic sensorimotor polyneuropathy characterized by distal axonal-loss neuropathy can be seen in chronic arsenic exposure. The clinical course of arsenic neurotoxicity in patients with coexistence of thiamine deficiency is only anecdotally known but this association may potentially lead to severe consequences.We describe a case of acute irreversible axonal neuropathy in a patient with hidden thiamine deficiency who was treated with a short course of arsenic trioxide for acute promyelocytic leukemia. Thiamine replacement therapy and arsenic trioxide discontinuation were not followed by neurological recovery and severe polyneuropathy persisted at 12-month follow-up.Thiamine plasma levels should be measured in patients who are candidate to arsenic trioxide therapy. Prophylactic administration of vitamin B1 may be advisable. The appearance of polyneuropathy signs early during the administration of arsenic trioxide should prompt electrodiagnostic testing to rule out a pattern of axonal neuropathy which would need immediate discontinuation of arsenic trioxide. She had a medical history of lobular carcinoma of the left breast treated with mastectomy and chemotherapy in 2012, Hashimoto thyroiditis, arterial hypertension. There was no prior neurological disorder and physical examination was unremarkable. Coagulation tests showed reduced prothrombin time ratio (59%) and normal activated partial thromboplastin time, a slightly reduced fibrinogen and increased D-dimer (8634 \u03bcg/L). Bone marrow evaluation was consistent with acute promyelocytic leukemia (APL) according to French-American-British (FAB) classification system. The patient was started on all-trans retinoic acid (45 mg/m2) according to protocol APL0406Although polyneuropathy is common following arsenic trioxide therapy of subjects with acute promyelocytic leukemia (APL), symptoms are generally mild and they disappear after completion of arsenic treatment. In November 2014, a 72-year old Caucasian woman was admitted to this Unit with fever and pancytopenia , neurological symptoms were attributed to sodium-related hyperosmolarity.Over the following days an impaired level of consciousness and lethargy was noticed. Progressive and appropriate normalization of natriemia did not improve neurological dysfunction.Additional diagnostic procedures were performed. A CT scan of the brain did not reveal abnormalities related to the acute clinical picture, showing only age-related mild cerebral and cerebellar atrophy. Cerebrospinal fluid showed only mild protein elevation.Plasma levels of vitamin B1 were low and supplementation was started. Over the following 5 days the patient showed a slow but progressive full recovery of cognitive functions.Unexpectedly, at normalization of cognitive function, a pattern of symmetric peripheral neuropathy involving upper and lower limbs became clinically evident. Physical examination showed that left and right hands were severely weak, particularly the abductor pollicis brevis, with mild strength reduction in the proximal arms. Deep-tendon reflexes were absent. There was bilateral foot drop, and the patient was unable to walk. Strength in the ankle dorsiflexors, extensor hallucis longus, extensor digitorum brevis, and toe flexors was severely compromised. There was no muscle atrophy or fasciculation, and the remainder of the neurologic examination was normal. Electromyography (EMG) showed a severe sensory-motor axonal neuropathy of the upper and lower extremities with a greater reduction of sensory action potential.Meanwhile on day 28 arsenic trioxide had been stopped according to the therapy protocol. Bone marrow evaluation showed molecular remission. At that time the patient was bedridden because of a severe neurological impairment, so we chose not to administer consolidation therapy as it would have been required according to standard protocol.Over the following on 6 months from arsenic trioxide discontinuation, the patient regained full proximal muscle strength but with almost complete persistence of marked distal weakness of the hands,ly finger and wrist extensors, weakness of foot dorsiflexors bilaterally and the inability to maintain an upright position. Neurological examination and EMG were substantially unchanged at the 12-month follow-up evaluation.We believe that occult thiamine deficiency exacerbated arsenic trioxide neurotoxicity causing an unexpected and irreversible distal axonal symmetric neuropathy. This is the first report of acute and irreversible axonal neuropathy in a patient treated with arsenic trioxide with a background of thiamine deficiency. Peripheral neuropathy has long since been associated with the use of arsenic. Several clinical studies have been published on ATO treatment of patients with APL .2\u201312 AltSevere and irreversible arsenic neurotoxicity in the setting of thiamine deficiency can be explained by their common metabolic target. In fact, thiamine deficiency and arsenic exposure severely impair pyruvate dehydrogenase (PDH) activity, an enzyme responsible for converting glucose to energy in high yield. As neural tissues are highly dependent on carbohydrates for energy production and cellular metabolism, it is tempting to speculate a synergic detrimental neuropathic effect leading to the severe toxicity observed in our patient. Of interest, we found electrophysiological findings consistent with acute axonal dysfunction without pattern of demyelination. This type of damage is the classic electrophysiological and histopathological finding in beriberi neuropathy whereas arsenic axonal toxicity characteristically coexists with segmental demyelination.17In conclusion, occult thiamine deficiency may contribute to arsenic toxicity and the combination may cause irreversible axonal neuropathy which must be considered when monitoring APL patients on arsenic trioxide therapy. Prophylactic administration of thiamine may be considered in this setting."} +{"text": "Mental disorders affect up to 40 % of all individuals living in Europe at least once a life time. Serious mental disorders with chronic or relapsing course like major depression bipolar disorder and schizophrenia are disabling and often disintegrating disorders. The early identification of subjects being at risk for serious mental disorders holds the promise of early intervention and better long-term outcomes. However, still reliable early indicators are largely missing to date. Like in dementia research major research initiatives need to be developed to address those urgent issues.New MRI imaging technique, genotyping, gene methylation analyses, metabolom analyses, validated questionnaires for the assessment of psychosocial risk factors.Advanced statistical modeling of brain imaging data, support vector machine approaches, systems integration of OMICS data; data mining approaches for risk marker identification.The identification of peripheral risk indicators of severe mental diseases is probably limited to rare but highly penetrative genetic variants. Possibly gene-methylation patterns that emerge in the light of abuse and traumatization be constitute another source of valuable information. The non-invasive MRI imaging technologies might be very promising but still time consuming and expensive. Especially functional MRI studies are only feasible in specialist centers. The most promising approach seems to create a set of specific markers throughout the different levels of information to integrate biological, psychosocial and structural information on each subject."} +{"text": "Spontaneous cortical activity can show very complex collective emerging features, with, in some cases, the alternation of \"down states\" of network quiescence and \"up states\" of generalized spiking and neuronal depolarization . Results"} +{"text": "THHOBO data loggers and rainfall was recorded daily using GENERALR wireless rain gauges. Thin plate spline (TPS) was used to interpolate, with the degree of data smoothing determined by minimizing the generalized cross validation. The dataset provide information on the status of the current climatic conditions along the two mountainous altitudinal gradients in Kenya and Tanzania. The dataset will, thus, enhance future research.Climate change is a global concern, requiring local scale spatially continuous dataset and modeling of meteorological variables. This dataset article provided the interpolated temperature, rainfall and relative humidity dataset at local scale along Taita Hills and Mount Kilimanjaro altitudinal gradients in Kenya and Tanzania, respectively. The temperature and relative humidity were recorded hourly using automatic onset Specifications TableValue of the data\u2022The data provide information on the status of the climatic conditions along the two mountain altitudinal gradients in Kenya and Tanzania, and includes data accessible for reuse.\u2022The data are important to farming communities, agricultural extension agents, government institutions, international and local non-governmental organizations engaged in agricultural interventions, including useful data to researchers, students and academics.\u2022The data can be used for mapping and spatial modeling in a geographical information system (GIS).\u2022The data is valuable for improvements computational facilities, insufficient climate data and reliable downscaling at a local scale.\u2022The data are important in making confidentially informed decisions, giving scientists accurate spatially continuous data cross a region for making justified interpolation.12R wireless rain gauges were installed at station across study sites to keep track of daily temperatures, relative humidity and rainfall, respectively x\u2013y coordinates position and altitudes were recorded using a Global Positioning System (GPS) (German eTrex Vista(R)). The thin plate spline (TPS) algorithm 2); (ii) the Root Mean Square Error (RMSE); and (iii) the Relative Root Mean Square Error (RMSEr).The details of the sites have been described in our previous study"} +{"text": "Diverse monogenic autoinflammatory diseases share responsiveness to interleukin (IL)-1 blockade. This study explored the utility of anakinra (an IL-1 receptor antagonist) as a treatment option for clinically heterogeneous systemic inflammatory disease with autoinflammatory presentations where a genetic cause was not defined.A total of ten adult cases with ongoing inflammatory episodes, where alternative diagnoses, including malignancy and infection, were evaluated. Genetic screening was also performed to exclude known genetic causes of autoinflammatory disorders (e.g. cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), etc.)All patients had presentations that were atypical of recognised autoinflammatory disorders and all were negative on genetic screening. Eight of ten cases showed rapid responsiveness to anakinra with the ability to subsequently taper alternative immunosuppression. Good responses to anakinra were maintained with inadvertent drug discontinuation being linked to disease flares.The spectrum of poorly defined clinical and genetic autoinflammatory disorders that show responsiveness to anakinra is considerable. In fact, responsiveness to anakinra appears to be useful in diagnosis given the characteristically rapid onset of efficacy and symptomatic improvement."} +{"text": "Aging may lead to pathologies due to the physiologic decline or aberrancy in the functions of adult stem cells, whose intrinsic capacity for self-renewal helps maintain tissue homeostasis. The majority of cancers arise from replication-induced somatic mutations in adult stem cells , which pAPC or CTNNB1 mutations, which are found in >90% of early colon adenomas [mut) in late colon adenomas drive their malignant transformation to cancer by further promoting WNT activation through \u03b2-catenin nuclear localization [per se, even when targeted to murine colon stem cells to constitutively activate their intestinal stem cell program, was capable of initiating colon adenomas but not invasive colon cancers [Hitherto, the initiation of colon cancer has been attributed mainly to the aberrant activation of WNT signaling as a result of adenomas . Indeed,lization . However cancers . Nearly cancers . Thus thmut further increases this tumorigenic and dedifferentiation program [mut to dedifferentiate APC mutated colon adenoma cells depends on their moderate plasticity, since KRASmut by itself in the cellular context of differentiated epithelial cells cannot induce the embryonic stem cell-like program [in vivo plasticity model in which the achievement of high plasticity, as exemplify by KRASmut mediated induction of the embryonic stem cell-like program in colon adenomas, optimizes colon cancer initiation. Currently, there are two conflicting theories for the colon cancer cells of origin. The top-down theory requires that differentiated crypt top colon cells undergo dedifferentiation to become the colon cancer cells of origin. The bottom-up theory suggests that crypt base WNT activated colon stem cells, which give rise to colon adenomas, are the colon cancer cells of origin [in vivo plasticity model helps explain the paradoxical findings that lend support to both the top-down and bottom-up theories on the colon cancer cells of origin.We have found that embryonic stem cell-like program activation is a major mechanistic driver of colon cancer initiation, and the presence of KRAS program . The abi program , 7. We hf origin . Howevermut tumors.Intriguingly, embryonic stem cells arise at the beginning of human ontogeny and cancer cells arise dramatically toward the end. Thus cancer cells have come nearly full circle in reactivating the embryonic stem cell-like program, which imparts greater phenotypic plasticity to thrive with environmental variations. Cancers may be the unfortunate failed manifestations of nature's quest for the fountain of youth. Nevertheless, the inhibition of the embryonic stem cell-like program offers novel therapeutic strategies to prevent cancer and inhibit KRAS"} +{"text": "A striking property of the mutualism between figs and their pollinating wasps is that wasps consistently oviposit in the inner flowers of the fig syconium, which develop into galls that house developing larvae. Wasps typically do not use the outer ring of flowers, which develop into seeds. To better understand differences between gall and seed flowers, we used a metatranscriptomic approach to analyze eukaryotic gene expression within fig flowers at the time of oviposition choice and early gall development. Consistent with the unbeatable seed hypothesis, we found significant differences in gene expression between gall- and seed flowers in receptive syconia prior to oviposition. In particular, transcripts assigned to flavonoids and carbohydrate metabolism were significantly up-regulated in gall flowers relative to seed flowers. In response to oviposition, gall flowers significantly up-regulated the expression of chalcone synthase, which previously has been connected to gall formation in other plants. We propose several genes encoding proteins with signal peptides or associations with venom of other Hymenoptera as candidate genes for gall initiation or growth. This study simultaneously evaluates the gene expression profile of both mutualistic partners in a plant-insect mutualism and provides insight into a possible stability mechanism in the ancient fig-fig wasp association. Mutualisms are ubiquitous in nature and often enhance the nutrition, protection, and/or reproduction of participating partners see , 2). Yet. Yet2]).Ficus spp.) and fig wasps arose >80 million years ago ).Use of only a subset of available flowers by foundresses cannot be explained by physical limitations in ovipositor length or egg number , 23, 24.Based on observations that foundresses are selective in choosing flowers for oviposition, West and Herre proposedFicus obtusifolia, a monoecious fig that grows natively in lowland forests in Panama. Specifically we compared metatranscriptomes of gall and seed flowers before and after fig wasps entered syconia to determine (1) biochemical and metabolic differences between these two flower types that may influence oviposition by foundress wasps, and (2) gene expression in floral tissue at gall initiation ). The high level of expression of these genes suggests that fig wasps were undergoing embryogenesis when gall flowers were collected.The hymenopteran transcript with the highest level of expression was assigned to the gene properly . AdditioA maternal secretion, which is deposited in every flower that receives an egg, has been associated with the initiation of gall growth in fig flowers , 67, 68.th highest expressing in all Hymenoptera transcripts) was assigned to icarapin, which has an active role in honeybee venom [Nasonia vitripennis, the only well-studied venom among wasps in the superfamily of Chalcidoidea, eight genes coding for proteins harboring signal peptides also shared homology with genes coding for venom proteins. Three are hypothetical proteins and the remaining five match genes predicted as serine protease, lysosomal acid phosphatase, chymotrypsin, lipase, and metalloproteinase (Table G in Eulophus pennicornis [Only 196 (2.8%) of the Hymenopteran transcripts observed here contain a signal peptide Click here for additional data file.S1 FileNumber of transcripts assigned to taxonomic groups for each sample (Table A). Overrepresented GO terms of up-regulated genes in receptive gall flowers compared to receptive seed flowers (Table B). Transcripts assigned to overrepresented GO terms associated with chalcone synthase in receptive and pollinated gall flowers (Table C). Transcripts uniquely expressed in receptive gall flowers (Table D). Transcripts assigned to overrepresented GO terms associated with carbohydrate metabolism in receptive gall flowers (Table E). Overrepresented GO terms of up-regulated genes in pollinated gall flowers compared to receptive gall flowers and pollinated seed flowers (Table F). Transcripts with assignment to Hymenoptera (Table G).(XLSX)Click here for additional data file."} +{"text": "Women seeking to become pregnant and pregnant women are currently advised to consume high amounts of folic acid and other methyl donors to prevent neural tube defects in their offspring. These diets can alter methylation patterns of several biomolecules, including nucleic acids, and histone proteins. Limited animal model data suggests that developmental exposure to these maternal methyl supplemented (MS) diets leads to beneficial epimutations. However, other rodent and humans studies have yielded opposing findings with such diets leading to promiscuous epimutations that are likely associated with negative health outcomes. Conflict exists to whether these maternal diets are preventative or exacerbate the risk for Autism Spectrum Disorders (ASD) in children. This review will discuss the findings to date on the potential beneficial and aversive effects of maternal MS diets. We will also consider how other factors might influence the effects of MS diets. Current data suggest that there is cause for concern as maternal MS diets may lead to epimutations that underpin various diseases, including neurobehavioral disorders. Further studies are needed to explore the comprehensive effects maternal MS diets have on the offspring epigenome and subsequent overall health. Mounting evidence suggests that developmental exposure to extrinsic factors leads to pronounced epigenetic and phenotypic effects, commonly referred to as the \u201cdevelopmental origin of health and disease (DOHaD)\u201d Barker, . Epigene12, and zinc , folate (vitamin B9), betaine (trimethylglycine), choline, Vitamin BAnimal model studies have examined how maternal methyl supplemented (MS) diets impact the epigenome and/or phenotypic outcomes in developing offspring Table . Some ofOther factors likely interact with maternal diet to influence the net effect of these diets. Examples include genetic background, sex, developmental windows of exposure, and tissue/cell-specific vulnerabilities, which are discussed below.vy/aA offspring), pregnant a/a female mice exposed to the endocrine disrupting compound (EDC) bisphenol A (BPA) gave birth to a greater percentage of yellow coat color compared to brown coat color (vy/aA) offspring coat color animals that are concomitantly less prone to these adult diseases. Combined prenatal treatment with a BPA and methyl-supplemented diet in these females was reported to offset the BPA-induced shift in coat color distribution from metabolic deleterious yellow morphs to an increase in brown coat color, healthier offspring within this allele is hypomethylated, vyA/a status) over several generations (through F5) to increase percentage of pseudoagouti animals possessing a methylated IAP promoter site , an extracellular modulator of bone morphogenetic protein signaling, exhibit midline facial and jaw defects. However, maternal MS diet prevented their jaw defects promoter with metabolic disorders, discussed above, and FuAxin mice exhibiting tail dysmorphogenesis, or \u201ckinky\u201d tail to high concentrations of folic acid resulted in newborn mouse pups exhibiting disrupted cerebral gene expression for transcripts and their protein products implicated in normal neural development in children for maternal consumption of prescription prenatal vitamins (containing > 1 mg of folic acid) and ASD incidence in offspring , as well as tissue/cell specificity and concentration and duration of exposure to these nutritional supplements. All of these factors should be considered when employing maternal MS diets to combat fetal disease.Comprehensive long term animal and human epidemiological studies should be undertaken to assess the global effects of these nutraceuticals and to resolve the current conflicting data in regards to maternal MS diet. Until then, women requesting prenatal/perinatal vitamin support should be advised against consuming methyl supplements, in doses that exceed the current recommendations for preventing fetal neural tube defects.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Salmonella enterica serovar Typhimurium monophasic variant strains involved in a long-term salmonellosis outbreak that occurred in central Italy in 2013 to 2014.Here, we present the draft genome sequences of 19 Salmonella is a Gram-negative foodborne pathogen distributed worldwide. Even if few lineages have been detected, its antibiotic resistance pattern is very heterogeneous, spanning from multidrug-resistant to largely susceptible strains .Nineteen strains, chosen among clinical and environmental isolates on the basis of their spatial-temporal distribution and familiar kinship, were subjected to whole-genome sequencing together with three unrelated strains as outgroups. Genomic DNA was extracted by Qiagen EasyPrep, libraries were prepared using the Hi-Q sequencing kit, and sequencing was performed on a PGM Ion Torrent platform. Raw reads were submitted to the SRA repository , while bramework plus somN50 values and GenBank accession numbers.The results from the genome annotation are summarized in The availability of the assembled sequences allowed us to better understand antibiotic resistance mechanisms and to clarify genomic relationships among the isolates.The sequences described here have been deposited at GenBank under the accession numbers indicated in"} +{"text": "The genomic sequences of phages isolated on mycobacterial hosts are diverse, mosaic and often share little nucleotide similarity. However, about 30 unique types have been isolated, allowing most phage to be grouped into clusters and further into subclusters . Many toWe computed tetranucleotide usage deviation, the ratio of observed counts of 4-mers in a genome to the expected count under a null model . Tetranuhttps://github.com/bsiranosian/tango_final.Genome analysis based on tetranucleotide usage shows promise for evaluating host-parasite coevolution and gene exchange within the mycobacteriophage population. These methods are computationally inexpensive and independent of gene annotation, making them optimal candidates for further research aimed at clustering phage and determining evolutionary relationships. Code for genome analysis and data used in this project are freely available at"} +{"text": "Upogebia deltaura upon temporal variation in the abundance of genes representing key N-cycling functional guilds. The abundance of bacterial genes representing different N-cycling guilds displayed different temporal patterns in burrow sediments in comparison with surface sediments, suggesting that the burrow provides a unique environment where bacterial gene abundances are influenced directly by macrofaunal activity. In contrast, the abundances of archaeal ammonia oxidizers varied temporally but were not affected by bioturbation, indicating differential responses between bacterial and archaeal ammonia oxidizers to environmental physicochemical controls. This study highlights the importance of bioturbation as a control over the temporal variation in nitrogen-cycling microbial community dynamics within coastal sediments.In marine environments, macrofauna living in or on the sediment surface may alter the structure, diversity and function of benthic microbial communities. In particular, microbial nitrogen (N)-cycling processes may be enhanced by the activity of large bioturbating organisms. Here, we study the effect of the burrowing mud shrimp Upogebia deltaura and Callianassa subterranea, which are active and abundant decapods that create large, complex burrow systems in marine sediments , bacterial communities exhibited less seasonal change in structure than those communities inhabiting surface sediment compared with those within tidal flat surface and subsurface sediments to investigate temporal variation in the abundance of specific bacterial and archaeal genes representing key N-cycling functional guilds within sediment samples taken from the walls of amoA); bacterial denitrifiers (nirS) and bacteria capable of the anammox process (Planctomycetes-specific 16S rRNA). Clone library analysis confirmed the specificity of each of the primer pairs used for subsequent q-PCR. In particular, sequence analysis showed that the Planctomycetes-specific 16S rRNA primers used here specifically targeted anammox bacteria, as shown previously and \u2018sampling month\u2019. Bacterial 16S rRNA and nirS gene abundances showed no significant variation with either sediment category or sampling month. However, the abundances of each of the other genes studied varied significantly with sampling month Fig. . The metnirS varied significantly with sampling month, and as for bacterial amoA and anammox 16S rRNA, there was a significant interaction between sampling month and sediment category ; this effect was not evident for surface sediments. We may interpret these differing seasonal patterns in gene abundance within the context of environmental factors known to impact upon microbial community dynamics in coastal sediments.In general, the abundances of all genes in surface sediments were highest in both July 2009 and 2010, and lowest in May, with an additional peak in March Fig. showed sFor example, variation in microbial community abundance and activity in surface sediments is generally assumed to be driven by changing environmental conditions, such as pH and salinity, or stochastic processes, such as sediment turnover during a storm. On seasonal timescales, the most important regulators of N-cycling functional guild abundance may be temperature, which exerts a major control over all life processes with the blooming populations of autotrophs has been shown to adversely affect benthic ammonia oxidizing bacteria (AOB) abundance , during irrigation events . Ammonia oxidizing archaea (AOA) have been found in greater abundance than AOB in a variety of benthic marine and estuarine environments amoA copies per cell from marine sediments by denitrification (nirS) and anammox. Nr-removal processes play a critical role in coastal sediments, where terrestrial run-off can stimulate eutrophication events in coastal waters, particularly during autumn, when both precipitation rates and the input of agricultural nutrients into estuarine waters are high . The impacts of bioturbation on the activity of the denitrifying bacteria could therefore be an important consideration in future models of the benthic response to coastal environmental change.The activity of amoA target specifically the \u2018high-ammonium\u2019 ecotype identified by Sintes and colleagues is directly influenced by bioturbation activity, and such effects vary between different bacterial and archaeal N-cycling guilds. These data are interpreted with the caveat that the PCR primers used here target specific bacterial and archaeal phylotypes and/or ecotypes; for example, our primers for archaeal lleagues . We alsoS Rusch, . Howevera priori factors used here: sediment category (surface vs. burrow) and sampling month. This study therefore highlights the importance of temporal variation coupled to macrofaunal bioturbation activity in driving microbial community dynamics in coastal sediments. In particular, this study emphasizes the importance of the often overlooked interactions between macrofaunal and microbial communities upon key biogeochemical cycling processes within coastal benthic ecosystems. Our suggestions for the ways in which shrimp behaviour influence gene abundance patterns may act as a useful starting point for future investigations into the environmental controls on microbial functional diversity and activity.It is also worth noting that the presence of a functional gene does not mean that function is operating within the specific environment, and an important continuation to this study would be to identify whether these genes correlate with the relevant biogeochemical rate processes. Nevertheless, we have observed gene abundances that fit within the ranges of previously reported values for these genes in similar marine environments Table and vary"} +{"text": "Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disorder of unknown etiology with a wide range of clinical manifestations. Since CRMO is a systemic disorder that can affect multiple skeletal sites, whole-body imaging techniques (whole body bone scintigraphy -WBBS- or whole body magnetic risonance -WBMRI-) provide major contribution to the initial diagnostic approach, as well as during follow-up.To compare WBMRI with WBBS in the assessment of bone lesions in patients with CRMO.We retrospectively evaluated all WBMRI examinations performed between January 2010 and December 2014 in 18 patients with clinical, laboratory and histology findings suggestive for CRMO.WBMRI were evaluated independently by two experienced paediatric radiologists, who eventually reached consensus. All patients also underwent WBBS within four weeks; WBMRI and WBBS findings were compared. Signal hyperintensity compared with normal bone on STIR images and increased tracer activity in bone delayed scans on WBBS were considered indicative of disease involvement.WBMRI and WBBS showed 225 and 132 lesions, respectively. In the appendicular skeleton, WBMRI demonstrated 143 lesions and WBBS 66 lesions; in the axial skeleton, WBMRI demonstrated 63 lesions and WBBS 18 lesions. WBMRI demonstrated joint involvement in 19 sites and WBBS in 48. The higher concordance between the two methods was observed in the sacroiliac joint (13 lesions for both methods); the higher discordance was observed in spine (WBMRI showed 55 lesions and WBBS 5) and in sterno-clavicular joint (WBMRI showed 2 lesions while WBBS 12).Both WBBS and WBMRI confirmed to be useful tools for the detection of CRMO lesions, as it is reported in literature. Discordance between WBBS and WBMRI is probably due to several factors. In the evaluation of axial skeleton (in particular of the spine), WBMRI shows higher spatial resolution than planar WBBS, but tomographic acquisition (SPECT) enhances the sensitivity of WBBS. Moreover, age-related conversion of hematopoietic marrow to fatty marrow in children may create a confusing appearance on MRI and may be misleading. Finally, in particular in WBMRI performed during treatment and follow-up, clinical relevance of the WBMRI-positive but WBBS-negative lesions is unclear, as still debated in current literature."} +{"text": "Clarkia (Onagraceae) sister taxa. Consistent with our predictions, one outcrosser (C. unguiculata) exhibited faster pollen germination and less variation in pollen tube growth rate (PTGR) among pollen donors than its selfing sister species, C. exilis. Contrary to our predictions, the selfing C. xantiana ssp. parviflora exhibited faster PTGR than the outcrossing ssp. xantiana, and these taxa showed similar levels of variation in this trait. Pollen performance following self- vs. cross-pollinations did not differ within either selfing or outcrossing taxa. While these findings suggest that mating system and pollen performance may jointly evolve in Clarkia, other factors clearly contribute to pollen performance in natural populations.We tested three predictions regarding the joint evolution of pollen performance and mating system. First, due to the potential for intense intrasexual competition in outcrossing populations, we predicted that outcrossers would produce faster-growing pollen than their selfing relatives. Second, if elevated competition promotes stronger selection on traits that improve pollen performance, then, among-plant variation in pollen performance would be lower in outcrossers than in selfers. Third, given successive generations of adaptation to the same maternal genotype in selfers, we predicted that, in selfing populations (but not in outcrossing ones), pollen would perform better following self- than cross-pollinations. We tested these predictions in field populations of two pairs of The evolutionary and ecological factors that have promoted the diversity of plant sexual reproductive strategies have been a long-standing area of inquiry among evolutionary biologists. The evolutionary transition between outcrossing and selfing, in particular, has received considerable attention, in part because mating system shifts are widespread and have occurred independently within and across numerous taxa ,2,3. IntPollen performance traits are often genetically based ,21,22,23Evidence from studies conducted in natural populations suggests that pollen competition may regularly result in conditions favoring rapid pollen tube growth. First, although pollen limitation has been detected experimentally in many wild plant populations , theRecently, we proposed three predictions regarding the evolution of pollen performance in predominantly self-fertilizing and outcrossing taxa . Our preSecond, because selfing reduces the number of distinct pollen genotypes deposited on individual stigmas, the comparatively stronger opportunity for selection on pollen performance traits in outcrossing taxa should have purged variation in these traits more effectively in outcrossers relative to selfers. Accordingly, we predicted that outcrossing taxa would harbor less genetically based variation among individual pollen donors in pollen performance traits than closely related selfing taxa. This prediction is based on the expectation that intense pollen competition among pollen genotypes will result in selection favoring rapid pollen germination and/or growth in outcrossing taxa. It should also be noted that maternal plant identity and environmental factors such as temperature and resource availability may also contribute to among-donor variation in pollen tube growth and germination in outcrossing taxa ,63,64,65i.e., combinations of alleles at different loci that result in particularly high performance) that influence pollen performance are likely to be reliably and consistently inherited over multiple generations and thus accumulate in populations. In other words, because the pollen of selfers experiences successive generations of pollen germination and pollen tube growth in genetically consistent maternal plant tissue, their pollen should evolve to be particularly well adapted to grow within its parental genotype. By contrast, because outcrossers typically mate with multiple, genetically distinct partners over their lifetimes, such beneficial epistatic interactions are more likely to break down due to recombination, and are therefore less likely to remain stable in outcrossing taxa than selfing taxa. Moreover, outcrossers should experience strong selection favoring the ability of pollen to perform well in a wide variety of stigmatic and stylar genotypes, while selection favoring such tolerance may be comparatively weak in autogamous selfers, whose pollen grains rarely germinate on foreign maternal genotypes. Consequently, we hypothesized that in regularly selfing taxa, pollen should have evolved to perform better following self-pollinations than following cross-pollinations. By contrast, in habitually outcrossing taxa, we predicted that pollen would either perform better following cross-pollinations than self-pollinations or thats e.g., ,67,68).,68.i.e.,Clarkia tembloriensis (Onagraceae) populations and cultivated in growth chambers provides preliminary support for our predictions. Smith-Huerta . The objective of these analyses was to assess the effect of pollination type on PTGR and the proportion of the style length travelled by viable pollen grains. Therefore, zero values, which were associated with pollen grains that did not germinate or whose tubes failed to enter the style 2.5 hours post-pollination, were excluded from these analyses. Temperature-adjusted performance traits for unguiculata were calculated using the residuals from linear regressions in which a given pollen performance trait (PTGR or the proportion of the style traveled) was regressed on temperature at the time of pollination (\u00b0C). For xantiana and parviflora we used the residuals from polynomial regressions in which a given measure of pollen performance (PTGR or the proportion of the style travelled) was regressed on (temperature at style harvest) and (temperature at style harvest)2 because these regressions gave a better fit than the linear regressions. See 2r values associated with these models. For the Stark Creek exilis population, we controlled statistically for the effect of temperature by using the residuals from polynomial regressions in which PTGR or the proportion of the style traveled was regressed on temperature at the time of pollination (\u00b0C) and (temperature at the time of pollination)2. See 2r values associated with these models. For each taxon, variance components associated with the random effects of Pollen Donor and Pollination Type nested within Pollen Donor were estimated using the REML method for each temperature-adjusted pollen performance trait. For unguiculata, xantiana,and parviflora, we conducted these two-factor analyses after initial models including three random effects indicated that pollen performance did not differ significantly between populations of the same species or subspecies. The 95% confidence intervals spanning the variance components associated with the Population effect included zero. All analyses were performed using JMP 9.0 (SAS Institute).We calculated Clarkiaexilis and its outcrossing sister species, C. unguiculata, in a manner that is consistent with the hypothesis that pollen competition promotes the evolution of rapid pollen performance in outcrossing taxa relative to their selfing counterparts. Plants from unguiculata populations exhibited faster or more frequent pollen germination than plants from exilis populations; unguiculata pollen tubes were more likely to have entered the style within 2.5 hours of pollination. Surprisingly, we found that C. xantiana ssp. parviflora exhibited faster PTGR and greater proportional distance travelled within the style than its outcrossing counterpart, C. xantiana ssp. xantiana. These contrasting patterns suggest that gamethophytic evolution following mating system transitions is likely to involve a variety of genetic and ecological factors. The extent to which the evolution of pollen performance traits is influenced either by local environmental conditions or by strong correlations with plant traits other than mating system in the Clarkia taxa studied here, however, merits further investigation. Case studies evaluating additional pairs of sister taxa are needed before generalizations regarding the joint evolution of mating system and pollen performance can be made. Nevertheless, the contrasting patterns that we observed in the two pairs of Clarkia sister taxa are likely driven in part by differences in the magnitude of gametophytic competition in unguiculata and xantiana populations. In populations characterized by consistent pollen limitation, such as xantiana, selection on pollen performance traits may be weak or neutral. Consequently, this study highlights the importance of evaluating the joint evolution of pollen performance and mating system in field populations, where abiotic and biotic ecological factors may influence the phenotypic expression of and ultimately the evolution of sexually selected traits. Differences between selfers and outcrossers in the diversity of potential pollen donors that arrive on stigmas have been predicted to drive the evolutionary divergence of sexually selected traits, such as the speed by which pollen grains germinate and travel through the style. Here we demonstrate that pollen performance differs under field conditions between"} +{"text": "Patients with chronic renal failure may develop sensorineural hearing loss. Cochlear implantation has rarely done after organ transplantation. Herein, we report on a 33-year-old kidney transplantation recipient who underwent cochlear implantation for her progressive sensorineural hearing loss in Khalili Hospital Cochlear Implant Center, affiliated to Shiraz University of Medical Sciences. The implantation was done successfully with no complications. Cochlear implantation may be an appropriate therapeutic option for sensorineural hearing loss caused by chronic renal failure. Cochlear implantation has revolutionized the treatment of profound hearing loss. This procedure is relatively safe and it becomes the treatment of choice for both children and adults. Most of the patients reported improved quality of life, speech recognition and communication. Recently, patients with chronic diseases like chronic renal failure with hearing impairment, have also considered for cochlear implantation. Chronic kidney disease may result in high frequency sensorineural hearing loss (SNHL). The probable causes include uremia , congeniA 15-year-old Iranian girl developed chronic renal failure due to post-streptococal glomerulonephritis. Although she was on maintenance hemodialysis for seven months, she developed end-stage renal disease and underwent living non-related kidney transplant in 1992. One month later, she was treated for pleural effusion and pneumonia and received the ototoxic drug, amikacin for several weeks and developed bilateral progressive SNHL confirmed by pure tone audiometry and auditory brainstem response audiometry. She was then referred to our center and received a powerful hearing aid which was not successful to increase her speech awareness threshold. Therefore, she was considered for cochlear implantation. Before performing the procedure, multidetector high resolution computed tomography of temporal bone revealed normal anatomy of the temporal bone including mastoid, middle ear, inner ear and internal auditory canal with no evidence of mastoiditis or pathologic findings. The cochlear turns in both sides appeared normal with normal semicircular canals. After evaluation, the right ear was selected for the implantation. An advance bionics prosthesis (HiRes 90 K) was used and the active electrode was inserted fully in an appropriate position in the year 2011. After the operation, the patient was hospitalized in the ENT ward for 24 hours and discharged in good condition with antibiotics. She continued her routine immunosuppressant drugs till now without any signs of wound infection or other complications.Hearing aids are the principle means of auditory rehabilitation for patients with SNHL. Hearing aids also have important roles in the management of conductive hearing loss. Implantable hearing aid has several advantages for patients with hearing loss such as increasing gain and dynamic range, reducing feedback, reducing maintenance, improving appearance and being free to occlude one of the ear canals . CochleaHearing loss is one of the most common debilitating conditions in patients who begin renal replacement therapy. The incidence of hearing loss in children is 8.6% . The effFor cochlear implantation, immunosuppressive drugs can be continued preoperatively without dose adjustments , 5, 9. FWe concluded that cochlear implant may help properly selected renal transplant recipients with SNHL."} +{"text": "Mungos mungo), a cooperative mammal in which multiple females conceive and carry to term in each communal breeding attempt. As predicted, lower ranked females had lower reproductive success, even among females that carried to term. While there were no rank-related differences in faecal glucocorticoid (fGC) concentrations prior to gestation or in the first trimester, lower ranked females had significantly higher fGC concentrations than higher ranked females in the second and third trimesters. Finally, females with higher fGC concentrations during the third trimester lost a greater proportion of their gestated young prior to their emergence from the burrow. Together, our results are consistent with a role for rank-related maternal stress in generating reproductive skew among females in this cooperative breeder. While studies of reproductive skew frequently consider the possibility that rank-related stress reduces the conception rates of subordinates, our findings highlight the possibility of detrimental effects on reproductive outcomes even after pregnancies have become established.Dominant females in social species have been hypothesized to reduce the reproductive success of their subordinates by inducing elevated circulating glucocorticoid (GC) concentrations. However, this \u2018stress-related suppression' hypothesis has received little support in cooperatively breeding species, despite evident reproductive skews among females. We tested this hypothesis in the banded mongoose ( The stress-related suppression hypothesis proposes that dominant females suppress subordinate reproduction through behaviours that lead to chronic elevations in circulating glucocorticoids (GCs) and consequent reproductive downregulation \u20134. Notabin utero or early post-natal development and affect offspring health, condition and survival [While socially induced GC elevations have frequently been considered a potential cause of reduced conception rates among subordinates, they also have the potential to compromise the outcomes of established pregnancies. For example, elevated GCs during pregnancy may impact survival ,7. Whilesurvival ,8, whethMungos mungo). Banded mongooses live in stable cooperatively breeding groups comprising a \u2018core\u2019 of breeding adults that reproduce three to four times per year, alongside a subset of younger individuals that breed occasionally [Here, we test these three predictions with a detailed investigation of faecal glucocorticoid (fGC) concentrations and reproductive success in female banded mongooses between December 2010 and April 2014. All animals were marked and habituated to close observation (less than 5 m). Groups were observed every 1\u20134 days to record all breeding events. We ran generalized linear mixed models (GLMMs) using the lme4 package with PoiPregnancy can be detected at around 40 days by swelling of the abdomen and birtWe collected 218 faecal samples from 35 females prior to and during gestation . Full details of sample collection and hormone analysis including validations are given in . In brie(a)We calculated three measures of reproductive success for each female recorded as having given birth: (i) the number of fetuses, (ii) the number of emergent offspring, and (iii) the proportion of fetuses surviving to emergence. We fitted each of these three measures as a response variable in GLMMs. Rank (determined by ranked age following ) was fit(b)We fitted fGC concentrations as a response variable in a GLMM with rank as the main predictor of interest. As GC concentrations may vary within a breeding attempt, we also fitted an interaction between rank and stage of pregnancy as well as fixed effects of female age, group size, rainfall and pre-conception body mass to control for other factors which may contribute to fGC variation.(c)We fitted the number of emergent offspring and the proportion of fetuses surviving to emergence as response variables in two separate GLMMs with fGCs during the third trimester as the predictor of interest. We focused this analysis on fGCs in the third trimester because that is when we saw the clearest difference in fGCs between low- and high-ranking females.3.p = 0.041; figure\u00a01a) and the proportion of fetuses surviving to emergence . There was no effect of rank on the number of fetuses carried by a female (p = 0.87). We found a significant interaction between female rank and pregnancy stage on fGC concentrations: lower ranking females did not differ from higher ranking females prior to conception or during the first trimester but had elevated fGCs during the second and third trimesters and a lower proportion of their fetuses survived to emergence . Full model outputs are included in the electronic supplementary material S1.Lower ranking females that carried to term experienced lower reproductive success than higher ranking females, both when measured as the number of assigned offspring , both when measured as the proportion of fetuses surviving to emergence and the number of emergent offspring. Although higher and lower ranked females had similar fGC concentrations prior to gestation and during the first trimester, lower ranked females showed significantly elevated fGC concentrations during the second and third trimesters. These results highlight the possibility that stress-related suppression of subordinate reproduction arises through gestational effects that compromise offspring survival either during the latter stages of pregnancy or soon after birth (prior to emergence from the burrow). Accordingly, females that experienced higher fGC concentrations during the third trimester had fewer emergent pups and a lower proportion of fetuses surviving to emergence.in utero, this rank-related difference in reproductive success could well have arisen from pre-natal developmental impacts on offspring survival either during late pregnancy or during the early post-natal period. A role for rank-related maternal stress during late gestation in generating these effects on offspring survival would be consistent with experimental evidence that late-gestational GC elevations can inhibit offspring development [Rank-related differences in reproductive success among female mammals commonly occur due to differences in conception rates, either because subordinate females exercise reproductive restraint or because their ability to conceive is compromised by active interference by dominant females ,19. By celopment ,20. In telopment , play a per se. However, the gestational GC elevations of lower ranked females could arise at least in part from energetic differences during gestation. For example, subordinates may be competitively excluded from resources by dominant females. Alternatively, as intra-sexual conflict among females may frequently be resolved without overt physical conflict, these GC elevations could also reflect responses to more subtle rank-related outcomes, such as social isolation [The stress-related suppression hypothesis posits that elevated GC concentrations observed in lower ranking females are a result of aggression from dominant females. However, conspicuous aggression among female banded mongooses is rare outside of eviction events . As suchsolation . Either"} +{"text": "How receptions of sensory inputs information turn into perceptions in our brain? To address these questions, we proposed method reconstructs the neuronal tracts by applying the shortest path graph algorithm between functional regions in the Drosophila brain. With these neuronal tracts, we analyze and draw a network diagram of projection neurons (PNs) relaying sensory input to higher brain centers in the Drosophila brain. Drosophila is a widely used genetic model system for understanding human biology ,2. WhileThe network diagram shows hierarchical structure, small-world characteristics, and is composed of functional modules corresponding to the sensory modalities. This ultimate goal of such an atlas is to identify connectivity between neurons for understanding the function/circuit relationships."} +{"text": "Improving NK cell persistence in\u2009vivo via autocrine IL-2 and IL-15 stimulation, enhancing tumor targeting by silencing inhibitory NK cell receptors such as NKG2A, and redirecting tumor killing via chimeric antigen receptors, all represent approaches that hold promise in preclinical studies. This review focuses on available methods for genetic reprograming of NK cells and the advantages and challenges associated with each method. It also gives an overview of strategies for genetic reprograming of NK cells that have been evaluated to date and an outlook on how these strategies may be best utilized in clinical protocols. With the recent advances in our understanding of the complex biological networks that regulate the ability of NK cells to target and kill tumors in\u2009vivo, we foresee genetic engineering as an obligatory pathway required to exploit the full potential of NK-cell based immunotherapy in the clinic.Given their rapid and efficient capacity to recognize and kill tumor cells, natural killer (NK) cells represent a unique immune cell to genetically reprogram in an effort to improve the outcome of cell-based cancer immunotherapy. However, technical and biological challenges associated with gene delivery into NK cells have significantly tempered this approach. Recent advances in viral transduction and electroporation have now allowed detailed characterization of genetically modified NK cells and provided a better understanding for how these cells can be utilized in the clinic to optimize their capacity to induce tumor regression Natural killer (NK) cells are immune cells primarily found in the blood, liver, spleen, bone marrow, and to a lesser extent, in lymph nodes . They weNK cells can mediate cytotoxicity via multiple distinct mechanisms. Degranulation is the most studied cytotoxicity pathway, where NK cells release cytotoxic granules upon contact with the target. Cytotoxicity via this pathway is dictated by a balance of signals from an array of germline encoded activation and inhibitory cell surface receptors. Most activation receptors need simultaneous co-stimulation by other activation receptors to trigger NK cell cytotoxicity . One excin\u2009vivo persistence, and doubts regarding their ability to migrate to tumor tissues following adoptive infusions. Although recent data have shown CMV reactivation reduces the risk for AML relapse following HSCT following hematopoietic stem cell transplantation (HSCT) and that adoptively infused mature donor NK cells could induce remission in AML patients , 10. Desing HSCT potentiain\u2009vivo holds potential to advance the efficacy of NK cell-based cancer immunotherapy. However, until relatively recently, the genetic manipulation of NK cells has proven to be challenging. Viral transduction, successfully used for T cells, has been associated with low levels of transgene expression and unfavorable effects on cell viability when used with NK cells. Recent optimization of viral transduction and the establishment of electroporation technologies for efficient gene transfection have revived the enthusiasm for studies evaluating genetic modification of NK cells. Investigators around the world are now exploring the potential of multiple different NK cell modalities to genetically reprogram with the overall aim of further improving upon their capacity to kill tumors in cancer patients. One example of how this technique can be utilized is to introduce genes into NK cells coding for gamma-cytokines (IL-2 and IL-15) to induce independence from the obligate need of exogenous cytokines for proper in\u2009vivo persistence and expansion post infusion. This and similar strategies may further improve the efficacy of NK cell-based immunotherapy, as tumor regression following adoptive NK cell infusions in AML patients has been reported to be dependent on their ability to expand in\u2009vivo resulted in an average 69 and 71% transduction efficiency, respectively .More recently, studies evaluating transduction of NK cells using lentiviral vectors have been pursued. In contrast to transduction with retro- and adenoviral vectors, lentiviral vectors can incorporate transgenes into the genome of non-dividing cells. Further, lentiviral vectors allow for gene modification of NK cells without altering their phenotypic and functional properties as occurs following stimulation with i.e., cytokines. The first report on the successful use of lentiviral vectors for genetic modification of NK cells was performed in primary murine NK cells , with suIn summary, viral transduction of NK cells results in variable transduction efficacies and may require multiple rounds of transduction and/or post transduction cell enrichment to achieve acceptable transgene expression. Further, viral associated cell death and the need for post-transduction enrichment may compromise the clinical utility of this approach. Finally, although the risk may be low, the possibility of viral-induced insertional mutagenesis and immunogenicity , 44 occuelectroporation (including nucleofection) or lipofection. Since the latter has been used only in a few studies human NK cells and the transcription activator-like effector nucleases (TALEN) technologies, the recently developed clustered regularly interspaced short palindromic repeats (CRISPR) technique has rapidly become a popular tool for targeted gene integration . The CRIin\u2009vivo persistence and expansion, tumor tissue migration, and the tumor targeting capacity of adoptively infused NK cells donors were found to have substantially augmented ADCC following electroporation with mRNA coding for the HA-CD16 compared to those who carry the low-affinity CD16-158F (LA-CD16) polymorphism , 66, sev LA-CD16 . Recentl HA-CD16 . These dIntroduction of genes that render NK cells insensitive to suppressive cytokines such as TGF-\u03b2, thereby preserving their cytotoxicity, has also been studied. Yang et al. generated an NK-92 cell line resistant to the suppressive effects of TGF-\u03b2 by genetically modifying them to express the dominant negative mutant form of TGF-\u03b2 type II receptor (DNT\u03b2RII) on their surface . Adoptivin\u2009vitro and in a preclinical mouse model exploiting the role for CAR19-expressing Genetic engineering of NK cells to make them cytokine independent and thereby improve persistence, while boosting their cytotoxic capacity, may be one avenue to further explore. The advantage with this approach would be that exogenous cytokines would be unnecessary following NK cell infusion, which may reduce the risk of mobilizing regulatory T cells that directly suppress NK cell cytotoxicity . Challenin\u2009vivo homing of infused gene engineered NK cells have yet been published.Migration to the tumor tissue is another aspect governing proper tumor targeting. This aspect has been largely overlooked and could potentially improve clinical outcome if infused NK cells are redirected to the tumor site instead of circulating non-specifically into mostly non-tumor-bearing tissues. No studies aimed at improving the in\u2009vitro have been explored. Introduction of CARs represent the most studied and developed approach that has recently reached clinical evaluation , thereby giving genetically reprogramed NK cells an additional layer of target specificity. However, many additional preclinical studies will be needed before these approaches can reach clinic.As discussed above, numerous strategies for redirecting or boosting NK cell tumor killing on Table . Expressex vivo manipulation.The choice of method for genetic reprograming of NK cells is another important factor that needs to be considered when taking genetically engineered NK cells to clinical evaluation. Viral transduction has the advantage of stable expression; however, as mentioned above, viral transduction of NK cells, especially primary cells, does not always lead to a satisfactory level of transgene expression and may require multiple rounds of transduction followed by selection of transgene positive cells. Moreover, proper expression of transgenes induced by viral transduction can take days, which may be of disadvantage since the lifespan of an NK cell may be relatively short following adoptive transfer . Future studies are warranted to better understand if multiple infusions of transfected NK cells can compensate transient transgene expression or if stable transgene expression is a prerequisite for inducing clinical responses following adoptive transfer of genetically engineered NK cells. Studies are also needed to fully understand the lifespan of NK cells, particularly those that have undergone in\u2009vivo (ex vivo for clinical infusion (The optimal method for genetic manipulation of NK cells to be used in a clinical trial may also depend on what NK cell preparation is used Box . The advin\u2009vivo . Moreoveinfusion . IdeallyBox 3Anti-tumor antibodies and CAR T cells have established immunotherapy as a viable treatment option for patients with cancer. Given their rapid and efficient method of recognizing tumor cells, NK cells represent a unique immune cell to genetically reprogram in an effort to improve the outcome of cell-based cancer immunotherapy. However, technical and biological challenges associated with gene delivery into NK cells have significantly tempered this approach. Viral transduction of NK cells initially resulted in low transgene delivery efficiencies that often required multiple rounds of transduction and/or cellular enrichment to achieve acceptable numbers of transgene expressing cells. Nevertheless, recent improvements in retro- and lentiviral transduction of NK cells have led to a flurry of preclinical studies on gene engineered NK cells. A number of studies have also shown that NK cells can be genetically reprogramed using mRNA electroporation. In contrast to viral transduction, this approach offers high transfection efficiencies without compromising their viability and does not require high-level biosafety laboratories. Although promising preclinical data on mRNA electroporated NK cells have emerged recently, concerns have been raised regarding the clinical utility of this approach as it only results in transient transgene expression.in\u2009vivo, and with rapid developments in clinically compliant techniques to genetically manipulate NK cells, we foresee genetic engineering as an obligatory pathway to exploit the full potential of adoptive NK cell immunotherapy in patients with cancer.Recently initiated clinical trials will soon give insight into the potential effectiveness of cell-based cancer immunotherapy strategies that utilize genetically modified NK cells. Nevertheless, further optimization of both viral transduction and electroporation of NK cells is still needed before this approach can be fully exploited in the clinic. With the recent advances in our understanding of the complex biological networks that regulate the capacity of NK cells to target and kill tumors The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Mitochondrial fusion-fission dynamics play a crucial role in many important cell processes. These dynamics control mitochondrial morphology, which in turn influences several important mitochondrial properties including mitochondrial bioenergetics and quality control, and they appear to be affected in several neurodegenerative diseases. The molecular machineries behind mitochondrial fusion and fission events are relatively well known. The regulation of fusion and fission events beyond the molecular machinery involved is less clear, fusion and fission are not random occurrences but form a cycle whereby fission typically follows fusion. Mitochondrial fission machinery may somehow sense mitochondrial length and become active when the mitochondrion is oversized and cease when mitochondria are smaller. In contrast, mitochondrial fusion events depend heavily on mitochondrial trafficking. Fusion only takes place when two mitochondria meet and motile mitochondria will be more likely to encounter one another. In cultured cortical neurons, for example, only one in every 14th contact between mitochondria results in fusion. The purpose of this presentation is to provide insight into the complex crosstalk between different processes involved in mitochondrial fusion-fission dynamics and to discuss the potential physiological purpose of mitochondrial fusion and fission."} +{"text": "Numerous complex regulatory mechanisms influence the development and function of the peripheral and central nervous system. Among them, hormones belong to the most potent regulatory factors. Various particles known for their hormonal activity serve as neurotransmitters. Additionally, hormones secreted systemically modulate the function of the nervous system both on the brain level and in peripheral organs. Thyroid function has been shown to play a crucial role in the proper cognitive development but also in many other aspects of nervous system activity, in mechanisms involving direct interaction with intrinsic regulatory circuits or indirectly by systemic effects exerted e.g. on the circulatory system or metabolic pathways. Due to these close relations with the nervous system function, disturbances of thyrometabolic state are associated with a vast spectrum of neurological signs and symptoms including: mood and cognitive disorders, headache, ophthalmoplegia, tremor and other movement disorders, muscle weakness etc. Both hyper- and hypothyroidism may cause psychiatric symptoms like depressive or anxiety disorder, memory deficits, executive inability and even psychosis. The severe decompensated hypothyroidism may result in myxoedema coma - a life-threatening condition with sequentially progressing encephalopathic symptoms. Steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAAT) represents another form of encephalopathic disorder associated with thyroid disease and causing potentially serious clinical complications. In the periphery, the thyrometabolic disturbances may affect muscle function resulting in subjective tiredness and low exercise tolerance and in some cases in objective myopathic signs. Also peripheral nervous system may be affected, mainly in hypothyroid patients, with greater tendency to develop peripheral polyneuropathy and entrapment neuropathies such as carpal tunnel or Guyone canal syndromes.Importantly, the autoimmune thyroid disease has been shown to coexist with other autoimmune processes which may potentially cause neurological symptoms such as myasthenia, Guillain-Barre syndrome or pernicious anaemia. Such conditions have to always be taken in consideration as differential diagnoses in patients presenting with neurological signs and symptoms associated with thyroid disease."} +{"text": "Coronary stent fracture is a known complication of coronary arterial stent placements. Multiple long-term risks are also associated with drug eluting stents. 64-slice multidetector CT (MDCT) coronary angiography has been shown to detect poststent complications such as instent stenosis, thrombosis, stent migration and stent fractures. We report a case of stent fracture in a patient who underwent RCA stenting with associated RCA perforation and almost complete thrombosis of the RCA and peristent fibrinoid collection. This is a rare case of stent fracture with perforation of the RCA. The paper highlights the role of 64-row multidetector computed tomography (MDCT) in evaluation of such poststent placement complications. Stent fracture (SF) has been suggested as one of the leading risk factors of thrombosis and instent restenosis (ISR) in patients who have intracoronary drug-eluting stent (DES) implants ; howeverA 65-year-old male patient presented with a tuberculous knee joint effusion and occasional chest pain. He also had a drug eluting stent inserted in the mid RCA, two years back. However, the patient had recurrent angina within a month of stent placement. A catheter angiography done at that time revealed total occlusion of the RCA stent, with grade III collaterals. He was now referred to our department with a request for CT chest to exclude pulmonary tuberculosis. The CT chest revealed no signs of pulmonary tuberculosis but revealed an irregular localised pericardial fluid collection along the RCA stent . A dedicStent fracture is an important and potentially serious complication of drug-eluting stents (DES) . IncreasNakazawa et al. have graded stent fractures into five categories and conc64-slice CT coronary angiography is an extremely fast and accurate imaging modality available for the evaluation of stents and their complications. It is found to be more sensitive in detecting stent fractures than conventional catheter angiography. Besides demonstrating in-stent thrombosis, it can effectively evaluate stent fractures, migrations, buckling, or collapse; rare complications such as perforations and aneurysms. This is a rare case of long standing stent fracture with RCA rupture and associated in-stent total occlusion and highlights a unique complication of stent placement: stent fracture causing coronary arterial rupture and subsequent stent migration. It also highlights the utility of 64-row MDCT imaging in effectively demonstrating such serious complications; which may or may not be convincingly shown on conventional catheter angiography."} +{"text": "In contemporary oncology practices there is an increasing emphasis on concurrent evaluation of multiple genomic alterations within the biological pathways driving tumorigenesis. At the foundation of this paradigm shift are several commercially available tumor panels using next-generation sequencing to develop a more complete molecular blueprint of the tumor. Ideally, these would be used to identify clinically actionable variants that can be matched with available molecularly targeted therapy, regardless of the tumor site or histology. Currently, there is little information available on the post-analytic processes unique to next-generation sequencing platforms used by the companies offering these tests. Additionally, evidence of clinical validity showing an association between the genetic markers curated in these tests with treatment response to approved molecularly targeted therapies is lacking across all solid-tumor types. To date, there is no published data of improved outcomes when using the commercially available tests to guide treatment decisions. The uniqueness of these tests from other genomic applications used to guide clinical treatment decisions lie in the sequencing platforms used to generate large amounts of genomic data, which have their own related issues regarding analytic and clinical validity, necessary precursors to the evaluation of clinical utility. The generation and interpretation of these data will require new evidentiary standards for establishing not only clinical utility, but also analytical and clinical validity for this emerging paradigm in oncology practice. Traditional pharmacogenomic applications used to direct molecularly targeted therapy rely on testing tumor tissue for a single genomic marker followed by using tumor-marker specific therapy. There are several established pharmacogenomic applications that are used clinically to aid in treatment decisions for breast, colon, lung and other solid-tumor cancers Table 1). With advances in high-throughput \u2013omic technologies and plummeting costs of next-generation sequencing (NGS), researchers have begun to move beyond testing single genes, to multi-gene panels, to sequencing the entire human cancer genome in order to better understand the underlying molecular pathways driving tumorigenesis. With adClinically available NGS tests are used to characterize an individual\u2019s cancer genome through targeted sequencing of pre-specified candidate genes believed to provide clinically actionable molecular targets. Using a single test to detect a broad spectrum of genomic alterations in the biological pathways from a single biopsy is thought to be a more efficient treatment decision process than the single-marker single-treatment approach,,An established clinical test integrating NGS technology for tumor DNA sequencing requires a standardized protocol with details describing pre-analytic, analytic and post-analytic processes. The pre-analytic variables include the patient\u2019s clinical characteristics as well as details describing the collection and preparation of tumor samples. The analytic variables that may affect the precision and accuracy of the targeted sequencing of pre-specified molecular targets refer to the actual sequencing process itself and are related to the specific NGS platform used to conduct the massively parallel sequencing as well as individual laboratory procedures. The post-analytic variables relevant to NGS include variant calling, functional and clinical interpretation, reporting results to clinicians, and data storageThe expanded reach of NGS platforms provides researchers with a much more comprehensive picture of a tumors genomic architecture. In an effort to leverage the technical advances in sequencing technology and expanded vision of a tumors molecular signature several NGS platforms have been integrated into commercially available solid-tumor sequencing panels to identify clinically actionable variants (Table 2). Despite the lack of consensus as to what constitutes a clinically actionable variant, three general categories may be used to classify variants: 1) variants linked to an FDA-approved drug within a specific tumor type; 2) variants linked to an FDA-approved drug outside of the patients specific tumor type; 3) variants linked to non-FDA approved drugs in preclinical testing or early phase clinical trialsTo date, the application of multi-marker tumor panels using NGS has primarily focused on individuals with advanced metastatic disease who have exhausted standard therapies for their particular condition. In such cases, these tests may provide unconventional therapeutic options against an otherwise refractory disease. It is unclear at what point this testing and treatment strategy will become a part of the standard molecular profiling of newly diagnosed malignancies, expanding the potential population impact. As evidence emerges on driver-mutations common across a number of cancer types, newly developed molecularly targeted therapies will provide a means to improve cancer treatment outcomes across a number of cancers with common biological/molecular mechanistic pathways. A more complete picture of an individual\u2019s tumor genome may also be integrated within existing frameworks including age, disease burden, and histologic/molecular features for developing more effective cancer treatment and management strategies-This approach to cancer therapy has received widespread interest from patients, healthcare providers and payersIn a working paper, UnitedHealth spoke to the larger contextual issues of using molecular testing in clinical oncology. A broad emphasis was placed on the expanding opportunities for molecularly targeted therapy using tumor genome sequencing and for improving the process of determining the effectiveness of molecular testing-The analytic workflow of FoundationOne\u2122, hybrid-capture libraries sequenced with Illumina HiSeq2000, was shown to have an analytic sensitivity between 95% and 99% and a positive predictive value greater than 99% using pooled cell lines as the reference standard ,There appears to be consistency in the pre-analytic factors across the commercially available tests related to tissue sample requirements, collection and preservation (Table 2). All the organizations listed in Table 2 report the sequencing is done in Clinical Laboratory Improvement Amendments (CLIA) certified facilities. While this does provide a limited amount of standardization, the fundamental requirements to establish analytic validity requires a reliable reference standard to align and annotate massively parallel sequence dataTable 3 shows the vast array of molecular targets included in the commercially available tumor panels, with only 34 genes included in all three tests . FoundationOne was reported to detect at least one clinically actionable variant in 76% of samples (N=2200) with an average of 1.57 clinically actionable variants detected per sample (range: 0 to 16)There is a growing body of evidence identifying genomic alterations common across multiple cancer typesBenefits At this time there is no evidence of improved treatment outcomes from using the tests described in Table 2 to direct molecularly targeted therapy in solid-tumors. In addition to the absence of evidence of clinical utility for the commercially available tests, there is also a need to further explore the validity and utility of the underlying hypothesis driving the development and implementation of these tests. One challenge in developing studies investigating the general hypothesis as well as establishing clinical utility is the limited generalizability due to diversity in the evolving panel composition and variation in the clinical interpretation and treatment recommendations . There is a need to standardize the composition of panels and develop standard criteria for classifying variants as clinically actionable. It may also be necessary to prioritize specific variant/therapy combinations when multiple variants with associated therapies are identified, as there may be overlapping toxicities and drug-drug interactions. Characteristics of studies investigating clinical utility, including molecular heterogeneity of study participants as well as specific study designs will also impact generalizability.HarmsNone of the test descriptions included details of patient consent or how incidental findings would be communicated to clinicians or patients. As these tests are intended to be implemented at the point of care, such protocols may be left to the ordering physician and their home institution to determine processes for informed consent, delivery of appropriate pre-test genetic counseling, and disclosure of incidental findings. Given the analytic workflow of the available tests (Table 2) and diverse panel composition (Table 3) it is uncertain how the ACMG recommendations,Another potential harm from implementing this testing and treatment strategy arises from uncertainty in the cost-benefit ratio of the off-label use of expensive chemotherapeutic drugs. As mentioned previously, these tests are currently being offered to patients with advanced disease in whom time spent delivering ineffective therapy may pose a significant risk as a wasted opportunity. Many of the available drugs are associated with well characterized adverse effects (e.g. cardiotoxicity from the kinase inhibitors)Several ongoing clinical trials have incorporated the commercially available tests (Table 4). Designed as feasibility assessments, two non-randomized trials are using FoundationOne (Foundation Medicine) to identify participants with metastatic breast cancer (IMAGE)Recent advances in sequencing technology provide new opportunities for genomic medicine. With these opportunities come the promises of personalized medicine that are changing oncology practice. However, aspects of analytic and clinical validity and clinical utility of the current paradigm shift has yet to be clearly established. Developing the necessary evidence to establish clinical validity and utility may require novel thinking to adapt to the dynamic challenges associated with implementing NGS tumor sequencing into clinical practice. Researchers must also address several limitations in the underlying concepts of this approach including patient selection, analytic workflows, characteristics of the tumor panels (performance characteristics and panel composition), study design, and outcome selection. Several ongoing clinical trials are investing both the feasibility and utility of incorporating NGS technology into clinical practice and will help define the evidentiary standards for evaluating such tests.The GAPP Knowledge Base (GAPP KB) was searched using the term \u201cnext-generation sequencing\u201d to identify commercially available multi-marker solid tumor tests using NGS technology. A Google search supplemented the GAPP KB search for eligible tests as well. The following search string was used to search PubMed to identify relevant systematic reviews and guidelines:(((neoplasms/therapy[mesh]) OR (neoplasms/genetics[mesh]) OR (neoplasms/diagnosis[mesh])) AND OR (molecular targeted therapy/methods[mesh]) OR (genetic testing[mesh]) OR )) AND (humans[mesh])In addition to searching PubMed, the commercially available tests websites were searched to identify relevant literature pertaining to the analytic validity, clinical validity, and clinical utility of the respected test. Ongoing studies were identified in clinicaltrials.gov by searching on the trade name of each commercially available test and company offering the tests described in Table 2. This was supplemented by using the term \u201cnext-generation sequencing\u201d to identify additional studies not using any of the tests listed in Table 2."} +{"text": "Background. Cisplatin is a well known platinum-based chemotherapeutic agent used for the treatment of various malignant tumours. A frequent side effect of cisplatin therapy is ototoxicity. Unfortunately, currently there are no available treatments. Material and Methods. Experimental, clinical studies and reviews published between 2004 and 2014 in the English medical literature concerning ototoxicity were selected using Medline, PubMed, and Google Scholar databases. Inclusion criteria were cisplatin-induced ototoxicity and therapy aimed at preventing or curing this disorder. Molecular mechanisms and clinical, audiological, and histological markers of cisplatin-induced ototoxicity are described. Moreover, experimental and clinical strategies for prevention or treatment of hearing loss were also reviewed. Results and Discussion. Experimental studies demonstrate a wide range of otoprotective molecules and strategies efficient against cisplatin-induced hearing loss. However, only dexamethasone proved a slight otoprotective effect in a clinical study. Conclusion. Further research must be completed to bring future therapeutic options into clinical setting. Cisplatin (cis-diamminedichloroplatinum II) is a well-known chemotherapeutic alkylating agent very effective in the treatment of various malignant tumors, especially squamous cell cancers of the head and neck regions, in both the pediatric and adult age groups . Though A review of the literature from 2004 to 2014 was performed, using the Medline, PubMed, and Google Scholar databases. The search terms included cisplatin-induced hearing loss, protective therapy for inner ear diseases, intratympanic therapy, systemic therapy, and gene therapy. Only original experimental and clinical research papers were included. A total of 43 relevant papers were selected for the present review.Cisplatin inflicts injuries mainly to outer hair cells, progressing from the third to the first row and to some extent to inner hair cells of the organ of Corti in the basal turn of the cochlea followed by alterations in sensorial cells situated in the apex. Cisplatin also targets supporting cells, marginal cells of the stria vascularis, and the spiral ligament . The vesMolecular mechanisms of cisplatin-induced hearing loss involve the creation of reactive oxygen species and depletion of antioxidant glutathione and its regenerating enzymes as well as increased rate of lipid peroxidation, oxidative modifications of proteins, nucleic acids damage by caspase system activation , and S-nOxygen free radicals in the cochlea are produced principally in the wake of nicotinamide adenine dinucleotide phosphate oxidase 3 isoform (NOX3) activation. NOX3 is known to be upregulated by cisplatin. Cochlear tissues fight the oxidative stress by means of antioxidant defence systems including glutathione, glutathione reductase, superoxide dismutase, and catalase . CisplatThe extent of ototoxicity due to cisplatin administration can be assessed clinically through measurements of hearing loss by means of pretreatment and follow-up serial audiologic tests and experimentally through histological examinations . The forIn experimental animals, hearing loss after cisplatin treatment can be assessed by audiological study of the auditory brainstem responses where threshold measurement defines the lowest intensity of sound stimulus that evokes a clear, visually detectable, reproducible waveform .\u03b1) and other inflammatory cytokines were also detected by immunostaining in the outer hair cells, stria vascularis, spiral ligament, and spiral ganglion neurons in cisplatin exposed cochleae [Histologic examinations of inner ear after cisplatin administration reveal destruction primarily of outer hair cells and to some extent inner hair cells and associated nerves, degeneration of the vestibular organs, stria vascularis edema, and detachment of the myelin sheath of the spiral ganglion cells . Light mcochleae .2 are used the hearing impairment may progress from high frequencies to involve the middle frequencies. Reducing the total amount of cisplatin by limitation of the total dose per cycle, dose intensity and the cumulative dose would diminish the antitumor effect which is not desirable. Various otoprotective compounds have been tested both in experimental animals and humans. If given systemically, they should be nontoxic, must attain efficient concentrations in the inner ear to protect labyrinthine tissues from cisplatin ototoxicity, and should not hamper the antitumor effect of cisplatin. Higher concentrations of otoprotective molecules can be achieved by intratympanic administration. This latter route provides direct access of the protective agents to inner ear structures while avoiding systemic side effects and interference with the antineoplastic activity of cisplatin [Cisplatin pharmacokinetics in the inner ear after intravenous injection is influenced by its strong binding to the plasma proteins rendering a large part of it nonactive and by the barrier systems in the cochlea, the blood-perilymph barrier, separating blood from perilymph, and the intrastrial fluid-blood barrier, separating blood from endolymph . The amoisplatin .Several otoprotective molecules and strategies against cisplatin-induced ototoxicity have been tested in experimental animals. Some, like diethyldithiocarbamate, exerted important side effects in humans . A summaHyperbaric oxygen therapy consists of intermittent inhalations of 100% oxygen at a pressure higher than 1\u2009atm and is used as adjuvant therapy in pathological processes like soft tissue infections, radiation injury, gas gangrene, and decompressive disease. Its main effect is tissue hyperoxygenation through plasma dissolved oxygen and was successfully tested in guinea pigs as a protective agent against cisplatin ototoxicity. Efficacy of otoprotection by hyperbaric oxygen therapy after cisplatin administration was evaluated by otoacoustic emissions following hyperbaric treatment and by scanning electron microscopy examination. The study confirmed that cisplatin induces dose-dependent cochlear alterations consisting of cellular lesions and significant hair damage in outer hair cells. Analysis of anatomical changes in cochlear outer hair cells indicated signs of otoprotection against cisplatin in animals treated with hyperbaric oxygen therapy although in functional studies distortion product acoustic emission were absent reflecting a certain degree of hearing loss, most probably reversible and related to experimental artefacts. The study concluded that hyperbaric oxygen therapy has otoprotective effects against cisplatin-induced ototoxicity. However, further studies are necessary to test other effects of high pressure oxygen on the cochlea .Another study investigated the effect of epigallocatechin gallate (EGCG) on the transcription factor STAT1, an important mediator of cell death. STAT1 phosphorylation is involved in both hair cells and support cells transformation after experimental exposure of mouse utricule to cisplatin. EGCG proved its efficiency as an otoprotective agent against cisplatin ototoxicity due to its inhibition of STAT1. The hypothesis was further supported by the failure of EGCG to provide protection against cisplatin in STAT1-deficient mice .Former studies showed that lactate injected intratympanically in guinea pigs treated with ototoxic levels of cisplatin allowed near total preservation of otoacoustic emissions . Since lMost of the existing studies focus on exogenous administration of antioxidants. Pharmacological activation of intrinsic defence mechanisms against oxidative stress in the inner ear caused by cisplatin therapy also proved helpful as showed by an experimental animal study using systemic administration of thiamine pyrophosphate (TPP). Thiamine pyrophosphate functions as coenzyme for peroxisomes being a crucial factor for energy metabolism, antioxidation, and myelinisation of nerve cells. Its intraperitoneal injection increased the level of natural antioxidants like glutathione and antioxidant enzymes and reduced the content of malonildialdehyde, an indicator of lipid peroxidation following increased levels of oxygen reactive species resulting from cisplatin toxicity. The histologic evaluation of cochleae harvested from TPP treated animals showed preservation of the morphology of the organ of Corti and outer hair cells and no destruction of spiral ganglion cells and stria vascularis following cisplatin therapy .The wide range of therapeutic molecules studied for their otoprotective effect against cisplatin-induced ototoxicity also includes sertraline, an antidepressant with neuroprotective effects in rats . The selAn experimental single dose model of cisplatin ototoxicity in guinea pigs showed the otoprotective effect of systemic histone deacetylase inhibitor sodium butyrate. Distortion product otoacoustic emissions testing were chosen to provide a sensitive assay of the functional state of outer hair cells after systemic cisplatin insult on the cochlea. The systemic administration of the otoprotective agent avoided the side effects of the more invasive tympanic local route of administration. Moreover, sodium butyrate did not interfere with the tumoricidal effect of cisplatin providing both protections from reactive oxygen species and a certain degree of antitumor activity according to former reports. Acetylation of different cell proteins, including histones, is responsible both for the protective effect against oxidative stress and for the cell division inhibition and subsequent anticancer activity. The experiment's weak point is that it only showed the effect of sodium butyrate in a single dose of cisplatin model whereas in clinical practice cisplatin is typically given repeatedly at a couple of weeks intervals for several months .\u03b2 [The unique isoform of NADPH oxidase, NOX3, found in the cochlea and its involvement in the generation of reactive oxygen species was at the base of an animal study showing the efficacy of short interfering RNA in preventing cisplatin ototoxicity by reducing the expression of NOX3 in outer hair cells, spiral ganglion cells, and stria vascularis in the rat. Auditory brainstem responses were used to certify reduced threshold shifts in cisplatin treated animals who received transtympanic NOX3 siRNA. Since cisplatin administration has been previously associated with upregulation of NOX3 in the inner ear, Nox3 is thought to be a major source of free radicals in the cochlea following cisplatin exposure. The resulting free radicals initiate the inflammatory process in the cochlea by activating signal transducer and activator of transcription-1 (STAT1), followed by activation of p53 and increase in inflammatory mediators like TNF-alpha and interleukin-1\u03b2 . A singl\u03b2 .Among various strategies that have been devised in experimental settings to prevent cisplatin ototoxicity, minocycline, a tetracycline derivative, proved its partial efficacy in vivo and in vitro. The anti-inflammatory and neuroprotective properties of minocycline have been previously reported. The biochemical mechanisms involve caspase-1 and caspase-3 inhibition, which decreases the amount of interleukin-1 and prevents apoptosis. The protective effect of minocycline has been tested both on cisplatin treated cell cultures and in experimental animals which underwent cisplatin intraperitoneal therapy after systemic administration of the otoprotective agent. Cell viability assays showed that minocycline had a protective effect against cisplatin toxic action. Yet, minocycline failed to protect cells at higher concentrations of cisplatin. Recordings of auditory brainstem responses and evaluation of the scanning electron microscopy sections of inner ears harvested from minocycline plus cisplatin treated animals indicated a partial preservation of the function and morphology of the outer hair cells as compared to those from animals treated with cisplatin alone .The effect of intraperitoneal administration of erdosteine on cisplatin-induced ototoxicity in a guinea pig model was also studied. Erdosteine is a thiol derivative with established antioxidant properties due to its active sulfhydryl groups following liver first-pass metabolism. Pre- and posttreatment auditory brainstem responses measurements were performed in living animals while outer hair cell counts were analyzed by scanning electron microscopy of the cochleae removed from euthanized animals. Although the study had limitations , the results outlined the systemic administration of erdosteine as a promising therapeutic strategy for cisplatin-induced ototoxicity .In a first murine model for cisplatin-induced ototoxicity, it was shown that intratympanic dexamethasone prevents hearing loss in a frequency related manner. Evoked brainstem responses audiometry indicated that 8\u2009kHz and 16\u2009kHz stimulus elicited responses in cisplatin plus dexamethasone treated mice while high frequency stimulus (32\u2009kHz) perception was affected. Apparently, cisplatin had deleterious effects on outer and inner ear cells situated in the basal turn of the cochlea despite intratympanic administration of protective dexamethasone . FurtherThe intratympanic administration of dexamethasone avoids diminishing the tumoricidal activity of cisplatin. Downregulating apoptosis genes in tumour cells are responsible for this common side effect of systemic steroid therapy . An expeOtoprotection with dexamethasone against cisplatin-induced age-related hearing loss was investigated in a guinea pig model following observations that persons older than 65 years account for more than half of the newly diagnosed malignancies. Hearing loss due to the aging process shares the same cause with hearing loss due to ototoxic chemotherapeutic agents. A single dose of cisplatin was administered intraperitoneally in old mice preceded and followed by dexamethasone injected intratympanically to counteract the cisplatin toxic effect on inner ear hair cells. Pre- and posttreatment auditory brainstem responses were recorded to evaluate hair cell function. The results of the study pointed out that no synergistic action between age related hearing loss and cisplatin-induced hearing loss exists since threshold shifts were smaller in older animals than those in young mice. Another finding of the study was that the protective effect of dexamethasone against cisplatin-induced ototoxicity was a function of stimulus frequency in old mice. Susceptibility to otoprotective effect of dexamethasone was higher in mid to basal cochlear regions (at and above 24\u2009kHz) in old mice, whereas in young mice, dexamethasone bestowed more protection in apical regions of the cochlea (at 16\u2009kHz and below). Age-related changes of the mechanism of distribution of dexamethasone in scala tympani perilymph after round window membrane application in guinea pigs seem to account for the frequency dependent otoprotective effect .Intratympanic dexamethasone failed to protect against cisplatin-induced ototoxicity in a multidose cisplatin ototoxicity mouse model. The study was prompted by typical clinical protocols of cancer treatments which require administration of multiple, smaller cisplatin doses, exerting their curative effect through cumulative dosing. Contrary to previous experimental studies, the mice received five doses of cisplatin throughout five days, mimicking the cumulative exposure seen in malignant tumours treatment. Intratympanic dexamethasone was administered on the same days as the intraperitoneal cisplatin. The results mirrored by auditory brainstem responses threshold measurements demonstrated continued change in hearing thresholds several weeks after cisplatin exposure and no protective effect of intratympanic dexamethasone against cisplatin ototoxicity .An experimental study focused on systemic administration of steroid for protection against cisplatin-induced ototoxicity showed no otoprotection following several days' prophylaxis with a high dose dexamethasone treatment. Only a slight decrease of TNF-alpha expression in the cochlea was demonstrated by immunohistochemical staining of anatomical samples harvested from systemic cisplatin plus dexamethasone treated animals. Dexamethasone also seemed to protect stria vascularis from morphological alterations, probably owing this effect to higher concentrations of steroid in the lateral cochlear wall following increased cochlear flow and a naturally highly vascularised stria vascularis. Still, a functional otoprotective effect of systemic dexamethasone against cisplatin-induced hearing loss was not observed .Among naturally occurring molecules, Rosmarinic acid, a water-soluble polyphenolic compound extracted from Dansam-Eum, was tested for its protective effect against cisplatin-induced ototoxicity in laboratory settings. The results of the study showed that Rosmarinic acid inhibited cisplatin-induced caspase-1 activation providing protection against stereocilia loss in the primary organ of Corti explants .Another natural remedy, the Maytenus ilicifolia aqueous extract, was evaluated for its possible otoprotection in guinea pigs. Despite the well-known South America plant's antioxidant effects , functional tests did not demonstrate any protective action on the cisplatin exposed cochleae. Yet, the extract improved the clinical status and weight of guinea pigs and diminished mortality after cisplatin exposure .Resveratrol, a polyphenol found in grape skin and seed, has antioxidant, neuroprotective, and dose dependent antiapoptotic properties . Recent Intratympanic dexamethasone was clinically tested for its otoprotective effect in patients suffering from neoplastic diseases for which the treatment protocol included cisplatin. Intratympanic dexamethasone has already been tested clinically for the treatment of idiopathic sudden sensorineural hearing loss and Meniere disease . IntratyTranstympanic L-N-acetylcysteine was also clinically tested in head and neck cancer patients undergoing cisplatin therapy. Thiol compounds are known to either directly bind cisplatin or act as free radical scavengers. Based on that, their intratympanic administration was suggested to avoid the decrease of oncologic effectiveness of cisplatin and to reduce the oxidative stress caused by it. Intratympanic L-N-acetylcysteine was well tolerated by patients receiving multiple doses of cisplatin as part of their oncologic treatment. The relation between dose and otoprotection was not taken into account. Higher concentrations may have yielded better otoprotection. The study protocol required the L-NAC injection to be approximately 1 hour before systemic administration of cisplatin, for the sake of better timing. The outcome of the pure tone audiometry testing at 1 and 2 months after the last cycle of cisplatin showed that L-N-acetylcysteine was overall not significantly otoprotective. Still, hearing loss was reduced in two patients out of eleven who completed the study. The study protocol had several challenges like the difficulty in maintaining high enough concentrations of aqueous solution of L-N-acetylcysteine in the middle ear due to the technique of administration. Another study flaw was the different initial hearing thresholds due to preexisting hearing loss .http://clinicaltrials.gov/ct2/results?term=cisplatin+ototoxicity/) are listed in Few clinical studies tested systemic otoprotective molecules for preventing cisplatin-induced hearing loss. Amifostine, a phosphorylated aminothiol designed to protect against radiation damage, was known to counteract the toxic effect of different anticancer treatments without interfering with the tumoricidal effect. Although significant protection of amifostine against haematological toxicity after high dose carboplatin therapy in a child with medulloblastoma was reported , a cliniThe well-isolated inner ear organ makes it prone to targeted genetic therapies. Viral or nonviral gene vectors can be delivered through a transtympanic route without the risk of dispersing them and reaching other tissues with subsequent undesirable genetic alteration. Long term effects after single administration, cellular selectivity, and replacement of genetically flawed nucleic acid sequences are the main benefits of gene therapy. Common viral vectors include herpes simplex virus, recombinant adenoassociated virus, recombinant adenovirus, and adenovirus, used to amplify the expression of targeted genes. Cells are infected with the vectors (transfection) which transfer genes whose expressed proteins influence important processes like growth, oxidative stress, and apoptosis. Chemical transfection can also be achieved with plasmid vectors. Short interfering RNA can be used to shut down target genes.Among inner ear target genes dealt with by the gene therapy studies are ATOH1 (Math1), CAT , SOD1 (Cu/Zn superoxide dismutase), SOD2 (Mn superoxide dismutase), BDNF (brain-derived neurotrophic factor), HGF (hepatocyte growth factor), GJB2 (gap junction protein), Bcl-xL (B-cell lymphoma-extra large), FGF2 (basic fibroblast growth factor). The gene therapy modifies the synthesis of a wide range of proteins including neurotrophic factors , apoptosis mediators , oxidases , an antioxidant response regulator (Nfe2l2), a cytoprotective enzyme (HO-1), copper transporters (Ctr1), a nonselective cation channel (Trpv1), and protein Otospiralin (Otos).Cisplatin-exposed tissues can benefit from genetically induced upregulation of neurotrophic factors, inhibition of apoptosis, and generation of endogenous antioxidant enzymes.Experimental animal studies and in vitro experiments show the efficacy of gene therapy for cisplatin-induced ototoxicity. Clinical applications require further studies regarding safety, immunogenicity, and consequences of genetic manipulation .Another strategy to avoid cisplatin-induced hearing loss would be the pretreatment genotyping to find out patients at risk for the ototoxic effect of cisplatin . GeneticForty-three publications were reviewed concerning prevention or treatment of cisplatin induced ototoxicity. Publications were devised in either experimental or clinical studies. Experimental studies sustained the efficiency of hyperbaric oxygen therapy, epigallocatechin therapy, and intratympanic lactate. The latter two therapies provide exogenous antioxidants while pharmacologic activation of endogenous antioxidants by means of intratympanic thiamine pyrophosphate was consistent with higher levels of natural antioxidants. Oral sertraline, besides its otoprotective effect against cisplatin induced ototoxicity, also has therapeutic value concerning the depression occurring frequently in oncologic patients. Sodium butirate proved its efficiency against cisplatin induced hearing loss in a monodose cisplatin model. Yet, in clinical practice the patient receives multiple doses of cisplatin. The production of endogenous radicals of oxygen species was reduced after intratympanic administration of short interfering RNA which reduces the expression of NOX3 in the cochlea. Minocycline appeared to be efficient only at low doses of cisplatin while systemic erdosteine showed promising results. Dexamethasone in experimental studies combined efficiency against cisplatin induced ototoxicity with preservation of the tumoricidal activity of cisplatin. When older mice were treated, the dexamethasone was more otoprotective at higher frequencies compared to experiments including younger subjects. Rosmarinic acid also proved to be otoprotective while the Maytenus ilicifolia aqueous extract was not. Resveratrol had contradictory effects, systemic low doses, and in vitro administration preventing ototoxicity, whereas high oral doses seem to enhance cisplatin ototoxicity. There also were experimental studies which showed inefficiency of intratympanic N-acetylcysteine and intratympanic and systemic dexamethasone. N-Acetylcysteine also had a damaging effect on middle and inner ear structures.Clinical studies proved a minor otoprotective effect of intratympanic dexamethasone and no effect of systemic amifostine and intratympanic L-N-acetylcysteine. New perspectives are brought about by genetic therapy using viral vectors and genotyping to anticipate interindividual variability in cisplatin ototoxicity.Hearing loss prevention and treatment during cisplatin therapy for cancer needs further research to find new strategies and optimize old ones. The intratympanic route of administration along with the gene therapy appears to be the most attractive objective for further experimental and clinical studies."} +{"text": "The real benefit of alternative cannulation technique for repair of acute type A aortic dissection remains controversial.We evaluated our results of ascending aortic cannulation compared with femoral cannulation in acute type A aortic dissection.From January 2000 to December 2014, 121 patients were operated on for acute type A aortic dissection. Cannulation was accomplished in 79 patients through the ascending aorta and 42 patients through the femoral artery.Patient characteristics such as preoperative complications and shock status were almost similar between the groups. Although intraoperative parameters such as total cardiopulmonary bypass time, hypothermic circulatory arrest time, minimum bladder temperature and percentage of total arch replacement were also similar between the groups, ascending aortic cannulation significantly reduced arterial pressure on cardiopulmonary bypass circuit , core-cooling time and operation time . There were no significant differences in postoperative 30-day mortality and in-hospital mortality between the groups. However, incidence of temporary neurological dysfunction and respiratory failure as postoperative complications were significantly lower in the aortic cannulation group, although the incidence of stroke and renal failure did disclose any differences between the groups. Moreover, ascending aortic cannulation significantly reduced the hospital stay .The ascending aortic cannulation for repair of acute type A aortic dissection can be advantageous to rapid cooling after the establishment of cardiopulmonary bypass. It might offer benefit on the incidence of postoperative complications and the length of hospitalization in patients with of acute type A aortic dissection."} +{"text": "Maintaining DNA integrity is essential for cell survival and proper functioning. Therefore, many cancer therapies, including radiotherapy and several chemotherapeutic drugs, induce damage to the DNA leading to genomic instability . There aWe have used NMR based targeted profiling to compaWe observed several similarities in the metabolic responses caused by different DDRs and also identified specific metabolite markers on treatment with these DNA damaging agents. PARP inhibition restored most of the metabolic changes observed in MMS-treated cells suggesting that the metabolic response observed after MMS treatment may be predominantly due to PARP activation.In this study, we identified several similarities and differences in metabolic responses induced by different types of DDRs, which suggests the redirection of metabolic fluxes in a DNA damage-dependent manner. We also observed that recruitment of PARP during the DNA repair process can lead to widespread metabolic changes by observing the effect of PARP inhibition in MMS-treated cells. These results have identified novel metabolic responses in cancer cells following DNA damage and on inhibiting activity of proteins involved in DNA repair processes."} +{"text": "Helicobacter pylori infection remains one of the most challenging infectious diseases causing high mortality and morbidity. The prevalence of infection varies greatly between industrial and developing countries as well as between different geographic areas.Helicobacter pylori (H. Pylori) infection remains one of the most challenging infectious diseases causing high mortality and morbidity. The prevalence of infection varies greatly between industrial and developing countries as well as between different geographic areas and indirect (non-invasive). Direct methods involve biopsies of ulcer margins by endoscopy and microscopic examination, endoscopy with phenols staining, rapid urease test, and histological specimen culture and polymerase chain reaction. Indirect methods include antibody serology test, stool antigen test, urea breath test, examining of teeth plaque, urine and gastric juice examination have been completely observed by the author.None declared."} +{"text": "Naegleria fowleriBalamuthia mandrillarisAcanthamoeba species.Infections caused by free-living amebae (FLA) are severe and life-threatening. These infections include primary amebic meningoencephalitis (PAM) caused by B. mandrillaris and Acanthamoeba species infections treated with a miltefosine-containing regimen is small, it appears that a miltefosine-containing treatment regimen does offer a survival advantage for patients with these often fatal infections protocol in effect with the Food and Drug Administration to make miltefosine available directly from CDC for treatment of FLA in the United States. The expanded access IND use of miltefosine for treatment of FLA is partly supported by 26 case reports of FLA infection in which miltefosine was part of the treatment regimen . Miltefosine generally is well-tolerated, with gastrointestinal symptoms the most commonly reported adverse effects. Clinicians who suspect they have a patient with FLA infection who could benefit from treatment with miltefosine should contact CDC to consult with an FLA expert. For diagnostic assistance, specimen collection guidance, specimen shipping instructions, and treatment recommendations, clinicians should contact the CDC Emergency Operations Center at 770-488-7100."} +{"text": "We report a unique first case of benign heterotopic pancreas arising within the proximal hepatic bile duct, containing a focus of intraductal papillary mucinous neoplasm (IPMN). The condition was diagnosed on pathological explant after left hepatic lobectomy with total extrahepatic bile duct excision. The condition of heterotopic pancreas is a relatively common finding, where small foci of pancreatic rest tissue arise in intra-abdominal sites other than the pancreas. First described in 1727, aberrant pancreatic tissue is defined as ectopic location of pancreatic tissue without vascular, neural, or anatomic connections to the anatomically normal pancreas . The majAn obese otherwise healthy 47-year-old female (body mass index 36) presented with intermittent nausea and right upper quadrant discomfort after intentional weight loss of 27\u2009kg. The serum lipase was found to be mildly elevated at 132 units. Abdominal ultrasound demonstrated focal dilatation of the intrahepatic left hepatic ducts, and a subsequent contrast-enhanced magnetic resonance cholangiopancreatogram (MRCP) and endoscopic retrograde cholangiopancreatogram (ERCP) demonstrated an occlusive filling defect within the proximal main biliary tree . An intrThe imaging findings were concerning proximal hepatic duct cholangiocarcinoma (Klatskin tumor), although the CA19-9 was not elevated. The patient then underwent surgical exploration where a palpable filling defect was identified within the proximal hepatic duct. Intraoperative ultrasound demonstrated no additional lesions. For oncological clearance, a left hepatectomy with caudate lobectomy was completed, which required a triple right-sided bile duct Roux-en-Y reconstruction (two posterior and one anterior right bile ducts) over temporary externalized 5 French stents. No blood products were required, and no inflow occlusion was used. She had a smooth and relatively uncomplicated recovery other than a superficial wound infection.Surgical pathology demonstrated histological features consistent with heterotopic pancreatic tissue with IPMN contained within the proximal biliary tree .Sections showed superficial atypia with areas suggestive of papillary formation. There was also prominent bland duct proliferation with lobular architecture and microscopic foci of pancreatic acini surrounding the bile duct. The histological diagnosis was consistent with heterotopic pancreatic tissue. The superficial atypia with papillae suggests a low grade IPMN of the bile duct.At follow-up at 2 months, the patient had recovered fully, and the biliary stents were removed uneventfully.Continued advancement in cross-sectional and other imaging modalities facilitates early diagnosis and more precise treatment for hepatobiliary malignancies. We describe an extremely rare condition of IPMN arising within heterotopic pancreatic tissue obstructing the proximal hepatic duct. We believe this to be the first report of this condition arising within and obstructing the biliary tree. Interestingly SpyGlass cholangiography was able to demonstrate the lesion but was not able to precisely define the pathology. Furthermore, obstruction of the proximal biliary tree necessitated definitive resectional treatment. Had we been confident preoperatively of the benign nature of the filling defect, a less aggressive localized bile duct resection with hepatic parenchymal preservation could potentially have been entertained. However, the presence of IPMN change with potential for malignant transformation would still have provided concern. Preoperative diagnosis of heterotopic pancreas may be challenging and typically this is an incidental finding.Heterotopic pancreas is most commonly found in the proximal jejunal wall of the gastrointestinal tract. Pathological changes that occur within the native pancreas may also occur rarely within the heterotopic gland, including pancreatitis, abscess, and occasionally malignant transformation . IPMNs aIn conclusion, although the condition of heterotopic pancreas is usually asymptomatic and is often discovered incidentally, IPMN with potential for malignant transformation may rarely occur remotely within the biliary tree."} +{"text": "Hyperammonemic encephalopathy may occur when urease-positive bacteria in the urinary tract produce ammonium which directly enters systemic circulation. Predisposing conditions such as a neurogenic bladder can increase both urinary tract infection and urine stagnation.We describe the case of a 66\u00a0years old woman with a neurogenic bladder who twice developed hyperammonemic encephalopathy following urinary tract infection. During the second episode Escherichia coli and Enterococcus faecalis have been isolated in the urine. The neurologic examination showed psychomotor slowing, weak photomotor reflex, nystagmus in the lateral gaze and asterixis. The EEG showed triphasic waves which disappeared along with clinical recovery.Escherichia coli and Enterococcus faecalis are commonly considered urease-negative bacteria. Although frequently involved in urinary tract infections, their role in causing hyperammonemic encephalopathy have not been previously reported. Moreover, despite only one case with a neurogenic bladder have been described so far, our is the first patient with reoccurring hyperammonemic encephalopathy secondary to urinary tract infections. The occurrence of hyperammonemic encephalopathy is frequently related to liver disease and portal hypertension, where hepatic detoxification process is impaired. In patients with urinary divertion, vesico-colonic fistula or congenital anomalies affecting urinary tract function, ammonium may bypass portal circulation draining directly into the hypogastric veins and inferior vena cava. During urinary tract infections (UTI), urea splitting organisms may determine ammonium production primarily within the urinary system. There are rare conditions when the urine remains into a dilated bladder long enough to allow ammonium reach systemic circulation: this can be due to large diverticula , a neuroWe report the case of a patient with a neurogenic bladder who presented two episodes of hyperammonemic encephalopathy three years apart as a result of UTI. During the last episode, urine culture revealed Escherichia coli and Enterococcus faecalis which are considered urease-negative bacteria.A 66-years-old female, with a history of urinary retention and recurrent UTI, became progressively somnolent during one week, complaining at the same time dysuria and bladder pain, for which she had been assuming trimethoprim-sulfamethoxazole. She was conducted to our department after the execution of a brain CT and the detection of hyperammonemia (89\u00a0\u03bcmol/L) in the emergency room. The neurologic examination showed psychomotor slowing, weak photomotor reflex, nystagmus in the lateral gaze and asterixis. Her past medical history highlighted that, three years before, she had experienced a similar event . She underwent laboratory blood and urine tests, which showed increased pH (8.0) and a urinary tract infection caused by Escherichia coli and Enterococcus faecalis along with mild increase of serum creatinine, but without impairment of hepatic function; EEG showed alterations consistent with toxic metabolic encephalopathy Figure\u00a0. UnderlyHyperammonemic encephalopathy occurs when hyperammonemia causes glutamine-mediated effects on the brain, such as astrocytic swelling, cerebral edema, and raised intracranial pressure . An incrOur patient has been suffering from urinary retention for many years because of an idiopathic neurogenic bladder. Urinary retention not only predisposed her to the infection, but also increased the absorption of ammonia from the leftover urine through the bladder walls .Although hyperammonemic encephalopathy determines a similar clinical and EEG picture independently of the cause (UTI or hepatic failure), the urinary origin is likely to result in a faster (days or weeks) onset of the symptoms, compared with the chronic and peculiar clinical picture of patients with hepatic dysfunction.To our knowledge this is the first described case where urinary retention was associated with urinary tract infection and recurring hyperammonemic encephalopathy. Moreover no previous cases have been reported where urinary tract infection by Escherichia coli and Enterococcus faecalis caused hyperammonemia.The present case focuses on urinary tract infection related to neurogenic bladder as a potential cause of hyperammonemia, which nevertheless can lead to metabolic encephalopathy. It is important to underline that bacteria usually considered urease-negative may be related to ammonium production within the urinary tract.Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.UTI: Urinary tract infection; CT: Computed tomography; EEG: Electroencephalogram.The authors declare that they have no competing interests.All the authors have read and approved the manuscript. In addition all authors have contributed in the composition, write-up, and review of the manuscript."} +{"text": "However, recent experiments in which sensory-evoked local dendritic spikes were observed in vivo have provided valuable constraints on possible spatiotemporal patterns of synaptic input [Theoretical modelling and experiments e neuron ,2. Whileic input -5. For eic input . Here, win vivo [in vivo experiments [First, we adapted a detailed active compartmental model of a neocortical layer 2/3 pyramidal neuron [in vivo , such asin vivo occur preferentially when excitatory synaptic inputs are interspersed with inhibitory synaptic inputs. Furthermore, local spikes preceding backpropagating action potentials lead to the highest instantaneous dendritic spike frequencies. The highest sustained frequencies are generated by local spikes initiated sequentially in several neighbouring dendritic branches. Notably, only some of the high frequency dendritic events are effective in evoking action potential output, while others remain local. We use cluster analysis to establish the local and global conditions under which specific spatiotemporal patterns of synaptic input can influence neuronal output.Next we analyzed which spatiotemporal synaptic input patterns precede the generation of local dendritic events. We find that local spikes are preferentially triggered by excitatory synapses which are spatially and temporally clustered in the local dendritic branch and neighbouring branches. While there is great variability in the spatial distribution of synapses triggering local dendritic spikes, temporal patterns of excitatory synaptic input are stereotyped and tend to be sparse. High-frequency dendritic spikes similar to those observed In summary, we have derived spatial and temporal rules for synaptic input and identify input patterns that locally exploit the non-linear integration capacities of dendrites. Which computations can be implemented by spiking dendrites receiving such synaptic input patterns? These constraints on synaptic input patterns, together with the realistic intrinsic properties displayed by the model, put us in a position to investigate the role of dendritic excitability in shaping the input-output relation of the neuron."} +{"text": "RAS proteins are key signalling hubs that are oncogenically mutated in 30% of all cancer cases. Three genes encode almost identical isoforms that are ubiquitously expressed, but are not functionally redundant. The network responses associated with each isoform and individual oncogenic mutations remain to be fully characterized. In the present article, we review recent data defining the differences between the RAS isoforms and their most commonly mutated codons and discuss the underlying mechanisms. RAS proteins are membrane-bound small GTPases that act as molecular switches downstream of cell-surface receptors. Upon GTP binding, RAS changes conformation, revealing an effector-binding site that can interact with proteins harbouring a RAS-binding domain . RelocalIn the human genome, three genes encode HRAS, KRAS and NRAS. Alternative splicing of HRAS and KRAS generates protein variants with altered C-termini . The N-tDespite their similarity, RAS proteins are not functionally redundant. Furthermore, the oncogenic mutations that make RAS constitutively active may not all be equivalent in their functional consequences. We discuss the evidence for this together with the potential mechanisms underlying these phenomena.RAS proteins cycle between the inactive GDP-bound and the active GTP-bound conformations . This cyThe reason for the bias in RAS mutations associated with individual cancers is unclear, although several models have been proposed. One simple possibility is that isoform-specificity could mean that a more oncogenic network response is generated when KRAS is rendered constitutively active by mutation compared with the other RAS isoforms. This is supported by mouse models harbouring G12D mutated KRAS that exhibited widespread colonic hyperplasia and neoplasia. In contrast, NRAS G12D stimulated cell survival pathways . FurtherKRAS revealed a strong bias for rare codon usage resulting in significantly reduced protein translation compared with a codon-optimized KRAS sequence [RAS is known to induce senescence rather than proliferation [KRAS leads to low endogenous protein levels, meaning that oncogenically activated KRAS would not be expressed highly enough to induce the senescent phenotype. Absolute quantification of RAS isoform protein abundance in normal tissues has not been performed to date; however, comparative analysis of RAS isoform protein levels in a panel of cancer cell lines revealed that KRAS is typically the most abundant isoform of RAS isoforms change their orientation with respect to the membrane . The extKRAS knockout resulted in embryonic lethality [HRAS into the endogenous KRAS locus, resulting in normal embryonic development, but induced dilated cardiomyopathy during adulthood [Finally, relative expression differences of the isoforms will influence competition for regulator and effector binding and therefore signalling network responses. An example of this can be seen in studies of mouse development. Whereas ethality , a subsedulthood . This suRAS alleles, panels of cancer cell lines and mouse models.This illustrates the importance of studying isoform-specific function in an endogenous context, since a subset of isoform-specific differences may result from the disparity in their expression. Future work is likely to rely less on ectopic overexpression and more on isogenic cells harbouring endogenous wild-type and mutant RAS proteins exhibit a spectrum of isoform-, codon-, point-mutation- and context-specific network responses. These remain poorly understood, which precludes simple prediction of the likely consequences of any given mutation. Wherever possible, it is important to study RAS function in an endogenous context to avoid the perturbing influence of overexpression on the signalling networks. With the recent emergence of new cellular tools, xenopatient and genetically engineered mouse models and more sophisticated systems biology approaches to studying RAS function, there are likely to be significant improvements in our understanding of RAS biology in the near future."} +{"text": "Familial Mediterranean fever (FMF) is an autosomal recessive auto-inflammatory disease, presenting with recurrent episodes of fever and polyserositis. Diagnosis of FMF is may be challenging especially in pediatric population. Mitochondrial fatty acid oxidation disorders and porphyrias can present with periodic abdominal and muscle pain. Incidence of both FMF and inherited metabolic disorders (IMD) are increased in Turkish patients partially due to high consanguinity rates.The aim of the present study is determine the inherited metabolic disorders in differential diagnosis of Turkish pediatric FMF patients.174 patients who were diagnosed as FMF enrolled the study. In all patients, a fasting dry spot blood sample was taken for acyl-carnitine analyses by tandem mass spectrometry. Fresh, light-protected spot urine test was performed for porphobilinogen screening. Second-tier test with urine organic acid analysis and urine porphyrin metabolites were performed if pathologic findings were detected in acyl-carnitine profile or in porphobilinogen screening, for confirmation. An age matched healthy 50 children served as control group.Of the 174 patients diagnosed with FMF, none of our patients was diagnosed with porphyria; two patients with fatty acid oxidation defect, one with multiple acyl-CoA dehydrogenase deficiency and one with possible medium-chain acyl-CoA dehydrogenase deficiency were detected during the study.Our data revealed that screening for porphobilinogen for pediatric FMF patients is unnecessary, but an investigation of tandem mass based acyl-carnitine analyses can be helpful for the differential or additional diagnosis of FMF in developing countries that does not have nationwide expanded newborn screening programme."} +{"text": "Microglia are macrophage-like resident immune cells that contribute to the maintenance of homeostasis in the central nervous system (CNS). Abnormal activation of microglia can cause damage in the CNS, and accumulation of activated microglia is a characteristic pathological observation in neurologic conditions such as trauma, stroke, inflammation, epilepsy, and neurodegenerative diseases. Activated microglia secrete high levels of glutamate, which damages CNS cells and has been implicated as a major cause of neurodegeneration in these conditions. Glutamate-receptor blockers and microglia inhibitors have been examined as therapeutic candidates for several neurodegenerative diseases; however, these compounds exerted little therapeutic benefit because they either perturbed physiological glutamate signals or suppressed the actions of protective microglia. The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects. We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface. Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Recent evidence also suggests that neuronal and glial communication via gap junctions amplifies neuroinflammation and neurodegeneration. Elucidation of the precise pathologic roles of gap junctions and hemichannels may lead to a novel therapeutic strategies that can slow and halt the progression of neurodegenerative diseases. Microglia are macrophage-like immune cells that reside in the central nervous system (CNS), where they play multiple roles: presenting antigen to initiate immunological reactions, directing attack against non-self antigens, debris clearance, support of neuronal circuit development . CaMK activates neuronal nitric oxide synthase (nNOS) and increases the intracellular concentration of nitric oxide (NO). NO in turn inhibits mitochondrial respiratory chain complex IV, resulting in a rapid reduction in intracellular ATP levels. Ultimately, the loss of intracellular energy pools suppresses dendritic and axonal transport, leading to bead-like accumulation of cytoskeletal and motor proteins along neurites and the formation of neuritic beading. Thus, a low-energy state results in neuronal dysfunction. Persistence of this neuronal dysfunction eventually causes neuronal death [i.e., excitotoxic neuronal death or non-cell-autonomous neuronal death , metabolites , and nucleotides between adjacent cells . These toxic molecules are propagated from injured cells to healthier cells through gap junctions. Ischemic conditions also induce uncoupled hemichannels to open, leading to paracrine transfer of toxic molecules and an animal model of this disease, experimental autoimmune encephalomyelitis (EAE). In particular, downregulation of oligodendrocytic Cx32 and Cx47 and astrocytic Cx43 have been observed in the active lesions of MS patients and EAE mice , Cx43 (43gap 27), or Panx1 (10panx1) non-specifically block both connexins and pannexins (Block et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Multivariate analyses identified significant spatial and temporal variation in benthic fluxes, demonstrating key differences between the Northeast Pacific and Salish Sea. Moreover, Northeast Pacific slope fluxes were generally lower than shelf fluxes. Spatial and temporal variation in benthic fluxes in the Salish Sea were driven primarily by differences in temperature and quality of organic matter on the seafloor following phytoplankton blooms. These results demonstrate the utility of multivariate approaches in differentiating among potential drivers of seafloor ecosystem functioning, and indicate that current and future predictive models of organic matter remineralization and ecosystem functioning of soft-muddy shelf and slope seafloor habitats should consider bottom water temperature variation. Bottom temperature has important implications for estimates of seasonal and spatial benthic flux variation, benthic\u2013pelagic coupling, and impacts of predicted ocean warming at high latitudes.The upwelling of deep waters from the oxygen minimum zone in the Northeast Pacific from the continental slope to the shelf and into the Salish Sea during spring and summer offers a unique opportunity to study ecosystem functioning in the form of benthic fluxes along natural gradients. Using the ROV ROPOS we collected sediment cores from 10 sites in May and July 2011, and September 2013 to perform shipboard incubations and flux measurements. Specifically, we measured benthic fluxes of oxygen and nutrients to evaluate potential environmental drivers of benthic flux variation and ecosystem functioning along natural gradients of temperature and bottom water dissolved oxygen concentrations. The range of temperature and dissolved oxygen encountered across our study sites allowed us to apply a suite of multivariate analyses rarely used in flux studies to identify bottom water temperature as the primary environmental driver of benthic flux variation and organic matter remineralization. Redundancy analysis revealed that bottom water characteristics (temperature and dissolved oxygen), quality of organic matter (chl Marine carbon, nitrogen, and phosphate cycles are linked through their fixation by phytoplankton in surface waters and their remineralization in the water column and on the seafloor . The decOn the continental shelf, close benthic\u2013pelagic coupling typically occurs over time scales of days. The benthic community generally responds rapidly to increased particulate organic carbon (POC) flux to the seafloor, resulting in measurable increases in benthic respiration . This rein situ studies that utilize natural variation such as those that occur along environmental gradients could potentially highlight the main environmental drivers of benthic fluxes, organic matter remineralization and ecosystem functioning in natural systems 76], OPD Bio-irrigation may also have influenced oxygen uptake; Archer and Devol found thGiven that the marine nitrogen cycle arguably represents the most complex of all biogeochemical cycles in the ocean , a compla:phaeo and C:N), bottom water DO, and sediment MGS as the best predictors of silicate benthic efflux variation. Because we did not measure bio-irrigation, we cannot directly link silicate effluxes with this variable. However, increased oxygen penetration with bottom water oxygen concentration suggests higher bio-irrigation at the shallower and more oxygenated shelf sites than in deeper and oxygen-depleted slope sites on the NE Pacific. Lower oxygen concentration can also change macrobenthic community structure to one that primarily inhabits and reworks the surface of the seafloor and poorly bio-irrigates sediment at depth [Our study shows generally higher silicate effluxes from shallower shelf sites than deeper slope sites, with some seasonal variation. Silicate variation often reflects small-scale differences in sediment properties, bioturbation, and irrigation . Hammondat depth . Much hiat depth . Moreoveat depth suggesteat depth . We ther-2 d-1 in BC300) to release (697.0 \u03bcmol m-2 d-1 in SoGC-05). Although Nixon et al. [a:phaeo, porosity, MGS and prokaryote abundance can explain 88% of the variation in phosphate flux. Our study apparently encompassed most of the key drivers for phosphate flux, allowing us to predict benthic phosphate flux at these locations. These results are supported by a recent study that modelled benthic phosphate fluxes using three of the variables that we identified along with mineral bound inorganic phosphorous [Many factors influence seafloor phosphate fluxes , which vn et al. reportedn et al. reportedsphorous .a:phaeo and C:N ratios, 11.8 and 7.9% respectively) and sediment characteristics . In their Beaufort Sea study, Link et al. [a and phaeopigments, and bottom water dissolved oxygen as key environmental drivers of multivariate benthic flux variation. However, in contrast to our study, where temperatures varied by >5.5\u00b0C across sampling locations and dates, temperatures recorded at the time of sampling varied by <2\u00b0C and therefore contributed little to benthic flux variation, just as Rowe and Phoel [Multivariate dbRDA allowed us to examine all benthic fluxes simultaneously within the same analysis. Environmental drivers related to bottom water characteristics, quality of organic matter, and sediment characteristics, explained 51.5% of the variability in overall oxygen and nutrient fluxes. Bottom water characteristics explained most of the variability , followed by quality of organic matter in the same analysis to determine the best combination of environmental drivers for all benthic fluxes, hence of seafloor organic matter remineralization. On the other hand, the multiple linear regression approach analysed each benthic flux separately to determine the best combination of environmental drivers for each specific benthic flux. Given some commonalities in benthic fluxes but different degrees of influence by some environmental drivers on each benthic flux , the linear regression method identifies the environmental drivers of each benthic flux whereas the dbRDA method identifies the common environmental drivers that influence all benthic fluxes and examines seafloor organic matter remineralization as a whole.The dbRDA and multiple linear regression approaches identified some differences in environmental drivers of benthic fluxes. On the one hand, the dbRDA approach combines all benthic fluxes on flux rates of oxygen, nitrate, phosphate, silicate and, for the most part, ammonium, where flux rates changed only after oxygen decreased by 50\u201380% from ambient values , 74. Thia:phaeo and C:N ratios) following significant deposition of particulate organic matter to the seafloor and, to a lesser extent, sediment characteristics (MGS and porosity). Although multiple biological and environmental factors influence different seafloor flux rates (O2 and nutrients), our study used a suite of multivariate approaches in tandem to demonstrate that a subset of the large number of environmental variables measured could explain benthic flux variation. We also found that simultaneous and single flux analyses in tandem provided a more comprehensive understanding of the interplay between OM remineralization and flux of O2 and individual nutrients.Our study indicates strong variation in spatial and temporal flux, driven primarily by differences in bottom water characteristics (bottom water DO and temperature), quality of organic matter at our study sites allowed us to identify bottom water temperature as the key driver of benthic flux variation. These results indicate that current and future predictive models of organic matter remineralization and ecosystem functioning of shelf and slope soft-muddy seafloor habitats should consider bottom water temperature variation. Temperature could have important implications for estimates of seasonal and spatial benthic flux variation, benthic-pelagic coupling, and potential impacts of predicted ocean warming, particularly at high latitudes.S1 Appendix(DOCX)Click here for additional data file."} +{"text": "Human dental pulp inflammation can progress to periapical lesion formation and conventional root canal treatment (RCT) has been the traditional method for disease management. This observational study presents two cases of vital pulp therapy in mature molars diagnosed with irreversible pulpitis and associated with apical periodontitis. In these two clinical cases, the involved teeth had deep carious lesions with a history of spontaneous/lingering pain and radiographic examinations revealed the presence of apical radiolucencies. A conservative miniature pulpotomy (MP) using calcium-enriched mixture (CEM) was performed and the teeth were permanently restored with amalgam. Clinical evaluations indicated resolution of pain 24 hours after treatment; the teeth showed normal vitality, remained asymptomatic and maintained normal function after recall examinations. Furthermore, the 18-month radiographic evaluation showed healing of the apical lesions. Vital pulp therapy using the MP technique with CEM appeared successful in avoiding RCT intervention. These two reports of case outcome suggest that simple MP using a CEM bioregenerative technique may provide a favorable outcome for permanent teeth diagnosed with irreversible pulpitis and associated with apical periodontitis. Irreversible pulpitis is an inflammatory condition of the dental pulp characterized by long lasting or lingering pain after removal of a specific stimulus. If this inflammatory process progresses, immune responses in the periapical region, can advance and eventually lead to the development of apical periodontitis. It has been demonstrated that periradicular lesions may be detected before the actual necrosis of dental pulp . Scientipy (RCT) . Vital pulp therapy (VPT) is a simple, biologic, regenerative, conservative and economic method that shows a favorable success rate; treatment includes direct/indirect pulp capping and miniature/partial/complete pulpotomy using various pulp capping agents , 8. MiniMineral trioxide aggregate (MTA), which has the ability to induce hard tissue formation, is universally used in VPT but it hThis clinical report describes successful MP treatment of two mandibular molars diagnosed with irreversible pulpitis and associated with periapical involvement using CEM cement. Case 1A 38-year-old female presented to our clinic with the chief complaint of spontaneous and severe lingering pain provoked by chewing and exposure to cold fluids. The patient\u2019s medical history was noncontributory and clinically, the left mandibular second molar exhibited a deep carious lesion. The involved tooth responded with prolonged exaggerated pain (>10 seconds) to a cold test and demonstrated sensitivity to percussion. Radiographic examination revealed a deep carious lesion and complete root-end apical closure, widening of periodontal ligament and presence of a periapical lesion . AccordiA mouth rinse with 0.2% chlorhexidine gluconate was first initiated and the patient then received inferior alveolar nerve block anesthesia with 2% lidocaine and 1:80000 adrenalin . The tooth was isolated with a dental dam and then caries were completely excavated under magnification. The exposed surface of the dental pulp was lightly brushed with a sterile round diamond bur using a high-speed handpiece and copious water irrigation; the removal of the pulp did not exceed 1 mm. Hemostasis was achieved by irrigation with sterile saline solution and gentle application of moistened sterile cotton pellets for three min. CEM cement powder and liquid were mixed according to the manufacturer\u2019s instructions. A small bulk of the cement was gently condensed into the pulpal cavity using dry sterile cotton pellets. After 5 min [Case 2A healthy 40-year-old man was referred to our clinic with a chief complaint of spontaneous and temperature related pain including pain on chewing in the left mandible. Clinically, the mandibular left first molar exhibited an advanced distal carious lesion and was The patient was recalled after one week and the tooth was clinically asymptomatic. The tooth showed normal vitality to cold testing, with no evidence of clinical or radiographic pathology at the 18-month recall. An important radiographic finding was formation of a hard tissue bridge beneath CEM cement and complete resolution of the apical lesions .As our knowledge in pulpal biology and endodontic biomaterials advances, the initial management of vital teeth with associated apical lesions employing simple VPT procedures may now be considered a potential treatment strategy. VPT is a valuable treatment, particularly for teeth with open apices and vital pulps which are mechanically or cariously exposed -15. UsuaIn this report, two cases with irreversible pulpitis and symptomatic apical periodontitis were treated by MP using CEM bioceramic. Follow-up examinations demonstrated favorable outcomes that maintained pulpal vitality and promoted periapical healing using CEM as a VPT bioceramic. The biological response to VPT is highly influenced by the healing potential of the inflamed pulp as well as the biocompatibility and sealing ability of pulp capping agent . The sucMP is a conservative VPT strategy, which results in removal of injured odontoblast cells, operative debris, potentially infected tissue and exposes deeper layers of the pulp to the proximity of the capping agent where mesenchymal or dental pulp stem cells are present. The advantages of MP include better irrigation and cleaning of the surgical pulp wound from contaminated dentinal chips and accessibility to areas with less pulpal inflammation where hemostasis can be more easily attained. The procedure also creates adequate space for the suitable pulp capping agent or biomaterial, thus producing a superior three dimensional antibacterial seal . Current research data indicates that the hard tissue barriers generated under CEM cement are thicker than those produced by MTA and that the layer of odontoblast-like cells formed underneath the capping material appears to be more consistent in CEM specimens . It has The mechanism by which CEM encourages pulp healing still remains unclear. However, this feature may be attributed to several properties including sealing ability, antimicrobial effect, low cytotoxicity, similarity to dentine, hydroxyapatite formation and the ability to induce hard barrier formation , 27-30. Miniature pulpotomy provides an easy, conservative, and biologically-based treatment that maintains pulpal vitality and shows the ability to resolve emerging apical pathosis under certain conditions. Although more clinical trials with larger sample sizes and longer-term follow-ups may be required, using CEM cement or other bioceramic materials for MP may be considered an alternative option to conventional RCT in symptomatic vital permanent teeth diagnosed with irreversible pulpitis."} +{"text": "Measures of small-area deprivation may be valuable in geographically targeting limited resources to prevent, diagnose, and effectively manage chronic conditions in vulnerable populations. We developed a census-based small-area socioeconomic deprivation index specifically to predict chronic disease burden among publically insured Medicaid recipients in South Carolina, a relatively poor state in the southern United States. We compared the predictive ability of the new index with that of four other small-area deprivation indicators.To derive the ZIP Code Tabulation Area-Level Palmetto Small-Area Deprivation Index , we evaluated ten census variables across five socioeconomic deprivation domains, identifying the combination of census indicators most highly correlated with a set of five chronic disease conditions among South Carolina Medicaid enrollees. In separate validation studies, we used both logistic and spatial regression methods to assess the ability of Palmetto SADI to predict chronic disease burden among state Medicaid recipients relative to four alternative small-area socioeconomic deprivation measures: the Townsend index of material deprivation; a single-variable poverty indicator; and two small-area designations of health care resource deprivation, Primary Care Health Professional Shortage Area and Medically Underserved Area/Medically Underserved Population.Palmetto SADI was the best predictor of chronic disease burden (presence of at least one condition and presence of two or more conditions) among state Medicaid recipients compared to all alternative deprivation measures tested.A low-cost, regionally optimized socioeconomic deprivation index, Palmetto SADI can be used to identify areas in South Carolina at high risk for chronic disease burden among Medicaid recipients and other low-income Medicaid-eligible populations for targeted prevention, screening, diagnosis, disease self-management, and care coordination activities. In the United States persons with chronic conditions are overrepresented in Medicaid , a publiIncreasingly, small-area measures of social and material deprivation are usedAlthough the Townsend deprivation index, single-variable poverty index, and health care resource deprivation designations are used widely in health planning and evaluation, these measures may not be optimally suited for purposes of community health need assessment in all geographic regions or across diverse population groups. Indeed, a marked trend exists in the development of region/population-specific small-area deprivation indexes for health research. Since 2000, for example, deprivation measures have been constructed and applied in health studies in Quebec, Canada ; Verona,To our knowledge, no socioeconomic deprivation measure has been developed specifically for assessment of a Medicaid population in the United States. To facilitate health policy and programming, we developed a census-based small-area socioeconomic deprivation index optimized to predict chronic disease burden among Medicaid recipients in South Carolina, a largely impoverished Southern state where more than one in five residents are enrolled in the Medicaid system . Based oThe US Census Bureau provides detailed population and housing data at multiple geographic levels. US census and survey data products are updated regularly and are available online at no cost, making them especially valuable to state and local health planners with limited financial resources. We sought to create a census-based index of socioeconomic deprivation to predict chronic disease burden among South Carolina Medicaid enrollees at the ZIP Code Tabulation Area (ZCTA) level. Census-defined ZCTAs are comprised of whole census blocks and spatially approximate USPS five-digit ZIP Code mail delivery areas . These sBased on a literature review, we evaluated a range of Census 2000 population and housing indicators for inclWe evaluated chronic disease burden among South Carolina Medicaid recipients across five adverse chronic health conditions: cardiovascular disease (CVD); diabetes; end-stage renal disease (ESRD); hypertension; and obesity. These diagnostic categories are among the most common and costliest chronic conditions affecting South Carolina Medicaid enrollees. Chronic disease status for the state\u2019s approximately 1 million Medicaid recipients was determined using primary and secondary diagnosis codes contained in South Carolina Medicaid administrative data sets from fiscal year 2010 (July 2009 to June 2010) . ZCTA-leXi) using Fisher\u2019s Z-transformation to create a set of Z-score variables (Zi) defined for ni observations j = 1,\u2026,ni based on the associated original variableith predictor. This transformation ensures that each of the Z-score variables is standardized to have mean 0 and variance 1. We then calculated the mean correlation of each transformed variable across the set of five chronic condition prevalence rates. The single predictor with the highest mean correlation was the first component Condi)N = 392).In developing the new socioeconomic deprivation index, we sought to minimize the total number of census-based predictor variables while maximizing correlation with ZCTA-level Medicaid chronic disease rates. We scaled each predictor . Two chronic disease burden indicators\u2014one reflecting the presence of at least one chronic condition and the other representing the presence of two or more conditions\u2014were created for a random sample of 5,000 Medicaid recipients geocoded at the ZCTA level using recipient residential address data. Utilizing this sample, we performed logistic regression analyses to evaluate the ability of Palmetto SADI and four alternative measures of small-area deprivation to predict chronic disease burden among Medicaid enrollees based on their ZCTA of residence.AUCOo isAUCi is the area under the curve of the model estimated from the ith bootstrap sample.In these analyses Palmetto SADI, Townsend, and poverty were evaluated as continuous measures; PC-HPSA and MUA/MUP were modeled as binomial variables. We evaluated the performance of all models using the area under the Receiver Operating Characteristic curve (AUC). This statistic summarizes a model\u2019s discrimination, i.e., ability to correctly classify individuals\u2019 chronic disease status. AUC values close to 1 show near perfect discrimination. The model fit was evaluated using the corrected Akaike information criterion measure (AIC). This is a measure of the model\u2019s deviance or difference from a saturated (perfectly predicting) model. Lower values of AIC indicate a preferable model. Bootstrapping was used to estimate standard errors of the AUC and AIC values which allowed assessment of significant differences across models; by this approach, we generated 199 random samples (with replacement) from the original data and re-estimated each of the five models. Approximate standard errors were given by the standard deviation of results from the bootstrap samples. For example, the standard error of the observed area under the curve N = 1,024,034). We further derived two ZCTA-level chronic disease burden counts (presence of at least one chronic condition and presence of two or more conditions). We calculated odds ratios to assess associations between high socioeconomic deprivation as measured by Palmetto SADI, the Townsend index, and the poverty measure (top versus bottom quartile of each continuous deprivation measure distribution) and each of the seven chronic condition indicators . Similarly, we calculated odds ratios to evaluate associations between two binomial measures of health care provider resource deprivation and each of the seven chronic condition measures.Next, we derived ZCTA-level total Medicaid population and chronic disease counts for each of the five chronic conditions represented in logistic regression analyses, based on georeferenced data for the entire Medicaid population (N = 372). The operationalization of small-area deprivation measures for this set of ZCTAs is summarized in Table\u00a0We performed Ordinary Least Squares (OLS) and spatial regression analyses to further evaluate small-area deprivation measure associations with chronic disease burden at the ZCTA level, again based on georeferenced data for the entire Medicaid population. Chronic disease prevalence rates were calculated for five conditions . Two chronic disease burden prevalence rates (presence of at least one chronic condition and presence of two or more conditions) also were calculated. As in previous logistic regression analyses, Palmetto SADI and four alternative measures of small-area deprivation were modeled. Preliminary OLS regression analyses with spatial diagnostics (Moran\u2019s I) indicated statistically significant spatial autocorrelation in all models tested. Spatial regression models were employed to account for the spatial autocorrelation of modeled variables. Spatial regression results are reported. AIC and Schwarz Bayesian information criterion (BIC) values from spatial regressions were used to evaluate goodness of fit for each small-area deprivation model, with lower values indicating preferable models. To ensure greater prevalence rate stability and protect recipient confidentiality in mapped results, all ZCTA-level index validation analyses were restricted to ZCTAs with at least 30 Medicaid enrollees N = 37. The opeP < 0.001) and a significantly lower AIC (P < 0.001) compared to all four alternative models were highest when Palmetto SADI was used to identify high socioeconomic deprivation Table\u00a0.Table 4ZConsistent with logistic regression results, spatial regression analyses identified Palmetto SADI as the best small-area deprivation predictor of chronic disease burden among all Medicaid recipients at the ZCTA level. Compared to the four alternative deprivation models tested, the Palmetto SADI model yielded lower AIC and BIC values, thus indicating the preferability of the derived index Table\u00a0. SeparatFigure\u00a0We found significantly higher levels of chronic disease in high- versus low-deprivation ZCTAs, regardless of the deprivation measure used, a result that is consistent with a growing international body of literature indicating higher rates of wide-ranging adverse health outcomes in resource-poor communities , 30, 52.Although small-area deprivation measures have proven useful in geospatial assessments of population health and health inequality, such measures are subject to criticism, particularly in terms of variable selection and index construction . We baseBeyond the recognition of conceptual and methodological challenges associated with the construction of any socioeconomic deprivation measure, several limitations specific to the development, validation, and application of Palmetto SADI should be identified. First, chronic disease status was determined using diagnostic codes in Medicaid administrative data sets. Administrative data are widely used in health studies and the validity of such data sets has been established . More acAs indicated by specific policy or programming requirements, the methodology described might be used to construct census-based socioeconomic deprivation measures for both smaller and larger areas. \u201cTailored\u201d deprivation indexes also migThe development of Palmetto SADI is consistent with calls for better measures of social and health deprivation that permit the identification and reduction of health disparities across time and space and thatDecision making to prevent and more effectively manage chronic disease in vulnerable populations requires consideration of factors other than small-area socioeconomic deprivation. Palmetto SADI may be most valuable as a policy and program planning tool when combined with other small-area assessment strategies measuring such factors as healthy food availability , health As a predictor of chronic disease burden among South Carolina Medicaid recipients, Palmetto SADI outperformed all alternative small-area deprivation measures tested. Palmetto SADI can be used to identify areas in South Carolina at high risk for chronic disease burden among Medicaid recipients and other low-income Medicaid-eligible populations for targeted prevention, disease management, and care coordination activities."} +{"text": "In field conditions, plants are often simultaneously exposed to multiple biotic and abiotic stresses resulting in substantial yield loss. Plants have evolved various physiological and molecular adaptations to protect themselves under stress combinations. Emerging evidences suggest that plant responses to a combination of stresses are unique from individual stress responses. In addition, plants exhibit shared responses which are common to individual stresses and stress combination. In this review, we provide an update on the current understanding of both unique and shared responses. Specific focus of this review is on heat\u2013drought stress as a major abiotic stress combination and, drought\u2013pathogen and heat\u2013pathogen as examples of abiotic\u2013biotic stress combinations. We also comprehend the current understanding of molecular mechanisms of cross talk in relation to shared and unique molecular responses for plant survival under stress combinations. Thus, the knowledge of shared responses of plants from individual stress studies and stress combinations can be utilized to develop varieties with broad spectrum stress tolerance. Arabidopsis thaliana plants accumulate sucrose instead of proline more severely than the individual stresses increased indicating the synthesis of proline from glutamate. However, under combined stress, a decrease in the activity of P5CS and increase in the activity of ornithine aminotransferase (OAT) was observed suggesting that under the combined stress, proline synthesis occurred from ornithine through ornithine aminotransferase (OAT). The occurrence of proline synthesis through OAT has been observed in plants under some conditions . Cappelli is characterized by higher WUE and lower stomatal conductance compared to Ofanto. The combined stress led to a higher leaf temperature in Cappelli as compared to Ofanto plants heat stress response was found to be the most dominating (Supplementary Table T. aestivum plants by cDNA amplified fragment length polymorphism (cDNA-AFLP). The study revealed that 380 genes were modulated in all the three stress conditions. Out of 242 up-regulated genes, 44, 15, and 90 genes were specifically induced by heat, drought and combined stress, respectively. While 18 genes were commonly up-regulated in heat and drought stress, 51 and 24 up-regulated genes were common among individual heat, drought and the combined heat and drought stress, respectively. Therefore, in case of T. aestivum, the response under combined stress constituted more of unique than shared response. Similarly, transcriptomic analysis of individual and combined stressed Sorghum bicolor plants genes, dehydrin, photosynthesis related genes, and genes encoding enzymes involved in pentose pathway and anthocyanin biosynthesis , ROS detoxification enzymes, and enzymes involved in photosynthesis and glycolysis and thioredoxin peroxidase (TPX). Drought stress led to the induction of catalase (CAT) and glutathione peroxidase (GPX). However, under combined stress, genes encoding alternative oxidase (AOX), GPX, glutathione reductase (GR), copper\u2013zinc superoxide dismutase (CuZnSOD), and glutathione S transferase (GST) were found to be specifically induced.Although combined and individual stress response of plants constituted a number of commonly regulated genes, differences were observed in their expression levels in individual and combined stress conditions i.e., the expression was tailored to combined stress condition. For example, when compared to individual drought and heat stressed plants, combined stressed plants exhibited higher induction of HSP coding genes protein] was found to be up-regulated exclusively under heat stress. Sb01g021320 (homologous to LEA D34 protein) and Sb05g017950 were found to be up-regulated exclusively under drought and combined stress , small GTP-binding proteins, MYB transcription factors, transporters, aquaporin membrane intrinsic protein radiation, and nutrient stress dramatically alters the response of plants to biotic stresses. Similarly, interaction of plants with pathogens affects their responses to abiotic stresses. The outcomes of these interactions can either provide resistance or susceptibility toward any of the two stresses depending on the plant species, pathogen and stress intensity.L. esculentum, drought stress reduced infection of necrotrophic fungus Botrytis cinerea by 50% and suppressed the biotrophic fungus Oidium neolycopersici infection with concomitant two-fold increase in ABA compared to well-watered infected plants resulted in increased plant tolerance to drought stress due to de novo xylem formation resulting in enhanced water flow in a concentration dependent manner , increasing leaf senescence and resulting in premature defoliation , exhibit severe cell death, whereas in the drought acclimated plants the extent of cell death was much reduced causes pathogen-induced drought in Vitis vinifera by reducing water potential \u2014and resistance (R)\u2014gene mediated defense responses to P. syringae pathovars and viral elicitors were compromised at high temperatures, allowing increased growth of these pathogens and Tomato spotted wilt virus . TMV is able to overcome the N-gene mediated resistance at temperatures above 28\u00b0C in N. tabacum and combined drought and TuMV indicated the presence of both shared and unique molecular response in combined stressed plants which is responsible for synthesis of osmoprotectants galactinol and raffinose. The response characteristically seen under combined stresses in V. vinifera plants consisted of early induction of ABA biosynthesis gene, 9-cis epoxycarotenoid dioxygenase (NCED), and calceneurin B like interacting protein kinase (CIPK). Overall, drought stress and bacterial infection in this case led to activation of ABA mediated drought response that led to enhanced development of disease infection were more susceptible to viral infection. The authors observed that combination of heat and viral infection led to enhanced transcript accumulation of P3 gene, which is a marker for viral replication infection, eight also responded to abiotic stresses substantiating them as an important point of cross talk , Capsicum annum WRKY40 (CaWRKY40), MAPK like Gossypium hirsutum MPK16 (GhMPK16), and OsNAC6 have been successfully used to impart biotic and abiotic stress resistance to plants (Supplementary Table A number of transcription factors belonging to myeloblastosis (MYB) transcription factors family e.g., OsMYB4, ethylene responsive factors (ERF) like GmERF and botrytis-susceptible1 (BOS1) are important regulators of different hormone signaling pathways and have a role in imparting biotic and abiotic stress resistance to plants , glutathione-S-transferase F12 (GSTF12), mitogen activated protein kinase 9 (AtMAPKK9), MAPKK16 are common to drought and combined virus and drought stress response of A. thaliana plants subjected to combined drought and TuMV infection (Prasch and Sonnewald, The transcriptome analysis of The stress response mechanism of plants against the abiotic and biotic stress combinations is governed by interaction between responses evoked by individual stresses at both physiological and molecular level. As already stated, the interaction is governed by factors like severity of stresses, age of plant, and whether the plant is tolerant or susceptible to any one of the individual stress. Even plants belonging to same genus may show different molecular response to a stress combination (Aprile et al., The increasing demand for food, deteriorating environmental conditions as well as emergence of newly evolved pathogens have necessitated the development of crops which are better equipped to deal with biotic and abiotic stresses and produce better yields. The fact that occurrence of combination of stresses instead of individual stress are important challenges for crop production demands thorough and intensive studies to understand plants response to stress combinations. A couple of studies in this direction throwing light on shared and unique responses of plants under combined stresses have already been published. It is now required to extend these studies to major crop plants. For proper understanding of plants responses to combined stress which occur under field conditions, the experiments should be carefully designed so that they nearly mimic the field conditions. It is also pertinent to identify the stages vulnerable to the combined stresses by studying the stage specific effect of combined stresses on the transcriptome of different plants. The transcriptomic analysis of plants under combined stresses can generate useful and substantial information regarding common and unique genes modulated under combined stresses. The advances in NGS and high throughput sequence analysis platforms for precise detection and accurate quantification of even small changes in the transcriptome as well as the recently developed genetic engineering tools can be useful in exploring the molecular responses of plants under combined stresses.The reviewer Yasuhiro Ishiga declares that, despite having previously collaborated with the authors Muthappa Senthil-Kumar and Venkategowda Ramegowda, the review process was conducted objectively. The reviewer Ramu S. Vemanna also declares that, despite having previously collaborated with the author Muthappa Senthil-Kumar, the review process was conducted objectively. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "A major obstacle to anticipating the cross-species transmission of zoonotic diseases and developing novel strategies for their control is the scarcity of data informing how these pathogens circulate within natural reservoir populations. Vampire bats are the primary reservoir of rabies in Latin America, where the disease remains among the most important viral zoonoses affecting humans and livestock. Unpredictable spatiotemporal dynamics of rabies within bat populations have precluded anticipation of outbreaks and undermined widespread bat culling programs. By analysing 1146 vampire bat-transmitted rabies (VBR) outbreaks in livestock across 12 years in Peru, we demonstrate that viral expansions into historically uninfected zones have doubled the recent burden of VBR. Viral expansions are geographically widespread, but severely constrained by high elevation peaks in the Andes mountains. Within Andean valleys, invasions form wavefronts that are advancing towards large, unvaccinated livestock populations that are heavily bitten by bats, which together will fuel high transmission and mortality. Using spatial models, we forecast the pathways of ongoing VBR epizootics across heterogeneous landscapes. These results directly inform vaccination strategies to mitigate impending viral emergence, reveal VBR as an emerging rather than an enzootic disease and create opportunities to test novel interventions to manage viruses in bat reservoirs. A centrDesmodus rotundus) are the most important source of human and animal rabies, a lethal encephalitis transmitted by the bites of infected animals )Travelling waves have been identified in several other wildlife zoonoses (e.g. Ebola virus , rabies This study demonstrates the power of animal health surveillance systems to generate high-resolution insights into the spatiotemporal dynamics of zoonotic viruses that would probably be impossible to detect relying on studies within a wildlife reservoir alone. The travelling waves that we detected in Peru directly inform management of viral spillover from bats by providing recommendations for where and when livestock should be vaccinated and educational campaigns should be carried out, while creating a unique opportunity to trail experimental interventions in bat populations to block spatially replicated advancing epizootics."} +{"text": "It should be highlighted that \u2018cancer\u2019 is a namegenerically given to a widely heterogeneous group of diseases; in comparison to solidtumors, hematological neoplasms show a number peculiar features. Among the most relevant,it should be emphasized the urgency of starting anti-cancer therapy, as often required inhigh-grade hematological neoplasms as acute leukemia and aggressive lymphomas. Specificresearch on this subgroup is warranted, considering the potential prognostic impact of theunderlying neoplasm behavior and center-specific features .Advances in treatment of cancer patients and improved understanding of pathophysiologicalmechanisms behind malignant diseases contribute to increased survival and, consequently,increasing needs of intensive care support for this population. Currently,refusing ICU admissions based only on the type of hematological cancer is no longerjustifiable. Therefore, the intensive care specialty faces new challenges represented byseverely ill patients with malignant underlying diseases requiring, in addition totraditional intensive care, progressively more specific knowledge on oncology.In the past two decades, intensive care units (ICU) increasingly played a relevant role,both treating infective intercurrences and severe complications related to the canceritself and its therapy; and preventive admissions of high-risk patients undergoingchemotherapy. A suitable example of such cooperation is giving urgent intravenouschemotherapy to hematological patients during their ICU stay. This cooperation has beenshown feasible, adding a positive impact on selected patients\u2019 prognosis, including forthose with highly severe diseases.,5These new and progressive challenges require the intensivist to be capable of offering boththe best clinical care and appropriate advice for patient and family members regardingprognosis, therapeutic options and preferences. Therefore, some behavioral changes arerequired, particularly regarding improved cooperation between intensivists andoncologists/hematologists. In addition to influencing the clinical practice and decisionmaking on anti-cancer therapy, this interaction may contribute to appropriately selectpatients who may better benefit from intensive care.,7Now, the challenge is to evaluate if these findings translate into bedside benefits indifferent scenarios. So far, most ofthe studies assessing this population outcomes in Brazilian ICUs have included solidtumors, rendering difficult interpreting the results.Some independent aspects associated to poor prognosis in severely ill hematological cancerpatients have been identified, such as the need of invasive respiratory support, more organdysfunctions, poor performance status and neoplasm organ infiltrations. Although conducted inone single center, this study adds relevant information on the scenario of hematologicalpatients in Brazilian ICUs. The authors observed a high prevalence of cancer, 81.6% of thishematological patients\u2019 sample. This translated into one out every six ICU admissions inthis timeframe. The reported ICU and hospital mortality rates were 47.8% and 73.2%,respectively. Multiple factors may have contributed to such high rates. Among them, thedisease severity upon ICU admission, assessed by SAPS 3 score, was shown to be anindependent mortality predictor. These findings highlight the results of recent studiesstressing the relevance of early intensive care in severely ill patients. Expertrecommendations for widening criteria for admitting hematological cancer patients to theICU and full intensive care within the first days should be aligned with identifying earlystage of critical diseases. Ideally, before organ dysfunctions are installed. Thus, a possible intervention target isapparent, particularly in Brazil, where the access to intensive care is jeopardized bysystem ineffectiveness and/or shortness of intensive care beds. Recently a European study including hematological cancerpatients in 17 ICUs located in France and Belgium identified that ICU admission within thefirst 24 hours after hospital admission is associated to better survival rates incomparison to the a priori anticipated. The reported hospital mortalitywas 39%, and both cancer disease control and health-related quality of life followingdischarge were considered satisfactory, suggesting that appropriate cost-benefit ratio wasachieved.In this issue of RBTI, Barreto et al. report on the two-year assessment of 157hematological disease adult patients admitted to a general ICU in a Brazilian universityhospital. regards the encouraging hospital survivalrates found in patients undergoing noninvasive mechanic ventilation (NIMV). These rateswere similar to those found in patients requiring no respiratory support at all. Yet inpatients failing to NIMV, the mortality rate was high, even above the rate observed inpatients whose first respiratory support option was invasive mechanic ventilation. Theseresults confirm previous results,14 supporting both decisions for electinginvasive respiratory support in selected patients and the importance of earlyidentification of NIMV failure associated features. In the study by Barreto et al. thesubgroup failing to NIMV had more severe respiratory dysfunction and increased use ofhemodynamic support within the first 24 hours following ICU admission; this agrees with theliterature. According to thecurrent knowledge, upon identification of these features, invasive respiratory supportwould be the preferable starting strategy.Respiratory failure is known to be the main cause leading hematological patients tointensive care admission; another relevant contribution by Barreto et al. reportson relevant information about features of hematological diseases in severely ill patients.However, additional research is warranted to better understand the profile of thispopulation of patients, increasingly admitted to Brazilian ICUs. New data on long-termmortality, health-related quality of life following ICU discharge and characterization ofpossibly outcome-related ICU issues are necessary for better assessing the care provided tothese patients.The study by Barreto et al."} +{"text": "Maternal obesity during pregnancy is an important public health problem in Western countries. Currently, obesity prevalence rates in pregnant women are estimated to be as high as 30\u00a0%. In addition, approximately 40\u00a0% of women gain an excessive amount of weight during pregnancy in Western countries. An accumulating body of evidence suggests a long-term impact of maternal obesity and excessive weight gain during pregnancy on adiposity, cardiovascular and metabolic related health outcomes in the offspring in fetal life, childhood and adulthood. In this review, we discuss results from recent studies, potential underlying mechanisms and challenges for future epidemiological studies. Obesity, cardiovascular disease and type 2 diabetes are major public health problems. These common diseases have a large impact on morbidity and mortality in the general adult population \u20134. VarioIn Western countries, maternal obesity during pregnancy is an important adverse risk factor for an excessive nutritional in utero environment , 34. CurAs described previously, both maternal prepregnancy obesity and excessive gestational weight gain seem to have persistent effects on various childhood outcomes . This reMaternal prepregnancy obesity and excessive weight gain during pregnancy are important risk factors for a variety of adverse fetal outcomes Table\u00a0. A meta-It is well-known that maternal prepregnancy obesity and excessive gestational weight gain are associated with an increased risk of large-size-for gestational age at birth , 43. A rFewer studies assessed the direct influence of maternal obesity during pregnancy on placental and fetal cardiovascular and metabolic development. It has been shown that maternal prepregnancy obesity is associated with higher placental weight, placental vascular dysfunction, placental inflammation and alterations in placental transporters activity and mitochondrial activity \u201355. A stThus, both maternal prepregnancy obesity and excessive gestational weight gain lead to increased risks of adverse fetal outcomes. Overall, maternal prepregnancy obesity appears to be more strongly associated with adverse fetal outcomes than excessive maternal gestational weight gain , 47.Maternal prepregnancy obesity and excessive gestational weight gain are associated with an increased risk of obesity in childhood and adolescence Table\u00a0. A meta-Several studies aimed to identify critical periods of maternal weight during pregnancy for childhood outcomes. A study performed among 5154 UK mother-offspring pairs showed that especially gestational weight gain in the first 14\u00a0weeks of pregnancy was positively associated with offspring adiposity at 9\u00a0years of age . In lineThus, next to the risks of adverse fetal outcomes, maternal prepregnancy obesity and excessive gestational weight gain may lead to increased risks of adiposity and adverse cardiovascular risk factors in childhood and adolescence.Multiple studies have shown that a higher maternal prepregnancy body mass index is associated with a higher adult body mass index in the offspring, independent from socio-demographic and lifestyle-related confounding factors \u201376 Tabl. SimilarThus, in line with the associations of maternal prepregnancy obesity and excessive gestational weight gain with childhood outcomes, these adverse maternal exposures are associated with an increased risk of adiposity and cardiovascular and metabolic disease and mortality in the adult offspring.The major limitation of these observational studies is confounding. Various family-based socio-demographic, nutritional, lifestyle related and genetic characteristics may explain the observed associations of maternal prepregnancy body mass index and gestational weight gain with adverse health outcomes in the offspring. Few studies used more sophisticated study designs to obtain further insight into the role of confounding in the observed associations, including sibling comparison studies, maternal and paternal offspring comparisons analyses, Mendelian randomization studies, and randomized controlled trial analyses, as described previously .First, sibling comparison studies enable better control for potential confounding factors shared within families . A sibliSecond, several studies compared the strength of associations of maternal and paternal body mass index with offspring outcomes as an aid to further disentangle underlying mechanisms. Stronger associations for maternal body mass index suggest direct intrauterine mechanisms, whereas similar or stronger associations for paternal body mass index suggest a role for shared family-based, lifestyle-related characteristics or genetic factors . StudiesThird, Mendelian randomization approaches use genetic variants, known to be robustly associated with the exposure of interest and not affected by confounding, as an instrumental variable for a specific exposure . AssociaFourth, randomized controlled trials are considered as the golden standard for causality studies. Because randomized studies are difficult to perform when maternal prepregnancy obesity and excessive gestational weight gain are the major exposures of interest, previous studies focused on influencing determinants of obesity and excessive gestational weight gain, such as dietary factors and physical activity levels . Based oAltogether, results from studies specifically designed to explore the causality for the associations of maternal obesity\u00a0during pregnancy with offspring outcomes are not conclusive yet.The mechanisms underlying the associations of maternal obesity or excessive gestational weight gain with cardiovascular and metabolic disease in the offspring are not known yet. The fetal overnutrition hypothesis suggests that increased placental transfer of nutrients to the developing fetus in obese mothers and mothers with high levels of gestational weight gain, may subsequently affect fetal development, fetal fat deposition and the development of the hypothalamic-endocrine system that controls appetite and energy metabolism \u201393. ThesMaternal prepregnancy obesity and excessive gestational weight gain are complex traits, which reflect multiple components. Maternal prepregnancy obesity reflects maternal nutritional status, fat accumulation and low-grade inflammation, whereas maternal weight gain during pregnancy additionally reflects maternal and amniotic fluid expansion and growth of the fetus, placenta and uterus .Maternal prepregnancy obesity is an indicator of a poor quality maternal diet. Both macronutrients and micronutrients intake related to a Western diet may influence fetal cardiovascular and metabolic development, through influences on placental transfer and subsequently offspring fat deposition, adipocyte function, pancreatic function and food preference , 94. A sMaternal prepregnancy obesity and excessive gestational weight gain partly reflect maternal fat accumulation, which is important for fetal development . HoweverLow grade systemic inflammation may be involved in pathways leading from maternal obesity or excessive gestational weight gain to adverse offspring outcomes. Obesity is associated with low-grade systemic inflammation and oxidative stress, also during pregnancy \u2013118. AddBoth maternal obesity and excessive gestational weight gain as well as the correlated nutritional, body fat distribution, metabolic and inflammatory exposures may lead to programming effects in the offspring through several pathways.Epigenetic changes in the offspring are likely to play an important role in developmental programming . EpigeneOffspring from mothers with prepregnancy obesity or excessive gestational weight gain during pregnancy have higher fetal growth rates and are at increased risk of being born large for their gestational age. Higher birth weight is associated with an increased risk of obesity in later life . The assThe associations of maternal prepregnancy body mass index and gestational weight gain with adverse cardiovascular and metabolic outcomes in the offspring appear to be largely mediated through offspring obesity. However, direct cardiovascular and metabolic programming effects of maternal obesity during pregnancy may also be present . Animal Thus, multiple mechanisms may be involved in the intra-uterine pathways leading from maternal obesity and excessive weight gain during pregnancy to long-term adverse offspring health outcomes.Current evidence from epidemiological studies suggests that maternal obesity and excessive weight gain during pregnancy have important adverse consequences on cardiovascular and metabolic development from fetal life onwards, leading to disease in later life. Yet, there remain important issues to be addressed. These include identification of the extent of causality of the observed associations, the underlying exposures and their critical periods, the developmental adaptations, and the potential for development of preventive strategies Table\u00a0.Table\u00a03KFirst, despite extensive adjustment for potential confounding factors in these observational studies, residual confounding may still be an issue. The causality of the observed associations needs to be further addressed. Large observational studies that are able to apply more sophisticated methods, such as parent-offspring comparison studies, sibling comparison studies and Mendelian randomization-studies are needed to obtain further insight into the causality of the associations of interest. Long-term follow-up of participants in trials focused on reducing maternal weight throughout pregnancy will also provide further insight into the causality. Large meta-analyses are needed to obtain further insight into the strength, consistency and independency of the associations.Second, the underlying mechanisms of the observed associations of maternal obesity during pregnancy with offspring health outcomes remain unclear. Animals studies have identified multiple pathways that may be involved in these associations, but these pathways remain largely unexplored in humans. Maternal prepregnancy obesity and excessive gestational weight gain are complex traits, which reflect multiple lifestyle-related and biological components, which complicates identification of potential underlying pathways. Future studies may benefit from detailed assessments of the studied exposures and outcomes throughout the life-course, which could provide further insight into potential underlying mechanisms. Studies with repeated maternal weight measurements during pregnancy available can identify critical periods of maternal weight gain. To obtain further insight into the different components associated with offspring outcomes, studies are needed with more detailed measurements of maternal nutritional status, body composition, metabolic and inflammatory measures, pregnancy-related hemodynamic adaptations and fetal growth. For the offspring outcomes, more detailed measurements of growth, body composition and cardio-metabolic factors, including cardiac structures, endothelial function, pulse wave velocity, lipid spectrums and glucose responses, might also lead to further insight into the underlying growth, vascular and metabolic mechanisms present in the observed associations. Since early pregnancy appears to be a critical period for offspring outcomes, studies are needed with detailed maternal measurements from early pregnancy onwards to already assess their influence on placental and embryonic growth and development. Long-term follow up of participants in observational studies is needed to assess the influence on the risk of obesity and related cardio-metabolic disorders throughout the life-course. In addition, it is of interest to conduct follow-up studies of the third generation offspring from these large observational studies, as this may provide further insight into the intergenerational effects of maternal obesity during pregnancy on especially female offspring.Third, further research is needed focused on prevention of adverse health outcomes in offspring through optimizing maternal prepregnancy body mass index, weight gain and diet during pregnancy. Studies are needed to assess the optimal amounts of maternal weight gain for short-term and long-term maternal and offspring health outcomes to further improve the IOM recommendations for gestational weight gain. Identification of specific maternal dietary components associated with offspring health outcomes is needed to improve maternal dietary recommendations during pregnancy. Long term follow up of mothers and their children participating in randomized trials focused on improving maternal diet and reducing maternal weight throughout pregnancy will provide insight into the effectiveness of these maternal lifestyle interventions during pregnancy for improving long-term health of offspring.Maternal prepregnancy obesity and excessive weight gain during pregnancy seem to be important risk factors for an adverse in utero environment and long-term adverse cardiovascular and metabolic outcomes in the offspring. Well-designed epidemiological studies are needed to identify the extent of causality of the observed associations, the underlying exposures and their critical periods, the developmental adaptations, and the potential for development of preventive strategies to improve long-term health outcomes of offspring."} +{"text": "High cross-taxon congruence in species diversity patterns is essential for the use of surrogate taxa in biodiversity conservation, but presence and strength of congruence in species turnover patterns, and the relative contributions of abiotic environmental factors and biotic interaction towards this congruence, remain poorly understood. In our study, we used variation partitioning in multiple regressions to quantify cross-taxon congruence in community dissimilarities of vascular plants, geometrid and arciinid moths and carabid beetles, subsequently investigating their respective underpinning by abiotic factors and biotic interactions. Significant cross-taxon congruence observed across all taxon pairs was linked to their similar responses towards elevation change. Changes in the vegetation composition were closely linked to carabid turnover, with vegetation structure and associated microclimatic conditions proposed causes of this link. In contrast, moth assemblages appeared to be dominated by generalist species whose turnover was weakly associated with vegetation changes. Overall, abiotic factors exerted a stronger influence on cross-taxon congruence across our study sites than biotic interactions. The weak congruence in turnover observed particularly between plants and moths highlights the importance of multi-taxon approaches based on groupings of taxa with similar turnovers, rather than the use of single surrogate taxa or environmental proxies, in biodiversity assessments. Obtaining a good understanding of the mechanisms that underlie species richness and species composition presents one of the most significant challenges facing ecologists, biogeographers and conservation planners alike13485610Previous studies of diversity congruence have primarily focused on \u03b1-diversity within natural or semi-natural ecosystem, while few studies have focused on the effects of anthropogenic disturbance gradient on cross-taxa congruence in species turnover patterns121313861110186131721High cross-taxon congruence has been related both to similarities in the response patterns of these taxa to changes in environmental variables and to biotic interactions5192324212235242891322302662233Our study builds on earlier investigations showing that the \u03b1-diversity patterns of four taxonomic groups, vascular plants and three insect taxa , are highly non-congruent in our study area composed of plots situated along both altitudinal and anthropogenic gradients in an anthropogenically transformed mountainous landscape matrix5In establishing the degree of cross-taxon congruence in species turnover patterns across these four taxonomic groups, we particularly focused on the partial contributions of environmental factors and biotic interactions. We first of all hypothesize that a strong congruency exists between vascular plants and carabid beetles. Both taxa are chiefly composed of weak dispersers, with plants strongly relying on passive dispersal and with most carabid species known to chiefly disperse over limited distances of only up to 50\u2009mWe recorded a total of 415 vascular plant species, while 14692 specimens representing 110 species of geometrids and 1543 individuals representing 20 arctiinid species were caught in light traps, and 3663 carabids representing 73 species were sampled in the pitfall traps. Each study site and habitat had its own, unique species of vascular plants. For carabids, all study sites, but not all habitat types at all sites contained unique species. For geometrids, only woodland and grassland habitats harbored unique species. Two sites, Dayushu and Gaojiaying, and none of the habitats harbored unique arctiinid species .The non-metric multidimensional scaling (NMDS) showed that both moth assemblages formed very distinct study site-specific clusters . A clearThe turnover in all taxonomic groups was significantly correlated with elevation and also the habitat type \u2018cultivated land\u2019, with the latter being particularly significant for vascular plants and carabids (P\u2009<\u20090.001). Additionally, vascular plants were significantly correlated with all environmental variables except soil texture and landscape diversity (SHDI). Apart from elevation and cultivated land, carabid turnover was also significantly linked to the % of semi-natural land area (SNP), while arctiinid turnover was additionally correlated with changes in total N and soil texture .All comparisons of turnover patterns between pairs of taxa showed significant positive correlations in There are two contrasting views on the role of environmental conditions on cross-taxon congruence. A range of studies links significant cross-taxon congruence to common response patterns of the different taxa to changes in key environmental factors1618191017The most important environmental determinant of turnover across taxa was elevation, which commonly represents a whole array of environmental factors. These include temperature, radiation and barometric pressure, which all show monotonic responses to changes in elevation, as well as precipitationBeyond the influence of elevation, the strong overall congruence observed between the turnover in vascular plants and carabids can be explained by both of them additionally reacting strongly towards a similar set of additional environmental variables, particularly to land cultivation and the proportion of semi-natural land present in the plot vicinity. These parameters chiefly reflect the anthropogenic disturbance gradient, with the results confirming our expectations. Cultivation impacted on the species composition of both vascular plants and carabids due to its direct associations with habitat management43Biotic interactions, including trophic interactions, host\u2013parasitoid interactions, but also intraspecific interactions at the same trophic level, may promote cross-taxon congruence112416In contrast to our second hypothesis and these studies, the assemblage structure of the two herbivorous moth taxa which rely heavily on the vegetation as key food resource for their caterpillars and as nectar source of adult moths5292836et al.et al.et al.With most ground beetles being predatory or omnivorous244244Our results are indicative of a highly complex and variable interplay of environmental factors and potential biotic interaction in explaining cross-taxon congruence in turnover patterns of the investigated taxon pairs. These differentiations are also expected in relation to spatial scales and biogeographic processes acting within them21025Spatial differentiations in species assemblages also strongly relate to dispersal limitations, with the species composition between two sites generally increasing in dissimilarity with increased geographic distance26134A key finding of our study is the low congruence between vascular plants and herbivorous, pollinating moth taxa in this anthropogenically transformed landscape matrix, especially once the influence of abiotic factors is controlled for. Previous studies across a variety of taxonomic groups, natural ecosystems and spatial scales, have also reported low cross-taxon congruence of species turnover patterns between insect and other taxa or between different groups of insects49172021459132417However, our results also indicate that the subset of taxa could be representative of biodiversity4et al.Our study was conducted at four distinct sites in our large study region located within the mountain ranges between Beijing and the Inner Mongolian Plateau in northern China. The four study sites were located within the vicinity of four villages situated at elevations of about 500\u2009m, 900\u2009m, 1400\u2009m and 1650\u2009m, and therefore covering substantial proportions of the regional elevation gradient. Three representative habitat types were subsequently selected at each site according to the prevailing management intensity, natural vegetation and farming regime placed above a plastic funnel leading into a plastic bucket. The weak light source allows targeted attraction of moths from the direct vicinity of the trapet al.The exact latitude, longitude and elevation of each plot were established using maps and a Garmin GPS III. Differences in latitude and longitude between plots were subsequently transformed into geographic distances and treated separately, while changes in elevation were jointly considered with the other environmental parameters in the analysis. Five soil samples were randomly taken from the upper 20\u2009cm of the mineral soil at each plot and then mixed. These samples were analyzed for their contents in SOM, total nitrogen, and soil pH which we used here, the index provides an overview of changes in the structure of the entire assemblage. To investigate changes in vascular plant assemblages where complete sampling can be assumed, a S\u00f8rensen dissimilarity matrix based on presence\u2013absence data of all plant species per plot was calculated. All dissimilarity matrices were computed using COMPAH96Dissimilarities of species composition between sampling plots for each of the three insect taxa were calculated based on the Chord-Normalized Expected Species Shared index. This index is particularly tailored for cases where samples are incomplete, contain many rare species and are of different size and diversityWe tested the correlation between the dissimilarity matrices for each taxon and each environmental distance matrices using partial Mantel tests. When significant spatial correlationsin species turnover patterns were found across all four taxa , the geoWe finally used variation partitioning in a series of Multiple Regressions on distance matrices (MRMs) to quantify the proportion of variation in taxonomical dissimilarity between plots that can be explained by the dissimilarity matrix of another taxon, as well as by geographic and environmental distanceet al.We therefore adopted the procedure introduced by Jones All mantel tests and MRMs were calculated using the Ecodist-PackageHow to cite this article: Duan, M. et al. Disentangling effects of abiotic factors and biotic interactions on cross-taxon congruence in species turnover patterns of plants, moths and beetles. Sci. Rep.6, 23511; doi: 10.1038/srep23511 (2016)."} +{"text": "Advances in optical coherence tomography have enabled a better appreciation of the role of pathologic choroidal changes in a variety of retinal disease. A \u201cpachychoroid\u201d (pachy-[prefix]: thick) is defined as an abnormal and permanent increase in choroidal thickness often showing dilated choroidal vessels and other structural alterations of the normal choroidal architecture. Central serous chorioretinopathy is just one of several pachychoroid-related macular disorders. This review summarizes the current state of knowledge of the pachycoroid spectrum and the hallmark features seen with multimodal imaging analysis of these entities Rapid progress in retinal imaging has provided new insights into a variety of chorioretinal disorders. Advances in optical coherence tomography (OCT) are perfect examples of this trend. Following the first descriptions of retinal OCT imaging \u20133, the sThree different layers of choroidal tissue may be differentiated between Bruch\u2019s membrane and the sclera-choroidal junction: choriocapillaris is the innermost portion; Sattler\u2019s layer, composed of small oval vascular patterns, and Haller\u2019s layer consisting of large outer oval vascular patterns . This quThe term pachychoroid (pachy-[prefix]: thick) was proposed as a term indicating an abnormal and permanent increase in choroidal thickness, This entity often occurs in eyes with central serous chorioretinopathy (CSC) or CSC-like features \u201319. EyesCentral Serous ChorioretinopathyCentral serous chorioretinopathy is characterized by the presence of subretinal fluid often associated with serous pigment epithelial detachment (PED). Abnormalities of the choroidal circulation are believed to play an important role in the pathophysiology of this entity. Choroidal congestion and hyperpermeability have been frequently described in this disease \u201322. The Pachychoroid Pigment Epitheliopathyformae frustae of CSC, similar in nature to the findings often seen in the fellow eye of patients presenting with unilateral acute CSC.Pachychoroid pigment epitheliopathy (PPE) is a newly described entity with characteristic features on multimodal imaging of the macula . This enFundus examination often shows an orange-reddish appearance and absence of normal tessellation what indicates an underlying pachychoroid. Present changes in pigment include: RPE alterations that might be mistaken for age-related maculopathy (ARM), a pattern dystrophy of the RPE or non-neovascular age-related macular degeneration (AMD). These changes may include sub-RPE deposits similar in appearance to typical drusen.OCT imaging shows numerous, scattered small elevations of the RPE representing RPE hyperplasia and sub-RPE drusen-like deposits . OccasioIndocyanine green angiography (ICGA) reveals choroidal hyperpermability as mid-phase hyperfluorescence that co-existent with the areas of RPE disturbances.Fundus autofluorescence shows areas of granular hypoatuofluorescence and mixed stippled hyper- and hypoautofluorescence. Signs of antecedent subretinal fluid, such as gravitational tracts, zonal areas of hyperautofluorescence or focal areas of speckled hyperautofluorescence are never seen in PPE.Pachychoroid NeovasculopathyPachychoroid neovasculopathy (PNV) is considered a late complication of PPE and chronic CSC in patients who presumably carry a genetic risk for choroidal neovascularization . The uniOptical coherence tomography imaging in PNV shows a broad shallow elevation of the RPE representing neovascular proliferation within Bruch\u2019s membrane (26). This form of type 1 neovascularization is typically found overlying an area of localized choroidal thickening with dilated choroidal vessels .Indocyanine green angiography often shows both mid-phase patchy areas of choroidal hyperpermability and a discrete plaque of late hyperfluorescence corresponding to type 1 neovascular tissue.Eventually, polypoidal choroidal vasculopathy (PCV) may develop, within or at the margins of the slow-growing type 1 neovascular tissue. The polyps may produce an exudative maculopathy that includes both lipid deposition and hemorrhagic complications. The polyps are easily identified with ICGA as early focal areas of intense hyperfluorescence that may show either late leakage or \u201cwash-out\u201d appearance depending on their degree of activity.Enhanced depth imaging and SS OCT have enabled a better appreciation of the role of pathologic choroidal changes in CSC. Furthermore, they have helped defining an expanded spectrum of pachychoroid-related macular disorders. Recognition of these entities is important as they may mimic other diagnoses that have different natural courses and treatments. For example, the clinical appearance of PPE may simulate ARM, AMD, or pattern dystrophies. Similarly, without choroidal imaging, PNV may easily be mistaken for neovascular AMD.sui generis.The occurrence of PCV in eyes with PNV adds further evidence that PCV is a natural evolution of type 1 neovascular proliferation rather than a disease In our experience, eyes with exudation due to PNV, irrespective of the presence of PCV, are more resistant to anti-vascular endothelial growth factor (anti-VEGF) agents than eyes with choroidal neovascularization (CNV). This is presumably due to the typical AMD and myopic macular degeneration. Thus, the recognition of an underlying pachychoroid in neovascularized maculo- pathies may have important implications regarding their management. Since the photodynamic therapy is intended to reduce choroidal thickness and hyperpermeability, it surely warrants further exploration ,30."} +{"text": "Upper tract urothelial carcinomas (UTUC) have high prevalence rates in patients with chronic kidney disease (CKD), including dialysis patients and kidney transplant recipients. Analgesic nephropathy, Balkan endemic nephropathy, and aristolochic acid (AA) nephropathy share the common association with the development of CKD and UTUC. Genome studies allow identification of patients with genetic predisposition to Balkan endemic nephropathy and AA nephropathy. Furthermore, the identification of aristolactam deoxyribonucleic acid (DNA) adducts now provides robust evidence for AA exposure in UTUC patients, even in the absence of recallable exposure history. Diagnosis and treatment of UTUC in CKD patients are challenging. Clinical diagnosis of UTUCs in CKD patients with the available urological and imaging methods is much more difficult than in patients with normal renal function due to atrophic kidneys and poor excretory functions in these patients. High prevalence rates of contralateral upper tract and urinary bladder involvements of UC in CKD, either at presentation or recurrence, raise concerns of the necessity and techniques as well as perioperative risk of complete urinary tract exenteration. The standard treatment of radical nephroureterectomy with bladder cuff excision for UTUC patients may result in deterioration of renal function, rendering adjuvant chemotherapy unsuitable. This special issue collectively addresses these important topics regarding UTUC in CKD patients.The authors in one paper nominate three mutant genes in Balkan endemic nephropathy patients, which are associated with angiogenesis. This finding suggests that angiogenesis might play an important role in the development of Balkan endemic nephropathy. Another paper shows an elevated risk of urothelial carcinomas (UC) in ESRD patients with the analysis of a national wide cohort in Taiwan. Female patients have 9\u201318 folds of increased risk of UC as compared to 4\u201314 folds in male ESRD patients, which may reflect female predominance in AA consumption. One paper discusses the challenges of UTUC diagnosis in CKD patients. It reviews the detection rate of UTUCs in dialysis patients and kidney transplant recipients with the use of a variety of imaging and urological methods in the literature. Combination use of urological and imaging methods has been suggested for diagnosing UTUCs in symptomatic dialysis patients and kidney transplant recipients.Another paper develops a predictive model for postoperative renal insufficiency in UTUC patients undergoing radical nephroureterectomy, which help in selecting eligible patients for cisplatin based adjuvant chemotherapy. Older age, lower estimated glomerular filtration rate before surgery, smaller tumor size, renal pelvis tumor, and absence of hydronephrosis or multifocal tumors are predictors for ineligibility for adjuvant chemotherapy. One paper describes modified incision complete urinary tract exenteration for UC in dialysis patients, providing short operative time, early oral feeding, and no major perioperative complications of this modified surgical procedure. Another paper reviews epidemiological evidence of AA exposure associated with occurrence of nephropathy and UC, including AA exposure scenarios in Belgium, Taiwan, and the Danube River as well as occupational exposure in Chinese herbalists. The identification of aristolactam DNA adducts in these patients further corroborates biological plausibility of AA exposure contributing to the occurrence of UTUC.Li-Jen\u2009\u2009WangJo\u00eblle L.\u2009NortierBin\u2009\u2009Tean\u2009\u2009TehCheng-Keng\u2009\u2009ChuangShen-Yang\u2009\u2009Lee"} +{"text": "Tuberculosis (TB) remains a major global health problem, because (i) diagnosis is usually made too late to avoid spread of infection to contacts; (ii) vaccination with bacillus Calmette\u2013Gu\u00e9rin (BCG) does not prevent the most prevalent pulmonary disease; and (iii) defaulting from lengthy chemotherapy leads to an increase in drug resistant strains. The continued impact of human immunodeficiency virus (HIV) co-infections remains a major aggravating factor in TB resurgence. Intensive research on the specificity and function of immunological responses is of major importance since protective host defense is critically dependent on T cells, which selectively recognize only certain antigens and epitopes of the tubercle bacillus. Such knowledge is therefore necessary for designing a novel effective vaccine and better diagnostic tools. The specificity of the host immune response may also help to explain how the intracellular tubercle bacilli evade host resistance, probably by decoy pro-inflammatory actions of some of their antigens and/or immunomodulatory constituents, which lead to chronic infection and lung pathology.Mycobacterium tuberculosis (Mtb). The abundant occurrence of major histocompatibility complex (MHC) class II-permissive epitopes in tubercle bacilli has important implications for the development of both subunit vaccines and diagnostic tests proteins, and new HLA-class Ia or Ib (HLA-E) restricted Mtb epitopes, recognized by classical and non-classical CD8 T cells . Several test kits can detect latent Mtb infection with better specificity than the tuberculin based skin test. However, these kits still need improving on their sensitivity and fail to distinguish active TB from latent infection. Moreover, biomarkers for predicting the risk of latent TB progressing into active TB are yet to be found (be found , 3, 4. Fbe found .Identifying those antigenic determinants, which lead to host protection, is mandatory for designing more effective vaccination strategies. A recently failed vaccine trial in children employed Ag85A, which is highly immunogenic, but changes in its expression in infected cells could influence the susceptibility of infected cells to host immunity . Hence, Although classical CD4 and CD8 T cells recognize peptide epitopes bound to MHC, molecules with different chemical structures could be of potential importance. Thus, T cells recognizing lipid antigens may contribute to natural host protection and might potentially be exploited for subunit based vaccination . AnotherIn conclusion, further research on Mtb antigen and epitope specificities seems mandatory for realizing the crucially important aims of both prophylactic and post exposure vaccination against TB. Advancing the knowledge of antigenic determinants is essential also for differentiating patients with active TB from latently infected healthy subjects. There is potential in the ambitious search for specific immunological biomarkers for predicting the reactivation of TB in populations, both without and with HIV infection. These endeavors will undoubtedly need to be combined with better knowledge of the functional phenotypes of the respective T cell subsets. Other potential avenues are the construction of fusion proteins with improved vaccine adjuvanticity and the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Most health-care professional training programs lack educational curricula on substance use disorders and strategies for early intervention or referral to treatment. The University of Missouri-Kansas City Screening, Brief Intervention and Referral to Treatment (UMKC-SBIRT) training project educates baccalaureate nursing, advanced practice nursing, and master\u2019s of social work students through didactics threaded throughout coursework; role-plays with classmates and faculty; standardizes patient practice; and offers clinical experience to help students achieve competency.In year one of the training grant, students completed surveys prior to, immediately after, and 30 days after SBIRT training. Surveys covered attitudes and knowledge. Skills were assessed by expert coding of an audiotaped interaction with a standardized patient actor using an SBIRT fidelity scale. Qualitative feedback regarding training experience, knowledge, and attitudes was collected at post-training focus groups.Students showed increased knowledge of SBIRT, improved perceptions toward working with patients who use substances, increased comfort in dealing with substance use issues, and progress in developing skills to provide SBIRT interventions.Training on SBIRT can be readily implemented into nursing and social work education, improving future health professionals\u2019 perceptions and providing a valuable skill through which they can help patients lead healthier lives."} +{"text": "During aging, many neurodegenerative disorders are associated with reduced neurogenesis and a decline in the proliferation of stem/progenitor cells. The development of the stem cell (SC), the regenerative therapy field, gained tremendous expectations in the diseases that suffer from the lack of treatment options. Stem cell based therapy is a promising approach to promote neuroregeneration after brain injury and can be potentiated when combined with supportive pharmacological drug treatment, especially in the aged. However, the mechanism of action for a particular grafted cell type, the optimal delivery route, doses, or time window of administration after lesion is still under debate. Today, it is proved that these protections are most likely due to modulatory mechanisms rather than the expected cell replacement. Our group proved that important differences appear in the aged brain compared with young one, that is, the accelerated progression of ischemic area, or the delayed initiation of neurological recovery. In this light, these age-related aspects should be carefully evaluated in the clinical translation of neurorestorative therapies. This review is focused on the current perspectives and suitable sources of stem cells (SCs), mechanisms of action, and the most efficient delivery routes in neurorestoration therapies in the poststroke aged environment. With an increased aging population, the prevalence of age-related diseases will increase. The aging process is associated with a higher risk factor for stroke in both men and women and remains an important health issue without an accepted therapeutic strategy, except thrombolysis with recombinant tissue plasminogen activator for ischemic stroke , 2. StudStem cell therapy is focused on the functional improvement in the early stages after stroke rather than tissue replacement. Also, due to plastic capacity and tropism for damaged tissue, stem cells can be a useful tool for gene therapy in regenerative medicine , 9. CellAccording to their source, stem cells can be obtained from blastocyst cells (embryonic stem cells (ESCs)), adult stem cells (bone marrow derived stem cells (BMSCs) derived from peripheral blood or other tissues like adipose tissue), umbilical cord blood cells, and induced pluripotent stem cells (iPSCs). Bone marrow mononuclear cells (BM-MNCs), bone marrow derived mesenchymal stem stromal cells (BM-MSCs), umbilical cord stem cells (UCSCs), and neural stem cells (NSCs) are the most promising cells for recovery after cerebral ischemia. However, stem cells must be fully investigated for safety and therapeutic potential on animal models of neurological diseases in order to use it for clinical applications.Bone marrow derived mononuclear cells (BM-MNCs) are a promising tool for acute stroke therapy, but most preclinical trials were performed using young animals without comorbidities. Preclinical pilot studies using autologous BM-MNCs have already been performed. In one study, Savitz and colleagues showed that the IV administration of BM-MNC extracted from the iliac crest is safe and feasible in stroke patients between 18 and 80 years old . HoweverAlso, the administration route has a greater impact on the biodistribution, migration, and survival of transplanted stem cells. Using single photon emission computed tomography/computed tomography (SPECT/CT) and helical CT scan after intra-arterial (IA) and intravenous (IV) administration of BM-MNCs and BM-MSCs, M\u00e4kel\u00e4 end colleagues showed that the BM-MNCs accumulated in the spleen and bones and the BM-MSCs had relatively higher uptake in the kidneys. The IA transplantation decreased the deposition of BM-MSCs in the lungs and increased uptake especially in the liver. However, both administration routes using porcine model were found to be safe . IntrastIntrastriatal administration of the stem cell (SC) in the aged rats with striatal infarct leads to an elevated cell density in the ischemic area and can be monitored by magnetic resonance imaging (MRI). Injection of NPCs into lesioned striatum promotes a hypothetical neuronal network weeks later that can improve functional outcome .Preclinical data suggests that autologous bone marrow derived mononuclear cell therapy attenuates the effects of inflammation in the early posttraumatic brain injury period .One clinical trial indicated that the IV administration of 280.75 million BM-MNCs at 18,5 days after stroke onset is safe, but there is no beneficial effect of treatment on stroke outcome . Also, WIn the last decade, cells derived from the human umbilical cord (HUC) have emerged as a potential therapeutic alternative for stroke because of their capacity to differentiate into neural progenitor cells and their unlimited availability. Umbilical cells consist of a mixture of both hematopoietic stem cells (HSCs) and mononuclear fraction of mesenchymal stem cells (MSCs). An advantage of umbilical cord blood (UCB) derived cells is that the regulatory T-cells administration (1\u20135% from HUC cells) can prevent graft versus host diseases and can improve neurogenesis in the aging brain , 19.Studies on HUC-derived cell population in rat model showed that the IA administration of cord blood mononuclear cells (cbMNCs) and cord blood mesenchymal stromal cells (cbMSCs) at 24\u2009h after stroke onset is associated with a reduction in neurological deficit and infarct area . Also, icbMNCs tend to restore the reduction of brain-derived neurotrophic factor (BDNF) level after stroke, increase the glutathione peroxidase-4 (GPx-4) mRNA expression, and decrease the number of activated microglia resulting in decreased neuroinflammation and neuronal cell death and increased neurologic recovery , 22.Wharton's jelly, part of the umbilical cord, contains myofibroblast-like stromal cells originated from mesenchyme that possess many unexplored advantages compared with adult stem cells. Wharton's jelly derived cells may secrete macromolecules like glycoproteins, mucopolysaccharides, glycosaminoglycans, or extracellular matrix proteins and showed capacity to differentiate into neural progenitor cells which improved neovascularization, myelination, and neurogenesis in an animal model of stroke \u201325.However, other studies using cryopreserved cbMNC failed to demonstrate neurorestorative properties in spontaneously hypertensive rats (SHR) stroke model .Adipose derived stem cells (ASCs) can be obtained from adipose tissue with minimal side effects and are able to differentiate into multiple cells that play an important role in the recovery of damaged tissue. Studies before have showed that the ASCs, in specific condition, can differentiate into the cells that express neuronal markers (NeuN and nestin) and glial markers . In anim\u03b2) that can be increased in hypoxic conditions [ASCs were found to produce different growth factors like vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and transforming growth factor (TGF- stroke) , 29. In stroke) .The recently discovered possibility to reprogram human adult somatic cells (iPS) has added a very exciting tool to the profile of the available SC and provided new perspective for neurorestorative therapy. iPS possess the potential and characters of embryonic stem cells, self-renewal and pluripotency, which allow the production of unlimited amount of precursor cells or all cell types of the body. On the other side, iPS allow the possibility to create biobanks and to avoid graft rejection. An advantage is that iPS can be obtained from blood cells and fibroblasts that are easily accessible. Chau and colleagues proved that the iPS can improve recovery after stroke in neonatal rats (P7) and adult brain by multiple mechanisms that promote angiogenesis and neurogenesis and provide essential trophic factors \u201334. HoweDespite these exciting findings, these studies still lack proof of mechanisms of iPS that promote the improvement of functional outcome after stroke in aged brain.Although rehabilitation is important for improving functional recovery in the early stages after stroke, it does not provide a replacement for the lost neuronal cells and ultimately brain function. Neural tissue transplantation has been first explored as an experimental technique for tissue repair and functional recovery after stroke \u201339. The Many studies report that stem cell therapy in combination with other compounds appears to be more effective than monotherapies alone. Our group showed that the combination of BM-MSCs with granulocyte colony-stimulating factor (G-CSF) promotes angiogenesis in the ischemic area of the aged brain, without significant improvement of cognitive function , 44.Association of UCB cells with G-CSF was showed to reduce neuroinflammation, enhance neurogenesis, and improve functional outcome after traumatic brain injury (TBI) , 46.The study by Cui et al. revealed that a combination of subtherapeutic doses of UCB cells and simvastatin amplified endogenous angiogenesis and increased and enhanced vascular remodeling by increasing Ang1/Tie2 signalling pathway in the ischemic brain .Gene therapy has been described as a powerful tool in treating nerve injury. Pereira and colleagues showed that the vascular endothelial growth factor (VEGF) gene and granulocyte colony-stimulating factor (G-CSF), delivered using endothelial progenitor cells (EPCs), promote regeneration and improve functional outcome , 49.VEGF delivery using endothelial progenitor cells (EPCs) was found to increase migration and proliferation of human endothelial cells after ultrasonic microbubble transfection . EPCs caThe efficacy of stem cell therapies so far is discouragingly low mainly because the time course of interactions between host neuroinflammatory response, the main obstacle to exogenous-mediated neuronal precursor cells, and exogenously administered stem cells is still unknown. Although MSC transplantation into the brain has ascribed beneficial effects in preclinical studies of neurodegenerative or neuroinflammatory disorders , 54, onlTo conclude, these findings strongly suggest that UCB derived cells have significant neurogenic potential but this potential has to be used in a more efficient manner to treat neurological diseases like stroke in aged people. Antineuroinflammatory therapies are a potential target to promote regeneration and repair in diverse injury and neurodegenerative conditions by stem cell therapy. Therefore, the challenge now is to determine in detail the cross talk between different populations of immune cells and grafted neural stem progenitor cells (NSPCs) at different phases after stroke in aged brain. In"} +{"text": "Phragmites australis over four years to determine their effects on potential denitrification rates relative to three untreated Phragmites sites and adjacent sites dominated by native Typha angustifolia. Sediment ammonium increased following the removal of vegetation from treated sites, likely as a result of decreases in both plant uptake and nitrification. Denitrification potentials were lower in removal sites relative to untreated Phragmites sites, a pattern that persisted at least two years following removal as native plant species began to re-colonize treated sites. These results suggest the potential for a trade-off between invasive-plant management and nitrogen-removal services. A balanced assessment of costs associated with keeping versus removing invasive plants is needed to adequately manage simultaneously for biodiversity and pollution targets.Establishing relationships between biodiversity and ecosystem function is an ongoing endeavor in contemporary ecosystem and community ecology, with important practical implications for conservation and the maintenance of ecosystem services. Removal of invasive plant species to conserve native diversity is a common management objective in many ecosystems, including wetlands. However, substantial changes in plant community composition have the potential to alter sediment characteristics and ecosystem services, including permanent removal of nitrogen from these systems via microbial denitrification. A balanced assessment of costs associated with keeping and removing invasive plants is needed to manage simultaneously for biodiversity and pollution targets. We monitored small-scale removals of Invasive species are often presumed to degrade ecosystem functioning. By causing local extinctions, invasives are thought to reduce biodiversity , which iPhragmites australis were analyzed with a one-way ANOVA. A separate two-way ANOVA was used to compare Phragmites and Typha communities sampled at the reference sites at two additional sampling times . Measurements of sediment nitrogen and carbon collected August 2010-September 2012 were also analyzed with a two-way ANOVA to compare the three dominant vegetation groups. For each two-way ANOVA, potential interactions between vegetation type and sampling time were tested for significance.Differences in plant traits measured in September 2012 among the three dominant vegetation types that were sampled across all \u201csampling times\u201d , both before and after herbicide treatment. For these ANOVAs, significant impacts of herbicide treatment on dependent variables were tested as planned comparisons within the interaction term (treatment x sampling time). In the second statistical design, we compared four treatments for sampling times that occurred after herbicide treatment . For these ANOVAs, significance of herbicide treatment was assessed for the dependent variables listed above and additional measurements added in 2011 [total organic carbon and nitrogen content of sediments] using planned comparisons of treatments.Measurements of denitrification potential, sediment porewater nutrients, and total sediment organic content were analyzed at the stand scale using two-way ANOVA. Because the \u201cReference-The sediment properties and processes we measured are notoriously variable as a result of measurement difficulties and spatial variability , and samPhragmites sampling times were used to test for significant differences between sites where Phragmites was removed relative to sites where Phragmites was left intact. Planned comparisons of Reference-Typha and Reference-Phragmites were used to test whether sites dominated by plant species differed when left undisturbed. Though we attempted to control for phenology by sampling at peak biomass in each of our sampling years (late August/early September), we acknowledge that other factors such as temperature may influence sediment chemistry and microbial activity. The sampling conducted in June 2012 was added to provide further insight into the short-term trajectory of sediment recovery in treated sites. Planned comparisons of treatment and reference sites statistically control for interannual and seasonal variability when detecting treatment effects. All statistical analyses were performed in JMP [Planned comparisons of Ramshorn-Removal and Reference-d in JMP . Graphs d in JMP . CompletPeltandra virginica . For Phragmites-dominated communities, this correlation was weak and of small effect across all treatments throughout our study. Therefore, only results of porewater ammonium are reported. Following initial herbicide treatment, porewater ammonium concentrations in removal sites increased by over an order of magnitude relative to all vegetated sites .Phragmites-dominated reference locations Click here for additional data file."} +{"text": "Perineuronal nets (PN) form a specialized extracellular matrix around certain highly active neurons within the central nervous system and may help to stabilize synaptic contacts, promote local ion homeostasis, or play a protective role. Within the ocular motor system, excitatory burst neurons and omnipause neurons are highly active cells that generate rapid eye movements \u2013 saccades; both groups of neurons contain the calcium-binding protein parvalbumin and are ensheathed by PN. Experimental lesions of excitatory burst neurons and omnipause neurons cause slowing or complete loss of saccades. Selective palsy of saccades in humans is reported following cardiac surgery, but such cases have shown normal brainstem neuroimaging, with only one clinicopathological study that demonstrated paramedian pontine infarction. Our objective was to test the hypothesis that lesions of PN surrounding these brainstem saccade-related neurons may cause saccadic palsy.Together with four controls we studied the brain of a patient who had developed a permanent selective saccadic palsy following cardiac surgery and died several years later. Sections of formalin-fixed paraffin-embedded brainstem blocks were applied to double-immunoperoxidase staining of parvalbumin and three different components of PN. Triple immunofluorescence labeling for all PN components served as internal controls. Combined immunostaining of parvalbumin and synaptophysin revealed the presence of synapses.Excitatory burst neurons and omnipause neurons were preserved and still received synaptic input, but their surrounding PN showed severe loss or fragmentation.Our findings support current models and experimental studies of the brainstem saccade-generating neurons and indicate that damage to PN may permanently impair the function of these neurons that the PN ensheathe. How a postulated hypoxic mechanism could selectively damage the PN remains unclear. We propose that the well-studied saccadic eye movement system provides an accessible model to evaluate the role of PN in health and disease. Saccades are rapid conjugate eye movements that bring target images onto the fovea for exploring visual scenes, reading, and resetting the eyes during optokinetic or vestibular nystagmus. Two critical components of the brainstem saccade network are premotor burst neurons (PBN) and omnipause neurons (OPN). PBN include excitatory burst neurons (EBN) and inhibitory burst neurons (IBN) firing up to 1,000 spikes/s during saccades and in tPerineuronal nets (PN) are condensed, extracellular matrices of macromolecules ensheathing fast-firing neurons such as PBN and OPN. PN consist of a hyaluronic acid backbone attached to glycoproteins and chondroitin sulfate proteoglycans (CSPG) such as aggrecan (ACAN) and hyaluronan and proteoglycan link protein (HPLN1) . PN may Infarction, metabolic or degenerative disorders targeting PBN or OPN may slow or abolish saccades \u201313. DrawSimilar cases have been reported without neuropathologic evaluation \u201326, typiA previously reported healthy Ten months postoperatively, general neurological examination was notable only for diffuse hyporeflexia. Visual acuity, pupils, visual fields, and fundoscopic examination were normal. Straight-ahead fixation was steady, and no saccadic intrusions or nystagmus were seen with ophthalmoscopy. She made no reflexive saccades, and volitional saccades consisted of extremely slow eye movements that eventually reached the target, except for slightly faster downward saccades . PursuitEye movements were recorded with video-oculography. Horizontal saccades were absent during a random saccade paradigm, but sinusoidal smooth pursuit was normal across all frequencies tested. Vertical eye movements demonstrated similar findings. Additionally, rotary chair sinusoidal vestibular and optokinetic testing generated normal vestibular slow phases and optokinetic ocular following reflex, but absent vestibular and optokinetic quick phases of nystagmus.The patient was last examined two years later and was clinically unchanged except for some emerging memory complaints. She remained on warfarin for her mechanical valve. Subsequently, she developed cirrhosis attributed to increasing alcohol abuse. Memory loss remained mild. Eight years after her cardiac surgery, with an increased bleeding diathesis from over-anticoagulation and liver dysfunction, she developed massive hematemesis and melena from a bleeding peptic ulcer, profound anemia, shock, renal failure, and somnolence. She expired in hospice one week later.ex vivo 7 tesla MRI, as previously described [The whole brain was collected the day of death and fixed in 10% formalin for 2 weeks. Next, the brain was suspended in Fomblin for escribed . After r2O2 resulting in a bluish-black reaction product [After deparaffinizing and antigen retrieval by boiling the sections 3x10 minutes in a microwave in 0.01M citrate buffer (pH 6) the slides were transferred to 0.1M phosphate-buffered saline . Saccade-related neurons were identified by immunostaining with mouse monoclonal antibodies directed against non-phosphorylated neurofilaments and the calcium-binding protein parvalbumin . Antigen binding sites were detected with incubation with biotinylated horse antibodies recognizing mouse IgG for 2 h at room temperature. Following 3 buffer washes and an 1 h incubation with ExtrAvidin-peroxidase conjugates immunoreactivities were visualized with nickel-enhanced diaminobenzidine (DAB-Ni) and H product .PN were detected by immunostaining for different components with either mouse monoclonal anti-cat chondroitin sulfate proteoglycan , or anti- human aggrecan core protein , or polyclonal goat anti-human link protein . Synapses were identified with affinity-purified rabbit antibodies directed against the presynaptic vesicle protein synaptophysin , which was visualized by the avidin-biotin-technique and DAB-Ni as described above. In selected sections, double immunoperoxidase staining was applied to concomitantly detect PN or synapses and PAV-positive saccade-related neurons. Thereby, PN-related antibodies or synaptophysin were revealed by immunoperoxidase double staining with bluish-black DAB-Ni followed by immunodetection of PAV with plain DAB producing a brown reaction product.In selected sections, main components of PN were visualized by triple immunofluorescence labeling. The tissue was primarily blocked with 5% normal donkey serum in TBS (containing 0.3% Triton X-100) for 1 hour and then incubated with a cocktail consisting of polyclonal rabbit anti-CSPG [For normal controls, the brains of 4 subjects from the Neurobiobank Munich who died without any history of ocular motor or relevant neurological disorders were evaluated. All cases underwent identical neuropathological examination, immunostaining with monoclonal mouse antibodies against human-PHF-Tau , beta-Amyloid 17\u201324 , alpha-synuclein and polyconal rabbit anti-TDP-43 , as well as triple immunofluorescence labeling.Control 1 (shown in figures) was a 62-year-old male who died of pancreatic cancer without brain metastases or hepatic encephalopathy whose neuropathological examination demonstrated small old hemorrhages in the adenohypophysis, arteriosclerosis, and Braak stage I of Alzheimer changes . ControlWritten consent was obtained from all patient and control subjects or the next of kin for use of these tissue samples in research. The patient provided written consent for video recording (that authorizes publication among other uses). The next of kin of the patient has provided written informed consent for brain autopsy and (as outlined in the PLOS consent form) to publish these case details and the video. Control samples were collected as part of the Neurobiobank Munich. The Neurobiobank Munich and this research project have been approved by the ethics committee of the Ludwig Maximilians University.in vivo and ex vivo 7 tesla MRI studies [As previously reported, gross inspection of the brain was unremarkable and was studies . Atheros studies . The tisThe gross and histologic examination of the pons in the region of the abducens and omnipause neurons found no lesion. Staining the OPN area with LFB-PAS, GFAP, and CR3/43 showed no evidence of demyelination, reactive gliosis, or abnormal microglia activation . ImmunolImmunostaining patterns of HPLN1- and ACAN-based PN in the abducens nuclei and arouIn the nucleus raphe interpositus (RIP) of control subjects, all PAV-positive OPN were ensheathed by PN immunostained for ACAN, CSPG, or HPLN1 . In the The PAV-positive putative excitatory saccadic burst neurons in the PPRF and in the RIMLF were ensheathed only by fragments of PN, unlike in the control case . As alsoWe describe a patient with profound enduring saccadic palsy following cardiac surgery whose brain showed preserved saccade-generating neurons but disruption of the PN that are thought to be essential for normal functioning of these neurons. These findings raise a number of important issues for discussion regarding the localization of saccade dysfunction, the role of PN, broader damage to the central nervous system, mechanisms of injury, and implications for understanding PN function.Brainstem neurons that generate saccades (PBN and OPN) receive descending inputs from cortical eye fields, via the basal ganglia, superior colliculus, and cerebellum ,33. The Additional evidence that this selective saccadic palsy was due to a brainstem process comes from studies of chemical lesions or pharmacological inactivation of the PPRF, RIMLF, or OPN in macaque reporting selective slowing or absence of saccades with spared pursuit and vestibular eye movements \u201342. Suchselective saccadic palsy spares ocular motor nuclei and supranuclear pathways from the cerebral hemispheres, basal ganglia, and cerebellum involved in pursuit and vestibular eye movements. While there was some focal loss of cerebellar Purkinje cells, which are susceptible to ischemia or alcohol [We conclude that our patient\u2019s saccadic palsy was due to dysfunction of the brainstem saccade-generating network of neurons because of her isolated loss of horizontal, vertical, and torsional saccades and reflexive quick phases but preserved pursuit, vergence, and vestibular eye movements. This alcohol ,45, thes alcohol but have alcohol . The patThe main novel finding of this clinicopathologic study is that neurons in the brainstem reticular formation\u2019s saccadic network appeared histologically normal with preserved synapses despite their loss of function. However, our immunostaining demonstrated that PN surrounding OPN and EBN were absent or severely fragmented. Great methodological care ensured that poor PN staining was not due to effects of preservation, fixation, or postmortem delay by using three antibodies to detect different PN components (even in the same section with immunofluorescence). Furthermore, intact PN were present in adjacent related and unrelated (superior olive) areas. This finding supports the critical role current models place for OPN and EBN in generating normal velocity saccades . It alsoSeveral functions have been suggested for PN that may underlie the mechanism for malfunction of OPN and EBN . PN coulin vivo and in vitro spontaneous epileptiform discharges from the CA3 area months after global ischemia, combined with loss of GABAergic interneurons, a finding associated with aberrant sprouting of glutamatergic fibers leading to enhanced synaptic excitation and reduced synaptic inhibition in temporal lobe epilepsy models [Damage to PN might also explain other phenomena following cardiac surgery. PN surround GABAergic projection neurons in portions of the globus pallidus and substantia nigra as well as in subpopulations of striatal and thalamic inhibitory neurons . Hypoxiay models . WhetherHow could saccade-related PN be damaged during cardiopulmonary bypass while sparing the highly active neurons they enwrap? PN may be particularly vulnerable to hypoxia, as a focal cerebral ischemia rat model found that ischemia damages PN more than the ensheathed neurons in the peri-infarct zone . Unlike Selective saccadic palsy could be developed into an animal model to clarify the role of PN. Saccades are an ideal system for studying neural control of movement since they are well understood and can be measured precisely ,57. The Understanding the role of PN in different disorders may create therapeutic opportunities. Status epilepticus is associated with reduced PN-stabilizing components and aggrecan expression . The rolIn summary, this study provides the first evidence that saccadic palsy following cardiac surgery can be caused by damage to supporting tissues surrounding saccadic network neurons rather than to the neurons themselves. It also suggests an accessible model in which eye movements could be used to study the unique role and requirements of PN experimentally. However, some caution is required in interpreting our results, which rest on careful studies of one patient. More studies are required to confirm our findings, including examination of PN in patients without saccadic palsy who have died of exsanguination.S1 MovieTo make rapid head-free gaze shifts, the patient used exaggerated head turns associated with blinks; contraversive vestibular slow phases moved the eyes into the corner of the orbits until the head was maximally rotated, and then the eyes slowly drifted toward the target. She made no reflexive saccades. With the head fixed, volitional saccades consisted of extremely slow eye movements that eventually reached the target, except for slightly faster downward saccades. Pursuit was smooth and full in range both horizontally and vertically, even at higher frequencies. Visually enhanced vestibulo-ocular reflex was normal. When she viewed a horizontally rotating optokinetic drum, her eyes became fixed laterally in the orbits without any corrective quick phases. Torsional head rolling produced normal ocular counter-rolling but without any torsional quick phases. See text for additional details not shown in the movie.(M4V)Click here for additional data file."} +{"text": "We would like to comment on the excellent review by Chen and colleagues highlighting the safety and efficacy of combining extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) for fluid and electrolyte control .As a high-flow system equipped with heparin-coated membranes and circuits, ECMO requires no or only minimal additional anticoagulation to assure circuit patency ,3. In coFor these reasons, we strongly argue against the combined use of ECMO and CRRT within a single circuit. In addition, a separate CRRT device can perfectly run under a proper dedicated anticoagulation therapy . This permits avoidance of ECMO-induced anticoagulant dilution, resulting in less thrombotic events ."} +{"text": "The Drug Addiction Treatment Act of 2000 created an opportunity for primary care physicians and addiction treatment agencies to integrate, as primary care physicians became able to prescribe opiate treatment medications from their practices. Fourteen years later, a National Institute on Drug Abuse evidence-based practice implementation trial in Ohio is finding that physician capacity is becoming a primary barrier to use of buprenorphine. This presentation will document: a) the degree of the physician capacity barrier for specialty addiction treatment providers wanting to expand their buprenorphine programs; b) strategies being considered to overcome this barrier, including telemedicine; and c) what workflow challenges implementation of telemedicine can expect .The mixed-methods approach documents physician capacity limitations and to what degree telemedicine is being considered to remedy physician capacity shortfalls. Data collection includes written surveys from 47 treatment centers; qualitative interviews with 39 treatment centers; and patient simulations of VA telemedicine programs. For the data analysis, summary statistics are provided, including characteristics of organizational participants and buprenorphine prescribing patterns. The qualitative inductive analysis is designed to identify contextual and process factors that affect telemedicine implementation.Fifty percent (sample = 42) of Ohio treatment providers report lack of access to buprenorphine-prescribing physicians as a barrier to implementation and expanded use of buprenorphine. Thirty-eight percent of those identifying this barrier consider telemedicine as an option to access physician prescribers. Barriers to telemedicine implementation are technology incompatibility; inability for telemedicine sites and specialty treatment providers to agree on dosing protocols (including diversion prevention expectations); and workflow interruptions that occur due to patient and clinical information not being effectively transferred between telemedicine sites and community treatment providers. Organizational strategies to overcome lack of physician capacity and telemedicine implementation challenges are discussed.The lack of physician-prescribing capacity for buprenorphine is preventing this evidence-based practice from achieving higher penetration rates among specialty treatment providers. Telemedicine provides one solution to re-allocate the distribution of this scarce resource. However, there will also be challenges in implementing telemedicine that need to be understood, and evidence-based strategies need to be developed to overcome these challenges. Successful use of telemedicine may ultimately lead to greater integration between primary care and specialty addiction treatment.Clinicaltrials.gov NCT01702142NIDA 5R01DA030431-03"} +{"text": "Enthesitis Related Arthritis Category of Juvenile Idiopathic Arthritis (JIA-ERA) is the most common category of JIA seen in Asian Indians. Transcriptome analysis is a useful tool to analyse pathways involved in disease pathogenesis. Peripheral blood mononuclear cells (PBMC) and SFMC analysis showed involvement of innate immune cells in JIA-ERA. However PBMC/SFMC have variable number of different cells and that can affect interpretation. No data is available on cell type specific transcriptome analysis of blood and synovial fluid in children with JIA-ERA.To study the cell type specific transcriptome analysis of blood and synovial fluid in children with JIA-ERA.Six samples each of peripheral blood and synovial fluid were collected from patients with ERA-JIA. Blood from 6 healthy controls was also collected. Mononuclear cells were separated by density gradient centrifugation. B cells, T cells and monocytes were separated using MACS columns and purity assessed by flow cytometry. After RNA extraction and checking the quality of RNA (RIN > 8) microarray was done using Illumina chips WG 12 for whole PBMC/SFMC population, T cells, B cells and monocytes. Some of the significant genes were validated by qRT-PCR.Unsupervised hierarchical clustering revealed that cell subsets could be distinguished based on their gene expression profile. No significant differences were observed between PBMC of patients and healthy controls. Comparison of SFMC and PBMC reconfirmed the results seen earlier. Among T cells and B cells the differential athways identified were related to inflammation like Cell adhesion, antigen processing, cytokine and chemokine signaling,BCR signaling and leukocyte migration.Results obtained with monocytes are summarized below in table Monocyte probably play a major role in pathogenesis of JIA-ERA and TLR signalling may be the pathway involved.None declared."} +{"text": "Dear Editor-in-Chief,A recent article published in the Journal of Human Kinetics describeResistance exercise with blood flow restriction (REBFR) is considered alternative training for enhancing strength and muscle size (hypertrophy) to high intensity conventional resistance training . It is often recommended to include REBFR in clinical population, including hypertension (HTA), as this type of training carries a lower risk of injury. Additionally, it has been reported that REBFR is safe . For insTherefore, further investigation is required to assess the physiological effects on hypertensive subjects comparing: a) resistance training with different levels of blood flow restriction; b) different intensities in resistance training; c) REBFR versus traditional resistance training; d) REBFR versus traditional aerobic training in hypertensive subjects."} +{"text": "Cardiovascular disease (CVD) is the major cause of mortality in industrialized countries. Atherosclerosis is characterized by a long lag time between onset and clinical manifestations. There is evidence that CVD initiate before birth by developmental changes in utero. Genetic and environmental factors may interact in specific periods of life , giving rise to altered developmental plasticity and epigenetic modifications with abnormal phenotypic expression of genetic information without altering DNA sequence. Nutritional imbalances and other environmental clues may cause intrauterine growth delay, decreased gestational age, low birth weight and postnatal catch-up growth. Fetal exposure to maternal hypercholesterolemia has been associated with increased risk and progression of atherosclerosis. Oxidative stress seems to play a major role in the atherosclerotic process by activating both platelets and monocytes forming proinflammatory and proaterogenic substances, resulting in endothelial dysfunction, decreased flow-mediated dilation, and increased carotid intima-media thickness ,2. CVD p"} +{"text": "Orangutans are an endangered species whose natural habitats are restricted to the Southeast Asian islands of Borneo and Sumatra. Along with the African great apes, orangutans are among the closest living relatives to humans. For potential species conservation and functional genomics studies, we derived induced pluripotent stem cells (iPSCs) from cryopreserved somatic cells obtained from captive orangutans.OCT4, SOX2, KLF4, and c-MYC factors. Candidate orangutan iPSCs were characterized by global gene expression and DNA copy number analysis. All were consistent with pluripotency and provided no evidence of large genomic insertions or deletions. In addition, orangutan iPSCs were capable of producing cells derived from all three germ layers in vitro through embryoid body differentiation assays and in vivo through teratoma formation in immune-compromised mice.Primary skin fibroblasts from two Sumatran orangutans were transduced with retroviral vectors expressing the human We demonstrate that orangutan skin fibroblasts are capable of being reprogrammed into iPSCs with hallmark molecular signatures and differentiation potential. We suggest that reprogramming orangutan somatic cells in genome resource banks could provide new opportunities for advancing assisted reproductive technologies relevant for species conservation efforts. Furthermore, orangutan iPSCs could have applications for investigating the phenotypic relevance of genomic changes that occurred in the human, African great ape, and/or orangutan lineages. This provides opportunities for orangutan cell culture models that would otherwise be impossible to develop from living donors due to the invasive nature of the procedures required for obtaining primary cells.The online version of this article (doi:10.1186/s13104-015-1567-0) contains supplementary material, which is available to authorized users. Pongo pygmaeus) and Sumatra (Pongo abelii) .Gene expression scores and .cel files supporting the results of this article are available in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) repository [Series Accession Number GSE69603 and"} +{"text": "To examine acute alterations in lower-extremity sagittal plane joint moments due to isolated and/or combined experimental knee joint pain and effusion during walking.Nineteen able-bodied subjects walked four different conditions , with a week between each condition. We used previously-used injury models of pain and joinThe FANOVAs detected between-session differences for the involved (right) and uninvolved legs (left; Figure Stimulation of the receptors specific to joint pressure appears to cause higher impact on alterations in sagittal plane joint moment compared to the nociceptor stimulation. Simultaneous knee joint pain and effusion produced a summative effect on sagittal plane joint moments. Since knee joint effusion and pain are common symptoms in knee joint injuries, both variables should be controlled in acute and chronic phase of rehabilitation in order to avoid altered joint moments."} +{"text": "Increased aortic stiffness may lead to insufficient flow wave dampening and subsequent transmission of excessive pulsatile energy towards end-organs such as the brain. It has been shown that CMR-assessed aortic stiffness may augment cerebral small vessel disease in patients with hypertension, as assessed by conventional structural magnetic resonance imaging (MRI). However, in addition to these overt brain abnormalities, currently it is unknown whether aortic stiffening relates to subtle changes in brain tissue integrity, which may be a precursor to overt brain abnormalities. Diffusion tensor imaging (DTI) in the brain has been used to evaluate such subtle changes in tissue integrity. The aim of this study was to assess the association between aortic arch pulse wave velocity (PWV) as a marker of arterial stiffness and brain changes assessed by conventional structural MRI as well as DTI in patients with hypertension.78 patients with hypertension were prospectively included. Aortic imaging was performed using 1.5T MRI. To assess PWV over the aortic arch, one-directional through-plane velocity-encoded MRI was performed, planned perpendicular to the ascending aorta and additionally transecting the proximal descending aorta and grey matter integrity (Table Our data suggest that aortic arch stiffness is independently associated with changes in brain tissue integrity in patients with hypertension. Subtle changes in brain microstructure are related to increased stiffness of the aortic arch, even in absence of overt brain abnormalities.N/A."} +{"text": "Stroke is the leading cause of disability in the United States. Despite the high incidence and mortality of stroke, sensitive and specific brain-based biomarkers predicting persisting disabilities are lacking. Both neuroimaging techniques like electroencephalography (EEG) and non-invasive brain stimulation (NIBS) techniques such as transcranial magnetic stimulation (TMS) have proven useful in predicting prognosis, recovery trajectories and response to rehabilitation in individuals with stroke. We propose, however, that additional synergetic effects can be achieved by simultaneously combining both approaches. Combined TMS-EEG is able to activate discrete cortical regions and directly assess local cortical reactivity and effective connectivity within the network independent of the integrity of descending fiber pathways and also outside the motor system. Studying cortical reactivity and connectivity in patients with stroke TMS-EEG may identify salient neural mechanisms underlying motor disabilities and lead to novel biomarkers of stroke pathophysiology which can then be used to assess, monitor, and refine rehabilitation approaches for individuals with significant disability to improve outcomes and quality of life after stroke. Stroke is the fourth leading cause of death have shown promise in identifying neurophysiological mechanisms associated with network reorganization in the human brain after stroke. Neuroimaging approaches have identified functional neural correlates of impaired arm movements after stroke demonstrating relationships between brain function and motor impairment at rest and during isotonic contraction TMS can noninvasively and transiently modulate cortical excitability in the human brain or offline imaging approaches in response to a single TMS pulse has been repeatedly confirmed , several other TEP-based indices have been employed to index certain aspects of cortical reactivity or effective connectivity Table . For exaTMS-EEG has provided candidate biomarkers for a variety of different neurologic conditions. Altered TEPs, in particular a reduced N100 component of the TEP evoked at M1, have been identified in children with attention deficit hyperactivity disorder (ADHD) Electrical confounds: magneto-electric induction creates fast and high amplitude currents in the EEG electrodes and leads (during stimulation itself and when recharging capacitors) and also electrode-electrolyte interface polarization (Ilmoniemi and Kici\u0107, Concurrent TMS-EEG has the potential to improve our understanding of the neurobiology of stroke and stroke recovery by offering a sophisticated paradigm to non-invasively characterize human brain excitability and connectivity after stroke. Revealing the causal mechanisms of altered cortical excitability and cortical network reorganization has important clinical implications. If successful, TMS-EEG could provide new tools to improve prognosis, refine treatment approaches, monitor recovery trajectories and individualize care to improve recovery outcomes for patients after stroke.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "One of the most widely employed quantitative measurements for assessing tumour response to treatment is the tumour diameter (RECIST criteria), usually determined on cross-sectional CT or MRI. This simple measurement is relatively reproducible and reduction in the maximum tumour diameter by 30% or more following therapy is taken as a sign of effective treatment. However, new targeted therapies may be effective without significantly reducing tumour size and other quantitative response criteria are being evaluated.Some of the response criteria being evaluated combine tumour diameter measurement with other quantitative assessment (e.g. CT density). These have been applied towards the evaluation of gastrointestinal stromal tumours (CHOI criteria) and renal cell carcinoma (modified or revised CHOI criteria) undergoing multi-kinase inhibitor treatment; and hepatocellular carcinoma (modified RECIST criteria) treated with novel therapeutics or chemoembolization. In these clinical settings, the applications of such criteria for tumour response assessment have shown better correlation with clinical outcome compared with conventional RECIST criteria. When immunotherapy is administered, conventional RECIST criteria may erroneously ascribe the appearance of new lesions to disease progression; whereas this phenomenon is given due consideration within the immune-related response criteria (irRC).As quantitative imaging becomes increasingly important in oncology, quantitative indices are being applied and developed in CT, MRI and PET imaging for tumour response assessment. Using perfusion CT technique, the change in CT attenuation value with time resulting from the passage of contrast through tissue can be used to calculate quantitative vascular parameters such as permeability surface area product (PS), blood flow (F) and mean transit time (MTT). Using dual energy CT, it is possible to obtain quantitative iodine contrast distribution in soft tissue.MRI is a powerful multiplex imaging technique because depending on how the scans are performed, it can yield different quantitative information. Two of the most widely employed quantitative techniques for tumour assessment are dynamic contrast enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI). The former has been used in early phase trials for the assessment of antivascular/ antiangiogenic therapies. The latter has shown potential as an early response biomarker to a range of effective treatments including chemotherapy, radiotherapy, chemoemobolization treatment and novel therapeutics. Other clinical MR techniques include intrinsic susceptible contrast imaging and magnetic resonance spectroscopy (MRS). However, these have currently limited value for assessing tumour response to treatment.PET imaging using 18FDG tracer enables the semi-quantitative standardised uptake value (SUV) to be derived. PET imaging is increasing utilized for tumour response assessment, and forms the basis of standard criteria for assessment of tumour response in lymphoma. By performing dynamic imaging, it is also possible to calculate the quantitative tracer uptake in tissues. The strength of PET imaging is the range of radiolabelled tracers that are now available clinically to probe a range of tissue properties.In early phase trials, quantitative imaging other than tumour size measurements using CT, MRI or PET can provide mechanistic information about drug action, and also therapeutic effects on specific aspects of tumour biology . By using multimodality imaging, there is also an opportunity to corroborate imaging measurements made using one technique with another. However, quantitative techniques require a process of quality control and quality assurance; as well as knowledge of their measurement reproducibility so that they can be applied with confidence in clinical practice."} +{"text": "There are errors in the Data Availability section. The correct data availability information is as follows: The authors confirm that all data underlying the findings are fully available without restriction. All sequence data are in the Short Read Archive (SRA) at the NCBI database under accession numbers: bean LTD SAMN03223377, bean NOI SAMN03223381, bean NTD SAMN03223380, and bean LOI SAMN03223378."} +{"text": "Amyris is a renewable products company providing sustainable alternatives to a broad range of petroleum-sourced products. Amyris applies its industrial synthetic biology platform to convert plant sugars into a variety of molecules - flexible building blocks that can be used in a wide range of products.\u00ae, Amyris's brand of farnesene, a long-chain branched hydrocarbon, manufactured using our engineered microbes in fermentation.Amyris's initial portfolio of commercial products is based on BiofeneFirst generation renewable fuels have been an important part of the effort to reduce the world's petroleum dependence and greenhouse gas emissions associated with transportation fuels. However, these first generation renewable fuels have some limitations, ranging from lower energy density than petroleum fuels and lack of fungibility with existing petroleum distribution systems.Amyris renewable fuels are designed to be optimal transportation fuels. Specifically, our fuels are designed to be drop-in, cost competitive replacements for petroleum-derived fuels, compatible with existing engines yet with superior performance.Building on our Biofene hydrocarbon building block, we are currently selling renewable diesel in metropolitan areas in Brazil and are pursuing industry certification for our renewable jet fuel."} +{"text": "Clinically, pancreatic tumors have proven to develop resistance to available treatment options; however, efficacy might be achieved if the required levels of drugs reach the tumor site. Tumor microenvironment (TME) leads to extensive desmoplasia and chemo-resistance, contributing immensely to the invasive and metastatic process of pancreatic carcinoma . DesmoplOur study, published in Cancer Research , provideConsidering the huge fibrotic nature of pancreatic tumors and to overcome the vast heterogeneity observed within the tumors, we have prepared a PLGA [poly(lactic-co-glycolic acid)] based nanoparticle formulation of ormeloxifene and discussed its enhanced efficacy in an article published in Biomaterials . The forIn conclusion, management of TME using this novel therapeutic modality and potential delivery system might add clinical benefit to existing standard treatments utilizing combination treatment regimens. Our studies support the understanding that manipulation of TME may overcome the stromal barrier for effective treatments in pancreatic cancer."} +{"text": "Myeloid-derived suppressor cells (MDSCs) are a naturally occurring immune regulatory population capable of suppressing inflammation, and are often associated with cancer, chronic infection and traumatic injury . GrowingActivation of the inflammasome can be via endogenous damage-associated molecules termed DAMPs Figure . We havein vitro and in the context of GvHD [ex vivo suppressive capacity of MDSC was also reduced. The temporal nature of MDSC loss of function was addressed by applying multiple consecutive doses of MDSC-IL13 , resulting in enhanced overall survival, suggesting MDSC functionality is compromised early due to GvHD conditions and that maintaining a suppressive environment using repetitive MDSC infusions could overcome the loss of suppression of an individual MDSC infusion. In support of an inflammasome mediated loss of function, genetic ablation of the inflammasome-associated adaptor protein ASC (Apoptosis-associated speck-like protein containing a CARD) prevented MDSC inflammasome activation and resulted in improved survival relative to wild-type MDSC in GvHD mice. Moreover, ASC\u2212/\u2212 MDSC-IL13 recovered from day 5 post transplant recipients did not produce IL-1\u03b2 and better retained their capacity to suppress T cell proliferation ex vivo than wild-type MDSC-IL13 recovered from GvHD mice. The translational potential of these findings are supported by the fact that we observed human peripheral blood-derived MDSC to be susceptible to in vitro inflammasome activation and had reduced suppressive function under these conditions.Myeloid cells are uniquely responsive to their environment and in our efforts to improve MDSC function, we investigated their inflammasome activation status both of GvHD . In as l\u2212/\u2212 MDSC, and clinically viable options including mRNA or gene knockdown or knockout technologies such as sh/siRNA or nucleases that target one or more inflammasome components. Pharmacologic agents such as small molecule inhibitors designed to repress inflammasomes currently being developed to circumvent GvHD pathology are expected to act on transferred MDSC as well, and we would predict aid in maintenance of function. Other implications from this work include the potential to conversely promote inflammasome activation locally at the site of tumor burden for the purposeful enhancement of immune activation and anti-tumor immune therapy, as MDSC are nearly ubiquitously observed in the setting of solid tumors. Our findings suggest that the degree of inflammation is critical for MDSC functional support, and anti-tumor therapies may benefit from local or systemic priming of inflammasome activation, converting tumor-associated MDSC and releasing their suppressive potential.Myeloid cells play a critical role in developing, shaping and sustaining immune responses and are remarkably adaptable to their environment. Therefore, adoptive cell therapies using MDSC need to be tailored and monitored carefully, as culture conditions are vastly different then the conditions MDSC are exposed to upon transfer. An important question that remains is elucidating which inciting factors are involved in transplant/GvHD associated inflammasome activation. While ATP/P2x7R and Nlrp3/miR-155 are recognized as important targets with relevance in GvHD, a wide variety of factors are known to activate inflammasomes including DAMPs, bacterial & viral (dsDNA) products and environmental stimuli and may contribute to MDSC inflammasome activation. Whether it is possible or necessary to globally inhibit these upstream pathways for inflammasome activation is yet unclear. Our future aims are to produce higher functioning MDSC that are capable of sustained function in the harsh early post transplant setting of GvHD. Methods for tailoring MDSC to resist conversion include genetic alterations to prevent inflammasome activation, as seen using ASC"} +{"text": "It is becoming clear that immune cells play many important but sometimes conflicting roles in cancer. Immune profile changes at sites of immune-cancer interactions, such as the tumor microenvironment and tumor-draining lymph nodes (TDLNs), may represent a sensitive predictor of local and distant tumor metastasis. However, standard pathologic analysis of tumor sections has remained at the visual assessment of one marker per serial section level; it would be extremely useful to be able to visualize the distributions of multiple phenotyped immune and other cells in-situ in solid tumors to dissect the complex interplay between immune/stromal cells and cancer cells within tumors, tumor-draining lymph nodes (TDLNs), and blood. We generate immune profiles that include complete immunophenotyping and identification of cellular spatial relationships within and between the tumor microenvironment and TDLNs from formalin-fixed paraffin-embedded lymph node and tumor specimens from cancer patients using a combination of multiplexed IHC/IF, multispectral imaging, and automated image analysis which delivers quantitative per-cell measures of each marker. These per-cell intensities are then translated into a phenotype for each cell. We have found that immune cell populations as well as their spatial distributions and clustering patterns have strong correlation with clinical outcome."} +{"text": "A key systemic regulatory hormone is growth hormone (GH), which has a developmental role in virtually all tissues and organs. This review catalogs the impact of GH on tissue programming and how perturbations early in development influence GH function.Developmental programming of the fetus has consequences for physiologic responses in the offspring as an adult and, more recently, is implicated in the expression of altered phenotypes of future generations. Some phenotypes, such as fertility, bone strength, and adiposity are highly relevant to food animal production and The fundamental role of normal fetal development is best exemplified by pattern formation in the embryo. \u201cProgramming\u201d was a term coined in 1986 to reflect that events occurring c traits and the c traits ,4. The iRecent data highlight that the metabolic environment experienced by the fetus influences phenotypic expression and disease susceptibility in later life ,6. SmallIgf-2 gene with the paternal copy as the sole source of IGF-2 during development and the maternally inherited copy silenced. It is hypothesized that the maternal and paternal expression are balanced to maximally promote fetal growth while preventing excessive depletion of the dam\u2019s resources [Although not developmental programming, the most familiar illustration of developmental epigenetic imprinting is the insulin-like growth factor-2 (IGF-2) pathway. The methylation status differs between the paternally and maternally inherited esources . Anotheresources . The genesources to regulesources .Importantly, developmental programming may have multigenerational consequences transmitted through epigenetic modifications of the genome. Transgenerational epigenetic programming was initially recognized as a result of malnourishment. The Dutch famine, sometimes referred to as the \u201cHunger winter\u201d, is most often cited as the initial epidemiological human case study illustrating the impacts of nutritional stress upon both physical and behavioral traits in subsequent generations (reviewed in ). More rin utero [The accepted role of GH and the GH-IGF axis in tissue development is predominantly postnatal with other hormones assuming importance in utero . Yet GH in utero and calvin utero ,24. Thesin utero .in utero growth restriction. Furthermore, adult height is correlated with placental GH expression. Genetic variation within the sequence of the placental-form of GH is significantly associated with mature height confirming that altered expression of GH in utero governs longitudinal bone growth potential [Evidence that fetal perturbations program GH signaling is also emerging. A common model used to define the role of GH in developmental programming is the neonate that experienced impaired fetal growth, specifically SGA infants, who are characterized by compromised bone growth and reduced body mass. Infants having low birth weights trend to lower circulating GH as young adults indicatiotential . Immune otential indicatiBirth weight and neonatal growth is predictive of adult circulating GH levels suggesting that the intrauterine environment programs GH secretion or tissuin utero reduces birth weights of calves [in utero exerts long term consequences on the offspring possibly through alteration of maternal metabolic pathways and placental function.The role of GH in normal development was established decades ago through ablation studies and assessing the physiological consequences of the absence of GH. Additional models to characterize GH action elevate the hormone either through exogenous administration of GH, GH-transgene expression, or chemical compounds that induce GH. Elevated GH f calves , lambs [f calves , and rodf calves . In sheef calves . For rodf calves . Furtherf calves . Similarf calves . Ewes trf calves ,43. Takein utero growth inhibition and restore overall bone length [Elevated GH postnatally has significant effects on bone, muscle, and adipose. Human SGA infants given GH respond with increased bone growth velocity for the duration of GH treatment . In rodee length . GH exere length . Provisiin utero for lambs.Lambs given HMB during the first 3 postnatal weeks show elevated circulating levels of GH, IGF-1, and biochemical markers of bone turnover. However once the HMB treatment concludes, these indices all fall to control values indicating resistance to long term bone programming by HMB when provided postnatally . The faiThe enhanced gain accompanying elevated GH has a greater proportion of protein than normal tissue accrual in rodents. Rodent development is characterized by each unit of gain being composed of the same proportions of water, lipid, protein and ash across the entire growth phase, despite the speed of accrual . In contTherapeutic GH treatment of SGA children offers growth advantages as noted above, yet the elevated GH also reduces insulin sensitivity potentially increasing the risk of diabetes. Recent studies of children born SGA and treated with GH would suggest this is not a valid concern as they have normal insulin post-GH treatment . HoweverIn utero or postnatal exposure to elevated GH in a GH-transgenic mouse model increases adipose storage by increasing adipocyte hyperplasia, differentiation, and cellular lipid content [The role of GH in adipogenesis is complex. content ,54,55. A content . Postnat content . This ne content .in utero [The interplay with leptin adds more complexity to the influence of GH on adipose. Leptin, synthesized by adipose cells, regulates energy metabolism (reviewed in ) and infin utero with potEarly dysregulation of GH promotes adipogenesis which in turn elevates leptin that influences adipose function at later ages. Elevated GH in a GH-transgenic mouse model increases plasma leptin while miStudies in multiple mammalian species demonstrate that aberrant programming of adult tissue response is associated with stress-induced glucocorticoid secretion during fetal and perinatal development. Maternal stress in humans is known to impact neurological circuitry of the offspring: infants have an increased risk of neuropsychiatric disease when the mother experienced psychological stress during the first trimester (reviewed in ). SimilaEarly research demonstrated that adult GH secretory patterns are influenced by perturbations during the perinatal period. For example, male rats normally express a high amplitude secretory pattern of GH whereas females have low amplitude pulses within a higher basal background. Transient manipulation of sex steroids in the neonatal period can modify the GH secretory pattern to that of the opposite sex . GlucocoMothers who are undernourished during pregnancy give birth to SGA infants and when adult those children exhibit adult-onset obesity, insulin resistance, hypertension, and metabolic dysfunction. Maternal nutritional deprivation stress also is implicated in intergenerational epigenetic programming to alter future generations\u2019 growth and metabolic phenotypes. This phenomenon is suggested to account for the rising cases of human obesity, diabetes, and coronary disease (reviewed in ).Levels of placental GH found in maternal circulation are positively correlated with fetal birth weight and in times of maternal nutrient deprivation and SGA pregnancies, placental GH secretion is reduced . A recenAs noted above, there are generalized consequences of SGA on bone characteristics but SGA due to nutritional deprivation also programs bone through the GH- IGF axis. The necessity of adequate fetal and neonatal nutrition for normal bone growth and adult bone integrity was underscored by Eastell and Lambert in their review . In ratsAnother mechanism of nutritional programming on bone is by its effects on the formation of the embryonic skeletal anlage. Fetal and postnatal bone growth depends upon chondrocyte hypertrophy and hyperplasia. Fibroblast growth factors (FGF) and their cognate fibroblast growth factor receptors (FGFR) are key signaling molecules of chondrocyte function in developing bone. Activation of different FGFR family members both promote and inhibit chondrocyte proliferation . The FGFIn rats, restricting maternal dietary protein to induce intrauterine growth restriction enlarges abdominal adipose depots when animals are adult . The enlIntrauterine growth restricted babies, piglets, and rodent pups have reduced leptin at birth and then propensity for obesity at adulthood ; provisiPhysical stressors, often modeled with induced hypoxia, have been used to assess the epigenetic consequences of stress. Hypoxia-inducible factor 1 (HIF-1), induced under conditions of hypoxia to adapt to reduced oxygen supply, is also required for normal fetal tissue and skeletal development . The traGrowth hormone has a pivotal role in pre and postnatal development although its effects on intergenerational programming are as yet under studied. Given the plasticity of postnatal development, defining fetal and neonatal programming and the effect upon later phenotypes is important to maximize the expression of desirable traits in food animals. This is particularly important on the impact of more permanent epigenetic alterations of gene expression that may have future consequences. Historically, classical genetic selection has permitted extremely favorable phenotypic advances. The implementation of quantitative trait loci selection schemes for livestock based upon genomic signatures will accelerate genetic improvement. Overlaid upon genetic selection one must be mindful of the epigenetic programming that environmental perturbations can exert on future trait expression and how that may factor into selection schemes for agricultural livestock production in a changing environment. Better defined knowledge of the mechanisms of programming will facilitate incorporation of epigenetic factors into selection."} +{"text": "Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) is trigeminal autonomic cephalalgias which is characterized by repetitive short lasting, severe attacks. Headache attacks are distribution of the ophtalmic and maxillary trigeminal divisions and associated with ipsilateral autonomic phenomena .A growing body of literature has focused on brain magnetic resonance imaging (MRI) evidence of neurovascular compression in these syndromes. There is some evidence supporting microvascular decompression of the trigeminal nerve in selected patients who have medically refractory SUNCT and a demonstrable ipsilateral aberrant vessel on magnetic resonance imaging (MRI). Here, we describe two cases concerning a 52-year-adult and a 69-year-elderly with short-lasting, recurrent headache combined with cranial autonomic features. Pain was described as excruciating, and was non-responsive to most traditional analgesic drugs. We report two patients of SUNCT syndrome with MRI cisternography and tractography findings of neurovascular compression. We performed MRI cisternography and tractography for delineates structural changes in the trigeminal nerve. Pain was completely relieved after surgery that microvascular decompression.We suggest that SUNCT patients with brain MRI should always be performed with a dedicated view to exclude neurovascular compression. In this case reports we performed MRI tractography delineates structural changes in the trigeminal nerve for SUNCT. MRI tractography is the first reports for SUNCT patients in the literature."} +{"text": "In the framework of better risks management in hospital environment and in perspective to improve quality and safety care, university hospital center Farhat Hached Sousse (Tunisia) has developed a medical device-vigilance system in order to monitor incidents or risks of incidents that may arise through using medical devices allowed-on in market.Our objective is to determine medical staff knowledge\u2019s, attitudes and practices in university hospital center Farhat Hached Sousse (Tunisia) regarding medical device-vigilance system establishment.We conducted a descriptive study, type KAP , in December 2014, among all medical staff exercising at university hospital center Farhat Hached Sousse (Tunisia) who are in direct contact with medical devices. Measuring instrument used is a self-administered questionnaire, preestablished, and pretested. Seizure and data analysis was made by the SPSS software 20.0.More than half of participating physicians do not know, nor institution correspondent local )), neither existence of standardized form for reporting )). Concerning attitudes, majority of investigations )) shall notify interest of creating medical device-vigilance system. Participants in study report their desire to receive more information about medical device-vigilance system but they relate their desires to follow a training )).Our study highlights lack of information and training in field yet sensitive and heavily regulated. This needs to affirm medical nature relatively to medical device-vigilance by integrating it into health care professional\u2019s curriculum study but also by strengthening awareness and communication around medical device-vigilance system. Success system\u2019s functionality must be supported by promulgation laws and regulations and better organization of regulatory agencies.None declared."} +{"text": "Noma is a devastating ancient illness that causes severe facial disfigurement in >140,000 children every year mainly in Africa, South America and India. The cause of noma remains unknown but infection, oral hygiene and immune status likely all contributeEfforts have been deployed over the 2 past decades to identify microbial agents responsible for nomaResearch in the field of microbial identification has benefited from dramatic technical improvements. Until the late 90\u2019s culture based methods were predominantly used. More recently, culture-independent methods were used to identify bacteria in noma patients. We present three approaches used to study hundreds of gingival samples from noma patients and local control samples collected from villages near Zinder, Niger (Africa): large-scale cloning sequencing methods used at the beginning of 2000, high-density microarrays and high-throughput sequencing (HTS) devicesFusobacterium necrophorum as the causative agent of noma, while culture-independent methods identify higher levels of Fusobacteriales in healthy controls. Cloning-sequencing strategies identify disequilibrium in microbial communities from noma patients particularly in Fusobacteria, Prevotella intermedia and Peptostreptococcus genus abundance. This was also detected in studies using semi-quantitative microarrays. More recently, the utilization of HTS provided a detailed analysis of microbial flora in noma patients and identified Clostridiales, Bacteroidales, and Spirochaetales as indicators of noma. Our epidemiological investigations excluded the possible role of viruses such as cytomegalovirus or morbillivirus as possible significant contributor of noma diseaseCulture-based methods identified Although we identify a unique distribution and composition of microbial communities in noma wound sites compared to unaffected samples from the same mouths and healthy controls, the etiology of noma disease remains elusive. Future studies should include longitudinal sampling in high risk areas and detailed exploration of microbiota before and during development of lesionsNone declared."} +{"text": "Reviewing progress in the fabrication of diverse odorant and flavored sol-gels, shows us how different synthetic strategies are appropriate for practical application with important health and environmental benefits.Microencapsulation has become a hot topic in chemical research. Technology mainly used for control release and protection purposes. The sol-gel micro encapsulation approach for fragrance and aroma in porous silica-based materials leads to sustainable odorant and flavored materials with novel and unique beneficial properties. Sol-gel encapsulation of silica based micro particles considered economically cheap as capital investment in manufacturing is very low and environmentally friendly. Amorphous sol-gel SiO Encapsulation technology arouse as a sparkle in recent world accounting significant health and environmental benefits. Industry grow with wide range of applications in all fields specifically, Deodorants, food, oils, synthetic nitro and polycyclic musk's, detergents, cosmetics (perfumes), personal care , food (flavors), and home care (laundry and detergents) etc. given by Avnir and co-workers in 1984. Simple addition or entrapment of organic molecules in inner porosity of silica used as matrix at the onset of sol-gel process can be shown as below in Equation (1) Where Extraction and GC analysis performed for aroma load show total mass of sol-gel powders best described by following Equation (4)mi = mass of the aroma component in the extraction sample, mW the mass of water, mSE the mass of dry silica subjected to extraction Aroma retention of different components i in matrix found by Equation (5)Where the subscript 0 stands for the initial conditions and bergamot oil in different silica based microcapsules widely applied in perfumes and octylmethoxycinnamate (OMC) used initially as sunscreen but show endocrine disruption and estrogenic activity .The SPF calculations obtained for each subject and represented in Table Oils also commonly used in perfumes, cosmetics, agriculture, and food due to aromatic properties. On the basis of origin and composition, properties of EOs can be changed by encapsulation using widely used technique called coacervation. Lemon, thyme, citronella, vanilla, menthol, eucalyptol, clove, peppermint are some of EOs used (Martins et al., Microscopy, a powerful tool used to analyze microcapsule morphology. For example: Thyme oil droplets encapsulated as spherical particles demonstrated by optical microscopy and cryogenic scanning electron microscopy confirms rough surface with some pinholes, pores, and cracks of microcapsules. Release of Thyme oil affected by film thickness and polymer concentration whereas diffusion not only affected by polymer membrane but also by type of oil used. Such difference occurs due to hydrophilic characteristic of the oil (Ashraf et al., Sol-gel encapsulation of silica based micro particles considered economically cheap as capital investment in manufacturing is very low and environmentally friendly. Stobber process (Stober et al., TEOS used as a cheap solvent therefore main cost of sol-gel encapsulation supposed only for labor. An overall value of sol-gel products in global market in 2006 estimated $1 billion with annual growth rate of 6.3% until 2011 as shown in Figure Positive impacts of silica based materials involving sol-gel encapsulation leading to sustainable fragrances on human health and environment apart from technical and economical feasibility are highly appreciated. Comparing synthetic perfumes which are highly poisonous causing neuromodulations in human neuroblastoma cells at extremely low concentration with EOs, being natural renewable shows multiple human health benefits. Double encapsulation of EOs first caged in \u03b2-cyclodextrin following silica encapsulation using water based route turning oil to more stabilized and resistant toward temperature, humidity, and light. Today commercialized water based products also present in tone scale in broad variety are available. In US 50 largest companies generate about 70% of revenue from this industry. This technology also enables to produce and stabilize costly active ingredients by enhancing precision and effectiveness of actions and delivered where needed in required amount. First leading Europe's chemical engineering company, sol-gel technology Ltd. constructed in 2001 installed a plant in Israel. Green technology since, 1990s grow with advancement in nanomaterial synthesis (Dahl et al., In this article, we have discussed and demonstrated encapsulation technique based on silica micro particles and its applications in different fields which offer improved products for the benefit of human beings and are environmentally friendly. Sol-gel encapsulation proves highly flexible technology that can be applied to multiple systems. Further innovation to this unique process may include isolation of incompatible compounds through their independent encapsulation within a common formulation. In order to check biological properties of encapsulated materials in food, agriculture and cosmetic industry, supplementary studies are still required.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Ischemia/reperfusion injury (IRI) and organ failure especially IRI-induced remote and multiple organ failure contribute significantly to postoperative mortality and morbidity, and reperfusion induced oxidative stress plays a critical role in this pathology , 2.Reactive oxygen species (ROS) induced vascular endothelial dysfunction plays an important role in the development of IRI in various organs. In this special issue, Q. Yang et al. reported that the otherwise cardiac protective polymerized hemoglobin, when used at high dose, failed to alleviate cardiac IRI due to induction of oxidative damage in coronary artery. On the other hand, natural herbal extracts such as Licochalcone B as reported by J. Han et al. in this special issue conferred protection against myocardial IRI through attenuating ischemia-reperfusion induced oxidative damage.The intravenous anesthetic propofol possesses antioxidant capacity and has been shown to attenuate IRI in patients undergoing cardiac surgery and in animal models of myocardial and inte mitochondrial homeostasis play critical roles in Acute Organ Failure [ mitochondrial homeostasis alterations during these pathologies is largely unclear. In this special issue, S. Cao et al. provided genome-wide expression profiling of cardiomyocytes subjected to hypoxia-reoxygenation injury in an effort to uncover the roles of mitoKATP in energy homeostasis and its regulation.Disturbances of Failure and in p Failure , while tWe hope that the original and review articles presented in this special issue, representing the current advances in the oxidative stress-mediated ischemia-reperfusion injury, with respect to their potential impact in cellular survival pathways and therapeutic strategies, will stimulate further exploration of this important area. Despite diversity, it is our belief that the articles comprised in this special issue could represent an important advancement and contribution to improve our knowledge of the mechanisms governing reperfusion injury."} +{"text": "Tissue microarrays (TMAs) have become a valuable resource for biomarker expression in translational research. Immunohistochemical (IHC) assessment of TMAs is the principal method for analysing large numbers of patient samples, but manual IHC assessment of TMAs remains a challenging and laborious task. With advances in image analysis, computer-generated analyses of TMAs have the potential to lessen the burden of expert pathologist review.In current commercial software computerised oestrogen receptor (ER) scoring relies on tumour localisation in the form of hand-drawn annotations. In this study, tumour localisation for ER scoring was evaluated comparing computer-generated segmentation masks with those of two specialist breast pathologists. Automatically and manually obtained segmentation masks were used to obtain IHC scores for thirty-two ER-stained invasive breast cancer TMA samples using FDA-approved IHC scoring software.\u03ba=0.81) than between pathologists' masks (\u03ba=0.91), this had little impact on computed IHC scores (Allred; Although pixel-level comparisons showed lower agreement between automated and manual segmentation masks (The proposed automated system provides consistent measurements thus ensuring standardisation, and shows promise for increasing IHC analysis of nuclear staining in TMAs from large clinical trials. With the improvements in clinical outcome in women treated for breast cancer such that 5 year survival now approaches 90% and 10 year survival 80%, adjuvant clinical trials require very large numbers of patients and tissue samples for biomarker studies to drive changes in clinical practice. Many such large clinical trials have moved towards generating tissue microarrays staining or molecular analyses of a single TMA slide with representation from 20\u201340 patients and multiple samples per patient is an efficient use of human tissue, antibodies and laboratory processes, there remains the problem of skilled detection and assessment of biomarkers. Such reading of the biomarker status is laborious and time consuming, requiring expert assessment. Thus, there has been increasing attention paid to the potential for automated reading of breast TMA biomarker slides rather than relying on pathology review . HoweverIn previous studies comparing automated and manual IHC scores . Stained slides were scanned with lossy compression using an Aperio Scanscope XT on a \u00d7 20 objective with the optical doubler in place . Each slide was then segmented into the individual constituent stained spots, each spot representing a section from a tissue core.Breast TMAs were generated, for research purposes, from primary, previously untreated breast cancers using excess tissues from routine clinical practice after written, informed consent from the donor patients. Ethical permission was granted by Tayside Tissue Bank, Dundee, UK, under delegated authority of the Tayside Local Research Ethics Committee. In brief, surgically resected primary breast cancer from otherwise unselected patients was fixed in buffered formalin, stored at controlled temperature (18\u201322\u2009\u00b0C) overnight and processed to formalin-fixed paraffin-embedded blocks. Whole mount sections stained with Haematoxylin and Eosin were marked to highlight relevant invasive cancer or normal tissue to allow TMA generation of up to six 0.6\u2009mm cores per cancer. TMAs were then constructed using a manual tissue arrayer . Four micron TMA sections were cut, mounted onto poly-Thirty-two uncompressed TIFF format images of TMA spots from thirty-two breast cancers were used. The perimeter of each spot was delineated and pixels exterior to this perimeter were excluded from subsequent analyses. Each spot image was \u223c3000 pixels in diameter and contained invasive cancer.T) or non-tumour (N). Each spot took on average 23\u2009min to annotate by each pathologist; however the task of annotating TMAs was spread over several days.Tumour regions in the TMA spots were manually segmented using Aperio Technologies Spectrum Software with TMA Lab and the Webscope interface (Aperio Technologies). Segmentation involved manually tracing the boundaries of invasive tumour regions on a Wacom Bamboo Fun tablet (model CTH-461) using the stylus for precision; the software tool displayed filled regions overlaid on the TMA spot images as they were annotated. Each spot was annotated independently by two specialist breast pathologists (pathologist A and pathologist B), resulting in two sets of tumour masks. Pixels in each mask were labelled as either tumour assigned to each pixel. There are four possibilities when comparing a pixel's labels in two masks: , , and . However, there are qualitative differences between segmented regions that are not well captured by simply counting the numbers of pixels that fall into each of these four categories. Therefore, when comparing two segmentation masks, we categorised pixel label disagreements into three types as follows were passed to the scoring algorithm. The Aperio IHC algorithm identifies nuclei automatically and outputs a staining intensity score (ranging from 0 to 3) and an estimate of the percentage of positively stained cells. From these measurements, IHC scores (Allred score and Quickscore) were computed for manually and automatically obtained segmentation masks. Comparisons are reported to assess the extent to which differences in these segmentations affected scoring.The FDA-approved Aperio IHC Nuclear Version 10 algorithm (Aperio Technologies) was used to estimate ER scores based on the segmentation masks obtained. Only regions labelled as tumour and false negatives .In pixel-level comparison of manually hand-drawn segmentation masks, pathologists differed in their labelling of 9% of pixels . AutomatWhen distributions of agreements and disagreements were visualised , some vaIntensity scores and percentage of positive cells were measured by the Aperio IHC Nuclear algorithm (Aperio Technologies) when provided with segmented tumour regions. Percentage of positive ER cells computed by Aperio were also evaluated . Agreeme and 0.92 (Quickscore) .This study addressed the need for automated interrogation of TMAs using ER nuclear staining of primary breast cancer as an exemplar. Although previous studies have shown that image analysis can increase workflow and reduce inter- and intra-observer variability . However determining the impact of pixel-level disagreements in clinical practice is challenging. Therefore in this study, a method of categorising disagreements was presented, given the intended usage of the application is IHC scoring. Proportion of disagreement types , equivalent to USCAP 1% cut-off, resulted in almost complete agreement between all reported segmentations. Using Quickscores (cut-off >3), two TMA spots were labelled as ER+ve from automated segmentations and the same spots labelled ER\u2212ve from manually obtained segmentations. The remaining 30 spots, 20 ER+ve and 10 ER\u2212ve, were in complete agreement across all segmentations. Generally there was an overall agreement in treatment decisions, however results varied between scoring systems and non-standardized cut-offs. These discrepancies suggest more work may be required before automation is applied for treatment decisions as suggested for studies comparing visual and automated assessment of Ki67 markers in breast cancers (Despite pixel-level disagreements averaging 16% , computeThe automated segmentation method sometimes had difficulty distinguishing ER\u2212ve cancer cells from ER\u2212ve healthy epithelial cells. Availability of a greater number of TMA spots containing both ER\u2212ve cancer cells and ER\u2212ve healthy epithelial cells, along with accurate annotations of those spots for training, is therefore likely to be of substantial benefit. Indeed, increased volumes of annotated spots for training to more fully represent a range of staining conditions, tissue structures and artefacts can potentially improve segmentation accuracy and further align automated analyses with those of specialist pathologists. The impact of using larger volumes of annotations during training can be usefully explored in future work.In summary, the use of automated annotations for scoring breast TMAs using the methods developed for and exemplified in this study concord closely with expert pathology reviews. 27% of pixel disagreements relate to minor misalignment of drawn tumour boundaries. Classification differences rarely resulted in a change of overall score that would be likely to change clinical management. Using the exemplar of nuclear ER staining, the methods of automated annotation employed here hold promise for reducing the expert pathology time required and speeding up analysis of IHC-stained TMAs from large data sets drawn from clinical trials."} +{"text": "The degree of genetic differentiation among populations experiencing high levels of gene flow is expected to be low for neutral genomic sites, but substantial divergence can occur in sites subject to directional selection. Studies of highly mobile marine fish populations provide an opportunity to investigate this kind of heterogeneous genomic differentiation, but most studies to this effect have focused on a relatively low number of genetic markers and/or few populations. Hence, the patterns and extent of genomic divergence in high-gene-flow marine fish populations remain poorly understood.Gasterosteus aculeatus) distributed across a steep salinity and temperature gradient in the Baltic Sea, by utilizing >30,000 single nucleotide polymorphisms obtained with a pooled RAD-seq approach. We found that genetic diversity and differentiation varied widely across the genome, and identified numerous fairly narrow genomic regions exhibiting signatures of both divergent and balancing selection. Evidence was uncovered for substantial genetic differentiation associated with both salinity and temperature gradients, and many candidate genes associated with local adaptation in the Baltic Sea were identified.We here investigated genome-wide patterns of genetic variability and differentiation in ten marine populations of three-spined stickleback contains supplementary material, which is available to authorized users. While local adaptation is likely to be of commonplace occurrence, demonstrating its occurrence can be difficult and take substantial research efforts -3. TradiOutlier detection methods have become particularly popular in identifying population structuring and adaptive differentiation in marine fishes, which generally show very low levels of genetic differentiation in neutral marker genes -22 and iGasterosteus aculeatus; e.g., and log-transformed geographic distances separating sampling locations.To compare the patterns of genetic variability and differentiation in SNP markers with those in microsatellite markers, we retrieved data from 40 microsatellite loci genotyped for these same populations . A simplTo validate estimates of allelic frequency from the pool-seq data, we genotyped a subset of 30 SNPs from each of the individual fish used for the pooled DNA analyses using the iPlex Gold\u00ae assay on the MassARRAY\u00ae platform (Sequenom) system. This genotyping was performed by the Technology Centre of the Institute for Molecular Medicine Finland at the University of Helsinki. Allele frequencies from this data were estimated with a custom Perl script and compared to estimates from pooled data as obtained using the procedures above.Sequences underlying this study have been deposited in NCBI\u2019s Sequence Read Archive and accession numbers are SRR1596320, SRR1596321, SRR1596322, SRR1596323, SRR1596324, SRR1596325, SRR1596326, SRR1596327, SRR1596328, and SRR1596329."} +{"text": "The International Federation of Gynecologists and Obstetricians (FIGO) has recently revised the staging of ovarian cancer . It inclThe standard of care for patients with newly diagnosed advanced ovarian cancer has been comprehensive staging laparotomy and primary optimal surgical cytoreduction followed by adjuvant chemotherapy. However, the use of neoadjuvant chemotherapy followed by interval debulking surgery (IDS) as a suitable alternative is supported by multicenter randomized controlled trials . ImagingCT is the primary imaging modality used to stage ovarian cancer. It is complimentary to surgical staging identifying possible sites of unsuspected disease such as pelvic peritoneum, paraaortic nodes, diaphragm and chest ,4. The t"} +{"text": "A 27-year-old immigrant sought care for inflammatory nodular swelling lesions over the right arm extending upto the neck with axillary and cervical fistulas lasting for six months (A). His medical history was marked by a long forest stay due to conflicts in his homeland . A deep biopsy was made for infectious and histopathological examinations. Cultures were negative. Microscopy on hematoxylin and eosin stained sections showed nodular abscesses organized around multilobated grains showing Splendore-Hoeppli Phenomenon (B). Special stains were positive. Thus, the histological diagnosis of actinomycetoma probably due to Nocardia was given. In addition, laboratory tests revealed an active hepatitis B infection. After consulting hepatologists, treatment with trimethoprim-sulfametoxazol was introduced, substituted by amoxicillin clavulanate for months with partial clinical response. The evolution was characterized by the reduction of right arm lesions but extension of the infection to the chest wall."} +{"text": "We urgently need new therapies to improve outcomes after cardiac arrest. Initial studies typically target surrogate endpoints, and these studies help to inform subsequent larger trials that are powered to measure more patient-orientated clinical outcomes such as survival. The competing risk of death and premature assessment of neurological prognosis pose significant challenges to measuring these surrogate endpoints after cardiac arrest. We urgently need new therapies to improve survival with good neurological outcomes after cardiac arrest . CardiacCritical Care, Donnino and colleagues present the results of a randomized controlled trial targeting one such surrogate endpoint, the reversal of shock after cardiac arrest [In this issue of c arrest . Specific arrest . The triHowever, some experts may offer other potential interpretations for the apparent lack of a biological effect, including timing of medication initiation or inclusion of patients without adrenal insufficiency. Another possible explanation is that many patients died before they could achieve shock reversal, rendering this surrogate endpoint unable to discriminate between responders and non-responders. Indeed, more than two-thirds (34/50) of patients died before hospital discharge, and it is unclear how many died before shock reversal . The resUsing a surrogate endpoint becomes even more problematic when it does not actually sit on the causal pathway. Ideally, a surrogate endpoint should have a clear relationship as an intermediate event occurring between the exposure of interest and the more meaningful clinical outcome , in thisCurrent evidence-based guidelines now recommend delaying neurological prognostication for at least 72\u00a0h after return of spontaneous circulation owing to the inaccuracy of clinical examinations performed before this time point . As a co"} +{"text": "It is now well established that gut flora and chronic liver diseases are closely interrelated. This association is most evident at late stages of the disease: cirrhosis and impaired liver function are associated with intestinal bacterial overgrowth, small bowel dysmotility, increased gut permeability, and decreased immunological defenses, all of which promote bacterial translocation from the gut to the systemic circulation, leading to infections that in turn aggravate liver dysfunction in a vicious circle . For a lNAFLD encompasses a spectrum of hepatic pathology . Accumulation of triglycerides in hepatocytes (hepatic steatosis) is the most common liver phenotype in NAFLD. Some individuals with hepatic steatosis develop nonalcoholic steatohepatitis (NASH), a more severe type of liver damage characterized by hepatic inflammation and liver cell death. In some individuals with the NASH phenotype, liver regeneration cannot keep pace with the increased rate of hepatocyte death, and liver scarring (fibrosis) ensues. Over time, some of these individuals accumulate sufficient fibrosis to develop cirrhosis. Because cirrhosis dramatically increases the risk for both primary liver cancer and overall liver-related mortality, liver cirrhosis is the NAFLD phenotype that has the worst prognosis. Epidemiologic studies indicate that NAFLD is now the most common cause of liver disease in many countries, including the United States . It is eClostridium coccoides [The first evidence that gut dysbiosis might be involved in NAFLD pathogenesis was provided by a few cross-sectional studies that evaluated the association between gut microbiota and the liver phenotype in NAFLD patients. Using quantitative polymerase chain reaction (qPCR) for selected bacteria in a small cohort of 50 patients , Mouzaki et al. showed that NASH patients had decreased fecal Bacteroidetes and increased occoides . The negBlautia and Faecalibacterium genera. The increase in Proteobacteria was mainly explained by an increased abundance of Enterobacteriaceae, especially Escherichia, which was the only abundant genus within the whole bacteria domain exhibiting a significant difference between the obese and the NASH groups. Interestingly, Escherichia are known alcohol-producing bacteria, and serum alcohol concentration was significantly higher in NASH patients compared to obese or control groups.Zhu et al. screened the whole gut microbiota using 16S ribosomal RNA pyrosequencing in a pediatric cohort of 63 children that included 16 healthy controls, 25 obese subjects without known liver disease, and 22 patients with biopsy-proven NASH . They foThe Mouzaki and Zhu studies may seem quite conflicting, the first showing a decrease in Bacteroidetes and the second an increase. However, different populations were studied using different approaches (qPCR versus pyrosequencing). Both works were also limited by small sample size. Thus, further studies including larger and well-characterized cohorts are required to better identify the associations between gut microbiota and the various liver phenotypes observed in NAFLD.Cross-sectional studies allow for the discovery of potential associations between liver phenotype and certain gut bacteria, but they cannot establish a causal link. By using gut microbiota manipulations, recent animal studies have demonstrated direct roles for gut microbiota in each liver lesion observed in NAFLD: steatosis, NASH, fibrosis, and liver cancer.Conventional C57BL/6J mice fed with a high-fat diet (HFD) for 16 weeks generally display liver steatosis, hyperglycemia, and systemic inflammation (responders), but some mice are nonresponders, developing no metabolic disorder with this dietary manipulation . To explInterindividual differences in the intestinal microbiome and severity of NASH, a more serious NAFLD phenotype, have also been linked. Targeted disruption of the NLRP3 or NLRP6 inflammasome altered the gut microbiota and was associated with enhanced colonic inflammation and NASH in mice fed methionine-choline-deficient-diets . By studGut microbiota can also promote liver fibrosis, a known risk factor for NAFLD-related cirrhosis. In a recent study, mice fed a HFD before bile duct ligation (BDL) developed more severe liver fibrosis than control mice that were fed a standard chow diet before BDL . HFD-relA recent study established a link between the gut microbiota and NAFLD-related hepatocellular carcinoma . NeonataThere are thousands of bacterial species in the gut, and they all display an incredibly wide range of metabolic functions. Now that we realize that gut microbiota modulate NAFLD-related pathophysiology, the challenge is to decipher the mechanisms by which they exacerbate NAFLD severity . As mentNAFLD is associated with a higher prevalence of gastro-oesophageal reflux that reqIn summary, NAFLD is an extremely common, complex disease that results from interactions between susceptible polygenic backgrounds and environmental factors. Recent evidence has introduced gut microbiota as a new crucial player in this complex story. Deciphering the mechanisms linking gut microbiota to NAFLD and its severity will advance understanding of the disease\u2019s pathogenesis, thereby identifying new therapeutic targets that will ultimately improve the outcome in patients with this disease."} +{"text": "Injury to the central nervous system (CNS) results in oligodendrocyte cell death and progressive demyelination. Demyelinated axons undergo considerable physiological changes and molecular reorganizations that collectively result in axonal dysfunction, degeneration and loss of sensory and motor functions. Endogenous adult oligodendrocyte precursor cells and neural stem/progenitor cells contribute to the replacement of oligodendrocytes, however, the extent and quality of endogenous remyelination is suboptimal. Emerging evidence indicates that optimal remyelination is restricted by multiple factors including (i) low levels of factors that promote oligodendrogenesis; (ii) cell death among newly generated oligodendrocytes, (iii) inhibitory factors in the post-injury milieu that impede remyelination, and (iv) deficient expression of key growth factors essential for proper re-construction of a highly organized myelin sheath. Considering these challenges, over the past several years, a number of cell-based strategies have been developed to optimize remyelination therapeutically. Outcomes of these basic and preclinical discoveries are promising and signify the importance of remyelination as a mechanism for improving functions in CNS injuries. In this review, we provide an overview on: (1) the precise organization of myelinated axons and the reciprocal axo-myelin interactions that warrant properly balanced physiological activities within the CNS; (2) underlying cause of demyelination and the structural and functional consequences of demyelination in axons following injury and disease; (3) the endogenous mechanisms of oligodendrocyte replacement; (4) the modulatory role of reactive astrocytes and inflammatory cells in remyelination; and (5) the current status of cell-based therapies for promoting remyelination. Careful elucidation of the cellular and molecular mechanisms of demyelination in the pathologic CNS is a key to better understanding the impact of remyelination for CNS repair. Cnp1, which encodes 2\u2032,3\u2032-cyclic nucleotide phosphodiesterase in oligodendrocytes, show no structural abnormality in myelin but develop axonal swelling and degeneration (Myelin is a cholesterol rich extension of oligodendrocytes and Schwann cells (SCs) plasma membrane, which serves as a specialized insulation sheath for axons in the nervous system. Myelin facilitates axon signal conduction through enabling \u201csaltatory conduction\u201d (see review by neration . These sneration . Survivaneration . ConsideOligodendrocyte precursor cells (OPCs) and neural stem/progenitor cells (NPCs) are two endogenous cell populations, capable of replacing lost oligodendrocytes and remyelinating spared axons following injury . DespiteShiverer mice that lack MBP demonstrate dysmyelinated axons associated with axonal dysfunction and motor impairments . Node of Ranvier is the gap between two adjacent myelin sheaths and contains high concentrations of voltage-dependent Na+ channels on the axonal membrane and KCNQ K+ channels . Among these molecules, \u03b2IV-spectrin and ankyrin G play a major role in stabilizing the Nav channels at nodal region .In myelinated axons, node of Ranvier was characterized by the localization of voltage-gated sodium .Paranode is the adjacent segment to the node of Ranvier where myelin loops provide an anchor by tethering the myelin to the axonal membrane . Evidencmembrane . The parmembrane . Caspr imembrane . Caspr dmembrane . Upon receiving of an action potential, Nav channels open, allowing an influx of Na+ into the axon causing depolarization. After each depolarization, Na+/K+ ATPase pumps, located at the juxtaparanodal and internodal regions, exchange axonal Na+ for extracellular K+ . Sodium channel redistribution causes an overall increase in Na+ influx during impulse conduction and increased demand for ATP during repolarization . Inhibition of sodium channels and NCX has been shown to prevent axonal degeneration , a marker for axonal injury, whereas it is only expressed in 20% of axons, which are \u03b2-APP negative . Our investigations on dysmyelinated Shiverer mice and Long Evans Shaker (LES) rats elucidated the role of K+ channels in axonal function and non-specific (4-AP) blockers improved axonal conductance; however, this effect was shown to be more dependent on a combination of subunits as a specific blocker of Kv1.1 failed to improve axonal conduction significantly axons showed 2.2-fold increase in the size of stationary mitochondria sites and 47% increase in the velocity of motile mitochondria following demyelination showed normal OPC proliferation, differentiation and initiation of myelination. However, these FGF receptor null animals demonstrated defective myelin thickening during postnatal period and remained defective throughout their adulthood is another growth factor known to promote OPCs survival, migration, and differentiation into mature myelinating oligodendrocytes . Nrg-1 iCurrent evidence shows that remyelination is additionally limited by inhibitory modifications in the post-SCI niche caused by secondary injury mechanisms particularly in chronic SCI . Newly fin vitro and in vivo , Wnt signaling, and Semaphorin 3A (Sema3A) . LINGO-1Collectively, these findings demonstrate that endogenous remyelination was impeded by the inhibitory microenvironment following injury and activated astrocytes and microglia/macrophages seem to play pivotal roles in this inhibition. We will discuss recent studies on the role of resident glial cells and peripherally recruited immune cells in modulating oligodendrocyte replacement and remyelination following CNS injury.Astrocytes play critical role in several aspects of myelination in pathologic CNS including clearance of myelin debris, modulating the activity of oligodendrocytes, myelin maintenance, and renewal . Using aIntercellular connections between astrocytes and oligodendrocytes are critical for the proper physiology of oligodendrocytes. While there are no gap junctions between oligodendrocytes themselves, they are connected to astrocytes through gap junctions, which make oligodendrocytes indirectly interconnected . EvidencAstrocytes provide trophic support to oligodendrocytes by producing growth factors. In an ethidium bromide (EB) induced rat model of spinal cord demyelination, In vivo and in vitro observations have shown that CSPGs limit the ability of OPCs to migrate, mature and myelinate axons , a Toll-like receptor-4 (TLR-4) agonist, caused a significant increase in NG2feration . Interesferation . Of noteferation .Several mechanisms have been proposed for the positive role of macrophages in remyelination. Among the main proposed mechanisms are removal of myelin debris and prodAltogether, evidence indicates that the type of immune response is a determining factor that can promote or inhibit remyelination in demyelinating CNS lesions , these studies have suggested that remyelination is a key mechanism in promoting functional recovery following SCI and demyelinating conditions . When we transplanted brain-derived NPCs into the spinal cord of subacutely injured rats, we found that survival and oligodendrocyte differentiation of NPCs was limited in the injury microenvironment . Similarly, in our rat SCI studies, evidence of NPC-derived remyelination was confirmed with immunoelectron microscopy against YFP expression in transplanted YFP-NPCs in enhancing oligodendrocyte differentiation and maturation has been established in the CNS and PNS . GeneticAltogether, current evidence suggests that NPCs can be engineered to act as environmental modulators in addition to their role in cell replacement. This strategy presents a therapeutic avenue for improving microenvironment and optimizing the outcome of cell transplantation in CNS trauma and demyelinating diseases.Due to challenges with oligodendrocyte differentiation of NPCs, transplantation of differentiated glial-restricted precursors (GRP) and OPCs has been pursued in SCI and demyelinating conditions . Early sApplication of OPCs has also shown promising results in supporting remyelination. The potential of human ESC derived OPCs for remyelination has been evaluated in animal models of SCI and demyelination . These sOne important outcome of the Keirstead study was the inability of transplanted OPCs to remyelinate chronically demyelinated axons despite their survival and the capacity to differentiate into oligodendrocytes . This evEfficacy of transplanted OPCs has also been investigated in chronic demyelinating conditions. Transplantation of mouse ESC derived OPCs into a radiation induced rat model of cervical spinal cord demyelination 4 months after radiation therapy, showed successful survival, and migration of these cells toward the lesion and their capacity for oligodendrocyte remyelination . MoreoveIn addition to their role in replacing remyelinating oligodendrocytes, OPCs are known to enhance axo-neuronal growth and survival by producing growth factors such as brain derived neurotrophic factor (BDNF), IGF-1, glial derived growth factor (GDNF), neuregulins (NRGs), and neurotrophins that potOlfactory ensheathing cells (OECs) have been extensively examined for their potential for remyelination after SCI and demyelinating lesions . OECs arStudies by Another study in nonhuman primate demonstrated the ability of OECs to remyelinate spinal cord axons following demyelination lesions . In thisSince SCs and OECs demonstrate similar characteristics, their behavior and response have been compared in demyelinated spinal cord in co-transplantation studies , 2014. IWhile extensive evidence suggests a direct role for OECs in axonal ensheathing and remyelinating, there are also some reports that have questioned their myelinating capability in SCI . Boyd etRegardless of their direct role in axonal remyelination, OECS are shown to recondition injury environment by producing a host of trophic factors including NGF, BDNF, and CNTF that can support endogenous repair . Studiesin vitro and in vivo studies using specific markers of OECs and SCs is required to specifically distinguish these two cell populations and confirm the myelinating capacity of OECs.Collectively, while application of OECs has shown promising results in experimental models of SCI and demyelination, the ability of OECs for CNS remyelination is still a matter of debate due to their similarities with SCs and potential contamination of OEC cultures with SCs. Further While cell translation is a promising approach for enhancing remyelination following injury, graft rejection due to the host immune reaction poses a major challenge to the success of cell-based therapies . SuccessGeneration of induced pluripotent stem cells (iPSCs) using autologous somatic cells has opened new avenues for developing clinically feasible cell transplantation approaches . Since tin vitro (Shiverer mice, human iPSC-derived OPCs integrated with the host neonatal brain tissue after transplantation, differentiated to MBP expressing oligodendrocytes, remyelinated the dysmyelinated Shiverer axons, and constructed the nodes of Ranvier (Shiverer mice exhibited increased lifespan (Remyelination has been considered as a mechanism underlying the functional improvement observed in iPSCs transplantation strategies . A recenin vitro . In immu Ranvier . No tumolifespan .Table 1, we have listed cell therapies that have been developed to promote oligodendrocytes replacement and remyelination after SCI and MS conditions.Taken together, emerging evidence shows the potential and feasibility of transplanting iPSCs derived NPCs and OPCs for promoting oligodendrocyte replacement and remyelination in demyelinating conditions such as MS and traumatic CNS injury. While promising, the risk of tumorigenicity and proper cell differentiation of this therapy have yet remained to be carefully investigated. In The myelin sheath is an essential component in the CNS and PNS that ensures rapid signal transduction in axons through the nervous system. Myelinated fibers show a highly specialized and organized structure at the node of Ranvier that is vital to their proper functioning. Damage to oligodendrocytes due to trauma or disease results in demyelination that causes aberrant localization and expression of ion channels associated with axonal dysfunction. Although considerable remyelination occurs spontaneously by endogenous CNS progenitor cells, the quality and extend of myelination is not optimal to restore structural and physiological properties of injured axons. Emerging research evidence has uncovered several mechanisms by which oligodendrocyte differentiation and remyelination are regulated within the microenvironment of injury. Inhibitory role of activated glial cells and insufficient expression of promoting factors are major limiting factors that impede remyelination. Over the past years, extensive research efforts have been made to therapeutically promote remyelination following CNS trauma or demyelinating disease. Outcomes of the recent pharmacological and cell-based therapies indicate the impact of remyelination as a mechanism for improving function after injury. Further investigations are needed to develop effective and feasible repair strategies with potential for clinical translation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Hippocrates famously advised, \u201cLet food be thy medicine and thy medicine be thy food.\u201d Numerous plant-derived compounds are used as cancer therapeutics including antimitotics, topoisomerase inhibitors, and kinase inhibitors. Here we will review emerging evidence suggesting that diet derived small RNAs may be an inexpenisive, non-invasive and affordable way to deliver cancer treatments.RNA interference (RNAi), the use of short double-stranded RNA sequences to silence endogenous genes is emerging as the next generation of therapeutics. A well-designed RNAi molecule is able to differentially silence a mutated oncogene with just a single mutated base, leaving the wild-type unaffected. Further, due to the use of intrinsic cellular mechanisms for gene silencing, RNAi exerts an amplified stoichiometric effect, suppressing expression of thousands of mRNA transcripts per RNAi molecule. The challenge with the use of RNAi therapeutics remains their efficient uptake and transportation to target cells. Various delivery techniques are being investigated including viral delivery, engineered nanoparticles and modified nucleic acid chemistry. Each method faces a unique set of challenges including efficiency, safety, and immunogenicity. Utilization of therapeutics by the oral route promises low costs, minimal invasiveness, and high compliance, making this the holy grail of delivery methods.In 2012, a study demonstrated a dietary microRNA (miRNA) from rice was packaged and systemically circulated in consuming mice to silence a liver gene . Our worCells are known to release small vesicles (exosomes and microvesicles) from their membranes, packaging and protecting their contents . Though the biological role of these vesicles is still being explored, the packaging of specific subsets of cellular molecules suggests that exosomes function as mediators of systemic intercellular communication. Recent examples have also suggested that exosomes are able to cross barriers between species. Reports have described the detection of cow's milk-derived miRNAs in serum of the consumers at physiologically relevant concentrations . In mousC. elegans has been well described and transporters for these small RNAs characterized. Animal genomes contain sequences that are homologous to those responsible for the systemic RNAi effect seen in C. elegans. Could we impact dietary miRNA uptake by altering the localization and kinetics of these putative endogenous transporters? We favor a model where therapeutic plant-based miRNAs within the plant matrix display enhanced bioavailability compared to synthetic plant-based miRNAs. Scientists are in the process of expressing therapeutic miRNAs in crops plants to assess efficacy of these engineered foods fed to patients.The future of dietary miRNAs as therapeutics requires new tool development and mechanistic insights regarding uptake and delivery. Dietary miRNA studies are confounded by high variation and low copy number detection. These issues need to be addressed with judicious and standardized detection methods. Use of sensitive tissue sensors will help identify both the presence and functionality of low-level absorbed miRNAs. Dietary RNAi function in In addition, the milk-based approach to therapeutic miRNA delivery may prove especially useful in infants. The developing fetus and newborns may lack acquired \u2018protective' mechanisms in the gut that deter small RNA uptake in adults. Perhaps nature has already provided an ideal mechanism for the safe and efficient delivery of next generation therapeutics, allowing us to rekindle the notion of using foods as medicine."} +{"text": "Stenting of conduit stenoses are more commonly reported[2].Although percutaneous placement of intravascular stents in congenital heart disease is a common practice, there are few reports regarding native right ventricular outflow tract (RVOT) stenting in children In the preoperative setting, palliation of significant cyanosis by balloon valvuloplasty or RVOT stenting has been advocated by some as a means for reducing symptomatic cyanosis in patients with severe annular hypoplasia. Improvement in antegrade flow is thought to simultaneously enhance pulmonary arterial growth by augmenting pulmonary blood flow. [3]. Most of transcatheter interventions for relieving RVOT were done for conduit stenosis. There are few reports about native RVOT stenting, and to the best of our knowledge there are very few reports on native RVOT stenting in tetralogy of fallot (TOF) with absent left pulmonary artery A 9-year-old child was admitted with cyanosis noted from birth with failure to thrive, cyanotic spells and worsening cyanosis. The patient had undergone central modified Blalock- Tausig (MBT) shunt and right MBT shunt at the ages of three and six respectively. At this admission the child weighed 17 kg, had severe systemic desaturation (<55%) and severe cyanosis, digital clubbing and a New York Heart Association (NYHA) classification of class IV. Clinical examination revealed unremarkable pulmonary examination and 3/6 systolic heart murmur at pulmonary focus. EKG revealed normal sinus rhythm, right axis deviation and severe right ventricular hypertrophy (RVH). Echocardiography showed TOF anatomy, severe RVOT stenosis with 75 mmHg pressure gradient, RVH, abscent left pulmonary artery branch (LPA), non-functioning previous MBT shunts and major collateral arteries originating from descending aorta. On catheterization, both previous MBT shunts were occluded, the right pulmonary artery (RPA) was small with fairly acceptable arborization. Left lung was supplied by major collateral arteries originating from descending aorta and severe RVOT stenosis was present . RVOT st The arterial oxygen saturation rose to 83%. At six-month follow-up, his arterial oxygen saturation was maintained at above 80% and NYHA functional class was improved to class II. Palliative procedures for relieving RVOT stenosis include either surgical or transcatheter interventions. The indications for RVOT stenting are RV-to-PA conduit stenosis, residual infundibular stenosis after intracardiac repair, TOF with hypoplastic branch pulmonary arteries after palliative shunt surgery, pulmonary atresia after perforation of atretic segment, and RV hypertrophic cardiomyopathy and also as a bridge to surgery. RVOT stenting is also usually indicated in cases in those patients who are not amenable to total surgical repair. Our patient had absent LPA, small RPA and poor clinical condition. Thus, we carried out percutaneous RVOT stenting.RVOT stenting in such patients theoretically can lead to two major problems: overflow and edema of the right lung with resultant vasculopathy in the long term, and free pulmonary valve regurgitation with its consequences that include right ventricular dilatation and dysfunction. In our case, none of these complications occurred, because we chose the stent size with scrutiny and we did not sacrifice the pulmonary valve. Also we did not have complications such as stent migration, ventricular arrhythmias, collapse or fracture of the stent and recurrent stenosis during follow up. To our knowledge the patient has not undergone any curative operation by now. RVOT stenting provides an effective palliative modality for children with TOF and unfavorable pulmonary artery anatomy. Although re-stenosis can occur but it responds to re-dilatation.[4]. In conclusion native RVOT stenting is an effective and safe procedure in appropriately selected patients, especially in whom total correction is not possible. This procedure causes better growth of pulmonary artery branches, decreases right ventricular hypertrophy and increases left ventricular volume. Although many of these stents cannot be dilated to adult size, their efficacy in small infants and children in whom further surgery will ultimately be required is remarkable. In high risk patients such as our patient with severe cyanosis and high hemoglobin level and blood viscosity, the RVOT stenting decreases perioperative morbidity and mortality"} +{"text": "Impaired mucociliary clearance (MCC) is a hallmark of acquired chronic airway diseases like chronic bronchitis associated with chronic obstructive pulmonary disease (COPD) and asthma. This manifests as microbial colonization of the lung consequently leading to recurrent respiratory infections. People living with HIV demonstrate increased incidence of these chronic airway diseases. Bacterial pneumonia continues to be an important comorbidity in people living with HIV even though anti-retroviral therapy has succeeded in restoring CD4+ cell counts. People living with HIV demonstrate increased microbial colonization of the lower airways. The microbial flora is similar to that observed in diseases like cystic fibrosis and COPD suggesting that mucociliary dysfunction could be a contributing factor to the increased incidence of chronic airway diseases in people living with HIV. The three principal components of the MCC apparatus are, a mucus layer, ciliary beating, and a periciliary airway surface liquid (ASL) layer that facilitates ciliary beating. Cystic fibrosis transmembrane conductance regulator (CFTR) plays a pivotal role in regulating the periciliary ASL. HIV proteins can suppress all the components of the MCC apparatus by increasing mucus secretion and suppressing CFTR function. This can decrease ASL height leading to suppressed ciliary beating. The effects of HIV on MCC are exacerbated when combined with other aggravating factors like smoking or inhaled substance abuse, which by themselves can suppress one or more components of the MCC system. This review discusses the pathophysiological mechanisms that lead to MCC suppression in people living with HIV who also smoke tobacco or abuse illicit drugs. With the introduction of combination antiretroviral therapy (cART) dramatic declines in morbidity and mortality from HIV/AIDS have been seen can directly regulate MCC and this is evident in diseases like primary ciliary dyskinesia where attenuated ciliary beating leads to cough, infection, and airway obstruction and CBF activation rely on the common adenylate cyclase/cAMP/PKA pathway for activation making this pathway critical in maintenance of optimal MCC. HIV infection, environmental stimuli/pollutants like cigarette smoke and smoked substance abuse like crack cocaine, marijuana, methamphetamine can affect one or more components of the MCC system facilitating microbial colonization leading to recurrent lung infections and chronic airway diseases.CO (Diffusing capacity of the lung for carbon monoxide), and anatomic and radiographic emphysema , a significant proportion of HIV-infected individuals are cigarette smokers or smoked substance abusers . Almost 60% of People living with HIV are also smokers . Cocaine was also shown to suppress Cl\u2212 efflux in response to CFTR potentiators like \u03b22-agonsits and CBF depend on the adenylate cyclase/cAMP/PKA pathway. Hence therapeutics that potentiate this pathway can be used to restore MCC in HIV infected individuals and/or smoked substance abusers Figure . \u03b22-adre van As, , activat van As, , and con van As, . AlternaNormal mucociliary function fails with dysfunction of any one of the major components of the MCC apparatus namely mucus production, ciliary beating, and ASL depth maintenance fail. Suppression of MCC leads to an inefficient clearance of pollutants, pathogens, and allergens. This leads to chronic inflammation and microbial colonization which manifests as chronic airway diseases like asthma, chronic bronchitis associated with COPD, and recurrent lung infections pervasive in HIV infected individuals and/or smoked substance abusers. Smoked substance abuse can suppress MCC independently and an underlying HIV infection can have an additive effect as each of these can suppress one or more components of MCC system. Under these conditions, therapeutics that can restore CFTR function or CBF can restore MCC and prevent microbial colonization consequently decreasing the incidence of pneumonia in People living with HIV.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "V600BRAF mutant melanoma, but acquired resistance is almost universal. Early understanding of how melanomas acquire resistance to BRAFi via MAPK pathway reactivation has guided the development of specific BRAFi-anchored inhibitor combinations designed to overcome resistance. The first of these successful combinations has been between BRAF and MEK inhibitors. Combined BRAF/MEK targeted therapy improves upon BRAFi therapy but is still beset by acquired resistance. Thus, studying how melanomas escape from BRAFi and how these processes are similar or distinct from acquired resistance mechanisms to BRAFi+MEKi remains of the utmost importance to melanoma therapeutics. Recent whole-exome analysis of patient-paired melanoma samples obtained pre-BRAFi treatment and post-disease progression after initial responses have provided landscape genetic perspectives into the nature of tumor heterogeneity, clonal evolution, and core resistance pathways. This benchmark understanding is helping to guide and prioritize clinical studies of BRAFi-based combinations such as that between BRAFi and AKTi. Recent work on the genetic mechanisms of acquired BRAFi+MEKi resistance has shed key insights into the molecular limitations of this therapeutic approach but also novel therapeutic opportunities. Overall, genetic alterations affecting individual genes are not highly recurrent and collectively cannot account for a significant subset of clinical acquired resistance to BRAF or combined BRAF/MEK targeted therapies (MAPKi). Thus, understanding the entire spectrum of genetic and non-genetic mechanisms of acquired MAPKi resistance and the temporal continuum of these evolutionary processes promises to usher in a new era of personalized medicine for melanoma patients.BRAF inhibitors (BRAFi) elicit rapid antitumor responses in the majority of patients with"} +{"text": "The existing clinical biomarkers for prostate cancer (PCa) are not ideal, since they cannot specifically differentiate between those patients who should be treated immediately and those who should avoid overtreatment. Current screening techniques lack specificity, and a decisive diagnosis of PCa is based on prostate biopsy. Although PCa screening is widely utilized nowadays, two-thirds of the biopsies performed are still unnecessary. Thus, the discovery of noninvasive PCa biomarkers remains an urgent unmet medical need. Once metastasized, there is still no curative therapy. A better understanding of sustained androgen receptor signalling in castration resistant prostate cancer (CRPC) has now led to the development of more effective therapies. We need a better understanding of the molecular and cellular aspects of prostate carcinogenesis and progression. Identification of cancer initiating cells and therapies against these populations is a promising way forward to fight this disease."} +{"text": "During the last decades research all over the world has highlighted the deleterious effects of pollution on respiratory health of adults and children. Nevertheless, air pollution still represents a significant threat to health. Children are more sensitive than adults to pollutants for several factors: increased respiration relative to body size; physiologic immaturity of respiratory and immunologic systems; low metabolic capacity; longer life expectancy.2), ozone (O3), sulfur dioxide (SO2), may provoke cytotoxic and functional damages in the airways through oxidative stress and inflammation. During the last decades the amount of pollutants from vehicular traffic has significantly increased, especially in urban areas. Recent epidemiological studies have shown that vehicular traffic represents the main source of outdoor pollutants and that it may increase the risk of respiratory outcomes in children through short-term and long-term effects on airways, lung function and allergic sensitization [Several studies demonstrated an association between exposure to outdoor pollutants and respiratory diseases in childhood. Outdoor pollutants, such as nitrogen oxides (NOx), particulate (PM), carbon monoxide (CO), carbon dioxide . Indoor pollutants concentration depends on external environmental pollutants filtered inside buildings, pollutants generated inside buildings (domestic work) and pollutants generated by personal activities. Combustion products (tobacco smoke and wood burning), CO, CO2, volatile organic compounds (VOC), microbial agents , organic products are the most important indoor pollutants. There is growing epidemiological evidence that indoor allergen exposure may contribute to the development of allergic respiratory symptoms, such wheezing, coughing and asthma in children [third-hand smoke\u2019 (THS), represents a new concept in the field of tobacco control [Tobacco smoke is one of the environmental pollutants influencing morbidity and death rate in childhood as it is responsible for adverse health effects in both prenatal and postnatal life. Homes remain a site where children are dangerously exposed to environmental tobacco smoke (ETS). The combination of tobacco smoke pollutants which remain in an indoor environment, the so-called \u2018 control .Children still need to be protected with strict air quality standards, in order to improve their respiratory health. Therefore, policies that ensure better air quality are strongly desirable all over the world."} +{"text": "Recent studies report promising results regarding extracorporeal magnetic separation-based blood purification for the rapid and selective removal of disease-causing compounds from whole blood. High molecular weight compounds, bacteria and cells can be eliminated from blood within minutes, hence offering novel treatment strategies for the management of intoxications and blood stream infections. However, risks associated with incomplete particle separation and the biological consequences of particles entering circulation remain largely unclear. This article discusses the promising future of magnetic separation-based purification while keeping important safety considerations in mind. The direct removal of disease-causing compounds is an inherently attractive treatment modality for a range of pathological conditions, including intoxications and blood stream infections . While lMagnetic separation-based blood purification is especially attractive for the removal of high molecular weight compounds, which are poorly removed by conventional (diffusion-based) blood purifications systems Fig.\u00a0 2]. The. The2]. 18 single particles). Magnetic measurements for ultrasensitive magnetic nanoparticle detection are now increasingly being explored, which would allow detection of off-target accumulation of nanomaterial and biodegradation of nanomaterials, which in turn could initiate acute and long-term effects such as tumorigenesis, fibrosis and toxic effects.When bringing magnetic blood purification processes closer to clinical evaluation, safety of operation becomes pivotal. Extracorporeal blood purification has been suggested previously to provide a possible alternative to direct in vivo application (injection) of magnetic nanoparticles and to prevent off-target accumulation of magnetic capturing agents (e.g. in the liver or lung). Recent studies have shown that the capturing efficiency of magnetic iron oxide nanoparticles is significantly decreased under clinically desirable blood flow rates, thereby potentially compromising the procedure\u2019s efficiency and safety . Blood fOther important safety aspects include non-specific adsorption of blood constituents as well as activation of inflammatory reactions in the blood compartment . Such poUnfortunately, there is an ever growing disequilibrium between manuscripts reporting on the synthesis of new nanomaterials and their promising applications and studies actually performing comprehensive risk evaluation of the synthesized materials . At presIn summary, extracorporeal magnetic separation-based blood purification is a promising strategy to rapidly and selectively remove high molecular weight compounds from blood. The technique has been successfully evaluated in vivo in experimental settings investigating the clinically relevant scenarios of intoxication and sepsis in rat models . However"} +{"text": "Tissue-engineering technologies have progressed rapidly through last decades resulting in the manufacture of quite complex bioartificial tissues with potential use for human organ and tissue regeneration. The manufacture of avascular monolayered tissues such as simple squamous epithelia was initiated a few decades ago and is attracting increasing interest. Their relative morphostructural simplicity makes of their biomimetization a goal, which is currently accessible. The mesothelium is a simple squamous epithelium in nature and is the monolayered tissue lining the walls of large celomic cavities and internal organs housed inside. Interestingly, mesothelial cells can be harvested in clinically relevant numbers from several anatomical sources and not less important, they also display high transdifferentiation capacities and are low immunogenic characteristics, which endow these cells with therapeutic interest. Their combination with a suitable scaffold may allow the manufacture of tailored serosal membranes biomimetics with potential spanning a wide range of therapeutic applications, principally for the regeneration of simple squamous-like epithelia such as the visceral and parietal mesothelium vascular endothelium and corneal endothelium among others. Herein, we review recent research progresses in mesothelial cells biology and their clinical sources. We make a particular emphasis on reviewing the different types of biological scaffolds suitable for the manufacture of serosal mesothelial membranes biomimetics. Finally, we also review progresses made in mesothelial cells-based therapeutic applications and propose some possible future directions. Tissue engineering has emerged as a promising alternative to conventional medicine to achieve the healing and regeneration of human damaged tissues and organs. The manufacture of functionally optimal bioartificial tissues is an extremely complex process relying on a comprehensive stepwise combination of cells with scaffolds, extracellular matrices (ECM), and molecular signals. The achievement of such objective usually relies on the combination of advanced knowledge and skills from interdisciplinary specialists, making tissue engineering one of the most challenging fields of biomedical research.Elaborated bioartificial soft tissues and inclusively some bioartificial organs are under current experimental development and evaluation in laboratories and the surface of celomic visceral organs and water channels (aquaporins) used in experimental animal models for human inflammatory diseases. Their protective effects was found to be largely attributed to their hypoimmunogenicity and capacity to regulate innate immune cells functions through secretion of soluble and membrane-bound factors with potent immunosuppressive and/or immunomodulatory activities .+ and CD8+ T lymphocytes (T cells), through their secretion of the immunosuppressor TGF-\u03b2 to harvest mesothelial cells. Due to its largest size, the abdominal cavity is the predominant anatomical source from where mesothelial cells are harvested. Specific peritoneal sources and isolation procedures are reviewed below.2. Like other visceral mesotheliums, the omental mesothelium displays a high cellularity and can provide around one million mesothelial cells from each square centimeter of omental tissue could significantly improve their healing and reduce the score of peritoneal adhesions , which is the parietal mesothelium of the testicular cavity, has been identified as another reliable source of mesothelial cells derived from plants or animals are highly sophisticated molecules that emerged from millions of years of natural evolution. They are usually endowed with desirable properties such as high degradability, excellent biocompatibility, and biomechanical properties such as elasticity, tensile strength, and transparency, which make them excellent candidate materials in biomedical engineering applications . We below review different types of biologic materials that have been previously proposed or used in tissue engineering of diverse types of simple squamous epithelia or related tissues to generate scaffold with a desired form, porosity, and stiffness. Furthermore, and not less important, the polymer chitosan is particularly rich in chemical side groups, that allow covalent binding with other biomaterials to produce biodegradable biocomposites with increased strength and cell adhesion potential is considered as a new bioengineering treasure by a majority of the biomedical community. Its outstanding biophysical and biochemical properties such as robustness, flexibility, biocompatibility, biodegradability, and processing properties have prompted a general interest for its use in tissue-engineering applications . The prBioartificial functionalized SF fibrous scaffolds have been yet applied for tissue engineering of vascular endothelium and corneal endothelium biomimetics , or scaffolds subjected to posterior treatments (cross-linking) to improve their mechanical properties, can however lose biological properties such as poor cells adhesion index and may require surface treatments with basement membrane proteins. In that sense, different tissue-engineering applications aimed at reproducing and fixing a synthetic basement membrane on top of biologic or synthetic scaffolds to improve adhesive and functional properties of their surface. As example, a study demonstrated that electrospun SF/polycaprolactone meshes posteriorly coated with major basement membrane proteins such as collagen IV, laminins, entactins, and proteoglycans could improve The cellular homogeneity and density achieved in a bioengineered mesothelium or in other types of simple squamous epithelial-like tissues are two critical parameters. The static cell-seeding technique, which basically consists in the manual pipetting of a concentrated cells suspension onto the scaffold, has been shown to be a convenient approach for the establishment of mesothelial cells layers , this \u201csmart polymer\u201d is capable of hydrophobic to hydrophilic reversible transition in response to temperature changes. By only decreasing the culture temperature below its lower critical solution temperature (LCST) that is around 32\u00b0C in pure water, PNIPAAm become hydrophobic, and consequently force the release of cells monolayer from the dishes represents the main clinical strategy to prevent or reduce post-operative peritoneal adhesions .The development of new adhesion barriers remains however under current research due to the partial effectiveness of the commercially available adhesion barriers. A host of experimental approaches involving pharmacologic treatments and anti-adhesive polymers or molecules promoting endogenous mesothelialization are also under intense research arterial grafts seeded with mesothelial cells however generated markedly divergent outcomes, suggesting that the adhesion capacity of mesothelial cells on this type of synthetic material is reduced and thus strongly influences their long-term patency . Thin membranes created from electrospun bombyx mori silk fibroin (BMSF) are transparent and were shown to support the growth of human corneal epithelial (HCE) cells is made up of two types of synoviocytes: \u201cphagocytic or absorptive\u201d macrophage-like cells (Type A) and \u201csecretory\u201d fibroblast-like synoviocytes (Type B), these later accounting for around 80% of the total intimal cells Smith, . SynoviaInterestingly, a careful revision of the literature provides evidence of phenotypic similarities between fibroblast-like synoviocytes and mesothelial cells. Hence, both cellular phenotypes are mesodermal epithelial-like cells which display abundant microvilli on their apical membrane, a structural feature that is commonly found in cells secreting fluid Smith, . In addiThe evidence of phenotypic similarities between fibroblast-like synoviocytes and mesothelial cells stated above could lead to the suggestion that mesothelial cells may represent a putative cellular surrogate of fibroblast-like synoviocytes and suggest thus that mesothelial cells could be potentially useful for the regeneration of the synovial membrane lining.The vestibular duct is a small cavity filled with perilymph inside the cochlea of the inner ear. The scala vestibuli is separated from the scala media by a very thin membrane termed vestibular membrane or Reissner\u2019s membrane. The Reissner\u2019s membrane facing the scala vestibuli is covered by a monolayer of mesothelial cells. The opposite side facing the cochlear duct a cavity filled by endolymph is covered by an epithelium. A thin basal lamina separates the mesothelium and epithelium layers : Structural molecules produced by cells and excreted to the extracellular space within the tissues and that provide cohesive structure to hold tissues together.Great omentum: A large fold of the peritoneum hanging down from the stomach and containing abundant vasculature and perivascular adipose tissue.Heterologous transplant: Cells, grafts, or tissues derived from an individual of a different species in which they are transplanted, being therefore antigenically dissimilar.Immunomodulation: The adjustment of the immune response to a desired level through immunopotentiation, immunosuppression, or induction of immunologic tolerance.Immunosuppression: Reduction of the immune response, generally through the use of drugs, active molecules, or cells to prevent grafts rejection or control autoimmune diseases.Lineage tracing study: Identification and follow-up of all progeny of a single cell using different experimental strategies available for lineage tracing such as live-cell imaging, fluorescent reporter constructs, inducible gene expression, and inducible recombinases.Matrix: The intercellular substance of a tissue or the tissue from which a structure develops.Mesoderm: One of the three primary germ layers developing in the early embryo.Mesothelial cells: A type of simple squamous epithelial cells lining the walls of celomic body cavities and visceral organs located inside.Mesothelioma: Tumor arising from malignant transformation of mesothelial cells.Myofibroblast: A fibroblastic cell with some contractile properties and that is usually considered an intermediate cell between fibroblasts and smooth muscle cells.Parietal mesothelial cells: The mesothelial cells lining the parietal surface of serous body cavities.Polymeric molecules: Molecules of high molecular weight generated through polymerization of smaller molecules (monomers). They are produced either by living organisms or chemically.Regulatory T cells: A subtype of T lymphocytes with immunosuppressive properties and capacities to abrogate autoimmune diseases.Serosal membranes: Membranes lining serous cavities and composed of a single layer of simple squamous epithelial resting on a basement membrane underneath.Simple squamous epithelium: A simple epithelium composed by a single layer of thin and flat polygonal epithelial cells with secretive properties.Transdifferentiation: The transformation of a differentiated somatic cell into another type without the need of reverting into an intermediate pluripotent state.Vascular endothelium: The monolayer of cells lining the lumen of blood vessels.Visceral mesothelial cells: Mesothelial cells covering visceral organs inside body cavities.Visceral organs: Organs located within internal body cavities, especially those located within the abdomen.Christian Claude Lachaud, Abdelkrim Hmadcha, and Bernat Soria are inventors of the Patent filed by the Fundaci\u00f3n Progreso y Salud, Vissum Corporation and NewBiotechnic SA. Berta Rodriguez-Campins is an employee of NBT SA."} +{"text": "ETCO2 is currently the only parameter proven to correlate with the likelihood of return of spontaneous circulation (ROSC), although the prediction of long-term outcome based on ETCO2 values has not been established [2 adequately, invasive airway management is necessary and measured values are influenced by different lung pathologies.The goal of cardiopulmonary resuscitation (CPR) is to preserve the pre-arrest neurological state by maintaining sufficient cerebral blood flow and oxygenation, but the predictors thereof remain largely unknown. Despite recent attempts to improve the quality of basic and advanced life support, no monitored link to the neurological and physiological response of these CPR efforts has been established. The difficult decision to end pre-hospital resuscitation efforts is currently based on the circumstances of cardiac arrest, length of resuscitation efforts (if available), knowledge of pre-morbid physiological reserves, and (if present) end-tidal carbon dioxide measures the regional difference between oxygenated and deoxygenated hemoglobin, which expresses the difference in oxygen supply and demand. It determines cerebral tissue saturation non-invasively and independent of pulsatile flow. M\u00fcllner and colleagues were theAlmost 20\u00a0years after the first published study on cerebral saturation monitoring during CPR, a revival of cerebral saturation measurement during CPR is taking place. Recent published research measures cerebral saturation in patients with ongoing CPR at arrival to the emergency department, but different cerebral saturation devices and different methods for analysis of NIRS data are used. The latest research on NIRS in the CPR setting focuses on two main questions.Firstly, can cerebral saturation values predict ROSC or neurological outcome? Ito and colleagues observedThe second question recently addressed is whether cerebral saturation values can guide CPR efforts. Cerebral saturation measurements are probably more useful as a dynamic measurement instead of a static, single value. Hence, low cerebral saturation values could be interpreted as a need for interventions aimed at improving cerebral oxygenation during CPR. Sustained low cerebral saturation values, despite these interventions, could indicate futile CPR efforts. It has been noted that no patients with a mean cerebral saturation of less than 30% achieved ROSC . In contIn conclusion, preliminary data suggest that monitoring of cerebral saturation during CPR seems a likely predictor of both ROSC and neurological outcome and that it might have a role guiding CPR interventions. Although the current knowledge, obtained from small observational studies, is limited, both the further development of NIRS devices and the likely execution of well-designed large blinded observational trials, particularly in the difficult environment of out-of-hospital CPR, bode well for the future. A real-time monitoring tool providing vital information on the neurological and physiological response to CPR efforts and with predictive value for neurological outcome seems close at hand."} +{"text": "Stone tools provide some of the most abundant, continuous, and high resolution evidence of behavioral change over human evolution, but their implications for cognitive evolution have remained unclear. We investigated the neurophysiological demands of stone toolmaking by training modern subjects in known Paleolithic methods and collecting structural and functional brain imaging data as they made technical judgments about planned actions on partially completed tools. Results show that this task affected neural activity and functional connectivity in dorsal prefrontal cortex, that effect magnitude correlated with the frequency of correct strategic judgments, and that the frequency of correct strategic judgments was predictive of success in Acheulean, but not Oldowan, toolmaking. This corroborates hypothesized cognitive control demands of Acheulean toolmaking, specifically including information monitoring and manipulation functions attributed to the \"central executive\" of working memory. More broadly, it develops empirical methods for assessing the differential cognitive demands of Paleolithic technologies, and expands the scope of evolutionary hypotheses that can be tested using the available archaeological record. Enhancement of prefrontal executive control is seen as critical to the emergence of modern human cognition \u20134, but eExperimental replication of prehistoric behavior is a core research method in archaeology , 15 thatOur previous research examined brain responses to naturalistic stone toolmaking behavior execution , 21 and physical accuracy of predicted outcomes vs. their strategic appropriateness in achieving toolmaking goals. This manipulation approximates a conventional archaeological distinction between savoir-faire (know-how) and connaissance (knowledge about) in stone toolmaking . Although progress in archaeological and comparative research has fostered healthy skepticism regarding such naive appraisals , results5. Althou"} +{"text": "Transfer cells are ubiquitous plant cells that play an important role in plant development as well as in responses to biotic and abiotic stresses. They are highly specialized and differentiated cells playing a central role in the acquisition, distribution and exchange of nutrients. Their unique structural traits are characterized by augmented ingrowths of invaginated secondary wall material, unsheathed by an amplified area of plasma membrane enriched in a suite of solute transporters. Similar morphological features can be perceived in vascular root feeding cells induced by sedentary plant-parasitic nematodes, such as root-knot and cyst nematodes, in a wide range of plant hosts. Despite their close phylogenetic relationship, these obligatory biotrophic plant pathogens engage different approaches when reprogramming root cells into giant cells or syncytia, respectively. Both nematode feeding-cells types will serve as the main source of nutrients until the end of the nematode life cycle. In both cases, these nematodes are able to remarkably maneuver and reprogram plant host cells. In this review we will discuss the structure, function and formation of these specialized multinucleate cells that act as nutrient transfer cells accumulating and synthesizing components needed for survival and successful offspring of plant-parasitic nematodes. Plant cells with transfer-like functions are also a renowned subject of interest involving still poorly understood molecular and cellular transport processes. Products secreted by nematodes through their stylet induce the differentiation of root cells into feeding structures and the content of this secretion remains largely unidentified and RKN nematodes (family Meloidogynidae) are considered the major economically important plant parasitic species . FeedingFigures 2A,B; Root-knot nematodes induce galls composed of giant cells surrounded by neighboring cells (NCs), giving the root a shape of a knot genes genes ,b; polygenes PG; and pect PG; PE; ,b. This trans-differentiation of parenchyma vascular cells into giant or syncytial TCs.Apart from cell wall changes pathogens may also locally interfere with signaling pathways changing the concentration of sugars such as sucrose or plantFigure 3; Figures 1A and 3; As mentioned above, RKN species induce root galls containing giant-feeding cells in a large variety of plant hosts. In giant cells induced by RKN, wall thickening is observed as patches expanding, merging, branching and often of uneven cell wall material deposition at early stages of giant cell development suggesting an existing mechanism responsible for depositing irregular cell wall material of the Potato leaf roll polerovirus fused to GFP , although showing a strong reduction in wound callose and papillary callose formation after mechanical wounding and infection with Sphaerotheca fusca family were verified to be upregulated in young nematode feeding sites and three down-regulated genes in syncytia were validated by quantitative RT-PCR. While STP4, STP7, and STP12 belong to the STP sugar transport protein family, MEX1 and GTP2 are plastidial transporter genes, and SFP1 is a senescence-related monosaccharide transporter. A T-DNA insertion line of the most up-regulated gene (STP12) showed that insufficient sugar in feeding sites resulted in increased male ratios since females need higher sugar concentration in order to grow and reproduce , and PSK (phytosulfokines) are also associated with the RKN or CN feeding cell formation and the transport occurring within these solute transfer sites involving the feeding cell and numerous phloem and xylem elements along this sink. It remains ambiguous as to what switches ordinary plant cells into transfer-feeding cells that supply nematodes with solutes for their development and reproduction. These plant cellular morphological changes might be caused directly or indirectly by secreted products or feeding activity employed by the nematode during parasitism. What triggers and regulates the switch from apoplasmic to symplastic solute supply and the gating of PD is yet to be discovered. Further functional genetic approaches as well as microscopic studies will help to elucidate genes involved in this process in order to comprehend how nematode induced TCs operate.Nematode-induced syncytia or giant cells constitute a multinucleate model of TCs, and it is generally believed that wall protuberances arise as a result of nematode demand for nutrients. Although some information on solute supply has been mostly reported for syncytia induced by The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Endocannabinoids (eCBs) are bioactive lipids which primarily influence synaptic communication in the nervous system. They are synthesized by neurons but also by microglia, especially under inflammation. To exert their function, eCBs travel across the intercellular space. However, how eCBs move extracellularly remains obscure. Our recent evidence indicates that reactive microglia release extracellular vesicles (EVs), which may represent an ideal vehicle for the transport of hydrophobic eCBs. Hence, in this study we investigated whether microglial EVs carry eCBs and may influence neurotransmission. First we analyzed the eCB content of EVs and found a clear enrichment of anandamide (AEA) in EVs relative to parental microglia. This analysis revealed higher AEA levels in EVs shed from the plasma membrane (microvesicles), compared to those which originate from the endocytic compartment (exosomes). To bioassay the activity of vesicular AEA, we used patch clamp analysis of miniature inhibitory post-synaptic currents (mIPSC) on hippocampal neurons in vitro. Exposure of neurons to microvesicles (MVs) induced a significant decrease in mIPSC frequency, mimicking the action of CB1R agonists. The involvement of vesicular AEA in this phenomenon was inferred from the ability of the CB1R antagonist SR141716A to block the reduction of mIPSC frequency evoked by MVs. Western blot analysis showed that MVs induces an increase in ERK phosphorylation, which was completely inhibited by SR141716A. This indicate that CB1R activation by AEA-storing MVs translates into downstream signaling. Finally, consistent with a surface localization of AEA, MVs membranes maintained their capability to decrease mIPSC frequency. Overall, this study shows that microglial MVs carry AEA on their surface to stimulate CB1R on target GABAergic neurons thus playing a crucial role in the modulation of inhibitory transmission."} +{"text": "Trichomes are differentiated epidermal cells on above ground organs of nearly all land plants. They play important protective roles as structural defenses upon biotic attacks such as herbivory, oviposition and fungal infections, and against abiotic stressors such as drought, heat, freezing, excess of light, and UV radiation. The pattern and density of trichomes is highly variable within natural population suggesting tradeoffs between traits positively affecting fitness such as resistance and the costs of trichome production. The spatial distribution of trichomes is regulated through a combination of endogenous developmental programs and external signals. This review summarizes the current understanding on the molecular basis of the natural variation and the role of phytohormones and environmental stimuli on trichome patterning. Plants have evolved sophisticated morphological and chemical systems to cope with biotic and abiotic challenges. Differentiated epidermal cells such as leave hairs or trichomes represent one of these systems. Trichomes develop on above ground organs including seeds and fruits and occur in a large variety of morphologies. They can be single-celled or multicellular, branched or unbranched, and glandular or non-glandular, characteristics often used for species identification , 2008. TIn adverse environments, trichomes are beneficial because they influence the water balance, protect photosynthesis and reduce photoinhibition. Their density is negatively correlated with the rate of transpiration and thatSolanum lycopersicum) with its parasite Cuscuta pentagona on grapevine buds (Botrytis cinerea on harvested tomato (Phoma clematidina on clematis (Beauveria bassiana on poppy (Solanum berthaultii) and its resistance to Phytophthora infestans (Cicer arietinum) with Ascochyta rabiei the concentration of a highly acidic trichome exudate is crucial. At low concentrations the exudate promotes germination of Ascochyta rabiei conidia while at high concentrations germination is inhibited (Nicotiana tabacum) produce a potent inhibitor, T-phylloplanin, which inhibits germination of the oomycete Peronospora tabacina and negative regulators . GL2 encodes a homeodomain protein required for subsequent phases of trichome morphogenesis such as endoreduplication, branching, and maturation of the cell wall. The negative regulators are seven partially redundant single-repeat MYBs such as CAPRICE (CPC), TRIPTYCHON (TRY), ENHANCER OF TRY AND CPC 1, 2, 3 , and TRICHOMELESS1 and 2 promote trichome initiation and morphogenesis by inducn leaves and appln leaves . For then leaves .Arabidopsis (As mentioned above trichomes can be induced by wounding and insect attack and the bidopsis and thatbidopsis .CONSTITUTIVE EXPRESSION OF PR GENE (cpr) mutants lines mapping. The first QTL analysis discovered a major locus, named REDUCED TRICHOME NUMBER (RTN) in Arabidopsis thaliana and used recombinant inbred lines (RIL) derived from a cross between the low trichome density Ler and the medium density Col-accessions . With the availability of the 1001 Arabidopsis genomes association studies of the remaining candidate genes are now straight forward lines . Larkin cessions . This locessions and evencessions as majorT2 SAD2; , TTG2, C density . While t forward .Arabidopsis they are still not sufficient to explain all the naturally occurring variations in this plants species. Great potential for the identification of still missing regulators will come from next generation sequencing possibilities in combination with classical genetic, population genetic and comparative approaches using different plant species. There are already several examples where trichome patterning regulators from wild relatives or even crops and distantly related species such as cotton, tomato and hop have been successfully and functionally studied in the model plant Arabidopsis (Although the major players of trichome density regulation have been identified in the model plant bidopsis . HoweverThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Abdominal stab injury is potential life-threatening injuries. Operation should be considered if wound violate the peritoneal layer and/or complicated with hemodynamic compromise, peritonitis, impalement, or evisceration. It is well known there are several diagnostic tools to evaluate the necessity of operation for a patient with abdominal stab injury. Despite numerous diagnostic tools, including local wound exploration, CT, diagnostic peritoneal lavage, or FAST, were currently performed in emergent department neither of them has satisfying sensitivity and specificity. Abdominal wall ultrasonography has been used many abdominal wall disease, like hernia, abdominal wall hematoma. We used abdominal wall ultrasonography for diagnosis of abdominal wall stabbing injuryFeasibility of abdominal wall ultrasonography for diagnosis of abdominal wall stabbing injuryA 76-year-old man visited our emergent department due to multiple anterior abdominal stab wounds for suicide. His initially vital signs were relatively stable. Physical examination revealed multiple stabbing wound with bleeding, local tender over wound without rebounding tenderness. Laboratory finding is nothing particular. Patient received local wound exploration by senior surgical resident but inconclusive. Focused Assessment of Sonography for Trauma also showed negative result. Therefore, we perform the abdominal wall ulrasonography and revealed an apparent penetrating tract through the abdominal wall and disruption of peritoneal layer.(figure 2 and video 1) We use Toshiba Nemio in sterile method from start to finish. Computed tomography also revealed penetrating injury of abdominal wall and no obvious free air.(figure 3) Finally, the patient underwent the laparoscopic surgery and revealed four abdominal wall stab wounds at the mild abdomen near the umbilicus and the epigastric area(fiugre 4), perforation of transverse colon. Then he received laparoscopic repair of abdominal wall injury and colostomy. Patient was discharged smoothly after surgery.We performed the abdominal wall ultrasonography to evaluate the stab wound and successfully diagnosed the wound penetrating peritoneal layering. Moreover, in comparison with other diagnostic tools, abdominal wall ultrasonography can provide additional advantages, such as rapid, painless, non-invasion, non-radiation and more detail of wound tract structure. By using the ultrasonography, which could follow the tract of abdominal stab injury (the direct sign) and hematoma beneath the stab wound(the indirect sign) in another case(figure 5), or positive of FAST. Abdominal wall ultrasonagraphy can help clinicians to make the decision easier in further management of abdominal stab injury.The abdominal wall ultrasonography could demonstrate the tract of stab wound, and provide more detail of wound, and help the decision making, especially in hemodynamic stable patient. Further prospective study is need for evaluating the abdominal wall ultrasonograpy in stabbing wound."} +{"text": "We built a network of curated interactions between human proteins involved with centrioles, centrosomes, basal bodies and cilia to provide a global functional characterization of the Cilia/Centrosome Complex interactome (CCCI).http://string-db.org). Network analyses were performed using Cytoscape and communities were extracted using the MCODE algorithm. The gene-wise network was explored by Gene Ontology (GO) analysis. The transcription factor (TF) analysis was performed using information obtained from \"ConsSites\" and \"tfbsConsFactors\" track of the UCSC Genome Browser.Human ciliary genes were collected from available databases and interactions among genes were obtained from the STRING database and in ciliopathy genes. We found 11 communities enriched in 30 TFs. The identified TFs are involved in developmental processes, cell cycle control, in the immune response and in muscle differentiation.CCCI is a publically available tool, which will allow to clarify the roles of previously unknown ciliary functions and to elucidate the molecular mechanisms underlying ciliary-associated phenotypes."} +{"text": "Recent advances in biomaterial science and tissue engineering technology have greatly spurred the development of regenerative endodontics. This has led to a paradigm shift in endodontic treatment from simply filling the root canal systems with biologically inert materials to restoring the infected dental pulp with functional replacement tissues. Currently, cell transplantation has gained increasing attention as a scientifically valid method for dentin-pulp complex regeneration. This multidisciplinary approach which involves the interplay of three key elements of tissue engineering\u2014stem cells, scaffolds, and signaling molecules\u2014has produced an impressive number of favorable outcomes in preclinical animal studies. Nevertheless, many practical hurdles need to be overcome prior to its application in clinical settings. Apart from the potential health risks of immunological rejection and pathogenic transmission, the lack of a well-established banking system for the isolation and storage of dental-derived stem cells is the most pressing issue that awaits resolution and the properties of supportive scaffold materials vary across different studies and remain inconsistent. This review critically examines the classic triad of tissue engineering utilized in current regenerative endodontics and summarizes the possible techniques developed for dentin/pulp regeneration. A routine clinical treatment for infected or necrotic pulp tissue is root canal therapy (RCT) which involves the extirpation of injured pulp and the filling of root canal systems with bioinert synthetic materials. In spite of its satisfactory clinical efficacy in infection control and pain elimination, classical treatment modalities like RCT only seek to seal the space of root canal system without restoring its original function. Therefore, various complications such as tooth fractures and reinfection occur more often in teeth that have undergone RCT due to their loss of sensory function and consequent lack of natural defense mechanisms . The hisstitutes . in vitro cultured cells and scaffolds into target anatomic location [Tissue engineering, an emerging popular domain of bioscience, is a multidisciplinary research area with the ultimate aim of restoring, maintaining, and regenerating damaged/lost tissue with biologically engineered replacements through combining the principles of biology, medicine, and engineering . The advlocation . This re in vitro colony formation, and trilineage mesenchymal differentiation potential [Stem cells are commonly defined as clonogenic cells that exhibit remarkable long-term self-renewal and multilineage differentiation capacity. Based on their distinction in plasticity , stem cells can be further subdivided into embryonic stem cells (ESCs) and postnatal stem cells . Althougotential . Numerou in vitro [Gronthos et al. were the pioneers that identified and characterized a stem cell population within adult human dental pulp tissue , 10. Isoin vitro \u201313. Whenin vitro , 14. In in vitro , 14, 15. in vitro osteogenic/odontogenic, adipogenic, and neurogenic differentiation capacity when induced by respective stimuli. In vivo studies employing animal models also demonstrated the odontogenic capacity of SCAP [SCAP were initially isolated and characterized by Sonoyama et al. from the apical papilla, an embryonic-like soft tissue located at the apex of incompletely developed human permanent teeth . Similar of SCAP , 17. Typ of SCAP . Conside of SCAP . in vitro differentiation potential towards the osteogenic and adipogenic lineages compared to DPSCs [ In vivo transplantation of SHED loaded on scaffolds/tooth slices into immunocompromised mice has resulted in the formation of tissue that closely resembles physiological dental pulp in cellular morphology and histological architecture [SHED were first isolated by Miura et al. from vital pulp remnants of exfoliated deciduous teeth . Althougto DPSCs . In vivoitecture , 22. An itecture .\u2212/CD146\u2212 side population (SP) cells with type I and III collagen led to the formation of pulp-like tissues with capillaries and neuronal processes by day 14 [\u2212/CD146\u2212 SP cells and CD 105+ cells with stromal cell-derived factor-1 (SDF-1) successfully induced complete regeneration of pulp-like tissue with vasculogenesis and neurogenesis within 14 days. This was followed by further formation of a continuous dentin-like structure along the dentinal wall of root canals [Positive or negative isolation strategy is normally adopted for the selection of a specific, more homogeneous subpopulation of MSCs with optimal phenotypes. Recently, these techniques have also been reported in the fractionation of dental pulp stem cells, designed to isolate subpopulations that possess higher angiogenic and neurogenic potentials, both of which contribute to pulp homeostasis . In a cay day 14 . In a cat canals , 27. In \u2212 SP cells with SDF-1 yielded tissues that were morphologically identical to that derived by transplanted pulp CD31\u2212 SP cells and all three regenerated tissues possess functional properties similar to normal pulp [Given that the availability and quality of dental pulp tissue sharply decline with age, nonodontogenic stem cells have been investigated as alternative sources among which stem cells harvested from bone marrow and adipose tissue showed greatest promise owing to their advantageous biological properties and partially shared gene expression profile of various growth factors, extracellular matrix (ECM) proteins, and transcriptional regulators , 29. Ishmal pulp . Consistmal pulp . Further in vitro [ in vivo study demonstrated the formation of dentin-like and dental pulp-like structures upon transplantation of the reconstructed tooth germs derived from miPSCs together with epithelium and mesenchyme into mouse subrenal capsule [The generating of induced pluripotent stem cells (iPSCs) is a groundbreaking work that revolutionizes the present scenario of regenerative medicine. This can be realized through reprograming adult somatic cells or terminally differentiated cells back to a pluripotent state via overexpression of four defined transcription factors \u201334. Analin vitro . These N capsule . DespiteWhen cell-based therapy is adopted for dentin/pulp tissue regeneration, the procuring of a readily available stem cell source is of the highest priority. While the favorable properties of low immunogenicity and immunosuppression exhibited by oral-derived adult stem cells offer much possibility for allogeneic cell transplantation, these adult stem cells will likely express histocompatibility antigens upon differentiation and will thus not be able to sustain the immunosuppressed state \u201341. HencConventionally, infected or inflamed pulp tissue will be completely removed by pulpectomy in order to create a sterile environment for the subsequent restorative treatment. However, a considerable portion of healthy and vital pulp tissue might also be discarded as medical waste together with the necrotic dental pulp. Recently various studies have reported successful isolation of viable stem cells from inflamed dental pulp, but with conflicting regenerative effects on dentin/pulp tissue. Yazid et al. showed that MSCs obtained from primary inflamed pulp exhibited highly dysfunctional MSCs stemness and minimal immunoregulatory capacity . By contThe right time for banking cells is a thought-provoking question. There seems to be a noticeable progressive age-associated reduction in regenerative capacity of MSCs present in multiple adult organs including teeth . MoleculIn addition to the physical state of dental tissue, other general health-associated parameters like smoking and nutrition are possible factors that can influence the physiological activity of dental pulp cells (DPCs) and overall biological properties of dental pulp tissue, although the evidence is weak , 54.A scaffold is one of the three essential components of classic tissue engineering strategy. Functionally, scaffolds provide a three-dimensional (3D) temporary structural framework for cell seeding, adhesion, proliferation, and spatial distribution until their complete replacement by the newly synthesized matrix of endogenous host cells , 56. Cur in vitro and also facilitating pulpal tissue regeneration in a full-length root canal in vivo [Collagen, a major macromolecular constituent of dentin ECM with excellent biocompatibility, is the most extensively studied naturally occurring material for dental tissue engineering. Comparison of different natural polymers including collagen type I, collagen type III, chitosan, and gelatin suggests that hDPCs plated on collagens, particularly type I collagen, perform best in terms of proliferation and mineralization capacity . Combine in vivo . When cu in vivo . de novo regeneration of vascularized pulp-like tissue in an empty root canal space accompanied by deposition of dentin-like tissues along dentinal walls formed by newly derived odontoblast-like cells [Synthetic materials such as polylactic acid (PLA), polyglycolic acid (PGA), and their copolymer poly lactic-glycolic acid (PLGA) have attained approval from the United States Food and Drug Administration (FDA) for wide application due to their nontoxic properties. An earlier study demonstrated that PGA accelerated collagen deposition and appeared to be more conducive to DPCs proliferation compared to alginate or collagen scaffolds . A highlke cells .\u03b21 (TGF-b \u03b21), and TGF-b \u03b22, when platelets are activated [Platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) are other potential materials easily obtained from autologous blood and thus can minimize the risk of adverse immunological response. These can release many vasculogenesis-associated factors including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-b ctivated , 64. Recctivated , 65.In a nutshell, although both natural polymers and synthetic materials have demonstrated promising therapeutic effects on dentin/pulp regeneration, neither of them embraces all the favorable properties that can recapitulate the cellular physiological microenvironment. Natural polymers are usually afflicted with issues of purity and antigenicity. Synthetic polymers, albeit circumventing the potential risks of immunoreactivity and being more readily amenable to clinical applications with tailor-made physiochemical properties, still lack bioactive molecules present in native ECM that are necessary for cellular recognition and interaction, in addition to various technical challenges in regulating pore sizes and achieving high porosity structures .Recently, nanofibrous polymer scaffolds have been synthesized to biomimic ECM in structure and function. They appear superior to other scaffold materials at microstructural level or other morphological arrangements owing to their interconnected porous networks and advantages in high surface area to volume ratio . Most st in vivo. Comparisons of data extracted from different studies suggest that the fate of implanted stem/progenitor cells may be site-associated rather than being influenced by their origin, with a tendency to differentiate into the odontoblast phenotype when transplanted into the pulp chamber but into other cell lineages when transplanted into other target locations [ in situ dentin/pulp regeneration, may be lost during the transplantation process. It cannot be ruled out that the quiescent host stem cells residing in the niche of the transplantation site may be stimulated and recruited into the regenerated construct together with pulp-derived stem cells and thus pulp cell may lose its predominant effect on tissue mineralization [ in situ pulp regeneration is often disadvantaged by ischemic conditions due to the constricted opening at the root apex allowing for blood microcirculation while root fragments or tooth slices rarely face this problem. Despite the deficiency of ectopic models in mimicking the in situ tooth microenvironment in clinical practice, the implementation of orthotropic model encounters formidable challenges. After transplantation into the pulpectomized teeth, the fabricated tissue replacement has a tendency to adhere to the coronal portion of root canals, leaving the middle and apical parts incompletely filled [Several preclinical animal models based either on ectopic or on orthotropic transplantation approach have been developed to translate cell-based therapy into clinical reality. Although a substantial body of evidence has confirmed the regeneration of mineralized tissue, some studies still failed to detect the presence of dentin-like tissue but instead found tissues with bone-like morphology . This isocations . SCAP, alization . Additioy filled . This isy filled . In addiy filled , 82.The critical requirements for successful dentin/pulp regeneration are not confined to the morphogenesis of dentin/pulp-like tissue but should also be accompanied with angiogenesis and neurogenesis. It must be noted that the deposited dentin-like tissues on existing dentin structure are produced by the newly differentiated odontoblasts from the dentinal wall within the root canal space. Currently, potential strategies dedicated to optimizing stem cell-mediated dentin/pulp regeneration are directed towards two main objectives: firstly angiogenesis induction and, secondly, the promotion of tissue mineralization.The long-term survival of tissue-engineered implants largely depends on rapid establishment of adequate blood supply at the graft sites which functions as a conduit for nutrient transportation, oxygen delivery, and metabolic waste excretion. This principle is particularly relevant to dentin/pulp regeneration given that the opening at root apex is too constricted to allow for intracanal blood infusion . Due to ex vivo pulp cell culture and expansion are normally conducted. For these reasons, some investigators have tried to simulate the conditions of pulp hypoxia and explore how DPCs respond to low oxygen levels. Amemiya et al. demonstrated that canine DPCs under hypooxygenation conditions exhibited higher formazan production and growth rate compared to pulp cells incubated under normoxic conditions [ in vitro than those incubated under normoxic conditions [ in vitro and in vivo [\u03b1, ephrinB2, and VEGF [Hypoxia is a common phenomenon encountered by dental pulp tissue under both pathological and nonpathological conditions. Due to their unique anatomical structure that is surrounded by hard dentin with only a narrow opening at root apices, DPCs are typically susceptible to ischemia during traumatic injuries when surrounding vascular bundles are severely ruptured or during restorative treatment whereby local anesthetics containing vasoconstrictors slow down the velocity of blood microcirculation. Exposure to ischemia blocks the oxygen influx transported by the blood stream and thus disrupts the oxygen homeostasis of dental pulp . In addinditions . Subsequnditions , 86. Lid in vivo . Consistand VEGF . Collect\u03b1-smooth muscle actin and several mesenchymal and endothelial cell markers by perivascular cells [ in vitro and found that HUVECs dramatically facilitated the osteogenic/odontogenic differentiation of cocultured DPSCs compared with either DPSC-alone or HUVEC-alone cultures. In turn, DPSCs stabilized and increased the longevity of the preexisting HUVEC-formed vasculature [ ex vivo tubular-like networks than coculture of ECs with bone marrow mesenchymal stem cells (BMMSCs). Interestingly, this study not only proved the pericyte-like topography and potential function of DPSCs but also identified that the mechanism of DPSCs in angiogenic induction was VEGFR-2 dependent [ in vitro study demonstrated that coculture of SCAP and HUVEC under hypoxia enhanced the formation of vessel-like structure with increased tubular length and branching points and that the secretion of VEGF by SCAP might be utilized by HUVECs [ in vivo study implied that contribution of DPSCs to vascular morphogenesis when coimplanted with HUVECs not only was confined to the paracrine effects of secreted proangiogenic factors like VEGF, but also involved cell migratory mechanisms and corresponding scaffold disruption [In recent years, many research groups have succeeded in vascularizing artificial tissue constructs via codelivery of ECs with MSCs of various types. The significance of coculture system is based on the speculation that intricate signaling cross talk may be established among heterogenous cell populations, possibly regulated by direct cellular interaction or paracrine signaling . This hyar cells . Dissanaculature . DPSCs hculature , 94. Conependent . Anothery HUVECs . Furthersruption . While p in vitro culture system specifically for DPCs [Conventionally, stem cells are combined with exogenous scaffold materials to form a 3D engineered structure before transplanting into target sites. However, in addition to those biomaterial-associated problems, this well-recognized technique has long been questioned due to the inadequate cell migration and cell retention within the supporting scaffolds. Above all, the aforementioned biomaterials are far from being able to replicate the natural ECM or the surface of implantable device. A decade ago, Iohara et al. pioneered a 3Dfor DPCs . Unlike for DPCs . Considefor DPCs . in situ evaluation of scaffoldless delivery system is required in large animal models.Recently, a similar but different innovative \u201cscaffold-free\u201d approach developed for regenerative medicine, designated as \u201ccell sheet technology\u201d (CST), has become a popular topic of active research in the field of periodontal tissue engineering \u2013100. SupThe introduction of preengineered 3D tissue constructs into transplantation sites requires a viable and effective delivery system. In general, scaffold adopted for bone or another body tissue regeneration is often fabricated with a rigid structure in order to provide sufficient physical support. Proof-of-principle transplantation experiments have provided valuable mechanistic information for dentin/pulp regeneration when using relatively rigid scaffolds like PLLA casts with tooth slices or fragments to deliver pulp stem cells . However in vitro and locally delivered into engineered tissue.The lineage commitment and differentiation of dental stem cells during dentin/pulp tissue repair and regeneration markedly differ depending on multiple factors. Apart from their intrinsic gene expression and epigenetic profiles, the cellular fate of dental pulp-derived stem cells seems more likely to be determined by the bioactive signaling molecules within the local microenvironment , 108. Cu in vitro and in vivo [ in vitro study in which SCAP were cocultured with HUVECs, VEGF secreted by SCAP were metabolized by HUVECs to facilitate the formation of new vasculatures and the maturation of sprouted capillary networks [ in vivo study demonstrated that bFGF increased the survivability of DPSCs seeded on silk fibroin scaffold and resulted in the formation of pulp-like tissue replete with vasculature formation and calcium mineral deposition along the radicular dentinal wall after transplantation into SCIDM [Nakashima demonstrated recombinant human BMP2 and BMP4 induced tubular dentin and osteodentin formation on canine amputated tooth pulp when capped with inactivated dentin matrix , 111. St in vivo . In an inetworks . bFGF hanetworks , 117. Itnetworks . Notablynetworks . Recentlto SCIDM . However in vivo study further confirmed the efficacy of BMP-2 transfection therapy in potentiating tissue mineralization within the regenerated construct in favor of bone-like structure rather than dentin-like morphology [Loading scaffolds with bioactive drugs or protein molecules intended for promoting dental tissue regeneration has achieved favorable results . Neverthrphology . Howeverrphology . Additio de novo pulp regeneration in the full-length root. In addition, cells trapped within fibrin clots during revitalization/revascularization have neither a definite origin nor a predictable quantity and thus the phenotype of regenerated replacements filling in root canals cannot be well characterized, leading to variations in overall therapeutic efficacy. In comparison, cell transplantation based on the utilization of the meticulous triad of classic tissue engineering including stem cells, scaffolds, and signaling molecules has achieved promising outcomes. This cell-based method is capable of repairing tissue defects with an extensive size [ ex vivo cell manipulation, and ultimate shipping back to practitioners is a rather time-consuming process and the cost involved may be too excessive over relatively mature alternative therapies like dental implants or RCT. During the expansion period, cell senescence, loss of stemness, and microbial contamination are likely to occur, leading to biological deterioration and even cellular apoptosis. Worse still, MSCs are prone to experience malignant genetic transformation and thus arouse safety concern of tumorigenesis [Owing to the recent advances in the field of biomedicine, tissue engineering, and material science, great progress has been achieved in the development of regenerative endodontics. We are now at a stage of paradigm shift in endodontic treatment from traditional restoration to complete replacement of the compromised dental pulp tissues which can be realized by two scientifically meritorious approaches, cell transplantation and cell mobilization, including revitalization/revascularization procedure. While simple to operate, the cell mobilization approach may not be suitable to tissues with large size defects, especially in the circumstance ofive size , 122. Deigenesis . If thesTo date, no randomized clinical controlled trials have been conducted to compare the efficacy of cell mobilization or cell transplantation therapy and traditional endodontic treatment. Superior to tooth restoration, regenerative therapy is considered as a potential solution to address the deficiencies in tooth homeostasis, immune defense system, blood supply, and functional dentin-pulp complex formation. Moreover, it prolongs the life of natural dentition, defers the extraction fate of teeth with partially necrotic pulp, and thus ultimately improves the overall oral health-related quality of life. Collectively, additional studies in these fields should continue in order to work out a clinically translatable platform on dentin/pulp regeneration. Future research prospects in regenerative endodontics rely on the multidisciplinary collaboration of clinicians, biomaterial scientists, and engineers with expertise in their own fields and their joint contributions to the development of dentin/pulp regeneration therapy."} +{"text": "Existing literature suggests that organizational readiness for change (ORC) can influence implementing and sustaining an intervention program. Individual attitude toward innovation is one of the important components of ORC. There is a growing research effort to identify facilitators and barriers regarding positive attitudes toward innovation in clinical settings. The current study aims to explore how occupational stress and social support for work may affect attitudes toward innovation among health care providers in HIV clinics in China.323 health care providers were recruited from 42 HIV clinics across 12 cities/counties in Guangxi, China to participate in a self-administered survey including measures on demographics, work-related characteristics , occupational stress, social support for work (from the family and colleagues), and attitudes toward innovation. We conducted mediation analysis and Sobel testing to examine the relationship among variables of interest.After controlling for demographics and work-related characteristics , occupational stress was negatively associated with positive attitudes toward innovation while higher levels of social support from the family was associated with more positive attitudes toward innovation . Social support from the family significantly mediated the impact of occupational stress on attitudes toward innovation . However, no significant association was detected between social support from colleagues and attitudes toward innovation (p = 0.600).Social support for work from the family not only promotes attitudes favoring innovation, but also buffers the negative impact of occupational stress on attitudes toward innovation among health care providers in HIV clinics. Our findings suggest integrating both individual and family level factors into the strategies of improving ORC in HIV clinical settings."} +{"text": "The transdiagnostic theory of eating disorders proposes that clinical perfectionism, core low self-esteem, interpersonal problems and mood intolerance can maintain eating disorder psychopathology in some individuals. The current study aimed to explore eating disorder symptom severity as a function of these maintaining mechanisms in a community sample. Participants completed questionnaires online and were classified according to whether they met criteria for zero, one, or two or more mechanisms. A greater number of maintaining mechanisms was found to be significantly associated with higher global eating disorder examination questionnaire (EDE-Q) scores, and a higher prevalence of binge eating, purging and driven exercise. Moreover, participants with 2 or more maintaining mechanisms had more severe eating disorder symptoms than participants with 1, who in turn had more severe symptoms than participants with no maintaining mechanisms. Regression models evaluated the role of each maintaining mechanism in predicting different aspects of eating disorder pathology. Self-esteem, perfectionism and mood intolerance all predicted unique variance in global EDE-Q scores. There were differences in the maintaining mechanisms that predicted binge eating, purging and driven exercise. These results provide support for the transdiagnostic model of eating disorders and have implications for detecting and treating eating disorders in community samples.Peter Beumont Young Investigator award finalist stream of the 2014 ANZAED Conference.This abstract was presented in the"} +{"text": "Surgical resection of colorectal liver metastases is not achievable in more than 70% of the cases. Although the liver directed therapies have become a part of the stand of care, lack of a preclinical model impedes the assessment of toxicity and therapeutic benefits attributed several candidate drugs or treatment regimens that can be designed. In the present study we aim develop and characterize a rat colorectal liver metastasis model.Growth characteristics of CC-531 cells were determined in vitro followed by subcapsular liver implantation in syngeneic WAG/Rij rats. Tumor growth progression was followed over 3 weeks by ultrasound (US) and magnetic resonance imaging (MRI). Growth characteristics were also assessed by histopathology and immunohistochemistry in harvested tumor tissues.The doubling time of CC-531 cells was found be under 24hrs and all the implanted rats grew tumors. US imaging showed hypoechoic masses and MRI showed contrast enhancement representing complex tumor microenvironments. Hematoxylin and Eosin staining confirmed tumor growth and uniform CD31 staining in tumor confirmed even vessel density.CC-531 can be used as a metastatic rat tumor colorectal liver metastases model with well-defined characteristics that can be readily followed by imaging whilst having a therapeutic window for interventions. In interventional oncology, many animal models of disease have been utilized to understand ablative and trans-catheter intra-arterial therapies. To date, there are many models of orthotopic hepatocellular carcinoma in a rat model, including the Morris (McA-RH7777), NovikoffDeveloping this type of preclinical animal model of colorectal liver metastases can be challenging. One approach to achieving liver metastases is to implant colon cancer cells directly into the liver. This modThe current study focused on validating this model of colorectal liver metastases, which can be used rapidly and reliably in a preclinical setting. By using a subcapsular injection of metastatic cells, distinct tumors develop and progress in situ. Changes in their microenvironment can be monitored non invasively and continuously early after implantation . Though In conclusion, CC-531 is an immunocompetent and orthotopic translational rodent model of colorectal liver metastases mimicking tumor microenvironment with liver metastases easily established, tracked and characterized by US and MR imaging."} +{"text": "Apical HCM tends to have a favorable outcome compared to other types. The presence and extent of late gadolinium enhancement (LGE), reflecting myocardial fibrosis, is closely correlated with increased cardiac mortality and strongly associated with surrogates of arrhythmia and subsequent sudden cardiac death. This study sough to investigate the difference in cardiac magnetic resonance (CMR) and echocardiographic and clinical manifestations between apical hypertrophic cardiomyopathy (HCM) and non-apical HCM.A total of 350 consecutive patients diagnosed with HCM underwent CMR and echocardiography. Clinical characteristics including risk factors for sudden cardiac death were collected. Eighty-five patients were classified as apical type. On CMR, left ventricle (LV) volumetric parameters were measured, and the amount of LGE was calculated with gray-scale thresholds of 6 SD above the mean signal intensity for normal remote myocardium and also expressed as a ratio against total LV volume. Echocardiographic evaluations included left atrial volume index (LAVI), mitral inflow pattern, tissue Doppler of mitral annulus and LV dimension.Patients with apical HCM were less likely to present with history of syncope and have family history of sudden cardiac death than those with non-apical HCM . Functional class was also more favorable in apical HCM . CMR volumetric parameters were not different between the two groups except LV mass index . LGE was less frequently detected , and the amount of LGE was significantly smaller in apical HCM . The E/e level and LAVI were also lower in apical HCM patients .Apical hypertrophy shows relatively small burden of myocardial fibrosis and less severe diastolic dysfunction, and subsequently more favorable clinical manifestations in comparison with other HCMs. This may be one explanation of why most patients with apical HCM show a benign course of disease compared to non-apical HCM.None."} +{"text": "Differential accessibility of DNA to nuclear proteins underlies the regulation of numerous cellular processes. Although DNA accessibility is primarily determined by the presence or absence of nucleosomes, differences in nucleosome composition or dynamics may also regulate accessibility. Methods for mapping nucleosome positions and occupancies genome-wide (MNase-seq) have uncovered the nucleosome landscapes of many different cell types and organisms. Conversely, methods specialized for the detection of large nucleosome-free regions of chromatin have uncovered numerous gene regulatory elements. However, these methods are less successful in measuring the accessibility of DNA sequences within nucelosome arrays.Here we probe the genome-wide accessibility of multiple cell types in an unbiased manner using restriction endonuclease digestion of chromatin coupled to deep sequencing (RED-seq). Using this method, we identified differences in chromatin accessibility between populations of cells, not only in nucleosome-depleted regions of the genome , but also within the majority of the genome that is packaged into nucleosome arrays. Furthermore, we identified both large differences in chromatin accessibility in distinct cell lineages and subtle but significant changes during differentiation of mouse embryonic stem cells (ESCs). Most significantly, using RED-seq, we identified differences in accessibility among nucleosomes harboring well-studied histone variants, and show that these differences depend on factors required for their deposition.Using an unbiased method to probe chromatin accessibility genome-wide, we uncover unique features of chromatin structure that are not observed using more widely-utilized methods. We demonstrate that different types of nucleosomes within mammalian cells exhibit different degrees of accessibility. These findings provide significant insight into the regulation of DNA accessibility.The online version of this article (doi:10.1186/1471-2164-15-1104) contains supplementary material, which is available to authorized users. Eukaryotic genomes are wrapped around histone octamers to form nucleosome arrays, which are further packaged into the nucleus. Although chromatin compaction facilitates storage of large quantities of DNA within small nuclear compartments, it drastically reduces the accessibility of genomic DNA to proteins that require access. Nucleosomal DNA is relatively inaccessible to DNA binding proteins due to both the occlusion of approximately half of its surface by contacts with histones, as well as the distortion of the normal B-form structure that occurs when DNA is wrapped around a histone octamer . Consequin vivo.Although protection of DNA from nuclear factors by the formation of tight interactions with histones appears to be the major method by which DNA accessibility is regulated, many different isoforms of the histone octamer exist within most eukaryotes, each with distinct biochemical and biophysical properties \u20138. TheseAlong with differences in chromatin structure within distinct genomic regions in individual cell types, cell type-specific chromatin structural differences facilitate gene expression patterns specific to cells of different lineages . In embrMethods have been developed to study DNA accessibility based on either the protection of nucleosomal DNA from general endonuclease digestion or the differential solubility properties of open and closed chromatin. Deoxyribonuclease I (DNase I) , 19 prefet al. developed a genome-wide method to probe chromatin structure using restriction enzymes, finding that chromatin accessibility correlated broadly with gene expression in hematopoietic cell lineages and became progressively restricted during differentiation , plotted as in Figure\u00a0Additional file 2:a GEO:GSE0254, ploSequences of barcoded and biotinylated adaptors.(PDF 42 KB)Additional file 3:Sequences of qPCR primers for DHSs.(PDF 40 KB)Additional file 4:Sequences of qPCR primers for CTCF binding sites.(PDF 48 KB)Additional file 5:"} +{"text": "Lung cancer is difficult to treat with a poor prognosis and a five year survival of 15%. Current molecularly targeted therapies are initially effective in non-small cell lung cancer (NSCLC) patients; however, they are plagued with difficulties including induced resistance and small therapeutically responsive populations. This mini review describes the mechanism of resistance to several molecularly targeted therapies which are currently being used to treat NSCLC. The major targets discussed are c-Met, EGFR, HER2, ALK, VEGFR, and BRAF. The first generation tyrosine kinase inhibitors (TKIs) resulted in resistance; however, second and third generation TKIs are being developed, which are generally more efficacious and have potential to treat NSCLC patients with resistance to first generation TKIs. Combination therapies could also be effective in preventing TKI resistance in NSCLC patients. The focus of current lung cancer treatment has been shifted from more traditional options to newly developed molecularly targeted therapies. Many of the molecularly targeted therapies are utilized to target specific biomarkers that are commonly overexpressed and have important roles in tumorigenesis; these biomarkers contribute to cancer-related processes such as cell proliferation, survival and migration. While initially effective, many targeted therapies have been associated with increased drug resistance after their initial use. Acquired resistance to current molecularly targeted therapies in lung cancer presents a major clinical challenge. Current research focuses on identifying potential novel biomarkers and mechanisms involved in resistance to these therapies. There are several clinical challenges associated with current molecularly targeted therapies including the induction of various types of resistance mechanisms, which are not clearly defined, and the lack of effective combinatorial therapies designed to prevent and overcome the problem of drug resistance in lung cancer.Common molecularly targeted therapies target receptor tyrosine kinases (RTKs) including hepatocyte growth factor receptor (HGFR/c-Met), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), anaplastic lymphoma kinase (ALK), and endothelial growth factor receptor (VEGFR), which are commonly mutated in NSCLC cases . Recentlc-Met is a RTK for the ligand hepatocyte growth factor (HGF), which is secreted by mesenchymal cells and cancer cells . There hEpidermal growth factor receptor (EGFR) is a transmembrane receptor that plays an essential role in regulating cell proliferation, survival, and growth . EGFR TKThe anaplastic lymphoma kinase (ALK) is a RTK typically expressed in the central and peripheral nervous system regions ,20. ALK Overexpression of vascular endothelial growth factor (VEGF), an angiogenic factor, and its receptors are related to poor prognosis in NSCLC patients . BevacizBRAF is a member of the RAF serine/threonine protein kinases family. Mutations in BRAF have been shown to be associated with tumor development in NSCLC with a frequency of 2\u20133%. Recently, a BRAF inhibitor dabrafenib, the first drug of its class, is shown to be effective for the treatment of advanced NSCLC patients with BRAF V600E mutation in a phase II clinical study . HoweverAlthough current molecularly targeted therapies are very effective for NSCLC patients, almost all patients eventually acquire resistance to these therapies. To combat this resistance against first generation TKIs, second and third generation TKIs have been developed. These new generations of TKIs are either completing clinical trials or have been FDA approved to treat NSCLC patients. However, their therapeutic potential needs to be further validated and established. Various secondary mutations and alternative signaling pathways have been identified as distinct resistance patterns for several TKIs targeting EGFR, c-Met, and ALK. However, further studies are required to determine the specific mechanisms of acquired resistance to HER2, VEGFR and BRAF. Combinatorial strategies could be effective in overcoming TKI resistance in lung cancer patients. These strategies may require targeting both mutations involved in resistance and alternative signaling pathways."} +{"text": "Xanthomonas citri subsp. citri, three Candidatus Liberibacter spp and Citrus leprosis virus C (CiLV-C). In plant-pathogen interactions, the role of salicylic acid (SA) in activating defense related genes is well recognized seedlings grown in test tubes containing MS culture medium. The presence of the transgene will be evaluated by PCR using specifics primers that amplify part of the ubiquitin promoter and part of the gene. SABP2 expression levels in transgenic plants will be assessed through qPCR. After bud multiplication, transgenic plants will be evaluated for their response to citrus canker, HLB and leprosis.A total of 620 explants in three independent experiments were introduced and approximately 336 shoots were regenerated. The GUS histochemical test was performed and confirmed the transformation of 30 positive shoots. These shoots are being grafted onto Carrizo citrange ["} +{"text": "I first overview motor neuron developmental biology to provide some context for reviewing recent studies interrogating pathways that influence the generation of MN diversity. I conclude that motor neurogenesis from PSCs provides a powerful reductionist model system to gain insight into the developmental logic of MN subtype diversification and serves more broadly as a leading exemplar of potential strategies to resolve the molecular basis of neuronal subclass differentiation within the nervous system. These studies will in turn permit greater mechanistic understanding of differential MN subtype vulnerability using in vitro human disease models.Resolving the mechanisms underlying human neuronal diversification remains a major challenge in developmental and applied neurobiology. Motor neurons (MNs) represent a diverse pool of neuronal subtypes exhibiting differential vulnerability in different human neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). The ability to predictably manipulate MN subtype lineage restriction from human pluripotent stem cells (PSCs) will form the essential basis to establishing accurate, clinically relevant Human neurodegenerative disorders represent a spectrum of progressive and untreatable clinical diseases, characterized by selective loss of neurons, usually in a region-specific and/or subtype-specific fashion. There is a great experimental need for renewable sources of clinically relevant, region-specific, and subtype-specific neurons. Lineage restriction and the generation of neuronal diversity within the developing neuraxis are consequences of the interplay of multiple developmental signals, which are regulated in a spatiotemporal manner. Precise cellular and molecular mechanisms through which these complex sequential and progressive developmental processes are orchestrated remain unresolved. The ability to generate defined neuronal cell types from PSCs offers a unique experimental opportunity to study the developmental mechanism(s) underlying generation of neural diversity during human embryogenesis , 2 Figu. In turn in vitro with fidelity and precision , 1312, 1 postmitotically is a key determinant of neuronal subtype diversification [Experiments involving intercolumnar fate switching have demonstrated a consequent and congruent change in axonal trajection. For example, ectopic expression of Hoxc10 (lumbar) at thoracic levels causes a fate change to LMC MNs, which then project into the lower limb . These efication , 53, 54.fication , 54. Sucfication . ExperimAgainst the background of these studies, it is clear that the descriptive term \u201cMN\u201d is an oversimplification and the numerous motor neuronal subtype differences described above begin to demonstrate some of the necessary complexity inherent in MN diversification. The developmental biology that underpins MN differentiation is relatively well understood and thus provides a rational basis for using human stem cell-based systems to allow further elucidation of mechanisms responsible for generating MN subtype diversity. in vitro. PSCs respond predictably to developmental cues such that their fate can be systematically manipulated to differentiate into myriad cell lineages from any of the 3 germ layers. There are 3 principal properties that characterize PSCs: (i) the ability to self-renew, (ii) pluripotency [ in vitro culture conditions for the propagation of undifferentiated vertebrate tumor cell lines in the 1970s [ in vitro fertilization clinics [There are different sources of species-specific stem cells including embryonic, fetal, and adult varieties. Embryonic stem cells (ESCs) are a type of PSC thus possessing the greatest developmental potentialderived) , and also represents a potential problem because this cannot, at present, be predictably altered using extrinsic signals. This tissue specific \u201cmultipotency\u201d is a relative disadvantage when studying cell fate specification, where the pluripotent state represents an ideal investigative tool. Attempts to derive PSCs by different methods have partially tempered the ethical controversy in which the human ESC field is immersed . These e neurons . These d\u03b2 signaling superfamily permits highly efficient neural conversion of PSCs and represents the most widely adopted method employed to date [Predictable and scalable directed differentiation of PSCs to the neural lineage is necessary for studying human neural development, modeling disease, and drug discovery. Several well established methods can robustly achieve neural conversion of PSCs in chemically defined conditions \u201398. Effi to date .The elucidation of developmental inductive cues and transcriptional programmes for MN specification have bee in vitro work using human PSCs suggest that, soon after neural induction, precursors initially assume a rostral and dorsal positional identity through the combined actions of the BMP, WNT, and FGF signaling pathways, which have unique spatiotemporal influences on positional identity and cell fate decisions [ in vitro [Insights from developmental studies across different species and fromecisions , 6. Mousin vitro , 103. On versus simultaneous administration of morphogenetic signals is another interesting subject, which merits discussion here. In the case of motor neurons, for example, the first directed differentiation of MNs from mouse ESCs employed simultaneous administration of RA and Shh [ in vivo motor neuron lineage restriction.Important future studies would include systematic analyses of the requisite time for neural patterning prior to terminal differentiation, which has yet to be definitively addressed. Some studies have suggested that accelerated neural conversion and patterning protocols are possible. The question of sequential and Shh , whereas and Shh the cuesThere is an increasing wealth of literature around the mechanisms underlying neurodevelopment, revealing a remarkable and previously unrecognized extent of neuronal diversity. Functionally relevant differences in molecular phenotype, axonal projection, dendritic arborization, and electrophysiological attributes have been demonstrated between different neuronal subtypes throughout the neuraxis \u2013110. TheTo date, the vast majority of studies using ESCs have focused on deriving MNs generically, while comparatively few studies address the issue of motor neuronal subtype diversification. Most protocols for motor neuron specification from PSCs (either ESCs or iPSCs) utilize the application of a simplistic programme of morphogenetic signals to achieve neural patterning, followed by standard terminal differentiation conditions. Signaling mechanisms and transcriptional events involved in the postmitotic diversification of motor neuronal subtypes from human ESCs remain poorly characterized. Currently, no study has systematically investigated the influence of a morphogenetic signal during both MN precursor \u201cpatterning\u201d and terminal differentiation in order to establish their relative contributions to subtype choice during these distinct developmental stages. in vivo studies [MNs are a diverse collection of neuronal subtypes displaying differential vulnerability in different human neurodegenerative diseases. During embryogenesis, retinoid signaling contributes to caudal precursor specification generically and subsequent MN subtype diversification. RA typically results in a cervical or brachial positional identity , 106. Ag studies . Therefo studies . Collect studies , 111\u2013113 studies (a small studies .Separately, the use of suspension culture , 116 ver in vitro. Access to human PSCs allows questions around early cell fate acquisition to be addressed. Developmental competence to extrinsic morphogenetic signals during embryonic patterning is both spatially and temporally restricted. Human PSCs faithfully recapitulate the key milestones of neurodevelopment and thus permit studies that will improve our understanding of the relative contributions of extrinsic signals, cell-intrinsic transcriptional programmes, and intercellular/paracrine communication to direct cell fate decisions. This reductionist model system, together with the use of a fully defined cell culture medium, provides a unique experimental opportunity to understand the relevance of how signaling pathways function individually or combinatorially to direct lineage restriction at different developmental stages. In turn, such knowledge will permit more predictable manipulation of PSCs to generate desired progeny for experimental study. PSCs therefore represent an unparalleled opportunity to study human neurodevelopmental processes. It is likely that, for future strategies aimed at generating distinct subtypes of MN, controlled extrinsic morphogenetic instruction during both precursor specification and terminal differentiation will be key determinants of success. As a final remark, although there is a considerable degree of conservation in neuraxial systems between rodents and humans, important differences in architecture, computational power, and functional capacity exist. Such evolutionary divergence strongly reinforces the indispensability of human experimental systems to complement, but not replace, existing rodent-based approaches.Elucidating efficient protocols to generate enriched populations of MN subtypes has important biotechnological implications for disease modeling, drug discovery, and potentially cell-based therapy. Such approaches would permit comprehensive mechanistic studies of differential MN subtype vulnerability"} +{"text": "Peromyscus leucopus) utilized space and depredated two incidental prey items: almonds and maple seeds . We estimated mouse population densities with trapping webs, quantified mouse consumption rates of these incidental prey items, and measured local mouse activity with track plates. We predicted that 1) mouse activity would be elevated near full feeders, but depressed at intermediate distances from the feeder, 2) consumption of both incidental prey would be high near feeders providing less-preferred food and, 3) consumption of incidental prey would be contingent on predator preference for prey relative to feeders providing more-preferred food. Mouse densities increased significantly from pre- to post-experiment. Mean mouse activity was unexpectedly greatest in control treatments, particularly <15 m from the control (empty) feeder. Feeders with highly preferred food (sunflower seeds) created localized refuges for incidental prey at intermediate distances (15 to 25m) from the feeder. Feeders with less-preferred food (corn) generated localized high risk for highly preferred almonds <10 m of the feeder. Our findings highlight the contingent but predictable effects of locally abundant food on risk experienced by incidental prey, which can be positive or negative depending on both spatial proximity and relative preference.Abundant, localized foods can concentrate predators and their foraging efforts, thus altering both the spatial distribution of predation risk and predator preferences for prey that are encountered incidentally. However, few investigations have quantified the spatial scale over which localized foods affect predator foraging behavior and consumption of incidental prey. In spring 2010, we experimentally tested how point-source foods altered how generalist predators (white-footed mice, Predator foraging behaviors, and the resulting distribution of predation risk within a landscape, are influenced by what prey are available and where they are located. Optimal foraging theory provides a framework for predicting predator choice of prey on the basis of energetic profitability , as wellZea mays) spatially concentrate foraging by raccoons (Procyon lotor), increasing predation risk for nearby nests of wild turkeys and turtles /11 = 0.44. This subtle but potentially important reduction in risk is an important consideration when interpreting results showing elevated risk of generalist predation near artificial food sources [Regarding our second prediction, we did not observe a general pattern of depressed track activity at intermediate distances from either filled or empty feeders. This lack of result is likely related to the difference in spatial areas: for example, the annulus between radii of 10 and 25 m has an area 21 times larger than the circular area within 5 m of the feeder. Thus, the shift of a fixed amount of mouse activity from the annulus to the circle would cause an increase in activity density near the center 21 times greater than the corresponding decrease in the annulus. Such a subtle decrease in activity is likely to require very high sample size to reliably detect. However, even subtle modifications in predator activity, and thus predation risk, over large areas can disproportionately increase prey survival rates. Concentrating predation risk in space generally increases overall survival of relatively sessile prey because depletion of prey in high-risk areas quickly generates a negative spatial correlation between prey abundance and risk , 61. Jen sources , 63, 64.Regardless of the cause of spatial variations in mouse activity, we expected that consumption rates of incidental prey would reflect the local risk of discovery, as indicated by mouse activity, mediated by predator preference for these prey relative to the provided food treatment. Based on these expectations, our third prediction was that consumption rates for both incidental prey items would be elevated near feeders providing a less-preferred food (corn). This prediction was partially supported for almonds but not for maple seeds. On the other hand, sunflower seeds have higher energy density and protein content than corn, so we predicted that feeders providing sunflower seeds would elevate local consumption of almonds but depress consumption of less-preferred maple seeds. However, consumption of both almonds and maple seeds was depressed near feeders providing sunflower seeds. Taken together, these deviations from our predictions regarding consumption rates imply that the incidental prey items we deployed were consistently devalued relative to the food provided in feeders. Incidental prey may be devalued by handling time cost imposed by seeds being embedded in wax. However, predation by small mammals (mainly white-footed mice) was much greater for freeze-dried gypsy moth pupae affixed to burlap with beeswax than for naturally occurring gypsy moth pupae at the same microsites and times , so wax Sciurus niger) over-utilized poor-quality habitat patches [The findings of this study may be applied to other generalist consumers and their prey . Abundant food sources can decrease rodent predator activity levels , 58, inf patches and decr patches . DifferePanthera leo), deviated from optimal foraging expectations by choosing suboptimal prey based on prey group size, prey distance from the hunting group, and prey group composition [The results of this investigation may be broadly applied to predator and prey interactions. Optimal foraging theory provides a general predictive framework for predator foraging behavior and choice of prey. However, generalist predators can deviate from optimal expectations by altering their space use and consuming suboptimal prey. Large predatory mammals, like African lions (position . Avian cposition . Differe"} +{"text": "HIV transmission occurs predominantly across mucosal surfaces. An ideal preventive strategy would be to target HIV at mucosal entry sites to prevent infection. We developed a novel epithelial stem cells-based AIDS preventive approach in female macaques. This approach is based on the ability of therapeutic lentiviral vectors integrated in mucosal epithelial stem cells to induce virus-specific cellular immune responses at mucosal sites of viral entry. We first intended to expose the cervicovaginal tract to conditions used for intravaginal vaccine delivery and non-invasively image local tissues to determine the vaccination effects on epithelial integrity and generation of antigen-specific mucosal immune responses.Experimental cervicovaginal vaccinations were carried out on 12 uninfected female macaques, in conjunction with deliberate abrasion of epithelium using Depo-Provera, 4% nonoxynol-9 treatments, or gentle abrasions to reduce vaginal epithelial height and cell layers number. Longitudinal study was performed for baseline levels of hormones, antibodies, cytokine profiles during normal cycling with/without vaccination. Endoscopic colposcopy followed by optical coherence tomography (OCT) helped monitor macaque cervical-vaginal epithelium pre-, post-, without treatment to measure epithelial thickness changes. Colposcopy help visualizing the vagina and cervix. Blood samples and biopsies were collected at various time-points to evaluate immune responses to vaccination.OCT imaging provided quantitative measurements of epithelial changes and detected minute changes in epithelial thickness and morphology. Colposcopy and OCT imaging correlated with hormone levels and biopsies imaging. Depo-Provera gave better results in epithelium thinning but naturally cycling macaques showed clearer thickness differences. All collected secretions, biopsies and blood samples gave a better understanding of the correlation between menstrual cycle, hormonal level, epithelial thickness changes. Optimal conditions for vaccine delivery were determined and revealed virus-specific T cell response in all vaccinated animals.OCT is well suited for the examination of superficial mucosal layers and close underlying stromal structures of tissues. In this study, we demonstrated the feasibility of using epithelial stem cells as mucosal antigen-presenting cells to induce viral specific immune responses at mucosal sites, and improved our knowledge of the role of mucosal surfaces."} +{"text": "Granulomatosis with polyangiitis is a systemic disease resulting in necrotizing vasculitis of small- and medium-sized vessels. Cardiac involvement is rare and when present usually manifests with pericarditis and coronary artery vasculitis. We report here a case of granulomatosis with polyangiitis involving the native coronary arteries, bypass graft, and pericardium with interesting imaging findings on contrast-enhanced CT and MRI. A 57-year-old man with a history of chronic headaches presented to the emergency room with syncope. Contrast-enhanced CT demonstrated extensive soft tissue attenuation around the native coronary arteries and bypass graft. Contrast-enhanced MRI demonstrated enhancing nodular soft tissue surrounding the coronary arteries, bypass graft, and pericardium. Pericardial biopsy revealed a necrotizing granulomatous pericarditis with vasculitis concerning for granulomatosis with polyangiitis. The patient demonstrated MPO-positive and PR-3 negative serologies. After being discharged on rituximab and prednisone, follow-up CT 3 years later showed significant improvement of the soft tissue thickening surrounding the coronary arteries, bypass graft, and pericardium. Granulomatosis with polyangiitis (GPA) is a form of systemic vasculitis with necrotizing granulomatous inflammation of the upper and lower respiratory tracts and kidneys . GPA invThe literature concerning cardiac involvement is limited. The few case reports and general reviews show that the two most common histologic cardiac manifestations are pericarditis and coronary arteritis. The most frequent clinical manifestation is cardiac arrhythmias, typically supraventricular tachyarrhythmias. We report an unusual case of GPA initially presenting with cardiac involvement affecting the coronary arteries, bypass graft, and pericardium.A 57-year-old white male with history of Graves' disease with ophthalmopathy and coronary artery disease status after 3-vessel CABG presented to the ER after a syncopal episode during a doctor's office appointment. He had been having severe frontal headaches for several months with workup prior to this admission revealing an elevated ESR and bilateral temporal artery biopsies which were negative for giant cell arteritis. A lumbar puncture revealed elevated protein, increased opening pressure, elevated WBC, IgG index, and oligoclonal bands. A bone marrow biopsy performed for microcytic anemia was unremarkable.Given his history of syncope, a CT angiogram of the chest was performed to exclude a pulmonary embolism. No evidence of pulmonary embolism was seen; however, soft tissue attenuation around the coronary arteries, bypass graft, and pericardium raised concern for vasculitis Figures and 2. FA pericardial biopsy demonstrated dense scar tissue associated with a mononuclear infiltrate comprised mostly of nodular aggregates of monocytes and macrophages . Within Myeloperoxidase associated ANCA vasculitis with orbital pseudotumor and pericardial involvement was considered to be the most likely diagnosis. He was discharged after being placed on prednisone and rituximab. Subsequent contrast-enhanced chest CT 3 years later showed significant improvement of the soft tissue thickening around the coronary arteries, bypass graft, and pericardium .GPA affects multiple organ systems and may involve any part of the body. The upper respiratory tract is involved in nearly all patients. In addition, a vast majority of patients with GPA will also have pulmonary (90%) and renal (80%) involvement . ElevatiCardiac involvement is relatively rare in GPA even though autopsy results show that GPA related cardiac abnormalities are present in one-third of patients . CardiacThe coronary arteries are frequently involved in systemic arteritis. The inflammatory infiltrate damages the intima and may trigger the occurrence of coronary thrombosis. Morbini et al. report an extreme example of an elderly female with intimal inflammation in multiple sites of a coronary tree with and without atherosclerosis which triggered coronary thrombosis. She died after cardiac arrest from a clinically unrecognized systemic autoimmune-inflammatory disorder with necrotizing arteritis. Autopsy showed findings typical of GPA and systemic arteritis with fibrinoid necrosis and systemic arteritis. Although there were no clinical signs of cardiac involvement, the coronary arteries showed inflammation associated with multiple mural and occlusive thrombi .Ohkawa et al. reported a case of generalized GPA with extensive cardiac involvement at autopsy. Necrotizing angiitis and severe granulomatous inflammatory foci affected the common bundle of His and right bundle branch in addition to the myocardium .Cardiac valvular involvement is an uncommon manifestation of GPA. Espitia et al. reported the case of a 60-year-old woman with severe inflammatory aortic and mitral valvular involvement characterized by GPA with typical histopathological valvular lesions. Cardiac valvular involvement is a rare and potentially fatal complication of GPA and may misleadingly suggest infectious endocarditis .Currently, multiple imaging modalities are increasingly used as first-line noninvasive diagnostic tools to assess target-organ involvement in GPA, although biopsy with pathological testing represents the gold standard . In our To the best of our knowledge this is the first case report showing involvement of a bypass graft, native coronary arteries, and pericardium as the initial manifestation of GPA.In conclusion, cardiac involvement of GPA is rare. It must be included in the differential diagnosis when soft tissue thickening involves the coronary arteries and pericardium, even when no pulmonary or airway findings are identified."} +{"text": "On the evening of 13 November 2015, three terrorists equipped with military-grade firearms and explosive jackets penetrated Bataclan, a Paris music hall containing 1500 people [Immediately, RAID , the French national police counter-terrorism team, and the BRI (Research and Intervention Brigade) were engaged. As previously reported , 3, thesFirst, RAID police officers and tactical physicians proceeded to zoning. Priority was given to police operation and safety . They deWhile police operators were getting into position within the theater and thus repelling terrorists, two RAID tactical physicians performed triage in the combat zone , 4. TheyIn the combat zone, RAID tactical physicians applied tourniquets to 15 invalid patients [Once salvage therapies were performed , more thTwo tactical physicians joined the operation theater. They perform damage control resuscitation to casualties within the dressing station . SeveralThe initial tactical physicians then joined the assault team to act as forward medical officers. The remaining two terrorists committed suicide, detonating their bombs during a final assault, without causing additional fatalities.Because the environment remained under the threat of explosives, despite terrorists\u2019 neutralization, conventional rescue teams were maintained out of the exclusion zone until the end of mine-clearing operations. All five physicians continued to perform damage control resuscitation on invalid patients until they were transferred to the casualty receiving station. When conventional rescue teams received clearance to penetrate the theater, all living casualties had already been extracted. The teams discovered 89 fatalities.Owing to the mismatch between the number of casualties and tactical physicians, the latter first decided to secure non-invalid casualties before treating invalid patients with severe but accessible lesions. The tangle of numerous dead bodies might have hidden living casualties from tactical physicians\u2019 view, preventing the former from receiving care in time.Not all the concepts of damage control resuscitation were performed. Some of the casualties did not even receive damage control resuscitation, owing first to the aforementioned mismatch between the number of casualties and tactical physicians and second to an insufficient amount of available medical equipment.Maintaining conventional rescue teams out of danger was consistent with prehospital disaster plans. This appeared a safe option because mine-clearing operators discovered a bag filled with explosives. Of note, despite dynamic adaptation of the exclusion zone boundaries to the threat, post hoc analysis revealed that the distance between the dressing station within the theater and the casualty receiving station was excessive."} +{"text": "RECIST criteria use changes in tumour diameters to quantitatively obtain response assessments for traditional chemotherapeutic cancer treatments: Positive responses are identified by reductions in tumour size while tumour growth signifies non-response.transarterial chemo embolization (TACE) can be used alone or in combination. Local treatment, radiation therapy, immunotherapy and targeted therapy can each result in an increased tumour diameter in spite of treatment response at the cellular level and increased survival times. As a result, tumour diameter can no longer stand alone when assessing oncological treatment strategiesTraditional chemotherapies work primarily by damaging cells that are undergoing rapid growth and division. Immunotherapies work by stimulating the immune system to reject and destroy tumour cells. Targeted cancer therapies block the growth of cancer cells by interfering with specific molecules needed for tumour growth and carcinogenesis. These oncological treatments as well as stereotactic radiation therapy and local treatments, such as image-guided ablations and Tumour heterogeneity and contrast enhancement often change during treatment, and tumour enhancement combined with tumour size has been shown to be successful in assessing treatment response in gastrointestinal stromal tumours (CHOI criteria). Modified CHOI criteria could potentially be used for monitoring the effect of oncological treatment strategies in metastatic renal cell cancer and hepatocellular carcinoma.Dynamic contrast-enhanced imaging uses changes in tumour enhancement following the intravenous injection of a contrast media to create a time-versus-signal curve. From such curves, reliable quantitative estimates of blood flow, blood volume and permeability can be obtained. Diffusion-weighted MRI and PET can also be used to obtain quantitative measures of physiological processes. A major advantage of DWI-MRI and PET is the possibility of whole body coverage, while DCE imaging is limited to a single tumour or a comparatively small region.Although quantitative assessments of oncological treatment response using physiological parameters have been shown to be superior to size-based response in several studies, the methods mentioned are not yet standardized, and randomized multicentre studies have not yet been performed. When planning such studies, it is important to note that clinical endpoints such as progression free survival and overall survival are superior to morphological imaging results.In the routine assessment of oncological treatment responses, it is becoming increasingly important for the radiologists to know exactly what kind(s) of treatment that the patient has received. Simply reporting changes in tumour size using RECIST is no longer sufficient considering the large percentage of patients who receive advanced and often combined treatment regimens."} +{"text": "Our patient presented dramatically with a previously unrecognized FAP complicated by heart failure requiring heart transplantation at the age of 49 years and liver transplantation at the age of 51 years. Direct DNA sequencing of the TTR gene showed a heterozygous Glu89Lys mutation in the proband and her daughter (published in Transplantation 2011).Longitudinal follow-up with clinical scores with ancillary testings.After her double transplantation, the patient reported over the 8 subsequent years slowly progressive increasing pain and loss of sensation in the feet, slow bowel habit, and delayed urine flow. On examination, we found orthostatic hypotension, sensory loss, muscle weakness, and mild atrophy in the distal lower extremities with reduced Achilles tendon reflexes. Nerve conduction studies revealed a mild decrease of amplitude of motor and absent sensory action potentials and normal velocities except for bilateral slowing within the carpal tunnels. The sympathetic skin response and Sudoscan responses to electrical stimuli was normal in the palms but not in the soles. No complications were seen, such as acute rejection, portal vein thrombosis, or infectious diseases resulting from administration of immunosuppressive drugs.As already described, some late-stage patients continue to show FAP progression even after liver transplantation, and longstanding disease is correlated with increased morbidity related to continuing amyloid fibril formation."} +{"text": "TARVA is an NIHR HTA funded portfolio randomised controlled trial (RCT) comparing total ankle replacement (TAR) and arthrodesis (fusion) surgery in NHS patients aged 50-85 with end-stage ankle arthritis. 328 patients will be randomly allocated to TAR or arthrodesis on an equal basis.Clinician and patient treatment equipoise is critical to recruit surgeons and patients successfully.The TARVA Trial team has developed novel surgeon and patient engagement techniques involving technology and multi-media tools to achieve our aims. Examples include an award-winning video, a white-labelled patient information brochure, professional newsletters and blogs, and a particular focus on the use of social networking tools to engage both investigators and patients.http://anklearthritis.co.uk).The impartial trial information video featuring consultant foot and ankle surgeons and patients who have undergone TAR or fusion surgery can be accessed through the trial website (The pilot phase began with the randomisation of the first patient in March 2015. An overview of our techniques alongside recruitment data accumulated until November will be presented at the ICTM conference."} +{"text": "Planning malaria interventions requires the prediction of likely impacts of different intervention strategies. Simulation models can provide such predictions but weak information about pre-control levels of transmission, intervention coverage and access to care often makes it challenging to correctly parameterize them. We consider a number of low malaria transmission sites in Madagascar, with available historical prevalence and entomological inoculation rate (EIR) estimates (by mosquito sampling), giving disparate estimates of historical exposure. Information about implementation of Long Lasting Insecticide Nets (LLINs) and Indoor Residual Spraying (IRS), and access to healthcare, collated from malaria surveys and on-going cross-sectional studies were used to parameterise simulations of malaria transmission, prevalence and burden within the OpenMalaria platform. Multiple parameterisations were considered using various sources of data for pre-intervention transmission level, intervention coverage and access to healthcare. In some sites the simulated impact of existing vector control programs matches reasonably well the malaria prevalence measured in a recent national survey. In others it predicts lower than observed prevalence, very likely because the models do not capture residual local transmission foci. The simulations suggest that the most cost-effective vector control strategy would be to scale-up LLINs or IRS only, depending on the transmission level. Indeed, preliminary results show no additional benefit of IRS where LLINs were used. These preliminary results suggest that historical prevalence data, combined with current coverage information are potentially adequate for planning intervention strategies. The outcome of intervention scale-up is essentially unpredictable if baseline information is poor. Reproducing the observed epidemiology of malaria through simulations both provides confidence in the use of the model but serves as a basis for prospective studies that support decision-making, including cost-effectiveness analyses."} +{"text": "Reversing anthropogenic impacts on habitat structure is frequently successful through restoration, but the mechanisms linking habitat change, community reassembly and recovery of ecosystem functioning remain unknown. We test for the influence of edge effects and matrix habitat restoration on the reassembly of dung beetle communities and consequent recovery of dung removal rates across tropical forest edges. Using path modelling, we disentangle the relative importance of community-weighted trait means and functional trait dispersion from total biomass effects on rates of dung removal. Community trait composition and biomass of dung beetle communities responded divergently to edge effects and matrix habitat restoration, yielding opposing effects on dung removal. However, functional dispersion\u2014used in this study as a measure of niche complementarity\u2014did not explain a significant amount of variation in dung removal rates across habitat edges. Instead, we demonstrate that the path to functional recovery of these altered ecosystems depends on the trait-mean composition of reassembling communities, over and above purely biomass-dependent processes that would be expected under neutral theory. These results suggest that any ability to manage functional recovery of ecosystems during habitat restoration will demand knowledge of species' roles in ecosystem processes. Significant advances have been made in understanding the cascading effects of global environmental change on biodiversity loss and associated ecosystem functioning Restoration ecology has long sought to identify the mechanisms that determine trajectories of community assembly One effective platform for linking species responses to environmental change with the functional consequences of shifting trait composition has been to employ a response-effect trait framework In this study, we test the trait determinants of dung beetle community responses to experimental habitat restoration in the land-use matrix surrounding heavily degraded montane rainforest edges in Nigeria. Habitat loss, and subsequent degradation of rainforest edges due to cattle encroachment, fire, and altered biotic and abiotic conditions, are amongst the most severe drivers of biodiversity loss and alteration of ecosystem functioning in tropical forests Although terrestrial invertebrates are the second most represented taxa in studies investigating trait-mediated ecosystem processes This study was conducted in Afromontane forest at the Ngel Nyaki Forest Reserve, located on the Mambilla Plateau near the south-eastern border of Nigeria . No specific permissions were required regarding collection of invertebrate specimens in this location and our study did not involve any known endangered or protected species. The forest reserve is an outlying section of the West African montane forest network within the Cameroon Highlands ecoregion As part of the Nigerian Montane Forest Project (NMFP) aimed at protecting Ngel Nyaki Forest Reserve from land clearing, burning and cattle grazing, three fenced exclusion zones were established up to 200 m outside the dense sub-montane forest zone, 3 years prior to the sampling procedure. These regenerating sites could then be compared with degraded edge zones where no restoration in the adjacent matrix had been established . The lenth October to 29th November 2009. To quantify the interactive effects of habitat edges and adjacent matrix restoration on dung beetle community structure and associated ecosystem processes, we sampled dung beetle communities and dung removal rates along three replicate forest-to-matrix edge gradients in both degraded and regenerating sites (n\u200a=\u200a6). Although treatment-level replication was low, it is important to note that this is an experimental manipulation of matrix structure which was specifically targeted at a single experimental site where all edges had previously had a common history of edge degradation (just 3 years prior to sampling), and sampling completeness was high Sampling was conducted at Ngel Nyaki Forest Reserve during the late rainy season from 4Degraded edges spanned forest-to-matrix habitats that were fully exposed to anthropogenic threats typical of the area (such as intensive cattle grazing and fires), compared to the regenerating edges where these threats had been entirely excluded for three years . One addca 20 cm above the cup using wooden stakes. From this trap cover, dung bait was suspended with string so that the bottom of the bait was level with the rim of the cup. The bait was contained within muslin mesh which allowed the scent of the bait to easily permeate into the surrounding atmosphere but was fine enough to exclude insects from directly accessing the bait and thus altering its attractiveness. The cup was filled with approximately 200 ml of water and five drops of highly concentrated, odourless, and clear detergent which served to break the surface tension of the water. Pig dung was used as bait because omnivore dung is recognised as the most widely attractive to dung beetles We used pitfall traps baited with 40 g of pig dung placed at each distance across the edge gradient for two consecutive 24 hour periods (pooled 48 hour samples for each edge gradient transect) to ensure adequate sampling of the local community To quantify the impact of edge effects and matrix restoration on dung removal rates we placed experimental dung piles at each of the 101 sampling points and measured the proportion of dung removed in 24 hrs. Dung removal experiments were undertaken 1\u20132 days prior to baited pitfall trapping of dung beetles at each site, in order to avoid potential trap depletion effects on beetle communities that might otherwise have confounded dung removal rates. It should be noted that there could still have been potential interference of the removal experiment on pitfall trapping, as beetles that had already been attracted to dung placed out in the removal experiment may still have been buried in the soil, either laying eggs, provisioning brood balls, or already satiated. However, there is little reason to expect that this effect would have operated inconsistently across our treatments and is unlikely to have been systematically biased toward particular morphological traits of dung beetles, so we expect any such effect to have had a minor influence on our overall results. At each sampling point debris such as dead wood or leaves within a 15 cm radius of dung placement was removed down to the topsoil and 40 g of fresh pig dung was placed directly on top of the bare soil. This amount of dung was sufficient to avoid complete removal and allow reliable comparisons among sampling points, but still equal to the amount of bait used in pitfall traps so that dung removal rates could be realistically compared to sampled dung beetle communities. After 24 hours, the remaining dung was collected and, after removing any attached debris, dry mass loss was calculated after taking into account moisture content loss, yielding a rate of dung removed per 24 hrs see .2), multiplied by two for total wing area, which was then used to calculate wing loading as the ratio of body mass to total wing area. To take into account within-species trait variation, we measured multiple individuals within each species for all samples collected. However, for highly-abundant species, we used a randomized subsampling procedure so that at least 20 individuals were measured per sample for each abundant species or by variation in the abundances of species with differing traits, we used a hierarchical path modelling approach Second, dung removal rates might be dependent on average trait values expressed in a given community. To test this hypothesis, we included all measured traits within the path model. Because we suspected there could be collinearity among the trait predictors, we checked for correlations among variables while constructing the path model. In most cases, predictors within the GLMMs were sufficiently weakly correlated so that interpretation of the models was considered reliable (|r|<0.7) Third, we hypothesised that there might be a niche complementarity effect whereby community functional trait dispersion determines dung removal efficiency of dung beetle communities. As a measure of functional trait complementarity, we calculated a distance-based metric of trait functional dispersion (FDis) using the \u201cFD\u201d package A total of 4705 dung beetles were captured across all sites, comprising 33 species in 12 genera . Of thesDung removal rates also varied dramatically across habitat edge gradients, ranging from an average of >75% dung removal over a 24-hr period in the forest interior to \u223c0% removal in the matrix habitat . MoreoveResults from the multilevel path analysis revealed that dung removal rates were influenced by trait-dependent effects, over and above the positive influence of total beetle biomass on removal rates . First, Second, community-weighted trait composition also responded significantly to both edge effects and matrix restoration, but with variable responses across different traits. For instance, at degraded edge gradients there was a significant increase in mean pronotum width, wing loading and BSI of individual species from the forest into the matrix habitats . HoweverAs expected, variation in the trait-mean composition of species strongly influenced functional trait dispersion, particularly with respect to wing area, body mass, and pronotum width effects, together explaining 76% of variation in functional dispersion across samples. For our study system, however, there were no apparent direct influences of edge effects or matrix restoration on functional trait dispersion after controlling for variation in community-weighted trait composition. There was also no flow-on effect of functional trait dispersion on rates of dung removal, despite the strong association of trait composition with dispersion.Finally, the relative partitioning of trait mean effects, functional trait dispersion, and mass-dependent neutral effects did not capture all the potential proximate factors mediating the effect of anthropogenic disturbance on dung removal rates. There was a significant interaction effect between matrix restoration and edge effects that had a residual direct influence on dung removal rates at matrix restoration sites, although at degraded sites there was no residual direct effect of edge impacts on dung removal rates . This suWe demonstrate that matrix habitat restoration can have a profound influence on nutrient cycling-related ecosystem functioning at degraded tropical forest edges. For the removal of dung by dung beetles, the path to functional recovery depended not only on the random reassembly processes contributing to total dung beetle biomass , but also on the body sizes (i.e. pronotum widths) of recolonizing individuals. Given the importance of restoring ecosystem functioning in restoration efforts The key to determining the pathways through which matrix restoration drives functional recovery was the application of a response-effect trait framework within a path-modelling context. While this approach has been widely adopted in modelling human impacts on ecosystem processes within degraded systems, it holds untapped promise in a restoration context. From this analysis, we showed that matrix restoration substantially ameliorated the negative impacts of habitat edge effects on dung beetle biomass and community trait composition observed between forest and matrix habitats at the degraded sites. In particular, edge effects on community-weighted trait means of dung beetle pronotum width and wing loading at degraded edges were significantly reduced by the restoration of the adjacent matrix habitat. Given that small-bodied invertebrate species typically have lower physiological tolerance to anthropogenic disturbance In many ways, this rapid rate of recovery is surprising after just three years of experimental matrix regeneration. Many previous studies have suggested there can be long lag-times to faunal community re-assembly following revegetation, particularly for small-bodied species with low dispersal capacity 2 (despite maximum wing area of 1098.53 mm2), the key driver of variation in trait dispersion was the distribution of the few rare beetles with large body mass and relatively large wing area . Interestingly, there was a significant negative effect of community-weighted pronotum width on functional dispersion . We interpret this as species that are smaller than expected based on their body mass making a greater contribution to high trait dispersion.Surprisingly, matrix habitat restoration had no direct influence on community-wide trait dispersion at forest edges, but there were significant indirect effects observed via the mediating effects of community-weighted trait means on functional trait dispersion. In particular, there were highly significant effects of community-weighted mean body mass, pronotum width, and wing area on functional trait dispersion, with all three traits having equivalent standardized effect sizes. Because the vast majority of dung beetles captured (>86%) had a body mass of <10 mg (despite maximum body mass of 1543.07 mg) and wing area of <20 mmBy partitioning community-wide responses into separate trait-mean variables versus overall variability in community-level trait dispersion, our results demonstrate the varying sensitivity of different trait measures to environmental change. Functional trait dispersion was strongly affected by matrix habitat restoration at forest edges, but these effects were only manifested indirectly via the shared influence on multiple components of trait variation. No single trait response variable could explain the observed response in functional trait dispersion in its own right, suggesting the need to quantify multiple traits in order to capture their role in community assembly during restoration. At the same time, though, only very few trait responses were required (three in this case) to explain a relatively high proportion of the variation (76%) in community-wide trait dispersion.Trait determinants of community responses to environmental change also had a significant influence on rates of beetle-mediated dung removal. Although we found no niche complementarity effect on dung removal driven by variation in functional trait dispersion, there was a clear effect of community-weighted mean trait composition on dung removal rates, over and above neutral mass-dependent effects. This was demonstrated by the relatively large standardised effect size of community-weighted mean pronotum width on dung removal (\u22120.319), which had almost as strong a standardised effect on dung removal as total beetle biomass (0.342), supporting the claim that neutral processes alone may not be able to fully explain functional processes et al. Surprisingly, the mediating effect of community-weighted mean pronotum width on dung removal was negative, suggesting that in samples with a smaller weighted-average body size of dung beetles, the removal rate of dung was proportionately greater per unit mass of beetles. Many previous studies have pointed to the importance of large dung beetles in dung decomposition rates, whereby body size is assumed to be positively correlated with amount of dung sequestered In addition to mass- and trait-dependent effects, we also detected a significant residual interaction effect of our treatment drivers on overall rates of dung removal, with matrix restoration mitigating the low rates of dung removal observed at degraded edges significantly more than could be explained by recovery in dung beetle biomass or trait-dependence in reassembly processes alone. This is almost certainly due to unmeasured variation in environmental parameters along edge gradients, such as substantial reduction in dung desiccation rates at regenerating edges and facilitation or competition from other dung-associated organisms that are likely to alter removal rates differentially among regenerating and degraded edge gradients. Furthermore, it is possible that other unmeasured traits such as dung removal strategy or diel activity patterns could help to explain some of this residual variation. A better mechanistic understanding of these processes is still needed in order to understand how other contributing factors such as these might help to explain variation in ecosystem functioning following restoration.Overall, this experiment has shown that restoration of the matrix surrounding degraded tropical forest remnants can drive large increases in the biomass of organisms and their associated ecosystem processes, even over very short time periods. Interestingly, the enhancement of dung removal rates through restoration could not be explained solely as a function of increasing biomass of decomposer organisms without recourse to trait-dependence in ecosystem process rates. A notable proportion of variation in dung removal was explained by community-mean body size that in turn resulted in significant effects on dung removal, suggesting that \u2018neutral\u2019 measures of community assembly alone cannot explain functional outcomes of habitat restoration. Rather, we found that recovery of a suite of disturbance-sensitive species with low dispersal power and small body size, but high per capita dung removal efficiency (for their size), resulted in higher dung removal rates at habitat edges undergoing adjacent matrix restoration. The observed mediating effects of response and effect traits on dung removal are likely to have far-reaching consequences for heavily-degraded tropical forest remnants, through cascading changes in insect-mediated ecosystem functions such as nutrient cycling rates and secondary seed dispersal that can have strong deterministic impacts on plant communities S1 FigureLayout of edge gradient sampling transects.(DOCX)Click here for additional data file.S2 FigureEdge-gradient sampling design.(DOCX)Click here for additional data file.S3 FigureExample of the left hind wing of an individual male Onthophagus sp. 1.(DOCX)Click here for additional data file.S4 FigureContour plot demonstrating the combined effects of total beetle biomass and community-weighted mean body mass on proportion of dung removed.(DOCX)Click here for additional data file.S1 TableTrait mean values for dung beetle species.(DOCX)Click here for additional data file.S2 TableList of dung beetle species and their occurrences.(DOCX)Click here for additional data file.S3 TableAkaike Information Criterion (AIC) scores obtained from the edge function fitting procedure.(DOCX)Click here for additional data file.S4 TableComplete basis set of independence claims for the selected best-fit path model.(DOCX)Click here for additional data file.S1 AppendixMeasuring rates of dung removal.(DOCX)Click here for additional data file.S2 AppendixMeasurement of dung beetle traits.(DOCX)Click here for additional data file.S3 AppendixContinuous edge response models.(DOCX)Click here for additional data file.S4 AppendixConstructing generalised multilevel path models.(DOCX)Click here for additional data file."} +{"text": "Adult skeletal muscle possesses extraordinary regeneration capacities. After muscle injury or exercise, large numbers of newly formed muscle fibers are generated within a week as a result of expansion and differentiation of a self-renewing pool of muscle stem cells termed muscle satellite cells. Normally, satellite cells are mitotically quiescent and reside beneath the basal lamina of muscle fibers. Upon regeneration, satellite cells are activated, and give rise to daughter myogenic precursor cells. After several rounds of proliferation, these myogenic precursor cells contribute to the formation of new muscle fibers. During cell division, a minor population of myogenic precursor cells returns to quiescent satellite cells as a self-renewal process. Currently, accumulating evidence has revealed the essential roles of satellite cells in muscle regeneration and the regulatory mechanisms, while it still remains to be elucidated how satellite cell self-renewal is molecularly regulated and how satellite cells are important in aging and diseased muscle. The number of satellite cells is decreased due to the changing niche during ageing, resulting in attenuation of muscle regeneration capacity. Additionally, in Duchenne muscular dystrophy (DMD) patients, the loss of satellite cell regenerative capacity and decreased satellite cell number due to continuous needs for satellite cells lead to progressive muscle weakness with chronic degeneration. Thus, it is necessary to replenish muscle satellite cells continuously. This review outlines recent findings regarding satellite cell heterogeneity, asymmetric division and molecular mechanisms in satellite cell self-renewal which is crucial for maintenance of satellite cells as a muscle stem cell pool throughout life. In addition, we discuss roles in the stem cell niche for satellite cell maintenance, as well as related cell therapies for approaching treatment of DMD. Skeletal muscle is the most abundant tissue in the mammalian body accounting for approximately 40% of body weight, and is composed of multinucleated fibers that contract to generate force and movement. In addition, skeletal muscle possesses a remarkable ability to regenerate, and can go through rapid repair following severe damage caused by exercise, toxins or diseases. Muscle satellite cells were discovered by Alexander Mauro in 1961 , indicating the heterogeneity of quiescent satellite cells mice display reduced significant reduction in satellite cell number, resulting in the failure of muscle growth and neonatal lethality of most Pax7 KO mice mice display neural tube and cardiac chamber malformations, missing limb muscles which originate from migratory myogenic cells from somites, and die embryonically by day E14 satellite cells demonstrated the equivalent regenerative potency compared to wild-type satellite cells was significantly increased compared to wild-type myoblasts following intramuscular injection into regenerating mouse muscle and -206 (miR-206) are up-regulated, while Pax3 is down-regulated by miR-1 and miR-206 via direct binding of these miRNAs to the 3' untranslated region (UTR) of Pax3. This Pax3 down-regulation in activated satellite cells is also mediated by miR-27b pathway quiescent satellite cells were YFP(\u2212) cells, indicating that these YFP(\u2212) quiescent satellite cells have never expressed Myf5. Since Myf5 is one of the myogenic regulatory factors and known to regulate embryonic myogenesis, YFP(\u2212) satellite cells may be less committed cells compared to the YFP(+) population. In addition, the transplantation experiments clearly revealed that Pax7(+)YFP(+) cells preferentially underwent myogenic differentiation while Pax7(+)YFP(\u2212) cells were able to extensively contribute to generate satellite \u201cstem cell\u201d in regenerating muscle lineage using CreMyf5/+/loxP/loxPPax7 mice revealed that the majority of adult satellite cells originate from Myf5-expressing myogenic cells, and that the majority of satellite stem cells are replenished from Myf5-expressing cells /Myf5(\u2212) myogenic progenitor cells also give rise to Pax7-positive satellite cells during development self-renewing cells showed delayed muscle regeneration and reduced satellite cell self-renewal surrounding muscle cells is also known to undergo extensive remodeling during muscle regeneration. Consequently, excessive composition of interstitial ECM promotes the appearance of connective tissue or fibrosis in muscle under certain conditions such as those seen in DMD or aging muscles. Urciuolo and colleagues have recently demonstrated that an ECM protein, collagen VI, is critical as an extracellular niche protein to maintain the satellite cell pool (Urciuolo et al., in vitro. Satellite cells cultured on this substrate have shown higher potency of self-renewal than those cultured on traditional plastic dishes. Additionally, myoblasts cultured on hydrogel could promote the efficacy of cell engraftment and the reconstitution of satellite stem cells in vivo, indicating that substrate elasticity is also an important factor of satellite cell self-renewal (Gilbert et al., As described above, accumulating evidence has elucidated the signaling network for self-renewal in satellite cells while Gilbert and colleagues provide us new insight that the skeletal muscle microenvironment potentially regulates stem cell fate (Gilbert et al., In addition to cell commitment, recent reports indicate that physiological conditions in satellite cells may influence the regulation of self-renewal. Liu and colleagues have proposed that hypoxia does not affect myoblast proliferation but instead promotes satellite cell self-renewal through up-regulating Pax7 (Liu et al., It is widely accepted that satellite cells are essential for postnatal muscle growth and muscle regeneration. Despite high potency of myogenic differentiation in satellite cells, these cells are currently not applicable for cell transplantation therapy against DMD due to severe limitations, such as low cellular survival, incomplete myogenic differentiation, and especially poor satellite cell formation (Tedesco and Cossu, Recently, accumulating evidence has revealed the satellite cell heterogeneity and the molecular mechanisms of cell fate determination, specifically whether satellite cells differentiate into myocytes or self-renew as stem cells. These studies demonstrated that maintenance of the satellite cell pool is intrinsically and extrinsically regulated by many regulators. Novel knowledge about muscle regeneration through satellite cells may provide us new therapeutic approaches for DMD patients. Additionally, there are multiple unexplained muscular diseases, such as sarcopenia or muscle atrophy. In order to discover ideal therapies for muscular diseases, it is essential to explore fundamental molecular mechanisms of muscle satellite cells using new methodological technologies such as sequencing-mediated global gene regulation.Norio Motohashi and Atsushi Asakura wrote the manuscript. Both authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Preeclampsia is a unique pregnancy-related disease that affects 5-7% pregnancies worldwide. Placental architecture is modified in PE and eclampsia. Placental morphology and cellular arrangement are important for oxygen delivery from the mother to the fetus. Fetal growth and well-being after 20 weeks of gestation are dependent upon successful placental development. This, in turn, is achieved by an enhanced maternal blood supply to the placenta and growth/ differentiation of the gas-exchanging placental villi. Conversely, pregnancy with severe placental insufficiency exhibits abnormalities both in uterine artery and in umbilical artery Doppler, and results in adverse perinatal outcome. The evaluation of placental functioning is possible nowadays through ultrasound examinations. Sonographic images associated with placental lesions include cystic areas, heterogeneous appearance of the placental mass, and thick or thin placentas. Sonographic evidence of destructive placental lesions is defined as the evolution of irregular cystic spaces with echogenic borders \u2013 the echogenic cystic lesions. Histological examinations of placenta may confirm these antepartum observations. Decidual vasculopathy and accelerated villous maturity are considered indicative of uteroplacental vascular insufficiency. Perivillous fibrin deposition and intervillous fibrin are considered indicative of intervillous coagulation. Detailed sonographic evaluation of the placenta and histopathological confirmation after birth are used to identify lesions associated with preeclampsia, intrauterine growth restriction and adverse short and long-term perinatal outcome, but the presence of cystic images in the placenta is not uniformly associated with adverse perinatal outcome. Combining Doppler studies with placental texture studies may lead to satisfactory results. Abbreviations: PE = preeclampsia; IUGR = intrauterine growth restriction; PI = pulsatility index; RIH = rounded intraplacental haematomas; TV = trophoblastic villi; MRI = magnetic resonance imaging Because of lack of predictive early markers and effective pharmaceutical interventions, PE is a serious obstetric complication leading to increased maternal and fetal morbidity and mortality.Preeclampsia (PE) is a unique pregnancy-related disease that affects 5-7% pregnancies worldwide. It is associated with hypertension and proteinuria. Despite long years of research, the mechanisms underlying the cause and progression of PE remain poorly understood. Risk factors include maternal and paternal family history of PE, nulliparity, ethnicity and existing disorders with several vascular dysfunctions, hypertension or inflammation such as diabetes, chronic hypertension, obesity, kidney disease, systemic lupus erythematosus and antiphospholipid syndrome .Diagnostic procedures during pregnancy complicated with pregnancy-induced hypertension/ preeclampsia include clinical examinations , ultrasound examinations, laboratory testing, fetal well-being assessments. Detailed ultrasound examination of the fetus at 18\u201320 weeks also includes placenta-related information beyond the fetal measurements and morphology: determination of placental length and thickness, number of cord vessels, cord insertion, and the assessment of placental texture. Uterine artery Doppler evaluation is performed by color and pulsed Doppler mapping. Mean pulsatility index (PI) values > 1.45 or bilateral early diastolic notches are considered abnormal . The ultrasound appearance shows an echodense region inside an echolucent area (or a hypoechogenic image with a hyperechogenic rim), without demonstrable blood flow inside (a recently formed hematoma). Old hematomas within an infarcted area might not be identified by ultrasound, as they tend to appear echolucent; with time, a definitive diagnosis can only be made through histopathologic examinations .A detailed sonographic evaluation of cysts includes an evaluation of shape, size and content as well as the absence/ presence of blood flow around or inside the cyst. Cystic areas are frequently observed in association with preeclampsia, growth restriction or fetal demise. Well-defined rounded cystic areas in the placenta are related to a higher risk of preeclampsia and intrauterine growth restriction. Several authors describe them as \u201crounded intraplacental haematomas\u201d (RIH) and report that more than 50% of these cystic lesions were associated with placental infarcts reflecting maternal vascular underperfusion. Magnetic resonance imaging is also useful in diagnosing early placental insufficiency. Heparin is proposed as a treatment choice in preeclampsia with placental infarctions . Insertions of the umbilical cord into the placenta margin or into the fetal membranes (velamentous insertion) rather than into the main placental mass are associated with smaller placentas and smaller infants. Non-marginal, but markedly eccentric cord insertion associates with a weaker chorionic vascular distribution, inefficient transport gradient and a reduced birthweight for a given placental weight specifically vary in PE. The total numbers of TV are significantly lesser, indicating distal villous hypoplasia . Numerous avascular TV surround the arteriosclerotic stem villi, possibly reflecting failure of vascular organization (villitis). TV syncytiotrophoblasts invariably develop clusters and sprouts to form syncytial knots. Histomorphometric findings indicate that the PE placentas have less villous surface area and smaller diameters, whereas the density of the TV was significantly higher .Several studies propose the use of low molecular-weight heparin and aspirin when placental lesions suggestive of infarcts are observed in the ultrasound scan. The studies suggest that the identification of placental lesions with ultrasound in the absence of fetal growth restriction may be managed by antithrombotic treatment. The association of fetal testing may more correctly identify the appropriate time for fetal birth, avoiding in utero fetal demise [10]. Combining Doppler studies with placental texture studies may lead to satisfactory results. This is important for adequate referral to a tertiary perinatal center, for improved clinical outcome, both for mother and fetus .A detailed sonographic evaluation of the placenta and histopathological confirmation after birth are used to identify lesions associated with preeclampsia, intrauterine growth restriction and adverse short and long-term perinatal outcome, but the presence of cystic images in the placenta is not uniformly associated with adverse perinatal outcome [Pregnancies complicated by PE are reflected in the placenta both macroscopically and microscopically and may be diagnosed early by thorough placental serially ultrasound examinations. Although the placenta adapts well to the hypoxic condition in PE, the compensatory changes that occur are insufficient. These compensatory changes cause placental suboptimal development and placental dysfunction that leads to chronic fetal hypoxemia."} +{"text": "In vivo Cardiac Diffusion Tensor Imaging (cDTI) offers the potential to detect myocardial disarray and describe mean intravoxel myocyte orientation; however to date there is little quantitative cDTI data in the normal heart. In this study, we aim to establish the impact of physical and cardiac characteristics on cDTI parameters in a cohort of healthy volunteers.Myocardial disarray is considered an important histological feature of hypertrophic cardiomyopathy (HCM). In vivoWe recruited 46 healthy volunteers for cDTI at 3T. Three short axis mid-ventricular slices were acquired with multiple breath holds at the systolic pause. Data was post-processed with a platform, developed in-house, to create Fractional anisotropy (FA), Mean diffusivity (MD) and Helical Angle (HA) maps.Two of the original 46 volunteers were excluded due to ECG irregularities. Data was successfully acquired in the remaining 44 volunteers table . FA, MD Our data suggests that the cDTI parameters FA and MD, which describe intravoxel myocyte organisation and average myocardial diffusivity respectively, are independent of physical characteristics in healthy subjects. However, there is an association between age and epicardial HA which may be the result of age related loss in longitudinal function. Future NIHR cardiovascular BRU Royal Brompton Hospital & Imperial College."} +{"text": "Multipotent stem cells have been isolated from multiple sources including, bone marrow, adipose tissue, placenta, umbilical cord and cardiac tissue. It is predicted that large numbers of therapeutically-active cells isolated from these tissue sources will be required to treat patients inflicted with various disorders. Experimental evidence suggests that these various cell types can exhibit distinct characteristics depending upon tissue source and method of expansion: differential expression of cellular markers is sometimes detected, doubling times and expansion limits can differ, and physical differences that influence the ability of cells to adhere to various synthetic surfaces are observed. A novel prototype microcarrier recently developed by Pall promotes rapid attachment and growth of multiple cell types in stirred-tank reactors. Additionally, peptide-coating provides an alternative animal component-free substrate for cell expansion. These desirable attributes manifest in both serum-containing and animal component-free medium formulations.A spherical microcarrier with a chemistry that promotes rapid attachment and superior growth of multiple cell types under a variety of environmental condition has recently been developed. The microcarrier chemistry was optimized through an iterative process using these parameters to guide development. Figure Human bone marrow-derived mesenchymal stem cells expanded on this new microcarrier type reached acceptable cell densities in spinner cultures under a variety of environmental conditions. Harvest efficiencies achieved in small scale cultures were excellent, and cell identity was maintained. Conditions optimized in small-scale spinners were successfully employed in environmentally-controlled bioreactor. Cell harvesting optimization studies at larger scale are currently underway. Results to-date indicate that this novel microcarrier type will provide a superior substrate for large-scale propagation of MSCs under various environmental conditions.In conclusion, two novel animal protein-free microcarrier types that support excellent attachment and growth of human mesenchymal stem cells were generated; optimal surface charge density which promotes rapid cell attachment and subsequent growth was identified; peptide concentrations and coating conditions that support efficient growth of hMSCs were identified; excellent growth of cells was achieved; cell harvest at small scale demonstrated efficient removal of cells with standard enzymatic treatment; cell growth on novel microcarrier types was similar to that achieved with commercially-available collagen-coated microcarriers; environmental conditions were optimized to support excellent growth and harvest efficiencies from two liter bioreactors yielded reached 1 to 2.5 billion cells. Excellent harvest efficiencies from microcarriers were obtained using enzymatic treatment and application of moderate shear force. Harvest efficiencies of 97% with >95% viability were obtained with hMSC. Human mesenchymal stem cells retained the ability to differentiate into adipocytes and osteocytes after growth on novel microcarrier types."} +{"text": "A 30-year-old male, who underwent previous pars plana vitrectomy and silicone oil tamponade due to endogenous endophthalmitis originated from Klebsiella liver abscess, was referred for evisceration. At 2 months after vitrectomy with silicon oil tamponade, conjunctival chemosis and ocular pain were aggravated. Diffuse eyelid swelling and large subconjunctival mass with lipid droplets were noted. On MRI examination, subconjunctival mass and intra- and extraconal orbital mass around superior rectus muscle were observed. Excision of subconjunctival and orbital mass was performed. Histopathologic examination showed multiple silicone oil vacuoles surrounded by foreign body giant cells and fibrosis, which confirmed silicone oil granuloma. In a patient with suspicious melting sclera in diseases such as endophthalmitis, large silicone oil granuloma may be complicated in a rapid fashion after intravitreal silicone oil tamponade due to silicone oil leakage. Silicone oil has been widely used for decades in complex vitreoretinal surgeries. Although it has been known to be inert material, a number of complications such as cataract, glaucoma, and retinal toxicity have been reported . HoweverTo our knowledge, there have been no previous reports of early onset of large granuloma caused by extraocular migration of intravitreal silicone oil. We report subconjunctival and orbital silicone oil granuloma that resulted from the leakage of intravitreal silicone oil in a patient with endogenous endophthalmitis.A 30-year-old male suddenly developed left eyeball pain and visual loss with fever and chilling sensation. He was diagnosed as endogenous Klebsiella endophthalmitis that originated from liver abscess. He underwent pars plana vitrectomy and silicone oil tamponade in the left eye for severe endogenous endophthalmitis. The infection had been calmed down after the surgery until the eyelid swelling and chemosis were aggravated at 2 months postoperatively. He was referred to oculoplastic clinic for evisceration under the impression of uncontrolled endophthalmitis.On ophthalmologic examination, he had no light perception in the left eye. The intraocular pressure was 14\u2009mmHg in the right eye and 9\u2009mmHg in the left eye. And left upper eyelid showed diffuse swelling and redness with complete ptosis . Large uOrbital magnetic resonance image (MRI) examination showed shrinkage of the eyeball and large subconjunctival and orbital mass. The mass was located in superior part of the orbit between levator muscle and eyeball, surrounding superior rectus muscle. It demonstrated septate cystic form with low signal intensity in T1- and T2-weighted image and heterogenous enhancement in Gd-enhanced image .The authors performed excision of subconjunctival and orbital mass. Large subconjunctival mass was observed under the entire upper bulbar conjunctiva. The conjunctiva was separated from the underlying mass by blunt dissection. Granulomatous mass was removed and the Histopathology revealed silicone oil globules with inflammatory cellular infiltration. Multiple small and large lipid droplets (silicone oil) surrounded by foreign body giant cells were noted Figures . The fibAt 6 months after the surgery, the patient showed no evidence of recurrence. The patient was comfortable with no pain and showed good cosmesis wearing the prosthesis.Silicone oil is an established tamponade in treating complex vitreoretinal diseases such as retinal detachments, proliferative diabetic retinopathy associated with tractional retinal detachment . It is aIn the present study, silicone oil granuloma developed rapidly within 2 months through the melted sclera in a patient who underwent silicone oil tamponade for endogenous Klebsiella endophthalmitis originated from liver abscess. Endogenous Klebsiella endophthalmitis has generally poor prognosis in which most patients result in either no light perception or evisceration or enucleation . AlthougTo our knowledge, there have been no previous reports of early onset of silicone oil granuloma which was caused by large amount of silicone oil leakage through the melted sclera. Granulomatous inflammation associated with silicone oil leakage can develop rapidly progressing subconjunctival and orbital mass in patients with weakened sclera. In view of this case, surgeon should be prudent to perform silicone oil tamponade in a patient with suspicious melting sclera such as severe or uncontrolled endophthalmitis."} +{"text": "Hyrtios sp. extract induces apoptosis in human colorectal carcinoma RKO cells with different p53 status; Andrographolide induces apoptosis of C6 glioma cells via the ERK-p53-caspase 7-PARP pathway; and osthole induces human colon cancer cell death and inhibits migratory activity.Natural bioactives are generally referred to the compounds exclusive of essential nutrients that have specific biological activity to human. From several decades ago to now, cancer continues to be the leading lethal cause worldwide. Studies have shown that natural phytochemicals derived from certain plants have the capability to prevent carcinogenesis. In this special issue, we collected numerous studies which provide novel evidence to support the opinion. For instance, epigallocatechin gallate inhibits migration of human uveal melanoma cells; marine spongeWe also collected some review articles in this special issue. A paper evaluated the cancer therapeutic potential of cardiac glycosides. A paper proposed vitamin A as the potent anticancer agent on targeting cellular retinol binding proteins. Three other papers addressed the anticancer molecular mechanisms of betulin, Goniothalamin, and Zerumbone. In summary, it is therefore believed that the appropriate application of natural bioactives should be a supplementary and safe way that enhances the efficacy of cancer therapy.Yih-Shou HsiehShun-Fa YangGautam SethiDan-Ning Hu"} +{"text": "Endovascular aneurysm repair has revolutionized the therapeutic strategy for abdominal aortic aneurysm. However, hostile proximal aneurysmal neck and tortuosity of access vessels remain challenges in selecting optimal stent-grafts in abdominal aortic aneurysms with difficult anatomy.A 65-year-old woman complained of intermittent abdominal pain for one week. Computed tomography angiogram demonstrated a tortuous infrarenal abdominal aortic aneurysm with a tapered neck and a 136\u00b0 of infrarenal angulation. Aneurysmal dilatation and severe calcification of bilateral iliac arteries and tortuous aortoiliac access were also showed. Endovascular approach using Endurant stent-graft was attempted at an outside hospital, but failed because of the significant tortuosity of the abdominal aorta and iliac arteries. Since the patient refused to have open aneurysm repair, he was transferred to our hospital for further evaluation and possible EVAR with a different approach. EVAR was performed successfully using Gore Excluder stent-grafts . During the procedure, cannulation of the contralateral limb was unable to be achieved because of the tortuous aortoiliac course. Therefore, a snare was inserted from right radial artery, through the contralateral gate, to grasp the wire from left femoral artery. Two iliac stent-grafts were sequentially deployed with the lower end distal to the opening of the left internal iliac artery. Angiography confirmed complete sealing of the aneurysm with patency of bilateral renal arteries and external iliac arteries. The postoperative courses were uneventful and follow-up computed tomography angiogram at 6\u00a0months demonstrated patent bilateral femoral and renal arteries without endoleaks or stent migration.Although endovascular repair of aortic aneurysm with hostile neck and tortuous access is rather challenging, choosing flexible stent-grafts and suitable techniques is able to achieve an encouraging outcome. Endovascular aneurysm repair (EVAR) has revolutionized the therapeutic strategy for abdominal aortic aneurysm (AAA) with low operative mortality and morbidity, short hospital stay, and minimal blood loss compared with open repair ,2. The aA 65-year-old woman presented to an outside hospital with complaining of intermittent left-lower quadrant abdominal pain for one week. Computed tomography angiogram (CTA) demonstrated a severely tortuous descending thoracic aorta and an infrarenal AAA with maximum diameter of 80\u00a0mm and hostile neck during AAA repair has been associated with buttock claudication, impotence, colon ischemia and pelvic necrosis . But witAs far as we know, no data exist on direct comparison of the performance of different stent-graft type in EVAR for AAA, and optimal selection of stent-graft type in hostile neck remains unclear . A retroBeside hostile proximal neck anatomy, challenging artery access conditions such as small-caliber vessels, iliac tortuosity, excessive calcification and occlusive diseases, represent the second most common excluding factor for EVAR . TechnicEVAR in AAA with severely angulated neck and tortuous access is technically challenging. Choosing flexible stent-graft system and various alternative techniques may make the difficult cases feasible, and achieve an encouraging early outcome. Further long-term randomized studies are needed to confirm the safety and durability of EVAR in patients with hostile anatomy.Written informed consent was obtain from the patient for publication of this case report and any accompanying images. A copy of writen consent is available for review by the editor of this journal."} +{"text": "Patched 1 receptor, which senses the Sonic Hedgehog morphogen and limits its mobility in the limb bud. Second, evolutionary changes to the degree of programmed cell death between digits influence their development after their initiation. Similarly, evolutionary modification of leaf margin outgrowths occurs via two broad pathways. First, species-specific transcription factor expression modulates outgrowth patterning dependent on regulated transport of the hormone auxin. Second, species-specific expression of the newly discovered REDUCED COMPLEXITY homeodomain transcription factor influences growth between individual outgrowths after their initiation. These findings demonstrate that in both plants and animals tinkering with either patterning or post-patterning processes can cause morphological change. They also highlight the considerable flexibility of morphological evolution and indicate that it may be possible to derive broad principles that capture how morphogenesis evolved across complex eukaryotes.An open problem in biology is to derive general principles that capture how morphogenesis evolved to generate diverse forms in different organisms. Here we discuss recent work investigating the morphogenetic basis for digit loss in vertebrate limbs and variation in form of marginal outgrowths of angiosperm (flowering plant) leaves. Two pathways underlie digit loss in vertebrate limbs. First, alterations to digit patterning arise through modification of expression of the A key question in biology is how morphological diversity is generated. Although plants and animals evolved multicellularity independently, within each kingdom conserved gene regulatory networks (hereafter termed networks) control the development of one or more body parts. In this context evolution operates as a \u201ctinkerer,\u201d being strongly influenced by the materials currently at hand as well as prior history . Consequcis elements, leading to their mutation having a lower propensity to generate pleiotropic effects that would compromise development might be more readily available for evolutionary tinkering . HoweverTwo recent papers have explored the significance of patterning versus post-patterning events on development by studying digit loss in mammals and leaf shape formation in angiosperms and revealed a strong link between altered, species-specific gene expression domains and morphological variation. Both studies suggest considerable versatility in how evolutionary tinkering with developmental processes can ultimately arrive at similar phenotypes.Msx2 , a Shh receptor, is reduced toward the posterior limb bud. Ptch1 acts to restrict the spread of Shh by sequestration, thus reduction in Ptch1 expression leads to an expanded region of Shh activity and more uniform expression of its target genes, presumably causing a shift in limb axis symmetry to the space between digits III and IV transcription factors are expressed in the meristem to maintain its organ-generating potential (PIN-FORMED 1 (PIN1) efflux transporter, coupled to a self-reinforcing feedback of auxin on PIN1 expression and polarization, likely creates sequential local auxin activity maxima at the flanks of the SAM. This process appears to be self-organizing and the resulting auxin maxima are required for sequential primordium development (CUP-SHAPED COTYLEDON (CUC) genes mark the leaf primordium boundary and allow its separation by repressing growth at the flanks homeobox gene, of which a loss of function allele simplifies the leaf without causing pleiotropic phenotypes, suggesting a specific requirement for RCO in leaflet formation. RCO evolved in the Brassicaceae family from a gene duplication of LATE MERISTEM IDENTITY 1 (LMI1); originally identified in A. thaliana as a floral regulator (RCO is specifically expressed at the base of leaflets (Figure LMI1 is expressed more distally, in a complementary pattern, along the leaf margins. RCO does not appear to influence PIN1-mediated auxin patterning, but instead functions by repressing cellular growth between individual leaflets in C. hirsuta, a post-patterning process that allows leaflet separation. RCO was lost in A. thaliana during evolution, contributing to its leaf simplification, but re-introducing RCO into A. thaliana drives expression in basal regions of the leaf and increases leaf complexity, partially reversing the consequences of evolution. These results, together with a follow-up study in the sister species Capsella rubella and Capsella grandiflora by RCO is a key regulator of leaf shape and diversity in the Brassicaceae and provide a striking example of organ shape diversification by tinkering with local growth regulation at the flanks of a growing organ primordium (RCO study is that this gene was discovered through performing a forward genetics study in C. hirsuta and could not have been found in A. thaliana, where the gene has been lost, thus highlighting the importance of unbiased studies in diverse taxa for understanding the genetic basis for the evolution of form.Until recently, no genes had been identified that specifically influence leaflet formation without also affecting meristem function or leaf initiation. Such findings suggested that leaflets form through the redeployment of processes that acted earlier in development during leaf initiation . To idenegulator . They fos Figure , while Limordium . AnotherTaken together, these two studies illustrate how evolution can exploit both patterning and post-patterning processes to create morphological diversity in both plants and animals. It will be interesting to explore whether bias might exist for variations of either kind or for particular developmental pathways across different kingdoms. For example, plants and animals have evolved distinct biophysical properties and morphogenetic strategies that pose different constraints for evolution. Whereas animal morphogenesis involves the use of large-scale apoptosis and cell migration, these mechanisms are used to more limited extent or not aThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "LMNA-related congenital muscular dystrophy and other rare clinical entities). We performed imaging studies on a large cohort of subjects bearing either LMNA or EMD gene mutations; each patient enrolled displayed variable compromise on posterior legs\u2019 muscles, ranging from mild compromise on soleus and medial head of gastrocnemius to overt alterations on soleus, medial head of gastrocnemius[LMNA or EMD gene mutations and lead to hypothesize a common mechanism in the process of damage of skeletal muscles fibers.Laminopathies are a heterogeneous group of disorders related to alterations on genes coding for proteins of the nuclear envelope. Among these clinical entities, there are several diseases affecting mainly the cardiac and skeletal muscles. These disorders include forms with a selective cardiac compromise and muscular dystrophies (autosomal and X-linked forms of Emery-Dreifuss muscular dystrophy, Limb girdle muscular dystrophy 1B, rocnemius. Of note"} +{"text": "Though several implementation and quality improvement strategies have been shown to be effective in implementing programs and practices in routine clinical settings ,2, littlThe study tested the effectiveness of the implementation (IF) strategy hypothesizing that, compared to national technical assistance support alone, national support plus IF would improve implementation of PC-MHI. The RE-AIM Framework guided testing of the IF strategy's effectiveness ,9.Two regions were recruited to receive the IF strategy and two matched regions were recruited for comparison. Regional MH leadership identified primary care (PC) clinics unlikely to implement PC-MHI without assistance. PC clinics in comparison regions were matched to clinics in IF regions. The sample included 14 PC clinics, 174 PC providers and 98,758 PC patients. To evaluate implementation outcomes, administrative data was extracted for two six month periods, 9-15 months and 21-27 months following completion of an implementation plan at IF clinics. Generalized estimating equations were used to control for observations clustered within sites.Reach) than patients at comparison clinics. PC providers were more likely to refer at least one patient to PC-MHI (Adoption) than providers at comparison clinics and a greater proportion of PC providers' patients were referred to PC-MHI (Adoption) at IF clinics. There was no difference between IF and comparison clinics in the likelihood of patients being referred for a first time visit to specialty mental health care (Effectiveness) or the percentage of patients receiving same day access to PC-MHI (Implementation). Similar results occurred during the second six month period (Maintenance).For the first six month period, PC patients at clinics receiving IF were more likely to be seen by PC-MHI providers can help healthcare system change agents learn how to facilitate implementation of evidence-based programs. For two and a half years, we conducted monthly debriefing interviews with a national expert external facilitator (EF) who was mentoring and coaching two internal regional facilitators (IRFs) in facilitating implementation of a VA policy initiative for Primary Care-Mental Health Integration (PC-MHI) at eight primary care clinics. Interviews focused primarily on the EF's efforts to help the IRFs become experts in IF processes. We also conducted two semi-structured qualitative interviews with each facilitator, midway through and at the end of the intervention.Our qualitative content analysis revealed that although the EF helped IRFs learn general implementation facilitation knowledge and skills, the EF also identified IRFs' individual strengths and weaknesses and tailored mentoring and coaching activities to their characteristics. The EF used a variety of methods to help IRFs learn IF skills, including both active methods and participatory ones. She also used cognitive supports and psychosocial supports, as well strategies to promote self-learning. Additionally, the EF tailored the process to sites' implementation needs. Over time, the EF pulled back from IRFs, increasingly turning responsibility for IF activities over to them. IRFs responded differently to this process with one IRF independently \"breaking away\" and the other being \"pushed out of the nest.\" In addition to helping IRFs learn the skills they needed for facilitating PC-MHI implementation, the EF helped IRFs to identify and modify interpersonal styles that could hinder success of facilitation efforts.This study addresses the critical but understudied area of how implementation scientists can transfer facilitation skills that incorporate evidence-based implementation interventions and strategies to internal change agents to help healthcare organizations implement effective programs."} +{"text": "Vaccinations against infectious diseases are one of the major achievements in medicine in the last century and the most effective method for preventing infections. Concern about safety of vaccinations has been heightened by several reports of possible vaccine-induced autoimmune phenomena following various vaccinations. So far no study was able to show a casual connection between any vaccine and autoimmune syndrome.Few studies were published showing that induction of autoantibodies following various vaccination is possible, but without clinical significance. In few cases antibodies after vaccination were elevated even 6 months after vaccination. Induction of autantibodies, mainly antiphospholipid antibodies, in selected apparently healthy individuals was reported after influenza, hepatitis B and hepatitis A vaccination.Autoimmune manifestations reported have been only temporally related to the respective vaccine. Guillian Barre syndrome was described following vaccination against influenza and few other vacines, multiple sclerosis and arthritis were mainly reported after hepatitis B vaccination. There are some evidence to suggest a connection of reactive arthritis and rubella vaccine. Dermatomyositis was described following hepatitis B, tuberculosis, influenza and tetanus vaccinations. Recently a new syndrome Autoimmune-Autoinflammatory syndrome induced by adjuvants-ASIA has been described.Highlights of lecture:- autoimmune adverse events following vaccinations is possible in selected individuals but the risk of autoimmune disease after vaccination is, comparing to advantages of vaccination, negligible.- induction of autoantibodies in selected individuals after vaccination has no clinical significance.- new generation vaccine, mainly oriented on finding safer and effective adjuvants, are needed. At present few effective adjuvants are considered safe for use in humans.None declared."} +{"text": "Neural systems show a wide variety of complex dynamics on different time scales. Specifically, on the short time scale of neuronal activations (milliseconds to seconds), several theoretical models demonstIn this study we analyze how this coexistence of transient dynamics and cell assemblies can emerge in one neural circuit. The neural network, we investigate, consists of rate- based neurons with connections adapted by a generic combination of Hebbian plasticity and synaptic scaling . A subse"} +{"text": "Philadelphia chromosome positive acute lymphoblastic leukemia is classified as a very high-risk group and it requires an intensive chemotherapy regimen associated with tyrosine-kinase inhibitors and allogeneic hematopoietic stem cell transplant from related or unrelated HLA matched donor. Most times, intensive chemotherapy regimens are associated with prolonged and profound pancytopenia when the risk of invasive fungal infection increases. After Candida and Aspergillus species, Mucormycosis is the third frequent fungal infection in hematology patients and it is associated with a reduced overall survival. When suspected, immediate treatment is needed. We present the case of 24-year-old patient diagnosed with Philadelphia chromosome positive acute lymphoblastic leukemia who developed right rhino-sino-orbital fungal infection with a favorable response to systemic antifungal treatment and noninvasive surgery. Later, patient refused consolidation and allogeneic hematopoietic stem cell transplant from an unrelated HLA matched donor but accepted the first generation tyrosine kinase inhibitor (Imatinib) and maintained a complete hematological and molecular response.Abbreviations: ENT = ear nose throat; BMB = bone marrow biopsy; ALL = acute lymphoblastic leukemia; TKI = tyrosine kinase inhibitor; IFI = invasive fungal infection; BMB = bone marrow biopsy; HE = hematoxylin and eosin; IHC = immunohistochemistry; CD = cluster of differentiation; ob = objective; Tdt = terminal deoxynucleotidyl transferase It represents the most frequent form of acute leukemia in pediatric population. Opposite to paediatric population where complete remission is achieved in 75% of cases, in adult population the results are modest .Mucormycosis is a fungal infection from Mucorales species . The most frequent site of infection is the sinus and associates with brain extension. When Mucormycosis is suspected, urgent treatment should be started and it consists of surgical, antifungal treatment and correction of risk factors .BCR-ABL1 positivity for p190 transcript.Qualitative and quantitative molecular tests showed In February 2014, induction according to GMALL protocol was started and followed by febrile pancytopenia that required large spectrum antibiotics and antimycotic (Fluconazole).The bone marrow exam performed on day 14 of induction showed hypercellular marrow due to 75-80% blast infiltration. It was considered a treatment failure and the patient received salvage treatment according to GRAAL 2003 protocol and first generation tyrosine-kinase inhibitor (Imatinib), followed by prolonged febrile pancytopenia and grade 4 mucositis for which multiple broad-spectrum antibiotics and antimycotics (Voriconazole) were used.On day 14 of salvage regimen, the patient presented abrupt onset of right side headache followed by chemosis, photophobia and right ptosis.Bacterial screening including pharyngeal swab and palatine swab showed Zygomycetes filamentous fungi.Cerebral MRI showed pan sinusitis, inflammation of eye\u2019s structures and excluded cavernous sinus thrombosis.Right rhino-sinus-orbital Mucormycosis was suspected and liposomal B Amphotericin was started. ENT consult suggested radical surgery but due to the patient\u2019s refusal, right medial maxillectomy with complete resection of right inferior and medium nasal cornet and right anterior-posterior ethmoidectomy with mucocel derange from right retrobulbar recess were performed. Mycological exam of secretion taken during the procedure confirmed Mucormycosis invasive fungal infection.The patient\u2019s status improved after 33 days of liposomal B Amphotericin treatment and palliative surgical intervention.Although complete remission with salvage treatment was achieved, the patient refused consolidation treatment and allogeneic hematopoietic stem cell transplant from unrelated HLA matched donor and accepted Imatinib and Posaconasole treatment.12 months after the Mucormycosis episode, the patient maintained complete hematologic and major molecular remission without any signs of Mucormycosis infection.Table 1).The 5-year survival rate of adult population with ALL is 39%. 25% of this population presents positivity for Philadelphia chromosome and for those patients, the prognosis is reserved. Most patients receive intensive chemotherapy and tyrosine kinase inhibitors (TKI). Imatinib, first generation TKI, improved complete remission rate and increased the number of patients receiving hematopoietic stem cell transplants . In case of suspicion, urgent antifungal and surgical debridement treatment are required. The mortality rate of untreated Mucormycosis infection is of 70- 100%.Table 2) [5].Pagano and al. published a study in which the most affected organs were: lungs (47%), eye and face sinuses (25%), cerebral (19%) and extremely rare, small bowel (necrosis enterocolitis). The most common haematological diseases complicated with IFI are acute myeloid leukemia and acute lymphoblastic leukemia and surgical removal of necrotic tissues. It has been proved that immediate surgical debridement of necrotic tissues increases the rate of cure but sometimes, this maneuver is difficult in thrombocytopenic patients. For those patients, multidisciplinary strategy is most beneficial [The case report represents a double challenge: first, to induce the complete remission of progressive ALL and second, to treat Mucormycosis in a pancytopenia patient. The patient maintained complete remission after salvage treatment only with Imatinib and without allogeneic hematopoietic stem cell transplant. For Mucormycosis, the palliative surgical debridement and antifungal treatment (Amphotericin B followed by Posaconazole) were successful in curing IFI without physical mutilation and intact affected organ functions with good quality of life.In this case report, we presented a young patient who was treated unconventionally for Philadelphia positive ALL and Mucormycosis. Due to rapid Amphotericin B treatment and minimum surgical debridement of affected areas, the patient achieved an overall and disease free survival of 12 months with good quality of life. At the time of publication, the patient maintained complete hematological and molecular remission with first generation TKI (Imatinib).Acknowledgment: This work was supported by the grant PN 41-087/ 2007 from the Romanian Ministry of Research and Technology. The authors express the gratitude to European LeukemiaNet for their permanent support.Disclosures: None"} +{"text": "Chronic myelogenous leukemia is often treated using tyrosine kinase inhibitors such as dasatinib. Here we describe a rare case of inflammatory myopathy in a patient with chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib.A 69-year-old Caucasian man with imatinib-resistant chronic myelogenous leukemia achieved complete molecular remission in response to dasatinib therapy. However, from a normal initial serum creatine kinase level, he developed elevated serum creatine kinase levels and gradual-onset progressive muscle weakness after dasatinib therapy was initiated. Our patient was eventually diagnosed with inclusion body myositis. However, we were unable to determine the mechanism underlying the dasatinib-associated muscle weakness. Given the efficacy of dasatinib in the treatment of chronic myelogenous leukemia and our patient\u2019s mild symptoms of inclusion body myositis, he continued to receive dasatinib under close clinical and laboratory observation.Despite the wide use of dasatinib and its documented safety, we report a case of severe muscle injury of unknown etiology. Therefore, patients with chronic myelogenous leukemia receiving dasatinib and perhaps all tyrosine kinase inhibitors should be carefully monitored for signs of muscle injury, especially if this is associated with significant elevations in serum creatine kinase levels. Chronic myelogenous leukemia (CML) accounts for approximately 15\u201320% of all leukemia cases in adults in the USA . DasatinThe common side effects of dasatinib therapy include recurrent pleural effusions, myelosuppression, and rash. Other treatment-related adverse events include mild to moderate diarrhea, peripheral edema, and headache , 7. ElevA 69-year-old Caucasian man who was diagnosed with chronic phase CML in 1990 demonstrated a reasonable response to initial treatment with interferon and omacetaxine mepesuccinate (homoharringtonine), which was discontinued 14 years later when he began receiving imatinib mesylate (Gleevec) therapy. Our patient became resistant to imatinib one year after its first administration and developed accelerated phase disease; dasatinib was prescribed as second-line treatment. His initial serum CK level was normal. A marked elevation in his serum CK level was noted and in 7% of those resistant or intolerant to imatinib therapy (minimum follow-up of 36 months) . Other pWe have reported the case of a patient with CML who developed significantly elevated serum CK levels while receiving dasatinib therapy, and who was subsequently diagnosed with IBM. This is what we believe to be the first report of a patient developing muscle weakness while receiving dasatinib, although causality could not be established. Furthermore, the plausible mechanisms underlying dasatinib-induced muscle injury could not be determined. Although dasatinib has been widely used in clinical practice and is safe, based on our experience, severe muscle injury should be investigated. Patients with CML receiving dasatinib or other TKIs should be carefully monitored for symptoms or signs of muscle injury, especially if this is associated with significant elevations in serum CK levels. Further studies are needed to determine the underlying pathophysiology of muscle injury in such patients.Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal."} +{"text": "A 47-year-old male presented with a subacute inferior myocardial infarction (MI)complicated by inferobasal ventricular septal rupture (VSR) and underwent emergencysurgical repair of VSR with a pericardial patch. In the postoperative period he remainedhypotensive, with low exercise tolerance and a holosystolic murmur was present.Echocardiography showed persistence of VSR with left-right shunt and reveIn conclusion, this patient presented with an inferior MI complicated by rightventricular infarction, inferobasal VSR and inferior pseudoaneurysm with organizedthrombus inside. Mechanical complications are rare nowadays due to earlyrevascularization. The multimodality imaging approach is essential for their correctdiagnosis."} +{"text": "Lupus nephritis affects 30 to 70% of systemic lupus erythematosus (SLE) patients and its treatment remains insufficiently effective and excessively toxic. Although biomarkers for nephritis are being identified there is still no reliable way of predicting an impending renal flare or determining which patients will respond to therapy. Because human renal tissue cannot be obtained sequentially during remission and relapse, animal models are often used to study progression of lupus nephritis. To elucidate the molecular mechanisms involved in renal inflammation during the progression, remission and relapse of nephritis we performed a transcriptome analysis of renal tissue from two murine lupus models, NZB/WF1 mice that develop proliferative glomerulonephritis and NZM2410 mice that develop glomerulosclerosis with minimal inflammation.Kidneys from NZB/W F1 and NZM2410 mice were harvested at intervals during their disease course or after remission induction with either combination cyclophosphamide/costimulatory blockade or with BAFF inhibition. Genome-wide expression profiles were obtained from microarray analysis of perfused kidneys. Real-time PCR analysis for selected genes was used to validate the microarray data. Comparisons between groups using SAM, and unbiased analysis of the entire dataset using singular value decomposition and self-organizing map were performed.Few changes in the renal molecular profile were detected in pre-nephritic kidneys but a significant shift in gene expression, reflecting inflammatory cell infiltration and complement activation, occurred at proteinuria onset. Subsequent changes in gene expression predominantly affected mitochondrial dysfunction and metabolic stress pathways. Remission induction reversed most, but not all, of the inflammatory changes and progression towards relapse was associated with recurrence of inflammation, mitochondrial dysfunction and metabolic stress signatures. Endothelial cell activation, tissue remodeling and tubular damage were the major pathways associated with loss of renal function.Immune cell infiltration and activation is associated with proteinuria onset and reverses with immunosuppressive therapy but disease progression is associated with renal hypoxia and metabolic stress. Optimal therapy of SLE nephritis may therefore need to target both immune and nonimmune disease mechanisms. In addition, the overlap of a substantial subset of molecular markers with those expressed in human lupus kidneys suggests potential new biomarkers and therapeutic targets."} +{"text": "To review the spectrum of imaging findings of chemotherapy- induced cardiomyopathy in correlation with most common cytotoxic drugs and regimens.Cardio toxic effect of chemotherapy is a well-recognised problem in cancer patients. Cardio toxicity depends on multiple predisposing factors, specific components of the chemotherapy regimen, length of treatment, and dosage.We will present the spectrum of most common cardiotoxic chemotherapy agents and their combinations, specific effects on the myocardium, and imaging features of cardiomyopathies induced by chemotherapy.We will review pathophysiology of chemotherapy induced cardiomyopathy including:\u2022 Dose dependent cardiomyopathy\u2022 Predisposing conditions \u2013diabetes, presence of coronary artery disease, age.\u2022 Potential reversibilityWe will discuss imaging characteristics of chemotherapy induced cardiomyopathy\u2022 Imaging modalities \u2022 Importance of monitoring cardiac function during and after treatment\u2022 Distribution of late Gadolinium enhancement (LGE)\u2022 Emerging technologies for early diagnosis of cardiomyopathy in cancer patientsChemotherapy induced cardiomyopathy is a common problem among cancer patients, increasing long term morbidity and mortality and often leading to disability. Patients receiving chemotherapy treatment, particularly cardio toxic agents, should be routinely assessed for cardiac function to diagnose cardiomyopathy during the early phase of treatment and to prevent development of irreversible heart failure."} +{"text": "In medication-overuse headache (MOH) pain modulation is probably dysfunctional at cortical and subcortical level, resulting in disequilibrium between pain inhibition and facilitation. Volumetric grey matter changes have been found in cortical regions, but also in the brainstem , the latSurface-based morphometric analyses should complement volumetric findings, providing more specificity in the metric affected (thickness vs. gyrification). Whereas cortical thickness alterations probably rely on altered trajectories of cortical maturation or neurodegenerative processes, cortical folding (gyrification) abnormalities are thought to reflect early alterations to brain development.In the present study we investigated cortical thickness and gyrification in 29 patients with MOH according to International Headache Society criteria and 29 age- and gender matched controls, using FreeSurfer. Correction for multiple comparisons was performed.In patients with MOH cortical thickness was decreased in the left middle frontal gyrus compared to controls, whereas local gyrification was increased in the right fusiform gyrus and adjacent temporal regions, as well as in the right occipital pole.Decreased cortical thickness in frontal regions corresponds to decreased grey matter volume in similar regions. Increased local gyrification in the right fusiform gyrus corresponds to increased grey matter volume in the previous volumetric study. Increased gyrification in occipital regions might be related to increased susceptibility for cortical spreading depression."} +{"text": "To investigate the patterns and mechanisms of audiovestibular dysfunction in intracranial hypotension.We had consecutively recruited 16 adult patients with intracranial hypotension at the Dizziness Center of Pusan National University Hospital between November 2011 to November 2013. Spontaneous, gaze-evoked, and positional nystagmus were recorded using 3D video-oculography. Most patients had pure tone audiometry, and bithermal caloric tests.Out of the 16 patients with intracranial hypotension, five (31%) had neuro-otological symptoms along with the orthostatic headache. One of them presented with recurrent spontaneous vertigo and tinnitus mimicking meniere's disease (MD). Oculographic analysis documented abnormal eye movements in 38%, which include spontaneous downbeat nystagmus with variable positional modulation and positional upbeat nystagmus . During the attack of vertigo in the patient with MD-like symptoms, we observed unidirectional horizontal and torsional nystagmus with normal head impulse test. Bithermal caloric tests were normal in all patients who tested. Audiometry showed unilateral or bilateral sensorineural hearing loss in about half of the patients.Our study demonstrates that intracranial hypotension can induce higher frequency of audiovestibular dysfunction, which may be attributed to both irritation or dysfunction of the peripheral labyrinth or vestibulocochlear nerve, and brainstem or cerebellar dysfunction due to brain sagging.No conflict of interest."} +{"text": "Clinician related factors have been implicated as important reasons for low rates of recruitment to randomised controlled trials (RCTs). Clinicians can experience discomfort with some underlying principles of RCTs and experience difficulties in conveying them positively to potential trial participants. Recruiter training has been suggested to address identified problems but a synthesis of this research is lacking. We therefore systematically reviewed the available evidence on training interventions for RCT recruiters.Studies that evaluated training programmes for trial recruiters were included. Those that provided only general communication training not linked to RCT recruitment were excluded. Data extraction and quality assessment were completed by two reviewers independently.15 studies from 7,337 potentially eligible titles and abstracts were included in the review: three RCTs, three non-randomised controlled studies, six pre-test-post-test studies, two qualitative studies and a post-training questionnaire survey. Most studies were of moderate or weak quality. Training programmes were mostly set within cancer trials, and usually consisted of workshops with a mix of health professionals over one or two consecutive days covering generic and trial specific issues. Recruiter training programmes were well received and there was evidence that some increased recruiters\u2019 self-confidence in communicating key RCT concepts. There was, however, very little evidence that this training increased recruitment rates or patient understanding, satisfaction, or levels of informed consentThere is a need to develop training programmes that can enable recruiters to explain key concepts effectively and evaluate whether they lead to improved recruitment and informed consent in RCTs."} +{"text": "Carcinogenesis is an exceedingly complicated process, which involves multi-level dysregulations, including genomics (majorly caused by somatic mutation and copy number variation), DNA methylomics, and transcriptomics. Therefore, only looking into one molecular level of cancer is not sufficient to uncover the intricate underlying mechanisms. With the abundant resources of public available data in the Cancer Genome Atlas (TCGA) database, an integrative strategy was conducted to systematically analyze the aberrant patterns of colorectal cancer on the basis of DNA copy number, promoter methylation, somatic mutation and gene expression. In this study, paired samples in each genomic level were retrieved to identify differentially expressed genes with corresponding genetic or epigenetic dysregulations. Notably, the result of gene ontology enrichment analysis indicated that the differentially expressed genes with corresponding aberrant promoter methylation or somatic mutation were both functionally concentrated upon developmental process, suggesting the intimate association between development and carcinogenesis. Thus, by means of random walk with restart, 37 significant development-related genes were retrieved from a priori-knowledge based biological network. In five independent microarray datasets, Kaplan\u2013Meier survival and Cox regression analyses both confirmed that the expression of these genes was significantly associated with overall survival of Stage III/IV colorectal cancer patients. Colorectal cancer (CRC) is the third most common cancer in men and the second in women worldwide, accounting for roughly 694,000 deaths per yearIt is putatively accredited that carcinogenesis is caused by multi-level dysregulations, including genomics [majorly caused by somatic mutation and copy number variation (CNV)]468101112131617212223262728BRAF could activate MAPK pathway, thus influencing the massive dysregulation of gene activityCNV, aberrant promoter methylation and somatic mutation could all influence gene activation or suppression, thereby influencing the process of carcinogenesis. CNVs may alter gene dosage by changing the number of copies of a gene that is present in the genome303132The multi-level genomic dysregulations during carcinogenesis indicated that while looking into the dysregulation of gene expression in cancer, the aberrant patterns of multi-level events should also be paid considerable attention to shed light on the underlying intricate mechanisms of cancer initiation and deterioration. Therefore, the integrative analysis of cancer genomics, methylomics and transcriptomics is urgently needed to comprehensively dissect cancer etiology and provide clinical guidance.The Cancer Genome Atlas (TCGA) database is an immeasurable source of knowledge launched in 2005, which provides publicly available cancer genomic datasetsIn this study, we first collected genes with significant dysregulations with regard to DNA copy number, DNA promoter methylation, gene expression, and somatic mutation from TCGA paired samples. Differentially expressed genes (DEGs) with consistent aberrant promoter methylation or somatic mutation were found both exhibiting remarkable functional unity in developmental process. Gene to gene regulatory network was constructed by means of merging Human Protein Reference Database (HPRD), and Kyoto Encyclopedia of Genes and Genomes (KEGG) networks. By combining multi-dimensional genomic data of CRC and priori knowledge network, we applied a computational strategy, i.e. random walk with restart, to obtain the genes which were affected considerably by aberrant promoter methylation or somatic mutation. The most of these significant genes were connected in the network, and proven to hold profound prognostic information in late stage (Stage III/IV) patients, which might be helpful for constructing prognosis prediction models and providing novel tools to guide clinical implementations for this deadly disease.A schematic for the study is depicted in https://tcga-data.nci.nih.gov/tcga/). Four levels of paired data were downloaded, including 32 paired RNA sequencing level 3 data [raw counts and RNASeq by Expectation Maximization (RSEM) normalized read counts], 500 paired DNA copy number level 3 data and the risk score generated by these 37 significant genes were significantly associated with patient\u2019s OS. Multivariate Cox analysis indicated the risk score was an independent prognostic factor .Meta-analysis of 37 significant genes and risk score in five Clinicinfo data sets also confirmed the result of survival analysis with both fixed-effect model and rand53ALK could disrupt the development of central nervous system585960TIAM1, expressed in the base of intestinal crypts, established a fundamental role for Wnt-signaling pathway in the development and maintenance of normal intestinal physiologyTIAM1 and canonical Wnt-signaling pathways could significantly influence intestinal tumor formation and progressionThe booming amount of high-throughput and multi-dimensional genomic data usher us into a new era, when the tremendously complicated molecular mechanism of carcinogenesis were perceived and dissected in a more integrative perspective. In this study, we systematically analyzed CRC genomic data, including CNV, somatic mutation, DNA promoter methylation and gene expression, to discover novel and important molecules and genomic dysregulations in a more comprehensive manner. Paired samples in TCGA database were used to identify differential gene expression and genetic or epigenetic abnormalities, respectively, and collected three groups of candidate genes with differential gene expression pattern and upstream corresponding dysregulations. The result of GO analysis indicated the functions of DEGs with abnormal promoter methylation (Group B) and somatic mutation (Group C) both majorly concentrated on developmental process, of which the outcome is an anatomical structure , or organism over time from an initial condition to a later conditionPTCH1 is a key regulator of development, whose overexpression could drive skin carcinogenesis7172Notch1 signaling pathway, activated during development, are proven to be reactivated in the process of carcinogenesis7472767778It has been more than 150 years since Rudolf Virchow first advocated that neoplasms arise \u201cin accordance with the same law, which regulates development\u201d in 1858. Emerging evidences supported the cellular behavioral similarity between ontogenesis and oncogenesis, for instance, in the process of epithelial-to-mesenchymal transition (EMT)In our study, we adopted a simple and effective computational strategy to randomly walk DPRGs with aberrant promoter methylation or somatic mutation in HPRD and KEGG merged biological network. Random walk with restart was adopted to decipher gene to disease association in priori-knowledge based network, whose performance was proven to be much more superior to other methods, such as neighborhood approaches8081TGFBR1 is a central molecule in TGF-\u03b2 pathway, whose alteration could strikingly enhance the susceptibility to CRCEP300 may be a feature of gastric and colorectal cancersPRKCA and PRKCB are both member of Protein kinase C (PKC) family, which have a role in cell proliferation, differentiation, angiogenesis, and apoptosisPRKCB inhibition by enzastaurin could lead to mitotic missegregation and preferential cytotoxicity toward colorectal cancer cells with chromosomal instability; loss of PRKCA signaling is a general characteristic of colorectal tumors regardless of other underlying genetic defects, pointing to the importance of this pathwayThe majority of these significant genes were connected to form a relatively compact biological module , implyinSince candidate genes were collected based on aberrant patterns in multi-omic level of TCGA genomic data, we used microarray data sets with OS information from GEO database instead of TCGA to test the prognostic value of these significant genes. Recent expression profiling datasets lack of consistent results between the studies due to different technological platforms and lab protocols8791In summary, with the increasing availability of multidimensional genomic data, we collected genes with high rate of somatic mutation, differential expression, promoter methylation dysregulation and significant CNV, using paired samples in TCGA database. Three groups of DEGs with corresponding genetic or epigenetic abnormalities were obtained; the GO enrichment and overlapping analysis suggested DEGs with aberrant promoter methylation or somatic mutation were both functionally centering on developmental process. Random walk with restart was used to extract significant developmental genes most affected by aberrant promoter methylation and somatic mutation in merged regulatory network. In addition, the significant genes were closely related to OS of late stage patient. It is also very tempting that the identification of the functional regulators of these genes might be profusely beneficial to the discovery of new drug targets for CRC treatment. It is our hope that our preliminary exploration would be helpful for the further study upon cancer etiology and treatment guidance.How to cite this article: An, N. et al. Developmental genes significantly afflicted by aberrant promoter methylation and somatic mutation predict overall survival of late-stage colorectal cancer. Sci. Rep.5, 18616; doi: 10.1038/srep18616 (2015)."} +{"text": "In the above article (in vivo. While TEC-based constructs do not have the same ability as scaffold-based constructs to control the internal structures of regenerated tissues, they still have potential utility in certain clinical scenarios.Oxygen delivery is the greatest limiting factor to large-volume tissue engineering. Regenerating post-mastectomy breast tissue requires avascular adipose tissue to be transferred as thin \u201cmicro-ribbons\u201d to avoid central necrosis . Similar article , Morrisoin vivo soft tissue regeneration because its function does not depend on tissue microanatomy or organ gross anatomy. However, adipose tissue regeneration with TEC lacks major clinical utility because, with proper technique and recipient site preparation, large-volume autogenous adipose tissue transfers can already safely be performed for reconstruction of breasts and other soft tissue defects (Adipose tissue is an ideal model for defects . Alterna defects . ReproduMorrison has also contributed to other rodent TEC studies that have successfully regenerated large volumes of functioning pituitary , thymic Whole organ regeneration would require the vascularity associated with TEC and the internal anatomy associated with cell scaffold-based constructs. An intricate combination of TEC and a cell-scaffold based construct might create a solution; however, this concept seems well ahead of our current capabilities given the widely varied results Morrison and colleagues obtained using TEC in humans.Morrison and colleagues should be commended for their novel work. While these findings cannot yet impact clinical practice, they should encourage researchers to continue making strides towards translating tissue engineering breakthroughs to the clinical arena. TEC clearly has great potential for regeneration of human tissues, but before advancing any further, TEC must demonstrate the ability to consistently produce predictable outcomes.The authors have no conflicts of interest to disclose."} +{"text": "Salvinorin A is a potent and selective agonist of kappa opioid receptors in the brain. Recent studies in several animal models have revealed that Salvinorin A has anti-addiction, anti-depression properties and exhibits pronounced neuroprotective effects against hypoxia/ischemia induced brain damage, and have raised interest in potential clinical applications in several acute pathologies involving oxygen deficiency in the brain. This review focuses on the chemical and physical properties of Salvinorin A and their impact on development of a rational formulation to enable its translation from a research compound to a novel therapeutic agent. Salvinorin A (SA) is a psychoactive neoclerodane diterpenoid isolatedSince the discovery of SA as the only known naturally-occurring, non-nitrogenous kappa opioid receptor (KOR) agonist ,5] rese rese5] rIn this review we discuss the chemical and physical properties of Salvinorin A and their roles in the process of defining a rational translation pathway for formulating the drug substance into a clinically deliverable dosage form for acute medical situations.Physical and chemical properties of SA see reveal aLacking ionizable functional groups, Salvinorin A cannot form soluble salts. SA has eight hydrogen-bond acceptor sites, all oxygen atoms, and no hydrogen-bond donor groups. It would thus appear likely that its crystal lattice should comprise only weak non-bonded interactions between adjacent molecules and a resultant diminished lattice energy reflected in a low melting point. In factThe chemical stability of Salvinorin A has not been examined in published literature to date. Nonetheless, any clinically relevant formulation will need to circumvent hydrolytic conditions that may affect the ester and lactone moieties essential to the activity of SA at the KOR receptors. For example, hydrolysis of the acetate in SA produces the well-known derivative Salvinorin B which lacks KOR affinity. FurtherIn view of Salvinorin A\u2019s susceptibility to enzymatic degradation as well as being a substrate for P-glycoprotein efflux, the PO route of administration is clearly not viable. Not surprisingly due to the poor aqueous solubility of Salvinorin A, intravenous (IV) formulations described in numerous in vivo studies over the past 15 years have largely employed pharmaceutically unacceptable solvents . IV formulations using moderately high percentages of ethanol and propylene glycol as co-soDespite the poor apparent bioavailability of Salvinorin A when dosed via the oral cavity by recreational drug users, for acutIntranasal administration for direct to brain drug delivery offers several important advantages over other administration routes: rapid onset of therapeutic activity; bypassing the blood brain barrier; avoiding hepatic first pass metabolism. In the Inhalation of Salvinorin A via smoking or vaporization is well known to provide very rapid brain uptake and intense psychotropic effects, 19. InhIn this review we have examined the chemical and physical properties of Salvinorin A, a potential novel drug for neurological diseases, to define viable approaches to developing formulations that can be translated to clinically relevant dosage forms for treatment of acute onset illnesses outside a hospital setting. Salvinorin A exists as a stable stoichiometric hydrate and exhibits very poor solubility in aqueous vehicles. Intravenous administration may be achievable with elevated co-solvent vehicles or nanocrystalline suspensions, although its utility in the absence of medical staff is doubtful. Dosage forms targeting the oral mucosa appear worthy of further investigation: while the bioavailability is low, the ability to readily deliver high doses to the oral cavity (a highly accessible site) may allow maintenance of therapeutic drug levels in the brain. Intranasal drug delivery affords rapid, direct access of the drug to the brain bypassing the hepatic circulation. A multitude of choices for formulation and delivery devices exist, but patient to patient variability to this route of drug delivery remains uncertain particularly for administration by non-medical persons. Preferred among recreational drug users, delivery of Salvinorin A via inhalation offers clear advantages in terms of rapidly reaching therapeutic drug levels in the brain. For the purposes of acute treatment of an unresponsive patient, inhalation delivery may not be suitable."} +{"text": "Antiretroviral therapy (ART) currently enables long-term survival of persons living with HIV (PLWH), but the respite from escalating pandemic AIDS-related deaths is undermined by both emergence of drug-resistant HIV and failure to develop HIV vaccines . Such reAlthough binding of host self antigens by antibodies risks host damage, such binding may occur without resulting in appreciable harm. In support of this view, an apparent lack of pathological manifestations has been noted among healthy individuals who developed circulating antiplatelet autoantibodies subsequent to immunization with recombinant HIV gp160 ; and cerin vivo, to block infection without producing excessive damage. Such targeting of host self epitopes might be sufficient to block infection ; otherwise, infection still might be blocked by simultaneous binding of both host self- and pathogen-associated epitopes by synergistically acting antibodies . Furthermore, host self epitopes tend to be highly conserved, which could facilitate vaccine design for entire host populations. The risk\u2013benefit trade-off posed by host-reactive antibody-mediated immunity could be explored initially through passive immunization with monoclonal antibodies (mAbs), before committing to active-immunization strategies . The mAbs could be developed in tandem with specific antidotes for treating any adverse reactions that might occur, for instance, due to effector mechanisms such as complement activation and antibody-dependent cell-mediated cytotoxicity (ADCC). Antibody-mediated complement activation might be minimized by avoiding the juxtaposition of target epitopes , whereas damage due to any activated complement could be mitigated by complement-inactivating agents ; and damage due to ADCC might be addressed by suppression of natural killer (NK) cell activity. Such complications could pose barriers to regulatory approval, albeit perhaps less so for therapeutic versus prophylactic vaccines particularly where net benefit would be strongly compelling. Nevertheless, either or both complement activation and ADCC still might contribute to net benefit if they actually decreased pathogen replication [e.g., possibly with antibodies to the scavenger receptor CD36, which have been shown to inhibit HIV-1 release from infected macrophages by clustering newly formed virions at their site of budding , particularly against human rhinovirus (for which ICAM-1 serves as the major host receptor) . Anti-inThe scheme described herein thus shifts the focus of immunity-oriented approaches in health care, from immune destruction of specific targets back to the original object of vaccination, namely host protection against disease. This widens the scope of vaccines and immunotherapeutics, by placing due emphasis on immune targeting of host self epitopes as a potential means for host protection associated with negligible or justifiably limited host damage. More generally, immune targeting of epitopes may be broadly conceptualized in terms of high-level functional outcomes including both familiar consequences of conventional immunization regimens as well as less obvious and possibly even counterintuitive but nonetheless beneficial results . Such a perspective provides the basis for an expanded paradigm of biomedically enhanced immune function, the essence of which is concisely expressed as the idea of epitopes for protective immunity targeting antigens of pathogen and/or host (EPITAPH).The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Liposarcoma (LPS) is rare malignant tumor of fat cells in deep soft tissue that affects adults between the ages of 40 and 60 . This tuWDLPS and DDLPS subtypes have a characteristic feature of amplified region of chromosome 12q13-15 containing several well-known oncogenes such as MDM2, CDK4 and HMGA2 . We founNext, whole exome sequencing and targeted exome sequencing identified various known cancer related and novel genes recurrently mutated in different subtypes of LPS. MAPK, ErbB, JAK-STAT, Wnt, apoptosis, cell cycle, DNA replication and repair and axon guidance pathways were found to be potentially involved in liposarcomagenesis. We identified recurrent mutations in previously unidentified genes in LPS associated with DNA damage repair pathways. LPS tumors with DNA repair mutations could be completely dependent on other backup repair pathways for the survival which may be exploited to induce synthetic lethality as therapeutic approach in these tumors.Interestingly, we reported for the first time multi-region genomic analysis of single LPS patient's tumor signifying intra-tumor mutational and copy number heterogeneity. The current basis for most of the personalized medicine approaches depends on the genomic landscape of a single tumor biopsy sample. Due to the frequent large size of LPS tumors compared to other solid tumors, intra-tumor heterogeneity will lead to difficulties in identifying biomarkers and therapeutic targets. Our preliminary analysis of intra-tumor heterogeneity mandates the need for future detailed studies exploring the evolution of LPS tumors leading to progression.In summary, our recent work gave insights into global genomic spectrum of LPS cohort for development of novel therapeutic strategies and for understanding the pathogenesis this deadly disease."} +{"text": "Thymallus arcticus) and rainbow trout (Oncorhynchus mykiss) exhibited kilometer-scale movements among streams during the summer growing season. Although we monitored movements at a small fraction of all tributaries used by grayling and rainbow trout, approximately 50% of individuals moved among two or more streams separated by at least 7 km within a single summer. Movements were concentrated in June and July, and subsided by early August. The decline in movements coincided with spawning by anadromous sockeye salmon, which offer a high-quality resource pulse of food to resident species. Inter-stream movements may represent prospecting behavior as individuals seek out the most profitable foraging opportunities that are patchily distributed across space and time. Our results highlight that large-scale movements may not only be necessary for individuals to fulfill their life-cycle, but also to exploit heterogeneously spaced trophic resources. Therefore, habitat fragmentation and homogenization may have strong, but currently undescribed, ecological effects on the access to critical food resources in stream-dwelling fish populations.Stream-dwelling fishes inhabit river networks where resources are distributed heterogeneously across space and time. Current theory emphasizes that fishes often perform large-scale movements among habitat patches for reproduction and seeking refugia, but assumes that fish are relatively sedentary during growth phases of their life cycle. Using stationary passive integrated transponder (PIT)-tag antennas and snorkel surveys, we assessed the individual and population level movement patterns of two species of fish across a network of tributaries within the Wood River basin in southwestern Alaska where summer foraging opportunities vary substantially among streams, seasons, and years. Across two years, Arctic grayling ( River networks are hierarchically structured systems characterized by a continuum of downstream changes in biota and ecosystem processes, which generate coarse-scaled patterns of biotic and abiotic heterogeneity ,2. HowevMovement among habitats is one strategy animals have evolved to track spatially and temporally variable resources. For freshwater fishes, it has been widely acknowledged that relatively long-distance movements are necessary for the long-term persistence of populations . HoweverThymallus arcticus) and rainbow trout (Oncorhynchus mykiss) are two species of non-anadromous (resident) salmonids that co-occur in streams and rivers throughout western Alaska. Grayling and rainbow trout play a large ecological and economic role in the region, as they can often comprise the majority of resident stream biomass and are the mainstay of recreational fisheries )It is interesting to consider why movements at larger spatial scales are rarely documented in freshwater fishes. One explanation is that the range of observed movement distances will directly depend on the interplay between the finest spatial and temporal resolution studied (grain) and the size of the entire study area or duration by year and stream. Only \"returning\" fish were used in movement analyses.(DOCX)Click here for additional data file.S1 Figin (A) Hidden Creek, (B) Lynx Creek, (C) Teal Creek, and (D) Stovall Creek.(TIF)Click here for additional data file.S1 File(DOCX)Click here for additional data file."} +{"text": "Technology in cataract surgery is constantly evolving to meet the goals of both surgeons and patients. Recent major advances in refractive cataract surgery include innovations in preoperative and intraoperative diagnostics, femtosecond laser-assisted cataract surgery (FLACS), and a new generation of intraocular lenses (IOLs). This paper presents the latest technologies in each of these major categories and discusses how these contributions serve to improve cataract surgery outcomes in a safe, effective, and predictable manner. With cataract surgery regarded as the most widely performed surgical procedure, a demand exists for continued innovation and technology. The latest advances evolved through application of well-defined principles to current surgical goals and patient expectations. For example, femtosecond laser technology emerged after fifty years of employing laser technology in ophthalmology . TheodorMore than ever, patients have the desire to reduce their dependence on spectacles after cataract surgery. Physicians now have access to advanced diagnostics that can better quantify conditions such as dry eye, light scatter, and posterior corneal astigmatism. These technologies can enhance refractive measurements and appropriate IOL selection.McDonald recently reported that the postoperative prevalence of dry eye related symptoms is approximately 88% . AnalysiEvaluation of optical quality also aids in decision making between corneal or lens-based procedures. The C-Quant assesses straylight subjectively by utilizing a compensation comparison method . The AcuBoth anterior and posterior corneal astigmatism should be taken into account in IOL planning, particularly in patients desiring astigmatic correction. Inaccuracies arise when posterior corneal astigmatism is measured based on the assumption of a fixed-ratio relationship with the anterior curvature . The CasPatients with a history of corneal refractive surgery expect reduced dependence on spectacles after cataract surgery. The use of intraoperative aberrometry can adjunctively guide the future of IOL power selection . The OptThe use of the electroretinogram (ERG) has been well described and may have a novel application for refractive cataract surgery. Dr. Richard Mackool described the use of flash ERG testing with office-based electroretinography in preoperative cataract evaluation. It can provide an objective evaluation of macular function and could be useful in influencing lens selection for patients with conditions such as epiretinal membrane, diabetic retinopathy, and age-related macular degeneration. More studies evaluating ERGs in preoperative cataract assessment need to be done to further assess its value and implications .Femtosecond laser-assisted cataract surgery (FLACS) has realized increasing popularity. Noninferiority has been established relative to manual cataract surgery, and some reports have suggested superiority relative to manual methods . Potenti\u2122 by Alcon), Mayer et al. showed that redocking was unnecessary when a modified soft interface was used, even though some cases resulted in incomplete incisions requiring manual opening [The docking process using the femtosecond laser-eye interface uses a suction ring to stabilize the eye, thereby allowing imaging and laser delivery through a clear optical pathway. Considerations for docking include complete coupling, patient comfort, intraocular pressure elevation, and minimal distortion of anatomy to avoid disruption of the beam path. In a study using Alcon's LenSx platform to compare curved direct contact and modified soft interfaces ; Infinite Vision IOL ; and mechanically adjustable IOLs . These are currently being studied in vivo with promising preliminary results. The second category includes magnetically adjustable IOLs , light adjustable IOLs , and the Perfect Lens . The latter is a novel platform, which can be adjusted with the femtosecond laser based on the concept of refractive index shaping. The light adjustable IOL is currently in FDA clinical trials. Its mechanism involves the use of infrared light to polymerize photosensitive silicone macromers, which results in changes in lens morphology and optical properties .A new generation of optics with extended depth of focus, multifocal rotational symmetry and asymmetry, and accommodating capabilities offers promising strategies to advance functional vision in refractive cataract surgery. The Tecnis Symfony (AMO) is an extended depth of focus IOL that works by correcting chromatic aberration using diffractive optics and reduces glare and halo symptoms classically associated with conventional multifocal IOLs . MultifoAccommodating IOLs aim to simulate the natural mechanism of accommodation. The FluidVision IOL has silicone oil inside the lens that moves in response to ciliary contraction forces. An electroactive IOL with a liquid crystal that is sensitive to electric current is also in development . Dual accommodating IOLs designed for sulcus placement include the DynaCurve IOL and the Lumina IOL . The injThe future of refractive cataract surgery is exciting; in time, these new technologies may be the standard of care. With refinements of the latest technology, FLACS and other parallel advances will provide surgeons with the potential to perform an even safer, predictable, and effective surgery."} +{"text": "Escherichia coli (E. coli) strains that cause ABU have evolved from uropathogenic E. coli (UPEC) by reductive evolution and loss of the ability to express functional virulence factors. For instance, the prototype ABU strain 83972 has a smaller genome than UPEC strains with deletions or point mutations in several virulence genes. To understand the mechanisms of bacterial adaptation and to find out whether the bacteria adapt in a host-specific manner, we compared the complete genome sequences of consecutive reisolates of ABU strain 83972 from different inoculated individuals and compared them with the genome of the parent strain. Reisolates from different hosts exhibited individual patterns of genomic alterations. Non-synonymous SNPs predominantly occurred in coding regions and often affected the amino acid sequence of proteins with global or pleiotropic regulatory function. These gene products are involved in different bacterial stress protection strategies, and metabolic and signaling pathways. Our data indicate that adaptation of E. coli 83972 to prolonged growth in the urinary tract involves responses to specific growth conditions and stresses present in the individual hosts. Accordingly, modulation of gene expression required for survival and growth under stress conditions seems to be most critical for long-term growth of E. coli 83972 in the urinary tract.During asymptomatic bacteriuria (ABU), bacteria colonize the urinary tract for extended periods of time without causing symptoms of urinary tract infection. Previous studies indicate that many Normal flora furnishes the host with ecological barriers that prevent pathogen attack while maintaining tissue homeostasis. Despite their vast numbers and staggering molecular complexity, microbiomes of the gut, respiratory and urogenital tracts persist without triggering a destructive host response. This lack of destructive inflammation is fascinating and important, as it reflects exquisite molecular regulation of the host environment by commensal bacteria. Simultaneously, the host regulates permitted and unwanted paths of immune activation by discriminating attacking pathogens from beneficial commensals.The failure of asymptomatic carrier strains to trigger disease-associated signaling pathways and pathology has generally been attributed to their lack of virulence and, until recently, it was not clear if, in addition, asymptomatic carrier strains enhance their persistence by actively modifying the host environment. We have discovered that commensal bacteria modulate host gene expression to ensure that destructive immune activation will not occur . These iUTI constitutes a highly relevant model of microbial adaptation, in which the contrasting roles of pathogens and commensals are clearly displayed . PathogeEscherichia coli (UPEC) activate an innate immune response through virulence factor\u2013specific TLR4 signaling, the TRIF/TRAM adaptors, MAPK-, p38- and CREB phosphorylation and IRF3/IRF7, AP1-dependent transcription. We have shown that \u2212/\u2212Irf3 mice develop severe, acute symptoms accompanied by urosepsis and renal abscess formation, demonstrating that the innate immune response orchestrated by IRF-3 is crucial for bacterial clearance and for renal tissue integrity. Human disease relevance is suggested by an increased frequency of functionally relevant IRF3 promoter polymorphisms in about 70% of patients with recurrent acute pyelonephritis . The. The7]. oolgirls and was E. coli strain VR50, have been also shown to evolve from commensal strains by gaining colonization factors [Bacteria increase their fitness in new host niches by rapid adaptation to changing environmental conditions. They lose or gain genetic material and, through selection, new variants become fixed in the population. Evolution has mainly been assumed to favor virulence, which promotes host-to-host spread and tissue attack. Until recently, evolution of commensalism had not been considered. We have proposed that ABU strains evolve towards commensalism in human hosts, as defined by a reduction in overall genome size, inactivation of virulence genes and modifications of transcriptional regulators ,11. Some factors .E. coli 83972 genome revealed a common ancestry with uropathogenic E. coli strains but a smaller genome size due to multiple deletions and mutations, suggesting that this strain adapted to the human urinary tract by undergoing reductive evolution [fim deletion and several papG point mutations abolish fimbrial expression and adherence [Epidemiologic studies have established that the severity of UTI reflects the virulence profile of the infecting strain, with a higher frequency of tissue-attacking virulence factors expressed by UPEC strains than by most strains causing ABU ,14, despvolution ,16 . Reisolates with slower growth rates in urine were also less competitive relative to ancestor strain 83972. Many reisolates formed less biofilm than parent strain 83972. This phenotype could be correlated with motility and flagella expression [E. coli is modulated in response to the individual host. Further genome-wide, transcriptome and proteome analysis proved that these genomic changes altered bacterial gene expression, resulting in unique adaptation patterns in each patient affecting iron uptake strategies as well as protection against oxidative or nitrosative stress, general stress response, and utilization of different carbon sources [Diverse pheno- and genotypic comparisons uncovered striking differences among patients . So farE. coli 83972 monoculture populating the bladder [in vivo growth in the urinary tract could include phenotype switching. Alternatively, the occurrence of heterogeneous populations at symptomatic episodes may represent spontaneous stochastic events including minor transient populations [Interestingly, we observed phenotypic variation in the bladder . This ph bladder suggests bladder . Small c bladder . Therefoulations .E. coli 83972 colonizes the human urinary tract without inducing a strong immune response and can even actively suppress host gene expression. Genome comparison demonstrated that this strain is a deconstructed, attenuated uropathogen. Although we were able to shed some light on bacterial strategies and conditions which may promote attenuation and E. coli adaptation during prolonged colonization of the urinary tract, specific genomic features of strain 83972, which may account for all aspects of the asymptomatic bladder colonization, have not yet been identified. The detailed analysis of the molecular mechanisms required for the specific bacterium-host interaction resulting in a weak host response will be an important task for future studies to understand how this strain actively modifies the host environment in order to promote persistence."} +{"text": "Identification of disease causing mutations in genetically heterogeneous conditions such as intellectual disability by Sanger sequencing is time-consuming, costly and often unsuccessful. The advent of NGS techniques is paving the way for novel large scale approaches with an unforeseen diagnostic power. However, the plethora of variants of unknown significance detected by genome-wide approaches requires distinctive strategies to identify actually disease-related mutations. We recently showed that exome sequencing of patient-parent trios in sporadic cases of unspecific severe intellectual disability may unravel disease causing mutation in more than 50% of previously unsolved cases. Thereby it became also evident, that the current descriptions of phenotypes associated with mutations in a certain gene, are heavily biased towards certain recognizable patterns. However, while whole exome sequencing may currently provide theoretically the highest cost-efficient diagnostic power, it may miss mutations due to incomplete coverage of certain genes. Therefore in some phenotypes a \u201cclinical exome\u201d limited to a set of genes with currently known monogenic mutations may also be useful."} +{"text": "Prostate cancer remains significant public health concern amid growing controversies regarding prostate specific antigen (PSA) based screening. The utility of PSA has been brought into question, and alternative measures are investigated to remedy the overdetection of indolent disease and safeguard patients from the potential harms resulting from an elevated PSA. Multiparametric MRI of the prostate has shown promise in identifying patients at risk for clinically significant disease but its role within the current diagnostic and treatment paradigm remains in question. The current review focuses on recent applications of MRI in this pathway. An estimated 233,000 newly diagnosed cases of prostate cancer (CaP) are estimated for 2014, with a projected 29,480 CaP deaths in the same year [The shortcomings of PSA and prostate biopsy have propelled the search for alternative measures to improve its diagnostic yield and efficiency. Transrectal ultrasound (TRUS) guided biopsy of the prostate currently remains the gold standard for tissue diagnosis but itself has limitations. The systematic yet random and blinded sampling of TRUS biopsy served a useful purpose from its introduction in the 1980s, when biopsy of palpable, large-volume disease was representative of whole gland pathology. The introduction of PSA and subsequent identification of organ-confined, low volume disease have made TRUS biopsy gradually more antiquated and now CaP remains the only solid organ tumor diagnosed without tumor imaging and a directed sampling method.Multiparametric MRI (mp-MRI) of the Prostate. The role of prostate biopsy has evolved from a purely diagnostic tool to include one that informs clinical decision-making. As such, it is essential to ensure that the appropriate individuals receive a biopsy thus averting unnecessary harm and that biopsy information represents what it truly intends to measure. In an effort to improve on the current standard, PSA-derived markers, PSA kinetics, and patient characteristics including genomic profiling and imaging have all been investigated to refine patient selection with variable results. The application of mp-MRI of the prostate has emerged as a powerful tool that provides detailed anatomical and functional information where it is currently lacking. In addition to high resolution T2 weighted (T2W) imaging, the integration of diffusion weighted imaging (DWI), dynamic contrast enhanced (DCE) imaging, and spectroscopic imaging in combination has allowed radiologists to better identify areas of benign and potentially malignant disease , extracapsular extension (ECE), and even pelvic lymph node involvement. Recent series have reported sensitivity of >80% and specificity of >90 \u201325. SoylHigh-quality imaging is a fundamental component for patient selection for focal therapy of prostate cancer . Until rThe most valuable utilization of PSA remains after whole-gland treatment, where increases in PSA correlate well with disease recurrence. MP-MRI can be used to identify local recurrence after both radical prostatectomy and external beam radiation with functional imaging sequences driving detection in these patients . The addThe detailed anatomic information afforded from mp-MRI enables its versatile use intraoperatively where PSA falls short. Higher PSA values may provide generalized information, from which inferred risk is calculated based on large datasets but fails to provide patient-specific information that can guide surgery. Improved risk stratification, imaging, and novel therapeutic approaches have enhanced efforts for focal therapy in prostate cancer. Focal therapy techniques including high intensity focused ultrasound and laser induced thermal therapy are largely guided by real-time MRI. MRI can assist in tumor localization and probe placement in addition to treatment monitoring intraoperatively. Novel MR-TRUS fusion platforms for guidance of focal therapy are also beginning to emerge . MR TherOverdetection of clinically insignificant, low-grade, low-volume CaP has spurred the adoption of active surveillance (AS) as an accepted management strategy. AS allows patients with low risk disease to defer definitive therapy, potentially indefinitely, until objective evidence of disease progression is noted. PSA is utilized as both an entry criterion and a mainstay of surveillance in conjunction with random prostate biopsy for AS. MP-MRI and targeted biopsy are able to better differentiate those patients with indolent disease, selecting patients who better represent low-risk disease . Of patiInvestigation of novel technologies harnessing the properties of mp-MRI is showing promise in the staging of prostate cancer. Current models including the UCSF-CAPRA scoring system and the Partin tables integrate PSA to provide valuable insight into presence of metastasis and predictions of organ confined disease. Ultrasmall superparamagnetic particles of iron oxide (USPIO) have shown promise in the preoperative staging of bladder and prostate cancer patients, allowing for detection of metastasis. DWI combined with USPIO has demonstrated potential in discrimination of malignant versus benign pathology in even normal size lymph nodes, though wide adoption has been hindered due to variability in interpretation . In addiFinally, Positron emission tomography (PET) by itself demonstrates high sensitivity for prostate cancer detection but nonspecific uptake in benign lesions limits its diagnostic utility. However, PET/MRI has recently shown promise with a sensitivity and specificity for CaP detection in lesions >5\u2009mm being 84% and 80%, respectively, when correlated with whole mount pathology at radical prostatectomy . FurtherThe novel applications of MP-MRI are encouraging and but are not a panacea to our PSA woes. MRI interpretation is challenging, requiring considerable experience before proficiency. As mp-MRI has gained acceptance, the need for standardized protocols and reporting and high quality studies has been realized . DetermiPSA remains the cornerstone to screening, staging, and surveillance after treatment despite its numerous shortcomings. Currently, mp-MRI is proving an essential adjunct to supplement PSA in proper patient selection for biopsy, treatment, and surveillance. High-quality studies are required to validate the initial encouraging body of literature supporting the use of MRI in this arena."} +{"text": "Information derived from functional magnetic resonance imaging (fMRI) during wakeful rest has been introduced as a candidate diagnostic biomarker in unipolar major depressive disorder (MDD). Multiple reports of resting state fMRI in MDD describe group effects. Such prior knowledge can be adopted to pre-select potentially discriminating features for diagnostic classification models with the aim to improve diagnostic accuracy. Purpose of this analysis was to consolidate spatial information about alterations of spontaneous brain activity in MDD, primarily to serve as feature selection for multivariate pattern analysis techniques (MVPA). Thirty two studies were included in final analyses. Coordinates extracted from the original reports were assigned to two categories based on directionality of findings. Meta-analyses were calculated using the non-additive activation likelihood estimation approach with coordinates organized by subject group to account for non-independent samples. Converging evidence revealed a distributed pattern of brain regions with increased or decreased spontaneous activity in MDD. The most distinct finding was hyperactivity/hyperconnectivity presumably reflecting the interaction of cortical midline structures with lateral prefrontal areas related to externally-directed cognition. Other areas of hyperactivity/hyperconnectivity include the left lateral parietal cortex, right hippocampus and right cerebellum whereas hypoactivity/hypoconnectivity was observed mainly in the left temporal cortex, the insula, precuneus, superior frontal gyrus, lentiform nucleus and thalamus. Results are made available in two different data formats to be used as spatial hypotheses in future studies, particularly for diagnostic classification by MVPA. Mental disorders featuring depression as a predominant symptom and more specifically major depressive disorder (MDD) are important worldwide public health concerns. In recent years significant progress has been achieved regarding the identification of biological correlates and potential neural mechanisms involved in the pathogenesis of MDD. These scientific efforts comprise studies of genetic foundations, molecular mechanisms including neurotransmitter systems and structural as well as functional neuroimaging studies in MDD has applied stimulus-based acquisition protocols. Participants were confronted with predefined stimuli in the scanner, e.g., pictures of emotional faces. Brain activity in response to these stimuli was analyzed or the amplitude of characteristic low-frequency fluctuations (ALFF or fALFF). Functional connectivity (FC) can be operationalized as the temporal correlation of signal fluctuations in remote brain areas. Conventional FC-analyses are seed-based but FC-analyses in a wider sense include independent component analyses or complex graph theoretical network measures. A minority of studies has applied analyses of effective connectivity methods have been proposed to identify a subset of most informative features to be used with the aim to increase classification accuracy and pooled studies with SPECT and PET data search using the following query on August 20, 2013: (\u201cdepression\u201d OR \u201cdepressive\u201d) AND AND .We conducted a PubMed using the non-additive activation likelihood estimation (ALE) approach with coordinates organized by subject group (ALE-S method) to account for non-independent samples and 1000 permutations and a high resolution anatomical template with isotropic voxels in MNI space as distributed with GingerALE.Anatomical labels were automatically assigned in GingerALE. Visualizations were created using Mango for hypothesis-driven group comparisons and particularly for FS of spontaneous brain activtiy or single-photon emission computed tomography (SPECT) and less consistently the cingulate cortex and thalamus and derivative techniques: reduced anisotropy measures, a potential marker of fiber integrity, were observed in parts of the superior frontal white matter presumed to connect the dorsolateral prefrontal cortex and anterior cingulate cortex with subcortical nuclei with lateral frontal areas related to externally-directed cognition. Alterations that can be captured by rs-fMRI seem to differ from those identifiable with other neuroimaging modalities but show considerable overlap. Results of this meta-analysis are provided as coordinates and detailed maps in MNI space to be readily applicable for ROI selection in further rs-fMRI studies in MDD including feature selection for classification approaches with diagnostic intention. By emphasizing spatial precision and sensitivity this approach only provides limited information about the exact functional meaning of altered spontaneous brain activity in MDD.Benedikt Sundermann and Bettina Pfleiderer conceived and designed the study. Mona Olde l\u00fctke Beverborg and Benedikt Sundermann identified and screened the articles. Benedikt Sundermann, Bettina Pfleiderer and Mona Olde l\u00fctke Beverborg participated in final study selection and group assignment. Benedikt Sundermann and Mona Olde l\u00fctke Beverborg conducted the ALE-analyses. Benedikt Sundermann, Bettina Pfleiderer and Mona Olde l\u00fctke Beverborg participated in interpretation of the results. Benedikt Sundermann drafted the manuscript. All authors critically revised the manuscript for important intellectual content and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Combined PET/MR is a promising tool for simultaneous investigation of soft tissue morphology and function. However, contrary to CT, MR images do not provide information on photon attenuation in tissue. In the currently available systems issue is solved by synthesizing attenuation maps from MR images using segmentation algorithms. This approach has been shown to provide reason-able results in most cases. However, sporadically occurring segmentation errors can cause serious problems. Recently, algorithms for simultaneous estimation of attenuation and tracer distribution (MLAA) have been introduced. So far, validity of MLAA has mainly been demonstrated in simulated data. We have integrated the MLAA algorithm into thePhantom data were acquired using a whole body phantom with three cylindrical inserts filled with different substances . MLAA-estimated mu-maps of the phantom were compared to the mu-maps resulting from transmission measurements with an ECAT HR+ scanner. We also performed a first qualitative evaluation of the attenuation maps obtained in patient studies.Evaluation of the phantom study showed good concordance between measured and estimated attenuation coefficients for all types of substances used in the phantom. Evaluation of patient data showed some substantial improvements of the MLAA attenuation maps compared to the segmented MR-based attenuation maps.Preliminary results show that for the Philips Ingenuity PET/MR scanner the MLAA algorithm allows to obtain attenuation maps which outperform the MR based maps in several aspects. However, a more detailed analysis is still required to address the question of possible cross-talks in regions with high activity. Additionally, MLAA algorithm substantially increases computational burden leading to long processing times, which makes it currently impractical for clinical application."} +{"text": "Tracheal penetration of esophageal self-expanding metallic stents (SEMS) with/without tracheoesophageal fistula (TEF) formation is a rare occurrence. We report the case of a 66-year-old female patient with advanced esophageal squamous cell carcinoma who had undergone palliative esophageal stenting on three occasions for recurrent esophageal stent obstruction. On evaluation of symptoms of breathing difficulty and aspiration following third esophageal stent placement, tracheal erosion and TEF formation due to the tracheal penetration by esophageal stent were diagnosed. The patient was successfully managed by covered tracheal SEMS placement under flexible bronchoscopy. Esophageal SEMS placement has evolved into a first line approach for the palliative relief of dysphagia for patients with advanced esophageal cancer . The sucDespite the widespread use of esophageal SEMS placement for the numerous previously described indications, delayed prolapse and erosion of esophageal SEMS into the tracheobronchial tree are rarely reported , 3\u20136. HoA 66-year-old female presented with history of persistent cough and shortness of breath of 2-week duration. Cough used to worsen immediately on intake of liquids/solids and, for the same reason, patient complained of marked reduction in oral intake. There was no history of hemoptysis, wheezing, hoarseness of voice, or chest pain.Patient had been diagnosed with advanced stage carcinoma of the esophagus, 15 months ago. At that time, patient had been evaluated for symptoms of dysphagia, loss of appetite, and significant weight loss. Upper gastrointestinal endoscopy examination (UGIE) performed at that time revealed circumferential growth at 25\u2009cms from incisors and biopsy demonstrated moderately differentiated squamous cell carcinoma. Fine needle aspiration from a palpable right supraclavicular lymph node at that time also confirmed metastatic squamous cell carcinoma. Flexible bronchoscopy (FB) examination at that time was normal. In view of grade III dysphagia and metastatic disease, patient underwent covered esophageal SEMS placement in November 2012 and palliative chemoradiotherapy , radiotherapy) was concurrently administered. For recurrence of dysphagia six months following esophageal stenting, UGIE was performed which demonstrated tumor in-growth for which a covered SEMS was placed inside the previous stent. Tumor in-growth recurred nine months later for which another covered esophageal SEMS was placed inside the two previous stents. Symptoms of cough and dyspnea occurred one month following the third esophageal SEMS placement and the patient was referred to the pulmonary outpatient clinic.On examination, patient appeared emaciated. Pulse rate was 100/min, respiratory rate was 25/min, and rest of the vital signs and general physical examination were normal. On examination of the respiratory system, inspiratory crepitations were audible in bilateral lung bases. A clinical possibility of airway-esophageal fistula was considered and FB examination was performed.http://dx.doi.org/10.1155/2014/567582) On distal inspection, the wire mesh of the esophageal stent was seen over the posterior tracheal wall extending up to 1-2\u2009cms above the carina. A diagnosis of tracheal erosion of the esophageal SEMS with TEF was confirmed. The patient was unfit for any surgical intervention and therefore bronchoscopic management was planned.FB demonstrated prolapse and erosion of the proximal end of esophageal stent through the posterior tracheal wall and formation of tracheoesophageal fistula (TEF) through which bubbling secretions was visualized. was successfully deployed under flexible bronchoscopy and conscious sedation, to successfully cover the entire extent of the eroded esophageal SEMS and the TEF and four months had passed since tracheal SEMS placement.Reported major complications associated with the placement of esophageal SEMS include significant bleeding, tumor obstruction, stent migration, airway-esophageal fistulization, gastroesophageal reflux, aspiration pneumonia, and persistent chest discomfort . EsophagDespite these factors, delayed tracheal erosion and TEF formation due to esophageal SEMS is a rarely described occurrence. However, erosion of esophageal SEMS into adjacent structures apart from the trachea such as aorta, bronchi, carotid arteries, and vertebral arteries has been described and vascular perforation is usually associated with a fatal outcome , 8. AggrThe most important principle of management in the situation of tracheal erosion by esophageal SEMS is to stabilize the airway and to seal off the esophageal-respiratory communication. The same may involve a combination of or either of the following steps: esophageal stent removal and/or repeat esophageal stent placement/coaxial esophageal SEMS/tracheal covered SEMS placement/surgery in cases of benign disease . BronchoA prophylactic approach for the prevention of this complications has also been suggested wherein parallel tracheal and esophageal stenting may be considered especially in situations where the large esophageal tumor burden increases the propensity of airway obstruction following esophageal SEMS deployment. In fact, in case a covered esophageal SEMS completely prolapses into trachea, fatal asphyxiation may occur which may not occur in case an uncovered stent had been utilized wherein the wire mesh can allow ventilation to continue .The present case highlights the fact that, in rare circumstances, esophageal SEMS can penetrate into the tracheobronchial tree and present with emergent and often life threatening airway obstruction or aspiration. Occasionally, short of a frank rupture into the trachea, the stent can cause compression effect and tracheal lumen compromise also and sometimes a limited penetration by a stent wire has also been reported . EndoscoVideo of the flexible bronchoscopy examination demonstrating the presence of eroded esophageal SEMS into the trachea. Covered metallic tracheal stent is being deployed using the flexible bronchoscope to cover the prolapsed esophageal SEMS."} +{"text": "Rice growth is severely affected by toxic concentrations of the nonessential heavy metal cadmium (Cd). To elucidate the molecular basis of the response to Cd stress, we performed mRNA sequencing of rice following our previous study on exposure to high concentrations of Cd . In this study, rice plants were hydroponically treated with low concentrations of Cd and approximately 211 million sequence reads were mapped onto the IRGSP-1.0 reference rice genome sequence. Many genes, including some identified under high Cd concentration exposure in our previous study, were found to be responsive to low Cd exposure, with an average of about 11,000 transcripts from each condition. However, genes expressed constitutively across the developmental course responded only slightly to low Cd concentrations, in contrast to their clear response to high Cd concentration, which causes fatal damage to rice seedlings according to phenotypic changes. The expression of metal ion transporter genes tended to correlate with Cd concentration, suggesting the potential of the RNA-Seq strategy to reveal novel Cd-responsive transporters by analyzing gene expression under different Cd concentrations. This study could help to develop novel strategies for improving tolerance to Cd exposure in rice and other cereal crops. Cadmium (Cd) is a widespread heavy metal pollutant that is highly toxic to living cells. Accumulation of the nonessential metal Cd in plants is a major agricultural problem. Specifically, Cd is absorbed by the roots from the soil and transported to the shoot, negatively affecting nutrient uptake and homeostasis in plants, even in very small amounts. Many agricultural soils have become contaminated with Cd through the use of phosphate fertilizers, sludge, and irrigation water containing Cd. Cd exposure inhibits root and shoot growth and ultimately reduces yield. Furthermore, Cd accumulation in the edible parts of plants such as seed grains places humans at a risk because of its highly toxic effects on human health. Reducing the Cd concentration in plants below the maximum level indicated by the Codex Alimentarius Commission of FAO/WHO is necesCd causes oxidative stress and generates reactive oxygen species, which can cause damage in various ways such as reacting with DNA causing mutation, modifying protein side chains, and destroying phospholipids . VariousOryza sativa L. cv. Nipponbare) under a high Cd concentration using the RNA-Seq platform. A clear and detailed view of the transcriptomic changes triggered by Cd exposure is important to understand the gene expression network of the basal response to Cd stress. This could not be obtained from past studies using the microarray platform, but RNA-Seq can accurately quantify gene expression levels over a broad dynamic range with high resolution and sensitivity ) . Enriched GO terms significantly in each cluster may represent the functional categories in rice under Cd exposure. Enriched GO terms of gradually upregulated transcripts under Cd exposure include metal ion transport (GO:0030001) , which may function in Cd transport. Response to oxidative stress (GO:0006979) and responsive to oxidative stress (GO:0006979) were also included in cluster 3 and cluster 4, respectively. This suggested that they might function in defense against Cd. Enriched GO terms of gradually downregulated transcripts under Cd exposure include translation (GO:0006412), translation elongation (GO:0006414), DNA replication (GO:0006260), and DNA repair (GO:0006281) . Photosynthesis, light harvesting (GO:0009765), and photosynthesis (GO:0015979) were also included in both clusters. These may function in plant growth. Thus, these correspond to the observed changes in phenotype encoding iron-regulated transporter 1 (IRT1) was upregulated more than 5-fold under low Cd concentrations but responded only slightly under the high Cd concentration. IRT1s often transport Cd because of their low substrate specificity that may function in Cd transport under Cd exposure. The expression of 183 transport transcripts was compared between low and high Cd concentration treatments in roots and shoots at 1\u2009d, because Cd uptake from the hydroponic culture and efflux pumping are initial responses to Cd exposure (cificity \u201326, 30. We generated gene expression profiles for rice seedlings grown under low Cd concentrations. Phenotypic observations and constitutive gene expression indicated that low Cd concentrations cause growth retardation but are far from being fatal in rice. Several genes associated with defense systems were strongly upregulated; the expression of metal ion transporter genes tended to correlate with Cd concentration and GO enrichment analysis of the clustered genes based on their expression patterns, suggesting that our transcriptome profiles reflect responses to Cd in rice. Our data also suggest that it could be dangerous to eat plants that do not show specific Cd pollution symptoms growing in soil contaminated by small amounts of Cd. Establishing the exact composition and organization of the transcriptional network underlying the response to Cd exposure will provide a robust tool for improving crops in the future, for example, by creating low Cd uptake plants.Mapping of RNA-seq reads obtained from root and shoot samples to the reference IRGSP-1.0 genome sequence."} +{"text": "Immune-mediated pathogenesis has been suggested for idiopathic sensorineural hearing loss (iSNHL). Recent studies have investigated the relationship between iSNHL and autoantibodies against inner ear antigens, but specific tests are not available.To assess the positivity of autoantibodies against inner ear in a series of pediatric patients with idiopathic sensorineural hearing loss.We conducted a prospective, non-interventional observational study in a series of pediatric patients affected with iSNHL. Autoantibodies against inner ear , previously described in the serum of patients with Cogan's syndrome, were detected in our populations. The characteristics of children who resulted positive were also evaluated to verify if clinical data, disease progression and response to treatment could confirm an immune-mediated pathogenesis.Eleven patients were enrolled and 9 of them resulted positive for the inner ear antibodies detected. Non-organ specific autoantibodies were present in 5 children out of 9. An immune-mediated condition was diagnosed in 2 cases and minor immune manifestations were found in other 2 patients. In 5 cases hearing loss remained stable with no therapy, otherwise 4 children developed hearing loss progression. Two subjects were treated with steroids and methotrexate achieving hearing improvement. Another subject started methotrexate treatment showing hearing loss stabilization.Most of clinical characteristics and comorbidities described, added to immunologic tests results and to treatment efficacy, suggest an immune-mediated pathogenesis of hearing loss. Inner ear autoantibodies are not able to identify children affected with autoimmune sensorineural hearing loss but, integrated with clinical data, they can represent a diagnostic aid for the physician. Large prospective studies are needed to investigate usefulness, diagnostic and prognostic role of these autoantibodies.None declared."} +{"text": "Endovascular aneurysm repair (EVAR) is perhaps the most widely utilized surgical procedure for patients with large abdominal aortic aneurysms. This procedure is minimally invasive and reduces inpatient hospitalization requirements. The case involves a 72-year-old male who presented to the emergency department with right testicular ischemia two days following EVAR. Given the minimal inpatient hospitalization associated with this procedure, emergency physicians are likely to encounter associated complications. Ischemic and thromboembolic events following EVAR are extremely rare but require prompt vascular surgery intervention to minimize morbidity and mortality. Endovascular aneurysm repair (EVAR) is becoming the first-line treatment option for many patients with large abdominal aortic aneurysms (AAA) . IschemiA 72-year-old Caucasian male with a history of abdominal aortic aneurysm presented to the emergency department two days after abdominal aortic endovascular stent grafting. He presented with right flank, right lower abdominal, and right testicular pain. He reported persistent pain following surgery and was discharged from the hospital less than 24 hours prior to presentation on a bowel regimen and pain medication. Despite regular bowel movements and pain medication consumption, the pain persisted leading to his emergency department visit. He denied any recent fever, chills, headaches or vision changes, chest pain, shortness of breath, nausea, vomiting, dysuria, hematuria, or diarrhea. The pain is not improved with lying flat nor is the patient sexually active.On physical examination, his heart rate, blood pressure, respiratory rate, and temperature were within normal limits. Pertinent examination findings included a soft, exquisitely tender right testicle in vertical alignment with normal positioning and intact cremasteric reflex bilaterally. The pain persists despite testicular elevation. The abdomen was mildly distended with diffuse tenderness that was worse on the right. No peritoneal signs or costovertebral angle tenderness were noted. Femoral and dorsalis pedis pulses were present and equal bilaterally.Urology was consulted with coinciding history and physical exam findings. Following their clinical examination, urology recommended against performing emergent manual detorsion because the presentation was not consistent with testicular torsion. The patient subsequently underwent ultrasonographic evaluation of the sIntermittent torsion was considered less likely. This was followed by a computed topographic angiogram (CTA) study , which rAn abdominal aortic aneurysm (AAA) is an abnormal dilation of the major abdominal artery found in 5% to 10% of men aged 65 to 79 years , 5. SeveSurgical repair of AAA can be attained via open surgical repair (OSR) or endovascular stent grafting known as endovascular aneurysm repair (EVAR) . EVAR isOf the known complications of EVAR, leakage of blood into the aneurysm sac (endoleak) is most common. Additional complications include stent migration, aneurysm sac expansion, stent occlusion, and delayed rupture , 6. IschIn a case report by McKenna et al., a man of similar age presented with acute onset left scrotal pain following EVAR . One notIn the case presented, acute ischemia was suspected clinically and confirmed ultrasonographically. Blood flow to the right testicle was reduced with right testicular decreased echogenicity following EVAR, without clinical signs of torsion or infarction. As opposed to the previously mentioned cases, this patient was managed conservatively with symptom control and close observation and required no surgical intervention. Repeat ultrasound demonstrated stable blood flow to the right testicle and symptoms had resolved prior to discharge.The exact pathophysiology of testicular ischemia and infarction following EVAR is not clear as this is a rare complication with scarce literature. McKenna et al. report tEndovascular aneurysm repair is becoming the primary treatment option for many patients with operative AAA. Given the decreased intraoperative complications and reduced inpatient requirements, postoperative complications are more likely to occur at home and present to the emergency department for evaluation. These patients should be evaluated closely and in conjunction with vascular surgeons for potential end-organ damage secondary to acute ischemia and thromboembolic events."} +{"text": "Sustainable forest management is based on functional relationships between management actions, landscape conditions, and forest values. Changes in management practices make it fundamentally more difficult to study these relationships because the impacts of current practices are difficult to disentangle from the persistent influences of past practices. Within the Atlantic Northern Forest of Maine, U.S.A., forest policy and management practices changed abruptly in the early 1990s. During the 1970s-1980s, a severe insect outbreak stimulated salvage clearcutting of large contiguous tracts of spruce-fir forest. Following clearcut regulation in 1991, management practices shifted abruptly to near complete dependence on partial harvesting. Using a time series of Landsat satellite imagery (1973-2010) we assessed cumulative landscape change caused by these very different management regimes. We modeled predominant temporal patterns of harvesting and segmented a large study area into groups of landscape units with similar harvest histories. Time series of landscape composition and configuration metrics averaged within groups revealed differences in landscape dynamics caused by differences in management history. In some groups (24% of landscape units), salvage caused rapid loss and subdivision of intact mature forest. Persistent landscape change was created by large salvage clearcuts (often averaging > 100 ha) and conversion of spruce-fir to deciduous and mixed forest. In groups that were little affected by salvage (56% of landscape units), contemporary partial harvesting caused loss and subdivision of intact mature forest at even greater rates. Patch shape complexity and edge density reached high levels even where cumulative harvest area was relatively low. Contemporary practices introduced more numerous and much smaller patches of stand-replacing disturbance and a correspondingly large amount of edge. Management regimes impacted different areas to different degrees, producing different trajectories of landscape change that should be recognized when studying the impact of policy and management practices on forest ecology. Forest policy and management practices within the U.S. have changed substantially following widespread dissatisfaction with management overly focused on the production of wood fiber and game species habitat. Over the past several decades, managers of public and private lands have to varying degrees incorporated a much wider set of objectives including the protection or provision of amenities, biodiversity, and ecosystem services ,2. Much The sustainable management of forest landscapes and development of effective forest policy requires an understanding of the functional relationships between management practices, changes in landscape conditions, and ecological response. Abrupt changes in forest policy or other drivers of landscape dynamics make it fundamentally more difficult to evaluate these relationships. Because ecological processes operate over a wide range of temporal scales, responses to landscape change are time-dependent. Changes in species presence or abundance are frequently delayed following periods of rapid landscape change, and ecological communities take time to equilibrate to new landscape dynamics imposed by new management practices \u20138. DelayEmpirical studies of forest loss or fragmentation effects commonly rely on a space-for-time substitution , where rSatellite images provide the synoptic views needed to characterize forest conditions and landscape change. The ~40-year depth of the Landsat image archive in particular facilitates studies of forest landscape dynamics. However, there are relatively few retrospective analyses of landscape dynamics following abrupt changes in forest management practices. In the Pacific Northwest region of the U.S., Landsat image time series have been used to address the consequences of federal forest policy change e.g., ,17). Lan. Lan17])Choristoneura fumiferana (Clem.)), a native pest that causes widespread defoliation and mortality of balsam fir and spruce (Picea spp.) trees [The Atlantic Northern Forest of the northeastern U.S. encompasses roughly 11 million hectares within a transition zone between the northern boreal forest and the southern temperate deciduous-dominant forest. A substantial portion of this area lies within northern Maine, the largest contiguous block of undeveloped forestland in the nation (~4 Mha). Despite a long history of logging and commercial management for fiber production, major changes in management practices within recent decades have led to contemporary landscape conditions with little historical precedent. The spruce-fir forests of the region are subject to periodic infestations of the eastern spruce budworm (.) trees ,21. Main.) trees . Public .) trees in 1989 .) trees and less.) trees .Management practices in Maine have elicited concerns regarding the sustainable provision of forest values. During the budworm outbreak, salvage logging rates were well above recognized long-term allowable levels . RegenerThe objective of our research was to characterize predominant patterns of cumulative landscape change in the Atlantic Forest of northern Maine, and to evaluate how pre- and post-FPA management regimes have influenced landscape conditions across space and time. We used Landsat imagery and forest inventory data to develop and validate forest composition maps and a time series of forest harvest maps (1973\u20132010). We modeled predominant temporal patterns of harvesting and segmented a large study area into groups of landscape units with similar harvest histories. We then linked harvest history with changes in landscape composition and configuration in order to characterize the evolution of landscape conditions in response to forest management practices before and after abrupt change induced by the FPA. Our approach provided an objective synthesis of predominant patterns of change associated with specific landscape units, with the spatial and temporal resolution needed to attribute change to different management regimes.Acer rubrum, Acer saccharum, Betula alleghaniensis, Betula papyrifera, Fagus grandifolia) predominate across lower hilltops and at mid-slope. Spruce-fir species predominate where soil or microclimatic conditions exclude the more demanding hardwoods. Mixedwood stands commonly occur along ecotones or as a result of successional dynamics following disturbance. Shade-intolerant hardwood species are commonly found following intense disturbance. Periodic defoliation by spruce budworm is the most prominent form of natural disturbance. Windthrow is common but generally results in small canopy gaps [Our northern Maine, U.S.A. study region was defiopy gaps . Virtualopy gaps and rougForest harvest and composition maps were assembled from a time series of Landsat Multispectral Scanner (MSS), Thematic Mapper (TM), and Enhanced Thematic Mapper Plus (ETM+) images acquired during summer leaf-on conditions . ConsecuForest harvest maps were produced using a change detection procedure based on vegetation index values calculated from sequential Landsat images. As initially described by Sader and Winne , forest The improved sensitivity of the NDMI to partial canopy disturbance is generally attributable to the heightened sensitivity of mid-infrared wavelengths to differences in forest canopy structure, leaf area, and biomass ,35.We classified three-date NDMI and NDVI composites to produce forest change maps from TM/ETM+ and MSS image sequences, respectively. MSS imagery lacks a mid-infrared band required for calculation of the NDMI. This difference, coupled with reduced spatial and radiometric resolution, limits the efficacy of MSS imagery for detection of partial canopy disturbance. Disturbances mapped using MSS imagery (1973\u20131988) represent stand-replacing events, predominantly spruce budworm salvage clearcuts. Disturbances mapped using TM/ETM+ imagery (1988\u20132010) represent a wide range of intensities, and we differentiated two intensity classes interpreted as stand-replacing and partial canopy disturbance. The stand-replacing class was intended to represent harvests in which a new cohort was established following removal of a large proportion of the canopy, whether by clearcut as defined by the FPA ,37 or byHarvest maps were produced by unsupervised classification of overlapping three-date NDVI or NDMI image sequences . Classification of a three-date sequence mitigates the impact of cloud cover in the second image provided the first and third give clear views. An ISODATA algorithm applied to each three-date composite produced 50 statistical classes that were interpreted into forest disturbance, regrowth, and no-change information classes. Stand-replacing and partial harvest classes derived from TM/ETM+ imagery were differentiated based on the relative magnitude of NDMI change, guided by visual interpretation of Landsat imagery and available aerial photography. Confusion between light partial harvests and changes induced by factors such as atmospheric effects or interannual variability in forest phenology were resolved through on-screen editing . IndividWe produced a time series of maps depicting cumulative harvest impact (1975\u20132010) by overlaying successive harvest maps. For each time series date, a pixel was labeled as regenerating forest if preceding intervals included a harvest 1973\u20131988 or a stand-replacing harvest 1988\u20132010. A pixel was labeled as partially harvested if preceding intervals included only a single partial harvest. When preceding intervals included multiple partial harvests, pixels were labeled as regenerating forest, reflecting the anticipated ecological and silvicultural effects of multiple entries within the ~20-year period over which partial harvests were mapped (1988\u20132010). For each date of our time series, the result depicts the cumulative footprint of harvest operations since 1973.We mapped forest composition using equivalent unsupervised classification methods applied to each of the 1975 MSS and 2004 TM images. Dates were selected on the basis of cloud cover and image quality. For the purpose of forest type mapping, small areas of cloud cover in the 2004 image were replaced with data from the 2001 ETM+ image. Statistical classes produced from an ISODATA algorithm were aggregated to coniferous-dominant (>75% coniferous), deciduous-dominant (>75% deciduous), and mixed type classes through visual interpretation of Landsat imagery, with reference to available aerial photography and existing land cover maps. In some previously disturbed areas, exposed soils, woody debris, or herbaceous vegetation precluded the assignment of forest type and pixels were instead assigned to an indeterminate class. Patches less than 0.81 ha in size were removed and a 3x3 majority filter was applied to each map to consolidate patch boundaries and simplify the 2004 patch structure to more closely match the 1975 data.Assignment of ISODATA classes to forest types was subjective and sometimes difficult. A mistaken assignment could lead to bias in the representation of forest type extent. If for example pixels representing forest with a deciduous component of 70\u201375% were mistakenly committed to the deciduous-dominant class rather than the mixed class, the extent of the deciduous class would be overestimated according to the class definition of >75% deciduous. We used validation data obtained from field plots Program provides quality-assured measurements of forest attributes from a national network of field plots adhering to a systematic sampling design . We madeFIA estimates of forest age have been used to validate Landsat-derived disturbance time series under the assumption that trees sampled for age estimation germinated at the time of disturbance . HoweverIn Maine, the contemporary FIA inventory design was established in 1999, with 20% of plots surveyed annually during sequential 5-year cycles. Although data are available from plots measured during earlier inventories, coordinate locations are known for only a fraction of those plots. We therefore used data collected during contemporary inventory cycles to discriminate past harvest intensity. A harvest event identified by image interpretation was labeled stand-replacing provided FIA age dated stand origin to 1970 or later and field crews labeled the stand as either sapling or poletimber. However, for plots harvested after 1999, recorded stand age was an unreliable indicator of stand-replacing disturbance because age estimates frequently corresponded to a few residual stems rather than a newly established cohort. In these cases, intensity classes were discriminated using plot measurements made during consecutive 5-year inventory cycles; a harvest was labeled stand-replacing if plot basal area was reduced by >70%.Our validation sample of 509 plots was insufficient to produce reasonably precise accuracy estimates for individual time series intervals. We therefore aggregated intervals into six validation classes: 1973\u20131988 stand-replacing harvest, 1988\u20131999 stand-replacing harvest, 1988\u20131999 partial harvest, 1999\u20132010 stand-replacing harvest, 1999\u20132010 partial harvest, and intact mature forest . Map and reference validation class labels were assigned in a manner consistent with the construction of cumulative harvest maps. Where multiple entries occurred, labels were assigned based on the date of first stand-replacing disturbance. Where multiple partial harvests occurred, labels of either 1988\u20131999 or 1999\u20132010 stand-replacing were assigned based on the date of second entry. Map and reference labels were compiled into an error matrix. Overall accuracy, user accuracy (the complement of class commission error), producer accuracy (the complement of class omission error), and corresponding standard error estimates were calculated by poststratification ,43. AddiThe 1975 and 2004 forest type maps were validated using FIA plot measurements of coniferous and deciduous live tree basal area collected during 1980\u20131982 and 1999\u20132003 inventories, respectively. Differences in dates between maps and field inventories were resolved by excluding samples where intervening harvests occurred. For 2004 map validation, we excluded plots mapped as harvested from 1999\u20132004; for 1975, we excluded plots mapped as harvested from 1975\u20131982. A sample of 445 plots remained for validation of the 2004 map; only 70 plots were available for validation of the 1975 map. As previously described, we identified coniferous-dominant and deciduous-dominant class thresholds for which errors were best balanced and mapped class extents least biased. Following refinements made to improve consistency between maps, an error matrix was compiled for each map based on selected threshold values. Estimates of overall, user, and producer accuracy were calculated by poststratification ,43.To quantify harvest rates through time, identify trends, and associate trends with changes in landscape conditions, we tessellated our study area into landscape units using a 5 km square grid . A 5 km TX and are equivalent to the loading vectors or principal components of a PCA. The spatial amplitudes correspond to the PCA scores obtained by projecting the time series of X onto the subspace spanned by the EOFs.An EOF analysis identifies a sequence of uncorrelated patterns or modes of variability that characterize variation within a two-dimensional data set . EOF anaA traditional EOF analysis or PCA is sensitive to extreme observations and outliers, which can distort the outcome such that dominant modes of variability represent contrasts between anomalous and regular observations rather than patterns of variability within regular observations . We perfPaired EOFs and amplitude functions comprise orthogonal modes of variability, ordered by the amount of total variance explained. We modeled cumulative harvest time series as linear combinations of dominant EOFs, selected based on the proportion of overall variance explained by successive modes. By including only dominant modes, modeled time series represent statistically coherent variability in harvesting patterns that occurred over large portions of the study area. The ROBPCA algorithm provides a measure of orthogonal distance between samples and the subspace defined by dominant EOF modes. Unusually large orthogonal distances indicate outlying samples that do not conform to characteristic patterns defined by dominant modes. We identified 12 orthogonal outliers using the ROBPCA nominal cutoff value and exclTo classify predominant temporal patterns of harvesting from the EOF analysis and to associate those patterns with groups of grid cells, we performed an agglomerative hierarchical clustering of modelLandscape composition metrics were calculated for grid cells and averaged within groups to evaluate changes associated with predominant harvesting trends. Within our time series of cumulative harvest maps, available forestland was classified as either regenerating, partially harvested, or intact mature forest . The EOF and cluster analyses produced time series of cumulative harvest area, the reciprocal of intact mature forest area. We also produced time series of cumulative partial harvest and regenerating forest area to evaluate changes in harvest intensity associated with predominant harvesting trends. Available forestland was summarized by 1975 forest type to associate harvest history and landscape change with initial landscape composition. To evaluate composition change as a legacy of harvest practices, we quantified forest type change between 1975 and 2004 for areas harvested before 2004. Composition change in unharvested forestland was not evaluated as part of this research.Early successional and intact late successional forest patches are landscape elements of particular interest, given the expansion of partial harvest practices in the 1990s. Cumulative changes in the patch configuration of regenerating and intact mature forest were evaluated by calculating time series of landscape metrics. We selected a small number of metrics of general relevance to forest ecology that quantify primary aspects of class configuration thought to have been affected by changes in management practices. Metrics were calculated using Fragstats version 4.2 . Area-weHarvest validation classes were mapped with an overall accuracy of 88% . User anForest type classes for 1975 and 2004 were mapped with overall accuracies of 76% and 68%, respectively Tables . User anBy 2010, 61% of available forestland was mapped as harvested, and 40% regenerated by stand-replacing or multiple partial harvests. Averaged across all grid cells, harvest rates increased ca. 1985 and then remained quite constant at about 2% per year [Lepus americanus), are found at highest density within coniferous and mixed regenerating forest ~15\u201335 years post-harvest [Martes americana) [The changes in landscape composition and configuration we have quantified imply potentially important impacts on forest ecology and wildlife. Salvage clearcuts created large blocks of early successional forest habitat, benefitting the federally threatened Canada lynx (adensis) . In Main-harvest \u201359. The -harvest . Additioericana) . For speS1 AppendixDescription of image processing steps performed prior to forest harvest and composition mapping.(DOCX)Click here for additional data file.S2 AppendixDescription of the procedures used to validate cumulative forest harvest (1973\u20132010) and forest type maps (1975 and 2004), and a brief interpretation of validation outcomes.(DOCX)Click here for additional data file."} +{"text": "Fine needle aspiration (FNA) cytology is a well-established diagnostic method based on the microscopic interpretation of often scant cytological material; therefore, experience, good technique and smear quality are equally important in obtaining satisfactory results.We studied the use of fresh surgical pathology specimens for making so-called mock-FNA smears with the potential of cytohistological correlation. Additionally, we studied how this process aids the improvement of preparation technique and smear quality.Cytological aspirates from 32 fresh biopsy specimens from various sites: lung (20), lymph nodes (6), and breast (6) were obtained, all with a clinical diagnosis of tumor. Aspiration was performed from grossly palpable tumors. 25G needle and Cameco-type syringe holder was used with minimal or no suction.Unfixed surgical specimens provided sufficient cytological material that resulted in good quality smears. After standard processing of specimens into microscopic sections from paraffin embedded tissues, cytohistological case-series were created. No significant alteration was reported in tissue architecture on hematoxylin-eosin stained sections after the aspiration procedure. A gradual, but steady improvement was observed in smear quality just after a few preparations.Our study proved that surgical specimens may be used as a source of cytological material to create cytohistological correlation studies and also to improve FNA cytology skills. The use of very fine gauge needle during the sampling process does not alter tissue architecture therefore the final histopathological diagnosis is not compromised. We conclude that by using fresh surgical specimens useful cytohistological collections can be created both as a teaching resource and as improving experience. Fine needle aspiration cytology or biopsy (FNAC/FNAB) is a well-established diagnostic method used in many countries as a first-line diagnostic procedure aiding preoperative management of various palpable and non-palpable lesions. The history of needle biopsy spans several centuries; however, its use as a routine diagnostic technique was established mostly during the twentieth century To accelerate the learning process and experience of recognizing specific cellular morphology we propose here the use of fresh (i.e. unfixed) surgical pathology specimens as a source of creating FNA smears and cytohistological correlation series. This procedure also might serve as a model for learning the basics of FNAC including sampling and smear preparation. Our main objective was to demonstrate how fresh surgical specimens may used as a source for cytological material with respect to creating cytohistological correlation case series. Additional objective was to study the usefulness of surgical pathology specimens in the practice of fine needle aspiration technique including sampling and smear preparation.The study was conducted in Mures County Emergency Clinic/Spitalul Clinic Judetean de Urgenta Mures, university hospital within the University of Medicine and Pharmacy of Tirgu Mures. Upon submission a signed written informed consent was obtained from all patients acknowledging that bioptic specimens removed by surgery due to therapeutic considerations might undergo additional studies. For conducting our study we did use only some parts of the bioptic specimens, without altering in any way the final histological diagnosis. Since no additional tissues/cells were removed from any patient, other than it would anyway be removed, approval of the ethics committee was not necessary. Samples presented in this study were not described nor published in other study, including parts or the whole material.The authors of this article did not interact with any of the patients whose surgical pathology specimens constituted the main subject of this article. The identity of patients was protected at several levels. All cases were designated with an ID number, starting with one. After the cyto-histological correlation series were created only these ID numbers identified each case. From clinical data only tumor localization, size, age, sex and histopathological type was linked to the identification numbers. This way patient confidentiality was respected by anonymizing bioptic specimens. The obtained cyto-histological correlation cases were archived according to case numbers plus the above mentioned minimal clinical data, without any other data that could be linked to any individual .Fresh, unfixed, surgical biopsies, mostly whole-organs were used as the source for cytological material aspiration, prior formalin fixation. We obtained cytological aspirates from 32 fresh biopsy specimens from various sites: lung (20), lymph nodes (6), and breast (6). All organs were submitted to the pathology laboratory with a clinical diagnosis of tumor. Aspiration was performed exclusively from grossly palpable tumors. Cytological material was obtained using standard fine needle aspiration technique as described by Stanley A Cameco-type syringe holder mounted with a 10 ml three-piece syringe was used. For staining, we used two commercially available staining kits Cytocolor and Hemacolor and standard Papanicolaou stain. In each case, we used the following two gauge type needles: 23G and 25G .Aspired material was spread on standard pre-cleaned glass slides using the standard one-step method described by Stanley and colleagues and its modification Most of the surgical specimens provided sufficient cellular quantity using the standard FNA technique. However, material obtained from lesions showing extensive desmoplasia or were rich in conjunctive stroma resulted in less cellularity. Nevertheless all cytological metrials obtained resulted in sufficient and mostly good quality smears. All the specimens were processed according to specific protocols and paraffin-embedded tissue blocks were created. Thus from all lesions microscopic slides were made and stained with hematoxylin-eosin. This permitted the creation of cytohistological correlation pairs. As depicted in There was no perceivable morphological differences between smears prepared with material aspired with 23G or 25G needles, both proved to be sufficent. In more fibrous or desmoplastic lesion 25G needles, handled too firmly, had a tendency to bend.The one-step method described by Stanley prooved to be optimal in preparing cytological material obtained from fresh speciemens Fine-needle aspiration cytology or biopsy (FNAC/FNAB) is increasingly performed as an economical, safe and rapid minimally invasive technique for diagnosis of various lesions including tumors and non-neoplastic lesions Using fresh surgical pathology specimens offers the possibility to experiment with various smearing and preparation techniques, the ultimate goal being to produce good quality smears. Before performing FNA at the patient\u2019s side both dexterity and smear preparation skill may be improved by practicing on fresh surgical material without altering the histopathological interpretation of these specimens. Nevertheless there are few models described for practicing FNA technique, sampling and slide preparation. Some of these models include the use of fresh animal (beef and pork) liver introduced into a double layered latex glove, while others describe models made of silicone Finally, using surgical specimens also ensures that in addition to cytology, also paraffin-embedded tissue sections are also available at end of the day, enabling the development of the third foundation of cytodiagnosis, by the use of cytohistological correlation series see and 2.We described our experience of using surgical pathology specimens (tissue biopsies) for practicing FNAB proficiency. Fresh surgical pathology specimens, especially whole-organs may be used for training residents prior to the beginning of FNAB performance on patients in the clinical setting. Surgical specimens may be used as a source of cytological material to improve FNAB skills. These specimens also provide cytological material to study preparation conditions that may alter smear quality. We found that fresh surgical pathology specimens used prior formalin-fixation were a good source of cytological material and may be used for practicing sampling and smear preparation.Additionally, using biopsy specimens offers the great opportunity to study cytohistological correlations. The creation of cytological smears has little impact on a laboratory\u2019s financial expenses. No special equipment is needed and standard dyes (such as Papanicolaou and Romanowsky-types stains) may be used. For each specimen up to 3\u20134 cytological smears are optimal without significantly hindering grossing or delaying routine practice. Compared to standard histology additionally to glass-slides, stains and coverslips, only needles (with no larger gauge than 23\u201325G) and syringes and fixative are needed that may be acquired at low cost. We consider that the costs of such materials are far beyond the benefits the introduction of mock-FNA into daily routine may represent.Aspired material can also be used to study and experiment with the various conditions that may critically alter smear quality and potentially hinder the formulation of the correct diagnosis. To become proficient in sampling and smearing, it is necessary to perform many biopsies on patients. However, the process can be significantly accelerated by performing practice sessions with fresh surgical pathology specimens before attempting the procedure in the clinical setting."} +{"text": "Healthy hearing depends on sensitive ears and adequate brain processing. Essential aspects of both hearing and cognition decline with advancing age, but it is largely unknown how one influences the other. The current standard measure of hearing, the pure-tone audiogram is not very cognitively demanding and does not predict well the most important yet challenging use of hearing, listening to speech in noisy environments. We analysed data from UK Biobank that asked 40\u201369 year olds about their hearing, and assessed their ability on tests of speech-in-noise hearing and cognition.About half a million volunteers were recruited through NHS registers. Respondents completed \u2018whole-body\u2019 testing in purpose-designed, community-based test centres across the UK. Objective hearing (spoken digit recognition in noise) and cognitive data were analysed using logistic and multiple regression methods. Speech hearing in noise declined exponentially with age for both sexes from about 50 years, differing from previous audiogram data that showed a more linear decline from <40 years for men, and consistently less hearing loss for women. The decline in speech-in-noise hearing was especially dramatic among those with lower cognitive scores. Decreasing cognitive ability and increasing age were both independently associated with decreasing ability to hear speech-in-noise among the population studied. Men subjectively reported up to 60% higher rates of difficulty hearing than women. Workplace noise history associated with difficulty in both subjective hearing and objective speech hearing in noise. Leisure noise history was associated with subjective, but not with objective difficulty hearing.Older people have declining cognitive processing ability associated with reduced ability to hear speech in noise, measured by recognition of recorded spoken digits. Subjective reports of hearing difficulty generally show a higher prevalence than objective measures, suggesting that current objective methods could be extended further. The DTT choice of single digit words promotes easy understanding and the opportunity to \u2018fill-in\u2019 missed acoustic information, while steady-state, speech-shaped noise enables masking across the speech range, but does not allow the \u2018glimpsing\u2019 that can reduce masking in more complex noise. Overall, DTT performance correlates more closely with PTA than do some other SiN tests Self-report of hearing difficulties, using questionnaire instruments or often only one or two questions, has commonly been used to assess the prevalence of hearing loss in large epidemiological studies In this study we investigated the relation between DTT SRT and cognitive ability as a function of age, sex, socioeconomic status, and noise exposure. The results were compared with self-report of hearing difficulties and findings from other studies, including some previously unpublished data from the NIH Toolbox www.ukbiobank.ac.uk.Complete details of all UK Biobank procedures are available at This research was covered by the UK Biobank ethics agreement. Within England, UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC). All participants provided written informed consent.Participants , about one third of the participants of cards showing 3 and 6 pairs of shapes, respectively. The shapes were concealed and the participant was required to recall locations of matching shape pairs. Correct responses were confirmed. The Reaction Time test of processing speed sequentially presented twelve pairs of shapes. The participant pressed a button as quickly as possible if a pair of shapes matched. Finally, in the Digit Span (\u2018Numeric memory\u2019) test of verbal working memory participants were initially presented on the screen with two digits and were required to key in the digits in reverse order. After each correct response the digit sequence was increased by one. The task ended after two incorrect responses. Raw score was the maximum number of correctly recalled and ordered digits. Performance on the Prospective Memory, Reaction Time and Digit Span tests additionally depended on executive function and all tests depended on alerting and orienting attention.Variable numbers of participants completed each test , primariAnalysis of self-report measures used binary logistic regression. Standardised scores, which each maximised the variability within the sampled population, were derived for each cognitive test using principal components analysis. A composite score was defined as a simple sum of the five standardised scores. Both individual and composite cognitive scores were standardised to have zero mean and unit standard deviation, such that higher values corresponded to higher ability. Scores were grouped into deciles for analysis. Regression modelling techniques accounting for sex, socio-economic deprivation tone detection thresholds declined from 18\u201385 years (NIH Toolbox data (DOCX)Click here for additional data file."} +{"text": "The physiological role of CNS regeneration inhibitors in the na\u00efve, or uninjured, CNS remains less well understood, but has received growing attention in recent years and is the focus of this review. CNS regeneration inhibitors regulate myelin development and axon stability, consolidate neuronal structure shaped by experience, and limit activity-dependent modification of synaptic strength. Altered function of CNS regeneration inhibitors is associated with neuropsychiatric disorders, suggesting crucial roles in brain development and health.The growth inhibitory nature of injured adult mammalian central nervous system (CNS) tissue constitutes a major barrier to robust axonal outgrowth and functional recovery following trauma or disease. Prototypic CNS regeneration inhibitors are broadly expressed in the healthy and injured brain and spinal cord and include myelin-associated glycoprotein (MAG), the reticulon family member NogoA, oligodendrocyte myelin glycoprotein (OMgp), and chondroitin sulfate proteoglycans (CSPGs). These structurally diverse molecules strongly inhibit neurite outgrowth Proper function of the adult mammalian CNS requires precise assembly, refinement, and maintenance of an elaborate network of neuronal connections. During development, axon guidance molecules facilitate the formation of intricate neuronal networks. After this initial assembly, many circuits are refined in an activity-dependent manner during a short time period of heightened plasticity, called the critical period (CP). At the end of the CP, the fine tuning of networks is complete and they acquire their mature shape. Synaptic contacts in the mature brain are stable over long time periods , display striking similarities to Mag null mice, suggesting that gangliosides may be the primary receptors responsible for MAG-mediated axon protection -anchor. OMgp is expressed by OLs and neurons in the CNS , are extracellular matrix (ECM) proteoglycans that consist of a protein core with covalently attached glycosaminoglycan (GAG) side chains , and its homolog RPTP\u03c3 and long-term depression (LTD) of synaptic transmission are opposing forms of activity-dependent synaptic strength modifications, and are thought to underlie aspects of learning and memory formation signaling. At the cell surface, BDNF binds TrkB to activate several growth promoting pathways, including mTOR complex 1 (mTORC1) and MAP kinase/ERK. However, CSPG binding to RPTP\u03c3 attenuates activity of TrkB (Kurihara and Yamashita, NgR1 null mice show impaired memory function, including impaired fear extinction and consolidation (Park et al., NgR1 and NogoA have been associated with schizophrenia (Sinibaldi et al., Many human neuropsychiatric disorders are associated with defects in synaptic structure or function and may be caused by a shift in excitatory/inhibitory balance (Pittenger, CNS regeneration inhibitors play important physiological roles in the uninjured brain and spinal cord. The myelin-associated inhibitors MAG, NogoA, and OMgp regulate myelin formation and axon-myelin interactions. NogoA, OMgp, and CSPGs regulate synapse formation and maturation, and they influence activity-dependent synaptic strength. Growing evidence suggests that some CNS regeneration inhibitors participate in an intricate cross-talk with growth promoting molecules at the level of several key signaling molecules. This finely tuned balance of excitation and inhibition in the developing and mature CNS may be necessary for proper formation and function of neural networks.The physiological role of these molecules raises important considerations for therapeutic strategies designed to promote neural regeneration following injury. The acquisition of a large number of ligand-receptor systems that restrict neural network plasticity may have been a prerequisite that enabled the evolution of larger and more powerful neural networks. Larger and more complex brains may be more vulnerable to aberrant changes in synaptic connectivity and therefore, once fully developed, need to be consolidated and protected by molecules that constrain excessive network rearrangement. Following injury to the adult CNS, molecules that restrict aberrant growth and plasticity may be detrimental since they limit attempts to modify or rebuild nearby networks to compensate for lost neural circuits. Therefore, a deeper understanding of the physiological roles played by CNS regeneration inhibitors is of great interest both clinically and biologically.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Local field potentials (LFPs), measured using extracellular electrodes, provide information about local neuronal population activity. The development of multi-electrode arrays (MEAs) that measure LFPs simultaneously at different network locations has led to a renewed interest in the LFP as a measure of neuronal network activity . While tin vitro.Here, we describe two contributions to the effort to understand LFP generation in neuronal networks. First, we investigated reduced compartmental models to assess their suitability for producing realistic spatial LFP characteristics. We show that the chosen reduction method creates"} +{"text": "ICR-CTSU introduced EDC in 2012 necessitating the development of EDC specific training materials for participating sites.Training of site staff on EDC systems is essential to ensure data quality and returns are maximised. Guidance notes are issued to support standardised completion of case report forms. However, due to the technical nature of EDC, guidance notes alone provide insufficient support for most site staff. Provision of effective, consistent and timely EDC training across a trial's lifespan is a continuing challenge, particularly for large trials or those with long follow-up where site staff turnover is an added consideration.ICR-CTSU created a custom EDC system user guide, developed training slides and included instructional text within the EDC system. Since the implementation of EDC, ICR-CTSU have developed short training videos covering key topics including logging in, record navigation, data entry and query response. The videos illustrate the EDC screen view and are accompanied by scripted voice over guidance. Training materials are accessible online via the ICR-CTSU website.Whilst customised EDC system user guides and in-built instructions form the basis of site staff training, supplementary technical training is required. This can be provided to site staff individually through webinars, teleconferences and centre initiation visits, however the online training videos provide a more consistent and accessible resource. This solution should reduce demand on ICR-CTSU resources for ongoing site training."} +{"text": "Ischaemic heart disease is most prevalent in the ageing population and often exists with other comorbidities; however the majority of laboratory research uses young, healthy animal models. Several recent workshops and focus meetings have highlighted the importance of using clinically relevant models to help aid translation to realistic patient populations. We have previously shown that mice over-expressing the creatine transporter (CrT-OE) have elevated intracellular creatine levels and are protected against ischaemia-reperfusion injury. Here we test whether elevating intracellular creatine levels retains a cardioprotective effect in the presence of common comorbidities and whether it is additive to protection afforded by hypothermic cardioplegia.+ cardioplegic arrest, as used during cardiac surgery and donor heart transplant, was further enhanced in prolonged ischaemia (90 minutes) in CrT-OE Langendorff perfused mouse hearts .CrT-OE mice and wild-type controls were subjected to transverse aortic constriction for two weeks to induce compensated left ventricular hypertrophy (LVH). Hearts were retrogradely perfused in Langendorff mode for 15 minutes, followed by 20 minutes ischaemia and 30 minutes reperfusion. CrT-OE hearts exhibited significantly improved functional recovery (Rate pressure product) during reperfusion compared to WT littermates . Aged CrT-OE mouse hearts (78\u00b15 weeks) also had enhanced recovery following 15 minutes ischaemia . The cardioprotective effect of hypothermic high KThese observations in clinically relevant models further support the development of modulators of intracellular creatine content as a translatable strategy for cardiac protection against ischaemia-reperfusion injury. This was attributed to increased phosphocreatine (PCr) buffer capacity, elevated myocardial glycogen, improved \u2018energy reserve\u2019 and the ability of creatine to reduce the open probability of the mitochondrial permeability transition pore . CardiopRapid revascularization of ischaemic regions within the heart by thrombolysis or primary percutaneous coronary intervention remains at the clinical forefront to effectively treat AMI ,19. Pre-It should be noted that previous work from our laboratory has shown that very high myocardial [Cr] may itself cause LV hypertrophy and dysfunction , and defWe also performed experiments in mice aged 18 months since the ageing heart is known to have altered cardiac substrate metabolism , is more+ and Mg2+ ions to reduce metabolic demand and prolong ischaemic tolerance [ex vivo rat hearts [Cold, cardioplegic arrest of the heart remains the gold standard for effective myocardial protection during cardiac surgery and hearolerance . In thisolerance and in polerance undergoit hearts . Howevert hearts . These bt hearts and not ex vivo not in vivo experimental approaches and ideally we would have both. This reflects the limitations of having sufficient numbers of aged animals and the welfare implications of combining TAC surgery with ischaemia-reperfusion surgery. Furthermore, we did not perform tetrazolium staining in our ex vivo hearts since the period of reperfusion was insufficient for complete washout of NADH from necrotic tissue, which would lead to under-estimation of infarct sizes [During ischaemia, the heart undergoes many metabolic changes including a reduction in intracellular PCr . We did ct sizes . It is tct sizes .We have shown that elevating creatine levels in the mouse heart improves functional recovery following ischaemia-reperfusion even in the presence of old age or LVH. Both conditions previously associated with loss of cardioprotective efficacy. Furthermore, elevating intracellular creatine is additive to standard hypothermic cardioplegia for recovery from prolonged ischaemia. Together these findings support the development of small molecule activators that increase intracellular Cr , which wS1 File(DOC)Click here for additional data file."} +{"text": "Hemoptysis is a common complication in all kinds of surgery. However, it is rarely critical because it resolves with or without intervention.Here the authors present what is believed to be an unprecedented report of a case involving a fatal idiopathic bronchial hemorrhage complication during cardiac surgery. Eighty-five-year-old female with severe aorticvalve stenosis had elective aortic valve replacement. Subsequently, she developed diffuse bilateral severe idiopathic bronchial hemorrhage which required maximum intervention such as external bronchial ligation, V-A ECMO, coil embolization of bronchial artery and internal airway blockage by spigot.Airway bleeding is not a rare complication in cardiac surgery, but this case should increase awareness of this potentially life threatening perioperative complication.The online version of this article (doi:10.1186/s13019-016-0477-0) contains supplementary material, which is available to authorized users. Airway bleeding during or after heart surgery is common, but is rarely reported because it is generally minor and resolves spontaneously in most cases. Here the authors report an unusual case of exsanguinating diffuse airway bleeding during cardiac surgery. The complication required aggressive intervention measures such as extra-corporeal membrane oxygenation (ECMO), bronchial ligation, bronchial artery coil embolization and internal airway blockage using an intrabronchial spigot.The case involved an 85-year-old female with congestive heart failure caused by severe aortic valve stenosis. Aortic valve replacement with a bioprosthetic valve was conducted electively. After the ascending aorta was unclamped, anesthetist noticed blood coming up from the endotracheal tube. Intraoperative flexible bronchoscopy confirmed massive hemoptysis coming up from all peripheral bronchi and mainly from the bilateral inferior lobes. The left chest was inspected through additional anterolateral thoracotomy connected perpendicularly to median sternotomy wound at 4th intercostal space. And the left hilum was exposed and lower bronchus was ligated externally to reduce the amount of intrabronchial bleeding. Repeated bronchoscopy showed persisting large-volume airway bleeding have beThere is no doubt that systemic heparinization in cardiac surgery triggered the diffuse bronchial hemorrhage. Complete heparin reversal and expeditious weaning from cardiopulmonary bypass is reported to be the best and the only way to manage major hemoptysis \u20135. HowevUnderlying pulmonary disease such as bronchiectasia or tuberculosis can also cause perioperative hemoptysis. Pulmonary capillaritis such as Wegener\u2019s granulomatosis or Goodpasture syndrome are also known to be related to pulmonary hemorrhage . AlthougIn summary, this was a rare case of diffuse exsanguinating hemoptysis during cardiac surgery. Even after all the aggressive intervention and intensive care administered, the patient\u2019s respiratory status failed to show improvement in terms of lung compliance and oxygenation. Practicing cardiothoracic surgeons should note this unusual but catastrophic perioperative complication.All authors have approved the manuscript. Patient\u2019s family has agreed with submission of the case report. Upon acceptance, authors will transfer copyright to the Publisher. All authors have no ethical problem or conflicts of interest to declare."} +{"text": "This survey sought to evaluate differences in the understanding and management of shunt-dependent hydrocephalus among the senior North American Pediatric Neurosurgery membership.Surveys were sent to all active American Society of Pediatric Neurosurgeons (ASPN) members from September to November 2014. A total of 204 surveys were sent from which 130 responses were recorded, representing 64% of active ASPN membership. Respondents were asked 13 multiple choice and free response questions focusing on four problems encountered in shunted hydrocephalus management: Shunt malfunction, cerebrospinal fluid (CSF) overdrainage, chronic headaches and slit ventricle syndrome (SVS). Qualtrics\u00ae online survey software was used to distribute and collect response data.ASPN surgeons prefer three varieties of shunt valves: 41% differential pressure, 29% differential with anti-siphon device (ASD), and 27% programmable. Respondents agree shunt obstruction occurs most often at the ventricular catheter due to either in-growth of the choroid plexus (67%), CSF debris (18%), ventricular collapse (8%), or other reasons (9%). Underlying causes of obstruction were attributed to small ventricular size, catheter position, choroid plexus migration, build-up of cellular debris, inflammatory processes, or CSF overdrainage. The majority of respondents (>85%) consider chronic overdrainage a rare complication. These cases are most often managed with ASDs or programmable valves. Chronic headaches are most often attributed to medical reasons and managed with patient reassurance. The most popular treatments for SVS include shunt revision (88%), cranial expansion (57%) and placement of an ASD (53%). SVS etiology was most often linked to early onset of shunting, chronic overdrainage and/or loss of brain compliance.This survey shows discrepancies in shunt-dependent hydrocephalus understanding and management style among a representative group of experienced North American pediatric neurosurgeons. In particular, there are differing opinions regarding the primary cause of ventricular shunt obstructions and the origins of SVS. However, there appears to be general consensus in approach and management of overdrainage and chronic headaches. These results provide impetus for better studies evaluating the pathophysiology and prevention of shunt obstruction and SVS."} +{"text": "Isolated coarctation of aorta is usually diagnosed and treated surgically in most of patients during childhood, but optimal management strategies for adult patients with coarctation of aorta associated with stenosed bicuspid aortic valve are controversial.We aim to treat such rare patients successfully by less invasive two staged hybrid management.We report a case of 18 years old female with history of dyspnoea on exertion since 4 years, with complaints of headache and bilateral lower limb claudication, clinical findings revealed no characteristic clinical feature of Turner syndrome, on examination femoral pulses were delayed and diminished bilaterally, laboratory examination were unremarkable with negative karyotyping for Turner syndrome, chest x-ray showed enlarged cardiac silhouette with rib notching, echocardiography revealed severely stenosed bicuspid aortic valve with left ventricular hypertrophy, descending aortogram showed post ductal coarctation and collaterals, pressure analysis revealed gradient of 70 mmHg across coarctation. She underwent successful hybrid approach with percutaneous catheter balloon coarctoplasty (PCBC) with stenting in the first stage, followed by surgery for aortic valve replacement in the second stage.Post operatively she was asymptomatic and had uneventful recovery after each stage of management, post-operative echocardiography findings were within acceptable limits, and at 6 months follow up the mean echocardiographic aortic arch gradient was within acceptable limits.Two staged hybrid approach of (PCBC) with stenting for coarctation of aorta and aortic valve replacement for coexistent stenosed bicuspid aortic valve is a safe, less invasive and can be effective alternative to complete surgical approach, if done meticulously.Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal."} +{"text": "Giant cell reparative granuloma (GCRG) is a rare, benign intra osseous lytic lesion occurring especially in gnathis bone but also seen in feet and hands. It has similar clinical and radiological presentations than giant cell tumor, chondroblastoma, aneurysmal bone cyst, and hyperparathyroidism brown tumors but with specific histological findings We report a case of a GCRG of hallux phalanx in 18 years old patient appearing many years after enchondroma curettage and grafting. Radiographs showed a multiloculated osteolytic lesions involving whole phalanx with cortical thinning and without fluid-fluid levels in CT view. Expected to be an enchondroma recurrence, second biopsy confirmed diagnosis of GCRG with specific histological findings. Although if aetiopathogeny remains unknown, GCRG is reported to be a local non neoplasic reaction to an intraosseous hemorrhage. Our exceptional case claims that this tumor can appear in reaction to cellular disturbance primary or secondary. Giant cell reparative granuloma (GCRG) is a rare, benign intraosseous lytic lesion occurring especially in gnathic bones and also in hands and feet phalanx \u20133. It isA 13- year-old boy presented in emergency room with left hallux painful evolving for several months without any underlying trauma. The physical examination noted a localized swallowing of the dorsum of the right hallux base with no inflammatory local signs and a pain sensitivity induced by examination. Mobility of the adjacent joint was normal and no biological abnormalities were found. Radiographic examination showed a well-defined lytic lesion of the hallux proximal phalanx. Neither cortex erosion nor soft tissues abnormalities were noticed . An initInitially described by Jaffe in 1953,This case suggests a potential connection between GCRG and enchondroma and hypothesis that GCRG could appear in reaction of cellular disturbance primary or secondary to enchondroma surgical treatment."} +{"text": "Praelongorthezia praelonga (Hemiptera: Ortheziidae), an important pest of citrus orchards. The data presented in this article are related to the article entitled \u201cSeasonal prevalence of the insect pathogenic fungus Colletotrichum nymphaeae in Brazilian citrus groves under different chemical pesticide regimes\u201d C. nymphaeae, emerges through the thin cuticular intersegmental regions of the citrus orthezia scale body revealing orange salmon-pigmented conidiophores bearing conidial masses, as well as producing rhizoid-like hyphae that extend over the citrus leaf. By contrast, nymphs or adult females of this scale insect infected with Lecanicillium longisporum exhibit profuse outgrowth of bright white-pigmented conidiophores with clusters of conidia emerging from the insect intersegmental membranes, and mycosed cadavers are commonly observed attached to the leaf surface by hyphal extensions. These morphological differences are important features to discriminate these fungal entomopathogens in citrus orthezia scales.We describe symptoms of mycosis induced by two native fungal entomopathogens of the citrus orthezia scale, Specifications Table\u2022C. nymphaeae and L. longisporum.Data show symptoms of two important fungal diseases in the citrus orthezia scale caused by \u2022Simple and practical recognition of these entomopathogenic fungi can be achieved on the basis of their conspicuous morphological characters, including conidiophores and conidia, from mycosed scale insects.\u2022The importance of using morphological features based on symptoms of fungal diseases can serve as a guideline to facilitate recognition and quantification of these pathogens in citrus orthezia scale populations.1C. nymphaeae and L. longisporum of infected citrus orthezia scales with two native fungal pathogens, namely gisporum . Images 2L. longisporum or C. nymphaeae from citrus groves located in a commercial farm were taken to the laboratory to record the morphological features of mycosis in individuals of the citrus orthezia scale. Images of mycosed insects were acquired by using a stereo-microscope at 10\u201330\u00d7 magnification, while images of conidiospores were taken by phase-contrast and scanning electron microscopy. These morphological characters related to signs of fungal diseases were used as a guideline for identification and quantification of these fungal entomopathogens in this insect population during field surveys Field collected insects infected with"} +{"text": "Cancers depend on one or more ubiquitously activated oncogenes to survive and maintain their tumorigenic phenotype. The MYC oncogene is critically important in a variety of hematological malignancies, including Burkitt's lymphoma, acute lymphoblastic leukemia, and multiple myeloma. Cancers' reliance on few oncogenes, aptly termed oncogene addiction, presents an exploitable vulnerability. Indeed, targeted therapies inhibiting key oncogenes in a multitude of cancer types are routinely used in clinic . HoweverExperimental model systems of MYC oncogene inactivation in various cancers have revealed molecular mechanisms of oncogene addiction, escape from oncogene dependence resulting in tumor recurrence . InactivRecently, we gained insight into the mechanism of tumor recurrence. We found that when either of two tumor suppressor genes, ARF or p53, is lost or mutated, tumor recurrence rapidly always occurs . We prevWe found that ARF loss prevented MYC inactivation from inducing cellular senescence through a p53 independent mechanism . Our obsThe mechanism through which ARF regulates innate immunity is not clear. Analysis of gene expression revealed a signature of genes involved in innate immunity . ARF, itEmerging immunotherapies have intensified interest in the therapeutic role of the innate and adaptive immune system. Biologics targeted at tumor cells for enabling antibody-dependent cell-mediated cytoxicity (ADCC) rely on innate immune system for elimination of cancer cells . Since ACells undergoing senescence secrete factors that bolster the senescent phenotype in both autocrine and paracrine fashion by engaging innate immune system . ARF losOur research has uncovered ARF as a common regulator of senescence and tumor clearance that appears to require the innate immune system. However, there are several questions awaiting answers. First, we have identified innate immune-related gene expression changes due to ARF loss; yet direct causality of these changes in macrophage infiltration into regressing tumors has not been established. Second, the mechanism by which cellular senescence is dependent upon macrophage recruitment is unclear. Third, whether ARF loss in tumors affects other immune infiltrates, such as NK cells, monocytic and granulocytic myeloid cells, or even adaptive immune cells, needs to be investigated. Fourth whether ARF's effect on innate immune-related genes and recruitment of macrophages extends to other types of cancers remains to be determined. Finally, it is of paramount interest whether ARF status may influence efficacy of immunotherapies."} +{"text": "Cancer imaging is frequently at the cutting edge of new imaging techniques which are often rapidly incorporated into routine use.Skeletal metastatic disease is a frequent complication of neoplastic conditions, and results in specific challenges to the general radiologist and specialist oncological radiologist alike.Non-neoplastic conditions and normal variants may simulate skeletal metastases, and the radiologist must recognise such cases and avoid over-investigation and unnecessary treatment.This lecture will briefly review standard imaging techniques and demonstrate normal appearances, normal variants and non-neoplastic lesions that mimic primary and secondary skeletal malignancy, and will then review a spectrum of malignancy-associated bone lesions with the use of standard and more specialised imaging techniques, including PET MRI, PET CT and diffusion weighted imaging,.Expected post treatment imaging findings, and treatment-associated complications will also be discussed."} +{"text": "To investigate through Structural Equation Modelling (SEM), the relationship between parenting styles, teasing about body weight/shape or eating, internalization of the thin ideal and body dissatisfaction amongst eating disorders (EDs) and controls and to see whether the risk factor model differed across various European countries and ED subtypes.The total sample comprised 1373 participants(ED patients=618).The Cross-Cultural Questionnaire (CCQ) was used to assess the above-mentioned risk factors.SEM analyses showed that the best fitting model was one allowing risk paths to vary across countries . In all countries teasing about weight/shape or eating was associated with body dissatisfaction.There was a strong significant path from body dissatisfaction to ED.Teasing about weight/shape or eating also directly predicted EDs .There was however a weak effect of parenting on both teasing about weight/shape or eating and EDs directly.Risk models slightly varied across ED diagnoses.Our hypothesised model was partially confirmed; in particular the central role of teasing on EDs both directly and mediated by internalization of the thin ideal and body dissatisfaction was shown across five European countries.Conversely, the effect of parenting varied by country and therefore might have cross-cultural effects.Prevention & Public Health stream of the 2014 ANZAED Conference.This abstract was presented in the"} +{"text": "A hallmark feature of the neural system controlling breathing is its ability to exhibit plasticity. Less appreciated is the ability to exhibit metaplasticity, a change in the capacity to express plasticity . Recent advances in our understanding of cellular mechanisms giving rise to respiratory motor plasticity lay the groundwork for (ongoing) investigations of metaplasticity. This detailed understanding of respiratory metaplasticity will be essential as we harness metaplasticity to restore breathing capacity in clinical disorders that compromise breathing, such as cervical spinal injury, motor neuron disease and other neuromuscular diseases. In this brief review, we discuss key examples of metaplasticity in respiratory motor control, and our current understanding of mechanisms giving rise to spinal plasticity and metaplasticity in phrenic motor output; particularly after pre-conditioning with intermittent hypoxia. Progress in this area has led to the realization that similar mechanisms are operative in other spinal motor networks, including those governing limb movement. Further, these mechanisms can be harnessed to restore respiratory and non-respiratory motor function after spinal injury. As with most neural systems, a hallmark of the neural system controlling breathing is its ability to express plasticity; defined as a persistent (>60 min) change in neural network function after an experience/stimulus has ended after the stimulus is removed. Neuromodulators often work through metabotropic G protein coupled receptors, which alter cell excitability through covalent modifications of membrane channels. Modulation does confer system flexibility and can initiate cellular mechanisms resulting in plasticity is augmented by concurrent application of another (substance P).Plasticity (long-term) is a persistent (>60 min) change in function that outlasts the initiating stimulus , a long-lasting increase in phrenic motor output observed following acute intermittent hypoxia but otherwise the same AIH protocol in humans (Lee et al., per se (Ling et al., Enhanced pLTF could occur and/or be modified at any site in the neural network transmitting chemosensory activity to PMN; including chemoreceptors themselves, their afferent terminations in the nucleus of the solitary tract, neurons of the ventral respiratory column, raphe neurons, spinal phrenic interneurons and/or PMN Figure . There iAlthough relatively little is known concerning sites and signaling mechanisms of CIH metaplasticity, CIH-enhanced moderate AIH-induced pLTF is still serotonin-dependent (Ling et al., Because CIH elicits respiratory metaplasticity, we initially had contemplated CIH as a treatment option to restore respiratory control in clinical disorders that impair breathing capacity; such as cervical spinal injury (Fuller et al., Less intensive rAIH preconditioning protocols retain the ability to elicit plasticity and metaplasticity without the known pathogenic effects of CIH (Lovett-Barr et al., AIH-induced pLTF is modified by a number of other pre-treatments that enhance and diminish its expression (Mitchell et al., Of these, the best characterized is enhanced pLTF following CDR. Twenty-eight days following bilateral CDR, moderate AIH induced pLTF is doubled, with an equivalent increase in serotonin terminal density in the immediate vicinity of identified PMN (Kinkead et al., One week post-CDR, ventral spinal BDNF and neurotrophin-3 concentrations are increased (Johnson et al., Although considerable effort has been devoted to investigations of detailed cellular mechanisms giving rise to AIH-induced pLTF (Devinney et al., With our significant progress in understanding cellular mechanisms of AIH-induced pLTF, it is an advantageous model to study metaplasticity in respiratory motor control. Such studies are warranted from a basic science perspective, but also because rAIH is rapidly moving towards clinical application as a treatment for respiratory insufficiency in disorders that compromise breathing capacity (Lovett-Barr et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In plant leaves, resource use follows a trade-off between rapid resource capture and conservative storage. This \u201cworldwide leaf economics spectrum\u201d consists of a suite of intercorrelated leaf traits, among which leaf mass per area, LMA, is one of the most fundamental as it indicates the cost of leaf construction and light-interception borne by plants. We conducted a broad-scale analysis of the evolutionary history of LMA across a large dataset of 5401 vascular plant species. The phylogenetic signal in LMA displayed low but significant conservatism, that is, leaf economics tended to be more similar among close relatives than expected by chance alone. Models of trait evolution indicated that LMA evolved under weak stabilizing selection. Moreover, results suggest that different optimal phenotypes evolved among large clades within which extremes tended to be selected against. Conservatism in LMA was strongly related to growth form, as were selection intensity and phenotypic evolutionary rates: woody plants showed higher conservatism in relation to stronger stabilizing selection and lower evolutionary rates compared to herbaceous taxa. The evolutionary history of LMA thus paints different evolutionary trajectories of vascular plant species across clades, revealing the coordination of leaf trait evolution with growth forms in response to varying selection regimes. Although leaf morphology has evolved manifold variations across vascular plant species, there is strong evidence of a universal spectrum constraining leaf functioning from rapid resource capture to efficient resource use shaping trait evolution within lineages from 180 published and unpublished studies and electronic databases . Second, node ages were estimated using the bladj module of the Phylocom software + \u03c32dt, where the parameter \u03b1 controls the rate of adaptive evolution to the optimum to test for the existence of phylogenetic structure in the trait data. The PI model ignores phylogenetic relatedness across species as if they were placed at equal distance on a star phylogeny. It serves as a null hypothesis which supposes the absence of phylogenetic covariance in the trait distribution.\u03bb , while a value of \u03bb = 1 indicates that the phylogenetic pattern conforms to Brownian motion on the given phylogeny to \u22121, indicating strong negative association. It has an expected value of n is the number of tips, under the null hypothesis of no correlation between trait values and phylogenetic distance. We also calculated I within different classes of divergence time which were chosen to ensure a sufficient number of observations within each class. This was used to build a resulting phylogenetic correlogram, which represents how trait similarity among species varies with the time since their divergence. In theory, this temporal pattern allows one to discriminate the BM from the OU models : Pagel's \u03bb Pagel , BlomberDW, which measures the degree of divergence (or trait radiation) between the child clades of each node. An ancestral node was considered as diversifying when the corresponding DW value was higher than expected at random, and as conservative when DW was lower than expected at random. Significant divergence widths were detected by testing the statistic against the null hypothesis PI using permutations (n = 105) and correcting for multiple comparisons , indicate past diversifying events (trait radiation) followed by subsequent conservatism within daughter clades. On the other hand, significantly conservative nodes correspond to divergences of low amplitude between daughter clades thus displaying similar trait values and phylogenetic conservatism thereafter.We analyzed the phylogenetic signal at clade level using the analysis of traits procedure . This analysis can detect functionally diversifying and conservative ancestral splits in trait values across daughter clades to 1479.1 g.m\u22122 in Hakea leucoptera (Proteaceae). LMA ranges largely overlapped across the major clades in Tracheophyta, but on average, Lycopodiophyta and Monilophyta (ferns) exhibited the lowest LMA, while Gymnospermae showed the highest LMA compared to the other major clades . Of these 62 nodes, 12 corresponded to diversifying nodes with trait radiation , was investigated across a large set of vascular plant species. Using comparative phylogenetic methods and a global trait database of over 5000 species, we detected that leaf strategies were overall weakly, albeit significantly, conserved during the diversification of vascular plants. This low conservatism appeared to be associated with multiple regimes of stabilizing selection, that is differing adaptive optima across the major clades. Importantly, we highlight the strong interaction between the evolution of growth forms and of leaf strategies, with woody species displaying slower leaf diversification and higher conservatism in LMA than herbaceous plant species.Spermatophytae) on the other, and between Angiospermae and Gymnospermae (Fig. Angiospermae clade, diversity in LMA reflects the wide adaptive radiation of flowering plants into a range of ecological strategies, involving diverse growth forms and ecological niches both within and across habitats (Ricklefs and Renner, Angiospermae. In fossil floras, basal plant clades display a higher diversity of growth forms than is currently observed among extant species: treelike plants existed within Lycopodiophyta, as well as ruderal herbaceous taxa within gymnosperms (Rothwell et al. Leaf mass per area appeared significantly but weakly conserved. This low phylogenetic signal captures the fact that distantly related species may occupy similar positions along the leaf economics spectrum. The large variability found within clades here evidenced a pattern of functional convergence across clades over a broad phylogenetic scale. However, significant levels of trait conservatism imply that, to a certain extent, closely related species do tend to invest dry matter similarly within leaf tissues and hence occupy nearby positions along the leaf economics spectrum. In particular, evolutionary splits identified as conservative nodes were mostly found at the level of genera. As might be expected, the degree of similarity in resource-use strategies varied with the length of the period of common evolution along lineages (Hansen and Martins, mae Fig. . Within in natura set constraints on plant strategies that may directly or indirectly affect achievable LMA values. A recent study of the evolution of the leaf economics spectrum highlighted the nature of evolutionary forces on LMA (Donovan et al. Models of continuous trait evolution supported the hypothesis that stabilizing selection shaped the phylogenetic pattern in LMA, against the hypothesis of evolution by drift alone. Given the breadth of sampling in our dataset, over a large taxonomic scale and a range of ecological situations, the stabilizing selection we detected likely reflects selection against extreme phenotypes that infringe structural and physiological limitations to LMA. The phylogenetic patterns evidenced here showed simultaneously conservatism, mostly within genera, and convergence across large clades. Congruence between radiation and restrictive environmental conditions, such as within the Proteales, also suggests strong filtering effects that may lead to conservatism at larger phylogenetic scales and functional distinctiveness (Cornwell et al. Recent analyses of molecular sequences have shown that woody species have evolved more slowly than herbaceous species (Smith and Donoghue, The observed patterns in the evolution of LMA raise the issue of selective pressures resulting in different selection regimes at large evolutionary scales. Fossil evidence suggests that large spatiotemporal scale changes in climate and disturbance regime were partially responsible for the diversification of vascular plants Stebbins and thisBy exploring the evolutionary history of LMA we have revealed different evolutionary trajectories involving coordination and trade-offs between leaf traits and plant traits related to growth form. As a consequence, different optimal phenotypes of resource-use strategies have evolved in vascular plants setting fundamental limits on the structure and physiology of organisms and therefore on ecological processes within communities. Continuing advances in genomics (Leebens-Mack et al."} +{"text": "The intestinal epithelia rely on resident stem cells to undergo homeostatic growth as well as tissue repair upon injury. In response to insults elicited by pathological bacterial infection or tissue damaging chemicals such as dextran sodium sulfate (DSS), intestinal stem cells (ISCs) speed up their proliferation and differentiation to effectively replenish lost cells. Despite numerous studies, the regulatory mechanisms underlying the control of stem cell activity during homeostasis and regeneration still remain poorly understood.Drosophila adult midgut provides a powerful system to address these problems because sophisticated genetic tools are available to allow the manipulation of gene function in any cell types within the intestinal epithelia as well as in surrounding tissues. Our recent study, which was published in The Journal of Cell Biology, established a critical role of Hh signaling in the regulation of regenerative stem cell proliferation in Drosophila adult midguts [The Hedgehog (Hh) pathway governs animal development in species ranging from fruit fly to human. In additional to their role as morphogen to control cell differentiation and pattern formation in embryonic development, the secreted Hh glycoproteins also function as mitogen to regulate cell proliferation in adult tissue homeostasis and tumorigenesis . Hh sign midguts .Drosophila midguts constantly turn over and are replaced by new cells derived from ISCs localized at the base of the epithelia. ISCs divide to produce themselves and enteroblasts (EBs) that subsequently differentiate into more specialized cell types. Previous studies revealed that ISC proliferation was elevated upon intestinal injury caused by DSS feeding [Similar to mammalian intestines, feeding . Here we feeding .In searching for the effectors that mediate the Hh function in midguts, we found that Hh signaling in EBs upregulated several cytokines and mitogens, most notably, the JAK-STAT pathway ligand Upd2. Indeed, inaction of Upd2 in EBs blocked ISC proliferation induced by either DSS feeding or ectopic Hh signaling. Taken together, our study suggests that DSS stimulates Hh signaling in EBs where it increases the production of Upd2, which in turn activates the JAK-STAT pathway in stem cells to fuel their proliferation. Interestingly, a recent study revealed a similar Hh-JAK-STAT signaling axis that drives tumorigenesis in mouse skin , suggestupd2 or indirectly through an intermediate pathway. In this regard, it is interesting to note that the Hippo (Hpo) pathway is also involved in DSS-stimulated ISC proliferation [Drosophila midguts and perhaps also in other settings.How Hh production is upregulated upon injury remains poorly understood but our study revealed that DSS increased Hh expression in part through the JNK pathway although the precise mechanism remains to be further explored. Another unresolved issue is how Hh signaling regulates the production of Upd2. Hh could directly regulate the transcription of feration , raising"} +{"text": "Journal of Experimental Botany (pages 2573\u20132586), Rebetzke et al. take the debate forward, showing that wheat awns are associated with specific grain traits in different environments.Awns, which are derived from floral structures in grasses, are known to be critically important for photosynthesis and transpiration. However, arguments about the costs and benefits of their growth and development for crop grain yield are still ongoing. In this issue of Triticum dicoccoides (K\u00f6rn. ex Asch. & Graebner) Schweinf.], the awns flex as humidity levels change, which can help bury the seeds (T. durum and T. aestivum) have shorter or non-existent awns to facilitate grain harvesting, handling and storage . Therefore, raising grain yield is still the main goal for wheat breeding, particularly as recent decades have seen a reduced rate of increase in wheat yields globally. Increasing assimilate partitioning into wheat\u2019s grain-bearing structures, the spikes, is an important strategy for improving yield. The introduction of dwarfing Reduced height (Rht) genes greatly enhanced the partitioning of assimilates towards spikes . HoweverAwns can be considered an alternative target for the improvement of wheat grain yield through their known functions, including photosynthesis, carbohydrate storage and increased water-use efficiency four spring wheat populations with a range of diverse genetic backgrounds were developed containing multiple Near-Isogenic Line (NIL) pairs with variation for the presence and absence of full awns; (2) four separate sets of experiments representing a total of 25 environments were conducted depending on the germplasm and environments sampled; and (3) for comparisons a number of important agronomic traits were measured in multiple years and environments while some traits were related to spike morphology. Separate glasshouse studies were also undertaken.Manipulating source\u2013sink relations is an important strategy for wheat breeding. Spike morphology is a crucial phenotype for displaying the distribution of assimilates. Spike morphology-related traits demonstrate great variation under variable growth conditions. Therefore, environmentally induced plasticity of spike morphology-related traits can in principle show the redistribution of assimilates.The influence of wheat awns on grain yield can be summarized as a balance between the costs of awn setting and the benefits of awn functions. As hypothesized by Flowering time is commonly considered to be an important determinant for grain yield."} +{"text": "High-density lipoprotein (HDL) and its principal apolipoprotein A-I (ApoA-I) have now been convincingly shown to influence glucose metabolism through multiple mechanisms. The key clinically relevant observations are that both acute HDL elevation via short-term reconstituted HDL (rHDL) infusion and chronically raising HDL via a cholesteryl ester transfer protein (CETP) inhibitor reduce blood glucose in individuals with type 2 diabetes mellitus (T2DM). HDL may mediate effects on glucose metabolism through actions in multiple organs by three distinct mechanisms: (i) Insulin secretion from pancreatic beta cells, (ii) Insulin-independent glucose uptake, (iii) Insulin sensitivity. The molecular mechanisms appear to involve both direct HDL signaling actions as well as effects secondary to lipid removal from cells. The implications of glucoregulatory mechanisms linked to HDL extend from glycemic control to potential anti-ischemic actions via increased tissue glucose uptake and utilization. Such effects not only have implications for the prevention and management of diabetes, but also for ischemic vascular diseases including angina pectoris, intermittent claudication, cerebral ischemia and even some forms of dementia. This review will discuss the growing evidence for a role of HDL in glucose metabolism and outline related potential for HDL therapies. There is accumulating experimental and clinical evidence that HDL particles can control glucose metabolism via a variety of mechanisms . At a meThe action of HDL to move glucose from the circulation and into tissues has potential clinical relevance in terms of both reducing vascular complications by removing excess glucose from the circulation in the setting of T2DM, and also in providing adequate glucose to tissues for energy production, particularly in the context of ischemia. HDL therapeutics may therefore have application not only for the prevention and management of T2DM , but alsThis review will discuss the growing evidence for a role of HDL in glucose metabolism in the context of the evolving HDL hypothesis. It is now recognized that the main clinical variable used to assess HDL, HDL cholesterol, fails to provide an accurate representation of the multiple functions of heterogeneous HDL particles, which are composed of many hundreds of lipids and multiple proteins . The rolT2DM, insulin resistance and glucose intolerance are associated with low HDL cholesterol levels . While tOn the other hand, a recent Mendelian randomization study showed that genetically reduced HDL cholesterol does not associate with increased risk of T2DM . While tHigh-density lipoprotein has been implicated in the modulation of insulin secretion in cellular and animal studies with corroborating evidence from human intervention trials. The diverse functionality of HDL to combat cellular lipid accumulation, endoplasmic reticulum (ER) stress and apoptosis are three potential mechanisms that may preserve pancreatic beta cell function.Pancreatic lipid accumulation and lipotoxicity have been well-documented to inhibit insulin production and secretion . We haveAt the signaling level the HDL transporters ATP-binding cassette, sub-family A, member 1 (ABCA1) and ATP-binding cassette, sub-family G, member 1 (ABCG1) have both been implicated in HDL-mediated effects on insulin secretion. Beta cell-specific deletion of the ABCA1 and ABCGHDL may also influence insulin secretion via mechanisms other than cholesterol depletion, including via actions on insulin transcription . At doseThe ability of HDL to inhibit ER stress-induced beta cell apoptosis could be another important mechanism by which HDL may ameliorate beta cell dysfunction . Bioacti2+ influx and activation of calcium/calmodulin activated protein kinase kinase (CaMKK) . Subsequ (CaMKK) and faciin vivo effects of HDL on glucose disposal in the absence of a change in circulating insulin. Such effects may be mistakenly attributed to increased insulin sensitivity.Beyond glucose uptake, HDL has been shown to activate Akt in ApoA-I transgenic mice and directly enhance both glycolysis and glucose oxidation in mouse C2C12 muscle cells . These iTissue lipid deposition and chronic inflammation associated with obesity, metabolic syndrome and T2DM establishes a functional deficit in skeletal muscle and the heart, impairing how these metabolically active tissues respond to insulin. The insulin resistance associated with lipid accumulation and a pro-inflammatory milieu promotes lipolysis, increasing circulating free fatty acids, thus perpetuating dyslipidemia and insulin resistance . It is sin vivo is more complex due to the fact that increased glucose disposal relative to insulin may not necessarily reflect increased insulin sensitivity. As discussed in the previous section, such observations may actually be explained by direct actions of HDL on glucose disposal by mechanisms which do not involve insulin. Nevertheless, there are two recent in vivo studies consistent with the cellular studies, which suggest that HDL/ApoA-I can increase peripheral insulin sensitivity. The first of these employed intraperitoneal glucose and insulin tolerance tests in high fat diet fed mice treated for 2\u20134 weeks with lipid-free ApoA-I (8 mg/kg body weight) and showed improved glucose and insulin tolerance compared to untreated mice on the same high fat diet testing or hyperinsulinemic-euglycemic clamp studies to examine direct effects on insulin sensitivity. Definitive evidence for an effect of HDL on insulin sensitivity in humans is also lacking. However, HDL cholesterol elevation by CETP inhibition has been shown to improve glycemic control in the face of reduced plasma insulin in people with T2DM in the ILLUMINATE trial . As evidThe actions of HDL on glucose metabolism have potential benefit beyond vascular protection. The ability of HDL to stimulate tissue glucose uptake has implications for cellular metabolism in the brain, as well as for cell viability in other organs under ischemic/anoxic conditions where glucose becomes the predominant metabolic substrate. This latter mechanism may have particular relevance to ischemic vascular conditions, including coronary, cerebral and peripheral artery diseases.We have recently established that HDL increases insulin-independent glucose uptake in rat cardiomyocytes via an Akt signaling pathway . In thisInsulin resistance may directly contribute to the increased risk of ischemic heart disease and poorer outcomes after infarction in patients with T2DM . It is pThe emerging actions of HDL and its bioactive components on glucose metabolism in the myocardium may contribute to the demonstrated protective effects of HDL in the context of ischemia-reperfusion injury . Such acFor the same reasons that HDL-mediated effects on glucose metabolism may protect the ischemic myocardium, these actions may equally act in the brain to protect against transient ischemic attacks and stroke. In fact, the reliance of the brain on glucose for ATP production means that mechanisms controlling glucose uptake may be of even greater significance than in other organs. Even minor changes in cerebral blood flow have the potential to impact on neuronal viability via reduction in glucose supply. Indeed cerebral hypoperfusion and hypometabolism coincide in patients with dementia .The implications of reduced blood flow, and thus glucose supply to the brain, extend beyond acute stroke risk to Alzheimer\u2019s disease, which has a significant vascular component . In thisGiven the well-established positive actions of HDL on vascular function, it is not surprising that several co-morbidities associated with increased Alzheimer\u2019s disease risk are themselves associated with decreased HDL function . A role in vitro efficacy of ApoA-I at similar concentrations. More recently, in vitro primary cell culture experiments, suggest that plasma ApoA-I gains access to the CNS primarily by crossing the blood-CSF barrier via specific cellular mediated transport barrier . ApoA-I ransport . The bloransport , which mThere is now convincing evidence that HDL modulates glucose metabolism in multiple tissues. These actions have deepened our understanding of the pathophysiology of a variety of disease states associated with low or dysfunctional HDL. While there are still many unanswered questions relating to the underlying mechanisms and key HDL component(s) responsible for the metabolic effects, this opens up the possibility of targeting glucose metabolism with HDL therapeutics currently in development. Future preclinical investigations and clinical trials will determine the relevance of HDL-mediated modulation of glucose metabolism to both glycemic control as well as tissue glucose supply to vital organs including the heart and the brain, especially under ischemic conditions.AS, SH, BK drafted, critically revised and approved the final version of this review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. BK has received product from CSL Behring and patient plasma from Hoffman La Roche both for investigator initiated clinical trials, with no associated research funding. She has also partnered with Resverlogix to fund an investigator-initiated clinical trial."} +{"text": "Plasmodium falciparum-infected children with cerebral malaria (CM) die from respiratory arrest, but the underlying pathology is unclear. Here we present a model in which the ultimate cause of death from CM is severe intracranial hypertension. Dynamic imaging of mice infected with P. berghei ANKA, an accepted model for experimental CM, revealed that leukocyte adhesion impairs the venous blood flow by reducing the functional lumen of postcapillary venules (PCV). The resulting increase in intracranial pressure (ICP) exacerbates cerebral edema formation, a hallmark of both murine and pediatric CM. We propose that two entirely different pathogenetic mechanisms\u2014cytoadherence of P. falciparum-infected erythrocytes in pediatric CM and leukocyte arrest in murine CM\u2014result in the same pathological outcome: a severe increase in ICP leading to brainstem herniation and death from respiratory arrest. The intracranial hypertension (IH) model unifies previous hypotheses, applies to human and experimental CM alike, eliminates the need to explain any selective recognition mechanism Plasmodium might use to target multiple sensitive sites in the brain, and explains how an intravascular parasite can cause so much neuronal dysfunction.Most P. falciparum causes injury to a sensitive location such as the brainstem, where a small lesion could have fatal consequences infected mice, an accepted model for experimental cerebral malaria (ECM), in the context of recent advances in the understanding of the pathogenesis of human cerebral malaria (HCM). For the purpose of this Perspective, we focus on pediatric HCM, because African children with HCM tend to exhibit more BBB dysfunction, monocyte and platelet accumulation in the brain, and intracranial hypertension (IH) compared to adult HCM patients in Southeast Asia patients die from respiratory arrest cause death is not completely understood. Several models have been proposed over the decades to explain the pathogenesis of HCM expressing iRBC that bind to the endothelial protein C receptor (EPCR) ExtP. yoelii XL (PyXL)-infected mice, which develop hyperparasitemia without neurological signs , we found more platelets, CD8+ T cells, neutrophils, and macrophages accumulated in postcapillary venules (PCV) from PbA-infected mice with ECM compared to Arteriolar vasospasms during ECM with poor outcomes in pediatric HCM patients in Kenya Ute Frevert, the review process was handled objectively. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Foot ulceration is one of the most significant complications of diabetes, and will affect 15-20% of people with diabetes at some point in their lives. Such ulcers frequently become infected with very serious sequelae which can often lead to amputation making diabetes is the most common cause of lower extremity amputations. Infections cause increased morbidity which means that they represent significant clinical events, requiring immediate attention in relation to local and systemic complications thus requiring well-coordinated management. Unfortunately diabetic foot infections (DFI) frequently fail to display overt signs and symptoms of infection including purulence, erythema, pain, tenderness, warmth and induration. This makes it difficult for clinicians to detect infection, and to make timely interventions to limit the highly undesirable consequences of DFIs. Alternative means of rapidly diagnosing infection are urgently required.To determine if the presence/absence of microorganisms, and ultimately the presence of infection, are affected by diabetic foot ulcer (DFU) wound fluid pH.DFUs of patients (n=55) were assessed in terms of presence/absence of clinical signs of infection as part of their routine clinical appointment at a High-Risk Foot Clinic. Wound fluid samples were also collected from the DFUs by filter paper absorption and/or pipette aspiration. The pH of samples was determined using a micro-electrode pH meter. Bacteria in the wound fluid were recovered by 24hr incubation in Tryptone Soya Broth, and plating on selective agars which included; MacConkey Agar , Pseudomonas Agar Base (Pseudomonas spp). Chromocult Agar , Baird Parker Agar (Staphylococcus spp) and Columbia Blood Agar (Streptococcus spp). Organisms identified as Staphylococcus Aureus cultured on Muller Hinton Agar and and MRSA present detected using Oxacillin and Cefoxitin antibiotic disks.Sample pH values ranged from 6.2 to 8.5. Recovered bacteria included Pseudomonas, Enterobacter, Staphylococcus and Streptococcus spp. Correlations were observed between DFU fluid pH values, the presence/absence of these species and the presence/absence of clinical signs of infection. This presentation will discuss the potential clinical implications of these findings.pH conditions within DFUs influence bacterial presence/absence in these wounds. pH conditions also influence the presence/absence of clinical signs of infection. Timely monitoring of DFU fluid pH could enhance clinicians\u2019 abilities to rapidly detect and more effectively manage DFU infections. An improved understanding of the interactions between DFU pH and bacterial metabolism may identify ways to limit the duration and wider impact of DFU infections.Governance compliance statement - Ethical approval and research governance has been granted for the clinical study to take place and all research governance procedures are being adhered to during the completion of the study."} +{"text": "Cerebral collateral circulation is a subsidiary vascular network, which is dynamically recruited after arterial occlusion, and represents a powerful determinant of ischemic stroke outcome. Although several methods may be used for assessing cerebral collaterals in the acute phase of ischemic stroke in humans and rodents, they are generally underutilized. Experimental stroke models may play a unique role in understanding the adaptive response of cerebral collaterals during ischemia and their potential for therapeutic modulation. The systematic assessment of collateral perfusion in experimental stroke models may be used as a \u201cstratification factor\u201d in multiple regression analysis of neuroprotection studies, in order to control the within-group variability. Exploring the modulatory mechanisms of cerebral collaterals in stroke models may promote the translational development of therapeutic strategies for increasing collateral flow and directly compare them in term of efficacy, safety and feasibility. Collateral therapeutics may have a role in the hyperacute phase of ischemic stroke, prior to recanalization therapies. Cerebral collateral circulation is a subsidiary vascular network which is dynamically recruited after arterial occlusion and may provide residual blood flow to ischemic areas. Cerebral collateral flow during acute ischemic stroke is highly variable among different individuals and is emerging as a strong prognostic factor either in unselected stroke patients and in patients treated with intravenous rtPA or endovascular recanalization therapy . ExperimHere, we review the current methods for assessing cerebral collaterals during acute ischemic stroke and the most promising collateral therapeutic strategies, focusing on experimental stroke models.Many similarities, with some notable differences, exist between humans and rodents in term of cerebral collateral circulation. The circle of Willis includes the anterior communicating artery in humans, while this vessel is totally absent in rodents, whose proximal segments of anterior cerebral arteries (ACA) converge to form one single median artery called Azigos ACA. In case of occlusion of cervical arteries, the circle of Willis represents a compensatory system to rapidly redistributing blood flow in both species. In rodents, the pterygopalatine artery originates from the proximal internal carotid artery (ICA) and provide extracranial collateral connections between external carotid artery and ICA via many arterial branches to facial, orbital and meningeal districts. In both humans and rodents, each cerebral artery provides blood flow to its vascular territory ramifying along the cortical surface to form a pial arteriolar network, creating anastomotic connections among different vascular territories, known as leptomeningeal anastomoses (LMAs). LMAs are mostly developed between cortical branches of middle cerebral artery (MCA) and ACA or posterior cerebral artery. In case of proximal occlusion of a cerebral artery, dynamic blood flow diversion through these anastomoses may provide residual (retrograde) blood flow to the cortical surface of the occluded artery territory, distally from the occlusion.The anatomy of cerebral collaterals in acute stroke patients can be assessed using conventional digital subtraction angiography (DSA), CT angiography (CTA) or MR angiography (MRA), while their functional performance can be studied through tissue perfusion evaluation, via CT and MR perfusion techniques (PCT and PWI). At present, there is no agreement in clinical practice on which imaging should be performed, when after stroke and which patients would benefit most from cerebral collateral imaging. DSA is the gold standard for evaluating the recruitment of cerebral collaterals, but it is invasive and usually reserved for patients selected for endovascular procedures. CTA is able to provide direct visualization of collateral flow after arterial occlusion Fig.\u00a0 3]. How. How3]. In experimental stroke models, both the site and the duration of arterial occlusion are controlled. Continuous or repeated assessment of cerebral collateral flow could be performed, including pre-stroke assessment. For these reasons, preclinical research could play a crucial role for a deeper understanding of collateral response during cerebral ischemia and promote the translational development of collateral-based therapies. However, both cerebrovascular differences between different species and strains and inter-individual variability need to be meticulously considered to achieve effective results in this field .Although some techniques used in stroke patients, such as DSA or MRI, could be used in stroke models for assessing cerebral collateral flow \u201314, signLaser speckle contrast imaging (LSCI) providesIn contrast to LSCI, two photon laser scanning microscopy (TPLSM) is an optical technique providing quantitative measure of blood flow velocity and direction in single vessels, with depth resolution up to 1\u00a0mm. Single arterioles, venules and capillaries of both surface and subsurface vasculature are resolved after intravenous injection of dextran conjugated with a fluorescent dye. A cranial window is required and scanning procedure is time-consuming. Collateral response after occlusion of both pial and penetrating arterioles in rats were stu3 volume. Real-time relative cortical CBF values are obtained, while absolute CBF quantification cannot be achieved [Laser-Doppler flowmetry (LDF) is a well-established technique for tissue perfusion monitoring and is recommended to confirm successful occlusion and exclude subarachnoid hemorrhage in experimental ischemic stroke . Opticalachieved . Our groachieved . A custoThe use of any of these methods (or a combination of them) to monitor arterial occlusion and collateral perfusion cannot be over emphasized to improve accuracy of pre-clinical stroke research. Advantages and drawbacks, in terms of temporal and spatial resolution, invasiveness and affordability of each technique are shown in Table\u00a0Despite over 1000 putative neuroprotective agents obtained promising results in experimental stroke models , no succA well-recognized limitation of preclinical stroke models is outcome variability , particuThe variability of cerebral hemodynamics during ischemia has been largely neglected in preclinical research, as well as the influence of drugs on CBF . MonitorAnimal stratification by collateral flow during MCAO represents a promising tool to adjust for outcome variability in experimental stroke studies. Using cerebral collateral flow during MCAO as a covariate in multiple regression analysis may represent a simple method to stratify animals in term of pre-treatment perfusion deficit, reducing the within group variability and improving efficacy analysis in preclinical neuroprotection studies. Further studies are needed to determine the more suitable method, timing and statistical tool for collateral flow assessment in pre-clinical neuroprotection trials.Intravenous thrombolysis with rtPA (Alteplase) within 4.5\u00a0h from symptom onset (for any vessel occlusion) and endovascular thrombectomy within 6\u00a0h from symptom onset (for large vessel occlusion) are currently the best therapeutic options for acute ischemic stroke , 39. UnfIncreasing systemic blood pressure represents a first strategy. Phenylephrine, a selective \u03b11-adrenergic receptor agonist, causes systemic vasoconstriction with very limited effects on cerebral vessels. A 30\u00a0% augmentation of blood pressure obtained through phenylephrine infusion after distal MCAO induction in mice enhanced cortical CBF both in core and penumbra . In smalIncreasing intravascular volume may represents a second strategy. Cerebral blood volume augmentation by plasma expansion and haemodiluition could improve cerebral perfusion in experimental stroke models . HoweverInduction of selective cerebral vasodilation is a third strategy. Nitric oxide (NO) is a strong endogenous vasodilator with therapeutic potential for ischemic stroke . NO inha2 levels, causing pial arteriolar vasodilation and increased cortical perfusion in piglets [Selective cerebral arteriolar vasodilation could be obtained using acetazolamide, which inhibits carbonic anhydrase and consequently augments CO piglets . In clin piglets . Quite s piglets , was perCerebral flow diversion is a fourth strategy. Gravitational influences of head positioning after acute vascular occlusion may affect pressure gradients in cerebral circulation, which enhancement may promote leptomeningeal recruitment. Augmentation of cerebral perfusion and increased MCA blood flow velocity has been reported in stroke patients after flat head positioning , 61 and A limited number of clinical and preclinical stroke studies focused on cerebral collateral circulation. Generally, neuroprotective effects are being sought, whereas the contribution of collateral blood flow is rarely considered or just inferred. Preclinical stroke research has the potential to directly study the adaptive capacity and modulatory mechanisms of cerebral collateral flow during focal cerebral ischemia, using different methods and in different experimental conditions. These preclinical efforts are likely to be worthwhile and may produce useful translational concepts and direct comparisons of the different strategies to enhance cerebral collateral flow, including some therapeutic approaches which did not prove successful in past clinical trials conducted in the pre-thrombolysis era."} +{"text": "HEart and BRain interfaces in Acute ischemic Stroke (HEBRAS) study aims to assess whether an enhanced MRI set-up and a prolonged Holter-ECG monitoring yields a higher rate of pathologic findings as compared to diagnostic procedures recommended by guidelines .An effective diagnostic work-up in hospitalized patients with acute ischemic stroke is vital to optimize secondary stroke prevention. The Prospective observational single-center study in 475 patients with acute ischemic stroke and without known atrial fibrillation. Patients will receive routine diagnostic care in hospital as wells as brain MRI, cardiac MRI, MR angiography of the brain-supplying arteries and Holter-monitoring for up to 10\u00a0days. Study patients will be followed up for cardiovascular outcomes at 3 and 12\u00a0months after enrolment.By comparing the results of routine diagnostic care to the study-specific MRI/ECG approach, the primary outcome of HEBRAS is the proportion of stroke patients with pathologic diagnostic findings. Predefined secondary outcomes are the association of stroke localization, autonomic dysbalance and cardiac dysfunction as well as the effect of impaired heart-rate-variability on long-term clinical outcome.The investigator-initiated HEBRAS study will assess whether an enhanced MRI approach and a prolonged ECG monitoring yield a higher rate of pathological findings than current standard diagnostic care to determine stroke etiology. These findings might influence current diagnostic recommendations after acute ischemic stroke. Moreover, HEBRAS will determine the extent and clinical impact of stroke-induced cardiac damage.NCT02142413.Clinicaltrials.gov Variations and delays in the diagnostic procedures during hospitalization after acute ischemic stroke are common \u20133. At thRecent studies have shown that magnetic resonance imaging (MRI) and MR angiography are able to detect cardiac , 6, aortHEart and BRain interfaces in Acute ischemic Stroke (HEBRAS) study therefore aims to assess the detection rate of pathologic findings relevant to stroke etiology as obtained by an enhanced MRI set-up and a prolonged, non-invasive, commonly available Holter monitoring (of up to 10\u00a0days duration) in comparison to findings obtained by routine diagnostic procedures after acute stroke. In addition, the underlying pathophysiological mechanisms and the prognostic impact of stroke-induced cardiac damage are still poorly understood or the Find-AFRANDOMISED trial [Besides feasibility and diagnostic value of enhanced MRI, HEBRAS will assess the ability of extended systematic analysis of ECG-recording to improve AF detection compared to the current clinical standard, as similarly done in currently ongoing trials such as the ED trial , as wellED trial , 29. DetED trial . A fasteAnother unique feature of the investigator-initiated HEBRAS study is the systematic assessment of stroke-induced autonomic dysfunction and cardiac damage by using a laboratory data. It has long been recognized that acute cerebrovascular events may coincide with or trigger cardiac dysfunction and elevation of cardiac biomarkers such as troponin. Several studies reported on elevation of cTn in patients with acute ischemic stroke \u201332. HoweIn addition, natriuretic peptides have been shown to be independently associated with atrial fibrillation in stroke cohorts \u201336, but In summary, the HEBRAS study aims to clarify whether recent technical advantages can improve etiologic work up after acute ischemic stroke. This study has the potential to set essential modifications of current diagnostic standards after acute ischemic stroke, aiming at improving secondary stroke prevention. Moreover, the HEBRAS study will hopefully elucidate mechanisms of stroke-induced autonomic dysfunction and cardiac damage."} +{"text": "Autism spectrum disorders (ASD) are characterized by two seemingly unrelated symptom domains\u2014deficits in social interactions and restrictive, repetitive patterns of behavioral output. Whether the diverse nature of ASD symptomatology represents distributed dysfunction of brain networks or abnormalities within specific neural circuits is unclear. Striatal dysfunction is postulated to underlie the repetitive motor behaviors seen in ASD, and neurological and brain-imaging studies have supported this assumption. However, as our appreciation of striatal function expands to include regulation of behavioral flexibility, motivational state, goal-directed learning, and attention, we consider whether alterations in striatal physiology are a central node mediating a range of autism-associated behaviors, including social and cognitive deficits that are hallmarks of the disease. This review investigates multiple genetic mouse models of ASD to explore whether abnormalities in striatal circuits constitute a common pathophysiological mechanism in the development of autism-related behaviors. Despite the heterogeneity of genetic insult investigated, numerous genetic ASD models display alterations in the structure and function of striatal circuits, as well as abnormal behaviors including repetitive grooming, stereotypic motor routines, deficits in social interaction and decision-making. Comparative analysis in rodents provides a unique opportunity to leverage growing genetic association data to reveal canonical neural circuits whose dysfunction directly contributes to discrete aspects of ASD symptomatology. The description of such circuits could provide both organizing principles for understanding the complex genetic etiology of ASD as well as novel treatment routes. Furthermore, this focus on striatal mechanisms of behavioral regulation may also prove useful for exploring the pathogenesis of other neuropsychiatric diseases, which display overlapping behavioral deficits with ASD. The earliest clinical descriptions of autism highlighted two symptom domains, focusing on social behaviors and the regulation of motor output. Kanner's seminal article \u201cAutistic Disturbances of Affective Contact\u201d carefully described the profound social deficits of his patients, concluding \u201cthese children have come into the world with innate inability to form the usual biologically provided affective contact with people\u2026\u201d Kanner, . ShortlyFrom the outset, it is worthwhile considering the utility of exploring nervous system disease pathophysiology from the vantage of neural circuit dysfunction. This approach seeks to uncover alterations in defined, reproducibly interconnected sets of neurons that are responsible for discrete behavioral phenomenon seen in neuropsychiatric diseases such as schizophrenia , which can prevent excessive computational demands on cortical structures supporting goal-directed behavioral responding, the dorsal lateral striatum supporting automated behaviors and the nucleus accumbens mediating motivational states and reward processing , together with whole-exome and genome sequencing, has demonstrated a substantial amount of genetic heterogeneity underlying ASD etiology, with some estimates predicting that 300\u2013800 loci will eventually be associated with increased risk for ASD , a key repressor of translation at central synapses, has been a central model for exploring the pathogenesis of mental retardation and accompanying developmental disorders including autism in the development of ASD-associated behaviors.Through a series of experiments, a unifying mechanism emerged in which oxytocin signaling regulated the release of serotonin in the nucleus accumbens, which subsequently modulated excitatory synaptic strength by acting at presynaptic serotonergic receptors on excitatory afferent fibers Figure . DespiteApplying a similar \u201ccircuit dissection\u201d approach, we attempted to explore how ASD-associated mutations could promote development of the restricted and repetitive behaviors so frequently observed in ASD patients neurons either uniquely or more highly express ASD-associated genes such that loss-of-function is more acutely sensed, or (2) neurons do not express alternative family members of ASD-associated genes that would typically allow for genetic compensation. Using a computational approach that analyzed autism genetic datasets to correlate mutations to known biological networks, it was found that autism-associated mutations are preferentially found in genes whose expression levels are enriched in both populations of striatal medium spiny neuron, as well as cortical inhibitory and projection populations, deep cerebellar nuclei and layer 6 corticothalamic neurons examining heterozygous mutations, disease-associated point mutations or genetic modifiers, (2) exploration of environmental interactions with mutations (3) physiological analysis of behaviorally relevant circuits through selective optogenetic recruitment and (4) highly quantitative analysis to detect subtle changes in discrete components of complex behaviors. Even with these improvements, it is important to acknowledge the intra-species differences in brain complexity, genomic regulation and behavioral repertoire, which may place limits on the generalizability of rodent-based research findings and a McCabe Fund Award (University of Pennsylvania).The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Colorectal Carcinoma (CRC) is a heterogeneous disease with different molecular characteristics associated with the sites from which, the tumours originate. Such heterogeneity is compounded by the multitude of genetic and epigenetic variations acting as passengers or drivers of the tumour. Majority of CRC develops via chromosomal instability (CIN) pathway. CIN is often exacerbated by inactivation of the Wnt signalling pathway \"master regulator\" APC gene, activating mutations of KRAS or BRAF oncogenes, or deletions of the 18q, and 17p chromosomal regions with deleterious effects on the tumour suppressor genes TP53 and DCC. Defective Mismatch Repair (MMR) pathway results in a subtler form of genomic instability, namely Microsatellite Instability (MSI). High levels of MSI (or MSI-H) in sporadic CRC are usually caused by hypermethylation of the MLH1 promoter. In terms of methylation, the CpG island methylator phenotype (CIMP) pathway is the second most common pathway in sporadic CRC. CIMP-positive (CIMPp) CRC tumours are usually associated with the proximal colon of older females. CIMPp CRC tumours have better prognosis if the tumours are also MSI-H. However, CIMPp CRC tumours that are Microsatellite Stable (MSS) have poor clinical outcome. To gain insight into the molecular mechanisms underpinning CRC in Saudi Arabian patients, we profiled the DNA methylation frequency of key genes in 120 sporadic CRC cases. CRC tumours originating from the rectum, left, and right colons are represented in this cohort. Expression patterns of different proteins playing important role in CRC carcinogenesis also studied by using Immunohistochemistry (IHC) technique and their impact as CRC prognosticators was evaluated."} +{"text": "Arc-indexed odor networks of awake rats. Arc-indexed networks are sparse and distributed, consistent with current views. However Arc provides representations of repeated odors. Arc-indexed repeated odor representations are quite variable. Sparse representations are assumed to be compact and reliable memory codes. Arc suggests this is not necessarily the case. The variability seen is consistent with electrophysiology in awake animals and may reflect top-down cortical modulation of context. Arc-indexing shows that distinct odors share larger than predicted neuron pools. These may be low-threshold neuronal subsets. Learning\u2019s effect on Arc-indexed representations is to increase the stable or overlapping component of rewarded odor representations. This component can decrease for similar odors when their discrimination is rewarded. The learning effects seen are supported by electrophysiology, but mechanisms remain to be elucidated.We first review our understanding of odor representations in rodent olfactory bulb (OB) and anterior piriform cortex (APC). We then consider learning-induced representation changes. Finally we describe the perspective on network representations gained from examining Arc-indexed odor representations. These data modify our view of odor representations and their modulation by reward. How Arc expression is recruited by odor is also considered.Here we first characterize our understanding of odor representations in the olfactory bulb (OB) and anterior piriform cortex (APC). We next review learning-related modulation of those odor representations. Finally, we discuss data using It has long been recognized that odor representations require across-fiber coding technique to visualize Arc mRNA and characterize odor representations. Arc, as one of the immediate early genes, offers an important feature for examining representations repeatedly in the same animal early odor preference learning in rat pup Figure ; and (2)In the rat pup model vs. untrained rats (5%), with a reduction in the variable neuronal component. The overlap component did not show an absolute increase with training, but became a larger proportion of the representation. Thus, as in the rat pups (Shakhawat et al., Electrophysiology had not revealed learning differences in APC firing patterns for simple discriminations (Chapuis and Wilson, In the mixture discrimination, the two individual odor components were responded to as rewarded odors during behavioral probes, suggesting rats learned the components during mixture training or pattern-completed from partial cues. The degree of overlap between peppermint and vanillin in control rats was ~20% while overlap was ~45% in trained rats, consistent with the two odors becoming representationally highly similar (Shakhawat et al., In the difficult discrimination, the odor representation size was ~3% and did not change with learning (Shakhawat et al., The mechanisms for associating odor and reward, presumably resulting in the increases in stability components seen here, have been examined earlier. In the rat pup, norepinephrine paired with odor can alter behavior and AMPA receptor-mediated connectivity in OB (Cui et al., Arc imaging made possible was the finding of high variability in repeated odor representations and the finding of a high degree of overlap between representations of distinct odors. If cells encoding distinct odors were drawn at random from populations with replacement such that the same cell could participate in multiple representations, then the predicted overlap would be the representational size squared. In Arc studies, representational size varies from 1% to 10%, consistent with other estimates (e.g., Lin da et al., Arc.The two novel results that Arc itself indicates. While it is related to neuronal activation, neural firing cannot be its sole initiator. Mitral cells fire at high spontaneous levels (Rinberg et al., Arc activation. Arc recruitment is likely linked to glutamatergic excitatory synaptic driving (Cole et al., Finally we come to the issue of what Arc recruitment. Odor activation firing patterns in OB and APC are dynamic spatially and temporally (Friedrich and Laurent, Arc represent the initial pattern and its variability or the combined early and later patterns and their cumulative variability? This would be another contribution to the high variability observed.But even if that is the case, one must ask which driving patterns are encoded by Arc patterns, we would predict a larger stable component with increasing concentrations supporting more rapid discriminations.How many neurons are excited in a single synchronized odor representation? The size of odor representations appears to be normalized and varies less for concentration increases Cleland, than oneArc-indexed cell networks portray odor representations in both OB and APC as sparse and distributed consistent with current understanding. Arc-indexed networks also reveal a considerable variability in the awake mammalian odor representation consistent with the electrophysiological evidence. This methodology further reveals a larger component of common neuronal activation for distinct odors than predicted by theory. Appetitive learning modifies odor representations to increase the proportion of stable neurons. Network representations can also decrease the proportion of stable neurons when increased behavioral discrimination is required.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In August 2016, more than 10,000 athletes representing over 200 countries will converge inRio de Janeiro for the 'biggest sporting event on the planet'This special issue on SPORTS in the Brazilian Journal of Physical Therapy comes at anopportune time for practitioners who work with athletes of all levels of ability andthroughout various phases of their rehabilitation recovery. With contributions by aninternational group of 'elite' practitioners in their field, readers will be sure to findtheir topic of interest in this special SPORTS issue. These topics range from expertclinical commentaries and critical reviews to presentations of original research related tocommon sports injuries.While the World Cup generates an international enthusiasm for soccer, it also informs theviewer about the injuries to soccer players. The article \"SPORTS INJURIES PROFILE OF AFIRST DIVISION BRAZILIAN SOCCER TEAM: A DESCRIPTIVE COHORT STUDY\" by Reis and colleaguesprovides information from a descriptive cohort study regarding injury profiles in firstdivision Brazilian soccer players, including the influence of player's age and position oninjuries. An appropriate and relevant follow up to this manuscript is presented byHespanhol Junior and colleagues: \"MEASURING SPORTS INJURIES ON THE PITCH: A GUIDE TO USE INPRACTICE.\" This paper reviews the basic concepts of injury monitoring systems in sportsparticipation and encourages the implementation of these concepts in practice.Runners are featured in the manuscript \"MALE AND FEMALE RUNNERS DEMONSTRATE DIFFERENTSAGITTAL PLANE MECHANICS AS A FUNCTION OF STATIC HAMSTRING FLEXIBILITY\". In this article,Blase Williams and colleagues assess the effect of hamstring length on running mechanics inboth male and female runners and discuss the implications for injury. For athletes who havesustained a knee injury, the timing for when it is safe to return to sports can bechallenging. In the manuscript \"A CONCEPTUAL FRAMEWORK FOR A SPORTS KNEE INJURY PERFORMANCEPROFILE (SKIPP) AND RETURN TO ACTIVITY CRITERIA (RTAC),\" Logerstedt and colleagues discussa comprehensive system that focuses on specific indicators of rehabilitation progression,and present criteria for safe return to sports following knee injury.Patellar tendinopathy is a common problem in athletes whose sports require jumping. In thearticle \"PHYSICAL THERAPISTS' ROLE IN PREVENTION AND MANAGEMENT OF PATELLAR TENDINOPATHYINJURIES IN YOUTH, COLLEGIATE, AND MIDDLE-AGED INDOOR VOLLEYBALL ATHLETES\" Kulig andcolleagues discuss intervention strategies that include education, rehabilitation, trainingand return to sport that are athlete-specific. Patellar tendinopathy is not the onlycondition linked to sports involving jumping. Achilles tendinopathy is also common andhighly problematic in jumping activities. In the manuscript \"CLINICAL COMMENTARY OF THEEVOLUTION OF THE TREATMENT FOR CHRONIC PAINFUL MID-PORTION ACHILLES TENDINOPATHY\" Alfredsondiscusses the results of research that evolved and changed practice, including the newesttreatment for Achilles tendinopathy.Given that Golf will be returning to the 2016 Summer Games for the first time in 112 years,Evans and Tuttle's \"IMPROVING PERFORMANCE IN GOLF: CURRENT RESEARCH AND IMPLICATIONS FROM ACLINICAL PERSPECTIVE\" is a well-timed contribution. Using best evidence from biomechanicaland motor control research, the manuscript offers a pragmatic approach to enhancing golfperformance.Core stability is frequently a focus of an athlete's rehabilitation program, yet there islittle evidence to support the link between core stability and injury. The article bySilfies and colleagues, \"CRITICAL REVIEW OF THE IMPACT OF CORE STABILITY ON UPPER EXTREMITYATHLETIC INJURY AND PERFORMANCE\" provides an in-depth review of the existing scienceregarding core stability and its association between upper limb injuries and athleticperformance. The upper limb is also featured in the article by Cools and colleagues,\"PREVENTION OF SHOULDER INJURIES IN OVERHEAD ATHLETES: A SCIENCE BASED APPROACH.\" Theauthors discuss the key risk factors that may be used to guide injury prevention and returnto sports after shoulder injury.Finally, an in-depth commentary regarding the importance of study design for injury riskprediction is presented in the manuscript by Hewett and colleagues \"MULTI-CENTER TRIAL OFMOTION ANALYSIS FOR INJURY RISK PREDICTION: LESSONS LEARNED FROM PROSPECTIVE LONGITUDINALLARGE COHORT COMBINED BIOMECHANICAL -EPIDEMIOLOGICAL STUDIES.\" In their paper, the authorsillustrate the research process and emphasize the need for continued, collaborative work inprospective study designs.Passion and Transformation: this is the essence of theemblemParab\u00e9ns Brasil! Guest Co-editor, SPORTS Special IssueBrazilian Journal of Physical TherapyDeborah A. Nawoczenski PT, PhD"} +{"text": "The mixing problem of electroencephalography (EEG) in the presence of common source could affect directed functional connectivity measures, resulting in an incorrect directionality of information flow between two signals. Here we introduce directed Weighted Phase Lag Index (dWPLI), a signed version of Weighted Phase Lag Index (WPLI) and compare this measure to Granger Causality (GC), Symbolic Transfer Entropy (STE), Phase Slope Index (PSI), and directed Phase Lag Index (dPLI) under common source effects. Robustness of the measures was tested in both analytic and simulating ways.For the simulated time series, signals were generated from unidirectionally coupled autoregressive model and linearly mixed to achieve volume conduction and common noise effects.As expected from the analytic calculation, dPLI and dWPLI were unaffected by the volume conduction while PSI, GC and STE were largely affected. Figure . The meaFor the common noise case, only dPLI and dWPLI had their signs preserved. Figure . The meaFurthermore, the dWPLI outperformed dPLI for the common noise case which was also predicted from analytic calculation.Present study shows the common source effects might lead to biased results with incorrect directionality of information flow. Among the five directed functional connectivity measures, dWPLI is much less affected by common source effects."} +{"text": "Regular physical activity (PA) in the early school years is recommended by several scientific associations for primary prevention of cardiovascular disease. Long-term observational studies have shown that subjects who exercise regularly have significantly less coronary heart disease (CHD) and a reduced risk of cardiovascular disease (CVD). Exercise reduces serum triglycerides, increases serum high density lipoprotein-cholesterol, lowers the blood pressure in patients with primary hypertension . RegularRegular exercise, on the other end, is associated with potential adverse effects ; however, the absolute risk of kidney disease during exercise is low . ConsensExercise induces profound changes in the renal haemodynamics and in electrolyte and protein excretion. Proteinuria, hematuria and changes in serum electrolyte balance have been reported during intense PA; the increase in glomerular filtration may explain these transient alterations but the \u201cnutcracker\u201d compression on the renal vein may have a role. Haemoglobinuria and myoglobinuria may be observed under special exercise conditions .PA does not worse nor reverse kidney disease but may reduce cardiovascular risk in chronic renal disease . Childre"} +{"text": "Regenerative medicine has the promise to alleviate morbidity and mortality caused by organ dysfunction, longstanding injury and trauma. Although regenerative approaches for a few diseases have been highly successful, some organs either do not regenerate well or have no current treatment approach to harness their intrinsic regenerative potential. In this Review, we describe the modeling of human disease and tissue repair in zebrafish, through the discovery of disease-causing genes using classical forward-genetic screens and by modulating clinically relevant phenotypes through chemical genetic screening approaches. Furthermore, we present an overview of those organ systems that regenerate well in zebrafish in contrast to mammalian tissue, as well as those organs in which the regenerative potential is conserved from fish to mammals, enabling drug discovery in preclinical disease-relevant models. We provide two examples from our own work in which the clinical translation of zebrafish findings is either imminent or has already proven successful. The promising results in multiple organs suggest that further insight into regenerative mechanisms and novel clinically relevant therapeutic approaches will emerge from zebrafish research in the future. Regenerative medicine offers the promise of regaining organ function after acute or chronic injury. Regenerative approaches aim to promote, enhance and re-establish organ-specific repair processes to reconstitute organ structure and function after injury or in the setting of disease progression or treatment. Currently, the impact of the field of regenerative medicine in clinical practice is limited to a few specialized although highly successful practices, such as autologous bone marrow transplantation , partialRegeneration identified essential genes, and gave insight into the physiology and pathophysiology of a variety of disease states. These mutants also frequently highlighted the genetic diversity contributing to morphologically similar disorders, potentially providing insight into the varied responses to current therapeutics or providing a platform for rational development of treatment options. For example, many diseases affecting blood formation and red blood cell physiology have been either explained by or modeled in zebrafish mutants, including the identification of previously uncharacterized genetic defects causing human disease with disease phenotypes, including many tumor suppressors and oncogenes. The first iteration of these \u2018reverse genetic\u2019 approaches, known as TILLING , took adic level . Furtheric level , as wellic level . These iic level . Althougex utero enables efficient introduction of foreign nucleic acids by microinjection. Long used as an effective means to \u2018rescue\u2019 mutant phenotypes to prove causation and produce transgenic fluorescent-tagged reporters of select genes of interest, microinjection has also enabled both transient and targeted gene knockdown. Although not without the caveats of potential nucleotide toxicity or off-target effects, morpholino oligonucleotide (MO) injection has been effectively used to antagonize translation in an antisense manner, thus blocking or diminishing protein production and revealing gene function. Furthermore, the procedure is titratable, providing the ability to bypass phenotypes associated with early embryonic lethality. For example, in zebrafish, just as in mice, complete loss of Wnt signaling . APAP ovcetamol) . In thisIn addition to those discussed above, an increasing number of groups have utilized zebrafish to study regenerative repair after injury induced by a variety of methods in a broad array of organs, ranging from muscle repair after crush- or laser-induced injuries and retiAlthough many zebrafish studies have the goal of therapeutic relevance, actual translational application of findings from zebrafish investigations is still in its infancy relative to mammalian models. That said, recent investigations stemming from chemical screening approaches focused on highly conserved aspects of regenerative biology of a select organ system, as discussed above, have directly shown the full potential of the zebrafish model for discoveries in the field of regenerative medicine. Here, we summarize the major attributes of two such studies from our own work. These investigations exploited conserved regenerative models (blood and liver) and a chemical screening approach, combined with the vast array of established tools for modulating the pathways of interest. This facilitated translational testing in mammalian systems, enabling fast translational application of the results from zebrafish to humans.S-nitrosoglutathione reductase (GSNOR), which negatively regulates protein nitrosylation, was shown to mediate the effects of NO on liver growth. To determine conservation of effect in organ regeneration, models of both physical and chemical (acetaminophen) liver injury were used. Treatment with a novel GSNOR inhibitor (GSNORi) after liver resection in adult fish enhanced cellular proliferation and regeneration. In acetaminophen-exposed larvae and adults, GSNORi significantly prevented hepatocyte necrosis, enhanced proliferation, and improved survival alone and in combination with the current clinical therapeutic intervention, N-acetylcysteine. Significantly, the impact of GSNOR modulation is evolutionarily conserved, as GSNOR knockout mice and GSNORi-treated wild-type mice were similarly protected from acetaminophen-induced liver injury. GSNORi combines hepatoprotective and pro-proliferative properties, and represents a novel therapeutic approach for patients with toxic liver failure.As mentioned above, liver injury induced by acetaminophen exposure is the leading cause of acute liver failure. Identifying factors involved in regulation of embryonic liver growth could reveal conserved pathways with the potential to enhance liver regeneration after injury. We performed a chemical genetic screen in fluorescent reporter embryos , which rin vivo HSC reporters. In contrast, cyclooxygenase inhibition using both non-selective and specific inhibitors reduced HSC number. Adult irradiation recovery assays showed maintenance of the effect in regenerative repair, and murine embryonic stem cell differentiation studies showed conservation of function across vertebrate species. Long-term hematopoietic repopulation of the murine bone marrow following irradiation injury and limiting-dilution competitive transplantation of PGE2-exposed donor cells revealed increased in vivo regenerative potential in mammalian models. Subsequent investigations in zebrafish and mice indicated that PGE2 enhanced HSC function through cAMP-mediated enhancement of Wnt signaling, providing a useful biomarker for translational applications . In this study, both neutrophil engraftment and bone marrow chimerism will be assessed as primary clinical end points. Together, these examples from our own collaborative investigations indicate that zebrafish can be effectively used as a relevant preclinical therapeutic screening and regenerative model system that enables direct application and efficient translation to the clinical setting.Following collaborative discussions with transplant physicians and acquisition of toxicity profiles from earlier clinical endeavors, translational application of PGE2 in hematopoietic transplantation therapy clinical trials was approved by the FDA, the first such study to arise from a chemical genetic screening approach in zebrafish. In phase 1 trials primarily designed to establish safety, PGE2-treated HSC samples showed substantial changes in clinical end points, with both predominant engraftment of PGE2-treated cord blood samples and accelerated recovery of the blood counts in patients receiving the transplants compared to historical controls ; there wRegenerative medicine holds great promise for the alleviation of morbidity and mortality associated with organ failure or injury. Tissue repair and regeneration can be driven by modulation of the pathways that govern stem cell behavior and organ development. The zebrafish has traditionally been an excellent model to study early development and organogenesis, demonstrating high genetic and functional conservation with mammals. Given the inherent connection between developmental pathways and organ repair, this strength combined with a growing list of innovative regenerative models makes the zebrafish an ideal system to study regenerative processes, with the potential to translate relevant findings across species and toward clinical application. In light of the many promising projects mentioned here, developed over such a brief time frame, we anticipate an increasing number of valuable studies and novel therapeutics inspired by and discovered through zebrafish research will be developed in the field of regenerative medicine."} +{"text": "TissueMark for automated tumor annotation and percentage tumor nuclei measurement in NSCLC using computerized image analysis. Evaluation of 245 NSCLC slides showed precise automated tumor annotation of cases using Tissuemark, strong concordance with manually drawn boundaries and identical EGFR mutational status, following manual macrodissection from the image analysis generated tumor boundaries. Automated analysis of cell counts for % tumor measurements by Tissuemark showed reduced variability and significant correlation (p < 0.001) with benchmark tumor cell counts. This study demonstrates a robust image analysis technology that can facilitate the automated quantitative analysis of tissue samples for molecular profiling in discovery and diagnostics.The discovery and clinical application of molecular biomarkers in solid tumors, increasingly relies on nucleic acid extraction from FFPE tissue sections and subsequent molecular profiling. This in turn requires the pathological review of haematoxylin & eosin (H&E) stained slides, to ensure sample quality, tumor DNA sufficiency by visually estimating the percentage tumor nuclei and tumor annotation for manual macrodissection. In this study on NSCLC, we demonstrate considerable variation in tumor nuclei percentage between pathologists, potentially undermining the precision of NSCLC molecular evaluation and emphasising the need for quantitative tumor evaluation. We subsequently describe the development and validation of a system called Personalised medicine aims to stratify patients\u2019 cancers into new molecular subtypes who can benefit from individualised therapy \u20133. The tExtracting DNA and RNA from tumor cells in the context of FFPE samples is not straightforward. Most tissues containing tumor also contain a mixture of cell types such as non-neoplastic epithelial cells, mesenchymal tissue, inflammatory cells and acellular material such as mucin which has an influence on subsequent processes including nucleic acid isolation, PCR amplification and next generation sequencing . TherefoRAS, EGFR, BRAF mutational analysis, commercial tests such as Oncotype DX, Mammaprint, Prolaris and more recent clinical sequencing panels (e.g. Foundation One). Given that this role falls primarily to the pathologist, the rapid rise in the investigation of solid tumor molecular tests and their delivery in diagnostic molecular laboratories is putting a strain on pathology services. Molecular labs without in-house pathology competency, must transport slides to a qualified pathologist for review and manual annotation. The centralization of some molecular tests, despite having clear sample guidelines on their test request forms, must review the slides centrally and ensure sufficient tumor is present before macrodissection and analysis.Macrodissection is a manual process in which the region of tumor is physically scraped from the slide using a scalpel into a receptacle for subsequent nucleic acid extraction and molecular analysis. Marking the regions of viable tumor within tissue samples relies on the visual assessment of haematoxylin and eosin (H&E) tissue sections, usually by an experienced pathologist and typically performed at low power magnification. Manual macrodissection aims to enrich the proportion of neoplastic cell nucleic acid by removing non-tumor containing regions, not only increasing the likelihood of detecting a relevant mutation if it exists but also increasing the certainty that a mutant signature originates from the malignant cell isolate. Percentage tumor evaluation and macrodissection underpin most of the new and emerging molecular tests for solid tumors including et al . Us. UsTissuTissueMark image analysis method can overcome the shortfalls of visual estimation and provide a more objective measure of tumor cell sufficiency. In order to benchmark this, subjective visual estimations of tumor cell percentage accuracy were not sufficient. Instead we hand-counted a series of tissue images to get precise numbers of tumor and non-tumor cells and an absolute, gold standard measurement of percentage tumor nuclei. Similar types of manual cell counts were carried out by Smit et al was also computed for each tile to indicate the likelihood for tumor or non-tumor class membership. This could be presented as a ROC) curve, (iii) concordance index and (iv) false discovery rate (FDR). These are fully described in It was important to compare manually drawn tumor boundaries with boundaries generated using automated image analysis. Visual assessment by an experienced pathologist allowed us to determine the quality and accuracy of automated tumor annotation as well as a visual comparison between manual and automated annotation and an evaluation on whether deviations would have impact on molecular testing. These were largely subjective evaluations. In addition, however, we devised four methods to measure boundary differences: (i) inclusion rate vs. exclusion rate, (ii) receiver operating characteristic , previously genotyped for"} +{"text": "The global burden of ischaemic strokes is almost 4-fold greater than haemorrhagic strokes. Current evidence suggests that 25\u201330% of ischaemic stroke survivors develop immediate or delayed vascular cognitive impairment (VCI) or vascular dementia (VaD). Dementia after stroke injury may encompass all types of cognitive disorders. States of cognitive dysfunction before the index stroke are described under the umbrella of pre-stroke dementia, which may entail vascular changes as well as insidious neurodegenerative processes. Risk factors for cognitive impairment and dementia after stroke are multifactorial including older age, family history, genetic variants, low educational status, vascular comorbidities, prior transient ischaemic attack or recurrent stroke and depressive illness. Neuroimaging determinants of dementia after stroke comprise silent brain infarcts, white matter changes, lacunar infarcts and medial temporal lobe atrophy. Until recently, the neuropathology of dementia after stroke was poorly defined. Most of post-stroke dementia is consistent with VaD involving multiple substrates. Microinfarction, microvascular changes related to blood\u2013brain barrier damage, focal neuronal atrophy and low burden of co-existing neurodegenerative pathology appear key substrates of dementia after stroke injury. The elucidation of mechanisms of dementia after stroke injury will enable establishment of effective strategy for symptomatic relief and prevention. Controlling vascular disease risk factors is essential to reduce the burden of cognitive dysfunction after stroke. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. \u2022Ischaemic injury is common among long-term stroke survivors\u2022About 25% stroke survivors develop dementia with a much greater proportion developing cognitive impairment\u2022Risk factors of dementia after stroke include older age, vascular comorbidities, prior stroke and pre-stroke impairment\u2022Current imaging and pathological studies suggest 70% of dementia after stroke is vascular dementia\u2022Severe white matter changes and medial temporal lobe atrophy as sequelae after ischaemic injury are substrates of dementia\u2022Controlling vascular risk factors and prevention strategies related to lifestyle factors would reduce dementia after stroke This demands enormous resources from healthcare systems Deaths from stroke have declined in high-income countries and many middle- and low-income countries. The key element in this decline is reduced incidence of stroke 2The clinical diagnosis of stroke is usually accurate but the precise type of stroke and exact localization may be less straightforward. Determination of the pathological type of stroke is best achieved by early brain imaging usually computed tomography (CT) or by autopsy confirmation. In western countries, cerebral infarction accounts for approximately 80% of first-time strokes, and parenchymal brain haemorrhage for 20%. In Africa, however, the burden of haemorrhagic strokes are reported to be significantly greater by more than 10% at a ratio of 66:34 ischaemic to haemorrhagic 3Dementia developing after stroke is thought to be a clinical entity to define any type of dementia occurring subsequent to stroke injury irrespective whether it involves vascular, neurodegenerative or mixed processes. It can therefore entail a complex aetiology with varying combinations of large and small vessel disease as well as non-vascular neurodegenerative pathology. The development of dementia after stroke depends on several factors including the location and volume of the stroke, degree of related neuronal damage, presence of pre-existing cognitive impairment or other cerebral pathology. The direct influence of any specific genetic factor(s) is not clear. However, the heritability estimate for all ischaemic strokes was determined to be 38% but varied considerably by subtype with the greatest associated with large vessel (40%) and cardioembolic disease (33%) and lowest with small vessel disease (16%) Cognitive impairment or dementia after stroke is predominantly defined by dementia that occurred within three months after stroke onset. Irrespective, many stroke survivors develop delayed dementia beyond three months or only after recurrent stroke(s). The recognition of cognitive impairment in the acute phase after stroke may offer vital information to the clinician for early cognitive rehabilitation Recent prospective studies suggest stroke survivors may unmask or trigger varied pathologies including those attributed to subcortical VaD, multi-infarct dementia and even strategic infarct dementia The cognitive domains involved in the development of dementia after stroke may also vary depending on stroke characteristics such as stroke type, volume, numbers, location and severity. Regarding the stroke type, patients with ischemic strokes usually have higher survival rates than do those with hemorrhagic strokes, which explains why ischemic strokes lead to psychiatric morbidity more frequently than do hemorrhagic strokes In post-stroke cohorts, the presence of executive syndrome and depression is the predictor of poor long-term survival rather than depression itself Dementia associated with cerebrovascular diseases is clinically diagnosed using the widely accepted DSM IIIR or IV criteria. The apparent \u201cgold standard\u201d for diagnosis has been based on the results of the extensive neuropsychological examination, clinical presentation, and information from a close relative as well as the usefulness of R-CAMCOG Dementia after stroke may incorporate different types of dementias but these there is hardly any pathological confirmation for most of the clinical or prospective studies 4As the risk of death from strokes has declined, the number of stroke survivors with cerebral compromise and cognitive dysfunction has increased. Stroke survivors are at increased risk of cognitive impairment Cognitive impairment after stroke is a frequent but neglected consequence compared to other neurological deficits such as sensory or motor impairment 5In tandem with the age-related increased incidence of stroke itself, older age is the strongest risk factor for VCI and dementia after stroke . This isHypertension is the most common modifiable risk factor for stroke. Elevations in both systolic and diastolic blood pressures are associated with increased risk of stroke and by extension stroke related dementia . In addiStudies from general community populations indicate that VaD is more frequent in males than in females, but most studies suggested no substantial gender difference for the risk of dementia after stroke. Recent findings suggest this is attributable to neuroprotective role of adiponectin because of the relatively steeper decline of serum adiponectin levels associated with ageing in females than in males APOE) gene APOE \u05114 allele was reported to be associated with greater progression of cognitive decline The risk of dementia is likely more when vascular comorbid conditions occur. Thus, hypertension, atrial fibrillation, diabetes mellitus, myocardial infarction, and congestive heart failure can often co-exist in various proportions NOTCH3 and HTRA1 genes linked to cerebral autosomal dominant (CADASIL) and recessive (CARASIL) disorders. Both common and rare SNPs in the NOTCH3 gene show increased risk of age-related WM changes in hypertensive subjects HTRA1 gene were identified to be associated with hereditary SVD of unknown aetiology COL4A2 gene were identified to be associated with symptomatic small vessel disease, particularly WM disease and deep intracerebral haemorrhage Variants in genes associated with familial small vessel diseases of the brain 6Neuroimaging has been very useful to recognise that a combination or interaction of different types of brain lesion, including neurodegenerative markers, and preexisting underlying processing are players in the development of cognitive decline after clinical stroke. Brain lesion correlates of dementia after stroke include a combination of infarct features , the presence of WM changes , as well as brain atrophy 7Much of the current knowledge of the ischaemic injury cascade comes from experimental studies. The cascade consists of a complex series of events which are highly heterogeneous c and subsequent stimulation of caspase-3 whereas the extrinsic pathway is initiated by the activation of cell surface death receptors, which belong to the tumour necrosis factor superfamily, by Fas ligand, resulting in the stimulation of caspase-8. There is some evidence that ischaemic cell death may also be mediated by autophagy, which is activated during cerebral ischaemia for the bulk removal of damaged neuronal organelles and proteins Experimental studies suggest neuronal death following ischaemic injury is largely attributed to necrosis. However, recent developments indicate that significant cell death occurs by apoptotic as well as hybrid mechanisms (e.g. necroptosis) along an apoptosis\u2013necrosis continuum. While the infarcted core is necrotic be it macro- or microinfarction, within the penumbra caspase-mediated apoptosis is activated although secondary necrosis results from failure to implement the apoptotic signalling pathways fully, as they require energy. Ischaemic injury triggers two general pathways of apoptosis. The intrinsic pathway originates with mitochondrial release of cytochrome Neuroinflammation and immunodepression are also associated with stroke, ageing, and infection. These likely have a detrimental role in cognitive function after stroke Compared to neuroimaging correlates the pathological substrates associated with dementia after stroke or VaD have generally lagged behind. This is particularly true in defining those substrates associated with executive dysfunction. There is selective atrophy (30\u201340%) of pyramidal cells in layers III and V of the dorsolateral prefrontal cortex compared to the anterior cingulate and orbitofrontal cortices of the frontal lobe in subjects with dementia after stroke, VaD and, of mixed and AD versus normal ageing controls and those who did not have dementia after stroke 8Constant perfusion of the WM by deep penetrating arterioles is essential for functioning of axons and oligodendrocytes. Depending on the duration and severity of ischaemic or oligaemic injury, several features may be readily evident in the WM. These include activated microglia, clasmatodendritic astrocytosis, myelin breakdown, presence of axonal bulbs and degeneration, reactivation and loss of oligodendroglia. During subsequent (chronic) periods of arteriolar changes, perivascular spacing and apoptotic oligodendroglia are seen accompanied by degeneration of myelin and expression of hypoxia markers. WM hyperintensities as seen on brain T2-weighted or FLAIR magnetic resonance imaging (MRI) are associated with varying degrees of cognitive dysfunction in stroke, cerebral small vessel disease and dementia. The pathophysiological mechanisms within the WM accounting for cognitive dysfunction remain unclear. Stroke patients with more severe WM changes have an increased risk of recurrent strokes. Thus, the presence and severity of WM changes seen on MRI may be predictive of post-stroke dementia Recent clinicopathological studies 9Medial temporal lobe and global atrophy are both shown to be associated with dementia after stroke 10Several studies have consistently reported that cerebral silent infarcts detectable with computed tomography or MRI were independently predictive of dementia after stroke 11The risk of dementia after stroke is increased in patients with pre-stroke cognitive decline, with about one-third of patients meeting the criteria for AD and two-thirds meeting the criteria for VaD 12Any measure that reduces or controls vascular disease would be preventative for dementia after stroke Stroke is related to two- to nine fold increase in risks of dementia 13Cognitive impairment after ischaemic stroke injury is common in different populations. Although dementia after stroke is a clinical entity, current neuroimaging and pathological studies suggest that majority of older age-related dementia after stroke can be classed as VaD. Emerging small vessel disease associated genetic traits, severe WM changes and medial temporal lobe atrophy are important features in the development of dementia after stroke injury. The well-established relationship between vascular risk factors and dementia provides a rationale for the implementation of interventions. Control of vascular disease risk and prevention of recurrent strokes are obviously key to reducing the burden of cognitive decline and dementia after stroke.The authors declare no competing interests.Transparency document"} +{"text": "Acute myocardial infarction (AMI) is a major cause of death worldwide and affects both global and regional left ventricular function. Regional function can be determined by CMR i.e. wall thickening, and velocity encoded (VE) strain analysis. Aim: The aims of this study were to investigate how regional myocardial wall function, assessed by CMR velocity encoded strain and regional wall thickening, change after acute myocardial infarction and to determine if these variables can be used to differentiate between ischemic, adjacent and remote myocardium after experimentally induced myocardial infarction.Ten pigs underwent baseline CMR study for assessment of wall thickening and VE-strain. Ischemia was then induced for 40-minutes by intracoronary balloon inflation in the left anterior descending coronary artery. During occlusion, 99mTc tetrofosmin was administered intravenously and myocardial perfusion SPECT (MPS) was performed for determination of the ischemic area, followed by a second CMR study. Based on ischemia seen on SPECT, the 17 AHA segments of the left ventricle was divided into 3 different categories . Regional wall function measured by wall thickening and VE strain analysis was determined before and after ischemia.Changes in wall thickening and strain before and after ischemia are shown in Figure Both wall thickening and VE strain decrease significantly in both the ischemic and adjacent myocardium acutely after reperfused coronary occlusion. Differentiation thresholds for ischemic, adjacent and remote myocardium, could be determined. Thresholds will however, have limited applicability due to low sensitivity and specificity.Swedish Research Council, Region of Scania, Swedish Heart-Lung Foundation and the Medical Faculty at Lund University."} +{"text": "Cell Regeneration, Cai and colleagues reported that epithelial sheets derived from human induced pluripotent stem cells (iPSCs) can functionally substitute for tooth germ epithelium to regenerate tooth-like structures, providing an appealing stem cell source for future human tooth regeneration.A major challenge in stem cell-based bioengineering of an implantable human tooth is to identify appropriate sources of postnatal stem cells that are odontogenic competent as the epithelial component due to the lack of enamel epithelial cells in adult teeth. In a recent issue of Stem cell-based tissue engineering is a promising approach to replace or repair lost or damaged tissues or even organs in humans. Two major types of stem cells currently used in tissue engineering research and clinical application are embryonic stem cells (ESCs) and adult stem cells. However, ethical concerns in using ESCs and difficulties in isolation, expansion, and differentiation of adult stem cells limit their clinical application. The advent of iPSCs has provided a promising alternative source of stem cells for tissue bioengineering .Whole tooth bioengineering has given hope to dental replacement and regenerative therapy , 3. In tTooth development relies on reciprocal tissue interactions between ectoderm-derived dental epithelium and cranial neural crest-derived mesenchyme . In miceCell Regeneration , Cai and colleagues reported their studies on ameloblastic differentiation capability of integration-free human urine-derived iPSCs (ifhU-iPSCs) [Attempts have been made to identify alternative sources of human postnatal stem cells as the epithelial component for human whole tooth regeneration. It has been demonstrated that keratinocytes isolated from human foreskin and gingival epithelial cells isolated from patients\u2019 gingival tissue are able to differentiate into enamel-secreting ameloblasts when recombined with mouse embryonic molar mesenchyme that possesses odontogenic potential , 20. HowU-iPSCs) . They fiCertainly, identification of novel adult human stem cell sources is not yet the final solution for tooth regeneration. Based on the characteristic features of tooth development, to generate an implantable tooth germ in vitro, one of the cell sources, either epithelial or mesenchymal population, must acquire odontogenic potential to initiate regenerative process. In fact, despite the fact that human iPSC-derived epithelial cells as well"} +{"text": "Aeropyrum pernix and Sulfolobus tokodaii, were determined approximately 15 years ago. In these genome datasets, 47 and 46 tRNA genes were detected, respectively. Among them, 14 and 24 genes, respectively, were predicted to be interrupted tRNA genes. To confirm the actual transcription of these predicted tRNA genes and identify the actual splicing patterns of the predicted interrupted tRNA molecules, RNA samples were prepared from each archaeal species and used to synthesize cDNA molecules with tRNA sequence-specific primers. Comparison of the nucleotide sequences of cDNA clones representing unspliced and spliced forms of interrupted tRNA molecules indicated that some introns were located at positions other than one base 3' from anticodon region and that bulge-helix-bulge structures were detected around the actual splicing sites in each interrupted tRNA molecule. Whole-set analyses of tRNA molecules revealed that the archaeal tRNA splicing mechanism may be essential for efficient splicing of all tRNAs produced from interrupted tRNA genes in these archaea.Based on the genomic sequences for most archaeal species, only one tRNA gene (isodecoder) is predicted for each triplet codon. This observation promotes analysis of a whole set of tRNA molecules and actual splicing patterns of interrupted tRNA in one organism. The entire genomic sequences of two Creanarchaeota, Many tRNA molecules have been purified from original host organisms, and the respective tRNA nucleotide sequences were determined via direct RNA sequencing. Additionally, tRNA molecules are known to contain many different kinds of modified nucleotides.Mycoplasma carpicolum ..A. perniable arm . The predon stem . We alsotructure A\u2013C 15]..A. pernierformed . These aBy isolating cDNAs representing actual tRNA molecules and identifying the actual splicing events in the archaeal tRNA system, we have contributed important and useful information on expression and processing of tRNA genes."} +{"text": "Candida species are the most frequently found fungal pathogens causing nosocomial disease in a hospital setting. Such species must be correctly identified to ensure that appropriate control measures are taken and that suitable treatment is given for each species. Candida albicans is causing most fungal disease burden worldwide; the challenge lies in differentiating it from emerging atypical, minor and related species such as Candida dubliniensis and Candida africana. The purpose of this study was to compare identification based on MALDI-TOF MS to standard identification systems using a set of nosocomial isolates.HWP1).Eleven nosocomial samples were collected from 6 third-level hospitals in Bogot\u00e1, Colombia. All the samples were identified by combining MALDI-TOF MS with morphological characters, carbohydrate assimilation and molecular markers and cluster analysis, differences being revealed between Candida albicans, Candida africana, Candida dubliniensis reference spectra and two clinical isolate groups which clustered according to the clinical setting, one of them being clearly related to C. albicans.The present work describes the first collection of atypical Colombian Candida albicans-related and atypical C. albicans species, thereby overcoming conventional identification methods. This is the first report of hospital-obtained isolates of this type in Colombia; the approach followed might be useful for gathering knowledge regarding local epidemiology which could, in turn, have an impact on clinical management. The findings highlight the complexity of distinguishing between typical and atypical Candida albicans isolates in hospitals.This study highlights the importance of using MALDI-TOF MS in combination with morphology, substrate assimilation and molecular markers for characterising Candida albicans is the pathogenic fungus most commonly found in the general population; its ease of transmission in hospitals causes high comorbidity rates rCO_B isolates had a common hospital origin and more diverse clinical settings, lacking antifungal prophylactic guidelines. This factor could lead to less stressful conditions for nosocomial isolates and less selective pressure; the latter has been considered by Maubon et al., (2014) as beingC. albicans isolates require further molecular and susceptibility studies for understanding their ability to adapt (this includes phenotypic plasticity) and their potential for harming a vulnerable host.The clinical and epidemiological aspects of infection are relevant, since the pathological implications of these atypical"} +{"text": "The prodigious capacity of our brain to process information relies on efficient neural coding strategies. In engineered systems, bandwidth is often increased through multiplexing - multiple signals are simultaneously, yet independently, transmitted through a single communication channel. We have proposed previously that neural systems might implement the same sort of solution . Here, wa priori knowledge of which signal evokes which spikes) whereas treating all spikes as equivalent compromised STA measurement, especially for the fast signal (meaning that one needs to subdivide spikes according to their level of synchrony). Beyond simply measuring STAs, Figure To test our hypothesis, we built a feed-forward neural network comprising Morris-Lecar (ML) model neurons. All neurons received a common input constructed from two distinct signals, slow and fast, plus uncorrelated fast noise. According to our hypothesis, slow and fast signals are independently encoded by different types of spikes; in other words, differentially correlated output spikes, namely, asynchronous (Async) and synchronous (Sync), enable encoding of slow and fast signals, respectively. To assess the feasibility of the multiplexed coding scheme, recorded spikes were classified into two independent classes based on the peristimulus time histogram (PSTH) calculated from the entire set of neurons. Spikes whose instantaneous rates exceeded a threshold were designated \"Sync\" and all others were designated \"Async\". The spike triggered average (STA) was calculated for slow and fast signals using Sync and Async spikes, resulting in four different STAs. The Async-slow and Sync-fast STAs were clearly structured whereas the other two were not Figure . Using tOur results demonstrate the feasibility of multiplexed coding using synchronous and asynchronous spiking. Decoding the two signals requires that spikes are distinguished by their cross-correlation; this is difficult to do with experimental data in which only a subset of neurons are recorded, but it is straightforward for the brain using downstream neurons that operate as coincidence detectors or integrators that respond preferentially depending on input correlation."} +{"text": "Habitat loss and fragmentation are leading causes of species extinctions in terrestrial, aquatic and marine systems. Along coastlines, natural habitats support high biodiversity and valuable ecosystem services but are often replaced with engineered structures for coastal protection or erosion control. We coupled high-resolution shoreline condition data with an eleven-year time series of fish community structure to examine how coastal protection structures impact community stability. Our analyses revealed that the most stable fish communities were nearest natural shorelines. Structurally complex engineered shorelines appeared to promote greater stability than simpler alternatives as communities nearest vertical walls, which are among the most prevalent structures, were most dissimilar from natural shorelines and had the lowest stability. We conclude that conserving and restoring natural habitats is essential for promoting ecological stability. However, in scenarios when natural habitats are not viable, engineered landscapes designed to mimic the complexity of natural habitats may provide similar ecological functions. Coastal habitats host diverse ecological communities and provide numerous ecosystem services that affect the health, security and quality of life of human societies ,2. The dThe concepts of stability and resilience have been central foci of both fundamental ecology and applied conservation for at least the past half-century \u201314. StabThe utilization of engineered coastal structures such as vertical walls and revetments directly replaces natural shoreline habitats, disrupts land-water exchange, and alters the biophysical environment , potentially indirectly harming other natural habitats ,21,22. OAlthough the societal and ecological costs of coastal habitat degradation are becoming increasingly recognized \u201325, coasThis study involves the analysis of data resulting from routine fisheries research and monitoring efforts by the State of Alabama Department of Conservation and Natural Resources\u2014Marine Resources Division (ADCNR-MRD). ADCNR-MRD research and monitoring is regulated and permitted by the State of Alabama. ADCNR-MRD\u2019s standard protocol for sampling vertebrate fishes involves the live release of specimens when possible. This study did not involve endangered or protected species. The data analyzed and interpreted in this study were collected in Mobile Bay, Alabama USA .2 of bay water surrounded by 235 km of shoreline . The GSAEleven years of monthly data on coastal fish communities (2001\u20132011) were acquired from a fishery-independent state survey designed to monitor juvenile and adult finfish populations. The survey was initiated in 2001 with a randomly stratified sampling scheme throughout five zones in the northern and southern regions the bay across shoreline types using permutational multivariate analysis of variance (PERMANOVA) and non-metric multidimensional scaling (nMDS) analysis on Bray-Curtis distances . To quanAnalysis of the Euclidean distance in ordination space between mean annual fish community structure observed in all pairs of years revealed that temporal variability of fish communities was related to shoreline condition . CommuniTo determine whether these stability differences between shoreline conditions were present at sub- and super-annual periods, we computed the global wavelet power spectrum, which measures the average temporal variability at each period from 2001 to 2011. For average abundance, communities associated with natural shorelines had much lower temporal variance than that of the engineered shorelines at periods ranging from 2\u201340 months . For speWe found that natural landscapes support more stable fish communities than engineered landscapes. However, not all engineered landscapes performed identically. For instance, the stability of coastal fish communities was significantly higher near engineered shorelines characterized by rubble and riprap revetments than vertical walls or vertical walls with riprap. This finding suggests that structural complexity can in some instances reduce the negative effect of engineered structures on community stability. Natural habitats such as saltmarsh, oyster reef and submerged aquatic vegetation are structurally complex and widely recognized for providing essential habitat and nursery grounds for a variety of coastal species \u201334. On tBy analyzing community similarity and variability at annual and monthly intervals, we assessed typical fluctuations or trends of stability and evaluated the potential impacts of discrete events of disturbance. For both the sequential and overall annual time series analyses, communities associated with natural shorelines exhibited higher community similarity and fluctuated less than all engineered shoreline conditions. The global wavelet power analyses indicated that the high resilience of natural landscapes, which was observed at annual timescales, also applies at shorter time periods. During the 11 years that were examined in our study, the Alabama Gulf coast was impacted by several hurricanes and tropical storms including Allison in 2001, Ivan in 2004, Dennis, Katrina and Rita in 2005 and Ike in 2008. The Gulf of Mexico also experienced a massive oil spill following the explosion of the Deepwater Horizon drilling rig in 2010. However, studies of tidal marsh creeks following Ivan and seagrass meadows following Katrina found very little impact of the hurricanes on coastal habitats ,37. The Although engineered shorelines that mimic the complex structure of natural coastal habitats can partially restore community stability at local scales, preserving natural habitats may be important for community stability at both local and regional scales by \u201cspilling over\u201d via dispersal. Indeed, in fluctuating and interconnected metacommunities experiencing different environmental conditions , connectivity can have a large impact on community stability across scales ,40. In tThe legacy and extraordinary degree of shoreline alteration in Mobile Bay, like many other coastal systems, dates back far longer than comprehensive ecological monitoring, making it quite challenging to understand how current fish communities adjacent to different shoreline types actually compare to a natural coastal community. However, the emergence of landscape ecology and the availability of longer term data series on ecosystem change have greatly improved our ability to understand how human activities have transformed the structure and function of natural landscapes \u201346. For S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file."} +{"text": "Smoking during pregnancy increases the risks of many pregnancy-related complications. MiQuit is a tailored, self-help, text-message intervention developed to help pregnant smokers to stop. A pilot RCT investigated feasibility of recruitment of women attending hospital antenatal clinics by using NIHR Clinical Research Network (CRN) research midwives (RMs); findings will be used to plan a future definitive trial to investigate MiQuit efficacy. We aimed to describe the facilitators and barriers to trial recruitment that RMs perceived, and relate these to key recruitment processes.We conducted 14 semi-structured telephone interviews with RMs from 13 of 15 pilot trial recruiting centres. All interviewees had been involved in local study set-up, participant recruitment and follow-up. Data were transcribed verbatim, transcripts were coded simultaneously and inductive thematic analysis was used to analyse data.Emergent findings suggest a number of pertinent themes, most notably with participant identification and screening. For example, experienced RMs generally felt that a screening questionnaire intended to be given to all women attending antenatal clinics, and therefore prevent smokers from feeling unfairly targeted, was ineffective when used in the proposed manner and could cause greater discomfort on both sides. Instead, RMs indicated that they preferred to pre-identify smokers and discreetly approach them.Qualitative exploration of research staff views can help maximise the value of pilot work, identifying key aspects of trial design and conduct that may affect recruitment. We will discuss how these findings can assist planning a definitive trial, highlighting issues which may be generalisable to other studies."} +{"text": "Copy number variations (CNVs) consist of duplications or deletions of chromosomal regions ranging from a few hundred to more than a million bases in size, and are likely to play a role in phenotypic diversity and evolution. Recent advances in the identification and mapping of CNVs among normal individuals and in model systems, using bioinformatics and hybridization-based methods, are beginning to shed light on the functional importance of CNVs.Most CNVs are harmless; however, some are associated with human diseases including neurodevelopmental disorders. Hundreds of CNVs have been linked to neurological phenotypes, including autism, schizophrenia, and bipolar disorder. Some CNVs, such as duplications involving VIPR2 on 7q36.3 and deletions of NRXN1 on 2p16.3 have been identified in autism, schizophrenia, and bipolar disorder [Recently, model systems for human genetic disorders have emerged based on the use of human pluripotent stem cells (hPSCs). These approaches include human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). These models offer unique advantages for the study of developmental biology. hPSCs can be differentiated into various types of somatic cells including neurons to examine molecular and cellular mechanisms involved in disease causation. Differentiated hiPSCs have enabled the development of human in vitro model systems that capture the inherent pathologies based on the genetic background of the source material. These stem cell lines derived from patients with various diseases offer unique advantages for the study of inherited neurological disorders. Such patient-specific hiPSCs allow examination of underlying genetic factors in human organ systems that affect neural development.MRI scans and post-mortem studies of autism spectrum disorders suggest abnormal brain development due to initial brain overgrowth followed by premature growth arrest . DuplicaSchizophrenia is a complex genetic neurodevelopmental disorder that carries increased CNV burden. Using iPSC technology, Brennand and coworkers showed that hiPSC neurons from schizophrenia patients exhibit diminished neuronal connectivity and reduced neurite outgrowth and glutamate receptor expression . In addiNovel genome engineering approaches using ZFNs, TALENs, and CRISPRs have been applied to study specific functions in hPSCs. These tools provide the opportunity for correction of disease-causing mutations in patient-derived hiPSC models. Importantly, genetic and epigenetic instabilities, including enhanced de novo CNV induction have been observed during long-term propagation of hPSCs . These cStem cell technology using patient-derived hiPSCs with well-defined CNVs recapitulates the developmental programs that guide formation or malformation of brain region-specific neurons. The application of genomeediting tools to studies of hiPSCs will give important insights into the genome structural changes that underlie fundamental disease processes at the cellular level. These combined approaches are a boost to developmental neuroscience that could be transformative in the years ahead."} +{"text": "Nicotiana species in the graft union zone, within a tissue culture system. This has led to the formation of alloploid cells that, under laboratory conditions, gave rise to a novel, alloploid Nicotiana species, indicating that natural grafts may play a role in plant speciation, under certain circumstances.Grafting, an old plant propagation practice, is still widely used with fruit trees and in recent decades also with vegetables. Taxonomic proximity is a general prerequisite for successful graft-take and long-term survival of the grafted, composite plant. However, the mechanisms underlying interspecific graft incompatibility are as yet insufficiently understood. Hormonal signals, auxin in particular, are believed to play an important role in the wound healing and vascular regeneration within the graft union zone. Incomplete and convoluted vascular connections impede the vital upward and downward whole plant transfer routes. Long-distance protein, mRNA and small RNA graft-transmissible signals currently emerge as novel mechanisms which regulate nutritional and developmental root/top relations and may play a pivotal role in grafting physiology. Grafting also has significant pathogenic projections. On one hand, stock to scion mechanical contact enables the spread of diseases, even without a complete graft union. But, on the other hand, grafting onto resistant rootstocks serves as a principal tool in the management of fruit tree plagues and vegetable soil-borne diseases. The \u2018graft hybrid\u2019 historic controversy has not yet been resolved. Recent evidence suggests that epigenetic modification of DNA-methylation patterns may account for certain graft-transformation phenomena. Root grafting is a wide spread natural phenomenon; both intraspecific and interspecific root grafts have been recorded. Root grafts have an evolutionary role in the survival of storm-hit forest stands as well as in the spread of devastating diseases. A more fundamental evolutionary role is hinted by recent findings that demonstrate plastid and nuclear genome transfer between distinct Cucurbitae and Solanaceae species. Thus, the majority of recent grafting research concerns physiological and pathological aspects of vegetable grafting. Grafting also plays an important role in various types of physiological investigations . A broad range of classical grafting techniques can be found in igations , in partigations . An overigations . The hisigations . Undoubtresearch has openCapsicum annuum L.), old-stage homografts (58 days old plants) had slower graft-take than young-stage (34 days) homografts. Old-stage grafts had a lower percentage of xylem connections and seemed to suffer from drought stress are presumably always compatible. In heterografts, broadly speaking, intraspecific grafts are nearly always compatible, interspecific grafts (= rootstock and scion belonging to different species of the same genus) are usually compatible, intrafamilial grafts are rarely compatible, and interfamilial grafts are essentially always incompatible . Examinat stress . The timrequired but Yin ts e.g., .Graft incompatibility may be defined as failure to form a successful graft union. Yet, despite innumerous follow-ups of graftage in various types of plants, the reasons for graft incompatibility are still vague. Initial healing of the graft union does not in itself ensure long-term compatibility. In cucurbits, apparently successful grafts proved incompatible 25 days after grafting . In certSolanaceae, reciprocal grafts of tomato (Solanum lycopersicum L.) and pepper were considered severely incompatible, whereas tomato and eggplant (Solanum melongena L.) only moderately so, in comparison with compatible tomato homografts (Cucumis melo L.) onto 22 Cucurbitae rootstocks (Cucurbitae species (Castanea) species onto dwarfing rootstocks scions and quince (Cydonia oblonga Mill.) rootstocks. Prunasin, a cyanogenic glucoside, rises from the quince rootstock into the pear scion, where it is catabolized enzymatically by pear glycosidase to liberate cyanide at the graft interface. Cyanide \u2018poisons\u2019 the graft union tissues, causing cellular necrosis at the graft interface, leading to severe incompatibility (Prunus persica L. Batsch) grafted on myrobalan plum (Prunus cerasifera L. Ehrh) suggested a more general poisoning mechanism, due to progressive impairment of the phloem carbohydrate transport and accumulation of starch above the graft union , which presumably involves some kind of mobile RNA, was one of the pioneering findings in this area , in a distant organ , does not in itself prove its vascular transport, since this compound could also be synthesized in the presumably recipient organ. Therefore, grafting of genetically distinct mutants/transgenes is still being used as a principal means to distinguish between the site of biogenesis and the recipient organs . Roots oagnitude . FurtherSolanum tuberosum L.) tuberization by the graft transmissible miR156 is another recently studied case (Gibberellic Acid Insensitive (GAI) mRNA, including the anticipated changes in plant phenotype through a variety of tracks, including natural, underground root grafts. This avenue of disease transmission has been underestimated , just asSantalales) and dodder (Cuscuta sp.) transmit pathogens very efficiently, even among intergeneric and interfamilial plant species (Parasitic plants such as mistletoes (= parasitic plants in the order species . Dodder species .Persea americana Mill.) transferred a citrus viroid to avocado; the grafted citrus budwood remained viable for almost a year without forming a true graft union (Catharanthus sp.) seems to be unique in its ability to form distant interspecific grafts. The apple proliferation phytoplasma disease was transmitted from infected apple scions to periwinkle rootstocks rootstocks to overcome the Phylloxera grapevine plague (Citrus tristeza virus (Closterovirus) and other virus-like diseases exploited every possible graft combination had PGIP activity. PGIP was detected in xylem exudates of untransformed grapevine scions grafted onto transgenic rootstocks expressing pPGIP, indicating that the PGIP protein is graft\u2013transmissible. Such scions revealed improved tolerance toward grapevine diseases caused by Xylella fastidiosa and Botrytis cinerea also seem to play a role in rootstock-induced disease resistance. Polygalacturonase-inhibiting proteins (PGIPs) are plant cell proteins that specifically inhibit the cell wall degrading endo-polygalacturonases of plant pathogens . Leaf ex cinerea . Followi cinerea . This idFigure 2).Of all grafting issues, the least understood and most controversial is the \u2018graft hybrid\u2019 concept. According to this concept grafting may involve stock to scion transfer of genetic material (= graft transformation), leading to heritable changes in the scion. The scion which has acquired certain heritable traits from the rootstock is regarded as a \u2018graft hybrid.\u2019 However, graft transformations occur only under \u2018Mentor grafting\u2019 conditions, which presumably enforce the transfer of genetic material from stock to scion are removed throughout the experiment. Stock fruits are also removed in attempt to maximize flow of substances from the stock to the scion . InteresThe graft hybrid concept, which was developed and demonstrated by the Soviet horticulturist Solanaceae, in particular pepper (Within the \u2018graft hybrid\u2019 supportive evidence some specific characteristics can be defined. (a) The frequency of the appearance of variant plants is highly variable, sometimes below 1% . Thus, tr pepper , which ir pepper has beenr pepper but no fIn their review, Epigenetics refers to reversible heritable changes in genome function that occur without a change in the DNA sequence and may have morphological, physiological, and ecological consequences . ChangesSolanaceae . Root grafting could be induced artificially between potted l months . Naturall months . Althougl months , it may Assessment of the evolutionary significance of grafting involves discussion at two levels: its benefits for plant survival and its potential role in the formation of new species. The plausible ecological benefits of root grafting have been discussed by Addressing the significance of grafting as a potential evolutionary mechanism must take into account the ancient belief that grafting may give rise to new plant species . The \u2018grNicotiana species (Recent research has brought us much closer to a potentially real evolutionary grafting mechanism. In their early report species . Interes\u201c\u2026 do not lend support to the tenet of Lysenkoism that \u2018graft hybridization\u2019 would be analogous to sexual hybridization. Instead, our finding that gene transfer is restricted to the contact zone between scion and stock indicates that the changes can become heritable only via lateral shoot formation from the graft site.\u201dNicotiana species was thus obtained, tentatively named Nicotiana tabauca. Still, natural evolutionary formation of new species via this pathway would depend upon natural graft formation and emergence of adventitious lateral shoots, as previously discussed.However, in a more recent report Bock andNicotiana under tissue culture conditions require further confirmation with other plants in natural settings (The hypothetical possibility of cell fusion graft hybrids has already been mentioned by settings . It is dArabidopsis model has opened the way for meticulous, in-depth grafting research. The currently available molecular tools are expected to advance our understanding and eventually resolve the long standing grafting mysteries.While the technology of grafting has advanced tremendously, the long-term survival of grafted, composite plants is still somewhat unpredictable. The complexity of stock/scion interactions attains a new dimension when pathogenic agents enter the scenery. More enigmatic are the graft hybrid conundrum and the broader evolutionary significance of grafting. The extensive horticultural grafting research has not usually addressed these basic questions. The recently adopted The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "This is a case report of 22-year-old girl admitted with abdominal distension, vomiting, and chronic constipation since birth. Abdomen was distended, and perineal examination revealed imperforate anus with vestibular fistula (ARM). So far worldwide very few cases have been reported about anorectal malformation presenting in adulthood, and thus extremely little data is available in the literature about an ideal management of anorectal malformation in adults. In our case in the treatment instead of conventional procedure of posterior sagittal anorectoplasty (PSARP) anal transposition was done and till two years after the definitive treatment during follow-up patient has been doing well with Kelly's score of six. Our experience suggests that anal transposition provides satisfactory outcome in adults presenting late with anorectal malformation. Though anorectal malformation (ARM) is pediatric problem, in India because of poverty and ignorance one may encounter it in adults also. Posterior sagittal anorectoplasty (PSARP) is now accepted as a standard treatment in children, but there is very little literature guiding an ideal treatment of anorectal malformation in adults. Here we present a case of an adult female who was neglected since childhood and presented with congenital low type of anorectal malformation, we performed anal transposition which gave her a good outcome.22-year-old female presented with features suggestive of large bowel obstruction, chronic constipation since birth and regular passage of small quantity of stool through an opening in the perineum. Perineal examination revealed no separate anal opening , dry stoTransverse diameter inside the fistulous opening appeared very large on P/R exam and stool gave a firm feel to finger. X-ray abdomen showed loaded colon. She had no other congenital anomalies. In the first setting after primary resuscitation an emergency laparotomy was carried out and proximal diverting transverse loop colostomy was done to relieve the obstruction. After this under anesthesia stepwise instrumental evacuation of stool was performed through fistulous opening as hard and enormous quantity did not yield to conservative treatment, through either stoma or distal fistula. Few days later distal cologram showed decompressed distal colon and finally patient was planned for definitive procedure.Under spinal anaesthesia patient was put in lithotomy position, thorough examination was done, and previous clinical findings were confirmed. Tractions sutures applied to expose the operative area , Inj. AdDiagrammatic representation of the procedure has been shown sequentially in Figures Skin sutures were removed after 12 days and 2 weeks after the procedure sequential anal dilatation started, patient was continent. For 2 months along with anal dilator she was maintained on stool softener and high fibre diet. After 2 months stool softener use was tapered. Three months later distal loop cologram showed patent passage, so temporary colostomy was closed. Her anal manometry study was satisfactory. She had voluntary defecation without soling or constipation. She was advised to strictly follow dietary modification onwards. We used Kelly's score to assess her physiologic function during follow-up. At the end of 1 year she was continent without soiling or constipation. She could differentiate between feces and flatus and had strong effective squeeze, with Kelly's overall score of six. Though no objective evaluation was done, she was satisfied with perineal cosmetic outcome.The most common anorectal malformation defect in females is imperforate anus with vestibular fistula. In females this anovestibular fistula is a low type of disease and it opens near the vagina at the posterior fourchette and is directed posteriorly and upward with adhesion to posterior vaginal wall , 2. In aWe feel anal transposition provides satisfactory results in adult patients and also those presenting with anorectal malformation, it provides clear recognition of sphincteric complex with good cosmetic and functional outcome, and result is comparable with PSARP done for children."} +{"text": "The inflammatory response of sepsis results in organ dysfunction, including myocardial dysfunction. Myocardial dysfunction is particularly important in patients with severe septic shock who progress to a hypodynamic pre-terminal phase. Multiple aspects of this septic inflammatory response contribute to the pathogenesis of decreased ventricular contractility. Inflammatory cytokines released by inflammatory cells contribute as does nitric oxide released by vascular endothelium and by cardiomyocytes. Endotoxins and other pathogen molecules induce an intramyocardial inflammatory response by binding Toll-like receptors on cardiomyocytes that then signal via NF-\u03baB. These processes alter cardiomyocyte depolarization and, therefore, contractility. The particular role of the cardiomyocyte sodium current has not been characterized. Now new information suggests that the septic inflammatory response impairs normal depolarization by altering the cardiomyocyte sodium current. This results in decreased ventricular contractility. This is important because new targets for therapeutic intervention can be considered and new approaches to evaluation of this problem can be contemplated. Critical Care, Koesters and colleagues [In the previous issue of lleagues contribulleagues . Vasodillleagues . It coulThe septic inflammatory response involves a surprising number of intersecting pathways, many of which contribute to ventricular dysfunction. Pathogen-associated molecular patterns (PAMPs) released by infecting organisms bind innate immune receptors on inflammatory cells but also bind innate immune receptors in the heart and withCritical Care Koesters, Engisch and Rich investigate the role of cardiomyocyte sodium current [Alteration of intracellular calcium flux is a fundamental later step in the mechanistic pathway to decreased cardiomyocyte and ventricular contractility. In the previous issue of current . AlteratTo determine whether other channel currents could have contributed, additional characteristics of the septic action potential were measured. There was no significant change in resting potential, a property influenced by non-voltage gated K channels. Membrane resistance and action potential duration decreased only slightly in septic action potentials, suggesting a limited role, at best, for voltage gated K and Ca channels. Inhibition of the L-type Ca current reduced contractility, as expected.Thus, these novel results raise the possibility that sepsis-induced decreases in sodium channel flux may contribute to ventricular dysfunction during sepsis. This conjecture is based on similarity between sepsis-induced and tetrodotoxin-induced changes and therefore is not mechanistic proof of a role of the sodium channel. Nevertheless, moving the focus of investigation towards intracellular signaling expands our knowledge of potential mechanistic pathways contributing to myocardial dysfunction of sepsis. This is important because new targets for therapeutic intervention can be considered and new approaches to evaluation of this problem can be contemplated, possibly even based on surface measurements of electrical properties of the heart.ICAM: Intracellular adhesion molecule; NF-\u03baB: Nuclear factor kappa B; NO: Nitric oxide; PAMP: Pathogen-associated molecular pattern.The author declares that he has no competing interests."} +{"text": "Microvascular disease results in reduced skin blood flow (SkBF) and an increased risk of poor healing, ulceration and amputation, particularly in the lower extremity. Regular exercise is known to produce significant cardiovascular benefits and improved functional outcomes in people with chronic disease. However, it is unknown if these benefits also translate into improvements in SkBF. The purpose of this study was to evaluate the efficacy of exercise training on altering SkBF in adults by systematic review and meta-analysis.Relevant databases were searched to July 2014 for controlled trials evaluating the effect of exercise training interventions versus a non-exercise control on SkBF in adults.Eight studies met the inclusion criteria for this review. Individual studies employing an exercise intervention tended to have small sample sizes, with six of the eight studies showing a benefit of exercise but only three reaching statistical significance. Subsequent meta-analysis demonstrated aerobic exercise had a statistically significant effect on improving SkBF .To date, individual studies employing an exercise intervention have lacked sufficient power to detect clinically relevant benefits to SkBF, partially due to limited sample size. In primarily healthy previously sedentary adult cohorts, pooled analysis revealed a clear benefit of regular aerobic exercise on improving SkBF. Regular aerobic exercise provides a cost-effective option for improving SkBF in adults and may be of benefit to those with cardiovascular disease and metabolic disorders such as diabetes."} +{"text": "Graft ischemia results in inhibition of Na+\u2013K+ ATPase, inhibition of K+ ATP channels, drop of intracellular K+, and the absence of flow favors cell membrane depolarization (+ ATP channels would be associated with increased NADPH oxidase (NOX2) activity and increased production of reactive oxygen species (ROS) . Decreaspro IL18 . Both IL++-sensitive K+ channels during lung graft ischemia would be expected to provide protection through antagonizing membrane depolarization , which would attenuate ROS production, leading to abortion of inflammasomes priming and activation, and accordingly the release of pro-inflammatory cytokines.Accordingly, the enhancement of Caex vivo lung perfusion , which correlated with decreased incidence of primary graft dysfunction and chronic lung allograft dysfunction after transplantation (++-activated K+ channels (The Toronto team of lung transplantation has achieved significant inhibition of cytokines production within the lung graft through gene therapy during antation . Howeverantation . HO-1 cachannels .++-activated K+ channels during lung graft ischemia. Accordingly, further studies should be conducted to investigate the actual status of these channels during lung graft ischemia prior to transplantation. In addition, pharmacological activation of these channels could be a good target to protect the lung graft during transplantation, with corresponding improvement of the clinical outcome.These findings highlight the possible protective role of the enhancement of CaThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "This project is set out to: i) Establish a collection of astrocytoma cell lines generated from Saudi patients, ii) Select drug resistant brain tumour CSCs, iii) Characterize drug resistant brain tumour CSCs individually, and iv) Deduce common features for drug resistant brain tumour CSCs.The Cancer Stem Cells (CSCs) hypothesis proposes that malignant brain tumours are organized into aberrant cell hierarchies where a subset of parent CSCs replicate asymmetrically and unlimitedly to produce differentiated daughter cell ,2. Thesein vivo tumourgenic assays.A range of methodologies will be applied including, tumour cell line derivation methods, the clonogenic selection assay, cytogenetics profiles, neuronal cancer stem cells characterisation assays and Optimisation of methods used to establish astrocytoma cell lines generated from Saudi patients was completed. To date two novel primary astrocytoma cell lines have been derived. Full clinical data related to the cell lines was retrieved. Currently, optimisation of the clonogenic selection assay and immunostaining for cancer stem cells markers are under progress.Successful retrieval of primary astrocytoma cell lines was possible to accomplish. Important clinical information data relevant to the cell lines were obtained providing clear identification reference. Further work is required for the characterization of the drug resistant cancer stem cell component within these cell lines. Once completed, this research will assist in understanding some of the molecular mechanisms relevant to drug resistance, especially for patients in the Kingdom of Saudi Arabia."} +{"text": "Cumulative studies during the past 30 years have established the correlation between opioid abuse and human immunodeficiency virus (HIV) infection. Further studies also demonstrate that opioid addiction is associated with faster progression to AIDS in patients. Recently, it was revealed that disruption of gut homeostasis and subsequent microbial translocation play important roles in pathological activation of the immune system during HIV infection and contributes to accelerated disease progression. Similarly, opioids have been shown to modulate gut immunity and induce gut bacterial translocation. This review will explore the mechanisms by which opioids accelerate HIV disease progression by disrupting gut homeostasis. Better understanding of these mechanisms will facilitate the search for new therapeutic interventions to treat HIV infection especially in opioid abusing population. Substantial epidemiologic studies report a greater risk of human immunodeficiency virus (HIV) infection in opioid addicts . AlthougRecent studies focusing on the gastrointestinal (GI) immune system illustrate that the gut associated lymphoid tissue (GALT) is the primary target of HIV during all stages of infection and the The GI tract is considered the largest immunologic organ in the body and plays an important role in maintaining host immune homeostasis. Maintaining gut homeostasis requires balanced interactions among specialized epithelial cells, specialized lymphoid tissues, and commensal bacteria .Figure 1; The intestinal epithelium is the first line of defense in the gut luminal environment. The well-organized intestinal epithelial cells not only provide physical barrier preventing potential pathogen or antigen invasion, but also is integral for nutrient support and water transport thereby maintaining homeostasis of the whole organism . The smaThe major function of the colon is reabsorption of water and any remaining soluble nutrients from the food. The lack of villi in the colon results in a much smaller surface area compared to the small intestine. Organizationally, the epithelial stem cells are located in the lower parts of gut crypts and the differentiated cells migrate to the apical position and populate the colonic epithelial surface .To avoid para-cellular leak of bacteria from gut lumen, the intercellular junctions known as tight junctions join adjacent cells together by extending from the cytoskeleton proteins of one cell into the extracellular matrix, finally joining with the tight junction proteins of another cell . Tight jFigure 2). These cells can modulate the intestinal microenvironment by secreting antibodies, cytokines, or chemokines as well as mediate interaction with the enteric nervous system (ENS).Different types of immune cells are distributed in GALT like PPs and isolated lymphoid follicles, mesenteric lymph node (MLN), and the lamina propria. The major immune cell population within gut tissues includes macrophages, dendritic cells, mucosal mast cells, neutrophilic granulocyte, eosinophilic granulocyte, T lymphocytes, and plasma cells -17A, IL-17F, and IL-22 includes dendritic cells, macrophages, and neutrophils. These cells recognize antigens from the gut lumen and present them to adaptive lymphocytes (T cells and B cells) to initiate the immune responses. Various cytokines and chemokines produced by these APCs are also involved in the regulation of intestinal inflammation . Most land IL-22 . The rolnization .Taken together, both adaptive and innate immune cells are collectively important for maintaining homeostasis within the GI tract. Disruption of any cellular component may potentially predispose hosts to infections or initiate an abnormal immune response that accelerates disease progression.Salmonella due to impaired IgA production and diminished T cell response \u03bc-receptors, (ii) \u03b4-receptors, (iii) \u03ba-receptors, and (iv) non-classical opioid receptors . OriginaFigure 3), opioids exert both pharmacological and adverse effects in the gut, including alleviating abdominal pain, modulating GI motility, and suppressing intestinal immune functions.By activating these opioid receptors in intestinal tissues in the infected individuals. All these studies consistently showed that opioid abusers experience more severe neurocognitive defects including HIV-associated dementia , 2006. FFigure 5). As previously described, both HIV/SIV infection and morphine treatment can induce the intestinal epithelial barrier damage. Indeed, humans infected with HIV who use heroin have been shown to have greater amounts of LPS in their serum compared with non-users and HIV-1 susceptibility (CCR5 and \u03b14\u03b27 integrin) were also increased in morphine-treated animals . Recent Cumulative studies focusing on gut homeostasis help us recognize the central role of gut mucosal tissues in the pathogenesis of AIDS following HIV infection. Virus infection can induce compromised gut epithelial barrier function, abnormal immune activation within the gut tissues, and the dysbiosis in the gut microbiome, which in turn facilitates HIV replication and the disease progression.Additionally, more recent studies demonstrate that opioid abuse can disrupt gut homeostasis in the HIV-infected individuals. The severe disruption of gut homeostasis observed with opioids and models of HIV infection supports what is observed in the clinical studies as HIV patients who inject opioids have higher levels of bacterial translocation than patients who do not use opioids, which is likely why HIV patients who abuse opioids have more severe pathogenesis of HIV and develop AIDS much more quickly than non-users. However, the molecular mechanisms underlying the interactions of opioid abuse and HIV-induced enterotoxicity are still not well understood. Better understanding of these mechanisms may allow for therapeutic interventions to prevent or slow the pathogenesis in the gut following HIV infection, which will finally lead to more powerful strategy to control HIV disease progression especially in the opioid using and abusing population.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Bilateral vocal fold immobility may result from bilateral recurrent laryngeal nerve paralysis or physiologic insults to the airway such as glottic scars. The progression of mucosal injury to granulation tissue, and then posterior glottis stenosis, is an accepted theory but has not been photodocumented. This paper presents serial images from common postintubation injury to less common posterior glottic stenosis with interarytenoid synechia. Various pathologic conditions may be observed by the otolaryngologist following endotracheal intubation, including edema, ulcers, cartilage exposure, granulation tissue formation, or glottic stenosis. Management of the most common injuries is often conservative as granulation tissue and ulceration typically resolve spontaneously. The patients with progression to granulation formation are at risk of interarytenoid adhesion formation or early posterior glottic stenosis (PSG) and, therefore, should be closely monitored. While the majority of patients show some laryngeal injury after two days , less thIntubation trauma to the posterior commissure mucosa is theorized to cause ulceration, granulation, and then scar formation, which can fix the vocal cords , 2, 4\u20137.While numerous articles have described treatment methods for various stages of PGS based upon this theory, none has documented the progression from intubation injury to early posterior glottic stenosis , 9. We pInstitutional review board (IRB) exemption was obtained. This retrospective review of two cases demonstrates early posterior glottic stenosis formation after intubation. Patients complained of progressive voice complaints and exhibited reduced vocal fold mobility. The photomicrographs shown here document the progressive changes over two months (patient 1) and 6 months (patient 2) after acute endotracheal tube injury. Patient 1. A 23-year-old male with a history of traumatic multilimb amputation injury was emergently intubated. He presented with symptoms of acute dysphonia, breathy voice, and vocal fatigue following extubation.Early endoscopic examination of the patient after his hospitalization revealed granulation tissue overlying the mucosa of the medial surface of the bilateral vocal process of the arytenoid . ConservPatient 2. A 30-year-old male with traumatic brain injury after an assault required prolonged intubation. Following extubation, the patient was found to have a granuloma expanding the posterior commissure (mmissure . Transcummissure . SurgicaEndolaryngeal injuries continue to exist despite advances in endotracheal tube design and improvements in critical care management of patients on a mechanical ventilator. Mucosal injury typically occurs at one or more of the three most sensitive mucosal areas: the medial surfaces of the vocal process, the interarytenoid area, and the posterior subglottis along the inferior aspect of the cricoid cartilage .While temporary dysphonia and mucosal injury to the glottis following tracheal intubation are quite common, glottic stenosis is less common and reportedly varies from 4 to 14%, with higher rates following prolonged intubation , 6. DuraFactors such as local infection, inflammatory disorders, chronic disease states, hypotension, gastric reflux, tube mobility, and impaired pulmonary toilet are likely to be significant in the development of postintubation complications . AdditioBogdassarian and Olson divided PGS into four categories of increasing severity . Type 1 Early edema and granulation tissue usually resolve within three weeks but the authors recommend that the airway should be monitored closely for resolution of symptoms. Nonoperative treatment recommendations vary considerably and are beyond the scope of this discussion. Development of changes in voice or dyspnea on exertion or other aerodigestive complaints a few weeks to months after intubation should prompt suspicion of restrictive posterior glottic stenosis. Immobile vocal cords may be best assessed during operative direct laryngoscopy with palpation of the arytenoid complex. Laryngeal electromyography may also be used to differentiate immobile vocal folds from paralysis or other neurologic disorders.While postintubation injury is common, long-term complications are uncommon. This report demonstrates the development of PGS from postintubation granuloma, which has long been suspected but not documented. We emphasize the importance of serial examination of any patient who develops persistent voice alteration with findings of posterior glottic granulation tissue or with immobility or reduced mobility of the arytenoids after intubation. The photodocumentation shows the progression of common postintubation mucosal injury to much less common posterior glottic stenosis."} +{"text": "Mechanical ventilation in newborns, children and adults leads to lung injury and has been shown to induce the formation of proteinaceous lung oedema causing epithelial disruption and resulting in changes in lung perfusion. Lung injury leads to reduced compliance, worsening of shunt fraction and an inflammatory response that results from high end-inspiratory transpulmonary pressures (Ptp) and inadequate End Expiratory Lung Volume (EELV). Lung injury results if a lung is ventilated from collapsed state with each ventilator cycle. Thus the first concept of treatment in acute hypoxic respiratory failure is: \u201cOpen collapsed lung units and keep them open without overdistending them\u201d. The open lung is one in which there is little or no atelectasis and an optimal gas exchange. Lung recruitment strategies transiently increase Ptp to reopen the alveolar units not aerated or poorly aerated but recruitable.Lung recruitment maneuvers may restore EELV resulting in more stable alveoli, and reduce shear stress associated with the alveolar cyclic opening and closing. Lung recruitment can be performed in several ways: in delivery room with a T-piece device, in the NICU setting by using a conventional or high frequency oscillation (HFO) ventilator, and is commonly achieved by increase of end-expiratory lung volume with positive end expiratory pressure (PEEP) or end inspiratory lung volume by inspiratory holds or sustained inflation. Recruitment during both, HFO and CMV , follows similar concepts when using small tidal volume ventilation but is easier to achieve at bedside during HFO.- and/or death) were not improved.The Sustained Inflation maneuver (SI) applies a high pressure to the lung for a short period (30 sec) before returning to previous mean airway pressures. This volume recruitment strategy has been shown to be as protective as high frequency oscillatory ventilation (HFO) at similar lung volumes. Infants treated with a SI in delivery room had improved short-term respiratory outcomes , but major outcomes (BPD Bronchopulmonary dysplasiaRecent reports describe improvements in arterial oxygenation with the use of recruitment maneuvers during CMV and/or HFO. However, the impact of these strategies on patient important outcomes such as survival is still unclear.Further clinical studies are needed to evaluate the efficacy of SI, including selection of patients, setting of SI maneuver in terms of duration and peak pressure, timing of surfactant administration. Further studies are also needed to elucidate the impact of recruitment maneuvers during mechanical ventilation, including survival and BPD."} +{"text": "We generated a novel fully human anti-EGFR antibody showed lower toxicity and higher efficacy in the preclinical, toxicological and pharmacological studies when compared to a commercial drug Cetuximab. In this research, we aimed to understand the probably mechanism.Firstly, the mAb prefers binding to higher expression of EGFR. Its binding avidity on IgG form of the mAb to EGFR was equivalent to Cetuximab, while the Fab affinity was significantly lower. As a result, Higher EGFR expression tissues like tumor obtained the equivalent efficacy as Erbitux, while normal tissues with lower EGFR expression consequently showed lower toxicity.Secondly, the new mAb had higher concentration in tumor tissue than Erbitux. The accumulation of antibody in tumor local might induce stronger ADCC effect, and resulted in higher anti-tumor efficacy than Erbitux in a Hu-WBC NOD SCID xenograft mice model."} +{"text": "Localised prostate cancer, in particular, intermediate risk disease, has varied survival outcomes that cannot be predicted accurately using current clinical risk factors. External beam radiotherapy (EBRT) is one of the standard curative treatment options for localised disease and its efficacy is related to wide ranging aspects of tumour biology. Histopathological techniques including immunohistochemistry and a variety of genomic assays have been used to identify biomarkers of tumour proliferation, cell cycle checkpoints, hypoxia, DNA repair, apoptosis, and androgen synthesis, which predict response to radiotherapy. Global measures of genomic instability also show exciting capacity to predict survival outcomes following EBRT. There is also an urgent clinical need for biomarkers to predict the radiotherapy fraction sensitivity of different prostate tumours and preclinical studies point to possible candidates. Finally, the increased resolution of next generation sequencing (NGS) is likely to enable yet more precise molecular predictions of radiotherapy response and fraction sensitivity. Heterogeneity in tumour biology between prostate tumours results in a varied response to radiotherapy. At present no molecular tissue biomarkers are in routine clinical use to risk-stratify patients with localised prostate cancer. Instead, current management of localised prostate cancer is based upon established clinical risk factors including presenting PSA, clinical or radiological T (tumour) stage, and the total Gleason score. However, estimates of recurrence and survival vary considerably; for example, in the National Comprehensive Cancer Network (NCCN) intermediate risk group biochemical failure at five years following definitive local therapy varies from 2% to 70% . AlthougThe lethality of radiotherapy is centred on the creation of chromosomal lesions including DNA double strand breaks (DSB), which are particularly lethal when they cluster in close physical proximity to each other . Cells tAnother important radiobiological question at present is the radiotherapy fraction size sensitivity of prostate cancer, as measured by the alpha/beta ratio. An expanding body of evidence points to the alpha/beta ratio of prostate adenocarcinoma being as low as 1.5 , suggestRecent rapid progress in next generation sequencing techniques offers huge potential for personalisation of radiotherapy treatment, despite some of the required technological expertise being currently beyond the scope of most routine pathology laboratories. Other routinely available histopathological techniques such as immunohistochemistry (IHC) or genomic techniques such as fluorescent in situ hybridisation (FISH), comparative genomic hybridisation (CGH), and polymerase chain reaction (PCR) have identified many candidate biomarkers which with further validation could rapidly enter the clinic.Molecular biomarker development following prostatectomy has progressed at an accelerated pace compared to following radiotherapy due to limited tissue availability with the latter treatment . CriticsThis paper aims to review biomarkers predicting radiotherapy response in prostate cancer incorporating genomic signatures and individual candidates as well as biomarkers identified by longer established techniques. It does not address microRNA or biomarkers involved in the diagnosis of prostate cancer or prognostication outside of radiotherapy treatment; these were comprehensively reviewed in a recent paper in this journal .IHC enables direct evaluation of protein expression, which is advantageous as proteins are determinants of cellular function. Recent comprehensive genomic and proteomic work suggests that changes in nucleic acid do not necessarily translate to corresponding changes in protein expression . IHC is The Radiation Therapy Oncology Group (RTOG) 8610 and 9202 clinical trials of radiotherapy and varying lengths of androgen deprivation for localised prostate cancer have reported several biomarkers predicting outcome using IHC . A consiPollack et al. recently modelled the risk of distant metastases using expression of the above 5 candidates plus the apoptotic proteins Bcl-2 and Bax with competing risks hazard regression, adjusting for age, PSA, the Gleason score, T-stage, and treatment . The resThe role of hypoxia markers in prognostication following radiotherapy is more controversial. VEGF and HIF1-alpha were not included in the RTOG modelling of risk of distant metastases because an earlier RTOG study failed to demonstrate a significant association of VEGF with any survival outcomes following radiotherapy . HoweverThere are several possible reasons for conflicting data regarding hypoxic biomarkers and prediction of radiotherapy response. These include differences in the size of patient cohorts, NCCN risk group, and IHC cut points used to determine high expression of VEGF and HIF1-alpha. Furthermore, our understanding of how hypoxia impacts DNA repair is evolving rapidly. Recent studies suggest that hypoxia induces downregulation of proteins within the DNA double strand break repair pathways of homologous recombination (HR) and nonhomologous end joining (NHEJ) \u201349. ThisWith regard to DNA repair, error prone NHEJ operates in all phases of the cell cycle to repair DNA DSB; DNA PKcs has a key role in NHEJ by forming a synaptic complex bringing the free broken ends of DNA together with other ligating enzymes. Nuclear expression of DNA PKcs using IHC showed an independent association with biochemical recurrence after radiotherapy. However, other NHEJ proteins, also evaluated with IHC, such as Ku70, Ku80, and XRCC4 were not predictive of relapse .The TMPRSS2/ERG fusion is an important cellular rearrangement occurring in 50% of localised prostate tumours and ERG protein expression using IHC has been shown to be a robust surrogate for detecting the gene fusion . HoweverThere is thought to be direct cross talk between the EGFR cellular proliferation pathway and DNA repair. This provides a possible biological rationale for the observed correlation between high EGFR expression and poor prognosis following prostate radiotherapy . HoweverThe antiapoptotic protein Bcl-2 and proapoptotic Bax both have key roles in determining cell fate following radiotherapy. Independent prediction of survival outcomes has been demonstrated in some , 23, 43, in vitro clonogenic assays rodent cell lines with defects in NHEJ showed loss of fraction size sensitivity [ in vivo irradiated human skin showed that a 10-fold increase in the use of HR to repair radiation-induced DNA DSB towards the end of radiotherapy correlated with loss of fractionation sensitivity seen clinically [Identifying biomarkers of radiotherapy fraction size sensitivity is another area of unmet need. There is a tight association between proliferative indices and fraction size sensitivity of normal tissues . Normal sitivity , 66. In inically . On averinically . HoweverUse of a fluorogen with FISH, rather than a chromogen as in IHC, means that interpreting expression can be more straightforward than with IHC . In addiFISH has been used to demonstrate a role for biomarkers of cell proliferation such as PTEN and c-myc in predicting radiotherapy response. Loss of the tumour suppressor gene PTEN and amplification of the oncogene c-myc have both been associated with inferior outcomes following radiotherapy Table 2Table 2. PCR array involves synthesis and amplification of complimentary DNA (cDNA) prior to expression profiling. Although amplification can introduce bias, this multiplex technique is particularly useful when tissue and hence nucleic acid quantity is limited. A reduction in mRNA (messenger RNA) of the cell-cell adhesion molecule E-cadherin has recently been associated with poor outcome after radiotherapy, but not after primary androgen deprivation therapy alone using PCR array . The autCGH differs from Reverse Transcription Polymerase Chain Reaction (RT-PCR) in that it measures DNA copy number variations rather than messenger RNA expression. It thus enables a measure of genomic instability and can calculate the percentage of genomic alteration (PGA) per tumour sample. Today CGH arrays are able to evaluate global copy number variations with as little as 100\u2009ng of DNA . This isUsing CGH, copy number loss of several novel biomarkers with diverse functions has been proposed, as well as further validation of previously identified candidates including PTEN Table 3Table 3. A number of RNA expression signatures have been proposed to risk-stratify in localised prostate cancer , 75. TheThe first known DNA based signature to predict recurrence after EBRT has recently been reported and was Next generation sequencing (NGS) offers enormous potential for personalisation of treatment. It enables assessment of genomic events usually affecting more than 1\u2009kbp such as structural copy number alterations and chromosomal rearrangements including translocations, inversions, and recombination events. In addition, the powerful resolution of NGS also enables detection of events affecting less than 1\u2009kbp such as substitutions, insertions, and deletions . To our Fundamental aspects of cancer biology including DNA repair and hypoxia are intimately related to the efficacy of radiotherapy. It is therefore not surprising that over recent decades a number of promising tissue biomarkers have been developed using a range of molecular techniques. Whilst the majority of biomarker candidates are protein markers developed using IHC, markers of genomic instability using more quantitative techniques have shown excellent prognostic capability. Validation of these biomarkers is a priority so that the added benefit to standard clinical parameters can be clearly quantified and existing inconsistencies resolved. Development of predictive biomarkers that differentiate benefit from different local treatments and active surveillance would further enhance personalised management of early prostate cancer. Challenges include the need for standardised reproducible protocols and antibodies for IHC, together with the technical limitations of using very small biopsies for genomic techniques. However, technology continues to advance rapidly and the potential for molecular biomarkers to improve prediction of both sides of the therapeutic ratio of radiotherapy for localised prostate cancer is hugely promising."} +{"text": "Tool, protocol feasibility, recruitment process, electronic data capture, multi-centric clinical trials.The EHR4CR central query workbench supports pharma and CRO users in various stages of the multi-centric clinical trial lifecycle ranging from protocol feasibility, over subject identification and recruitment to clinical trial execution and adverse event reporting. It offers an intuitive graphical user interface for building, managing and executing formalized eligibility criteria queries Figure to suppoThe EHR4CR central workbench facilitates the patient recruitment process by offering workflow-driven administration and monitoring of the recruitment process for multi-centric trials. The study manager can select clinical sites of interest and invite them to participate in the study. Study metadata including protocol definition and formalized eligibility criteria queries are exchanged and synchronized with the participating clinical sites. The overall study status and individual clinical site participation status are continuously monitored and updated. The study manager is automatically informed about relevant changes occurring at each of the engaged clinical sites such as changes in the number of potential candidate patients, the number of consenting patients, patients in screening, included or excluded patients at each site.In order to support clinical trial execution workflows, the EHR4CR central workbench will provide \u201cRetrieve Form for Data Capture\u201d (IHE-RFD) capabiliProtocol feasibility functionality has been evaluated in three separate UAT rounds involving specialists from pharma and 11 pilot clinical sites. Subject identification and recruitment functionality is being evaluated. Support for clinical trial execution is still in development (November 2014).Pharma, CRO .http://www.ehr4cr.eu"} +{"text": "Gambusia) inhabiting tidal creeks across six Bahamian islands. We found that genital shape and allometry consistently and repeatedly diverged in fragmented systems across all species and islands. Using a model selection framework, we identified three ecological consequences of fragmentation that apparently underlie observed morphological patterns: decreased predatory fish density, increased conspecific density, and reduced salinity. Our results demonstrate that human modifications to the environment can drive rapid and predictable divergence in male genitalia. Given the ubiquity of anthropogenic impacts on the environment, future research should evaluate the generality of our findings and potential consequences for reproductive isolation.The aim of this study rests on three premises: (i) humans are altering ecosystems worldwide, (ii) environmental variation often influences the strength and nature of sexual selection, and (iii) sexual selection is largely responsible for rapid and divergent evolution of male genitalia. While each of these assertions has strong empirical support, no study has yet investigated their logical conclusion that human impacts on the environment might commonly drive rapid diversification of male genital morphology. We tested whether anthropogenic habitat fragmentation has resulted in rapid changes in the size, allometry, shape, and meristics of male genitalia in three native species of livebearing fishes (genus: Humans are altering ecosystems worldwide, but the evolutionary consequences of such impacts are poorly understood Palumbi . A wide Changes in environmental conditions commonly alter the strength or mode of sexual selection in diverse taxa human impacts alter the environment, (ii) ecological variation frequently influences the nature or strength of sexual selection, and (iii) sexual selection drives rapid and divergent evolution of male genital morphology. Understanding whether human impacts may ultimately drive genital diversification is critical because it carries important consequences for fitness, gene flow among populations, and the formation of new species. For instance, variation in male genital shape and size affects insemination and fertilization success in various taxa transfer sperm internally to females both cooperatively and coercively using a nonretractable, modified anal fin called the gonopodium. Gonopodium size varies greatly across poeciliid species, ranging from 20% to 70% of the body length and directly contacts the female during copulation Gambusia hubbsi Breder 1934 is known to inhabit the northwestern islands of the Great Bahama Bank , (ii) Gambusia manni Hubbs 1927 appears to inhabit all other islands within the Great Bahama Bank, as well as overlap with G. hubbsi on New Providence , and (iii) a yet unnamed species, Gambusia sp., inhabits the islands of the Little Bahama Bank . Bahamian tidal creeks are shallow, tidally influenced systems typically characterized by a relatively narrow creek mouth that broadens landward to wetlands dominated by Rhyzophora mangle (red mangrove). Most of the water flux in these systems arises from tidal exchange , so salinities in unfragmented systems are typically around 35 ppt and the biotic communities comprise marine taxa , Strongylura spp. (needlefish), and Lutjanus spp. inhabiting Bahamian blue holes where similar ecological differences over thousands of years have resulted in divergent evolution of male genital morphology. Specifically, we predict smaller gonopodia with more elongate and bony distal tips in unfragmented tidal creeks and larger gonopodia with more rounded distal tips possessing greater areas of soft tissue in fragmented tidal creeks across six Bahamian islands in March\u2013April 2010 using dip nets and minnow traps. For each species, we collected multiple populations from both fragmented and unfragmented tidal creeks on two separate islands due to concern that reduced visibility might bias the survey. We measured density of piscivorous fish using underwater visual census (UVC) methods , Nassau grouper (Epinephelus striatus Bloch 1792), jacks (Caranx spp.), and lionfish (Pterois spp.). Nearly all of the predators encountered in our surveys comprised known predators of Gambusia\u2014barracuda, needlefish, and snappers (>99%)\u2014with other potential predators rarely observed. We used our survey counts to calculate piscivore density (#/km2) for each site. We measured mosquitofish density using quadrat surveys, in which we counted all Gambusia individuals within 20 0.25 m2 quadrats within each tidal creek. We randomly chose quadrat locations across the microhabitats where Gambusia were observed, with all quadrats >2 m apart. For these surveys, the observer approached each predesignated area, stood still 1 m from the quadrat location, and waited 1 min prior to counting fish. We used the average of these 20 quadrat counts to calculate our estimate of Gambusia density (#/m2) for each site. This method proved highly effective due to water clarity and these fishes' general tendency to be undisturbed by our presence. We measured salinity and dissolved oxygen using a YSI 85 handheld multiparameter meter , water turbidity using an Oakton T-100 turbidimeter , and pH using a Hanna HI 98128 handheld meter . All six ecological parameters were measured multiple times over multiple years within a subset of tidal creeks to estimate repeatability\u2014all parameters exhibited significant repeatability, confirming that our snapshot estimates provided meaningful estimates for comparison among sites and the interaction between log10-transformed standard length and fragmentation status . Because we observed significant heterogeneity of slopes across fragmentation regimes , we could not simply interpret differences in relative gonopodium size\u2014rather, the key source of variation involved allometry. Thus, we conducted analyses specifically designed to test for among-population variation in allometric slopes.To test for shared and unique responses of gonopodium size to tidal-creek fragmentation across the species and islands, we conducted a GLMM as described above, but with logTo directly investigate potential differences in scaling relationships among populations, we calculated allometric slopes for each population with a sample size >5 . This excluded three populations. Because it remains unclear whether slopes calculated using ordinary least squares (OLS) or reduced major axis (RMA) regression is most appropriate for allometric studies . Gonopodial distal-tip shape was quantified for 235 fish . We captured three to five images of each gonopodial distal tip at 128\u00d7 magnification and stacked the photographs to comprise one composite image using Helicon Focus software to test for shared and unique effects of habitat fragmentation on gonopodial distal-tip shape across species and islands. The 15 relative warps served as response variables. Log-transformed gonopodial distal-tip centroid size, residual gonopodium size (from log-log regression of surface area on standard length), and log-transformed standard length were included as covariates to control for multivariate allometry, as all three factors could exhibit allometric effects on gonopodial distal-tip shape. These three potential sources of allometry exhibited low multicollinearity ; VIFs <10 are not considered problematic . We used this multivariate axis to visualize gonopodial distal-tip shape differences between fragmentation regimes in tpsRelw. Individual scores along d were employed in remaining analyses involving gonopodial distal-tip shape.To obtain a single value that described gonopodial distal-tip shape for each individual, we calculated scores along n = 235). We employed GLMs for analysis of meristics because the counts met assumptions of normality. We investigated shared and unique effects of habitat fragmentation on gonopodial distal-tip meristics across species and islands using separate GLMMs. Model terms included in each model mirrored that described above for gonopodial distal-tip shape .In addition to investigating potential divergence in multivariate gonopodial distal-tip shape, we wished to discover whether any traditional meristic characters on the distal tip have shifted as a result of habitat fragmentation. We counted the number of serrae on gonopodial fin ray 4a and the number of spines on gonopodial fin ray 3 from disGambusia density, salinity, turbidity, pH, and dissolved oxygen. For each environmental factor, our model included our five terms of interest. Consistent differences between fragmentation regimes were evident for piscivore density, Gambusia density, and salinity and were suggestive for turbidity , confirming that fragmentation status was not confounded with body size . Male Gambusia from fragmented tidal creeks exhibited a marginally nonsignificant trend toward possessing smaller gonopodia than counterparts in unfragmented sites , while the second best model included only salinity . These environmental factors tended to explain 50% to 60% (Gambusia density) as much variance as a term for \u2018fragmentation status,\u2019 suggesting that much of the observed allometric differences between fragmentation regimes ultimately derived from some aspects of Gambusia density and salinity.Explicit examination of mean population allometric slopes revealed significant differences in allometry between fragmented and unfragmented tidal creeks using both ordinary least squares and reduced major axis regression approaches Table . Populates Table . The topd, mosquitofish exhibited more rounded gonopodial distal tips with larger areas of soft tissue in fragmented tidal creeks, while males in unfragmented sites exhibited more elongate gonopodial distal tips with more densely positioned bony segments were largely attributed to differences in piscivore density and salinity and salinity . The second-best model found significant effects of piscivore density alone . These environmental factors explained 65% (top model) to 67% (second model) as much variance as a term for \u2018fragmentation status.\u2019 Thus, some aspects of piscivore density and salinity appear responsible for the majority of observed differences between fragmentation regimes in gonopodial distal-tip shape.Model selection revealed that differences in gonopodial distal-tip shape between fragmentation regimes , multiple aspects of male genital morphology exhibited consistent differences across six Bahamian islands, with some changes matching our Gambusia species that found males from environments experiencing reduced predation risk evolved larger gonopodia, resulting from trade-offs between natural and sexual selection under different ecological conditions . Differences in salinity might also indirectly contribute to this pattern if correlated with other unmeasured factors associated with resource availability, such as copepod or zooplankton density. Variation in population density or salinity could affect the relative strengths of selection on gonopodium and body size, potentially mediated by female preference or locomotor requirements for foraging and social/sexual behaviors, which could also contribute to allometric differences between populations confirms that genital shape can indeed affect sperm transfer, at least during forced copulations than those for altering overall distal-tip shape. However, multiple sources of allometry were associated with both number of serrae and spines on the gonopodial distal tip, and serrae number differed among species. Although we have little functional understanding of serrae and spine number, these meristics have often proved useful in taxonomic work in Gambusia fishes , our study revealed that habitat fragmentation ultimately resulted in consistent differences in multiple aspects of genital morphology. While we uncovered differences among species in some traits and among islands for some traits , the magnitude of differences between fragmentation regimes was typically as large or larger than these differences, and the nature of differences between fragmentation regimes did not significantly differ among species or islands. This suggests that human-induced ecological changes caused similar and strong selection on male genital morphology in fragmented tidal creeks and that population responses to similar selection were rapid, general, and repeatable.Gambusia affinis occurred over a roughly similar timescale as examined here (Langerhans et al. Although we did not test for a genetic basis for differentiation in gonopodial morphology in tidal-creek mosquitofish, previous work has demonstrated a genetic basis to population differences in gonopodial distal-tip shape and gonopodium size in congeners (Langerhans et al. Gambusia inhabiting fragmented and unfragmented tidal creeks have led to increased levels of reproductive isolation has not yet been investigated, but would provide valuable insight into the capacity of human impacts on the environment to promote the formation of new species on ecological timescales.Rapid differentiation of male genital morphology might result in reproductive isolation between ecologically dissimilar populations by inhibiting gene flow. Genitalia are vital for successful reproduction in internally fertilizing organisms, and mechanical and sensory incompatibilities might affect sperm transfer and fertilization success. Genital differences represent the first proposed mechanism of speciation Dufour , and to Drosophila buzzatti (Soto et al. Drosophila mediopunctata (Andrade et al. How general is the phenomenon of rapid genital differentiation associated with human-induced environmental changes? Although not yet a major focus of research, the idea that variation in ecological factors can affect the mechanisms of sexual selection influencing genital evolution is gaining traction (e.g., Rowe et al."} +{"text": "Corneal confocal microscopy (CCM) examination revealed a reduction of corneal small fiber sensory nerve number and branching in ALS patients. Quantitative analysis demonstrated an increase in tortuosity and reduction in length and fractal dimension of ALS patients\u2019 corneal nerve fibers compared to age-matched controls. Moreover, bulbar function disability scores were significantly related to measures of corneal nerve fibers anatomical damage. Our study demonstrates for the first time a corneal small fiber sensory neuropathy in ALS patients. This finding further suggests a link between sporadic ALS and facial-onset sensory and motor neuronopathy (FOSMN) syndrome, a rare condition characterized by early sensory symptoms , followed by wasting and weakness of bulbar and upper limb muscles. In addition, the finding supports a model of neurodegeneration in ALS as a focally advancing process.Although subclinical involvement of sensory neurons in amyotrophic lateral sclerosis (ALS) has been previously demonstrated, corneal small fiber sensory neuropathy has not been reported to-date. We examined a group of sporadic ALS patients with corneal confocal microscopy, a recently developed imaging technique allowing Corneal confocal microscopy has a number of comparative advantages over previous techniques such as skin biopsy, allowing non invasive, potentially repeatable and quantitative analysis of small sensory fibers at the microscopic level is a fatal disorder primarily characterized by progressive degeneration of upper (UMN) and lower motor neurons (LMN), in the brain and spinal cord = 5 years) were recruited consecutively, upon obtaining written informed consent. Seven age-matched healthy individuals served as controls and the sub-basal nerve plexus was imaged, as previously described .Between group differences were assessed with the Mann-Whitney test. In ALS patients, correlation between clinical and CCM data was investigated with Spearman\u2019s rank correlation (r). Statistical significance was considered at \u22121) compared with controls . These data suggest that a corneal sensory neuropathy exists in ALS patients. Amyotrophic lateral sclerosis-Functional Rating Scale-bulbar score was significantly related to CNL and CNFD ; coherently, ALS-SS-bulbar score was significantly related to both CNL and CNFD Figure , Table 2Our study demonstrates for the first time a corneal small fiber sensory neuropathy in sporadic ALS patients, consistent with previous clinical, pathological and neurophysiological studies showing subclinical sensory neuron involvement in this disease and confirming that neurodegeneration exceeds the neuronal system upon which clinical diagnosis relies involvement in sporadic ALS, contributing to the understanding of the pathomechanisms of this disease.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Skeletal muscle physiology is influenced by the presence of chemically reactive molecules such as reactive oxygen species (ROS). These molecules regulate multiple redox-sensitive signaling pathways that play a critical role in cellular processes including gene expression and protein modification. While ROS have gained much attention for their harmful effects in muscle fatigue and dysfunction, research has also shown ROS to facilitate muscle adaptation after stressors such as physical exercise. This manuscript aims to provide a comprehensive review of the current understanding of redox signaling in skeletal muscle. ROS-induced oxidative stress and its role in the aging process are discussed. Mitochondria have been shown to generate large amounts of ROS during muscular contractions, and thus are susceptible to oxidative stress. ROS can modify proteins located in the mitochondrial membrane leading to cell death and osmotic swelling. ROS also contribute to the necrosis and inflammation of muscle fibers that is associated with muscular diseases including Duchenne muscular dystrophy. It is imperative that future research continues to investigate the exact role of ROS in normal skeletal muscle function as well as muscular dysfunction and disease. Current research is revealing new perspectives regarding the biological significance of free radicals and other chemically reactive molecules in numerous physiological processes and pathological conditions. Reactive oxygen species (ROS), when generated in excess amounts, contribute to oxidative stress. ROS produced from contracting skeletal muscle are known to affect both muscle adaption and function can be produced within skeletal muscle fibers from L-arginine by NO\u2022 synthase (NOS). Three major isoforms of NOS exist: neuronal NOS (nNOS or NOS I); inducible NOS (iNOS or NOS II); and endothelial NOS (eNOS or NOS III) , which is a potent oxidizing agent via superoxide dismutases (SOD). However, H2O2 can, in turn, form highly reactive hydroxyl radicals (\u2022OH) through a Fenton reaction pathway. ONOOIncreases in ROS production are generated through a variety of signaling mechanisms. For example, interleukin (IL)-13 plays a critical role in the immune system maintaining normal homeostasis as well as responding to pathogens , and calcineurin all play a marked role in adaptation to events including exercise training affect mtDNA more extensively than nuclear DNA Table (Barbierc) Table . ROS indc) Table (Barbierc) Table . Accordic) Table .Since neurons continuously generate free radicals, a sufficient supply of endogenous antioxidants is necessary to maintain homeostasis (Galea et al., 2+ associated with muscular dystrophy (Table ROS are involved in the modulation of skeletal muscle contractions (Zuo et al., hy Table (Bellinghy Table . ROS oxihy Table (Goldstehy Table .The research reviewed in this article has identified many of the reactive species that affect skeletal muscle function. The pathways mediated by ROS/RNS signaling have been discussed as well as their role in skeletal muscle physiology. ROS have both beneficial and harmful effects on skeletal muscle function as they are ubiquitously involved in gene expression, immune responses, mitochondrial oxidative stress, skeletal muscle atrophy, as well as neuromuscular dystrophies. Redox-sensitive pathways continue to be an area of much needed research. Such studies in the future will shed significant insight into the exact role of ROS in health and disease.LZ designed the outline of the paper and wrote the paper; BP wrote the paper.This work was supported by OSUCOM-HRS Fund 013000.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The Affordable Care Act and the Medicaid redesign in New York City offer opportunities to explore alternative methods for measuring the effectiveness of behavioral health interventions. Quality of life (QOL) measures have been underutilized in substance use disorders treatment (SUDT). The objective of this study was to determine how a validated QOL instrument could be used in SUDT as a measure of health-related patient outcomes.t-tests. We examined change in QOL scores among OTP participants stratified by major health conditions.NYC outpatient drug treatment (DT) and opioid treatment programs (OTP) were invited to participate in a pilot evaluation. Newly admitted patients completed counselor-administered surveys at admission, and 90 and 180 days. Surveys included demographic and clinical items in addition to the World Health Organization QOL instrument, the WHOQOL-BREF ; scoringBetween July and September 2013, 1269 newly admitted patients were surveyed. Follow-up surveys were completed for 616 patients at 90 days (49%) and 336 at 180 days (26%). See Table Preliminary findings indicate that individuals in SUDT have lower QOL scores than healthy populations and experience improvements in QOL during treatment. Small positive changes among individuals with health conditions suggest the importance of integrating physical health care with SUDT. High dropout rates, multiple survey administrators, and an English-only survey instrument may limit our conclusions. Future investigations need to examine the feasibility of incorporating QOL measures into SUDT more broadly, including its impact on clinical interventions and longer-term patient outcomes, including maintenance of QOL gains achieved during SUDT."} +{"text": "Telomeres are dynamic nucleoprotein structures that protect the ends of chromosomes from degradation and activation of DNA damage response. For this reason, telomeres are essential to genome integrity. Chromosome ends are enriched in heterochromatic marks and proper organization of telomeric chromatin is important to telomere stability. Despite their heterochromatic state, telomeres are transcribed giving rise to long noncoding RNAs (lncRNA) called TERRA (telomeric repeat-containing RNA). TERRA molecules play critical roles in telomere biology, including regulation of telomerase activity and heterochromatin formation at chromosome ends. Emerging evidence indicate that TERRA transcripts form DNA-RNA hybrids at chromosome ends which can promote homologous recombination among telomeres, delaying cellular senescence and sustaining genome instability. Intriguingly, TERRA RNA-telomeric DNA hybrids are involved in telomere length homeostasis of telomerase-negative cancer cells. Furthermore, TERRA transcripts play a role in the DNA damage response (DDR) triggered by dysfunctional telomeres. We discuss here recent developments on TERRA's role in telomere biology and genome integrity, and its implication in cancer. Telomeres are nucleoprotein structures assembled at the extremities of eukaryotic chromosomes that protect chromosome ends. By doing so, telomeres prevent chromosome ends from being recognized as sites of DNA damage, protecting them from degradation and inappropriate recombination events due to erroneous activation of DNA repair pathways followed by a single-stranded G-rich 3\u2032 overhang. Electron microscopy and super-resolution fluorescence imaging have shown that telomeric DNA forms higher order structures where the 3\u2032 single-stranded overhang invades the homologous double-stranded region forming a telomeric loop (T-loop) pathway or members of the heterogeneous nuclear ribonucleoprotein family (hnRNPs) which bind TERRA, increases localization of TERRA at chromosome ends without affecting its overall levels or stability is bound by the ssDNA binding protein RPA which is required for activation of the ATR checkpoint .Telomerase is an established key target for cancer therapies Harley, . Yet recThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Compounds containing guanidine-related molecules have been used since medieval times to relieve symptoms of diabetes mellitus. Guanidine itself was too toxic but two linked guanidine rings (biguanides) were useful and generally safer. For 20 years, phenformin was used before adverse effects led to removal from the US and European markets. Metformin continues to be widely prescribed for diabetes treatment and is associated with improved survival compared to other diabetes drugs. With the current interest in using the more potent phenformin for cancer therapy, it is timely to review the risks, benefits, and potential contraindications.Nnmt). NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor for NAD+, an important cofactor linking cellular redox states with energy metabolism. NNMT expression is increased in adipose tissue and liver of obese and diabetic mice. Furthermore, NNMT knockdown in adipose tissue and liver using anti-sense oligonucleotides in mice on a high fat diet, protects against diet-induced obesity by augmenting cellular energy expenditure. This involves a novel mechanism which could provide new strategies for prevention and treatment of obesity and type 2 diabetes. Since NNMT is also elevated in many cancers, NNMT knockdown could be beneficial for cancer prevention and/or treatment.The adipose cell is as an endocrine organ in addition to its role in energy storage. Adipocytes secrete hormones, cytokines and other factors that influence energy balance, glucose homeostasis, insulin sensitivity and vascular biology. In humans with obesity and type 2 diabetes, expression of the Glut4 glucose transporter is down-regulated selectively in adipocytes resulting in systemic insulin resistance. Knocking out Glut4 selectively in adipocytes in mice increases the risk of diabetes while adipose-specific Glut4 overexpression confers enhanced glucose tolerance in spite of increased adiposity. To understand how adipocytes regulate glucose homeostasis and insulin sensitivity, we performed DNA microarray analysis of adipose tissue from mice with adipose-specific knockdown or overexpression of Glut4. The most highly reciprocally regulated gene is nicotinamide N-methyltransferase ("} +{"text": "Genome duplication is temporarily coordinated with sister chromatid cohesion and DNA damage tolerance. Recently, we found that replication fork-coupled repriming is important for both optimal cohesion and error-free replication by recombination. The mechanism involved has implications for the etiology of replication-based genetic diseases and cancer. To maintain genome stability, chromosome replication must faithfully preserve genome content in an optimal chromatin structural context. This requirement is met by temporal coordination of DNA replication with DNA damage tolerance (DDT), which promotes completion of replication, and with pathways associated with chromosome structural integrity, such as sister chromatid cohesion (SCC).et\u00a0al., we report that replicative helicase-coupled repriming is important for efficient error-free replication by template switching, thus preventing the high levels of mutagenesis and faulty strand-annealing events associated with genome rearrangements.Chromosome replication is carried out by the replisome machinery, which is initially assembled at replication origins.Cohesin is essential for SCC establishment during DNA replication.First, our study indicates that error-free replication following genotoxic stress is greatly influenced by replication fork-coupled repriming. When this repriming function is compromised, DNA metabolism events that are kinetically disfavored in wild-type cells and involve fork reversal and genome rearrangements become more frequent . The relThe repriming conditions that we recently described are not only associated with defective error-free DDT and altered replication fork architecture, but also negatively influence SCCNo potential conflicts of interest were disclosed."} +{"text": "Human tumours typically harbour multiple mutations in tumour suppressor genes and oncogenes. Histologically identical tumours in different patients often exhibit different combinations of genetic alterations and it is now also evident that considerable genetic heterogeneity can exist between cells within individual tumours. A major ongoing research challenge remains to determine the functional significance of this enormous genetic diversity and heterogeneity in terms of impact on tumour phenotypes and responses to therapies. Autochthonous mouse models of human tumours have provided many insights into the combinations of genetic alterations that are causal to tumour initiation and progression in different tissues. However, conventional germline-based genetic approaches, such as the generation of compound mutant mice based on transgenics and knockouts, are limited by the time and cost associated with extensive intercrossing of mouse lines. Faster and more powerful genetic tools are required to accelerate the functional annotation of cancer mutational cataloguing studies. Excitingly, several new viral vector-mediated genetic approaches offer the ability to directly modify the genome of somatic cells in mouse tissues and these have recently been applied to the rapid generation of complex mouse tumour models that harbour multiple genetic changes.Trp53 and Nf1 or that co-express oncogenic Hras and shRNA against Trp53 were employed to generate autochthonous mouse models of glioma [http://www.addgene.org/kits/mule-system/) that provides a highly flexible genetic toolbox allowing combinatorial gene knockdown, knockout, mutation or overexpression, together with tagging of infected cells with useful markers such as luciferase or fluorescent proteins [Hras and shRNAs against Cdkn2a or Trp53 or against both Trp53 and Pten, induced the formation of pleomorphic sarcomas that could be quantitatively monitored using luciferase-based imaging [Trp53 and activation of oncogenic Kras in germline-modified mice [The use of lentiviral gene delivery vectors for cancer modelling studies offers the advantage that the proviral DNA integrates into the genome of infected cells, providing heritability of the introduced genetic alterations. Injections of lentiviruses that co-express shRNAs against proteins . We demoied mice , validatTrp53, Lkb1 and Kras, together with a template for homology directed repair to insert an oncogenic Kras mutant into the endogenous locus, allowed the generation of lung tumours driven by three different genetic mutations [Trp53 and oncogenic Kras alleles provided a series of lung cancer models with complex genetic backgrounds [Eml4-Alk chromosomal rearrangement [Several genetically complex lung cancer models in mice have recently been generated using different types of viral vectors. Adenovirus and Adeno-associated virus (AAV) DNA remains episomal in infected mouse cells and is lost by dilution upon repeated cell division, which has historically limited the use of these vectors in tumour modelling. However, in the context of the CRISPR/Cas9 system, the episomal nature of viral infection is in fact advantageous as the introduced viral DNA represents a template that can be used for homology directed repair following Cas9-induced DNA double strand breakage. Taking advantage of transgenic mice expressing Cre-activatable Cas9, the intratracheal delivery of AAV9 viruses expressing Cre, luciferase, sgRNAs against kgrounds . Finallyangement .in vivo screens based on combinatorial genetics and will potentially allow experiments that better mimic intratumoural genetic heterogeneity. These new genetic tools will assist researchers in tackling the challenges of understanding the functional implications of the genetic complexities of human malignancies.These studies collectively highlight the new genetic power that is offered by the use of viral vector-mediated somatic genetics in wild type or germline modified mice. By employing different types of lentiviral, retroviral, adenoviral and AAV vectors, together with the use of cell-type specific promoters or infection of germline-modified mice that allow cell type-specific Cre, tTA or rtTA expression, it should be possible to specifically direct genetic modulations to diverse somatic cell types. The ability to clone libraries (eg. shRNA or sgRNA) into these viral expression vectors will pave the way for"} +{"text": "Neck dissection has traditionally played an important role in the management of patients with regionally advanced head and neck squamous cell carcinoma (HNSCC) treated with radical radiotherapy alone. However, with the incorporation of chemotherapy in the therapeutic strategy for advanced HNSCC and resultant improvement in outcome the routine use of post chemo-radiotherapy neck dissection is being questioned.Published data for this review was identified by systematically searching MEDLINE, CANCERLIT & EMBASE databases from 1995 until date with restriction to the English language.There is lack of high quality evidence on the role of planned neck dissection in advanced HNSCC treated with chemo-radiotherapy. A systematic literature search could identify only one small randomized controlled trial (Level I evidence) addressing this issue, albeit with major limitations. Upfront neck dissection followed by chemo-radiotherapy resulted in better disease-specific survival as compared to chemoradiation only. Several single arm prospective and retrospective reports were also identified with significant heterogeneity and often-contradictory conclusions.Planned neck dissection after radical chemo-radiotherapy achieves a high level of regional control, but its ultimate benefit is limited to a small subset of patients only. Unless there are better non-invasive ways to identify residual viable disease, the role of such neck dissection shall remain debatable. A large randomized controlled trial addressing this issue is needed to clarify its role and provide evidence-based answers. The optimal management of the neck in loco-regionally advanced head & neck squamous cell carcinomas (HNSCC) following primary chemo-radiotherapy remains controversial ,2. TradiPublished data for this review was identified by systematically searching the MEDLINE, CANCERLIT & EMBASE databases from 1995 until date with restriction to the English language. \"Head & Neck cancer\" OR \"HNSCC\" was combined with \"chemo-radiotherapy\" OR \"chemo-radiation\" as Medical Subject Heading (MeSH) terms and each of the following phrase used as text words: \"adjuvant neck dissection\"; \"planned neck dissection\"; and \"neck management\". Relevant cross-references were also considered.There is only one small randomized control trial (American Society of Clinical Oncology Level I In absence of high quality evidence, the best available evidence tempered with clinical judgment often guides decision-making. Two of the recently published reports ,12 somewArgiris et al evBrizel et al idApart from the afore-mentioned two reports, there are a few reasonably large studies (involving >50 patients: Table The potential benefit of planned neck dissection after a course of intensive chemo-radiotherapy in terms of improved regional control with or without an impact on survival needs to be weighed against the expected morbidity associated with the surgical procedure ,14,25. OPlanned neck dissection after radical chemo-radiotherapy achieves a high level of regional control, but its ultimate benefit is limited to a small subset of patients only. The morbidity of such dissection is small, but significant. Its impact on survival is yet to be completely realized. In the majority of patients it is either unnecessary because there is no residual disease in the neck or futile because of unsalvageable primary recurrence or distant metastases. Nevertheless, it is recommended that planned neck dissection be performed for patients with less than a complete response in the neck after combined modality therapy to optimize regional control, provided the primary is controlled and there is no evidence of distant metastases. It should also be performed as part of salvage surgery for locally persistent or residual disease at primary site. The criterion for planned neck dissection for patients with advanced nodal disease with a CCR in the neck following chemo-radiotherapy should incorporate not only the nodal staging but also the actual size of the involved lymph nodes. Unless there are better non-invasive ways to identify residual viable disease, which could include functional imaging like Positron Emission Tomography and biological assays like hypoxia markers, the role of such neck dissection shall remain debatable. A large randomized controlled trial across several institutions addressing these issues is needed to clarify the role of planned neck dissection in advanced HNSCC treated with primary chemo-radiotherapy and provide evidence-based answers.No source of funding involved in this reviewNone declared.Dr JP proposed the idea of systematic review on the issueDr TG did the literature search & prepared the manuscriptDr JP critically reviewed and revised the manuscript"} +{"text": "These newer options and various anti-tumor necrosis factor (anti-TNF) therapies are used as either first-line therapy or as an option when therapy is switched.The rising direct health care costs over the past 10 years attributable to Inflammatory Bowel Disease (IBD) is largely driven by expenditures on biological medications.non-medical switching or discontinuation of anti-TNF therapies is associated with worse clinical outcomes and increased health care resource utilization.2 In addition, uncontrolled moderate to severe IBD leads to a negative impact on the quality of life, work productivity, and increased risk for IBD-related surgeries and hospitalizations.3With an appropriate emphasis on value-based health care, cost implications of managing complex IBD patients are becoming increasingly important. However, Measuring validated clinical outcomes or surrogate markers of clinical outcomes whiles on different biologic therapies with different costs provides some guidance for cost-effective management in IBD.CC360, Chiorean et al report their findings on healthcare resource utilization and associated costs in a cohort of IBD patients switching to a second biologic agent. Their retrospective study titled \u201cEconomic Outcomes of Inflammatory Bowel Disease Patients Switching to a Second Anti-Tumor Necrosis Factor or Vedolizumab\u201d lends some insight to costs implications versus outcomes of switching out of class in patients failing initial anti-TNF agents.In this issue of fewer all-cause and IBD-related outpatient visits.The total and treatment costs were generally higher for patients switching to vedolizumab. The exception was in patients with ulcerative colitis who switched to golimumab. Regarding outcomes, adalimumab and other switchers had Our treatment choices when switching biologics in IBD patients should primarily be guided by each unique clinical scenario. This is particularly pertinent when there is not always a benefit in outcomes from using newer therapiesThe cohort studied was derived from claims data and disease severity was determined by proxy variables. In addition, there are other factors contributing to the costs including point of care costs, and unique contracts between health care systems and payers which cannot be evaluated in this study design.However, this study is one more reminder to be cognizant of economic implications versus desirable outcomes when switching biologic therapy."} +{"text": "Cyto-histopathological correlation is a key player in measuring quality in a quality programme . It was The Special Issue collected together articles dealing with various aspects of cyto-histological correlation and its role in cytological diagnosis routine. Gynecological samples form the highest proportion of all cytological specimens. Its cyto-histological correlation as a part of quality assurance programmes was covered in the literature ,2. AsatuThyroid fine needle aspiration cytology is important and expanding field of cytology. Preoperative diagnosis of rare medullary carcinoma is essential for lesion management, so Asia-Pacific international multi-institutional cytomorphological analysis of smears prepared with different staining methods has impact on practice improvement and quality worldwide . A Prof.Pulmonary cytopathology is an emerging field with personalized medicine and immunotherapy related techniques application to cytology specimens in growing proportion. Swedish colleagues studied concordance of PD-L1 expression between cytology and histology specimens in pulmonary non-small cell carcinomas; the concordance was better in bronchoalveolar lavage and bronchial brushing than in pleural effusions . This kiThe contributory role of cell blocks (CBs) in salivary gland cytology classified according to The Milan System for reporting Salivary Gland Cytology (MSRSGC) was demonstrated by Tommola et al. . The appNew cytopathology terminologies were also studied in three other papers ,13,14. TThe International System for Reporting Serous Fluid Cytology (TIS) was applied by Portuguese and Greek cytopathologists ,14. A seLast, but not least I thank all authors, reviewers, editors and editorial office staff who contributed to the success of this Special Issue."} +{"text": "Studies have shown that health education can improve dietary intake, exercise, and energy balance, which improves health outcomes and quality of life. However, diverse low-income older adults may have low self-efficacy coupled with potentially negative opinions regarding the aging process. Emerging research suggests that asset-based approaches utilizing persuasive and hopeful messages may be particularly effective with diverse populations of older adults who may be struggling with negative perceptions of self-efficacy. Research also shows that health behavior change interventions are most likely to be successful among diverse populations when they incorporate messages of resilience and facilitate information sharing and diffusion among participants. This presentation outlines the program curriculum development process of a student-led health promotion program by an interdisciplinary team of university researchers. Public health, dietetics, and communication faculty utilized Persuasive Hope Theory (PHT) and Self-Efficacy Theory to create a 15-week program to improve fruit and vegetable intake and physical activity among low-income adults aged 55+ living in Anchorage, Alaska. We will also detail the curricular components for this NIA-funded program which will be delivered in Fall 2022."} +{"text": "Understanding who will experience cognitive dysfunction and dementia is as important as identifying methods to combat such deterioration. This symposium seeks to highlight new advances in understanding cognitive deterioration and promote resilience in adulthood. Odd and colleagues utilized a national sample to show that 9-year decreases in executive function and episodic memory predicted increased risk of dying. Use of a brief cognitive assessment administered via telephone was unique \u2013 a method that may assist clinicians administering cognitive screenings to older adults in isolated areas. Graham and colleagues utilized a daily diary approach in 116 older adults (aged 60-90) to show that greater daily fluctuations in mindfulness were associated with higher episodic memory and executive functioning. Further, mediational evidence suggested that on days when mindfulness was greater, individuals perceived a younger subjective age. Willroth and colleagues provide evidence that higher scores on eudaimonic well-being in older adults (n=349) predicted greater cognitive resilience. Specifically, even though some participants had neuropathological burden , they did not exhibit pronounced cognitive declines. Using data from 14 longitudinal studies, Yoneda and colleagues examined the impact of physical activity on cognitive impairment and death. Multi-state survival analyses demonstrated engagement in more physical activity reduced risk of cognitive impairment and death. This symposium suggests that examining changes in cognition, incorporating subjective and objective indices of cognitive impairment, utilizing long-term longitudinal and daily diary designs, and testing key modifiable behaviors is crucial to understanding and promoting optimal cognitive functioning in adulthood."} +{"text": "Gordeeva et al. described a 3D embryoid body differentiation model and compared the spatiotemporal growth and patterning dynamics of embryoid bodies formed from different stem cell origins and culture conditions. Min et al. profiled the proteome and the protein phosphorylation of blastoids\u2013blastocyst-like 3D structures derived from extended pluripotent stem cells (EPSC). By comparing the protein expression profiles of EPSC blastoids with mouse blastocysts, they indicated that glucose metabolism is key to blastoid formation and brought new insights into the similarities and differences between blastoid and blastocyst at the proteome level. In addition, Luijkx et al. provided a comprehensive comparison of current protocols for mouse (Human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have enabled the modeling of human development and helped to illuminate mechanisms of monogenic disease, complex disease, and cancer. Lately, the striking ability of PSCs to self-organize has engendered three-dimension (3D) models of human development. The 3D embryonic cell models partially reconstruct the complex architecture of mammalian early embryonic structures and therefore hold great potential for stem cell and developmental studies. In this Research Topic, or mouse and humaor mouse blastoidex vivo organoid cultures has gained substantial attention as a model to study regenerative medicine and diseases in several tissues since the seminal work in 2009 . A clear example is the development of stem cell derived kidney progenitors and organoids that may be utilized to provide a reliable source of proximal tubule cells that are needed in commercializing the bioartificial kidney device. Liu et al. reviewed kidney disease model studies using in vitro tools including kidney organoids derived from normal human fetal/adult tissues, human PSCs and primary tissues of kidney cancer. They covered many topics including polycystic kidney disease and other genetic kidney diseases, and non-genetic kidney diseases. Both papers also discussed the remaining challenges of translating advances in kidney organoid research into new therapies.Chronic kidney disease (CKD) is a general term for heterogeneous disorders affecting kidney structure and function. When kidney function continues to decline, CKD patients may develop end-stage renal disease . Organ transplantation and dialysis continue to represent the only therapeutic options available. However, in the last two decades major advances in stem cell biology, gene editing, and bioengineering are now delivering options in regenerative medicine to treat CKD. Ramirez-Calderon et al. summarized the most advanced 3D methods for deriving human cardiac organoids from human PSCs and discussed the potential applications of cardiac organoids in the pharmaceutical and bioengineering fields, including the emerging question of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection in the heart.Human cardiac lineages can be differentiated in traditional two-dimensional monolayer culture or by adopting 3D culture methods. Klein et al. argue that paying due attention to culture environments is critical to improve the reproducibility and translation of preclinical research. They outline the main sources of cell culture environmental instability and deliver best practice recommendations, thus making an important step towards enhancing the physiological relevance of in vitro cellular models. Additionally, a higher resolution understanding of the molecular events unfolding during development or tissue homeostasis could guide better 3D differentiation protocols. Single-cell OMICs analysis promise to deliver unprecedented insights into human development and disease pathogenesis. In this Research Topic, Xu et al. applied single-nucleus RNA sequencing (snRNA-seq), which could resolve multiple cell types better than single-cell RNA sequencing (scRNA-seq), to profile cell types, dynamics of cellular composition, and hepatocyte differentiation trajectories during postnatal murine liver development. A complete understanding of the development of complex organs such as the brain requires not only cell type taxonomy (which scRNA-seq excels at) but also spatial information of cells or genes at the organ level. Cheng et al. applied Stereo-seq, a DNA nanoball patterned array-based high-resolution spatial transcriptomic technology, to medial structures in postnatal mouse brain. Their data provided subcellular distribution of 27,330 genes, region-specific gene regulatory networks, 41 cell types localized in different regions. This rich resource for developmental study is accessible as an open and interactive database (https://db.cngb.org/stomics/datasets/STDS0000139?tab=explore). Li et al. performed integrative scRNA-seq and single cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis in mesenchymal stem/stromal cells derived from placenta (PMSCs). Their data revealed subsets of PMSCs and nominated potential cis and trans regulatory factors in the subtypes.These primary research and reviews highlight the fact that organoids are heterogeneous in shape and size; moreover, the absence of blood supply and interactions with non-parenchymal cell types limit their potential. For these reasons, future works are needed to standardize organoid cultures, including co-cultures with other cells , and to improve cell maturation to generate more faithful models. To this end, improvements in culture methodology could make 3D stem cell models more robust and reproducible. Shams et al. showed that signaling through the chemokine receptor CXCR4 is essential to normal early activation, proliferation and self-renewal of muscle stem cells (or satellite cells), which are responsible for regenerating muscle fibers following acute skeletal muscle injury. Among mammals, deer has the unique ability to fully regenerate a lost organ, the antler. Guo et al. explored the gene expression changes during the activation of the pedicle periosteum (harboring stem-like cells) that triggers the initiation of antler regeneration. Their findings suggest that calreticulin (CALR), an androgen response gene, is likely a downstream mediator of androgen hormones for initiating antler regeneration.Besides high-through profiling of mRNA and chromatin accessibility, mechanistic dissection of regulatory pathways during tissue regeneration pays dividends for improving stem cell differentiation and developing novel therapies. In this regard, The topic editors hope the readers enjoy reading these new papers centered around stem cell models as much as we do. The exciting research advances summarized in this volume will undoubtedly have a positive impact on the translational values of stem cell models."} +{"text": "Community gerontology integrates scholarship on aging and communities through the lens of mesolevel environments, the diverse continua of settings linking micro and macro contexts of aging. This interdisciplinary symposium brings together research exploring the interconnections of older adults\u2019 engagement across and within the socio-ecological levels of their lived experiences, place-based communities, and policy contexts. Yeh et al.\u2019s paper elucidates the promises of visual methods in critical qualitative research with older adults to subvert power dynamics and advance social justice in gerontology. Latham-Mintus\u2019 paper explores how \u201cweak ties\u201d created by the interaction of social infrastructure within geospatial places and spaces can facilitate longer, healthier lives. Reyes\u2019 paper uses an intersectional life course perspective to explore placemaking as civic participation among Latinx immigrants and African American older adults across time and social environments. Plasencia\u2019s paper focuses on aging in community among diverse older adults using a photovoice to assess their perceptions and needs within the lived urban environment. Pope and colleagues explore how a multi-state sample of older adults perceive their roles in age-friendly initiatives at individual, organizational, and community levels. Taken together, the papers discuss and contextualize the multidirectional ways older adults engage their place-based communities within larger macro sociopolitical structures \u2013 an analysis that highlights the embeddedness of mesolevel community environments both within and between micro and macro spheres. This session further speaks to the importance of centering older adults\u2019 experiences in community gerontology by illuminating the ways older adults not only age in community but through layers of community."} +{"text": "Recent years have seen important progress in the characterisation and refinement of organoid culture systems. Here, we address several open questions in the field, including how closely organoids recapitulate the tissue of origin, how well organoids recapitulate patient cohorts, and how well organoids capture diversity within a patient. We advocate deeper characterisation of models using single cell technologies, generation of more diverse organoid biobanks and further standardisation of culture media.Organoids have become a prominent model system in pulmonary research. The ability to establish organoid cultures directly from patient tissue has expanded the repertoire of physiologically relevant preclinical model systems. In addition to their derivation from adult lung stem/progenitor cells, lung organoids can be derived from fetal tissue or induced pluripotent stem cells to fill a critical gap in modelling pulmonary development Customised media have been developed to expand specific cellular subpopulations from iPSCs; in the airways, basal cells and secretory progenitor cells have all been induced from iPSCs and, whein vivo tissue of origin remarkably well, despite the absence of stroma in vitro of single nucleotide variants (SNVs) and copy number alterations (CNAs). Although whole exome sequencing has been performed in some studies , others The extent to which lung cancer organoids diverge from tumour tissues at the phenotypic level is much less clear. Since organoid culture systems were originally developed to expand epithelial stem cells , it is uThe majority of lung organoid cultures are currently performed as mono cultures, although investigations of epithelial-fibroblast or epithin vivo complexity of epithelial-stromal or epithelial-immune interactions, nor systemic variables such as nutrient availability, mechanical forces and circadian rhythms.While we advocate a better phenotypic characterisation of lung organoids to investigate their resemblance to lung tissue, it must be emphasised that organoids will always remain a reductionist model. The generalisation or translational relevance of results obtained in this culture system is best validated using orthogonal model systems or datasets (including publicly available omics datasets). Moreover, it is not possible to reproduce the complete A second important aspect of organoid modelling is the extent to which it is possible to capture the biology of the target population. Primary human bronchial epithelial cell cultures can show wide inter-patient variability in differentiation potential and response to stimulation, and so studying sufficient numbers of patient cultures is crucial, particularly when studying phenomena that are likely to vary with biological characteristics of the donor, such as age and/or sex . At presOrganoids have been derived from patients across a wide range of respiratory diseases, including pulmonary fibrosis , primaryTo date, lung cancer research has benefited most from organoid-based disease modelling. As many hundreds of organoid lines have been developed by multiple laboratories worldwide, it is possible to assess the extent to which they reflect non-small cell lung cancer (NSCLC) patient cohorts. Surprisingly, organoid establishment rates are similar for lung squamous cell carcinomas or adenocarcinomas , despiteTo date, most studies have generated lung cancer organoids from surgical resections of primary tumours. To our knowledge, no organoid models have been generated from pre-invasive disease, but pre-cancer organoids would be particularly valuable to study events in early tumourigenesis. Since most lung cancer patients die from metastatic disease, representing these in organoid collections would be valuable. One study established organoids from malignant effusions from patients with advanced lung cancer with a high success rate , suggestAn alternative approach to deriving organoids from lung disease patient cohorts, is to use the available model systems to investigate specific hypotheses related to the disease process. In this regard, pluripotent cell-derived organoids have proved useful pulmonary fibrosis models. Introducing Hermansky-Pudlak syndrome (HPS) mutations associated with interstitial pneumonia using CRISPR-Cas9 promotes fibrotic changes in ES-derived lung organoids or iPSCsIntra-patient heterogeneity likely represents an understudied source of variation in lung organoid research. At present, authors typically report the diagnosis of the patient from whom organoids were derived and the tissue of origin. However, airway epithelial cell phenotype is known to vary in the proximal-distal axis within normal lungs with cells from the upper airways having distinct transcriptomic profiles , innate in vitro. Indeed, one study reported a low correlation of variant allele frequencies (VAFs) between organoids and original tumours in approximately half of the samples analysed (Lung cancers are genetically and phenotypically heterogeneous, but the extent to which this is maintained in lung cancer organoid cultures is so far poorly characterised. Given the variable establishment rates of lung cancer organoids, bottlenecks are expected that restrict heterogeneity analysed . Evidencanalysed and coloanalysed . This coanalysed , there ianalysed . The estanalysed . Evaluatin vivo processes, the ability of organoid collections to accurately reflect population level inter-individual variability and intra-patient heterogeneity (Lung organoids provide a cell culture platform to study lung development, stem/progenitor cell biology and disease pathogenesis. Several open questions remain, however, concerning their ability to recapitulate the tissue of origin and ogeneity . We advo"} +{"text": "Oncogenic viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), Epstein Barr virus (EBV), and Kaposi Sarcoma Herpes virus (KSHV) contribute to a significant proportion of the world\u2019s cancers. Given the sizeable burden of virus mediated cancers, development of strategies to prevent and/or treat these cancers is critical. While large population studies suggest that treatment with hydroxymethylglutaryl-CoA reductase inhibitors, commonly known as statins, may reduce the risk of many cancer types including HBV/HCV related hepatocellular carcinoma, few studies have specifically evaluated the impact of statin use in populations at risk for other types of virus mediated cancers.Studies of populations with HBV and HCV suggest a protective, dose-dependent effect of statins on hepatocellular carcinoma risk and support the theory that statins may offer clinical benefit if used as chemoprophylactic agents to reduce liver cancer incidence. However, no population level data exists describing the impact of statins on populations with other oncogenic viral infections, such as HPV, EBV, and KSHV.Further study of statin use in diverse, global populations with or at high risk for oncogenic viral infections is essential to determine the impact of statin therapy on virus mediated cancer risk. Cancers caused by infections represented more than 13% of the global cancer burden in 2018, including more than 1.2 million cancers caused by viruses for lipophilic statin users and 0.51 [0.31\u20130.85] for hydrophilic statin users) . In contIn contrast to HBV/HCV, few epidemiologic studies describe the impact of statin use on HPV-, EBV-, or KSHV-mediated cancers. For HPV, one retrospective cancer database study of 1638 individuals with head and neck cancers found a statistically significant inverse association between ever using a statin and death from HPV\u2009+\u2009head and neck cancers .Available data suggest a protective, dose-dependent effect of statins on HCC risk in populations with chronic HBV and/or HCV infections. Thus, statins may show clinical benefit if used as chemoprophylactic agents to reduce the public health burden of HCC, and randomized clinical trials evaluating the effectiveness of statins in HCC outcomes both with other therapies (NCT03275376) and to prevent recurrent HCC (NCT03024684) are ongoing. Trials being planned should include comparisons of lipophilic or hydrophilic statins in their designs.The promise of statins in preventing HCC warrants extrapolation of epidemiologic and clinical study of statin therapy to populations at risk for other oncogenic viral infections, particularly HPV, EBV, and KSHV. Importantly, despite the much larger global burden of cervical cancer, the only published study describing the impact of statins on HPV is in HPV-related head and neck cancers, which are predominantly diagnosed in men in high income countries. Future studies must rectify this disparity by evaluating the impact of statins on cervical cancer, particularly in low- and middle-income countries where cervical cancer rates are higher due to poor access to HPV vaccines and surveillance programs, but also in high income countries where cervical cancer remains an important cause of cancer morbidity and mortality despite robust HPV prevention programs. Statin therapy might prevent or slow the development of cervical cancer if initiated immediately after detection of high-risk HPV subtypes or cervical dysplasia in women undergoing cervical cancer screening. Though pre-clinical data suggest that statin therapy may ameliorate EBV-related cancers, no epidemiologic studies have evaluated statins in prevention or as an adjunctive therapy in at risk populations. Such studies are needed to determine whether statin intervention trials are warranted to prevent EBV-related cancers. Though KSHV afflicts a large proportion of the population, particularly in sub-Saharan Africa, no investigations into the ability of statin therapy to limit the development of KSHV-associated cancers exist; study of the relationship between KSHV and statins should be initiated via in vitro and animal model studies. Finally, HIV hugely impacts risk of morbidity and mortality in those co-infected with the oncogenic viruses covered in this Review, and several anti-retroviral therapies in widespread use are known to contribute to dyslipidemia. Future research should include investigation of statins as agents to prevent virus mediated cancers in people with HIV, as these individuals may have different outcomes or require different statin doses.The studies outlined in this article provide preliminary evidence that statins may induce mechanisms that slow virus-mediated cancer development, which should be further investigated in epidemiologic studies of populations at risk for HPV, EBV, and KSHV infection. Randomized trials and large community-based prevention trials prospectively evaluating use of specific statins in populations with or at high risk for oncogenic viral infections will be needed to further explore the potential benefit of statins in decreasing virus mediated cancer risk."} +{"text": "Co-occurrence of obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD) features is well stablished. Diagnosis of OCD increases the risk of a later diagnosis of ASD, and vice versa. Moreover, a recent combined genome-wide association study identified a shared polygenic risk between the two disorders. Our preliminary results also indicate that OCD patients have higher levels of autistic traits than individuals from the community.To determine which autistic dimensions are predictors of OC symptoms.39 OCD patients answered the Portuguese versions of the Autism-Spectrum Quotient for Adults and Obsessive Compulsive Inventory \u2013 Revised (OCI-R). Spearman correlation and linear multiple regression tests were performed using SPSS.The OCI-R global score showed positive correlations with some AQ dimensions . The regression model showed that attention to detail and attention switching explained 36% of obsessive-compulsive symptoms variance.Our results are in line with a dimensional perspective of psychopathological continua and indicate that the overlap between OCD and ASD occurs through shared neurocognitive processes. We suggest that, besides being a predisposing factor for social difficulties in ASD, attention to detail and deficits in attention switching may also lead to difficulties to dismiss repetitive thoughts or extinguish behaviours in OCD. Future studies should investigate the distinctive features and underlying processes between OCD/ASD."} +{"text": "Although minimally invasive percutaneous disc nucleoplasty (PDN) has been widely used for discogenic back pain or soft-disc herniation of the lumbar spine, complications can occur. Although rare, iatrogenic vascular injuries during PDN are serious complications that can be fatal without rapid diagnosis and effective management. Here, we present the case of a 38-year-old male patient with an injury to the right fifth lumbar artery that occurred during PDN, which was successfully treated using emergent transarterial embolization. To the best of our knowledge, this is the first report of successful transarterial embolization without open hematoma evacuation for a lumbar artery injury that occurred during PDN."} +{"text": "Regulatory T cells (Treg) are a major immunosuppressive cell subset in the pancreatic tumor microenvironment. Tregs influence tumor growth by acting either directly on cancer cells or via the inhibition of effector immune cells. Treg cells form a partially redundant network with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) that confer robustness to tumor immunosuppression and resistance to immunotherapy. The results obtained in preclinical studies, whereupon Treg depletion, MDSCs concomitantly decreased in early tumors whereas an inverse association was seen in advanced PCa, urge a comprehensive analysis of the immunosuppressive profile of PCa throughout tumorigenesis. One relevant context to analyse these compensatory mechanisms may be patients with locally advanced PCa undergoing neoadjuvant therapy (neoTx). In order to understand these dynamics and to uncover stage-specific actional strategies involving Tregs, pre-clinical models that allow the administration of neoTx to different stages of PCa may be a very useful platform.+ myofibroblastic cancer-associated fibroblasts (myCAF) and increased proportions of CD8+ cytotoxic T lymphocytes in the tumor. In order to understand these dynamics and to uncover stage-specific actional strategies involving Tregs, pre-clinical models that allow the administration of neoTx to different stages of PCa may be a very useful platform.Regulatory T cells (Treg) are one of the major immunosuppressive cell subsets in the pancreatic tumor microenvironment. Tregs influence tumor growth by acting either directly on cancer cells or via the inhibition of effector immune cells. Treg cells mechanisms form a partially redundant network with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) that confer robustness to tumor immunosuppression and resistance to immunotherapy. The results obtained in preclinical studies where after Treg depletion, MDSCs concomitantly decreased in early tumors whereas an inverse association was seen in advanced PCa, urge a comprehensive analysis of the immunosuppressive profile of PCa throughout tumorigenesis. One relevant context to analyse these complex compensatory mechanisms may be the tumors of patients who underwent neoTx. Here, we observed a parallel decrease in the numbers of both intratumoral Tregs and MDSC after neoTx even in locally advanced PCa. NeoTx also led to decreased amounts of \u03b1SMA PCa is one of the deadliest human neoplasms and is projected to become the second leading cause of cancer-related death worldwide by 2030 . Its poo+CD25+Foxp3+ T cells, are a subpopulation of lymphocytes that are crucial in maintaining tolerance to self-antigens and innocuous foreign antigens under physiological conditions, but can also be co-opted by tumor cells to avoid the host immune response . TAM. TAM+ mypatients .Even in locally advanced tumors, perioperative chemotherapy led to a parallel decrease in both Treg and MDSC which was associated with tumor shrinkage and prolonged survival. The results obtained in preclinical studies where after Treg depletion, MDSCs concomitantly decreased in early tumors whereas the inverse association was seen in advanced PCa, urge a comprehensive analysis of the phenotype and frequency of these major immunosuppressive cell subsets through pancreatic tumorigenesis. Such a \u201chuman\u201d example demonstrates that the reaction of Treg cells and MDSC in locally advanced PCa may not actually be antagonistic but concurrent, and that these two immune cell populations should not be perceived as being mutually suppressive or substituting. The question whether the compensatory network between Treg cells and MDSCs intensifies in patients with late-stage metastatic PCa, remains yet unexplored.Therefore, the underlying mechanisms behind the complex interplay between myeloid cells and Treg cells still needs further elucidation . A bette"} +{"text": "Our results imply that microorganisms classically considered as sulfate reducers control the potential for DNRA within coastal sediments when redox conditions oscillate and therefore retain ammonium that would otherwise be removed by denitrification, exacerbating eutrophication.The oscillating redox conditions that characterize coastal sandy sediments foster microbial communities capable of respiring oxygen and nitrate simultaneously, thereby increasing the potential for organic matter remineralization, nitrogen (N)-loss and emissions of the greenhouse gas nitrous oxide. It is unknown to what extent these conditions also lead to overlaps between dissimilatory nitrate and sulfate respiration. Here, we show that sulfate and nitrate respiration co-occur in the surface sediments of an intertidal sand flat. Furthermore, we found strong correlations between dissimilatory nitrite reduction to ammonium (DNRA) and sulfate reduction rates. Until now, the nitrogen and sulfur cycles were assumed to be mainly linked in marine sediments by the activity of nitrate-reducing sulfide oxidisers. However, transcriptomic analyses revealed that the functional marker gene for DNRA (nrfA) was more associated with microorganisms known to reduce sulfate rather than oxidise sulfide. Our results suggest that when nitrate is supplied to the sediment community upon tidal inundation, part of the sulfate reducing community may switch respiratory strategy to DNRA. Therefore increases in sulfate reduction rate in-situ may result in enhanced DNRA and reduced denitrification rates. Intriguingly, the shift from denitrification to DNRA did not influence the amount of N The permeable sandy sediments that fringe coastlines act as highly effective biocatalytic filters that remineralize organic carbon, and remove fixed nitrogen through denitrification \u20135. The mMany of the microorganisms within permeable sediments appear to be adapted to the oscillating oxic and anoxic conditions . Such adTypically, microorganisms in marine sediments employ different electron acceptors over depth, largely in accordance with their decreasing energy yield, which often leads to an apparent spatial separation of sulfate reduction from nitrate reduction \u201324. ThisSeveral lines of evidence suggest that sulfate reduction in intertidal permeable sediments should be tolerant of nitrate. Sulfate reducers are present and highly active in the upper layers of sediment, even though this area is frequently exposed to both nitrate and oxygen , 37\u201340. Desulfovibrio vulgaris can prevent this competitive inhibition of sulphite reductase via constitutive expression of periplasmic cytochrome c nitrite reductase (Nrf) to remove the nitrite, although there are contrasting reports as to whether this is also linked to energy generation http://enSupplementary InformationSupplementary Tables 4, 5"} +{"text": "Cancer therapies for older adults have accelerated at breakneck speed in the last few decades, necessitating evaluation of their delivery and uptake to ensure patients receive their maximum benefit. Among the vast array of evaluation tools available, those utilizing naturally occurring data\u2014data produced without intervention from a researcher\u2014are a powerful but underused tool. In this presentation, we will review two methods for examining naturally occurring data, participant observation and conversation analysis (CA), in an educational intervention study of multiple myeloma patients receiving autologous stem cell transplant. First, we will review how participant observation of nurse-led education visits (n=70) was incorporated to iteratively improve video-based education. Next, we will review use of CA in reviewing audio recordings containing reference to the education videos of 12 nurse-led education visits (1011 minutes of audio). Ultimately, understanding the purposes of and ways of using naturally occurring data have potential for improving the evaluation of patient education."} +{"text": "For this qualitative, pilot study, seven Massachusetts nursing home Directors of Nursing (DONs) were interviewed remotely about palliative care provision before and during the COVID-19 pandemic. Interview data were analyzed using thematic analysis. Palliative care addresses physical, emotional, psychological, and spiritual suffering that accompanies serious illness. Symptom management and goals of care is especially valuable for seriously ill nursing home residents. We investigated the solutions nursing home staff developed to provide palliative care during the COVID-19 pandemic despite restrictions on external resources. Before the pandemic, palliative care was delivered primarily by nursing home staff depending on formal and informal consultations from palliative care specialists affiliated with hospice providers. When COVID-19 lockdowns precluded these consultations, nursing staff did their best to provide palliative care, but were often overwhelmed by shortfalls in resources, resident decline brought on by isolation and COVID-19 itself, and a sense that their expertise was lacking. Advance care planning conversations focused on hospitalization status and options for care given COVID-19 resource constraints. Nevertheless, nursing staff discovered previously untapped capacity to provide palliative care on-site as part of standard care, building trust of residents and families. Nursing staff rose to the palliative care challenge during the COVID-19 pandemic, albeit with great effort nursing home payment and quality standards should support development of in-house staff capacity to deliver palliative care while expanding access to the formal consultations and family involvement that were restricted by the pandemic."} +{"text": "The population of family caregivers (FCGs) of persons with Alzheimer's Disease and related Dementias (ADRD) is growing, as is the proportion of males taking on this traditionally female role. Most caregiving research has mainly focused on females. Although female caregivers have reported more negative outcomes, men still report significant levels of burden. With the aging population and increased need for caregivers, there is a gap in knowledge exploring the male caregiving experience. Understanding male caregiving experiences can inform clinicians on developing future strategies to tailor support for this underrepresented group. The purpose of this qualitative descriptive study was to explore the experiences of male FCGs of people with ADRD. The Caregiver Identity Theory (CIT) was used to guide the study exploring participants\u2019 perception of self-identity within their caregiving relationship and self-identity as a male. Eleven male caregivers, recruited through social media and community resources, were interviewed by telephone or Zoom. Interviews were recorded, transcribed, and analyzed using thematic analysis. Four major themes emerged highlighting males\u2019 struggles with the unfamiliar caregiving role and changing identity; their acknowledgement of personal growth and discovery through caregiving, challenges in finding the \u201cright\u201d kind of support, and perceived reshaping of masculinity through the caregiving role. Male caregivers express unique experiences as FCGs suggesting future research is needed to explain gender differences in caregiving and identify additional factors that influence male caregivers\u2019 experiences. Furthermore, findings indicate clinicians should tailor support strategies for male FCGs\u2019 as they fulfill this potentially unfamiliar role."} +{"text": "Molecular psychiatry research needs a deeper characterization of emotional and cognitive neural underpinnings, along with a broader recognition of trauma-related circuitries and their involvement in shared pathological endophenotypes. One such endophenotype is unbalanced approach avoidance conflict (AAC), a highly recurrent trait of psychopathology. A translationally validated rodent model of AAC is the elevated plus maze (EPM) test, recently shown to be pharmacologically controlled in human and rodents via homologous neural substrates. Thanks to this test, we identified the involvement of the epigenetic enzyme LSD1 as a molecular restrainer of anxiety. We identified LSD1 aberrant regulation within the hippocampus of suicidal victims, suggesting its broad functional involvement in maladaptive behaviors. Interestingly, thanks to the parallel employment of rodent models, we evaluated a stress-related LSD1 homeostatic regulation that transiently limits memory formation-instrumental gene expression in the hippocampus upon trauma. Our work shed new light on epigenetic processes devoted to trauma resiliency through a negative regulation of anxiety plasticity.No significant relationships."} +{"text": "This quantitative cross-sectional sub project investigated the effects of organizational context and individual characteristics on psychological empowerment of care aides working in nursing homes. We analyzed data collected from 3765 care aides from 91 nursing homes across Western Canada between 09/2019 and 03/2020. From the random-intercept mixed effects regression models we identified significant predictors at different levels for each component of psychological empowerment. At the organizational outer context level: region and home ownership model. At the inner context (care unit) level: formal interactions , evaluation , culture , communication , and social capital . At the individual level: care aides\u2019 sex, language and job satisfaction.These findings suggest important ways in which contextual elements may influence staff quality of work life characteristics and underscore the need to consider context operating at different levels, as well as consider individual and contextual interaction."} +{"text": "Area-level residential instability (ARI), an index of social fragmentation, has been shown to explain the association between urbanicity and psychosis. Urban upbringing has been shown to be associated with decreased gray matter volumes (GMV)s of brain regions corresponding to the right caudal middle frontal gyrus (CMFG) and rostral anterior cingulate cortex (rACC).We hypothesize that greater ARI will be associated with reduced right posterior CMFG and rACC GMVs.Data were collected at baseline as part of the North American Prodrome Longitudinal Study. Counties where participants resided during childhood were geographically coded using the US Censuses to area-level factors. ARI was defined as the percentage of residents living in a different house five years ago. Generalized linear mixed models tested associations between ARI and GMVs.This study included 29 HC and 64 CHR-P individuals who were aged 12 to 24 years, had remained in their baseline residential area, and had magnetic resonance imaging scans. ARI was associated with reduced right CMFG and right rACC volumes . The interaction terms (ARI X diagnostic group) in the prediction of both brain regions were not significant, indicating that the relationships between ARI and regional brain volumes held for both CHR-P and HCs.Like urban upbringing, ARI may be an important social environmental characteristic that adversely impacts brain regions related to schizophrenia.No significant relationships."} +{"text": "Ancestral sequence reconstruction (ASR) infers predicted ancestral states for sites within sequences and can constrain the functions and properties of ancestors of extant protein families. Here, we compare the likely sequences of inferred nitrogenase ancestors to extant nitrogenase sequence diversity. We show that the most-likely combinations of ancestral states for key substrate channel residues are not represented in extant sequence space, and rarely found within a more broadly defined physiochemical space\u2014supporting that the earliest ancestors of extant nitrogenases likely had alternative substrate channel composition. These differences may indicate differing environmental selection pressures acting on nitrogenase substrate specificity in ancient environments. These results highlight ASR's potential as an in silico tool for developing hypotheses about ancestral enzyme functions, as well as improving hypothesis testing through more targeted in vitro and in vivo experiments. Ancestral sequence reconstruction (ASR) is widely used for modeling sequence properties and functions of ancient enzyme variants. Maximum-likelihood reconstructions combine substitution models with aligned sequence data and phylogenetic information to calculate the residue likelihood of aligned sites for all internal nodes in a tree . This apNitrogen-fixing nitrogenases are the lynchpin of Earth's biological nitrogen cycle, and have been extensively studied for their role in global biogeochemistry . Modern 2) fixation, modern nitrogenases can promiscuously reduce other linear, triple-bond-containing molecules at the FeMoCo active site (2), carbon monoxide (CO), acetylene (C2H2), and hydrogen cyanide . A library of plausible sequence ancestors for this collection of sites was generated, and their relative probabilities calculated. We applied a simple hypothesis-testing strategy: Are likely ancestral active site sequence states found within sampled extant nitrogenase diversity? We find that this is not always the case, permitting the possibility that early nitrogenase ancestors had substrate binding channels with properties distinct from modern enzymes.A higher affinity for alternative substrates in ancestral nitrogenases would likely require different amino acid residues in the substrate-binding part of the enzyme (the substrate channel), while preserving catalytic activity. As ASRs are inherently probabilistic, individual sites may be inferred to have several possible ancestral states with non-negligible probabilities. Variation across sampled extant diversity allows the combinations within likely ancestor sequences to explode, producing a far greater number of plausible sequence ancestors than can be experimentally tested. Here, we use ASR to reconstruct the amino acid identities of alignment sites directly interacting with the substrate binding channel in the common ancestor of the active site-containing nitrogenase subunit (Azotobacter vinelandii Nif (P > 0.10) in the predicted nitrogenase ancestor and Group II Nif of reconstructed ancestors contained substitutions yielding a combination not represented by extant sequences or physicochemical types . Of the The effects of substitution models and topology on predicted ancestor sequence and type were also evaluated by repeating tree construction and ASR under WAG + R10 (the highest likelihood non-LG model) and BLOSUM62 + R10 . Substitution models slightly impacted recovered tree topologies within recently diverged lineages but did not alter phylogenetic relationships between major nitrogenase types and their outgroups. Relative likelihoods for specific amino acids are generally conserved at sites 495, 496, and 603, and sample the same plurality at site 576 and site 348 . MoreoveChloroflexales bacterium ZM16-3. The top ten most-likely ASR residue combination physicochemical types were represented by very few extant sequences, and only within the divergent group of Nif that also contains the alternative nitrogenases. Divergent homologs within this clade may sample ancestral sequence patterns to a greater extent than type I or II nitrogenases. If so, characterizing these extant genes could provide useful analogs for ancestral phenotypes.These results suggest that the inferred ancestor of Nif, Vnf, and Anf nitrogenases most likely contained a substrate channel sequence distinct from that found in extant sequence space. Twenty-two of the 23 highest likelihood sequence combinations of the five variant substrate channel ancestral sites are not observed within known modern nitrogenases; the only represented sequence pattern occurs in only one observed extant enzyme, that of The conservative substitutions observed in the highest likelihood predicted ancestors are unlikely to radically influence substrate affinity or binding, at least when compared with the extant enzymes in the Nif/Anf/Vnf group. In the case of HCN, for example, because both modern Vnf and Nif Extant nitrogenases that remain unsampled and excluded from the tree could contain currently missing high-likelihood sequence combinations in the ASR. Additionally, likelihood ratios calculated from only a handful of sites do not represent overall sequence likelihoods, as site likelihoods are calculated independently. Thus, the most-likely ancestral site combinations in the substrate channel are unlikely to identify the sequence in the most-likely overall ancestor. However, the likelihood calculations for these substrate binding sites may be more informative for inferring ancestral phenotype changes than the overall ancestral sequence of the enzyme. Indeed, physicochemical type combinations predicted by the ASR are more robust to changes in substitution model and tree topology than sequence-level variation ; this unThe results highlight the value of ASR as a first step in evaluating enzyme evolution hypotheses. In some cases, ASR itself may prove sufficient to refute certain evolutionary hypotheses; for example predicted ancestral states may be sterically incompatible with hypothesized substrate interactions or protein folding. Such results would preclude additional experimental work. It is also possible that when ASR fails to identify combinations of key ancestral residues absent from extant diversity, the null hypothesis of uniform phenotype across the reconstructed history should be preferred. However, even in this case, ASR will efficiently identify key sites to target for mutagenesis for in vitro or in vivo analyses\u2014such as the novel sequence and type combinations sampled in this work.A. vinelandii (WP_012698832.1). Hits were included for molybdenum (NifD), vanadium (VnfD), and iron-only (AnfD) nitrogenases and manually curated to remove partial sequences, prune oversampled clades, and ensure the presence of conserved sequence features known to be critical for N2 reduction . The curated initial data set included 385 nitrogenase sequences and 385 outgroup sequences from light-independent protochlorophyllide oxidoreductases (nfaD; nif/anf/vnf ancestor as an internal node in the tree. The tree was rooted along the split between nitrogenases and the other oxidoreductases. Maximum-likelihood tree construction and subsequent ASR were performed in IQ-Tree (An initial data set of extant nitrogenase D-subunit homologs was constructed from hits gathered using BLASTp to search NCBI's non-redundant protein database with a query sequence from ductases . These iductases . Outgroues nfaD; was prof IQ-Tree , under t"} +{"text": "Transitions of care also exist within the operating room and contribute to an increased risk of adverse events.Hospitalized patients with severe infections may warrant intravenous (IV) antibiotics and surgical intervention for effective treatment of their infection. Surgical interventions require multiple transitions of care, which are well-studied sources of medication-related errors and inappropriate antimicrobial use. Furthermore, intraoperative bacteremia is common during elective surgeries. For patients requiring surgery for infection source control, maintaining adequate serum antibiotic levels may be particularly important in preventing bacteremia while infected tissue is surgically manipulated.Errors in antibiotic use in the perioperative period may negatively affect patient outcomes. Patients who experience diminished serum and tissue concentrations of antibiotics during surgical closure have higher risks of postoperative wound infections. no studies have investigated perioperative antibiotic use for inpatients already on IV antibiotic regimens. The lack of guidelines introduces further complexity because it allows for additional and potentially inappropriate antibiotic administration for patients already receiving broad-spectrum antibiotics. In this study, we examined the incidence and nature of inappropriate antibiotic use in the perioperative period among inpatients on IV antibiotic regimens.Although data exist on optimal timing of antibiotic administration for surgical antimicrobial prophylaxis,We conducted a retrospective cross-sectional study at a Veterans\u2019 Affairs medical center. We included all inpatients who underwent noncardiac surgery in 2019 who were aged >18 years or older and were on an IV antibacterial regimen prior to surgery. Patients receiving only surgical antimicrobial prophylaxis were excluded. Study and waiver of consent were approved by the Institutional Review Board of the VA Ann Arbor Healthcare System.Through manual chart review by 2 physicians, we collected information on prescribed IV antibiotic regimens and timing of antibiotic doses in the perioperative period. Errors were classified as follows: missed doses, delayed doses, additional doses of prescribed IV antibiotics, or additional surgical antimicrobial prophylaxis. Delayed antibiotics were administered between 2 and 4 hours after the scheduled administration time, and missed antibiotics were either omitted or administered at least 4 hours after the scheduled administration time. Administration of surgical antimicrobial prophylaxis was defined as an error in patients already receiving IV antibiotics with the same or broader antimicrobial coverage.Of the 290 inpatients who underwent surgery in 2019, 163 patients (56%) received an IV antibiotic regimen prior to surgery. Complete data were available for 153 patients (94%). Errors in antibiotic administration in the perioperative period were identified in 60 patients (39%). The most common error was a missed dose of an IV antibiotic, which occurred in 22 patients (39% of errors) was a missed dose of an antibiotic. Also, antibiotic overuse accounted for 36% of errors. For example, patients already on broad-spectrum antibiotics for their infection were given additional antibiotics for surgical site infection prophylaxis. We suspect that these errors are related to the multiple transitions of care in the perioperative period. Some errors are also likely related to documentation of medications administered during an anesthetic in a separate part of the electronic medical record than medications administered on the hospital ward.This study had several limitations. This was a single-center, retrospective study, and including multiple VA institutions would be a powerful next step. Second, the generalizability of these results may be limited because institutions using other electronic medical records may have different processes for documentation. However, we believe that the presurgical period in a patient\u2019s hospitalization represents an underrecognized opportunity for antimicrobial stewardship given the transitions of care involved. and misuse of antibiotics is common in these patients. Education-based stewardship interventions and clinical decision support tools implemented in surgical units have been shown to lead to reductions in antimicrobial consumption and improved trends in percentages of resistant bacterial strains. However, research evaluating interventions that specifically target perioperative antibiotic misuse for inpatients already on antibiotics for active infections is limited. This period may present a valuable opportunity for multidisciplinary stewardship intervention. Collaboration between antimicrobial stewardship programs, anesthesiology, and surgery departments should be encouraged to improve local practices in perioperative antibiotic prescribing and to address systems-based challenges that lead to inappropriate antibiotic use. Further research will be essential to the evaluation of outcomes of patients who experience errors in perioperative antibiotic administration.In conclusion, surgical patients account for significant proportions of inpatient antibiotic use,"} +{"text": "Socioemotional theories suggest that surviving challenging experiences enhances emotional resilience with age, yet the role of memories is overlooked in most models of emotion regulation. In parallel, cognitive accounts focus on age-related memory deficits associated with overlapping hippocampal neural representations across unique memories . We propose a novel framework supporting enhanced late-life reappraisal via hippocampal dedifferentiation of memory representations across current and past experiences. We review classic studies supporting mood benefits from integrated positive narratives following adverse autobiographical events. We also discuss multivariate neuroimaging evidence supporting overlapping hippocampal representations and ventromedial prefrontal cortex (vmPFC) involvement in meaning-making processes. We posit that greater hippocampal dedifferentiation across life memories may facilitate associative binding of current and past stressors as well as reappraisals in vmPFC. This process may provide avenues for generalizing past reappraisals to novel contexts and reducing cognitive demands of reappraisal. In addition, we discuss the possible age-related facilitation of this process, as a greater number of life experiences may become increasingly integrated with one another over the lifespan. These integrated neural associations may serve to make reappraisals from the past more readily accessible and applicable in new contexts over time, increasing routes to positive narratives following stress. We discuss future directions for testing components of the proposed model using multivariate neuroimaging methods. We conclude by briefly reviewing the possible clinical impact of mnemonic emotion regulation in promoting emotional well-being among older adults, using a strengths-based approach that leverages wisdom from experience and neural processes facilitated with age."} +{"text": "Despite growing research linking stressors with poorer cognition, less research explicitly considers stress from several sources, which often co-occurs and accumulate to influence health. We used the Global Gateway Harmonized data to examine whether higher cumulative stress is associated with lower levels of and faster decline in cognitive function. We fit linear mixed effect models to assess the stress-cognition associations. After adjusting for all covariates, baseline cumulative stress was associated with lower baseline cognitive function in both HRS and ELSA . Unexpectedly, higher baseline cumulative stress was associated with slower cognitive decline in HRS but not in ELSA. The stress-cognition associations may differ among adults in the US and the UK. Future research should investigate how cumulative stress may operate differently to influence cognitive function across different populations."} +{"text": "Developmental theories suggest that midlife and older adulthood are stages in which individuals may begin to focus their time on contributing to society . During these stages, individuals may engage in socially responsible behaviors that protect against negative affect resulting from a lower sense of purpose in later life . Social responsibility includes both subjective measures of an individual\u2019s felt contribution to society and objective measures reporting actual time volunteering in different settings . We utilized data from the Midlife in the United States Refresher survey study and Biomarker Project to explore how self-perceptions of generativity and time spent volunteering predicted negative affect for individuals in midlife and older adulthood. Preliminary analyses indicate that higher generativity (p<.001) and older age (p<.001), but not average time spent volunteering, were associated with higher negative affect. Further, we considered age as a potential moderator for the associations between generativity, volunteering, and negative affect. Age significantly interacted with generativity (p<.01), such that the effects of generativity on reducing negative affect decrease with age. Age did not significantly interact with time spent volunteering. Discussion will focus on how actual engagement in socially responsible behaviors and perceived societal contributions might yield different outcomes regarding protection against negative affect in mid- and later-life. Future directions may include exploring daily indicators of time spent volunteering, generative beliefs, and affect."} +{"text": "The purpose of this study is to determine whether a 12-week exercise course influences obese African American older women\u2019s health capabilities and life satisfaction levels. Participants, who passed an initial screening and pre-assessment, were asked to measure current health capabilities and life satisfaction levels both prior to, and following, the 12-week exercise training. Researchers found that improvement in health capabilities, although there were no significant differences following exercise training participation, while obese African American older women had significantly higher life satisfaction levels. The findings suggest that a 12-week exercise training can be beneficial to enhance obese African American older women\u2019s health capabilities and life satisfaction levels. Professionals in the field of gerontology and exercise should provide the appropriate exercise trainings so that obese African American older women would be able to optimize their life satisfaction levels."} +{"text": "Sarbecovirus), given that several closely related viruses have been discovered and sarbecovirus\u2013host interactions have gained attention since SARS-CoV-2 emergence. We assessed sampling biases and modelled current distributions of bats based on climate and landscape relationships and project future scenarios for host hotspots. The most important predictors of species distributions were temperature seasonality and cave availability. We identified concentrated host hotspots in Myanmar and projected range contractions for most species by 2100. Our projections indicate hotspots will shift east in Southeast Asia in locations greater than 2\u00b0C hotter in a fossil-fuelled development future. Hotspot shifts have implications for conservation and public health, as loss of population connectivity can lead to local extinctions, and remaining hotspots may concentrate near human populations.Global changes in response to human encroachment into natural habitats and carbon emissions are driving the biodiversity extinction crisis and increasing disease emergence risk. Host distributions are one critical component to identify areas at risk of viral spillover, and bats act as reservoirs of diverse viruses. We developed a reproducible ecological niche modelling pipeline for bat hosts of SARS-like viruses (subgenus Global Rhinolophus affinis , Rhinolophus marshalli (virus BANAL-236) and Rhinolophus pusillus (virus BANAL-103) ..SarbecovRhinolophus pearsonii . Most species' populations are currently declining (n = 8) or have unknown population trends . Local species loss values were almost twice the number of maximum gain . Along with climate change mitigation, strategies for maintaining landscape-level habitat connectivity will allow populations to reach refugia and lower extinction risk. This could be done by developing landscape connectivity surfaces that maximize diversity hotspot extensions, with monitoring effective dispersal through genetics [There are conservation implications from our findings. Range contractions are projected for several species, even for species using variable habitats, such as genetics ,86 and pgenetics .Our results identify broad regions where bats reported positive for sarbecoviruses most probably occur and co-occur. These hotspots coincide, but are not restricted only to Rhinolophidae diversity hotspots and to hOur future projections assume models using present data perform adequately. However, our models do not account for biotic components that also interfere with suitability, so we are limited to inferences of distribution derived from landscape and climate drivers. Projections will therefore need validation with new data and new predictions. Related, small changes may be relevant for local health and conservation initiatives, and coronavirus hosts are a focus of increasing research . Data ch"} +{"text": "Candida albicans, non-albicans strains including C. auris, Aspergillus and Fusarium isolates from worldwide sources.ARIA is a new annual global surveillance initiative collecting yeast and fungal isolates from worldwide designed to determine resistance to antifungal agents and trends over time. The ARIA program was developed in 2020 to provide a repository of recent clinical fungal isolates with known susceptibility profiles and to monitor resistance trends over time. ARIA reports the susceptibility patterns of its earliest data concerning echinocandins, second-generation triazoles, and fluconazole against clinical Isolates were collected from hospital worldwide during 2020, shipped to a central laboratory and re-identified by MALDI-TOF or molecular methods. MIC tests were performed by broth microdilution method in line with CLSI susceptibility testing standards. Percentage of susceptibility was calculated according to CLSI breakpoints. Antifungals tested were amphotericin B (AMB), anidulafungin (ANID), fluconazole (FLU), isavuconazole (ISA), micafungin (MIC), posaconazole (POS), and voriconazole (VOR). All testing was performed according to CLSI M27-A4 and M38-A2 methodologies.See table.Ongoing antifungal resistance surveillance like the ARIA program is of utmost importance in order to monitor the efficacy of traditional empirical therapy and for the development of novel antifungal agents. This repository and ongoing ARIA program will provide a resource to better support the biopharmaceutical industry\u2019s goals to develop new and more potent antifungal agents.All Authors: No reported disclosures."} +{"text": "Are nursing homes exposed to potential hurricane-related inundation more likely to meet Centers for Medicare & Medicaid Services criteria for adequate emergency preparedness?In this cross-sectional study of 5914 nursing homes, a higher prevalence of emergency preparedness deficiencies among nursing homes exposed to hurricane-related inundation in the Mid-Atlantic region was observed. Exposure status remained positively associated with the presence and number of emergency preparedness deficiencies after adjustment for facility characteristics, with the converse for facilities within the Western Gulf Coast.These findings suggest opportunities to reduce regional heterogeneity and improve the alignment of nursing home emergency preparedness with surrounding environmental risks. This cross-sectional study estimates the prevalence of nursing homes that are subject to severe hurricane-related inundation within the Coastal Atlantic and Gulf Coast states and evaluates whether exposure status is associated with adherence to emergency preparedness standards across regulatory regions. Whether US nursing homes are well prepared for exposure to hurricane-related inundation is uncertain.To estimate the prevalence of nursing homes exposed to hurricane-related inundation and evaluate whether exposed facilities are more likely to meet Centers for Medicare & Medicaid Services (CMS) emergency preparedness standards.This cross-sectional study included CMS-certified nursing homes in Coastal Atlantic and Gulf Coast states from January 1, 2017, to December 31, 2019. The prevalence of facilities exposed to at least 2 feet of hurricane-related inundation used models from the National Hurricane Center across coastal areas overseen by 5 CMS regional offices: New England, New York metropolitan area, Mid-Atlantic region, Southeast and Eastern Gulf Coast, and Western Gulf Coast. Critical emergency preparedness deficiencies cited during CMS life safety code inspections were identified.The analysis used generalized estimating equations with binomial and negative binomial distributions to evaluate associations between exposure status and the presence and number of critical emergency preparedness deficiencies. Regionally stratified associations (odds ratios [ORs]) and rate ratios [RRs]) with 95% CIs, adjusted for state-level fixed effects and nursing home characteristics, were reported.Of 5914 nursing homes, 617 (10.4%) were at risk of inundation exposure, and 1763 (29.8%) had a critical emergency preparedness deficiency. Exposed facilities were less likely to be rural, were larger, and had similar CMS health inspection, quality, and staffing ratings compared with unexposed facilities. Exposure was positively associated with the presence and number of emergency preparedness deficiencies for the nursing homes within the Mid-Atlantic region . Conversely, exposure was negatively associated with the number of emergency preparedness deficiencies among facilities within the Western Gulf Coast . The associations for the number of emergency preparedness deficiencies remained after correction for multiple comparisons.The findings of this cross-sectional study suggest that the association between exposure to hurricane-related inundation and nursing home emergency preparedness differs considerably across the Coastal Atlantic and Gulf regulatory regions. These findings further suggest that there may be opportunities to reduce regional heterogeneity and improve the alignment of nursing home emergency preparedness with surrounding environmental risks. It is also uncertain whether nursing homes at increased risk of exposure are adequately prepared to safeguard residents upon encountering environmental hazards.Nursing homes\u2019 emergency preparedness is vital due to projected increases in the frequency with which coastal communities are exposed to severe weather events.11 This requires that facility administrators and staff assess, document, and plan for potential hazards, including severe weather events, that are expected to impact their geographical region.11 Emergency preparedness is then audited by state survey agencies, which are overseen by CMS regional offices.11The paucity of information regarding nursing homes\u2019 preparedness for local environmental hazards may be attributed, in part, to the inherent complexity of characterizing small-area variation in environmental exposures. Because environmental exposures vary across communities, the Centers for Medicare & Medicaid Services (CMS) has advised an all-hazards approach to emergency preparedness.12 nursing home management and staff and the superstructure of state survey agencies and CMS regional offices may not be well positioned to appraise and prepare for potential environmental hazards. Therefore, the CMS encourages partnerships with municipal agencies to ensure that nursing homes are embedded within community disaster planning and response.13 Despite this recommendation, nursing home integration into community disaster preparedness efforts remains variable.15 Prior assessments of nursing home emergency preparedness, moreover, have identified widespread deficiencies in critical competencies that include appropriate specification of evacuation routes and preparedness to shelter residents in place.16 These preventable deficiencies heighten the risk of resident morbidity and mortality following exposure to severe weather events.17Considering their competing responsibilities,In this study, we estimate the prevalence of nursing homes that are subject to severe hurricane-related inundation within Coastal Atlantic and Gulf Coast states. We then evaluate whether exposure status is associated with adherence to emergency preparedness standards by nursing homes across regulatory regions overseen by 5 CMS regional offices. The results of this study should inform practices and policies designed to align nursing home emergency preparedness with the hurricane-related inundation risk to which facilities are exposed.STROBE) reporting guideline. This research was deemed exempt from review and informed consent by the Yale University Institutional Review Board under 45 CFR 46.104.This cross-sectional study followed the Strengthening the Reporting of Observational Studies in Epidemiology , leading to a final analytic sample of 5914 facilities.We utilized the CMS Provider Information Catalog to identify certified nursing homes within states that are at risk of exposure to hurricane-related inundation along the Coastal Atlantic and Gulf Coast regions as per the National Hurricane Center (NHC) (n\u2009=\u20096167).20 Our primary exposure threshold was informed by the US National Weather Service determination that roads are impassable at inundation heights above 18 to 24 inches,21 which would preclude the safe ground evacuation of residents and transport of essential medications or subsistence provisions. The NHC data do not project inundation within levee systems because its predictions are constrained to land that is normally dry.19 We classified the 46 nursing homes within leveed areas as exposed because levee systems are both subject to failure and concentrated in areas with disproportionate risk of severe flooding.22We defined exposed nursing homes as those at risk of at least 2 feet of inundation during Saffir-Simpson Hurricane Wind Scale category 1 to 5 hurricanes as per the NHC storm surge hazard maps.19 Briefly, the NHC storm surge hazard maps aggregate maximum inundation heights, assuming a high-tide initial water level.19 Storm surge events occur when the height of water generated by a storm rises above that of normal astronomical tides.19Inundation, the height of water above the ground surface, is estimated by subtracting the height of land elevation from that of the storm surge.19 The NHC uses the Sea, Lake, and Overland Surges from Hurricanes (SLOSH) model to simulate a representative sample of hypothetical storms, resulting in 2 data products.19 The first, maximum envelopes of water, represents the maximum inundation resulting from tens of thousands of hypothetical storms, with varying meteorological assumptions.19 The second represents the maximum composite value across the maximum envelopes of water.19The methods used by the NHC to model inundation have been described previously.23 From the 252 potential emergency preparedness deficiencies, we selected a subset deemed to be most critical in accordance with prior literature and emergency preparedness guidance . We used LTCFocus (Long-Term Care Focus) data to link lagged (2018) indicators of the payer mix and quantified the percentage of residents within each facility primarily insured by Medicaid.We first estimated the percentage of nursing homes at risk of exposure to at least 2 feet of hurricane-related inundation using their geocoded addresses. We described facility characteristics for the full sample and compared these characteristics among facilities according to their inundation exposure status. We also assessed the prevalence of critical emergency preparedness deficiencies across the nursing homes within each CMS regional office designation (described hereinafter).We evaluated associations between location within an inundation-exposed area and emergency preparedness deficiencies (presence and count) using generalized estimating equations with binomial and negative binomial distributions, respectively, clustered by facility identification numbers, with robust standard errors. To address potential confounding, the models were adjusted for facility characteristics.30 we included fixed effects for state within each stratified model. We used the Benjamini-Krieger-Yekutelli correction to account for multiple comparisons.31 In sensitivity analyses, we reran the models for the 5 regional office strata after increasing the severity of the inundation exposure threshold to at least 4 feet and at least 6 feet. We conducted analyses using ArcGIS Pro (Esri), Python, version 3 (Python.org), and Stata, version 17 (StataCorp LLC). Two-sided P\u2009<\u2009.05 indicated statistical significance.We stratified our analysis across the 5 CMS regional offices overseeing state survey agencies along the Coastal Atlantic and Gulf Coast. Regional office 1 of the CMS oversees New England ; regional office 2, the New York metropolitan area (New York and New Jersey); regional office 3, the Mid-Atlantic region ; regional office 4, the Southeast and Eastern Gulf Coast ; and regional office 6, the Western Gulf Coast (Louisiana and Texas). Regional office 5 was not evaluated because it oversees Midwestern states. To adjust for state-level variation in inspection practices and patterns,The most common emergency preparedness deficiencies among the 5914 nursing homes related to appropriate emergency preparedness training and procedures, as well as the establishment and maintenance of an emergency preparedness program , exposure status appeared to be protective against emergency preparedness deficiencies. New England facilities demonstrated a similar pattern for the presence and number of critical emergency preparedness deficiencies, although these associations were not statistically significant. The most prevalent deficiencies are related to the ability of nursing homes to safely shelter in place or evacuate residents. Especially concerning is the high prevalence of inadequate subsistence provisions or standby power systems, as these factors may prompt unnecessary evacuations and thereby compound risks to vulnerable residents.34 The stark regional variation in emergency preparedness by exposed nursing facilities suggests that it may be useful to isolate and disseminate the strategies used by nursing home administrators, staff, and regulators within high-performing regions.35 Because Western Gulf Coast nursing homes exhibited emergency preparedness adherence that was well aligned with the local environmental risks , they could potentially serve as a model for other regions. Possible explanations for the risk-responsive emergency preparedness of nursing homes in the Western Gulf Coast may include reforms following their prior experience in hurricane response.36 For example, Gulf Coast nursing home residents incurred substantial morbidity and loss of life in the wake of Hurricanes Katrina and Rita.36 Ensuing investigations determined that inadequate emergency preparedness and inappropriate evacuation decisions contributed to these costs, prompting increased federal, regional, and state oversight.37Considering the differential susceptibility of nursing home residents to external stressors, emergency preparedness should be better aligned with the likelihood and severity of exposure to environmental hazards, including hurricane-related inundation. Projected increases in the intensity and geographic distribution of hurricanes within coastal regions further heighten the importance of this issue.15 we suggest that state survey agencies and CMS regional offices consider stronger oversight and enforcement of these partnerships. Because it would be impractical for CMS regional offices to appraise and monitor environmental risks, partnerships with local and regional emergency planning agencies should be relied upon to identify facilities exposed to salient regional and local environmental hazards. In turn, regulators could identify which facilities should be prioritized for oversight based upon their historical audit performance. A regulatory framework that is responsive to environmental hazards might involve a relatively greater inspection frequency for facilities that have outstanding critical emergency preparedness deficiencies and are at disproportionate risk of exposure to regionally concentrated environmental hazards .15 Although facilities meeting these criteria should receive more intensive oversight, these changes may produce a cost-effective and more efficient allocation of oversight responsibilities.39 These partnerships may also offer valuable insight as to the alignment between facilities\u2019 exposure risk and their structural ability to withstand inundation, as determined by available building code guidance.40In addition to learning from high-performing regions, improved integration of nursing homes into local disaster planning agencies may better align emergency preparedness with the magnitude of environmental risks to which facilities are exposed. Based on our results, which support concerns that nursing homes may be poorly integrated into community disaster response models under the CMS all-hazards framework,41 Second, physical processes affecting water levels outside of the areas for which the SLOSH models are validated cannot be modeled.19 Because the storm surge hazard maps represent maximum inundation scenarios, without probabilities corresponding to hurricane category, it would be desirable to repeat this analysis with a broader range of risk scenarios as such data products become available. We refrained from incorporating assumptions regarding the respective probabilities of Saffir-Simpson Hurricane Wind Scale categories to avoid compounding uncertainties across distinct climate models as risk projections continue to evolve.42 Third, the NHC data are constrained to hurricane-related inundation and may, therefore, underestimate inundation exposure due to factors including heavy rainfall.43 It would be instructive to replicate this analysis using geospatial data that reflect the risk of severe flooding due to multiple potential causes.This study has some limitations. Our ability to classify exposure is restricted to information aggregated within the NHC storm surge hazard maps. The developers of this resource note several potential limitations regarding the assumptions required to build this product. First, the data products do not account for increases in water levels due to waves, which may result in the underestimation of inundation by 10% to 50%.We cannot exclude the possibility that state surveyors were more vigilant in issuing emergency preparedness deficiencies based on perceived inundation risk. To address this limitation, we conducted sensitivity analyses that evaluated associations between emergency preparedness and increasingly severe exposure thresholds. Because regulators\u2019 sensitivity to exposure increments has not been previously evaluated, we used a multiplicative scale to test the effect of large differences in inundation thresholds. Although the results of our additional analyses did not suggest a dose-response association between exposure severity and the likelihood of critical emergency preparedness deficiencies, they cannot rule out differences in the behavior of state surveyors or regional oversight practices.14 Nonetheless, the CMS standards subsume foundational competencies that are well aligned with national emergency preparedness guidance and prior literature.25 Moreover, inadequate emergency preparedness has contributed to adverse resident outcomes during prior emergencies due to severe weather events.2Our evaluation assumes that administrative deficiencies are reasonable indicators of nursing homes\u2019 emergency preparedness, but adherence to CMS emergency preparedness guidance does not necessarily ensure effective execution of organizational emergency planning or response.Additionally, the observational nature of this study precludes our ability to isolate organizational or regulatory behaviors and practices that may underlie regional differences in the emergency preparedness of nursing homes at increased risk of exposure to hurricane-related inundation. Complementary qualitative analyses may help to elucidate the mechanisms underlying regional variation and identify practices that better align emergency preparedness and local environmental risk.Ensuring adequate nursing home emergency preparedness is vital to the safety and well-being of vulnerable older persons, especially as community exposure to hurricane episodes is projected to increase. We demonstrated considerable regional variability in the emergency preparedness of nursing homes exposed to hurricane-related inundation. We observed an association between emergency preparedness and potential inundation exposure for Mid-Atlantic nursing homes, suggesting that these exposed facilities with critical emergency preparedness deficiencies should be prioritized for remediation. Given their competing responsibilities and lack of formal training in this domain, nursing home administrators and staff may require additional support with their assessment and response to environmental risks under an all-hazards approach. Based on our findings, CMS regional offices may need to enhance enforcement of nursing home partnerships with local emergency planning agencies, which are better equipped to appraise and address environmental risks. Finally, the favorable preparedness of nursing homes within the Western Gulf Coast region suggests that this region could serve as an exemplar of risk-responsive emergency planning and oversight."} +{"text": "Crisis management Managing crises often requires diverging from predetermined plans. In this paper, we investigate how public health authorities in Finland acted, what kind of roles they adopted and how the expected roles and actions appeared in relation to the legislative framework and preparedness plans during the COVID-19 pandemic. Based on inter-country comparisons, Finland has managed COVID-19 pandemic relatively well. The study provides qualitative insights on pandemic governance in a decentralized multi-stakeholder public health system.Semi-structured interviews (n = 53) with key public health actors at central, regional and local levels were conducted during March 2021-February 2022. The data was analysed with thematic analysis.The predetermined roles and duties for pandemic management were not unequivocal in practice and appeared unrealistic considering the resources of the public health system. Responsibility was divided between several actors, but lack of interaction enhanced emerging tensions between them. Local and regional actors experienced national steering intervening in operational decisions. At central level distrust towards the capabilities of local and regional actors was expressed. The pandemic was framed and managed as a health crisis despite of its wider societal effects. This challenged local and regional decision-making, where wider societal impacts had to be considered.Public health authorities in Finland interpreted their roles and responsibilities in pandemic governance in various ways: some actors adopted more active agency than others and the roles were not always in line with the existing regulative framework.\u2022\u2002Interpretation of the roles outlined in preparedness plans are context dependent and may lead to conflicts between different actors.\u2022\u2002In a system with multiple actors at multiple levels, building trust and improving interaction are important for coordinated action."} +{"text": "Prostate cancer (PCa) is the leading cause of male cancer deaths in Africa. In USA, African American men (AA) experience higher mortality rate compared to European American men (EA). While socioeconomics factors contribute toward these disparities, distinct molecular mechanisms in AA remain important drivers. For example, in previous work, we discovered that PCa form AA men harbored a significantly higher expression of Aminopeptidase N (ANPEP) as compared with EA. Aminopeptidase N regulates immune cell function and mediates tumor cell migration but its role in PCa remains uninvestigated.We explored ANPEP expression related to a range of genomic classifiers in multiple datasets. We then prospectively examined the differentially expressed genes in PCa tissues collected from 120 AA and 120 EA patients enrolled on the VANDAAM clinical trial. We further correlated ANPEP expression with various signatures related to immune and metabolic activity. We also experimentally examined the expression of ANPEP in different components of tumor microenvironment.In the VANDAAM study, ANPEP represents the top differentially expressed gene between AA and EA men. Our data driven approach revealed that ANPEP correlates with signature of cholesterol transport and androgen signaling. Interestingly, these signatures dominate in PCa with high macrophage infiltration. Deconvolution of immune cell content using computational approaches indeed demonstrated that only AA patients with high ANPEP expression significantly accumulated high content of inflammatory macrophages. Further experimental findings showed that ANPEP indeed represents a marker of tumor-associated macrophages, a type of immune cells known to contribute to PCa progression.We have identified ANPEP as a macrophage-related gene with a potential role in cholesterol metabolism and AR signaling in AA. Future work will focus on the functional role of ANPEP activity in the tumor immune microenvironment using Liquid chromatography-high resolution mass spectrometry and explants derived from AA and EA PCa patients."} +{"text": "Freezing of gait (FoG) is a paroxysmal and sporadic gait impairment that severely affects PD patients\u2019 quality of life. This review summarizes current neuroimaging investigations that characterize the neural underpinnings of FoG in PD. The review presents and discusses the latest advances across multiple methodological domains that shed light on structural correlates, connectivity changes, and activation patterns associated with the different pathophysiological models of FoG in PD. Resting-state fMRI studies mainly report cortico-striatal decoupling and disruptions in connectivity along the dorsal stream of visuomotor processing, thus supporting the \u2018interference\u2019 and the \u2018perceptual dysfunction\u2019 models of FoG. Task-based MRI studies employing virtual reality and motor imagery paradigms reveal a disruption in functional connectivity between cortical and subcortical regions and an increased recruitment of parieto-occipital regions, thus corroborating the \u2018interference\u2019 and \u2018perceptual dysfunction\u2019 models of FoG. The main findings of fNIRS studies of actual gait primarily reveal increased recruitment of frontal areas during gait, supporting the \u2018executive dysfunction\u2019 model of FoG. Finally, we discuss how identifying the neural substrates of FoG may open new avenues to develop efficient treatment strategies. There hAlthough FoG in PD patients is more prevalent when the patients are OFF dopaminergic treatment (60%) than when ON (36\u201338%) , FoG shoNotably, the prevalence of PD in our aging population is predicted to substantially increase by approximately 30% by 2030 , with a 1.1The knowledge about the neural mechanisms controlling human gait is still incomplete, mainly due to the complexity of the human locomotor system and the technical limitations of studying locomotion. Accordingly, the current knowledge about the neural control of human gait is primarily derived from animal models. Studies on gait regulation in animals revealed widespread neural circuitries spanning different nervous system levels, including cortical, subcortical, brainstem, and spinal cord structures . HoweverThe neural networks that govern human gait are organized in an evolutionary hierarchy see that proThe top of the gait control hierarchy comprises higher-level control centers in the cerebral cortex and the basal ganglia (BG) that modulate indirectly and directly the locomotor regions\u2019 activity in generating efficient volitional gait regulation. At rest, the globus pallidus internus (GPi) and the substantia nigra reticularis (SNr) provide constant GABAergic inhibitory signals to the MLR/PPN that restrict the information flow in the spinal cord and prevent unwanted movements. During motor activity, input from frontoparietal areas can amplify or reduce these inhibitory signals . In partIn conclusion, the neural systems underlying gait control in humans comprise complex mechanisms with intertwined structures, in which higher-order cortical areas indirectly regulate the output of the locomotor regions via established reciprocal connections with subcortical structures. This hierarchical bi-directional organization allows the human gait control system to adapt its motor output to changing intentions and environments flexibly. However, this flexible planning and execution of walking movements is deficient in PD patients since the underlying neurodegenerative disease process affects the gait control system at different levels.1.2Five non-exclusive pathophysiological models have been proposed to explain the origin of FoG in PD . These mabnormal gait pattern generation\u2019 hypothesis proposes that the asymmetric and uncoordinated gait preceding episodes of freezing . Due to the deficient cortico-subcortical crosstalk, the signals from the cognitive, motor, and limbic cortical areas overwhelm the limited processing capacity of the striatum in PD patients and lead to an overinhibition of brainstem structures, eventually manifesting in FoG (decoupling\u2019 between posture preparation (SMA) and step initiation (the motor cortex) causes multiple dysfunctional anticipatory postural adjustments that are manifested as knee trembling during FoG \u2018freezing results g in FoG . Anotherring FoG . The bre changes . This mo changes . Finallye of FoG . AccordiThe apparent heterogeneity of the mechanisms underlying FoG in PD proposed by the five non-exclusive pathophysiological models of FoG indicates that consensus on the neurological underpinnings of FoG is far from reach and, consequently, extensive research is warranted to unravel the complexities of this phenomenon. Studies employing imaging techniques contribute valuable new data for a better understanding of the physiology and pathophysiology of human gait control. Identifying major neural substrates of FoG may open new avenues for developing novel and efficient treatment strategies for FoG in PD patients. This review summarizes and critically evaluates the recent imaging studies on FoG in PD across multiple methodological domains to shed light on structural correlates, connectivity changes, and activation patterns associated with the pathophysiology of FoG in PD patients. Furthermore, the disparate imaging results are related to current pathophysiological models of FoG in PD. For a complementary review that discusses electrophysiological findings in light of the pathophysiological models of FoG, the reader is referred to the recent review by 2The review encompasses articles not previously covered or thoroughly discussed by recent reviews on FoG in PD patients . The incThe PubMed database and Google Scholar were used to collect the articles with the search queries \u2018Parkinson\u2019 AND \u2018Freezing of gait\u2019 AND . After a systematic assessment of the articles\u2019 eligibility, the total number of reported articles in this review is 40 articles. These articles were divided into 18 resting-state MRI studies , 13 task-based MRI studies , and 9 functional near-infrared spectroscopy (fNIRS) studies.In order to further assess the quality of evidence provided by the different imaging studies, we systematically graded each reported study based on six pre-defined criteria, i.e., studied sample, clinical groups, FoG/gait assessment, correction for multiple comparisons, control for differences in covariates, and experimental design structural connectivity investigate abnormalities in WM tracts by diffusion tensor imaging (DTI) and examine mainly mean diffusivity (Md) and fractional anisotropy (FA). Several findings have emerged from different WM connectivity studies, despite differences in experimental methods and analysis approaches, namely whole-brain voxel-wise analysis and region of interest (ROI) correlation analysis.Several structural connectivity studies report patterns of WM abnormalities that constitute potential biomarkers supporting the \u2018interference model\u2019, i.e., deficient crosstalk between cortical areas and the BG. Notably, structural imaging studies revealed a distributed pattern of reduced WM tracts connecting subcortical structures, encompassing the cerebellum , subthalper se but may be related to other confounding factors such as cognitive impairment and general (motor) deficits associated with Parkinson\u2019s disease.Other structural imaging studies align with the \u2018executive dysfunction\u2019 model of FoG, which proposes a decoupling between the frontal lobe and the BG. These studies report WM tract disruptions between frontal areas and subcortical structures and dist3.2A promising approach to investigate the neural mechanisms underlying FoG in PD patients is resting-state fMRI (rs-fMRI). This neuroimaging approach has been extensively used in studying the neural correlates of FoG in patients with PD as it permits the assessment of the whole brain without an experimental task. Rs-fMRI quantifies the functional connectivity between spatially disparate neural networks by detecting fluctuations in spontaneous BOLD signals across the whole brain . The parSeveral rs-fMRI studies reveal a reorganization of the intrinsic functional connectivity (FC) within higher cortical regions and subcIt is well established that PD patients, and those suffering from FoG in particular , rely moDysfunctional network connectivity between subcortical and cortical areas extended beyond cognitive and sensorimotor areas, also affecting visuospatial networks. In PD patients with FoG, abnormal FC was observed between the visual cortex, mainly of the right hemisphere, and left caudate , right PSeveral studies converge in reporting a decrease in resting-state FC between several cortical areas along the dorsal stream of visuomotor processing . In partThe significant findings derived from resting-state fMRI (rs-fMRI) studies primarily support the \u2018interference\u2019 or the \u2018perceptual dysfunction\u2019 models of the pathophysiology of FoG in PD. These findings should nevertheless be treated with caution, given several inherent limitations of the rs-fMRI method in FoG in PD. On the one hand, rs-fMRI studies of FoG mainly adopt a cross-sectional approach that compares the neurophysiological changes of PD patients with FoG with those of healthy controls or PD patients without FoG at a given time. A fundamental shortcoming of such a cross-sectional approach is the failure to consider the contribution of interindividual variability in FoG severity within groups of PD patients with FoG. In particular, the sole comparison of resting-state FC changes in PD patients with FoG versus healthy controls can be even more problematic than the comparison of PD patients with FoG with PD patients without FoG, as the former comparison cannot differentiate between specific neuroanatomical/-physiological changes related to FoG and those related to other more general deficits in Parkinson\u2019s disease. To circumvent these limitations of cross-sectional approaches, the alternative study design adopted by On the other hand, rs-fMRI studies can only indirectly correlate resting state FC to FoG measures, as these studies relate neurophysiological changes measured when lying supine in the MRI scanner to objective or subjective gait assessments obtained outside the scanner. Except a few studies that related resting-state FC changes with objective measures of FoG recorded during a turning or walking task before the scanning session, most of the rs-fMRI studies on FoG in PD related resting-state FC changes with subjective self-reports of FoG, i.e., using the FoG-Questionnaire. However, the reliability of subjective recall of FoG symptoms may be hampered by cognitive deficits. An alternative objective assessment tool of FoG that can be considered in future rs-fMRI studies is the rating instrument developed by 4Task-based fMRI studies can detect real-time correlations of neurophysiological alterations with gait-related performance measured during the scanning session. These studies mainly adopt virtual reality (VR) and motor imagery (MI) paradigms that correlate neurophysiological changes with foot-pedaling performance and with the mental simulation of pre-instructed (gait-related) actions, respectively. In addition to VR and MI paradigms, a recent study adopted a novel paradigm of dorsal or plantar foot-flexion movement in response to auditory stimuli, which meant to approximate the sensorimotor activity during normal gait without inducing episodes of FoG . Importa4.1In combination with functional neuroimaging, virtual reality (VR) paradigms were used in several studies to explore the underlying pathophysiology of FoG in PD patients. Virtual reality is supposed to permit an objective and safe evaluation of FoG in PD patients in an ecologically valid environment. The reported VR paradigms consist of first-person perspective navigation. Participants navigate using MRI-compatible foot pedals through a virtual environment that displays several triggers known to produce FoG in PD patients . In these studies, FoG is measured as an episode of motor arrest, consistently defined across studies as an abnormally long period of between-footstep latency compared to the mean between-footstep latency computed during normal walking. Measures of these motor arrests were positively correlated with self-reported severity of FoG , suggestShine and colleagues conducted a series of VR studies revealing consistent alterations in BOLD activation levels and functional connectivity (FC) changes between cortical and subcortical regions of PD patients with FoG. Increased activation in frontoparietal regions was negatively related to freezing severity, whereas reduced activity in the BG, thalamus and pre-In agreement with the findings reported by Shine and colleagues, further VR studies revealed abnormal functional connectivity (FC) patterns between cortical and subcortical structures . NotablyMost of the above-reported abnormalities concentrate on the \u2018hyper-direct\u2019 pathway see , comprisDespite differences in the implemented VR experimental paradigms, most of the neuroimaging findings revealed by task-based VR paradigms support the predictions made by the 'interference model' . Taken t4.2Motor imagery (MI) paradigms are adopted to assess and modulate gait impairments in PD patients. MI is defined as the mental simulation of action without overt execution . MI simuFollowing the reported hypoactivation in subcortical regions in VR studies , imagingSeveral MI studies revealed abnormal patterns of activation encompassing cortical areas along the dorsal visuomotor pathway that were more pronounced in the right hemisphere of PD patients with gait impairments . During Studies adopting MI paradigms report various neurophysiological changes that primarily show agreement with either the \u2018interference\u2019 or the \u2018perceptual dysfunction\u2019 models of FoG in PD. The variability in observed findings across MI studies is partly due to the differences in complexity across the implemented MI paradigms and differences in the studied samples of PD patients. The latter is particularly problematic for a cross-studies comparison since the included patients show a wide range of disease severity. Moreover, the lack of FoG assessments in some MI studies renders it difficult to precisely distinguish between neurophysiological changes associated with general symptoms of PD and those mainly linked to FoG in PD.4.3Functional near-infrared spectroscopy (fNIRS) is a neuroimaging method that recently gained popularity in studying the neurophysiology of gait impairments and FoG in PD. Like fMRI, this technique detects hemodynamic changes (of oxygenated and deoxygenated hemoglobin) in cerebral blood flow produced by neurovascular coupling. Being both portable and wireless, fNIRS permits measurements of brain activity during actual walking, i.e., while being in an upright position, thus having the advantage of also assessing the postural and balance control mechanisms involved in bipedal gait (in contrast to the supine position when lying in an MRI scanner). Moreover, fNIRS studies allow the direct correlation of neurophysiological changes with real-time behavioral gait metrics measured by wearable gait sensors. Studies investigating prefrontal activity with fNIRS during a walking task converge on reporting higher activity within the PFC and the Furthermore, studies assessing the effect of dopamine treatment on the recruitment of executive functions during gait indicate that PD patients with FoG exclusively employ executive functions to alleviate the loss of movement automaticity, as evidenced by increased recruitment of the PFC during gait . In contSince all fNIRS studies to date were restricted to the investigation of frontal brain regions associated with executive functions, i.e., the PFC and the DLPFC, their findings are largely discussed in light of the \u2018executive dysfunction\u2019 model of FoG in PD. Nevertheless, some fNIRS results indicate a potential reliance on other strategies, e.g., visuospatial strategies, to compensate for the loss of gait automaticity in PD patients with FoG. Given that dual-task turning requires higher cognitive control than single-task turning and, consequently, higher activation of the PFC, the counterintuitive observation of lower recruitment of PFC in PD patients suffering from FoG during dual-task turning suggests5meta-analysis of neuroimaging studies revealed that gait impairments in PD are associated with lower SMA and higher CLR activation in PD patients and discusses the neural correlates in light of the different pathophysiological models of FoG. Although the imaging findings do not converge on a single pathophysiological model of FoG, evidence suggests that FoG in PD is associated with more than a single neural mechanism. The studies converge on highlighting functional decoupling between cortical and subcortical regions as well as abnormal activation patterns, particularly within frontoparietal and parieto-occipital regions and the striatum. The current review demonstrates that despite multiple pathophysiological insights across the different studies, systematic comparisons are limited due to differences in neuroimaging modalities and targeted brain mechanisms. Notably, the potential differential neural substrates underlying FoG during walking and FoG during gait initiation remain unaddressed. Thus, developing novel experimental paradigms that tackle this distinction is warranted. Besides, future studies should adopt multimodal neuroimaging and address the above-mentioned limitations that currently hamper comprehensive imaging studies of FoG in PD patients. These future imaging studies will hopefully permit the improvement of current treatment strategies and set the ground to devise novel treatments for FoG in PD that are tailored to the individual patient and thus more efficient.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} +{"text": "Ecologists usually find that plant demography changes along with plant size and environmental gradients, which suggests the effects of ontogeny-related processes and abiotic filtering. However, the role of functional traits underlying the size\u2013 and environment\u2013demography relationships is usually overlooked. By measuring individual-level leaf traits of more than 2700 seedlings in a temperate forest, we evaluated how seedling traits mediated the size\u2013 and environment\u2013demography relationships. We found leaves were larger for taller seedlings; leaf economics traits were more conservative in taller seedlings and under high-light and low-elevation conditions. Structural equation modelling showed that a higher survival probability for taller seedlings was indirectly driven by their larger leaf area. Although taller seedlings had lower growth rates, larger and more resource-conservative leaves could promote the growth of these tall seedlings. Environmental variables did not influence seedling survival and growth directly but did influence growth indirectly by mediating trait variation. Finally, species-specific variation in traits along with size and environments was associated with the species-specific variation in seedling survival and growth. Our study suggests that not only plant ontogeny- and environment-related ecological processes, but functional traits are also important intermediary agents underlying plant size\u2013 and environment\u2013demography relationships. The seedling stage is a bottleneck stage for plant survival and growth because of the production of more individuals than could occupy open spaces and their general susceptibility to surrounding abiotic and biotic environments . Given tWith the increasing number of studies exploring seedling survival and growth, especially in permanent forest dynamics plots, most studies find that seedling height is the most important factor influencing survival and growth, and superior to other biotic and abiotic factors . Ac; )"} +{"text": "Transcatheter heart valve (THV) embolization is a rare complication of transcatheter aortic valve implantation (TAVI) generally caused by malpositioning, sizing inaccuracies and pacing failures. The consequences are related to the site of embolization, ranging from a silent clinical picture when the device is stably anchored in the descending aorta to potentially fatal outcomes . Here, we present the case of a 65-year-old severely obese woman affected by severe aortic valve stenosis who underwent TAVI complicated by embolization of the device. The patient underwent spectral CT angiography that allowed for improved image quality by means of virtual monoenergetic reconstructions, permitting optimal pre-procedural planning. She was successfully re-treated with implantation of a second prosthetic valve a few weeks later."} +{"text": "Editorial on the Research TopicAdvances in rehabilitation intervention after limb amputationThe tenth anniversary of the Boston Marathon Bombings is soon approaching on April 15, 2023. This mass casualty event highlighted the extraordinary role of bystanders and first responders who applied tourniquets, highly skilled trained trauma teams at the five Boston level I Trauma academic medical centers, followed by high quality, coordinated acute rehabilitation care in ensuring the best possible outcomes for the survivors pressures and residuum muscle activation after transfemoral osteomyoplastic amputations (OTFA) during brisk and self-paced gait compared to the performance with that of intact controls. They showed that RSI pressures were distributed throughout the residuum-socket and that muscles were engaged and often co-contracted at key times during the gait cycle. Their recommendations include enhancing specific therapeutic exercises as part of OTFA rehabilitation to improve control activation of hip adductors, hamstrings, and quadriceps in the intact and distal-residual limbs, thereby optimizing overall gait performance stability and reducing excessive energy expenditure. This study highlights that new reconstruction techniques require that new, patient-centered rehabilitation protocols be developed and studied.Efforts to incorporate newer technical developments in amputation surgery and reconstruction demonstrate a shift toward an outcomes-oriented approach in amputee care \u201313. SurgKhetarpaul et al. focuses on the interdisciplinary team approach (Frontiers | Socioecological model-based design and implementation principles of lower limb preservation programs as partners for limb-loss rehabilitation programs\u2014A mini-review. Their review article can be helpful to healthcare institutions and organizations seeking to develop, expand, or refine their ability to provide comprehensive limb care. The model system of care includes presurgical planning, postsurgical and early pre-prosthetic rehabilitation care, and prosthetic and lifelong care. Rehabilitation care includes coordination with community resources, such as peer support, and vocational, recreational, and driving assessment. The emphasis on prior mental health concerns and new concerns that arise with limb loss should also be addressed by mental health professionals in the multidisciplinary care provider team model.When treating individuals with severe limb trauma, important decisions around limb salvage vs. amputation and optimal amputation level are ideally made through an interdisciplinary approach to optimize both surgical and functional outcomes . The lasapproach as the mWe are confident that this series of articles will advance the multidisciplinary surgical and rehabilitation care that takes place before and after limb amputation and will provide a successful framework for ongoing research."} +{"text": "Drosophila. We use embryos that greatly differ in length and, importantly, possess distinct length-scaling characteristics of the Bicoid (Bcd) gradient. We systematically analyze the dynamic movements of gap gene expression boundaries in relation to both embryo length and Bcd input as a function of time. We document the process through which such dynamic movements drive both an emergence of a global scaling landscape and evolution of boundary-specific scaling characteristics. We show that, despite initial differences in pattern scaling characteristics that mimic those of Bcd in the anterior, such characteristics of final patterns converge. Our study thus partitions the contributions of Bcd input and regulatory dynamics inherent to the AP patterning network in shaping embryonic pattern's scaling characteristics.How patterns are formed to scale with tissue size remains an unresolved problem. Here we investigate embryonic patterns of gap gene expression along the anterior-posterior (AP) axis in PatternDrosophila, the maternally-derived morphogenetic protein Bicoid (Bcd) forms a concentration gradient along the AP axis to instruct embryonic patterning .Prof Jun Ma was supported by National Key R&D Program of China [2021YFC2700403 & 2018YFC1003203], National Key R&D Program of China [2021YFC2700403 & 2018YFA0800102], 10.13039/501100001809National Natural Science Foundation of China [31871249].Prof Feng He was supported by Data will be made available on request.The authors declare no competing interests."} +{"text": "Liver diseases are responsible for over 2 million deaths each year and the number is rapidly increasing. There is a strong link between edibles, gut microbiota, liver fat and the liver damage. There are very limited therapeutic options for treatment specifically for Alcoholic liver disease (ALD) and Non-Alcoholic liver disease (NAFLD). Recently, identified Edible Exosomes-like nanoparticles (ELNs) are plant derived membrane bound particles, released by microvesicular bodies for cellular communication and regulate immune responses against many pathogens. Many studies have identified their role as hepatoprotective agent as they carry bioactive material as cargoes which are transferred to recipient cells and affect various biological functions in liver. They are also known to carry specific miRNA, which increases the copy number of beneficial bacteria and the production of lactic acid metabolites in gut and hence restrains from liver injury through portal vein. Few in-vitro studies also have been reported about the anti-inflammatory, anti-oxidant and detoxification properties of ELNs which again protects the liver. The properties such as small size, biocompatibility, stability, low toxicity and non-immunogenicity make ELNs as a better therapeutic option. But, till now, studies on the effect of ELNs as therapeutics are still at its infancy yet promising. Here we discuss about the isolation, characterization, their role in maintaining the gut microbiome and liver homeostasis. Also, we give an outline about the latest advances in ELNs modifications, its biological effects, limitations and we propose the future prospective of ELNs as therapeutics. Liver diseases have pathological spectra ranging from simple steatosis to hepatitis to cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is one the most common diet and fat associated non-communicable disease. Presently, 25%-35% and 5%-15% of the general population of Western and Asian countries, respectively, are affected by this disease. This proportion is even higher in people with type 2 diabetes (60%-70%), and in those who are obese or morbidly obese (75%-92%) compared to the general population. Like alcoholic liver disease there is no effective treatment to date for NAFLD. In the absence of a proven effective therapy, we must follow a multi-disciplinary approach in NAFLD treatment. Treatment is mainly directed towards weight loss and risk factor reduction, as most patients are obese or have metabolic syndrome. Dietary modification plays a key role since a carbohydrate-rich diet, especially with high fructose, is the major cause of obesity, insulin resistance and NAFLD development.in vitro and in vivo are related to gastrointestinal cell lines or diseases such as inflammatory bowel diseases, gastric cancer, colitis, etc. so far reported.Liver disease patients also exhibit gut bacterial overgrowth, enhanced gut permeability and increased paracellular leakage of gut luminal antigens, factors that promote liver damage. A dietary intervention in obese or overweight subjects, consisting of administering an energy-restricted high protein diet during six weeks, increased the diversity of species in the gut, along with decreased adiposity, which reverted to basal levels after the diet was stopped. Dietary components are not only consumed by the host (humans) but also by the gastro-enteric microbiota. The kind of diet we consume effects the microbiota composition as well as the nutritional, toxicological, and biochemical components availability after processing of food in the gut. Though hepatoprotective dietary products have been identified, there is still a need for further investigation to completely understand the mechanism of action of various components in the diet. The major problem is that to attain a certain amount of nutrient, gut microbiota modulation, a large quantity has to be consumed. Hence, a prospective solution to it can be Edible exosomes-Like Nanoparticles (ELNs). ELNs are small membrane vesicles which carry various biomolecules as cargoes The liver is one of the vital organs which readily acts as scavenger, contributes in immune surveillance, and is the only organ to have regenerative property. Gut derived products transported into liver by portal vein to liver and in feedback gut receive bile hence forming the interface of gut-liver axis. This interface maintains the gut homeostasis by maintaining the gut microbiota and host immune cells. Mostly in liver diseases this barrier has found disrupted leads to invasion of microbes and microbial particles inside host tissue. There are many therapeutic options which are available for various liver diseases are based on synthetic drugs, prebiotics, probiotics and synbiotics. In this review, we have summarised about ELNs in accordance to their structure, biochemical composition and bio-availabity to target cells, and their promising future therapeutic applications in liver diseases as this could be one of the potent prebiotics which will be safe, efficient and affordable for the treatments.For isolation of ELNs, there exist various methods, among which differential ultracentrifugation is considered the gold standard. Firstly, edible part of plants are grounded in to juice using mixture then further procedure followed to remove large plant debris or fibres and other unwanted aggregates. Differential ultracentrifugation involves a multistep process that includes low speed centrifugation i.e. 1000 \u00d7 g to get rid of larger particles or fibres, followed by medium- speed centrifugation of 10,000 \u00d7 g for removal of larger debris and intact organelles. At last, high-speed ultracentrifugation of 100,000- 150,000 \u00d7 g was used for pelleting down exosomes or exosome-like particles Like other mammalian EVs, ELNs can be characterized by various ultrasensitive microscopic methods that are Transmission Electron Microscopy (TEM), Scanning Electron Microscopy (SEM) or Atomic force Microscopy (AFM) and for structural analysis at subcellular level ELNs ultrastructural analysis has been reported by cryo-Electron Microscopy. Where the cup shaped spherical subcellular structures can be seen with their double membranous lipid bilayer and hence identified as ELNs. Characterization of mammalian EVs is also possible by Flow-cytometry as they have specific markers according to their cell of origin. But for ELNs till now there are no specific markers reported, hence this restricts us from using various methods for their characterization. For determination of size and charge of these particles, Dynamic Light Scattering (DLS) has been extensively used. Now days to analyse their size along with concentration Nanoparticle Tracking Assay (NTA) has been followed as it can analyse the Brownian motion of these particles with respective size and concentration. To determine the dispersity or their repulsive nature to avoid aggregation along with stability Zeta analyser can be used to calculate their membrane potential Fig. .The variable surface glycoprotein and lipid compositions among all EVs acts as ligands which are responsible for bio-distribution and specific binding to target cells. Mostly, ELNs uptake had been identified by various ways such as membrane fusion, phagocytosis, macro-pinocytosis and receptor mediated endocytosis. Membrane fusion generally depends on same membrane fluidity of both ELNs and membrane of target cell which requires a low pH 5 Lactobacilus, PC- enriched grapefruit derived ELNs and these were preferentially taken up by Ruminococcaceae whereas the PA and PC depleted vesicles are not taken up by these bacteria. Considering the in vivo bioavailability of this ELNs PA enriched vesicles generally accumulate in gut whereas PC enriched vesicles reach out to liver when given orally. Still the need of understanding the effect of membrane lipid composition in uptake of ELNs by their target cells is open for research.Bio-distribution mainly depends on several factors like parent cell source, uptake mechanism of ELNs by target cells and their retention in circulation along with the membrane composition. Studies of mammalian EVs, RBC-derived EVs showed a gradual uptake by liver (44.9%), bone (22.5%), skin (9.7%), muscle (5.8%), spleen (3.4%), kidney (2.7%) and lung (1.8%). EVs of mammalian cells have specific markers or receptors according to their parent cells which helps them in easy availability to their target cells with the respective ligands for interaction In vivo oral administration of ELNs are well explained by pharmacodynamic study of Acerola ELNs (AELNs) using PKH26 fluorescent dye. They mainly reach out to mice intestine, liver, bladder and ovary after 1hr of consumption All plant derived EVs have been reported to carry different types of proteins, and nucleic acids as cargos which play a substantial role in intercellular communication. Nucleic acids i.e. miRNAs have been detected. EVs also carries DNA, that can be used for identification of translational biomarkers or mutational modifications in parent cells but their physiological significance is currently unknown.In 2006, for the first time presence of functional extracellular RNA was reported in murine stem-cell derived EVs Lactobacillus rhamnassus GG (LGG) that results in production of lactic acid and its derivatives which acts as ligands to activate anti- inflammatory pathways in host mitigates Clostridioides difficile infections (CDI) which is a leading cause of antibiotic resistant colitis Clostridiaceae, Ruminococcaceae and Lachnospiraceae hence regulate the production of short chain fatty acids (SCFAs) that helps in enhancing intestinal immunity in mice Plant derived ELNs are present in our diet and reach the gut with daily intakes. They can also able to withstand the digestive juices and the harsh condition during digestion of food, hence maintains their integrity at gut. Many studies reveals the therapeutic implications of various plant- derived ELNs in mitigating diseases concerned to intestinal barrier and gut microbiota homeostasis such as colitis, inflammatory bowel diseases, colorectal cancer. Ginger derived ELNs carrying miR396e were successfully taken up by ost Fig. 30. At tMany therapeutic studies using ELNs have been reported till date. Most studies explaining the biological significance of ELNs reported against dextran sulphate sodium (DSS) induced colitis, inflammatory bowled diseases and on gut- microbiota. ELNs had shown their potentials like anti-inflammatory, anti- cancerous and anti-oxidant effects by changing the fate of recipient cells. There are few clinical trials which are already registered for liver diseases Table .Zhuang et al. 2015 reported the hepatoprotective effect of ginger-derived ELNs (GELNs) against alcohol-induced liver damage in mice. They identified Shogaol, the dehydrated analogue of gingerol activates the nuclear factor erythroid 2-related factor 2 (Nrf2) in a TLR4/ TRIF-dependent manner lead to the expression of liver detoxifying/ antioxidant genes like HO-1, NQO1, GCLM, and GCLC. Apart from antioxidant defences, Nrf2 also have critical roles in modulating various cellular processes like hepatocyte proliferation during liver regeneration, inflammation [Nrf2 is involved in maintaining hepatocyte identity during liver regeneration] Fig. and drug in vitro.CD98 have a potential role in Non- alcoholic fatty liver diseases (NAFLD), hence co-localization of garlic ELNs indicates to be a promising target for both therapeutic and drug therapy in vivo, but due to the reduced absorption of triglycerides at jejunum, helps in systemic reduction of lipid which might lead to amelioration of steatosis. With increase in gene expression of junctional proteins such as CLD1, OCLN, ZO1 it also enhance the recovery of barrier permeability in colitis. Its contribution in concentration of amino acids and bioactive lipids in the jejunum, which are deficient in obese patients, could accelerate the restoration of intestinal functions during weight loss in obese patients.In context to metabolic syndrome diseases like hyperlipidaemia, obese- associated intestinal complications, OELNs increases the villi size in jejunum by lowering the fat absorption and chylomicrons production by targeting microsomal triglyceride transfer protein (MTP) hence reduced the plasma lipid concentration. It also acts upon angiopoietin-like protein-4 (ANGPTL4) Apart from oral administration of ELNs, the effect of Shiitake mushroom ELNs intraperitoneally alleviates haemorrhage and cell death in fulminant hepatic failure within 6 hrs administration Clostridial clusters IV and XIVa of Firmicutes helps in lowering the pH of colon thereby inhibit growth of pathogens In vivo studies using OELNs also suggests inhibition in lipid absorption at intestinal epithelia and at liver as well which also makes them perfect candidates to mitigate metabolic syndromes associated to liver diseases Lactobacillus, Bifidobacteria, Enterobacter, Bacteroides, Clostridium produces bileFaecalibacterium prausnitzii along with Bifidobacterium releases cholines Lactobacilluslactobacillus and streptococcus as well along with push them to produce metabolites which help in inter-bacterial communication in the gut E.coli they also strengthen the gut immunity and proof their selves as potential therapeutic elements. Hence targeting gut microbiota using ELNs for therapeutic interventions like probiotics could help in developing chronic liver diseases and the metabolic syndromes that are associated to liver. Apart from gut microbes in gut-liver axis, from physiological point of view there exist a strong correlation between High fat Diet and insulin resistance in development of Type 2- Diebetes Various studies suggested that alteration in gut microbiota i.e. gut dysbiosis leads to several diseases. Small intestinal bacterial overgrowth (SIBO) results into production of endotoxins leads to damage intestinal epithelia known as leaky gut and this translocation resulting into hyper inflammation, bacterial peritonitis, hyperdynamic or portal hypertension states. The strategic distal position of liver downstream to gut makes it the most effective organ by the endotoxins or microbiota produced components among other distal organs lactobacillus rhamnassus GG (LGG) used as probiotics and found to give promising results in recovery of disordered gut hence improving liver disease conditions. Before reaching to their site of action i.e. intestinal region live probiotic bacteria had to tolerate the bactericidal effects of various gastric juices, one of the challenges in applications of probiotics. Their preservation in different climatic zones accordance with transportation also found as obstacles. The gut microbiota varies from one person to another the species of bacteria could be same but the strains varies accordingly. Hence considering probiotics as a common solution cannot be fruitful.Interface of gut-liver axis constitute the multilayer defence of physical, humoral and immunological barrier to protect the body from primary exposure of endotoxins and other infectious particles that entered through gut. Liver diseases resulted due to alcoholic and non- alcoholic associated parameters. Alcohol breaches the barrier and this injury compels specific changes in gut microbiota that can enhance alcohol induced liver diseases. Continuous alcohol consumption increases endotoxin producing bacteria and reduction in autochthonous taxa that produces short- chain fatty acids (SCFAs) leads chronic liver disease to cirrhosis and alcoholic hepatitis Considering the therapeutic approaches, scientists surmount many challenges mainly safety delivery of therapeutic molecules to reach specific target site, low toxicity and economic production costs. Formation of such cost effective pharmaceutical molecules or nanoparticles with low immunogenicity, cytotoxicity needs complex fabrication processes In development of pristine plant derived nanovesicles (PNVs), the major concern was the preparation of uniform-sized with efficient loading of desired drug molecules to reach specific target site. For which researchers employed the Bligh and Dyer technique based on hydration of a lipid that earlier used for the fabrication of liposomes in vivo have seen to be effective against brain GL- 26 brain tumour Aiming to the specificity and biocompatibility with lesser side effects PNVs encapsulated with desired molecules has been implemented against various diseases. It improves the delivery of therapeutic drug molecules that mainly involves hydrophobic drugs, siRNAs, miRNAs or proteins as they easily penetrate into tissues and with an enhanced circulation period. Grape fruit EVs (GfEVs) has been found as efficient carriers for the delivery of exogenously loaded Alexa fluor tagged Bovine Serum Albumin (BSA) and Heat Shock Protein 70 (HSP 70) into Peripheral Blood Mononuclear cells and colon cancer cells. They found as safe, potential and effective carrier for the delivery of exogenous proteins as compared to the proteins without EVs ELNs can be considered as the future of therapeutics specially for the gut and liver diseases. With the advancement of technology, the techniques to isolate, enumerate and characterize makes it much easier to use it as therapy. Not only this, the cargoes information in ELNs, and its association with restoration of gut microbiome homeostasis, hepatoprotective role makes it more potent as treatment option Fig. . With re"} +{"text": "Methods and Applications in Exercise Physiology aimed to highlight the latest experimental techniques and methods relating to research and practice. In this series, we capture recent advances in measurement techniques for 1) cardiorespiratory exercise testing, 2) athletic performance, and 3) health monitoring.Exercise physiology is pivotal in optimizing health and performance as it influences various aspects of life, from sports performance to clinical rehabilitation and occupational health. 2peak measured by a single graded exercise test (GXT) is representative of an individual\u2019s true maximum capacity, Hebisz et al. found no appreciable differences with verification tests performed 15\u00a0min after the GXT (cycling) or on a separate day. The ventilatory threshold and respiratory compensation point are other common markers of cardiorespiratory fitness measured during GXTs. Kim et al. developed and validated an automated method to identify these inflection points objectively. Together, these studies help to improve the way we measure key indicators of cardiorespiratory fitness.Valid assessment of maximum oxygen uptake and ventilatory threshold have been hallmarks of cardiorespiratory exercise testing for assessing athletic performance. Investigating whether VOHu et al. analyzed the results of twelve studies, concluding that although tDCS does not significantly improve upper limb muscle strength, significant improvements in upper limb endurance performance can be achieved. Alternatively, the study by Lu et al. shows that tDCS can significantly improve muscle strength and explosive force of the non-dominant knee. Taken together, tDCS shows promise in offering an avenue to improve indicators of muscular performance.Improvements in athletic performance are synonymous with enhanced muscular strength and endurance. Recent research has sought to elucidate if non-invasive brain stimulation technology can promote these outcomes. Transcranial direct current stimulation (tDCS) induces focal and transient changes in cortical excitability by applying a low-intensity direct current to the scalp. In a systematic review, Date et al. have shown that surface EMG of Brachialis muscle activity accurately reflects intramuscular EMG. As such, surface EMG offers a non-invasive, easy to perform, less uncomfortable technique for research and clinical practice. On the sports field, COD performance plays a pivotal role in match-winning situations. Among youth basketball players, Chen et al. demonstrated that 505 COD performance measured with the COD timer app could be used to accurately capture timing data, compared to more expensive timing gate methods. Confirmation that these less expensive methods are valid and reliable will enable a broader range of applications for these performance assessments.Simpler and more accessible approaches have also been proposed for measuring muscle activity and change of direction (COD) performance. While monitoring muscle activity has conventionally involved intramuscular electromyography (EMG), which is invasive and requires specialized expertise, Zhang et al. examined the accuracy of a flash glucose monitoring device among overweight/obese persons during sitting and walking before, during, and after an individual\u2019s postprandial peak. Although absolute glucose readings from the flash glucose monitoring device underestimated plasma glucose, its overall accuracy was clinically acceptable during postprandial sitting and walking conditions in overweight or obese young adults, highlighting the potential for this technique to have widespread health-monitoring implications.To help individuals with diabetes or poor glucose control improve glycemic control, continuous glucose monitoring has increasingly been adopted as a novel and feasible tool. Potter et al. investigated whether an abdominal circumference-focused method of percent body fat estimation accurately represented dual-energy x-ray absorptiometry. Their large-scale study of participants from the US Marine Corps concluded that the abdominal circumference estimate of percent body fat provides a field expedient method to classify individuals for obesity prevention but was not suitable for research-grade assessments.Body composition assessment has been an important aspect of research in exercise physiology for decades. Assessment techniques range widely in expense, required expertise, and validity. In favour of developing low-cost and readily applicable measurement techniques, Overall, this special issue on the methods and applications used in exercise physiology showcases the many diverse advances being made to the techniques used in research and practice. Less expensive methods that require minimal expertise and can be easily applied in field settings will continue to enhance our ability to measure, understand, and enhance human health and performance."} +{"text": "Aedes aegypti [Dengue is a mosquito-borne viral infection transmitted to humans, caused by four types of dengue virus (DENV) and primarily carried by the species Pakistan first reported an epidemic of Dengue fever in 1994 and since November 2005 annual recurrence has become apparent . AccordiThis higher than usual monsoon rainfall raises an alarming concern for a potential outbreak of dengue fever in the country. Pakistan is already dealing with 6th wave of COVID-19 and an outbreak of Cholera , hence aNone required.None.Muttia Abdul Sattar, Hadia Nadeem. All authors contributed the same.None.Name of the registry:Unique Identifying number or registration ID:Hyperlink to your specific registration (must be publicly accessible and will be checked):Muttia Abdul Sattar.None required."} +{"text": "Digital solutions to HPV vaccination by Hopfer S, Dyda A and Brandt HM. (2022). Front. Digit. Health. 4:972234. doi: 10.3389/fdgth.2022.972234Editorial on the Research Topic The rapid growth and diffusion of digital solutions, technologies and online media consumption is changing the landscape of implementing health behavior change campaigns and interventions as well as how individuals and families access and consume health information , 2. NoveMassey et al.; Zhang et al.; Sundstrom et al.; Buller et al.; Hopfer et al.). The special issue also presents feasibility studies on web-based or mobile applications that tailor vaccine information to parents, adolescents, and young adults through a variety of approaches. Most digital solutions presented are stand-alone, yet one intervention presents digital efforts integrated as a component of a multi-level clinic intervention to reach rural populations and reduce missed HPV vaccine recommendation opportunities . Other studies suggest that mobile apps could be used to complement clinical pediatric well-child visits or could be disseminated by state health departments, school health officials, and pharmacy chains. The advantages of digital health not only become apparent by the structural channel affordances that lend themselves to greater engagement and tailoring with audiences but also accommodate busy schedules of parents and young adults.This special issue showcases predominantly social media studies as digital solutions that show promise for reaching parents and youth about HPV vaccination , such as those reported by Sundstrom et al. and Buller et al., to deliver vaccine messaging through trusted peers presents a promising approach for increasing HPV vaccination. Another benefit of digital interventions is the ability to deliver vaccine messaging in other languages e.g., Spanish to Latinx communities or target vaccine messaging via parent personas . Social media studies delivered vaccine messaging across multiple channels testing the impact of disseminating through different platforms in private and public groups, synchronous/asynchronous discussion groups, webinars, bi-weekly emails, weekly messaging, and lifestyle messaging .Digital approaches inherently hold promise to make vaccine information more accessible for many populations who might otherwise not be reached and where messaging can be targeted to reach subgroups. Digital strategies may be delivered Zhang et al.), another study focused regionally on South Carolina and yet another on rural Colorado (eno & Dempsey). These U.S. regions are characterized by low HPV vaccination rates and high HPV-cancer incidence.Geographic targeting can also be achieved with digital messaging: one study focused on Northern rural California with low vaccination and high cancer rates , showcases the potential to take advantage of answering parent and youth questions real-time and debunking misinformation, but also answering questions asynchronously through newsletters, blogs, discussion forums, chat rooms, and portals . A devoted moderator who can respond real-time to questions and correct misinformation was a recurring theme in combination with more automated digital interventions. The flow of unsolicited, real-time comments from parents give insight into vaccine concerns as well as exposure to circulating rumors and misinformation. Predominant vaccine concerns remain around HPV vaccine confidence and HPV complacency.Engagement, as observed through analysis of comments and posts while another study applied dialog theory to segment HPV vaccine videos and adapt them to the social media environment . An ideal area of opportunity lies in strengthening the integration of theoretical foundations into digital health solutions in HPV vaccination.Communication and behavior change theories were adapted to understand the digital health environment: these ranged from social cognitive theory (SCT), diffusion of innovation (DOI), extended parallel process model (EPPM), 3C model of vaccine hesitancy, and a champion network approach. One study integrated persona theory with health communication and human-centered design , highlighting the emerging nature of digital solutions to increase vaccination. However, data on outcomes was also presented with results from randomized trials . This accrued evidence from the studies in this special issue on digital solutions highlights the various ways in which digital approaches are likely to increase HPV vaccination rates particularly in relation to increasing access and improving health promotion reach, through peer- and trusted channels and messengers. Use of narratives and informal peer dialogue show promise to increase user engagement in the digital environment while also being able to answer and debunk circulating rumors real-time . Social media platforms offer one strategy to make information accessible . Additional strategies of using peer-champions , point-of-care delivered vaccine messages , and real-time tailoring also show promise as digital solutions to increase HPV vaccination.A number of these studies were in the development or piloting stage ("} +{"text": "Migraine is a highly prevalent disorder with significant economical and personal burden. Despite the development of effective therapeutics, the causes which precipitate migraine attacks remain elusive. Clinical studies have highlighted altered metabolic flux and mitochondrial function in patients. In vivo animal experiments can allude to the metabolic mechanisms which may underlie migraine susceptibility. Understanding the translational relevance of these studies are important to identifying triggers, biomarkers and therapeutic targets in migraine.Functional imaging studies have suggested that migraineurs feature metabolic syndrome, exhibiting hallmark features including upregulated oxidative phosphorylation yet depleted available free energy. Glucose hypometabolism is also evident in migraine patients and can lead to altered neuronal hyperexcitability such as the incidence of cortical spreading depression (CSD). The association between obesity and increased risk, frequency and worse prognosis of migraine also highlights lipid dysregulation in migraine pathology. Calcitonin gene related peptide (CGRP) has demonstrated an important role in sensitisation and nociception in headache, however its role in metabolic regulation in connection with migraine has not been thoroughly explored. Whether impaired metabolic function leads to increased release of peptides such as CGRP or excessive nociception leads to altered flux is yet unknown.Migraine susceptibility may be underpinned by impaired metabolism resulting in depleted energy stores and altered neuronal function. This review discusses both clinical and in vivo studies which provide evidence of altered metabolic flux which contribute toward pathophysiology. It also reviews the translational relevance of animal studies in identifying targets of biomarker or therapeutic development. Migraine is a highly prevalent and disabling disorder, affecting over 1 billion people worldwide . In addiMigraine is a prevalent feature of both mitochondrial and metabolic disorders , which Sensitization of the trigeminovascular system and cortical hyperexcitability are two mechanisms thought to be crucial to pathophysiology of migraine.The trigeminovascular system is composed of trigeminal sensory neurons innervating the dura mater as well as cerebral and pial blood vessels. They synapse in the pars caudalis of the ipsilateral spinal trigeminal nucleus. The main projection of these nociceptive fibres is the ventral posteromedial thalamic nucleus, which then relays to the primary sensory cortex. This system is fundamental to nociception and migraine pathophysiology . TrigemiHyperexcitability of the cerebral cortex is also thought to contribute towards migraine pathophysiology . It has Glucose is the major energy substrate of the brain. It diffuses across the blood\u2013brain-barrier via the glucose transporter GLUT1 and can be taken up by neurons via GLUT3 . Its majGlucose metabolism is fine-tuned within and among cells to ensure maintenance of adequate concentrations of substrates. At rest, the metabolism of the brain is compartmentalised between neurons and astrocytes; neurons can rely on both glycolytic and oxidative metabolism, whereas astrocytes tend to be primarily glycolytic and can metabolically support neurons . At timeIn vivo murine models have been useful in providing in-depth understanding of mechanisms linking abnormal glycolysis and migraine\u00a0Table . In rodeIn clinical practice, migraineurs often report that attacks are precipitated by fasting or skipping meals, and indeThe gold standard to assess cerebral glucose uptake in vivo in patients is 18F-Fluorodeoxyglucose PET (18F-FDG PET) which has provided further evidence for the role of downregulated glycolysis in migraine. The cerebral areas affected by glucose hypometabolism appear to be different in episodic migraineurs compared to chronic patients. In episodic migraineurs both with and without aura, hypometabolism has been detected in temporal , and froIn the absence of sufficient oxygen, lactate is produced via anaerobic glycolysis of pyruvate\u00a0Fig. , hence, 1H-MRS) studies during CSD, [Results of animal and clinical studies suggest that lactate excess may be related to CSD. This hypothesis was corroborated in rat proton magnetic resonance spectroscopy , \u201361 with Importantly, such direct associations with cholesterol and LDL may provide an explanation for the increased cardiovascular and stroke risk in migraine , 64. TheAn association between obesity and headache is also evident in secondary headache disorders including idiopathic intracranial hypertension (IIH). IIH is characterised by raised intracranial pressure and features headache with migraine-like characteristics . Over 90Prolonged activity neurons leads to upregulated \u03b2-oxidation and consequently increased reactive oxygen species (ROS) and peroxidated fatty acids , 75. UsiFatty acids also play a role in modulating neuroinflammation, which is a function potentially of benefit in neurodegenerative diseases . Hence, Healthy neurons rely primarily on oxidative phosphorylation for energy, a process hosted by mitochondria which are vital organelles.+ allows quantification of changes in mitochondrial redox potential [For the investigation of mitochondrial function in vivo, most models utilise CSD as a mechanism of migraine. Use of two-photon fluorescent imaging to measure the ratio of autofluorescent reduced NADH to non-fluorescent NADotential . Using totential , 83, 84.otential . Moreoveotential . Dural eotential . In thes31P-MRS). Studies in migraine have consistently highlighted primary mitochondrial dysfunction in patients as evidenced by increased ADP in those with aura and FHM [31P-MRS studies of mitochondrial cytopathies and some neurodegenerative conditions such as amyotrophic lateral sclerosis [31P-MRS data in patients may reciprocate findings in CSD animal models, since migraine with aura patients most frequently demonstrate alterations in mitochondrial function. Results regarding changes in ATP concentrations remain divided, with most studies either not reporting ATP levels, or concentrations remaining unchanged or similar to that of controls [The modality of choice to investigate mitochondrial function in vivo in humans is 31-Phosphorus magnetic resonance spectroscopy supplementation. CoQ10 is an electron acceptor in the electron transport chain which has been shown to improve mitochondrial respiration in mitochondrial cytopathies . SeveralInsulin has become a hormone of interest in migraine since numerous studies have identified insulin resistance in patients \u2013109. ResAnimal studies have revealed that insulin may potentially modulate the release of CGRP. In particular, insulin can induce the release of CGRP via sensitization of neuronal Transient Receptor Potential Cation Channel Subfamily V Member 1 (TRVP1\u2014Fig.\u00a0CGRP is also able to regulate insulin secretion via TRPVAlthough antagonism of CGRP signalling has demonstrated significant efficacy in migraine prophylaxis, the effects on insulin function have not yet been assessed in patients. CGRP receptor antagonism in mice has shown moderate improvements in oral glucose tolerance . CGRP-\u03b1 Amylin is a pancreatic hormone co-released with insulin in response to food intake . It loweWhilst CGRP has become a popular target for migraine therapeutics, the therapeutic potentials of amylin antagonism have not yet been fully explored. Pramlintide, an amylin receptor agonist, is currently licensed for diabetes in the United States . It may The pathophysiology of migraine is evolving and may also feature mitochondrial and metabolic deficits. Moreover, migraine is prevalent in those with mitochondrial disorders and structural and biochemical impairments in electron transfer chain have been identified in migraineurs . Interes"} +{"text": "Endovascular therapy for acute ischemic stroke secondary to large vessel occlusion (LVO) is time-dependent. Prehospital patients with suspected LVO stroke should be triaged directly to specialized stroke centers for endovascular therapy. This review describes advances in LVO detection among prehospital suspected stroke patients.Clinical prehospital stroke severity tools have been validated in the prehospital setting. Devices including EEG, SSEPs, TCD, cranial accelerometry, and volumetric impedance phase-shift-spectroscopy have recently published data regarding LVO detection in hospital settings. Mobile stroke units bring thrombolysis and vessel imaging to patients.The use of a prehospital stroke severity tool for LVO triage is now widely supported. Ease of use should be prioritized as there are no meaningful differences in diagnostic performance amongst tools. LVO diagnostic devices are promising, but none have been validated in the prehospital setting. Mobile stroke units improve patient outcomes and cost-effectiveness analyses are underway. Endovascular therapy (EVT) using mechanical thrombectomy with or without intravenous thrombolysis (IVT) has been proven superior to standard medical care, including IVT alone for patients with acute ischemic stroke secondary to large vessel occlusion (LVO) , 2. MoreIn 2021, a multi-society consensus statement from leading stroke and emergency medical services (EMS) experts recommended that regional stroke destination plans prioritize the transportation of suspected LVO patients to Comprehensive Stroke Centers (CSC) for emergent EVT when within acceptable transportation times . CSCs prEMS transportation of IVT and EVT eligible LVO stroke patients to a closer non-EVT center may facilitate faster IVT; however, IVT recanalization rates are low for LVO stroke, and interfacility transfers for EVT are associated with treatment delays and worse outcomes \u201315. In sThis review details the use of varying methods of LVO identification in patients with suspected stroke, including updates in clinical prehospital stroke scales performed by EMS personnel, various portable medical devices, and mobile stroke units.The American Heart Association (AHA)/American Stroke Association (ASA) provides the Mission Lifeline: Stroke EMS Acute Stroke Routing Algorithm as a model for prehospital LVO triage using currently available prehospital stroke scales . The firWith consensus statements and triage algorithms now available, the remaining question is which validated stroke severity tool to use. Overall, the data quality has dramatically improved since the 2018 systematic review that determined there is insufficient evidence to conclude that any single severity tool is better than the others . This isThe ACT-FAST Stroke Algorithm created by Zhao et al. has also been validated in the prehospital setting and includes a unique treatment eligibility screen step. The algorithm provides a binary positive or negative result with relatively high and balanced sensitivity (75.8%) and specificity (81.8%) when using an extended definition of LVO that includes proximal LVOs plus M2s, P1s, and symptomatic stenoses. However, direct comparisons with the severity tools prospectively and simultaneously evaluated in the studies above are difficult because ACT-FAST was omitted. Most striking is the difference in positive predictive values (PPVs), which exceeded 50% for the ACT-FAST extended LVO definition. In comparison, most severity scores studied by Nguyen et al. in the Netherlands had PPVs in the 20% range . DiffereGiven the similarities in stroke severity tool performance and goal of widespread adoption by EMS providers, ease of use is a reasonable consideration when choosing among them. The easiest approach in the USA would be to change the CPSS, which is currently used as a positive or negative prehospital stroke identification screen, into a stroke severity tool with scores ranging from 0 to 3 , 31. TheWith so many reasonable choices, our focus should shift from which severity tool to use to clarifying our diagnostic and patient care priorities. Most prehospital stroke severity tools have multiple possible scores and choosing a lower score cutpoint would allow for higher sensitivity (not missing an LVO treatment opportunity) to be prioritized over specificity. More false positives would accompany this shift in priorities because these tools are not simultaneously sensitive and specific. However, it is important to prioritize sensitivity in highly morbid diseases with time-sensitive and profoundly effective interventions like EVT for LVO stroke.This is not as daunting as it may seem. Multiple modeling studies have found that LVO triage may not result in overwhelmed stroke centers or missed thrombolysis opportunities , 36, 41.Ultimately, prehospital stroke severity tools are limited by their sensitivity and specificity tradeoffs. Hopefully, the addition of the technologies discussed below will someday allow for highly sensitive and highly specific LVO triage that will expedite access to EVT while minimizing false positives.There has been increasing interest and research in portable and non-invasive external diagnostic devices for prehospital LVO stroke identification and triage. We will briefly discuss various forms of biometric devices reported in the peer-reviewed literature, including electroencephalography with or without somatosensory evoked potentials, transcranial Doppler, cranial accelerometry, and volumetric impedance phase-shift spectroscopy .Electroencephalography (EEG) analyzes normal and abnormal brain electrical activity by transducing electrical potential differences on the patient\u2019s scalp. EEG is primarily used to diagnose seizures and manage epilepsy. It has been used to monitor cerebral ischemia, particularly in the intraoperative setting during carotid artery surgery and, more recently, in acute ischemic stroke . EEG canA recent publication by Sergot and the EDGAR Study Group investigated a portable LVO-detection device (PLD) that used EEG combined with somatosensory evoked potentials (SSEPs) to identify LVO stroke in emergency departments \u2022. The stTranscranial Doppler (TCD) is a safe ultrasound-based method of evaluating cerebral hemodynamics and documenting blood flow in the middle cerebral artery. A pulsed Doppler ultrasound transducer is used to assess intracerebral blood flow through cranial \u201cwindows\u201d . A systeCranial accelerometry is used to measure the headpulse and has been investigated as a tool to diagnose LVO stroke by the authors of this review. Headpulse refers to nearly imperceptible head movements with each cardiac contraction cycle in response to blood flow forces transmitted via the carotid and vertebral arteries. This is measured using accelerometers in contact with the skull combined with electrocardiogram leads. Patients with LVO stroke may have chaotic head pulse patterns that do not correlate with cardiac contraction cycles; this is hypothesized to be due to the obstruction of blood flow on one side by the LVO. Cranial accelerometry alone was 73% sensitive and 87% specific for LVO in an initial study . In a suVolumetric impedance phase-shift spectroscopy (VIPS) technology involves passing low-power electromagnetic waves through the brain to detect asymmetries and electrolyte concentration changes . A devicAt present, none of the LVO devices in development have reported the results of external validation, prehospital feasibility, or diagnostic accuracy studies in ambulances with suspected stroke patients. As investigators design these studies, it will be critical to follow the Standards for Reporting of Diagnostic Accuracy Studies (STARD) guidelines. Many peer-review journals require completion of the STARD checklist during submission, and more importantly, adherence to their guidance will reduce the impact of avoidable biases, increase transparency, and enable researchers to draw meaningful conclusions from new studies as the field advances .The concept of mobile stroke units (MSUs) was published in 2003 by Fassbender to \u201cbring treatment to the patient, rather than the patient to the treatment\u201d and was first established in Germany in 2008 . MSUs tyA recent publication by Ebinger and colleagues in Berlin demonstrated an association between MSUs and improved functional outcomes in acute ischemic stroke patients . They coThe BEST-MSU study is the first multicenter randomized controlled trial comparing standard ambulance care versus MSU care, including prehospital thrombolysis. It began in 2014 in Texas and has demonstrated the safety and feasibility of MSUs, the reliability of telemedicine technology, as well as faster door-to-groin puncture times for patients requiring thrombectomy . ResultsPrehospital triage of patients with suspected LVO to EVT centers is now recommended. The Mission Lifeline: Stroke EMS Triage Algorithm provides a framework that includes neurological examination-based prehospital stroke severity tools. Decisions regarding which severity to tool to use can likely be based on ease of use as prospective comparative studies did not demonstrate meaningful performance differences. Standard score cutpoints of many of these tools favor specificity over sensitivity, which will lead to many missed LVO strokes. Sensitivity should be prioritized, and CPSS \u2265 2 provides similar performance compared to other sensitive stroke severity tool cutpoints but would not require significant training to implement. Several LVO stroke diagnostic devices have published peer-review initial studies, but each device will require prehospital validation before becoming available for use. Mobile stroke units improve patient outcomes and, when available, can perform vessel imaging on scene to diagnose or rule out LVO stroke. Cost-effectiveness analyses are planned. Ongoing improvements in prehospital LVO triage will likely require tailoring the diagnostic approach to the needs of each region."} +{"text": "Termites are a prototypical example of the \u2018extended phenotype\u2019 given their ability to shape their environments by constructing complex nesting structures and cultivating fungus gardens. Such engineered structures provide termites with stable, protected habitats, and nutritious food sources, respectively. Recent studies have suggested that these termite-engineered structures harbour Actinobacteria-dominated microbial communities. In this review, we describe the composition, activities, and consequences of microbial communities associated with termite mounds, other nests, and\u00a0fungus gardens. Culture-dependent and culture-independent studies indicate that these structures each harbour specialized microbial communities distinct from those in termite guts and surrounding soils. Termites select microbial communities in these structures through various means: opportunistic recruitment from surrounding soils; controlling physicochemical\u00a0properties of nesting structures; excreting hydrogen, methane, and other gases as bacterial energy sources; and pretreating lignocellulose to facilitate fungal cultivation in gardens. These engineered communities potentially benefit termites by producing antimicrobial compounds, facilitating lignocellulose digestion, and enhancing energetic efficiency of the termite \u2018metaorganism\u2019. Moreover, mound-associated communities have been shown to be globally significant in controlling emissions of methane and enhancing agricultural fertility. Altogether, these considerations suggest that the microbiomes selected by some animals extend much beyond their bodies, providing a new dimension to the \u2018extended phenotype\u2019. This review discusses how and why termites select for beneficial microbial communities by constructing mounds, nests, and fungal gardens, and explores the ecological and biogeochemical impacts of these termite-engineered communities. Mounds contain complex networks of internal chambers that facilitate gas exchange, harbour the colony, and allow food storage or fungiculture , instead cultivates bacterial combs as a food source to chemically analyze the degree of pretreatment of lignin and polysaccharides during the fungus garden maturation in O. formosanus laboratory colonies; this revealed that the fungus-comb microbiome contributes to significant polysaccharide and lignin cleavage, leaving the mature comb enriched in more digestible cellulosic oligomers that are eventually ingested by termite host or, primarily in the case of fungus-farming termite combs and subterranean C. formosanus opportunistically recruits potentially defensive Streptomyces from surrounding soils and provides favourable nutrients for their proliferation , all of which is rapidly consumed to subatmospheric levels by mound communities and Methylocystis methanotrophs, which appear to be kinetically adapted to elevated methane concentrations (Chiri et al. In addition to providing multifaceted benefits to termites, the microbial communities associated with termite nesting structures offer a range of ecosystem services Fig.\u00a0. Of thesTermite-associated bacteria also enhance soil fertility, especially in savanna and dryland regions, by mediating various supporting services. Termite nest and mound soils promote growth of a wide range of plants both in natural environments and agricultural settings Watson . It was With respect to provisioning services, termite nesting communities are also relevant for understanding and tackling the antimicrobials arm race. Hundreds of novel natural products have been identified from termite nests, especially combs of fungus-farming termites, often with potent antibacterial or antifungal properties (Sujada et al. Increasing evidence suggests that the microbial communities residing within termite nesting structures engage in symbiotic relationships with termites. The microorganisms benefit from a relatively stable and selective habitat, high nutrient availability, and pathogen exclusion mechanisms. The microorganisms recruited to termite nesting structures likely span the spectrum of commensals to mutualists, though the majority appear to benefit termites by mediating antimicrobial production, lignocellulose digestion, and nutrient recycling. Yet in other respects, mound-associated bacteria are atypical of classical symbionts: they are generalist bacteria that can adopt both free-living and mound-associated lifestyles; are opportunistically recruited and sustained through normal nest-building and digestive activities of termites; and exhibit strong geographic variations in community composition even within species. However, strong arguments have been presented that animals can dependably acquire microbial symbionts if potential symbionts are widely distributed and promiscuous associations can form (Moran and Sloan"} +{"text": "The corporate political activities of harmful industries, including the use of agnogenic (ignorance or doubt producing) practices and the construction of dystopian narratives, directed at influencing policymaking are well documented. However, the use of agnogenic practices by industry-funded organisations who deliver industry-favoured education-based measures remains unexplored. This study aims to build understanding of this by analysing three UK gambling industry-funded youth education programmes that represent key policy responses to gambling harms.Using a published typology of corporate agnogenic practices the ways that evidence is used within the programmes\u2019 resources to legitimise their content and implementation were analysed. Programme evaluations and claims about the programmes\u2019 evidence base and effectiveness were also analysed.Agnogenic practices, including confounding referencing, misleading summaries and evidential landscaping, that resemble those adopted by harmful industries are used within gambling industry-funded youth education programmes and by the charities that oversee their delivery. These practices serve corporate interests, distort the limited evidence in support of youth gambling education measures, and legitimise industry favoured policies.This novel study demonstrates that agnogenic practices are used to construct utopian narratives that claim that gambling industry-favoured youth education programmes are evidence-based and evaluation-led. These practices misrepresent the literature and evaluation findings and may undermine effective policymaking to protect children and young people from gambling harms.\u2022\u2002Gambling industry-funded education programmes warrant greater scrutiny and conflicts of interest need to be addressed.\u2022\u2002The methods and findings of this study are of relevance to other contexts and areas in the field of the commercial determinants of health given other harmful industries adopt similar approaches."} +{"text": "Editorial on the Research TopicAdvancing the understanding of surgical management for degenerative spine conditionsDegenerative spine conditions are common in adults, especially among the elderly. In parallel with the aged tendency of population worldwide, the prevalence of degenerative spine diseases has been increasing. There has also been an increasing trend in spine surgery worldwide \u20133. HowevQian et al. that may because the laminoplasty releases dorsal spinal cord from compression in pinching cervical spondylotic myelopathy (PCSM). Yang et al. took advantage of finite element analysis of CT images and found the maximum stress in involved segments of cervical spondylotic myelopathy (CSM) was higher compared with the control group. Two papers summarized theoretical knowledge of certain spine diseases. Xu et al. gave a detailed and authoritative review for ponticulus posticus, including the epidemiology, pathology, anatomy, clinical presentation, radiographic examination and surgical significance of ponticulus posticus. Mei et al. gave us a rare case of camptocormia related to Parkinson's disease and reviewed the literature on camptocormia.Learning the basic knowledge of spinal disorders helps to give us an overall understanding of surgical treatment. Several papers in this Research Topic gave us their understandings of pathogenesis of some spine diseases. The reason why cervical sagittal curvature of certain patients will be lordotic after laminoplasty is unclear. As pointed out by Wasinpongwanich et al. in their systematic review and meta-analysis, summarized fusion rate, operative time, clinical outcomes, complications for transforaminal lumbar interbody fusion (TLIF) vs. other techniques used in lumbar spine diseases. Focusing on elderly patients with single-level thoracolumbar severe osteoporotic vertebral compression fracture (sOVCF), Zhou et al. provided evidence for the effects of percutaneous kyphoplasty (PKP) with vs. without posterior pedicle screw fixation (PPSF) on long-term spinal sagittal balance. Due to limited guideline information on whether indirect decompression is sufficient after oblique lumbar interbody fusion (OLIF), Tseng et al. compared the effectiveness of the indirect decompression by OLIF with direct posterior decompression among lumbar foraminal stenosis patients. Radiofrequency denervation, as a common interventional treatment for chronic low back pain, has different emerging types such as pulsed radiofrequency denervation. In their systematic review, Li et al. comprehensively reviewed literature on radiofrequency denervation therapy in treating facet joint-derived chronic low back pain and compared efficacy of different radiofrequency denervation interventions using network meta-analysis.A number of papers in the current Research Topic focused on comparing different surgical procedures used in spine surgery. Chen et al. evaluated the learning curve of UBE using the cumulative summation (CUSUM) method analysis.Understanding the learning process of surgical techniques is beneficial to surgeons who hope to master one surgical technique. For the past few years, unilateral biportal endoscopic (UBE) has become a popular technique for spinal surgery. However, even for skilled spinal surgeons, there may be obstacles in the learning process of UBE technology. To this end, Briguglio et al. tried to develop a hemoglobin-based prediction model to predict long-term recovery after spine surgery but regrettably, this model may not be reliable due to the low specificity. Nevertheless, as indicated by Briguglio et al. preoperative hemoglobin, interestingly, is one of the key laboratory biomarkers to predict long-term recovery after spine surgery. Identifying prognostic factors for patients who received spine surgery is also of great importance. By finding out factors which could provide prognostic information for patients, we may forecast the future outcomes in patients with a particular health condition and thus choose more suitable treatment under a specific situation. The risk factors for postoperative shoulder imbalance are rarely reported in adult scoliosis (AS). Hence, Ke et al. performed a detailed assessment of risk factors related to radiography in AS patients who underwent correction surgery. Deng et al. gave a comparison of sagittal balance and functional outcomes in lumbar fracture surgery patients using different intermediate pedicle screws with different insertion depth. Wei et al. examined risk factors of bone graft nonfusion for spinal tuberculosis patients who underwent lesion removal, bone graft fusion and internal fixation.Prognosis research is of great importance in the context of current spine surgery. Several papers published in this Research Topic developed prediction model and investigated prognostic factors in different kinds of spine surgery. Clinical prediction models have plenty of applications in clinical practice. For instance, clinical prediction models help us to decide whether we need further testing, whether we need to start a treatment and which treatment need to be performed . BriguglJin et al. compared the subsidence rate in zero profile anchored spacer (ROI-C) and conventional cage and plate construct (CPC) in patients undergoing anterior cervical decompression and fusion (ACDF). Cases series by Florence et al. provided eight cases who had hardware complications after placement of interspinous process devices (IPDs) and gave us experience in management of high risk IPD patients.Complications after surgery also deserve more attention. Focusing on postoperative cage subsidence, a common complication after spine surgery, Xu et al. developed a new surgical plan for adults with tibial-eminence fracture (TEF) and assessed the clinical effectiveness of day case arthroscopic-surgery treatment. Interestingly, thromboelastography (TEG) markers could forecast the occurrence of ecchymosis after total knee arthroplasty (TKA), as found by Chen et al.This Research Topic also included papers related to other orthopedic surgery, which give an additional view for spine surgery. For instance, We sincerely thank all authors who contributed to the current Research Topic \u201cAdvancing the Understanding of Surgical Management for Degenerative Spine Conditions\u201d. We appreciate the reviewers' valuable comments and constructive suggestions. Also, we express our gratitude to the editorial team for their support.We unfeignedly hope that articles in this Research Topic will help surgeons make the right decisions and inspire researchers to give a further exploration of surgical management for degenerative spine conditions."} +{"text": "Botrytis, Colletotrichum, and Fusarium.Crop plants are constantly exposed to diverse biotic stressors during their lifetime. Fungal pathogens represent a predominant biotic stress of crops and account for 80-85% of known diseases leading to significant yield losses. Host plant resistance against fungal pathogens is due to diverse factors such as plant genetic background, physiological status, agroecological, and environmental conditions. In addition, the microbiome associated with host plants has also been shown to contribute to resistance by producing metabolites that modulate host plant defense pathways or exhibit antimicrobial properties. The advancement in next-generation sequencing (NGS) technology for genome/RNA sequencing and modern omic approaches such as proteomics, metabolomics, and interactomics have profusely helped to define host plant resistance mechanisms. These technological advances have made possible introgression of resistance traits into agronomically important varieties by traditional or molecular breeding. Recently, the application of highly sophisticated biotechnological tools using RNAi or CRISPR-Cas9-based gene editing has enabled us to precisely manipulate the integration and expression of key genes for enhanced host resistance. This special issue compiles articles that highlight mechanisms underlying host plant-fungal interactions that govern susceptibility or resistance to fungal pathogens including Botrytis cinerea (B. cinerea) negatively impacts strawberry production worldwide. The fungus preferentially infects flowers and fruits of strawberry. Using B. cinerea resistant and susceptible cultivars and global mRNA sequencing, Xiao et\u00a0al. demonstrated higher expression of defense-related genes and lower expression of genes associated with cell wall degrading enzymes and peroxidases in the resistant cultivar during early stages of infection. The authors also showed increased expression of calcium signaling pathway related genes namely CPKs, RBOHDs, CNGCs, and CMLs and genes associated with jasmonic acid, auxin, and phenylpropanoid metabolism in the resistant cultivar. The work presented here could be useful for future breeding efforts or transgenic manipulation of candidate genes to improve gray mold resistance in strawberry.Gray mold disease in strawberry caused by the necrotrophic fungus B. cinerea, Zhao et\u00a0al. delineated the molecular basis of resistance. Using resistant and susceptible genotypes and a combination of tools including gene expression, quantification of metabolites, and microscopy, the authors dissected leaf-associated factors in woodland strawberry potentially contributing to resistance against the fungus. Higher basal (in absence of the fungus) expression of resistance related genes rather than induction of genes in response to the fungus was observed in the resistant genotype. Metabolites such as total phenolics, total flavonoids, glucose, galactose, citric acid, and ascorbic acid were positively correlated with B. cinerea resistance, whereas H2O2 and sucrose were negatively correlated with resistance. The authors suggested higher innate antioxidant profile of leaves as one of the key factors contributing to resistance against the fungus.In another study addressing strawberry leaf resistance against Hordeum vulgare L. var. nudum), Tibetan hulless barley grown in higher elevation regions, is not fully understood. Using genome and transcriptome mining through bioinformatics, Wang et\u00a0al. demonstrated the role of specific members of the TLP gene family in biotic (powdery mildew) and abiotic stress tolerance. Analysis of promoter regions of this gene family showed presence of putative transcription factor binding motifs associated with growth and development, hormone signaling, light and stress responses. Gene expression analysis using qRT-PCR validated the induction of specific members of TLPs in response to sodium salicylate and methyl jasmonate treatments. The work presented here provides future opportunities for crop improvement in Qingke which is a staple crop in Tibet.In plants thaumatin-like proteins (TLPs) have been implicated in a wide range of physiological processes including stress response and growth and development. The role of this gene family in Qingke is an economically important tree species and highly susceptible to the fungal pathogen Colletotrichum fructicola. Zheng et\u00a0al. dissected the role of specific plant secondary metabolites in resistance against this fungus using C. paliurus resistant and susceptible cultivars. Through multiomic approaches namely mRNA sequencing and metabolomic analyses, the authors demonstrated that early induction and reprogramming of the flavonoid biosynthetic pathway potentially contribute to resistance to C. fructicola. The information presented here provides valuable information on biomarker/s for future resistance breeding in C. paliurus and/or using natural flavonoid extracts from a resistant cultivar as an antifungal treatment against this fungus.Wheel wingnut . The authors found that faba bean\u2013wheat intercropping under field conditions significantly improved Fusarium wilt disease severity in comparison to monoculture of faba bean plants. Reduction in cellular contents of H2O2 and O2 accompanied by increased expression and activities of superoxide dismutase and catalase enzymes in the roots of faba bean plants were observed when intercropped with wheat. In addition, reduced benzoic acid and cinnamic acid in the rhizosphere soil of faba bean plants improved the stability of root cells. The authors used a reverse approach and showed that exogenous application of benzoic acid and cinnamic acid to the roots of faba bean plants increases Fusarium wilt symptoms under greenhouse conditions. This demonstrates the role of allelopathic compounds in the rhizosphere of faba bean crop in resistance to Fusarium wilt.Overall, the work presented in this volume advances our understanding towards plant-fungal interactions and sets a good foundation for future breeding approaches to improve crop resistance to fungal pathogens.All authors listed have made substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "Phaeodactylum tricornutum (UTEX 466) using different loadings of fungal pellets (Aspergillus sp.) and model the process through kinetics and equilibrium models. Active P. tricornutum cells were not required for the fungal-assisted immobilization process and the fungal isolate was able to immobilize more than its original mass of microalgae. The Freundlich isotherm model adequately described the equilibrium immobilization characteristics and indicated increased normalized algae immobilization under low fungal pellet loadings. The kinetics of algae immobilization by the fungal pellets were found to be adequately modeled using both a pseudo-second order model and a model previously developed for fungal-assisted algae immobilization. These results provide new insights into the behavior and potential applications of fungal-assisted algae immobilization.Immobilizing microalgae cells in a hyphal matrix can simplify harvest while producing novel mycoalgae products with potential food, feed, biomaterial, and renewable energy applications; however, limited quantitative information to describe the process and its applicability under various conditions leads to difficulties in comparing across studies and scaling-up. Here, we demonstrate the immobilization of both active and heat-deactivated marine diatom The insights and modeling techniques demonstrated here will help to provide industrially relevant benchmarks for the immobilization of other species of commercial or environmental interest and provide necessary data for future techno-economic and life cycle assessments."} +{"text": "Social isolation is prevalent among community dwelling older adults. Low income older adults living in subsidized housing may have increased risk for social isolation. To examine resident experiences and perspectives relating to their social connections during the COVID-19 pandemic, we conducted semi-structured interviews with 13 older adults (62+) who are English, Spanish, and Mandarin speaking recruited from a large non-profit affordable housing organization with communities in 22 states. Twelve housing communities were identified based on distributions of socio-demographic factors and prevalence of self-reported social isolation l in the housing community\u2019s annual survey of residents in order to maximize site diversity. We used qualitative thematic analysis methods to examined participants\u2019 views about their social connections before and during the COVID-19 pandemic, as well as their personal and the housing community\u2019s strategies to mitigate experiences of social isolation. Emerging themes include loss of common facilities and opportunities to socialize with other residents due to COVID-19 restrictions, and increased use of technology to stay connected."} +{"text": "Neighborhoods are diverse and may or may not present opportunities for stress reduction or social engagement depending on their qualities. Based on the stress connectome , psychosocial stress may accelerate cognitive aging, which explains place-based disparities in cognitive function. This study examines two attributes of the neighbourhood environment, and their potential to influence cognitive function through semantic fluency.Using aggregated baseline data from N=1,010 neighborhoods with 5 or more respondents in the Canadian Longitudinal Study on Aging, we examined the effects of neighborhood greenness and cohesion on aggregates of age-, sex-, and education-adjusted cognitive test scores. Participants were community-dwelling adults aged 44 and above. Semantic fluency was assessed using the Animal Fluency Test (AFT). Delayed recall was assessed using Rey\u2019s Auditory Verbal Learning Test (RAVLT), whereas executive function was assessed using Mental Alternation Test (MAT). Neighborhood qualities were found to affect delayed recall and executive function through semantic fluency . Semantic fluency fully mediated the effects of neighborhood attributes on cognitive function. Further stratifying these neighborhoods by socioeconomic status showed that cohesion has stronger effects in poorer neighborhoods (B indirect=.104) than richer neighborhoods (B indirect=.066). The effect of greenness was no longer significant upon stratification. Neighborhoods offer an important social arena for adults in mid- and late-life to practice conversing, especially in poorer neighborhoods, which improves cognitive function. Creating opportunities for socialization by improving cohesion and neighborhood parks may reduce place-based disparities in cognitive health. Causality remains to be ascertained."} +{"text": "Examining the neural circuits of fear/threat extinction advanced our mechanistic understanding of several psychiatric disorders, including anxiety disorders (AX) and posttraumatic stress disorder (PTSD). More is needed to understand the interplay of large-scale neural networks during fear extinction in these disorders. We used dynamic functional connectivity (FC) to study how FC might be perturbed during conditioned fear extinction in individuals with AX or PTSD. We analyzed neuroimaging data from 338 individuals that underwent a two-day fear conditioning and extinction paradigm. The sample included healthy controls (HC), trauma-exposed non-PTSD controls, and patients diagnosed with AX or PTSD. Dynamic FC during extinction learning gradually increased in the HC group but not in patient groups. The lack of FC change in patients was predominantly observed within and between the default mode, frontoparietal control, and somatomotor networks. The AX and PTSD groups showed impairments in different, yet partially overlapping connections especially involving the dorsolateral prefrontal cortex. Extinction-induced FC predicted ventromedial prefrontal cortex activation and FC during extinction memory recall only in the HC group. FC impairments during extinction learning correlated with fear- and anxiety-related clinical measures. These findings suggest that relative to controls, individuals with AX or PTSD exhibited widespread abnormal FC in higher-order cognitive and attention networks during extinction learning and failed to establish a link between neural signatures during extinction learning and memory retrieval. This failure might underlie abnormal processes related to the conscious awareness, attention allocation, and sensory processes during extinction learning and retrieval in fear- and anxiety-related disorders. Conditioned fear inhibition is achieved by the repeated presentations of the conditioned stimulus in the absence of the unconditioned stimulus. This fear extinction process is critical for fear reduction in the aftermath of trauma exposure or when exposed to fear- and anxiety-inducing stimuli. Failure to appropriately extinguish fear could contribute to the maintenance of anxiety-related symptoms, which is thought to characterize posttraumatic stress disorder (PTSD) and anxiety disorders , 2. PavlMost human neuroimaging studies have yet to establish a connection between cognitive/attention networks and the subjective measures of fear and anxiety. Recent studies started to emerge in support of the LeDoux-Pine concept. For example, meta-analyses revealed the engagement of multiple cortical regions during the fear conditioning and extinction tasks , but theIn this study, we examined the dynamic changes of large-scale FC across extinction learning in healthy individuals and in patients diagnosed with anxiety disorders or PTSD. We estimated whole-brain connectivity of participants during different timepoints of extinction learning, compared the FC change between groups, and evaluated the relevance of extinction-induced FC changes to various fear- and anxiety-related clinical metrics. Based on our previous study , and givWe analyzed data from a total of 338 individuals (see Supplementary Methods). Of those, 77 were healthy controls (HC), 91 were diagnosed with anxiety disorders (AX), 81 were diagnosed with PTSD, 89 were trauma-exposed non-PTSD controls (TENC) procedure , r\u2009=\u20090.48, p\u2009<\u20090.001), but not in the AX group or the PTSD group . Steiger\u2019s Z test confirmed that the HC group showed significantly higher correlation than the other two groups . A significantly positive correlation between \u0394FC and vmPFC activation was also observed in the HC group using the network identified with HC vs. PTSD group as a control group, we conducted additional FC analyses comparing the PTSD to TENC. These additional analyses mostly replicated the results of HC vs. PTSD analyses (see Supplementary Results for details); revealing a significant network component that mainly involved connections between the DMN with other networks , supporting the robustness of the identified canonical variate. We then calculated the canonical loadings to examine how the individual clinical measure and connectivity contributed to the canonical variate in the HC and AX groups . The canonical loadings indicated that the symptom measure positively contributed to the clinical variate, while \u0394FC negatively correlated with the connectivity variate in the TENC and PTSD groups and patients diagnosed with anxiety disorders (AX) or PTSD. From early to late extinction learning, HC exhibited an increase in FC that was specific to the conditioned cue. The AX and PTSD groups exhibited widespread FC impairments during extinction learning. The relative FC reductions in patient groups were predominantly in the interactions between the default mode network (DMN), frontoparietal control network (CON), somatomotor network (SMN), and attention networks (DAN/VAN). The extinction-induced FC changes were predictive of vmPFC activation during extinction recall only in the HC group. FC changes during extinction learning positively and negatively correlated with FC during recall in the HC and the AX groups, respectively. Finally, extinction-induced FC was associated with subjective measures of fear- and anxiety-related clinical metrics.Animal literature shows that learning-induced plasticity can change both neural activity and neuronal synchronization . Neural Prior fear extinction studies have focused predominantly on neural circuits associated with expression and inhibition of conditioned threat responses. The conscious awareness of fear, and the feeling of no longer being afraid, would require multiple cognitive processes, including perception, attention, conscious awareness, and memory construction. These multi-level processes are likely to require coordinated interactions between distributed brain regions . A recenThe distinct dysfunction in some networks and the partial overlap in some others across the AX and PTSD groups suggest both divergent and shared mechanistic impairments pertinent to fear inhibition across these psychopathologies. While there was an overlap in the FC dysfunction across multiple brain regions between the patient groups, the dlPFC\u2014a region known for its contribution to cognitive control and regulation \u201344, appeWe observed a positive correlation between extinction-induced \u0394FC and vmPFC activation during memory recall only in the HC group. The vmPFC plays a key role in inhibiting threat response , 20, 49.We specifically focused our analyses on the connectivity during CS+ processing since our previous study on healthy controls showed that connectivity during CS+ processing increased from early to late extinction learning, and predicted the magnitude of extinction memory . The ideWe observed abnormal connections extensively involved CON and DMN in the PTSD group when comparing it with either the non-exposed controls or trauma-exposed controls. This result suggests that the connectivity alterations in the PTSD group are not merely a result of the traumatic exposure. There is evidence showing that traumatic exposure per se may alter activation and functional connectivity , 53, 54.The dynamic nature of extinction learning-induced neural plasticity is overlooked to some degree in prior studies as many neuroimaging studies average functional brain activation across extinction learning. However, a few prior studies suggested the dynamic changes of activation during the fear conditioning and extinction paradigm in PTSD and healthy participants , 31. SpeSupplemental material"} +{"text": "Positive affect is important for physical health, well-being, and relationships. Yet, most studies of dementia care dyads have focused on negative outcomes, such as depression and caregiver burden. We present findings from studies that address this important research gap. The first two speakers present findings from actor partner interdependence models using secondary data from a randomized controlled trial of persons with early-stage dementia (PWD) and their spouses. Specifically, Dr. Monin will show that actor quality of life is significantly related to positive affect cross-sectionally, controlling for functional status of each partner and PWD behavioral symptoms. Ms. Piechota will present longitudinal findings demonstrating that when spouses were high in difficulty regulating emotions, the PWD\u2019s positive affect decreased over three months, controlling for intervention arm and covariates. The second two speakers will present findings from two different studies of persons living with behavioral-variant frontotemporal dementia (bvFTD), Alzheimer\u2019s disease (AD), and controls that engaged in laboratory conflict discussions. Dr. Brown will show that caregivers of individuals with bvFTD reported greater decreases in positive emotion across the discussion relative to caregivers of individuals with AD and language variants. She will also discuss how caregivers who reported greater decreases in positive emotion had higher levels of depressive symptoms, controlling for their partner\u2019s diagnosis and level of cognitive impairment. Finally, Dr. Chen will provide evidence that bvFTD caregivers had lower emotional well-being according to the SF-36 than AD caregivers and controls, and this effect was fully mediated by bvFTD caregivers' lower positive emotional connections."} +{"text": "Increasing travel times to the nearest diagnostic facilities and cancer centers are correlated with decreasing prevalence of breast cancer diagnosis and increasing stage of cancer at diagnosis. Moi Teaching and Referral Hospital (MTRH), in Uasin Gishu County, houses the only public cancer center in western Kenya. A MTRH program, the Academic Model Providing Access to Healthcare Breast and Cervical Cancer Control Program (ABCCCP) hosted health fair breast cancer screening events and mentored nurses at local health facilities to complete clinical breast exams (CBEs). The objective is to understand the effect of the ABCCCP in reducing geographic barriers for breast cancer screening/early diagnosis.This is a retrospective review of the 61,392 patients who underwent breast cancer screening at a ministry of health facility in western Kenya from 2017-2021. ABCCCP hosted health fairs targeted at communities and mentored nurses at health facilities to complete clinical breast exams (CBEs) to target individual patients. Facility distances from MTRH were mapped via Google Maps. Descriptive analyses were performed to a significance of \u03b1 < 0.05.Two-thirds of the screening/early diagnosis CBEs occurred in five of the 22 counties in western Kenya: Busia, Uasin Gishu, Trans-Nzoia, Bungoma, and Kakamega. However, these five counties only had 25% of all ABCCCP screening sites in western Kenya. Only Uasin Gishu and Kakamega provided chemotherapy while Busia and Trans-Nzoia had additional programming promoting preventative healthcare through integration of community health volunteers. In these five counties, no association between the distance of the ministry of health facilities from MTRH and number of CBEs completed existed.ABCCCP programming reduced some geographic disparities in breast cancer screening/diagnosis in the top five counties. It may be result of the number of mentored nurses and health fair events. Further work should be completed to understand if a relationship between geographic distance from MTRH and the stage and treatment patterns of these patients is also reduced by ABCCCP."} +{"text": "Research from across the globe has consistently shown that young sexual and gender minority individuals are at a higher risk for depression, anxiety, and suicidal thoughts and behaviors when compared to heterosexual youth, including during early childhood and later adolescence. A sizeable body of research has attributed the elevated risk to increased exposure to specific social stressors related to navigating a stigmatized minority identity, including stressors such as victimization and other interpersonal and social difficulties in, for example, the school environment. Yet, relatively less is known about the early developmental timing of such disparities in childhood and how LGBT+ youth navigate school climates. As a sensitive developmental period, childhood and adolescence may be a particularly challenging time for sexual and gender minority youth to navigate cisnormative and heteronormative school contexts. Exposure to oppressive norms, particularly in school environments, has only recently become the subject of research. Additionally, research has been limited on how supportive school climates may be protective but stigmatizing school environments may drive LGBT+ trajectories towards suicidal behaviors and shape how they may navigate self-disclosure of cooccurring identities and mental health status in school settings, particularly when such stigmas may prevalently intersect. This workshop aims to further explore these novel aspects around developmental and school-based risk and protective factors shaping the mental health of sexual and gender minority children and adolescents. This workshop includes five empirical presentations that span from examining the developmental timing of mental health disparities, the role school-based experiences play in shaping and driving these disparities, to how sexual and gender minority youth may navigate their school context and how supportive climates may be protective for mental health. First, Arjan van der Star will present longitudinal evidence on how sexual identity formation precedes the onset of sexual orientation-based mental health disparities and the role that peer difficulties play in driving these as early as pre-teen years. Next, Niolyne Jasmin Bomolo will present findings from a qualitative study that unravel how school-based experiences shape individual trajectories toward suicidal attempts among LGBT+ adolescents. Third, Wouter Kiekens will explore how normative cultures in school environments may drive sexual attraction-based mental health disparities among a large sample of adolescents. Fourth, Lourdes Cantarero Ar\u00e9valo will present findings on how LGBT+ adolescents living with mental conditions navigate self-disclosure in school environments. Finally, Sandra Sevic will present results on how supportive school environments may be protective for gender minority mental health.\u2022\u2002Negative school-based experiences put sexual and gender minority youth at elevated risk for adverse mental health as early as middle childhood.\u2022\u2002Intersecting stigmas around minority identities and mental health problems may further complicate how sexual and gender minority children and adolescents navigate their school environments."} +{"text": "In recent years, targeting tumor specific metabolism has gained an interest as a promising therapeutic strategy. We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is highly prevalent in ovarian carcinoma patients and contributes to elevated mitochondrial metabolism in ovarian tumor models. The SDHA overexpressing tumor cells are highly metabolically active, relying on both glycolysis and oxidative phosphorylation in mitochondria to meet their energy requirements. Further, we found that those cells are particularly vulnerable to deprivation of essential nutrients such as glucose and glutamine, which led to a substantial reduction of ATP yield. Lastly, we identified an anti-metabolic compound shikonin, which demonstrated a potent anti-tumor efficacy against SDHA overexpressing ovarian cancer cells. Overall, we strive to advance scientific knowledge by uncovering the previously unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which holds untapped opportunities for therapeutic intervention.We discovered that the overexpression of mitochondrial enzyme succinate dehydrogenase (SDHA) is particularly prevalent in ovarian carcinoma and promotes highly metabolically active phenotype. Succinate dehydrogenase deficiency has been previously studied in some rare disorders. However, the role of SDHA upregulation and its impact on ovarian cancer metabolism has never been investigated, emphasizing the need for further research. We investigated the functional consequences of SDHA overexpression in ovarian cancer. Using proteomics approaches and biological assays, we interrogated protein content of metabolic pathways, cell proliferation, anchorage-independent growth, mitochondrial respiration, glycolytic function, and ATP production rates in those cells. Lastly, we performed a drug screening to identify agents specifically targeting the SDHA overexpressing tumor cells. We showed that SDHA overexpressing cells are characterized by enhanced energy metabolism, relying on both glycolysis and oxidative phosphorylation to meet their energy needs. In addition, SDHA-high phenotype was associated with cell vulnerability to glucose and glutamine deprivation, which led to a substantial reduction of ATP yield. We also identified an anti-metabolic compound shikonin with a potent efficacy against SDHA overexpressing ovarian cancer cells. Our data underline the unappreciated role of SDHA in reprogramming of ovarian cancer metabolism, which represents a new opportunity for therapeutic intervention. The reprogramming of cellular metabolism is a hallmark of cancer allowing tumor cells to survive and proliferate. The Warburg effect is an established signature of cancer metabolism and refers to the observation that tumor cells preferentially use glucose via glycolysis pathway rather than oxidative phosphorylation (OXPHOS) in mitochondria for energy production . The relSDHA gene amplification or overexpression is highly prevalent in ovarian carcinoma patients compared to other tumor types, which indicates its potential importance in reprogramming of ovarian cancer metabolism.To gain a greater insight into the ovarian cancer metabolism, we interrogated metabolic phenotypes of patient-derived xenografts (PDXs) developed from patients\u2019 ovarian tumors . We usedSuccinate dehydrogenase (SDH) also known as mitochondrial complex II, couples oxidation of succinate to fumarate with reduction of ubiquinone to ubiquinol, thus directly connecting the mitochondrial electron transport chain (ETC) with the tricarboxylic acid (TCA) cycle . SDH conIn this work, using various in vitro and in vivo ovarian cancer models, we investigated the biological consequences of SDHA overexpression and its impact on tumor phenotype. Our findings revealed that SDHA overexpression is associated with the improved ability of cells to survive and generate colonies in anchorage-independent conditions. This is an important feature of metastatic ovarian tumor cells that are able to survive and spread in peritoneal fluid (ascites) within the abdominal cavity. Further, we showed that the overexpression of SDHA enhanced ovarian cancer metabolism reflected as increased mitochondrial respiration and ATP production rate. Lastly, we performed a drug screening and identified an anti-metabolic compound shikonin known to disrupt glycolysis and amino acid metabolism ,20. We sAltogether, our study demonstrated that SDHA upregulation frequently occurs in ovarian cancer and contributes to reprogramming of energy metabolism towards highly metabolically active phenotype. Importantly, we showed here that SDHA overexpressing tumor cells can be effectively targetable by anti-metabolic compounds such as shikonin, which represents a new opportunity for therapeutic intervention in ovarian cancer.2 and 95% O2 atmosphere. Cell lines were tested for Mycoplasma by Idexx BioAnalytics and were found negative for any contamination. Human fallopian tube tissues and established PDX tumor models were obtained from the PDX-PCT core facility at OMRF ..29]. We In conclusion, this study demonstrated that the SDHA overexpression contributes to metabolic enhancement associated with significantly increased mitochondrial respiration as well as glycolysis in some of the cell lines leading to increased ATP production rate.As another approach to assess the impact of SDHA upregulation on cellular metabolism, we tested ovarian cancer dependence on nutrients essential for tumor growth. We deprived ovarian cancer cells of selected metabolic nutrients such as glucose or glutamine, or replaced glucose with galactose in culture medium. Glucose is required by cells to produce ATP via glycolysis, and to fuel TCA cycle with pyruvate. Replacing glucose with galactose forces cells to rely almost exclusively on mitochondrial OXPHOS for ATP production . GlutamiTo determine if SDHA overexpression redirects cellular metabolism in response to nutrient deprivation, we cultured selected ovarian cancer cell lines in low glucose, low glutamine or galactose medium and assessed cellular respiration by the Seahorse XF Cell Mito Stress Test . We obseTo better understand cellular energetics in SDHA overexpressing ovarian cancer cells deprived of nutrients, we quantified ATP production rate. We observed that ovarian cancer cells showed substantial metabolic plasticity, which enabled the cells to switch between glycolysis and oxidative phosphorylation to adapt to changing nutrient conditions during experiment . Our datFurther, we analyzed a total ATP production rate in OVCAR3 cell lines in conditions with low glucose or low glutamine supply. Following glucose deprivation, OVCAR3 cells were capable to fully compensate for a loss in glycolytic ATP production by increasing their mitochondrial ATP production rate E. Such mCollectively, these findings indicate that SDHA overexpressing cell lines are not able to fully compensate for the loss of ATP production following glucose or glutamine deprivation, which results in a significant drop in a total ATP yield. In contrast, the corresponding SDHA-low cells demonstrated an improved metabolic capacity allowing them to better maintain a constant ATP production rate in nutrient deprived conditions. These data also suggest that SDHA overexpressing cells can be more sensitive to a deficiency in essential nutrients or cellular stress.We reasoned that SDHA overexpressing cells could be particularly vulnerable to drugs disrupting glucose and/or glutamine metabolism. To identify agents specifically targeting the SDHA overexpressing ovarian cancer cells, we utilized a custom compound library (from Seleckchem) composed of 64 anti-metabolic compounds . First, Lithospermum erythrorhizon plant) is a Chinese herbal medicine that has been known for its anti-inflammatory and anti-microbial activity [Next, we selected 7 the most potent anti-metabolic compounds and evaluated their efficacy in SDHA-high vs. SDHA-low cell lines. We observed that both shikonin and methotrexate significantly reduced viability of SDHA-high cell lines when compared with SDHA-low counterparts, however the shikonin was the most effective agent in specifically killing SDHA overexpressing cells B. Furtheactivity . More reactivity ,20. NextCollectively, we identified a highly potent compound shikonin that effectively kills SDHA overexpressing ovarian cancer cells. The SDHA overexpression strongly sensitized cancer cells to shikonin, which exhibited a profound anti-tumor efficacy superior that seen with traditional chemotherapy.The reprograming of cellular metabolism is an essential mechanism of tumorigenesis. The metabolic plasticity allows cancer cells to adapt to various unfavorable microenvironmental conditions and sustain uncontrolled cell proliferation, which promotes tumor progression and metastasis ,41. In tSuccinate dehydrogenase has been previously studied in the context of its deficiency in some rare disorders and malignancies ,15,16,17In the present study, our initial findings highlighted a potential importance of SDHA upregulation in ovarian cancer and set the stage for further more rigorous research. First, we performed an analysis of SDHA expression in a collection of healthy fallopian tubes and HGSOC PDX models, which showed that SDHA protein levels are significantly lower in fallopian tubes than in PDX tumors. Further, we observed that ovarian PDXs and established ovarian cancer cell lines exhibit a range of SDHA expressions. Importantly, the percentage (23.5%) of SDHA-high PDX tumors in our data set is consistent with the percentage (19%) of ovarian tumors harboring amplification and/or overexpression of SDHA in patients population (TGCA data set) . Our finTo evaluate the SDHA biological functions in ovarian cancer, we assessed the effect of SDHA overexpression on cell proliferation and in vivo tumor growth. The in vitro experiments revealed that SDHA upregulation is associated with a reduced cell proliferation in some cell lines, while in other cell lines the proliferation of cells is only marginally affected. In vivo data showed a tendency towards reduced tumor growth rate in mice bearing OVCAR3 tumor model. Our findings are in agreement with published studies. For instance, Xu et al., reported that the overexpression of SDHA in renal carcinoma cells inhibited cell proliferation in vitro and suppressed tumor growth in a nude mouse model in vivo . DiffereFurther, our work demonstrated that SDHA overexpression is associated with a generation of significantly more and larger cancer cell colonies in anchorage-independent conditions. It has been shown that aggressive and metastatic tumor cells are able to survive and rapidly propagate in the absence of anchorage to the extracellular matrix, while less tumorigenic or normal cells undergo growth inhibition and/or apoptosis (a process known as anoikis) . These dIn the present study, we set out to investigate the differences in bioenergetic profiles of ovarian cancer cell lines overexpressing SDHA vs. their respective SDHA-low counterparts. The cell lines showed a substantial diversity in their bioenergetic requirements, which was associated with the SDHA overexpression status. Our data consistently demonstrated that the cell lines with SDHA overexpression showed a significantly higher mitochondrial respiration, and tended to have higher maximal and reserve glycolytic capacity. This highly metabolically active phenotype of SDHA overexpressing cells was reflected by significantly increased total ATP yield. Variability in bioenergetic profiles and metabolic plasticity have been previously described in ovarian cancer and other tumor types by others ,32,48,49In our study, we also noted that all cell lines regardless of SDHA status preferentially used glycolysis pathway to fulfill their energy requirements as assessed by higher rates of ATP production from glycolysis than from OXPHOS, which is also in agreement with published data ,51,52. SIn different sets of experiments, we deprived ovarian cancer cells of glucose or glutamine to determine if SDHA overexpression redirects cellular metabolism in response to nutrient deficiency. The cells showed substantial metabolic plasticity switching between glycolysis and oxidative phosphorylation to adapt to changing nutrient conditions. We observed that glucose limitation significantly reduced ATP production from glycolysis that has been compensated with a higher ATP yield from OXPHOS, while glutamine deprivation increased glycolytic ATP yield suppressing ATP production via mitochondrial respiration. Such metabolic flexibility allows cells to become more resilient in variable conditions of tumor microenvironment ,9,32,53.In summary, our work provided novel insights into the role of SDHA upregulation in reprogramming of energy metabolism in ovarian cancer. We showed that SDHA overexpressing cells are highly metabolically active, relying on both glycolysis and oxidative phosphorylation to meet their energy needs. While this phenotype may not drive a higher proliferation rate, it improves cells\u2019 ability to survive anchorage-independent conditions. Importantly, we found that ovarian cancer cells with elevated SDHA are more vulnerable to deprivation of both glucose and glutamine, which is associated with a substantial reduction of ATP yield in those cells. Lastly, we implemented a drug screening strategy and identified anti-metabolic compound shikonin, which demonstrated a specific and potent efficacy against SDHA overexpressing ovarian cancer cells. Our future directions will be focused on pre-clinical testing of shikonin as a promising therapeutic approach for SDHA-amplified tumors. This work is a major step towards our long-term goal, to develop innovative ways to precisely target ovarian cancer-specific metabolism to improve treatment options for ovarian cancer patients."} +{"text": "Starter Lactic Acid Bacteria (LAB) are responsible for converting lactose to lactic acid during cheese manufacturing and, as a result, play a critical role in defining the attributes of the final product. There is great interest in isolating novel starter LAB strains to provide alternatives to existing industry cultures or to help enhance the quality and safety of cheeses traditionally made without starter cultures addition [1].The Fast-Slow Differential Agar (FSDA) medium was developed in 1984 and still remains the standard to rapidly differentiate fast and slow milk-coagulating lactic streptococci and thus avoid screening a large number of isolates for acid production capacity [2]. However, we found that FSDA was unable to selectively isolate fast acid-producing strains from young, traditional, starter-free Izmir Brined Tulum cheeses, due to the presence of a diverse microbiome including Non-Starter LAB and spoilage Gram-negative microbiota .\u2022Nalidixic acid is an antibiotic that primarily inhibit Gram-negative bacteria [4].\u2022Ascorbic acid and yeast extract stimulate the growth of lactic streptococci [5] and were added to complement skim milk in creating an environment favoring the growth of lactose-positive, casein peptides-utilizing LAB.\u2022The pH indicator bromocresol purple enabled the chromogenic discrimination between LAB with different acid production capability.Here, we describe a modified FSDA (mFSDA) with increased selectivity and recovery efficiency towards lactic streptococci, which was successfully used to rapidly isolate potential starters from Tulum cheeses [1] and could similarly outperform FSDA in raw milk cheeses and other varieties containing high levels of \u201cbackground\u201d microbiota. The main differences between FSDA and mFSDA media consist in the presence of nalidixic acid, ascorbic acid and yeast extract in mFSDA. These targeted additions provide mFSDA with a two-prong selectivity that (I) suppresses unwanted microbiota, and (II) increases the recovery efficiency of lactic streptocci adept to using milk nutrients. Specifically: Specifications tableThe composition of mFSDA medium is provided in For mFSDA bromocresol purple was chosen over litmus as it was reported to be equivalent to litmus by the developers of the FSDA medium Schleiferilactobacillus harbinensis, while most potential spoilage microorganisms were unable to grow on mFSDA except for Bacillus subtilis. Most of the LAB species tested also produced acid, except for some species normally associated with the Non-Starter LAB microbiota, such as Levilactobacillus brevis, Lentilactobacillus parabuchneri and Latilacobacillus curvatus.The mFSDA medium was initially validated using a bank of 27 Gram-positive and Gram-negative bacteria isolated from raw milks, dairy plants and cheeses during previous projects and stored in the Teagasc DPC culture collection . ResultsFollowing this successful validation, we tested the ability of mFSDA to isolate potential starter streptococci strains from young Izmir Brined Tulum cheeses. Due to the absence of starter addition during manufacturing, young samples of this traditional cheese variety can accumulate spoilage Gram-negative microbiota A key trait of a starter culture for cheese production is the ability to grow rapidly in milk and reduce the pH to \u2264 5.3 in 6 hours. On the other hand, non-starter LAB grow slowly in milk and do not cause such a pH reduction as they are generally lactose-negative and use peptides and free amino acids released from casein by the action of the starter LAB and residual chymosin in the cheese as their nitrogen source Streptococcus infantarius subsp. infantarius and Streptococcus macedonicus, were confirmed to be good acid producers when grown in 10% reconstituted skim milk.In agreement with this, results of the related study In conclusion, the newly developed mFSDA medium affords the same rapid and direct selection of fast acid-producing strains of lactic streptococci as the original FSDA medium while enhancing the recovery efficiency in environments containing background Gram-negative microbiota.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} +{"text": "Eosinophilic esophagitis (EoE) is a complex, chronic, allergic disease that commonly presents as dysphagia in young adults. Co-occurring allergic or atopic disease, including food allergies and asthma are seen in approximately 70% of cases. Allergy to house dust mite (HDM) tropomyosin, Der p 10, and cross-reactivity to shrimp has been well described. We discuss a presentation of EoE in the setting of positive HDM skin prick testing that subsequently improved with dietary elimination of shrimp, that has never been described in the literature.To highlight an underlying mechanism in EoE and the importance of a multidisciplinary approach to this disease.A 45-year-old male with a medical history significant for ulcerative colitis and asthma was seen by his outpatient gastroenterologist following three weeks of new-onset dysphagia and subjective intermittent food bolus impaction. The patient was pre-emptively started on daily proton pump inhibitor prior to endoscopy, but discontinued this within less than two weeks as he felt like it induced loose bowel movements. Esophagogastroduodenoscopy (EGD) was performed and revealed proximal esophageal furrows. Histology of esophageal biopsies was compatible with EoE: distal esophagus >100 eosinophils/hpf with eosinophil degranulation, mid and proximal esophagus >25 eosinophils/hpf with eosinophil degranulation. The patient self-identified that his episodes of dysphagia and food bolus impaction were associated with shrimp ingestion, thus he eliminated shrimp from his diet.Dermatophagoides pteronyssinus and farina) but negative testing to shrimp, despite clinical improvement with dietary shrimp elimination. Thus his EoE was attributed to HDM cross-reactivity, specifically to the Der p 10 antigen. Follow-up EGD and biopsy to confirm endoscopic and histologic remission with shrimp elimination is scheduled in two months.Two-month clinical follow-up demonstrated symptomatic remission despite no other active treatment or additional food elimination. Consultation with an allergist demonstrated the patient had positive skin prick testing to HDM shrimp, but often only demonstrate positive skin prick testing to HDM (with negative testing to shrimp). This case demonstrates a role for involvement of an allergist and skin prick testing in select cases of EoE, as this may result in a relatively simple food elimination and avoidance of further therapeutic interventions.NoneNone Declared"} +{"text": "Prehospital airway devices are often classified as either basic or advanced, with this latter category including both supraglottic airway (SGA) devices and instruments designed to perform endotracheal intubation (ETI). Therefore, many authors analyze the impact of SGA and ETI devices jointly. There are however fundamental differences between these instruments. Indeed, adequate airway protection can only be achieved through ETI, and SGA devices all have relatively low leak pressures which might compromise both oxygenation and ventilation when lung compliance is decreased. In addition, there is increasing evidence that SGA devices reduce carotid blood flow in case of cardiac arrest. Nevertheless, SGA devices might be particularly useful in the prehospital setting where many providers are not experienced enough to safely perform ETI. Compared to basic airway management devices, SGA devices enable better oxygenation, decrease the odds of aspiration, and allow for more reliable capnometric measurement by virtue of their enhanced airtightness. For all these reasons, we strongly believe that SGA devices should be categorized as \u201cintermediate airway management devices\u201d and be systematically analyzed separately from devices designed to perform ETI. Prehospital airway management devices are often classified as either basic or advanced. According to many recent prehospital studies, both supraglottic airway (SGA) devices and devices designed to perform endotracheal intubation (ETI) represent the advanced category and are therefore analyzed jointly ,2,3,4. IThere are fundamental differences between SGA and ETI devices. While mastering ETI requires considerable clinical expertise , even moIn addition, in studies differentiating ETI from SGA device insertion, clinical outcomes are often different between groups. For instance, a recent study reported the highest mortality and the lowest rate of good neurological performance after out-of-hospital cardiac arrest when SGA devices were used . The reaFurther supporting the separate categorization of SGA devices to explore cardiac arrest related outcomes, a recent simulation study unexpectedly discovered that chest compressions were significantly shallower when ventilation was performed when SGA devices were in place than when bag-valve mask devices were used . Should Even though we are of the opinion that systematically categorizing SGA devices separately from ETI and BVM devices is scientifically sound and could help optimize prehospital care protocols, fellow authors and researchers may disagree with us for diverse reasons. Indeed, researchers working in systems where ETI capacities are always available may consider that analyzing SGA devices separately is not worthwhile. However, many prehospital providers are neither allowed nor trained to perform prehospital ETI, and SGA devices represent the next best option in such situations. In addition, other researchers might consider that almost all emergency prehospital providers should have been taught and allowed to use SGA devices by now. While we are convinced that enabling the vast majority of prehospital providers to use SGA devices is an important objective since these devices readily improve oxygenation and ventilation in many situations, certified paramedics are still not allowed to use such devices in certain regions of the world .We are aware that acknowledging a new category of airway management devices could be considered controversial since different opinions regarding airway management devices have been expressed in the literature, and some authors may even consider our position as provocative. Nevertheless, given the aforementioned differences and the impact they may have on clinical outcomes, we strongly believe that an intermediate airway management category incorporating all SGA devices should be acknowledged. By allowing the specific appraisal of the clinical impact of these devices, policy changes could subsequently be considered in certain settings where airway management resources are scarce."} +{"text": "Cognitive control decline is a major manifestation of brain aging that severely impairs the goal-directed abilities of older adults. Magnetic resonance imaging evidence suggests that cognitive control during aging is associated with altered activation in a range of brain regions, including the frontal, parietal, and occipital lobes. However, focusing on specific regions, while ignoring the structural and functional connectivity between regions, may impede an integrated understanding of cognitive control decline in older adults. Here, we discuss the role of aging-related changes in functional segregation, integration, and antagonism among large-scale networks. We highlight that disrupted spontaneous network organization, impaired information co-processing, and enhanced endogenous interference promote cognitive control declines during aging. Additionally, in older adults, severe damage to structural network can weaken functional connectivity and subsequently trigger cognitive control decline, whereas a relatively intact structural network ensures the compensation of functional connectivity to mitigate cognitive control impairment. Thus, we propose that age-related changes in functional networks may be influenced by structural networks in cognitive control in aging (CCA). This review provided an integrative framework to understand the cognitive control decline in aging by viewing the brain as a multimodal networked system. Over the past 20 years, the proportion of older adults in the population has expanded rapidly . AdvanceTo date, a major focus in neurocognitive aging research was linking cognitive control declines to specific regions . From thAccumulating evidence has suggested that CCA can arise from changes in connectivity among brain networks . NetworkMultiple large-scale networks facilitate specialized mental functioning for cognitive control . These nDecreased functional segregation occurs with aging . FunctioPreliminary evidence has suggested that decreased functional segregation of the TPN is associated with a decline in cognitive control with age. For example, in older adults, lower intra-connectivity within frontoparietal and attention network indicates worse cognitive control, and enhanced inter-connectivity between the frontoparietal and dorsal attention networks is associated with cognitive control decline . FunctioFunctional integration reflects the integrated processing of information during tasks and usually manifests as enhanced functional connectivity . EnhanceFunctional integration among the frontoparietal network may be an important neural indicator of the cognitive control ability during aging. In older adults, functional connectivity between prefrontal and parietal cortex, i.e., within the frontoparietal network, positively predicts their performance during tasks requiring cognitive control . FurtherFunctional integration between frontoparietal network regions and task-specific regions is associated with CCA (as illustrated in Finally, functional integration, as measured by network efficiency properties, declines with aging. Network integrative processes can be viewed as the communication efficiency measured by graph-theoretic properties . In addiCognitive control relies on functional antagonism between large-scale networks. Functional antagonism differs from functional segregation. Functional segregation usually refers to positive functional connectivity, where blood-oxygen dynamics between regions are predominantly positively correlated, whereas functional antagonism refers mainly to negative connectivity, where the blood oxygen level-dependent signals between paired regions are predominantly negatively correlated . FunctioDeclines in functional antagonism are important neurological indicators of the decreased cognitive control in older adults (as illustrated in Aging-related changes in the functional connectivity of large-scale networks are important contributors to CCA. Specifically, decreased functional segregation, integration, and antagonism are associated with worse behavioral performance measured by control-based tasks in older adults . DespiteAnatomically, a large number of isotropic axons are \u201cbundled\u201d together to form white matter fibers. These fibers form a structural network that ensures the transmission of electrical signals across brain regions . In healAge-related structural changes in the white matter involve both decreases in white matter volume and impairment of structural connections . Voxel-bBoth white matter loss and structural disconnection suggest a decrease in neural signaling capacity and are associated with decreased cognitive control . In oldeFunctional networks may serve as mediators of the cognitive control decline triggered by structural network damage. The impairment perspective proposes that damage to structural connections can weaken functional connectivity. Studies have shown that structural connections support functional connectivity in healthy older adults. For example, However, the damage perspective cannot explain some of the existing empirical results and may lead to a view of functional connectivity compensation (A relatively intact structural network may be a prerequisite for functional connectivity compensation, while severe lesions in the structural network can trigger reduced functional connectivity. When considering a network as a whole, a marked similarity between functional and structural networks can be observed . StructuStructural and functional networks show complex interactions affecting CCA. Because structural connections support and constrain functional connections, it could be concluded that structural connection damage triggers cognitive control decline by weakening functional connectivity. However, when the structural network is locally damaged but globally preserved, the effects on functional connectivity may be compensated through third-party structural pathways and may counteract the cognitive control decline associated with the structural damage. Functional compensation determined by preservation of the structural network should be considered in future explorations of network mechanisms underlying CCA.Aging-related changes in structural and functional connectivity among networks are involved in decreased CCA. However, to date, CCA-related network mechanisms have been established based on correlative evidence . In the Common and unique network mechanisms underlie cognitive control. Cognitive control can be divided into three core subcomponents: working memory, inhibitory control, and cognitive flexibility . All thrAging-related network mechanisms underlying the different subcomponents of cognitive control may be both shared and unique. Declines in functional connectivity within the frontoparietal network are associated with decreased CCA ; howeverpriori variable. In future, researchers should systematically collect multimodal imaging data, select targeted connections or networks, and construct mediating and moderating multivariate models to clarify how structural and functional networks interact and influence CCA.Multimodal network mechanisms for CCA are mostly theoretical, and empirical studies are rare. The impairment perspective suggests that CCA follows the pathway of \u201cstructural connectivity impairment \u2192 functional connectivity impairment \u2192 cognitive control decline.\u201d However, the compensation view suggests that if the structural network is mostly preserved, the compensation of functional connectivity can be occurred through third-party structural pathways, as manifested by increased functional connectivity and cognitive control maintenance. When the structural network is severely disrupted, the functional network will be damaged and result in declines in cognitive control. Thus, structural and functional networks act together in a complex way in CCA, and the degree of structural network impairment may be an important a Notably, communication models and multilayer network analyses that emerge from network science would offer approaches to explore the structure\u2013function coupling of brain networks . By formWhether changes in dynamic functional connectivity are involved in decreased CCA should be examined. Dynamic functional connectivity refers to the time-varying fluctuations of functional networks . CognitiCognitive control decline is a salient feature of aging. Abnormalities in the functional segregation, integration, and antagonism of functional networks suggest that disrupted spontaneous network organization, failed information co-processing, and increased endogenous interference in cognitive control are related to reduced CCA. Severe damage to the structural network can induce cognitive control decline by weakening functional connectivity. Nevertheless, a relatively intact structural network can ensure the compensation of functional connectivity, to delay the decline in CCA. Future research should introduce network neuroscience approaches and investigate the multimodal network mechanisms of aging-related cognitive control decline.HX: writing and revising the article, drafting, and proofreading references. QH and AC: reviewing and revising the manuscript and giving critical comments. All authors contributed to the article and approved the submitted version."} +{"text": "Arthropod bite mastitis is rarely encountered in imaging practices but can occur in all regions of the world. Diagnosis is often challenging as the offending agent is rarely identified. While most manifestations are self-limited, severe presentations can mimic malignant processes such as Paget\u2019s disease and inflammatory breast cancer (IBC). This case demonstrates the diagnostic challenges sometimes encountered with arthropod bite mastitis as well as imaging findings both prior to and after interventions. While insect and arachnid bites occur worldwide, mastitis resulting from these arthropod bites remains a rare clinical entity with few case reports described -3. ArthrA 56-year-old woman presented with a three-month history of a right breast erythematous macular rash with scaling, which persisted despite the application of a topical antibiotic. The patient reported no antecedent trauma as well as no associated drainage, fever, or chills. During this time, she worked in a grocery store and began handling boxes of produce. At times, she noted occasional spiders and insects around the produce containers.Initial diagnostic mammography demonstrated an asymmetry with architectural distortion and skin thickening in the inferior right breast, with associated non-specific hypoechoic tissue on targeted ultrasound Figure . Punch bA short-term follow-up mammogram in four months demonstrated progressive skin thickening and an enlarging asymmetry in the inferior right breast, with a questionable underlying mass on targeted ultrasound Figure . The finAlthough clinical presentations are rare, arthropod bite mastitis can occur worldwide and should be considered in breast imaging workups ,4. In maNo specific diagnostic imaging criteria are available for arthropod bites, although superficial edema and inflammation are expected . DiagnosIf arthropod bite mastitis is expected, clinical follow-up and possible short-interval follow-up imaging (three to six months) may be suggested to ensure a benign clinical exam or resolution of imaging findings. Specific treatments depend upon the arthropod responsible for the bite, with pharmacologic and nonpharmacologic approaches providing relief . When clSevere presentations of arthropod bite mastitis can mimic breast malignancy, including Paget\u2019s disease and inflammatory breast cancer. Diagnosis is often challenging, and a biopsy may be needed to exclude an underlying malignant process. Awareness of this entity and reliable clinical information such as symptom onset and duration are key to preventing unnecessary additional interventions."} +{"text": "Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for new therapeutics that otherwise have shown significant successes in disease control. Hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and is widely targeted in drug development. We found that resistance to the HGF-neutralizing antibody drug candidate rilotumumab in glioblastoma cells was acquired through HGF overproduction and misfolding, which led to stress-response signaling and redirected transport inside cells that sequestered rilotumumab and misfolded HGF from native HGF and activated Met receptor. Resistant cells were more malignant but retained their sensitivity to Met kinase inhibition and gained sensitivity to inhibition of stress signaling and cholesterol biosynthesis. Defining this rapidly acquired, multisystem scheme improves our understanding of drug resistance and suggests strategies for early detection and intervention.MET and HGF genes, with evidence of rapidly acquired intron-less, reverse-transcribed copies in DNA, was also observed. These changes enabled persistent Met pathway activation and improved cell survival under stress conditions. Point mutations in the HGF pathway or other complementary or downstream growth regulatory cascades that are frequently associated with targeted drug resistance in other prevalent cancer types were not observed. Although resistant cells were significantly more malignant, they retained sensitivity to Met kinase inhibition and acquired sensitivity to inhibition of ER stress signaling and cholesterol biosynthesis. Defining this mechanism reveals details of a rapidly acquired yet highly-orchestrated multisystem route of resistance to a selective molecularly-targeted agent and suggests strategies for early detection and effective intervention.Drug resistance is a long-standing impediment to effective systemic cancer therapy and acquired drug resistance is a growing problem for molecularly-targeted therapeutics that otherwise have shown unprecedented successes in disease control. The hepatocyte growth factor (HGF)/Met receptor pathway signaling is frequently involved in cancer and has been a subject of targeted drug development for nearly 30 years. To anticipate and study specific resistance mechanisms associated with targeting this pathway, we engineered resistance to the HGF-neutralizing antibody rilotumumab in glioblastoma cells harboring autocrine HGF/Met signaling, a frequent abnormality of this brain cancer in humans. We found that rilotumumab resistance was acquired through an unusual mechanism comprising dramatic HGF overproduction and misfolding, endoplasmic reticulum (ER) stress-response signaling and redirected vesicular trafficking that effectively sequestered rilotumumab and misfolded HGF from native HGF and activated Met. Amplification of MGMT which encodes an alkyltransferase capable of repairing the DNA damage. The issue has become even more vexing with the development of highly selective agents such as those targeting the epidermal and hepatocyte growth factor pathways. Acquired resistance to gefitinib or erlotinib in lung adenocarcinomas is a prevalent response to prolonged treatment and occurs through HGF pathway activation and other molecular mechanisms , often through increased expression of hanisms . Ant. AntMGMTHGF and MET genes are expressed in human glioma and medulloblastoma, where their increased relative abundance frequently correlates with tumor grade, tumor blood vessel density and poor prognosis . Quantitative PCR analysis showed that the mRNA transcript levels for HGF v1 and v3, the full-length variants, were more than 600- and 100-fold more abundant in the resistant cell line relative to the parental, respectively and the most significant IPA \u201cMolecular and Cellular Function\u201d identified was \u201cCellular Growth and Proliferation\u201d . Twenty-six IPA \u201cCanonical Pathways\u201d were identified as having significant overlap with the dataset by right-tailed Fisher\u2019s Exact test and the Benjamini\u2013Hochberg (B\u2013H) multiple test correction , and group 6 pathways are consistent with a cellular origin of GBM. Phenotypic groups 1 and 2 however\u2014stress signaling and immune-related pathways\u2014suggested processes and pathways by which autocrine HGF/Met activation could evade contact with rilotumumab.P. pastoris) provide low yields of active protein unless they are specifically engineered to overexpress protein disulfide isomerase(s) to facilitate the correct disulfide bond pairing required for proper folding or smaliewed in ,69,70,71HGF and MET gene amplification and HGF protein super-production; (2) downregulation of ER-resident disulfide isomerases contributing to significant HGF protein misfolding; (3) induction of ER stress-response signaling and intracellular HGF and Met protein retention; and (4) dramatically increased rilotumumab uptake and degradation through a shift to caveolar endocytosis and activation of antigen presentation pathways. Together, these changes provided intracellular seclusion of properly folded HGF and Met proteins from rilotumumab and maintained HGF/Met signaling dependence for cell growth and survival.Acquired drug resistance obstructs the effective treatment of many cancers and occurs through various mechanisms, often involving the elimination of drug from target cells or new defects in proto-oncogenes or tumor suppressors that revitalize essential growth and survival signaling pathways. Here we report a novel route to acquired resistance. In glioblastoma cells that require autocrine hepatocyte growth factor (HGF)/Met signaling for proliferation and survival, resistance to the HGF neutralizing monoclonal antibody rilotumumab was acquired through a complex interplay of several intracellular systems: (1) Unlike other acquired drug-resistance mechanisms, mutation of the gene encoding the drug target, loss of critical negative regulators downstream of the drug target, and/or activation of alternative mitogenic pathways parallel to the target were not observed. Despite the number and diversity of the subcellular systems involved, resistance developed rapidly in GBM cells in which HGF is an important oncogenic driver. Defining this mechanism also revealed targetable co-acquired dependencies for survival in resistance cells: cholesterol synthesis needed for caveolar uptake and ER-stress signaling as well as continued sensitivity to small-molecule Met tyrosine kinase inhibitors. These findings suggest strategies for the early detection of this form of resistance and for effective intervention."} +{"text": "The COVID-19 pandemic impacted predoctoral psychology training at the graduate, practicum, and internship levels including a greater reliance on telehealth and evolving learning needs. However its unique impact on geropsychology training has not been explored. The Building Bridges workgroup for predoctoral training faculty levels, we describe opportunities and barriers to address evolving geropsychology training needs during the pandemic as determined through working group discussion. Negative impacts to training identified include: decreased opportunities for 1) face-to-face patient care and 2) telehealth care due to disparities in telehealth access and utilization in older adults. Other impacts on the geropsychology pipeline include declining opportunities to see older adults at practicum sites. Conversely, increased media attention to the impact of COVID on older adults\u2019 physical and mental health may lead to graduate students\u2019 having greater interest in geriatric mental health and reinforcing a geropsychology career. Recommendations for training programs to address the long-term ramifications of the pandemic will be offered."} +{"text": "The continued demographic shifts in population aging are coupled with an increase in self-identified, LGBTQ+ individuals entering older age. While they share some common age-related experiences with non-LGBTQ+ individuals, they also face unique challenges as they age, including additional intersectional pressures beyond their sexual or gender identity. These challenges are exacerbated by pre-existing health inequities and heteronormative social support systems. Of particular concern is the ability to locate affirming and accessible social and health services. Gerontologists have a critical role in assisting older LGBTQ+ individuals in navigating complex social systems. To do so requires they have the appropriate education to develop the cultural humility needed to understand and assist these individuals. It necessitates the engagement of gerontology and geriatric education programs in educating future gerontologist professionals about LGBTQ+ older individuals. Critically, it requires the identification of appropriate instructors who are equipped to educate on LGBTQ+ aging topics."} +{"text": "Social support from family provided benefits for coping during the COVID-19 pandemic; however, not all older adults had access to family. The present study investigates how older adults without access to traditional family ties conceptualized their social relationships throughout the first two years of the pandemic. A subsample of eight older adults without direct access to traditional family ties were identified from a larger 5-wave interview study conducted between April 2020 and June 2022. Transcripts were holistically coded and three overarching themes emerged: constraints of place, redefining family, and feelings of isolation and closeness. The first theme addressed having family members living far away and uncertainty of when they would get to see them again. However, these distance barriers could be overcome through technology. The second theme illuminated that during the pandemic, those without access to traditional family ties redefined their social relationships by developing fictive kin from neighbors, colleagues, and friends. The third theme highlighted that some older adults felt they were lacking strong social networks and were concerned they had nobody to contact if they needed help, while others felt that despite limitations, their social relationships grew closer due to connection through alternative forms of communication (e.g. texting). Results from this study clarify how traditional family ties were challenged and strengthened during physical distancing for some older adults. These findings extend the literature on how fictive kin forms in older adulthood during temporary crises and suggests potential avenues for social connection for older adults lacking traditional family support."} +{"text": "Recent investigations of the mechanisms through which stress may impact cardiometabolic health point to the potential importance of cognitive tendencies in this relationship. This study examined the associations between vigilance and stress coping with metabolic risk, and whether these associations varied by race and life course socioeconomic status (SES). Data come from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study, a cohort of urban adults . Vigilance was measured by the MacArthur Reactive Responding subscale; stress coping was measured by the Brief Cope scale. Metabolic risk was operationalized by metabolic syndrome z-scores (MetS-Z). Linear mixed models were used to examine longitudinal associations between cognitive tendencies and MetS-Z; interaction terms were used to examine effect modification by race and life course SES. Black participants reported higher adaptive coping; participants experiencing persistent poverty or downward mobility reported higher vigilance and avoidant coping and lower adaptive coping. Overall, vigilance was not associated with metabolic risk. Avoidant and adaptive coping were inversely associated with baseline MetS-Z and further varied by sociodemographic factors. Higher adaptive coping was associated with lower MetS-Z among White adults, while higher avoidant coping was associated with lower MetS-Z among Black adults. Lower stress coping were associated with higher MetS-Z among White participants with low lifecourse SES or downward socioeconomic mobility. In sum, stress coping may modulate the stress-health relationship, but these associations must be interpreted within the intersection of contextual factors."} +{"text": "Enterobacterales (CRE) presents a major threat to public health. CRE employ two molecular mechanisms to evade carbapenems: 1) expression carbapenemases (CPases), which efficiently hydrolyze carbapenems or 2) disruption of porins, which reduces carbapenem influx to levels that can be hydrolyzed by certain beta-lactamases. Diagnosing mechanisms underlying carbapenem resistance is important for infection control and to administer appropriate treatments.The global spread of carbapenem-resistant Enterobacterales isolated from hospitals in Massachusetts and California using broth microdilution assays at 14 inocula spanning four orders of magnitude. They represented 30 isolates encoding CPases and intact porins, 46 isolates with disruptions in one or both of the porins responsible for carbapenem influx (OmpC and OmpF), 25 encoding CPases with disrupted porins, and two controls encoding intact porins and no CPases.We measured Meropenem and Ertapenem minimum inhibitory concentrations (MICs) for 103 clinical We observed that the two mechanisms result in distinct profiles; first the carbapenem MICs of CPase-encoding strains show a strong inoculum dependence , whereas the MICs of porin deficient strains remain largely constant at all inocula . The synergistic action of these two mechanisms leads to high-level resistance that we termed \u201chyper-CRE\u201d . Together these factors explain the level of resistance in nearly all our CRE isolates. To validate the hyper-CRE phenotype, we successfully employed CRISPR-based gene editing to show that knocking out the major porin in CPase-producing strains elevates their carbapenem resistance to hyper-CRE levels.in vitro AST assays but are truly resistant in vivo.We also determined 18% of our isolates changed susceptibility classification within the Clinical Laboratory and Standards Institute (CLSI) recommended inoculum range. This is worrisome for the treatment of infections with strains that are deemed susceptible via Overall, our approach has demonstrated that measuring MICs at different inoculum can yield crucial diagnostic information about mechanisms of resistance which has important implications for patient care, infection control, and surveillance of emerging CPases.All Authors: No reported disclosures."} +{"text": "A growing body of literature suggests that inclusion of ultra-processed foods (UPFs) in the diet may be associated with various non-communicable diseases, including obesity, cardiometabolic diseases, and increased mortality. However, one of the most underrated research topics is represented by the potential role of diet for mental disorders. The aim of this study was to explore whether there was an association between UPF consumption and mental health outcomes in a cohort of southern Italian individuals.Demographic and dietary data from 1572 adults living in southern Italy was collected. Food items were categorized by the level of processing according to the NOVA classification. Multivariate logistic regressions were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between UPF intake and mental health outcomes, including sleep quality and depressive symptoms.Individuals in the highest quintile of UPF intake were more likely to have low sleep quality compared to those with the least intake . Among the main component of sleep quality, high UPF intake was associated with sleep latency and efficacy individually. No apparent associations were found between UPF intake and depressive symptoms. However, when considering different age groups, younger individuals (age <40 y) consuming more UPF were more likely to have depressive symptoms than low consumers .These findings show a potential association between UPF consumption and mental health outcomes. Further studies are needed to understand whether the retrieved relation depends on alteration of the physiological feeding patterns leading to food-anticipatory and binge-type behaviors or on nutritional and non-nutritional factors triggering pro-inflammatory pathways.\u2022\u2002Ultra-processed food consumption is associated with worse sleep quality and depressive symptoms in Italian adults.\u2022\u2002The detrimental associations between ultra-processed food consumption and depressive symptoms seem stronger among younger individuals."} +{"text": "We conducted participatory design research for long term care (LTC) socially assistive robotic activities comprised of social, cognitive and physical components and enhanced human-robot (HRI) and human-human interactions (HHI). Repeated sessions were conducted with 10 geriatric experts and 12 LTC residents (ages 70\u201392). Two robots, animal and humanoid, were used in combination with virtual reality. Four collaborative activities for paired older adults were designed and evaluated: playing drums to music, completing paintings, a fishing game, and training a dog with simple commands. Within each activity, three levels of difficulty were designed. Stakeholder feedback was obtained through observations and interviews. Numerous modifications were made following each session that addressed hardware, software and activity issues. Modifications were necessary both for the HRI and HHI aspects of the activity. Our experience demonstrates the necessity for participatory design in the deployment of technology for LTC settings."} +{"text": "The Age-Friendly University (AFU) initiative aims to increase the participation of age-diverse older adults in higher education communities. The present study investigated age-friendly practices across 23 institutions in the United States. The ICCS Inventory , which identifies 192 potential age-friendly campus practices was completed by administrators representing major campus units. A heat map was used to graphically represent age-friendly practices and identify where universities differed in the presence of those practices. Heat map findings indicated campuses are low in some auxiliary services that assist retired faculty and staff. However, campuses consistently gave retired faculty and staff access to university library services. Campuses also had limited age-friendly teaching and learning services. None of the campuses reported having resources to help faculty deliver teaching materials in formats specifically geared toward older learners. In addition, none of the campuses reported having teaching and learning staff visiting campus departments to provide resources for older learners, and very few campuses offered courses that focused on aging and age diversity issues. Common age-friendly practices were seen with respect to providing instructional technology support for faculty/staff/students and community partnerships for intergenerational activities. Physical environment and personnel evidenced the most frequent age-friendly practices likely because they are mandated by the ADA . Overall, the present study highlighted the areas where college campuses are most age inclusive, while also revealing areas for improvement in age inclusive practices."} +{"text": "Markers of functional aging can be used to track biological aging longitudinally and how it changes in response to the environment, e.g., drugs. We aimed to investigate how different drug classes may alter functional aging trajectories using data from the National E-infrastructure of Aging Research (NEAR) in Sweden. Data were harmonized across several longitudinal cohorts of aging for general cognitive performance, grip strength, walking speed, sensory ability , lung function and assessment of frailty using the accumulation deficit model known as the frailty index. Selected drug classes were lipid lowering, glucose lowering and blood pressure lowering medications that are commonly used in old adults. Preliminary analysis using data from one longitudinal cohort shows that using glucose lowering drugs was associated with lower frailty. Additional analyses are ongoing to increase sample sizes. We anticipate that several drug classes may be important for changing functional aging trajectories in late life."} +{"text": "The cornea is a transparent avascular structure located in the front of the eye that refracts light entering the eyes and also serves as a barrier between the outside world and the internal contents of the eye. Like every other body part, the cornea may suffer insult from trauma, infection, and inflammation. In the case of trauma, a prior infection that left a scar, or conditions such as keratoconus that warrant the removal of all or part of the cornea (keratoplasty), it is important to use healthy donor corneal tissues and cells that can replace the damaged cornea. The types of cornea transplant techniques employed currently include: penetrating keratoplasty, endothelial keratoplasty (EK), and artificial cornea transplant. Postoperative failure acutely or after years can result after a cornea transplant and may require a repeat transplant. This minireview briefly examines the various types of corneal transplant methodologies, indications, contraindications, presurgical protocols, sources of cornea transplant material, wound healing after surgery complications, co-morbidities, and the effect of COVID-19 in corneal transplant surgery. The cornea is an avascular tissue that is transparent due to the arrangement of its component cells, its avascularity and the metabolic processes its endothelium carries out . It measWe searched the Pubmed database using the following search criteria; \u201ccorneal transplantation\u201d [MeSH Terms] OR OR \u201ccorneal transplantation\u201d [All Fields] OR (\u201ccornea\u201d [All Fields] AND \u201ctransplantation\u201d [All Fields]) OR \u201ccornea transplantation\u201d [All Fields]. Given that this study was focused on CT in the last decade, we narrowed the search criteria to 2012 to 2023, resulting in a return of 3021 results. The search words using only \u201ctransplant\u201d or \u201ckeratoplasty\u201d or other single words were not considered in our minireview to avoid an overabundance of potentially impertinent studies. This search strategy was limiting and could have potentially and unintentionally excluded opinion leaders in this field of research. A Prisma Table was also generated, showing further stratification steps.Corneal transplantation (CT) is indicated via any processes leading to loss of corneal transparency, with neuroretinal integrity and optimal visual potential otherwise preserved . CT is uCTs are among the most common procedure performed in many tertiary eye centers worldwide ,10,11,12Proper patient selection is key to yielding reasonable CT outcomes. A thorough corneal, anterior and gross posterior segment evaluation, in addition to a systemic workup, should ideally be carried out prior to qualifying all potential CT candidates. With regard to preoperative corneal evaluation, the depth of corneal tissue scarring and evidence of corneal ectasia should be determined. Detection of keratic precipitates indicates active or latent migration and deposition of immune moieties. The resultant hyperimmune sensitization disrupts the ocular immune privilege, decreasing the chances of post-graft tissue survival by more than four-fold . EstabliWhen significant corneal stromal haze or widespread leucomatous scarring impairs intraocular evaluation, imaging modalities such as anterior segment-ocular coherence tomography (AS-OCT), ultrasound biomicroscopy (UBM), and B scan ultrasonography can be respectively utilized to gain a gross outline of individualized intraocular integrity. Corneal central thickness (CCT) measurements with pachymetry have, in the past, been correlated with corneal endothelial cell (CEC) loss , mostly Under normal circumstances, the trilaminar cornea is devoid of lymphocytes. The cornea\u2019s innate defense systems are provided by bacteriostatic enzymes in the tear film, the equilibrium of microbiome/normal flora on the ocular surface and the corneal epithelial barrier attributes . This inStandardized procedures of donor corneal tissue viability analysis are usually followed prior to harvesting and cryopreservation with corneal banks . With reRooij et al. conducted a comparative analysis of three standard methods of CT for the management of Fuchs endothelial dystrophy. They found that there was no significant difference between improvement using conventional PK, inverted mushroom PK and DSAEK .Globally, the need for donor corneal tissue to ease the burden of avoidable corneal blindness far outweighs the availability of viable graft tissue for CT . The demSafe strategies for extending the viability period of donor tissue before allografting have been explored . GlyceroAutologous graft sourcing also represents a viable strategy in rare cases where healthy corneal tissue on the contralateral side may not be of great functionality due to late comorbid ocular disease . HomonymCorneal transplantation of autologous tragal perichondrium with an amniotic membrane overlay has been reported to yield symptomatic relief among patients with bullous keratopathy compared to controls . CulturiA common complication of wound healing is neovascularization. Topical bevacizumab application post-CT four times daily for 24 weeks was found to statistically reduce the occurrence of neovascularization . Better Immune rejection after CT has been successfully managed via donor-derived, tolerogenic dendritic cells . A blockIn cases where there is a severe corneal ulceration threatening the integrity of the globe, a penetrating keratoplasty can be the last chance of saving that eye . The keyCorneal donation involves identifying a potential donor eye, preparing the eye for removal of the graft, extraction of donor tissue and storage. Therefore, the preparation of corneal grafts takes up a critical stage in this regard due to the high demand for cornea tissue and relatively lower supply ,48. IntrHagenah and Winter reviewed recent trends in globe disinfection before graft extraction . They su2 in 14% of its participants and co-morbidities in corneal transplant medicine.The ECD can be a very important indicator of the eventual viability of the graft. Gupta and Gupta examined 100 eyes that received corneal transplants within a two-year period over periodic intervals. They reported that the most endothelial cell loss was seen in patients undergoing a repeat graft, while keratoconus-grafted eyes showed the lowest loss . AnotherThis relative scarcity of corneas for transplant puts their storage on the front burner for many researchers. The numbers of overall grafts properly stored and the eventual viability of the grafts when needed for eventual transplant are two key indices that can advise on the progress of corneal tissue storage development. Garcin et al. developed an active storage device which they called a bioreactor and compared its preservation abilities versus the organ culture storage technique. They published results showing that the bioreactor had a 23% higher rate of endothelial cell survival than the organ culture technique . They alFailure of the cornea graft (PGF).Immunological reaction by the host to the graft .Non-immunological factors such as spontaneous decompensation, glaucoma and diseases ,61. WounOther distinct factors .Generally, the causes of CT failure have been classified into:The cornea endothelium is an inner barrier to edematous damage from aqueous humor breaching into the cornea. Endothelial cell count (CEC) is therefore essential to assess the ability of the eye to retain this protective ability. Studies have shown that the CEC is significantly reduced when corneas are extracted for grafting . Jafarinp = 0.815).Cytokine elevation has also been observed in eyes that suffered CT failure , althougWound dehiscence is a common complication post-CT. A study was conducted in the Riyal Eye and Ear hospital to assess the incidence and clinical demographic of 72 eyes who visited a center for surgery . PeriopeCorneal opacities impede intraoperative visualization during cataract extraction and vitreoretinal surgery . PerformClinicians should also note that patients receiving immune checkpoint medication are at risk of CT rejection . Common Another study at a different center reported an incidence of microbial keratitis in 4.77% of 1508 eyes that had undergone CT . NatamycNon-infective unforeseen events can also complicate the CT process. Jarstad et al. reported a case of cardiac failure in an otherwise healthy young adult during CT surgery that was successfully managed . AnotherRare conditions like monoclonal gammopathy of undetermined significance are also implicated, especially in the presence of elevated levels of abnormal M proteins . Paniz-MAs with any grafting procedure, immunologic interactions between the host and donor tissue can be problematic. However, non-immunologic factors can also be a factor in the loss of CEC, even with patients receiving autologous CT . Repeat The avascularity and degree of sensory innervation of the cornea ensure the maintenance of its structural integrity and function. A deviation from the regular structural integrity and outline precipitated by cornea diseases is the fourth leading cause of blindness worldwide. Most visual impairments resulting from cornea morbidities are avertible and reversible. Cornea transplantation is a required surgical intervention in cornea diseases which results in a deep lamellar cornea structural deformity; however, as with most solid-organ transplants, the risk of transmission of infectious diseases to the handlers of donor tissues and recipients cannot be overlooked. The Eye Bank Association of America (EBAA) released updated recommendations and policy changes with the advent of the COVID-19 pandemic .The COVID-19 pandemic resulted in acute and chronic shortages of donor corneas in a healthcare system that already had a long list of patients waiting ,99. A stSeveral questions regarding the spread and transmission of SAR-CoV-2 in tears and ocular tissues have been asked. The first was to identify the presence of SAR-CoV-2 in tears which may enable its transmission and subsequent infection of ocular tissues . In a stThe shortage of donor tissue during the COVID-19 pandemic also had positive results. Clinicians reported an innovative procedure and were able to use a single donor cornea for four different recipients undergoing CT for different conditions . AnotherA 15-year review of corneal donations in southern Africa revealed that cultural beliefs have led to a marked reduction in donation numbers . HoweverGain et al. conducted a systematic review of reports on corneal transplant medicine and eye banks. They then conducted interview series among specialists spanning 148 different countries. In total, they reviewed 184,576 surgeries using 283,530 corneas obtained from 742 cornea banks. Their work concluded that there was indeed a scarcity of corneas worldwide. Their calculated availability was estimated at only one cornea for every 70 eligible transplant patients. They suggested an acceleration of alternative/artificial solutions such as keratoprostheses .The first CT took place in 1884 using a bovine cornea . CT has Amagai et al. reported the successful development of a novel tissue carrier for donor graft tissue . They vaTissue-engineered construct models for corneal endothelial keratoplasty have shown greater pharmacoeconomic potentials than those working with donor tissue . UltraviAzithromycin treatment regimen has been reported to reduce the incidence of high-risk allograft rejection in murine models . PreoperSteroid therapy after ocular surgery is indicated for the prevention of inflammation and also for its immunosuppressive properties. Poinard et al. conducted a study to assess the adherence of cornea transplant receivers to prescribed postoperative steroid therapy . SteroidTrone et al. also conducted a pilot study (Phase II) as part of a clinical trial to assess the safety of a new dropless PK which incorporated a subconjunctival steroid implant . FourteeAs already stated, conventional keratoplasty involves allogeneic transplantation of corneal tissue: tissue-specifics depending on the disease section of the cornea . NotablyKeratoprestheses require a clear central optic zone to enable refraction onto the retina. Historically, early KPro material consisted of convex glass sheets which served as optics surrounded by metallic rims made of silver, quartz, platinum and like materials . AttemptRetrospectively, the Boston type-1 KPro (with its phakic and aphakic models) and the Osteo-odonto KPro have reportedly recorded proven highest success rates. The use of the temporary Eckardt KPro and other retrievable soft contact lens media has been successfully trialed for posterior segment visualization during vitreoretinal procedures with combined keratoplasty ,143. EyePreoperative preparation requires ocular imaging and biometric analysis to determine anterior chamber depth; gross morphological iridocorneal angle integrity; crystalline lens presence/position; also, and retinal function and integrity (which may require electrophysiology in doubtful cases).Major complications reported post-KPro implantation include glaucoma, persistent autoimmune reaction with cases of coexisting system autoimmune disease -driven responses can help to avert further sight loss following KPro implantation.Corneal specialist surgeons should be globally incentivized to encourage uptake, training, and retraining in modern techniques of allograft transplantation. The major impediment to optimal management of corneal blindness aside from donor shortage remains post-CT rejection/graft failure. Finding solutions may depend on the rate of progress regarding the incorporation of either biological material or procedural modulation of stem cell differentiation to avascular corneal-like tissue, especially for immune-mediated graft failure. There will certainly be limitations to this approach, specifically in the exploitation of totipotent embryonic stem cells. Strategies to prolong the viability time of donor grafts would also serve to minimize cost effectiveness preoperatively. Demand for CT may also decrease if current advances in local ocular stem cell application and amniotic membrane transplantation reduce the incidence of corneal scarring following chemical injury and deep corneal ulceration."} +{"text": "There is a huge resource gap in mental health service provision & service utilisation in LAMIC including Pakistan. SOUL Programme has been established in the City of Larkana, on charitable donations, which utilises principles of home-based outreach and produces clinical and functional outcomes.SOUL programme focuses on collaborative working with patients & families. The objectives include recognition, treatment, family education & psychosocial support to maximize clinical, functional & occupational outcomes.Single cohort intervention with innovative service structure and culturally relevant open label intervention design developed with local academic psychiatric unit in Larkano, Pakistan. Training was provided to local mental health professionals on diagnosis, delivering care & use of recognized clinical outcome measures.We have recruited a cohort of 160 patients on continual basis over time. Our analysis show a higher BPRS and lower GAF ratings for men in comparison to female cohort at the baseline. Our Ten year follow up has demonstrated statistically significant clinical / functional improvement on BPRS, CGI & GAF measures. The mean differences recorded for the individual measures after 12 months were BPRS, CGI-I and GAF and were all statistically significant. Innovative home-based community mental health intervention shows significant improvements in clinical and functional outcomes (with good effect size).SOUL Programme is a highly effective and cost-efficient intervention model for treatment of schizophrenia in a developing country setting. Our 10 year follow up study confirms the feasibility of this intervention model through close working with families of our patients.No significant relationships."} +{"text": "Yet, the relationship in humans between maternal overweight/obesity during pregnancy and fetal hypothalamic development remains largely unknown. Here, using an international multi-site diffusion tensor imaging (DTI) dataset, we test the hypothesis that maternal pre-pregnancy BMI is associated with newborn offspring HTH mean diffusivity .An extensive body of animal literature supports the premise that maternal obesity during pregnancy can alter the development of the fetal hypothalamus with implications for offspring obesity risk using a high-resolution atlas-based definition of HTH. A total of n\u2009=\u2009231 mother-child dyads were available for this analysis . The association between maternal pre-pregnancy BMI and newborn offspring HTH MD was examined separately in each cohort using linear regression adjusting for gestational age at birth, postnatal age at scan, sex, whole white matter mean diffusivity, and DTI quality control criteria. In post hoc analyses, additional potentially confounding factors including socioeconomic status, ethnicity, and obstetric risk were adjusted where appropriate.HTH MD was independently quantified in two separate BMI-matched cohorts and remained significant after adjusting for cohort-relevant covariates.The distribution of maternal pre-pregnancy BMI was comparable across sites but differed by ethnicity and socioeconomic status. A positive linear association between maternal pre-pregnancy BMI and newborn offspring HTH MD was observed at both sites (These findings translate the preclinically established association between maternal obesity during pregnancy and offspring hypothalamic microstructure to the human context. In addition to further replication/generalization, future efforts to identify biological mediators of the association between maternal obesity and fetal HTH development are warranted to develop targeted strategies for the primary prevention of childhood obesity.The online version contains supplementary material available at 10.1186/s12916-023-02743-8. Childhood obesity is a major global public health challenge as it increases the likelihood of adverse obesity-related disorders in later life as well as their development at earlier ages and withObesity is a highly multi-factorial phenotype , and theAnimal models suggest that the HTH exhibits developmental plasticity during the fetal period as it develops in the context of, and adapts to, variation in maternal overnutrition \u201320, whichuman HTH in the context of interindividual variation in maternal overnutrition remains limited, it is supported by at least two recent studies. First, we recently reported on an association between maternal circulating saturated free fatty acid concentration (sFFA) during pregnancy and newborn offspring HTH microstructure indexed using diffusion tensor imaging (DTI)-based mean diffusivity (MD), that, in turn, was prospectively associated with early childhood adiposity ) difference in infant HTH MD (HTH MD weighted average across cohorts). While the HTH MD phenotype used here is non-specific to the underlying microstructure, the observed direction of association is consistent with several microstructural phenotypes of obesity that reduce barriers to diffusion including reduced axonal outgrowth , gliosisThe U.S. Endocrine Society has argued that obesity should be conceptualized as a disorder of the energy homeostasis system , rather The two cohorts analyzed here differed in maternal age, gestational age at delivery, and pre-pregnancy BMI. Cohort differences in maternal age and gestational age at delivery were in the expected direction \u201341, and Several potentially confounding factors were associated with offspring HTH MD above and beyond maternal pre-pregnancy BMI, and these warrant further discussion. Within site 2, OB risk, maternal education, and maternal ethnicity were all associated with HTH MD. Notably, OB risk and maternal education were not associated with HTH MD within site 1, suggesting that these are not replicable and/or robust observations in the context of this study . However, because site 2 demonstrated a substantially higher prevalence of OB risk, and because maternal education measures may reflect different socioeconomic pressures in different settings, these issues likely warrant further investigation. Relatedly, while significant at both sites, the effect sizes of postnatal age at scan and global measures of MD were markedly different across sites despite similar central tendencies. One explanation for this discrepancy could be differences in sample homogeneity where a larger proportion of variance is available for attribution to variance in maternal BMI. Alternatively, this observation could simply be due to differing approaches to handling low quality data wherein one excelled at removing measurement error relative to the other. Finally, the association between maternal ethnicity and offspring HTH MD suggesting lower neonatal HTH integrity among Hispanic neonates could not be tested at site 1 due to a high degree of ethnic homogeneity. However, because the direction of effect is consistent with higher rates of pediatric obesity among the Hispanic community , and becThe importance of identifying the role of BMI in the intergenerational transfer of obesity lies in its potential use as a screening tool for risk management . In addition, from the perspective of a developing fetus, BMI is representative of the diverse metabolic gestational milieu in which the fetal brain develops. However, what BMI contributes in terms of representation, it lacks in specificity. That is, apart from generically informing policy and public awareness about the importance of maintaining a healthy pre-conceptional weight, this work provides limited insight into targeted interventions on the biological pathways of obesity risk transfer from mother to her offspring. For this reason, and because BMI alone is not always perfectly reflective of metabolic status , future efforts should aim to identify the specific ligands and conditions sufficient and necessary for the intergenerational transmission of obesity.Weight stigma is among the most pervasive forms of discrimination within society, and is associated with adverse psychological (depression) and physiological (stress) conditions linked to increased weight gain. ItLimitations of this study include the focus on a relatively healthy population, lack of gestational biological data, limited spatial resolution, and lack of specificity provided by the outcome (MD). Class I obesity represented roughly 10% of the study population and thus this study is likely underpowered to draw obesity-specific conclusions. To address this shortcoming, future studies would benefit from oversampling class I obesity and above to further identify consequences for fetal development specific to the obese condition. The current study did not collect or consider several developmentally important maternal ligands including the feeding-related hormones leptin and ghreIn conclusion, the findings from the current study represent a significant conceptual advance to the literature by providing translational evidence of a robust association between maternal pre-pregnancy BMI and newborn offspring hypothalamic microstructure . Importantly, because maternal BMI is potentially modifiable (at least in the short term) through diet, exercise , and/or Additional file 1: Table S1. More Parsimonious Model Site Comparison: Maternal Pre-pregnancy BMI and Offspring Hypothalamic (HTH) Mean Diffusivity (MD). Maternal Pre-pregnancy BMI is associated with offspring HTH MD in a more parsimonious model excluding adjustment for white matter mean diffusivity. Table S2. Parsimonious Model With Sex Interaction Site Comparison: Maternal Pre-pregnancy BMI and Offspring Hypothalamic (HTH) Mean Diffusivity (MD). No evidence for a sex-specific association between maternal pre-pregnancy BMI and offspring infant HTH MD at either site (p\u00a0>\u20090.1)."} +{"text": "Epichlo\u00eb endophytes from mutualistic to parasitic. The change in symbiosis outcome would be explained by the negative effects of the plant physiological responses on the endophyte performance. Furthermore, we posit that endophytes may protect the mutualism by the induction of plant defence hormone responses and antioxidants.Plants commonly form mutualistic associations with fungal endophytes. We put forward the hypothesis, with supporting evidence, that certain plant physiological responses to stress [i.e. phytohormones and reactive oxygen species (ROS)] change the symbiosis between plants and Epichlo\u00eb caused by the disruption in the endophyte-derived benefits and growth of the symbionts within plant tissues . We descEpichlo\u00eb-based production of alkaloids, diminish the herbivore resistance of symbiotic plants, and compromise the mutualism phenotypes in symbiotic plants than non-symbiotic plants exposed to the same treatment (whereas the endophyte did not affect the reproductive effort of plants not exposed to ozone) that increase the fitness of symbiotic plants in situations of stress by phytopathogens (Achnatherum inebrians against the phytopathogen Blumeria graminis was increased by the presence of endophytes that boosted plant defences by inducing SA-related responses (Curvularia lunata pathogen was documented in A. sibiricum plants associated with endophytes that induced plant JA-related defence responses (Alternaria solani was shown in Solanum lycopersicum plants symbiotic with Serendipita indica root endophytes that primed JA/ethylene host defence responses (athogens . The resEpichlo\u00eb can also enhance antioxidant levels that generally increase the fitness of symbiotic plants under stressors that increase ROS-associated oxidative damage (Elymus dahuricus plants was increased by the presence of endophytes that enhanced contents/activities of several antioxidants that reduced the oxidative damage within plant tissues (L. perenne plants was also increased by endophytes that enhanced the contents/activities of several antioxidants within symbiotic plants (e damage (Ueno et tissues . SimilarHere we have highlighted that the effects of environmental stressors can compromise the mutualism between plants and endophytes by the induction of plant physiological responses. Whereas phytohormone- and ROS-related responses were considered independent here, in reality the whole-plant response to stresses involves the interaction between both pathways ("} +{"text": "Although a large number of studies have shown brain volumetric differences between men and women, only a few investigations to date have analyzed brain tissue volumes in representative samples of the general elderly population.We investigated differences in gray matter (GM), white matter (WM) and intracranial volumes (ICVs) between sexes in individuals above 66 years old using structural magnetic resonance imaging (MRI).Using FreeSurfer version 5.3, we automatically obtained the ICVs, GM and WM volumes from MRI datasets of 84 men and 92 women. To correct for interindividual variations in ICV, GM and WM volumes were adjusted with a method using the residuals of a least-square-derived linear regression between raw volumes and ICVs. We then performed an ANCOVA comparing men and woman including age and years of schooling as confounding factors.Women had a lower socioeconomic status overall and fewer years of schooling than men. The comparison of unadjusted brain volumes showed larger GM and WM volumes in men. After the ICV correction, the adjusted volumes of GM and WM were larger in women.After the ICV correction and taking into account differences in socioeconomic status and years of schooling, our results confirm previous findings of proportionally larger GM in women, as well as larger WM volumes. These results in an elderly population indicate that brain volumetric differences between sexes persist throughout the aging process. Additional studies combining MRI and other biomarkers are warranted to identify the hormonal and molecular bases influencing such differences."} +{"text": "Although rural-to-urban migration has been well researched, how gender shapes processes and outcomes, including later life health outcomes, has not been thoroughly investigated. Guided by a life course perspective, this study explores gender differences in rural-urban migration patterns and its association with mental health in later life among Chinese older adults. Exploiting rich life history data from the China Health and Retirement Longitudinal Study, we employ sequence analysis to identify the typical migration trajectories of Chinese older adults. Moderated mediation analysis is then used to examine gender-specific health pathways linking migration trajectories and later-life mental health. The results indicate that: men and women follow different migration trajectories across the life course. Men are more likely to migrate between rural and urban areas, and to migrate multiple times. Rural migrants who settled in urban regions have better mental health in later life than return migrants or rural non-migrants; the gender gap in mental health is marginally smaller among early urban settlers than rural non-migrants. Household income and Hukou conversion mediate the relationship between migration trajectories and later-life mental health among older people of rural origin. Household income in later life has stronger mediation effects for migrant men than for migrant women. The study suggests that a life course perspective and awareness of gender dynamics should be incorporated in policymaking to reduce the rural-urban divide and gender-based inequality in mental health."} +{"text": "Prejudice, stigmatization and discrimination behaviors causes social stress and lead vulnerability to mental and physical health problems in Transgender and Gender Nonconforming (TGNC) individuals. The prevalence of mental disorders that can be associated with \u201cminority group stress\u201d, especially major depression and anxiety disorders, are known to be higher in the TGNC group in comparison to general population.The aim of this study was to reveal the impact of minority stress on TGNC individuals\u2019 mental health. Resilience factors like gender identity pride, social support, community connectedness expected to diminish the negative impact of stigmatization and discrimination.The study sample consisted of 48 volunteered participants who consulted to Psychiatry Department for gender transition process. After semi-structured interview, applicants were given Gender Minority Stress and Resilience Scale-Turkish Form (GMSR-Tr), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Perceived Stress Scale (PSS), Multidimensional Scale of Perceived Social Support (MSPSS).s= .727), BAI , PSS . For psychological resilience, the strongest positive relationship was found with the community connectedness subscale ; the strongest negative relationship was observed with the internalized transphobia subscale .Analysis revealed a negative correlation between the stress subscales of GMSR-Tr scale and BDI (p< .001; rOur study presented the importance of internalized transphobia and protective effect of resilience factors for mental health outcomes of TGNC individuals exposed to minority stress. The depression, anxiety and stress scores decreases with increasing psychological resilience."} +{"text": "Given the onset of COVID-19, older adults who recently lost their significant others feel more stressed. There yet exist a study utilizing smartphones for web-based delivery of mindfulness intervention among bereaved older adults. Therefore, this study aimed to test the initial efficacy of an app-based mindfulness-meditation (AMM) to alleviate stress and depressive symptoms and improve stress resistance, social support, and self-esteem in Korean older adults experiencing bereavement. Participants included 22 Korean older adults who had been bereaved within the preceding year. AMM involved sound therapy, breathing exercises, and narrated meditation sessions, and the program was conducted over eight weeks. The linear regression results showed that stress level among participants was significantly lower after the intervention, with decreased scores from the baseline. By confirming that AMM is an effective way of reducing stress, more active usage of devices like smartphones should be promoted to develop mental health interventions for older adults."} +{"text": "We later discuss the necessity to update the current GEA models to predict both regional- and local- or micro-habitat\u2013based adaptation with mechanistic ecophysiological climate indices and cutting-edge GWAS-type genetic association models. Furthermore, to account for polygenic evolutionary adaptation, we encourage the community to start gathering genomic estimated adaptive values (GEAVs) for genomic prediction (GP) and multi-dimensional machine learning (ML) models. The latter two should ideally be weighted by de novo GWAS-based GEA estimates and optimized for a scalable marker subset. We end the review by envisioning avenues to make adaptation inferences more robust through the merging of high-resolution data sources, such as environmental remote sensing and summary statistics of the genomic site frequency spectrum, with the epigenetic molecular functionality responsible for plastic inheritance in the wild. Ultimately, we believe that coupling evolutionary adaptive predictions with innovations in ecological genomics such as GEA will help capture hidden genetic adaptations to abiotic stresses based on crop germplasm resources to assist responses to climate change.Leveraging innovative tools to speed up prebreeding and discovery of genotypic sources of adaptation from landraces, crop wild relatives, and orphan crops is a key prerequisite to accelerate genetic gain of abiotic stress tolerance in annual crops such as legumes and cereals, many of which are still orphan species despite advances in major row crops. Here, we review a novel, interdisciplinary approach to combine ecological climate data with evolutionary genomics under the paradigm of a new field of study: genome\u2013environment associations (GEAs). We first exemplify how GEA utilizes Letter to Karl Freiesleben, June 1799.\u201cI shall endeavor to find out how nature\u2019s forces act upon one another, and in what manner the geographic environment exerts its influence on animals and plants. In short, I must find out about the harmony in nature\u201d Alexander von Humboldt\u2014 Crop wild relatives (CWR) and landraces are well known for providing new alleles for plant breeding . They alVigna subterranea), chickpea (Cicer arietinum), cowpea (V. unguiculata), grass pea (Lathyrus sativus), groundnut (Arachis hypogaea), marama bean (Tylosema esculentum) (Lupinus mutabilis) (Phaseolus acutifolius) , sorghum (Sorghum bicolor), and finger millet (Eleusine coracana) or pearl and proso millets . Many of these crops have interesting drought-tolerance traits and some capacity to grow in compacted soils. Cowpeas, groundnuts, and lesser known cereals are already traditional food sources and biocultural components for vulnerable areas, especially in Sub-Saharan Africa and parts of Asia and Latin America , tarwi (tabilis) , and tepifolius) constitu America .Yet, despite their tolerance to drought and heat plus their high nutritional quality, the utilization of these orphan crops is limited partly because of the poor characterization of their genetic background . TherefoStill, a major question to harness crop prebreeding for climate change pressures is whether there is enough heritable variation in traits associated with tolerance to abiotic stress. In this context, genomic characterizations of reference collections comprising CWR, landraces, and orphan crops that span contrasting habitats offer a straightforward scenario to identify natural standing adaptation to abiotic pressures .The spirit behind this novel approach is to detect genomic regions that correlate with habitat heterogeneity as an indication of the natural selection imprint to environmental gradients . Since tGlycine WCR; or For orphan crops, rather than nondomesticated natural plant species, fewer GEA studies have been undertaken. Although still limited to the easier-to-grow annual grain species compared to perennial and root/tuber crops, GEA is starting to make important contributions to genetic analysis of landraces and WCR germplasm, often richly represented in the world\u2019s major gene banks for crop species. The analytical pipeline for GEA studies is shown in Historically, based on the technological improvements in sequencing and SNP detection and as a means to improve GEA, the field has moved from the candidate gene approach into fulin situ ecological georeferencing of accessions, and by 2) revealing the genomic architecture of adaptation via cutting-edge predictive models using georeferencing and statistical downscaling and machine learning (ML) , capableOverall, CWR and landraces undeniably harbor unique adaptations to abiotic stresses, rarely present in the cultivated and improved genepools . HoweverGP works either on the basis of shared relatedness or on the basis of linkage disequilibrium (LD) between the SNP marker loci and the genetic variants that underlie phenotypic variation . The relThe predictive ability of GP models may be further biased depending on whether the entire SNP set is used, or the most predictive SNP data are chosen after the GWAS-type analysis , the latde novo GWAS-based GEA estimates gathered from other (or even the same) panels (Better approaches to be implemented and reported include 1) weighted GP models using ) panels and 2) o) panels . GP can ) panels . GEAVs c) panels would be) panels , high-th) panels , and ML-) panels .Next-generation GEA models and GEAVs will allow the use of \u201cexotic\u201d parents for targeted predictive prebreeding in crop species. They offer feasible methodologies to trace the sources of abiotic stress adaptation and tolerance targeting crop resources in low-income countries, which are also the most vulnerable to climate change. Here, we have discussed strategies to implement the latest-generation predictive e.g., and genoModern GEA approaches will allow further studies of evolutionary conservatism, parallelism, and convergence in the genetic architecture of adaptation to various types of abiotic stresses across a wide range of environments, landraces, and wild accessions . ApproacHow genetic diversity and genomic divergence arise and are shaped based on ecological pressures is one of the main questions in molecular evolution and has ST statistic (A). Once the potential confounding demographic patterns have been accounted for, it is then feasible to disentangle genuine signatures of environmental adaptation (B) from spurious concurring genetic drift due to genomic constraining features. Finally, these combined summary statistics can ultimately redound in prebreeding efforts aiming to introgress exotic adaptive variation into elite lines (C), for instance, via backcrossing (BC) schemes for abiotic and biotic stresses.Therefore, GEA efforts can be enhanced by exploring SNP density and statistics of site frequency spectra in associated vs. nonassociated regions . Figure ad hoc multiple hypotheses to which scale epigenomic marks regulatand sRNA , and mayeritance , eventuaeritance .e.g. GEAVs), as well as the identification of underlying factors that may facilitate or constrain future adaptive responses to changing climate.Ultimately, GEA is empowering the understanding on how plant genomes interact with their environment while shaping adaptive phenotypes. Such mechanistic insights of the genome functionality in the wild promise leveraging the characterization of landraces and CWR to assist prebreeding efforts through multi-dimensional adaptive scores (Lastly, GEA studies offer new possibilities to efficiently unlock crop diversity for climate adaptation . Unexplo"} +{"text": "In preclinical animal models, researchers can, within the same thin slice of tissue, probe activity within neurons [e.g., immediate early gene protein products and deprivation on stria terminalis white matter and function have a reciprocal relationship that facilitates global and integrative brain processes and found connection features that distinguish preterm and term-born infants. Their approach revealed novel insights into the global manner in which preterm birth impacts neurodevelopment, identifying local intra-network functional connections and long-range inter-network structural connections that differentiate between pre-term and term-born infant brains.In this current Research Topic, authors demonstrated the breadth of how multimodal neuroimaging can surpass unimodal neuroimaging across developmental, clinical and methodological domains. Zhu et al. presented new methodology featuring brain network construction under a unified framework of joint fMRI and DWI . Their method considered relationships between multiple brain regions and a PageRank algorithm that extracts significant node information from the unified network. Zhu et al. applied their method to a clinical problem\u2014classifying epilepsy diagnoses, comparing normal controls (NC), frontal lobe epilepsy (FLE) and temporal lobe epilepsy (TLE). Their methods achieved the highest classification accuracy compared to unimodal methods when classifying against NC and achieved among the highest accuracies when classifying FLE v. TLE.Tang et al. developed a new interpretable hierarchical graph representation learning framework for brain network regression analysis using multimodal MRI data. They used this approach to predict a variety of affective, somatic, cognitive and behavioral measures and found that the proposed framework achieved the best performance compared to baseline methods; this was attributed to extraction of graph local structures as low-level features and preservation of these into high-level space hierarchically.Sun et al. developed new methods that capitalize on synergies between PET and DWI data, using DWI-derived structural connectivity and PET intensity to denoise PET images. Their CONNectome-based Non-Local Means (CONN-NLM) filter provides more informative denoising by weighting similar-intensity PET voxels and highly connected voxels more heavily. This yielded greater PET image quality and lesion contrasts and produced superior denoising effects compared to filters not utilizing DWI data.Babaeeghazvini et al. reviewed the convergence of structure and function with associations between white matter microstructure and electro-encephalography (EEG). They note that white matter microstructure may influence the velocity of communication between brain regions and across hemispheres, and that amplitudes and latencies of event-related potential components may reflect pathological differences in structure; yet, the diversity of findings calls for more standardization of EEG analysis.Finally, To conclude, the field would benefit significantly from effective use of multimodal approaches in the methods development space and in basic, clinical and translational research. This requires open science and enhanced accessibility of tools that process and analyze multimodal neuroimaging data. Future directions can include enhanced integration of \u201cneurochemical\u201d imaging modalities with structural and functional modalities. The reports highlighted in this topic are an excellent demonstration of how multimodal approaches can improve methodologies, predictive power and clinical classification abilities to ultimately identify neural markers of psychopathology risk and guide more targeted treatments.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-03727-5, published online 20 December 2021Retraction of: The Editors have retracted this Article.there is insufficient justification for the grouping of the patients who belong to clinically heterogeneous cohorts with multiple different psychiatric disease presentations;the study lacks objective outcome measures; andthere are concerns about the validity of the therapeutic intervention tested\u2014specifically that Tenoten contains antibodies diluted beyond the point at which any active molecules are expected to be present and there is no molecular analysis to support the presence of molecules at these dilutionsAfter publication of this Article concerns were raised regarding the design of the study and the robustness of its central conclusions. Post-publication peer review has confirmed that:The Editors therefore no longer have confidence in the conclusions presented.Vladimir Anatolevich Parfenov, Dina Rustemovna Khasanova, Pavel Rudolfovich Kamchatnov and Alexey Borisovich Glazunov disagree with this retraction. Enver Ibragimovich Bogdanov, Tatiana Markovna Lokshtanova, Aleksandr Vitalevich Amelin, Natalya Nikolaevna Maslova, Nataliia Vyacheslavovna Pizova, Galina Nikolaevna Belskaya, Evgeny Robertovich Barantsevich, Gulsum Abdurahmanovna Duchshanova, Saltanat Ualihanovna Kamenova and Oleg Vladimirovich Kolokolov did not respond to correspondence from the Editors about this retraction."} +{"text": "Racial and ethnic health disparities are fundamentally connected to neighborhood quality. For example, racial and ethnic minorities are more likely to live in neighborhoods with signs of physical disorder , and physically disordered environments have been noted to associate with increased risk for chronic illness. Given that older adults may spend more time in their neighborhoods than younger adults as they transition out of the workforce, examining associations between neighborhood physical disorder and health among older minorities is of critical importance. Using 2016-2018 Health and Retirement Study (HRS) data, a representative sample of US adults aged 51 years and older , we conducted a series of weighted linear regressions to examine links between neighborhood disorder as rated by third parties and both participant-perceived neighborhood safety and self-rated health. Study results indicated that higher neighborhood physical disorder was significantly related to more neighborhood safety concerns among non-Hispanic White and Hispanic residents, but not among non-Hispanic Blacks. On the other hand, neighborhood physical disorder was significantly associated with poorer health among all racial/ethnic groups. These patterns persisted after adjusting for education, sex, age, and census tract concentrated disadvantaged, population density, and racial/ethnic diversity. Our results indicate that community level interventions targeting neighborhood physical disorder may improve community health and minimize racial/ethnic health disparities."} +{"text": "Additional abnormal uptake in the right axillary artery, aortic arch, and left femoral artery corresponded to the insertion sites for arterial inflow during cardiopulmonary bypass. Knowledge that FDG accumulation may occur at the insertion sites of an extracorporeal-circulation device enables unnecessary tests to be avoided.A 37-year-old man with previous heart transplantation for dilated cardiomyopathy underwent screening for malignancy under posttransplantation immunosuppression."} +{"text": "Health inequalities partially remain due to differences in diet between socioeconomic groups. Examining the association between socio-ecological factors and the diet of socioeconomically disadvantaged (SED) individuals can enhance the development of interventions to decrease health inequalities.In total, 278 SED adults residing in two Flemish municipalities completed a survey addressing sociodemographics, diet, health and their perceptions of the food environment. The objective food environment was examined by assessing food retailer information in street network-based buffers of 500m and 1000m around participants\u2019 addresses. Linear regression was used to test assumptions.Individual factors such as poor subjective health , food insecurity and living alone were negatively associated with healthy dietary habits such as daily fruit and vegetable (FV) consumption. Positive perceptions on the availability of FV were positively associated with daily FV consumption. Objective food environmental factors showed a stronger association with unhealthy dietary habits. A greater amount of retailers within 1000m walking distance was negatively associated with fast-food and sugar-sweetened beverages (SSB) consumption . More supermarkets within 500m distance was negatively associated with SSB consumption, while more convenience stores within a 1000m distance was positively associated with SSB consumption.Our findings suggest that factors associated with the diet of SED adults differ according to food and drink items. Interventions focused on this population should take these differences into account.Individual and food environmental factors are both associated with the diet of socioeconomically disadvantaged adults but differ according to food and drink items.Individual factors and perceptions of the food environment more likely associated with a healthy diet. Objective factors of the food environment were more likely associated with an unhealthy diet."} +{"text": "Impaired reproductive health is a worldwide problem that affects the psychological well-being of a society. Despite the technological developments to treat infertility, the global infertility rate is increasing significantly. Many infertility conditions are currently treated using various advanced clinical approaches such as intrauterine semination (IUI), in vitro fertilization (IVF), and intracytoplasmic injection (ICSI). Nonetheless, clinical management of some conditions such as dysfunctional endometrium, premature ovarian failure, and ovarian physiological aging still pose significant challenges. Stem cells based therapeutic strategies have a long-standing history to treat many infertility conditions, but ethical restrictions do not allow the broad-scale utilization of adult mesenchymal stromal/stem cells (MSCs). Easily accessible, placental derived or amniotic stem cells present an invaluable alternative source of non-immunogenic and non-tumorigenic stem cells that possess multilineage potential. Given these characteristics, placental or amniotic stem cells (ASCs) have been investigated for therapeutic purposes to address infertility in the last decade. This study aims to summarize the current standing and progress of human amniotic epithelial stem cells (hAECs), amniotic mesenchymal stem cells (hAMSCs), and amniotic fluid stem cells (hAFSCs) in the field of reproductive medicine. The therapeutic potential of these cells to restore or enhance normal ovarian function and pregnancy outcomes are highlighted in this study. Over the past few daces, a substantial decline in fertility rate is observed around the world . Both ecDespite the availability of cutting-edge therapies to restore or enhance infertility, some pathological conditions such as the dysfunctional uterus, persistent atrophic/thin endometrial lining, and loss of regeneration capacity of endometrial tissue lower the success rate of these treatments. For instance, successive embryo implantation failure due to a dysfunctional uterus or immune rejection remains the main reason for IVF treatment failure. Similarly, the inefficient process of endometrial tissue regeneration due to the loss of stem cells in the basalis layer of endometrium leads to pathological conditions such as intrauterine adhesion (IUA) or endometrial atrophy. Stem cell-based regenerative therapies hold the great capability of replenishing the functional deficit cell reservoir to address such pathological conditions .Due to the differentiation ability into germ cells and oocyte-like cells, stem cells may adopt the following mechanisms to repair ovarian functions; i) heal injured reproductive tissues by replenishing healthy cells, ii) restore or increase the number of secondary and mature follicles, iii) improve microenvironment by secreting paracrine factors and ameliorate ovarian function, iv) immune regulation by secreting anti-inflammatory factors, and v) regulate the hormonal levels that maintain estrous reproductive cycles and stimulate ovulation such as E2 (Estradiol), AMH (Anti-M\u00fcllerian hormone), and FSH (Follicle-stimulating hormone). Despite the great success of stem cell therapeutics in reproductive disease management, the ethical concerns, heterological nature, low yield, and lower ex-vivo proliferation rate of adult stem cells limit their clinical translation . ConversStem cells isolated from the umbilical cord have well-established therapeutic uses and are discussed in literature excessively . Other eMesenchymal stromal/stem cells (MSCs) derived from the avascular mesenchymal matrix of the human amniotic membrane (hAM) offer a beneficial option to replace adult MSCs \u201311. LimiThe studies that explored the role of hAMSCs to promote ovarian function in natural or premature ovarian aging (NOA or POA) or premature ovarian failure/inefficacy (POF/POI) mouse models are listed in Table \u03b3, TNF\u03b1), induction of anti-inflammatory molecules (TGF-\u00df), and regulation of the Treg cell population were found critical in improving the number of glands and reducing fibrotic areas in ovaries [Yin et al. and Gan ovaries .In vivo studies demonstrated that hAMSCs harbor the great ability to colonize uterine tissue and ovarian stroma which helps achieve the utilization rate of hAMSCs thus the desired outcomes. However, various strategies were adopted and compared to improve the homing of stem cells, e.g., repeated vs. single transplantation of hAMSCs , direct In a few comparative studies, the therapeutic potential of hAMSCs in recovering ovarian functions was found superior to other cells such as hAECs , 26 or aThese inherent characteristics of hAMSCs suggest multiple clinical applications in the field of reproductive biology. However, due to the lack of human studies, clinical uses of hAMSCs are mostly theoretical until now and need further optimization in the preparation and banking procedures.Human amniotic epithelial stem cells (hAECs) have been entertained as another possible source of endometrial regeneration or restoring ovarian function. The hAECs comprise a major portion of the epithelial cell layer of the basement membrane of hAM. The stem cell markers expression profile of hAECs, i.e., CD73, CD90, and CD105 positive, while negative for hematopoietic markers CD34 and CD45) is remarkably similar to MSCs. However\u03b2/Smad signaling pathway that resulted in a reduction of cell apoptosis thus improving follicle formation [Wang et al. performeormation \u201334.Until now, only two studies have assessed the therapeutic efficiency of hAECs for the treatment of IUA Table . Li et aInfertility or obstetrical infertility complications may occur after cesarean section due to injury to the endometrium and subsequent collagen deposition. In a recent study, the hAECs were used to treat cesarean scar defect (CSD) conditions in a rat uterine scar model . After 3Amniotic fluid is enriched with different types of stem cells in all three phases of pregnancy. Stem cells derived from human amniotic fluid (hAFSCs) are characterized by well-established stem cell surface markers , 40. AFSWhile still in an early stage of development, hAFSC-based in vivo studies show promising results to preserve follicle cells and prevent ovarian dysfunction Table . In a stIn a recent study, mesenchymal stem cells from amniotic fluid (hAFMSCs) were explored to study their potential and mechanism to rescue ovarian senescent cells . The amnGiven the ease and availability of placental membranes, which are considered a medical waste following delivery, unexpectedly no clinical studies have been published evaluating the role of amniotic-derived stem cells in restoring ovarian functions in humans. Similar to other fields of medicine, the inherent properties of ASCs warrant their success in the setting of endometrial-driven, chemotherapy-induced, or age-related infertility. However, based on studies reported so far, significant challenges still exist before the translation of these cells in clinical studies. Such as addressing the successful differentiation of ASCs in germ cells in culture, defining the route and time of administration of cells to increase effectiveness, use of precise animal models, and addressing long-term fertility benefits. Future studies should continue to elucidate regulatory mechanisms induced by the amniotic stem cells in ovarian recovery for successful manipulation of these cells in treating infertility.Amniotic tissue or fluid-derived human amniotic cells exhibit stem cell properties with low immunogenicity or tumorigenesis making them theoretically superior to other stem cells. Many studies were performed using mouse models of chemotherapy treated premature ovarian failures, age-related ovarian failure, or other related infertility pathological conditions. These in vivo investigations reported the fundamental findings to understand the mechanisms of actions of ASCs in restoring fertility outcomes. These studies suggest that ASC transplantation promotes follicle formation, endometrial regeneration, glandular development, and restores hormone levels . These physiological improvements are carried out due to paracrine, anti-inflammatory, and immune regulatory properties of ASCs. Although these studies provide a theoretical foundation for their application in infertility-related health issues, future studies are warranted to confirm these results for their successful translation into clinical applications."} +{"text": "An 80-year-old Caucasian female patient presented with a two-year history of intensively itching skin rash located on her left lower leg and mild swelling of the proximal interphalangeal and metacarpophalangeal joints, accompanied by morning stiffness around these joints, lasting at least one hour before maximal improvement . She repPresence of intensively pruritic erythematous papules located on the left pretibial surface was established clinically . SymmetrImmunological testing for antinuclear antibody (ANA) and Scl 70 was negative. The cutaneous pathological changes presented required a wide spectrum of differential diagnoses, including pretibial myxedema, necrobiosis lipoidica, the small papular form of cutaneous sarcoidosis, T-cell lymphoma, lichen ruber planus and Arndt-Gottron scleromyxedema. Histopathological evaluations on skin biopsies revealed hyperkeratosis, focal acanthosis, subepithelial structures that stained pink with hematoxylin-eosin and mild to moderate mononuclear infiltrate around single vessels . SubepitThe findings were characteristic of amyloid deposition and a diagnosis of lichen amyloidosis was made. No clinical or laboratory evidence of systemic amyloidosis was presented. Systemic therapy consisting of bilastine (20 mg daily) and acitretin (15 mg daily) was started, with topical application of 0.1% mometasone furoate cream, which produced a satisfactory therapeutic response. The patient was referred to a rheumatological unit for further therapy with biological agents.Localized cutaneous amyloidosis encompasses several conditions characterized by deposition of amyloid or amyloid-like proteins in the dermis, including macular amyloidosis and lichen amyloidosis.Lichen amyloidosis is a primary form of localized cutaneous amyloidosis that is clinically manifested through hyperkeratotic erythematous to brownish papules, while amyloid deposition can be seen via specific histological staining in previously normal skin without any evidence of visceral involvement.Although cutaneous lesions may be seen in up to 40% of patients with primary and myeloma-associated systemic amyloidosis, their presence results from tissue deposition of immunoglobulin light chain material derived from a circulating paraprotein.,Although the etiology is not fully understood, chronic irritation to the skin has been proposed as possible etiological factor.,,Treatment options include potent topical steroids under occlusion, intralesional steroids, topical dimethylsulfoxide and etretinate.We have described a rare association between lichen amyloidosis and rheumatoid arthritis in an 80-year-old female patient, without evidence of systemic amyloid involvement. To the best of our knowledge, this is the first reported case of primary cutaneous amyloidosis in a patient with rheumatoid arthritis, in contrast to the much more frequent association of rheumatoid arthritis with systemic amyloidosis, the pathogenetic relationship remains unclear. It is also unclear whether lichen amyloidosis might be the first clinical manifestation of the initial systemic involvement, in which cutaneous lesions can be seen in up to 40% of the patients,"} +{"text": "The use of selectiveserotonin reuptake inhibitors (SSRIs) is an independent risk factor for bleeding events. Antidepressants and oral anticoagulants (OACs) are often prescribed together as depression and anxiety often coexist with cardiovascular diseases, atrial fibrillation and thromboembolic disorders. Serotonin is released from platelets in response to vascular injury, promoting aggregation. Inhibition of serotonin transporter (responsible for the uptake of serotonin into platelets) can lead into a reduced ability to form clots and a subsequent increase in the risk of bleeding. Direct oral aticoagulants (DOACs), rivaroxaban, apixaban and edoxaban are primarily metabolized via CYP3A4. The co-administration of antidepressants with inhibitory effects on CYP3A4 may theoretically interact with them.Presentation of a case of upper gastrointestinal bleeding after initiation of Apixaban in a patient taking Sertraline and literature review.We carried out a literature review in Pubmed electing those articles focused on bleeding risk between newer direct oral antigulants and selective serotinin reuptake inhibitors.A 66-year-old woman sought medical assistance for generalized ecchymosis and melena. She was diagnosed with atrial fibrillation treated with apixaban 7 days ago. Concomitant treatment between apixaban and sertraline was the possible cause of upper gastrointestinal bleeding and ecchymosis. We had to switch sertraline into vortioxetine (with less dregree of serotonin reuptake inhibition) and add proton-pump inhibitor (Omeprazole) in order to decrease the risk of bleeding.SSRIs increase the risk of gastrointestinal bleeding, much more in case of concomitant use of oral anticoagulants. If SSRI use cannot be avoided, monitor closely and prescribe proton pump inhibitors."} +{"text": "Past research shows that discriminatory experiences may reduce sense of purpose among older adults, though these associations are inconsistent across groups. Work is needed both to understand the nuanced role discrimination plays on individuals\u2019 sense of purpose, whether it leads to feeling derailed from life goals, and if effects differ for younger versus older adults. The current study asked 354 American adults (age 19-74) to complete daily surveys over the course of two weeks, to examine whether experiencing discrimination during that two-week period led to a decline in purposefulness. Overall, findings suggest marked stability in sense of purpose during this short timeframe. However, greater daily discrimination predicted decreases in sense of purpose, and increases in derailment over the two weeks. While these associations were similar across age, older adults did report less discrimination at baseline. Findings will be discussed with a focus on successful aging among marginalized groups."} +{"text": "Individuals with substance use disorders are considered unpredictable and violent by the public. Besides, health care workers (HCW) may have negative attitudes towards them, despite their knowledge about addiction; which is related to lower quality of care. In Turkey, addiction service users are predominantly male, over ninety percent; while women make up a large percentage of psychiatrists.The present study aims to evaluate if the HCWs level of stigma towards individuals with substance use disorder changes due to gender and mental health sector experience of the HCWs.Within an online survey, participant HCWs answered Attitudes Towards Treatment of Substance Use Disorders Scale, Substance Addiction Stigmatization Scale, Alcohol Addiction Stigmatization Scale; in addition to sociodemographic questions.Three hundred ninety-eight HCWs were included in the analyses. 22.7% of them (n=91) were recruited in mental health sector. Mental health care workers had lower levels of stigma towards individuals with alcohol use disorders and substance use disorders and, lower levels of stigma towards addiction treatments . Among mental health care workers, women scored higher numbers of stigmatization towards alcohol use disorder and addiction treatments . On the other hand, women and men in other HCWs groups did not differ from each other in terms of stigmatization measurements The gender of mental health care workers may be related to stigmatization towards addictive disorders. Future research should evaluate underlying factors.No significant relationships."} +{"text": "Despite well-recognised benefits, Irish breastfeeding rates remain suboptimal. Although associations between breastfeeding and allergic disease are well-researched in younger children, evidence for continued effect in older children is sparse. This Irish prospective cohort study investigated associations between breastfeeding and allergic disease at age nine.The study sample included all nine-year-old children enrolled in the Growing Up in Ireland Infant Cohort Study whose mothers had participated in both Wave 1 and Wave 5. Mothers self-reported infant feeding practices at nine months and allergic diseases at nine years. Multiple logistic regression was used to generate adjusted odds ratios (aOR) for associations between breastfeeding and allergic diseases; re-weighting was applied to enhance generalisability.Response rate was 72% . Most mothers (53%) had ever-breastfed their child; younger mothers, smokers and those of lower socioeconomic status were significantly less likely to have ever-breastfed. Compared to never-breastfeeding, ever-breastfeeding was protective against asthma and eczema at age nine. Ever-breastfeeding increased the risk of atopic rhinitis ; the association with food allergy was inconclusive . Breastfeeding \u22656 months was protective against asthma and any allergic disease . Exclusive breastfeeding (3-5 months) was protective against asthma and eczema .This study provides new evidence suggesting breastfeeding may be protective against asthma and eczema but may increase the risk of atopic rhinitis in older Irish children. Results must be considered in light of high Irish allergic disease prevalence and action in support of breastfeeding prior to and following birth prioritised accordingly.Findings lend support to a protective association between breastfeeding and asthma and eczema in later childhood and indicate breastfeeding may play a role in allergic disease prevention.Breastfeeding may reduce the risk of asthma and eczema in Irish children: findings should be used to drive impactful breastfeeding promotion and reorientate cultural norms in favour of breastfeeding."} +{"text": "Medicaid home and community-based services (HCBS) provide integral health-related and personal care to support community-dwelling older adults. Growing literature suggests that states with more generous HCBS expenditures may delay or substitute costly nursing home care, but evidence is limited on the impact of HCBS spending on transitions to residential care settings like assisted living. This study determines the association of state Medicaid HCBS generosity\u2014HCBS spending as a percent of total long-term services and supports expenditure\u2014on the probability of incident transitions to residential care settings or nursing homes. Publicly available HCBS expenditure data was linked to a nationally representative sample of 7,197 community-dwelling older adults participating in the National Health and Aging Trends Study from 2011-2018. A discrete-time, competing risk regression model estimated the association between HCBS generosity and transitions from community to residential care settings or nursing homes, adjusting for sociodemographic, socioeconomic, and health factors. Most older adults remained in the community (93.7%). Incident transitions into residential care settings were twice as likely to occur compared to transitions to nursing homes . Older adults residing in states with higher HCBS generosity (one percentage point increase) are less likely to transition to nursing homes . Greater HCBS generosity was not associated with transitions to residential care setting. Assessing HCBS generosity on transitions elucidates important contextual factors affecting the movement of older adults across the care continuum."} +{"text": "Physical intimacy is assumed to benefit well-being through stress-buffering and mood-improving processes. Although partnered older adults often report wishing for and experiencing physical intimacy, inquiries about how intimacy is linked to affect and stress in older couples\u2019 daily lives remain scarce. We examined self-report and salivary cortisol data from 120 German couples obtained up to seven times per day over seven consecutive days. In moments when participants experienced more physical intimacy, women reported less negative affect, and men more positive affect. Experiencing more overall physical intimacy was associated with more positive affect and less negative affect in women, and lower daily cortisol in men. More overall intimacy wished was related to more negative affect in women and men, and to higher daily cortisol in men. We conclude that physical intimacy relates to indicators of well-being in older couples\u2019 daily lives and consider routes for future inquiry."} +{"text": "These neuroinflammatory processes serve to protect or remove degenerative cells and attempt to clean out amyloid plaques. Can AD-affected neurons contribute with a malfunctioning protein degradation mechanism to this process? A recent elegant study by Lee and coworkers5 has analyzed in several genetic mouse models of AD the major cytoplasmic recycling process of cells termed autophagy.Alzheimer\u2019s Disease (AD) with synaptic dysfunction and cognitive decline is a devastating age-associated neurodegenerative disease accounting for about two thirds of all cases of dementia.5 which subsequently fuse with endosomes and eventually lysosomes (autolysosomes) for content degradation and its release for recycling and expand the cellular membranes to blebs. Such PANTHOS-containing neurons were identified by the authors in post-mortem human AD brain samples as well.\u03b2-peptide deposition, is transported to the membrane through the secretory pathway along the endomembrane system,1 thus ER incorporation into PANTHOS structures provides these autophagic vacuoles with significant amounts of APP that can be proteolytically processed in endosomes/lysosomes. Strikingly, Lee et al. demonstrate that PANTHOS structures contain amyloid plaques with increasing levels of maturation over time concomitant with a compromised neuronal morphology.APP, the source of AEarly PANTHOS-containing neurons are not associated with reactive astrocytes or activated microglia. Therefore, initial autophagic defects, deacidified autolysosome accumulation, PANTHOS build-up and initial plaque formation evades detection by inflammation-mediating neighboring cells. Only when PANTHOS-containing neurons lose structural integrity, they are surrounded by activated astrocytes/microglia. At this advanced stage PANTHOS-containing neurons merge to larger structures likely giving rise to extracellular senile plaques that are eventually released into the extracellular space of the brain.4 Consequently, plaque formation should be viewed primarily as a cell-autonomous rather than a non-cell autonomous process.These findings of the authors imply several ground-breaking new insights into the possible mechanism of AD-associated plaque formation. Foremost, amyloid plaque formation considered to occur extracellularly due to APP proteolysis turns into an intracellular process followed by a release of already formed and matured plaques into the extracellular environment.The generation and accumulation of deacidified autolysosomes occurs long before histological signs of plaque formation and at stages when neurons appear to be healthy at large. This cellular metabolic signature could probably be exploited for diagnostic purposes of initiating AD or related neurodegenerative diseases at stages when preventive measure would still have major effects.Based on the author\u2019s finding the view on neuroinflammatory mechanisms in association with AD may be seen from a different perspective. The first contribution of reactive glia to AD progression may be a late one, when amyloid plaques have already formed and matured inside PANTHOS-containing neurons. But by promoting neuronal cell death of late-stage PANTHOS-neurons, glia might serve as a can opener causing the release of plaque material into the brain environment. This would promote plaque spread, turns further plaque growth from an intracellular into an extracellular process and enables plaque contact and influence possibly with glia.Besides providing crucial novel insights into cell biological processes of amyloid plaque formation, like any exciting research new important question arise. What is so far missing, is a careful assessment about the role of neuroinflammation, since the authors did not elucidate precisely when neuroinflammation starts and what it contributes to the observed phenotype. It also remains unclear which mechanism mediates reduction in vATPase-activity, and why some autophagosomes are poorly acidified, while others show a properly acidic pH-milieu. Autophagy is a process common to all cells. Why are cholinergic neurons of the forebrain affected first by AD, are they more sensitive to PANTHOS formation? Reestablishing proper acidic conditions in poorly acidified autolysosomes in AD mouse models at early stages should prevent PANTHOS-formation and subsequent establishment of histological features as well as AD symptoms in these animals. Such a rescue would further provide evidence that amyloid plaque formation is initiated in a cell-autonomous process by autophagy defects in neurons themselves. This could trigger a plethora of new drugs or even the development of preventive strategies.Neurofibrillary tangles as a hallmark of late AD stages do not appear in PANTHOS-neurons until stages of their destruction. Are these deficits inherent to the genetic mouse models that are unable to phenocopy NFT formation like in human AD brains? To investigate the relationship between PANTHOS-forming processes and neurofibrillary tangle appearance will be an interesting area of research.1 strongly support the notion that, months before plaques develop, A\u03b2 accumulates in faulty lysosomes neurons, and that this finally disturbs neuronal functioning and might cause neuronal death, leaving behind amyloid plaques. This supports therefore the hypothesis that lysosome dysfunction is an early, causal, and, most importantly, pathogenic process in AD.Overall the findings described in Lee et al."} +{"text": "Surgical boot camps are becoming increasingly popular in Otolaryngology\u2013Head and Neck Surgery (OHNS) residency programs. Despite pioneering virtual reality and simulation-based surgical education, these boot camps have lacked critical appraisal. The objective of this article was to examine the adoption and utility of surgical boot camps in OHNS residency training programs around the world.Ovid Medline and PubMed databases were systematically searched in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for scoping reviews. Additionally, a grey literature search was performed.Inclusion criteria were peer-reviewed publications and grey literature sources that reported on OHNS boot camps for the novice learner. The search was restricted to human studies published in English. Studies were excluded if they were not examining junior trainees.. Following removal of duplicates, screening, and full text review, 16 articles were included for analysis. Seven major boot camps were identified across various academic sites in the world. Most boot camps were one-day intensive camps incorporating a mixture of didactic, skill specific, and simulation sessions using an array of task trainers and high-fidelity simulators focusing on OHNS emergencies. Studies measuring trainee outcomes demonstrated improvement in trainee confidence, immediate knowledge, and skill acquisition.A total of 551 articles were identifiedSurgical boot camps appear to be an effective tool for short term knowledge and skill acquisition. Further studies should examine retention of skill and maintenance of confidence over longer intervals, as little is known about these lasting effects. Upon completing medical school, junior trainees enter post-graduate training programs with dramatically increased responsibilities. To address the concern regarding trainee skill inadequacy, surgical boot camps were developed to help develop skillsets from interpreting diagnostic imaging to performing surgical procedures .The educational design of most surgical boot camps is a combination of didactic learning and small group simulation sessions. Both governing medical educational bodies of Canada and the United States have embraced competency-based educational frameworks for post graduate medical education (PGME) . These fLiterature examining the role of surgical boot camps has been extensively covered over the past decade. The majority of studies have examined the following outcomes: knowledge and technical skills acquisition, team communication skill development, and individual confidence improvement \u20136. MoreoA scoping review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis scoping review (PRISMA-ScR) guidelines was performed in February 2021 . The resFour reviewers independently screened all abstracts to identify studies that fulfilled the predetermined eligibility criteria. Any disagreement between the reviewers was resolved by consensus. Qualitative data from each included study was extracted using standardized data forms including the study\u2019s title, author(s), year of publication, education themes, and outcomes assessed.A total of 21 articles were identified by Ovid Medline, 527 articles by PubMed, and 3 articles from a grey literature search. Following the removal of the duplicate records, 530 abstracts were screened , acute airway obstruction from angioedema (43%), and facial/neck trauma (29%). The most common task trainers were surgical airway (71%), epistaxis (57%), peritonsillar abscess drainage (43%), and bag mask ventilation with tracheal intubation (29%). High fidelity cadaveric and mannequin-based task trainers for task specific procedures appear to be the current trend. All studies that used high fidelity simulation scenarios used the Laerdal SimMan\u00ae adult simulator. SimMan\u00ae offers a highly realistic training model with real time neurological and physiological function.Despite some of the diversity in task trainers and simulations used across the world, the principal theme in all boot camp curricula appeared to be management of emergency situations and on-call scenarios. The goal was to have junior trainees leave the camp equipped with the skillset to identify and triage acute emergencies, perform basic minor airway procedures, and communicate and activate emergency protocols. We noted that trainee participation in introductory boot camps appears to improve their confidence, immediate knowledge acquisition, and immediate improvement in procedural skills in comparison to traditional didactic methods of learning , 91, 93.Despite strongly positive outcomes from boot camps and simulation training, criticisms of the lack of evidence to suggest long-term retention exist , 67. ThrAlthough boot camps are typically delivered at the beginning of OHNS programs because they are introductory, consensus on when they should be offered is lacking. When surveying American OHNS program directors, a slight majority felt boot camps should be offered within the first few months of residency . InteresBoot camp style training programs for junior OHNS are becoming widely adopted across the world. Fuelled by the utilization of simulation technology to deliver time-effective education for common OHNS emergencies, these programs embrace the educational shift towards competency-based accreditation standards for residency programs. A number of studies have justified this form of education to improve trainee\u2019s performance, confidence, and skill in the short term. However, current literature has failed to examine a number of important long-term outcomes. Future studies that examine the effect of OHNS boot camps on long term outcomes will play a critical role justifying widespread adoption of boot camps for resident education."} +{"text": "Without comprehensive accountability for citizen values, divergent stakeholder interests complicate rather than address problems. Second, the oral health community remains disconnected from the broader health community. Although oral diseases and noncommunicable diseases share common risk factors and sequelae, oral health systems rarely benefit from innovations in other areas of health care.Therefore, a complex systems problem exists, characterized by limited accountability for incorporating citizen values and research evidence on the effectiveness of oral health programmes and interventions at systems level; for seeking greater integration with broader health systems; and for identifying the critical junctures where path dependencies can be overcome. Inertia and inaction will leave us with a persistent, albeit largely preventable, burden of oral diseases. A different approach is needed to improve oral health systems. Evidence-informed deliberative processes provide one promising approach. Citizen panels can gather citizens with diverse backgrounds and experiences to collectively deliberate about key oral health-system problems, options to address them and key implementation considerations. The gathered citizen values can then be used in policy-making processes to counter narrow stakeholder interests that perpetuate a separation of oral health from the broader health system and that block efforts to improve governance, financial and delivery arrangements.Recent studies describe the role of citizen deliberations for context-specific health policy-making.,Deliberative processes can also be leveraged at the community level.On the clinical practice level, citizens with experience as patients can be involved in deliberations about quality improvement. Iterative reflective learning based on patient feedback can spur quality improvement.Lancet Commission on Oral Health and the World Dental Federation\u2019s Vision 2030 reportIn the oral health context, however, take-up of deliberative approaches as outlined above is currently limited. To ensure access to essential oral health care for everyone without causing financial hardship, the oral health community needs to commit to harnessing citizen values via evidence-informed deliberative processes. Describing the problem without identifying actionable solutions and implementation strategies is no longer an option. Recent developments such as the WHA74.5 Resolution,"} +{"text": "The outcome of first-episode psychosis (FEP) varies and may be predicted by several baseline measures. In the Helsinki Early Psychosis Study, young adults with FEP (n=97) from the Helsinki area in Finland were broadly assessed as soon as possible after first psychiatric contact for psychosis. Age- and gender-matched population controls were also assessed (n=62). The participants were followed up via appointments and medical records. We present both published and unpublished results on predictors of 12-month clinical, functional, and metabolic outcomes. More severe cognitive deficits at the beginning of treatment predicted several outcomes such as occupational status and functional level \u2013 beyond baseline positive and affective symptom levels, but not when negative symptoms were accounted for. More severe baseline obsessive-compulsive symptoms were predictive of a lower rate of remission, whereas a higher level of anxiety symptoms predicted better functional outcome, when the severity of positive symptoms was adjusted for. Adverse childhood experiences measuring cumulating psychosocial stress did not predict occupational status or functional level when positive and negative symptoms and neurocognition were controlled for, whereas in controls having experienced school bullying was associated with lower functioning. Insulin resistance in early psychosis appeared as an early marker of increased vulnerability to weight gain and abdominal obesity in young adults with FEP. Further, increased waist circumference predicted worsening low-grade inflammation, increasing further the cardiovascular risk. In sum, we have found different types of prognostic markers in FEP. Identifying the individuals at risk of less favorable outcomes could affect treatment choices in FEP.No significant relationships."} +{"text": "Lipid droplets (LDs) are spherical, single sheet phospholipid-bound organelles that store neutral lipids in all eukaryotes and some prokaryotes. Initially conceived as relatively inert depots for energy and lipid precursors, these highly dynamic structures play active roles in homeostatic functions beyond metabolism, such as proteostasis and protein turnover, innate immunity and defense. A major share of the knowledge behind this paradigm shift has been enabled by the use of systematic molecular profiling approaches, capable of revealing and describing these non-intuitive systems-level relationships. Here, we discuss these advances and some of the challenges they entail, and highlight standing questions in the field. Lipids constitute essential building blocks for cell membrane structures, powerful sources of energy through \u03b2-oxidation, and modulators of cell compartment transactions and cell signaling and behavior . Howeverlipid bodies; or adiposomes in early studies\u2014constitute a safe and efficient means to store lipids, particularly for organisms exposed to environments with intermittent nutrient availability. They appeared early in evolution and can be found across all eukaryotic phyla studied, and in virtually all cell types of higher metazoans are localized to the crowded surface of the LD, through mechanisms still undergoing characterization . Recent The particular ultrastructure of LDs, with a spherical core devoid of any molecules apart from triacylglycerides and cholesterol species, favored their long-standing view as relatively inert inclusions floating in the cytoplasm, passively subject to growth and consumption cycles . This viWhile relatively labile under routine immunolabeling procedures involving cell permeabilization with detergents, LDs are cell structures particularly amenable for imaging and extraction of rich multiparametric information . Their characteristic spherical morphology and the availability of highly specific cell/tissue permeable dyes for neutral lipids facilitate automated segmentation routines and the computing of their number, size and relative position across extensive datasets Figure . This kiBecause LD formation and function are significantly conserved across eukaryotic phyla , differeSaccharomyces cerevisiae is a first prominent example: the versatility and ease of use of this model unicellular eukaryote allows for the combinatorial interrogation of genetic interactions across the whole genome, using different readouts\u2014from subcellular imaging to relative survival across different limiting growth conditions\u2014; this allows for the precise mapping of genetic networks and enzyme complexes to as yet unparalleled resolution ; or the o below) . Innovato below) , have alCaenorhabditis elegans is a multicellular model system whose use in research largely developed during the birth of molecular biology to exert its function. Recent C. elegans screening studies have also provided insights onto the regulation of the formation of nuclear LDs (nLD); apart from COPI components and the seipin homolog SEIP-1, the authors identified the nuclear inner membrane NEMP-1/Nemp1/TMEM194A as a required gene for nLD formation as an important regulator of lipid accumulation in adult flies .A recent genome-wide siRNA screen was performed for regulators of LD biogenesis in THP1 human macrophages . This stAn emerging subfield in cell biology is the study of interorganelle communication through specialized structures, commonly referred to as membrane contact sites (MCSs), which allow for the regulated interchange of molecules and information to achieve coordinated functioning . Studyinbona fide LD proteins are indeed specific substrates for ERAD E3 ligases (see below) organizing LD distribution through their cooperation with the LD-ER linker seipin . Systemae below) . Anotherr seipin . Interesr seipin , and ther seipin . All ther seipin ; its molWhile the close apposition of LDs to mitochondria and its link with fatty acid consumption had been early suggested , specifiPeroxisomes enable \u03b2-oxidation of very long chain fatty acids in metazoans, and participate of fatty acid catabolism to its completion in yeast or plants . Recent Contacts between LDs and subcompartments of the endosomal system have also been described , but theDrosophila ; this particular study demonstrated the recruitment of RNA binding proteins participating in viral RNA replication to LDs . Histones, which can be toxic for cells when mislocalized or secreted ; ERAD appears coordinated with lipid metabolism (particularly cholesterol biosynthesis) through the control of different enzymes for each protein across different cell compartments, as located by specific bona fide markers. These correlative approaches have been rather successful on describing the proteomes of different cell compartments including LDs, especially in studies using machine-learning approaches to describe distribution changes across conditions can be nditions .in vitro and in vivo; after subsequent affinity purification, mass spectrometry allows for the identification of labelled cell proteome subsets. A variety of applications have been also derived to inform of specific events such as posttranslational modification or interorganelle communication nication . A relatm radius . Becausem radius . These msee previous section).Bersuker, Olzmann and collaborators fused the APEX2 ascorbate peroxidase to inertThese studies have provided reference lists of \u2018core\u2019 LD proteins, extremely valuable to understand how responsive this subproteome is, what stimuli regulate their localization to LDs, and what molecular mechanisms underpin such localization . Surprisde novo biosynthesis and triacylglycerol conjugation, respectively)\u2014and LD tethering to replication factories through the RAB18 GTPase and accessory proteins such as Annexin A3 (ANXA3) , induce LD formation and engage in complex interactions through their surrounding phagophore with these organelles, presumably to utilize their resources also induce the formation of LDs in the host cell, can liberate lipases to obtain free lipids from host LDs, and actively uptake these free lipids for the completion of their biological cycle . Other F (ANXA3) . Intraceesources . Eukaryoal cycle .However, this model of LDs as solely \u201ccomforting pantries\u201d for intracellular invaders does not fit with different lines of evidence. First, formation of LDs is actively promoted in the cell by the activation of pathogen pattern recognition receptors (PRRs) by their microbial invader product , such as bacterial surface lipopolysaccharides (LPS) and glycolipids or nucleUsing an experimental system where LD formation is induced in liver upon starvation and LPS administration in mice (thus minimizing effects from reduced food intake upon exposure to LPS), we applied multiplexed isobaric labeling and tandem mass spectrometry to profile the proteome of purified hepatic LDs, and its response to PRR activation . We obseLeveraging on variability across biological replicates, which can capture relevant biochemical relationships , hierarcListeria monocytogenes or herpes simplex virus type 1 is an amphiphilic peptide with prominent roles in innate defense against bacterial infection . Its preDrosophila antimicrobial defense upon recruitment by the Jabba protein support these are general principles Figure . Howeverbacteria . The ovebacteria and conttb types .C. trachomatis-infected epithelial cells found changes associated with LD metabolic reprogramming (both increased lipid usage and anabolism), and identified PLIN2 as a perilipin protein specifically enriched upon infection , a report on the proteomic composition of LD-rich fractions purified from nfection . Of note helices ; studiesWhile cell-based high-content screenings on LD biology have been fruitful, recent developments of these technologies could allow for the systematic interrogation of how these structures are regulated in contexts closer to physiological conditions, and how they relate to many other tissue components and markers. Automated culture and high-content analyses of organoids that capture tissue microenvironment properties have been reported . Recent de novo phospholipid synthesis are important parameters determining the size and coalescence of LDs (4P) species accumulate in large LDs of cells depleted of the ORP5 regulator, which has been proposed to supply phosphatidylserine from PI4P constitute a versatile means to modify the function, localization, stability, and interactions of proteome subsets in a coordinated manner. Protein phosphorylation comprises a large share of PTMs, driving signaling pathways for the transduction of different cues, including several modulating LD functions. An example is the regulation of LD growth and dynamics by different nodes of nutrient state sensing networks in the cell . FastingThe advancements brought by functional genomics and molecular profiling to all fields in cell biology are particularly prominent in LD research, as their characterization may have lagged as compared to other cell compartments, and some of their emerging functions were particularly unexpected. Novel unbiased technologies will surely contribute to uncover new systems-level aspects of the roles of LDs in cell function and their emerging relationships with other cell structures, such as the nucleus and the secretory apparatus."} +{"text": "Demands of caregivers of persons living with dementia (PLWD) are often influenced by the context of their caregiving situation. This study examines factors associated with caregiving burden in terms of task time and task difficulty among paid and unpaid caregivers of PLWD. Cross-sectional baseline survey data were analyzed from 110 paid and unpaid caregivers of PLWD participating in a larger NIH-funded study assessing the feasibility of using a novel in-situ sensor system. Oberst Caregiving Burden Scale constructs of task time and task difficulty served as dependent variables. Two least squares regression models were fitted, controlling for contextual items related to the caregiver, care recipient, and caregiving logistics. Caregivers whose care recipients were female , had more chronic conditions , and had lower Mini-Mental State Exam scores reported higher task time burdens. Caregivers whose care recipients had other paid caregivers and spent more months/years caring for their care recipients reported higher task time burdens. Caregivers\u2019 task time burden was positively associated with their emotional stress level . Caregivers\u2019 task difficulty burden was positively associated with their emotional stress and depressive symptomatology . Results reinforce the relationship between caregiver burden and mental health. While the care recipient\u2019s disease profile and needs were drivers of task time burden, which may also require coordination with other paid caregivers, task difficulty was emotionally driven. Findings highlight the importance of caregiver support services and programming for mental health."} +{"text": "Certified community forests combine local governance with forest certification and aim to serve multiple objectives including forest protection, restoration, human wellbeing and equitable governance. However, the causal pathways by which they impact these objectives remain poorly understood. The ability of protected area impact evaluations to identify complex pathways is limited by a narrow focus on top-down theoretical, quantitative perspectives and inadequate consideration of local context. We used a novel mixed-methods research design that integrates the perspectives of multiple actors to develop a generalized conceptual model of the causal pathways for certified community forests. We tested the model using a combination of statistical matching, structural equation modelling and qualitative analyses for an agroforestry landscape in Tanzania. We found certified community forests positively impacted human wellbeing, equitable governance and forest restoration. Equitable governance had the largest impact on wellbeing, followed by crop yield and forest resource availability. Timber revenues varied widely between villages and the average effect of financial benefits did not impact wellbeing due to the immature stage of the certified timber market. We identified positive interactions and trade-offs between conservation and agriculture. Our findings suggest that no simple solution exists for meeting multiple objectives. However, developing understanding of the pathways linking social and conservation outcomes can help identify opportunities to promote synergies and mitigate negative impacts to reconcile competing objectives.This article is part of the theme issue \u2018Understanding forest landscape\u00a0restoration: reinforcing scientific foundations for the UN Decade on Ecosystem Restoration\u2019. However, over the last 50 years the roles of PAs have expanded to include human wellbeing and equitable governance objectives ,2. Some Certified Community Forests (CFs) represent a new generation of PAs seeking to meet the expanding role of PAs, by combining two recent trends in forest PA governance: (i) decentralization\u2014transferring governance responsibility from central governments to local actors in efforts to enhance equitable governance; (ii) forest certification to increase the financial benefits and equitable benefit sharing to incentivize sustainable management . Forest Analysis of causal pathways can be used to explain the complex processes by which PAs impact outcomes . Win-winHowever, the presence of negative interactions between social and ecological outcomes would result in trade-offs between PA objectives. For example, if conservation governance is perceived as being unfair, this could lead to conflicts and local resistance , as occuAdvances in the field of impact evaluation have seen the mainstreaming of statistical matching to exclude alternative explanations and attribute observed differences to the intervention . Howevera priori hypotheses of how PAs impact wellbeing or conservation using exclusively quantitative approaches. This top-down framing of a study system excludes local perspectives and has been described as creating a \u2018bottleneck\u2019 in dialogue [Secondly, impact evaluations tend to test dialogue , which mdialogue ,26. GreaWe aim to advance methods to evaluate the success of conservation and restoration interventions. We identify and test the causal pathways by which certified CFs impact human wellbeing and forest restoration for a case study in Tanzania. Specifically, we evaluate win-win assumptions of PA governance by testing pathways of (i) equitable governance, (ii) financial benefits, (iii) interaction effects and (iv)\u00a0trade-offs.We advance on existing evaluation methodologies by (i)\u00a0combining statistical matching with a conceptual model (ii) integrating top-down theoretical perspectives with bottom-up perspectives of local actors to promote inclusive consideration of alternative explanations from marginalized actors. We thereby contribute to two key knowledge gaps of the United Nations Decade on Restoration: (i) methods for designing interventions, and monitoring restoration success; (ii) linkages between the health of ecosystems and the flow of services to communities .. 2 (a)Tanzania provides an excellent test case of the challenges to reconcile forest restoration and human wellbeing objectives as national development policies aim to expand both agricultural and PA land uses, while CFs are often established on forests already considered to be degraded and economically marginal . We focu (b)Our conceptual model aimed to integrate actor perspectives with hypothesized pathways derived from conservation science literature . We consA thematic analysis of transcripts was then undertaken to identify actor perspectives of the main pathways linking certified CFs with conservation and human wellbeing impacts by identifying logical causal statements that were similar between independent consultation sessions. Identified pathways were then converted into a connected sequence of indicators linking CF governance via one or more causally linked mechanisms to human wellbeing and conservation impacts . The overall conceptual model was then composed of these main pathways. Indicators may be connected to more than one pathway if the causal logic suggested interactions between indicators from different pathways.All indicators in the conceptual model were included in a quantitative questionnaire to collect data on community perceptions of all indicators, which were then used to test the model. Our conceptual model emphasizes measuring \u2018bottom-up\u2019 community perceptions, rather than externally measured data sources because perceptions are important drivers of local behaviour and success of conservation interventions . (c)To improve the causal inference of our study we used statistical matching to compare certified CFs to control villages that represent the counterfactual situation\u2014what would have happened in the absence of the intervention . This apThe questionnaire was undertaken with 955 people from the nine villages with certified CFs and 10 matched control villages, with at least 50 respondents per village stratified by gender, local elite status and wealth category . The questionnaire was undertaken at the scale of individuals rather than whole households since the concept of wellbeing contains subjective elements which cannot be generalized across households . (d) (i)Multidimensional human wellbeing provides a comprehensive measure of social impacts. Wellbeing indicators were identified following the Wellbeing Indicator Selection Protocol by a sub (ii)Miombo woodlands were the dominant forest type in the study landscape. Normalised difference vegetation index (NDVI) correlates with ground vegetation biomass and productivity under low to medium vegetation density conditions such as the Miombo woodlands . NDVI ch (iii)Equitable governance concerns notions of fairness , in rela (e)We tested the conceptual model by structural equation modelling using PiecewiseSEM in R . Latent We included socio-economic indicators for local elite status and gender in models to account for any systematic perception biases between actors. To account for residual imbalances in the distributions of confounding variables between treatment and control groups we included orthogonal sets of confounding variables as predictors of response variables . We thenr2 values (the variance explained by fixed effects).For continuous variables, we report standardized path coefficients, which estimate the expected change in the response variable (e.g. wellbeing) as a function of the change in the explanatory variable (e.g. equitable governance), in units of standard deviation. For categorical variables (e.g. governance treatment versus control group), we report the model-estimated means for each factor level . For allp < 0.05). Finally, we critically reviewed the conceptual model through triangulation with the qualitative data to assess whether the identified pathways and trends were representative of different village cases and actors sampled. This served as a verification check to ensure inclusive representation of pluralistic perspectives, particularly potentially marginalized or minority actors whose perspectives might otherwise be masked by reporting normative trends.We assessed the overall model fit by Shipley's test of d-separation, accepted when Fisher's C statistic is higher than a significance level , with mean scores of all equitable governance indicators higher in villages with certified CFs than control villages. In turn, equitable governance positively impacted human wellbeing both directly (standardized estimate = 0.18) and indirectly . The indWe have a lot of forest here and we work to manage it. But we have a limited number of customers and so the villagers here have not yet felt the actual benefit of this forest. But if we could get many customers to buy our timber then every member of this village could realize the importance of managing the forest - Village Natural Resource Committee Secretary, village 11.Second, a financial benefits pathway blue, , wherebyHowever poor economic performance was not the case in all villages. Annual timber revenue was highly variable between certified CFs . The size of certified CFs was also highly variable , with larger CFs generating more revenue. Some differentiation in timber revenue spending was observed between villages; the highest timber producing village able to undertake additional, larger-scale and more diverse community development projects, including (i) building new village government offices, (ii) installing primary school sanitation facilities, (iii) improved village healthcare provision targeting facilities for pregnant women and disabled patients and health insurance for village natural resource committee members, (iv) building a village-run guesthouse, (v) payment for forest patrols, planning meetings and patrol equipment, (vi) payment for professional forestry and governance training services from the supporting NGO MCDI and the district government forest office. An FSC-certified sawmill factory run by a sustainable timber production company called Sound and Fair had also been established in this village in 2017 to further up-scale timber production and revenue generation, providing additional employment opportunities.Third, a conservation pathway green, showed tWe are funding our own forest management activities. We pay even from our own village basket for meetings and patrols - Village Natural Resource Committee member, village 2.Fourth, positive interaction pathways were hypothesized from social to conservation outcomes yellow, with posThe government extended the national forest reserve boundary and so we have been left with a small area for farming. That land, it was very fertile, it was supporting us to have high production and we had a lot of food surplus. But now we have little food because we harvest very little \u2013 Community member, village 1.Fifth, trade-off pathways were hypothesized between conservation and agriculture red, . Focus gLarger certified CFs were also suggested by MCDI to have more economic potential for timber revenue, creating a trade-off between land uses. However, testing of our conceptual model did not show an impact of certified CFs on perceived land availability or knock-on impacts of perceived land availability for farming on crop yield or timber revenue.. 4We found evidence of both win-win and trade-off pathways from certified CF governance to forest recovery and human wellbeing. Certified CFs positively impacted (i) equitable governance and (ii) forest recovery and both pathways positively impacted wellbeing, supporting win-win assumptions that positive social and conservation outcomes can occur together and are causally linked. However, additional hypothesized win-win pathways of (iii) financial benefits from certified CFs and (iv) improved attitudes towards conservation did not impact either wellbeing or forest restoration, suggesting that the importance of these pathways was limited in our case study. The limitation of the economic pathway linking forest governance to wellbeing may be due to the FSC timber market being at an early stage of development and operating sub-optimally. While some villages were able to generate significant FSC timber revenue, which was used to deliver integrated programmes to improve human wellbeing, concerns were raised by other villages about the challenges of accessing timber markets. Nevertheless, these findings agree with other research suggesting that equitable governance can be a more important driver of successful conservation than financial incentives . FinallyBy disaggregating the impacts of PA governance into multiple pathways it is possible to identify which aspects of an intervention are performing well and which aspects are failing. In our case study, the governance equity component of certified CFs had a positive impact, in contrast to other CF programmes in Tanzania . HoweverBy comparing quantitative and qualitative findings it is possible to explore how variation in contextual factors can lead to alternative outcomes. Not all CFs showed poor financial performance. The village that\u00a0 established the largest CF, was also generating the most timber revenue, which was spent on diverse community projects, including additional income generation schemes such as a village-run guesthouse. The economic potential of this village had also attracted the establishment of an FSC-certified sawmill, in contrast to other villages which struggled to attract timber buyers. This more economically successful village, contrary to the general trend identified by modelling analyses, suggests that improved financial performance may require villages to dedicate significant land area to CFs and that strategies are needed to improve engagement with timber markets.The positive interaction pathways suggest the potential for virtuous cycles to occur over time , where pThe trade-off pathways, whereby forests provide both ecosystem benefits and costs for agriculture and potential agricultural land-shortages caused by expansion of PAs, suggest that the study landscape represents a microcosm of global challenges to reconcile forest conservation with rural development objectives ,5. We diOur research design sort to embrace a complex systems perspective. However, several simplifications were necessary to aid interpretation. To support a statistical comparison, we employed a binary distinction between the governance approaches of certified CFs and control villages. However, we recognize that within this overarching governance grouping, varying governance arrangements exist. To move beyond a coarse binary description of governance approaches, we employed qualitative methods to highlight outlying cases that contrasted with the normative quantitative trends reported. However further exploration of the within-group variation in governance approach would be possible through more in-depth case study research . Both huOur novel methodology illustrates the utility of a mixed methods approach for developing and testing theory of complex systems, with quantitative analyses showing overall trends, while qualitative analyses identifying alternative pathways missed by normative analyses. The integration of multiple actor perspectives provided a more comprehensive and contextualized understanding of pathways that balanced assumed positive and negative impacts of forest governance on people and forest recovery. By integrating views of actors from the global south our methodology makes progress in operationalizing calls for a pluralistic perspective of conservation challenges , to impr"} +{"text": "Xenopus laevis, have revealed that efference copies (ECs) of the spinal motor program that generates axial- or limb-based propulsion directly drive compensatory eye movements. During fictive locomotion in larvae, ascending ECs from rostral spinal central pattern generating (CPG) circuitry are relayed through a defined ascending pathway to the mid- and hindbrain ocular motor nuclei to produce conjugate eye rotations during tail-based undulatory swimming in the intact animal. In post-metamorphic adult frogs, this spinal rhythmic command switches to a bilaterally-synchronous burst pattern that is appropriate for generating convergent eye movements required for maintaining image stability during limb kick-based rectilinear forward propulsion. The transition between these two fundamentally different coupling patterns is underpinned by the emergence of altered trajectories in spino-ocular motor coupling pathways that occur gradually during metamorphosis, providing a goal-specific, morpho-functional plasticity that ensures retinal image stability irrespective of locomotor mode. Although the functional impact of predictive ECs produced by the locomotory CPG matches the spatio-temporal specificity of reactive sensory-motor responses, rather than contributing additively to image stabilization, horizontal vestibulo-ocular reflexes (VORs) are selectively suppressed during intense locomotor CPG activity. This is achieved at least in part by an EC-mediated attenuation of mechano-electrical encoding at the vestibular sensory periphery. Thus, locomotor ECs and their potential suppressive impact on vestibular sensory-motor processing, both of which have now been reported in other vertebrates including humans, appear to play an important role in the maintenance of stable vision during active body displacements.Vertebrate locomotion presents a major challenge for maintaining visual acuity due to head movements resulting from the intimate biomechanical coupling with the propulsive musculoskeletal system. Retinal image stabilization has been traditionally ascribed to the transformation of motion-related sensory feedback into counteracting ocular motor commands. However, extensive exploration of spontaneously active semi-intact and isolated brain/spinal cord preparations of the amphibian Gaze stabilization during both self-generated and passive motion is essential for constantly maintaining retinal image acuity as a prerequisite for stable perception of the visual world . During While the sensory-motor transformations subserving gaze stabilization are well documented for passive head/body motion, the processes operating during self-generated movements have remained more elusive. Over the last decade, however, evidence has accumulated that intrinsic copies of the actual motor commands responsible for an animal\u2019s propulsive axial or limb movements may also provide a source of neuronal signals for retinal image stabilization . Due to Xenopus laevis, consisting of the head\u2014including inner ears, eyes and eye muscles\u2014along with the still-attached and isolated spinal cord may provide a functional blueprint that extends to other vertebrates, including humans.Here, we review evidence for the involvement of this novel mechanism during rhythmic undulatory and limb-based swimming in larval and juvenile Xenopus, which occurs mostly in the horizontal plane, both eyes oscillate in conjugation during left-right head excursions resulting from undulatory tail movements pathway that is known to be involved in producing conjugate eye movements , the ocular motor performance remains exclusively coordinated with the tail undulations, without any evident VOR contributions to eye motion . The strThe suppression of vestibular afferent influences during high-intensity larval swimming might be spatially specific to inputs from the horizontal semicircular canals, or might represent a generalized filtering process that applies to all vestibular signals irrespective of their peripheral origin. To distinguish between these two possibilities, the influence of locomotor ECs on inputs from vestibular endorgans other than the horizontal semicircular canals was tested during passive motion around the longitudinal (roll) axis. In fact, an imposed left-right head roll motion caused a strong modulation of the LR nerve discharge that increased and decreased in strength during contra- and ipsiversive movements, respectively. The directionality of these evoked ocular motor responses and the low frequency (0.1 Hz) of the motion stimulus were consistent with the activation of vestibular signals predominantly arising from the gravitoinertial stimulation of utricular hair cells . SignifiXenopus tadpoles can be conferred by locomotor ECs rather than by VOR-producing sensory-motor transformations, this mechanism also has hitherto unsuspected implications for issues ranging from the evolution of the horizontal semicircular canals to the maintenance of postural stability during locomotion in human patients with vestibular disorders synapse in the vestibular nuclei, or peripherally, at the synaptic connection between hair cells and vestibular nerve afferent fibers in the inner ear endorgans themselves at which the suppression of spatially-specific signals in the VOR circuitry occurs, nor the underlying neurophysiological mechanism(s), have been fully established. Such an understanding requires identifying the anatomical pathways that convey the intrinsic CPG-derived signals and the suppressive processes operating at single or multiple synaptic levels. In principle, establishing these underlying features benefits from the simple organization of the VOR circuitry, which is comprised of a three-neuronal reflex arc for integrating angular and translational/gravitoinertial sensory signals . This shemselves .Xenopus, such an efferent neuron activation was indeed revealed by multi-unit recordings from the central severed ends of the anterior and posterior branches of a vestibular nerve nerve . During l) nerve , that thl) nerve .2+ transients were recorded in practically all efferent neuronal somata (of which there are 10\u201315 per side located in rhombomere 4), with onsets and durations that were strictly correlated with those of the accompanying spinal Vr bursting burst discharge recorded in vestibular nerve branches indicated that the latter activity precisely encodes swim episode duration and any changes in Vr burst cycle frequency and intensity. This faithful coupling thereby ensures that the major parameters of propulsive motor commands are conveyed to the sensory periphery.The proportion of efferent neurons that are activated during locomotion was assessed by somatic calcium imaging during episodes of fictive swimming monitored by spinal Vr recordings. During swim episodes, Cabursting . FurtherXenopus preparations with intact vestibular endorgans and preserved peripheral and central nerve connections (en passant during rotational stimuli applied in different spatial planes alone, and during the occurrence of spontaneous fictive swimming (The impact of locomotor-related efferent neuron bursting on vestibular sensory encoding of head/body motion was evaluated in semi-intact larval nections . Vestibuswimming . In the swimming , left. Hswimming , the measwimming . HoweverThe functional significance of the differential effects of efferent neuronal activity on the spontaneous firing of vestibular afferents and their sensitivity to motion stimuli might be related to the push-pull operation of the vestibular system itself. Here, the encoding of immobility relies on bilaterally-balanced population resting discharge rates throughout the afferent neuronal assemblage . AccordiAnother potential site for a suppressive action of locomotor ECs on sensory-motor processing resides within the central circuitry of the vestibular nuclei . Since vAlthough the selective suppression of ocular motor output in tadpoles during horizontal, but not vertical, head rotation is based on a spatial specificity, likely related to the plane of head undulations during axial swimming, an alternative explanation might involve a difference in the dynamic spectrum of activated vestibular afferent units during motion in the two rotational planes. Roll motion stimulation in the vertical plane activates sensory elements in the vertical semicircular canals but is also a highly effective gravito-inertial stimulus for the utricle, thereby activating a large proportion of hair cells/afferent vestibular fibers with more tonic response dynamics . This isAn involvement of cerebellar and local vestibular circuits in the gating of body motion-related sensory signals during locomotion would not be unexpected given previous knowledge of their roles in the control of gaze stabilization . In contIn an evolutionary context, locomotor EC-driven eye movements might constitute a vestige of an ancestral mechanism, appearing in early vertebrates before rotational motion-encoding semicircular canals had appeared . AlthougXenopus laevis, considerably less is known for such a role in other vertebrates. In lamprey, an extant jawless vertebrate species, the use of semi-intact, head-immobilized preparations after optic nerve transection and labyrinth ablation has very recently provided direct evidence that spinal CPG-derived ECs contribute to compensatory eye movements, coordinated with swimming undulations in the horizontal plane (Xenopus. This idea has been further supported by experimental galvanic stimulation of bilateral inner ear endorgans in human patients, which caused smaller trajectory deviations during running than walking (While the functional processes and underlying neuronal pathways by which locomotor ECs can stabilize gaze have been unequivocally demonstrated in the amphibian al plane . Howeveral plane . Furtheral plane . The remal plane or pre-pal plane and animal plane . In addial plane and humaal plane , resultaal plane , then ECal plane , 2022. A walking , again c walking , 2022.ex vivo brain-spinal cord preparations of neonatal mice with spatio-temporal characteristics reminiscent of those described in Xenopus. This ocular motoneuronal pattern complied with rhythmic eye movements, mostly in the horizontal plane, which occurred in phase with the forelimb gait pattern during treadmill-elicited locomotion in decerebrated animals. Moreover, the ascending locomotor signals were likely to derive from cervical cord neurons that connect directly with abducens motoneurons, similar to the situation found in amphibians (More direct evidence for locomotor EC-driven eye movements has recently been discovered in mice, where the existence of a comparable spino-ocular motor coupling has been established by multi-methodological approaches . Brieflyphibians . Thus, sphibians .in vitro experiments on larval and young adult Xenopus laevis provided the initial demonstration that efference copies of axial- as well as limb-based locomotor commands are able to elicit retinal image-stabilizing eye movements. This intrinsic feed-forward mechanism is spatio-temporally specific, functionally appropriate and dynamically adaptive, being capable of initiating gaze-stabilizing eye movements according not only to the immediate strength of ongoing locomotion but also to its mode, even throughout the transitional period of metamorphic development as one locomotor strategy progressively replaces the other. The ability to provide retinal image stability during the change in body format, propulsive motion profile and associated visual demands derives from a remarkable rewiring plasticity of spino-ocular motor coupling pathways that co-exist in the metamorphosing animal. While the impact of predictive locomotor efference copies matches the specificity of reactive sensory-motor transformations, the two fundamentally different signals do not simply summate in the production of image-stabilizing ocular motor commands. Rather, depending on the intensity of spinal CPG activity, the horizontal VOR is selectively suppressed, at least in part by an attenuation of the motion signal encoding at the sensory periphery in the inner ear. Significantly, this gaze-stabilizing mechanism that relies on locomotor EC signaling is not merely idiosyncratic to amphibians with their simpler and more stereotyped locomotor movement profiles, but evidently is also employed by other vertebrates, including humans. Recent studies in both Xenopus and mice (Maintaining visual world stability during locomotion is a major challenge for all vertebrates. Avoiding retinal image slip due to passive or self-generated head/body motion is traditionally ascribed to the transformation of mechanosensory feedback signals into ocular motor commands that offset perturbing head movements to ensure stable eye position in space. However, this generally acknowledged concept has been challenged over the past decade by increasing evidence that ascending neuronal pathways enable the propulsive CPG circuitry in the spinal cord to directly access and drive the brainstem ocular motor system during locomotion. Various types of and mice suggest and mice . This meHS and JS wrote the first draft of the manuscript. FL made the figures. HS, FL, and JS reviewed and edited the final version of the manuscript. All authors contributed to the article and approved the submitted version."} +{"text": "Due to antibiotic overutilization, development of antimicrobial stewardship (AMS) in the outpatient setting has become a necessary focus for AMS programs. The cornerstone of AMS is utilization of antimicrobial prescribing data to provide feedback to individual providers and compare providers to each other in order to promote improved prescribing practices. Respiratory infections, especially conditions that never require antimicrobials, are a common target for this feedback. We aimed to create interactive data visualization dashboards of end-users prescribing for these respiratory and otic conditions in order for AMS and urgent/quick care program staff to identify potential areas of intervention.A multidisciplinary work group consisting of data analysts, infectious diseases physicians, urgent/quick care physicians, and infectious diseases pharmacists determined dashboard content, layout, and comparison charts. Graph types were tested to determine optimal visual output. Using the electronic medical record ICD10 and antimicrobial prescription data was extracted for the encounter with focus on ICD10 codes for respiratory and otic conditions which never require antimicrobials. Rates were calculated as number of antimicrobial prescriptions over total number of visits for these conditions.A multi-faceted dashboard was developed in Tableau\u00ae to view antimicrobial prescribing rates. Dashboard capabilities include the option to view individual provider prescribing rates compared to other de-identified providers, overall clinic prescribing rate, or individual rate compared to clinic rate. This allows for quick direct comparison of antimicrobial prescribing on the same graph by clinic to identify outliers and allows visualization of trends in prescribing rates by clinics and providers over time .Never Antimicrobial Prescribing Rate ComparisonScatter plot comparing individual prescribers rate of prescribing for never antimicrobial eventsClinic Antimicrobial Prescribing Rate TrendClinic prescribing rate trend over time for never antimicrobial eventsPrescriber and Clinic Antimicrobial Prescribing Rate TrendIndividual prescriber rate compared to clinic rate over time for never antimicrobial eventsWe developed an interactive outpatient AMS dashboard to visualize prescribing of antimicrobials for never respiratory and otic conditions. These dashboards can be used by providers along with AMS and clinic leadership to determine areas of intervention in the urgent/quick care setting.Kelly M. Percival, PharmD, Gilead Sciences Inc: Advisor/Consultant Patrick M. Kinn, PharmD, MPH, Gilead Sciences: Advisor/Consultant Dilek Ince, MD, Evergreen: Member of data monitoring board|Gilead Sciences: Grant/Research Support|Leidos: Grant/Research Support|Moderna: Grant/Research Support."} +{"text": "Pelvic fractures are common in cases of blunt trauma, which is strongly associated with mortality. Transcatheter arterial embolization is a fundamental treatment strategy for fatal arterial injuries caused by blunt pelvic trauma. However, vascular injuries due to blunt pelvic trauma can show various imaging findings other than arterial hemorrhage. We present a pictorial review of common and uncommon vascular injuries, including active arterial bleeding, pseudoaneurysm, arteriovenous fistula, arterial occlusion, vasospasm, and active venous bleeding. Knowledge of these vascular injuries can help clinicians select the appropriate therapeutic strategy and thus save lives. Pelvic fractures are not rare and account for approximately 3% of skeletal injuries . Pelvic Transcatheter arterial embolization (TAE) is the fundamental treatment strategy for patients with fatal arterial injuries caused by blunt pelvic trauma , 5. HoweTAE is the fundamental treatment strategy for active arterial bleeding due to pelvic fractures . Embolizn-butyl cyanoacrylate (NBCA) is useful for both selective and non-selective embolization; however, an experienced operator is desirable to prevent NBCA-related complications, such as reflux and non-target embolization . Ant. Ant8]. Resuscitative endovascular balloon occlusion of the aorta (REBOA) is an important method for treating severe hemorrhagic shock due to pelvic trauma. In this procedure, occlusion of the aorta with a balloon catheter is conducted to increase proximal arterial pressure and maintain organ blood flow while controlling downstream bleeding . HoweverThe formation of pseudoaneurysms in patients with blunt pelvic trauma, although rare, may occur immediately after the injury or later in the clinical course . PseudoaEndovascular treatment of traumatic pseudoaneurysm is usually effective Fig.\u00a0 16]. Th. Th16]. AVF is an abnormal anastomosis between arteries and veins and does not involve capillaries. Traumatic AVF can develop if arterial bleeding influxes into an adjacent injured vein . On radiBecause traumatic AVF can cause heart failure after highly variable latency periods , AVFs shThe middle layer of blood vessels is made up of smooth muscles, and smooth muscle cells may contract and become spasmodic following external compression, stretching, or endothelial injury due to trauma . Active Arterial occlusion is caused by transmural injury or dissection with a thrombus . Active Traumatic occlusion of the main trunk of the common/external iliac artery can cause critical lower limb ischemia, making recanalization crucial . VasculaBleeding due to pelvic fractures occurs more frequently from veins (80%) than from arteries (20%); the main venous sources of bleeding are the presacral plexus and prevesical veins . PeritonActive venous bleeding can be visualized using CT as the extravasation of contrast material in venous phase images without extravasation in arterial phase images Fig.\u00a0 20]. Il. Il20]. Transcatheter venous embolization with NBCA can potentially control critical bleeding from the iliac vein. However, it may cause some complications, such as leg swelling, deep vein thrombosis, and pulmonary embolism by obstruction of venous flow . EndovasWhen surgical treatment is chosen for a venous injury, balloon catheters can reduce bleeding and help obtain the necessary visualization of the operative field by occluding the proximal and distal portions of the injury .Endovascular treatment is effective for vascular injuries due to blunt pelvic trauma. Knowledge of the various forms and imaging findings of vascular injuries is essential for the astute planning of treatment strategies and life-saving maneuvers."} +{"text": "Events that occur in utero set the trajectory for later-life diseases and longevity. Compelling data exist for interactions between developmental programming and aging, but the underlying mechanisms are not clearly defined. Fetal exposure to glucocorticoids (GC) is associated with alteration in hepatic enzymes and metabolic function in later life. We previously reported increased hepatic lipid accumulation and obese phenotype in middle-age male baboons exposed to GC as fetuses. The mitochondria play significant roles in cellular processes including stress responses and possibly a nexus between developmental programming and aging. The present study investigated the long-term effects of in utero GC exposure on mitochondrial bioenergetics using hepatocytes derived from aging baboons . Mitochondrial bioenergetics of both left and right lobe liver hepatocytes were examined as well as potential sex differences in mitochondrial function. Cell viability following isolation was similar among sexes and liver lobes but hepatocytes from males were highly energetic compared to females. Significant bioenergetic differences were observed in hepatocytes isolated from female baboons\u2019 left and right liver lobes, with higher basal, maximal, and ATP-linked respiration in left lobe hepatocytes compared to the right lobe. These lobe-specific bioenergetic differences were absent in males. Interestingly, H2O2-induced oxidative stress significantly modified male baboon hepatocyte bioenergetics but females were unaffected, suggesting mitochondrial resilience in females compared to males. These data demonstrate that early life exposure to GC elicits a sex-specific effect on mitochondrial function. These mitochondrial differences might drive differences in cell senescence between males and females."} +{"text": "This survey study uses 2020 American Hospital Association data to assess strategies of US hospitals serving vulnerable populations in addressing social needs during the COVID-19 pandemic. We used 2020 American Hospital Association (AHA) survey data to assess such strategies among rural hospitals, critical access hospitals (CAHs), and safety-net hospitals (SNHs) in the US.Hospitals may play a critical role in alleviating health inequities by addressing underlying social determinants of health (SDOH). Public interest in addressing social needs during the COVID-19 pandemic has been accompanied by substantial health system investments in SDOH.AAPOR reporting guideline.The Harvard School of Public Health Institutional Review Board approved this survey study. The AHA obtained respondent informed consent, with the agreement that hospitals would remain anonymous. The study followed the We used the 2020 AHA Annual Survey Social Determinants of Health Supplement, which surveyed hospitals\u2019 efforts across 3 domains: screening for SDOH, programs/interventions to address SDOH, and community partnerships to address SDOH. The first domain assessed whether hospitals screened across 9 SDOH types. The second domain reported on whether hospitals had programs and/or interventions to address these SDOH. The third domain assessed whether hospitals worked with 14 types of external community partners to address SDOH, participate in community health needs assessments, and implement SDOH initiatives. We created 3 index scores across each domain responded to the SDOH items . In adju6The results of this survey study suggest that rural hospitals, CAHs, and SNHs are not doing more and, in some cases, are engaging in fewer strategies to address the SDOH of their vulnerable populations, especially regarding community partnerships. This finding may be attributable to limited financial resources, workforce constraints, limited community resources and institutional partnerships, and lack of incentives.Study limitations include limited granularity of categorial responses of hospital efforts, potential variability and unreliability of respondent accuracy, and limited generalizability. The AHA survey also does not validate whether hospitals implemented the reported strategies or their effectiveness. Addressing resource barriers that hospitals serving vulnerable populations may face in implementing SDOH initiatives should be considered a key state and federal policy strategy for improving health equity."} +{"text": "In humans, various dietary and social factors led to the development of increased brain sizes alongside large adipose tissue stores. Complex reciprocal signaling mechanisms allow for a fine-tuned interaction between the two organs to regulate energy homeostasis of the organism. As an endocrine organ, adipose tissue secretes various hormones, cytokines, and metabolites that signal energy availability to the central nervous system (CNS). Vice versa, the CNS is a critical regulator of adipose tissue function through neural networks that integrate information from the periphery and regulate sympathetic nerve outflow. This review discusses the various reciprocal signaling mechanisms in the CNS and adipose tissue to maintain organismal energy homeostasis. We are focusing on the integration of afferent signals from the periphery in neuronal populations of the mediobasal hypothalamus as well as the efferent signals from the CNS to adipose tissue and its implications for adipose tissue function. Furthermore, we are discussing central mechanisms that fine-tune the immune system in adipose tissue depots and contribute to organ homeostasis. Elucidating this complex signaling network that integrates peripheral signals to generate physiological outputs to maintain the optimal energy balance of the organism is crucial for understanding the pathophysiology of obesity and metabolic diseases such as type 2 diabetes. In most mammalian species, the size of the brain and adipose depots are inversely correlated, indicating compensatory buffering strategies to protect against starvation . HoweverThis review highlights the coordinated reciprocal signaling between the CNS and white adipose tissue. We are discussing the integration of afferent signals from the periphery in neuronal populations of the mediobasal hypothalamus as well as the efferent signals from the CNS to adipose tissue and its implications for adipose tissue function. Furthermore, we are focusing on central mechanisms that regulate resident immune cell function in adipose tissue depots and subsequently contribute to organ homeostasis.The brain interacts with white adipose tissue depots through distinct efferent sympathetic nerves, releasing the catecholamine norepinephrine (NE) from their nerve terminals. In white adipose tissue (WAT), sympathetic nerve terminals are located adjacent to >90% of adipocytes, forming a dense network of sympathetic arborizations . Importa\u03b1- and \u03b2-adrenoceptors (\u03b1- and \u03b2-ARs) on adipocytes (s protein and activation of adenylate cyclase (AC), which increases intracellular cAMP levels. High cAMP levels activate protein kinase A (PKA), which phosphorylates hormone-sensitive lipase (HSL) and perilipin-A (PLIN1). This initiates a signaling cascade that leads to the activation of lipases, such as adipose triglyceride lipase (ATGL) and monoglyceride lipase (MGL) or \u03b1/\u03b2 hydrolase-domain 6 (ABHD6), allowing triglycerides to be hydrolyzed sequentially into fatty acids (FA) and glycerol , which is co-stored with NE, is released from sympathetic nerve terminals and inhibits lipolysis by binding to its receptor NPYR1 . NPY recvia afferent sensory feedback in order to maintain thermoregulation.Lipolysis increases the availability of free fatty acids which in turn activate local WAT afferents that mediate acute induction of thermogenesis in distant BAT depots . This davagus efferent axis regulates fat mass gain , the ventromedial hypothalamus (VMH), the dorsomedial hypothalamus (DMH), the lateral hypothalamus (LH) and the paraventricular nucleus of the hypothalamus (PVH) . These nThe most well-defined neurocircuit in the context of integrative physiology is the melanocortin system, which consists of the functionally antagonistic anorexigenic proopiomelanocortin (POMC)-expressing neurons and the orexigenic agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) of the mediobasal hypothalamus . POMC neImportantly, both AgRP and POMC neurons express receptors for leptin, insulin and other energy-state communicating hormones and are therefore subject to feedback regulation .PVH) dynamically regulates the sympathetic innervation downstream of leptin-sensitive AGRP and POMC neurons in the ARC in white adipocytes enhances sympathetic activity mRNA . Pharmacvia the circulation, but also through sensory innervation of adipose depots. Sensory nerve endings allow for the detection of local leptin levels directly in the adipose tissue depot . ATMs frvia the production and secretion of acetylcholine, which acts on adipocytes via acetylcholine receptors, stimulating the PKA pathway and subsequently inducing thermogenic gene expression has been shown to decrease food intake in mice and inhibit adipocyte development . NPFF isin vivo and in vitro studies have shown anti-inflammatory effects mediated by melanocortin agonists acting on macrophages expressed in adipose tissue resident immune cells . Severalrophages . For exarophages . Activatrophages . Howeverrophages . These lrophages .via neurotransmitter release.It is clear that ATMs impact the innervation of adipose tissue in numerous ways and vice versa the adipose tissue innervation directly impacts ATM functions via the neuroregulatory receptor RET, which ultimately leads to an increased cytokine secretion , thereby regulating adipocyte function and energy expenditure were recently shown to be indirectly regulated by the SNS . Activatenditure . Mice wienditure . Notablyenditure .via the IL-17F effector cytokine (The neurotransmitter acetylcholine (ACh) is an important contributor to immune cell function [for review see and Cox] and B ccytokine . TGF\u03b21 pcytokine . CollectUnderstanding the complex signaling networks that integrate energy availability signals from adipose tissue in the CNS to generate physiological outputs is crucial for understanding the pathophysiology of obesity and metabolic diseases such as type 2 diabetes. The findings discussed in this review clearly highlight the importance of the melanocortin system in the CNS-adipose crosstalk. However, specific neuronal populations in the mediobasal hypothalamus modify the activity of melanocortin neurons. Defining the exact molecular nature of these regulatory neurons has proven challenging. Owing to their structural and functional diversity, our current understanding of the neurocircuits involved in the control of adipose tissue is still limited. Recent technical advances in neuroscience have led to the possibility of identifying and characterizing the neurocircuits involved in the control of adipose tissue homeostasis. Identifying druggable targets on these specific neuronal populations is a prerequisite for developing novel interventions and therapeutic approaches for obesity and associated metabolic diseases."} +{"text": "Cognitive reserve (CR) refers to adaptability allowing for better cognitive outcomes given the degree of brain changes or other risk factors for cognitive decline. Despite significant research efforts, our knowledge of cognitive reserve proxies remains limited. Studies predominantly use a single sociodemographic variable as a proxy measure when CR can manifest in multiple domains. Studies also tend to rely on older samples, whereas adversity factors of cognitive performance may have differing onset ages, suggesting different risk or protective mechanisms at different ages. We examine two cohort datasets spanning from early adolescence up to the cusp of mid-adulthood to evaluate the role of CR proxies across over 100 variables. Defined as a moderator between a cognitive outcome and structural brain measure, these variables cover behavioral, environmental, physical and mental health, and psychological trait domains. Using cross-validated regularized regression, we identified dozens of factors acting as CR proxies . We then use a within-family design to examine the moderation effect over and above genetic and environmental covariates. For example, adolescents who read more tend to show better cognitive performance given their gray matter volume . This study aims to identify factors that could be targeted with scalable prevention and intervention efforts earlier in life to maximize cognitive functioning."} +{"text": "Cartilage diseases affect a large population worldwide and are associated with a significant burden to patients and society. Osteoarthritis (OA) is the most common chronic joint disorder and the fastest growing cause of disability. Cartilage focal defects, predisposing to early OA and degeneration impair the function of many joints, including the articular joint, intervertebral disc and temporomandibular joint. Presently, no effective therapy is available, except for palliative care primarily used to delay invasive and often suboptimal surgical interventions. Regenerative medicine therapies directed at the early stage of osteoarthritis, and tissue engineering approaches to reconstruct cartilage defects provide great potential for cartilage and joint repair in the future. This current research topic represents a collected series of articles in this field. Highlights are summarized below.Liu et al. provided a timely review describing the factors that affect cartilage homeostasis and function, and the emerging regenerative approaches that are informing the future treatment options. Tissue engineering approaches combining cell and biomaterial strategies to reconstruct the complex and functional cartilage tissue are still under active research. Two review articles in the current topic have described the use of 3D printing technology in cartilage tissue reconstruction in general and for irregularly shaped cartilage in particular . Electrospun gelatin/polycaprolactone (GT/PCL) nanofiber membranes at optimum GT/PCL ratio were used to support in vivo cartilage regeneration from autologous chondrocytes in a swine model . Also xenogeneic acellular cartilage matrix (ACM) materials encapsulated with autologous chondrocytes showed capacity to promote cell proliferation and cartilage formation in goat, with only a minor immune-inflammatory response . This provides scientific evidence for future clinical application of ACM in cartilage tissue engineering. Next to biomaterials, appropriate cell sources are important for cartilage repair. Combined physioxia and fibronectin adherence have shown to select and propagate a meniscus progenitor population that can potentially be used to treat meniscal tears or defects . Additional stimuli can further enhance the cartilage repair potential of cells. For example, a magnetic field applied to magnetic nanoparticles-loaded cells decreased cellular senescence and enhanced chondrogenic capability of adipose-derived mesenchymal stem cells . Senescence can also be targeted using a senolytic peptide, fork head box O transcription factor 4-D-Retro-Inverso (FOXO4-DRI), which removed the senescent cells among chondrocytes .Bi et al. have established an model combining transection of the anterior and posterior cruciate ligaments, and the meniscus, and a cartilage defect in rhesus macaques, which closely resembled the pathophysiological processes of spontaneous knee OA in humans.Last but not least, appropriate animal models for OA are still lacking and play a pivotal role in the development of regenerative therapies."} +{"text": "Whole-exome and targeted sequencing are widely utilized both in translational cancer genomics and in the setting of precision medicine. The benchmarking of computational methods and tools that are in continuous development is fundamental for the correct interpretation of somatic genomic profiling results. To this aim we developed synggen, a tool for the fast generation of large-scale realistic and heterogeneous cancer whole-exome and targeted sequencing synthetic datasets, which enables the incorporation of phased germline single nucleotide polymorphisms and complex allele-specific somatic genomic events. Synggen performances and effectiveness in generating synthetic cancer data are shown across different scenarios and considering different platforms with distinct characteristics.https://bitbucket.org/CibioBCG/synggen/.synggen is freely available at Bioinformatics online. The interrogation of next-generation sequencing (NGS), principally whole-exome (WES) and targeted sequencing (TS), is rapidly becoming a preferred approach for the exploration of large tissue and liquid biopsy-based cohorts, especially in the context of precision medicine. In this setting, a precise benchmarking of the large collection of computational tools that are continuously developed is fundamental for the correct interpretation of somatic genomic profiling results. Although many simulators of synthetic cancer genomes and NGS data have been developed in the last years combine these reference models and a set of user-specified germline and somatic genomic profiles to create synthetic sequencing files (FASTQ format).Synggen is a tool written in C programming language to generate synthetic NGS files, in the form of WES or TS experiments, representing heterogeneous cancer genomes and matched controls. The tool provides two execution modes which allow to (i) exploit a set of control (non-cancer) NGS sequencing files (BAM format) to generate three Read Depth Model (RDM), which measures the average intra-sample depth of coverage variability by calculating the probability, across all input files, of observing sequencing reads at any captured genomic region and position; only reads aligning at the lowest genomic coordinate are considered when paired-end data is used; (ii) a Quality Model (QM), which measures the distribution of base qualities across sequencing read positions; (iii) Position-Based Error (PBE), which measures for each captured genomic position [not representing a common single nucleotide polymorphism (SNP)] the probability of observing platform-specific systematic errors supported by high quality reads and bases and point mutations (PMs). Phased SNPs are used to realistically represent the genetic background of specific individuals and to generate both cancer and matched control samples. Somatic CNAs are defined as allele-specific copy numbers and are incorporated across all affected WES/TS captured regions to modulate the RDM distribution and to adjust SNP allelic fractions. Of note, both overlapping and nested somatic copy number alterations can be represented samples (BAM files) available from The Cancer Genome Atlas dataset, focusing on patients having high (>80%) tumor content WES (Sure Select All Exome v3) cancer tissue samples. Generation of synthetic NGS cancer data was instead tested for increasing number of sequencing reads produced. A cancer sample was generated with tumor content at 80% and incorporating patient-specific germline SNPs and patient-specific somatic CNAs and PMs (details in the To demonstrate the effectiveness of synggen in generating benchmarking datasets, we simulated two liquid biopsy cfDNA scenarios considering data produced in We developed synggen to perform fast and scalable generation of cancer and matched control WES and TS synthetic data without the need for intermediate FASTA files generation and exploiting multi-threaded computation. Synggen allows to emulate platform-specific NGS data characteristics and allows to incorporate germline-phased SNPs and complex somatic allele-specific copy number alterations and point mutations. In addition, it allows to create clonal and sub-clonal events across different tumor content scenarios enabling the generation of large-scale complex benchmarking datasets. Synggen is easy to use and is provided with a collection of additional scripts to simplify further its usability.Conflict of Interest: none declared.btac792_Supplementary_DataClick here for additional data file."} +{"text": "Both pain and mental illness associate with work disability. However, few studies have examined the association of concurrent pain and mental distress with sickness absence (SA). We examined separate and joint associations of chronic pain, multisite pain, and mental distress with total and long-term all-cause SA among young and midlife municipal employees.As part of the Young Helsinki Health study, baseline data were collected in 2017 from 19-39-year-old employees of the City of Helsinki, Finland. Chronic (\u22653 months) pain, multisite (\u22652 body sites) pain and mental distress were reported by 3911 respondents. Register data on total (>1 day) and long-term ((>11 workdays) SA for the following year were obtained from the employer and the Social Insurance Institute of Finland with respondents\u2019 informed consent. Negative binomial regression analyses were performed with sociodemographic, socioeconomic, and health-related factors as confounders. The interaction of gender was examined.Chronic pain, multisite pain, and mental distress were associated with total SA. Chronic multisite pain was associated with long-term SA , and chronic pain and multisite pain with long-term SA among those with mental distress. For women, there was a synergistic interaction of multisite pain to the association with total SA .Chronic and multisite pain associate with SA among young and midlife employees. The associations are generally stronger among women and particularly among those with concurrent mental distress. Interventional studies are needed to confirm if early symptom recognition and support could reduce sickness absence.\u2022\u2002Chronic pain and pain at multiple body sites associate with sickness absence among young and midlife employees, particularly among women and those with concurrent mental distress.\u2022\u2002Interventional studies are needed to confirm if sickness absence could be reduced by early recognizing pain and mental distress among employees and providing preventive and therapeutic services."} +{"text": "Although research has shown that food insecurity may lead to sleep problems due to mental illness, it remains unclear whether physical health also mediates this relationship in addition to poor mental health. We investigated whether frailty and depressive symptoms mediated the association of food insecurity with sleep deficiency among community-dwelling older adults. We analyzed the baseline data of the Longitudinal Study of Ageing and Health in the Philippines, a study with national representative sample of adults aged 60 years or older . Sleep deficiency was conceptualized as self-reported sleeping less than 6 hours, complaining about trouble with falling asleep and staying asleep, and/or having non-restorative sleep. Food insecurity was defined as being hungry and not having enough food in the past three months in the household. Frailty was operationalized using modified definitions under Fried\u2019s criteria. Depressive symptoms were assessed using the Center for Epidemiological Studies-Depression Scale. Covariates included socio-demographics , health , and lifestyles . Mediation analysis was performed using PROCESS macro. The results from bootstrapping showed that the indirect effects from food insecurity through frailty and depressive symptoms onto sleep deficiency were significant, but the direct effect from food insecurity to sleep deficiency was not . The results suggested that the effects of food insecurity on sleep deficiency were fully mediated through frailty and depressive symptoms among community-dwelling older Filipinos. Preventing frailty and depression may help improve sleep health among individuals being food insecure."} +{"text": "The incidence of Anti-NMDA receptor encephalitis is 1.5 per million population per year but it has only been described sporadically in the paediatric population. The median age of onset is 21 years old. In children, seizures, abnormal movements, insomnia, and irritability are more frequently identified than psychosis or abnormal behavior. Early detection and treatment can improve treatment outcomes.Presentation of a case of a paediatric patient with Anti-NMDA receptor encephalitis displaying homicidal behavior towards her family membersCase reportA 12 year old with no significant past psychiatric and medical history, was brought in by police to the hospital after she attempted to stab her mother with a knife. She had low grade fever, headaches and lethargy prior to presentation. Organic workup revealed serum and CSF anti-nmda receptor to be positive. She received early treatment with steroids and intravenous immunoglobulins and no longer harboured further homicidal ideations.Initial suspicion of anti-NDMA receptor encephalitis should be raised and early auto-immune workup performed in paediatric patients presenting with acute change in behavior especially in young females with no past medical or psychiatric historyNo significant relationships."} +{"text": "The importance of resilience factors in the positive adaptation of refugee youth is widely recognised. However, their actual mechanism of impact remains under-researched. The aim of this study was therefore to explore protective and promotive resilience mechanisms on both negative and positive mental health outcomes. Promotive resilience is seen as a direct main effect and protective resilience as a moderating effect.Cross-sectional study with 160 Syrian youth aged 13-24 years, who recently resettled in Norway. A multi-dimensional measure for resilience was used to explore the potential impact of resilience factors on pathways between potentially traumatic events from war and flight (PTE), post-migration stress, mental distress and health-related quality of life (HRQoL). Analyses included regression, moderation and moderated mediation using the PROCESS macro for SPSS.A direct main effect of resilience factors (promotive resilience mechanism) was found for HRQoL and general mental distress, but not for post-traumatic stress disorder (PTSD). No moderating effects of resilience factors (protective resilience mechanism) were found. Post-migration stressors mediated the effects of PTE, and this indirect effect was present at all levels of resilience. Relational and environmental level resilience factors and combined amounts had more impact than individual level factors.Despite high risk exposure and mental distress, resilience was also high. The direct main effect of resilience factors and less impact on PTSD, suggests universal resilience building interventions may be beneficial, compared to exclusively targeting groups with high symptom levels. These interventions should target relational and environmental resilience factors as well as individual coping techniques. Additionally, reducing current stress and symptoms could increase the efficacy of resilience factors already present.\u2022\u2002Refugee youth may have both high levels of risk and high resilience.\u2022\u2002Universal resilience interventions should focus on relational and environmental support, as well as individual resilience."} +{"text": "In the setting of structural heart disease, ventricular tachycardia (VT) is typically associated with a re-entrant mechanism. In patients with hemodynamically tolerated VTs, activation and entrainment mapping remain the gold standard for the identification of the critical parts of the circuit. However, this is rarely accomplished, as most VTs are not hemodynamically tolerated to permit mapping during tachycardia. Other limitations include noninducibility of arrhythmia or nonsustained VT. This has led to the development of substrate mapping techniques during sinus rhythm, eliminating the need for prolonged periods of mapping during tachycardia. Recurrence rates following VT ablation are high; therefore, new mapping techniques for substrate characterization are required. Advances in catheter technology and especially multielectrode mapping of abnormal electrograms has increased the ability to identify the mechanism of scar-related VT. Several substrate-guided approaches have been developed to overcome this, including scar homogenization and late potential mapping. Dynamic substrate changes are mainly identified within regions of myocardial scar and can be identified as local abnormal ventricular activities. Furthermore, mapping strategies incorporating ventricular extrastimulation, including from different directions and coupling intervals, have been shown to increase the accuracy of substrate mapping. The implementation of extrastimulus substrate mapping and automated annotation require less extensive ablation and would make VT ablation procedures less cumbersome and accessible to more patients. These dynamic changes may play a critical role in the tachycardia mechanism when conduction velocity slows and tissue refractory periods lengthen. Dynamic substrate changes lie mainly within regions of myocardial scar or the SBZ and can be identified as functional delay in electrograms by introducing timed extrastimuli.The fundamental hypothesis of substrate mapping for scar-mediated VT is that surrogates of the isthmus can be identified. These surrogates include electrocardiographic indications for electric discontinuity such as fractionation, split potentials, LPs, and long potentials, also evident as sites displaying activation slowing.,Myocardial scar definition is a key step of any substrate-based ablation approach.High-density, multielectrode catheters can also enhance the possibility of detailed activation mapping of even poorly tolerated VTs because a complete map is faster to obtain. Recently, it has been shown that there is higher freedom from VT recurrence in patients with a fully mappable diastolic pathway recording after an ablative procedure.The use of high-resolution mapping technologies may have a role in improving clinical outcomes.,The advantages of multipolar catheters are (1) higher mapping density and better substrate definition; (2) higher detection of LAVAs and voltage channels; and (3) higher accuracy in identifying and delineating near-field component (LAVAs) and differentiating from far-field signals.Ripple mapping is a mapping tool that shows both voltage and propagation channels into the scar in a single dynamic display. This technology has the advantage of displaying complex or continuous fractionated local EGMs as time-dependent propagation, rather than choosing a single annotation for timing. Jamil-Copley and colleagues,,Fractionated EGMs are recorded in regions where infarct healing causes wide separation of individual myocardial fibers while distorting their orientation. These anatomic changes likely cause slow and inhomogeneous activation.In the setting of post\u2013myocardial infarction cardiomyopathy, specific EGM signatures are expressions of distinct electrophysiological phenomena. De Bakker and colleaguesMartin and colleagues,,Pace mapping is a technique used to localize the exit site of postinfarct re-entry VT circuits.,De Chillou and colleaguesCharacterization of scar regions is important for the initiation and maintenance of VT re-entry circuits, known as conducting channels (CCs).,Isochronal crowding is defined as local deceleration of propagation in a region within scar with bunching of isochrones (>2 isochrones within 1-cm radius).As re-entrant VT requires fixed or functional localized conduction slowing, Brunckhorst and colleaguesFunctional block has also been defined as an area of the myocardium that is not electrically excitable at shorter coupling intervals but is excitable at relatively long cycle lengths.Among all identified LP in a given substrate, it is not known which zone of late activation most commonly provides the substrate for re-entry. In addition, LPs may be unrelated to any VT circuits and may represent unnecessary ablation targets. The most delayed LPs are not necessarily most functionally specific for re-entry.The insight that decrement precedes unidirectional block was first described in atrial tissue sections in studies undertaken by Lammers and colleagues.,Jackson and colleaguesAcosta and colleaguesFunctionally guided substrate modification approaches that consider both activation and voltage patterns guided by extrastimuli (sense protocol) have been described as alternatives to extensive ablation required to homogenize scar , Video 1Porta-S\u00e1nchez and colleagues,EGM annotation methods based on the maximal negative derivative of the extracellular potential or maximal voltage may be inaccurate in nonuniform anisotropic tissue. Detected EGMs are strictly dependent on electrode orientation, respective to wavefront propagation, which rapidly changes directions resulting in a changeable recording according to the vector line of assessment. As a result, catheters may not identify low-voltage EGMs propagating orthogonal to their orientation, potentially missing critical arrhythmic substrate.,Arenal and colleaguesIn the study by Martin and colleagues,Brunckhorst and colleagues reported that changing the activation sequence produced a >50% change in EGM amplitude at 28% of sites and a >100% change at 10% of sites, but only 8% of sites had an EGM amplitude classified as abnormal (\u22641.5 mV) with one activation sequence and normal (>1.5 mV) with the other activation sequence. Electrically unexcitable scar (6% of sites) was associated with lower EGM amplitude but could not be reliably identified based on EGM amplitude alone for either activation sequence.,SURVIVE-VT (Substrate Ablation versus Antiarrhythmic Drug Therapy for Symptomatic Ventricular Tachycardia) has shown that a substrate-based catheter ablation procedure was associated with a significantly lower rate of implantable cardioverter-defibrillator shocks, cardiovascular death, and hospitalization for worsening heart failure.It remains to be seen whether functional substrate mapping may further improve patient outcomes in an early ablation strategy, but as a technique, it would be optimally placed to be used as a first-line safe strategy for substrate guided VT ablation.Additionally advances in mapping technology continue to play a key role in improving resolution of functional signals. Multipolar electrode catheters with 1-mm electrodes and variable interspacing have been introduced to overcome limitations in mapping in a unidirectional manner. The Advisor HD Grid Mapping Catheter (Catheter Sensor Enabled) is a multipolar catheter with electrodes equally interspaced along each spline and arranged in a grid configuration. The catheter simultaneously records EGMs along and across different orthogonal vectors when point acquisition is set in the bidirectional WAVE configuration. As well as enabling an increase in the near-field-to-far-field signal ratio, it can provide omnipolar EGMs that are independent of the incident wavefront and the fixed interelectrode spacing along and across splines, allowing calculation of conduction velocities.Current substrate modification procedures employing extensive substrate modification covering the entirety of the abnormal substrate are associated with long procedural times and may be unfeasible in unstable patients with limited cardiac reserve and large substrates."} +{"text": "Agave . Today Agave cultivation, primarily for beverage production, provides an economic engine for rural communities throughout Mexico. Among known dryland-farming methods, the use of rock piles and cattle-grazed areas stand out as promising approaches for Agave cultivation. Identifying new cultivation areas to apply these approaches in Arizona, USA and Sonora, Mexico warrants a geographic assessment of areas outside the known ranges of rock piles and grasslands. The objective of this study was to predict areas for dryland-farming of Agave and develop models to identify potential areas for Agave cultivation. We used maximum entropy (MaxEnt) ecological-niche-modeling algorithms to predict suitable areas for Agave dryland farming. The model was parameterized using occurrence records of Hohokam rock piles in Arizona and grassland fields cultivated with Agave in Sonora. Ten environmental-predictor variables were used in the model, downloaded from the WorldClim 2 climate database. The model identified potential locations for using rock piles as dryland-farming methods from south-central Arizona to northwestern Sonora. The Agave-grassland model indicated that regions from central to southern Sonora have the highest potential for cultivation of Agave, particularly for the species Agave angustifolia. Results suggest that there are many suitable areas where rock piles can be used to cultivate Agave in the Sonoran Desert, particularly in the border of southeastern Arizona and northwest Sonora. Likewise, cattle-grazing grasslands provide a viable environment for cultivating Agave in southern Sonora, where the expanding bacanora-beverage industry continues to grow and where different Agave products can potentially strengthen local economies.For centuries, humans occupying arid regions of North America have maintained an intricate relationship with Agave genus and indigenous groups and rural communities in arid regions has been crucial to creating sustainable agroecosystems in arid regions in Mexico and North America .The area highlighted in grey was the study area used to create suitability models for (TIF)Click here for additional data file.S2 Fighttps://gadm.org/index.html].The shapefiles and data used to construct the map were obtained from GADM [(TIF)Click here for additional data file.S3 FigPublished under a CC BY license, with permission from Michael T. Searcy, original copyright 2022.(TIF)Click here for additional data file.S4 FigHighlights in red indicate the variables selected for the study.(TIF)Click here for additional data file."} +{"text": "Accumulating evidence suggests asymmetrical responses of cerebral blood flowduring large transient changes in mean arterial pressure. Specifically, theaugmentation in cerebral blood flow is attenuated when mean arterial pressureacutely increases, compared with declines in cerebral blood flow when meanarterial pressure acutely decreases. However, common analytical tools toquantify dynamic cerebral autoregulation assume autoregulatory responses to besymmetric, which does not seem to be the case. Herein, we provide the rationalesupporting the notion we need to consider the directional sensitivity of largeand transient mean arterial pressure changes when characterizing dynamiccerebral autoregulation. Cerebral autoregulation (CA) has commonly been described as the ability of the cerebralvasculature to react to steady-state (static CA) or transient (dynamic CA: dCA) arterialblood pressure (ABP) changes. The roles of these physiological responses are to maintaincerebral perfusion to meet the brain\u2019s demand and minimize blood flow variations.Therefore, the extent of the vessels\u2019 vasomotion (i.e. vasoconstriction or vasodilation)will be proportional to the ABP magnitude change, whether ABP increases or ABPdecreases. The hypothesis behind the presence of directional sensitivity of the cerebralpressure-flow relationship resides in the role brain blood vessels play against ABPtransient surges to protect the microcirculation from overperfusion. Therefore, it isthought dCA would be more efficient when ABP acutely increases in comparison with acuteABP decreases. Using an autoregulatory gain calculation between middle cerebral artery meanblood velocity (MCAv) and MAP, Tzeng et\u00a0al. demonstrated a smaller gain when MAP acutelyincreased compared with MAP decreases. We demonstrated a directional sensitivity of the cerebral pressure-flowrelationship by examining changes in MCAv in response to transient increases anddecreases in MAP induced by repeated squat-stands .24 Initially, these changes werecalculated from a seated baseline, an approach that has been criticized. This calculation was further refined byusing the largest concurrent MAP oscillations without an independent resting baseline,and by adjusting for time intervals. In addition to demonstrating a directional sensitivity in the MCA4 and in the posterior cerebral artery using this novel calculation, we suggested the hysteresis-like pattern isfrequency-dependent .4 Abetter autoregulatory capacity was also demonstrated during the squatting phase(transient increase in MAP) of repeated squat-stands using the autoregulatory index.There is growing evidence of cerebral pressure-flow relationship directional sensitivityduring large transient mean arterial pressure (MAP) oscillations. In healthyindividuals, the first observation of a directional sensitivity was reported whencomparing acute increases and decreases in ABP with drugs infusions. The activation of cerebral SNA in response to an acute elevation in MAP wouldserve to protect the brain microcirculation from overperfusion and to reduce the risk ofhemorrhagic stroke. Another potential mechanism underlying this hysteresis-like patterncould be a differing intrinsic myogenic activity when ABP increases, compared with ABPdecreases. However, previous work suggests intrinsic myogenic activity influences dCAduring oscillations below 0.07\u2009Hz and calcium-channel blockade impairs dCA in humans during oscillatory lower bodynegative pressure at frequencies between 0.03 and 0.08\u2009Hz.Differences in cerebral sympathetic nervous activity (SNA) in response to transient MAPincreases, compared with MAP decreases, could potentially explain this directionalsensitivity of the cerebral pressure-flow relationship. Indeed, data in sleeping lambsindicate SNA recorded in the superior cervical ganglia is activated during acute ABPincreases but not acute ABP decreases.9. Interestingly, Katsogridakis et\u00a0al. usedthigh-cuffs inflation and deflation to induce large transient MAP changes. This method has been shown to have extremely large variations in dCA metrics,even when tests are performed just minutes apart. Nonetheless, whether specific methodsto induce significant MAP changes are partly responsible for the directional sensitivityof the pressure-flow relationship remains to be elucidated. Further research will thusbe necessary to ensure this phenomenon is not method-dependent.Of note, there are studies reporting the absence of asymmetry in the cerebralpressure-flow relationship Nonetheless, further studies are needed, as we still do not know whether thishysteresis-like pattern remains present in other physiological and pathological states.In addition, all studies focusing on the directional sensitivity of dCA to date includedmeasures of cerebral blood velocity and MAP. The monitoring of volumetric cerebral bloodflow and cerebral perfusion pressure in future studies is encouraged to provide more meaningful results not only inregards to the directional sensitivity of the cerebral pressure-flow relationship, butalso for all the other metrics quantifying dCA.Directional sensitivity could be highly relevant to consider while studying CBFregulation in diverse populations. Since there are many physiological contexts and clinical/pathological states involving acute and large changes in MAP, the direction of MAP has the potential ofbeing an important variable to consider when examining dCA. We have recently reportedthat directional sensitivity of the cerebral pressure-flow relationship is present insedentary and endurance-trained participants, but absent in resistance-trained individuals.It becomes clear there is asymmetrical sensitivity of the cerebral pressure-flowrelationship during large transient MAP changes. We now need to better understand itsunderlying mechanisms and refine the current analytical tools to assess dCA, in order toeventually optimize the management of ABP in clinical populations. Replication ofstudies in various centers using different models of forced ABP oscillations (e.g.oscillatory lower body negative pressure) will also be crucial. The presence ofasymmetrical sensitivity has important implications on quantification of dCA usingstandard analysis on forced ABP oscillations. For example, transfer function analysis, acommon analytical tool to quantify dCA, assumes autoregulatory responses to be linearand symmetric, which is not the case. From now on, we consider we cannot solely useanalytical methods that do not consider the direction of large transient MAP changeswhen characterizing dCA. It will remain crucial the scientific and medical community isaware of this important characteristic of the cerebrovasculature until a global changeis undertaken by our community to take MAP direction into account in the assessment ofdCA and acute manipulation of ABP within the clinical setting."} +{"text": "HIV-positive patients with schizophrenia spectrum disorders experience burden of double stigma. Comorbid pathology may alter structure of stigma and shall be considered in development of individual destigmatization programs.Study of psychiatric stigma features in HIV-positive and HIV-negative patients with schizophrenic disorders.ISMI , PDD \u2013 to study stigma in 70 patients divided into three groups with respect to their diagnosis ; BPRS \u2013 to assess psychiatric status, RSAS \u2013 to assess anhedonia. Dispersion analysis , Spearman and Pearson correlation were used.Patients with comorbid HIV-infection showed increased level of perceived stigma, although they resisted the stigma internalization better than others did (Table 1).Patients with schizotypal disorders and patients at early stages of HIV infection experienced the most alienation and frailty to internalization of stigma .Correlation relationship between social anhedonia and perceived stigma observed in patients with HIV infection.Comorbid HIV infection in psychiatric patients contributes to the psychiatric stigma structure. Differentiated approaches in rehabilitation of HIV-positive mental patients should be used."} +{"text": "Schizophrenia spectrum disorders are among the most debilitating mental disorders and evidence on its pathophysiological underpinnings is scant. The brain-derived neurotrophic factor (BDNF) appears to be involved in the pathophysiology of these complex psychiatric disorders.The present study investigates the longitudinal variation of serum BDNF levels in a 24-month observational cohort study of Sardinian psychotic patients (LABSP). This study assessed the variation in BDNF serum levels and its relationship with psychopathological and cognitive changes. Further, we also examined if genetic variations within the BDNF gene could moderate these relationships.Every six months 105 LABSP patients were assessed for their BDNF serum levels, as well as for a series of psychopathological, cognitive, and drug-related measures. Four tag single nucleotide polymorphisms (SNPs) within the BDNF gene were selected and analyzed using Polymerase Chain Reaction (PCR). Longitudinal data were analyzed using mixed-effects linear regression models (MLRM).Analysis showed significantly lower peripheral BDNF levels in psychotic patients with depressive and negative symptoms. BDNF levels were also decreased in patients scoring lower in cognitive measures such as symbol coding and semantic fluency. In addition, Val66Met polymorphism within the BDNF gene significantly moderated the relationship between the severity of negative symptoms and BDNF levels.Our findings are consistent with previous literature suggesting that peripheral BDNF levels are associated with some cognitive domains and mood disruption in major psychosis. The results also suggest the lack of association between most BDNF genetic variants, except Val66Met polymorphism, with the severity of negative symptoms.No significant relationships."} +{"text": "The present review is a historical perspective of methodology and applications using inert liquids for respiratory support and as a vehicle to deliver biological agents to the respiratory system. As such, the background of using oxygenated inert liquids (considered a drug when used in the lungs) opposed to an oxygen-nitrogen gas mixture for respiratory support is presented. The properties of these inert liquids and the mechanisms of gas exchange and lung function alterations using this technology are described. In addition, published preclinical and clinical trial results are discussed with respect to treatment modalities for respiratory diseases. Finally, this forward-looking review provides a comprehensive overview of potential methods for administration of drugs/gene products to the respiratory system and potential biomedical applications. Aerosol drugs have been delivered to the lungs for several thousand years . The useDuring the last 20\u00a0years, the combination of nanocrystal technology combined with an inert perfluorochemical vehicle has demonstrated the efficacy of large volume drug delivery to the entire lung because of the vehicle physical-chemical properties . FurtherThe use of liquids for respiratory support is reviewed in this section, as well as the physical properties of fluid used and the rationale for using specific liquids.2; CO2) and diffusion gradients at atmospheric conditions limited the functional use of saline solution to provide adequate gas exchange was investigated as respiratory media; however, these oils, although having high gas solubility, also demonstrated toxic effects . Perfluo2 and CO2 are specific to respiratory gas exchange and carried only as dissolved gases with solubilities ranging as much as 16 and three times greater, respectively, in PFC than in saline. Oxygen solubilities range from 35 to 70\u00a0ml gas per deciliter at 25\u00b0C . It is noteworthy that perflubron is the only medical grade perfluorochemical approved by the FDA for emergency medical use. While many properties of PFC liquids vary, they do provide relatively low surface tension and viscosity, and are more dense than both water and soft tissue.Please refer to at 25\u00b0C . The carVariations in specific physicochemical properties of the PFC liquids are significant to their use as respiratory media and as vehicles for the administration of biological agents. Fluids of higher vapor pressure may volatilize from the lung more rapidly than liquids having lower vapor pressure. Fluids with greater spreading coefficients (dependent on surface tension) may distribute more easily in the lung than fluids whose spreading coefficients are lower . Fluids The initial preclinical studies in liquid spontaneous breathing and ventilation support were directed at breathing in unusual environments such as deep sea diving, zero gravity, and space travel . It was Subsequently, several separate investigational new drug applications were approved by the FDA to investigate the safety and efficacy of PFCs, mainly PFOB, as a liquid breathing media in neonates. While animal studies over the years showed significant efficacy and safety of liquid breathing, clinical studies using several techniques in humans had mixed outcomes. The findings from non-clinical and clinical studies are summarized below.2 requirements that are characteristics of ventilator-induced lung injury . These studies supported the use of liquid ventilation as a superior source of respiratory support when compared with gas media with spontaneous breathing or conventional mechanical ventilation (CMV). Various studies also demonstrated short-term beneficial physiologic responses in lung function because of improved alveolar recruitment and significant preservation of normal histological structure of the lung . Non-clig injury .Recent studies continue to show PFOB improves oxygenation in animaAnimal studies consistently support the safety of PFOB, as few negative effects have been reported. Studies show PFOB is not absorbed systemically and causes no long-term harm . SeveralEarly clinical studies demonstrated that infants with severe RDS, meconium aspiration, and CDH tolerated liquid PFC in their lungs and were able to effectively exchange gas and maintain cardiovascular stability .Consistent with those studies and animal studies, additional published reports indicated PFOB increased gas exchange in adultMost importantly, the utility of PFOB was demonstrated in a multicenter study of premature infants with severe RDS refractory to other available treatments . ThirteeMore recently, lavage with PFC has been shown to be safe for treatment of persistent and difficult-to-treat lung atelectasis . BronchoFollow-up imaging studies up to 20\u00a0years after treatment with PFOB in humans demonstrated no negative effects from this treatment . The stuIn early liquid ventilation studies, it was reported that PFOB usage in adults increased lung compliance , which iSystemic administration of therapeutics to target the lung is faced with numerous challenges secondary to potential degradation by serum and hepatic enzymes and rapid renal clearance. Compromised pulmonary blood flow in the injured lung may further limit passive diffusion of the drug from the blood into the lung parenchyma. Retention of the therapeutics in the lung is also often suboptimal. These challenges can be mitigated by local administration of therapeutics through inhalation or airway instillation . HoweverSome studies have successfully demonstrated that lungs filled with PFC liquid have the ability to deliver active and inactive agents for the diagnosis and treatment of respiratory disorders.Respiratory infections affect distally located alveoli with bacteria and viruses multiplying in the alveolar cells. Distal lung distribution of intra-tracheally delivered anti-infective agents is essential to halt disease progression. In a newborn lamb model of acid lung injury, gentamicin administration during tidal liquid ventilation using PFC resulted in significantly higher lung gentamicin levels compared with intravenous administration . This teIn an animal model of meconium aspiration syndrome, partial liquid ventilation improved regional distribution of intratracheally administered radio-labelled surfactant compared with conventional mechanical ventilation. There was more uniform distribution of surfactant between the lungs as well as between both ventral and dorsal regions of the lungs. Such uniform distribution was associated with improved systemic oxygenation . PFC wasInhalational smoke-induced acute lung injury is characterized by airway epithelial injury leading to excess leakage of plasma substrates into large airways and the formation of fibrin casts. Interventions to prevent or treat airway casts are limited. In this regard, PFC has been used for intratracheal administration of plasminogen activators (tissue plasminogen activator [tPA] and single-chain urokinase plasminogen activator [scuPA]) for management of airway clot and fibrinous cast formation associated with smoke-induced acute lung injury. Enzymatic activities of the plasminogen activator following dispersion and storage in PFC were preserved, and PFC administration alone did not impact physiologic or histological differences. In contrast, PFC-facilitated plasminogen activator delivery resulted in significantly better physiologic and histologic outcomes. PFC-facilitated delivery of plasminogen activator demonstrated improved outcomes than achieved by nebulization of plasminogen activators alone .2 during liquid ventilation potentially could be different compared with the gas-filled lung.Drug delivery during PFC PLV respiratory support has been demonstrated with other soluble gases in PFOB such as inspired nitric oxide (NO). NO administration with PLV in surfactant-depleted adult pigs resulted in a significant improvement in gas exchange and decrease in pulmonary artery pressure, most notably without deleterious effects on systemic hemodynamic conditions . In a coTwenty-two percent of all pediatric hospital admissions are due to respiratory illness. Genetic lung diseases account for increased morbidity and mortality . GeneticCRISPR-Cas9 gene editing provides an unprecedented opportunity to manipulate genes in somatic cells. Editing technologies have demonstrated clear therapeutic promise in non-human primates and early human clinical trials . New appThe postnatal lung presents important limitations to airway delivery because of the substantial mucus and surfactant barrier at the air-epithelial interface, repulsive charge interactions at the cell membrane, and unequal reagent distribution due to the heterogeneity of lung disease with some areas being overinflated and others collapsed . Further2 and CO2 solubility of PFC liquids allows effective gas exchange, even in lungs filled with fluid. PFCs also reduce surface tension, which assists lung volume recruitment at reduced inspiratory pressures by eliminating the air-liquid interface. Importantly, PFC liquids effectively penetrate collapsed regions of the lung to facilitate access to under-ventilated regions. This is particularly important in non-homogenous lung diseases such as surfactant protein diseases, in which PFC liquids could simultaneously facilitate delivery of therapies, increase gas exchange, and improve pulmonary function. Several groups have exhibited the superior effectiveness of PFC liquids as vehicles for pulmonary distribution of genetic cargo (The fluid-filled fetal lung physiology could be partially mimicked in postnatal lungs with PFC liquids because of their high spreading coefficients and intriguing properties for pulmonary distribution of biological agents. The high Oic cargo . PFC liqic cargo . Use of ic cargo . Many stic cargo . As suchic cargo . By adapThe fact that aqueous solutions are not readily soluble in PFCs is an important consideration for PFC drug delivery. Some research projects have circumvented this barrier by relying on bulk flow turbulent mixing . HoweverWhen lung parenchymal disease and/or injury are present in the lung, pulmonary ventilation and perfusion are compromised. Ventilation can be irregular and perfusion may be inhibited by ventilation-perfusion mismatch. The route of therapy administration is hindered by these abnormalities, rendering standard intravenous and aerosol/endotracheal tube delivery ineffective in delivering therapeutic agents to the affected area.Liquid ventilation with an inert respiratory gas solubility is a revolutionary mode for respiratory support, as well as delivery of drug/gene product to the respiratory system. As noted, inert perfluorochemical liquids have low viscosity and high oxygen and carbon dioxide capabilities . The phyThe use of PFC liquid in the respiratory system enhances ventilation and perfusion matching, boosting exposure of the drug/gene product to the circulation, successfully reaching required therapeutic serum drug levels . Studies"} +{"text": "The Management and Supervision Tool (MaST) helps NHS mental health care professionals identify patients who are most likely to need psychiatric hospital admission or home treatment, due to severe mental illness, through a Risk of Crisis (RoC) algorithm driven by electronic health record (EHR) data analytics. We describe the derivation and validation of the MaST RoC algorithm, and its implementation to support preventative mental healthcare in the NHS.The RoC algorithm was developed and evaluated with EHR data from six UK NHS trusts using Ordered Predictor List propensity scores informed by a priori weightings from pre-existing literature, as well as real-world evidence evaluating the associations of clinical risk factors with mental health crisis using NHS EHR data. Mental health crisis was defined as admission to a psychiatric hospital or acceptance to a community crisis service within a 28-day period. Predictor variables included age, gender, accommodation status, employment status, Mental Health Act (MHA) status (under section or Community Treatment Order), and previous mental health service contacts . Data were analysed using Ordered Predictor List propensity scores. The algorithm was derived using structured EHR data from 2,620 patients in a single NHS trust and externally validated using data from 107,879 patients in five other NHS trusts. Qualitative and quantitative data on feasibility, acceptability and system efficiency impacts of MaST implementation were obtained through staff surveys and local audits.The factors associated with greatest propensity for mental health crisis included recent previous crisis, multiple previous crises, higher number of mental health service contacts in recent weeks, MHA section, accommodation status and employment status. The RoC algorithm identified 64% and 80% crises in its top quintile. Sentiment analysis of staff surveys suggested that the use of MaST improved productivity by reducing time taken to access patient information to support caseload management that was previously difficult to obtain through manual review of EHRs. The systems efficiency audit revealed a reduction in duration of crisis and inpatient admissions following MaST implementation.The MaST RoC algorithm supports the identification of people more likely to use crisis services in NHS mental health trusts, is feasible to implement, and improves systems efficiency. EHR-derived algorithms can support real-world clinical practice to improve outcomes in people receiving NHS mental healthcare."} +{"text": "Aedes-borne flaviviruses. Domestic dogs may be useful sentinels for West Nile virus.We tested 294 domestic pet dogs in Mexico for neutralizing antibodies for mosquito-borne flaviviruses. We found high (42.6%) exposure to West Nile virus in Reynosa (northern Mexico) and low (1.2%) exposure in Tuxtla Gutierrez (southern Mexico) but very limited exposure to Aedes spp. and Culex spp. mosquitoes, the endemicity of human arboviral diseases is incongruent with these vector distributions . Canine exposure to WNV was widespread, and we found a higher prevalence of neutralizing antibodies to WNV in dogs from Reynosa than in those from Tuxtla Gutierrez . The lower reported numbers of WNV cases in Mexico might be in part because of the high seroprevalence of antibodies for other flaviviruses, which have been shown to protect against severe clinical infection from WNV, thus leading to reduced testing (Culex mosquitoes in the study area. Our data suggested substantial WNV enzootic activity in Reynosa and corroborated prior observations of high use of dogs as blood meal hosts by Aedes-borne flaviviruses suggests not an absence of these viruses circulating in these communities but that dogs are likely insensitive sentinels of the viruses\u2019 transmission in Mexico. In Chiapas, 7,972 human cases of dengue and 763 cases of Zika had been reported during 2016\u20132020 (Ae. aegypti in southern Texas and northern Mexico feed on dogs (,The relative lack of canine exposure to Cx. quinquefasciatus mosquitoes, a primary vector of WNV, use high numbers of dogs for blood meals. Therefore, domestic pet dogs may be useful sentinels of WNV transmission, as previously suggested in other regions (Our study suggests substantial WNV enzootic activity in Reynosa, Mexico and corroborates observations that Additional information about the usefulness of domestic dogs as sentinels for West Nile virus."} +{"text": "Efforts to find disease-modifying treatments for Alzheimer\u2019s disease (AD) have been largely unsuccessful. The relative lack of progress and the age-related incidence of AD suggest that modulation of aging per se may be a useful alternative treatment approach. Therapeutics aimed at preventing or reversing aging should be effective in preventing or reversing dementia and the pathology associated with progressive AD. Epigenetic dysregulation of neuronal gene expression occurs with age, propagating deficits in cellular homeostasis. Regulators of epigenetic processes, such as histone deacetylases (HDACs), are well documented and may represent promising therapeutic targets. HDAC activity becomes dysregulated with age and in AD. An intriguing concept is that HDAC inhibition effectively forestalls AD pathology measured more broadly, addressing the notion that rectifying homeostatic gene expression may be the critical step in ameliorating AD pathogenesis at the earliest stage of disease initiation. HDAC inhibitors target several pathways associated with aging and AD neuropathology including loss of synaptic function, mitochondrial dysfunction, increased oxidative stress, and decreased autophagy activity. Since transcriptional levels of numerous genes are shown to decrease with increasing age, a recovery of their transcriptional activity through HDAC inhibition could prevent or delay age-associated declines in neurological function and provide pathways for treating AD. The prevalence of neurodegenerative diseases is expected to soar with the number of elderly individuals in both developed and developing countries now rising dramatically. Efforts to find disease-modifying treatments have been largely unsuccessful. These efforts have focused mainly on identifying pathogenic mechanisms specific to each disease process. The relative lack of progress with these approaches and the age-related nature of neurodegenerative disease incidence suggests that modulation of aging per se may be a useful alternative approach for delaying the onset or retarding the progression of neurodegenerative conditions ,2. This AD is a complex heterogeneous pathology that impacts multiple aspects of neuronal physiology. The predominant hypothesis guiding AD therapeutic development for the last two decades has been that amyloid initiates a cascading series of events, including phosphorylation and aggregation of tau protein, that lead to pervasive neuronal degeneration. The repeated observation that rare early-onset familial AD mutations increase pathogenic amyloid through perturbations of beta/gamma-secretase function, promoted the notion that targeting amyloid is a potential therapeutic approach. Unfortunately, failures of a number of clinical trials have called into question amyloid as the primary therapeutic target. This demands careful reconsideration of AD disease etiology and justifies why alternative strategies for therapeutic development should be explored.Epigenetic dysregulation of neuronal gene expression occurs with age, propagating deficits in cellular homeostasis. Regulators of epigenetic processes, such as histone deacetylases (HDACs), are well documented and may represent promising therapeutic targets. The gradual and escalating dysfunction of essential cellular processes could link all of the cellular AD phenotypes into a complex cascade, in which amyloid is either a late-stage effector or simply a biomarker of the disease process. In support of this view, numerous transcriptional analysis studies have examined genetic dysregulation in AD and found metabolic processes, oxidative stress, protein degradation, synaptic function and transcriptional regulation to be impacted ,6. Gene HDAC inhibition is a powerful approach to stimulate transcriptional changes within neurons. HDAC activity becomes dysregulated with age and in AD and has been shown to decrease synaptic plasticity in mouse models ,14. The Our published observations that phenylbutyrate (PBA), an HDAC inhibitor, attenuated amyloid plaque development in the PS1delta9/APPswe double transgenic mouse line and partially restored cognitive function , set theHDAC inhibitors target several pathways associated with aging and AD neuropathology. Synaptic pathology is increasingly of interest in assessing AD pathology and is linked to normal aging as well ,20. GeneClosely linked with synaptic pathology, mitochondrial dysfunction leading to decreased ATP production and increased ROS resulting from impaired electron transport chain function appears prominently in both aging and AD \u201330. The Autophagy plays a key role in neuronal physiology and pathology. It degrades cell organelles and misfolded proteins by fusing autophagosomes with lysosomes to prevent buildup of wastes within the cell and promote homeostasis and organelle self-renewal. Misfolded proteins can induce autophagy in primary neurons and this induction can be impaired under neurodegenerative disease conditions ,33. ExprThere is now a growing consensus that increased histone acetylation with globally elevated transcription might be beneficial at older ages as it contributes to reversion of age-dependent decline in expression of metabolic, stress response, and reparative genes involved in homeostasis and health span. There is thus a rationale for targeting deacetylation with inhibitors to activate expression of specific genes. Since transcriptional levels of numerous genes are shown to decrease with increasing age, a recovery of their transcriptional activity through HDAC inhibition could prevent or delay age-associated declines in neurological function and enhance intervention of AD."} +{"text": "Esophageal atresia, diaphragmatic hernia and abdominal wall defects provide examples of congenital anomalies which have been shown to have poorer neurodevelopmental outcomes in the face of prematurity, with associated increased surgical complexity, higher relative cumulative doses of medications, longer hospital and intensive care stay and increased rates of feeding difficulties, compared with infants who experience either prematurity or congenital anomalies alone.Preterm infants are more likely to be born with congenital anomalies than those who are born at full-term. Conversely, neonates born with congenital anomalies are also more likely to be born preterm than those without congenital anomalies. Moreover, the comorbid impact of prematurity and congenital anomalies is more than cumulative. Multiple common factors increase the risk of brain injury and neurodevelopmental impairment in both preterm babies and those born with congenital anomalies. These include prolonged hospital length of stay, feeding difficulties, nutritional deficits, pain exposure and administration of medications including sedatives and analgesics. Congenital heart disease provides a well-studied example of the impact of comorbid disease with prematurity. Impaired brain growth and maturity is well described in the third trimester in this population; the immature brain is subsequently more vulnerable to further injury. There is a colinear relationship between degree of prematurity and outcome both in terms of mortality and neurological morbidity. Both prematurity and relative brain immaturity independently increase the risk of subsequent neurodevelopmental impairment in infants with CHD. Non-cardiac surgery also poses a greater risk to preterm infants despite the expectation of normal Congenital anomalies which require surgery during the neonatal period predispose infants to brain injury and subsequent neurodevelopmental impairment, including both cardiac and non-cardiac lesions . Contribin utero or ex utero status. The impaired in utero environment may compromise brain growth and development due to placental dysfunction, uterine dysfunction, maternal ill health, infection, or injury is a risk to term-born neonates, then the additive impact of prematurity is potentially cumulative. Hunt et al. reported the 8-year-old outcomes of three cohorts of extremely preterm infants who underwent a surgical procedure during their NICU admission . They foWalsh et al. specifically excluded congenital anomalies from a group of preterm infants less than 30\u00a0weeks gestation included in a study comparing MRI at term-equivalent age and 2-year outcome between those who did and did not receive surgery and anesthesia . A relatMost major neonatal surgery is time-critical such that pre-operative MRI is very challenging to obtain. Those researchers who have managed to obtain such images are subject to extreme bias as the more complex or unwell infants are least likely to have been able to access the MRI scanner prior to surgery. Fetal imaging would be the obvious solution to exploring brain growth prior to non-cardiac surgery but has not yet been widely explored to date.Congenital heart disease (CHD) makes up the largest cohort of infants with congenital anomalies requiring neonatal surgery and has provided a helpful model to understand the impact of impaired fetal development on the growing brain. Fortunately, cardiac anomalies often have a slightly longer window of opportunity to allow pre-operative imaging than non-cardiac surgical anomalies. Furthermore, there is an extensive literature exploring fetal MRI in this population.per se. This potential link has been confirmed by MRI studies linking cerebral oxygenation with impaired growth in fetuses with CHD and neurodevelopmental impairment in CHD, even in early term-born infants. A study of 971 consecutive neonates with critical CHD was stratified by gestational age and adjusted for severity of lesion, against a reference group of neonates born at 39\u201340\u00a0weeks gestation. The risk of cerebral injury increased 2-fold in the 37\u201339\u00a0week gestation group; 8-fold in the 34\u201337\u00a0week gestation group and 25-fold in infants less than 34\u00a0weeks gestation at birth . In the surgery . Ortinau surgery , but Bel surgery .There has been much debate regarding optimal timing of surgery for infants born prematurely with critical CHD . IntentiBoth critical CHD and non-cardiac congenital anomalies which require neonatal surgery, increase the risk of brain injury and subsequent neurodevelopmental impairment compared with healthy infants. MRI patterns of impairment suggest different mechanisms are at play between the two surgical groups, with myelination delay more prominent in the cardiac group and gyral maturation delays more common in the non-cardiac group. However, both types of lesions place the neonate at risk of further brain injury throughout their peri-operative and intensive care course. The additive burden of prematurity is complex but combines the vulnerable states of both prematurity and relative immaturity such that an increased risk of brain injury and subsequent neurodevelopmental impairment is inevitable.Many studies (including my own) have attempted to simplify and homogenize research findings, by excluding preterm infants from explorations of congenital anomalies on injury and outcome, when in fact this is exactly the group who needs the most attention. Rather than excluding infants with anomalies from studies of preterm neurodevelopment and preterm infants from studies of congenital anomalies, future studies should focus specifically on minimizing risk to preterm infants with comorbid congenital anomalies. This could include health-service research exploring the multidisciplinary team requirements to merge best practices across clinical craft groups with a patient-centered focus. Studies of the impact of developmental care practices in preterm infants could be extended into the surgical and cardiac environment. Further studies should provide gestation-based dosing for commonly used anesthetic and analgesic agents. Follow-up programs should incorporate later preterm infants than historically included, to allow for the potentially additive impact of surgical complexity.A more concerted focus on these high-risk infants should obviate the increased risk of impairment through improvements in patient-centered, developmentally appropriate care, which carefully balances pain management, nutritional support and brain-protective strategies from fetal or neonatal diagnosis to childhood and beyond."} +{"text": "Benefits of the stay-at-home order imposed in Italy to prevent SARS-CoV-2 transmission need to be weighed against its impact on citizens\u2019 health. In a country with a solid familial culture and where welfare relies on households, confinement drastically decreased support provided by elder relatives, which may have worsened mental health.A web-based cross-sectional study was conducted on a representative sample of Italian adults during lockdown (27th of April-3rd of May 2020). We asked 3156 subjects to report on reduced help in housework and childcare from retired parents to assess confinement impact on mental health through validated scales before and during the lockdown.Overall, 1484 (47.0%) subjects reported reduced housework help from parents, and 769 diminished babysitting support. Subjects reporting reduced housework help had worsened sleep quality and quantity , depressive and anxiety symptoms , compared to those reporting unreduced help. Worsening in sleep quality and quantity , depressive and anxiety symptoms was also associated with reduced babysitting help. In subjects with poorer housing and teleworking, mental health outcomes were worse.Confinement came along with reduced familial support from parents, negatively impacting mental health. Social networks and support within families provided by older relatives act as a resilience factor and a potential vulnerability that affects mental health outcomes. Health and social services response should be designed to address mental health needs and mitigate long-term health costs caused by the pandemic's unprecedented stressfulness and unknown duration.National lockdown measures came along with reduced housework help supply for a large proportion of adult parents who presented increased mental health symptoms with unsatisfactory quality of life.A global, multi-level socioeconomic interdisciplinary approach is needed to inform evidence-based family and welfare policies and prevention strategies centred on population wellbeing."} +{"text": "The topic of older adult loneliness commands increasing media and policy attention around the world. Are surveys of aging equipped to measure it? We assess the measurement of loneliness in large-scale aging studies in 31 countries. In each country, we document available loneliness measures, examine correlations between different measures, and assess how these correlations differ by gender and age group. There is substantial heterogeneity in available measures of loneliness across countries. Within countries with multiple measures, the correlations between measures are high (range .38-.78). Differences by age and gender group are relatively small. Correlations between loneliness measures and living alone and being without a spouse are positive and similar in magnitude across countries, supporting construct validity. We establish that even single-item measures of loneliness contribute meaningful information in diverse contexts, with reliable and consistent measurement properties within many countries."} +{"text": "In utero exposure to maternally-derived antigens following chronic infection is associated with modulation of infants \u2018immune response, differential susceptibility to post-natal infections and immune response toward vaccines. The maternal environment, both internal (microbiota) and external also modulates infant's immune response but also the clinical phenotype after birth. Vertical transmission of ubiquitous respiratory pathogens such as influenza and COVID-19 is uncommon. Evidence suggest that in utero exposure to maternal influenza and SARS-CoV-2 infections may have a significant impact on the developing immune system with activation of both innate and adaptive responses, possibly related to placental inflammation. Here in, we review how maternal respiratory infections, associated with airway, systemic and placental inflammation but also changes in maternal microbiota might impact infant's immune responses after birth. The clinical impact of immune modifications observed following maternal respiratory infections remains unexplored. Given the high frequencies of respiratory infections during pregnancy , the impact on global child health could be important. On the other hand, a decreased expression of placental TLR mRNA (TLR 6 and 7) was observed along with suppression of pro-inflammatory placental cytokines production (IL-1 and TNF). Different knock-out experiments using TLR deficient mice suggest a critical role of maternal TLR signaling in the protection against asthma in their progeny.The factors associated with farm exposure and modulation susceptibility to atopic disease is likely multifactorial . Animal progeny . This prOverall these data indicate that prenatal exposure to a specific maternal microbial respiratory environment is associated with modification of immune responses at birth with a potential clinical impact during infancy.Lactobacillus exposure through maternal supplementation led to decreased Th2 cytokines and lung inflammation following RSV infection in their neonates . Fetal immune cells show signs of activation as assessed by TNF-\u03b1 and IFN-\u03b3 production. Immune activation is probably non-specific as no sign of SARS-CoV-2 sensitization, has been observed , possibly related to alveolar macrophages dysfunction . StudiesWe have reviewed the different mechanisms associated with acute maternal respiratory infections that could possibly impact infant's immune responses.Previous research in the field of allergy and chronic maternal infections have highlighted the impact of maternal exposure to specific microbial respiratory environment and immune modulation related to chronic infections on infant's immune responses. Susceptibility toward infection and response to vaccines in infancy are modulated after exposure to chronic maternal infection, without vertical transmission while susceptibility toward immune-mediated diseases is impacted by the respiratory maternal environment , 8, 19.in utero sensitization seems infrequent after exposure to maternal respiratory infections such as influenza and COVID-19.In this mini-review, we show that part of these mechanisms are also observed during maternal respiratory infections, namely induction of innate immune responses and placental inflammation. On the other hand, Maternal microbiota editing may also have an impact on infants \u2018immune responses. During pregnancy, disturbance in the mother microbiota either as a result of infection or stress linked to sexual hormones might influence infant health through several ways. Following lung-gut microbiota crosstalk, additional effects may be associated with upper respiratory infections during pregnancy. Alterations in the lung microbiota profile have been associated with several respiratory diseases such as pneumonia or viral infection . DysbiosMaternal respiratory infections such as influenza and COVID-19 are associated, beside upper and respiratory tract inflammatory responses, with systemic and placental inflammatory responses. Studies performed during the COVID-19 pandemic indicate that neonates exposed to respiratory infections have distinct innate but also adaptive responses, independently of virus-specific immune activation, as sensitization appears infrequent \u201333. ResuModulation of placental TLR responses is associated with differential risk of atopic diseases during infancy. The impact of maternal influenza or COVID-19-induced placental inflammation on the risk of atopic diseases during infancy is undetermined.Finally, responses to vaccines at birth or during infancy, might also be impacted following disturbances of both adaptive and innate immune responses, as previously shown following chronic maternal infections with protozoans or helminths , 7. NotaMost of the literature reviewed here was related to influenza and COVID-19. Other respiratory infections such as RSV and human metapneumovirus (HMPV) are highly prevalent worldwide and also reported during pregnancy as causes of acute respiratory illnesses \u201356. MoreMaternal vaccination is recommended during pregnancy for both influenza and COVID-19; whether maternal vaccination is associated with dampening of inflammatory immune response following respiratory infection remain to be demonstrated."} +{"text": "The task switching paradigm is widely used to examine cognitive switching, a critical subcomponent of cognitive control. Studies on aging suggest that switching is particularly vulnerable to age-related changes in cognition. However, the effects of manipulating the stimulus dimension on task switching performance is relatively understudied. In this study, 13 younger adults and 13 older adults completed a novel cued task-switching paradigm requiring speeded same-different judgments based on a perceptual (color) or conceptual dimension of the stimuli. Task switching performance was measured using switch cost, which is the difference in accuracy between switch and repeat trials. Overall both YA and OA exhibited switch costs, indicating increased cognitive demand when switching between judgments compared to repetition of the same judgement. In regard to group differences, YA and OA performed similarly when performance was collapsed across the stimulus dimensions; however, when examined separately, OA exhibited worse performance than YA when making conceptual judgements. These results highlight the importance of examining carefully manipulated stimulus-related factors in task switching paradigms to advance our understanding of cognitive control and aging."} +{"text": "Health-related behavior correlates in critical ways with the current epidemic of chronic diseases. Modifiable behaviors increase the risk of chronic disease. Despite there are well-identified behaviors, efforts at behavior change are clinically-challenging and frequently ineffective.We aim to establish how the current evidence and latest neuroscientific knowledge about behavioral change allow the most reliable assessment of patients with refractory health-related behaviors that negatively impact health outcomes.We performed a literature review using Pubmed databases and UpToDate. The search included \u201cbehavioral change\u201d and \u201chealth-related behavioral change\u201d[MeSH Terms].Habitual behavior consists of behavioral patterns operating below conscious awareness and acquired through context-dependent repetition. Behavioral change is a complex multi-level field of intervention. The Health Belief Model allows a careful description of the patient\u2019s perceived vulnerability, perceived disease severity, self-efficacy, and change motivation. The identification of social variables is critical since they correlated with poor health outcomes, particularly in chronic diseases. Temperament and character traits can have a strong influence on the difficulty of changing habitual behavior. Psychopathology, if present, must be addressed because it can be a notable factor of behavior instability and correlates negatively to health outcomes. Assertive and efficient communication skills in the clinical context are imperative. Motivational interviewing skills can allow effective behavioral change.Interventions addressing behavior change require careful, thoughtful work that leads to a deep understanding of the nature of what motivates people. Intervention based strategies focused on behavioral change must undergo further investigation in the future.No significant relationships."} +{"text": "Lo non-classical monocytes promotes resolution of perinatal liver injury in a murine model of perinatal hepatic inflammation. Our research also identifies a potential co-regulatory role between neutrophils and non-classical monocytes. Further work is needed to understand how neutrophils regulate other myeloid populations during perinatal liver inflammation. Elucidating the mechanisms that govern perinatal liver injury and repair may lead to the development of immune-directed therapies that can be used to mitigate the devastating effects of diseases like BA.Perinatal liver inflammation can have life-threatening consequences, particularly in infants and young children. An example of a hepatic inflammatory disease during infancy is biliary atresia (BA), an obliterative cholangiopathy that rapidly progresses to hepatic fibrosis and liver failure. The aggressive nature of BA in neonates compared to the pathogenesis of inflammatory liver diseases in adults, suggests that the mechanisms responsible for restoring tissue homeostasis following inflammation are impaired in affected infants. This article reviews our recent findings demonstrating that the relative abundance of Ly6c The maturation of the immune system is a complex process that undergoes major transitions during fetal and neonatal development . ThroughLo non-classical monocytes promote resolution of rhesus rotavirus-mediated perinatal hepatic inflammation,\u201d we demonstrate the importance of monocyte subsets in mitigating inflammatory insults to the perinatal liver. Using a rhesus rotavirus (RRV) model of perinatal liver injury, we investigated changes in composition of the hepatic myeloid immune compartment in late-gestation fetuses and in neonatal pups [Lo non-classical monocytes observed at this time. Since Ly6cLo non-classical monocytes exert anti-inflammatory and pro-reparative functions [In our recent study, \u201cLy6ctal pups . Our iniunctions \u20137, we hyLo non-classical monocytes. Using anti-Ly6g targeted neutrophil depletion [Hi classical monocyte depletion [Lo non-classical monocytes within RRV-injected neonatal livers. Importantly, antibody-mediated depletion of neutrophils and Ly6cHi classical monocytes increased both the percentage and the absolute number of Ly6cLo non-classical monocytes, indicating both a proportional and numerical expansion of these cells. Furthermore, the rise in Ly6cLo monocytes was associated with disease resolution in the neonate, supporting the idea that Ly6cLo non-classical monocytes play a role in resistance to perinatal liver injury and resolution of disease. To confirm Ly6cLo non-classical monocytes are responsible for disease resolution and resistance [Lo non-classical monocyte function in the setting of neutrophil and classical monocyte depletion [Lo non-classical monocytes mitigate perinatal liver inflammation [To test this hypothesis, we manipulated the myeloid compartment within the neonatal liver to resemble the fetal environment, thereby establishing an abundance of Ly6cepletion , and antepletion , we expasistance , we usedepletion \u201312. Blocammation .Lo non-classical monocytes [Lo non-classical monocytes reveals a co-regulatory relationship between these two cell populations that are important for tissue repair and healing [Recent evidence suggests that neutrophils play a vital role in regulating and orchestrating inflammation and tissue repair through their interaction with the innate and adaptive immune systems \u201316. Seveonocytes , suggest healing .An intriguing mechanism by which neutrophils may influence other myeloid populations during inflammation may involve the regulation of myeloid precursors and hematopoietic progenitors . We haveThe liver is known to serve as the primary hematopoietic organ throughout fetal life as it harbors the hematopoietic stem cell (HSC) niche . Soon afHi myeloid cells, and Ly6cLo and Ly6cHi monocytes in the setting of tissue injury and systemic disease [In addition to the liver, the spleen can also contribute to the overall hematopoietic activity during neonatal development and inflammation via EMH ,36. Howe disease ,38. ThesUnderstanding the immune response to liver injury during perinatal development is particularly important as the dynamic transitions in hematopoiesis during this time may establish a unique environment that is susceptible to injury and inflammation. Since the liver and spleen are believed to contribute to hematopoiesis in the setting of perinatal liver inflammation, it is important to understand the kinetics of neonatal emergency hematopoiesis to highlight the possible mechanisms by which myeloid populations may contribute to liver injury and repair. Insights gained into perinatal liver inflammation mechanisms will undoubtedly lead to tailored therapies for infants and children who suffer from the devastating consequences of perinatal liver injury."} +{"text": "Immune checkpoints are small molecules present on the cell surface of T-lymphocytes. They maintain self-tolerance and regulate the amplitude and duration of T-cell responses. Antagonism of immune checkpoints with monoclonal antibodies (immune checkpoint inhibitors) is a rapidly evolving field of anti-cancer immunotherapy and has become standard of care in management of many cancer subtypes. Immune checkpoint inhibition is an effective cancer treatment but can precipitate immune related adverse events (irAEs). Thyroid dysfunction is the most common endocrine irAE and can occur in up to 40% of treated patients. Both thyrotoxicosis and hypothyroidism occur. The clinical presentation and demographic associations of thyrotoxicosis compared to hypothyroidism suggest unique entities with different etiologies. Thyroid irAEs, particularly overt thyrotoxicosis, are associated with increased immune toxicity in other organ systems, but also with longer progression-free and overall survival. Polygenic risk scores using susceptibility loci associated with autoimmune thyroiditis predict development of checkpoint inhibitor associated irAEs, suggesting potentially shared mechanisms underpinning their development. Our review will provide an up-to-date summary of knowledge in the field of thyroid irAEs. Major focus will be directed toward pathogenesis (including genetic factors shared with autoimmune thyroid disease), demographic associations, clinical presentation and course, treatment, and the relationship with cancer outcomes. Immune checkpoint inhibitors (ICIs) are a rapidly expanding class of medications. At present, over 2000 clinical trials have been completed or are in progress to evaluate more than 30 different ICIs . The maiImmune checkpoints are small molecules present on the cell surface of T-lymphocytes . NormallThe etiology of irAEs is yet to be fully elucidated. Potential mechanisms include activation of polyclonal T-cell populations, loss of regulatory T-cell function, and expansion/activation of self-reactive, antigen-specific T-cells . IrrespeThyroid irAEs are the most common endocrine toxicity related to ICI-treatment . From clThyroid irAEs are typically identified incidentally during routine monitoring of thyroid function as part of ICI-treatment protocols . Most thOnset of thyrotoxicosis usually occurs within 3 months of first ICI-exposure , 7. OverIsolated hypothyroidism without a preceding thyrotoxic phase can occur. Most cases of isolated hypothyroidism are biochemically subclinical and may be related to non-ICI factors such as non-thyroidal illness syndrome. Subclinical hypothyroidism without a preceding thyrotoxic phase typically normalizes spontaneously without need for thyroid hormone replacement , 15. OveIdentification of reliable thyroid irAE risk factors has been elusive. To date, no reliable risk factors of thyroid irAEs have been identified, although clinical and biochemical associations have been documented in retrospective cohort studies . Female The etiology and biological drivers of irAEs remain elusive. It is possible that patients who experience irAEs may share a premorbid immunological state prior to ICI-initiation. A recent study using mass cytometry time of flight analysis identified higher levels of activated CD4+ memory T-cells and increased diversity in the T-cell receptor as pretreatment predictors of severe irAEs irrespective of the organ involved . These svia multiple mechanisms as evidenced by phenotypic differences in presentation, antithyroid antibody positivity rates, and differential association with cancer survival outcomes thyrotoxicosis to biphasic thyroiditis to isolated overt and severe hypothyroidism. This indeed may be the case, although more likely thyroid irAEs arise outcomes .Genetic factors associated with lifetime risk of autoimmune thyroid disease have been implicated in the risk of developing thyroid irAEs during ICI-treatment , 22. Keyvia and therefore thyroid dysfunction is more rapidly progressive following ICI-treatment than in other autoimmune thyroid conditions should have TSH-receptor antibody level (TRAB) measured to exclude Graves\u2019 disease . In sevePatients with established hypothyroidism may experience transient effects on thyroid function following ICI-treatment . Compensde novo related to ICI-treatment, is unmasked by ICI-treatment, or is a coincidental occurrence remains unknown. Similarly, thyroid eye disease (TED) has been reported (Graves\u2019 disease (GD) has been reported following ICI-treatment . Whetherreported . ReactivObservational studies repeatedly document an association between irAEs and improvement in cancer outcomes , 30. OwiInterestingly, abnormal TSH level (elevated or low) prior to initiation of ICI-treatment has been associated with inferior cancer outcomes irrespective of thyroid function changes post-ICI initiation in one study . HoweverFurther research is required to better inform our understanding of thyroid irAEs and their relationship to thyroid autoimmune conditions occurring outside the cancer immunotherapy setting. Enhanced characterization of the immune phenotype and T-cell subsets driving thyroid irAEs may allow for identification of patients at risk of thyroid (and other) irAEs and inform future research to uncouple the efficacy of ICIs from the risk of developing treatment related irAEs. Understanding the effects of immune checkpoint inhibition on the thyroid gland could also inform use of these agents for treatment of primary thyroid malignancies and prevention of autoimmune thyroid disease.Thyroid irAEs are a frequent complication of anti-PD-1 based ICI-treatment. Recent work has begun to unravel the molecular mechanisms underpinning development and their relationship to other autoimmune thyroid conditions. Regular monitoring of thyroid function during ICI-treatment is required, as although most cases of thyroid irAEs are asymptomatic and manageable, severe presentations with thyroid storm or myxedema can occur. Development of thyroid irAEs is associated with improved PFS and OS, especially overt thyrotoxicosis which may be a surrogate marker of patients experiencing a more robust immune response to ICI-treatment. When hypothyroidism occurs, it is usually permanent and treatment with thyroid hormone replacement will be required. Familiarity with thyroid irAEs among health professionals is important to facilitate efficient diagnosis and appropriate treatment of this increasingly common thyroid disease.All authors listed have made a substantial, direct, and intellectual contribution to the work. All authors approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Systemic amyloidosis is a diseased condition where misfolded proteins deposit in various organs in the form of amyloids, and transthyretin deposition, termed ATTR amyloidosis, can be either an age-related amyloid formation from misfolded wild-type TTR (ATTRwt) or by hereditary TTR malfunction due to mutation in the TTR gene (ATTRv). Although ATTRwt amyloidosis can cause various diseases, such as cardiac failure, conduction disturbances, arrhythmias and carpal tunnel syndrome, it is still under-recognised considering its clinical significance. Here the authors report a case of ATTRwt amyloidosis leading to carotid stenosis requiring surgical intervention. To the best of our knowledge, the current report is the first that described histopathological evidence of amyloid deposition in the carotid artery due to ATTRwt amyloidosis. TTR gene (ATTRv) [Systemic amyloidosis refers to a diseased condition where misfolded proteins deposit in various organs in the form of amyloids . Various (ATTRv) . Althoug (ATTRv) . Here thA 77-year-old Japanese male with a past medical history of acute cardiac infarction was diagnosed with a right carotid artery stenosis which progressed in three years . A digitThe hematoxylin and eosin-stained surgical specimen revealed carotid intima\u2019s eccentric fibrosis, compatible with arteriosclerotic change . Masson\u2019Amyloid cardiomyopathy refers to the myocardial deposition of amyloid fibers causing cardiac dysfunction, and it comprises AL amyloidosis and ATTR amyloidosis . AlthougOn the other hand, ATTR amyloidosis was considered a much infrequent rare condition compared with AL amyloidosis. However, extensive research has been pursued on ATTR amyloidosis due to its clinical significance in heart failure and it has recently been reported that amyloid deposits derived from plasma transthyretin are present in the heart of up to 25% of elderly individuals . Tafamid"} +{"text": "Bi-directional associations between depression and cognitive functioning are magnified among aging individuals, challenging behavioral health providers who treat older adults experiencing clinical and subsyndromal depression. This symposium contributes to the science and practice of assessing and treating later-life depression while also attending to issues in professional training. The first paper presents pre-treatment data from the multi-site Optimum Study of older adults experiencing treatment-resistant depression (n = 529). The relevance of positive psychological constructs is supported with analyses showing important relationships among cognitive functioning, social participation, and psychological well-being. The second paper describes the development of an updated measure to assess behavioral health providers\u2019 knowledge of later life depression, including brain health concerns. Psychometric data for the measure were generated from a random pool of licensed social workers (N=900) who were mailed the survey packet. The third presentation features an experimental study demonstrating that foundational information about aging, including debunking misconceptions about cognitive aging, influenced continuing education preferences of generalist Licensed Professional Counselors (LPCs). Among the randomly generated pool of LPCs (N = 120), participants who received aging-specific information were more likely to later choose an aging-specific continuing education option. The fourth paper highlights recommendations for mental health practitioners working in primary care and general medical settings with older adults who have co-existing depressive symptoms and cognitive concerns. The fifth and final presentation describes cognitive behavioral clinical tools to address brain health concerns in the context of later-life depression, using the new Brain Health module of a published client workbook."} +{"text": "While a growing body of evidence points to potentially modifiable individual risk factors for Alzheimer\u2019s Disease and Related Dementias (ADRD), the contexts in which people develop and navigate cognitive decline are largely overlooked. Geographic variation in ADRD rates suggest that environmental risk and protective factors may be important in cognitive aging and dementia caregiving. Community hazards are often heavily concentrated in underserved and underrepresented neighborhoods. This symposium aims to identify specific built, social, and natural environmental features associated with cognitive aging outcomes. The papers provide much-needed evidence on the role of neighborhoods and community networks for cognitive health and well-being among diverse older adults. First, Godina finds significant associations between neighborhood greenspace and microstructural indicators of brain health. Second, Westrick investigates the role of neighborhood disadvantage on long-term memory aging of older adults with and without a cancer diagnosis in later-life. Third, Finlay presents a new concept of Cognability to demonstrate which constellation of positive and negative neighborhood features may contribute most to healthy cognitive aging. Fourth, Nkimbeng identifies community networks and resources needed to inform dementia education and support care among African immigrants. Fifth, expert discussant Besser will share how these findings may inform upstream health promotion and reduce ADRD risk. She will discuss critical future research directions and methods to investigate environments of cognition. The symposium advances research assessing contexts of aging, and may inform public health and policy efforts to ameliorate community barriers and create more equitable opportunities to promote healthy aging in place."} +{"text": "Fall risk assessment traditionally focuses on objective physical performance. Balance confidence, a subjective measure of physical function, may provide important information to better predict fall risk and guide assessment and intervention strategies. This study examines the associations of balance confidence congruency with physical performance measures and fall occurrence. One-hundred-fifty-five community-dwelling adults aged 60 and over completed a comprehensive fall risk assessment including physical performance tests , activities-specific balance confidence (ABC) scale, and self-reported falls in the past year. Four groups were created based on congruency between balance confidence (low vs. high) and each physical performance measure or overall fall risk category . Poison regression analyses, adjusted for age and gender, tested the association between group membership and number of falls in the past year. Participants with high balance confidence and at fall risk based on 4-stage balance performance , or high balance confidence and at fall risk following the STEADI screening algorithm were at increased risk of more falls compared to participants in the group with high balance confidence and not at fall risk. These results suggest that older adults who overestimate their balance relative to their physical performance may be at increased fall risk, and that participant subjective reporting of physical performance should be paired with objective physical performance measures to better identify older adults at fall risk."} +{"text": "Maintaining a sense of purpose promotes mental and physical well-being in older adults . Drawing on one\u2019s sense of purpose is thus important for late life resilience. How older adults\u2019 sense of purpose manifests in their everyday lives remains understudied. This study used qualitative methods to amplify older adults\u2019 voices regarding purpose and resilience through analysis of their life stories. This study 1) explored what factors contribute to maintaining purpose in older adulthood, and 2) identified how older adults draw on their purpose during major challenges, particularly in the context of the COVID-19 pandemic. Eighteen older men and women participated in semi-structured life story interviews that asked about participants\u2019 individual interpretations of purpose in their lives and their experiences navigating the COVID-19 pandemic. Thematic analysis was conducted using established methods . To address the first research question, analyses revealed that older individuals largely maintain their purpose through engaging in acts of service to others, fostering connections with close others, and actively setting and achieving goals. Regarding the second question, older adults described how drawing on purpose through acts of service and connections with others fostered resilience through the COVID-19 pandemic. Overall, older adults\u2019 own expressions of their life stories illuminated how they are guided by purpose. Findings demonstrate the functionality of purpose in late life and how purpose can be practically fostered, specifically within the context of universally challenging experiences such as the COVID-19 pandemic."} +{"text": "Despite the benefits of palliative and end-of-life (PEOL) care for individuals with life-limiting illness, barriers to accessing this care persist among older adults experiencing homelessness. A number of studies have identified barriers to PEOL care from the perspectives of unhoused individuals and other relevant stakeholders; however, few empirically studied interventions exist to support evidence-based guidelines for PEOL care for this population. This scoping review aimed to identify PEOL interventions for adults experiencing homelessness. The search was conducted in May 2021 and yielded 480 results, from which 50 full-text articles were closely reviewed for inclusion. Sources were included if they reported findings of original, empirical research or quality improvement projects evaluating PEOL services tailored for individuals experiencing homelessness. A total of 13 articles representing 12 studies published between 2006-2021 were included in the review. Over half (n = 7) of the studies described interventions to promote advance care planning documentation, five described interventions embedding PEOL services within homeless shelters, and one described a community outreach program to increase access to PEOL services. Nearly all studies reported positive outcomes on participant perspectives, advanced directive completion rates, or cost analysis. None of the studies included clinical palliative care outcomes. Although most studies reported promising results, service and healthcare providers expressed concerns about continuing challenges and longevity of the programs. The body of literature encompassing PEOL interventions for people experiencing homelessness is limited but growing. Future research may benefit from the inclusion of clinical outcomes and efforts to reduce structural barriers to providing care."} +{"text": "Healthcare systems have become complex and fragmented, negatively affecting healthcare access and navigation. This is especially the case for socio-economically vulnerable people, who encounter organisational and administrative hindrances trying to access care. These difficulties have worsened during Covid-19. Scholarly literature recognises that - by moulding navigation practices - social capital may mediate between potential and realised access to healthcare. However, little is known about how this mediating work practically unfolds.This case study aimed to understand how social capital might affect healthcare navigation practices. To do so, we investigated how the People\u2019s Health Lab (PHL), a community-based organisation, supported socio-economically vulnerable people in navigating healthcare during the Covid-19 pandemic in Bologna, Italy. Nine months of participant observation were conducted both in person and digitally from July 2020 to March 2021. Twelve semistructured interviews were also conducted with volunteers of the organisation. Fieldnotes and interview transcripts were analysed through Thematic Analysis.PHL support activities addressed barriers to healthcare navigation by vulnerable people, which were found to be services fragmentation, bureaucracy and Covid-19 restrictions. Volunteers of the PHL connected vulnerable individuals to health services in manifold, flexible ways, working without standard operative protocols and relying on informal personal contacts within public services. This was found to be key in enabling navigation of healthcare during the first three waves of the pandemic.Our study provides evidence about how structural, linking social capital - the material and nonmaterial resources mobilised through the relationships between heterogeneous groups - can mediate access to fragmented healthcare systems by shaping navigation practices.\u2022\u2002Contemporary healthcare systems \u2013 including universal ones \u2013 have become complex and fragmented, posing access and navigation challenges to their users, especially those socio-economically vulnerable.\u2022\u2002Linking social capital can mediate access to fragmented healthcare systems by flexibly mobilising material and nonmaterial resources through informal relationships between heterogeneous groups."} +{"text": "Cancer immunotherapy has gained significant attention in recent years and has revolutionized the modern approach to cancer therapy. However, cancer immunotherapy is still limited in its full potential due to various tumor immune-avoidance behaviors and delivery barriers, and this is seen in the low objective response rates of most cancers to immunotherapy. A novel approach to immunotherapy utilizes image-guided administration of immunotherapeutic agents directly into a tumor site; this technique offers several advantages, including avoidance of potent toxicity, bypassing the tumor immunosuppressive microenvironment, and higher therapeutic bioavailability relative to systemic drug administration. This review presents the biological rationale for locoregional image-guided immunotherapy administration, summarizes the existing interventional oncology approaches to immunotherapy, and discusses emerging technological advances in biomaterials and drug delivery that could further advance the field of interventional oncology. Immunotherapy with immune checkpoint inhibitors has revolutionized cancer care by stimulating the body\u2019s adaptive immune system to detect, engage, and eliminate cancerous cells . Recent The field of interventional radiology is well-poised to drive innovation in cancer immunotherapy. Image-guided interventions have already been used to establish several novel and minimally invasive approaches to cancer treatment, including radiofrequency/thermal tumor ablation, trans-arterial chemoembolization, and targeted delivery of yttrium-90 (Y-90) emitting microspheres . These tThe basis of cancer immunotherapy lies in transforming the adaptive immune system to be able to recognize and eliminate previously unrecognizable tumor tissue, resulting in sustained antitumor activity from the body\u2019s natural immune mechanisms. Current approaches utilize immunotherapy alone as well as in conjunction with conventional chemotherapeutics/radiation depending on the type and stage of tumor . In a tyA significant barrier to this natural process is the ability of tumor cells to evade detection by the immune system and downregulate the cellular immune response. Various mechanisms are utilized by cancers to prevent immunogenicity, ranging from intrinsic regions of hypoxia and elevated lactate levels to production of immunosuppressive cytokines that directly deactivate T cell responses . AdditioLocoregional delivery of immunotherapy utilizing interventional oncology approaches can avoid many of the obstacles associated with current immunotherapy approaches. Using image guidance from X-ray fluoroscopy, ultrasound, magnetic resonance imaging, or computed tomography, an interventional radiologist can utilize a vascular or percutaneous approach to a tumor site and selectively administer immunotherapy directly within a tumor. One significant benefit to this approach is limited off-target effects/systemic toxicity as the therapeutic remains localized within the tumor site. This also allows for lower therapeutic doses to be delivered while concurrently achieving a higher drug concentration within tumors. Another major advantage is the ability to effectively handle metastatic lesions by individual targeting of tumors and immune system potentiation, potentially sparing the patient from systemic effects . The objAs previously described, the immunosuppressive tumor microenvironment poses a significant challenge to both traditional anticancer and novel immunotherapy approaches, so the key goal of immuno-oncology remains to induce the immune system despite these barriers. Tumor ablation and the resulting immune activation from the necrosis-associated DAMPs has proven to be a viable mechanism for this strategy and several techniques are already widely utilized in clinical practice by interventional radiologists to cause tumor immunogenic cell death. Endovascular therapies such as trans-arterial chemoembolization (TACE) and trans-arterial radioembolization (TARE), percutaneous methods including radiofrequency ablation (RFA) and cryoablation, and stereotactic laser-guided approaches have demonstrated tumor volume reduction with consequent immune activation, and immunotherapy can be utilized similarly alongside these techniques for synergistic therapeutic effects .Oncolytic virotherapy is a novel technique that re-engineers human viruses for cancer destruction and DAMP production. The drug talimogene laherparepvec is the first and at present only FDA approved intratumoral immunotherapy and is used to treat advanced melanoma. TVEC utilizes an attenuated herpes simplex virus, type 1 (HSV-1) which has been engineered to produce granulocyte-monocyte colony stimulating factor (GM-CSF); the double stranded DNA virus can directly and preferentially lyse tumor cells, producing DAMPs and activating the previously latent adaptive immune system. TVEC has demonstrated a well-tolerated and durable response rate in a 2015 Phase III clinical trial, although 5-year survival remained low with monotherapy . ClinicaAdditionally, several other viruses have been identified to have oncolytic properties, including adenovirus, poliovirus, measles virus, and coxsackievirus; though these therapeutics are still in early clinical trials, they have demonstrated oncolytic ability in preclinical models and could open up new therapeutic avenues against a wide range of malignancies . NotablySystemic administration is the conventional approach for oncolytic virus delivery but therapeutic outcomes against solid tumors continue to be modest . The maivia intratumoral delivery as well.Checkpoint inhibitors have proven to be one of the most transformative advances in modern immunotherapy. The immunosuppressive checkpoints mentioned earlier can be blocked by therapeutics to allow for a more potent immune response, and several drugs have received FDA approval for use against various solid and hematologic malignancies . Pembrolvia the cyclic GMP\u2013AMP synthase (cGAS) \u2013 stimulator of interferon genes (STING) pathway. Activation of these pathways promotes transcription of pro-inflammatory cytokines and interferons which can allow for more potent antitumor responses cells can contribute to tumor elimination by phagocytosis and cytotoxic mechanisms. The innate immune system is especially sensitive to external antigens, with dedicated sensing pathways for bacterial toxins and nucleic acids esponses . Therape2668770) . Similar2668770) . HoweverCAR-T cells, which are T cells engineered for anti-cancer activity, have demonstrated significant activity against various types of hematological malignancies. Multiple formulations of systemic CAR-T cell therapeutics have received FDA approval for use against B-cell acute lymphocytic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma . HoweverNanoparticle-mediated drug delivery is rapidly gaining popularity in clinical applications and may offer solutions to delivery limitations imposed by the immunosuppressive tumor microenvironment. Nanoparticles are defined as materials with a size range between 1 and 100 nm and can be synthesized from a variety of materials, including lipids, polysaccharides, and inorganic compounds. These structures can encapsulate therapeutics and be engineered to navigate biological barriers and deliver their payload to a disease site in a controlled, targeted fashion . Though via T cell targeting nanoparticles achieved stronger T cell activation than systemic administration of the therapeutic in mouse models. Lipid nanoparticles containing a TGF-\u03b2 inhibitor were synthesized with anti-CD8 antibodies conjugated to the particle surfaces and injected into mice expressing B16 melanoma, achieving high concentrations in tumor sites. The group further demonstrated the ability to specifically target tumor reactive lymphocytes by conjugating anti-PD-1 antibodies to the particle surfaces against the fibrinogen-like protein (FGL1) gene; the nanoconstructs aimed to deliver metformin to block PD-L1 to prevent T cell suppression while simultaneously using siRNA against FGL1 to block another anti-inflammatory pathway. Of note, a pH trigger was utilized in these nanoparticles as the reaction of metformin with CO2 results in the low-pH-activated endosomal escape of the nanoparticle payload. l groups .in vitro and in vivo cellular penetration in preclinical studies, and clinical trials may soon be possible with these novel therapeutics (These studies highlight the ability to engineer nanosystems for targeted delivery and demonstrate a clear potential for applications of nanoparticle technology in cancer immunotherapy. Basic science and clinical research in nanoparticles is highly active with many promising developments on the horizon. Magnetic biomaterials such as iron oxide nanoparticles are being explored for magnetic hyperthermia, a technique which oscillates nanoparticles in an alternating magnetic field to cause heat-induced death and DAMP generation of tumor tissue. Magnetic nanoparticles can also be engineered for highly precise targeting to tumor sites along with magnetic-mediated drug delivery and cellular uptake . CRISPR-apeutics . Technolapeutics . Image-gThe field of interventional oncology as a whole is burgeoning with technological and clinical advancements, and many of the discipline\u2019s most impactful discoveries are just starting to show their promise. Intratumoral administration of cancer immunotherapy in particular has significant potential to alter the landscape of cancer treatment in the coming years, both independently and in conjunction with conventional treatment strategies. Many treatment-resistant or difficult-to-reach malignancies could become accessible with further advances in locoregional therapeutic administration. Moreover, the exciting developments in biomaterials and biotechnology will further enhance the precision and efficacy of locoregional immunotherapy. It is important to keep in mind that many of these technologies are still being validated in preclinical models or early-stage clinical trials and are still several years away from seeing widespread therapeutic applications in humans. However, the promising results demonstrated by the various studies covered in this review and beyond signal high and rapidly growing interest and expectations for a revolutionary approach to cancer treatment from scientists, clinicians, and patients.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "Worse physical and mental health are risk factors for cognitive decline in older adults. In Puerto Rico, existing healthcare services are lacking, further exacerbating this risk. This study examines how mental and physical health factors affect subjective cognitive decline for older adults in Puerto Rico. Data comes from the 2020 Behavioral Risk Factor Surveillance System, restricted to adults age 60+ residing in Puerto Rico (n = 1603). Subjective cognitive decline was measured with two dichotomous variables (no/yes): increases in confusion or memory loss and difficulty making decisions in the past year. Multivariate logistic regression models were run for each outcome variables. Predictor variables were number of days in past month with poor mental health, diagnosis of depression or mood disorder, self-rated health, and access to healthcare services, along with covariates. Higher number of days with poor mental health , diagnosis of depression or mood disorder , and cost barriers to accessing healthcare were associated with increased odds of increased confusion or memory loss. Significant predictors of increased odds of decision-making difficulty included higher number of days of poor mental health , diagnosis of depression or mood disorder , and worse self-rated health . To promote better cognitive health, intervention efforts should focus on those with poor mental and physical health, including identify strategies to improve access to healthcare services."} +{"text": "Normal respiratory functioning is essential for survival. Injuries or obstructions to airways, lungs or respiratory neural networks can have catastrophic consequences. Every breath places the lungs at the mercy of environmental air quality, which can contain pollutants, noxious gasses, and pathogens, driving or exacerbating acute and chronic respiratory conditions. Airway inflammatory diseases can compromise airflow through excessive mucus and airway wall edema, remodeling, and/or bronchoconstriction. Glottic proximity to the esophagus makes aspiration a constant threat. Indeed, aspiration frequently causes pneumonia and can lead to sudden, lethal airway obstructions. Neurological trauma or pathology may interfere with respiratory processes, with dire consequences for breathing and airway clearance. While impaired sensory function is problematic, so too is hypersensitivity, contributing to conditions such as chronic cough.It is therefore unsurprising that the respiratory system is equipped with many precise defensive mechanisms that collectively safeguard against risks, but our understanding of these processes is incomplete. This research topic brings together established experts and emerging future leaders to describe the state-of-the-art understanding of pulmonary defenses in health and disease, paving a direction for future research.Lin et al.). Interestingly, select RARs responded immediately, an effect mediated by 5-HT3 receptors, known to be expressed by some vagal sensory neurons .The respiratory system contains diverse sensory nerve fibers that monitor the physical and chemical environment of the airways and lungs. Subsets of mechanosensitive fibers, the slowly (SARs) and rapidly (RARs) adapting receptors, respond to changes in airway smooth muscle tone and distension and lung volume, providing essential volume-related feedback to brainstem neural networks governing breathing and autonomic neural control. Lin et al. performed single unit RAR and SAR recordings in anesthetized rats, observing that serotonin administration profoundly altered RAR firing, although the response was often delayed and hypothesized to occur secondary to serotonin-induced changes in pulmonary mechanics . Mazzone et al. presented new insights into the potential role of neuroimmune mechanisms in sensory nerve plasticity: a mouse model of severe respiratory viral infection showed vagal sensory neuron mobilization of the alarmin HMGB1 (High Mobility Group Box protein 1) and provided evidence that HMGB1 can act on vagal sensory neurons via its cognate receptor RAGE (receptor for advanced glycation end-products) to induce neuronal firing and increased sprouting of neurites . This provides a potential mechanism for altered sensory neuron sensitivity and structure in pulmonary diseases and may suggest a previously unrecognized target for anti-HMGB1 therapy, currently being developed for use in patients.Airway sensory nerve plasticity may induce further respiratory pathology and morbidity. The state-of-the-art review by Drake and colleagues summarizes evidence that such plasticity occurs in asthma and chronic cough. Biopsy samples from both patient groups show increased nerve fiber density and changes in neurochemical phenotype, while advances in RNA sequencing, 3D microscopy and physiological assays are beginning to shed light on possible mechanisms involved and eventual functional implications . Sood et al. investigated deep breath-induced bronchodilation in patients with chronic cough versus patients with classic asthma, cough-variant asthma and healthy controls. Their surprising finding was that the deep inspiration index was significantly lower in cough with normal airway sensitivity versus individuals with either asthma or healthy controls, suggesting that the bronchodilating effect of deep inspiration is impaired in chronic cough without asthma . Bai et al. provided an overview of the perplexing problem of why women are more likely to develop chronic cough than men and disproportionately prone to poor quality of life resultant from cough. Evidence for mechanistic and sociological differences is presented, providing a strong interrogation of sex- and gender-differences in a common respiratory condition and highlighting the need for more research into this important clinical observation . Sykes and Morice reviewed the state of play in chronic cough and cough hypersensitivity clinical research, including the current pipeline of antitussives. They contrasted this with the topic of cough hyposensitivity, highlighting the \u2018two faces\u2019 of cough presented to clinicians and the challenge of developing effective antitussives that suppress unwanted coughing while preserving defensive cough needed to protect against aspiration (Sykes and Morice).Coughing is a critical defensive mechanism for keeping the airways clear from potentially dangerous inhaled, aspirated or locally produced substances. However, altered cough sensitivity leading to excessive coughing is a common, often-debilitating problem. Conversely, insufficient coughing predisposes to early death from aspiration pneumonia. Olsen et al. investigated the cough-suppressing actions of two centrally antitussive drugs (GABA agonist baclofen and opiate codeine) in cats. They showed that neither appears to suppress spinal circuits involved in chest wall and abdominal motor drive, but likely exert their antitussive effects via the brainstem (Defense of the pulmonary system is inarguably essential; however, more research is required to fully elucidate the mechanisms and consequences of pulmonary defensive processes. In submissions originating from four continents and reflecting the efforts of established experts and emerging researchers, this research topic describes the cutting-edge understanding of pulmonary defenses in health and disease. Readers are provided with insight into processes including cough hyper and hypo -sensitivity, sensory neural mechanisms, and sex differences in pulmonary defense, providing strong foundations for future inquiry."} +{"text": "There are two common hypotheses to explain such high comorbidity between nicotine dependence and schizophrenia (SZ): self-medication for decreasing psychiatric symptoms or common environmental risk factors can predispose to both nicotine dependence and other risky behaviors in SZLittle is known about the influence of cigarette smoking comorbidities such substance use disorder (SUD), criminal history, or risky decision among patients with SZ.The Iowa Gambling test (IGT) was administered to thirty-nine patients with SZ of whom 69% reporting cigarette smoking. Both groups were evaluated using a socio-demographic questionnaire and clinical assessment using PANSS and self-report questionnaire the Barratt Impulsiveness Scale (BIS-11). To evaluate decision making was evaluated with the Iowa Gambling Task (IGT).The full SZ sample performed worse on the IGT then normal population. Smokers with SZ performed significantly worse than nonsmokers on the IGT primarily because they preferred \u201cdisadvantageous\u201d decks to a greater degree. The PANSS and impulsivity tendencies (BIS-11) did not predict overall performance on the IGT. Smokers with SZ had impaired affective decision-making. Behavior suggested preferential attention to the frequency amount of gain and inattention to amount of loss suggesting impairments in risk/reward decision-makingThis study is the first to compare IGT in smokers and nonsmokers with SZ with adjustment of SUD, criminal history, and existing tattoo to further examine IGT performance. These results support the hypothesis that comorbidities between nicotine dependence and SZ can be linked to other common factor that is associated with other externalizing behaviors in SZ.No significant relationships."} +{"text": "Certain percentage of the first-episode schizophrenia patients presents with negative symptoms, which persists over the year and influence treatment outcomes . Treatment of negative symptoms has been a significant continuous clinical challenge. Majority of recently published guidelines recommend antipsychotic monotherapy as the standard of care, recommending antipsychotic combination therapy only after a failed trial with clozapine . However, real-life forces clinicians to look for possible combinations of medications early on, especially to tackle negative symptoms. The systematic review of global prescribing practices covering four decades found the pooled median rate of antipsychotic combination therapy approximately 20% . One of the largest retrospective studies every conducted assessed rehospitalisation rates and the long-term use of antipsychotic polypharmacy in schizophrenia. Antipsychotic combination treatment was associated with an approximate 10% lower relative risk of psychiatric rehospitalisation compared with antipsychotic monotherapy . Real-world effectiveness study of antipsychotic monotherapy vs. polypharmacy in schizophrenia from Eastern Europe is also supporting this approach . At the same time antipsychotic combination therapy can increase the total antipsychotic dose burden, frequency of adverse effects, potential drug-drug interactions and incur additional costs. In our recent naturalistic study in schizophrenia outpatients (n=120) with insufficient effectiveness of previous antipsychotics therapy on negative symptoms, we were able successfully switch therapy form several different antipsychotic combinations to monotherapy and gain clinical benefits .No significant relationships."} +{"text": "Sleep complaints and disorders are two of the most common disturbances to health and well-being in later life. This study examined how evening electronic media use and daytime sedentary behaviors affect subsequent sleep hours and perceived sleep quality, and whether consistent sleep hours moderate these associations. Data were drawn from 241 older adults (Mage = 74.02) from the Daily Experiences and Well-being Study who completed ecological momentary assessments and wore an accelerometer for four days on average. A series of conditional fixed-effects models indicated that older adults reported more sleep disturbances on nights following the evening computer use. Sedentary behaviors and evening television viewing were not associated with sleep quantity and quality. Older adults with more consistent hours of bedtime reported better sleep quality regardless of their evening electronic media use and daytime sedentary behaviors, thereby highlighting the importance of sleep regularity in later life."} +{"text": "Background: Diversion of resources from infection prevention activities, personal protective equipment supply shortages, conservation (extended use and reuse) or overuse with multiple gown and glove layers, and antimicrobial prescribing changes during the COVID-19 pandemic might increase healthcare-associated infection (HAI) incidence and antimicrobial resistance. We compared the incidences of Clostridioides difficile infection (CDI), methicillin-resistant Staphyloccocus aureus bloodstream infection (MRSA BSI), and vancomycin-resistant enterococci bloodstream infection (VRE BSI) reported by California hospitals during the COVID-19 pandemic with incidence data collected prior to the pandemic. Methods: Using data reported by hospitals to the California Department of Health via the NHSN, we compared incidences in the second and third quarters of 2020 (pandemic) to the second and third quarters of 2019 (before the pandemic). For CDI and MRSA BSI, we compared the standardized infection ratios , and we calculated the P values. No adjustment model is available for VRE BSI; thus, we measured incidence via crude incidence rates . We calculated incidence rate ratio (IRR) with 95% CI for VRE BSI. To examine the possible effect of missing data during the pandemic, we performed a sensitivity analysis by excluding all facilities that had incomplete data reporting at any time during either analysis period. Results: Incidence measures and numbers of facilities contributing data in prepandemic and pandemic periods are shown in Table P = .05 for either MRSA BSI or CDI between the prepandemic and pandemic periods . Crude VRE BSI incidence increased during the pandemic compared to the prepandemic period . Excluding facilities with incomplete data had minimal effect. Conclusions: We found insufficient evidence that MRSA BSI or CDI incidence changed in California hospitals during the pandemic relative to the prepandemic period; however, there was a significant increase in the crude incidence of VRE BSI. Next, we will include interrupted time series analyses to assess departure from long-term trends, including a risk-adjusted model for VRE BSI. Additionally, we will evaluate for changes in central-line\u2013associated bloodstream infection incidence and antimicrobial resistance among HAI pathogens.Funding: NoDisclosures: None"} +{"text": "Using 2018 Medicare data, we examined the relationship between dual eligibility and injury-related emergency department use among a cohort of assisted living residents . We fit multilevel models with random intercepts at the assisted living community and license type levels. The baseline rate of injury-related emergency department emergency department use was 0.17. After controlling for resident characteristics , license type characteristics , and assisted living community characteristics , being dually eligible for Medicare and Medicaid was associated with a 12% increase in the probability of having an injury-related emergency department visit . Assisted living communities that serve duals may have fewer resources and staff to provide personal care, potentially leading to increased rates of injuries."} +{"text": "Immunotherapy for allergy has been practiced for over 100 years. Low-dose repeated exposure to specific allergen extracts over several months to years can successfully induce clinical tolerance in patients with allergy to insect venoms, pollen, house dust mite, and domestic animals. Different regimens and routes for immunotherapy include subcutaneous, sublingual, oral, and intralymphatic. Food allergies have been difficult to treat in this way due to high anaphylactic potential and only recently the first immunotherapy for peanut allergy has received regulatory approval. Several clinical trials have indicated high efficacy in desensitisation of peanut-allergic individuals using oral immunotherapy, which allows for safer administration of relatively high allergen concentrations. Still, the risk of adverse events including serious allergic reactions and high anxiety levels for patients remains, demonstrating the need for further optimisation of treatment protocols. Here we discuss the design and outcomes of recent clinical trials with traditional oral immunotherapy, and consider alternative protocols and formulations for safer and more effective oral treatment strategies for peanut allergy. Arachis hypogaea) is an immunoglobulin E (IgE)-mediated hypersensitivity, which tends to develop early in life and is typically lifelong with resolution in only 20% of affected children ..13].4 and IgA and initial increase followed by a decrease in serum food-specific IgE . Th. ThLactoesponses , 40, andThe long-term follow-up study PPOIT2 published in 2017 aimed toAnother Australian interventional study (ACTRN12617000914369) will assIn addition to whole peanut protein preparations and adjunctive therapeutics, alternative allergen forms for immunotherapy are being researched and trialled to overcome the associated adverse events of exposing the gastrointestinal tract to whole allergenic protein. DNA vaccines and peptide therapeutics are under investigation for other routes of administration and could be considered for OIT. Hypoallergenic preparations also offer an alternative. These interventions potentially could decrease treatment duration, the need for strict medical supervision and may lead to higher patient adherence.A novel immunotherapeutic approach utilises intradermal administration of plasmid DNA encoding peanut allergens and is currently being tested for safety, tolerability, and immune response in a Phase 1 trial (NCT03755713) in 20 paVaccination with plasmid DNA will need further proof against apprehensions about the safety of this vaccine type, categorised as gene therapy. Issues have been raised due to the hypothetical risk of integration of the vaccine itself into the genome or long-term persistence of the administered plasmid DNA that could lead to triggering the production of anti-DNA antibodies . These aOther vaccination approaches are currently undergoing pre-clinical testing in animal studies. A study performed by Storni et al. used peanut-sensitised mice to demonstrate a protective effect of vaccination with extracts of roasted peanut or the single allergens Ara h 1 or Ara h 2 coupled to immunologically optimised Cucumber Mosaic Virus-derived virus-like particles (CuMVtt) . ModifieThe alteration of allergenic protein structure and function influences immunoreactivity and allergenicity . Amongstin vitro basophil reactivity to PVX108, providing further support for an improved safety profile of PVX108 over whole allergen immunotherapies [An alternative approach to prevent IgE-mediated adverse events is to utilise T-cell reactive peptide fragments of the allergen that are not recognised by antibodies . Australherapies .OIT enables the administration of much higher doses of allergen with greater safety than other routes of administration of AIT. The recently approved peanut OIT product PALFORZIA represents a promising treatment option for peanut-allergic patients to increase the threshold of clinical tolerance for protection from accidental ingestion and possibly achieving sustained unresponsiveness. Clinical data collection of healthcare providers in the REMS program will help ongoing research in assessing the effectiveness of PALFORZIA in the real-world setting and guide future clinical trial design for OIT.This and other new strategies to enhance the safety and efficacy of immunotherapy for peanut allergy are currently under clinical exploration. Promising trends amongst different protocols and methods to improve OIT success with decreased adverse events are to alter OIT protocols regarding timing and dosing: a lower allergen delivery dose and a slow, delayed escalation rate in OIT treatment seem approachable in the near future.Adjunctive therapy with biologics in parallel to OIT protocols may help to mitigate risk and improve tolerability, especially in highly allergic individuals. Many trials using the biologic Omalizumab as adjunctive treatment in OIT have shown a raised threshold tolerance dose of OIT treatment, thereby reducing the risk of severe adverse reactions. Other biologics such as Abatacept are not optimal for extended use, which limits their application in OIT protocols. Dietary supplements such as probiotics have been shown to improve treatment tolerability with decreased adverse effects over longer periods of time, presenting a cost-effective adjunct treatment with OIT.Alternative formulations that circumvent exposure of the gastrointestinal tract to IgE-reactive, whole allergenic proteins, such as peptides, DNA vaccines, and other hypoallergenic preparations, could present a safer, more cost-effective approach for OIT for peanut-allergic individuals.More studies are needed to fully elucidate the best protocol to achieve sustained unresponsiveness. Most current clinical trials include objective laboratory biomarker analysis in patients undergoing OIT protocols . The rap"} +{"text": "Gos is a declarative Python library designed to create interactive multiscale visualizations of genomics and epigenomics data. It provides a consistent and simple interface to the flexible Gosling visualization grammar. Gos hides technical complexities involved with configuring web-based genome browsers and integrates seamlessly within computational notebooks environments to enable new interactive analysis workflows.https://github.com/gosling-lang/gos), and documentation with examples can be found at https://gosling-lang.github.io/gos.Gos is released under the MIT License and available on the Python Package Index (PyPI). The source code is publicly available on GitHub ( Existing genomic visualization tools are tailored towards specific tasks and as such are limited in terms of expressiveness .clinvar.ipynb notebook contains a custom visualization to view human genetic variants from the ClinVar database (We provide a set of Jupyter notebooks (doi: 10.5281/zenodo.7321052) demonstrating how genomics visualizations may be created, combined and controlled with Gos. The getting-started.ipynb and navigation.ipynb notebooks introduce a basic concepts of the Gosling grammar through the declarative Python API, with sections detailing data-binding, creation of custom Tracks and Views and programmatic viewer navigation. The data-loading.ipynb notebook displays an identical visualization for a dataset hosted remotely, on the local filesystem, as well as a Pandas DataFrame, demonstrating the versatile data capabilities of our library.The Gos is a Python library for authoring interactive genomics visualizations via the Gosling grammar. Instead of editing deeply nested and repeated JSON data structures, users write simple Python programs which emit valid Gosling JSON specifications. Python scripts may therefore be repurposed to accommodate new data sources, offering a convenient utility to produce custom visualizations as a part of traditional bioinformatics pipelines.Beyond this core functionality, Gos provides a unified framework to iteratively visualize genome-mapped data within interactive computational notebooks. Responsive genomics visualizations are woven between code and prose, and optional utilities host local and in-memory datasets without requiring users to exit the analysis environment or save intermediate results to disk. Gos connects flexible web-based genomics visualization with the larger scientific Python ecosystem, and we anticipate this integration can foster the use of numerical and machine learning libraries to actualize higher-level genomics visualization tools such as recommendation systems ("} +{"text": "Maintaining a sense of purpose promotes mental and physical well-being in older adults . Drawing on one\u2019s sense of purpose is thus important for late life resilience. How older adults\u2019 sense of purpose manifests in their everyday lives remains understudied. This study used qualitative methods to amplify older adults\u2019 voices regarding purpose and resilience through analysis of their life stories. This study 1) explored what factors contribute to maintaining purpose in older adulthood, and 2) identified how older adults draw on their purpose during major challenges, particularly in the context of the COVID-19 pandemic. Eighteen older men and women participated in semi-structured life story interviews that asked about participants\u2019 individual interpretations of purpose in their lives and their experiences navigating the COVID-19 pandemic. Thematic analysis was conducted using established methods . To address the first research question, analyses revealed that older individuals largely maintain their purpose through engaging in acts of service to others, fostering connections with close others, and actively setting and achieving goals. Regarding the second question, older adults described how drawing on purpose through acts of service and connections with others fostered resilience through the COVID-19 pandemic. Overall, older adults\u2019 own expressions of their life stories illuminated how they are guided by purpose. Findings demonstrate the functionality of purpose in late life and how purpose can be practically fostered, specifically within the context of universally challenging experiences such as the COVID-19 pandemic."} +{"text": "Dear Editor,Airway protection and maintaining patency during neurosurgical cases requiring prone positioning, is of paramount importance. Due to complexity of procedure , it becomes difficult to manipulate an airway once the surgery commences: With provision of video laryngoscopes (VDL) it becomes easier to identify airway edema and other related abnormalities."} +{"text": "The bi-directional relationship between mental and physical illness is well established. Therefore, in order to lower the already high mortality rates associated with psychiatric disorders, physical health issues must be closely monitored in this population . A recent Lancet commission highlights emerging strategies and recommendations for improvement of physical health outcomes in patients with chronic mental disorders. These strategies involve better integration of physical and mental health care, combined with broader implementation of lifestyle interventions to reduce elevated cardiometabolic risk and attenuate medication side-effects [3].To assess psychiatrists\u2019 confidence levels in physical healthcare competencies; to explore whether confidence was related to learning opportunities.Physical healthcare learning objectives were extracted from the Irish College of Psychiatrists\u2019 training curriculum. An electronic questionnaire was sent to 50 psychiatrists in one Irish healthcare region with a catchment area of c. 450,000. Participants had to rate confidence levels for each competency on a five-point Likert scale and the availability of learning opportunities for attaining each competency.66% response rate was achieved. A majority reported confidence in cardiovascular examination, interpreting blood results and evaluating comorbidities. A minority reported confidence in interpreting imaging, electrocardiograms and recognising medical emergencies. This corresponds to a relative paucity of learning opportunities.Clinical implication Programmes for trainee doctors and CME opportunities for consultant psychiatrists would benefit from an emphasis on physical health examination and modules on interpreting investigations and the recognition of medical emergencies."} +{"text": "Airborne aerosols reduce surface solar radiation through light scattering and absorption , influence regional meteorology, and further affect atmospheric chemical reactions and aerosol concentrations. The inhibition of turbulence and the strengthened atmospheric stability induced by ADEs increases surface primary aerosol concentration, but the pathway of ADE impacts on secondary aerosol is still unclear. In this study, the online coupled meteorological and chemistry model with integrated process analysis was applied to explore how ADEs affect secondary aerosol formation through changes in atmospheric dynamics and photolysis processes. The meteorological condition and air quality in the Jing-Jin-Ji area in January and July 2013 were simulated to represent winter and summer conditions, respectively. Our results show that ADEs through the photolysis pathway inhibit sulfate formation during winter in the JJJ region and promote sulfate formation in July. The differences are attributed to the alteration of effective actinic flux affected by single-scattering albedo (SSA). ADEs through the dynamics pathway act as an equally or even more important route compared with the photolysis pathway in affecting secondary aerosol concentration in both summer and winter. ADEs through dynamics traps formed sulfate within the planetary boundary layer (PBL) which increases sulfate concentration in winter. Meanwhile, the impact of ADEs through dynamics is mainly reflected in the increase of gaseous-precursor concentrations within the PBL which enhances secondary aerosol formation in summer. For nitrate, reduced upward transport of precursors restrains the formation at high altitude and eventually lowers the nitrate concentration within the PBL in winter, while such weakened vertical transport of precursors increases nitrate concentration within the PBL in summer, since nitrate is mainly formed near the surface ground. They pe3) concentration. Atmospheric aerosols cause significant attenuation of ultraviolet radiation and affect photolysis rates and species chemical cycles . In 2013nditions . The airnditions . But und22.5 concentration is shown in The overall modeling methodology for the study is detailed previously in Following our previous analyses , three sTo further explore these impacts, process analysis (PA) technology was appl3\u22122 in January and July, respectively. Decreased solar radiation weakens surface turbulence and reduces the daily maximum PBL height. The perturbation of ADEs on solar radiation and the PBL is presented in To provide insight into how ADEs affect sulfate concentration, the vertical distribution of sulfate concentration and related process responses to ADEs is presented in 2 concentration and sulfate formation. Compared with winter, ADED changes sulfate by promoting sulfate formation in July , resulting in weakened nitrate formation at around 900 m in winter. Conversely, the transport direction of nitrate is bottom up in July. Therefore, restrained upward transport of NOx increases the formation of nitrate in the near-surface layer.The ADE impacts on nitrate are then investigated. The vertical profile of nitrate affected by ADEs is presented in The vertical distribution of the nitrate IPR response to ADEs is presented in 42.5 and its components. (2) ADEs through the photolysis pathway inhibit sulfate formation during winter in the JJJ region and promote sulfate formation in July. The differences are attributed to the alteration of effective actinic flux affected by aerosol optical depth (AOD), solar zenith angle, and SSA. (3) ADEs through the dynamics pathway act as an equally or even more important route compared with the photolysis pathway in affecting secondary aerosol concentration in both summer and winter. (4) ADEs through dynamics traps formed sulfate within the PBL, which increases sulfate concentration in winter. Meanwhile, the impact of ADEs through dynamics is mainly reflected in the increase of gaseous-precursor concentrations within the PBL, which enhances secondary aerosol formation in summer. (5) Reduced upward transport of precursors restrains the formation of nitrate at high altitude and eventually lowers the nitrate concentration within the PBL in winter, while such weakened vertical transport of precursors increases nitrate concentration within the PBL in summer, since nitrate is mainly formed near the surface ground.In addition to directly deteriorating air quality, aerosol diminishes solar radiation due to light scattering and absorption, thereby influencing regional meteorology and further modulating air quality. The impact of ADEs on secondary aerosol is more complicated than primary aerosol. This study quantified the impacts of ADEs on secondary inorganic aerosol using the two-way online coupled meteorology and atmospheric chemistry model (WRF\u2013CMAQ) with integrated process analysis. The main pathways through which ADEs affect aerosol concentrations were examined. The key conclusions are the following. (1) ADEs reduce solar radiation and decreases PBL height, concentrating aerosol in the near-ground layers. In this analysis, ADEs improved the model performance for simulating PMSupplement1"} +{"text": "The normal decline in skeletal muscle mass that occurs with aging is exacerbated in patients with chronic obstructive pulmonary disease (COPD) and contributes to poor health outcomes, including a greater risk of death. There has been controversy about the causes of this exacerbated muscle atrophy, with considerable debate about the degree to which it reflects the very sedentary nature of COPD patients vs. being precipitated by various aspects of the COPD pathophysiology and its most frequent proximate cause, long-term smoking. Consistent with the latter view, recent evidence suggests that exacerbated aging muscle loss with COPD is likely initiated by decades of smoking-induced stress on the neuromuscular junction that predisposes patients to premature failure of muscle reinnervation capacity, accompanied by various alterations in mitochondrial function. Superimposed upon this are various aspects of COPD pathophysiology, such as hypercapnia, hypoxia, and inflammation, that can also contribute to muscle atrophy. This review will summarize the available knowledge concerning the mechanisms contributing to exacerbated aging muscle affect in COPD, consider the potential role of comorbidities using the specific example of chronic kidney disease, and identify emerging molecular mechanisms of muscle impairment, including mitochondrial permeability transition as a mechanism of muscle atrophy, and chronic activation of the aryl hydrocarbon receptor in driving COPD muscle pathophysiology. Chronic obstructive pulmonary disease (COPD) patients are often affected by more severe limb skeletal muscle atrophy than is typical of normal aging , with moIn addition to skeletal muscle atrophy, there are many other manifestations of adverse limb muscle impact in COPD . It is iTo further test for manifestations of mitochondrial dysfunction in COPD limb muscle, in one of our prior studies we used a histochemical diagnostic approach to identify muscle fibers with severe mitochondrial respiratory capacity impairment and observed a markedly elevated abundance of muscle fibers exhibiting depletion of mitochondrial complex IV activity but relatively normal (or elevated) mitochondrial complex II activity in vastus lateralis muscle biopsies of COPD patients . This phIt is noteworthy that muscle fibers with complex IV deficiency typically exhibit a compensatory upregulation of mitochondrial biogenesis and mtDNA copy number in a futile attempt to restore the bioenergetic capacity of the muscle fiber (futile because the high burden of mutated mtDNA templates precludes biogenesis of properly functioning mitochondria). Whereas in age-matched control subjects fibers with complex IV deficiency and normal or elevated complex II activity (Cox-/SDH+) exhibited greater than 2-fold higher levels of mtDNA copy number compared to normal muscle fibers (Cox+/SDH+), this was not seen in COPD patient muscle and thisFurther to the relevance of specific mitochondrial enzymatic abnormalities in COPD, a recent study using a mouse model of pulmonary emphysema observed a down-regulation of subunit c of complex II (SDH) that was associated with lower muscle respiratory capacity and greater muscle fatigability. In addition, genetic gain of function experiments to rescue complex II in mice with emphysema improved muscle respiratory capacity and reduced fatigability . Amongstvia actin cleavage , and inflammation, amongst others. These consequences are further compromised during acute exacerbations of disease severity, which can occur secondary to bacterial or viral infections . As a re2 supply through modulation of bioenergetic stress . Their results showed that hypoxia further exacerbated both the decline of muscle mass and shift towards type IIx fibers seen with bed rest exposure in the etiology of COPD muscle impairment, there is growing evidence that long-term cigarette smoking plays a key role in initiating the muscle impairments with COPD (as summarized in in vitro recapitulates the muscle atrophy (The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with a wide variety of endogenous and exogenous ligands that leads to increased transcription of detoxifying pathways, including cytochrome P450 enzymes such as Cyp1A1 Figure , above. atrophy and mito atrophy . Finally atrophy , and the histone H2A variant gamma-H2AX (\u03b3H2AX). These senescence markers were recently evaluated in the context of aging human skeletal muscle using immunolabeling of muscle cross-sections from young (18\u201335\u00a0years) vs. old (>70\u00a0years) subjects. The authors noted that despite using numerous commercially available antibodies for each senescence marker, \u03b3H2AX was the only one detectable in human muscle, and strikingly it did not evidence an increase with aging and instead was elevated exclusively in myonuclei of obese vs. lean subjects . KeepingAnother biomarker of aging that has received some attention in the context of COPD skeletal muscle impairment is the anti-aging hormone \u03b1-klotho (hereafter referred to as klotho). Klotho serves as a co-receptor for fibroblast growth factor 23 to activate a variety of fibroblast growth factor receptors throughout the body , and is Skeletal muscle of COPD patients is characterized by an exacerbated degree of atrophy relative to age-matched healthy subjects. They also exhibit other manifestations of skeletal muscle impairment, including exacerbated fatigue, weakness, a fast fiber shift, mitochondrial dysfunction, and an accumulation of denervated muscle fibers that is associated with a failed reinnervation transcriptional profile. Notably, COPD patient skeletal muscle exhibits evidence of an increased frequency of mitochondrial permeability transition events, where recent evidence identifies mitochondrial permeability transition as a mechanism of muscle atrophy operating through mitochondrial ROS and caspase 3. There are likely multiple contributing factors underlying the skeletal muscle alterations in COPD, including chronic TS exposure, systemic hypoxia, systemic hypercapnia, and inflammation. Notably, smoking mouse models show that chronic TS exposure without overt lung disease can cause muscle atrophy, mitochondrial impairment, and neuromuscular junction alterations, underscoring the likely role of long-term TS exposure in initiating the muscle impairment in COPD. Furthermore, recent evidence suggests that chronic activation of the AHR in skeletal muscle is likely to play an important role in driving these TS-induced muscle alterations as constitutive activation of the AHR without TS exposure recapitulates many of the same muscle phenotypes induced by chronic TS exposure. In addition to TS-mediated AHR activation, the higher circulating level of the tryptophan metabolite kynurenine seen in COPD patients, which is likely a consequence of impaired renal function, can also activate the AHR. This suggests multiple pathological insults involved in COPD may converge upon the AHR in causing skeletal muscle toxicity. Although an exacerbated accumulation of senescent cells in COPD muscle seems unlikely to underlie the exacerbation of aging muscle phenotypes , reduced circulating levels of the longevity-promoting klotho protein have been reported in COPD and some evidence suggests this may contribute to the adverse muscle phenotypes. In conclusion, COPD patient skeletal muscle alterations are likely to be driven by a combination of factors, some of which precede COPD disease diagnosis , and others that are part of the COPD patient\u2019s systemic milieu and disease comorbidities . Based upon emerging evidence, preclinical models examining the potential of approaches targeting the mitochondrion and the aryl hydrocarbon receptor may be valuable in seeking new targeted therapies for treating and preventing adverse skeletal muscle impact in COPD patients."} +{"text": "There is a growing consensus on brain networks that it is not immutable but rather a dynamic complex system for adapting environment. The neuroimaging research studying how brain regions work collaboratively with dynamic methods had demonstrated its effectiveness in revealing the neural mechanisms of schizophrenia.To investigate altered dynamic brain functional topology in first-episode untreated schizophrenia patients (SZs) and establish classification models to find objective brain imaging biomarkers.Resting-state-functional magnetic resonance data for SZs and matched healthy controls were obtained(Table1).Power-264-template was used to extract nodes and sliding-window approach was carried out to establish functional connectivity matrices. Functional topology was assessed by eigenvector centrality(EC) and node efficiency and its time-fluctuating was evaluated with coefficient of variation(CV). Group differences of dynamic topology and correlation analysis between Positive and Negative Syndrome Scale(PANSS) scores and topology indices showing group differences, which also were used in establishing classification models, was examed.The CV of node efficiency in angular and paracingulate gyrus was larger in SZs. There are 13 nodes assigned into several brain networks displaying altered CV of EC between groups. Fluctuation of EC of the node in DMN, which was lower in SZs, showed negative correlation with PANSS total scores. Dynamic functional topology of above nodes was used to train classification models and demonstrated 80% and 71% accuracy for support vector classification(SVC) and random forest(RF), respectively.Dynamic functional topology illustrated a capability in identifying SZs. Aberrated dynamics of DMN relevant to severity of patient\u2019s symptoms could reveal the reason why it contributed to classification.No significant relationships."} +{"text": "Left ventricular rupture following prosthetic mitral valve replacement might be avoided by valve-sparing techniques and vigilance at the time of debridement to maintain or support annular integrity.See Article page 48.,DavidAlthough performing prosthetic MVR is not usual, few surgeons have had the misfortune of having to deal with LV rupture. Bright red blood emanating from the posterior pericardium upon separation from cardiopulmonary bypass following MVR is universally accompanied by a sinking feeling in the operator. Should an ill-prepared surgeon attempt lifting the heart to locate the bleeding source in this setting, the maneuver may prove fatal. As outlined by David,,Predispositions to this complication include female patients, a small LV cavity, advanced age, severe mitral annular calcification, and implantation of higher-profile bioprosthetic valves. Vigilance and patch correction at the time of annular debridement may avoid type 1 LV disruption, whereas avoiding deep debridement involving the papillary muscles can mitigate type 2 LV disruption. Posterior leaflet and total leaflet sparing MVR operations have nearly eliminated this complication.Greek mythological reference to Achilles' heel symbolizes that despite overall strength, a focal vulnerability may lead to downfall. Surgeons are well versed in the reproducible techniques of prosthetic MVR. Valve-sparing methods and adaptive strategies to address mitral annular calcification are the established necessary standards to avoid this potential vulnerability and circumvent this pitfall. Vigilance can often save patients from this often fatal problem."} +{"text": "The Building Our Largest Dementia (BOLD) Infrastructure for Alzheimer's Act (PL115-406) supports public health agencies to develop a uniform dementia infrastructure across the US. Applying a robust public health approach to ADRD that emphasizes data driven decision-making and action along with primary, secondary, and tertiary prevention strategies for persons living with dementia and their caregivers. Recipients of the BOLD Public Health Programs funds are expanding jurisdiction Dementia coalitions, updating, or creating Dementia Strategic Plans, and implementing strategies from those plans that address a wide variety of life-course strategies for brain health and dementia, including risk reduction. This presentation will explain how risk reduction is integrated and provide examples of several activities being planned and implemented by recipients."} +{"text": "Ectodermal dysplasias (ED) are inherited disorders involving congenital abnormalities of different ectodermal structures, the most prominent presentation being adontia/hypodontiaIn this article, we present a brief overview of several pediatric cases of ED with a short review of the odontological manifestations.We report several cases of children consulting in the pediatric department for abnormal teeth, with or without systemic manifestations.The clinical examination of these patients revealed insufficient and abnormal dentition, with rare beveled teeth and thin and rare hair, as well as eyelashes and eyebrows.Also, parents reported episodes of hyperthermia without sweating from an early age.Dental radiography confirmed the diagnosis of ectodermal dysplasia.Ectodermal dysplasias (EDs) are a group of various inherited disorders involving abnormal congenital development of at least two ectodermal structures . The management of these rare disabling conditions is still mainly symptomatic. The traditional removable prosthesis can be an option to replace missing teeth. However, implants provide the best long-term results and prognosis. In particular, dental implants are commonly used in oral reconstruction of ED patients, but long-term data on bone augmentation and bone resorption, aesthetic outcomes, and implant success are needed.in utero.EDs are a myriad of heterogeneous conditions encompassing several inherited embryopathies affecting teeth and other ectoderm-derived structures Diagnosis is essentially clinical, confirmed by radiology and genetics which can specify the causal mutation; treatment is mainly conservative."} +{"text": "This presentation will review the current state of knowledge about severe maternal perinatal mental illness. Severe disorders are associated with a higher prevalence of somatic difficulties during pregnancy, poorer quality of pregnancy follow-up and potential impairment of infant care. These children are therefore very vulnerable and require specific care. We will present how graduated care coordinated and above all integrated between psychiatry, obstetrics, neonatal pediatrics and child protection services allows for early and effective preventive interventions, both for the child\u2019s development and maternal mental health. The concept of shared parenting will be particularly developed.No significant relationships."} +{"text": "Editorial on the Research TopicDevelopmental origins of health and disease: Impact of preterm birthin utero environment that precipitates the early birth. Further, preterm birth has been associated with impaired structural and function development of organ systems in the offspring, thus making preterm birth a unique predisposing factor for adult disease scores, but late preterm birth mothers had even higher depressive symptoms; both of which may affect the care provided to their respective infants.\u201d Both Motte-Signoret et al. and Gonzales-Garcia et al. studied small for gestational age or intrauterine growth restricted (IUGR) infants. Motte-Signoret measured growth factor (GF), insulin growth factor 1 (IGF1), and insulin resistance in small for gestational age (SGA) infants. SGA infants demonstrated resistance to GF and IGF1 with insulin resistance. These findings could explain initial defects in early catch-up growth, risks for later catch-up growth, and higher prevalence of metabolic syndrome in later life. Gonzales-Garcia compared the Fenton 2013 growth charts to those from the International Fetal and Newborn Growth Consortium for the 21st Century (Intergrowth 21st) Project (IW-21) for assessing to intra-(IUGR) and extrauterine (EUGR) growth restriction in very low birthweight infants. There was concordance between the charts for IUGR growth trajectories but not for EUGR infants. The dynamic IW-21 was more restrictive but better predicted morbidities in EUGR infants.Reports on the negative effects of preterm birth included identifying predictors of severe necrotizing enterocolitis (NEC) and impaired neurodevelopmental outcomes and indicated that early identification of risk factors might ultimately lead to improved outcomes. Lin et al. sought to identify predictive indicators of necrotizing enterocolitis (NEC) by comparing biomarkers between NEC with portal venous gas (PVG) and NEC without PVG. C-reactive protein (CRP), fibrinogen degradation product, and blood glucose demonstrated predictive value for NEC-PVG. Current outcomes of the Neuroprem 2 cohort study were reported by Lugli et al. Out of 502 very preterm infants 9.6% had severe disability and 5.4% had cerebral palsy. Gestational age and periventricular hemorrhage were most highly associated with severe disability. Along these same lines, Wibowo et al. measured bone mineral content in newborns and found it lower in underdeveloped countries, higher in males, and negatively correlated with maternal cigarette usage. Hole et al. utilized a preterm piglet model to study early motor development. Preterm piglets took shorter steps than term piglets in early stages of walking but rapidly adapted with no differences within 3 days. Overall conclusions from the combined studies were that early interventions are needed to prevent later delays.Khasawneh et al. retrospectively analyzed determinates of late hospital discharge. The majority of all preterm births analyzed were late preterm infants. While several parameters such as gestational age and maternal and neonatal morbidities were correlated with length of stay , there was no correlation between length of stay after birth and later readmission.In summary, growth restriction and small birth weight can have permanent consequences on the metabolic health of the infant. Furthermore, the morbidities associated with preterm birth such as NEC, and motor and neurodevelopmental disabilities are likely to contribute to deficits in the quality of life once these infants reach adulthood. Prematurity and SGA should be considered overall risk factors for adult health and quality of life."} +{"text": "Understanding how trajectories of positive and negative affect relate to dementia risk and underlying structural brain variables is important for dementia prevention. We examined associations between annually assessed Positive and Negative Affect Scale subscales and dementia risk (2000-18) among cognitively-intact community-dwelling women from the Women\u2019s Health Initiative Study of Cognitive Aging (years 2000-2010) and Magnetic Resonance Imaging Study (2005-2006). Joint latent class mixture models were constructed to identify latent classes of women with similar trajectories of affect and dementia risk over time. Multinomial and logistic regressions examined whether structural MRI measures predicted latent class membership . Two latent classes of positive affect (high stable:88% and decreasing:12%) and four classes of negative affect were identified. With the high stable trajectory as referent, women with decreasing positive affect were more likely to develop dementia . The odds of being classified as this high-dementia risk group were increased among women with more (per SD) global small vessel ischemic disease , deep white matter SVID , and smaller parahippocampal volumes . For negative affect, with minimal stable negative affect as referent, women with smaller hippocampal volumes were more likely to be classified as having moderate decreasing negative affect while emerging negative affect was associated with higher dementia risk . These findings highlight the importance of changes in affect in later-life with dementia risk and potential underlying role of cerebrovascular disease and medial temporal lobe structures."} +{"text": "Adenoviruses are commonly used as efficient high-capacity vectors and excellent gene delivery vehicles. Their applications range from basic molecular research to gene therapy and recombinant viral vector vaccines. Adenoviral vectors are currently used in regenerative and cancer therapies, and as first-generation COVID-19 vaccines. Despite their widespread use and constant progress, various challenges and safety concerns still limit the application of adenoviral vectors to their fullest potential. Our Special Issue, \u201cNew Aspects of Adenoviral Vaccine Vectors and Adenoviral Gene Therapy\u201d, presents five excellent original research articles and reviews on adenoviral vector development, recent trends in adenovirus-mediated oncolytic therapies, and lessons learned from current large-scale adenoviral vector vaccination programs.An in-depth review article by Erwan Sallard and colleagues provides the latest insights into adenoviral vector design and reiterates lessons learned from adenovirus-based COVID-19 vaccines [A research article by Xiang Du and colleagues summarizes an in vivo proof of concept for a replication-competent adenovirus vector vaccine against a morbillivirus of veterinary importance . They shNora Bahlmann and colleagues contribute new data on improved adenovirus vectors for oncolytic and gene therapies . Their rA thorough review by Wen-Chien Wang and colleagues recapituPaola Blanchette and Jose Teodoro comprehensively review the characteristics of oncolytic adenoviruses that are currently undergoing clinical trials for cancer therapy . Their oThis collection of articles provides valuable new insights into various properties of adenoviral vectors in vaccine and gene therapy settings\u2014a topic that has been studied for decades but is more relevant than ever, as there have never been so many individuals injected with a recombinant adenovirus vector."} +{"text": "Communication is fundamental for dementia care and identifying evidence for strategies that facilitate or impede communication is needed. We analyzed 221 videos from a randomized controlled trial of a family caregiver telehealth intervention (FamTechCare) using Noldus second-by-second behavioral coding of communication behaviors and breakdowns in interactions between 53 caregiver-person with dementia dyads. Coded data from 3,642 30-second observations were first analyzed using penalized regression for feature selection to identify strategies most important for predicting prevention and successful repair of communication breakdown. Bayesian mixed modeling was then used to identify communication strategies associated with successful versus unsuccessful prevention and repair of communication breakdown taking into account of the dyadic structure of our data. Results showed that given our data, communication breakdown was associated with caregivers changing topic , ignoring , making commands and taking over the task . Successful repair of breakdown was associated with caregivers verbalizing understanding , tag questions, , and silence while ignoring and changing topic were associated with unsuccessful repair . These results provide evidence for development and testing of evidence-based communication strategy training for family caregivers of persons with dementia. Future analyses will identify effects of dementia stage, diagnosis, and dyad characteristics on associations."} +{"text": "Mycobacterium tuberculosis DNA present in their stool samples, which can augment current diagnostic gaps. Optimizing extraction of DNA from stool for analysis via sequencing technologies is a paramount initial step to ensure accuracy of downstream sequencing applications.Next generation sequencing (NGS) is quickly coming to the forefront of diagnostic tools to provide efficient, highly informative information from patient samples. Recently, it was established that patients with pulmonary Tuberculosis (TB) have Mycobacterium bovis derived from BCG were used as a model for Mtb. Human stool samples were spiked with varying known concentrations of BCG and extracted with four different DNA extraction kits . Each sample was subjected to quantitative polymerase chain reaction using designed primers and probes specific for identifying Mtb infection from stool. The samples underwent further analysis to assess overall DNA yield (Qubit fluorometer), DNA fragment length (Agilent tape measure), and DNA purity (Nanodrop spectrophotometer).Attenuated strains of Overall, the Fast DNA Spin Kit for Soil extraction kit showed the most optimal results. DNA isolated via this method showed the lowest cycle thresholds of Mtb amplification, indicating the most preserved amount of BCG specific DNA. In addition, this method showed the highest overall DNA yield and highest proportion of long DNA fragment lengths. Fluorometric analysis showed significant contamination in the 230 nm wavelength range, which was amended with an additional AMPure bead cleanup step.Quantiative PCR of Spiked BCGQuantitative PCR Cycle Threshold Values by Different DNA Extraction KitsThe MPFast Soil Extraction kit, when compared to three other DNA extraction kits, performed the best on stool samples for isolating BCG DNA. Overall DNA yield, DNA length, and amount of specific BCG DNA were best optimized with this method and provided the best samples for sequencing analysis. This critical step is the first of many to realize the promise of stool-based NGS.DNA QuantityQuantity of Total DNA by Different DNA Extraction KitsSpectrophotometric AnalysisAnalysis of Absorption of Extracted DNA by Different DNA Extraction KitsSpectrophotometric ResultsSpectrophotometry Results of DNA Samples Extracted by Different DNA Extraction KitsLennard A. Meiwes, n/a, German Center for Infection Research (DZIF): Grant/Research Support."} +{"text": "Inner strength is a person\u2019s internal process of moving through challenging circumstances, such as receiving a diagnosis of Mild Cognitive Impairment (MCI). This study describes experiences of inner strength using qualitative methodologies to identify themes within semi-structured dyadic and individual interviews with persons diagnosed with MCI within 12 months at a Memory Center and their care partners. We analyzed data in NVivo using reflexive thematic analysis methods. Trustworthiness was maintained through vetted interview guides, verbatim transcription, field notes, peer group analysis, and audit trails. One overarching theme and three subthemes explained inner strength. An overarching theme, Finding Ways to Live with It, described how participants live within the circumstances of MCI. Three subthemes were Defining Strength by Recalling the Past, Seeking Relief and Dwelling in It, and Finding Purpose & Meaning. Implications include supporting inner strength at the time of MCI diagnosis through reminiscence therapy and meaning making interventions."} +{"text": "There is growing interest in whether linked administrative data have the potential to aid analyses subject to missing data in cohort studies. We aimed to identify predictors of cohort non-response in linked administrative data and examine whether inclusion of these variables in principled methods for missing data handling can help restore sample representativeness.Using linked 1958 National Child Development Study (NCDS) and Hospital Episode Statistics (HES) data, we applied a multi-stage data-driven approach to identify HES variable which are predictive of non-response at the age 55 sweep of NCDS. We then included these variables as auxiliary variables in multiple imputation (MI) analyses to see if they helped restore sample representativeness in terms of early life variables which were essentially fully observed in NCDS and relative to external population data .We took as our starting point 57 variables derived from HES data based on the presence or number of different types of appointments/admissions, diagnostic codes and treatment codes. After application of our multi-stage data-driven approach we identified five HES variables that were predictive of non-response at age 55 in NCDS. For example, cohort members who had been treated for adult mental illness were almost 3 times as likely to be non-respondents . Inclusion of these variables in MI analyses did help restore sample representativeness. However, there was no additional gain in sample representativeness relative to analyses using only previously identified survey predictors of non-response (i.e. NCDS rather than HES variables).In our applications, inclusion of HES predictors of NCDS non-response in analyses did not improve sample representativeness beyond that possible using survey variables alone. Whilst this finding may not extend to other analyses or NCDS sweeps, it highlights the utility of survey variables in handling non-response."} +{"text": "The Art of WarRecent technological advances have expanded our understanding of how artificial stimulation interacts with the living nervous system . Song and Martin found that cathodal tsDCS can selectively target voltage-dependent calcium channels to modulate motoneuron activity, informing therapeutic treatment strategies to achieve rehabilitation goals after injury; in particular, to increase muscle force.Significant research efforts have focused largely on developing non-invasive or minimally invasive stimulation techniques in discriminating the MI condition from rest. Moreover, they showed that st-SES influences functional connectivity of the fronto-parietal network, but through different frequency bands for different subjects. These findings can potentially help to optimize guidance strategies to adapt to different types of MI-BCI users.In addition, motor imaginary (MI)-based brain-computer interface (BCI) must overcome multiple issues to be commercially usable, especially related to signal quality and subject-variation for severe treatment-resistant depression. Steele et al. proposed a fronto-medial ECT electrode placement that would maximize the EF in specific sagittal brain regions, whilst minimizing EF in sub-regions of the bilateral hippocampi. Such outcomes suggest electrode location can significantly reduce cognitive and non-cognitive side-effects.An optimal implantation region improves not only stimulation performance but also the long-term stability of implantable microelectrodes, as well as reducing side effects features and joint angles as inputs. A similar idea has been used historically in other neuromodulation fields since various stimulation parameters have been shown to evoke distinct neurological and physiological responses. Conversely, elicited physiological effects, both for targeted and untargeted neurons, can guide stimulus parameter tuning for many neural systems, including the brain et al. have proposed a new biophysical model of myelin ultra-structures by simulating cytoplasmic channels in the myelin sheath as a low-impedance route, while previous models approximate the myelin sheath as an insulation layer et al. further investigated how cytoplasmic channels affect EF across the myelin sheaths, concluding that the externally applied EF can control myelin growth. These new findings indicate the possibility of using electrical modulation to treat degenerative neural diseases. Neurodegenerative progression can affect the neuroprosthetic performance using a biophysically detailed computational model of the human cochlea (Bai et al., Electrical stimulation performance cannot be significantly improved by only optimizing the device in isolation without considering the biophysical complexity of the target nerve system (Abbasi and Rizzo, The Chinese characters shown in the Editorial refer to the origin of each subtitle in the ancient literature The Art of War by Sun Tzu.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "Adequate reproductive and maternal healthcare services utilization are significant in reducing maternal deaths, however, the prevalence rate of contraceptive use remains low, with inadequate maternal health services utilization among rural women in Nigeria. This study examined the influence of household poverty-wealth and decision-making autonomy on reproductive and maternal health services utilization among rural women in Nigeria.The study analyzed data from a weighted sample of 13,151 currently married and cohabiting rural women. Descriptive and analytical statistics including multivariate binary logistic regression were conducted using Stata software.An overwhelming majority of rural women (90.8%) have not used modern contraceptive methods, with poor utilization of maternal health services. About 25% who delivered at home received skilled postnatal checks during the first 2 days after childbirth. Household poverty-wealth significantly reduced the likelihood of using modern contraceptives , having at least four ANC visits , delivering in a health facility and receiving a skilled postnatal check . Women's decision-making autonomy regarding their healthcare significantly increased the use of modern contraceptives and the number of ANC visits, while women's autonomy on how their earnings are spent positively influenced the use of maternal healthcare services.In conclusion, the use of reproductive and maternal health services among rural women was associated with household poverty-wealth and decision-making autonomy. Government should formulate more pragmatic policies that will create awareness and promote universal access to reproductive and maternal healthcare services. In the context of global health priority, the levels of utilization of reproductive and maternal health services are parts of the indicators in measuring the level of healthcare performance, delivery system and developmental indices . The useMaternal healthcare including optimal ANC visits, delivery in a health facility and skilled postnatal check after delivery are significant mediations required during pregnancy and after childbirth for positive maternal and child health outcomes . AlthougIn sub-Saharan Africa, which Nigeria is part of, previous studies have shown the existence of urban-rural disparity in the use of maternal and reproductive health services by demonstrating that urban women tend to use modern contraceptives and maternal health services compared to rural women \u201314. NotwThis study examined household poverty-wealth and decision-making autonomy as predictors of reproductive and maternal health services utilization among rural women in Nigeria. The outcome is expected to provide up-to-date information, relevant policy and programmatic recommendations towards achieving sustainable development goals targets of universal access to quality reproductive and maternal health services; and reducing maternal and child deaths.The study utilized data obtained from the 2018 Nigeria Demographic and Health Survey (NDHS). The survey is a cross-sectional study and data were generated using standardized interviewer-administered questionnaires from a nationally representative sample of women aged \u201349 on soThe outcome variables selected for this study were based on empirical evidence which includes; 1) the use of contraceptive methods, 2) the number of ANC visits, 3) facility delivery services and 4) the postnatal check provider. Information on these outcome variables as generated from the 2018 NDHS was re-categorized from their original frequency ranges in the dataset. Therefore, women who used a modern contraceptive method, had at least four ANC visits during their most recent pregnancy, delivered in a public or private hospital and skilled postnatal check of a mother during the first 2 days after childbirth/before discharge from a doctor, nurse/midwife or auxiliary nurse/midwife were categorized as \u20181\u2019 and \u20180\u2019 if otherwise.The main explanatory variables in this study are household poverty-wealth and women's decision-making measures including the following three subjects: 1) decision on respondent's healthcare, 2) decision on large household purchases, and 3) decision on how to spend respondent's earnings. Therefore, women who made independent decisions on any of the three subjects represent decision-making autonomy and may influence seeking healthcare for themselves . In thisp<0.05 and measures of association were expressed as odds ratio with 95% confidence intervals.Data analysis was conducted with Stata software (version 15) at univariate, bivariate and multivariate levels. The dataset was carefully checked for missing values which were excluded and weighted with the appropriate sampling weights as per the Demographic and Health Survey sampling scheme. At the bivariate level, unadjusted logistic regression as shown in Description of the study population: The weighted descriptive statistics of the women as presented in Reproductive and maternal healthcare services utilization: Unadjusted and bivariate analysis: The unadjusted and bivariate results as presented in p<0.05. However, except for employment status and health insurance coverage, all the main explanatory variables and other covariates are significantly associated with receiving postnatal care from a skilled provider during the first 2 days after childbirth at p<0.05.Adjusted multivariate analysis of the utilization of reproductive and maternal healthcare services by explanatory variables: The adjusted logistic regression analysis results presented in This study examined the influence of household poverty-wealth and decision-making autonomy on reproductive and maternal health services among rural women in Nigeria. The findings of this study revealed that despite the efforts in encouraging the use of modern contraceptive methods, the prevalence of modern contraceptives among rural women is still alarmingly low corroborating different studies in Congo and EthiThe findings further revealed that rural women found in poor households were less likely to use modern contraceptive methods relative to those in rich households. This corroborates previous studies in sub-Saharan Africa including Nigeria that the poverty-wealth dimension in rural areas is a big factor contributing to the lack of modern contraceptive use \u201331. AlsoThis study showed that rural women's decision-making autonomy regarding their healthcare is a significant predictor of using modern contraceptive methods and having at least four ANC visits during pregnancy. The findings corroborate previous studies that women who can make independent decisions on their reproductive health were more likely than those whose husbands solely made such decisions to use modern contraceptives , 35 and The findings of this study further confirmed an observation that younger women were less likely to use modern contraceptives compared to their older counterparts . PlausibIn conclusion, this study found that the prevalence of modern contraceptives is still alarmingly low, while optimal ANC visits during pregnancy and delivery in health facilities are poorly utilized among rural women. Some rural women who delivered at home subsequently sought skilled medical attention from health facilities. Generally, reproductive and maternal health services utilization were negatively influenced by household poverty-wealth. Women's decision-making autonomy regarding their healthcare and earnings are significant predictors of reproductive and maternal health services utilization. There is a need for some unified skilled postnatal home-visit services outside health facilities through linkages with healthcare providers. Also, the government should formulate more pragmatic policies that will create awareness, educate and promote adequate reproductive and maternal healthcare services utilization among disadvantaged women.The study has some limitations including the use of secondary data from a cross-sectional study which restricts study variables. As a result, the cause-effect association between the explanatory and outcome variables is rather temporary and may not be ascertained. However, the findings are essential for the formulation of more pragmatic policies geared toward achieving universal access to reproductive and maternal healthcare services."} +{"text": "Previous research has demonstrated that self-concealment of sexual orientation may negatively affect the wellbeing of lesbian, gay, and bisexual (LGB) adults . Additionally, studies have indicated that internalized homophobia significantly predicts depressive symptoms in LGB older adults . The present study examined how internalized homophobia may mediate the predictive relationship between self-concealment on depression symptoms in LGB older adults. As part of a larger study, participants (Nf301) responded to several questions and measures including the Sexual Orientation Self-Concealment Scale, The Internalized Homophobia Scale, and the Center for Epidemiological Studies Depression Scale. Using the Baron and Kenny\u2019s Method for Mediation (1986), the data analysis indicated that internalized homophobia fully mediates the relationship between self-concealment and depression severity (ps < .05). These results suggest that older adults who self-conceal their sexual orientation may experience an increase in depressive symptoms because of internalized homophobias. These findings may help clinicians better understand the mechanisms contributing to the high rates of depressive symptoms within the older LGB population. Furthermore, the findings suggest that cognitive restructuring of thoughts related to internalized homophobia and self-concealment may improve depressive severity in older LGB adults."} +{"text": "Molecular Cancer, Wang and his colleagues have now placed seven types of tumors in a unified analytic framework [Circular RNAs (circRNAs) are a subgroup of single-stranded endogenous RNAs which exert differential expression pattern between normal and cancerous tissues and function as important regulators in cancer initiation and progression. However, comprehensive characterization of circRNA landscape across cancer types is still lacking. In a recent article published in ramework , all wit, demonstrating circLIFR may serve as a therapeutical target in metastatic cancer. Consistently, the RNA-seq results suggested the ability of circLIFR to alter the expression pattern of some metastasis-related genes involved in cell adhesion and epithelial-mesenchymal transition (EMT). Collectively, this study by Wang et al. certainly illustrates the comprehensive circRNA profiles in multiple solid tumors and highlights the potential of circRNAs as important diagnostic tools or therapeutic targets.Through rRNA depleted transcriptome sequencing, the authors identified a total of 59,056 circRNAs, the majority of which were lowly expressed, while a subset of circRNAs exhibited much higher abundance than their cognate linear transcripts, indicating their biological significance in homeostasis. Using stringent criteria, the authors pictured the distinct circRNA expression signatures among seven types of solid tumors. The dysregulated circRNAs exhibited cancer-specific expression or shared common expression pattern across cancers, implying their diverse functions in cancer progression and their diagnostic potential in multiple cancers. Among the aberrant circRNAs, circLIFR showed an overall downregulation in tumors. Significantly, circLIFR was experimentally validated as a bona fide circRNA which inhibited tumor metastasis in vitro and in vivo"} +{"text": "The derivative was shown to be non-toxic and safe, upon consumption position in polysaccharides led to the development of various molecules exhibiting remarkable inhibition against anti-HSV in vitro derived from a herbaceous perennial plant Radix Cyathulae officinalis Kuan demonstrated dramatic viral inhibition after phosphorylation as compared to unphosphorylated RCPS . Intereal., 2010). Anotheal., 2017). This hin vitro . An in-in vitro and has been shown to be effective against HPV by direct binding to viral capsomeres and further downregulating PI3K/Akt/mTOR pathway on the cell surface. In an attempt to investigate this behavior, 3,6 O sulphated chitosan was explored al., 2018 [This isal., 2020 [This isal., 2020 [This isal., 2020; Woo et al., 2020). in vitro, and in vivo along with promising clinical trials are needed for better outcomes. Since future viral outbreaks are quite predictable, it is important to design a non-immunogenic, non-toxic and targeted drug delivery system to effectively deliver polysaccharide based antviral drugs to the infected population without any serious side effects and quicker recovery. The benevolent nature, biocompatibility, ease of availability, low cost and non-toxic profile of polysaccharides, claim their anti-viral potential with enhanced therapeutic response. The development and discovery of polysaccharide-based drugs, antibodies and vaccines may prove beneficial in arresting episodes confronted during acute respiratory distress syndrome, particularly in COVID 19 pneumonia. Chemical modification further ameliorates the challenges faced with unmodified polysaccharides. In fact, a combination of chemically modified polysaccharides and anti viral therapeutics, with a change in route of administration may play a decisive role in combating pandemics and epidemics. In a time where viral genome sequencing has unraveled sophisticated molecular pathways responsible for the survival of viruses, genomic epidemiology along with microfluidics can also play a crucial role in mapping evolutionary behaviour and understanding the virulent nature of mutating strains. Despite significant advances in the use of polysaccharides as excipients in recent years, the exact mechanism of viral interaction and signaling pathway is not clear. This necessitates delving into high throughput screening strategies for these dangerous viral infections for tangible patient outcomes. In fact, an amalgamation across different pharma sectors along with the latest AI tools can fully leverage the antiviral potential of polysaccharides. Identifying potent biomarkers may also help, design polysaccharide-based anti-viral drug candidates to further gain an in-depth understanding and dynamics of infection.Polysaccharides can be future candidates for mitigating viral infections, but more Rabab Fatima, Parteek Prasher and Kamal Dua contributed equally.The authors declare no conflict of interest."} +{"text": "This article outlines the evolving definition of rejection following kidney transplantation. The viewpoints and evidence presented were included in documentation prepared for a Broad Scientific Advice request to the European Medicines Agency (EMA), relating to clinical trial endpoints in kidney transplantation. This request was initiated by the European Society for Organ Transplantation (ESOT) in 2016 and finalized following discussions between the EMA and ESOT in 2020. In ESOT\u2019s opinion, the use of \u201cbiopsy-proven acute rejection\u201d as an endpoint for clinical trials in kidney transplantation is no longer accurate, although it is still the approved histopathological endpoint. The spectrum of rejection is now divided into the phenotypes of borderline changes, T cell-mediated rejection, and antibody-mediated rejection, with the latter two phenotypes having further subclassifications. Rejection is also described in relation to graft (dys)function, diagnosed because of protocol (surveillance) or indication (for-cause) biopsies. The ongoing use of outdated terminology has become a potential barrier to clinical research in kidney transplantation. This article presents these perspectives and issues, and provides a foundation on which subsequent articles within this Special Issue of Transplant International build. The approved histopathological endpoint for clinical trials of kidney transplantation is the presence or absence of biopsy-proven acute rejection (BPAR) . This enOver time, the spectrum of rejection has broadened, with distinctions made between two major subtypes: T cell-mediated rejection (TCMR) and antibody-mediated rejection (AMR) . Deeper Furthermore, the strategy of performing protocol biopsies in the early years following transplantation has been adopted by several European centers, to detect subclinical rejection and guide ongoing patient management . It has \u2022 Suspicious (borderline) for acute TCMR (henceforth simplified to \u201cborderline changes\u201d)\u2022 Acute TCMR \u2022 Chronic active TCMR (caTCMR)\u2022 Acute/active antibody-mediated rejection (aAMR)\u2022 Chronic antibody-mediated rejection (cAMR)\u2022 Chronic active antibody-mediated rejection (caAMR).The classification of allograft rejection has often been modified over the years, such that six histological rejection phenotypes are widely described , 6:\u2022 SusBorderline changes represent less severe inflammation scores than aTCMR. The threshold of inflammation used for diagnosis of borderline changes varies among centers, because between 2005 and 2017 the Banff Classification stated that retaining the i1 threshold for borderline changes with tubulitis (t) > 0 was permitted . In addiIn the 1990s, a diagnosis of aTCMR was based on a clinical definition and/or a clinicopathological definition , 13. TheThe impact of inflammation in atrophic areas (i-IFTA) on graft outcomes has been widely demonstrated , 14\u201316, per se. The response of caTCMR to increased doses of immunosuppressive therapy has not been studied function. Protocol (surveillance) biopsies are performed, per definition, at the time of stable graft function to detect subclinical inflammation . IndicatFinally, although molecular diagnostics of kidney transplant rejection has been validated prospectively in a multicentric fashion and is cESOT has come to the following conclusions:\u2022 The use of BPAR as an endpoint for clinical trials in kidney transplantation is no longer accurate.\u25cb Using outdated and/or non-specific definitions, such as BPAR, compromises the future of high-quality clinical research, especially for interventions that are targeted at one rejection subtype.\u2022 Kidney transplant rejection should be classified by its phenotypes\u2014borderline changes, TCMR, and AMR (the two latter having subtypes), and in relation to the nature of graft (dys)function .\u2022 The CHMP acknowledged that histological subclassifications of rejection have evolved during the last decade.\u2022 The CHMP agreed that the histological subtype of rejection is a useful specification and noted that this detailing might be very informative in profiling efficacy of immunosuppression.\u2022 The CHMP commented that the reason for undertaking a protocol or indication biopsy should be taken into consideration when defining endpoints for clinical trials."} +{"text": "Crop domestication is a co-evolutionary process that has rendered plants and animals significantly dependent on human interventions for survival and propagation. Grain legumes have played an important role in the development of Neolithic agriculture some 12,000\u2009years ago. Despite being early companions of cereals in the origin and evolution of agriculture, the understanding of grain legume domestication has lagged behind that of cereals. Adapting plants for human use has resulted in distinct morpho-physiological changes between the wild ancestors and domesticates, and this distinction has been the focus of several studies aimed at understanding the domestication process and the genetic diversity bottlenecks created. Growing evidence from research on archeological remains, combined with genetic analysis and the geographical distribution of wild forms, has improved the resolution of the process of domestication, diversification and crop improvement. In this review, we summarize the significance of legume wild relatives as reservoirs of novel genetic variation for crop breeding programs. We describe key legume features, which evolved in response to anthropogenic activities. Here, we highlight how whole genome sequencing and incorporation of omics-level data have expanded our capacity to monitor the genetic changes accompanying these processes. Finally, we present our perspective on alternative routes centered on de novo domestication and re-domestication to impart significant agronomic advances of novel crops over existing commodities. A finely resolved domestication history of grain legumes will uncover future breeding targets to develop modern cultivars enriched with alleles that improve yield, quality and stress tolerance. Domestication refers to an evolutionary process causing remarkable changes in plant morphology and physiology in response to the selection pressures created by anthropogenic activities . The proPisum sativum L.), faba bean (Vicia faba L.), lentil (Lens culinaris L.), grass pea (Lathyrus sativus L.) and chickpea (Cicer arietinum L.) are some of the world\u2019s oldest domesticated crops and arose in the Fertile Crescent of Mesopotamian agriculture. These legumes accompanied cereal production and formed important dietary components of early civilizations in the Middle East and the Mediterranean (Glycine max L.) and adzuki bean (Vigna angularis L.) accompanied cultivation with rice (Oryza sativa L.) in China, whereas domestication of common bean (Phaseolus vulgaris L.) and cowpea (Vigna unguiculata L.) occurred in Andes/Mesoamerica and sub-Saharan Africa, respectively. Other pulse crops such as pigeonpea (Cajanus cajan L.), mungbean (Vigna radiata L.) and urdbean (Vigna mungo L.) were domesticated in India and barley (Hordeum vulgare), along with the grain legume crops such as pea and lentil. Wheat and barley were claimed to be originated in slightly drier, open parkland steppes along with wild grasses, while pulse crops including lentil, pea, chickpea and Vicia spp. originated in the clearings of nearby woodlands and rocky talus slopes , it has been suggested that soybean domestication occurred simultaneously at multiple sites to its current status as a South Asian and spring-sown Mediterranean crop has become a standard approach to study crop domestication and evolution. Linkage disequilibrium (LD) encompasses alleles at two or more loci having non-random association, and patterns of LD decay reflect recombination rates in the population. For instance, resequencing of 302 soybean accessions including wild, landraces and breeding lines revealed the extent of LD decay , with wiGenome sequencing of multiple accessions has revealed a loss of genetic diversity in breeding improved cultivars in different grain legume crops. For instance, the genome sequencing of pea and Pigeonpea revealed the most diverse single nucleotide polymorphisms (SNPs) in wild accessions in comparison to landraces and cultivars . The genC. reticulatum has early domesticated into desi type (common in South Asia and sub-Saharan Africa), whereas kabuli (common in West Asia and Mediterranean regions) were subsequently derived involved in snare membrane traffic, wound-inducible protein and an amino acid transporter and PAVs but lower CNVs as compared to kabuli . These f derived . The rolnsporter . Similartication . CNVs artication .FLP, MYB12) as the adaptive changes during shifting environments influencing the two key flowering-related genes SOC1 and FT. The growing sequence data on whole genomes of diverse accessions will likely enrich the knowledge about the genetic underpinnings of the plant phenotypes that were changed during domestication and improvement of grain legume crops.The genomic evolution rate profiling (GERP) score reveals the genomic regions that remain evolutionarily constrained (GERP\u2009>\u20090) and indicates purifying selection, such as 29 Mb in chickpea and 237.ronments . In commronments . With a ronments . The stuThe potential of CWRs and landraces has been historically recognized for supplying new genetic variation to plant breeding programs . The valCWRs often encounter broad and contrasting environmental conditions across their native range. Over evolutionary time, these exert differential selection pressure that leads to the formation of specifically adapted ecotypes. Drought is one of the main abiotic stresses acting in the Mediterranean and Middle East region, where progenitors of many cultivated crops occur and have to cope with water availability during the vegetation period.CWRs provide a key to counteract the effects of climate change on the world\u2019s food supply. To fully understand and exploit this process, studies in the geographical centers of origin are needed that combine ecology, physiology and genetics. With modern genomics tools, geospatial analysis combined with systematic phenotyping, it is highly desirable to revisit wild accessions and prioritize their use for breeding tolerance to various stresses. In particular, some local adaptations found in CWRs might maximize fitness in specific habitats, especially in the current climate change context .Environmental conditions such as soil salinity, cold and drought stress represent a major constraint on agricultural productivity. Water availability is a primary factor controlling the distribution of vegetation over the earth\u2019s surface. Crop yields are more dependent on an adequate supply of water than on any other single factor, and environmental stress represents the primary cause of crop yields losses . Many otGmCHX1-conferring salt tolerance to wild soybean G. soja (Lens odemensis and Lens tomentosus) were identified as displaying tolerance to drought (Arachis duranensis) maintains a relatively high rate of transpiration and photosynthesis rate under dehydration treatment mapping revealed a novel gene- G. soja . Similar drought , and ada drought . Reduced drought . Variati drought , and roo drought . Similarreatment . Adaptivreatment , where treatment . Wide vareatment . Recent ted crop .rhg1 and Rhg4 have been identified from wild soybean controlling resistance against the soybean cyst nematode (SCN), which is one of the major threats limiting soybean production and drought was evident in a recent research (AsECHI) from Arachis stenosperma reduced the infection rate by 30% as well as accelerating post-drought recovery. In pigeonpea, CWRs are known to possess resistance against a variety of biotic and abiotic stresses encompasses features that are absent in the wild progenitors or \u2018differentially\u2019 manifested in cultivated species, such as changes in seed retention, seed size, inflorescence and plant architecture and flowering synchronization. There is an ongoing debate about the number of domestication events and centers for a given crop. Two domestication centers have been reported for common bean: Central America and the Andes , and potGmHs1-1, encoding a calcineurin-like metallophosphoesterase transmembrane protein, was found to influence seed coat permeability in soybean gene was implicated in seed coat permeability in common bean , and this gene not only represses Dt1 that prevents terminal flowering but also activates genes that promote flowering is common and well conserved in legumes and cereals and pea (Dpo) demonstrated it to be a monogenic trait; however, later several QTLs affecting this trait were also discovered underlying flowering time are also known to affect flowering in soybean in order to promote flowering. In course of narrow-leaf lupine domestication, this requirement has been removed and widely exploited by plant breeders to develop early-flowering varieties of L. angustifolius. It has been shown that the loss of vernalization requirement in narrow-leaved lupin is associated with a deletion in the promoter and de-repressed expression of a Flowering Locus T (FT) homolog , encoding a dirigent-like protein expressed in the sclerenchyma of differentiating endocarp and modulating the mechanical properties of the pod through lignin biosynthesis (C. arietinum ICC 4958\u2009\u00d7\u2009C reticulatum ICC 17160) and intra- (ICC 4958\u2009\u00d7\u2009C. arietinum ICC 8261) specific recombinant inbred lines revealed major QTL for flowering time in chickpea (GI (GIGANTEA) ortholog during chickpea domestication through conferring flowering time adaptation.In the legumes, single locus control of pod dehiscence was found in lentil , pea We and chicynthesis . Table 2chickpea . Like otchickpea , pea and seed length (AhDPB2) , 62 SNPs showed association with frost tolerance and provided superior haplotypes associated with the frost damage (A genome-wide association study (GWAS) is an alternative approach to associate genomic variations with domestication phenotypes in diverse germplasm collection. GWAS of 203 accessions combined with transgenic and RNA-Seq experiments in groundnut facilitated the identification and validation of genes for seed weight ((AhDPB2) . Likewis(AhDPB2) and a to(AhDPB2) . By usint damage . The cont damage and PAV t damage in soybet damage correspot damage . Other Gt damage and commt damage and flowt damage , pod indt damage , pod mort damage and seedt damage in commot damage . The stuC. reticulatum supported its contribution to early phenology, crucial to transitioning from winter to summer crop led authors to report a significant loss of diversity during domestication, and most of the diversity (87%) was found in the wild than G. max . Decades of research have enlightened the impact of SVs in crop evolution and agricultural adaptations. Compared to SNPs, SVs can directly alter the genic expression by modifying the copy number and can cause large-scale perturbations of cis-regulatory regions (CHS) gene expression in yellow soybean and Arachis kempff-mercadoi ICG 8164\u2009\u00d7\u2009Arachis hoehnei ICG 8190), respectively , and the QTL analysis identified 42 potential QTL governing significant PVs for plant growth habit, height, plant spread and flower color (P. fulvum or P. elatius) in the genetic background of P. sativum offer a valuable resource for genetic research and breeding by using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) editing of key domestication loci such as fas, lc, CLV3 , an orphan Solanaceae crop, showed the potential of CRISPR\u2013Cas9 editing for de novo domestication by altering one was achieved by Vigna stipulacea.V. stipulacea, resulting in the recovery of mutants with notable reductions in seed dormancy and pod shattering. Given the species-rich legume family, there is large potential to domesticate novel legume crops for both human food and animal feed. This effort has been recently demonstrated in hairy vetch (Vicia villosa) . Anothervillosa) , these pvillosa) .While legume CWRs have not yet been subjected to de novo domestication, several traits that could be targeted in these species spring to mind. Perhaps the first of these is seed shattering, which in e.g. common bean as in ceThe process of redomestication represents an important opportunity for cultivated species to adapt to new ecotype. Besides de novo domestication that could deliver entirely new crops, the wild species or existing crops can be redomesticated by changing the artificial selection pressures toward plant traits catering to future requirements . At the Since the beginning of agriculture, grain legumes have been important ingredients as protein complement sources to starch-rich cereal diets. The domestication of cereal crops has been intensively researched, resulting in the identification and cloning of domestication genes. In recent years, carbonized remains and genetic studies have helped establishing the role of grain crops in old as well as new world agriculture. A very recent example of this is the identification of a WD40 gene as being important in the domestication of grain yield in both rice and maize with a wide range of other genes putatively also following this trend . As suchDomestication of cereals and grain legumes has shown different trajectories as exemplified from the time lines of grain size enlargement . GeneticIndeed, we are convinced that combined evidence from archeobotanical, pangenomes, multi-omics science and cultural shifts will enlighten future crop improvement strategies to rapidly develop modern cultivars of grain legume crops. That said, this will be no easy task and will certainly require both multi-disciplinary and multi-national approaches; however, in principle, the necessary technologies are all in hand and studies concerning the adaptation of our major crops to novel environments will undoubtedly help in efforts to create a more sustainable global agriculture that is more resistant to extreme climacteric events.pcac086_SuppClick here for additional data file."} +{"text": "Curricular intervention studies have examined if instruction in aging and gerontology affects undergraduates\u2019 attitudes, knowledge, and perceptions towards older adults. However, less is known about curricular impact on undergraduates\u2019 intentions to work with older adults. By identifying factors that increase undergraduates\u2019 intentions to work with older adults we may elucidate meaningful points of intervention to enhance pursuit of careers in the geriatric workforce. The current study examined baseline data from a longitudinal study examining the impact of an upper-level adult development psychology course on student attitudes towards working with older adults. It was hypothesized that there would be positive associations between attitudes towards working with older adults, knowledge about aging, and positive attitudes towards older adults. Participants were 19 undergraduate students enrolled in upper-level undergraduate psychology courses. Participants completed validated, self-report questionnaires related to their attitudes towards working with older adults, ageism attitudes, and attitudes and knowledge about aging. Bivariate correlation analyses were used to examine cross-sectional associations among main outcome variables. More positive explicit attitudes towards older adults were significantly associated with more willingness to work with older adults . Additionally, knowledge of aging was positively correlated with perceived social norms around working with older adults . These initial findings suggest that knowledge and positive attitudes about aging may positively impact attitudes towards working with older adults. Future work will assess curricular impact on undergraduates\u2019 intentions to work with older adults, as well as evaluate predictors of change in intentions."} +{"text": "Transcatheter aortic valve replacement (TAVR) has transformed the treatment of aortic stenosis and should ideally be performed as a totally percutaneous procedure via the transfemoral (TF) approach. Peripheral vascular disease may impede valve delivery, and vascular access site complications are associated with adverse clinical outcome and increased mortality. We review strategies aimed to facilitate TF valve delivery in patients with hostile vascular anatomy and achieve percutaneous management of vascular complications. Minimally-invasive transcatheter aortic valve replacement (TAVR) has supplanted surgical aortic valve replacement (SAVR) as the preferred mode of treatment in the majority of patients with severe aortic stenosis ,2. The tFailure of vascular closure devices (VCD) to achieve access site hemostasis following valve implantation and sheath removal may lead to severe bleeding, as well as limb ischemia . PercutaCalcified, stenosed and tortuous ileofemoral arteries characterize patients with \u201chostile\u201d vascular anatomy and may impede valve delivery and increase susceptibility to vascular injury during TAVR. In such patients, SAVR may potentially enable valve replacement without the need for instrumentation of the peripheral vasculature. However, patients with peripheral vascular disease often have co-morbidities which are associated with increased surgical risk and may therefore benefit from percutaneous valve delivery. Alternative vascular access approaches were developed in order to enable TAVR in patients with hostile vascular anatomy in whom TF valve delivery was considered technically challenging. No randomized trials have compared these different approaches; however, the TF route is considered the least invasive. The aim of the present review is to summarize novel techniques which may facilitate totally percutaneous TF valve delivery.Peripheral vascular disease (PVD) is common in patients referred for TAVR ,12, and Vascular calcification ,24,25, tUse of VCD to achieve hemostasis decreases wound complications and duration of hospitalization compared to surgical cut-down ,31,32,33Early detection and rapid management of VC is crucial. Manual compression may achieve hemostasis in cases of minor access site bleeding, and protamine sulfate may be safely administered to reverse anticoagulation . Severe Percutaneous management of VC and vascular repair may be facilitated by placement of a 0.014\u2033 300-cm length \u201csafety\u201d wire within the femoral artery prior to puncture of the primary vascular access site . The safety wire is delivered via a secondary vascular access site and is uThe contralateral femoral artery was traditionally used for secondary vascular access in TF TAVR procedures. Alternative secondary access sites include the ipsilateral distal branches of the femoral artery ,41,42, rThe CFA is subject to repetitive stress and flexion at the hip joint. Implantation of balloon-expandable stents within the CFA is unsafe due to risk of stent fracture, compression, restenosis and branch occlusion ,47. NitiStents grafts (SG), which are covered with impermeable membranes such as polytetrafluoroethylene, may be used for excluding vascular tears and perforations and maintaining arterial integrity. Balloon-expandable SG, which were previously used for endovascular repair of iatrogenic vascular injury , have beStents were implanted in 10\u201324% of patients undergoing TF TAVR and achieved hemostasis in 98\u2013100%. During follow-up, the stents maintained near-universal patency with a low rate of asymptomatic strut fracture. Anecdotal data suggests that repeat vascular access and deployment of a VCD may be possible within a vessel that was previously treated by SG implantation . A liberThe CFA should be punctured at least 1 cm above the bifurcation in order to enable SG implantation without compromising outflow to the superficial femoral artery or profunda. Decision to implant SG is usually made following sheath removal, when control angiography reveals evidence of VCD failure. Long sheaths may be used for SG delivery; however, they require upsizing of the secondary vascular access . Alternatively, SG may be delivered by a sheathless technique in order to minimize vascular trauma at the secondary access site. Stent grafts are typically delivered antegradely, from the contralateral femoral artery . Alternatively, ipsilateral distal vascular access within the superficial femoral artery or profunda ,41,42 anPre-procedural assessment of the femoral artery anatomy may show that the vascular anatomy is unsuitable for deployment of a VCD. In some patients, attempts to perform pre-closure with a suture-based VCD at the beginning of the TAVR procedure, prior to sheath insertion, may fail. Performing TF TAVR despite the inability to utilize a VCD may necessitate surgical vascular repair of the femoral artery. Patients at increased risk for complications of vascular surgery may benefit from a percutaneous method for achieving access site hemostasis following valve implantation and sheath removal. We assessed the feasibility of a strategy of planned stent graft implantation within the femoral artery for achieving access site hemostasis in a cohort of patients undergoing TF TAVR, in whom vascular pre-closure was not possible 60]..60].These patients were considered at increased risk for complications of vascular surgery due to advanced age, frailty, co-morbidities, or immobility. Stent graft implantation achieved access site hemostasis in all patients. During follow-up, 30-day mortality was zero, one-year mortality was 27%, and none of the patients required additional vascular interventions.Recent evolution of techniques and devices for treating severely diseased ileofemoral occlusive vascular disease, as well as novel strategies for utilizing SG for management of access site vascular complications, offer the opportunity to expand the role of totally percutaneous TF TAVR to patients with PVD . A systematic approach to procedural planning and management of vascular complications increases the likelihood of procedural success .Development of TAVR systems with lower device profiles, as well as novel VCD designs with improved efficacy, may expand the role of TF TAVR and decrease the need for alternative vascular access in patients with hostile vascular anatomy."} +{"text": "Mitochondria regulate numerous cellular processes including metabolism, gene expression, motility and migration, as well as cell division, repair and death. Due to their ability to dynamically remodel, distribute throughout the cell, and interact with other organelles, mitochondria can perform its functions by acting locally or globally. The field of mitochondrial dynamics has thus grown from simple textbook observations of a static \u201ckidney-bean\u201d like energy producing structures to an organelle that works by dynamically changing its architecture and association with other organelles. The importance of the dynamic mitochondrial network and how integral it is to cellular function is highlighted by a growing list of diseases associate with defects in this process . This ReYu et al.). These data identify selective binding dynamics of DRP1 adapter proteins to explain their non-overlapping roles in DRP1 recruitment to mitochondria in healthy cells that gets disrupted in disease caused by the loss of adaptor proteins to mitochondria by adaptor proteins . In theiproteins .2+ mobilization from ER to mitochondria. This was supported in cells from patients carrying OPA1 GTPase or GED domain mutations. Their study substantiates the role of OPA1 in modulating ER-mitochondrial coupling and shows even when mutant and WT OPA1 proteins are present together in patient cells, ER-mitochondrial Ca2+ homeostasis is disrupted, contributing to autosomal dominant optic atrophy .Unlike DRP1-mediated outer mitochondrial membrane (OMM) fission, Optic atrophy-1 (OPA1) regulates inner mitochondrial membrane (IMM) dynamics, mutations in which leads to dominantly inherited optic neuropathy that causes vision loss . Both OMBonjour et al. examined how the mitochondrial ultrastructure changes during mouse eosinophil maturation and in inflammatory disease. They performed high-resolution mitochondrial ultrastructure analysis using transmission electron microscopy (TEM) and 3D tomography. This uncovered a reduction in mitochondrial area by 70% during eosinophil development that was attributed to increases mitophagy in immature eosinophils. They show that mitochondria form extensive contacts with other mitochondria and cellular organelles at a higher frequency in immature versus mature eosinophils. During asthma-induced inflammation, mitochondrial cristae remodeling occurs and mitochondrial contacts with granules increases. This highlights cell-specific mitochondrial ultrastructure remodeling that is responsive to increased inflammation, expanding the growing body of work highlighting mitochondrial ultrastructural changes in immune cell activity.Complimenting the mechanistic studies of mitochondrial shape change, Willingham et al. review subcellular specialization of mitochondrial structure and function in skeletal muscle and how plasticity of these mitochondrial features regulates function and physiological adaptations of skeletal muscle . The review by Pangou and Sumara explore the connection between mitosis and cell division by discussing the regulation of mitochondria by mitotic machinery and how in turn mitochondrial function and inheritance regulates mitosis. They discuss the mitochondrial dynamics during mitosis and how its dysregulation is linked to diseases (Pangou and Sumara 2022). The discussion of mitochondrial involvement in cell division is also covered by Madan et al., who examine this for polarized epithelium and how mitochondrial dynamics and metabolism play a role during epithelial-mesenchymal transition and cell migration for wound healing, inflammatory responses and tissue remodeling . Extending this discussion to the pathological condition of tumor metastasis, Boulton and Caino have explored how the molecular mechanisms of mitochondrial dynamics affect the growth, metabolism, and invasiveness of tumor cells. They discuss how mitochondrial fission machinery regulates growth factor and ROS signaling that drive metastasis through regulation of tumor cell and its microenvironment (Boulton and Caino. 2022).Expanding on the Original Research, Review Articles included in this Research Topic provide a comprehensive overview of contributions of mitochondrial dynamics to various physiological functions. In their minireview, Together the primary research articles and reviews collected in this Research Topic highlight how control over the mitochondrial spatial, temporal and structural changes drive cell-type specific signaling, to support cellular function in healthy and diseased states. We thank the authors for their contributions and expert insights, the collection of which in this Research Topic will add new insights into the growing recognition of mitochondrial dynamics and its subcellular architecture in driving diverse physiological processes."} +{"text": "As working family caregivers navigate work and care responsibilities, the work environment may contribute to their psychological well-being and physical health outcomes. Working caregivers who provide multi-generational care experience greater vulnerability when compared to non-sandwiched caregivers . This vulnerability could be mitigated by supportive work characteristics . Informed by the life course perspective, this study compared the psychological well-being and physical health of working sandwiched and filial caregivers, and the moderating role of work characteristics (decision authority and supervisor support). Sandwiched and filial caregivers from the Midlife in the United States (MIDUS-II) Survey provided information about their background, caregiving, employment, well-being, and health via a set of questionnaires and phone interview. Regression analyses showed that sandwiched caregivers exhibited lower levels of generativity than filial caregivers. Moderation analyses revealed that sandwiched caregivers with greater decision authority trended toward exhibiting greater autonomy than other caregivers. Sandwiched caregivers with greater decision authority also exhibited significantly less difficulty with instrumental activities of daily living (IADLs) than other caregivers. Finally, sandwiched caregivers with greater than average supervisor support trended toward exhibiting higher level of generativity as compared to other caregivers. Results highlight the impact of sandwiched caregiving on autonomy, generativity, and IADLs in the context of decision authority and supervisor support. Findings may inform workplace programs and policies aimed at enhancing caregivers\u2019 sense of decision making and increasing supervisor support in order to promote caregivers\u2019 psychological well-being and physical health."} +{"text": "Automatically synthesizing consistent models is a key prerequisite for many testing scenarios in autonomous driving to ensure a designated coverage of critical corner cases. An inconsistent model is irrelevant as a test case ; thus, each synthetic model needs to simultaneously satisfy various structural and attribute constraints, which includes complex geometric constraints for traffic scenarios. While different logic solvers or dedicated graph solvers have recently been developed, they fail to handle either structural or attribute constraints in a scalable way. In the current paper, we combine a structural graph solver that uses partial models with an SMT-solver and a quadratic solver to automatically derive models which simultaneously fulfill structural and numeric constraints, while key theoretical properties of model generation like completeness or diversity are still ensured. This necessitates a sophisticated bidirectional interaction between different solvers which carry out consistency checks, decision, unit propagation, concretization steps. Additionally, we introduce custom exploration strategies to speed up model generation. We evaluate the scalability and diversity of our approach, as well as the influence of customizations, in the context of four complex case studies. Motivation. The recent increase in popularity of cyber-physical systems (CPSs) such as autonomous vehicles has resulted in a rising interest in their safety assurance. Since existing tools and approaches commonly represent CPSs as (typed and attributed) graph models )."} +{"text": "Lower extremity ischemia due to extrinsic arterial compression by venous stent placement is a rare but increasingly recognized occurrence. Given the rise of complex venous interventions, awareness of this entity is becoming increasingly important to avoid serious complications.A 26-year-old with progressively enlarging pelvic sarcoma despite chemoradiation developed recurrent symptomatic right lower extremity deep venous thrombosis due to worsening mass effect on a previously placed right common iliac vein stent. This was treated with thrombectomy and stent revision, with extension of the right common iliac vein stent to the external iliac vein. During the immediate post-procedure period the patient developed symptoms of acute right lower extremity arterial ischemia including diminished pulses, pain, and motorsensory loss. Imaging confirmed extrinsic compression of the external iliac artery by the newly placed adjacent venous stent. The patient underwent stenting of the compressed artery with complete resolution of ischemic symptoms.Awareness and early recognition of arterial ischemia following venous stent placement is important to prevent serious complication. Potential risk factors include patients with active pelvis malignancy, prior radiation, or scarring from surgery or other inflammatory processes. In cases of threatened limb, prompt treatment with arterial stenting is recommended. Further study is warranted to optimize detection and management of this complication. Lower extremity ischemia due to extrinsic arterial compression by adjacent venous stents is a rare occurrence. Given the rise of complex venous interventions, awareness of this entity is becoming increasingly important to avoid serious complications including amputation. This case report describes a patient with pelvic sarcoma who developed lower extremity ischemia after the external iliac artery became compressed by an adjacent venous stent. Existing literature including risk factors and potential mechanisms are highlighted.A 26-year-old with progressively enlarging spindle cell sarcoma of the right pelvis despite multiple rounds of systemic and radiation therapy developed deep venous thrombosis and pulmonary embolism due to mass effect on the right iliac vein. This was treated with mechanical thrombectomy, inferior vena cava (IVC) and bilateral kissing common iliac vein stents, as well as initiation of therapeutic anticoagulation. The patient responded well until approximately two months after the procedure, where he presented to the emergency department with 1\u00a0week of worsening lower extremity swelling and pain. Physical exam was notable for diffuse pitting edema of the right lower extremity. Although the swelling limited mobility, there were no focal motor or sensory deficits. The extremity was warm and well perfused with 2\u2009+\u2009doppler signals from the popliteal, posterior tibialis, and dorsalis pedis arteries. The left lower extremity was normal.Right lower extremity ultrasound demonstrated acute deep venous thrombosis of the common femoral vein extending to the calf veins. Computed tomography (CT) venogram demonstrated thrombus throughout the right iliac vein and IVC stents with compression of the external iliac vein by the enlarging pelvic mass Fig.\u00a0. Given tWhile in the interventional radiology suite, posterior tibial vein access was obtained to infuse alteplase and perform venography, which demonstrated flow-limiting thrombus extending from the right popliteal to the common iliac vein. There was minimal flow to the IVC with extensive filling of collaterals Fig.\u00a0. The popWhile in the recovery unit, the patient\u2019s leg appeared mottled. Bedside doppler revealed diminished signals in the right popliteal, posterior tibialis, and dorsalis pedis arteries. After approximately 4\u00a0h the patient reported pain, decreased sensation to the dorsum of the foot, and impaired motor movement of the toes and ankle.A CT angiogram was performed, demonstrating high grade narrowing right external iliac artery adjacent to the newly placed right external iliac vein stent Fig.\u00a0. There wThe patient returned to interventional radiology for arterial angiography. The left common femoral artery was accessed and a 7 French destination sheath was advanced proximal to the right external iliac artery. Angiogram demonstrated severe focal narrowing along the right external iliac artery adjacent to the external iliac vein stent Fig.\u00a0. Two ovePost-procedure, there was return of 2\u2009+\u2009doppler signals throughout the right lower extremity. The previously noted acute motor and sensory deficits resolved. In addition to continuing therapeutic lovenox, the patient was started on 75\u00a0mg of clopidrogel daily to maximize arterial stent patency. The patient experienced significant improvement of lower extremity swelling and pain. Comfort care measures were ultimately pursued given progression of cancer.There has been a growing interest in complex venous interventions, owing to device improvements and increasing evidence to support catheter-based therapies for appropriately selected patients (Vedantham et al. Early recognition of this entity is important, as long-term sequelae from untreated limb ischemia can be devastating. One report describes the need for transfemoral amputation and subsequent issues with wound healing which required additional surgery (Trinidad et al. In almost all published cases where ischemia was detected early, endovascular stenting of the compressed artery was effective for revascularization. We thus recommend angiography and stenting as the primary initial therapy. Since delayed diagnosis can have serious morbidity, there should be a low threshold to bring the patient to the angiography suite. If the situation is not emergent and the clinical picture is unclear, CT angiogram can be considered to rule out other potential causes of ischemia, such as hematoma or distal thromboembolism. Vascular surgery should also be engaged early if there is suspicion for compartment syndrome or the need for open revascularization (Filtes et al. Although the risk factors for this phenomenon have not been rigorously studied, there are common themes within the published literature. Case reports have described this complication among patients with active pelvic malignancy, previously irradiated fields, prior pelvic surgeries, or other inflammatory processes (Filtes et al. While there is no clear trend, use of certain stents may contribute to the occurrence of this complication. Case reports have described this complication in the presence of both covered and uncovered stents, as well as self-expanding and balloon-expandable stents (Filtes et al. This complication was also observed when using Viabahn self-expandable stents during a similar case at our institution, as well in another case report (Subramaniam et al. The most frequently reported location of arterial compression after iliocaval stenting is the external iliac artery (Filtes et al. This case report raises the question of whether routine assessment of lower extremity arterial supply should be performed prior to any iliac vein intervention. In our case, checking pulses prior to our venous intervention was valuable for rapidly diagnosing an arterial problem, since a dramatic loss of arterial doppler signal should not occur after a venous intervention. Since this is easy to perform, we recommend routine perioperative pulse checks for patients who undergo complex venous interventions. Intra-procedural pulse-oximetry monitoring of the toes may also be useful to quickly assess for decreased arterial perfusion and guide whether immediate angiography should be performed (Kwasnicki et al. Although severe stenosis may manifest with clinically overt signs of threatened limb, more subtle effects of ischemia may go undiagnosed or misattributed to other etiologies, such as post-thrombotic syndrome. Thus, more objective assessments of arterial perfusion using non-invasive vascular studies including ABIs, PVRs, and doppler ultrasound should be considered in high risk patients. Rigorous peri-procedural evaluation of patients with peripheral artery disease or diabetes may also be beneficial to identify subclinical cases of decreased arterial perfusion, so that future issues with wound healing can be minimized. Ultimately, more research is warranted to effectively diagnose and manage this complication.Extrinsic arterial compression secondary to venous stent placement is a rare but increasingly recognized complication following iliac vein stenting. Potential risk factors include patients with active pelvis malignancy, prior radiation, or scarring from surgery or other inflammatory processes. In cases of threatened limb prompt treatment with arterial stenting is recommended minimize serious long-term sequelae. Further study is warranted to optimize detection and management of this complication."} +{"text": "Persons with newly diagnosed Alzheimer\u2019s disease and related dementias (ADRD) and their care partners confront multiple challenges. These challenges have been even greater during the COVID-19 pandemic, where supportive resources often are limited or even discontinued. We conducted semi-structured interviews with 21 care partners of persons who were recently diagnosed with ADRD (2019-2020) to explore their lived experiences of adjusting to the new role. Directed and conventional content analyses were used and were informed by the life course theory. Care partners perceived difficulty in accessing medical and social services for their loved ones, particularly during the pandemic. Despite experiencing distress, some care partners chose not to seek help for fear of contracting COVID-19. This study provides insights on the unmet needs of care partners during a pandemic and highlights that effective, long-term strategies are needed to continue providing person-centered care to persons with ADRD and their families."} +{"text": "Treatment of acute ischaemic stroke (AIS) focuses on rapid recanalisation of the occluded artery. In recent years, advent of mechanical thrombectomy devices and new procedures have accelerated the analysis of thrombi retrieved during the endovascular thrombectomy procedure. Despite ongoing developments and progress in AIS imaging techniques, it is not yet possible to conclude definitively regarding thrombus characteristics that could advise on the probable efficacy of thrombolysis or thrombectomy in advance of treatment. Intraprocedural devices with dignostic capabilities or new clinical imaging approaches are needed for better treatment of AIS patients. In this review, what is known about the composition of the thrombi that cause strokes and the evidence that thrombus composition has an impact on success of acute stroke treatment has been examined. This review also discusses the evidence that AIS thrombus composition varies with aetiology, questioning if suspected aetiology could be a useful indicator to stroke physicians to help decide the best acute course of treatment. Furthermore, this review discusses the evidence that current widely used radiological imaging tools can predict thrombus composition. Further use of new emerging technologies based on bioimpedance, as imaging modalities for diagnosing AIS and new medical device tools for detecting thrombus composition in situ has been introduced. Whether bioimpedance would be beneficial for gaining new insights into in situ thrombus composition that could guide choice of optimum treatment approach is also reviewed. Occlusion of a cerebral artery by a thrombus results in acute ischaemic stroke (AIS). Treatment of AIS aims to recanalise the occluded artery, promptly and efficiently, either by intravenous thrombolysis via recombinant tissue plasminogen activator (r-tPA) or mechanical removal of the thrombus via endovascular thrombectomy (EVT). In most countries, less than 15% of AIS patients are able to avail r-tPA treatmentUntil recently, there was limited availability of the thrombi that cause strokes. Available samples were mainly limited to occasional postmortem tissue and the clots removed in the course of thrombectomy device clinical trials. Since the success of clinical trials demonstrating effectiveness of mechanical thrombectomy in AIS patients with large vessel occlusions, more occluding thrombi removed during EVT procedures are available for analysis, allowing us to gain insights into thrombus composition.Perhaps the most characteristic feature of AIS thrombi retrieved by thrombectomy is the marked heterogeneity observed. A range of studies have described gross characteristics such as size, shape, morphology, consistency .Using H&E staining, AIS thrombi can be broadly classified into three subtypes, RBC rich, fibrin rich, or mixed. H&E staining cannot differentiate between fibrin and platelets. Nonetheless, using H&E staining, initial studies found that the composition of AIS thrombi is highly variable .6\u201310et al demonstrated that MSB staining can reliably identify platelet-rich areas.Some studies have employed Martius scarlet blue (MSB) staining, which provides better differentiation between fibrin and platelet components.CD42b immunohistochemical staining was used to study the platelet organisation within thrombi. Platelets were observed covering the fibrin layers, located at the periphery of RBC-rich arteriogenic thrombi or were clustered within fibrin rich cardioembolic thrombi.Activated neutrophils release histones and granule proteins embedded in web-like assembly of DNA filaments called neutrophil extracellular traps (NETs), for killing pathogens. Recent data have shown that NETs actively take part in thrombus formation by interacting with RBCs, platelets and platelet adhesion molecules such as fibronectin, fibrinogen and vWF, aiding formation of the thrombus scaffold with fibrin meshwork.Although rare, occasionally AIS thrombi have components found in atherosclerotic plaques such as calcification, cholesterol crystals and arterial wall components.Other methods such as scanning electron microscopy (SEM), atomic force microscopy, fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy have also recently been used to study AIS thrombi.The TOAST classification categorises ischaemic stroke based on aetiology into five subtypes: (1) large-artery atherosclerosis (LAA), (2) cardioembolism (CE), (3) small-vessel occlusion, (4) stroke of other determined aetiology and (5) stroke of undetermined aetiology/cryptogenic.The composition and structural arrangement of a thrombus, is governed by the local haemodynamic conditions during clot formation.Several studies have suggested that cryptogenic strokes are primarily cardiogenic in origin, based on histological analysisIt has been also observed that extent of WBCs in AIS thrombi can varyThrombus composition can influence the efficacy of thrombolysis by r-tPA. Previous research has shown that RBC-rich thrombi respond better to r-tPA than platelet-rich or white thrombi.A recent study that investigated arrangement of thrombus components speculated that RBC-rich areas which have thin fibrin arrangements might be most prone to degradation by r-tPA.SEM has advanced understanding of the characteristics of thrombolysis-resistant clot which was shown to have a thick, compact outer shell made of densely compacted thrombus components including fibrin, vWF and aggregated platelets and this made the thrombi less susceptible to thrombolysis.et al did not find any correlation of thrombus components with recanalisation after EVTThrombus composition may play an important role in successful removal of thrombus via EVT. A study by Ahn The mechanical characteristics of thrombi are related to composition. An in vitro study with clots prepared from human blood found that thrombi with RBC content of 20% or above have increased viscosity and elasticity compared with clots with low RBC content.Higher WBC percentage in thrombi has been shown to negatively correlate with recanalisation and clinical outcome such as National Institutes of Health Stroke Scale (NIHSS) score at discharge and modified Rankin Scale score upto 90 days.et al found a trend suggesting the presence of vascular wall components was associated with lesser recanalisation success.Calcified emboli are quite rare in AIS patients with large vessel occlusions, but when present, calcification is associated with poor recanalisation and higher mortality.Patients have the best outcomes after EVT if the entire thrombus is retrieved in a single pass.AIS thrombus can be identified by CT and MRI. However, studies investigating the association of thrombus imaging with recanalisation have largely utilised CT imaging . CT is mIsodense clots on non-contrast CT (NCCT) correlate with a high fibrin/platelet content and are more resistant to thrombolysis and EVT.The vessel sign observed on gradient eco imaging (GRE) in AIS patients is called SVS. The SVS on GRE imaging is defined as a hypointense signal that spreads outside the actual thrombus periphery. The SVS is observed in 50%\u201385% of AIS patients with large vessel occlusion, particularly in RBC rich thrombus, while a lack of SVS usually suggests presence of fibrin-rich thrombus .35Thrombus permeability or perviousness is the degree to which blood is able to flow through a thrombus structure. Thrombus perviousness is the residual flow that is quantified using simultaneous measurement of thrombus attenuation on NCCT and single-phase CT angiography, called \u2018thrombus attenuation increase\u2019 (TAI). Increased perviousness gives high TAI.Imaging characteristics such as HAS and SVS have been linked to stroke aetiology. Some single centre studies have correlated SVS with cardioembolic aetiology in AIS.The prognostic value of SVS for recanalisation is debatable. SVS has been variously shown to be a negative predictor of early recanalisation after IV r-tPA treatmentThrombus permeability is potentially an important predictor of AIS treatment. It has been associated with better functional outcome, smaller final infarct volume, and higher recanalisation following IA r-tPA or IV r-tPA.Imaging techniques are the best way of visualising thrombus in situ, and the only way to visualise thrombi in in vivo environments. In the case of thrombi dissolved by r-tPA or thrombi not retrieved via EVT, clot imaging is the only resource for characterisation. While post thrombectomy analysis of clot composition is very valuable to improving our understanding, EVT can damage or cause structural changes in the thrombus during the removal procedure.Intraprocedural devices with dignostic capabilities or new clinical imaging approaches are needed for better guidance of device selection prior to EVT.Biological tissues possess electrical properties and these properties are dependent on morphological, physiological and pathological conditions of the tissue and the frequency of the applied electrical signal.The bioimpedance measured with applied alternating current varies with the frequencyElectrical Impedance Spectroscopy (EIS) is carried out by measuring the electrical impedance of biological tissues over a frequency range. Since the electrical response of tissues is determined by their cellular components and the dimension, internal structure and arrangements of the constituent cells, tissues with different morphological and physiological properties give rise to characteristic impedance spectra.Based on EIS principles, clinical applications have been developed, especially in the field of oncology. SciBase, Dilon Technologies, Zilico, are some of the companies that developed medical devices with CE and/or FDA (US Food and Drug Administration) approval. These devices can discriminate healthy tissues from cancerous tissues with high sensitivity and specificity.et al demonstrated that based on EIS measurements, blood clot analogues can be classified into RBC rich or platelet and fibrin rich clots.EIS-based sensors are being developed for blood components such as WBCsSome studies have also demonstrated the feasibility of utilising balloon catheters mounted with microelectrodes for EIS measurements. The integration of four microelectrodes onto a catheter is made possible using a flexible and ultralight polyimide foil. Using such a system in atherosclerotic animal models, intravascular EIS measurements differed significantly in aortic plaques compared with normal aortic tissues.In recent years, mechanical thrombectomy has facilitated the analysis of thrombi retrieved during the EVT procedure and marked heterogeneity has been observed. Restricted availability of thrombi other than ones found in LVOs that are easily retrievable limits the current knowledge of AIS thrombi. Further studies will improve understanding of aetiology and its correlation to thrombus composition and clinical outcome. New emerging methods such as EIS, could be beneficial for gaining new insights into pathophysiological mechanisms of thrombus formation and identifying clot characteristics in situ in the acute care setting, aiding in selection of better treatment options for the AIS patients."} +{"text": "Subjective age has traditionally been considered by comparing felt age to chronological age, with those who feel younger reporting more adaptive developmental outcomes. Here we consider a new approach: subjective age discordance, which compares felt ages to the ideal ages of participants. Across eight study days, 116 older and 107 younger adults reported their daily felt and ideal ages. On the majority of days, both older and younger adults idealized ages younger than they felt. The opposite pattern, idealized ages older than felt ages, was rare and primarily seen in younger adults. Days when felt ages were less discordant from ideal ages were characterized by higher levels of positive affect than days with greater subjective age discordance. These findings suggest that positive developmental outcomes can occur not only from feeling younger, but through a greater alignment of ideal and felt ages."} +{"text": "Pressure overload hypertrophy of the left ventricle is a common result of many cardiovascular diseases. Androgens show anabolic effects in skeletal muscles, but also in myocardial hypertrophy. We carefully reviewed literature regarding possible effects of androgens on specific left ventricular hypertrophy in pressure overload conditions excluding volume overload conditions or generel sex differences. Pressure overload hypertrophy (POH) of the left ventricle is a common result of diseases like arterial hypertension, aortic valve stenosis, hypertrophic obstructive cardiomyopathy or aortic coarctation and is associated with increased morbidity and mortality \u20134. Thus,via the enzyme 5 alpha reductase (via androgen receptors (AR), but DHT shows twice the affinity for the AR and a ten-fold more potent effect on signalling pathways when compared to Testosterone (Testosterone in the human body is mainly produced by the gonads (by the Leydig cells in testes in men and by the ovaries in women) and in smaller amounts by the adrenal glands in both sexes. Conversion to DHT takes place eductase . Both hoosterone . Both hoosterone . In humaosterone , 16. Totosterone . A thirdosterone .via androgen receptors (AR) and induce myocardial hypertrophy via two different ways: 1) in a DNA binding-dependent manner (genomic pathway) where androgens bind to the AR, translocate into the nucleus and act like a transcription factor or 2) in a non-DNA binding-dependent manner where androgens bind to the AR and activate rapid 2nd messenger signalling cascades, for example . Next to low serum levels of DHT these patients showed low degree of left ventricular muscle mass despite severe aortic valve stenosis and pressure overload . Our finData from animal studies and the few existing human data suggest that anti-androgenic therapy has the potential to improve cardiac function and remodelling in heart failure and to reduce or prevent cardiac hypertrophy in pressure overload conditions. Next to the detrimental pro-hypertrophic cardiac effects, Testosterone replacement therapy has been associated with prostate cancer, polycythemia and obstructive sleep apnea and many long-term effects are still unknown , 45. ThuOn the other hand, excessive reduction of serum androgen levels should be prohibited, especially in male patients. Very low levels of Testosterone in elderly men with Testosterone deficiency have been associated with increased cardiovascular risk and mortality and positive cardiovascular effects have been described for Testosterone replacement therapy in these patients \u201349. TestThe study situation currently remains controversial and future studies are required to determine, whether and if yes what kind of anti-androgenic therapy might be a treatment option at least for time-restricted therapy in patients with severe AS waiting for surgical or interventional relieve of pressure overload.Testosterone and/or its active metabolite DHT increase the hypertrophic response of left ventricular myocardium to pressure overload in animal models and associations were seen in human subjects. Anti-androgenic treatment to lower Testosterone and/or DHT levels should be discussed as a possible treatment option to reduce cardiac hypertrophy; however, possible negative effects of low serum levels of Testosterone onto vascular and metabolic health have to be taken into consideration. Future studies should focus on cardiac-specific anti-androgenic therapy in order to prevent myocardial hypertrophy in pressure overload conditions without negatively affecting general patient health in women and men.All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication."} +{"text": "There is literature describing unilateral or focal pulmonary edema due to mitral regurgitation. The proposed mechanism is a regurgitant jet propelling blood towards the orifice of a particular pulmonary vein within the left atrium, which selectively pressurizes that vein. The increased hydrostatic pressure is transmitted to the pulmonary capillaries that drain into that vein, causing focal consolidation. A 62-year-old female presented with acute hypoxic respiratory failure. Her dyspnea started suddenly and she was unresponsive when she arrived at the emergency department via emergency medical services. Her initial oxygen saturation was 23% and she was immediately intubated. Sequential chest radiographs demonstrated dense consolidation in the right upper lung field and then opacification of the right hemithorax. These asymmetric lung findings were suspicious for infectious etiology but she was afebrile with no respiratory secretions and had normal inflammatory markers. Echocardiography showed a ruptured anterior papillary muscle causing a flail mitral valve leaflet with severe mitral regurgitation. The patient developed cardiogenic shock; she had an intra-aortic balloon pump placed for afterload reduction and was taken to the operating room for an emergency mitral valve replacement. Her clinical status rapidly improved and she made a full recovery. As in this case, acute mitral regurgitation can present with sudden life-threatening respiratory failure and cardiogenic shock so prompt diagnosis is critical. This is often misdiagnosed as pneumonia or other respiratory illnesses. Awareness, early diagnosis, and treatment of this entity could provide significant morbidity and mortality benefits for patients. Shortness of breath is a common chief complaint seen in the emergency department and carries a broad differential diagnosis. Chest radiography, a valuable and commonly used tool, can help clinicians narrow differential diagnoses and provide appropriate patient care. Unilateral infiltrates on chest radiography, often seen in bacterial pneumonia, may evoke an infectious etiology of dyspnea. However, focal or unilateral pulmonary edema has been described in patients with mitral regurgitation from numerous causes, including spontaneous valve perforation , valve pA 62-year-old female presented to the emergency department with acute respiratory failure. Her past medical history included obstructive sleep apnea with the use of bilevel positive airway pressure at night, obesity hypoventilation syndrome, systemic hypertension, pulmonary hypertension, mild to moderate mitral regurgitation complicated by pulmonary edema, asthma, and the use of home oxygen . A transthoracic echocardiogram performed five months before the presentation during hospitalization for dyspnea showed normal biventricular size and function, mild left atrial dilation, normal mitral valve structure with mild to moderate regurgitation, and a mildly elevated pulmonary artery systolic pressure. A chest radiograph performed one month before the presentation showed no evidence of pulmonary edema. Her home medications included furosemide, losartan, inhaled fluticasone and vilanterol, promethazine syrup, nebulized albuterol, and benzonatate.Per the patient\u2019s husband, she was in her normal state of health until awakening in the morning and feeling short of breath after using the restroom; the shortness of breath was refractory to albuterol nebulizer treatments self-administered at home for a presumed asthma exacerbation. At that time, she appeared to have labored breathing, prompting the patient and her husband to call emergency medical services (EMS). In the ambulance, she was initially alert and awake with a normal mental status but suddenly became unresponsive; her oxygen saturation dropped to 20% and her heart rate increased to 160 beats per minute. She arrived at the emergency department via EMS, unresponsive, with an oxygen saturation of 23% and sinus tachycardia; initial examination revealed diffuse rhonchi and a Glasgow Coma Scale (GCS) score of six. She was immediately intubated; she required high ventilator settings (fraction of inspired oxygen (FiO2) at 100%, positive end-expiratory pressure (PEEP) at 16 mbar), and neuromuscular blockade to achieve adequate oxygenation.Initial chest radiography demonstrated mild cardiomegaly, background interstitial pulmonary edema, and a dense consolidation in the right upper lobe with a patchy opacity at the right lung base. Figure .A subsequent chest radiograph showed nearly complete opacification of the right hemithorax and progressive opacification of the left lung base Figure .These asymmetric lung findings were suspicious for an infectious etiology, including coronavirus disease 2019 (COVID-19) and bacterial pneumonia. She tested negative for COVID-19 . She had a mild leukocytosis without neutrophilic predominance, and inflammatory markers were not consistent with severe infection confirmed severe mitral regurgitation and showed a ruptured anterior papillary muscle Figure .The TEE showed severe systolic flow reversal in the right upper pulmonary vein and only mild systolic flow reversal in the other three pulmonary veins. Figure\u00a0The pulsed-wave Doppler images demonstrate pulmonary vein flow reversal, noting the highest degree of flow reversal in the right superior pulmonary vein Figures -9.She was taken to the operating room for emergent bioprosthetic mitral valve replacement. Afterward, her clinical status improved; she began to void, her pulmonary artery pressures were corrected, and she was extubated 72 hours after the presentation. Subsequent chest radiography showed rapid resolution of the asymmetric infiltrates Figure .This was a dramatic presentation of spontaneous, non-ischemic papillary muscle rupture, causing severe acute mitral regurgitation and respiratory failure from the resulting flash pulmonary edema. The patient was critically ill within one to two hours of symptom onset. Of particular interest is the initial chest radiograph showing asymmetric opacification with dense consolidation of the right upper lobe. This appearance was initially concerning for an infectious etiology, which could have delayed the diagnosis.Focal or unilateral pulmonary edema has been described in patients with mitral regurgitation from numerous causes, including spontaneous valve perforation , valve pSchnyder et al. found that 9% of patients with severe mitral regurgitation had chest radiography findings that were \"localized or predominant\" in the right upper lobe . Attias There is a proposed mechanism for localized pulmonary edema due to mitral regurgitation. Typically, systolic or diastolic left ventricular failure leads to increased pressure within the left atrium, which is transmitted symmetrically to each of the pulmonary veins. This leads to increased hydrostatic pressure within pulmonary capillaries, causing a uniform degree of pulmonary edema throughout the lungs. It is thought that asymmetric pulmonary edema is due to a mitral regurgitant jet that propels blood selectively towards the orifice of a particular pulmonary vein within the left atrium. If a regurgitant jet causes increased pressure within that pulmonary vein, it would transmit increased hydrostatic pressure selectively to the pulmonary capillaries that drain into that pulmonary vein, causing focal edema.This mechanism is supported by Kashiura et al., who described two cases of unilateral pulmonary edema from severe acute mitral regurgitation. The first case involved an eccentric jet blowing towards the right side of the left atrium and a patient who presented with right-sided opacities. The second case involved a jet blowing towards the left side of the left atrium and a patient who presented with left-sided opacities . In thisAs in this case, acute mitral regurgitation can present with sudden life-threatening respiratory failure and cardiogenic shock, so prompt diagnosis is critical. This is often misdiagnosed as pneumonia or other respiratory illnesses. Patients with unilateral lung opacification due to mitral regurgitation have delays in diagnosis and worse outcomes compared to similar patients with bilateral pulmonary edema. In this case, the key to the diagnosis was the reported history of sudden-onset dyspnea that rapidly progressed to respiratory failure.In conclusion, acute mitral regurgitation should be considered in the differential diagnosis for patients with focal pulmonary opacities or complete opacification of a hemithorax in the appropriate clinical context, such as sudden-onset hypoxic respiratory failure, especially if vitals, examination, and laboratory biomarkers are inconsistent with severe infection. Awareness, early diagnosis, and treatment of this entity could provide significant morbidity and mortality benefits for patients. In this case, the findings support the previously proposed mechanism of a regurgitant jet selectively pressurizing a pulmonary vein, leading to focal consolidation."} +{"text": "It is often challenging to engage and retain rural Latinx and Native Americans in psychosocial interventions after stroke, despite the fact that these populations tend to experience poorer health outcomes. Although strategies for effective patient-provider communication exist, few studies focus on the cultural aspects of engagement and retention of diverse dyads in a rural context. The aim of this study is to describe barriers to engagement and retention of diverse rural dyads in post-stroke psychosocial interventions, as well as to elucidate specific strategies to address these barriers. Semi-structured interviews were conducted with Nf14 clinical providers with extensive experience serving diverse rural couples and families. Qualitative data were analyzed using interpretive description methods. Seven key barriers were identified, grouped broadly into: 1. Those presented by providers and 2. Those existing within dyads themselves . Providers offered specific culturally-informed strategies to overcome barriers which in turn may increase engagement and minimize attrition. Providers and researchers may benefit from these insights as they work to communicate with, build trust, and meet the unique needs of these populations."} +{"text": "More specifically, they found that university students are more likely to update beliefs concerning grade expectations following positive rather than negative prediction errors.Behavioral results suggest that learning by trial-and-error relies on a teaching signal, the prediction error, which quantifies the difference between the obtained and the expected reward. Evidence suggests that distinct cortico-striatal circuits are recruited to encode better-than-expected (positive prediction error) and worst-than-expected (negative prediction error) outcomes. A recent study by Villano et al. Virtually all animals use past rewards and punishments to modify their future course of actions (a process referred to as reinforcement learning). Behavioral and computational theories suggest that reinforcement learning relies on a teaching signal, the prediction error (PE), which quantifies the difference between the obtained and the expected reward. PE minimization across trials and repetitions enables to efficiently learn and adapt their behavior accordingly.2. A direct implication of these neurobiological observations is that learning from positive and negative PEs could be independently modulated at the behavioral level3.Neurophysiological studies across rodents, monkeys and humans collectively suggest that reinforcement learning processes are largely underpinned by dopamine-mediated neural plasticity of the cortical-subcortical connections and that positive and negative PEs are encoded across dissociable circuits that recruit different cortical and subcortical structures of the brainUntil recently, however, prior studies were carried out in relatively constrained and \u201caseptic\u201d experimental settings. Most of the tasks employed implemented quite artificial learning scenarios, which potentially casts doubt on the ecological and real life validity of these findings.1 has overcome this limitation by investigating how humans integrate positive and negative PEs when updating their belief concerning consequential real life outcomes. More specifically, in a large scale study, they asked 625 university students to predict their grades during four consecutive semesters.A recent study from Villano et al.At the macroscopic level, participants learned to modify their expectations concerning future grades in a manner compatible with prediction error minimization. However, a more fine-grained analysis showed signs that could be considered as an \u201coptimistic\u201d bias: on average participants learned more following positive as opposed to negative PEs. The results support the idea of distinguishable neural networks for positive and negative prediction errors by showing an optimistic bias manifesting at the behavioral level.4.The authors also report that participants who presented symptoms consistent with anxiety and depression, also showed a reduction in optimistic learning bias. This finding is consistent with prior evidence showing similar learning rate modifications in depression and anxietyAltogether, this study provides evidence for prediction error-based learning outside of the laboratory, in real life scenarios. It also provides evidence for the fact that learning from positive and negative prediction errors are functionally dissociable. Both findings are consistent with decades-long neurobiological investigations of the computational mechanisms underlying reinforcement learning."} +{"text": "Certain neuropsychiatric symptoms (NPS), namely apathy, depression and anxiety demonstrated great value in predicting dementia progression representing eventually an opportunity window for timely diagnosis and treatment. However, sensitive and objective markers of these symptoms are still missing.To investigate the association between automatically extracted speech features and NPS in early-stage dementia patients.Speech of 141 patients aged 65 or older with neurocognitive disorder was recorded while performing two short narrative speech tasks. Presence of NPS was assessed by the Neuropsychiatric Inventory. Paralinguistic markers relating to prosodic, formant, source, and temporal qualities of speech were automatically extracted, correlated with NPS. Machine learning experiments were carried out to validate the diagnostic power of extracted markers.Different speech variables seem to be associated with specific neuropsychiatric symptoms of dementia; apathy correlates with temporal aspects, anxiety with voice quality and this was mostly consistent between male and female after correction for cognitive impairment. Machine learning regressors are able to extract information from speech features and perform above baseline in predicting anxiety, apathy and depression scores.Different NPS seem to be characterized by distinct speech features which in turn were easily extractable automatically from short vocal tasks. These findings support the use of speech analysis for detecting subtypes of NPS. This could have great implications for future clinical trials.No significant relationships."} +{"text": "To protect themselves from contracting the SARS-CoV-2 virus, many older adults managing multiple medical conditions experienced increased social isolation. The objective of our qualitative research study was to describe how older Veterans receiving care from the United States (US) Department of Veterans Affairs (VA) healthcare system, and their caregivers, managed increased social isolation during the pandemic. We recruited Veterans and their caregivers residing in rural and urban areas who received care from either a tele-palliative care or a tele-geriatrics clinic connected to one VA Medical Center, inviting them to participate in phone interviews. From May-September 2021, we interviewed N=23 participants (n=9 Veterans and n=14) caregivers. We applied a deductive and inductive approach to thematic analysis to analyze interview data. Findings revealed that while caregivers experienced increased anxiety, which they attributed to pandemic-related changes, they also expressed solidarity in that others were experiencing similar stressors. Many caregivers and Veterans shared experiences of increased loneliness, which some found difficult to manage as communication with their social networks was sparse. At the same time, the pandemic made them value relationships with others more than before. Some Veterans noted they kept busy with hobbies and did not feel much loneliness despite increased isolation. Caregivers caring for Veterans with dementia stated they experienced confusion about their narrower social networks because they could not remember reasons why they were not regularly spending time with them. Findings demonstrate the need to identify strategies and policies to better support caregivers and older Veterans during times of crisis."} +{"text": "Hospitalizations for severe injection related infections (SIRI) amongst persons who inject drugs (PWID) are often complicated by patient directed discharge (PDD), incomplete antibiotic treatment and 90-day readmission. Despite a strong association with improved clinical outcomes, medications for opioid use disorder (MOUD) remain significantly underutilized in this patient population. Beginning in January of 2022, our institution revised several key policies that had limited inpatient use of MOUD while also implementing a new order set to facilitate MOUD inductions. This study seeks to quantify the clinical impact of these interventions in PWID admitted with SIRI.We first performed a retrospective analysis of all PWID hospitalized with SIRI between January 2018 and December 2020 to establish baseline rates of PDD, antibiotic completion and 90-day readmission in patients who received MOUD compared to those who did not. Subsequent analyses will utilize a quasi-experimental design to compare the same clinical outcomes in patients admitted before and after institutional guideline revision and MOUD order set implementation.A total of 97 patients were included in our baseline assessment, of which 21 (21.6%) received MOUD while hospitalized. Of patients receiving MOUD, 11 (52.4%) were new inductions. Use of MOUD was associated with significantly lower rates of PDD and significantly higher rates of antibiotic completion .Our baseline data agrees with existing literature in finding MOUD to be an effective way of reducing PDD and increasing antibiotic completion in PWID admitted with SIRI. However, overall MOUD utilization was low, particularly after accounting for the effect of individuals prescribed MOUD prior to admission. Forthcoming data will assess the impact of institutional guideline revision and MOUD order set implementation on PDD, antibiotic completion and hospital readmission in PWID admitted with SIRI.All Authors: No reported disclosures."} +{"text": "Many existing Alzheimer\u2019s disease (AD) caregiving interventions focus narrowly on thechallenges and needs of a primary caregiver rather than the family systems in which they areembedded. We advance a family systems framework by invoking convoys of caregiving to adaptan existing AD caregiver intervention to Middle Eastern/Arab American families in metroDetroit (N=56). The composition of caregiving networks is described, followed by assessment ofcare burden, depressive symptoms, care satisfaction and family conflict. Results show thatsiblings and children are the predominate support network members who accompanied theprimary caregiver to the program. Paired t-tests show that care burden and family conflictdecreased while caregiving satisfaction increased following program participation. Depressivesymptoms did not change. Findings illuminate how convoys of care may serve as valuablesupport resources, yet may also be the source of stress and conflict."} +{"text": "The various application markets are facing an exponential growth of Android malware. Every day, thousands of new Android malware applications emerge. Android malware hackers adopt reverse engineering and repackage benign applications with their malicious code. Therefore, Android applications developers tend to use state-of-the-art obfuscation techniques to mitigate the risk of application plagiarism. The malware authors adopt the obfuscation and transformation techniques to defeat the anti-malware detections, which this paper refers to as evasions. Malware authors use obfuscation techniques to generate new malware variants from the same malicious code. The concern of encountering difficulties in malware reverse engineering motivates researchers to secure the source code of benign Android applications using evasion techniques. This study reviews the state-of-the-art evasion tools and techniques. The study criticizes the existing research gap of detection in the latest Android malware detection frameworks and challenges the classification performance against various evasion techniques. The study concludes the research gaps in evaluating the current Android malware detection framework robustness against state-of-the-art evasion techniques. The study concludes the recent Android malware detection-related issues and lessons learned which require researchers\u2019 attention in the future. Since this study focused on Android malware obfuscation, we had selected \u2018Android malware, \u2018malware obfuscation\u2019, and \u2018malware evasion\u2019 as our search terms. The search results in 511 research from journals and conferences\u2019 proceeding database. The search results mainly records are from IEEE, journals and conferences distributions as per The list of collected articles represent the Android malware obfuscation and detection frameworks. It included the three types of the malware analysis techniques static, dynamic and hybrid techniques in the last decade from 2011 to early 2021. Hence, we collected Android malware frameworks for the last decade and innovative contributions that appeared in high-ranked journals or conferences such as IEEE, ACM, and Springer.Since, this paper explored the last 10 years\u2019 research to evaluate the Android detection frameworks against evasion techniques, we focused on experimental malware detection articles using static, dynamic and hybrid analysis techniques, excluding the unrelated articles. We excluded articles that are not Android specific malware detection such as IOS and Windows based operating system. In addition, we excluded all other languages and include only English language research to avoid translation overhead in future.As shown in We scrutinise Android malware detection academic and commercial frameworks while a large portion of the past work concentrated on commercial anti-malware solutions. This study examines different evasion techniques that hinder detecting malicious parts of applications and affect detection accuracy by reviewing state-of-the-art Android malware studies and issues limiting the detection of evasion techniques. It is worth noting that this work differs from related works that examine detection methods, as we go through evasion techniques that let malware evades detection methods.In the section, we discussed the Android application architecture. Subsequently, we investigate the Android operating system (OS) weaknesses. This background highlights the seriousness of some drawbacks to rationalize the necessity of establishing this review and explain the essential terms to support the readers of this study.Android application, Android app, or APK refers to the Android application from now on and throughout this paper. APK is a compressed file; an unzipping program extracts its files and folders. This segment explains the APK components and their contents, as some terms are essential in this study. APK developers use development tools that occasionally require simple programming experience from young developers. The Android app runs on Dalvik or ART equivalent to Java Virtual Machine (JVM) in a desktop environment. The APK structure consists of many files and directories; the main file is Classes.dex Java bytecode; it includes the classes and is packed together in a single .dex file. The AndroidManifest.xml file contains deployment specifications and the required permissions from Android OS. Resources .arsc is compiled resources, and Res folder is un-compiled resources.The Android system must install the APK file so that the end-user can utilize the application\u2019s functionalities. The Android system only accepts APK with a valid developer certificate, called developer identifier. Individual developers keep their certificate keys; there is no Central Authority (CA) server to maintain developers\u2019 keys, and thus no chain of trust between app stores and developers.a)Activities: The user interface that end-users interact with and that communicates with other activities using intents.b)Services: Android application component runs as a background process and bonds or un-bonds with other Android system components.c)Broadcast and Receivers Intents: send messages that all other applications or individual applications receive.d)Content Providers: It is the intermediate unit to share data between applications.End-users need to run the installed applications, while other apps run as a service in the OS background. Therefore, the Android application\u2019s main components are as follows:(a) Open Source:The advantage of Android source code\u2019s openness helps developers\u2019 communities enhance the OS and add more features. Therefore, the Android community improves Android OS daily. But, this contradicts with the security concerns when malware writers take this advantage. It makes their job more straightforward than in closed source firmware, which commonly triggers new vulnerabilities and malware attacks .(b) End-users Security Awareness:End-users understanding malware\u2019s seriousness plays a vital role in early prevention and detection when using feedback and reviews. However, the end-users feedback system is insecure and easily polluted by fake comments . End-use(c) Third-party Apps Market:via tools such as the ADB tool in Android SDK, which increases the probability of installing malicious apps The Coarse Granularity of Android Permissions:i.e., one permission that provides access to entire Internet protocols and all sites. There is no competent permission administration or sufficient permission documentation, leading to excess permissions Developers\u2019 Signatures:Android application developers have to sign their apps with their developer key before uploading the developed application to the market. There is no external party to authenticate developers\u2019 signatures and thus no confidentiality or integrity . Hence, (f) Application Version Update:Android applications usually enhance their functionalities in the form of version updates. The security frameworks analyze the application during installation, and the update process downloads new services/features without security precautions or checks .(g) USB Debugging:USB debugging is a valuable feature for Android Application development; it helps developers be more productive and efficiently troubleshoot applications. It allows direct installation of an application to the Android device using Android SDK tools such as the ADB tool. In addition Expo framework has the (h) Dynamic Code Loading (DCL):DCL is an Android OS feature that enables benign Android applications to call another APK or malicious code to compile and execute it in real-time. However, malware developers use this feature to load their malicious codes dynamically after the detection framework ranked the malicious app as benign.(i) Inter-application Communication (intent):Android OS uses the inter-application intent system to deliver a message from and to applications. Malware developers sniff, modify, or gain knowledge, compromising data integrity and privacy . The intWith some insight into the Android applications\u2019 development design, we list the Android system\u2019s weaknesses and definitions for the readers of this study. The following is a list of Android flaws and characteristics that malware authors and attackers abuse.This section represents our taxonomy of the currently used evasion techniques and research studies on detecting obfuscated malware. Our taxonomy focuses on classifying the related studies with the same objectives and goals to harvest a comprehensive collection of material and comparative conclusions. When scrutinizing many existing studies, we find it more appropriate to study the evasion detection capabilities of each studied framework after introducing the evasion techniques that hinder malware analysis and detection. This section presents the taxonomy of detection techniques for the ground truth relation between the detection methodology and the evasion ability. Android applications have powerful tools and techniques to secure and protect their applications from being reverse-engineered. Conversely, malware authors are using obfuscation tools and techniques to evade detection. Therefore, evasions, or in other terms, transformation techniques, are techniques that try to defeat Android malware detection and rank the malware applications as benign.As displayed in Polymorphic malware is the malware category that keeps changing its characteristics to generate different malware variants evading malware detectors. Polymorphic malware encrypts part of the code embedding malicious code. The polymorphic malwares encrypt itself with variable encryption keys but maintaining the malicious code body unaltered. Polymorphic malware is an advanced version of oligomorphic malware. The oligomorphic malware encrypts the malicious code to defeat source code static analysis based malware detection. Usually, the malware decrypts the malware using the same techniques. However, the oligomorphic malware decrypts the encrypted malicious code using different deyrptor to make decryptor analysis more difficult. The static analysis analyze the decryptor to find the encryption key that enable the detection of the malware. Hence, the static analysis approach is not effective with oligomorphic malware. Polymorphic malware continuously change the decryptor technique to make it more difficult to the source code static analysis approach. These symptoms are indications of the presence of malicious code in an application. In this section, we discuss the polymorphism evasions subcategories, which are package transformation and encryption.(a) Repacking (RPK): It is the process of unpacking the APK file and repacking the original application files but signing the APK file with a developer security key . This wa(b) Package Renaming (PKR): Every Android application has a unique package name. For instance, com.android.chrome is the package name of Google Chrome. PKR uses multilevel techniques to obfuscate the application classes except for the main Class, for instance, \u201cFlattenPackageHireachey\u201d or \u201cRepackageClass\u201d options . As showThis algorithm is applied relatedly to form the multilevel PKR obfuscation. The GinMaster family contains a malicious service that can root devices to escalate privileges, steal confidential information. Later, it receives instructions from a remote server to download and install applications without user interaction. The malware can successfully avoid detection by mobile anti-virus software by using polymorphic techniques to hide malicious code, obfuscating class names for each infected object, and randomizing package names and self-signed certificates for applications. Therefore, PKR evades the malware detection technique and causes false negatives, proven by (c) Identifier Renaming (IDR): Identifier is another APK parameter representing the application developer\u2019s signature. Classes, methods, and fields consider bytecode identifiers, as a signature is generated based on. Malware authors change developer identifiers using many obfuscation tools such as ProGuard and DexGIn this section, we study types of package transformation, which are Repacking (RPK), Package Renaming (PKR), and Identifier Renaming (IDR).Data Encryption as DEN, Bytecode Encryption as BEN, and Payload Encryption as PEN. This paper examines the following types of evasions:a)Data Encryption (DEN): This evasion technique tends to encrypt specific data vital for the malicious action and decrypt the encrypted data later, which modifies the malware application characteristics to evade the detection techniques . The datb)Bytecode Encryption (BEN): using ProGuard or DashOc)Payload Encryption (PEN): Malware authors use payload encryption as in DroidDream malware Some Android malware families encrypt data values inside the code, compiled code or payload, and decrypt the payload whenever desirable. This paper refers to Metamorphic malware is more complex than polymorphic malware that shows a better ability to evade detection frameworks. Malware authors adopt metamorphic malware so to make metamorphic malware detection harder than leveraging polymorphic malware. The metamorphic malware writes new malicious code that varies in each iteration using the same encryption and decryption key. For example, Opcode ngrams adopts tCode Reordering (CRE), Call Indirection (CIN), and Dead Code Insertion (DCI).a)Code Reordering (CRE): This transformation changes the order of the code by inserting the standard \u201cgoto\u201d command to maintain the proper program instruction order.b)Call Indirections (CIN): CIN is an object-oriented feature used dynamically to reference specific values inside the code; CIN creates code transformation evasion, obfuscating the call graph detection techniques . Malwarec)Dead Code Insertion (DCI): Malware inserts junk code into the sequence of the application to ruin its semantics. This type of transformation makes the malware more difficult to analyze . AnDarwiCode obfuscation is an evasion technique initially used to protect applications from piracy and illegal use by many obfuscation techniques. Conversely, malware authors use code obfuscation techniques to evade malware detections. In this study, we highlight three types of code obfuscation the Native Exploits (NEX), Function Inlining and Outlining (FIO), Reflection API (REF), Dynamic Code Loading/Modification (DCL/DCM), and Anti-debugging (ADE).a)Native Exploits (NEX): Android applications call native libraries to run system-related functions. The malware uses a native code exploit to escalate the root privilege while running . Unfortub)Function Inlining and Outlining (FIO): Inlining and outlining are compiler optimization techniques options. Inlining replaces the function call with the entire function body, and the outlining function divides the function into smaller functions. This type of transformation obfuscates the call graph detection technique by redirecting function calls and creating a maze of calls .c)Reflection API (REF): Reflection API is a technique to initiate a private method or get a list of parameters from another function or class, whether this class is private or public. Android developers legitimately use it to provide genericity, maintain backward compatibility, and reinforce application security. However, malware authors take advantage of this feature and use it to bypass detection methods. Reflection evasion facilitates the possibility to call private functions from any technique outside the main class. Recently few studies highlighted the reflection effect on code analysis and considered reflection during the analysis process .d)Dynamic Code Loading/Modification (DCL/DCM): Since Java has the capability of loading code at runtime using class loader methods, Android malware application dynamically download malicious code using the dynamic code loading (DCL). The DCL and DCM techniques provide advanced evasion capability to malware authors, and improper use can make benign applications vulnerable to inject malicious code. For instance, the Plankton malware family uses dynamic code loading to evade detection methods. As being the first malware with DCL that stealthy extend its capabilities on Android devices. It installs an auto-launching background application or service to the device, collecting device critical information to a server. The server sends the malicious class payload URL link to the background service using an HTTP_POST message containing a Dalvik Bytecode jar malicious payload file. In the following trigger of \u201cinit\u201d event of the main application, the malicious payload is invoked using the \u201cDexClassLoader\u201d class. Due to the unavailability of the dynamically loaded code during Android malware static analysis, the DCL and DCM evasion technique is another transformation technique that is a big challenge for static analysis . Althouge)Anti-debugging (ADE): The malware developer presumes the limitation of Android that only one debugger can be attached to a process using ptrace functionality . Hence, This section explains the advanced code transformation techniques that are more sophisticated in hindering the malware detection frameworks. We include advanced evasion techniques, such as Virtual Machine Aware (VMA). Another side of anti-emulation evasion is detecting automatic user interaction emulation, which refers to as Programmed Interaction Detection like the monkeyrunner tool used in many frameworks, for instance, the Droidbox (a)Virtual Machine Aware (VMA): The dynamic analysis requires either an Android virtual machine emulator or a physical device to install the suspected application. Scientists studied the possibility of detecting the running environment fingerprints to differentiate between an emulator and a physical device . Androidb)Programmed Interaction Detection (PID): Android malware is an event-driven application that needs a particular series of user interactions to launch malicious actions. Therefore, dynamic analysis requires a running environment user/gesture interaction. Malware writer refers to PID obfuscation as code coverage. Some researchers have tried to address code coverage; however, it remains a challenge to detect it.The primary objective of anti-emulation evasion is to detect the running environment of the sandbox and benignly masquerade as a clean application instead of launching the malicious code, which we refer to as Droidbox sandbox Droidbox .a)VirtuRepacking (RPK), Package Renaming (PKR), and Identifier Renaming (IDR). Encryption transformation includes Data Encryption (DEN), Bytecode Encryption (BEN), and Payload Encryption (PEN). The metamorphism subcategories are obfuscation transformation, advanced code transformation, and anti-emulations transformation. The code obfuscation subcategory includes Code Reordering (CRE), Call Indirection (CIN), and Dead Code Insertion (DCI). Advanced code transformation includes Native Exploits (NEX), Function Inlining and outlining (FIO), Reflection API (REF), Dynamic Code Loading/Modification (DCL/DCM), and Anti-debugging (ADE) evasion techniques. Last but not least, anti-emulation transformation includes Virtual Machine Aware (VMA) and Programmed Interaction Detection (PID).We scrutinize the top Android malware detection frameworks against the two main evasion categories based on the introduced definitions of Android malware evasion techniques. The first category is polymorphism, which consists of package transformation and encryption transformation. Package transformation includes Many researchers examine first category is logic-based techniques classification algorithms to classify the application as benign or malware Vulnerability Check: The vulnerability check method scans all existing Android apps and Android system versions against common security threats. APSET collectsb)Monitoring Logs: Android systems use process monitoring tools and network monitoring tools. Mobile-Sandbox uses theThis section explains the Android vulnerability check and monitors the system logs after installing the application. Therefore, post-installation analysis reports the security issues and malicious activity to the end-users.Android malware detection frameworks perform static, dynamic, or hybrid analyses to analyze features for malware detection techniques, which classify the apps as benign or malware. Hence, we identify the following application analysis methodologies.a)Signature-based: This paper classifies the signature-based method under static analysis detection because the signature-based detection approach builds its frameworks with static Android application characteristics. As such, DroidAnalytics uses a sb)permission-based detection castoff decompressing the APK package; it extracts the malicious symptoms using permission and signature matching analysis. Likewise, Triggerscope (Permission-based: APK Auditor is a stagerscope uses pergerscope .c)Androidmanifest file and source code; it scrutinizes the code by listing the native calls, API calls, and URL addresses. It uses machine learning classification to discriminate between malware and benign apps. Likewise, DroidMat or a scanning agent on an Android smartphone/device. Next is opening a suitable Android operating environment in a physical device or emulator, which we hereafter refer to as a sandbox. The sandbox isolates the application to protect the analysis device from possible malicious attacks. Later, the dynamic analysis starts system logging and network monitoring tools and captures the default system logs.Sandbox Emulator: Most researchers Supervised Model:Supervised machine learning bases its model on a labelled dataset. The framework splits the dataset into two subsets; first subset is for training and creating the classification model, and the second subset is for testing and validating the trained classification model. Most researchers split the data into 70% training and 30% testing subsets, but some split the data into 50% for training and 50% for testing .(b) Unsupervised Model:In the unsupervised model, apps are unlabeled. The unsupervised model recognizes the class of the applications without knowing which App is malware or benign. Researchers use unsupervised models to learn the covert pattern of the unlabeled data .(c) Reinforcement Learning:The machine exposes itself to an environment where it trains itself continually using trial and error. This machine learns from experience and tries to capture the best possible knowledge to make accurate business decisions. An example of reinforcement learning is the Markov Decision Process .Based on collected characteristics or so-called features , differeTo understand the supervised model classification performance, ML introduces the confusion matrix to calculate the performance measures as per True Positive (TP) represents the number of malware correctly classified.False Positive (FP) accounts for the number of benign apps classified erroneously as malware.True Negative (TN) represents the number of correctly classified benign apps.False Negative (FN) accounts for the number of malware apps classified erroneously as benign.The ML performance measures represent the accuracy of the Android malware detection classification frameworks. y-axis and FPR is the x-axis. Every point in the ROC curve represents one confusion; it is all based on TP and FP values. Area Under the Curve (AUC) is the area under the ROC curve representing the aggregation of the ML trained model (The Receiver Operating Characteristic (ROC) curve plots the TPR against FPR where TRP is the ed model .Researchers or commercial companies have developed the evasion test benches to study the robustness of the currently available anti-malware applications or protect their software packages from piracy issues. The first test benches trials were ADAM and DroiWe have explored the last 10 years\u2019 research to evaluate the Android detection frameworks against evasion techniques discussed in evasion techniques section. We studied Android malware detection frameworks for the last decade from 2011 to early 2021, as listed in vs polymorphism evasions. We examine the three main static, dynamic, and hybrid frameworks (a) Package Transformation:\u2013 RPK - Repacking Evasion Detection:Detecting repacking evasion is possible using static analysis and detection techniques; Dempster\u2013Shafe investig\u2013 PKR - Package Renaming Detection:Static analysis frameworks such as DroidoLytics and Droi\u2013 IDR Identifier Renaming Evasion Detection:DroidOlytics , AndroSiIn summary, most Android malware detection frameworks based on static analysis can detect package transformation techniques . However, most detection frameworks based on dynamic and hybrid analysis inadequately evaluate or report their resilience against IDR evasion techniques. The study spotted 20 papers that scrutinized the RPK evasion using static analysis, and only 10 papers scrutinized IDR. The study spotted nine papers that scrutinized the IDR evasion using static analysis, and only one paper scrutinized IDR using dynamic analysis.(b) Encryption Transformation Evasion Detection:Static analysis detects encryption evasion techniques; many studies, such as DexHunter , DroidKi(a) Code Obfuscation Detection:Code obfuscation consists of CRE, CIN, and DCI; we explain each evasion detection framework in the following list:\u2013 CRE - Code Reordering Evasion Detection:ResDroid , AnDarwi\u2013 CIN - Call Indirections Evasion Detection:As shown in \u2013 DCI - Dead Code Insertion Evasion Detection:AnDarwin conducte(b) Advanced Code Transformation Detection:It consists of NEX, FIO, REF, DCL, and ADE evasions explained in this section.\u2013 NEX Evasion Detection:DroidAPIMiner uses sta\u2013 FIO Evasion Detection:vs function inlining and outlining FIO evasion, as shown in AAMO evaluate\u2013 REF Evasion Detection:As shown in \u2013 DCL Evasion Detection:Some Android malware detection frameworks propose and evaluate their methods to detect DCL evasion, for instance, DroidAPIMiner , PoeplauADE Evasion Detection: Only the static analysis DexHunter consider\u2013 Anti-emulation DetectionAnti-emulation evasions consist of VMA and PID evasion techniques; the following is the insight of detection framework analysis:\u2013 VMA Evasion Detection:As a countermeasure for the VMA evasion technique, researchers equip anIn general, the dynamic analysis framework Q-floid introduc\u2013 PID Evasion Detection:Programmed Interaction Detection is fortunate to evade automated dynamic analysis using the inherent difference between key runner and human interaction patterns . InsteadSingh enhancesIn this section, this paper synthesizes the last decade\u2019s Android malware detection framework using three methodologies. First is identifying the evasions techniques requiring more attention from the research community. The second represents the potential evasion resilient detection techniques by reporting each framework\u2019s number of considered evasion techniques. The third summarizes the three types of Android application analysis with the number of frameworks that evaluated evasions techniques by bubble plot chart. Finally, we provide a to-do list and learned lessons from all the examined frameworks.The static analysis radar graph shown in etc. Besides each point number representing the number of Android malware detection frameworks that evaluated its proposed model against this evasion technique or point in the radar graph. For example, 15 malware detection frameworks consider the RPR evasion technique; thus, the RPK label points to 15, as displayed in We selected the Radar graph to demonstrate that static detection studies could detect package transformation evasions and basic code obfuscation; however, advanced transformation techniques and anti-emulation were neither studied nor evaluated. Concerning DCL, Pektas , in 2014Until today, many static analysis researchers depends on permissions ; howeverResearchers assume that dynamic analysis covers all the simple obfuscations and transformation techniques. Hence many of the dynamic analysis frameworks ignored However, a few researchers evaluate their frameworks against specific evasion techniques, as reflected in the radar graph of the hybrid malware detection frameworks, as shown in Most of the recent dynamic analysis researches confirmeThe Hybrid analysis techniques are suggested by many researchers and have been set in their future plan to overcome the resiliency issue of complex obfuscation techniques. However, it is a shocking fact that the examined 26 Android malware detection frameworks using hybrid analysis, that only nine frameworks just consider few evasion techniques such as RiskRanker that hasThe systematic evasion detection map is illustrated in Researchers have concentrated on Android malware static analysis in the last few years, which requires less time and effort than dynamic analysis. They tried to overcome the static analysis weaknesses against evasion attacks, which is why many researchers evaluated their frameworks to check the anti-obfuscation capabilities, as presented in (a) Obfuscation datasetAndroid malware development is always one step ahead of malware detection techniques, which means malware detection still requires many efforts to catch up with malware development. To achieve this objective, we share several insights drawn from our analysis.(b) Obfuscation detection framework performanceOne of the most important is to keep on updating and standardizing obfuscated malware datasets. We recommend standardizing this dataset by the research community trusted institutions and being available upon validated requests for research purposes. Despite some available obfuscated datasets such as PRAGuard sharing (c) Metamorphism evasion:The performance of the Android malware framework degraded over time since new malware variants, and obfuscations techniques were generated PetaDroid . Hence, (d) Standard Evasion Benchmarking:Static detection is unable to detect most of the metamorphism evasion techniques because of the dynamic characteristics of metamorphism. However, there is still a lack of dynamic and hybrid frameworks to detect metamorphism evasions. It is therefore beneficial to focus more on developing dynamic and hybrid methods.(e) Android Exploits:We suggest building a comprehensive and collaborative benchmarking framework for Android malware detection evasion techniques that aims to improve the quality of research and add to the body of knowledge in Android malware detection studies. The benchmark consists of a list of evasion techniques based on the detection methods that have been evaluated. As a result, detection methods are tested against a standardized list of malware evasion techniques to determine whether they are capable of detecting malware evasions.(f) Code Integrity Verification:As mentioned earlier, Android is based on Linux OS; it has inherited Linux exploits. Recently, malware authors developed and published the Android exploit code Dirty-Cow CVE-2016-5195 . The Dir(g) Process Authentication:Verification means that the application integrity is authenticated against repackaging by guaranteed third-party authentication authorities. (h) Triggering Malicious Code Assurance:Some researchers leverage the process of model authentication to eliminate the need for an external Certification Authority (CA) that protects the system from many exploits . HoweverThe process of ensuring the malicious code runs during the dynamic analysis sandboxing. TriggerScope staticalGlobal evasion techniques make Android malware more advanced and sophisticated, which was our motivation for this study. We aim to highlight the most critical weaknesses of Android malware detection frameworks, mainly when malware uses different evasions techniques. Therefore, this study scrutinizes top Android malware detection frameworks against 18 evaluation test benches to evaluate the effectiveness of the evasions detection techniques in Android malware detection frameworks. Therefore, the study introduces a new evasion taxonomy that categorizes the evasion techniques into two main groups, polymorphism and metamorphism, where each group has branches; the polymorphism group includes package transformation, and the encryption metamorphism group contains code obfuscation, advanced transformation, and anti-emulation branches. The study also pointed out the lack of research in evaluating the malware detection against different evasion techniques; hence we scrutinized the frameworks based on every evasion technique and categorized the evaluations based on the malware detection methods. Our analysis results conclude a lack of research evaluating the current Android malware detection framework robustness against state-of-the-art evasion techniques. We also concluded that static analysis based detection is easily evaded with simple obfuscation.On the contrary, dynamic and hybrid analyses address advanced code transformation techniques and other advanced evasions. However, preliminary studies have evaluated their frameworks against evasion techniques. The missing framework evaluations are due to the lack of standard benchmark evasion datasets with updated standard malware datasets and the lack of comprehensive test benches tools to assess the efficiency of the existing and future frameworks. This study advises the research community to exert more effort into detecting anti-emulation evasion as indicated in the map of evasions and detection techniques. We also plan to create a standard evaluation framework to include all types of evasion techniques and consider the new generation of malware that combines multiple evasion techniques.10.7717/peerj-cs.907/supp-1Supplemental Information 1It is the process of unpacking the APK file and repacking the original application files but signing the APK file with a developer security key.Click here for additional data file.10.7717/peerj-cs.907/supp-2Supplemental Information 2Click here for additional data file."} +{"text": "Social withdrawal is an early and common feature of psychiatric disorders. Hypothalamic-pituitary-adrenal (HPA)-axis activation through increased salivary cortisol (sC) and sympathetic activation through increased salivary alpha-amylase (sAA) may play a role.We aimed to study whether the link between increased sC and sAA on the one hand and depression on the other hand is mediated by social withdrawal.In this cross-sectional, observational study, sC and sAA measures were measured in seven saliva samples in 843 participants . Social withdrawal was assessed through the Brief Symptom Inventory (BSI)-, the Short Form 36-, and the Dutch Dimensional Assessment of Personality Pathology social withdrawal subscales, and analyzed using linear regression and mediation analyses. On average, participants were 44.0 years old .Basal and diurnal sAA were unrelated to any social withdrawal scale and depression. Certain sC measures were positively associated with the BSI social withdrawal subscale . We found limited support for statistical mediation by social withdrawal on the relationship between evening sC and depression.Thus, although we found no support for a role of basal and diurnal sAA in social withdrawal, HPA-axis activation may partly aggravate social withdrawal in depressive disorders."} +{"text": "Dysfunction of both microglia and circuitry in the medial prefrontal cortex (mPFC) have been implicated in numerous neuropsychiatric disorders, but how microglia affect mPFC development in health and disease is not well understood. mPFC circuits undergo a prolonged maturation after birth that is driven by molecular programs and activity-dependent processes. Though this extended development is crucial to acquire mature cognitive abilities, it likely renders mPFC circuitry more susceptible to disruption by genetic and environmental insults that increase the risk of developing mental health disorders. Recent work suggests that microglia directly influence mPFC circuit maturation, though the biological factors underlying this observation remain unclear. In this review, we discuss these recent findings along with new studies on the cellular mechanisms by which microglia shape sensory circuits during postnatal development. We focus on the molecular pathways through which glial cells and immune signals regulate synaptogenesis and activity-dependent synaptic refinement. We further highlight how disruptions in these pathways are implicated in the pathogenesis of neurodevelopmental and psychiatric disorders associated with mPFC dysfunction, including schizophrenia and autism spectrum disorder (ASD). Using these disorders as a framework, we discuss microglial mechanisms that could link environmental risk factors including infections and stress with ongoing genetic programs to aberrantly shape mPFC circuitry. The medial prefrontal cortex (mPFC) controls complex cognitive and emotive functions, including decision making, memory, social interactions and mood . These fMicroglia are increasingly recognized as key players in synapse development and refinement . Microglvia membrane-bound receptors. This represents one key mechanism by which microglia engulf synaptic compartments and C4B recently shed light on the molecule\u2019s role in synaptic refinement within the retinogeniculate system provided new insight into mechanisms through which C4-dependent pathways sculpt synapses . In thisvia aberrant microglial pruning. It is possible that yet undiscovered genetic variation in other pruning-relevant molecules also contributes to disease risk or etiology. As such, we need a more precise understanding of how and when these molecules shape microglial pruning. It will be important to determine whether biological events can elevate C4 expression during adolescence or provoke C4 production outside of its developmentally appropriate time window, leading to pathological circuit modifications via microglial effectors. Individuals with a higher C4A copy number may exhibit particularly strong increases in C4 in certain situations, and, therefore, experience increased vulnerability in particular contexts. These findings also raise the intriguing possibility that an individual\u2019s risk of developing schizophrenia might be mitigated via interventions that modify microglial pruning activity. Along this vein, minocycline, an antibiotic previously shown to reduce synapse pruning in rodent models during which activity increases dendritic spine density in the dLGN . During In the past decade, numerous studies have corroborated the idea that microglia sculpt developing neuronal circuits . AligninNew work indicates that microglia use different signaling pathways to regulate dendritic spines depending on the stage of development . In bothMECP2 from all GABAergic interneurons recapitulated most behavioral features of Rett\u2019s syndrome, a form of ASD, while deletion in specific regions or other broad cell types only recapitulated some features \u2014non-toxic viruses that are commonly used to manipulate gene expression in the brain. To advance the field, new approaches are needed for spatially restricted manipulation of these cells. In the meantime, as we learn more about the molecular mechanisms guiding neuron-glia interactions in mPFC, we can use neuronally-targeted AAVs to manipulate their interactions in a spatially and temporally restricted manner. With such tools in hand, we can determine when and how microglia regulate specific classes of mPFC synapses. Future studies can investigate to what extent microglia play simultaneous roles in pruning and synaptogenesis within mPFC\u2014potentially at different classes of synapses\u2014and whether microglia may toggle between states that promote synapse formation vs. pruning.When investigating the roles of microglia in mPFC and sensory circuit development, it will also be important to consider potential contributions from astrocytes. Astrocytes shape circuit development in similar ways to microglia. Astrocyte-secreted proteins regulate synaptogenesis and promIn addition to directly modulating synapse development, astrocytes signal to microglia to alter microglial function. For example, astrocyte-derived IL-33 signals to microglia to promote microglial synapse engulfment and neural circuit maturation in the thalamus and spinal cord . AstrocyStudies from the past decade corroborate the notion that microglia and other immune system factors sculpt developing neuronal circuits . The worAll authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication."} +{"text": "Inflammatory or kidney-related metabolic biomarkers have been correlated with cognition and risk for developing dementia among older adults. Using the China Health And Retirement Longitudinal Study, we investigated the cross-sectional correlations between metabolic biomarkers and cognitive outcomes that were ascertained in the same wave, as well as measures lagged by data collection waves. After excluding participants with diagnoses of dementia, we analyzed the association of each biomarker with scores from cognitive tests. We then identified biomarkers that showed consistent associations across waves. Having elevated CRP (1-3 mg/L) was positively associated with cognitive test scores; whereas abnormal levels of Creatinine were associated with poorer outcomes. These results provide biomarker evidence of the importance of kidney function and inflammation in dementia research."} +{"text": "In 2020, we observed an increase in inpatient postoperative patient deteriorations. Preliminary case reviews suggested gaps in sepsis care.To identify key drivers associated with effective care escalation and sepsis care in the inpatient surgical setting as part of the initial planning phase of a large improvement initiative.Our multidisciplinary team included surgical nurses, surgical providers, medical providers, patient safety experts, subject matter experts in pediatric sepsis, and subject matter experts in escalation of care. This team formally reviewed cases involving postoperative deterioration to identify causes of gaps in sepsis care and applied its learnings to the development of a key driver diagram. Themes from the key driver diagram included (1) Enhance recognition of deterioration and subsequent escalation of care and (2) Optimize postoperative patient placement. The team hosted a mini-Kaizen event with frontline team members focused on the first theme, the output of which included consensus agreement on two focus areas and a fishbone diagram to identify/prioritize opportunities in postoperative care escalation.Causes of gaps in sepsis care included barriers to care escalation that could limit generalizability of sepsis resources to the inpatient surgical setting. Figure 1 shows the key driver diagram.We aim to highlight challenges associated with postoperative sepsis care in an inpatient pediatric surgical setting."} +{"text": "Reports have documented national and state-level increases in drug overdose\u2013related emergency department visits, emergency medical services incidents, and deaths among racial and ethnic minority groups in the United States during 2020 amid the COVID-19 pandemic , compared with 119.7% (from 66 to 145) among Hispanic persons . By sex To improve evidence-based drug overdose prevention and response efforts among persons who use opioids in Nevada, particularly among young male Hispanic persons who have experienced overdoses involving illicitly manufactured fentanyls, a better understanding of the underlying risks for the recent increase in overdose deaths is needed. Naloxone can reverse the effects of overdose from opioids, such as illicitly manufactured fentanyls. Although evidence of naloxone administration for opioid-involved deaths was higher among Hispanic persons in 2020, only approximately one in three of those Hispanic decedents had evidence"} +{"text": "Recent reports are indicating an inverse association between lithium in drinking water and suicide mortality observeThe inverse ecological association should be verified by individual data on the biological monitoring of lithium exposure, such as between the serum concentration of lithium and the number of suicide events. Case-control studies analyzing this have been reported. Kanehisa et al. (2017) reporteFinally, Szklarska and Rzymski (2019) reporteThe author declares no conflict of interest.None."} +{"text": "The extraction and exploration of cellulose-based polymers is an exciting area of research. For many years, wood was considered the main source of cellulosic compounds because of its abundance in nature ,2. HowevRizal et al., in a very compelling and critical overview of the worlds\u2019 current situation regarding cotton waste fibers and their ineffective processing mechanism to mitigate their environmental impact, provided evidence of new work being conducted to employ these wastes in functional products. Indeed, different pre-treatment techniques were identified for their efficiency in extracting cellulose nanocrystals from cotton wastes, and many applications in the packaging and biomedical fields were highlighted . Neto etNano-fibrillated cellulose extracted from waste peels of citrus sinensis by a chemical method involving alkali and acid hydrolysis and modified with silver nanoparticles also synthesized using extract of citrus sinensis skins as a reducing agent were engineered for heavy metal sorption. Data found these isolates and nanoparticles especially effective in removing cadmium and chromium particles from pharmaceutical effluent samples . Rizal eWang et al., engineered a flexible SERS substrate based on regenerated cellulose fibers, obtained from wastepaper, modified with gold nanoparticles through dry-jet wet spinning method, an approach turned eco-friendly by using ionic liquids. The gold nanoparticles were incorporated on the regenerated fibers through electrostatic interaction. The SERS scaffolding system was found very effective for identifying toxins and chemicals like dimetridazole in aqueous solutions . RecycleIn the field of drug delivery, Al-Rajabi et al., explored a green synthesis method for developing a thermo-responsive cellulose hydrogel using cellulose extracted from oil palm empty fruit bunches. The thermo-responsiveness was guaranteed by the incorporation of Pluronic F127 polymer onto the hydrogels. A sustained release of silver sulfadiazine was observed over time. In the end, it was seen that the thermo-responsive cellulose-based hydrogel could give rise to cost-effective and sustainable drug delivery systems using abundantly available agricultural biomass ["} +{"text": "GSA\u2019s revised KAER Toolkit for Primary Care Teams provides useful information for referring individuals and families to community resources following a neurocognitive disorder diagnosis. Mental health practitioners must develop competencies and professional identities within integrated care teams to facilitate this process. This presentation outlines post-assessment suggestions for clinicians across disciplines in building such teams. There may be needs for serial assessment of specific individual capacities, treatment plans to facilitate shared decision-making between individuals and family care partners, and evaluations of the family care partner\u2019s capacity to provide care. Behavioral health providers assist patients, families, and health care teams across a range of residential settings in understanding and implementing treatment recommendations. Emerging science indicates the value of initiating planning discussions with lifestyle modifications to enhance functioning within dyads. Culturally responsive strategies will be suggested for engagement in planning for future care."} +{"text": "Somatic mutations are DNA variants that occur after the fertilization of zygotes and accumulate during the developmental and aging processes in the human lifespan. Somatic mutations have long been known to cause cancer, and more recently have been implicated in a variety of non-cancer diseases. The patterns of somatic mutations, or mutational signatures, also shed light on the underlying mechanisms of the mutational process. Advances in next-generation sequencing over the decades have enabled genome-wide profiling of DNA variants in a high-throughput manner; however, unlike germline mutations, somatic mutations are carried only by a subset of the cell population. Thus, sensitive bioinformatic methods are required to distinguish mutant alleles from sequencing and base calling errors in bulk tissue samples. An alternative way to study somatic mutations, especially those present in an extremely small number of cells or even in a single cell, is to sequence single-cell genomes after whole-genome amplification (WGA); however, it is critical and technically challenging to exclude numerous technical artifacts arising during error-prone and uneven genome amplification in current WGA methods. To address these challenges, multiple bioinformatic tools have been developed. In this review, we summarize the latest progress in methods for identification of somatic mutations and the challenges that remain to be addressed in the future. Previoulifespan . Somaticlifespan . Once filifespan . The scalifespan .Somatic mutations have increasingly been implicated in various diseases. Somatic mutations in oncogenes and tumor-suppressor genes are the major cause of cancer . Accumulet al. analyzed the tri-nucleotide sSNV profiles across 30 cancer types and successfully identified 27 mutational signatures (Different mutational processes generate distinct profiles of mutational genomic contexts, termed \u201cmutational signatures,\u201d and the landscape of somatic mutations observed in tissue samples or single cells often reflects the combined impact of multiple mutational processes . The largnatures . The catgnatures . A similgnatures as well gnatures .Theoretically, sequencing reads from reference and mutant alleles of a given mutation should follow a binomial sampling process, where the expected number of mutant reads is positively correlated with total depth and mutant allele fraction. The mutant allele fraction is one of the key variables for somatic mutation detection, which is largely determined by the timing of the occurrence of the mutation and the selective pressure acting on the cell carrying the mutation . SomaticEarly attempts on somatic mutation calling were made in cancer studies, where the sequencing data from a tumor sample were typically compared to a matched normal control sample obtained from the same donor. Strelka and VarSAlthough clonal expansion events led by driver mutations are not rare in healthy tissues, they usually involve relatively small clones, making it hard to attain high allele fractions in bulk tissue sequencing . MoreoveTargeted ultra-deep sequencing has been widely used as a cost-efficient strategy to increase sequencing depth and thus improve sensitivity in detecting somatic mutations, especially for screening mutations in cancer-related genes . HoweverSomatic mutation in single-cell data has emerged as a powerful endogenous marker to comprehend underlying mutational mechanisms across different cell types , and to Early pioneering works have demonstrated success in applying bulk-sequencing-based methods to sSNV calling in single cells , despitein silico mixture of multiple single cells, and outperformed other tools on calling clonal mutations.Single cells may share some somatic mutations if those mutations occurred in their common ancestral cell . CompareSomatic mutations can also be called from other types of sequencing data beyond DNA sequencing data. RNA-MuTect identified exonic somatic mutations from bulk RNA-seq data by comparing mutation calls against DNA sequencing of a matched control sample . SomaticMany bioinformatic methods have been developed to study somatic mutation in healthy and diseased human samples using bulk or single-cell sequencing . In bulkIn the past decade, genomic studies have benefited from the development of single-molecule sequencing technologies that can directly read nucleotide sequences from DNA or RNA molecules and deliver much longer reads than previously available NGS technologies . Long se"} +{"text": "Organized by the Alzheimer's disease and related dementias (ADRD) Interest Group, this symposium aims to highlight unique approaches to address 1) ADRD risk reductions through social and biological factors, and 2) quality of life of those with dementia. The first two presentations introduce remote communication technologies used for behavioral interventions, one for preventing social isolation and the resultant cognitive decline using video-chats by recruiting socially isolated older adults with mild cognitive impairment (MCI). The results of the recently completed randomized controlled trial provide evidence of a positive effect on cognition suggesting enhanced cognitive reserve. Another is for delivering a behavioral symptom intervention for community-dwelling persons with ADRD using telehealth. Researchers will highlight the feasibility, opportunities, and challenges of remote behavioral interventions. The third presentation focuses on micro-level communication between persons living with dementia and their family caregivers. By examining video-recorded home care observations, findings suggest caregiver education on positive interactions could facilitate more meaningful interaction with persons with ADRD. The fourth presentation explores pain among those with ADRD, a multifaceted phenomenon with health and functional consequences. Using the NHATS dataset, researchers show a continued need to detect and address pain in clinical settings particularly among persons with ADRD. The symposium concludes with a presentation using the CHARLS study to investigate correlations between inflammation or kidney-related metabolic biomarkers and cognition. Results provide longitudinal evidence of an association of kidney function and inflammation with cognitive test scores supporting the need to broaden dementia etiology research beyond the amyloid-cascade theory."} +{"text": "This cross-sectional study investigates trends in out-of-pocket costs for unmixed and novel glucagon formulations among patients with Medicare Advantage and commercial insurance from 2010 to 2020. We assessed trends in wholesale acquisition cost (WAC), an estimate of the manufacturer\u2019s list price, for glucagon formulations over time using the AnalySource drug pricing database. Next, we examined trends in OOPCs paid by patients using the Optum deidentified Clinformatics Data Mart, which includes administrative claims from large commercial and Medicare Advantage (MA) health plans. Analyzed claims included any formulation of glucagon from January 1, 2010, through September 30, 2020. Given that there were only 24 prescription fills of novel premixed liquid glucagon injection, it was excluded from analysis . There are multiple possible reasons that may underly this trend, including MA plans passing on higher WAC to beneficiaries or beneficiaries choosing plans with more cost sharing over time.Our study has several limitations. Results may not generalize to patients who are insured through traditional Medicare or Medicaid or are uninsured. In addition, we were unable to assess instances in which high OOPCs prevented patients from filling the prescription (primary nonadherence) or the association of manufacturer patient-assistance programs and coupons with OOPCs for commercial beneficiaries.Cost-sharing should not serve as a major barrier to accessing glucagon for MA and commercially insured patients. Further work should assess other barriers to guideline-concordant glucagon uptake among patients at risk of severe hypoglycemia. Such barriers may include awareness among patients and primary care, emergency, and diabetes clinicians of the availability of this potentially life-saving treatment. In addition, future studies may examine the association of novel glucagon formulations, which had similar OOPCs to those of unmixed glucagon and may be easier to administer, with uptake in the coming years."} +{"text": "Lower socioeconomic status African American older adults living with dementia and their family caregivers face unique advance care planning challenges, including achieving appropriate preference-consistent healthcare near the end of life. The purpose of this project within a larger multi-stakeholder study is to assess community stakeholder perspectives on the needs of African American older adults living with dementia and their family caregivers. Diverse community-based organization leaders (n=9) were interviewed and identified the following thematic needs: Reframing of Advance Care Planning, Clarification of Misinformation, and Expansion of Available Resources. Community leaders expressed strong desires to assist families with advance care planning. The use of creative, culturally-tailored, non-traditional approaches to this process offers innovative ways to promote advance care planning through community engagement. This will change the narrative on advance care planning from a cultural perspective while embracing diversity, enriching discovery, and reimaging aging in the community"} +{"text": "Vitiligo is an autoimmune disease of the skin that results in localized or disseminated white macules. One common feature of several existing classification protocols is the distribution of the disease into two main subtypes, non-segmental vitiligo (NSV) and segmental vitiligo (SV). SV is characterized by depigmentation spreading within one or more skin segments while NSV is widespread. Several clinical-epidemiological observations suggest that SV has distinct autoimmune pathophysiology compared to NSV. Furthermore, the clinical distribution pattern of SV lesions closely resembles other melanocyte mosaicism diseases. These observations led us to hypothesize that SV is caused by a localized autoimmune reaction targeting epidermal mosaicism melanocytes. Here, we proposed examples of experimental approaches to assess mosaicism in SV patients. According to an international consensus, vitiligo is classified into three main groups: Segmental (SV), Non-Segmental (NSV), and mixed vitiligo (coexistence of SV and NSV).Reports suggest differences in the biological mechanisms underlying the pathogenesis of SV as compared to NSV. For example, serum levels of TWEAK (Tumor Necrosis Factor-like Weak inducer of Apoptosis) were significantly higher in SV compared to NSV patients.17de novo mutation or retrotransposition occurred delineates the extent of tissues/cells involved in the mosaicism. The hypothesis to be tested suggest that genetic mosaicism in SV occurred at some point during skin/melanocyte differentiation. Different approaches can be applied to test the mosaicism hypothesis in SV, each aiming to detect a distinct type of mosaicism. Here we proposed examples by adapting designs applied to study the host response to infections, detect somatic mutations in cancers and evaluate embryonic development.23Mosaicism designates individuals encompassing at least two cell populations derived from a single zygote but with distinct genotype or epigenetic profiles.de novo mutation occurred during skin differentiation in one segment, a contralateral healthy skin could be used to establish the melanocyte\u2019s \u201cnormal\u201d profile would be performed using DNA extracted from melanocytes from hypochromic and contralateral skin from the same individuals. Variants detected in contralateral tissues would be used to exclude germline variants. Algorithms designed to detect tumor cells, such as MuTect2,None declared.Gerson Dellatorre: Study concept, writing and approval of the final manuscript.Vinicius Medeiros Fava: Study concept, writing and approval of the final manuscript.Marcelo T\u00e1vora Mira: Writing and approval of the final manuscript.Caio Cesar Silva de Castro: Study concept, writing and approval of the final manuscript.None declared."} +{"text": "Developing efficient cognitive training for the older population is a major public health goal due to its potential cognitive benefits. A promising cognitive training target is executive control, critical for multitasking in everyday life. The aim of this pilot study was to establish the feasibility and acceptability of the Breakfast Task in older adults, a new web-based cognitive training platform that simulates real-life multitasking demands. Research Design andA community-based sample of 24 cognitively healthy participants aged between 60 and 75 underwent an online 5-session training protocol. Each session lasted 40 minutes and occurred twice a week at participant\u2019s homes. Game performance was recorded, and participants completed questionnaires at baseline and after the intervention.Feasibility metrics showed overall high recruitment (82.7%), adherence and retention rates (100%). Acceptability was considered good based on participant`s quantitative and qualitative responses. On average, participants rated the game as interesting, enjoyable and did not report difficulties in accessing the game online or in understanding the instructions. Moreover, participants showed a learning curve across sessions, improvement in most game outcomes and benefits from the emphasis change approach. Discussion and Implications: The findings provide preliminary support for the feasibility and acceptability of the Breakfast Task training platform with community-dwelling older adults and demonstrate potential cognitive benefits. Results suggest the value of further research investigating the Breakfast Task features and dose-response relationship, as well as its efficacy in older adults via larger randomized controlled trials."} +{"text": "Acipenser fulvescens), during the early larval period in response to weekly treatments using chemotherapeutants commonly used in aquaculture relative to untreated controls. The effects of founding microbial community origin (wild stream vs. hatchery water) were also evaluated. Gut communities were quantified using massively parallel next generation sequencing based on the V4 region of the 16S rRNA gene. Members of the phylum Firmicutes and Proteobacteria were the dominant taxa in all gut samples regardless of treatment. The egg incubation environment (origin) and its interaction with chemotherapeutant treatment were significantly associated with indices of microbial taxonomic diversity. We observed large variation in the beta diversity of lake sturgeon gut microbiota between larvae from eggs incubated in hatchery and wild (stream) origins based on nonmetric dimensional scaling (NMDS). Permutational ANOVA indicated the effects of chemotherapeutic treatments on gut microbial community composition were dependent on the initial source of the founding microbial community. Influences of microbiota colonization during early ontogenetic stages and the resilience of gut microbiota to topical chemotherapeutic treatments are discussed.Antibiotics, drugs, and chemicals (collectively referred to as chemotherapeutants) are widely embraced in fish aquaculture as important tools to control or prevent disease outbreaks. Potential negative effects include changes in microbial community composition and diversity during early life stages, which can reverse the beneficial roles of gut microbiota for the maintenance of host physiological processes and homeostatic regulation. We characterized the gut microbial community composition and diversity of an ecologically and economically important fish species, the lake sturgeon ( Developing therapeutic regimes that limit stress-induced microbial infection or that reduces the occurrence of high mortality events in aquaculture is essential to successful fish production ,2,3. In 2O2), and sodium chloride (NaCl2) diversity measures in the lake sturgeon larval GI tracts as a function of egg origin (wild vs. hatchery). The test was performed instead of parametric tests that assume a normal distribution. Next, the effects of chemotherapeutants and egg origin on measures of microbial gut community diversity were estimated based on a generalized linear model (GLM) using suitable probability distributions in R program (v3.0.2) using glm. The GLM method has been shown to have high efficiency when estimating parameters, yielding interpretable estimates that also avoid transformation bias ,54. p-vaWe included several packages implemented in program R to estimate (beta [\u03b2]) diversity measures quantifying bacterial community compositional differences between samples and ecological statistics at the bacterial OTU level. Briefly, vegan was usedNext, we performed multivariate hypothesis testing to quantify differences in community composition among samples originating from different groups based on locations of egg origins and exposed to different chemotherapeutant treatments using the adonis function in progrAnalyses investigated whether host origin and/or chemotherapeutant treatment had a significant effect on microbial community structure. NMDS and PERMANOVA were performed on fish gut communities within each origin group to determine whether chemical treatments had effects on fish gut microbiota. Under the null hypothesis, chemotherapeutant treatments were not expected to significantly affect fish gut community taxonomic composition within an origin group, in part because eggs from both hatchery and wild origins were exposed to peroxide during incubation that was believed to reduce and taxonomically homogenize samples for all treatments and both origins. PERMANOVA analyses that indicated significant treatment effects were then analyzed using post hoc tests using betadisper and permutest functions followed by a Tukey test to determine which treatment(s) differ significantly in larval lake sturgeon gut bacterial taxonomic composition.To determine the operational taxonomic units (OTUs) that most likely explained differences in microbial larval lake sturgeon gut community composition between fish from different origins and among different chemotherapeutant treatment groups, we next employed linear discriminant analysis (LDA) effect size (LEfSe) methods . In geneThe algorithm first identified features (OTUs) that were statistically different among origin groups based on the nonparametric factorial Kruskal\u2013Wallis (KW) rank sum test. Additional tests assessed the consistency of differences using unpaired Wilcoxon rank sum tests. In the final step, LEfSe used LDA to rank each differentially abundant taxon in order of the difference in abundance based on an LDA Score . Results represent a scale indicating \u201cimportance\u201d of an OTU in origin group differences in microbiota composition .https://huttenhower.sph.harvard.edu/galaxy/, accessed 20 November 2014).To run LEfSe, a tabular file was generated from a shared file that contained no singletons in the program mothur v.1.39.5. The tabular file consisted of taxonomic relative abundance in gut community samples from the four different origin samples that were all exposed to four chemotherapeutant treatments. This tabular file was transferred using an online bioinformatics toolkit developed by the Huttenhower lab to perform LEfSe analyses . Phyla detected in the remainder of the gut community included Acidobacteria, Bacteroidetes, and Verrucomicrobia that collectively comprised 30% of gut communities. A total of 144 samples were retained after quality filtering was performed in the sequence pipeline analyses. Comparisons of lake sturgeon larvae gut microbial community composition at the level of phyla indicated that three major phyla dominated more than 65% of total community abundance across all fish samples . One exception was WB larvae exposed to salt (mean 58%) and WC fish exposed to peroxide (mean 50%) that were relatively low compared to other treatments had a lower percentage of Firmicutes (mean range from 51\u201366%). Proteobacteria relative abundance was likewise relatively uniform across treatments with the exception of WB fish that were treated with chloramine-T, CT (6%). Actinobacteria were present at 1% in fish that were not exposed to any chemotherapeutant (control) and only in fish from HA and WC origin groups. At the genus level, Firmicutes were represented by two genera, Clostridium_sensu_stricto & unclassified genera from family Clostridiaceae. We found that Clostridium_sensu_stricto were the most dominant genus for all fish of hatchery origin (except for HA fish exposed to peroxide), whereas all fish of wild origin had unclassified taxa from Clostridiaceae family (mean range: 29\u201362%) as the most abundant genus across any treatment and WC control fish (mean 1.4%).The relative abundance of the most dominant phylum, eatments a. When creatment b. Generaeatments b. The onp > 0.05). Statistical analyses based on the generalized linear model (GLM) indicated that gut communities of individuals exposed to certain treatments had significantly different levels of taxa richness, but not on the inverse Simpson indices ordination of BC dissimilarities in microbial taxonomic composition of gut communities was performed to visualize community compositional relationships among larval gut samples associated with fish from different egg origin and exposed to different chemotherapeutant treatments. Four NMDS plots were generated, including To quantitatively test for gut community compositional differences among chemotherapeutant treatment and origins, PERMANOVA was performed. Comparisons of microbial OTU beta diversity across samples from the controlled groups indicated that gut microbial communities from control groups were not significantly influenced by the egg origin . Subsequp = 0.012). However, the effect of chemotherapeutant treatment was not evident between fish from eggs collected in different regions of the stream , although a significant interaction was observed between origin group and treatment . Chemotherapeutant treatments had significant effects on larval gut microbiomes between individuals from different hatchery families as indicated by PERMANOVA test results and Methylocystis (Phylum Proteobacteria). Both genera were present in high abundance in the guts of fish exposed to the peroxide treatment, and for genus Clostridium_XVIII. The taxa were also abundant in the guts of fish from the salt treatment in high abundance, while fish exposed to the salt treatment had Peptoniphlus and Luteimonas that were in higher abundance compared to individuals from other treatments to other chemotherapeutant treatment groups . LEfSe analyses performed with fish from the wild group detected two differentially abundant taxa associated with genus ents see c.Understanding interactions between microbes and the host surfaces they colonize is important to aquatic animal health and aquacultural production ,35. PoteIn this study, we found little evidence for the influence of commonly used chemotherapeutant treatments applied topically in water baths to larval lake sturgeon prophylactically on gut microbiome composition. Data did indicate greater influence of microbial founder effects (hatchery vs. wild stream origin), which may be explained by exposure to environmental sources during earlier life stages or influences of genetic effects ,74. ResuAll chemotherapeutants used in our study are commonly used for the treatment of external pathogens rather than orally administered to fish. In fish aquaculture, prophylactic treatments are widely used to control pathogenic bacteria disease outbreaks that commonly occur in hatcheries during vulnerable early life stages. Chloramine-T and peroxide are widely used to control and eliminate infection associated with flavobacteriosis . OverallThere are several potential explanations for the comparatively small effects of chemotherapeutant treatments on larval gut microbial communities. One explanation is that the externally administered treatment did not enter the digestive tract in significant enough concentrations or duration to alter the gut community. When larval fish are provided chemotherapeutants prior to feeding, rather than during feeding, microbial compositional stasis suggested that the chemicals may not enter the gastrointestinal tract. Alternatively, the effect of the treatment may not have been evident due to the short treatment duration (15\u201360 min bath immersion) and weekly periodicity of chemotherapeutant treatments. Exposure to chemotherapeutants, consistent with our methodology, may not have been of sufficient concentration to result in quantifiable changes in gut community composition. In addition, fish were returned into their tank partition after treatments, and that may have allowed rapid recolonization of gut microbiota from the surrounding water. Further, chemotherapeutant treatments were administered at seven-day intervals, potentially allowing community recovery. The microbial communities may have exhibited resiliency to chemotherapeutant treatment; returning to a similar compositional state during the several day period between the timing of treatment and sampling for gut interrogation. Further studies are warranted to quantify the amount of any compound entering the gut during the treatment period to ascertain causal relationships.Thymus vulgaris essential oil (TVEO) on microbiota composition, compared with a control diet without TVEO over a 5 week period. Their study indicated high similarities between gut microbiota in treated and non-treated fish, and TVEO induced negligible changes in gut microbiota profiles. Essential oils include volatile liquid fractions produced by plants that contain the substances usually responsible for defenses against pathogens and pests due to their antibacterial, antiviral, antifungal, and insecticidal activities [In the LEfSe analyses, three out of thousands of microbial taxa appeared to be tied to differences between untreated fish in a hatchery and the wild. After fish were exposed to chemical treatments, different taxa were reported to be differentially abundant. Those taxa, however, are not among the dominant taxa. It is unclear how treatment differentially affected the relative abundance of these taxa. Results could indicate that the gut microbiota were either resistant or exhibited resilience in community composition, where treatment-based changes were short-lived and communities rapidly returned to their original state . The comtivities . We concFirmicutes, Proteobacteria, and Actinobacteria, that dominated the lake sturgeon larval gut community across all samples are Gram-negative bacteria. Many studies have shown that Gram-negative bacteria are resistant to commercially available antibiotics partly due to their thick cell wall structure compared to Gram-positive bacteria [Enterobacteriaceae include a group of bacteria known as extended-spectrum beta-lactamase (ESBL) Enterobacteriaceae that can confer resistance to antibiotics via production of the \u03b2-lactamase enzyme, which can inactivate certain \u03b2-lactam antibiotics [We detected three major phyla samples . The mosbacteria ,78. Enteibiotics .Firmicutes that were detected in fish guts across all families and treatments was primarily represented by Unclassified Clostridiaceae1 and taxa Clostridium sensu stricto. Although Clostridia are Gram-positive, these bacteria have been identified as part of commensal gut microbiota that plays major roles in the maintenance of the gut homeostasis. Several features associated with Clostridium spp. could explain why this taxon can thrive in the gut and can likewise be resistant to prophylactic treatments administered in our study. In humans, Clostridium spp. are involved in defenses inside the intestinal microecosystem along with gut-associated lymphoid tissue (GALT), and confer resistance against pathogen infections. This taxon is thought to have immunological tolerance [Clostridium spp. exhibit the ability to form endospores, which offers this bacteria ecological advantages for survival under adverse conditions [Another major phylum, olerance . In addinditions ,81.Comprehensive studies on adverse effects of antibiotic use to the gut microbiomes were reported in other fish species ,37,39 anCarassius auratus gibelito) [Aeromonas. The results were consistent with findings from another study conducted to evaluate the effects of orally administered antibiotics to gibel carp [Relatively few studies have been conducted addressing the effects of chemotherapeutants administered topically in water baths on fish gut microbial communities as conducted in this study. Most studies have been conducted on salmonids or tilapia ,45,75 anibelito) , and havibelito) reportedbel carp . ImportaA prerequisite for developing a strategy for microbial pathogen control is a knowledge of resident aquatic microflora associated with fish larvae, and how interactions between larvae and microflora occur. De Schryver & Vadstein suggesteFish produced from wild eggs show greater community diversity compared to artificially produced fish in the hatchery b. Thus, In fishes, microbial binding to host cell surfaces is often mediated through the interactions of bacterial carbohydrate binding proteins (lectins) with host cell surface carbohydrates ,85. StreSeveral studies of gut microbiota in fish with different genetic backgrounds have documented that host genotype (broadly defined) may contribute to compositional heterogeneity among individuals in fish gut microbiota, at least to some extent. Abdul Razak et al. studied Coregonus spp.) species pairs and their reciprocal hybrids were reared in captivity under a controlled environment. Analyses revealed significant effects of the host genetic background on the taxonomic composition of the transient microbiota. Navarrete et al. [Onchorhynchus mykiss). Full-sibling fish from four non-related families were fed two diet regimes in comparison to the control group. Results showed that some relative abundance of several bacterial taxa differed among trout families, indicating that the host genotypes may influence gut microbiota composition. In addition, the authors reported that the effect of diet on microbiota composition was dependent on the trout family. Studies on other organisms, such as chickens, also showed that under a common diet and husbandry practices, gut microbiota composition differed between two lines [Another study demonstre et al. assessedght, LW) . Findingght, LW) indicateFindings in this study detail observed differences in microbial founding sources and chemotherapeutic treatments to developing microbial communities during early ontogenetic stages. These results provide an insight into the consequences of prophylactic treatments and host-microbe interactions. Our study serves as a baseline providing information on the indirect effects of chemotherapeutant intervention that could either positively or negatively affect the normal gut microbiota. Results of minor effects associated with use of chemotherapeutants prophylactically suggest that topical use at the ontogenetic stage and concentration used may not have negative indirect effects on resident gut microbial communities. Thought should be given to the selection of locations to collect gametes to bring into culture. Future work could profitably focus on identifying microbial taxa that colonize the external surfaces of the fish to see how external treatments impact the colonization of external microbes. Further studies are also warranted that would compare the effects of treatments when administered following pathogen infection."} +{"text": "Transgender and gender-independent individuals (TGI) encounter myriad barriers to accessing affirming healthcare. Healthcare discrimination and erasure exposure among TGI individuals is vital to understanding healthcare accessibility, utilization behaviors, and health disparities in this population. Exposure to gender identity-related healthcare discrimination and erasure in childhood may contribute to TGI adults\u2019 healthcare utilization behaviors. The commonality of childhood exposure to gender identity-related healthcare discrimination and its relationship to healthcare avoidance during the early months of the COVID-19 pandemic among TGI adults were explored. TGI adults aged 18 to 59 (N = 342) in the United States were recruited online during the summer of 2020. Among individuals who reported childhood exposure to gender identity-related healthcare discrimination, 51% reported experiencing two or more distinct forms of discrimination. Hierarchical logistic regression indicated that exposure to healthcare discrimination in childhood significantly increased the odds of healthcare avoidance during the early months of the COVID-19 pandemic, after accounting for demographic factors and self-reported COVID-19 symptoms . These findings suggest that childhood exposure to gender identity-related healthcare discrimination is a prominent barrier to the utilization of healthcare for TGI adults, even during a global pandemic. Gender identity-related stigmatization, discrimination, and erasure in healthcare settings serve as central barriers to the accessibility and utilization of healthcare for individuals who embody transgender and gender independent (TGI) identities ,2. TGI iTerminology. The term transgender and gender nonconforming (TGNC) is umbrella terminology used to refer to individuals whose gender identities, gender roles, and gender expressions do not align with or conform to the gender norms associated with their sex assigned at birth , significantly predicted healthcare avoidance during the early months of the COVID-19 pandemic over and above the covariates. For each one-point increase in the childhood healthcare discrimination measure, respondents were 30% more likely to have avoided needed healthcare in the early months of the COVID-19 pandemic due to anticipation of gender identity-related discrimination.A hierarchical logistic regression analysis was condThis study expands the literature about TGI individuals\u2019 healthcare experiences and utilization behaviors ,10,12,18Independent of an individual\u2019s age, race/ethnicity, income level, disability/neurodivergent identity, and health insurance coverage status, lifetime exposure to healthcare discrimination predicted avoiding needed healthcare in the past year when they anticipated encountering gender identity-based discrimination, even despite this past year including pandemic conditions. Findings indicate that higher levels of lifetime exposure to varied forms of healthcare discrimination significantly increase the likelihood that TGI individuals will avoid needed healthcare due to anticipation of gender identity-based discrimination in healthcare settings. These findings demonstrate the considerable toll that healthcare discrimination has on TGI individuals in instances when they must consider the potential risks of seeking or avoiding healthcare beyond gender-affirming care when it is needed. These findings demonstrate the considerable toll that healthcare discrimination has on TGI individuals in instances when they must consider the potential risks of seeking or avoiding healthcare beyond gender-affirming care when it is needed. The postponement and avoidance of healthcare have been found to have detrimental outcomes ,24. As oHealthcare institutions and providers can work to ensure that these barriers of cisgenderism and cisnormativity are replaced with affirmation and a conceptualization of gender as a more expansive, nonbinary construct . It is iInclusive forms and records would also support TGI individuals in conveying the manner in which their gender identity intersects with their bodies to healthcare providers. TGI individuals may conceal their gender identities to avoid discrimination in healthcare settings which has healthcare accessibility and outcome implications . The useTGI individuals, particularly youth, their families, and their doctors, are being increasingly targeted by legislation and executive orders issued by governors that restrict the accessibility of gender-affirming care in states across the U.S. . DespiteCausal inferences could not be made in this study due to its cross-sectional design. Longitudinal cohort studies should be employed to expand knowledge regarding TGI identity development and healthcare accessibility barriers. This study used an online and non-probability sampling method, thereby lessening its representativeness of the diversity that exists among the TGI population. Despite the geographical representativeness of the U.S, the most marginalized tier of this population were unable to be accessed; as such, these results cannot be generalized to all TGI individuals. Future studies should strive to utilize probability sampling. While this study captured the reported prevalence of healthcare discrimination and healthcare avoidance behaviors associated with the discrimination faced in healthcare settings by this population, it did not investigate exposure to discrimination in specific healthcare settings . Future studies should assess exposure to erasure and discrimination within specific healthcare specialties. This study garnered information about respondents\u2019 disabilities/neurodivergence but did not inquire about participants\u2019 diagnoses of specific chronic health conditions.Notwithstanding these limitations, this study provides information that is critical to understanding the health behaviors and subsequent health implications for the TGI population. This study provides evidence of the persistence of myriad institutional, structural, and ideological barriers to transgender and gender-independent individuals\u2019 abilities to access healthcare, with associations of deleterious health behaviors generally, amidst a global pandemic, and has articulated numerous clinical and policy implications for future consideration."} +{"text": "Background: Autosomal-dominant facioscapulohumeral muscular dystrophy (FSHD) is a muscular dystrophy with associated retinal abnormalities such as retinal vessel tortuosity, focal retinal pigment epithelium defect and large telangiectasia vessels. Methods: Case report of an FSHD 16-year-old female referred for blurred vision in both eyes (20/40), evening fever and shoulder muscle weakness over the past month preceding assessment. A multimodal assessment including visual acuity (VA), microperimetry (MP), multifocal electroretinogram (mfERG), optical coherence tomography (OCT), fluorescein angiography (FA) and fundus autofluorescence (FAF) was performed. Results: OCT showed pseudocyst macular abnormalities and disruption of the photoreceptor layer with no signs of macular ischemia/exudation. Macular function showed foveal impairment recorded by mfERG and MP as a reduction of the response amplitude density and retinal sensitivity, respectively. No medical treatment was prescribed. After three years, patient\u2019s VA slightly improved to 20/32. OCT showed resolution of bilateral pseudocyst macular changes and persistence of photoreceptor disruption. By contrast, mfERG recordings remained abnormal for impaired foveal function and microperimetry mean sensitivity was reduced as well. Conclusions: This multimodal assessment showed persistent VA impairment at three years follow-up associated to abnormal foveal function and reduced retinal sensitivity, with spontaneous resolution of morphological macular changes, suggesting a retinal neurodegenerative process on the basis of the disease. After three years, the patient\u2019s visual acuity slightly improved to 20/32 in both eyes. The repeated SD-OCT scans showed spontaneous resolution of bilateral pseudocyst macular changes and persistence of photoreceptor disruption , morphological and functional (mfERG and microperimetry) assessment for studying the macular area.This multimodal assessment allowed for the finding of a persistent visual acuity impairment at three years follow-up that is associated to abnormal foveal function and reduced retinal sensitivity, with resolution of morphological macular changes, thus suggesting that visual acuity changes can be associated to foveal outer layers of retinal neurodegeneration, similarly to that found by our group in several neurodegenerative diseases .Bilateral visual impairment in a case of FSHD followed for three years was secondary to macular degeneration trait and not associated to vascular retinal barrier damage. The self-resolved macular abnormalities lead us to think that the pseudocyst changes could be an epiphenomenon of FSHD disease, possibly due to retinal vacuolization, whose pathogenic mechanisms need to be clarified by larger studies correlating signs of supposed vasculopathy and macular dystrophy appearance."} +{"text": "Severe childhood malnutrition impairs growth and development short-term, but current understanding of long-term outcomes is limited. We aimed to identify studies assessing neurodevelopmental, cognitive, behavioural and mental health outcomes following childhood malnutrition.We systematically searched MEDLINE, EMBASE, Global Health and PsycINFO for studies assessing these outcomes in those exposed to childhood malnutrition in low-income and middle-income settings. We included studies assessing undernutrition measured by low mid-upper arm circumference, weight-for-height, weight-for-age or nutritional oedema. We used guidelines for synthesis of results without meta-analysis to analyse three outcome areas: neurodevelopment, cognition/academic achievement, behaviour/mental health.We identified 30 studies, including some long-term cohorts reporting outcomes through to adulthood. There is strong evidence that malnutrition in childhood negatively impacts neurodevelopment based on high-quality studies using validated neurodevelopmental assessment tools. There is also strong evidence that malnutrition impairs academic achievement with agreement across seven studies investigating this outcome. Eight of 11 studies showed an association between childhood malnutrition and impaired cognition. This moderate evidence is limited by some studies failing to measure important confounders such as socioeconomic status. Five of 7 studies found a difference in behavioural assessment scores in those exposed to childhood malnutrition compared with controls but this moderate evidence is similarly limited by unmeasured confounders. Mental health impacts were difficult to ascertain due to few studies with mixed results.Childhood malnutrition is associated with impaired neurodevelopment, academic achievement, cognition and behavioural problems but evidence regarding possible mental health impacts is inconclusive. Future research should explore the interplay of childhood and later-life adversities on these outcomes. While evidence on improving nutritional and clinical therapies to reduce long-term risks is also needed, preventing and eliminating child malnutrition is likely to be the best way of preventing long-term neurocognitive harms.CRD42021260498. High mortality risk and impaired growth are well-recognised short-term risks of childhood malnutrition.While there is increasing appreciation of longer-term risks for survivors, notably adult cardiometabolic non-communicable disease, other longer-term risks have been poorly described.There is strong evidence that malnutrition impairs neurodevelopment and academic achievement in childhood which has significant implications for future well-being and prospects of those affected.Childhood malnutrition is associated with impaired cognition and behavioural problems with evidence of effects through to adolescence and adulthood but the effect of nutritional treatment and interplay with childhood adversity, coexisting illness such as HIV and environmental factors in influencing these outcomes is unclear.Study findings imply that there are likely to be long-term effects of childhood malnutrition on cognition and well-being lasting through adolescence and adulthood.Long-term needs of malnutrition survivors need to be carefully considered in treatment programmes. Further research is needed on the effects of nutritional therapy, adversity and environmental factors to tailor future interventions, particularly with regard to mental health which has been little researched.Severe childhood malnutrition is widespread and has a high disease burden concentrated in low-income and middle-income settings.5Understanding long-term outcomes following child malnutrition is especially important because improved treatment has thankfully resulted in more children with malnutrition surviving into adolescence and adulthood.Causal pathways linking malnutrition with neurodevelopment, cognition, behaviour and mental health are complex. Previous studies have found children admitted to hospital with severe malnutrition often have severe developmental delays with significant implications for ongoing development, well-being and potential future capital.10A 1995 review found school-age children who suffered from early childhood malnutrition generally had poorer IQ levels, cognitive function, school achievement and greater behavioural problems than matched controls and, to a lesser extent, siblings.We searched MEDLINE, EMBASE, Global Health and PsycINFO for studies published between 1 January 1995 and 6 January 2022 using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.10.1136/bmjgh-2022-009330.supp1Supplementary dataWe included studies from low-income and middle-income countries reporting neurodevelopmental, cognitive, school/academic achievement, mental health or behavioural outcomes in children under five exposed to malnutrition compared with children without malnutrition . We defined childhood malnutrition as undernutrition using standard definitions (definitions which are commonly measured in research and often related to severe adverse outcomes)14 15We included cross-sectional, cohort, case-control and controlled trial study designs which had a comparator group not exposed to childhood malnutrition. We excluded conference papers and reviews which did not include original data. We excluded studies which failed to define how malnutrition, child neurodevelopment, cognition, school/academic achievement, mental health or behaviour were measured. We also excluded studies looking at specific sub-populations of children . No language restrictions were placed on studies.Titles and abstracts were screened by two independent reviewers . The full texts of titles and abstracts chosen by any reviewer were then independently reviewed by two reviewers against our selection criteria. We also screened reference lists of included studies. Data extraction of included studies was done by one of AK or MGo into a standard template . Data extraction was subsequently checked by a second separate reviewer . Disagreements regarding inclusion of full texts and data extraction were resolved through mutual discussion.We assessed study quality using the National Institute for Health and Care Excellence (NICE) quality appraisal checklist.We grouped studies into three outcome areas: neurodevelopmental, cognition/academic achievement and mental health/behavioural outcomes (with some studies reporting outcomes from more than one category). We differentiated tools which measured general neurodevelopmental outcomes from those which specifically measured only cognition or academic language tests. We undertook a narrative synthesis of results within each of these areas as diverse outcomes and measurement tools precluded meta-analysis. We followed the Synthesis without meta-analysis (SWiM) reporting guidelines for analysing and reporting results.17For neurodevelopmental studies we grouped studies and compared results by neurodevelopmental assessment tool used. For studies investigating cognition/academic achievement, we grouped those that measured IQ or executive function and those that measured either school or language performance/assessment results. For mental health/behaviour studies, we grouped studies that used behavioural assessment tools and then into groups by mental health condition or domain assessed.For each study outcome where available, we recorded the unadjusted and adjusted results in cases and controls, reported effect sizes, and results from any statistical significance tests. When synthesising results by the groupings described above, we used vote counting by direction of effect to assess the number of studies which recorded differences between cases and controls. We summarised results in tables showing the number of studies with an effect on each outcome area. We also recorded the age group at which outcomes were measured to compare results between studies. Using SWiM guidelines we used vote counting in conjunction with study quality scores to summarise the strength of conclusions.Thirty studies met our selection criteria .18\u201347 FuStudy quality scoring is included in We identified nine studies assessing neurodevelopmental outcomes of malnutrition . A summaWe identified 12 studies (three from BNS) assessing cognitive outcomes of malnutrition . A summaEleven studies investigated cognition using several tools assessing intelligence and executive function . Eight oWe identified 14 studies (8 from BNS) assessing mental health and behavioural outcomes of malnutrition . A summaSeven studies (five from BNS) investigated different mental health outcomes .19 26 39Our review finds strong evidence that exposure to malnutrition in childhood impairs neurodevelopment and academic achievement. There is moderate evidence that childhood malnutrition is associated with impaired cognition and is associated with more behavioural problems throughout childhood and adolescence. However, there is uncertainty around the relative contributions of malnutrition and other associated factors to these outcomes. Research investigating mental health outcomes in children with malnutrition is inconclusive and there are few studies investigating specific mental health domains such as depression. These results have implications for policy-makers surrounding the long-term care needs of those treated for childhood malnutrition and there is a need for research exploring how nutritional therapies and social interventions affect these outcomes.Due to study heterogeneity, we were unable to perform a meta-analysis of any results. We therefore, used published guidelines to synthesise results and determine the strength of evidence for each outcome area. Despite this, there are still limitations given potential publication bias of positive associations between malnutrition and the outcomes investigated. Our review, however, builds on previously published evidence which has suggested links between malnutrition and poorer IQ levels, cognitive function, school achievement and greater behavioural problems.48Impaired neurodevelopment in childhood is likely linked to subsequently poorer academic achievement in childhood and adolescence and may also be linked to increased behavioural problems seen in some studies.While there is still uncertainty around the relative contributions of associated medical and social factors, there is increasing evidence from this review that the early impacts of malnutrition are related to worse academic, cognitive and behavioural outcomes compared with well-nourished peers. Preventing and decreasing childhood malnutrition is therefore of key importance to prevent serious long-term neurocognitive issues in affected children, particularly given the ongoing high malnutrition prevalence in many low-income and middle-income settings. Further research is needed on how to optimise treatment and to best support ongoing care for survivors to improve outcomes in the long term."} +{"text": "Monoclonal Gammopathy of Undetermined Significance (MGUS) is an understudied precursor of multiple myeloma (MM), the second most prevalent hematologic malignancy in the US. MGUS is incidentally diagnosed, and its significance is unclear as only 1% per year transition to MM. MGUS is highly prevalent among adults aged \u2265 50 years. In this presentation, we will review mixed-method approaches. Using healthcare claims and electronic health records from patients in central Massachusetts, we applied group-based trajectory modeling and conditional Poisson regression. These analyses were complemented by a qualitative analysis of in-depth interviews with providers and MGUS patients. Together, these methodologies provided a comprehensive evaluation of the impact of MGUS on healthcare utilization in older adults. The qualitative analysis provided a better understanding of the patient and provider factors influencing healthcare utilization after an MGUS diagnosis. The presentation will highlight how the use of these methodologies provide different perspectives among understudied premalignant conditions."} +{"text": "Urban residency benefits cognition in later life. In China, the household registration system (hukou) creates another place-based advantage/disadvantage for cognitive aging. We exam the interplay of rural/urban residence and hukou across the life-course in creating cumulative advantage/disadvantage in cognitive aging trajectories using longitudinal data from the 2011-2018 China Health and Retirement Longitudinal Study and its Life History Survey. Results from linear mixed effect models show that always urban dwellers with urban hukou exhibited the highest level of cognitive function and the slowest decline, and the always rural dwellers with rural hukou had the worst cognitive function and experienced a faster decline. Rural-to-urban shifts had better cognitive health than always rural dwellers, but the advantages depend on urban hukou attainment and specific mechanisms. This research suggests cumulative advantage/disadvantage in cognitive aging by residence and hukou throughout life and demonstrates that institutional discrimination and exclusionary policy may create inequality in aging processes."} +{"text": "The current study addresses how cancer and aging influence older adults' health trajectories differently. The unique cross-sequential design allowed the study to compare the health changes between long-term (5 years +) older cancer survivors and demographic-matched older adults without a history of cancer in the same geographic area within the same period by merging two longitudinal studies. The study also captured comprehensive information on health disparities over time. General linear models were employed. The findings showed that neither previous cancer experience nor aging affects health trajectories in later life. Conversely, comorbidities, being African American, female, having less than a college degree, and living alone significantly decreased the health trajectory in later life for all older adults. Moreover, when compared to other groups, older African American cancer survivors reported low scores in self-reported health after controlling for other conditions."} +{"text": "Pure cutaneous recurrence after breast-conserving surgery is rare and presents a unique challenge to clinicians. Some carefully selected patients may be amenable to further breast-conserving therapy. We present the case of a 45-year-old female with a cutaneous recurrence of previously treated right breast cancer along the operative scar in the upper outer quadrant. The patient underwent a further wide local excision with lateral intercostal artery perforator flap with a skin paddle reconstruction. We achieved volume replacement with this technique, disease control, and a pleasing cosmetic result. Breast-conserving surgery (BCS) is a well-established treatment modality for patients with early breast cancer and offers good cosmesis, low rates of recurrence, and survival outcomes comparable to mastectomy ,2. In paA 45-year-old female was diagnosed with a cutaneous breast cancer recurrence in the upper outer quadrant of her right breast approximately 10 years after a lumpectomy for early breast cancer Figures . At the BCS with adjuvant treatment achieves survival rates equivalent to those seen in patients treated with a mastectomy, while also achieving favorable cosmetic outcomes and low rates of locoregional recurrence . The risA completion mastectomy is usually the treatment modality of choice for ipsilateral breast cancer recurrence. More recently, further BCS has emerged as a feasible option in select patients. Alpert et al. published outcomes of completion mastectomy versus further BCS in 146 patients with ipsilateral breast cancer recurrence . After aOncoplastic techniques have continued to develop and offer patients good oncological outcomes with excellent cosmesis. In 1979, anatomical studies by Kerrigan and Daniel provided a sound understanding of intercostal vessels and skin flaps in the surgical repair of large trunk defects . FocusinHamdi et al. elaborated on the utility of intercostal perforator (ICAP) flaps in breast reconstructive surgery in 2006 . The conThe modified LICAP flap with a skin paddle is a novel way to replace volume and associated cutaneous defects in the breast tissue. Examples include cutaneous recurrence of breast cancer, as described, in patients who have had previous scar retraction or even skin necrosis where skin and volume replacement is required. It is not limited to just cutaneous recurrences, which are rare in themselves. The procedure offers both excellent oncological margins and cosmetic results and is suitable in carefully selected patients who participate in multidisciplinary treatment planning."} +{"text": "The purpose of this study was to identify the association between physical/mental health problems and depressive symptoms among older Black Americans (age \u2265 65) using the 2018 Health and Retirement Study (N = 812). People with multiple medical conditions face substantial emotional difficulties including depressive symptomatology. The study of depressive symptoms among older Black Americans is an emerging area of research. Several existing studies reported a higher prevalence of depressive symptoms among this population. They also experience a disproportionate burden of multimorbidity, both physically and mentally. For statistical analysis, depressive symptoms were measured with the eight-item CES-D scale . Physical multimorbidity was measured by asking whether respondents had ever been diagnosed with seven diseases . Mental multimorbidity was measured by asking whether they had ever been diagnosed with three diseases . Covariates included gender, marital status, and income (logged). A negative binomial regression showed that (a) higher numbers of physical health problems were associated with higher depressive symptoms ; (b) higher number of mental health problems were also related to higher depressive symptoms among older Black Americans . These findings underscore the importance of identifying and managing depressive symptoms among older Black Americans, who present with greater physical/mental health multimorbidity."} +{"text": "Personal networks are a key component in the provision of social support for older adults. Such support is particularly critical during the COVID-19 pandemic, when traditional avenues of social engagement or assistance are disrupted. Here, we use nationally representative data from the National Social Life, Health, and Aging Project that assesses older adults\u2019 pre-pandemic personal networks and receiving instrumental help and emotional support during the pandemic. We find that larger pre-pandemic confidant networks predict higher odds of receiving needed help and support, higher odds of receiving help and support more often than before the pandemic, and lower odds of being unable to get help. Denser pre-pandemic networks also predict higher odds of receiving instrumental help and support during the pandemic, while having a greater proportion of kin in pre-pandemic networks predicts higher odds of receiving pandemic help for non-white older adults only. Together, results suggest that features of older adults\u2019 pre-pandemic confidant network structure and composition can provide underlying conditions for receiving social support during the pandemic."} +{"text": "Pulmonary Langerhans cell histiocytosis (PLCH) is an uncommon diffuse cystic lung disease that occurs almost exclusively in young adult smokers. High-resolution computed tomography of the chest allows a confident diagnosis of PLCH in typical presentation, when nodules, cavitating nodules, and cysts coexist and show a predominance for the upper and middle lung. Atypical presentations require histology for diagnosis. Histologic diagnosis rests on the demonstration of increased numbers of Langerhans cells and/or specific histological changes. PLCH is one of the few diseases in which bronchoalveolar lavage (BAL) has a high diagnostic value and can in some circumstances replace lung biopsy. We present a case of PLCH in an elderly non-smoker. Chest imaging revealed the presence of advanced interstitial lung disease with a fibrocystic pattern. BAL cellular analyses disclosed a macrophage pattern with CD1a phenotype that strongly supports the PLCH diagnosis, even in the setting of atypical clinical presentation and a lack of smoking exposure. PLCH is extremely rare in non-smokers and could represent a distinct phenotype. BRAF-V600E mutation on the BAL cytology specimen and/or whole blood NGS for mutations and fusions in genes of the MAPK-ERK and related pathways provide supplementary diagnostic evidence, especially for atypical PLCH, and could stratify different pathological phenotypes [PLCH is a rare disorder (<5% of ILD cases) of unknown etiology that occurs predominantly in young smokers (>90% of patients) . PLHC beenotypes . The limenotypes . Unfortu"} +{"text": "Conventional structural neuroimaging methods can identify changes in cortical thickness but cannot relate these changes to specific cortical layers due to a lack of sensitivity. However, several indirect measures sensitive to changes specifically occurring in supragranular cortical layers were developed recently .The aim was to assess the ability of these novel measures to detect cortical layers thickness characteristics potentially associated with risk or resilience to developing schizophrenia.43 first-episode schizophrenia (FES) male patients, 29 non-converted individuals at ultra-high risk of psychosis , and 43 matched healthy controls (HC) underwent structural MRI at 3T Philips scanner. Images were processed via FreeSurfer and MATLAB to derive two markers specific to supragranular thickness change: gyral-sulcal thickness differences (GSTD) and gyral-sulcal intrinsic curvature differences on pial surface (GSCD).GSCD measures were increased in temporal, parietal and occipital cortices, whereas both GSTD and GSCD were increased in the right frontal cortex in FES compared to HC. No GSTD or GSCD were changed in ncUHR compared to HC, and GSCD was decreased in the frontal cortex compared to FES.Our findings from the indirect measures indicate a potential predominance of supragranular thinning in FES and suggest that a supragranular thinning in the right frontal lobe might be associated with precipitating risk and/or illness effects of schizophrenia. At the same time, no clear supragranular markers directly associated with resilience or risk mechanisms were identified. The work was supported by RFBR grant 20-013-00748."} +{"text": "Our first objective is to investigate how between subject differences in the likelihood of record linkage consent and record linkability determine the composition of and so risks of biases in estimates from linkable business datasets. The utility of datasets linking information from multiple sources is compromised by such non-linkage biases, but both components of the linkage process have rarely been considered. Our second objective is to introduce methods for evaluating non-linkage bias risks in datasets. Such evaluations can inform linkage method choice and assessment of the validity of linked dataset findings. Previous work, often lacking non-linked subject information on non-sample dataset covariates, tends to utilise overall linkage rates as quality measures, but in the related area of survey non-response correlations between analogous response rates and non-response biases are weak.We utilise the UK 2010 Small Business Survey (SBS) dataset. If a survey subject consents to record linkage, an attempt is made to append their Inter-Departmental Business Register (IDBR) identifier (if one exists), enabling linkage to other surveys etc. Given this, we evaluate bias risks arising from variation in subject linkage consent and identifier appendability, as well as its product, overall linkability, utilising representativeness indicators developed to evaluate survey non-response bias risks. These measure risks in terms of sample-subset similarity (representativeness) given an attribute covariate set obtained from the sample dataset, based on variation in subject inclusion propensities estimated by logistic regression, and are decomposable to assess correlates of inclusion propensity variation. Specifically, we use the CV (the standard deviation of inclusion propensities divided their mean), computed given nine attribute covariates describing business demography and perceived performance.We give full details in our presentation. Briefly, overall CVs suggest the linkable dataset exhibits substantial non-representativeness and non-linkage bias risk. Decompositions suggest main impacts on the linkable dataset are under-representation of very small businesses , due to being both less likely to consent and less likely to have an identifier appended, and under-representation of businesses unable / refusing to respond to survey items, due to being less likely to consent.Our analyses provide evidence of non-linkage bias risks in linked SBS datasets caused by under-representation of several sample subgroups. Each is explicable given known IDBR under-coverage or knowledge of business response processes. We also conclude that representativeness indicators are an easily applied method by which such risks can be evaluated."} +{"text": "Driven by the aim of realizing functional robotic systems at the milli- and submillimetre scale for biomedical applications, the area of magnetically driven soft devices has received significant recent attention. This has resulted in a new generation of magnetically controlled soft robots with patterns of embedded, programmable domains throughout their structures. This type of programmable magnetic profiling equips magnetic soft robots with shape programmable memory and can be achieved through the distribution of discrete domains (voxels) with variable magnetic densities and magnetization directions. This approach has produced highly compliant, and often bio-inspired structures that are well suited to biomedical applications at small scales, including microfluidic transport and shape-forming surgical catheters. However, to unlock the full potential of magnetic soft robots with improved designs and control, significant challenges remain in their compositional optimization and fabrication. This review considers recent advances and challenges in the interlinked optimization and fabrication aspects of programmable domains within magnetic soft robots. Through a combination of improvements in the computational capacity of novel optimization methods with advances in the resolution, material selection and automation of existing and novel fabrication methods, significant further developments in programmable magnetic soft robots may be realized. Variation of the material distribution and magnetic profile has enabled MSRs to demonstrate shape-forming and navigational abilities far beyond those of current soft robots (Programmable magnetic soft robots (MSRs) are typically formed through the combination of magnetic particles with soft elastomeric materials, and are controlled wirelessly t robots . Their pt robots presentst robots , shape-ft robots and origt robots .An idealized approach to the development of programmable MSRs is illustrated in This review aims to highlight the most significant developments and challenges specific to the optimization and fabrication of programmable domains for biomedical MSR applications. Following a review of programmable MSRs presented in the literature, we first consider specifically recent developments in optimization procedures, including physics-based modelling, deep learning and genetic algorithm protocols. This is followed by examination of novel fabrication methods across lithographic patterning, direct ink writing and direct laser writing that both support fabrication of optimal designs and limit optimization flexibility. We conclude the review with a discussion focused on the main current challenges and future directions of optimization and fabrication methods for the advancement of programmable MSRs.Many MSR designs rely on magnetic profiling approaches, as depicted in via UV curing, which fixed characteristic magnetization properties to individual target domains. Early research into MSR profiling was largely limited to non-programmable materials with heterogeneous magnetic distributions, typically restricting shape-forming and navigational abilities to planar deformations . More rein vivo environments such as the endometrium . Another key challenge remains in capturing the MSR\u2019s underlying physics at high fidelity and across a range of voxel scales. This includes interpreting viscous and frictional forces and self-interaction between magnetic regions at submillimetre scales. It is therefore pertinent to investigate methods with reduced computational burden and integration with realtime predictive model data, such that programmable MSR behaviours may be optimized with ever-increasing accuracy and reliability .Deep learning optimization integrates statistical modelling with iterative neural network computation to derive voxel configurations for desired deformation. The integration of deep learning algorithms with MSR fabrication has potential to significantly improve the selectivity and computational reach of MSR optimization, in turn paving the way for a new generation of optimized programmable MSRs.via experiment, which is arduous, or via simulation, which reintroduces the aforementioned errors in modelling assumptions. This presents a significant challenge to adoption in deep learning-based optimization of programmable magnetic domains to impart varied magnetic properties between cured layers. LP realizes exceptional applicability for single and multidirectional voxel magnetization, ranging from binary magnetization patterning in 1D to arbitrary multi-layer encoding in 3D programmable materials. It has therefore played an integral role, alongside studies into magnetic, complex 3D shape configurations, for biomedical MSR prototypes (In terms of programmable MSR fabrication, LP comprises a family of additive methods which involve embedding magnetic particles within curable substrates, followed by selective magnetization and composite curing (ototypes .via selective curing of a UV resin. Embedded particles were first magnetized with an external magnetic field. A template was then utilized to expose particular composite regions to UV light, locking in the embedded particle magnetizations. This automated process was used to fabricate 2D elastomeric MSRs with programmable magnetic anisotropies and facilitated the development of a bio-inspired undulatory swimming robot which utilized encoded travelling wave motion along its length to achieve flagellar motion, commonly observed in spermatozoa and bacterial cells. This may hold promising applications for minimally invasive navigation throughout complex vasculature or cerebral spinal fluid (A digital light processing lithographic method was developed by al fluid .In contrast, A lithographic approach was also taken by in vivo application (Current challenges for LP voxel-encoding lie in the limited availability of biocompatible materials . Future lication .DIW couples digitally-driven methods of fused deposition modelling with programmable magnetization to produce voxelated structures with readily encoded magnetic anisotropies . DIW incA similar method was developed by At present, DIW suffers from deteriorating print quality at submillimetre scales, largely as the scale of embedded magnetic particles is approached. Additionally, shorter voxel lengths at the submillimetre scale induces weaker magnetic densities between adjacent voxels. Both of these issues reduce the MSR\u2019s overall sensitivity to external magnetic actuation, as well as its ability to achieve deformations of greater complexity . Future via optical additive manufacturing. A magnetic field programs anisotropies throughout each printed voxel layer, whilst a laser scans across target regions for localized encoding of magnetic anisotropies. The application of heat by laser scanning prevents thermal diffusion of magnetic particles to non-target regions, whilst rapid cooling fixes the selected magnetization patterns before consecutive layers are printed. The integration of DLW with pre-existing fabrication methods presents promising opportunities for the rapid, automated fabrication of programmable domains at micrometre scales (Direct laser writing couples digitally-driven laser curing with programmable magnetization to selectively encode magnetic anisotropies at submillimetre scales. Similar to previous methods, DLW involves embedding magnetic particles within curable elastomeric matrices, often e scales .via global laser heating and individual voxel-programming at resolutions of 30\u00a0\u00b5m. The method was used to encode various magnetization profiles on a flower-inspired six-arm gripper robot (er robot . The sixCurrently, limitations in laser penetration depth remain a significant challenge in DLW, in turn limiting the method\u2019s expansion to rapid 3D fabrication and programming . Future in vivo drug delivery. To support flexible, rapid fabrication of MSRs, Other fabrication methods, including injection molding and magnetic spraying, have also played an essential role in the development of programmable MSRs for biomedical applications. Low-pressure injection molding methods for soft continuum MSR fabrication have recently been presented . Lloyd eIt is evident that, even within a short period, significant developments in the optimization and fabrication of programmable domains have played an integral role in miniaturizing and improving the functionality of bio-inspired MSRs. As indicated in via the integration of reliable and computationally efficient optimization procedures with flexible fabrication methods. To maximize this potential, it is therefore pertinent to address the resolution, material, computational and automation challenges that affect the presented optimization and fabrication methods.As outlined, the field holds exceptional potential via experimental data integration due to difficulty of reliable data collection at such scales. At present, optimization via genetic algorithms remains the most promising method, largely due to its operation with model-free experimental arrangements, capability of unlimited search space sizes and potential for increased adoption across various digitally-driven programmable MSR fabrication methods.The computational capacity of physics-based modelling remains a significant hurdle in determining optimal voxel behaviours at submillimetre scales and across the full spectrum of underlying physical interactions which influence programmable MSR actuation. With the identified need for improved models to capture the dynamics, material properties and interaction forces, the required current and potential computational burden of physics-based modelling is significant. The integration of real data to tune adaptive models may be pursued to reduce the computational burden of future physics-based model methods. In deep learning methods, the trade-off between experimental data and simulation data use remains a significant challenge to widespread adoption. Efforts to reduce modelling assumption errors, particularly within underlying FEM models, may be applied for improved reliability of simulation-driven deep learning methods. The choice to utilise experimental data within future optimization procedures may depend on the voxel scale and resolutions applied throughout MSR geometry, with submillimetre scales less likely to be optimized Additionally, significant challenges in the resolution, material selection and automation of current fabrication techniques must also be addressed. The limited availability of biocompatible materials remains a significant hurdle for current LP methods, however, additional research into the use of gelatin and hydrogel-based materials may improve the method\u2019s potential as a widely adopted programmable MSR fabrication procedure. Furthermore, several LP and other fabrication techniques comprise a series of manual steps, reducing the efficiency of the overall MSR fabrication process and hence limiting both its reproducibility and scalability for high-volume fabrication. These manual processes, however, bring greater flexibility for precise domain assembly, as observed in It is widely anticipated that improvements in the capacity of both statistical and physics-based optimization coupled with further improvements to the resolution, material selection and automation of existing and novel fabrication methods will pave the way for further novel programmable MSRs. If an appropriate voxel resolution can be achieved across both optimization and fabrication aspects of MSR development, extended shape-forming abilities and improved biocompatibility hold the potential to unlock novel applications at the milli- and submillimetre scales."} +{"text": "Each local authority in England must develop a Health and Wellbeing Strategy (HWS) in collaboration with NHS partners to plan and support delivery of local improvements in health and wellbeing. HWSs often draw on diverse sources but few are informed by consultative exercises involving citizens. South Tyneside Council in Northern England sought to ensure their new HWS was community-informed, specifically including seldom-heard groups and individuals. Specific objectives of this community insights research were to:1.Target sampling and recruitment activities at typically marginalized, vulnerable or otherwise underrepresented groups2.Explore the health and wellbeing-related views and priorities of these groups to address health inequalitiesA mapping exercise was undertaken to identify organisations who might act as gatekeepers to accessing participants from underrepresented groups. Focus groups were held in settings-based venues where members would be comfortable and known to one another. Representatives of voluntary and community sector (VCS) organisations often helped to co-facilitate the discussions.119 participants took part in 16 group discussions. Three were held online, two were outdoors, while 11 involved community venues where the groups regularly met. We reached older and younger people, minority ethnic groups, and vulnerable men and women, including residents who had experienced homelessness, mental health issues, substance misuse, offending, domestic violence and learning disabilities. Participants were largely concerned with the wider determinants of health , shifting the narrative away from individual lifestyle factors that tend to be the focus of much public health discourse.Gatekeepers from the VCS were essentially gateways, enabling us to include underrepresented voices in local consultation processes and generate new insights to inform the South Tyneside HWS.Public health strategy development can address health inequalities through community-informed consultative exercises involving seldom heard members of vulnerable communities.Community consultations seeking to reach typically underrepresented groups require gatekeepers acting as gateways, and meeting participants where they are comfortably located at community venues."} +{"text": "End-stage renal disease (ESRD) causes age-accelerating disease and disproportionally affects older and minority patients; the preferred treatment is kidney transplantation (KT). Rates of KT have risen 5-fold for older adults since 1990 but there is great heterogeneity in KT outcomes by frailty and waitlist status. The person-environment fit theory posits that improving a person\u2019s lived environment will facilitate optimal individual functioning. We recruited a balanced sample of 20 participants with respect to their frail/ pre-frail and inactive/ active waitlist status to explore personal experience and the lived environment through the use of photovoice, gaining insight into the person-environment fit of those older adults awaiting KT. We will discuss IRB issues, recruitment and logistical tips with using Photovoice. This work will help to inform what vulnerable and marginalized older adults awaiting KT must be prepared for psychologically and physically, including modifications needed to their lived environments."} +{"text": "Metabolic acidosis, a common complication in patients with chronic kidney disease (CKD), results in a multitude of deleterious effects. Though the restoration of kidney function following transplantation is generally accompanied by a correction of metabolic acidosis, a subset of transplant recipients remains afflicted by this ailment and its subsequent morbidities. The vulnerability of kidney allografts to metabolic acidosis can be attributed to reasons similar to pathogenesis of acidosis in non-transplant CKD, and to transplant specific causes, including donor related, recipient related, immune mediated factors, and immunosuppressive medications. Correction of metabolic acidosis in kidney transplantation either with alkali therapy or through dietary manipulations may have potential benefits and the results of such clinical trials are eagerly awaited. This review summarizes the published evidence on the pathogenesis and clinical consequences of chronic metabolic acidosis in kidney transplant recipients. CalcineRejection can cause tubulitis and ischemic tubular dysfunction, affecting H + ATPase activity and anion exchanger leading to RTA . HoweverLastly, hyperkalemia, a common occurrence post kidney transplantation also contributes to development of acidosis. Hyperkalemia decreases ammonia generation and transport in proximal tubule and collecting duct respectively, leading to impaired ammonia excretion and subsequent metabolic acidosis . Of the 2 level less than 22\u00a0mmol/L at three months post-transplant was associated with increased risk of graft loss and death censored graft failure , metabolic acidosis defined as the serum total CO failure . Similar failure ; however failure . This poPost transplantation anemia is common in kidney transplant patients with prevalence being reported around 30\u201350% of the patients . The pat2 vitamin D3 by proximal tubule, increasing calcium excretion and serum PTH levels, thus promoting bone resorption sorption . In vitreoclasts . Additioeoclasts , therefoeoclasts .Individuals with advanced kidney disease often have reduced muscle mass and exercise tolerance . PhysicaMetabolic acidosis has been shown to be an independent risk factor for all-cause mortality in CKD . These fThere is a paucity of evidence attesting to the benefits of metabolic acidosis correction in kidney transplant recipients. In fact, in a large retrospective study of 4741 kidney transplant recipients sodium bicarbonate therapy was associated with higher risk of graft failure . HoweverIn a small randomized controlled trial aimed to investigate the effect of sodium bicarbonate therapy on vascular endothelial function in 20 kidney transplant recipients , the sodData on dietary fruits and vegetable consumption as a measure of metabolic acidosis correction in kidney transplant recipients is even scarcer. In CKD, a diet rich in fruits and vegetables favorably affects acid-base metabolism, neutralizes diet-induced acid, and has been shown to be cardio-protective . In a prMetabolic acidosis is an understudied, highly prevalent complication in kidney transplant recipients. In addition to mechanisms described in metabolic acidosis of CKD, calcineurin inhibitors play a central role in its development and maintenance, through dysregulation of tubular transport proteins involved in acid load handling. Additional research aimed to unfold the mechanisms and consequences of metabolic acidosis present post kidney transplantation will help inform future large intervention trials designed to correct it, in an attempt to prevent allograft loss and improve overall survival in kidney transplant recipients."} +{"text": "Do physician group practices participating in bundled payments among Medicare beneficiaries exhibit similar or different changes in episode outcomes compared with participating hospitals?This cohort study with a difference-in-differences analysis found that physician group practices participating in bundled payments had associated savings with surgical but not medical episodes, whereas participating hospitals had savings associated with both episode types.The findings of this cohort study suggest that policy makers should consider the comparative performance of participant type when designing and evaluating future bundled payment models. Hospital participation in bundled payment initiatives has been associated with financial savings and stable quality of care. However, how physician group practices (PGPs) perform in bundled payments compared with hospitals remains unknown.To evaluate the association of PGP participation in the Bundled Payments for Care Improvement (BPCI) initiative with episode outcomes and to compare these with outcomes for participating hospitals.This cohort study with a difference-in-differences analysis used 2011 to 2018 Medicare claims data to compare the association of BPCI participation with episode outcomes for PGPs vs hospitals providing medical and surgical care to Medicare beneficiaries. Data analyses were conducted from January 1, 2020, to May 31, 2022.Hospitalization for any of the 10 highest-volume episodes included in the BPCI initiative for Medicare patients of participating PGPs and hospitals.The primary outcome was 90-day total episode spending. Secondary outcomes were 90-day readmissions and mortality.The total sample comprised data from 1\u2009288\u2009781 Medicare beneficiaries, of whom 696\u2009710 received care through 379 BPCI-participating hospitals and 1441 propensity-matched non\u2212BPCI-participating hospitals, and 592 071 received care from 6405 physicians in BPCI-participating PGPs and 24 758 propensity-matched physicians in non\u2212BPCI-participating PGPs. For PGPs, BPCI participation was associated with greater reductions in episode spending for surgical but not for medical episodes . Hospital participation in BPCI was associated with greater reductions in episode spending for both surgical and medical episodes.This cohort study and difference-in-differences analysis of PGPs and hospital participation in BPCI found that bundled payments were associated with cost savings for surgical episodes for PGPs, and savings for both surgical and medical episodes for hospitals. Policy makers should consider the comparative performance of participant types when designing and evaluating bundled payment models. This cohort study evaluates the association between bundled payments and episode outcomes per medical and surgical episodes for physician groups compared with hospitals participating in the Medicare bundled payments initiative. Along with hospitals, PGPs participated in model 2 of Medicare\u2019s Bundled Payments for Care Improvement (BPCI) initiative,10 assuming accountability for the quality and costs of medical and surgical episodes spanning hospital admission and up to 90 days of postacute care. Although PGP participation in BPCI was associated with reduced Medicare payments and improved quality for joint replacement episodes,11 data are lacking for the hundreds of groups participating in other medical and surgical episodes.Although hospital participation in bundled-payment programs has been well studied,12 We addressed this knowledge gap by evaluating the association between PGPs and hospitals participating in BPCI model 2 on episode outcomes and comparing PGP vs hospital performance.To coordinate participation in future payment models, policy makers must understand the dynamics of PGP vs hospital performance, particularly given the evidence from other payment models indicating that physician groups may perform differently than hospitals in managing quality and costs.STROBE) reporting guideline.13This study was approved by the University of Pennsylvania Institutional Review Board and informed consent was waived because only historical data with minimal risk of harm were used. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology and a subsequent intervention period . The study sample included Medicare fee-for-service beneficiaries receiving care through BPCI PGPs and hospitals for 1 of 10 episodes, each defined by a set of Medicare Severity-Diagnosis Related Group codes: the top 5 highest-volume medical episodes and the top 5 highest-volume surgical episodes . We excluded beneficiaries with end-stage kidney disease or insurance coverage through Medicare Advantage, as well as beneficiaries who had any non-Inpatient Prospective Payment System claims, lacked continuous primary Medicare fee-for-service coverage during or in the 12 months preceding the episode, or died during the index hospital admission.3 We excluded episodes between January 1, 2013, and September 30, 2013, to account for the transitional period during which PGPs and hospitals may have implemented care process changes in anticipation of BPCI.We constructed episodes beginning with hospital admission and spanning 90 days after hospital discharge, capturing episodes beginning on or before September 30, 2017. To avoid bias arising from Medicare precedence rules for overlapping episodes between participating PGPs and hospitals, we followed prior methods and constructed naturally occurring episodes by assigning overlapping ones to the earlier hospitalization.12 and those with any BPCI PGPs or BPCI hospitals were defined as BPCI Markets. We categorized patients based on hospitalization for 1 of 10 episodes of interest through BPCI PGPs, non-BPCI PGPs, BPCI hospitals, or non-BPCI hospitals. Patients receiving care through BPCI PGPs and hospitals were categorized as \u201cBPCI-both.\u201dWe used Medicare claims data (2011-2018) to identify BPCI PGPs and BPCI hospitals. Groups and hospitals that never participated in any of the 48 episodes in BPCI were categorized as non-BPCI PGPs and non-BPCI hospitals. We used propensity scores to match BPCI with non-BPCI PGPs and BPCI with non-BPCI hospitals , and other responses were classified in the \u201cother\u201d category.The study exposures were dichotomous indicators of PGP participation and hospital participation in BPCI. To reflect participant entry into BPCI at different times, participation indicators were time-varying and specific to each PGP or hospital. Groups and hospitals were considered as participants after enrolling in BPCI, regardless of subsequently dropping out. Covariates were chosen based on prior studies and included patient demographic and clinical variables, such as age, sex, and disease severity (defined using Elixhauser comorbidities), as well time-varying market variables, such as Medicare population size and Medicare Advantage penetration.The study\u2019s primary outcome was 90-day total episode spending . Secondary outcomes were 90-day readmissions and 90-day mortality. We also evaluated a number of exploratory spending and utilization outcomes (eMethods 2 in 18 We used a difference-in-differences (DID) method to mimic a 2\u2009\u00d7\u20092 factorial experiment comparing BPCI participation among hospitals and PGPs. Per the factorial design, we classified the treatment groups to reflect patient exposure to BPCI hospitals, BPCI PGPs, both (BPCI-both), and neither (non-BPCI). This approach enabled the comparison of episode performance for BPCI PGPs (vs non-BPCI) and BPCI hospitals (vs non-BPCI), as well as between BPCI PGPs and BPCI hospitals).Characteristics between the propensity-matched BPCI and non-BPCI PGPs and BPCI and non-BPCI hospitals were compared using standardized differences of means and proportions.19 Nonparticipating PGPs and hospitals were assigned the same treatment indicators as their propensity matched organizations. We evaluated medical and surgical episodes separately because they involve different care processes that may have different associations with outcomes.19In adjusted analyses, DID models included PGP- and hospital-specific indicators of BPCI participation as treatment to reflect the time-varying nature of BPCI participation\u2014that is, the fact that PGPs and hospitals could start participating at different times. This approach contrasted with traditional DID models, in which the baseline and treatment periods are fixed regardless of timing of actual contract initiation.We used generalized linear models with identity links and normal distributions for all outcomes. All models included episode (Medicare Severity-Diagnosis Related Group code) and market fixed effects to generate within-episode type, within-market estimates that addressed time-invariant episode type, and geographic differences. Models also included time fixed-effects to account for secular trends. Robust standard errors were clustered at the hospital level.20 we assessed the relationship between the primary outcome and potentially time-varying market-level covariates and how those covariates changed over time across the 4 study groups .Final model specifications for the primary outcome included only covariates deemed as potential confounders according to this process as being in the BPCI PGP group. Finally, we repeated analyses for the mortality outcome by including individuals who died during index hospitalization.In response to an association observed between BPCI participation and differential changes in mortality that, to our knowledge, has not been previously described in the literature, we conducted post hoc analyses to explore robustness. First, we described selection based on observable and unobservable patient characteristics. Second, we tested approaches to mitigate bias from unobserved clinical severity of patients. Third, we repeated analyses using our modeling approach, but using data from that earlier time period, to assess the ability to replicate those mortality results.The total study sample comprised 2011 to 2018 Medicare claims data for 1\u2009288\u2009781 beneficiaries, of whom 696\u2009710 patients received care through 379 BPCI hospitals and 1441 propensity-matched non-BPCI hospitals; and 592\u2009071 patients received care from 6405 physicians in BPCI PGPs and 24\u2009758 propensity-matched physicians in non-BPCI PGPs.Compared with non\u2212BPCI-participating hospitals, participating hospitals tended to be larger, nonprofit, teaching hospitals located in urban areas and markets with larger populations and smaller proportions of low-income individuals . In contrast, there were no differential changes in spending between BPCI PGP and non-BPCI groups or between BPCI-both and non-BPCI groups . The BPCI hospitals had differentially greater reductions in total episode spending compared with BPCI PGPs .In adjusted analysis of medical episodes , but not between BPCI PGP and non-BPCI groups . Compared with the non-BPCI group, there were differential decreases in mortality for BPCI PGPs and BPCI hospitals . The BPCI hospitals and BPCI PGPs did not exhibit comparatively differential changes in mortality or readmissions. The BPCI hospitals differed from nonparticipants with respect to exploratory outcomes for medical episodes , BPCI PGP group , and BPCI-both compared with the non-BPCI group. The magnitude of spending changes did not differ between BPCI hospitals and PGPs .In adjusted analysis . In contrast, there were no differential changes in readmissions for the BPCI hospital or BPCI-both groups compared with the non-BPCI group .Compared with patients in the non-BPCI group, those in the BPCI PGP group had differentially greater changes in 90-day readmissions and BPCI hospitals compared with patients in the non-BPCI group. The magnitude of these changes was not different for BPCI hospitals vs BPCI PGPs . Compared with nonparticipants, BPCI hospitals and PGPs differed in exploratory surgical episode outcomes (eTable 10 in Mortality changed differentially for patients cared for through BPCI PGPs (difference, \u20130.5 pp; 95% CI, \u20130.8 to \u20130.2 pp; 3 that found no association between BPCI hospital participation and differential mortality changes.Compared with the main study analyses, results of sensitivity analyses were qualitatively similar (eFigures 7-12 in In this cohort study with DID analysis, participation of PGPs and hospitals in BPCI was associated with cost savings for surgical episodes; however, only hospital participation was associated with cost savings for medical episodes. Hospital and PGP participation were associated with different patterns of changes in postacute utilization and mortality. For example, for medical episodes, hospital participation in BPCI was significantly associated with reductions in length of stay at skilled nursing facilities, whereas PGP participation was not. For surgical episodes, PGP participation in BPCI was associated with reductions in home health use, whereas hospital participation was not. These findings pose 3 implications.11 Although it is only one aspect of a payment model\u2019s success, spending reductions are critical because policy makers increasingly judge the viability of bundled payment programs by their cost savings.22First, these findings underscore the benefit of engaging PGPs in episode-based payment models. This analysis adds to prior work by describing the association of PGP participation in BPCI with cost savings for multiple surgical episodes, extending beyond hip and knee replacements.12 demonstrating that PGPs may be more successful than hospitals at reducing spending in population-based payment models, such as acute care organizations. Future work should elucidate drivers underlying this distinction. For example, hospitals may be better positioned to coordinate with postacute care organizations such as skilled nursing facilities given their high volume of shared patients. These strategies may be particularly important for medical conditions where the episode cost savings come from reductions in postacute care facility length of stay rather than reductions in the proportion of individuals discharged.3 Policy makers may consider these facets of performance when considering participant types in future alternative payment models.Second, these study findings affirm the suitability of hospitals to bundled payment models, specifically highlighting their relative advantage over PGPs in achieving cost and potential quality outcomes for medical conditions. These findings contrast with prior researchThird, these study findings emphasize the need for future research on the drivers of cost savings and quality improvements under bundled payments. Our results regarding BPCI-participating PGPs point to the importance of changes in readmissions and postacute care utilization in determining episode savings. Yet as observed from BPCI-participating hospitals, different patterns of utilization changes may drive savings for different episode types. Specifically, in these findings medical episode savings were associated with reductions in length of stay within skilled nursing facilities, whereas surgical episode cost savings came from fewer discharges to skilled nursing facilities.Additional work is also needed to assess the relationship between bundled payments and quality improvements. Although differential mortality reductions were observed by this study, there was also evidence of observable and unobservable favorable patient selection under bundled payments. This makes definitive conclusions regarding changes in health care quality challenging. Clarity on whether apparent quality changes represent true improvements, patient selection, or measures of both is highly relevant to policy and should be the focus of future studies.This study had some limitations worth noting. Findings may have been subject to residual confounding; however, we mitigated concerns by using a DID design that accounted for unobserved heterogeneity and patient and hospital characteristics. We evaluated the highest-volume episodes under a single program; however, BPCI model 2 was the direct basis for ongoing PGP and hospital participation in BPCI Advanced. Also, we did not include more recent data from BPCI Advanced because physician group participation files were not available. Moreover, we were unable to match physicians or identify episodes using tax identification number-level information owing to a lack of data availability. However, our approach using all episodes per National Provider Identification number and any participation in BPCI was conservatively biased toward the null hypothesis. Furthermore, to our knowledge, mortality reductions have not been previously described, and although we tested the robustness of the findings using a range of sensitivity and post hoc analyses, the analyses suggested the presence of unobservable patient selection that precluded definitive conclusions regarding any changes in health care quality. Despite conducting sensitivity analyses using alternative modeling approaches for episode spending as the primary outcome, future work should assess the use of modeling approaches beyond ordinary least-squares for other outcomes.This cohort study with DID analysis found that PGP participation in BPCI was associated with cost savings for surgical episodes but not for medical episodes, whereas hospital participation in BPCI was associated with savings for both episode types. Policy makers should consider the comparative performance of participant type when designing and evaluating future bundled payment models."} +{"text": "Bronchopulmonary sequestration (BPS) and hybrid lesion of congenital pulmonary airway malformation (CPAM) are congenital lung lesions typically presenting with systemic vascular connection. We describe and categorize this atypical systemic vascular anatomy in congenital lung lesions.In a medical chart review from 2005 to 2020 patients with systemic vascular connection of congenital lung lesions were identified. Clinical and radiological data were collected and compared. Two experienced pediatric radiologists reviewed postnatal thoracic contrast-enhanced computed tomography scans to describe and categorize atypical vascular anatomy. We completed our findings with a review on vascular anatomy in congenital lung lesions.A total of 21 patients with congenital lung lesions had systemic arterial supply; with seven of these additionally having systemic venous drainage. Origin of the feeding arteries from the aorta or aortic main branches was described as supra-diaphragmatic (descending thoracic aorta) in nine and infra-diaphragmatic in ten patients . In two patients with hybrid lesions both supra- and infra-diaphragmatic arterial feeders were found. Additional systemic venous connection of supra-diaphragmatic type drains into the azygos-hemiazygos system (4/21) while the infra-diaphragmatic type (3/21) drains into caval vein, portal or splenic vein.Various variants of systemic arterial and venous connection of congenital lung lesions can be found. Classification of systemic arterial connection as well as venous drainage of congenital lung lesions as supra-diaphragmatic and infra-diaphragmatic types is intuitive, simple and may be important for the surgeon to avoid unanticipated situations and to perform safe resections. Congenital pulmonary lesions are occasionally detected in prenatal ultrasound examinations. The most common lesions are congenital pulmonary airway malformation (CPAM) and bronchopulmonary sequestration (BPS). Atypical systemic blood supply is a characteristic feature of BPS, but there is also a number of CPAMs presenting with systemic vascular connection referred to as hybrid lesions . PrenataThis is a retrospective chart review performed in a tertiary perinatal center in a large Austrian city. After institutional review board approval, all patients with BPS and CPAM were identified in prenatal, neonatal and surgical database from 2005 to 2020. Only patients with systemic vascular connection of congenital lung lesion were included. Medical records were reviewed for pre- and postnatal clinical data; complications and outcome of treatment were assessed. Two experienced pediatric radiologists reviewed postnatal CECTs (iodixanol) to precisely describe the atypical anatomy of both arterial and venous systemic connection of congenital pulmonary lesions. We focus on description and categorization of vascular anatomy of these congenital lung lesions. A literature review on vascular characteristics in congenital lung lesions completes our data.From 2005 to 2020, 48 patients with either BPS or CPAM were treated at our department of pediatric surgery in a tertiary university hospital. In 39 cases these congenital lung lesions were identified in prenatal ultrasound examination. Postnatal CECT scan did not depict systemic vascular supply in 25 of 48 patients with congenital lung lesions\u2014these were \u201cclassical\u201d CPAM. In two patients, prenatally diagnosed congenital lung lesion was not confirmed postnatally: one child had a normal CECT scan and the other showed small vascular connections between the thoracic aorta and the pulmonary artery in the absence of a lung lesion.In 21 cases postnatal CECT depicted systemic vascular connection of congenital lung lesions: nine extralobar bronchopulmonary sequestrations (EBPS), five intralobar bronchopulmonary sequestrations (IBPS) and seven hybrid lesions. CECT scans were performed with general anaesthesia at a median age of 95 days (range 1\u2013218 days) in all patients. In seven of these 21 patients, systemic vascular supply had been identified prenatally .n = 4) and the abdominal aorta (n = 6). Further possible supra- and infra-diaphragmatic types of arterial feeders in congenital lung lesions are presented in n = 2) or infra-diaphragmatic types (n = 1). Maximum diameter of the arterial systemic branches ranged from 1.0 to 5.0 mm (median = 2.3 mm).Arterial blood supply of the congenital lung lesion was categorized as supra-diaphragmatic and infra-diaphragmatic, depending on the origin of the arterial branch . Supra-dSeven of twenty-one cases of congenital lung lesions with systemic arterial supply additionally had atypical systemic venous drainage . Supra-dOpen surgical resection of BPS and hybrid lesion was performed in all 21 patients with congenital lung lesion and systemic vascular supply. Postoperative complications were found in three patients (3/21). In two patients pneumothorax urged chest tube insertion in the postoperative phase. One patient had postoperative hemothorax due to blood oozing from injured intercostal vessels necessitating revision surgery within 8 h. No bleeding occurred from the ligated atypical systemic arteries or veins. At follow up 6 months after surgery all patients presented without any complaints.In congenital lung lesions, systemic vascular connection of the lesion is a frequent and characteristic finding. Atypical arterial and venous vessels play an important role in diagnosis and classification of these lesions. BPS may be diagnosed prenatally by depiction of a lung mass with systemic arterial connection. It is well-known that intralobar and extralobar bronchopulmonary sequestration may be distinguished by venous return of the lesion: IBPS drains via pulmonary veins while EBPS drains systemically. An overlap between BPS and CPAM has been found and this congenital lung lesion has been described as hybrid lesion\u2014a CPAM with systemic vascular connection . It is nSystemic arterial supply in congenital lung lesions seems to frequently originate from the thoracic or abdominal aorta . NeverthIn our series five patients had more than one systemic artery. As described in the sparse literature on this subject, this may not be a rare finding and evenThe most distal systemic arterial feeder in our series originated from the celiac trunk; but even arterial supply coming from a renal artery has been described . In thisAtypical systemic venous drainage occurs less frequently than atypical arterial supply in congenital lung lesions, as the majority of intralobar BPS show normal venous drainage via pulmonary veins. Nevertheless, systemic venous drainage may also be found in IBPS . Supra-dIn congenital lung lesions, atypical systemic vascular connection is a major cause of morbidity: high output cardiac failure, congestive heart failure or hemoptysis may occur . AlthougThe high degree of variability of systemic vascular anatomy necessitates clear and intuitive classification of this systemic arterial and venous connection in congenital lung lesions. Based on the origin of systemic arteries and veins we differentiate supra-diaphragmatic and infra-diaphragmatic vascular types of congenital lung lesions. This differentiation has practical-surgical relevance: as the diaphragm separates abdominal and thoracic cavity, vascular injury during surgery in congenital lung lesion with infra-diaphragmatic arterial supply may cause fatal intraabdominal bleeding. Therefore, our classification may contribute to correct preoperative evaluation to avoid unanticipated vascular complications.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.SK: study conception and design. FS, MS, and JK: data collection. SK, FS, MS, and JK: analysis and interpretation of results and draft manuscript preparation. All authors reviewed the results and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Medial prefrontal cortex (mPFC) interacts with distributed networks that give rise to goal-directed behavior through afferent and efferent connections with multiple thalamic nuclei and recurrent basal ganglia-thalamocortical circuits. Recent studies have revealed individual roles for different thalamic nuclei: mediodorsal (MD) regulation of signaling properties in mPFC neurons, intralaminar control of cortico-basal ganglia networks, ventral medial facilitation of integrative motor function, and hippocampal functions supported by ventral midline and anterior nuclei. Large scale mapping studies have identified functionally distinct cortico-basal ganglia-thalamocortical subnetworks that provide a structural basis for understanding information processing and functional heterogeneity within the basal ganglia. Behavioral analyses comparing functional deficits produced by lesions or inactivation of specific thalamic nuclei or subregions of mPFC or the basal ganglia have elucidated the interdependent roles of these areas in adaptive goal-directed behavior. Electrophysiological recordings of mPFC neurons in rats performing delayed non-matching-to position (DNMTP) and other complex decision making tasks have revealed populations of neurons with activity related to actions and outcomes that underlie these behaviors. These include responses related to motor preparation, instrumental actions, movement, anticipation and delivery of action outcomes, memory delay, and spatial context. Comparison of results for mPFC, MD, and ventral pallidum (VP) suggest critical roles for mPFC in prospective processes that precede actions, MD for reinforcing task-relevant responses in mPFC, and VP for providing feedback about action outcomes. Synthesis of electrophysiological and behavioral results indicates that different networks connecting mPFC with thalamus and the basal ganglia are organized to support distinct functions that allow organisms to act efficiently to obtain intended outcomes. The ability to act based on the current incentive value of action outcomes is a defining feature of purposive or goal-directed behavior, one that distinguishes goal-directed responses from stimulus-elicited habits that are unaffected by changing outcome values . Goal-diWe focus on behavioral and electrophysiological studies that allow direct comparisons between mPFC, the basal ganglia, and thalamus. Rodent mPFC corresponds to regions of primate cingulate cortex . It is aGoal-directed responses are guided by the incentive value of anticipated action outcomes . Much ofAlthough questions remain about their precise roles it seems clear that PL, IL, and MO are important for anticipating the incentive value of potential action outcomes. Neurophysiological recordings of brain activity have confirmed that neurons in these areas fire in anticipation of action outcomes and provided evidence that this information is also represented in other areas that give rise to goal-directed behavior. Human functional magnetic resonance imaging (fMRI) studies show that anticipation of monetary awards is associated with cortical activation in midcingulate/supplementary motor and insular areas distinct from areas of anterior and posterior cingulate cortices activated during award delivery . Electron = 50) in rats performing a dynamic DNMTP task (n = 63) exhibited increased activity within 0.2 s after reward delivery began and lasted until 1 s after it ended. They did not respond following unrewarded incorrect choices. It is unclear from timing data whether these responses are related to consummatory activity or reward delivery. Other studies have provided evidence that neurons in orbitofrontal cortex and mPFC encode information about the identity and subjective value of rewards analyses have revealed two levels of organization in learned action sequences: actions initiating learned sequences or chunks of learned sequences have elevated RTs reflecting the cost of planning an organized sequence ahead of time while actions later in sequences (or chunks) exhibit reduced RTs reflecting the benefits of performing a practiced sequence . Bailey While fMRI analyses have revealed preparatory activity in multiple brain regions, including motor, somatosensory, and parietal regions, only signals originating in contralateral supplementary motor and premotor regions consistently predict the type of sequential finger movement executed . AC cortAdaptive responding requires constant updating of sensory information to guide ongoing actions in dynamic environments. M2 plays a critical role in flexibly mapping sensory signals to motor actions, consistent with its prominent connections to sensory and association cortices and motor control areas . EarlierConvergent evidence indicates that cingulate areas of mPFC monitor current actions and outcomes, provide error feedback and information about reward value and manage conflict when there is competition between potential actions or strategies . ContingLesions or inactivation of mPFC affect the ability of organisms to adapt when contingencies between stimuli, actions, and outcomes are changed during extinction learning . ElectroTo respond adaptively in dynamic contexts organisms must constantly update information about environmental conditions and action-outcome contingencies across short and long timescales. mPFC is interconnected with important memory systems and has functional properties that seem well suited for this purpose see . mPFC isLonger-term memories promote adaptive responding by gradually integrating information across time, a function that allows organisms to adjust to lasting changes in the external environment or response contingencies. All areas of mPFC receive projections from the hippocampal-entorhinal cortex network and the BLA , importaAll areas of mPFC have afferent and efferent connections with multiple nuclei in central thalamus . These aThe central lateral (CL), paracentral (PC), and central medial (CM) rostral intralaminar nuclei project to distinct areas of mPFC and striatum that are connected by corticostriatal projections. These appear organized to control cortical-basal ganglia networks and thus the selection of goals, actions, and sensory signals . The venLesion and inactivation studies have confirmed the dependence of mPFC function on distinct contributions of different thalamic nuclei see . MD lesiLesions damaging the rostral intralaminar nuclei have effects comparable to mPFC lesions on DMTP and DNMTP: producing delay-independent deficits for egocentric DMTP and DNMTP that affect both speed and accuracy of choice responses with more limited effects on allocentric radial maze DNMTP . IntralaThe anterior thalamic AM and IAM nuclei are important nodes in pathways linking the hippocampal system with PL and AC areas of mPFC . AM and Striatum, the input side of the basal ganglia, receives projections from virtually all areas of cerebral cortex and the limbic system . These cLesion studies have demonstrated functional specialization at the level of the broad channels of information flow in dorsolateral, dorsomedial, and ventral striatum. Dorsolateral and dorsomedial striatum have also been dissociated for tasks used to distinguish goal-directed and habitual action control. Treatments disrupting dorsolateral striatum increase sensitivity to outcome devaluation and contingency degradation, interfere with execution of species-specific and learned sequential actions, and bias animals toward spatial rather than response-related cues in navigation while disruption of dorsomedial striatum blocks sensitivity to outcome devaluation and contingency degradation, decreases dependence on spatial navigation cues and increases reliance on habit learning . These fThe multiple striatal subnetworks revealed by large-scale mapping studies indicate that striatal specialization extends beyond the broad division into dorsomedial, dorsolateral, and ventral domains. Ventral striatum is considered an important link between limbic systems encoding reward and aversion and motor circuits . It receLesions or inactivation of ventral pallidum produce delay-dependent impairment of RT and accuracy of DMTP, comparable to effects of mPFC, central thalamic, and ventral striatal lesions . Cross-iMedial prefrontal cortex is organized as a hub for multiple large-scale neural networks that give rise to prospective, concurrent, and retrospective processes that support adaptive goal-directed behavior . ElectroAnatomical evidence indicates that mPFC is organized along a dorsal to ventral gradient, with more dorsal areas closely linked to sensory and motor cortices and ventral areas of mPFC receive more prominent connections with amygdala and limbic areas of cortex, including hippocampal and parahippocampal areas . Lesion Medial prefrontal cortex has reciprocal connections with multiple central thalamic nuclei that have distinct effects on adaptive goal-directed responding . This inMediodorsal is the main source of focal thalamic projections to middle layers of mPFC and accordingly is often emphasized in treatments analyzing the role of thalamus in mPFC function. Recent studies have elucidated a role for MD regulating signal processing properties of mPFC neurons and stressed its importance for rapid trial-by-trial learning and complex decision making . LesionsDorsal and ventral areas of striatum are comprised of distinct subdomains defined by open loop projections from functionally specific areas of cerebral cortex and the limbic system, closed loop projections from subregions of prefrontal cortex, and thalamostriatal projections primarily from midline and intralaminar nuclei. Both electrophysiological and behavioral findings (reviewed above) are consistent with the hypothesized distinction between ventral striatum processing reward signals and facilitating the motivational control of performance and dorsal striatum forming associations between sensory, motor, and limbic inputs to guide action selection and support the acquisition of goal-directed actions . Large-sThalamus serves as an important integrative center for cortico-basal ganglia networks as nodes connecting basal ganglia to cortex and as the source of thalamostriatal projections that terminate on medium spiny neurons in striatum . MD is a(1)Medial prefrontal cortex (mPFC) interacts with the basal ganglia and thalamus to support functions that allow organisms to control actions intended to obtain desired outcomes . These include prospective anticipation of potential action outcomes, selection and maintenance of motor goals, and motor preparation; concurrent control and monitoring of ongoing actions; and retrospective updating of information and strategies to guide future behavior.(2)Medial prefrontal cortex is organized with dorsal regions prominently connected with sensory and motor cortices controlling motor planning, prospective decision making, motor response memory, and flexible responding based on trial-specific sensory cues. Ventral areas have more prominent connections with hippocampus, amygdala, and limbic areas of cortex and are important for anticipating action outcomes, fear learning and extinction, and systems memory consolidation.(3)Electrophysiological recordings during DNMTP reveal neurons with responses related to actions and outcomes distributed throughout mPFC. Although there is no sudden transition apparent when electrodes are driven ventrally through mPFC, there are significant trends for neurons with responses related to motor preparation, lever press actions, and movements between levers to be distributed in dorsal mPFC and neurons with responses related to reward anticipation, movements toward reinforcement, and memory delay to be more frequent in ventral mPFC. Inactivation of central thalamus affects the expression of action- and outcome-related responses in mPFC. The inclusion of choice responses during DNMTP trials engages mPFC neurons to respond to task-relevant information.(4)Lesion studies indicate that dorsal striatum is important for associative and sensorimotor control and ventral striatum for reward and motivational control of goal-directed behaviors. Deficits produced by striatal lesions parallel the effects of lesions damaging anatomically related areas of mPFC. Large scale mapping studies have described extensive reconfiguration and integration of corticostriatal projections into striatal subnetworks that provide a structural basis for information processing and functional heterogeneity within striatum.(5)Multiple thalamic nuclei have afferent and efferent connections with mPFC that appear organized to control different aspects of goal-directed responding. The mediodorsal nucleus (MD) is the main source of focal thalamic input to middle layers of mPFC. Recent evidence indicates that MD amplifies and sustains activity in mPFC neurons that encodes information about actions and outcomes important for rapid trial-by-trial learning, complex decision making, and working memory. The intralaminar nuclei have thalamostriatal and thalamocortical projections that control transmission of information in cortico-basal ganglia networks. Behavioral studies have confirmed that intralaminar lesions have broad effects on functions that depend on mPFC and striatum. The ventral medial nucleus has prominent connections with dorsal regions of mPFC and adjacent sensorimotor cortex that support integrative motor responses. The ventral midline reuniens and rhomboid nuclei provide a critical link between mPFC and hippocampus and play a critical role in spatial and contextual memories and systems memory consolidation. The interoanteromedial (IAM) and anterior medial (AM) nuclei are nodes in pathways linking mPFC with hippocampus important for allocentric spatial learning and memory. While lesion studies indicate that mPFC lesions do not impair allocentric spatial memory, reciprocal connections with AM and IAM provide a link between mPFC and hippocampal-related systems that mediates this function.(6)Comparisons of neuronal activity in mPFC, MD thalamus, and ventral pallidum (VP) reveal important similarities and differences for information represented in these areas in rats performing a dynamic DNMTP task. Neurons in mPFC exhibit responses related to motor preparation, reward anticipation, and prospective memory delays not observed in VP. Responses related to motor preparation and prospective memory delays are also not observed in MD. Although reward anticipation responses are observed in MD, these are delayed and less robust. This suggests that mPFC exerts top-down control of prospective processes anticipating action outcomes, selecting motor goals, and preparing to execute action sequences. VP, by contrast, is dominated by neurons with responses related to reward delivery and reward-related actions consistent with evidence that VP provides feedback about action outcomes and affects the vigor of outcome-related responses.RM was primarily responsible for writing the article. MF, EK, and BG contributed to the writing and discussion. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Population aging in Singapore has encouraged the development of ambient smart communities to support healthy aging. Poor understanding of the living activities that address both clinical and biological concerns may plague efficient aging service designs and community health programs. We have designed a new computational workflow to identify important living activities for older adults in Singapore. We investigated innovatively three pillars of human life aspects: activities, clinical health, and biological health to identify living activities that are significantly associated with both clinical health and biological health. Cross-sectional data analyses were performed on 1356 community-living Chinese older adults of 65\u201380 years old in the Singapore Longitudinal Aging Study II (SLASII) cohort. 7 out of 29 living activities were found significantly associated with clinically healthy aging and showed improved prediction accuracy towards health status in machining learning schemes. Furthermore, biological age has been computed by screening and modeling 66 biomarkers. 15 out of the 29 living activities were found significantly associated with biologically healthy aging. Checking the overlapping living activities, we have found that physical exercise and cognitive-simulating activities are the most important activities for healthy aging: such as jogging regularly and reading, writing, and doing puzzles often. We regroup participants into active and non-active groups according to these two activities. The Keplan-Meier survival analysis showed statistically significant differences in survival time between the active and non-active groups (p < 0.001) in an 8-year longitudinal study. The workflow, results and biomarkers may provide references for future health program design improvement."} +{"text": "Disparities in vaccination uptake among migrant populations are well documented. WHO and ECDC have sought renewed focus on participatory research that engages migrants in co-producing tailored initiatives to address vaccination inequities and increase coverage.This community-based participatory research study aims to engage Congolese migrants in co-developing a tailored approach to increase vaccine uptake. Phase 1 used poster walls and in-depth interviews with Congolese migrants (n = 32) to explore COVID-19 vaccination beliefs, experiences, and preferred information sources and communication methods, analysed iteratively and thematically in NVivo.Institutional distrust has shaped this population\u2019s interpretation of the pandemic response and enabled vaccine misinformation and conspiracy theories to take hold. We found complex information networks and preference for Francophone, African and social media. Limited English proficiency and preference for the oral tradition restricted engagement with official public health messaging. Suspicion of government motives, low knowledge, and culturally specific perceptions about vaccination contributed to belief that breakthrough infections and need for COVID-19 boosters imply the vaccine is not effective. The population felt coerced by vaccination reminders and mandates, and were resultantly more hesitant to accept COVID-19 vaccination.The population\u2019s specific characteristics suggest that existing and trusted interpersonal networks and oral communication in first languages should be harnessed to spread credible information and encourage vaccine uptake, and mandate policies are unlikely to be effective. Training local role models to facilitate vaccination dialogues and myth-bust may be effective at changing behaviour. The next phases will gather more information from key stakeholders and engage migrants in workshops to co-design insight-driven, tailored interventions.\u2022\u2002Global policy-setting organisations have called urgently for participatory research that engages migrants in the co-production of tailored initiatives to address vaccination inequalities.\u2022\u2002Populations with strong interpersonal networks and low trust in public institutions may be receptive to tailored, community-centred dialogue approaches using local messengers and role models."} +{"text": "Pulmonary vein thromboses (PVT) is a complication of lung malignancy and can be complicated by arterial embolic phenomenon. Patient is a 69-year-old female with a history of coronary artery disease and recent pneumonia seen on chest x-ray who presented with progressive headache, left arm numbness and abdominal pain. She was found to have numerous bilateral strokes, bilateral renal infarction and splenic infarction. CT Chest showed a right upper lobe mass compressing the pulmonary veins with filling defects concerning for thrombus. Diagnosis of PVT is made with CT angiogram, echocardiogram and MRI. Treatment consists of anticoagulation and treatment of underlying factors. Pulmonary vein thromboses (PVT) is a described complication of lung malignancy , lung re2Patient is a 69-year-old female with history of coronary artery disease, ulcerative colitis, hypothyroidism, hyperlipidemia and recent pneumonia seen on chest x-ray who presented with progressively worsening headache, transient left arm numbness and abdominal pain. CT head was negative for acute hemorrhage. National Institute of Health Stroke Scale was 1. Neurology was consulted who recommended MRI brain. MRI showed multifocal acute and subacute infarcts in the supratentorial and infratentorial brain; in the bilateral frontal parietal cortical regions; occipital temporal regions; right thalamus and bilateral cerebellum. CT abdomen and pelvis showed bilateral renal infarctions and numerous splenic infarctions. The morning after admission the patient developed acute onset facial droop and slurred speech. CT head showed subacute right middle cerebral artery (MCA) and bilateral posterior cerebral artery (PCA) infarcts without hemorrhage, herniation or mass-effect/midline shift. CT angiogram of the neck was negative for any acute narrowing or aneurysm. CT perfusion showed a moderate sized area of ischemia in the left occipital and right temporal occipital lobes with large surrounding penumbra. CT angiogram of the head showed interval development of two noncalcified, soft thrombi located in the right MCA bifurcation and left MCA. Patient was taken for mechanical thrombectomy of the left MCA with good angiographic results with Thrombolysis in Cerebral Infarction score of 2c. Patient had worsening neurological exam overnight with increased somnolence which prompted repeat imaging. CT head overnight showed subacute right MCA/PCA, left MCA and left cerebellar infarctions, increasing edema with a 2 mm midline shift, no signs of herniation and subarachnoid hemorrhage. Transthoracic echocardiogram was negative for left atrial or left ventricular thrombus. CT Chest showed large right upper lobe mass with associated mediastinal and right hilar lymphadenopathy. The mass was compressing the pulmonary veins with filling defects concerning for thrombus. Due to the extensive stroke burden the patient was unable to receive systemic anticoagulation and the patient was transitioned to comfort measures. Transesophageal echocardiogram, biopsy of the mass and thrombophilia workup were deferred because of the family's decision to transition to hospice care.3PVT can be an unfortunate complication of malignancy, especially pulmonary malignancy. The case demonstrates a large right upper lobe lung mass compressing the pulmonary veins. External compression likely caused stasis and coupled with a hypercoagulable state in the setting of malignancy led to the development of pulmonary vein thrombosis. Subsequent thromboembolic phenomena led to diffuse infarction in multiple organ systems. Due to the acuity of the patient's symptoms and clinical deterioration, the gold standard imaging tests were unable to be obtained. Diagnosis can be challenging but detection of PVT is increasing with improvements in imaging technique. Typically, a combination of imaging techniques are used to best diagnose PVT. CT scan with IV contrast with timing for the pulmonary venous system is the best diagnostic technique . Transes-Patients with diffuse arterial emboli should be evaluated for pulmonary vein thrombosis, left atrial thrombus, left ventricular thrombus and systemic shunts-Workup includes CT imaging with timing of contrast to evaluate the pulmonary veins, MRI/MR venogram, transthoracic echocardiogram and transesophageal echocardiogram-Systemic anticoagulation should be initiated when diagnosis is suspected to avoid diffuse arterial embolizationThis work was performed as part of employment under Naples Community Hospital Healthcare System. The authors listed above are all employed within this system.The authors listed above certify that they have no financial or non-financial interest in the subject matter or materials discussed in this manuscript."} +{"text": "Impaired cognitive ability and its misperception contribute to poor decision-making of older adults; yet their impact on health-related decisions is less known. We examined how self-perceived and actual cognition were associated with chronic disease awareness using a nationally representative sample of Chinese older adults. Blood biomarkers data were collected in 2015 to identify participants\u2019 dyslipidemia and diabetes status. Among participants with identified dyslipidemia or diabetes, disease awareness was defined as self-reported diagnosis of the conditions as of 2018. Objective and subjective cognition were respectively assessed using the Mini-Mental State Examination and self-rated memory. The associations of subjective and objective cognition with chronic disease awareness were determined by weighted logistic regressions. Among 4,578 adults aged 60 and older with complete measurements, 1,442 and 759 individuals were identified having dyslipidemia and diabetes, with proportions of disease awareness being 38.0% and 58.1%, respectively. Individuals with mild or severe cognitive impairment had lower odds of dyslipidemia awareness; and those with severe cognitive impairment had lower odds of diabetes awareness than cognitively intact counterparts. However, adjusting for objective cognition, older adults with better subjective cognition had lower odds of dyslipidemia and diabetes awareness. Such associations were stronger for individuals with rural status, lower education, or living without children. Our findings highlight the great challenges deteriorated cognitive function and misperception may pose to chronic disease awareness, as well as the importance of targeted supports particularly for those more disadvantaged."} +{"text": "The incidence and societal burden of cancer is increasing globally. Surgery is indicated in the majority of solid tumours, and recent research in the emerging field of onco-anaesthesiology suggests that anaesthetic-analgesic interventions in the perioperative period could potentially influence long-term oncologic outcomes. While prospective, randomised controlled clinical trials are the only research method that can conclusively prove a causal relationship between anaesthetic technique and cancer recurrence, live animal (in vivo) experimental models may more realistically test the biological plausibility of these hypotheses and the mechanisms underpinning them, than limited in vitro modelling. This review outlines the advantages and limitations of available animal models of cancer and how they might be used in perioperative cancer metastasis modelling, including spontaneous or induced tumours, allograft, xenograft, and transgenic tumour models. In 2020, an estimated 18 million cancer cases were newly diagnosed (excluding nonmelanoma skin cancer), accounting for approximately 10 million cancer related deaths ,4.The original hypothesis that the anaesthetic technique during primary cancer resection surgery of curative intent might influence the risk of cancer recurrence or later metastasis was first proposed over a decade ago . This inTo ultimately prove these hypotheses, large prospective randomised-controlled clinical trials are required to establish if a causal relationship exists between anaesthetic techniques and the risk of cancer recurrence following primary cancer surgery. However, pre-clinical laboratory models, primarily in vivo animal models, retain an important role in translational cancer research for several reasons . FirstlyThe emergence of onco-anaesthesiology as a distinct clinical subspecialty has driven the exploration of translational research utilising animal models of cancer, traditionally undertaken by oncology researchers. Therefore, we aimed to summarise animal models of cancer commonly encountered within in vivo translational cancer research and how they may be applied to ongoing research in onco-anaesthesiology.Animal models of cancer may be classified in a variety of ways. Most simply, they are either spontaneous or induced and mammalian or non-mammalian. Alternatively, they may be categorized by the method of inducing cancer occurrence. However, spontaneously occurring cancers may occur in genetically engineered animal strains or such genetic-engineering may be induced following exposure to various carcinogens, so there is some cross-over in these descriptions. Non-mammalian animals such as zebrafish benefit from being high-throughput and low-cost, ideal for molecular investigation and chemical screening studies, however, significant phenotypical differences limit their usefulness for translational research so they will not be discussed further . Table 1A xenograft model involvesThe advantages of xenograft models are that they are relatively inexpensive when using commercially available cancer cell lines and attractive for translational research due to the ability to mimic cancer cell biological traits and the direct evaluation of therapeutic targets in human derived cancer tissue ,16. HoweAn allograft model involvesThe main advantage this has over xenograft models is the ability to evaluate the host animal\u2019s cancer-related immune response when assessing the effect of potential therapeutics. Compared to xenografts, allografts produce larger tumours that metastasize more quickly and reliably, enabling consistency when assessing for clinically relevant endpoints . They doThe preservation of the host immune response underpins why these models are often favoured for investigation in onco-anaesthesiology, where immunomodulation by anaesthetic drugs is one of the most frequently proposed mechanisms to explain how differences in perioperative pharmacotherapy may influence cancer outcomes ,25,26 A Testing potential therapeutics on spontaneous cancers that develop in household pets is an ofTransgenic models of canceTransgenic cancer models may play a significant role in onco-anaesthesiology research as they allow for testing of drug effects on the onset and progression of an expected cancer in immunocompetent animals, such as what has already been performed with morphine, which had no effect on the onset of cancer development but did hasten cancer progression . HoweverIn conclusion, there are several in vivo animal models of cancer that may be utilized for conducting translational research in onco-anaesthesiology. Whilst xenograft models are attractive for the ability to tailor the cancer cell biology around the human cancer under investigation, a lack of any representative immune response severely hinders its suitability for onco-anaesthesiology research. Transgenic models demonstrate significant promise in providing representative animal cancers and may be used alone or as donors for allogenic models. Multiple transgenic mouse colonies and cancer cell lines are commercially available to enable rapid integration of in vivo mouse models into novel research, however, due care must be taken to ensure the model chosen is most appropriate for the hypothesis under investigation."} +{"text": "The COVID-19 pandemic highlighted the significance of vaccination for older adults (OA), however, more health benefits could be gained with vaccination against influenza, pneumococcal disease, herpes zoster and tetanus as their uptake remains rather low. As healthcare professionals (HCP) play an important role in the vaccination decision making of OA, this study identifies obstacles in vaccination communication between HCP and OA.80 in-depth structured interviews have been conducted with HCPs in Hungary (HU), Italy (IT), the Netherlands (NL) and France (FR). Participants were general practitioners, medical specialists, public health physicians, occupational physicians, pharmacists, geriatricians, specialists elderly care and nurses. The interview included questions on HCPs\u2019 perceptions regarding information provision to OA on vaccines. Data were analyzed cross-country, using thematic analysis.Preliminary results reveal that a factor hindering HCPs to initiate conversations with OA on vaccines was lack of time . In hospitals this was often due to (acute) clinical problems taking precedence over discussing vaccines . In ambulatory settings the high number of patients waiting to be seen prevented discussing vaccines with OA (HU). Moreover, HCPs sometimes forgot to discuss vaccines with OA . Patient factors hindering the conversation of HCPs on OA vaccines were a negative attitude and lack of understanding the information provided . Also, misinformation on vaccines , as well as anti-vax beliefs from patients (NL) or their relatives hampered the conversation on vaccines. HCPs mentioned their need to learn communication skills to convince OA on vaccines .HCPs encounter various obstacles in communicating with OA about vaccines. Lack of time and not recognizing the opportunity to discuss vaccines are important barriers for initiating vaccine conversations.\u2022\u2002Providing HCPs with communication strategies is important to support HCPs in discussing vaccines with OA.\u2022\u2002Reminder systems are important to help HCPs remember address vaccination."} +{"text": "Many of the competencies that trainees in psychiatry are required to achieve can be linked to leadership in the broadest sense, yet specific training is not often systematically provided. The West Midlands Psychiatry Leadership Development Programme aims to support the acquisition of important leadership skills already set out in the curriculum through provision of high-quality specialist leadership content within the existing programme. Here we present the findings of a scoping exercise exploring the views and attitudes towards leadership training held by higher trainees in psychiatry within the West Midlands.All psychiatry higher trainees within West Midlands Deanery were invited to complete an anonymous online survey using Survey Monkey in November 2021. This survey incorporated questions about their preferred learning styles, confidence in their leadership skills and barriers to accessing leadership opportunities, generating both quantitative and qualitative data.37 responses were received. All subspeciality training programmes were represented. Almost half of respondents (46%) were ST6 or above and most were in training full time (84%).Trainees expressed a preference for experiential learning about leadership (87%) as well as small group teaching (62%) and interactive workshop style content (62%).Awareness of leadership opportunities was typically via their peer group (81%) or clinical supervisor (60%). Only 52% of trainees were aware of leadership opportunities within the Deanery.Only 54% felt that existing leadership training met their curriculum requirements. Less than half of trainees (46%) felt confident to evidence their leadership experience within their training portfolio.One-fifth of trainees (21%) reported experiencing barriers to leadership development. These included: inadequate awareness of opportunities, lack of senior support, time constraints and difficulty matching interests with available opportunities.Key results included:Trainees expressed interest in the redevelopment of a regional leadership training programme which would support them to achieve their curriculum competencies and prepare them for life as a consultant psychiatrist. The new multi-faceted regional leadership programme will offer resources in a variety of formats including webinars, podcasts, optional interactive workshops and action learning sets. It is hoped that this flexible programme, linked to the Medical Leadership Competency Framework, will better meet the needs of higher trainees as they pursue their own personal leadership journeys."} +{"text": "Previous studies have found relatively good physical health in doctors, whereas several studies now report relatively high levels of stress and burnout among them. With the exception of higher suicide rates, we have less evidence of poorer mental health among doctors than among other professionals. The elevated suicide rate may represent the tip of an iceberg of frustration and inadequate mental health care among medical doctors. There are very few longitudinal studies that can identify possible risk factors and causality. The Longitudinal Study of Norwegian Medical Students and Doctors (NORDOC) has since 1993/94 followed repeatedly two cohorts of medical students (N=1052) in seven waves during 25 years (Facebook: @docsinrush). Outcomes presented here are on mental health, burnout and problematic drinking. There are two main hypotheses with regard to possible risk factors. First, it may be due to individual factors such as personality traits, past mental health problems etc. Second, contextual stress may influence mental health among doctors, whether this be unhealthy working conditions or negative life events (i.e. stress outside of work). The presentation will give and overview of both individual and work-related predictors of stress and mental health problems among Norwegian physicians. Individual and organizational interventions to reduce stress and physician burnout will also be dealt with.No significant relationships."} +{"text": "Evidence suggests that besides having stigmatizing misconceptions towards people with mental illness, medical students and doctors often resist seeking help for their own mental issues. This is a vulnerable group for stress and other mental health problems, due not only to professional burden but also high perfectionism and low self-compassion.To analyse the relationship between mental health stigma (MHS) and other variables related to personality and emotional states in a sample of medical students.634 medicine and dentistry students answered to a survey including sociodemographic data, self-perception of psychological health/SPPH and the Portuguese validated versions of: Link\u2019s Perceived Discrimination and Devaluation (PDD) scale to assess MHS and its two dimensions - social stigma/SocS and self-stigma/SelS; Depression Anxiety Stress Scale (DASS-21); Neff\u2019s Self-Compassion Scale (SCS); and Big Three Perfectionism Scale (BTPS). Correlations, t-student tests and linear regressions were performed with SPSS 27.0.Stigma correlated negatively to SPPH and positively to DASS, the negative poles of SCS and BTPS second-order factors . No gender differences in MHS were observed. Participants with higher mean levels of total and SelS had significantly higher scores in all DASS dimensions and lower SPPH; participants with higher SocS also scored higher in DASS, but didn\u2019t reveal lower SPPH. Isolation was a significant predictor of SocS ; isolation and narcissistic perfectionism were significant predictors of SelS .Our results highlight the importance of including MHS as a main need in the curricula of future doctors.No significant relationships."} +{"text": "Mental disorders, such as depression, anxiety, and autism, have become one of the leading causes of disability worldwide with a high lifetime prevalence. Individuals with these disorders exhibit marked social and cognitive impairments, which are often closely associated with brain alterations both structurally and functionally. However, success rates of pharmacological and behavioral interventions vary widely and affected individuals often suffer from residual symptoms. Further, some of these interventions are characterized by severe side effects and induce high drop-out rates. Therefore, innovative brain modulation approaches that can directly target and regulate the involved brain circuits are of great translational potential for these disorders.Kerr et al. explored an innovative dyadic rt-fMRI NF protocol in which mothers attempted to down-regulate the anterior insula activity of their children. Based on an independent support vector machine-based classifier, Pereira et al. trained patients with depression to match their own neural activity with the neural activity corresponding to the \u201chappiness emotional brain state\u201d of a healthy participant via rt-fMRI NF training and found improvement in clinical symptoms associated with training success. Orth et al. conducted a systematic review of rt-fMRI NF studies targeting brain activations within the frontostriatal circuitry given that it is a common target for the treatment of aberrant behaviors in various psychiatric and neurological disorders. Their overview emphasizes the relevance to address network connectivity rather than localized excitability only.Our Research Topic aimed to improve our understanding of how innovative brain modulation approaches affect human behavior and neural responses and provide an overview on recent progress in the field. The articles that were published in this Research Topic bring us new insight on how brain modulation approaches such as real-time functional magnetic resonance imaging (rt-fMRI) neurofeedback (NF) training, transcranial magnetic stimulation (TMS), and transcranial direct current stimulation (tDCS) can be applied to modify emotion regulation and brain activity/connectivity in healthy or clinical populations. More specifically, in a proof-of-concept study on emotion regulation Cheng et al. investigated the asymmetric role of the bilateral ventrolateral prefrontal cortex (VLPFC) in cognitive reappraisal and found that while the left VLPFC is responsible for the semantic process of generating and selecting appraisal strategies based on the goal of emotion regulation, the right VLPFC is mainly involved in inhibiting inappropriate negative emotions and thoughts. Huang et al. demonstrated that a 4-week intervention of high-frequency repeated TMS on the left dorsolateral prefrontal cortex (lDLPFC) decreased the temporal variability of resting-state functional connectivity (rsFC) in the cortico-thalamo-cerebellar circuit (CTCC), with higher alteration in rsFC temporal variability between the left DLPFC and right posterior parietal thalamus predicting a higher remission ratio of negative symptom severity. Importantly, in the support vector regression analysis the pattern of rsFC temporary variability within the CTCC predicted the efficacy of high-frequency rTMS intervention on negative symptoms of schizophrenia. By combining tDCS with TMS, Alkhasli et al. revealed that excitatory intermittent theta-burst (iTBS) to a tDCS-inhibited lDLPFC yielded more robust functional connectivity to various areas as compared to excitatory iTBS to a tDCS-enhanced DLPFC. This suggests feasibility of using tDCS to modulate subsequent TMS effects on the DLPFC which may be of translational potential for the treatment of depression. In addition to these direct brain modulation approaches, Wang et al. demonstrated that open motor skill training (table tennis experts vs. matched non-experts) may be associated with greater activation in brain regions involved in visual processing during language processing tasks (word and semantic judgement tasks). These findings bridge the complex interplay between short- and long-term neuromodulation and behavioral training effects.Using the online single-pulse TMS technique, In conclusion, studies in the Research Topic applied highly innovative approaches to modulate human brain functions in healthy or clinical populations, with some of them reporting promising improvement in clinical symptom severity. We believe findings from these studies does not only improve our understanding of neural mechanisms underlying these brain modulation approaches, but also inspire future studies aiming to translate neuromodulatory approaches from different disciplines into clinical applications.SY and KM drafted the manuscript. JZ and XZ critically revised the manuscript. All authors contributed to the article and approved the submitted version."} +{"text": "Evidence documents racial/ethnic disparities in access, quality of care, and quality of life (QoL) among nursing home (NH) residents who are Black, Indigenous and persons of color. Yet, little is known about mechanisms for these disparities. This presentation examines the mechanisms for racial/ethnic disparities in QoL in high-proportion BIPOC facilities while highlighting variability in QoL disparities across these facilities. The presentation uses data from a 5 year mixed-methods project involving 96 resident interviews; 61 staff interviews; and 614 hours of observations in high proportion BIPOC facilities in MN, coupled with resident clinical Minimum Dataset assessments linked with survey data on residents\u2019 QoL. The findings show significant racial/ethnic disparities in QoL with need for system level changes. Given the increasing racial/ethnic diversity of NHs, ensuring equity in QoL for BIPOC residents is an urgent priority for NHs to remain relevant in the future."} +{"text": "The process of matching skeletal muscle blood flow to metabolism is complex and multi-factorial. In response to exercise, increases in cardiac output, perfusion pressure and local vasodilation facilitate an intensity-dependent increase in muscle blood flow. Concomitantly, sympathetic nerve activity directed to both exercising and non-active muscles increases as a function of exercise intensity. Several studies have reported the presence of tonic sympathetic vasoconstriction in the vasculature of exercising muscle at the onset of exercise that persists through prolonged exercise bouts, though it is blunted in an exercise-intensity dependent manner . The collective evidence has resulted in the current dogma that vasoactive molecules released from skeletal muscle, the vascular endothelium, and possibly red blood cells produce local vasodilation, while sympathetic vasoconstriction restrains vasodilation to direct blood flow to the most metabolically active muscles/fibers. Vascular smooth muscle is assumed to integrate a host of vasoactive signals resulting in a precise matching of muscle blood flow to metabolism. Unfortunately, a critical review of the available literature reveals that published studies have largely focused on bulk blood flow and existing experimental approaches with limited ability to reveal the matching of perfusion with metabolism, particularly between and within muscles. This paper will review our current understanding of the regulation of sympathetic vasoconstriction in contracting skeletal muscle and highlight areas where further investigation is necessary. As mentl muscle . Consisteceptors .1-adrenergic receptor agonist, phenylephrine, was only reduced during heavy-intensity exercise, whereas the vascular response to the selective \u03b12-adrenegic receptor agonist, clonidine, was diminished during mild- and heavy-intensity exercise. P2X-receptor responsiveness was attenuated during heavy-intensity exercise, whereas NPY-Y1 receptor responsiveness was blunted across exercise intensities -adrenergic receptors, it is theoretically possible that NE binding to \u03b2-adrenergic receptors may oppose SNS mediated vasoconstriction. However, sympathetic vasoconstrictor responsiveness was not augmented following \u03b2-adrenergic receptor blockade in male and female rats, indicating that \u03b2-adrenergic receptors do not oppose sympathetic vasoconstriction in contracting skeletal muscle or contribute to functional sympatholysis .Collectively, the available data related to changes in receptor responsiveness during exercise suggest that the distribution of post-synaptic receptors between muscles and in different vascular segments combined with muscle recruitment patterns may result in local modulation of vascular resistance that would serve to distribute blood flow between and within muscles and facilitate perfusion to metabolism matching during exercise. However, the definitive study to demonstrate this has not been completed.2 catalyzed by the enzyme NO synthase (NOS), which exists in endothelial (eNOS), neuronal (nNOS), and inducible (iNOS) isoforms . Tetrahydrobiopterin (BH4) is an essential cofactor required for NO production by NOS enzymes (4 administration. A reduced ability to inhibit sympathetic vasoconstriction during muscular contraction has been reported in humans with duchenne muscular dystrophy (The cellular mechanism(s) responsible for a decline in receptor responsiveness during exercise has not been fully elucidated, however the vasoactive molecule nitric oxide (NO) and intravascular adenosine triphosphate (ATP) have been the focus of investigation . NO is p enzymes . eNOS anisoforms . Tetrahy enzymes . Several enzymes . In cont enzymes . Acute uystrophy and in gystrophy that do ystrophy .Exercise training has also been used to investigate sympatholysis . In ratsGiven that NOS enzymes are expressed differentially across skeletal muscles , it seem+ channels) does not alter the ability of exogenous ATP to blunt \u03b1-adrenergic receptor mediated vasoconstriction , contrast enhanced ultrasound (CEU), and diffuse correlational spectroscopy (DCS/NIRS).NIRS-ICG has been applied to investigation of blood flow in skeletal muscle and the results compare favorably with dye dilution MRI methods during knee extension exercise . The tecContrast enhanced ultrasound requires infusion of microbubbles which are smaller than red blood cells to allow them to pass through the skeletal muscle microcirculation. As described by Diffuse correlational spectroscopy (DCS) is an emerging noninvasive technology that has been applied during exercise by several laboratories . CombiniAn example of how these techniques might be employed would be to apply DCS/NIRS sensors bilaterally to one limb that remains resting and the other limb which performs contractions across a range of exercise intensities. Sympathetic nerve activity could be activated reflexly to both limbs by using lower body negative pressure (LBNP) or cold pressor stimuli. Greater vasoconstriction in inactive skeletal muscle compared to active skeletal muscle would support redistribution of blood flow.The above example suggests an experimental approach to demonstrate redistribution of blood flow between muscles. Finding a method to study redistribution of blood flow within a muscle to more active fibers is more problematic. The fundamental problem is that microvascular units are not precisely aligned with muscle motor units. Constriction of a terminal arteriole reduces perfusion to all the capillaries supplied by that arteriole which means that perfusion cannot be exclusively directed to active muscle fibers or a single fiber type .Although not discussed in this focused review, there is ample evidence that aging, sex, obesity and various disease states modulate sympatholysis and impairments in sympatholysis have functional consequences for exercise performance. Further exploration of the effects of sympatholysis in these populations/conditions is warranted.Our current understanding is that the matching of skeletal muscle blood flow to metabolism involves a complex interplay between local vasodilation and sympathetic vasoconstriction that restrains local vasodilation and directs blood flow to active muscles, while also maintaining total peripheral resistance and blood pressure.The presence of tonic vasoconstriction in inactive tissue and exercising limbs is well established, and some studies have demonstrated that tonic vasoconstriction contributes to the distribution of blood flow within the limb during exercise. Numerous studies in a variety of experimental models have also demonstrated that sympathetic vasoconstriction is blunted in contracting muscle (sympatholysis). While investigators have done outstanding work to characterize the phenomenon of sympatholysis and identify some potential mechanisms involved in the process, direct experimental evidence that sympatholysis is involved in the matching of perfusion to metabolism is lacking.Despite the sound logic that sympatholysis would facilitate the distribution of blood flow between and within muscles during exercise, currently available technology and experimental approaches make the definitive study to demonstrate that sympatholysis contributes to the matching of perfusion to metabolism infeasible in the dynamically exercising animal or human. Until there is new evidence provided, researchers should refrain from speculating that functional sympatholysis can redirect blood flow to active fibers within a muscle."} +{"text": "Invasive\u00a0hemodynamic assessment of patients with an LVAD may improve readmission rates, but early detection of nonresponders-to-therapy can lead to earlier LVAD therapy and transplant listing.18.See Article page Left ventricular assist devices (LVADs) constitute important advanced therapy for patients with heart failure. Despite improvements in LVAD technology, optimal hemodynamic management remains challenging. In addition, frequent readmission, hemocompatibility-related adverse events, and thromboembolic complications limit the effectiveness of LVAD therapy.3The development of implantable hemodynamic monitoring (IHM) allows continuous, remote measurement of pulmonary artery pressure, which is known to improve outcomes in patients with heart failure.Utilization of IHM technology for ongoing monitoring and optimization of LVAD therapy in the outpatient setting is reviewed. A patient vignette describes IHM use in a patient before and after LVAD therapy to demonstrate improvement in pulmonary artery pressures after LVAD implantation, thereby allowing cardiac transplant listing. However, limited evidence to date does not support a recommendation for routine use of IHM in patients with an LVAD. Further study of IHM in this patient population is suggested.,Current era LVAD complications that limit transplant potential include pulmonary hypertension but are increasingly related to gastrointestinal bleeding, blood transfusion, and sensitization events or debilitating stroke.Increased adoption of IHM in patients with an LVAD (and advanced heart failure) has the potential to alter the transplant landscape by improving listing candidacy or status justification for patients in outpatient settings. These benefits may potentially lower waitlist time and mortality with earlier transplantation, obviating the need for prolonged hospital admission before cardiac transplantation.Lambert and Teuteberg"} +{"text": "Venous anomalies are typically asymptomatic and may be discovered unexpectedly at the time of implantation of a cardiac implantable electronic device. We report a case of leadless pacemaker implantation in a patient with hypoplasia of the left brachiocephalic vein who had previously undergone multiple interventions for relapsing right-sided breast cancer. The prevalence and etiology of this anatomic variant remain unknown. However, awareness of its existence may prevent complications during left-sided interventions. such as placement of a central venous line or a cardiac implantable electronic device. Alternative diagnostics and implantation strategies are discussed. Venous anomalies are typically asymptomatic and may be discovered unexpectedly at the time of implantation of a cardiac implantable electronic device. Rarely, venous anomalies result from chemotherapy or radiotherapy. We report a case of leadless pacemaker implantation in a patient with a severely hypoplastic left brachiocephalic vein who had previously undergone multiple cycles of radiotherapy for relapsing right-sided breast cancer.A 78-year-old woman with symptomatic transient third-degree atrioventricular block was referred for dual-chamber pacemaker implantation. The patient had a history of 2 right-sided breast cancer relapses, for which she underwent repeated surgeries and radiation therapy cycles between 1983 and 1993. A venogram at the time of implantation showed the absence of a left brachiocephalic vein, with drainage of the left jugular and subclavian veins into a left hemi-azygous vein (,,The prevalence of this anatomic variant remains unknown, and the etiology of an absent or hypoplastic brachiocephalic vein remains speculative.\u2022An absent or hypoplastic left brachiocephalic vein is rare, but this possibility should be kept in mind when performing left-sided interventions.\u2022The major tributaries of the superior and inferior vena cava derive from distinct embryologic veins.\u2022Venous anomalies are most often solitary. When a venous anomaly is discovered, alternative transvenous implantation strategies should be considered.\u2022Leadless pacemaker implantation can be successfully performed in patients with abnormal upper-body venous drainage as an alternative to surgical epicardial leads.We report a rare case of brachiocephalic vein hypoplasia discovered at the time of left-sided pacemaker implantation. Although this anatomic variation is rare, knowledge of its existence may allow avoidance of vascular complications. In this patient with a history of repeated right breast cancer surgery, alternatives included implantation of a leadless pacemaker, a transvenous femoral pacemaker, or epicardial leads. Investigation of the lower-body venous drainage anatomy revealed no further anomalies, and a leadless pacemaker was implanted."} +{"text": "An 85-year-old male who had been prescribed prasugrel presented to the emergency department (ED) after a motor vehicle collision and developed progressive neurological deficits. Computed tomography imaging demonstrated epidural thickening from the second through seventh cervical vertebrae, and magnetic resonance imaging was notable for a cervicothoracic epidural hematoma. The patient underwent emergent decompression with a favorable outcome.Cases of traumatic spinal epidural hematomas are rarely seen in the ED. These are part of a small subset of operative neurological emergencies that benefit from urgent surgical intervention. An 85-year-old male presented to the emergency department (ED) after a motor vehicle accident with abdominal pain, neck pain, and stool incontinence. The patient\u2019s medication list included prasugrel, but it was unclear whether he was taking it. Exam was notable for cervical and thoracic spine tenderness, decreased rectal tone, decreased bilateral upper extremity sensation, and mild weakness of the right lower extremity. Cervical spine computed tomography (CT) demonstrated dorsal epidural thickening from the second through seventh cervical vertebrae .On reassessment, the patient had loss of sensation below the seventh thoracic dermatome and markedly diminished bilateral lower extremity strength and reflexes concerning for ascending paralysis due to spinal cord compression. Magnetic resonance imaging (MRI) of the complete spine showed a cervicothoracic epidural hematoma .Orthopedic spine surgery performed emergent decompression, and the patient experienced rapid postoperative improvement in strength and sensation.A spinal epidural hematoma is a collection of blood between the spinal canal dura and vertebrae.3Given the non-specific clinical findings, spinal epidural hematomas are challenging to diagnose.5What do we already know about this clinical entity?A spinal epidural hematoma is a collection of blood between the spinal canal dura and vertebra that presents as back or neck pain with progressive neurological deficits.What is the major impact of the image(s)?Cases of traumatic spinal epidural hematomas are part of a small subset of neurological emergencies that benefit from early recognition and surgical intervention.How might this improve emergency medicine practice?Correlation of presentation with computed tomography and magnetic resonance imaging is essential to diagnose spinal epidural hematomas."} +{"text": "The no-touch saphenous vein with surrounding pedicle tissue harvesting techniquepreserved endothelium and vessel wall integrity and demonstrated improvedlong-term saphenous vein conduit patency that was comparable to internalthoracic artery conduit patency. Despite improved saphenous vein conduit patencyrates, there is a possibility that no-touch saphenous vein harvest may increasewound complication rates by increased tissue disruption, including venous andlymphatic channels. Comprehensive strategies to minimize leg wound complicationsafter no-touch saphenous vein harvest are discussed. An elasticated bandage was applied to the legwound after surgery and was replaced by a compression stocking from the2nd postoperative day. The compression stocking was kept in placefor 1 to 2 months postoperatively for prevention of leg swelling. TheJackson-Pratt drain was removed when the amount of drained fluid decreased to< 10 mL daily. Leg wound complications in the SV harvesting site were definedas infection or wound disruption that needed additional repair or secondaryintention healing. Leg wound complications developed in eight of 518 patients(1.5%) who received no-touch SV graft and underwent wound closure using theaforementioned strategies from 2017 to 2021 (unpublished data). All eightpatients recovered after secondary intention healing.After protamine administration to normalize the prolonged activated clotting timeat the end of CABG, a Jackson-Pratt drain was inserted into the SV harvestingsite and the leg wounds were closed in layers: interrupted 3-0 absorbablesutures to the subcutaneous tissue, interrupted 4-0 subcuticular absorbablesutures, and additional staples or zip surgical closure method for the skin. Zipskin closure is a noninvasive skin closure system, and it has several advantages forwound healing such as providing better cosmetic results, facilitating woundhealing, and reducing infection riskThe rate of wound complication after not-touch SV harvest may be minimized bypreoperative evaluation of lower limb vascular status, selection of an adequatevein, creation of a precise skin incision, careful harvesting of the vein, placementof a drain in the vein harvest site, and meticulous closure of the skin wound."} +{"text": "Physical activity contributes to the prevention of chronic illness as well as promotion of physical and mental health, but most adults remain inactive. Chronic illness affects mainly middle aged and older adults, and very little objectively measured data on physical activity behaviours and associated health outcomes of this population is published. The aims of this study are to: 1. Objectively measure physical behaviour outcomes of adults participating in the Move for Life study; 2. Develop distinct activity profiles based on six behaviour variables; 3. Investigate whether health outcomes differ across the activity profiles.Participants were Irish adults aged 50 years and older. Using the activPAL, objectively measured data were collected on average daily: light intensity physical activity (hours); moderate to vigorous intensity physical activity (minutes); step count; time in bed (hours); standing time (hours); and waking sedentary time (hours). Data were obtained on chronic illness and health service utilisation. Validated questionnaires were used to collect data on wellbeing, loneliness and social isolation. Hierarchical cluster analysis using squared Euclidian distance was used to cluster behaviours based on similarity, using SPSS version 26. Regression models explored associations between health outcomes and activity profiles, adjusted for age and sex.Data from 485 participants were analysed, and four activity profiles were identified: sedentary , low active , moderate active and higher active . We will present the differences across the activity profiles for chronic illnesses, multi-morbidity, health service utilisation and validated health tools, comparing to data from the Irish Longitudinal Study on Ageing (TILDA) and the English Longitudinal Study on Ageing (ELSA).The use of physical activity behaviour clusters may identify people with multi-morbidity and higher utilisation of health services. These findings could be factored into the development of future targeted physical activity interventions."} +{"text": "Coastal wetlands are not only among the world\u2019s most valued ecosystems but also among the most threatened by high greenhouse gas emissions that lead to accelerated sea level rise. There is intense debate regarding the extent to which landward migration of wetlands might compensate for seaward wetland losses. By integrating data from 166 estuaries across the conterminous United States, we show that landward migration of coastal wetlands will transform coastlines but not counter seaward losses. Two-thirds of potential migration is expected to occur at the expense of coastal freshwater wetlands, while the remaining one-third is expected to occur at the expense of valuable uplands, including croplands, forests, pastures, and grasslands. Our analyses underscore the need to better prepare for coastal transformations and net wetland loss due to rising seas. Landward migration of coastal wetlands under rising seas will transform coastlines but not compensate for seaward losses. Societal perspectives of the value of coastal wetlands have changed greatly in the past century coasts . Of the Our analyses indicate that freshwater forested wetlands and freshwater marshes collectively represent two-thirds of the total area available for wetland migration across the conterminous United States . Upland One of the critical limitations of prior landward migration studies is that they have focused exclusively on tidal saline wetlands without explicit consideration of adjacent freshwater wetlands . AlthougSome freshwater wetlands can migrate landward along river corridors into adjacent freshwater wetlands. However, that migration does not result in new wetland formation because it occurs at the expense of other freshwater wetland classes. Coastal freshwater wetlands that cannot migrate landward into uplands due to topographic barriers are particularly vulnerable to rising sea levels that lead to the landward migration of tidal saline wetlands . For exaTo complicate matters, there is much uncertainty regarding the long-term stability and potential extent of tidal saline wetland migration into adjacent freshwater wetlands. Many of these freshwater wetlands are positioned at elevations that may be equivalent to, below, or just slightly higher than tidal saline wetlands. Thus, these coastal freshwater wetlands are also highly vulnerable to coastal drowning under higher sea level rise rates. Further, in areas with organic-rich biogenic soils, there are critical questions regarding the likelihood of landscape-scale tidal saline migration given the potential for peat collapse and conversion of freshwater wetlands to open water that is too deep for plant establishment and the landward migration of tidal saline wetlands through biogeomorphic feedbacks between inundation, plant growth, and sedimentation. The second process involves the landward migration of wetlands into adjacent upslope or upriver lands. Our analyses focus exclusively on the second process\u2014the landward migration of wetlands.https://coast.noaa.gov/slr), the NOAA Office for Coastal Management has produced several related products including national-scale tidal datum data, derived from NOAA\u2019s vertical datum transformation tool , and Coastal Change Analysis Program (C-CAP) land cover class migration data at 0.1524-m net sea level increments. We obtained these data, which we used in combination with other land cover, elevation, and levee data sources, to identify areas available for the landward migration of tidal saline wetlands and freshwater wetlands.Our landward migration analyses examine the upslope and upriver movement of two broad wetland classes: (i) tidal saline wetlands and (ii) freshwater wetlands. To our knowledge, there is not a national-scale dataset that quantifies the migration potential of these two broad wetland classes into adjacent freshwater wetland and upland land cover classes. However, as part of the NOAA Sea Level Rise Viewer effort the inland limit of the MSLRMM-derived future estuarine land cover classes to define the upper boundary of the future tidal saline wetland zone (table S3) and (ii) the MSLRMM-derived future freshwater wetland classes to define the upper boundary of the future freshwater wetland zone (table S4). However, for some areas , we developed complementary analyses using the MSLRMM approach in combination with elevation data and MSLRMM-derived future MHWS data (tables S5 and S6).To define the lower boundary of the future tidal saline wetland zone, we used the upper boundary of the current estuarine land cover classes , which was determined using NOAA\u2019s 2016 C-CAP data . The state and estuary-scale data are available as a U.S. Geological Survey Date Release ("} +{"text": "Applications of dual-energy computed tomography and virtual non-contrast technique in neuroimaging are still emerging. While the role of DECT in differentiating parenchymal hemorrhage and contrast media after mechanical revascularization is well recognized, the value of DECT in evaluation of brain ischemia in post resuscitation patients who have received intravenous (IV) iodinated contrast is not well documented. We present a challenging case where DECT helped explain hyperattenuation in cortical grey matter and deep grey nuclei as well as cerebellar hemispheres in a comatose patient post cardiac arrest following massive pulmonary embolism. Applications of dual-energy computed tomography (DECT) and virtual non-contrast (VNC) techniques in neuroimaging are still emerging. While the role of DECT in differentiating between brain parenchymal hemorrhage and leaked contrast media after mechanical revascularization is well recognized 19-year-old female with no significant past medical history with only reported medication intake of oral contraceptive pills initially reported increasing dyspnea for 1-2 weeks preceding collapse with initial return of consciousness following bystander cardiopulmonary resuscitation. She subsequently lost consciousness, and Emergency Medical Services found her to be in ventricular fibrillation followed by pulseless electrical activity. She underwent pan-CT scanning with IV contrast earlier in the management which demonstrated massive pulmonary embolism resulting in right heart strain and manifestations of multi-organ failure. Within 24-hours of presentation the patient underwent percutaneous pulmonary artery thrombectomy and inferior vena cava filter placement. Serial head CTs performed are discussed below. Patient expired, following a short course, from multisystem failure.Serial CT imaging of the head was obtained that demDECT facilitates material differentiation based on different peak voltage acquisitions (high and low). Materials demonstrating equal Hounsfield densities at 120 kVp imaging can be distinguished by assessing energy dependent changes of attenuation of respective materials In our case, serial non-contrast CTs of the head demonstrated progressively increasing attenuation of the subarachnoid spaces that was attributed to pseudo subarachnoid hemorrhage appearance (vascular engorgement) secondary to severe diffuse cerebral edema and recent resuscitation from cardiopulmonary arrest, as has been previously described The VNC technique proved 2 things. First, the subarachnoid hyperattenuation was from contrast retention within the vasculature, and second and more importantly, the extensive hyperattenuating brain parenchymal areas that were bright on iodine maps were hypodense on the subtracted VNC images representing ischemic tissue retaining contrast. The VNC images confirmed underlying areas of brain infarction with extensive hypoattenuation in a pattern typical of diffuse hypoxic/ischemic insult. Hence DECT helped reveal widespread cerebral and cerebellar infarctions by confirming contrast retention in the areas of infarction.In conclusion, DECT with VNC is valuable in assessing brain parenchymal hyperdensities seen on a non-contrast CT in the setting of post resuscitation hypoxic/ischemic injury with prior history of IV iodine contrast administration. It differentiates contrast retention from hemorrhage and reveals underlying parenchymal infarction.Written informed consent for all pertinent details of this case was obtained from patient's representative."} +{"text": "The sympathetic nervous system maintains metabolic homeostasis by orchestrating the activity of organs such as the pancreas, liver and white and brown adipose tissues. From the first renderings by Thomas Willis to contemporary techniques for visualization, tracing, and functional probing of axonal arborizations within organs, our understanding of the sympathetic nervous system has started to grow beyond classical models. In the present review, we outline the evolution of these findings and provide updated neuroanatomical maps of sympathetic innervation. We offer an autonomic framework for the neuroendocrine loop of leptin action, and we discuss the role of immune cells in regulating sympathetic terminals and metabolism. We highlight potential anti-obesity therapeutic approaches that emerge from the modern appreciation of SNS as a neural network vis the historical fear of sympathomimetic pharmacology, while shifting focus from post- to pre-synaptic targeting. Finally, we critically appraise the field and where it needs to go. Anatomical dissections in the 17 Oxford) and subs Oxford) . Jacques Oxford) . Neurons Oxford) . By the esponse) and the The canonical model of bivalent and oppositional autonomic function is inadequate in describing metabolic control, as some metabolic tissues receive innervation exclusively from sympathetic neurons, including brown adipose tissue (BAT) and white adipose tissue (WAT), and in others like the liver, the sympathetic innervation seems to play the crucial role in hepatic homeostasis. While the SNS has long been acknowledged as an essential arm of metabolic control, the modern experimental toolkit has afforded a more consolidated appreciation of the sympathetic contribution to metabolic homeostasis. In this review, we first outline how sympathetic neurons control the metabolic activity of the pancreas, liver, and adipose tissues. Then, we describe how these processes are related to immune function and dysregulated by the inflammatory responses that characterize metabolic diseases. Finally, we highlight emerging therapeutics targeting key sympathetic processes to reverse metabolic disease.Sympathetic innervation is crucial for the regulation of pancreatic insulin and glucagon release and the control of glucose homeostasis, particularly by protecting against hypoglycemia during fasting and by increasing blood glucose during periods of elevated demand, such as by physical, inflammatory or psychological stress.panel A). Preganglionic sympathetic fibres in the greater thoracic splanchnic nerves provide inputs to coeliac ganglia neurons, which in turn provide postganglionic fibres to the pancreas. In addition, the vagus nerve provides preganglionic parasympathetic supply to a network of intrapancreatic ganglia. Neurons from the intrapancreatic ganglia then provide postganglionic cholinergic innervation to the exocrine and endocrine pancreas. Both vagal and spinal sensory fibres carry afferent sensory information from pancreas with their cell bodies in the nodose and dorsal root ganglia, respectively.Gross anatomical dissections and histological analyses of fixed pancreatic tissue, primarily in dogs and cats, provided an early anatomical framework for sympathetic, parasympathetic and somatic pancreatic innervation Figure , panel AMethodological limitations in classic histology \u2013 namely poor stain tissue specificity and inadequate image resolution \u2013 led to conflicting reports regarding the distribution of sympathetic nerve fibres within pancreas . Improvepanel B). Still, tissue sectioning an entire organ is laborious and tracing filamentous structures across serial sections is both time consuming and prone to artefacts. Tissue clearing, light sheet microscopy and image analysis have enabled the best 3-dimensional imaging and quantification of pancreatic innervation to date. Studies applying these methods in mice highlight sympathetic innervation to intrapancreatic ganglia, islets and vasculature (panel B). Quantification of TH+ innervation across hemipancreata confirmed relatively even distribution through the pancreas but suggested TH+ innervation is enriched in mouse islets compared to the exocrine pancreas, representing 3% of islet volume + sympathetic fibres allowed for 3D reconstruction and quantification of sympathetic innervation across the entire pancreas. In mice, such studies showed TH+ fibres distributed evenly throughout the pancreas and the culature . Sympathculature , together with neuropeptides such as galanin and neurStudies examining the roles of pancreatic sympathetic nerves on glucagon release have been more consistent. Splanchnic and pancreatic nerve stimulation increased pancreatic glucagon release into either the portal or systemic circulation in many species, including humans . In someHowever, splanchnic nerve stimulation and pharmacological studies do not specifically target pancreatic innervation, and it is possible that effects on other organs innervated by the coeliac ganglia, such as the liver, or modified by systemic adrenergic receptor antagonists may indirectly alter pancreatic insulin release. An additional challenge is discerning which changes to beta cell function are due to direct sympathetic neuronal signalling, and which are secondary to changes in islet blood flow, as evidence amounts for the parallelism of insulin secretion and vasodilation . FurtherSome studies have assessed whether sympathetic innervation also regulates the exocrine functions of the pancreas. Early studies in guinea pigs suggested so since NA administration potentiated cholecystokinin-induced amylase release . HoweverRecent intriguing work has suggested that pancreatic sympathetic innervation may play a role in the development, maintenance and remodelling of islet structure. Genetic or pharmacological ablation of sympathetic innervation in mice altered pancreatic islet structure reduced plasma insulin and impaired glucose tolerance. The effects on islet structure were partly reversed by beta-adrenergic receptor agonists . In addiUnlike the liver or adipose tissue, the pancreas receives dense parasympathetic innervation and islet expression of cholinergic receptors M2 and M3. Studies using electrical stimulation of the efferent vagus nerve lowered blood glucose while acdb/db mice, recent work reported remodelling of pancreatic ducts close to islets and increased sympathetic innervation of the islet-duct boundary nerves, but not the vagus branch innervatin the liver (parasympathetic), would inhibit this effect . Followial cells . Electroal cells . In addial cells .T. Belengeri, Forssman and Ito used fluorescence microscopy to show sympathetic nerve fibres in close apposition to hepatocytes in the peripheral zone of the lobule where parenchymal cells, sinusoidal lining cells and Kupffer cells also appeared to be innervated specific staining suggested cholinergic hepatic input to hepatic vessels, bile ducts and intralobularly in close apposition to hepatocytes and sinusoids . In modenervated . Auto-ra Mulatta . However Mulatta .Retroviral PRV tracing studies have mapped the neuroanatomical origin of hepatic sympathetic nerves. Two studies report sympathetic neurons originating from the coeliac superior mesenteric complex, aorticorenal and suprarenal ganglia, which are in turn innervated by splanchnic preganglionic neurons located in the intermediolateral column of the spinal cord (T7\u2013T12) Figure . PerhapsSince Claude Bernard\u2019s early lesion studies, a more consolidated appreciation on the function of hepatic autonomic innervation has been sought. In the 1960s, Shimazu and colleagues established that electrical stimulation of rabbit splanchnic nerve was sufficient to increase the hepatic gluconeogenetic enzymes glycogen phosphorylase and glucose-6-phosphatase . FurtherDespite the evidence that the liver is strictly innervated by the sympathetic nervous system, recent functional studies defend different perspectives. In one study, it was shown that surgical resection of the hepatic branch of the vagus nerve in rats would prevent the effects of brain-infused insulin on hepatic glucose production . Since ten passant fibres related to the sympathetic nervous system, impacted afferent signals, or have influenced surrounding organs, such as the adrenal glands or the pancreas. Even though the authors show no changes in corticosterone and glucagon one hour after the illumination, blood glucose increased quickly (within 15 min) and it is possible that hormone levels were affected in the first minutes.Another study used optogenetic approaches to identify the circuit by which pro-opiomelanocortin (POMC) neurons control blood glucose . In a fiBrown Adipose Tissue (BAT) performs non-shivering thermogenesis by dissipating the mitochondrial H+ gradient across the mitochondrial inner membrane while circumventing ATP synthase. Metabolic substrate is thus oxidised without generating chemical stores of energy, instead generating heat . BAT is BAT was recognised as relevant to the physiology of rodents and human infants as their large surface area to volume ratios required additional support in maintaining core body temperature . Only wiBAT has an impressive ability to use energy \u2013 it consumes more glucose per gram than any other peripheral tissue when stimulated, except perhaps the brain and estiSympathetic innervation has emerged as an important regulator of BAT thermogenesis - since the initial descriptions of the central role of sympathetic stimulation for maintenance of body temperature upon cold exposure and its Ucp1 mRNA , increases weight without affecting feeding behaviours and inhibits physiological responses to cold challenges. In denervated subjects - all of these processes can be acutely resolved via NA injection . More recp1 mRNA , but theUnderstanding structural, functional, and molecular changes associated with upregulated BAT thermogenesis could help unearth important pathways for potentiating its activity in humans. Imaging studies utilizing sectioning methods reported that cold exposure increases sympathetic nerve density and arborisation of BAT but modebeiging in WAT premotor neurons expressing POMC/CART in the hypothalamus , DMH and VMH nuclei) and in the brainstem, ii) spinal cord and iii) stellate ganglion . Additio obesity . By cont outflow , suggestGiven the complexity of hypothalamic networks, the precise signalling involved in downstream activation of sympathetic activity still needs to be further understood - however, it should be noted that its investigation has been focused on central pathways and assumed noradrenergic signalling as the single effector mechanism responsible for the observed phenotypes, a major caveat also present in studies investigating sympathetic functions in other tissues.(Nrg4) was significantly upregulated with BMP8b overexpression, and down-regulated in BMP8b knockouts. Exogenous application of NRG4 promoted sympathetic axon growth and branching, suggesting BAT could dynamically remodel surrounding tissue in response to BMP8b in mice increases sympathetic innervation and BAT vascularisation, even in mice housed at warm temperatures . Transcrto BMP8b . Similarto BMP8b . CLSTN3\u00dfto BMP8b . AdipocyFinally, emerging evidence suggests BAT is an integrated metabolic tissue with endocrine functions and roleNoradrenergic signalling has long been known to cause WAT lipolysis. Challenges presented by imaging adipose tissues and manipulating its function have meant that an understanding of how NA is supplied and regulated within WAT has been elusive until recently. Early imaging studies suggested that WAT received some innervation but the Only with recent advances in two-photon imaging and tissue clearing it has been possible to visualise entire sympathetic arborizations as well as confirm the presence of neuro-adipose junctions. In 2015, Zeng and colleagues used optical projection tomography approach to reconstruct 3D images of entire inguinal fat pads. Two photon microscopy of catecholaminergic reporter mice labelled with lipophilic dye showed that 50% of all neurons innervating fat pads were sympathetic, and bouton-like structures innervated 8% of adipocytes. Advanced tissue clearing preparations have allowed for direct imaging of entire fat pads . In 2017More macroscopically, retrograde tracing techniques have aimed to map the neuroanatomical origin of pre- and post-ganglionic fibres innervating WAT and suggest that distinct fat pads receive innervation from distinct populations of neurons. Early fluorogold retrograde tracing studies in Siberian Hamsters claimed dense cell bodies projecting to inguinal WAT (iWAT) from T13 abdominal sympathetic ganglion, although the study did not provide representative micrographs of ganglia . More moet al. likely caused tracer to diffuse via the inguinal canal to infect abdominal organs, highlighting a common pitfall in retrograde viral tracing studies.While most neuroanatomical studies tend to present harmonious findings, a 2017 study received a lot of attention and offered a different framework of iWAT neuroanatomy. The authors used an Alexa-dye-conjugated Cholera Toxin Subunit B (CTB) injection into iWAT and reported labelled neurons almost exclusively in the coeliac ganglia \u2013 a structure providing visceral sympathetic innervation to kidney, liver and GI organs. The authors reported very few cells innervating iWAT originating from either the spinal cord or lumbar dorsal root ganglia . These rSome deeper adipose pads also appear to be supplied by post-ganglionic neurons that synapse not in the paravertebral sympathetic chain but in mid-line autonomic ganglia. Using a green fluorescent protein labelled adeno-associated retrograde virus tracing technique, Cardoso et al observed cell bodies of the efferent sympathetic nerves innervating gonadal WAT (gWAT) in the aorticorenal ganglion . In addiIndirect evidence of sympathetic-induced lipolysis has existed for over 60 years - plasma free fatty acid concentrations were noted to increase with noradrenaline administration in rats and with electrical stimulation of adipose nerves in dogs, and these changes were inhibited by trimethaphan camphorsulfonate ganglionic blockade and peripheral \u00df-adrenergic antagonism . The anaDirect evidence that sympathetic activation was sufficient to drive lipolysis has only emerged since the advent optogenetic and chemogenetic techniques that can stimulate or inhibit the activity of molecularly defined neuronal populations. By crossing TH-Cre mice to a Cre-dependent ChR2 line, Zeng et al showed optogenetic activation of tissue specific sympathetic neurons released NA (as measured by ELISA assay) and chronic stimulation depleted fat mass in illuminated areas . SimilarSimilarly, the functional spatial control of SNS signalling is poorly understood. The apparatus for spatially restricted control of lipolysis is present \u2013 WAT is innervated from discrete spinal levels and sympathetic ganglia and local SNS-WAT communication is performed at the Neuron-Adipose Junction. Functional evidence based on limited NATO methods do support the notion of some regional specialisation in lipolysis. In response to a 16 hour fasting challenge, sympathetic outflow is significantly higher in iWAT over epididymal WAT (eWAT) , while iFinally, ambiguity still surrounds the morphological changes to sympathetic axons during cold and fasting challenges \u2013 namely, whether sympathetic arborisations change their density or localisation to facilitate lipolysis. Earlier studies suggested an increase in neuronal arborisations and increases in TH+ neuron density in WAT after cold acclimatization but these observations were based on analysis of tissue sections that poorly represent the entire fat pad . Whole t2 of iWAT per sample, while Chi\u2019s protocol lasted only for 7 days and analysed ten cubic \u2018representative\u2019 areas of unspecified size. In addition, Blaszkeiwicz used the pan-neuronal marker PGP9.5 for neuronal quantification, whereas Chi used TH, specific for sympathetic neurons. Recently, Willows and colleagues quantified neurite densities across entire adipose tissues using mechanical compression method, and found a non-significant increase in neurite densities in cold adapted mice, but only examined four mice in a proof-of-concept study that appears to play important roles in the regulation of metabolism. Because BeAT exhibits increased mitochondriogenesis and expresses a significant amount of UCP-1, it is thought that it has the capacity to generate heat through uncoupling of the electron transport expression which could be replicated by \u03b23 adrenoceptor agonism . UCP-1 p beiging .beiging and thermogenesis. 3D imaging of tissue cleared iWAT shows adipocyte-specific PRDM16 knockouts are unable to keep the regional differences in SNS density within the different sub-regions in iWAT, whereas the WT control showed a notable regional difference in medial vs lateral sub-regions of iWAT , a transcriptional regulator, is sufficient to initiate differentiation of beige adipocytes in subcutaneous WAT , and imp of iWAT ; this re of iWAT . BidirecHomeostatic neuroendocrine feedback loops maintain homeostasis via afferent (sensory) signals that are integrated and processed centrally to generate efferent (motor) outputs. In the context of metabolism, leptin is the primary afferent signal, information regarding metabolic state is computed primarily in the hypothalamus, and the SNS signalling acts as the effector arm .Leptin is an adipokine synthesised proportionally to adipose tissue mass. Global increases in fat mass raise plasma leptin concentrations to increase energy expenditure and reduce food intake . ConversImmediately following leptin\u2019s discovery , the preSympathetic signalling is an important mechanism by which leptin increases energy expenditure. Early studies noted that chronic \u03b23-adrenergic agonist treatment mimicked leptin application, reducing adipose tissue mass and leptin expression while sparing lean tissue mass in mice . Some muBy deduction, SNS signalling was the most likely mediator of leptin\u2019s effects on energy expenditure. This was bolstered by studies showing intravenous (IV) infusion or intra-hypothalamic delivery of leptin increases nerve activity to BAT. These measurements came from extracellular electrodes implanted over local neurovascular peduncles, so the activity of non-sympathetic neurons was also measured . Similaret al. (Leptin crosses the blood\u2013brain barrier (BBB) to bind to Leptin receptors (LepR), predominantly in the ARC, VMH, DMH and medial preoptic nuclei (MPO) and latet al. . Functioet al. . Also, cet al. . In addiet al. . Intereset al. , and thoet al. . Specifiet al. ), regulaMPO LepR+ neurons have recently been implicated in regulating both energy expenditure and thermogenesis in response to internal energy state . SimilarThe advent of techniques that allow tissue-specific control of neurons has yielded direct evidence of the necessity of SNS function to elicit leptin-induced energy expenditure. In 2015, Zeng and colleagues found tissue-specific genetic ablation of sympathetic neurons within a fat depot inhibited the lipolytic effect of leptin . SimilarLeptin resistance \u2013 a blunted response to leptin signalling, a weakened effector arm of this neuroendocrine homeostatic feedback loop \u2013 has emerged as an important pathological change in the development of obesity . This stInsulin resistance and hyperinsulinemia are associated with obesity and are connected with hypertension problems in obese subjects. However, similarly to leptin resistance, the mechanisms involved in the dysregulation of this neuroendocrine loop are still under study. Insulin resistance and hyperinsulinemia are associated with obesity and are associated with hypertension problems in obese subjects. However, similarly to leptin resistance, the mechanisms involved in the dysregulation of this neuroendocrine loop are still under study.Central insulin signalling is another important afferent signal in the metabolic feedback loop. There is accumulating evidence that insulin crosses the BBB into the brain and regulates different peripheral tissues and systemic metabolism and deletion of insulin receptors in the brain increases food intake and promotes obesity . ICV insHowever, other studies have shown the opposite. Insulin action in the brain is a critical regulator of WAT metabolism with inhibitory effects on sympathetic output. Thus, in lean rats, the sympathetic outflow to fat tissue is reduced and lipolysis suppressed after central insulin administration; but, like an inverse regulation, mediobasal hypothalamus insulin increases de novo lipogenesis in adipose tissue . NeverthStudies with neuron-specific insulin receptor knockout models have postulated some neuron populations as key players integrating the insulin signal. Thus, insulin signalling in POMC and NPY/AgRP neurons has an important role in regulating energy balance . InsulinSympathetic innervation of metabolic tissues is essential for maintaining metabolic health, but metabolic dysregulation increase the propensity for neuropathy within these tissues. Such an autonomic neuropathy may trigger or exacerbate metabolic diseases, initiating a positive feedback cycle seemingly difficult to break.Peripheral sensorimotor neuropathies are common in patients with metabolic syndromes, especially diabetes. While obese adipose tissue takes on a fibrotic quality that is difficult to image , 3D imaget al to observed liver neuropathy or in leptin deficiency . Liu anduropathy . In aliguropathy . In thisuropathy .Understanding the mechanisms by which SNS signalling to metabolic tissues is altered in disease states remains an important question in designing effective therapeutics. In recent years, the interactions between SNS, metabolic organs and local immune cells have emerged as a key contributor to pathological signalling changes. The central role of these interactions have led to the development of the growing field of neuroimmunometabolism, which investigates how these systems are interconnected and how these connections can be explored for therapeutic interventions.The presence of the relevant apparatus for SNS signalling, immune cells and adipokines to interact has been known for some time. All primary and secondary immune organs are innervated by postganglionic sympathetic nerves and bothAlbeit only a few studies have investigated the interplay between sympathetic signalling and immune modulation in the pancreas, recent work has supported a role for pancreatic sympathetic innervation in immune modulation and protection from autoimmune diabetes in mice . In one et al. used three-dimensional immunoimaging to evaluate the liver sympathetic innervation in samples from NAFLD patients, and revealed increased sympathetic axonal sprouting associated with mild nerve degeneration in the early stages of disease and a significant loss of sympathetic innervation in advanced steatohepatitis specialized in phagocytosis and participating in the innate responses. Interestingly, these cells were shown to be innervated by sympathetic fibres and to express adrenergic receptors . Evidencepatitis . They al increase from 10% of the adipose tissue resident immune cells to 50% and tend to change from M2 anti-inflammatory to a M1 pro-inflammatory phenotype, producing proinflammatory cytokines including IL-6, IL-1\u03b2 and TNF-alpha and paracrine factors. Proinflammatory ATMs were indirectly associated with insulin resistance, vascular remodelling, and increased adiposity, but over the last decade their role as architects of lipolytic signalling has been increasingly accepted. Indeed, among the tissues discussed in the present review, the adipose tissue is the one in which immune populations and their interplay with autonomic signaling are most extensively described .beiging of WAT and causing a significant and sustained weight loss in obese mouse models . Cruciale models . Likewise models reportede models .et al. onto adipocytes and incubated with Met-Enk to onserve an upregulation of Ucp1 data from WAT . Paralelipocytes . Ultimatutgrowth . Thus, bCollectively, these findings establish a novel homeostatic role of tissue macrophages and other immune cells that can control sympathetic innervation. Any disruption between this neuroimmune crosstalk might impact the nerve integrity and tissue function with a considerable final effect on metabolism.Obesity is a leading cause of morbidity and mortality globally, but until recently, anti-obesity pharmaceuticals have had poor therapeutic efficacy and tolerance. The prolipolytic signalling of the sympathetic nervous system has attempted to be exploited by sympathomimetics - compounds that stimulate sympathetic nerves by inhibition of MA uptake or direct stimulation of peripheral adrenoceptors . They haClassically, the mechanism of action of sympathomimetic-induced weight loss was thought to be central, by suppressing appetite and promoting locomotion. The addictive properties of sympathomimetic are due to nigrostriatal monoamine release; cardiovascular toxicity is thought to be caused by a combination of central and peripheral stimulation. This view was challenged by Mah\u00fa and colleagues, who brought attention to the contribution of the brain on the peripheral readouts of sympathomimetics , while p\u00df3-adrenoceptor agonists have also received attention due to their ability to promote BeAT differentiation and formation in rodents, but poor selectivity and systemic administration of early \u00df3 agonists caused intolerable side-effects .Recent attention emerged surrounding Mirabergon, a specific \u00df3 agonist already used to treat urinary urge incontinence. In 2015, Cypess and colleagues measured 18F-FDG uptake in PET scans to show a 200mg dosing regimen of Mirabegron increases human BAT metabolic activity, while also increasing BAT glucose uptake and increasing resting metabolic rate by 230\u00b140 kcal/day . SubsequRelative to brain research, sympathetic neuroscience is lagging several decades behind - owing to the dispersed and difficult anatomical access and technical limitations that the developments we envision will likely surpass. These will be necessary to overcome the conceptual barrier that stagnated in the era of adrenergic receptor pharmacology, which solely accounts for post-synaptic adrenergic targeting in organs. Although such models account for the action of a few adrenergic drugs that are routinely used in the clinic , sympathetic nerves are seldom considered as a neural circuit, whereby pre-synaptic manipulations of a node within the network might not be predicted by post-synaptic adrenoceptor agonism or centrally acting sympathomimetics which have a widespread top-down action. Moreover, the assessment of adrenoceptor subtype expression across cell types mainly originates from bulk tissue techniques that do not account for expression by resident immune cells. Only single nuclei sequencing has parsed apart tissue heterogeneity, particularly that of WAT&BAT, which cannot be analyzed by conventional cell sorting.Moreover, the linearity of post-synaptic agonism falls apart as adrenoceptors are also expressed in sympathetic neurons, suggesting that feedforward or feedback circuits may exist among ganglia. Whether intra- and inter ganglionic circuitry exists is an open question, despite the highly suggestive TH+ axon bundles between every two ganglia along the paravertebral sympathetic chain. Such ganglionic circuits can be influenced by resident immune cells that cleanse norepinephrine or produce neuromodulators such as opioids. Thus, the field needs to rise from the era of post-synaptic adrenoceptor pharmacology to that of neural networks. As such, the classic view that SNS is responsible for the \u2018fight or flight\u2019 response antagonised by the PNS is an incomplete description of autonomic metabolic control in light of the modern neuronal network theory. Not only do adipose tissues and liver receive innervation exclusively from the SNS, but PNS in the heart can act as a cardioprotective buffer whilst sympathofacilitator drugs exert effective control of metabolic tissues to facilitate weight loss and restore the homeostasis of the neuroendocrine loop of leptin action.Current molecular genetic technologies widely used in the brain have had limited success with SNS circuits. Dissections of the murine paravertebral sympathetic chain of ganglia are complicated, and retrograde tracing with a non-replicative non-polysynaptic virus has low transduction efficiency, perhaps due to the cleansing of viral particles by immune cells resident in sympathetic tissues. PRV retrograde tracing pioneered mapping the efferent postganglionic sympathetic innervation of BAT, which seems consensual across species. However, the innervation of WAT is more variable across species and the location of the fat depot. Similarly, the origin of the sympathetic innervation of the liver is inconsistent and seems restricted to the perivascular space. Unlike liver and adipose tissues, and more aligned with conventional autonomic paradigms, the pancreas possesses both sympathetic innervation and parasympathetic innervation with opposing effects. Differential sympathetic activation would be advantageous for selective targeting and treatment of organ-specific dysfunction, including immune and metabolic pathologies. Except for central leptin action, it is debatable whether manipulations of upstream brain circuits would recruit a top-down response that is cardioneutral and specific to metabolic organs. Centrally acting sympathomimetics such as amphetamines and MCR8 agonists recruit widespread and cardiotoxic sympathetic drive, indicating that higher-order manipulations may not be more targetted than those of lower order at the postganglionic level. Drawing a parallel with the organization of other descending axes such as sensory-motor circuits: lesions or stimulations of higher order brain structures produce effects that are more widespread relative to peripheral manipulations, for instance, when comparing the sensory-motor deficits originating from the stroke of the central medial artery to those arising from peripheral lesions. This organizational principle could also apply to the sympathetic axis, whereby peripheral postganglionic targeting may be more specific than higher-order pre- sympathetic central circuits. Thus, manipulations of sympathetic postganglionic neurons may be a means to achieve metabolic control while identifying neural circuits, or nodes within them, that preserve cardiovascular health. Critical to this endeavour will be to generate transgenic CRE/DRE driver lines for subpopulations of neurons that could be systematically used as molecular handles for remote activation/inhibition via minimally invasive technologies, such as chemogenetics or magnetogenetics, for a causal assessment of the exact neuronal pathways of the sympathetic-metabolic axis. Realistic maps with single-neuron resolution akin to the MouseLight Project are still missing. A functional understanding of SNS circuitry in-vivo will require the development of non-invasive genetically encoded activity reporters that can be sensed in deep-seated sympathetic ganglia \u2013 possibly capitalizing on optoacoustic as an enabling technology.Obesity-induced sympathetic neuropathy is a cause and effect of metabolic disease \u2013 weakening the sympathetic efferent arm in the neuroendocrine loop of leptin action. Reversing obesity-induced sympathetic neuropathy may be a step towards re-establishing body weight homeostasis, and this will require deciphering the cross-talk among sympathetic-resident immune cells. This prospect promises \u201csympathoprotective\u201d immunotherapeutic targets and could offer a new generation of safe and effective anti-obesity treatments."} +{"text": "Colorectal cancer (CRC) represents the third most prevalent cancer worldwide and a leading cause of mortality among the population of western countries. However, CRC is frequently a preventable malignancy due to various screening tests being available. While failing to obtain real-time data, current screening methods (either endoscopic or stool-based tests) also require disagreeable preparation protocols and tissue sampling through invasive procedures, rendering adherence to CRC screening programs suboptimal. In this context, the necessity for novel, less invasive biomarkers able to identify and assess cancer at an early stage is evident. Liquid biopsy comes as a promising minimally invasive diagnostic tool, able to provide comprehensive information on tumor heterogeneity and dynamics during carcinogenesis. This review focuses on the potential use of circulating tumor cells (CTCs), circulating nucleic acids (CNAs) and extracellular vesicles as emerging liquid biopsy markers with clinical application in the setting of CRC screening. The review also examines the opportunity to implement liquid biopsy analysis during everyday practice and provides highlights on clinical trials researching blood tests designed for early cancer diagnosis. Additionally, the review explores potential applications of liquid biopsies in the era of immunotherapy. According to the GLOBOCAN database, colorectal cancer (CRC) is the third most prevalent cancer worldwide, representing the second leading cause of cancer-related mortality around the globe . Albeit Despite the high mortality rates observed in the advanced stages, CRC is frequently a preventable malignancy through screening methods . The vasEven with the various screening technologies available, with colonoscopy representing the gold standard, adherence to CRC screening programs remains suboptimal among some populations ,10. EndoThe aim of this article is to review the existing data on liquid biopsies and their clinical application in detecting early-onset CRC. In addition, the review discusses the available methods for implementing liquid biopsies in everyday practice and offers highlights on clinical trials investigating blood tests designed for screening and early cancer detection. The review also discusses the challenges met during the analysis of liquid biopsy components and its potential future applications in the era of immunotherapy.Recent research has been shedding light on a new diagnostic approach suited for cancer patients, the liquid biopsy. Liquid biopsy comes as a simple, minimally invasive diagnostic tool, attempting to overcome the limitations of conventional tissue biopsy by providing more comprehensive data on tumor heterogeneity and dynamics at different junctures in cancer development . Liquid Originally described in 1869, CTCs are now gaining clinical importance in the management of patients with cancer . Tumor cCTCs can be successfully enriched through various procedures that exploit the dissimilarities observed between tumor cells and other circulating blood cells. These methods attempt to isolate CTCs based on their particular physical characteristics and their contrasting expression of cell surface proteins .Positive enhancement methods, also known as label-dependent, use specific antibodies targeting molecular markers expressed by CTCs (cell-surface antigens). The membrane protein most commonly used during positive enhancement selection is the epithelial cell adhesion molecule (EpCAM), however, other cytoplasmic markers expressed by CTCs may be exploited . EpCAM iOnce the sample has undergone enrichment processes, CTCs require individual recognition. CTC detection can be achieved through immunocytology, molecular biology, or functional assays . The mosCTCs can be extensively characterized using a range of techniques. Profiling proteins expressed by CTCs represents one of the most commonly used methods and it requires immunostaining with antibodies to specific markers of cell proliferation and apoptosis . A diffeThe available scientific data showed the importance of CTCs in different CRC stages. In the nonmetastatic setting, the CTCs count was found to be lower, therefore, the cutoff for many of the clinical trials conducted was set for \u22651 CTC/7.7 mL of blood, while in the metastatic setting, the cutoff was set higher (\u22655 CTCs/7.5 mL of blood) . Even ifIn this regard, a prospective clinical study was presented at ASCO GI 2018 . The stuMoreover, CTCs were shown to evaluate patients\u2019 prognoses and predict metastasis and recurrence. A meta-analysis including 1847 patients from 11 studies revealed that an increased CTC baseline count represents an independent and strong prognostic factor for OS and PFS in metastatic CRC . By analHowever, despite promising results reported by clinical trials, the scientific community will have to overcome several limitations in order to further use the information provided by CTCs in clinical practice.The analysis of circulating nucleic acids (CNAs) represents a novel minimally invasive approach, able to assess the tumor and its molecular characteristics while allowing a more accurate description of tumor heterogeneity and evolution in time. CNAs, more specifically, circulating tumor DNA (ctDNA) and circulating microRNA (miRNA), are generally isolated from blood; however, other biological fluids could represent a source of CNAs . CNAs enNumerous amounts of cell-free DNA (cfDNA) fragments are detected in blood plasma as a result of cellular death, with sizes ranging between 180 and 200 base pairs . It has The blood samples collected require a series of manipulations in order to identify ctDNA and then further analyze the material for genetic aberrations. Firstly, samples are subjected to sequential centrifugation, isolating plasma as the main source for cfDNA . ctDNA iExtensive research focusing on circulating DNA (cDNA) analysis has successfully discovered its clinical utility in CRC screening. A series of markers indicative of aberrant DNA methylation have been described and utilized to detect CRC in early stages and precancerous lesions Table 1Table 1.Tumor suppressor gene septin-9 (SEPT9) is one of the most widely researched methylation markers in CRC pathogenesis. A study conducted by Warren et al. evaluateSeveral multi-cancer detection tests have been thoroughly analyzed as potential screening tools in a new era of preventive medicine . CancerSCirculating miRNAs represent the purpose of extensive research focusing on cancer biomarkers. miRNA can be identified in biological fluids as a result of tissue injury and apoptosis or following active selective secretion by CTCs and tumor cells from the primary site or metastases ,93. The Even though the interest in miRNA as a liquid biopsy biomarker is relatively novel, research has already found its potential value for CRC screening .Several miRNA clusters appear up-regulated in CRC , of whicPresent in all biological fluids, exosomes represent cell-derived nanovesicles with sizes ranging from 30 to 150 nm in diameter . ExosomeAn increasing amount of evidence has identified exosomes as essential participants in cancer development processes. Exosomes secreted by tumor cells have been found responsible for alterations in the immune response that lead to suppression of antitumor response . In addiExosome concentration in biological fluids is relatively low, thus making their isolation, detection and further analysis relatively challenging. Isolation of exosomes can be achieved based on their physical properties (size and density), electromagnetic characteristics, or according to their immunological properties . IsolatiExosomal microRNAs have been attracting considerable attention as promising biomarkers suitable for cancer diagnosis. Multiple exosomal miRNAs have been studied, with some of them showing substantial value in identifying early cases of CRC .Research has identified several significantly up-regulated miRNAs in the setting of CRC, including cases of early-stage disease. One study found miRNA-23a to have an important diagnostic accuracy with an area under the curve (AUC) of 0.953, while miRNA-1246 and miRNA-21 also showed encouraging results . OverexpOver the past few years, immunotherapy has changed the treatment paradigm for many cancer types. In CRC, the MSI-high phenotype was associated with a significant response to immune checkpoint inhibitors (ICIs) . MoreoveTo date, liquid biopsies are investigated for use as biomarkers to predict and evaluate the response to immunotherapy. CTCs, circulating DNA (cDNA), circulating RNA (cRNA) and exosomes hold a generous amount of tumor-related information. Moreover, liquid biopsies may provide a more comprehensive and dynamic overview of the tumor microenvironment and heterogeneity than single-site tissue biopsies . The utiA better selection of the patients receiving immunotherapy could be guided by specific somatic mutations detectable in cDNA. In this regard, a genomic mutation signature was developed to characterize immunophenotypes and predict response to immunotherapy in gastrointestinal cancers . As mentRAS assessment in mCRC is essential to select patients suitable for anti-EGFR therapy. The concordance between tissue detection and somatic mutations detected in ctDNA appeared high in patients with advanced tumors, supporting blood-based testing. Moreover, ctDNA was shown to be highly useful for monitoring treatment response. However, some clinicopathological features, including tumor histology (mucinous) and metastatic sites , negatively influenced RAS detection in ctDNA . Along wImmunotherapy and targeted therapy are major therapeutic breakthroughs in cancer care, and one of the most challenging concerns is proper patient selection. To overcome these shortcomings, liquid biopsy-based biomarkers represent a promising tool, hence they require detection methods with sufficient specificity, sensitivity and predictive power .Despite many pieces of scientific evidence highlighting the potential benefits of liquid biopsies in cancer care, numerous limitations remain for their clinical use.CTCs have great potential as diagnostic, prognostic, predictive, as well as monitoring tools. However, their translation into clinical practice is still restricted amid their isolation from the bloodstream . To corrFor exosomal segregation, ultracentrifugation is thought to be the most efficient method. Although convenient and requiring reasonable costs, ultracentrifugation encounters several limitations. A significant concern is the co-purification of lipoproteins and protein aggregates along with EVs . Hence, ctDNA is a small fraction representing about 0.01% of cfDNA. One of the main logistical reasons limiting the extensive use of cDNA-based analysis is represented by their feasibility outside the academic cancer centers . The avaEven if several logistic and biological limitations are encountered at the present moment, liquid biopsies will more likely become a fundamental tool in the management of CRC patients in all stages of disease-related interventions. Evaluation of ctDNA levels in patients with stage II CRC has led to a decrease in adjuvant chemotherapy administration while maintaining a favorable recurrence-free survival (DYNAMIC II study) . AdditioDespite the implementation of extensive programs designed to diagnose CRC in the early stages, the adherence of the general population to screening protocols remains unsatisfactory. Liquid biopsy comes as a novel, minimally invasive tool, adequate for early diagnosis of malignancy while also attempting to overcome the limitation showed by traditional CRC screening and tissue sampling methods. Research has proved that liquid biopsy analytes and biomarkers offer valuable information regarding carcinogenesis and could indeed single out individuals at risk for developing CRC or those presenting early-stage CRC otherwise undetected during conventional screening tests.Since FDA has taken the necessary steps to approve CellSearch System for CTC detection and enhancement during clinical studies, the scientific community could soon implement the test in everyday clinical practice. In addition, studies have identified numerous methylation markers indicative of malignancy. In this regard, the detection of SEPT9 gene methylation in DNA fragments derivative from tumor masses is the most widely explored sequence and therefore experiences more promising results. As a result of thorough research, the SEPT9 methylation model comes within reach of validation for current practice, with tests such as Epi proColon expressing significant diagnostic values for CRC early detection. Several extensively researched miRNAs are also approaching clinical utility in everyday practice. miRNA-92a proves relevant sensitivity and specificity values in detecting early CRC cases, as well as advanced adenomas, while panels including multiple miRNAs show improved accuracy when compared to single markers. Additionally, exosomal miRNA-23a has been shown to differentiate patients with early-stage disease with high accuracy, indicating that protocols defining its clinical applicability could be imminent.However, in order to successfully isolate compelling biomarkers, blood samples require complex manipulation techniques that often show unsatisfactory efficiency and prove to be time-consuming and costly. Studies conducted thus far have demonstrated encouraging accuracy, yet further research is critical in order to validate liquid biopsy as a screening and early diagnostic technique. Furthermore, the utility of liquid biopsies in the era of precision medicine is an important frontier that demands thorough inquiry."} +{"text": "Elder abuse by family caregivers is an often-overlooked phenomenon that affects many older adults. Especially, retirement-aged children caring for their oldest-old parents with dementia may be at greater risk of engaging in harmful or abusive behaviors, given their own age-related health issues and other competing caregiving demands. Most of the elder abuse literature has focused on general demographic predictors of elder abuse, regarding the caregiver, care recipient, and the care environment. Less attention has been paid towards relationship factors, which may play a large role among these parent-child dyads. This study examined how relationship factors are associated with potentially harmful caregiver behaviors , which have been identified as \u201cearly warning signs\u201d for elder abuse. Relationship factors of interest include positive and negative relationship quality measured by caregivers\u2019 mean scores on the support and conflict subscales on the Quality of Relationship Inventory (QRI). We conducted in-depth interviews with 88 caregivers (65+) who are caring for their parents with dementia (90+) as the part of the Boston Aging Together Study. Regression models revealed that relationship conflict was significantly associated with higher levels of PHCB, accounting for caregiver, care recipient, and care environment characteristics. The creation of screeners to identify \u201chigh conflict\u201d care dyads could prove useful in the early detection and intervention of potential elder abuse cases, given that caregivers may be more willing to report negative aspects of their relationship than more obviously harmful or abusive behaviors."} +{"text": "Vascular risk factors including hypertension, diabetes and dyslipidaemia promote diverse pathological mechanisms in the brain leading to cerebral hypoperfusion and ultimately cognitive decline in people. Medial temporal, medial frontal and anterior cingulate atrophy has been closely associated with diabetes and medial temporal lobe atrophy is associated with hypertension in people with Alzheimer\u2019s disease (AD).To assess if hypertension, diabetes and dyslipidaemia have differential effects on different brain locations using brain imaging in people with AD.18F] fluorodeoxyglucose- positron emission tomography (FDG-PET) data of 970 participants from two large Phase III multi-centre clinical trials of a novel tau aggregation inhibitor drug Leuco-Methylthioninium (LMTX)meeting research criteria for mild to moderate AD. Vascular risk factor data including hypertension, diabetes and dyslipidaemia were collected and quantification of FDG PET hypo-metabolism was done by calculating Standardized Uptake Value Ratio(SUVR).The current study is based on [Hypertension, diabetes and dyslipidaemia were found to have differential effects on brain locations in people with AD. When people with hypertension, diabetes and dyslipidaemia were compared to those without, mean SUVR was increased significantly in both left and right parietal and occipital lobes and decreased in left and right anterior cingulate gyri in hypertensives. SUVR was significantly higher in both left and right temporal lobes in diabetics andlower in both left and right anterior cingulate gyri in people with dyslipidaemia.Vascular risk factors including hypertension, diabetes and dyslipidaemia have differential effects on different brain regions, measured using SUVR analysis of FDG-PET.The FDG-PET data was taken from participants of two large phase III clinical trials sponsored by TauRx Therapeutics (Singapore). TauRx Therapeutics has contributed towards my studentship during my PhD but the data related to drug used in the clinical tria"} +{"text": "Novel opportunities to examine how life experiences connect to health and mortality through biological aging have increased due to the affordability of genomic analysis. Although epidemiological studies suggest associations between stress and accelerated biological aging, most if not all measures in the past have been global, data cross-sectional, and from primarily white samples. As part of a completed measurement study, a diverse sample provided detailed stress measures, including EMA and lifetime stress assessments, and consented to future analysis of their blood samples. We successfully used decade-old blood samples to estimate methylation-based epigenetic clocks and examined them within the context of various stress measures as a preliminary phase of a future longitudinal study. Additional whole genome sequencing will also allow for future work that incorporate continuous measures of genomic ancestry when examining lifetime discrimination-related stress, rather than simply testing for demographic group differences."} +{"text": "Electrocardiography and high-sensitivity cardiac troponin testing are routinely applied as the initial step for clinical evaluation of patients with suspected non-ST-segment elevation myocardial infarction. Once diagnosed, patients with non-ST-segment elevation myocardial infarction are commenced on antithrombotic and secondary preventative therapies before undergoing invasive coronary angiography to determine the strategy of coronary revascularisation. However, this clinical pathway is imperfect and can lead to challenges in the diagnosis, management, and clinical outcomes of these patients. Computed tomography coronary angiography (CTCA) has increasingly been utilised in the setting of patients with suspected non-ST-segment elevation myocardial infarction, where it has an important role in avoiding unnecessary invasive coronary angiography and reducing downstream non-invasive functional testing for myocardial ischaemia. CTCA is an excellent gatekeeper for the cardiac catheterisation laboratory. In addition, CTCA provides complementary information for patients with myocardial infarction in the absence of obstructive coronary artery disease and highlights alternative or incidental diagnoses for those with cardiac troponin elevation. However, the routine application of CTCA has yet to demonstrate an impact on subsequent major adverse cardiovascular events. There are several ongoing studies evaluating CTCA and its associated technologies that will define and potentially expand its application in patients with suspected or diagnosed non-ST-segment elevation myocardial infarction. We here review the current evidence relating to the clinical application of CTCA in patients with non-ST-segment elevation myocardial infarction and highlight the areas where CTCA is likely to have an increasing important role and impact for our patients. It accounts for 6% of all Emergency Department attendances in the UK, resulting in approximately 350,000 hospitalisations each year. In contemporary practice, the application of high-sensitivity cardiac troponin assays for the diagnosis of myocardial infarction is central to clinical pathways for acute chest pain. This has resulted in marked improvements in the detection of not only myocardial infarction but also myocardial injury, substantially altering the prevalence of the diagnoses of unstable angina and myocardial infarction. Moreover, high-sensitivity cardiac troponin assays can expedite the exclusion of myocardial infarction through so-called \u2018rule-out\u2019 pathways. Indeed, less than one in five patients are ultimately diagnosed with an acute coronary syndrome. However, because of their high sensitivity, these assays also have issues of specificity, and a large proportion of cardiac troponin elevations are unrelated to atherosclerotic plaque disruption or even not myocardial infarction.Acute chest pain is one of the commonest presentations to the Emergency Department, with half of the patients subsequently being hospitalised for assessment of suspected acute coronary syndrome. Furthermore, neither cardiac troponin concentration thresholds nor background cardiovascular risk factors are sufficient to identify underlying mechanisms of myocardial injury nor determine the subtypes of myocardial infarction. Therefore, invasive coronary angiography plays a pivotal role in the management of high-risk patients with acute chest pain, including those with cardiac troponin elevation.The differentiation between the various mechanisms responsible for myocardial injury and distinctive subtypes of myocardial infarction is critical because those with a classic or Type 1 myocardial infarction attributable to atherosclerotic plaque disruption are more likely to benefit from intensive pharmacotherapy and coronary revascularisation. Interestingly, only a half or less of patients admitted with cardiac troponin elevation are diagnosed with Type 1 myocardial infarction. Moreover, CTCA is cost-effective and reduces length of stay in patients with acute chest pain and without cardiac troponin elevation. To exclude underlying obstructive coronary artery disease, the European Society of Cardiology guidelines recommend CTCA for those with chronic coronary syndrome and a lower likelihood of the presence of haemodynamically significant stenosis, and for those with suspected acute coronary syndrome and a normal or inconclusive cardiac troponin concentration. However, it remains unclear whether patients with non-ST-segment elevation myocardial infarction would also benefit from CTCA by improving their downstream management and treatment. This review will examine the latest advances in CTCA in patients with acute chest pain, discuss the potential application of CTCA in those with suspected non-ST-segment elevation myocardial infarction, and highlight potential future developments in this area.Computed tomography coronary angiography (CTCA) has diagnostic accuracy and prognostic performance comparable to invasive coronary angiography in the diagnosis of obstructive coronary artery disease. It is associated with enhancing clinical diagnosis, better targeting of treatments, and improving clinical outcomes in patients with stable chest pain. Finally, an elevation in cardiac troponin in the absence of symptoms or signs of ischaemia is termed myocardial injury and can be acute or chronic (persistently elevated). Although non-ischaemic aetiologies account for the majority of cardiac troponin elevations, differentiating and classifying myocardial injury and myocardial infarction are not always straightforward even among a panel of experts with pre-specified guidance.Any elevation of a cardiac troponin concentration above the 99th centile upper reference limit defines myocardial injury. Under such a pre-requisite, myocardial infarction is diagnosed by a rise and fall in cardiac troponin in the context of clinical symptoms or electrocardiographic signs suggestive of myocardial ischaemia. Based on underlying pathophysiology contributing to oxygen supply\u2013demand imbalance, myocardial infarction is further subclassified into five types: atherothrombosis (Type 1), acute mismatch between oxygen supply and demand unrelated to atherosclerotic plaque disruption (Type 2), cardiac death presumably due to myocardial ischaemia (Type 3), and consequences of coronary procedures (Types 4 and 5). Currently, cardiac magnetic resonance imaging is recommended in patients with cardiac troponin elevation of undetermined aetiology. Based on the pattern of injury and dysfunction, it may distinguish myocardial infarction from myocardial injury, or alter a location of the infarct-related artery in non-ST-segment elevation myocardial infarction. However, the pattern of myocardial injury on imaging is not always specific for a disease or pathophysiological process, and the availability of cardiac magnetic resonance imaging service is limited.The presence of coronary atherosclerosis is a pre-requisite for Type 1 myocardial infarction and a common observation in Type 2 myocardial infarction. Although assessing coronary artery anatomy may aid in the distinction between myocardial injury and myocardial infarction, invasive coronary angiography has many limitations, especially when the infarct size is small. In those with cardiac troponin elevation in the absence of obstructive coronary artery disease, CTCA has greater sensitivity for the detection of atherosclerotic plaques and the identification of the infarct-related artery than invasive coronary angiography. Conversely, CTCA demonstrates that three-quarters of patients with cardiac troponin elevation and low clinical suspicion for acute coronary syndrome have no or minimal atherosclerotic plaques. Consequently, the likelihood of Type 1 myocardial infarction is extremely low when all coronary arteries are free from atherosclerotic plaques. Finally, it also offers an opportunity to evaluate other cardiothoracic structures and recognise alternative causes of myocardial injury. Therefore, CTCA provides important information to help guide the diagnosis and classification of aetiologies for myocardial injury trial. In this trial, 1023 out of 2147 patients with non-ST-segment elevation acute coronary syndrome underwent CTCA before invasive coronary angiography. Using invasive coronary angiography as the gold standard, the negative-predictive value for CTCA to exclude any diameter stenosis \u226550% was 91%. Among 24 patients who were falsely excluded by CTCA, only three had a lesion with diameter stenosis \u226550% in a major epicardial coronary artery by invasive coronary angiography. The positive-predictive value for CTCA to identify diameter stenosis \u226550% was 88%. Among 92 patients who were falsely included by CTCA, 17 had a non-diagnostic scan and 19 had previous coronary stenting. The negative-predictive value for patients with cardiac troponin elevation, an ischaemic electrocardiographic change, and a GRACE score >140 was 89%, 95%, and 95%, respectively. The overall negative- and positive-predictive values of CTCA remained similar when considering diameter stenosis \u226570% as the cut-off. Thus, CTCA has very similar diagnostic performance to invasive coronary angiography in the setting of non-ST-segment elevation myocardial infarction. It has excellent negative-predictive value and rarely misses an obstructive atherosclerotic lesion in a major epicardial coronary artery.CTCA has excellent diagnostic performance compared to invasive coronary angiography in patients with stable chest pain and a low-to-intermediate pre-test probability of coronary artery diameter stenosis \u226550%.Non-ST-segment elevation myocardial infarction represents three-quarters of all contemporary myocardial infarctions, but many do not have obstructive coronary artery disease at the time of invasive coronary angiography. Implementation of CTCA was associated with a slight increase in the immediate use of invasive coronary angiography. However, around 50% of patients were directly discharged from the Emergency Department after CTCA, and fewer patients required subsequent non-invasive functional testing for myocardial ischaemia, resulting in shorter lengths of stay and a reduced cost at the Emergency Department. Similarly, compared with routine functional ischaemia testing, CTCA was associated with a higher rate of invasive coronary angiography and subsequent coronary revascularisation but again shorter lengths of stay.Prior to the advent of high-sensitivity cardiac troponin testing, randomised controlled trials of low-risk patients with acute chest pain reported that rates of invasive coronary angiography and coronary revascularisation within usual clinical care were low at less than 6 and 3%, respectively .42 ImpIn the era of high-sensitivity cardiac troponin testing, three randomised controlled trials have evaluated the clinical effectiveness of CTCA in patients presenting with suspected or diagnosed non-ST-segment elevation myocardial infarction . The Bet In the overall RAPID-CTCA trial population, the rate of invasive coronary angiography was lower with CTCA than with standard of care (54% vs \u200961%) although there was no difference in the rates of coronary revascularisation. For those with cardiac troponin elevation in the RAPID-CTCA trial, the findings remained consistent, suggesting CTCA allows for the better selection of patients for coronary revascularisation even in higher risk patients. In the CARMENTA trial, both cardiac magnetic resonance imaging and CTCA reduced the proportion of patients referred to invasive coronary angiography during index hospitalisation and at one year (88 and 70% vs \u2009100%). In contrast, the diagnostic yield for the presence of diameter stenosis \u226570% was greater with CTCA than with cardiac magnetic resonance imaging or standard of care . Thus, these three trials demonstrate that CTCA reduces the requirement for invasive coronary angiography without affecting the use of coronary revascularisation especially in patients with suspected non-ST-segment elevation myocardial infarction. This has implications for resource management in hospitals where CTCA can help efficiently identify those who require invasive coronary angiography and access to coronary revascularisation.Reflecting the lower risk trial population, only a minority of patients in the BEACON trial underwent invasive coronary angiography (13\u201317%) or coronary revascularisation (7\u20139%), and the 30-day rates of these procedures were unaffected by CTCA.There is always a concern that the introduction of new tests will lead to so-called test inflation where new or incidental findings will lead to further testing. Indeed, in low-risk and asymptomatic populations, this is an inherent concern. However, in general, CTCA was associated with a reduced need for downstream or layering of testing in patients with non-ST-segment elevation myocardial infarction. In keeping with the rates of invasive coronary angiography, CTCA was associated with a reduced requirement for downstream non-invasive ischaemia testing. This was seen across all three trials and resulted in similar lengths of stay. Overall, these trials would suggest that CTCA has no or minimal impact on length of stay but does reduce the need for downstream non-invasive ischaemia testing without impacting on overall healthcare costs in the RAPID-CTCA trial and 0.64 in the CARMENTA trial.Downstream clinical event rates are clearly determined by the length of follow-up and the risk of patients included in the trials. The follow-up duration of the BEACON trial was 30 days, and there was only one death and four possible recurrent acute coronary syndromes in 500 patients. The one-year event rate of death or myocardial infarction was comparable between the RAPID-CTCA (6%) and the CARMENTA (4%) trials. Nevertheless, patients with cardiac troponin elevation in the RAPID-CTCA trial appeared to have the highest risk as the one-year rate of death or myocardial infarction reached 8%.Overall, contemporary trials enrolling higher risk patients including those with non-ST-segment elevation myocardial infarction have suggested that early CTCA can lead to accelerated management and tailored investigations and treatments but does not have a major impact on near- and short-term major adverse cardiovascular events. The high sensitivity and negative-predictive value of high-sensitivity cardiac troponin assays have meant that there is little scope for CTCA to identify unrecognised cases of non-ST-segment elevation myocardial infarction. Thus, there is no opportunity to prevent recurrent immediate or intermediate clinical events for those already diagnosed with non-ST-segment elevation myocardial infarction. However, CTCA does have a role in identifying those with cardiac troponin elevation who do not have Type 1 myocardial infarction and thereby improves on specificity for the diagnosis of non-ST-segment elevation myocardial infarction. However, those clinical variables may not always represent a target that could be modified to improve outcomes, and the recommended risk scores and models do not always have good long-term discriminative performance. In contrast, cardiac imaging can potentially identify treatable targets, recommending treatment selection, as well as providing more powerful risk stratification.Initial risk stratification is essential in the clinical pathway for non-ST-segment elevation myocardial infarction in order to allocate appropriate therapies proportionate to the projected risk. Currently recommended risk stratification schemes using clinical variables offer good predictive value for near- and short-term outcomes. a finding that was recently reaffirmed in the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial. For patients with suspected or diagnosed non-ST-segment elevation myocardial infarction, similar excellent risk prediction is seen with CTCA. In the VERDICT trial, the long-term (a median of 4.2 years) follow-up of 978 patients who underwent CTCA suggested that the presence of diameter stenosis \u226550% by CTCA was associated with an increased risk of major adverse cardiovascular events independent of cardiac troponin elevation. In addition, the presence of diameter stenosis \u226550% in left main coronary artery, proximal left anterior descending artery, or two or more vascular territories by CTCA identified patients at the highest risk of long-term adverse outcomes. Finally, among those without diameter stenosis \u226550% by CTCA, the subsequent findings of invasive coronary angiography did not further distinguish patients at increased risk.In patients with stable chest pain, CTCA-defined risk stratification is superior to functional testing for myocardial ischaemia, On the other hand, most cardiac troponin elevations are related to either Type 2 myocardial infarction or myocardial injury. Again, the differentiation between Type 1 myocardial infarction, Type 2 myocardial infarction, and myocardial injury can be challenging, and the optimal investigations and treatments for these conditions remain to be established. This has led to the design of several clinical studies investigating the use of CTCA in patients with suspected or diagnosed non-ST-segment elevation myocardial infarction is currently recruiting patients with intermediate risk and a cardiac troponin concentration within three times upper reference limit to evaluate the effect of coronary calcium scoring on diagnosis and management for patients in the observe zone. Another two studies, the Coronary CT Angiography for Improved Assessment of Suspected Acute Coronary Syndrome With Inconclusive Diagnostic Work-up and the Prospective RandOmised Trial of Emergency Cardiac CT will throw light on the effectiveness of CTCA in patients with a \u2018non-diagnostic\u2019 cardiac troponin concentration under the current clinical pathway.The atherosclerotic plaque burden measured by calcium score is a simple gauge for long-term cardiovascular outcomes independent of diameter stenosis, Beyond qualitative assessment, semi-automated quantification allows for a reproducible and detailed breakdown of atherosclerotic plaque morphology study showed that two-thirds of patients with Type 2 myocardial infarction had coronary artery disease of any severity, of which half had not been identified previously. In addition, many of them were not treated with preventative therapies, suggesting missed treatment opportunities. Further substudies of the DEMAND-MI study and the DEFINing the PrEvalence and Characteristics of Coronary Artery Disease Among Patients With TYPE 2 Myocardial Infarction Using CT-FFR study will use CTCA-based techniques to explore the prevalence of coronary artery disease, haemodynamically significant stenosis, and plaque characteristics among patients with Type 2 myocardial infarction. This information will increase our understanding of pathogenesis of Type 2 myocardial infarction and suggest potential treatment opportunities.Additional computational fluid dynamics and advanced molecular imaging may enhance the identification of adverse features that are culprit for incident acute coronary syndrome. the specificity of CTCA in discriminating anatomical (\u226550% diameter stenosis) or functional obstruction remains imperfect. Fractional flow reserve derived from CTCA is a promising approach that improves discrimination of those at higher risk for future events. However, its use has not resulted in further improvement of major adverse cardiovascular events in patients with stable chest pain. The CArdiac cT in the treatment of acute CHest pain-2 (CATCH-2) trial showed that additional computed tomography perfusion imaging further reduced the utilisation of invasive coronary angiography in low-risk patients with acute chest pain, but it was underpowered to evaluate clinical outcomes. These findings are not definitive, and the role of CTCA-derived fractional flow reserve or computed tomography myocardial perfusion remains to be established in non-ST-segment elevation myocardial infarction. Ultimately, any advanced computed tomography-based functional assessment will need to demonstrate incremental diagnostic and prognostic value over CTCA in the value-based health care.Although CTCA is excellent at identifying normal coronary arteries and avoiding unnecessary invasive coronary angiography, Thus, the greatest opportunity for CTCA to improve long-term clinical outcomes in those with acute chest pain may be in those who have myocardial infarction excluded but may still be at a high risk of future long-term cardiovascular events. Two ongoing randomised controlled trials, the Randomized Evaluation of Coronary Computed Tomographic Angiography in Intermediate-risk Patients Presenting to the Emergency Department With Chest Pain and the Troponin in Acute Chest Pain to Risk Stratify and Guide EffecTive Use of Computed Tomography Coronary Angiography trials, will determine the effectiveness of CTCA on long-term (\u22653 years) major adverse cardiovascular events in such patients.The principal advantage of CTCA is to identify unrecognised coronary atherosclerosis regardless of stenosis severity as an opportunity to apply preventative interventions, such as antiplatelet and statin therapies. The benefit of such interventions take many years to accrue as demonstrated in patients with stable chest pain.In patients with suspected non-ST-segment elevation myocardial infarction, electrocardiography and high-sensitivity cardiac troponin testing will remain the initial step for clinical evaluation, and invasive coronary angiography is still the routine clinical tool to determine the strategy of coronary revascularisation. CTCA has an increasingly important role in avoiding unnecessary invasive coronary angiography and reducing downstream non-invasive functional testing for myocardial ischaemia especially among those with low or intermediate risk. Moreover, CTCA is an excellent gatekeeper for the cardiac catheterisation laboratory, provides complementary information for patients with myocardial infarction in the absence of obstructive coronary artery disease, and can highlight alternative or incidental diagnoses for patients with non-ST-segment elevation myocardial infarction. There are several ongoing studies evaluating CTCA and its associated technologies that will define and potentially expand its application in patients with suspected or diagnosed non-ST-segment elevation myocardial infarction."} +{"text": "Men using cholesterol-lowering statin medications have been found to have lower risks of both advanced and fatal prostate cancer in multiple registry-based studies and prospective cohort studies. Statin use has also been associated with longer survival among men already diagnosed with prostate cancer. Mechanisms responsible for purported anti-cancer effects of statins are not well understood but may offer insight into prostate cancer biology.We summarise epidemiological data from studies of statins and prostate cancer and discuss to what extent these findings can be interpreted as causal. Additionally, lipid-mediated and non-lipid-mediated mechanisms that may contribute to potential anti-cancer effects of statins are reviewed. Finally, we consider treatment settings and molecular subgroups of men who might benefit more than others from statin use in terms of prostate cancer-specific outcomes.Data from prospective observational studies generally reported a lower risk of fatal prostate cancer among statin users. There is some evidence for serum cholesterol-lowering as an indirect mechanism linking statins with advanced and fatal prostate cancer. Window-of-opportunity clinical trials show measurable levels of statins in prostate tissue highlighting potential for direct effects, whilst observational data suggest possible statin-driven modulation of prostate microenvironment inflammation. Additionally, emerging data from registry studies support a potential role for statins within the context of androgen deprivation therapy and anti-androgen treatment.Prospective and registry-based studies support a lower risk of advanced and fatal prostate cancer in statin users relative to non-users, as well as better outcomes among prostate cancer patients. The few randomised-controlled trials conducted so far have short follow-up, lack identified molecular subgroups, and do not provide additional support for the observational results. Consequently, additional evidence is required to determine which men may experience greatest benefit in terms of prostate cancer-specific outcomes and how statin effects may vary according to molecular tumour characteristics. Statins are competitive antagonists of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, whose activity is rate-limiting for the biosynthesis of cholesterol and derivatives via the mevalonate pathway. While the evidence supporting the role for statins in cardiovascular disease prevention is unequivocal , mountinThis review discusses epidemiological evidence supporting a potential role for statins in prostate cancer prevention, particularly prevention of fatal disease. Whilst underlying mechanisms behind statin effects in cancer are currently unclear, we review evidence from epidemiological studies that may support existing theories and provide greater understanding of prostate cancer biology. This is followed by an evaluation of data exploring the timing of statin use alongside, and potential synergy with, androgen deprivation therapies (ADT). Finally, we review current data regarding which patients may benefit more from statin use. Our companion review discusses mechanistic evidence of anti-tumour effects of statins from laboratory studies .Following the first report of a stronger association of pre-diagnosis statin use with advanced, metastatic and fatal prostate cancer , the majTwo prospective cohort studies addressed this question by following cancer-free men long term. Findings from the Health Professionals Follow-up Study, with 801 fatal prostate cancers diagnosed amongst 44,126 men during 24 years of follow-up, showed a 24% lower rate of fatal prostate cancer in pre-diagnosis statin users vs. non-users (hazard ratio (HR) 0.76; 95% CI 0.60\u20130.96) [In addition, registry-based studies have explored effects of pre- and post-diagnosis statin use on prostate cancer-specific mortality. A UK registry study reported that the association between post-diagnosis statin use and prostate cancer-specific mortality was strongest amongst pre-diagnosis statin users . In contGiven that any clinical trial of statins is more feasible among men already diagnosed with prostate cancer, it is informative to evaluate the effect of post-diagnosis statin use on prostate cancer-specific outcomes. Indeed, all three aforementioned studies reported similar magnitudes of association between post-diagnosis statin use and reduced prostate cancer-specific mortality. Specifically, the Finnish Randomised Study of Screening for Prostate Cancer showed that post-diagnosis statin use was associated with a 20% (95% CI 0.65\u20130.98) lower rate of prostate cancer-specific mortality, with stronger associations among those using higher doses of statins and for longer durations . The magBefore taking next steps, a central question is whether bias from confounding and other sources may affect reported associations between statin use and prostate cancer outcomes as they do in studies of other commonly used medications . For exaAppropriate analytic methods as well as prospective study designs help reduce potential sources of bias. Prospective cohort studies address confounding through adjustments for detailed measures of modifiable and non-modifiable risk factors for prostate cancer and competing causes of death, with registry studies using medical diagnoses and medications as proxies. As it is ultimately unknowable if confounding and bias was successfully controlled in observational studies, results from existing randomised trials need to be considered.The Cholesterol Treatment Trialists\u2019 Collaboration pooled data from 27 major randomised-controlled trials of statin therapy, including 1877 incident prostate cancers and 211 prostate cancer deaths over a median follow-up of 4.8 years, with null results . A doublIdentification of mechanisms linking statins and prostate cancer could provide a biological rationale to support epidemiological associations. Unfortunately, the mechanisms responsible for purported statin anti-cancer effects are still unclear though two broad categories have been proposed: lipid-mediated and non-lipid-mediated, for which we have summarised the epidemiological evidence below. Our companion review considers mechanistic evidence from laboratory studies .Statins have a pronounced effect on serum lipid levels, reducing low density lipoprotein (LDL) cholesterol by 30\u201360%, total cholesterol by 23\u201328% , and triIn a meta-analysis of six studies, the association between high versus low categories of total serum cholesterol and high-grade or advanced prostate cancer tended to be slightly more pronounced than for total prostate cancer . SeveralAn additional consideration is that serum lipid levels may not reflect tumour lipid levels. In a randomised-controlled trial, 160 men were treated with radical prostatectomy after randomisation to high-intensity atorvastatin (80\u2009mg daily) or placebo for at least 28 days . MetabolOne approach to teasing apart the mechanism is to compare associations of statin versus non-statin cholesterol-lowering drugs with prostate cancer, though this can be challenging due to the overlap in use of statin and non-statin cholesterol-lowering medications and therefore necessitates large studies. A registry study from the Canadian province of Saskatchewan found thSeveral studies have found measurable statin levels within the prostate tissue itself. The ability of statins to access the prostate supports the potential for direct physiological effects of statins unrelated to systemic lowering of circulating cholesterol and other lipid species. Two window-of-opportunity trials measured statin concentrations in prostate tissue after roughly 4 weeks of statin treatment. A Canadian pilot trial randomised men with localised prostate cancer to 80\u2009mg fluvastatin for 4\u201312 weeks prior to their scheduled radical prostatectomy. Fluvastatin was detected in prostate tissue of 10 (36%) of 28 patients evaluated, and mean intraprostatic fluvastatin concentration in these ten patients was 9.7\u2009ng/g or 24\u2009nM, while mean serum fluvastatin levels were tenfold higher (200\u2009nM) . AnotherReduction of systemic and local inflammation is one of the best described non-cholesterol-lowering effect of statin use. Results from secondary analyses of cardiovascular disease clinical trials demonstrate that statins lower plasma levels of the inflammatory biomarker C-reactive protein , 35 in aTwo prostate cancer chemoprevention trials, REDUCE and the Prostate Cancer Prevention Trial (PCPT), provided opportunities for assessing the association of statin use with benign prostate inflammation among men undergoing study-mandated, PSA-independent prostate biopsies. REDUCE, which recruited men with elevated baseline PSA but a negative prostate biopsy, found lower risk of chronic histological inflammation of negative biopsies in statin users versus non-users and suggested lower odds of severe acute histological inflammation . By contA window-of-opportunity clinical trial which administered atorvastatin to 158 men scheduled to undergo radical prostatectomy in Finland examined intraprostatic inflammation as a secondary endpoint. Among men with high-grade disease randomised to atorvastatin, histological inflammation score was slightly lower . FinallyAlthough potential mechanisms discussed above are grouped into lipid-mediated and non-lipid-mediated categories, it is important to note that statins have pleiotropic effects, and so these may not be mutually exclusive. Mechanisms are challenging to tease apart in epidemiological studies, and country-specific prescribing patterns and differences in treatment protocols may hinder direct comparison of findings from various studies.One major consideration is whether it is appropriate to analyse statins together as a class or whether their effects and mechanisms need to be considered according to the statin type or subgroup. While many studies reported the prevalence of use of various statin types and doses (previously summarised in ), most wIn addition to statin type, few observational studies have been able to accurately account for variations in serum cholesterol levels throughout statin therapy. The previously mentioned ARIC study by Mondul et al. performed a stratified analysis by pre-statin serum cholesterol level and found similar associations between statin use and fatal prostate cancer in both groups . MurtolaGiven a cardiovascular risk profile that places most men with prostate cancer at high cardiovascular event risk , these mAs a first step towards answering this question, several studies explored the association between post-diagnosis statin use and prostate cancer-specific mortality, stratified by tumour characteristics at diagnosis. An analysis of the Health Professionals Follow-up Study reported that post-diagnosis statin use was not associated with lower prostate cancer-specific mortality overall , but found an inverse association among men diagnosed with higher stage prostate cancer , not present among men with stage T1 disease . An obseTMPRSS2:ERG fusion (ERG) status [Examining associations with subgroups defined by pathological and molecular features could highlight not only the most statin sensitive prostate tumours but could also bring to light new molecular targets that may be susceptible to other treatment modalities. Efforts to identify molecular biomarkers of prostate tumours that may be particularly susceptible to statins are now underway, which would enable more precise identification of men predicted to benefit. Within the prospective Health Professionals Follow-up Study, we reported a lower risk of PTEN-null prostate cancer among cancer-free men who used statins compared to non-users and no association between statin use and PTEN-intact prostate cancer . The ass) status . As ERG ) status , height ) status , physica) status , and lyc) status further As statins are associated with reduced risk of advanced prostate cancer and androgen deprivation therapy (ADT) is the main treatment for this patient subgroup, it is not surprising that recent investigations have focused on statins in the context of patients managed with ADT Table\u00a0. A 2017 By inhibiting androgen synthesis in the testes, ADTs lower systemic androgen levels, limiting androgen signalling pathways driving prostate cancer survival and proliferation. However, tumour progression inevitably occurs in spite of low availability of circulating androgens through a variety of documented mechanisms including intratumoral androgen synthesis from cholesterol . As suchWith a view to understanding which point in clinical progression that the tumour may be most sensitive to statins, a number of studies reporting lower prostate cancer-specific mortality in statin users Table\u00a0 performeAside from blocking intratumour cholesterol ester accumulation, which may primarily affect advanced tumours with the necessary enzymatic machinery to synthesise intratumoral androgens, an alternative hypothesis as to why statins may synergise with ADT lies in their potential effect on adrenal androgens such as dehydroepiandrosterone (DHEAS), a precursor to the more potent dihydroxytestosterone (DHT) and testosterone. As adrenal androgens continue to be synthesised despite orchiectomy or pharmaceuticals that modulate gonadotropin-releasing hormone, which largely target testicular androgen synthesis, they are thought to be one of the mechanisms of tumour resistance to ADT . A pre-sSecond generation anti-androgens, including abiraterone acetate, interfere with the androgen signalling axis in multiple organs including the adrenal glands as well as the prostate itself. As such, the aforementioned downregulation of adrenal androgens by statins suggests a mechanism whereby statins could complement downregulation of adrenal androgens by abiraterone to improve prostate cancer outcomes. As statins compete with abiraterone for SLCO-mediated influx there were initial concerns that statins may be antagonistic to abiraterone and therefore interfere with treatment efficacy. However, a US hospital-based cohort study found a trend towards longer duration of abiraterone response among men with CRPC using statins . The retTo date, the observational data summarised in our review shows a narrowing of focus for the promise of statin for prevention of all prostate cancer to prevention of fatal prostate cancer. Results showing an inverse association between statins and fatal prostate cancer risk are promising. While this is particularly encouraging given these patients currently have limited effective treatments and shorter survival times, biomarkers may help identify and subsequently target the molecular subgroups that are most likely to benefit from statin therapy. Given that statins are comparatively safe, in addition to support for improved prostate cancer-related outcomes in statin users, it could be argued that most men with prostate cancer should receive a statin. A central consideration here is that men with prostate cancer, particularly those receiving ADT , are at It is critical that these questions be evaluated using randomised-controlled trials. With advances in molecular profiling of prostate cancer, resulting biomarkers may aid in more efficient selection of participants for clinical trials of statins as well as become appropriate intermediate endpoints in such trials.As one of the world\u2019s most prescribed medications, statins are well-established and clinically safe drugs. For prevention and treatment of prostate cancer, as summarised in this review, the most pronounced and robust associations have been observed between statin use and outcomes related to advanced prostate cancer. A key consideration is the high burden of cardiovascular disease among men with prostate cancer , 71, witOur review shows that statins are not a cure-all, but the hype surrounding this class of drugs is understandable. Prostate cancer research motivated by potential statin effects has advanced our understanding of prostate cancer biology with regards to both cholesterol and lipid metabolism (see partner review of mechanistic data) as well With many observational studies supporting the hypothesis that statins may protect against fatal prostate cancer, there is hope that statins could form part of a multipronged therapeutic strategy. Ultimately, the focus should be on testing this hypothesis in patients using randomised-controlled trials. Furthermore, translational research integrating epidemiological data and lab-based investigations could help identify biomarkers of statin sensitivity. Such biomarkers would be beneficial to define molecular subgroups for subsequent examination in observational and trial-based settings."} +{"text": "Exercise intensity has been suggested to influence acute appetite-regulating gut hormone responses after exercise. High intensity interval training (HIIT) with near maximal to maximal intensity or sprint interval training (SIT) with supramaximal intensity might induce greater effects on gut hormones compared to moderate intensity continuous training (MICT), while current findings were inconsistent regarding the effects of these popular training methods.This systematic review and meta-analysis aimed to synthesis the findings in the literature and explore the impact of exercise modality on acylated ghrelin (AG), glucagon-like peptide-1 (GLP-1) and peptide YY (PYY).After searching the major databases to find articles published up to May 2022, twelve studies that compared hormone responses to HIIT/SIT and MICT were identified and included in the analysis.A random-effects meta-analysis showed that HIIT/SIT and MICT decreased AG concentration and increased GLP-1 and PYY concentration compared with no exercise control group, while interval training protocols, especially SIT protocols, elicited greater effect sizes in suppressing AG levels at all of the analysed time points and PYY immediately post-exercise compared to MICT.Acute SIT with lower exercise volume appears to be a more advantageous approach to decrease plasma AG concentration and potentially suppress hunger to a greater extent compared to MICT, despite the similar effects of HIIT/SIT compared to MICT in increasing anorectic hormones . Future studies are needed to further investigate the impact of moderators on the variability of changes in gut hormones after interval trainings."} +{"text": "Immunization programs are key preventive interventions and have largely contributed to reducing the burden of infectious diseases and decreasing related morbidity, mortality and healthcare costs. The study aimed to investigate coverage regarding diphtheria, tetanus, and acellular pertussis (dTap) - Inactivated Poliomyelitis Vaccine (IPV) and Human Papilloma Virus (HPV) vaccine and attitudes towards vaccinations among undergraduate university students in Southern Italy.This cross-sectional study was conducted among 327 students through an anonymous online questionnaire and included socio-demographic characteristics, attitudes towards vaccinations overall and specifically on dTap-IPV and HPV, reasons for having received or not vaccinations and willingness to receive vaccinations.One third of the students were concerned about serious adverse effects of vaccines and 95% believed that vaccines for uncommon diseases are useless. During adolescence, 89% of the sample received the mandatory dTap-IPV vaccine booster. Among unvaccinated students, 45% were unwilling to get vaccinated against dTap-IPV because they believed not to be at risk of infection (59%) and had lack of recommendation (35.3%). Regarding vaccination against HPV, 67% had received the recommended schedule. Among those who did not receive it, 34% were unwilling to get vaccinated because they did not feel at risk of HPV infection (41%). Interestingly, 16% of the sample disclosed some barriers to access vaccination centers. Moreover, 30% declared that HPV vaccination was discouraged by healthcare professionals (HCPs).Vaccination uptake is worryingly low and national objective coverage seems not still achieved. Likewise, risk perception of vaccine-preventable diseases was low and it seems negatively impact on the intention to get vaccinated. Improving vaccine confidence among HCPs is crucial as they have been shown to have the potential to influence patient vaccination uptake.Skilled communication with a trusted HCP could increase acceptance of vaccine during adolescence and address vaccine hesitancy.Strategies to disseminate information on vaccines should be established to increase mandatory and recommended vaccines coverage."} +{"text": "The Appalachian region is often characterized by poor health outcomes and economic depression. Health centers (HCs) are community-based and patient-directed organizations that deliver comprehensive, culturally competent, high-quality primary healthcare services in high need areas, including Appalachia, where economic, geographic, or cultural factors can hinder access to healthcare services.The study compares the clinical quality performance in preventive care and chronic disease management between Appalachian HCs and their non-Appalachian counterparts.Using 2015 Uniform Data System (UDS) health center data, bivariate and multivariate linear regression analyses examine the association of Appalachian HC with performance on preventive and chronic care clinical quality measures (CQMs).In the multivariate analysis, patients served at Appalachian HCs are more likely to receive colorectal cancer screening and pediatric weight assessment and counseling than at non-Appalachian HCs. No statistically significant differences in performance observed among other CQMs. The percentage of Medicaid patients and total physician FTEs have positive associations with preventive care in colorectal and cervical cancer screening, pediatric weight assessment and counseling, and tobacco screening and cessation intervention as well as chronic disease management of aspirin therapy for ischemic vascular disease and hypertension control in the multivariate model.Overall Appalachian HCs perform as well as or better than non-Appalachian HCs in delivering preventive and chronic care services. Further examination of clinical quality improvement programs, insurance payer mix, and practice size among Appalachian HCs could advance the replication of clinical quality success for clinics in similar underserved communities. The Appalachian region is a geographically and culturally distinctive region of the U.S. extending from New York to Alabama characterized by largely rural geography and resiliency assets that include strong social cohesion, family ties, social support, and spiritual belief.7Health centers (HCs) are community-based and patient-directed organizations that deliver comprehensive primary health care services and receive federal grant funding from the Health Resources and Services Administration (HRSA). HCs provide services in high-need areas, including Appalachia, where economic, geographic, or cultural factors hinder access to affordable primary care services. Annually, HCs are required to report clinical quality measures (CQMs) into HRSA\u2019s Uniform Data System (UDS). This study uses the national 2015 UDS data to examine the differences in clinical quality performance in preventive care and chronic disease management between the Appalachian HCs and their non-Appalachian counterparts.The HRSA\u2019s 2015 UDS data contain health center organizational-level data for patient sociodemographic, services provision, workforce, clinical quality measures, cost, and revenues.This cross-sectional study examines six preventive care and three chronic care CQMs reported in the UDS. The preventive measures consist of the following:cervical cancer screening: percentage of women aged 21\u201364 years who received timely Pap tests to screen for cervical cancer;colorectal cancer (CRC) screening: percentage of patients aged 50 to 75 years who had appropriate screening for colorectal cancer, which could be a colonoscopy within the last 10 years, a flexible sigmoidoscopy within the last 5 years, or an annual fecal occult blood test (FOBT), including the fecal immunochemical (FIT) test;body mass index (BMI) screening and follow-up plan: percentage of patients aged 18 and older with a documented BMI during the most recent visit or within the 6 months prior to that visit and when the BMI is outside of normal parameters, a follow-up plan is documented;weight assessment and counseling for nutrition and physical activity for children and adolescents: percentage of patients aged 3\u201317 years who had evidence of BMI percentile documentation and who had documentation of counseling for nutrition and who had documentation of counseling for physical activity during the measurement year;tobacco use and screening and cessation intervention: percentage of patients aged 18 years and older who were screened for tobacco use at least once during the measurement year or prior year and who received cessation counseling intervention and/or pharmacotherapy if identified as a tobacco user; andscreening for depression and follow-up plan: percentage of patients aged 12 years and older screened for clinical depression using an age appropriate standardized tool and follow-up plan documented.The chronic disease management clinical quality measures are as follows:aspirin therapy for patients with ischemic vascular disease;blood pressure control (as defined by hypertensive patients with a blood pressure less than 140/90); andrate of uncontrolled diabetes, that is, diabetic patients with a hemoglobin A1c (HbA1c) > 9%.Bivariate and multivariate linear regression analyses examined the association between being an Appalachian health center and performance on preventive and chronic care clinical quality measures. Other covariates in the regression model include patient characteristics, total number of physician full-time equivalent (FTE) as a proxy for practice size, and patient-centered medical home (PCMH) recognition status. HRSA has supported HC\u2019s implementation of PCMH practice transformation to improve clinical quality through effective care coordination and holistic care. Patient characteristics were composed of percentage of racial/ethnic minority patients, percentage of patients at or below 100% of the federal poverty level (FPL), and percentage of Medicaid patients. Statistical analyses were conducted using SAS version 9.3.In In the multivariate linear regression analysis as exhibited in Our findings demonstrate that patients receiving health care in Appalachian HCs experience quality of preventive and chronic care on par with patients served at non- Appalachian HCs. In particular, receiving care at Appalachian HCs is not associated with lower cervical cancer screening rate, which suggests Appalachian HCs are making strides towards addressing risk factors associated with receipt of cervical cancer screening such as lack of routine source of medical care, self-image insecurity, cultural stigma, as well as misperceptions about health and cancer.10Of particular interest are findings of positive associations between Appalachian HC and preventive CQMs of CRC screening and pediatric weight assessment and counseling. The CRC screening CQM performance in Appalachia HCs may reflect targeted clinical quality improvement initiatives by HCs and professional organizations to expand CRC screening modalities beyond colonoscopy, address financial barriers, and enhance trust in patient\u2013provider relationships towards screening recommendation adherence.The primary limitation of this study is that findings from 2015 UDS cross-sectional data do not allow for causal inferences. In addition, the Appalachian HC definition includes any HC with a clinical service delivery site in an Appalachian county, which may potentially lead to the inclusion of primary care service sites in border counties incorporated into CQM data reported at the HC organizational level.Overall, Appalachian HCs perform better than or comparable to their non-Appalachian counterparts in delivering preventive and chronic care services. Additionally, study findings suggest that HCs may be providing effective primary care that helps offset health care related disparities expected in Appalachia communities. In particular, barriers to Appalachian health disparities can be overcome by culturally competent care delivered in organizations such as HCs that utilize PCMH model of care with strong care coordination and case management to improve CQMs in Appalachian communities.What is already known about the subject? Health disparities in the Appalachian region reflect broader trends in rural America, which include higher prevalence of obesity, diabetes, hypertension, cancer mortality, lower life expectancy, and lower adoption of preventive screening.What is added by this report? The Appalachian health centers performed better or comparable than their non-Appalachian counterparts in delivering high quality primary care in preventive and chronic disease management.What are the implications? Future research on clinical quality improvement programs, insurance payer mix, and practice size among Appalachian health centers could advance the replication of clinical quality success for clinics in similar underserved communities."} +{"text": "Individuals differ in the extent to which they represent their goals as hoped-for versus feared states. We examined the role of such goal representations for how everyday affective experiences and goal pursuit are intertwined. When goals are represented as hoped-for states, we expected stronger associations between daily positive affect and goal pursuit. In contrast, when goals are represented as feared states, we expected stronger associations between daily negative affect (particularly fear) and goal pursuit. We used seven days of repeated daily life assessments from 238 older individuals . At baseline, participants reported three goals they planned to pursue over the study period and the extent to which each goal referred to something they hoped-for or feared. During the daily life assessments, participants reported their current affective states and momentary goal pursuit three times per day . Multilevel analyses regarding participants\u2019 most salient goal provide initial evidence supporting the expected interactions of goal representations on everyday affect\u2013goal pursuit links. Specifically, individuals with a strong hope-focus in their goals engaged in more goal pursuit when positive affect was up than individuals whose goals were low in hope-focus. In contrast, those with feared goals engaged in more goal pursuit when reporting increased fear. Findings are discussed in the context of the possible selves literature. Future analyses will examine lead-lag effects to address the temporal order underlying affect-goal pursuit associations."} +{"text": "Despite concerns regarding the risks of ionizing radiation from computed tomography (CT) imaging, the rates of abdominal pelvic CT (APCT) utilization in the emergency department (ED) continues to increase for patients with inflammatory bowel disease (IBD).To determine the factors that drive decisions on when to perform APCT imaging in the ED for patients with IBD and to determine if differences exist between physician specialties.We performed a quantitative, web-based survey between November 2021 and August 2022. Structured questions for Crohn\u2019s disease (CD) and ulcerative colitis (UC) were developed with input from stakeholders in gastroenterology, surgery, and emergency medicine. Surveys were disseminated to Canadian physicians in each of the three specialities through personal emails, and by newsletter from national specialty organizations. Between specialty comparisons were performed by Chi-squared and Fisher exact tests where appropriate.A total of 208 participants responded to our survey: median age 44 years (IQR 37-50), 132 (63%) male, and 141 (68%) in an academic practice. Survey participants included 81 (39%) gastroenterologists, 35 (17%) surgeons and 92 (44%) emergency physicians.There were significant differences between specialties in the perceived rates of positive findings from APCT imaging. In UC, gastroenterologists felt inflammation alone was more common than emergency physicians and bowel obstruction and septic complications less common than surgeons and emergency physicians. In CD, surgeons felt bowel obstructions, septic complications and bowel perforations were more common compared with gastroenterologists and emergency physicians.There were significant differences between specialties in the types of clinical presentations that drove decisions to arrange APCT imaging . In UC, gastroenterologists were less likely to order APCT imaging for diarrhea with rectal bleeding, abdominal pain without peritoneal findings and fever than surgeons and emergency physicians. In CD, there were similar practice patterns between specialities except gastroenterologists were less likely to order APCT imaging for diarrhea with rectal bleeding than surgeons.Our survey identified key differences between physician specialties in the perceived rates of positive findings from APCT imaging and practice patterns of CT utilization. These findings will help to guide the development of future multidisciplinary consensus guidelines for the appropriateness of CT imaging in the ED for patients with IBD.NoneNone Declared"} +{"text": "Antenatal depression and antenatal anxiety adversely affect several obstetric and foetal outcomes, and increase the rate of postnatal mental illness. Thus, to tackle these challenges the need for social support during pregnancy is vital.This study examined the association between domains of social support and antenatal depressive and anxiety symptoms among Australian women.Our study used data obtained from the 1973\u201378 cohort of the Australian Longitudinal Study on Women\u2019s Health (ALSWH), focusing upon women who reported being pregnant (n=493). Depression and anxiety were assessed using the Center for Epidemiological Studies Depression (CES-D-10) scale, and the 9-item Goldberg Anxiety and Depression scale (GADS) respectively. The 19 item-Medical Outcomes Study Social Support index (MOSS) was used to assess social support. A binary logistic regression model was used to examine the associations between domains of social support and antenatal depressive and anxiety symptoms.After adjusting for potential confounders, our study found that the odds of antenatal depressive symptoms was about four and threefold higher among pregnant women who reported low emotional/informational support and low social support respectively compared with their counterpart. In addition, the odds of antenatal anxiety symptoms was seven times higher among pregnant women who reported low affectionate support/positive social interaction .Low emotional support and low affectionate support have a significant association with antenatal depressive and anxiety symptoms respectively. As such, targeted screening of expectant women for social support is essential.No significant relationships."} +{"text": "Despite efforts by the WHO to support local surveillance strategies in developing countries, there is a lack of robust public health surveillance frameworks. As a result, early infectious disease outbreak detection and response remain a significant challenge for local health systems in low-resource settings such as sub-Saharan African countries. In contrast, the growing digital infrastructure, especially in the mobile phone sector, and the global availability of extensive digital data offer promising solutions to enhance and strengthen epidemiological surveillance. Yet, there is little insight into concepts of utilisation and transfer into local public health practice. Using Tanzania as an example, a novel electronic surveillance and early outbreak alert framework is being developed that links signals on emerging diseases with relevant contextual Open Data for rapid outbreak risk assessment. The concept focuses on haemorrhagic fever diseases, specifically dengue virus disease, which is increasingly spreading in sub-Saharan Africa. A data stack framework forms the core of the system, which augments electronic information on the occurrence of acute haemorrhagic fever syndrome, e.g., collected via mobile phone-based surveillance tools, with openly available socio-ecological context data specific to dengue. Preliminary results on the data and information flow within the surveillance framework are presented and strategies for an automated indicator-based risk assessment for dengue outbreaks will be discussed, supplemented by an agent-based simulation framework to model possible short-term outbreak scenarios. In addition, adequate data inputs, identified through an appraisal of various data sources available for Tanzania, are outlined. The framework could serve as a blueprint for designing locally implementable early warning and decision support systems integrated with existing digital surveillance infrastructure.\u2022\u2002Digital health surveillance and Open Data offer great potential for early outbreak detection and supporting health decisions but require tailored solutions to benefit low-resource settings.\u2022\u2002Building on existing digital surveillance infrastructure, the framework may serve as a blueprint for designing an enhanced surveillance and decision support system for infectious disease outbreaks."} +{"text": "Coping styles refer to cognitive and behavioral patterns used to manage the demands of stressors. This study aimed to characterize associations between coping styles and cognitive functioning across non-Hispanic Black and non-Hispanic White older adults. Cross-sectional data comes from the Michigan Cognitive Aging Project . Coping styles are measured with COPE inventory. Global cognition was a composite of five cognitive domain factor scores derived from a comprehensive battery. Results show that Black older adults reported more emotion-focused coping than Whites, but there were no differences in problem-focused coping. Less emotion-focused and greater problem-focused coping were each more strongly associated with better global cognition among Black older adults, who showed disproportionately worse cognitive performance in the context of less adaptive coping. Coping style may be a particularly important psychosocial resource for cognitive health among Black older adults who may have less access to compensatory resources than Whites."} +{"text": "Cell senescence and inflammation are interconnected mediators of aging and age-related disease. Recent advances in molecular and cellular profiling methods and research models are aiding in our ability to decipher mechanisms through which senescent cells drive inflammatory dysfunction, and inversely, to discover mechanisms through which aging immune cells may drive senescence, inflammation, and pathology. This symposium will feature exciting advances that span the emerging conceptual framework of how senescence and inflammation influence mammalian aging. Dr. Birgit Schilling will discuss the use of advanced mass spectrometric methods for profiling the senescent cell proteome, which reveal new insights into protein pathways and mechanisms of aging and disease. Dr. Matt Yousefzadeh will share how endogenous DNA damage can invoke cellular senescence, which enhances inflammation in both a cell autonomous and non-autonomous manner to drive tissue dysfunction and impact health. Dr. Daniel Tyrrell will discuss discovery of a novel population of age-associated CD8 T-cells that enhance local tissue senescence and inflammation and promote atherosclerosis. Dr. Xu Zhang will share a characterization of senescent cells in skeletal muscle using single-cell RNA-sequencing and the potential recruitment of immune cells by senescent fibroadipogenic progenitors. Dr. Marissa Schafer will discuss cell senescence as a mediator of age-related brain inflammatory cell composition and senescent cell targeting as a strategy to prevent cognitive decline. Importantly, discoveries discussed in this symposium may reveal new avenues for therapeutic development, to ultimately improve human healthspan."} +{"text": "We can understand the ecology and evolution of plant thermal niches through thermal performance curves (TPCs), which are unimodal, continuous reaction norms of performance across a temperature gradient. Though there are numerous plant TPC studies, plants remain under-represented in syntheses of TPCs. Further, few studies quantify plant TPCs from fitness-based measurements , limiting our ability to draw conclusions from the existing literature about plant thermal adaptation. We describe recent plant studies that use a fitness-based TPC approach to test fundamental ecological and evolutionary hypotheses, some of which have uncovered key drivers of climate change responses. Then, we outline three conceptual questions in ecology and evolutionary biology for future plant TPC studies: (i) Do populations and species harbour genetic variation for TPCs? (ii) Do plant TPCs exhibit plastic responses to abiotic and biotic factors? (iii) Do fitness-based TPCs scale up to population-level thermal niches? Moving forward, plant ecologists and evolutionary biologists can capitalize on TPCs to understand how plasticity and adaptation will influence plant responses to climate change. Variation in plant performance across temperatures are illustrated with a thermal performance curve (TPC), where performance peaks at a benign temperature and decreases to zero as temperature becomes cooler or warmer. Thermal performance curves have been useful for understanding evolution and plasticity, especially in response to climate change. However, most plant TPCs in the literature are based on physiological traits of single leaves, rather than individual fitness which would more directly approximate how populations might respond to changes in temperature. We describe what has been done and necessary next steps that utilize TPCs to determine how plants will respond to climate change. Temperature is among the most important global drivers of productivity and biodiversity to geothThermal performance curves are unimodal, continuous reaction norms of performance, defined as any metric of an organism\u2019s ability to function, across a temperature gradient ; Fig. 1AHere, we convey the value of fitness-based TPCs for addressing key questions in plant ecology and evolutionary biology. By fitness-based TPCs, we mean TPCs that are quantified through performance traits that are measured at the individual level or above . We do not discuss TPCs characterized by short-term, subindividual traits (e.g. photosynthesis) or the physiological or molecular mechanisms underlying such TPCs as these topics are already well-studied (Mollugo verticillata (Mimulus), species with broader TPCs experienced greater temperature variation across their ranges relative to species with narrower TPCs evolved narrower thermal performance breadth rely on measurements of the same individuals across multiple temperatures and can take only a few minutes to quantify e.g. , fitnessGiven that these fitness proxies typically do not encompass the full life cycle, a key knowledge gap is whether fitness-based TPCs capture the relationship between temperature and the long-term growth rates of natural populations . M. verticillata. Second, using populations spanning the northern half of the geographic range of M. cardinalis, Two studies have combined species distribution models (SDMs) with TPCs to investigate the hierarchical nature of niche breadth and predict how plant populations and species will respond to climate change. First, Mimulus species with greater genetic variation for thermal tolerance have evolved broader TPCs. They were unable to fit TPCs to each genotype (represented by full-sibling seed families) to evaluate whether species with greater genetic variation for TPC parameters have evolved broader TPCs, because hierarchical TPC models that could simultaneously estimate multiple genotype-level TPCs from a population-level average TPC were not yet available. Rather, they focused on genetic variation for thermal reaction norms at the two lowest and the two highest experimental temperatures. They found that species with broader TPCs had greater among-genotype variation in slopes of reaction norms at both the cold (15\u201320 \u00b0C) and hot (40\u201345 \u00b0C) ends of the temperature gradient. Future work is needed to evaluate whether plant populations have sufficient genetic variation for TPC parameters to respond to climate change, and to further develop modelling approaches that can account for variation at multiple biological levels is \u22651, indicating demographic stability or growth, whereas a TPC describes a performance metric for a biological entity . While extreme temperature events may drive short-term acclimation responses at the subindividual level (In the strictest sense, the thermal niche represents the set of temperatures across which population growth rate (Daphnia (Previous work has estimated TPCs using population growth rate as the response variable in short-lived organisms including Daphnia . Such stin situ. Ultimately, we hope that this viewpoint paves the way for including plants in future syntheses of TPCs and deepening our understanding of the ecological and evolutionary determinants of plant responses to climate change.Thermal performance curves are an ideal tool for fundamental and applied research in plant ecology and evolution. Here, we have described plant TPC studies that have tested hypotheses about plant adaptation and plasticity, with important implications for predicting responses to climate change. Several hypotheses, however, remain untested, including those about the roles of genetic variation in the evolution of niche space at the population level and beyond, controls of biotic interactions on realized niche space, and whether fitness-based TPCs determined in experimental settings can be scaled up to represent population-level niche space"} +{"text": "This symposium uses data from the National Social Life, Health & Aging Project to examine how and for whom older adults\u2019 social relationships and experiences changed with the advent of the COVID-19 pandemic. Zhang et al. examine video call usage among older adults with hearing impairment and how this might mitigate loneliness. They find that although this population reported greater loneliness during the pandemic, video calls attenuated this relationship in a dose-response manner. Wilder et al. evaluate 2015 resilience and socioeconomic status as predictors of older adults\u2019 reports that the pandemic led to a positive change in their lives. Results revealed greater odds of reporting a positive impact of the pandemic for those with higher education, adjusting for resilience. Compernolle et el. assess differences by cognitive status in changes in mental health from pre- to during the pandemic. Higher 2015 cognitive functioning was associated with greater pandemic loneliness, with decreased pandemic emotional support partly explaining this association. Copeland & Liu investigate the role of 2015 personal networks in receiving instrumental and emotional support during the pandemic, finding that larger and denser pre-pandemic confidant networks each predicted higher odds of receiving various types of support during the pandemic. Wong et al. explore whether and for whom relationship quality changed since the pandemic started. Two-thirds of partnered respondents reported unchanged relationship quality, and Black respondents were more likely to report improved relationship quality. These investigations highlight sub-group differences in older adults\u2019 changes in experiences, behavior, and well-being since the pandemic began."} +{"text": "Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract. Due to an increased risk of developing colorectal cancer, regular surveillance for dysplastic lesions via colonoscopy is recommended. Invisible dysplasia is the abnormal development of cells noted on pathology with no visible lesion seen during colonoscopy. Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease leading to progressive stricturing and fibrosis of the bile ducts. There is significant association between PSC and IBD, as up to 80% of patients with PSC having underlying IBD. Drug induced liver injury (DILI) is a common cause of acute liver failure in most Western countries. Most cases of DILI are self-limited, with resolution of laboratory and clinical findings after cessation of the offending agent.To describe a case of invisible colonic malignancy and possible idiosyncratic drug-induced liver injury from vedolizumab (VDZ) in a patient with ulcerative colitis (UC), PSC and autoimmune hepatitis (AIH) overlap syndrome.Patient consent was obtained. Information from electronic records was extracted, including admission notes and procedural reports. A literature review was performed using Pubmed.A 32-year-old Caucasian female with UC on VDZ with PSC and AIH had multiple colonoscopies performed demonstrating multifocal low-grade dysplasia. However, she remained resistant to surgery. She presented to clinic with tea-coloured urine, fatigue, and scleral icterus. Investigations revealed conjugated hyperbilirubinemia with elevation in hepatocellular liver enzymes. Imaging was consistent with large duct PSC, and liver biopsy showed grade 2 chronic hepatitis raising the possibility of large bile duct obstruction. She underwent liver transplant assessment and VDZ was held. Her bilirubin and liver enzymes recovered. Given multiple colonoscopies showing multifocal dysplastic changes and the patient declining other biologics, she would ultimately undergo total proctocolectomy with end ileostomy. Pathology demonstrated mucinous adenocarcinoma with a signet ring component.Both mucinous adenocarcinoma and signet ring carcinoma are more aggressive malignancies associated with poor prognosis. Found more often in younger patients, they are often diagnosed in later stages with lymphovascular invasion. Here, there was no evidence of metastases in any of the 40 lymph nodes examined, which indicated more favourable prognosis.The mechanism by which VDZ potentially causes liver injury is unknown. Multiple therapies for PSC-AIH overlap and IBD were entertained as causative agents. However, significant improvement in clinical symptoms and serologic parameters following cessation of VDZ was temporally suggestive.This case simultaneously highlights the importance of both timely colectomy in IBD patients with high-risk features during surveillance and early recognition and cessation of potential causative medications which induce liver injury.NoneNone Declared"} +{"text": "Within Ohio\u2019s MyCare demonstration, two distinct care management models were selected by the participating MyCare Ohio health plans (MCOPs): fully-delegated waiver care management and waiver service coordination. The purpose of this presentation is to describe the components of care management operating in MyCare Ohio. Qualitative interviews with n=91 Area Agency on Aging (AAA) and n=131 MCOP care management personnel were audio-recorded, transcribed, and checked for accuracy prior to thematic coding in Dedoose. Results indicate that comprehensive care management is the core element of MyCare Ohio. Fully-delegated care management models were viewed by participants as beneficial to reducing confusion for members however \u2018scope creep\u2019 challenged the already strained AAAs. Effective teamwork was identified for waiver service coordination models but the division of labor and communication needed between the AAA and MCOP care management personnel created tensions. The discussion will focus on practice recommendations for training, caseloads, and support staff."} +{"text": "Teaching Point: Intravertebral venous collateral formation can occur in thoracic venous obstruction syndrome and mimic metastatic bone lesions on contrast-enhanced imaging: vanishing bone metastases. Intravertebral venous collateral formation can occur in thoracic venous obstruction syndrome and mimic metastatic bone lesions on contrast-enhanced imaging.A 60-year-old man was admitted to the emergency department complaining of headaches, dyspnea and deterioration of consciousness during the past few days. He has a history of esophageal cancer treated with surgery and adjuvant radiochemotherapy. Clinical examination revealed swelling of the face, neck and upper limbs, as well as turgidity of the jugular veins and stridor.A contrast enhanced computed tomography (CT) scan of the neck and chest was performed. It showed a superior vena cava obstruction with various venous collaterals and 2 11.Multiple high-density bone lesions were also detected in several cervical and thoracic vertebral bodies . These fSpine magnetic resonance imaging (MRI) performed two days later didn\u2019t reveal any vertebral signal abnormalities . Nor werTherefore, we can conclude that the dense intravertebral images on the contrast-enhanced CT imaging resulted well from contrast accumulation in intravertebral venous collaterals .Venous dilatation and relative blood stagnation can be present when the superior vena cava is obstructed. Most frequent venous collateral pathways are via the azygos, hemiazygos, intercostal veins and vertebral venous plexuses. In some cases, intravertebral collaterals can also be involved. These intraosseous venous collaterals are located in the vertebral bodies and drain into vertically oriented veins in the spinal subarachnoid space 45.4Therefore, stagnation of intravenous contrast material in these intravertebral collaterals can mimic condensing bone metastases on CT scans after contrast administration , hence tIn literature, there are limited number of case reports describing such vanishing bone metastases. One of the first descriptions of this peculiar aspect was in 2009 by Jesinger and colleagues .Vanishing metastases appear to be an underdescribed entity and should not be confused for malignant lesions."} +{"text": "Anxiety disorders (ADs) are pervasive, detrimental, and associated with numerous psychiatric disorders; however, their etiology and effective treatment strategies are not yet fully explored.We aimed to study whether the symptom severity of ADs is related to mindfulness and metacognition among adults. In addition, we wanted to compare metacognition and mindfulness between patients with ADs and healthy controls (HC).Two hundred participants were enrolled in this study. Structured clinical interview, sociodemographic form, Five Facet Mindfulness Questionnaire-Short Form (FFMQ-S), Metacognition Questionnaire-30 (MCQ-30), and Hamilton Anxiety Rating Scale (HAM-A) were administered. Multivariate analysis of covariance (MANCOVA) was conducted to compare the groups in terms of mindfulness and metacognition. Correlation and multiple linear regression analyses were performed to measure the association between anxiety symptom severity, mindfulness, and metacognition.The main finding indicates that Positive Beliefs about Worry are associated with reduced symptom severity of ADs. Furthermore, the results suggest that HC have more Positive Beliefs about Worry and Nonjudging of Inner Experience compared to patients with ADs, who use Negative Beliefs about Uncontrollability and Danger and Need to Control Thoughts to a greater extent.This study suggests that dysfunctional metacognitive beliefs may influence symptom severity of ADs among adults. We advise that focusing on reducing maladaptive metacognitions may be beneficial while treating ADs in adultsNo significant relationships."} +{"text": "The pancreas exhibits remarkable inherent cellular plasticity in response to injury. To prevent inflammatory injury or death, acinar cells can undergo transient acinar-to-ductal metaplasia (ADM) by suspending normal cell functions and adopting characteristics of ductal cells. However, persistent ADM in the setting of chronic pancreatitis predisposes to pancreatic cancer. Less frequently, acinar cells have also been found to undergo acinar-to-adipocyte transdifferentiation, but the mechanisms and clinical significance of this process are largely unknown. Recent studies have identified that the Hippo signaling pathway and its effectors are vital for pancreatic development and function.YAP is highly expressed in normal pancreatic ducts and transiently in acinar cells undergoing ADM, suggesting a dual role for YAP in (1) the homeostatic maintenance of pancreatic ductal cells, and (2) the regenerative response to injury in acinar cells. However, little is known about the cell type-specific effects of YAP/TAZ on pancreas homeostasis and regeneration.Yap/Taz in both acinar cells and ductal cells using the previously described CluCreERT mouse line. We also established a pancreatic ductal cell-derived organoid system. The efficiency of in vitro Cre recombinase induction was confirmed in Yapfl/fl;Tazfl/fl;CluCre-ERT;LSL-tdTomato (YTKO) ductal organoids.We investigated the homeostatic functions of Yap and Taz in the pancreas by conditionally ablating We observed severe atrophy and a pancreatitis-like phenotype in the pancreata of YTKO mice following tamoxifen induction. At later time-points, YTKO pancreata were progressively remodeled \u2013 the exocrine pancreas was almost entirely replaced by adipose tissue and large hyperplastic ductal structures. We will perform further lineage tracing experiments to determine whether infiltrating adipose cells derive directly from transdifferentiating acinar cells. YTKO pancreatic ductal organoids exhibited disrupted survival and proliferation, evidenced by increased expression of cleaved Caspase3 and decreased EdU incorporation compared to vehicle-treated controls.Although some flexibility in cell fate potential is beneficial for the regenerative capacity of the pancreas, dramatic changes in cellular identity can have disastrous consequences. Overall, this study revealed that disruptions in Hippo signaling in the adult murine pancreas led to failure of regeneration and the complete remodeling of the exocrine pancreas, and has shed light on the previously uncharacterized role of Hippo signaling in acinar-to-adipocyte transdifferentiation. The potential contribution of fatty infiltration of the pancreas to the pathogenesis of diabetes mellitus and pancreatic cancer merits further exploration.CIHR, OtherFonds de recherche du Quebec - Sante (FRQS)None DeclaredCELLULAR & MOLECULAR GASTROENTEROLOGY"} +{"text": "The coated alloy was co-cultured with bone marrow mesenchymal stem cells and showed excellent biocompatibility and osteoinductivity in vitro. A further exploration of the underlying mechanism by quantitative real-time polymerase chain reaction and western blotting revealed that the enhancement effects are related to the upregulation of genes and proteins involved in the Wnt/\u03b2-catenin pathway. In vivo experiments showed that the TiCu/TiCuN coating significantly promoted osteoporotic fracture healing in a rat femur fracture model, and has good in vivo biocompatibility based on various staining results. Our study confirmed that TiCu/TiCuN-coated Ti promotes osteoporotic fracture healing associated with the Wnt pathway. Because the coating effectively accelerates the healing of osteoporotic fractures and improves bone quality, it has significant clinical application prospects.Osteoporosis results in decreased bone mass and insufficient osteogenic function. Existing titanium alloy implants have insufficient osteoinductivity and delayed/incomplete fracture union can occur when used to treat osteoporotic fractures. Copper ions have good osteogenic activity, but their dose-dependent cytotoxicity limits their clinical use for bone implants. In this study, titanium alloy implants functionalized with a TiCu/TiCuN coating by arc ion plating achieved a controlled release of copper ions Osteoporosis is a common orthopaedic disease characterized by bone microstructure destruction and bone loss. As the bone quality declines, the bone microstructure is destroyed. The bones become very fragile over time, and eventually, fractures can occur in response to minimal external force. Osteoporotic fractures are difficult to treat. Because of the decline in bone quality, postoperative fractures that do not heal or delayed healing can occur. Fracture healing generally occurs in three phases: inflammation, osteogenesis and bone remodelling . Bone reThe implants currently used to fix fractures are mainly made of stainless steel, medical titanium alloy or cobalt chromium molybdenum alloy, and have high mechanical strength, excellent biocompatibility and maintain optimal stability , 6. HoweCopper is an indispensable trace element in the human body and is involved in most metabolic reactions as an important coenzyme . In addiin vitro corrosion resistance tests. Further in vitro and in vivo studies are needed to assess osteogenic activity.Titanium nitride (TiN) is a very hard and stable material , 18, witin vivo by promoting Wnt/\u03b2-catenin signalling pathway, and promote the formation of callus at the fracture site, thereby accelerating fracture healing ; the Science and Technology Commission of Shanghai Municipality [22YF1422900 and 21002411200]; the Shanghai Municipal Key Clinical Specialty, China [shslczdzk06701]; Huangpu District Industrial Support Fund [XK2020009]; the National Facility for Translational Medicine (Shanghai), China [TMSZ-2020-207]; and the Shanghai Engineering Research Center of Orthopedic Innovative Instruments and Personalized Medicine Instruments and Personalized Medicine [19DZ2250200].Conflicts of interest statement. The authors have no conflicts of interest relevant to this article.rbac092_Supplementary_DataClick here for additional data file."} +{"text": "Acute upper limb ischemia in a patient with thoracic outlet syndrome is a rare but serious clinical disorder. If the disease is not treated promptly due to underdiagnosis, it could lead to distal artery embolization and limb-threatening ischemia. Revascularizing upper extremity arteries in a timely manner could rescue ischemic limbs and improve the patient\u2019s quality of life. We reported here a case of a patient who presented with bilateral upper limb ischemia caused by arterial thoracic outlet syndrome.A 63-year-old woman who presented with sudden bilateral upper extremity cold, numbness, pulselessness, and altered temperature sensation was first diagnosed with arterial thoracic outlet syndrome. The patient had performed a lot of pull-up and lat pull-down exercises in the 2 months prior to the onset of the above symptoms. Color Doppler ultrasonography showed thrombosis in the right axillary artery and left subclavian and axillary artery. The patient received Rotarex mechanical thrombectomy combined with drug-coated balloon percutaneous transluminal angioplasty (PTA) to complete revascularization of the upper extremities and achieved a full recovery finally.Complete endovascular revascularization for treating arterial thoracic outlet syndrome is a minimally invasive and effective method, especially for upper extremity ischemic lesions caused by nonbone compression. Arterial thoracic outlet syndrome (TOS) is a group of disorders manifested with upper extremity ischemia or aneurysmlike disease caused by external compression of subclavian or axillary arteries at the thoracic outlet . ArteriaDecompression of the thoracic outlet is the classic therapy, including cervical rib excision, release of scalenus, and vascular thrombectomy and reconstruction . HoweverWe report a rare case of acute ischemia of bilateral upper extremities caused by arterial thoracic outlet syndrome. Rotarex mechanical thrombectomy combined with a drug-coated balloon was used to reconstruct the upper extremity blood flow, and finally, the patient fully recovered.A 63-year-old female patient presented with acute bilateral upper extremity cold, pulselessness, and altered temperature sensation. The patient described that she had performed a lot of pull-up and lat pull-down exercises in the 2 months prior to the onset of the above symptoms. The physical examination showed that typically marked bilateral upper extremity ischemia manifesting with radial and ulnar artery blood flow were out of palpable and cold sensation in upper limbs. The patient was diagnosed with arterial thoracic outlet syndrome after clinical provocation tests and computed tomography (CT) results The patient received anticoagulant and antiplatelet therapy after hospitalization. An 8F Rotarex mechanical thrombectomy system was used to reduce the thrombus burden in the axillary artery and the subclavian artery. To decrease the risk of ectopic embolization, we adopted a strategy of slowly pushing the Rotarex catheter from proximal to distal end of the artery. Before the aspiration of thrombus in the distal artery, we performed repeated aspiration in the proximal artery aiming to reduce the amount of thrombus fully. Then, 3-, 5-, and 8-mm Mustang balloon catheters were useArterial thoracic outlet syndrome is usually present with upper extremity ischemia or aneurysm caused by chronic external compression of the subclavian artery or axillary artery when passing through the defined anatomical space called thoracic outlet. Bony abnormalities such as abnormal cervical rib and first rib, anomalous development of anterior scalene muscle, and other soft tissues contribute to subclavian/axillary artery stenosis, occlusion, thrombosis, and aneurysm. The innovation of endovascular technology makes it possible to treat arterial thoracic outlet syndrome through a more minimally invasive surgical approach.First, the diagnosis of arterial TOS needs to be carefully distinguished. Patients with arterial TOS usually present with obvious symptoms of limb ischemia such as cold feeling, pulseless, and altered temperature sensation. In addition to pain, numbness, and paresthesia, some neurogenic TOS patients also manifested intermittent finger paresthesia, discoloration, and coldness in the absence of thromboembolism in the subclavian artery. The ischemic manifestations of the upper extremities are mainly attributed to vasospasm mediated by sympathetic nerve plexus compression rather than true arterial TOS , 13. ColThe congenital abnormality of anterior scalene muscle, cervical rib, the first rib, and other factors lead to the compression of the subclavian/axillary artery, resulting in intimal hyperplasia, thrombosis, and aneurysm in arterial TOS. Traditional surgery requires thoracic outlet decompression, artery release, thrombectomy, and subclavian\u2013axillary artery bypass grafting, causing extremely traumatic injury and bleeding. The advancement of endovascular intervention provides new treatment possibilities. Pantoja et al. comparedRotarex thrombectomy combined with drug-coated balloon dilation achieved good initial clinical results and a satisfactory arterial patency rate in treating arterial TOS; however, a strict case screening is required. For arterial TOS caused by bone compression, it is still necessary to decompress the neurovascular bundle first . Further"} +{"text": "This study examined Alzheimer\u2019s disease (AD) knowledge and its predictors among Korean Americans (KAs). A total of 268 KAs in the Greater Washington metropolitan area participated in the study and completed a cross-sectional survey. Using the Alzheimer\u2019s Disease Knowledge Scale (ADKS), overall and domain knowledge was assessed. Multiple regression analyses were conducted with predictors including exposure to AD, social engagement, sources and frequency of health-related information, stigmatic beliefs , English proficiency, and education. KAs reported 59% accuracy in overall AD knowledge. They were most knowledgeable about assessment and diagnosis domain and least knowledgeable about caregiving domain. Regression analyses showed that having more education is associated with greater overall and certain domain knowledge. Having more pity stigmatic beliefs is related to greater knowledge in both life impact and caregiving domains while having less pity stigmatic beliefs is associated with more risk factor knowledge; having less social distance stigmatic beliefs is associated with greater life impact knowledge; and having less antipathy stigmatic beliefs is related to better caregiving knowledge. Our findings revealed areas of misconceptions and knowledge gaps in KAs which need to be addressed in educational interventions. Different knowledge status across the domains demonstrates a multi-dimensional nature of AD knowledge. Multivariate findings confirmed the robust role of education in AD knowledge. Effect of different AD stigmatic beliefs on certain AD knowledge domains suggests ways of how stigma change can be efficient for the purpose of increasing AD domain knowledge in KAs."} +{"text": "COVID-19 raises serious concerns regarding its unknown consequences for health, including psychiatric long term outcomes. Historically, influenza virus has been responsible for pandemics associated with schizophrenia. Epidemiological studies showed increased risk for schizophrenia in children of mothers exposed to the 1957 influenza A2 pandemic. Controversy remains concerning the mechanisms of pathogenesis underlying this risk.We aim to review the evidence for the association between influenza infection and schizophrenia risk, the possible pathogenic mechanisms underlying and correlate these findings with the schizophrenia hypothesis of neurodevelopment.We reviewed literature regarding evidence from epidemiological, translational animal models and serological studies using medline database.The biological mechanisms likely to be relevant account to the effects of infection-induced maternal immune activation, microglial activation, infection-induced neuronal autoimmunity, molecular mimicry of the influenza virus, neuronal surface autoantibodies and psychosis with potential infectious antecedents. Influenza infection may fit into the theory of the neurodevelopment of schizophrenia as a factor that alters the normal maturation processes of the brain (possible second or third hit).Influenza infection has multiple pathogenic pathways in both pre and post natal processes that might increase the risk of schizophrenia or psychosis. The existing evidence regarding the relationship between influenza virus and psychosis might help us draw similar long-term concerns of COVID-19.No significant relationships."} +{"text": "Little is known how adults\u2019 memories of parental acceptance-rejection in childhood influence their behavior toward their aging parents. Grounded in interpersonal acceptance-rejection theory (IPARTheory), this study attempts to better understand how early parent-child relationships affect adult offspring who provide care to their parents in later life. Data were collected from 41 adult offspring. Findings revealed that adults who felt rejected by their parents in childhood reported fewer positive caregiving behaviors toward their now aging parents, were less satisfied with social activities with their parents, spent less time with them or visited them less frequently, and revealed less overall concern for their aging parents. Results were consistent with IPARTheory\u2019s expectations that if parents reject their children, then parents place their own dependent old age at the risk of counter rejection: As you sow, so shall you reap. Such findings may help researchers, clinicians, and practitioners better understand the well-being of aging adults."} +{"text": "Pain is endemic for residents of long-term care homes, with many residents experiencing pain daily. Given that healthcare aides provide most daily care for residents, they are ideally situated to deliver timely assessment and non-drug interventions for managing resident pain. In this Cochrane-style systematic review, we searched 7 databases to identify intervention studies that included long-term care residents aged \u226560 years who received interventions to reduce chronic pain. Interventions were either delivered by healthcare aides at the resident level or were directed at healthcare aides to improve their pain management practices. We screened 400 titles/abstracts and 152 full-text articles. Nine studies met inclusion criteria and were included in a narrative review. Due to the limited number of studies and variety of study designs, data were insufficient to perform meta-analyses or thematic analysis. Three studies described pain interventions delivered by healthcare aides at the resident level reporting significant improvement of pain. Six studies described pain interventions delivered to healthcare aides. Results of these interventions were inconsistent; 2 reported significant improvements in pain-related outcomes , 3 reported insignificant changes, and 1 reported a positive correlation between measured pain and pain medication use. We concluded that despite the paucity of research in this area, this systematic review provides preliminary support for pain interventions by healthcare aides for long-term care residents. Future research exploring interventions for healthcare aides to take greater roles in pain management could unlock further improvements in resident care."} +{"text": "Although clinical parameters such as unexplained syncope or a family history of WPW may correlate with increased risk, most commonly the risk is estimated based on parameters observed during episodes of clinical tachycardia or variables measured during electrophysiology study (EPS).This case involves a 16-year-old female patient with WPW and episodes of supraventricular tachycardia since the neonatal period. Owing to increasingly frequent and prolonged episodes of supraventricular tachycardia with symptoms including severe chest pain and near-syncope, she was referred for EPS and catheter ablation. Her baseline ECG demonstrated ventricular pre-excitation with a pattern consistent with left anterolateral accessory pathway .Figure\u00a01At diagnostic EPS, local ventricular pre-excitation with earliest activation was identified at the distal coronary sinus catheter. Ventricular pacing also demonstrated eccentric and nondecremental ventricular-atrial conduction at the anterolateral aspect of the coronary sinus. The antegrade accessory pathway effective refractory period was 270 ms with 600 ms cycle length drive train. There was persistent antegrade accessory pathway conduction with rapid atrial pacing at 260 ms. Induced orthodromic reciprocating tachycardia converted into atrial fibrillation with a single-interval SPERRI of 228 ms; however, the majority of R-R intervals were in the range of 350\u2013400 ms . Atrial In patients with WPW, it is generally accepted that the risk of sudden death is related to the characteristics of the accessory pathway(s). The mechanism of sudden death is reported as atrial fibrillation with rapid antegrade accessory pathway conduction leading to ventricular fibrillation.For adult patients with WPW, high-risk is defined as the SPERRI during atrial fibrillation \u2264250 ms, the presence of multiple accessory pathways, an accessory pathway refractory period \u2264240 ms, or atrioventricular reentrant tachycardia precipitating pre-excited atrial fibrillation.Atrial flutter and atrial fibrillation are proposed to be related entities and may transform into one another, as demonstrated with our patient.Invasive risk stratification for pediatric patients with WPW is imperfect. The relationship of atrial fibrillation and atrial flutter may offer an explanation for sudden death or life-threatening events in children who have low-risk pathways by invasive electrophysiologic testing. Catheter ablation should be considered at the time of EPS if safe and feasible."} +{"text": "Physical therapists often treat pain and functional limitations associated with chronic musculoskeletal conditions common in aging adults. While patient report improvement after physical therapy, these results do not translate to sustained physical activity. This is a lost opportunity to support aging adults in adopting behaviors proven to improve quality of life and reduce comorbidity burden. We conducted semi-structured interviews with 30 physical therapists to understand how they support adoption of physical activity and identify what is needed to improve uptake. Physical therapists endorse physical activity as essential in the management of MSK conditions. Eliciting motivation, addressing psychosocial needs, and empowering patients to actively engage in solutions were identified as significant challenges in the effort to change physical activity. At the clinician level, physical therapists identified the need for improved skills in motivational interviewing and person-centered communication. Improved coordination with mental health providers and community resources were identified as environmental needs."} +{"text": "Amidst global shifts in the distribution and abundance of wildlife and livestock, we have only a rudimentary understanding of ungulate parasite communities and parasite-sharing patterns. We used qPCR and DNA metabarcoding of fecal samples to characterize gastrointestinal nematode (Strongylida) community composition and sharing among 17 sympatric species of wild and domestic large mammalian herbivore in central Kenya. We tested a suite of hypothesis-driven predictions about the role of host traits and phylogenetic relatedness in describing parasite infections. Host species identity explained 27\u201353% of individual variation in parasite prevalence, richness, community composition and phylogenetic diversity. Host and parasite phylogenies were congruent, host gut morphology predicted parasite community composition and prevalence, and hosts with low evolutionary distinctiveness were centrally positioned in the parasite-sharing network. We found no evidence that host body size, social-group size or feeding height were correlated with parasite composition. Our results highlight the interwoven evolutionary and ecological histories of large herbivores and their gastrointestinal nematodes and suggest that host identity, phylogeny and gut architecture\u2014a phylogenetically conserved trait related to parasite habitat\u2014are the overriding influences on parasite communities. These findings have implications for wildlife management and conservation as wild herbivores are increasingly replaced by livestock. They arHistorically, sampling limitations have impeded community-level multi-host/multi-parasite analyses. Gastrointestinal nematodes parasitize many different large mammalian herbivore species, yet accurate taxonomic identifications\u2014necessary to quantify diversity and identify host-sharing networks\u2014typically requires retrieving adult specimens from dead hosts or culturing larvae. Moreover, while several databases document host-species\u2013parasite relationships ,13, dataFor diverse large-herbivore assemblages, such as those found in African savannahs, such approaches could address knowledge gaps about patterns and determinants of parasite prevalence, diversity and sharing in locations where wild and domestic hosts overlap . SeveralThree host-specific predictors are often proposed as correlates of parasite species richness across systems and species: body size , geographical range size , and population density (and thus intraspecific transmission opportunities) ,26. A reBecause sympatric herbivores share many of the same food and water resources that serve as transmission routes for gastrointestinal parasites , studiesWe used DNA metabarcoding of the ITS-2 region to analyse gastrointestinal nematode DNA (Strongylida) in fecal samples from a diverse community of wild and domestic large herbivores in an East African rangeland. Strongylida are among the most common metazoan parasite groups in large herbivores and infect various parts of the digestive tract, including the stomach and intestines. While taxonomic reference data for nematodes remain limited, DNA metabarcoding enables comparative analysis of diversity and composition by clustering sequences by similarity even when taxonomic names are lacking, as has been validated for both parasitic and free-living nematodes ,35 ), richness and phylogenetic diversity? We hypothesized that, in addition to strong effects of host species identity on parasite assemblages , hosts t. 22 of semi-arid thorn-scrub savannah managed for wildlife conservation and livestock production ) (b)a,b; electronic supplementary material, figure S9), demonstrating the role of a few generalists in connecting the network. The high centrality of giraffe and camel\u2014intriguing given that each is the only local member of its family and that both feed overwhelmingly in the overstorey\u2014suggest that these species are infected by generalist parasites and may play an important role in cross-species transmission depending on their movement and density. One clear management implication is that regularly deworming camels, as done successfully for sheep and goats at our site, might help limit parasite transmission to wildlife . The same is true for donkeys, which had the highest centrality of the three equids and are likely to share parasites with the endangered Grevy's zebra and near-threatened plains zebra.Our finding that host\u2013parasite links were highly aggregated aligns with previous studies showing that most parasites specialize on few hosts while only a few have broad host ranges ,81. Parafigure 3Our finding of phylogenetic influence on network centrality metrics is consistent with the likelihood that closely related hosts share ecological, anatomical and immunological traits that shape host\u2013parasite coevolution. Indeed, models based on herbivore parasite records suggest (c)While the DNA barcode we sequenced can effectively distinguish parasitic nematode species across a wide range of hosts , it is lOur raw data contained low-abundance mOTUs that generated a highly interconnected host\u2013host sharing network, but filtered data using mean RRA greater than or equal to 2% per species were more concordant with prior studies ,13. WhilWe could not identify 48% of parasite mOTUs to species due to gaps in genetic resources for many wildlife parasites . While t. 5We show that host phylogeny and digestive strategy explain a high degree of variance in parasite community composition and sharing across a diverse community of wild and domestic large herbivores. While additional work is needed to maximize the value of parasite metabarcoding data, this approach holds enormous promise to shed light beneath the tip of the biodiversity iceberg. Use of these methods in studies with spatially or temporally stratified sampling designs will allow researchers to capture multi-host parasite dynamics that have long remained elusive. Our finding of substantial parasite sharing at the livestock-wildlife interface suggests that regularly deworming camels and donkeys could be an effective local management intervention to reduce transmission between livestock and several globally threatened and near-threatened ungulates. More broadly, our results suggest that changes to domestic animal communities or their parasite loads will impact parasitism in sympatric wild hosts."} +{"text": "The minimal dimension of critical isthmus regions may be less than 1 cm in more than 25% of circuits mapped.A 73-year-old man with history of dilated cardiomyopathy and left ventricular (LV) ejection fraction of 39%, complete heart block status post permanent pacemaker placement 15 years ago with upgrade to biventricular implantable cardioverter-defibrillator 2 years ago, presented with recurrent episodes of VT and appropriate implantable cardioverter-defibrillator therapies despite antiarrhythmic drug therapy with sotalol. Cardiac magnetic resonance imaging showed midmyocardial delayed enhancement with full-length midmyocardial scar from the basal anteroseptum to inferoseptum . He undeIn anticipation of mapping a septal VT, a linear multielectrode catheter was placed in the septal right ventricular outflow tract (RVOT) and an ablation catheter was positioned on the LV basal anterior septum via transseptal approach. A diagnostic 2F microcatheter was placed into the distal coronary sinus to record within the AIV and SPV . During d, proving critical circuitry confined within the interventricular septum , a balloon technique was not implemented. However, VT remained reinducible at a faster rate and therefore additional ablation were performed at 50 W from the LV and RV septum. VT has not recurred for 9 months at the time of this report.A second VT with left bundle branch block morphology with VLMNA and TTN, are associated with VT recurrence rates that are among the highest in structural heart disease.LMNA variants in particular have been shown to have high rates of arrhythmia recurrence, progression of cardiomyopathy to end-stage heart failure, and high mortality.Catheter ablation for drug-refractory VT in patients with dilated cardiomyopathies, particularly in those with genetic mutations such as ,,Lamin cardiomyopathy classically involves the septum and periaortic region and seems to be predominantly related to reentry in and around regions of scar. Periaortic VTs have been increasingly described with regard to reentrant mechanism and circuit characteristics.,Prior studies have not demonstrated localized reentry completely confined within the intramural septum, which is the novelty of this report. These descriptions reiterated the propensity of LMNA to predominantly involve the septum,Strategies such as substrate modification via transcoronary venous ethanol may warrant further consideration, particularly when a full-length septal scar is present on magnetic resonance imaging, which portends a poor prognosis.Owing to high rates of recurrent VT associated with lamin cardiomyopathies, early collaboration and consultation with a heart failure team is warranted to discuss advanced management options, given modest outcomes from ablation and high risk of mortality from progression of heart failure. This case provides further mechanistic insights into the nature of septal VTs in this challenging patient population that may be entirely missed by traditional endocardial and epicardial mapping techniques.In midmyocardial septal scar substrates, SPV recordings may provide critical intramural information to elucidate the spatial dimensions and location of circuit-challenging VTs. Localized reentry recorded from a single bipole pair can be confined completely within the septum, which cannot be fully characterized from either endocardial surface."} +{"text": "Grandparent-headed families in South Korea have been growing prominent in the country\u2019s cultural landscape. Approximately 153,000 Korean grandparent-headed households existed in 2015; this number is expected to double by 2035. This qualitative study explored Korean custodial grandparents\u2019 experiences of raising grandchildren and the cultural significance of multigenerational caregiving in Korea. Using a phenomenological approach, semistructured interviews with 22 custodial grandparents were conducted. Significant functions of patrilineality and stigma surrounding divorce for Korean grandparent-headed families were found. Considering the complicated cultural factors, social/family service programs must pay attention to the unique needs of grandparent-headed families and consider the circumstances related to grandparents\u2019 positions in the family . Korean government programs and policies could better help marginalized grandparent-headed families with an empowerment approach to help marginalized grandparent-headed families gain positive attitudes toward their caregiving situation."} +{"text": "Keratosis obturans is estimated to occur among 4 to 5 patients among 1000 new otological cases.A previously healthy 22 year-old Malay gentleman presented to our clinic with a two-month history of worsening left otalgia with bloody otorrhea. There was also left sided reduced hearing followed by asymmetry on the left side of face for the past 1 week. Patient claimed that there was no recent or any recurrent upper respiratory tract infection prior to this.Further history from patient revealed that he had similar complaints a year ago involving the right ear with no facial asymmetry. Patient was diagnosed with right aural polyp and polypectomy was done under local anaesthesia in another government hospital. However, patient defaulted his follow-up as the problem resolved completely.Upon examination, patient was comfortable, not septic looking and afebrile. Facial nerve examination revealed House\u2013Brackmann Grade III lower motor neuron palsy as there was loss of left nasolabial fold and drooping of left angle of lip. Otoscopic examination revealed a polypoidal mass occluding the entire left ear canal covered with bloody, foul smelling otorrhea . Right eA high-resolution computer tomography (HRCT) scan of temporal was obtained, which revealed non-enhancing soft-tissue mass occupying left external auditory canal, left Prussak's space and middle ear with erosion of left scutum. The left inner ear was intact with normal right ear structures. There was no evidence of facial canal dehiscence or erosion; however signs of inflammation over the tympanic segment of facial canal were noted .Figure 2Patient underwent microscope-guided examination under anaesthesia which revealed polypoidal mass occupying entire lateral third of ear canal with whitish keratin-like debris noted medial to the mass. Polypectomy and aural toileting was commenced. As tympanic membrane appeared bulging, myringotomy and grommet insertion was performed. Histopathologic examination revealed cyst wall covered with stratified squamous epithelium containing lamellated keratin flakes suggestive of keratosis obturans Post-opeKeratosis obturans can be of two types: Inflammatory type or silent type.Keratosis obturans usually affects younger age group, occurs bilaterally and manifests as severe otalgia, conductive hearing loss and widened ear canal.Computer tomography typically demonstrates soft tissue plug in bilateral external ear canal with evidence of ballooning of the osseous part. In our patient, his main complaint was severe otalgia and otorrhea which was followed by unilateral facial weakness and hearing loss. Although rare, few cases of keratosis obturans, presenting with facial weakness have been reported.Clinical differential diagnosis for mass in aural canal with facial nerve palsy includes external auditory canal cholesteatoma, neoplasms of external canal and malignant otitis externa. It is important to distinguish the diagnosis, as management of each of the differential diagnosis is notably different. Hence, thorough and detailed history, physical examination, radiological examination and most importantly histopathological examination is crucial prior to a diagnosis. Histopathological examination of the biopsied or excised mass is the main modality of diagnosis, more so when there is an atypical or rare presentation.As for management, keratosis obturans usually requires frequent aural toileting to remove the keratin plug and topical medication. This may be done under general anaesthesia especially among non-cooperative patients. Split skin graft and canalplasty method have also been reported for refractory keratosis obturans.Albeit commonly regarded benign, keratosis obturans may result in devastating complications including facial nerve palsy as in our patient. Hence, high clinical suspicion and prompt management among clinicians are of dire importance as absence of typical clinical features usually lands both the attending physician and patient in dilemma.The authors declare no conflicts of interest."} +{"text": "The COVID-19 pandemic caused severe disruptions in healthcare systems and societies and exacerbated existing inequalities for women and girls across every sphere. Our study explores health systems responses to gender equality goals during the COVID-19 pandemic and which role these goals play in pandemic recovery policies.We apply a qualitative comparative approach. Country case studies were collected in March/April 2022. The sample comprised Australia, Brazil, Germany, United Kingdom and USA, reflecting conditions of high to upper-middle income countries with established public health systems, democratic political institutions and gender equality policies. Selected topics: maternity care/reproductive services, violence against women, and gender equality/female leadership.All countries tried to keep essential maternity and reproductive services open, but strong limitations applied especially for prevention and counselling services; at the same time, digitalisation/telemedicine supported service expansion. Violence against women and children strongly increased during the pandemic. Routine services were partly kept open and new helplines occasionally established, but no action was taken to scale-up mental health support and respond to new demand. A push-back of gender equality was observed across countries in all areas of health and social care, often coupled with strong increase in intersecting social inequalities; participation of women in decision-making bodies was generally weak and not monitored.Across countries, gender equality policies cracked under the pressure of the COVID-19 pandemic; this is true for countries with male and female political leaders, and for different areas of SDG5 and health. There is an urgent need for more effective intersectional gender equality policies and improved participation of women in global health and in health system recovery plans.\u2022\u2002Health systems failed to take action to protect SDG5 goals; gender and intersecting inequalities strongly increased during the pandemic.\u2022\u2002Building back better after COVID-19 will only be possible with an intersectional gender equality programme and feminist policy approaches."} +{"text": "Observational studies suggest psychosocial factors such as social support and loneliness are associated with vulnerability for frailty in older adults, but less is known about the generalizability of these putative psychosocial mechanisms in underrepresented groups. Thus, we evaluated whether better telecommunication social support and lower levels of loneliness were associated with decreased frailty and increased functional ability using a unique longitudinal cohort of rural South African older adults. We conducted generalized estimating equation and robust regression analyses using cross-sectional data from 347 participants in the HAALSI Dementia Cohort. Social support via telecommunication and self-reported loneliness were measured using standard assessments and modeled as exposure variables. Outcomes were frailty (measured using Fried\u2019s frailty phenotype) and functional status . Lower level of telecommunication social support was associated with higher impairment in ability to perform IADLs. This association persisted after additional adjustments for depression and vascular risk factors . No associations were observed in relating telecommunication social support and loneliness with frailty. Among rural South African Black older adults, lower telecommunication-based social support was associated with greater risk of impairment in functional ability. Although further validation is required for possible reverse causality, our findings suggest that future intervention studies focused on promoting telecommunication-based social support to preserve independent functioning may be merited."} +{"text": "Poor physical function has been linked to greater depressive symptoms among older adults. On the other hand, older adults\u2019 perceptions of positive and negative age-related changes provide personal strength and vulnerability to stressful events, respectively. We therefore expected that positive self-perceptions of aging (SPA) would be associated with fewer depressive symptoms, while negative SPA would be related to greater depressive symptoms, beyond the effect of physical function. We further tested the hypotheses that positive SPA would buffer the association between physical function and greater depressive symptoms, whereas negative SPA would exacerbate this association. This study used data from 108 older adults (mean age = 81.09) in independent-living or retirement communities. Results from a linear regression revealed that more positive SPA and less negative SPA were associated with fewer depressive symptoms, even after controlling for physical function, both types of SPA, and other covariates. In contrast, physical function was no longer significantly associated with depressive symptoms , after controlling for both types of SPA. There were no significant moderating effects of positive and negative SPA. Findings suggest that how positively and negatively older adults perceive their own aging may be important for their mental health while experiencing less physical function in late life."} +{"text": "Most children with developmental disabilities (DD) live in resource-limited countries (LMIC) or high-income country medical deserts (HICMD). A social contract between healthcare providers and families advocates for accurate diagnoses and effective interventions to treat diseases and toxic stressors. This bio-social model emphasizes reproductive health of women with trimester-specific maternal and pediatric healthcare interactions. Lifelong neuronal connectivity is more likely established across 80% of brain circuitries during the first 1000 days. Maladaptive gene-environment (G x E) interactions begin before conception later presenting as maternal-placental-fetal (MPF) triad, neonatal, or childhood neurologic disorders. Synergy between obstetrical and pediatric healthcare providers can reduce neurologic morbidities. Partnerships between healthcare providers and families should begin during the first 1000 days to address diseases more effectively to moderate maternal and childhood adverse effects. This bio-social model lowers the incidence and lessens the severity of sequalae such as DD. Access to genetic-metabolomic, neurophysiologic and neuroimaging evaluations enhances clinical decision-making for more effective interventions before full expression of neurologic dysfunction. Diagnostic accuracy facilitates developmental interventions for effective preschool planning. A description of a mother-child pair in a HIC emphasizes the time-sensitive importance for early interventions that influenced brain health throughout childhood. Partnership by her parents with healthcare providers and educators provided effective healthcare and lessened adverse effects. Effective educational interventions were later offered through her high school graduation. Healthcare disparities in LMIC and HICMD require that this bio-social model of care begin before the first 1000 days to effectively treat the most vulnerable women and children. Prioritizing family planning followed by prenatal, neonatal and child healthcare improves wellness and brain health. Familiarity with educational neuroscience for teachers applies neurologic diagnoses for effective individual educational plans. Integrating diversity and inclusion into medical and educational services cross socioeconomic, ethnic, racial, and cultural barriers with life-course benefits. Families require knowledge to recognize risks for their children and motivation to sustain relationships with providers and educators for optimal outcomes. The WHO sustainable development goals promote brain health before conception through the first 1000 days. Improved education, employment, and social engagement for all persons will have intergenerational and transgenerational benefits for communities and nations. Accurate clinical decisions require serial assessments across developmental time beginning before conception . A dual Accurate clinical decision-making is particularly crucial for children who have increased risks for neurologic sequelae such as those with developmental disabilities (DD). DD consist of a constellation of functional deficits that are expressed beginning early in life, adversely affecting a child\u2019s physical, learning, or behavioral performance . ChildreA maternal-child pair medical case history is discussed to highlight the importance of time-sensitive diagnostic assessments from pre-conception through adolescence for successful interventions. Maternal and childhood adverse effects were addressed. Revised educational plans through her school years integrated maternal-pediatric healthcare histories into successful educational experiences. A dual diagnostic approach is discussed that teaches recognition of the maturational potential of any child according to principles of developmental neuroplasticity applied to clinical decision-making and therapeutic interventions. All healthcare providers and educators require knowledge and skills to implement the same diagnostic and educational approaches for the most vulnerable children in LMIC and HICMD.This child was previously included in a discussion of a diverse group of children who were diagnosed with genetic disorders . NeuroloThis maternal-child pair presented to healthcare providers and educators in a HIC. A serial diagnostic approach considered recognition of clinical phenotypes expressed by this woman, MPF triad, neonate, and child. Systems science application applied an understanding of etiopathogenesis pathways to the child\u2019s neurologic sequelae. Time-dependent medical and scholastic resources were offered to preserve health while she completed high school education. Joint attention by her mother and healthcare providers addressed adverse childhood effects that potentially could reduce long-term benefits from interventions in response to early life expression of DD.Mother was a 28-year-old gravida 2 para 1\u20132 woman with asymptomatic Sjogren\u2019s Disease and class 3 obesity prior to conception. She followed a weight reduction plan which included bariatric surgery before pregnancy and achieved a lower body mass index. Her healthcare providers noted the inherited risks for this pregnancy consisting of an older child with autism spectrum disorder and parental anxiety disorders. Mother received behavioral interventions to manage her anxiety both before and during her pregnancy. A high-risk maternal fetal medicine service managed her autoimmune disease. No immunosuppressive medications were recommended given she remained asymptomatic for Sjogren\u2019s disease after conception.An AV block on a fetal EKG was later documented during third trimester abdominal sonography at 28 weeks GA. Despite maternal treatment with digitalis, this dysrhythmia progressed to nonimmune hydrops fetalis at 32 weeks\u2019 gestation secondary to cardiac failure. Labor induction and delivery was electively performed without complications after antenatal dexamethasone administration. No fetal distress occurred during delivery with a clinically stable female preterm newborn. She received 1- and 5-min Apgar scores of 6 and 7 without the need for advanced resuscitative interventions. Her anthropometric measurements were within appropriate gestational age ranges.The child subsequently required neonatal intensive care for multiple system-specific complications. Multiple cardioversions for cardiopulmonary arrest and severe hypotension/bradycardia were required to treat repetitive sudden heart block during her first week of life until effective digitalis dosing was established. Pulmonary disease, anemia and nutritional supplementation required medical interventions during the neonatal time. Neonatal cranial sonography did not document intraventricular hemorrhage or periventricular leukomalacia.Histological examination of the placenta at 10 days of life documented chronic villitis and maternal malperfusion lesions consisting of underdevelopment of the placental vasculature including decidual necrosis. These microscopic findings were supplemented by gross descriptions of a hyper coiled umbilical cord (2/cm) with a 1 cm marginal insertion.The child initially expressed hypotonia which later resolved with expression of age-specific developmental reflexes. Bulbar dysfunction initially required gavage feedings because of poor oropharyngeal function. Gradual transition to oral feeding was achieved during her early months of infancy.She required a permanent cardiac pacemaker at 11 months for persistent heart block for continued episodes of hypotension that remained unresponsive to medication adjustments. Cardiogenetic testing confirmed a long QT syndrome type II (G604S-KCNH-2), which was also confirmed for one parent.Developmental delay with borderline microcephaly (5%) was documented on serial assessments during her first 2 years of life. Vision and hearing evaluations were normal. No seizures occurred. Early intervention therapies were provided to supplement and support parental care. Primary care included social work support to address adverse childhood effects. Developmental testing documented cognitive, motor, social and language deficits. Sufficient skill acquisition was achieved during her preschool yea to matriculate into mainstream classes. She advanced through primary and middle school grades assisted by individual educational planning.She presented with status epilepticus associated with an acute hypertensive event at age 10 years. Brain lesions consistent with posterior reversible encephalopathy syndrome were noted on neuroimaging. Her pediatric intensive care successfully controlled seizures after stabilization of severe hypertension. With resolution of her encephalopathic state and renal dysfunction, she was discharged to home on antiepileptic medication. No neurologic regression occurred without further seizures. Antiepileptic medication was discontinued after a three-year interval.She experienced cognitive and behavioral challenges into adolescence. Cooperation between family and the school\u2019s multidisciplinary team of teachers and therapists offered revised interventions at school and home to address all medical challenges based on information provided to healthcare providers. Mental health care addressed her generalized anxiety and socialization challenges with educational accommodations and counselling. Functional neurological disorders included psychogenic seizures during adolescence were addressed with resolution. Dysautonomic symptoms of postural orthostatic tachycardia syndrome were recognized and managed with preventive interventions.Individualized educational plans (IEP) accommodated this child\u2019s expressive language delay, reading disability, hyperkinesis with short attention and lower limb spasticity, beginning during her preschool and primary school grades. Ambulation without ankle supports was achieved before her middle school years. She received psychotropic medications to manage anxiety without the use of stimulant medications. Serial neuropsychometric testing after age five years documented cognitive abilities within the normal range with subtest deficiencies in attention, reading and executive planning. She received educational accommodations through high school graduation. Behavioral interventions addressed her anxiety and socialization challenges which challenged her into adolescence. She successfully graduated high school with plans to pursue a nursing career.This next section reviews the systems science associated with the prenatal expression of diseases affecting this maternal-child pair. Applicability for effective horizontal and vertical approaches to diagnosis and treatment for a comparable woman in a LMIC and HICMD will be compared with the healthcare delivery received by this mother-child pair. Advocacy by healthcare providers regarding healthcare resources must consider diversity and inclusion to achieve optimal outcomes for healthcare and school readiness.Any child with a genetic disorder exemplifies G x E interactions that can begin before conception with time-dependent expression that are influenced by adverse maternal and childhood acquired conditions. Phenotypic presentations may first appear during pregnancy or after birth . For thiInteractions between familial genetic risks and acquired conditions affected this maternal-placental fetal (MPF) triad and neonate with adverse consequences into early childhood. Etiopathogenetic pathways across developmental ages during her first 1000 days altered phenotypic expressions of her brain disorders. Global developmental delay with borderline microcephaly were early phenotypes. A hypertensive disorder was a later childhood expression of this genetic disorder. Cognitive/behavioral and mental health disorders became more dominant phenotypes during her adolescent development.This child\u2019s fetal presentation at 28 weeks GA with heart block occurred after activation of an inherited channelopathy by maternal autoantibodies despite mother\u2019s asymptomatic Sjogren\u2019s disease . AutoantWithout clinical symptoms and the risk for adverse effects of corticosteroid use, mother received no treatment after conception. She alternatively was followed by a high-risk obstetrical service that monitored her based on maternal levels of care relevant to the this HIC health system.Pregnancy management for a woman in a LMIC or HICMD with asymptomatic Sjogren\u2019s disease might advocate for more proactive medical interventions to maximize chances for favorable outcomes despite less available prenatal and neonatal services. Earlier steroid treatment despite no maternal clinical signs may be the more practical therapeutic option. Treatment prior to conception or early first trimester for any woman identified with autoimmune disease might avoid or lessen the severity of fetal cardiac disease, hydrops fetalis and prematurity. Long QT syndrome may still present at older postnatal ages. However, with greater brain maturity, less severe neurologic sequalae may result because of increased resilience to brain injury. Benefit from immunomodulators other than steroids in the fPreventive healthcare training for maternal care by physicians, nurse practitioners and midwives in a LMIC and HICMD must prioritize preventive care to offset less access to expensive high-risk maternal fetal medicine and neonatal intensive care services. WHO guidelines for maternal and neonatal levels of care , have emOther non-infectious inflammatory conditions accompanied this mother\u2019s Sjogren\u2019s disease. Her obesity and anxiety worsened similar inflammatory disease pathways subserved by this autoimmune disorder. Suboptimal placental implantation and development began 2\u20138 days after conception given this exaggerated pro-inflammatory state. The placenta\u2019s shared genetic endowment between parents and fetus more likUse of corticosteroids, weight reduction and treatment for anxiety before conception in LMIC and HICMD could help delay or avoid trimester-specific placental diseases for a percentage of MPF triad This preventive approach could avoid fetal cardiac failure, hydrops fetalis and prematurity.Prematurity is a complex adverse outcome. Trimester-specific G x E interactions to the MPF triad involve placental dysfunction resulting in prematurity . SuboptiCurrent fetal surveillance tests cannot fully document placental disease pathways affecting many MPF triads. Training of healthcare providers particularly in LMIC and HICMD must anticipate these adverse effects of placental-cord pathology without the availability of fetal surveillance testing to document abnormalities. Chronic or acute diseases are often undetectable using fetal sonographic assessments of fetal heart patterns, Doppler flow indices and biophysical scores to assess fetal well-being. Appropriate measures of fetal growth and function does not exclude risks from placental disease with adverse outcomes to the fetal nervous system.Training of placental-cord development and pathogenesis enhances the provider\u2019s understanding of time-dependent etiopathogenesis that contributes to sequelae such as DD. Placental-cord disease pathways are associated with diseases expressed by the woman, MPF triad and neonate. This perspective improves clinical decision-making, effective interventions, and prognosis. Despite normal fetal surveillance testing, postnatal pathological examinations may document trimester-specific disease pathways. Future prenatal structural and functional placental imaging studies will offer more effective diagnosis and interventions to improve outcomes for affected MPF triads before fThree placental disease mechanisms cumulatively contribute to an understanding of adverse effects to the fetal brain. Knowledge of these disease entities are essential for maternal-pediatric healthcare providers to advocate for improved medical delivery particularly in LMIC and HICMD.Maternal immune activation (MIA) was the initial pathologic process that presented shortly after conception for this MPF triad. MIA represents immune intolerance between the embryo and the mother . SuboptiMIA is associated with reduced energy substrate delivery, waste removal, and deprivation of essential growth factors as embryonic-fetal maturation advances into second and third trimesters . MIA conIschemic placental syndrome (IPS) was the second placental disease that developed later during this pregnancy given postnatal gross and histological placental-cord findings. Prenatal sonographic measurements described preserved fetal growth for this child without fetal growth restriction. However, abnormal placental angiogenesis from IPS can still reduce placental blood flow to the fetus without current fetal surveillance detection. Defective spiral artery remodeling after 12 weeks GA results from abnormal precursor trophoblastic cellular development that begins during early first trimester ,21 with Marginal cord insertion with hypFetal inflammatory response (FIR) is a third pathologic mechanism that potentially affected placental structure and function in addition to MIA and IPS . Often uMaternal autoantibodies , the metabolic syndrome and elevated endogenous steroid and norepinephrine production cumulatively contributed to this mother\u2019s non-infectious pro-inflammatory state into the third trimester.FIR type I is the more predominant etiopathogenetic mechanism closer to delivery. Two disease pathways have been identified with FIR Type I, contributing to fetal brain injuries. Asphyxia occurs from inflammatory mediator-induced vasoconstriction within the placenta/cord and fetal brain blood\u2013brain barrier vasculature resulting from direct effects by pathogens and abnormal cytokines on blood vessel caliber size and contractile responsivity. A second cytokine-associated mechanism with FIR Type I contributes to this asphyxial neuronal damage. Mitochondrial dysfunction within the cytosol and altered genetic expression within nuclei result in injury from cytokines with cell death or dysfunction in surviving neurons .Fetal brain maldevelopment and/or injury therefore potentially result from the cumulative effects of MIA, IPS and FIR to a vulnerable MPF triad across three trimesters. Altered embryonic-fetal brain structures during the first trimester impair multiple neuronal cell precursors within transient region with abnormal proliferation, differentiation, and migration. Abnormal neuronal connectivities later alter the cortical mantle during the second and third trimesters with abnBalanced development of excitatory and inhibitory neuronal precursor activities is required for normal fetal brain maturation and function. An altered excitatory/inhibitory ratio resulting from these placenta-cord diseases contribute to altered brain circuitries expressed as DD, mental health disorders and epilepsy .Present standards of maternal levels of care for thisFour \u201cgreat neonatal neurological syndromes\u201d comprise most children who require neonatal neurocritical care . NeonataG x E vulnerabilities of this maternal-child pair exemplified how prenatal and postnatal diseases contributed to EP and later DD.Developmental and destructive brain processes define EP with trimester-specific disease pathways that later influenced postnatal disease factors . Risks fOver 80% of nearly 15 million preterm children are born in LMIC . IncreasThese efforts will lower the prevalence and severity of EP for vulnerable MPF triads such as those exposed to healthcare disparities in LMIC and HICMD.Postnatal complications of prematurity further increased risks for EP following fetal cardiac failure with hydrops fetalis. An elective premature delivery with later postnatal medical complications occurred. Multiple pointes de torsade required emergent cardioversions during her first week of life to treat her cardiac decompensation. These events represented cumulative postnatal risks for injury from cerebral hypoperfusion. Additional adverse conditions of prematurity included pulmonary disease, anemia and gastrointestinal immaturity which contributed to reduced oxygen and nutrient delivery.Current conventional postnatal cranial sonography and conventional brain MRI studies documentSuch diagnostic and therapeutic advances will be first available to MPF triads and neonates in HIC where there is greater access to research protocols. Research protocols in LMIC and HICMD require strategies for best practices to deliver technologies to those who are most vulnerable with healthcare disparities. Maternal-pediatric hospitals in these countries and regions require research efforts that compare different preventive, clinical and wellness study protocols to best deliver healthcare to women and children to reducDevelopmental delay during this child\u2019s first 1000 days represented postnatal clinical expression of previously acquired fetal and neonatal brain disorders. Early interventions supported by parental commitment offered greater healthcare and educational opportunities. Preschool expression of DD was replaced during school years with neurocognitive and mental health challenges as she matured into adolescence.Primary pediatric care partnering with early intervention programs need to offer all children opportunities to address medical and developmental needs. Support for early diagnosis and rehabilitative interventions must begin during the first 1000 days. Challenges are greater with more limited access to preventive, clinical and wellness resources in LMIC and HICMD. Community-based primary care with the ability to provide early intervention programs must be accompanied by wellness programs to minimize adverse childhood effects.Communicable and non-communicable diseases during childhood further complicate healthcare with adverse effects educational achievement. An acute hypertensive crisis with a cerebrovascular complication for this child at 10 years of age presented a new medical challenge. Her neurologic presentation of posterior reversible encephalopathy syndrome was assoSudden systemic hypertension potentially alters cerebral blood flow preferentially to posterior brain regions where cerebral vasculature is highly susceptible to the adverse effects of increased systemic blood pressure. Persons with hypertensive disorders throughout their lifespan can experience brain injuries from this disease. The etiopathogenesis responsible for the clinical presentation of encephalopathy and seizures impairs function within the neurovascular unit . Risks for stroke and/or hemorrhage are known complications. A percentage of affected persons, however, exhibit transient or reversible neuroimaging findings as the acute clinical symptoms resolve. This child fortunately did not experience permanent injuries expressed by more severe sequelae.Intensive care management for this child included emergent treatment for status epilepticus and acute hypertensive crisis. Seizures were successfully controlled with resolution of neuroimaging findings on follow-up brain MRI images. Medication discontinuation without seizure reoccurrence after a three-year course of antiepileptic drug treatment was achieved. No apparent regression of her neurologic abilities resulted from these medical events.Healthcare systems in LMIC and HICMD need to prioritize continuity of medical delivery when childhood diseases present that require hospitalizations. Management of childhood medical complications present greater challenges when there is less access to advanced hospital-based medical care. WHO guidelines offer suggestions for improved hospital services for children confronted with acute illnesses in LMIC and HICMD . HealthcBrain maturation during adolescence involves accelerated synaptogenesis that reflects adaptative or maladaptive neuroplasticity. More complex brain connectivities are needed for optimal adult neurologic function. Increased neural network complexity is required to achieve sophisticated cognitive reasoning and social intelligence requiredMental health challenges accompany DD which may intensify during adolescence. This child\u2019s anxiety, mood instability, and problems with social interactions were adolescent expressions of abnormally increased synaptogenesis which potentially could further limit her adult performance. She experienced functional neurologic disorders and mental health challenges at home and in school despite lessening of earlier life DD. Continuity of psychiatric interventions and social supports by her family helped her through graduation. Continued mental health care by family and healthcare providers will be needed as she prepares for a career, establishes social relationships, and confronts life challenges .Mental illness expressed during childhood more likely is associated with brain disorders during the first 1000 days. Children in a LMIC or HICMD may not experience the same degree of recovery as the child presented for this discussion. Neuron-specific cell processes may result in atypical brain development starting during fetal life with more severe expressions of childhood neurocognitive/behavioral disorders including mental health disorders into adulthood. Public health resources must recognize the importance of mental health care and social problems to address childhood adverse effects. These risks are greatest for those with DD who experience healthcare disparities .Two longitudinal/cross-sectional cohorts present results applicable to the importance of preclinical diagnosis of mental health disorders. Comparisons of neuroimaging and genetic data sets suggested more accurate prediction of mental health disorders prior to clinical expression. Region-specific growth of the cerebral cortex was documented using detailed neuroimaging protocols based on large pediatric cohorts. These studies preceded mental illness and general psychopathology as expressed throughout childhood . These MThese neurodiagnostic advances will benefit children with DD who may also present with mental disorders. Availability for such diagnostic testing is needed in LMIC or HICMD for children at highest risk for mental health disorders accompanying DD.Healthcare policy therefore must advocate for mental healthcare in these vulnerable populations. Unfortunately, cultural misperceptions of DD and mental illness impede these efforts. Criminalization and religious demonization of people with these disorders result in exclusion of children with DD from receiving adequate healthcare and education. Support for families must respect religious, ethnic, and racial perspectives to properly direct interventions. Appropriate services need to be prioritized by community-religious leaders, policy makers, healthcare providers, and educators.The maternal-child pair used for this discussion stresses the continuum of prenatal and postnatal risks that began with maternal autoimmune disease, obesity, and anxiety. Fetal cardiac disease and complications of prematurity were adverse outcomes associated with these conditions. MPF triad phenotypes more broadly reflect multiple maternal diseases pandemic . SeventeLawmakers and health policy leaders in both HIC and LMIC must adopt bio-social models of care that advocate for optimal care for all persons across the lifespan. This social contract by healthcare providers ,85 benefThe mother-child pair chosen for this review represented a family living in a comparatively resource-rich community. Her parents\u2019 access to the internet and community services provided information and guidance to receive maternal and pediatric healthcare, minimize adverse childhood effects and plan educational interventions as their daughter\u2019s medical and school challenges were identified. Teachers and therapists effectively applied knowledge of educational neuroscience applicable to her specific scholastic needs. Healthcare and educational services remained available for this family throughout high school.Healthcare strategies must address cultural, financial, and political barriers to care beginninPrinciples of ontogenetic adaptation help explain long term effects of positive and negative neuroplasticity . Time-deWith advances in medical care into adulthood, longer life expectancy for older survivors with DD requires a greater priority for inclusion regarding optimal educational attainment during childhood to achieve better employment and societal interactions as adults . There iAs estimates for life expectancy increase for people with DD, acute and convalescent medical services and quality home care delivery must be anticipated to assist aging families and their proxies. Adults with moderate intellectual disability and cerebral palsy may potentially live into their fifties, assuming stable health without accidents or chronic illnesses. Milder clinical expressions of disability now experience similar life expectancy estimates as healthy populations without DD ,92,93.Communicable and noncommunicable diseases disproportionately affect more women and children in LMIC and HICMD. Maternal health consequences after genitourinary infections, hypertensive disorders, and diabetes mellitus are examples of prevalent maternal conditions that adversely affect fetal brain health presenting as diseases of the MPF triad and neonate. The great neonatal neurologic syndromes of encephalopathy, seizures, stroke, and EP are postnatal expressions of trimester-specific diseases after birth. Childhood neurologic disorders such as DD are further influenced by ongoing diseases or adverse conditions.Diversity and inclusion for healthcare and education delivery are essential for optimal outcomes. Integrating developmental origins and life course theories into clinical and public health practices will serThe WHO sustainable development goals advocate for all women and children. Transactional models to achieve these goals require healthcare policies that integrate the continuity of maternal and pediatric healthcare beginning before conception when first addressing a girl\u2019s reproductive health. These goals are later integrated with advocacy for pregnancy planning and optimal maternal preventive care during and between pregnancies. Communities require resources provided by public health programs for effective nutrition, health care, housing, and sanitation to maximize life-course health during and between each pregnancy.Preventive healthcare education and resources require support by a nation\u2019s public health infrastructure that can effectively provide medical and educational services to children and families that recognize and overcome geographic-cultural barriers. With public health efforts, effective educational plans can be initiated at the earliest ages to optimize the school performance of a child with DD, applying educational neuroscience by teachers recognizing ethnic, racial, and cultural context. These actions will benefit the most vulnerable with healthcare disparities in LMIC and HICMD.While these efforts potentially have significant global impact, wide gaps remain between preclinical diagnosis of DD and implementation of interventions for women of reproductive age between and during their pregnancies. The WHO sustainable development goals recently highlighted brain health across the lifespan to promote adaptive neuroplasticity starting during critical-sensitive periods. This emphasis on brain health must advocate for women, children, and adolescent health, with interventions that begin during the first 1000 days and continue into adulthood .Every Newborn Action Plan presented by the WHO further emphasizes strategies to reduce neonatal morbidity and mortality. Success of this plan also advocates for prenatal health of women and MPF triads to maximize the benefits for neonates who require resuscitation, transport, and neonatal intensive care .International cooperation among government and nongovernmental organizations must advocate for a woman\u2019s right for optimal health care and educational services for her children within their community. Such advocacy must be maintained from childhood through adulthood for healthy children and those with DD. Future research protocols need to address maternal and pediatric health disparities by applying public health initiatives that educate women and families to advocate for resources to sustain health into adulthood. Effective partnerships will improve the woman\u2019s health and quality of life throughout life beyond her reproductive years as well as for her children and successive generations.Future biomarkers can potentially apply genetic-metabolomic, neurophysiologic and neuroimaging technologies for pre-"} +{"text": "Peer support complements traditional models of chronic kidney disease (CKD) care through sharing of peer experiences, pragmatic advice, and resources to enhance chronic kidney disease self-management and decision-making. As peer support is variably offered and integrated into multi-disciplinary CKD care, we aimed to characterize healthcare providers\u2019 experiences and views on peer support provision for people with non-dialysis-dependent CKD within Canada.In this concurrent mixed methods study, we used a self-administered online survey to collect information from multi-disciplinary CKD clinic providers on peer support awareness, program characteristics and processes, perceived value, and barriers and facilitators to offering peer support in CKD clinics. Results were analyzed descriptively. We undertook semi-structured interviews with a sample of survey respondents to elaborate on perspectives about peer support in CKD care, which we analyzed using inductive, content analysis.We surveyed 113 providers from 49 clinics. Two thirds (66%) were aware of formal peer support programs, of whom 19% offered in-house peer support through their clinic. Peer support awareness differed by role and region, and most referrals were made by social workers. Likert scale responses suggested a high perceived need of peer support for people with CKD. Top cited barriers to offering peer support included lack of peer support access and workload demands, while facilitators included systematic clinic processes for peer support integration and alignment with external programs. Across 18 interviews, we identified themes related to peer support awareness, logistics, and accessibility and highlighted a need for integrated support pathways.Our findings suggest variability in awareness and availability of peer support among Canadian multi-disciplinary CKD clinics. An understanding of the factors influencing peer support delivery will inform strategies to optimize its uptake for people with advanced CKD.The online version contains supplementary material available at 10.1186/s12882-022-02776-w. Chronic kidney disease (CKD) is a complex condition that affects 13% of the population globally and, in its most advanced stage, can result in kidney failure requiring dialysis or transplantation as life-sustaining therapy , 3. PeerPeer support may augment traditional models of multi-disciplinary CKD care by enabling peer validation of patients\u2019 experiences and exchange of pragmatic resources for living well with their disease \u20138. Peer Limited research on peer support for people with kidney disease suggests that variability in awareness and promotion within kidney care programs poses a barrier to peer support uptake . While aWe used a concurrent mixed methods approach to understand how peer support is perceived and delivered in multi-disciplinary CKD clinics across Canada . This inEligible participants included healthcare providers from multi-disciplinary CKD clinics across Canada. We purposively sampled eligible providers through the CKD Clinic Network, a pan-Canadian organization of providers and managers from multi-disciplinary CKD clinics who care for persons with advanced, non-dialysis-dependent CKD , 26. A nA self-administered online survey was developed by the investigators based on findings from previous work and related peer support and self-management literature experienced in qualitative research and with no prior relationships with participants completed all interviews, which were audio-recorded and lasted approximately 30-40\u2009min. A question guide was used to prompt discussion about the promotion and integration of peer support programs in CKD clinic care and their perceived need to address identified care gaps groups are in silos\u201d limited their availability to a broader range of people with CKD. Despite the potential value of integrating peer support within CKD clinics as an \u201cadjunct\u201d to existing support services, providers considered it critical to clarify the scope of services through clear boundaries and expectations.Ranked barriers and facilitators from survey responses and those reported in interviews with supporting quotes are compared in Table\u00a0Survey respondents emphasized inconsistent awareness of peer support among clinic providers as a main barrier to integrating peer support. Interviews identified additional challenges posed by recent increases in virtual technology use. The latter issue made it difficult to identify patients who might benefit from peer support during clinic encounters and to offer peer support virtually to patients with limited access to technology. Interview and survey participants also identified barriers of workload demands, competing priorities, and lack of adequate time and resources to discuss or offer peer support.Across surveys and interviews, participants underscored having systematic approaches to offering peer support in clinics as a facilitator. This included processes for routine staff education about available programs and clear role definitions among team members as to who discusses peer support with patients. The importance of close relationships with external organizations to foster collaboration in peer support delivery was highlighted more frequently in interviews than surveys. Although leadership and management support were ranked highly as facilitators in the survey, participants did not emphasize this during interviews.Integrated findings across quantitative and qualitative phases suggest that despite variable awareness of peer support availability, participants appreciated the value of peer support for people with CKD. A lack of systematic processes for introducing peer support within and across CKD clinics meant that many providers were unable to consistently offer it to their patients. Participants expected that attempts at integrating peer support within CKD clinics would be met with challenges, including high workload demands and competing priorities for CKD clinic staff. The importance of addressing accessibility challenges through tailored peer support options was also emphasized across participants. Despite anticipated difficulties, providers offered suggestions for integrating peer support into CKD clinic care with appropriate organizational supports and collaboration.Participants across roles recognized that provider awareness of peer support was necessary to effectively promote programs to their patients. However, awareness was lower than anticipated and varied by role and region, which may point to variability in how CKD clinics operate and in peer support availability across the country. Although our results differ from other studies reporting higher awareness of peer support among staff in kidney care programs, poor knowledge of peer support practicalities has been identified as a major barrier to uptake of peer support programs among people with varying stages of kidney disease , 14, 33.In our study, peer support referral and embeddedness with other clinic support offerings were inconsistent given both limited resources and lack of formalized practices. Participants also described a lack of role clarity related to offering and/or integrating peer support within their clinics. Whereas nephrologists and nurses commonly assumed that social workers were the most appropriate team member to discuss peer support, social workers indicated it should be a shared responsibility. In contrast, respondents from other studies suggested peer support referral fit within the nursing scope of practice , 33. TakParticipants emphasized the importance of tailoring peer support delivery to their local context as a way of addressing lower receptivity and access to peer support among CKD patients, yet faced challenges in doing so in the clinic setting. As Canadian CKD clinics operate under regional health authorities and comprise different models of care and resources , 27, 35,Wood et al. recently reported on experiences related to the adoption of a national peer support program for patients across various kidney disease contexts, including dialysis, in the United Kingdom (UK) . In thisFindings from our study offer practical considerations for the provision of peer support as part of routine CKD care. CKD clinics may provide an optimal setting for offering or embedding peer support due to their provision of longitudinal care using a multi-disciplinary, team-based approach \u201322. Our Our study was strengthened by its inclusion of healthcare providers and CKD clinics from across Canada and exploration of complementary aspects of an important care issue for patients with CKD . HoweverIn this study we noted variability in how healthcare providers from CKD clinics across Canada promoted and offered peer support opportunities to patients and their caregivers. Our findings suggest that factors such as streamlined referral processes, collaboration between programs, and program adaptation to fit local contexts could encourage peer support awareness and uptake. A clearer picture of how peer support is currently offered to patients with non-dialysis-dependent CKD and providers\u2019 needs related to peer support delivery can inform strategies to optimize its integration into CKD care. Future work to establish and evaluate systematic approaches to peer support in comprehensive CKD care are needed.Additional file 1. Consolidated Criteria for Reporting Qualitative Research (COREQ): completed checklist reporting on qualitative results according to recommended guidelines.Additional file 2. Peer support in CKD survey: questions included in the online survey.Additional file 3. Interview guide: questions used in the semi-structured interviews with a subset of healthcare providers.Additional file 4. Characteristics of in-house peer support: description of integrated peer support programs from respondents indicating peer support delivery within their clinic.Additional file 5. Characteristics of peer support processes: description of clinic processes from respondents indicating peer support awareness.Additional file 6. Likert scale responses: responses to Likert scale questions about perceived need, interest, and impact of peer support."} +{"text": "Halophyte [Cynodon plectostachus (K. Schum.) Pilg.] and non-halophyte grasses (Lolium perenne L. and Panicum maximum Jacq.) clustered along increasing soil salinity. Halophytic grasses [Panicum antidotale Retz. and Dicanthum annulatum (Forssk.) Stapf] congregated with Medicago sativa L., a non-halophytic legume along a gradient of increasing photosynthesis. Halophytic grasses had strong yield-salinity correlations. Medicago sativa L. and Leptochloa fusca L. Kunth were ubiquitous in their forage biomass production along a continuum of medium to high salinity. Forage crude protein was strongly correlated with increasing salinity in halophytic grasses and non-halophytic legumes. Halophytes were identified with mechanisms to neutralize the soil sodium accumulation and forage productivity along an increasing salinity. Overall, halophytes-non-halophytes, grass-forbs, annual-perennials, and plant-bacteria-fungi synergies were identified which can potentially form cropping systems that can ameliorate saline soils and sustain forage productivity in salt-affected arid regions.Soil salinity limits crop productivity in arid regions and it can be alleviated by crop synergies. A multivariate analysis of published data ( Forage crops and rangeland species have immense potential to rehabilitate and improve the natural ecosystem services besides providing forage supply to livestock and wildlife. They maintain soil health by regulating environments against the effect of climate change and pollution. In arid regions, these benefits from vegetation have been jeopardized by adverse environmental conditions, particularly endemically marginal precipitation . Traditi\u20131 and sodium accumulation greater than 15% ions which replace potassium (K+) ions in plant biochemical functions how consistent are mechanisms of tolerance to salinity among forage species in different habitats, (ii) do species converge in their salinity tolerance mechanisms, (iii) what are the possible synergies among species in their adaptation to saline soils, and (iv) how can mechanisms of species tolerance and synergies be used to design forage cropping systems adapted to saline soils. Hence this article reviews and reanalyzes published data to determine crop yield loss to soil salinity, species mechanisms of salinity tolerance and ecosystem services, and their potential synergies which can be used to design forage cropping systems for sustainable and resilient agroecosystems.\u20131). Subsequently, crop species were categorized according to their ecosystem services reported in saline soils in arid and semi-arid habitats across continents. These involved studies spanning 1\u20135 years conducted in field conditions, each with a non-saline soil control besides an increasing magnitude of treatment to strongly saline soils. The criteria of + ion accumulation in crop biomass and their role in reducing soil salinity (bioremediation). Lastly, supporting services were crop microbe interactions that support nutrient cycling in forage cropping systems. The identified synergies were used as indicators to illustrate the model cropping systems that can alleviate soil salinity and enhance forage crop productivity and nutritive value.This article provides a synthesis of correlations between salinity tolerance mechanisms and ecosystem services of forage crops. The first stage was to determine forage crop yield losses to soil salinity and discuss its tolerance. Thereafter, attempts were made to determine if forage crop species converge in their mechanisms of salinity tolerance and what this implies to forage productivity. In this regard, tolerance was considered the ability to maintain photosynthesis and dry matter yields with increasing salinity up to 200 mM NaCl concentrations in the propagation medium . Salinite (saturated paste extract), and crop duration and cited authors. Additional variables including accumulated soil organic carbon, forage dry biomass, forage crude protein, soil EC change, and Na+ ion uptake. Data were subjected to the multivariate analysis procedure to determine correlations between variables and accordingly relationships among forage crop species. In doing so, the FactoMiner package was deployed to conduct principal component analysis (PCA) which also involved standardizing data according to the deviation of individual variates from the sample mean divided by sample standard deviation Thwaites and Panicum antidotales Retz. have been reported to retain similar shoot moisture with increasing salinity levels from 0 to 140 mM NaCl (+ ions in the media around roots (Imperata cylindrica (L.) P. Beauv., Eragrotis amabilis (L.) Wight and Arn., Cynodon dactylon (L.) Pers., and Digitaria ciliaris (Retz.) Koeler Thwaites grown in saline environments up to 140 mM NaCl Kunth which enhanced photosynthesis up to 400 mM NaCl (+ and Cl\u2013 ions as well as their role in generating reactive oxygen species. This is exemplified in enhanced exudation of Na+ and Cl\u2013 ions by Sporobolus spicatus (Vahl) Kunth at 400 mM NaCl Koeler , Festuca mM NaCl , and Agr mM NaCl . Under itabolism . Potassitabolism . Potassiectively . In thise shoots . In the mM NaCl . In addi mM NaCl . Maintai mM NaCl . Species mM NaCl . Festuca mM NaCl , which d2 and O2 . These mCynodon plectostachyus (K. Schum.) Pilg.), a halophytic grass, clustered together with non-halophytes including perennial ryegrass (Lolium perenne L.) and guinea grass (Panicum maximum Jacq.) and less proximately with Setaria sphacelata (Schum.) Stapf and Hubb. and Pennisetum hybridus, all of which had close associations with increasing soil salinity. Alfalfa which is a non-halophyte clustered with halophytes namely marvel grass (Dicanthum annulatum (Forssk.) Stapf) and blue panicum grass along increasing photosynthesis. Saltgrass (Sporobolus spicatus (Vahl) Kunth) which is a halophyte, stood alone with strong and near equitable contribution to increasing relative yield, photosynthesis and salinity. Saltgrass is reported to restrict the Na+ uptake with increasing soil salinity and secrete excess salts at night (Lotus corniculatus L.), a non-halophytic legume, congregated with halophytic grasses including intermediate wheatgrass , and blue panicum grass associated with reducing salinity, photosynthesis, and relative yield. Intermediate wheatgrass has C3 photosynthetic machinery and wheat (Triticum aestivum L.) which are considered marginal halophytes. These annual grain crops are commonly diversified with annual legumes in time or space. Nevertheless, their proximal grouping with birdsfoot trefoil suggests a potential coexistence, for instance, in living mulch or in prolonged rotations. Living mulch refers to maintaining a perennial legume crop in an annual cropping system. Oat (Avena sativa L.), a halophytic annual grain, and Pennisetum purpureum Schumach., a non-halophytic grass, had near neutral contribution to salinity, photosynthesis, and relative yields hence potential candidates for long perennial annual rotations. Overall, the results of PC indicate a convergence of halophytes and non-halophytes in their physiology and yield response to salinity. This suggests possibilities for synchrony of diverse species functional groups in their adaptation to salinity stress which can support synergies that enhance overall forage productivity. In broad sense, such coexistence and facilitation can compensate for generally low forage productivity of halophytes as It is of primary significance that grass and forb species mechanisms of salinity tolerance translate to sustainable forage biomass production and resilience to further exposure to salt stress. at night . This inachinery and is lSynergies refer to the simultaneous increase or decrease in the provisioning of ecosystem services . Forage \u20131 to 41 dS m\u20131 are analyzed in sections \u201cProvisioning Ecosystem Services of Forage Production\u201d to \u201cSupporting Ecosystem Services for Soil and Animal Health.\u201dOverboard, crop diversification to mimic the stability of primary production and resilience of natural vegetation to disturbances is increasingly appealing to the design of sustainable agroecosystems . For exa\u20131. Blue panicum grass and Rhodes grass followed a similar pattern.As shown in + over Na+ ions in grass and lower crude protein than legumes. As depicted here, grasses are versatile in their range of crude protein concentration, some of which march that of legumes. A combination of grasses and forbs to generate forage of NDF \u2264 50% and crude protein \u2265 20% of dry matter is recommended to support animal and ruminal microbial energy needs which invigorate animal health and reproduction . The balvia improved soil structure and therefore enhanced infiltration of Na+ ions down the soil profile , a halophyte, can extract an estimated 1 ton of Na+ ions ha\u20131 year\u20131. This subsequently enhanced plant water and K+ ion retention together with shoot biomass in succeeding barley (Hordeum vulgare L.). Saltwort has similar potential, for instance, accumulating up to 125 g of Na+ ion kg\u20131 of dry matter within a span of 1 year , saltmeadow cordgrass (3 dS m\u20131), and blue panicum grass (2 dS m\u20131) are reported to have intermediate effects on biological N fixation by sweet clover (\u223c100%) and alfalfa (90\u201370%) except at 20 dS m\u20131 . It is suggested that N fixing bacteria release indole acetic acid at levels that safeguard the symbiotic process and plant growth from severe levels of soil salinity with annual grain-legume mixtures in a sequence that extends through fallow periods. The halophyte is designed not only to adapt in marginal weather conditions but also able to absorb Na+ ions and supply surface mulch for the next annual grain-legume crop mixture. The fourth system is an annual grain monocrop-legume monocrop in rotation. This system advances the benefits of optimum forage productivity and cover crops over at least 3 years of rotation. Overall, the cropping systems suggested here are designed to exploit the ecosystem services that enhance N and P supplies and optimize forage productivity and nutritive value. These systems are also developed to sequester carbon and alleviate salt buildup and toxicity in a gradual process that leads to sustainable forage production in areas prone to salinity.All of the above information showed that there is overwhelming evidence that soil microbes are ingredients of ecosystem sustainability by virtue of their roles in soil nutrient cycling. Soil microbial communities rely on energy from their plant hosts, and when established, they can revitalize crops against the effects of soil salinity and support forage productivity and nutritive value. This potential has not been fully exploited in orchestrated cropping systems to alleviate soil salinity and its effects on ecosystem health. This article explored species mechanisms and synergies that can be incorporated in cropping systems to alleviate the challenges of soil salinity and sustain forage productivity in arid regions. It is clear that halophytic and non-halophytic forage crop species have convergent mechanisms of salinity tolerance manifested in enhanced photosynthesis and productivity. There are indicators of ubiquity of ecosystem services of both halophyte and non-halophytic species along a continuum of increasing soil salinity. Potential grass-forb, annual-perennial, halophytes-non-halophytes, and plant-bacteria-fungi synergies against effects of soil salinity were identified. These synergies can be harnessed in designing sustainable forage cropping systems that ameliorate saline soils and improve nutrient cycling to sustain optimum forage productivity.The original contributions presented in the study are included in the article/DA and AN conceived and designed the study. AN supervised the work. DA, EA, AH, and AE collected and analyzed the data. DA drafted the manuscript. AH, LK, KD, and AN validated the data analysis and reviewed all the versions of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Post-traumatic stress disorder (PTSD) and abnormal spirometry are highly prevalent mental and health conditions in World Trade Center (WTC) responders. We tested the hypothesis that PTSD symptomatology and abnormal spirometry are conjointly and synergistically associated with poorer cognitive performance. A total of 1,326 responders from the WTC Health Program took part in the study. PTSD symptomatology was assessed using the PCL-IV, and we calculated the FEV1/FVC ratio to measure pulmonary function. Cogstate assessments measured cognitive performance. Linear regressions were employed to evaluate PTSD and pulmonary function on cognitive performance while adjusting for age, sex, education, smoking status, and comorbidity. Higher PTSD symptomatology and lower pulmonary function were independently and conjointly negatively associated with cognitive performance. Further, a significant synergistic effect was present in that higher severity of PTSD symptomatology in the presence of lower pulmonary function was associated with poorer cognitive performance . Results suggested that chronic stress and lung damage might share underlying biological mechanisms, including inflammatory and oxidative stress pathways, which may also be affecting the brain. Early intervention efforts to mitigate preventable cognitive decline in high-risk populations should be studied."} +{"text": "Background: Many patients suffering from schizophrenia spectrum disorders continue having distressing auditory hallucinations and paranoid ideations despite receiving current treatment. Virtual reality assisted treatment offers the potential of advancing current psychotherapies for psychotic symptoms by creating virtual environments that can elicit responses mirroring real-world settings. In two large-scale randomised clinical trials, we are investigating whether targeted virtual reality assisted psychotherapy can reduce psychotic symptoms and increase daily life functioning and quality of life. The CHALLENGE trial examines whether nine sessions of virtual reality-assisted psychotherapy is superior to nine sessions of standard treatments in reducing the severity, frequency, and distress of auditory hallucinations in patients with psychosis. In the Face your Fears trial we are investigating whether virtual reality assisted cognitive behavioral therapy (CBT) is superior to standard CBT in reducing levels of paranoid ideation in patients with psychosis spectrum disorders. Methods: The CHALLENGE and Face your Fears trials are randomised, assessor-blinded parallel-groups superiority clinical trials, allocating a total of 266 and 256 patients, respectively to either the experimental intervention or a control condition. The trials are currently enrolling patients; thus, no quantitative data is available yet. The main objective of this presentation is to give a qualitative account of this new psychotherapeutic methods as it is applied in both trials. Results: Qualitative data comprising case descriptions and video material will be presented at the conference. Discussion: The preliminary findings indicate great potential for these innovative treatments albeit important concerns regarding implementation will be raised.No significant relationships."} +{"text": "Research has repeatedly demonstrated that greater affective reactivity to daily stressors is associated with detrimental health outcomes . However, most research has only considered linear effects, which precludes an examination of whether moderate levels of stress reactivity may be beneficial. Using daily diary data from the National Study of Daily Experiences we fit multilevel SEMs to simultaneously model daily within-person associations between stress and negative affect , and individual differences in the linear and quadratic associations between stress reactivity and life satisfaction, psychological distress, and chronic conditions. Significant quadratic effects were found for each of the three outcomes , indicating a U-shaped pattern where both low and high levels of stress reactivity were associated with poorer health, whereas moderate levels of daily stress reactivity predicted better health outcomes. The results suggest that some affective response to daily stressors can be beneficial."} +{"text": "Medication nonadherence is associated with numerous negative health outcomes among older adults, including myocardial infarction, stroke, preventable hospitalizations, and increased risk of decline in self-reported health status. Maintaining continuous use and access to needed medications in later life has important implications for quality and length of life. A primary barrier shown to interfere with medication adherence in older adults is an inability to pay for medication. Relative to their younger counterparts, older adults have more financial protections that increase access to needed prescription medication through health insurance coverage. Despite these added protections, older adults are more likely to experience financial insecurity, with some evidence suggesting that COVID-19 accentuated existing vulnerabilities. Data are derived from the Health and Retirement Study (HRS), leveraging data drawn from the 2016, 2018, and 2020 study waves . Logistic models were used to evaluate the association between five COVID-19 related financial setbacks , and medication nonadherence among adults 60+. Results show that net of pre-COVID financial vulnerabilities and socioeconomic status, individuals who reported being unable to pay medical bills and those unable to pay rent/mortgage after the start of the pandemic reported higher odds of not taking/filling their prescription medication due to cost. Results suggest that greater financial protections for housing and medical bills among financially vulnerable older adults will increase medication adherence."} +{"text": "Computed tomography angiography (CTA) has been the gold standard imaging modality for vascular imaging due to a variety of factors, including the widespread availability of computed tomography (CT) scanners, the ease and speed of image acquisition, and the high sensitivity of CTA for vascular pathology. However, the radiation dose experienced by the patient during imaging has long been a concern of this image acquisition method. Advancements in CT image acquisition techniques in combination with advancements in non-ionizing radiation imaging techniques including magnetic resonance angiography (MRA) and contrast-enhanced ultrasound (CEUS) present growing opportunities to reduce total radiation dose to patients. This review provides an overview of advancements in imaging technology and acquisition techniques that are helping to minimize radiation dose associated with vascular imaging. Patient radiation exposure is a known consequence of several common forms of medical imaging but has been deemed acceptable in a variety of conditions where the benefit of diagnosing or excluding an underlying medical condition outweighs the potential adverse effects of patient radiation exposure. Computed tomography (CT) and CT angiography (CTA) are the medical imaging methods with the highest radiation exposure, accounting for approximately half of the total radiation exposure in the United States Report No. 184) [Current generations of CT scanners generate peak energies between 80 to 140 kV, with the majority using a tube potential of 120 kV, according to the International Commission on Radiological Protection (ICRP) Publication 135 [A single CT examination can range anywhere from 1\u201330 mSv in adult patients depending on the type of scan, CT scanner, and the region of the body measured, while CTAs can reach 100 mSv in some cases . While avol). Some example reference values of CTDIvol include 25 milligray (mGy) for the adult abdomen, 15 mGy for the pediatric abdomen, and 75 mGy for the adult head [vol and the scanning length in centimeters (cm). Facility registries, such as the CT Dose Index Registry, as well as the development of guidelines (including the ACR Appropriateness Criteria), have been implemented to promote further radiation reduction throughout the medical imaging field [Commonly accepted radiation exposure limits for various examinations are developed by the ACR and must be validated regularly for accreditation for each CT scanner used at a given facility, termed the Computed Tomography Dose Index Volume (CTDIult head . Dose Leng field . Even wiT), a relative measure of the radiosensitivity of organs to radiation, include the stomach, colon, lung, bone marrow, and breast [Patients who undergo surveillance or postoperative scans are exposed to additional radiation even after the initial identification and intervention of the underlying medical condition. While ongoing surveillance scans are often indicated, the lifetime cumulative radiation exposure of continued surveillance scans may breach even the highest lifetime radiation exposure recommendations. Intraoperative exposure to radiation by fluoroscopy is another source of considerable radiation exposure used in a wide variety of procedures, including the guidance of intravascular catheters and for confirmation of orthopedic hardware placement. Organs with the highest tissue weighting factor is commonly used to evaluate coronary artery disease (CAD) and is preferred over invasive coronary angiography for patients with low\u2013intermediate risk of CAD . The useAs radiation reduction techniques continue to evolve in other areas of CT imaging ,14,15,16A literature search was performed using the PubMed database and Google search engine. Databases were searched using the keywords \u201cradiation reduction techniques\u201d, \u201cmagnetic resonance angiography radiation reduction\u201d, and \u201ccomputed tomography angiography radiation reduction\u201d. Some specific searches for relevant topics such as the new MAGNETOM FreeMax magnetic resonance imaging (MRI) system was performed using Google, as well as further exploration of topics around the use of AI in radiation reduction techniques.The most efficacious strategies for radiation reduction adhere to the as low as reasonably achievable (ALARA) principle in which acquisition techniques are optimized to answer the clinical question, while reducing patient radiation exposure as much as possible .A simple but often overlooked method of radiation reduction includes reducing and/or optimizing the scan length, which has proven especially effective for radiation reduction in coronary CTA (CCTA) scans ,18. ScanAutomatic tube current modulation (ATCM) enables CT scanners to alter tube current based on density differences in tissue attenuation, utilizing lower tube current when possible and subsequently resulting in lower radiation exposure . Larger New, sophisticated CT image reconstruction techniques require less patient radiation exposure to produce diagnostic level imaging quality. Advances in imaging reconstruction due to increased computer processing speeds allow for increased image processing complexity while retaining acceptable processing times.Iterative reconstruction (IR) is one such example that reduces radiation exposure from 40\u201363% when compared to using filtered back projection (FBP) techniques for CCTA; new hybrid IR techniques are expected to further reduce dose exposure in the future ,21,22,23Other methods of radiation exposure reduction take advantage of the increased processing power now possible with modern computers, such as electrocardiogram (ECG)-controlled tube current modulation (ECTCM), a technique that reduces radiation exposure during periods of the cardiac cycle when the resulting image would be unused . More soAI shows promise as another method of radiation reduction through various methods but most notably in image reconstruction. Convolutional neural networks (CNN) are AI algorithms developed to recreate standard-dose images from low-dose computed tomography (LDCT) scans . Deep leAI is also able to reduce radiation exposure by automating CTA tube voltage by dynamically selecting the appropriate voltage based on the patient\u2019s anatomy and size, all while maintaining adequate image quality . AnotherRadiation dose exposure reduction is also possible via the implementation of a dual-source CT (DSCT), which allows for faster image acquisition due to two detectors acquiring perpendicular images simultaneously while maintaining temporal resolution. DSCT is particularly effective in patients who cannot remain still . Using DAnother advancement in the field of CT is dual-energy CT (DECT). DECT is particularly advantageous in the assessment of pulmonary embolus (PE) and the evaluation of chronic thromboembolic pulmonary hypertension (CTEPH) . StudiesImportantly, the photon counting detector in DECT machines can apply a threshold that enables the filtering of unwanted noise, allowing the scans to be performed at lower radiation doses . Some stVirtual monoenergetic images (VMI), acquired using DECT, involve using either the projection domain or image domain to generate superior, blended images of high and low energy acquisitions, taking advantage of the high contrast offered in low keV scans while also benefitting from the low noise of the high keV acquisition . VMI+, cDECT also offers an alternative to traditional contrast scans through virtual non-contrast images. These DECT scans are used to calculate the calcium score (CaSc) for coronary artery disease risk stratification. In the past, the level of radiation exposure via traditional angiographic imaging modalities led to this risk stratification method being downgraded . CalciumDECT is also under investigation as a method of evaluating myocardial ischemia. Using color-coded-iodine perfusion maps, DECT scans can serve as an indirect perfusion marker and provide functional information regarding the patient\u2019s coronary artery disease. Such information further increases the utility of DECT when compared to traditional CCTA, which only includes anatomic information . Other sWhile many methods to reduce radiation exposure from CT or CTA scans have successfully limited radiation exposure, alternative imaging methods using non-ionizing imaging techniques can supplement, and in some cases replace, traditional irradiating scanning modalities. The ACR Appropriateness Criteria offers clinicians radiologist-approved imaging recommendations for various clinical indications, including a qualitative assessment of the amount of radiation exposure for a given technique, allowing clinicians to select viable alternative imaging methods which result in less or no radiation exposure .Magnetic Resonance Angiography (MRA) is a notable radiation-free alternative to CTA. Radiation exposure from CTA scans is significant, delivering some of the highest radiation dose exposure on a per scan basis of any medical imaging modality. MRA is capable of high-resolution cross-sectional, multiplanar imaging (often without contrast) in a wide variety of applications. In a meta-analysis comparing MRA with CTA, the results show that the two imaging modalities have the same diagnostic value for intracranial aneurysm evaluation, albeit with a limited sample size .Both non-contrast MRAs (NC-MRAs) and contrast-enhanced MRAs (CE-MRAs) offer unique utility based on acquisition methods. Advantages of non-contrast studies include the absence of concern for nephrogenic systemic fibrosis (a condition associated with some of the gadolinium-based contrast agents that may be used in contrast-enhanced MRA), the relative simplicity and non-invasive nature of the scanning procedure compared to scans with contrast, and rapid repeatability of the scans which is particularly beneficial if initial scans are nondiagnostic due to motion artifacts or technical issues . The abiWithin the MRA imaging modality, multiple non-contrast techniques are available based on the region of interest. Flow-independent MRA is often utilized for imaging slow blood flow through veins and diseased arteries with a tradeoff in imaging quality from artifacts generated by off-resonant regions . Flow-deFor patients with renal dysfunction, QISS was developed to evaluate peripheral artery disease (PAD) without the need for contrast material. Requiring only 7 to 8 min on average for a whole-leg exam, QISS drastically reduces scan time when compared to the time of flight (TOF) methods that frequently take an hour or more for a whole-leg exam. QISS is also less prone to artifacts than TOF-MRA, and portions of the exam acquired with motion artifacts can easily be repeated when identified, resulting in only a 1-to-2-min prolongation of the exam time. QISS has also shown promise as a non-contrast, radiation-free imaging technique in diagnosing pulmonary embolism with a sensitivity and specificity of 86.0% and 93.3%, respectively, in a recent study . The priA third non-contrast MRA technique is subtractive 3D MRA. The cardiac-gated subtractive 3D fast spin-echo technique provides image quality comparable with CTA without the off-resonance artifacts that are prominent with flow-dependent MRA techniques. Other subtractive methods include flow-sensitive dephasing (FSD) and arterial spin labeling (ASL). FSD takes advantage of flow-dependent signal reductions between peak systole and end-diastole, resulting in arterial contrast after dephasing gradients are applied along the vessel length. ASL, another subtraction-based imaging acquisition method, is most commonly used as an MRA equivalent of x-ray digital subtraction angiography (DSA) for perfusion imaging of the brain but is also capable of imaging the extracranial carotid arteries. New developments in ASL imaging, such as 3D pointwise encoding time reduction MRA (PETRA-MRA), are in closer agreement with DSA when compared to TOF-MRA in the evaluation of intracranial stenosis . AdditioThe final two notable techniques of non-contrast MRA acquisition include velocity-selective 3D MRA and phase contrast MRA. Velocity-selective MRA is beneficial in slow flow settings where alternative methods such as IFDIR and ASL-based MRA techniques may result in low penetration of tissues. A primary limitation of this method is that artifacts are prominent in a non-uniform magnetic field setting. Phase contrast is an advantageous technique in cardiac imaging, providing quantitative values for shunts and valvular disease. Phase contrast is unique amongst imaging modalities in that the more complex 4D (otherwise known as 3D cine) acquisitions are capable of simultaneously displaying vessel anatomy and flow rates. Like many other MRA techniques, phase contrast is primarily limited by lengthy scan times and the need for complex image processing.In some scenarios, contrast-enhanced MRA (CE-MRA) is a helpful technique for imaging flow-related phenomena . CE-MRA Cardiac MR (CMR) is an imaging modality commonly used for long-term surveillance of adult congenital heart disease (ACHD), which is preferred over alternative methods due to the lack of radiation as well as the ability to avoid the rib spaces . CompareRegarding MRA performance, a systemic meta-analysis demonstrates sensitivity and specificity of 91% and 88%, respectively, for TOF-MRA of the extracranial arteries . HoweverOne common barrier to utilizing MRA as an alternative to CTA revolves around the availability and/or accessibility of scanners, as well as the relative difficulty that many claustrophobic patients experience due to the traditional scanner design. The prolonged scanning times of MRAs compared to CTAs create additional difficulty for some patient groups. With recent advancements in MR design and reconstruction, new scanners are attempting to mitigate many of the issues associated with MR, including increasing the bore size to accommodate larger patients and reduce claustrophobia. For example, the FDA recently approved a 0.55 Tesla (T) magnet with a larger bore design (80 cm). Importantly, this product has substantial cost savings compared to other scanners due to the lower field power, which allows the scanner to be lighter and easier to transport . AdditioWhile poor resolution has traditionally been associated with lower-powered magnets, some aspects of a low-field strength are beneficial to the image acquisition process . Low-fieContrast-enhanced ultrasound (CEUS) has many advantages over other imaging modalities, including low-cost, non-nephrotoxic contrast agents and a low rate of complications compared to iodinated contrast agents . CEUS isDynamic feedback, a feature unique to the ultrasound (and CEUS) modality, allows for real-time feedback that is particularly advantageous in targeted biopsies where examiners can distinguish between vascularized and non-vascularized tissue . This tyImportant limitations of CEUS include the intralesional gas formation, which limits the utility of ultrasound. Ultrasound utility is limited in areas where the acoustic window may be obstructed by rib shadows which may be further complicated by an intervening bowel gas as well as patient respiration and immobility . FurtherAs discussed previously, a variety of techniques have been developed to reduce radiation exposure that focus on the scanning modality itself. While these methods have been well-studied, other methods of radiation reduction that are unrelated to the imaging modality are effective and may be more easily to implement, especially when financial limitations are a limiting factor when attempting to reduce radiation exposure.In cases where regular surveillance of vascular pathology is required, performing surveillance scans using an approach that alternates between irradiating (CTA) and non-irradiating (MRA) imaging modalities may be a reasonable method to reduce radiation exposure in high-risk patients. As previously described in a publication regarding endovascular repair surveillance , alternaThe creation and implementation of CT imaging protocols requires a team approach, often made up of radiologists, physicists, and CT technologists. Studies have shown that the more individuals involved in the process, the more variable the radiation dose. Employing external medical physicists is associated with increased radiation exposure in lung cancer screening (LCS) exams compared to internal medical physicists, while using any type of medical physicist is associated with lower radiation exposure overall . FurtherPatients at risk of high lifetime radiation exposure should receive special consideration regarding imaging modality selection, as many may require long-term, regular screening for potentially life-threatening pathology.In children, radiation reduction is of paramount importance due to the detrimental effects that cumulative radiation exposure may have on a child\u2019s development and risk of cancer. Kawasaki disease, which requires monitoring for evaluation of coronary aneurysms, can result in high radiation exposure in children as coronary CTA has been the predominant surveillance method . The JapGenetic aortic syndromes, the most common of which is Marfan syndrome, are genetic conditions that require regular imaging for monitoring of the aortic diameter, which is an important predictor of potentially life-threatening aortic aneurysms and aortic dissections . As a reVascular Ehlers-Danlos (previously Ehlers-Danlos type IV) is another aortic syndrome that requires special consideration because of the potential for high radiation exposure. Although no evidence-based guidelines have been developed, institutions have a range of screening recommendations for patients with Vascular Ehlers-Danlos, ranging from regular screening for vascular abnormalities of the arterial tree to a single transthoracic echo in adults with no further follow-up ,52. DoppLoeys-Deitz syndrome, another aortic syndrome, overlaps with Marfan syndrome and/or Vascular Ehlers-Danlos, depending on the specific subtype . Due to Turner syndrome is another condition in which cardiovascular imaging is recommended for bicuspid aortic valve and aortic isthmus stenosis, two congenital cardiovascular malformations that are commonly seen with Turner syndrome . The recBicuspid aortic valve, independent of patients with Turner syndrome, is the most common cardiovascular malformation with a prevalence of 1000\u20132000/100,000 . PatientOutside of genetic conditions, many patients may have more common conditions that require special consideration regarding lifetime radiation exposure. Radiation therapy can be a life-saving treatment for patients with a variety of malignancies, however the impact of cumulative dose should be considered when imaging these patients . Other pThrough various advancements both in imaging acquisition and processing, the average radiation dose has drastically fallen over the last decade. Various institutions have successfully established protocols that reduce radiation through a combination of decision-making algorithms and careful coordination amongst multiple clinicians involved in the individual\u2019s care. CT technique remains the modality of choice for most indications related to vascular imaging. However, several advancements both with CT technology as well as alternative imaging modalities have contributed to opportunities for significant reductions in radiation exposure .DECT allows for more accurate tissue characterization while at the same time requiring lower maximum energy ranges when compared to traditional CT scans. Through this novel technique, a wide range of clinical applications show promise when imaged with DECT, including lung and myocardial perfusion studies, calcium subtraction imaging for coronary artery disease evaluation, detection of portal and deep vein thrombosis, and PE detection, all with benefits of lower or equivalent radiation exposure without the need for exogenous contrast administration.The development of the low-field MRI offers a radiation-free alternative that will gradually become more accessible to a larger subset of the population. By reducing setup costs and other barriers through the novel design of new scanners, MRI may become the imaging modality of choice in the coming years for a wide variety of clinical indications and various screening exams. In specific situations, such as the intensive care unit (ICU) and ED, smaller, portable MRI systems have been shown to be effective, improving efficiency by reducing personnel required due to the portability of the scanner while also improving patient care with a bedside solution that negates the potentially detrimental transportation of the patient that would have previously been a necessity.MRA has proven to be a reliable alternative for radiation reduction, particularly in scenarios where CTA may be traditionally deployed. Multiple studies have found that MRA is comparable to CTA in diagnosing various vascular pathology while offering superior image quality in certain situations such as in the setting of severe atherosclerosis and some metallic artifacts. New techniques allow for the dynamic assessment of blood flow in evaluating pathologic changes in the vessels. Other methods reduce scan time, further reducing the time discrepancy that remains a predominant critique of MRA compared to CTA\u2019s rapid scan times. While CTA will likely remain the predominant modality of choice, advancements in MRA acquisition techniques continue to narrow the gap between MRA and CTA, offering a capable and radiation-free alternative for a variety of indications.Another promising radiation reduction development is deploying AI and scanner learning to acquire low-dose, diagnostic quality scans. With rapid advancements in DL algorithms, AI can reduce radiation exposure by improving the image quality of low-dose images while also reducing processing times compared to traditional iterative reconstruction techniques. Outside of the image quality domain, AI can improve patient positioning during the scan, optimizing the patient\u2019s location within the scanner which reduces radiation exposure. The diagnostic yield of various exams can also be enhanced through AI, allowing clinicians to improve their decision-making process by leveraging the large volumes of data available.While reducing radiation exposure through various hardware and software advancements will continue to reduce total exposure, improving the decision-making process of ordering scans and reducing unnecessary scans is another method of reducing radiation exposure that should be considered. Making decision-making support systems using information technology available for clinicians increases the diagnostic yield of the scans ordered while also reducing both the exposure to the patient and the volume of scans at the medical center .Unfortunately, many medical imaging facilities continue to utilize legacy scanners that limit access to modern radiation reduction techniques. DECT-capable scanners have not been widely adopted as many facilities continue to use legacy CT scanners. MRI accessibility is even more limited due to the higher cost associated with this technology. The development of new image acquisition methods that could be applied to existing scanners to improve the diagnostic quality of low-dose scans may prove useful in situations where new equipment may be cost-prohibitive or financially impractical.Numerous benefits of CT often prevent consideration of other modalities. These benefits include the widespread availability of CT scanners in most hospitals as well as other factors such as staffing and scan duration ,55. ThisGiven the widespread availability of CT and a variety of other factors already discussed, many trials and research studies have focused on CTA\u2019s diagnostic performance and efficiency rather than MRA or other techniques. For example, CTA was the predominant imaging modality used to identify proximal large-artery occlusion in various trials where mechanical thrombectomy was shown to be superior to noninterventional approaches . CTA alsThe development of AI for widespread use also raises some concerns. Lack of verifiability across imaging platforms, as well as the subjective human ratings that are relied upon during the approval process for AI deployment, have been called into question . CollaboVascular imaging constitutes a robust volume of imaging in many modern radiology practices, ranging from smaller private practice settings to larger referral centers. Traditional methods for evaluating vascular pathology often involved high levels of radiation exposure to patients; however, modern techniques and advances in vascular imaging have significantly reduced radiation doses associated with this segment of diagnostic imaging. A variety of dose reduction techniques and strategies have been developed and applied to CTA imaging which remains the most accessible method to evaluate vascular pathology. Recent advances in alternative non-ionizing imaging modalities have either reduced and/or eliminated differences in sensitivity and specificity between CTA and alternative modalities. However, cost and accessibility remain potential obstacles to realizing the widespread use of these alternative modalities. In particular, technological advances in the sector of MRA imaging have been so rapid that research evaluating performance compared to CTA has been slow to catch up. As researchers further evaluate and confirm the performance of these advances in vascular imaging for both ionizing and non-ionizing radiation imaging techniques, radiologists and clinicians should expect patient radiation exposure associated with imaging of vascular pathology to continue to decrease."} +{"text": "A number of recent studies have shown that human exposures to a wide range of endocrine-disrupting chemicals (EDCs) may increase the risk of disease across the lifespan by altering the homeostasis or action of endogenous hormones, or other signaling chemicals of the endocrine system. Commonly investigated EDCs include chemicals widely applied in commercial and industrial products, such as per- and poly-fluoralkyl substances (PFAS), polychlorinated biphenyls (PCBs), bisphenol A (BPA), phthalates, and certain pesticides. Our understanding of human health risks associated with exposure to EDCs remains limited. The early development period might be more vulnerable to exposures to EDCs, but depending on the outcomes, relevant exposure windows may include several periods throughout the entire lifespan. In this Special Issue, we include seven epidemiological studies that address different aspects of human health risks associated with exposures to EDCs.Two epidemiological studies assessed potential associations between EDCs exposure and human reproductive health effects. First, an Italian study considered serum and follicular level of phthalates and BPA among 122 women undergoing oocyte retrieval for in vitro fertilization [Next, a cross sectional study of 1058 Danish men age 18\u201321) evaluated whether the use of personal care products (PCPs) that potentially contain multiple EDCs affected semen quality [1 evaluatThe following two studies published in this issue evaluated the effect of EDCs on maternal health, including preeclampsia and adiposity. The risk of developing preeclampsia in pregnancy was evaluated in relation to exposure to PFAS in a case-control study from Sweden. The study includes 296 cases diagnosed with preeclampsia and 580 controls pregnancies without preeclampsia identified through the Swedish medical birth register . PFAS waA study in a population with a high prevalence of obesity from the Pacific Island nation of Samoa evaluated the association of dietary BPA exposure and adiposity among 399 mother\u2013child pairs . The stuNext, we have also included two articles that assessed associations between EDC chemical exposures and neurological outcomes in children. A California study evaluated whether maternal pregnancy exposure to agricultural pesticide compounds affects offspring\u2019s risk for cerebral palsy (CP) . CP is tAnother study from Taiwan examined childhood urinary levels of multiple EDCs, including several phthalates metabolites, para-hydroxybenzoic acids, and BPA, on the susceptibility to attention-deficit/hyperactivity disorder (ADHD) . ADHD isFinally, this issue also included a methodological study that explored the challenges when distinguishing the confounding or mediating role of obesity in epidemiological analyses that aim to estimate EDCs exposure effect on other chronic health outcomes . The stuIn summary, the seven manuscripts included in the present Special Issue highlight the complexity when studying human health effects associated with endocrine-disrupting chemicals. The included papers demonstrated small steps in our continued understanding of the exposure effects of various EDCs on human health. This area of research is far from complete and greater efforts would be needed from the scientific community to understand whether and how these extremely widespread chemicals may influence health and disease risk in the populations."} +{"text": "Ex vivo mitral models are fundamental to mitral research and this diligently designed study provides an apt reminder of the strengths of this modelling modality in enhancing our understanding of mitral disease processes and spawning research hypotheses especially in areas where the evidence base is limited such as PM rupture. This commendable hypothesis generating work suggests the presence of sub-phenotypic groups within those with PM rupture, the characterization of which could allow for more precise and efficacious interventional strategies and sets the stage for further study in this challenging research area. Given the acuity and rarity of PM rupture, such information would be difficult to derive from clinical studies.The anatomical and functional complexities of mitral valve pathologies render clinical decision-making and intervention challenging particularly in emergent settings such as acute papillary muscle (PM) rupture. Although rare since the advent of percutaneous coronary intervention, PM rupture carries a dismal prognosis, with a recent multicentre study published in this journal revealing an in-hospital mortality of 24.9% in those undergoing surgical intervention . Given tex vivo mitral modelling are also apparent. Indeed, porcine models are not patient specific and do not fully emulate the complex biomechanics and anatomical variations of human mitral tissue nor would they simulate the various aetiologies of PM rupture and the concomitant sequalae such as left ventricular dysfunction and arrhythmia. Validation of such models is difficult, thereby limiting their translational value to only experimental use. Large-scale use of animal tissue within ex vivo simulators may also be costly and carry ethical implications.Despite the robust study design, the limitations of ex vivo platforms, therefore enhancing their effectiveness. Indeed, it is unlikely that ex vivo platforms will be rendered obsolete with the advent of these novel technologies.The advent and rapid evolution of disruptive technologies in medicine\u2014namely three-dimensional (3D) printing, computational modelling, machine learning and extended realities\u2014and advances in cardiac imaging have the scope to revolutionize mitral modelling. Moreover, they bear the translational potential to facilitate \u2018personalized\u2019 cardiac care and improve clinical outcomes by offering patient-specific procedure planning, surgical simulation training and procedural augmentation. Such technologies are also capable of being integrated with et al. [By integrating volumetric cardiac imaging, material technologies and software engineering, 3D printing transforms digital objects into 3D replicas through multi-layered material deposition over a digitally defined geometry. Advances in cardiac imaging\u2014notably in cardiac CT and 3D transoesophageal echo (TOE)\u2014enable rendering of highly accurate 3D images of cardiac structures. Progress in software engineering, particularly with the integration of machine learning (ML), now enables highly accurate and rapid delineation of anatomical boundaries in a process known as segmentation [et al. . Such plThe domain agnostic nature of ML enables identification of complex associations within big data with the efficacy of such models increasing with volume of inputted data. The quantitative nature of structural heart imaging naturally lends itself to ML and such methods have found a myriad of applications in mitral modelling particularly in automating and enhancing mitral segmentation to rapidly produce accurate 3D mitral replicas in the quest for point of care 3D printing. ML methods and 3D printing have also been successfully integrated to produce a hyper-realistic simulation platform for training in minimally invasive mitral valve surgery .et al. where augmented reality optimized intraprocedural TOE guidance facilitated more safer NeoChord implantation in a porcine model [Extended realities technologies harbour promise in the arena of mitral valve modelling and intervention particularly in surgical training, virtual proctoring and procedure planning . There ine model .Despite the rapid evolution of disruptive technologies, there is cause for caution amidst this riot of innovation. These technologies are relatively nascent, costly and carry their own inherent limitations. Indeed 3D-printed mitral replicas are as yet unable to accurately model mitral tissue and the complexities of mitral biomechanics such as deformation. The accuracy of 3D-printed replicas is also dependent on the quality of cardiac imaging from which they are derived and despite significant advances in this area, important limitations still apply. Computational flow dynamics offer high fidelity simulation of stress and deformation, but widespread clinical application is stifled by cost and complexity. Meanwhile, extended reality technologies face technical challenges associated with interfacing high volume multimodality data and issues associated with motion induced sickness in operators. Headsets can be cumbersome and could cause procedural hindrance. Much of the research with these technologies comprises of small proof of feasibility studies and comparison between studies is challenging given their heterogeneity.In essence, disruptive technologies look set to continue their rapid evolution and play an instrumental role in the quest for personalized cardiac care; however, careful consideration is required to their limitations when contemplating widespread clinical translation. Pragmatism would dictate that hybrid modelling through integration of these technologies\u2019 may optimize their efficacy and this may represent the next translational step in this exciting field."} +{"text": "Empathizing with others\u2019 pain appears to recruit the whole pain matrix, including a collection of frontal regions involved in the affective, motivational, cognitive, and attentional dimension of pain.This research explored how the modulation of interoceptive attentiveness (IA) can influence the frontal activity related to the emotional regulation and sensory response of observing pain in others.22 healthy participants were required to observe face versus hand, painful/non-painful stimuli in an individual versus social condition while brain hemodynamic response (oxygenated [O2Hb] and deoxygenated hemoglobin [HHb] components) was measured by functional Near-Infrared Spectroscopy (fNIRS). The sample was divided into experimental (EXP) and control (CNT) groups and the EXP group was explicitly required to focus on its interoceptive correlates while observing the stimuli.In the individual condition, higher brain responsiveness was detected for painful confronted to non-painful stimuli, and a left/right hemispheric lateralization was found for the individual and social condition, respectively. Besides, both groups showed higher DLPFC activation for face stimuli displayed in the individual condition compared to hand stimuli in the social condition. However, face stimuli activation prevailed for the EXP group, suggesting the direct interoceptive phenomenon has certain features, namely it manifests itself in the individual condition and for pain stimuli.We can conclude that IA modulation promoted the recruitment of internal adaptive regulatory strategies engaging both DLPFC and somatosensory regions towards emotionally relevant stimuli . Therefore IA could be trained for promoting emotion regulation and empathic response."} +{"text": "Sentinel lymph node biopsy (SLNB) has been the standard of care for clinically node-negative women with invasive breast cancer (IBC) and is also performed for women with ductal carcinoma in situ (DCIS) with high-risk features undergoing breast conservation surgery (BCS). Despite national guidelines, there is still controversy on whether to perform SLNB when the risk of metastasis is low or when it does not affect survival or locoregional control.National guidelines indicate that SLNB should not be routinely performed in women over 70 years of age with early-stage hormone receptor-positive (HR+) Her2 negative IBCSimilarly, one-third of ASBrS surgeons surveyed recommend SLNB for DCIS with high-risk features when guidelines advocate against it. Surgeons in academic settings were less likely to perform SLNB in this setting.Despite national guidelines, most surgeons favor SLNB in older patients with early-stage HR+ Her2 negative IBC. Clinical factors such as tumor grade, stage, and histology may be used to predict nodal positivity in this population to tailor the omission of SLNB to the subset with low-risk features."} +{"text": "Cancer among older adults is pervasive, putting excessive strain at the individual, caregivers, and wider society levels. In our symposium, we bring together researchers from varied disciplines\u2014with a focus on easing the strain of cancer on older adults by identifying important gaps in care and developing and implementing innovative methods for improving health services. First, Carrion will discuss the multifactorial experience of fears and beliefs about cancer and cancer prevention in 57 older Latino men. Krok-Schoen will discuss the longitudinal association between religiosity and cognitive functioning among older adults with hematological cancers. Next, Seaman will discuss engaging hard-to-reach patients and those who underutilize the health system. Blackberry will then describe an implementation and impact framework of a five-year research program to improve care in older people with cancer. Lastly, Halpin will discuss the 36-month implementation of a video-based patient education program for patients with multiple myeloma who are preparing for autologous stem cell transplant. Understanding the development and implementation of programs aimed at improving health services among older adults with cancer will help improve understanding potential methods for identifying and addressing health services challenges in these populations."} +{"text": "Interactions between species above- and belowground are among the top factors that govern ecosystem functioning including soil organic carbon (SOC) storage. In agroecosystems, understanding how crop diversification affects soil biodiversity and SOC storage at the local scale remains a key challenge for addressing soil degradation and biodiversity loss that plague these systems. Yet, outcomes of crop diversification for soil microbial diversity and SOC storage, which are key indicators of soil health, are not always positive but rather they are highly idiosyncratic to agroecosystems. Using five case studies, we highlight the importance of selecting ideal crop functional types (as opposed to focusing on plant diversity) when considering diversification options for maximizing SOC accumulation. Some crop functional types and crop diversification approaches are better suited for enhancing SOC at particular sites, though SOC responses to crop diversification can vary annually and with duration of crop cover. We also highlight how SOC responses to crop diversification are more easily interpretable through changes in microbial community composition . We then develop suggestions for future crop diversification experiment standardization including (1) optimizing sampling effort and sequencing depth for soil microbial communities and (2) understanding the mechanisms guiding responses of SOC functional pools with varying stability to crop diversification. We expect that these suggestions will move knowledge forward about biodiversity and ecosystem functioning in agroecosystems, and ultimately be of use to producers for optimizing soil health in their croplands. Because soil microbes drive soil functioning, their diversity is a major target for improving agricultural soils, which have lost between one-third and one-half of their organic carbon relative to natural vegetation due to conventional management practices . Crop diLessons learned from plant and microbial ecology of natural/unmanaged systems is helpful in explaining site-level differences in relationships among plant diversity, microbial diversity, and ecosystem functioning of managed agroecosystems. In a grassland biodiversity experiment, positive effects of plant diversity on soil fungal diversity occur through increased aboveground biomass production and thus supply of organic substrates . This meZea mays L.), likely because corn produces higher amounts of biomass with low C:N ratio, which can contribute considerably to SOC accumulation and/or soybean (Glycine max L.) as a focal crop, (3) use Illumina next-generation sequencing to generate sequence data for bacterial and/or fungal communities in bulk soil, and (4) provide sequencing data publicly or by request. We specifically use studies that provide next-generation sequencing data, following the recent movement toward DNA-based analyses of microbial communities as a metric for soil health crop diversification experiment in corn and soybean cropping systems in the southeastern United States . Along wJuglans regia L.)-based agroforestry on bacterial diversity are positive overall alone or in a six-species mixture decrease SOC by about 20% relative to a fallow control or wheat (Triticum aestivum L.) cover crop in the winter fallow corn-soybean cropping systems significantly decreases soil bacterial diversity plots. One way to optimize sampling effort is to increase subsamples collected and homogenized for each plot. In the 2, and thus the numbers of composited subsamples for SOC soils of a long-term tillage experiment , within- for SOC should b for SOC and coul for SOC . VerticaFigure 1K). We performed an additional power analysis to identify how many replicates it would take to detect a significant effect after only 5 years of agroforestry given the observed effect size, and found that replication would have to increase by two orders of magnitude can prevent detection of significant changes in SOC and microbial community diversity. Soil microbial diversity, in particular, can vary significantly at local or field-scales . Howeveragnitude . Thus, wagnitude , 2H.diversified\u2013meansimplified)/pooled standard deviation. Using these observed effect sizes and an alpha level of 0.05, we determined the achievable statistical power given a range of sample sizes from 2 to 100 + is one factor to consider to robustly measure diversity of soil microbial communities. To determine how soil sample size influences the ability to detect crop diversification effects on soil microbial diversity, we conducted a power analysis of results from to 100 + . This anto 100 + to detecAdditionally, when characterizing soil microbial communities, it is important to consider optimizing sequencing depth and accounting for relic DNA. Inadequate sequencing depth would lead to underestimation of actual diversity, whereas excess sequencing depth would be a resource intensive effort. The case studies highlighted here obtained paired end sequence read lengths of 250\u2013300 bases per sequence, which should be sufficient for 16S gene regions and for most ITS gene regions . However(A) indicates sufficient sampling depth. The absence of leveling off in (B) indicates insufficient sampling depth, which may hinder insights gained from this dataset about how soil microbial diversity responds to crop diversification. Given this variation in apparent soil microbial diversity in agroecosystems, future studies would benefit from pilot tests to determine the adequate sequencing depth for overall diversity in the systems.Sequencing depth for soil microbial characterization. To illustrate the importance of sequencing depth in understanding soil microbial diversity, we plotted species abundance curves of fungal amplicon sequence variants (ASVs) identified in Identifying coordinated changes (or lack thereof) in SOC and soil microbial diversity can advance our understanding of diversity-ecosystem functioning relationships in agroecosystems, but determining the mechanisms that underlie SOC changes can help us to explain such relationships. Carbon cycling frameworks have increasingly understood microbial influences on SOC storage, but reconciling this framework with changes to SOC under crop diversification remains a major challenge. That is, we have seen a common pattern where corn production systems accumulate more SOC than soybean systems. However, according to the Microbial Efficiency-Matrix Stabilization (MEMS) framework, higher-quality litter (such as that of soybean) decomposes more quickly, thereby increasing readily available carbon , which can then be stabilized and protected through associations with the mineral soil matrix . This miTwo case studies presented here measure readily available fractions of SOC , which cRecent global analysis has identified strong positive linkages among plant diversity, soil microbial diversity, and SOC in agroecosystems, but these linkages at the site level are quite idiosyncratic. Here, we have discussed contingencies upon plant functional type, number of crop species, field location, and experimental duration in determining how soils respond to crop diversification. Overall, we have described the role of crop functional type (more so than number of species) in how soils respond to crop diversification, with corn contributing more to SOC accumulation in agroecosystems compared to soybean and wheat. Still, higher microbial diversity is not always an outcome of crop diversification or an indicator of increased SOC, and site-to-site and year-to-year variation can introduce significant inconsistency in the effectiveness for any one crop diversification strategy. Though crop diversification does not have consistent effects on soil microbial diversity, it does consistently shift microbial community composition. Further, soil microbial diversity has no strong associations with SOC within sites, but SOC is generally a significant predictor of soil microbial community composition. Thus, despite the limited scope of our analysis of five case studies, we find strong evidence that microbial diversity is a less important mediator of crop diversification effects on SOC compared to microbial community composition. Moving forward, given a combination of more subtle effects that occur in early years of implementation of crop diversification and inherent spatial and temporal variation in SOC and soil microbial communities, we need to optimize sampling efforts and sequencing depths that aid robust estimates of change. We also need to integrate agroecosystems into current theory on soil microbe-carbon interactions. Such efforts will improve our understanding of plant diversity-ecosystem functioning in agroecosystems.RW, SK, and SJ conceived the project. RW acquired and processed the raw sequence data with substantial input from SK. RW conducted statistical analyses. All authors contributed to writing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Digital Mental Health holds strategic potential in fulfilling populations\u2019 mental healthcare unmet needs, enabling convenient and equitable access to mental healthcare. However, despite strong evidence of efficacy, uptake by mental healthcare providers remains low and little is known about factors influencing adoption and its interrelationship throughout the Digital Mental Health adoption process.This study aimed at gaining in-depth understanding of factors influencing adoption and mapping its interrelationship along different stages of the Digital Mental Health adoption process.This work adopted a qualitative approach consisting of in-depth semi-structured interviews with 13 mental healthcare professionals, including both psychologists and psychiatrists. The interviews were transcribed and analysed thematically, following Braun and Clarke\u2019s method.In this communication, we will describe how digital technology is currently used by clinicians to deliver mental healthcare. We identify potential factors influencing Digital Mental Health adoption and characterize the different identified stages inherent to this appropriation process: i) Pondering appropriate use; ii) Contractualizing the therapeutic relationship; iii) Performing online psychological assessment; iv) Adapting and/or developing interventions; v) Delivering Digital Mental Health interventions; and vi) Identifying training unmet needs. A discussion on how different factors and its interrelationship impact the adoption process will also be performed.By characterizing mental healthcare providers journey throughout the Digital Mental Health adoption process, we intend to inform ecosystem stakeholders, such as researchers, policy makers, societies and industry, on key factors influencing adoption, so policies, programs and interventions are developed in compliance with this knowledge and technology is more easily integrated in clinical practice."} +{"text": "Salmonella typhimurium were shown to exhibit increased MNase sensitivity specifically at genes implicated in immune responses. Increased sensitivity at the \u22121-nucleosome permitted transcription factor and RNA Pol II binding events. This system illustrates how cytoplasmic signals induce altered chromatin states to produce a specific cellular response to a stimulus. Innate immune activation is a longstanding model for inducible promoters, transcriptional activation, and differential nucleosomal sensitivity in response to immune activation and offers a model that may be largely applicable to other specific cellular responses including viral infection and cancer. Previous work has shown that early transformation events are associated with prolonged nucleosome occupancy changes that are not observed later in cancer progression. Herein, we propose a model in which we suggest that detailed studies of nucleosomal occupancy and sensitivity in response to specific stimuli will provide insight into the regulation of nuclear events in cancer and other biological processes.The nucleosome, consisting of ~150bp of DNA wrapped around a core histone octamer, is a regulator of nuclear events that contributes to gene expression and cell fate. Nucleosome organization at promoters and their associated remodeling events are important regulators of access to the genome. Occupancy alone, however, is not the only nucleosomal characteristic that plays a role in genome regulation. Nucleosomes at the transcription start sites (TSSs) of genes show differential sensitivity to micrococcal nuclease (MNase) and this differential sensitivity is linked to transcription and regulatory factor binding events. Recently, lymphoblastoid cells treated with heat-killed The nucleosome has long been considered a regulator of nuclear events. Consisting of ~150bp of DNA wrapped 1.65 times around a histone octamer, the nucleosome serves as the functional subunit of chromatin \u20134. SimilThe availability of massively parallel sequencing technologies in the early 2000s allowed for more detailed studies that mapped nucleosome occupancy in a highly time-resolved manner and provided insights into the dynamics of nucleosome remodeling. Time-resolved studies demonstrated widespread transient changes in nucleosome occupancy in response to reactivation of Kaposi\u2019s sarcoma associated herpesvirus (KSHV) to produce a transient intermediate chromatin conformation favorable to an immune response followed by a return to the basal state . SimilarThis type of transient remodeling may also play a role in response to other stimuli including viral infections and resulting immune-mediated pathologies like those seen in acute SARS-CoV-2 infections and persistent systemic symptoms classified as Post-Acute Sequelae of COVID-19 (PACS). Chromatin remodeling complexes are essential for viral infection and replication indicating a direct role for chromatin dynamics during viral infection . InitialSalmonella typhimurium. However, increased sensitivity at the \u22121 nucleosome in highly expressed genes is observed 20 minutes after stimulation which is consistent with the timeframe for the innate immune response to bacterial stimulation [Nucleosome mapping is often achieved by digesting crosslinked chromatin in micrococcal nuclease (MNase) to produce ~150bp fragments which correspond to nucleosome-protected immune-specific regions Figure . Biochemmulation ,26. MNasmulation . The posGenomic instability and altered chromatin organization are the hallmark of the transformed phenotype and are associated with cancer progression. Features of chromatin organization are regulated by ATP-dependent chromatin remodeling complexes . MutatioSalmonella example above. The longer-lived nucleosome sensitivity changes explain differential gene activation through altered regulatory factor accessibility in conditions, such as high-grade cancers, where nucleosome occupancy appears largely static.Early grade adenocarcinomas show widespread nucleosome depletion at transcription start sites particularly in genes associated with chromatin structure and cancer progression. While it is unknown exactly how long this remodeled state persists, an appealing explanation is that this remodeled state persists longer than physiologically expected due to dysregulation of ATP-dependent chromatin remodeling complexes. Consistent with this explanation, differential occupancy is reduced in higher grade tumors , hintingThe above observations suggest that measurements of nucleosome occupancy and sensitivity will provide valuable insights into gene expression and cell fate outcomes in cancer progression. We propose a model to explain these relationships . In this"} +{"text": "Person-centered care (PCC), or delivery of care consistent with preferences, can improve outcomes for residents in long-term care (LTC). However, PCC has not been universally adopted. Few studies focus on measuring specific barriers to meeting resident preferences, hindering identification of actionable targets to improve PCC delivery. The purpose of this study was to develop and test the content validity of a survey that measures staff barriers to fulfilling resident preferences for daily care and activities. Item sets comprised of barriers and preferences were informed by a review of literature and a descriptive, qualitative study with 19 LTC staff. An expert panel (n=8) was convened to test content validity, and content validity indices (CVI) were calculated. The initial survey consisted of 12 item sets assessing whether knowledge gaps, resident characteristics , family, facility rules/policies, availability of options, or staffing/workload functioned as barriers to meeting resident preferences for daily care and activities . Revisions informed by expert feedback resulted in a total of 17 items sets. Second round testing with experts (n=10) revealed overall improved item sets . These findings indicate that the survey items have initial content validity in measuring staff barriers to meeting resident daily care and activity preferences. Further psychometric testing with LTC staff is needed prior to implementing the survey, which will represent the first tool of its kind for supporting measurement of staff-derived targets for PCC interventions and policy change."} +{"text": "Socioemotional selectivity theory postulates that limited future time perspective (FTP) motivates older adults to prioritize emotionally meaningful goals, explaining documented age advantages in emotional well-being. During the early months of the COVID-19 pandemic, we collected data from 945 community dwelling adults and 156 assisted living facilities residents living in the United States . Participants reported their FTP using the scale developed by Carstensen and Lang (1996), as well as the frequency and intensity of sixteen positive and thirteen negative emotions. Age association with limited FTP was comparable to past studies. Contrary to our hypotheses, limited FTP was associated with lower emotional well-being across ages and suppressed (rather than mediated) a general trend towards higher emotional well-being in older ages. Findings suggest that there may be conditions under which perceptions of limited time horizons have negative implications. Theoretical implications are discussed."} +{"text": "Medicaid Accountable Care Organizations (ACO) are increasingly common, but the network breadth for maternity care is not well described. The inclusion of maternity care clinicians in Medicaid ACOs has significant implications for access to care for pregnant people, who are disproportionately insured by Medicaid.To address this, we evaluate obstetrician-gynecologists (OB/GYN), maternal-fetal medicine specialists (MFM), certified nurse midwives (CNM), and acute care hospital inclusion in Massachusetts Medicaid ACOs.Using publicly available provider directories for Massachusetts Medicaid ACOs (n = 16) from December 2020 \u2013January 2021, we quantify obstetrician-gynecologists, maternal-fetal medicine specialists, CNMs, and acute care hospital with obstetric department inclusion in each Medicaid ACO. We compare maternity care provider and acute care hospital inclusion across and within ACO type. For Accountable Care Partnership Plans, we compare maternity care clinician and acute care hospital inclusion to ACO enrollment.Primary Care ACO plans include 1185 OB/GYNs, 51 MFMs, and 100% of Massachusetts acute care hospitals, but CNMs were not easily identifiable in the directories. Across Accountable Care Partnership Plans, a mean of 305 OB/GYNs , 15 MFMs , 85 CNMs , and half of Massachusetts acute care hospitals were included.Substantial differences exist in maternity care clinician inclusion across and within ACO types. Characterizing the quality of included maternity care clinicians and hospitals across ACOs is an important target of future research. Highlighting maternal healthcare as a key area of focus for Medicaid ACOs\u2013including equitable access to high-quality obstetric providers\u2013will be important to improving maternal health outcomes. Accountable Care Organizations (ACOs) are a payment and delivery model designed to incentivize the provision of high-quality care at lower cost. Evidence of reduced spending in Medicare ACOs compared to traditional payment models has prompted states to experiment with the use of ACOs in their Medicaid programs \u20134. PreliDistinct in structure from Medicare ACOs where Medicare enrollees with traditional Medicare assigned to ACOs can visit any primary care or specialist clinician accepting Medicare , MedicaiAs of 2020, over half of physicians nationally are participating in at least one ACO of any type with just over a quarter of physicians participating in a Medicaid ACO . PhysiciMost research on clinician participation in Medicaid ACOs has focused on primary care clinicians , but theAs alternative payment models, including ACOs, become more common in all insurance types, understanding the differences in provider network breadth in Medicaid ACOs is increasingly important to ensure patient access to care. In Medicaid ACOs, adequate networks of OB/GYN providers are essential to ensuring high quality care for women. In this study, we quantify maternity care provider inclusion in Massachusetts Medicaid ACOs, implemented starting in March 2018, and analyze differences in provider inclusion by specific Medicaid ACO type.Using publicly available provider directories for Massachusetts Medicaid ACOs and data on provider supply, we quantified inclusion of obstetrician-gynecologists (OB/GYN), maternal-fetal medicine (MFM) specialists, certified nurse-midwives (CNM), and acute care hospitals with obstetrics departments in Medicaid ACOs. We then compared the number and type of providers across ACO types, across ACOs within ACO type, and to the total number of providers within Massachusetts.In Massachusetts, Medicaid ACO models were implemented starting in March 2018 with two ACO distinct models available as of 2021 , 28. TheWe analyzed obstetric provider inclusion in the 13 ACPP ACOs and three PCACOs operating in Massachusetts Medicaid in January 2021. We analyzed the inclusion of OB/GYNs, MFMs, and CNMs using ACO provider directories available online between December 2020 and January 2021. Five ACPP ACOs provided print directories generated directly from online directories located on the ACO websites. Eight ACPP ACOs provided separate, distinct printed directories available on the ACO websites. The three PCACOs utilized the MassHealth provider network for specialists, and we used the MassHealth online directory for these ACOs. Enrollment data for each ACO is determined as of July 2018 .For ACPP plans, clinicians included in the analysis were those listed in the categories of obstetrician, obstetrician/gynecology, gynecology, or maternal-fetal medicine within the provider directories. For certified nurse midwives (CNM), the directories which included CNMs had a separate section listing those who were included. For directories including a provider identification number (such as an NPI), the identifier was extracted, and duplicates were removed to determine the total number of providers included in that plan. For all others, duplicates were removed manually based on clinician name. If provider directories included practice names, we did not count these practices towards the number of included clinicians; we checked a number of these by hand in each directory to ensure that the majority of clinicians practicing in those organizations were included in the provider directory and discuss in the results where there were any deviations from this. We were not able to include family medicine physicians who provide maternity care due to the difficulty of systematically identifying these specific physicians.For the PCACO plans, we searched the online provider directory by specialty for \u201cObstetrics (OB/GYN)\u201d and included individual clinicians in the count. MFMs were not classified separately in the online provider directory but were included within OB/GYN provider listings. To determine MFM inclusion, MFM providers listed within the 2019 Massachusetts Registration of Provider Organizations Physician Roster (MA RPO) were manually identified within the covered Medicaid OB/GYN providers . The MA The Medicaid waiver implementing the Medicaid ACOs includes a policy that PCACOs may designate a \u201creferral circle\u201d of ACO-preferred specialists that patients may visit without a required PCP referral ; howeverThe total number of OB/GYNs and CNMs in Massachusetts for comparison to provider directories is based on estimates from the Area Health Resources File from the Health Resources and Services Administration . We calcWe used the MassHealth Enrollment Guide (January 2019) to determine hospital inclusion for each ACO, limited to in-state acute care hospitals with an obstetrics department that conducts deliveries . Acute cThe primary outcomes of this study are the number of 1) Maternity care clinicians including OB/GYN physicians, MFM physicians, and CNMs and 2) acute care hospitals with obstetrics departments included in each of the Massachusetts Medicaid ACO plan types.Descriptive statistics for ACO provider inclusion were calculated; these statistics give equal weight to each ACO. Comparisons were made between ACO types and to the number of practicing physicians in MA. For ACPPs, which have different numbers of included physicians, we compare the number of included clinicians to the ACO enrollment. All analyses were conducted using Microsoft Excel.Across Accountable Care Partnership Plan ACOs, there was substantial variation in number of providers included . The meaPrimary Care ACOs utilize the full Massachusetts Medicaid specialist network, and therefore all ACOs of this type have the same OB/GYN inclusion of 1185 OB/GYNs and MFM inclusion of 51 . In addiWe compared these included clinician numbers to the total practicing obstetric clinicians in Massachusetts according to the AHRF. The AHRF notes there are 1,046 OB/GYNs, which is higher than the number of OB/GYNs included in any ACPP provider networks; however, it is smaller than the number of OB/GYNs listed in the PCACO network. The number of practicing Maternal-Fetal Medicine from the MA RPO is 61. The number of practicing CNMs in Massachusetts from AHRF is 345.The percentage of hospitals with obstetrics departments included also varied substantially within and across ACO types . AccountFinally, we examine variation in provider inclusion in ACPP ACOs by enrollment. First introduced in 2011, Medicaid ACOs are a relatively new value based payment model, and there is limited prior research characterizing the breadth of provider networks in these ACOs . In thisThe few prior studies on Medicaid ACOs in maternal health care show Medicaid ACO participation resulted in an improvement of the timeliness of prenatal care initiation in the first trimester but did not increase the total receipt of adequate prenatal care ; state MAnother important finding is that some Medicaid ACOs did not include any CNMs, and the PCACOs did not easily identify any included CNMs. CNMs attend over 17% of births in Massachusetts, including almost 20% of births covered by Medicaid . MidwifeACPPs that had high numbers of member enrollment had correspondingly high levels of provider and hospital inclusion. However, among plans that had lower member enrollment, provider and hospital inclusion varied widely. MFMs are crucial for managing maternity care for high-risk patients, yet fewer than 10 MFMs were included in a majority of ACPP ACOs, particularly in ACPP ACOs with low member enrollment. This has important implications regarding access to care for Medicaid insured individuals. As many ACOs with low levels of enrollment are located outside of major metropolitan areas, a smaller network could lead to increased distances to the nearest provider, as well as fewer options in selecting a specific clinician. Maternity care availability (including providers and insurance coverage) in rural areas is critical for ensuring adequate perinatal care, and reduced access is an ongoing issue throughout the nation .The study had several limitations. First, given the known limitations of online provider directories , 62, ourIn this study, we examine variation in the maternity care provider inclusion in Medicaid ACOs in Massachusetts, which is critically important for access to care for Medicaid enrollees. We find substantial differences across ACO types and within ACO type. Understanding the role of maternity care provider inclusion in Medicaid ACO contracts and Medicaid risk adjustment and payment policy may be an important area of future research to understand incentives of Medicaid ACOs that improve maternal health care and health outcomes. Additionally, measuring the quality of included obstetric clinicians and hospitals, particularly for maternal healthcare, is an important area for ensuring equitable health care for Medicaid enrollees. As Medicaid ACOs expand nationally, ensuring that maternal healthcare is an area of focus\u2013including sufficient and equitable access to high quality maternity care providers\u2013will be important to ongoing efforts to improve maternal health outcomes.S1 TableNote: Directories were accessed in December 2020/January 2021. Links updated as of November 2022. Due to a change in insurer ownership, BMC HealthNet provider directories are no longer available online.(DOCX)Click here for additional data file."} +{"text": "This cross-sectional study examines the association between the complexity of consumer guidelines for COVID-19 vaccination and identification of eligibility. The US Centers for Disease Control and Prevention also released guidance on prioritization.2 The survey measured demographic factors, COVID-19 vaccine eligibility criteria, and perceived eligibility for vaccination. States a priori selected for this analysis based on having greater than 75 participants were the 5 largest states by population and Georgia (Georgia was oversampled). To determine participant vaccine eligibility, vaccine prioritization guidelines of each state were extracted from government communications identified as female; mean age was 45 years . The In this study, higher guideline complexity was negatively associated with correct identification of COVID-19 vaccine eligibility during vaccine scarcity in the US. When developing guidance, health agencies must balance precision and clarity. Increased precision may lead to greater complexity and lower target audience comprehension. Our findings suggest potentially large public health implications for complex guidelines. This study is limited owing to ecological design, social desirability bias, and potential misclassification of vaccine eligibility owing to self-reported data.More complex vaccine guidelines were associated with lower participant comprehension, potentially hindering eligible persons from seeking vaccines during a period of scarcity. To optimize public health communication, brevity and simplicity should not be undervalued."} +{"text": "It has been reported that diabetes mellitus affects 435 million people globally as a primary health care problem. Despite many therapies available, many diabetes remains uncontrolled, giving rise to irreversible diabetic complications that pose significant risks to patients\u2019 wellbeing and survival.In recent years, as much effort is put into elucidating the posttranscriptional gene regulation network of diabetes and diabetic complications; RNA binding proteins (RBPs) are found to be vital. RBPs regulate gene expression through various post-transcriptional mechanisms, including alternative splicing, RNA export, messenger RNA translation, RNA degradation, and RNA stabilization.Here, we summarized recent studies on the roles and mechanisms of RBPs in mediating abnormal gene expression in diabetes and its complications. Moreover, we discussed the potential and theoretical basis of RBPs to treat diabetes and its complications. \u2022 Mechanisms of action of RBPs involved in diabetic complications are summarized and elucidated.\u2022 We discuss the theoretical basis and potential of RBPs for the treatment of diabetes and its complications.\u2022 We summarize the possible effective drugs for diabetes based on RBPs promoting the development of future therapeutic drugs. According to a survey by the International Diabetes Federation (IDF), DM is a major health problem affecting 435 million people worldwide . In 20212O2) are important factors in pancreatic \u03b2-cell, functioning in cellular signaling processes and regulation of glucose-stimulated insulin secretion (GSIS) ; the National Natural Science Foundation of China ."} +{"text": "Physical activity is beneficial for older adults to maintain health and help manage chronic diseases but relies on routine participation. Some older adults continue with physical activity behaviors as they age, whereas others are negatively affected by impaired functional abilities, physical disabilities, and unmet psychosocial needs. This symposium presents quantitative and qualitative data on physical and psychosocial factors that can influence physical activity among older adults with varying levels and types of physical abilities. The first presentation will focus on aging into the disability associated with knee osteoarthritis, the leading cause of mobility decline among older adults that generally onsets after the fifth decade of life. The second presentation will focus on aging with a disability, specifically how health perspectives evolve when aging with a spinal cord injury. The third presentation will highlight how the COVID-19 pandemic has influenced outdoor physical activity among older adults when indoor activities became limited. The fourth presentation shifts perspectives to clinicians, specifically physical therapists, to explore the needs for addressing physical activity in the clinic. The fifth presentation outlines a physical activity intervention program and its implementation for community-dwelling older adults. Together, these presentations will provide practical insights for designing a person-centered program to improve physical activity for older adults including those aging into disability or aging with disability."} +{"text": "Bothersome urinary symptoms plague many older adults and disproportionally affect women. Underreporting of symptoms and general stigma/embarrassment associated with incontinence has negatively impacted the availability of treatments, as research cannot be championed if the severity of the problem is not apparent. Available therapeutics have limited efficacy and are often not recommended in aged patients. Lower urinary tract function has a long and rich history in animal studies; while much of the underlying anatomy has been described, including neural control mechanisms, the impact of aging has only just begun to be addressed. Recent work has provided strong evidence that neural control over micturition is significantly impacted by aging processes. This mini review discusses recent findings regarding how aging impacts the neural control mechanisms of micturition. With increasing age comes an increased incidence of lower urinary tract symptoms (LUTS), most prevalent in women and institutionalized populations . The sevThe bladder demonstrates complex neural regulation of its function despite a seemingly simple design. Control over the urinary bladder occurs as both an involuntary reflex and a conscious process. In cortical regions of the central nervous system (CNS), cortical function acts to suppress the voiding reflex until micturition is desired . Conversvia both somatic (conscious) and autonomic (unconscious) pathways and has been previously well reviewed as the bladder expands, and the level of afferent nerve firing is proportional to bladder volume. The PAG relays this information to the cerebral cortex in humans, allowing for conscious input over the voiding reflex . The autg reflex . Higher Functional changes in the urinary bladder are common in older adults, regardless of if they are symptomatic. The phenomena of overactive bladder (OAB) and underactive bladder (UAB) describe symptom complexes; diagnosis of detrusor underactivity (DU) or detrusor overactivity (DO) require clinical urodynamic assessment . DU and Like many other faculties, the CNS suffers in the aged environment. Functional MRI (FMRI) studies have demonstrated decreased blood flow, brain shrinkage, and metabolic dysfunction in the brains of older adults . In oldeDuring urine storage, adrenergic (sympathetic) inputs from the hypogastric nerve act on beta-adrenoceptors in the bladder wall, inducing relaxation, and act on alpha-adrenoceptors in the urethra, inducing contraction. Together, this allows for accommodation of increasing bladder volumes while maintaining relatively low pressure. Adrenergic and cholinergic receptor expression decreases with aging at both the mRNA and protein levels . EmptyinLUTS are a common, costly problem: billions of dollars are spent annually on the treatment and management of incontinence and related urinary problems. Nearly half of women over 65\u00a0years experience urinary incontinence\u2014allowing for acceptance of LUTS as \u201cthe new normal\u201d with aging\u2014yet many remain continent throughout their lives, implying simply possessing an old bladder is not the sole prerequisite for developing urinary dysfunction and/or symptoms. LUTS significantly decrease quality of life and are a driving force in institutionalization. Available pharmacologic therapeutics pose many unfortunate and undesirable side effects: anticholinergic medications, for example, have been associated with increased cognitive symptoms with little improvement in LUTS. Surgical interventions can be challenging in older adults, limiting the realistic use of neuromodulatory devices for sacral nerve stimulation.Aging negatively impacts function across many systems, including the CNS. Vascular deficits are observed with aging: ischemia in the brain and bladder have been demonstrated, undoubtedly affecting urinary function . Alterat"} +{"text": "JCI, Hindy and colleagues report on their evaluation of a multi-ethnic cohort of over 5,000 participants without known CVD. High suPAR levels correlated with incident CVD and atherosclerosis. Genetic analysis revealed two variants associated with the suPAR-encoding gene (PLAUR) with higher plasma suPAR levels. Notably, a mouse model with high suPAR levels possessed aortic tissue with a proinflammatory phenotype, including monocytes with enhanced chemotaxis similar to that seen in atherogenesis. These findings suggest a causal relationship between suPAR and coronary artery calcification and have clinical implications that extend to inflammatory disorders beyond CVD.Atherosclerosis contributes to the majority of deaths related to cardiovascular disease (CVD). Recently, the nonspecific inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) has shown prognostic value in patients with CVD; however, it remains unclear whether suPAR participates in the disease process. In this issue of the Despite decades of research and improvement in outcomes, cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide . AtherosAtherosclerosis is a diffuse, slowly progressing disease that in most cases remains asymptomatic for decades. It begins with subendothelial accumulation and retention of low-density lipoprotein particles, triggering an inflammatory response . CirculaOver the last 10 years, soluble urokinase plasminogen activator receptor (suPAR) has emerged as a nonspecific inflammatory biomarker with predictive and prognostic value in patients with CVD . suPAR iJCI, Hindy et al. (PLAUR) gene associated with higher plasma suPAR levels. One variant (rs4760) was confirmed experimentally in vitro and in vivo to lead to higher suPAR levels. The authors very nicely demonstrate that expression of the rs4760 PLAUR missense variant in human embryonic kidney (HEK) cells in in vitro and in in vivo mouse experiments resulted in an approximate seven-fold increase in suPAR levels, providing strong evidence that the rs4760 variant caused the high suPAR levels observed in humans. Through Mendelian randomization, the authors found that suPAR levels, predicted by the specific missense variant rs4760, were causally linked to atherosclerotic phenotypes in the UK Biobank, notably coronary artery disease, myocardial infarction, and peripheral arterial disease mice that exhibited increased circulating levels of suPAR to mimic increased suPAR levels observed in the clinic. Genetic overexpression of suPAR in a murine model of atherosclerosis using Pcsk9-AAV coupled with a Western diet led to a two-fold increase in atherosclerotic plaque size with large necrotic cores and macrophage infiltration in the TgsuPAR mice compared with WT mice. The authors determined that, prior to atherosclerosis, the aortic tissue isolated from TgsuPAR mice secreted higher levels of C-C motif chemokine ligand 2 (CCL2) and exhibited higher numbers of monocytes. Furthermore, monocytes isolated from the circulation and aortic tissue of TgsuPAR mice exhibited a proinflammatory phenotype with enhanced chemotaxis, which contributes to atherogenesis ..suPAR trThe clinical data demonstrating the causal relationship between suPAR and coronary artery calcification and the data for cumulative incidence of CVD events presented by Hindy and authors are powerful and striking . The aut"} +{"text": "The authors had 5 indications for PLLA injections and used subjective before and after photographs to evaluate its effectiveness. It would have been powerful to see a more objective assessment of volume retention such as three-dimensional imaging or patient reported outcome metrics using validated survey instruments (Video). The authors present a retrospective review of 241 patients who underwent facelift surgery with fat grafting, associated with Poly-L-Lactic Acid (PLLA) injections for facial volume maintenance after surgery.An important detail of this study was that the authors used an off-label dilution of PLLA, a common practice in facial aesthetics, reporting no complications or nodule formation in this series. Integrating facial fillers into postsurgical maintenance regime is especially helpful in patients with very low body mass index and inadequate fat donor sites. This paper reflects current clinical facial aesthetic surgery practices on facial volumization. In addition to PLLA, in our practice and many others, the use of different filler types such as hyaluronic acid (HA) and calcium hydroxyapatite is also very helpful for ongoing facial volumization and rejuvenation."} +{"text": "Walking ability is a robust predictor of health outcomes in aging. Compelling evidence supports meaningful interrelations between walking and cognition, notably when the former is performed under dual-task conditions that place increased demands on attention and executive control resources subserved by the prefrontal cortex (PFC) . Indeed,2) and deoxygenated hemoglobin (Hb) and is uniquely suited to examine task-related changes in brain hemodynamic responses during active walking [Due to the limitations inherent in traditional neuroimaging methods such as magnetic resonance imaging (MRI), our ability to understand and quantify how the brain is functionally involved in gait control during active walking has been limited. Nonetheless, recent studies using functional Near-Infrared Spectroscopy (fNIRS), a noninvasive optics-based neuroimaging modality, have begun to shed light on the functional brain correlates of walking. This technology uses light in the near infrared range (650-950nm) to quantify changes in oxygenated . Our stu2 levels in the PFC across experimental conditions were assessed during active walking using fNIRS Imager 1100 . Magnetic resonance imaging was performed in a 3 T Phillips scanner . The scanner was equipped with a 32-channel head coil. FreeSurfer software package (http://surfer.nmr.mgh.harvard.edu/) was used to extract cortical thickness measures in 68 brain regions (34 in each hemisphere). The results revealed that thinner cortex in specific regions in the frontal, temporal, parietal and occipital lobes as well as the cingulate cortex and insula was associated with inefficient increases in fNIRS-derived HbO2 from single to dual-task walking conditions, notably the analyses controlled for several covariates including gait and cognitive performance. These findings indicate that multiple brain regions are involved in volitional control of walking in older adults. Furthermore, reduced cortical thickness maybe an important causal factor implicated in neural inefficiency in aging and possibly in other clinical populations.Cortical thickness and gray matter volume are genetically and phenotypically distinct. Therefore, our recent investigation was designed to determine the effect of cortical thickness on changes in the hemodynamic response in the PFC across walking task conditions to further elucidate interactions between structural and functional brain systems of locomotion . Communi"} +{"text": "Teaching Point: Cystic dystrophy of the duodenal wall is often associated with underlying heterotopic pancreas and easily assessed with advanced and noninvasive imaging modalities such as CT scan and MRCP. A 56-year-old man presented with recurrent epigastric pain, projectile vomiting, and weight loss. He had a history of chronic alcohol abuse and acute necrotizing pancreatitis one year prior.Physical examination revealed a tenderness with sensation of induration in the epigastric region.Laboratory tests showed high level of lipase 870 U/L; (870 UI/L) other results were unremarkable.Contrast-enhanced computed tomography (CT) scan showed aCDDW is a rare condition characterized by the presence of cysts within thickened duodenal wall. It often reflects cystic and inflammatory changes of aberrant pancreatic tissue into the duodenal wall, also referred to as pancreatic heterotopia . CDDW ocContrast-enhanced CT scan and magnetic resonance imaging (MRI) are helpful for this challenging diagnosis. Demonstration of mural thickening, stenosis of duodenal lumen, and cysts within the duodenal wall or in the paraduodenal groove are the key features. Small remnants of pancreatic tissue within duodenal wall having the same morphological and hemodynamic behavior as normal pancreas parenchyma may be detected. MRCP is superior in demonstrating dilatation of small pancreatic ducts into pancreatic remnants .ERCP remains the modality of choice in confounding cases. It may confirm the intramural location of the cysts and demonstrate signs of chronic pancreatitis. Using a fine-needle aspiration, ERCP may rule out duodenal adenocarcinoma, which is the main differential diagnosis of CDDW. Groove pancreatitis still the main complication of CDDW. in such cases, conservative treatment is recommended. However, surgical options such as pylorus-preserving pancreatectomy and the Whipple procedure are necessary to alleviate recurrent symptoms ."} +{"text": "Widowhood is associated with decreased emotional well-being, particularly increased depression. Prior research suggests that religiosity may help improve mental health among widowed individuals. However, longitudinal studies exploring the role of religiosity on emotional well-being among widowed older adults is lacking, as are studies which examine different dimensions of religiosity. This longitudinal study analyzed data from the 2006-2018 waves of the nationally representative Health and Retirement Study (HRS). Ordinary least squares (OLS) regression analysis was used to examine the relationship between widowhood and depression as well as the role of religiosity as a moderator of this association. Analysis was stratified by gender to further explore these interactions. Results show that men and women show similar levels of depression at widowhood, but men are far less likely to be depressed prior to widowhood. Women also show a better recovery pattern over time post-widowhood. Furthermore, religiosity (particularly attending church) is an effective way of coping with widowhood and mitigating depression for both genders. However, men are significantly less religious than women. This study highlights the long-term effects of widowhood on depressive symptomology among older adults. Practical implications of this study include intervention development around increased screening and treatment for depression for widowed older adults as well as connecting this vulnerable population with resources. These findings may also inform program outreach (such as hospice bereavement services) that aim to facilitate healthy grieving among widowed older adults."} +{"text": "Dyadic coping is a daily interpersonal process that married couples use to manage stress and maintain their marriage. However, little is known about its mediating role in the association between empathic response and marital quality among same-sex and different-sex couples. This study aimed to examine the extent to which dyadic coping mediates the association between empathic response and marital quality, focusing on middle-aged men and women in same-sex and different-sex marriages. We used dyadic data from the Health and Relationships Project (HARP), including 124 gay, 171 lesbian, and 124 straight couples. Results from the actor-partner interdependence mediation model (APIMeM) showed that dyadic coping within couples mediated the association between empathic response and marital quality for all couple types . More empathic response was associated with better dyadic coping, which led to higher marital quality. While such mediated paths did not differ significantly between gay and lesbian couples, direct associations between empathic responses and marital quality were only significant among lesbian couples. Additionally, there were gendered patterns within straight couples; while female spouses\u2019 empathic response was associated with their and their male spouses\u2019 marital quality through the couple\u2019s dyadic coping, such a mediated path was not significant for male spouses\u2019 empathic response. These findings suggest dyadic coping as an effective strategy for enhancing marital quality among same-sex and different-sex married couples, but the mediating role of dyadic coping is gendered in different-sex marriages."} +{"text": "With a rapidly aging global population, declines in cognition and functional abilities are an increasingly salient challenge and fear among many older adults. Researchers and clinicians often study changes in cognition and changes in functional limitations as separate trajectories although they frequently co-occur. In this study, we used two-stage structural equation modeling (SEM) to estimate longitudinal trajectories of cognitive and functional limitations using data from the Health and Retirement Study (2010-2016) . First, individuals\u2019 longitudinal factor scores were estimated for cognition and functional limitations . A bivariate latent trajectory model was then fit to these scores. Model fit was acceptable . Parameter estimates showed that, on average, cognition declined slightly (-.08SD/decade) and functional limitations increased gradually (0.38SD/decade). Importantly, individual cognitive declines were significantly correlated with increases in functional limitation . This study fills an important research gap by using advanced statistical modeling (bivariate latent growth models) to examine the joint trajectory of cognition and functional decline which underscores the need to consider the interplay of these two abilities. Methods that quantify both individual and group trajectories can aid in better identification of aging patterns and lead to new ways of thinking about interventions to reduce the burden of concurrent decline."} +{"text": "Accumulating evidence indicates the existence of cancer stem cells (CSCs) sub-populations which fuel cancer growth and maintain stemness in different cancers. In addition to the genetic and phenotypic variabilities that differentiate CSCs from non-CSCs counterparts, CSCs adopt a flexible metabolic strategy to sustain their oncogenic and stemness properties, in order to survive and propagate in a hostile tumor microenvironment (TME). TME factors and metabolites exert context-dependent influence on cancer stemness. In addition, the metabolic landscape in TME is complicated by the crosstalk between CSCs and tumor-infiltrating cells. In this review, we will summarize the metabolic interaction between CSCs and various microenvironmental factors and review how this interplay regulates cancer stemness and tumorigenesis.An increasing body of evidence suggests that cancer stem cells (CSCs) utilize reprogrammed metabolic strategies to adapt to a hostile tumor microenvironment (TME) for survival and stemness maintenance. Such a metabolic alteration in CSCs is facilitated by microenvironmental cues including metabolites such as glucose, amino acids and lipids, and environmental properties such as hypoxic and acidic TME. Similarly, metabolites uptake from the diet exerts critical imprints to the metabolism profile of CSCs and directly influence the maintenance of the CSC population. Moreover, CSCs interact with tumor-infiltrating cells inside the CSC niche to promote cancer stemness, ultimately contributing to tumor development and progression. Understanding the underlying mechanisms of how CSCs employ metabolic plasticity in response to different microenvironmental cues represents a therapeutic opportunity for better cancer treatment. Emerging evidence has suggested that tumor cells inside a tumor bulk are heterogenous with variable genetic, phenotypic and functional profiles . Among wCSCs reside in the tumor microenvironment (TME) where heterogeneous cell populations interact with one another . The intReprogramming cellular metabolism is considered as one of the core hallmarks of cancer ,16, by wExtracellular metabolites could exert either tumor-promotive or -suppressive effect in different cancers . Their a+CD117+ CSCs isolated from epithelial ovarian cancer patients showed increased glucose uptake while CSC phenotype could still be maintained under glucose deprivation environment [+ liver CSCs [Glucose, as the primary energy-producing metabolite, has been shown in different cancers to either promote or suppress CSCs. A study observed that hyperglycaemia resulted in enhanced invasion and stemness of breast CSCs by reducing the tumor suppressing microRNA miR-424 . Howeverironment . Similarver CSCs . These sAmino acids are another important group of metabolites which influence CSC stemness . GlutamiExtracellular lactate impacts cancer cells and CSCs through diverse mechanisms ,32,33,34In addition to glucose, amino acids and lactate, lipids also play critical roles in regulating the stemness trait of CSCs. In ovarian CSCs, the provision of exogenous fatty acid sources such as palmitoleic acid and oleic acid rescued CSCs from ferroptosis-induced cell death which was resulted from the inhibition of fatty acid lipogenesis enzyme stearoyl-CoA desaturase (SCD1) . In relaCSCs consume metabolites in the TME, at the same time CSCs also actively remodel the TME by their altered metabolite secretome in order to establish a supportive ecosystem for tumor initiation and progression . Under hKetone bodies, comprising of acetone, acetoacetate and beta-hydroxybutyrate (\u03b2-HB), possess both pro-tumor and anti-tumor properties . IncreasMetabolic plasticity could be observed in CSCs exhibiting flexible energy metabolic strategy, that enables them to cope with energy demands in response to changing nutrient availability and environmental stress 54,55,5,555,56. Under hypoxia, CSCs rely on glycolysis rather than OXPHOS to maintain their survival . Zhou etAcidic extracellular microenvironment, termed acidosis, is another physical environmental factor that influences CSC metabolism and functions ,69,70,71In addition to the alteration of physical properties of the TME, extracellular metabolites also contribute to the reprogramming of CSC metabolism. High glucose concentrations in the culture media promoted glucose metabolism in pancreatic and ovarian CSCs as evident by the activation of glucose transporter 1 (GLUT1) . In anotThe reprogrammed metabolic strategies in CSCs represent therapeutic opportunities. Drugs targeting glucose metabolism exert effect on glycolytic CSCs, as exemplified by the use of 2-DG ,78,79. ODiet determines the nutrient availability in the microenvironment where CSCs are exposed to, that in turn alters CSC metabolism .+ intestinal stem cell pool through the activation of peroxisome proliferator-activated receptor-related signaling pathway [+ CSCs pool and promoted tumorigenesis through JAK2/STAT3 signaling in colon cancer [+ CSCs [High fat diet has been correlated with higher cancer incidence and worse prognosis , and it pathway . In oral pathway . In high pathway . Similarn cancer . Moreove [+ CSCs .Increased dietary intake of cholesterol and high cholesterol level have been implicated to facilitate tumor development and progression . Ehmsen Other types of diets have also been implicated in regulating CSCs. For example, a fasting-mimicking diet was observed to lower the glucose level and reduce the expression of stemness markers in breast CSCs . AccumulResults from the above studies indicate that dietary metabolites possess either promotive or suppressive role in the maintenance of CSC phenotypes in various types of cancers. Deciphering the mechanisms of such dietary effects on CSCs would shed light on novel therapeutic opportunities.The presence of heterogeneous cell populations within the tumor bulk are well characterized in different cancers ,94. CSCsCancer associated fibroblasts (CAFs) are fibroblastic cells residing in the TME that possess regulatory functions on cancer cells and CSCs . CAFs fu+ liver CSCs induced tumor angiogenesis [Endothelial cells (ECs) are functional cells that line the vascular system and are recruited to the TME for angiogenesis ,107. Unlogenesis . Wang etogenesis . Similarogenesis . In glioogenesis . Despite+ tumor-infiltrating T cells shifted their metabolism from glycolysis towards fatty acid catabolism [Immune evasion is one of the major hallmarks of CSCs . The mettabolism . Furthertabolism . The inttabolism . Proteintabolism ,125,126.tabolism . HoweverThe TME is comprised of various cellular and non-cellular components which reside with CSCs in the tumor bulk and continuously affect and modify the behaviors of CSCs. Metabolic plasticity displayed by CSCs enables flexible switching of their metabolic strategies to accommodate and survive in the hostile TME. In reverse, CSCs produce and secrete various proteins and metabolites to influence the neighboring microenvironment. This bidirectional interaction not only sustains the aggressive tumor behaviors but also protects and enhances tumor survival in response to stress and environmental insults.Given the importance of metabolic reprogramming in the maintenance of cancer stemness, elucidating the underlying molecular mechanisms which drive the metabolic plasticity of CSCs will likely reveal novel metabolic vulnerabilities and therapeutic targets to combat CSC-driven tumor development and progression. Current research efforts have been put to identify activated or mutated metabolic enzymes which play roles in promoting certain metabolic pathways to support cancer development and progression. Clinical trials with the use of small molecular inhibitors to target different metabolic enzymes has been underway . MetformDespite the enthusiasm of the development of metabolic therapies to target CSC metabolism for cancer treatment, concern and criticism were raised regarding the validity of experimental results using in vitro culture which deviates from the physiological environment . In part"} +{"text": "The aim of this study was to investigate the role of a synthetic dermal matrix, Biodegradable Temporising Matrix (BTM), for coverage of complex wounds. The authors defined complex wounds as wounds not amenable to reconstruction with skin grafting alone due to an inherent avascularity of the wound bed, such as the presence of exposed bone, tendinous or neural structures.A retrospective review of a prospectively maintained database of complex wounds as defined above was carried out. Clinical and operative notes were reviewed along with review of an extensive photographic database demonstrating wound healing progress using staged dermal matrix (BTM) and autologous skin graft reconstruction.55 patients were identified who underwent staged dermal matrix and autologous skin graft reconstruction for complex wounds affecting a wide variety of patient demographics, treatment indications and body sites. Wound aetiology varied between burn injury, non-burn related trauma including degloving injury and infective complications. We discuss caveats relating to successful application of a dermal matrix, technique tips, prevention and management of complications.Dermal substitutes play an integral role in providing biological wound cover for avascular wound beds which may otherwise require complex distant flap or microsurgical free flap reconstruction. BTM is a completely synthetic dermal matrix comprised of a 2-mm-thick sheet of biodegradable polyurethane foam bonded to a non-biodegradable polyurethane sealing membrane. Our department has developed significant expertise in the use of BTM throughout its development from initial animal studies through to recent human clinical trials. The synthetic composition of BTM does not require rapid neo-vascularisation for its integrity or survival. As such, two-stage BTM reconstruction has proven robustness in the face of unfavourable wounds compared with other popular dermal matrices, physiologically covering avascular structures, allowing for early graft take, expediting rehabilitation and mobilisation with excellent scar cosmesis and limited contracture formation.Dermal matrices such as BTM play an important role in complex wound healing, frequently achieving excellent results with a low complication profile. BTM has been used successfully in cases where biological matrices would not routinely be considered as demonstrated by this clinical series. It has provided a valuable alternative to free-tissue transfer in patients with significant co-morbidities, vascular insufficiency and/or those for whom long operations are undesirable."} +{"text": "The COVID-19 pandemic in NYC, the epicenter of the US crisis, revealed indisputable evidence that social determinants of health and disparities in comorbid health risk factors produce higher burdens of disease and death among racial and ethnic populations. We conducted a needs assessment of SDoH among 1400 patients in several ambulatory care clinics to explore the impact among older adults, across different clinical populations. Among older adults with HIV (OAH), we found lower rates of food and housing insecurity compared to older adults without HIV. Despite higher levels of COVID knowledge and prevention adherence, we also found significantly higher levels of isolation, loneliness, depressive symptoms, and anxiety among OAHs compared to those without HIV. Access to Ryan White entitlements did buffer some impacts but preexisting high burdens of mental health issues were exacerbated, perhaps due to heightened perceptions of increased vulnerability to COVID-19."} +{"text": "There is an abundance of evidence for the widespread presence of this spinal reflex arch originating from virtually every visceral organ and thus having a substantial role in blood pressure control. Additionally, this review highlights specific endogenous eicosanoid species, which modulate the activity of afferent fibers involved in this reflex, through their interactions with transient receptor potential (TRP) cation channels.The spinal cord is an important integrative center for blood pressure control. Spinal sensory fibers send projections to sympathetic preganglionic neurons of the thoracic spinal cord and drive sympathetically-mediated increases in blood pressure. While these reflexes responses occur in able-bodied individuals, they are exaggerated following interruption of descending control \u2013 such as occurs following spinal cord injury. Similar reflex control of blood pressure may exist in disease states, other than spinal cord injury, where there is altered input to sympathetic preganglionic neurons. This review primarily focuses on mechanisms wherein visceral afferent information traveling Physiological mechanisms of blood pressure control involve complex interactions between neural and humoral factors, which work hand-in-hand to ensure optimal delivery of nutrient rich blood to all the cells of the body. In regulating blood pressure, particularly important are the effects of the sympathetic nervous system. Sympathetic postganglionic neurons innervate blood vessels to regulate vascular smooth muscle tone and peripheral resistance. The rostral ventrolateral medulla is arguably one of the most critical cites for establishing baseline blood pressure as it sends tonic impulses to sympathetic preganglionic neurons located within the intermediolateral cell column of the thoracic spinal cord. Although the spinal cord is often described as a mere relay station between the brainstem and the periphery, clinical and experimental evidence highlights the important role of intraspinal reflex circuits in blood pressure regulation.via spinal nerves influences sympathetic nerve activity and blood pressure. Special emphasis is placed on descending inhibitory control of sympathetic preganglionic neurons and how interruption of this inhibition, as occurs following spinal cord injury, leads to aberrant spinal reflex control of blood pressure. Additionally, we propose that the spinal sensory input may contribute to tonic control of blood pressure in able bodied individuals. Finally, we highlight endogenous modulators of this neurocircuitry and their potential roles in regulation of blood pressure in healthy and diseased states.In this review we summarize available evidence that suggests intraspinal reflex circuits can directly and independently orchestrate profound reflex-mediated changes in blood pressure, especially when descending inhibitory pathways are interrupted, as in patients with spinal cord injuries. We primarily focus on mechanisms wherein visceral afferent information traveling via a spinal reflex arc \u2013 independent of central processing within the brain. The effect of visceral stimulation on systemic blood pressure was first empirically demonstrated in seminal works by Sir Charles Sherrington. He showed that distension of hollow visceral organs such as the urethra, bile duct or rectum in spinalized or decerebrate animals led to moderate increases in blood pressure, which were associated with a series of involuntary motor responses and spinal pathways. Stimulation of cranial afferent nerve fibers is generally associated with cardiovascular depressor responses, while spinal afferent stimulation generally evokes pressor responses within and surrounding visceral organs, are relayed to the central nervous system esponses . First oesponses . Within nal cord , the lower visceral organs are arguably less innervated by vagal afferent fibers and are densely innervated by thoracolumbar and/or sacral (pelvic) afferent fibers, whose cells bodies are located within dorsal root ganglia. The nerve bundles of these spinal sensory neurons are composed of thinly myelinated A\u03b4 and unmyelinated C fibers ,b. TheseVisceral mechano sensation has been extensively studied and mechanosensitive afferent fibers arising from the viscera are important drivers of sympathetic reflexes .Low threshold mechanosensitive afferent fibers innervate mucosal membranes and muscle layers of the visceral organs and are tonically active . They arHigh threshold mechanosensitive afferent fibers innervate blood vessels in the mesentery and mucosal membranes and muscle layers of visceral organs. These fibers are involved in detecting urgency, changes in mesenteric arterial pressure and mechanically induced pain.Silent mechanosensitive afferent fibers are mostly involved in signaling pathological visceral changes . These fIt is well established that mechanosensitive A\u03b4 and C-fibers drive sympathetic responses to mechanical stimulation of the viscera . HoweverThe above described functional organization for processing of afferent information exists within most spinal segments and highlights potential of intraspinal circuitry to influence spinal visceral reflexes originating from various spinal segments.As described above, the viscero-sympathetic reflex, similar to spinal motor reflexes, is integrated at the level of the spinal cord. Various visceral reflex arcs are contained within the spinal cord and are involved in normal gastrointestinal and urogenital physiology. As indicated below, activation of most spinal visceral reflexes is preserved following upper thoracic spinal cord injury and is associated with increases in systemic blood pressure.Micturition reflex: During the storage phase of the micturition reflex, pelvic sensory afferents send slow impulses into the spinal cord, which drive involuntary contraction of the internal urethral sphincter and relaxation of the detrusor muscle, both of which are needed to facilitate urine retention and are mediated via sympathetic efferent fibers. Importantly, bladder filling is associated with a progressive increase in activity of other regional sympathetic efferent fibers and in systemic blood pressure results in reflex increases in sympathetic nerve activity and blood pressure . Sympathetic fibers innervating the bladder neck, prostate, seminal vesicles, and vas deferens are activated and drive the emission phase of ejaculation across the plasma membrane. TRP channels are activated by a wide range of physiological and pathophysiological signals and respond to both chemical ligands and physical stimuli. In addition, many of the mammalian TRP channels are thermo-sensitive and can be directly activated by cold or hot temperatures family. To date, 28 mammalian TRP channels have been identified salt-sensitive hypertension or can be indirectly activated via three major enzyme systems: the cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) pathways. Eicosanoid molecules play a critical role in inflammatory signaling (2 (PGE2), clearly indicate that binding of PGE2 to its G protein coupled receptors (EP1-4) on the surface of TRP channel expressing neurons promotes hyperalgesia by driving phosphorylation of TRP channels thereby increasing excitability to mechanical, thermal and chemical stimuli (reviewed in via direct interactions (Eicosanoids are bioactive metabolites derived from polyunsaturated fatty acids (PUFAs) and generated ignaling , and theractions . Such inractions .Interestingly, many of the eicosanoids that promote afferent hyperexcitability through interactions with TRP channels are derived from \u03c9-6 PUFAs, which are abundant in Western diets. This has led us and others to hypothesize that dietary PUFA content may directly influence the excitability of TPR expressing C and A\u03b4 fibers. Evidence to support this hypothesis was recently published by the laboratory of K.M. Hargeaves . Specifivia intraspinal circuitry. However, it is important to highlight that similar sympathetic responses can be generated by spinal afferent information arising from somatic afferents . As in t reflex) . While i reflex) . However reflex) . This lein vivo electrophysiology recording will be an important tool for understanding the role of eicosanoids in altering spinal afferent excitability. Furthermore, additional studies into the role of dietary PUFA content and eicosanoid-TRP interactions in regulating baseline sympathetic nerve activity are needed.We have briefly highlighted the potential role of eicosanoid-TRP interactions in modulating the afferent limb of the viscero-sympathetic reflex circuitry. However, many mechanistic issues remain to be resolved and via chronic activation of the viscero-sympathetic reflex circuitry. Consistent with this notion, a large Danish cohort study found the risk for developing hypertension was significantly reduced among patients undergoing surgical colectomy when compared to patients undergoing other surgical procedures (It is notable that inflammatory conditions involving the viscera, such as inflammatory bowel disease, lead to the development of visceral afferent hyperexcitability . Interesocedures . Future ZM and CR: idea, writing, and editing. DO\u2019L: idea and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Kefir is an easy to administer per feeding tube probiotic yogurt that does not contain the risk of powdered probiotics, which may contaminate patient wounds or intravenous lines. Previous studies show patients taking probiotics may decrease hospital-acquired infections (HAI) although kefir has not been well studied. We hypothesized that kefir would be well tolerated and prevent infections among critically injured patients including patients with burn injury on enteral nutrition (EN).We performed a retrospective review of adult critically injured patients at a level 1 trauma and burn center from January 2018 to March 2021 who received EN. Patients with a history of clostridium difficile (C. diff) were excluded. Patients who received kefir were given 120ml twice daily. The kefir protocol was improved with input from clinical stakeholders. The rate of C. diff, catheter-associated urinary tract infection (CAUTI), and central line-associated blood stream infection (CLABSI) were compared between patients who received kefir and those who did not. Incidence rate ratios (IRR) and corresponding 95% confidence intervals were calculated to assess differences in these rates.3,814 patients met criteria, 545 of whom received kefir (14%). Suggested improvements to the kefir protocol by stakeholders were changing flavored to plain kefir to decrease the amount of carbohydrate, change to lactose-free kefir to improve usage in lactose intolerant patients, and educate nurses on flushing feeding tubes to avoid clogs.None of the incidence rates of HAI were significantly different between patients who received kefir and those who did not (Table 1). Crude IRRs suggest that C. diff infections may have occurred less frequently among patients who received kefir while the reverse occurred for CLABSI infections, though these results are not significant.The kefir implementation was refined by stakeholder feedback. Although no clear benefit of kefir was observed with HAI reduction, future research should investigate the potential association between kefir use and C. diff."} +{"text": "Background: Numerous studies have shown that trauma-focused psychological treatments for PTSD are effective .Results: Were preceded by changes in for most measures, changes in cognitive factors preceded changes in PTSD symptoms, but not vice versa.Study 2 Methods: Patient and therapist ratings of working alliance were taken repeatedly. Autoregressive, cross-lagged models were used to examine whether working alliance predicted PTSD symptom severity at the next assessment point and vice versa.Results: Higher patient and therapist working alliance was associated with lower PTSD symptoms. Crossed-lagged associations were found for therapist-rated alliance, but not for patient-rated alliance. A better working alliance at the start of treatment predicted treatment outcome. For most measures, changes in cognitive factors preceded changes in PTSD symptoms, but not vice versa.Conclusions: Study 1 extended previous findings that that cognitive and behavioural processes suggested by theoretical models of PTSD play a key role in driving symptom improvement during trauma-focused CBT. Changes in cognitive factors preceded symptom change. This result suggests that monitoring these processes during therapy may help therapist in maximising treatment outcomes in individual patients, and may also point to further ways of optimising treatments in general. Study 2 suggested that working alliance may be an important factor in setting the necessary conditions for effective treatment, but did not find evidence of a temporal precedence of changes in working alliance driving symptom change."} +{"text": "The ultimate goal for vaccination is the generation of a safe and effective immune response that protects against diseases. Adjuvants are included to enhance and direct vaccine responses. Precisely how adjuvants and indeed vaccine formulations influence the innate immune response and the subsequent cell- and antibody-mediated arms of the adaptive immune system are being characterized and clarified. Identification of safe but potent vaccine adjuvants, particularly those directed at mucosal sites, which generate long-lasting immunological memory and are effective against intracellular and extracellular pathogens is a high priority for public health and the health of veterinary species. After they are identified, tremendous amounts of work must be done to fine-tune adjuvant production, stabilization, and purification before commercialization. We launched this special issue to highlight recent basic research in vaccine formulation for infectious diseases and assess the adjuvant mechanism of action.Alcaligenes spp. that inhabit Peyer\u2019s patches in the gut [Alcaligenes lipid A may be a safe and effective Th17-type adjuvant.The following is a synopsis of the results reported in seven original articles. Systemic or mucosal adjuvants that promote T helper 17 (Th17)-type immunity are being investigated. Chaffey et al., 2021) assessed whether an intramuscular injection of adjuvants with ovalbumin in mice could induce an antigen-specific Th17-type immune response [021 asses the gut . Ex vivoMucosal vaccines need potent mucosal adjuvants to be effective. Razim et al. developed and characterized nanoadjuvant candidates (NACs) composed of silicon oil and cationic detergents and organic solvents for intranasal application . They idAssessing whether FDA-approved drugs can be repurposed as vaccine adjuvants is an important way to potentially fast-track adjuvant approval. Miltefosine (MTF) is an FDA-approved anti-leishmaniasis drug. Lu et al. assessed its adjuvant potential by immunizing mice via an intraperitoneal injection with hemagglutinin from influenza followed by intranasal challenge . The micAvian metapneumovirus (aMPV) is a virus that is the causative agent of turkey rhinotracheitis in turkey flocks and swollen head syndrome in chickens leading to significant morbidity and mortality throughout China. Bao et al. performed intramuscular injections of inactivated aMPV/B strain LN16 formulated with commercially available immune-stimulating complexes and measured the resultant immune response . They deFour review articles in this issue highlight the production, purification, and formulation of interferon-based biopharmaceuticals , the effTaken together, this special issue contains 11 relevant research and review articles focused on various aspects of the adjuvant mechanism of action and novel vaccine formulations that should be explored further for use in human and veterinary vaccines."} +{"text": "FGFR inhibitors evolved as therapeutic options in cholangiocarcinoma and urothelial malignancies. Given the implications of FGFR pathway in various physiological functions, FGFR inhibitors are known to cause unique toxicities. In this review, we summarized the physiology of FGF/FGFR signaling and briefly discussed the possible mechanisms that could lead to FGFR inhibitor resistance and side effects. In addition, we proposed treatment guidelines for the management of FGFR-inhibitor-associated toxicities.FGFR2 fusions or rearrangement, and erdafitinib in metastatic urothelial carcinoma with FGFR2 and FGFR3 genetic aberrations, lead to their accelerated approval by the United States (USA) FDA. Along with these agents, many phase II/III clinical trials are currently evaluating the use of derazantinib, infigratinib, and futibatinib either alone or in combination with immunotherapy. Despite the encouraging results seen with FGFR inhibitors, resistance mechanisms and side effect profile may limit their clinical utility. A better understanding of the unique FGFR-inhibitor-related toxicities would invariably help us in the prevention and effective management of FGFR-inhibitor-induced adverse events thereby enhancing their clinical benefit. Herein, we summarized the physiology of FGF/FGFR signaling and briefly discussed the possible mechanisms that could lead to FGFR inhibitor resistance and side effects. In addition, we proposed treatment guidelines for the management of FGFR-inhibitor-associated toxicities. This work would invariably help practicing oncologists to effectively manage the unique toxicities of FGFR inhibitors.Fibroblast Growth Factor receptor (FGFR) pathway aberrations have been implicated in approximately 7% of the malignancies. As our knowledge of FGFR aberrations in cancer continues to evolve, FGFR inhibitors emerged as potential targeted therapeutic agents. The promising results of pemigatinib and infigratinib in advanced unresectable cholangiocarcinoma harboring FGFR gene aberrations have been implicated in human malignancies . In . In 8]. TP53 gene thereby activating the cancer-associated fibroblasts promoting the tumorigenesis in FGFR aberrations . Given this expanding role of FGFR inhibitors in cancer care, a thorough knowledge on their unique side effects will aid in preventing unnecessary dose reductions and interruptions. It is important that patients be educated about these FGFR-inhibitor-related unique side effects and possible preventive mechanisms. Along with effective management of drug-related toxicities, a special focus is to be made on expanding our knowledge on resistance to FGFR-inhibitors. As determined in preclinical models, combination regimens such as synergistic inhibition of FGFR inhibitors and mTOR or MAPK pathway inhibitors may further be evaluated to bypass the resistance mechanisms.FGFR inhibitors are a unique class of emerging targeted therapies that have shown promising results in tumors harboring"} +{"text": "Myocardial infarction leads to pathological changes in the heart, including loss of cardiomyocytes and degradation of the cardiac extracellular matrix (ECM). These changes result in wall thinning, infarct enlargement, and development of scar tissue. Such remodeling ultimately leads to end-stage heart failure ,2. To adIn order to address these limitations, Silveira-Filho et\u00a0al. investigMany studies in the field of cardiac tissue engineering address remodeling timepoints immediately after ischemic wounding. However, this acute approach is not realistic because most of the remodeling in clinical ischemic heart disease occurs undetected over long periods of time, leading to extensive ventricular thinning, scarring, and progressive heart failure. The experimental time course followed in this study attempted to recapitulate extensive remodeling in the validation of PECUU-ECM patches by addressing ischemic wounds 8\u00a0weeks after myocardial infarction. This study found PECUU-ECM patches were efficacious in reversing the negative remodeling seen in advanced stages of ischemia, offering great potential for clinical translation. Additionally, the authors\u2019 rationale for incorporating PECUU patches within the biohybrid patch was its slower degradation rate relative to that of poly(ester urethane)urea (PEUU). This slower degradation rate ultimately led to better remodeling outcomes in post-infarcted rats given a PECUU patch compared to those given a PEUU patch over their infarcted hearts. Despite the slower rate of degradation, PECUU patches favorably did not form encapsulations typically caused by nondegradable material. These findings point to the importance of polymer selection in the development of cardiac patches. Notably, there are still some challenges this study needs to address in the future. The biohybrid patch used is mechanically compatible with rat myocardium, yet how these patches may influence the contractility and electrophysiology of human myocardium and whether the patches will withstand the pressures of a full adult human cardiac load upon implantation remain to be investigated . If implRecent advances in the field of cardiac tissue engineering include the use of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to produce engineered heart tissue (EHT) . In the The PECUU-ECM technology engineered by Silveira-Filho et\u00a0al. shows prThe authors have reported that they have no relationships relevant to the contents of this paper to disclose."} +{"text": "In mucosal barrier interfaces, flexible responses of gene expression to long-term environmental changes allow adaptation and fine-tuning for the balance of host defense and uncontrolled not-resolving inflammation. Epigenetic modifications of the chromatin confer plasticity to the genetic information and give insight into how tissues use the genetic information to adapt to environmental factors. The oral mucosa is particularly exposed to environmental stressors such as a variable microbiota. Likewise, persistent oral inflammation is the most important intrinsic risk factor for the oral inflammatory disease periodontitis and has strong potential to alter DNA-methylation patterns. The aim of the current study was to identify epigenetic changes of the oral masticatory mucosa in response to long-term inflammation that resulted in periodontitis.ROBO2, PTP4A3), cell adhesion (LPXN) and innate immune response . Enrichment analyses implied a role of epigenetic changes for vesicle trafficking gene sets.Genome-wide CpG methylation of both inflamed and clinically uninflamed solid gingival tissue biopsies of 60 periodontitis cases was analyzed using the Infinium MethylationEPIC BeadChip. We validated and performed cell-type deconvolution for infiltrated immune cells using the EpiDish algorithm. Effect sizes of DMPs in gingival epithelial and fibroblast cells were estimated and adjusted for confounding factors using our recently developed \u201cintercept-method\u201d. In the current EWAS, we identified various genes that showed significantly different methylation between periodontitis-inflamed and uninflamed oral mucosa in periodontitis patients. The strongest differences were observed for genes with roles in wound healing (Our results imply specific adaptations of the oral mucosa to a persistent inflammatory environment that involve wound repair, barrier integrity, and innate immune defense.The online version contains supplementary material available at 10.1186/s13148-021-01190-7. Genetic studies of chronic inflammatory diseases focused primarily on identifying DNA variants that confer disease risk through genome-wide association studies . MorThe oral masticatory mucosa locates to the alveolus/tooth complex and the hard palate and comprises all parts of the oral mucosa that are involved in chewing. Its position at the entrance to the gastrointestinal tract and respiratory systems entails its direct exposition to a diverse microbiota and various other environmental stressors such as tobacco smoke. If the mucosal barrier is impaired, pathogens can invade into subjacent tissue layers and promote periodontal inflammation. Persisting inflammation causes gingival bleeding and leads to the loss of connective tissue and alveolar bone with subsequent tooth loss, which determines the clinical characteristics of the common oral inflammatory disease periodontitis. In the etiology of periodontitis, persistent gingival inflammation is the most important risk factor , followeCYP1B1 (cytochrome P450 family 1 subfamily B member 1) and AHRR (aryl-hydrocarbon receptor repressor). Several EWAS have identified these associations for cells of the alveolar for the top 10 differentially methylated genes in the GO term \u201csynaptic vesicle cycle\u201d."} +{"text": "Traumatic brain injury (TBI) is common among older adults, with significant public health costs, and advanced age is a risk factor for poor outcomes after TBI. Older Veterans with TBI-related cognitive and emotional dysfunction without dementia may benefit from cognitive rehabilitation, particularly executive function training, and technology may promote optimal functioning for these patients by increasing access to such treatments. Dr. Kornblith will present pilot data on one such promising group intervention, Goal-Oriented Attentional Self-Regulation (GOALS), administered via in-home video telehealth. Themes gleaned from qualitative feedback collected throughout the intervention and post-treatment feedback questionnaires include the importance of communication and a smooth process with clear instructions for joining study sessions. Preliminary data suggest that only minor adaptions to the existing GOALS protocol are required for telehealth delivery and that delivering group-based executive function training to older TBI-exposed older Veterans with cognitive complaints via telehealth is feasible and acceptable."} +{"text": "Long-lasting changes in neural pain circuits precipitate the transition from acute to chronic pain in patients living with inflammatory bowel diseases (IBDs). While significant improvement in IBD therapy has been made to reduce inflammation, a large subset of patients continues to suffer throughout quiescent phases of the disease. Peripheral and central mechanisms contribute to the transition from acute to chronic pain during active disease and clinical remission. Lower mechanical threshold and hyperexcitability of visceral afferents induce gliosis in central pain circuits, leading to persistent visceral hypersensitivity (VHS). In the spinal cord, microglia, the immune sentinels of the central nervous system, undergo activation in multiple models of VHS. Using the Dextran Sodium Sulfate (DSS) model of colitis, we found that microglial G-CSF was able to sensitize colonic nociceptors that express the pain receptor TRPV1. While TRPV1+ nociceptors have been implicated in peripheral sensitization, their contribution to central sensitization via microglia remains unknown.Here we investigated the mechanisms of microglia activation to identify centrally acting analgesics for chronic IBD pain.Using Designer Receptors Exclusively Activated by Designer Drugs (DREADD) expressed in TRPV1-expressing visceral neurons that sense colonic inflammation, we tested whether neuronal activity was indispensable to control microglia activation and VHS. We then investigated the neuron-microglia signaling system involved in visceral pain chronification.We found that chemogenetic inhibition of TRPV1+ visceral afferents prevents microglial activation in the spinal cord and subsequent VHS in colitis mice. In contrast, chemogenetic activation, in the absence of colitis, enhanced microglial activation associated with VHS. We identified a purinergic signaling mechanism mediated by neuronal ATP and microglial P2RY12 receptor, triggering VHS in colitis. Inhibition of P2RY12 prevented microglial reactivity and chronic VHS post-colitis.Overall, these data provide novel insights into the central mechanisms of chronic visceral pain and suggest that targeting microglial P2RY12 signaling could be harnessed to relieve pain in IBD patients who are in remission.CCC"} +{"text": "Retaining older adults in clinical trials has often been a challenge for researchers. Clinical trial procedures, aimed at improving fidelity, often offer barriers to frail older adults who have challenges traveling to medical centers and enduring long clinical assessment visits. During the COVID-19 pandemic, we modified the procedures of two randomized controlled trials. COMPASS: A novel transition program to reduce disability after stroke is a clinical trial examining the efficacy of a transition home program that provides home modifications and self-management strategies compared to stroke education. HARP: Removing home hazards for older adults living in affordable housing is a pragmatic trial examining the effectiveness of a home hazard removal program for residents of low-income housing. Modifications to the trials were designed to reduce human contact but in some cases reduced the burden on trial participants. Modified procedures addressed retention, assessment of endpoints and intervention methods."} +{"text": "Tumor heterogeneity is one of the hallmarks of glioblastoma multiforme (GBM). Morphology within a given GBM tumor can be extremely variable where some regions of the tumor have a soft, gel-like structure while other areas are dense and fibrous. Abnormal mechanical stress and tissue stiffening caused by cancer proliferation are believed to affect vascularity by compressing structurally weak blood vessels and restricting the supply of nutrients and oxygen to the tissue. These effects contribute to a hypoxic microenvironment that promotes disease progression and chemoresistance. The genetic and molecular mechanisms that govern tissue stiffness within GBM tumors, however, are largely unknown. Magnetic Resonance Elastography (MRE) is an emerging technique for quantifying tissue stiffness non-invasively.We have evaluated 10 GBM patients by MRE imaging obtained prior to surgical resection. During surgery, 2\u20137 stereotactically navigated biopsies were collected from locations within the tumor with varying degrees of measured stiffness. Biopsies were processed to extract RNA, proteins, polar metabolites and lipids. Biomolecules were analyzed on relevant -omics platforms .Differential expression and gene set enrichment analysis of patient paired biopsies indicate an overall increase in macrophage infiltration and extracellular matrix re-organization associated with increased tumor stiffness. Among the most highly upregulated genes in stiff tumor tissue were lymphatic endothelial hyaluronic acid receptor 1 (LYVE-1) and macrophage receptor with collagenous structure (MARCO), both of which have been associated with immune cell infiltration and tissue stiffness.Our preliminary findings offer novel insights into tumor morphology in GBM that can be inferred from imaging prior to surgery. This can be used to identify tumor regions with high risk of progression and infiltration, thereby informing and guiding surgical strategy and may ultimately lead to novel treatment strategies."} +{"text": "Roney et al. review recent advances in how axonal endolysosomal trafficking, distribution, and functionality maintain distal degradation capacity in neuronal health and become disrupted in several neurodegenerative diseases. Lysosomes serve as degradation hubs for the turnover of endocytic and autophagic cargos, which is essential for neuron function and survival. Deficits in lysosome function result in progressive neurodegeneration in most lysosomal storage disorders and contribute to the pathogenesis of aging-related neurodegenerative diseases. Given their size and highly polarized morphology, neurons face exceptional challenges in maintaining cellular homeostasis in regions far removed from the cell body where mature lysosomes are enriched. Neurons therefore require coordinated bidirectional intracellular transport to sustain efficient clearance capacity in distal axonal regions. Emerging lines of evidence have started to uncover mechanisms and signaling pathways regulating endolysosome transport and maturation to maintain axonal homeostasis, or \u201caxonostasis,\u201d that is relevant to a range of neurologic disorders. In this review, we discuss recent advances in how axonal endolysosomal trafficking, distribution, and lysosomal functionality support neuronal health and become disrupted in several neurodegenerative diseases. Lysosomes are dynamic, membrane-bound, acidic organelles that play a central role in the degradation of intracellular and extracellular cargos. More than 60 hydrolytic enzymes that are active under acidic environments within the lysosomal lumen facilitate degradation of complex biological macromolecules, including proteins, lipids, nucleic acids, and carbohydrates . LysosomNeurons are highly polarized cells consisting of a cell body, complex dendritic arbors, and a single long axon with extensive branches and terminals that can span several tens to hundreds of centimeters in length. Given this extended morphology, neurons require efficient bidirectional transport mechanisms to coordinate clearance of endocytic and autophagic cargos generated distally by lysosomes that are relatively enriched in the cell body. Efficient transport is critically important in maintaining neuron growth, survival, and function but particularly challenging in distal axons and terminal branching regions. Accumulation of autophagic vacuoles (AVs) and lysosome-like organelles characterizes axonal pathology in several neurodegenerative diseases associated with lysosome dysfunction, reflecting disruptions at various steps in the maturation and trafficking of endolysosomal and autophagic organelles . In thisLysosomes serve as terminal degradation hubs for endocytic and autophagic components. Extracellular materials internalized by endocytosis, intracellular components sequestered by autophagy, and newly synthesized lysosomal proteins reach endolysosomes through highly regulated trafficking routes. Endolysosomal trafficking from early endosomes (EEs) to late endosomes (LEs) and finally to mature lysosomes is essential for delivering target endosomal proteins for degradation . TransitThe unique compartmental features of neurons add yet another layer of complexity to lysosome maturation. As in other cell types, neuronal lysosomes receive cargos through the endocytic, autophagic, and biosynthetic pathways. Because of their extreme morphological features, neurons require coordinated bidirectional transport mechanisms to maintain a steady-state distribution of the endolysosomal system in the axon, dendrites, and cell body. Degradative lysosomes are predominantly located in the cell body , represeEarly work measuring the pH of axonal endocytic cargos demonstrated an increasing frequency of acidic organelles as cargos moved from distal to proximal , suggestL-phenylalanine 2-naphthylamide in neurons showed enriched hCTSD puncta in somatodendritic regions of layer 5 cortical neurons and hippocampal CA1 neurons . AlthougNeurons require efficient transport mechanisms to maintain a steady-state distribution of endolysosomes throughout the cell. Kinesin and dynein motors drive long-distance transport along microtubule (MT) tracks in axons and dendrites, whereas myosin motors mediate short-range movement along actin filaments enriched in growth cones and synaptic regions . BidirecBorcs7 (encoding a BORC subunit) develop progressive axonal dystrophy and motor dysfunction, indicating a critical role of BORC-dependent axonal lysosome transport for maintaining axon integrity and neuron function in vivo mouse dystrophic axons contain immature lysosomes with low levels of proteases, representing a population of lysosomal intermediates distinct from mature lysosomes in the cell body and thus facilitates retrograde LE transport from axonal terminals toward the soma . Deletinradation and enharadation . Interesradation that is radation , althougGlued transport and positioning responds to alterations in cytoplasmic pH. Acidification of the cytosol causes lysosome dispersal into neuronal processes, whereas cytosolic alkalization shifts LE/LY distribution to the cell body , suggestDegradation of autophagic cargos depends on their dynamic interactions with endolysosomes, which supply the hydrolytic enzymes needed for substrate degradation . Both thIn axons, autophagosomes predominantly form at distal terminals , then suThus, the maturation of these distal AVs into autolysosomes is tightly linked to their retrograde transport. Scaffolding proteins, including JIP1, HTT-associated protein 1 (HAP1), and JIP3 , regulatAlthough dynein-driven retrograde transport of autophagosomes was suggested, a fundamental question remained as to how autophagosomes generated at distal axons acquire dynein motors for retrograde transport toward the soma. Using live rat dorsal root ganglion neurons combined with molecular disruption of autophagosome fusion with LEs or impairment of dynein\u2013snapin (motor\u2013adaptor) coupling, a study revealed a motor-adapter sharing model in which LE-loaded dynein\u2013snapin complexes are shared by autophagosomes upon their fusion . BlockinRecent evidence further revealed the role of lysosomes in axonal autophagosome maturation and clearance. Lysosomes that transport from the soma into axons target autophagic cargo to facilitate local AV maturation and cargo degradation. These lysosomes contain active lysosomal enzymes and are continuously delivered to distal axons from the cell body . DisruptLysosome dysfunction and impaired trafficking are linked to the pathogenesis of rare and common neurodegenerative diseases, including frontotemporal lobar degeneration (FTLD), Alzheimer\u2019s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington\u2019s disease (HD), Parkinson\u2019s disease (PD), and lysosomal storage disorders (LSDs) such as Niemann-Pick disease type C NPC; . In thesTMEM106B, encoding a transmembrane protein primarily localized on LEs and lysosomes, have been linked to several neurodegenerative diseases, including FTLD interacts with DIC leads to enhanced recruitment of JIP4 to AV membranes, inducing abnormal activation of the anterograde motor kinesin be differentially regulated in response to certain stimuli and signaling pathways; (2) associate with unique endolysosome subpopulations at different maturation stages or with specific functions; (3) selectively target to organelles within different segments of long axons; (4) play cell type\u2013specific roles depending on their expression levels within a given neuronal subtype; or (5) serve overlapping or partially redundant functions. Therefore, further work is needed to examine these possibilities, which will conceptually advance our understanding of how these motor\u2013adaptor transport complexes are regulated and coordinated to sustain efficient clearance capacity in distal regions under physiological conditions and become disrupted under pathological conditions.Moreover, many other important issues also need to be addressed in future studies. For example, do neuronal lysosomes in the periphery or distal regions serve as environmental or metabolic sensors to activate transcriptional pathways in the soma and promote lysosomal adaptation to stress? What are the upstream signaling events that regulate neuronal lysosome trafficking within axons and positioning at sites of high axonostatic demand or under autophagic stress? What role do cytoskeletal modifications play in modulating axonal lysosomal movement? How do interactions with other organelles such as the ER or mitochondria contribute to lysosome positioning and local degradation capacity in axons? Do these dynamic events change throughout development and aging? Addressing these questions will help advance our understanding of neuronal endolysosomal transport and lysosomal functionality under physiological conditions and how impaired trafficking and lysosomal dysfunction contribute to neurodegenerative diseases. Understanding the disease-linked mechanisms underlying axonostatic failure is critical for designing potential therapeutic strategies that target axonostatic restoration to support neuronal survival and function."} +{"text": "Theories suggest that with increasing age, adults more effectively regulate their emotions and seek to limit high physiological arousal. Prior research indicates physical activity attenuates negative affect reactivity to stress, but also increases physiological arousal. The present study extends prior work by examining age-related differences and changes over time in the extent of attenuation. Participants , from the National Study of Daily Experiences completed 8 end-of-day assessments of their negative emotions, stress, and physical activity across 3 measurement bursts spaced approximately 10 years apart. Results from three-level multilevel models suggest that when full random effects are specified, physical activity does not attenuate negative affect reactivity to stress. Additionally, extent of attenuation did not differ with age or change over time. Discussion pertains to how these findings advance theoretical understanding of socioemotional development and to methodological nuances of random effects and non-normally distributed data."} +{"text": "Prior studies of caregiving characteristics by type of caregivers are inconsistent, particularly those who are spouses and adult children. This study examined caregiving characteristics between spouses and adult children of cognitively impaired older adults. We analyzed phone-screening data from an ongoing trial of a dyadic sleep intervention program for persons with dementia and their caregivers. Data included spouse caregivers (n=52) and adult child caregivers (n=24). Nearly all participants (95%) lived with their care recipients (91% with dementia). Types of caregiving activities were measured by activities of daily living [ADLs] and instrumental ADLs [IADLs] with their levels of intensity . Care recipients\u2019 sleep was measured by the Neuropsychiatric Inventory-Nighttime Behavioral Subscale (8 items). Analyses included Pearson correlations and t-tests. Adult child caregivers helped their care recipients at significantly higher levels as indicated by their measure of dependence in dressing , continence , laundry , and transportation than spouse caregivers. Adult child caregivers also reported their care recipients having more difficulty falling asleep and having more numbers of sleep problems than spouse caregivers . The findings suggest that adult child caregivers may involve higher levels of caregiving responsibilities during daytime and nighttime, compared to spouse caregivers. Further research needs to explore complimentary ways to involve spouse and adult child caregivers in the care of this vulnerable population."} +{"text": "ABSTRACT IMPACT: This study advances our understanding of potentially key drivers in the early formation of pancreatic cancer, a disease with few treatment options and poor patient outcomes. OBJECTIVES/GOALS: Patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) have a 5-year survival rate of \u02dc9%. A key driver of poor patient outcomes is late-stage diagnosis. A better understanding of PDAC onset is needed. This study was developed to understand how extracellular vesicles may be involved in the early formation of PDAC. METHODS/STUDY POPULATION: Extracellular vesicles (EVs) were isolated from several human PDAC and normal pancreatic cell lines, using ultracentrifugation with filtration or size exclusion chromatography. We next treated normal pancreatic cell lines with cancer cell EVs (cEVs). Next generation sequencing was used to measure global gene expression changes after treatment. Validations were performed using qPCR and luciferase activity assays. Multi-omics characterization of EVs was accomplished using mass spectrometry based proteomics, metabolomics and lipidomics analysis. RESULTS/ANTICIPATED RESULTS: We found that normal cells upregulated a variety of stress response pathways in response to cEVs. Lipid synthesis was also severely downregulated in these cells. We further validated activation of the unfolded protein response (UPR) in normal cells treated with cEVs. Multi-omics characterization of cEVs identified several enriched proteins, lipids and metabolites which may play a role in the activation of the UPR. DISCUSSION/SIGNIFICANCE OF FINDINGS: Our results indicate that cEVs induce stress, and in particular the UPR, in normal pancreatic cells. Long-term UPR can impact a variety of cancer hallmarks. The UPR can mediate progression of pancreatic intraepithelial neoplasia (PanIN) to PDAC. Our results highlight a potential role for cEVs to alter the function of normal cells, aiding disease onset."} +{"text": "Few studies have explored the underlying pathways between environment cognition and mental health in older adults. We tested the mediation effects of physical activity and place attachment in the relationship between environmental cognition and mental health, based on a survey study of 1,553 older adults in Hong Kong using structural equation model. The results showed that significant relationship between negative environmental cognition on access to convenient stores, leisure facilities, clinics, community centers, religious places and lower mental health can be explained by lower daily average physical activity time. Place attachment can significantly mediate the positive effect of positive environmental cognition towards all types of services on mental health. Findings from this study have policy implication for urban planning and age-friendly community design"} +{"text": "Studies have demonstrated a link between sensory impairment and dementia risk, but little is known about the presence of beta-amyloid plaques in individuals with single and multisensory impairments. Sensory function and amyloid PET imaging were measured in 170 BLSA participants from 2012 to 2019. Log-binomial regression models were used to examine the prevalence ratios (PR) of amyloid positivity for individual sensory impairments and across categories of impairments. While crude associations indicate associations of vision impairment and impairments in all four senses with amyloid positivity, these associations were insignificant after adjusting for age, sex, race, and education. There were no other crude and adjusted associations. These results suggest sensory impairments may be related to dementia independent of AD pathology. Future studies with larger sample sizes are warranted."} +{"text": "Aging is the most prominent risk factor for cognitive decline, yet behavioral symptomology and underlying neurobiology can vary between individuals. Certain individuals exhibit significant age-related cognitive impairments, while others maintain intact cognitive functioning with only minimal decline. Recent developments in genomic, proteomic, and functional imaging approaches have provided insights into the molecular and cellular substrates of cognitive decline in age-related neuropathologies. Despite the emergence of novel tools, accurately and reliably predicting longitudinal cognitive trajectories and improving functional outcomes for the elderly remains a major challenge. One promising approach has been the use of exosomes, a subgroup of extracellular vesicles that regulate intercellular communication and are easily accessible compared to other approaches. In the current review, we highlight recent findings which illustrate how the analysis of exosomes can improve our understanding of the underlying neurobiological mechanisms that contribute to cognitive variation in aging. Specifically, we focus on exosome-mediated regulation of miRNAs, neuroinflammation, and aggregate-prone proteins. In addition, we discuss how exosomes might be used to enhance individual patient outcomes by serving as reliable biomarkers of cognitive decline and as nanocarriers to deliver therapeutic agents to the brain in neurodegenerative conditions. Age-related cognitive decline remains a prominent public health concern, with Alzheimer\u2019s Disease (AD) accounting for the majority of dementia diagnoses . DespiteAging is the most prominent risk factor for cognitive decline, but behavioral symptomology and underlying neurobiology can vary between individuals. Indeed, some individuals exhibit significant cognitive impairments in comparison to age-matched controls, while others maintain intact cognitive functioning or display only minimal decline . AlthougAPOE, APP, PSEN1 etc.) as well as rare genetic variants whose primary function is to translocate biological substrates between cells . Exosomethe cell . While tthe cell . Of notethe cell . Regardithe cell .in vitro supernatant vs. clinical plasma/serum), processing generally involves isolation and characterization followed by biological interpretation of exosomal quantity and contents utilizing complementary biochemical techniques . Renewedys etc.) . Given tys etc.) . The capys etc.) . It shouys etc.) ; howeverys etc.) .Attempts have been made to categorize exosomes according to their net advantages or disadvantages for CNS homeostasis, yet such a dichotomous distinction may be misleading. For instance, accumulating evidence illustrates exosomes facilitate symbiotic dynamism between neurons and oligodendrocytes, whereby activity dependent synaptic transmission triggers exosomal secretion from oligodendrocytes that contain essential myelin components ; subsequently, internalization of these exosomes amongst proximal neurons enhances cellular viability . ConversA large quantity of exosome research has focused on their capacity to incorporate and transport microRNAs (miRNAs). These short non-coding RNAs function as post-transcriptional regulators of gene expression by binding to complementary pairing sites on mRNA across various locations within a cell, including the nucleus, cytoplasm and subcellular compartments, such as stress granules . Such biin silico analysis linked these miRNAs to stress response and neurotrophic signaling pathways, findings suggested miRNA mediated regulation of these biological processes may increase risk for cognitive decline . While a large set of miRNAs showed significant positive correlations with age, another set maintained significant negative correlations with cognitive performance, including those miRNAs selectively expressed in the brain. In turn, functional annotation of miRNAs associated with poor performance revealed several biological pathways, including neurotrophin signaling, whose miRNA-mediated regulation may be important mediators of cognitive decline . Further decline . Interes decline .To gain more reliable insights into the neurobiological mechanisms of cognitive decline, additional investigations have interrogated the role of miRNAs from brain derived exosomes. After isolating neural exosomes from AD plasma samples, researchers recently identified a set of significantly upregulated and downregulated miRNAs which were predicted to regulate several homeostasis pathways in the CNS, including steroid biosynthesis and mTOR signaling . In anotin vivo delivery via exosomes was capable of ameliorating memory deficits in rodents otherwise induced by intracerebral application of A\u03b2 oligomers; furthermore, researchers inferred these benefits may be attributed to the increased synaptic phosphorylation of calmodulin-dependent kinase II whose inase II . Similarpathway) .To expand our understanding for the role of exosomal miRNAs in mediating the underlying mechanisms of cognitive decline, several lines of inquiry require elucidation, some of which are addressed below. For one, we currently lack a comprehensive understanding of the mechanisms within recipient cells that are modulated by exosomal miRNAs. Previous evidence suggests miRNAs released by exosomes remain functional in their recipient cells, capable of directly downregulating the expression of target transcripts, similar to endogenous effects in parent cells . Interesinflamm-aging, is a common feature of normal aging. Higher levels of neuroinflammation are a risk factor for age-related cognitive decline and the accumulation of neuropathological hallmarks , which ultimately resulted in the disruption of plasma membrane integrity as well as elevated neurotoxicity ; increase anti-inflammatory cytokines ]; in turn, this is associated with the mitigation of pathological peptides and the preservation memory capacities . Interestingly, such beneficial effects on cognition and neuroinflammation were comparable when exosomes were specifically targeted to the brain or administered systemically, highlighting the capacity of these EVs to exert their effects across the BBB , 2019. FTo enhance our understanding of exosomal-mediated neuroinflammation and associated risk for cognitive decline, several lines of evidence require further interrogation. Most prominently, further studies are needed to characterize the contents of exosomes which are responsible for alterations in CNS inflammation. Along with pathogens , a variety of molecules can induce immune responses in the brain, including reactive oxygen species (ROS), purine metabolites , calcium-binding proteins and lipotoxic ceramides . In addiEvidence indicating the association between aggregate-prone proteins and age-related cognitive decline is abundant, with increasing data suggesting their spread between CNS cells can be facilitated through exosomes . It shou1\u201342, pTau-181 and pTau-S396 in neuronal exosomes isolated from blood samples could differentiate AD patients from controls, as well as those patients with MCI who remained cognitively stable from those who illustrated progressively declining MMSE scores. Furthermore, intracerebral injection of such exosomes into healthy adult mice induced a significant accumulation of pTau in CA1 pyramidal neurons, compared to those exosomes from stable MCI participants , individuals who illustrated higher exosomal A\u03b21\u201342 levels maintain an 11.1- and 8.5-fold increased risk for significant cognitive deterioration at 2 and 3 year follow-up assessments, respectively, compared to MCI participants who remained cognitively stable via exosomes is capable of increasing translation of these proteins in recipient cells; such exploitation of host cell gene expression machinery could facilitate the accumulation of protein aggregates in otherwise healthy CNS cells may synergistically compromise CNS homeostasis . Such a NS cells . AnotherNS cells . FurtherPredicting individual cognitive trajectories in aging can be important for diagnostic purposes, and the adoption of exosomes as biomarkers may prove particularly useful in this respect. Clinical assessment alone can fail to discriminate those individuals who maintain cognitive resilience from those who develop MCI, as well as those MCI patients who go on to develop dementia . AlthougNumerous studies have used miRNAs isolated from blood-derived exosomes as biomarkers to classify individuals who are exhibiting late life cognitive dysfunction. Compared to blood samples, available evidence suggests measures of exosomal miRNAs obtained from CSF samples offer similar accuracies in distinguishing individuals with age-related cognitive impairment . HoweverAlthough there is no consensus on which individual miRNAs or groups of miRNAs from exosomes best predict cognitive impairment, some consistent evidence has emerged. For example, levels of miR-342-3p in plasma exosomes were significantly lower in AD participants compared to controls and correlated with poor cognitive performance among elderly, cognitively unimpaired individuals in a separate study . SimilarIn addition to cross-sectional investigations, several studies have used exosomes as biomarkers to predict longitudinal variation in cognitive decline. Using neurally derived exosomal concentrations of aggregate-prone peptides, researchers can predict individuals who progress from MCI to AD-dementia within 36 months , as well as cognitively sound individuals who develop dementia up to 10 years later . IncreasTo enhance the utilization of exosomes as reliable and valid biomarkers, several important limitations should be considered. When examining their associations with cognitive decline, researchers should take steps to differentiate the tissue-specific as well as the cell-specific origin of exosomes. Indeed, data indicate exosomes from the CNS contain significantly different molecular contents depending on an individual\u2019s cognitive capacities as well as their cellular origin , while such differences in content can subsequently induce distinct functional consequences for recipient cells . InvestiDespite limitations, the implementation of exosomes as biomarkers for age-related cognitive decline offers several advantages. As mentioned previously, exosomal sampling is more cost effective and less invasive than currently available biomarkers . Furthermore, exosomes derived from the CSF and blood offer similar accuracy for identifying individuals exhibiting cognitive decline, while neuroimaging and blood derived exosomes exhibit similar specificity for distinguishing dementia cases from healthy controls . Meanwhiin vitro . For inseatment) . Researceatment) . Similareatment) .Perhaps the greatest advantage offered by exosomes is their capacity to transverse the BBB due to their small size, endogenous biological properties, and low immunogenicity, which has otherwise been a major obstacle in treatment development for cognitive decline . This ha1\u201340, A\u03b21\u201342, plaques) can reliably improve performance on cognitive tasks and inhibit biological processes associated with cognitive impairment, including the dysregulated expression of pro- and anti-inflammatory cytokines (IL1-\u03b2 and IL-10), the activation of CNS immune cells and the deposition of A\u03b2 (A\u03b2plaques) . Additioplaques) . Togetheplaques) .1.While the clinical development of therapeutic interventions faces a variety of hurdles, the consideration of exosomes as a novel delivery vehicle for future nanotherapeutics may prove to enhance outcomes for those individuals vulnerable to age-related cognitive pathologies. In this context, the use of un-modified exosomes isolated from adipose mesenchymal stem cells is currently being investigated for AD-dementia in clinics (NCT04388982). Although the study is only exploring the safety and efficacy of exosome treatment in patients, data from secondary outcome measures that include AD biomarkers based in A\u03b2 plasma/CSF measures, PET scans, and neuropsychological tests, may further encourage the development of engineered vesicles for the treatment of age-related cognitive decline. The current composition proposes exosomes are uniquely suited to improve our mechanistic understanding as well as enhance patient outcomes for the growing public health challenge of age-related cognitive decline. We highlight how the analysis of exosomes can improve our understanding of varying mechanisms in age-related cognitive decline, including the role of miRNAs, neuroinflammation and aggregate-prone proteins . Despite these contributions, we suggest specific areas of inquiry that warrant further interrogation, including the elucidation mechanisms in recipient cells that are modulated by exosomal miRNAs, the characterization of exosomal contents that are responsible for alterations in neuroinflammation and the examination of other aggregate-prone peptides in exosomes that may synergistically increase risk for late life cognitive impairment. Moreover, we discuss how exosomes might be used to enhance outcomes for elderly individuals by serving as reliable biomarkers and therapeutic agents.To improve the reliability of studies going forward, consistent nomenclature coupled with protocol modifications that enhance the discrimination of EVs could be particularly effective. Due to similar biophysical properties , isolation techniques developed for exosomes can inadvertently lead to results that are derived from samples containing a variety of different EVs . SimilarSeveral additional limitations hinder the further application of exosomes discussed herein. Notably, it remains unknown whether concurrent variation in exosomes and cognitive capacities is reflective of a causal or reverse-causal association. In other words, it is difficult to determine if exosomal differentiation contributes to divergent cognitive trajectories, or if such differences are secondary to other biological processes that otherwise increase risk for cognitive deterioration in aging. A lack of data measuring time-dependent variation in the profiles of neuronal exosomes contributes to this lack of understanding, and potentially inhibits researchers from adequately controlling for the effects of aging. Although a limited set of investigations have employed longitudinal designs , future MD and VP conceived and designed the study. MD and AL conducted the literature search. MD, AL, and VP wrote the manuscript. TF and MW edited the final manuscript. All authors have read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "One of these involve a de novo heterozygous variant in an X-linked gene (ARHGEF9) in a female individual. We hypothesize the skewed X-inactivation may result in primarily expression of the pathogenic variant. We anticipate identifying additional candidate variants in coding regions of genes previously not associated with EMAS or pediatric epilepsies as well as in noncoding regions of the genome. DISCUSSION/SIGNIFICANCE OF IMPACT: Despite the genetic heterogeneity of EMAS, our initial analysis identified de novo pathogenic or likely pathogenic variants in 15% (6/40) of our cohort. As the cost continues to decline, short read genome sequencing represents a promising diagnostic tool for EMAS and other pediatric onset epilepsy syndromes. CONFLICT OF INTEREST DESCRIPTION: The authors have no conflicts of interest to disclose. SD has consulted for Upsher-Smith, Biomarin and Neurogene on an unrelated subject matter. GLC holds a research collaborative grant with Stoke therapeutics on unrelated subject matter.OBJECTIVES/GOALS: Epilepsy with myoclonic-atonic seizures (EMAS) is a childhood onset epilepsy disorder characterized by seizures with sudden loss of posture, or drop seizures. Our objective was to use short-read genome sequencing in 40 EMAS trios to better understand variants contributing to the development of EMAS. METHODS/STUDY POPULATION: Eligibility for the cohort included a potential diagnosis of EMAS by child neurology faculty at Children\u2019s Hospital Colorado. Exclusion criteria included lack of drop seizures upon chart review or structural abnormality on MRI. Some individuals had prior genetic testing and priority for genome sequencing was given to individuals without clear genetic diagnosis based on previous testing. We analyzed single nucleotide variants (SNVs), small insertions and deletions (INDELs), and larger structural variants (SVs) from trio genomes and determined those that were likely contributory based on standardized American College of Medical Genetics (ACMG) criteria. RESULTS/ANTICIPATED RESULTS: Our initial analysis focused on variants in coding regions of known epilepsy-associated genes. We identified pathogenic or likely pathogenic variants in 6 different individuals involving 6 unique genes. Of these, 5 are"} +{"text": "Teaching point: The probable mechanism of pseudoaneurysm formation related to metastatic neoplasm is a tumor embolus penetrating and destroying the vessel wall.Pulmonary artery pseudoaneurysm (PAP) related to metastatic neoplasm is rare. We describe a unique case of multiple PAPs secondary to metastatic uterine leiomyosarcoma and demonstrate the serial chest computed tomography to support the theory that the tumor begins as a tumor embolus, followed by infiltration and breakdown of the vessel wall, leading to aneurysmal dilatation and invading the perivascular tissue. Figure 1). Computed tomography pulmonary angiography (CTPA) was performed to rule out acute pulmonary thromboembolism and showed innumerable heterogeneously enhanced masses scattered in both lungs, surrounding segmental branches of pulmonary arteries. Multiple fusiform pulmonary artery pseudoaneurysms surrounded by soft tissue masses were also noted . A review of serial chest computed tomography (CT) revealed tumor emboli in the peripheral branches of pulmonary arteries , which finally developed into pseudoaneurysms with surrounding soft tissue masses .A 49-year-old female with known uterine leiomyosarcoma and lung metastasis with multiple tumor thrombi in pulmonary arteries was receiving palliative chemotherapy. Prior to her fourth chemotherapy session, the patient developed acute-onset dyspnea. Chest radiograph revealed a larger size of the multiple well-defined pulmonary masses scattered in both lungs; therefore, progressive pulmonary metastasis was suspected . The serial chest CT also showed gradual dilatation of peripheral branches of right pulmonary arteries ; this could be due to tumor growth and continued destruction of vessel walls.A similar mechanism of pathogenesis is thought to have occurred in this case. From the serial chest CT, the PAPs with surrounding soft tissue masses had previously shown intraluminal thrombus and dilated pulmonary artery, which resembled tumor thrombus (Abnormal dilatation of the pulmonary arteries and veins was also observed in the patient\u2019s CTPA with similar findings previously described in a reported case of metastatic uterine sarcoma . The onlIn conclusion, PAPs caused by metastatic neoplasm may firstly begin as tumor emboli, later progressing into pseudoaneurysms as we elucidated in the serial chest CTs and CTPA findings in this case."} +{"text": "Previous studies have shown that engaging in musical activities throughout the lifespan may buffer age-related decline in auditory and motor function, as well as in general cognitive function. MRI studies have demonstrated that individuals with musical training and experience exhibited greater grey matter volume and functional connectivity in extensive brain regions, especially in auditory and motor systems, compared to matched controls with no particular musical training or experience. Therefore, musical activity is a potential protective factor for brain health across lifespan. However, how lifespan musical experience shapes functional connectivity in older adults is still unknown. The current analysis investigated whether general musical experience (Goldsmith Music Sophistication Index) is associated with functional connectivity in older adults , focusing on seed regions in primary motor areas and primary auditory regions and their functional connectivity towards other areas throughout the whole brain. We found that older adults with more musical experience showed greater functional connectivity between anterior superior temporal gyrus and insula , and between posterior superior temporal gyrus and cerebellum . However, musical experience and music-related functional connectivity was not significantly correlated with general cognitive functions in our sample. Overall, our findings suggest that older adults with more musical experience might be more efficient in some aspects of auditory processing and auditory-motor skills, but this may not transfer towards domain-general cognitive tests. Our results support the notion that even non-professional engagement in musical experiences may afford benefits to the aging brain."} +{"text": "Dear Editor,we read with great interest the study by Vetrugno et al. where thWe propose a brief case to suggest taking Inferior Vena Cava Filter (IVCF) placement into account as a prevention tool for recurrent fat embolism (FE) in selected patients. A 16-years old male was involved into a motor-scooter accident reporting right femoral shaft fracture and left tibia shaft fracture. External fixation was provided as a bridge treatment to surgery. A few hours later he suddenly developed respiratory failure and coma and was admitted to our Intensive Care Unit (ICU) for supportive care. Cerebral Computed Tomography (CT) was normal; total body CT scan with contrast excluded pulmonary thromboembolism (PTE) and showed diffuse interstitial and alveolar edema; electroencephalogram identified status epilepticus for which antiepileptic drugs were started. Cerebral magnetic resonance imaging revealed a \u201cstarfield\u201d pattern compatible with the diagnosis of cerebral fat embolism. Patent foramen ovale was excluded. He was treated conservatively with mechanical ventilation with gradual improvement of his respiratory status, whereas neurologic impairment needed prolonged sedation. During his stay in the ICU he underwent sudden unexplained respiratory distress episodes, suggesting that embolization was possibly recurring. When stable, on day 7 of hospitalization, the patient was scheduled for surgical treatment. An IVCF was placed the day prior to surgery with the aim of stopping more fat emboli from spreading during intramedullary nailing of femur and tibia (Fig. Although IVCF insertion is discouraged for primary prevention of PTE in both orthopaedic surgery and majoDespite scarce evidence, we reckon that IVCF could improve prognosis in selected patients with FES, especially those presenting high risk factors, after accurately weighing risks and benefits. This measure may also help to earlier stabilize the patient so that definitive surgical treatment of the fractures is promptly provided.In conclusion, the study by Vetrugno et al. shed light on risk factors related to FES. However, further research is necessary to identify the best treatment and prevention strategies. Structured studies and prospective evaluation are needed to establish the effective benefits of IVC filter placement in similar cases."} +{"text": "Given the frequent overlap between biological plant invasion and ecological restoration efforts it is important to investigate their interactions to sustain desirable plant communities and modify long-term legacies both above- and below-ground. To address this relationship, we used natural reference, invaded and created vernal pools in the Central Valley of California to examine potential changes in direct and indirect plant effects on soils associated with biological invasion and active restoration ecosystem disturbances. Our results showed that through a shift in vegetation composition and changes in the plant community tissue chemistry, invasion by non-native plant species has the potential to transform plant inputs to soils in vernal pool systems. In particular, we found that while invasive plant litter decomposition was driven by seasonal and interannual variability, associated with changes in precipitation, the overall decomposition rates for invasive litter was drastically lower than native species. This shift has important implications for long-term alterations in plant-based inputs to soils in an amplifying feedback to nutrient cycling. Moreover, these results were independent of historic active restoration efforts. Despite the consistent shift in plant litter decomposition rates and community composition, we did not detect associated shifts in below-ground function associated with invasion by non-native plants. Instead, soil C:N ratios and microbial biomass did not differ between invaded and naturally occurring reference pools but were reduced in the manipulated created pools independent of invasion levels. Our results suggest that while there is an observed invasive amplifying feedback above-ground this trajectory is not represented below-ground, and restoration legacies dominated 10 years after practices were applied. Restoration practices that limit invasive plant feedbacks and account for soil legacy recovery, therefore offer the best solution for disturbed ephemeral ecosystems. Applications of restoration practices in wetland systems frequently must contend with plant invasion by non-targeted species, and these invading plants can undermine restoration goals through impacts both above- and below-ground. In this study we examined the impacts of invasive plants among natural and created vernal pools in California and found that invasion had a large effect on the plants present in the community and especially influenced plant litter decomposition rates. These invasive species caused changes can have implications for long-term alterations in plant-based inputs to soils; however, we did not detect associated shifts in below-ground function associated with invasion by non-native plants. The vegetation community has a key role in influencing soil properties through increased soil physical stabilization , alterinThe impact of changes in plant\u2013soil feedbacks associated with plant invasion on ecosystem processes is varied as well In restoration ecology, a common response to increased threat from invasive species is to implement management strategies to reduce the prevalence and spread of the incoming plant species ; howeverseeVernal pools are shallow ephemeral wetlands found in flat to low slope grasslands with poorly draining soil that facilitates ponding. They are predominately precipitation-fed and defined by abrupt edges delimited by locations of ponding . HistoriTo examine the consequences of invasion in the context of restoration through plant\u2013soil feedbacks on ecosystem processes, we examined a series of natural reference pools dominated by native species, naturally occurring pools invaded by non-native plants and created vernal pools dominated by non-native plants all located in a grassland site in central California. Among these contrasting restoration and invasion legacies we asked three primary questions: (i) How does invasion and restoration in vernal pool systems influence above-ground litter decomposition? (ii) How might shifts in above-ground community composition impact litter inputs to soils? (iii) Have shifts in above-ground community composition prompted changes in below-ground ecosystem function? Within this framework we hypothesize that ecosystem processes being driven by the above-ground presence of invasive plants will increase both carbon and nitrogen into the soil through altered plant litter and decomposition rates causing positive feedbacks, yet the plant material chemical ratios will favour increased nitrogen and thus increase microbial biomass in the invaded sites regardless of restoration status. Alternatively, active restoration, such as creating a disturbance of scraping the topsoil layer, has the potential to expose new soil layers lowering overall carbon and nitrogen content and increasing C:N ratios, pH and altering soil texture thereby producing lasting effects below-ground that could potentially overshadow the impacts of biotic invasion.seeseeWe conducted our experiment in the Central Valley of Solano County, CA, USA . This region experiences a strong seasonality, with most precipitation falling during the winter months between November and February, a mean annual temperature of 20.1 \u00b0C, and mean annual rainfall of 500 mm . In our study site located at the Travis Air Force Base, Solano County, CA, both naturally occurring \u2018reference\u2019 vernal pools, that have existed in a single grassland meadow for decades, as well as pools created for restoration purposes are present across the 15-ha study site. This meadow contains a network of pool basins and upland grassland vegetation representative of regional vernal pool and grassland systems see. To examseeOver time (approximately in years 2006\u201308), a subset of the naturally occurring pools in this landscape also became dominated by invasive non-native annual grasses (hereafter \u2018invasive\u2019) while other pools eluded invasion, maintaining native species see. Given tWe also assessed variation in the chemistry of plant tissues from 18 vernal pool species as well as upland dominant species common to the site and surrounding grassland communities, to examine community-scale changes in stoichiometry and tissue chemistry from individual plants distributed across the site. These metrics were selected to target potential plant inputs on nutrient and carbon cycling among the three different vernal pool types. Specifically, we measured plant tissue concentrations of nitrogen (N), cellulose, lignin and carbon (C), and calculated the associated ratios between these components carbon:nitrogen (C:N) and lignin:nitrogen (L:N). All plant species were collected during peak biomass in 2011 coinciding with species composition surveys as measurement of growing season standing pools of plant chemistry. Cellulose and lignin, which are important components in litter decomposition and photodegradation . Plant Cin situ above-ground plant decomposition rates through the utilization of litter bags. While using vegetation from peak biomass prevents the potential for nutrient translocation and resorption and consequently influences tissue chemistry, plant inputs in this system do not commonly undergo full senescence prior to mowing and deposition on the landscape, similar to N = 72 litter bags above field-collected invasive litter and N = 72 litter bags below). While 1 cm of litter has been shown to impact vernal pool vegetation structure ; thus, we used recently cut foliage, collected from both upland and pool areas across the larger research site, for key species during spring peak biomass the season prior to field implementation to determine tructure , placingTo examine environmental and biotic drivers of vernal pool litter decomposition we installed litter bags for two winter wet seasons during the period when ponding is expected and one summer dry season, as well as comparing species effects on decomposition for the first wet season. We installed \u2018wet season\u2019 litter bags in the fall prior to any substantial precipitation (2011\u201312 and 2012\u201313) and removed them in the spring after pools dried down and the annual vegetation had bolted. These field incubations for the winter wet decomposition studies lasted from September to April. We placed the \u2018dry season\u2019 litter bags (2013) in the field just after spring drydown and removed them before any substantial autumn rains (April\u2013September).Lolium multiflorum, an non-native invasive annual grass species that is ubiquitous in both created and invaded reference pools at the study site , only the invasive grass L. multiflorum was used in the sequential litter bag deployments (wet season 2012\u201313 and dry season 2013) due to low site-level abundance of the native grass P. californicus.For the first year of the study, we were able to include litter bags for both the dominant native and invasive species for the wet season 2011\u201312 sampling period to test for species-level non-native invasive versus native decomposition differences. The invasive species litter was composed of pure udy site . The natN = 72 at 125 cm3 each) were placed on dry ice immediately upon sampling. Samples were kept cold at 4 \u00b0C until processed, with the majority of soil analyses completed within 1 month of field collection .We collected bulk soil samples during peak flowering and peak above-ground plant biomass (April) in 2011 as the annual plants are dependent on soil processes while active during this brief period of highest productivity. Three soil samples were collected per pool, with one sample at each of three elevational plot locations within each pool . Soil samples (We obtained soil moisture through the gravimetric soil moisture method (% soil moisture = 100 * (fresh weight \u2212 dry weight)/dry weight). We measured soil pH using a 1:3 soil to water ratio on soil subsamples, where the pH subsample was measured three times to calculate a mean value for each elevational location within each pool. We used a subset of the pool bottom soils to obtain soil texture using a modified version of For all univariate data analysis, we used linear mixed-effects models in R version 4.0.0 in the lFor our multivariate analyses, we examined differences among pool types based on community-scale chemistry traits, including tissue C, N, lignin and cellulose. Community composition was used to scale chemistry traits based on abundance of dominant plant species present in vegetation plots during the same year as tissue sample collection for chemical analysis (2011). We created species traits matrices based on multiplying species counts by species-level chemical traits, thereby creating four independent species trait matrices scaled by species presence, in addition to the community composition matrix of species counts that included all species present in each plot. These trait and composition matrices were examined for differences among pool types using a permutational multivariate analysis of variance (perMANOVA) test based on a Bray\u2013Curtis dissimilarity matrix (R package Adonis). Multiple comparisons among pool types were conducted using the function pairwiseAdonis, which accounts for multiple comparisons and uses a Bonferroni correction . We applF2, 69 = 4.9, P < 0.01) with different compositions in reference pools from pools created through creation or affected by invasive species , N , lignin and cellulose , suggesting differences in the drivers of decomposition linked with invasion.Finally, decomposition differed substantially associated with species selection where the created pools (C:N-10.7) were significantly lower than the reference (C:N-11.7) and invaded pools (C:N-11.8). We found that soil microbial biomass C when compared across pool types also varied . The lowest average microbial biomass was found in the created pools and was significantly lower than the reference pools based on effect size.Many of the fundamental physical soil properties we measured did not differ among vernal pool types associated with invasion or creation ; howeverThe introduction of invasive species can alter the ecosystem through a variety of pathways creating amplifying feedbacks that exacerbate further ecosystem changes . To combseePhragmites australis, however, shows a similar decrease in decomposition rates driven by higher C:N ratios and higher concentrations of lignin ultimately promoting nutrient competition for native plant species (Invasive species can alter ecosystems through a wide variety of pathways, ranging from shifts in community interactions to changes in nutrient cycling and physical ecosystem properties and this species .While we observed that invasive non-native decomposition was slower than native species in our study, an alternate positive feedback to soil nutrients associated with invasive effect on the ecosystem has been noted in this vernal pool system . Here thLong-term averages of litter decomposition are driven largely by climate and microbial biomass and the Restoration ecology focused on evaluating restoration success in depressional wetlands more generally has suggested that the nutrient composition of vegetation is an important metric in evaluating long-term restoration success .Differences in plant community composition, tissue chemistry and decomposition rates can have a cascade of effects on the below-ground, such as speed of nutrient cycling, microbial community composition (While a direct effect of a restoration legacy was observed below-ground in soil C:N and generally in extracted microbial biomass C, not all soil metrics tested demonstrated this artefact of restoration nor demonstrated a change solely due to invasion, in contrast to studies comparing reference and restored pools with greater differences in vegetation community structure (i.e. woody plants; Similar interacting processes likely influenced our findings for differences in soil pH among pool types that were not connected to either invasion or restoration independently. Invasive plants have been shown to alter the soil pH, both increasing and decreasing depending on the invasion type and magnitude , and we In summary, despite strong changes in above-ground plant contributions the soil metrics directly linked to plant inputs did not show the same response to the plant invasion. Instead, organic soil components exhibited a legacy of vernal pool active restoration from the decade prior. This study demonstrates that while above-ground vegetation may vary strongly in its abundance and composition and produce conditions that facilitate further invasion, this signal does not necessarily translate below-ground even after multiple years of invasion. The success of a restoration project is often based solely on the above-ground vegetation, and in this regard, further restoration efforts to minimize invasive species presence is required for our vernal pools. However, this study illustrates an opportunity to limit long-term effects of altered above-ground plant\u2013soil feedbacks on below-ground processes should additional restoration occur. The importance of this time lag in establishing altered community feedbacks within the ecosystem provides a window of opportunity for adaptive management practices aimed at ecosystem recovery.The following additional information is available in the online version of this article\u2014plab042_suppl_Supplementary_Figure_S1Click here for additional data file."} +{"text": "ABSTRACT IMPACT: Identifying factors associated with opioid overdoses will enable better resource allocation in communities most impacted by the overdose epidemic. OBJECTIVES/GOALS: Opioid overdoses often occur in hotspots identified by geographic and temporal trends. This study uses principles of community engaged research to identify neighborhood and community-level factors associated with opioid overdose within overdose hotspots which can be targets for novel intervention design. METHODS/STUDY POPULATION: We conducted an environmental scan in three overdose hotspots\u2019\u2018 two in an urban center and one in a small city\u2019\u2018 identified by the Rhode Island Department of Health as having the highest opioid overdose burden in Rhode Island. We engaged hotspot community stakeholders to identify neighborhood factors to map within each hotspot. Locations of addiction treatment, public transportation, harm reduction programs, public facilities , first responders, and social services agencies were converted to latitude and longitude and mapped in ArcGIS. Using Esri Service Areas, we will evaluate the service areas of stationary services. We will overlay overdose events and use logistic regression identify neighborhood factors associated with overdose by comparing hotspot and non-hotspot neighborhoods. RESULTS/ANTICIPATED RESULTS: We anticipate that there will be differing neighborhood characteristics associated with overdose events in the densely populated urban area and those in the smaller city. The urban area hotspots will have overlapping social services, addiction treatment, and transportation service areas, while the small city will have fewer community resources without overlapping service areas and reduced public transportation access. We anticipate that overdoses will occur during times of the day when services are not available. Overall, overdose hotspots will be associated with increased census block level unemployment, homelessness, vacant housing, and low food security. DISCUSSION/SIGNIFICANCE OF FINDINGS: Identifying factors associated with opioid overdoses will enable better resource allocation in communities most impacted by the overdose epidemic. Study results will be used for novel intervention design to prevent opioid overdose deaths in communities with high burden of opioid overdose."} +{"text": "In retrospect, the yet to be resolved refractory nature of adult cardiomyocytes with respect to cell cycle progression and cell division necessitates the need for an innovative approach to promote adult cardiomyogenesis.Cardiomyocyte loss followed by scar formation is the leading cause of heart failure upon pathological injury, chronic or acute stress, and aging. Despite decades of investigation, therapeutic development to enhance cardiomyocyte turnover and restore the structural and functional integrity of the heart has been limited due in part to the inherent lack of proliferative capacity within adult cardiomyocytes. A therapeutic solution to the conundrum of post-mitotic cardiomyocytes has long been sought after, leading to a range of pre-clinical interventional approaches including (but not limited to) overexpression of cell cycle proteins, induction of systemic hypoxemia, as well as transcriptional and hormonal regulation. The consensus outcome reveals dedifferentiation rather than proliferation potential of adult mammalian cardiomyocytes based upon phenotypic changes such as (1) loss of myofibrillar structure; (2) expression of stem cell markers; and (3) exhibition of immature metabolic functions. In an effort to illustrate the myocardial therapeutic significance of PR, Chen et al., demonstrated that short-term myocardial introduction of OSKM reprograms cardiomyocytes to a fetal phenotype evidenced by (1) transcriptome resembling neonatal and embryonic developmental stages; (2) expression of \u03b1-SMA; and (3) morphological rearrangement and cell cycle re-entry in vitro. Regardless of the time of induction, in vivo OSKM expression promoted structural recovery of the heart following myocardial infarction; however, functional results varied among induction regimens.Cellular reprogramming via the four pluripotency factors, OCT4, SOX2, KLF4, and MYC (OSKM), is a promising approach to epigenetically remodel somatic cells of various lineages into an induced pluripotent stem cell state. Partial reprogramming (PR) via the transient introduction of OSKM reverses age-associated phenotypes and promotes the regenerative potential of adult tissues such as skeletal muscle. From cardiomyocyte-specific overexpression of cyclins to transdifferentiation of fibroblasts into myocytes, to differentiating induced pluripotent stem cells (iPSCs) into cardiomyocytes, time and again, the results indicate that such approaches are unlikely to translate directly into clinically relevant therapies. And yet, each new insight into cardiomyocyte biology increases the knowledge base necessary to design better informed regenerative therapies. The current findings by Chen et al. reveal a threshold of cardiomyocyte dedifferentiation in adult mice, after which cardiac function declines and cardiac tumors form, in contrast to lower vertebrates and neonatal mammals, which tolerate greater cardiac plasticity.Driving cell cycle progression to achieve true proliferation in adult mammalian cardiomyocytes represents a longstanding goal in the ongoing effort to repair damaged myocardiumet al. highlight the challenge of associating clinically relevant cardiac repair with endogenous cardiomyocyte cell cycle progression. All of the partial reprogramming regimens result in reduced scar size in infarcted hearts, and post-injury therapeutic treatment yields the most 5-Ethynyl-2\u2032-deoxyuridine (EdU) + cardiomyocytes. However, the best functional outcomes are observed in the pre-injury treatment group, whereas no functional improvement is observed in the post-injury therapeutic treatment cohort. Salvage, cell cycle progression, and function appear disconnected in this repair model.Creating pre-clinical models of cardiac repair that reflect clinically therapeutic scenarios remains an ongoing challenge in cardiac research. Differentiation of cardiac progenitor cells, iPSCs, or reprogrammed cardiomyocytes into functional, mature myocytes remains a major roadblock for translational applications. Experimental treatments that coincide with myocardial injury tend to represent cardioprotective salvage models rather than therapies that replace damaged myocardium post-injury. Functional outcomes may be improved; however, cardiac patients are unlikely to receive regenerative treatment at the time of a cardiac event. Interestingly, the infarction injury results presented by Chen . Reagents that track cell cycle in real-time, such as various transgenic fluorescence ubiquitination cell cycle indicator reporter animal models, can provide dynamic readouts of cell cycle status in vitro and in vivo. Perhaps the most convincing data demonstrating cardiomyocyte proliferation in the current publication are live imaging videos tracking tagged cells going through karyo and cytokinesis. Of course, the next crucial step in the regenerative process is to convert these dedifferentiated reprogrammed proliferating cardiomyocytes into functional adult cells that contribute to cardiac function. Whether comparable division and re-differentiation occur in damaged reprogrammed hearts remains to be demonstrated.Identifying true cardiomyocyte replication represents another point of contention among researchers. Mature cardiomyocytes are generally post-mitotic; however, their nuclei can undergo changes that appear to reflect proliferation, such as DNA synthesis in response to stress, binucleation or karyokinesis without cytokinesis, or increases in ploidy during aging. Measures of cell cycle re-entry such as EdU, phospho histone H3, even aurora B kinase, are insufficient to definitively prove full cardiomyocyte cellular division\u20138. Reprogrammed cardiomyocytes in an adult heart are not equivalent to developing cardiomyocytes maturing in concert with associated systemic postnatal hormonal changes. Studies have shown that the paracrine, metabolic and structural milieu of an adult mammalian heart favor cellular hypertrophy or senescence over cardiomyocyte proliferation. The myocardial environment in most heart disease patients is probably even less conducive to proliferation and repair, underscoring the challenge of transforming reprogrammed cells into new functional new myocytes. Nonetheless, while the gap between basic research findings and clinically relevant cardiac therapies remains unbridged, cumulative research findings are essential to successful development of those therapies.Systemic context plays a crucial role in myocardial regenerative potential. Metabolic and paracrine factors, and the state of the extracellular matrix all have an enormous impact on cardiomyocyte cell cycle activityet al., represent substantial translational hurdles. How can cardiomyocyte reprogramming be administered safely and titrated to avoid the deleterious effects observed in over-reprogrammed hearts? Would this be possible given the enormous variability among human cardiac patients? Perhaps the real takeaway lesson from this and similar studies investigating cardiomyocyte proliferation lies in understanding what makes an adult cardiomyocyte healthy and capable of cell cycle re-entry to the point of replication. From a preventative medicine point of view, a more realistic approach may be to identify lifestyles and habits that support the more youthful and proliferative cardiomyocyte phenotypes identified in partial reprogramming models. Transcriptomic and proteomic profiling studies comparing youthful and diseased or senescent cardiac phenotypes may provide therapeutically relevant targets for suppressing senescence-associated secretory phenotype, inflammation, or oxidative stress in a time and a dose-dependent way to encourage myocardial healing. Evaluating signaling pathways associated with youthful or proliferative phenotypes could also reveal safer, more reliable targets. Ultimately, combinatorial therapies incorporating multiple restorative strategies probably hold the most promise for improving cardiac patient outcomes.Many questions about cardiomyocyte proliferation remain unanswered from the basic and clinical perspectives, perhaps the most important being: can adult human cardiomyocytes be coaxed to divide in response to injury on a therapeutically relevant level, and is it possible to quantify this proliferation in recipient human patients? Experiments performed in young adult mice in no way reflect the systemic profile of human heart patients, many of whom are elderly or have underlying comorbidities such as hypertension, diabetes, or other metabolic dysregulation. Timing and dosage of a hypothetical reprogramming therapy, in light of the results presented by Chen In summary, the holy grail of physically mending damaged human hearts remains elusive. Considerable time, resources, and effort have gone toward understanding myocardial injury, repair, aging, and possible regeneration in vertebrate animal models. Approaches including cell therapy, tissue engineering, and driving adult mammalian cardiomyocytes to proliferate in response to damage as documented in neonatal hearts, or adult fish and reptile systems, have yielded valuable new insights into cardiac biology. Moreover, although a marketable therapy to repair pathologically challenged human hearts has not yet materialized, this goal has inspired incredible scientific creativity and a deeper understanding of cardiac cellular and molecular biology. Put another way, research findings cannot be valued solely on their immediate translational relevance, or unduly influenced by increasing pressure to produce therapies and cures. However, clinically driven studies that build on collective basic and translational research findings bring cardiac medicine closer to curing or even preventing heart disease altogether."} +{"text": "The COVID-19 pandemic posed new challenges for caregivers. This study examines the prevalence of pandemic care challenges and their associations with caregiver mental health and interpersonal well-being in a nationally representative sample of 311 caregivers who participated in the June 2020 National Poll on Healthy Aging. We consider seven care challenges and supports as key predictors of caregiver mental health and interpersonal well-being in bivariate tests and ordinary least squares regressions. Each care challenge/support was endorsed by between 13-23% of caregivers. Difficulty getting needed medical care was the most predictive challenge associated with increased caregiver stress, depressive symptoms, and worsened interpersonal well-being. All care challenges predicted an increase in caregiver stress. Effective caregiver tools and supports must consider changing policies and care needs, especially during a pandemic."} +{"text": "Self-reported cognitive difficulties are common in older adults and may be an early indicator of future cognitive decline or dementia. In past retrospective reports, cognitive difficulties have been linked with differences in social engagement or social relationships among older adults. However, little is known about how self-reported cognitive difficulties in daily life, such as memory lapses, relate to older adults\u2019 daily social experiences. This study examined how self-reported cognitive difficulties were related to older adults\u2019 daily social interactions and loneliness. Data were drawn from 312 community-dwelling older adults (aged 70 to 90 years) who reported their social interactions and loneliness throughout the day (five times) as well as cognitive difficulties at the end of each day for 14 days. Multilevel models revealed that participants reported fewer memory lapses on days when they reported more frequent interactions with family members (p=.041). Higher levels of disruptions to daily activities caused by cognitive difficulties, in turn, predicted higher levels of loneliness the next day (p=.006), but not changes in social interactions the next day. At the between-person level, more memory lapses in daily life were associated with less frequent social interactions with friends, but more frequent unpleasant social interactions and higher levels of loneliness on average. These results suggest that older adults\u2019 self-reported cognitive difficulties were dynamically associated with their social interactions and loneliness at the daily level and played an important role in older adults\u2019 social life and well-being."} +{"text": "ABSTRACT IMPACT: This study provides insights on how to replicate a successful initiative for preventing unintended teen pregnancy. OBJECTIVES/GOALS: Reducing unintended teen pregnancy is a national health priority, and a recommended strategy is to increase awareness and availability of long-acting reversible contraception (LARC). The Rochester LARC Initiative did this, and teen LARC use rose from 4% to 24%. The goal of this study is to determine key elements for replicating the intervention. METHODS/STUDY POPULATION: Our initiative used an innovative approach we call \u2018community detailing\u2019 to deliver education about LARC to adults working with teens. We analyzed the intervention goals, design components, implementation strategies, and public health outcomes. Our analysis was informed by the CDC model for Promoting Science-Based Approaches to Teen Pregnancy Prevention Using Getting to Outcomes (PSBA-GTO), Diffusion of Innovations, and RE-AIM framework for implementation outcomes. We compared our model with characteristics of LARC-promotion efforts, as well as successful health education campaigns. We tabulated the components of our intervention across theoretical domains, aiming to determine essential elements of effective design, adaptation, and dissemination & implementation. RESULTS/ANTICIPATED RESULTS: The initiative incorporated multiple components common to successful health education programs: measurable behavior-change outcomes; formative research before roll-out; tailored communications for different audiences; speakers who were credible, knowledgeable and skilled communicators; content that was new to recipients and essential for decreasing barriers to desired behaviors. It included elements of successful LARC promotion/teen pregnancy prevention programs, such as organizing information by effectiveness of methods and using youth-empowering messaging. It differed from other successful programs by offering discussions to adults who work with teens in both medical and community settings. This analysis also highlights unintended positive ripple effects. DISCUSSION/SIGNIFICANCE OF FINDINGS: These results establish how community detailing is effective for disseminating actionable information about the safety, efficacy and availability of LARC. These insights could inform other prevention initiatives. An anticipated practical product of this study will be a user-friendly manual for replicating the LARC Initiative in other locations."} +{"text": "Drug-induced myocarditis is a rare, but underrecognized complication of clozapine therapy for schizophrenia. We present a case of clozapine-induced myocarditis with recovery of cardiac function after drug cessation and summarize the literature to highlight the variable presentation of this condition. A 29-year-old man presented from a psychiatric hospital with 2 days of sudden onset, progressive chest pain, and troponin elevation after recently initiating clozapine therapy.The patient had a history of alcohol abuse and treatment-resistant schizoaffective disorder with multiple suicide attempts. After intentional ingestion of acetaminophen and lithium, he was involuntarily hospitalized for intensive treatment, including initiation of clozapine therapy.The differential diagnosis included acute coronary syndrome, myopericarditis from viral or drug-induced etiology, pulmonary embolism, and pneumonia. The patient first noted substernal chest pain worse with deep inspiration 8 days after clozapine initiation. Symptoms worsened over the following two days. Electrocardiogram (EKG) demonstrated ST elevations most prominent in V2-V3 . Serum lChest pain persisted, and he was transferred to the cardiology service. Cardiovascular exam was notable for tachycardia without murmurs or rubs. He had no peripheral edema or elevated jugular venous pressure. Lungs were clear. Cardiac magnetic resonance (CMR) imaging showed global hypokinesis with a left ventricular (LV) ejection fraction (EF) of 45% Figure and subtMyocarditis was suspected based on a clinical syndrome of chest pain and elevated troponin in the setting of a known causative medication and low pretest probability for coronary artery disease. CMR confirmed the diagnosis by the updated Lake Louise Criteria . This caClozapine-induced myocarditis (CIM) is a drug-related myocarditis with variable presentation ranging from mild symptoms to fulminant myocarditis. The mechanism of toxicity to cardiomyocytes is unclear. In animal models, clozapine induces serum catecholamine excess that causes cardiac inflammation and myocyte apoptosis through tumor necrosis factor-alpha-mediated pathways . At autoThe true incidence of CIM is difficult to ascertain due to underdiagnosis of subclinical or mild presentations and may be underrecognized; thus, a high index of suspicion is required . ShortneCardiovascular complications resulting from antipsychotic medications are not limited to myocarditis. Patients with schizophrenia treated with antipsychotics are at higher risk of sudden unexplained death than the general population . CardiovWhen CIM is suspected, cardiology consultation should be obtained with inpatient monitoring for arrhythmia and heart failure. Aside from drug withdrawal, no specific treatment for CIM has been identified. Patients with LV systolic dysfunction warrant guideline-directed medical therapy (GDMT) in the absence of contraindications. Close cardiology follow-up and repeat echocardiography after clozapine cessation and initiation of GDMT should be individualized.Intriguingly, published literature reports cases of clozapine reinitiation in patients with severe schizophrenia refractory to alternate antipsychotics despite prior drug withdrawal due to CIM. Rechallenge with clozapine can be successfully achieved with intensive monitoring with swift discontinuation of the drug for any sign of myocardial injury . In one The patient was not reinitiated on clozapine and instead was treated with lithium and electroconvulsive therapy. Repeat echocardiography 2 weeks later demonstrated recovery of LV function Figure .Patients with schizoaffective disorders treated with antipsychotics are at higher risk for sudden unexplained death. CIM is a rare but likely an underrecognized complication of clozapine therapy and a mechanism of sudden cardiac death. Treating psychiatrists and consulting cardiologists must maintain high index of suspicion for CIM with withdrawal of clozapine in the acute setting to reduce poor outcomes. In the long term, care must be patient-centered with consideration of underlying psychiatric and cardiovascular disease severity.To recognize the clinical presentation of drug-induced myocarditis, associated with the use of clozapineTo illustrate the role of noninvasive testing in diagnosis of clozapine-induced myocarditisTo understand the importance of a multidisciplinary approach involving both psychiatry and cardiology specialists in managing clozapine-induced myocarditis"} +{"text": "Visual representation of the community in materialsPositive FramingStatistics and graphs should be minimalAppropriate reading level and minimizing jargonABSTRACT IMPACT: Advanced spatial analysis techniques are used to target a community education intervention for Immigrant and African American women to increase breast cancer screening. OBJECTIVES/GOALS: We are addressing breast cancer screening disparities through the development of the COmmuNity kNowlEdge to aCtion Toolkit (CONNECT). CONNECT implements a mixed-methods approach using GIScience, community education, and social media to mitigate the impact of breast cancer screening disparities for Immigrant African and African American women. METHODS/STUDY POPULATION: We used advanced spatial analysis techniques, Spatially Adaptive Filters (SAF) to reveal mammography screening rates below the state level. SAF create screening maps of This new information allows lay health educators to identify and engage their communities in the Breast Cancer Champions program. We transformed and curated existing cancer educational material into culturally relevant educational training for lay health educators. Lay health educators participate in educational trainings and receive stipends for conducting formal and informal breast cancer education and screening events. RESULTS/ANTICIPATED RESULTS: We have identified four principles for designing culturally relevant education materials.Due to COVID-19, our breast cancer champions are engaging with their community in socially responsible ways . Our social media campaign, which began in October has already attracted over 1000 followers. DISCUSSION/SIGNIFICANCE OF FINDINGS: Despite the disruption of COVID-19, our project continues reduce breast cancer screening disparities. We have developed and created culturally appropriate materials and are currently training Champions. By incorporating an online presence into our community outreach, we are increasing the ways we connect with our community."} +{"text": "The local vascular inflammation is not only caused by SARS-CoV-2 infection but also accelerated by gut dysbiosis-caused systemic inflammation and decreased anti-inflammatory mechanisms.On the other hand, brain pathological changes could further increase gut dysbiosis. It has been well demonstrated that the gut-brain axis has bidirectional effects.An appreciation of the role of intestinal dysbiosis in the cytokine storm in COVID-19 neurological comorbidity has therapeutic implications. Modulation of gut dysbiosis to improve gut microbiota could be achieved by various approaches such as probiotics, prebiotics, faecal microbiome transplantation and dietary modification.Data sharing is not applicable to this article as no new data were created or analysed.The authors report no competing interests."} +{"text": "Bladder cancer is a heterogeneous disease that is composed of epithelia with varying transcriptional, mutational and lineage signatures. The epithelia of bladder tumors can also undergo pronounced changes in transcriptional and phenotypical qualities in response to progression, treatment related stresses and cues from the tumor microenvironment (TME). We hypothesize that changes in epithelial tumor heterogeneity (EpTH) occur due to the evolving content of epithelial subpopulations through both Darwinian and Lamarckian-like natural selection processes. We further conjecture that lineage-defined subpopulations can change through nongenomic and genomic cellular mechanisms that include cellular plasticity and acquired driver mutations, respectively. We propose that such processes are dynamic and contribute towards clinical treatment challenges including progression to drug resistance. In this article, we assess mechanisms that may support dynamic tumor heterogeneity with the overall goal of emphasizing the application of these concepts to the clinical setting.Acquired therapeutic resistance remains a major challenge in cancer management and associates with poor oncological outcomes in most solid tumor types. A major contributor is tumor heterogeneity (TH) which can be influenced by the stromal; immune and epithelial tumor compartments. We hypothesize that heterogeneity in tumor epithelial subpopulations\u2014whether de novo or newly acquired\u2014closely regulate the clinical course of bladder cancer. Changes in these subpopulations impact the tumor microenvironment including the extent of immune cell infiltration and response to immunotherapeutics. Mechanisms driving epithelial tumor heterogeneity (EpTH) can be broadly categorized as mutational and non-mutational. Mechanisms regulating lineage plasticity; acquired cellular mutations and changes in lineage-defined subpopulations regulate stress responses to clinical therapies. If tumor heterogeneity is a dynamic process; an increased understanding of how EpTH is regulated is critical in order for clinical therapies to be more sustained and durable. In this review and analysis, we assess the importance and regulatory mechanisms governing EpTH in bladder cancer and the impact on treatment response. Tumor heterogeneity (TH) has been referred to as the \u201cRosetta Stone\u201d of cancer progression and therapeutic response ,2. The iWithin a single tumor, TH encompass both the tumor microenvironment, including stromal and immune cells, as well as the cell autonomous epithelial compartment. TH is also regulated by acellular components such as stromal and connective tissues. Together, such elements form a plastic tumor milieu which can change dynamically during tumor progression and in response to therapeutic challenges.When considered on a patient population scale, TH is typically extensive and contributes towards the complexity of understanding for when and how often to administer a drug for optimal clinical response. In some instances, drugs that are considered beneficial on a population scale can induce adverse disease progression on certain tumor types, thus highlighting the need for assigning tumor-specific treatments.While bladder cancer presents as a mutational disease, genetic changes continue to occur in pretreated tumor progression and in response to therapy. Thus, the mutational landscape not only has implications for immune cell infiltration but contributes towards the pool of cells capable of clonal expansion, treatment resistant disease and metastasis. Growing evidence supports that lineage transdifferentiation is an important mechanism for cancer cells to adapt to the stress of therapy ,10 incluRecently, single-cell technologies have greatly leveraged our ability to understand the remarkable transcriptional diversity present in bladder cancers. Such technologies provide opportunities to understand the evolutionary changes in tumor cell composition commencing from pretreated primary tumors through to post-treatment, resistant metastasis. We will address the importance of single-cell technologies to increase our understanding of EpTH both with respect to bulk changes in subpopulations as well as single-cell changes in cellular identity (lineage transformation). Improved single-cell techniques will provide the sensitivity and spatial information needed to address critical questions of whether EpTH can be experimentally manipulated to enhance treatment and reduce lethal phenotypes including bladder cancers with neuroendocrine-like (NE-like) signatures. While such processes have proven to be reversible under certain experimental conditions ,13, the As the importance of TH and relevance for tumor progression encompass a large body of information, our discussion and analysis will focus on the tumor epithelial compartment.Clinical bladder cancer typically presents with substantial pathological heterogeneity and a high mutational burden . MultiplIn an effort to reconcile previously published MIBC classification schemes, large-scale studies conducted by Kamoun et al. analysed 1750 transcriptomic profiles from 18 datasets and have identified a consensus molecular classification of MIBC that includes six molecular subtypes: luminal papillary (LumP), luminal nonspecified (LumNS), luminal unstable (LumU), stroma-rich, basal/squamous (BaSq) and NE-like .In this instance, consensus classifiers were associated with distinct mRNA signatures which strongly associated with clinical outcome and overall survival . The utiStrikingly, only approximately 30% to 40% of residual bladder tumors following NAC or immunotherapy were of the same lineage subtype as the pretreatment tumors ,24. In aMolecular analysis using bulk RNA seq data has increased our understanding of TH and the potential clinical utility in selecting patients for different systemic treatment . HoweverThe use of single transcriptomic technologies such as single-cell RNA sequencing (scRNA-seq), single-cell DNA seq (scDNA-seq) and spatial sequencing (sp-seq) in research will prove superior for defining clinically viable information, over bulk molecular analysis, by allowing the ability to study TH and to characterize rare cell epithelial subpopulations ,29. HoweIntratumoral molecular and genetic heterogeneity have been associated with poor prognosis in multiple cancers including lung cancer, head and neck cancers and chronic lymphocytic leukemia ,30,31,32Together, these findings demonstrate significant intratumoral heterogeneity in bladder cancer and suggest that categorical molecular subtyping may not be adequate for optimal therapeutic outcomes.Mechanisms promoting Intra-EpTH in pretreated bladder tumors can be broadly divided into mutational and nonmutational. Mutational mechanisms induce heterogeneity in genomic DNA which in turn can translate to phenotypic heterogeneity. Nonmutational mechanisms of heterogeneity induce phenotypic variability without any genetic modifications . The prePretreated urothelial carcinoma is characterized by a high mutational burden that contributes to TH. With a median of 8.1 mutations per mega base pair, bladder cancer ranked 11th in terms of mutational burden when compared with 166 other cancer types . PhylogeMultiple genetic driver mutations are associated with bladder cancer carcinogenesis and progression . Cells wDrivers of bladder cancers with high mutational burden remain poorly understood. Although DNA replication occurs with high fidelity, occasional transcriptional errors still occur even in the absence of mutagens, thereby introducing de novo genetic mutations. This stochastic mutational process is involved in tumorigenesis and disease progression . ExposurThe apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) can induce tumoral genetic heterogeneity leading to an APOBEC mutational signature present in urothelial cancers and other solid tumors . Using wThe genetic heterogeneity in tumor epithelial plays a significant role in disease progression and development of drug resistance largely due to either de novo or acquired therapy-resistant clones . High inAlthough mutational burden has been associated with response to immune checkpoint inhibitors (ICI), recent evidence suggests that tumors with high Intra-TH have decreased response to ICI. Using a preclinical melanoma mouse model, investigators evaluated the association of total mutational burden and intra-TH with respect to antitumor immunity . They shAs opposed to mutational mechanisms where variability in cellular DNA is the source of heterogeneity, nonmutational drivers of tumoral heterogeneity do not involve modification in the cellular genetic code. Embryological development is an example of nonmutational process of changing heterogeneity where cells with the same DNA code differentiate into multiple cellular phenotypes. Different from genetic heterogeneity, tumor cells contributing toward nonmutational heterogeneity can be highly plastic and have important contributions towards tumor development ,58.At a baseline or pretreatment setting, fluctuating cellular transcription constitutes a source of cellular heterogeneity. Upon the exposure to drugs, cells meeting a threshold of resistance-related gene expression will survive and be selected for ,60. For Cellular plasticity represents the capacity of cells to adopt different phenotypes and switch between different lineage identities . TogetheIn bladder cancer, cellular plasticity has been observed by Yang et al. using single-cell sequencing to demonstrate that nonstem cells, in urothelial cancers, can acquire stem-like properties and develop self-renewal capabilities . CellulaEMT is a tightly regulated process involved in embryonal development and in tissue healing and represents the most studied example of cellular plasticity . EMT shoThe formation of epithelia with neuroendocrine qualities constitutes another lineage occurring frequently during therapeutic stress Figure B. For exTaken together, this suggests that plasticity is important in the evolution of bladder cancer. We conjuncture that plasticity represents a clinically important resistance mechanism as cells switch from a treatment-sensitive lineage to treatment-resistant lineages in order to accommodate the stress of therapy.While mounting evidence supports that lineage plasticity is a bona fide mechanism for cancer cells to adapt to therapy, less is understood as to whether plasticity can be reversed in a controlled manner. Due to its important role in tumor progression and aggressiveness, EMT represents an attractive target for the development of targeted therapies. Multiple pathways regulating EMT are being investigated as potential treatment targets with clinical trials investigating drugs capable of targeting EMT being conducted in solid tumors such as breast cancer, lung cancer and colorectal cancer ,97. InteIn response to drug exposure, a subpopulation of cancer cells termed drug-tolerant persisters (DTPs) will acquire a poorly differentiated phenotype and enter a dormant, slow-cycling and drug tolerant state Figure C. DTPs cAlthough tolerant cells may pre-exist in the tumor, it has been shown that some cells become DTPs through EMT and phenotype plasticity following drug exposure ,102,103.In basal-like breast cancer cell lines, exposure to MEK and PI3K/mTOR inhibitor resulted in development of DTPs through epithelial plasticity driven by therapeutic challenge . In EGFRTumor heterogeneity is a dynamic process that serves an important role in tumor progression and response to therapies. Changes in TH through clinical evolution are likely a consequence of both changing proportions of lineage defined subpopulations as well as processes of cellular plasticity. Understanding how clinically approved therapies regulate these processes on a temporal scale will help define therapies. Adaptive therapy is an example of a novel treatment approach that incorporates these concepts and aims to maintain a population of treatment-sensitive cells to prevent the expansion of treatment-resistant cell populations B.Using mouse models of breast cancer, Enriquez-Navas et al. showed that low doses of paclitaxel are effective in controlling tumor volume and preventing unopposed proliferation of treatment-resistant cell populations . AdaptivA better understanding of cancer cell heterogeneity and plasticity will allow clinicians to consider tumor heterogeneity in a dynamic and adaptive fashion, rather than in a static manner in the elaboration of new treatment approach.Tumor heterogeneity and cellular plasticity are hypothesized to play important roles in the evolution and management of bladder cancer. The limitations of homogenous and static classifications of urothelial cancer need to be acknowledged. The heterogeneous and dynamic nature of this disease should be emphasized paving the way for further research on specific mechanisms regulating the dynamics of tumor subpopulations and cellular plasticity."} +{"text": "Dislocation of inferior vena cava filter (IVCF) is a rare complication with potential IVC perforation and other life-threatening risks requiring early diagnosis and in-time retrieval. Most of dislocation IVCF in the past have been shelved or removed by open surgery. It is very difficult to retrieve the filters by interventional technology.Here we report a 49-year-old man suffering from dislocation of IVCF implanted due to deep vein thrombosis (DVT) in the right femoral vein. Successful retrieval of the IVCF using double sheaths docking technique was done soon after confirmation of the dislocation. Importance of monitoring and early detection of dislocation of IVCF should be emphasized to avoid further complications.The double vascular sheaths docking technique can be considered as a preferential option in difficult operative situation. DVT in lower extremities occurs under conditions of venous endothelial damage, blood hypercoagulation, and stasis. The main risks of DVT include early fatal pulmonary embolism (PE) and late pulmonary hypertension. For patients with anticoagulation contraindications and recurrent DVT, IVCF should be implanted to prevent fatal PE. Furthermore, monitoring on IVCF status is critical to guarantee its\u2019 thrombus capture effect and reduce filter-derived complications.IVCF-derived adverse events have been reported as placement issues 45.1%), IVC penetration (29.9%) and IVC filter fracture (27.1%) [%, IVC peWe report an insidious case of IVCF leg dislocation, potentially leading to perforation of the vena cava. Double sheaths docking technology was used to successfully retrieved the IVCF, verifying the importance of timely handling of IVCF migration.A 49-year-old man with DVT in right femoral vein following ruptured cerebral aneurysm underwent retrievable IVCF implantation to prevent fatal PE. Pharmoco-mechanical thrombectomy was performed with angiojet system . During the surgery, a leg of the filter was found to be dislocated Fig.\u00a0A, which IVCF is an absolutely therapeutic choice for avoiding fatal PE when conventional anticoagulation is contraindicated or deemed ineffective . A retriThis case revealed filter leg dislocation and axial migration of the filter. The dislocated filter leg may not only causes perforation of the inferior vena cava, resulting in retroperitoneal hematoma , and cauDislocation of the IVCF is a rare and serious complication, calling for our sufficient attention. Monitoring on IVCF status is critical to guarantee its\u2019 thrombus capture effect and reduce filter-derived complications. The double vascular sheaths docking technique can be considered as a superior method."} +{"text": "OBJECTIVES/GOALS: Clinical trials are the gold standard for developing evidence-based medicine. However, 20% of pediatric randomized clinical trials are discontinued and about 30% of completed trials go unpublished. Although patient recruitment is the most cited barrier to completing clinical trials, trials funded by academia are more likely discontinued compared to those funded by industry. This study is an attempt to gain additional insights into clinical trials in academic pediatrics. METHODS/STUDY POPULATION: Junior pediatrics faculty (Instructors and Assistant Professors) were recruited to participate in an online survey through RedCAP. The physicians were asked if they had prior experiences with clinical trials and whether they have interest in participating in clinical trials. Those interested were asked three additional questions: what role they were interested in, barriers to participating and interventions they thought would educate them about participating in clinical trials. RESULTS/ANTICIPATED RESULTS: Ninety two (92) out of 119 (77%) junior pediatrics faculty completed the survey. Twenty (20) pediatric subspecialties were represented and respondents were on various academic pathways. A third of the respondents (35%) had previously participated in clinical trials. A majority of the faculty respondents are on the clinical educator pathway. The 13 respondents who were not interested in clinical trials indicated their preference for patient care, education and quality improvement. Of those interested in clinical trials, the top three preferred roles were site co-investigator (68%), help designing future protocol (47%) and site principal investigator (44%). Other than time, the top barriers to participation were a lack of awareness of what it takes to lead or engage in clinical trials (53%) and a lack of training on clinical trials (45%). Mentoring from an experienced clinical trialist emerged as the top preferred intervention (78%). DISCUSSION/SIGNIFICANCE OF IMPACT: Although limited to one institution, the findings of this study provide insights into pediatric faculty interest in clinical trials. If academic pediatricians are provided with mentoring, there could be an uptick in completed and published clinical trials involving pediatric populations."} +{"text": "Through leveraging the known advantages of musical engagement and socialization, choir interventions are known to facilitate psychological and cognitive benefits for persons with dementia (PwD). Surprisingly, no research has explored whether social singing may also confer neurological advantages. In this study, we employed functional near infrared spectroscopy (fNIRS) to investigate the cortical correlates of both social and solo singing in PwD (n=13). Paired-sample t-tests were used to evaluate within-person differences in frontal cortical activation between the social vs solo singing. Results showed significant activation differences in three frontal channels, with social singing requiring comparatively less frontocortical activation. These findings indicate potential neural benefits of social singing \u2013 with less frontal activation being a proxy for greater reliance on intact proceduralized systems \u2013 and serve to highlight the utility of fNIRS in better understanding the neural correlates underlying the benefits of social singing interventions for PwD."} +{"text": "In 2017, the United States Comprehensive Addiction and Recovery Act (CARA) expanded authorization to prescribe buprenorphine for opioid use disorder (OUD) to nurse practitioners (NPs). Compared to physicians, NPs were required to complete 16 additional hours of training on controlled substance prescribing before a buprenorphine waiver application. As this differential additional education mandate was seen as a potential barrier, we evaluated the impact of this requirement on both NP waiver acquisition and prescribing of controlled substances, comparing NPs who obtained waivers to those who had not.Through 2016\u20132018 Oregon Prescription Drug Monitoring Program and linked NP licensure data, we identified factors associated with waiver acquisition at baseline (2016) and evaluated changes in controlled substance prescribing before (2016) and after waiver acquisition (2018). Using chi-square and Mann-Whitney U testing, we calculated and described controlled substance prescribing types, rates, and patient level quantities including co-prescribing of benzodiazepines and opioids by NPs. Multivariable linear regression compared prescribing by waivered and non-waivered NPs for significant changes in non-buprenorphine controlled substance prescribing.Waivered NPs were more likely to have a psychiatric certification, have prior disciplinary action, and have generally higher levels of non-buprenorphine controlled substance prescribing than their non-waivered counterparts. While there was a significant increase in opioid prescriptions per patient among waivered NPs, following CARA implementation, co-prescribing of benzodiazepines and opioids significantly declined among waivered NPs relative to non-waivered NPs.Although educational requirements were rescinded in 2021 for most applicants, enhanced opioid prescribing training should be incorporated into professional educational offerings regardless of regulatory mandate. We recommended continued focus on education regarding avoidance of high risk prescribing such as co-prescribing of opioids and benzodiazepines. NPs who acquire waivers may take on higher risk patients already using opioids, and these findings may represent transitions in practice and patient setting. United States federal law and regulation expanded access to buprenorphine for treatment of opioid use disorder (OUD). In 2016 Congress passed the Comprehensive Addiction and Recovery Act (CARA) which extended prescriptive authority for office-based treatment with buprenorphine to nurse practitioners (NPs) for up to 30 patients beginning in 2017 . StudiesUnlike physician assistants, who are required to practice with a supervising physician, NPs have autonomous practice in many states. As of December 2021, 24 states and the District of Columbia confer full scope of practice to NPs without a requirement for physician involvement in prescribing decisions . States NPs are granted full prescriptive authority for scheduled drugs in the state of Oregon, which was among states with the largest increase in NP prescribing of buprenorphine, particularly in very rural areas after implementation . NPs in In late 2020, the Trump administration promulgated rule changes to remove the DEA waiver requirement for physicians who prescribe buprenorphine to fewer than 30 patients . AlthougThe effect of these additional educational requirements on non-buprenorphine controlled substance prescribing has not been evaluated. It is critical to examine how and if expanded educational requirements impacted prescribing of controlled substances overall. While OUD is the target of buprenorphine therapy, prescribers authorized to provide it are not restricted from continued prescribing of opioids or other controlled substances such as benzodiazepines which can create risk for patients, and a history of substance abuse diagnosis is associated with high dose benzodiazepine prescribing by primary care providers .Characteristics of NPs who prescribe buprenorphine and where they practice likely differ from those who prescribe controlled substances generally. County level variables which facilitate buprenorphine prescribing include treatment capacity, overdose rate, and percentage of male non-Hispanic white population . PrescriThe objectives of this study were: 1) to describe characteristics of NPs who obtained a waiver in Oregon to prescribe buprenorphine (waivered) compared to those who did not (non-waivered) and 2) to evaluate changes in non-buprenorphine controlled substance prescribing following CARA implementation between waivered and non-waivered NPs. We hypothesize that increased educational components for waivered NPs would change controlled substance prescribing as measured by key variables associated with patient use and dispensing patterns.n\u2009=\u2009396,385) prescriptions. This dataset includes information on drug name, strength, quantity dispensed, days\u2019 supply, date dispensed, and prescriber. NP characteristics were determined through a Drug Enforcement Agency (DEA) number linked demographic and licensure database from the Oregon Board of Nursing. The Board of Nursing licensure database contains demographic and practice information such as age, NP specialty certifications, licensure date, and prior professional disciplinary action.We excluded all non-NP prescribers from this study as well as any prescriptions for buprenorphine products . We included all NPs with one or more prescriptions for either an opioid or benzodiazepine prescription dispensed by a pharmacy and entered into the Oregon Prescription Drug Monitoring Program (PDMP) database from January 1, 2016 to December 31, 2018 and licensure time was categorized into five-year increments by the Oregon Health Authority prior to data release. For professional certification, we identified if NPs had a psychiatric or mental health specialty certification. DEA waiver-status was provided by Oregon\u2019s PDMP program.Our first objective was to identify factors associated with NP waiver acquisition. We compared demographic and licensure characteristics between NP who ultimately received an waiver and those who did not. We also used PDMP dispensing data to compare controlled substance prescribing patterns between these two groups of NPs using 2016 (pre-CARA) as the baseline year. For each NP, we calculated the number of unique patients to whom they prescribed opioid analgesics, the average number of opioid prescriptions they prescribed to each patient, the number of patients to whom they prescribed long-term opioid therapy, and the number of patients who received at least one opioid prescription at or above 90 morphine milligram equivalents (MME) per day . We consP-values less than 0.05 were considered statistically significant. All analyses were performed using Stata/SE 15.1 .Our second objective was to evaluate changes in controlled substance prescribing among waivered NPs relative to those who were not. Using the prescribing metrics described above, we used multivariable linear regression to compare changes in prescribing patterns in 2018 relative to 2016 (prior to CARA waiver acquisition) across groups. In each regression model, the dependent variable was operationalized as the within NP difference in each prescribing metric; independent variables included waiver status, age, years in practice, psychiatric specialty, prior discipline, and the prescribing metric at baseline (2016). p\u2009<\u20090.001) and have had prior discipline than non-waivered NPs.Of the 3321 NPs identified in the Board of Nursing licensure data, 187 were identified as acquiring a wavier by the Oregon Health Authority. Demographic and prescribing characteristics for these NPs are summarized in Table p\u2009<\u20090.001). Prior to waiver acquisition, waivered NPs wrote significantly more opioid prescriptions per patient than non-waivered NPs and had more patients with long-term opioid therapy . NPs who became waivered also prescribed benzodiazepines to more patients and with higher intensity than those who did not. Waivered NPs co-prescribed opioids and benzodiazepines to more patients than those who were not .Of the NPs included, 1450 had one or more controlled substance prescription in Oregon\u2019s PDMP in 2016. At baseline (2016 pre-CARA), waivered NPs were more likely to have prescribed controlled substances than non-waivered NPs , initial waiver acquisition required additional training above and beyond that which was required by physicians. Although continuing education can improve performance, its link to patient outcomes is tenuous . While tHowever, additional support is needed to engage other healthcare professionals who might facilitate or limit buprenorphine access. For example, a recent study found 20% of pharmacies limited buprenorphine access for patients with OUD . InclusiOur results found that waivered NPs significantly changed their practice regarding the high-risk co-prescribing of benzodiazepines and opioids as compared to non-waivered NPs. Given the removal of the educational mandate to become a waivered prescriber, consideration should be given to multiple methods of continued support and interprofessional education regarding not only safer provision of controlled substances but also effective ongoing treatment of substance use disorders."} +{"text": "Spinal cord injury (SCI) leads to irreversible functional impairment caused by neuronal loss and the disruption of neuronal connections across the injury site. While several experimental strategies have been used to minimize tissue damage and to enhance axonal growth and regeneration, the corticospinal projection, which is the most important voluntary motor system in humans, remains largely refractory to regenerative therapeutic interventions. To date, one of the most promising pre-clinical therapeutic strategies has been neural stem cell (NSC) therapy for SCI. Over the last decade we have found that host axons regenerate into spinal NSC grafts placed into sites of SCI. These regenerating axons form synapses with the graft, and the graft in turn extends very large numbers of new axons from the injury site over long distances into the distal spinal cord. Here we discuss the pathophysiology of SCI that makes the spinal cord refractory to spontaneous regeneration, the most recent findings of neural stem cell therapy for SCI, how it has impacted motor systems including the corticospinal tract and the implications for sensory feedback. Traumatic spinal cord injury is most commonly caused by compression, laceration and contusions which lead to severe impairment of motor/sensory function below the level of injury . The magThe initial traumatic event that may comprise fractures and/or dislocation of the vertebral column results in disruption of the vasculature, neurogenic shock and alterations in ion and neurotransmitter release. Ultimately this will set the stage for the secondary phase of injury ,5,6,7 inThe lack of repair following spinal cord injury is due to both cell intrinsic factors and the extrinsic injury environment . NeuronsWhile the first traumatic damage leads to immediate and often serious impairment of neurological function, the secondary phase usually dictates the full magnitude of injury. Inflammatory cells and resident glia including astrocytes and oligodendrocyte progenitor cells become reactive at the lesion that culminates in a permanently remodeled tissue ,26,27 F. As a heAnother main component that limits axonal growth is the physical barrier formed at the lesion site. SCI usually results in a breakdown of the blood spinal cord barrier (BSCB) and vascular permeability . FollowiIn efforts to increase axonal regeneration and recovery of function, experimental approaches targeting the environment at the injury site such as inhibiting molecules associated with scar and myelin debris ,31,44 haOne strategy to restore functional connectivity between severed spinal cord segments is the transplantation of neural progenitor cells (NPCs). NPCs have high therapeutic potential for reconstruction of the injured spinal cord tissue, since they can proliferate and differentiate into neurons and glia ,53. In aA major issue in these earlier techniques was a lack of retention of neural tissue within the injured spinal cord parenchyma that resulted in poor cell survival and failure of axonal growth. Later studies successfully overcame this issue by providing a more appropriate source or substrate for axonal growth. An experimental model using a peripheral nerve inserted into the lesion in the CNS showed extensive growth of axons from transplanted neurons along the \u201cneuron-free conduits\u201d . Later, Although experimental studies in the 1980s showed a gradual improvement of cell survival, integration and axonal growth, there was no evidence of functional improvements. Only in the 1990s did intraspinal fetal grafts placed into the site of SCI in adult and newborn rats show some improvements in functional outcomes ,58,64. TThe concept of neuronal relays is applicable when new neural circuits support and establish new connections across the site of injury. Specifically, descending host motor axons that project into stem cell grafts ,69,70 esAs previously discussed, SCI usually results in a large lesion area that damages not only the central gray matter, but also the surrounding white matter axon tracts that connect the brain with the rest of the body. Although damage of local spinal cord gray matter neurons primarily affects local segmental functions, disruption of white matter axon tracts is the major cause of neurological deficits below the level of injury ,78. UnliNeural stem/progenitor cell transplants have the potential to reconnect damaged axons since transplant-derived neurons can function as neuronal relays for disrupted pathways. First, transplant-derived neurons can serve as new neuronal targets attracting injured host axons that regenerate into and innervate the graft. A typical example is the robust regeneration of corticospinal (CST) axons into neural progenitor cell grafts . Second,In order to successfully generate neuronal relays by transplanted neural stem/progenitor cells in the injured spinal cord, a continuous transplant that completely fills the lesion site is needed. Excellent tissue integration with the surrounding host parenchyma and direct contact of transplants with the host tissue are additional pre-requisites for the ingrowth and outgrowth of axons . Large aAs an alternative approach, neural stem/progenitor (NSC/NPC) cells have been transplanted into remaining spared portions of the spinal cord, rostral and caudal to the lesion epicenter rather than in the lesion epicenter itself ,84. MostIn order to function as neuronal relays, a large proportion of transplanted NSC/NPC must differentiate into neurons that can reconnect injured circuits. Freshly dissociated rodent embryonic spinal cord-derived neural stem/progenitor cells usually differentiate into ~30% neurons and ~50% glia when embedded in a growth factor cocktail containing fibrin matrix within 7 weeks after transplantation . In contFor the formation of neuronal relays, propriospinal neurons and interneurons might be ideal as these neurons serve as natural \u201crelays\u201d in the intact spinal cord . In precIn general, transplant-derived neurons share many similarities with developing neurons. This includes a high intrinsic growth capacity allowing for axon extension into surrounding areas and remote regions. Transplanted neural stem/progenitor cells supported by fibrin-containing growth factors survive and differentiate into healthy neurons that can robustly extend their axons into host white matter over very long distances to innervate host gray matter. As many as 29,000 axons were shown to emerge from rat NPC grafts in caudal direction in the rat . Graft-dThe traditional source of neural stem/progenitor cells from the developing CNS contains various stages of NSCs and progenitor cells. Fetal CNS tissue, such as brain and spinal cord, can either be directly transplanted without prior dissociation , dissociAn alternative means to generate neural stem cells or neural progenitor cells is the use of pluripotent stem cells including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). ESCs are derived from the inner cell mass of the early blastocyst and have unlimited proliferative potential, therefore providing an unlimited resource of stem cells. In addition, ESCs are able to differentiate into a variety of cell types including neural cells . iPSCs hIn order to replace lost neurons and glia and to generate functional neuronal relays for CNS repair, pluripotent stem cells need to be induced to differentiate into neural cell lineages, especially to neural stem/progenitor cells or even early-stage neurons through a process called neural induction and differentiation. Early studies used a method of embryoid body (EB) formation and manual selection of neural rosettes after spontaneous differentiation or neural induction using growth factors or co-culture with PA6 stromal cells. Recent studies have focused on manipulation of specific signaling pathways such as inhibition of BMP, TGF beta and WNT pathways by proteins and/or small molecules for neural induction. In addition, the early stage neuroectoderm can be patterned by different morphogens to produce distinct rostro-caudal, dorsoventral and mediolateral neurodevelopmental lineages ,93.Interestingly, in caudal spinal neurodevelopment, neural progenitors are derived from transient neuro-mesodermal progenitors that are capable of generating both spinal cord neural and mesodermal progenitors . This prAdditional studies with human ESC- or iPSC-derived neural stem/progenitor cells in animal models of SCI are needed to support the safety, feasibility and potency of these cells for clinical translation.An alternative approach and short-cut is direct conversion of somatic cells into induced neural stem cells (iNSCs) ,96. InteDescending motor tracts represent key elements to voluntary motor control in humans. One such pathway, the corticospinal tract (CST), commands its voluntary motor control not due to its connections with the motor cortex, but its immediate and direct access to spinal and motor interneurons within the spinal cord . In humaTo address this, we and others have used neural progenitor cell transplantation into a lesion cavity to provide a fortuitous substrate for axon regeneration and reinnervation ,104,110.This concept of neural relays was further supported when rhesus monkeys with a cervical spinal cord injury received a human caudal neural progenitor cell graft and showed CST axons growing into the graft for up to 500 \u00b5m . Other aInterestingly, more modern techniques have revealed the molecular signature of the adult corticospinal neuron as it regenerates after injury. Surprisingly, translational profiling indicated that during an early time after injury, CST neurons reverse back towards an immature developmental state and take on a gene expression profile similar to embryonic day 18 CST neurons . This prOne might ask if this strategy is feasible to establish the primordial circuits of the CST required for appropriate interneuron and motoneuron innervation within the spinal cord, leading to restored cortico-motor circuits for precise motor control. In the developing CST circuit in infant rhesus monkeys, CST fibers terminate within the intermediate zone of the spinal grey and no CST fibers innervate the motoneuron pools of the ventral horn . During Given that modern tools of neuroscience have unveiled that adult regenerating CST neurons regress back towards an embryonic fate while undergoing active regeneration, one can hypothesize that activation of this intrinsic developmental program can be harnessed to drive new CST circuit formation, and that in combination with training-induced adaptation, projections towards the appropriate targets within the spinal cord can be achieved.Most studies examining NSC-mediated behavioral improvements and formation of novel circuits have focused on descending motor systems, whereas restoration of sensory function from levels below a site of SCI has not received the same attention. Without doubt, there is a good rationale to focus on motor systems and specifically CST axons, one of the most important pathways for fine motor control. However, without any sensory feedback, precise supraspinal motor control will be difficult to achieve. Besides the important role of sensory feedback in motor control, regaining sensory function in areas below the lesion site could prevent or reduce some of the worst secondary complications from spinal cord injury including life threatening autonomic dysreflexia, detrusor sphincter dyssynergia that can lead to kidney failure, and pressure skin lesions, one of the leading secondary complications after SCI. In addition, pain at or below a site of SCI is highly prevalent in the SCI population, particularly in patients with incomplete injuries, severely impairing the quality of life ,122. ThuAscending sensory projections include the dorsal column system, which is mainly responsible for fine discriminative touch and conscious proprioception. It is the only system with direct long primary sensory neuron projections from ipsilateral DRGs to dorsal column nuclei (Nucleus gracilis/Nucleus cuneatus) and one of the most investigated systems in spinal cord regeneration. It has long been appreciated that the intrinsic regenerative capacity of these neurons can be enhanced by lesions of their peripheral axons ,124. TheEvidence for synaptic connections between sensory axons and different types of NSC graft-derived neurons also comes from several more recent studies. In mice with dissociated E13 fetal NPC grafts in lesions at level C4, retrograde transganglionic labeling of DRG neurons was observed as low at the upper lumbar spinal cord . As the These data raise the question whether sensory innervation of graft-derived neurons is a random process or whether formation of synapses between sensory axon and graft-derived neurons is more selective and specific. In studies examining sensory axon regeneration into syngeneic E14 rat NPC suspension grafts in a dorsal column lesion, neurons expressing dorsal horn markers were not only clustered but also aligned in laminae-like patterns similar to the mature spinal cord . This unTaken together, the studies described above strongly suggest that mouse, rat and human NSC grafts are innervated by host sensory projections and therefore fulfill the first major prerequisite for functional sensory relays. There is also ample evidence for the second prerequisite, namely that primary sensory axons extending into NSC grafts form functional synapses, and that there is at least a preference if not some specificity in the graft-derived neuron population that receives sensory input. Regarding the third requirement for a sensory relay, namely innervation of relevant host sensory target nuclei by graft-derived axons, information is sparser, although NSC graft-derived axons extend into rostral direction in virtually every study. In immunodeficient rats with hiPSC-derived NSC grafts to C5 lateral hemisections, GFP-labeled graft-derived axons were found in dorsal column nuclei, medulla and midbrain and cerebellum, all sensory target nuclei . WhetherAt level and below level pain after spinal cord injury is highly prevalent, in particular in SCI patients with incomplete injuries. An area of potential concern is the possibility that NSC transplantation worsens or induces pain symptoms either by inappropriate new connections or by influencing the pain circuitry in the surrounding host spinal cord. Most studies have not reported any potential sensory adverse effects of NSC grafts but specific functional tests that can detect nociceptive sensitization were not always conducted. On the contrary, using stem cells differentiated towards inhibitory lineages, amelioration of pain-like behaviors has been reported. While SCI-related neuropathic pain has many underlying mechanisms, spinal disinhibition (loss of inhibitory activity) resulting in hyperactivity of the pain circuitry plays an important role in the pathophysiology of pain. Thus, a localized increase in inhibitory neuronal activity or innervation by transplants of inhibitory interneurons could be an effective means of modulating pain.Inhibitory neuronal progenitors obtained from the medial ganglionic eminence have been the focus of one set of studies. In animal models of peripheral neuropathies, grafting embryonic MGE-derived precursors into the lumbar spinal cord profoundly reduced pain-like behavior . TranssyDespite the detrimental outcomes after SCI, there is no effective treatment to restore functional connectivity of the injured spinal cord. One promising strategy is to reconstruct the lesion site with neural stem/progenitor cell grafts (NSC/NPC) as transplanted cells can differentiate into neurons that may re-connect disrupted spinal neural circuitry. Recent studies from our and other groups support the concept of neuronal relay formation by transplant-derived neurons.First, embryonic and pluripotent stem cell-derived NPCs can be transplanted into a lesion cavity and differentiate into neurons and glia. These developmentally early stage grafts integrate with the host tissue without generating a glial \u201cscar\u201d between host and graft , where gSecond, recent work not only demonstrates successful regeneration of both descending supraspinal motor axons and ascending sensory axons into NSC/NPC transplants, but also the formation of functional synaptic connections. Corticospinal optogenetic stimulation in the motor cortex showed a clear calcium response in graft-derived neurons in the spinal cord, indicative of action potentials initiated by host motor circuitry . TranssyThird, host axons growing into these NSC/NPC grafts within the lesion cavity appear to have at least some specificity. Regenerating motor circuits extended their axons into the graft and formed synapses with premotor interneurons and motor neurons, avoiding sensory interneuron clusters within the graft . In turnFourth, NSC/NPC grafts support functional improvements after injury. NSC/NPCs with spinal identity placed into clinically relevant models of SCI resulted in functional improvement in hindlimb ,110 and Although the above studies support the role of NSC/NPC grafts as a potential therapeutic intervention for SCI, meaningful functional improvements in the clinic will likely require additional advances. While a large proportion of corticospinal axons penetrate into NSC/NPC grafts in the lesion site, most of these axons are located within the first 1 mm of the rostral host/graft interface. Intensive rehabilitation can strengthen and even reshape newly formed circuitry to promote functional outcomes after injury as rehabilitation can strengthen synapses , lead toFinally, potential adverse effects associated with NSC/NPC transplantation need to be addressed before clinical translation, including possible over-growth or tumor formation and transplant-induced pain. Consistent and reproducible protocols for the production of a sufficiently large number of cells under defined conditions have to be generated. Potency assays and cellular characterization with minimum acceptance criteria need to be established, and in vivo dose\u2013response curves for efficacy and toxicity have to be completed. Parallel progress in the generation and transplantation of neuronal subpopulations most relevant for the formation of neuronal relays may further enhance the formation and efficacy of novel neuronal circuits. Thus, additional preclinical studies are warranted to support and improve the safety and efficacy of NSC/NPC therapy. Progress over the next years is likely to advance neural stem cells for the generation of neuronal relays in SCI towards clinical trials."} +{"text": "The continuing COVID-19 pandemic has necessitated changes to research protocols and approaches to mitigate health risks to both study participants and researchers. This is particularly true of studies exploring the biopsychosocial well-being and personal perspectives of older adults and those at elevated risk of COVID-19 complications. While videoconferencing platforms have enabled remote work and social activities, reliance on them may potentially exclude some individuals . Persons living with dementia (PLWD) may experience difficulties navigating videoconferencing systems and building rapport with interviewers, though the inclusion of PLWD in research is necessary to ensuring their equitable representation. This presentation disseminates promising practices and lessons learned from a longitudinal study conducting remote interviews on sensitive topics with PLWD and their care partners (CP). Findings are drawn from a case study of the Better Together Dementia Care Study, an 18-month longitudinal study of PLWD (N=8) and their CPs (N=13), which implemented remote interviewing in Summer 2020 to gather data on the quality-of-life, resilience, relationship quality, adverse childhood experiences, mistreatment, and health status of PLWD. Researchers were able to interview most enrolled PLWD (n=7) via videoconferencing. Paper surveys were mailed to phone-interviewed participants, enabling them to view questions and answer choices in concordance with verbal queries. Researchers also tested a protocol asking CPs to leave the room while PLWD answered questions on sensitive topics. Findings support the use of remote interviewing with PLWD and provide insights to guide replication of these approaches."} +{"text": "Similar to humans and laboratory animals, reproductive aging is observed in wild species-from small invertebrates to large mammals. Aging issues are also prevalent in rare and endangered species under human care as their life expectancy is longer than in the wild. The objectives of this review are to (1) present conserved as well as distinctive traits of reproductive aging in different wild animal species (2) highlight the value of comparative studies to address aging issues in conservation breeding as well as in human reproductive medicine, and (3) suggest next steps forward in that research area. From social insects to mega-vertebrates, reproductive aging studies as well as observations in the wild or in breeding centers often remain at the physiological or organismal scale (senescence) rather than at the germ cell level. Overall, multiple traits are conserved across very different species (depletion of the ovarian reserve or no decline in testicular functions), but unique features also exist . There is a broad consensus about the need to fill research gaps because many cellular and molecular processes during reproductive aging remain undescribed. More research in male aging is particularly needed across all species. Furthermore, studies on reproductive aging of target species in their natural habitat (sentinel species) are crucial to define more accurate reproductive indicators relevant to other species, including humans, sharing the same environment. Wild species can significantly contribute to our general knowledge of a crucial phenomenon and provide new approaches to extend the reproductive lifespan. Reproductive aging is a process involving a combination of multiple intrinsic and extrinsic factors affecting the whole organism and more directly the reproductive organs as well as the quality of germ cells. Reproductive aging in human and laboratory animals has been studied for decades at the physiological, hormonal, cellular, and molecular levels. As gamete quality declines more rapidly in women than in men, reproductive aging leads to infertility, increased miscarriages, and birth defects . The menCaenorhabditis elegans and Drosophila melanogaster has conserved properties in the process of mammalian ovarian aging during aging are associated with declining reproductive performance. This can be used as a predictor of fertility longevity in cattle; however, it still remains largely unexplored in sheep and other farm species . DomestiCoturnix japonica) males demonstrated that similar to mammals, plasma androgen levels decline gradually, being accompanied by a loss of reproductive behavior . For instance, aging in the drosophila model still remains understudied in males. However, recent reports have shown that, not only sperm, but also seminal fluid are both qualitatively and quantitatively affected by age with each component making distinct contributions to declining reproductive performance in older males . Studiesbehavior . Interesbehavior .Antechinus sp.) to negligible reproductive senescence . Even th glaber) . This isThe objectives of this review are to (1) present conserved as well as distinctive traits of reproductive aging in different wild animal species (2) highlight the value of comparative studies to address aging issues in conservation breeding as well as in human reproductive medicine, and (3) suggest next steps forward in research.The study of reproductive senescence in free-ranging populations is invaluable as it allows to better understand fundamental aspects, such as mate choice, sperm competition, or environmental impact. Furthermore, short- and long-lived wild species exhibit unique characteristics that inform our understanding of aging processes. An overview of the impact of aging on reproductive traits (including some observed in humans) in selected wild mammalian species (from rodents to non-human primates) is presented in Meles meles), there is strong evidence for a gradual decline in sex-steroid levels with age in both sexes, which is even followed by over 2 years of post-reproductive life (Acinonyx jubatus) after the age of 9, which is even older than the average life expectancy (In carnivores like the European badger (ive life . Interespectancy .Cervus elaphus) stags show a faster decline in annual breeding success than females that went through successive gestations and lactations (Canis rufus), reproductive aging in males also is observed while there is no evidence for reproductive aging in wild female wolves , there is no consequence of early life reproduction; however, for a given number of offspring, females that weaned more sons than daughters experience earlier senescence (In bighorn sheep (nescence . OffspriPan troglodytes), females with high number of years spent gestating and lactating during their reproductive lives have a delayed ovulatory attrition (Papio sp.) also suggested that reproductive senescence occurs later in females than males , calf survival decreases with maternal age because of less maternal investment , although reproduction does not entirely cease until the age of 65 year old, females have a relatively long post-reproductive life or the f glaber) .Castor fiber), earlier breeding opportunities lead to earlier senescence through resource-dependent mechanisms , chimpanzees (Pan troglodytes), and chamois (Rupicapra rupicapra). Notably, some species rather show an increase in fertility as they age . As seenconomus) . Lastly,An overview of the knowledge about the impact of aging on reproductive traits (including some observed in humans) in selected wild non-mammalian species is presented in Somniosus microcephalus), reptiles , and some birds .Gryllus campestris) investing more in early reproduction may senesce faster and die younger (Setophaga caerulescens) older males tend to have longer sperm cells, which may be advantageous in post-copulatory sexual selection (Leucopsar rothschildi) or birdsschildi) .Zoo animal populations represent an ideal model to study reproductive aging process since lifespan is frequently longer than in the wild, so repeated observations under controlled conditions are possible. Reproductive aging also represents a major issue in conservation breeding, especially for genetically valuable individuals that are too often not reproducing .Heterocephalus glaber) colonies has generated intriguing data. Unusually large ovarian reserve in naked-mole rat provides one mechanism to account for this species\u2019 protracted fertility. However, whether germ cell nests in adult ovaries contribute to the long reproductive lifespan remains to be determined (Research on naked mole rat (termined .Mustela nigripes), has revealed that even modest aging decreases sperm production and libido while abnormal sperm number increases (Arctictis binturong) show that males of advanced ages still produce good quality semen and cheetahs (Acinonyx jubatus) . As repojubatus) .Ailuropoda melanoleuca) cub by artificial insemination with frozen-thawed semen in one of the oldest females in captivity . A good illustration is the recent birth of a giant panda (aptivity . While aAcinonyx jubatus), uterine environment in aging females is the real issue while oocyte quality is not affected (in vitro fertilization (IVF) on oocytes from old donors and transfer the resulting embryos into young recipient females that quickly dies after the breeding season (As highlighted in g season . Except Acinonyx jubatus), nothing is known about the influence of aging in gamete quality (success of fertilization and early embryo development) or uterine environment reported above could suggest some research areas or questions in humans, for instance:\u2022Understanding rapid vs. absence of decline in fertility.\u2022Exploring sustained oocyte quality in felids (and other species having induced ovulations).\u2022Examining the influence of parental age on offspring reproductive health .\u2022Characterizing the impact of allostatic load known for very long lifespan.\u2022Using the systems biology approach to better understand and mitigate reproductive aging.Regarding mitigations and treatments, expanding reproductive life could be achieved through, hormonal treatments also are crucial to define more accurate reproductive metrics that are relevant to species, including humans, sharing the same habitats. We must keep building bridges between the ecology of senescence and areas of research in reproductive science. Repeated observations in zoo animals also will remain invaluable sources of information to decipher the mystery of reproductive aging.In sum, wild species can potentially contribute to the general knowledge of a crucial phenomenon. Comparative models will help to understand the fundamental mechanisms underlying reproductive aging and then develop new approaches to extend the length and the quality of reproductive lifespan, which will ultimately impact overall health.PC and MA contributed equally to the preparation and the writing of the manuscript. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "ABSTRACT IMPACT: This study aims to advance the understanding of the biological mechanisms associated with feeding disturbances in infants born to diabetic mothers through non-invasive salivary gene expression analyses and body composition measurements at birth. OBJECTIVES/GOALS: To determine if non-invasive salivary gene expression analyses and body composition measurements at birth could elucidate biological mechanisms associated with aberrant feeding behaviors and disrupted metabolic profiles commonly seen in infants born to diabetic mothers. METHODS/STUDY POPULATION: This prospective cohort study enrolls subjects born at \u226535 weeks\u2019 gestation without a history of intrauterine growth restriction or major congenital anomalies. The diabetic cohort is defined as infants born to mothers with gestational diabetes or type 2 diabetes. The primary outcome is salivary expression of the hunger signaling genes, AMPK and NPY2R. Secondary outcomes include infant body composition measurements, obtained by skinfold measurement and/or air displacement plethysmography, and salivary expression of the adipokines, leptin, ghrelin, and adiponectin. Multiple logistic regression will be used to determine which factors are associated with AMPK and NPY2R expression. RESULTS/ANTICIPATED RESULTS: We propose that poor oral intake seen in infants of diabetic mothers may be due to alterations in the expression of hunger signaling genes resulting in a diminished feeding drive in these large for gestational age infants. In addition, infant adiposity and the expression of genes involved in the adipoinsular axis will be inversely proportional to feeding volume intake. Namely, increased neonatal fat mass will be associated with increased expression of leptin and decreased expression of ghrelin and adiponectin. DISCUSSION/SIGNIFICANCE OF FINDINGS: Infants of diabetic mothers are at higher risk of poor oral feeding in the newborn period. This study aims to elucidate the link between neonatal body composition, adipoinsular axis, and hunger signaling to explain this unique feeding phenotype."} +{"text": "Hematopoietic cells and their microvesicles have recently emerged as novel markers of cardiovascular risk. The crosstalk between these vesicles and endothelial dysfunction or vascular damage is a field of continuous progress. Additionally, thromboinflammation represents an emerging concept in cardiovascular diseases. In hypertension, the role of signaling pathways in hypertension remains also under investigation. Realizing the unmet needs of increased awareness of treating physicians and active researchers in this complex setting, we launched our Special Issue on \u201cMolecular Advances in Hypertension and Blood\u201d. Our issue has addressed both sides of the coin by publishing four articles that are summarized in this editorial. Firstly, we published an experimental study providing evidence that certain molecular pathways may be involved in myocardial remodeling in the settings of arterial hypertension and chronic kidney disease. Secondly, an in vitro study revealed a novel immune-modulatory effect of Ticagrelor, which is widely used in patients with hypertension and cardiovascular disease. Thirdly, another translational study assessed endothelial injury and pro-coagulant activity using circulating microvesicles in survivors of allogeneic hematopoietic cell transplantation, compared to a control population matched for traditional cardiovascular risk factors. Lastly, a review article delineated the role of Toll-like receptors in the pathogenesis of essential hypertension.Hematopoietic cells and their microvesicles have recently emerged as novel markers of cardiovascular risk ,2,3. TheAll articles submitted to us for this Special Issue underwent a rigorous peer review process. Ultimately, four articles were published. Three of these articles detail original research into (i) signaling pathways in arterial hypertension and chronic kidney disease, (ii) evidence suggesting a novel immune-modulatory effect of Ticagrelor, and (iii) endothelial injury and pro-coagulant activity in survivors of allogeneic hematopoietic cell transplantation. This Special Issue also includes one review that discusses the role of Toll-like receptors in essential hypertension. These four articles are discussed below.(i) Bodganova and colleagues aimed to delineate the pathophysiology of myocardial remodeling in arterial hypertension and chronic kidney disease. The authors induced early chronic kidney disease in spontaneously hypertensive rats and compared myocardial remodeling with controls. Chronic kidney disease in these rats was associated with increased FGF23 and decreased renal a-Klotho, along with increased systolic blood pressure, myocardial mass index, cardiomyocyte diameter and myocardial fibrosis. Myocardial remodeling was correlated with increased expression of calcineurin/NFAT and \u03b2-catenin. TRPC6 protein levels and mRNA expression were also elevated. Therefore, the authors concluded that Wnt/\u03b2-catenin and TRPC6/calcineurin/NFAT signaling pathways may be involved in myocardial remodeling of arterial hypertension and chronic kidney disease, potentially mediated by the FGF23 and \u03b1-Klotho axis [(ii) Mitsios and colleagues investigated the effects of Ticagrelor on inorganic polyphosphates released by thrombin-activated platelets and stent-induced neutrophil extracellular traps (NETs) in ST elevation myocardial infarction (STEMI). The authors stimulated neutrophils from healthy individuals and patients receiving Ticagrelor to produce NETs, and further incubated them with plasma from the infarct-related artery of STEMI patients. Then, they assessed the effects of Ticagrelor on NETs and tissue factor loading. Ticagrelor attenuated NETs induced by inorganic polyphosphates and inhibited stent-induced NET release. Considering the clinical need for novel antithrombotic strategies targeting inflammation, their findings highlighted an important and novel immune-modulatory effect of Ticagrelor .(iii) Gavriilaki and colleagues studied 45 survivors of allogeneic hematopoietic cell transplantation without established cardiovascular disease and 45 control individuals matched for traditional cardiovascular risk factors. Circulating microvesicles (MVs) of different cellular origins (platelet and erythrocyte) were increased in alloHCT compared to controls. Endothelial MVs were increased only in recipients of a myeloablative conditioning. These results suggested that endothelial dysfunction and increased thrombotic risk in alloHCT survivors, independently of traditional cardiovascular risk factors .(iv) Lazaridis and colleagues reviewed the role of Toll-like receptors into essential hypertension considering that subclinical inflammation has been implicated in the pathogenesis of the disease. Toll-like receptors have emerged as novel effectors in the inflammatory background, which is evident from the very early stages of hypertension. This review has highlighted the contribution of innate immunity in the pathogenesis of hypertension and clarified the role of TLR signaling in promoting inflammation and hypertensive vascular damage .Taking into account the multi-disciplinary character of this Special Issue, we hope that it will inspire researchers and clinicians to continue their explorations into novel advances in blood and hypertension."} +{"text": "Upper motor neuron (UMN) is a term traditionally used for the corticospinal or pyramidal tract neuron synapsing with the lower motor neuron (LMN) in the anterior horns of the spinal cord. The upper motor neuron controls resting muscle tone and helps initiate voluntary movement of the musculoskeletal system by pathways which are not completely understood. Dysfunction of the upper motor neuron causes the classical clinical signs of spasticity, weakness, brisk tendon reflexes and extensor plantar response, which are associated with clinically well-recognised, inherited and acquired disorders of the nervous system. Understanding the pathophysiology of motor system dysfunction in neurological disease has helped promote a greater understanding of the motor system and its complex cortical connections. This review will focus on the pathophysiology underlying progressive dysfunction of the UMN in amyotrophic lateral sclerosis and three other related adult-onset, progressive neurological disorders with prominent UMN signs, namely, primary lateral sclerosis, hereditary spastic paraplegia and primary progressive multiple sclerosis, to help promote better understanding of the human motor system and, by extension, related cortical systems. Upper motor neuron (UMN) is the term traditionally used for motor neurons within the central nervous system proximal to the spinal motor neuron. Dysfunction of the upper motor neuron in neurological diseases manifests with well-recognised clinical features, including (i) increased muscle tone at rest and in response to passive velocity-dependent muscle stretch , (ii) pyDysfunction of upper motor neurons is well recognised in several inherited and acquired neurological diseases. Inherited disease with prominent clinical features of UMN dysfunction include hereditary spastic paraplegia, leukodystrophies, such as Alexander\u2019s and Krabbe disease, and craniovertebral junction anomaly. Acquired disease of the central nervous system with prominent features of UMN dysfunction include neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and primary lateral sclerosis (PLS), inflammatory disorders such as primary progressive multiple sclerosis (PPMS) and paraneoplastic encephalitis, chronic infection with human T lymphotrophic virus-1 (HTLV)-1 and syphilis, cerebrovascular events such as ischemic and haemorrhagic stroke or cerebral palsy and rare spinal cord ischemia due to vascular malformation.The pathophysiology of neurological diseases where UMN dysfunction predominates may yield novel insights into the complexity and division of function of the pathways that subserve motor control ,4, incluAmyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disorder of the human nervous system, exhibiting prominent features of upper motor neuron dysfunction . The terAmyotrophic lateral sclerosis is characterised by preferential patterns of muscle wasting and weakness. Specifically, the split hand , split hClinical UMN signs are variably manifest in ALS phenotypes. The extensor plantar response is evident in approximately half of ALS patients , while bDespite varying ALS phenotypes , the hisThe initial utility of imaging in neurological disease of the brain and spinal cord was for structural assessment of tissue, which was clinically difficult to visualise. Brain and spinal cord imaging in ALS diagnosis was used for exclusion of other disorders with characteristic imaging features . Though Reconstructing fibre pathways using tractography, detecting metabolite markers of neuronal integrity or cell turn-over using magnetic resonance spectroscopy (MRS), assessing cortical networks using resting-state functional MRI (R-fMRI) techniques and assessing grey matter perfusion with arterial spin labelling (ASL) are newer technologies being developed to assess functional changes in the upper motor neuron in disease which maThe technique of electrical stimulation of the motor cortex to record motor evoked potentials in target upper limb muscles was developed in the eA consistently reported neurophysiological abnormality in ALS, is the phenomenon of cortical hyper excitability thought to result from a loss of inhibitory pathways mediated via GABA-A receptors ,39,40. HA receptors and enhanced by glutamatergic and noradrenergic pathways [Several other neurophysiological measures also provide insights into upper motor neuron pathology in ALS. The motor-evoked potential (MEP) amplitude reflects a summation of complex corticospinal volleys and the pathways . An incrpathways ,47 earlyCentral motor conduction time (CMCT) represents the time from stimulation of the motor cortex to the arrival of the corticospinal volley at the spinal motor neuron . CMCT isB receptors in the latter part [Cortical silent period (CSP) designates the interruption in EMG generated by voluntary motor activity in a target muscle following stimulation of the contralateral motor cortex. CSP is mediated by spinal mechanisms in its early part and cortical inhibitory mechanisms acting via GABAter part . Reductiter part ,39,53 anThe motor threshold (MT) reflects the ease of stimulation of the corticomotor neuron and reflects the density of projection of corticomotorneurons on the spinal motor neuron ,54. MT iPrimary Lateral Sclerosis (PLS) is an adult-onset, sporadic, slowly progressive neurodegenerative disorder of the upper motor neuron. The term is attributed to Charcot , who desDemographically, PLS is a non-familial disorder with slight male preponderance, low incidence ,61 and sHistopathology in PLS has been obtained in a few clinically well-defined cases , showingNeuroimaging in PLS has been limited and is usually undertaken in PLS as a subset of ALS cohorts. No clear diagnostic neuroimaging markers have been identified in PLS. MRI changes reported in PLS have included (i) atrophy specifically of the precentral gyrus , (ii) reCortical neurophysiology studies using transcranial magnetic stimulation reveal motor cortex inexcitability in PLS with inaHereditary spastic paraplegia (HSP) is a genetically diverse group of inherited disorders resulting in length-dependent dysfunction primarily of the corticospinal axons, though other spinal tracts such as the posterior columns may also be involved. They are now understood to be a family of genetic disorders causing dysfunction primarily of extremely long corticomotor axons due to a variety of genetic mutations, affecting pathways involved in the maintenance of axonal health and integrity . The inhHereditary spastic paraplegia (HSP) has been categorised based on genetic inheritance into autosomal dominant, autosomal recessive or X-linked primary Histopathology in HSP is limited due to the relatively normal lifespan of patients with pure HSP . NeuropaNeuroimaging in HSP was initially a tool to exclude mimic causes of spastic paraplegia. Atrophy of the spinal cord without anteroposterior flattening measured most often at the cervical cord level is the most reported finding in pure and complicated forms of HSP . StudiesCortical changes were not noted in a group of patients with the autosomal dominant (AD) genetic HSP when using the transcranial magnetic stimulation technique to probe motor cortex hyperexcitability with motPrimary progressive multiple sclerosis (PPMS) has been studied under the category of inflammatory disorders of the central nervous system. PPMS is clinically an insidious-onset slowly progressive pure upper motor neuron disorder presenting with gait dysfunction . FeatureInterestingly, a case report of a patient with a clinical diagnosis of PPMS and a family history of Pelezaeus\u2013Merzbacher disease revealed a point mutation in the proteolipid protein1 (PLP-1) gene . PLP-1 cThe role of inflammatory cells causing pathological changes in the cerebral cortex and spinal cord in PPMS has been well described , with B Along with the wider subject of multiple sclerosis, PPMS has been extensively studied using neuroimaging modalities, and current diagnostic criteria require the presence of typical brain or spinal cord lesions for the diagnosis of PPMS . The lesCortical excitability using transcranial magnetic stimulation technique did reveThis review summarises the salient features of four adult-onset neurological diseases with progressive and prominent upper motor neuron signs, with emerging key differences in their pathophysiological mechanisms. An improved understanding of the upper motor neuron has been promoted by studies exploring the pathophysiology of these disorders.Amyotrophic lateral sclerosis (ALS) is now recognized as a TDP-43 proteinopathy . HoweverPrimary lateral sclerosis (PLS) is also thought to be a TDP-43 proteinopathy , though Hereditary spastic paraplegia (HSP) is emerging as a disorder of a heterogenous family of genes which code for proteins involved in axonal transport, resulting in a length-dependent motor disorder affecting primarily the lower limbs ,77. OthePrimary progressive multiple sclerosis (PPMS) is increasingly being recognized as a neurodegenerative disorder, with neuroinflammation being the pathogenetic mechanism for neurodegeneration ,95. Nota"} +{"text": "The spinal cord (SC) is a complex structure containing several neuronal circuits related with motor function of the upper and lower limbs, operating under the influence of higher centres. Central nervous diseases can change the responses of the spinal motor circuits leading to its dysfunction. Over the last decade, there has been a growing interest in the study of trans-spinal direct current stimulation (tsDCS) as a potential therapeutic tool to modulate spinal circuits through the application of electric currents delivered non-invasively . ComputaA literature narrative review was carried out through Pubmed database and manual search, considering the following selection criteria: research papers published in journals with impact factor in the areas of neuroscience, neurophysiology and biomedical engineering from 2008 to 2018; use of keywords related with the topic ; written in English. A qualitative analysis was performed over the literature selected considering the following items: electrode montage; tsDCS protocol; methods for assessing motor responses; observed changes; computational results; induced electric field (EF) distribution.Discussion and conclusions: Literature review indicates that experimental findings mainly depend on electrode polarity and position over the SC. tsDCS is a tool amenable to modulate motor circuits excitability in the spinal cord. This intervention can have clinical implications in the treatment of conditions like spasticity. However, future studies should consider EF magnitude and its orientation relative to spinal neurons. We propose that future clinical protocols should be guided by computational modelling to increase the chances of consistent positive results [Published studies showed different neuromodulation effects on the motor responses of the lower limb. Whereas some studies reported a reduction of spinal motoneurons excitability using anodal tsDCS, others described higher motor unit recruitment with cathodal stimulation T10\u2013T12), suggesting modulation of Ia-motoneuron (MN) synapse. Other authors failed to replicate a modulatory effect applying tsDCS . Modelli, suggest results ."} +{"text": "Hope has been associated with increased pain tolerance and has been incorporated in interventions targeting chronic pain . Research suggests that African Americans with osteoarthritis (OA) pain experience greater pain severity and disability compared to non-Hispanic White individuals . Although the literature is limited, there is some evidence to suggest racial/ethnic differences in hope . The current study examined race as a moderator of the association between hope and pain in a sample of older adults. Experience sampling (ESM) data was used from a multi-site study examining non-Hispanic White and African American individuals with knee osteoarthritis (OA). Participants completed the Adult Hope Scale during baseline interviews and self-reported momentary pain during 28 ESM calls. Multilevel models revealed a significant interaction between hope and race (p = .04). Specifically, greater hope was associated with decreased momentary pain, and this association was stronger for African American compared to non-Hispanic White individuals. Results suggest that high levels of hope may be particularly protective for African American chronic pain patients. These findings can help inform existing and future interventions focused on enhancing hope in chronic pain populations."} +{"text": "Spinal cord injury (SCI) results in multiple pathophysiological processes, including blood\u2013spinal cord barrier disruption, hemorrhage/ischemia, oxidative stress, neuroinflammation, scar formation, and demyelination. These responses eventually lead to severe tissue destruction and an inhibitory environment for neural regeneration.cAMP signaling is vital for neurite outgrowth and axonal guidance. Stimulating intracellular cAMP activity significantly promotes neuronal survival and axonal regrowth after SCI.However, neuronal cAMP levels in adult CNS are relatively low and will further decrease after injury. Targeting cAMP signaling has become a promising strategy for neural regeneration over the past two decades. Furthermore, studies have revealed that cAMP signaling is involved in the regulation of glial cell function in the microenvironment of SCI, including macrophages/microglia, reactive astrocytes, and oligodendrocytes. cAMP-elevating agents in the post-injury milieu increase the cAMP levels in both neurons and glial cells and facilitate injury repair through the interplay between neurons and glial cells and ultimately contribute to better morphological and functional outcomes. In recent years, combination treatments associated with cAMP signaling have been shown to exert synergistic effects on the recovery of SCI. Agents carried by nanoparticles exhibit increased water solubility and capacity to cross the blood\u2013spinal cord barrier. Implanted bioscaffolds and injected hydrogels are potential carriers to release agents locally to avoid systemic side effects. Cell transplantation may provide permissive matrices to synergize with the cAMP-enhanced growth capacity of neurons. cAMP can also induce the oriented differentiation of transplanted neural stem/progenitor cells into neurons and increase the survival rate of cell grafts. Emerging progress focused on cAMP compartmentation provides researchers with new perspectives to understand the complexity of downstream signaling, which may facilitate the clinical translation of strategies targeting cAMP signaling for SCI repair. Spinal cord injury (SCI) is a devastating neural trauma with an incidence of 54 patients per million people in the United States , the subacute phase (2 days to 2 weeks), the intermediate phase (2 weeks to 6 months), and the chronic phase (>6 months) , which include nine transmembrane members and one soluble member . tm-ACs are downstream effectors of G-protein coupled receptors (GPCRs) that are activated by extracellular molecules, AC1 and AC8 are also directly activated by Ca2+. sAC is activated by intracellular bicarbonate, Ca2+, and ATP , and oligodendrocyte-myelin glycoprotein (OMgp) and thereby induce Arg-1 (an M2 macrophage biomarker) expression tend to exhibit lower GFAP expression and a preserved nonreactive morphology with slender processes, indicating that the increase in Epac2 activity might attenuate the activation of astrocytes. As observed in ex vivo SCI models, S-220-treated spinal cords show a closer relationship between neurite profiles and astrocyte processes, whereas nontreated spinal cords exhibit collapsed growth cones when confronted with RAs are activated to become reactive astrocytes (RAs) that exhibit cellular hypertrophy and extended processes. RAs subsequently migrate to the periphery of the lesion site, express cell adhesion molecules, and ultimately transform into scar-forming astrocytes (SAs) that adhere to each other to form the glial scars , neural stem and progenitor cells (NSPCs), bone marrow stromal cells (MSCs), and olfactory ensheathing cells (OECs). These cell grafts provide permissive matrices to synergize with the cAMP-induced inherent growth capacity of neurons. Researchers previously injected Schwann cells and db-cAMP into the lesion site of SCI models and delivered rolipram subcutaneously for 2 weeks. The combination treatment significantly promoted axonal regeneration growth and myelination, leading to improved motor function recovery further investigating the roles of cAMP signaling in different cells, particularly glial cells, under physiological and pathological conditions; (2) promoting the entry of combination strategies into preclinical or clinical trials to further confirm their safety and efficacy; and (3) comprehensively elucidating cAMP compartmentalization to more precisely modulate spatiotemporal intracellular cAMP signaling. All of these efforts will promote the development of new therapeutic strategies for SCI and ultimately benefit the patients.GZ and JG wrote the manuscript. ZW drew the figures. SH and YL helped write the manuscript and reviewed the manuscript. All authors reviewed and approved the final manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Determining ways to improve hip fracture recovery in older adults is important, however recruitment of this target population into clinical trials is challenging. Multimodal interventions that target multiple mechanisms of recovery may improve outcomes, but each component presents unique recruitment barriers. While exercise interventions have been shown to be beneficial for hip fracture recovery, offering exercise following completion of conventional physical therapy can be viewed as a burdensome time commitment. Hormone replacement therapy may hold promise for overcoming anabolic resistance, but concern about adverse side effects can also deter participation. STEP-HI is a multisite trial testing whether exercise and testosterone can improve hip fracture recovery in older women. In this talk, recruitment barriers experienced in STEP-HI and strategies employed to overcome these barriers will be discussed. Strategies include: partnering with hospitals, skilled nursing facilities and orthopedic surgeons. providing talks and education materials; and featuring past participant testimonials in recruitment materials."} +{"text": "Researchers are encountering increasing challenges in recruiting participants for healthcare research. We conducted semi-structured individual interviews to identify participant barriers to research and recommendations for overcoming these challenges. We recruited 17 patients and eight caregivers who were approached to participate in a randomized control trial. We also recruited 31 primary care physicians. Using grounded theory, three researchers independently coded the transcripts and then met to compare codes and reconcile discrepancies. Themes from patient and caregiver interviews included time constraints, privacy concerns, lack of research familiarity, disconnect with research institution, self-perceived health status, and concerns with study randomization and repetitive questions. Physician-identified barriers focused on time constraints and study randomization. Patient and caregiver recommendations for study recruitment included various recruitment techniques. Physician recommendations were related to incentives. Although patients and caregivers prefer that their physicians recruit them for health-related research studies, physicians identified time constraints as a barrier to research involvement."} +{"text": "This systematic review aims to evaluate the effect of nicotine replacement therapies (NRTs) on measures of agitation amongst nicotine-dependent adult psychiatric inpatients.Since the introduction of the smoke-free policy for all psychiatric facilities, a psychiatric admission is likely to upset a nicotine-dependent individual's normal routine of nicotine consumption. In addition to the physiological effects of nicotine withdrawal (NW), the interpersonal dynamic which nurse-led guardianship of nicotine products constructs presents stressors to the nicotine dependent patient.Several systematic reviews evaluating changes in objective measures of agitation amongst smoking patients in medical critical care units have found varied results, with some demonstrating worsening agitation with NRT use. We therefore believe that there is sufficient equipoise in the use of NRT to prompt a review of studies amongst psychiatric inpatients.This review identified English language studies through developed search strategies in PubMed/MEDLINE, EMBASE, PyschINFO, PSYCHLit, Cochrane databases, and Google scholar. The bibliographies of notable papers were explored. Hand searches of five major psychiatric journals were conducted. Peer reviewed studies of any study design were included if they reported primary data of adult psychiatric inpatients. Studies were extracted from 1990 \u2013 present, this was felt appropriate as nicotine replacement patches became available in 1992.Search strategies were informed by MeSH search terms and included multiple conceptions of \u201cagitation\u201d, including variations on; agitation, irritability, and arousal to capture the concept from broad academic constructions. The quality of studies was assessed with the Newcastle-Ottawa and Cochrane Collaboration tools.This review follows PRISMA guidelines, and an application for PROSPERO registration has been submitted pending acceptance.Two studies were identified which matched inclusion criteria. A double-blinded randomised placebo-controlled trial of 40 nicotine-dependent inpatients from Allen et al. reported a significant 23% reduction in Agitated Behaviour Scores at 24 hours following NRT administration on admission compared to their matched placebo controls. Yet a retrospective cross-sectional analysis from Okoli using scores for NW identified more severe withdrawal symptoms including \u201crestlessness\u201d and \u201canger/irritability\u201d than nicotine-dependent patients not provided with NRT.Despite considerable commentary within literature there is presently only one study providing moderate evidence of a positive benefit to measures of agitated behaviour from the use of NRT amongst nicotine-dependent psychiatric inpatients. There is currently very low evidence whether NRT improves or exacerbates the agitation associated with NW amongst nicotine-dependent psychiatric inpatients."} +{"text": "Robust evidence of fetal programming of adult disease has surfaced in the last several decades. Human and preclinical investigations of intrauterine insults report perturbations in placental nutrient sensing by the mechanistic target of rapamycin (mTOR). This review focuses on pregnancy complications associated with placental mTOR regulation, such as fetal growth restriction (FGR), fetal overgrowth, gestational diabetes mellitus (GDM), polycystic ovarian syndrome (PCOS), maternal nutrient restriction (MNR), preeclampsia (PE), maternal smoking, and related effects on offspring birthweight. The link between mTOR-associated birthweight outcomes and offspring metabolic health trajectory with a focus on sexual dimorphism are discussed. Both human physiology and animal models are summarized to facilitate in depth understanding. GDM, PCOS and fetal overgrowth are associated with increased placental mTOR, whereas FGR, MNR and maternal smoking are linked to decreased placental mTOR activity. Generally, birth weight is reduced in complications with decreased mTOR and higher with increased mTOR . Offspring display obesity or a higher body mass index in childhood and adulthood, impaired glucose and insulin tolerance in adulthood, and deficiencies in pancreatic beta-cell mass and function compared to offspring from uncomplicated pregnancies. Defining causal players in the fetal programming of offspring metabolic health across the lifespan will aid in stopping the vicious cycle of obesity and type II diabetes. Decades of research have revealed that many diseases diagnosed over a lifetime have fetal origins. As a response to various exposures during the developmental period, such as maternal over/under-nutrition, chemicals, and stresses, fetal organs may be mal-programmed due to their inherent plasticity during development. The concept of fetal programming suggests that nutritional and environmental events that occur during critical periods of pregnancy cause permanent effects on the fetus and the long-term health trajectory of the offspring. A robust and important area of research investigating the developmental origins of health and disease (DOHAD) hypothesis has made huge strides in understanding the fetal programming of adult chronic and non-communicable diseases. Myriad epidemiological studies provide evidence of this association as it relates to risk for obesity, hypertension, cardiovascular disease, and diabetes ,2. HowevMechanistic target of rapamycin (mTOR) is a serine/threonine kinase that serves as a core component of mTOR complex 1 and mTOR complex 2. mTOR is activated by growth receptors, such as insulin growth factor (IGF) and insulin receptors, via IRS and the PI3K cascade. Direct downstream targets phosphorylated by mTOR include ribosomal protein S6/S6K1 and 4E-BP1, both involved in protein synthesis, ULK1, which inhibits autophagy, and others see . Newer sMaternal-placental-fetal units act in coordination to meet the needs of the fetus and to support the mother simultaneously. Within this coordinated system, mTOR senses and integrates nutrient signals ,8. As suThis narrative review will focus on the relationship between alterations in placental mTOR signaling associated with intrauterine complications and offspring metabolic health. First, placental mTOR signaling and associated birth weight outcomes will be reviewed for each pregnancy complication, with a special focus on sexual dimorphism within each pregnancy complication if data are available. Subsequently, the offspring metabolic health trajectory will be evaluated through discussions of obesity, insulin sensitivity, and pancreatic beta-cell mass and function. Human pathophysiology is reviewed with discussion of important animal studies to better facilitate readers\u2019 understanding.Fetal growth restriction (FGR) is defined as fetal weight below the 10th percentile for gestational age. FGR affects up to 10% of all pregnancies in the United States and carries an increased risk of perinatal mortality and morbidity. Long-term FGR complications include higher risk for hypertension, cardiovascular disease and type II diabetes . FGR invIn human pregnancies, mTOR activity has been shown to be decreased in placentas of FGR/growth-restricted babies . AlteredFGR itself is biased toward males in the human context . In factMaternal obesity during pregnancy elevates the risk of pregnancy complications and large-for-gestational-age babies . SituatiA Swedish study revealed a positive correlation between maternal BMI during the first trimester of pregnancy, birth weight, and placental insulin and mTOR signaling. These findings were accompanied by an inverse correlation between birth weight and AMPK signaling . These dMale sex has been defined as an independent risk factor for macrosomia or fetal overgrowth in humans , perhapsmTOR signaling is a key pathway in mediating maternal-fetal nutrient transport as described above . BrieflyA study of human GDM placentas showed increased mTOR signaling as determined by phosphorylated p70S6K (downstream mTOR target) in GDM compared to normal term placentas . Other sMetformin treatment for GDM introduces another aspect to placental mTOR regulation during pregnancy. Metformin is an anti-diabetic medication commonly prescribed to women with GDM that targets AMPK and subsequently blunts mTOR signaling. Metformin can be transported into fetal blood circulation. Therefore, mTOR signaling in the placenta and developing fetus can be reduced in response to metformin treatment for GDM. In human studies, metformin-exposed offspring are at increased risk for fetal growth restriction and catch-up growth during mid-childhood . In a muGDM is associated with higher birth weight and increased risk for macrosomia , with 15Polycystic ovary syndrome (PCOS) is an endocrine disorder that commonly affects women of reproductive age. Obesity and insulin resistance commonly characterize PCOS and can present PCOS mothers with an increased risk for GDM and hypertension . PCOS moLimited human studies have assessed the direct relationship between placental mTOR, PCOS and pregnancy outcomes. One study addressed whether mTOR signaling was increased in PCOS placentas from uncomplicated pregnancies. However, this study found no effect on mTOR signaling in the PCOS placenta versus controls . In a stHuman and preclinical studies segregating results by sex are lacking in PCOS.Maternal nutrient restriction (MNR) is a phenomenon leading to placental insufficiency and FGR. MNR captures both low protein diets and calorie restriction. Perhaps the most striking evidence linking human MNR to placental insufficiency is the 1944\u20131945 Dutch Famine, where severe calorie restriction during critical periods of pregnancy resulted in low birth weights and reduced placenta masses .In a baboon model, MNR reduced fetal weights by 13%. This reduction in weight was accompanied by a decrease in placental mTOR signaling and AKT/insulin signaling as determined by Western blot analysis . A rat sRoseboom et al., 2011 reported sexual dimorphic effects in severity of reduction of placental size and area in the Dutch Famine cohort. The effect of MNR during the Dutch Famine on the placental area was more severe for male offspring compared to female . PreclinPreeclampsia (PE) is a hypertensive disorder that occurs during pregnancy. Human studies have presented mixed results surrounding the relationship between PE and birth weight.Human placentas from pregnancies complicated by PE exhibit a mild decrease in phosphorylated mTOR but an increase in downstream phosphorylated 4E-BP1 . A signiMild PE has been associated with normal fetal growth of male offspring and growth restriction of female offspring at neonatal stage . A potenThe Centers for Disease Control and Prevention estimate that 12% of women smoke during pregnancy in the United States. Maternal smoking is associated with lower birth weight. For example, an analysis of the Tasmanian Infant Health Survey revealed that maternal prenatal smoking was associated with lower placental and birth weight . The HeaA preclinical model determined that dams exposed to secondhand smoke for 4 days had offspring with decreased placental and fetal weights (FGR), decreased trophoblast invasion, and decreased activation of placental phospho-mTOR, phospho-p70 and phospho-4E-BP1 .Maternal smoking during pregnancy has adverse impacts on fetal programming and offspring health. However, there is a lack of preclinical models of smoking, which limits our understanding of causal factors. In addition, a need for stratification by sex in human investigations and mechanism-driven studies with sex as a biological variable are needed to determine whether there is a sexual dimorphic effect of maternal smoking on offspring metabolic health and resilience.The relationship between birth weight and risk for obesity across the lifespan is well-established. Several findings indicate higher BMI in childhood and adulthood in the offspring of mothers with pregnancy complications. Placental mTOR has been implicated in programming offspring tissues to be more sensitive to a metabolic challenge .Observational studies suggest that the offspring of GDM mothers are more likely to develop childhood obesity (or higher BMI) compared to offspring not exposed to maternal hyperglycemia. This finding has been repeated in several studies across the globe . HoweverSeveral epidemiological studies have reported an association between maternal smoking and childhood/adolescent obesity ,71, possYoung adult males from the Dutch Famine cohort were at greater risk of developing obesity following exposure to nutrient restriction in utero. This finding was specific to enduring severe under-nutrition during first half of pregnancy . SimilarDirect mTOR deletion in the placenta resulted in offspring with obesity outcomes that were different between sexes. Neither male nor female offspring with placental mTOR knockout developed obesity when subjected to a normal chow diet for 12-weeks. However, when metabolically challenged with a high-fat diet , females became more obese as compared to littermate controls, whereas male offspring on a high-fat diet did not develop obesity [Multiple pregnancy complications are associated with reduced placental mTOR signaling and low birth weight. Low birth weight also has a connection to insulin resistance in adulthood. Due to the timescale needed to study the development of insulin resistance in adulthood, there are limited human studies investigating this relationship in a longitudinal manner. However, evidence from the Dutch Famine cohort and preclinical models have substantiated this relationship .Individuals from the Dutch Famine cohort have reported low birth weight due to prenatal exposure to under-nutrition. In adulthood, this cohort displays impaired glucose tolerance and insulin resistance possibly related to inadequate insulin secretion or action . AnotherA 2002 study was the first to link maternal smoking to development of early adult-onset diabetes . Since tFemale offspring with placental mTOR knockout in utero displayed high-fat diet-induced insulin intolerance in adulthood, accompanied by hyperinsulinemia. On the other hand, male offspring with placental mTOR knockout had comparable glucose and insulin tolerances to littermate controls .Determining the relationship between placental mTOR and offspring pancreatic beta-cell mass and function comprises a newer area of research. Direct placental mTOR knockout gives rise to sexually dimorphic effects on beta-cell mass compensation, discussed in more detail below. The relationship between intrauterine insults such as preeclampsia and nutrient restriction, which have previously been associated with altered mTOR signaling in the placenta, have been studied in the RUPP model of preeclampsia and in maternal low-protein diet investigations ,59.In the gestational hypertension RUPP model, increased beta-cell death, reduced beta-cell area, and decreased mTOR protein level in the offspring fetal pancreas were reported . In respDirect ablation of placental mTOR reduced placental weight in the female offspring but did not alter beta-cell mass in both male and female neonates. Adult female and male offspring showed normal glucose homeostasis under a normal chow diet. While adult female offspring with mTOR knockout in utero demonstrate high-fat diet-induced insulin resistance, they have normal beta-cell mass and function compared to littermate controls .Differences in placental and fetal gene expression, epigenetic mechanisms, and hormone levels have been identified early in fetal development. Dearden et al., in 2018, elegantly reviewed several mechanisms mediating sexual dimorphic programming leading to adult metabolic disruption . DespiteThe importance of mTOR signaling in the placenta to regulate fetal development and programming of metabolic organs is gaining momentum. The link between perturbed placental mTOR and adverse birth weight outcomes has been assessed in several pregnancy complications, and a robust relationship between birth weight and offspring metabolic health trajectory has been defined. However, longitudinal studies and mechanistic investigations are lacking in the current body of research. Longitudinal human studies, as well as preclinical studies designed to follow mother and offspring from pre-conception, through gestation, and across the lifespan are needed to draw causal conclusions. Mechanistic studies investigating molecular changes occurring in response to placental mTOR perturbations both locally in the placenta and systemically throughout the developing fetus will be necessary to understand the sexual dimorphic metabolic outcomes observed. In addition to those highlighted in the previous section, several other mechanisms mediating sexual dimorphism include alterations in inflammation, nutrient transport, and hypoxia in the placenta and developing fetal tissues."} +{"text": "In 2016, catastrophic flooding in south Louisiana claimed 13 lives with billions of dollars in damage to homes and communities in the decade after Hurricanes Katrina and Rita devastated the US Gulf Coast. In this study, we tested the inoculation hypothesis which predicts that older adults will be less distressed than younger adults due to their prior experience with severe weather events. Participants were 218 predominately middle-aged and older adults who varied in current and prior flood experience: less than half (40%) did not flood in 2016, 31% had flood damage, and 29% had relocated permanently inland after catastrophic losses in the 2005 Hurricanes Katrina and Rita and they flooded again in 2016. Depression symptoms were assessed with the 9-item Patient Health Questionnaire (PHQ-9). Emotion regulation strategies were measured using the Cognitive Emotion Regulation Questionnaire-Short Form. Results indicated that the older adults had fewer symptoms of depression and were less likely to report self blame for flood-related adversities compared to younger adults. The two age groups did not differ significantly on the emotion regulation strategies of acceptance, reappraisal, positive refocusing, other blame, and perseveration. Age was inversely associated with symptoms of depression and the maladaptive strategies of self blame for flood-related misfortune and perseveration over losses. These data support the inoculation hypothesis and suggest that prior severe weather experiences, which are likely for older adults living in hurricane prone areas, are important for post-flood resilience. Implications of these findings for disaster planning and age-sensitive interventions to mitigate adversity are considered."} +{"text": "Bilateral giant inguinoscrotal hernia (GIH) is rare and creates significant challenge in surgical management. The main concern of hernia reduction to abdominal cavity is development of abdominal compartment syndrome (ACS). Different approaches for prevention of ACS after surgery have been suggested.We report a case of 68-year-old male with bilateral inguinoscrotal hernia for 20\u00a0years reaching just below midpoint of thigh. He presented with difficulty in micturition and mobility. Preoperative investigations were normal. He underwent bilateral mesh repair without any preoperative or intraoperative adjunct measures. No significant complication occurred in postoperative period.Bilateral GIH is rare and the patients usually present late. GIH has been classified into three types on the basis of extension. Type I GIH can be managed with simple hernioplasty, in both unilateral and bilateral cases. Measures like resection of hernia contents and measures to enlarge intraabdominal space are warranted in type II and III GIH. Abdominal volume can be increased by utilising techniques like Pre-operative Progressive Pneumoperitoneum (PPP), injection of Botulinum toxin A (BTA) in the anterior abdominal wall, and rotation of viable tissue. The measures can be used either alone or in combination.Type I GIH can be treated with simple hernioplasty with safety with monitoring for features of ACS and respiratory complications postoperatively. However, additional measures like resection of hernia contents or procedures to enlarge intra-abdominal space are warranted for type II and III GIH. \u2022Surgical management of bilateral giant inguinoscrotal hernia is challenging as reduction of hernia contents to abdominal cavity may lead to development of abdominal compartment syndrome (ACS) and cardiorespiratory complications.\u2022We report a case of bilateral GIH managed with bilateral mesh repair with postoperative monitoring for features of ACS and cardiorespiratory complications.\u2022There was no significant complication in the postoperative period and no recurrence in six month follow-up period. This case report has been reported in line with the SCARE Criteria 2A 68-year-old male, known case of bilateral inguinoscrotal hernia for 20\u00a0years presented to our center with complaint of increasing difficulty in micturition for past two years. He had multiple episodes of acute urinary retention that required catheterization. The patient couldn't walk and sit properly. The swelling had become irreducible with time. He didn't have abdominal pain, distension, and vomiting. He didn't have any co-morbidities.Physical examination revealed bilateral massive inguinoscrotal swelling that descended to just below midpoint of inner thigh in the standing position . There wPatient underwent elective exploration via inguinoscrotal approach in tertiary care hospital by a team of general and gastrointestinal surgeons and mesh hernioplasty performed on bilateral inguinal region. Intra-operatively, large hernia sac was present containing omentum and small bowel with only the proximal ileum A and B. A double-layered closure by prolene surgical mesh was done followed by reconstruction of the wall. This was followed by exploration of contralateral left inguinoscrotal hernia. Intraoperatively, we found hernia sac containing omentum and small bowel with only the proximal jejunum lying within the sac. Adhesiolysis was done and manual reduction of hernia content was done through the deep inguinal similar to left inguinal hernia. Closure was done with Prolene Mesh followed by reconstruction of wall and bilateral inguinal drain was placed .Fig. 3ClPostoperatively, there was early return of bowel movement and mobilization. His intraabdominal pressure was monitored routinely to avoid abdominal compartment syndrome. No respiratory complication was seen during his stay in hospital. On the seventh postoperative day, the drain was removed before discharge. Small postoperative inguinal seroma developed which resolved within few weeks without surgical intervention. There was no evidence of recurrence at six months during follow up.3Giant inguinoscrotal hernia (GIH) is defined as hernia extending below the midpoint of inner thigh of a patient in erect position In 2013, Akpo conducted a study focusing on psychosocial aspects of bilateral GIH. The patients visited medical facility either due to inability of penetration or denial of sexual intercourse by partners. They presented late because of financial constraint or neglect of the disease despite understanding that surgery is necessary for treatment. These patients also experience difficulty in movement like our patient and at times face acute complications like bowel obstruction and acute retention of urine. These consequences significantly impair their quality of life. Our patient also experienced multiple episodes of acute retention of urine which can possibly be due to constrictive effect of enlarged scrotum on buried penis. In the same study, Akpo also gave classification of bilateral GIH for the first time Considering the rarity of the disease and unavailability of standard approach, dilemma exists among healthcare providers for management of GIH Trakarnsagna A et al. classified GIH into three types on the basis of extent of hernia sac, based on which management principles differ. In type I GIH (hernia that extends between midpoint of inner thigh and the midpoint of the mid-inner thigh and suprapatellar margin), hernioplasty with forced reduction with post-operative intra-abdominal and intra-thoracic pressure monitoring is considered enough. However, in other types, resection of contents or increased intra-abdominal volume procedures is warranted to prevent intra-abdominal hypertension One study conducted among 32 patients with type I GIH including a case of bilateral GIH showed that laparoscopic surgery using Transabdominal Pre-peritoneal (TAPP) approach with negative pressure drain can be performed with safety and low post-operative complications In type II and type III GIH with loss of domain, additional procedures to prevent ACS should be considered. Various approaches used for prevention are resection of hernia contents and procedures to enlarge intra-abdominal volume The techniques mentioned earlier are either used alone or in combination for GIH as mentioned in some recent studies Despite emergency surgical intervention, a rare case of fatality in bilateral GIH has been reported in an obese patient presenting with respiratory distress 4Type I GIH, including bilateral GIH, can be treated safely with simple hernioplasty. However, patient should be monitored vigilantly for features of ACS and respiratory complications during the postoperative period. In type II and type III GIH, additional measures like resection of hernia contents or procedures to enlarge intra-abdominal space are required.The case report is exempt from ethical approval in our institution.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Sunil Basukala (SB), Sabina Rijal (SR), Narayan Thapa (NT), Rakesh Kumar Gupta (RKG) = Study concept, Data collection, and surgical therapy for the patientSB, SR, Bishnu Deep Pathak (BDP) = Writing - original draft preparationRM, SR, BDP = Editing and writingNT and RKG = senior author and manuscript reviewer.All the authors read and approved the final manuscript.Sunil Basukala.Not applicable.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.Not commissioned, externally peer-reviewed.None."} +{"text": "Previous research suggests depressive symptoms and loneliness are increasingly prevalent among older adults living in lower-income neighborhoods. The purpose of this study was to examine the extent to which neighborhood socioeconomic status (SES) was associated with depressive symptoms and loneliness among a sample of older adults from the Healthy Heart and Mind Study ; 66.7% women; 40.6% African American). It was hypothesized that older adults living in neighborhoods with greater socioeconomic disadvantage would report more depressive symptoms and loneliness than those residing in neighborhoods with less socioeconomic disadvantage. Depression was assessed with the Beck Depression Inventory-II (BDI-II), and loneliness was assessed using the Revised University of California, Los Angeles (UCLA) Loneliness scale. Neighborhood SES was measured with the Area Deprivation Index (ADI), which allows rankings of neighborhoods by SES disadvantage both statewide and nationally. After controlling for demographic variables , linear regression analyses showed that greater neighborhood SES disadvantage was associated with higher depression scores and higher loneliness scores . These findings highlight the importance of neighborhood context on mental health in older adults, as underserved populations are more likely to experience declines in mental health under strenuous circumstances. Future research should investigate the impact of neighborhood SES on mental health in aging adults."} +{"text": "Aging elicits dramatic changes to DNA methylation (DNAm), however the causes and consequences of such alterations to the epigenome remain unclear. The utility of biomarkers of aging based on DNAm patterns would be greatly enhanced if in vitro models existed that recapitulated physiological phenotypes such that modulation could garnish mechanistic insights. Using DNAm from serially passaged mouse embryonic fibroblasts, we developed a marker of culture aging and asked if culture phenotypes, like exhaustive replication, are epigenetically analogous to physiological aging. Our measure, termed DNAmCULTURE, accurately estimated passage number and was shown to strongly increase with age when examined in multiple tissues. Furthermore, we observed epigenetic alterations indicative of early cultured cells in animals undergoing caloric restriction and in lung and kidney fibroblasts re-programmed to iPSCs. This study identifies culture-derived alterations to the methylome as physiologically relevant and implicates culture aging as an important feature in known epigenetic aging phenomena."} +{"text": "Researchers worldwide are repeatedly warning us against future zoonotic diseases resulting from humankind\u2019s insurgence into natural ecosystems. The same zoonotic pathogens that cause severe infections in a human host frequently fail to produce any disease outcome in their natural hosts. What precise features of the immune system enable natural reservoirs to carry these pathogens so efficiently? To understand these effects, we highlight the importance of tracing the evolutionary basis of pathogen tolerance in reservoir hosts, while drawing implications from their diverse physiological and life-history traits, and ecological contexts of host-pathogen interactions. Long-term co-evolution might allow reservoir hosts to modulate immunity and evolve tolerance to zoonotic pathogens, increasing their circulation and infectious period. Such processes can also create a genetically diverse pathogen pool by allowing more mutations and genetic exchanges between circulating strains, thereby harboring rare alive-on-arrival variants with extended infectivity to new hosts . Finally, we end by underscoring the indispensability of a large multidisciplinary empirical framework to explore the proposed link between evolved tolerance, pathogen prevalence, and spillover in the wild. Plasmodium knowlesi (Rattus norvegicus) and domestic species that are known to share more zoonotic pathogens with humans than other animal taxa can remain infected with the Marburg virus for 7 months after inoculation , a small number of individuals can shed Brucella abortus, the causative agent of brucellosis, persistently at a high level for more than 2 months . Growing evidence suggests that besides causing severe flu-like symptoms in humans , host-pathogen interactions have been traditionally viewed as purely antagonistic. Consequently, studies on pathogen defense have primarily focused on mechanisms that host typically use to resist infections by activating immune responses . This biIn this review, we are primarily addressing how disease tolerance in reservoir species can be intrinsically linked to the maintenance and transmission of pathogens and their spillover. We first discuss why and how tolerance might naturally evolve during long-term association between natural hosts and pathogens as an effective strategy. We then outline the favorable ecological and evolutionary contexts vis-\u00e0-vis host-pathogen tolerogenic interactions that may maximize the spillover risk where individuals can harbor high viral titers without showing any significant morbidity, suggesting features of infection tolerance (Hemignathus virens) from low-elevation regions show a reduced rate of weight loss and better physiological condition even during the acute-phase infection with Plasmodium relictum than their high-elevation counterparts, indicating their higher tolerance to pathological effects of avian malaria (Microtus agrestis), mature males can maintain better body condition than immature males while harboring very high macro- and micro-parasite loads, again indicating a higher tolerance (Bufo americanus) and green frogs (Rana clamitans) also show characteristics of relatively higher tolerance to Echinostoma trivolvis, a locally abundant trematode species, compared to younger tadpoles , the natural reservoirs for the Marburg virus, lack the induction of several pro-inflammatory genes that are classically implicated in primate filoviral pathogenesis such as CCL8, FAS, and IL6 and African green monkeys (Chlorocebus aethiops) infected with SIV show acute early inflammation, but they also possess regulatory mechanisms to rapidly control such responses; for example, they use anti-inflammatory inhibitory cytokines such as transforming growth factor-\u03b2 (TGF-\u03b2) and IL-10 infected with Sin Nombre virus (SNV) also upregulate cytokines that correspond to Treg responses, prolonging the viral presence (R. norvegicus) infected with Seoul virus (SEOV) not only reduce the pro-inflammatory mediators such as interleukin-6 (IL-6) or TNF-\u03b1 in their lungs but also increase the expression of regulatory factors TGF-\u03b2 proliferation, tolerating the effects of viral infection populations performed by Hayward and coworkers from two locations with a different coevolutionary history of infection by bacterium Mycoplasma gallisepticum was particularly helpful here and higher levels of anti-inflammatory cytokine (IL-10) isolated from regions with longer exposure to heartworm (Dirofilaria immitis) also showed higher tolerance compared to populations with little exposure to the parasite . In anotparasite . These rparasite . In rode strongly supports this possibility where small isolated populations had a higher abundance of henipaviruses and extended within-host latency and chikungunya virus (CHIKV) possibly derived from a bat-isolated orthoreovirus (Perameles bougainville), which exhibited genomic properties of both the Papillomaviridae and the Polyomaviridae family of viruses (Rousettus leschenaultii bats for 2 years found recombinants of RdRp (RNA-dependent RNA polymerase) and p10 genes in Ro-BatCoV GCCDC1 within as early as 5 months since the initial surveillance began and SIV (retrovirus) might persist together in their natural hosts sooty mangabeys , which s (CHIKV) . Althoug (CHIKV) . For exa (CHIKV) . This is (CHIKV) . Also, ireovirus . In thisreovirus . Another viruses . These oce began .Pathogens, especially viruses, can evolve much faster than their hosts, presenting numerous mechanisms to avoid immune sensing . SIV, foConversely, host-pathogen tolerogenic interactions over an evolutionary timescale might also lead to progressive loss of immune evasion mechanisms in the pathogen, potentially reducing their infectivity to future hosts. Perhaps, one of the best-documented examples includes Myxoma virus (MYXV), which is highly pathogenic to European rabbits, with a case fatality rate close to 100% . The samFinally, recent vaccination studies in poultry birds can also offer some important clues on how tolerance can in principle influence the pathogen persistence and diversity. This is particularly true for vaccines that operate by reducing the disease symptoms , rather than preventing the infection, pathogen replication, and transmission . InfectiAnother example is live vaccination with attenuated strains of porcine reproductive and respiratory syndrome virus (PRRSV), which prevents the development of disease symptoms in pigs but does not protect them against contracting the infection . In factHost immune strategies, ecology, and pathogen prevalence all play instrumental roles in facilitating spillover, but studying them in isolation is far from ideal given the complex interactions that are involved therein. Costly immune responses might evolve to act at suboptimal levels in the wild due to constraints from available resources and physiological states . AlthougOur understanding of emerging diseases from natural reservoirs has increased substantially over the past two decades , but unfTransmission dynamics might also be contingent on intermediate hosts and vector populations . UnderstLong-term tracking of pathogens and disease with altered species interactions is perhaps most relevant for rapid land-use changes in recent decades \u2013 deforehttps://www.globalviromeproject.org; https://ibol.org/programs/bioscan), the extension of the International Barcode of Life Program . Finally, proactive programs aimed at pandemic prevention also critically need more spatial and temporal information describing key changes in ecological communities and environmental parameters to better understand why circulation and transmission risk of zoonotic pathogens might vary across ecosystems. A recent web-based application \u2018SpillOver\u2019 is particularly useful to gain some of these insights , was operational until recently to identify broad patterns of emerging pathogens with pandemic potential in geographical regions that are disease hotspots such as the Republic of Congo, China, Egypt, India, and Malaysia . However Program , and theinsights . In addiAn integrated program to catalog pathogens across species, populations, and locations will prepare a unique stage to subsequently ask more mechanistic questions; for example, explaining the macro-scale structural variations, using diverse metrics of host immunological, ecological, and physiological parameters. However, multiple challenges need to be overcome to conduct any meaningful analyses. Below, we describe the indispensability of accepting the challenges and testing the natural variation in immune strategies and their complex interplay with life-history to explain EID prevalence and emergence.Batrachochytrium salamandrivorans that usually infects amphibian skins as a proxy in a wild population of cyprinid freshwater fish , tolerance was quantified by assessing eye cataract formation as a degree of pathology against increasing burden of eye fluke Diplostomum pseudospathaceum (Ovis aries) populations to distinguish how natural selection acts separately on three functionally distinct isotypes of antibodies against a prevalent nematode parasite Teladorsagia circumcincta . In Atlaathaceum . All theumcincta . Future Anolis sagrei lizards also used body condition, locomotor performance, and survival to the end of the breeding season as a function of infection with Plasmodium parasites feeding on a low protein diet showed increased tolerance to Photorhabdus luminescens , however, found increased tolerance to skin penetrating nematode Aplectana sp. when maintained on proteinaceous insect diets found multiple such highly polymorphic sites in the receptor regions, which interacts with the spike proteins of a coronavirus isolated from the same species of bats named as SARSr-CoV rapidly evolved to antagonize host restriction factor tetherin by acquiring mutations in the accessory protein Vpu within merely four passages through an atypical HIV-1 host species pigtailed macaques can help us to partially overcome the uncertainties associated with quantifying parasite burden and estimating fitness traits in the wild .Yet it might be challenging to answer some of the most fundamental questions, such as do hosts actually evolve tolerance to their natural pathogens? If so, how do we track such evolutionary processes? Besides gathering clues from comparative studies using various host populations, laboratory experimental evolution using tractable animal models (with known biology and genomic information) can be an excellent alternative to test these possibilities . They caArmigeres subalbatus is a natural vector for the zoonotic filarial worm Brugia pahangi whom they can tolerate, but not the morphologically and biologically similar pathogen Brugia malayi , which is crucial for their tolerance and survival against chikungunya virus and dengue virus, respectively (Aedes populations lacking (or with inherently lower) viral tolerance; (2) impose long-term viral selection to directly test whether stronger tolerance is correlated with increased vDNA synthesis; and (3) finally, test whether such evolved tolerance can be reversed by reducing vDNA synthesis (using reverse genetics) to verify its functional role and the dynamics of noninfectious diseases (e.g., increased risk autoimmune disorders in geographical regions where improved hygiene has reduced pathogen burden;"} +{"text": "In the immediate postoperative period, cell-free hemoglobin (CFH) and lactate dehydrogenase (LDH) were significantly lower in the study group than in the control group . Moreover, patients treated with the magnetic levitation pump showed lower creatinine and indirect bilirubin [Increased plasma concentrations of circulating cell-free hemoglobin (CFH) are supposed to contribute to the multifactorial etiology of acute kidney injury (AKI). In their recent article: \u201cThe role of cell-free hemoglobin and haptoglobin in acute kidney injury in critically ill adults with ARDS and therapy with VV ECMO.\u201d, Graw et al. identified a cohort of 1044 ARDS patients with CFH and haptoglobin measurements before initiation of ECMO therapy. They concluded that in critically ill patients with ARDS requiring therapy with VV ECMO, increased plasma concentration of CFH were an independent risk factor for AKI. Among patients with increased CFH concentrations, higher plasma haptoglobin concentrations might protect from CFH-associated AKI ["} +{"text": "During the publication process of the original article an errorUn Jung KangThe correct corresponding authors are:Luis Concha-Marambio, Roland G. Heym, Claudio Soto, Byron Caughey and Un Jung KangThe incorrect corresponding author was:The publisher apologizes for the inconvenience caused to the authors and readers."} +{"text": "Standard treatment of Parkinson\u2019s disease involves the dopaminergic medications. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an important neurosurgical intervention often used as alternative treatment to drug therapy; however, it can be associated with increase of impulsive behaviors. This descriptive review focused on studies investigating the correlation between Deep brain stimulation of the subthalamic nucleus and impulsivity in Parkinson\u2019s disease patients, arguing, the action\u2019s mechanism and the specific role of the subthalamic nucleus. We searched on PubMed and Web of Science databases and screening references of included studies and review articles for additional citations. From initial 106 studies, only 15 met the search criteria. Parkinson\u2019s Disease patients with and without Deep Brain Stimulation were compared with healthy controls, through 16 different tasks that assessed some aspects of impulsivity. Both Deep brain stimulation of the subthalamic nucleus and medication were associated with impulsive behavior and influenced decision-making processes. Moreover, findings demonstrated that: Impulse Control Disorders (ICDs) occurred soon after surgery, while, in pharmacological treatment, they appeared mainly after the initiation of treatment or the increase in dosage, especially with dopamine agonists. The subthalamic nucleus plays a part in the fronto-striato-thalamic-cortical loops mediating motor, cognitive, and emotional functions: this could explain the role of the Deep Brain Stimulation in behavior modulation in Parkinson\u2019s Disease patients. Indeed, increase impulsivity has been reported also after deep brain stimulation of the subthalamic nucleus independently by dopaminergic medication status. Deep brain stimulation of the sub-thalamic nucleus (STN-DBS) is an important neurosurgical intervention that could determine, as well as dopaminergic medication, relevant side effects such as increased impulsivity.The studies analyzed in this review showed that after the surgical intervention, impulsivity improves independently by dopamination medication status. These findings could help to individuate contrasting data about the role of DBS on impulsivity in PD patients.Future research should include the study of other factors, such as genetic predisposing, direct effect on limbic part of STN, cognitive outcome or depression scores, and should conduct larger, prospective, controlled trials to better clarify how different subcomponents of impulsivity can be modulated both by dopaminergic drugs and STN-DBS.decisional forms, including delay discounting ;reduced sensitivity to adverse outcomes (negative prediction errors) during learning;reflection impulsivity (rapid decision-making);risk-taking and response conflict (slowing and errors with competing responses);motor forms, such as response inhibition .Parkinson\u2019s disease (PD) is a neurodegenerative disorder due to loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and it is characterized by tremor, rigidity, and bradykinesia . AlthougDeep brain stimulation (DBS) is an adjunctive therapy to reduce some of the symptoms of an advanced stage that responds to levodopa Deep brain stimulation (DBS) is an adjunctive therapy in reducing some of the symptoms of advanced, levodopa-responsive. It improves motor disability by 33%\u201467%, motor fluctuations by 73%\u201483%, and dyskinesias caused by levodopa \u201315. DBS This descriptive review focuses on the studies that investigated the effect of STN-DBS on impulsivity in PD patients and argued its possible mechanisms of action.The sample population included PD patients with STN DBS;Studies provided a neuropsychological assessment of impulsivity and neurocognitive performances;Data compared the performance of PD patients on/off stimulation and on/off medication and healthy controls (HC);We excluded studies on PD patient with dementia or affected by other neurological or major psychiatric disorders;Animal studies and published in non-peer reviewed research were excluded;We excluded case studies.Studies were identified in PubMed and Web of Science databases (November 2007 \u2014 January 2020). The search combined the following terms: (\"impulsive behavior\" [MeSH Terms] OR (\"impulsive\" [All Fields] AND \"behavior\" [All Fields]) OR \"impulsive behavior\" [All Fields] OR \"impulsive\" [All Fields]) AND (\"deep brain stimulation\" [MeSH Terms] OR (\"deep\" [All Fields] AND \"brain\" [All Fields] AND \"stimulation\" [All Fields]) OR \"deep brain stimulation\" [All Fields]) AND (\"parkinson disease\" [MeSH Terms] OR (\"parkinson\" [All Fields] AND \"disease\" [All Fields]) OR \"parkinson disease\" [All Fields] OR \"parkinsons\" [All Fields]). The search terms were identified in the title and abstract. We selected only English texts. After duplicates had been removed, articles were evaluated based on the title, abstract, and text. Studies that examined impulsivity in PD patients were included, after they fulfilled the following criteria:Of 108 studies identified, 15 met the inclusion criteria task , 28 and Reference examinedThe effects of DBS on impulsivity were also investigated by other tasks involving inhibitory control or response selection under conflict. In Simon task, that produced conflict from response impulses in patients with PD and HC, responses were faster and more accurate when relevant (color) and irrelevant features of an imperative stimulus corresponded to the same response, but slower and less accurate when these features signaled conflicting responses . STN-DBSSince it is not yet clear what aspects of PD are actually caused by Basal Ganglia (BG) dysfunction, investigStimulation of the ventromedial STN through its close connection to the nucleus accumbens loop potentially induces ICD . These cSTN plays a key role in inhibition processes, which permit the suppression of premature actions and to block interference from irrelevant stimuli. Altered decision-making is associated with cognitive impulsivity, which is considered the inability to weigh the consequences of immediate and future events and, consequently, delay gratification . Lesion Two studies hypothesized that STN DBS selectively improves inhibitory functions , 41. ThiStudies on impulsivity in PD patients highlighted conflicting results. DA seems to represent the main risk factor that leads to \u201creflection impulsivity\u201d. Indeed, ICDs predominantly occurred subsequent to treatment initiation or dosage increase particularly related to the effects of the DA , 25. HowContrasting data suggest that STN-DBS significantly improves the proficiency of reactive inhibitory control , 41 and The etiology and pathogenesis of treatment-induced impulsivity in PD remain unknown , though"} +{"text": "While spinal interbody cage options have proliferated in the past decade, relatively little work has been done to explore the comparative potential of biomaterial technologies in promoting stable fusion. Innovations such as micro-etching and nano-architectural designs have shown purported benefits in in vitro studies, but lack clinical data describing their optimal implementation. Here, we critically assess the pre-clinical data supportive of various commercially available interbody cage biomaterial, topographical, and structural designs. We describe in detail the osteointegrative and osteoconductive benefits conferred by these modifications with a focus on polyetheretherketone (PEEK) and titanium (Ti) interbody implants. Further, we describe the rationale and design for two randomized controlled trials, which aim to address the paucity of clinical data available by comparing interbody fusion outcomes between either PEEK or activated Ti lumbar interbody cages. Utilizing dual-energy computed tomography (DECT), these studies will evaluate the relative implant-bone integration and fusion rates achieved by either micro-etched Ti or standard PEEK interbody devices. Taken together, greater understanding of the relative osseointegration profile at the implant\u2013bone interface of cages with distinct topographies will be crucial in guiding the rational design of further studies and innovations. Solid bony fusion is an essential requirement for successful spinal arthrodesis surgery that allows for stability of adjacent vertebrae \u20134. A comEnhancements to implant topography and architecture, including surface treatments and porous technologies, can putatively accelerate osseointegration and osteoconduction, which is key to long-term biomechanical function of interbody devices , 14, 15.The purpose of this article is to critically assess the tissue engineering potential of modified implant surfaces in spinal surgery, in particular with respect to the ability of activated surface and scaffold designs to accelerate or enhance osseointegration and structural stability following spinal instrumented arthrodesis procedures. We review a new imaging modality, dual-energy computed tomography (DECT), which allows for additional image post-processing and material characterization not possible with conventional systems. Finally, we discuss the rationale for two recently initiated randomized clinical trials designed to evaluate the rate of early osseous fusion using DECT within either activated Ti or PEEK lumbar interbody cages. Taken together, we believe that new insights will soon be gained to help elucidate the potential relative efficacy of microscopic lattice structures in accelerating the process of osseointegration and fusion.While current lumbar interbody cage designs are generally associated with favorable radiologic and clinical outcomes \u201323, fullA recent in vitro evaluation showed that implants bearing a trabecular scaffolded topography enhance cellular proliferation, bone matrix formation, and mineralization with increased mechanical strength by 20% for compression strength and 60% for compressive modulus . FurtherOne critical implant property that can play a role in osteoconduction and osseointegration is the three-dimensional geometry and intricately designed porosity. Specifically, interbody cage porosity accommodates bone ingrowth with the potential to yield improved implant fixation , 31. A mImplant surface roughness and surface finish also may play a significant role in promoting osseointegration . An earlAnother study compared osseointegration when alumina and a multiphase calcium phosphate (MCD) were used as the blast media. Blasted Ti alloy (Ti6Al4V) cylinders were implanted into rabbit tibiae and then evaluated two and four weeks after implantation. The histologic results showed the MCD to elicit significantly greater volume of new bone formation . A more Intriguingly, the combination of nanostructures onto microroughened surfaces may synergistically enhance the production of osteoblast differentiation markers and local factors important for bone formation compared to unmodified microrough controls . Indeed,Yet another factor that can influence the biomimetic properties of the bone\u2013implant interface is the modulus of elasticity. Specifically, 3DP can design implants with an elasticity modulus resembling natural or cadaveric tissue. As a result, a better elastic recovery, biodegradability and cytocompatibility is expected , 46. MorA number of activated Ti cages are commercially available but with no long-term clinical evidence supporting their relative efficacy in promoting early osseointegration and fusion , 49. A r\u00ae or Trial 2: straight-shaped Medtronic AdaptixTM) versus PEEK cages.Clinical confirmation of enhanced osseointegration or bony fusion through activated Ti cages remains lacking. As such, the principal author (HFF) has designed two separate randomized double-arm single-blinded studies in patients undergoing either single- or double-level instrumented arthrodesis procedures to compare radiologic and clinical outcomes using either activated Ti cages implanted at each level of single- or contiguous double-level lumbar arthrodesis procedures. Both cages will be used in conjunction with milled local autograft bone generated as part of the spinal decompression portion of the procedure. Clinical and radiographic outcomes are being collected at regular intervals post-operatively. The primary outcome measure of effectiveness is radiographic bony fusion as assessed by an independent neuroradiologist at 6 months post-operatively, which grossly corresponds to the early phase of expected fusion following lumbar interbody cage placement. Radiographic bone fusion will be graded by the method of Brantigan and Steffee as modified to describe the Fraser definition of locked pseudoarthrosis with a Grade BSF-3 being considered successful bone fusion. Grade BSF-3 is defined by radiographical fusion presenting bone bridges within at least half of the fusion area with at least the density originally achieved at surgery Figs. \u20134 54\u201359\u20135954\u201359.With current X-ray tube technology, it is not possible to generate monochromatic spectra for scanning and greater artifact is expected with a polychromatic beam. As such, the potential for diminished artifact stems from the ability of VMIs to simulate what would be expected with a monochromatic X-ray beam. Furthermore, VMI images can be generated at a wide range of energies with unique advantages depending on the problem at hand and material of interest Fig. . By geneFinally, DECT scans can be used to generate basis material decomposition maps. While the feasibility depends on the specific material of interest and its physical properties, these maps can be used to estimate the distribution and concentration of certain materials, which is not possible using conventional CT imaging. One such example, virtual non-calcium maps, are used to demonstrate marrow edema , 68, 69.Enhanced implant-bone integration and fusion rates may have significant clinical benefits, particularly in more complicated clinical scenarios where fusion may be delayed, such as in osteoporosis, smokers, or with concomitant immunosuppressant use. The results of these two trials should provide relevant information regarding the relative efficacy of activated Ti surfaces in accelerating the process of osseointegration and fusion. Novel insights in this regard are likely to be gained with DECT imaging, whose potential advantages include enhanced artifact reduction. Our conclusions should also assist in the design of further multicenter studies evaluating potential clinical benefits, either for similar degenerative conditions or for more complex reconstructions such as in adult spinal deformity."} +{"text": "COVID-related safety concerns mandated suspension of our ongoing trial testing the effects of movement and social engagement in older adults with early-stage dementia and their caregivers (dyads). Participant vulnerability and the requirement for group social interaction complicated intervention resumption. We present results from a successful pilot to rapidly and iteratively optimize study interventions for remote delivery targeting intervention mediators based on participant feedback. Three-dyad groups completed cycles of intervention via Zoom immediately followed by an interview with open-ended and quantitative feedback. Cycles were repeated until no new information was solicited, then repeated with new participants. Optimization revealed needs for technological support, more intensive movement, and social connection. Specifically, the inability to make eye contact, see others\u2019 full body, and technology-associated timing asynchronies impeded social connection in the movement group. We will present practical tips for crafting remote group interventions for caregiver/person living with dementia dyads."} +{"text": "Voriconazole is a broad-spectrum triazole antifungal used to treat invasive fungal infections. It is commonly used prophylactically in immunocompromized patient cohorts, including transplant recipients. Diffuse periostitis is a very rare complication of chronic voriconazole use. It is associated with diffuse bone pain, elevated serum alkaline phosphatase and fluorine levels. Characteristic imaging findings include periosteal thickening with a dense, nodular, irregular and often bilateral pattern. We describe the case of a 71-year-old female who presented with multifocal bone pain six years following double lung transplantation. Her post transplantation course had been complicated by a life threatening episode of sepsis secondary to Scedosporium apiospermum, a rare invasive fungal infection following which lifelong prophylaxis with oral Voriconazole was commenced. We discuss the characteristic clinical and imaging manifestations of this rare condition. A 71-year-old female presented with diffuse bone pain involving the shoulders and multiple ribs. On examination there was slightly reduced strength in both upper extremities, full although painful range of motion in the shoulder joints and diffuse tenderness at both shoulders and over multiple left-sided ribs. Her history was significant for double lung transplantation for emphysema six years previously. The post-transplantation course was complicated by severe sepsis due to Scedosporium apiospermum, a rare invasive fungal infection, requiring critical care admission. The patient was subsequently commenced on oral voriconazole as prophylaxis to mitigate against further fungal infection.). A diagnosis of voriconazole-induced periostitis was made based on these characteristic imaging appearances, in combination with the patient's history. This was supported by a significantly elevated serum alkaline phosphatase value of 220 U/L , a characteristic laboratory finding in voriconazole induced periostitis.Radiographs of the chest and shoulders were obtained . ChangesThe patient was commenced on an analgesic regime which resulted in significant symptom improvement. The possibility of discontinuing voriconazole prophylaxis was considered, but ultimately the significant benefit in terms of mitigation against fungal infection was considered to outweigh symptoms which were now well-controlled and the patient continued on lifelong voriconazole.Immunosuppression post-transplantation increases patients susceptibility to infection, which may be life-threatening. Voriconazole is commonly used in both the treatment and prophylaxis of fungal infections in organ transplant recipients.Frequently reported side effects of voriconazole include nausea and vomiting, visual disturbances, rash, abnormal liver function tests, QT prolongation, headaches and hallucinations. In 2009 the first cases of voriconazole induced periostitis were reported in 5 lung transplant patients receiving long-term prophylactic treatment with voriconazole Voriconazole is a tri-fluorinated compound. Several studies have shown that this increased fluoride level may play a role in the mechanism of how voriconazole causes periostitis Characteristic imaging features of periostitis include periosteal thickening, with new bone formation which tends to be dense and irregular. This is generally bilateral but may be asymmetric. Nuclear medicine imaging techniques such as bone scintigraphy or single photon emission computed tomography (SPECT) demonstrate radiotracer uptake at affected sites. The differential diagnosis for periostitis is broad, including entities such as hypertrophic osteoarthropathy, hypervitaminosis A, venous stasis and infection. The patient's clinical history (as well as the distribution of periositis) are crucial to accurate diagnosis.Voriconazole induced periostitis typically resolves following medication discontinuation (or in some cases dose reduction) In summary, though uncommon, voriconazole-induced periostitis is an important diagnosis for radiologists to be aware of in the post-transplant or otherwise immunocompromized patient. Accurate diagnosis requires assimilation of the relevant imaging characteristics and patient history.Informed consent has been obtained for the publication of this case report.None."} +{"text": "This multicenter care innovation program wassupported by a Centers for Medicare & Medicaid Services (CMS) Health CareInnovations Award. It includes transitional care nurses (TCNs) and social workers (SWs)who staff the GEDI WISE level 1 GEDs and conduct geriatric assessments , engage in conversationsabout goals of care, and assist with care coordination.JAMA Network Open, Hwang et al3 measured the cost savings associated with TCN orSW evaluations at GEDI WISE sites. Using entropy balancing, they compared the totalMedicare costs for 30 and 60 days after the index ED visit among an intervention groupof fee-for-service Medicare beneficiaries who received a TCN or SW evaluation and acontrol group of fee-for-service Medicare beneficiaries who did not. Whereas the priorGEDI WISE studies evaluated the association of this care model with ED visits andhospital admission rates, in this study Hwang et al3 conducted a more comprehensive evaluation of costs of care bylooking at total Medicare costs\u2014including inpatient, outpatient, home health,hospice, and skilled nursing facilities claims. In doing so, they not only quantifiedthe cost savings related to avoidance of hospitalization and ED revisits but alsodetermined whether the cost savings were offset by increased care costs related to homehealth referrals or transfer to skilled nursing or acute rehabilitation facilities.Hwang et al3 found that after entropybalancing, patients who received the TCN or SW intervention had a mean 30-day savings of$2436 per beneficiary at 1 site and $2905 per beneficiary at the other site. The costsavings persisted at 60 days, with a mean savings of $1200 at 1 site and $3202 at thesecond site.Elsewhere in This study provides important evidence demonstrating the cost efficiency of thisenhanced care model for geriatric emergency care. Evidence that higher-quality models ofcare, such as GEDs, can reduce health care costs should catalyze the adoption of thesemodels. This is more likely to happen when the savings generated benefit the entityshouldering the costs. However, in the GEDI WISE program, the savings went to the payer,in this case Medicare, while the costs of sustaining this intervention beyond thegrant-funded period were borne by the hospitals. Asking hospitals to spend their ownmoney to save Medicare money is unlikely to be sustainable. Growth of this care modelrequires that health care systems also benefit financially from the cost savings.6 In these advanced ACO reimbursement models, theorganization receives additional revenue when savings are generated and quality of careis maintained or improved. Another mechanism for funding advanced geriatric emergencycare models is through collaboration with Medicare Advantage plans, given that theseplans benefit from reducing costs while improving quality of care. Health care systemsshould collaborate with ACOs and/or their local Medicare Advantage plans whenimplementing a GED model of care because these parties all stand to benefit from thesavings demonstrated in this study.The traditional way Medicare has incentivized individual clinicans, hospitals,and health care systems to adopt new services is to directly pay for it\u2014allowingclinicians and health care systems to submit bills for the services they have provided.While this is a mechanism that could be used to reimburse facilities for a TCN or SWconsultation or a similar GED care model, creating new billing codes is an arduous andprolonged process and not likely to create additional revenue for GEDs anytime soon. CMSis encouraging the adoption of value-based care models in which organizations financially benefit from providing high-value care.CMS is accomplishing this by encouraging organizations to take on financial risk formanaging patient populations in risk-sharing Accountable Care Organization (ACO) models.These models hold organizations responsible for financial risk if they provide low-value care to their patient populations.7 Wemust consider how geriatric care models developed in large academic EDs in metropolitanareas can be disseminated to small EDs in rural locales. Telehealth is an obviousanswer. Through a telehealth platform, a single TCN or SW could conduct consultationsacross multiple EDs, improving efficiency and expanding access to this care model.Home-based care alternatives are another option that is cost saving for payersand revenue generating for hospitals. Instead of admitting an older adult with complexcare needs to the hospital, a GED could admit that patient to a hospital-at-home programor leverage telehealth and/or remote monitoring programs for follow-up. Telehealth mayalso be a viable solution for disseminating GED models of care across the United States.While the GEDI WISE sites are level 1 GEDs in large metropolitan areas, at least 18% ofolder adults reside in rural areas.The next phase of research into models for geriatric emergency care must examinethe association of GEDs with carefully selected, patient-centered outcomes that mattermost to older adults. This research may include evaluation of GED care models onphysical functioning, cognition, and quality of life. For instance, does avoidance ofhospitalization through the GED model of care result in improved physical activity andprevent functional decline? Will GED models of care prevent delirium in older adultswith acute medical care needs? Do GED initiatives improve quality of life in olderadults requiring emergency care? Quality of life is a measure that encompasses anindividual\u2019s physical, mental, emotional, and social functioning and could serveas a composite patient-oriented outcome in future studies evaluating the consequences ofgeriatric emergency care innovations.Now that the cost savings of enhanced geriatric emergency care are clear, we needto consider how we can leverage payer models to increase adoption of these programs anddisseminate them to nonmetropolitan areas. We also need to conduct robust research toevaluate the association of GEDs with outcomes among older adults using apatient-centered approach and focusing on what matters most to this population. Throughthis framework, we can increase access to high-quality, cost-effective,geriatric-centric emergency care in the United States for older adults."} +{"text": "The development of antimicrobial drug resistance has encouraged scientists to develop alternate methods to combat infectious pathogens associated with dental diseases. Therefore, it is of interest to predict interactions for catechin (a plant derivedcompound) with protein targets in the red complex pathogens using computer aided network tools. However, in vitro and in vivo studies are warranted to confirm the antimicrobial effect of catechin andgallolyl catechins) on the dental pathogens. Drug resistance to pathogens has reached alarming numbers in recent times. A global burden of antibiotic resistant organisms in the community as well as hospital settings is seen due to indiscriminate use of antibiotics. Oral micro flora is a complexenvironment wherein there is interplay between host and pathogens causing infectious diseases. Several pathogens of the oral cavity such as Enterococcus faecalis, Streptococcus mutans etc. are known to contain proteins responsible for drug resistant phenotypes,2. SelecThe mechanism underlying the anti-microbial activity of catechin against red complex pathogens is investigated using available computer aided predictive tools.The strains of red complex pathogens sich as Porphyromonas gingivalis ATCC 33277, Treponema denticola ATCC 35405 and Tannerella forsythia ATCC 43037 available in the STITCH database were selected for the analysis virulence factors; (2) information and storage processing; (3) cellular process and (4) metabolism. The virulence factors are identified using a support vector machine (SVM)algorithm, which classifies proteins based on their amino acid composition and sequence pattern .VirulentPred is a yet another SVM based method, used for automated prediction of virulent proteins based on the sequences . The scoCatechin is a major component of green tea known for its antioxidant, anti-inflammatory, anti-proliferative activities. Bai et al. has shown the antimicrobial activity of catechin against a canine dental pathogen . Itis oWe document the predicted interaction targets for catechin (a plant derived compound) with protein targets in the red complex pathogens using computer aided network tools. However, in vitro and in vivo studies are necessary to verify the antimicrobial effectof catechin and gallolyl catechins) on the dental pathogens."} +{"text": "Targeted anti-cancer therapies have revolutionised melanoma patient care; however, cures remain uncommon due to acquired drug resistance that results in disease relapse. Recent insights from the clinic and experimental settings have identified a key role for metabolic plasticity, defined as the flexibility to utilise different nutrients and process them in different ways, in both disease progression and response to targeted therapies. Here, we discuss how this plasticity creates a moving target with important implications for identifying new combination therapies.Resistance to therapy continues to be a barrier to curative treatments in melanoma. Recent insights from the clinic and experimental settings have highlighted a range of non-genetic adaptive mechanisms that contribute to therapy resistance and disease relapse, including transcriptional, post-transcriptional and metabolic reprogramming. A growing body of evidence highlights the inherent plasticity of melanoma metabolism, evidenced by reversible metabolome alterations and flexibility in fuel usage that occur during metastasis and response to anti-cancer therapies. Here, we discuss how the inherent metabolic plasticity of melanoma cells facilitates both disease progression and acquisition of anti-cancer therapy resistance. In particular, we discuss in detail the different metabolic changes that occur during the three major phases of the targeted therapy response\u2014the early response, drug tolerance and acquired resistance. We also discuss how non-genetic programs, including transcription and translation, control this process. The prevalence and diverse array of these non-genetic resistance mechanisms poses a new challenge to the field that requires innovative strategies to monitor and counteract these adaptive processes in the quest to prevent therapy resistance. Cancer cells must continuously reprogram their metabolism in order to maintain proliferation and survival in response to changes in the surrounding microenvironment. Metabolic reprogramming in cancer is therefore rarely static but instead a highly dynamic process that allows rapid adaptability. This demand for metabolic adaptability requires both the flexibility to utilise different metabolic substrates and the ability to process metabolic substrates in different ways . CollectMetastasis is the leading cause of all cancer-related deaths and involves the elaborate reprogramming of many distinct cellular processes that allows cellular extravasation and invasive dissemination, circulation, and subsequent colonisation of distant tissues by cancer cells . The metThe first clear evidence of metabolic plasticity in melanoma metastasis comes from an elegant study by Piskounova and colleagues using melanoma patient-derived xenotransplant (PDX) models . Using aFurther evidence supporting a role for metabolic plasticity during melanoma progression and metastasis comes from a study investigating the role of peroxisome proliferator-activated receptor \u03b3 coactivator \u03b1 (PGC1\u03b1), a master regulator of mitochondrial function . During Metabolic plasticity has also been linked with the development of site-specific melanoma metastases. Analysis of a large melanoma patient cohort identified significant upregulation of OXPHOS specifically in brain metastases when compared to patient matched extracranial metastases Figure A. AnalysReprogrammed fatty acid metabolism has also been extensively linked with melanoma progression and metastasis . FurtherFlexibility in fuel usage has also emerged as a major factor that can facilitate melanoma metastasis. Melanoma cells of varying oncogenic backgrounds display highly glycolytic phenotypes in which 60\u201380% of glucose is converted to lactate, and this activity is enhanced to 90% or more in hypoxia . Using iThere is also clinical and experimental evidence supporting a role for alterations in lipid uptake in melanoma progression and metastasis. Analysis of melanoma patients in The Cancer Genome Atlas (TCGA) identified a gene signature that includes fatty acid uptake genes caveolin-1 (CAV1) and cluster of differentiation 36 (CD36), and the fatty acid oxidation (FAO) gene carnitine palmitoyltransferase 1C (CPT1C), that predicts for significantly worse overall survival . A clearOverall, these studies highlight the inherent plasticity of melanoma metabolism and how this can directly promote metastatic progression of disease. Importantly, these data also highlight that these events can occur independently from acquisition of new genetic events, indicated by the reversible nature of metabolome alterations observed in metastatic cells derived from different tissue origins. They also reveal the diversity of fuel sources melanoma cells can utilise to survive in different microenvironmental niches, another key feature of plasticity. As such, this inherent metabolic plasticity creates a moving target for therapeutic interventions and consequently poses a major challenge to effective therapy. Indeed, metabolic plasticity has emerged as a key feature of adaptive response and resistance to current standard-of-care oncogene targeted therapies for melanoma, and this aspect of metabolic plasticity in melanoma is discussed in detail below.V600 melanoma patients, and the Food and Drug Administration (FDA) has approved three combination therapies; dabrafenib/trametinib, vemurafenib/cobimetinib and encorafenib/binimetinib. Exceptional response rates and low toxicities are two major advantages of these targeted therapies over other anti-cancer therapies currently available in melanoma. However, despite their success in improving overall survival, persistence of a residual disease that eventually acquires resistance and drives disease relapse is a major barrier to achieving cures. Indeed, the dabrafenib plus trametinib combination in BRAF mutant melanoma patients has a 34% 5-year overall survival rate [Activating mutations in BRAF (V600) occur in approximately 40% of all melanoma patients and have led to the development of molecular targeted therapies directed against BRAF and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK), two kinases in the mitogen-activated protein kinase pathway (MAPK) . BRAF anHistorically, genetic drivers of resistance to targeted therapies have been the major focus, and more than 20 genetic mechanisms of acquired resistance have been identified in melanoma so far . The preGlucose is a major fuel source for melanoma, and in general, melanoma cells display an elevated glycolytic phenotype at the expense of oxidative mitochondrial respiration ,50,51. IV600 also regulates the microphthalmia-associated transcription factor (MITF), a melanocyte lineage transcription factor, which is a crucial determinant of the response to BRAFi. Treatment with BRAFi leads to MITF dependent regulation of PGC1\u03b1, which subsequently promotes mitochondrial biogenesis, OXPHOS and response to oxidative stress in BRAFV600 melanoma cells tRNA (U34 enzymes) are key players of rewired protein synthesis observed upon resistance to MAPK targeted therapy in melanoma [34 enzymes promote glycolysis through direct translational regulation of HIF1\u03b1 mRNA that consequently maintains high levels of HIF1\u03b1 protein to facilitate reactivated glycolytic networks in MAPKi resistant melanoma cells. Together, these data clearly show a role for glucose metabolism in acquired resistance, in addition to its role in the early MAPKi response.In addition to glucose consumption being a useful biomarker of the early targeted therapy response in melanoma (discussed above), reactivation of glucose uptake and glycolysis has also been observed upon acquisition of BRAF inhibitor resistance. Following early suppression of glucose consumption upon treatment with the BRAF inhibitor vemurafenib, subsequent increases in glucose uptake as assessed using FDG uptake in treated tumours tightly correlated with emergence of resistance . Consistsistance , restorent cells . Translamelanoma . MechaniFurther to glucose, increased dependence on glutamine has also been demonstrated in cells with acquired resistance to single agent BRAF inhibitors , and theThe ability to utilise alternative fuel sources such as glutamine and lipids is concordant with elevated mitochondrial biogenesis and oxidative metabolism signatures identified in MAPKi resistant melanoma patients ,58. IndeAltogether, these studies highlight a key role for metabolic plasticity across all major phases of the targeted therapy response and development of resistance in melanoma.The inherent plasticity of melanoma metabolism and the flexibility to use diverse fuel sources provides a survival advantage necessary to colonise harsh microenvironments and survive inhibition of metabolic pathways. Consequently, this creates a moving target for therapeutic interventions and poses a major challenge to effective therapy. While some activity with single agents has been observed in preclinical models, metabolic inhibitors will likely be most useful in combination with current anti-cancer targeted therapies. Indeed, targeting mitochondrial oxidative metabolism in melanoma has been shown to cause metabolic compensation through both glucose and glutamine utilisation in mouse models . MoreoveStrategies that target multiple metabolic pathways at the same time have shown some success. As discussed above, co-inhibition of mitochondrial metabolism with MAPKi, which effectively suppresses glycolysis, can improve the response and overcome acquired resistance to targeted therapies ,55,57,58Targeting metabolic features of drug tolerant cells that persist following treatment with anti-cancer therapies also represents a therapeutic opportunity to overcome acquired resistance and tumour relapse. Further characterisation of SMC populations that transiently emerge following exposure to therapy in melanoma tumours may therefore prove useful therapeutically. If the SMCs are precursors to other drug tolerant cellular states , then idAnother approach that warrants further investigation is targeting regulatory pathways underpinning plasticity in the metabolic network, and the available data suggests this occurs at the transcriptional and translational level. An extensive list of transcription factors has been directly linked with metabolic plasticity during melanoma metastasis and adaptive resistance to MAPKi . However, in general, therapeutically targeting transcription factors remains a challenge, and most efforts in melanoma have been directed at targeting downstream activated pathways (see above). Targeting translational mechanisms may offer an alternative approach, and multiple aspects of selective and global mechanisms of translational regulation are under investigation and have proven useful in preclinical settings. Silvestrol is a naturally occurring member of the flavagline family of compounds that inhibits cap-dependent translation by targeting eIF4A ; howeverA growing body of evidence now highlights the inherent plasticity of melanoma metabolism and how this can directly promote metastatic progression of disease and response to anti-cancer therapies. Importantly, adaptive metabolic reprogramming can occur independently from acquisition of new genetic events. This is indicated by the reversible nature of metabolome alterations observed in metastatic cells derived from different tissue origins and in melanoma cells that show transient and reversible activation of metabolic pathways as they acquire therapy tolerance and resistance. These studies also reveal the diversity of fuels melanoma cells can utilise to survive in different microenvironmental niches during both metastasis and response to anti-cancer therapies, which is another key feature underpinning metabolic plasticity. Targeting metabolic plasticity is therefore predicted to have therapeutic benefit in melanoma patients; however, the maximal benefit is likely to be achieved by combining therapies directed against metabolic plasticity with current anti-cancer therapies directed against MAPK signalling. Moreover, because plasticity creates a moving target for therapeutic interventions, an attractive approach would be to exploit the specific regulatory molecules that facilitate plasticity in the metabolome."} +{"text": "Thermal therapies such as radiofrequency ablation (RFA) are gaining widespread clinical adoption in the local treatment of skeletal metastases. RFA has been shown to successfully destroy tumor cells, yet the impact of RFA on the quality of the surrounding bone has not been well characterized. RFA treatment was performed on femora of rats with bone metastases (osteolytic and osteoblastic) and healthy age matched rats. Histopathology, second harmonic generation imaging and backscatter electron imaging were used to characterize changes in the structure, organic and mineral components of the bone after RFA. RFA treatment was shown to be effective in targeting tumor cells and promoting subsequent new bone formation without impacting the surrounding bone negatively. Mineralization profiles of metastatic models were significantly improved post-RFA treatment with respect to mineral content and homogeneity, suggesting a positive impact of RFA treatment on the quality of cancer involved bone. Evaluating the impact of RFA on bone quality is important in directing the growth of this minimally invasive therapeutic approach with respect to fracture risk assessment, patient selection, and multimodal treatment planning. Skeletal bone metastases occur in one third of all cancer with freIn its use, a radiofrequency (RF) generator supplies an alternating current to a probe inserted into the tissue to be treated. Frictional heat induced by the electric current creates a thermal ablation zone. The RF circuit may be completed using grounding pads in unipolar designs or with RFA leads to a coagulative necrosis within seconds to minutes and distinct defined tissue changes are visible after RFA dose delivery . TypicalArchitecture and tissue level material properties of bone impact its strength and are regulated through the mineral and organic (primarily collagen) components of their ultrastructure \u201316. The In the organic component of bone tissue, the distribution and orientation of collagen type I fibrils are responsible for bone\u2019s ductility and toughness . The recPrevious work by our group demonstrated different effects of various types of metastases on rat bone quality , 29\u201331. Foxn1rnu rats through intracardiac injection under general inhalation anaesthesia. The intracardiac injection of luciferase transfected human ZR-75-1 (ATCC\u00ae CRL-1500\u2122) breast cancer cells resulted in the development of osteoblastic metastases within 56 days. Intra-cardiac injection of 1.5 x 106 luciferase transfected HeLa cells . Th. Th38]. BMDD of healthy and metastatic bone is modified post-RFA. In healthy bone, regardless of the age of the model (Day 21 or Day 84), average mineral content is unchanged post-treatment. However, younger healthy bone (Day 21), demonstrates greater heterogeneity post treatment which may be due to the shorter recovery period. In the osteolytic bone metastases model, due to the aggressive nature of tumor growth, longer observation periods are not possible. In comparison to older healthy bone (Day 84), which is monitored for 28 days post-treatment and hence undergoes several remodeling cycles; age-matched younger healthy bone (Day 21) is only monitored for 7 days post-treatment . SeveralPost-RFA treatment, osteoblastic bone tissue demonstrated an enhanced mineralization profile with improved homogeneity. Higher mineralization values (CaPeak) and elevated mineral content (CaMean) are observed post-RFA . It is eOur earlier work evaluating bone quality secondary to skeletal metastatic involvement has considered Raman spectroscopy in addition to SHG and BSE to assess changes in bone quality in pathologic vertebrae . In thisIn this study, the impact of RFA on the mineral and organic components of healthy and metastatic bone were assessed. In the context of skeletal metastases, RFA resulted in a more homogenous bone tissue by replacing the diseased bone with more mature, highly mineralized bone. RFA treatment was shown to be effective in targeting tumor cells and promoting subsequent new bone formation. RFA did not negatively impact healthy bone tissue. The positive impact of RFA on bone quality in metastatically involved bone is important in directing the utilization of this growing local minimally invasive therapeutic approach with respect to fracture risk assessment, patient selection and multimodal treatment planning."} +{"text": "Mobility, physical activity and social engagement are important to healthy aging and independent living among older adults. This symposium includes four related studies on these issues. Dr. Lien Quach and her team examined racial and ethnic disparities in social engagement among community-living older adults using data from the national Health and Retirement Study. The analysis found that Asians and Hispanics had significantly lower social engagement score compared with non-Hispanic Whites, advocating for further investigations of the causes of racial disparities in social engagement. Dr. Su-I Hou\u2019s study examined the impact of physical activity and social relationship on social engagement. The study found positive impacts of more physical activity, better social relationships and volunteers on social engagement. The results have important implications to promotion of social engagement among older adults participating in aging-in-community programs. Dr. Ladda Thiamwong\u2019s study demonstrated the benefits of using assistive health technology (AHT) to assess the relationships between fall risks, body compositions and objectively measured physical activity in older adults. Dr. Thiamwong\u2019 will discuss the research protocol and preliminary results. Dr. Li\u2019s Health Aging and Neighborhood Study examined variations of older adults\u2019 driving behaviors by sex, age, race, income, health status and housing density of the neighborhoods. The study found substantial differences in mobility and driving patterns by both personal characteristics and neighborhood living environment. The findings have important implications to community programs that support older adults aging in place."} +{"text": "Although researchers have identified medications that relieve symptoms of Multiple Sclerosis (MS), none are entirely effective and some persons with multiple sclerosis (PwMS) use alternatives. Our study compared cannabis use among PwMS (N=135) and persons diagnosed with arthritis (N=582) or cancer (N=622) who participated in the Illinois medical cannabis program. We tested for significant differences across psychological well-being, quality of life and three behavioral outcomes, and also considered effects of co-occurring prescription opioid use. A majority of all individuals used cannabis to address pain and improve quality of sleep. PwMS reported lower levels of productivity, exercise and social activity, and cannabis was less helpful with improving these particular outcomes. Most persons used cannabis for sleep or digestive problems and we found no differences across groups in terms of well-being and quality of life. This comparative evaluation suggests cannabis mechanisms are not specific as much as they impact common processes."} +{"text": "Previous research suggests a decline in body mass index (BMI) among older adults is associated with negative health outcomes, including mild cognitive impairment (MCI) and incident dementia . However, few studies have examined BMI longitudinal trajectories and how they change after MCI diagnosis among older African Americans. To characterize trajectories of change in BMI among older African American participants with no cognitive impairment at baseline we used data from the Minority Aging Research Study, MARS . We constructed piecewise linear mixed-effects models that included a random intercept and two random slopes. The first slope began at baseline. The second slope began at MCI diagnosis allowing for acceleration in the rate of decline after the diagnosis. The results showed BMI declined over time , and there was a faster decline after MCI . In a second model controlling for age, higher education was associated with a lower BMI at baseline but slower decline before MCI . However, after MCI the decline of participants with higher education was faster . These results suggest an accelerated decline in BMI following MCI diagnosis, with higher education related to an even faster BMI decline, possibly a consequence of cognitive reserve."} +{"text": "Humans require a plethora of higher cognitive skills to perform executivefunctions, such as reasoning, planning, language and social interactions, whichare regulated predominantly by the prefrontal cortex. The prefrontal cortexcomprises the lateral, medial and orbitofrontal regions. In higher primates, thelateral prefrontal cortex is further separated into the respective dorsal andventral subregions. However, all these regions have variably been implicated inseveral fronto-subcortical circuits. Dysfunction of these circuits has beenhighlighted in vascular and other neurocognitive disorders. Recent advancessuggest the medial prefrontal cortex plays an important regulatory role innumerous cognitive functions, including attention, inhibitory control, habitformation and working, spatial or long-term memory. The medial prefrontal cortexappears highly interconnected with subcortical regions and exerts top-down executive control over various cognitivedomains and stimuli. Much of our knowledge comes from rodent models usingprecise lesions and electrophysiology readouts from specific medial prefrontalcortex locations. Although, anatomical disparities of the rodent medialprefrontal cortex compared to the primate homologue are apparent, current rodentmodels have effectively implicated the medial prefrontal cortex as a neuralsubstrate of cognitive decline within ageing and dementia. Human brainconnectivity-based neuroimaging has demonstrated that large-scale medialprefrontal cortex networks, such as the default mode network, are equallyimportant for cognition. However, there is little consensus on how medialprefrontal cortex functional connectivity specifically changes during brainpathological states. In context with previous work in rodents and non-humanprimates, we attempt to convey a consensus on the current understanding of therole of predominantly the medial prefrontal cortex and its functionalconnectivity measured by resting-state functional MRI in ageing associateddisorders, including prodromal dementia states, Alzheimer\u2019s disease,post-ischaemic stroke, Parkinsonism and frontotemporal dementia. Previouscross-sectional studies suggest that medial prefrontal cortex functionalconnectivity abnormalities are consistently found in the default mode networkacross both ageing and neurocognitive disorders such as Alzheimer\u2019sdisease and vascular cognitive impairment. Distinct disease-specific patterns ofmedial prefrontal cortex functional connectivity alterations within specificlarge-scale networks appear to consistently feature in the default mode network,whilst detrimental connectivity alterations are associated with cognitiveimpairments independently from structural pathological aberrations, such as greymatter atrophy. These disease-specific patterns of medial prefrontal cortexfunctional connectivity also precede structural pathological changes and may bedriven by ageing-related vascular mechanisms. The default mode network supportsutility as a potential biomarker and therapeutic target for dementia-associatedconditions. Yet, these associations still require validation in longitudinalstudies using larger sample sizes. Jobson et al. convey that the medial prefrontal cortex functional connectivity inman exhibits disease-specific alterations across dementia associated disorders.These abnormalities appear to precede structural changes and may be driven byageing-related vascular mechanisms. This mainly affects the large-scale defaultmode network, thus providing potential biomarkers and therapeutic targets. Greater understanding of the significance of the prefrontal cortex (PFC) is probablyowed to the serendipitous discovery after the unusual accident suffered by PhineasGage in 1848. The iron-tamping rod he had used on the railroad had pierced throughhis orbitofrontal lobe and changed him forever from once a respectable family manquickly into an ill-tempered irrational individual. We now know that a plethora ofhigher cognitive skills in order to perform crucial executive functions, such asreasoning, planning, language and social interactions, are regulated predominantlyby the PFC which contains the orbitofrontal region.Brodmann gave the first topographical description of the \u2018frontal\u2019 and\u2018precentral\u2019 regions of the primate frontal lobe, which possessed adefinitive granular pyramidal layer IV as a prominent characteristic. Although theanterior cingulate cortex (ACC), which contains agranular needed to performvarious complex cognitive tasks.,Electrophysiological evidence in rodents recording multiple single cells usingtetrodes has equally resulted in a mixed picture of changes in neuronal ensemblefiring rates and patterns in that only a few mPFC neurons discharge spatialworking memory transient signals differently during delay periods of maze tasks,with some cell assemblies predicting spatial locations.Non-human primate studies have instead largely suggested the dlPFC is essentialfor working memory, as early influential lesion studies exhibited evidence thatdlPFC damage, particularly involving the principal sulcus is a key executivefunction mediated by the PFC and can be defined as the ability to adaptbehaviour with changing environmental contingencies.,Set-shifting ability is typically assessed in the clinic by utilizing theWisconsin Card Sorting Test (WCST), which ultimately involves a shiftingresponse by the individual switching their attention between variable perceptualcategories based upon changing card-sort rules.,Set-shifting procedures have additionally been modified for testing ofstructure\u2013function relationships in rodents with substantial similarityto non-human primates. For example, Birrell and Brown designed a seminalset-shifting task for rats, which included extra-dimensional, intra-dimensionaland reversal learning stages akin to the monkey version. However, findings inrats were different from those in monkeys because mPFC lesions demonstratedsimilarly impaired extra-dimensional set-shifting, whilst ACC lesions impairedintra-dimensional set-shifting.,Human studies assessing cognitive flexibility processes have largely implicatedsimilar PFC subregions compared to the animal literature, thus emphasizing thesuitable translatability of the models. Specifically, individuals largely withdlPFC and mPFC damage have reported difficulties performing set-shifting duringthe WCST, such as inabilities to switch to a new rule as well as random andperseverative errors.,,,,,,Lesion studies of the mPFC have also been shown to play a role in impairedreversal learning, specifically when rodents are presented with complex imagesusing touchscreens.,,,,As with other domains of executive function, attention is a complex cognitiveprocess with various components that seem to depend on differing PFC subregions.Attention enables the brain to allocate sensory resources efficiently for theimmediate goal whilst ignoring alternative irrelevant inputs.The apparent agreement of findings from rodents to humans is perhaps undeniableas the 5-CSRTT was initially developed by Carli et al.,,It has been debated over several years whether rodent mPFC studies are relevant todefine human dlPFC functions, whilst others have suggested that rodent mPFC mightbetter represent the ACC.,Animal behavioural tasks of cognition adapted from human versions have enableddetailed investigation of brain areas by utilizing naturalistic paradigms. However,limitations arise if factors are not controlled such as food restriction, lack ofmotivation, susceptibility to stress and malaise or sense/locomotor impairments,which may be apparent for the prior studies analysing executive functions. Beforeanimals perform behavioural tasks, it may therefore be necessary to ensure that theycritically assess the cognitive function under investigation precisely, asexemplified by modified T-maze or operant procedures developed for working memory orcognitive flexibility respectively.,,In man, there is a clear deterioration in cognitive function during normal ageing,often with an observable reduction in information processing speed, which is notdependent on executive functioning.Studies utilizing rodent models have thus not only suggested that mPFC cognitivefunctioning is substantially affected by ageing in seemingly complex ways but haveadditionally aided in elucidating the underlying pathophysiology ofageing-associated neurological disorders that are susceptible to dementia.Specifically, authors demonstrated with a photothrombosis model that revealed significant differences between ageing anddementia-associated disorders in terms of mean connectivity to brain regionsinvolving the mPFC. The current data present 41 published studies totalling 2473subjects with an average of 60 per study . The mos,There is a consistent decrease in mPFC\u2013PCC FC in healthy aged individuals. Althoug,,,Furthermore, the PCC-insula reduced FC association has been positively correlatedto cognitive tests including those for executive function, along with decreasedFC with ageing in ACC connections to the insula as part of the salience network , which is predominantly characterized by executivedysfunction. Indeed, svMCI subjects exhibit significant declines in numerousDMN-associated regions compared to controls, which may result structurally fromsubcortical WM lesions that directly and indirectly impair fibre tractsessential for transmitting cerebral FCs. These regions specifically include thePCC/precuneus, mPFC, ACC, hippocampus, parietal cortices and superior frontalgyrus/middle frontal gyrus.,,,Approximately 30% of elderly stroke survivors develop delayed dementia(known as post-stroke dementia), with most cases closely resembling criteria forVaD diagnosis.,,,,However, lowered mPFC/ACC-precuneus FC was conversely demonstrated by utilizingsimilar group ICA/region-of-interest methodologies and rather reflects theimpact upon structural damage facilitating cognitive disturbances as adisconnection syndrome.,,Parkinson\u2019s disease as a neurodegenerative disorder is typicallycharacterized by progressive motor dysfunction, but patients also show cognitivedecline with executive deficits, memory impairment and often dementia inadvanced stages.,,,However, similar disparities in trends as demonstrated in the prior vascularstudies, are prevalent within the Parkinson\u2019s disease studies. As mPFC FCchanges compared to controls did not appear in two studies, which instead onlyshowed significant FC decreases that associated with cognitive performance orlower GM volume structurally between the precuneus/PCC and subcortical/motor areas ormedial temporal gyrus.,,Despite stringent Parkinson\u2019s disease clinical criteria, there remains asubstantial misdiagnosis rate with atypical Parkinsonian disorders (APDs), suchas multiple system atrophy (MSA) and progressive supranuclear palsy (PSP), eventhough APDs account for 10\u201320% of Parkinsonism subjects.The most common form of FTD is the behavioural variant, which has previously beenshown to account for approximately half of all frontotemporal lobar degeneration. Learning and plasticity are supported and shaped byneurotransmitter systems in the brain. Cholinergic neurotransmission playsimportant roles in synaptic plasticity, glial remodelling and the regulation ofinflammation. In addition, dopamine, and tonic GABAergic signallingNevertheless, it is still arguably difficult to ascertain confidently that the FCdysfunctions are valiThe role of the mPFC within cognition, ageing and dementia is diverse, yet seeminglyfundamental for a range of critical cognitive operations. Animal work utilizinglesions and electrophysiology paired with behavioural tasks has refined ourunderstanding by demonstrating precise mPFC subregions perform distinct executivefunctions. However, much of the equivalent rodent functions lack direct anatomicalhomology to primates, which implicates the lPFC instead. Such a disparity mayreflect inconsistencies in mPFC terminology across studies as well as inadequaciescontrolling cognitively influential factors; therefore, further clarification of PFCterminology and rs-fMRI methodologies across the field is likely necessary.Moreover, rodent models of ageing have exhibited substantial decline in the abilityto perform tasks assessing mPFC-related executive functioning. Whilst rodent modelsof dementia-associated pathophysiological processes in PIS, VaD as well asadditional neurodegenerative disorders have distinguished crucial inabilities toperform several behavioural paradigms tasking the mPFC. Studies examininglarge-scale brain connections have comprehensively shown that the mPFC\u2019slinks to heteromodal brain areas are integral for effectively coordinating numerousyet explicit cognitive paradigms, with the DMN exemplifying an extensively reportedinterconnectivity network that contains the mPFC as one of its central nodes.Existing rs-fMRI studies implicate mPFC FC variances during ageing anddementia-linked conditions between pairwise regions and globally within large-scalenetworks. Aberrations involving the DMN anterior and posterior sub-systems have beenpersistently reported across disorders, along with distinct patterns ofneuropathological changes that may preclude structural defects and subsequentcognitive deterioration. In addition, some findings remain uncertain within thedisorders due to methodological or sample inconsistencies, future validation couldthus enable translation into effective biomarkers for earlier diagnosis ortherapeutic intervention against pathological cognitive decline.Accordingly, future work is essential for deciphering if the identified trends ofreorganized FC intensity across disorders remain by replicating the rs-fMRIprotocols whilst utilizing larger cohort sample sizes, which likely would remove anyconfounding effects of detected chance observations. Future rs-fMRI studiestargeting the mPFC should also be conducted upon a longitudinal basis, which wouldenable a clearer understanding of how the disorders progressively worsen cognitionthrough modifying mPFC FCs over the entire clinical course of an individual\u2019slifetime. This would clarify the remaining knowledge gap concerningstructure-functional relationships and if FC changes definitively precede or evenaugment atrophy of the GM and WM tract changes, thereby further elucidating theunderlying pathophysiological sequalae of these disorders. Moreover, conductingfuture rs-fMRI studies that focus specifically upon the impact of ageing anddementia-associated disorders within PFC-associated networks other than the DMNwould better clarify how this important region is more broadly affected. Perhaps,future studies should also have a closer selection of individuals with comparablecognitive performances and clinical features that may further remove any patientheterogeneity effects responsible for divergent results. Detailed biochemical andmolecular biology assessment of circuit-level receptors responsible mechanisticallyfor the mPFC connectivity alterations would be most helpful, perhaps through use ofagonists/antagonists targeting these receptors within rodent models, thereby furtherenabling the elucidation of refined pharmacological targets as a therapeuticintervention. Ultimately, use of network-based techniques may reconcile differencesthat remain within the field of mPFC cognitive function across species from a globalintegrated perspective by surveying the entire PFC and brain as a whole. Suchdeductions are particularly important considering the FCs between the mPFC withextra-frontal areas including the dlPFC are consistently implicated as necessary forcognition within both health and disease states.Data sharing is not applicable to this article as no new data were created oranalysed. The summarized data incorporated in the review are however available inBrain Communications online.This work was supported by previous grants from the Alzheimer\u2019s Research UK(ARUK PG2013\u201322) and Medical Research Council, UK .The authors report no competing interests.fcab125_Supplementary_DataClick here for additional data file."} +{"text": "Background Despite the development of geriatrics surgery process quality indicators (QIs), few studies have reported on these QIs in routine surgical practice. Even less is known about the links between these QIs and clinical outcomes, and patient characteristics. We aimed to measure geriatrics surgery process QIs, and investigate the association between process QIs and outcomes, and QIs and patient characteristics, in hospitalized older vascular surgery patients. Methods This was a prospective cohort study of 150 consecutive patients aged \u2265 65 years admitted to a tertiary vascular surgery unit. Occurrence of geriatrics surgery process QIs as part of routine vascular surgery care was measured. Associations between QIs and high-risk patient characteristics, and QIs and clinical outcomes were assessed using clustered heatmaps. Results QI occurrence rate varied substantially from 2% to 93%. Some QIs, such as cognition and delirium screening, documented treatment preferences, and geriatrician consultation were infrequent and clustered with high-risk patients. There were two major process-outcome clusters: (a) multidisciplinary consultations, communication and screening-based process QIs with multiple adverse outcomes, and (b) documentation and prescribing-related QIs with fewer adverse outcomes. Conclusions Clustering patterns of process QIs with clinical outcomes are complex, and there is a differential occurrence of QIs within older vascular surgery patients, suggesting process QIs alone may be unreliable targets for quality improvement. Prospective intervention studies are needed to understand the causal pathways between process QIs and outcomes to help prioritize care processes that are most clearly linked to improved outcomes."} +{"text": "This session will provide updates on how the pandemic led to horrific situations in long-term care facilities and how the pandemic influenced major federal efforts to address elder abuse, neglect, and exploitation."} +{"text": "Peripheral arterial disease (PAD) is a vascular condition disproportionately affecting adults > 60 and the leading cause of disability for adults > 50. Because PAD is marked by severe leg pain and sometimes lower extremity amputation, quality of life (QOL) and wellbeing may be compromised however, we understand little about these constructs in this population. Furthermore, surgical care providers lack a comprehensive understanding of how individuals think about wellbeing and what is important to individuals during surgical care. We conducted a qualitative photographic elicitation study (n = 60) in one academic multidisciplinary PAD clinic to understand specific aspects of QOL of older individuals with PAD. Guided by interpretive description, a methodology pioneered in nursing, we analyzed data within and across five clinical symptom severity categories to examine for QOL constructs, impact on everyday life, understanding of disease, and desired treatment. Results demonstrate that individuals do not fully understand PAD diagnosis or its implications . Disease-specific knowledge was prevalent among patients experiencing lower extremity amputation but those suffering from wounds or gangrene had limited understanding. Furthermore, patients\u2019 descriptions of QOL conflicted with the conceptualization of QOL in clinical practice and research. That is, many participants describe QOL based on activities they are capable of performing despite limitations. Results demonstrate the need for integrating gerontological knowledge into clinical care to improve quality of care for older adults."} +{"text": "Pennisetum glaucum) is a staple cereal crop for semi-arid regions. Its whole genome sequence and deduced putative gene sequences are available. However, the functions of many pearl millet genes are unknown. Situations are similar for other crop species such as garden asparagus , chickpea (Cicer arietinum) and Tartary buckwheat (Fagopyrum tataricum). The objective of the data presented here was to improve functional annotations of genes of pearl millet, garden asparagus, chickpea and Tartary buckwheat with gene annotations of model plants, to systematically provide such annotations as well as their sequences on a website, and thereby to promote genomics for those crops.Pearl millet counterparts identified by BLASTX. Conserved domains in protein sequences of those species were identified by the HMMER scan with the Pfam database. The resulting data was deposited in the figshare repository and can be browsed on the Terse Genomics Interface for Developing Botany (TGIF-DB) website (http://webpark2116.sakura.ne.jp/rlgpr/).Sequences of genomes and transcripts of pearl millet, garden asparagus, chickpea and Tartary buckwheat were downloaded from a public database. These transcripts were associated with functional annotations of their Pennisetum glaucum) is a staple cereal crop for semi-arid regions. Its whole genome was sequenced and putative gene sequences were deduced [Asparagus officinalis), chickpea (Cicer arietinum) and Tartary buckwheat (Fagopyrum tataricum) [Arabidopsis thaliana and rice (Oryza sativa) are dicot and monocot model species, respectively, and have better functional annotations for each gene sequences that were deduced from the genome sequences of pearl millet, garden asparagus, chickpea and Tartary buckwheat as well as genome annotation files in the general feature format (GFF) were downloaded from the International Pearl Millet Genome Sequencing Consortium (IPMGSC) website , the Asp Arabidopsis or rice.Some proteins of the species used do not appear to have conserved domains and/or any close homolog in eitherSome pearl millet genes have been characterized by targeted analyses (,3; for e"} +{"text": "Research suggests that social resources positively influence the health and well-being of lesbian, gay, bisexual, and transgender (LGBT) aging adults, but their access to social resources may vary according to LGBT identity. Using data from Aging with Pride: National Health, Aging, and Sexuality/Gender Study , multivariate models tested how access to social resources varied by LGBT identity and whether the effect of LGBT identity showed additional variations by sociodemographic characteristics among aging LGBT adults. Lesbian respondents had larger social networks than gay respondents, while gay respondents had smaller networks than transgender respondents. Lesbian respondents had more social support and community belonging than other identity groups. Bisexual male respondents and transgender respondents had less support than gay respondents and bisexual male respondents reported less community belonging than gay respondents. Education and age moderated the association between LGBT identity and social support. Findings highlight the importance of considering social support separately from social network size with the understanding that large social networks do not necessarily provide ample social support and this distinction was particularly relevant for transgender respondents who had larger social networks, but less social support than gay respondents. Results also suggest that feelings of LGBT community belonging vary among LGBT identity groups. Health and human service professionals should not only consider the sexual and gender identity of their aging LGBT clients, but also consider the clients\u2019 additional sociodemographic characteristics when assessing their access to social resources."} +{"text": "Personal social networks play a fundamental role in the daily lives of older adults. Although many studies examine how life course factors and personal preferences shape network formation, fewer consider how the places in which older adults live present opportunities and obstacles to cultivate social relationships. In the present study, we explore how geographic context is associated with the ability to interact with non-overlapping social groups within one\u2019s personal network . This unique network formation offers older adults access to diverse social stimuli, non-redundant information, and social autonomy. By analyzing data from the Person-to-Person Health Interview Survey (N=709), we found that a minority of respondents reported the ability to bridge social groups within their networks. Respondents residing in rural and semi-rural counties engaged in fewer non-overlapping social groups compared to those residing in urban counties. These findings suggest that the communities in which older adults live condition opportunities for accessing unique social resources. Identifying the link between geographic residence and personal network structure has important implications for how individuals navigate the uncertainty and elevated support needs of later life. Additional research adopting a social network perspective is needed to provide insight into geographic health disparities occurring among the older population."} +{"text": "Middle-aged and older adults with mental health conditions have a high likelihood of experiencing comorbid physical health conditions, premature nursing home admissions, and early death compared with the general population of middle-aged and older adults. An emerging workforce of certified older adult peer support specialists aged 50 years or above is one of the fastest growing mental health workforces and may be a suitable community-based workforce to simultaneously support the mental health, physical health, and aging needs of middle-aged and older adults with a serious mental illness. Older adult peer support specialists are people with a lived experience of aging into middle age and older adulthood with a mental health condition. This presentation will present three single-arm pilot studies examining how certified older adult peer support specialists\u2019 incorporate technology, including text messaging, ecological momentary assessments, and smartphone applications into practice and clinical outcomes among older adults with serious mental illness."} +{"text": "Increasing research points to the relevance of educational attainment for positive emotional experiences and physical functioning across adulthood. However, little is known about how age-related developments in positive affect and physical functioning differ by educational attainment. This study used longitudinal data of 10,893 individuals (60\u201380 years) from the Health and Retirement Study to examine whether educational attainment moderates trajectories of positive affect and physical functioning and their interrelations over 12 years. Initial results from multiple-group bivariate growth models revealed that individuals with less formal education have lower positive affect and poorer physical functioning at baseline. There was, however, no evidence that longitudinal changes in positive affect, longitudinal changes in physical health, and coupled changes between both variables varied with educational attainment. These initial findings suggest that lower educational attainment is primarily related to lower levels of positive affect and physical functioning, but not to greater age-related declines or their interrelations."} +{"text": "This symposium brings together four papers that address racial health disparities by investigating stressful aspects of social relations at different points in the life course. Cleary and colleagues focus on racial disparities in psychological health by testing cross-sectional effects of intergenerational stress over time. In particular, they investigate effects of network composition on the relationship between mothers' stressors and their children's depressive symptoms at three time points over 23 years. Camacho and colleagues use longitudinal data from the National Social Life, Health and Aging Project to examine cognitive decline among U.S. African-American, Latino, and White adults aged 60 and above. Results indicate loneliness predicted greater global cognitive decline over time in all groups. However, race differences in this association were found across cognitive function domains. Turner and colleagues consider dementia caregiving challenges among non-Hispanic Blacks. Data from five focus groups were analyzed to reveal distinctive challenges to caregiver health during the COVID-19 pandemic including increased burden and barriers to service access. Finally, Sol and colleagues examined the bidirectional association between loneliness and self-rated health over time among a racially diverse sample. Findings illustrate racial patterns in how loneliness at midlife influences health in later life. Antonucci will discuss the role of stress from social relations as a means to fully understand racial disparities in health across the life course."} +{"text": "It remains challenging to quantify the pace of aging across lifespan due to lack of comprehensive longitudinal measurements across wide range of age. In Baltimore Longitudinal Study of Aging, we have measured the longitudinal trajectories of more than 30 phenotypes across four pre-identified domain - body composition, energy regulation, homeostatic mechanisms and neurodegeneration/neuroplasticity, among participants with age between 20+ and 90+. We implemented a two-stage approach to summarize the longitudinal trajectories of these phenotypes across four domains into a summarized score. We demonstrated that higher summarized score is associated with slower decline in both cognitive and physical functions, across different stages of adulthood. Our results imply that deep longitudinal profiling contains rich information and may potentially replace diseases as an early endpoint in trials targeting at aging. Further, understanding the underpinning of longitudinal phenotypic trajectories may provide clues to the biological mechanisms of aging."} +{"text": "Antiphospholipid syndrome is an antibody mediated pro-thrombotic state leading to various arterial and venous thromboses. The syndrome can be either primary or secondary to other autoimmune diseases, commonly systemic lupus erythematosus. Cardiac involvement, in particular valvular disease is common in patients with antiphospholipid syndrome, occurring in about a third of these patients. Valvular diseases associated with antiphospholipid syndrome often occur as valve thickening and non-bacterial vegetation or Libman-Sacks endocarditis. Deposits of antiphospholipid immunoglobulin and complement components are commonly observed in the affected valves, suggesting an inflammatory process resulting in valvular vegetation and thickening. Libman-Sacks endocarditis has a high propensity towards mitral valve, although haemodynamically significant valvular dysfunction is rare.We present a successful aortic valve replacement with cardiopulmonary bypass in a 48\u2009years old lady with antiphospholipid syndrome, who has severe aortic regurgitation as a result of Libman-sacks endocarditis. Antiphospholipid antibodies were positive and the clinical data showed both negative cultures and infective parameters. Surgically resected vegetations revealed sterile fibrinous and verrucous vegetations on aortic valve. Valve replacement and the course of cardiopulmonary bypass was uneventful, and the patient was discharged well.Classically Libman-Sacks endocarditis is often and more commonly associated with autoimmune diseases such as systemic lupus erythematosus, although it can occur in both primary and secondary antiphospholipid syndrome. It is not a common entity, and it is a frequent underestimated disease as most clinicians do not routinely screen for valvular lesion in patients with antiphospholipid syndrome unless they are symptomatic. However, due to its high prevalence of cardiac involvement, clinicians should have a high index of suspicion in the attempt to minimize cardiovascular and haemodynamic complications. Valve surgery in patients with antiphospholipid syndrome carries considerable early and late morbidity and mortality, usually caused by thromboembolic and bleeding events. The perioperative anticoagulation management and haemostatic aspect of antiphospholipid syndrome present an exceptional challenges to clinicians, surgeons, anaesthetists and laboratory personnel. Antiphospholipid syndrome (APS) is a rare coagulative disorder with antiphospholipid antibody mediated pro-thrombotic state mainly characterised by hypercoagulable complications. Cardiac manifestations of APS include arterial or venous thromboses, valve diseases, coronary artery disease, intracardiac thrombus, pulmonary hypertension and dilated cardiomyopathy, with the functional impairment of heart valves being the most common manifestation, which commonly associated with Libman-Sacks endocarditis. Libman-Sacks endocarditis, also known as non-bacterial thrombotic, verrucous, or marantic endocarditis, originally described in patients with systemic lupus erythematosus, is a well-known complication of APS. We present a successful aortic valve replacement in a 48\u2009years old lady with aortic valve Libman-sacks endocarditis and APS who presented with acute pulmonary oedema.A 48\u2009years old lady was admitted to cardiology ward complaining of progressively worsening breathlessness, orthopnoea and chest discomfort for 1\u2009month. Coexisting medical conditions include chronic hypertension on treatment, with 2 episodes of spontaneous miscarriages previously and 1 episode of transient ischemic attack 3\u2009years ago.Clinically, she was haemodynamically stable with a wide pulse pressure. Finger clubbing was noted with livedo reticularis rashes over bilateral upper and lower limbs without ulcers or thrombophlebitis. Her peripheral pulses were bounding with water-hammered pulse, and a grade III diastolic murmur was heard during cardiac auscultation. In addition, she has elevated jugular venous pressure, crepitation over both lung bases, and bilateral pedal oedema.2 was seen on aortic valve and Erythrocyte sedimentation rate (ESR). Otherwise the reports were not suggestive of occult infection with normal white cell count, C-reactive protein (CRP), and negative blood cultures. D-dimer was positive but there was no features suggestive of deep venous thrombosis or pulmonary embolism. Further serological investigations revealed positive antinuclear antibody (1:640), Lupus anticoagulant (LA), anti-smith antibodies, direct and indirect coombs\u2019 test. Subsequent bone marrow aspiration and cytogenetic study showed a grossly normal specimen. She was thus treated as acute pulmonary oedema secondary to severe aortic regurgitation, precipitating by aortic valve vegetation with newly diagnosed antiphospholipid syndrome. Therapeutic enoxaparin therapy was initiated perioperatively.She underwent aortic valve replacement, and intraoperative exposure of aortic valve revealed verrucous thickening of aortic leaflets with vegetations involving all three cusps, with rolled edge on left coronary cusp. No perforation or destruction of cusp tissue was identified. A mechanical valve was implanted following the excision of aortic valve. The course of cardiopulmonary bypass was uneventful. Subsequent microscopic findings of the valve specimen confirmed the diagnosis of Libman-Sacks endocarditis Fig.\u00a0.Fig. 2EPostoperatively, oral anticoagulation therapy was started with international normalized ratio (INR) target of 2.5 to 3.5 with subcutaneous enoxaparin as bridging therapy. There was no excessive bleeding or major thromboembolic complications occurred during in-patient stay. Corticosteroid therapy was started at 2\u2009months postoperatively by Hematology team. She was well and free of complications at 6\u2009months and 1\u2009year follow-up. Clinical examinations and echocardiography demonstrated satisfactory aortic valve function. The microbiological culture of the excised vegetations revealed sterile specimens.Antiphospholipid syndrome (APS) is a multi-system disorder of autoimmune aetiology. This syndrome is defined clinically by arterial and venous thrombotic events as well as recurrent pregnancy loss, with serologically positive antiphospholipid antibodies including lupus anticoagulant (LA) and anticardiolipin antibodies (aCL). It was originally described and most often found in patients with systemic lupus erythematosus (SLE), however, even patients without features of autoimmune disease may harbour antiphospholipid antibodies and suffer from thromboembolic events, thus leading to the distinction of primary and secondary APS. APS affects 2% of population and SLE is found in 40% of patients with APS . The preAPS comprises a wide array of clinical features such as venous and arterial thromboses, recurrent pregnancy loss and even thrombocytopenia. Heart valve disease is the most common cardiac manifestation in patients with APS, and it is defined in the absence of rheumatic and infective endocarditis. It was reported as high as 32\u201338% of valvular lesion occur in patients with APS by transthoracic echocardiography , 5. WhenThe role of antiphospholipid antibodies in the pathogenesis of Libman-Sacks endocarditis remained unclear, probably the result of autoimmune antibodies being directed against the negatively charged phospholipids on the endothelial membranes, either due to micro injuries secondary to stress or turbulence, or induction of autoantibodies by molecular mimicry caused by infectious agents , 10. MicPatients with APS often present with thromboembolic events from other systems rather than cardiac manifestation, most commonly cerebrovascular ischemic events, which is apparent in this case study where patient had transient ischemic attack years ago. These thromboembolic episodes might be due to direct effect of antiphospholipid antibodies or intermittent dislodgement of Libman-Sacks vegetations. Majority of valvular impairment associated with Libman-Sacks endocarditis are mild with minor insignificant haemodynamic disturbance without clinically overt disease , 14. OnlDiagnosing Libman-Sacks endocarditis often necessitates the exclusion of rheumatic valve disease and infective endocarditis. Most clinicians do not routinely screen for valvular lesion in APS patients unless the patient is symptomatic or in the presence of new murmur. Recently, the international consensus committee has revised the definition of APS associated cardiac valve lesion with the following criteria: Coexistence of laboratory criteria of APS along with echocardiography detection of lesions, and/or regurgitation and/or stenosis of mitral or aortic valve, with the defining valve lesions of thickness more than 3\u2009mm, localized thickening involving the leaflet\u2019s proximal or middle portion, and irregular nodules on the atrial face of the edge of the mitral valve, and/or the vascular face of the aortic valve . HoweverUnlike infective endocarditis where the valve needs to be completely excised to remove infected tissue, repair and preservation of the valve is possible in selected patients with Libman-Sacks endocarditis, thus eliminating the need for lifelong anticoagulation therapy. The indications for surgery remain dispute, and the outcomes of surgical valvular replacement have been limited to case reports or series. However, we agreed on the clear indications for surgical intervention, which include severe valvular dysfunction, large vegetations and recurrent embolization despite therapeutic anticoagulation. Furthermore, non-bacterial thrombotic endocarditis may have much greater surgical risk for vegetation embolization than infective endocarditis due to the risk of thromboembolism . To dateAortic valve replacement is deemed necessary due to severe valvular regurgitation causing significant symptomatic ventricular dysfunction. The selection of mechanical valve in this case was based on the existing unavoidable need for lifelong anticoagulation therapy. A mechanical valve may be theoretically more advantageous over a tissue valve considering the younger age of patients at the time of surgery in regards to the risk of structural valve deterioration, and the need for lifelong anticoagulation. However, the use of tissue valve has increased progressively over the years to allow for easier and safer monitoring and management of anticoagulation therapy, with regards to prevention of thromboembolic events and bleeding complications, compounded by the complex monitoring of anticoagulation due to presence of antibodies, and the possible coexisting thrombocytopenia . This isIt is well recognized that patients with APS undergoing surgical valve replacement surgery with cardiopulmonary bypass are at much greater risk of thrombotic and bleeding episodes. Perioperative management of patients with APS undergoing cardiac surgery is a major concern and remains challenging due to significant risk of thrombosis with the cessation of anticoagulation therapy; as well as bleeding secondary to excessive anticoagulation or coagulation factor deficiency . FurtherLibman-Sacks endocarditis is not a common entity and is frequently underestimated as majority valvular involvement in patients with APS are asymptomatic and often diagnose incidentally. It is difficult to detect Libman-Sacks endocarditis, and the diagnosis often requires strong clinical suspicion with exclusion of more common valve lesions such as rheumatic or infective endocarditis. We hope that this case study is able to emphasize Libman-Sacks endocarditis as a cause of valvular heart disease not only in systemic lupus erythematosus, but also in primary APS. Early detection and prompt treatment of valvular disease in APS may halt the progression of valvular dysfunction since valve replacement surgery in APS carries significant perioperative morbidity and mortality."} +{"text": "Twenty-eight states have provided nursing homes (NHs) with immunity from legal liability related to COVID-19. This study places these provisions in the context of prior actions protecting NHs from legal action and explores factors influencing the adoption of such immunity provisions across states. It uses cross-sectional data to examine patterns of policy adoption and to assess states\u2019 likelihood of adopting immunity provisions using multivariate methods. Variables of interest include information on state political, socioeconomic, programmatic, and COVID-19-related characteristics as well as data on campaign contributions and lobbying activity at the state level. Factors significantly related to NH immunity provision adoption included measures of state fiscal health (unemployment), ideology (percent legislators Democrat), governing capacity (unified government), and NH characteristics . Population density and Medicaid as a percentage of state general fund expenditures proved significant as well. Against these complex influences, organizations lobbying on behalf of NH residents and their families have found themselves ineffectual in creating avenues for accountability. Results indicate that enforcing accountability for NH deaths during the COVID-19 pandemic is a complex process, constrained by available policy tools and made more complicated by factors external to the NH environment that contributed to high death rates. Historically, the NH industry has been successful in avoiding consequences for poor quality care, a pattern that has persisted in that NHs have generally been successful in avoiding liability for negligence during the COVID-19 pandemic."} +{"text": "Pregnant patients may present with multiple complex comorbidities that can affect peripartum management and anesthetic care. The preanesthesia clinic is the ideal setting for early evaluation of high-risk pregnant patients. Comorbidities may include cardiovascular pathology such as valvular abnormalities, septal defects, aortopathies, arrythmias and cardiomyopathies. Additional comorbidities\u00a0include pulmonary conditions such as obstructive sleep apnea as well as preexisting neuromuscular and skeletal disorders that may impact anesthetic management. Hematologic conditions involving both bleeding diathesis and thrombophilias may present unique challenges for the anesthesiologist. Patients may also present with endocrinopathies including diabetes and obesity. While not as common, high-risk patients may also have preexisting gastrointestinal conditions such as liver dysfunction, renal failure, and even post-transplant status. Ongoing and prior substance abuse, obstetric conditions such as placenta accreta spectrum disorders, and fetal conditions needing ex utero Intrapartum treatment also require advanced planning. Preanesthesia evaluations also help address important ethical and cultural considerations. Counseling patients regarding anesthetic considerations as well as addressing concerns will play a role in reducing racial and ethnic disparities. Anticipatory guidance by means of pre-anesthetic planning can facilitate multidisciplinary communication and planning. This can allow for an impactful and meaningful role in the care provided, allowing for safe maternal care and optimal outcomes. While caring for pregnant patients, current anesthesia guidelines emphasize the importance of a communication system between obstetric providers, anesthesiologists, and members of multidisciplinary teams .\u00a0Women aEarly evaluation of high-risk pregnant women in preanesthetic clinics can enable optimal care. Preanesthetic clinics facilitate comprehensive patient assessment and optimization and provide education regarding obstetric management and anesthetic options for labor and delivery . The AmeCardiovascular systemThe physiological changes of pregnancy can aggravate preexisting cardiac disease. Cardiovascular disease is a leading cause of maternal mortality. The severity of the maternal condition should not be underestimated and attributed to the \u201cnormal\u201d symptoms of pregnancy . A multiPatients with cardiac disease typically fall into the following broad categories-congenital versus acquired, valvular (stenotic versus regurgitant), septal or shunt lesions, pulmonary hypertension, ischemic heart disease, cardiomyopathies, aortopathies and arrythmias. Risk stratification models may be used to determine the best hospital for antenatal management and delivery ,34.\u00a0For Improvements in cardiac surgery have resulted in female babies with previously fatal congenital conditions surviving to reach sexual maturity .\u00a0AcquireThe effects of valvular disease in pregnancy vary based on several factors including type of lesion and severity. Ventricular dysfunction due to regurgitant valves can lead to heart failure and arrhythmias. Aortic regurgitation during pregnancy can be tolerated in the absence of left ventricular dysfunction. Stenotic valves are typically more concerning and when combined with the decreased systemic vascular resistance and increased blood volume in pregnancy, it can lead to syncope and congestive heart failure respectively. Echocardiographic measurement of valve areas is usually preferred to flow gradients during assessment since the latter can be expected to increase in pregnancy because of increased cardiac output and may not give as accurate an assessment . Mitral Mortality due to pulmonary hypertension remains high during pregnancy despite advanced therapies. Vaginal delivery under appropriate analgesia is generally recommended. To avoid a rapid decrease in systemic vascular resistance that can cause cardiopulmonary decompensation, incremental epidural-only anesthesia with careful titration of local anesthetics is suggested, as general anesthesia with positive-pressure ventilation could increase pulmonary vascular resistance and right-to-left shunt .\u00a0GeneralHypertrophic obstructive cardiomyopathy is frequently inherited and presents with left ventricular outflow obstruction. Tachycardias, hypovolemia and vasodilatation are poorly tolerated. Peripartum cardiomyopathy is the development of heart failure in the last month of pregnancy or within five months of delivery . A smallFor patients with syndromic (e.g. Marfan\u2019s syndrome) and non-syndromic (e.g. ACTA2 gene mutations) familial aortopathies, monitoring blood pressure, symptomatology and surveillance imaging should be done throughout pregnancy to reduce risk of aortic dissections ,39. For Creation of a delivery plan, discussion of anesthetic and analgesic options, and discussion regarding invasive hemodynamic monitoring are part of the preanesthetic evaluation. Patients with severe left-sided obstructive heart disease including coarctation of the aorta and stenotic valvular lesions, pulmonary hypertension, and cardiomyopathies may have particularly poor outcomes and difficulty tolerating labor, surgery, and anesthesia -35. HighFor most cardiac patients, vaginal delivery remains the safest option, barring obstetric indications for cesarean delivery. Vaginal delivery is associated with decreased blood loss and hemodynamic changes and reduced risk of thrombosis and infection . A \u201ccardAnxiety and pain during labor can lead to increased afterload, decreased uteroplacental perfusion, and potential cardiovascular collapse. Neuraxial labor analgesia results in greater cardiopulmonary and hemodynamic stability and should be initiated as early as possible during labor.As mentioned, parturients with cardiac disease may require invasive monitoring that includes placement of arterial, central venous and pulmonary artery catheters and transthoracic echocardiography. Central venous access allows for infusion of vasoactive drugs . PulmonaRespiratory systemPregnant women with obstructive or restrictive lung diseases may be seen in the preanesthetic clinic .\u00a0Asthma The physiological changes of pregnancy worsen sleep-disordered breathing, a spectrum of conditions of increasing severity from loud snoring to obstructive sleep apnea (OSA). All obstetric patients should be assessed for OSA as it increases the risk of adverse maternal, fetal, and neonatal outcomes . If OSA Cystic fibrosis patients begin pregnancy with mixed obstructive and restrictive lung disease, often with chronic lower respiratory tract infections . PulmonaRestrictive lung disease can occur secondary to intrinsic (e.g. sarcoidosis) or extrinsic (e.g. kyphoscoliosis) factors. Antenatal assessment should also include determination of respiratory reserve and functional status including exercise capacity testing and home oxygen requirements .\u00a0Neurological, neuromuscular and skeletal disordersPregnant patients with neurological disorders neuromuscular disorders or musculoskeletal disorders may also be encountered. Early consultation allows accurate documentation of any pre-existing neurological deficit and management. Delivery should be done in a tertiary care center with access to services such as neurology, neurosurgery, and radiology.\u00a0Pregnant women with epilepsy face several challenges. Increased seizure frequency is observed in some due to the pharmacokinetic and hormonal changes of pregnancy. Anticonvulsant drug levels can decrease during pregnancy which is explained by decreased plasma protein binding and the greater drug clearance . MaternaMultiple sclerosis is a chronic autoimmune inflammatory demyelinating disease with an onset commonly occurring during the childbearing years. A lower relapse rate is thought to occur during pregnancy, with an increased relapse rate in the first three months postpartum. Patients should be counseled about this risk that exists irrespective of the type of anesthetic . AssessmArnold-Chiari malformations (ACM) are congenital anomalies in which the cerebellum herniates through the foramen magnum, displacing the lower pons and medulla. Of the four types described, type I is the most common. The condition is associated with an impaired flow of cerebrospinal fluid (CSF) from the fourth ventricle and dynamic or static herniation of brain tissue. It has been shown that cerebrospinal fluid pressure increases with uterine contractions by a mean of 2.5 mmHg, and that the elevation of intracranial pressure (ICP) is much greater during the second stage of labor. While neuraxial techniques have been found to be a safe and viable anesthetic option, correct interpretation of imaging tests and multidisciplinary input, including that of neurology and neurosurgery, should be elicited before deciding on anesthetic management in patients with known increases in ICP ,48.Women with cerebral aneurysms or intracranial space-occupying lesions present unique peripartum challenges. For patients with unruptured cerebral aneurysms, while mode of delivery does not seem to alter the incidence of rupture, most women tend to undergo cesarean delivery . EpiduraIdiopathic or benign intracranial hypertension is a common condition, characterized by raised intracranial pressure without related pathology in either the brain or the composition of cerebrospinal fluid. The main symptom is headache, and the cardinal sign is papilledema . TreatmeSpinal dysraphisms are neural tube closure birth defects that may be open or closed and are commonly seen in the lumbosacral area. In patients with surgically corrected open spinal dysraphisms, the terminal portion of the spinal cord typically lies at a vertebral level lower than normal. Dysraphisms may be inherently associated with the tethered cord syndrome. Patients often\u00a0develop minor sensory, motor, and functional deficits of the lower limbs, bowel and bladder. Closed defects may or may not be associated with cutaneous stigmata. A tethered spinal cord has implications for neuraxial anesthesia with increased risk due to its association with a low-lying spinal cord, need for imaging, and often abnormal preanesthetic neurological status . If spinWith improvements in management and rehabilitation, more women with spinal cord injury are conceiving children. Women with spinal cord injuries may give birth vaginally. Patients with spinal cord injury at the level of T6 or above are at risk of developing autonomic hyperreflexia. Although pain perception is impaired in these women at or above T10, neuraxial anesthesia is the treatment of choice for pain arising from the pelvic organs. Early neuraxial labor analgesia is advisable. Continuous intraarterial blood pressure monitoring should also be considered during the peripartum period .\u00a0Myasthenia gravis is an autoimmune disorder characterized by episodes of skeletal muscle weakness that are made worse by activity. The course of disease during pregnancy is highly variable. The maternal physiological changes of pregnancy may require adjustments in the doses of anticholinesterase drugs. Patients may experience progressive respiratory compromise secondary to diaphragmatic elevation during pregnancy. Preanesthetic evaluation should assess the extent of bulbar and respiratory involvement and overall baseline muscle strength. Pulmonary function testing should be done if there is respiratory compromise. Since the uterus consists of smooth muscle, the disorder generally does not affect the first stage of labor. The second stage of labor requires the use of striated muscle, so an assisted vaginal delivery may be required . Early nRare neuromusculoskeletal disorders that have multisystem manifestations include myotonic dystrophies, neurocutaneous syndromes like neurofibromatosis and tuberous sclerosis, and Guillain-Barre syndrome. In muscular dystrophies, cardiorespiratory involvement may be varied. Neuraxial techniques are preferred for labor analgesia and cesarean delivery. Severe disease may result in both airway and spinal abnormalities presenting challenges . In neurMusculoskeletal disorders including the inflammatory arthritides rheumatoid arthritis and ankylosing spondylitis can affect perioperative planning for the obstetric patient. Systemic manifestation involving the cardiovascular and respiratory system should be ruled out. Neuraxial anesthesia may also be technically challenging do to calcified interspinous ligaments and osteophyte formation limiting the patient\u2019s ability to flex forward. Unexpectedly high blocks have been reported . ChallenScoliosis is a lateral deviation in the vertical axis of the spine with severity being determined by measurement of the Cobb angle. Most cases of scoliosis are idiopathic; however, some are associated with neuromuscular conditions such as myotonic and muscular dystrophies, Marfan\u2019s syndrome, rheumatoid disease, osteogenesis imperfecta and achondroplasia. Pregnancy exacerbates the severity of the spinal curvature and cardiopulmonary abnormalities including restrictive lung disease and pulmonary vascular resistance. Neuraxial anesthesia may be offered, however it may be technically difficult with increased possibility of complications such as aberrant local anesthetic spread. Patients with achondroplasia are often delivered by cesarean delivery due to an inadequate maternal pelvis outlet with a normal-sized fetus. The small stature and spinal stenosis in these patients necessitate a reduction in the dose of local anesthetic required, therefore an epidural or combined spinal-epidural anesthesia may allow for better titration of the local anesthetic dose .Parturients who have had prior back surgeries may also have scar tissue or removal of the ligamentum flavum that could pose an anatomic challenge for epidural placement and for anesthetic administration . If a paHematological disordersCommon causes of thrombocytopenia during pregnancy include gestational thrombocytopenia, autoimmune thrombocytopenic purpura, and hypertensive disorders of pregnancy. Gestational thrombocytopenia is a benign self-limiting condition and accounts for most of the thrombocytopenia seen during pregnancy . In most6/L is likely to be very low in obstetric patients with thrombocytopenia secondary to gestational thrombocytopenia, immune thrombocytopenia (ITP), and hypertensive disorders of pregnancy in the absence of other risk factors [If thrombocytopenia is discovered during pregnancy, an assessment of bleeding history and etiology is necessary. The risk of spinal epidural hematoma associated with a platelet count \u226570,000 \u00d7 10 factors . For pat factors .Congenital coagulopathies include von Willebrand\u2019s disease which is divided into several subtypes based on quantitative and qualitative defects in the von Willebrand factor (vWF), which binds to collagen at sites of vascular injury, mediates platelet adhesion and aggregation, and serves as a carrier protein for coagulation factor VIII. A hematology consultation should be obtained early in pregnancy. These parturients should be tested for functional VWF and factor VIII concentration, as low levels are often be treated prior to delivery with therapies including desmopressin and von Willebrand factor concentrates. Case series have demonstrated safe spinal, epidural, and combined spinal-epidural anesthesia, and neuraxial anesthesia is considered an option for patients with normalized VWF:RCo, factor VII, and VWF antigen concentrations .Common thrombophilias diagnosed in pregnancy include Factor V Leiden deficiency and protein C and S deficiency. ACOG has recommended thromboprophylaxis for pregnancies complicated by inherited thrombophilias, which present challenges for neuraxial anesthesia about which the patient should be counseled . The SocEndocrine disordersGestational diabetes accounts for the majority of women with diabetes, followed by type I diabetes and type 2 diabetes . MaternaPatients with obesity are at a higher risk of anesthetic and obstetric complications and should have a formal preanesthesia evaluation . A thoroPregnant women likely exhibit overt or symptomatic hypothyroidism at a much lower rate than nonpregnant women. However, the required replacement of thyroid hormone in clinically hypothyroid patients often increases during pregnancy and is titrated to serum TSH levels. Patients with hyperthyroidism are treated with methimazole and propylthiouracil. Radioactive iodine is contraindicated in pregnancy. Patients with severe, untreated hyper- or hypothyroidism may present with unexplained tachycardia (hyperthyroidism) or bradycardia (hypothyroidism), abnormal weight gain for gestational age, or a visible or palpable goiter . This caGastrointestinal disordersPregnant patients with chronic liver disease or end-stage liver disease who are pre-transplant are at increased risk for both obstetric and anesthesia-related complications . They arParturients with chronic kidney disease or end-stage renal disease are anemic, experience hemodynamic alterations and electrolyte imbalances and are at increased risk for gastric aspiration. Although uncommon, pregnancy has been reported in women undergoing hemodialysis . AnticoaSubstance abuse disordersTobacco and alcohol are among the most commonly used substances during pregnancy and can cause anesthetic complications in addition to their teratogenic effects . AnestheThere is a high prevalence of opioid use during pregnancy, with risks of maternal withdrawal, neonatal abstinence syndrome, and increased analgesic needs due to opioid intolerance or opioid-induced hyperalgesia . ParturiHigh-risk obstetric and fetus-related considerationsPatients with placenta accreta spectrum disorders benefit from an early preanesthetic consultation. These cases involve multidisciplinary care and coordination involving maternal-fetal medicine, gynecology-oncology, obstetric anesthesiology, urology, general and trauma surgery, interventional radiology and neonatology, with potential need for massive transfusion . The obsEx utero intrapartum treatment is a specialized surgical technique developed to establish cardiopulmonary support safely and efficiently at delivery while maintaining placental bypass. The technique involves planned partial delivery of the fetus via hysterotomy while maintaining uterine relaxation and placental support, allowing for the establishment of neonatal cardiopulmonary stability in a controlled manner . Early aWe have included the following tables for further guidance. Tables Anesthesiology consultations for complex obstetric patients foster\u00a0optimal outcomes. They can help facilitate multidisciplinary care and enable shared decision-making. Furthermore, understanding the physiologic changes during pregnancy and the complex interplay between systemic comorbidities can improve the care provided. Finally, improved communication with patients regarding expectations, and anesthetic and peripartum planning can improve parturients\u2019 satisfaction with their delivery experience and potentially reduce maternal morbidity and mortality."} +{"text": "Struvite stones represent the most common cause of the rapidly growing staghorn calculiwhose predisposing factors include female sex, stasis from urinary tract malformationsor obstruction, neurogenic bladder, among othersWe read with great interest the work of Danilovic et alThe authors found a similar frequency of metabolic abnormalities in 24-hour urine testsbetween groups, but only important for hypocitraturia. There was no significantdifference in new events between groups, and treatment of metabolic abnormalities amongpatients with MAP stones rendered them prone to the same risk for a new event as thosewithout any metabolic disturbance.2, especially concerninglower rates of urinary calcium, due to secondary hyperparathyroidism, as alreadydemonstrated in primary struvite urolithiasis populationsAlthough metabolic abnormalities in pure struvite stone formers indeed appear to be morecommon than previously reported, the profile of metabolic alterations differ amongreports. Iqbal et alNevertheless, the study by Danilovic et al"} +{"text": "Hip dislocation after hip arthroscopy is an uncommon postoperative complication. We report a case of a 51-year-old woman who underwent right hip arthroscopy and presented with an anterior hip dislocation on postoperative day five. The index surgery involved capsulotomy, cam lesion debridement, and femoroplasty for an anterosuperior labral tear and cam-type femoroacetabular impingement. The patient underwent an uneventful recovery course until eight weeks postoperatively she developed iliopsoas bursitis. Her symptoms were managed conservatively with activity modification and physical rehabilitation. Complete resolution of symptoms was reported by the six-month follow-up visit, and no further dislocations or instability had been reported at 12 months. Anterior hip dislocation is a rare complication following hip arthroscopy and patients may experience persistent iliopsoas bursitis several months following successful reduction. Hip arthroscopy (HA) is a surgical procedure increasing in popularity in recent years due to its relatively low complication rate and less invasive approach compared to traditional hip surgery ,2. Hip dThe patient is a 51-year-old woman who underwent right hip arthroscopy with labral repair and femoroplasty with cam lesion debridement. After failing years of conservative management for unremitting right hip and groin pain, she elected to undergo right hip arthroscopy. Following surgery, she was made partially weight-bearing with an early range of motion to assist in recovery. She experienced an uneventful postoperative course until day five. While cleaning her kitchen, she extended and externally rotated her operative leg resulting in sudden and severe right hip pain accompanied by a fall to the ground and an inability to bear weight.Upon presentation, her right leg was shortened and externally rotated with intact neurovascular function. Radiographs revealed right anterior hip dislocation without evidence of acute fracture Figure .She was consciously sedated, closed reduced, and placed in a knee immobilizer Figure .Postreduction computed tomography (CT) revealed an impaction-type fracture in the anterior aspect of the femoral head Figure .Magnetic resonance imaging (MRI) was also obtained, which revealed an impaction fracture involving the anterior margin of the right femoral head and neck junction Figure .Surgical pathology of the cam resection and femoroplasty ruled out the presence of bony pathology. By one week postoperatively, she was able to ambulate with a walker. Physical examination revealed painless hip flexion greater than 100 degrees, extension to neutral, internal rotation to 35 degrees, and abduction to 45 degrees. However, she still experienced a sensation of anterior hip popping and had crepitus anteriorly. Initial MRI and CT scan were re-reviewed, and the labral repair appeared to be intact. She was advised to limit external rotation and hyperextension of the hip with protected weight-bearing and crutch use.By six weeks postoperatively, her preoperative anterior hip popping and crepitus had entirely resolved. She experienced no pain in the anterior hip capsule and no apprehension with hyperextension or external rotation. The patient had a stable gait without the use of assistive devices and was able to perform a full crouch without difficulty.The patient did not remain symptom-free during her continued follow-up visit. By eight weeks postoperatively, she experienced a re-intensification of her right hip pain that she characterized as a deep ache in the joint. Her hip occasionally locked and was accompanied by a sense of instability. She denied a history of trauma - other than the recent hip dislocation - or inciting events. Physical examination revealed palpable crepitus in the anterior acetabular margin at 60 degrees to 90 degrees of flexion. Both internal and external rotation aggravated these symptoms. The patient could ambulate, although she preferred to take small steps with her right lower extremity to reduce pain. Radiographs of the right hip revealed a well-maintained joint surface and joint line architecture with no gross bony abnormalities.Subsequent MRI revealed right iliopsoas bursitis with filling defects in the joint recesses and the iliopsoas bursa suspicious for synovial proliferation and small intra-articular bodies Figure .Additionally, new-onset small focal cartilage loss and osteochondral impaction injury in the femoral head secondary to microtrauma and instability were identified.\u00a0Her symptoms were managed conservatively with activity modification and physical rehabilitation. Complete resolution of symptoms was reported by a six-month follow-up, and no further dislocations or instability had been reported at 12 months.HA is a low-risk, minimally invasive procedure with numerous indications, including acetabular labral tears, FAI, chondral lesions, osteochondritis dissecans, ligamentum teres injuries, snapping hip syndrome, iliopsoas bursitis, and loose bodies .\u00a0Hip artWith such an exceedingly low complication rate, post arthroscopic hip dislocation has not been well documented. The majority of cases of hip dislocation after HA reported have been anterior hip dislocations -13. AlteOur patient underwent a transverse limb capsulotomy of the anterior joint capsule without repair, rim trimming of the acetabular margin, and femoroplasty with cam lesion resection. Interestingly, our patient experienced anterior hip dislocation only five days post arthroscopy. The patient also sustained a femoral head fracture, intra-articular loose bodies, and focal cartilage loss that resulted from the original injury. We can postulate from our experience that intraoperative distension and stretching of the anterior joint capsule may create instability and thus the risk for dislocation and subsequent injuries. Prior studies reported dislocation events that occurred immediately in the recovery room , on postInciting mechanisms vary depending on the activity level of the individual. Less active individuals frequently report a low energy twist or fall ,10,11. AOur patient was diagnosed with new-onset iliopsoas bursitis eight weeks following closed reduction of her post arthroscopic anterior hip dislocation. Six other cases describe further complications that required additional surgery: residual pain and apprehension treated with arthroscopic capsular plication , gross hAnterior hip dislocation after HA is an uncommon postoperative complication of an otherwise safe and well-regarded procedure. Surgeons must be aware of the surgical and patient-specific risk factors that contribute to postoperative hip instability in order to optimize patient safety in both the acute and chronic stages of recovery. Furthermore, the presence of iliopsoas bursitis, degenerative arthritis, and other causes of continued hip pain following closed hip reduction is an important topic that requires further investigation as the incidence of these complications is likely to rise with a growing number of hip arthroscopy procedures. This case emphasizes the need to investigate safer techniques to minimize postoperative complications, avoid dislocation after hip arthroscopy, and successfully manage resulting pathology."} +{"text": "Implementing intergenerational programming amidst the COVID-19 pandemic has required creativity, partnership, and dedication to the work. Most intergenerational programs involving in-person meetings or events are accompanied by guidelines to protect participant health and safety. Programming is routinely cancelled or postponed due to poor weather or contagious illness, particularly when a vulnerable population is involved. The needs for safety precautions and continued intergenerational contact were both amplified during the pandemic, leading many to modify or innovate ways to engage generations rather than eliminate contact for extended periods. Technology has afforded new approaches to engage young people and older people with each other; non-technological ways have also proven effective. This symposium will address strategies used to implement intergenerational programs during the pandemic. Authors will highlight lessons learned and strategies they expect to retain in the future. The first paper describes a pivot in nutrition programming designed for a shared site with preschool children and frail older adults. In paper two, authors discuss their partnership-based approach shifting to remote offerings of Cyber-Seniors programming. Paper three addresses how MentorUp Service-Learning expanded its reach by adaptations to virtual programming for older adults in retirement communities. The final paper presents evaluation data comparing arts programming delivered in-person pre-pandemic and again virtually during the pandemic. In each case, researchers and community partners learned techniques to maintain their programmatic foci. Some projects developed strategies they plan to maintain post-pandemic. Donna Butts, Executive Director of Generations United serves as the symposium discussant."} +{"text": "This session examines innovative approaches to effectively address the aging services workforce needs in rural, Midwestern settings. Presenters will explore career pathways and transfer opportunities in gerontology education, as well as best practices for addressing the educational, professional and personal needs of diverse student populations."} +{"text": "Objectives are to detail the model, pilot funding mechanism, early research findings and infrastructure investments. METHODS/STUDY POPULATION: The health research system has widely acknowledged challenges that can delay research translation to systems that advance health for chronically disadvantaged health disparity population groups. MSM\u2019s vision is to lead the creation and advancement of health equity. The vision-aligned strategic plan prioritized formalization of a TX TM implementation priority. The study population was the institution\u2019s research faculty and leaders, research administration, and communication arm. Through a cross-institutional working group, a plan was deployed to 1) assess the institutional landscape, 2) review the grey and peer reviewed literature on translational research and 3) invest in a pilot research funding mechanism. RESULTS/ANTICIPATED RESULTS: Over $700K has been invested in TX TM implementation. Over half of research faculty completed an institutional landscape assessment to identify translational research expertise, interests and points of interest in new collaboration. The most frequently cited collaborative research interests were clinical research with human subjects, patient-centered outcomes and laboratory-based research with human subjects/specimens. Funded multidisciplinary and/or community-engaged pilot studies investigate the role for circadian rhythms and shift work, cultural variables influencing mental health among Haitians living in the US and integrating prescription reconciliation telehealth in primary care. DISCUSSION/SIGNIFICANCE OF IMPACT: TX TM requires interdisciplinary collaboration across translational research spheres and beyond the academy. Institutional investment, infrastructure support and senior-level champions are central to awareness and rewarding such scholarship towards scaling approaches that advance health equity. CONFLICT OF INTEREST DESCRIPTION: Coined at Morehouse School of Medicine (MSM), Tx TM symbolizes an approach and scientific philosophy designed to intentionally promote and support convergence of interdisciplinary approaches and scientists to stimulate exponential advances for the health of diverse communities.OBJECTIVES/GOALS: Morehouse School of Medicine (MSM), T"} +{"text": "Inpatient falls are a persistent problem and despite research efforts during the last decade, inpatient fall rates have not significantly decreased. Older adults have an estimated 50% greater inpatient fall rate than younger adults. How older adults perceive their own fall risk affects their adherence to fall prevention recommendations. The aim of this phenomenological study was to gain a deeper understanding of the lived experiences of being at risk for falling in the hospital among older adults aged 65 years and older (N=9). Participants were interviewed twice using video conferencing within two weeks of hospital discharge. The audio-recorded interviews were transcribed, and then analyzed using van Manen\u2019s interpretive phenomenological method. The Health Belief Model expanded with the concepts of independence, fear of falling, embarrassment, dignity, and positivity effect served as the theoretical framework. Five major interpretive themes emerged: Relying on Myself, Managing Balance Problems in an Unfamiliar Environment, Struggling to Maintain Identity, Following the Hospital Rules, and Maintaining Dignity in the Relationships with Nursing Staff. These themes describe how the participants thoughtfully planned their mobilization to avoid falls. This process was influenced by their struggling to remain independent, following the hospital fall prevention rules out of politeness, and experiencing both positive and negative relationships with nursing staff. Hospitalized older adults employed their self-efficacy to manage balance problems in the hospital. These findings have not been previously documented in the literature. Fall prevention interventions supporting hospitalized older adults\u2019 self-management of fall risk are needed."} +{"text": "The 2019 Global Assessment Report (GAR2019) on Disaster Risk Reduction , the ideThe current special issue primarily focuses on how cascading disaster risk can be analyzed and modeled\u2014to support decision-making about disaster mitigation, preparation, and response. The special issue covers cascading impacts triggered by multiple hazard types, cascading impacts triggered by extreme rainfall events and by ground deformation, and the cascading impacts of business and infrastructure disruptions. Specific issues concerning the risk of cascading hazards for oil storage infrastructure and for underground railways are also analyzed, alongside potential mitigation measures. Other papers outline the importance of organization within social networks and of public health provision for cascading disaster management.Mignan and Wang analyzedHuggins et al. focused Cando-J\u00e1come et al. used an Dubaniowski and Heinimann used an Zhang et al. developeWang et al. analyzedChen et al. focused Harada et al. providedThe current special issue on Cascading Disaster Modelling and Prevention includes several examples of how cascading disaster analysis supports a more preventative and pro-active approach to cascading disaster risk. Case study reviews and other data analyses have illustrated how cascading impacts are triggered by multiple hazard types, and can be characterized by severe infrastructural and organizational disruptions. Relevant analyses have been conducted for specific sites, namely oil depots and underground railway systems. In both cases, innovative approaches to analytical modeling have identified key targets for cascading hazard mitigation. The remaining pair of special issue papers highlight the potential to learn from prior disasters, which have already affected large populations and broad geographical areas. Flexible and well-networked capacities remain paramount, especially where mitigation has not been achieved or where key targets for mitigation have not yet been identified. Analytical efforts are ongoing to help ensure that larger scale cascading disaster management can leverage more of the analytical precision that characterizes site-specific analyses."} +{"text": "Theoretical and empirical evidence suggests the existence of a general perceived stress factor overarching different life domains. The present study investigated the general perceived stress relative to domain-specific perceived stress as predictors of 26 diverse health outcomes, including mental and physical health, health behaviors, cognitive functioning, and physiological health indicators. A bifactor exploratory structural equational modelling approach was conducted in two samples from the Health and Retirement Study. Across the two samples, perceived stress was well-represented by a bifactor structure where there was a robust general perceived stress factor representing a general propensity towards stress perception. Meanwhile, after controlling for the general factor, specific factors representing perceived stress in different life domains were still clearly present. The general perceived stress factor was the most robust predictor of the majority of health outcomes. Age, sex, personality traits, and stressor exposure were found as possible diathesis underlying the general perceived stress factor."} +{"text": "Peak intra-articular load distribution for active squatting was lateral-heavy, contrasting to the medial-heavy distribution observed in passive intraoperative measurements, for all specimens. These aspects should be given due consideration while assessing intraoperative and postoperative joint stability following TKA.Ligament balancing during total knee arthroplasty (TKA) often relies on subjective surgeon experience. Although instrumented tibial trays facilitate an objective assessment of intraoperative joint balance through quantification of intra-articular joint loads, postoperative clinical assessment of joint balance relies on passive stress tests quantifying varus\u2013valgus joint laxity. This study aimed at correlating the intraoperative and postoperative metrics used to assess joint balance while also comparing joint loads obtained during passive assessment and active functional motions. Four experienced surgical fellows were assigned a fresh-frozen lower limb each to plan and perform posterior-stabilised TKA. An instrumented tibial insert measured intraoperative intra-articular loads. Specimens were then subjected to passive flexion\u2013extension, open-chain extension, active squatting, and varus\u2013valgus laxity tests on a validated knee simulator. Intra-articular loads were recorded using the instrumented insert and tibiofemoral kinematics using an optical motion capture system. A negative correlation was observed between mean intraoperative intra-articular loads and corresponding mean postoperative tibial abduction angle during laxity tests (medial: R = \u22120.93, Total knee arthroplasty (TKA) is an established surgical procedure to treat severe osteoarthritis in the knee; however, joint instability has been reported as a major cause of postoperative patient dissatisfaction . Soft-tiVerasense , a smart tibial tray compatible with already existing TKA designs, facilitates the quantitative measurement of soft-tissue balancing during TKA by measuring intraoperative loads in situ in the medial and lateral compartments at the points of contact between the femoral condyles and tibial plateaux ,7. With While intra-articular loads are used to achieve joint stability intraoperatively, clinical assessment of postoperative joint stability typically relies on passive tests, such as the stress tests quantifying the varus\u2013valgus laxity of the knee at multiple flexion angles , performMoreover, while this manual passive postoperative assessment of joint stability is performed at constant flexion angles, the aim is to have desired postoperative joint stability for dynamic activities of daily living, such as walking, over the entire range of knee flexion. Active motions differ from their passive counterparts primarily owing to active muscle force production, as well as their often closed-chain nature resulting in higher joint contact forces .Therefore, the primary aim of this in vitro study was to correlate intraoperative intra-articular loads to the postoperative tibiofemoral abduction measured during the varus\u2013valgus stress tests, hypothesizing a negative correlation between the two parameters. The secondary aim of this study was to compare intra-articular loads measured intraoperatively to those measured postoperatively during passive and active motions, with the hypothesis that active motions would alter load distribution between the medial and lateral compartments owing to a change in joint dynamics and muscle force production.Four fresh-frozen cadaveric specimens were obtained from the institute body donation programme following ethical approval by the local ethics committee. None of the specimens had signs of lower limb disorder or prior surgical intervention.Magnetic resonance imaging and full leg radiographs were obtained for each specimen to design specimen-specific cutting blocks for the TKA surgery using the VISIONAIRE protocol . Rigid marker frames with reflective spheres (diameter = 12 mm) were attached to the femur and tibia using bicortical bone pins. Computed-tomography (CT) scans obtained for each frozen specimen in full extension were used to identify the location of the markers relative to anatomic landmarks in order to define a joint coordinate system for the femur and tibia .Each lower limb was thawed for 24 h before resecting it 32 cm proximally and 28 cm distally to the knee joint. Care was taken to preserve the joint capsule, ligaments, and tendons while dissecting the surrounding skin and subcutaneous tissue. The femur and tibia were embedded in metal pots using acrylic resin in a physiologic orientation. Tendons of the quadriceps and the hamstrings were carefully exposed and prepared to be attached to an electromechanical actuator for dynamic control and passive springs for constant tensile load application, respectively.Each of the four specimens was randomly allotted to one of four experienced surgical fellows scores > 85%) ,12. SurgFollowing implantation, each specimen was mounted on a previously validated physiological knee-joint simulator and subjThe specimen was kept moist during experimental testing with phosphate-buffered saline solution to mitigate tissue-drying effects. The order of tasks performed was randomized to avoid potential bias. Each task was performed in triplicate by a single operator.A six-camera motion capture system was used to track the motion of the femur and tibia. Intra-articular loads in the medial and lateral compartments of the knee were recorded during all tasks using the custom company software .p < 0.05). Peak intra-articular loads in the medial and lateral compartments were calculated for passive flexion\u2013extension, open-chain extension, and active squatting, and compared to values obtained intraoperatively.The recorded trajectories of markers on the femur and tibia were processed further to calculate tibiofemoral kinematics for each specimen using a custom code based on joint coordinate systems defined using anatomical landmarks obtained from CT. The relationship between postoperative joint laxity, measured using the tibial abduction angle during varus\u2013valgus stress tests, and intraoperative intra-articular load was assessed for each specimen using the Pearson correlation test than in flexion (4.4 \u00b1 2.4\u00b0) postoperatively . Mean po = 0.04) .Peak total intra-articular load across the range of knee flexion was higher for actively loaded tasks\u2014open-chain extension and squatting\u2014as compared to passive measurements, with the peak load during squatting being the highest amongst all tasks for three out of the four specimens . For allIn the case of peak loads for intraoperative measurements, passive flexion\u2013extension, and open-chain extension, loads in the medial compartment were higher than those in the lateral compartment for three out of the four specimens; however, for active squatting, loads in the lateral compartment were higher than those in the medial compartment for all specimens .Ligament balancing is vital in the successful outcome of TKA ; howeverOne of the highlights of this study was the participation of four experienced surgical fellows, each performing specimen-specific TKA. The same implant was used by all fellows to avoid implant-specific variability in postoperative biomechanics; however, specimen-specific cutting guides were based on the preoperative surgical planning performed by each fellow. Moreover, although trained at different institutions globally, the fellows followed standard surgical norms of joint balancing during TKA ,3. This Intra-articular loads measured during TKA revealed that all specimens were tighter in extension, thereby leading to higher loads, than in flexion . MoreovePostoperative joint laxity largely corroborated with intraoperative intra-articular loads, since it was ensured that implant sizes and/or component alignments were not altered following intraoperative joint balancing assessment with the instrumented tibial trays. Postoperative tibial adduction and abduction during the varus and valgus stress tests, respectively, were higher in flexion than in extension , therebyPeak total intra-articular load over the range of knee flexion was higher for dynamic loaded tasks as compared to static measurements , with thHowever, this was not the case for one specimen (Spec 2), which exhibited such high intra-articular loads during intraoperative measurements already that the differences in peak loads between passive and active motions were minimal, as compared to those observed in other specimens . MoreoveAlthough this unique cadaveric simulator study included state-of-the-art instrumented sensors, one of the main shortcomings of the study was the small sample size. Future studies should not only look to include a larger number of specimens but also increase the number of static flexion angles used to test intraoperative intra-articular loads and corresponding postoperative joint laxity, thereby facilitating a better correlation analysis of the two parameters with statistical and clinical significance. Another limitation was the underlying assumption that Verasense sensors could sustain intra-articular pressure encountered during the actively loaded squatting motion, often reaching ~16 MPa , withoutA conformance between intraoperative intra-articular joint loads and postoperative joint laxity was observed, although the correlation between these parameters was not statistically significant for all specimens. Moreover, there was a stark discrepancy in peak joint load distribution across the medial and lateral compartments between passive tasks and active functional motions. These aspects should be given due consideration while performing a joint balancing procedure during TKA, as well as clinically assessing postoperative joint stability."} +{"text": "Entrapment peripheral neuropathies are clinically characterized by sensory impairment and motor deficits. They are usually caused by mechanical injuries, but they are also a frequent manifestation of metabolic diseases, toxic agent exposure, or systemic fibrotic disorders. Here we describe the clinical, radiological, and histopathological features of a novel progressive fibrotic disorder characterized by progressive multifocal fibrosing neuropathy. We identified two patients who presented with severe and progressive peripheral neuropathic symptoms sequentially affecting multiple sites. These patients presented with severe and progressive multifocal, sequentially additive peripheral neuropathic symptoms. Extensive nerve conduction and radiological studies showed the sequential development of multifocal motor and sensory peripheral neuropathy in the absence of any exposure to known infectious, inflammatory, or fibrotic triggers and the lack of family history of compression neuropathies. Extensive clinical and laboratory test evaluation failed to support the diagnosis of any primary inflammatory or genetic peripheral neuropathy and there was no evidence of any systemic fibrosing disorder including Systemic Sclerosis, lacking cutaneous fibrotic changes and cardiopulmonary abnormalities. The clinical course was progressive with sequential development of motor and sensory deficits of upper and lower extremities displaying proximal predominance. Histopathological study of tissues obtained during nerve release surgeries showed severe perineural fibrosis with marked accumulation of thick collagen bundles encroaching the peripheral nerves. There was no evidence of vasculitic, inflammatory, or vascular fibroproliferative lesions. We suggest that the clinical findings described here represent a previously undescribed fibrotic disorder affecting peripheral nerves, and we propose the descriptive term \"Progressive Multifocal Fibrosing Neuropathy\" to refer to this novel disorder. Despite the inherent limitations of this early description, we hope this is would contribute to the identification of additional cases. Peripheral neuropathies caused by nerve compression or entrapment syndromes manifest clinically by sensory impairment and motor deficits. They most commonly result from chronic mechanical injuries of nerve tracts in fibro-osseous canals or compression by other tissue structures, including tendons, ligaments, and muscles , 2. SlowHere, we describe two patients who developed a novel disorder characterized by severe and progressive peripheral neuropathy with multifocal and sequential involvement of multiple sites. Extensive neurological and histopathological studies demonstrated that this process was caused by encroachment of nerve tracts by the accumulation of large amounts of excessive fibrotic tissue in the absence of genetic or acquired neurological disorders or systemic inflammatory or fibrotic diseases. Therefore, it is suggested that this clinical entity represents a previously undescribed fibrotic disorder affecting the peripheral nerves.Both patients were referred to the Scleroderma Center at Thomas Jefferson University for evaluation of a systemic fibrosing disorder causing progressive neuropathy affecting multiple peripheral nerves. Appropriate laboratory tests for the assessment of SSc and SSc-like disorders, including autoantibody testing, nail-fold video-capillaroscopy, pulmonary function tests, high-resolution chest computed tomography, and echocardiograms were performed. Neurological evaluations, including extensive clinical and electrophysiological assessment, were performed by a neuromuscular neurologist (M.C.D); and radiological studies included resonance imaging (MRI), and ultrasonography. Histopathological studies of biopsies from affected nerves and surrounding tissue obtained during decompression surgeries were performed. The tissues were stained with hematoxylin\u2013eosin (H&E), and Masson\u2019s Trichrome stains, immunohistochemistry studies for inflammatory cell markers including CD3, CD8, CD20, and CD68 were performed. A search for peripheral myelin protein (PMP22) gene mutations to exclude hereditary neuropathy with liability to pressure palsies (HNPP) was performed in both patients .A 37-year-old female presented with three months history of severe pain localized to the left genital area. An initial evaluation was negative for infectious etiologies. Owing to the persistence of symptoms, an MRI was performed. The study disclosed soft-tissue edema surrounding the left pudendal nerve , silica, organic solvents, pesticides, radiation, occupation/hobby exposures, or other identifiable environmental factors. No family history of a similar syndrome was found. Laboratory testing in both cases showed the absence of eosinophilia and tests for antinuclear antibody were negative. Repeated analysis failed to show elevation of inflammatory markers (ESR and CRP). Genetic testing did not disclose any peripheral myelin protein 22 (PMP22) mutations. An echocardiogram did not show signs of pulmonary hypertension or myocarditis, and pulmonary function tests (PFTs) were normal. There was no clinical or laboratory evidence to suggest the diagnosis of diabetes mellitus.Given the fact that the findings of EMG/NC studies correlated with the clinical picture in both patients and provided imaging evidence of entrapment neuropathy, lumbar puncture and CSF analysis were not performed.MRI of the pelvic area showed marked perineural edema surrounding the left pudendal nerve of patient 1 and right pudendal nerve in patient 2 , 18, an Given the fact that several systemic fibro-inflammatory conditions have been related to an exogenous triggering agent, an extensive and detailed inquiry was performed but failed to disclose any toxic exposure. Although patients with more than one neuropathic compressive syndrome affecting the same extremity, usually associated with thoracic outlet syndrome have been described and a \u201cdouble crush mechanism\u201d was proposed for those cases , 22, in An extensive review of the published medical literature indicates that there was no previously described syndrome or disease with the clinical and histopathological findings described in this report and the cases and the cases studied and reported appear to be unique. Therefore, it is suggested that this may represent a novel clinical entity descriptively termed \"Multifocal Progressive Fibrosing Neuropathy\". The most important features distinguishing Multifocal Progressive Fibrosing Neuropathy from SSc, TOS, EF, EMS, and NSF, and other neurological diseases frequently causing neuropathy are listed in Tables Finally, we can hypothesize that owing the absence of inflammation in immunopathological studies but significant fibrosis, these patients could benefit from the use of antifibrotic drugs."} +{"text": "JCI, Arinze et al. explore the role of tryptophan metabolites in chronic kidney disease\u2013associated (CKD-associated) peripheral arterial disease. The authors used mouse and zebrafish models to show that circulating indoxyl sulfate (IS) blocked endothelial Wnt signaling, which impaired angiogenesis. Plasma levels of IS and other tryptophan metabolites correlated with adverse peripheral vascular disease events in humans. These findings suggest that lowering IS may benefit individuals with CKD and ESKD.Patients with end-stage kidney disease (ESKD) have increased vascular disease. While protein-bound molecules that escape hemodialysis may contribute to uremic toxicity, specific contributing toxins remain ambiguous. In this issue of the The use of chronic dialysis in patients with end-stage kidney disease (ESKD) is one of the miracles of modern medicine with which we can keep patients with kidney failure alive; however, dialysis does not completely remove the many uremic toxins . PatientJCI, Arinze et al. provide in vivo evidence in mouse and zebrafish animal models that circulating IS (at concentrations found in humans with CKD) blocks Wnt signaling in the endothelium and impairs angiogenesis in a Wnt ligand\u2013independent fashion . The autWhile the in vivo findings compellingly link IS with PAD, several questions remain unanswered. The hind-limb ischemia model is a comparatively acute model focusing on capillary bed density that may only reflect part of the pathophysiology of PAD associated with CKD. Although increased concentrations of IS have been associated with PAD in hemodialysis patients, IS does not seem to have any substantial association with other cardiovascular outcomes . ConsequTaken together with other published studies, Arinze\u2019s study shows that activation of AhR by IS and other tryptophan metabolites is now implicated in multiple pathophysiologic processes associated with CKD, including glomerular injury, renal fibrosis, atherogenesis and cardiovascular disease, protein energy wasting, renal anemia, loss of bone mineralization, and cognitive dysfunction . Finding"} +{"text": "A 93-year-old man living in a nursing home presented to our emergency department with altered mental status. Examination revealed hypotension and severe hypoxia. Chest radiograph showed infiltrates in the right upper lobe, and computed tomography of the abdomen and pelvis demonstrated a left femoral neck fracture. A point-of-care transthoracic echocardiogram (TTE) revealed an enlarged right ventricle, severe tricuspid regurgitation, and numerous white floating dots moving toward the right atrium from the inferior vena cava (IVC), leading to the diagnosis of fat embolism syndrome (FES).Although imaging studies can facilitate diagnosis, the diagnosis of FES is typically made by clinical history and presentation, making a swift diagnosis often difficult in those who are critically ill. Recent case reports have described that TTE can detect fat emboli, seen as flowing hyperechoic particles in IVC. This image demonstrates the utility of TTE to diagnose FES. A 93-year-old man living in a nursing home presented to our emergency department with altered mental status, which occurred suddenly over the previous one hour. An initial history elicited from the nursing home staff failed to identify any risk factors. Examination revealed hypotension and severe hypoxia with oxygen saturation of 85% on 15 liters per minute oxygen with a non-rebreather mask. Chest radiograph showed infiltrates in the right upper lobe, but contrast computed tomography (CT) showed no pulmonary embolism. Suspecting an occult organ pathology, we ordered CT of the abdomen and pelvis, which demonstrated a left femoral neck fracture. Further inquiry of the nursing home staff revealed that the patient had fallen earlier on the same day, striking his hip on the floor. A point-of-care transthoracic echocardiogram (TTE) revealed an enlarged right ventricle, severe tricuspid regurgitation, and numerous white floating dots moving toward the right atrium from the inferior vena cava (IVC) , leadingFat embolism syndrome is a rare condition defined by the presence of fat globules in respiratory circulation.What do we already know about this clinical entity?Fat embolism syndrome (FES) is defined by the presence of fat globules in respiratory circulation; its diagnosis is often challenging.What is the major impact of the image(s)?Floating fat emboli can be detected using point-of-care ultrasound, which facilitates the diagnosis of FES.How might this improve emergency medicine practice?Point-of-care transthoracic ultrasound is an essential diagnostic tool to evaluate patients with suspected FES.VideoTransthoracic echocardiogram. The video shows numerous white floating dots moving toward the right atrium (RA) from the inferior vena cava (IVC) suggestive of fat embolism syndrome."} +{"text": "Delivery of serious illness communication (SIC) is necessary to ensure that all seriously ill patients receive goal-concordant care. However, the current SIC delivery process contains barriers that prevent the delivery of timely and effective SIC. In this paper, we describe the current bottlenecks of the traditional SIC workflow and explore how a hybrid artificial intelligence-human workflow may improve the efficiency and effectiveness of SIC delivery in busy practice settings. High-quality and timely SIC enables and enhances decision-making and care planning through the process of cultivating patients\u2019 prognostic awareness and translating their values and priorities into patient-centered recommendations. The iterative and non-linear process of SIC requires frequent and early conversations to ensure that clinicians accurately understand patients\u2019 evolving goals, values, and priorities and to make patient-centered recommendations throughout the illness trajectory.Serious illness communication (SIC) is an essential component of palliative care that ensures the delivery of goal-concordant care. SIC is often defined as the conversations between clinicians and patients with serious illness about their goals, values, and prioritiesThe traditional SIC delivery process consists of a series of conversations where gathering, interpreting, and integrating SIC data occur within a clinical encounter followed by manual clinician documentation in the electronic health record (EHR) post-visit. This process can be broken down into the following steps: determining patient eligibility for SIC; gathering and interpreting information ; conducting a therapeutic conversation with the goal of shared decision-making; documenting the conversation; and making SIC documentation accessible to others in the EHR Fig. . However2. Second, patients and/or clinicians may be unclear about the optimal timing and when to make such conversations a priority2. Third, clinicians often lack time to conduct SIC2 and to document these conversations adequately3. Fourth, standards for EHRs to facilitate consistent, accurate documentation that is easily accessible to all care team members are lacking4. Therefore, in addition to training more clinicians to be competent in SIC, a novel workflow that addresses these barriers will be necessary to ensure that all seriously ill patients receive timely and effective SIC that informs their care in real time and naturally results in documentation of patients\u2019 goals and preferences that is visible to others. We propose that a hybrid artificial intelligence (AI)-human workflow can improve this process by helping clinicians identify patients with SIC needs more accurately; promoting upstream data collection to facilitate more efficient in-person shared decision-making; reducing clinician documentation burden by streamlining the SIC documentation process; facilitating seamless sharing of patient goals and preferences via accurate and efficient identification of SIC documentation in the EHR; and providing real-time feedback to clinicians on their SIC skills.First, most clinicians lack SIC training and feel unprepared to have these difficult conversations with their patients5. Moreover, systematic methods to identify patients with palliative care needs are lacking6. To solve this problem, AI researchers have developed machine learning algorithms to generate more accurate mortality predictions to facilitate earlier SIC and palliative care delivery8. Some researchers have demonstrated that coupling AI-generated mortality predictions with behavioral nudges to clinicians can improve SIC frequency9. However, critics have expressed worry about using mortality predictions alone for identifying populations with palliative care needs because a reductionistic interpretation of these results may lead to further propagation of algorithmic or other systemic biases leading to inequitable care and patient harm10. Therefore, others have suggested alternative metrics that identify patients at risk of worsening serious illness to train predictive algorithms\u2014including functional decline, deteriorating quality of life, escalating caregiver burden, or psychosocial or spiritual distress10. Some accountable care organizations are already using claims-based algorithms to identify high-cost patients who would benefit from earlier palliative care11, but greater effort is needed to mitigate algorithmic bias, especially among commercially available products that are widely used12. Moreover, additional methods to identify SIC-eligible patients should be considered since EHR-based algorithms often have performance gaps13.Patients with serious illness often experience delayed SIC because clinicians are poor at prognosticating life expectancy for terminally ill patients, usually erring on the side of optimism16, but the technology to date is mature enough to support its use in SIC as a basic data-gathering agent. One could imagine SIC conversational agents that would collect information about the patient\u2019s prognostic awareness and priorities prior to in-person visits. Doing so would enable clinicians to maximize face-to-face time on higher-order cognitive and emotional tasks that would lead to earlier shared decision-making. Conversational agents may also give patients time to reflect and discuss issues with trusted persons prior to meeting with the clinician.The use of conversational agents (aka chatbots) has largely been unexplored in palliative care. Conversational agents that are emotionally aware or use unconstrained natural language input are nascent in health care18. In one study, older adults utilized multiple-choice responses to converse with an agent that provided spiritual counseling, which reduced anxiety and increased the intent to create a last will and testament17. In another, machine learning algorithms allowed the agent to collect patient-reported outcome measures and display empathy to the users\u2019 free text responses18. Although conversational agents were well-received in these preliminary studies, some patients will prefer to have the entire SIC with their clinicians directly, obviating the need for a chatbot. Further studies need to be conducted on actual patients with serious illness and should assess if conversational agent-led SIC triggers emotional distress in patients or actually enhances the patient-clinician relationship. Moreover, deploying conversational agents may inadvertently widen inequities in certain populations, particularly patients with limited English proficiency, health information technology literacy, or broadband access.To date, no studies on conversational agents have been conducted on patients with serious illness, but proof-of-concept studies in the general population have demonstrated the acceptability of conversational agents that address palliative care-related topics3. NLP-enabled dictation software has demonstrated the ability to reduce medical documentation time while maintaining documentation quality19 and is already commercially available20. Such technology would reduce the time clinicians spend manually writing notes and minimize recall bias since the content of the conversation is transcribed verbatim during the conversation and not hours later, typical of much documentation. As a result, nuanced details of the conversation are readily captured in real time leading to higher quality notes with less clinician effort.AI can also streamline the SIC documentation process and potentially improve the quality of SIC documentation via natural language processing (NLP)\u2014a form of machine learning designed to understand, interpret, or manipulate human language. Missing or incomplete documentation in the EHR regarding patient preferences for life-sustaining treatment is common and contributes to medical errors related to end-of-life care4. In its current state, identifying SIC documentation in the EHR typically involves a manual chart review that possibly includes a keyword search or utilization of note filters. NLP-enabled software that identifies free text SIC documentation would likely reduce the time and effort clinicians spend looking for this information and prevent inadvertent oversight of patient preferences leading to goal-discordant care. AI-assisted chart reviews have demonstrated higher accuracy and shorter time for extracting relevant patient information compared with standard chart reviews21. Additionally, NLP has demonstrated the ability to identify SIC documentation accurately from EHR data and, in some cases, more accurately than human coders24. However, the accuracy of NLP to identify SIC documentation largely depends on the quality of the gold standard dataset created by human annotation used to train the model. Consequently, widespread implementation of NLP-enabled software to identify SIC documentation likely remain years away since high-quality annotated examples to train generalizable models are lacking, and adapting NLP models between different datasets often require additional training or fine-tuning25. In the interim, some health systems have created a centralized location for SIC documentation in the EHR to improve SIC documentation identification26, but compliance with utilizing these modules will likely remain an issue and additional NLP assistance will optimize the identification of SIC documentation in the EHR27.NLP also has the potential to address barriers resulting from poor EHR design that prevent or inhibit the extraction and flow of meaningful advanced care planning information across the care continuum28. Automated speech analysis and communication feedback will likely take years to manifest because not only do technical and logistical barriers remain 28, but also greater consensus is needed to define and measure basic communication quality and outcomes29. Researchers are currently utilizing NLP to analyze audio recordings of SIC to characterize and understand the naturally occurring features of these complex conversations32, such as identifying intentional pauses that foster empathy, compassion, and understanding, aka \u201cConnectional Silences.30\" This type of research will guide future efforts to develop ways of automating the measurement of SIC quality in real time, allowing for immediate feedback to improve clinician performance.Finally, AI has the potential to improve SIC delivery by providing speech analysis and personalized feedback to clinicians regarding their communication skillsIn conclusion, a hybrid AI-human SIC workflow may improve the efficiency and effectiveness of SIC delivery in busy practice settings. Some of the AI technology are available for widespread use presently , whereas others are emerging technologies that are being developed and studied . This proposed paradigm still requires that clinicians undergo some SIC training to capitalize on the assistance provided by AI, as well as additional research to avoid unintended consequences of AI implementation. That said, a semi-automated approach to SIC delivery holds tremendous promise and would likely improve current SIC workflow by optimizing clinical manpower and efficiency while increasing the likelihood that these critically important conversations will occur effectively and in a timely fashion."} +{"text": "Alcohol (ethanol) use and misuse is a costly societal issue that can affect an individual across the lifespan. Alcohol use and misuse typically initiates during adolescence and generally continues into adulthood. Not only is alcohol the most widely abused drug by adolescents, but it is also one of the most widely abused drugs in the world. In fact, high rates of maternal drinking make developmental ethanol exposure the most preventable cause of neurological deficits in the Western world. Preclinical studies have determined that one of the most consistent effects of ethanol is its disruption of hippocampal neurogenesis. However, the severity, persistence, and reversibility of ethanol\u2019s effects on hippocampal neurogenesis are dependent on developmental stage of exposure and age at assessment. Complicating the neurodevelopmental effects of ethanol is the concurrent development and maturation of neuromodulatory systems which regulate neurogenesis, particularly the cholinergic system. Cholinergic signaling in the hippocampus directly regulates hippocampal neurogenesis through muscarinic and nicotinic receptor actions and indirectly regulates neurogenesis by providing anti-inflammatory regulatory control over the hippocampal environmental milieu. Therefore, this review aims to evaluate how shifting maturational patterns of the cholinergic system and its regulation of neuroimmune signaling impact ethanol\u2019s effects on adult neurogenesis. For example, perinatal ethanol exposure decreases basal forebrain cholinergic neuron populations, resulting in long-term developmental disruptions to the hippocampus that persist into adulthood. Exaggerated neuroimmune responses and disruptions in adult hippocampal neurogenesis are evident after environmental, developmental, and pharmacological challenges, suggesting that perinatal ethanol exposure induces neurogenic deficits in adulthood that can be unmasked under conditions that strain neural and immune function. Similarly, adolescent ethanol exposure persistently decreases basal forebrain cholinergic neuron populations, increases hippocampal neuroimmune gene expression, and decreases hippocampal neurogenesis in adulthood. The effects of neither perinatal nor adolescent ethanol are mitigated by abstinence whereas adult ethanol exposure-induced reductions in hippocampal neurogenesis are restored following abstinence, suggesting that ethanol-induced alterations in neurogenesis and reversibility are dependent upon the developmental period. Thus, the focus of this review is an examination of how ethanol exposure across critical developmental periods disrupts maturation of cholinergic and neuroinflammatory systems to differentially affect hippocampal neurogenesis in adulthood. This rsee . The devsee (see ). One resee . Ethanol exposure exerts adverse consequences on the brain throughout the lifespan, with deficits evident from exposure during perinatal development through adulthood. The spectrum of ethanol\u2019s adverse effects produces enormous individual, interpersonal, and societal costs. For example, the robust teratogenic effects of ethanol exposure egnancy) makes feegnancy) . Of noteegnancy) . Furtheregnancy) . The preegnancy) . Howeverncy) see.Each section of this review will discuss the adult impact of ethanol exposure on these systems during discrete neurodevelopmental windows: perinatal, adolescence, and adulthood. Incubation effects, persistence, and reversibility will be discussed, with sex differences highlighted when applicable. The goal of this review is to highlight the molecular underpinnings of ethanol\u2019s impact on hippocampal neurogenesis across the continuum of the lifespan.in utero and neonatal) development induce long-lasting neurodevelopmental consequences on neurological structure and function due to alterations in development of neurocircuitry and other neurobiological systems, permanently shifting maturational trajectories in both the brain and body. One of the most ubiquitously known teratogens is ethanol, and the consequences of ethanol exposure during perinatal development are devastating. These consequences were first documented in 1968 by Paul Lemoine , therebirth see.see . In addThe myriad of developmental and pharmacological variations in rodent FASD models complicates translation of findings to the human literature, particularly when results vary by experimental design. For example, the characteristic facial dysmorphology evidenced in children with FASD has been specifically linked to ethanol-induced cell death during early embryonic exposure (mouse embryonic days 7\u20139) are not see , findinsee see. Althougsee see. As suchsee see. The lacseeHuman studies of FASD indicate prior alcohol exposure results in attenuated age-related increases in hippocampal volume across adolescent development . HoweverseeFuture studies will need to elaborate on these findings, particularly in relation to perinatal ethanol-driven effects on adult hippocampal neurogenesis versus gliogenesis as well as potential sensitivity differences in males versus females. Examination and reporting of both sexes is particularly critical, as some studies have found differences solely in one sex but not the other see. For exaseeThe cholinergic system rapidly develops during the early neonatal period in rodents see, and is 1) ethanol-induced decreases in adult basal forebrain cholinergic neurons may result from caspase-3-mediated apoptotic cell death during critical neonatal developmental windows, and 2) reductions in adult populations of basal forebrain cholinergic neurons after neonatal ethanol exposure do not recover despite long periods of abstinence. These findings have been reproduced across a variety of mammalian species, from mice to primates, suggesting a high level of congruency in this literature. Moreover, neonatal ethanol-induced loss of basal forebrain cholinergic neurons is accompanied by diminished evoked acetylcholine efflux in the adult hippocampus as assessed using in vivo microdialysis, indicating that perinatal ethanol exposure persistently disrupts basal forebrain-hippocampal cholinergic neurocircuitry the critical role of acetylcholine in neurogenesis, 2) the likely contribution of acetylcholine reductions to loss of neurogenesis in these model, and 3) the therapeutic potential of compounds which target the cholinergic system in FASD.Loss of basal forebrain cholinergic neurons and subsequent diminution of acetylcholine efflux in the hippocampus have critical implications for cognitive and behavioral deficits in FASD and preclinical models of FASD. For example, deprivation of choline, which is an essential nutrient and critical component of acetylcholine synthesis, exacerbates perinatal ethanol-induced deficits in motor development in early life . Conversult rats . This suult rats , furtherOne of the mechanisms by which perinatal ethanol-induced disruption of basal forebrain-hippocampal cholinergic neurocircuitry may affect adult hippocampal neurogenesis is through long-term alterations in cholinergic receptor activation in adulthood. Both muscarinic and nicotinic receptors directly affect neuroprogenitor pools and indirectly regulate the hippocampal environmental milieu. Muscarinic M1 receptors are abundant in the adult hippocampus, where they colocalize with newborn cells in the dentate gyrus to play a key role in hippocampal cell proliferation . In factInterestingly, the sole study reporting that ethanol exposure across gestation decreases adult cell proliferation parallelIn contrast to muscarinic receptors, nicotinic receptors have received little attention in relation to the lasting effects of perinatal ethanol exposure, with a single study reporting that hippocampal \u03b17 nicotinic receptor density in adulthood is unaffected by perinatal ethanol exposure . Howeversee . While see . Microglsee . Interessee . Future Specifically, prenatal ethanol exposure increased CCL6, IL-21, IL-10ra, and TNF\u03b1 expression in the developing brain of male and female rats, relative to age-matched controls, on E17 , with feThe effects of perinatal ethanol on innate immune activation are further exacerbated in adulthood. This is in part due to the fact that perinatal ethanol has cascading repercussions on immune regulation of the developing cholinergic system to impact later neuroimmune signaling dynamics in adulthood. For example, some studies suggest perinatal ethanol sensitizes later innate immune gene responses in adulthood, in part due to diminished capacity for cholinergic anti-inflammatory feedback that leads to an exaggerated proinflammatory neuroimmune response. Prenatal ethanol exposure dramatically exacerbates the adult response to modest innate immune challenges (25\u00a0\u03bcg/kg lipopolysaccharide [LPS]), evidenced by exaggerated hippocampal gene expression of IL-1\u03b2 and IL-6 in male rats but not female rats, relative to controls . SimilarIn addition, persistent increases in CCL2 signaling by perinseeCollectively, these findings indicate that perinatal ethanol-induced acute induction of proinflammatory signaling cascades may be an early underlying factor in developmental cholinergic deficits by contributing to their programmed cell death during rodent neonatal or human third-trimester development. In adulthood, these developmental deficits in cholinergic function may unmask greater impairments under conditions of neuronal stress, potentially through alterations in muscarinic and nicotinic receptor activation and consequential augmented disruption of the proinflammatory signaling in the hippocampal environmental milieu, reflecting a vicious cycle that may drive both impairments in neurogenesis and greater cognitive deficits in high-complexity tasks see.1) ethanol-induced alterations during perinatal development persistently impact development by changing gene transcription, 2) some consequences of perinatal ethanol will emerge over time in conjunction with developmental changes in epigenetic regulation of gene expression, and 3) pharmacological interventions which aim to reverse perinatal ethanol-induced developmental effects will be most effective if they also reverse perinatal ethanol-induced epigenetic changes.Children with FASD have several complications due to large-scale cell death induced by prenatal alcohol exposure coupled with broad shifts in epigenetic regulation of gene expression. Epigenetics is the modulation of gene expression in the absence of alterations to DNA, making it a master director of brain development by altering gene accessibility to transcriptional machinery across time . For exaThe emergence of ethanol\u2019s cascading consequences on neurodevelopment over time complicates interventions aimed at reversal of neurological and behavioral deficits in models of FASD. In fact, the majority of current pharmacological intervention strategies approved for children with FASD target other neuropsychiatric comorbidities, such as the use of stimulants for the highly co-morbid diagnosis of attention deficit hyperactivity disorder in FASD children, with few treatment strategies aimed to prevent or reverse FASD pathophysiology itself . These cThe positive preclinical effects of choline supplementation on FASD behavioral and neurological outcomes have given it a spotlight in clinical trials, several of which are ongoing . HoweverAdolescence is a period of rapid brain maturation with extensive myelination, synaptic pruning, and neurogenesis, highlighting that remodeling of molecular circuitry is a critical component of this developmental period that parallels rapid behavioral and cognitive growth . Adolesc1) National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA), which evaluates the progressive disruption of neurodevelopment and behavioral alterations with alcohol exposure across adolescence in humans, and 2) the Neurobiology of Adolescent Drinking in Adulthood (NADIA) consortium, which uses rodent models of adolescent intermittent binge ethanol exposure to examine mechanisms underlying ethanol\u2019s long-term molecular and cognitive-behavioral changes in adulthood (via an intermittent dosing regimen that results in the high BECs (>150\u00a0mg/dl) that are achieved in human adolescents . Findinnts (see ). This sNeurogenesis during adolescent development is on average four-fold greater than during early adulthood , and thisee a failure to assimilate signals driving successful integration into existing hippocampal circuitry or 2) hypersensitivity to the stimulation of cell death executioner pathways.The enduring loss of hippocampal newborn neurons after AIE most likely involves both subtle disruptions in the neuroprogenitor cell proliferating pool as well as more robust findings involving decreased survival of neuroprogenitors as they differentiate into neurons and integrate into hippocampal circuitry expression of pNF-\u03baB p65 . This phAdolescent binge ethanol exposure causes a loss of basal forebrain cholinergic neurons immediately following the conclusion of ethanol treatment that persists well into adulthood , paralleling AIE-induced lasting reductions in hippocampal neurogenesis and proinflammatory induction. The observed 20\u201330% reduction in basal forebrain cholinergic neuron number following adolescent binge ethanol exposure is consistent across both mouse and rat studies in both 1) concurrent induction of caspase activity of these neurons during critical neurodevelopmental windows during the brain\u2019s growth spurt, and 2) failure to restore ChAT immunoreactivity with pharmacological or environmental interventions . In parorebrain . Similarorebrain .Both HMGB1 and phosphorylation of NF\u03baB p65/p50 have been implicated in pathways that modify epigenetic machinery, although their roles are complex, depending in part on co-activation of other factors. Thus, HMGB1 and NF\u03baB p65/p50 can have distinct functions under normal physiological versus pathological conditions. For example, under normal physiological developmental conditions, nuclear HMGB1 promotes the formation of transcription complexes by overcoming limitations with tightly bent DNA . In contseeEthanol-induced epigenetic silencing shines light on potential mechanisms for recovery with interventions that reverse this epigenetic silencing , and in Despite the loss of basal forebrain cholinergic neuron phenotype, behaviorally-evoked acetylcholine in the hippocampus during reversal learning in adulthood is slightly, but non-significantly, blunted by prior adolescent binge ethanol exposure . This fivia decreased nAChR\u03b17 activation on immunocompetent glia is at the juncture of both persistent inductions in neuroinflammatory signaling cascades, induction of apoptotic executioner caspases, and reductions in survival of adult newborn neurons.Adolescent brain maturation shows developmental reductions in nicotinic cholinergic receptor expression . InteresseeAIE persistent induction of neuroimmune genes as well as reduction in hippocampal neurogenesis corresponds with impairments in a variety of learning and memory tasks, including discrimination learning and reveDuring the adolescent developmental period, changes are governed by alterations in epigenetic regulation of cholinergic and neuroimmune genes, driving an environmental imbalance in the hippocampal environmental milieu which is unfavorable to the successful adult birth, maturation, and integration of newborn hippocampal neurons. This suggests that in the absence of intervention, both adolescent ethanol-induced loss of neurogenesis , basal fAlcohol use disorder (AUD) is highly prevalent in Western society, with estimates of up to 29% of adults suffering from AUD at some point in their lifetime . This disee , rodentsee . CollectPreclinical studies indicate that adult chronic binge ethanol exposure decreases hippocampal neuroprogenitor cell proliferation and neurogenesis even in seeAdult ethanol-induced suppression of hippocampal cell proliferation is further complicated by withdrawal periods, as there is some evidence for a brief burst in cell proliferation 1\u00a0week into abstinence . Howeverin vivo microdialysis studies in adults after long-term 3-month ethanol exposure in drinking water, acetylcholine efflux in the hippocampus was significantly reduced by 57%, relative to controls (The basal forebrain cholinergic system is profoundly affected by ethanol during early development, with both perinatal and AIE exposure reducing basal forebrain cholinergic neuron expression in addition to decreasing cholinergic regulation of the hippocampus. However, adult alcohol exposure does not produce as rapid or robust an effect on the basal forebrain cholinergic system. Just as intermittent ethanol exposure across adolescence but not adulthood produces deficits in adult hippocampal neurogenesis , adolesccontrols . This efChronic ethanol exposure in adulthood can also disrupt cholinergic receptors, but this finding is complex and largely depends on subtype. For example, 10 weeks of ethanol consumption decreases hippocampal nicotinic receptor expression independently from altering binding affinity . In contThe loss of hippocampal nicotinic receptor expression could underlie sensitivity to neuroinflammatory induction after chronic ethanol in adulthood, as microglial nicotinic \u03b17 receptors play critical negative feedback role for proinflammatory cascades. Thus, loss of activation at nicotinic \u03b17 receptors is suggestive of a loss of anti-inflammatory feedback and chronic induction of proinflammatory signaling cascades in the brain of individuals with AUD. In support of this concept, an increase in neuroinflammation in post-mortem human brains with AUD is one of the most prevalent clinical findings , and prephox NADPH oxidase subunit, TNF\u03b1, and IL-1\u03b2 as well as greater morphological changes in microglia (The effect of ethanol on hippocampal neuroinflammation can be magnified under conditions which challenge the immune system, such as a LPS or polyI:C innate immune challenge. Ten days of intragastric administration of ethanol in mice potentiates proinflammatory responses in brain to a lipopolysaccharide-TLR4 innate immune challenge which included CCL2, COX-2, gp91icroglia . Similaricroglia . These nicroglia . NeuroimTherapeutics under investigation for AUD often exhibit anti-inflammatory components. Given the critical role of the cholinergic system in regulating anti-inflammatory feedback, it is unsurprising that many of these restorative interventions center around the cholinergic systems. Rodent and human studies suggest successful therapeutic targets at both cholinergic muscarinic M4 receptors and nicoThese mechanisms linking neuroinflammation and neurogenesis are particularly important when examining sex differences as human females are more likely than men to experience organ damage following long-term alcohol use, including greater brain damage in general and more specifically loss of hippocampal volume , and areThe molecular mechanisms of ethanol-related neuronal damage and related intervention strategies circulate around the cholinergic system, neuroinflammation, and the mechanistic mediators of these systems on hippocampal neurogenesis regardless of developmental window, suggestive of certain central commonalities within the effects of ethanol on these systems. However, across the neurodevelopmental landscape, while the mechanisms may overarchingly be consistent, various systems display differing sensitivities in the magnitude and reversibility of ethanol-related disruptions. For example, in models of FASD, ethanol produces seemingly irreversible deficits in the cholinergic system, and one of the key factors in treatment for FASD focuses on preventing rather than reversing this neuronal damage. If unmitigated, the irrecoverable loss of cholinergic neurons is a hindrance to the functional recovery of ethanol-related damage, and later life consequences of this disruption include greater neuroinflammatory responses and decreases in neurogenesis when neural systems are challenged. As females tend to be diagnosed with FASD later than males, this suggests that intervention strategies may be particularly difficult for this population as females have a greater likelihood of missing early intervention therapeutic windows.In contrast, adolescence is marked by epigenetic-mediated suppression of basal forebrain cholinergic phenotypes, which is exciting from a therapeutic standpoint as reversal of epigenetic machinery in cholinergic neurons similarly restores their phenotypic expression, which consequently also restores the hippocampal neuroinflammatory-trophic balance as well as ethanol-mediated deficits in hippocampal neurogenesis. This balance between persistence and reversibility after adolescent ethanol exposure highlights a shift in the mechanisms driving ethanol-induced loss of hippocampal neurogenesis and neurocognitive impairments from the cholinergic system as the central mediator to neuroimmune dysregulation playing a greater role.This shift becomes more apparent in adulthood, where hippocampal neuroimmune induction in both preclinical models and in human postmortem tissue from individuals diagnosed with AUD persists long after ethanol exposure and seem to drive long-term cellular consequences, including hippocampal damage and deficits in neurogenesis. While abstinence reverses some of these deficits in males, females exhibit greater sensitivity to ethanol-related brain damage, with emerging studies finding that females require more aggressive intervention strategies than males.in utero or in adolescence increases drinking behaviors at later developmental windows (The shifts in vulnerability of cholinergic versus neuroimmune systems over development suggests that efficacy of interventions aimed at restoring ethanol-related damage to hippocampal neurogenesis and cognitive function must take a developmental approach. However, a limitation of preclinical models of FASD, adolescent binge drinking, and AUD is that often alcohol exposure in humans is not isolated to a single developmental period. In fact, prior exposure to ethanol either windows . Thus, a windows . This do"} +{"text": "Objective: To examine differential relationships between communication technology use and social connectedness among paid and unpaid caregivers providing care for middle-aged and older adults. Methods: This nationwide study utilized a cross-sectional Qualtrics panel survey from caregivers, ages 50 years and older (n=504) of middle-aged and older adults. About 17% were paid (n=86) and 83% (n=418) were unpaid caregivers. Primary outcomes were caregivers\u2019 sense of belonging to their local community and social bonds. The primary predictor of interest was caregivers\u2019 use of communication technology (texting/communication applications). A multivariable regression analysis was performed to predict each outcome based on communication technology use, separately among paid and unpaid caregivers. Multivariable regression analyses were repeated after including the caregivers\u2019 payment status (paid/unpaid) and the interaction term between the caregivers\u2019 payment status and the use of communication technology. The models were adjusted for caregivers\u2019 age, education, financial status, place of residence, and total weekly hours of caregiving. Results: Use of communication technology had a statistically-significant positive association with sense of belonging only among paid caregivers . The relationship between use of communication technology and sense of belonging was significantly different between paid and unpaid caregivers (p=.005). Use of communication technology was significantly associated with social bonds only among unpaid caregivers . There was no statistically-significant differential association between communication technology use and social bonds. Conclusion: Communication technology may play differential roles in linking paid and unpaid caregivers with their community and interpersonal groups. Additional efforts should examine mechanisms that provide meaningful caregiver support."} +{"text": "They report optimized diffusion at an intermediate temperature between cryogenic and room temperatures. Most commendably, they combined results from three distinct optical techniques to support their hypothesis for this non-monotonic temperature dependence. Photoluminescence measurements suggested phonon scattering was the predominant impediment to transport at higher temperatures, while Raman characterization of micro strains indicated that a 2D disorder potential was the primary obstacle at lower temperatures. Pump probe experiments and associated theoretical modeling were performed to further corroborate the hypothesis. While open questions remain on exciton transport in TMD monolayers, new and exciting opportunities are emerging for controlling exciton transport in van der Waals heterostructures.Excitons\u2014charge-neutral quasiparticles comprised of bound electron hole pairs\u2014can be formed within a wide range of semiconductors, including monolayer transition metal dichalcogenides (TMDs). The ongoing development towards practical excitonic devices necessitates a fundamental understanding of exciton transport in TMDs. Excitons in TMD monolayers exhibit ultrafast population relaxation times and correspondingly short diffusion lengths. In their article, Qi, Luo, and coworkers investigated how phonon scattering and disorder influence exciton diffusion in a WSe"} +{"text": "Persistent postoperative pain (PPP) after cardiac surgery is a significant complication that negatively affects patient quality of life and increases health care system burden. However, there are no standards or guidelines to inform how to mitigate these effects. Therefore, in this review, we will discuss strategies to prevent and manage PPP after cardiac surgery. Adequate perioperative analgesia may prove instrumental in the prevention of PPP. Although opioids have historically been the primary analgesic approach to cardiac surgery, an opioid-sparing strategy may prove advantageous in reducing side effects, avoiding secondary hyperalgesia, and decreasing risk of PPP. Implementing a multimodal analgesic plan using alternative medications and regional anesthetic techniques may offer superior efficacy while reducing adverse effects. According to the International Association for the Study of Pain, PPP is defined as pain that persists beyond 3 months after surgery, can be continuous or intermittent, and is attributable to the surgical insult, excluding other potential etiologies. Up to 43% of patients suffer PPP at 3 months after cardiac surgery. A meta-analysis that included 11\u2009057 cardiac surgical patients across 23 studies demonstrated a 37% incidence of PPP in the first 6 months and up to 17% at 2 years after surgery. A retrospective analysis of 35\u2009817 cardiac surgical patients registered in a national administrative claims database of private payers revealed that nearly 1 in every 10 patients who were previously opioid na\u00efve developed opioid use that persisted >3 months after surgery and associated higher oral morphine equivalents prescribed with an increased risk of persistent opioid use. Patients with PPP experience decreased health-related quality of life, effectively rendering the surgical intervention a means to displace the focus of their suffering instead of alleviating it. Beyond suffering, pain impedes critical postoperative rehabilitation, resulting in functional disability that prevents return to work and a normal life. On a larger scale, PPP can result in medicolegal actions, disparate economic impact, and increased medical costs and resource utilization.Persistent postoperative pain (PPP) is a devastating complication that affects both patients and health care systems. The incidence of moderate to severe PPP can vary widely based on surgery type, from <5% to >80% of cases performed. Risk factors for PPP after cardiac surgery include young age, female gender, preexisting pain, anxiety, a catastrophizing mindset, higher body mass index, and a history of osteoarthritis.7 Of note, more intense acute postoperative pain has been associated with a greater incidence and severity of PPP.7Of cardiac surgical patients with PPP, half have reported it to be moderate to severe and most have described it as neuropathic in quality, the primary location of pain in the chest, the next being the leg in patients having undergone saphenous vein harvesting.9 Likewise, aggressive preventive analgesia has been associated with decreased PPP. Therefore, adequate understanding and management of perioperative pain constitutes a fundamental strategy in PPP prevention following cardiac surgery. Risk factors for acute postsurgical pain include young age, longer duration of surgery, and thoracotomy, as compared with surgical access at other sites receptor blocking activity of methadone, which has been associated with the prevention of opioid-induced hyperalgesia. A perioperative, opioid-sparing strategy utilizing analgesic alternatives and adjuncts may ultimately mitigate the risk of developing PPP and additional opioid-induced side effects, while also conferring additional benefits versus opioids alone.24 It is important to clarify, however, that prevailing evidence and expert opinion support opioid-sparing but not opioid-free techniques. Not only do opioids, when dosed in moderation, have longstanding efficacy, the absolute avoidance of them has actually been shown to cause harm.Cardiac anesthesia has historically relied on significant opioid administration due to their potent analgesia amid a favorable hemodynamic profile,tion see .15 Whe24 Acetaminophen, gabapentinoids, and ketamine have all been previously described as providing both effective analgesia and offering opioid-sparing benefit.28 Rafiq and colleagues conducted a prospective randomized controlled trial (RCT) examining multimodal analgesics versus opioids following cardiac surgery through median sternotomy. The authors found a combined regimen utilizing dexamethasone, gabapentin, ibuprofen, and acetaminophen provided superior analgesia (decreased numeric rating pain scores) through postoperative day 3 and decreased incidence of nausea and vomiting versus morphine and acetaminophen alone. Despite these findings during the acute pain period, a recent systematic review and meta-analysis regarding gabapentinoids observed no clinically significant analgesic effect to support their routine perioperative use. Further literature remains limited or not yet assessed regarding gabapentinoid use in the prevention of chronic poststernotomy pain.30The application of multimodal analgesics may play particular importance in preventing PPP as this more inclusive approach has been described as providing optimal acute pain management with potentially fewer side effects when compared with a traditional opioid-based strategy. With regard to acetaminophen (paracetamol) administration, the authors found 2 of 4 RCTs demonstrating significantly decreased Visual Analogue Scale (VAS) scores and one of these publications demonstrating significantly decreased opioid consumption.3134 Of 3 RCTs examining nonsteroidal anti-inflammatory drug (NSAID) analgesics and cardiac surgery, 2 trials demonstrated decreased VAS, and opioid consumption with NSAID use.36 Although the authors acknowledge the literature remains sparse regarding acetaminophen and NSAID use specific to cardiac surgery, Bignami and colleagues conclude that the use of multimodal analgesia provides synergistic pain relief with fewer adverse effects. Although VAS scores permit readily obtainable data gathering, more comprehensive assessments including functional and disability data may provide more reliable and objective measures in assessing pain. Direct comparisons of differing pain-related studies are often complicated by heterogeneity in outcome assessment and the use of non-patient-centric endpoints such as morphine equivalents. There are numerous validated patient satisfaction and quality of life questionnaires that better capture more meaningful outcomes related to improved pain control rather than relying on VAS scores alone.39A subsequent systematic review conducted by Bignami and colleagues examined perioperative pain management modalities and cardiac surgery including multimodal analgesics. Among the 40 RCTs with analgesics including NSAIDs, gabapentin, pregabalin, lidocaine, steroids, ketamine, NMDA blockers, fentanyl, nitrous oxide, venlafaxine, and the antiarrhythmic mexiletine, only intravenous ketamine provided a statistically significant, albeit modest, reduction in the incidence of postsurgical chronic pain. In a subsequent review of postoperative chronic pain prevention, Reddi similarly concluded that ketamine may reduce chronic pain after surgery while suggesting gabapentin and pregabalin as promising but requiring additional robust studies prior to recommendation. In a recent review of chronic poststernotomy pain, Kleiman and colleagues similarly found no evidence to support the use of transdermal lidocaine, glucocorticoids, or dexmedetomidine in decreasing chronic pain. In contrast, the authors acknowledge the effectiveness of acetaminophen, gabapentinoids, and ketamine in providing opioid-sparing analgesia, but describe their utility in preventing chronic poststernotomypain as limited or not yet examined.Beyond the acute postoperative period, the role of systemic pharmacologic therapies in preventing the development of chronic pain after surgery has also been examined. Chaparro and colleagues conducted a meta-analysis of RCTs with systemic drugs administered perioperatively and evaluated pain 3 or more months following surgery. Multimodal analgesics have often been combined with targeted regional anesthetic techniques to reduce opioid requirements, enhance pain control, and potentially reduce systemic analgesics and their accompanying side effects including delirium, hypotension, bradycardia, bleeding, and sedation. Neuraxial anesthesia serves as one regional technique that may be considered in cardiac surgery via thoracic epidural analgesia (TEA) or spinal anesthesia.44 TEA has been shown to provide effective analgesia with decreased VAS scoring and reduced opioid consumption postoperatively,27 yet no evidence supports a definitive decrease in developing chronic pain following TEA or intrathecal opioid administration. The risk of spinal hematoma has historically been shown to be 1:1528 for TEA and 1:3610 for spinal anesthesia, but the risk for TEA has more recently been shown to be as low as 1:3552. The 2018 guidelines released by the American Society of Regional Anesthesiologists states there is insufficient evidence to determine whether the risk of epidural hematoma with neuraxial procedures is increased with the use of the level of anticoagulation required for cardiopulmonary bypass (CPB). The decision to employ neuraxial anesthesia as part of any opioid-reducing analgesic strategy should always consider a risk-benefit calculation regarding epidural hematoma formation in the vulnerable cardiac surgery patient population.49The application of regional anesthesia provides a diverse array of potentially opioid-sparing pain management methods in accordance with a multimodal analgesic strategy. The ability to administer local anesthetics through regional anesthesia may be particularly favorable in high-risk surgical candidates as these techniques may reduce or outright avoid adverse effects associated with opioid administration.4952 The risk of epidural hematoma formation proves notably relevant within cardiac surgery due to the frequent anticoagulation requirement for patients undergoing cardiopulmonary bypass. Similar to TEA, there exists no evidence to support thoracic PVB in the prevention of chronic poststernotomy pain.Thoracic paravertebral block (PVB) serves as alternative regional anesthetic technique utilized for analgesia related to cardiac surgery. Thoracic PVB consists of a type of peripheral nerve block with option for continuous catheter placement similar to TEA, yet PVB may be performed under direct ultrasound guidance. When compared with TEA, thoracic level PVB has been found to provide comparable analgesic efficacy and improved side effect profile, including theoretically less risk of epidural hematoma formation in the anticoagulated patient.27 without effect on chronic pain development. Similarly, ultrasound-guided parasternal intercostal nerve block performed presternotomy has demonstrated significantly lower postoperative pain scores versus saline injection or nonregional, morphine-based regimen. Studies assessing intrapleural block for sternotomy pain are limited, and similar to continuous wound catheters, have not yet examined their relationship with regard to developing PPP.Various other regional anesthetic techniques including emerging, ultrasound-guided peripheral nerve blocks have been applied for poststernotomy analgesia and cardiac surgery at large. Surgeon administered parasternal block has been shown to provide improved postoperative analgesia and reduced opioid requirements,55 The erector spinae plane (ESP) block presents a novel fascial plane block that was first described in 2016 for thoracic neuropathic pain and has since been applied as an easier to perform alternative to PVB to multiple procedure types involving the chest wall and abdomen.57 Few clinical studies assessing the ESP block for cardiac surgery have taken place, but initial data reveal promising analgesic efficacy and reduction in opioid consumption, while the need for replication via blinded RCTs persists.58 Similar analgesic studies have evaluated both the pectoral nerve and serratus anterior fascial plane blocks with encouraging results. The pectoralis (Pecs) nerve block entails dual interfascial plane injections (Pecs I and Pecs II) with the aim of anesthetizing the chest wall. Kumar and colleagues examined postoperative bilateral pectoralis nerve block following midline sternotomy, demonstrating both significantly decreased duration of ventilator dependence and improved pain scores utilizing the regional technique. Currently, no published evidence exists evaluating the more laterally performed serratus anterior nerve block approach specific to sternotomy pain, yet studies have shown improved pain scores following other thoracic surgical interventions.Promising, emerging peripheral nerve blocks of the chest wall occur most often using direct visualization with ultrasound guidance, potentially adding to their safe application.62 Through incorporation of multiple individuals, a multidisciplinary, perioperative pain team may optimally treat complex pain through specialization, communication, and education among providers and patients. Such a team would be well positioned to combine clinical management with pain research.In addition to the consulting anesthesiologist\u2019s role in managing opioid-sparing, multimodal analgesia, a multidisciplinary approach may provide the ideal strategy in preventing PPP in the cardiac surgery patient.63 Because mediastinitis has been associated with developing chronic pain, the more selective skeletonization harvest may prove warranted, particularly in the diabetic patient population. Minimizing sternal retractor trauma, removing sternal wires posthealing, and prophylactic sternal plating in high-risk individuals has been suggested to minimize chronic pain contributions. Minimally invasive techniques have been used to decrease the degree of tissue traumatization, acute postoperative pain, intraoperative time, perioperative bleeding, and the incidence of sternal wound infections and recovery time. In addition, the removal of chest drainage tubes on the first postoperative day, as compared with days 2 or 3, has been associated with improved pain scores without an increased risk of requiring chest tube reinsertion.Procedural considerations should be discussed with surgical colleagues as multiple operative variables may influence the development of PPP. For example, obtaining bilateral internal thoracic artery grafts via pedicled harvest rather than skeletonization has been associated with an increased risk of developing mediastinitis after coronary artery bypass graft (CABG). exacerbates acute postoperative pain. Despite the likelihood of a link between this altered pathophysiologic state and sensitization to pain signaling, this mechanism has not been investigated. There have been numerous studies comparing patients having undergone CABG surgery performed either with or without CPB, but none have specifically evaluated differences in pain following these techniques.Surprisingly, it is unknown if the well-described state of heightened systemic inflammation associated with the use of CPB68 Interestingly, patients on cannabinoids may have higher tolerance to opioids and NSAIDs, requiring higher doses.There are some classes of home medications that may affect perioperative analgesia. To optimize analgesia while minimizing relapse and overdose, it is recommended for patients taking low-dose buprenorphine and methadone to continue those medications throughout the perioperative period.7074 Early involvement of a pain psychologist or integrative pain team may offer valuable insights to both identify and address these psychological risk factors outside of the cardiothoracic anesthesiologist and surgeon\u2019s area of expertise.75Addressing patients\u2019 psychological comorbidities may also play a key role within a multifaceted approach to PPP prevention after cardiac surgery. Patients may present with preexisting psychological risk factors for the development of chronic pain including anxiety, depression, posttraumatic stress disorder, and pain catastrophizing.7679 Multimodal analgesia has remained central to ERAS protocols as this strategy may offer decreased opioid exposure in addition to potentially reducing recovery times, complications, and improving cost expenditures with surgery.81 Similarly, regional anesthesia has been increasingly implemented as part of a multimodal strategy in cardiac surgery and related ERAS protocols to reduce opioid consumption.83 The addition of emerging truncal fascial plane blocks for pain optimization presents a promising new area within cardiac ERAS.84 Because cardiac ERAS pathways often highlight opioid-sparing strategies and acute pain management optimization,86 implementation of these protocols aligns with addressing the aforementioned factors thought to contribute to PPP.Many of the aforementioned pain management components and multidisciplinary approach relevant to cardiac-related PPP have been integrated as part of comprehensive, enhanced recovery after surgery (ERAS) protocols. ERAS pathways including those specific to cardiac surgery continue to gain popularity and aim to incorporate multiple objective variables to optimize patient experience, perioperative efficiency, and improve outcomes.Although prevention is likely the most impactful strategy to decrease the burden of PPP after cardiac surgery, this may not always be possible. There are a variety of treatment options for PPP including medications see , surgery88 Indeed, the most updated 2015 Food and Drug Administration (FDA) black box warning for non-ASA NSAIDs advises against their use in patients prior to or after CABG, emphasizing the potentially increased risk for heart attack or stroke in patients with underlying cardiovascular disease. Furthermore, the use of non-ASA NSAIDs for cardiac surgical patients has been associated with acute kidney injury, whereas ASA use has been shown to be protective.Medical management of PPP involves targeting the various pathways and mechanisms of pain. NSAIDs decrease the production of inflammatory cytokines and chemokines such as prostaglandins. This may be particularly helpful in the acute phase of injury for patients, but also plays a role in chronic musculoskeletal pain and associated flares. Both the acute and long-term risks of NSAID use needs to be considered, especially in the cardiac surgery population, and the distinction between acetylsalicylic acid (ASA) and other NSAIDs is warranted. Renal injury, increased risk of myocardial infarction and stroke are all potential adverse events that the cardiac surgery population may already have a higher baseline risk for developing when using non-ASA NSAIDs. There is evidence that it inhibits COX centrally and acts through other non-COX mechanisms as well. This agent has a better safety profile without a demonstrated association with hepatic dysfunction, although caution should be taken in patients with acute liver injury.Acetaminophen or paracetamol is a known cyclooxygenase (COX) inhibitor, although it does not exert its effect through peripheral inhibition of this enzyme as the non-steroid anti-inflammatory class of medications.5 These agents have a generally favorable safety profile with nausea, sedation, and dizziness being some of the more common side effects and caution should be taken for patients with baseline renal dysfunction.Gabapentin and pregabalin bind to the alpha2delta subunit of calcium channels and are used in treating many different types of chronic pain. They are most well studied and effective for neuropathic pain. For cardiac surgery patients that have a neuropathic component to their pain, these may be a reasonable treatment option and studies have shown that approximately half of cardiac surgical patients with PPP do have a neuropathic component to their pain. The primary site of action is likely augmentation of the descending inhibitory pathways, although there are likely additional mechanisms of action that provide analgesic benefit. SNRIs including duloxetine have been studied for a variety of neuropathic pain conditions and shown to provide significant benefit. For most patients, SNRIs are better tolerated and have a better side-effect profile when compared with TCAs.Additional neuropathic agents including serotonin and norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants (TCAs) may also play a role in the management of PPP that has a significant neuropathic component.There is limited evidence regarding the use of dexamethasone specifically regarding the treatment postoperative pain in cardiac surgery patients. One randomized double blinded, placebo-controlled study of 300 postoperative patients who had coronary revascularization surgery did not find a difference in opioid consumption or severity of postoperative pain for the first 2 days after surgery. Patients should have treatment goals that may include pain reduction and functional improvement and they should respond favorably to low doses of opioids. Practically, the number of patients who should require and would benefit from chronic opioid therapy is likely low, although this has not been studied in this population.Chronic application of opioids needs to be carefully weighed with the risks. Chronic use needs to be carefully monitored and the appropriateness of ongoing therapy evaluated by pain management specialists.99 Cryoablation of neural tissue has been utilized for treatment of various painful conditions. The first study of cryoablation of the intercostal nerves was done in 1980 for pain associated with thoracotomy and reported significantly reduced analgesic use in the group that received the intercostal cryoablation. Perhaps the most relevant study pertinent to this review was done in 2000 for patients undergoing minimally invasive cardiac surgery via minithoracotomy. This study reported reduced pain scores, although no difference was seen in analgesic consumption. Neuromodulation is a field that has continued to develop and there are case reports and small studies of patients who may benefit for spinal cord stimulation for chronic, refractory angina or in one case truncal complex regional pain syndrome following sternotomy.103 A limitation of these techniques may be anticoagulation for patients with cardiovascular disease and further research is needed to determine which patients would benefit most from these advanced and more invasive techniques. Surgery can also be an option for a small subset of patients who have a clear mechanical component to their pain. This would include patients with sternal malunion or sternal wire fracture, although these are relatively rare complications and are likely not significant contributors to PPP for most patients.Beyond medical management, interventional pain procedures may be appropriate for certain patients. Patients who have had a minimally invasive procedure performed via thoracotomy may develop intercostal neuralgia or post-thoracotomy pain. Treatment with intercostal nerve blocks, paravertebral blocks, trigger point injections, or thoracic epidural steroid injections may be treatment options. Treatment of chronic pain is an off-label use for most of these therapies given the relatively limited evidence, but for patients with refractory pain they may be appropriate to trial. Depending on the characteristics and location of the patient\u2019s pain, topical agents such as lidocaine, diclofenac, or capsaicin can be considered. In patients with muscle spasms or myofascial pain, muscle relaxants can provide some symptom relief. Physical therapy is important for recovery in strength and function after surgery, but there can be further benefits for patients who go on to develop chronic pain. Dry needling can target pain with a myofascial component and therapists can work to improve function in patients who are deconditioned due to inactivity from their pain. Psychological therapy in the form of cognitive behavioral therapy, cognitive function therapy, acceptance and commitment therapy, biofeedback, and mindfulness can be helpful for patients with chronic pain, particularly when there are complicating psychosocial factors. The importance of a comprehensive approach to the treatment of chronic pain with therapy , medication, interventions, and adjunctive therapies cannot be understated.For refractory neuropathic pain antiepileptic agents , NMDA receptor antagonists such as memantine and infusions including ketamine or lidocaine are treatment options to consider.PPP and opioid use remain vital pain management concerns in providing optimal anesthetic care surrounding cardiac surgery. Further best practices data are required through future research study in multiple areas including the following:Further studies identifying patient risk factors for the development of PPP after cardiac surgeryResearch needed to assess the effect of cardiac surgical procedure type and intraoperative interventions on pain outcomesResearch examining the inflammatory state and role of intraoperative CPB use in the development of chronic painResearch addressing the consequence of acute pain management and its effect on the development of PPPLarge-scale RCTs assessing systemic, multimodal analgesics in the development of chronic pain following cardiac surgeryLarge-scale RCTs evaluating regional anesthesia applied to cardiac surgery and the development of chronic painHead-to-head comparative studies assessing novel, ultrasound-guided regional anesthetic techniques with cardiac surgeryResearch assessing secondary hyperalgesia therapies as potential preventative measures to developing chronic painResearch needed to assess the effect of psychological and behavioral interventions on the development of chronic postsurgical painLarge-scale RCTs assessing ERAS pathway implementation and the development of chronic painLarge-scale RCTs evaluating neuromodulation and spinal cord stimulator therapy for chronic poststernotomy pain106 Current literature suggests both prevention and treatment of PPP should optimally include multimodal pharmacology, regional anesthesia, and multidisciplinary involvement.62 Future research is required in this vulnerable patient population to confirm best practices in PPP prevention and treatment as part of an enhanced recovery after cardiac surgery pathway.Persistent postoperative pain after cardiac surgery represents a significant complication negatively affecting patients and health care systems. Adequately treating acute pain following cardiac surgery remains paramount as severe postoperative pain and opioid-induced hyperalgesia may increase the risk of developing PPP."} +{"text": "OBJECTIVES/GOALS: Environmental factors may significantly increase the risk of or buffer against Alzheimer\u2019s disease and related dementias, yet strategies to address cognitive decline and impairment to date largely overlook the role of neighborhoods. This mixed-methods study is the first to examine potential links between access to eateries and cognitive function. The goal is to inform place-specific interventions to help aging individuals reduce risk for cognitive impairment through neighborhood community and design. METHODS/STUDY POPULATION: Following an exploratory sequential mixed-methods design, seated and mobile interviews with 125 adults aged 55-92 (mean age 71) living in the Minneapolis (Minnesota) metropolitan area suggest that eateries, including coffee shops and fast-food restaurants, represent popular neighborhood destinations for older adults and sources of wellbeing. To test the hypothesis that these sites, and the benefits they confer, are associated with cognitive welfare, we analyzed data from urban and suburban dwelling participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study, a national racially diverse sample of older Americans followed since 2003 . RESULTS/ANTICIPATED RESULTS: Qualitative thematic analysis of how older adults perceived and utilized local eateries include sites of familiarity and comfort; physical and economic accessibility; sociability with friends, family, staff, and customers; and entertainment . Quantitative results from multilevel linear regression models demonstrate a positive association between density of eateries and cognitive functioning. Taken together, these results complicate our understanding of fast-food settings as possible sites of wellbeing through social interaction and leisure activities. DISCUSSION/SIGNIFICANCE OF IMPACT: The results contribute new evidence towards an emerging ecological model of cognitive health. Understanding whether and how retail food environments can help buffer against cognitive decline among older adults provides novel opportunities to promote wellbeing in later life through community interventions and neighborhood design."} +{"text": "Long implicated in aversive processing, the amygdala is now recognized as a key component of the brain systems that process rewards. Beyond reward valuation, recent findings from single-neuron recordings in monkeys indicate that primate amygdala neurons also play an important role in decision-making. The reward value signals encoded by amygdala neurons constitute suitable inputs to economic decision processes by being sensitive to reward contingency, relative reward quantity and temporal reward structure. During reward-based decisions, individual amygdala neurons encode both the value inputs and corresponding choice outputs of economic decision processes. The presence of such value-to-choice transitions in single amygdala neurons, together with other well-defined signatures of decision computation, indicate that a decision mechanism may be implemented locally within the primate amygdala. During social observation, specific amygdala neurons spontaneously encode these decision signatures to predict the choices of social partners, suggesting neural simulation of the partner\u2019s decision-making. The activity of these \u2018simulation neurons\u2019 could arise naturally from convergence between value neurons and social, self-other discriminating neurons. These findings identify single-neuron building blocks and computational architectures for decision-making and social behavior in the primate amygdala. An emerging understanding of the decision function of primate amygdala neurons can help identify potential vulnerabilities for amygdala dysfunction in human conditions afflicting social cognition and mental health. Here weThe amygdala is a collection of nuclei located in the anterior part of the medial temporal lobe. It participates in a range of functions including emotion, learning, memory, attention and reward-guided behavior. Based on its anatomical connections, classical views considered the primate amygdala an interface between (i) hypothalamic and brainstem areas related to endocrine and autonomic functions, and (ii) limbic and neocortical regions related to cognitive functions . The amyEarly lesion studies suggested that amygdala damage in monkeys affects an animal\u2019s ability to identify reinforcing stimuli . SubsequIn the present review, we focus on the neuronal signals mediating the primate amygdala\u2019s more recently acknowledged functions in economic decision-making and in predicting others\u2019 decisions in social contexts. We also consider key factors that influence the reward signals of amygdala neurons, which provide important inputs to decision processes.2Primate amygdala neurons respond to conditioned, reward predicting stimuli and track the changing value of these stimuli during learning . AccordiThese theoretical concepts demand to ask whether conditioned reward processing in amygdala neurons follows reward contingency rather than reward pairing. Lesions in the amygdala make rats insensitive to changes in background reward, indicating a general role in contingency-dependent learning . To follThus, typical reward-conditioned responses in primate amygdala neurons reflect reward contingency rather than stimulus-reward pairing. Such acquired responses to reward-predicting stimuli would constitute useful inputs to neuronal mechanisms underlying informed economic decision-making. The specific mechanisms by which amygdala neurons process reward contingency from comparing stimulus-based reward and background reward remain to be uncovered.3Given that amygdala neurons acquire responses to rewarding events and thatReward amount scaling is reflected in the responses of primate amygdala neurons to reward receipt : these rThe amygdala neurons reviewed above faithfully identify by their response which reward is the better one in any changing distribution of rewards. This quantitative reward code could provide critical inputs to an economic decision process. An important open question is whether the same amygdala neurons that encode quantitative reward-magnitude information are also sensitive to reward probability. Processing of both reward probability and magnitude in individual amygdala neurons would provide a substrate for computing key statistical properties of reward distributions, including expected value and variance.4The predicted time of future reward fundamentally affects behavior, as evidenced in the temporal difference model of reinforcement learning and the The forms of sensitivity to temporal reward structure described above would allow amygdala neurons to participate in timing processes underlying learning and decision-making. Recent studies, described below, uncovered time-sensitive amygdala signals in decision tasks that require planning ahead and tracking progress over extended periods ,5. Howev5Neuronal decision processes involve the translation of graded, parametric value signals, reflecting the evidence for the decision, to signals predicting the animal\u2019s categorical choice. Primate amygdala neurons seem well suited to contribute to such reward-based decision processes. As described above, their flexible, context-sensitive value signals provide a substrate for integrating relevant evidence to decision inputs. An explicit choice signal computed from such values could also be broadly distributed by the amygdala, given its diverse efferent connections. Furthermore, lesions studies demonstrated essential amygdala contributions to decision-related processes including reinforcer devaluation ,44, stimIn a series of studies, we examined the activity of primate amygdala neurons in a sequential economic decision-making task ,4,5. In During performance of the save-spend task, a significant number of amygdala neurons predict the monkeys\u2019 save-spend choice on individual trials . These cMore recent findings extend our beginning understanding of the amygdala\u2019s decision functions. One study examined amygdala neurons in monkeys tracking the changing values of multiple visual stimuli and balancing exploration-exploitation decisions . During The data reviewed above suggest that primate amygdala neurons play a much more direct role in decision-making than traditionally thought. Specifically, the observation of explicit value-to-choice transitions in individual neurons and othe6The best rewards are often distant, requiring careful planning and stepwise, sequential choices to reach internally set goals. In the save-spend task described above , amygdalA distinct type of amygdala neuronal activity observed in the save-spend task explicitly signals the monkeys\u2019 progress through a saving sequence . ProgresThus, the activity of amygdala neurons reflects the value and temporal structure of an animal's plan to obtain distant reward goals, and tracks the stepwise progress toward that goal. By specifying prospective reward goals, these amygdala signals could provide direction for behavioral plans encoded in frontal lobe areas ,55. This7Primates do not only make choices individually but also observe the choices of their social partners. By observing their partners, primates can learn the values of objects to inform own decision-making and to predict their partners\u2019 choices and intentions. The amygdala may play an important role in these social processes. Its neurons process social cues, such as faces and amygA recent study examined the activity of amygdala neurons in a social situation in which two monkeys observe and learn from each other\u2019s reward-based choices B. BeyondThe observed functional types of amygdala neurons C suggestThe amygdala is unlikely to perform these sophisticated operations in isolation. The anterior cingulate cortex contains neurons that predict partner\u2019s choices during competitive interactions , neuronsThus, recent data suggest important contributions of primate amygdala neurons in social decision-making and predicting others\u2019 choices. These data may help explain the effects of amygdala lesions on social behaviour ,61, the 8The findings reviewed above suggest an emerging account of how amygdala neurons and circuits contribute to individual decision-making and social decision simulation. A role for the primate amygdala in implementing a decision mechanism is consistent with observed value-to-choice conversions in individual amygdala neurons , with adHow do amygdala decision signals relate to decision signals found in other brain structures? The amygdala and orbitofrontal cortex receive prominent sensory inputs from all modalities , which pThe reviewed parallel neurophysiological studies on amygdala decision and social functions also inform the broader question of whether the amygdala is specialized for social behavior, as suggested by the Social Brain Hypothesis , or whetThe decision signals and planning activities in amygdala neurons described above may inform our understanding of amygdala dysfunction in human psychiatric conditions, including mood disorders that impact on the motivation to make decisions and pursue future rewards . The amyNone."} +{"text": "While the development of communication competencies in medical schools plays a pivotal role in the curriculum, studies show that students\u2019 communication skills and patient-centred attitudes may vary based on gender and ethnicity. The goal of this study was to investigate the socio-demographic factors that influence medical students\u2019 communication abilities and, more specifically, to what extent their attitude toward communication skills learning and patient orientation associate with communication abilities. Our population included medical students admitted in 2017. Used tools included a communication score, the patient-provider orientation and communication skills attitudes scales.. There was a significant association between gender, native tongue, attitudes towards communication skills learning and communication skills OSCE performance. In conclusion, to support medical students to improve their communication proficiency and attitudes towards the importance of clear communication and patient-oriented care, medical educators should consider teaching and assessment strategies that address socio-cultural aspects of communication.Three hundred and sixty-five students participated in the study . Female and German native speaking students had a better communication skills OSCE performance, were more patient-oriented and had more positive attitudes toward communication skills learning than male and non-native speaking students One of the main roles of a physician articulated in national medical curriculum frameworks of learning objectives is being a communicator . DespiteThe main method to assess medical students\u2019 communication skills are the objective structured clinical examinations (OSCEs). Widely used as an outcome measure for academic success in medicine, OSCEs generally assess students\u2019 knowledge and skills in history taking, diagnostic tests interpretation, communication, and physical examinations and were shown to improve students\u2019 communication skills . Given tPhysicians\u2019 competencies are referred to in curriculum documents as medical knowledge, clinical skills and professional attitudes . AlthougMedical students\u2019 declining positive attitudes toward social issues raise coThe goal of this study was to address this gap and investigate which factors influence medical students\u2019 communication skills OSCE performance and, more specifically, to what extent medical students\u2019 attitudes towards communication skills learning and patient orientation are associated with the communication skills OSCE performance.This is an observational study examining communication competencies of medical students at one German medical school. Students had started studying medicine in 2017 and were in their second or third year of study. At the end of the fourth and fifth semester, students take two in person OSCEs containing ten five minutes stations , 13 and Socio-demographic data as well as data on attitudes towards communication skills learning and patient orientation were collected as part of a survey conducted electronically at the end of the OSCE.Patient orientation was measured with the patient-provider orientation scale . The insAttitudes towards communication skills learning were assessed with the communication skills attitudes scale (CSAS) . The CSAThe data were collected between July 2019 and February 2020.We report on descriptive analyses of socio-demographic characteristics and communication skills OSCE performance. A one-way between subjects ANOVA/post hoc Bonferroni procedure was conducted to compare the effect of mother tongue on the communication score. We used the T-test to investigate the effect of gender on the communication skills OSCE performance, attitudes towards communication skills learning and patient orientation. Correlation coefficients and backward multiple linear regression models were then calculated to investigate the extent to which gender, mother tongue, attitudes towards communication skills learning and patient orientation are associated with the communication skills score.The sample consisted of 365, 2nd or 3rd year medical students who completed all five stations of the composite communication skills OSCE. Students were aged on average 24.8 (\u00b1\u20093.5) years; the majority were female and German native speakers .There was a significant effect of mother tongue on students\u2019 communication skills OSCE performance, attitudes towards communication skills learning and patient orientation. The communication skills score of native speakers and bilingual medical students was significantly higher than the communication skills score of non-native speakers. German native speakers reported significantly lower NAS and more positive patient oriented attitudes than bilingual or non-native speakers. Female students scored higher on PAS and the communication skills score, lower on NAS and were more patient oriented than male students. Age seemed to play a role in attitudes development in that older students reported more positive and less negative attitudes towards communication skills learning Table .Table 2DOur regression model explaining 20.7% of the variance revealed that expressing less negative attitudes towards communication skills learning, being a native speaker, and female gender were significantly associated with a higher communication skills score. Positive attitudes, age and patient orientation were excluded from the model due to lack of statistical significance Table .Table 3RA composite OSCE focused on communication skills was developed to investigate associations between medical students\u2019 communication skills OSCE performance, attitudes towards communication skills learning, patient orientation and socio-demographic characteristics.In our study, we found gender differences in the communication skills score in favour of women, a finding which is in line with previous research , 16, 17.Native speakers as well as bilingual students had significantly better communication skills scores than non-native speaking students. This gap in exam results was also observed in studies from the Netherlands and the UK, which showed that students that belonged to specific ethnic minority groups underperformed in communication and clinical problem-solving tests , 18. LanThe communication skills score in our study was associated with less NAS, a finding which is congruent with previous research that indicated a link between poorer communication skills and less patient-centred attitudes . BesidesIn conclusion, medical educators need to consider different curriculum design approaches to address attitudes and socio-cultural aspects of communication skills. Such approaches include: supporting peer assisted learning and assessment methods to encouThis study was conducted at one university in Germany. However, research results are coherent with previous international findings and therefore relevant to an international audience of medical educators. This is a cross-sectional study on students\u2019 communication skills in the first half of their studies. A longitudinal study design that allows the observation of attitudes and skills evolution could strengthen claims of decline in communication skills as students progress towards graduation. Finally, we used a validated tool for the self-reporting of attitudes towards communication skills learning. A direct observation of attitudes may have yielded a more robust assessment. Future research should address these gaps as well as the effectiveness of curriculum interventions as proposed above by using both quantitative and qualitative research methods."} +{"text": "As examples, the present commentary tries to integrate responses of AHR and NAD+-consuming enzymes into infectious and stress-induced inflammatory responses, the latter exemplified by nonalcoholic fatty liver disease (NAFLD). TCDD toxicity models in sensitive species provide hints to molecular AHR targets of energy metabolism including gluconeogenesis and glycolysis. AHR research remains challenging and promising.Aryl hydrocarbon receptor (AHR) research has shifted from exploring dioxin toxicity to elucidation of various physiologic AHR functions. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is known to exert cellular stress-mediated sterile inflammatory responses in exposed human tissues but may be lethal in sensitive species. Inflammation can be thought of as the extreme end of a spectrum ranging from homeostasis to stress responses (sterile inflammation) and to defense against infection (infectious inflammation). Defense against bacterial infection by generation of reactive oxygen species has to be strictly controlled and may use up a considerable amount of energy. NAD Aryl hydrocarbon receptor (AHR) research has shifted from exploring dioxin toxicity to elucidation of various physiologic AHR functions. AHR has been characterized as ligand-activated, multifunctional transcription factor and environmental sensor is known to exert sterile inflammatory responses in exposed tissues the commentary tries to integrate functions of AHR and NAD+-consuming enzymes in infectious and sterile inflammatory responses. TCDD toxicity models in sensitive species are discussed since they provide hints to molecular AHR targets in energy metabolism.Elucidation of AHR functions is challenged by dependence upon cell type, cellular context, and species differences, the latter suggested by TCDD toxicity in sensitive species leading to wasting syndrome and lethality or a chain of ADPR units to proteins. PARP1 is the most abundant and best studied enzyme and belongs to the poly(ADP-ribosylating) proteins. It is mostly involved in DNA repair. With regard to cooperation with AHR, TCDD-induced PARP7/TiPARP (TCDD-inducible PARP) has been characterized as repressor of AHR expression may stimulate anti-inflammatory responses and prevent NASH and sterile inflammation as examples.Accumulating evidence suggests that AHR is involved in infectious and sterile inflammatory responses. These processes may use up a considerable amount of energy. Therefore, energy metabolism has to be metabolically adapted have been demonstrated. In addition, both AHR and CD38 are constituents of a signalsome of neutrophils (Bunaciu et al. Multiple sources of endogenous, phytochemical and microbial AHR ligands have been identified allowing intense interaction of the receptor and sensor between barrier organs and the environment. Connections between AHR and NAD+-consuming enzymes in tissue-dependent inflammatory diseases have been discussed using two examples: infectious colitis and obesity-mediated NAFLD and NASH. In intestinal inflammation, beneficial effects have been discussed in homeostasis, microbial defense and the resolution phase of inflammation, provided that AHR is transiently activated. In NASH, both AHR and CD38 may be involved in anti-inflammatory processes. Therefore, both AHR-activating and CD38-inhibiting phytochemicals and microbial products as well as NAD+ boosting compounds may provide therapeutic options. However, anti-inflammatory tolerance mechanisms bear the risk to facilitate autoimmune diseases and carcinogenesis. Therefore, clinical studies have to evaluate risks and benefits in particular cases. The discussed perceptions may be applicable to inflammatory diseases of other organs including skin and lung.Roles of AHR and NAD+-dependent nuclear SIRT1 and mitochondrial SIRT3 as key regulators of gluconeogenesis and glycolytic enzymes. Hence, AHR research remains a challenging and promising field.TCDD toxicity is known to be species dependent leading to wasting syndrome and lethality in sensitive species (Poland and Knutson"} +{"text": "Cancer is one of the primary causes of death that can affect any organ of the body. Cancer originates from transforming normal cells to tumour cells that often rapidly propagate and invade into adjoining tissues. Cancer cells spreading into other tissues are so called metastases, which is highly associated with death in humans. As to the World Health Organization, lung, colon and liver cancers are among the top ranked cancer types with high mortalities in recent years. The burden of cancer can be largely reduced with proper prevention, early diagnosis, effective treatment, and appropriate palliative care. Cancer treatment remains challenging, largely due to the complexity of its etiology and frequent occurrence of drug resistance.Targeted therapies are preferably adopted in cancer treatment for years. Such treatment alone or in combination with conventional chemotherapies have improved the survival of many cancer patients including those with tumours considered as incurable. Although clinical successes have been achieved in many cases, the failure rate of cancer targeted therapies remains disappointingly high. This is possibly due to the misapplication of therapies targeting pan-essential genes, the dysfunction of which leads to dose-limiting toxicities and/or the compromised therapeutic efficacy resulted from drug resistance.Drug resistance is either early intrinsic or late acquired . The verDrug resistance is the primary obstacle to achieve satisfactory clinical outcomes in carcer targeted therapies as numerous patients are inherently or adaptively resistant to existing regimens. Furthermore, there are deadly cancers without effective systemic therapies at present, like human uveal melanoma and gastProteins that play essential roles in cell division, cell cycle progression and/or cell death continue to be valid therapeutic targets in cancer treatment. For instance, histone deacetylases (HDACs) that are enzymes responsible for removing acetyl groups from proteins, are widely involved in cellular processes. Their inhibitors have shown clinical potentials against specific malignancies and are under pre-clinical and clinical evaluations to treat various cancers .As to gastroesophageal cancer , targeted therapies against EGFR/HER signalling have been extensively evaluated. Despite the reduced side effects compared to that of conventional chemotherapies, a panel of tyrosine kinase inhibitors (TKIs) downregulating EGFR/HER signalling yielded unsatisfactory outcomes in clinical trials. Thus, emerging drug targets like the store-operated Ca2+ entry (SOCE) , attractDrug resistance pronouncedly compromises the clinical effectiveness of cancer therapies; there are multiple mechanisms contribute to such therapeutic defect. ATP binding cassette (ABC) transporters are important membrane proteins responsible for cellular efflux of substances including many commonly used drugs. Overexpression of ABCs has been widely observed in tumour cells, which notably leads to clinical failure of cancer targeted therapies . One of In colorectal cancer, irinotecan is clinically used in treating its metastatic disease. It is known that ABCG2/BCRP-mediated drug resistance remarkedly impacts on the pharmacokinetic performance of irinotecan and consequently, limits the clinical applications of this agent . The inein silico analysis have both been adopted to design adjuvant cancer regimens. Overexpressed oncogenes and common biological processes like ubiquitination are preferable targets for adjuvant therapies. Computer modelling-facilitated chemical modification has been widely applied in designing combined therapies in addition to traditional chemotherapies such as cisplatin and doxorubicin with severe side effects. The pre-clinical tests regarding these adjuvant regiments are often conducted on malignant cell lines and tumour xenograft models. However, clinical predictions based on these studies may be suboptimal due to the loss of tumour characteristics in immortalised cell lines and expected species differences between human and animals. Therefore, it is highly desired that confirmative evaluation can be performed on tumour tissue-derived primary cell lines, which better preserve tumour characteristics and genetic variations.Empirical approaches and One emerging area in cancer drug research is the incorporation of machine learning algorithms with the advance of artificial intelligence . With thIt is thought that novel drug delivery carriers can greatly improve effectiveness, safety and targetability of agents. Research has widely investigated unconjugated or conjugated liposomes, polymeric micelles, microspheres and nanoparticles in delivering cancer targeted therapies. The advance in drug delivery technology adds credits to existing cancer targeted therapies with enhanced stability and biocompatibility, improved targeting as well as reduced drug resistance . The draOverall, the ongoing battle against drug resistance associated with cancer targeted therapies is a great challenge in biomedical research. Continuous efforts, multidisciplinary collaborations and long-term monitoring will be required to ensure the progress in this field."} +{"text": "ABSTRACT IMPACT: Understanding how perceived discrimination affects Asian Americans can help stakeholders target subgroups that are at highest risk of discrimination-related behaviors and design culturally appropriate interventions to ensure equitable access to healthcare. OBJECTIVES/GOALS: The COVID-19 pandemic has exposed longstanding anti-Asian racism in the US. Yet, effects of discrimination on Asian American health are unknown, partly because diverse Asian American populations are analyzed in aggregate. We aim to understand how perceived discrimination affects healthcare utilization among different Asian American subgroups. METHODS/STUDY POPULATION: We examine the association of perceived discrimination with healthcare utilization using the California Health Interview Survey (CHIS). In the CHIS, respondents reported whether they would\u2019ve gotten better medical care if they belonged to a different race. We examine the association between these responses and physician visits within the past year, in the survey years 2003, 2004 and 2016-2017. We adjust for covariates based on the Andersen Health Behavior model. Subsequent modeling examines potential mediating and moderating factors such as limited English proficiency, immigration status, income, and survey year. Asian American subgroups analyzed include Asian Indian, Korean, Chinese, Filipino, Vietnamese, Japanese, and other Asian. RESULTS/ANTICIPATED RESULTS: Results will highlight how perceived discrimination incentivizes or disincentivizes certain Asian subgroups to utilize healthcare. Asian American subgroups have differing and diverse experiences with discrimination due to their historical and cultural differences; results will elucidate how discrimination affects these subgroups. Results will be compared to non-Hispanic Whites, who represent the racial group least likely to experience discrimination in the US. Mediation and moderation analysis will help understand how traditionally cited factors for healthcare utilization interact with perceived discrimination on Asian Americans. DISCUSSION/SIGNIFICANCE OF FINDINGS: Asian American subgroups are understudied, despite Asian Americans being one of the fastest growing racial groups in the US. Understanding how perceived discrimination affects Asian Americans can help stakeholders target subgroups that are at highest risk of discrimination-related behaviors and design culturally appropriate interventions."} +{"text": "Microbes are routinely engineered to synthesize high-value chemicals from renewable materials through synthetic biology and metabolic engineering. Microbial biosynthesis often relies on expression of heterologous biosynthetic pathways, i.e., enzymes transplanted from foreign organisms. Metallocluster enzymes are one of the most ubiquitous family of enzymes involved in natural product biosynthesis and are of great biotechnological importance. However, the functional expression of recombinant metallocluster enzymes in live cells is often challenging and represents a major bottleneck. The activity of metallocluster enzymes requires essential supporting pathways, involved in protein maturation, electron supply, and/or enzyme stability. Proper function of these supporting pathways involves specific protein\u2013protein interactions that remain poorly characterized and are often overlooked by traditional synthetic biology approaches. Consequently, engineering approaches that focus on enzymatic expression and carbon flux alone often overlook the particular needs of metallocluster enzymes. This review highlights the biotechnological relevance of metallocluster enzymes and discusses novel synthetic biology strategies to advance their industrial application, with a particular focus on iron-sulfur cluster enzymes. Strategies to enable functional heterologous expression and enhance recombinant metallocluster enzyme activity in industrial hosts include: (1) optimizing specific maturation pathways; (2) improving catalytic stability; and (3) enhancing electron transfer. In addition, we suggest future directions for developing microbial cell factories that rely on metallocluster enzyme catalysis. Escherichia coli cluster; (ii) a catalytic MoFe protein (the \u03b12\u03b22-tetramer NifDK) containing four complex metalloclusters: two M-clusters (or FeMo cofactor), and two P-clusters hydrogenase (MBH) from Ralstonia eutropha holds a special [4Fe-3S] cluster that enables the enzyme to reduce O2 into harmless water hydrogenases -hydrogenase-3 (Hyd-3) from its natural electron donor formate. An engineered Hyd-3 covalently attached to a ferredoxin from Thermotoga maritima accepts electron from pyruvate instead, and sustains in vivo hydrogen production when co-expressed with a pyruvate-ferredoxin oxidoreductase (PFOR) [The physical linkage of metalloenzymes with electron carriers can also be employed to engineer alternative electron transfer pathways with improved efficiency. For instance, alternative electron donors have been engineered in e (PFOR) .E. coli. Attachment of a hydrogenase and a ferredoxin on a synthetic protein scaffold improved hydrogen production by three-fold [Since the physical interaction between partner proteins is critical for electron transfer, their spatial organization can be optimized to enhance electron flux through desired metabolic pathways. Optimized spatial organization of electron donor and acceptor proteins increases their chance of physical contact, and reduces cross-talk with other cellular pathways . Moleculree-fold . The useree-fold . Other sree-fold .Eukaryotic organisms, such as yeast or microalgae, are essential hosts in the development of microbial cell factories. As many industrial bioprocesses use eukaryotic microbial hosts, implementing biotechnologically relevant pathways in these organisms is crucial to the large-scale production of chemicals. Unfortunately, attempts of transferring pathways that rely on the activity of bacterial metallocluster enzymes into eukaryotes have encountered limited success. For instance, many bacterial FeS enzymes involved in industrially relevant pathways display little-to-no activity when expressed in yeast, and common synthetic biology interventions have failed to improve their activity . AttemptThe barriers to the functional expression of recombinant metallocluster enzymes in eukaryotic organisms are analogous to those that exist between bacterial species: (i) inefficient maturation and/or electron supply due to incompatibilities between phyla-specific systems; and (ii) oxidative stress. The co-expression of bacterial FeS maturation and reducing pathways in yeast is unfortunately insufficient to enhance enzymatic activity, as demonstrated for the enzymes IspG and IspH . Other sE. coli cell chassis to determine that electron transfer pathways from chloroplasts, but not mitochondria, are capable of supporting bacterial nitrogenase systems [Engineering nitrogen fixation in eukaryotes by expressing bacterial nitrogenases has been a long-sought goal due to the cost of synthetic nitrogen fertilizers; however, nitrogen fixation in plants for self-fertilization has not been achieved due to difficulties in expressing functional nitrogenase systems . Neverth systems . More re systems . This woThe aim of making biology easier to engineer is the central goal of synthetic biology. To this purpose, tools and standardized principles for manipulating DNA have been developed over the past two decades. Genetic engineering technologies have enabled the engineering of a wide range of organisms with novel biological functions, including biotechnologically relevant microbial cell factories. However standard synthetic biology tools focused on genetic manipulation have faced challenges in engineering pathways that rely on many catalytically powerful metalloenzymes. Here, we presented an outline of the obstacles to the functional expression and optimization of heterologous metallocluster enzymes in biosynthetic pathways. We also described novel synthetic biology strategies and investigations that could enable harnessing their full biotechnological potential. Such efforts are focused on overcoming obstacles specific to the functional requirements of catalytic metallocluster enzymes: (i) engineering essential supporting pathways involved in enzyme stability and maturation; and (ii) engineering pathways for electron supply that sustain redox active catalysis. The combination and further development of these strategies could be used to optimize novel microbial cell factories with economically viable yields.However, major challenges to the full exploitation of these engineering approaches remain, as our fundamental knowledge on the biochemistry and barriers to the heterologous expression of metallocluster enzymes is still very limited. Indeed, synthetic biologists cannot easily predict the transferability of a given metallocluster enzyme, nor anticipate what will be required for their activation in heterologous hosts. More studies of phylogenetic compatibility and functional requirements will help develop intuitive rules for harnessing heterologous metallocluster enzymes. To this purpose, original research at the intersection between biochemistry, metabolomics, functional genomics, and synthetic biology is necessary. For instance, large-scale cellular assays could be developed to screen the in vivo functionality of relevant metallocluster enzymes in foreign hosts, and to address the barriers to their transferability and catalytic activity . FurtherMoreover, recent advances in synthetic biology have enabled de novo engineering of artificial metallocluster enzymes by incorporating catalytic metallocofactors (including abiotic cofactors) into designed protein scaffolds. These artificial enzymes catalyze a remarkable range of natural and synthetic reactions , and theBesides their potential for microbial biosynthesis, metallocluster enzymes participate in a wide range of key biological processes across kingdoms, including some of technological importance, such as antiviral or antib"} +{"text": "Dear readers,The Journal of Innovations in Cardiac Rhythm Management, Alqam et al.1 assess the discontinuation of anticoagulation after typical flutter ablation. Although retrospective and nonrandomized, their study offers important information that can help physicians managing patients with atrial flutter.In this issue of 2 recommended adherence to AF anticoagulation in patients with a history of AF ablation, regardless of procedural success or failure. Continuous or frequent electrocardiographic monitoring to screen for AF recurrence should also be considered in patients in whom anticoagulation discontinuation is being weighed based on patient values and preferences.2 Some well-designed nonrandomized studies8 have found that catheter ablation for AF reduces the risk of stroke; stopping anticoagulation after successful ablation can also be safely accomplished in some patients if careful rhythm monitoring is performed.Meanwhile, no randomized studies have investigated the continuation versus cessation of oral anticoagulation after catheter ablation for atrial fibrillation (AF). A 2017 expert consensus statement on catheter and surgical ablation of AFThe field of cardiac rhythm monitoring has rapidly expanded in recent years. I believe the discontinuation of anticoagulation after AF ablation can be safely accomplished in selected patients when paired with careful rhythm monitoring; however, randomized clinical studies that consider different monitoring practices and groups of patients remain critical.Sincerely,md, fhrs, faccMoussa Mansour, Editor in ChiefThe Journal of Innovations in Cardiac Rhythm ManagementMMansour@InnovationsInCRM.comDirector, Atrial Fibrillation ProgramJeremy Ruskin and Dan Starks Endowed Chair in CardiologyMassachusetts General HospitalBoston, MA 02114"} +{"text": "Community-based participatory research (CBPR), a bottom-up approach that community stakeholders and academics are involved equitably, is an effective approach for enhancing relevance and value in public health research and has gained popularity in recent decades. However, little is known about how CBPR can be used in mental health studies with older adults. This systematic review examined the current state of knowledge about how CBPR approach has been adopted in mental health research among older adults in different societies. According to the PRISMA guidelines, we searched five major databases and screened the literature using these criteria: 1) journal articles reporting use of CBPR in mental health research among older adults, 2) articles published in English language, 3) studies conducted in any settings with any mental health research. Initial search found 3,227 articles and preliminary screening identified 23 eligible articles. We found that around 90% of studies were conducted in the West. Most studies adopted CBPR to develop community-based mental health interventions or to revise current interventions or models while addressing the cultural needs of their studied population. Few studies adopted CBPR to evaluate existing mental health workshops or programmes. The extent of involvement of older adults in the CBPR approach varied across studies, from questionnaire design to programme evaluation. Our review uncovered ways of CBPR implementation across different societies and elements of successful implementation in CBPR practices in mental health research among older adults."} +{"text": "Pathology education conventional methods have been disrupted by the Corona-Virus Disease 2019 (COVID-19) outbreak, compelling a re-evaluation of the means of educational interactions from the undergraduate to the postgraduate level. This commentary explores how the COVID-19 outbreak has challenged pathology education.We reviewed the current challenges and determined the potential implications of virtual technologies on modern pathology education for the future of pathology competency learning and assessment.The challenges are partly due to transferring from in-person teaching to a virtual education. Other reasons are shifting away from discipline-based teaching to organ-system based in medical curriculum and additional pressures on pathology faculties, such as increased demand for pathology services, lack of time, and learning resources. Keeping the national standards in pathology education even in the constant disruptions from pandemic outbreaks are current challenges. Pathology expertise will need to use emergent technologies in providing educational material to ensure quality pathology education. However, virtualization of pathology education produces a value of digital pathology and web-based pathology training materials. Medical students could review clinical cases remotely with their supervisors and gain the pathology competencies necessary for clinical practice. We need new innovative strategies, and we suggested the following steps to take advantage of the current opportunity to meet the challenges: evaluating the available digital training materials for formal pathology education, investing in the virtual infrastructure for competency-based pathology education, expanding student/residents exposure to pathology educational cases through virtual platforms; applying digital pathology solutions for virtual pathology education. Pathology education conventional methods have been disrupted by the COVID-19 outbreak, compelling a re-evaluation of the means of educational interactions from the undergraduate to the postgraduate level , 3. ThisWorldwide, the health systems confront with a shortage of pathologists .Pathology Education in Modern Medical CurriculaPathology is the vital component of diagnostic strategies and central to medical education , 5. PathThe most medical curriculum has already reformed toward horizontal integration of courses, case presentation in the preclinical phase. The undergraduate medical education shifted away from discipline-based teaching to organ-system based in the medical curriculum. These changes affect pathology education at the undergraduate level. Moreover, forming medical educator teams composed of various medical specialists increasing the role that interdisciplinary teams play in medical education. Integration of disciplines has eliminated formal pathology classes in many medical schools , 6. HoweWith current educational policies to reduce transmission of COVID-19, Pathology departments and multidisciplinary networks should evaluate where the virtual educational technologies fit into their new educational plans in an integrated medical curriculum.Keeping the Competency-based Pathology Education The pathology competencies represent the mini-mum requirements of what the national pathology education board has agreed upon to educate undergraduate medical students for practice and for entry into any residency program.Pathology competency-based education focuses on applying pathology knowledge into practice, clinical reasoning, and pathology diagnostic skills.Keeping the competency-based standards in pathology education even in constant disruptions from pandemic outbreaks are current challenges of pathologists. The ability to gain a broad knowledge of the physiological and pathological processes of each organ system, the competency to apply disease mechanisms to explore the pathobiology, and the competency to improve the pathology diagnostic and therapeutic skills through lifelong learning is essential in becoming a competent physician .Pathology Education Challenges in Shifting to Virtual Learning Pathology education's main general challenges are deciding how much to change the courses, adapting to online education, determining the efficiency and effectiveness of virtual learning, and maintaining student engagement . The othWe Need new Innovative Strategies, and We Suggested the Following Steps to Take Advantage of the Current Opportunity to Meet the Challenges. However, contextual priorities may lead medical education experts to make individualized decisions based on unique circumstances.Evaluating the free available web-based pathology training materials for formal pathology education1) The studies indicate that medical students adopted the online resources as a learning tool, and a combina-tion of supervised small group discussions and the self-directed web-based (online) format improved path-ology teaching , 9. Web-The educational impact-not availability- of pathology web resources is a key for a successful transition to effective virtual pathology education. Therefore, pathology educational experts should evaluate the online videos according to national standards in pathology education whether they contribute to pathology education at the undergraduate and postgraduate levels. Some publicly available websites illustrate pathological principles, present rare disorders that are less relevant to undergraduate education. Some studies indicate that YouTube as a popular online video sharing website is an informative and accurate media of histopathology (cellular pathology) learning for both undergraduates and postgraduates. Moreover, autopsies were present on the site .Besides, Case X is an online platform that provides case-based learning materials and video-based medical cases. Online Case X helps student\u2019s clinical reasoning through self-directed learning . Self-diInvesting in the Virtual Infrastructure and Products for Competency-based Pathology Education and Assessment2) The innovative learning technologies will change the future of pathology education and can facilitate training pathology with interactive simulation learn-ing . The intThe virtual educational products need massive infrastructures, including management software and hardware for clinical simulation, case designing tools, and cloud-based eLearning. Pathology content experts should support the virtual system for developing specific learning objectives, pathologic cases, providing updated educational material, virtual supervision, and support .The virtual reality (VR) platform and interactive virtual learning tools can respond to specific issues for pathology discipline that is practical in training and competency assessment . The Advancements in VR technology make its use as a training and assessment tool in online objective structured clinical examination (OSCEs) and Virtual OSCEs (VOSCEs) possible , 13. The formative \u2018\u2018online OSCE\u2019\u2019 for pathology education could assess the disease recognition skills in pathology residents. A sequence of stations presents high-quality specimen images, and the residents should answer the questions and determine the organ and diagnosis within a time limit. After the deadline, they can find the correct answers and case histories of the specimens .Moreover, this can include standardized virtual patient resembling a real patient encounter in virtual stations. Variety of tools are applied in the health care system such as medical history taking, examination, diagnosis, laboratory/ imaging tests, and treating the VP. The system helps medical students master main pathology competencies, including disease mechanisms, organ system pathology, and diagnostic and therapeutic pathology skills. Besides, automated scoring is complementary to assess their progress. Virtual simulation provides the necessary tools to provide benchmarking, better preparing them for real-world medical practice.Expanding Pathology residents\u2019 Exposure to Educational Cases Through Virtual Platforms3) Previous studies showed that some pathology educational programs should increase the residents\u2019 exposure to pathology cases and practice because pathology subspecialty training programs require residents to apply for fellowships as early as the end of their specialty training. Also, studies indicate that changes in pathology specialty curricula and educa-tional activities have affected resident choices of fellowships , 15..\u00a0Keeping the national standards in pathology education are current challenges. Pathology expertise will need to use emergent technologies in providing educational material to ensure quality pathology educationThe clinical pathology cases presented through a patient\u2019s laboratory data or images by detailed explanations help the learner to understand and apply diagnostic principles and incorporate morphologic or laboratory results for accurate diagnosis and treatment. Virtual discussion forums provide the context for sharing the core educational points to promote clinical reasoning.Applying Digital Pathology Solutions for Virtual Pathology Education4) Virtualization of pathology education produces a value of digital pathology; it also assists medical universities to support the continuing education of pathologists in the COVID-19 crisis.Digital pathology (DP) becomes the necessary components in clinical pathology service and cellular pathology training. Pathologists require innovative DP tools and artificial intelligence for digital-enabled care. Residents need these tools to acquire their pathology competencies necessary for the practice of pathology during their early years and discover which subspecialty areas most interest them .DP provides real-time access to clinical/ pathology cases and virtual simulation-based education technologies provide the necessary tools to review clinical cases remotely with supervisors and discuss cases with a histopathologists consultant through virtual conferencing during this pandemic.Some DP technology products are also ready for deployment on the virtual medical education platforms. England\u2019s national health systems (NHS) partners from Oxford, Belfast, Nottingham Universities, and PathLAKE Features University are creating fully digital cellular pathology laboratories with a database of anonymous scanned slide images. These university diagnostic labs are developing AI algorithms for their generated slides , 17.Pathology education is witnessing a paradigm shift where scientific progress and technological advances are growing faster than pathologists\u2019 workforces. Digital pathology and AI algorithm for image analysis would promote pathologic diagnosis. Such technologies and innovations are still in their early stages, but the future is promising. Applying digital pathology solutions for virtual pathology education will increase the efficiency of individual pathologists.We have described the challenges of keeping pathology education on track during the pandemic, and how virtual education platforms and digital technologies in pathology can provide real-time solutions to pathology competencies development. Pathology aca-demic departments should evaluate new technologies and encourage routine adoption of virtual education for digital native medical students. Moreover, the virtual platforms allowed the pathology educators to use DP with providing a safer and more efficient education during the COVID-19 crisis.The following four steps were suggested for utilizing the formal pathology education (from the undergraduate to the postgraduate) to support uninterrupted learning and assessment: 1) Evaluating the free available web-based patho-logy training materials for formal pathology education. 2) Investing in the virtual infrastructure and pro-ducts for competency-based pathology education and assessment.3) Expanding pathology residents\u2019 exposure to educational cases through virtual platforms. 4) Applying digital pathology solutions for virtual pathology education.The Advancements in DP make it a pathology competencies training and assessment tool. The technologies still need to progress before virtual OSCEs become a comprehensive assessment plat-form. Despite this, the future is promising."} +{"text": "Hypertensive disorders of pregnancy (HDP) contribute to adverse gene-environment interactions prior to conception and continue throughout pregnancy. Embryonic/fetal brain disorders occur from interactions between genetic susceptibilities interacting with acquired diseases or conditions affecting the maternal/placental fetal (MPF) triad. Trimester-specific pathophysiological mechanisms, such as maternal immune activation and ischemic placental syndrome, contribute to adverse peripartum, neonatal and childhood outcomes. Two diagnostic approaches provide timelier diagnoses over the first 1000 days from conception until two years of age. Horizontal analyses assess the maturation of the triad, neonate and child. Vertical analyses consider systems-biology from genetic, molecular, cellular, tissue through organ networks during each developmental niche. Disease expressions associated with HDP have cumulative adverse effects across the lifespan when subjected to subsequent adverse events. Critical/sensitive periods of developmental neuroplasticity over the first 1000 days are more likely to result in permanent sequelae. Novel diagnostic approaches, beginning during pre-conception, will facilitate the development of effective preventive, rescue and reparative neurotherapeutic strategies in response to HDP-related trimester-specific disease pathways. Public health policies require the inclusion of women\u2019s health advocacy during and beyond their reproductive years to reduce sequelae experienced by mothers and their offspring. A lower global burden of neurologic disease from HDP will benefit future generations. Two diagnostic approaches assist in the prediction of brain health or disease throughout the life-span. Over theBoth diagnostic approaches allow the fetal/neonatal neurologist (FNN) to anticipate adverse outcomes from any disease process that may potentially affect the developing nervous system across time-periods. This analytic process can be applied to pathophysiological mechanisms associated with specific categories of disease affecting the MPF triad, such as from hypertensive disorders of pregnancy (HDP). Brain health or disease experienced after HDP during critical/sensitive developmental time-periods over the first 1000 days will more likely remain permanent across the lifespan. Novel diagnostic approaches, starting during pre-conception are required that potentially can be applied to all levels of maternal care across the three trimesters. These advances will lead to effective and timelier neurotherapeutic interventions that combine preventive, rescue and reparative strategies for the developing brain in response to the diseases and adversities associatThis analytic approach requires a working knowledge by an interdisciplinary team of practitioners regarding the maturing embryonic/fetal brain within the MPF triad across three trimesters in association with HDP. Such an approach will better select the appropriate diagnostic tests and treatment interventions that are patient-centric from a developmental perspective regarding a vulnerable MPF triad.The practitioner is confronted with a spectrum of HDP disorders in women, including hypertensive diseases before conception, gestational hypertension, early and late preeclampsia, HELLP syndrome and eclampsia. For this discussion of potential sequelae after HDP, no single diagnostic test or therapeutic intervention will be effective for all women at all times before and during pregnancy. New obstetrical research will offer the clinician with different options and timing that can be standardized for maximal effectiveness, beginning prior to conception. This will be discussed in HDP affects 5\u20137% of the world population of women and their offspring. In one recent study, as many as 7\u201315% of the world\u2019s population of women will experience HDP when assessed on a per-woman basis . Given sImproved diagnostic algorithms of HDP will help reduce the global burden of neurologic disease. As discussed at the conclusion of this review, this should be a public health priority for women and their offspring given the high prevalence of HDP. International efforts, such as the sustainable development goals proposed by the WHO ,9, must Transgenerational followed by early pregnancy G \u00d7 E influences subject the MPF triad to HDP, with different expressions of neurologic sequelae by the offspring. Pre-conceptional genetic susceptibilities have been identified through investigations such as high-throughput genome-wide association studies (GWAS) and epigenetic studies . ImproveCandidate genes and pathways responsible for sequelae are more accurately identified by integrated bioinformational analysis . DifferiCo-morbidities associated with maternal diseases and adversities further augment genetic/epigenetic effects beginninCross-species expression of the MPF triad structure and function suggests preserved evolutionary biological processes, with either beneficial and adverse outcomes in humans . This trStructural markers detected by fetal surveillance using sonography and more detailed fetal neuroimaging with magnetic resonance imaging include a wider range of detectable brain lesions, including major malformations with or without lethality to region-specific lesions represented by focal developmental anomalies and destructive lesions. The form and severity of these anatomical biomarkers depend on the trimester-specific timing and specific pathophysiological pathways that were activated by G \u00d7 E interactions associated with HDP as well as other diseases entities with similar harmful effects from hypoxia/ischemia, inflammation and coagulopathy. Early pregnancy anomalies range in severity from neural tube defects, holoprosencephaly and schizencephaly to focal cortical dysplasias. During the latter half or pregnancy, destructive lesions predominate and may accompany earlier anomalous lesions associated with HDP-related effects, such as the maturing MPF triad experiences in on-going disease.G \u00d7 E interactions result in different neurologic sequalae specific to pre-conception and the trimester-specific time-periods when the MPF triad is affected by HDP. Primary prenatal neurologic structural/functional disorders without systemic involvement may occur. Secondary brain lesions alternatively result from multi-systemic conditions that also contribute to adverse neurologic outcomes. Disease processes, such as maternal immune activation and ischG \u00d7 E interactions associated with HDP continue to be expressed after birth as the great neonatal neurological syndromes (GNNS) of encephalopathy (NE), seizures (NS), stroke (NSK) or encephalopathy of prematurity (EP) . The sevPediatric infections, trauma and multi-systemic diseases later in childhood may further worsen sequelae after HDP, stressing the continuity of risk from G \u00d7 E interactions during postnatal maturation. Both communicable and noncommunicable childhood diseases contribute to adverse outcomes, involving hypoxic/ischemic, inflammatory and hemostatic disease pathways. Biosocial adversities affecting the child within the family and community contribute to the extent and complexity of sequelae. Developmental disorders, such as intellectual disability, autism and cerebral palsy, as well as behavioral/cognitive deficits and epilepsies, are potential sequalae expressed throughout childhood and adolescence. Each disorder may either present independently or as co-morbidities. Associations with HDP need to be considered.Sequalae later present with maturation into adulthood. The aging brain\u2019s pathophysiological mechanisms will result in long-term responses to the prenatal conditions of HDP, as well as to other adverse diseases or conditions affecting the MPF triad. Diverse sequalae include cerebrovascular diseases, dementias, adult-onset epilepsy and neurodegenerative disorders. G \u00d7 E interactions at the end of the lifespan are significantly influenced by permanent maladaptive developmental neuroplasticity that occurred during the first 1000 days.Complex MPF triad G \u00d7 E interactions from HDP early during pregnancy profoundly impairs neuronal and glial progenitor cells within transitory brain structures . DisruptMulti-potential precursor populations undergo proliferation, differentiation and migration during the first twenty weeks within multiple transient structures , such asAltered progenitor cell populations within the neuroectoderm or yolk sac later promote abnormal connectivity during the second half of pregnancy with postnatal neurologic sequelae A, B. AltImpaired brain development during the first half of pregnancy associated with HDP affects the interactions of multiple neuronal, glial, and angiogenic precursors, particularly within the developing neurovascular unit . Deficient pro-angiogenic growth factors, such as placental growth factor and vascImmune intolerance between the mother and embryo/fetus from abnormal placental implantation and development result in maternal immune activation (MIA), which later influences the expression of multiple psychiatric and neurological disorders over the life-span . SpecifiConsideration of G \u00d7 E interactions over the first 1000 days begins with an understanding of the vulnerability from MIA effects after infectious and non-infectious inflammatory conditions, particularly during early pregnancy. A broad range of diseases and conditions result in MIA, including HDP, and affect the maturing components of the MPF triad, with altered fetal brain connectivity. While prevalence estimates of MIA remain imprecise, a significant percentage of children and adults later express early and long-term neurologic disorders from maladaptive developmental neuroplasticity as a result of MIA associated with diseases such as those from HDP. Improved neurotherapeutic interventions need to be developed in order to apply an understanding of MIA in relatDisordered cellular migration, dendritic arborization, synaptogenesis and myelination within the developing fetal brain is predominant during the latter half of pregnancy. These developmental fetal brain stages are particularly active within the maturing cortex and subplate zone . AnomaloDi Renzo introduced the term \u201cthe great obstetrical syndromes\u201d (GOS) 2009), referring to abnormal maternal, placental and fetal outcomes as a result of abnormal placental angiogenesis. A growing list of adverse outcomes from GOS can affect the MPF triad. Phenotypes specific to each of the three triad components include preeclampsia, diabetes, morbidly adherent placenta, abruptio placenta, premature rupture of membranes, fetal growth restriction, fetal demise, and prematurity. All these conditions adversely affect MPF triad health, with impairment to fetal brain development specific to the developmental stage. Abnormal placental angiogenesis during the second half of pregnancy consists of incomplete spiral artery remodeling and shallow embedding A,B. This09, referHDP are expressions of abnormal placental angiogenesis associated with IPS . PathophAdverse trimester-specific conditions from HDP can negatively impact peripartum events close to and including labor and delivery . ObstetrAdverse intrapartum events associated with HDP may only later be identified during neonatal or childhood time-periods. Whether sentinel or gradual in onset, presumed fetal distress detected during labor and delivery by surveillance testing is also a poor proxy that cannot reliably identify the presence or timing of brain injury. The peripheral chemoreflex remains primarily an adaptive response, activated during uterine contractions to protect against primarily brain, cardiac and adrenal injuries in most situations as the child descends the vaginal tract. Specific clinical scenarios can result in intrapartum fetal brain injury , particuComplex disease conditions represented by HDP are best interpreted by applying horizontal and vertical analytic perspectives to anticipate risk or occurrence of brain injuries prior to, as well as during, labor and delivery. Interdisciplinary consensus reports periodically update the evolving scientific bases for these analyses ,49. CompComplex phenotypes after birth are expressed collectively as the great neonatal neurological syndromes (GNNS). Similar to the GOS, trimester-specific G \u00d7 E interactions affect the MPF triad during postnatal life, expressed as the GNNS. Differences from GOS include: 1) clinical presentations include events specific to the peripartum and neonatal time-periods; (2) phenotypic expressions of GNNS are not reliably detected across trimesters for all maternal levels of care, particularly with seemingly low-risk pregnancies, (3) early and later pregnancy factors cumulatively affect MPF triad components closer to delivery expressed as the GNNS. NE, NS, NSK, and EP are the four major GNNS categories [ clinicalNegative outcomes associated with the GNNS occur despite adjustments in obstetrical management closer to delivery to conditions associated with HDP. Introduction of resuscitative interventions and neurocritical care may not significantly alter antepartum adverse outcomes ,3. FNN aAcute infections, metabolic-toxic and traumatic etiologies may best explain peripartum or neonatal-acquired encephalopathies and/or brain injuries expressed by the GNNS. Alternatively, trimester-specific MPF triad G \u00d7 E interactions associated with HDP have a varying clinical expression during peripartum and neonatal time-periods, based on the timing and etiologies associated with brain anomalies or injuries superimposed on acute disease. Childhood neurologic disorders may later present, despite neonatal neurocritical care interventions for the GNNS as well as in the absence of early neonatal disease expression. Neonatal evaluations specific to each GNNS have been discussed in more detail elsewhere and are applicable to clinical assessment after HDP . NE, NS,Paradoxically, lower mortalities and adverse neurological outcomes such as periventricular leukomalacia, intraventricular hemorrhage and cerebral palsy have been retrospectively reported in specific studies of extremely and very preterm infant populations when associated with HDP, compared with cohorts without HDP . HDP mayDiagnostic strategies to assess the GNNS requires a time-sensitive interpretation of serial examinations, neuroimaging, electroencephalography and blood/serum studies throughout the neonatal hospitalization . Multi-sOne important diagnostic test regarding the timing and etiology of brain injuries should include gross and microscopic examinations of the placenta, cord and uterus. While the completed pathology report may not be available until after the first week of life, findings often more accurately estimate an antepartum time-period to diseases that precede events closer to delivery. Trimester-specific pathophysiological mechanisms may better explain different disease processes associated with HDP after pathological analyses of the placenta, cord and uterus. This explanation will better assist the family for both diagnostic accuracies, as well as prognosis and anticipatory care. Revised pathological classifications have strengthened these chronic associations . HoweverDuring the first two years of life, the expression of developmental disorders and epilepsies ,58 may bChildren who experienced the GOS and GNNS after diseases such as HDP more likely require earlier medical interventions at older ages. Hospitalizations, may require pediatric neurointensive care for a moPediatric neurology consultations in the clinic or hospital settings may originate from primary-care practitioner or pediatric subspecialist referrals when communicable and noncommunicable diseases worsen neurologic function associated with organ-specific systemic diseases. Congenital heart disease (CHD) is the most common anomalous organ system disease of childhood that can be associated with HDP, with sequelae including cognitive/psychiatric disorders . ContinuInvolvement during the first 1000 days facilitates continued pediatric neurology consultative input throughout childhood into adolescence. This continuity of care more effectively addresses ongoing or new conditions affecting brain health when clinical disorders are expressed in association with HDP. Clinical expression requires brain maturation.Epileptic, behavioral/cognitive and mental health disorders are assoNeurologic and mental health disorders associated with HDP may only become clinically apparent with maturation into adulthood . These sCombined developmental origins and life-course approaches to diagnosis and prognosis therefore stress the relevance of the first 1000 days to neurologic/psychiatric diseases presenting across the life-span. Cerebrovascular, cognitive, epileptic and neurodegenerative disorders into oldCurrent practice guidelines and stress conventional management strategies to control HDP . PregnanAdverse effects by HDP on embryonic and early fetal brain development within the MPF triad requires neurotherapeutic interventions, targeted to immature neuronal populations and connectivities that may be impaired during the first half of pregnancy. Pre-conception testing will target inherited genomic biomarkers associated with hypertensive disorders affecting a future pregnancy . The nexReduced burden of neurologic disorders across the lifespan from conditions associated with HDP should constitute one of multiple sustainable goals required for maternal and pediatric health initiatives . SignifiImprovements in both person-centric and population-based healthcare define a nation\u2019s medical, economic and social well-being. Cooperation between government, industry, and nonprofit entities collectively strengthen healthcare policy for populations specific to resource-rich and poor nations. This advocacy must include medical deserts within resource-rich nations. Health disparity research augments efforts to address prenatal and early childhood brain disorders in association with HDP required by public health programs. This is exemplified by the WHO Millennium sustainable goals , which can more effectively reduce disease burden and financial costs, as well as elevate the quality of life . The sigInterventions need to be offered that are gender-specific and sensitive to sexual-orientation, specifically recognizing the unique aspects of healthcare relevant to women and men . Outcome"} +{"text": "Stem-cell derived in vitro cardiac models have provided profound insights into mechanisms in cardiac development and disease. Efficient differentiation of specific cardiac cell types from human pluripotent stem cells using a three-step Wnt signaling modulation has been one of the major discoveries that has enabled personalized cardiovascular disease modeling approaches. Generation of cardiac cell types follow key development stages during embryogenesis, they intuitively are excellent models to study cardiac tissue patterning in primitive cardiac structures. Here, we provide a brief overview of protocols that have laid the foundation for derivation of stem-cell derived three-dimensional cardiac models. Further this article highlights features and utility of the models to distinguish the advantages and trade-offs in modeling embryonic development and disease processes. Finally, we discuss the challenges in improving robustness in the current models and utilizing developmental principles to bring higher physiological relevance. In vitro human cardiac models are complimentary tools that allow mechanistic interrogation in a reductionist way. The unique advantage of utilizing patient specific stem cells and continued improvements in generating reliable organoid mimics of the heart will boost predictive power of these tools in basic and translational research. Over the past decade, several strides made in stem cell research has led to unparallel opportunities to study human diseases in vitro. Cardiovascular diseases (CVD) comprising of congenital heart disease, heart failure, stroke and hypertension contribute toward nearly one-third of all deaths worldwide , 2. CardThe heart forms from the mesodermal embryonic tissue from anterior primitive streak. The cardiac specification and differentiation take place after the lateral movement of the anterior region into splanchnic mesoderm. This tissue further self-organizes into three distinct regions where the cardiac crescent or first heart field (FHF) is \u2018sandwiched\u2019 between head folds and second heart field (SHF). During the morphogenetic movements, the heart regions lie in close contact with pharyngeal or foregut endoderm . TranscrFrom a molecular point-of-view, orchestration of T-box containing transcription factors such as TBX20 and TBX5 trigger chamber and septa formation while BMP driven TBX2 and TBX3 driven activation leads to atrioventricular canal and outflow tract. Cardiac neural crest influx into the outflow tract and complete septation is completed around week 12 in humans where it resembles the heart structure morphologically . Heart bIn vitro differentiation of cardiomyocytes (CMs) from iPSCs follow sequential stages observed during embryonic development, wherein heart forming progenitor cells arise from the mesodermal cell layer sandwiched between the ectoderm and endoderm in the primitive streak. Cardiomyogenesis in vertebrates is driven by classes of growth factor proteins such as wingless/INT (WNTs), bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs) , 10. ConMost recently, there has been a surge in cardiac \u2018organoid\u2019 models which are self-organized, spatially restricted clusters of cardiac-specific cell types derived from pluripotent stem cells. Some organoid models have been touted as new tools to study several congenital and developmental disorders such as hypoplastic left heart syndrome (HLHS) where the left ventricle fails to form due to mutation in NOTCH1 gene . SeveralDevelopmental cardiac organoid-like models do not serve as an attractive tool to perform investigations in a reductionist manner due to lack of high fidelity in cellular composition and niche. Diseases where the pathophysiology is unclear in vivo due to complex microenvironment could benefit from engineered tissue-like structures that can be manipulated in a modular fashion. Several protocols have been developed in recent years to generate major non-myocyte cell types of the heart from iPSCs such as endothelial cells , cardiacBoth cardiac organoid and heart-on-a chip models are excellent surrogates to understand several important aspects of heart function during development and disease. However, it is important to acknowledge that utility in predicting in vivo functions will remain limited due to stochastic self-patterning variability between every batch of stem cell differentiation. In addition, several factors that currently rely on self-assembly time need to be coupled with controlled delivery of cues. For example, in addition to progenitor-cell types, cardiogenesis is driven by a combination of long- and short-range paracrine interactions, gene regulatory networks and ECM-guided geometrical cues. Efforts toward obtaining blueprints of stage-wise development will enable us to isolate and embed temporal cues in these models to influence multi-axial patterning and cellular organization, rather than focusing on autonomous self-assembly under different conditions. Another important aspect in cardiac models is obtaining innervation and vascular anastomoses which provide feedback on carbon dioxide, dissolved oxygen and fluid pressure. Technical challenges that prevent widespread use of cardiac models can be addressed through standardized characterization of stem cell sources, using well-defined platforms and most importantly choosing the right model in the context of use . With inCurrently, both ECM and ECM-free cardiac models are proving useful as an obligate substitute for pre-clinical animal models, to validate clinical observations and as a screening tool for therapeutics or toxicology. With success through continued efforts in addressing some of the discussed challenges, we must revisit our expectations and utility of the model based on evidence and reproducibility. For example, current 2D and 3D tissue engineered models with limited heart-like features would be useful from a reductionist approach to understand cell specific mechanism or direct pharmacological response. Future availability of morphologically and spatially defined organoid mimics will further assist in mapping direct and indirect interactions due to concerted cellular response and fluidic stress. Such systematic approach toward building complexity will drive utility-based research in cardiovascular organoid biology as a complimentary tool and not a panacea for studying multifactorial cardiovascular diseases."} +{"text": "To the Editors,Endovascular treatment of carotid artery disease has gone through fast-paced evolution since the advent of balloon angioplasty and stents three decades ago. Nevertheless, it was not until significant improvements in neuroprotection were achieved that carotid artery stenting became a solid contender to the gold standard carotid artery endarterectomy. Embolic protection devices, such as proximal common and/or external carotid artery balloon occlusion devices and internal carotid artery filters paved the way toward a safer and more definitive strategy. The concept of flow reversal in the early 2000s,Carotid artery calcific disease remains a challenge in patients undergoing carotid artery stenting regardless of whether it is done via a transfemoral or transcarotid approach. By far, the most challenging scenario is circumferentially calcified internal carotid artery plaques that can cause inadequate expansion of stents and limited luminal gain despite vigorous pre- and post-dilation of the lesion.The two main strategies use either atherectomy devices or the new intravascular lithotripsy (IVL) balloon. We have reported both use of orbital atherectomy"} +{"text": "Although loneliness and social isolation are often discussed together, they are mainly examined separately. The few studies examining both concepts simultaneously focus usually on the wider category of older people (65+), with no or little attention to very old age. Our main aim was to investigate loneliness and social isolation in combination among near-centenarians and centenarians. Analyzing data from the Fordham Centenarian Study , we found no or very weak associations between loneliness and social isolation. Combining measures of loneliness and social isolation we built a typology with four different groups . The factors that most strongly predicted the distribution among these four groups were gender, widowhood, education, and self-rated health. Findings highlight the importance of jointly studying both concepts to better understand social risks in very old age."} +{"text": "Fusarium, continue to be a major threat to agricultural crops worldwide. In this issue, Tracanna and coworkers implement a targeted amplicon sequencing approach to identify conserved domains and specific metabolic pathways shared among soil samples with antagonistic activities against Fusarium culmorum. They also introduce dom2BGC, an open-source annotation platform that builds co-occurrence networks of natural product-associated domains across samples and aids in putative gene cluster reconstruction. When coupled with metagenomics, functional amplicon sequencing and the dom2BGC pipeline can aid in identifying mechanisms and potential metabolites associated with particular microbiome-associated phenotypes.Soil-dwelling microorganisms associated with plant roots carry out essential processes that promote plant growth and productivity. In addition to these beneficial functions, the rhizosphere microbiome also serves as the first line of defense against many plant pathogens. While many rhizobacteria are capable of producing antifungal natural products, fungal pathogens, such as those belonging to the genus Soils are biologically diverse habitats and represent some of the most complex ecosystems found in nature . As sustInvestigations into the rhizosphere have shown that this is a complex and dynamic environment . Plants Fusarium species being among the most devastating. While a previous study identified soil samples with antagonistic activity against Fusarium culmorum are a large class of bioactive natural products and are typically biosynthesized in an assembly line-like fashion by nonribosomal peptide synthetases (NRPSs). Adenylation domains are essential components of the NRPS assembly line and are responsible for selecting the amino acid building blocks that get incorporated into the natural product. Using degenerate primers, adenylation domains were PCR amplified from rhizosphere DNA collected from four of the authors\u2019 soil samples possessing activity against programs . Furtherin silico amplicons extracted from the antiSMASH and MIBiG databases. Taxonomic diversity and community structure relationships are calculated across sample sets, and domain co-occurrence networks establish biosynthetic distribution patterns that can be used to explain microbiome-associated phenotypes. While a similar PCR-based targeting approach was used in the discovery of the malacidins, the bioinformatics program eSNaPD (With the adenylation sequences from the rhizosphere microbiomes in hand, the authors developed an automated annotation platform to assist with comparative analyses across the sample sets. Briefly, dom2BGC annotates biosynthetic domains based on similarities with m eSNaPD that iniF. culmorum.Using the dom2BGC platform, the authors identified community structure overlap between adenylation domain profiles from suppressive rhizobacteria and were able to map the sequences to multiple taxonomic groups. From the co-occurence patterns, dom2BGC was also successful at reconstructing multiple biosynthetic gene clusters. Results from the amplicon clustering were validated using 10\u00d7 metagenome assembly and demonstrated that dom2BGC is a powerful platform for identifying functional elements in complex microbial communities. Detailed analysis of the amplified adenylation domains suggested an enrichment of cyclic and branched lipopeptide-producing biosynthetic clusters in the soil samples possessing antifungal activity, and bioinformatic analysis of the metagenomic data revealed several siderophore, lipopeptide, and 2,4-diacetylphloroglucinol gene clusters. It was speculated that the agents associated with the respective gene clusters could be responsible for the antagonistic activity against Tracanna and coworkers demonstr"} +{"text": "Palliative care is included within the universal health coverage goal of the sustainable development goals as an essential health service and is considered a human right.COVID-19 patients and their families report multidimensional symptoms, ranging from those that are physical, to psychosocial, spiritual and existential distress from the threat to survival.In our recent review of African COVID-19 case management guidelines, we found few palliative care approaches and a focus on clinical management to the neglect of important psychosocial and spiritual stressors affecting morbidity and outcomes.The supply of medical products, including palliative medicines, has also been disrupted by the pandemic, even more so in countries still experiencing increased cases, including Kenya, South Africa and Uganda.Before the pandemic strained African health systems, only 5\u201311% of people requiring palliative care had access. The negative impact on services has heightened the risk of unnecessary suffering in patients with COVID-19 and other serious illnesses. Therefore, policy-makers in Africa must try to lessen the impact of the pandemic on palliative care services by integrating palliative care within the COVID-19 response. This integration involves training family caregivers and community health-care workers caring for COVID-19 patients and other seriously ill patients whose home care by specialist teams has been disrupted by pandemic restrictions, and ensuring ongoing funding for palliative care services.African institutions must rapidly expand palliative care training to health-care professionals outside palliative care services and support the training with clear, comprehensive case management guidelines focused on palliative care. Service providers must also urgently collaborate with researchers in adapting palliative care delivery approaches and testing new technology-based service delivery models, such as mobile health applications."} +{"text": "Knowledge of school attendance problems (SAPs) is needed to inform treatments targeting SAPs and protecting youths from negative outcomes associated with SAPs.This study examined the school absence, absence categories , sociodemographic characteristics, and mental health problems among youths seeking psychological treatment for SAPs.The study used a cross-sectional design. Sociodemographic and clinical characteristics of 152 help-seeking youths with SAPs and their parents were examined. The data were derived from the baseline assessment conducted before treatment start.Older youths, youths with mental health problems, and youths whose parents had mental health problems exhibited higher levels of absence. Lower levels of non-excused absence were found among youths with highly educated fathers, and youths living with both parents. Many youths had clinical levels of anxiety, depression, or \u2018emotional and behavioral difficulties\u2019.The study highlights the need for early intervention, addressing a broad range of mental health problems.NCT03459677.ClinicalTrials.gov: School attendance problem (SAP) refers to difficulty attending school or absence from school that is problematic because of its frequency and/or duration while studies addressing truancy have focused on non-excused absence . Sociodemographic characteristic and mental health problems are often described for distinct subgroups of youths with SAPs are more likely to be effective for youths presenting high levels of school absence together with a complex clinical presentation including anxiety, depression, and/or behavioral disorders.S1 Table(PDF)Click here for additional data file."} +{"text": "Previous research indicates volunteering promotes well-being of individuals and communities. Volunteering in later-life may buffer some of the negative health effects experienced during retirement, facilitating opportunities for older adults to engage in meaningful activities and stay active. The current study examined characteristics of older adults who volunteered outside of participation in a regular cognitive monitoring study. All 124 members of a regular cognitive monitoring study, requiring completion of a 15-minute cognitive online test once a month, with complete data on personal characteristics, volunteer activities, as well as study adherence and dropout rates were included. ANCOVA and logistic regression analyses adjusted for sociodemographic characteristics were used to assess differences between volunteers and non-volunteers. Results indicated that volunteers were less educated (p<.05), and slightly more likely to be younger and women compared to non-volunteers. There were no differences in cognitive performance (ps>.05). Volunteers had lower scores for neuroticism (p=.02) and were marginally higher agreeable and extraverted (ps<.09). Volunteers needed more reminders to complete the monthly test (ps<.01) but had lower dropout rates (p=.001). The most frequent type of volunteer activity reported was religious. Volunteers were motivated mainly by altruism, although most reported multiple reasons such as building social relationships and feeling important. Findings provide information about characteristics that can help identify older adults who are likely to volunteer. Results regarding study adherence may have implications for promoting recruitment and retention among older adult volunteers."} +{"text": "Inflammatory biomarkers and sex hormones have been investigated as independent risk and resilience factors for cognitive decline in older adults. Many sex hormones are anti-inflammatory and there is emerging evidence that sex hormones may buffer the risk for cognitive decline associated with higher inflammation. However, few studies have included concurrent examination of inflammation and sex hormones in studies of cognitive performance and cognitive aging. A diverse sample of older adults had blood drawn before and after a two-week measurement burst that included three cognitive tests (6x per day) assessing working spatial memory, perceptual speed, and feature binding. Testosterone, estradiol, estrone, and six basal cytokine concentrations were quantified. Composite scores of basal inflammation were calculated. Multilevel modeling indicated that heightened inflammation related to poorer spatial working memory performance . In addition, sex hormones moderated the association of cytokine concentration with perceptual speed . Decomposition these interactions revealed that heightened inflammation predicted poorer performance, but only among individuals with lower sex-hormone concentrations. This study provides evidence of immune and hormonal-by-immune associations with performance in two cognitive domains in older adults. Examining the functional crosstalk between immune and sex hormone functioning will improve understanding of risk and resilience factors related to cognitive performance and help predict cognitive decline in older adults."} +{"text": "ABSTRACT IMPACT: Our data identify a novel candidate for combination strategy in melanoma treatment, and can inform clinicians in their decision-making process regarding therapeutic intervention for melanoma patients. OBJECTIVES/GOALS: Soluble adenylyl cyclase (sAC) is a novel source of cyclic AMP (cAMP). In melanoma, nuclear sAC localization has an established diagnostic utility and we newly found that nuclear sAC functions as a tumor suppressor by inhibiting Hippo pathway, which affects treatment response. Here, we examine the effect of nuclear sAC on melanoma treatment response. METHODS/STUDY POPULATION: We developed a doxycycline inducible system for increasing sAC activity only in the nucleus. We assessed whether nuclear sAC activity affects treatment response, using BRAFV600 human melanoma cell lines. Using a clonogenic assay, we examined how nuclear sAC activity affects growth inhibition in the presence of a BRAF inhibitor, vemurafenib. Our findings will be confirmed in vivo using tumor xenografts. After tumor formation in NSG mice, mice will be randomized to be fed normal or doxycycline chow for nuclear sAC induction, then subdivided to receive vehicle or vemurafenib to examine the effect of nuclear sAC activity on treatment response in vivo. We will also compare melanoma biopsies collected before and after treatment with BRAF inhibitors to assess how nuclear sAC staining affects tumor morphology in vivo. RESULTS/ANTICIPATED RESULTS: So far, nuclear sAC activity has rendered SkMel178 and M263 cell lines more susceptible to vemurafenib. Cell viability was inversely correlated both with vemurafenib and with doxycycline concentration. Cell viability after vemurafenib treatment was dramatically reduced when nuclear sAC was activated. It appears that nuclear sAC enhances the sensitivity of BRAF mutant melanomas to vemurafenib in vitro. We anticipate that xenografts of these cells in mice will be more susceptible to vemurafenib when nuclear sAC is activated. We also anticipate that positive nuclear sAC staining will correlate with a favorable response to therapy. DISCUSSION/SIGNIFICANCE OF FINDINGS: Targeted therapy with BRAF inhibitors is used in late-stage melanomas, but its use is limited as patients invariably acquire resistance. Here, we identified nuclear sAC activation as a novel candidate for combination strategy. Our data will also inform clinicians how best to integrate this biomarker into their decision-making regarding therapy."} +{"text": "There remains a lack of knowledge on marital satisfaction of African Americans generally, but particularly older African Americans. In addition, only a handful of studies investigate satisfaction among couples who are unmarried. With data from the National Survey of American Life, this study examined the correlates of romantic and marital satisfaction among older African Americans. Findings reveal that married older African Americans were slightly more satisfied with their relationship than individuals who were either remarried or unmarried but in a romantic relationship. Among older African American married adults, older age was associated with higher marital satisfaction, and men had higher levels of marital satisfaction than women. Also, married older African Americans with lower family incomes reported higher marital satisfaction. Given the limited research on older African Americans couples, either married or unmarried, this study offers valuable implications for individuals and professionals engaging these couples in practical settings."} +{"text": "In Japan, care managers engage frail older adults to support their assisted living in long term care insurance system. However, due to the lack of some or all supervision, many care managers face problems such as low work engagement and high turnover rate. This study aims to examine what types of supervision have positive effects on work engagement and turnover intensions of care managers in Japan. The sample of 241 care managers were asked whether they have received individual supervision in the workplace (ISVW), individual supervision in the community (ISVC), group supervision in the workplace (GSVW), or group supervision in the community (GSVC). Independent samples t-tests and one-way ANOVAs were conducted to examine the effectiveness of each types of supervision on work engagement and turnover intension. T-tests showed that only GSVW was significantly related to work engagement . Whereas, only ISVW had a significant effect on turnover intensions . One-way ANOVAs revealed that 28 care managers receiving GSV had significantly higher work engagement than 92 care managers who did not receive any SV . 40 care managers receiving both ISV and GSV showed significantly lower turnover intentions than 92 care managers who received neither ISV nor GSV . Since the results have implications for the importance of supervisions to enhance work engagement or to reduce turnover intension of care managers, a larger sample will need to confirm these effects."} +{"text": "One of the well reported but difficult to manage symptoms of spinal cordinjury (SCI) is neurogenic lower urinary tract dysfunction (NLUTD). The type ofNLUTD is variable based on location and extent of injury. SCI affects more malesand NLUTD is especially debilitating for men with incomplete injury. This reviewsummarizes the anatomical basis of NLUTD in SCI and discusses current diagnosticand management strategies that are being utilized clinically. The last twosections address new innovations and emerging discoveries with the goal ofincreasing scientific interest in improving treatment options for people withSCI. Areas warranting further investigation are pinpointed to address currentgaps in knowledge and/or appropriate technology. These pThe spinal level of SCI causes distinct neuroanatomical disruption patternsresulting in different treatment strategies. Suprasacral lesions produce neurogenicdetrusor overactivity (NDO) and a noncentralized sacral spinal reflex. Sacral lesions directly involve the spinalmicturition center and cause mixed NLUTD symptoms and detrusor underactivity . Pudenda2.Prompt evaluation of lower urinary tract function is important consideringits cause of increased morbidity and mortality and high prevalence in SCI(70%\u201384%) male victims. Clinical patterns can help determine the presence ofNLUTD and help localize the lesion to guide conservative, pharmacologic, andsurgical therapies. Several guidelines exist for evaluating NLUTD including EuropeanUrological Association, Joint Societe Internationale D\u2019Urologie-InternationalConsultation on Urologic Diseases (SIU-ICUD), and Japanese clinical guidelines\u201312. ConsWorkup begins with a thorough history and physical exam especially with focuson male urologic history regarding benign prostate hypertrophy, urinary infrequency,and any urologic malignancies. Review of the initial trauma and severity of the SCIwith a validated system like the ASIA score is first performed. It is important toconsider factors in a male\u2019s medical history, like severe hypertension orhistory of acute angle closure glaucoma, that may contraindicate the use ofmedications in the treatment in NLUTD . AbladdBladder function can be objectively evaluated using urodynamic studies atleast once within the months following injury and can measure bladder sensitivity.For incomplete SCI, this can help determine return of function. Video urodynamicsserve as the gold standard for those with NLUTD. It is generally recommended toperform the first urodynamic study 3\u20136 month following injury.Electromyography may evaluate external urethral sphincter function. The resultingmorphologies based on the information gained regarding intravesicular pressure,detrusor activity, bladder compliance, bladder sensitivity, and bladder storagecapacity can help diagnose NLUTD, differentiate between the different subtypes, suchas those that involve detrusor overactivity or DSD, localize the level of SCI,identify the extent of injury on ASIA scale, give prognosis, and monitor treatmenteffect.Post-void residuals can be measured using bladder ultrasound or cleanintermittent catheterization. Other non-neurogenic conditions can be ruled out usingrenal and pelvic ultrasonography. MRI or CT of the brain can rule out otherneurogenic causes, particularly in the setting of polytrauma where the brain may beaffected and cause disruption of the pontine micturition center. MRI of the spinecan reveal spinal cord compromise that may be amenable to surgical intervention withpossible subsequent symptom improvement .This isDilation of the ureters, calyxes, and hydronephrosis should be considered inthose with NLUTD. The upper urinary tract can be evaluated using ultrasound andmagnetic resonance urography . Several3.3.1SCI is unique from other NLUTD etiologies in that it is oftenaccompanied by traumatic injuries and spinal shock syndrome. These factorscreate distinct phases of treatment for urologic issues affecting males: theacute recovery phase, post-acute rehabilitation phase, and long-term managementphase . Allowin3.2SCI patients may require indwelling catheterization during the acuterecovery phase until renal and cardiovascular function is optimized andurodynamic parameters improved .Beyond Pharmacological treatments of NLUTD generally target neuromuscularjunctions in the smooth muscle of the detrusor or internal urethral sphincter.Antagonism of alpha-1 adrenergic receptors relaxes the internal sphincter andbladder neck to improve voiding. Terazosin and tamsulosin are two of the mostwell-studied \u03b11 antagonists and both have been demonstrated to reduceautonomic dysreflexia and improve urodynamics, especially in males \u201322. AntaChemodenervation of the detrusor by botulinum neurotoxins (BoNT) hasalso emerged as a minimally invasive treatment for NLUTD in men with incompleteSCI. The most commonly used BoNT serotype is onabotulinumtoxin A (BoNT/A),commercially known as Botox . Althoug3.3via implantation ofexternally-controlled electrodes at the sacral nerve roots may be considered incases where conservative management fails to adequately control symptoms orproduces unfavorable side effects. The Brindley Procedure, combined sacralanterior root stimulation (SARS) and rhizotomy of dorsal sacral rootsS1\u2013S5 can be considered in NLUTD patients where conservative managementfails [Neurostimulation ntfails . Deafferntfails \u201330. The ntfails \u201332.4.As outlined above, bladder storage and micturition are controlled by acomplex interplay between the smooth muscle of the lower urinary tract, the striatedmuscle of the urethral sphincter, the cerebral cortex, pontine micturition center,sacral micturition center, and both the sympathetic and parasympathetic portions ofthe peripheral nervous system. In incomplete SCI, the range of damage is variable,and, therefore, may affect different elements of these cascades, which explains thedifferent etiologies and presentations of NLUTD after SCI. Despite this complexity,a simplified view of NLUTD after SCI may be described as improper sensory awarenessfor the need to void or improper stimulus delivery to cause the bladder to void.Therefore, new treatment options have focused on the use of sensors to monitorbladder pressure parameters, neuromodulation to deliver precise stimulation to causethe micturition cascade, and combined closed-loop neuromodulation systems to bothsense bladder fullness and void. Some of the key findings were highlighted above incurrent treatments section but the experimental approaches are addressed furtherbelow and may be especially valuable for males with SCI. Outline of promisingapproaches highlighted in Urodynamic testing is a known study that examines the parasympathetic andsympathetic function of the urinary system, enabling examiners to evaluate bladderand urinary sphincter function and integrity . ClinicaMany of the recent innovations have been as a result of improved targetingof electrical stimulation and noninvasive modalities . Traditi5.Technical considerations to improve outcomes of bladder dysfunction andmicturition continue to be explored in experimental animal models of SCI. Thesediscoveries encompass portable and reliable urodynamic monitoring, percutaneous orimplantable devices for specific neuromodulation of bladder control, and thecombination of these elements into biofeedback devices to approach restored bladderfunction after SCI. As described, innovations in urodynamic testing aim to guidecare management in real time for men with incomplete SCI. Several groups haverecently used porcine models of bladder physiology to investigate submucosalimplantation of sensors for localized bladder function . ImplantAmbulatory urodynamic monitoring (AUM) is used to permit specificmeasurement of functional status in clinic. However, sensitivity and portabilityremain significant challenges since the aim of AUM is to reproduce bladderdysfunction in the clinic setting and requires connection to an external powersource. For increased sensitivity, wearable telemetric devices would provide morerelevant functional assessment during the course of a patient\u2019s dailyactivities . Novel dReal-time monitoring, notification, and subsequent intervention forincreased intravesical pressure would enable timely voiding and minimize theincidence of complications in patients with SCI . Treatme6.The management of NLUTD after SCI in males is continuing to evolve. Standarddiagnostic tools are being optimized for widespread applicability. In this review,we highlighted the underlying anatomical contribution and current diagnosticstrategies. We delved into current treatment approaches and highlighted the newinnovations and emerging discoveries. Research is proceeding regarding improvedtreatment options in this patient population both for men with incomplete andcomplete SCI."} +{"text": "Spatially resolved transcriptomic data demand new computational analysis methods to derive biological insights. Here, we comment on these associated computational challenges as well as highlight the opportunities for standardized benchmarking metrics and data-sharing infrastructure in spurring innovation moving forward. To preserve such spatial information, advances in imaging technologies have enabled high-throughput in situ, targeted transcriptomic profiling of pre-selected RNAs at molecular and single-cell resolution2. In addition, technologies based on spatially resolved RNA capture followed by sequencing have enabled non-targeted, genome-wide transcriptional profiling at the 10-100\u2009\u00b5m pixel resolution3. Though the suitability of each spatial transcriptomics technology in addressing a particular biological question will currently involve balancing the need for experimental throughput versus spatial resolution, with current imaging-based technologies generally\u00a0offering higher spatial resolution but lower experimental throughput and current sequencing-based technologies generally\u00a0offering higher experimental throughput but lower spatial resolution, all of these resulting large-scale spatially resolved transcriptomic data demand new computational methods to take advantage of this new spatial information to derive biological insights.Advances in single-cell sequencing technologies have enabled high-throughput transcriptomic profiling for individual cells, allowing the characterization and discovery of transcriptionally distinct cell types and cell states. However, current protocols require dissociating cells from tissues, thereby losing potentially valuable spatial information that may inform how cell types and cell states are organized within tissues and how such organization may ultimately impact phenotype and function4, generalized linear models5, and spatial autocorrelation analysis6 have been developed to identify genes whose expression exhibits significant spatial variability. Some of these methods can also classify different patterns of spatial variation, such as linear or periodic gene expression4, as well as identify spatial features such as gene expression hotspots7. Such identification of spatially variable genes can lend insight into position-specific phenotypes as well as developmental and migration gradients. Spatial information can also augment the identification of putative cell\u2013cell communication networks. With single-cell sequencing data, cell\u2013cell communication inference has relied on identifying coordinated expression of known ligand\u2013receptor pairs8. Computational methods that leverage the added spatial information from spatially resolved transcriptomic data using graph convolutional neural networks9, optimal transport approaches10, and spatial cross-correlation analysis6 can narrow down candidates to ligand\u2013receptor pairs that are spatially colocalized, potentially indicative of autocrine or paracrine signaling. Furthermore, spatially resolved transcriptomic data with co-registered imaging data present additional sources of heterogeneity, such as morphological variability, which can be used for clustering, as differences in morphology can be a proxy for differences in cell states or other functional phenotypes such as cell cycle position, transformation, or invasiveness. Computational methods that incorporate spatial and morphological information in addition to gene expression information have been applied to further dissect heterogeneity in single-cell populations to identify clusters of single cells that are not only transcriptionally distinct but also morphologically and spatially distinct12. Although these aforementioned computational methods can be applied to both single-cell resolution and multi-cell pixel-resolution spatially resolved transcriptomic data, interpretation of the resulting trends with multi-cell pixel-resolution data will need to take into consideration potential confounding from pixels containing cells of different cell types.Given the nascency of such high-throughput spatially resolved transcriptomic technologies, new computational methods for analyzing the resulting data are still actively being developed. Already, computational methods leveraging Gaussian processes14. Integrating additional information such as cellular transcriptional composition and prior knowledge of cell type-specific gene expression can further enhance segmentation performance, particularly with crowded but transcriptionally distinct cells16. However, for cells with more complex morphologies such as neurons, additional computational methods for reliable cell segmentation are still needed. Beyond ensuring more accurate estimation of single-cell gene counts, reliable segmentation opens the door to additional downstream computational methods to incorporate subcellular spatial information. For example, by accurately accounting for the subcellular location of RNA counts, these downstream methods enable the prediction of future cellular transcriptional states by inferring RNA velocity in situ or the characterization of the subcellular spatial heterogeneity of RNAs and its functional impact18.Data from spatially resolved transcriptomic technologies present unique analytical challenges and opportunities. For spatially resolved transcriptomic data from in situ imaging-based technologies, individual identified RNA molecules must be aggregated into cells to achieve single-cell resolution transcriptomic profiling. Therefore, reliable cell segmentation is needed to fully dissect the heterogeneity of single cells in their spatial context, as well as to probe their morphological features and to characterize their intracellular variability. Several cell segmentation pipelines exist and work well with images of cells in culture or fluorescent labeled cells21 or by applying generative modeling approaches22. Although these deconvolution approaches infer the proportional representation of cell types within multi-cellular\u00a0pixels, additional methods are needed to further dissect the spatial organization of cell types and enable the inference of sub-pixel spatial information.Likewise, spatially resolved transcriptomic data from sequencing-based, pixel-resolution, spatially resolved RNA capture technologies present a different set of unique analytical challenges. In particular for technologies with larger pixel sizes, transcripts from multiple cells may be captured in each spatially resolved pixel. As such, each resulting spatially resolved transcriptomic profile may reflect multiple cells of different cell types, thereby hindering the identification of cell-type-specific spatial organizational patterns. To overcome this challenge, several computational methods have been developed to deconvolve cell-type mixtures within each multi-cellular\u00a0spatially resolved pixel, often by integrating the cell-type-specific transcriptomic profiles derived from a suitable single-cell reference23.Still, additional computational methods for analyzing spatially resolved transcriptomic data are needed. Notably, although computational methods have been developed to identify and characterize spatial gene expression patterns, we find that additional methods to systematically characterize and statistically evaluate how such patterns relate to anatomical features of tissues such as blood vessels or organ borders are still needed to understand the relationship between structure and phenotype. Furthermore, current computational methods generally limit spatial analysis to individual tissue sections or multiple contiguous sections from the same sample. To analyze samples collected from different individuals, time points, or perturbations, we anticipate that additional computational methods for aligning to a common coordinate system will be needed to compare, contrast, and characterize differences in spatial gene expression patterns and cellular organizationAs these spatially resolved transcriptomic technologies become more widely adopted, we anticipate that beyond the development of new computational methods for spatially informed data analysis, such computational methods must be implemented and made accessible as robust and usable software. This is needed to ensure that users can apply these technologies and analyze the resulting data effectively and efficiently. We believe the software developed to preprocess and analyze spatially resolved transcriptomic data should therefore adhere to best practices in open-source software development, such as providing adequate documentation of software functionality and maintaining responsive issue tracking. Further, support mechanisms need to be made available to promote and incentivize such adherence. Adherence to such best practices will be especially critical to ensure that these technologies and tools are accessible to researchers with more limited computational expertise. Moreover, as these spatially resolved transcriptomic technologies and protocols are further developed to enable data collection from larger tissue sections with more genes and cells across more samples, analytical algorithms and software implementations that are scalable with respect to runtime and memory will also be critical to ensure that these technologies and tools are accessible to researchers with more limited computational resources.24, further efforts are needed to encourage adoption by enhancing their ease of use, offering comparable features to existing in-house pipelines, while maintaining flexibility across available technological platforms, as well as demonstrating robustness and reproducibility across use cases.As current spatially resolved transcriptomic technologies continue to mature, we believe standardized metrics and benchmarks will need to be created, to enable comparisons across these technologies, in particular with regards to detection sensitivity, specificity, and capture efficiency. Such standardized metrics and benchmarks will be important for understanding which technologies may be better suited for specific biological questions such as those that demand detection of lowly expressed genes or single-nucleotide variations. Such standardized metrics and benchmarks will also facilitate the development of computational methods for harmonized analysis of data across multiple technologies. In particular for spatially resolved transcriptomic data from in situ imaging-based technologies, standardized metrics for reporting confidence in spot calling, gene identification, and gene-to-cell assignment remain to be established. We anticipate that such specific standardized metrics will be useful in mitigating error propagation to downstream analyses that may lead to incorrect biological interpretations. For example, errors in spot calling, gene identification, and cell segmentation may lead to inaccurate cellular gene expression counts that result in the misidentification of seemingly new, transcriptionally distinct cell types that are the result of propagated technical errors. One challenge towards establishing a set of standardized metrics for spatially resolved transcriptomic data from in situ imaging-based technologies is related to the current dearth of uniform preprocessing pipelines. Many of the current spatially resolved transcriptomic in situ imaging-based protocols rely on in-house image preprocessing pipelines. Although uniform preprocessing pipelines are being established25. Further, it makes readily accessible not only the processed gene counts but also raw sequences, as well as metadata on the machines and organisms used to generate the data and metrics regarding the quality of the data such as base call quality scores. Establishing a similar infrastructure for spatially resolved transcriptomic data from in situ imaging-based technologies may prove to be more complex given the range of protocols and modalities that exist and the sheer size of the raw imaging data as well. However, establishing such an accessible data-sharing infrastructure will be especially important for accelerating the development of computational methods to analyze such spatially resolved transcriptomic data, as it ensures the availability of a wide range of data for method testing and enables the characterization of method performance with respect to data quality. We envision that additional discussion and collaboration from the community will be needed to establish the form of processed data and range of standardized metrics most useful for all invested parties, from those interested in developing new computational methods to those interested in further enhancing the technologies, and those interested in probing deeper into datasets for biological insights.In addition, we find that an accessible and centralized infrastructure is currently still needed for sharing spatially resolved transcriptomic data, in particular from in situ imaging-based technologies. Such an accessible and centralized infrastructure already exists for RNA-sequencing dataIn conclusion, spatially resolved transcriptomic technologies offer an exciting new way of probing the intricate spatial mechanisms at play within tissue ecosystems. Computational methods are needed to enable the characterization of tissue heterogeneity using the high informational content data obtained from such spatially resolved transcriptomic technologies. Still, there remains a need for targeted perturbation, experimental validation, and investigation of generalizability to validate the insights gained from applying these computational methods. For example, although computational methods have been developed to integrate spatial and morphological information in single-cell clustering, further validation is needed to understand if new cell clusters identified through such integrative approaches represent meaningful functional heterogeneity. Furthermore, investigating the extent to which spatial and morphological characteristics of cells are independent of their gene expression can lend insights into other cell intrinsic and cell extrinsic factors that influence cell phenotype. Likewise, intracellular spatial heterogeneity and its functional consequences remain to be characterized. Ultimately, computational methods for analyzing spatially resolved transcriptomic data offer the potential to identify and characterize the heterogeneity of cells within their spatial contexts and contribute to important fundamental biological insights regarding how tissues are organized in both the healthy and diseased settings."} +{"text": "This session will provide updates on how the pandemic led to horrific situations in long-term care facilities and how the pandemic influenced major federal efforts to address elder abuse, neglect, and exploitation."} +{"text": "Pseudomonas aeruginosa (PSAR) is challenging to treat due to its multiple resistance mechanisms, limited anti-PSAR agents, and population pharmacokinetic (PK) variances. Beta-lactam antibiotics (BLA) are commonly used to treat PSAR infections and although they have a wide therapeutic index, suboptimal exposures may lead to treatment failure and antimicrobial resistance while high exposure may result in adverse effects. Certain patient populations may benefit from BLA therapeutic drug monitoring (TDM) due to their significant PK variability. The purpose of this study was to compare clinical outcomes in patients with PSAR pneumonia (PNA) or bloodstream infection (BSI) receiving BLA with and without the guidance of TDM.Retrospective, parallel cohort study conducted at UF Shands Gainesville and UF Health Jacksonville evaluating five years of patients with PSAR PNA or BSI. TDM group was defined for routine BLA TDM compared to nonroutine BLA TDM service (non-TDM). Patients were excluded if they died before a culture result, transferred in with a positive PSAR culture, were transplant recipients, cystic fibrosis or burn injury patients. The primary outcome was a composite of presumed clinical cure defined as the absence of the following: all-cause in-hospital mortality, escalation, and/or additional antimicrobial therapy for PSAR infection after 48 hours of treatment with primary susceptible regimen due to worsening clinical status or transfer to a higher level of care.Two-hundred patients were included . The overall primary composite outcome of presumed clinical cure occurred in 73% of patients . A post-hoc multivariate analysis was conducted to assess predictors of not attaining clinical cure.While there was no difference in the primary composite outcome of presumed clinical cure, future studies can use these data to assess TDM patient selection and whether a bundled care approach of BLA regimens with known clinical benefit, early TDM-guided dose optimization, and continued clinical assessment improves outcomes in patients with PSAR PNA or BSI compared to use of each modality individually. All Authors: No reported disclosures"} +{"text": "Difficulties in parent-child interaction are easily observed and are a potential target for early intervention. This study aimed to assess the utility of observation of parent-child interaction in the first year of life in identifying children at risk of developing later psychopathology, using a rigorous systematic review method.EMBASE, CINAHL, PsycINFO, MIDIRS, MEDLINE and Cochrane Library databases were searched using MeSH terms and keywords, and reference lists screened. Two authors independently reviewed papers for inclusion and completed data extraction. All peer reviewed papers studying the association between an independent observation of parent-child interaction and later childhood psychopathology in community-based samples were included. Studies based on \u2018high risk\u2019 samples were excluded. Results were synthesised qualitatively due to high heterogeneity.18,226 papers were identified, nine were included in this study. Childhood psychopathology was associated with fewer positive parent-infant interactions, lower parent vocalisation frequency and lower levels of adult speech and activity. Maternal sensitivity was inversely related to separation anxiety and oppositional defiant/conduct disorders were associated with lower shared look rates. Disruptive behaviour disorders were associated with higher frequency of child vocalisation. Pervasive developmental disorders were associated with \u2018abnormal\u2019 maternal infant interactions, as assessed by community health nurses using a standardised measure.Included studies reported small samples, and several of these samples overlapped. Some studies were of poor quality, but were included due to a paucity of available data. The findings may therefore have limited generalisability. Difficulties in parent-child interaction are easily observed and assessments could be made by non-specialists such as health visitors or general practitioners. Such difficulties may be an early indicator of later childhood psychopathology. Childhood psychiatric diagnoses (with the exception of Autistic Spectrum Disorders) appear associated with level of maternal activity . Assessments may identify at-risk families for early intervention, but further work is required to develop and validate reliable methods for risk stratification in community-based practice."} +{"text": "The emergence of multicellularity is strongly correlated with the expansion of tyrosine kinases, a conserved family of signaling enzymes that regulates pathways essential for cell-to-cell communication. Although tyrosine kinases have been classified from several model organisms, a molecular-level understanding of tyrosine kinase evolution across all holozoans is currently lacking. Using a hierarchical sequence constraint-based classification of diverse holozoan tyrosine kinases, we construct a new phylogenetic tree that identifies two ancient clades of cytoplasmic and receptor tyrosine kinases separated by the presence of an extended insert segment in the kinase domain connecting the D and E-helices. Present in nearly all receptor tyrosine kinases, this fast-evolving insertion imparts diverse functionalities, such as post-translational modification sites and regulatory interactions. Eph and EGFR receptor tyrosine kinases are two exceptions which lack this insert, each forming an independent lineage characterized by unique functional features. We also identify common constraints shared across multiple tyrosine kinase families which warrant the designation of three new subgroups: Src module (SrcM), insulin receptor kinase-like (IRKL), and fibroblast, platelet-derived, vascular, and growth factor receptors (FPVR). Subgroup-specific constraints reflect shared autoinhibitory interactions involved in kinase conformational regulation. Conservation analyses describe how diverse tyrosine kinase signaling functions arose through the addition of family-specific motifs upon subgroup-specific features and coevolving protein domains. We propose the oldest tyrosine kinases, IRKL, SrcM, and Csk, originated from unicellular premetazoans and were coopted for complex multicellular functions. The increased frequency of oncogenic variants in more recent tyrosine kinases suggests that lineage-specific functionalities are selectively altered in human cancers. Tyrosine kinases propagate cellular signals through the phosphorylation of tyrosine residues on protein substrates. Forming a monophyletic group within the larger protein kinase superfamily, tyrosine kinases diverged from serine\u2013threonine kinases prior to the emergence of opisthokonts , which aA classification of the protein kinome into evolutionarily and functionally related families (here on referred to as the KinBase classification) was achieved two decades ago following the sequencing and comparative genomic analyses of model organism genomes including human , mouse , sea urcIn addition to the uniquely evolved features across different tyrosine kinase families, similarities across some tyrosine kinase families have also been noted. For example, the recently termed \u201cSrc module,\u201d which consists of a tyrosine kinase domain and N-terminal SH3 and SH2 domains, is found across the Src, Abl, Tec, and Csk families, and structural and solution studies have determined that a similar autoinhibitory configuration of the Src module is shared across members of the Src, Abl, and Tec families . BecauseHere, we determine a novel hierarchical, constraint-based classification of the tyrosine kinome that newly identifies three evolutionary subgroupings of tyrosine kinase families based on the selective conservation of sequence motifs in the kinase domain, which encode common autoinhibitory conformations. In addition, we illustrate an evolutionary timeline of how unique kinase functions have expanded on shared subgroup-specific features through duplication events, selection of family-specific motifs, and domain shuffling to give rise to the vast repertoire of tyrosine kinase signaling observed throughout metazoans. A closer examination of tyrosine kinase phylogeny in light of constraint-based tyrosine kinase subgroups reveals new insights into the evolutionary conservation or divergence of subgroups, as well as the unique signaling features that may have emerged from three separate monophyletic clades of receptor tyrosine kinases. In particular, we note the early emergence of two major clades of holozoan tyrosine kinases distinguished by the presence (or absence) of an insert between the \u03b1D and \u03b1E helices of the kinase domain, where tyrosine kinases containing the insert comprise the majority of metazoan receptor tyrosine kinases. Our classification of the tyrosine kinome and the approach used in this study set a new precedent for the classification and evolutionary study of protein kinases and other large protein families.To generate a comprehensive classification of the holozoan tyrosine kinome, we generated a multiple sequence alignment of 44,639 tyrosine kinase sequences spanning 586 species . We then used the Bayesian Partitioning with Pattern Selection (BPPS) algorithm to classify aligned sequences into hierarchical clusters based on the patterns of conservation and variation in aligned tyrosine kinase domain sequences A Neuwal, 2014. ENext, we reclassified 34,954 tyrosine kinase sequences from the UniProt reference proteomes database into the optimized hierarchy by quantifying the extent to which individual sequences match cluster-specific motifs . We define this reclassification as a constraint-based classification because this post-processing step eliminates spurious or divergent sequences from clusters that do not score over an optimal cut-off score due to their lack of cluster-specific patterns. The spurious sequences eliminated from each cluster are categorized within the unclassified family .The new constraint-based hierarchical classification of tyrosine kinases, which is broadly similar to the KinBase classification of the tyrosine kinome, reveals several novel subgroupings. In particular, the constraint-based classification defines three new subgroupings of tyrosine kinase families which account for nearly half of the tyrosine kinome: the Src module (SrcM) subgroup, the insulin receptor kinase-like (IRKL) subgroup, and the fibroblast, platelet-derived, and vascular growth factor receptors (FPVR) subgroup . The SrcBy examining the sequence constraints that define each of the three novel subgroups in light of existing crystal structures, we observe that subgroup-specific motifs are located in known regulatory regions of the kinase domain. For example, the SrcM subgroup conserves a highly distinguishing GxM motif in the \u03b23-\u03b1C loop and a GxKF motif in the activation loop that both form important interactions associated with a common Src-like inactive conformation in the activation loop A Xu et . This SrIn order to infer when each of these tyrosine kinase subgroups and families emerged in evolution, we organized tyrosine kinase subgroups and families based on taxonomic conservation . TyrosinIn order to further explore the functional diversity of SrcM, IRKL, and FPVR tyrosine kinases, we surveyed the diversity of protein domains present across these subgroups and analyzed their conservation across holozoan taxa . As prevThe IRKL and FPVR subgroups encompass the majority of receptor tyrosine kinase families and, despite sharing common kinase domain mechanisms within these subgroups , have diHis260) in the \u03b1E helix which tyrosine kinases selectively lost upon diverging from the serine/threonine kinases . By integrating our constraint-based classification of tyrosine kinases with our phylogenetic tree A, we can kinases online group of serine/threonine kinases. Holozoan tyrosine kinases (Group A) also form a monophyletic clade that is distinct from a paraphyletic group of divergent tyrosine kinase sequences found in pre-opisthokonts (Group B), such as those found in the amoebozoans nhardtii . This correlation between the presence of the longDE insert with the presence of transmembrane and extracellular domains, alongside evidence that the insert plays important roles in kinase activation and protein recruitment for downstream signaling, suggests that the longDE insert evolved as a means to facilitate downstream intracellular signaling upon the activation of receptor tyrosine kinases by extracellular signals. In addition, though the DE insert is difficult to align across families due to the lack of sequence conservation, the DE insert is alignable within families and often conserves sequence motifs including phosphorylatable tyrosine, serine, or threonine residues, suggesting that individual receptor tyrosine kinase families along the longDE clade have rapidly and frequently evolved the longDE insert in family-specific contexts, presumably to carry out family-specific downstream signaling functions. We also note that the longDE tyrosine kinases highly conserve a unique activation loop methionine, which is not observed in shortDE tyrosine kinases C; howeveInterestingly, the shortDE clade in the tyrosine kinase phylogeny, which predominantly consists of cytoplasmic tyrosine kinases, includes two monophyletic clades of receptor tyrosine kinases: the EGFR family of receptor tyrosine kinases and a separate monophyletic clade that includes the Eph and choanoflagellate-specific RTKC families of receptor tyrosine kinases. Thus, our phylogeny suggests at least three independent origins of highly expanded receptor tyrosine clades, with the majority of receptor tyrosine kinases emerging from the longDE clade. That these disparate branches along the tyrosine kinase phylogeny have convergently evolved to include transmembrane and extracellular domains highlights the importance of relaying extracellular signals into intracellular responses across various signaling niches. Although the longDE receptor tyrosine kinases are distinguished by extra functionalities imparted by the longDE insert, the Eph and EGFR families also exhibit unusual signaling functions so far unobserved in other longDE receptor tyrosine kinases. Eph receptor tyrosine kinases have a unique capacity for bidirectional signaling, where the binding of ephrin ligands, which are also membrane bound, can activate signaling both in the receptor-bearing cell, as well as in the ligand-bearing cell . FurtherThe classification of protein kinases into evolutionarily related families has provided the foundation for decades of comparative sequence-structure-function studies on protein kinases . Here, wWe constructed a new representative phylogenetic tree of the holozoan tyrosine kinome which revealed larger evolutionarily related clades of tyrosine kinases associated with additional defining features A. DividiThe expansion and diversification of the tyrosine kinome across the animal kingdom highlights its central role in metazoan biology. Although many previous studies have speculated on the role of tyrosine kinases in the evolution of multicellularity , our finGiven the important roles of tyrosine kinases in multicellular metazoan biology, it comes as no surprise that sequencing efforts have identified many disease-related variants across the tyrosine kinome . MultiplWe sampled alternative classification hierarchies ab initio, using the omcBPPS algorithm which emPhe43) and ending at the \u03b1I helix (PKALys292). Kinase sequences which did not span from at least the \u03b23-Lys to the DFG-Asp were deemed fragmentary and removed from the alignment. The UniProt sequence set contained 12,137 tyrosine kinase sequences. The nr sequence set was further purged at 98% sequence identity and contained 17,071 tyrosine kinase sequences. We performed hierarchical clustering on both sequence sets using omcBPPS. For both sequence sets, we optimized the \u201cminnats\u201d parameters (minnat\u2009=\u20091 and minnat\u2009=\u20095) which changed the minimum log-likelihood required to form a cluster. All runs were performed twice. To create a consensus of the hierarchical classification schemes found by multiple runs of omcBPPS, we used the mcBPPS algorithm. Clusters which were consistently identified throughout multiple runs were refined using the mcBPPS algorithm and NCBI nonredundant (nr) proteins database . Within lgorithm . We ran Using our consensus model, we developed quantitative means of evaluating how well any given sequence fit into each of the clusters defined by our model which implements NumPy array-based sequence alignment manipulation. All sequence features were represented as Boolean arrays as a function of the full sequence alignment. More complex queries pertaining to multiple sequence features (such as the presence of a given domain in a given taxon) were constructed by Boolean algebra. These Boolean arrays were applied as filters to our sequence alignment using NumPy indexing routines . SequencAfter we classified our representative set of tyrosine kinase into discrete clusters, we determined the taxonomic conservation of each cluster. We determined the source of each tyrosine kinase sequence using the organism identifier number (OX) provided in the FASTA header of UniProtKB sequences. OX numbers were traced back to their parent node identifiers using the nodes dump file provided in the NCBI taxdump database. All node identifiers were translated to their respective scientific names using the taxonomy names dump file. We determined the distribution of taxa across each cluster of tyrosine kinases and selected an optimal mix to depict diverse taxa ranging from unicellular pre-metazoans to more complex metazoans such as chordates online. Intron/exon annotations were mapped using Scipio . Intron We produced protein domain annotations for each full-length tyrosine kinase sequence using the NCBI Conserved Domain Database database of conserved protein domains one randomly selected sequence from each cluster-taxon pair based on online etellanii , and 4) tellanii , with Motellanii . Branch tellanii . Resultstellanii online. The consensus tree with the highest bootstrap support values for the three major tyrosine subgroups was selected as the final tree. The optimal substitution model for our final topology was determined to be LG+R8 based on the Bayesian Information Criterion as determined by ModelFinder . We rootWe compared our tree to previously published phylogenies which also sampled diverse tyrosine kinase families . HoweverMolecular Biology and Evolution online.msab272_Supplementary_DataClick here for additional data file."} +{"text": "Although clinical guidelines recommend that people showing signs of cognitive decline engage in Advance Care Planning (ACP) while they still have decision-making capacity, too often this opportunity to clarify values and treatment preferences is missed among patients and their families. In reflection of the paucity of empirical data on factors influencing how this planning process begins for families experiencing cognitive decline, this study explored facilitators and barriers to ACP among adult children of parents showing signs of early- to mid-stage dementia, with a particular focus on relationship quality. Among this sample (N = 315), relationship quality positively and significantly predicted advance care planning engagement . Financial burden weakly and positively predicted ACP engagement , while both psychological burden and financial burden negatively and significantly predicted relationship quality. This study validates the use of the ACP Engagement Survey (ACPES) adapted for surrogates among adult children of people experiencing cognitive decline and contributes to a scarce literature on the impact of relationship quality on ACP engagement."} +{"text": "Current 3D cardiac organoid cultures have shown their utility in modelling key developmental hallmarks of heart organogenesis, but the complexity of the organ demands a more versatile model that can investigate more fundamental parameters, such as structure, organization and compartmentalization of a functioning heart. This review will cover the prominence of cardiac organoids in recent research, unpack current in vitro 3D models of the developing heart and look into the prospect of developing physiologically appropriate cardiac organoids with translational applicability. In addition, we discuss some of the limitations of existing cardiac organoid models in modelling embryonic development of the heart and manifestation of cardiac diseases.Medical research in the recent years has achieved significant progress due to the increasing prominence of organoid technology. Various developed tissue organoids bridge the limitations of conventional 2D cell culture and animal models by recapitulating Congenital heart defects (CHD) affects approximately 0.4\u20135% of live births worldwide, making it the most common form of congenital disease . Despitein vivo (The advent of pluripotent stem cells (PSCs), of both embryonic stem cells (ESC) and induced pluripotent stem cell (iPSC) origins differentiated into various cell lineages, provides novel insights to embryonic development and regenerative biology . Human iin vivo . These fin vitro tissue cultures have been widely used in multiple research fields to model their in vivo organ counterparts. Self-organized from stem cell populations, these organoids have the potency to undergo multiple divisions and differentiate into various appropriate cell types to confer structural and cell composition resembling in vivo organs o organs . Kidney,o organs . Cell-ceo organs . As suchin vitro model that can capture such a complex system, maintain, and mature the various cell types will be even harder to achieve. While cardiac organoid technology is still in its infancy, a number of research groups have developed methods to generate 3D cardiovascular tissue using either a pure CM starting population or a mixture of CMs, CFs and ECs and aggregating them into Engineered Heart Tissues (EHT) or on scaffolds , epicardial cells, endocardial cells, smooth muscle cells, cardiac fibroblasts (CF) and endothelial cells (EC) with compositions that can vary with age or due to myocardial damage and remodelling . PSC-dercaffolds (Eschenhcaffolds . A summaEmbryoid bodies (EBs) are aggregate masses of PSCs cultured in suspension and are widely used for differentiation into various tissue lineages. CMs were first derived using EBs generated using murine stem cells . Since tTo overcome the stochastic nature of EB-CM models resulting in widely varied cell compositions and cell number, cardiac spheroids have been aggregated using specific cell composition and number. A number of research groups have explored aggregating tissues of varying compositions appropriate to study specific archetypes of cardiac developmental diseases or health. Hanging drop culture has been used to aggregate CMs, ECs and CFs in a 3:1:6 ratio for spheroids to measure the cardiotoxicity of doxorubicin, a widely used cancer drug . Anotherin vivo early heart and foregut endodermal anlagen of the developing embryo, with layered myocardium and endocardium, vascular network, and anterior-posterior foregut patterning (On the other hand, cardiac organoids are more strictly defined as 3D cardiac structures that were self-organized from either PSCs or multipotent progenitors. This direction is highly popular of late, with many recent works on utilizing either murine and human PSCs to generate cardiac organoids attempting to recapitulate cardiogenesis . Interestterning . By natuA popular method to overcome the maturation limitation of these spheroid and organoid models is long-term culture within bioreactors. Bioreactors supply biochemical signals by improving media circulation around the organoids to ensure higher mass transfer, physiological relevant gradient of nutrients and sufficient removal of waste products . In addiEngineered heart tissues are amongst the oldest and most utilized 3D tissue construct made up of aligned CMs with the ability to propagate contractions along a plane . While tEHTs have also been adapted to contain the appropriate cell composition for modelling specific diseases. ECs and/or CFs have been aggregated to study neovascularization and cardiac fibrosis . PurifieHowever, there are limitations to EHTs as a modelling platform. It requires a high initial cell count for aggregation, within a complex equipment setup that prevents high throughput screens . In addiEHT constructs of 3D CM tissues was popularized alongside several other hydrogel/polymer based matrixes for patterning . ConceptSimilarly, hydrogels and polymers have been utilized to create 3D scaffolds as a biomimetic approach to recapitulate human cardiac tissue . While EWhile cardiomimetic scaffolds have been developed to provide a geometrically and environmentally appropriate 3D architecture for CM seeding, simple folded scaffolds have also been developed to promote cardiac chamber formation . These hAlternatively, precise control of cellular composition and spatial distribution of individual cells can be achieved via 3D bioprinting. Hydrogels and decellularized extracellular matrix have been developed into bioinks that serve as a scaffold for individual cell types to be printed on . Of notein vitro heart models limit research in understanding these disorders. While much effort has been poured into generating the 3D CM models described in in vivo development.Congenital heart defects occurring during the first 8\u00a0weeks of embryonic development are detrimental to the growing embryo\u2019s ever-increasing metabolic demands during embryogenesis. However, inaccuracies in the in vitro models were shown to recapitulate various aspects of cardiogenesis. Earlier work by There have been significant recent advances in the field of developmental cardiac organoids, which were intrinsically formed by taking advantage of the self-organizing and patterning capabilities of either murine or human hPSCs. These Consistently, in vivo heart (in vitro organ/tissue formation to mimic cardiogenesis from the early to mid-gestation stages, and thus does not require complex differentiation protocol. Therefore, the heart organoids represent a promising research tool to study developmental diseases for drug testing.Developmental organoids can also possess the capability to be used as a disease modelling tool, particularly for drug testing. Heart organoids were generated using mouse ESCs by utilizing FGF4 and extracellular matrix, emulating the developmental processes of the vo heart . These hAs mentioned, several organoid platforms have focused particularly on the disease modelling and drug screening purposes of the model . These mvia Wnt signaling modulation, and extensively detailed its capability in modelling cardiac development and diabetes-induced congenital heart disease. These hHOs were mainly comprised of myocardial tissue, with epicardial tissue organized near the exterior surface of the organoids. In addition, these hHOs recapitulate the functional and structural features of the developing fetal heart, exhibiting robust contraction and action potential waves reminiscent of the PQRST waves, and expressed well defined sarcomeres surrounded by gap junctions, mitochondria and t-tubules. As a proof of concept, pregestational diabetes impacted the cardiac development of these hHOs, resulting in irregular arrhythmic contraction, metabolic dysfunction and structural organization in accordance with the phenotype observed in vivo.Of note, Myocardial infarction and drug cardiotoxicity has been recently modelled in a cardiac microtissue organoid model as well . The uniin vivo. However, current cardiac organoid models fall short in developing important structural and morphological elements unique to the heart. Particularly, cardiac architecture, most notably being the heart chambers are absent, and thus related elements such as the septa and valves are also missing. As such, CHD affecting these missing elements in the in vivo developing heart cannot be accurately modelled.Collectively, developments in 3D cardiovascular disease models have demonstrated the ability of patient-derived cardiac organoids to recapitulate developmental processes of cardiogenesis, as shown by ultrastructural, gene expression, histochemical characteristics with resemblance to the developing heart in vivo (Cardiac progenitors within the embryonic heart specifies their subtype early in development, primarily during heart field specification . Howeverin vivo . Furtherin vitro, working in tandem with classical models for accurate phenotyping of disease and drug effects. However, the lack of functional cardiac chambers limits the utility of these organoids in the disease modelling space. The closest model in achieving self-organized chambers currently available is the hHO model by Lewis-Israeli et al., detailed previously in + endocardial cells (Lastly, the missing structural elements of current cardiac models results in the failure to model mechanical functional changes such as myocardial wall thickness, pressure loading and ejection fraction. Heart disease often present with pathological cardiac remodeling, causing hypertrophic growth, irreversible decompensation and thinning of the myocardium and dilatation of the failing heart . Classical cells . Howeveral cells . Such anDrawing from the approaches of the tissue organoid systems currently generated, intrinsically formed chambered cardiac organoids should theoretically be achievable. Judging by the rapid pace of advances in the space of cardiac organoid development in recent years, there is promise that such an organoid model will soon be developed and be scalable for high-throughput disease modelling. Lately, there has been increasing interest in utilizing microfluidic systems such as organ-on-a-chip platforms for use in preclinical analysis. These chip-based systems are the preferred platform for industry-level research\u2014completely automated high throughput derived organ-models are screened within highly reproducible fabricated chips. Organ-chip systems have been adapted to allow for vascularization in a number of tissue types, recently reviewed by in vivo heart in place, future in vitro cardiac modelling will be able to better support downstream preclinical pharmaceutical research in discovering cures and preventing cardiotoxic drugs from slipping through.While 3D CM cultures currently exist and are routinely used for studying development, drug screening and disease modelling, they often portray an incomplete picture of associated effects on a human heart. The strong demand required to bridge the technology and knowledge gap will enable researchers to better study heart development and cardiovascular diseases for research and translational purposes. Hence, future direction for cardiac organoid research is currently focused on generating physiologically appropriate chambered cardiac organoids paired with an appropriate high-throughput modelling platform that can simultaneously assess multiple cardiac functional parameters. With more faithful models of the"} +{"text": "Socioeconomic status (SES) is one of the most robust predictors of health. The source of SES-health associations is heavily debated; one approach is investigating neighborhood-level environmental characteristics. Challenges include selection effects and the possibility of reverse causation: people choose their neighborhoods. Longitudinal twin research can overcome these issues by assessing location choice over time as well as twin similarity; however, few existing twin studies have incorporated neighborhood-level data, and none of those focus on aging. Using longitudinal data from the Swedish Adoption/Twin Study of Aging, the current study examined the impact of location at various points in life. Location at birth and in 1993 were available for 972 participants. Birth years ranged from 1926 to 1948; mean age in 1993 was 54.55 (range = 35-67). Thirty-nine percent of the sample had moved to a different county between birth and midlife: individuals who moved had significantly higher parental SES and had achieved significantly higher education. Moreover, identical twin concordance for geographic mobility (77%) was significantly higher than fraternal twin concordance (65%), indicating a modest but significant genetic contribution. Geographic mobility did not impact identical twin similarity on a functional aging factor (corrected for age and education), but fraternal twins concordant for mobility were more similar than discordant twins, suggesting genetic contributions to mobility may also impact health. Ongoing retrieval of location information for twins born 1900-1925 and geocoding of location information available at 9 waves of data collection will allow for expanded investigation of the SES-health relationship at the neighborhood level."} +{"text": "METHODS/STUDY POPULATION: This study involves refractory epilepsy patients with implanted intracranial electrodes and moderate-to-severe traumatic brain injury (m/sTBI) survivors. In epileptic patients, we will identify connectivity of cortical regions via the ANT, which probes components of attention and a CC task that probes implicit learning. We hypothesize that modulation of attention and learning can be seen at the network level. In TBI we will assess improvement following two attention rehabilitation paradigms behaviorally; and use our results from epileptic patients to guide measurement of treatment-related neuroplastic change via scalp electroencephalography. RESULTS/ANTICIPATED RESULTS: When the proposed objectives are complete, we expect to determine how the implicit learning rate in m/sTBI changes as a result of both direct attention and metacognitive-strategy training, and discern the neuroanatomical networks associated with attention and implicit learning based on connectivity results. We expect to identify intracranial regions and networks that exhibit modulatory effects associated with attention and implicit learning. Additionally, we anticipate that deficits in attention will be mitigated following training and hypothesize that implicit learning rate will improve in TBI patients as a result of both attentional rehabilitation paradigms. DISCUSSION/SIGNIFICANCE OF IMPACT: Characterizing intracranial activity in epilepsy patients will give electrophysiology data unattainable in TBI patients. This intracranial perspective will enable us to propose mechanisms of action that may result from our interventions and enable critique of current rehabilitation treatments.OBJECTIVES/GOALS: 1) Investigate the network level interactions of attention and learning during an attention network task (ANT) and an implicit learning contextual cueing (CC) task. 2) Assess the effect attention rehabilitation strategies have on"} +{"text": "In the last decade, cold water immersion (CWI) has emerged as one of the most popular post-exercise recovery strategies utilized amongst athletes during training and competition. Following earlier research on the effects of CWI on the recovery of exercise performance and associated mechanisms, the recent focus has been on how CWI might influence adaptations to exercise. This line of enquiry stems from classical work demonstrating improved endurance and mitochondrial development in rodents exposed to repeated cold exposures. Moreover, there was strong rationale that CWI might enhance adaptations to exercise, given the discovery, and central role of peroxisome proliferator-activated receptor gamma coactivator-1\u03b1 (PGC-1\u03b1) in both cold- and exercise-induced oxidative adaptations. Research on adaptations to post-exercise CWI have generally indicated a mode-dependant effect, where resistance training adaptations were diminished, whilst aerobic exercise performance seems unaffected but demonstrates premise for enhancement. However, the general suitability of CWI as a recovery modality has been the focus of considerable debate, primarily given the dampening effect on hypertrophy gains. In this mini-review, we highlight the key mechanisms surrounding CWI and endurance exercise adaptations, reiterating the potential for CWI to enhance endurance performance, with support from classical and contemporary works. This review also discusses the implications and insights (with regards to endurance and strength adaptations) gathered from recent studies examining the longer-term effects of CWI on training performance and recovery. Lastly, a periodized approach to recovery is proposed, where the use of CWI may be incorporated during competition or intensified training, whilst strategically avoiding periods following training focused on improving muscle strength or hypertrophy. Cold water immersion (CWI) is a strategy aimed at enhancing recovery from strenuous exercise, typically involving the submersion up to the waist or mid-torso for ~5\u201320 min in temperatures between ~8 and 15\u00b0C (Versey et al., Meta-analyses and experimental research in general show that CWI can beneficially influence the recovery of physical performance (Montgomery et al., In this mini-review, we have adopted an introspective approach in discussing the molecular mechanisms and rationale surrounding CWI and endurance exercise adaptations. Moreover, we review and discuss key studies which provide information on the applied scenarios where CWI can be utilized to promote physical recovery and adaptation whilst avoiding potential negative effects on hypertrophy and strength gains.Cold stimulus is a physiological stressor capable of triggering primary signals and downstream cascades implicated in exercise-induced improvements in muscle oxidative function (Ihsan et al., Seminal work by Spielgeman's group in the late 90's generated major breakthroughs in the mechanisms underpinning mitochondrial biogenesis (Puigserver et al., Whilst CWI was not conceived as a strategy specifically meant to supplement exercise adaptations, there was substantial interest in examining how recovery-based CWI might influence skeletal muscle adaptations to endurance exercise (Ihsan et al., Although such molecular responses would expectedly improve endurance performance in the longer term, Yamane et al. reportedIn contrast to Yamane et al. initial While these findings refute suggestions that CWI might counteract endurance adaptations, it nevertheless questions whether post-exercise CWI is an effective strategy to promote muscle adaptations resulting in improved exercise performance. Indeed, changes in acute signaling response (Ihsan et al., While some studies have shown that CWI can enhance physical recovery following resistance exercise (Vaile et al., 2 supply and utilization (Ihsan et al., Complimenting these mechanisms, we suggest that the attenuated increase in muscle mass observed following CWI and resistance training may be part of a macro-level mechanism protecting the oxidative profile of the muscle. This is supported by D'Souza et al. demonstrWhile we rationalize that the dampened increase in muscle mass observed following CWI is a compensatory mechanism improving oxidative function, further research is needed to understand how this might influence athletic function and performance. For instance, it is currently unknown if CWI influences the regulation of muscle mass following aerobic exercise, and whether this hypothetical trade-off involving the attenuated increase in muscle mass and strength might be beneficial to endurance performance. On the other hand, co-assessment of muscle aerobic function within these resistance training studies (Frohlich et al., Athletes embark on a variety of training sessions such as cardiovascular conditioning, strength/resistance training, technical, and tactical work. In sports science practice, CWI is likely to be incorporated at various instances to promote recovery, particularly when recovery time between sessions is limited. Caution should be warranted against the regular use of CWI particularly following resistance exercise sessions.Recent work examininTraining frequency reported within these applied studies surmounts to at least 10 sessions per week . PerhapsAnother key feature of these studies , and perCold water immersion is widely utilized by athletes during training and competition. Given that both a cold stimulus and exercise are independent stressors capable of enhancing muscle oxidative function, there remains substantial interest in examining how this modality might influence adaptations to exercise. Although post-exercise CWI up-regulates mitochondrial-related signaling, longer-term changes in protein content and result in vascular adaptations, these changes do not seem to translate to improved endurance performance. As such, further research is required to elucidate how endurance performance can be improved through its positive molecular signaling outcomes for CWI to be incorporated to enhance exercise-induced oxidative adaptations. It must be re-iterated that CWI does not impair aerobic training adaptations, and can be incorporated as a recovery modality following endurance training if needed. In contrast, regular CWI recovery incorporated into a resistance training program will dampen strength adaptations, and therefore the use of this modality following resistance exercise sessions should be discouraged. However, there is emerging data showing no impairments in strength gains in athletes incorporating regular use of CWI during intensified training periods; this either indicates that the recovery benefits conferred by CWI may outweigh its dampening effects on hypertrophy response, or the negative effects of CWI on strength may be circumvented by programing CWI following technical or aerobic conditioning sessions. In this regard, \u201crecovery periodization\u201d may be an important approach, where the use of CWI may be incorporated during competition or intensified training, whilst strategically avoided following training focused on improving muscle strength or hypertrophy.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The aerial portion of a plant, namely the leaf, is inhabited by pathogenic andnon-pathogenic microbes. The leaf\u2019s physical and chemical properties, combined withfluctuating and often challenging environmental factors, create surfaces that require ahigh degree of adaptation for microbial colonization. As a consequence, specificinteractive processes have evolved to establish a plant leaf niche. Little is known aboutthe impact of the host immune system on phyllosphere colonization by non-pathogenicmicrobes. These organisms can trigger plant basal defenses and benefit the host by primingfor enhanced resistance to pathogens. In most disease resistance responses, microbialsignals are recognized by extra- or intracellular receptors. The interactions tend to bespecies specific and it is unclear how they shape leaf microbial communities. In naturalhabitats, microbe\u2013microbe interactions are also important for shaping leaf communities. Toprotect resources, plant colonizers have developed direct antagonistic or hostmanipulation strategies to fight competitors. Phyllosphere-colonizing microbes respond toabiotic and biotic fluctuations and are therefore an important resource for adaptive andprotective traits. Understanding the complex regulatory host\u2013microbe\u2013microbe networks isneeded to transfer current knowledge to biotechnological applications such asplant-protective probiotics. Microbial colonization of above-ground parts of plants is a dynamic and interactiveprocess that requires a high degree of adaptation. Understanding complexhost\u2013microbe\u2013microbe interactions is key to new strategies for plant protection. This review examines how aerial parts of plants, particularly leaves, are colonized bymicrobes. The first section (\u2018Colonizing leaf surfaces\u2019) dissects biotic and abiotic factorsthat shape leaf microbial communities and determine the quality and quantity ofcolonization. We discuss pre-formed barriers, such as the cuticle, that restrict plant hostcolonization, and environmental conditions that enhance selection pressures. As aconsequence of the extreme conditions on leaves, the properties and generation of biofilmsthrough quorum sensing (QS) are considered. Leaf colonization by microbes is not onlyimpacted by host and environmental factors but also by resident microbes, includingpathogens that can severely perturb microbial communities. The second section(\u2018Microbe\u2013microbe\u2013host interactions\u2019) discusses effects of microbial communities on hostsusceptibility to pathogens and the impact of plant pathogens and endophytes on microbialhost colonization and community composition. A particular focus is on microbe\u2013microbeinteractions that are often mediated via the plant host. Individual plant cells also havethe capacity to steer microbial activities by pre-formed or induced structures and compoundsthat influence microbial growth on the leaf surface. The third section (\u2018Role of the plantimmune system in shaping the phyllosphere microbiome\u2019) considers the role of the plantimmune system on microbial host interactions with a focus on plant leaf colonization,leaf\u2013microbe outputs, and microbial diversity.6\u2013107 cells cm\u20132 of leaf area ,lettuce (Lactuca sativa), and neotropical forest and poplar treesconsists of four major bacterial phyla, namely Proteobacteria,Firmicutes, Bacteroidetes, andActinobacteria , and other treeleaves , and nitrogen fixation (nifH) gene markers,Methylobacterium and Sphingomonas species were highlyabundant in the plant leaf environment of three species, namely A.thaliana, Trifolium repens, and Glycine max fungal infection andEscherichia coli O157:H7 (EcO157) colonize fresh leafy vegetables suchas lettuce (Lactuca sativa) via damaged leaf tissue and can causefood-borne disease outbreaks whichregulates colonization as an important priming event in microbial community interactionswith the plant .ResearcPseudomonas syringae pv. syringae B728a strains onbean (Phaseolus vulgaris) leaves indicated that this hygroscopicbiosurfactant increases diffusion of water across a waxy leaf cuticle surface whichattracts moisture and nutrients to benefit the bacteria , ormation . SimilarN-acyl-l-homoserine lactone and quinolones as QS molecules, whereas modified oligopeptides are commonly used by Gram-positive bacteria for communication betweencells enhancedsusceptibility of various Brassicaceae species to fungal mildew pathogens and Erwinia toletana(olive knot cooperator) stabilize the community and exchange QS signals, and thiscooperation results in a more aggressive disease on olive plants (Oleaeuropaea) leaf-associated strains with QQ activity fordisruption of AHL-mediated QS, by using the biosensor reference strainChromobacterium violaceum CV026. These bacterial quorum quenchers canbe used as effective biocontrol agents against plant pathogens (Endophytes utilize QS to act against pathogenic microbes by expressing QS inhibitors(QSIs) to attenuate the activity of AIs, or quorum quenching (QQ) enzymes to disruptsignaling molecules. For example, AHL lactonase enzyme (a potent quorum quencher) presentin endophytic bacteria has been reported to inhibit the plant pathogens rotovora , 2001, Bngiensis , and Entasburiae . Ma et aInplanta experiments on Phaseolus lunatus have shown that, if apathogen was introduced to the plant on the same day or before inoculation with anendophyte, disease resistance was more strongly reduced than when the endophyte hadalready colonized the host . Similarly, different strains of the pathogenic fungusFusarium oxysporum can act as microbial antagonists against otherF. oxysporum strains and intracellular receptors which recognize microbial or modified host molecularsignatures and retain plant health and secure plant propagation. Surface immune receptors are members of a diversefamily of ligand-binding proteins that sense microbial, environmental, developmental, andnutritional cues . The intThe activation of plant immune responses by mobilizing a network of defense and stresshormone pathways has been extensively characterized in binary plant\u2013pathogen interactions. High-thIn this section, we consider evidence that abiotic and biotic stress responses modulatemicrobial consortia on leaves and discuss the consequences for plant fitness. It is becomingclear that microbial community structure throughout a plant host\u2019s life cycle is dynamic andmodulated by the innate immune system, which itself is tuned to environmental changes.P. syringae bacteria and riceresistance to the rice blast fungus, Magnapothe oryzae (ethylene-insensitive2 (ein2) mutantdisplayed an altered bacterial leaf community compared with wild-type plants, suggestingthat ethylene signaling is important for modulating the leaf microbiota ] that is defective inPTI and the MIN7 vesicle trafficking pathway (affecting the aqueous apoplasticmicroenvironment) and a constitutively activated cell death1(cad1) mutant had altered endophytic bacterial leaf diversity in protecting Arabidopsis against infection by afungal necrotrophic pathogen, B. cinerea (Actinobacteria(Strepotmycetes sp.) are able to activate plant biosynthesis ofsalicylic acid (SA) and promote leaf defense responses against fungal pathogens , which favor NLR expression in thephyllosphere , is often mediatedby intracellular NLR receptors which recognize certain pathogen-delivered virulencefactors (effectors) to induce immunity reduce microbial diversity within leaf habitats and stabilizemicrobial communities among wild plants in leaf tissues and grapevine against necrotrophic (B.cinerea) fungi have been studied extensively in vitro (P. syringae pathovar tomato (Pst) to Arabidopsis rootsattracted Bacillus subtilis and led to IP upon Pstinfection affecting microbial diversity on crops such as potato against biotrophic(The plant phyllosphere is a highly competitive and challenging habitat for microbes tocolonize. Pre-formed barriers such as the hydrophobic cuticle, stomata, or cell wallstructures require specific adaptation for the microbes, and persistence of microbesstrongly depends on their ability to interact with others. Thus understanding microbiotaassembly and persistence in the plant phyllosphere requires investigating ecological factorsthat shape pre-formed plant structures and therefore directly act on host\u2013microbe andindirectly microbe\u2013microbe interactions. Microbe\u2013microbe interactions in turn not onlyimpact microbial behavior but can impact host fitness by antagonizing plant pathogens.Pathogen invasion generally has a significant negative effect on host fitness caused bytissue damage, nutrient loss to invaders, and reallocation of resources to immuneactivation. Successful pathogenesis on the other hand is a complex process that requiresmultiple steps of host colonization and reproduction, and is generally the result oflong-term co-evolution (The downside is, however, that this pool is highly dynamic and probably requires a stableco-existence of different microbial species in one habitat in order to express beneficialtraits. Interconnected networks between organisms can be an important element in providing abuffer against perturbations since such links help to recruit microbes to fulfill specificfunctions in cases where another organism that, for example, provides importantantimicrobial compounds or enzymes within the network is lost.A main goal to develop strategies to protect the phyllosphere from pathogen invasion, suchas wheat from rusts, is to identify probiotics that can either stabilize the naturalcommunity or become stable on its own. One major effort to develop such probiotics istherefore understanding the multistep process of establishing a niche and defending thisniche. Only once we know how to combine traits for stability with our desired traits such asplant protection will we be able to develop products that can replace the majority of ourcurrent agrochemicals."} +{"text": "Geum peckii Pursh, Rosaceae) is a globally rare and endangered perennial plant found only at two coastal bogs within Digby County and at several alpine sites in the White Mountains of New Hampshire (USA). In Canada, the G. peckii population has declined over the past forty years due in part to habitat degradation. We investigated the culturable foliar fungi present in G. peckii leaves at five locations with varying degrees of human impact within this plant species\u2019 Canadian range. Fungal identifications were made using ITS rDNA barcoding of axenic fungal cultures isolated from leaf tissue. Differences in foliar fungal communities among sites were documented, with a predominance of Gnomoniaceae . Habitats with more human impact showed lower endophytic diversities (10\u201316 species) compared to the pristine habitat (27 species). Intriguingly, several fungi may represent previously unknown taxa. Our work represents a significant step towards understanding G. peckii\u2019s mycobiome and provides relevant data to inform conservation of this rare and endangered plant.Eastern Mountain Avens ( Phialocephala scopiformis, produces rugulosin, which inhibits the feeding of the spruce budworm, Choristoneura fumiferana. Consequently, the Canadian forestry industry inoculates spruce seedlings with P. scopiformis to improve host health ..https://Geum peckii. We documented 51 ascomycete fungi from the classes Sordariomycetes, Leotiomycetes, Dothideomycetes, and Eurotiomycetes. Endophytic fungal species richness changed with habitat degradation status, suggesting that this may influence the fungal assemblage present within leaves. A core fungal assemblage was documented for the first time in this plant host, from multiple sites throughout its Canadian range. Additionally, we present new host records for Rosaceae and make valuable linkages between host plants in the habitats and shared endophytes within Geum peckii that warrant further ecological investigation. By approaching plant conservation from a mycological perspective, we provide the first mycobiome assessment of G. peckii, an understudied component of the habitat. This new knowledge aids in ongoing conservation and propagation of this endangered plant species.In summary, we present the first preliminary survey of foliar endophytic fungi from the rare and endangered Eastern Mountain Avens,"} +{"text": "Objective determination of burn wound healing potential remains elusive and significantly impacts decision making for surgery, the extent of tissue excised intraoperatively and the use of donor site-sparing alternative tissue therapies. Indocyanine green angiography (ICGA) has promise as an adjunct to evaluate healing potential, but feasibility has limited adoption in clinical practice. Delayed fluorescence imaging of indocyanine green (ICG), in a method called second-window ICG (SWIG), is a new technique used intraoperatively to guide tumor resection via increased peritumoral endothelial permeability. The objective of this study is to examine ICGA and SWIG fluorescence in burns requiring excision and grafting, and to correlate SWIG fluorescence to microscopic localization of inflamed and necrotic tissue.ex-vivo to determine the presence of fluorescence in the tissue compared to that remaining within the wound bed. Excised tissue was processed for histologic analysis of cellular architecture, viability, inflammation and necrosis. Macroscopic ICGA and SWIG fluorescence images were compared to the associated microscopic tissue sections to determine the presence of inflammatory infiltrate, localization of non-viable tissue, and co-localization of ICG fluorescence.Deep partial thickness, indeterminate depth or full thickness burns were identified in adult patients scheduled for excision and grafting. 24 hours prior to surgery, baseline bright light and fluorescence images were obtained before the administration of up to 5 mg/kg ICG intravenously. ICGA was performed within 5 minutes of infusion initiation. On the day of surgery, bright light and SWIG fluorescence images were obtained before and after burn excision. The excised tissue was imaged ICGA imaging performed preoperatively demonstrated variable fluorescence throughout the burns without a clear cutoff value to delineate deep partial versus full thickness burns. SWIG imaging revealed a speckled fluorescence pattern prior to burn excision that became diffuse after excision suggesting a potential utility of SWIG to intraoperatively identify excision completion. ICGA and SWIG fluorescence demonstrated an inverse relationship, and SWIG fluorescence was associated with non-viable tissue.ICGA imaging alone was unreliable to delineate the need for surgical intervention. SWIG imaging of burn injuries may represent a valuable tool to guide the extent of excision intraoperatively and reduce unnecessary excision of viable tissue. Further studies are needed to understand SWIG fluorescence at the inflammation-necrosis border and how ICGA fluorescence along with SWIG can synergistically improve detection of healing potential in burn patients."} +{"text": "Biomolecules, titled \u201cOral Regenerative Medicine: Current and Future\u201d, covers the dental field and focuses on craniofacial tissue regenerative therapy. Dental pulp and periodontal tissue-derived cells are well-known as major cell sources in the dental field. Dental pulp stem cells (DPSCs) are promising cell sources for biomineral tooth complexes [2+-ATPase (PMCA) in rat and human odontoblasts mediates dentin mineralization [2+ homeostasis in odontoblasts. They suggested that PMCA not only plays a critical role in physiological dentin formation but also in the pathological reactionary dentin formation induced by multiple external stimuli. It is also used in the application of high-pH dental materials on the dentin surface. Dental and oral tissues maintain homeostasis through potential reparative or regenerative processes. This native biological regulation ensures appropriate oral function and provides systemic health conditions through ideal digestion and intake of nutrition. Even if some tissues break down, general dental treatment or the administration of growth factors can help them to recover. However, a large disruption of oral tissues due to tooth loss, malignant diseases, and severe trauma can cause irreversible tissue loss in the oral cavity. To compensate for this, artificial materials, such as prostheses and dental implants, support the improvement in human quality of life. We need to consider both native biological elements and biomedical products. This Special Issue of omplexes . Pilbaueomplexes . The automplexes . In thisomplexes . Schmidtomplexes . The autlization . This stAmong oral tissues, the periodontium is also permanently exposed to mechanical forces resulting from chewing, mastication, or orthodontic force. Brockhaus reported on the preservation and remodeling processes within the periodontium through periodontal ligament fibroblasts during orthodontic tooth movement. Tooth movement by mechanical stress initially decelerates the periodontal ligament fibroblast cell cycle and proliferation. After adapting to environmental changes, cells can regain periodontium homeostasis, affecting their reorganization . DieterlThis Special Issue suggests the importance of understanding the relationship between both the cell source and effective regeneration. Physiological functional recovery is the most essential problem and the ultimate purpose of regenerative therapy. A deeper understanding of the pathological background and genetic basis and cellular signaling in local-systemic regulation is essential in dental tissue regeneration."} +{"text": "Following ischemic stroke, polymorphonuclear neutrophils (PMNs) are rapidly recruited to the ischemic brain tissue and exacerbate stroke injury by release of reactive oxygen species (ROS), proteases and proinflammatory cytokines. PMNs may aggravate post-ischemic microvascular injury by obstruction of brain capillaries, contributing to reperfusion deficits in the stroke recovery phase. Thus, experimental studies which specifically depleted PMNs by delivery of anti-Ly6G antibodies or inhibited PMN brain entry, e.g., by CXC chemokine receptor 2 (CXCR2) or very late antigen-4 (VLA-4) blockade in the acute stroke phase consistently reduced neurological deficits and infarct volume. Although elevated PMN responses in peripheral blood are similarly predictive for large infarcts and poor stroke outcome in human stroke patients, randomized controlled clinical studies targeting PMN brain infiltration did not improve stroke outcome or even worsened outcome due to serious complications. More recent studies showed that PMNs have decisive roles in post-ischemic angiogenesis and brain remodeling, most likely by promoting extracellular matrix degradation, thereby amplifying recovery processes in the ischemic brain. In this minireview, recent findings regarding the roles of PMNs in ischemic brain injury and post-ischemic brain remodeling are summarized. PMNs are first line immune invaders in the ischemic brain. PMN recruitment after experimental ischemic stroke is highly coordinated in a spatio-temporal way. PMNs accumulate within capillaries and venules of the ischemic brain territory within the first hour after ischemic stroke , followeEvidence in humans supports the idea that PMNs have detrimental consequences on stroke outcome. Hence, PMNs of ischemic stroke patients produce and release significant amounts of reactive oxygen species (ROS) and proteases, such as neutrophil elastase, as shown in peripheral blood within the first 6 hours post-stroke . Under ivia which PMNs in peripheral blood aggravate secondary ischemic brain damage are PMN stalls resulting in microvascular occlusions even under conditions of successful arterial reopening within 6 hours of symptom onset aggravated neurological recovery assessed by the mRS score, increased stroke mortality and increased infection susceptibility . BesidesEx vivo, the treatment of blood clots obtained from ischemic stroke patients with DNAse-1 significantly increased tPA-induced thrombolysis in comparison to tPA alone and Hertie-Stiftung .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Key challenges include poor graft survival, low donor neuron localization to the host retina, and inadequate dendritogenesis and synaptogenesis with afferent amacrine and bipolar cells. In this review, we summarize the current state of experimental RGC transplantation, and we propose a set of standard approaches to quantifying and reporting experimental outcomes in order to guide a collective effort to advance the field toward functional RGC replacement and optic nerve regeneration.As part of the central nervous system, mammalian retinal ganglion cells (RGCs) lack significant regenerative capacity. Glaucoma causes progressive and irreversible vision loss by damaging RGCs and their axons, which compose the optic nerve. To functionally restore vision, lost RGCs must be replaced. Despite tremendous advancements in experimental models of optic neuropathy that have elucidated pathways to induce The retina is embryologically derived from central nervous system (CNS) neuroectodermal progenitors. The mammalian retina, therefore, like the rest of the mammalian CNS, lacks inherent regenerative capacity . RetinalRetinal diseases have been pioneering targets for therapeutic cell transplantation in medicine ,12, withendogenous RGCs following experimental injury [Molecular targets relevant to achieving critical milestones in functional RGC replacement, particularly the achievement of RGC survival and axon regeneration, have been elucidated by studying l injury . For exal injury ,20. Insul injury , overexpl injury , inductil injury , deletiol injury ,25,26, al injury in endogl injury . RGC-extl injury ,29. Morel injury , establil injury .By comparison, in vivo transplantation of exogenous primary RGCs or stem cell derived RGCs remains a field in its infancy. Nonetheless, pioneering transplantation studies have recorded light-evoked electrophysiological responses from donor RGCs and docuRGC transplantation strategies require generating lineage committed progenitors or terminally differentiated neurons in sufficiently large quantities. The source of donor cells for transplantation into humBRN3b-dependent tdTomato and murine Thy1.2 have facilitated purification of RGCs and longitudinal cell tracking in transplantation studies [ESCs are derived from the inner cell mass of embryonic blastocysts , and the studies .Adult human somatic cells, after appropriate induction, can dedifferentiate and resemble ESCs in morphology, and have the capacity for multilineage differentiation and self-renewal . When auA limitation to cellular differentiation in two dimensional culture is a lack of multi-cellular organization, which is overcome by three dimensional cultures of self-organizing organoids . These \u201cTaken together, characterization of robust RGC differentiation from multiple cell lineages and culture conditions have paved the way for stem cell-based replacement strategies as a promising approach to optic nerve regeneration. The tools now exist to study, in earnest, RGC transplantation in vivo. In order to maximize generalization of protocols and experimentation worldwide, standard descriptions of donor cell characteristics are critical when reporting RGC transplantation results. Such studies should explicitly describe the parental stem cell line or source, differentiation culture conditions, the stage of RGC or progenitor at harvest, RGC purification technique and yield, and the expression of a standard set of canonical RGC markers. Ideally, critical results should be replicated with multiple independent lines of donor RGCs. Critically, we do not know the developmental state for donor cells\u2014whether fully mature RGCs, developing RGCs, or lineage-committed progenitors\u2014that will yield the best engraftment results. Whether stem cells or organoids are used as a source of donor RGCs, the isolation process should maximize purity in order to limit aberrant tissue overgrowth or teratoma formation from undifferentiated cell populations. Furthermore, RGCs survive poorly in organoids during prolonged culture , presumaA critical prerequisite to studying interactions between donor RGCs and the host retina is robust survival of transplanted neurons. Unfortunately, this has been a formidable obstacle in most studies to date (see below). One of the difficulties in comparing survival rates across multiple methodologies stems from unstandardized methods of reporting survival, either as an absolute number, a percentage of transplanted cells, or by providing the density of surviving cells. The transplantation route plays a critical role in discerning donor cell survival. Administration to the basal (vitreous) side of the retina via intravitreal injection provides the most direct access to the inner retina, without the need for potentially disruptive transparenchymal migration . MoreoveIn nearly all cases, where reported, intraocular transplantation of RGCs has yielded low rates of neuronal survival, far below what would be required to restore visual function in advanced optic neuropathy . Develop2 [2 [Purified postnatal mouse RGCs transplanted into rat recipients survive at a typical rate of about 1% , althoug2 . However2 [2 pathway is particularly relevant to RGC survival and regeneration following injury . DownregBax subfamily of Bcl-2-related proteins is essential for JNK-dependent apoptosis [Dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) are other key sensors in the RGC injury response . Upon dapoptosis , and itspoptosis . Initiatpoptosis . Deletiopoptosis . In addipoptosis , indicatpoptosis . Based on extensive work identifying critical regulators of injury-related RGC death, there are myriad intracellular pathways that could be targeted pharmacologically or transgenically to promote donor RGC graft survival following transplantation in the eye. Although manipulating neuronal survival pathways may seem like an obvious and feasible method to attenuate undesirable death of transplanted cells, we must also acknowledge the importance of these cellular pathways in driving malignant transformation. For instance, deregulation of PI3K/Akt mTOR signaling contributes to the initiation, development, and acceleration of multiple types of cancer . A majorPromotion of donor RGC survival by modulation of neurotrophic factor delivery may be an alternative to or compliment to directly targeting cell-intrinsic death signaling cascades. Soluble neurotrophins, such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), and glial cell line-derived neurotrophic factor (GDNF), regulate neuron growth and survival . The binBDNF and NGF signal via tyrosine-receptor kinases (Trk) receptors to promote cell survival, or via neurotrophin receptor p75 (p75), which induces neuronal apoptosis. Indeed, the effects of NGF on RGC survival depend on the relative expression of these dueling receptors . SpecifiBDNF is developmentally critical to RGC survival. By binding to the TrkB receptor, BDNF triggers activation of the Ras/MEK/extracellular signal-regulated kinase (ERK) pathway . Under nCNTF belongs to the IL-6 family of cytokines and binds a heterotrimeric membrane receptor complex composed of CNTF receptor-\u03b1, gp130, and the leukemia inhibitory factor receptor (LIF-R) . CNTF prGiven their strong potential for neuroprotection, trophic factors delivered concomitantly with RGC transplantation may substantially improve graft survival. However, clinical translation is limited by inefficient delivery of these agents. Intravitreal protein injection has a short therapeutic duration due to rapid clearance. Slow release formulations are being explored and have yielded promising results . Given tNumerous aspects of the recipient ocular microenvironment into which donor RGCs are transplanted influence their survival, including innate and adaptive immune system reactivity; blood flow, oxygen, and nutrient supply; and reactive gliosis .Autologous cell transplantation is generally well accepted by the recipient, although some genetic manipulations can generate immunological responses . However+ T cells are activated through the binding of MHC class I and T cell receptors, particularly in the presence of non-matching major histocompatibility complex [Whereas the vitreous cavity and the subretinal space are relatively immune privileged when compared to other sites, damage to the blood ocular barrier and local inflammatory cytokine production can be induced by both neurodegenerative disease and the transplantation procedure itself . Intraocen, HLA) ,125,126.en, HLA) ,127.Editing of individual HLA genes in iPSCs to establish \u201cuniversal donor cells\u201d has been proposed for evasion of both T cell activity caused by HLA mismatching and natural killer (NK) cell activity. Genetic manipulation, such as the transgenic expression of HLA-E or HLA-G on porcine endothelial cells inhibits NK cell cytotoxicity and adhesion . GeneticThe transplantation technique itself is critical to consider when evaluating factors that might affect transplanted RGC survival. To date, the majority of studies have injected cells directly into the vitreous cavity, where the supply of oxygen and nutrients is subject to passive diffusion from the uveal vasculature. During development, the lens and the developing inner retina are first vascularized by the hyaloid canal, composed of the hyaloid artery, vasa hyaloidea propria, and tunica vasculosa lenti, which lie within the vitreous cavity. However, at birth in humans and postnatally in mice, these vessels regress as retinal vessels are prioritized, leaving the vitreous cavity unperfused . In ordeIt is critical to recognize that RGC transplantation will only be necessary because a primary neurodegenerative process caused extensive death of endogenous RGCs. Glaucoma, optic neuritis, and ischemic optic neuropathy are the most common neurodegenerative diseases characterized by RGC loss, but each one has unique pathophysiologies ,133. OncInnate neuroinflammatory processes influence donor RGC survival following injury and are principally mediated by retinal macroglia (astrocytes and M\u00fcller glia) and microglia. Under normal conditions, astrocytes play a key role in maintaining homeostasis in the CNS, controlling angiogenesis, contributing to the extracellular matrix (ECM), and maintaining the blood retinal barrier. Upon disruption or injury, reactive glia undergo complex alterations in gene expression, morphology, and function. Reactive astrocytes are promoted by JAK/STAT signaling, which leads to the release of a variety of soluble mediators that activate inflammation within the CNS ,136. His2 (PGE2) synthesis, which contributes to neuronal death [2+ concentrations and induces CREB-mediated transcription of apoptotic proteins, resulting in cell death [Some of the effectors of neuroinflammatory toxicity have been elucidated. In response to CNS injury or neurodegenerative disease, multiple cell types produce cyclooxygenase-2 (COX-2), leading to prostaglandin Eal death . Anti-inal death . Glial aal death ,145. Nonll death . Thus, nDonor cells arriving at the retina from the vitreous cavity encounter the retinal basement membrane (the ILM), local astrocytic and M\u00fcller glial reactivity, and local inflammatory cells that impede spontaneous cell migration into the retina ,147. EndThe ability of transplanted RGCs to migrate spontaneously into the recipient retina is inconsistent across published studies, which may be related to differences in graft and host species, or to the methodologies of determining graft localization. Our previous ex vivo work has identified that the ILM is a major barrier to both human RGC somal and neurite engraftment; we have found that donor human RGC migration into the host mouse retinal parenchyma rarely occurs spontaneously . DisruptAvailable evidence supporting donor integration is typically derived from en face confocal micrographs illustrating close proximity between donor cells and host RGCs, or from histological sections, again relying on proximity to the endogenous RGCs. However, such demonstration typically lacks the spatial resolution to distinguish the anatomical layers at the vitreoretinal interface. Because the RGCL is in close proximity to the ILM, donor RGCs that are external to the retinal parenchyma (within the posterior vitreous cavity) but juxtaposed to the retina can easily be mistaken for having \u201cintegrated\u201d into the retina, both in retinal flat mounts and in histological sections . TherefoA combination of analyses using histological sections and en face evaluation of retinal flatmounts will provide a compromise between complete topographic imaging and depth resolution;Flatmount microscopy should be performed with high resolution confocal or multiphoton microscopy using a high magnification objective in order to create shallow depth of field;High depth resolution is attained by minimizing slice interval distance and pinhole aperture diameter (if single photon microscopy is employed);Z-stack reconstructions should be assessed using an orthogonal slice viewer to compare the localization of the donor cell to those of nearby endogenous cells;A secondary marker that outlines the boundary of the retinal parenchyma should be included when possible, such as immunofluorescent laminin delineation of the ILM .Although retinal cross sections can clearly demonstrate the relationship between transplanted RGCs and endogenous RGCL, applying this method to completely survey entire eyes is unfeasible. To help meet this challenge, we propose the following considerations for microscopic inspection of donor RGC localization within the host retina : A combiScrutinizing donor RGC integration using this robust approach sets a benchmark for accurate assessment of donor cell localization. The reported outcomes from the localization analyses should include the absolute number and percentage of total surviving RGCs in each of the retinal layers as well as outside of the retinal parenchyma. Somal localization is important because donor RGCs with cell bodies remaining outside of the host retina can rarely exhibit parenchymal neurite ingrowth, which may be distinguished from fully integrated donor cells.In our experience, we observe negligible spontaneous donor human RGC integration into the host RGCL when the ILM remains intact, whereas somal integration is greatly enhanced by enzymatic disruption of ILM , suggestWe have observed a propensity for transplanted RGCs to cluster when cultured on organotypic retinal explants with intact ILM . ProteolConsidering this challenge, studies of RGC transplantation should include quantitative characterizations of cellular dispersion and retinal coverage. We have employed spatial analytic tools to describe the topography of donor RGCs cultured on the retinal surface ex vivo , and theAfter overcoming barriers to localization of transplanted RGCs within the recipient retina, dendrite targeting of the IPL necessarily precedes synaptogenesis to achieve true functional integration into the visual neurocircuitry. Donor RGCs are unlikely to sprout neurites without specific external cues . One sucThe proper targeting of donor cell dendrites to the mature host IPL is an understudied aspect of RGC transplantation. Developmental studies reveal that RGC dendritic lamination in the IPL is guided by signaling through cell surface receptors, and dendrite localization is reinforced and stabilized by neuronal activity . RGCs utRetinal flatmounts are superior to histological section for characterizing complex dendritic arbors of RGCs within the IPL;Additional secondary tissue samples for histological sectioning can, however, be useful for correlation of sublaminar neurite localization with multiple immunohistochemical markers that define RGC subtype;It is of interest to characterize the topographical spacing among integrated RGCs. Reported metrics may include nearest neighbor and density recovery profiles of integrated donor RGCs;When possible, metrics describing dendritic architecture should be described for individual cells; if individual arbors are not resolvable from overlapping RGCs, then metrics should be normalized to the number of donor RGCs contained within a region of interest;Dendritic architecture and localization within the recipient retina should be assessed using high resolution microscopy; it may be necessary to tile images in order to capture entire dendritic arbors at high resolution;Integrated dendritic arbors can be convoluted and should be resolved and traced using 3D rendering software ;Useful metrics to describe dendritic arbors include total neurite length, number of neurite segments, neurite density, dendritic Sholl analysis , and neuIn order to robustly characterize the dendritic outgrowth of donor RGCs, we raise the following considerations:developing RGCs express both MAP2 and Tau until definitive specification of an axon [If neurite integration is to be evaluated, detailed characterization of neurite identity will be needed. In mature RGCs, dendrites and axons are defined by the expression of MAP2 and Tau, respectively . Neurite an axon . Therefo an axon . This fiThere are over 40 subtypes of RGCs, each having dendritic arbors precisely restricted to specific lamina within the IPL . Such heViral transsynaptic tracers make it possible to decipher complex circuit connectivity. Individual viruses have defined directionalities of travel and benefit from intracellular replication that propagates reporter signal generation . The mosThere are numerous paradigms available to restrict uncontrolled propagation of virus across multiple synapses, to specify neuronal subtypes for primary infection (starter cells), and to not only label but also genetically modify synaptically coupled partner neurons through payload packaging. Typically, viruses used for synaptic circuit tracing are modified and incapable of infectivity and/or replication without helper genes that are supplied to starter neurons separately. Through the use of Cre-dependent helper gene expression in conjunction with Cre reporter lines, one could, for instance, restrict starter cells to retinal neuronal subtypes of interest and probe donor RGCs for evidence of viral transsynaptic spread following transplantation . A compaLarge scale visualization of neuronal activity can be achieved by imaging genetically encoded fluorescent indicator proteins. Various optical reporters have been devised in response to vesicle release, membrane voltage change , and calElectrophysiology and synaptic histology remain useful for characterizing specific examples of functional synapses. Whole cell patch clamping of donor RGCs facilitates recording of light-evoked electrophysiological responses in retinal flatmount preparations. So long as controls are included to exclude the possibility of recording from intrinsically photosensitive RGCs, electrophysiologic responsivity to light implies stimulus conduction from bipolar cells downstream of photoreceptor transduction. Characterization of specific responses to light permits classification of donor RGCs based on electrophysiological properties.Synapses in retinal neurons are unique in that they require rapid and sustained release of neurotransmitters in order to achieve graded synaptic output in response to a dynamic range of light signal intensity. Consequently, retinal synapses require a several fold higher number of vesicles than conventional synapses that transmit action potentials elsewhere . SynaptiThese techniques may prove useful in future transplantation studies examining factors that regulate synaptogenesis between donor RGCs and the mature recipient retinal neurons. Synthetic synaptic organizers have been developed that are capable of inducing functional excitatory synapses within the CNS . Their fOne major consideration that is required for all transplantation studies is the possibility of intercellular material exchange ,189,190,Using human stem cells in RGC transplantation requires balancing safety and efficacy against potential risks and ethical considerations. Ethics concerns surrounding ESC use has largely been avoided with iPSCs as an alternative stem cell source. However, colonies expanded from a single iPSC display more heterogenous gene expression compared to ESCs , elevatiRecent scientific advances have enabled RGC production from a wealth of human stem cell sources for both disease modeling and RGC replacement within the visual pathway. Developments in stem cell biology and regenerative neuroscience have brought the field of optic nerve regeneration from science fiction to scientific possibility. Nonetheless, tremendous challenges for translating this potential to actual vision restoration for human patients lie ahead. Improving transplant survival remains the primary short-term goal, as it sets the foundation for subsequent study of functional integration. Advanced differentiation protocols may provide reliable RGC subtype specification and expand the donor source repertoire. As imaging techniques continue to improve, we anticipate significant progress in the ability to assess migration, localization, synaptogenesis, and axonogenesis in vivo.It is not well established how closely transplanted human stem cell derived RGCs resemble developing or mature neurons. This distinction may be important because the molecular machinery governing growth and regeneration potentially involves separate sets of regulatory mechanisms . For exa"} +{"text": "This study explored the role of tested contextual factors in high Medicaid (under resourced) nursing homes performance. Four nursing homes in geographically diverse states were purposefully selected for site visits based on high and low performance indicators. Eight nursing home administrators and directors of nursing, and twenty-one nursing staff and providers of support services were interviewed. Data were analyzed using an inductive thematic approach with NVivo 12 Plus. Within and across case analysis was used to compare participants\u2019 perspectives across nursing homes and across administrators and staff. Several themes provide insight into varied influences of contextual factors on these nursing homes\u2019 performance: focus on quality care, team-based approach, community support and engagement, and staffing retention. Providing quality care to residents was strategic priority in all facilities, which was enhanced by an adopted team-based leadership approach, open-door policy and home-like atmosphere. Community reputation and availability of local training opportunities for CNAs affected nursing staffing which some facilities addressed using creative retention strategies. These research findings will facilitate interventions, such as leadership training and organizational development activities, aimed at improving the performance of low performing facilities in terms of lower costs and better quality."} +{"text": "The purpose of this study was to examine whether frailty status moderates the association between social participation and attitude towards using gerontechnology. The sample was Korean older adults without cognitive impairment who completed an online survey. The attitude towards using gerontechnology was measured with two questions from the Senior Technology Acceptance Model , asking whether using technology is a good idea and whether they like the idea of using technology. Social participation was assessed by asking whether the participants engage in social or community activities on a scale of 1\u201310. Frailty status was determined based on the Korean Groningen Frailty Indicator (K-GFI). Covariates were age, gender, marital status, employment status, education level, and household income. Results from regression analyses showed significant interaction between frailty status and social participation on attitude towards using gerontechnology. Specifically, social participation was associated with positive attitude towards using gerontechnology among non-frail older adults. This association was not significant among frail older adults. Our findings suggest that the relationship between social participation and attitude towards using gerontechnology might differ by physical health status. Among older adults who are physically healthy and actively participate in social activities, the attitude towards using gerontechnology might be more positive due to greater exposure to new technology-related information. Future studies need to address alternative ways to enhance technology-friendliness among older adults with poor physical health."} +{"text": "Caenorhabditis elegans), fruit flies (Drosophila melanogaster), and zebrafish (Danio rerio): prominent model systems in which anatomical and genetic analyses have defined fundamental principles by which epidermal cells govern SSN development.Somatosensory neurons (SSNs) densely innervate our largest organ, the skin, and shape our experience of the world, mediating responses to sensory stimuli including touch, pressure, and temperature. Historically, epidermal contributions to somatosensation, including roles in shaping innervation patterns and responses to sensory stimuli, have been understudied. However, recent work demonstrates that epidermal signals dictate patterns of SSN skin innervation through a variety of mechanisms including targeting afferents to the epidermis, providing instructive cues for branching morphogenesis, growth control and structural stability of neurites, and facilitating neurite-neurite interactions. Here, we focus onstudies conducted in worms ( Why focus on these model systems? Our understanding of patterns and mechanisms of Somatosensory neuron (SSN) innervation in human skin is limited by several challenges. First, human skin exhibits remarkable diversity in its structure across anatomical locations, varying in thickness, permeability, and cellular composition. Single-cell RNA-seq (scRNA-seq) studies demonstrate the presence of multiple distinct subpopulations of fibroblasts, keratinocytes, and other dermal cells at various locations in mammalian skin provide solutions to many of these problems. Chief among them, these organisms offer transparent skin and ex utero development that renders SSNs optically accessible, providing a direct window into SSN development in vivo. These systems also offer sophisticated genetic toolkits that facilitate manipulation of gene function with single-cell resolution, reagents to simultaneously and independently visualize skin cells and SSNs, and a repertoire of epidermal cells and SSNs whose developmental origins and peripheral morphologies are defined.The model systems discussed here and motor neurons that traverse the body and receive instructive epidermal cues. The touch receptor neurons (TRNs), sensory neurons PVD and FLP, and motor neurons provide instructive examples of different modes of epidermal signaling that contribute to skin innervation patterns. First, the bipolar mechanosensory TRNs ALM and PLM extend distinctive anterior and posterior processes, and their polarized outgrowth is controlled by epidermal cues. Epidermal cells ensheath axons of these neurons, providing insight into the developmental origin and function of this specialized epidermis-SSN interaction and is surrounded on the basal surface by a basement membrane has served as a powerful experimental system for analysis of SSN dendrite morphogenesis, cell spacing, and dendrite-epidermis interactions that shape innervation patterns. Unlike vertebrate dorsal root ganglion (DRG) neurons, cell bodies of Drosophila SSNs are located in the periphery, where sensory organ precursors delaminate from the ectoderm early during embryogenesis and give rise to neurons in a highly stereotyped spatiotemporal birth order organs or chordotonal (cho) organs; as discussed below, studies of cho neuron development have revealed roles for epidermal cues in guiding SSN migration and orienting dendrite outgrowth on the basis of larval dendrite arborization patterns , and muscle.Each larval segment contains >10 different epidermal cell types, transcriptionally specified on the basis of their position along the anterior-posterior (AP) axis within each parasegment have distinct experimental advantages for the analysis of SSN/skin interactions. Zebrafish are amenable to forward and reverse genetic screens; reverse genetic manipulation is particularly attractive since the large, externally fertilized eggs are easy to inject with antisense morpholino oligonucleotides or CRISPR-Cas9 ribonucleoprotein complexes. The small size of the larvae and automated behavioral assays additionally make high-throughput chemical screens feasible periderm layer is derived from the enveloping layer organs contain bipolar mechanosensory neurons that extend a single unbranched dendrite, and a subset of these neurons (v\u2019ch1 and lch5) migrate along the epidermis to their final position, rotating during migration to orient dendrite outgrowth or frazzled (fra), which encodes an attractive DCC family Netrin receptor, prevent v\u2019ch1 migration and randomize the direction of dendrite outgrowth in mouse skin, in which a local secreted factor orients neurite positioning and Drl2, which signal through the Rho guanine nucleotide exchange factor (GEF) Trio and Rho1 to locally destabilize the actin cytoskeleton and prevent dendrite extension beyond the Wnt5 source and Wnt (Wingless) ligands illustrate two additional principles of peripheral guidance by secreted cues. First, extrinsic guidance signals can work in concert with intrinsic mechanisms for neurite spacing to fine-tune peripheral arborization patterns. Self-avoidance signaling mediated by the Drosophila homophilic adhesion molecule Dscam1 promotes sister dendrite spacing in da neurons controls the density of body wall innervation . Third, how are short- and long-range Ret signaling coordinated? Mav exerts short and long-range effects on C4da dendrite growth, yet Mav exhibits limited diffusion, so internalized Mav likely regulates growth throughout the arbor. In vertebrates, internalized Ret-GDNF complexes mediate long\u2013range retrograde signaling from the periphery together with GFR\u03b11\u20133 as well as increased epidermis-ECM adhesion that is thought to reduce the permissivity of the ECM to dendrite growth , NLP-29, triggers this degeneration , which promotes ECM adhesion , whereas non-peptidergic nociceptors project through the SS and innervate the stratum granulosum likewise regulates dendrite positioning of Many types of cutaneous receptors form specialized terminal structures with epidermal components that contribute to somatosensation -enriched microdomains on epidermal membranes adjacent to sensory neurites to the cortex of the epidermal membrane surrounding the invaginating neurite and numerous septate junction proteins family member, is required for sheath formation, and EPB41 proteins function as interaction hubs that organize specialized plasma membrane domains , controls this developmental restriction of C4da plasticity and engulf dendrite debris generated via laser-induced damage . What are the cells that mediate engulfment and digestion of neurite debris in the skin? Surprisingly, neither macrophage-like hemocytes in Drosophila, many studies have focused on Draper (drpr), an engulfment receptor, as an important component in both epidermal and non-epidermal phagocytic clearance of axon debris downstream of engulfment receptors often rely on the same set of phagocytic machinery to recognize and engulf synapses, cell corpses, or debris . In DrosDrosophila requires the CD36 family member Croquemort and in human skin samples from patients with atopic dermatitis (AD), epidermal fibers often penetrate through the tight junction barrier and avoid pruning by keratinocytes. These observations raise the interesting possibility that aspects of pathological itch in AD may be due to aberrant SSN pruning by epidermal cells. It is possible that similar mechanisms may be at play in other skin diseases, lending to their pathologies, but this requires more careful investigation.Questions remain about epidermal involvement in neurite pruning and debris removal in adult animals, as well as whether these features are conserved in mammalian systems. Intriguingly, one recent study in mice found that epidermal SSN fibers often reside directly beneath keratinocyte tight junctions that form below the outer, cornified layer and time? C. elegans presents an appealing system to address these questions, given the morphological stereotypy and limited cellular diversity. Finally, how do different SSNs achieve type-specific innervation patterns in response to similar extracellular cues? Neuron type-specific expression of receptors for these cues has been a focus of recent study, but additional mechanisms likely contribute including cell- and context-dependent signal transduction, as well as spatial tuning of receptivity to signals within SSN arbors.Despite the recent progress, substantial questions remain to be answered about epidermal control of SSN innervation. One pressing question is the extent to which epidermal diversity contributes to innervation patterns. A necessary prerequisite to answering this question is a deeper sampling of epidermal cell types. Even within model systems, this question is understudied, hence leveraging positional information embedding in the CY, EP, JR, and JP wrote this manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Me & My Wishes is a novel systematic approach for long-term care residents living with dementia to record videos about their care preferences that can be shared with staff and families in care plan meetings. To understand how the videos were utilized in Goals of Care (GOC) conversations, we coded and analyzed transcripts of recorded care plan meetings at the time of sharing the video using a priori codes derived from GOC conversation elements. Coding discrepancies were resolved in team meetings; finalized codes were summarized to derive themes. Thirty-four care plan meeting conversations between residents (n=34), family members (n=29) and staff (n=35) were analyzed. Residents appreciated sharing personal histories and preferences via video, while staff members appreciated deeper understanding of residents\u2019 care preferences. Two themes described care plan meeting conversations: Everyday Care - a checklist-style assessment of the resident\u2019s daily care , activities engaged in and satisfaction with care; and Clarifying Care Goals - checking the resident\u2019s treatment preference , explaining hospice, or confirming the resident\u2019s contact person. Several elements of GOC were not discussed and conversations lacked depth and comfort evidenced by apologetic language and abrupt transitions of topics rather than exploring alignment of goals with care preferences. Me & My Wishes videos are a mechanism for residents to voice preferences. Standardized guidance, which is lacking in long-term care, is needed to help care teams engage in meaningful conversations to ensure alignment of goals and treatment preferences."} +{"text": "Whether increased formal long-term care (LTC) reduces informal LTC use by serving as a substitute or has a complementary role that boosts both informal and formal LTC use has been an important issue for evaluating LTC policy effectiveness. We described trends in in-home LTC use among older adults and LTC availability in relation to changes in LTC policy in Japan. In addition, we examined whether these trends differ by living arrangements, gender, income, and disability levels. We used five waves of repeated cross-sectional data starting in 1999 to 2017. The use of both informal and formal LTC types combined increased until 2006 and then gradually decreased while remaining higher than in 1999. Although implementing the LTC program may have temporarily contributed to the complementary use of both LTC types, eligibility limitations brought about by LTC reform potentially reduced the effects of formal LTC\u2019s complementary role."} +{"text": "Microbial communities are constantly challenged with environmental stressors, such as antimicrobials, pollutants, and global warming. How do they respond to these changes? Answering this question is crucial given that microbial communities perform essential functions for life on Earth. Our research aims to understand and predict communities\u2019 responses to change by addressing the following questions. (i) How do eco-evolutionary feedbacks influence microbial community dynamics? (ii) How do multiple interacting species in a microbial community alter evolutionary processes? (iii) To what extent do microbial communities respond to change by ecological versus evolutionary processes? To answer these questions, we use microbial communities of reduced complexity coupled with experimental evolution, genome sequencing, and mathematical modeling. The overall expectation from this integrative research approach is to generate general concepts that extend beyond specific bacterial species and provide fundamental insights into the consequences of evolution on the functioning of whole microbial communities. Microbial communities perform pivotal functions, from the cycling of elements through Earth\u2019s ecosystems to the digestion of complex foods that shape human health and disease. Many of these functions emerge from the interaction of multiple species working as a collective . For exaAchieving such understanding is extraordinarily difficult given that microbial communities are incredibly diverse in terms of numbers of different microbes, genes, and interactions. Progress on this problem requires both top-down studies that deal with the complexity of natural communities and bottom-up research that uses simpler experimental setups . My reseRapid evolution can impact short-term ecological dynamics, and these altered ecological dynamics can feedback to affect subsequent evolutionary change . Eco-evo4\u2013Acinetobacter johnsonii and Pseudomonas putida, two bacterial species that were originally isolated from a polluted aquifer in Denmark . Thus, bA. johnsonii and P. putida in natural communities and different genotypes (evolutionary responses). What is the relative contribution of ecological versus evolutionary processes to mediating responses to change? We previously discussed how adaptive evolution mediated by settings . What resettings , 20. Filsettings . This exOne important ecosystem function is plant litter decomposition, which is performed by microbial communities . I have recently joined a collaboration, The Loma Ridge Climate Change Experiment, aiming to understand how the plant litter microbiome responds to drought in Southern California , 23. We Using an integrative research approach based on evolution experiments of simple microbial consortia, whole-genome sequencing, and mathematical modeling, we have gained general insights into the mechanisms by which microbial communities respond to environmental change. We are currently working to understand how these responses affect community-level functions important for ecosystem functioning. The next exciting research directions will be (i) to study whether natural selection can act on community-level properties and (ii)"} +{"text": "ABSTRACT IMPACT: This study is designed to address a critical gap in our understanding of how aging patients and caregivers recognize and respond to clinically important changes in heart failure symptoms during vulnerable transitions. OBJECTIVES/GOALS: Research on family involvement in heart failure (HF) symptom response is limited. Our objective is to examine HF symptom monitoring processes in couples after HF hospitalization, and quantify how coupled symptom assessments predict symptom response, patient clinical events, care strain, and dyad health during the high-risk post-discharge period. METHODS/STUDY POPULATION: This is an ongoing T2 translational study that employs an intensive longitudinal design. Adults aged \u226565 years hospitalized for HF and their caregiving spouse/partner are enrolled. The target n is 48 dyads. Over 5 weeks of follow-up, dyads complete daily diaries assessing patient HF symptoms. Clinical biomarkers of HF severity are also collected. Primary study endpoints are dyads\u2019 HF symptom response behaviors and caregiver strain; secondary endpoints are dyads\u2019 health status and patient clinical events. Dyadic dynamics of symptom assessment will first be characterized using dyadic autoregressive time series models. Subsequently, we will extract cross-partner effect parameters from the time series models and test whether dyadic effects predict the trajectories of each of our endpoints. RESULTS/ANTICIPATED RESULTS: This study is currently underway. In line with our study hypotheses, we anticipate that couples who assess patient symptoms similarly (dyadic agreement), and whose symptom assessments accurately reflect clinical severity, will be more likely to respond to symptoms appropriately with lower stress to the caregiving partner, and have better trajectories of health . Characterizing dyadic symptom dynamics will provide important insight into the day-to-day process of symptom recognition in couples. Further, quantifying dyadic symptom dynamics in relation to our endpoints will provide information on the clinical value of dyadic symptom agreement, and whether it might be a target for future interventions to support better symptom response and health outcomes for both dyad members. DISCUSSION/SIGNIFICANCE OF FINDINGS: This project innovates on existing paradigms by applying family-level theory and techniques to better understand and support interventions for couples during post-discharge HF transitions - a vulnerable period for older adults that has traditionally been studied almost exclusively at the patient-level, with marginal success."} +{"text": "A 33-year-old male presented to the emergency department following a motor vehicle collision with complaints of right eye pain after hitting his head on the steering wheel. Point-of-care ultrasound (POCUS) revealed retinal detachment and an anterior lens dislocation.Lens dislocations following blunt head trauma can often be diagnosed using POCUS. Anterior ocular lens dislocation is a rare but vision-threatening result of head trauma. This case highlights how POCUS can facilitate early detection of ocular pathology, such as lens dislocation, and improves patient outcomes. A 33-year-old man with a history of blindness in his right eye from a congenital cataract presented to the emergency department with blunt head trauma sustained during a motor vehicle collision. He complained of right eye pain and foreign body sensation. On examination, a round white object was visualized within the anterior chamber; his head was otherwise atraumatic. The patient stated that the white spot had been present prior to the accident but had now changed in size and appearance, noting that the spot had enlarged following his injury.Fluorescein staining showed no abnormalities, and intraocular pressures were normal . Light perception was not present. Slit lamp examination demonstrated a round, white-speckled object in the dependent portion of the anterior chamber. Bedside ocular ultrasonography revealed a retinal detachment and an anterior dislocation of a cataract lens through the iris \u20133. OphthCrystalline lens dislocation, or ectopia lentis, occurs primarily after blunt head trauma.5Patients can present with eye pain and visual changes ranging from light distortion to loss of vision.What do we already know about this clinical entity?Anterior ocular lens dislocation is a potential result of blunt head trauma. If unrecognized, it can block the anterior chamber causing elevated intraocular pressures.What is the major impact of the images?The sonographic appearance of anterior lens dislocation has not been well described in emergency medicine literature. These are some of the first reported images.How might this improve emergency medicine practice?Because anterior lens dislocation can result in vision loss, accurate diagnosis is important. Point-of-care ultrasound can be used to diagnose lens dislocations.Ultrasonography can aid in the diagnosis of all types of lens dislocations and assess for additional ophthalmologic pathology, including retinal detachment and vitreous hemorrhage."} +{"text": "The Weathering Hypothesis states BIPOC face more stressors, by which over a lifetime they are subjected to the negative consequences of stress . Using ecological momentary assessments, we examined whether subtle discrimination moderated the within-person stressor slope on positive and negative affect. We predicted emotional wellbeing would be worse at stressor moments, and those with greater discrimination experience would be more impacted by stressors. Participants were 334 diverse adults from Bronx, New York. Positive affect decreased and negative affect increased significantly at stressor moments (p<.0001). Unexpectedly, subtle discrimination was not a significant moderator for the within-person stressor slope on positive affect and negative affect. Unlike the predictions of the Weathering Hypothesis, these results show that prior discrimination experiences may not exacerbate responses to stressors and entail additional risk in daily life."} +{"text": "Pain is generally concomitant with an inflammatory reaction at the site where the nociceptive fibers are activated. Rodent studies suggest that a sterile meningeal inflammatory signaling cascade may play a role in migraine headache as well. Experimental studies also suggest that a parenchymal inflammatory signaling cascade may report the non-homeostatic conditions in brain to the meninges to induce headache. However, how these signaling mechanisms function in patients is unclear and debated. Our aim is to discuss the role of inflammatory signaling in migraine pathophysiology in light of recent developments.Rodent studies suggest that a sterile meningeal inflammatory reaction can be initiated by release of peptides from active trigeminocervical C-fibers and stimulation of resident macrophages and dendritic/mast cells. This inflammatory reaction might be needed for sustained stimulation and sensitization of meningeal nociceptors after initial activation along with ganglionic and central mechanisms. Most migraines likely have cerebral origin as suggested by prodromal neurologic symptoms. Based on rodent studies, a parenchymal inflammatory signaling cascade has been proposed as a potential mechanism linking cortical spreading depolarization (CSD) to meningeal nociception. A recent PET/MRI study using a sensitive inflammation marker showed the presence of meningeal inflammatory activity in migraine with aura patients over the occipital cortex generating the visual aura. These studies also suggest the presence of a parenchymal inflammatory activity, supporting the experimental findings. In rodents, parenchymal inflammatory signaling has also been shown to be activated by migraine triggers such as sleep deprivation without requiring a CSD because of the resultant transcriptional changes, predisposing to inadequate synaptic energy supply during intense excitatory transmission. Thus, it may be hypothesized that neuronal stress created by either CSD or synaptic activity-energy mismatch could both initiate a parenchymal inflammatory signaling cascade, propagating to the meninges, where it is converted to a lasting headache with or without aura.Experimental studies in animals and emerging imaging findings from patients warrant further research to gain deeper insight to the complex role of inflammatory signaling in headache generation in migraine. Pain is generally concomitant with an inflammatory reaction of varying intensity at the site where the nociceptive fibers are activated. Migraine is probably no exception; there is ample experimental evidence, mostly from rodents, suggesting that the nociceptive trigeminocervical afferents mediating the headache can be activated by a sterile meningeal inflammatory process . This prProlonged activation and sensitization of primary and central nociceptors within the trigeminocervical complex are thought to underlie the throbbing headache and allodynia during migraine. Rodent experiments suggest that a sterile meningeal inflammation initiated by release of peptides from trigeminocervical C-fibers and activation of resident inflammatory cells could contribute to sustained activation and sensitization of meningeal nociceptors \u201317. SuppMeningeal nociceptive fibers can release a number of vasoactive peptides including calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), substance P and neurokinin-A upon prolonged activation , 21. By 2 PBR28 PET may also provide insight into the relationship between inflammatory signaling and headache in secondary headache disorders. As in migraine, parenchymal inflammation can also play a role in post-seizure headache, as suggested by studies showing activation of the neuroinflammatory cascade in seizure models , 180. SiIn conclusion, experimental studies in animals and emerging imaging findings from patients warrant further research to gain deeper insight into the complex role of inflammatory signaling in headache generation. Research over the past 50\u2009years have revolutionized our understanding of migraine, however, many unanswered questions and controversies remain. We need cutting-edge tools to directly and comprehensively study the complex nociceptive mechanisms in experimental animals and also high-resolution advanced imaging technologies to assess the significance of basic findings in the clinic. Admittedly, current experimental and clinical methods have shortcomings to provide unequivocal evidence for competing hypotheses."} +{"text": "Panel A) while brain MRI showed no obvious abnormalities in the basal ganglia region. Contrast-enhanced computed tomography showed renal and splenic infarction (Panel B). Moreover, a transoesophageal echocardiogram showed a mobile mass attached to the aortic valve moving back and forth between the ascending aorta and the left ventricular outflow tract . Based on these findings, we concluded that ischaemic stroke due to cardiac mass was the underlying cause of the hemichorea in this patient. During the hospitalization, the patient had an exacerbation of involuntary movements. Repeat echocardiography revealed the reduction in the size of the mass and brain MRI showed acute multiple cerebral infarctions. Therefore, we decided to surgically remove the residual mass to prevent further embolic events. Histopathological examinations with haematoxylin\u2013eosin staining revealed papillary fibroelastoma (Panel D), a rare primary cardiac tumour, with organized thrombus (Panel E). After the surgery, we started anticoagulation with warfarin for the prevention of thrombotic event. His hemichorea disappeared 6 months after the onset of symptoms.A 74-year-old man presented to our hospital with acute onset of right hemichorea. He had no medical history of hereditary disease, inflammatory, or endocrine disorders that could be associated with involuntary movement. Although the patient had no clinical findings suggestive of infective endocarditis, it was not possible to accurately differentiate between tumour, thrombus, and sub-clinical endocarditis. Brain diffusion-weighted magnetic resonance imaging (MRI) revealed multiple cerebellar infarctions Brain magnetic resonance imaging showing cerebral infarction. (Panel B) Contrast-enhanced computed tomography showing renal and splenic infarction. (Panel C) Echocardiogram showing a mobile mass attached to the aortic valve. (Panels D and E) haematoxylin\u2013eosin staining showing papillary fibroelastoma (Panel D) and organized thrombus (Panel E).(Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance."} +{"text": "Mycobacterium tuberculosis. It may show wide variability of clinical symptoms and imaging appearance, ranging from asymptomatic with a normal radiographic examination to severe joint pain along with joint destruction, osteomyelitis, and abscess formation. This article presents radiographic and MR imaging appearance from a case of tuberculous septic arthritis with large abscess formation mimicking soft tissue tumor.Tuberculous septic arthritis is an infection that occurs inside the joint or synovial fluid and joint tissues caused by We reported a 32-year-old female with a slowly enlarging lump on her right proximal thigh within the last 4 months along with slowly progressing joint pain. Both radiographic and MR images showed destruction of the femoral head and acetabular roof, with a formation of large rim-enhanced abscess that extending superficially and distally until mid-thigh. The patient underwent open drainage surgery and excisional biopsy. Histopathological examination showed chronic granulomatous inflammation caused by tuberculous infection.MR imaging combined with radiographic and clinical information played a very important role in the diagnosis of tuberculous septic arthritis with abscess, and to differentiate it from soft tissue neoplasms. Tuberculosis; Septic arthritis; Infectious arthritis; Abscess In Indo2We reported a 32-year-old female patient who came to the hospital after being referred from another hospital to have further treatment for a soft tissue tumor of her right thigh. She complained of a slowly enlarging lump on her right proximal thigh in the last 4 months, with intermittent sub febrile temperature and mild but slowly progressing pain. She was unable to walk unsupported. Physical examination showed a large fusiform soft tissue mass in the right thigh with a diameter of 84 cm, limited range of motion, moderately firm in palpation, and tenderness of the right hip . In the 2.1An AP radiograph of the right femur was obtained, showed a large lobulated soft tissue mass on the lateral side of the proximal femoral region and was assessed as a soft tissue tumor . HoweverLaboratory test showed microcytic hypochromic anemia, increased white blood cells (WBC) count, , increased c-reactive protein (CRP) , increased erythrocyte sedimentation rate (ESR) and increased lactate dehydrogenase (LDH) . Other laboratory findings were unremarkable.2.2The large lobulated cystic mass may be consistent with a large abscess formation, and its connection with the abnormality of the right hip may support the diagnosis of chronic infection. Other potential diagnoses related to fluid-filled mass in musculoskeletal lesions were true cystic lesions (such as seroma) and cystic-appearing solid neoplasm (myxofibrosarcoma and myxoid liposarcoma that contain high mucin component).2.3The patient underwent open drainage surgery and excisional biopsy and the specimens were sent to the Pathology Department.2.4The histopathology examination showed chronic granulomatous inflammation caused by tuberculous infection . The pat3Joint destruction with adjacent tumor-like mass has several differential diagnoses, including tuberculous septic arthritis, malignant soft tissue tumor, and pyogenic septic arthritis. Their clinical appearance may look similar, especially with the formation of a large painful mass. It becomes important to differentiate infection from the formation of tumor-like abscess from malignant soft tissue tumor, as they have completely different therapy. Malignant soft tissue tumors should be evaluated with core biopsy so that the clinicians can give appropriate chemotherapy, whereas infection would need immediate abscess drainage, antibiotics and debridement procedures. Delayed management may cause further destruction of the joint and results in irreversible disability, and worsened prognosis.The potential pitfall in the radiographic interpretation, in this case, is the large size of the soft tissue mass, which may divert the reader's attention from the hip joint abnormality. Another potential misinterpretation is whether these two findings are two separate entities or whether they are associated. Without MR imaging, this can be quite challenging since the extent of the mass is quite huge compared to the degree of hip joint destruction.Tuberculous septic arthritis is a chronic disease with long progressive clinical and radiological changes. Saraf SK et al has intrFluid-filled mass in the musculoskeletal system may have several differential diagnoses, including true cystic lesions (abscess and seroma) and cystic-appearing solid neoplasm (myxofibrosarcoma and myxoid liposarcoma that contain high mucin component) . Seroma Both cystic appearing solid neoplasm and tuberculous septic arthritis may show the same painful mass-forming lesion, with no apparent local infection signs such as redness or warmth on the lump, but MR imaging and blood examination may help to differentiate them. Cystic-appearing solid neoplasm may show heterogeneous signal intensity with inhomogeneous enhancement but without increased leukocyte and CRP level, whereas tuberculous abscess formation will show thin and smooth wall enhancement with the increased number of leukocytes and CRP. Therefore, tuberculous abscess formation is more likely than cystic-appearing solid neoplasm in this patient.Staphylococcus aureus. As the pathogen produces proteolytic enzymes, pyogenic septic arthritis usually has an acute onset, more rapid, and more progressive [Pyogenic septic arthritis can affect all age groups with no specific range of age. The most common pathogen is gressive . It alsogressive showed bM.\u00a0tuberculosis does not produce proteolytic enzymes like pyogenic pathogens, it shows less inflammation process and relative joint space preservation compared to pyogenic septic arthritis which is characterized by a more aggressive course, prominent inflammation, and progressive joint space loss [MR imaging and clinical manifestation may help differentiate pyogenic from tuberculous septic arthritis. As ace loss . The mosThe patient had open drainage surgery and excisional biopsy, and histopathology examination showed chronic granulomatous inflammation caused by tuberculous infection. Histopathology examination and good response of clinical condition after the anti-tuberculosis drug combination administration made the diagnosis of tuberculous septic arthritis in this patient.4The presented case was confirmed as tuberculous septic arthritis with large soft-tissue abscess formation. Tuberculous septic arthritis should be considered as one of the differential diagnoses in slow-progressing monoarticular joint pain, especially in endemic countries. As the disease progresses slowly and may cause irreversible joint destruction, early diagnosis is crucial to improve the patient outcome. MR imaging, combined with the radiograph and clinical information, played an important role in the diagnosis of tuberculous septic arthritis and differentiation to pyogenic septic arthritis or other cystic-appearing neoplasms.All authors listed have significantly contributed to the investigation, development and writing of this article.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.Data will be made available on request.The authors declare no conflict of interest.\u2022The case presented shows variability of clinical symptom and imaging appearance, ranging from asymptomatic with the radiographic presentation could mimicking other abnormalities such as pyogenic septic arthritis and soft tissue tumor lesion.\u2022The patient with monoarticular joint pain that has slow progress symptoms, especially in endemic countries, tuberculous septic arthritis should be considered as one of differential diagnosis\u2022MR imaging can be beneficial to differentiate pyogenic from tuberculous septic arthritis with the most significant imaging characteristic to differentiate tuberculosis from the pyogenic abscess is the abscess wall.No additional information is available for this paper."} +{"text": "Sepsis is a life-threatening syndrome induced by aberrant host response towards infection. The autophagy-lysosomal pathway (ALP) plays a fundamental role in maintaining cellular homeostasis and conferring organ protection. However, this pathway is often impaired in sepsis, resulting in dysregulated host response and organ dysfunction. Transcription factor EB (TFEB) is a master modulator of the ALP. TFEB promotes both autophagy and lysosomal biogenesis via transcriptional regulation of target genes bearing the coordinated lysosomal expression and regulation (CLEAR) motif. Recently, increasing evidences have linked TFEB and the TFEB dependent ALP with pathogenetic mechanisms and therapeutic implications in sepsis. Therefore, this review describes the existed knowledge about the mechanisms of TFEB activation in regulating the ALP and the evidences of their protection against sepsis, such as immune modulation and organ protection. In addition, TFEB activators with diversified pharmacological targets are summarized, along with recent advances of their potential therapeutic applications in treating sepsis. Sepsis is the most common and severe syndrome that can affect a population of critically ill patients . Each yeTranscriptional factor EB (TFEB) is a member of the microphthalmia (MiTF/TFE) transcriptional factor family . TFEB biThe ALP mainly consists of the autophagy machinery and its associated lysosomal degradation processes . This paIt has been extensively demonstrated that the ALP is beneficial for balancing the immune response and protecting organ function during sepsis. A recent review article described autophagy features extensive crosstalk with innate immune cells, thereby exerting influence on phagocytosis in neutrophils, degranulation in mast cells, along with differentiation and migration in NK cells . Researc2+-dependent exocytosis in the lysosomes bearing the CLEAR element mRNA has been shown to reduce the expression of TFEB and impair the TFEB-dependent autophagic process , polysaccharides and peptides) can modulate the ALP by activating TFEB . These a2+-calcineurin modulators agonists and other natural compounds have been shown to upregulate the mRNA expression of TFEB, thereby activating the ALP and enhancing the cellular clearance machinery . MoreoveIn addition to small molecular activators, other larger biomolecules, such as polysaccharides, peptides and miRNAs, can also regulate the activity of TFEB. A few recent studies have reported that polysaccharides and peptides can activate TFEB and enhance the ALP process by inhibiting mTOR activity or promoGiven that the impairment of ALP in sepsis results in unresolved infection, inflammation, organ injury, and immunodysfunction, researchers have begun to investigate TFEB modulators in preclinical models to examine their therapeutic efficacy in ameliorating sepsis-induced dysfunction by promoting autophagy and lysosomal functions.Mycobacterium tuberculosis and Salmonella typhimurium). It is notable that opportunistic pathogens, such as mycobacterial species, can commonly induce secondary infection in post-sepsis patients or trigger sepsis in patients who are immunocompromised. Moreover, pathogens like Mycobacterium tuberculosis inhibit autophagy and lysosomal function by inducing miR-33 dependent inactivation of TFEB instead of endotoxemia models or otherwise tested in clinical settings. Moreover, most TFEB activators target the upstream regulators of TFEB, such as mTORC1 and Car events . Therefor events . Therefo"} +{"text": "Various few-shot image classification methods indicate that transferring knowledge from other sources can improve the accuracy of the classification. However, most of these methods work with one single source or use only closely correlated knowledge sources. In this paper, we propose a novel weakly correlated knowledge integration (WCKI) framework to address these issues. More specifically, we propose a unified knowledge graph (UKG) to integrate knowledge transferred from different sources . Moreover, a graph attention module is proposed to sample the subgraph from the UKG with low complexity. To avoid explicitly aligning the visual features to the potentially biased and weakly correlated knowledge space, we sample a task-specific subgraph from UKG and append it as latent variables. Our framework demonstrates significant improvements on multiple few-shot image classification datasets."} +{"text": "Desmosomes are critical adhesion structures in cardiomyocytes, with mutation/loss linked to the heritable cardiac disease, arrhythmogenic right ventricular cardiomyopathy (ARVC). Early studies revealed the ability of desmosomal protein loss to trigger ARVC disease features including structural remodeling, arrhythmias, and inflammation; however, the precise mechanisms contributing to diverse disease presentations are not fully understood. Recent mechanistic studies demonstrated the protein degradation component CSN6 is a resident cardiac desmosomal protein which selectively restricts cardiomyocyte desmosomal degradation and disease. This suggests defects in protein degradation can trigger the structural remodeling underlying ARVC. Additionally, a subset of ARVC-related mutations show enhanced vulnerability to calpain-mediated degradation, further supporting the relevance of these mechanisms in disease. Desmosomal gene mutations/loss has been shown to impact arrhythmogenic pathways in the absence of structural disease within ARVC patients and model systems. Studies have shown the involvement of connexins, calcium handling machinery, and sodium channels as early drivers of arrhythmias, suggesting these may be distinct pathways regulating electrical function from the desmosome. Emerging evidence has suggested inflammation may be an early mechanism in disease pathogenesis, as clinical reports have shown an overlap between myocarditis and ARVC. Recent studies focus on the association between desmosomal mutations/loss and inflammatory processes including autoantibodies and signaling pathways as a way to understand the involvement of inflammation in ARVC pathogenesis. A specific focus will be to dissect ongoing fields of investigation to highlight diverse pathogenic pathways associated with desmosomal mutations/loss. The desmosome is integral for maintaining structural integrity in tissues undergoing constant mechanical stress such as the heart Najor . The carEmerging new evidence has revealed that defects in protein degradation trigger the structural remodeling underlying the desmosomal disease, ARVC is a multiprotein enzymatic complex consisting of eight subunits (CSN1-8), with known functional roles in controlling ubiquitin-mediated protein degradation as it has been shown to de-neddylate and inactivate cullin RING E3 ubiquitin ligases and action potential propagation between cardiac muscle cells as a means to synchronize coordinated cardiac muscle contraction are directly linked to the inherited cardiac arrhythmia, Brugada syndrome channel to the cardiac intercalated disc -deficient mice, revealing arrhythmogenic pathways in mice distinct from classic desmosomal structural alterations and remodeling may be an initiating factor to this inflammatory response resulting in ventricular arrhythmias (ventricular tachycardia) that could be indistinguishable from proven ARVC patients crossed to the Ribotag mouse as a means to identify ribosome-resident transcriptionally changes in inflammation in cardiomyocytes to the desmosome and one found in the cytosol ; however, future studies should focus on how these pathways work cooperatively to degrade desmosomal proteins in the context of human ARVC-associated desmosomal mutations. Desmosomes are an essential hub for electrical homeostasis in the cardiomyocyte. Recent work highlights that diverse arrhythmogenic pathways may relate to specific desmosmomal proteins with PKP2 mutations/loss while other desmosomal proteins, such as DSP may impact classic CX43 channel functions, which may drive electrical dysfunction in the absence of structural disease in ARVC. Further work is required to dissect whether all desmosomal proteins equally impact these distinct channel functions or whether there are adapter proteins associated with the desmosome that may uniquely mediate desmosome-associated arrhythmias. Additional findings suggest that inflammatory signaling pathways may play an important role in the pathogenesis of ARVC associated with desmosomal mutations. Early infiltration of immune cells and autoantibodies provide new evidence for better clinical diagnosis of ARVC; however, there remains limited direct evidence of the relationship between desmosomal loss/deficiency and recruitment of immune cells in ARVC progression, which should be a focus for future studies."} +{"text": "Laparoscopic surgery has been undermined throughout the COVID-19 pandemic by concerns that it may generate an infectious risk to the operating team through aerosolization of peritoneal particles. There is anyway a need for increased awareness and understanding of the occupational hazard for surgical teams regarding unfiltered escape of pollutants generated by surgical smoke and other microbials. Here, the aerosol-generating nature of this access modality was confirmed through repeatable real-time methodology both qualitatively and quantitively to inform best practice and additional engineering solutions to optimize the operating room environment. Laparoscopic surgery has been undermined throughout the COVID-19 pandemic by concerns that it may generate an infectious risk to the operating team through aerosolization of peritoneal particles. There is anyway a need for increased awareness and understanding of the occupational hazard for surgical teams regarding unfiltered escape of pollutants generated by surgical smoke and other microbials. Here, the aerosol-generating nature of this access modality was confirmed through repeatable real-time methodology both qualitatively and quantitively to inform best practice and additional engineering solutions to optimize the operating room environment. First, formal smoke studies were used to detail room ventilation dynamics around the operating table during surgical simulation scenarios with and without positive-pressure room ventilation (25 room air exchanges per h). For this, an Air-Trace smoke generator created low levels of isokinetic, isothermal smoke via a 25-mm duct. The scenarios replicated personnel and equipment conditions for surgical procedures with varying complexity of set-up with the smoke generator hose positioned at the simulated operative site.Thereafter, flow studies were performed during actual elective operations with varying degrees of intraoperative electrocautery . For this, a light sheet generated by a galvanometer optical laser scanner was used to illuminate a two-dimensional (2D) slice of the surgical airspace during surgery and imaged with an 8\u2009K Ultra-High Definition camera whose absence of diffraction limitation enabled resolution of droplets larger than 2 \u00b5m (visible as scintillations within the laser sheet). Simultaneous extracorporeal airspace sampling was performed during these operations after investigator training using a particle counter to measure 30-s periods both at baseline and then episodically during the procedure by positioning the device\u2019s isokinetic probe inlet 10\u2009cm from the target areaVideo 1 and Appendix S1). Increased crowding of the operating table with people and equipment caused increased local air stagnation. Intraoperative footage during patient operations showed smoke and particles (evidenced as scintillations) moving similarly during surgery, notable even with the instruments in situ, as well as during manoeuvres including trocar instrumentation, and venting and specimen removal . Aerosol and particle leakage into the OR airspace was most evident during the operative phase of intra-abdominal dissection using hook cautery.Smoke studies revealed effective dissipation of smoke by positive-pressure room ventilation with the OR fully empty, as expected. However, during simulated operative scenarios, smoke behaviour was significantly different, with evident upwards drift from the operating site enveloping members of the surgical team . Counts were particularly increased during electrocautery dissection of the gallbladder from the liver bed during cholecystectomy compared with dissection of the mesoappendix during appendicectomy, which in turn was associated with higher counts than were observed during intra-abdominal reduction of a parastomal hernia (done without cautery dissection). Trocar venting caused the highest concentration of particulate effluvium.Particle counts confirmed increasing particulate concentration after initiation of the operation, reaching extracorporeal airspace levels in excess of 1\u00d710This study focused on establishing methods and indicative data regarding the operative airspace particulate contamination occurring during laparoscopy, using open procedures as control in a simulation study as well as in two common general surgical laparoscopic operations that employ electrocautery to different extents (versus a laparoscopic operation without electrocautery). This is important as many surgical teams feel any such occupational hazard to be either theoretical or mitigated anyway by room ventilation and perhaps standard surgical maskshttps://www.gov.uk/government/collections/health-technical-memorandum-disinfection-and-sterilization) is not powerful enough to counteract the local airspace environment created by surgical teams carrying out their work. This means that there is relative stagnation of haze in the operative airspace above the abdomen during laparoscopic operation, with entrainment towards surgical team members likely induced by movement, body heat, and electrostaticityThe evaluations in this study reflect actual workspace conditions of OR teams, corroborating simulation data with live intraoperative flow visualization and sensitive particle counting . Together, these show that the surgical team is exposed to considerable amounts of particles and pollutants during laparoscopy. Indeed, aerosol (containing gas and particles) leaks continuously from the patient during laparoscopic operations, with such flue comprising the constituents of the pneumoperitoneal gas including any noxious components present. The local OR airspace pollution is particularly marked during the cautery dissection phase of the operation, and occurs constantly rather than just at the time of instrument insertion and removal,,,Although investigation of COVID-19 infectivity owing to laparoscopic access is ongoing, the pandemic has already caused considerable reflection regarding the aerosol-generating capability of laparoscopy, and encouraged re-examination of practice and equipment from this new perspectiveThe implications of the present study regarding aerosolization at laparoscopy extend beyond the present pandemic. The results provide insight into both mechanism and degree as well as assessment methodology for future evaluations, including those of mitigation strategies. Although practice adviceznab114_Supplementary_DataClick here for additional data file."} +{"text": "With the current spotlight on systemic racism and the need to address health inequities, it is critical to develop culturally appropriate strategies for recruiting research study participants from racial/ethnic minority groups. Empirical studies have highlighted that people from racial/ethnic minority groups have poorer health outcomes compared to non-Hispanic Caucasians. However, racial/ethnic minority groups remain underrepresented in healthcare research. Several factors may contribute to the lower participation of racial/ethnic minority groups. Sequelae of atrocities in healthcare research on African American/Black people in the US during slavery and Jim Crow eras were widespread and persistent. Discrimination against people of Hispanic descent and increased anti-Asian discrimination have also been documented. Fear and mistrust of the health system and researchers have been identified as critical barriers to participation in clinical research for these populations. Further, health research teams rarely reflect the racial/ethnic diversity of the US population, hindering diversity in recruiting study participants. Inadequate ethnic/racial minority groups participation in study populations not only weakens external validity of empirical studies, but research interventions and policies being implemented may not be culturally appropriate to all populations. Therefore, systemic strategies to improve recruitment of racial/ethnic minority groups should: 1) increase preferential funding to incentivize research teams becoming more racially/ethnically diverse; 2) increase recruitment of racial/ethnically diverse healthcare researchers; 3) use community-based participatory research designs to build trust among racial/ethnic minority populations; 4) provide training on culturally appropriate research study recruitment strategies to the academic communities; 5) apply a prism of intersectionality for representation throughout the research cycle."} +{"text": "Indoor room transition is an underexplored real-world activity outcome. We estimated the stability and variability of indoor room transitions and their associations with mild cognitive impairment (MCI) in older adults. Older adults living-alone from the Oregon Center for Aging & Technology (ORCATECH) and the Minority Aging Research Study (MARS) were included. Room transitions were detected using passive infrared motion sensors in bathroom, bedroom, kitchen, and living room. The hourly number of room transitions was used to calculate the interdaily stability and intradaily variability of room transitions. MCI was operationalized by the Clinical Dementia Rating equaled 0.5. Generalized estimating equations models adjusted for demographics, health, and environmental factors revealed that older adults with MCI had a lower interdaily stability of room transitions than cognitive healthy peers . A pervasive-sensing system deployed in homes can obtrusively measure room transition activities to inform cognitive health in older adults."} +{"text": "Existential distress is a significant source of suffering for patients facing life-threatening illness. Psychedelic-Assisted Therapies (PAT) are novel treatments that have shown promise in treating existential distress, but openness to providing PAT may be limited by stigma surrounding psychedelics and the paucity of education regarding their medical use. How PAT might be integrated into existing treatments for existential distress within palliative care remains underexplored.The present study aimed to elucidate the attitudes of palliative care clinicians regarding treatments for existential distress, including PAT. We recruited palliative care physicians, advanced practice nurses, and spiritual and psychological care providers from multiple US sites using purposive and snowball sampling methods. Attitudes toward PAT were unknown prior to study involvement. Semi-structured interviews targeted at current approaches to existential distress and attitudes toward PAT were analyzed for thematic content.Nineteen respondents were interviewed. Identified themes were 1) Existential distress is a common experience that is frequently insufficiently treated within the current treatment framework; 2) Palliative care providers ultimately see existential distress as a psychosocial-spiritual problem that evades medicalized approaches; 3) Palliative care providers believe PAT hold promise for treating existential distress but that a stronger evidence base is needed; 4) Because PAT do not currently fit existing models of existential distress treatment, barriers remain.PAT is seen as a potentially powerful tool to treat refractory existential distress. Larger clinical trials and educational outreach are needed to clarify treatment targets and address safety concerns. Further work to adapt PAT to palliative care settings should emphasize collaboration with spiritual care as well as mental health providers and seek to address unresolved concerns about equitable access.The online version contains supplementary material available at 10.1186/s12904-021-00889-x. Existenlization , 6. Evidlization and targlization \u201313.Psychedelic-assisted therapies (PAT), which apply psychotherapeutic approaches to altered states of consciousness produced by agents such as psilocybin, 3,4-Methylenedioxymethamphetamine (MDMA) or ketamine, may be potent treatments for patients facing existential distress in the setting of LTI. Randomized-controlled crossover trials using psilocybin have demonstrated reduced depression, anxiety and fear of death in patients with cancer- associated anxiety or depression \u201316, withWhether PAT become broadly implemented within palliative care will depend not only upon the results of larger clinical trials but also the attitudes of health care providers in a position to recommend PAT. Qualitative studies of palliative care providers have identified key themes regarding attitudes toward the use of PAT in palliative settings , 29, as We conducted qualitative semi-structured interviews with palliative care physicians, advanced practice nurses, chaplains, psychologists, and social workers currently working in palliative care settings within the United States.Participants were recruited via email between May 2019 and August 2020 using a combination of purposive and snowball sampling methods. Participants were not selected for knowledge about or known positions regarding PAT. Participants provided informed consent and were not directly compensated; one randomly-selected participant received an online gift card after study completion. Recruitment continued until interviews failed to reveal significant new thematic content.The interview guide was developed by an interdisciplinary team including experts in palliative care (M.L.) and PAT (B.K.) and was directed at two key research questions: (1) How do palliative care providers view their role regarding existential distress and its treatment? (2) What are their attitudes toward PAT as potential treatments for existential distress in LTI? The final interview guide is available in Recorded interviews were conducted by H.N. via phone, Zoom video conferencing software, or in person. Interviews ranged in duration from 32 to 52\u2009min, and concluded once participants had responded to all sections of the semi-structured guide and had been offered the chance to extrapolate further on earlier responses. Recorded audio from each interview was transcribed using Microsoft Word and de-identified prior to qualitative analysis. After the interview, participants completed an online survey covering basic demographics, clinical setting, and health care experience.Transcriptions were uploaded to Dedoose software version 8.3 and coded using a grounded theory approach , 34. IniThemes, subthemes, and representative quotations were then sent to a subset of 5 participants for validation. Criteria for validation was \u2265.78 agreement for each individual theme and subtheme.Thematic saturation was achieved after 19 interviews. Table\u00a0Four major themes and 15 subthemes were identified. All major themes and 13 subthemes met validation criteria, and are featured in Fig. All participants identified existential distress as an important and relevant concept for their clinical palliative care work.Respondents described existential distress as commonly arising both in the anticipation of dying as well as in response to changes in physical and psychosocial capabilities earlier in the course of illness. Existential distress was described as a disruption of, or challenge to, pre-existing sources of meaning or valued identities. Respondents noted a relationship between existential distress and psychiatric illness, though made a clear distinction between the two.The absence of relationships or adequate social support was linked to greater likelihood of a patient meeting difficulty in resolving existential distress. However, concern for unmet emotional, relational, or financial needs for family members was also seen as a source of distress, and LTI was noted to give rise to existential distress through the exacerbation of prior traumas and unresolved interpersonal conflicts.Respondents also described care of patients\u2019 families as a critical part of their clinical role, and noted challenges to identity and meaning among caregivers for those with LTI. Respondents identified their own existential distress as an occupational hazard of working with patients at the end of life.Refractory distress was reported across all types of clinical settings. Factors associated with refractory cases included late referral to palliative care, pre-existing psychiatric illness or trauma history, and young age, especially when the patient was a young parent.Respondents, especially those from smaller hospitals or outpatient groups, pointed to barriers including limited time for visits, absence of specialty interventions and insufficient staffing to meet patient needs. Patient resource limitations were cited as a barrier to effective treatment in all settings.All respondents endorsed existential distress treatment as falling within their scope of practice, with specific roles and degree of involvement differing across professional disciplines.Respondents described existential distress as often overlooked or treated with discomfort by medical practitioners, especially primary consulting teams and oncologists. Physician and advanced practice nursing respondents reported an absence or paucity of training on existential distress treatment prior to specialization in palliative care. Palliative care approaches to existential distress were described as contrasting with a general medical culture focused on biological models of diagnosis and treatment.Participants endorsed therapeutic interpersonal techniques as the primary intervention for existential distress, including active empathic listening and nonjudgmental exploration of patients\u2019 distress. More complicated cases were described as requiring specialist intervention with providers of spiritual care or psychotherapy, of which the most common types were meaning-centered, cognitive behavioral, and mindfulness-based psychotherapies. Helping patients repair or build new personal relationships was seen as integral to reducing existential distress.Respondents expressed interest in expansion of research and clinical access to PAT. However, not all were enthusiastic proponents and reservations or skeptical attitudes were common.PAT was identified as a potentially powerful addition to the palliative care \u201ctoolkit\u201d and respondents described PAT as facilitating meaning-making by allowing patients new perspectives through which to reframe their existential struggle. Respondents endorsed the use of PAT through compassionate use provisions, describing PAT as providing hope for patients experiencing refractory existential distress. Respondents saw PAT as an alternative to controversial interventions for end-of-life distress, such as palliative sedation or physician aid-in-dying.At the same time, participants identified the current evidence base as insufficient and cited a need for further PAT research and greater education on PAT within palliative care departments before they could feel confident in its use. Participants described PAT as late-line interventions to be used only after other therapies had failed.Participants also expressed concerns about stigma for patients receiving PAT, as well as fears about stigmatization from other medical providers for providing PAT. Participants reported concerns that use of PAT would trigger relapse for patients with substance use disorders, and expressed worries about lasting psychological harm from dysphoric psychedelic experiences. Attitudes were more negative toward LSD and positive toward psilocybin and ketamine.Participants expressed confidence in the safety of PAT in properly controlled settings. Respondents emphasized key safety considerations for PAT, including rigorous screening for cardiac disease or history of mania or psychosis, skilled supervision during medication-facilitated sessions, and longitudinal psychotherapy follow-up to integrate these experiences.Providers struggled to identify clearly how PAT could fit into the current treatment paradigm, with fundamental questions unanswered regarding for whom PAT might be an appropriate and accessible treatment.There was no clear consensus around the relative benefits of delivering PAT to patients early in their course of LTI, later while admitted as inpatients, or even while on hospice. Respondents similarly failed to present clear agreement about which palliative care patients should be considered for PAT. Some described psychiatric and trauma histories as important indicators of patients who might benefit most from PAT, while others expressed concern regarding PAT for patients with any psychiatric comorbidity.Providers described interest in PAT as concentrated within specific sociocultural groups, such as younger patients in urban settings. Respondents estimated greater interest in West Coast and Northeastern states than in the Southern US. Participants identified patient groups for whom PAT might not be appealing, such as particular religious groups, and described PAT as cost-prohibitive and likely to exclude poor and underserved communities.The present study reports attitudes toward the treatment of existential distress using PAT within a representative sample of palliative care professionals. PAT were seen as holding promise to improve the treatment of existential distress within palliative care settings, especially in refractory cases. Overall, respondents identified further research and outreach as necessary before PAT can be expanded in palliative care settings, and identified several unresolved barriers to implementation of PAT in palliative care settings.One of the most striking features of these interviews was the emphasis on interdisciplinary collaboration within palliative care, a central cultural tenet of the field. Notably, both subthemes that failed validation touched on questions of role boundaries, and likely were rejected due to perceived violations of this core value.Physicians and advanced practice nurses have limited roles in the treatment of existential distress as compared to chaplains and social workers\u201d (Theme 2) was drawn from descriptions of medical providers serving primary screening roles and triaging cases of existential distress to spiritual care or mental health care providers. However, the language of this subtheme was poorly considered, and respondents in the validation sample emphasized a team-based approach to the treatment of existential distress in which distinct roles are equally valuable.\u201c\u201cPAT would mark a significant change in how and by whom existential distress is treated\u201d (Theme 4). Feedback on this subtheme suggests that while respondents agree PAT would require greater involvement of psychiatrists and other mental health providers, palliative care providers would prefer to expand the umbrella of palliative care rather than referring cases to outside collaborators. This reflects the growing field of psycho-oncology and the greater incorporation of psychiatric and mental health providers into the multidisciplinary palliative care team. Furthermore, respondents reported strong interest in obtaining training in PAT within palliative care departments, despite no explicit question directed at this topic.Similarly, the second unvalidated subtheme dealt with the possibility of PAT marking a greater involvement of psychiatrists and other mental health practitioners in existential distress care: This study, by exploring current standards of care and attitudes toward PAT in a sample reflective of the interdisciplinary culture of palliative care, improves upon and further contextualizes recent investigations of attitudes toward PAT among palliative care providers. Those studies, which addressed perspectives of a diverse group of experts in palliative care, oncology and PAT and a smExpansion of research into PAT in palliative care settings will be facilitated by the clear identification of a target population. While some participants reported an ideal of offering access to PAT for all patients facing life-threatening illness, PAT were commonly seen as intensive treatments indicated only after conventional methods have failed. Perceptions of PAT as late-line therapies may be reflective of stigma around psychedelics and thus subject to change with greater education about PAT. Still, many participants saw conventional treatments of existential distress as largely adequate, which invites us to consider the exact treatment gap PAT might fill.The greatest need for PAT may be within populations especially likely to suffer from refractory existential distress, such as younger adults or patients with significant trauma histories. Further research would be best directed at identifying risk factors for poor response to conventional psychotherapy and spiritual counseling. Alternatively, referral to PAT could be triggered by specific shifts in the course of treatment associated with significant unmet existential needs, such as cancer recurrence, hospice enrollment, or transition from standard cancer therapies to phase I clinical trials .Notably, the characteristics of patients with refractory existential distress overlapped with those of patients deemed too ill or unstable to be safely considered for PAT. Further studies are needed to clarify which psychiatric comorbidities are contraindications for PAT. Without this, the great challenge is that the window of opportunity \u2013 patients sick enough for PAT but not sick enough to be at risk of destabilization \u2013 may be narrow.Similarly, if treatment for existential distress is more limited in less-resourced settings, PAT is not well-situated to amend this treatment gap. Even if PAT are covered by insurance, the significant time demand of treatments may perpetuate problems of power and access that continue to plague American medicine, with marginalized groups unable to benefit equitably from these therapies. Research efforts to date have failed to adequately include diverse samples, with patients of color underrepresented in PAT studies . FurtherRespondents in our sample described meaning-enhancing interpersonal interventions, including both spiritual care and psychotherapeutic frameworks, as the core of conventional existential distress treatment. That meaning-making specifically mediates benefits of some conventional treatments underscoOur findings suggest that PAT might be most easily integrated into palliative care practice if delivered in a manner consistent with current first-line meaning-enhancing approaches of psychotherapy and spiritual counseling. As researchers explore synergies between PAT and specific therapeutic modalities in other clinical contexts , 42, effBroader collaboration between PAT and faith traditions will not be without challenges. While psychedelic agents are important sacraments for some spiritual communities , 44, resThese findings also suggest the importance of maintaining emphasis on PAT\u2019s meaning-enhancing effects. Psilocybin\u2019s FDA designation as a breakthrough therapy for major depressive disorder , 46, whiPositive and stigmatizing views toward PAT were both common, often co-occurring within the same interview. This demonstrates the complicated way in which providers integrate new information about the therapeutic potentials of PAT with decades-old understandings of psychedelics as dangerous and illegal agents. While concerns about potential risks of PAT for patients with cardiac comorbidities echoe the exclusion criteria of recent studies, respondents also voiced concerns that do not track with recent evidence. Fears that PAT might trigger relapses among patients with substance use disorders contrasts with observations that psychedelics decrease patterns of problematic substance use in naturalistic settings \u201349; PAT These examples highlight the importance of education to dispel longstanding misconceptions regarding carefully monitored psychedelic use and promote data-driven understandings of the risks associated with PAT. While the present study was underpowered to assess variations in knowledge and attitudes toward PAT across professional classes, further survey-based research should seek to better classify these patterns, as has been demonstrated in larger samples of psychiatrists and psycConvenience and snowball recruiting methods may have resulted in bias toward the cultures and institutional orthodoxies of included sites. Attitudes may be culturally specific and not necessarily generalizable outside the US. The sample of respondents was skewed toward younger and less experienced clinicians, who may be more likely to have positive views toward psychedelic therapies . While tPalliative care providers describe existential distress as a common source of suffering for patients with LTI. Current treatments emphasize enhancement of sources of meaning and rely on interdisciplinary coordination. Clinicians view PAT as promising treatments for refractory existential distress, though concerns regarding access and exclusionary criteria currently limit their potential scope. Further research and education regarding psychedelic interventions are needed before PAT can be more widely adopted in palliative care settings, especially to address safety concerns and clarify a target population. Close collaboration with spiritual care and mental health providers and adaptations of PAT to existing meaning-focused approaches will facilitate integration into current practice. Educational outreach should address misconceptions regarding risks of substance use and psychological harm. Broader access to PAT research and greater diversity of study samples will improve generalizability and promote equitable treatment outcomes.Additional file 1. Semi-structured interview protocol."} +{"text": "Identifying preference of older adults supports person-centred care. The most sophisticated instrument is the preference for everyday living inventory (PELI). The PELI has been translated into German language and tested in different care settings. For people who experience difficulties communicating their preference the PELI has been combined with photographs. The voice of older immigrants could lead to an enhancement of the PELI as well other preference tools. Thus, our symposium title: Variety of identifying and assessing preferences of everyday living of older adults. Our symposium includes four presentations: Dr. Bergmann will present data from a preference study in three different care settings in Germany. The results indicate that the importance of certain preferences distinguishes between the care settings. Dr. Vanessa Burshnic will present data from her content validity study of photographs used to supplement the Preferences for Everyday Living Inventory-Nursing Home (PELI-NH) from the perspective of older adults. Content analysis revealed thematic codes describing participants\u2019 photograph preferences including image quality, context, subject diversity, and relevance to long-term care. Mike Rommerskirch-Manietta will present results from a review to identify Instruments which can be used to assess preferences for everyday living of older adults. Interestingly instruments either represent multiple or only one domain. The study from Viktoria Peters-Nehrenheim does focus on preferences of older immigrants. She will present results how older immigrants (first generation) define preferences and how they can be assessed. Prof. Van Haitsma will be our discussant."} +{"text": "The drastic demand for geriatrics-trained providers in medical and mental healthcare persists years after the Institute of Medicine first highlighted this need . New innovative approaches must instead optimize the current workforce through leveraging existing geriatric experts\u2019 knowledge and skills related to working aging adults. This symposium will highlight four approaches spanning post-licensure education to using technology to deliver specialized services and training. First, Dr. Gregg will discuss the evaluation of an advanced topics workshop in Geropsychology which has significantly enhanced depth of Geropsychology competencies for psychologists working in primarily rural areas. Next, Dr. Asghar-Ali will describe the multi-modal interactive geriatric educational opportunities for interprofessional staff developed by the South East Texas Geriatric Workforce Enhancement Program (SETx GWEP). He will discuss how these training opportunities have been tailored to address the impact of COVID-19 and healthcare disparities among older adults. Third, Dr. Filips will present an evaluation of a consultation model in which a geriatric psychiatrist provides tele-consultation in a 5-state region to rural aging Veterans with complex medical and behavioral comorbidities. Finally, Dr. Beaudreau will describe adaptations to a national VA Problem Solving Training program for mental health clinicians of older Veterans with complex comorbidities. Dr. Karel, VA National Geriatric Mental Health Director, will serve as discussant and comment on the ways in which these novel approaches are meeting the ever-growing need for competent geriatric mental health providers."} +{"text": "A 40-year-old man, a laborer from Bihar (eastern India), presented to the surgical department with multiple large nodular swelling and discharging sinuses over the left foot with a duration of six months. These lesions began as small nodules that progressively increased in number and size and developed multiple sinuses. On examination, the swelling was painless and firm. He had no significant medical history. Computed tomography showed extensive osteolytic destruction of the tarsal and metatarsal bones. Magnetic resonance imaging demonstrated involvement of soft tissue with multiple sinus tracts . Gram stMycetoma pedis is used to describe chronic granulomatous disease caused by true fungi (eumycetoma) or filamentous bacteria (actinomycetoma).,The term Madura foot or"} +{"text": "Recruiting and enrolling older adults with cognitive impairment is challenging under the best of circumstances. This symposium will begin with an introduction to best practices for recruitment of older adults living with cognitive impairment, followed by four presentations describing recruitment successes and challenges across multiple settings. The first presentation describes COVID-19 pandemic-related factors that have influenced recruitment and enrollment of older adults with cognitive impairment in an intervention study of a physical activity smartphone app. Strategies and procedural alterations to facilitate achievement of enrollment goals for technology-based interventions are discussed. The second presentation describes researchers\u2019 recruiting experiences with older adults with mild cognitive impairment (oaMCI)-care partner dyads for a pilot, platform trial of biopsychosocial interventions. There were differences in study disinterest between oaMCI and study partners that may require specialized communication messaging and strategies for dyad engagement. The third presentation features recruitment adaptations for an Internet-delivered behavioral intervention study with oaMCI and insomnia. Anticipated concerns of oaMCI using technology or accessing the Internet were not significant barriers to recruitment, while fewer oaMCI endorsed sleep concerns than expected. The last presentation demonstrates the potential for telephone-based outreach to increase dementia knowledge and cognitive risk. Working with faith-based health educators to reach rural, ethnically-diverse older adults, researchers will describe how to promote inclusivity and successfully recruit oaMCI within the community. Presenters and participants are encouraged to dialogue on how recruitment and retention barriers may be avoided as well as to share success stories from their own research with oaMCI."} +{"text": "ABSTRACT IMPACT: Successful implementation of this control strategy will result in a commercially available ivermectin-treated birdfeed that the public can use to protect themselves from infection with West Nile virus (WNV) by reducing mosquito survival and thereby suppressing WNV transmission around their homes. OBJECTIVES/GOALS: We assessed the efficacy and feasibility of ivermectin (IVM)-treated birds as a mosquito control strategy for local reduction of West Nile virus (WNV) transmission. We conducted a randomized field trial in backyard chickens and developed a mathematical model informed by field data to predict the impact of treated wild birds on transmission. METHODS/STUDY POPULATION: We placed 48 chickens in four treated and four untreated control flocks in backyards coops across Davis, CA and administered IVM daily in feed to treated flocks (Jul-Sep 2019). We assessed entomological indices weekly around each coop, monitored serum IVM levels in treated chickens, and tested for WNV antibodies in all chickens. Shifting our focus to wild birds, we developed a spatially-implicit mathematical model of WNV transmission near IVM-treated birdfeeders. Model parameters for bird movement were based on our telemetry of 27 birds in Fort Collins, CO (Aug-Sep 2020). Using the model, we predicted optimal deployment of treated feeders to provide local WNV control. RESULTS/ANTICIPATED RESULTS: WNV seroconversions were reduced in treated vs. untreated flocks, indicating a reduction in WNV transmission intensity at treated coops (P = 0.03). A sustained, but insignificant reduction in number of infected mosquitoes was observed near treated coops (P = 0.59); small sample sizes and below normal WNV prevalence in the study area limited our power. We anticipate that optimal spacing and number of IVM-treated birdfeeders required for effective WNV control in neighborhoods will depend on feeder usage rates by common bird species irrespective of WNV competence; broad availability of IVM-treated bloodmeals to mosquitoes will be more effective in reducing transmission than targeting the few species responsible for viral amplification. DISCUSSION/SIGNIFICANCE OF FINDINGS: IVM is a novel method for controlling zoonotic pathogens in the US and has the potential for targeted mosquito control to reduce pesticide usage. Evaluating spatial deployment of IVM-treated bird feed for local reduction in WNV transmission is a stepping stone to commercial deployment of this WNV control strategy."} +{"text": "A key challenge for scholars who study aging is identifying a pool of research volunteers willing to participate. Toolkits and strategies acknowledge the differences in recruitment needed for older adults relative to younger adults, but there is little information about variations among older adult research volunteers. Based on a community sample of older adults age 60+, this study evaluates differences across seven specific motivators across three broad categories: values/altruism, personal growth/improvement, and immediate gratification. We then identify and evaluate four typologies of older adult volunteers based on the combinations of motivations the older adults in our sample identify as important to participation in research studies. Based on these analyses, we describe how our results might inform recruitment and retention practices in aging studies. Further, we will discuss how these results will help shape our technology-based reminder system with a greater understanding of motivations."} +{"text": "Previous studies suggest that falls among community-dwelling older adults living with dementia (OLWD) harm the health and wellbeing of their family/friend care partners. However, little is known about the process through which falls impact care partners. We conducted a grounded theory analysis using 59 semi-structured interviews with care partners of OLWD who were recently hospitalized and had a history of falls. We identified several areas of care partners\u2019 functioning that were affected by falls in positive and negative ways: everyday life, health management for OLWD, and interactions with healthcare providers. Both the fall events and fall risks had negative consequences of reducing care partners' self-care activities and work productivity. Other adverse consequences of fall risks were (1) care partners\u2019 fatigue and conflicts with OLWD due to the intense requirement of daily monitoring, and (2) hesitance to ask healthcare providers for assistance because clinicians frequently did not teach care partners how to address fall risks and might recommend institutionalization. However, OLWD's fall events became a transition point for some care partners to seek support and gain more information and skills about managing OLWD\u2019s health conditions, which might reduce care partners\u2019 burden in the long term. Because OLWD\u2019s falls may have negative and positive consequences for care partners, both problem-solving and strength-based fall management approaches are needed. These strategies focus on developing and sustaining care partners\u2019 self-care, developing collaborative relationships with OLWD, enhancing successful capacity for OLWD\u2019s health management, and cultivating partnerships with healthcare providers."} +{"text": "Maintaining cognitive function in later life is key to healthy aging because cognitive impairments compromise everyday functional abilities, impeding independent living. Numerous studies have discovered early life experiences and lifestyle behaviors over the lifespan to have substantial influences on cognitive functioning with age. Especially, subtle brain changes related to dementia occur as early as midlife, and lifestyle factors in midlife influence neuropathological development, suggesting that midlife is a critical period for preserving cognitive health in later life. This study investigated the association between lifestyle behaviors in midlife and cognitive performance in later life using 12-year follow-up data from the Korean Longitudinal Study on Aging (KLoSA). Cognitive function was assessed with the Harmonized Cognitive Assessment Protocol (HCAP) for KLoSA. Eight thousand respondents from the KLoSA sample were administered HCAP neuropsychological tests. Hierarchical multiple regression analyses were used to examine whether health-promoting lifestyles at baseline (2006) predicted cognitive function in 2018 after controlling for health-related covariates. We identified a positive influence of health-protective behaviors at baseline on language abilities in 2018 . In addition, health-promoting behaviors covering interpersonal relationships, social engagement, optimistic outlook, and positive attitudes at baseline were predictive of language abilities , executive function , and the visuospatial ability in 2018. This study highlights the importance of midlife health-promoting lifestyles in maintaining cognitive health in later life."} +{"text": "This study focuses on long-term care (LTC) state Medicaid policy and its impact on caregiver decisions and experiences. It examines respondents\u2019 general knowledge of LTC state policies and services, challenges with navigating LTC policies and services, and decision-making pathways based on these factors. Using purposive sampling, 63 family caregivers across eight states participated in open-ended qualitative interviews (2019-2020) until thematic saturation was reached. Questions broadly examined caregivers\u2019 experiences and decisions, focusing on decisions made around type of care setting and experiences with LTC state policy. States were selected to represent variation in Home and Community Based Service (HCBS) expenditures as a percentage of total Medicaid long-term services and support expenditures. While LTC policies and services vary significantly by state, we identified many parallels in caregiver experiences and perceptions across states, as respondents often lacked specific knowledge about LTC policies and services and how to access them. Overarching themes include LTC policy navigation challenges, distrust in state-funded LTC services and supports, and moral expectations of caregiving. To manage these challenges, caregivers employed coping strategies such utilizing informal support networks, hiring care coordination assistance, and \u201cstretching things thin\u201d to fill the policy and service gaps. Study findings highlight potential strategies to improve LTC services across states. There is a need to improve community trust with state services by employing transparent regulatory and evaluation procedures for LTC. Wider access to case management may improve communication and knowledge of available services to maximize benefit from HCBS expansions."} +{"text": "The longitudinal associations between hearing impairment and higher-level functional measures and the potential confounding role of vestibular function have not been assessed. We investigated these associations in 831 participants of the Baltimore Longitudinal Study of Aging (2012\u20132019). Hearing was measured using pure-tone audiometry and categorized using WHO standards. Physical function was assessed with the Health Aging and Body Composition Physical Performance Battery and walking endurance with time to walk 400 meters. Multivariable regression models tested the hypotheses that participants with hearing impairment have poorer physical outomes. In a subset, we further adjusted for vestibular function. Hearing impairment was associated with decrements in higher-level physical performance and walking endurance, and faster decline over time, regardless of vestibular function. Among participants with any hearing impairment, hearing aid users were faster in the 400-m walk. Early screening for higher-level functional loss among older adults with hearing loss is warranted."} +{"text": "Self-determination is a core value of person-centered care. Research has shown residents and families want to be involved in decisions about care. Care conferences are one existing structure where residents and families can engage in decision-making about care goals. However, there are few tools to support effective engagement. To inform future tool development, this study sought to understand what resident and family stakeholders value about engaging in care conferences. In virtual meetings, 16 stakeholders identified 3 key areas of engagement: being informed about health/well-being, influencing care goals, and advocating for needs. They indicated current approaches do not achieve these engagement goals, which is particularly problematic during COVID when families cannot engage in person. Stakeholders offered ideas for supporting engagement such as provision of data before the conference. The study has implications for individualizing care conferences and encouraging resident and family engagement in decision-making both during and beyond COVID."} +{"text": "This cross-sectional study evaluates the out-of-pocket costs of diagnostic breast imaging services incurred by commercially insured women who underwent additional imaging evaluation and procedures after screening mammography. We performed a retrospective analysis using a national commercial claims database with individual-level demographic information and inpatient, outpatient, and pharmacy claims for health care plan members residing in all 50 US states. Claims information included both OOPCs for plan members and total standardized reimbursements.This cross-sectional study was deemed exempt from University of Michigan Institutional Review Board approval owing to use of deidentified data and followed the Strengthening the Reporting of Observational Studies in Epidemiology , ultrasonography (US), magnetic resonance imaging (MRI), and biopsy were followed by additional breast imaging examinations or procedures. After applying exclusions, the final cohort included 325\u2009900 women with 418\u2009378 additional breast imaging examinations or procedures.Out-of-pocket costs varied substantially across women and type of imaging received and generally increased over time . For exaCost sharing also increased throughout the study period . Among w3Although the ACA largely eliminated OOPCs for screening mammography, our findings suggest that among commercially insured women ages 40 to 64 years, OOPCs for additional breast imaging evaluations and procedures after screening are common, nontrivial, and increasing. This trend coincides with the rapid rise in high-deductible health care plans that has been observed during the same time frame as the study period.This study has some limitations. We did not include OOPCs for related care such as office visits and pathology expenses, likely underestimating the total patient contributions. In addition, we could not distinguish between diagnostic evaluations for abnormal screening vs those for symptoms. We were also unable to discern the number of women who had an abnormal screening but did not undergo a subsequent evaluation or procedure.4 Although the association between OOPCs and receipt of one-time diagnostic testing has not been described (to our knowledge), it is possible that higher cost sharing could deter women from undergoing diagnostic evaluation following screening mammography, thus undermining the goal of the ACA to remove barriers to screening. The benefit design of health care plans must acknowledge that cancer screening often requires multiple steps and remove financial barriers for patients to complete the screening process.Consumer cost sharing is associated with decreased use of evidence-based medical care."} +{"text": "Although African Americans have lower rates of anxiety in childhood than other racial and ethnic minority groups, they seem to experience escalating rates during emerging adulthood. Despite this, few studies have examined factors associated with anxiety during emerging adulthood among African American populations. The current study investigated the extent to which late adolescent family relationships affect anxiety problems among African American emerging adults. Informed by family development theory, family cohesion was hypothesized to indirectly effect anxiety problems through self-regulation. This model was tested with three waves of data from African Americans participating in the Maryland Adolescent Development in Context Study. Study findings were consistent with the hypothesized model: family cohesion forecasted decreased anxiety problems, indirectly, via increased self-regulation. This finding suggests that families may be an important promotive process for anxiety problems during emerging adulthood. Prevention programs that target family processes may be able to reduce anxiety problems in emerging adult African Americans. Anxiety is characterized by heightened, relentless fears and worries about everyday events . Clinicafamily cohesion in promoting the development of youths\u2019 autonomy and their ability to navigate new contexts.Racial and ethnic group differences in anxiety rates and severity have been observed. Although African Americans have lower rates of anxiety in childhood than other racial and ethnic minority groups, they seem to experience escalating rates during emerging adulthood , 14. MorFamily cohesion describes nurturant communication, warmth, emotional support, and involvement between family members \u201318. In gAlthough these studies suggest that cohesive families may reduce poor psychological outcomes in emerging adulthood, the extent to which family cohesion is associated with anxiety problems among African American emerging adults is not well studied, despite close family ties being culturally important for many African American families . Data onWe further hypothesized that self-regulation may be a mechanism through which family cohesion affects anxiety problems during emerging adulthood. Self-regulation refers to individuals\u2019 ability to control their emotions, behaviors, and thoughts . EmerginTaken together, theory and extant research suggest that cohesive families may act as an emotional safety net which supports the development of self-regulation during emerging adulthood. With this safety net in place, emerging adults may feel comfortable exploring new opportunities while navigating the potential emotional turmoil of this challenging developmental period. The extent to which family cohesion forecasts self-regulation and reduced anxiety problems among African Americans emerging adults is not well studied. The current study addresses this gap. Informed by family development perspectives and previous research, family cohesion is hypothesized to indirectly effect anxiety problems through self-regulation. This hypothesis was tested via a secondary analysis of three waves of data from African Americans participating in the MADICS Study of Adolescent Development in Multiple Contexts (MADICS) controlling for antecedent family support.Youth and their families were recruited from 23 middle schools in Prince George\u2019s County, Maryland , 46. PriThe MADICS was a longitudinal study investigating psychological and behavioral determinants of developmental trajectories of youth living in Prince George\u2019s County, Maryland, a county located near Washington, D.C. , 46. MAD\u03b1 = .69) and Wave 4 (\u03b1 = .68). Closeness with family members at Waves 3 and 4 were measured using five items from the Iowa Youth and Family Study indicated that the indirect effect of family cohesion on anxiety problems through self-regulation was significant.Descriptive statistics and bivariate correlations for the 886 African Americans participating in Wave 4 of MADICS are presented in Informed by family development perspectives on emerging adult mental health, this study investigated the effects of family cohesion during late adolescence on self-regulation and anxiety problems as African Americans transition into emerging adulthood. Three key findings emerged. First, family cohesion in late adolescence was significantly related to increased self-regulation in emerging adulthood. Second, self-regulation was significantly related to reduced anxiety problems in emerging adulthood. Third, family cohesion in late adolescence indirectly effected anxiety problems in emerging adulthood through self-regulation.The first finding suggests that family cohesion during late adolescence is an important process for supporting self-regulation during emerging adulthood. This finding is consistent with and extends previous research on family effects among children and adolescents . In addiOur findings suggest that self-regulation is an important factor in reducing anxiety problems among emerging adults. This is in line with similar findings in investigations of children and emerging adults. For example, a study of children between the ages of 8 to 12 found that highly regulated children were able to manage negative emotions such as worry, sadness, and anger, which suggests that self-regulation may be an important promotive factor for anxiety problems . SimilarThe indirect effect finding suggests that self-regulation may act as a mechanism through which family cohesion during late adolescence affects downstream anxiety. Similar results were reported by Brody and Ge in a stuStudy findings have several implications for prevention. Prevention programs working to reduce anxiety problems in African Americans prior to and during the transition to adulthood should consider targeting enhancing family cohesion. The Adults in the Making (AIM) prevention program is an example of a program that seeks to increase family cohesion in order to improve emerging adult outcomes . FamilieThe current study has several limitations. First, the sample comprised of African American youth living in Maryland, so these findings may not generalize to African American youth living in other cities or regions of the United States. Second, these findings are correlational. Experimental designs using preventive interventions could beIn summary, family cohesion in late adolescence was indirectly related to changes in anxiety problems in emerging adulthood through self-regulation. This finding suggests that families continue to serve as important promotive processes for self-regulation and anxiety problems during the transition to emerging adulthood. Prevention programs that incorporate the family may be able to reduce anxiety problems in emerging adult African Americans.S1 Table(DOCX)Click here for additional data file."} +{"text": "Christopher Abbosh and Charles Swanton discuss circulating tumor DNA as a potential biomarker for neoadjuvant treatment response in solid tumors. Three studies presented within this special issue of PLOS Medicine focus on evaluation of circulating tumor DNA (ctDNA) as a response biomarker in early-stage solid tumours. Both Yaqi Wang and Pradeep Chauhan and their respective colleagues evaluate ctDNA as a tool capable of predicting complete pathological response (pCR) in locally advanced rectal cancer (LARC) and muscle invasive bladder cancer (MIBC), respectively ,2. JeannQuantitation of ctDNA kinetics over time can act as a dynamic biomarker of tumour response to targeted therapies, immunotherapy and radiation therapy \u20136. In a In relation to the latter point, Wang and colleagues draw attention to the potential for deferral of surgery in patients exhibiting complete clinical response following neoadjuvant chemoradiation treatment for LARC . This isThe study from Wang and colleagues supports prior findings from Murahashi and colleagues who also evaluated post-treatment ctDNA kinetics in patients undergoing neoadjuvant treatment for LARC . In MuraLike the application of ctDNA in LARC, Chauhan and colleagues asked whether evaluation of urinary ctDNA (utDNA) could differentiate pCR from non-pCR in patients being treated with neoadjuvant therapy for MIBC . DevelopTie and colleagues explored ctDNA as a curative-therapy response biomarker in CRLM. Within a cohort of patients who underwent neoadjuvant chemotherapy, they noted a median 40.93-fold decrease in ctDNA levels during treatment with 13 of 18 evaluable patients exhibiting absence of ctDNA detection pre-cycle 4 of treatment: all 4 patients with pCR in the resection specimen experienced ctDNA clearance prior to cycle 3 or 4 of neoadjuvant treatment. However, ctDNA clearance during neoadjuvant chemotherapy had no impact on 5-year relapse free survival (RFS) when compared to lack of ctDNA clearance. In contrast, the team identified that ctDNA detection after surgery was a strong predictor of reduced RFS, with patients who were ctDNA positive following curative therapy (surgery +/- adjuvant therapy) exhibiting a 5-year RFS rate of 0% versus 75.6% in ctDNA negative patients. These data highlight the importance of associating ctDNA clearance dynamics during neoadjuvant treatment with post-operative survival endpoints, since in this study ctDNA clearance with neoadjuvant chemotherapy did not translate into reduced risk of disease recurrence following surgery.Supporting ctDNA as a neoadjuvant response biomarker in other tumor types, data in non-small-cell lung cancer (NSCLC) from the neoadjuvant CheckMate-816 study, a randomized, phase III study comparing neoadjuvant platinum chemotherapy with or without nivolumab in stage IB-IIIA NSCLC, highlighted that ctDNA clearance at day 1 cycle 3 post-combination chemotherapy and immune checkpoint inhibitor treatment associates with pCR . Stage IIn conclusion, the findings presented in this special issue add to an emerging literature highlighting a need to explore the translational potential for ctDNA assessment as a response biomarker in the neoadjuvant setting. These data are particularly relevant in LARC and MIBC where treatment response biomarkers that are not reliant on pathological examination of resection specimens are required to guide non-operative management decisions. The data from Tie and colleagues suggest that the capability of neoadjuvant chemotherapy-induced ctDNA clearance to act as a surrogate of long-term survival benefit from curative intent therapy could be absent in CLRM, however the sample size in this study was modest which may have limited ability to detect an association. It is conceivable that the utility of ctDNA as a neoadjuvant response biomarker may vary by therapeutic class and solid tumour type. To address this issue, it will be important for prospective interventional trials to incorporate ctDNA clearance kinetics as an endpoint to determine surrogacy of these measures for survival across solid-tumour types. Finally, to gain understanding of the relative merits and disadvantages of ctDNA-based response metrics versus conventional clinical measures of response , direct comparison of ctDNA clearance with these approaches is warranted."} +{"text": "Heritability of cognitive ability changes across late adulthood, although whether genetic variance increases or decreases in importance is not understood well. We performed a systematic review of the heritability of cognitive ability derived from longitudinal twin studies of middle-aged and older adult twins. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, articles were identified in APA PsycINFO and Clarivate Web of Science electronic databases. Identified articles were screened by title and abstract; remaining full-text articles were then fully evaluated. Reference sections served as an additional method for identification of relevant articles. In total, 3,106 articles were identified and screened, 28 of which were included and were based on data from 10 longitudinal twin studies published from 1994-2021. There are large genetic influences on an initial level of cognitive performance across domains whereas there are small to moderate genetic influences on change in performance with age. Evidence was less definitive about whether the same or different genetic factors contribute to both level and change. Non-shared environmental influences appeared to drive individual changes in cognitive performance. Heritability tended to either be stable or decline after 65 years, possibly because of the increasing importance of non-shared environmental influences on cognitive ability. Recent studies report increases in heritability across specific subtests and domains. Shared environmental variance accounted for little variance in cognitive ability. Emerging research questions and future directions for understanding genetic and environment influences in the context of gene-environment interplay are highlighted in this review."} +{"text": "Level\u00a0of Difficulty: Advanced.)We present 3 cases of superior vena cava (SVC) syndrome following percutaneous right ventricular assist device (RVAD) placement. Each case underscores the importance of early recognition of SVC syndrome in patients with percutaneous RVAD insertion via the internal jugular vein and calls for heightened awareness of device-associated complications. ( At present, device-related SVC syndrome accounts for up to 40% of all cases . PatientSVC syndrome can arise in postsurgical settings or as a consequence of iatrogenic obstruction to venous drainage. Currently, heart transplantation and ventricular assist devices may be used in end-stage heart failure that is unresponsive to interventional treatments. Although bicaval anastomosis during heart transplantation is preferred because of anatomic and hemodynamic benefits, this method effectively limits the distensibility of the SVC to the circumference of the suture line and may precipitate SVC syndrome with post-transplant RVAD use . AlthougAlthough both postsurgical and iatrogenic causes of SVC syndrome can develop secondary to a disruption in hemodynamic stability , scant literature has reported the onset of SVC syndrome after percutaneous RVAD cannulation via the right internal jugular vein . As the A 61-year-old man presented with restrictive cardiomyopathy with biventricular failure and underwent orthotopic heart transplantation (OHT). The patient had a dual-chamber implantable cardioverter-defibrillator (ICD) that was removed following OHT. A postoperative transesophageal echocardiogram (TEE) revealed a moderately dilated right ventricle (RV) with normal function. Postoperative day 2, the patient became profoundly hypotensive and unresponsive to vasopressors, and because of high central venous pressure (CVP) and RV dysfunction, the patient underwent RVAD extracorporeal membrane oxygenation. Approximately 30 hours later, the patient had marked swelling of the head and upper extremities and a CVP of 45\u00a0mm\u00a0Hg . The patA 55-year-old man presented with acute decompensated left ventricular systolic heart failure and cardiogenic shock that required an intra-aortic balloon pump; he underwent LVAD and RVAD implantation. One week before LVAD placement, the patient\u2019s biventricular ICD was removed because of sepsis. Shortly after, central RVAD support was switched to percutaneous support with no complications. Approximately 45 hours following placement of the device, the patient exhibited rapidly progressive head and neck swelling suggestive of SVC syndrome. After removal of a preexisting left internal jugular central venous line, the patient experienced improved facial edema, and signs of SVC syndrome resolved.A 50-year-old man with a history of HeartMate II explant for recovery presented with recurrence of heart failure with a reduced left ventricular ejection fraction of 10% and associated RV dysfunction. After implantation of LVAD and RVAD support, the patient experienced facial edema, orbital swelling, and underwent emergent venogram that showed near occlusion of the SVC and 2. DThe diagnosis of SVC syndrome is accomplished using clinical picture and supplementary imaging modalities like chest radiography, contrast-enhanced computed tomography scanning, duplex ultrasound, conventional catheter-based digital subtraction venography, and magnetic resonance venography . These tFor nonmalignant causes of SVC syndrome, including placement of a dual-lumen cannula, there are several strategies for preventing venous congestion. In the setting of transplant, preoperative SVC imaging can reveal anatomical variance in caval diameters; significant discrepancy between host and donor may increase risk for bicaval stenosis and subsequent venous congestion. Likewise, we suggest performing a venogram before RVAD placement in patients with preexisting leads or central lines because it may reveal subclinical stenosis. Similarly, venous obstruction can be circumvented via imaging of the SVC-RA junction among patients before device placement; however, this approach poses a significant challenge because of poor validation of ranges for cross-sectional radiographic sizing across different imaging modalities .In addition, the SVC is a compliant vasculature, and its sizing is likely dependent on the hemodynamic status at the time of measurement. More informative imaging techniques may be accomplished via computed tomography venography, but this approach carries a substantial radiation dose and is poorly validated because venous size chiefly depends on intrathoracic pressure and volume status . An alteVenous scarring from preexisting intravascular leads may result in reduced distensibility and may precipitate venous congestion after percutaneous RVAD cannulation. For example, SVC syndrome following pacemaker implantation can occur secondary to the formation of vegetations or via thrombosis after endothelial disruption . In all Here, we describe 3 cases of SVC syndrome following percutaneous dual-lumen cannulation for extracorporeal life support. Patients with signs of SVC syndrome, including facial and chest edema, dyspnea and cough, and nonpulsatile distended neck veins, experienced improvement following either device explantation or removal of the accompanying central venous catheter within the left internal jugular and subclavian venous system. By considering multiple etiologies for SVC syndrome, we hypothesize that appropriate RV support and early recognition of SVC syndrome are critical for preventing venous obstruction.The authors have reported that they have no relationships relevant to the contents of this paper to disclose."} +{"text": "Transgender persons who came of age in the late 1960s are considered LGBTQ+ elders - The Stonewall Generation. These persons experience unique bio-psychosocial challenges, often complicated by a history of a lack of access to good medical care and social supports. Discrimination and bias can influence the provision of care and the protection of privacy for transgender or gender non-conforming persons. Staff training is essential to provide ethical care for aging trans persons who require residential care. This presentation examines current staff training modules of 100 Long Term Care (LTC) facilities, assessing training needs to provide affirming, culturally competent, and ethical care for sexual and gender minorities.Keywords: cultural competence; Long Term Care; staff training; transgender"} +{"text": "The present study aims to identify personality and socioeconomic factors that contribute to midlife cognitive functioning across middle adulthood. Specifically, we examined how the growth trajectories of personality and socioeconomic factors across 12 years predict subsequent cognitive functioning, using data from a large sample of Mexican-origin adults . Personality was assessed using the Big Five Inventory, which assesses the Big Five domains as well as specific facets of each domain; economic stress was assessed using measures of negative economic events and economic hardship . Cognitive functioning was assessed using the NIH Cognitive Toolbox with measures of memory, language, and executive function. Findings from this work will help identify intervention targets for promoting healthy cognitive aging in midlife and beyond in Mexican-origin adults."} +{"text": "This session will provide updates on how the pandemic led to horrific situations in long-term care facilities and how the pandemic influenced major federal efforts to address elder abuse, neglect, and exploitation."} +{"text": "Data harmonization methods facilitate further use of existing studies and research resources. Most statistical harmonization methods require pooling data across studies, which is complex and requires careful scrutiny of source data. Most methods require datasets to have common items for linking a common construct across studies: this necessitates the qualitative process of pre-statistical harmonization. Here, we document pre-statistical harmonization of items measuring behavioral and psychological symptoms which represent problematic behaviors among people with dementia administered in a national survey (ADAMS), evaluations conducted at Alzheimer\u2019s Disease Research Centers (NACC), and in six randomized trials . We describe our approach to review question content and scoring procedures to establish comparability across items prior to data pooling. We identified 327 items from 15 instruments across these eight studies. We found considerable cross-study heterogeneity in administration and coding procedures for items that measure the same domain. For example, eight items were coded as count variables in some studies but as categorical variables in others. Moreover, of the 359 items, 191 are conditionally dependent on values of another item. These issues around item response heterogeneity and conditional dependency needed to be resolved prior to estimation of item response theory models for statistical co-calibration. We leveraged several rigorous data transformation procedures to address these issues, including re-coding and winsorization. This study provides guidelines for how future research may acknowledge and address similar issues in pooling behavioral and related instruments."} +{"text": "The Arabidopsis genome encodes ten Argonautes proteins showing distinct expression pattern as well as intracellular localisation during sexual reproduction. Dear Editor,Small RNAs (sRNAs) are key regulators of gene expression. The importance of reproduction-specific sRNAs has been recognized in plants . Beyond Arabidopsis AGOs are detected in mature ovules before fertilization. Within the female gametophyte, their accumulation seems to be particularly enriched in the egg cell compared with the central cell. Preferential AGO expression in the egg cell was confirmed using previously published female gametophyte transcriptome data obtained by laser-capture microdissection , we could detect expression of 8 out of 10 on limit . mCherryon limit . GFP-AGOon limit . Based oon limit . This dion limit and suggWe then analyzed AGO accumulation patterns in the differentiated zygote at the heart-stage As previArabidopsis AGO1 and AGO4 have been shown to shuttle between the cytoplasm and the nucleus although their respective steady-state subcellular localizations seem to reflect their involvement in either PTGS or TGS . In agreArabidopsis, yet they are often marred by biological incongruities such as the use of overexpression promoters or C-terminal fusions known to affect AGO functions. The uniform set of tools presented in this study might help bridging this gap across the plant RNA silencing community.To conclude, our study reveals a clear asymmetry of AGO expression between the gametes and accessory cells before fertilization and between the embryo and endosperm lineage after fertilization. A summary of their expression pattern in reproductive tissue can be found in Schematic representation of the constructs used in this study. RT-qPCR results assessing AGOs expression levels in inflorescence of wild-type and complemented lines. Complementation of ago mutants. Additional channels and LUTs corresponding to the pictures of Additional pictures.\u2002Arabidopsis AGO transcription patterns extracted from microarray data of LCM-dissected female gametophytes (tophytes confirmi Additional pictures of AGOs expression pattern in mature pollen counter stained with DAPI. AGO accumulation in germinating pollen tube. Paternal expression in the early zygote of AGOs expressed in sperm cells. Additional channels and LUT corresponding to the pictures of \u2002Arabidopsis AGO transcription patterns extracted from microarray data of LCM-dissected seeds at the pre-globular stage (ar stage confirmi Primers used in this study. Materials and Methods.kiab474_Supplementary_DataClick here for additional data file."} +{"text": "Pulmonary vein stenosis (PVS) is a known complication after radiofrequency ablation of atrial fibrillation (RAAF) and is often misdiagnosed owing to lack of awareness regarding PVS among noncardiologists. Misdiagnosis results in unnecessary treatment; therefore, greater understanding of PVS can improve the management of these patients.We report the case of a 38-year-old man with a history of RAAF who presented with massive hemoptysis. His symptoms persisted despite undergoing transcatheter bronchial artery embolization on two occasions.Pulmonary computed tomography angiography revealed a completely occluded left superior pulmonary vein. Considering the patient\u2019s history of RAAF, we diagnosed him with RAAF-induced PVS and performed left superior lobectomy after which hemoptysis did not recur.Unexplained massive hemoptysis should alert clinicians regarding the possibility of RAAF-induced PVS. Balloon angioplasty and stent placement are used to treat PVS; however, their efficacy is controversial considering the high recurrence rates associated with these interventions. Hemoptysis is an important clinical manifestation of respiratory diseases. Common causes of hemoptysis observed in clinical practice include bronchitis, bronchogenic carcinoma, bronchiectasis, infections, and tuberculosis.. Additionally, a high-density stripe observed in the left upper lobe suggested chronic inflammation . Medical treatment with vasopressin and hemagglutinin was ineffective. Left bronchial artery angiography revealed an enlarged bronchial artery showing an extensive branching pattern, and contrast agent extravasation was observed in the left upper lung field . We performed transcatheter bronchial artery embolization using polyvinyl alcohol embolization particles , gelatin sponge particle embolic agent and fibered platinum coils . Hemoptysis was controlled immediately after the procedure; however, massive hemoptysis recurred on the second day. Repeat angiography revealed that an ectopic bronchial artery originating from the left internal thoracic artery was the source of hemorrhage ; therefore, we performed transcatheter embolization of the ectopic bronchial artery. Unfortunately, hemoptysis was controlled only for 2 days after the procedure and recurred thereafter.The patient was referred to the emergency department at our hospital because of massive hemoptysis. He reported a history of catheter ablation performed for atrial fibrillation, 10 days prior to presentation. Chest radiography did not reveal any positive findings. Thoracic computed tomography (CT) scan revealed scattered ground-glass opacities in the left upper lobe, suggesting alveolar hemorrhage A. Additiammation B. Medicang field A. We permorrhage B; theref. Based on his history of RAAF, hemoptysis was attributed to RAAF-induced PVS in this patient. The patient underwent left superior lobectomy after which hemoptysis did not recur.Pulmonary CT angiography was performed to detect potential ectopic bronchial arteries, and complete occlusion of the left superior pulmonary vein was accidently discovered during this examination A and B. ,Since it was first reported in 1998,Most patients with PVS present with dyspnea, recurrent cough, expectoration, chest pain, flu-like symptoms and hemoptysis. Recurrent hemoptysis was the predominant symptom in our patient, and although hemoptysis is not rare in patients with PVS, hemoptysis associated with RAAF-induced PVS is relatively rare when considering the overall common causes of hemoptysis. The pathophysiological mechanism contributing to hemoptysis in patients with PVS remains unclear. We concluded that hemoptysis was attributable to increased pulmonary vascular resistance secondary to PVS. Magnetic resonance imaging and pulmonary vein CT angiography are valuable noninvasive diagnostic tools for PVS. Both modalities provide useful information regarding the site and extent of PVS, but the low spatial resolution associated with these modalities is a limitation; therefore, cardiac catheterization and pulmonary artery angiography remain the gold standard for the diagnosis of PVS.Transcatheter bronchial artery embolization is widely used as a safe and effective treatment to prevent hemoptysis; however, it is ineffective in patients with RAAF-induced PVS because these patients develop hemoptysis secondary to elevated pulmonary vein pressure and reduced venous backflow. Therefore, treatment in these patients is primarily aimed at relieving the obstruction and increasing blood flow through the pulmonary veins. The main treatment modalities for PVS include balloon angioplasty and/or stent implantation. Both methods are known to successfully alleviate symptoms; however, high rates of restenosis have been observed over the long-term follow-up. Compared with balloon dilation, stent implantation is associated with a relatively low restenosis rate, particularly with the use of stents measuring >10\u00a0\u200bmm in diameter. Long-term anticoagulant therapy is necessary after the procedure to avoid pulmonary vein thrombosis. A recent study has reported the use of drug-eluting stents to reduce the restenosis rate,In conclusion, PVS is a complication of RAAF that is often misdiagnosed owing to lack of adequate awareness regarding this condition among noncardiologists. Unexplained massive hemoptysis should alert clinicians regarding the possibility of RAAF-induced PVS in patients with such a clinical presentation. Pulmonary vein CT angiography is a valuable noninvasive method to diagnose PVS. Minimally invasive treatments, such as balloon dilation and pulmonary vein stenting have been used to treat PVS; however, their efficacy remains controversial owing to the relatively high recurrence rates associated with these interventions.Written informed consent was obtained from patients for publication of this case reports and any accompanying images.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} +{"text": "Declines of large-bodied herbivorous reptiles are well documented, but the consequences for ecosystem function are not. Understanding how large-bodied herbivorous reptiles engineer ecosystems is relevant given the current interest in restoration of tropical islands where extinction rates are disproportionately high and reptiles are prominent as herbivores.Conolophus subcristatus), large-bodied herbivores known to feed on many plant species. We characterized plant communities on each island by developing high-resolution (<1 cm2) aerial imagery and delineating extent of plant associations and counting individual plants on each.In this study, we measured the ecosystem-level outcomes of long-term quasi-experiment represented by two adjacent islands within the Galapagos Archipelago, one with and the other without Galapagos land iguanas (In the presence of iguanas there was dramatically less woody plant cover, more area with seasonal grasses, and many fewer cacti. Cacti had a more clumped distribution where iguanas were absent than where iguanas were present.This study provided strong evidence that Galapagos land iguanas can substantially engineer the structure of terrestrial plant communities; therefore, restoration of large-bodied reptilian herbivores, such as land iguanas and giant tortoises, should be regarded as an important component of overall ecosystem restoration, especially for tropical islands from which they have been extirpated. ReptileConolophus subcristatus, C. marthae and C. pallidus) and giant tortoises (Chelonoidis spp.) once dominated as the only large-bodied herbivores present in the Galapagos Islands reproduction while enhancing sexual reproduction via seed dispersal away from adult plants where bird predation on seeds is intense aerial imagery and delineating extent of plant associations on each. Our study provided an opportunity to ask questions about the role of reptilian herbivores on structuring the plant communities of islands, including impacts on keystone plants, as well as to explore the ramifications of restoring reptile populations on islands to promote ecosystem recovery , Bouteloua disticha (Poaceae), Cyperus anderssonii (Cyperaceae), Panicum laxum (Poaceae), Sporobolus pyramidatus (Poaceae); woody plants\u2014Acacia rorudiana (Mimosaceae), Bursera graveolens (Burseraceae), Maytenus octogona (Celastraceae), Parkinsonia aculeata , and Scutia spicata (Rhamnaceae); succulents\u2014Sesuvium edmonstonei (Aizoaceae), and cactus\u2014Opuntia echios (Cactaceae).The Galapagos Islands are a volcanic archipelago straddling the equator 1000 km west of continental Ecuador . ClimateZalophus wollebaeki) to enter the island for resting. A final biotic difference known to occur between the islands other than presence/absence of land iguanas was the former existence of a small cohort of goats using the Geospatial Data Abstraction Library for geo encoding, warping and tiling supported with Python 3.4 and Imagemagick software in R in R . To measge) in R .versus its extent in the eight neighboring grid cells and 1,777 grid cells on South Plaza island (iguanas present) . Vegetatid cells indicateid cells revealedThis study provides evidence that large-bodied, herbivorous reptiles can substantially engineer the structure of terrestrial plant communities. Not only was woody vegetation far less extensive on the island with land iguanas, the spatial pattern of woody vegetation also differed insofar as it tended to be surrounded by more woody vegetation in the presence of iguanas than in their absence. Land iguana impacts on cactus\u2014a keystone species for the entire vertebrate community\u2014were also substantial, reducing cactus abundance and altering spatial distribution of cactus.We suspect the dramatic contrasts in vegetation between islands were due primarily to herbivory by iguanas. Land iguanas consume fruits, flowers, leaves and shoots of woody plants, including those of species that dominated on the Plazas Islands . TargeteLand iguana herbivory might well have a cascading effect on the biotic community of small oceanic islands, by influencing other terrestrial vertebrates through changes in habitat structure and composition. One important interaction likely resulting from iguana herbivory with impacts on many other species on the Plazas Islands involves marine mammals. Sea lions cannot navigate through woody vegetation when seeking basking sites, and occupy more sparsely vegetated areas facilitated by iguanas. Sea lions deposit prolific amounts of guano with attendant changes in the soil chemistry . Notablyvia trampling and altering soil chemistry through deposition of feces sea lions affecting vegetation. This said, many parts of South Plaza Island remain inaccessible to sea lions and those areas still evidence the general differences observed in vegetation between North and South Plazas Islands.A primary limitation of our study is that it represents a pseudo-replicated design with one replicate within each treatment. Unfortunately given the widespread extinctions of island forms of large-bodied reptilian herbivores elsewhere in Galapagos and around the world , there aWhy land iguanas do not occur on North Plaza Island is not clear. The species\u2019 habitat is characterized as \u201cdry areas with low growing shrubs and Opuntia cactus\u201d which deversus absence of land iguanas. We provide evidence that land iguanas substantially engineer the structure of plant communities. This study suggests that the widespread extinction of reptile herbivores, which once served as the dominant herbivore in many tropical oceanic ecosystems, might have profound implications for the status of these ecosystems, and the species that comprise them, today. Restoration of large-bodied reptilian herbivores, such as land iguanas and giant tortoises, should be regarded as an important component of restoration in ecosystems where they have been extirpated.Understanding how large-bodied herbivores engineer ecosystems is relevant today given widespread, current interest in reintroducing extant species back to places from which they were extirpated in historical times . With ma10.7717/peerj.12711/supp-1Supplemental Information 12) aerial imagery and delineating extent of plant associations and counting individual plants on each .Plant communities characterized on each island by developing high-resolution and North Plaza Island (iguanas absent).Click here for additional data file."} +{"text": "ABSTRACT IMPACT: This qualitative study describes health system barriers to high-quality care for Latino older adults with Alzheimer\u2019s Disease and Related Dementias OBJECTIVES/GOALS: Compared to non-Latino Whites, Latino older adults are more likely to receive low-quality dementia care such as high-risk medications or services. Caregivers play a critical role in managing medical care for persons with dementia (PWD). Yet little is known about the perceptions and knowledge of dementia quality of care among Latino caregivers of PWD. METHODS/STUDY POPULATION: We used a qualitative research design and conducted interviews with Latino caregivers of PWD and caregiver advocates. We recruited both from community organizations, senior centers, and clinics. Our interview guide focused on experiences of caregiving, interactions with medical system, and knowledge and experiences managing behavioral and eating problems. We used Grounded Theory methodology for coding and analysis, focusing on contrasting and comparing experiences within and between caregivers and caregiver advocates. RESULTS/ANTICIPATED RESULTS: Preliminary results from interviews with two caregivers and two caregiver advocates illustrate that caregivers of persons with dementia have a difficult time receiving high quality care from primary care clinicians. All participants noted that many primary care doctors didn\u2019t know how to diagnose ADRD and dismissed critical symptoms as part of old age. Caregivers also reported that they wished they had more information on what to expect with ADRD disease progression, noting they received little information from the formal medical care system. With respect to behavioral problems, caregiver advocates noted that primary care doctors often did not provide non-pharmacological alternatives to behavioral problems. DISCUSSION/SIGNIFICANCE OF FINDINGS: Findings from our pilot study demonstrate that there is a clear need to train primary care physicians who serve Latino older adults on ADRD care. Improved diagnosis and management could improve outcomes among Latino older adults with dementia."} +{"text": "COVID-19 upended in-person educational programming in areas such as classroom instruction within academic institutions, engagement of adult learners, and training of direct care workers. In-person educational offerings were forced, as a result of health restrictions, to pivot into either asynchronous or synchronous web-based instruction. This panel discussion will discuss lessons-learned in cyber-pedagogy in three areas: 1) Faculty Consultation: Faculty who teach online regularly and have completed training in quality online educational practices are experts who were called upon to assist others with transitioning courses to an online format. This presentation outlines the ways in which certified online instructors, at one academic center, tutored and assisted faculty in the health sciences with online instruction. 2) Adult Learning: The rapid transition to online learning has implications for adult learners pertaining to accessibility, diverse learning and technology abilities, and course and peer engagement. This presentation will explore strategies that faculty can utilize to offer adult learners differentiated learning and engagement opportunities. This discussion will also highlight the nexus among these pedagogical strategies and the Age-Friendly University Global Network, providing guidance for how universities can connect online learning methods to the Age-Friendly University principles. 3) Workforce Training: The direct care workforce employed in community-based services and support programs and long-term care settings tend to receive little or no training in geriatric care. This presentation will discuss how educational trainings offered through a Geriatric Workforce Enhancement Program transitioned onto web-based platforms in order to accommodate these ongoing educational needs throughout the pandemic."} +{"text": "Existing research has identified significant risk factors for experiencing social isolation in later life including chronic health conditions, mobility impairments, and living alone among others. Although many older people who live alone maintain active social lives, living alone remains a top predictor of social isolation. Less is known about other types of risk factors, such as place-based risks and social exclusion. Despite calls to examine the role of place and social exclusion in social isolation risk, few studies have investigated the links. Models of isolation risk have often omitted place-based factors and social exclusion and focused largely on individual-level risks. In order to address these gaps, this paper presents the findings of 17 in-depth, qualitative interviews with community-dwelling older people who live alone (aged 65-93). Participants were recruited using a theoretical sampling strategy to ensure that a diverse range of neighbourhood types were represented among the participants . Interview transcripts were analyzed using a constructivist grounded approach resulting in several major themes. Participants described aspects of their local environments as shaping their risk of isolation including infrastructure and amenities delivered in place, and neighbourhood makeup, among others. These themes are further examined through the lens of place-based exclusion and used to conceptualize how dimensions of both place and social exclusion fit into the model of known isolation risk factors. An adapted model of risk is presented to guide future research and intervention planning."} +{"text": "As COVID-19 lockdowns began in Canada last spring, family caregivers (FCGs) of people living with dementia (PLWD) found themselves facing a catch-22: they and their family members were often most at risk of severe outcomes should they contract the virus, yet the public health measures put in place also detrimentally affected their ability to continue providing care. To understand the nuances of caregiver experiences during the pandemic, we conducted 9 focus groups with 19 FCGs of PLWD in the Calgary region in summer 2020. Caregivers reported negative outcomes resulting from decreased services for both themselves and the PLWD, including increased isolation, poor mental health, and accelerated dementia progression. Caregivers also emphasized the importance thinking beyond the binary of either locking down or opening up; rather, we must find creative solutions to safely continue providing supports to caregivers. This presentation explores FCG suggestions for balancing COVID-19 risk against caregiver needs."} +{"text": "Axons in the adult mammalian nervous system can extend over formidable distances, up to one meter or more in humans. During development, axonal and dendritic growth requires continuous addition of new membrane. Of the three major kinds of membrane lipids, phospholipids are the most abundant in all cell membranes, including neurons. Not only immature axons, but also severed axons in the adult require large amounts of lipids for axon regeneration to occur. Lipids also serve as energy storage, signaling molecules and they contribute to tissue physiology, as demonstrated by a variety of metabolic disorders in which harmful amounts of lipids accumulate in various tissues through the body. Detrimental changes in lipid metabolism and excess accumulation of lipids contribute to a lack of axon regeneration, poor neurological outcome and complications after a variety of central nervous system (CNS) trauma including brain and spinal cord injury. Recent evidence indicates that rewiring lipid metabolism can be manipulated for therapeutic gain, as it favors conditions for axon regeneration and CNS repair. Here, we review the role of lipids, lipid metabolism and ectopic lipid accumulation in axon growth, regeneration and CNS repair. In addition, we outline molecular and pharmacological strategies to fine-tune lipid composition and energy metabolism in neurons and non-neuronal cells that can be exploited to improve neurological recovery after CNS trauma and disease. Developing axons in the mammalian nervous system can extend very long distances . After rContinuous addition of new membrane is required during axon and dendrite growth ,24, streA schematic representation of membrane expansion during axonal and dendritic growth, stretch growth of integrated axons, myelin formation and repair, sealing of membrane ruptures and axon regeneration. PPV: plasmalemmal precursor vesicles.Membrane expansion in developing axons is mediated by polarized exocytosis of plasmalemmal precursor vesicles that are anterogradely transported to the growth cone ,36. New A schematic representation of the assembly of the exocyst octameric protein complex that controls the tethering of secretory vesicles to the plasma membrane prior to SNARE-mediated fusion. Soluble N-ethylmaleamide attachment proteins (SNAP), vesicle associated membrane proteins (VAMP) and syntaxis form the core machinery of vesicle fusion also known as the SNARE complex . WhereasAfter axotomy, rapid sealing of disrupted membranes is necessary to restore boundary integrity of the axonal compartment, to equilibrate ion concentration and to counteract osmotic stress . These sFormation of a new growth cone at the axonal stump also requires insertion of new membrane into the neurolemma ,59. A prAnother recent study in adult CNS neurons has shed light on the specific changes in lipid metabolism that contribute to axon regeneration. After axotomy, expression of the phosphatidic acid phosphatase enzyme lipin 1 increase in retinal ganglion cells . MechaniProm1, which encodes the membrane glycoprotein Prominin-1, acts as a positive regulator of peripheral nerve regeneration in adulthood [Prom1 forced expression enhances axon regeneration via Smad2-dependent signaling and inhibits the expression of genes related to cholesterol biosynthesis [During early stages of development, immature neurons exhibit an extraordinary axon growth and regenerative capacity ,62,63. Adulthood . Prom1 fynthesis . In the adult CNS, the vast majority of cholesterol is present in myelin sheaths and plasma membranes. After SCI, disruption of cellular membranes and myelin sheaths cause an excess of cholesterol to accumulate in the extracellular space. Of interest, cholesterol depletion has been shown to promote axon growth in vitro and regeneration of peripheral nerves in vivo . By loweThe neuronal cell bodies in sensory, sympathetic and parasympathetic ganglia are wrapped by satellite glial cells . The impTogether, experimental evidence suggests that rewiring lipid metabolism can be manipulated for therapeutic gain as it favors axon regeneration both in the central and peripheral nervous systems. Whether pharmacological and molecular strategies lowering cholesterol synthesis promote neurological recovery after SCI is unknown and deserves further attention in future investigations. Drosophila have shown that dendrite expansion in larva neurons relies on cell-autonomous production of lipids [srebp mutant. SREBP acts as a basic helix\u2013loop\u2013helix leucine zipper transcription factor that binds to sterol regulatory elements to control the expression of genes that encode key enzymes of both fatty acid and cholesterol metabolism [srebp mutant larvae. In turn, cell-autonomous production of fatty acids is necessary for correct dendritic development and function. A genetic screen in dendritic arborization sensory neurons of the Drosophila larval peripheral nervous system has identified the easily shocked (eas) gene, which encodes the ethanolamine kinase , as a c mutants , causing mutants . Eas mut neurons ,86. ThusMyelin is constituted by multiple overlapping layers of a specialized membrane spiraling around axons . Myelin During normal brain development, astrocyte-derived fatty acids constitute a significant portion of lipids incorporated into CNS myelin . RemarkaAs result of CNS trauma and disease, myelin sheaths along the axon can be severely damaged. De novo fatty acid synthesis via fatty acid synthase is critical for CNS myelin formation after demyelination injury. Genetic depletion of fatty acid synthase from OPC has no effect on proliferation and differentiation along the oligodendrocyte lineage, yet is necessary for accurate CNS myelination . TreatmeIn mammals, the ability to regenerate and repair the CNS declines with age ,117. In Recent evidence suggests that a delicate balance in lipid synthesis and homeostasis is crucial during myelin formation and remyelination during CNS development, as well as after injury or disease. Strategies targeting lipid composition of the myelin membrane may exert contradictory responses where a lipid-enriched diet may rescue myelination defects while excess lipids trigger oligodendrocyte death and inflammation. Learning how to fine tune lipid composition in myelin membranes via extracellular lipid supply, lowering cholesterol levels or promoting its clearance with spatial precision without causing adverse effects represent important areas of future investigation. As discussed above, lipids are necessary for proper sealing of the plasma membrane, formation of a new growth cone and regeneration after axonal injury. These energy demanding processes require optimal mitochondrial transport and adenosine triphosphate (ATP) production ,122,123.As axons reach their target field during late stages of development, formation of collateral branches and synaptic contacts allow neurons to establish complex connectivity patterns ,131,132.Mitochondria trafficking and anchoring along the axons needs to be tightly regulated to respond to altered energy requirements . To meetMitochondrial positioning along the axon is important as it enables local energy supply . AccumulO-linked \u03b2-N-acetylglucosamine (O-GlcNAc) post-translational modification of serine and threonine residues of proteins acts as a nutrient sensor and metabolic mediator [worms, a decrease in O-GlcNAc levels promotes axon regeneration by adopting glycolysis as the primary source of energy [O-GlcNAc levels fail to regenerate after blocking glucose transport or inhibiting glycolysis, increasing O-GlcNAc levels act on mitochondrial function and enhance axon regeneration in Caenorhabditis elegans through FOXO/DAF-16\u2013dependent mechanisms [O-GlcNAc levels drive distinct branches of the insulin pathway to promote regeneration in worms may help explain these seemingly contradictory results. How does cellular metabolism contribute to neuron repair after axotomy? By linking glucose metabolism to the hexosamine biosynthetic pathway, mediator . One dayf energy . Whilst chanisms . The facAs glial cells are metabolically coupled to axons, they may provide energy metabolites to support axon survival and function ,156,157.Together, the above examples underscore the importance of achieving optimal mitochondrial transport and glial metabolism as they are necessary for energy production to fuel axon growth and regeneration. Whether mitochondrial transport may be linked to nutrient and energy sensing is not known. It is also not clear whether mitochondria have memories, allowing them to respond rapidly to changes in environmental nutrient and energy levels. The extent to which boosting energy metabolism and mitochondria trafficking may be sufficient to promote functionally relevant regeneration and CNS repair under different experimental conditions awaits confirmation. After CNS trauma and disease, altered lipid metabolism and lipid accumulation in neurons and various tissues in the body can be harmful, as it causes permanent cellular damage . To undeUnder normal physiological conditions, excess energy is stored in depots of white adipose tissue (WAT) in the form of triacylglycerides. WAT depots include abdominal and subcutaneous fat ,163 Fig. To mobiGeneration of body heat by external stimuli like temperature or food is called adaptive thermogenesis and is further classified as either shivering or non-shivering thermogenesis. By controlling the non-shivering thermogenic function, brown adipose tissue (BAT) plays a crucial role in maintaining whole-body energy balance. BAT\u2019s unique ability to produce heat relies on the mitochondrial uncoupling protein 1 (UCP1), which disengages oxidative phosphorylation from the electron transport chain to produce heat instead of energy in the form of ATP . IncreasRecent evidence suggests that innervation of adipose tissue may play a critical role in lipid mobilization and endocrine signaling ,170,171.More than 100 years ago, Dogiel reported neurons of unknown origin innervate WAT . DecadesSensory neurons also innervate WAT. In fact, T13-L3 neuronal cell bodies can be visualized upon retrograde tracing in WAT . SimilarUnlike WAT, BAT segments bilaterally . As noreLipolysis and adaptive thermogenesis are necessary to control a healthy energy balance. Neurons that connect the hypothalamic regions and innervate WAT and BAT form a \u2018leptin sensitive\u2019 closed loop. The arcuate nucleus in the hypothalamus is one such CNS region that critically senses leptin levels to promoIndividuals that sustained an injury to the brain or spinal cord may have lower life expectancy due to chronic secondary complications that develop months and years after injury. Bladder and bowel dysfunction can cause anxiety, social isolation and depression after SCI . SympathIt is important to note that adiposity in SCI individuals and healthy individuals is not exactly the same. Within a year after injury, SCI individuals lose bodyweight, mostly in lean muscle mass . The draAt least half of individuals with SCI has >30% of their total body mass as adipose tissue, indicating SCI individuals are at high risk of developing metabolic syndrome Figure . AdiposeA rise in triglycerides in the liver may be caused by increased storage after de novo synthesis, reduced breakdown, or impaired secretion in the form of very-low-density lipoproteins (VLDL). Under pathological conditions like obesity, fatty acids are converted into triglycerides. These are stored as neutral lipid droplets as they no longer get converted into energy substrates by oxidation. With more incoming fatty acids adding to the pool of stored lipid droplets in the liver, the de novo synthesis of lipids increases, thereby causing lipid accumulation within the liver ,225. As Proper insulin signaling in the liver orchestrates the critical steps of VLDL secretion . HoweverMore than half of the triglycerides deposited in the liver originates from circulating fatty acids and ~25% of the triglycerides comes from de novo lipogenesis . Given tA gradual rise in whole-body adiposity compromises the balance between fatty acid uptake and secretion with negative impacts on the liver metabolic profile. Despite recent progress, a thorough mechanistic understanding of liver pathology after SCI is still lacking. As the liver represents the primary site for drug metabolism, reducing hepatic metabolic dysfunction may boost efficacy of SCI medications and repair strategies. As circulating free fatty acid levels increase due to adiposity, the glucose-fatty acid cycle, also known as the \u2018Randle\u2019 cycle , destabiCardiovascular complications represent the leading cause of death in chronic SCI individuals ,242,243.We have discussed evidence suggesting that reprogramming lipid metabolism, boosting mitochondrial transport and neuron-glia metabolic coupling promote survival and regeneration of injured axons. Whereas large amounts of lipids are necessary during development to grow axons, dendrites and myelin sheaths, dysregulation of lipid metabolism, impaired mitochondrial functions and excess lipid accumulation through the body including in non-adipose organs can be harmful as they cause lipotoxicity and increased levels of fatty acids. Not only do such detrimental conditions contribute to axon regeneration failure, but also to insulin resistance, cardiovascular disease and metabolic syndrome, thus leading to poor neurological outcomes and a diminished quality of life. In addition, spatial and temporal alteration of circulating fatty acids may compromise CNS function and repair under pathological conditions including CNS trauma and neurodegenerative diseases. Correct positioning of organelles for membrane trafficking, lipid exchange and energy production requires a complex interplay between various organelles and molecular motors . The fab"} +{"text": "Strong social relationships and social engagement are crucial for both successful aging and successful community re-entry after incarceration. Here, we utilized a mixed methods approach to understand the impact of incarceration on social relationships and social engagement among formerly incarcerated community-dwelling African-American adults aged >50. Participants in the 2012 or 2014 waves of the Health and Retirement Study answered questions regarding prior incarceration, social relationships, and participation in social activities. Additionally, we utilized key informant interviews to further explore how incarceration might impact relationships and social engagement. This presentation will describe quantitative associations between prior incarceration and social relationship structure & function. Further, we will use our qualitative interview data to further explore possible explanations for our findings. Finally, we will describe how MCUAAAR Scientist/Faculty interactions facilitated this work."} +{"text": "OBJECTIVES/GOALS: People engaging in high-risk substance use or experiencing food insecurity or housing instability are at increased risk to develop end-stage kidney disease. This study will examine associations between these risk factors, patient indicators of socioeconomic position, and hospitalization rates and quality of life after initiation of hemodialysis. METHODS/STUDY POPULATION: The proposed study will leverage a prospective cohort design. We will enroll a convenience sample of 330 participants from the same large dialysis organization. Participants will complete measures of socioeconomic position ; substance use; food insecurity; housing instability; and quality of life at baseline. We will follow participants for 6 months and extract hospitalization counts from the dialysis facility medical record. RESULTS/ANTICIPATED RESULTS: We will generate risk scores from measures of substance use, food insecurity and housing instability. We will conduct multiple logistic regression to generate odds ratios comparing risk group membership by indicators of socioeconomic position. We anticipate that low or medium-risk groups will differ from high risk groups by indicators of socioeconomic position. We will conduct Poisson regression to generate incidence rate ratios for 6-month hospitalization rates comparing low or medium-risk and high-risk groups. Lastly, we will conduct multiple linear regression to generate beta coefficients for changes in quality of life scores comparing low or medium-risk and high-risk groups. We anticipate that high-risk groups will have higher hospitalization rates and lower quality of life scores. DISCUSSION/SIGNIFICANCE OF IMPACT: As the prevalence of end-stage kidney disease continues to increase, there is a need for tertiary prevention interventions that reduce costly inpatient utilization and improve health-related quality of life. The proposed study will lay groundwork for the development of interventions to improve patient outcomes and reduce Medicare spending."} +{"text": "Oral health is a global public health concern. The four papers in this symposium capture various understudied risk and protective factors in oral health and dental care among older adults in China. The first paper examined the relationship between social isolation, loneliness, and tooth loss among Chinese older adults, using the Chinese Longitudinal Healthy Longevity Survey. The findings suggest that higher levels of social isolation, rather than loneliness, were associated with fewer remaining teeth and accelerated tooth loss over time. The second paper investigated urban-rural disparities in dental care utilization among Chinese adults aged 18 to 65 years old, using the 2019 New Era and Living Conditions in Megacities Survey. The findings demonstrate urban residents were more likely to visit dentists than rural residents. Besides socioeconomic status, health attitudes/behaviors, and oral health needs, health insurance coverage was considered an important enabling factor to promote dental care use in this population. The third paper examined the relationship between denture use and cognitive decline among Chinese older adults, using data from the Chinese Longitudinal Healthy Longevity Survey. The findings indicate that denture use is protective against cognitive decline over time in later life. The fourth paper examined the prevalence of self-reported orofacial pain symptoms and their correlates at the last year of life among Chinese older adults. Low socioeconomic status, smoking, chronic conditions, oral hygiene practice, and natural teeth condition were associated with such symptoms. This symposium offers valuable insights to improve oral health and dental care in older adults in China."} +{"text": "ABSTRACT IMPACT: This project aims to better understand mechanisms of sensory and motor deficits in individuals with ASD with the goal of informing diagnosis and treatment development. OBJECTIVES/GOALS: Over-reliance on both visual and proprioceptive feedback have both been observed during motor behavior in persons with Autism Spectrum Disorders (ASD), suggesting that separate sensory feedback processes may be selectively altered during different behaviors. The objective of this study is to clarify sensory mechanisms of fine motor control in ASD. METHODS/STUDY POPULATION: Participants with ASD (N=43) and controls (N=23) matched on age (10-20 yrs) and non-verbal IQ completed tests of precision gripping. Participants were instructed to press on force sensors with their index finger and thumb so that a moving bar corresponding to their force output reached and stayed as stable as possible at the level of a stationary target bar. Visual feedback was manipulated by changing the visual gain of the force bar . The force bar moved more per change in force output at higher gains. Proprioceptive feedback was manipulated by applying 80 Hz tendon vibration at the wrist to induce an illusion of muscle contraction. This was compared to a condition with the tendon vibrator turned off. Force variability (standard deviation) and regularity (sample entropy) were examined. RESULTS/ANTICIPATED RESULTS: Controls showed increased force variability with the tendon vibration on compared to off ; however, the ASD group showed no difference in force variability between the tendon vibration conditions . Individuals with ASD had stronger age-associated reductions in force variability relative to controls across tendon vibrator and gain conditions . The ASD group also had greater age-associated increases in force regularity relative to controls, especially at higher gain levels . Unlike the ASD group for whom regularity increased with age in both tendon vibration conditions, controls only showed these age-related gains when the tendon vibrator was off . DISCUSSION/SIGNIFICANCE OF FINDINGS: Our findings indicate that while controls integrate proprioceptive and visual feedback online to accurately adjust fine motor behavior, persons with ASD rely mostly on visual feedback. Our results suggest delayed development of sensory integration and reduced reliance on multisensory feedback during online fine motor control in persons with ASD."} +{"text": "Although cognitive decline has previously been associated with mobility limitations and frailty, the relationship between sustained attention and gait speed is incompletely characterized. To better quantify the specificity of the sustained attention and gait speed association, we examined the extent to which this relationship is unique rather than accounted for by executive functioning and physical health characteristics. 58 middle-to-older-aged community-dwelling adults without overt illness or diseases participated in the study. Each participant completed a 4-meter gait speed assessment and validated neuropsychological tests to examine various domains of executive functions including working memory , inhibitory control , and task switching . Multiple physical and vascular risk factors were also evaluated. Sustained attention was assessed using the gradual onset continuous performance task (gradCPT), a well validated go/no-go sustained attention task. A series of linear regression models were created to examine how different aspects of cognition, including sustained attention and traditional measures of executive functioning, related to gait speed while controlling for a variety of physical and vascular risk factors. Among all predictors, gradCPT accuracy explained the most variance in gait speed and was the only significant predictor when accounting for executive functioning and other physical and vascular risk factors. The present results indicate that sustained attention may be uniquely sensitive and mechanistically linked to mobility limitations in middle-to-older adults."} +{"text": "Inflammaging characterized with increased low grade inflammation in older adults is common determinant of unhealthy aging; and is a major risk factor of morbidity and mortality in older adults. The precise origin of inflammation in older adults is not known, however, emerging evidence indicate that increased intestinal epithelial permeability (leaky gut) and abnormal (dysbiotic) gut microbiota could be one of the key source. However, no preventive and treatment therapies are available to reverse the leaky gut and microbiome dysbiosis in older adults. Here, we presented the evidence that a human-origin probiotics cocktail containing 5 Lactobacillus and 5 Enterococcus strains isolated from healthy human infant gut can ameliorate aging-related metabolic, physical and cognitive dysfunctions in older mice. We show that the Feeding this probiotic cocktail prevented high-fat diet\u2013induced (HFD-induced) abnormalities in glycose metabolism and physical functions in older mice and reduced microbiota dysbiosis, leaky gut, inflammation. Probiotic-modulated gut microbiota reduced leaky gut by increasing tight junctions on intestinal epithelia, which in turn reduced inflammation. Mechanistically, probiotics increased bile salt hydrolase activity in older microbiota, which in turn increased taurine deconjugation from bile acids to increase free taurine abundance in the gut. We further show that taurine stimulated tight junctions and suppressed gut leakiness. Further, taurine increased life span, reduced adiposity and leaky gut, and enhanced physical function in Caenorhabditis elegans. Whether this novel human origin probiotic therapy could prevent or treat aging-related leaky gut and inflammation in the elderly by reversing microbiome dysbiosis requires evaluation."} +{"text": "Function by Roy et al.\u201cChoose your parents wisely\u201d is a popular adage coined by the British Philosopher Bertrand Russell, and often used when discussing issues such as socioeconomic position and genetic contributions to disease risk. When it comes to vascular function, a predictor of cardiovascular disease risk, the recent study in HCR) and vice versa (HCR-mtLCR). Specifically, HCR female offspring were backcrossed with male LCR via inbreeding, and this backcross procedure was repeated over several generations to generate the LCR-mtHCR and HCR-mtLCR. The investigators performed echocardiography to assess cardiac function and left ventricular mass, wire, and pressure myography to assess arterial vasodilatory function (with and without PVAT) and mechanics, macroscopic tissue imaging of PVAT, and bioenergetic assays with vascular smooth muscle cells (VSMCs).The investigators studied rats artificially selected (within-family) for intrinsic aerobic endurance running capacity to generate LCR and HCR male rats.HCR) but decreased left ventricular mass and several indices of cardiac performance in HCR-mtLCR relative to HCR.Compared to HCR, LCR rats had higher body mass, epididymal fat mass, and blood pressure. Regarding cardiac measures, HCR rats presented higher left ventricular mass than LCR rats see . CompareHCR), however, it did not reduce vascular function in HCR-mtLCR. Using mesenteric arterioles and plotting internal lumen and external diameters with intraluminal pressure curves, the authors revealed that the arterioles from LCR rats exhibited hypotrophic remodeling . Moreover, mitochondrial swap did not have an effect on either the LCR or HCR phenotype.The key findings were that compared to HCR, LCR rats presented with lower endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilation in mesenteric resistance arteries. Mitochondrial swap rescued endothelium-dependent and endothelium-independent vasodilation in LCR to what extent intrinsic exercise capacity and mitochondrial DNA influence vascular function in female and older rodents, (2) if the reduced endothelium-dependent vasodilation in LCR rats is mediated by reduced NO synthesis and/or bioavailability or a combination of NO and/or other vasodilators or prostacyclin), (3) the role of mitochondrial ROS and other vascular sources of ROS in contributing to the vascular phenotypes associated with HCR and LCR, and (4) determining whether exercise, similar to mitochondrial swapped conplastic strains, can also rescue endothelial dysfunction in LRC rodents .,HCR on LCR rodents demonstrates that mitochondrial DNA is an essential oddment to the protective phenotype conferred by high CRF. These findings will hopefully pave the way for exciting future research to determine mitochondrial-based targets to help prevent and treat cardiovascular disease.At the population level, we cannot do much to improve an individual\u2019s intrinsic CRF. Indeed, the HERITAGE family study established that intrinsic capacity and trainability are genetically heritable in humans."} +{"text": "The coexistence of expiratory central airway collapse and diaphragmatic paralysis presents a diagnostic and treatment challenge. Both entities are underrecognized causes of dyspnea, cough, sputum production, and orthopnea. Optimal treatment must be individualized and is best achieved by a multidisciplinary team. We present a case of a patient with profound functional impairment from dyspnea and hypoxemia due to expiratory central airway collapse, complicated by bronchiectasis from recurrent respiratory infections, and diaphragmatic paralysis. There are a myriad of causes of dyspnea, hypoxemia, and excessive sputum production. Identifying the relevant contributors to patient's presenting concerns is critical for appropriate management. Expiratory central airway collapse (ECAC) involving either the cartilaginous tracheal wall or the posterior membranous portion may be suggested by computed tomography imaging of the chest obtained during forced expiration and confirmed by dynamic bronchoscopy. Fluoroscopy and diaphragm ultrasound are used to diagnose diaphragmatic paralysis. Surgical management includes tracheobronchoplasty and diaphragmatic plication. ECAC and diaphragm paralysis both compromise gas exchange during surgery but the effect can be mitigated by the use of intraoperative extracorporeal membrane oxygenation (ECMO).A 54-year-old man presented with progressive shortness of breath, cough, and recurrent pneumonia. Chest examination was notable for reduced bilateral lung excursion, coarse breath sounds diffusely, and paradoxical breathing in the supine position. Pulmonary function testing suggested severe restriction with FVC of 27% predicted, FEV 1 28% predicted, normal FEV1/FVC ratio, and respiratory muscle strength < 10% predicted.Computed tomography (CT) of the chest revealed basilar bronchiectasis and bilateral diaphragmatic elevation with associated atelectasis. Dynamic CT showed anterior displacement of the posterior tracheal wall at the distal trachea, bilateral main stem bronchi, and bronchus intermedius. Electromyogram demonstrated bilateral phrenic neuropathy and left brachial plexus neuropathy. Ultrasound confirmed the absence of diaphragm movement bilaterally. He had progressive clinical decline requiring near constant noninvasive positive pressure ventilation (NPPV). Dynamic bronchoscopy showed severe expiratory central airway collapse (ECAC) with >90% collapse of the trachea, main stem bronchi, and bronchus intermedius . A stentThe initial surgery was aborted due to the inability to maintain adequate oxygenation during single lung ventilation. One week later, the procedure was successfully completed through right thoracotomy under venous-venous extra-corporeal membrane oxygenation (VV ECMO) support. Central airway stabilization was achieved by suturing a knitted polypropylene mesh to the posterior membrane of the trachea and bilateral main bronchi. Due to persistent ventilator dependency, left diaphragm plication through a left thoracotomy was performed 5 days postoperatively. He was discharged home on postoperative day #23.At follow-up evaluation, he no longer required NPPV and regained independence in activities of daily living. Pulmonary function testing showed improvement with FVC of 53% predicted, FEV1 42% predicted, and respiratory muscle strength 13% predicted. CT of the chest demonstrated improved lung volumes . DynamicAlthough diagnostic parsimony encourages identifying a single unifying explanation for one's symptoms, this case illustrates the veracity of Hickam's dictum: \u201cA man may have as many diseases as he damn well pleases .\u201d We hypUnilateral or bilateral dysfunction of the diaphragm can result from phrenic nerve dysfunction, neuromuscular junction disease, or myopathy. Paradoxical respiratory efforts and decline in FVC while supine suggest DP with confirmation achieved with fluoroscopy, ultrasound, or phrenic nerve EMG. Symptomatic unilateral disease that cannot be explained by another underlying disease process may be amenable to plication. Bilateral DP can be managed by noninvasive positive-pressure ventilation and treatment, if available, of the underlying cause. Diaphragmatic pacing may be beneficial if phrenic nerve function is intact. The goal of plication is at eliminating the paradoxical upward motion of the paralyzed diaphragm and decreasing the basilar parenchymal compression. Although historically performed via a thoracotomy, plication can also be performed effectively with minimally invasive robotic, thoracoscopic, or laparoscopic techniques . SurgicaRecognition of large airway dysfunction during expiration as a cause of chronic respiratory symptoms is gradually increasing. Two patterns have been described in ECAC: (1) tracheobronchomalacia (TBM) in which the cartilaginous component of the anterolateral tracheal wall collapses on forced expiration and (2) excessive dynamic airway collapse (EDAC) in which there is anterior displacement of the posterior (membranous) tracheal wall during expiration . When clWhen the degree of airway collapse is severe, surgical repair should be considered. A preoperative stent trial with uncovered self-expandable metallic stents is strongly advised to estimate the potential surgical benefit prior to surgical intervention . In our Our technique for tracheobronchoplasty involves plication of the redundant posterior membrane of the trachea and mainstem bronchi and fixation to a semirigid permanent (polypropylene) permeable mesh. The standard approach is through a right thoracotomy, although minimally invasive robotic and thoracoscopic approaches have also been reported to be feasible but with unknown long-term results .We hypothesize that basilar bronchiectasis in this patient was due to inadequate airway clearance from both ECAC and DP resulting in recurrent lower respiratory infections. Medical management of bronchiectasis to improve airway mucous clearance was limited due to compromised large airways from ECAC and weak cough from DP.VV ECMO is used most commonly in acute respiratory distress syndrome and in patients with advanced lung disease requiring transplant either intraoperatively or as a bridge to lung transplantation. As the use of ECMO increases, understanding the surgical implications of this therapy is critical. In a review of 563 patients on ECMO, 269 required noncardiac surgery. There was no difference in outcomes between those needing or not needing surgery . AnticipBoth ECAC and bilateral diaphragmatic dysfunction, with associated bronchiectasis, synergistically lead to dyspnea, cough, respiratory infections, and severe functional impairment in this patient. Demonstration of the improvement in clinical outcomes with an airway stent trial before entertaining surgical correction of ECAC is critical to optimize patient selection. As demonstrated, surgical intervention for both ECAC and diaphragm paralysis can dramatically improve the quality of life and functional capability. Intraoperative ECMO may permit definitive surgical treatment of ECAC in patients with gas exchange abnormalities that would otherwise preclude surgery.This case elucidates three critical concepts to comprehensive patient-centered care. The importance of thoroughly investigating all the relevant contributors to a patient's symptoms, with specific attention to those for which therapy can be offered, is illustrated. Additionally, the novel use of ECMO demonstrates the need to embrace unconventional surgical approaches as mandated by the patient's clinical scenario. Finally, it was only the multidisciplinary team-based approach to care, involving pulmonologists, interventionalists, thoracic surgeons, anesthesiologists, and intensivists that allowed successful management of this patient's complex presentation."} +{"text": "Racial minorities and educationally disadvantaged experienced more housing loss, unemployment, and financial strain during the 2007-2009 Great Recession. These hardships may heighten stress and amplify persistent and growing health inequities, which were further worsened by the recent COVID-19 pandemic. It is therefore essential to identify factors that contribute to individual differences in vulnerability so that more effective interventions can be implemented, especially in older adult populations who may face unique economic hardships tied to age discrimination. According to the reserve capacity model, higher levels of psychosocial resources, including psychological well-being, can protect against the negative health outcomes related to heightened stress exposure. This study tested the intersections between recession hardship, pre-existing vulnerability defined as racial and educational disadvantage, and psychological well-being as predictors of biological indicators of chronic allostatic load. Chronic allostatic load was assessed with cardiovascular reactivity and recovery to acute mental stress and systemic inflammation . Biological data came from a national sample of adults known as the Midlife in the US Study that completed assessments after the recession. Multiple regression models revealed that more widespread recession hardship predicted greater biological dysregulation. Tests of three-way interactions revealed that the association between recession hardship and biological dysregulation was strongest among respondents with combined disadvantages of low educational status and low levels of psychological well-being. This study connected a major economic event to individual variation in health vulnerability and identified potential biological pathways to future disease outcomes."} +{"text": "Compared to non-dementia caregivers, family/friend caregivers of individuals with dementia experience more negative caregiving consequences. One reason is the myriad of negatively impacted life domains including: managing symptoms; family communication; financial and legal matters; and finding and coordinating services. Few psychometrically tested measures exist for assessing the range of potential unmet needs of dementia caregivers. Such a measure would describe the frequency and correlates of unmet needs and provide a key outcome for intervention research. This study tested the psychometric properties of a comprehensive measure of unmet needs, the BRI Unmet Need Instrument. Data from 192 family/friend dementia caregivers was used to test reliability and four validity types. Results showed total unmet needs, as well as its nine subscales, had good reliability . Discriminant validity was confirmed through factor analyses of the 45 unmet needs and items in measures of depression and care-related strain. Unmet need items loaded on separate factors that were deemed acceptable (.72-.38). Predictive validity was assessed by the association with depression, which was significant and an acceptable range . Convergent validity was confirmed by significant associations with three caregiver strain measures, mastery , emotional strain , and relationship strain . Good structural validity for nine predetermined unmet needs subscales was found using principal component analysis (loadings = .82-.39). Results suggest the BRI Unmet Needs Instrument is a ready-to-use, reliable and valid comprehensive measure."} +{"text": "The extant literature highlights the physiological and psychological benefits of active lifestyles among older adults, though there is a considerable gap in scholarship for sexual minority groups. Utilizing the Social Integration Model, we hypothesize that social activities enhance individual psychological well-being, but those effects differ by one\u2019s social identities. Using a national AARP foundation survey of adults (45+), this study examines whether individuals\u2019 activities predict loneliness and depressive symptoms of heterosexual (n=2905) and LGBTQ adults (n=318). We utilize an index of diverse activities, which includes, social technology use, meeting with friends, and volunteer activities. Multiple linear regression is used to study cross-sectional associations of loneliness and depressive symptoms on the diverse activity index. Results show that a wider array of activities correspond with higher psychological well-being and lower loneliness, and this association is higher for LGBTQ older adults. We discuss implications for counseling and wellness programming for LGBT older adults."} +{"text": "Although insurance companies are increasingly paying for home-based palliative care (HBPC), enrollment remains low. To identify patient and caregiver perceived barriers to HBPC and their recommendations for overcoming these barriers, we conducted semi-structured individual interviews. Our interview protocol elicited participants\u2019 perspectives on HBPC services; positive and negative aspects of the palliative program explanation; and suggestions for improving HBPC messaging. Seventeen patients and eight caregivers who were eligible for a randomized controlled trial of HBPC were interviewed. Themes related to HBPC referral barriers included reluctance to have home visits, enrollment timing, lack of palliative care knowledge, and patients\u2019 self-perceived health condition. Themes related to recommendations for overcoming these obstacles included ensuring that HBPC referrals come from healthcare providers or insurance companies and presenting HBPC more clearly. Findings reinforce the need for palliative care education among seriously ill patients and the importance of delivering palliative care information and referrals from trusted sources."} +{"text": "Maternofetal stress induces fetal programming that restricts skeletal muscle growth capacity and metabolic function, resulting in intrauterine growth restriction (IUGR) of the fetus. This thrifty phenotype aids fetal survival but also yields reduced muscle mass and metabolic dysfunction after birth. Consequently, IUGR-born individuals are at greater lifelong risk for metabolic disorders that reduce quality of life. In livestock, IUGR-born animals exhibit poor growth efficiency and body composition, making these animals more costly and less valuable. Specifically, IUGR-associated programming causes a greater propensity for fat deposition and a reduced capacity for muscle accretion. This, combined with metabolic inefficiency, means that these animals produce less lean meat from greater feed input, require more time on feed to reach market weight, and produce carcasses that are of less quality. Despite the health and economic implications of IUGR pathologies in humans and food animals, knowledge regarding their specific underlying mechanisms is lacking. However, recent data indicate that adaptive programing of adrenergic sensitivity in multiple tissues is a contributing factor in a number of IUGR pathologies including reduced muscle mass, peripheral insulin resistance, and impaired glucose metabolism. This review highlights the findings that support the role for adrenergic programming and how it relates to the lifelong consequences of IUGR, as well as how dysfunctional adrenergic signaling pathways might be effective targets for improving outcomes in IUGR-born offspring. Intrauterine growth restriction (IUGR) is the result of fetal developmental programming aimed at increasing the chances of surviving poor intrauterine conditions by promoting thrifty growth and metabolism. Unfortunately, these same developmental changes also diminish metabolic health and quality of life after birth . The linLow birthweight in livestock due to IUGR is a barrier to the economic sustainability of meat production, as these animals exhibit greater early-life mortality and lifelong performance deficits . Severe The establishment and characterization of several animal models for IUGR provides the opportunity to study the fetal programming mechanisms underlying IUGR pathologies in livestock and humans . CurrentThere is a broad range of causes for IUGR in livestock and humans that result in varying degrees of fetal growth restriction, which have been reviewed in greater detail elsewhere . In liveIUGR is necessitated by the increase in nutrient requirements to support normal fetal growth and the inability of the compromised placenta to meet them. Peak placental development occurs from the mid-1st trimester to the late 2nd trimester, which is from approximately day 30 to 100 of gestation in sheep and day 50 to 90 in humans . Most ma2 by the placenta creates chronic fetal hypoxemia and hypoglycemia muscles from near-term IUGR fetal sheep exhibited 20\u201350% reductions in the proportion of oxidative fibers relative to glycolytic fibers . Changestrations . This imtrations .Glucose homeostasis in the IUGR fetus and offspring is further impeded by reductions in pancreatic islet mass and function . \u03b2 cellsgreater-than-normal fat deposition as juveniles , which are expressed in tissue-specific combinations throughout the body modestly reduces glucose uptake but increases glycogen breakdown, glucose oxidation, and protein synthesis described in earlier sections. Additional work is warranted to more thoroughly characterize the observed adrenergic programming, but existing evidence indicates that it almost certainly contributes to the persistent deficits in muscle mass and glucose oxidation exhibited by IUGR-born offspring . By 60 days of age, these lambs exhibited substantial improvements in growth, muscle mass, and body symmetry (In vivo and ex vivo metabolic studies showed that daily clenbuterol injections at least partially recovered glucose-stimulated insulin secretion and skeletal muscle glucose oxidation, which was reflected by improvements in early-life whole-body O2 consumption rates (The identification and characterization of adrenergic programming mechanisms in IUGR tissues provides a target for potential treatment and intervention strategies. Indeed, animal studies have begun to provide the fundamental basis for adrenergic manipulation as a strategy to improve growth and metabolic outcomes in IUGR fetuses and offspring. In IUGR fetal sheep, pharmaceutical blockade of elevated adrenergic activity ecretion . Althougecretion . Moreovexidation . Althougon rates . Howeversymmetry . Greateron rates , 2021.2 supplementation was used to improve fetal oxemic status in sheep, metabolic improvements exceeded the impact on apparent adrenergic tone. Specifically, acute fetal normoxia improved insulin secretion in the IUGR fetus prior to reductions in circulating norepinephrine (2 content (The complexity of IUGR programming means that targeting adrenergic dysfunction alone is unlikely to fully recover growth and metabolic deficits in their entirety. For example, adrenal demedullation of IUGR fetal sheep did not improve deficits in pancreatic islet development and only partially corrected insulin secretion . Moreovenephrine , and dai content . Recent content , glucoco content , and poo content in the d"} +{"text": "Polymeric hydrogels are fascinating platforms as 3D scaffolds for tissue repair and delivery systems of therapeutic molecules and cells. Among others, methacrylated gelatin (GelMA) has become a representative hydrogel formulation, finding various biomedical applications. Recent efforts on GelMA-based hydrogels have been devoted to combining them with bioactive and functional nanomaterials, aiming to provide enhanced physicochemical and biological properties to GelMA. The benefits of this approach are multiple: i) reinforcing mechanical properties, ii) modulating viscoelastic property to allow 3D printability of bio-inks, iii) rendering electrical/magnetic property to produce electro-/magneto-active hydrogels for the repair of specific tissues , iv) providing stimuli-responsiveness to actively deliver therapeutic molecules, and v) endowing therapeutic capacity in tissue repair process . The nanomaterial-combined GelMA systems have shown significantly enhanced and extraordinary behaviors in various tissues that are rarely observable with GelMA. Here we systematically review these recent efforts in nanomaterials-combined GelMA hydrogels that are considered as next-generation multifunctional platforms for tissue therapeutics. The approaches used in GelMA can also apply to other existing polymeric hydrogel systems. \u2022Physicochemical properties of GelMA hydrogel.\u2022Role of nanomaterials for engineering bio-functional GelMA hydrogel.\u2022Diverse biomedical applications of nanostructured GelMA hydrogel.\u2022Promising directions for nano-inspired GelMA bioink formulation.\u2022Applications and challenges of advanced GelMA-nanomaterial platforms. Compared to other biomaterial platforms used for regenerative purposes, hydrogels have an increasing demand owing to their close resemblance to the cellular microenvironment . These mBulcke et al. synthesized one such representative hydrogel formulation in the year 2000 popularly known as Gelatin methacryloyl or GelMA . GelMA oIn this review we emphasize multifunctional GelMA platforms with nanomaterials from different aspects, including its fabrication, crosslinking, polymeric\u2013nanophase interactions, and its application as tissue therapeutics with future perspectives. The key objective is to provide critical analysis of multifunctional GelMA-nanomaterial platforms as versatile substrates and insights about their current challenges and future directions from a biomaterial point of view to their regenerative applications. Even though, many conceivable applications of these multi-functional materials are known, we focus more on its biomedical applications highlighting its current trends in regenerating tissues. shows th2Hydrogel formation occurs by the cross-linking of polymer chains dispersed in an aqueous medium through numerous mechanisms, including physical gelation, ionic interactions, and chemical crosslinking . Most of2) and hydroxyl (-OH) groups are mainly involved in this substitution reaction where methacryloyl groups are introduced onto gelatin. The polymerization of GelMA occurs in an aqueous state by a free radical mechanism in presence of a photoinitiator. The UV irradiation of the photoinitiator causes the generation of free radicals by homolytic cleavage which initiates chain-growth polymerization. In the second step chain propagation occurs between methacryloyl groups present on the polymeric chain and finally terminates between a propagating chain and another free radical . M. M83]. Mractions . Polar ac groups ,22,24. Bc groups . Other ic groups . The BGnc groups . This hy3.3The hydrogels integrated with metallic nanomaterials have become an evolving area in developing customized multi-responsive constructs for tissue repair. Nano-biomaterials based on metals and their oxides have been shown to possess desired physical properties such as conductivity of electricity (gold-based) , magnetiNavaei and colleagues reported a photopolymerizable hybrid platform based on GNR encapsulated within GelMA hydrogels . This na3.4Among the multitude of GelMA platforms developed for tissue engineering, polymeric nanomaterial incorporated ones have attained a remarkable interest. These structures are similar to the macromolecule-centered components in the human body and are often considered to be good candidates for drug delivery purposes since they offer spatial and sequential control over drug/gene/growth factor release owing to the tailored physical properties, manageable degradation as well as their capability to resist the degradation of labile biomolecules .Such delivery systems can impact therapeutically advantageous properties of drug delivery and are set to possess clinical importance . CompareSeveral polymeric nanomaterials such as hyperbranched polymers, dendrimers, nanopolysaccharides, proteins like ferritin, etc. have various hydrophobic or hydrophilic units available for conjugation with the functional groups of hydrogels . These pI) acted as the delivery system for VEGF which efficiently transfect myocardial tissues which could facilitate local myocardial neovascularization at the injected sites, reduces fibrosis, and potentially improve cardiac function in an in-vivo AMI model as indicated in (N-isopropylacrylamide-co-acrylamide) nanogels loaded with DOX by entangling it within the GelMA prepolymer before photocrosslinking [A biocompatible injectable hydrogel gene delivery system developed by Paul and colleagues also showed its efficacy in specific delivery of vascular endothelial growth factor (VEGF), a signaling protein that supports angiogenesis that is necessary for the regeneration of damaged cardiac tissues for acute myocardial therapy (AMI) . GelMA icated in . This naslinking . This naslinking ,261,262.4Tissue repair and reconstruction using nano-engineered hydrogels have been developed as a promising medical strategy to the existing replacement therapies for the healing of damaged tissues . Tissue 4.1Many new developments have been made in engineering bone tissues by using hydrogel as a multifunctional platform during the last decade. Even though hydrogel-based materials display excellent bio functionality it possesses demerits such as poor mechanical stability and low processability making it unsuitable for bone tissue regeneration ,290,291.. However, single-layered GelMA hydrogels often fail to regenerate multiple tissue defects such as osteochondral defects possibly due to the mismatched stiffness of the hydrogels relative to cartilage and subchondral bones. On the other hand, bilayered GelMA hydrogels based on mussel-inspired chemistry without nanomaterial engineering have been shown to restore such defects [Owing to many fascinating potential uses of multicomponent GelMA-based materials, their design and synthesis have been a focus of substantial research over the last few years defects ,297.ve and gram \u2212ve bacterial contamination both in-vitro and in-vivo rat cranial bone defects. The overall results show the effective role of nAg/HNTs/GelMA hybrid hydrogels in dealing with infected bone defects. In another study, Xin and co-workers embedded MBGN into GelMA hydrogel by an amide reaction to construct a hybrid membrane that can act as a substitute for periosteum [GelMA-nanomaterial interfaces provide an appropriate matrix environment and facilitate controlled growth factor delivery at different points of bone regeneration. In an early attempt studies using GNP encapsulated GelMA hydrogels (GNP/GelMA) revealed that the presence of GNP might promote cell spreading, osteogenic differentiation, and basic phosphatase activities of ADSCs . In respriosteum . This Geriosteum . The higNaturally occurring hydroxyapatite (HA) incorporated microfabricated GelMA platforms were exploited for modular tissue engineering to mimic native osteons, which are basic structural units of mature bones . These bPrevious studies thus highlight the vital role of inorganic components in regenerating bones by regulating mechanical properties and cellular differentiation. Except for inorganic components, some biodegradable organic components have also been introduced to impart specific functions into the GelMA hydrogel. For instance polylactic acid, a biodegradable polyester was introduced into 3D printed GelMA constructs consists of bioactive GNPs through filament freeform fabrication technique for regenerating diseased bones . It was Many nanocomposites were examined actively for their potential use in soft tissue engineering but these hydrogels cannot often mineralize thereby limiting their usage in engineering bone tissues . Recent 4.2The hydrogel wound dressing is considered as best wound treatment technique because of its excellent biocompatibility, moisture resistance, and ability to activate immune cells to promote wound healing . PolymerMany GelMA-based materials were reported to show tissue adhesiveness. However, due to the poor mechanical properties of GelMA, various functional nanomaterials were mainly added to improve the mechanical properties. Assmann and colleagues developed a highly elastic adhesive hydrogel that could act as tissue sealants . The dev+ released from the hydrogel also concurrently exhibits antibacterial activity. It was shown that the NIH 3T3 fibroblasts cultured on these substrates grow and multiply extensively on soft 15% GelMA hydrogels compared to other sets. AgNPs incorporated within the GelMA matrix even at a higher concentration of 150\u00a0\u03bcg/ml showed no significant toxicity, which agrees to the optimum Ag+ ion concentration required to destroy both gram +ve and gram -ve bacterial strains also possess enhanced electrical conductivity and superior mechanical properties ,264,360.4.4Nerve tissue regeneration is an advanced and fast-developing area that assures replacement or repairment of injured, diseased nerve tissues or treating major neurological disorders that are difficult to rectify employing a normal clinical approach . Among tDifferent approaches to fabricate NGCs have been introduced in recent years to overcome the typical limitations related to nerve grafting . Differe5The 3D bioprinting arose as an innovative approach that utilizes a computer-aided process to fabricate cell-laden constructs of defined geometries that support soft or hard tissue regeneration or alternate for organ replacements . Self-he. The presence of two independent entwined polymer chains in this bio-ink conjugated themselves via a distinct cross-linking mechanism allows precise control over its characteristics. The presence of nSi enhances the mechanical stiffness and tissue adhesiveness by exerting reversible electrostatic interactions within the hydrogel chains. Being a printable hydrogel formulation this could be utilized for the fabrication of various mechanically robust cellularized structures [Nanoengineered ionic covalent entanglement bio-ink (NICE), a novel smart bio-ink developed by Chimene and colleagues for 3D bone bioprinting is one of a kind . This biructures . Furtherructures . These iructures . The ostructures . This syImproved cytocompatibility and bioactivity are the most essential requirements in nanomaterials intended to be used in developing new bio-ink. Many inorganic ions are capable of inducing cellular differentiation. So there exists massive promise for these ions for effective use in bone regeneration. The role of strontium (Sr) in the remodeling and engineering of bone tissues has been reported in recent years . A low cThe regeneration of cardiac tissues using nanoengineered hydrogels also profusely progressed due to the new insights of converging microscale technologies with stem cell biology. Even though a lot of noteworthy studies have been done focused on developing bio-engineered cardiac constructs or patches for functional tissue replacement, a clinically applicable engineered cardiac structure representing the morphological, physiological, and functional properties of natural myocardium remains the challenge . Surfact3D bioprinting of soft tissue constructs was always a challenge for biomedical researchers since it lacks the desired mechanical properties . Advance6The nano-structured hydrogels of succeeding generations have got potential to transform or replace the existing systems for various tissue engineering applications. The superior characteristics owned by multi-functional hybrid systems, which lack in their hydrogel counterparts enable them for various applications. Being a dominant hydrogel formulation of recent times, the future direction on GelMA-nanomaterial platforms certainly includes balanced optimization in all aspects says physical, chemical as well as biological. Next-generation nano-engineered GelMA is being progressively evaluated for its various clinical applications. Even though the non-functionalized nanomaterial and GelMA interactions could result in useful material characteristics, the resultant hybrid composites lack control over many key properties including stimuli responsiveness and physiological degradation. To overcome these drawbacks different strategies have been introduced in which modifying GelMA hydrogel network by incorporating multifaceted nanomaterials of various types is the most common approach. Our research group also recently focused on developing similar systems by functionalizing antioxidant nanomaterials such as cerium oxide (CeO2) using macromolecules such as dendrimers which would interact with the hydrogel physically or chemically and resulted in multi-responsive scaffolds of better stiffness and microarchitecture. Nowadays more efforts are also made in designing hydrogels with long-term biocompatibility that will aid desired biological behavior. The reviewed literature proposes that the development of novel synthetic routes, functionalizing strategies, and fabrication technologies for GelMA-nanomaterial hybrid systems will continue in the coming years and more priority will be given to research for its personalized applications. Microfabrication approaches for knowing the cell-nanophase communication is one such attempt. Microscale technologies are emerging as a prevailing technology to solve the many existing challenges in tissue engineering. Studies conducted using CNT reinforced hybrid microgels and hyperbranched polyesters have shown the effective utilization of microscale technologies for cell entrapping on pre-defined patterns resulting in different functional tissues of interest. Engineered GelMA hydrogel holds a groundbreaking role in hastening the progress in clinical therapeutics by converging biological and bio-fabrication approaches. Apart from the advances, there are many challenges linked to the clinical translation of photocrosslinkable hydrogels like GelMA. The most important factor is the conversion of various synthetic strategies towards successful regeneration methods and procedures by accepting good manufacturing practices (GMP) while conserving the envisioned capacity for tissue regeneration. Furthermore, evaluations on nano-functionalized constructs are mandatory before the clinical applications to limit the concerns related to biosafety. Certain nanocomposite hydrogels could be applicable only in culturing specific cell types compared to non-functionalized GelMA hydrogel platforms, due to the intrinsic material characteristics. Consequently integrating universal functionalities is also important to attain tissue engineering applications in a broader range. GelMA-based hydrogel constructs have not been completely applied for clinical applications due to limitations concerning their biosafety associated with using UV radiations used for crosslinking which can damage cellular DNA by oxidation and also could result in sudden inheritable changes. Assessing the biosafety for both cell-free and cell encapsulated GelMA-nanomaterial platforms is thus of utmost importance to ensure safe and effective usage for its future biomedical applications.The authors declare no competing financial interest."} +{"text": "Malignant paediatric nervous system tumours, such as Medulloblastoma, Neuroblastoma and ATRT commonly harbour tumour cells with stem-like features which are highly tumorigenic and resistant to conventional cancer therapies. These tumours can exhibit high lethality and may result in severe sequelae, including cognitive and motor deficits that significantly affect patients\u2019 quality of life. Oncolytic virotherapy is a novel therapy class that exploits viruses that preferentially infect and destroy tumour cells. These viruses present a unique advantage in targeting highly heterogeneous cancers, such as nervous system tumours, as they possess a secondary mechanism of action through which they induce a tumour-specific immune response. Clinical studies employing oncolytic virotherapy have in general reported low toxicity and minimal adverse effects, deeming oncolytic virotherapy as a potentially attractive and safer intervention against paediatric tumours.The Zika virus (ZIKV) is capable of infecting and destroying neural stem-like cancer cells from human embryonal Central Nervous System (CNS) tumours in vitro and in vivo. Infection of CNS tumour cells with ZIKV effectively inhibits tumour metastasis in mice and, in some cases, induces complete tumour remission. Neuroblastoma arises from immature nerve cells and multiple Neuroblastoma cell lines are susceptible to ZIKV infection and oncolysis. These initial findings have demonstrated the potential for a ZIKV-based virotherapy against paediatric nervous system tumours and warrants examination into the molecular mechanisms through which ZIKV executes its oncolytic ability. My research goal is to elucidate the mechanisms which are of paramount importance for ZIKV-induced oncolysis of brain tumour and Neuroblastoma cells. Utilising global expression omics profiling of ZIKV infection and mapping of viral protein-host protein interactions will identify these mechanisms both at the cellular pathway and molecular levels. These collectively will inform our understanding of how we can employ a future ZIKV-based virotherapy against paediatric nervous system tumours."} +{"text": "Outpatient peer support groups have been demonstrated to help patients reintegrate with the community and improve self-acceptance following burn injury. Despite this, there is little data examining who desires participation. This is especially true for minority and socio-disadvantaged populations. The purpose of this study is to examine factors that influence desire to participate in burn survivor groups and actual participation rates.Patients attending outpatient clinic were asked about participation in burn survivor group, interest in joining a group, and administered National Institute of Health Patient-Reported Outcomes Measurement Information System (PROMIS) Managing Emotions (ME) and Managing Social Interactions (MSI) questionnaires. Patient demographics, total body surface area burned (TBSA), initial hospital length of stay (LOS), and surgical intervention were collected from the medical record. While controlling for age and gender, indicators of injury severity and scores on PROMIS questionnaires were each examined for associations with survivor group interest using Firth or standard binary logistic regression.70 patients completed surveys in English and Spanish . Current or past participation in burn survivor group was low , with greater interest in joining burn survivor group . Most patients interested in burn survivor group were Spanish speaking . Interest in joining a burn survivor group was associated with all collected measures of injury severity (Table 1). Scores on ME and MSI were not significantly associated with burn survivor group interest .There is a gap between interest and participation in burn survivor group, particularly among Spanish speaking patients. Patients with increase in TBSA, LOS, and undergoing surgery were more likely to express interest in burn survivor group participation. Interestingly, patients\u2019 self-reported outcomes on emotional distress and interactions with others were not related to interest in burn survivor group."} +{"text": "For couples affected by HIV, and serodifferent couples in particular, pregnancy desire is often juxtaposed against the risk of HIV transmission between the couple and the potential neonate leading to thinking about measures to minimize risk of HIV transmission. We assess the use of fertility awareness methods [FAM] and evaluate the drivers of alignment between indicators of fertility and sexual behavior among HIV-serodifferent couples desiring pregnancy.HIV-serodifferent couples from Thika, Kenya were enrolled into an open-label pilot evaluation of safer conception strategies. Women responded to daily 7-item short message service [SMS] surveys on FAM and sexual activity. Menstrual cycles were categorized as having condomless sex aligned, not aligned, or partially aligned to the predicted peak fertility. We used binomial logit models with generalized estimating equations to assess alignment between condomless sex during peak fertility days and FAM results. We used Cox proportional hazards to compare pregnancy incidence among months with sex and peak fertility aligned and mis-aligned.A total of 6929 SMS surveys across 252 menstrual cycles of 65 women were included. Reporting \u201csticky\u201d cervical mucus and positive ovulation prediction kit [OPK] result were associated with increased likelihood of alignment of condomless sex during peak fertility. Pregnancy incidence was statistically similar among periods with sex aligned and not aligned with peak fertility.Among women engaged in a comprehensive safer conception program, a moderate percentage of women aligned condomless sex and predicted peak fertility days at least once. While FAM, particularly cervical mucus and OPK, are an inexpensive option for couples to consider using as a component of their safer conception strategies, antiretroviral-based strategies remain important to minimize risk. HIV-serodifferent couples are partnerships where one partner is living with HIV and the other is not. For these couples, the desire to become pregnant can be in contrast to the risk of transmitting HIV either to the baby or between the couple. Safer conception strategies can be used to reduce the risk of HIV transmission during pregnancy attempts, and they include fertility awareness methods [FAM] which involve timing condomless sex to the time when a woman is most likely to become pregnant during her menstrual cycle, called the peak fertility window. FAM include tracking menstrual cycles, monitoring cervical mucus, measuring daily body temperature, and using an ovulation prediction kit [OPK].Seventy-four HIV-serodifferent couples were enrolled in a clinical study in Kenya. Each wanted to become pregnant and all were trained to track FAM. Women reported their sexual activity and FAM indicators via text message every day.Sexual activity was better aligned to the peak fertility window when women found their cervical mucus to be \u201csticky\u201d and if they had a positive OPK result. The use of these FAM indicators to align condomless sex with peak fertility did not affect pregnancy outcomes.While FAM indicators are an inexpensive option for HIV-serodifferent couples to consider using as a part of their safer conception strategies, other HIV prevention strategies remain important to minimize risk.For heterosexual couples who desire pregnancy, augmenting the probability of conception by estimating days with peak fertility and having sex on those days is an important method to achieve reproductive goals. Fertility awareness methods (FAM) are used to identify peak fertility days and optimally time condomless sex to these days to improve chances of conceiving . For peoFor couples affected by HIV, and serodifferent couples in particular, pregnancy desire is often juxtaposed against the risk of HIV transmission between the couple and the potential neonate leading to thinking about measures to minimize risk of HIV transmission. HIV-serodifferent couples can employ any number of \u201csafer conception\u201d strategies to reduce HIV risk during pregnancy attempts, including timing of condomless sex to peak fertility and use of condoms at all other times, antiretroviral therapy (ART), pre-exposure prophylaxis (PrEP), and/or reproductive assistance technologies when fertility may be compromised \u201310. TailSeveral studies have assessed the use of FAM indicators to improve the time-to-pregnancy , 13, andThe Safer Conception Intervention for Partners was an open-label pilot evaluation of a comprehensive safer conception package that enrolled 74 heterosexual HIV-serodifferent couples between March 2016 to April 2018 in Thika, Kenya : 0\u20131), and were in their partnerships for 2\u00a0years (IQR: 1\u20133\u00a0years). Approximately half of the women were living with HIV (47.7% and 53.3% were HIV-negative and in a partnership with a person living with HIV) and, of these women, two-thirds were virally suppressed , similar pregnancy incidence rate pattern was observed across alignment categories Table . Across Among HIV-serodifferent couples engaged in a comprehensive safer conception program to minimize HIV transmission during pregnancy attempts, a moderate percentage (71%) of women aligned condomless sex to predicted peak fertility periods at least once. After training women and couples on the use of FAM indicators, there was high uptake of the use of FAM methods reported via SMS (65 of 74 couples). Across similar settings in Africa, couples and women desiring pregnancy are not often aware of safer conception methods or have low uptake of methods such as timed intercourse \u201323. TherSticky cervical mucus and positive OPK results allow women to self-estimate their peak fertility period and reporting these characteristics was associated with timing of condomless sex in our cohort. Other studies have found that cervical mucus status is the strongest indictor of upcoming fertility days and that self-tracking mucus characteristics reduces the time-to-pregnancy , 24. OurPrevious fecundity studies have demonstrated that tracking FAM improves fertility rates , 12, 13.Our analysis had several limitations including that this was a small sample of couples attempting pregnancy and may not be broadly generalizable. Further, there may be misclassification of the time-varying characteristics since study visits were not timed to menstrual cycles and most data points for time-varying confounding factors straddled two consecutive cycles. We conducted sensitivity analyses to assess whether there was a meaningful effect of misclassification when matching menstrual cycle data to in-clinic interviews, and we found a similar magnitude and same direction for all associations. Finally, the pregnancy incidence rates may indicate misreporting of sexual activity or misclassification of fertility periods since the aligned definition of sex only within the peak fertility period had a lower pregnancy incidence than partial or non-aligned.Safer conception interventions improve reproductive health outcomes of heterosexual HIV-serodifferent couples attempting pregnancy and uphold the reproductive rights of HIV-serodifferent couples to satisfy their desires to attempt pregnancy . The FAM"} +{"text": "OBJECTIVES/GOALS: Parents\u2019 empathy toward their children affects their parenting, which can in turn impact child outcomes. Although parental empathy is theoretically distinct from trait empathy, current literature relies on largely self-report measures of parents\u2019 trait empathy. Thus, the current study evaluated new analog assessments of parental empathy. METHODS/STUDY POPULATION: One parental empathy analog measure was created based on parents\u2019 responses to open ended prompts describing scenarios that elicit different emotions in children. These responses were used to create short scripts. A second analog task was created using 20 sec audio clips of children expressing the different emotions wherein participants respond with how they feel hearing the emotions and separately, how they believe the child feels. After an initial pilot, both versions of the EMPAT-E were administered to 120 families enrolled in a prospective longitudinal study. Parents completed self-report measures of trait empathy and parental empathy, as well as the EMPAT-ES and EMPAT-EA analog tasks. RESULTS/ANTICIPATED RESULTS: Internal consistency of both the EMPAT-ES and EMPAT-EA tasks are expected to be robust, demonstrating the reliability of these novel assessments of parental empathy. Results are also expected to demonstrate the construct and convergent validity of both analog tasks. These new measures of parental empathy are expected to be significantly associated with measures of trait empathy. Specifically, parents\u2019 responses indicating how they believe the child feels in the analog are expected to be strongly related to their reported emotion recognition abilities and responses indicating how analog items made parents feel are expected to be related to parents\u2019 empathic concern. Finally, parents\u2019 responses to the analog tasks are anticipated to be strongly associated with parents\u2019 self-reported parental empathy. DISCUSSION/SIGNIFICANCE OF IMPACT: Valid, novel assessments of parental empathy can impact the parenting literature as well as community intervention and prevention efforts with parents. Such analog tasks can bolster parenting research but they may also be translated to the community setting as a training tool wherein parents are taught new skills that promote more positive parenting."} +{"text": "Caregiver self-care may be impacted by the household environment. We evaluated the impact of support quality and total household occupancy on a validated measure of self-care neglect in caregivers of patients with heart failure. Multivariate regression modeling was used to examine predictors of self-care neglect and we introduced an interaction term between support quality and household occupancy. The main effects model included terms for years of caregiving experience, hours caregiving daily, support quality, and total household occupancy . The interaction term between support quality and household occupancy contributed significantly (p < .05) to the respecified model . We suggest that the potential benefit of total household occupancy on caregiver self-care depends on perceived support quality. Clinicians should assess quality of household resources with caregivers during interactions."} +{"text": "We report on launching a dental initiative that addresses healthy aging and oral health, focusing on prevention and changing the false belief that aging inevitably involves deterioration in oral health. Our project integrates the age-friendly health system's principles into specialty dental care at Eastman Institute for Oral Health, URMC. We established an oral health-centered framework with project elements of the 4Ms - what matters, medication, mentation, and mobility. We developed pilot 4Ms templates integrated into dental charts to implement healthy-aging key oral health processes, including oral health assessment, treatment planning, and oral hygiene support. We engaged all members of the dental team through educational sessions for providing care for patients affected by Alzheimer\u2019s disease and related dementias. We leveraged on locally available interdisciplinary resources and the collaboration reflecting undergoing efforts at the University of Rochester Division of Geriatrics and the Finger Lakes Geriatric Education Center, a Geriatric Workforce Enhancement."} +{"text": "TM. The library simulates even complex bio-models and supports deterministic Ordinary Differential Equations; Stochastic Differential Equations; constraint-based analyses; recent SBML and SED-ML versions; exchange of results, and visualization of in silico experiments; open modeling exchange formats (COMBINE archives); hierarchically structured models; and compatibility with standard testing systems, including the Systems Biology Test Suite and published models from the BioModels and BiGG databases.Studying biological systems generally relies on computational modeling and simulation, e.g., model-driven discovery and hypothesis testing. Progress in standardization efforts led to the development of interrelated file formats to exchange and reuse models in systems biology, such as SBML, the Simulation Experiment Description Markup Language (SED-ML) or the Open Modeling EXchange format. Conducting simulation experiments based on these formats requires efficient and reusable implementations to make them accessible to the broader scientific community and to ensure the reproducibility of the results. The Systems Biology Simulation Core Library (SBSCL) provides interpreters and solvers for these standards as a versatile open-source API in Javahttps://draeger-lab.github.io/SBSCL/ and via Maven Central.SBSCL is freely available at Bioinformatics online. TM programming library that numerically solves systems biology models in multiple mathematical frameworks. A popular file format for representing computational models in a standard way and facilitating the exchange of models between different tools is the Systems Biology Markup Language is an open-source, cross-platform pure JavaDifferential equation solver: The most fundamental feature of SBSCL is simulating ODEs. Version 2.1 adds interpreters and solvers for SDEs to support the latest SBML standards. SBSCL efficiently implements three deterministic numerical solvers (Constrained optimization solver: SBML Level 3 (http://www.scpsolver.org), a linear programming API with support for various solver backends. This lightweight abstraction allows users to define model constraints and an objective function and solve the corresponding optimization problem.Result tables and plots: Since viewing is an essential aspect of understanding the results of a simulation experiment, SBSCL provides experiment output in graphical and tabular form, which it can export in conventional formats such as Comma-Separated Values (CSV).Archival format support: Working toward exchangeability and reproducibility, SBSCL v2.1 supports the Open Modeling EXchange format (OMEX) format as input. These archive files contain the information on running simulation experiments based on SBML and SED-ML (Hierarchical model simulations: The SBML extension package comp enables encoding complex and coupled biological systems that can be distributed or hierarchically structured. SBSCL v2.1 efficiently supports the simulation of this addition, including the automatic assembly of models from multiple and possibly remote input files.Tests against benchmark suites: A crucial part of implementing new features is providing robust testing of the added functionality and use-cases. SBSCL tests all newly added features against the SBML Test Suite in a continuous integration approach. SBSCL provides full testing support against the genome-scale models from the BiGG Models database and kinetic models from the BioModels database.in silico experiment definition SED-ML file or wrapped within OMEX archives. Benchmarks of SBSCL using the SBML Test Suite and a broad range of published models from relevant databases ensure its correctness and reliability (see The open-source library SBSCL simulates complex biological models in various frameworks specified in SBML format, optionally together with their lity see . With thbtab669_Supplementary_DataClick here for additional data file."} +{"text": "Effective treatment of established tumors requires rational multicombination immunotherapy strategies designed to target all functions of the patient immune system and tumor immune microenvironment. While these combinations build on the foundation of successful immune checkpoint blockade antibodies, it is increasingly apparent that successful immunotherapy will also require a cancer vaccine backbone to engage the immune system, thereby ensuring that additional immuno-oncology agents will engage a tumor-specific immune response. This review summarizes ongoing clinical trials built upon the backbone of cancer vaccines and focusing on those clinical trials that utilize multicombination (3+) immuno-oncology agents. We examine combining cancer vaccines with multiple checkpoint blockade antibodies, novel multifunctional molecules, adoptive cell therapy and immune system agonists. These combinations and those yet to enter the clinic represent the future of cancer immunotherapy. With a cancer vaccine backbone, we are confident that current and coming generations of rationally designed multicombination immunotherapy can result in effective therapy of established tumors. Throughout the 20th century, chemotherapy rapidly evolved from using single agents as a monotherapy to highly integrated multicombination therapy, utilizing multiple chemotherapeutic agents combined with surgery, radiation, molecularly targeted therapies and immuno-oncology agents . Each agTo date, the most mature immuno-oncology agents are immune checkpoint blockade (ICB) antibodies, which enable an already present immune infiltrate to promote tumor killing. While seven ICB agents have been FDA approved in multiple cancer indications as monotherapy , they doengage the immune system through the induction of tumor-antigen specific immunity, expand the specific tumor immune response, enable the immune response to ensure prolonged and persistent antitumor activity, and ensure an evolving immune response, preventing tumor escape . Th. ThQuick"} +{"text": "This positioning paper aims to discuss current challenges and opportunities for artificial intelligence (AI) in fungal lung disease, with a focus on chronic pulmonary aspergillosis and some supporting proof-of-concept results using lung imaging. Given the high uncertainty in fungal infection diagnosis and analyzing treatment response, AI could potentially have an impactful role; however, developing imaging-based machine learning raises several specific challenges. We discuss recommendations to engage the medical community in essential first steps towards fungal infection AI with gathering dedicated imaging registries, linking with non-imaging data and harmonizing image-finding annotations. Aspergillus species are ubiquitous, saprophytic fungi with airborne conidia that grow on organic matter. Aspergillus fumigatus is the principal causative agent of human aspergillosis, which can range from allergy to invasive aspergillosis (IA), a life-threatening infection in immunocompromised hosts, with a further cohort of susceptible individuals developing chronic pulmonary aspergillosis [Relatively few fungal species can infect humans; however, certain fungi can cause life-threatening systemic infections in susceptible patient populations. gillosis (CPA). Cgillosis . The agegillosis , 4. CPA gillosis .Individuals with both invasive and chronic pulmonary aspergillosis unfortunately have significant morbidity and high mortality. In part, this relates to challenges in diagnosis, difficulty in distinguishing fungal infection from other infections/illnesses and detecting breakthrough infection or treatment failure . DiagnosWithin clinical medicine, over the last decade there has been significant increased interest in the application of machine learning and artificial intelligence (AI) for complex decision making including diagnosis and guiding therapeutic decision making .Regarding in vivo medical imaging, AI is transforming radiological diagnosis with mature developments related to oncology in breast and chesComputed tomography (CT) represents the imaging modality of choice for lung infection diagnosis. AI for lung CT imaging bears some specific risks and challenges due to the lack of image standardization and multiple sources of variability . However, radiological societies are working toward reporting standards for AI tools \u201317 that detection with predictive value for inference of CPA severity or mortality within a time frame rather than mimicking expert precise contouring.CT enables localization of CPA-related pathological signs such as We have shown , 23 Fig that a wAlthough quantitative scoring algorithms have been developed, further work is needed in defining a standard protocol for reporting radiological findings on CPA lung lesions. This is important to refine future annotation task and to benchmark new imaging AI tool against human radiological scoring . Given tTo progress the field, there is a need to develop a dedicated imaging cohort with a critical size, large diversity , and linked with diagnostic data , and treatment information as possible in international registry datasets . For iniFor an imaging cohort to be used in AI, it requires some annotation, and here, a concerted community effort will be required from a number of specialists to agree on the ground-truth expert source and the granularity of the image annotation . Building large imaging cohorts remains tedious but can have very clear impact for fungal lung disease which currently suffers from two challenges: (1) current diagnostic uncertainty and need for subjective amalgamation of multiple observations with high levels of uncertainty; (2) difficulty in determining treatment response because of challenges in monitoring effects using quantitative radiological markers.Further integration with other omics and electronic health record data \u201329 is alIn summary, the application of machine learning and AI presents a unique opportunity within fungal lung infection with the potential to improve diagnosis through early detection, standardization of imaging markers and their quantitative longitudinal monitoring , to impr"} +{"text": "This study describes the development of a prototype bi-spectral microbolometer sensor system designed explicitly for radiometric measurement and characterization of wildfire mid- and long-wave infrared radiances. The system is tested experimentally over moderate-scale experimental burns coincident with FLIR reference imagery. Statistical comparison of the fire radiative power retrievals suggest that this novel system is highly reliable for use in collecting radiometric measurements of biomass burning. As such, this study provides clear experimental evidence that mid-wave infrared microbolometers are capable of collecting FRP measurements. Furthermore, given the low resource nature of this detector type, it presents a suitable option for monitoring wildfire behaviour from low resource platforms such as unmanned aerial vehicles (UAVs) or nanosats. This could include combining MWIR and LWIR bands in a single camera\u2014for example, by using butcher block filters near the focal plane array, or with a filter wheel. Moreover, the development of a less resource-intensive thermal offset compensation method would likely be required. This could potentially be achieved by using a lightweight mechanical shutter, or by using temperature measurements at strategic points in the camera and correcting the images accordingly."} +{"text": "Candida, Cryptococcal, Aspergillus and Trichophyton species is described herein, highlighting the need for defined species-specific antifungal breakpoints, and for Malassezia and Wickerhamomyces anomalus species which also have zoonotic potential. Novel compound phendione showed promising antimicrobial activity, with MICs determined for both fungal and bacterial species. The biocidal options investigated also showed potential to act as intermediate-level disinfectants, where peracetic acid proved most effective against fungal spore formers. Fungal skin infections and iatrogenic disease of companion animals continue to be an ongoing issue for veterinarians, where misdiagnosis or inapt medical treatment result in secondary conditions within animals. The widespread use of antifungals in both modern medicine and agriculture has resulted in concomitant resistance in species, where zoonotic transfer poses a risk to public health. Studies described herein assess the resistance of pathogenic species isolated from companion animals to a battery of conventional antimicrobial agents. Levels of resistance were detected using recognised in vitro methods, where additional novel therapeutic and biocide options were also extensively investigated. Results show high levels of resistance to the three main families of antifungal agents, namely caspofungin, Amp B and fluconazole. Resistance in Microsporum, Trichophyton, and Epidermophyton species. Superficial zoophilic skin infections (dermatomycosis) are also caused by non-dermatophyte fungal species such as Malassezia, Aspergillus and Candida . Dermal tissue may become infected following colonisation of the cutaneous tissue and dermal follicles with opportunistic and pathogenic fungi. Animal mycoses is a common reoccurring issue globally, with zoonosis a risk in companion animals, where humans are continually exposed to infectious propagules . Dermal Invasive and systemic fungal disease can result from movement of the fungal species transdermally via open wounds . SystemiWickerhamomyces anomalus is a zoonotic and nosocomial yeast, associated with the production of lethal mycotoxins having a mortality rate of 38% in adults and 42% in paediatric patients globally . Student\u2019s T tests were conducted to determine significance levels (p < 0.05) of bacterial susceptibility to treatment using Minitab 16 . All the experiments were performed three times with three plate replicates for each experimental data point, providing a mean result for each test species and antifungal susceptibility (\u00b1standard deviation). The logC. albican to non-albican species, as well as rarer non-Candida species. This study presents eight examples of specific clinical cases that required greater application of existing fungal diagnostics and improved overall fungal diagnostic capability, where CBPs were lacking for many fungal pathogens. The presence of resistant species in companion animals such as those described herein, represents an often-unrecognised route of disease transmission, where zoonosis poses a significant risk. The development of new treatment options is, therefore, essential for both animal and human medicine, where test agent phendione showed promising potential as both an antifungal and antibacterial agent. Additionally, test biocidal options triameen and peracetic acid both showed high levels of antifungal activity. In particular, the peracetic acid-based disinfectant shows promise for controlling the spread of microbial species in veterinary settings, also being active against spore formers. The phenomenon of immunosuppression has been recognised as a major contributor of increasing fungal disease, where more and more patients with chronic immunosuppressing conditions require antifungal treatment as part of their treatment plan. This rising rate of infection has been accompanied by increasing levels of antifungal resistance, where fungal pathogens are following the same pattern of exposure-resistance as seen with bacteria in the imminent antibiotic crisis. In order to defeat AMR, accurate and timely diagnosis is of utmost importance, where selection of fungal therapy must now also consider the shift in predominance from"} +{"text": "Widowhood is associated with decreased emotional well-being, particularly increased depression. Religiosity may help improve mental health among widowed individuals. However, longitudinal studies exploring the role of religiosity on emotional well-being among widowed older adults is lacking, as are studies which examine this relationship using different dimensions of religiosity. This study analyzed data from the 2006-2016 waves of the nationally representative Health and Retirement Study (HRS). Trajectories of depression among older adults >50 years were examined to explore patterns of depression among those entering widowhood and the potential impact of religiosity on depressive symptoms during widowhood. Ordinary least squares (OLS) regression analysis was used to examine the association between widowhood and depression as well as the role of religiosity as a moderator of this association. Older adults experienced an increase in depressive symptomology after the onset of widowhood, and although the levels of depressive symptomology decrease post-widowhood, they do not return to their pre-widowhood levels. Additionally, high religious service attendance and higher intrinsic religiosity were both associated with lower depressive symptomology. High religious service attendance moderated the relationship between widowhood and depression. The relationship between high religious service attendance and depression was stronger among widowed older adults living alone. This study highlights the long-term effects of widowhood on depressive symptomology among older adults. The findings also suggest that higher religious service attendance can lessen the effects of widowhood on depressive symptoms, especially for those living alone. These findings may inform intervention development around increased screening and treatment for depression."} +{"text": "Testosterone treatment increases muscle mass, strength, and leg power in menopausal women, hypogonadal men, older men with mobility limitation, COPD and ESRD. Testosterone's effects on muscle mass and strength are augmented by exercise training and growth hormone. Testosterone treatment improves some measures of physical performance, such as stair climbing power and aerobic capacity; the improvements in gait speed have been modest. Testosterone increases muscle mass by inducing the hypertrophy of type 1 and 2 muscle fibers, and by increasing satellite cell number. Testosterone promotes the differentiation of mesenchymal progenitor cells into myogenic lineage and inhibits their differentiation into adipogenic lineage by activating Wnt-target genes, including follistatin that plays an important role in mediating testosterone's effects on the muscle. Testosterone also increases polyamine synthesis in the muscle. Combined administration of testosterone plus multi-component exercise intervention that includes functional training may be needed to improve function and mobility in older adults."} +{"text": "Crocidura sp.) and a single rodent (Lophuromys sikapusi). Although these cases were only once-off detections, it provided evidence of the first known lyssavirus species has an association with non-volant small mammals. To investigate further, retrospective surveillance was conducted in 575 small mammals collected from South Africa. Nucleic acid surveillance using a pan-lyssavirus quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) assay of 329 brain samples did not detect any lyssavirus ribonucleic acid (RNA). Serological surveillance using a micro-neutralisation test of 246 serum samples identified 36 serum samples that were positive for the presence of MOKV neutralising antibodies (VNAs). These serum samples were all collected from Gerbilliscus leucogaster (Bushveld gerbils) rodents from Meletse in Limpopo province (South Africa). Mokola virus infections in Limpopo province have never been reported before, and the high MOKV seropositivity of 87.80% in these gerbils may indicate a potential rodent reservoir.The reservoir host of Mokola virus (MOKV), a rabies-related lyssavirus species endemic to Africa, remains unknown. Only sporadic cases of MOKV have been reported since its first discovery in the late 1960s, which subsequently gave rise to various reservoir host hypotheses. One particular hypothesis focusing on non-volant small mammals is buttressed by previous MOKV isolations from shrews ( Lyssavirus genus, all capable of causing a fatal encephalitic disease and dogs (Canis familiaris), most commonly reported to be infected with MOKV. This has led to the hypothesis that the reservoir of MOKV might be a prey species that interacts with domesticated animals via a prey-to-predator pathway , four in Nigeria and one in Cameroon in the Central African Republic , a rabies-related lyssavirus, represents one of 17 recognised species within the Non-volant small mammals were captured and sampled in accordance with the field procedure guidelines of Sikes and Gannon during tn = 329) using TRIzol\u2122 reagent , followed by nucleic acid surveillance using a pan-lyssavirus quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) assay as previously described were subjected to serological surveillance using a micro-neutralisation test as previously described were extracted from brain samples (Gerbilliscus leucogaster) tested from Meletse at the cut-off 1:25 serum dilution between the individual gerbils is expected since previous molecular characterisation assays performed on the Gerbilliscus genus have recorded intra-species genetic variation that range from 1% to 20% (Aghov\u00e1 et al. Of the 36 gerbils showing MOKV seropositivity, only 28 were genetically identified with the CytB barcoding PCR assay . The samGerbilliscus genus are nocturnal and terrestrial, exhibit no sexual dimorphism (Skinner & Chimimba Gerbilliscus leucogaster, however, is less arid adapted and can be found along rivers and drainage lines in open grasslands and wooded savannas (Dempster G. leucogaster rodents are not well-understood, however, studies have reported a communal nature (De Graaff Steatomys and Rhabdomys genera occurring at Meletse.Members of the Dempster . The breMore nucleic acid and serological surveillance studies in non-volant small mammal populations are required to obtain a better understanding of MOKV distribution, prevalence and its potential reservoir species. Brain and serum samples in this study were collected from seemingly healthy small mammals in areas that do not coincide with areas where previous MOKV cases have been reported in South Africa. Surveillance should be expanded to areas where MOKV spillover infections in cats and dogs have previously been reported. Furthermore, because lyssavirus distribution and dynamics might be influenced by seasonality, surveillance efforts should also include samples that were collected in different seasons and over multiple years. This expansion, together with representative sample sizes of certain non-volant small mammal species, will collectively increase the possibility of identifying more of these animals that are infected or that have previously been exposed to MOKV."} +{"text": "Mountain regions are important places for biodiversity, where organisms could persist throughout prolonged periods and accumulate genetic divergence as well as promote speciation. Roles of mountains for biodiversity have been exclusively discussed in regions that have specifically diverse species or covered with ice-sheets during the Pleistocene glacial periods, whereas the importance of mountainous regions in East Asia has been less disputed. High mountains in the Japanese Archipelago, located at the eastern edge of the Eurasia continent, have one of southernmost populations of alpine and arctic-alpine plants that are also distributed in the northern Pacific and/or the circumarctic regions. Phylogeographic studies on the Japanese alpine plants have excluded their possible ephemeral occurrence during the current warm period, and rather, suggest persistence of alpine plants throughout several cycles of climate changes in the Pleistocene on high mountains in central Honshu, the main island of the Japanese Archipelago. In this review, I look through decade long phylogeographic studies and show complicated patterns of range dynamics of Japanese alpine plants. In addition, I note recent findings of genetic relationships of Japanese populations of alpine and/or arctic-alpine plants with those in northern regions and their possible ecological divergence in the Japanese Archipelago. Taken together, I provide several issues for understanding historical processes that established distribution of alpine plants following climate changes as well as their diversification and propose importance of Japanese populations of alpine plants on biodiversity in alpine communities across broader range, especially in the northern Pacific region. Mountain regions harbour a high terrestrial biodiversity Gift et Kron et P. F. Stevens ex Galasso, Banfi et F. Conti mostly dominate in the plant communities on the high mountain ridges, whereas snow-bed species occurring in the northern Pacific region including Phyllodoce aleutica (Spreng.) A. Heller, Primula cuneifolia Ledeb., and Sieversia pentapetala (L.) Greene form large communities at moist part of mountains covered with snow until late summer. Accordingly, alpine plants in the Japanese Archipelago have long been recognized to have originated by cold-adapted species in northern regions that spread southward during the Pleistocene cold periods and have survived climatic warming on high mountains , which has small seeds with moderate dispersal ability in capsule, using three inter genetic spacers of plastid DNA D.Don A.Heller strongly supported the scenario of colonization history occurring at least twice during different glacial periods. Such scenario was\u00a0likely\u00a0shared among 11 species including five preliminary investigated species Fig.\u00a0, whereasC. nipponica and K. procumbens and only a few alpine plants are distributed compared to central Honshu (ca. 3000\u00a0m), species exclusively occurring in higher part of mountains such as ens Fig.\u00a0b have li500\u00a0m comComparing geographic patterns of genetic variation enables us to infer a shared history of prolonged refugial isolation and/or postglacial range expansion. In particular, comparative phylogeography would be an efficient approach to identify locations of refugia during the last glacial period and infer postglacial dispersal processes in various temperate and alpine species in Europe and North America Makino provides the first sufficient evidence for the lack of genetic structure in pDNA haplotypes , which encodes one of red and far-red light receptors, evolved with divergent selection, where amino acid replacements exclusively occurred on a domain for light perception (the PHY domain). In addition, a similar study on A. nana found that natural selection on amino acid changes resulted in clinal patterns of allele frequencies on PHYE between its northern and southern populations (Ikeda and Setoguchi PHYE (Ikeda and Setoguchi C. nipponica) and higher latitude (Cardamine bellidifolia) (Ikeda et al. A. thaliana, this finding implies that light and temperature sensitivity of phytochromes may be involved in ecological divergence between these sister species. In A. thaliana, phyE is involved in regulation of ecologically important traits such as flowering or seed germination at lower temperature (Halliday and Whitelam PHYE truly reflected divergence in ecologically important traits are required to address this issue. Since genome-wide investigations could examine natural selection through genomic scan (Luikart et al. Furthermore, genetic footprints of divergent selection between the northern and southern populations suggest ecological roles for maintaining genetic structure. Ikeda et al. investigDecades long phylogeographic studies confirmed the importance of high mountains in central Honshu for alpine plants to persist throughout the climate changes in the late Pleistocene. On the contrary, these studies show that genetic uniqueness exclusively in central Honshu is not the single common pattern of genetic structure across Japanese alpine plants. Instead, there are four major patterns of genetic structure including the lack of genetic structure. Owing to the less glaciated history and subsequent possible prolonged persistence of alpine plants in the Japanese Archipelago, genetic structures of Japanese alpine plants were likely shaped by multiple historical events including migrations and/or range separation occurring during different periods. In addition, Japanese alpine plants contain species with various ecological characters as well as habitat preference, which may have influenced genetic structures as well. Thus, assessing demographic history as well as ecological characters is crucial to fully understand historical processes how alpine plants shaped the current distribution patterns in Japan.Notably, the recent phylogeographic studies demonstrated that some alpine plants in Japan could have migrated northward, especially into the northern Pacific region, providing novel insight that alpine plants in Japan are not necessarily relict of cold adapted species distributed around Bering Straits. Further comparative studies could open new avenue for understanding the Pleistocene dynamics of alpine communities across broader ranges encompassing the northern Pacific region. Given potential ecological divergence of alpine plants within Japan, high mountains in Japan may have definitely played important roles for diversification of alpine plants not only in the archipelago but in northern East Asia as well as the northern Pacific region."} +{"text": "Recent efforts to identify novel bacterial structured noncoding RNA (ncRNA) motifs through searching long, GC-rich intergenic regions (IGRs) have revealed several new classes, including the recently validated HMP-PP riboswitch. The DIMPL (Discovery of Intergenic Motifs PipeLine) discovery pipeline described herein enables rapid extraction and selection of bacterial IGRs that are enriched for structured ncRNAs. Moreover, DIMPL automates the subsequent computational steps necessary for their functional identification.https://github.com/breakerlab/dimpl.The DIMPL pipeline is freely available as a Docker image with an accompanying set of Jupyter notebooks. Full instructions for download and use are available at Bioinformatics online. Discovery and validation of the over 45 known classes of metabolite- or elemental ion-binding riboswitches , 2017. HIn this article, we introduce DIMPL (Discovery of Intergenic Motifs PipeLine), a bioinformatics pipeline which automates the process of total genome analysis by extracting IGRs, filtering them by length and nucleic acid composition, and collecting the data necessary to identify candidate motifs and assign their possible functions. DIMPL also provides reproducible techniques for identifying genomic regions enriched for ncRNA through support vector machine (SVM) classifiers. Although our primary objective in creating DIMPL was to accelerate the discovery of novel riboswitch classes, it can also be used to identify a wide-range of other intergenic nucleic acid and protein motifs such as upstream open reading frames, short open reading frames, ribosomal protein leader sequences, selfish genetic elements and other structured RNA motifs of unknown function.The DIMPL computational pipeline consists of two primary stages: (1) genome analysis and (2) draft motif analysis. For the genome analysis stage of DIMPL, the user begins by entering the Uniprot ID for a microbial genome for which there are Rfam annotations. DIMPL proceeds to automatically request the latest genomic sequence and protein annotations accessibIn the next step, the tool uses a SVM classifier to identThe draft motif analysis portion of DIMPL is performed in parallel on all IGRs that have met the selection criteria. The process begins by using Infernal 1.1.3 to searcde novo for each genome analyzed using the IGR %GC content and nucleotide length as the features, the presence/absence of a structured RNA as the class labels and a set of hyperparameters that have been weighted to select a contiguous region of a genome\u2019s %GC versus length plot. The primary purpose of the SVM classifier is to perform an enrichment of IGRs that reduces the number subjected to the more computationally intensive steps in the pipeline. Applying the SVM-RBF algorithm allows DIMPL to accomplish this goal in a systematic and reproducible manner.The SVM enrichment of IGRs in DIMPL uses a radial basis-function (RBF) kernel and is implemented with scikit-learn (www.github.com/breakerlab/dimpl. The DIMPL pipeline is built primarily in Python and is distributed as a Docker image with allDIMPL provides an integrated collection of tools to streamline the process of identifying novel structured ncRNA motifs, including new riboswitch candidates, on a genome-wide scale. It relies on established methods of enriching bacterial IGRs for ncRNA motif discovery (btab624_Supplementary_DataClick here for additional data file."} +{"text": "Bone fracture healing and osteoblast differentiation are impaired with advanced age. Using a combination of parabiosis and proteomic models, we identified apolipoprotein E (ApoE) to be an aging factor in bone regeneration. Circulating levels of ApoE increased with age in patients and in mice. ApoE impaired bone fracture healing by decreasing bone deposition in the fracture callus which subsequently decreased the mechanical strength of healed tissue. Osteoblasts serve as the sole bone forming cells within the body. In tissue culture models, ApoE treatment decreased osteoblast differentiation and activity which led to decreased matrix formation and mineralization. This inhibition of osteoblast differentiation relied on down-regulation of the Wnt/\u03b2-catenin pathway. In mouse models, aged bone repair was rejuvenated when we lowered circulating ApoE levels using a hepatotropic AAV-siRNA model \u2013 serving as a proof of concept that ApoE can be targeted to improve bone repair in an older population. While promising, knockdown of circulating ApoE in such a fashion is likely not translatable to patient care. Thus, current work in our laboratory is focused on developing treatment strategies that temporally decrease circulating ApoE levels and consequently improve bone healing after acute injury and/or surgical orthopedic procedure in the geriatric population."} +{"text": "N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) family. SNARE proteins embedded in opposing membranes spontaneously assemble to drive membrane fusion and cargo exchange in vitro. Evolution has generated a diverse complement of SNARE regulatory proteins (SRPs) that ensure membrane fusion occurs at the right time and place in vivo. While a core set of SNAREs and SRPs are common to all eukaryotic cells, a specialized set of SRPs within neurons confer additional regulation to synaptic vesicle (SV) fusion. Neuronal communication is characterized by precise spatial and temporal control of SNARE dynamics within presynaptic subdomains specialized for neurotransmitter release. Action potential-elicited Ca2+ influx at these release sites triggers zippering of SNAREs embedded in the SV and plasma membrane to drive bilayer fusion and release of neurotransmitters that activate downstream targets. Here we discuss current models for how SRPs regulate SNARE dynamics and presynaptic output, emphasizing invertebrate genetic findings that advanced our understanding of SRP regulation of SV cycling.Membrane fusion is a universal feature of eukaryotic protein trafficking and is mediated by the soluble Regulated secretion is mediated by a large cohort of SNARE regulatory proteins (SRPs) that control the timing and localization of SNARE assembly , the soluble NSF attachment proteins (SNAPs) and Unc18 function in both constitutive and regulated secretion, others like Unc13, Complexin (Cpx), Synaptotagmin 1 (Syt1), Rab3-interacting molecule (RIM), and Tomosyn (Tom) provide unique temporal and spatial control of regulated secretion.Eukaryotes rely on membrane-bound organelles to organize and transport material between cellular compartments . Transpoassembly . AlthougSaccharomyces cerevisiae, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster for SV fusion can be approximated by measuring AZ Pr, which varies across neuronal subclasses and within the AZ population of a single neuron . Followi+ influx . Releasee neuron . Most SV sorting . Reforme release .2+-dependent fusion. After fusion, NSF and SNAPs disassemble the SNARE complex to recharge individual SNARE proteins for further cycles of release. Intrinsic SNARE properties protect SNAREs from spontaneous reassembly post-fusion with help from the SRPs Unc18 and Tomosyn. Finally, RIM and Rab3 cooperate with Unc13 to re-position endocytosed SVs for subsequent docking and priming. Each of these steps provide avenues for modulation of SV release that can impact synaptic strength and plasticity.In this review we examine current models for how SRPs guide SNAREs through their assembly/disassembly cycle, focusing on insights from invertebrate genetic studies of SV fusion. We also highlight biochemical approaches that guided reverse genetic experiments and provided context for interpreting genetic studies. The biochemistry and genetics of mammalian SV fusion have been described in prior reviews . Key invLipids form stable bilayer membranes that innately repel each other through electrostatic forces and hydration repulsion . Bindingtrans-SNARE complex, with transmembrane segments residing on separate compartments and full SNARE assembly being temporarily arrested are immobile and lack detectable SV release are embryonic lethal, but retain uncoordinated movements that indicate a low level of residual SV release in the second SNARE motif of the protein displays a similar phenotype, indicating multiple t-SNARE mutations can alter SNARE dynamics in a manner that enhances fusion at lower temperatures and blocks release at elevated temperature have not been characterized electrophysiologically though they display locomotor defects that suggest RIC-4 is essential for normal synaptic function and enhance SV fusion in C. elegans is essential for SV fusion, yet strongly inhibits both evoked and spontaneous release when overexpressed is highly stable and resistant to SDS denaturation, indicating a large input of cellular energy is required to break the complex apart mediates neuronal SNARE complex disassembly (comatose) . Many coex apart . Althougaralysis . Accumularalysis and a praralysis mirror taralysis , 2001. Tcomatose mutations cause adult paralysis and synaptic transmission defects, the role of NSF at larval NMJs has been difficult to ascertain. NSF1 null mutants are lethal, but die over a developmental window that spans from late embryogenesis to the pharate adult stage mutants, suggesting SNAPs are not fully redundant cargo release and for some SVs at a few central mammalian synapses on the plasma membrane, impaired neurotransmitter release and enlarged SVs have normal AZ dense body projections and Ca2+ channel clustering, but fail to accumulate SVs that normally surround the AZ due to defective Cpx binding show a dramatic increase in evoked neurotransmitter release prevents its ability to inhibit SV availability, thereby enhancing SV release to facilitate plasticity and memory formation . Additioclusters . In Drosclusters . Short iisoforms , suggestBoth authors wrote and edited the manuscript, contributed to the article, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Dementia is an increasingly important public health problem with known vascular contributors. Respiratory function, measured by peak expiratory flow (PEF), may be a novel modifiable risk factor in reducing the risk of dementia along the vascular pathway. We investigated the association between PEF and incident dementia in older adults from the National Health and Aging Trends Study (NHATS). Using NHATS criteria, participants were categorized as having or not having probable incident dementia during NHATS Rounds 2-4, spanning three years. Of 3,622 participants with available PEF and covariate data, 543 (15.0%) had incident cases of dementia. Quartile of baseline PEF was analyzed as a predictor of incident dementia using logistic regression models, while controlling for several health and sociodemographic covariates. The fourth quartile of PEF had statistically significantly decreased odds of incident dementia when compared to the first PEF quartile . Significantly reduced odds of incident dementia were found when comparing the third and second PEF quartiles to the first PEF quartile, as well . These relationships were dose-dependent so that increasing PEF quartile levels were more protective against incident dementia. PEF may be considered as an easily administered, low-cost measure of respiratory function and a possible screening tool for dementia risk. Improving PEF may reduce dementia risk through vascular mechanisms . Future research should explore these potential causal pathways between PEF and dementia."} +{"text": "The COVID-19 pandemic has led to social distancing protocols, subsequently increasing social isolation for older adults. The purpose of this study was to explore the relationship between social connectedness and mental health outcomes. Leveraging NHATS, a nationally representative study , we examined the association between the method of social connectedness and mental health outcomes. Descriptive analyses revealed older adults are using various methods to remain connected with their social networks during COVID-19. Findings from all of the linear regression analyses indicated phone or video calls are associated with negative affect, whereas in-person visits are associated with lower levels of negative affect. These findings suggest substituting in-person visits with video calls or phones may not be sufficient to relieve their loneliness and negative affect. Future studies should investigate this effect on physical or emotional health outcomes."} +{"text": "We developed comprehensive multi-domain profiles of psychosocial stress in urban-dwelling, racially and ethnically diverse adults and evaluated associations with cognitive function. Participants completed psychosocial stress measures tapping into ten domains and tasks of processing speed, working memory, and episodic memory. Latent profile analyses controlling for age yielded four-profiles: high neighborhood stress, moderate versus high work stress and daily discrimination, and high health and relationship stress. Profiles significantly differed in income, age, and employment status. The profile with moderate work stress and daily discrimination and the profile with high neighborhood stress each had significantly lower working memory than the other profiles. The finding of lower working memory among individuals in the moderate work stress and daily discrimination profile was not due to sociodemographic variables. Results highlight the potentially cumulative influence of different contextual stressors on cognition."} +{"text": "ABSTRACT IMPACT: As newborn screening is now available for X-linked adrenoleukodystrophy, there is a need to establish meaningful disease markers to detect the onset of the severe demyelinating cerebral form of this disease at the earliest possible stage, and to quantify early disease progression to evaluate the relative efficacy of therapies. OBJECTIVES/GOALS: Longitudinal testing of neurocognitive and motor function using smartphone and tablet-based applications holds promise for early detection and quantification of brain white matter changes in patients with adrenoleukodystrophy (ALD) and other rare demyelinating diseases, but this methodology requires validation in pediatric populations. METHODS/STUDY POPULATION: We developed an iPad application with a game-like interface to assess interhemispheric transfer across the corpus callosum, the brain structure where cerebral demyelinating disease typically begins in patients with ALD. Feasibility data from remote test administrations with healthy children were collected to analyze and speed and timing of finger tapping movements requiring bimanual coordination on a touchscreen. RESULTS/ANTICIPATED RESULTS: Among our pilot sample of healthy school-aged children, age-related improvements in finger tapping speed were observed in both single-hand and alternating-hand conditions. Results indicate that remote testing using iPad applications is a viable way to collect psychometric testing data rapidly in pediatric populations and is feasible during a pandemic. Next steps in this research project will be: (1) evaluating the stability of repeated test administrations (test-retest reliability), (2) assessing agreement between performance on our iPad application and validated measures of interhemispheric transfer and fine motor function, and (3) comparing performance of children with known corpus callosum white matter abnormality to performance of healthy children. DISCUSSION/SIGNIFICANCE OF FINDINGS: Brief neurocognitive tests that can be frequently administered may have the ability to capture subtle brain changes in developing children. Approaches enabling remote testing will facilitate research during the covid-19 pandemic and are especially well-suited for data collection in rare disease populations."} +{"text": "Older adults with dementia rely on others to recognize and treat their pain and will ultimately become dependent. Family caregivers (FCGs) play a crucial role in pain management, yet limited data is available regarding the factors that impact their abilities. This qualitative descriptive study sought a deep understanding of FCGs perception of their abilities to manage pain for a loved-one with dementia. A sample of 25 adult family caregivers of community-based older adults with dementia was recruited in central Virginia. Participants were 29 to 95 years old, predominantly white, married, female, and high school graduates. We conducted semi-structured interviews that were audio recorded and analyzed using constant comparative analysis. Participants\u2019 who perceived greater competence with pain management reported less pain for their loved-one, and their level of confidence was influenced by 3 factors: progress and stage of dementia: this increases the complexity of care, affecting FCGs ability to manage pain and engendering a self-perception of incompetence; developing adaptive mechanisms: built self-efficacy and improved FCGs perceived competence;, and support from professionals: a greater degree of support alleviated FCGs concerns and instill new skills, Effective pain management depended on family caregivers\u2019 belief in their own abilities, and perceived competence could be improved by learning new skills or making adaptations. Professional care givers need to routinely assess FCGs abilities and provide adequate interventions."} +{"text": "We evaluated nucleic acid amplification testing (NAAT) for Zika virus on whole-blood specimens compared with NAAT on serum and urine specimens among asymptomatic pregnant women during the 2015\u20132016 Puerto Rico Zika outbreak. Using NAAT, more infections were detected in serum and urine than in whole blood specimens. Zika virus (ZIKV) infection during pregnancy can cause severe brain and eye malformations and is associated with neurodevelopmental abnormalities in affected infants within 12 hours of collection, and stored according to Food and Drug Administration and CDC guidelines (https://www.hologic.com) at Vitalant Research Institute performed quality-control testing by singleplex NAAT years; specimen collection was evenly distributed by trimester of pregnancy . Of the specimen . A totalAmong 28 women who tested positive by NAAT, 8 were by whole blood, 10 by urine, and 20 by serum . Among tThis study provides information about laboratory testing to maximize detection of ZIKV infection among asymptomatic pregnant women. In this small sample of ZIKV NAAT\u2013positive asymptomatic pregnant women, no additional ZIKV-positive cases were identified by whole-blood NAAT beyond those identified through tests of other samples. This finding contrasts with other studies that note prolonged detection, higher viral load, and greater sensitivity of whole-blood NAAT versus NAAT on other specimens (All asymptomatic ZIKV-positive women had detectable ZIKV in NAAT of urine or serum samples in our study. Although previous studies detected ZIKV RNA in urine more frequently than in serum (This large study comparing NAAT for ZIKV on serum, urine, and whole-blood specimens is unique in that the study population is among asymptomatic pregnant women. Although studies have mentioned lack of overlap between different specimens tested by NAAT (Our detection of acute ZIKV infections by NAAT is likely low because the study occurred 2\u20133 months after the peak of the Puerto Rico outbreak (These findings support CDC guidance to perform NAAT on asymptomatic pregnant women during outbreaks when ZIKV is widely circulating ("} +{"text": "Pediatric fecal matter transplant (FMT) clinical trials relying on \u201chealthy\u201d donor stool use screened adult donor stool, likely assuming safety and efficacy. However, we consider how adult donor stool could instead be posing risks of atypical development or transmission of early disease, which could be prevented with age-matching donors and recipients for FMT.The gut microbiome has been identified as a potential therapeutic target to combat pediatric intestinal and extraintestinal diseases through FMT. FMT involves the transfer of \u201cnondiseased\u201d stool into the gastrointestinal (GI) tract of an individual with the disease in attempts to replenish the gut microbiota and ameliorate adverse GI symptoms. Currently, no standard methodology exists for clinical trials investigating FMT efficacy. Key elements such as donor selection processes are often based on drastically different criteria but usually involve adult stool donors even in pediatric FMT clinical trials. We consider how the usage of adult donors may be of concern when considering the long-term implications of FMT on pediatric health. The pediatric microbiome plays an important role in immune, GI, and neurological development and to introduce adult donor stool to an already dysbiotic microbiome could lead to atypical maturation. Furthermore, selection of nondiseased stool is based on current screening protocols. Screened and deemed \u201cnondiseased\u201d adult donor microbiota could be showing early disease markers for diseases that are not yet visible with current donor screening protocols, putting pediatric recipients at risk for disease development. Current pediatric guidelines have yet to consider these specific pediatric risks, which could be jeopardizing the long-term health and development of pediatric patients and influencing the future of pediatric therapeutics.The microbiota is largely shaped in early childhood. Antibiotic usage in early childhood has shown to increase the risk of acquiring conditions such as inflammatory bowel disease (IBD), asthma, allergy, and eczema , 2. ThisThroughout childhood, adolescence, and adulthood, age is associated with drastic differences in composition and functional gene potential of the microbiome . Age greIn a pediatric FMT clinical trial, considerations for donor stool should include both microbial factors, such as similarity of microbial species between donor and recipient, as well as factors for host intestinal tolerance toward the donor microbes. Because the gut microbiota of young children, adolescents, and adults are all distinct, the necessary microbiota across development is crucial for typical neurological, immunological, and GI development \u20134, 6. IfClostridioides difficile infection (rCDI) (NCT02134392). In these pediatric trials, the age of the stool donor is listed as either an adult or is not mentioned in study record details.In the pediatric population, active FMT clinical trials include treatment of intestinal colonization of extended-spectrum resistant Enterobacteriaceae (NCT02543866), IBD (NCT03399188), autism spectrum disorder (NCT03426826), ulcerative colitis (NCT03582969), Crohn's disease (NCT03378167), and refractory Methodology within FMT clinical trials vary with donor selection procedures being a particular area of heterogeneity . Fecal dScreening efforts are established to not only ensure stool viability but robustly reduce the chance of transmitting infection or active medical comorbidities from donor to recipient . ScreeniDonor selection methodology is a particularly large area of ambiguity. For example, a systematic review of FMT clinical trials reported before 2017 determined that out of 85 FMT clinical trials, almost 50% of published studies did not report donor selection eligibility criteria in their publications . This reTrial method heterogeneity and uncertainty surrounding true efficacy further exacerbates the concerns for safety in FMT clinical trials. Safe stool is as safe as how it has been screened, and screening can only include testable pathogens already established to directly cause disease. However, the definition of what can cause disease is constantly evolving. For example, FMT has revealed the possibility of transmission of diseases previously assumed as nontransmissible. A patient developed issues with significant weight gain following an FMT from a healthy, but overweight, donor leading to FMT guidelines to suggest screening for donor body mass index . This poCurrent pediatric guidelines suggest donor selection should involve adults aged 18 and older based on medicolegal considerations . While aEarly life disruptions to the microbiota can already increase an individual's susceptibility to a variety of immune, metabolic, neurological, and psychiatric diseases . This phEarly disease markers for a variety of gut microbiome associated diseases have not yet been identified. These early disease markers could be characteristic changes occurring in the gut of an adult donor, years before diagnosis of disease, and invisible with current stool-screening guidelines. It is established that bidirectional communication between the brain and GI tract has been implicated in a variety of neurological diseases. Transmission of early disease markers from a variety of diseases could occur; here, we will illustrate the issue using Parkinson's disease (PD) as an example. PD has characteristic changes in the GI tract including constipation and gut dysbiosis with increased inflammation and reduced short-chain fatty acid production. Adults with REM-sleep behavior disorder, a prodromal stage of PD, already have the same pattern of dysbiosis . ConstipTo contextualize early disease marker transmission using specific evidence from pediatric FMT, a study of the gut microbiome of pediatric recipients following FMT with \u201chealthy\u201d adult donor stool showed the potential for acquisition and persistence of antimicrobial genes from the donor . AlthougWe are concerned that adult donors beginning to generate characteristic microbiome profiles of adult-onset disease could be acting as FMT donors for pediatric FMT trials, potentially generating long-term implications for the recipient child with their GI tract being introduced to characteristic pathogenic changes in childhood. Matching pediatric FMT recipients with pediatric donors could largely reduce the possibility of adult-onset neurodegenerative disease marker transmission and allow for less interruption of age-specific maturation of the gut microbiota.With past efforts focused on the promotion of immediate safety for pediatric FMT recipients, the field is ready for conversations surrounding long-term safety and healthy development in pediatric FMT recipients. Optimal donor selection should be a focus of these conversations, with considerations of matching donors and recipients by age being prioritized. Age-matching could reduce the exacerbation of the child's atypical immune, GI, metabolic, and neurological development to allow for parallel interplay of microbiota development with typical physiological development.The idea of age-matching is not without an introduction of its own novel risks, such as possible transmission of childhood-onset diseases including asthma or allergy to pediatric recipients. However, we argue this phenomenon could still occur with the introduction of adult donor microbiota because it could be affecting typical immunological development. Furthermore, screening for risk factors for allergy and asthma, such as antibiotic usage, mode of delivery, and formula feeding in pediatric donors, could aid to protect against this occurrence.A joint-position paper from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition similarly argues that further research into age-matching is warranted due to concerns of long-term efficacy and safety with adult donors . Age-matCurrently pediatric FMTs are changing children's lives, treating persistent, and sometimes otherwise incurable, diseases, demonstrating the power of the approach. FMT trials explore increasingly diverse applications for pediatric intestinal and extraintestinal diseases and long-term clinical considerations for health and development will be increasingly important. Given the increasingly recognized role of the gut microbiome in adult diseases including neurodegenerative disorders, we believe choosing age-matched donors for pediatric FMTs will likely be the best safe-guard to reduce potential future complications.At time of submission all clinical trials statuses mentioned in the manuscript are listed as: NCT02543866 (recruiting), NCT03399188 (recruiting), NCT03426826 (recruiting), NCT03582969 (recruiting), NCT03378167 (recruiting), and NCT02134392 (recruiting).https://clinicaltrials.gov/.Current trial statuses can be accessed at AM conceived the opinion and drafted manuscript. BF and SA-C contributed expertise to review and critique final manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Transposable element sequences are usually vertically inherited but have also spread across taxa via horizontal transfer. Previous investigations of ancient horizontal transfer of transposons have compared consensus sequences, but this method resists detection of recent single or low copy number transfer events. The relationship between humans and domesticated animals represents an opportunity for potential horizontal transfer due to the consistent shared proximity and exposure to parasitic insects, which have been identified as plausible transfer vectors. The relatively short period of extended human\u2013animal contact (tens of thousands of years or less) makes horizontal transfer of transposons between them unlikely. However, the availability of high-quality reference genomes allows individual element comparisons to detect low copy number events. Using pairwise all-versus-all megablast searches of the complete suite of retrotransposons of thirteen domestic animals against human, we searched a total of 27,949,823 individual TEs. Based on manual comparisons of stringently filtered BLAST search results for evidence of vertical inheritance, no plausible instances of HTT were identified. These results indicate that significant recent HTT between humans and domesticated animals has not occurred despite the close proximity, either due to the short timescale, inhospitable recipient genomes, a failure of vector activity, or other factors. Drosophila was the first case of inferred HTT [Transposable elements (TEs) are DNA sequences that can move or copy themselves to new locations in genomes . This prrred HTT , with thrred HTT . While Hrred HTT , evidencrred HTT ,18. Probrred HTT ,19.Despite an increasing number of ancient HTT events being detected, studies evaluating evidence for more recent HTT are lacking. The use of consensus TE sequences when inferring HTT, while necessary for evaluating large-scale transfers across millions of years between many genomes, also prevents the detection of transfers currently in single or low copy numbers in the recipient genome. Human domestication of animals is a ready example of species sharing an environment conducive to HTT on a shorter timescale, on the order of tens of thousands of years or less . FeatureThe existence of high-quality reference genomes for humans and most domesticated animals finally makes the detection of low- and single-copy HTT events possible. Despite the close physical contact and other factors that make HTT more likely to be present, we expected the rarity of successful TE invasion and a lack of adequate time for any transferred TEs to become ubiquitous in the population to result in no detectable HTT events, even when searching millions of individual elements between human and domestic animal genomes. Here, we provide a comprehensive search for individual HTT events between humans and domestic animal species.https://genome.ucsc.edu/ accessed on 30 May 2021). Only intervals longer than 100 bp were included. The search was also limited to retrotransposons based on a lack of evidence for significant DNA TE activity in mammals outside of the Vespertilionidae family of bats for a time period far exceeding the history of animal domestication by humans [https://www.R-project.org/ accessed on 30 May 2021), and reference genomes downloaded from UCSC. TE intervals from non-chromosomal scaffolds were removed for species with chromosomal assemblies, while TE intervals were used in full for genomes without chromosome-level assemblies. A 400 bp decoy sequence (hg38 chr1:1000000\u20131000400) containing no TEs was appended to each retrotransposon multifasta; this sequence served as a positive control to verify that megablast was functional in the event of zero high-identity hits for a given pairwise comparison. Pairwise comparisons of reference mRNA sequences downloaded from UCSC were also performed as a positive control for vertical inheritance in a subset of domestic animal species.Reference genomes and retrotransposon genomic intervals for human (GRCh38/hg38) and thirteen domestic animal species were downloaded from UCSC Table Browser using the RepeatMasker (rmsk) track were performed in the command line using BLAST+ version 2.8.1 . The humper year . Using tper year . Verticaper year .Pairwise megablast queries of 27,949,823 retrotransposons from the reference genomes of humans and thirteen domestic animal species revealed zero insertion events consistent with HTT . InitialThirty-seven human TEs also yielded high-identity hits in two or more domestic animal species ; high idHelicoverpa armigera [For the eight SINE hits initially detected as unique to human and one other species, manual inspection with the 100 Species MultiZ alignment track in UCSC Genome Browser revealed strong conservation across multiple vertebrate genera and orders , providiarmigera . Indicatarmigera ,54. WhilThe lack of HTT between humans and domestic animal species was consistent with the study expectations. We chose domestic species due to humanity\u2019s history of unnaturally close proximity, shared parasitization by plausible HTT vectors (which have served as HTT vectors in other clades), and rapid expansion of human and domestic animal population sizes. An illustrative case is the BovB element, which has proliferated rapidly in species as divergent as bovines and squamates and ultimately makes up 12% of the cattle genome . HoweverOur search demonstrates a lack of evidence for recent HTT between humans and domestic species. Prior identification of HTT events used consensus sequences of transposons derived from multiple paralogs within a species, compared to consensus or individual insertions in an unrelated species. The advantage of our study is in the ability to detect HTT resulting in few or even single insertion events. Still, the use of reference genomes allows for the possibility of HTT detection failure due to population heterogeneity, somatic HT, inadequate genome coverage or errors (particularly over repetitive regions) or other factors. However, the lack of plausible horizontally transferred elements within human and animal reference genomes provides adequate evidence to assume that the phenomenon is not common or widespread."} +{"text": "This case study explores an employer-initiated biweekly group support call for home care aides implemented by a large New York City-based home care agency during the COVID-19 pandemic. Specifically, we investigate how agency staff used information gathered through these calls to intervene into existing agency communication and support systems for aides. Our single-site case study analyzes detailed notes from almost 100 support calls that took place between April 2020 and March 2021, as well as interviews with agency staff from communications, human resources, nursing, and other departments that support aides. We compare and contrast new communication and support mechanisms advanced in conjunction with these calls with agency systems pre-pandemic. Our findings suggest that while calls were initially targeted toward providing emotional and operational support, staff also advocated for more systemic supports. We discuss the sustainability of these new efforts, as well as ongoing barriers and gaps."} +{"text": "ABSTRACT IMPACT: Up to 33% of patients of patients who undergo reconstruction have hostile defects with coexisting soft tissue and osseous defects due to prior radiation, prior failed cranioplasty or concurrent infections we seek to identify optimal strategies for these patients based on the experience of a southeastern tertiary referral center. OBJECTIVES/GOALS: Scalp and calvarial defects in patients may result from a number of etiologies including trauma, burns, tumor resections, infections, osteoradionecrosis, or congenital lesions. Our objective was to retrospectively evaluate the use of alloplastic reconstruction alongside autologous reconstruction for high risk cranial defects. METHODS/STUDY POPULATION: An IRB approved retrospective review of patients who underwent cranioplasty of a hostile site at a Southeastern tertiary referal center between January 2008 and December 2018 was performed. The patients were stratified into three groups based on the type of implant used: autogenous (bone), alloplastic , or mixed (combination of both types of graft). The primary outcome metric was a complication in the year following cranioplasty, identified by flap or bone graft failure, necrosis, or infection. Statistical analysis included t-tests and chi-square tests where appropriate using SPSS. RESULTS/ANTICIPATED RESULTS: There were 43 total cases in this time period; 15 autogenous, 23 alloplastic, and 5 mixed. The purely autogenous group had the highest complication rate (85%) and the alloplastic group had the lowest complication rate (38%). When stratified by specific material used for reconstruction , overall complication rate was statistically significant with PEEK implants having the lowest complication rate (21%). The analysis documented an overall complication rate that was statistically different between the three groups (p=0.012). DISCUSSION/SIGNIFICANCE OF FINDINGS: This analysis interestingly found that in the setting of hostile cranial defects, cranioplasties would benefit from the use of prosthetic implants instead of autologous bone grafts, not only for avoidance of donor site morbidity but also for decrease in overall complications."} +{"text": "ABSTRACT IMPACT: This study will be used to culturally tailor interventions to reduce maternal and infant health disparities in a Marshallese community. OBJECTIVES/GOALS: Inadequate prenatal care is associated with adverse birth outcomes including preterm births, low birth weight infants, and neonatal mortality. Marshallese Pacific Islanders are less likely to receive early and consistent prenatal care compared to other racial/ethnic groups and are thus at a higher risk for maternal and infant health disparities. METHODS/STUDY POPULATION: This article used a qualitative comparative analysis method to compare and contrast the perceived barriers to prenatal care for the prospective of Marshallese mothers and Maternal Health Care Providers (MHCPs). RESULTS/ANTICIPATED RESULTS: Marshallese mothers and MHCPs identified the same structural barriers to prenatal care: health insurance, transportation, and language. The socio-cultural barriers to prenatal care were depicted quite differently by Marshallese mothers verses MHCPs. DISCUSSION/SIGNIFICANCE OF FINDINGS: While the description of structural barriers were consistent among Marshallese mothers and MHCPs, the socio-cultural barriers and the value assigned to those barriers was quite different. Understanding the perspectives from both lenses is an important step towards addressing the barriers to prenatal care among Marshallese."} +{"text": "Vulnerable older adults, such as physically impaired or care-dependent individuals, are vastly underrepresented in psychotherapy research. Improving their inclusion in randomized controlled trials is necessary to determine the effectiveness of psychotherapy in this population. This study is the first to systematically evaluate strategies to recruit home-living vulnerable older adults with clinically significant depression into a large randomized controlled psychotherapy trial. Potential participants were approached directly or via cooperation with gatekeepers .The initiator of the first contact with the study team and successful recruitment strategies were recorded. Referral strategies were compared with respect to number of inquiries and inclusion rates; study personnel\u2019s time investment; and participant characteristics .Most of the N=197 participants were included via gatekeeper-referral and referral by medical practitioners led to highest inclusion rates =8.964, p<.05). Most participants were referred from a hospital setting (50.3%), whereas referral numbers by medical practices were low (15.9%). Participants who initiated the first contact themselves had higher inclusion rates and were less functionally and cognitively impaired.Including home-living vulnerable older adults into psychotherapy trials requires simultaneous implementation of diverse recruitment strategies. Medical practitioners and psychologists, especially in hospitals, are the most effective recruitment strategy, but self-referral via media is most cost-efficient in terms of time investment."} +{"text": "Lasionycteris noctivagans (silver-haired bat), Tadarida brasiliensis (Mexican free-tailed bat), and Eptesicus fuscus (big brown bat) after bat exposures that occurred during August 2021. This increase in bat-associated human rabies deaths in the United States followed only three deaths during the previous 48 months. The cases during fall 2021 occurred in two adults and one child, all male, from Idaho, Illinois, and Texas. Initial symptoms included pain and paresthesia near the site of exposure progressing to dysphagia, altered mental status, paralysis, seizure-like activity, and autonomic instability. All three patients had recognized direct contact with a bat approximately 3\u20137 weeks before symptom onset and died approximately 2\u20133 weeks after symptom onset. The deaths were associated with three bat species: own bat) . All thrRabies is a zoonotic disease transmitted primarily through virus-laden saliva from the bite of an infected mammal. The typical incubation period from exposure to symptom onset is 3\u201312 weeks. Rabies is nearly always fatal once symptoms develop but nearly always preventable when PEP is administered in accordance with the recommendations of the Advisory Committee on Immunization Practices.Preventing transmission of rabies from bats to humans can be accomplished by 1) avoiding contact with bats, 2) safely capturing and testing bats implicated in human exposures, and 3) seeking rapid evaluation for PEP when direct bat contact occurs and rabies cannot be ruled out. Two of the bat-associated cases in fall 2021 were considered avoidable exposures: one was attributed to a bat roost in the patient's home, the other to the patient picking up the bat with his bare hands. Safely excluding bats from homes and instructing persons not to touch bats can prevent rabies exposures.Bats are ecologically critical species with seasonal activity patterns. Although bat activity is reduced in winter months, increased human-bat contacts often occur again in late spring to early fall ("} +{"text": "Older adults with mild behavioral impairment (MBI), or the presence of late-life neuropsychiatric symptoms, have a unique cognitive phenotype. However, the neural correlates associated with MBI-related cognitive changes is not well understood. The goal of this study is to examine if specific regions of the brain moderate the relationship between the presence of MBI and performance on tasks of cognition. Data from the National Alzheimer\u2019s Coordinating Center was utilized for this study. Participants were included in our analyses if they were cognitively healthy or had mild cognitive impairment (MCI). Multiple domains of cognitive performance were evaluated. The neuroanatomical regions included hippocampus, caudal anterior cingulate (ACC), rostral ACC, entorhinal, and parahippocampal gray matter volume; and caudal ACC, rostral ACC, entorhinal, and parahippocampal mean cortical thickness. Hippocampal, entorhinal, and parahippocampal cortical gray matter volume moderated the relationship between MBI and performance on tasks of episodic memory. Left rostral ACC cortical gray matter volume and entorhinal and parahippocampal mean cortical thickness moderated the relationship between MBI and performance on language tasks. Hippocampi cortical gray matter volume also moderated the relationship between MBI and performance on processing speed tasks. Persons with smaller brain sizes in these areas were more negatively affected in these cognitive domains if they had MBI. These results suggest that the association between smaller brain volumes and cognition was stronger among persons with MBI. These findings suggest that older adults with MBI may perform worse on these tasks due to neurodegeneration that is present."} +{"text": "Institutions of higher education need to become more age friendly. Creating an on-campus lifelong learning program can offer older adults opportunities to audit classes and engage in multigenerational classrooms, but can also promote intergenerational learning when instructors consciously use pedagogy that fosters engagement between learners from various generations. Promoting intergenerational learning to facilitate reciprocal sharing of expertise between generations is also the fourth principle of the Age Friendly University framework. This qualitative interview study examines the perspectives of 27 faculty members who have opened their face to face classrooms to older adult auditors to 1) Explore perceived benefits and challenges associated with having older adults in the college classroom and to 2) Determine what levels of intergenerational learning may be taking place. Compared to lecture-based courses, faculty whose pedagogy promotes discussion, sharing, and small group work reported detailed examples of older adult learners and traditionally-aged college students engaging in course-related discussion. The unique, historical and diverse perspectives of older adults improved the quality of education for students, and fostered in-depth learning. Challenges related to older adult auditors included poor/limited attendance, sharing of strong opinions/dominating class discussion, sensory/mobility and technology accessibility. Recommendations include training to promote intergenerational engagement in college classrooms."} +{"text": "Bradyrhizobium diazoefficiens . Using gene-level network and duplication functional traits to predict accessory gene distributions across environments, genes predicted to be superfluous are more likely lost in high stress, while genes with multi-functional roles are more likely retained. Genes with higher probabilities of being lost with stress contain significantly higher proportions of codons under strong purifying and positive selection. Gene loss is widespread across the entire genome, with high gene-retention hotspots in close spatial proximity to core genes, suggesting Bradyrhizobium has evolved to cluster essential-function genes in discrete genomic regions, which may stabilise viability during genomic decay. In conclusion, pangenome evolution through genome streamlining are important evolutionary responses to environmental change. This raises questions about impacts of genome streamlining on the adaptive capacity of bacterial populations facing rapid environmental change.Bacteria have highly flexible pangenomes, which are thought to facilitate evolutionary responses to environmental change, but the impacts of environmental stress on pangenome evolution remain unclear. Using a landscape pangenomics approach, I demonstrate that environmental stress leads to consistent, continuous reduction in genome content along four environmental stress gradients in naturally occurring populations of A pervasive challenge in microbial ecology is detecting how natural microbe populations respond to environmental change. Prokaryotes have highly variable intraspecific genome content, described as a pangenome , 2. WithOne approach in detecting changes in evolutionary pressures on genome evolution, such as ecological adaptation, is to determine how natural environmental variation, putative agents of natural selection, predict the distribution of genomic variation. Landscape genomics has been a powerful approach in uncovering the genetic basis of adaptation, traditionally detecting putative adaptive loci or SNPs on a single reference genome, and effectively concentrating adaptive discovery to the core genome of a species. However, little attention so far has been given to uncovering patterns of accessory genome variation across the environment . Here, IGenome reduction represents a major change in the accessory genome. Prokaryotic genomes are thought to be under constant decay due to a mutational bias towards deletion , 13. OneBradyrhizobium diazoefficiens, which was previously sampled across a contiguous and environmentally complex heterogeneous landscape or low stress [large negative z-score]) appear to be under strong selection are under stronger selective pressure, having significantly higher proportion of codons under purifying or positive selection compared to accessory genes randomly distributed with respect to environmental stress. Because accessory genes that only occur in extreme ends of the stress gradient and increase in population differentiation (Fst) with high stress in core genes, when compared to aridity and acidity. The observed decrease in the efficiency of selection provides strong evidence of either weaker selection and/or smaller effective population size in the core genome at high heat and salinity stress. Consistent with this study\u2019s finding, theoretical models predict that increased population differentiation (Fst) can be a result of decreased effective population size through increased population sub-division . The conThe pervasive genome decay along soil and climate-related stress gradients also has implications regarding evolvability in bacterial populations. The observed loss of genetic diversity (at the gene level) with increasing stress prompts future questions and experiments on the upper bounds of genome decay that microbial populations can tolerate with increasing environmental stress. The loss of genetic diversity also raises questions about how genome streamlining impacts the ability for bacterial populations to evolutionarily respond to environmental change when already faced with stressful conditions.Supplemental InformationSupplementary interactive 3D version of Figure 6"} +{"text": "Nature Photonics (2022)10.1038/s41566-021-00921-9Thermal radiation is commonplace in our everyday life, exemplified by natural sunlight and infrared thermometers. When an object emits thermal radiation, a radiative cooling process carrying away energy from the object occurs spontaneously. Hence, the control of thermal radiation or radiative cooling is beneficial not only to the development of practical cooling techniques, but also to the exploitation of renewable energy resources. An emerging field of thermal photonics provides exciting opportunities for manipulating the radiative process artificially. In this review article, Shanhui Fan from Stanford University and Wei Li from Changchun Institute of Optics, Fine Mechanics and Physics, Chinese Academy of Sciences have discussed fundamental concepts involved in radiative cooling and summarized principles for tailoring thermal radiation with photonic structures. The story starts with the demand of daytime radiative cooling and introduces photonic concepts and recent advances in this area. Inspired by the daytime radiative cooling, more scenarios such as solar cell cooling, thermal management of outdoor colored objects and cooling textiles have been proposed. Thermodynamics in radiative cooling is finally discussed for harvesting outgoing thermal radiation. We anticipate these fruitful discussions can help readers walk into thermal photonics and motivate researchers to find novel applications of radiative cooling."} +{"text": "ABSTRACT IMPACT: This study aims to provide insight into naturally acquired immunity against severe malaria, thereby laying the foundation for the design of novel vaccine candidates to prevent severe disease as well as monoclonal antibody therapies to treat severe malaria. OBJECTIVES/GOALS: Severe malaria is caused by parasite surface antigens that contain high sequence diversity. Nevertheless, P. falciparum-exposed individuals develop antibody responses against these antigens. Our goal is to isolate antibodies with broad reactivity to understand how disease protection is acquired. METHODS/STUDY POPULATION: Our study cohort consists of Ugandan adults living in a malaria-endemic region with high transmission intensity, who are protected against severe malaria. Using fluorescently labeled probes of parasite surface antigens, we have isolated antigen-specific B cells from these donors. We then expressed the corresponding monoclonal antibodies in vitro. These antibodies were screened against a library of variant surface antigens to determine antibody breadth and potential to inhibit interaction of the parasite surface antigen with host receptors, a critical step in pathogenesis. Additionally, using a panel of variant surface antigen mutants, we have predicted the epitopes targeted by the broadest monoclonal antibodies. RESULTS/ANTICIPATED RESULTS: We have identified three monoclonal antibodies with exceptionally broad reactivity and inhibitory activity against our panel of severe disease-inducing variant surface antigens. We have identified two major sites targeted by these broadly reactive antibodies. The first site was associated with the largest breadth, but limited inhibitory potential, while the second site showed high-affinity antibody binding and inhibition of receptor binding. Interestingly, two of these three antibodies were very similar in structure, even though they were isolated from different donors. Isolation of antigen-specific B cells from additional donors will enable us to identify how common such broadly reactive antibodies are and allow the identification of additional epitopes DISCUSSION/SIGNIFICANCE OF FINDINGS: This study is the first to isolate broadly reactive antibodies that are likely to protect against severe malaria in naturally immune individuals. Further characterization of antibody-antigen interactions will inform the development of this surface antigen as a vaccine candidate for malaria."} +{"text": "Exercise training decreases abdominal fat in an intensity-dependent manner. The fat loss effect of exercise has been intuitively thought to result from increased fat burning during and after exercise, defined by conversion of fatty acid into carbon dioxide in consumption of oxygen. Nevertheless, increasing exercise intensity decreases oxidation of fatty acids derived from adipose tissue despite elevated lipolysis. The unchanged 24-h fatty acid oxidation during and after exercise does not provide support to the causality between fat burning and fat loss. In this review, alternative perspectives to explain the fat loss outcome are discussed. In brief, carbon and nitrogen redistribution to challenged tissues (muscle and lungs) for fuel replenishment and cell regeneration against abdominal adipose tissue seems to be the fundamental mechanism underlying the intensity-dependent fat loss effect of exercise. The magnitude of lipolysis (fatty acid release from adipocytes) and the amount of post-meal carbon and nitrogen returning to abdominal adipose tissue determines the final fat tissue mass. Therefore, meal arrangement at the time when muscle has the greatest reconstruction demand for carbon and nitrogen could decrease abdominal fat accumulation while increasing muscle mass and tissue repair. Exercise decreases abdominal fat mass, especially at high intensity. This outcome is not causally associated with fat burning, but better explained by carbon and nitrogen redistribution. Since abdominal fat tissue constantly releases fatty acids into circulation under post-absorptive condition with natural cell deaths, exercise diverts more post-meal carbon and nitrogen to muscle for energy repletion and cell regeneration after phagocytosis and stem cell homing. This in turn leads to concurrent fat mass loss and muscle mass gain. Respiratory ventilation during high-intensity aerobic exercise amplifies the competition for post-meal carbon and nitrogen against adipose tissues. TherefoLipolysis appears to be more relevant with fat loss than fatty acid oxidation. Exercise increases plasma epinephrine levels at high intensities . EpinephThe physiological significance of the enhanced release of fatty acids from lipolysis without the corresponding increase in fatty acid oxidation during and after exercise remains unclear. However, a proposed role of adipocyte-derived fatty acids in tissue repair has been recently described elsewhere . Fatty aThe first basic assumption of fat burning theory is that fat cell death has no role in fat loss. However, this assumption is unlikely valid since fat cells are continuously dying and regenerating throughout our life. Approximately 8.4% of subcutaneous abdominal adipocytes are renewed annually with an average half-life of 8.3 years in human adults . AbdominThe second basic assumption of the fat burning theory is that muscle and fat cells are not interconvertible in a human body. However, we could not preclude the possibility that the fat mass loss concurrent with muscle mass gain after exercise training is associated with conversion between muscle and fat progenitor cells, derived from circulating bone marrow stem cells. Conversion from muscle satellite cells to an adipogenic lineage contributes the development of obesity and muscle mass loss in animals . GlucoseFurther evidence of this mechanism comes from the wide array of exosomes (containing nucleic acids or peptide) released from exercising skeletal muscle implicating the crosstalk between muscle and fat tissues. Adipose tissues are a major source of circulating exosomes containing a variety of mediators, which may influence muscle development . Some nuThe third assumption of the fat burning theory is that the increased carbon and nitrogen demands for airway epithelial cells regeneration in lungs does not contribute to fat loss during and after exercise. However, the possibility that the fat loss effect of high-intensity aerobic training due to competition for carbon and nitrogen between lungs and adipose tissues cannot be excluded . The lunDuring unfed conditions, visceral adipose tissues continuously releases fatty acids into circulation , togetheStudies employing dual energy X-ray absorptiometry have also provided solid support for the carbon and nitrogen redistribution effect of exercise training by the evidence of concurrent increases in lean body mass and decreases in fat mass . This nuLipoprotein lipase (LPL) attached on the surface of endothelial cells in capillary lumen determines relative partition of circulating triglycerides to muscle and adipose tissues after meals. The molecular size of triglyceride carried by chylomicron and VLDL is too large to transport across cell membrane of adipocytes from blood unless it is locally hydrolyzed by LPL in the adipose and muscle tissues. Relative LPL expression in adipose tissue and muscle tissues thus determines the daily distribution of circulating triglycerides (chylomicron and VLDL) partitioning into adipose tissues and skeletal muscle after meals. This ratio is substantially influenced by exercise training, in which trained women have relatively higher (\u223c8 times) muscle-to-adipose tissue LPL ratio compared to their untrained state . This suFatty acids (from lipolysis) are continuously released from abdominal adipose tissue into the circulation and fat cells are continuously dying in normal human adults. The size of adipose tissue is determined by the magnitude of nutrient competition from muscle and lungs for cell regeneration and energy replenishment after exercise. This is varied by types of exercise (aerobic or resistance exercise). Despite the fact that lower exercise intensity relies more on fatty acid oxidation, high-intensity exercise training (anaerobic in nature) provides a superior abdominal fat loss effect than low- and moderate-intensity exercise training. Given the fact that exercise does not increase 24-h fatty acid oxidation during and after exercise training, the carbon and nitrogen redistribution theory is more suitable to explain the abdominal fat loss outcome of exercise training than fat burning theory. This reasonably explains why low- and moderate-intensity exercise often fail as strategies for fat loss despite the greater percentage of fatty acid oxidation compared with high intensity exercise. Studies on inter-tissue communication during exercise (such as muscle-derived extracellular vesicles) for post-meal carbon and nitrogen redistribution are promising and may provide useful application to normalize body composition and prevent obesity. Furthermore, the role of fatty acids on repairing post-exercise damage deserves further investigation. More data are needed to support the carbon and nitrogen redistribution theory on fat loss effect of exercise.Both authors contributed significantly to this work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Objective: This study aims to identify multiple dimensions of religiosity among young adults at the beginning and end of the transition to adulthood, and describe how transition patterns of religiosity in early adulthood are associated with filial elder-care norms in midlife. Background: There is a broad consensus that religiosity is multidimensional in nature, but less is known regarding transitions in multiple dimensions of religiosity from early to middle adulthood and predicted filial eldercare norms as a function of those religiosity transitions. Methods: The sample consisted of 368 young adults participating in the Longitudinal Study of Generations in 2000 (mean age = 23 years) and 2016 waves. We conducted a latent class and latent transition analyses to address our aims. Results: We identified three religious latent classes among young adults in both 2000 and 2016 waves: strongly religious, weakly religious, and doctrinally religious. Staying strongly religious young adults between 2000 to 2016 waves reported higher filial elder-care norms in the 2016 Wave than those who were in staying weakly religious, staying doctrinally religious, and decreasing religiosity transition patterns between 2000 to 2016 waves. Conclusion: Our findings suggest that religiosity is still an important value for young adults shaping their intergenerational relationships with their aging parents. Keywords: religiosity, filial eldercare norms, young adults, transition to adulthood"} +{"text": "A major component of The Middle Tennessee GWEP involves delivery of an annual regional geriatrics update conference. Formerly in-person, the planning committee transformed the 34th Annual Update Conference to a virtual platform within a six-month period. The University partner provided a Zoom platform with licensing and training of program staff. National marketing was achieved through professional societies and purchased e-mailings. Participants numbered 79, including 8 disciplines. Presenters were instructed on platform techniques including screen sharing, polling function, and breakout rooms to enhance audience participation. REDCap registration captured demographic information and facilitated evaluations and post-attendance intention-to-change surveys. Lessons learned were shared with community partners and advisory board members who demonstrated changes in service delivery models and training of new staff to support care to greater numbers of clients and participants. Virtual platforms can extend outreach for valuable learning and service outcomes and maintain high levels of satisfaction among target audiences."} +{"text": "Chronic ocular graft-versus-host disease (oGVHD) is an ocular comorbidity of graft-versus-host disease (GVHD) that usually occurs concurrently with systemic manifestations. Failure to detect and treat oGVHD in its early stages may lead to progression of ocular signs and symptoms leading to oGVHD that is refractory to conventional treatment.We report the clinical course of a 19-year-old male and a 59-year-old female with severe and progressive chronic oGVHD without concurrent systemic signs of chronic graft-versus-host disease (cGVHD). Although their systemic conditions had been stable, both suffered from severe oGVHD and were referred to our clinic. Both cases exhibited marked improvement in conjunctival inflammation and fibrotic changes after amniotic membrane transplantation (AMT). Both cases underwent keratoplasty eventually to stabilize ocular surface conditions and to improve visual function.We reported the clinical outcomes of 2 cases of chronic oGVHD without concurrent systemic comorbidities that were treated with AMT. The clinician should be aware that cGVHD may persist in target organs even in the absence of concurrent systemic comorbidities following seemingly successful systemic treatment. A multidisciplinary team approach is essential in the early detection and therapeutic intervention for chronic oGVHD. Dry eye disease (DED) is the most frequent ocular manifestation after haematopoietic stem cell transplantation (HSCT) , 2, and The human amniotic membrane (AM) is reported to exert anti-inflammatory and anti-scarring actions \u20139, and aIn this article, we report the clinical outcomes of 2 cases of refractory chronic oGVHD without long-term systemic comorbidities, both of which were treated with AMT and keratoplasty to achieve clinical improvement.A 19-year-old Japanese male with a history of acute myelogenous leukaemia (AML) who underwent reduced intensity allogeneic HSCT (mini-transplantation) in March 2005 was referred to the Keio University Dry Eye outpatient clinic in October 2005 complaining of severe ocular pain, difficulty opening his eyes and foreign body sensations after acute and chronic skin GVHD were completely stabilized. Prior to mini-transplantation, no ocular surface abnormality was noted at the previous hospital, and he started to suffer from newly developed symptoms of DED in May 2005, after alleviation of acute skin GVHD. Systemic prednisolone (PSL) had been tapered from 40 to 20\u2009mg/day in July and was discontinued in August 2005. Just after cessation of PSL, bilateral lid swelling and severe ocular pain had emerged. PSL (15\u2009mg/day) was restarted to treat skin chronic GVHD in October 2005. Skin chronic GVHD was well controlled by this treatment. At the first visit to Keio University Dry Eye outpatient clinic in October 2005, severe DED, extensive trichiasis, corneal conjunctivalization, corneal ulcer, spontaneous lacrimal punctal occlusion, and active corneal neovascularization were observed in both eyes who underwent allogeneic bone marrow transplantation (BMT) without irradiation in May 2010 was referred to the Keio University Dry Eye outpatient clinic in September 2013 as she developed refractory chronic oGVHD. After BMT, she developed acute skin GVHD and was successfully treated with systemic tacrolimus (2\u2009mg/day) and PSL (30\u2009mg/day), which was tapered over almost 1 year. In early 2011, just after tapering of treatment for acute skin GVHD, she developed DED and transient difficulty opening her mouth, which was diagnosed as chronic ocular and oral GVHD. She had been suffering from symblepharon, LSCD and conjunctivalization in her right eye, and she had been previously treated with contact lenses, commercially available eye drops, autologous serum and topical cyclosporine and tacrolimus, yet her ocular surface condition had not improved. At the first visit to Keio University Hospital in 2013, severe conjunctival fibrosis of the upper conjunctiva and fornix shortening, partial LSCD and conjunctivalization of the upper cornea on her right eye were observed (Fig.\u00a0Chronic oGVHD is an immune-mediated fibrotic disease that usually occurs concurrently with systemic comorbidities, and its aetiologies are multifactorial and still largely unknown. Currently available treatments such as eye drops, oral medications or punctal plugs are often insufficient to control severe ocular surface inflammation and excessive fibrosis, and additional therapeutic interventions such as AMT, corneal transplantations, and COMET are indicated for this intractable disease. The availability of such surgical interventions is limited, and the indications for these interventions should be considered carefully. Therefore, it is vital to detect oGVHD in the early phase to prevent severe ocular complications.AMT has been reported to be effective in treating refractory ocular surface diseases, including Stevens-Johnson syndrome and ocular cicatricial pemphigoid , 10. CliIn both cases the fornix was successfully reconstructed and long-term maintenance was achieved after AMT. However, a minor recurrence of corneal conjunctivalization in case 2 and corneal perforation in case 1 were observed after AMT, and both were treated with corneal keratoplasty.Although acute skin GVHD in cases 1 and 2 and transient chronic oral GVHD in case 2 were observed, oGVHD continued to progress rapidly even after stabilization of systemic conditions. Both cases resulted in severe oGVHD during or after tapering of systemic corticosteroids or immunosuppressants and AMT was required to reconstruct the fornix and to prevent corneal conjunctivalization due to LSCD.The limbal stem cell region has been reported to be infiltrated by inflammatory cells based on confocal microscopy observations in chronic oGVHD . FurthercGVHD patients are immunocompromised, and monitoring for ocular surface infections as well as systemic conditions is imperative. However, ocular manifestations may become apparent even after stabilization of systemic GVHD, as we experienced in the two cases reported herein. We suspect that these patients had hidden or latent mucosal or exocrine gland GVHD involving several mucosal surface barrier regions. The clinician therefore should be aware of the possibility of subclinical mucosal inflammation in cGVHD and the possibility of exacerbation of such inflammation especially at cessation or tapering of systemic anti-inflammatory medication. A multidisciplinary team approach is essential in determining the optimal timing for tapering of systemic anti-inflammatory medication in order to minimize the risk of chronic oGVHD."} +{"text": "To report pooled prevalence of all mental disorders among the general prison population in the United Kingdom (UK). This includes individuals in Young Offender Institutions (YOI), youth custody and adult prisons across all categories. A secondary aim explores possible sources of heterogeneity by performing subgroup and meta-regression analysis across certain covariates (e.g. sex of prisoner). We hypothesise that contemporary estimates of mental disorders are higher than the general population.Prevalence of mental health problems among prisoners are considerably higher than the general population; this poses an important public health concern. Individuals who require diversion to appropriate psychiatric services are becoming embroiled in the revolving door of the criminal justice system. However, there are no up-to-date reviews assessing prevalence of mental disorders across the general prison population in the UK. This study aims to address this gap.We conducted a systematic search of PsycINFO (1923 \u2013 October 2019), MEDLINE (1946 \u2013 October 2019), EMBASE (1947 \u2013 October 2019) and Web of Science of articles reporting prevalence of mental disorders in UK prison populations (PROSPERO registration number: CRD42019132685). The Joanna Briggs Institute (JBI) Appraisal Checklist for Studies Reporting Prevalence Data assessed study quality and bias. Pooled prevalence of each mental disorder was calculated using Stata statistical software 16.0 via the metaprop command. Forest plots present prevalence estimates with study weights and associated 95% confidence intervals (CI). Overall, 20 studies satisfied inclusion criteria, comprising of 12,335 prisoners across England, Wales and Scotland.We identified higher rates of neurotic disorders , personality disorders , alcohol and drug dependence . The lowest prevalence rates included schizophrenia , panic disorders , adjustment disorders and intellectual disability . Meta-regressions for psychotic disorder and personality disorder revealed no significant differences across study year, sample size and gender.Our prevalence estimates of mental disorders in prisons are higher than the general English population. However, we should acknowledge the influence of considerable heterogeneity. These findings demonstrate the need to quantify current prevalence of mental disorders amongst prisoners in the UK. We recommend for the government to consider performing an up-to-date census of psychiatric morbidity to facilitate service provision."} +{"text": "ABSTRACT IMPACT: This project seeks to identify unique host responses that are biomarkers for specific urethral pathogens, and which can be used in the development of point-of-care (POC) STI diagnostics. OBJECTIVES/GOALS: How Chlamydia trachomatis (CT) and other common STIs, e.g. Neisseria gonorrhoeae, evade immunity and elicit pathology in the male urethra is poorly understood. Our objective is to determine how STI-infected urethral epithelial cells, as well as the uninfected \u2018bystander\u2019 cells with which infected cells communicate, respond to CT and other STIs. METHODS/STUDY POPULATION: We evaluated how immortalized urethral cell lines - including transduced human urethral epithelial cells (THUECs) - respond to increasing doses of CT infectious particles using in vitro one-step progeny assays performed in the presence or absence of cycloheximide, a drug that inhibits eukaryotic protein synthesis. We will perform concurrent single-cell RNA sequencing (scRNA-seq) and multiplex cytokine analyses to determine how different CT doses impact the transcriptomes of infected and bystander urethral epithelial cells and modulate cytokine production of the overall monolayer. Results of these experiments will inform the feasibility of performing similar analyses in situ using urethral swabs from men with clinically diagnosed urethritis. RESULTS/ANTICIPATED RESULTS: Our results demonstrate that immune-competent urethral cell monolayers strongly resist CT infection, unless most of the cells are simultaneously infected. This suggests that uninfected bystander cells sense CT-infected cells and secrete soluble factors that may act to limit CT proliferation in infected cells and to inform remaining uninfected cells that a potential pathogen is present. We anticipate that our scRNA-seq and cytokine analyses will identify both specific effector pathways that protect against CT and intracellular signals that modulate them. We speculate that these pathways and signals may differ during infection with CT and other STIs. Importantly, we anticipate that our in vitro model of CT infection will be highly representative of in situ immune responses observed in urethras of infected men. DISCUSSION/SIGNIFICANCE OF FINDINGS: In men, common STIs including CT are usually managed syndromically due to a lack of POC diagnostics. By determining how STIs elicit urethral inflammation and identifying countermeasures that STIs use to evade urethral immunity, we can identify host responses that serve as biomarkers for urethritis, generally, and for specific urethral pathogens."} +{"text": "Understanding the neurobiological underpinnings of pedophilic behavior may contribute to a more comprehensive characterization of these individuals on a clinical ground, a pivotal step forward for the development of more efficient therapeutic rehabilitation strategies.Pedophilia is a disorder of public concern because of its association with child sexual offense and recidivism. Previous neuroimaging studies of potential brain abnormalities underlying pedophilic behavior, either in idiopathic or acquired pedophilia, led to inconsistent results. This study sought to explore the neural underpinnings of pedophilic behavior and to determine the extent to which brain alterations may be related to distinct psychopathological features in pedophilia. To this aim, we run a coordinate based meta-analysis on previously published papers reporting whole brain analysis and a lesion network analysis, using brain lesions as seeds in a resting state connectivity analysis. The behavioral profiling approach was applied to link identified regions with the corresponding psychological processes. While no consistent neuroanatomical alterations were identified in idiopathic pedophilia, the current results support that all the lesions causing acquired pedophilia are localized within a shared resting state network that included posterior midlines structures, right inferior temporal gyrus and bilateral orbitofrontal cortex. These regions are associated with action inhibition and social cognition, abilities that are consistently and severely impaired in acquired pedophiles. This study suggests that idiopathic and acquired pedophilia may be two distinct disorders, in line with their distinctive clinical features, including age of onset, reversibility and The online version contains supplementary material available at 10.1007/s11682-020-00442-z. Pedophilia is a paraphilic disorder included within the Diagnostic and Statistic Manual of Mental Disorder identify the brain regions consistently impaired in idiopathic and acquired pedophilia; (ii) determine whether the two forms of pedophilia are associated with overlapping or distinct brain networks; (iii) link topographically defined regions with corresponding psychological processes, testing which kind of experiments are most likely to activate a given region, to give a cognitive/psychological meaning to the detected alterations.In order to identify brain regions consistently impaired in idiopathic pedophilia, a coordinate based meta-analysis using the Activation Likelihood Estimation (ALE) method was performed AND . A search for studies in review and meta-analysis articles and a reference tracing were also performed.To be included in the analysis, studies had to meet the following criteria: (i) use structural (sMRI) or functional (fMRI) MRI; (ii) perform a whole brain analysis analysis were excluded); (iii) be original peer-reviewed data; (iv) include both pedophilic individuals and a healthy control group (HC) or pedophilic individuals who committed and who did not commit sexual abuse; (v) have a sample size of at least five individuals per group; (vi) report results in a standardized coordinate space .Literature screening and selection was performed according with the PRISMA guidelines method version 3.0.2. This algorithm treats activated foci of brain regions as three-dimensional Gaussian probability distributions centered at the given coordinates ; therefore, they did not present a spatially defined lesion that could be outlined. In order to identify the neural structures consistently impaired in bvFTD, a coordinate based meta-analysis was run on papers presenting structural or functional abnormalities in patients with bvFTD vs. healthy controls on the axial image of a standardized template using the MRIcron software of patients with lesions functionally connected to each individual voxel. A stability analysis was performed by replicating the analyses using three different control groups, each with 25 healthy subjects . Analyses were performed using SPM-CONN (2018b) adopting standard preprocessing and denoising steps.Second, traced lesions were used as individual seeds in a seed based connectivity analysis, using resting state fMRI data from one hundred healthy subjects randomly selected from a freely available dataset: http://www.brainmap.org/), to reveal the Behavioral Domain and Paradigm Classes consistently associated with these regions.To link topographically defined brain regions with the corresponding psychological process, we ran a behavioral profiling approach across databases of aggregation from activations experiments was impaired in nine patients, spared in four, while no data were available for the remaining six cases.Lesion localization was very heterogeneous, as reported in Table Though the individual lesions had different locations, the lesion network mapping analysis revealed that 95% of them were part of a single brain network defined by functional connectivity with posterior midline structures , including the posterior cingulate cortex (PCC) and precuneus; the bilateral OFC ); the right inferior temporal gyrus , the left calcarine gyrus and the left fusiform gyrys identify consistent alterations associated with acquired and idiopathic pedophilia; (ii) understand whether and to what extent the two forms of pedophilia may share the same biological substrate; (iii) investigate whether consistent brain abnormalities may explain psychopathological features typically detected in pedophiles.Of relevance, the lesion network mapping technique revealed that the neural bases of acquired pedophilia localize to a common resting state network, despite the high spatial heterogeneity of the individual lesions. Overall, these data support a shared neurobiological substrate in acquired pedophilia, as they reveal that the lesions chronologically associated with acquired pedophilic behavior are all functionally connected with a network involving the OFC areas, the posterior midline structures, the right inferior temporal gyrus and the left fusiform gyrus.On the contrary, the ALE meta-analysis of whole brain neuroimaging studies in idiopathic pedophilia revealed no spatially convergent findings across studies, suggesting that idiopathic pedophilia does not have consistent brain alterations that may be detected by structural or functional neuroimaging investigations. However, when lowering the statistical threshold, a few clusters of spatial convergence emerged in the superior frontal gyrus, middle cingulate and middle occipital gyrus. The different findings obtained from the analyses in idiopathic and acquired pedophilia may suggest that the two conditions may not rely on a shared neural base. Of note, the amygdala, which had been reported to be consistently impaired in pedophilia , specifically theory of mind (posterior midline structures), emotion recognition (right OFC), impulse control (right OFC), semantic interpretation of cues . It is noteworthy that these results match well with the aberrant behavior pattern described in acquired pedophiles. The observation of altered activity in a key region for impulse inhibition fits perfectly with previous evidence from single case description of patients with acquired pedophilia, in whom dis-inhibition is invariably present model of causation . Results of neuroimaging analyses, however, strongly reflect cognitive/behavioral deficits observed in those patients, corroborating the plausibility of our analysis. Second, the lesion network analysis was run using only a relatively small sample of healthy controls (one hundred subjects). The additional analyses we run, however, corroborated the robustness of the results, which remained stable using different control groups of 25 healthy controls. Finally, in the lesion network mapping analysis we could not take into account potential medication effects in the individual patients. However, the original papers indicate that drugs were usually administered after symptoms insurgence, thus the impact of pharmacotherapy for the purposes of the current study is limited. Future studies should assess potential effects of pharmacotherapy.In summary, the results of this study pinpoint aberrant brain activity related to acquired but not to idiopathic pedophilia. All the lesions causing acquired pedophilia localized to a shared resting state network including the posterior midlines structures, the right inferior temporal gyrus and the bilateral OFC, regions consistently involved in social cognition, theory of mind, emotion recognition and action inhibition. Alterations of these neuropsychological functions have been consistently described in individual reports of acquired pedophiles, in line with the observed results. Interpreting these findings in light of the INUS model of causation is relevant to better characterize these patients and to develop novel therapeutic and rehabilitative strategies ESM 2(PDF 370 KB)ESM 3(DOC 92.5 KB)ESM 4(PDF 486 KB)ESM 5(DOC 47.0 KB)"} +{"text": "The optimal blood pressure (BP) management in acute ischaemic stroke (AIS) and acute intracerebral haemorrhage (ICH) remains controversial. These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist physicians in their clinical decisions regarding BP management in acute stroke.The guidelines were developed according to the ESO standard operating procedure and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. The working group identified relevant clinical questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available evidence, and made specific recommendations. Expert consensus statements were provided where insufficient evidence was available to provide recommendations based on the GRADE approach. Despite several large randomised-controlled clinical trials, quality of evidence is generally low due to inconsistent results of the effect of blood pressure lowering in AIS. We recommend early and modest blood pressure control (avoiding blood pressure levels >180/105\u2009mm\u2009Hg) in AIS patients undergoing reperfusion therapies. There is more high-quality randomised evidence for BP lowering in acute ICH, where intensive blood pressure lowering is recommended rapidly after hospital presentation with the intent to improve recovery by reducing haematoma expansion. These guidelines provide further recommendations on blood pressure thresholds and for specific patient subgroups.There is ongoing uncertainty regarding the most appropriate blood pressure management in AIS and ICH. Future randomised-controlled clinical trials are needed to inform decision making on thresholds, timing and strategy of blood pressure lowering in different acute stroke patient subgroups."} +{"text": "Social support exchanges are an integral part of older adults\u2019 well-being. Yet, we know little about how older adults' marital status may influence their support exchanges with different social partners in everyday life, and whether the effect of support exchanges on daily well-being vary by marital status. Adults aged 65+ (N = 278) completed an initial interview about their background and close social networks; then, participants reported whether they provided or received support from their close social partners and rated their psychological well-being for 5 to 6 days. Multilevel logistic models revealed that married older adults were more likely to provide or receive daily support from their close partners than widowed or divorced older adults. However, with respect to specific non-spousal ties, married older adults were less likely to provide support to siblings, friends or others compared to divorced older adults. Although married older adults were more likely to receive support from children than divorced older adults, they were less likely to receive support from siblings and friends compared to widowed or divorced older adults. Furthermore, receiving support from other familial ties was associated with reduced daily well-being for widowed older adults whereas married older adults were able to maintain their daily well-being in such situation. Findings highlight the central role siblings and friends play in unmarried older adults' daily support networks and suggest that receiving support could have differential impact on daily well-being depending on older adults\u2019 marital status."} +{"text": "As prevalence decreases in pre-elimination settings, identifying the spatial distribution of remaining infections to target control measures becomes increasingly challenging. By measuring multiple antibody responses indicative of past exposure to different pathogens, integrated serological surveys enable simultaneous characterisation of residual transmission of multiple pathogens.Here, we combine integrated serological surveys with geostatistical modelling and remote sensing-derived environmental data to estimate the spatial distribution of exposure to multiple diseases in children in Northern Ghana. The study utilised the trachoma surveillance survey platform to collect information on additional identified diseases at different stages of elimination with minimal additional cost. Geostatistical modelling of serological data allowed identification of areas with high probabilities of recent exposure to diseases of interest, including areas previously unknown to control programmes. We additionally demonstrate how serological surveys can be used to identify areas with exposure to multiple diseases and to prioritise areas with high uncertainty for future surveys. Modelled estimates of cluster-level prevalence were strongly correlated with more operationally feasible metrics of antibody responses.This study demonstrates the potential of integrated serological surveillance to characterise spatial distributions of exposure to multiple pathogens in low transmission and elimination settings when the probability of detecting infections is low. Following implementation of successful interventions, one of the primary challenges for neglected tropical disease programmes is identifying areas with remaining disease transmission. As disease prevalence decreases, these infections become increasingly rare and hard to detect. Serological assays measure long-lived disease-specific antibody responses indicating past exposure to pathogens and increase the probability of detecting disease transmission. Here, we integrate serological assays with environmental and spatial data to map priority areas for surveillance for multiple neglected tropical diseases in Northern Ghana using the two-stage cluster-based survey platform established for trachoma surveillance. The use of multiplex bead assays measuring exposure to multiple pathogens allows integrated surveillance of diseases of interest to the national control programme. We identify areas with high risks of transmission to selected diseases as well as areas with high uncertainty which are priorities for future control and surveillance efforts. Together, this highlights the utility of multiplex serological platforms as a tool for integrated surveillance and mapping of neglected tropical diseases. Neglected tropical diseases (NTDs), such as trachoma, schistosomiasis, onchocerciasis, lymphatic filariasis and soil-transmitted helminthiases, cause substantial public health burdens globally. With increasing investment in NTD control, elimination and eradication programmes, community-based surveys are used to monitor impacts of interventions, identify residual transmission and target high-risk populations ,2. TheseAs transmission of infectious diseases decrease, the probability of detecting infections becomes correspondingly low and requires prohibitively large sample sizes to identify infections. For many diseases, this also corresponds with more pronounced spatial heterogeneity, with transmission concentrated in specific geographic areas or sub-populations \u20139. SerolThe development of multiplex serological assays increases the operational feasibility of serological techniques by enabling measurement of a broad range of responses with high repeatability from limited blood samples. Multiplex bead assays (MBA) are a well-validated method to measure population-level serological responses to a wide panel of NTDs, malaria, vaccine preventable diseases and other infections . These aDespite increasing collection of serological data, challenges remain in translating these data into actionable programmatic information . SpatialHere, we adapt a commonly used Gaussian mixture model and binomial geostatistical models to describe the spatial distribution of antibody responses to multiple diseases in a population-based survey of children in Northern Ghana. Conducted as part of routine surveillance for trachoma elimination, this survey utilised a two-stage cluster-sampling population-based survey design and identified very low levels of the sign \u201ctrachomatous inflammation\u2014follicular\u201d, a finding supported by estimates of seroconversion rates \u201329. AlthThis study was approved by the Ghana Health Service Ethics Review Committee (GHS-ERC: 03/07/15) and the London School of Hygiene & Tropical Medicine (10285). Written informed consent was sought from parents or guardians of all participating children. Verbal assent was additionally obtained from children who were able to provide this. The CDC investigators were not considered to be engaged in human subjects research.www.getodk.org).This study was conducted in the Northern, North East, Savanna and Upper West regions of Ghana in a predominantly rural agricultural population . The cliChlamydia trachomatis), Wb123 lymphatic filariasis (Wucheria bancrofti), Ov16 onchocerciasis (Onchocerca volvulus), NIE strongyloidiasis , soluble egg antigen (SEA) schistosomiasis (Schistosoma mansoni), rp17 and TmpA yaws , VSP3 giardiasis (Giardia lamblia). Glutathione s-transferase (GST) was used as a negative control. MBA were conducted using standard methods )Within this setting, serological data support other estimates of NTD burdens and associated environmental risk factors within Northern Ghana. These results are consistent with previous findings of very low prevalence of trachoma and additionally demonstrate how serology may be employed to identify areas for post-elimination surveillance for potential recrudescence ,28. AddiO. volvulus transmission. However, lymphatic filariasis MDA ceased in 2014, and these serological data indicate an increase in onchocerciasis previously unknown to GHS and as a direct result of the integrated surveillance approach, GHS decided to start MDA specifically for onchocerciasis in this focus . While further work is required to confirm transmission and disease burdens may have changed since 2015, this identifies a priority area for surveillance.Geostatistical modelling of serological data representing exposure to multiple pathogens has important implications for survey design. The systematic and random population-based sampling strategy used for trachoma mapping enabled assessment of the distribution of other NTDs; this approach would not have been feasible with purposive sampling. For example, this study identified a focus of onchocerciasis with a significant prevalence of anti-Ov16 antibodies in children aged 1\u20139 years in Saboba-Cherepon. Previous mapping of onchocerciasis in this area through the Rapid Epidemiological Mapping of Onchocerciasis (REMO) in 2009 determined this to be an area of hypo-endemicity, not requiring onchocerciasis specific MDA at that time. Since then, the area has been treated for lymphatic filariasis, which includes the delivery of ivermectin and the expectation had been this would also impact on For control and elimination programmes needing to make operational decisions quickly without access to technical expertise needed to develop geostatistical models, very simple metrics can be applied to identify locations at high risk of transmission. While the relationship between arithmetic mean MFI values and estimated seroprevalence is not linear, prioritising control activities at clusters with the highest mean MFI values would likely ensure that interventions are reaching communities with the highest seroprevalence. This agrees with previous studies showing high correlation between mean quantitative antibody levels and other infection-based metrics of NTD transmission ,24. As sDespite the value of this approach, this study had several important limitations. As this study does not include adults, further validation of these methods may be required in settings with very high historical transmission and exposure in older age groups. While serological surveys of children are likely to be a better marker of recent rather than historical exposure, the utility of this approach will vary for specific diseases and associated risk factors. For trachoma, young children under 9 are believed to be the primary source of infection. In contrast, children aged under 5 years have lower risks of onchocerciasis and schistosomiasis, which predominantly impact school-aged children and adults with high-risk occupational activities. This highlights a key methodological challenge of integrated surveys targeting multiple diseases with different risk groups and transmission mechanisms. Additionally, this analysis relied on a single dataset collected over one time point. These diseases may additionally have differing immune responses, antibody kinetics and infection periods and longitudinal data may be able to more accurately identify recent infections or characterise transmission . The uncDespite these limitations, this study demonstrates how integrated serological surveillance can characterise the spatial distribution of exposure to multiple pathogens. An adaptable framework is provided to understand the spatial and environmental factors driving transmission in elimination settings when infection data are rare. As countries approach elimination, this study additionally highlights the need for innovative surveillance approaches utilising population representative sampling to maximising efficiency by collecting data across multiple diseases. Applying these techniques can provide valuable information for control programmes needing to identify and target remaining foci of infection.S1 TextTable A. Priors used for proportions in three component mixture models. Table B. Spatial and environmental covariates. Fig A. Disease-specific antibody responses for all included children, i. Density plots of log-transformed MFI values, ii. Age distributed antibody responses. Fig B. Antibody densities by age categories. Fig C. Relationships between mean posterior estimates of seroprevalence and arithmetic mean MFI per cluster for: A) Trachoma; B) Filariasis; C) Onchocerciasis; D) Strongyloides; E) Schistosomiasis; F) Giardiasis.(DOCX)Click here for additional data file."} +{"text": "Glutathione is an intracellular antioxidant that neutralizes reactive oxygen species and prevents tissue damage. Dietary supplementation with the glutathione precursors glycine and n-acetylcysteine supports the maintenance of normal glutathione levels in several age-related diseases, but the optimal doses and their efficacy in healthy elderly are not established. We report results from a randomized controlled clinical trial in 114 healthy volunteers (mean age = 65 years) receiving glycine and n-acetylcysteine (GlyNAC) at three different doses for two weeks . Older subjects showed increased oxidative damage and a lower reduced-to-oxidized glutathione ratio (GSH:GSSG) compared to young subjects, but unchanged total glutathione levels. GlyNAC did not increase levels of circulating glutathione compared to placebo treatment, the primary study endpoint. However, stratification analyses suggest that subjects with high oxidative stress and low glutathione status responded with glutathione generation. We find that unrelated to glutathione status, healthy aging was associated with lower levels of fasting glycine that can be increased towards those observed in young subjects with supplementation. Using preclinical models, we find that tissue glycine depletion is a common feature of healthy aging. Supplementation of old mice with glycine efficiently improved age-related decline of mitochondrial respiratory function in skeletal muscle and prevented a gene program associated with protein catabolism observed in control-treated animals. In conclusion, GlyNAC is safe and well-tolerated and may selectively increase glutathione levels in older subjects with oxidative stress and glutathione demand. Our data further suggest that glycine may support mitochondrial function independently of NAC."} +{"text": "Suicide rates increase over the life-span, necessitating concern in older adults. Recent studies suggest that anxiety disorders are associated with suicidal thoughts and behavior. The present study examined the association between anxiety symptoms and suicide risk (Suicide Behaviors Questionnaire-Revised), testing whether the association differs between younger and older adults. Depression symptoms were controlled for in the analyses. In a sample of 944 participants (46% 60+ years), anxiety symptoms, depression symptoms, and suicide risk were lower among older adults (60+ years) than younger adults . Age moderated the significant association between anxiety symptoms and suicide risk . Results indicate that an increase in anxiety is associated with a smaller increase in suicide risk for older adults than younger adults. The need for suicide risk screening among individuals with elevated anxiety symptoms is critical, especially for younger adults."} +{"text": "This session will provide updates on how the pandemic led to horrific situations in long-term care facilities and how the pandemic influenced major federal efforts to address elder abuse, neglect, and exploitation."} +{"text": "Although numerous risk factors are reported in the literature, many are non-modifiable and management of the injury remains difficult. Lower leg muscle structure and function are modifiable characteristics that influence tibial loading during foot-ground contact. Therefore, this study aimed to determine whether long-distance runners with MTSS displayed differences in n\u2009=\u200920) and matched asymptomatic controls (n\u2009=\u200920). Means, standard deviations, 95\u2009% confidence intervals, mean differences and Cohen\u2019s d values were calculated for each variable for the MTSS symptomatic and control limbs.Lower leg structure was assessed using ultrasound and a measure of lower leg circumference to quantify muscle cross-sectional area, thickness and lean lower leg girth. Lower leg function was assessed using a hand-held dynamometer to quantify maximal voluntary isometric contraction strength and a single leg heel raise protocol was used to measure ankle plantar flexor endurance. Outcome variables were compared between the limbs of long-distance runners suffering MTSS (MTSS symptomatic limbs displayed a significantly smaller flexor hallucis longus cross-sectional area, a smaller soleus thickness but a larger lateral gastrocnemius thickness than the control limbs. However, there was no statistical difference in lean lower leg girth. Compared to the matched control limbs, MTSS symptomatic limbs displayed deficits in maximal voluntary isometric contraction strength of the flexor hallucis longus, soleus, tibialis anterior and peroneal muscles, and reduced ankle plantar flexor endurance capacity.Differences in lower leg muscle structure and function likely render MTSS symptomatic individuals less able to withstand the negative tibial bending moment generated during midstance, potentially contributing to the development of MTSS. The clinical implications of these findings suggest that rehabilitation protocols for MTSS symptomatic individuals should aim to improve strength of the flexor hallucis longus, soleus, tibialis anterior and peroneal muscles along with ankle plantar flexor endurance. However, the cross-sectional study design prevents us determining whether between group differences were a cause or effect of MTSS. Therefore, future prospective studies are required to substantiate the study findings. Medial tibial stress syndrome (MTSS), more commonly known as shin splints, is one of the most common forms of exercise induced lower leg pain . ResearcTwo risk factors for MTSS that could easily be modified is structure and function of the lower leg muscles that contribute to the changes in lower leg girth seen in individuals who develop MTSS. Authors have previously reported that compared to asymptomatic controls, MTSS symptomatic individuals displayed less lean lower leg girth , reducedin vivo lower leg muscle cross-sectional area (CSA) or thickness to determine whether reduced lean lower leg girth associated with MTSS is due to atrophy of specific lower leg muscles or a uniform reduction in lower leg muscle size. A better understanding of how lower leg muscle composition differs between MTSS symptomatic and asymptomatic controls will provide evidence to develop future intervention studies that target specific lower leg muscles to treat or prevent MTSS.Lean lower leg girth is a circumferential measure of lower leg muscle bulk measured while a participant is standing and then corrected for adipose tissue thickness. Lean lower leg girth, however, does not provide information regarding how individual lower leg muscle composition affects the overall circumference measurement. To date, no study could be located that has assessed in vivo structural composition measurements. Researchers have previously reported that when matched to asymptomatic controls, MTSS symptomatic individuals display less ankle plantar flexor endurance, increased flexor hallucis longus plantar flexion torque and a greater isokinetic evertor strength compared to invertor muscle strength measured the lower leg muscle thickness and CSA, lean lower leg girth and lower leg MVIC strength of a convenience sample of two females and four males on two separate occasions. Intraclass correlation coefficients for lower leg muscle thickness all >\u20090.671) and CSA , lean lower leg girth (0.992) and lower leg MVIC strength confirmed the measurements were moderate to highly reliable. The ankle plantar flexor endurance protocol has previously been shown to have excellent test-retest reliability [71 and CSp\u2009<\u20090.05) differences in the outcome variables between the 20 MTSS symptomatic and 20 matched control limbs. The effect size was calculated using Cohen\u2019s d where 0.2, 0.5 and 0.8 were considered small, moderate and large, respectively [Descriptive statistics were calculated for each variable for the MTSS symptomatic and control limbs. Nine of the eleven MTSS symptomatic participants experienced bilateral symptoms. Therefore, a mixed-model linear regression design was used to determine whether there were any significant at the middle and distal thirds of the medial margin of the tibia, which coincides with the site of MTSS pain. Given the findings of Naderi et al. [A thinner SOL and lower SOL MVIC strength, combined with a thicker GL, could be compensatory strategies by MTSS symptomatic participants to reduce SOL traction on the tibia. Naderi et al. prospecti et al. and thati et al. . FurtherMTSS symptomatic limbs in the current study also displayed a significant deficit in ankle plantar flexor endurance capacity compared to control limbs. This is unsurprising given the significantly lower ankle plantar flexor muscle strength, notably reduced SOL strength, considering its endurance capacity associated with postural tasks . These fThe FHL and TA help control medial longitudinal arch (MLA) height and attenuate ground reaction forces during the stance phase of gait. Naderi et al. concludeAnother possible explanation for the lower strength of FHL, P, SOL and TA in MTSS symptomatic participants could be due to pain and associated neuromuscular adaptations. Although the mechanics are not entirely understood, individuals who experience pain (e.g. lower back pain) display altered muscle activation patterns and morphological muscle changes . FurtherIt is acknowledged that, as a cross-sectional study, we cannot determine whether the between group differences identified in this study were a cause or effect of MTSS development. Furthermore, the small sample size prevents definitive conclusions from being made. We were also not able to assess the structure of tibialis posterior due to constraints of our ultrasound probe. Tibialis posterior contributes to ankle plantar flexion and foot inversion and, therefore, assists in reducing the negative tibial bending moment during the stance phase of gait. Future research should be prospective in design and assess the structure and function of tibialis posterior to determine its role in resisting negative tibial bending moments.Compared to well-matched control participants, runners suffering MTSS symptoms displayed less FHL CSA and SOL thickness but greater GL thickness, as well as lower FHL, SOL, P and TA MVIC strength and ankle plantar flexor endurance capacity. These differences may contribute to the slow recovery time typically seen by MTSS patients because they might be less able to withstand the negative tibial bending moment generated during midstance, which can cause greater tibial strains. Furthermore, future investigation of asymptomatic runners using a prospective design is required to determine whether the between group differences identified in this study are consistent in runners who develop MTSS."} +{"text": "ABSTRACT IMPACT: Access to intracranial recording in our epileptic sample provides a unique opportunity to characterize neurological activation patterns associated with attention and implicit learning; this foundational physiological understanding will serve to better guide cognitive rehabilitation techniques in TBI patients that aim to improve functioning across these cognitive domains. OBJECTIVES/GOALS: 1) Investigate the network level interactions of attention and learning during an attention network task (ANT) and an implicit learning contextual cueing (CC) task. 2) Assess the effect that attention rehabilitation strategies have on behavioral and neural responses pre/post-attentional intervention. METHODS/STUDY POPULATION: This study involves refractory epilepsy patients (rEP) with implanted intracranial electrodes and moderate-to-severe traumatic brain injury (m/sTBI) survivors. In rEP, we are identifying network level modulations of cortical regions via the ANT, which probes components of attention and a CC task that probes implicit learning. We hypothesize that modulation of attention and learning can be seen at the neuronal level. In TBI we will assess improvement following two behavioral attention rehabilitation paradigms; and use our results from epileptic patients to guide measurement of treatment-related neuroplastic change via scalp electroencephalography. RESULTS/ANTICIPATED RESULTS: Preliminary behavioral results from the rEP cohort are in line with previous studies and the intracranial data is suggestive of region- and task-specific modulations in memory and attention related systems. Following completion of recruitment, we expect to more concretely identify regions and networks that exhibit modulatory effects associated with attention and implicit learning. Additionally, we anticipate that deficits in attention will be mitigated following training and hypothesize that implicit learning rate will improve in TBI patients as a result of both attentional rehabilitation paradigms. DISCUSSION/SIGNIFICANCE OF FINDINGS: Characterizing intracranial activity in epilepsy patients will give electrophysiology data unattainable in TBI patients. This intracranial perspective will enable us to propose mechanisms of action that may result from our interventions and enable critique of current rehabilitation treatments."} +{"text": "Fifteen Veterans Administration Medical Centers (VAMCs) offer geriatric specialty care telehealth services through a hub and spoke model to patients at affiliated community-based outpatient clinics (CBOCs). These services are not used to the extent they could be. Through interviews with 50 staff and providers at rural CBOCs we identified several implementation facilitators and barriers. CBOC-level barriers included space constraints, low staffing, internet connection issues, and limited knowledge of services available and referral processes. Patient-level barriers included discomfort with technology, cognitive decline, and inability to travel to the CBOC. We found that champions within the CBOC and iterative, targeted outreach from the hub helped facilitate uptake of services. We entered the identified barriers into the CFIR-ERIC (Consolidated Framework for Implementation Research-Expert Recommendations for Implementing Change) Implementation Strategy Matching Tool to help generate targeted strategies that will be used to refine each hub\u2019s implementation approach."} +{"text": "Relationship research has suggested that health among spouses is interdependent and should be considered jointly. Using data from the 2008/2010 and 2016/2018 waves of the Health and Retirement Study , we investigated the joint influence of married partners\u2019 individual and shared cumulative biological risk on future health outcomes. Two risk indicators were constructed to indicate biological health in different domains. Individual grip strength, walk speed, lung function, and cystatin-C were biomarkers selected to construct frailty risk whereas blood pressure, pulse, waist circumference, C-reactive protein, glycohemoglobin, high-density lipoprotein cholesterol, and total cholesterol were biomarkers used to construct cardiometabolic risk. Shared risk was calculated as the number of risks the partners shared. We employed multilevel Poisson regression models to nest partners within couples and examine the effects of individual and shared cumulative risks on future functional limitations. Heckman correction was performed to correct potential selection bias. Our unadjusted models showed individual and shared risks are associated with greater future functional limitations. Further, shared cardiometabolic risk moderated the effect of individual risk . In the adjusted models, the direct associations between shared risks and future functional limitations were explained by indicators of partner selection and shared experiences. In the fully adjusted model, the cross-level interaction for frailty risk became statistically significant. The unique set of dynamics shown in our study offered new insights into understanding how couples influence one another in the context of multisystem biological health."} +{"text": "Most prior research on caregivers\u2019 mental health focused on individual or household factors, we know much less about the influence of neighborhood factors on mental health of spousal caregivers. The current study fills the gap in our knowledge by examining the association of neighborhood characteristics and depressive symptoms among spousal caregivers. We used data from 2006 to 2016 waves of the Health and Retirement Study, which includes 2,362 spousal caregivers. Negative binomial regression models were estimated to examine the association of perceived neighborhood disorder and neighborhood social cohesion with depressive symptoms. A greater perceived neighborhood disorder was associated with higher CES-D scores, which indicates more depressive symptoms. On the other hand, a higher level of neighborhood social cohesion was associated with lower CES-D scores. When they were included in the same model, the association between neighborhood disorder and depression disappeared, while respondents who reported higher levels of neighborhood social cohesion continue to exhibit lower CES-D scores than those lived in less cohesive neighborhoods. This study highlights the importance of neighborhood contexts in understanding caregivers\u2019 well-being. Findings of this study suggest that neighborhood social cohesion may attenuate the negative effects of neighborhood disorder. Therefore, enhancing positive characteristics of the neighborhood may promote well-being of spousal caregivers."} +{"text": "Research on professional burnout during the pandemic has focused on hospital-based health care workers. This study examined the psychological impact of the pandemic on home-based primary care (HBPC) providers. We interviewed 13 participants from six HBPC practices in the New York including medical/clinical directors, program managers, nurse practitioners, and social workers and analyzed the transcripts using inductive qualitative analysis approach. HBPC providers experienced emotional exhaustion and a sense of reduced personal accomplishment. They reported experiencing grief of losing many patients at once and pressure to adapt to changing circumstances quickly. They also reported feeling guilty for failing to protect their patients and reduced confidence in their professional expertise. Strategies to combat burnout included shorter on-call, regular condolence meetings to acknowledge patient deaths, and peer support calls. Our study identifies potential resources to improve the well-being and reduce the risk of burnout among HBPC providers."} +{"text": "Despite successful defect coverage by means of complex skin or muscle flaps, particularly large and deep problematic wounds with exposed bradytrophic tissues after soft tissue loss are very susceptible to surgical revision.A dermal matrix, consisting of native collagen supplemented by an elastin hydolyzate was first used for the treatment of burns, predominantly those that were full-thickness. Subsequently, its use was extended to defect coverage especially after soft tissue loss caused by degloving injuries.52 patients with exposed bradytrophic tissues caused by severe burn or degloving injuries were treated the same way.In all patients operative debridement showed soft tissue loss with free bone or free periostal structures, exposed tendons or joint capsules.In all patients after accurate wound bed preparation defect coverage was performed with collagen-elastin matrix and unmeshed split skin grafts in combination with negative pressure wound therapy for fixation of dermal matrix and split skin grafts.Two-years follow up of these collagen-elastin matrix procedures in defect coverage showed an excellent functional outcome:Up until now, no areas with unstable scars have occurred, no surgical scar revisions were required. The patients were still able to wear normal footwear, clinical gait analysis showed perfect functional outcome.The application of collagen-elastin matrix in patients with exposed bradytrophic tissues after severe burn or degloving injury treated so far represents an excellent reconstruction method, from initial coverage to scar development."} +{"text": "Whether slowing disease progression or combatting the ills of advancing age, the extensive utility of exercise training has contributed to the outright declaration by the American College of Sports Medicine that \u2018exercise is medicine\u2019. Consistent with general framework of adaptation, the advantages of exercise training are indiscriminate\u2014benefitting even the most susceptible clinical populations. Still, the benefit of exercise training presupposes healthy adaptation wherein progressive overload matches sufficient recovery. Indeed, a difference exists between healthy adaptation and non-functional over-reaching \u2014a difference that may be blurred by cancer treatment and/or comorbidity. Recent advances in smartwatches make them ideally suited to non-invasively monitor the physiological stresses to exercise training. Resolving whether individuals are successfully adapting to exercise training via load monitoring bears clinical and practical relevance. While behaviour-change research aims to identify positive constructs of exercise adherence, further attention is needed to uncover how to optimise exercise prescription among cancer populations. Herein, we briefly discuss the constituents of exercise load monitoring, present examples of internal and external load and consider how such practices can be applied to cancer populations. The systemic benefits of exercise training are irrefutable.A difference exists between healthy adaptation and non-functional over-reaching \u2014a difference that may be blurred by cancer treatment and/or comorbidity.Smartwatches are ideally suited to non-invasively monitor the physiological stresses to exercise training.Resolving whether individuals are successfully adapting to exercise training via load monitoring bears clinical and practical relevance.The benefit of exercise training presupposes healthy adaptation wherein progressive overload matches sufficient recovery. However, one of the most challenging barriers of exercise prescription is knowing how and when to modulate frequency, intensity and duration for continued improvement .et al were some of the concerns surrounding exercise training in cancer patients assuaged.In the last 20 years, considerable momentum has been achieved within in the field of exercise oncology\u2014now recognised as subdiscipline of oncology research.10.1136/bmjsem-2021-001134.supp1Supplementary dataFrom a practical perspective, recent advances in smartwatches make them ideally suited to non-invasively monitor the physiological stresses to exercise training. Such an approach extends the reach beyond laboratory settings and the need for expensive instruments to evaluate progress. Given the current challenges attributed to the COVID-19 pandemic, having remote access to individual exercise training responses is an attractive option to strengthen home-based exercise. Resolving the nuances of healthy adaptation and recovery will assuredly influence exercise prescription with related effects on injury risk and exercise adherence as well. The exercise training dose\u2013response relationship is akin to a pharmacological investigation evaluating the efficacy of a medication. Indeed, a difference exists between healthy adaptation and non-functional over-reaching Though the absolute workload is appreciably higher among athletic populations, the same principles of training, recovery and adaptation apply to cancer populations. While the implementation of exercise load monitoring may vary, the importance of individualising such an approach cannot be overstated. Since age, cardiorespiratory fitness and non-exercise stressors all contribute to the rate of recovery, it is unsurprising to observe large within-person/between-person differences emerge regarding exercise tolerance and subsequent adaptations. Therefore, to promote further sophistication in the field of exercise oncology, the present viewpoint briefly discusses the constituents of exercise load monitoring, presents examples of internal and external load and considers how such practices can be applied to cancer populations.It is customary to delineate the quantification of exercise training load into internal and external constructs. Internal training load reflects physiological ) and psychological ) stressors, whereas external training load represents metrics of work performed such as distance travelled, steps per day or repetition counts. Consensus indicates a combined approach yields a clearer perspective about the inherent oscillations involving exercise adaptation and recovery.2) share a linear relationship at submaximal intensities. Given the combined effects of blood volume expansion, increased stroke volume and heightened parasympathetic outflow, one of the most prominent phenotypic attributes of exercise training is a lowered HR at rest and during exercise. Since HR fluctuates daily, a single measurement provides little useful interpretive information such that repeated measurements and consideration for adequate hydration are essential. Unlike the transient changes in HR over the course of a day, resting HR when measured under standardised conditions is thought to reflect global cardiovascular health. Thus, changes in resting HR over days may be indicative of physiologic or psychologic stressors, whereas alterations over weeks may represent increased (or decreased) cardiorespiratory fitness.7Wearable health monitoring technologies including smartwatches have become a familiar sight. Owing to the non-invasive capabilities of photoplethysmography, infrared light is used to measure the volumetric variations of blood circulation\u2014making it possible to measure and record HR in real time. At the onset of exercise, sympathetic activity rises to produce an intensity-dependent increase in HR. As such, HR and oxygen uptake modification. This common shortcoming is thought to interfere with study reproducibility, interpretation and cross-study integrationAccess to wearables can expedite the collection of internal and external load data, however, having a system in place to make meaningful inferences about adaptive responses can be challenging. Numerous research publications have endeavoured to extract the most from exercise training in elite athletes\u2014yet such efforts are still gaining traction in cancer populations.Resolving whether individuals are successfully adapting to exercise training via load monitoring bears clinical and practical relevance. While behaviour-change research aims to identify positive constructs of exercise adherence, further attention is needed to uncover how to optimise exercise prescription among cancer populations. Consideration for measurement error notwithstanding, there is need to identify early signs of maladaptation, including the smallest worthwhile change,"} +{"text": "While existing microbots display effective propulsion, their functionalities decrease dramatically upon decreasing the robot size. Accordingly, it is desired to customize microscale robots for their specific mission and body location. Selecting the microbot constituents with task-specific tailored functionalities will enhance their practicality in performing their primary mission. A myriad of synthetic microbots, based on various propulsion mechanisms and different designs and materials, have thus been developed7. New functionalities and capabilities have been added to these tiny machines, including fast motion in complex biological media, large cargo-towing force, collective behavior and excellent biocompatibility for use in living systems. These attractive capabilities have paved the way to sophisticated microscale robotic devices capable of performing complex tasks and have motivated researchers to explore exciting new important in vivo biomedical applications ranging from targeted drug delivery to precise surgery and intracellular biosensing10. While the scaling down of robotic platforms has tremendous potential for advancing the treatment and diagnosis of patients, it also brings fundamental engineering challenges such as power sourcing, motion control and tracking, integration of multifunctionality, safety and related recovery and degradation capabilities11. Unlike large robots, the tiny footprint of microbots greatly hampers the ability to integrate multiple functions (without compromising their dimensions). For example, important microbot operations, such as drug delivery and cleaning out clogged arteries, have completely different requirements and hence rely on largely incompatible functions, which are extremely challenging to combine with a single microscale robot.Over the past 15 years the field of microbots has exploded with many teams from around the globe contributing to major innovationsConsidering the major challenges of fabricating multifunctional microscale robots, a key question arises: is the future hold for general-purpose universal microbots capable of performing a wide range of tasks or to simple microbots tailored to meet the demands of specific applications and target locations Fig.\u00a0? Big rob2, but these fabrication methods also face critical miniaturization constraints, which limit their functional capabilities to few basic functions. Instead, future multifunctional microscale robots could rely on smart multi-responsive materials capable of imparting several mission-specific functions into a single portion of such a microbot for executing multiple tasks. Such bio-inspired responsive materials can enable programmable, reconfigurable mobile microscale robots and increase the adaptability of such microbots for complex operations without scaling up the robot\u2019s footprint12. For example, smart biomarker responsive materials can lead to theranostic microbots, performing \u201csense and release\u201d functions by detecting disease-specific marker to trigger autonomous release of their embedded therapeutic payload13. Such route can enable diabetes theranostic applications based on autonomous closed-loop glucose-responsive insulin-delivery gated acoustic vehicles14.In contrast, the preparation of multifunctional microscale robots requires a paradigm shift from the traditional mechanical assembly fabrication route used for preparing larger (millimeter) scale robots, e.g., ingestible capsules. While these larger robots commonly rely on different sections to obtain their different functions, microbots are too small to be prepared by such mechanical assembly fabrication route. Some efforts have been devoted to advanced rolled-up and template deposition techniques for fabricating microbots with several functional unitsAdvanced robotics fabrication and functionalization technologies are paving the way to new robotic capabilities which are attractive for a wide range of biomedical applications. However, despite of these tremendous technological advances, it is extremely challenging to design and efficiently manufacture multifunctional microbots capable of performing diverse tasks. Considering the tiny dimensions of microbots and the largely different operational requirements of different microbot applications and body locations, the design of small-scale multi-purpose robots faces distinct challenges. Typical strategies for preparing large multi-purpose robots cannot be adapted to the microscale.11. Despite the major progress towards developing such bio-inspired microbots there is still a long way for the performance of synthetic microbots to compete with the sophistication of nature\u2019s biomotors. A multidisciplinary collaboration in science, engineering and medicine and researchers trained with cross-disciplinary research skills are vital for addressing critical barriers for translating microbots into the clinical practice toward establishing a new era in the treatment of diseases.The efficiency of microbots to perform their main mission will be greatly improved by using simple robot design custom-made specifically to this mission. Designing the microscale robots with task-specific tailored materials and functionalities will allow customization of microbots for their primary biomedical mission and will enhance their practicality and efficiency in performing this mission. Incorporating additional features that are not essential for this specific biomedical operation can greatly compromise their effectiveness to perform their main task. Complex biomedical operations, requiring multiple tasks, will require multifunctional microbots based on new advanced fabrication techniques. In particular, bio-inspired responsive materials offer tremendous promise for designing theranostic microbots, integrating the sense and release functions. Alternately, it may be possible to combine different single-function microbots in swarms for performing different operational tasks"} +{"text": "Growing evidence shows that the thalamus, beyond serving as an information relaying center, has key roles in motivated behaviors contribute to both normal and abnormal salience processing.The hypothesis-and-theory by Qui\u00f1ones-Laracuente et al. examined the time-dependent recruitment of pre-limbic (PL) prefrontal inputs onto PVT following auditory fear learning. The authors showed that PL to PVT projections are activated by conditioned stimuli (CS) 7 d, but not 2 h, following learning. In contrast, the PL-amygdala circuit is preferentially recruited 2 h following learning. In addition, unit recordings of Layer VI PL neurons, the origin of projections to PVT, exhibit increased cue-induced inhibition at later, but not earlier, time points. Together, these results suggest that PL signaling of simple fear associations shifts with time toward inhibitory modulation of PVT, which may underlie disinhibition of PVT neurons and subsequently enhanced central amygdala output.In our collection, five articles exclusively focus on PVT. The original research article by Matzeu and Martin-Fardon reported that posterior PVT injections of orexin-A peptide promotes reinstatement of extinguished cocaine seeking after intermediate (2\u20133 weeks), but not protracted (4\u20135 weeks), abstinence. Intermediate but not protracted abstinence is associated with an upregulation of orexin 2 receptor expression in PVT, while orexin cell numbers increase after both intermediate and protracted abstinence. This work extends previous work on the role of hypothalamic orexin (hypocretin) neurons in PVT in addiction-related behavior but not reward value (incentive information). In contrast, activity of PVT neurons that fire immediately before reward delivery is correlated with reward value but not predictive information. Together, these data capture the heterogeneity of PVT responses to discrete processes involved in cue-induced motivated behaviors.Rowson and Pliel provide a timely review on the sex-dependent effects of acute vs. chronic stress on PVT, and outline the implications of this dimorphism for motivated behaviors. Consistent with the idea of PVT as a complex integrator of varied physiological signals, Petrovich elegantly discusses the role of PVT in controling feeding behavior. Petrovich describes a framework whereby PVT integrates homeostatic and hedonic needs to feed with physiological and environmental stress signals, ultimately guiding the balance between food seeking and consumption.PVT is also a regulator of stress in action selection. Further discussion of afferents of each structure leads to the hypothesis that Pf and OFC together contribute to internal state representation during action selection either through direct Pf to OFC projections or convergence of their respective inputs onto striatal cholinergic interneurons.Two reviews focus on ILN, recently implicated in goal-direct behaviors and individual central thalamic nuclei in delayed conditional discrimination tasks through lesion studies in rodents. The authors review electrophysiological findings in MD and mPFC during adaptive goal-directed behaviors, which suggest that MD affects both action and outcome-related neuronal responses in mPFC.Finally, We appreciate these excellent contributions. These articles not only summarize the current findings on the role of individual thalamic nuclei mediating motivated behavior, but also raise intriguing questions about how thalamus exerts these effects. We hope that this issue gives impetus to ongoing work in the field to better characterize the role of thalamus in motivated behaviors and related disorders.XL and MJ took the lead in writing this editorial. GM contributed to its finalization. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Purpose: The purpose of this study was to assess whether there was an association between care-recipient relationship type and the QoL of older adults and their informal caregivers, and whether this association pertained to older adults\u2019 cognitive function. Methods: This was a secondary data analysis. Older adults (n=1230) and their informal caregivers (n=1871) were identified from participants in the National Health and Aging Trends Study (NHATS) Round 5 and the National Study of Caregiving (NSOC) II. A series of bivariate and multivariable regression models examined the associations among the care-recipient relationship type and QoL in older adults and their informal caregivers, adjusted for socio-demographic variables as well as cognitive functioning. Results: Both older adults and caregivers\u2019 QoL outcomes varied by the type of relationship. Recipients cared for by adult-child caregivers or multiple caregivers experienced higher functional limitation than those cared by spousal caregivers . \u201cOther\u201d caregivers, such as siblings, friends, etc., had lower odds of experiencing negative emotional burden than spousal caregivers . \"Other\" caregivers were also 51% less likely to experience social strain than spousal caregivers. Lower odds of experiencing negative emotional burdens were also found with multiple caregivers. The association between adult-child caregivers and social strain was explained by the recipients\u2019 cognitive function. Conclusions: Care-recipient relationship type impacts the QoL in both recipients and their informal caregivers. This association appears to be affected by care recipients' cognitive function level."} +{"text": "Most clinical studies supporting procalcitonin (PCT)-guided management of lower respiratory tract infections have been performed in adults. There is a paucity of studies evaluating the clinical impact of PCT use in children and limited data informing age-appropriate PCT cut-offs; diagnostic accuracy in immunocompromised children; patient subgroups most likely to benefit from PCT testing; whether PCT adds value beyond available rapid molecular viral diagnostics; and optimal implementation strategies for PCT-guided treatment. At the present time there is little evidence to support routine use of PCT to aid management of paediatric pneumonia. Procalcitonin (PCT) is a biomarker that shows promise in identifying bacterial infection and is increasingly used in patients of all ages. Several PCT assays are approved by the US FDA for prediction of mortality and to guide antimicrobial management in sepsis and lower respiratory tract infection (LRTI). However, the vast majority of clinical studies supporting PCT-guided management have been done in adults. Few rigorous, interventional studies have evaluated the impact of PCT use in children, in whom its clinical utility is unclear. At the present time there is little evidence to support routine use of PCT to aid management of paediatric pneumonia.et al.P\u2009<\u20090.001). However, more recently, the ProACT trial enrolled 1656 adults with LRTIs from 14 US emergency departments and randomized them to management using a PCT testing and treatment algorithm versus usual care. The primary outcome was antibiotic days by 30\u2009days after enrolment.Despite extensive evaluation in adults, it is still not clear whether use of PCT provides benefit for management of adult LRTI. Schuetz P\u2009=\u20090.039). In another RCT, Esposito et al.P\u2009<\u20090.05), and fewer antibiotic days . Both the above trials enrolled subjects before 2010, prior to widespread use of molecular viral diagnostics; had a small sample size; did not include many subjects with severe CAP; and did not report compliance with the PCT algorithm, so the applicability of these studies to current practice is unclear.In contrast to the numerous published adult LRTI PCT trials, there are only two paediatric RCTs evaluating PCT use in paediatric pneumonia. The ProPAED trial enrolled 337 subjects <18\u2009years old with LRTIs in two emergency departments in Switzerland and randomized them to receive either PCT-guided antibiotic management or usual care.,et al.Several observational studies highlight the limitations of PCT as a diagnostic aid for management of paediatric pneumonia. Twenty years ago a study of 72 children hospitalized with CAP found greater positive and negative predictive values of PCT than other biomarkers, including C-reactive protein and WBC count, for differentiating bacterial and viral causes of pneumonia.Additional paediatric-specific evaluations of PCT in LRTI are clearly needed to address numerous questions about PCT, including determining appropriate age-based PCT cut-offs, diagnostic accuracy in immunocompromised children, and patient subgroups most likely to benefit from PCT testing. In some studies of paediatric sepsis and LRTI, low PCT values may reduce antibiotic use among patients with low acuity illness and low likelihood of having bacterial infection; thus, PCT may be most promising for ruling out rather than ruling in bacterial disease, but further studies are needed to confirm this.In conclusion, the clinical utility of PCT to guide diagnosis and antibiotic management of paediatric pneumonia is unproven due to a paucity of paediatric studies. Even in adult populations, where numerous evaluations of PCT have been conducted, results are conflicting regarding whether use of PCT provides clinical benefit. There are several questions around PCT implementation and impact in paediatrics that are promising areas for future research. The existing body of evidence is not convincing that PCT adds anything beyond what other, cheaper biomarkers (like C-reactive protein) or clinical assessment can provide for management of paediatric pneumonia.None to declare."} +{"text": "The COVID-19 pandemic caused significant disruptions for people and institutions across healthcare settings. Clinical trials are an important research tool to test interventions in real-world healthcare settings and provide high quality evidence that supports older adults\u2019 longevity and wellness. Clinical trialists must consider how to account for unpredictable and ever-changing environmental contexts. The COVID-19 pandemic is a specific example of a changing context that impacted all stages of the clinical trials process from planning, to administration, and outcomes. Reflecting on ways clinical trialists navigated their studies during the COVID-19 pandemic may unlock opportunities to design flexible clinical trials that meet the needs of older adults in real-world environments. This symposium highlights five clinical trials for older adults that occurred during the COVID-19 pandemic. Dr. Carpenter will discuss lessons learned in implementing a palliative care intervention in nursing homes. Brianna Morgan will describe the pivots needed to complete a clinical trial testing an advance care planning website for nursing home residents with dementia. Dr. Nuckols will describe obstacles and opportunities to implementing a randomized controlled trial on hospital nursing units, including implications for medication safety. Dr. Pevnick will highlight barriers and facilitators to implementing a pharmacist-led intervention to reduce hospital readmissions. Dr. Stark will share novel procedures for conducting clinical trials in the community that reduce burden for older adult participants while maintaining fidelity. Presenters will address practice transformations that researchers can bring forward to design flexible clinical trials that meet the needs of older adults in different healthcare contexts."} +{"text": "The medial prefrontal cortex (mPFC) has robust afferent and efferent connections with multiple nuclei clustered in the central thalamus. These nuclei are elements in large-scale networks linking mPFC with the hippocampus, basal ganglia, amygdala, other cortical areas, and visceral and arousal systems in the brainstem that give rise to adaptive goal-directed behavior. Lesions of the mediodorsal nucleus (MD), the main source of thalamic input to middle layers of PFC, have limited effects on delayed conditional discriminations, like DMTP and DNMTP, that depend on mPFC. Recent evidence suggests that MD sustains and amplifies neuronal responses in mPFC that represent salient task-related information and is important for detecting and encoding contingencies between actions and their consequences. Lesions of rostral intralaminar (rIL) and ventromedial (VM) nuclei produce delay-independent impairments of egocentric DMTP and DNMTP that resemble effects of mPFC lesions on response speed and accuracy: results consistent with projections of rIL to striatum and VM to motor cortices. The ventral midline and anterior thalamic nuclei affect allocentric spatial cognition and memory consistent with their connections to mPFC and hippocampus. The dorsal midline nuclei spare DMTP and DNMTP. They have been implicated in behavioral-state control and response to salient stimuli in associative learning. mPFC functions are served during DNMTP by discrete populations of neurons with responses related to motor preparation, movements, lever press responses, reinforcement anticipation, reinforcement delivery, and memory delay. Population analyses show that different responses are timed so that they effectively tile the temporal interval from when DNMTP trials are initiated until the end. Event-related responses of MD neurons during DNMTP are predominantly related to movement and reinforcement, information important for DNMTP choice. These responses closely mirror the activity of mPFC neurons with similar responses. Pharmacological inactivation of MD and adjacent rIL affects the expression of diverse action- and outcome-related responses of mPFC neurons. Lesions of MD before training are associated with a shift away from movement-related responses in mPFC important for DNMTP choice. These results suggest that MD has short-term effects on the expression of event-related activity in mPFC and long-term effects that tune mPFC neurons to respond to task-specific information. To survive in a dynamic environment organisms must be able to adapt efficiently to changes in conditions, responding in ways that optimize favorable consequences. Behavioral ecologists have demonstrated that foraging animals select among food patches of different quality in a way that maximizes food intake while reducing energy costs plays a critical role in adaptive goal-directed behavior has dense reciprocal connections with the agranular medial cortex and adjacent motor and cingulate areas. Afferent inputs to VM include branches of axons that also innervate MD and GABAergic projections from the basal ganglia. Thalamocortical neurons in VM have dense widespread projections to layer 1 in agranular medial and adjacent motor and cingulate cortices and less dense projections in parietal and occipital cortices that appear organized to control integrative motor responses Vertes, . The antAnatomical analyses indicate that rodent mPFC is homologous to primate anterior cingulate and premotor cortices and lacks an area homologous to primate dlPFC Preuss, . Here weEarly studies of delayed response deficits in monkeys designed around the octagonal hub used for radial DNMTP tasks . In VSRTIt has been argued that mPFC is important for evaluating actions and outcomes along multiple dimensions and rhomboid (Rh) nuclei in the ventral midline thalamus are important sources of thalamic input to the hippocampus and mPFC that appear organized to modulate mPFC\u2014hippocampal interactions , and hippocampal lesions had no significant effect on RT or accuracy and others that were directionally specific and fired during movements from the base to the sample and from the base to the choice levers . Lever press-related responses included neurons firing during all four lever presses and others that fired only during base lever presses .Of 1,335 isolated neurons recorded with moveable tetrode arrays, 458 (34.3%) exhibited criterion event-related activity of which 445 (33.3%) exhibited temporal patterns of activity related to actions or outcomes that were characterized as normalized population peri-event time histograms PETH; , 8. ThesN = 191) included reinforcement anticipation that fired beginning 0.7 s before predictable times of reward and persisted for an average of 2.7 s throughout reward delivery; reinforcement excitation that fired within 0.2 s after reward delivery and remained elevated for an average of 3.0 s; error responses that fired within 0.2 s of when the expected reward was not delivered; delay (D) responses (n = 58) that started firing within 0.4 s of when sample rewards were delivered and continued until the delay lever press; and post-reinforcement (PR) responses (n = 16) that began after reward delivery ended when rats disengaged from drinking spouts where rewards were delivered.Outcome related responses along with single examples for base lever press , reinforcement excitation , and reinforcement anticipation . Although the data were insufficient for vector or decoding analyses , lever presses (both LPE and BLP), and preparatory responses . VentralEach of the response types observed in rodent mPFC during dDNMTP represents task-specific aspects of goal-directed behavior that are consistent with mPFC functions identified by behavioral analyses of lesion effects. PFC relies on working memory to temporarily maintain information not available to the senses to support adaptive goal-directed responding. This is thought to be represented by persistent neuronal firing during delay intervals , day 2 , and day 3 aligned with reinforced sample and correct choice and unreinforced incorrect choice . Event-related responses observed on day 1 largely disappeared with thalamic inhibition on day 2 and recovered substantially on day 3. Averaged across all neurons studied, day 2 thalamic inhibition reduced normalized activity during critical response windows to 46.9% of the day 1 response and this recovered to an average of 79.5% during day 3 recovery. Mixed model ANOVAs revealed significant effects of inactivation on day 2 and significant recovery on day 3 based on normalized activity during critical response windows. These effects did not interact with response type, the effect of thalamic inhibition on average firing rate , location of neuron in dorsal vs. ventral mPFC, or muscimol dose. These results show that dDNMTP event-related responses are reduced nonspecifically in mPFC with behaviorally-significant inactivation of MD and IL.Francoeur et al. examinedOptogenetic studies have provided evidence that MD amplifies and sustains behaviorally-relevant information in PFC supports multiple functions required for adaptive goal-directed behavior: working memory, flexible trial-by-trial response selection, attending to task-relevant information, encoding relationships between actions and their consequences, and organizing and executing action sequences. mPFC lesions produce delay-independent impairments of egocentric (response-related) DMTP and DNMTP tasks that affect RT and accuracy of responding. They spare comparable allocentric tasks.2.During the dDNMTP task, mPFC functions are served by discrete populations of neurons with responses related to preparation to respond, movements between levers, lever press responses, reinforcement anticipation, delivery of or lack of expected reinforcement, and memory delay following reinforcement. Population analyses show that these different response types effectively tile the temporal interval from when dDNMTP trials are initiated until they end.3.No individual thalamic nucleus can fully account for the broad effects of mPFC lesions on adaptive goal-directed behavior. Lesions of specific nuclei have distinct effects on behavior consistent with their anatomical connections.(a)MD has very limited effects on egocentric DMTP or DNMTP tasks that depend on mPFC. While some reports find no significant effect of MD lesions on these tasks, others have described delay-dependent deficits that spare RT or impaired acquisition that disappears with training. The reports of delay-dependent deficits are consistent with evidence that MD sustains and amplifies neuronal responses that represent behaviorally-relevant information in mPFC. Impairments in the acquisition are consistent with evidence that MD interacts with PFC to detect and encode action-outcome contingencies that are the basis of goal-directed learning.(b)Rostral intralaminar and VM nuclei affect speed and accuracy of responding based on learned conditional rules, effects consistent with their prominent connections with striatum and motor cortices, respectively. Like mPFC lesions rostral intralaminar and VM lesions produce delay-independent impairments affecting response speed and accuracy for egocentric DMTP and DNMTP tasks while sparing allocentric DNMTP.(c)Anterior thalamic and ventral midline Re and Rh nuclei affect allocentric spatial function, consistent with their prominent connections with the hippocampal system. Anterior thalamic lesions spare egocentric DMTP and DNMTP tasks affected by mPFC lesions. ReRh lesions affect tasks that depend on both mPFC and hippocampus.(d)Dorsal midline nuclei integrate inputs from visceral-, arousal-, and emotion-related areas of the brain and influence cortical and subcortical circuits related to mPFC function. They are important for behavioral-state control of adaptive responding and response to salient stimuli in associative learning. Dorsal midline lesions spare DMTP and DNMTP tasks that depend on mPFC.4.During the dDNMTP task, most MD neurons with criterion event-related responses (237/254) exhibit temporal patterns of firing that closely match response types in mPFC. A preponderance of these are movement and reinforcement-related responses critical for dDNMTP choice. MD lesions made before initial training selectively decrease the number of movement-related responses in mPFC.5.Drug inactivation of MD and adjacent intralaminar nuclei broadly suppresses the expression of event-related activity in mPFC during the dDNMTP task. Optogenetic studies suggest that MD amplifies and sustains behaviorally-relevant information in the PFC, a process that might help tune mPFC neurons to respond to task-relevant information during goal-directed behavior or suppress the expression of event-related activity during more prolonged drug inactivation.RM was primarily responsible for writing the article. MF and BG contributed to writing and discussion of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The management of unruptured cerebral aneurysms in elderly patients remains controversial.Key challenges including frailty, cognitive dysfunction, reduced life expectancy, vasculopathy and poor prognosis with aneurysm rupture add complexity to endovascular and surgical decision making not encountered with younger demographics.A thorough understanding of available treatment options, likelihood of treatment success and associated risks weighed against the risk of aneurysm rupture informs patient discussion and management.Unruptured cerebral aneurysms are increasingly identified in elderly patients as the global life expectancy continues to rise and non-invasive vascular imaging becomes more prevalent. The optimal management of unruptured aneurysms in elderly patients remains controversial. Variability in life expectancy, comorbidities and rupture risk coupled with heterogenous endovascular and surgical treatments contribute to a paucity of clear guidelines, and current management is highly individualized. Elderly patients present unique considerations including frailty, cognitive dysfunction, vasculopathy, reduced life expectancy and overall worse prognosis in case of rupture which shape the risks and likelihood of success of endovascular and microsurgical treatment. In this review, we provide a comprehensive overview of unruptured cerebral aneurysms in the elderly, with a particular focus on the natural history, key challenges associated with advanced age, management and future innovations to further refine treatment. Life expectancy is increasing at unprecedented rates. By 2050, the proportion of individuals 65 years or older will more than double from 8.1% to 21% [Multiple guidelines regarding the management of unruptured cerebral aneurysms in the general population have been established by cornerstone neurosurgical trials . OptimalThe prevalence of unruptured cerebral aneurysms in the elderly and the association between age and aneurysm development remain controversial. Several autopsy reports describe an increased prevalence of unruptured cerebral aneurysms with advancing age. Inagawa et al. reviewed 10,259 autopsies performed in New York, NY and found the incidence of unruptured cerebral aneurysms highest in patients over 60 years, with a peak prevalence of 1.2% in the seventh decade of life . In the The incidence of aneurysm rupture and association with advanced age has been evaluated in multiple prospective studies. In the general population, the overall risk of rupture per patient-year at risk is 0.6\u20131.3% . The IntThe overall rupture rate in elderly patients appears similar to the general population. A pooled analysis evaluating 1896 patients 70 years and older with 2227 unruptured aneurysms reported an annual rupture rate of 1.6% . AdditioFrailty is defined as a decrease in homeostatic reserve and is closely associated with increasing age . FrailtyNumerous attempts have been made to quantify frailty based on phenotypic characteristics, functional deficits, social situations and medical comorbidities, with the modified frailty index (mFI) representing a well establish metric of physiologic reserve. Including five (mFI-5) or eleven (mFI-11) factors, based on the original 70-item Canada Study of Health and Ageing Frailty Index, the mFI predicts morbidity and mortality across all subspecialties . In neurBrain frailty resulting from intrinsic damage to small perforating arterioles, endothelial dysfunction, blood\u2013brain barrier breakdown and inflammation is an additional marker of poor cerebral reserve in elderly patients, and is readily evident on advanced imaging as white matter hyperintensities, microbleeds, prominent perivascular spaces, lacunar infarcts and cerebral atrophy. Baseline brain frailty scores on magnetic resonance imaging and computed tomography are associated with poor functional outcomes following lacunar and non-lacunar stroke . Brain fPreserved cognitive function is particularly relevant in elderly patients, as any neuropsychological decline either from the anxiety of harbouring an unruptured aneurysm or as a direct consequence of treatment may have dramatic consequences on quality of life, independence and overall life expectancy. Patients with unruptured cerebral aneurysms may harbour cognitive impairments at baseline, which can influence long-term outcomes. Fukunaga et al. evaluated 30 patients with unruptured cerebral aneurysms and described neuropsychological impairment in three . Haug etCurrent literature is inconclusive regarding cognitive outcomes following elective aneurysm treatment. ISUIA reported impaired cognitive function in 3.2\u20137.1% of patients who underwent either clipping or coiling at 1 year after treatment . Particuvs. after treatment of an unruptured aneurysm. Srivatsan et al. evaluated Montreal Cognitive Assessment scores following elective coiling of unruptured aneurysms in 33 patients and found no difference compared to baseline scores [Additional studies, however, report no difference in cognitive function before e scores . Similare scores . Few stue scores .Given the lack of definitive guidelines, conflicting outcomes regarding cognitive function following treatment, and few studies in the elderly, neurocognitive prognosis must be highly individualized. New evaluations in elderly patients should emphasize the anxiety of harbouring an unruptured aneurysm, which may improve with definitive aneurysm repair. Cerebrovascular cognitive reserve, baseline ischaemic white matter disease and evidence of vascular cognitive impairment are particularly important. Meticulous surgical dissection and endovascular technique may minimize parenchymal injury and preserve cognitive function post-operatively. Nevertheless, patients with extensive chronic ischaemic changes may be unfavourable candidates for treatment due to increased susceptibility to long-term neurocognitive changes, as seen in the landmark studies such as ISUIA .et al. performed a life expectancy analysis of patients with unruptured aneurysms with and without repair based on prospective data from ISUIA to identify circumstances under which aneurysm repair would be beneficial [The long-term risks of unruptured cerebral aneurysms in the elderly are challenging to determine based on the existing literature. As life expectancy declines, the likelihood of rupture combined with comorbidities that are more likely to cause death may call into question the benefit of aneurysm treatment. Vindlacheruvu neficial . They foPre-existing medical conditions and comorbidities, along with age, predict remaining life years following hospitalization. One year survival after first admission for heart failure or initiation of dialysis is 67% and 45.5%, respectively ,33. EldeChronic hypertension and atherosclerotic disease, common comorbidities that increase with advancing age, may accelerate vessel or aneurysm calcification, reduce arterial compliance, increase vessel tortuosity and narrow parent vessels, thereby complicating treatment. Atherosclerotic aneurysm calcification is more common in larger aneurysms and in older patients, and is associated with increased morbidity following clipping. In a study of 208 patients treated with clipping or coiling of unruptured aneurysms, the presence of calcification in an aneurysm was the sole marker of adverse outcome . In addiet al. found that arterial stenosis and tortuous anatomy limits the spread of microcatheter tension, may increase the risk of intra-procedural aneurysm rupture and plaque mobilization, decreases the rate of complete occlusion, and may necessitate the use of adjuvant stent or balloon assistance, which increases the risk of in-stent thrombosis and arterial dissection [Intracranial atherosclerotic disease adjacent to cerebral aneurysms also influences the efficacy and complication profile of endovascular treatment. Gao ssection . While essection .et al. analysed outcomes of elderly patients with aneurysmal subarachnoid haemorrhage stratified by age and clinical presentation [Advanced age is recognized as a poor prognostic indicator after subarachnoid haemorrhage, and the overall worse outcome in elderly patients following aneurysm rupture has important implications regarding patient counselling and management. Lanzino et al. evaluated the relationship between age and outcome in aneurysmal subarachnoid haemorrhage using data from the multicentre randomized trial of nicardipine in subarachnoid haemorrhage . They reentation . They reCoiling provides a minimally invasive alternative to open surgery for treatment of intracranial aneurysms. Coiling is generally the favoured treatment in elderly patients despite a lack of supportive randomized controlled trials. For ruptured aneurysms, the landmark International Subarachnoid Aneurysm Trial (ISAT) in 2002 and 2015Coiling of unruptured aneurysms in the elderly appears overall to be safe and effective. Hwang et al. coiled 122 saccular unruptured aneurysms in 96 consecutive patients 70 years or older; they successfully occluded the aneurysm with no adverse clinical events in 95.9% of cases . A meta-Elderly patients may be particularly prone to complications following coiling of unruptured aneurysms. Khosla et al. compared the complication profile associated with elective coiling of intracranial aneurysms between elderly and non-elderly patients, reporting major complications with and without neurologic disability more prevalent in patients 65 years and older . IschaemAdjuvant techniques for coil embolization, including balloon assistance and stent assistance, have been studied only modestly in the elderly, potentially due to their relatively infrequent usage. In a meta-analysis by Sturiale et al. evaluating 21 studies with 1511 elderly patients undergoing endovascular treatment of both ruptured and unruptured aneurysms, only 5% utilized balloon assistance and 3% utilized stent assistance . BalloonMicrosurgical clipping of unruptured aneurysms is a more invasive alternative to endovascular treatment, and elderly patients are less likely to tolerate clipping as compared to younger patients. Barker et al. compared age-dependent outcomes in 3498 patients who underwent clipping or coiling for unruptured aneurysms . When divia a supraorbital or pterional approach in 62 non-frail elderly and 198 non-elderly patients reported no increase in complication rates, hospital duration, aneurysm recurrence, morbidity or mortality with advanced age [via a supraorbital or pterional approach, sufficient drilling of the frontal skull base or sphenoid ridge, and wider subdural spaces in elderly patients improved aneurysm access and minimized excessive brain retraction, contributing to lower rates of neurological morbidity, mortality and cognitive dysfunction compared to standard clipping.Increased morbidity, mortality and institutionalization following discharge for microsurgical clipping of unruptured aneurysms in elderly patients suggests the need for less invasive surgical techniques focussed on minimal tissue disruption. The superciliary keyhole approach has been advocated as an alternative to pterional craniotomy for anterior circulation aneurysms, but validation in elderly patients has not been described . A retronced age . A minimFlow diverting stents are approved for the treatment of cerebral aneurysms of the internal carotid artery. Their reduced porosity creates a scaffolding for endothelialization across the cerebral aneurysm neck, reducing intra-luminal flow and allowing for slow obliteration. No recurrences have been reported once occlusion is achieved, and flow diversion has become a standard treatment for wide-necked saccular or fusiform internal carotid artery aneurysms for which traditional endovascular and surgical treatments are limited.Elderly patients have reduced but acceptable rates of aneurysm occlusion following flow diversion. Kuhn et al. evaluated the effects of age on aneurysm occlusion following flow diversion for treatment of unruptured cerebral aneurysms . At 12\u20131Older patients treated with flow diversion are more likely to harbour aneurysms of larger size, complex morphology and within the posterior circulation compared to younger counterparts which, along with increased frequency of comorbidities, atherosclerosis and arterial tortuosity, raises concern for increased morbidity and mortality. Brinjikji et al. reviewed age-related outcomes following pipeline reconstruction of unruptured aneurysms in 711 patients and found increasing age associated with higher neurological mortality . Patientvia inhibition of cyclooxygenase-2 (COX-2), supporting the inflammatory hypothesis of aneurysm formation and rupture [Aspirin lowers rates of aneurysm rupture in animal models rupture . In a sm rupture .Preliminary prospective and retrospective studies suggest that aspirin is safe in patients with unruptured aneurysms and may lower the risk of aneurysmal subarachnoid haemorrhage. A prospective, multicentre observational study that followed patients with unruptured cerebral aneurysms and ischaemic cerebrovascular disease found that aspirin was safe in patients with concurrent small unruptured cerebral aneurysms and was associated with low rate of aneurysm rupture . Hasan eAspirin may also limit aneurysm growth. A prospective cohort study following 272 patients with unruptured aneurysms 7\u2009mm or smaller, 113 of which were on aspirin continuously, found that aspirin was associated with a low risk of aneurysm growth . An addiStatins have anti-inflammatory effects in various vascular diseases, but their protective effects on the formation and progression of cerebral aneurysms remain unclear. A multicentre case\u2013control study compared 117 patients with aneurysmal subarachnoid haemorrhage to 304 patients with incidental, unruptured cerebral aneurysms and found a lower rate of statin use in rupture cases, suggesting an inverse relationship between statin use and aneurysm rupture . AlternaFuture alternatives to stratify treatment decisions in high-risk elderly patients, evaluation of new endovascular devices and microsurgical innovation will continue to improve elderly patient outcomes. Wall enhancement on black-blood MRA, observed more frequently in unstable, growing and ruptured aneurysms ,73, may The optimum management of unruptured cerebral aneurysms in elderly patients remains undefined. The process of ageing presents unique considerations and challenges, and management is currently individualized, requiring precise knowledge of natural history and risk of rupture that must be weighed against an individual\u2019s comorbidities, life expectancy, treatment-related risks and likelihood of treatment success. This report provides a comprehensive review of unruptured cerebral aneurysms in the elderly, with a special focus on the key challenges that this age group presents, including frailty, cognitive dysfunction, reduced life expectancy, vasculopathy and poor prognosis in case of rupture. These challenges determine the risk, benefit and likelihood of success of both surgical and endovascular treatments, drive innovative surgical techniques, and contribute to the trend in endovascular treatment in patients of advanced age. While coiling with or without adjunctive techniques or flow diversion will continue to increase, robust preclinical studies regarding the role in neuroinflammation in aneurysm development, growth and rupture represent potential future targets that may be particularly relevant to the elderly population. We anticipate that this review will provide a clinical framework for managing unruptured aneurysms in this challenging cohort, which will only enlarge with time as the population ages."} +{"text": "Many studies have reported that dietary fibers play a crucial role in promoting intestinal health of the host, since it strengthens functions of epithelial barrier and meanwhile maintains intestinal homeostasis of the host by modulating gut microbiota and short\u2010chain fatty acid (SCFA) production. Pig is a good animal model to study effects of dietary fiber on gut health and microbial community. This review has summarized the relevant knowledge available based on roles of various dietary fibers in gut health and energy metabolism of pigs and humans. Evidences summarized in our review indicated that modulating intestinal microbial composition and SCFA production by consuming specific dietary fibers properly could be conducive to health improvement and disease prevention of the host. However, types of dietary fiber from edible foods exert divergent impacts on gut health, energy metabolism, microbial composition, and SCFA production. Therefore, more attention should be focused on different responses of various dietary fibers intake on host metabolism and health. Modulating intestinal microbial composition and short\u2010chain fatty acid (SCFA) production by regulating specific dietary fibers intake properly could be conducive to host health improvement and disease prevention. Types of dietary fiber from edible foods exert divergent impacts on gut health, microbial composition, and SCFA production. More specifically, gut microbiota intensify integrity of the gut barrier comprised by intestinal epithelial cells, suppress colonization of enteric pathogens, and produce antibacterial peptides in the mucus layer of host intestine to identify the specific mechanisms of SCFA produced from dietary fiber fermented by gut microbiota on functions of animal tissues and organs, (2) to clarify the relationship between host health and gut microbiota shaped by the dietary intervention with dietary fibers, (3) to further illustrate different responses of various dietary fibers derived from edible foods and their combinations on host health. Overall, we suggest that more attention should be focused on specific chemical constituents and physical characteristics of various dietary fibers when they take actions in regulating host metabolism and health.None of the authors had a financial or personal conflict of interest in relation to the present study.Pan Yang: Conceptualization (supporting); Data curation (supporting); Formal analysis (lead); Investigation (lead); Visualization (lead); Writing\u2010original draft (lead). Jinbiao Zhao: Conceptualization (lead); Data curation (lead); Formal analysis (supporting); Funding acquisition (lead); Project administration (lead); Writing\u2010review & editing (lead).Not applicable.All authors consent that raw data presented in this review are available after publication. Please contact author for data requests."} +{"text": "Theories of age and emotional wellbeing posit that older age is associated with better affective well-being through avoidance or minimization of distressing experiences and prioritizing positive experiences and emotions. To test these theories, researchers have examined change in affect associated with negative interpersonal experiences in daily diary studies, given the compromising effects these interpersonal stressors exert on daily affect. In contrast, age differences in the potential affect-enhancing effects of positive interpersonal experiences have been comparatively neglected. Using the second wave of the National Study of Daily Experiences, we evaluated age differences in the frequency of daily negative and positive interpersonal interactions, as well as the affective responses to these interpersonal interactions. Positive and negative affect, as well as negative and positive interpersonal interactions were assessed on eight consecutive evenings. Analyses included 818 participants who experienced both negative and positive interpersonal interactions during the 8-day protocol. Preliminary results revealed increased frequency of negative interpersonal interactions and decreased frequency of positive interpersonal interactions with age (ps<.01). Further, negative interpersonal interactions were associated with increases in negative affect and decreases in positive affect (ps<.01), while positive interpersonal interactions were associated only with increased positive affect (p<.01). Finally, modest evidence of age-related reductions in the affective impact of negative, but not positive, interpersonal interactions emerged (p=.03). Discussion will focus on how studies of interpersonal interactions in daily life can inform theories of aging and promote emotional wellbeing throughout adulthood and later life."} +{"text": "As the coronavirus disease 2019 (COVID-19) spread in the early days of the pandemic, governments neglected World Health Organization (WHO) guidance and imposed travel restrictions. These public health measures employed varied levels of restrictiveness at national borders, in some cases banning all travel between countries. Where these border control measures were undertaken for domestic political reasons, enacted without consideration of public health evidence, they divided the world when solidarity was needed most.With the emergence of the Omicron variant, national governments once again returned to international travel restrictions, posing challenges for the rule of law in global health governance. Future reforms of global health law must account for this continuing impulse to enact travel restrictions, ensuring that international legal obligations reflect evolving public health evidence.International Health Regulations, 2005 revision; IHR (2005) govern how countries address collective threats in global solidarity; yet international travel bans can drive countries apart through economic isolation, trade disruptions, discriminatory restrictions and rights violations.The In the early COVID-19 response, we remained concerned where national governments bypassed WHO\u2019s public health recommendations in a rush to impose travel bans that targeted specific countries in ways that exacerbated political divisions, blocked essential goods and deflected from established mitigation measures \u2013 including travel advisories, diagnostic testing and quarantine policies.We continue to be concerned, however, that many governments are still reflexively deploying discriminatory travel restrictions to meet domestic political imperatives, prioritizing government action without sufficient justification in public health evidence. The latest round of travel restrictions, enacted in response to the Omicron variant, reveal the often-pernicious effects of such decision-making on low- and middle-income countries. When South Africa transparently reported a new variant of concern, countries immediately limited travel to and from South Africa, in some cases expansively targeting additional Southern African countries, without consideration of WHO guidance and despite updated evidence of variant spread well beyond the targeted countries.The mixed public health success of travel restrictions during the pandemic calls into question IHR (2005) obligations in the context of evolving public health knowledge.,In reforming global health law to reflect evolving public health knowledge, IHR (2005) revisions and pandemic treaty negotiations must provide flexibility in implementing evidence-based travel restrictions while strengthening WHO guidance to reflect epidemiologic data, facilitate health equity and support international cooperation."} +{"text": "The chemical diversity of natural products is established by an elegant network of biosynthetic machinery and controlled by a suite of intracellular and environmental cues. Advances in genomics, transcriptomics, and metabolomics have provided useful insight to understand how organisms respond to abiotic and biotic factors to adjust their chemical output; this has permitted researchers to begin asking bigger-picture questions regarding the ecological significance of these molecules to the producing organism and its community. Our lab is motivated by understanding how select microbes construct and manipulate bioactive molecules by utilizing vanadium-dependent haloperoxidase (VHPO) enzymology. This commentary will give perspective into our efforts to understand the unique VHPO-catalyzed conversions which modulate the activities within two ecologically relevant natural product families. Through enhancing our knowledge of microbial natural product biosynthesis, we can understand how and why these bioactive molecules are created. Natural products (NPs), also known as secondary or specialized metabolites, are composed of small organic molecules that have long been appreciated for their therapeutic potential . The marAs the tools of chemical ecology have matured, researchers have been able to ask more targeted questions about the factors that elicit NP production. With modern genomic, transcriptomic, and metabolomic profiling techniques, the field has started to reify links between secondary metabolite production and the specific internal state of a single organism while considering its surrounding community. The signal-molecule-based activation of silent NP BGCs has emphasized the role that the local microbiota plays in the elicitation of diverse community-modulating NPs , 10. OurStreptomyces and other bacteria site-specifically halogenate small molecules to elicit precise biosynthetic transformations (One of the many unique features of the marine biosphere is the relative abundance of vanadium and its subsequent utilization by microbial and macroalgal communities . In the rmations . We intermations .The most explored area of site-specific VHPO biosynthetic enzymology has involved the diverse naphthoquinone-based family of meroterpenoids. These mixed polyketide-terpene NPs are produced by marine and soil actinobacteria and exhibit a range of useful Gram-positive antibacterial, cytotoxic, and antifouling activities . DespiteStreptomyces NP biosynthesis but also within less established marine and terrestrial microbes.Of the THN-derived meroterpenoids, the napyradiomycins are uniquely well suited for hypothesizing \u201chow-and-why\u201d NPs are interconverted by VHPOs and other accessory enzymes in the marine biosphere. Over 50 unique napyradiomycins have been isolated, and new molecules continue to be discovered . Some ofPseudomonas species (Microbulbifer host species while increasing their toxicity toward other bacteria (Although less established than their roles in constructing endogenous NPs via biosynthetic routes, there is increasing evidence to suggest that VHPOs may modulate exogenous quorum sensing molecules. A macroalgal VHPO has been previously established to disrupt bacterial communication through homoserine lactone degradation and bromofuranone production to minimize surface fouling . The alk species . These m species . We are bacteria . This VHin vitro enzymology with ecologically relevant marine bacterial homologs. Pending the generalizability of this halogenation biochemistry, we aim to begin assessing the in vivo activities of these VHPOs in axenic cultures and within simulated communities alongside known AQ producers. Transcriptomic and metabolomic analyses using liquid coculturing experiments may provide insight into the role of VHPO-mediated AQ modification. Imaging mass spectrometry in combination with solid-phase coculturing conditions can additionally assess the spatial localization of quorum sensor production, interconversion, and microbial interactions. We envision that a rigorous understanding of AQ halogenation enzymology will enable us to target specific ecological questions regarding the significance of VHPOs in marine microbiology.We intend to initially investigate the impact of AQ-modulating VHPOs using In comparison to common terrestrial transition metals like iron, molybdenum, and zinc, the full extent of the biological and ecological roles that vanadium plays is less well understood , 12. Muc15\u2013"} +{"text": "Numerous microbial diversity surveys conducted over the past decade have attempted to link specific ASD biomarkers to gastrointestinal tract disturbances, but results generated across cohorts and studies remain inconsistent. This commentary discusses multidirectional interactions between the host, the microbiome, and external factors germane to autism. Recent studies posit the heritability of the gut microbiome itself, confounding attempts to discern heritable from nonheritable effectors in neurodevelopmental disorders. Elucidating the ever-evolving gut microbiome\u2019s role in modulating the ASD phenotype will most certainly require new experimental methodologies and designs. In a recent paper published in Elucidating the countless factors contributing to the etiology of autism is incredibly challenging. Upon entering this field \u201clate\u201d in my career, I was then, and remain today, awestruck at both how much and how little is known about this disorder. Over the past decade, even the very definitions of the core symptoms of autism spectrum disorder (ASD) have changed. Between 2010 and 2015, both the number of known cistrons associated with autism whose unprecedented size would otherwise preclude meaningful study, and innovative techniques enabling the segregation of features of the host from those of its microbiome.Finally, the scientific community desperately needs to bolster the current understanding of the complex interplay between genetic-driven and heavily microbiome-influenced systems. Within this vein, we must explore whether exposure to detrimental environmental factors early in life coupled with innate genetic susceptibility might impair brain development. Addressing such questions will require novel experimental design frameworks, emerging analytical tools capable of leveraging data sets (both preexisting publicly available data sets and"} +{"text": "This symposium brings together four papers that address racial health disparities by investigating stressful aspects of social relations at different points in the life course. Cleary and colleagues focus on racial disparities in psychological health by testing cross-sectional effects of intergenerational stress over time. In particular, they investigate effects of network composition on the relationship between mothers' stressors and their children's depressive symptoms at three time points over 23 years. Camacho and colleagues use longitudinal data from the National Social Life, Health and Aging Project to examine cognitive decline among U.S. African-American, Latino, and White adults aged 60 and above. Results indicate loneliness predicted greater global cognitive decline over time in all groups. However, race differences in this association were found across cognitive function domains. Turner and colleagues consider dementia caregiving challenges among non-Hispanic Blacks. Data from five focus groups were analyzed to reveal distinctive challenges to caregiver health during the COVID-19 pandemic including increased burden and barriers to service access. Finally, Sol and colleagues examined the bidirectional association between loneliness and self-rated health over time among a racially diverse sample. Findings illustrate racial patterns in how loneliness at midlife influences health in later life. Antonucci will discuss the role of stress from social relations as a means to fully understand racial disparities in health across the life course."} +{"text": "Plant genebanks provide genetic resources for breeding and research programs worldwide. These programs benefit from having access to high-quality, standardized phenotypic and genotypic data. Technological advances have made it possible to collect phenomic and genomic data for genebank collections, which, with the appropriate analytical tools, can directly inform breeding programs. We discuss the importance of considering genebank accession homogeneity and heterogeneity in data collection and documentation. Citing specific examples, we describe how well-documented genomic and phenomic data have met or could meet the needs of plant genetic resource managers and users. We explore future opportunities that may emerge from improved documentation and data integration among plant genetic resource information systems. Genebanks offer a broad range of plant genetic diversity for use in research and breeding programs. For decades, crop researchers have collected phenotypic trait data on genebank accessions. New high-throughput technologies facilitate the collection of phenomic data . Similarly, smaller-scale DNA marker data have been eclipsed by more comprehensive genomic data for characterizing collection genetic diversity. With these large datasets, the challenges of digital information management are becoming as important as managing the physical collection of germplasm. Databases that integrate data types, promote standardized data collection and documentation methods, incorporate appropriate analytical tools and provide user-friendly access will help curators and users of plant genetic resources (PGR) to manage, locate and identify diversity of agronomic and horticultural importance . TanksleTriticum aestivum L.] variety \u2018Jagger\u2019 and maize [Zea mays L.] inbred line \u2018B73\u2032). An example of homozygous/heterogeneous accessions are landraces of self-pollinating crops that are comprised of an assortment of different genotypes. Heterozygous/homogeneous accessions include clonally maintained but originally outcrossing crops . Heterozygous/heterogeneous accessions are represented by wild species accessions and outcrossing landraces. As wild species accessions are regenerated, the extent of heterozygosity may decrease [Cicer arietinum L.] [Genome-wide association analysis has enabled PGR to contribute more extensively to marker/gene discovery in most species. Diversity subsets from genebank collections are a readily available resource to perform GWAS using a range of markers from simple sequence repeats (SSRs) to SNPs from GBS or SNP arrays . Whole-gtiva L.] ; soybean) Merr.] ; chickpeinum L.] ) and perinum L.] . GWAS isPlant breeders and researchers require an understanding of the phenotypic/phenomic data that are available. This includes documentation about how the data were collected, such as the numbers of individuals sampled and experimental field designs (particularly for heterogeneous accessions), as well as the use of standardized descriptors and ontologies. Most of the traits important to breeders exhibit significant genotype \u00d7 environment interactions so the full environmental context under which phenotypic measurements were made is necessary ,48. HighPisum sativum L., and many fruits. However, pea and other new crop ontologies are under development. Other harmonious crop ontologies can be found on Planteome [Beginning in the 1990s, an evolution occurred from simple, formal phenotypic descriptors to the machine-readable ontologies available today, wherein the controlled vocabulary includes not only trait definitions but also relationship terms, so that complex phenotypic information can be processed by computer. Phenotypic descriptors for PGR have been published for over 100 crops under the auspices of the CGIAR centers IPGRI and Bioversity International . Bioversity used these to develop crop ontologies and the Crop Ontology Curation Tool . These olanteome and Agrolanteome . The goalanteome . As geneHigh-quality genebank collections contain well-curated passport, phenotypic, and genotypic data. Acquiring these data is challenging due to resource limitations and the vast size of most genebank collections. Success depends upon partnerships between genebanks and user communities. As they become available, genomic and phenomic data can help guide collection management and improve the value of the collection. These data permit the identification of collection gaps, which can be filled with new acquisitions . They alGenomic and phenomic data can provide knowledge applicable to curation, such as whether accessions are correctly assigned to taxon, whether they are redundant, or whether they differ when they should not . They caLens species and Lens culinaris Medik. sub-species, are difficult for non-taxonomists to identify. Wong et al. [Availability of accession-level genomic data for genebank collections has facilitated taxonomic identification of unusual or hybrid species. Lentils, which include g et al. used seqGenotyping the maize Ames Panel revealed several interesting findings related to curation . First, Hordeum vulgare subsp. spontaneum C. Koch.) collection\u201d [Solanum tuberosum L.) accessions with a 12K SNP array and identified putative misclassified accessions [Lactuca sativa L.) PGR in the USDA collection lack genetic diversity, hindering genetic advances in this important crop [Genomic data have provided useful information about genetic gaps in collections. Previously, geographic coverage was the primary criterion for targeting plant acquisitions and assembling core collections. Correlation of geographic gap-filling and genomic gap-filling has shown the advantage of using genomic data. The IPK genebank analyzed GBS data for 21,405 barley accessions to identify gaps in the collection. They found \u201ca pronounced under-representation of some regions of the world in IPK\u2019s wild barley offer numerous visualizations and capabilities connected to genebank accessions. Maize SNP data were used to establish an IBS relationship matrix among 2800 inbred lines, and this matrix was used to populate a tool called \u201cTYPSimSelector\u201d ,97, wherLooking forward, data curation will likely involve the use of persistent identifiers (PIDs) such as Plant Introduction (PI) numbers or Digital Object Identifiers (DOI) for sample identification. Through the adoption of BrAPI, the GRIN-Global information management system can become interoperable with Breeding Insight and crop-specific databases. Several databases, including Bridge IPK and GermCurrent and future genebank users, as well as curation teams, will increasingly require access to high-quality genomic and phenomic data. Access to genetic diversity information could help ensure phenotypic data are collected from an adequate number of individuals. Integration of genomic and phenomic data for heterogeneous accessions requires special attention to DNA polymorphism and elevated or complex patterns of phenotypic variance. Technological advances in information management systems have focused primarily on specific crops. Future efforts should consider the relative heterogeneity of genebank accessions and how it can be effectively managed when data are collected. Systems must be user-friendly and widely applicable to diverse customers. In addition, they must be adaptable and scalable, to support new genomic and phenomic technologies. Future research should focus on ensuring that tools are available to effectively use genomic and phenomic data for informed curation decisions.Sorghum bicolor (L.) Moench) demonstrated the power of this approach for selecting accessions for high biomass from a large PGR collection [Increasingly sophisticated artificial intelligence methods and sequence data lead to the question of whether every accession must be phenotyped to choose accessions for gene(s) or trait(s) of interest. Advances in statistical prediction may change how characterization data can select germplasm for further evaluation. FIGS (Focused Identification of Germplasm Strategy) applies machine learning (ML) algorithms and environmental data to identify candidate accessions associated with a trait of interest . In Barillection . Improvellection ,107."} +{"text": "Arteriogenesis is one of the primary physiological means by which the circulatory collateral system restores blood flow after significant arterial occlusion in peripheral arterial disease patients. Vascular smooth muscle cells (VSMCs) are the predominant cell type in collateral arteries and respond to altered blood flow and inflammatory conditions after an arterial occlusion by switching their phenotype between quiescent contractile and proliferative synthetic states. Maintaining the contractile state of VSMC is required for collateral vascular function to regulate blood vessel tone and blood flow during arteriogenesis, whereas synthetic SMCs are crucial in the growth and remodeling of the collateral media layer to establish more stable conduit arteries. Timely VSMC phenotype switching requires a set of coordinated actions of molecular and cellular mediators to result in an expansive remodeling of collaterals that restores the blood flow effectively into downstream ischemic tissues. This review overviews the role of VSMC phenotypic switching in the physiological arteriogenesis process and how the VSMC phenotype is affected by the primary triggers of arteriogenesis such as blood flow hemodynamic forces and inflammation. Better understanding the role of VSMC phenotype switching during arteriogenesis can identify novel therapeutic strategies to enhance revascularization in peripheral arterial disease. In peripheral arterial disease (PAD), atherosclerosis limits blood flow to the lower extremities and represents approximately 25% of the global burden of cardiovascular disease and 1.7% of the overall global burden of disease . The curThe endogenous revascularization after ischemic insult involves multiple biological processes including vasculogenesis, angiogenesis, and arteriogenesis. While vasculogenesis occurs mainly during embryonic life, experimental evidence has shown that vasculogenesis contributes to adult neovascularization at least to repair the damaged capillary networks. In vasculogenesis, blood vessels form de novo via the differentiation of progenitor vascular cells into discrete vascular cells such as endothelial cells ,11, smooNevertheless, most of our knowledge about the pathophysiology of arteriogenesis is based on experimental animal studies of arterial occlusion. The terms collateralization and arterialization are often confused with arteriogenesis and are poorly defined . This reWhen a primary arterial trunk is occluded, it leads to a pressure drop downstream of the arterial network subsequently creating a pressure gradient across pre-existing collateral circulation and forcing the diversion of blood flow through the collaterals. The altered blood flow generates hemodynamic forces in collateral arterioles and arteries triggering two vascular responses: short-term vasodilation and long-term expansive vascular remodeling . The shoSynthetic smooth muscle cells migrate from the media to the subendothelial space (intima) where they proliferate abundantly and produce ECM components including collagen, elastin, and proteoglycans to the subintimal space resulting in the formation of a new layer of SMC . At thisUpon successful arteriogenesis, the collaterals exhibit an extensive outward and hypertrophic remodeling, which is associated with the transformation of a small microvascular resistance vessel into a large conductance artery . The smoVascular smooth muscle cells in the adult vasculature are not terminally differentiated cells. They possess extensive plasticity such that it can be stimulated to undergo a structural and functional transition into proliferative/migratory/synthetic phenotype or undergo an extreme phenotypic change into osteochondrocyte-like cells , foam-liThe mature contractile phenotype of SMCs is morphologically characterized by low numbers of protein synthesis organelles, e.g., rough endoplasmic reticulum, Golgi apparatus, or free ribosomes . They deThe molecular basis of sustaining the SMC contractile state has been explained by maintaining CArG\u2013SRF\u2013Myocardin complex . Any heaSeveral pathways transduce signals from cell surface receptors or integrins in response to the surrounding environmental factors to maintain the contractile phenotype. The RhoA/ROCK signaling triggers actin polymerization increases post-translational modification of MRTFs and releases it to the nucleus to induce contractile gene expression . TGF\u03b2 enThe loss of the contractile phenotype occurs via growth factors such as Platelet-derived growth factor-BB (PDGF-BB), FGF, and EGF that activate MAPK cascade via the Ras/Raf/MEK/ERK pathway. The MAPK activation can phosphorylate and activate TCF proteins such as Elk-1 to displace MYOCD or induce SRF-dependent transcription of early response growth, dedifferentiation genes, and repression of smooth muscle contractile genes . ERK canUpon arterial occlusion, the increase of blood flow and intravascular pressure in the bypass collaterals can generate two primary forces: fluid shear stress and circumferential wall tension . The fluIn contrast, after arterial occlusion, early vasodilation of collaterals leads to a rapid decrease in the intra-luminal pressure. Thus, according to Laplace\u2019s formula, we expect that the circumferential wall stress would not change significantly in the early stage. In addition, the diminished blood pressure in downstream vessels is much lower than the proximal arterial pressure; thus, this pressure is unlikely to cause a significant stretch force on medial SMC at this phase. Indeed, the SMC in small arteries and arterioles generally react to the acute rise of intraluminal pressure by contraction (myogenic response) to regulate the tissue blood flow ,90. HoweThe increase in fluid shear stress force is transmitted to the SMC by diffusible molecules such as nitric oxide (NO) . NO is sMost collaterals tend to be tortuous small arteries . The steEndothelial surface glycocalyx and its components can act as a mechanoreceptor and can transmit mechanical stimuli to the cytoskeleton, which can then activate downstream signaling pathways such as PI3K/AKT/eNOS and NF\u03baB . The plaIn contrast, the alterations in the intraluminal pressure in the later stages of arteriogenesis can be extended to exert a mechanical force on the cellular components of VSMCs, which act as a mechanosensor to initiate subsequent signal transduction events . Medial Additionally, activation of integrin receptors, stretch-activated cation channels, and G proteins are also observed in SMC membranes of collateral vessels in response to stretch forces . These fCyclic stretching is a critical inducer of MCP-1 expression in SMC of remodeling collaterals . It goveThe arterial wall strain is chronically elevated in systemic hypertension conditions. The small arteries and arterioles remodel inwardly through a eutrophic process of rearrangement of the same SMC around a smaller lumen . ConversThe initial phase of collateral vasodilation is driven by fluid shear stress and occurs within the early stage of post-occlusion. However, this vessel enlargement accounts for a small proportion of final vessel expansion, and it slows following shear stress normalization . The appEndothelial cells in pre-existing collaterals are the first effectors to initialize an inflammatory process following arterial occlusion . In resphighCCR2highCX3 CR1low) and tissue repair (Ly6 ClowCCR2lowCX3 CR1high) in mouse [high) are detected mainly in the collaterals during the early phase of arteriogenesis whereas the anti-inflammatory monocytes (Ly6 Clow) predominate the collaterals during the growth and expansion phase of arteriogenesis [high monocytes are more likely to differentiate into M1 macrophages, which secrete various pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-12, and TNF\u03b1. They exhibit high proteolytic activity [low monocytes may differentiate into M2 macrophages, which secrete anti-inflammatory cytokines such as IL-10 and TGF\u03b21 and express growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), thus promoting collateral remodeling and expansion [Medial SMCs also contributes to initiating or amplifying stretch-induced inflammation in collateral remodeling . They prin mouse . The infogenesis . Ly6 Chiactivity . In contxpansion . Many ofxpansion ,145,146.xpansion . Other fxpansion ,149.Monocytes and macrophages are an important source of metalloproteinases and other proteases such as cathepsins during vascular repair process . During Other inflammatory cell populations have been reported to infiltrate the collateral sites during arteriogenesis, e.g., neutrophils , mast ceArteriogenesis is a physiological remodeling response of the collateral arteries in the occlusive arterial diseases. Despite the dramatic outward remodeling of collaterals, blood flow is restored only up to 40\u201350% of the unblocked artery without intervention. One reason for the limited restoration of blood flow is the premature normalization of fluid shear stress (primary trigger of arteriogenesis). This natural compensatory capacity is diminished even further in subjects with co-morbid diseases such as diabetes . Using aVascular smooth muscle cells play a central role during arteriogenesis due to their plasticity. Phenotypic switching of the contractile VSMC to a synthetic state is a critical cellular event that sustains the growth and outward remodeling of collaterals. In contrast, VSMC re-differentiation back to their contractile state is important to regain vascular functions and prevent inappropriate hypertrophic remodeling of collaterals that could perturb the blood flow for distal ischemic tissues. The physiological normalization of fluid shear can lead to a premature switch of synthetic VSMC to a contractile quiescent phenotype; this switch eventually attenuates the collateral wall growth and remodeling. It has been shown that growth factor therapy can stimulate angiogenesis and also is able to stimulate arteriogenesis ,163. ManTargeting vascular smooth muscle cell phenotype switching has been suggested to be a therapeutic approach for tackling other vascular diseases such as atherosclerosis and hypertension. However, since the dynamics of VSMC phenotype switching are different in arteriogenesis, the timing of intervention would be challenging to achieve effective therapy. Another challenge of targeting VSMC in arteriogenesis is that several cellular events of atherosclerotic plaque development are also involved in arteriogenesis. For instance, extracellular matrix degradation, VSMC migration, and proliferation are activated in both arteriogenesis and atherogenesis. The stimulation of arteriogenesis through agents that promote VSMC proliferation or positive arterial remodeling could have side effects on the aggravation of atherosclerotic plaques in PAD patients who typically suffer from atherosclerosis. While many experimental studies have been conducted to investigate the molecular mechanisms of VSMC phenotype regulation in the context of atherosclerosis, the molecular mechanisms of VSMC phenotype switching that specifically control arteriogenesis in ischemic vascular disease remain largely unknown. Previous studies have been carried out to trace the VSMC phenotype dynamics in vascular repair and atherosclerosis models. Further studies are required for VSMC lineage tracing studies during arteriogenesis. These can help to identify novel specific molecular targets for therapeutic arteriogenesis of peripheral arterial disease patients."} +{"text": "Heritability of cognitive ability changes across late adulthood, although whether genetic variance increases or decreases in importance is not understood well. We performed a systematic review of the heritability of cognitive ability derived from longitudinal twin studies of middle-aged and older adult twins. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, articles were identified in APA PsycINFO and Clarivate Web of Science electronic databases. Identified articles were screened by title and abstract; remaining full-text articles were then fully evaluated. Reference sections served as an additional method for identification of relevant articles. In total, 3,106 articles were identified and screened, 28 of which were included and were based on data from 10 longitudinal twin studies published from 1994-2021. There are large genetic influences on an initial level of cognitive performance across domains whereas there are small to moderate genetic influences on change in performance with age. Evidence was less definitive about whether the same or different genetic factors contribute to both level and change. Non-shared environmental influences appeared to drive individual changes in cognitive performance. Heritability tended to either be stable or decline after 65 years, possibly because of the increasing importance of non-shared environmental influences on cognitive ability. Recent studies report increases in heritability across specific subtests and domains. Shared environmental variance accounted for little variance in cognitive ability. Emerging research questions and future directions for understanding genetic and environment influences in the context of gene-environment interplay are highlighted in this review."} +{"text": "Glutathione is an intracellular antioxidant that neutralizes reactive oxygen species and prevents tissue damage. Dietary supplementation with the glutathione precursors glycine and n-acetylcysteine supports the maintenance of normal glutathione levels in several age-related diseases, but the optimal doses and their efficacy in healthy elderly are not established. We report results from a randomized controlled clinical trial in 114 healthy volunteers (mean age = 65 years) receiving glycine and n-acetylcysteine (GlyNAC) at three different doses for two weeks . Older subjects showed increased oxidative damage and a lower reduced-to-oxidized glutathione ratio (GSH:GSSG) compared to young subjects, but unchanged total glutathione levels. GlyNAC did not increase levels of circulating glutathione compared to placebo treatment, the primary study endpoint. However, stratification analyses suggest that subjects with high oxidative stress and low glutathione status responded with glutathione generation. We find that unrelated to glutathione status, healthy aging was associated with lower levels of fasting glycine that can be increased towards those observed in young subjects with supplementation. Using preclinical models, we find that tissue glycine depletion is a common feature of healthy aging. Supplementation of old mice with glycine efficiently improved age-related decline of mitochondrial respiratory function in skeletal muscle and prevented a gene program associated with protein catabolism observed in control-treated animals. In conclusion, GlyNAC is safe and well-tolerated and may selectively increase glutathione levels in older subjects with oxidative stress and glutathione demand. Our data further suggest that glycine may support mitochondrial function independently of NAC."} +{"text": "Practitioners frequently tailor programming to meet participant characteristics and logistic constraints, or to incorporate diverse participants, such as intergenerational programming. Adapted programming may be responsive but reduce impact on outcomes. With growing interest in and limited availability of intergenerational protocol, implementation science guides program tailoring to ensure that youth and older adults mutually benefit from adapted programming. We integrated guidelines for tailoring interventions (Framework for Reporting Adaptations and Modifications-Expanded: FRAME) and evidence-based intergenerational practice. We illustrate how program fidelity can be supported in intergenerational settings using examples from an adapted USDA-approved preschool nutrition curriculum delivered intergenerationally. Program acceptability, appropriateness, and feasibility were rated favorably by program stakeholders, and observational implementation data suggest fidelity can be maintained using evidence-based intergenerational strategies. Our findings support the potential for protocol developed for one age group to benefit youth and older adults when it is adapted using implementation and intergenerational guidelines."} +{"text": "Are eusociality and extraordinary aging polyphenisms evolutionarily coupled? The remarkable disparity in longevity between social insect queens and sterile workers\u2014decades vs. months, respectively\u2014has long been recognized. In mammals, the lifespan of eusocial naked mole rats is extremely long\u2014roughly 10 times greater than that of mice. Is this robustness to senescence associated with social evolution and shared mechanisms of developmental timing, neuroprotection, antioxidant defenses, and neurophysiology? Focusing on brain senescence, we examine correlates and consequences of aging across two divergent eusocial clades and how they differ from solitary taxa. Chronological age and physiological indicators of neural deterioration, including DNA damage or cell death, appear to be decoupled in eusocial insects. In some species, brain cell death does not increase with worker age and DNA damage occurs at similar rates between queens and workers. In comparison, naked mole rats exhibit characteristics of neonatal mice such as protracted development that may offer protection from aging and environmental stressors. Antioxidant defenses appear to be regulated differently across taxa, suggesting independent adaptations to life history and environment. Eusocial insects and naked mole rats appear to have evolved different mechanisms that lead to similar senescence-resistant phenotypes. Careful selection of comparison taxa and further exploration of the role of metabolism in aging can reveal mechanisms that preserve brain functionality and physiological resilience in eusocial species. Eusocial animals, characterized by reproductive division of labor, cooperative brood care, and overlap of generations, can have extraordinary lifespans. Eusocial hymenopteran queens may live 100 times longer than solitary insects. In some eusocial species there is a similar lifespan differential between queens and workers . Naked mHarpagnathos salatator, workers can facultatively become reproductive upon queen loss declines with age (superoxide dismutase (SOD), lowers levels of protein carbonylation (a measure of oxidative damage) and extends lifespan store sperm from a single insemination for life, allowing sperm counts to reliably estimate queen age . Queens Caste theory can be aMost aging comparisons with NMRs involve studies of other taxa. Mutant dwarf mice with growth hormone mutations exhibit pedomorphic traits and have at least 50% longer lifespans than wild-type mice, and fewer aging-associated diseases . ExperimReticulitermes speratus reproduce in hypoxic, hypercapnic chambers, conditions that enhance their reproductive output (Harpegnathos saltator (Brain metabolism is little explored in eusocial and solitary species . Is enere output , althouge output . Future saltator hint at saltator will allEusocial insects and eusocial mammals share aging phenotypes despite phylogenetic divergence, but different mechanisms appear to have evolved to facilitate delayed aging in their nervous systems. The striking difference in worker and reproductive lifespan in eusocial insects is less pronounced in NMRs, further suggesting the evolution of multiple pathways to achieve long and healthy lifespans in eusocial taxa. To enable precise comparisons between vertebrate and invertebrate taxa, similar methodologies, such as quantifying levels of homologous biochemical markers of aging or comparisons among divergent taxa must be applied. Integration of theories of aging and development in eusocial and solitary species will enhance our understanding of how social organization shapes aging phenotypes and mechanisms that promote longevity.YG, MM, and JT wrote the manuscript. YG and JT provided the funding. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Lack of insurance or funds for dental services, lack of access to dental offices, fear of dentists, and avoidance of dental offices during COVID can lead to oral health problems in older adults. Brushing, flossing, and drinking fluoridated water can protect teeth when dentists are unavailable. Limiting intake frequency of carbohydrates and chewing sugarfree gum after eating add protection. A recent systematic review and meta-analysis confirmed the effectiveness of sugarfree gum in reducing caries, in children and adults who chewed sugarfree gum compared with those who did not chew. Chewing sugarfree gum significantly reduced caries increment, with a prevented fraction of 28 percent, roughly equivalent to the prevented fractions for fluoride toothpastes and supplements. A follow-up systematic review provides further evidence that chewing sugarfree gum reduces the numbers of Streptococcus mutans in the oral cavity. Finally, chewing sugarfree gum could alleviate symptoms of xerostomia and may reduce caries."} +{"text": "Manis javanica) achieved notoriety during the Coronavirus disease pandemic because of flawed evidence suggesting that pangolins could be intermediate hosts . Native to Java (thus javanica), their habitat includes Southeast Asia, especially the Indomalayan archipelago and Sunda Islands. Humans hunt pangolins for their meat, consume their blood as an elixir, and use their scales and other body parts as ingredients for crafting leather products and nonefficacious medications. Linnaeus named the genus"} +{"text": "The search for novel prostate cancer biomarkers is one of the major topics in recent urologic research. Given the still unsatisfactory performance of the available diagnostic biomarkers in the detection of significant prostate cancer cases and the lack of prognostic and predictive biomarkers with high specificity, there is still an urgent need for new biomarkers. This special issue presents nine original research papers and two reviews elucidating novel developments in prostate cancer biomarkers. Interestingly, two major topics were in focus, microRNAs (miRNAs) as biomarkers ,2,3,4 anThe fast-growing field of miRNA biomarkers in liquid biopsies reflects the high expectations raised in the implementation of miRNA diagnostics. Freds\u00f8e and colleagues analyzed 92 circulating miRNAs in plasma samples of 753 patients and found distinct regulation of miRNAs in patients with benign prostatic hyperplasia (BPH), localized prostate cancer, and advanced prostate cancer with large overlaps between the groups [Using urine and urinary cells, respectively, is the second major approach in minimally invasive liquid biopsies for PCa detection. Borkowetz and colleagues used urinary sediments to analyze a 12-miRNA panel by qPCR [Successful implementation in routine clinical use requires standardization of miRNA measurements. Konoshenko and coworkers evaluated the diagnostic potential of ratios constructed from a panel of 12 cell-free miRNAs, using urine extracellular vesicles, clarified urine, and plasma. Eight miRNAs combined into six ratios showed maximum stability and 97.5% accuracy in separating PCa patients from the control group . In a seBlood and urine are also profitable sources of metabolites, which have recently been used in numerous disease states. Yang and colleagues conducted a study searching for urine metabolite biomarkers for the detection of PCa. They found twenty differentially expressed urine metabolites in a cohort of 50 prostate cancer patients compared to non-cancerous individuals . The comWhile liquid biopsies are an upcoming promising tool of non-invasive PCa diagnostics, verification of biomarkers in tissues is mandatory to prove PCa being the primary cause of the alterations in liquid biopsy biomarkers. Latosinska and colleagues present a proteomic study comparing the proteome of PCa tissue with benign prostatic hyperplasia (BPH), a common co-morbidity especially in aged patients . They dePatients with GS \u2264 6, i.e., at low risk, are eligible for active surveillance. Yu and colleagues asked whether multiparametric MRI (mpMRI) can be a substitute or supplement of traditional tools as PSA, digital rectal examination, and transrectal ultrasound-guided biopsy (TRUS) . They reTwo papers in this special issue elucidate oxidative stress related enzymes and peptides as potential biomarkers in PCa. As shown by Veljkovi\u0107 and colleagues, xanthine oxidase (XO) activity was significantly higher in tumor tissue compared to heathy controls and strongly correlated with serum PSA levels . The autFinally, two reviews provide updates on prognostic and predictive omics-derived biomarkers for therapy of advanced PCa and especially of serum biomarkers in metastatic disease ,11. In tSaxby and colleagues focused on serum biomarkers , which can be used in conjunction with PSA as prognostic or predictive biomarkers for metastatic PCa. Forty-three were analyzed and revealed numerous biomarkers with potential value for identifying patients with advanced PCa and of value for the development of targeted treatment strategies. However, while basic data are available, clinical validation in prospective trials is urgently needed to bring them to routine use in clinical practice.This special issue elucidates some important aspects of PCa biomarker development and their potential clinical benefit and highlights advanced techniques of biomarker discovery. The future of those biomarkers strongly depends on prospective multicenter clinical diagnostic studies, which hopefully will find the support of the major funding agencies."} +{"text": "Daily oral pre-exposure prophylaxis (PrEP) is highly effective at preventing HIV when used as directed among men who have sex with men (MSM). However, challenges with uptake and adherence to daily oral PrEP have prompted the development of new modes of administration, including a long-acting, intramuscular injectable. We sought to explore the treatment characteristics that may influence the willingness and uptake of long-acting injectable PrEP as opposed to the daily pills among a racially diverse sample of MSM.Between January and May 2021, we actively recruited 28 HIV-negative MSM who lived in Philadelphia, PA during the past 12 months using social networking sites and a community listserv. Qualitative data collection used a hybrid approach in which 4 focus groups and 10 semi-structured interviews were conducted virtually. Focus groups were kept racially and ethnically homogenous to identify differences in emerging themes related to PrEP willingness and preferences for specific prevention modalities.Participants discussed differing levels of interest and willingness to use long-acting injectable PrEP as opposed to the daily pills. The main perceived facilitator for injectable PrEP included convenience of use such as having fewer concerns with adhering to daily pills. Perceived barriers to injectable PrEP included (1) a dislike of needles as well as (2) concerns of potential side effects and (3) lower treatment efficacy . While Black and Latinx MSM reported experiences of racism and discrimination within the healthcare system, they also reported greater willingness to consider intramuscular injectables if their healthcare providers would provide in-depth information about the risks and benefits of this new modality. Our findings provide important guidance for the development and promotion of future strategies to enhance the uptake of long-acting injectable PrEP to address the HIV epidemic among MSM. Primary care providers should play a key role in ameliorating concerns related to hesitancy towards injectable PrEP, including emphasizing ease of dosing, effectiveness, and safety of long-acting PrEP to prevent infection.All Authors: No reported disclosures"} +{"text": "Supportive marital relationships may reduce partners\u2019 problematic health behaviors, whereas unhappy relationships may lack efficacious spousal monitoring of health and increase the likelihood of using maladaptive coping strategies, such as heavy alcohol use, to deal with relationship problems. We used pooled data from the 2014 and 2016 waves of the Health and Retirement Study to examine how both partners\u2019 perceptions of marital quality were associated with heavy drinking. Our analytic sample included married couples in which both spouses were over age 50, completed the leave-behind psychosocial questionnaire, and provided non-missing data on marital quality and alcohol use . Measures included both positive and negative dimensions of marital quality and controls for sociodemographic, economic, health, household and marital characteristics. Using Proc Glimmix, we estimated a dual-intercept Actor-Partner Interdependence Model (APIM), in which separate equations were computed simultaneously for husbands and wives. For husbands, higher negative marital quality was associated with an increase in the odds of their own heavy drinking (OR=1.27), but there was no significant association between wives\u2019 marital quality and husbands\u2019 heavy drinking behavior. For wives, marital quality was not significantly associated with their own heavy drinking, but husbands\u2019 higher ratings of both negative and positive marital quality increased the risk of wives\u2019 heavy drinking . Results suggest that marital quality is associated with heavy drinking in later life: self-ratings of marital quality matter for men, whereas spousal perceptions of marital quality are more important for women."} +{"text": "Pre-pandemic, evidence existed that intergenerational service-learning programs support knowledge of aging and positive attitudes and perceptions . As spring 2020 COVID-19 lock downs and public health warnings urged physical distancing of community dwelling older adults, growing concern about the unintended consequences of increased social isolation on mental and physical health prompted the Secretary\u2019s Office of Pennsylvania Department of Aging to design a pilot project with university faculty for virtual intergenerational social interaction. The Department identified older adults at the highest risk for social isolation . The resulting pilot project is fully integrated as a high impact practice into eight sections of recreational therapy and gerontology courses with participation by 210 undergraduate students and 210 older adults for 9 weeks of both the fall and spring semesters. Students, who received extensive classroom instruction aimed at avoiding negative stereotypes of older adults as helpless and dependent, called their assigned partner several times a week for at least an hour of communication. Using the UCLA loneliness scale, community-dwelling older adults reported frustration with isolation due to the pandemic. Those with low and moderate loneliness reported positive feelings about program and looking forward to interactions with students. Students gained virtual communication skills that may contribute to telehealth competencies, intervention skills such as assessment, life review/reminiscence, mindfulness techniques, and leisure education. Moreover, an analysis of student reflections revealed positive changes in attitudes toward older adults and the ability to enjoy common interests despite age differences."} +{"text": "OBJECTIVES/GOALS: Pancreatic cysts are comprised of both precancerous mucinous lesions and non-mucinous lesions with minimal malignant potential. Our goal is to improve our ability to classify the type of cyst using a combination of novel radiomic features and cyst fluid proteolytic activity. METHODS/STUDY POPULATION: Preoperative pancreatic protocol CT images from 30 patients with proteolytic assay characterization, followed by surgical resection with a pathologically confirmed pancreatic cyst diagnosis between 2016-2019 will be used in this study. We will contour images using the widely available software 3D Slicer, and extract radiomic features using IBEX software. We will analyze area under the ROC curves to identify the radiomic features that best differentiate mucinous from non-mucinous cysts, and identify features to be cross validated. The predictive ability of identified radiomic features combined with proteolytic assay will be determined by performing multiple logistic regression analysis and comparing AUROC analysis. We will determine sensitivity and specificity for individual, as well as combinations of, analytes to determine the optimal classifier. RESULTS/ANTICIPATED RESULTS: We anticipate that the predictive ability, sensitivity, and specificity of utilizing radiomic features combined with proteolytic assay data will exceed the performance of any individual test. DISCUSSION/SIGNIFICANCE OF IMPACT: This work is designed to provide a predictive radiomic model that will enable us to better identify mucinous cysts that require further evaluation, and potentially prevent unnecessary surgery in other patients. Ultimately, we would like to improve the accuracy of noninvasive radiographic evaluation using radiomic markers. CONFLICT OF INTEREST DESCRIPTION: Dr. Charles Craik is a co-founder of Alaunus Biosciences, Inc."} +{"text": "Black adults and women are more likely to experience serious cognitive decline in older age than their white and male counterparts. Evidence suggests perceived discrimination is associated with poor cognition in older adults, though the mechanisms remain unclear. Perceived discrimination has been linked to elevated inflammatory markers, such as C-reactive protein (CRP), which increases risk for worse cognitive functioning. Yet, little research has investigated whether CRP is implicated in the association between discrimination and cognition among Black older adults or if this relationship differs by gender. Using 2006-2016 data from Black adults \u226565 years old(N=1343) in the nationally representative Health and Retirement Study, random effects linear regression models (1) tested the association between discrimination and cognitive functioning; (2) explored whether this relationship differed for women and men; and (3) assessed whether elevated CRP mediated the association between discrimination and cognitive functioning. More frequent discrimination was associated with worse cognitive functioning , though gender did not moderate this relationship. Elevated CRP was significantly associated with worse cognitive functioning . Discrimination remained statistically significant in this model, indicating no mediation by CRP. Of note, inclusion of depressive symptoms and cardiometabolic conditions accounted for the association between both discrimination and CRP with cognitive functioning. These findings demonstrate the need for more within-group research on older Black adults documenting the complex relationship between discrimination, inflammation, and cognitive health. This approach will provide greater understanding of the biopsychosocial mechanisms underlying disparities in cognitive functioning in Black adults."} +{"text": "Between the years 1999-2008, a substantial increase in nursing home use occurred among Black and Latinx older adults, while white older adults\u2019 use of nursing homes decreased. These disparate trends suggested potential racial and ethnic disparities in options for preferred long-term services and supports (LTSS) settings. Over the last decade, several initiatives have been put in place to support LTSS needs in the community. However, it is unclear whether Black and Latinx older adults are continuing to use nursing home services at disproportionate rates. We used LTCfocus data for 2011-2017 to explore current trends in nursing home use and access among Black and Latinx older adults in light of these current initiatives. Our findings reveal a continued rise in Black and Latinx older adults\u2019 use of nursing homes while white older adults\u2019 use continues to decline. More notably, there has been a decline in nursing homes servicing these minority groups."} +{"text": "ATP channels may provide analgesia and attenuate opioid tolerance and withdrawal OBJECTIVES/GOALS: Our long term goal is to develop therapeutics for the treatment of the overuse of opioids. The objective of this application is to test novel KATP channel-targeting prodrugs in rodent models of neuropathic and inflammatory pain in addition to opioid tolerance after chronic morphine administration. METHODS/STUDY POPULATION: In one study, two different measures for chronic pain were implemented in mice. Male and female mice (n=10) were subjected to spinal nerve ligation (SNL) or intraplantar injection of Complete Freund\u2019s Adjuvant (CFA) to induce neuropathic and inflammatory pain, respectively. Administration of KATP channel prodrugs attenuated mechanical hypersensitivity after SNL or CFA compared to vehicle . In a separate study, changes in mechanical hypersensitivity were tested while mice undergo chronic morphine treatment with administration of the prodrugs. Tolerance was measured as the loss of antinociception, and withdrawal is measured \u02dc24 hours after the final morphine injection. RESULTS/ANTICIPATED RESULTS: Intrathecal administration of either KATP channel prodrugs significantly attenuated mechanical hypersensitivity after SNL and significantly attenuated mechanical hypersensitivity after CFA in mice. We predict that intrathecal administration of these prodrugs will also attenuate morphine tolerance and withdrawal in mice. This hypothesis is based off our previous data indicating non-water soluble KATP channel agonists produce analgesia and attenuate morphine tolerance in mice. DISCUSSION/SIGNIFICANCE OF FINDINGS: Pharmaceutical strategies to utilize KATP channels for therapeutics have been hindered due to the low solubility and low ability to cross the neurovascular unit. Newly developed, water-soluble KATP channel openers could be useful pharmaceutical strategy to reduce chronic pain, opioid tolerance, and withdrawal in human populations.ABSTRACT IMPACT: Pharmacological activation of K"} +{"text": "Standard of care for patients with glioblastoma (GBM) includes resection with concurrent temozolomide (TMZ) and radiotherapy, with inevitable disease recurrence. Upon recurrence, tumors are often resistant to first-line therapies and/or have infiltrated eloquent or deep brain regions, precluding repeat resection. There is currently no standard of care for recurrent GBM and patients succumb to their disease burden within 12- 15 months of their initial diagnosis of recurrence, exposing an unmet need to find novel therapies to treat recurrent disease. Bromodomain and extraterminal (BET) proteins are chromatin readers that affect transcription of genes. The oral BET inhibitor (BETi) OTX-015 has shown promise in a dose-escalation, phase I study in patients with acute leukemia and other BET inhibitors are currently in phase I studies for the treatment of primary brain tumors. We have recently shown that BET inhibition increases DNA damage and mitotic catastrophe in oncogenic cells by increasing transcription-replication conflicts and downregulating expression of key DNA damage checkpoint proteins, and have also shown its efficacy in decreasing tumor burden and improving survival when combined with TMZ in intracranial mouse models of glioma. We have also demonstrated that BETi's synergize with Olaparib by downregulating expression of the BRCA-driven DNA damage repair pathway and further leverages additive effects when triply combined with other DNA damaging agents such as Lomustine to decrease tumor burden and improve survival in patient-derived mouse models of GBM and medulloblastoma. We therefore hypothesize that the synergistic and additive effects of this triple combination seen in our preclinical studies will achieve therapeutic benefits in patients with recurrent GBM."} +{"text": "Skeletal muscle has recently arisen as a novel regulators of Central Nervous System (CNS) function and aging, secreting bioactive molecules known as myokines with proteostasis and metabolism-modifying functions in targeted tissues. We have recently generated a novel transgenic mouse with enhanced muscle proteostasis via moderate overexpression of Transcription Factor E-B (TFEB), a powerful master regulator of cellular clearance and proteostasis. We have discovered that the resulting enhanced skeletal muscle proteostasis function can significantly ameliorate proteotoxicity in the aging CNS and improve cognition and memory in aging mice. These neuroprotective benefits are markedly reminiscent of those observed in the aging CNS post-exercise, suggesting enhancing muscle proteostasis may be sufficient to replicate the local and systemic effects of exercise. Identification of pathways regulating crosstalk between skeletal muscle and CNS may yield targets with high therapeutic potential for diseases of the aging CNS."} +{"text": "Mature cystic teratoma (MCT) is a common benign ovarian germ cell tumor. It is more predominantly seen in premenopausal women and contains at least two or more well-differentiated germ cell layers. It is termed a dermoid cyst if the ectodermal tissue is the predominant component. The complications of a dermoid cyst include torsion, malignant degeneration, rupture, and infection. The incidence of a ruptured dermoid cyst is around 1%-2% resulting in chemical aseptic peritonitis from spillage of the cyst contents. Usual clinical presentation is with diffuse abdominal or pelvic pain and abdominal distension. Around 93-96% of dermoid cysts demonstrate fat in the cyst cavity however, minimal or no fat poses diagnostic challenges. In this case, we discuss a rare case of spontaneously ruptured lipid-poor and thyroid tissue-rich left ovarian dermoid presenting with chemical peritonitis. Special magnetic resonance (MR) Imaging sequences such as fat saturation imaging, chemical shift imaging, and gradient-echo imaging assist in detecting scant amounts of fat in the cyst cavity or cyst wall. Teratomas are the most common ovarian germ cell tumors which arise from primitive germ cells . ConstitA 33-year-old nulligravida presented to the emergency department with acute onset of non-radiating left lower quadrant abdominal pain. The patient reported worsening pain with movement, which gets relieved by lying still. She also reported a progressive increase in abdominal girth over the past several weeks. Denied new vaginal bleeding, discharge, or usage of contraception. Diagnostic imaging with ultrasonography (US), computerized tomography (CT), and magnetic resonance imaging (MRI) were performed in the emergency room and are described in Figures Discovering findings of a ruptured adnexal mass on imaging, the patient underwent exploratory laparotomy with left salpingo-oophorectomy. Intraoperative findings revealed a ruptured left ovarian cyst on the inferior aspect emanating serous fluid into the peritoneal cavity. The tumor was identified as mature lipid-poor cystic teratoma on the frozen section. The postoperative recovery was uneventful. The histopathology of the resected specimen is shown in Figures Ovarian germ cell tumors (OGCTs) are a group of tumors that include benign (mature cystic teratoma [MCT]) or malignant neoplasms . TeratomUltrasonography (US) is the first line of imaging used in the evaluation of adnexal masses . DiffereIn combination with findings from US, the CT assists in additional fat detection with a sensitivity of 93%-98% . The HouT1-weighted and T2-weighted MRI in MCTs will show a hyper-intense signal representing sebaceous fluid. It can be differentiated from hemorrhagic cyst by fat suppression, chemical shift artifact, or gradient-echo imaging. The fat becomes hypointense on fat-saturated MR Figure , 6, wherThis case study emphasizes the importance of a multimodality approach to complex pelvic masses that present with pelvic pain. Advancement imaging modalities like Pelvic MRI can detect acute complications from these masses like torsion or rupture. Hence, aiding in more accurate diagnosis and pre-operative planning. Surgery is performed for definitive diagnosis and treatment. In the current case of the ruptured teratoma leading to peritonitis, the patient underwent exploratory laparotomy and salpingo-oophorectomy with peritoneal lavage. The ascitic fluid was serous without significant fat content. Histologically, the tissue demonstrated abundant colloidal material and minimal fat consistent with Struma ovarii.\u00a0The tumor is termed struma ovarii when the thyroid tissue is predominant and comprises >50% of the tumor .In the emergency room setting initial work up for pelvic pain in female patients starts with a good quality ultrasound examination. Upon discovery of a complex mass further evaluation should be done with a pelvic MRI with IV contrast. Pelvic MRI can help identify immediate complications and determine the correct surgical approach. Identifying components of MCTs across multiple imaging modalities assist in differentiating adnexal masses. The wide range of presence of fat in the dermoid cyst makes it easily detectable on CT and MR imaging. Although some cases demonstrate low fat, using special techniques such as fat suppression MRI plays a vital role in early detection and emergency management. Once rupture and peritonitis are suspected, patients should be managed by emergent laparotomy (lower spillage rate than laparoscopy) followed by cystectomy."} +{"text": "Metastasis is an inefficient process in which the vast majority of cancer cells are fated to die, partly because they experience oxidative stress. Metastasizing cancer cells migrate through diverse environments that differ dramatically from their tumor of origin, leading to redox imbalances. The rare metastasizing cells that survive undergo reversible metabolic changes that confer oxidative stress resistance. We review the changes in redox regulation that cancer cells undergo during metastasis. By better understanding these mechanisms, it may be possible to develop pro-oxidant therapies that block disease progression by exacerbating oxidative stress in cancer cells.Oxidative stress often limits cancer cell survival during metastasis, raising the possibility of inhibiting cancer progression with pro-oxidant therapies. This is the opposite strategy of treating patients with antioxidants, an approach that worsened outcomes in large clinical trials. Metastasis is the leading cause of death in patients with cancer because disseminated disease is no longer curable by surgery and is often therapy-resistant . MetastaCancer cells must be plastic to survive metastasis . GeneticMultiple factors contribute to the death of cancer cells during metastasis, including immune-mediated destruction , growth + are important sources of reducing equivalents for oxidative stress resistance is generally considered an antioxidant, but it exists in oxidized and reduced forms and when it is infused intravenously it selectively kills cancer cells by acting as a pro-oxidant . This isDietary interventions could also have pro-oxidant effects. Ketogenic diets may suppress metastasis partly by increasing oxidative stress in cancer cells . KetogenNew technical approaches to study metastasis, including whole-body imaging of metastasis patterns , improveIn at least some cancers, metastasizing cells appear to experience unusually high levels of oxidative stress, raising the possibility that these cells might be particularly sensitive to pro-oxidant therapies. It is an open question whether such therapies could prevent disease progression in patients with high-risk primary or regionally metastatic lesions. Nonetheless, this merits deeper study in preclinical models. Beyond this big-picture question, there are a number of pressing biological questions central to understanding redox regulation during metastasis: Does oxidative stress limit the survival of metastasizing cells from all cancers or only certain cancers?What causes the oxidative stress experienced by metastasizing cells?Are anabolic pathways downregulated in metastasizing cells to preserve reducing equivalents? Does this sometimes lead to dormancy in metastatic cells?How is mitochondrial function modulated in metastasizing cancer cells as compared with the primary tumors from which they arise?Do micrometastases continue to experience oxidative stress? For how long?To what extent do interactions with immune and stromal cells influence oxidative stress in cancer cells?Do differences in oxidative stress among distinct metastatic sites influence organotropism?"} +{"text": "Candidalusitaniae, a previously unreported cause of candidal vaginitis .Increasing use of short-course antifungal therapies in patients with recurrent vulvovaginitis may enable theemergence of less-common, more resistant yeast strains as vaginal pathogens. We report the case of a patient withchronically symptomatic and repeatedly treated vaginal candidiasis whose infection was attributable to"} +{"text": "The G-protein-coupled receptors (GPCRs) constitute one of the largest and most ancient superfamilies of membrane proteins. They play a central role in physiological processes affecting almost all aspects of the life cycle of an organism. Availability of the complete sets of putative members of a family from diverse species provides the basis for cross genome comparative studies.Tetraodon complement with the availability of complete sequence of the freshwater puffer fish Tetraodon nigroviridis. Almost all 466 Tetraodon GPCRs (Tnig-GPCRs) identified had a clear human homologue. 189 putative human and Tetraodon GPCR orthologous pairs could be identified. Tetraodon GPCRs are classified into five GRAFS families, by phylogenetic analysis, concurrent with human GPCR classification.We have defined the repertoire of GPCR superfamily of Tetraodon and human genomes displays a high level of orthology and supports large-scale gene duplications in Tetraodon. Examples of lineage specific gene expansions were also observed in opsin and odorant receptors. The human and Tetraodon GPCR sequences are analogous in terms of GPCR subfamilies but display disproportionate numbers of receptors at the subfamily level. The teleost genome with its expanded set of GPCRs provides additional and interesting comparators to study both evolution and function of these receptors.Direct comparison of GPCRs in The G-protein-coupled receptors (GPCRs) constitute one of the largest and most ancient superfamilies of membrane proteins, accounting for 1\u20132% of the vertebrate genome. GPCRs are characterized by the presence of highly conserved molecular architecture encoding seven transmembrane (TM) hydrophobic regions linked by three extracellular loops that alternate with three intracellular loops [GPCRs have been aggressively pursued as drug targets due to their central role in physiological processes affecting almost all aspects of the life cycle of an organism . Almost Drosophila; additional species provide new comparators for GPCR studies. Teleost fish, Tetraodon nigroviridis is one of the smallest known vertebrate genomes. It has all the specialized functions of higher vertebrates and can be a good vertebrate model system to study [T. nigroviridis genome now allows for the identification and analysis of its full set of GPCRs. Here, we describe the genome wide survey of Tnig-GPCR repertoire and a detailed analysis of opsin, fish-odorant receptors (FOR) and taste receptors (T1R).The completion of several other vertebrate and invertebrate genome sequencing projects paves the way for \"functional genomics\". The quest for assigning function to putative gene products exploits the sequence and structural similarities to known genes and further could be elucidated using molecular biology techniques ,10. Suchto study ,15. The Tetraodon nigroviridis genome (>90% sequence coverage) has shown that it possesses one of the smallest known vertebrate genomes and revealed a set of 27,918 predicted genes, much similar to the number of predicted genes in human genome [Tetraodon genome, we developed a comprehensive strategy . For almost all Tnig-GPCRs, a putative human GPCR homologue could be identified. 189 putative human and Tetraodon GPCR orthologous pairs are identified , whereas about two fold as many GPCR sequences as in fugu and about three fourth of the zebrafish GPCRs [Tetraodon also has similar numbers of frizzled receptors as expected in mammals and fish genomes. Some of the gene families in Tetraodon like opsins and fish odorant receptors have shown species-specific expansions similar to trace amine receptors in zebrafish [Tetraodon like other known fish genomes [Rhodopsin family in sh GPCRs . Tetraodebrafish . However genomes .Tetraodon and humans show many GPCRs for which there are two copies in Tetraodon but one in the human genome. Chromosomal distribution of putative Tetraodon-human GPCR orthologous pairs and corresponding Tnig-GPCR paralogs show correspondence between two different chromosomal regions in Tetraodon genome to one region in the human genome , rhodopsin (R), adhesion (A), frizzled (F) and secretin (S) (GRAFS classification) ,23,24.Te 368 see ; A, 29; ebrafish ,25.Tetraodon. These OR genes are found in clusters of 3\u20134 members in the Tetraodon genome, located on different chromosomes. They display higher sequence identity within a cluster suggesting tandem duplication events might be responsible for OR gene family expansion in Tetraodon as observed in the genomes of every vertebrate organism investigated earlier, including zebrafish, mice and humans [Tetraodon ORs with fish odorant receptor subfamily members grouped them into six clusters of orthologues with very high boot strap support were identified in fish odorant receptor (FOR) subfamily of rhodopsins in d humans . Phyloget Figure . In teleh Figure . High diTetraodon genome taste receptors in e Figure . They haTetraodon GPCRs and found high level of orthology with human counterparts. The human and Tetraodon GPCR sequences are analogous in terms of GPCR subfamilies, but display disproportionate number of receptors at the subfamily level. The teleost genome, with its expanded set of GPCRs, provides an additional and interesting model to study both evolution and function of these receptors. The availability of repertoire of Tetraodon GPCRs will facilitate further studies through \"functional genomics\" and \"reverse pharmacological\" strategies to match their cognate ligands and to elucidate biological functions. Systematic mutation of Tetraodon GPCRs will help to determine their neural, developmental and behavioral roles. They might also yield novel insights into the physiological functions and mutational pathologies of their human homologues in particular and other vertebrate homologues in general.We have identified and analyzed repertoire of Tetraodon nigroviridis are obtained from NCBI and Genoscope Tetraodon Genome Browser [12 [Tetraodon nigroviridis EST hits, as there were few or no Tetraodon nigroviridis EST sequences available in the database.Sequences of the Browser . HumanGP Browser Sequence alignment of the T1Rs of Tetraodon, human and rat are aligned with the rat mGluR1 metabotropic glutamate receptor (Accession no. P23385). Ligand binding residues of mGluR1 are highlighted in red. The C-terminus is not shown. Potential transmembrane segments are indicated using arrows.Click here for fileTransmembrane Helix (TMH) prediction of human GPCRs by different TMH prediction programs A dataset of 327 annotated human GPCRs are predicted for Transmembrane Helices (TMH) by HMMTOP, SOSUI, TMHMM and MEMSAT. A range of 6\u20138 predicted TM helices acquired maximum coverage to predict 7TM domain region.Click here for file"} +{"text": "Bacsi A, Choudhury BK, Dharajiya N, Sur S, Boldogh I. 2006. Subpollen particles: carriers of allergenic proteins and oxidases. J Allergy Clin Immunol 118:844\u2013850.During the flowering season, high humidity and moisture trigger the release of pollen grains from grasses, trees, and shrubs. Allergens contained in these pollen grains can cause reactions in the skin, eyes, and upper and lower respiratory tracts. Seasonal asthma also is associated with pollen exposure.How pollen allergens contribute to inflammation in the lower airways has puzzled researchers since few pollen grains reach the peripheral airways due to their size. In this report, NIEHS grantees Sanjiv Sur and Istvan Boldogh, with colleagues at the University of Texas Medical Branch in Galveston, present new findings suggesting that fragments of pollen grains, called sub-pollen particles (SPPs), are capable of reaching the lower airway regions and causing the clinical symptoms associated with seasonal asthma.Ambrosia artemisiifolia) and redroot pigweed (Amaranthus retroflexus) pollen grains. They also used an experimental mouse model of asthma to challenge sensitized mice with intranasally applied SPPs.This same research team recently reported that ragweed pollen grains contain intrinsic NAD(P)H oxidases, and that exposure to them generates oxidative stress in the airway epithelium within minutes of exposure. In the current study, the investigators analyzed bronchial epithelial cells after exposure to hydrated short ragweed H oxidase activity. Exposure of cultured cells to SPPs caused significant increases in the generation of reactive oxygen species and induced airway inflammation in laboratory mice. Pretreatment of the SPPs with NADH and NAD(P)H oxidase inhibitors reduced their ability to increase reactive oxygen species in the airway epithelial cells and reduced airway inflammation.This is the first report to demonstrate the presence of allergenic proteins and oxidase activity in SPPs of respirable size. The study provides insight into the potential role of SPPs in seasonal asthma and suggests that oxidase inhibitors may be useful therapeutic agents in reducing or preventing oxidative damage and inflammation."} +{"text": "We examined the expression of pancreatic secretory trypsin inhibitor (PSTI) in colorectal cancer by immunohistochemical staining using an anti-PSTI antiserum, an in situ hybridisation technique utilising sulphonated PSTI cDNA probe, and a Northern blot hybridisation method, using a 32P-labelled PSTI cDNA probe. Immunohistochemically, PSTI was detected in 80 of 95 (84%) colorectal cancer cases. Analyses with in situ hybridisation as well as Northern blot hybridisation demonstrated PSTI mRNAs in immunohistochemically positive cases, showing PSTI could be produced in colorectal cancerous cells. Histologically well or moderately differentiated adenocarcinoma showed higher incidence of PSTI immunoreactivity than the other types. Furthermore, the intensity of the immunohistochemical staining for PSTI increased the more cases advanced, particularly in regard to depth of invasion and tumour size. Thus, PSTI expression is widespread in colorectal cancer, and occurs more commonly in advanced cases. Considering the suggestion that PSTI is a growth-stimulating factor as an well as inhibitor to proteolytic proteinase, the present findings may indicate that PSTI expressed in colorectal cancerous cells may play a role possibly closely associated with tumour development."} +{"text": "Adjuvant psychological therapy (APT) is a newly developed cognitive behavioural treatment which has been designed specifically to improve the quality of life of cancer patients by alleviating emotional distress and inducing a fighting spirit. We report a phase I/II study which evaluates APT in routine clinical practice. A consecutive series of 44 outpatients with various cancers referred for psychiatric consultation and receiving APT at the Royal Marsden Hospital was studied. Standardised self-report questionnaires were used to measure anxiety, depression and four principal categories of mental adjustment to cancer, namely, fighting spirit, helplessness, anxious preoccupation and fatalism. Statistical comparisons between pre-therapy scores and scores after an average of five APT sessions revealed significant improvement in anxiety, depression, fighting spirit, anxious preoccupation and helplessness. Fatalism scores showed the same trend, but the changes were smaller. Patients with advanced disease showed as much improvement as those with local or locoregional disease. Present results indicate improvement in both psychiatric symptoms and mental adjustment to cancer associated with APT. Whether this association is causal remains to be determined by randomised controlled trials. Such a trial is in progress."} +{"text": "Melospiza melodia) to quantify long-term effects of parental immune experience on offspring immune response. We experimentally vaccinated parents with a novel antigen and tested whether parental vaccination influenced the humoral antibody response mounted by fully grown offspring hatched the following year. Parental vaccination did not influence offspring baseline antibody titres. However, offspring of vaccinated mothers mounted substantially stronger antibody responses than offspring of unvaccinated mothers. Antibody responses did not differ between offspring of vaccinated and unvaccinated fathers. These data demonstrate substantial long-term effects of maternal immune experience on the humoral immune response of fully grown offspring in free-living birds.Knowledge of the causes of variation in host immunity to parasitic infection and the time-scales over which variation persists, is integral to predicting the evolutionary and epidemiological consequences of host\u2013parasite interactions. It is clear that offspring immunity can be influenced by parental immune experience, for example, reflecting transfer of antibodies from mothers to young offspring. However, it is less clear whether such parental effects persist or have functional consequences over longer time-scales, linking a parent's previous immune experience to future immune responsiveness in fully grown offspring. We used free-living song sparrows ( Variation in host immunity to parasitic infection is thought to underpin major evolutionary processes, including host\u2013parasite coevolution, inter-sexual selection and the evolution of sex, and to influence host and parasite population dynamics to test whether parental exposure to a novel antigen influenced the future humoral immune response of fully grown offspring. During September 2004, we vaccinated a sample of song sparrows with tetanus toxoid. Twelve months later, we tested whether baseline tetanus antibody titre or primary antibody response differed between fully grown offspring of vaccinated and unvaccinated parents. Our use of a novel antigen to assess humoral immunity allows us to distinguish long-term effects of parental vaccination from effects of subsequent natural parasite exposure on offspring immune response or released without vaccination (n=28). Approximately 40 further colour-ringed individuals were observed but not captured. Then, during September 2005, we measured baseline tetanus antibody titres and the primary antibody response to tetanus vaccination in adult song sparrows and their fully grown offspring that had hatched during 2005 . Briefly, sparrows were mist-netted, blood sampled, vaccinated with 70\u200a\u03bcl of tetanus toxoid and released. Individuals were recaptured and blood sampled ca 10 days later. Tetanus antibody titres in baseline and post-vaccination plasma samples were quantified by enzyme-linked immunosorbent assay. Tetanus response was estimated as the difference between post-vaccination and baseline antibody titres. Fieldwork was approved by the University of British Columbia Animal Care Committee.During September 2004, we mist-netted song sparrows on Mandarte as part of a wider study of individual variation in immune response. Captured individuals were vaccinated with 70\u200a\u03bcl of tetanus toxoid in the pectoral muscle and released (f), and the period between baseline and post-vaccination blood samples, since these variables influence tetanus response in song sparrows . Eleven mothers (of 21 offspring) and 10 fathers (of 19 offspring) had been vaccinated in 2004. Ten mothers (of 25 offspring) and 13 fathers (of 27 offspring) had not been vaccinated. Vaccinated and unvaccinated parents did not differ with respect to in 2005 .Across all 46 offspring, baseline antibody titres averaged 7.2\u00b10.7 units and did not differ between offspring whose parents had and had not been vaccinated the previous year . TetanusFicedula hypoleuca) chicks.Previous studies have demonstrated increased antibody titres in eggs or young chicks of parents exposed to specific immune challenges . In songParus major) exposed to nest parasites during laying produced offspring that were more likely to recruit locally , these patterns are not an artefact of selective vaccination-induced mortality in poor quality parents.Maternal antibody transfer may particularly benefit young offspring whose own immune systems have not yet developed, but has also been suggested to permanently alter offspring immune function , but it Such long-term consequences of maternal vaccination may represent direct, permanent effects of maternal antibody transfer on offspring immunology (Although substantial, the increased tetanus response in offspring of vaccinated mothers was considerably lower than the average secondary antibody response measured in 2005 in seven parents that had also been vaccinated in 2004 (4488\u00b1664 units, see also"} +{"text": "Three intraperitoneal human ovarian cancer xenografts were used to assess the antitumour activity of intraperitoneal therapy with liposome encapsulated MTP-PE. MTP-PE led to significant prolongation of survival in all three xenograft models, but with varying efficacy. In one tumour model (OS), 80% of mice were cured of tumour by twice weekly therapy for 4 weeks, whereas in another xenograft model (LA), the median survival time was approximately doubled compared to PBS injected and placebo liposome injected controls . The antitumor efficacy of MTP-PE did not correlate with the extent of peritoneal neutrophil infiltration after intraperitoneal therapy. Combined therapy with liposome encapsulated MTP-PE and recombinant murine granulocyte-macrophage colony stimulating factor led to increased survival of mice bearing the LA and HU xenografts, compared to tumour bearing mice treated with either agent singly."} +{"text": "When you're a single-celled organism at the bottom of the food chain, it pays to be resourceful. Diatoms, highly successful photosynthetic plankton responsible for 40% of the net primary production in the oceans, undergo seasonal population explosions called phytoplankton blooms that attract billions of krill, copepods, and other grazing predators. As a defense, wounded diatoms release aldehyde compounds that minimize future diatom casualties by compromising the hatching success of grazers. But these diatom-derived aldehydes can also kill diatoms.In a new study, Assaf Vardi, Chris Bowler, and their colleagues investigated the possibility that the contrasting effects of aldehydes reflect their role as \u201cinfochemicals\u201d that trigger different responses attuned to changing conditions in the diatoms' habitat. The authors found that different concentrations of aldehydes produce different diatom responses. At low doses, aldehydes induce resistance to the compound's toxic effects. High aldehyde concentrations, on the other hand, trigger cell death, which may lead to termination of a bloom. Thus, diatom-derived aldehydes regulate the population dynamics of both diatoms and their predators.Thalassiosira weissflogii is a ubiquitous, cosmopolitan species; Phaeodactylum tricornutum is a standard model for understanding diatom biology.To investigate aldehyde effects on diatom cell fate and population dynamics, the authors studied how two cultured diatom species responded to a highly reactive aldehyde called decadienal. Reactive compounds like decadienal are likely to generate a variety of potentially harmful molecules called reactive oxygen species (ROS). But the authors detected increased levels of just one ROS, nitric oxide, an unstable compound involved in a wide range of physiological processes. Monitoring nitric oxide levels with a nitric oxide\u2013sensitive fluorescent dye and time-lapse imaging revealed that both diatom species experienced similar bursts of nitric oxide production about five minutes after decadienal treatment.Treated cells succumbed to decadienal in a time- and dose-dependent manner, with significant increases in fatalities above a specific threshold. Below this threshold, cells survived, but underwent cell cycle arrest. To clarify nitric oxide's role in cell death, the authors stimulated nitric oxide production without using decadienal by using molecules called nitric oxide donors. Next, they pretreated cells with a nitric oxide inhibitor before exposing them to decadienal. The number of dying cells increased along with the levels of nitric oxide in the first experiments, and incidence of decadienal-related cell death decreased with the inhibitor. These results clearly implicate nitric oxide in cell death.P. tricornutum cells that express a calcium-sensitive bioluminescent protein, they tracked changes in intracellular calcium levels in response to aldehydes. As predicted, intracellular calcium levels spiked following decadienal exposure. None of the nitric oxide donors stimulated intracellular calcium production, suggesting that nitric oxide functions downstream of calcium. And, indeed, the nitric oxide synthase that produces nitric oxide was shown to be calcium-activated: after perceiving ambient aldehyde levels, the cell undergoes transient calcium increases that result in nitric oxide production.How does the cell stimulate nitric oxide production? Since plant and animal cells use calcium to perceive a wide range of environmental signals, Vardi et al. reasoned that diatoms might, too. Using Interestingly, nitric oxide production levels varied among the diatoms. Some cells showed rapid increases in nitric oxide production while their neighbors showed delayed responses, suggesting that the signal to produce nitric oxide was propagating through the diatom population. Healthy cells sensed the level of stressed cells in their midst by detecting the wounded cells' aldehyde-generated signal. Cells pretreated with a lower dose of decadienal before receiving a higher dose had far better survival and growth rates than cells treated with only a single high dose. These results suggest that lower decadienal doses may immunize cells, stimulating resistance to normally lethal aldehyde concentrations. This induced resistance may provide diatoms who escape grazing predators with a better chance of surviving the toxic aldehydes released by the dying diatoms.Altogether, these results suggest that decadienal-like aldehydes not only affect the reproductive capacity of grazers but also act as infochemicals that monitor stress levels in diatom populations. During phytoplankton blooms, this stress surveillance system can induce resistance or death. The authors propose that this differential response, regulated by the sophisticated use of intracellular calcium and nitric oxide signals, may determine the fitness and succession of phytoplankton communities.The finding that diatoms use chemical signaling for cell\u2013cell communication provides new insights into the cellular mechanisms mediating biotic interactions at the population level and challenges traditional concepts of phytoplankton bloom dynamics. With thousands of different diatom species potentially producing a diverse array of aldehydes, these reactive compounds may prove to be even more versatile than shown here\u2014and may be a key factor contributing to the ecological success of these organisms. Now researchers can begin to unravel the mechanisms that endow one group of molecules with the means to mediate such diverse responses."} +{"text": "We are pleased to see that our Essay has sparThere seems to be no disagreement with our main theses\u2014antidepressant advertisements do not accurately represent the evidence base from psychopharmacology, experimental psychiatry, and neuroscience; are not strictly based on the United States Food and Drug Administration (FDA)-approved prescribing label; and may mislead consumers.We believe many have bought into the serotonergic hypothesis of depression/generalized anxiety/social anxiety/obsessive-compulsive disorder/panic disorder/post-traumatic stress/bulimia/premenstrual dysphoric disorder largely because the serotonin reuptake inhibitor (SSRI) medications are licensed for these conditions. We reemphasize that pathophysiology cannot be established through clinical efficacy , yet thiAt the date of this letter, the advertising we presented in our Essay is still widespread, and quite visible on consumer advertising Web sites of SSRI manufacturers."} +{"text": "Chinese hamster ovary (CHO) cells were exposed in vitro to combinations of bleomycin and misonidazole under hypoxic conditions. Only one drug was present at any given time and cells were washed before being exposed to the second drug. Both drugs induced potentially lethal damage (PLD). This damage was repaired under hypoxic conditions very rapidly, and bleomycin-induced PLD was repaired more rapidly than misonidazole-induced PLD. If, after the combined treatment, cells are kept in hypoxia, much of the damage can be repaired."} +{"text": "Airway inflammation increases during acute exacerbations of COPD. Extrinsic factors, such as airway infections, increased air pollution, and intrinsic factors, such as increased oxidative stress and altered immunity may contribute to this increase. The evidence for this and the potential mechanisms by which various aetiological agents increase inflammation during COPD exacerbations is reviewed. The pathophysiologic consequences of increased airway inflammation during COPD exacerbations are also discussed. This review aims to establish a cause and effect relationship between etiological factors of increased airway inflammation and COPD exacerbations based on recently published data. Although it can be speculated that reducing inflammation may prevent and/or treat COPD exacerbations, the existing anti-inflammatory treatments are modestly effective. Exacerbations are a cardinal feature of the natural history of moderate and severe Chronic Obstructive Pulmonary Disease (COPD). PatientTreatment decisions for COPD patients are frequently made according to exacerbation rates. In the ATS/ERS guidelines it is stated that patients with frequent exacerbations should be initiated a trial of inhaled steroids. Systemiwhy inflammation is increased during COPD exacerbations. For practical purposes an attempt is made to categorize aetiological factors of increased inflammation into extrinsic or intrinsic, as it can be seen in table how increased inflammation is associated with the pathophysiology of COPD exacerbations.Although evidence for increased inflammation on COPD exacerbations has been reviewed previously, there has been little focus on why inflammation increases and which the consequences of this increase are,10. InveBacterial infections are generally considered to be the most common causes of COPD exacerbations. It is estimated that more than 40% of all exacerbations are of bacterial origin,11,12. AThe most common bacteria connected to COPD exacerbations are non-typable H. Influenzae, S. Pneumoniae, and M. Cattarhalis,11,12. TAirway bacteria initiate airway inflammation through several interconnecting mechanisms. The surface of bacteria allows the complement system to be activated through the alternative pathway, while specific surface molecules of the bacteria, called Pathogen-Associated Molecular Patterns (PAMPs), bind to pattern recognition receptors on a variety of leukocytes and initiate signalling pathways that lead to the activation of NF-\u03baB and production of proinflammatory cytokines. Once acA significant number of studies in stable COPD patients suggest that airway bacterial infections are associated with increased airway inflammation(18\u201321). Finding a relationship between bacteria and inflammation on stable COPD adds weight to the argument that bacteria may play a causative role in airway inflammation during COPD exacerbations.Soler et al used protected specimen brush and bronchoalveolar lavage sampling to determine inflammatory cell counts, levels of cytokines concentrations and microbial patterns in stable COPD patients and found that increased neutrophils and tumour necrosis factor-alpha levels may be related to bronchial colonization. IncreasA large prospective longitudinal study by Sethi et al addressed the hypothesis that patients with bacterial-positive exacerbations show increased inflammation compared to bacterial-negative exacerbations. Among HConsistent with these observations, airway inflammation can be decreased with treatment of the infection. Early evidence came from a relatively small study, which showed that neutrophilic mediators' levels may decrease after treatment of bacterial exacerbations. GompertIn conclusion, three major findings support the hypothesis that bacterial infections are actively implicated in the mechanisms of increased airway inflammation during COPD exacerbations: 1) bacterial infections increase airway inflammation in colonized stable COPD patients 2) bacterial-positive exacerbations show increased inflammation (particularly of neutrophilic type) compared to bacterial-negative exacerbations and 3) eradication of bacteria after a bacterial exacerbation is accompanied by a significant decrease in airway inflammation. A summary of these findings is presented in table Respiratory viruses are important triggers of COPD exacerbations. Initial studies using serology and cell cultures for detecting viral infections suggested that 30% of COPD exacerbations are related to viral infections -30. LatePossible mechanisms of viral-induced inflammation have been described. The airway epithelial cell is the principal host cell for most respiratory viruses. Viral rThere is convincing data that viruses induce inflammation in asthma. In animFurther to these observations, two recent studies showed that viral airway infections during COPD exacerbations are related to airway eosinophilia,40. ThisAtypical pathogens with potential importance in acute exacerbations include M. Pneumoniae, C. Pneumoniae and Legionella spp. Considerable confusion exists in the literature regarding the significance of these potential pathogens in acute exacerbations of COPD. This isin vivo studies on the effect of PM exposure on airway inflammation in COPD patients. There is also lack of information on airway inflammation during PM exposure induced COPD exacerbations, which may be due to difficulties in defining such exacerbations.Epidemiologists have linked ambient particulate air pollution (PM) exposure with exacerbations of pre-existing pulmonary diseases, such as COPD. PM-mediAn imbalance between oxidants and antioxidants may be involved in the development of COPD exacerbations. Almost a decade ago Rahman et al showed that plasma Trolox equivalent antioxidant capacity is decreased in patients presenting with acute exacerbation of COPD. Recent Oxidant stimuli induce cellular expression of inducible nitric oxide synthase and heme-oxygenase-1(HO-1) and increase nitrotyrosine formation. We have shown that there is increased HO-1 expression and nitrotyrosine formation in the airways of COPD patients during severe exacerbations relatively to stable state and that this is accompanied by an increase in indices of neutrophilic inflammation, i.e. neutrophil numbers, MPO and IL-8 levels. EvidencOxidative stress induces the transcription of various inflammatory factors, such as nuclear factor-kappaB (NF-\u03baB) and activator protein-1 (AP-1). It has Activated neutrophils and other inflammatory cells can in turn release reactive oxygen species and increase airway oxidative stress. Because oxidative stress can induce inflammation and vice versa, it is not clear which of the two, oxidative stress or inflammation, is primarily involved in the mechanisms of COPD exacerbations-[the chicken and egg problem].Alterations in innate and adaptive immunity are implicated in COPD pathogenesis. EvidencAccording to our observations changes in lymphocyte subpopulations occur during severe COPD exacerbations. In specAlthough Saetta et al also found increased T cell numbers in endobronchial biopsies from chronic bronchitis patients on mild exacerbations, no difference was detected in CD4 or CD8+ve cell numbers. This diIt would be logical to assume that small increases in airway inflammation in patients with already increased baseline levels of inflammation can easily trigger a COPD exacerbation. This presumes the existence of an inflammatory threshold, above which exacerbation occurs. In relation to this hypothesis, Bhowmik et al showed that COPD patients with frequent exacerbations (\u2265 3 episodes/year) have increased baseline sputum IL-6 and IL-8 levels. HoweverOn the contrary, Gombertz et al did not detect any difference in neutrophilic mediators (including IL-8) between frequent (\u2265 3 episodes/year) and infrequent exacerbators. InteresIn conclusion, data relating baseline airway inflammation to exacerbation frequency are rather controversial. Part of the existing confusion may be due to significant heterogeneity among COPD patients and to the existence of several factors, like bacterial colonization and bronchiectasis that may increase airway inflammation. In particular, COPD patients with bronchiectasis may represent a distinct group characterized by higher rates of bacterial colonization, increased baseline levels of airway inflammation and longer symptom recovery times at exacerbation.Episodes of COPD exacerbations are characterized by an acute increase in a patient's baseline dyspnoea, cough and/or sputum production. Severe Increased airway inflammation induces many pathologic changes on the airways. Accumulation of inflammatory cells in the airway mucosa by itself causes airway wall thickening. Inflammatory cells can release potentially harmful mediators, such as proteases and reactive oxygen species. NeutropA brief summary of the pathophysiologic events that may link airway inflammation to the symptoms of COPD exacerbations and to respiratory failure is given in figure Increased airway inflammation would be also expected to increase lung tissue oxygen demand and oxygen consumption. In patients with acute lung injury no relation has been found between pulmonary oxygen consumption and lung inflammation, but there is no relevant data in COPD exacerbations.Despite the increasing recognition of the importance of airway inflammation in the development of COPD exacerbations, there is still confusion regarding the role of anti-inflammatory strategies in the prevention and treatment of COPD exacerbations,94. TherOther drugs with anti-inflammatory properties, like methylxanthines and mucolytic agents seem not to be effective on COPD exacerbations. B-agoniIt has been long postulated that airway inflammation may be increased during COPD exacerbations and this may be involved in the pathophysiology of exacerbations. There is now sufficient data to support such a hypothesis. Firstly, there are accumulating observations for increased inflammation during COPD exacerbations. Secondly, specific aetiological factors for this increase have been identified. Thirdly, possible mechanisms that may link airway inflammation with the pathophysiology of exacerbations have been unmasked. Despite significant advances in our understanding of the role of inflammation in COPD exacerbations, the existing anti-inflammatory treatments remain modest and there is little overall benefit for the patient. Further research is needed to target therapies to the appropriate patient populations and to develop new therapeutic strategies.The author(s) declare that they have no competing interests."} +{"text": "Site of first recurrence, disease-free interval (DFI), female sex steroid receptors, ploidy measurements as well as histological grading have been analysed as potentially valuable predictive factors in 313 cases of recurrent breast cancer. Univariate and multivariate analyses show histological grading, site of recurrence and disease free interval to be useful prognostic variables when assessing prognosis once disease has recurred. High concentrations of oestrogen receptors (ER) were found in patients with bone metastases, whereas lower concentrations of ER were related to visceral recurrences. Ploidy measurements failed in this study to give any predictive information once disease recurred."} +{"text": "Internationally there is a 4-fold variation in age-adjusted incidence rates for childhood leukaemia , with only slightly greater worldwide differences specifically for acute lymphocytic leukaemia (ALL) and for acute nonlymphocytic leukaemia (ANLL). Total leukaemia rates are highest among Hispanic populations in Costa Rica and Los Angeles , due primarily to elevated ALL incidence, while low rates occur among US blacks, Kuwaitis, Israeli non-Jews, and Bombay Indians. In most populations the patterns for ALL are similar to those for total leukaema, with peak incidence at ages 1-4 and a decline thereafter. Lower and more uniform rates are generally observed at all ages for ANLL. Age-adjusted rates for ANLL appear to vary substantially among some populations with uniform ALL incidence rates and yet appear to be similar in other populations with variation in ALL rates . Possible variation among registries in completeness of childhood leukaemia ascertainment and accuracy of diagnosis by cell type should be assessed, while case-control investigations among populations with very high and very low rates may provide useful information about the cell-type specific determinants of childhood leukaemia."} +{"text": "Giardia lamblia has been intensively studied. We have performed a sequence survey project resulting in 2341 expressed sequence tags (EST) corresponding to 853 unique clones, 5275 genome survey sequences (GSS), and eleven finished contigs from the diplomonad fish parasite Spironucleus salmonicida (previously described as S. barkhanus).Comparative genomic studies of the mitochondrion-lacking protist group Diplomonadida (diplomonads) has been lacking, although S. salmonicida from its human parasitic relative G. lamblia were identified such as nineteen putative lineage-specific gene acquisitions, distinct mutational biases and codon usage and distinct polyadenylation signals.The analyses revealed a compact genome with few, if any, introns and very short 3' untranslated regions. Strikingly different patterns of codon usage were observed in genes corresponding to frequently sampled ESTs versus genes poorly sampled, indicating that translational selection is influencing the codon usage of highly expressed genes. Rigorous phylogenomic analyses identified 84 genes \u2013 mostly encoding metabolic proteins \u2013 that have been acquired by diplomonads or their relatively close ancestors via lateral gene transfer (LGT). Although most acquisitions were from prokaryotes, more than a dozen represent likely transfers of genes between eukaryotic lineages. Many genes that provide novel insights into the genetic basis of the biology and pathogenicity of this parasitic protist were identified including 149 that putatively encode variant-surface cysteine-rich proteins which are candidate virulence factors. A number of genomic properties that distinguish Our results highlight the power of comparative genomic studies to yield insights into the biology of parasitic protists and the evolution of their genomes, and suggest that genetic exchange between distantly-related protist lineages may be occurring at an appreciable rate in eukaryote genome evolution. Giardia lamblia , which is a major cause of water-borne enteric disease in humans in both industrialised and developing countries .The sequences reported here were deposited in GenBank at the National Center for Biotechnology Information [Genbank:JOA co-constructed the second GSS library, finished the sequence of seven contigs, carried out the EST and GSS assemblies, all phylogenetic and most bioinformatic analyses, and drafted and coordinated the editing of the manuscript. \u00c5MS co-constructed the second GSS library, carried out the majority of the GSS sequencing, and performed initial bioinformatic analyses. DSH grew the organism, purified nucleic acids, constructed the EST library, and carried out some of the initial EST sequencing. CAM constructed the lambda and the initial GSS libraries, carried out the majority of the EST sequencing, the initial GSS sequencing and the sequencing and assembly of three lambda clones. PLD carried out some of the initial EST sequencing. SGS provided advice on the analyses of molecular biological aspects and drafted these parts of the manuscript. RPH performed part of the analyses of cysteine rich and putative mitosomal proteins. JML, MAR, RPH, and AJR co-initiated and supervised the project in their respective laboratories, provided advice on the analyses and edited the manuscript. All authors read and approved the final manuscript.A table showing the characteristics of the finished contigs.Click here for fileComplete list of gene annotations.Click here for fileA table showing the genes putatively involved in LGT events.Click here for filePhylogenetic trees 1\u201325 for genes putatively involved in LGT events and listed in Additional file 3.Click here for filePhylogenetic trees 26\u201350 for genes putatively involved in LGT events and listed in Additional file 3.Click here for filePhylogenetic trees 51\u201372 for genes putatively involved in LGT events and listed in Additional file 3.Click here for file"} +{"text": "A world first pineapple EST sequencing program has been undertaken to investigate genes expressed during non-climacteric fruit ripening and the nematode-plant interaction during root infection. Very little is known of how non-climacteric fruit ripening is controlled or of the molecular basis of the nematode-plant interaction. PineappleDB was developed to provide the research community with access to a curated bioinformatics resource housing the fruit, root and nematode infected gall expressed sequences.Arabidopsis homologues, both MIPS based and Gene Ontology functional classifications, and clone distributions. The online resource can be searched by text or by BLAST sequence homology. The data outputs provide comprehensive sequence, bioinformatic and functional classification information.PineappleDB is an online, curated database providing integrated access to annotated expressed sequence tag (EST) data for cDNA clones isolated from pineapple fruit, root, and nematode infected root gall vascular cylinder tissues. The database currently houses over 5600 EST sequences, 3383 contig consensus sequences, and associated bioinformatic data including splice variants, The online pineapple bioinformatic resource provides the research community with access to pineapple fruit and root/gall sequence and bioinformatic data in a user-friendly format. The search tools enable efficient data mining and present a wide spectrum of bioinformatic and functional classification information. PineappleDB will be of broad appeal to researchers investigating pineapple genetics, non-climacteric fruit ripening, root-knot nematode infection, crassulacean acid metabolism and alternative RNA splicing in plants. Ananas comosus (L.) Merrill] is the third most important tropical fruit after banana and mango. Pineapple fruits are classified as non-climacteric, as there is no respiratory burst or spike in ethylene production during ripening and exogenous application of ethylene does not rapidly accelerate fruit ripening. Much has been learnt about the control of fruit ripening in climacteric fruit using tomato as a model system. In particular, manipulation of genes involved in the ethylene biosynthetic pathway and a MADS box transcription factor have led to altered ripening characteristics . Those cContig consensus sequences containing a polyA tail were analyzed for open-reading frames using EditSeq sequence analysis software and were BLASTX searched against the GenBank nr protein database . Contig Edited clone sequences generally assembled into contigs with 97\u2013100% homology. However, the contig assembly report occasionally revealed incidences where some clones clustered with between 90\u201397% homology or that some clones did not cluster into existing contigs due to homology somewhat below the 90% threshold. An inspection of these clone sequences and contigs revealed the presence of apparently unspliced intron sequence, and/or the absence of exon sequence in some of the clones. A comparative analysis to other clone sequences within the contig alignment and to homologous protein coding sequences in GenBank verified that 120 clones contain an apparent \"mis-splicing\" event. The putative splice variant clones containing un-spliced intron sequence and/or missing spliced exon sequence are listed in the pineapple bioinformatic resource. The presence or absence of a putative splice variant is also reported in contig/clone search outputs.Despite precautions to remove nematodes from root tissues prior to library construction, it was anticipated that there would be some contamination of the pineapple gall libraries with nematode derived sequences. All contig consensus sequences containing root and gall EST's were BLASTN searched against the GenBank dbEST and BLASTX searched against the GenBank nr database. Matches to known nematode sequences were manually inspected and 77 contigs identified as containing a putative nematode sequence. All contigs containing putative nematode sequence are listed within the online pineapple bioinformatic resource.Arabidopsis thaliana.The pineapple EST sequencing project was initiated as a first step toward identifying genes involved in and the molecular basis of non-climacteric fruit ripening and the nematode-plant interaction. The online pineapple bioinformatics resource was developed to house EST sequence information and associated bioinformatic data in a user-friendly format. PineappleDB can be freely accessed via the internet, and currently contains BLAST and text search tools to efficiently mine the dataset for clones and contigs of interest. The resulting search outputs contain comprehensive information on the clone and contigs including cloneID, contig number, number of clones in each contig, nearest BLASTX match, accession number of match, length of match, percent similarity, putative annotation, splice variants, MIPS based functional classifications, Gene Ontology classifications, and the distribution of clones from each library fig. . Links aPineappleDB houses the first reported collection of EST sequences isolated from pineapple. PineappleDB will grow as more EST sequence information becomes available. Furthermore, we have initiated a pineapple microarray project and it is anticipated that gene expression data will be incorporated into the online pineapple bioinformatics resource in the future. The EST database will periodically be upgraded as annotation, functional classification, and gene ontology information is updated.The PineappleDB resource can be accessed via j.botella@uq.edu.auContact: Dr. Jos\u00e9 R Botella at *The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint first authors. RM was responsible for data collection, the bioinformatic pipeline and manuscript preparation. MC developed the online database and undertook batch BLAST processes. JR-K contributed to the fruit EST editing and identification of full length coding sequences. DJF participated in the conception, design and co-ordination of the study and helped complete the manuscript. JRB designed, supervised and coordinated the project."} +{"text": "Foetal acinar components associated with the development of the hamster pancreas have been previously defined with the aid of an antifoetal pancreas serum. In immunohistology this antiserum also stained malignant ductal cells in N-nitrobis (2-oxopropyl) amine (BOP)-induced pancreatic adenocarcinoma. It did not stain adult pancreas structures including acini, ducts and islets of Langerhans. In this study, re-expression of foetal acinar antigens was disclosed before formation of tumours. Adenocarcinomas were not detected by conventional histology before the 24th week following initiation of the chemical treatment. However, staining with the antiserum was observed from the 7th week appearing in the apex of some acini cells having an almost normal histological appearance. Later, foetal acinar expression was frequently associated with evident morphological alterations in acini like dyskaryosis, enlarged cytoplasm or lumina. Staining of ducts with marked atypical epithelium and of neoplastic ducts was also observed. It was not detected in other pancreatic lesions viz. cystadenomas, mucoid glands and regular hyperplastic ducts. Acinar dedifferentiation as assessed by expression of foetal components preceded formation of tumours in all instances."} +{"text": "The occurrence of different intercellular junctions in epithelial rat skin tumours induced by methylcholanthrene was investigated using thin sections and freeze-fracture replicas examined by electron microscopy. Tumours which appeared first were basal cell carcinomas. Later, different tumours of hair follicle and of sebaceous gland origin were formed. Finally, in the majority of tumours a squamous component evolved. Metastases developed from the squamous carcinomas exclusively. Desmosomes and gap junctions were detected in basal cell carcinomas whereas, in squamous carcinomas, tight junctions were also seen. While all three types of junction were found in the primary squamous tumours, the tumour metastases in lymph nodes and lungs contained only desmosomes."} +{"text": "A monoclonal antibody, H317, has been used for the sensitive and specific detection of placental-type alkaline phosphatase (PLAP) in sera, solubilized tissue extracts and fixed tumour tissue sections from patients representing a variety of ovarian tumours. PLAP was detected in over 30% of these sera and in most solubilized tumour tissue extracts. There was no association between circulating PLAP levels and either tissue extract levels or immunohistological staining of ovarian tumour tissue sections with H317. Nevertheless, immunohistology demonstrated the heterogeneity of cellular localization of PLAP within different tumours, and can often be of value in localizing tumour tissue."} +{"text": "Numbers of intestinal goblet cells containing specific acid mucins were determined in male Sprague-Dawley rats receiving azoxymethane with or without jejunoileal bypass (JIB). Controls had injections of vehicle and sham bypass. Thirty weeks postoperatively colorectal length and crypt depth were increased by azoxymethane and further increased by JIB. JIB doubled the yield of intestinal tumours (P less than 0.01). Goblet cells containing sulphomucins normally predominated throughout the intestinal tract. Contents of sulphomucins and especially sialomucins were consistently higher in the small bowel and colon of rats receiving azoxymethane alone, but again the highest values were observed in animals with azoxymethane plus JIB. Both small-bowel bypass and azoxymethane stimulate adaptive growth of the colon and small bowel remaining in circuit. Goblet-cell hyperplasia is a feature of this response, and sialomucins are preferentially secreted by the adapting epithelium."} +{"text": "It is suggested that most childhood acute lymphoblastic leukaemias and some other paediatric cancers are chemo-curable because they arise in stem cell populations that are functionally transient, chemosensitive and programmed for apoptosis. Most adult acute leukaemias are chemo-incurable at least in part because they originate in relatively drug resistant stem cells with extensive self-renewal capacity. The latter property in turn increases the probability of clones evolving with multi-drug resistance. Particular mutations may superimpose additional adverse features on leukaemic cells."} +{"text": "In plants, tandem, segmental and whole-genome duplications are prevalent, resulting in large numbers of duplicate loci. Recent studies suggest that duplicate genes diverge predominantly through the partitioning of expression and that breadth of gene expression is related to the rate of gene duplication and protein sequence evolution.Arabidopsis, there are 53 MST genes that form seven distinct subfamilies. We created profile hidden Markov models of each subfamily and searched EST databases representing diverse land plant lineages to address the following questions: 1) Are homologs of each Arabidopsis subfamily present in the earliest land plants? 2) Do expression patterns among subfamilies and individual genes within subfamilies differ across lineages? 3) Has gene duplication within each lineage resulted in lineage-specific expansion patterns? We also looked for correlations between relative EST database representation in Arabidopsis and similarity to orthologs in early lineages.Here, we utilize expressed sequence tag (EST) data to study gene duplication and expression patterns in the monosaccharide transporter (MST) gene family across the land plants. In Arabidopsis, one or a few genes within most subfamilies have much higher EST database representation than others. Most highly represented (broadly expressed) genes in Arabidopsis have best match orthologs in early divergent lineages.Homologs of all seven MST subfamilies were present in land plants at least 400 million years ago. Subfamily expression levels vary across lineages with greater relative expression of the STP, ERD6-like, INT and PLT subfamilies in the vascular plants. In the large EST databases of the moss, gymnosperm, monocot and eudicot lineages, EST contig construction reveals that MST subfamilies have experienced lineage-specific expansions. Large subfamily expansions appear to be due to multiple gene duplications arising from single ancestral genes. In Arabidopsis MST gene family are ancient in land plants and show differential subfamily expression and lineage-specific subfamily expansions. Patterns of gene expression in Arabidopsis and correlation of highly represented genes with best match homologs in early lineages suggests that broadly expressed genes are often highly conserved, and that most genes have more limited expression.The seven subfamilies of the Large proportions of genes within genomes are members of hierarchical gene families and superfamilies. Gene families appear to evolve through a combination of tandem, segmental and whole genome duplication (polyploidy) events. A number of researchers in the first half of the twentieth century observed relationships between chromosome duplications and morphological variation . In 1970More recent theoretical and empirical work suggests that gene duplicates are retained more frequently than the classical model permits and that new function or expression arises through the processes of neo- and subfunctionalization ,6. In suPlant genomes contain large fractions of duplicate loci due to the frequent occurrence of segmental duplications and polyploidy events. Following a polyploidy event, there is a rapid loss of duplicate loci in the transition to functional diploidy and the remaining duplicate loci undergo rapid functional divergence . Recent +-sugar symporters localized in the plasma membrane (see references below).In this study, we investigate the monosaccharide transporter (MST) gene family in land plants. MSTs are found in all three domains of life, have fundamental importance in carbohydrate flux and are highly conserved across lineages. All MST proteins are characterized by 12 hydrophobic membrane-spanning domains separated by interconnecting cytoplasmic and extracellular loops, with cytoplasmic N- and C-terminal domains . This hiArabidopsis thaliana genome reveals 53 MST genes that cluster into seven subfamilies on phylogenetic analysis and whisk ferns (Psilotaceae) that form a monophyletic group which is sister to the seed plants . Text file output from the Click here for filehmmbuild component of the HMMer software package.Profile HMMs for each MST subfamily . Text file output from the Click here for filehmmbuild component of the HMMer software package.Profile HMMs for each MST subfamily . Text file output from the Click here for filehmmbuild component of the HMMer software package.Profile HMMs for each MST subfamily . Text file output from the Click here for filehmmbuild component of the HMMer software package.Profile HMMs for each MST subfamily . Text file output from the Click here for filehmmbuild component of the HMMer software package.Profile HMMs for each MST subfamily . Text file output from the Click here for filehmmbuild component of the HMMer software package.Profile HMMs for each MST subfamily . Text file output from the Click here for fileAlignment of MST subfamily profile HMM consensus sequences. Multiple sequence alignment of consensus sequences generated from profile HMMs for each of the seven MST subfamilies. Sequences were aligned using the ClustalW option in the AlignX component of the VectorNTI package. Amino acid residues highlighted in yellow indicate 100% identity across sequences.Click here for fileArabidopsis thaliana EST database.Summary of identified MST ESTs in Click here for fileMarchantia polymorpha, Selaginella lepidophylla, Ceratopteris richardii).Summary of identified MST ESTs in small databases (Click here for filePhyscometrella patens and Physcomitrella patens subsp. patens EST databases.Summary of identified MST ESTs in Click here for filePinus taeda EST database.Summary of identified MST ESTs in Click here for fileZea mays EST databaseSummary of identified MST ESTs in Click here for fileLycopersicon esculentum EST databaseSummary of identified MST ESTs in Click here for file"} +{"text": "PCR-based microsatellite polymorphisms have proved their power in genetic linkage analysis and other identification methods, due to their high information content and even distribution over the chromosomes. In the present study we applied microsatellite polymorphisms to detect loss of heterozygosity in fresh (snap-frozen) and in archival ovarian tumour tissue. Clear allele losses were found in fresh and paraffin embedded tumour samples. Conventional Southern analysis of flanking markers on the same tumour DNA samples confirmed the observed losses detected by microsatellite polymorphisms. Titration experiments suggest that loss of heterozygosity remains detectable in tumour samples despite 60% contamination with normal DNA. This technique provides a fast and reproducible alternative to conventional Southern blotting in the detection of loss of heterozygosity, with the crucial additional advantages of minimal sample requirements, making archival material available for genetic investigation."} +{"text": "Human colon adenocarcinoma cells (LoVo) resistant to the new antitumor agent FCE 24517 [benzoyl-mustard derivative of distamycin A] (LoVo/24517) are resistant to the selecting agent and related molecules as well as to vinblastine, with marginal or no resistance to other antitumour drugs. Treatment with verapamil, tamoxifen, nicergoline or cyclosporin A only partially restores the activity of FCE 24517 against LoVo/24517 cells. Such results suggest that resistance mechanisms possible specific for this class of compounds are operating."} +{"text": "From 1,211 breast cancers, 15 oestrogen receptor (ER) negative-progesterone receptor (PgR) positive breast cancers by conventional dextran coated charcoal steroid binding assays in cytosol were reassessed using Elisa techniques with monoclonal antireceptors antibodies in the cytosolic and nuclear fractions, and immunocytochemistry on cryostat sections. Three categories of results were found in this series. Two tumours were false negative ER due to receptor sites occupancy by hormonal contraceptive treatment. A second group of ten tumours, with high PgR concentrations and immunoreactive ER, corresponds to non ER-binding forms of receptors. One PgR positive tumour was found to be devoid of PgR by using monoclonal antiPgR antibodies might contain a progesterone binding cyst protein. Only two tumours were found to be true ER negative-PgR positive by all methods. This rare phenotype deserves further study of the regulation of the PgR gene."} +{"text": "The metastatic sites of infiltrating duct (IDC) and infiltrating lobular carcinoma (ILC) have been compared using both clinical and autopsy data. The following statistically significant differences were found: Lung parenchymal metastases were more common in IDC. Bone trephine biopsies were more likely to be positive in ILC. Carcinomatous meningitis was associated almost exclusively with ILC. Peritoneal/retroperitoneal metastases of distinctive pattern occurred in ILC. There was often associated linitis plastica-like involvement of the stomach wall and diffuse infiltration of the uterus. Hydronephrosis was a common secondary phenomenon."} +{"text": "Mutagenicity and cytotoxicity are basic cellular effects of cigarette smoke which underlie the development of lung cancer and chronic obstructive airways disease. This study reports that, on a weight-for-weight basis, cigarette smoke condensates from low, middle and high tar cigarettes produce similar mutagenic effects detected by induced sister chromatid exchanges and similar cytotoxic effects detected by vital dye exclusion in human leucocytes. These findings, taken with the strong evidence that smokers extract more smoke from lower tar cigarettes to compensate for low nicotine yields, suggest that the health dangers associated with smoking these \"safer\" products are underestimated."} +{"text": "Mexipyrgus churinceanus) and a molluscivorous cichlid (Herichthys minckleyi), we examined three components of this interaction: 1) spatial variation in two putative defensive traits, crushing resistance and shell pigmentation; 2) whether abiotic variables or frequency of molariform cichlids are associated with spatial patterns of crushing resistance and shell pigmentation and 3) whether variation in primary productivity accounted for small-scale variation in these defensive traits.Recent models suggest that escalating reciprocal selection among antagonistically interacting species is predicted to occur in areas of higher resource productivity. In a putatively coevolved interaction between a freshwater snail and snail defensive traits. However, crushing resistance and frequency of pigmented shells were negatively correlated with molariform frequency. Crushing resistance and levels of pigmentation were significantly higher in habitats dominated by aquatic macrophytes, and both traits are phenotypically correlated.M. churinceanus exhibit striking variation at small spatial scales often associated with differences in primary productivity, substrate coloration and the frequency of molariform cichlids. These local geographic differences may result from among-habitat variation in how resource productivity interacts to promote escalation in prey defenses.Crushing resistance and pigmentation of Mexipyrgus churinceanus.Spatial variation in defensive traits is common in many antagonistic interactions -3. The gMexipyrgus churinceanus as well as its polymorphic fish predator Herichthys minckleyi are endemic to the isolated Cuatro Ci\u00e9negas valley in the Mexican Chihuahuan desert . Increased resource availability probably allows greater investment in costly shell material, leading to the prediction that hotspots may occur in areas with greater food resources for snails.Alternatively, variation in shell strength might be primarily a response to biotic influences. We address whether spatial variation in snail defenses is associated with two biotic factors: molariform frequency and resource productivity. If molariform H. minckleyi, and this divergence occurs at very small spatial scales in a geographically mosaic fashion, we predict there will be no significant positive autocorrelation at small spatial and genetic distances. In the current study, we determine genetic distances between snail populations from a previously published study of mtDNA sequence variation in Mexipyrgus [A critical assumption of these population-based measures of phenotypic divergence is that they are statistically independent. This assumption may be violated because nearby snail populations may experience similar predation pressure because cichlids are more mobile than these brooding snails. To address this issue we assess whether the similarity of shell defensive traits among nearby populations can be attributed to either geographic proximity or genetic similarity -25. Genexipyrgus .Mexipyrgus. First, we examine spatial variation in two putative defensive traits, crushing resistance and shell pigmentation. Then, we tested whether abiotic or biotic variables account for spatial patterns of crushing resistance and shell pigmentation. Finally, we determine whether variation in primary productivity accounts for small-scale variation in these defensive traits.We address three questions concerning the evolution of defenses in 2 = 43.9%, p < 0.0001), whereas shell shape explained little variation in crushing resistance . We next used analysis of covariance to examine the effect of population on crushing resistance using size as a covariate. The interaction term (shell size by population) was not significant (p = 0.24), and there was a highly significant effect of population on size-adjusted crushing resistance . There was considerable spatial variation in size-adjusted crushing resistance, ranging from 42.3 Newtons in a Rio Mesquites population to 92.3 Newtons in a Tierra Blanca population , indicating the absence of autocorrelation among populations at any scale.Mean and standard errors of crushing resistance and shell size are presented in Table ion Fig. . The cor2 = 310.7, n = 19, p < 0.001). The correlograms of pigmentation frequency and all distance measures were not significant (see figure b distance classes), again indicating the absence of autocorrelation among populations at any scale.There was considerable variation in the frequency of pigmentation among populations Fig. and therp = 0.19) or conductivity . Similarly, there was no significant correlation between pigmentation frequency and temperature or conductivity . In contrast, there were significant negative correlations between molariform frequency and both size-adjusted crushing resistance .There was no significant correlation between size-adjusted crushing and temperature , crushing resistance was higher where Nymphaea was abundant . Similarly, RM1 had significantly higher crushing resistance than nearby RM3 . The Los Remojos populations did not differ significantly in size-adjusted crushing resistance . In the paired adjacent populations, the frequency of pigmented shells was significantly higher in darker versus lighter substrates in all 3 comparisons: Rio Mesquites 1 and 3 ; Los Remojos N and S ; and Tio Candido N and S .In the two of the three paired adjacent populations that differ in t Figure . For exaMexipyrgus churinceanus in Cuatro Ci\u00e9negas and the presence of the molariform cichlids are suggestive of coevolutionary selection [Pronounced geographic differences in prey defenses are probably common ,27. Whilelection ,15, the Mexipyrgus churinceanus requires an assessment of phenotypic variation and the spatial autocorrelation of these traits among populations at small genetic and geographic distances. There is significant spatial variation in M. churinceanus crushing resistance and pigmentation at small spatial scales suggesting that certain factors may cause this mosaic distribution of snail defensive traits. In paired populations separated by very small linear and genetic distances, elevated crushing resistance occurs in habitats containing extensive Nymphaea stands. Crushing resistance is dramatically lower in light colored substrates lacking Nymphaea. Because Tio Candido and Rio Mesquites populations represent distinct lineages based on mtDNA sequence differentiation [Mexipyrgus feeds extensively . Increased resource availability likely allows greater investment in costly shell material, and experiments that manipulate resource availability to test its effect on Mexipyrgus shell strength would provide a further test of this hypothesis.To address whether prey defenses have evolved independently across the geographic range of ntiation , it suggCamellia host plant indicate that escalation in armaments only occurred in southern latitudes [Mexipyrgus is the result of coevolutionary interactions between endemic snails and the molluscivorous morph of H. minckleyi [Nymphaea habitats, increased snail crushing resistance may reduce molariform fitness due to increased costs of crushing, while papilliform fitness is higher due to increased availability of plant material for shredding. We plan to experimentally test whether these alternative cichlid morphs have fitness trade-offs in different resource environments, and more quantitatively measure resources available to Mexipyrgus.Although there is considerable documentation of hotspots and coldspots in coevolved antagonistic interactions, how spatial processes and community composition promote coevolution and generate selection mosaics has received less attention. A recent study of herbivorous weevils and their atitudes . More noinckleyi . SurprisMexipyrgus shell pigmentation is also associated with different substrate coloration and there is no evidence of genetic or spatial autocorrelation among populations. In the three geographically-paired populations, snails with pigmented bands were significantly more common in Nymphaea habitats and unbanded snails were more common where the benthic substrate was light and marled- colored. Unbanded snails are probably more cryptic against lighter benthic substrates and banded snails are more cryptic against the darker substrates found in association with Nymphaea. This type of background matching by prey under selection from highly visual predators is common in many organisms [Microspatial variation in rganisms -30 and eNymphaea is absent, investment in crushing resistance may be constrained due to resource limitation, so that crypsis is the most effective defense against molariform predation. We suspect that investment in shell pigmentation is not as costly as having more robust shells, and that snails are capable of inexpensively modifying their pigmentation in Nymphaea habitats to increase crypsis. Whether correlational selection acts on pigmentation patterns and shell strength in these habitats requires a deeper understanding of the phenotypic plasticity in both traits. One hypothesis is that increased pigmentation in these environments does not increase background matching, and pigmentation only increases due to correlational selection on crushing resistance. This hypothesis could be easily refuted if predation success on banded shells is less in Nymphaea habitats. Given evidence for inducible defenses in snails [The positive relationship between the two snail traits across environments suggest that pigmentation and crushing resistance may represent phenotypically-correlated traits. In resource-poor environments where n snails -33, we aH. minckleyi undoubtedly use their jaws to crush snails, Cuatro Ci\u00e9negas may represent an ideal system for investigating mosaic predator-prey coevolution. In future studies, we plan to examine local adaptation of molariforms, escalation of molariform traits in resource rich environments, and heritability and phenotypic plasticity of both crushing resistance and pigmentation across resource gradients.Spatial variation in two prey defense traits, crushing resistance and shell pigmentation, exhibits striking variation at small spatial scales often associated with habitat differences in primary productivity and substrate coloration. These local geographic differences may result from among-habitat variation in how resource productivity interacts to promote escalation in prey defenses. Because molariform Mexipyrgus churinceanus from various drainages throughout the entire Cuatro Ci\u00e9negas basin , and whether these correlations change as a function of geographic and/or genetic distance. Under the spatial mosaic hypothesis, we predicted no positive autocorrelations of geographically-adjacent or genetically-similar populations. We estimated Moran's I using Passage . Moran'sariation using a To assess the potential influence of abiotic factors on shell strength, we measured temperature and conductivity in the 19 populations . Conductivity measures were temperature compensated. Above ground flow connects a few of the populations examined here, but the abiotic factors of each are influenced by large discharge from separate isothermal springs . Therefoet al [To estimate the relationship between frequency of molariforms and both size-adjusted crushing resistance and frequency of pigmented shells, the frequency of molariforms in ten populations was obtained from two sources. The frequency in Mojarral Oeste, North Tio Candido, Tio Candido, Los Remojos Negro, and Los Remojos Blanco was estimated in 2001 by Kloeppel , and waset al . Fish weNymphaea is associated with variation in snail crushing resistance and pigmentation, we compared the crushing resistance and frequency of banded snails (Log likelihood tests) in three pairs of adjacent populations in the Rio Mesquites, Los Remojos, and Tio Candido. These paired populations are in very close proximity to one another . In these paired populations, substrate coloration differed dramatically due to the presence or absence of Nymphaea beds. We also examined the phenotypic correlation between mean population estimates of the number of bands and crushing resistance. We conducted all statistical analyses in SPSS [To address whether the presence or absence of in SPSS .All authors conceived the study and participated in its design and conducted field work. SGJ performed statistical analysis and drafted the manuscript. CDH and FJGL helped with revisions of the manuscript. All authors read and approved the final manuscript."} +{"text": "As animal extinctions continue at the rate of one every 16 years, it's unclear how declining biodiversity will disturb ecosystem dynamics. Of special concern are the pollinators, essential players in the reproductive biology of plants, the earth's primary producers. Millions of years of evolutionary coadaptations lie behind the perfect pairing of pollinator proboscis anatomy with plant flower structure, as well as the mechanisms plants use to attract reproductive assistants to their food rewards. Agave plants emit musky aromas that attract lesser long-nosed bats to nectar stores within their flowers, for example. As the bats travel from flower to flower, pollen collects and then falls from their fur, facilitating cross-pollination.These mutually beneficial relationships are sometimes so specialized that the loss of one species threatens the existence of the other, raising troubling questions about the likely consequences of declining diversity in pollination networks. In a new study, Colin Fontaine et al. tackled this question by experimentally manipulating plant and pollinator interactions under natural conditions. The authors found strong functional relationships between different pollinators and plant communities, with the highest plant community sustainability associated with the most diverse group of pollinators. These findings suggest that loss of biodiversity in pollination networks may threaten the persistence of plant communities.For their study, the authors chose plants with easy and harder access to food rewards\u2014three open-flower and three tubular-flower species\u2014and insects with short and longer mouthparts\u2014three syrphid fly and three bumblebee species. In the spring of 2003, Fontaine et al. set up 36 plant communities in nylon-mesh enclosures in a meadow 80 kilometers (about 50 miles) southwest of Paris, after sterilizing the soil to destroy seeds and pathogens. They planted 30 adult plants in each plot at the same density, and then captured and released local pollinators into the cages during the flowering season . To test all the possible plant\u2013pollinator combinations, the authors set up three plant treatments , then applied three pollination treatments to each plant treatment.A month after the first pollination treatments, the authors tallied all the fruit on each plant, then randomly selected five fruits per plant (excepting one plant species from each group that would have required harvesting the fruit) to estimate seed production per plant. During the seedling season, they totaled the plants and the seedlings to measure plant population and reproductive success. Pollinator identity determined fruit production, with bee-pollinated plants most productive, and the different plant groups responded differently to the two pollinator groups. As expected, short-mouthed syrphid flies pollinated only open flowers, while bees pollinated both plant types. As a result, tubular flowers produced far fewer fruits with syrphid pollinators while open-flower fruit production remained the same regardless of pollinator. Fruit production increased along with both plant and pollinator diversity. Seed production was a bit more complicated. Though bee-pollinated open flowers produced fewer seeds per plant than those pollinated by syrphids, higher fruit production compensated by producing more seedlings. Fruit production increased with pollinator diversity. As for long-term effects on plant reproductive capacity and success, tubular plant communities had fewer plants at the seedling stage than openflowered plants (and even fewer when pollinated by syrphids). The plant species number and total plant number increased when both pollinator groups were present, and were highest with maximum plant and pollinator diversity. Seedling production showed a similar pattern: mixed plant communities treated with both pollinators yielded the most seeds.What happened? Not surprisingly, the pollinators stuck to their preferred plant: syrphids visited mostly open flowers, and bees visited mostly tubular flowers. Bees can pollinate open flowers but prefer tubular flowers when they have the choice, suggesting that bees may not fill a void left by a different pollinator. The presence of both pollinators allowed more appropriate pairings between insects and flowers\u2014each performing a complementary role\u2014leading to increased pollination efficiency and plant reproductive success.Liza GrossWhile the study offers an admittedly pared down view of pollination networks, it demonstrates the value of studying the functional effects of pollination networks in the field. These results show that losing a species affects plant\u2013pollinator communities, and that such losses may ultimately trigger further reductions in biodiversity, possibly reverberating through the food chain. With as many as 70% of plant species dependent on animal pollinators and at least 82 mammalian pollinator species and 103 bird pollinator species considered threatened or extinct, this is sobering news. \u2014"} +{"text": "James and Lange proposed that emotions are the perception of physiological reactions. Two-level theories of emotion extend this model to suggest that cognitive interpretations of physiological changes shape self-reported emotions. Correspondingly false physiological feedback of evoked or tonic bodily responses can alter emotional attributions. Moreover, anxiety states are proposed to arise from detection of mismatch between actual and anticipated states of physiological arousal. However, the neural underpinnings of these phenomena previously have not been examined.We undertook a functional brain imaging (fMRI) experiment to investigate how both primary and second-order levels of physiological (viscerosensory) representation impact on the processing of external emotional cues. 12 participants were scanned while judging face stimuli during both exercise and non-exercise conditions in the context of true and false auditory feedback of tonic heart rate. We observed that the perceived emotional intensity/salience of neutral faces was enhanced by false feedback of increased heart rate. Regional changes in neural activity corresponding to this behavioural interaction were observed within included right anterior insula, bilateral mid insula, and amygdala. In addition, right anterior insula activity was enhanced during by asynchronous relative to synchronous cardiac feedback even with no change in perceived or actual heart rate suggesting this region serves as a comparator to detect physiological mismatches. Finally, BOLD activity within right anterior insula and amygdala predicted the corresponding changes in perceived intensity ratings at both a group and an individual level.Our findings identify the neural substrates supporting behavioural effects of false physiological feedback, and highlight mechanisms that underlie subjective anxiety states, including the importance of the right anterior insula in guiding second-order \u201ccognitive\u201d representations of bodily arousal state. Recent theory distinguishes between two levels of emotional experience: phenomenology and awareness The importance of second-level appraisal mechanisms to emotional judgments is highlighted by false feedback experiments Recent studies of interoceptive awareness In the present study, we examined neural activity associated with effects of false feedback of arousal state (heart rate) on emotional evaluations. Our approach differed from that of Valens We first examined the influence of physiological feedback on behavioural ratings of intensity of face stimuli in a repeated measures ANOVA. We observed a significant multivariate interaction of expression type and feedback on attributed emotional intensity , in addition to a significant main effect of facial expression . Planned contrasts revealed a significant interaction between expression and feedback . Further, the emotional intensity of neutral faces was rated significantly higher during false relative to true feedback . Across all conditions, the emotional intensity of neutral expressions was rated significantly lower than either angry or happy expressions see We next examined the influence of isometric exercise in a repeated measures ANOVA, including the factors exercise (present absent) emotion and feedback . Exercise did not alter behavioural ratings of emotional expressions, and did not differentially influence false feedback effects.2\u200a=\u200a0.751] diastolic and mean arterial pressure , stroke volume cardiac output and heart rate relative to the no-exercise condition and exercise isometric exercise was associated with significant increases in systolic . This interaction was observed in the right anterior insula cortex and alsoWe next examined evidence for a cardiac synchronous/asynchronous comparator mismatch function for the anterior insula cortex during interoceptive demand. Predicated on the on the notion that interoceptive information has greater salience when processing ambiguous stimuli, we hypothesised that this would enable us to test for a comparator function of insula cortex in responding to mismatches in cognitive and interoceptive representations of physiological state, even at conditions of low bodily arousal. Thus, we specifically tested for a greater difference between asynchronous and synchronous cardiac feedback during the processing of neutral expressions, relative to the same difference during the processing of either happy or angry expressions; i.e. [ > ]. Significant interactions were observed in three regions; bilateral anterior insula cortex and dorsal cerebellum .As detailed above, exercise did not alter behavioural ratings of facial expressions-and showed no interaction with false feedback when rating neutral expressions. As a consequence we did not focus our investigations on exploration of neural correlates of non-significant behavioural interactions. Nevertheless, mapping of changes in first level representation within consciously accessible interceptive cortices, notably right anterior insula, was of direct interest.In both exercise and rest conditions, the pattern of activity reflecting the influence of feedback veracity on rating of facial expressions was maintained, with significant interactions observed within right amygdala, bilateral posterior insula and right anterior insula. Within the right anterior insula cortex, the mean BOLD signal change in response to face stimuli portraying neutral expressions predicted individual differences in the magnitude of intensity ratings of these stimuli in the context of false feedback .Pursuing the relationship between cerebral activity and false feedback induced biasing of emotional judgements, we used parametric analyses to examine within each participant the relationship between trial-by\u2013trial behavioural ratings of neutral faces and regional BOLD activity. Again, within the right anterior insula cortex, we observed a significant association between BOLD activity and attributed intensity of neutral expressions during false feedback . IncreasThe present study demonstrates the influence of false feedback of physiological arousal on emotional appraisal of facial expressions through engagement of a discrete set of brain regions implicated in social and motivational behaviour. This neuroanatomical matrix encompasses brain regions that have been implicated functionally in the encoding of external emotional cues , representation of internal visceral information (insula cortex) and the contextual synthesis of emotional information for declarative awareness (anterior insula/operculum).Our findings suggest a central integrative role for the anterior insula cortex. This region mapped differential influences of false feedback of arousal on differential processing of emotion, was sensitive to the timing of cardiac feedback and predicted within and across participants the degree to which behavioural ratings were altered during false physiological feedback. Together these novel data reveal neural substrates supporting the second level appraisal of emotional information, arising from an integration of perceptual processing within the context of physiological feedback representations, and influencing subjective affective judgement. Previous studies report right anterior insula engagement during conscious processing of emotional stimuli and in response to evoked physiological arousal responses False feedback of increased cardiac rate during rest enhanced the perceived intensity of neutral facial expressions but not angry or happy facial expressions. This is consistent with previous findings within the false feedback literature that the influence of physiological feedback is greatest during ambiguous judgements Anatomically, Craig argues that the specialised contribution of right anterior insula in conscious interoception derives from a remapping of mid and posterior viscerosensory representations We anticipated a contribution from amygdala to the emotional appraisal task. Patients with selective amygdala lesions show impairments in general social behaviour that correlate with deficits in emotional judgments of face stimuli Behaviourally, false physiological feedback enhances attention to stimuli presumed to be physiologically arousing Overall, we report the modulation of intensity judgements of face stimuli, particularly neutral faces by false feedback of physiological arousal state. Our neuroimaging data indicates engagement and interaction of three systems governing; first, initial representation and homoeostatic control of bodily arousal (insula); second, \u2018automatic\u2019 encoding of emotionally salient events and; third, visual and cognitive appraisal of stimuli . Further, our observations suggest a critical role for right anterior insula cortex in integrating information across these systems to support a second-level representation of emotionality that underpins subjective and behavioural experiences arising from false feedback. We did not observe any direct influence of first level physiological arousal on intensity judgements in the current study despite inducing significant increases in cardiovascular responses through isometric exercise. It is likely that misattribution of arousal is most probable where participants are unaware of the cause of their physiological arousal (i.e. excitation transfer effects). We did not observe misattributed arousal in the present study, presumably because first-level physiological arousal could be correctly attributed to isometric exercise.The present study represents the first investigation of neural responses during both false feedback and exercise induced arousal. We observed an interaction of emotion and feedback on subjective measures, and a parallel interaction within regions implicated in cognitive appraisal, emotional processing and interoception. Our findings suggest an integrative contribution of right anterior insula cortex in second level representations of emotion that, in turn, predict individual differences in emotional behaviour. In sum, our findings provide insight into emotional appraisal mechanisms proposed in two-level theoretical models of emotion and identify the functional neuroanatomical substrate for hierarchical emotional appraisals of the social brain.Twelve healthy right handed individuals gave informed written consent to take part in this study which was approved by the joint ethics committee of the Institute of Neurology and the National Hospital for Neurology and Neurosurgery, Queen Square, UK. Participants were screened to exclude psychiatric or systemic medical disorders and current medication usage.Before scanning, each participant was familiarised with the task and procedures. Participants were informed that we were interested in the effects of different facial expressions on heart rate during exercise and rest. Individual heart beats were recorded via a pulse oximeter linked to the task computer and were audible as tones (pulses) through headphones. Participants were also informed that the tones were essentially irrelevant, but were generated to allow us to measure heart responses. During questioning after the study, no participant said that this cover story raised suspicions.true feedback, tones were presented synchronous with individual heartbeats. During asynchronous feedback, tones were delayed by half the inter-beat interval. During false feedback, no-exercise tones were presented at a rate ten percent faster than the preceding exercise heart rate, whereas exercise tones were presented at a rate 10 percent slower than the preceding no-exercise heart rate. Afterwards, participants completed another three minutes of the emotional appraisal task in the alternative exercise condition (either exercise or no-exercise) and with all three feedback conditions. The order of feedback and exercise conditions was randomized. In sessions where a no-exercise condition followed an exercise condition, a 90-second pause followed the instruction to relax grip, to allow exercise associated arousal to decline. At debriefing, participants were asked about their perceptions of heartbeat feedback. All participants were unaware (i.e. did not declare on direct questioning) of the manipulations of the auditory feedback of their heart rate . Further, participants confirmed that they remained focused on the face rating task.During the experimental task , a compu3 T1-weighted structural scans were acquired from each participant.Functional echo-planar datasets sensitive to BOLD (Blood Oxygen Level Dependent) contrast were acquired at 1.5 Tesla (Siemens Sonata) The sequence, minimizing orbitofrontal signal dropout http://www.fil.ion.ucl.ac.uk/spm/), employing spatial realignment and sequential co-registration . Structural scans were segmented into CSF, grey and white matter images and iteratively normalized to standard space using a single generative model Images were pre-processed using SPM5 of discrete contrasts within the general linear model. Subsequent second-level group random effects analyses were performed on the SPM contrast images of first level canonical HRF responses to permit formal inferences about population effects Peripheral physiological responses were also explored outside the scanner in an independent group of eight healthy right handed participants because recording equipment was not compatible with the fMRI environment. Participants were given identical task instructions and completed the experimental task while a finger cuff recorded beat-to-beat blood pressure with a Finometer . This allowed a reconstruction of brachial artery pressure from cardiological measures were obtained, including arterial pressure at systole and diastole, stroke volume, cardiac output, left ventricular ejection time, total systemic peripheral resistance, and heart rate."} +{"text": "I read the paper by Chi et al. with interest. The authors found a greater hypoxia response gene expression in carcinomas than stromal cells grown in vitro, but were not sure of the underlying explanation (see Discussion in ). The unThe differences in mitotic activity could also explain greater hypoxia-related gene expression in clear-cell carcinoma compared with chromophobe carcinoma, normal tissue, or oncocytoma, as clear-cell carcinomas are more active mitotically. Did the authors compare the hypoxia gene expression with mitotic activity in various tumors?"} +{"text": "Many biological problems such as the detection of co-expressed genes, co-regulated genes, and transcription factor binding motifs rely heavily on the analyses of these image patterns. The increasing availability of ISH image data motivates the development of automated computational approaches to the analysis of gene expression patterns.Staining the We have developed algorithms and associated software that extracts a feature representation of a gene expression pattern from an ISH image, that clusters genes sharing the same spatio-temporal pattern of expression, that suggests transcription factor binding (TFB) site motifs for genes that appear to be co-regulated (based on the clustering), and that automatically identifies the anatomical regions that express a gene given a training set of annotations. In fact, we developed three different feature representations, based on Gaussian Mixture Models (GMM), Principal Component Analysis (PCA), and wavelet functions, each having different merits with respect to the tasks above. For clustering image patterns, we developed a minimum spanning tree method (MSTCUT), and for proposing TFB sites we used standard motif finders on clustered/co-expressed genes with the added twist of requiring conservation across the genomes of 8 related fly species. Lastly, we trained a suite of binary-classifiers, one for each anatomical annotation term in a controlled vocabulary or ontology that operate on the wavelet feature representation. We report the results of applying these methods to the Berkeley Drosophila Genome Project (BDGP) gene expression database.Our automatic image analysis methods recapitulate known co-regulated genes and give correct developmental-stage classifications with 99+% accuracy, despite variations in morphology, orientation, and focal plane suggesting that these techniques form a set of useful tools for the large-scale computational analysis of fly embryonic gene expression patterns. This technique localizes specific mRNA sequences in tissues/cells by hybridizing a labeled complimentary nucleotide probe to the sequence of interest in fixed tissues. Visualizing the probe by colorimetric or fluorescent microscopy allows for the production of high quality images recording the spatial location and intensity of gene expression.A large body of work analyzing DNA micro-array data from microorganisms has demonstrated the value of gene expression analysis in understanding gene function and dissecting gene regulation -3. Whilein situ databases, such as the Berkeley Drosophila Genome Project (BDGP) gene expression pattern database , sh, shin siIn Figure In regard to the automatic annotation of gene expression patterns, we also collected statistics of the use of the ontology annotation terms (results not shown). The percentage of genes corresponding a common annotation term ranges from less than 1% to about 20%. Given this small fraction, it is unlikely that our image-based gene clustering results in Figures Our image analysis methods can be applied to 3D gene expression patterns or other types of aligned image patterns in different contexts. For example, in we definin situ hybridization brain images of 20,000 genes were aligned to a standard reference atlas. The effective clustering and recognition of these gene expression patterns, based on various image features , could in situ fly gene expression patterns. We have successfully extracted useful local and global image features, and used these to automatically cluster and annotate gene expression patterns with high reliability. Our techniques provide useful tools for the large-scale computational screening of fly embryonic gene expression patterns, as well as the aligned image patterns for similar problems in other model systems.We have developed a set of automatic image analysis methods for For the BDGP database, 2D embryonic images of gene expression patterns were acquired using a digital camera. In a typical image, a single embryo resides in the central part of the image and presents a lateral view. Only lateral views were used, but the embryo can otherwise have an arbitrary orientation. As the embryonic region has much richer texture information than the image background, the embryo can be segmented by thresholding the local variance of a small region (e.g. 3 \u00d7 3 pixels) around each pixel. The pixel is binarized to \"foreground\" if the variance is larger than a predefined threshold (e.g. 2), otherwise to \"background\". Binarization classifies most embryo pixels as \"foreground\" and most background pixels as \"background\", thus producing a mask image that essentially captures the embryonic region. For a segmented embryo, we computed the principal direction along which the variation of all embryonic pixel-coordinates is the greatest and considered this the anterior-posterior axis of the embryo. We then rotated the image to make this axis horizontal. Finally, the embryonic region was cropped and its size was standardized to 400 pixels wide and 200 pixels high.in situ gene expression images in the BDGP database for 1,700 fly genes. We found that about 67% of the images have only one embryo region in the center, and can be easily segmented based on thresholding the pixel variance. These 20,000 extracted image patterns were automatically rotated so that their longest axes are horizontal. We developed a web-based image pattern browser at [We processed about 30,000 owser at , which cowser at .In analyzing the data, we further ignored all images that were not of a lateral view of the embryo. While most images are lateral views, a significant fraction is taken from difference vantage points, such as along the dorsal/ventral axis or some tilted angle. From these viewpoints it is especially difficult to understand the 3D pattern as the embryo is clear and one is essentially seeing the 2D projection of the stain along the viewing axis. It remains an open problem how to effectively use such additional data.For the experimental results reported, we focused on a set of 456 genes. We separated the lateral and dorsal views manually and also adjusted the orientations of these images to assure these images are compared in the correct way, i.e. anterior is at the left and dorsal is up. If in a particular stage-range a gene has multiple images, our computer program merged these images and used their mean-image as the \"representative\" for this gene. In this way, the image clustering and annotation algorithms would not be biased by the image-numbers of genes. Due to the great variation of the quality of the BDGP 2D image patterns, these processing steps were necessary to produce meaningful results.Abbreviations of the anatomical annotations used throughout the paper:AM amnioserosaAAISN amnioserosa anlage in statu nascendiAISN anlage in statu nascendiAEA anterior endoderm anlageAEAISN anterior endoderm anlage in statu nascendiAEP anterior endoderm primordiumAMP anterior midgut primordiumCMP cardiac mesoderm primordiumCB cellular blastodermCLP clypeo-labral primordiumDEA dorsal ectoderm anlageDEAISN dorsal ectoderm anlage in statu nascendiDECP dorsal ectoderm primordiumDEDP dorsal epidermis primordiumDPMP dorsal pharyngeal muscle primordiumEAISN endoderm anlage in statu nascendiECBG embryonic central brain gliaECBN embryonic central brain neuronECNS embryonic central nervous systemEDE embryonic dorsal epidermisEH embryonic hindgutELDV embryonic/larval dorsal vesselELCS embryonic/larval circulatory systemELO embryonic/larval oenocyteEM embryonic midgutEOLP embryonic optic lobe primordiumEFP external foregut primordiumFA foregut anlageFAISN foregut anlage in statu nascendiFP foregut primordiumGC germ cellHMPP head mesoderm P2 primordiumHMA head mesoderm anlageHA hindgut anlageHPP hindgut proper primordiumIHP inclusive hindgut primordiumLC lateral cordLCG lateral cord glia.LCN lateral cord neuronLVMP longitudinal visceral mesoderm primordiumMA mesectoderm anlageMEP mesectoderm primordiumMIP midline primordiumMAISN mesoderm anlage in statu nascendiMLP midline primordiumMP mesectoderm primordiumNOVNS neuroblasts of ventral nervous systemOSA oenocyte specific anlagePC pole cellPTEA posterior endoderm anlagePTEP posterior endoderm primordiumPMP posterior midgut primordiumPCEA procephalic ectoderm anlagePCEAISN procephalic ectoderm anlage in statu nascendiPCEP procephalic ectoderm primordiumPCN procephalic neuroblastsPEA procephalic ectoderm anlagePEP procephalic ectoderm primordiumPCP protocerebrum primordiumPMP posterior midgut primordiumPP proventriculus primordiumPTEAISN posterior endoderm anlage in statu nascendiSDP salivary duct primordiumSGBSA salivary gland body specific anlageSGDSA salivary gland duct specific anlageSGBP salivary gland body primordiumSNSSA sensory nervous system specific anlageSMP somatic muscle primordiumS subsetTP tracheal primordiumSNSP sensory nervous system primordiumSNSSA sensory nervous system specific anlageTMA trunk mesoderm anlageTMAISN trunk mesoderm anlage in statu nascendiTMP trunk mesoderm primordiumVEA ventral ectoderm anlageVECP ventral ectoderm primordiumVEPP ventral epidermis primordiumVNCP ventral nerve cord primordiumVNA ventral neuroderm anlageVSCSA ventral sensory complex specific anlageVM ventral midlineVMP visceral muscle primordiumVNC ventral nerve cordVP visual primordiumThe authors declare that they have no competing interests."} +{"text": "Adherent cells from carcinomatous pleural effusions of lung cancer patients were tested for their ability to suppress natural killer (NK) cell activity, and the mechanism involved in the suppression of NK cell activity was determined. Adherent effusion cells (AEC) were isolated from malignant pleural effusions of patients by centrifugation discontinuous Ficoll-Hypaque gradients and adherence to serum-coated plastic dishes, and large granular lymphocytes (LGL) were purified from the peripheral blood of normal individuals by centrifugation on discontinuous Percoll gradients and further depletion of high-affinity sheep erythrocyte rosette formation. LGL-mediated lysis of K562 cells was suppressed when LGL were cultured with AEC for 20 h, then washed and tested in a 4-h 51Cr release assay. More profound suppression of NK cell activity was observed when cytotoxicity was assayed in flat-bottomed wells rather than in round-bottomed wells. Cytotoxicity assays conducted at the single cell level in agarose revealed that the frequency of LGL binding to K562 cells and of dead conjugated target cells was reduced after overnight contact with AEC. In agarose microdroplet assays, functional LGL from normal donors exhibited definitive motility, expressing polarized shape. In contrast, a small number of LGL with non-polarized configuration migrated from the agarose droplet after overnight culture with AEC. These results indicate that functionally suppressed NK cells lose their motility, binding capacity and killing activity, which could be responsible for the suppression of NK cell activity by AEC."} +{"text": "Arrhythmogenic right ventricular dysplasia/cardiomyopathy is a disorder characterized by frequent ventricular tachycardia originating from the right ventricle and fibro-fatty replacement of right ventricular myocardium. Though the disorder was originally described during surgical ablation of refractory ventricular tachycardia, catheter ablation of tachycardia is one of the options for patients not responding to anti arrhythmic agents. Direct current fulguration was used in the initial phase followed by radiofrequency catheter ablation. In the present day scenario, all patients with risk for sudden cardiac death should receive an implantable cardioverter defibrillator. Radiofrequency catheter ablation remarkably reduces the frequency of defibrillator therapies. Direct current fulguration can still be considered in cases when radiofrequency ablation fails, though it requires higher expertise, general anesthesia and carries a higher morbidity. Newer mapping techniques have helped in identification of the site of ablation. In general, the success rate of ablation in arrhythmogenic right ventricular dysplasia is less than in other forms of right ventricular tachycardias like right ventricular outflow tract tachycardia. Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD) is a disorder characterized by fibro-fatty replacement of the right ventricular myocardium, frequent ventricular tachycardia originating from the right ventricle and right heart failure. It was originally described by Fontaine et al during surgical ablation of refractory ventricular tachycardia . The firThough historically the original description of ARVD was during surgical ablation, pharmacological therapy was the initial mode of treatment in most cases. Surgical ablation by right ventricular disconnection was resorted to in resistant cases . PeroperThe initial reports on catheter ablation in ARVD were using direct current fulguration -8. One oRadiofrequency catheter ablation for ARVD has been in use since early nineties . It has Entrainment mapping can be used to characterize reentry circuits in ARVD to guide ablation -15. The Endocardial mapping can detect abnormal fragmented electrograms with delayed potentials. Pacemapping confirms the ablation site by producing a QRS morphology identical to the clinical VT . RecentlThree dimensional Real-time Positioning Management System (RPM) has also been used for guiding ablation in ARVD . RPM useO'Donnell et al have highlighted the electrophysiological differences between patients with ARVD and right ventricular outflow tract tachycardia (RVOT VT) . Though Ablation of ventricular tachycardias in ARVD still remains a clinical challenge, though more and more cases are being reported in the literature -23."} +{"text": "Glutathione S-transferase (GST) isoenzyme expression is altered in a variety of neoplasms and the enzymes are implicated in metabolism of carcinogens and resistance to drugs, including cisplatin. We have studied GST Alpha, Pi, Mu and microsomal isoenzyme expression by immunohistochemistry in normal and cryptorchid testes, intratubal germ cell neoplasia (ITGCN), seminoma and non-seminomatous germ cell tumours. In 16 stage II-IV malignant teratoma intermediate (MTI) both orchidectomy and post-treatment residual surgical masses were studied. All four isoenzymes were strongly expressed in Leydig and Sertoli cells. GST Pi was absent from normal spermatogonia but strongly expressed by the neoplastic germ cells of ITGCN and seminoma. GST Pi was strongly expressed in all elements of teratoma, irrespective of differentiation. There were no qualitative differences in expression between primary and post-chemotherapy metastases. GST Alpha expression in teratoma correlated with epithelial differentiation. GSTs may be important in normal spermatogenesis and protection of germ cells from teratogens and carcinogens. They may have a role in testicular tumour drug resistance but this role is not well defined. GST Pi is a new marker for ITGCN."} +{"text": "Using an indirect immunohistochemical technique on paraffin sections, employing a polyclonal antibody to the acidic form of glutathione-S-transferase (GST), we have evaluated cytoplasmic and nuclear staining in a series of 67 cervical biopsies including normal non neoplastic tissue, immature squamous metaplasia, all grades of cervical intraepithelial neoplasia (CIN) and invasive carcinomas of keratinising and non-keratinising types. No differences in cytoplasmic staining between the varied lesions studied were seen. However, there were marked differences in nuclear staining. While normal non-neoplastic stratified squamous epithelium showed weak staining of the lower one-third of the epithelium only, in immature squamous metaplasia and in all grades of CIN there was intense nuclear staining in all layers of the epithelium. Invasive carcinomas showed generally less intense nuclear staining than CIN lesions. Endocervical cell nuclei also showed intense nuclear staining. These findings indicate that GST is of limited use as a marker of transformation in the human cervix uteri."} +{"text": "Agouti-related protein encodes a neuropeptide that stimulates food intake. Agrp expression in the brain is restricted to neurons in the arcuate nucleus of the hypothalamus and is elevated by states of negative energy balance. The molecular mechanisms underlying Agrp regulation, however, remain poorly defined. Using a combination of transgenic and comparative sequence analysis, we have previously identified a 760 bp conserved region upstream of Agrp which contains STAT binding elements that participate in Agrp transcriptional regulation. In this study, we attempt to improve the specificity for detecting conserved elements in this region by comparing genomic sequences from 10 mammalian species. Our analysis reveals a symmetrical organization of conserved sequences upstream of Agrp, which cluster into two inverted repeat elements. Conserved sequences within these elements suggest a role for homeodomain proteins in the regulation of Agrp and provide additional targets for functional evaluation. Agrp expression is restricted to a discrete population of neurons that sense the levels of peripheral energy stores, and is dramatically elevated by deficits in energy balance.AGRP is an orexigenic, hypothalamic peptide whose role in energy homeostasis has been conserved during vertebrate evolution. In a wide range of species, including mammals Agrp mRNA levels Agrp regulation, where STAT3 represses and FoxO1 stimulates Agrp transcription. However, conserved STAT binding sites in the Agrp promoter region do not function as simple repressor elements and, paradoxically, are required for fasting induced stimulation of Agrp transcription AGRP neurons directly receive information about energy stores from leptin, an adipocyte-derived hormone that circulates at levels proportional to fat mass. Diminished levels of circulating leptin correspond to increased Agrp expression. For example, AGRP neurons directly mediate the orexigenic effects of glucocorticoids Agrp mRNA levels Agrp expression Support for this also stems from the observation that peripheral energy signals other than leptin regulate Agrp expression in transgenic mice and that contain regions of high sequence conservation between mouse and human, including a 760 bp region located immediately upstream of AgrpCross-species comparative sequence analysis has facilitated the detection of functional elements that participate in transcriptional regulation Agrp expression in vertebrates suggests that sequence comparisons of disparate vertebrate species provide an appropriate evolutionary scope for identifying Agrp regulatory elements. However, Agrp genomic sequences from distantly related vertebrate species have diverged to the extent that regional conservation is no longer detectable using traditional alignment methodologies Agrp genomic region from ten mammalian species, representing several different orders and all three subclasses of mammalia. Our analysis reveals a symmetrical organization of conserved sequences upstream of Agrp, which cluster into two inverted repeat elements (IREs). The proximity of the elements to Agrp and the nearly perfect evolutionary conservation of their specific constituent sequences in all ten mammalian species and in chickens suggest a role in Agrp regulation. In addition, the resolution of the conserved elements provided by this approach allows general predictions concerning putative trans-regulatory factors.The inclusion of sequences from multiple, divergent species sharing a commonly derived phenotype improves the resolution of comparative sequence analysis. The conserved nature of Agrp locus for chimpanzee (Pan troglodytes), human (Homo sapiens), dog (Canis familiaris), mouse (Mus musculus), and rat (Rattus norvegicus) was obtained from publicly available genome assemblies on the UCSC genome browser (http://genome.ucsc.edu). Genomic sequence for other species, including chicken , cat (Felis catus), cow (Bos taurus), tenrec (Echinops telfairi), platypus (Ornithorhynchus anatinus), and opossum (Monodelphis domestica), was obtained from the trace sequence archives at NCBI (http://www.ncbi.nlm.nih.gov) and assembled using SeqMan . Our assembly of chicken genomic sequence at the Agrp locus differed from the publicly available genome assembly (Chicken v1.0), since additional trace sequence was available. Notably, the chicken sequence corresponding to the STAT site and inverted repeat element is not present in the public assembly. Our assembly of the chicken Agrp locus is provided as supplementary material Agrp regulatory sequences has been previously interrogated using mouse transgenic models Approximately 1.8 kb of genomic sequence from the Agrp exons, the STAT sites, and the IREs, we modified the concept of an RS score, such that the score for constraint represents the sum of constrained alignment columns in these regions while ignoring unconstrained alignment columns. In this way, the constraint score reflects the level of sequence conservation within a particular region without penalizing unconstrained positions surrounding Agrp, each one flanking a conserved STAT binding element Agrp underwent a duplication that occurred prior to mammalian radiation, and portions of the duplicated region have been subjected to purifying selection such that specific sequences (those corresponding to the STAT elements and IREs) are maintained in two closely related copies.As shown in Agrp locus, we aligned 1.8 kb of Agrp genomic sequence from 10 mammalian species \u2013 human, chimpanzee, mouse, rat, cow, dog, cat, tenrec, opossum, and platypus - with multi-lagan. We then used GERP Agrp locus and compares the position of constrained sequences with annotated elements. Based on this approach, the level of evolutionary constraint for sequences overlapping the IREs and the STAT binding sites are extremely high relative to other genomic regions Agrp coding sequences in this alignment of species transcription factors, which are generally involved in the regulation of development and cell fate but also function post-developmentally to modulate cell type specific gene expression. While HD transcription factors represent a large family of proteins with over 100 members, most display restricted expression patterns that are predictive of function. Several HD transcription factors are regionally expressed in the hypothalamus.PomcOrexinGonadotropin Releasing Hormone (GnRH) GnRH has been extensively studied, due in part to an immortalized cell line which has retained important characteristics of endogenous GnRH neurons. Multiple HD transcription factors cooperatively bind to the sequences upstream of GnRH, regulating not only cell type specific expression but also dynamic, physiologic responses by serving as scaffolds for additional cofactors Agrp regulation proposed by Kitamura and colleagues to integrate observations regarding input from other signals and the organization of conserved sequences identified in this analysis.HD transcription factors have been previously implicated in the regulation of neuropeptide gene expression, and conserved HD binding sites have been identified in the regulatory regions of other hypothalamic neuropeptide genes, including Agrp defined by mouse/human sequence conservation, the IREs and STAT binding sites comprise the majority of non-coding sequence conserved among mammals. Only two other non-coding sequences, which are both \u223c15 bp in length, meet the threshold for constraint set by GERP FoxO1 is capable of recognizing non-canonical FoxO1 binding sites in some species, (2) FoxO1 regulates Agrp expression only in a subset of mammalian species, (3) or FoxO1 associates with Agrp upstream regions through a mechanism that does not involve a direct interaction with the putative FoxO1 binding sites. Notably, direct interactions between forkhead and HD transcription factors have been previously described and implicated as a general mechanism for post-developmental regulation of gene expression In contrast to the STAT binding sites, the putative FoxO1 binding sites identified by Kitamura and colleagues, which are located between to the IREs and STAT binding sites, are not well-conserved Click here for additional data file.Text S2A FASTA file containing the mammalian sequences used for GERP analysis.(0.02 MB TXT)Click here for additional data file."} +{"text": "Despite its popularity and rapid advancements in the field, many obstacles for cancer therapy PG still need to be overcome. By borrowing scientific systems from other disciplines such as cancer diagnosis, and therapeutic information from the diversity of tumor origins, categories and stages, cancer therapy PG may hopefully be improved. Furthermore, to quickly acquire genetic and pathologic information and seek therapeutic interventions, possible breakthroughs may come from beyond \u2013 changing the cancer therapeutic landscapes. The next generations of PG protocols and hospital routines for searching deadly cancer pathogenic pathways versus drug-targeting predictions are of great clinical significance for the future. Yet, progress of cancer therapy PG is entering into a bottleneck stage owing to simple model of relevant techniques and routines. Promoting or even innovating present PG modular is very necessary. This perspective highlights this issue by introducing new initiatives and ideas. Cancer is a common disease that claims the lives of about 7\u201310 million people annually across the world. As a result, cancer remains a great medical challenge worldwide . Many efDespite the popularity of cancer therapy PG, human genetic information used for forecasting disease risk, therapeutic agent options, drug characteristics (doses/toxicities and responses to cancer) in individual humans have not been perfected yet. The similarities and differences of PG between cancer therapy and other disease therapies are important for future scientific investigations and therapeutic improvements. Possible future perfections are proposed herein.Drug ADME studies by polymorphism analysis of individual metabolic enzymes and approximately 300 human metabolic enzyme genes and molecules have been subjected to PG investigations and clinical applications . TechnicThe paramount task of greatest therapeutic significance is to find the biologic relationships between disease progression (tumor genetic mutations/invasive/remote metastasis) and therapeutic outcomes (relevant anticancer drugs selections and applications). Ninety percent of cancer deaths are caused by neoplasm metastasis and cancNeoplasm metastasis treatment is different from primary tumor treatment ,12\u201316. AOne of the thorniest problems in clinical cancer trials is the occurrence of multidrug resistance (MDR) in tumor cells or tissues. Soon after cancer chemotherapy, a series of drug transporter or DNA repair molecules, such as ATP-binding cassette transporters (ABC transporters), p-glycoprotein , MDR-related proteins (MRPs) and so on, work together to dramatically offset therapeutic efficacies and decide the nature of drug resistances and therapeutic failure in individual cancer patients. Thus, detecting polymorphisms of these genes and relevant biological molecules helps to predict the occurrence of drug resistance in tested cancer patients .Predictions of drug responses against cancers and toxicity to the human body are indispensable parts of cancer therapy. The polymorphisms or epigenetic information of drug-targeted genes, tumor environmental molecules, drug metabolic enzymes, tumor suppressive genes, metastatic-related or cancer stem cell-related molecules can impact on the chemotherapeutic outcomes for cancer patients . Proper Anticancer PG and PG for other disease therapies generally share the same analytical routines and technical supporting systems (mostly single nucleotide polymorphisms [SNPs]) of drug-related or DME genes \u2013 the same as for other disease therapies. Since the DME genes for anticancer drugs are biologically identical in human bodies and regarded as parallel systems, no difference has been applied between anticancer therapy and other disease therapies in general hospital protocols and routines. Despite the homogeneity of human metabolic enzymes, etiologic and pathogenic processes between cancer and other diseases are diversified greatly. For example, the etiologies of most diseases initiate in a fixed string of genes and molecules \u2013 pathogens commonly come from outside infections. Moreover, drug targets for most disease categories are fixed and can be repeated again and again. Cancer drug responsiveness prediction is, nonetheless, different because cancer comprises different diseases with pathogenesis of unlimited growth and metastasis. The great diversity and unresolved mechanisms of action for cancer progression and proliferative or metastatic inhibitions make current cancer therapy PG at its initial stages. Much effort must be created and verified for cancer therapy PG improvements that can save the life of a great numbers.Anticancer drugs, especially cytotoxic anticancer drugs, are highly toxic. Most cytotoxic anticancer drugs are even carcinogenic and can cause secondary tumors after administrations of higher than tolerated drug dosages. Approximately 1\u201310% of normal humans are deficient in one or several wild-type human metabolizing enzymes from one or several genetic polymorphisms. These patients cannot transform anticancer prodrugs into active metabolites (low-active drug components and responses) or reduce active metabolite clearance rates that lead to higher active metabolite concentrations in human plasma and toxicity. Increasing active anticancer drug or metabolite concentrations in patients\u2019 plasma or normal tissues means significantly harmful impacts on cancer patient treatments, or even the cost of a patient's life ,8\u201310 Fi. Yet incDifferent from other types of diseases, cancer is caused by a wide diversity of oncogenic mutations and environmental matrix and factors (such as vasculature activators like EGF or VEGF etc.) that support the transformations of normal cells into malignant ones . More seTumor growth and metastasis are determined by different cancer genes or hallmarks. Neoplasm metastasis is caused by the interactions of cancer cells and human environments . TheoretAfter the advent of cancer therapy PG, we have never attempted any new initiatives outside the boundary of the PG norm and technical routines that are different from widely practiced PG protocol in cancer therapy PG. If we stay on this course and in these mindsets, we might never have the opportunity to overcome the drawbacks and pitfalls of current cancer therapy and make a difference to now. Creative ideas and novel PG techniques for improving in cancer therapy are welcomed.Human cancer is a unique type of disease that in which a great diversity backgrounds of gene mutations and malfunctioning biomolecular profiling are found. According to general PG mindsets and routines, beside ADME-related metabolizing enzymes (\u2248300), at least the same amount of oncogenic genes can be mutated. From our past experience, at least 5\u201310 oncogenic genes or biomolecules will normally be found in tumor tissues among advanced cancer patients. Since a huge amount of human genes are related to cancer growth, metastasis, drug toxicities/responses, an indispensable topic is to design a high efficient strategy that can solve this technical difficulty. Brand-new strategies relevant to human gene and therapeutic prediction, even outside of current available polymorphisms information, might help us realize our dreams of making a difference to PG systems. However, this interesting topic seems unlikely to be solved by conventional PG routines in utilities.Since cancer is a complicated disease, conventional cancer therapy needs more than one anticancer drug. As a result, anticancer drug therapy PG is different from other PG diseases. These differences for complex therapeutic recipes call for new ideas and PG routines. Obviously, the next generations of anticancer therapy PG systems must be capable of predicting complicated clinical circumstances and situations in clinical cancer trials. How can this goal be realized? It needs to build the technical capability of translating biological modular into therapeutic optimizing paradigms. Technical innovations and computational data analytical systems can guide us into new clinical horizon and predict complex formulae of cancer treatment recipes.Apart from genetics of metabolic enzymes, anticancer drug targeting genes and oncogenic- or metastatic-related genes are other parts of personalized cancer therapy ,27\u201336. ADespite great monetary support and quick technical improvements, cancers remain to be an unresolved enigma and of therapeutic significance. Development of drug resistance, drug-induced severe side effects, cancer stem cells and tumor metastasis contribute to the majority of therapeutic failures in clinical cancer trials. Due to the poor drug specificity of many cytotoxic drugs, normal tissues are also damaged by such cancer treatments. As a result, the highest tolerated drug dosages cannot kill all tumor populations of large tumor volumes. Induction of drug resistance after conventional trials, cancer stem cells (mystery characteristics of tumors) and neoplasm metastasis and so on are the real culprits for therapeutic failures. Those PG systems designed to analyze genetic status of tumor or human tissues should be omnipotent for predicting both toxicity and efficacy of drugs in individual cancer patients. The present anticancer therapy PG systems are proving too little and too incapable for advanced cancer patients.Since oncogenic- or metastatic-related genes or molecules are too diversified and disconnected, it is hard to find optimal drugs utilizing present PG systems and routines. Apart from PG systems, other personalized cancer therapy strategies such as drug sensitivity testing (DST) or canceThe overall theme of PG is the right drug for the right patient, by analyzing human genetics variations that play roles on predicting drug toxicities or responses. However, current PG systems are more suitable for fixed small ranges of pathological processes and change slightly after its advent. New knowledge coming from clinical case reports, doctors\u2019 experience or hypothesis-driven systematic studies ought to provide a useful foundation for updating PG systems, especially cancer therapeutic PG systems and routines. After accumulating enough clinical data and large-scale human genome drafting, computation and validating, framing different genetic markers and pathogenic-related therapeutic efficacies are followed. Finally, we need to transform our knowledge and understanding from empirical into successful clinical paradigms . PossiblSince genetic variations between individuals and disease progressions are not negligible, relationships between individual genes and drug therapeutic outcome are the priority. Much supportive information on this issue can easily come from other cancer biological or therapeutic advancements. Also, technical innovations can be implemented after absorptions of new fruits of scientific discoveries. However, basic rules behind the scenes are not understood yet.An approximately 1\u20135% difference between different races or ethnic groups is present worldwide. Presently, PG studies are heavily reliant upon European descendants (Caucasian) ,39. ThesDetermining the toxicities, activities and blood concentrations of anticancer drugs by PG plays an important role in clinical cancer trials. In spite of these utilizations, PG is not very useful for choosing the most suitable anticancer drugs from the large anticancer drug arsenal (\u224884 anticancer agents or drugs licensed in the USA) and 178 Two cancer therapy PG systems (drug-oriented PG and pathogenesis-oriented PG) have been categorized & 4. OptMoreover, potential new PG systems need an ingenious design via integration of two systems and scientific investigations supporting improvement of PG routines.Presently, cancer therapy PG, however, is only superior for drug dosages or toxicity determinations by SNPs of drug ADME profiling.An imbalance between the rapid development of genotyping technology and the slow pace of genetic testing marketing is generally met. The great degree of uncertainty in interpreting drug responses to tumor progressions, stem cells or metastasis PG has not been the breakthrough in cancer therapy worldwide. Despite a lot of successful stories, presently cancer therapy PG does not develop into compulsory routines, even in developed countries. A shortage of large sample-sized retrospective or clinical cohort studies has been reported . MoreoveGWAS are always the priority for PG technical updating. Owing to the invention of next-generation sequencing (NGS) techniques, human genome sequencing can be a joint effort between biomedical students and mathematical or physics students or scholars in the future. For these undertakings, mathematics or physics students and scholars will prove to be more adept than biomedical students in the postgenomic study age. Since the tremendous speed-up and low budget of genotyping human genomes by NGS comparedBioinformatics (omics technology) are more advantageous for quantifying specific gene or biological molecular changes than those used by current PG systems. At first, we need to detect the clinical data of both PG and bioinformatics. Then, ingeniously designing a new generation of PG techniques or systems that can provide genetic information of both quantity and quality, even omnipotent systems, are possible routes to renew PG techniques for cancer therapy predictions. Cooperating merits from NGS and GWAS or other new techniques may improve cancer therapy PG or even change the landscape of personalized cancer therapies worldwide. Then, improvements of predicting therapeutic efficacies, toxicity and outcomes may be realized by integrating growing bodies of diagnostic or pathological profile information.Anticancer drug responses in tumor tissues and human bodies, especially those of cytotoxic anticancer drugs, are often multigenetic and multifactorial ,45. PresNo central dogma or paradigms of cancer therapy PG are capable of being universally utilized. Borrowing ideas and lessons from other scientific disciplines, hypothesis-driven data collections and workable computations for revealing the relationship of cancers diversity and a variety of therapeutic options are important resources for inventions of new generations of PG systems. In future, cancer therapy PG might transform from a number of genetic testing modalities into omnipotent, science-guarded and high-throughput predictive systems. The summary table outlines the roadmap and avenues of future directions of cancer therapy PG past and in future.Briefly, PG in clinics might no longer be considered a hobby in the future. Increasing occurrences of mandatory PG trials might be required in most advanced countries, or even become indispensable worldwide.Since we speculate that key breakthroughs of anticancer PG may not come from simply increasing the sample-size of clinical PG data, it relies on injections of insights and breakthrough of other disciplines, biological/medical discoveries or developments of new generations of anticancer drugs and rulePresent cancer therapy PG systems are imperfect for large populations of cancer deaths . Possible future cancer therapy PG advancements may come from ideas and outcomes of other researchers instead of keeping up present mindsets and hospital routines.Techniques and strategies for prediction of both toxicity and efficacy in individual cancer patients.Pharmacogenetics (PG) study, especially drug absorption, distribution, metabolism and excretion molecules, such as metabolic enzyme genes and dose-optimizing.Description of established PG protocols and routines, comparisons between cancer therapy and other disease therapies.Outlook of different categories of PG techniques, such as drug-targets and disease-based genetic systems.Discover and predict the relationship between cancer pathology and treatments by PG practice in individual cancer patients.Find ways of pinpointing the diversity of pathologic origin and different therapy of primary, stem or metastatic cells or tissues in each cancer patient and be able to maximize the efficacy of drugs or therapy.Lacking established relations between therapeutic outcomes and PG applications.Limitations and shortcomings of conventional PG techniques and systems.The importance of neoplasm metastasis, multidrug resistance and cancer stem cells in cancer therapeutic outcome improvements.Comparisons of therapeutic efficacies between primary tumors and metastatic nodules.Create some original, innovative systems or biomedical software for integrating diversified and combinative pathological, pharmacological and clinical information into utility paradigms.Invest more money into developments of effective antimetastatic drugs or cancer stem cell inhibitors.Construct usable anticancer drug combinative PG systems.Promote genome-wide association studies, especially among different ethnic groups, races and/or tumor types and stages."} +{"text": "Fusobacterium nucleatum and Porphyromonas gingivalis were highly increased within tissues, comprising 15\u201340% of the total bacteria. Furthermore, biofilm formation within the tissue was observed by Alcian Blue staining and atomic force microscopy, where degradation of fibers was prominent. Taken together, bacteria formed complex biofilm communities within gingival tissues that may serve as a reservoir for persistent infection. This novel finding may instigate new research into therapeutic strategies to treat periodontitis.Periodontitis is caused by dysbiosis of subgingival plaque that results in increased bacterial invasion into gingival tissues. Although shifts in subgingival microbiota from healthy to periodontitis have been well characterized, the characteristics of bacterial communities located within gingival tissues have not been studied. To characterize microbiota within the tissues of periodontal lesions in comparison with plaque microbiota, gingival tissues and subgingival plaque were obtained from the same tooth of patients with periodontitis (n = 7). A pyrosequencing analysis of the 16S rRNA gene revealed that species richness and diversity were not significantly different between the two communities. However, inter-subject variation in intra-tissue communities was smaller than that in plaque communities. Intra-tissue communities were characterized by decreased Firmicutes and increased Fusobacteria, compared with the plaque communities. Particularly,"} +{"text": "Apis mellifera) implicated in elevated colony mortality rates worldwide and facilitated through vector transmission by the ectoparasitic mite Varroa destructor. Clinical, symptomatic DWV infections are almost exclusively associated with high virus titres during pupal development, usually acquired through feeding by Varroa mites when reproducing on bee pupae. Control of the mite population, generally through acaricide treatment, is essential for breaking the DWV epidemic and minimizing colony losses. In this study, we evaluated the effectiveness of remedial mite control on clearing DWV from a colony. DWV titres in adult bees and pupae were monitored at 2 week intervals through summer and autumn in acaricide-treated and untreated colonies. The DWV titres in Apistan treated colonies was reduced 1000-fold relative to untreated colonies, which coincided with both the removal of mites and also a turnover of the bee population in the colony. This adult bee population turnover is probably more critical than previously realized for effective clearing of DWV infections. After this initial reduction, subclinical DWV titres persisted and even increased again gradually during autumn, demonstrating that alternative non-Varroa transmission routes can maintain the DWV titres at significant subclinical levels even after mite removal. The implications of these results for practical recommendations to mitigate deleterious subclinical DWV infections and improving honeybee health management are discussed.Deformed wing virus (DWV) is a lethal virus of honeybees ( Apis mellifera). At highly elevated titres, it causes wing deformities in developing pupae, resulting in flightless adults that die shortly after emerging , , . I. IVarroacaricide . However removed .Varroa mite removal treatment to evaluate the time necessary to clear a DWV infection from a honeybee colony after mites are removed. Such information would be valuable for improving honeybee health management and colony survival by optimizing the duration and the timing of acaricide treatments.The aim of this study was to quantify the DWV infection dynamics during and following a \u2122 according to manufacturer recommendations while the other colony received no mite-control treatment. Apistan\u2122 is a potent synthetic pyrethroid acaricide with up to 98\u2013100% efficacy against Varroa mite infestation , , . T. TVarroatic bees .7 virus particles/bee are usually sufficient for successful oral infection of larvae or adult bees . D. D7 viruult bees . As brooult bees , 42]. S. S7 viruult bees .Varroa control treatments are administered too late in the season, the overwintering bees will have already been reared under Varroa-infested conditions and may be too ill-affected by virus infections to survive the winter, even if the mite treatment itself was effective at removing the mites.Honeybee colony death most often occurs during the winter months in temporal climates during the sensitive overwintering phase of the annual colony cycle . The lonVarroa treatment regime is probably more critical than previously realized. Highly infected adult bees must be replaced with a new generation of adults reared in a Varroa\u2013free environment, so that new and progressively healthier bees will nurse and feed the larvae of the long-lived overwintering bees. By conducting our study over the summer months it was possible to observe the influence of the bee population dynamics in addition to mite removal on DWV infections. A previous study using Apistan treatment in the late summer showed high DWV titres in adult bees (> 1010 copies / bee) and pupae (> 109 copies / bee) over the entire 6-week study , [, [Varroae spring , causingS1 FileVarroa mite removal and a bee population turnover.Persistence of subclinical deformed wing virus infections in honeybees following (XLSX)Click here for additional data file.S1 TablePrimer sequences and performance indicators, including the melting temperature of PCR products, for the RT-qPCR assays for DWV and internal reference gene RP-49.(PDF)Click here for additional data file."} +{"text": "Normal, youthful arteries generally maintain constant radius/wall thickness ratios, with the relationship being described by the Laplace Law. Whether this relationship is maintained during aging is unclear. This study first examines the Laplace relationships in postmortem coronary arteries using a novel method to correct measurements for postmortem artifacts, uses data from the literature to provide preliminary validation, and then describes histology associated with low circumferential stress. Measurements of radius and wall thickness, taken at sites free from atheromas, were used with national population estimates of age-, gender-, and race-specific blood pressure data to calculate average circumferential stress within demographic groups. The estimated circumferential stress at ages 55-74 years was about half that at ages 18-24 years because of a disproportionate increase of wall thickness relative to artery radius at older ages, violating the expected relationships described by the Laplace Law. Arteries with low circumferential stress (estimated at sites distant from atherosclerosis) had more necrotic atheromas than arteries with high stress. At sites with low stress and intimal thickening, smooth muscle cells (SMCs) were spread apart, thereby diminishing their density within both the intima and media. Thus, older arteries displayed both low circumferential stress and abundant matrix of low cellularity microscopically. Such changes might alter SMC-matrix interactions."} +{"text": "Extracorporeal membrane oxygenation (ECMO) is a therapeutic option used increasingly in the treatment of severe acute respiratory distress syndrome (ARDS). Choosing an adequate cannula type and insertion site can be a challenge. The insertion of a bi-caval dual lumen catheter in the superior vena cava instead of two venous single-lumen catheters facilitates mobilisation and physiotherapy of patients, and hence is being used more and more .A middle-aged patient was admitted to our hospital after severe multiple trauma. Before admission to our hospital, damage control surgery including bilateral diaphragmatic repair and ileotransversostomy was performed.The postoperative course was complicated by disseminated intravascular coagulation (DIC). Six days after the accident, the patient could be stabilized to be eligible for transportation to the hospital by an air rescue service. The patient was transferred directly to the Surgical ICU under controlled mechanical ventilation.Within the first 24\u00a0h after admission, the respiratory function deteriorated to ARDS. Advanced respiratory support, including veno-venous ECMO, was applied to sustain gas exchange in the hope it could improve survival. Because of the underlying complex abdominal trauma we tried to insert a bi-caval dual lumen catheter into the right jugular vein. Due to surgical reconstruction of the bilateral diaphragmatic rupture and consecutive anatomical changes, several attempts to place either the guide wire or the catheter tip into the inferior vena cava (IVC) under transthoracic and transoesophageal echocardiography visual guidance failed; both guide wire and dual lumen catheter could not bypass the right ventricle to the IVC..Therefore, we decided to insert two single lumen catheters into the right jugular and femoral vein, whereupon ECMO treatment could be performed without further technical problems. In a post-hoc reconstruction of the thoracic computed tomography (CT) scan we discovered an altered path of IVC transition into the right atrium following surgical repair of the bilateral diaphragmatic rupture Fig.\u00a0.Fig. 1PIn patients with right-sided diaphragmatic rupture and surgical reconstruction we recommend a three-dimensional reconstruction based on three-dimensional echocardiography or CT of the venous inflow to the right atrium before attempting to insert a bi-caval dual lumen catheter . Notwith"} +{"text": "The immune system has evolved pairs of activating and inhibitory receptors that modulate the magnitude of immune responses, enabling the maintenance of immune homeostasis. Inhibitory signaling dampens the immune response, which prevents inflammatory damage to the host. It has now become increasingly clear that viruses have evolved means of exploiting the inhibitory signaling pathways of the immune system in order to blunt the responses that would otherwise abrogate infection. Recent evidence demonstrates how viruses exploit inhibitory receptors both for host cell entry and to down-regulate antiviral responses for enhanced viral pathogenesis. Both acute and chronic viral infections also induce expression of intermediates of inhibitory signaling for improved odds of survival within the intracellular environment. This review highlights and synthesizes from recent findings how medically important viruses exploit the inhibitory pathways that maintain immune homeostasis for successful human infection.The rapid initiation and timely termination of the immune response are coordinated by paired receptors expressed on immune cells. Paired receptors consisting of activating and inhibitory receptors recognize self and non-self ligands. They are essential for maintaining self-tolerance, mounting an immune response during infection, and modulating the intensity of the response to prevent autoimmunity and inflammatory damage to bystander cells . ActivatAlthough activating and inhibitory signals are integrated for immune homeostasis, they might not contribute proportionately to signaling output due to dominant inhibitory signaling, as exemplified by natural killer (NK) cell responses . NK cellThe complexity of signal integration is further underscored by how signaling outcome is tuned by viral manipulation of inhibitory signaling. Coevolution of viruses and their hosts has resulted in viruses acquiring strategies for attenuating immune responses to favor viral replication and disease in humans. Viruses are known to utilize inhibitory receptors for host cell entry, which also initiate inhibitory signaling to down-regulate antiviral responses for enhanced viral replication. The recent use of quantitative temporal viromics, which profiles proteomic changes in viral and host cell proteins over time, has demonstrated how viruses also dramatically alter the expression of cell surface proteins to counter the host cell\u2019s defenses . FinallyThe viral life cycle starts with host cell entry, which involves direct fusion with cell membrane or ligating an appropriate receptor to trigger endocytosis, pinocytosis, or macropinocytosis. Use of inhibitory receptors during host cell entry could thus simultaneously initiate inhibitory signaling to dampen the immune response for enhanced viral replication .CD300a is an inhibitory receptor that belongs to the CD300 family of transmembrane receptors. It binds cell surface phosphatidylserine and phosphatidylethanolamine (PE), which are exposed following increased levels of intracellular calcium during human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) infection . InteracDENV is also known to ligate leukocyte immunoglobulin-like receptor B1 (LILRB1) , an inhi+ T cells, and binding of HIV-1 to DCIR promotes infection of DCs and CD4+ T cells .,42.+ T cnfection . T cell feration ,45.+ T cells, rapidly inducing a transcriptional state synonymous with T cell exhaustion or respihaustion . AntigenA substantial body of work has now refined our mechanistic understanding of how various medically important viruses manipulate inhibitory signaling for survival within the host cell. Given that members of a virus family share many conserved structural and non-structural proteins, it is plausible that viral strategies to manipulate inhibitory signaling could be relevant to a broader range of viruses than those discussed here. Understanding how viruses exploit inhibitory signaling could lead to rationally designed interventions that interrupt these critical virus\u2013host interactions. The potential of an anti-PD-L1 antibody in reducing viral reservoirs in HIV-1 patients was recently evaluated in a clinical trial (NCT02028403). We anticipate that a combination of therapies targeting critical steps of the viral life cycle and boosting different arms of the immune response could provide recourse for both acute and persistent viral infections."} +{"text": "The discovery of RNA interference (RNAi) has been a major scientificbreakthrough. This RNA-guided RNA interference system plays a crucial role in awide range of regulatory and defense mechanisms in eukaryotes. The key enzyme ofthe RNAi system is Argonaute (Ago), an endo-ribonuclease that uses a small RNAguide molecule to specifically target a complementary RNA transcript. Twofunctional classes of eukaryotic Ago have been described: catalytically activeAgo that cleaves RNA targets complementary to its guide, and inactive Ago thatuses its guide to bind target RNA to down-regulate translation efficiency. Arecent comparative genomics study has revealed that Argonaute-like proteins arealso encoded by prokaryotic genomes. Interestingly, there is a lot of variationamong these prokaryotic Argonaute (pAgo) proteins with respect to domainarchitecture: some resemble the eukaryotic Ago (long pAgo) containing a completeor disrupted catalytic site, while others are truncated versions (short pAgo)that generally contain an incomplete catalytic site. Prokaryotic Agos with anincomplete catalytic site often co-occur with (predicted) nucleases. Based onthis diversity, and on the fact that homologs of other RNAi-related proteincomponents (such as Dicer nucleases) have never been identified in prokaryotes,it has been predicted that variations on the eukaryotic RNAi theme may occur inprokaryotes. TtAgo fromThermus thermophilus and RsAgo fromRhodobacter sphaeroides. Like eukaryotic Argonautes, bothTtAgo and RsAgo are long pAgos that areco-purified with oligonucleotide guides , themajority of which are complementary to plasmids. Together with the observation thatTtAgo target DNA,this has led to the conclusion that both pAgos play a role in host defense .However, apart from these similarities there are important functional differencesbetween the two bacterial Argonaute proteins. The guides acquired byRsAgo are mRNA-derived RNA oligonucleotides that target the templatestrand of plasmid genes. As RsAgo lacks a catalytic site, it mostlikely requires a partner nuclease for target cleavage. In contrast,TtAgo acquires DNA guides that allow targeting of AT-rich sequences ofdouble-stranded plasmid DNA. Whereas the functional nuclease site ofTtAgo catalyzes nicking of a single targeted DNA strand, twoTtAgos loaded with overlapping complementary guides can generatedouble-stranded DNA breaks. Recent studies by us and the working group of Alexei Aravin have described molecularanalyses of two distinct bacterial Argonautes, These studies have revealed interesting variations on the eukaryotic RNAi theme. Severalbasic features of these two variant pAgos remain elusive, concerning mechanistic detailsof both guide acquisition and target interference. Moreover, apart from the twocharacterized prokaryotic Argonautes, many more pAgo variants exist, that may differ infunctionality with respect to (i) guide preference (RNA/DNA), (ii) target specificity(RNA/DNA), and (iii) catalytic mechanism (nuclease activity). Apart from providinginsights in the evolution of the prokaryotic Ago variants and their eukaryoticcounterparts, future research will aim at revealing the molecular basis for the distinctfunctionality of these different pAgo variants. Moreover, gained insights will result inan interesting set of novel nucleases that may allow for dedicated geneticengineering."} +{"text": "Coral reefs are among the most biodiverse and productive ecosystems on Earth, and provide critical ecosystem services such as protein provisioning, coastal protection, and tourism revenue. Despite these benefits, coral reefs have been declining precipitously across the globe due to human impacts and climate change. Recent efforts to combat these declines are increasingly turning to restoration to help reseed corals and speed-up recovery processes. Coastal restoration theory and practice has historically favored transplanting designs that reduce potentially harmful negative species interactions, such as competition between transplants. However, recent research in salt marsh ecosystems has shown that shifting this theory to strategically incorporate positive interactions significantly enhances restoration yield with little additional cost or investment. Although some coral restoration efforts plant corals in protected areas in order to benefit from the facilitative effects of herbivores that reduce competitive macroalgae, little systematic effort has been made in coral restoration to identify the entire suite of positive interactions that could promote population enhancement efforts. Here, we highlight key positive species interactions that managers and restoration practitioners should utilize to facilitate the restoration of corals, including (i) trophic facilitation, (ii) mutualisms, (iii) long-distance facilitation, (iv) positive density-dependence, (v) positive legacy effects, and (vi) synergisms between biodiversity and ecosystem function. As live coral cover continues to decline and resources are limited to restore coral populations, innovative solutions that increase efficiency of restoration efforts will be critical to conserving and maintaining healthy coral reef ecosystems and the human communities that rely on them. Coral reefs are one of the most biodiverse and productive ecosystems on Earth, and provide critical services to at least 500 million people throughout the world . In addiFor many decades, the paradigm in coastal restoration has been to minimize negative interactions between transplant neighbors . This paWith increased consideration of facilitation in ecological theory , recent Trophic facilitation occurs when one species is positively impacted through the feeding activities of another species. One example includes trophic cascades where predators, by suppressing densities of primary consumers, can increase densities of basal prey species such as plants has been studied for decades. Results of comparative and experimental studies have shown that herbivorous fish and urchins are critical for the success of corals, and this positive interaction is general across almost all regions where corals occur . BecauseDrupella snails in the Western Indian Ocean , which provide substantial nutrition to corals and enhance skeletal deposition is one of the most well-known reciprocal positive interactions that can encourage healthy coral reef functioning. While coral reefs provide habitat, CCA is critical for cementing and stabilizing reef structure and facilitating settlement of coral larvae . Reef-dwseastars . Similarseastars , predatiseastars , and verseastars . Many fiseastars .Despite these many examples of mutualisms that support coral success, few studies to date have examined or experimented with incorporating species-specific mutualisms into restoration. One recent study that seeded a reef with sponges prior to transplanting corals found significant increases in rubble consolidation that in turn enhanced coral survivorship in that environment . SimilarPositive interactions can also occur between species that are not in contact but separated by distances of tens or thousands of meters . Long-diDecades of research has shown that the health, productivity, and biodiversity of coral reefs is directly related to their proximity to tropical seagrass meadows and mangrove forests. For example, both habitats facilitate corals by reducing stressors such as sedimentation or nutrient pollution from coastal development and runoff that may smother corals or enhance algal overgrowth . SeagrasDiadema) that live within the interstitial matrices of larger corals found increasing density significantly reduced coral growth within the first three months of transplantation, likely due to competition for space (Montipora digitata in high density (spaced 10-cm apart) and low density (spaced 20-cm apart) plots over 15 months. These studies suggest that studies examining the effects of density on coral transplants may have varied results depending on spacing between colonies. For endangered Caribbean acroporid corals, recent experimental research shows a unimodal relationship may exist, with positive density effects occurring at moderate levels but negative density effects occurring at higher densities and planting configuration of staghorn coral Acropora ensities . Howeverxcrement While most of these studies examine colony-specific metrics, such as growth and survivorship of individual corals, the effects of density are likely affected by environmental stressors and temporal scales. Although ecological theory suggests that positive density dependency may emerge under high stress conditions in coral reefs, no studies to date have examined how the impacts of density vary across a stress gradient. For instance, because of the tendency of branching corals to fuse, higher density plots may enhance structural resistance to wave energy such as intense storms , due to a history of restoration methods that take advantage of their high growth rates and ease of propagation through fragmentation (Orbicella spp.). In addition, Caribbean branching corals can be more susceptible to natural enemies such as predators and disease relative to conspecifics, however this facilitation stopped when nutrient enrichment was introduced to plots. Diverse coral species facilitated A. cervicornis growth and survivorship by reducing the number of coral predators that attacked plots of A. cervicornis or in areas where stress is not an issue but recruitment limitation is impeding natural recovery . For newHarnessing naturally-occurring positive interactions in restoration designs has recently been suggested and demo (1)Identifying specific trophic linkages or food webs that promote coral health and transplanting corals in areas with where these food webs are robust and protected. (2)Identifying mutualisms between corals and other reef- or coral-associated organisms that promote coral health and enhancing or protecting these mutualistic partners. (3)Locating sites for coral restoration close to healthy and well-functioning seagrass and mangrove habitats and protecting these habitats from extractive or destructive uses. (4)Identifying species-specific density effects for corals of restoration interest to take advantage of transplant densities that facilitate coral growth or survivorship. (5)Exploring the legacy of former reef-builders or occupiers, such as coral skeletons left behind, for use in coral transplantation. (6)Determining ways in which increased coral diversity facilitates the success of coral transplants as well as the long-term success of the restored coral reef community to environmental fluctuations and disturbances ."} +{"text": "Drosophila imaginal disc cells exhibit preferred cell division orientations according to location within the disc. These orientations are altered if cell death occurs within the epithelium, such as is caused by cell competition or by genotypes affecting cell survival. Both normal cell division orientations, and their orientations after cell death, depend on the Fat-Dachsous pathway of planar cell polarity (PCP). The hypothesis that cell death initiates a planar polarity signal was investigated. When clones homozygous for the pineapple eye (pie) mutation were made to initiate cell death, neither Dachsous nor Fat was required in pie cells for the re-orientation of nearby cells, indicating a distinct signal for this PCP pathway. Dpp and Wg were also not needed for pie clones to re-orient cell division. Cell shapes were evaluated in wild type and mosaic wing discs to assess mechanical consequences of cell loss. Although proximal wing disc cells and cells close to the dorso-ventral boundary were elongated in their preferred cell division axes in wild type discs, cell shapes in much of the wing pouch were symmetrical on average and did not predict their preferred division axis. Cells in pie mutant clones were slightly larger than their normal counterparts, consistent with mechanical stretching following cell loss, but no bias in cell shape was detected in the surrounding cells. These findings indicate that an unidentified signal influences PCP-dependent cell division orientation in imaginal discs. Oriented cell division influences how animal tissues grow, especially in tissues where cells are not very motile\u20134. It isDrosophila is altered in the vicinity of apoptotic cells. The. The53].pie homozygous clones to those of pie heterozygous or wild type cells at comparable locations pathway of tumor suppressors, 60\u201363. s mutants. Cell dict growth. Recent ct growth, 68. Thi"} +{"text": "Direct comparisons revealed that EOs showed greater response to cannabis cues in the dorsal striatum than LOs . Within-group analyses revealed that EOs showed greater neural response to cannabis cues in the dorsal striatum, whereas LOs exhibited greater neural response to cannabis cues in the ventral striatum. Although cross-sectional, these findings are consistent with recent addiction theories suggesting a progressive shift from ventral to dorsal striatal control over drug-seeking behavior and highlight the importance of age of onset of cannabis use on the brain and cognition.Addiction theories posit that addiction is the result of a progressive transition from voluntary to habitual, compulsive drug use\u2014changes that have been linked, in animals, to a shift from ventral to dorsal striatal control over drug-seeking behavior. Thus, we hypothesized that early-onset (EOs) cannabis users versus late-onset (LOs) cannabis users might exhibit, respectively, greater dorsal versus ventral striatal response to drug cues. We used functional magnetic resonance imaging and an event-related blood oxygen level-dependent backward-masking task to evaluate striatal responses to backward-masked cannabis cues in EOs (<16 years old, These transitions include a shift from ventral to dorsal striatal control over behaviors that contribute to habitual and progressively compulsive drug seeking.10\u201312 The majority of the research supporting this theory has been conducted in animal models; however, recent human studies on age of onset of cannabis use may provide additional support for such brain changes and impairments in prefrontal inhibitory control. Specifically, early (before age 16) onset of cannabis use (EO) has been associated with structural connectivity differences of the orbitofrontal cortex (OFC),13 decreased white matter integrity in fibers connecting the right and left dorsolateral prefrontal cortex,14 and increased functional connectivity between the OFC and prefrontal and motor regions.15 Furthermore, research indicates that EO cannabis users (EOs) perform worse than late-onset (age 16 or later) cannabis users (LOs) across a variety of neurocognitive domains, including measures of sustained attention, impulse control, and executive functioning.17 Together, these findings suggest that EO of cannabis use may contribute to morphological alterations in prefrontal brain regions that are associated with cognitive control deficits observed in EOs.Although cannabis use may lead to alterations in the brain and cognition, these changes occur over time. Indeed, addiction theories posit that substance use disorders are the result of \u201ca series of transitions from initial voluntary drug use to habitual, and ultimately compulsive drug use\u201d19 and investigated the associations between striatal activity and cannabis craving. Based on the research described above, we expected that EOs would show neural response to backward-masked cannabis cues in the dorsal striatum, whereas LOs would show neural response to cannabis cues in the ventral striatum. Because research suggests that heightened motivational/emotional states lead to heightened sensitivity to associated cues,20 we also hypothesized that cannabis craving would correlate with these cannabis cue-related activations and that different association patterns would emerge in EOs and LOs.While morphological and cognitive changes have been well characterized in EOs, it remains unknown whether age of cannabis use onset is differentially associated with ventral or dorsal striatal activity or control over cannabis use. Thus, the current study explored potential differences in striatal activity during cannabis cue exposure among EOs and LOs who report similar patterns of cannabis use. We compared striatal responses to cannabis cues presented during a functional magnetic resonance imaging (fMRI) backward-masked cannabis cue paradigm19 Participants were 41 treatment-seeking individuals who met the DSM-IV21 criteria for cannabis dependence. Participants were medically stable, educated, and had no concomitant serious comorbid psychiatric or substance use disorders (except nicotine dependence). See All study procedures adhered to the Declaration of Helsinki and were approved by the University of Pennsylvania Institutional Review Board. Details of the recruitment process and selection criteria were reported previously.As part of a larger study, participants completed baseline questionnaires, interviews, and an MRI session. Participants were asked to abstain from alcohol and illicit substances for the 24\u2009h before the MRI session and completed a urine drug screen and alcohol breathalyzer. All participants were positive for cannabis use and negative for other substance use.22 and the Addiction Severity Index23 measured lifetime alcohol and substance use and age of onset of cannabis use. Based on the existing literature and that age 16 is when significant brain changes typically occur,24 participants were grouped as EO (<16 years old) or LO (\u226516 years old). Lifetime cannabis exposure was quantified using gram years.25 The Marijuana Craving Questionnaire-Short Form (MCQ-SF)26 measured self-reported baseline cannabis craving using a scale covering behavioral experiences associated with aversive and appetitive aspects of drug motivation. The magnitude of cannabis craving was assessed before the neuroimaging session and was determined by summing items of the MCQ-SF.Cannabis, alcohol, and other drug use during the preceding 30 days was assessed with the Timeline Follow-Back interview,19 Briefly, imaging data were analyzed using statistical parametric mapping . Imaging analyses were focused on regions of interest (ROIs) in the dorsal and ventral striatum. The ROIs were created using the Harvard\u2013Oxford probabilistic anatomical atlas provided with the FMRIB Software Library.27 To control for type 1 error, neural activity within the ROI mask of each voxel was considered significant at a nominal alpha level of p<0.01 and a cluster extent of 50 contiguous resampled voxels as determined via Monte Carlo simulations using 3dClustSim Analysis of Functional NeuroImages software28 (http://afni.nimh.nih.gov/).A detailed description of the backward-masking cannabis cue paradigm, imaging parameters, and analyses are provided in previous publications.2 =4.37, p=0.04); however, small sample size prevented the exploration of potential sex differences in the current analyses.As noted in p<0.01, k>50 voxels). Analyses among EOs revealed greater response to backward-masked cannabis cues in the dorsal striatum, whereas LOs showed greater response to backward-masked cannabis cues in the ventral striatum . There were no significant correlations among LOs.Correlation analyses between cannabis craving scores and As hypothesized, preliminary analyses revealed that EOs and LOs showed different patterns of neural response to backward-masked cannabis cues, with EOs showing greater response within the dorsal striatum compared to LOs. When examining groups separately, EOs exhibited neural response to backward-masked cannabis cues in the dorsal striatum, yet LOs exhibited neural response in the ventral striatum. It is important to note that the EO and LO groups reported similar patterns of recent cannabis use, and as such, findings are not due to differences in recent cannabis use. Furthermore, groups did not show significant differences in lifetime cannabis use, suggesting that striatal activation findings in EOs and LOs were specific to age of onset of cannabis use and not due to history of daily use or duration of use. Correlation analyses revealed that dorsal striatal activations in EOs correlated with cannabis craving. Although cross-sectional, these preliminary findings are the first of their kind and suggest that differential striatal activation between EOs and LOs may reflect cannabis-induced alterations in neuroplasticity during early adolescent maturation that strengthened reward-related associations in EOs and possibly accelerated the shift from voluntary occasional use to habitual compulsive use.13\u201315 provide evidence that EOs also exhibit striatal brain changes that may underlie habitual, compulsive cannabis use, whereas LOs exhibit a pattern of neural activity in the ventral striatum that is characteristic of voluntary cannabis use, which may be regulated by prefrontal control processes. Although compulsivity and impulsivity were not assessed in the current study, future research in a larger sample could explore these hypotheses more fully.Our findings, in conjunction with previous research demonstrating altered prefrontal structure and function,Limitations should be considered when interpreting the findings. First, sample size is moderate; thus, future studies should include a larger sample with greater diversity to validate these findings and ensure generalizability. Furthermore, we did not assess or control for the influence of menstrual cycle phase/gonadal hormones, cannabis withdrawal symptoms, or motivations for treatment, and as such, it remains unclear as to whether these factors influenced findings. Finally, this study used a cross-sectional design, so it is not possible to know whether EOs exhibited ventral striatal activation earlier in their addiction. Longitudinal studies will be helpful in parsing the effects of these factors on cannabis cue reactivity.In summary, EOs and LOs exhibited differential patterns of striatal response to backward-masked cannabis cues, with EOs demonstrating dorsal striatal response and LOs showing a ventral striatal response. This differential pattern of striatal response parallels recent hypotheses of drug addiction, through which a series of transitions from initial voluntary use to habitual, compulsive use involve transitions from ventral to dorsal striatal control. Although additional research is warranted, our findings are the first neuroimaging findings among cannabis users to demonstrate differential striatal responding to cannabis cues in EOs and LOs."} +{"text": "The redox balance modulation is also highly dependent on the level of physical activity. For example, both high-intensity exercise and inactivity, representing the two ends of the physical activity spectrum, are known to promote oxidative stress. Numerous to-date studies indicate that hypoxia and exercise can exert additive influence upon redox balance alterations. However, recent evidence suggests that moderate physical activity can attenuate altitude/hypoxia-induced oxidative stress during long-term hypoxic exposure. The purpose of this review is to summarize recent findings on hypoxia-related oxidative stress modulation by different activity levels during prolonged hypoxic exposures and examine the potential mechanisms underlying the observed redox balance changes. The paper also explores the applicability of moderate activity as a strategy for attenuating hypoxia-related oxidative stress. Moreover, the potential of such moderate intensity activities used to counteract inactivity-related oxidative stress, often encountered in pathological, elderly and obese populations is also discussed. Finally, future research directions for investigating interactive effects of altitude/hypoxia and exercise on oxidative stress are proposed.Increased oxidative stress, defined as an imbalance between prooxidants and antioxidants, resulting in molecular damage and disruption of redox signaling, is associated with numerous pathophysiological processes and known to exacerbate chronic diseases. Prolonged systemic hypoxia, induced either by exposure to terrestrial altitude or a reduction in ambient O Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are constantly produced within the living cells , exercise likely drives more oxidative stress than systemic hypoxia per se. This hypothesis is congruent with the findings of Sinha et al. ]. The following section recaps the up-to-date studies scrutinizing the influence of activity during prolonged hypoxic/altitude exposures.Besides increasing oxidative stress, acute hypoxic exercise may also, at least transiently, alter antioxidant capacity performed upon acute exposure and following 13-day of acclimation did not increase oxidative stress. It is also important to note that the employed oral antioxidant supplementation was inefficient in reducing hypoxia-induced oxidative stress. Very informative data on the effects of chronic exercise training during prolonged hypoxic exposures on oxidative stress and antioxidant status have also been derived from investigations related to altitude training in (mostly) endurance athletes. The vast majority of these studies were performed using the Live-High Train-Low altitude training modality (LHTL) first introduced by Levine and Stray-Gundersen performed twice daily throughout the 10-day hypoxic confinement period was shown to improve antioxidant capacity and thereby blunt hypoxia-related oxidative stress in untrained individuals , mostly underlined by augmented antioxidant capacity. On the other hand, performing exercise of higher-intensities seems to additively increase hypoxia-induced oxidative stress. This might compromise adaptations to hypoxic training in athletes and also prove detrimental for individuals who exhibit chronically elevated systemic oxidative stress levels. These observations need to be taken into account while providing expert-advice on altitude/hypoxic training, as well as guidelines for high altitude sojourns in vulnerable populations. Given that the exact mechanisms of the interactive effects of hypoxia and physical activity on redox balance are not entirely clear, future well-controlled investigations should scrutinize different dose-response effects of both in healthy as well as patient populations.TD, GM, and VP: Drafted the manuscript, revised the manuscript critically for important intellectual content, and approved the final version of the manuscript submitted.This study was supported by the Institut Universitaire de France.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "COPD is a common inflammatory disease of the airways, alveoli and microvasculature that is under-diagnosed in smokers at risk for the disease. The majority of COPD patients have mild airway obstruction. Symptomatic smokers with mild COPD are at higher risk for earlier mortality and poorer perceived quality of life than non-smokers. Moreover, dyspnoea and activity restriction are common among smokers with minor spirometric abnormalities. Tobacco-related inflammatory injury of the lungs manifests as heterogeneous physiological impairment with highly variable clinical expression. Thus, simple spirometry provides only a crude assessment of disease pathophysiology, especially in the early stages of the disease.1, plethysmographic lung volumes and resting inspiratory capacity being within the normal range.Several studies have shown consistent physiological abnormalities on oscillometry, together with abnormal configuration of the mid-volume maximal expiratory flow-volume loop and increased pulmonary gas trapping, which collectively point to the presence of extensive small airway dysfunction despite FEVE/VCO2 nadir) is common in mild COPD and mainly reflects high physiological dead space and thus a preponderance of lung units with high ventilation-perfusion ratios. This presentation explores the clinical consequences of this heterogeneous physiological impairment in smokers with unremarkable spirometry.Recent exercise studies in symptomatic smokers with or without mild COPD have highlighted that exercise limitation is common and is multifactorial but that respiratory factors such as increased dynamic mechanical constraints are contributory. Lung microvascular inflammation, disruption of the alveolar-capillary interface and reduced pulmonary perfusion are increasingly identified in smokers with minor spirometric abnormalities. In this context reduced ventilatory efficiency during exercise (high V"} +{"text": "Tumour microenvironment (TME) is a key determinant of tumour growth and metastasis. TME could be very different for each type and location of tumour and TME may change constantly during tumour growth. Multiple counterparts in surrounding microenvironment including mesenchymal-, hematopoietic-originated cells as well as non-cellular components affect TME. Thus, therapeutics that can disrupt the tumour-favouring microenvironment should be further explored for cancer therapy. Previous efforts in unravelling the dysregulated mechanisms of TME components has identified numerous protein tyrosine kinases, while its corresponding inhibitors have demonstrated potent modulatory effect on TME. Recent works have demonstrated that beyond the direct action on cancer cells, tyrosine kinase inhibitors (TKIs) have been implicated in inactivation or normalization of dysregulated TME components leading to cancer regression. Either through re-sensitizing the tumour cells or reversing the immunological tolerance microenvironment, the emergence of these TME modulatory mechanism of TKIs supports the combinatory use of TKIs with current chemotherapy or immunotherapy for cancer therapy. Therefore, an appropriate understanding on TME modulation by TKIs may offer another mode of action of TKIs for cancer treatment. This review highlights mode of kinase activation or paracrine ligand production from TME components and summarises the findings on the potential use of various TKIs on regulating TME components. At last, the combination use of current TKIs with immunotherapy in the perspectives of efficacy and safety are discussed. Protein phosphorylation, one of the most prevalent post-translational modification of protein, is tightly regulated by specific protein kinase that transfer phosphate group to the amino acid residue . To our The binding of ligand such as growth factors or cytokines to the extracellular domains of RTKs initiate the signalling cascade by changing its structure and kinase activation. Whereas the non-RTKs which lack of extracellular domains mainly serves as the downstream effector of RTKs . UnderstKinase inhibition in tumour cells by tyrosine kinase inhibitors offers promising clinical benefit to cancer patients, especially, who have tumour with mutated kinases . NonetheEndothelial cells are known to play pivotal role in tumour neovascularization. The role of TKIs in endothelial cells has been identified either through direct action on endothelial cells or through mediating the communication between endothelial cells and tumour cells. Earlier studies observed the PKI 166, epidermal growth factor receptor (EGFR) inhibitor attenuated EGFR activation in tumour associated endothelial cells and caused cell apoptosis. The action is deemed to be EGFR-specific as it was not observed on EGFR-negative mice . SubsequGiven that several target receptors act as endothelial cell regulators, multi-targeted tyrosine kinase inhibitors are also being evaluated for better therapeutic outcome. The dual tyrosine kinase inhibitor AEE788 is utilized to inhibit EGFR and VEGFR binding on endothelial cells and resulted in apoptosis in both tumour and endothelial cells . The intCancer associated stromal cell, comprised of approximately 40% of total tumour volume , plays aFibroblast/stromal cells highly expressed PDGF receptors; production of PDGF ligands by cancerous cells triggered the up-regulation of fibroblast growth factors (FGF) by fibroblast which favours of tumour angiogenesis and proliferation. Notably, bone marrow stromal cells highly express PDGFR\u03b2, while minimally detected in cancer cells. Therefore, there are emerging strategies targeting PDGFR or FGF on fibroblast in regressing tumour cell growth. For instances, inhibition of PDGFR by imatinib declined the secretion of FGF-2 and FGF-7 by cancer associated fibroblast resulted in reduced tumour progression ; combinaThe acquired resistance of tumour cells towards TKI has been frequently reported , 54. TheApart from endothelial cells and fibroblast, mesenchymal stem cells are also able to secrete EGF and express EGF receptor. Suppressing EGF receptor using AG1478 therefore suppressed mesenchymal stem cells mediated mammosphere formation . YoshidaEarly findings postulated that the osteoblast, bone marrow precursor cells in bone marrow microenvironment tend to produce substances for instance HGF which further promotes cancer cell proliferation and migratory activities. Intervention of NK4, HGF inhibitor or imatinib mesylate declined the cancer cells functions in the presence of osteoblast , 73. As The immunosuppressive environment, which primarily composed of myeloid-derived suppressor cells (MDSCs), regulatory T lymphocytes (Treg) and tumour associated macrophages, promoted escape of tumour cells from immune surveillance . AccumulMyeloid-derived suppressor cells MDSCs, the bone marrow derived heterogenous suppressor cells, has been shown to positively correlate to cancer progression. In advanced stage of cancer patients, tumour may induce expansion of MDSCs and in turn resulted in suppressive action of innate and adaptive immune response by high populations of MDSCs in tumour microenvironment . SunitinIn addition to VEGFR/c-KIT as therapeutic target of MDSCs, the use of AZD4547, the FGFR inhibitor has also been proposed as a target of MDSCs action. AZD4547 reduced breast cancer proliferation and migration through declining the MDSCs population while enhancing T populations . ConsistAccumulating studies have related the cross-talk between MDSCs and regulatory T subset, generally, MDSCs recruited and supported the activation of T regulatory populations . Thus, iDasatinib, a multikinase inhibitor, reduced T cellular proliferation, its associated cytokine production and cellular response , 103. ThOn the other hand, many small molecules inhibitors may acquire resistance upon disease progression whereby single treatment may not sufficient in altering the immunosuppressive tumour microenvironment. The VEGFR inhibitor, axitinib has been shown to increase CD4 (+) and CD8 (+) T population, while progressive patients showed increase regulatory T subset and PD-1 expression following axinitib treatment . LikewisMuch of the past and current efforts in eliminating the tumour associated macrophages (TAMs) have focussed on blocking TAMs survival or recruitment, inhibiting TAMs function and re-polarizing the TAMs phenotype that favour tumour regression. Typically, the c-fms kinase, or known as CSF1 receptor is a ligand-activated kinase that modulate monocytes and macrophage survival and proliferation . The potTherefore, apart from macrophage depletion, therapeutic strategies in re-programming TAMs immunosuppressive phenotype towards anti-tumour profile by TKIs intervention have also emerged as potent TAMs-targeted cancer therapy. For instances, sorafenib treatment stimulated IL12, IL18 and IL6 production in TAMs after LPS priming, which further supported natural killer cells function . Tie2 reAccumulating studies postulate the BTK was activated/phosphorylated upon Toll like receptors (TLR) stimulation , and actRecruitment of mast cells to tumour microenvironment has been shown to promote pancreatic cancer cell survival and inhibition of mast cell degranulation led to cancer cell death. Intervention of PCI-32765, the BTK inhibitor, declined mast cells degranulation and cancer cell growth . The samExtracellular matrix ECM components including fibronectin, laminin and collagen have been shown to determine the fate of cancer cells whether to remain dormant or proliferative . It was It has been proposed in various types of human cancers that immunotherapeutic regimen could offer favourable outcome, though large-scale randomized, placebo-controlled trials shall be carried out prior to its application. Given the accumulating reports on acquired resistance of TKIs, the use of TKIs alone as first-line treatment seems challenging in spite of its better prognosis. TKIs treatment often gain rapid but not durable tumour response, which result in early improvement of survival curve of cancer patients without clear beneficial effect on the overall survival. The effect of TKIs could be strategically complemented by immunotherapy, which induces a low percentage but highly durable tumour response . This noFurthermore, safety of the combination use is still contradicting and unclear. Some studies have reported the increased risk of adverse reaction after combination therapy, including higher incidence of grade 3/4 liver enzyme elevation (40\u201370%) and high incidence of interstitial lung disease (38%) . A lot oThe development of acquired resistance remain as the major clinical challenge to TKIs treatment, despite TKIs are still the first line therapeutic regimen for many malignancies. For instances, non-small cell lung cancer patients who initially well responded to EGFR inhibitors, erlotinib or gefitinib had host adaptive response and tumor growth within 6\u201312\u00a0months , 157. MaAlso, it is believed that cancer cells develop an immunosuppressive microenvironment for evasion from immune surveillance upon TKIs intervention. Although the detailed mechanisms of acquired immune evasion is not yet understood, previous studies suggested that the inducible expression of immune checkpoints PD-1/PD-L1 may be involved. Notably, the elevated expression of PD-L1 was observed in EGFR-resistant tumor biopsy compared to pre-treated tumor samples. This suggests the activation of immune checkpoint may hinder the treatment efficacy of TKIs to cancer patients . FurtherWith recognition of the actions of TKIs on TME, our previous studies have also suggested the beneficial role of complementing TKIs with immune-modulatory therapy. Complementary treatment using PHY906, a composite herbal formula that had potential to increase the therapeutic index of cancer treatments in multiple clinical trials, was recently identified to modulate TME in sorafenib-treated hepatocellular carcinoma (HCC). This immune-modulatory effect of PHY906 improved the anti-tumour TME signature and thereby enhanced the efficacy of sorafenib . An actiIn past decade, tyrosine kinase inhibitors targeting at tumour cells represent a promising therapeutic agent for cancer patients; yet, the use of TKIs in modulating tumour microenvironment is still in its infancy. The recent advances we summarized here emphasize the potential use of TKIs for re-educating or normalizing the dysregulated tumour microenvironment for cancer treatment. An understanding of the modulatory effect of TKIs on tumour microenvironment could expedite the maximal use of TKIs on cancer therapy as well as re-positions the existing TKIs as combination cancer treatment. Furthermore, phosphorylated status of target protein could also be determined by protein phosphatase, which belongs to another group of protein involved in microenvironment status of tumour cells, is worthy for further exploration. Much more efforts, either pre-clinically or clinically, is therefore anticipated in order to maximize the efficacy and safety for patients."} +{"text": "Macropinocytosis has long been known as a primary method for cellular intake of fluid-phase and membrane-bound bulk cargo. This review seeks to re-examine the latest studies to emphasize how cancers exploit macropinocytosis to further their tumorigenesis, including details in how macropinocytosis can be adapted to serve diverse functions. Furthermore, this review will also cover the latest endeavors in targeting macropinocytosis as an avenue for novel therapeutics. Macropinocytosis is an endocytic pathway that leads to internalization of large patches of plasma membrane along with extracellular fluid through irregularly formed vesicles called macropinosomes. When compared to endosomes originating from coated vesicles, macropinosomes are significantly larger by a factor of up to a thousand-fold and pancreatic cancer cells. When macropinocytosis is upregulated in GBM cells by a quinine-derivative chemical, Vacquinol-1, massive membrane ruffling and macropinocytosis lead to cell death through excessive vacuolization and deformations in the plasma membrane family receptors, where exosomes shed by cancer cells can internalize into distant cancer cells in a paracrine fashion through binding with RTKs via macropinocytosis in an H-Ras dependent manner to evade TNF-related apoptosis-inducing ligands (TRAILs) and subsequent apoptosis of one particular PIP5K, I\u03b3i2, leads to decreased oncogenic growth of breast cancer cells (Thapa et al., Another therapeutic venture includes disrupting cancer cell metabolic activity through inhibition of macropinocytosis (Zeitouni et al., Lastly, other therapeutic ventures have shown that hyper-stimulating macropinocytosis in cancer cells can lead to non-apoptotic cell death known as methuosis (Li et al., As cancer cells frequently employ macropinocytosis to aid in receptor regulation and internalize essential metabolites, extensive efforts have been underway in utilizing macropinocytosis to deliver cytotoxic therapeutics specifically into cancer cells. Some anti-cancer agents innately undergo macropinocytosis, such as AS1411, which internalizes into various cancer cells through cell-surface nucleolin-dependent mechanisms that activate macropinocytosis only in malignant cells (Reyes-Reyes et al., Potent cancer therapeutics that exhibit excessive, systemic toxicities or unstable pharmacokinetics from hydrophobic profiles are excellent candidates for conjugation to yield chemical conjugates or nanoparticles. The resultant conjugates or nanoparticles can be engineered to yield greater specificity and enhanced pharmacokinetics. In many other examples, synthetic conjugates comprising any combination of small chemicals, lipids, proteins, genetic components, and chemical scaffolds can be developed to form nanoparticles that can then be internalized into target cells via macropinocytosis. Nanoparticles, which vary widely in composition, size, chemical charge, and shape, all contribute to distinct, cellular specificities and in endocytic mechanisms (Kettler et al., Another intriguing therapeutic front includes conjugating cytotoxic payloads onto albumin primarily for enhancing drug pharmacokinetics and because albumin has long been observed to accumulate within solid tumors through macropinocytosis Kratz, . An examAnother component commonly used for conjugation is the poly-arginine peptide. As poly-arginine peptides induce macropinocytosis and cancer cells generally have increased macropinocytosis, efforts have been underway in conjugating poly-arginine peptides with cytotoxic compounds. These conjugates can be employed to deliver a variety of materials into cells, including cytotoxic reagents against cancer cells (Biswas et al., in vitro, with therapeutic proteins either electroporated into exosomes or intracellularly incorporated through targeted overexpression of genes in the cell cultures (Munson and Shukla, As cancers routinely internalize exosomes, a logical maneuver includes formulating therapeutics that mimic exosomes. Exosomes can be derived from same-host cells to avoid inducing immune responses (Hall et al., Mycobacterium smegmatis (Baltierra-Uribe et al., Salmonella (Francis et al., Plasmodium sporozoites, or malaria, also infiltrate into host hepatocytes by inducing macropinocytosis through the EphA2 receptor (Kaushansky et al., If cancers commonly exploit macropinocytosis for efficient endocytosis of scarce nutrients and proteins, it is not surprising that various pathogens also infiltrate into host cells through this pathway. Pathogens such as viruses and bacteria commonly enter human cells by activating macropinocytosis through receptor-dependent means. Several examples include human cytolomegavirus (Hetzenecker et al., Macropinocytosis appears to play vital roles across a variety of neurodegenerative diseases as well, and this has been comprehensively reviewed (Zeineddine and Yerbury, Cancer cells, in addition to pathogens and neurodegenerative diseases, all exploit macropinocytosis for its efficiency in endocytosis. In particular, cancer cells seem to possess increased macropinocytic activity to fulfill diverse functions that include metastasis, metabolism, and signal transduction Figure . For thiKH wrote the manuscript, SB edited the manuscript, BL selected the review topic and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Eurosurveillance invites authors to submit papers in the categories, Research articles, Surveillance and Outbreak reports, Reviews and Perspectives for a special issue on advanced diagnostics to inform public health policy.Recent advances in laboratory technology, including the application of qualitative and quantitative molecular diagnostics, proteomics (e.g. MALDI-TOF MS) and genomics, particularly whole genome microbial sequencing (WGS) and metagenomics are transforming the field of clinical and public health microbiology. The use of advanced methods enables unprecedented capability and capacity for rapid and comprehensive pathogen detection, quantitation and characterisation, when applied to clinical and environmental samples. Advanced diagnostics may therefore impact public health policy during specific incidents or on a wider scale.Topics of interest may include, but are not limited to:\u2022 Focused reviews portraying pathogen- or disease-specific use of advanced diagnostics in public health microbiology or practical aspects of integrating new diagnostics in public health;\u2022 Advanced laboratory tools for generating data that inform risk assessment and risk management;\u2022 Possible role of rapid diagnostic testing in public health and cross-border health security;\u2022 Moving to culture-independent public health microbiology;\u2022 Policy and Regulatory aspects of harnessing new technologies for public health.eurosurveillance@ecdc.europa.eu.The submission deadline is 15 April 2018. If you would like to submit a paper or ask for more information, please see our instructions for authors regarding article formats or contact the editorial team at"} +{"text": "Cerebrovascular disease (CVD) is often present in old age and may be associatedwith microstructural pathology of white matter (WM) and cognitive dysfunction.The current review investigated the relationship between CVD, cognitive statusand WM integrity as assessed by diffusion tensor imaging (DTI).DTI studies were searched on ISI and Pubmed databases from 2002 to 2012.Studies evidenced DTI changes in WM as associated with vascular disease andprovide increasing support for DTI as a valuable method for early detectionof CVD.DTI parameters can serve as important biomarkers in monitoring vasculardisease progression and treatment response and may represent a surrogatemarker of WM tract integrity. Depending on thesite, intensity, and severity, CVD may either cause or contribute to furthercognitive decline.2 Earlier reportsdescribe CVD pathology as a consequence of blood perfusion deficits generated byhypoxia, hypoperfusion and hemorrhage which in turn result in neuronal injury,necrosis, apoptosis and ischaemic penumbra.2 The presence and severity of CVD hinge on non-modifiablerisk factors such as ageing, gender and genetics but also on several other variablessuch as smoking, systemic arterial hypertension, diet and metabolic diseases.Structural studies have identified subcortical hyperintensities as macroscopic whitematter (WM) changes which have been cited by several reports as associated with CVD,mood disorders, executive dysfunction and higher conversion to dementia. Morerecently, the underlying pathology associated with normal-appearing WM as well asits clinical significance has become the main focus of investigation.3Cerebrovascular disease (CVD) occurs in one third of the populationin vivo.6 One of themost useful of these techniques is diffusion tensor imaging (DTI), which issensitized to the motion of water molecules as they interact within tissues, thusreflecting characteristics of their immediate structural surroundings.8 Earlier DTI studies used a region-of-interest (ROI) analysisapproach, with brain areas being delineated manually or with semi-automatedmethods.11 However the ROI approach has a number ofdrawbacks, such as difficulty precisely replicating and delineating anatomicalregions as well as the use of pre-selected brain areas rather than consideringdiffusion changes in the whole brain.12 To improve the objectivity and interpretability of DTI studies,Tract-Based Spatial Statistics (TBSS) was developed to enable DTI scans to becompared across subjects more robustly.13 TBSS is based on voxel-wise analysis, which approaches thewhole brain without any a priori selection of regions. Anotheradvantage of TBSS is that it minimizes the problem of misalignment.14 To date, the vast majority ofstudies have concentrated on the role of FA in cognitive disorders.17 However, a rangeof factors influence FA decreases, including myelination, axon density, axondiameter and intra-voxel coherence of fiber orientation.19Therefore, there is an increasing awareness of the limitations of single FAmeasurements, and of the need to investigate how other DTI indices change over the course of bothvascular and neurodegenerative diseases.15In recent years, novel methods of neuroimaging have enabled WM microstructureintegrity to be investigated 2 the influence ofmilder vascular risk factors such as controlled hypertension, or high normal bloodpressure is largely unknown.2Another promising topic of DTI investigation is the common pathological routesbetween CVD and Alzheimer's Dementia (AD), especially the landscape involvingneurodegenerative and vascular changes. Cerebral atherosclerosis is associated witha higher risk of AD while cardiovascular risk factors are associated withclinically-diagnosed AD and vascular dementia (VaD).20 Thesimilarities in association between cardiovascular risk factors and dementiadiagnosed as AD or VaD underline the relevance of CVD for aging-related cognitivedecline in general and the flaws in simplistic diagnostic categories.20 Although vascular and degenerationprocesses often overlap, relatively few studies have focused on the interactionbetween these two pathologies. Conversely, no serum or plasma biomarker has beenestablished as a reliable biomarker of CVD compared to other types of dementia andnon-demented individuals.20There is an open field of investigation on DTI and CVD. To date, the majority ofstudies conducted have investigated only WM abnormalities in relation toneurodegeneration predominantly among AD patients but the pathological processes ofWM associated with vascular disease are not yet fully understood. In contrast to thedamaging effects of CVD and untreated hypertension on diffusion-based parameters ofWM,This review investigated the main results of DTI studies in patients with CVD. Weaimed to discuss these results and the integration of diffusion findings withstructural data and WM microscopic pathology and progression of cognitive impairmentin relation to vascular disease.A systematic review of DTI studies on CVD was performed by searching data from ISIand Pubmed web databases from the first DTI studies in 2002 (January) to 2012 (May).The search strategy included key words aimed at investigating a broader spectrum ofprimary vascular disorders affecting subcortical areas, particularly white-matterlesions: DTI, vascular dementia, subcortical disease, white-matter, neuroimaging,dementia, MCI, blood vessels.All abstracts were independently read by six authors and those studies which complied with the inclusion criteria were selected forfurther reading. A manual search was also performed to retrieve articles related tothis subject found among the references of the selected studies. The articles whichsatisfied all the following criteria were included for further reading and analysis.For inclusion, articles had to:[1] have at least one DTI parameter, such as FA;21[2] be cohort, cross-sectional, or case-control studies with at least onecriterion for vascular dementia and mild cognitive impairment, vascular type as developed by theNINDS research group;4 and[3] provide data on cognitively impaired patients \u226560 years ofage, with or without clinical diagnosis of dementia;[4] include a comprehensive neuropsychological assessment.The Pubmed electronic search retrieved 156 articles. Only 12 remained eligible forfurther analysis. 22 The classical viewin which vascular disease was related to WM hyperintensity (WMH) burden has beenprogressively substituted by new insights on the pathological development of brainvascular disease and its dynamic interaction with neurodegeneration. DTI paperssupport previous evidence from genetics and biomarkers25 showingthat vascular disease plays an important role in the development and clinical courseof AD.26 The ensuing topics coveraspects of the pathology and clinical features of the studies.The majority of studies evidenced diffusion changes in WM as associated with vasculardisease and supported DTI as a valuable method for the early diagnosis ofCVD.The pathological basis of vascular changes. There is growing evidencefrom DTI studies demonstrating that macroscopic and microscopic changes in WM resultfrom distinct pathological processes which have been described by some authors as WMlesion formation and WM atrophy.27Both processes result from a complex combination of independent factors such as age,hypertension, metabolic and degeneration, but there is no established modelexplaining these underlying changes.2826 whereas temporal and occipital lobes weredescribed by another study.29 In athird study, periventricular areas were described as more susceptible to ischemicinjury.30The territorial pattern of progression of WM changes has been discussed in somepapers with equivocal findings. Parietal WM and the centrum semiovale were reportedas the regions most associated with the vascular pathology27 Additionally,one study showed that atrophy of the corpus callosum was significantly associatedwith changes in diffusion in deep WM hyperintensities. According to Schimidt etal.,31 such findings canfurther etiologic understanding of age-related WM damage because they argue againsta diffuse pathological process as the origin of WMH.Among the WM tracts most susceptible to damage due to atrophy of WM were thosecomponents of the limbic system (which comprise the anatomic substrate ofAlzheimer's disease) such as the fornix, the cingulum tracts and in the region ofthe hippocampus.Correlation of WM changes with clinical variables. Diabetes andhypertension32 have beencited as the most important clinical variables associated with CVD. Hypertension hasbeen associated with reduction in WM volume35 and increase in WMH burden.38 In a recentinvestigation,39 theeffects of Mean Blood Pressure were present both in subjects with mildcardiovascular risk and those with established hypertension. Hence, significanteffects of cognitive decline were present even in individuals outside thehypertensive range.39 Takentogether, these findings support that systemic vascular function is an importantvariable to be considered in the investigation of cognitive changes also in thecontext of patients without known vascular disease or overt brain vascularchanges.Use of overlapping DTI indices in the differential diagnosis between vasculardisease and neurodegeneration. Contrasting with earlier reports, recentevidence in vascular disease has attempted to investigate WM pathology through thecombination of FA and non FA indices15 thus following a general tendency seen in otherstudies, e.g. those with Alzheimer individuals.40 The overlap between axial and radial diffusionincreases was associated with atrophy of WM in different regions , while acuteaxonal injury results in a decrease in diffusion parallel to the fibers .27 Theseincreases suggest decreased packing within a voxel.43 An alternative explanation is that apparentincreases in axial diffusion may stem from a loss in fiber coherence among regionswith fiber crossing.44 Early reports characterize thevascular pathology of subcortical areas by extensive occlusion of arterioles andmicro-atherosclerosis. One study28showed statistically significant FA and MD differences in areas of WMH burden andthose with apparent normal WM. FA-MD and MD-DR overlaps may thus reflectdemyelination and axonal loss within the fibers and early vascular disease. However,as the interpretation of multiple indices is not clearly established, furtherstudies should comprehensively analyze the application of DTI indices to theunderstanding of complex interactions between vascular disease and degeneration. regions and coulCorrelation between DTI and neuropsychological testing. One outpatientstudy20 analyzed theassociation of brain structural parameters and cognitive tasks and found a greatercoefficient of correlation with diffusion indices than with WM volume or WM burdenrated by the Fazekas scale.20 In alarge multicenter study conducted by the LADIS multicenter group,31 which included 340 patients withvarying degree of macroscopic WMH (leukoaraiosis), the correlation of microscopicchanges in normal-appearing brain tissue was more strongly related to executive andmemory impairment than WM volume and WMH burden. A similar conclusion was found bythe Rotterdam study (28 Findings from these three studies31 evidence agreater variability of WM microscopic pathology and support non-FA indices assensitive biomarkers for assessing the integrity of WM independently of otherstructural measurements such as atrophy of white and gray matter or WM burden.Future studies should evaluate the usefulness of multiple diffusion parameters asbiomarkers of cognitive decline in research and their applicability in monitoringresponses to therapeutic interventions and treatment success.am study in whicham study .28 Findi39 DTI parameterscan serve as important biomarkers in monitoring vascular disease progression andtreatment response and may represent a surrogate marker of WM tract integrity.Therefore, the studies discussed in the current review encourage the use of multiplediffusion indices as important tools for the diagnosis of microscopic changes in WMassociated with early-onset vascular disease.This summary of findings demonstrates that loss of integrity in normal-appearing WMpoints to an independent process of WMH burden and may reflect a constellation ofpathophysiological interactions, including ageing, neurodegenerative mechanisms andalso vascular disease. Current evidence highlights the increasing importance ofvascular health as a major component of general neural aging as demonstrated byprevious studies."} +{"text": "Inspired by natural photonic structures , researchers have demonstrated varying artificial color display devices using different designs. Photonic-crystal/plasmonic color filters have drawn increasing attention most recently. In this review article, we show the developing trend of artificial structural color pixels from photonic crystals to plasmonic nanostructures. Such devices normally utilize the distinctive optical features of photonic/plasmon resonance, resulting in high compatibility with current display and imaging technologies. Moreover, dynamical color filtering devices are highly desirable because tunable optical components are critical for developing new optical platforms which can be integrated or combined with other existing imaging and display techniques. Thus, extensive promising potential applications have been triggered and enabled including more abundant functionalities in integrated optics and nanophotonics. Rather than using colorant-based pigmentation, structural color filtering devices ,5,6,7,8 Furthermore, investigations on magnetophotonic composites and relevant devices ,71,72,73In general, the working principle of dyes or pigments is based on light-matter interaction which in fact is that they can absorb light of only certain wavelengths and reflect the remaining frequency bands of the spectrum, leading to resonance peaks in either transmission or reflection. People have long benefited from nature\u2019s capability of creating coloration. The famous Morpho butterfly wings were onepn) on top of a glass substrate (refractive index = sn), which can function as a planar waveguide. Periodicity, width, and height are labeled as L, d and h, respectively. Generally speaking, these 2D nanogratings can work as filters under phase-matching conditions. Diffracted waves can be generated and the reflected energy can be dramatically strengthened within certain frequency ranges. These 2D color filters exhibit unique optical properties compared with 1D nanogratings which have strong angle dependency on incident light. Theoretically, one can avoid relying on grating coupling for resonance mode excitation to minimize angle sensitivity. Different from grating coupling, plasmon-assisted resonators and nano-antennae normally need a large density for effectively scattering light to either viewers\u2019 eyes or photodetectors in the visible range. The angle dependence for plasmonic crystals is directly related to the surface plasmon polariton excitation via grating coupling which limits the practical applications due to relatively low coupling efficiencies since it is inherently angle-dependent because of momentum matching conditions. Overcoming this angle-dependent spectrum response will allow these structural filters to be integrated into practical applications such as high resolution visual displays, miniature hyperspectral imaging, and high sensitivity sensing devices.Inspired by distinctive Morpho butterfly wings, reflective photonic crystal color filters consisting of nanogratings were proposed and experimentally fabricated . As showNote that these 2D photonic crystal filters utilized the coupling between the incident light and the resonant modes (guided-mode resonance) to generate individual colors. Such filters show high reflectance (>70%) and angular tolerance and they can suppress the incident-angle dependency and enhance the chromatic properties compared with traditional 1D color filters, leading to useful applications for display techniques. The geometry can also be further optimized to make the optical effect close to being independent of the tilt angle and therefore enable wide use in ambient light conditions, paving the way to more practical applications in displays. The pioneering experiments on angle robust optical devices were performed by Wu and coworkers who utilFurthermore, the reflectivity for s- and p-polarization is different. For s-polarization, it does not change greatly in the Brillouin zone, while for p-polarization it lessens through the range. Thanks to the fast development of nanotechnology, color filters can be fabricated by using electron-beam lithography (EBL) and nanoimprint lithography (NIL) followed by inductively coupled plasma reactive ion etching (ICP-RIE) to transfer patterns from resists to silicon substrates. However, one should note that the crystallinity of the fabricated silicon color filters may affect the device performance significantly. For instance, the maximum reflectance is reduced tremendously for amorphous silicon due to large internal absorption. Therefore, the reflectance spectrum may vary due to different silicon crystallinity properties and various refractive indices. Using NIL and multi-scan excimer laser annealing, 2D photonic crystal color filters were experimentally demonstrated by Cho and coworkers . This coPlasmon-assisted nanophotonic devices have drawn particular attention in recent years because of their tremendous latent capacity for new imaging and display technologies ,87,88 siUsing simple nanostructures, various color filters have been demonstrated, including nanoslit antennae , ultrathAs shown in The development of plasmon related/enhanced reflective filtering devices is mainly limited by efficiency since metals have significant absorption at visible frequencies. To receive acceptable reflected energy, normally, high aspect ratio structures are needed, resulting in challenging fabrication processes. Normal lift-off processes are only effective for thin devices because resists can be hardly removed if they are covered by thick metal films. One feasible solution to overcome the difficulties mentioned above is to use a dry etching method to transfer patterns (top-down fabrication process). By using argon ion milling, large aspect ratio silver nanorods were fabricated and reflTo experimentally demonstrate the reflection-mode color filtering devices, high aspect ratio nanorod arrays were fabricated in silver films by using EBL followed by argon ion milling. Inter-rod spacing of 20 nm smallest was achieved to reveal blue color as shown in Structural color pixels can outperform their chemical counterparts since they can bear long-time constant illumination with stronger light intensities. In addition, they can achieve high compactness and resolution beyond the diffraction limit with wide tunability and highly stable device performance. Moreover, structure color filtering devices can enable high efficiency and low power consumption with dramatically slimmed dimensions and enhanced resolution. However, the incident angle tolerance limits the practical applications of such optical components. To achieve more promising applications, thinner spectral response is desired for vivid colors with high angle tolerance. Researchers have made every effort to realize angle robust optical filters with narrow broad spectral response and high optical performance to yield a superior color contrast. To obtain angle-insensitivity, one has to avoid relying on grating coupling for plasmonic mode excitation. In contrast to grating coupling, plasmon assisted resonators and antennae have been experimentally demonstrated as candidates for structure colors which have advantageous features such as brilliancy and color vividness. Gratings in metal surfaces without involving diffraction effects can be used to control the light polarization so that it is possible to use an analyzing polarizer to manipulate the transmitted colors, which are largely independent of the angle of incidence. Significant work remains to develop a reflective display that can provide a bright and full-color image comparable to printed media with low power consumption as a new class of display element, which allows the full-color emission from a single pixel under a broad range of ambient lighting conditions. However, one can still obtain individual colors based on tuning the incident angle of white light illuminated onto nanostructures. Instead of adjusting geometry parameters, different color outputs can be achieved via incidence scanning with a fixed design. Using a single plasmonic chip, photon-plasmon coupling interactions can be triggered and further engineered to reach continuous color tuning effects across the whole visible range .2) can be realized by using interference lithography to define patterns and ion milling to transfer patterns. As demonstrated in A large functional area devices are enabled which may pave the way for next generation display productions. However, researchers still need to further improve the optical performance of color filtering devices for more practical applications. Filters with both high transmission intensity and narrow passing band are critical to produce high throughput and low-cost optical components for new optical devices. Additionally, high speed actively tunable devices are extremely important for future development of multiple-functional assemblies. In practice, low-cost and high-throughput approaches are desired because they are more suitable for industrial applications."} +{"text": "Since the seminal finding almost 50\u00a0years ago that exercise training increases mitochondrial content in skeletal muscle, a considerable amount of research has been dedicated to elucidate the mechanisms inducing mitochondrial biogenesis. The discovery of peroxisome proliferator-activated receptor \u03b3 co-activator 1\u03b1 as a major regulator of exercise-induced gene transcription was instrumental in beginning to understand the signals regulating this process. However, almost two decades after its discovery, our understanding of the signals inducing mitochondrial biogenesis remain poorly defined, limiting our insights into possible novel training modalities in elite athletes that can increase the oxidative potential of muscle. In particular, the role of mitochondrial reactive oxygen species has received very little attention; however, several lifestyle interventions associated with an increase in mitochondrial reactive oxygen species coincide with the induction of mitochondrial biogenesis. Furthermore, the diminishing returns of exercise training are associated with reductions in exercise-induced, mitochondrial-derived reactive oxygen species. Therefore, research focused on altering redox signaling in elite athletes may prove to be effective at inducing mitochondrial biogenesis and augmenting training regimes. In the context of exercise performance, the biological effect of increasing mitochondrial content is an attenuated rise in free cytosolic adenosine diphosphate (ADP), and subsequently decreased carbohydrate flux at a given power output. Recent evidence has shown that mitochondrial ADP sensitivity is a regulated process influenced by nutritional interventions, acute exercise, and exercise training. This knowledge raises the potential to improve mitochondrial bioenergetics in the absence of changes in mitochondrial content. Elucidating the mechanisms influencing the acute regulation of mitochondrial ADP sensitivity could have performance benefits in athletes, especially as these individuals display high levels of mitochondria, and therefore are subjects in whom it is notoriously difficult to further induce mitochondrial adaptations. In addition to changes in ADP sensitivity, an increase in mitochondrial coupling would have a similar bioenergetic response, namely a reduction in free cytosolic ADP. While classically the stoichiometry of the electron transport chain has been considered rigid, recent evidence suggests that sodium nitrate can improve the efficiency of this process, creating the potential for dietary sources of nitrate to display similar improvements in exercise performance. The current review focuses on these processes, while also discussing the biological relevance in the context of exercise performance. Strenuous exercise can increase the energetic demands of skeletal muscle by 100-fold over resting requirements, placing an enormous challenge on bioenergetic pathways to maintain concentrations of adenosine triphosphate (ATP), the basic unit of energy within muscle. Skeletal muscle is equipped with an intricate series of enzymatic reactions that resynthesize ATP to ensure cellular survival during these conditions. The diverse reactions buffering ATP fluctuations within muscle display a continuum of speed relative to the capacity for ATP production. For instance, the breakdown of phosphocreatine (PCr) can produce ATP extremely rapidly for a relatively short period of time, while in contrast, aerobic metabolism within mitochondria produces ATP at a lower maximal rate, but essentially has a limitless capacity. As a result, aerobic metabolism dominates ATP production during most continuous exercise situations, highlighting the importance of mitochondria to overall metabolic homeostasis. This simplistic view of metabolism is efficient for teaching purposes as it enables \u2018compartmentalization\u2019 of each system; however, in reality, there is considerable integration between each bioenergetic process. Historically, an increase in mitochondrial content represents a fundamental exercise training response , contribIt has been known for almost a century that elite athletes have a higher maximal rate of oxygen consumption, higher maximal mitochondrial enzymatic activities, and ultimately improved performance. While originally attributed to genetics, Holloszy\u2019s landmark research in 1967 demonstrated the remarkable plasticity of skeletal muscle to increase mitochondrial content and improve exercise capacity . This seIn 1984, Holloszy postulated that an increase in mitochondrial content would alter the sensitivity of oxidative metabolism to ADP , and, inSpecifically, ADP activates glycogen phosphorylase kinase to covalently modify phosphorylase, while AMP allosterically regulates phosphorylase by increasing the sensitivity of the enzyme to glycogen, promoting glycogen breakdown. In the context of phosphofructokinase, ADP and AMP decrease the sensitivity of the allosteric inhibitory binding site for ATP, essentially removing an inhibitor for enzymatic flux, while ADP also inhibits PDH kinase activity, maintaining PDH in an active state and promoting pyruvate flux towards aerobic respiration. As a result, a reduction in cytosolic ADP levels, and the subsequent production of AMP, as occurs following training , provideGiven that increasing mitochondrial content represents a key mechanism for the improvement in exercise performance following training, it is understandable that research has focused on elucidating the molecular events responsible for the initiation of mitochondrial biogenesis. The induction of mitochondrial biogenesis requires the transcription of proteins contained within both the nuclear and the mitochondrial DNA genomes. The mitochondrial proteome consists of ~1600 proteins, the vast majority of which are encoded within the nucleus, as the mitochondrial DNA only encodes for 13 subunits of the electron transport chain and proteins required for messenger RNA translation within this organelle . The inA large body of literature has been devoted to studying the role of energy turnover and activation of AMP activated protein kinase (AMPK) as a key signal to induce mitochondrial biogenesis. However, high-intensity interval training and \u2018classical\u2019 endurance training result in similar accumulations of mitochondrial proteins, suggesting this process is not directly influenced by the rate of ATP hydrolysis . In addi2+/calmodulin-dependent protein kinase (CaMKII)] and reactive oxygen species (ROS)-mediated processes. Activation of CaMKII has been shown to induce the nuclear translocation of PGC-1\u03b1 and the expression of mitochondrial genes [The other \u2018signals\u2019 implicated in the regulation of mitochondrial content include calcium [specifically Caal genes , while pal genes . While Ral genes . Howeveral genes , 25, a ral genes . Moreoveal genes . These dal genes reportedal genes , potentiThe notion that mitochondrial ROS contributes to exercise-induced mitochondrial biogenesis may help explain the lack of mitochondrial biogenesis observed in humans consuming antioxidants while exercise training . In thisThe induction of mitochondrial biogenesis, and the subsequent improvement in mitochondrial ADP sensitivity, has become synonymous with exercise training adaptations. This classical working model is premised on the belief that mitochondrial \u2018function\u2019 remains unaltered following a chronic training intervention. However, evidence is starting to accumulate to suggest that mitochondrial ADP transport is a regulated process, raising the possibility that lifestyle interventions can influence mitochondrial ADP sensitivity in the absence of the induction in mitochondrial biogenesis.The phosphate shuttling mechanism for energy transfer between matrix and cytosolic compartments includes three major protein complexes see Fig.\u00a0: voltageTraditional dogma stipulates that mitochondrial function is not externally regulated beyond the provision of substrates required for oxidative phosphorylation. This belief extends from Holloszy\u2019s original observation that in vitro assessments of mitochondrial stoichiometry (P/O ratios: ADP consumed per oxygen atom) remain constant following chronic training . HoweverGiven the relative novelty of identifying mitochondrial ADP transport as a regulated process, very little evidence has been generated with respect to nutritional approaches to augment this process. However, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation has been shown to alter the lipid composition of mitochondrial membranes in association with an increase in mitochondrial ADP sensitivity . IntriguOne of the most characterized responses to exercise training is an improvement in ADP sensitivity, sparing muscle glycogen and improving exercise capacity. Historically, these responses were exclusively attributed to an increase in mitochondrial content. However, recent evidence has accumulated to show that mitochondrial ADP transport is a highly regulated process. A better understanding of the molecular signals influencing the proteins directly controlling mitochondrial ADP transport, namely miCK and ANT, is required, as this knowledge could result in novel training programs aimed at optimizing muscle performance. While beetroot juice appears to influence excitation\u2013contraction coupling, as opposed to mitochondrial bioenergetics, a key event in the observed improvement in exercise capacity may involve the increase in mitochondrial ROS. In addition, given the link between mitochondrial ROS and mitochondrial biogenesis, consumption of beetroot juice while training may induce mitochondrial biogenesis and indirectly improve ADP sensitivity. EPA/DHA supplementation similarly increases mitochondrial ROS emission rates, and because PUFAs are potent ligand activators of PPARs, incorporating PUFAs into a training program may augment chronic adaptations. This is particularly interesting, as EPA/DHA supplementation directly improves mitochondrial ADP sensitivity. Clearly, compelling evidence for a nutritional intervention that improves mitochondrial bioenergetics beyond the typical exercise-mediated responses does not exist. The recent advancement in our understanding of the regulation of mitochondrial ADP transport has elucidated gaps in our working models that need to be addressed. However, the awareness of these knowledge gaps creates the possibility for unique experimental approaches to be designed with the aim to improve exercise performance in the future."} +{"text": "Prominent etiological conceptions of psychosis implicate abnormal cortico-striatal circuits. Dysfunction in these critical systems, responsible for filtering information and modulating higher-order function, may account for heterogeneous presentations of symptoms and characteristics of psychosis. Collectively, a body of work from our group and from other teams indicates that evaluating select motor behaviors and abnormalities, which directly reflect function of these circuits, may be a useful method for understanding and predicting the neural underpinnings of psychosis. In the context of the psychosis risk period, partitioning clinical high-risk (CHR) youth based on objective behavior may help guide early detection and intervention efforts, and provide a novel perspective on different etiological pathways or patient subtypes.Using an unsupervised machine learning approach, 69 CHR young adults were included in a K-means cluster analysis based on their performance on instrumental measures of psychomotor slowing, dyskinesia, and neurological soft signs (NSS)\u2014distinct motor domains affected across the psychosis spectrum. We also recruited a group of 70 matched healthy controls (HC) for comparison. All participants were also assessed with a resting-state functional connectivity analysis (rcfMRI). The resulting CHR group clusters and HCs were then compared on positive and negative symptoms, multiple cognitive domains, and cortical-striatal seed based resting state analysis.Results of a 3-cluster solution suggest that there are subtypes of CHR individuals who show psychomotor slowing, average motor performance, and impairment on measures of dyskinesia as well as NSS domains for motor coordination, sequencing and sensory integration. The cluster of individuals showing dyskinesia and abnormal NSS also have more severe negative symptoms and impairment on a number of cognitive domains. Furthermore, the clusters of CHR individuals who show psychomotor slowing and the cluster showing dyskinesia and abnormal NSS have different cortical-striatal connectivity compared to UHR who show average motor behavior and healthy controls.These results provide evidence for etiological theories highlighting altered cortico-striatal networks and the importance of examining motor behavior prior to the onset of psychosis. Taken together, this approach may reflect a novel strategy for promoting tailored risk assessment as well as future research developing individualized medicine."} +{"text": "There are great concerns about the impacts of soil biodiversity loss on ecosystem functions and services such as nutrient cycling, food production, and carbon storage. A diverse community of soil organisms that together comprise a complex food web mediates such ecosystem functions and services. Recent advances have shed light on the key drivers of soil food web structure, but a conceptual integration is lacking. Here, we explore how human-induced changes in plant community composition influence soil food webs. We present a framework describing the mechanistic underpinnings of how shifts in plant litter and root traits and microclimatic variables impact on the diversity, structure, and function of the soil food web. We then illustrate our framework by discussing how shifts in plant communities resulting from land-use change, climatic change, and species invasions affect soil food web structure and functioning. We argue that unravelling the mechanistic links between plant community trait composition and soil food webs is essential to understanding the cascading effects of anthropogenic shifts in plant communities on ecosystem functions and services. As increasingly evidenced by empirical studies, soil food webs play a key role in the functioning of terrestrial ecosystems7. Soil food webs affect carbon (C) cycling (with consequences for C storage and hence mitigation of elevated atmospheric carbon dioxide concentrations) and nutrient cycling. On the one hand, soil food webs play an important role in controlling the supply of nitrogen (N) to plants by mineralizing organic N. However, N mineralized through the soil food web does not necessarily result in nutrients freely available for plants8. Soil food webs can promote retention of N in the soil system either directly through sequestration in their living or dead biomass or indirectly through changes to soil chemistry or structure, thereby preventing it from getting lost through leaching and denitrification. It has been shown how shifts in the composition, network structure, and connectivity of soil food webs can alter the rates of these important ecosystem processes10. The soil food web further plays an important role in disease suppression and plant protection against root pathogens12. Finally, the soil food web is critical to ecosystem resistance and resilience against environmental disturbances and climate change. For example, studies have shown that fungal-based soil food webs associated with extensively managed grasslands were more resistant to experimental drought than bacterial-based food webs associated with intensively managed crop production13. Collectively, these recent advances indicate that changes in soil food web composition and connectivity have important consequences for ecosystem functioning14.The soil food web consists of a large diversity of organisms differing in size and function. This includes root-associated biota such as pathogens or mutualists, saprotrophs involved in breaking down dead organic matter, and a variety of invertebrate consumers and predators at higher trophic levels15, soil food webs are often simplistically described in terms of distinct trophic levels. Trophic levels are composed of organisms that occupy the same level in a food chain. In the soil food web, this would be primary consumers , secondary consumers , and higher-level consumers or predators . These inputs form the basal resource pool for the soil food web18 . Each of web18 . Althoug24. This implies that anthropogenic shifts in plant community composition could have major impacts on soil web structure, as has been shown for urban green spaces, for example25. Here, we follow a simple framework describing three mechanistic pathways of how shifts in plant community composition drive soil food webs , and bacteria are more specialized to break down simple, labile organic compounds 33. However, this traditional view has recently been challenged, and evidence has emerged that fungi may use organic compounds that are more labile than previously expected34. Second, there has been increasing interest in exploring how live plant roots affect soil food webs 42. Although each of these three pathways has been studied for individual plant species, these plant-mediated mechanisms are less well understood for plant communities44. We argue that together these three pathways largely explain the responses of soil food web structure and functioning to changes in plant community productivity, diversity, and composition. Finally, we propose that using a trait-based approach to help understand the mechanisms behind these drivers could provide further guidance.In recent years, it has been shown that individual plant species differ in their effects on the soil communities they supportod webs . First, od webs . The cheod webs . Root ch46 provides new avenues for understanding how shifts in plant communities can influence soil food webs. In plant community ecology, aboveground plant functional traits such as specific leaf area, leaf nutrient content, and leaf dry matter content have been widely used in place of taxonomic diversity measures to explain ecosystem processes and function50. Recently, recognition of the importance of root traits has gained increasing attention53, and greater focus has been put on linking root traits such as root dry matter content, nutrient content, and root architecture to soil processes. For example, changes to root traits associated with exudation could shift C allocation in the rhizosphere and have implications for the soil organisms involved in decomposition and C cycling54. Furthermore, biotic root traits that aid in nutrient acquisition, such as arbuscular versus ectomycorrhizal colonization, impact on the nutritional quality and total quantity of shoot and root litter that enters the soil food web55. To further elucidate the functional linkages between plant communities and the soil food web, recent work has developed and applied a trait-based approach to soil microbes57 and soil fauna60. It has been proposed that investigating the relationship between \u2018effect traits\u2019 and \u2018response traits\u2019 across plant and soil communities could enable better predictions of ecosystem function61.The increased use of functional trait-based approaches in plant community ecology62. However, in affecting soil food web complexity and diversity, trait variability is probably at least as important as community-weighted mean trait values. Therefore, to better understand how plant community trait composition affects the soil food web, we use the concept of trait packing and diversity. High trait packing in a plant community means a high diversity or variation in litter and root traits, leading to more complex, diverse, and stable soil food web structure and function strongly control litter decomposition rates, which are determined in part by the substrate quality available to the microbes63. Therefore, inputs of chemically and structurally highly diverse litter, due to high trait packing within the plant community, could foster the development of a trait-packed microbial community and a more diverse soil food web that could help maintain the delivery of multiple ecosystem functions related to nutrient and C cycling and plant productivity. Furthermore, changes to plant community trait composition that affect indirect interactions initiated by belowground predators could change the productivity and defense strategy traits of soil organisms on lower trophic levels in ways that affect soil food web connectivity64, which is important because more tightly connected soil food webs are known to promote nutrient retention9.In trait-based ecology, there is often a strong focus on community-weighted mean traits unction . If a stBelow, we explore this framework of trait packing and diversity and, more generally, shifts in litter and root trait values. We focus on areas of research that illustrate how anthropogenic disturbances can affect plant community trait values, leading to shifts in soil food webs. Specifically, we focus on (1) land-use change and secondary succession, (2) climate change and species loss, and (3) plant invasions and range shifts because they are all topical areas of research that are heavily driven by anthropogenic disturbance. We show that under these different scenarios, changes to plant community traits can generate major shifts in the soil food web, leading to positive or negative effects on how soil ecosystems function.67. For example, root exudate chemical traits have been shown to slow down soil microbial processes, and cereal crops cause slower phosphorus mineralization compared with legumes and this is potentially because of differences in exudate chemical composition68. Crop species and varieties may also strongly vary in root nutrient acquisition strategy, root chemical composition, and root architectural traits 69. Although studies so far have focused mostly on coarse traits, such as C:N ratio and specific root length, such trait differences can impact upon microbial communities68 and higher trophic levels of the soil food web70. Crop species also vary in their attractiveness to soil pests and pathogens, such as host-specific nematodes, because of their distinct root chemistry traits71. Given these inter-specific differences in crop traits, moving from monoculture cropping to mixed cropping would add traits to the system, thereby increasing trait packing and leading to positive effects on soil food web diversity and functioning increased fungi and bacteria and those nematode groups that fed upon them. Interestingly, these two litters were also most effective in suppression of plant-parasitic nematodes. Taken together, agricultural practices that promote plant trait packing and diversity will likely generate higher connectivity in the soil food web, which will lead to increased resistance and resilience to anthropogenic disturbances in cropping systems80.Plant trait shifts associated with agricultural practices strongly drive soil ecosystem functions. Crop residues and crops with contrasting root traits can have major impacts on soil food web functioningtioning . Mixed cructure , Leslie81. Depending on the management and grazing intensity after abandonment, plant communities typically develop toward species-rich grassland or forest83. Successional changes in plant community composition result in important shifts in litter and root traits, and increases in plant diversity result in more trait packing 9. Furthermore, increased dominance of slow-growing, later-successional plant species, which more strongly depend on associations with mycorrhizal fungi than early species, could shift the fungal community from fast-growing and pathogenic species to slower-growing, beneficial species87. This could affect the rate of C flow through the soil food web8.A relatively large body of research has focused on how shifts in plant community composition after conversion of agricultural land to (semi)natural systems affect soil food webs and their functioningpacking . For exa89 and how climate-induced changes in plant community composition can cause major shifts in root and litter trait spectra 92. Warming affects plant physiology and phenology and ultimately can result in altered plant dominance and shifts in range distributions of plant species (see \u2018Plant invasions and range shifts\u2019 section below). However, changes in precipitation regime, such as longer and more intense droughts, could be expected to most dramatically affect plant community trait spectra, at least in short to moderate timescales93. For example, along an aridity gradient, root tissue density and specific root length may shift to more conservative values with increasing aridity, and the diversity of acquisition trait values may increase, facilitating a wider array of resource acquisition strategies under conditions of water stress94. In old-field communities, experimental drought shifted plant cover dominance from a woody, N-fixing sub-shrub to a C3 bunchgrass and had far-reaching consequences for soil food web structure. Moreover, microbial enzyme activities and nematode feeding group composition indicated higher soil food web complexity but slower rates of nutrient cycling in soils beneath the sub-shrub compared with the grass, most likely because of high concentrations of polyphenolics and lignin in organic residues from the sub-shrub43. In general, drought- and other climate-induced changes in plant trait spectra could greatly modify or counteract direct climate impacts on the soil food web96.Climatic changes driven in part by anthropogenic activities can strongly influence plant community composition. An increasing number of studies have shown how plant traits are related to climatic adaptation98. In turn, loss of species from the plant community will lower litter and root trait diversity and packing litter inputs caused by deciduous shrub removal may have detrimentally impacted on the microbial and nematode communities because these two groups are highly dependent on such inputs as both direct and indirect food sources101. For randomly assembled plant communities, the effects of lower plant species and functional group richness on soil biota are mostly negative but weaker for soil biota occupying higher levels in the soil food web102. For nematodes, these effects of plant species and functional group diversity have been linked to changes in litter quality 103, but potential effects mediated through shifts in root nutrient acquisition, architectural, and chemical traits remain to be tested.Climate change not only may alter plant species composition but also can result in species losspacking . Althoug104, and debate concerning the consequences of plant invasions for ecosystem functioning continues105. Invasive plants generally have higher values for traits associated with growth rate, tissue nutrient content, and competitive ability compared with natives107. Therefore, invasive plants can introduce novel traits into the existent plant community that could affect the soil food web. For example, allelopathic chemicals produced by the invasive treeAilanthus altissima can hinder soil microbial activity and thereby nutrient mineralization, while high litter production can increase earthworm abundance, potentially offsetting this negative effect108. Furthermore, invasion by the forbSolidago gigantea increased fungal biomass and had disproportionate cascade effects on certain fungal-feeding nematode taxa that were probably due to disparate feeding abilities among the nematodes109. In contrast, invasion by a grass resulted in less allocation of C to higher trophic levels of soil nematodes compared with a native grass species110. Taken collectively, traits associated with contrasting functional groups of invasive plants could lead to reduced trait packing but that native congeners tended to use top-down control through changes to the microbial community. This finding corroborates the novel weapons hypothesis113 and showcases the role that range-expanding plant traits can play in changing the soil food web. Range-expanding plants might also escape their enemies in the soil food web 114, and this, combined with favorable climatic conditions, could lead to successful establishment115. Furthermore, range-expanding plants might fail to find suitable decomposer organisms for their litter 116 because of mismatches in litter chemistry traits and soil organisms specialized in breaking down this litter. Finally, range-expanding plants may not establish mycorrhizal associations has the potential to introduce new species with new traits into the community and have repercussions for the soil food web. The widening of niche envelopes that leads to range expansionood web .95, which link more strongly to ecosystem processes and function. (5) Soil food webs often respond slowly and show remarkable resistance to environmental changes. Hence, the effects of shifts in plant community composition may become apparent only at larger timescales. This requires long-term studies and awareness of long-lasting soil legacies. (6) Many studies exploring the relationships between plant communities and soil food webs use observational approaches122. Although observations allow coverage of large spatial and temporal scales , these studies do not disentangle the mechanisms. We advocate for additional empirical studies explicitly manipulating litter and root trait spectra and diversity. Only through continued research will we be able to better understand how anthropogenically driven shifts in plant community composition will affect complex soil food web interactions and the ecosystem services that they provide.Anthropogenic shifts in plant community composition and diversity are likely to have major implications for the composition and function of soil food webs as well as the services they provide. Much recent progress has been made, and our trait-based conceptual model provides guidance for future studies to elucidate the underlying mechanisms of how shifts in plant community traits could lead to cascade effects belowground. The following areas in particular warrant future attention: (1) We know relatively well how functional differences among individual plant species affect soil food webs, but much less is known about the effects of complex plant communities where multiple species coexist and interact. Here, it would be of interest to separate the effects of community-weighted mean values from the diversity of traits represented in the community. (2) The majority of studies inferring changes in soil food web functioning focus exclusively on microbes or use soil nematode communities as indicators of soil food web structure. These approaches have yielded important insights, but to fully understand the role of soil food webs in how shifts in plant community composition affect soil ecosystem functioning, we need to look at whole soil food webs, including organisms at higher trophic levels. (3) Knowledge about the quality and quantity of substrate required by soil microbes and fauna is increasing, and ideas about interactions between different trophic levels are being revised. However, further studies are needed to understand the complex transferring of energy between the different organisms in the soil food web. Therefore, it is integral to investigate how energy transfer within the soil food web is driving key ecosystem processes and to focus particularly on the traits involved. (4) Plant trait-based research has seen a steep increase in activity in recent years, including new research explicitly focusing on root traits. However, the traits most commonly used in these studies are not always the most meaningful in terms of their importance for the functioning of soil communities. Instead of focusing on coarse traits, such as C:N ratios of shoots and roots, it would be more ecologically informative to look at the molecular construction of plant-derived C and N compounds, such as phenolics and their derivatives, which are known drivers of soil microbial activity and resource use efficiency"} +{"text": "Heavy metals are naturally occurring in the earth\u2018s crust but anthropogenic and industrial activities have led to drastic environmental pollutions in distinct areas. Plants are able to colonize such sites due to several mechanisms of heavy metal tolerance. Understanding of these pathways enables different fruitful approaches like phytoremediation and biofortification.Therefore, this review addresses mechanisms of heavy metal tolerance and toxicity in plants possessing a sophisticated network for maintenance of metal homeostasis. Key elements of this are chelation and sequestration which result either in removal of toxic metal from sensitive sites or conduct essential metal to their specific cellular destination. This implies shared pathways which can result in toxic symptoms especially in an excess of metal. These overlaps go on with signal transduction pathways induced by heavy metals which include common elements of other signal cascades. Nevertheless, there are specific reactions some of them will be discussed with special focus on the cellular level.The online version of this article (doi:10.1186/1999-3110-55-35) contains supplementary material, which is available to authorized users. Basal heavy metal tolerance is presumably found in all plant species. Thereby, they run a complex system consisting of uptake/efflux, transport/sequestration and chelation Figure\u00a0. These kThis review will provide an overview about these tolerance mechanisms with focussing on the cellular level and signalling pathways induced by metals. The discussion of some examples will underline the multitude and complexity of signals and responses. It will trigger further work on responses towards heavy metals in plants especially in the way of low, environmentally relevant metal concentrations.The majority of plants can be classified as non-accumulator plants. Nevertheless, all have to cope with heavy metals for nutrition purposes and growing in metalliferous soils, respectively. Hence, they have to possess finely tuned mechanisms for living with even toxic heavy metals Hall 2006. Thea and b transporter family across biological membranes. Thereby, HMA2 and HMA4 drive metal efflux out of the cell in A. thaliana protein family) is highly overexpressed in the aforementioned hyperaccumulating plants compared to their closed related non-accumulators and organic acids like citrate which will be discussed in the next chapter. Functionalities of GSH (thiol and carboxylic groups) make it suitable for complex formation with heavy metals are sulfur containing proteins inherently being highly flexible in their structure. This flexibility allows different coordination geometries for binding of different metals. Nevertheless, each MT exhibits preferences for a special metal ion due to coordination residues other than cysteine and differences in folding and stability in dependence on the bound metal ,Redox-active metals can directly generate ROS via Fenton like reactions and the Haber-Weiss cycle , there was no significant change of GSH whereas the amount of GSSG increased upon exposure of moderate uranium concentrations (\u2264 10\u00a0\u03bcM) in cell suspensions of canola (Brassica napus) is impaired by heavy metal accumulation. This can be one reason for conflicting results regarding the GSH content upon metal exposure. Furthermore, the different points of sampling time should be attended. Copper or cadmium amendment in This reductive activity eliminates ROS generated either directly or indirectly by metals. The detoxification of ROS is GSH dependent. Such GSH consuming processes and an excess of ROS induce GSH synthesis exhibited decreased levels of SOD, GR and CAT towards cadmium contact whereas Avena strigosa (Cd tolerant accumulator) showed increased activities towards the same Cd concentrations , Nramps , the cation diffusion facilitator (CDF) family, the ZIP family, ABC transporters (ATP-binding cassette), cation antiporters and other putative transition metal transporters. A more detailed overview is provided by reviews written by Guerinot , Hall anAs it was mentioned before, metal sequestration in distinct cellular compartments plays a pivotal role in metal tolerance and supplement with essential metals. For this purpose cells provide a coordinated set of transport systems in each cellular membrane. An important metal sink in metal tolerant plants is the vacuole. A prominent example is the transport of metal-phytochelatin complexes into the vacuole by an unknown ABC transporter or by cation/proton exchanger (CAX) . Proton fluxes can establish so-called \u201cpH-signatures\u201d in the cytoplasm . FER encodes bHLH which controls the expression of genes with key functions in iron acquisition such as the iron-regulated transporter (IRT) and the ferric oxidase reductase (FRO) orthologs in tomato during iron starvation in plants. A detailed review concerning this was published recently gene expression was detected As it was discussed in a previous chapter heavy metal exposure can cause imbalances in the cellular redox homeostasis either by being itself redox-active or by replacing other metal ions (sometimes even redox-active ions) in biomolecules. A recently discussed issue in animal cells is the zinc coordination with sulphur donors of cysteine resulting in a redox switch with reversible oxidoreduction of the sulfur donor linked to zinc association and dissociation Maret . This phArabidopsis. These cascades end up by phosphorylation of transcription factors interacting with gene promoters and thus inducing gene expressions. It should be noted that there are differences between metal-sensitive and metal-tolerant plants: ROS-MAPK signals cause several cellular damages like interruption of hormonal signalling, programmed cell death in metal-sensitive plants. In contrast, metal-tolerant plants are able to accumulate repair proteins such as chitinases and heat shock proteins (HSP). A more detailed overview provides a recently published review by Lin and Aarts which can activate mitogen-activated protein kinase (MAPK) cascades in a plant species and metal dependent manner (Gupta and Luan nd Aarts . HoweverOther important elements are the soluble redox couples like glutathione or NAD(H), NADP(H) which provide a buffering system in the cytoplasm Noctor . Local p2005aAlmost all plants exhibit a basal metal tolerance when facing heavy metals. Some species are even capable of hyperaccumulation running different tolerance reactions compared with nonaccumulating plants. However, general tolerance mechanisms are based on exclusion, chelation and sequestration processes Figure\u00a0.Attention should be paid on signal transduction pathways induced by metals because they use common signal elements which can be also elicited by other environmental stresses. The critical evaluation of triggered signals and their responses is mandatory for understanding metal homeostasis. The challenge in the future will be the investigation of multiple stress factors as it occurs under real environmental conditions.Predictions about health risk which is caused by metal accumulation in crop plants failing visible symptoms of phytotoxicity.Generation of genetically engineered plants having an enhanced accumulation of metals valuable for nutritional purposes (biofortification).Clean up of metal contaminated soils (phytoremediation) and mining of rare metals which are accumulated in plant tissues (phytomining).Special focus should put on low, environmentally relevant heavy metal concentrations. Therefore, the further development of sensitive detection methods and the combination of different approaches are necessary. These tools enable for instance new insights in the metalloproteome and its interactions . Further knowledge about metal tolerance in plants is mandatory for several purposes:"} +{"text": "The varicella zoster virus affects the central or peripheral nervous systems upon reactivation, especially when cell-mediated immunity is impaired. Among varicella zoster virus-related neurological syndromes, meningoradiculitis is an ill-defined condition for which clear management guidelines are still lacking. Zoster paresis is usually considered to be a varicella zoster virus-peripheral nervous system complication and treated with oral antiviral therapy. Yet in the literature, the few reported cases of herpes zoster with mild cerebral spinal fluid inflammation were all considered meningoradiculitis and treated using intravenous antiviral drugs, despite absence of systemic signs of meningitis. Nevertheless, these two clinical pictures are very similar.We report the case of an alcohol-dependent elderly Caucasian man presenting with left lower limb zoster paresis and mild cerebral spinal fluid inflammation, with favorable outcome upon IV antiviral treatment. We discuss interpretation of liquor inflammation in the absence of clinical meningitis and implications for the antiviral treatment route.From this case report we suggest that varicella zoster virus-associated meningoradiculitis should necessarily include meningitis symptoms with the peripheral neurological deficits and cerebral spinal fluid inflammation, requiring intravenous antiviral treatment. In the absence of (cell-mediated) immunosuppression, isolated zoster paresis does not necessitate spinal tap or intravenous antiviral therapy. Varicella zoster virus (VZV) is an exclusively human virus primarily causing chickenpox . After aHere we report the case of an alcohol-dependent older man with zoster paresis in the context of a VZV-associated meningoradiculitis. This clinical entity is not precisely defined in the literature and clear management guidelines about oral versus IV antiviral therapy are scant . ClearlyA 74-year-old Caucasian man was admitted to the Emergency Room, addressed by his general practitioner for a 3-day history of progressive lower left limb weakness. He complained of a non-traumatic lumbar pain since 10\u00a0days. Shortly after, a skin rash appeared on his lower back and extended to the left lower limb. He did not have fever or other new neurological complaints (in particular there was no urine or bowel retention or incontinence). His medical history showed arterial hypertension ; alcohol dependence (with macrocytosis and lower limb polyneuropathy) and benign prostate hypertrophy managed using tamsulosin. Otherwise, he took Aspirin Cardio\u00ae and tramadol.In addition to lower limb peripheral length-dependent abnormalities , the initial neurological assessment revealed significant weakness in hip flexion (M3) and foot dorsiflexion (M2), absence of the left patellar reflex and disturbed position sense on the lower left limb. The Leri sign was positive on the left side. On general examination, clusters of small erythematous vesicular lesions were present on the anterior and internal sides of his left thigh and upper leg. A few similar lesions were also seen on the left part of the lower back. In summary, the clinical picture of the patient showed left L3\u2013L4 sensory-motor deficit associated with radicular zoster. A lumbar computerized tomography (CT)-scan excluded local compression (there was only degenerative lumbar discopathy) and the skin smear was positive for VZV DNA but negative for Herpes simplex virus 1 and 2. The lumbar puncture and showed mainly motor improvement . A few days after admission he developed postherpetic neuralgia that improved with pregabaline and subsequent amitriptyline and a fentanyl patch. Unfortunately analgesic overtreatment led to acute encephalopathy that was reversed with dose adjustment. The patient was then transferred to a stationary neurorehabilitation center before returning home.The patient described here had zoster paresis associated with mild inflammation and VZV activity in the CSF; leading to treatment mainly by IV acyclovir. The very few reported cases of VZV meningoradiculitis in the literature can be divided into two groups. The first corresponds to radiculitis without meningitis symptoms \u201316. The peripheral nervous system complication [If meningoradiculitis comprises clinical meningitis with peripheral nerve root involvement, then it should be treated, as with any other VZV-CNS complication, using IV antiviral drugs after spinal tap and other necessary investigations , 6, 12. lication . Such palication . The VZVlication , 15 to tlication , 16? Morlication . Along tNone of the frequently reported immunosuppressive states triggering VZV reactivation were fouIn conclusion, the patient had VZV cutaneous infection with radiculitis coincident with mild CSF inflammation. Reactivation of VZV was most probably precipitated by age- and alcohol-induced cell-mediated immunosuppression. He was diagnosed with meningoradiculitis and treated with IV acyclovir, despite the absence of clinical meningitis. In available published cases, we did not find a consensual definition or management scheme for meningoradiculitis. The presence of CNS symptoms or abnormal CSF findings did not allow discrimination of severe from benign cases and these patients were generally IV treated. However, well-designed clinical trials are needed to review severity criteria for patients with VZV-associated (meningo)-radiculitis, to study the efficiency of oral versus IV antiviral treatment and establish clear guidelines for management. Mild elevation of inflammatory markers in the CSF is not specific or sensitive enough to establish a diagnosis of meningitis without evocative clinical symptoms. Therefore we suggest that until otherwise demonstrated, the term \u201cmeningoradiculitis\u201d should be used for and IV antiviral drugs prescribed to patients with clinical meningitis associated with neurological peripheral deficit in the context of VZV infection. Patients with isolated VZV radiculitis should be exempt from CSF investigations and be given oral antiviral treatment, unless they are subject to any condition or pathology decreasing immunity, in particular CMI, in which case CSF workup and IV antiviral therapy may be necessary."} +{"text": "Immune therapy has shifted the paradigm of modern cancer treatment: Instead of targeting the tumor itself, it focuses on enhancing tumor recognition and destruction. Harnessing the immune system by using monoclonal antibodies, adoptive T cell transfer or checkpoint inhibitor (CPI) therapy increased progression free survival with less side effects compared to conventional therapy . CheckpoThree of the major questions that arise for caregivers and scientists are: 1) Should pre-therapeutic screening be implemented to assess risk for fatal cardiovascular events and adjust mono- vs. combination CPI therapy? Certain features of the immune system may predispose to immune related adverse events, such as specific HLA phenotypes or composition of their T cell subtypes. 2) Should patients undergoing CPI therapy receive regular surveillance tests for early signs of cardiovascular adverse events? Which non-invasive technologies should be used? 3) Would local therapy be beneficial if cardiotoxicity develops? During CPI therapy, troponin elevation, changes in ECG, arrhythmias, and inflammation or ischemia on cardiac MRI have been observed -clinical signs that will likely guide therapy in the future. In some reported cases that tested for the most common viruses known to cause myocarditis , viral serologies from peripheral blood were negative in all patients . For genIn the event of increasing troponin levels, Wang and colleagues recommend to hold immunotherapy until troponin levels and ECG abnormalities normalize Figure 6]. In . In 6]. While these conclusions and recommendations reflect our interpretation of findings from case reports and case series, no guidelines for the treatment of immune related myocarditis have been published as of today due to limited availability of clinical data.Assuming an immune antigen reaction similar to an allograft rejection or a rheumatic disease, similar pathomechanisms have to be explored to widen treatment options for this rare but often fatal complication. In one reported case of CPI related and steroid resistant myocarditis, treatment with equine anti-thymocyte globulin (ATGAM) led to regression of the disease . Similar"} +{"text": "Streptococcus pyogenes infection at 5, 12, and 18 hours post infection and correlated this to parameters of infection. The platelet population in ex-vivo blood samples showed no increased integrin activation or surface presentation of CD62P, however platelet-neutrophil complex formation and plasma levels of CD62P were increased during bacterial dissemination and the progression of sepsis, indicating that platelet activation had occurred in vivo. Platelet-neutrophil complex formation was the most discriminatory marker of platelet activation. Platelet-neutrophil complexes were increased above baseline levels during early sepsis but decreased to significantly lower levels than baseline during late sepsis. The removal of these complexes from the circulation coincided with a significant increase in organ damage and the accumulation of platelets in the liver sinusoids, suggesting that platelet activation in the circulation precedes accumulation of platelets in damaged organs. The results demonstrate that monitoring platelet activation using complementary methods may provide prognostic information during the pathogenesis of invasive S. pyogenes infection.Platelets contribute to inflammation however, the role of platelet activation during the pathophysiological response to invasive bacterial infection and sepsis is not clear. Herein, we have investigated platelet activation in a mouse model of invasive W. Win vitobserved . The aimS. pyogenes AP1 infection , . PN. PN25]. Among the few studies of PNC formation in sepsis patients, PNC formation has been detected although other parameters of platelet activation were not increased . PNC levIntravital microscopy of liver sinusoids directly treated with LPS has demonstrated platelet dependent stimulation of neutrophil extracellular trap formation and locaS1 Fig(PDF)Click here for additional data file."} +{"text": "Stem cells are undifferentiated and pluripotent cells that can differentiate into specialized cells with a more specific function. Stem cell therapies become preferred methods for the treatment of multiple diseases. Oral and maxillofacial defect is one kind of the diseases that could be most possibly cured by stem cell therapies. Here we discussed oral diseases, oral adult stem cells, iPS cells, and the progresses/challenges/perspectives of application of stem cells for oral disease treatment. Stem cells are undifferentiated and pluripotent cells that can produce more new stem cells and differentiate into specialized cells with a more specific function such as skin cells, bone cells, and blood cells , PDLSCs (N = 4), OESCs (N = 12), DPSCs (N = 5), adipose derived stem cells , SHED (N = 1), nasal stem cells (N = 1), and HSCs (N = 1). As outlined in Table N = 3, with autologous SHED or DPSCs), dental diseases correlated with tooth extraction , graft vs. host diseases with oral complications , facial diseases , and Xerostomia/Sj\u00f6gren's Syndrome . Among them, three trials have reported results. The clinical trials with reported results will be discussed below.Stem cell therapy has become a promising alternative in dentistry and maxillofacial rehabilitation since it could provide better physiological structure and functions . Bio-Oss scaffolds were transplanted together with PDLS cell sheets for the chronic periodontitis therapy in a completed clinical trial (NCT01082822). Commercially available collagen scaffolds (collagen fleece) are used to hold autologous BM-MSCs enriched with autologous fibrin glue in clean room facilities for regeneration of periodontal tissues in periodontal infrabony defects in an ongoing clinical trial (NCT02449005). For adult periodontitis patients, the surgical implantation of autologous MSCs with a 3D woven-fabric composite scaffold and platelet-rich plasma showed no clinical safety problems but decreasing trend of mobility and significantly improved changes in clinical attachment level, pocket depth, and linear bone growth uses a bioengineered product composed of mesenchymal stem cells and a patented cross-linked matrix of autologous plasma for bone maxillary cysts refilling. Platelet rich fibrin (PRF) and bone allograft are used to load the buccal fat pad derived stem cells for the treatment of alveolar bone loss in maxillary sinus augmentation (NCT02745379) and in posterior mandible augmentation (NCT02745366). Tissue engineered construction based on a synthetic tricalcium phosphate and autologous MSCs obtained from oral mucosa is used for maxilla alveolar process reconstruction in patients with verified diagnosis partially edentulous maxilla and alveolar bone atrophy (NCT02209311). Similarly, MSCs obtained from bone marrow are mixed with bicalcium phosphate to augment the alveolar ridge (NCT02751125).Stem cells are applied without scaffolds in most clinical trials . Intravenously infused allogeneic MSCs suppressed autoimmunity by directing T cells toward Treg and Th2, while suppressing Th17 and Tfh responses, and restored salivary gland secretory function in both mouse models and Sj\u00f6gren's Syndrome patients who have been resistant to multiple standard treatments (NCT00953485). The study suggests that allogeneic MSC treatment may provide an effective therapy for Sj\u00f6gren's Syndrome patients . Allogeneic human DPSCs are injected in local infected periodontal tissue for the treatment of chronic periodontal disease (NCT02523651) and a clinical trial UMIN000002050 aims to establish human dental pulp stem cell bank for dental diseases that extraction of tooth is necessary for treatment. A clinical trial is ongoing to clarify the efficiency of autologous SHED to regenerate pulp and periodontal tissue in the patients with immature permanent teeth and pulp necrosis (NCT01814436).Human PDLSCs, as well as DPSCs, SHEDs, and bone marrow stem cells have been studied to regenerate periodontal tissues were related to the aspect ratio-dependent cellular internalization, suggesting the promising use of CeNMs to protect stem cells from the ROS-insult environments and ultimately improve the stem cell potential for tissue engineering and regenerative medicine into a confined space, where biological function and viability of biomaterials are preserved within the printed construct (Murphy and Atala, in vitro without stemness loss or function change; try to speed up self-renewal of the in situ stem cells and precisely control their differentiation. For allogeneic stem cells, the in vitro expand technology is also very important and the technology to lower down the immune rejection is urgently needed. Besides the immune suppression drugs, regulatory immune cells such as Treg and Breg (Sun et al., In summary, there are endogenous/autologous and exogenous/allogeneic adult stem cells and iPS cells for oral disease treatment. As compared in Table BY, YQ, and NZ summarized the literature, wrote the manuscript, and prepared figures. BC, HO, and JD provided critical comments and wrote part of the manuscript. JS supervised all the works and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer VD, VT and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review."} +{"text": "Melatonin administration to high cholesterol-treated and high fat-treated rats has been shown to suppress body weight and visceral adiposity. In addition, in various animal models related to obesity, metabolic syndrome, and diabetes, melatonin has beneficial efficacy in ameliorating various metabolic symptoms, including attenuating weight gain, lowering blood pressure (BP), and improving insulin resistance. This systematic review aims to investigate whether melatonin or melatonin agonists significantly attenuate metabolic side effects among psychiatric populations treated with atypical antipsychotics.Four randomized controlled trials were identified through a comprehensive literature search using MEDLINE, EMBASE, and the Cochrane Library on 22 October 2015. These four trials (including three melatonin studies and one ramelteon study) included 138 patients, of whom 71 were treated with melatonin or ramelteon and 67 were treated with a placebo. Because of high heterogeneity, we did not carry out a meta analysis.Melatonin was beneficial in lowering blood pressure among bipolar disorder patients; this blood pressure-lowering effect was not prominent among schizophrenic patients. Melatonin appeared to improve lipid profiles and body composition and attenuated weight gain among both schizophrenic and bipolar disorder patients. Ramelteon showed a significant efficacy in lowering total cholesterol level.Despite the few studies included, this systematic review provided promising evidence of the potential benefits of melatonin and its agonists in attenuating one or more components of metabolic syndrome among psychiatric patients using atypical antipsychotics."} +{"text": "Sarcopenia, or loss of skeletal muscle mass and quality, has been studied as part of aging and adverse health outcomes in elderly patients but has only recently been evaluated as a separate condition in cancer patients and important indicator of adverse outcomes. Currently, its definition and method of assessment are still being debated. Sarcopenia within an increasingly obese population has led to a subgroup with sarcopenic obesity, at even higher risk of adverse outcomes. Yet, sarcopenia often goes undiagnosed in these patients, hidden beneath higher body mass index. Identifying sarcopenic and sarcopenic obese subpopulations would allow for more effective treatment plans and potential avoidance of suboptimal outcomes, as well as the chance to intervene and combat these modifiable risk factors. This review will examine available literature on the definition and methods of evaluating sarcopenia and sarcopenic obesity, summarize the effectiveness of sarcopenia and sarcopenic obesity as predictors of outcomes after gastrointestinal cancer surgery, including colorectal cancer resection, liver resection, and pancreatic resection, and outline strategies to minimize the impact of sarcopenia. It is clear that untreated sarcopenia and sarcopenic obesity can be associated with suboptimal post-operative outcomes, especially infections and disease-free or overall survival. Sarcopenia, the loss of skeletal muscle mass and quality that occurs as part of natural aging, can be exacerbated by systemic illnesses. Within the last 10\u00a0years, this geriatric syndrome has received increasing attention as a possible predictor of adverse outcomes after surgery ) are at higher risk of adverse outcomes, including disability oncologic surgery outcomes, including colorectal cancer resection, liver resection, and pancreatic resection, and promising methods by which these risk factors can be modified.Early definitions of sarcopenia rely upon measures of muscle mass and neglect a functional specification. Evidence suggests the relationship between low muscle mass and adverse outcomes is not linear or direct; rather, they are linked when low muscle mass is associated with muscle weakness or time required to complete five chair stands were also useful standards. Muscle strength was assessed through unadjusted grip strength and muscle mass via body mass-adjusted appendicular lean mass that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment,\u201d which encompasses varying levels of body fat and muscle loss , computerized tomography (CT)-derived total body fat (TBF), or dual x-ray energy absorptiometry (DXA)/bioelectric impedance analysis (BIA)-derived body fat is an overlooked contributor index (the sum of lean soft-tissue masses for the arms and legs adjusted by height) Fig.\u00a0 (Baumgarht) Fig.\u00a0 and thosht) Fig.\u00a0, total pht) Fig.\u00a0, and psoht) Fig.\u00a0.Fig. 1CoMuscle mass has traditionally been measured using BIA or DXA disability than lean sarcopenic, non-sarcopenic obese, or patients with normal body composition and impaired short-term outcomes after surgery noted that there is currently no objective, accessible, accurate measure of a patient\u2019s condition before undergoing hepatectomy -sarcopenia and short-term outcomes than with TPA-sarcopenia , a measure of psoas muscle density and fatty infiltration, along with TPA (Joglekar et al. While sarcopenia assessment can help identify cancer surgery patients at risk of worse outcomes, it is important to note that sarcopenia and SO themselves are modifiable. The most effective interventions to date are physical exercise and adequate nutritional protein intake (Deutz et al. The impact of sarcopenia on post-operative oncologic outcomes and its usefulness as a predictor is still unclear and often conflicting, particularly in the case of hepatectomy for colorectal liver metastases and hepatectomy for hepatocellular carcinoma. However, sarcopenia is promising as a predictor of short-term outcomes following colorectal cancer surgery and long-term outcomes following hepatectomy for hepatocellular carcinoma. SO is promising as a predictor of long-term outcomes following hepatectomy for hepatocellular carcinoma and short-term outcomes following pancreatic resection. The other associations need additional clarification, as studies provided inconsistent results.There remains considerable variation in definition, cutoffs, and assessment methods for sarcopenia and SO, which makes translation to clinical practice complicated. Recent criteria incorporating both grip strength and appendicular skeletal muscle allow more clinically meaningful associations with long-term outcomes and are preferred to definitions excluding a functional component (Studenski et al. Sarcopenia and SO may predict short- and long-term outcomes, and effective identification of patients at risk of poorer outcomes from cancer surgery allows for tailored interventions. As clinicians become increasingly aware of this subtle form of malnutrition, addressing sarcopenia preoperatively can optimize outcomes for at-risk patients.Further research is needed to reach consensus regarding the ideal manner of assessing sarcopenia in order to predict outcomes after various cancer surgeries and across cancers in a broad clinical sense. The prevalence and impact of SO in various cancer surgeries requires further examination. Risk of mortality associated with SO for all types of patients should be further evaluated (Prado et al."} +{"text": "The conventional view that neuroinflammatory lesions contain strictly pro- and anti-inflammatory cytokines is being challenged. Some proinflammatory products e.g. TNF-\u03b1 are crucial intermediates in axon regeneration, oligodendroglial renewal and remyelination. A more functional system of nomenclature classifies cytokines by their neuro \u2018protective\u2019 or \u2018suppressive\u2019 properties. Beyond the balance of these \u2018environmental\u2019 or \u2018extrinsic\u2019 signals, specific \u2018intrinsic\u2019 determinants of cytokine signalling appear to influence the outcome of axoglial regeneration. In this commentary, we examine the potential importance of cytokine-induced histone modification on oligodendrocyte differentiation. Neuroinflammation mediates the release of astrocytic leukaemia inhibitory factor (LIF) and erythropoietin (EPO) which potentiates oligodendrocyte differentiation and myelin production. Meanwhile, histone deacetylation strongly suppresses important inhibitors of oligodendrocyte differentiation. Given that LIF and EPO induce histone deacetylases in other systems, future studies should examine whether this mechanism significantly influences the outcome of cytokine-induced remyelination, and whether epigenetic drug targets could potentiate the effects of exogenous cytokine therapy. Amongst an array of important extracellular signals, astrocytes release leukaemia inhibitory factor (LIF) and erythropoietin (EPO) which are neuroprotective cytokines that promote the differentiation of OLs and preserve the integrity of the myelin sheath , or more directly, the DNA itself (DNA methylation). Previous studies have shown that the process of (re)myelination is dependent on a variety of epigenetic remodelling mechanisms including histone modification, DNA methylation and miRNAs pathway. McCool et al. showed that withdrawal of LIF leads to a global increase in histone acetylation that mimicked the effect of trichostatin A, a histone deacetylase inhibitor myelination. Histone deacetylation is associated with the repression of important inhibitors of oligodendrocyte differentiation and neurotrophic cytokines such as LIF and EPO have demonstrated a potential to induce these HDACs in other systems. Future research should specifically examine the epigenetic processes that occur downstream of LIF and EPO in oligodendrocytes. This could lead to a novel therapeutic approach to demyelinating disease that incorporates epigenetic drug targets e.g. HDACs to bolster the efficacy of exogenous cytokine therapy."} +{"text": "Climate change is driving the thinning and retreat of many glaciers globally. Reductions of ice-melt inputs to mountain rivers are changing their physicochemical characteristics and, in turn, aquatic communities. Glacier-fed rivers can serve as model systems for investigations of climate-change effects on ecosystems because of their strong atmospheric\u2013cryospheric links, high biodiversity of multiple taxonomic groups, and significant conservation interest concerning endemic species. From a synthesis of existing knowledge, we develop a new conceptual understanding of how reducing glacier cover affects organisms spanning multiple trophic groups. Although the response of macroinvertebrates to glacier retreat has been well described, we show that there remains a relative paucity of information for biofilm, microinvertebrate, and vertebrate taxa. Enhanced understanding of whole river food webs will improve the prediction of river-ecosystem responses to deglaciation while offering the potential to identify and protect a wider range of sensitive and threatened species. The sustained dependency of human society on hydrocarbons is predicted to increase global near-surface temperatures, particularly across the second half of the twenty-first century respond to glacier retreat, predominantly with a Northern Hemisphere focus because this is where most of the relevant research has been undertaken. This knowledge is then integrated within a new conceptual framework that considers simultaneous responses of biota to shrinking glaciers as part of multitrophic river ecosystems. This new multitaxonomic response framework is used subsequently to explore the consequences for how whole-river food webs can be expected to respond to ongoing glacier retreat. Such an approach is required to inform alpine conservation strategies by providing a holistic food-web context for the multiple cold-environment endemic species that are found in glacier-fed rivers around the world dominating biofilm formation remains limited in comparison with that of macroinvertebrates shelter within the riparian vegetation and rocky banks of glacier-fed rivers, across the Pyrenean Region and the absence of predators, including American mink mirrors the dependency of the Iberian desman for cold running waters, hunting insects, crustaceans, frogs, and fish below 2500 meters\u2019 altitude inhabits slow-flowing rivers and lakes of forested alpine floodplains , which is more heavily dependent on diminishing ice-melt reaches and Soricinae (water shrew) are found in localized populations figure . The IbeSalamandra salamandra) and alpine newt favor zones of reduced glacier influence, including alpine woodland rivers below 2500 meters requires fast-flowing, highly oxygenated, cobbled river reaches for larval development (figure Rana temporaria) persists within mountain woodlands and meadows below 2300 meters, using rivers and lakes for larval development and overwintering in open water to avoid freezing conditions have also colonized low-velocity proximal glacial streams in Arctic Canada and Norway, particularly where they are warmed by upstream glacial lakes and the Pyrenean brook newt (C. asper) preferentially occupy high-velocity mountain rivers in the Pyr\u00e9n\u00e9es, increasing their density and in turn biomass with reducing glacier influence and meiofauna (rotifers and nematodes), the relationship between taxonomic richness and reducing glacier influence appears to be linear, resulting in increases in biomass with glacier retreat figure . HoweverBaetis alpinus, Lednia tumana, and Rhyacophila angelieri) but can be found at multiple trophic levels within diatoms , algae , and vertebrates and both epilithic diatoms and detritus released from the glacier was probably consumed by microbes and then assimilated by macroinvertebrates.In a detailed mountain-river food-web study, Clitherow and colleagues used gutSalvelinus malma) and America dipper (Cinclus mexicanus), absent from the Austrian glacial food webs. In addition, Khamis and colleagues (Perla grandis) in spring-fed, in situ experimental mesocosm channels. Their results suggested that the future range expansion of this species will increase trophic height (and therefore food-chain length) and body-size spectrums through invasion, intraguild predation, and interference competition and that other taxonomic groups can serve as differential indicators of climate change in mountain-river systems. It also holds value beyond alpine rivers because the reorganization of communities within glaciated headwaters will intrinsically influence the species pools available to colonize downstream reaches, potentially reshaping their assembly processes (Brown and Milner"} +{"text": "The patient had been taking appetite suppressant for the last 7 days.Electrocardiography showed no abnormalities although both serum creatinine kinase-MB (3.59ng/mL) and troponin I were elevated. Coronary angiography revealed extensive and abrupt lumen narrowing in the obtuse marginal with a subtle intraluminal defect within the distal part of the vessel . Optical The etiology and pathogenesis of spontaneous coronary artery dissection are not completely understood, but primary disruption with bleeding of vasa vasorum and intramedial hemorrhage have been proposed as the underlying mechanisms. Alternatively, an intimal tear may result in separation of coronary wall layers with the creation of a false lumen. Pressure-driven expansion of this lumen induces axial propagation of the dissection and true lumen compression, causing myocardial ischemia. Eventually, as occurred in the current case, angiography shows a long eccentric narrowing without the presence of a visible intimal flap.Spontaneous coronary artery dissection is an unusual, underdiagnosed disease, and its clinical presentation ranges from unstable angina to sudden cardiac death. This condition predominantly affects young women without classical cardiovascular risk factors, and it is increasingly diagnosed in those who are not in the peripartum period. specially in doubtful cases by angiography. Optimal treatment is still controversial and includes medical management for asymptomatic patients with normal coronary flow. Percutaneous coronary intervention with stenting or coronary artery bypass graft operation should be considered for patients with ongoing ischemia, clinically unstable or spontaneous coronary artery dissection involving the left main or multiple proximal coronary dissections. Favorable prognosis has been reported in patients managed conservatively since resolution and healing can occur over time. The present case is the first documenting spontaneous coronary artery dissection and healing by high resolution imaging OCT.Thus, an invasive imaging modality, such as OCT or intravascular ultrasound, should be the gold standard to diagnose spontaneous coronary artery dissection,"} +{"text": "Cognitive decline is a frequent but undervalued aspect of multiple sclerosis (MS). Currently, it remains unclear what the strongest determinants of cognitive dysfunction are, with grey matter damage most directly related to cognitive impairment. Multi-parametric studies seem to indicate that individual factors of MS-pathology are highly interdependent causes of grey matter atrophy and permanent brain damage. They are associated with intermediate functional effects representing a balance between disconnection and adaptive connectivity changes. Therefore, a more comprehensive MRI approach is warranted, aiming to link structural changes with functional brain organization. To better understand the disconnection syndromes and cognitive decline in MS, this paper reviews the associations between MRI metrics and cognitive performance, by discussing the interactions between multiple facets of MS pathology as determinants of brain damage and how they affect network efficiency. Although about 40 to 70% of MS patients develop significant cognitive decline,-,in vivo characterization of GM pathology remains challenging. Detection of focal GM lesions, especially in the cortical GM, requires advanced magnetic resonance imaging (MRI) techniques, such as high-resolution 3D-T1 and 3D-FLAIR,,Although MS has been traditionally classified as a white matter (WM) disease, involvement of grey matter (GM) by demyelination and neurodegeneration has become evident in all stages of the disease.-,,It has been suggested that WM lesions and inflammatory processes have stronger influence as determinants of GM damage in early stages of MS,,,,,,,,,-,-,,,,,,MRI is the main modality used to assess pathological changes in MS and it has been used to quantify WM lesions,,,,-,,,The neurodegenerative process in MS is likely to precipitate changes in brain function. Conventional MRI data has been compared to neuropsychological tests scores to relate MS pathology to cognitive performance.This paper reviews the associations between MRI metrics and cognitive performance in MS, by discussing the interactions between multiple facets of MS pathology as determinants of brain damage. We also present an overview of new imaging analysis techniques studying structural and functional brain networks towards accessing the interplay between structural damage, functional changes and cognitive outcome. ,Cognitive dysfunction in MS is heterogeneous and usually affects multiple cognitive domains. The more frequently affected domains are memory, attention, information processing speed and executive functions.,Risk factors of cognitive symptoms in MS are not completely understood, but studies have suggested that sex, age and genetic predisposition may play a role. For instance, several studies reported that cognitive symptoms are more severe and occur more often in male patients than in female patients.Neuropsychiatric factors are an important aspect to consider when assessing cognitive performance in patients with MS: studies have shown that cognitive fatigue might be partially responsible for decreases in performance of tasks that require sustained mental effort.,Not surprisingly, progressive MS phenotypes present worse cognitive performance than early relapsing remitting MS (RRMS) or CIS patients.,Although cognitive deficits can be found in early stages of the disease, they are usually a feature of advanced disease. Natural history studies suggest that the cognitive decline tends to progress with increased disease duration and, once it appears in MS patients, it is unlikely to remit.White matter (WM) lesions. Depicting WM lesions disseminated in the CNS is indispensible for the diagnosis and early clinical management of MS.,,,,,,,,,,,,,,,It has been suggested that lesion location might be a stronger determinant of neurological dysfunction in MS,,,Most studies evaluating associations between lesion load and cognition were performed in patients with relative short disease duration. Baseline T2-hyperintense and T1-hypointense lesion loads are significant short-term predictors of disability and cognitive decline in patients with clinical isolated syndromes (CIS)Gray matter (GM) lesions. Renewed interest in MS GM pathology has revealed that the prevalence of GM lesions is high,,,,Double inversion-recovery (DIR) is a relatively new MRI sequence that selectively nulls the signals from WM and cerebrospinal fluid (CSF), leaving only GM and lesions visiblein vivo visualization of the most prevalent subtype - subpial lesions.Although DIR has considerably improved GM lesion detection, a post-mortem evaluation uncovered that about 80% of cortical lesions remain undetected at 1.5T.Despite the fact that multiple studies have shown the clinical relevance of cortical lesions, there are still several limitations to the assessment of cortical lesions in routine clinical practice. First, specific MRI sequences to detect cortical lesions, such as DIR and PSIR, are not available on most clinical scanners. The availability of ultra-high field scanners for clinical practice is even more limited. Second, DIR imaging is prone to artifactsDiffuse MS pathology. Quantitative MRI techniques, such as magnetization transfer imaging (MTI) and diffusion tensor imaging (DTI), enable quantification of the extent and severity of structural changes occurring in NABT outside focal lesions.,,,,,,,,Several studies have shown that correlations between cognitive deterioration in MS and markers of diffuse MS pathology are stronger than correlations observed between cognitive decline and WM lesion load.,,Evidence suggests that MTR and DTI can be used to probe neurodegeneration and might have prognostic value. First, MTRHowever, most of the MRI parameters used to investigate NAWM and NAGM abnormalities are pathologically unspecific, and might correspond to (combinations of) demyelination, inflammatory processes or neurodegeneration.Brain atrophy. Brain atrophy is considered to be an end-stage phenomenon, strongly correlated to permanent brain damage / neurodegeneration. Patterns of GM atrophy are being identified from early stages of MS onward,,,,,,Global cortical thinning is mild in early stages of MS such as CIS and increases with disease severity,,Despite these efforts, it is still not well understood which pathological factors determine GM atrophy in MS. Previous studies showed associations between GM atrophy with WM,,,,-Traditional models of brain function employ modular paradigms, in which brain areas are postulated to act as independent processors for specific neural functions.,,,Most DTI studies show signs of microscopic damage/disconnection in several WM pathways involved in cognition. The fiber bundles more frequently associated with neuropsychological performance are the cingulum,,,,,,,Some of the disrupted WM connections are anatomically related to the default mode network (DMN).These results are difficult to interpret. Increased connectivity in cognitively preserved patients could be a sign of beneficial functional reorganization or compensatory mechanisms to sustain normal function, delaying the cognitive decline. Alternatively, it could be a maladaptive response secondary to the disruption of inhibitory WM connections. In this context, one would expect positive correlations between signs of WM disconnection and increased functional connectivity. Louapre et al.,,Different studies found similar results in structuralCognitive decline is an important source of disability in MS patients and an undervalued aspect of disease progression. Even though cognitive impairment is partly related to macroscopic lesion load, focal damage might play an indirect role as a cause of further tissue damage. Reflective of permanent damage and tissue loss, atrophy markers show stronger correlations with cognitive tests, but regional damage in target structures provides limited information about their specific relevance for a given cognitive domain and the integration between brain areas and systems. A more holistic investigation of brain networks seems to better capture the mechanisms of brain damage and adaptation encountered in cognitive dysfunction. However, multimodal imaging techniques and network analyses are still in their infancy and, although it is possible to visualize the associative areas more frequently affected in cognitive impaired MS subjects, we still lack a more specific comprehension of the interplay between function and structure to better understand initial adaptation and subsequent collapse of brain networks."} +{"text": "Oscillations in neuronal activity tie the pathophysiology of schizophrenia to alterations in local processing and large-scale coordination, and these alterations in turn can lead to the cognitive and perceptual disturbances observed in schizophrenia. Here, we focus on the dual role of fast-spiking, parvalbumin (PV+) networks in the generation of gamma oscillations and critical periods of brain plasticity.We generated a mouse model of reduced recurrent inhibition only within local PV+ cell networks by selective removal of GABAA receptor alpha1 subunits (PV-\u03b11 KO mice). Electroencephalography (EEG), PV+ immunohistochemistry, perineuronal net (PNN) labeling and redox balance were compared to cortical measures of brain plasticity that are typically limited to a critical period early in life.PV-\u03b11 KO mice exhibit chronically enhanced gamma-oscillations and extended juvenile forms of cortical plasticity into adulthood. Acute pharmacological suppression of excitatory input restored E-I balance onto these disinhibited PV+ cells and returned baseline EEG power to normal levels, preventing the extended plasticity. Enhanced gamma oscillations were further found to compromise the integrity of perineuronal nets (PNNs) surrounding PV+ cells, elevating oxidative stress and the turnover of metallopeptidases and structural components of the PNN. All of these aspects were also reversed by pharmacological dampening of excitation onto PV+ cells.Cortical gamma oscillations are associated with plasticity and cognition. Our results provide a cellular explanation of how elevated gamma oscillations may promote ectopic brain plasticity by regulating the extracellular matrix which normally stabilizes cortical circuitry. These results carry broad implications for subjects at-risk for schizophrenia who exhibit heightened gamma oscillations prior to psychosis onset ."} +{"text": "Delphinapterus leucas) populations occur between July-November. Our goal was to develop population-specific beluga habitat selection models that quantify relative use of sea ice and bathymetric features related to oceanographic processes, which can provide context to the importance of changing sea ice conditions. We established habitat selection models that incorporated daily sea ice measures and bathymetric features to establish quantitative estimates of habitat use for the Eastern Chukchi Sea (\u2018Chukchi\u2019) and Eastern Beaufort Sea (\u2018Beaufort\u2019) populations. We applied \u2018used v. available\u2019 resource selection functions to locations of 65 whales tagged from 1993\u20132012, revealing large variations in seasonal habitat selection that were distinct between sex and population groups. Chukchi whales of both sexes were predicted to use areas in close proximity to Barrow Canyon as well as the continental slope in summer, although deeper water and denser ice were stronger predictors for males than females. Habitat selection differed more between sexes for Beaufort belugas. Beaufort males selected higher ice concentrations (\u226540%) than females (0\u201340%) in July-August. Proximity to shore (<200 km) strongly predicted summer habitat of Beaufort females, while distance to the ice edge was important for male habitat selection, especially during westward migration in September. Overall, our results indicate that sea ice variables were rarely the primary drivers of beluga summer-fall habitat selection. While diminished sea ice may indirectly affect belugas through changes in the ecosystem, associations with bathymetric features that affect prey availability seemed key to habitat selection during summer and fall. These results provide a benchmark by which to assess future changes in beluga habitat use of the Pacific Arctic.There has been extensive sea ice loss in the Chukchi and Beaufort seas where two beluga whale ( Ursus maritimus) and ice-associated pinnipeds such as seals and walruses use sea ice as a platform for foraging, reproduction, and resting . Seas. SeasUrsng are ice-associated cetaceans that utilize a broad range of habitats from open water, loose annual pack ice, sea ice edge, and multi-year pack ice )Males likely segregate from females as they mature to exploit alternative prey resources and reduce competition with females and calves, as do other socially-structured cetaceans (e.g. ). We fouDue to reductions in sea ice over recent decades as well as projections for continued loss ,81, therAlthough mitigation of sea ice loss primarily requires global reduction of greenhouse gas emissions, habitat models can help inform management of anthropogenic activities and conservation planning efforts that will increasingly need to identify seasonally important areas for this critical species. Our results suggest that belugas select habitat based on a number of factors. Sea ice variables were rarely the most significant factors affecting beluga summer-fall habitat selection compared with bathymetric features. This suggests perhaps sea ice loss may not impact beluga habitat use. However there are other ways changing sea ice cover could affect belugas, and a recent study showed Chukchi belugas shifted fall migration timing as sea ice freeze-up occurred later in the 2000s . Other e"} +{"text": "The understanding of mitochondria and their quality control in cancer genesis and progression is increasing exponentially. While the Warburg hypothesis depicts mitochondria as silent within a glycolytic tumorigenic environment, it is now known that in malignant cells mitochondria are constitutively active, priming malignant reprogramming and promoting survival. Thus, in cancer cells mitochondria supply energy, provide building blocks for new cells, control redox homeostasis and define oncogenic signals commanding programmed cell death . Two othm) which provides a putative target for anti-cancer therapy. Mitochondrial redox molecules conjugated to triphenylphosphonium (TPP) exploit such differences and accumulate within the mitochondria as a selective therapeutic approach.Intrinsic aspects of mitochondrial function in cancer cells allow for the selective targeting of tumorigenic cells, including differences in mitochondrial membrane potential (\u0394\u03c8Biel and Rao, describe how these TPP-conjugated antioxidants trigger a mitophagy-mediated resistance mechanism . The rolm reported in aggressive cancer cells leading to sustained mitophagy [The pharmacological control of mitophagy could in turn be tested as a way to improve the therapeutic efficacy of chemotherapy. Hitherto, few selective non-toxic inducers of mitophagy have been developed, i.e. Urolithin A and the itophagy . The autitophagy . InteresThis work re-invigorates the field of mitophagy in the progression and management of tumours. Discovering whether mitophagy induction is a feature of less aggressive cancer cells could unveil the culling of non-abiding mitochondria as a mechanism to reprogram cells towards metastatic tendencies. Conclusively, this research brings into focus mitochondrial life-cycle modulation as a key effector in cancer cell divergence and reveals therapeutic implications for the pharmacological fine-tuning of mitophagy to overcome chemotherapy resistance ."} +{"text": "Whilst associations between polygenic risk scores (PRSs) for schizophrenia and various phenotypic outcomes have been reported, an understanding of developmental pathways can only be gained by modelling comorbidity across psychopathology, something no studies have done to date. We examine how genetic risk for schizophrenia relates to a broad range of adolescent psychopathology using a latent modelling approach, and compare this to genetic risk for other psychiatric disorders, to gain a more comprehensive understanding of development pathways at this age.PRSs for schizophrenia, major depressive disorder, neuroticism and bipolar disorder were generated for individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Multivariate linear regression was used to examine relationships of these PRSs with psychopathology factors modelled within i) a correlated factors structure, and ii) a bifactor structure.The schizophrenia PRS was associated with an increase in factors describing psychotic experiences, negative dimension, depression, and anxiety, but once modelling a general psychopathology factor specific effects above this persisted only for the negative dimension. Similar factor relationships were observed for the neuroticism PRS, with a (weak) specific effect only for anxiety once modelling general psychopathology.Psychopathology during adolescence can be described by a general psychopathology construct that captures common variance as well as by specific constructs capturing remaining non-shared variance. Schizophrenia risk genetic variants identified through genome-wide association studies mainly index negative rather than positive symptom psychopathology during adolescence. This has potentially important implications both for research and risk prediction in high-risk samples."} +{"text": "Drugs of abuse have the capacity to hijack the cellular and neurocircuit mechanisms mediating reward learning, forming non-adaptable, compulsive behaviors geared toward obtaining illicit substances. Here, we discuss current findings demonstrating how drugs of abuse alter intrinsic and synaptic LHb neuronal function. Additionally, we discuss evidence for how drug-induced LHb alterations may affect the ability to predict reward, potentially facilitating an addiction-like state. Altogether, we combine The ability to accurately predict rewarding or aversive outcomes throughout life is a critical adaptive behavior that promotes survival and allows avoidance of threatening or unpleasant confrontations. This adaptive ability is attributed to an evolutionarily conserved hedonic neurocircuit which consists of an interwoven network linking forebrain, midbrain and hindbrain regions, that together systematically regulate the release of monoamines and reward outcomes , a brain region that sends inhibitory input to dopamine neurons in the ventral tegmental area (VTA). During negative RPEs, LHb neurons are activated and send excitatory signals to RMTg inhibitory neurons which project to and inhibit dopamine neuron firing to a tail pinch have decreases in firing rates during cocaine microiontophoresis application are decreased shortly after cocaine administration (0\u201310 min post injection), but this transient inhibition progresses to increased firing activity (15\u201335 min post injection) in specific neuronal populations cocaine self-administration causes increases in LHb neuron excitability as measured using AR-mediated inhibition is decreased at entopeduncular nucleus (EPN)-to-LHb neuronal synapses (measured in brain slices) amplitude are observed along with increases in the ratio of currents mediated by AMPA- and NMDA-type glutamate receptors (AMPAR/NMDAR) onto LHb neurons that specifically project to the RMTg increases spontaneous action potential firing and membrane excitability in LHb neurons measured using These results suggest that the increased LHb activity may serve as a neural mechanism to facilitate drug-induced negative affect. Therefore, inhibiting LHb neuronal output could potentially prevent drug-induced anhedonia. To this end, low dose (0.25 g/kg) ethanol-induced conditioned place aversion is reversed to conditioned place preference (CPP) following lidocaine-induced LHb inhibition , likely invoking negative RPE signaling in the LHb and subsequent LHb-induced dopamine neuron inhibition Figure . TherefoGiven that positive RPE is associated with the phasic firing of dopamine neurons, and that negative RPE is associated with LHb signaling, one would expect that the acquisition or maintenance phase of drug self-administration (a positive RPE paradigm) might be independent of LHb control. In agreement with this, it has been shown that LHb lesions do not alter heroin or cocaine self-administration administration during the acquisition or maintenance phases, as LHb lesioned animals seek and obtain similar amounts of drug compared to non-lesioned animals (Wang et al., The LHb regulates dopamine neuron firing during negative RPE signaling and provides instructive signals for reward-seeking behaviors (Matsumoto and Hikosaka, In addition to regulating negative RPE, the LHb is critically involved in learning and memory processes that are associated with avoidance behaviors (Stamatakis and Stuber, In conclusion, we reviewed evidence supporting the importance of the LHb in regulating reward learning and updating of reward-related information. In preclinical experiments, lesioning the LHb or inhibiting LHb function elicits similar impairments in reward prediction when compared to human patients suffering from drug abuse. However, more work is needed in animal models of drug abuse to understand whether and how drugs of abuse facilitate reward-related learning impairments mediated by LHb function.NG, PN and YD developed the focus of this review. NG and PN wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Orchids are known for both their floral diversity and ecological strategies. The versatility and specialization in orchid floral morphology, structure, and physiological properties have fascinated botanists for centuries. In floral studies, MADS-box genes contributing to the now famous ABCDE model of floral organ identity control have dominated conceptual thinking. The sophisticated orchid floral organization offers an opportunity to discover new variant genes and different levels of complexity to the ABCDE model. Recently, several remarkable research studies done on orchid MADS-box genes have revealed the important roles on orchid floral development. Knowledge about MADS-box genes' encoding ABCDE functions in orchids will give insights into the highly evolved floral morphogenetic networks of orchids."} +{"text": "Emerging research indicates that exercise combined with cognitive training may improve cognitive function in older adults. Typically these programs have incorporated sequential training, where exercise and cognitive training are undertaken separately. However, simultaneous or dual-task training, where cognitive and/or motor training are performed simultaneously with exercise, may offer greater benefits. This review summary provides an overview of the effects of combined simultaneous vs. sequential training on cognitive function in older adults. Based on the available evidence, there are inconsistent findings with regard to the cognitive benefits of sequential training in comparison to cognitive or exercise training alone. In contrast, simultaneous training interventions, particularly multimodal exercise programs in combination with secondary tasks regulated by sensory cues, have significantly improved cognition in both healthy older and clinical populations. However, further research is needed to determine the optimal characteristics of a successful simultaneous training program for optimizing cognitive function in older people. Age-associated cognitive decline, which can progress to mild cognitive impairment and dementia, are growing public health concerns with no known cure. Regular exercise has been shown to provide some cognitive benefits in healthy and cognitively impaired older adults , and/or whether the cognitive training was conducted prior to or after exercise training. For instance, a 16-week RCT in older adults observed no cognitive benefits when exercise training was delivered after the cognitive training and memory training, are associated with cognitive improvements in healthy older adults , P < 0.01), but there were no differences between the combined intervention and cognitive training alone. Secondary analysis also revealed that the effect size for sequential interventions was less than those for simultaneous interventions , but did not include exergaming or more recently published studies. Another review of 13 studies also reported that simultaneous dual-task training interventions including low-intensity activity performed with a secondary cognitive or motor tasks, can benefit both physical function and the cognitive abilities of older adults in dual-task situations on cognitive function have been observed following a 12-week exergaming (Nintendo Wii) trial in one study involving 32 independent living older adults aged 65\u201378 years , exergaming typically includes cognitive challenges embedded within realistic physical activities, whilst providing virtual feedback. One of the first RCTs of exergaming for older adults revealed a promising differential cognitive benefit of exergaming or motor tasks requiring divided attention , have improved multiple cognitive abilities in older adults of simultaneous exercise and cognitive-motor training that promotes cognitive improvement in older adults. Based on the available data, interventions incorporating functional stepping exercises of exposure, with a training frequency between 1 and 3 times per week Table , but notThe neurophysiological mechanisms underlying the cognitive improvements observed through combined cognitive and exercise training are yet to be identified; however cognitive and exercise training may stimulate similar neurobiological processes which produce a synergistic response. Exercise and cognitive training both increase cerebral blood flow remain to be determined, studies incorporating moderate-intensity multimodal training in combination with secondary tasks involving a functional response to sensory cues have improved executive abilities and memory, which may prolong functional independence in older adults. However, further research is needed to determine if these improvements can be maintained, and even prevent or delay the onset of cognitive impairment and dementia. Finally, an understanding of the neurobiological mechanisms underpinning any cognitive improvements available from combined exercise-cognitive training in older adults also requires further investigation.JT and RMD wrote the manuscript and RLD, CM, and LM reviewed the draft versions. All authors have read and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BY and handling Editor declared their shared affiliation."} +{"text": "Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has increasingly been performed for the diagnosis and staging of thoracic malignancies. Findings of a necrotic lymph node raise concern for infectious process and malignancy. A hypoechoic area on ultrasound/EBUS within a lymph node without blood flow is suggestive of pathologies like infections or malignancy. Inspection of the fluid could suggest a diagnosis; clear aspirates usually suggest bronchogenic or mediastinal cysts and purulent material suggests abscesses or necrotic lymph nodes. Growing tumor cells require a blood supply; if the vascular stroma is insufficient due to rapidly growing malignant tumors this could lead to large central areas of ischemic necrosis. Necrotic aspiration of lymph nodes is not always of infectious etiology. Aspiration of fluid in EBUS-TBNA is a rare occurrence, and malignancy should be considered when purulent fluid material is obtained. We present an elderly woman who underwent bronchoscopy with EBUS-TBNA for evaluation of upper lung nodule and mediastinal lymphadenopathy. Pus-like material was obtained on needle aspiration and endobronchial biopsy and mediastinal core biopsy revealed squamous cell carcinoma. Ultrasound imaging has become part of the armamentarium of the pulmonologist; EBUS-TBNA plays an important role in the evaluation and diagnosis of several diseases especially malignancy .EBUS-TBNA is well accepted and increasingly being used as a safe minimally invasive procedure for the diagnosis and staging of lung cancers; it carries an overall sensitivity of 89% and a negative predictive value of 91% . It is aA 71-year-old woman from Dominican Republic was admitted for dyspnea, fever, and nonproductive cough of one-day duration. Her medical history was significant for diabetes mellitus, systolic heart failure, gastric B-cell lymphoma treated with chemotherapy, and surgically treated basal cell carcinoma of forehead. She was a heavy smoker with 40 packs/year. She denied alcohol or illicit drug use. Family history was noncontributory. There were no sick contacts, recent traveling, or occupational exposures and no history of exposure to tuberculosis.Initial examination showed an elderly woman on respiratory distress. Chest auscultation revealed bibasilar crackles and diffuse expiratory wheezing. There were no palpable lymphadenopathy, organomegaly, or skin lesions. The rest of exam was unremarkable. Significant laboratory findings included elevated Pro-BNP; there was no leukocytosis and renal and liver function was normal. A right sided thoracentesis was performed with pleural fluid analysis revealing transudative effusion with pleural/serum LDH ratio of 0.12 and pleural/serum protein ratio of 0.19.Patient was treated for exacerbation of heart failure with diuretics and antibiotics were given for presumptive community acquired pneumonia with clinical improvement.Chest-roentgenogram (CXR) on admission showed bilateral pleural effusion and infiltrates which rapidly improved suggesting a diagnosis of heart failure rather than pneumonic process . A chestPatient underwent flexible fiberoptic bronchoscopy (FFB) that revealed a small endobronchial lesion at the right upper lobe before the takeoff of anterior segmental bronchus. Endobronchial biopsy (EB) of the EBL as well as transbronchial biopsy (TBBx) of right upper nodule and EBUS-TBNA of the right paratracheal and subcarinal lymph nodes was performed. A 19\u2032\u2032 gauge needle was used for the EBUS-TBNA with a total of four needle passes per lymph node. Twenty ml of purulent appearing fluid was aspirated from the right paratracheal lymph node . AspiratAspiration of liquid material in EBUS-TBNA is uncommon. A hypoechoic area on ultrasound/EBUS within lymph nodes without blood flow is suggestive of pathologies like infections or malignancy. Inspection of the fluid is suggestive of a diagnosis; clear aspirates suggest bronchogenic or mediastinal cysts and purulent material suggests infection or rarely necrotic lymph nodes. Growing tumor cells require a blood supply; if the vascular stroma is insufficient due to rapidly growing malignant tumors this could lead to large central areas of ischemic necrosis , 5. Othe Histoplasma capsulatum leading to mediastinal abscesses and necrotic mediastinal lymphadenopathies [ Streptococcus related mediastinitis and mediastinal abscesses have also been reported in the literature [Necrotic mediastinal lymphadenopathy has been described in a wide variety of pathologies which include infectious and noninfectious etiologies. Tuberculosis is one of the most common infectious causes, especially in areas with high prevalence of tuberculosis . Other iopathies , 10. Bacterature .Noninfectious causes include histiocytic necrotizing lymphadenitis which is a benign lymphadenitis, characterized by enlarged lymph nodes with histopathological findings of proliferation of lymphocytes and histiocytes, nuclear debris, and necrotic lesions affecting mainly young women ; systemiLymphomas also may present as necrotic mediastinal lymphadenopathy. Usually metastases present more frequently as parenchymal lung nodules, but these are closely followed by mediastinal lymphadenopathy and pleural effusions .The initial differential diagnoses in our patient were infectious etiologies versus malignancy due to the strong medical history of malignancies and imaging findings. Bronchoscopic findings were conflicting, inspection revealed an endobronchial lesion, and EBUS sampling revealed cyst-like structure and aspirated material looked purulent. It is also important to note our patient had no clinical signs to suggest a rheumatologic disorder. To our knowledge, 2 cases of EBUS-TBNA of mediastinal lymph node revealing purulent material with a final diagnosis of malignancy have been reported in the English literature , 5. In bThe increased use of EBUS-TBNA to assess mediastinal diseases will likely lead to an increase in the number of patients with malignancies presenting with purulent aspirate. We suggest neoplastic conditions, especially squamous cell carcinoma, to be included in the differential diagnosis in patients where the EBUS guided needle aspiration reveals purulent material. Specimens should be analyzed to evaluate for infections like tuberculosis, fungal, and bacterial infections as well as malignancy."} +{"text": "Aortic mycotic aneurysms are a rare but life-threatening potential complication of infective endocarditis. Rapid deterioration of the vascular wall in highly focal areas makes these pseudoaneurysms particularly prone to rupture, resulting in uncontrolled aortic hemorrhage. While computed tomography angiography (CTA) is the imaging modality of choice for the evaluation of mycotic aneurysms, it is not routinely performed in patients with known or suspected infective endocarditis (IE). However, current valvular heart disease guidelines support the use of cardiac CTA in cases of IE and suspected perivalvular extension when there is inadequate or ambiguous visualization on echocardiography. Here, we describe a case of IE in which cardiac CTA was used for two purposes: to assess perivalvular complications and to define coronary anatomy in a patient with a suspected embolic myocardial infarction. Subsequent detection of an aortic root mycotic aneurysm not previously demonstrated on transthoracic or transesophageal echocardiography allowed for timely and uncomplicated surgical intervention, while avoiding invasive coronary angiography. Mycotic aneurysm (MA) is a rare, potential complication of infective endocarditis that carries significant mortality risk. The pathogenesis begins with bacterial infiltration into the vessel wall, which may occur directly through trauma, by local extension from an existing infection, or by seeding from a distant site via septic embolism or bacteremia. A robust inflammatory response ensues, resulting in rapid, focal wall degeneration . InfectiA 67-year-old male with a known bicuspid aortic valve was admitted with fevers and chest pain one month following a dental procedure. Upon initial presentation to an outside hospital, he was reportedly found to have an elevated troponin of 2.78\u2009ng/mL and minor ST-segment elevations on ECG. Blood cultures drawn on admission grew alpha-hemolytic streptococci sensitive to penicillin and ceftriaxone. Both transthoracic and transesophageal echocardiograms demonstrated a subcentimeter aortic valve vegetation , moderatDue to vegetation size and the absence of heart failure symptoms, the patient was initially treated medically. A peripherally inserted central catheter was placed, and he was discharged on appropriate antibiotic therapy following negative repeat blood cultures. He subsequently returned five days later with persistent fever and new, severe left flank pain. Abdominal computed tomography demonstrated a wedge-shaped area of hypoattenuation consistent with a renal infarct . Blood cCardiac computed tomography angiography (CTA) was then performed to better visualize potential perivalvular extension and provide concomitant assessment of coronary arterial disease. CTA was performed using a prospective ECG triggered acquisition using a 64-slice scanner during the administration of a triphasic contrast injection protocol . CTA revealed an eight-millimeter mycotic aneurysm of the aortic annulus extending into the intervalvular fibrosa and no residual aortic valve vegetation . AdditioMycotic aneurysms have widely varying clinical presentations depending on their location, the duration of infection, and patient comorbidities. The most common presenting symptoms are largely nonspecific, ranging from isolated leukocytosis or elevated erythrocyte sedimentation rate to bacteremia and fulminant sepsis . This maDue to exceedingly low incidence, little is known about the natural progression of mycotic aneurysms. Thrombosis, rapid enlargement, and even spontaneous regression are possible, though there are no known imaging findings that can accurately predict the clinical course . The repCTA is the imaging modality of choice for the diagnosis of mycotic aneurysms . By contIn this particular case, CTA identified a small but clinically relevant mycotic aneurysm that had not been visualized on either transthoracic or transesophageal echocardiography. The detailed assessment of both the coronary anatomy and the infarcted area allowed for confirmation of the embolic nature of the patient's MI and ruled out any atherosclerotic coronary disease requiring intervention during surgery.Resting or first-pass perfusion deficits can often be detected in patients with acute or chronic infarction with any modern CT scanner (64-slice or more) equipped to do coronary CTA. Cardiac MRI performed 8\u201310 minutes following gadolinium contrast (delayed enhancement) is a well-validated technique to detect myocardial scar (fibrosis) from any etiology based on the known retention of contrast material in areas of fibrosis. Scar (areas of hyperenhancement on delayed imaging) in a coronary distribution, as seen in this case, is typical of a myocardial infarction from a coronary etiology. Similarly, an additional noncontrast cardiac CT scan performed 8\u201310 minutes following the initial cardiac CTA can also be done to assess for scar (hyperenhancement on CT), similar to cardiac MRI. In this case, a delayed CT scan was not performed due to the presence of the previously performed delayed enhancement MRI and to reduce patient radiation exposure.Finally, this case highlights the advantage of cardiac CTA for coronary artery examination in lieu of high-risk catheterizations and nicely portrays its supplementary roles in both preoperative planning and the assessment of perfusion defects. It additionally demonstrates the utility of cardiac CTA for precise perivalvular assessment in infective endocarditis, particularly in cases of clinical suspicion for perivalvular extension and inadequate visualization on echocardiography."} +{"text": "An efficacious vaccine for HIV remains elusive. Numerous groups have isolated antibodies from HIV infected individuals that can bind and neutralise antigenically diverse HIV strains, so-called broadly neutralising antibodies (bNAbs) . HIV bNAEBioMedicine, In the current issue of The complex interplay between viral escape and Env conformation observed by Bradley et al. and others gives some pause to reductionist approaches focussing on recapitulating single bNAb specificities by immunisation. Favourable linkage interactions between different bNAb epitopes, shown here for the MPER and the CD4 binding site or V3 loop, suggests vaccines simultaneously targeted to multiple epitopes may be advantageous. While targeting the MPER by vaccination may be difficult due to described self-mimicry and frequent generation of autoantibodies , the resThe authors declare no conflicts of interest."} +{"text": "Brain-machine interfaces (BMI) may support motor impaired patients during activities of daily living by controlling external devices such as prostheses (assistive BMI). Moreover, BMIs are applied in conjunction with robotic orthoses for rehabilitation of lost motor function via neurofeedback training (restorative BMI). Using assistive BMI in a rehabilitation context does not automatically turn them into restorative devices. This perspective article suggests key features of restorative BMI and provides the supporting evidence: In summary, BMI may be referred to as restorative tools when demonstrating subsequently (i) operant learning and progressive evolution of specific brain states/dynamics, (ii) correlated modulations of functional networks related to the therapeutic goal, (iii) subsequent improvement in a specific task, and (iv) an explicit correlation between the modulated brain dynamics and the achieved behavioral gains. Such findings would provide the rationale for translating BMI-based interventions into clinical settings for reinforcement learning and motor rehabilitation following stroke. Such supported movements facilitate the detection of motor intention even in the absence of actual movements and motor evoked potentials (MEP) operant learning and progressive evolution of specific brain states/dynamics, (ii) correlated modulations of functional networks related to the therapeutic goal, (iii) subsequent improvement in a specific task, and (iv) an explicit correlation between the modulated brain dynamics and the achieved behavioral gains. Such findings would provide the rationale for translating BMI-based interventions into clinical settings for reinforcement learning and motor rehabilitation following stroke.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Some rodents produce ultrasonic vocalizations (USVs) for social communication using an aerodynamic whistle, a unique vocal production mechanism not found in other animals. The functional anatomy and evolution of this sound production mechanism remains unclear. Using laryngeal airway reconstruction, we identified anatomical specializations critical for USV production. A robust laryngeal cartilaginous framework supports a narrow supraglottal airway. An intralaryngeal airsac-like cavity termed the ventral pouch was present in three muroid rodents (suborder Myomorpha), but was absent in a heteromyid rodent (suborder Castorimorpha) that produces a limited vocal repertoire and no documented USVs. Small lesions to the ventral pouch in laboratory rats caused dramatic changes in USV production, supporting the hypothesis that an interaction between a glottal exit jet and the alar edge generates ultrasonic signals in rodents. The resulting undulating airflow around the alar edge interacts with the resonance of the ventral pouch, which may function as a Helmholtz resonator. The proposed edge-tone mechanism requires control of intrinsic laryngeal muscles and sets the foundation for acoustic variation and diversification among rodents. Our work highlights the importance of anatomical innovations in the evolution of animal sound production mechanisms. Rats et al. )"} +{"text": "There are approximately 1 billion people living with chronic lower limb disability, many of whom are wheelchair users.Review cardiometabolic and neuromuscular risk profiles of wheelchair users, benefits of regular exercise and the causes of neuromuscular upper limb and hip injuries that hinder regular adherence.Literature published between 2013 and 2017 was adopted according to the standard practices for systematic reviews (PRISMA) through Crossref Metadata and Google Scholar searches. Individual paper quality was evaluated using a modified Downs and Black Appraisal Scale.The literature search identified 16 600 papers which were excluded if they were non-English, non-peer-reviewed or published before 2013. Finally, 25 papers were accepted, indicating that sedentary wheelchair users have poor cardiometabolic risk profiles (PCMRP) because of a lack of physical activity, limiting their quality of life, characterised by low self-esteem, social isolation and depression. Their predominant mode of physical activity is through upper limb exercises, which not only improves their cardiometabolic risk profiles but also precipitates neuromuscular upper limb overuse injuries. The primary cause of upper limb injuries was attributed to poor wheelchair propulsion related to incorrect chair setup and poor cardiorespiratory fitness.Wheelchair users have a high body mass index, body fat percentage and serum lipid, cholesterol and blood glucose concentrations. Empirical investigations illustrate exercise improves their PCMRP and cardiorespiratory fitness levels. Although literature encourages regular exercise, none discusses the need to individualise chair setup in order to eliminate wheelchair pathomechanics and upper limb neuromuscular injuries. Wheelchair users must be encouraged to consult a biokineticist or physiotherapist to review their wheelchair setup so as to eliminate possible incorrect manual wheelchair propulsion biomechanics and consequent overuse injuries. Many wheelchair users suffered injuries to the spinal cord, spinal nerves and cauda equina, and also underwent lower limb amputation vascular and circulatory diseases precipitated through type 2 diabetes mellitus or peripheral vascular diseases, (2) trauma, (3) surgical removal of tumours and (4) congenital deformities review the cardiometabolic risk profile and cardiorespiratory fitness status of wheelchair users, (2) determine the benefits of regular exercise, (3) determine common neuromuscular injuries adversely influencing wheelchair users adhering to regular exercise therapy and (4) identify wheelchair propulsion pathomechanics as the primary culprit of upper limb overuse and hip injuries. Previous literature encourages wheelchair users to engage in physical activity and exercise but they do not describe the initial challenges (such as muscle and neuromuscular pain and injuries) that users experience. The novelty of this commentary lies in the review of common neuromuscular injuries sustained by wheelchair users when they begin an exercise programme and which may prevent them from continuing with the programme. The identification of the cause of these upper limb overuse injuries among spinal cord injured (SCI) wheelchair users is unique to this review. This is the first commentary to discuss the abnormal force-couple relationships of the shoulder and hip muscles because of poor wheelchair setup and propulsion pathomechanics.The authors followed the standard practices for systematic reviews (PRISMA). The definitions were guided by the PRISMA checklist for participants, interventions, comparisons, outcomes and study designs (PICOS). The participants in this study were wheelchair users; the intervention was not necessarily a therapeutic intervention but is interpreted as an exposure, namely, the effect of exercise therapy on the well-being of wheelchair users. The outcomes of interest were (1) exercise therapy interventions for wheelchair users, (2) the effects of exercise therapy on wheelchair users\u2019 health and (3) common overuse injuries of physically active wheelchair users. The exclusion criteria were (1) publications prior to 2013, (2) literature not related to the health and physical status of wheelchair users, (3) psychological therapeutic interventions, (4) non-English papers and (5) non-peer-reviewed papers.A literature search of peer-reviewed and professional journal publications was conducted in the following search engine: Crossref Metadata database, an academic meta-database which comprises the following search engines: PubMed, Medline, Science Direct, Ebscohost, CINAHL and Google Scholar . The keyThe hierarchy of evidence and quality of appraisal tool were adapted from Abdullah, McDonald and Jaberzadeh Table 1Table 1. The quality of each paper was appraised using a modified Downs and Black Appraisal Scale, which examined the quality of randomised controlled trials and non-randomised papers cardiometabolic risk profile, (2) benefits of regular exercise to wheelchair users and (3) common neuromuscular injuries from upper extremity exercises.Wheelchair users often lead sedentary lifestyles and consequently have poor cardiometabolic profiles are living with chronic disability and spend a considerable amount of time in wheelchairs Kate . Most ofThe most common overuse injuries include shoulder impingement, rotator cuff tendinitis, biceps tendinitis, lateral epicondylitis, ulnar neuropathy, De Quervain\u2019s tenosynovitis and carpal tunnel syndrome (Apple, Cody & Allen Manual wheelchair propulsion is categorised by the contact and recovery phases. Contact phase occurs when mechanical power is delivered to the wheelchair through hand contact with the rim of the wheel (Slowik et al. Sprigle and WillSagittal plane analysis identifies an anterior pelvic tilt with increased hip flexor tightness and lumbar lordosis Sprigle Figure . An anteIn an attempt to reduce wheelchair propulsion pathomechanics, scientists and engineers have redesigned the appearance and functionality of wheelchairs. Sports wheelchairs have undergone drastic and revolutionary design modifications in order to enhance sports performance and improve adherence to physical activity programmes. These ergonomic modifications improve the biomechanics of the user, which in turn curtails the incidence of upper limb overuse injuries (Sindall et al. It is recommended that manual wheelchair users have their wheelchairs reviewed in order to ensure that the wheelchair setup is ergonomically designed to meet their individual needs. Treatment and rehabilitation of the aforementioned overuse injuries pose a significant challenge because these individuals are primarily reliant on the upper limbs for weight-bearing activities and for mobility. It is further recommended that before starting an exercise programme, all wheelchair users should first receive clinical clearance from their medical practitioner regarding their participatory readiness. They must thereafter consult a biokineticist or a physiotherapist who will conduct a critical review of their wheelchair propulsion biomechanics in an attempt to prevent injuries. The biokineticist or physiotherapist should also prescribe an individualised therapeutic exercise programme.Wheelchair users have poor cardiometabolic risk profiles, low self-esteem and are at risk for socially withdrawn lives. Those who regularly exercise enjoy improved cardiorespiratory fitness and reduced cardiometabolic risk as well as reduced levels of depression and a consequently enhanced quality of life. Unfortunately, many wheelchair users who wish to be physically active are further restricted by upper limb overuse injuries. The primary cause of these injuries is wheelchair propulsion pathomechanics as a result of incorrect chair setup and limited cardiorespiratory fitness. It is therefore recommended that wheelchair users consult a biokineticist or physiotherapist before engaging in an exercise regime, so as to alleviate poor wheelchair propulsion biomechanics which may predispose them to overuse injuries. Medical practitioners, as well as the family and friends of wheelchair users, must encourage them to adhere to regular aerobic, muscle strength, and flexibility exercises in order to improve their quality of life."} +{"text": "Endotherms regulate their core body temperature by adjusting metabolic heat production and insulation. Endothermic body temperatures are therefore relatively stable compared to external temperatures. The thermal sensitivity of biochemical reaction rates is thought to have co-evolved with body temperature regulation so that optimal reaction rates occur at the regulated body temperature. However, recent data show that core body temperatures even of non-torpid endotherms fluctuate considerably. Additionally, peripheral temperatures can be considerably lower and more variable than core body temperatures. Here we discuss whether published data support the hypothesis that thermal performance curves of physiological reaction rates are plastic so that performance is maintained despite variable body temperatures within active (non-torpid) endotherms, and we explore mechanisms that confer plasticity. There is evidence that thermal performance curves in tissues that experience thermal fluctuations can be plastic, although this question remains relatively unexplored for endotherms. Mechanisms that alter thermal responses locally at the tissue level include transient potential receptor ion channels (TRPV and TRPM) and the AMP-activated protein kinase (AMPK) both of which can influence metabolism and energy expenditure. Additionally, the thermal sensitivity of processes that cause post-transcriptional RNA degradation can promote the relative expression of cold-responsive genes. Endotherms can respond to environmental fluctuations similarly to ectotherms, and thermal plasticity complements core body temperature regulation to increase whole-organism performance. Thermal plasticity is ancestral to endothermic thermoregulation, but it has not lost its selective advantage so that modern endotherms are a physiological composite of ancestral ectothermic and derived endothermic traits. The basic principles of thermodynamics dictate that the rates of physiological functions in both endotherms and ecotherms are sensitive to changes in temperature , for example, let their body temperature vary considerably with environmental temperature and Przewalski's horse lowered peripheral temperatures in winter, with concomitant decreases in heart rates during activity and rest , physiological reaction rates shifted with seasonal and altitudinal changes in climate. R. fuscipes from two populations living in cold high altitude climates had significantly lower body temperatures compared to those from two warm coastal populations . These data indicate that adaptation or developmental processes lower the mode of thermal performance curves in cold climates, which would be beneficial for rats experiencing lower body temperatures.In rats from warm climates, residuals of state 3 rates were lowest at 33\u00b0C and increased with temperature. In contrast, state 3 rates of cold-climate rats were highest at 33\u00b0C and decreased with increasing temperature represent the best studied mechanism that allows cells to detect changes in their environment directly (Nilius and Voets, Cyprinus carpio; Gracey et al., Hyla japonica; Sugimoto and Jiang, Temperature can also have direct effects on post-transcriptional processes, such as mRNA degradation, splicing, and translation efficiency. For example, temperature-dependent expression patterns of cold-inducible proteins are determined by the thermal sensitivity of post-transcriptional mechanisms (Sonna et al., The cold-shock RNA-binding protein RBM3 binds mRNAs to maintain translational efficiency (Peretti et al., Peripheral cells and tissues may also mount autonomous responses to local changes in temperature by indirect thermosensory pathways, where temperature-induced imbalances in cellular metabolites trigger compensatory responses. In skeletal muscle, decreasing temperatures cause an energy deficit, resulting in an increase in the AMP:ATP ratio (Towler and Hardie, The concept that endotherms have high and stable body temperatures despite environmental temperature fluctuations (Scholander et al., The mechanisms that mediate thermal plasticity are highly conserved among animals, and their broad range of functions is likely to preclude negative selection. For example, thyroid hormone action is essential for a broad range of physiological responses in animals, and is highly conserved across taxa (Heyland and Moroz, FS and AL conceived the ideas, prepared the manuscript and figures, and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "When exposed to stress, the hypothalamic-pituitary-adrenal axis is hyperactivated, which can cause the enlargement of the pituitary gland. Hence, pituitary gland volume could be a biomarker of stress present in psychosis. However, it remains unclear if individuals with psychosis have larger pituitary gland than healthy people. Previous studies investigating this question used small samples and reported inconsistent results. In the current study, we used an automated multi-atlas segmentation method to investigate the differences between pituitary gland volumes in a large sample of individuals on the psychosis spectrum.Data collection was completed across six sites in the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium with a total of 755 participants included in the study - 174 individuals with schizophrenia (SZ), 115 with schizoaffective disorder (SZA), 167 with psychotic bipolar disorder (PBD), and 299 healthy controls (HC). Structural magnetic resonance images were acquired and pituitary gland volumes were obtained using the automated MAGeT-Brain algorithm. General linear model and post-hoc independent t-tests were used to analysis the differences between subgroups of patients using clinical diagnosis and agnostic Biotype classification (Biotype 1 being the most cognitively impaired). We also explored potential effect of antipsychotic intake, symptoms severity and duration of illness. In all analyses, we used Bonferroni correction for multiple comparisons and entered confounds as covariates .Overall, the pituitary gland volumes were not significantly different between patients and HC. No significant main effect of diagnosis was observed, but SZ patients had trending larger pituitary volume compared to HC . We observed a significant main effect of Biotype (p=.003), with Biotype 1 having significantly larger pituitary gland than HC and Biotype 2 (p=.004 and p=.013). In the patients group, no significant relationship between the pituitary gland and the amount of antipsychotic intake was observed . Significant correlations with the pituitary gland volume were observed with symptoms severity , and with the duration of illness . Importantly, Biotypes did not significantly differ in terms of symptoms severity nor duration of illness.As a group, individuals with psychosis do not have abnormal pituitary gland volume, but larger pituitary gland is related to shorter duration of illness and greater symptoms severity. Therefore, larger pituitary gland volume could be a state-related biomarker of psychosis. Moreover, while we did not observe any significant subgroup differences using clinical diagnosis, our results suggest an increase in pituitary volume in biotype 1 patients compared to HC. These findings clarify previous inconsistent reports, and encourage further investigation of stress biomarkers in individual with psychosis with lower cognitive abilities. In the future, this could lead to the development of more targeted treatments for this specific subgroup of patients."} +{"text": "BluePen Biomarkers provides a unique comprehensive multi-omics biomarker discovery and validation platform. We can quantify, integrate and analyze genomics, proteomics, metabolomics and lipidomics biomarkers, alongside clinical data, demographics and other phenotypic data. A unique bio-inspired signal processing analytic approach is used that has the proven ability to identify biomarkers in a wide variety of diseases. The resulting biomarkers can be used for diagnosis, prognosis, mechanistic studies and predicting treatment response, in contexts from core research through clinical trials. BluePen Biomarkers provides an additional groundbreaking research goal: identifying surrogate biomarkers from different modalities. This not only provides new biological insights, but enables least invasive, least-cost tests that meet or exceed the predictive quality of current tests. The company was founded by experts from the field of biomarker discovery and validation at the University of Pennsylvania, which complements the bioinformatics expertise provided by Emerald Logic from Aliso Viejo . A major goal of the company is to address the problem of poorly predictive biomarkers that was identified by George Poste in his provocative 2011 article in Nature [BluePen Biomarker's team of management and scientific advisors comprises leading biomedical scientists who provide a coordinated approach to fully integrated biomarker solutions;Genomics, proteomics, metabolomics and lipidomics research is conducted in BluePen Biomarkers\u2019 laboratories using state-of-the-art instrumentation;The products of multi-omics research are integrated using sophisticated bioinformatics based on combinatorial signal processing and analytic approaches developed by Emerald Logic to provide a fully integrated biomarker solution ;The fundamental conviction of the company's founders is that any intervention that has a biologic outcome will have a detectable predictive biomarker signature. The challenge is to detect that signature;The comprehensive multi-omics systems biology platform available at BluePen Biomarkers coupled with Emerald Logic's innovative signal processing approach provides a powerful solution to the biomarker needs of academia as well as pharmaceutical and biotech industries ;The substantial expertise available within the company provides a unique resource for assessing potential clinical biomarker needs;Biomarker discovery and validation can be tailored to the particular project under consideration;BluePen Biomarkers now provides a commercial multi-omics platform that can quickly yield highly predictive biomarkers.BluePen Biomarkers was established in April 2016 in Philadelphia PA through a collaboration between the University of Pennsylvania's Center for Innovation, Blueprint Bio and Emerald Logic from Aliso Viejo , which is sometimes known as whole transcriptome shotgun sequencing. RNA-Seq, which is conducted by next-generation sequencing (NGS) using an Illumina HiSeq 3000 instrument, has largely replaced microarray analysis for the quantification of mRNA transcripts in a biofluid sample at a given moment in time. This can provide biomarker signatures of particular disease states. RNA-Seq can also be used to assess alternative gene-spliced transcripts, post-transcriptional modifications, gene fusion, mutations/single-nucleotide polymorphisms, different populations of RNA, total RNA, micro-RNA and transfer-RNA;Proteomics analyses normally involve targeted quantification of the major proteins that are identified as being upregulated by the RNA-Seq data. Analyses are conducted using nanospray ionization coupled with two-dimensional ultraperformance liquid chromatography/high-resolution mass spectrometry (UPLC-HRMS/MS) coupled with parallel reaction monitoring (PRM). These studies are conducted on a Thermo Q Exactive HF Hybrid Quadrupole-Orbitrap mass spectrometer operating in a targeted mode. Validation of differentially regulated proteins is conducted using rigorous stable isotope dilution UPLC-HRMS. Stable isotope-labeled protein standards are generated using stable isotope labeling by amino acids in cell culture (SILAC) based methodology ;Metabolomics and lipidomics analyses are conducted on serum samples that have been extracted using Bligh and Dyer methodology ,7. For bwww.lipidmaps.org). This means that BluePen Biomarkers can potentially discover lipid biomarkers where no standards are available to confirm structures. In this case, total synthesis is conducted using the extensive synthetic expertise that is available within the company so that absolute structural confirmation can be conducted before embarking on extensive clinical studies;Stable isotope-labeled metabolite and lipid standards are generated using stable isotope labeling by essential nutrients in cell culture (SILEC) methodology . There aBioinformatics analyses are conducted by Emerald Logic using a proprietary analytic platform that they have developed. This will identify signals in mRNA, protein, metabolite and lipid expression between cases and controls. An optimal panel of biomarkers will then emerge with maximal clinical specificity and sensitivity for a particular indication.Whole blood is normally provided to BluePen Biomarkers for genomics analysis; whereas serum is normally supplied for proteomics, metabolomics and lipidomics analyses. However, buffy coat or peripheral blood monocytes (PBMCs) are sometimes provided for proteomics analyses and platelets are sometimes provided for metabolism studies or specific mitochondrial protein quantification . BluePenDeveloping clinically useful biomarkers in biofluids is a complex process that often results in failure . TherefoQuantitative biomarker studies generally require the most sensitive means of detection possible ,11. The An authentic stable isotope-labeled analog of a biomarker is identical to the endogenous molecule, except for its mass . The resThe search for small molecule biomarkers that are predictive of cardiovascular disease, neurodegenerative diseases and cancers has been particularly intense and frustrating . HoweverBluePen Biomarkers was established in April 2016 to provide a coordinated approach to fully integrated biomarker solutions;The products of multi-omics research are integrated using sophisticated bioinformatics based on combinatorial signal processing and analytic approaches developed by Emerald Logic to provide a fully integrated biomarker solution;BluePen Biomarkers believes that by linking biomarker discovery and validation with the sophisticated bioinformatics provided by Emerald Logic that it will be possible to rationally approach the development of biomarkers for specific diseases;RNA-Seq is used to assess the potential utility of transcript profiling for biomarker analysis and upregulation of relevant proteins is confirmed by targeted proteomics;BluePen Biomarkers uses methods based on UPLC-HRMS for proteomics, metabolomics and lipidomics methods on their Thermo Q-Exactive HF instruments;This provides the only commercial multi-omics platform currently available that can quickly yield highly predictive biomarkers;The fundamental conviction of the company's founders is that any intervention that has a biologic outcome will have a detectable predictive biomarker signature."} +{"text": "Negative symptoms are core features of schizophrenia and can be grouped into two domains. These are apathy including anhedonia, avolition and asocialty as well as diminished expression including blunted affect and alogia. A large body of research found that ventral striatal hypoactivation is linked to negative symptoms. In particular, it has been shown that this neural correlate is specific for apathy but not diminished expression. Here, we investigated whether this dissociation can also be found in ventral striatum volume.We included brain structural T1 MRI data of 60 patients diagnosed with schizophrenia (SZ) and 58 healthy controls (HC). Negative symptoms in these groups have been assessed using the Brief Negative Symptom Scale (BNSS). We performed voxel-based morphometry (VBM) using the statistical parametric mapping package . We performed a region of interest (ROI) analysis of ventral and dorsal striatal volume between patients with schizophrenia and healthy controls. Furthermore, we analyzed the correlation of right and left ventral striatal volume with apathy and diminished expression in patients with schizophrenia. Moreover, we analyzed potential group differences in gray matter volume in an exploratory whole-brain analysis. Finally, we performed an exploratory whole-brain linear regression to identify potential correlations between the two negative symptom dimensions and gray matter volume. Patients with schizophrenia showed no differences in ventral striatal volume compared to healthy controls. Apathy or diminished expression did not correlate with ventral or dorsal striatal gray matter volume in patients with schizophrenia. In the exploratory whole-brain analysis we found significant less gray matter volume in the right insula of schizophrenia patients compared to healthy controls . Our exploratory whole-brain linear regression revealed no significant correlation between apathy or diminished expression and gray matter volume changes in patients with schizophrenia.Although a correlation of apathy and ventral striatal volume has been shown in a previous study with fewer subjects, we could not reproduce this finding in a larger group of 60 patients with schizophrenia . However, while these negative findings do not support the association between apathy and ventral striatal volume, there may be more subtle brain structural changes linked to the pathophysiology of apathy, which cannot be detected by voxel based morphometry. The gray matter reduction in the right insula in subjects with schizophrenia replicated findings from previous studies in schizophrenia ."} +{"text": "Medical students matriculating in the coming years will be faced with treating an expansive increase in the population of older lesbian, gay, bisexual, and transgender (LGBT) patients. While these patients face healthcare concerns similar to their non-LGBT aging peers, the older LGBT community has distinct healthcare needs and faces well-documented healthcare disparities. In order to reduce these healthcare barriers, medical school curricula must prepare and educate future physicians to treat this population while providing high quality, culturally-competent care. This article addresses some of the unique healthcare needs of the aging LGBT population with an emphasis on social concerns and healthcare disparities. It provides additional curricular recommendations to aid in the progressive augmentation of medical school curricula.Abbreviations: Liaison Committee on Medical Education (LCME); LGBT: Lesbian, gay, bisexual, transgender In the year 2000, 1 to 2.8 million lesbian, gay, bisexual, or transgender (LGBT) adults aged 65 and older were living in the United States . As suchRecently, the Association of American Medical Colleges (AAMC) published a 300+ page resource for medical educators outlining the implementation of curricular and institutional climate changes to improve the healthcare of LGBT and gender nonconforming patients . The pusOlder LGBT adults experience significant health disparities related to aging . In a poAging LGBT individuals experience a wide array of physical and psychological healthcare concerns synonymous with their heterosexual, binary, or gender-conforming peers . HoweverWith these \u2018chosen families\u2019 comes significant differences in caregiving and social support networks in the older LGBT community. While studies of the general US population indicate that between 25\u201344% of caregivers are male, within the LGBT community there is an even percent of male and female LGBT caregivers . Thus suConsiderations regarding \u2018chosen families\u2019 and unique caregiving responsibilities impact decisions related to retirement and end-of-life care. Completion of a living will or durable power of attorney is approximately 29% for both LGBT adults and non-LGBT adults . HoweverIn accordance with LCME accreditation Standard 7.6 emphasizing culturally competent care and development of solutions for healthcare disparities , studentIn addition to addressing concerns related to health disparities, medical students must be advised about the unique support systems and potential stressors in order to provide improved, culturally competent care to their future patients. This can be accomplished by increasing exposure of students to older LGBT adults by utilizing a panel of local community members. This panel could be modeled from The Gay and Grey Program (GGP)\u2019s trainings given by older LGBT adult volunteers to students and professionals in Portland, Oregon . OverallIn addition, complex end-of-life care decisions and the legal experiences of LGBT patients with \u2018chosen families\u2019 could be addressed in medical school ethics courses by utilizing a Problem Based Learning (PBL) approach. Unlike traditional passive learning with professor-designed didactic lectures, PBL involves active learning with dynamic interactions between learners and teachers . StudentIn order to educate a new generation of physicians equipped to provide culturally competent care, specific gaps in knowledge must be assessed. There are well-documented gaps in the cultural competency of LGBT older adult patients among health and social service providers . Gaps inSocietal problems of perceived discrimination, coupled with a lack of adequate training for future physicians, may contribute to unmet healthcare needs of the older LGBT patient population. Increased cultural competency related to physician-patient relationships must be addressed through progressive augmentation of medical school curriculum. As current and future healthcare providers, we must see that the needs of older LGBT adults are adequately addressed in medical education in order to ensure well-rounded, culturally competent care."} +{"text": "Gilles de la Tourette syndrome (GTS) is a sensorimotor disorder where the sensitivity to external and internal stimuli might be increased and unwanted responses to such stimuli cannot be sufficiently suppressed.Transcranial magnetic stimulation (TMS) studies indicate that, at rest, axonal excitability of cortico-spinal neurons and intra-cortical inter-neurons was consistently normal in GTS. However, synaptic excitability in cortico-spinal neurons and the SICI circuit may be lower than normal. In addition, an electrophysiological marker of sensory motor integration, SAI, was reduced in the baseline state consistent with reduced efficiency of synaptic inhibition. Given the possible influence of sensory inputs in triggering the release of tics reduced SAI may be a direct physiological reflection of increased access of sensory input to motor output in GTS. Experiments examining control of voluntary movements revealed that in GTS motor cortex excitability increases less than in controls when preparing a movement even though intra-cortical inhibition (i.e. SICI) normalises.In GTS the gain of many motor circuits may be reduced and hence less sensitive to small changes in input from other areas. These cortical changes may constitute an adaptive response to abnormal basal ganglia-motor cortex inputs."} +{"text": "Implementation of interprofessional clinical guidelines for the prevention ofneuropathic diabetic foot ulceration has demonstrated positive effects regardingulceration and amputation rates. Current foot care recommendations are primarilybased on research regarding the prevention of ulcer recurrence and focused onreducing the magnitude of plantar stress (pressure overload). Yet, foot ulcerationremains to be a prevalent and debilitating consequence of Diabetes Mellitus. Thereis limited evidence targeting the prevention of first-time ulceration, and thereis a need to consider additional factors of plantar stress to supplement currentguidelines.The first purpose of this article is to discuss the biomechanical theoryunderpinning diabetic foot ulcerations and illustrate how plantar tissueunderloading may precede overloading and breakdown. The second purpose of thiscommentary is to discuss how advances in biomechanical foot modeling can informclinical practice in the prevention of first-time ulceration.Research demonstrates that progressive weight-bearing activity programs to addressthe frequency of plantar stress and avoid underloading do not increase ulcerationrisk. Multi-segment foot modeling studies indicate that dynamic foot function ofthe midfoot and forefoot is compromised in people with diabetes. Emerging researchdemonstrates that implementation of foot-specific exercises may positivelyinfluence dynamic foot function and improve plantar stress in people withdiabetes.Continued work is needed to determine how to best design and integrate activityrecommendations and foot-specific exercise programs into the currentinterprofessional paradigm for the prevention of first-time ulceration in peoplewith Diabetes Mellitus. Exercise is often overlooked in current ulcer prevention guidelines.Abnormal plantar loading and foot function may contribute to ulceration.Progressive weight-bearing programs can be considered for ulcer prevention.Foot-specific exercises may improve foot function and ulcer prevention.Continued study may endorse inclusion of exercise into current guidelines.,Approximately one out of eleven adults, equating to 415 million people worldwide, havediagnosed or undiagnosed Diabetes Mellitus (DM)--,Among the numerous multi-system health consequences of DM, foot ulceration is an all toocommon problem. Lifetime prevalence estimations of foot ulceration in people with DM areas high as 25%, with a yearly incidence rate of 2-4%,recurrence,first-time ulceration. Yet, the evidenceto guide preventative efforts of first-time ulceration is strikingly limitedClinical guidelines have been developed to direct treatment and prevention strategiesfor foot ulceration, and are regularly updated based on current evidence---Biomechanical research has been an integral component underlying our understanding oftissue breakdown and in the development of ulcer prevention guidelines. For example, theuse of specialized footwear and/or insoles to relieve zones of high plantar pressure isfounded on the biomechanical theory that plantar tissue overload creates tissuebreakdown. While off-loading footwear is vital to ulcer healing and important to theprevention of ulcer recurrence, it is less clear how and when to apply the tissueoverloading principle to the prevention of first-time ulceration. Recent evidencesuggests that too much off-loading, as measured by decreased weight-bearing activityfrequency, may be counterproductive in ulcer prevention effortsThe purposes of this article are to present the contemporary biomechanical theoryunderpinning diabetic foot ulcerations and to discuss how advances in research andbiomechanical foot modeling can inform and influence clinical practice in the preventionof first-time ulceration.-,-overloading via momentary high stress or the accumulation ofundetected and repeated low to moderate stress on an area of the plantar neuropathicfootrepetition ofmechanical loading is as important as the magnitude of loading and howrepeated exposure to episodes of stress lowers the threshold of tissueinjury,-Neuropathic foot ulceration begins with insufficient blood glucose control, and it is acombination of intrinsic and extrinsic elements that beset the foot of an individualwith DM. Peripheral neuropathy coupled with the external stress of weight bearing hasbeen recognized historically as the primary pathway to neuropathic ulcerationunderloading may precede mechanical overloading of plantartissue. People with DM and peripheral neuropathy (DMPN) have reduced or variableweight-bearing activity prior to ulceration,,Therefore, external mechanical stress is a composite value that includes direction ofload application, time , and magnitude (force/area),,-Current ulcer prevention guidelines advocate for an interprofessional approach thatincludes physicians, nurses, physical therapists, orthotists, caregivers, and patients.A comprehensive strategy, including regular glucose monitoring, patient education, dailyfoot inspection, regular foot screenings and care, and footwear modification, isrecommendedmagnitude of plantarloading (pressure) are commonly combined with reduced weight-bearing activity todecrease the repetition of loading. Evidence suggests footwearintervention should aim for a pressure relief target value of 30% to reduce andredistribute plantar pressure and thus mitigate the potential for tissue breakdownand the assessment of the pressure-relievingeffects of the prescribed custom footwear/insoles. Further, footwear intervention iscontingent on patient adherence, as adherence below 80% negatively affects the footwearefficacy,,Contemporary recommendations for footwear intervention primarily ascribe to theoverloading theory of ulceration and remain an important aspect of ulcer prevention.Footwear interventions aimed at reducing the re-ulceration rates. While thepositive effects of footwear intervention are clear, differences in study designs andfootwear/insole strategies (over-the-counter vs. custom) have created different resultsacross studies. Nevertheless, a recent randomized clinical trial (RCT) that followedbest practice guidelines demonstrated that people with DMPN had less ulcer recurrencewhen wearing custom footwear with monitored pressure relief (<200 kPA or 25%reduction at targeted forefoot/midfoot sites) versus a custom footwear only groupIn a systematic review, van Netten et al.,,Recommendations for prevention of first-time ulceration also rely on the overloadingparadigm previously described. Rizzo et al.While the need for more research regarding footwear intervention and foot screeningpractices remains important, additional factors that may also prevent first-time tissuebreakdown should be considered. These factors include the frequency of weight-bearingactivity and the quality of dynamic foot function. Weight-bearing activity frequency isan important consideration as it pertains to plantar tissue tolerance to stress. Ratherthan reducing weight-bearing activity prior to tissue damage in the at-risk patient,maintenance or progression of weight-bearing activity may helpavoid tissue underloading. An understanding of dynamic foot function and how the footmay be internally stressed during each step of every day in a patient with DMPN isequally important. Abnormal stress secondary to altered dynamic foot function fromneuropathic tissue changes may expedite deformity and plantar tissue damage. Withcontinued research focused on weight-bearing activity and dynamic foot function,interventions to modify these factors may advance and warrant inclusion in clinicalguidelines.increase the risk for futureulceration,,While exercise (including weight-bearing activity) is recommended to improve glycemiccontrol, current guidelines are vague regarding how clinicians should dose andpromote exercise in people with DM who are at risk for ulceration. Further, activityincrease in people with DM is complicated by co-morbid medical conditions. Yet,equally important is the idea that plantar tissue may already be deconditioned priorto first-time ulceration. Research demonstrates that too much off-loading duringpreventative care may potentially ,Efforts to increase weight-bearing activity and promote plantar tissue resilience andglycemic control in people with DMPN are promising regarding tissue breakdown. TwoRCTs demonstrate that ulcer rates do not increase following an intervention toincrease weight-bearing activity,reduce ulceration risk has yet to be delineated. Apossible barrier to the development of such a protocol is the lack of an establishedbiomarker toguide the assessment of plantar tissue integrity. The inability to definitivelyassess tissue integrity and adjust activity dosage in a patient-specific mannerlikely precludes inclusion of weight-bearing activity regimens in currentpreventative guidelines. For this reason, it is relevant to consider not only howoften the foot is stressed during weight-bearing activity, but alsohow it is stressed.At present, conscientious patient instruction should include a program of regulardaily weight-bearing activity in an attempt to improve glycemic control andpotentially maintain plantar tissue integrity-In-vivo assessment of dynamic foot function fosters hypotheses generation about howinternal structures are performing and consequently stressed during weight-bearingactivity. Additionally, dynamic foot function represents the behavior of the footduring the time period when the primary extrinsic stimulus of ulceration occurs. Dynamic foot function can be assessed using single- or multi-segmentmodeling approaches . Single--Single-segment modeling investigations of foot biomechanics in people with DMPN haveproduced mixed results regarding factors potentially linked to tissue breakdown.There have been variable findings regarding passive ankle joint mobility, anklemotion during walking, and forefoot plantar pressure,,,-,,st metatarsal and lateral forefoot sagittal plane ROM, duringwalking to elevated forefoot plantar pressures in people with DMPN. Changes in DMPNmulti-segment kinematics are also present during higher-level tasks. Hastings etal.Studies employing multi-segment foot modeling approaches have identified changes inkinematics during walking in people with DM and DMPN and in people with DMPN with ahistory of ulceration,,The use of multi-segment models in diabetic foot research demonstrates how morespecific modeling approaches can better link regions of foot dysfunction to regionsof diabetic foot pathology ; however, relationships between foot kinematics and plantarpressures are commonly generated from data collected during separate walking trials.Giacomozzi et al.,both ankle andmidfoot power may better reflect the degree of internal stresses, particularly at themidfoot, during functional tasks in people with DMPN. DiLiberto et al.and midfoot as factors of abnormal dynamic foot function inpeople with DMPN. Specifically, the reduced active mechanism support at the archraises questions regarding abnormal internal stresses on passive structures at bothregions of the foot. The cumulative effect of this kinetic pattern may contribute tothe development and/or progression of midfoot deformityApplication of single- and multi-segment modeling approaches has also advanced ourunderstanding of kinetic performance in people with DMPN. Studiesusing single-segment foot models demonstrate a reduction in peak ankle plantarflexionpower during walking in people with DMPN, as compared to healthy controls,Changes in DMPN dynamic foot function have been attributed to neuropathic tissuechanges such as decreased tissue extensibility and muscle atrophy/fatty infiltration. Recent research specifically supportsthe relationship between neuropathic muscle changes, multi-segment foot kinematics,and deformity in people with DMPN. Hastings et al.There is increasing focus on how to design intervention strategies to improve dynamicfoot function in people with DM who are at risk for ulceration,-Some studies have demonstrated promising biomechanical results by incorporatingfoot-specific exercises in people with DMPNPreservation of plantar tissue integrity and foot function for the prevention offirst-time neuropathic foot ulceration is a challenging endeavor for people with DMPNand their care providers. The effectiveness of preventative interventions is predicatedon blood glucose control, the advancement of the neuropathic process, and plantar tissueintegrity. It is imperative for clinicians to address the interplay between themagnitude (pressure), frequency (weight-bearing activity), and quality (dynamic footfunction) of foot stress. One of the most difficult challenges is to determine how tostrike an effective balance between too much (overloading) and too little (underloading)stress. When deciding between parameters of loading, the clinician is advised that thethreshold for tissue damage is contingent on both the current state of the foot tissueand how it will be stressed in the future.While there is room for improvement regarding foot-screening procedures to best evaluatetissue integrity and predict injury, recent research offers insight that may augmentcurrent clinical guidelines. In addition to the interprofessional approach and foot carepractices described previously, advising patients on interventions to address thefrequency and quality of stress should be considered. A progressive and well-monitoredweight-bearing activity regimen that includes walking, balance, and leg strengtheningcan positively influence patient health and function. Activity regimens not only promoteglycemic control, potentially slowing the effects of neuropathy, but also possiblydecrease the potential of plantar tissue underloading. Further, multi-segment modelinginvestigations suggest that addressing dynamic foot function is an additional supplementfor the prevention of first-time ulceration. Specifically, assessment of forefoot andmidfoot mobility, as well as assessment of intrinsic and extrinsic muscle strengthshould be part of routine foot screening examinations. Examination findings should guideclinical decisions for implementation of progressive exercise programs to improvedynamic foot function or direct patients to other appropriate interventions/careproviders . Continued work is needed to determine how to best design andintegrate activity recommendations and foot-specific exercise programs into the currentinterprofessional paradigm for the prevention of first-time ulceration in people withDiabetes Mellitus."} +{"text": "Postpartum haemorrhage (PPH) is a major cause of maternal mortality and morbidity worldwide. Experimental and clinical studies indicate that prolonged oxytocin exposure in the first or second stage of labour may be associated with impaired uterine contractility and an increased risk of atonic PPH. Therefore, particularly labouring women requiring cesarean delivery constitute a subset of patients that may exhibit an unpredictable response to oxytocin. We mapped the evidence for comparative studies investigating the hypothesis whether the risk for PPH is increased in women requiring cesarean section after induction or augmentation of labour.clinicaltrials.gov and the WHO registry platform. We identified a total of 36 controlled trials investigating the exogenous use of oxytocin in cesarean section. Data were extracted for study key characteristics and the current literature literature was described narratively.We performed a systematic literature search for clinical trials in Medline, Embase, Web of Science, and the Cochrane Library (May 2016). Additionally we searched for ongoing or unpublished trials in Our evidence map shows that the majority of studies investigating the outcome PPH focused on prophylactic oxytocin use compared to other uterotonic agents in the third stage of labour. Only 2 dose-response studies investigated the required oxytocin dose to prevent uterine atony after cesarean delivery for labour arrest. These studies support the hypotheses that labouring women exposed to exogenous oxytocin require a higher oxytocin dose after delivery than non-labouring women to prevent uterine atony after cesarean section. However, the study findings are flawed by limitations of the study design as well as the outcome selection. No clinical trial was identified that directly compared exogenous oxytocin versus no oxytocin application before intrapartum cesarean delivery.Despite some evidence from dose-response studies that the use of oxytocin may increase the risk for PPH in intrapartum cesarean delivery, current research has not investigated the prepartal application of oxytocin in well controlled clinical trials. It was striking that most studies on exogenous oxytocin are focused on PPH prophylaxis in the third stage of labour without differing between the indications of cesarean section and hence the prepartal oxytocin status.The online version of this article (10.1186/s12884-017-1584-1) contains supplementary material, which is available to authorized users. Postpartum haemorrhage (PPH) is a major cause of maternal mortality and morbidity worldwide \u20134. ApproThe most widely used uterotonic drug for augmenting labour or to maintain uterine contractility during labour is oxytocin , 16. OxyConsidering that PPH rates are higher in cesarean section compared to spontaneous labour , particuWe adhered to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) protocol for identifying, screening and eligibility of studies to conduct the present research work ). Furthermore, significantly more women in the labouring group compared to the non-labouring group required additional uterotonic agents . (ii) The other dose-response study from Balki et al. estimated the minimum effective intravenous dose of oxytocin required for adequate uterine contraction after cesarean delivery for labour arrest, however, without using an active control group [From 36 studies identified, 8 studies (1705 patients) included solely women requiring intrapartum cesarean delivery, mainly because of labour arrest \u201333. Howeturients . Thirty-ol group \u201332. WhetOur mapping also revealed that the majority of studies investigating PPH rates for different treatment groups are focused on prophylactic uterogenics and included women with different types of cesarean delivery (intrapartum and prelabour cesarean section). However, the PPH rates given in these studies were not stratified according to the indications for cesarean section. In addition, the prepartal oxytocin status was not considered as confounding factor by conducting subgroup analyses \u201363.ClinicalTrials.gov Identifier: NCT01869556 and NCT02794779). The estimated completion date for both studies is by the end of 2017. In addition, we identified HOLDS, a multicentre, double-blind randomised controlled trial to compare standard and high dose regimens of oxytocin for women with confirmed delay in the first stage of labour (http://www.isrctn.com/ISRCTN99841044). This trial randomises 1500 women and measure differences in rates and complications associated with cesarean section. If this study provides a subgroup analysis of PPH rates in those women requiring cesarean sections, important insights addressing the present research question will be given.The search for ongoing and unpublished studies identified 2 RCTs which may provide subgroup data estimating the blood loss and risk for PPH after cesarean section for labour arrest Checklist. (DOC 60 kb)Additional file 2:Search Strategy in Medline (OvidSP). (DOCX 14 kb)"} +{"text": "Evolving multicellularity is easy, especially in phototrophs and osmotrophs whose multicells feed like unicells. Evolving animals was much harder and unique; probably only one pathway via benthic \u2018zoophytes\u2019 with pelagic ciliated larvae allowed trophic continuity from phagocytic protozoa to gut-endowed animals. Choanoflagellate protozoa produced sponges. Converting sponge flask cells mediating larval settling to synaptically controlled nematocysts arguably made Cnidaria. I replace Haeckel's gastraea theory by a sponge/coelenterate/bilaterian pathway: Placozoa, hydrozoan diploblasty and ctenophores were secondary; stem anthozoan developmental mutations arguably independently generated coelomate bilateria and ctenophores. I emphasize animal origin's conceptual aspects related to feeding modes, cell structure, phylogeny of related protozoa, sequence evidence, ecology and palaeontology. Epithelia and connective tissue could evolve only by compensating for dramatically lower feeding efficiency that differentiation into non-choanocytes entails. Consequentially, larger bodies enabled filtering more water for bacterial food and harbouring photosynthetic bacteria, together adding more food than cell differentiation sacrificed. A hypothetical presponge of sessile triploblastic sheets (connective tissue sandwiched between two choanocyte epithelia) evolved oogamy through selection for larger dispersive ciliated larvae to accelerate benthic trophic competence and overgrowing protozoan competitors. Extinct Vendozoa might be elaborations of this organismal grade with choanocyte-bearing epithelia, before poriferan water channels and cnidarian gut/nematocysts/synapses evolved.This article is part of the themed issue \u2018Evo-devo in the genomics era, and the origins of morphological diversity\u2019. Bacteria and protists greatly exceed vertebrates in different kinds of organism too. Lamarck thought unicells so evolutionarily recent that they had not yet had time to inexorably become multicellular. Not so; they existed billions of years longer than complex multicells and may outlive them. There are hordes of excellent unicellular niches; multicellularity is often selectively disadvantageous. Yeasts evolved multiply from multicellular filamentous ancestors; Myxozoa are parasitic unicells that evolved from animals with nervous systems (early-branching Cnidaria), losing epithelia, connective tissue, nerves and 70% of genes as useless, only their multicellular spores keeping nematocysts . So how Multicellularity evolves in two ways. Naked cells, as in animals and slime moulds, evolve glue to stick together. Walled cells modify wall biogenesis to inhibit the final split that normally makes separate unicells, so daughters remain joined. The ease of blocking that split allowed almost every group of bacteria, fungi and plants (and many chromists) to evolve multicellular walled filaments, more rarely two-dimensional sheets, most rarely three-dimensional tissues. Tissues require more geometric control of daughter wall orientation, as in embryophyte green plants and chromist brown algae; both can grow longer than blue whales. Evolving tissues is selectively harmful to many walled multicells whose filaments are best for reproductive success. Almost all multicells retain unicellular phases , so adhesion is temporally controlled and developmentally reversible\u2014except for purely clonal vegetatively propagating plants or \u2018colonial\u2019 invertebrates (evolutionarily transient) the only organisms that are never unicellular.2O, CO2 and minerals) just as does a single cell; so does a saprotrophic bacterial or fungal filament. However, a phagotrophic amoeba could not aggregate into a multicellular body and still locomote and feed the same way. Nor could most other protozoa. Many amoebae have become multicellular, but only temporarily for spore dispersal, not feeding. Aggregative multicellularity has produced multispore fruiting bodies numerous times in fundamentally different protist lineages to switch from intracellular phagocytosis, as in amoebae or ciliates, to eating with a multicellular mouth and gut, whose cells have novel functions and structures absent in their unicellular ancestors. Animal feeding is effective only if novel cell types cooperate at a higher organizational level; most give up the ability to feed or reproduce, huge selective disadvantages not easily overcome.In 1866, James-Clark discovered choanoflagellate protozoa and their feeding on bacteria trapped by a collar surrounding their undulating cilium that generates the water current that draws them towards it. He noted that sponge collar cells (choanocytes) have the same structure and feeding method, correctly suggesting that sponges evolved from a choanoflagellate . Often sAmong extant animals, only sponges could have evolved directly from protozoa without changing feeding mode. The key problems in understanding animal origins are therefore how and why sponges evolved from a craspedid-like stem choanoflagellate and later generated all other animals. I attempt to explain both after briefly outlining enabling protozoan innovations. I shall emphasize simple conceptual aspects of the choanoflagellate/animal transition, often overlooked but more important than discovering extra protozoan genes suitable as precursors to animal functions. Such ancestral features exist in both choanoflagellates and more distant protozoan relatives of substantially different cell structures and feeding mode .In the light of site-heterogeneous trees using 187 protein sequences ,17, figuSulcozoan flagellates clearly could not have retained their characteristic locomotory or feeding modes had they evolved glue to stick together as a multicellular organism; such mutants would necessarily quickly starve to death. Nor could their immediate ancestors\u2014three successive groups of swimming, not gliding flagellates collectively called excavates because their ventral groove looks more obviously scooped out ,17. The Knowing the structure and evolutionary potential of the closest relatives and ancestors of animals and thatDictyostelium has a \u03b2-integrin-like adhesion protein [Integrins and associated molecules used for epithelial cell adhesion to extracellular matrix (ECM) were secondarily lost by choanoflagellates and fungi; without full genomes for the deepest branching Sulcozoa, the exact point of origin is unclear : though protein and its protein \u2014or even why\u2014but defining the selective forces that promoted the fundamental differentiation between sponge feeding cells (choanocytes) and non-feeding cells and between cells that stick together as epithelia and connective tissue cells embedded separately in a gelatinous mesohyl. Did epithelia evolve first or did epithelia and mesenchyme coevolve?Carchesium, Zoothamnion); some algal, e.g. chrysophyte Dinobryon. Mucilaginous multicellular branching structures are formed by Rhipidodendron (cercozoan chromists) or Phalansterium (uniciliate Amoebozoa). As no branching protists evolved a multicellular tissue, similar \u2018colonial\u2019 choanoflagellates are probably not directly relevant to animal origins. Nonetheless, they show that various linked flagellates can still feed in the same way as when unicellular, and their frequency suggests that branching stalks advantageously enable them to sweep prey from a much larger water volume than can one sessile cell. Filtering more water by a different sessile body form is, I argue, the selective advantage that made sponges.Four different ways of making multicellular choanoflagellates exist. Many become \u2018colonial\u2019 sessile organisms by evolving thin extracellular stalks that join cells together to form branched tree-like structures analogous to corals or plants ,10. OtheProterospongia choanojuncta, but I doubt this had a potential to yield a sponge. Sponge collars also join laterally often by a second mucus mesh to achieve 100% removal of suspended bacteria [More rarely, choanoflagellate multicells arise by linking adjacent cells by their collar microvilli as in bacteria , showingDiaphanoeca sphaerica, where cells often clump in hollow balls with cilia pointing inwards [Diaphanoeca, like other loricates (Acanthoecida), are tiny cells suspended within a much larger lorica of siliceous strips porous to water currents carrying prey. Aggregating porous loricas by connecting longitudinal strips allows colonial feeding despite cilia pointing inwards, as the collar outer surface that traps food still faces outwards. Water and bacteria can pass through the lorica mesh or wide interlorica spaces, so feeding mode is unchanged compared with unicells; cell bodies are not in contact so could not evolve into an epithelium to make a sponge. Acanthoecida are necessarily an evolutionary dead end.The loricate inwards , exempli inwards was mislSphaeroeca is a multicellular planktonic craspedid whose colonies are hollow balls with a surface cell monolayer, associated by cell bodies not collars, analogous to the alga Volvox that Hardy [Salpingoeca rosetta reversibly makes little multicellular balls, a capacity influenced by bacteria [Non-loricates (Craspedida) never aggregate with cilium facing inwards like sponges as that would suicidally stop collar-based feeding. at Hardy invoked bacteria . Numerou4.Willmer emphasized the basic dichotomy between ciliated epithelial and non-ciliated, amoeboid, connective tissue cells as fundamental to animal development . Figure\u00a0Dictyostelium dead stalk cells.The primary dichotomy between uniciliate choanocyte and non-ciliate pinacocyte is also mirrored by that between sperm and egg. Therefore, part of the same gene switches needed for somatic differentiation could also be used to differentiate gametes. Once a three-layered structure with just two somatic cell types evolved, presponges could become quite large (compared with choanoflagellate unicells); selection for rapid establishment of a large embryo would strongly favour oogamy by modifying choanocytes, presumably hermaphrodite. The animal bauplan was in place once a selective force for ever-larger filtering structures built from two dissimilar cell types existed: two germ line and two soma cell types. Accidental fragments could also reproduce vegetatively as choanocytes retained pluripotency . There wAnother selective advantage of evolving mesenchyme and massive tissues perhaps gave extra impetus to early animal evolution. Mucilage easily harbours bacterial symbionts potentially able to provide enough extra food to repay a presponge several times over the trophic and reproductive costs of non-feeding cells. Cultivating cyanobacteria in ECM mucilage would make the photophagotrophic consortium an extremely effective competitor with merely branched choanocyte-only colonial choanoflagellates. Lichen fungi can survive solely by cultivating cyanobacteria; a presponge could be even better off, being also a phagotroph able to grow far faster than a lichen in bacteria-rich water. Great Barrier Reef sponges 1\u20132 m high are often red through being packed with cyanobacteria whose biomass is greater than that of the sponge cells. Lake Baikal giant freshwater sponge tissues cultivate green algae. Both habitats are oligotrophic, making internal algae especially advantageous, but even in habitats rich in particulate food, the majority of sponge species are often photosynthetic . In orgaExtra cell types could be added relatively simply to help presponges to grow bigger and be less susceptible to environmental damage. An individual could grow basally across a rock and erect multiple laminae. Spatial controls evolved to prevent laminae from interfering with each other. Presumably, various morphologies and arrangements and ratios of the two basic cell types were experimented with, giving different compromises between maximizing feeding and mechanical stability. An early innovation necessary for large structures was to increase the ECM-synthesizing cells initially perhaps by evolving a third cell type\u2014the ancestral archaeocyte that left the epithelium, entering the mesohyl for secreting ECM in all directions, making a triploblastic tissue with mesenchyme sandwiched between two epithelia. Nowadays archaeocytes and choanocytes are the demosponge stem cells, expressing PIWI double-strand RNA-binding domain proteins whose short-RNA related functions are associated with germline and stem cell maintenance in higher animals as well 5.Site-heterogeneous multigene trees maximally support choanoflagellates being sisters to animals ,33; theySite-heterogeneous multigene trees equally strongly show sponges as a clade, disproving Nielsen's assumption that eumetazoa are more closely related to homoscleromorphs than others, and invalidating his twin assumptions that ancestral animals were lecithotrophic and eumetazoa secondarily lost lecithotrophy . His sug6.This presponge was not a sponge, for it lacked an aquiferous system (AS) with incurrent pores (ostia) and larger excurrent osculum or oscula. AS architecture has two advantages: (i) it increases food supply by pumping much larger water volumes past the choanoderm; (ii) compared with the essentially \u2018free-living gills\u2019 of the presponge, placing the choanoderm inside a globular or encrusting body protects choanocytes from damage by sand and other things swept against them by vigorous water currents and from damage by the currents themselves. Essential innovations making a sponge were (i) controlled formation of ostia of appropriate size, frequency and distribution; (ii) rearrangement of pinacocytes and choanocytes to internalize the latter, make a more compact less easily damaged body, and optimize water flow through internal choanoderm-lined channels. Ostia are intercellular in all Homoscleromorpha and most demosponges, but are formed by channels through specialized porocytes in Calcarea and not obviously homologous contractile porocytes in a few haplosclerid demosponges. I suspect they originated not by evolving a new cell type but by spatially controlling pinacocyte contacts and geometry; porocytes evolved later independently in Calcarea and haplosclerids. If so, ostia arose as part of the supracellular rearrangements that made an axially polarized water channel system. This major innovation almost certainly depended on prior evolution of morphogen gradients and homeobox and other spatially controlled switch genes that sponges share with Eumetazoa ,38. BeneChlamydomonas and could be a general property of eukaryote cilia that evolved during the origin of two structurally and behaviourally dissimilar cilia in the eukaryote cenancestor [Ephydatia, oscular sensory cilia lack the centre-pair microtubules as in eumetazoan sensory cilia [Making AS development and functioning more efficient probably entailed differentiating pinacocyte subtypes: specialization of some as myocytes to exert some control on oscular and ostial opening; and multiplication of non-epithelial mesohyl cell types. The branched mesohyl cells that synthesize a variety of neurotransmitters are obvious candidates for precursors of eumetazoan nerve cells, requiring only the origin of electrosensitve channels to cause action potentials and synapses to make a nerve net. The syncytial body form and calcium/potassium action potentials of hexactinellid glass sponges are secondary, not the ancestral condition for sponges, as hexactinellids are related to demosponges not the deepest lineage . They arancestor . In the ry cilia . Early sry cilia with a hThe greater complexity of true sponges over presponges required planktonic ciliated larvae for dispersal to new fixed sites that grew big enough to transform immediately into a tiny triploblastic sponge with internal choanoderm able to feed at once. Abundant egg yolk enabled more rapid development than feeding by surface choanocytes, making sponge larvae lecithotrophic unlike planktotrophic presponge and ancestral eumetazoan ciliated larvae. Larvae evolved phototaxis using cryptochromes , not rhoThe phrase \u2018from amoeba to man\u2019 epitomizing Haeckel's early phylogenetic views doubly misleads. Amoebae are not primitive but arose from zooflagellate ancestors independently in each of the three ancestrally biciliate eukaryotic supergroups . Epithel7.Hydra [Trichoplax (unlike sponges) has numerous presynaptic protein precursors as well as gap junctions, chemical and electrical synapses probably both originated after the pre-cnidarian lineage diverged from placozoa yielding an anthozoan-like stem coelenterate. Thus, neither muscular [1The larger larvae of true sponges provided a novel, hitherto unexploited, food for predators. One stem sponge lineage, I suggest, evolved nematocysts to catch and digest them, thereby becoming the ancestor of coelenterates , a clade on the best multigene trees . NematocHydra ), and thHydra , and synHydra ; very feHydra . As Tricmuscular nor cilimuscular initiateKey to neurogenesis was a multicellular precursor with neurotransmitter-making cells and already adjacent receptor and effector cells linkable by evolving synapses under a strong selective advantage, exactly as this flask cell to nematocyte transition postulates without missing links or improbable events. Thus, improving the sessile zoophyte lifestyle by increasing survival (e.g. against waves tearing settling larvae from rocks) at the crucial, but uniquely vulnerable, pelagic\u2013larval/benthic\u2013adult transition was, I contend, the selective force for evolving synapses, ultimately leading to brains, culture and science. Synapses evolved to make ciliated larval settlement faster and more effective by neural coordination of concerted banks of nematocysts under the control of ciliated sensors that selected the best sites. Flask cell precursors concentrate at the aboral pole. Nematocysts remain there to mediate settlement but concentrated also around the osculum (making it a mouth) and along ancestral anthozoan protosepta to trap food.+ and K+ channels (both originating in bacteria) were modified to generate sodium/potassium action potentials in longer nerve cell branches for distant coordination of feeding responses, making eating more efficient\u2014a selective advantage an automatic corollary of this explanation of synaptic origin. Action potentials evolved many times, thus easily\u2014not only in hexactinellids, but also filamentous fungi, plants and ciliate protozoa [Adding synaptic junctions not only between sensory cells and nematocysts, but between sensory cells and branched pre-existing branched transmitter-making cells and myocytes, would establish local neuromuscular control by a nerve net. This speeded oscular contraction making it an effective mouth, its reversible closure plus adhaerens junctions being key innovations for initial extracellular digestion of larger prey caught by oral and septal nematocysts. Having established neuromuscular synapses, pre-existing voltage-dependent Naprotozoa . Axons eper se does not make nerves.Before tentacles evolved, partially redirected ciliary currents (importing food and exporting waste through the mouth) likely made an asymmetric single-siphonoglyph protopharynx; and eight functionally complementary nematocyst-rich septa and Ctenophora.Without giving reasons, Nielsen unjustifiably asserted \u2018it seems impossible to derive eumetazoans from an adult sponge\u2019 , p. 148.8.I have argued that the ancestral coelenterate was a bilateral octomerous stem anthozoan that lost choanocyte microvilli as neurally controlled nematocyst/tentacle feeding on larger prey improved, its mouth evolving from the osculum, and ostia closed suppressing water channels, yielding a single body cavity, the coelenteron. Choanoderm and endoderm are homologous , as are Contrary to dogma, Anthozoa, Scyphozoa and Cubozoa are mostly triploblastic with true mesoderm \u201374. The Probably before Medusozoa originated, a stem coelenterate switched completely from benthic to planktonic life by evolving multiaxonemal macrocilia and comb plates and losing nematocysts no longer required for settlement and accelerating oral and sexual development. This radical shift in adaptive zone and developmental fate of the ancestral planula larva entailed numerous unique innovations giving Ctenophora such a different body form from crown cnidarian adults, and unique embryology. In Cnidaria, the larval nervous system is concentrated largely aborally but degenerates during metamorphosis after settlement, being replaced by an oppositely polarized adult system with an oral focus . UnsurprPolypodium, a tentaculate triploblastic polypoid cnidarian (class Polypodiozoa) whose highly modified planula endoparasites sturgeon oocytes [Polypodium triploblasty supports treatment as a separate class outside diploblastic Hydrozoa [Polypodium clade might be sister to Hydrozoa, as some trees indicate [Ideas that the nervous system evolved twice or was lost by sponges \u201356 are u oocytes . PolypodHydrozoa , their aindicate . Myxozoaindicate might haindicate , as expeBeroe [Others advocate one neural origin and invoke tree artefacts, giving more supporting details . Saying Beroe ). The beBeroe with no Rapid divergence of Anthozoa (benthic nematocystous adults) and Ctenophora neatly partitioned the Early Cambrian adaptive zone for predating larger prey. By not settling, ctenophores could evolve anal pores at the statocyst pole, enabling more efficient unidirectional ingestion and defecation currents independently of unianal bilateria, allowing secondary biradial gut symmetry by losing the siphonoglyph . Like ctenophores, early adult anthozoa probably relied on ciliary feeding (often helped by mucus secretion as in scleractinia). More complex barbed nematocysts and toxins evolved divergently only after bilateria arose and became cnidarian prey.9.Renilla) or by apical invagination (Alcyonium); the stomodaeal cavity/invagination joins the coelenteron secondarily when the two separating epithelia at the stomodaeal base degenerate, making a novel opening [Renilla to fuse basally with the side of the developing coelenteron wall before the breakthrough, would immediately connect the pharyngeal cavity not with the coelenteron but through the body wall to the outside develops separately from the coelenteron cavity by an apical inwardly projecting tissue mass that secondarily develops an inner cavity almost without further modification, and separated its mechanical functions from those of a gut. The new through gut could retain digestive and absorptive functions, likely improved by modifying their positional control to regionally differentiate the former pharynx and be suppressed in the former coelenteron, now coelom. By focusing on burrowing and processing ingested sediment, nematocysts were lost and tentacles modified in function to simple mouthparts (or lost in some lineages). Such a radical change would necessarily dramatically affect embryology; unsurprisingly, thereupon two different ways immediately arose to stabilize mouth/anus formation in this protobilaterian: the proterostome/deuterostome bifurcation.Sequence phylogeny makes it virtually certain that the deuterostome ancestor was non-cephalized, whether a burrower like acorn worm or tentaculate like pterobranchs, possibly colonial like tunicate and salp. All these could readily have arisen from this tentaculate/burrowing intermediate. Lophotrochozoa also appear primitively to have had non-cephalized tentaculate or burrowing forms. The common ancestor of both groups can be argued to have been a tentaculate form, retaining pharyngeal ciliary currents that Anthozoa use in feeding, but a better burrower than burrowing sea anemones. This protobilaterian would be preadapted as ancestor of all major deuterostome and lophotrochozoan groups; acquiring ecdysis and very different mouthparts was more radical, yielding a priapulid-like ecdysozoan ancestor. Site-heterogeneous multigene analyses show that deuterostome acoels lost gut ,85 and pSarcophyton mitochondrial genome [Although lacking synapses, sponge tissues and embryology are as complex as in Cnidaria ,88\u201391; Hl genome confirmel genome . Radial Drosophila eyes; these eyes evolved independently by modifying eukaryote cells (not strictly homologous with the bacteria that invented rhodopsin) and arranging them into contrasting supracellular structures. It is too often overlooked that structural homologies like those of tetrapod limb bones are at a higher level of organization than are transcription factors or building blocks such as collagen that they may share with morphologically non-homologous arthropod or annelid limbs and can often be recognized unambiguously entirely independently of gene sequences; there is almost certainly no \u2018pentadactyl-limb gene\u2019. Non-homologous structures are often built partly of homologous components.Hyman's assertion that non10.Haootia might be a muscular cnidarian impression [Acetabularia being superficial. Acetabularia is not syncytial; its form requiring cell walls is adapted for photosynthesis. Habitat proves that Vendozoa were not generally phototrophs [Codium are never quilted. Absorptive feeding by filamentous syncytial fungi like zygomycetes would cease if they evolved that body form. Large fungal fruiting bodies are non-trophic for spore dispersal. Syncytial sponges evolved secondarily from cellular ancestors. The largest protozoan syncytia (myxogastrid Mycetozoa) are naked phagotrophs with no architectural potential to evolve a vendozoan body form, unassignable to any protist group. Vendozoan complexity required extensive connective tissue to make quilt seams as struts supporting two outward facing trophic epithelia. Broken frondule internal structure [Rejecting the then prevalent idea that Ediacaran macrofossils antedating the Cambrian explosion included bilateria , I arguepression . Howeverpression , his anatotrophs . Syncytitructure suggestsThat Vendozoa were osmoheterotrophs is implaPhalansterium and spongomonads are possibilities that in principle might retain their feeding mechanism after evolving a multicellular differentiated tissue. But I strongly doubt any did, as evolving a multicellular phagotroph with tissues is difficult (see above) except via a flagellate/sponge pathway, and vendozoan timing just before sponges and eumetazoa can hardly be mere coincidence. Vendozoa flourished 580\u2013541 Ma, becoming extinct at the Cambrian explosion approximately 541 Ma. Their reduced disparity and diversity 5 Ma before the Cambrian explosion [It is theoretically possible that Vendozoa arose independently of sponges by evolving a connective tissue in another colonial flagellate group\u2014xplosion I attribFunisia [Eocyathispongia [Several simpler, seemingly non-quilted, sessile Ediacaran fossils could also be presponges, e.g. the tubular Funisia . The 1 mispongia is more ispongia . Crown sispongia . Unique Kimberella may belong here [Eocyathispongia) new subhylum Varisarca: Diagnosis: extinct macroscopic sessile multicells inferred to be ciliary filter feeding phagotrophs with epithelial/ECM organization; body form: variable arrangements of thin sheets, neither arranged in a quilted array , nor having ostia and internal water channels (unlike Porifera); non-mobile as adults. Etymology Vari variable sarco Gk flesh signifies variable body forms of epithelioid/ECM presponge fleshy organization.I regard Vendozoa as the oldest phylum of kingdom Animalia, distinct from Porifera, Placozoa and Eumetazoa. I divide it into subphylum Petalonamae for petaong here ) and forTrichoplax be direct descendants of presponges.Vendozoa likely had Wnt/catenin axial patterning and ciliated planktonic larvae for dispersal, as without an AS they could not have easily brooded larvae as most sponges do (perhaps secondarily as protection after coelenterates evolved). If Placozoa are sisters of Eumetazoa as most multigene trees suggest, Placozoa were secondarily simplified by AS or coelenteron loss, evolving neotenously by prolonging the usual larval presettling benthic creeping phase by evolving extracellular digestion of benthic microbes and losing metamorphosis. Only if nested within Eumetazoa (Coelenterata plus bilateria) as some unconvincing trees suggest, need they have lost neurons also, like Myxozoa. Only if branching deeper than sponges and Eumetozoa, which multigene trees mostly exclude, could 11.The Cambrian explosion is the most striking animal example of ultrarapid origins of novel body forms: Simpson's quantum evolution, convincingly attributed to the invasion of previously unexploited major adaptive zones . Some leThere truly was an Early Cambrian explosion of animal (and protist) phyla, now ecologically and evolutionarily quite easy to understand. Such an explosion is expected for the very reasons that Darwin and Simpson convincingly explained. When a bilaterian with through gut and coelom arose, it created a new competitor-free adaptive zone and was bound to diversify rapidly into all body plans developmentally readily made by simple modifications and able to survive ecologically . It woulA widespread explanatorily empty speculation that many groups originated long before their objective fossil dates is fuelled by deep uniformitarian prejudices about evolutionary rates that palaeontology long ago refuted, and three other prejudices/biases that synergistically led to the notion of a \u2018slow burning fuse\u2019\u2014a journalistic slogan, not critical evolutionary thought, evaluation or synthesis. First is excessive confidence in the certainly false idea of a \u2018molecular clock\u2019 and in the reliability of current implementations of oxymoronic \u2018relaxed clock\u2019 computer programs . Second 12.The best way to understand megaevolutionary events is by a coherent synthesis unifying data of every kind using explicit reasoning and well-tested explanatory principles. Haeckel's idea that animals evolved from a protozoan ancestor directly via a gastraea with triploblastic body, mouth, gut and anus, and that the animal archetype was a flatworm-like bilateral mobile predator like us minus coelom and anus must be wrong. A gastraea is far too complicated to evolve in one step. Instead, a choanoflagellate became a triploblastic sponge (arguably in two separate stages), a sponge became an anthozoan cnidarian, stem anthozoa generated pelagic ctenophores and independently an ancestral sessile bryozoan-like bilaterian, whose headless zoophyte descendants independently evolved morphologically contrasting heads through inventing burrowing, crawling or swimming, in annelids, molluscs, arthropods and vertebrates; all acoelomate bilateria arose secondarily by coelom occlusion. Nematocyst-triggered origin of neurons and zoophyte origin of bilateria adumbrated here put sessile headless animals central to eumetazoan and bilateria origins, just as they are to the already widely accepted choanoflagellate-sponge transition . All three problems are more deeply illuminated by a unifying zoophyte perspective than by Haeckel's anthropomorphic, self-mobile adult bias. Sessile presponge headless zoophytes with dispersive ciliated larvae were the first animals; muscle-driven mobility is secondary. Heads followed rather than led basic animal innovations. Can a simpler path fit the facts?"} +{"text": "Persea americana Miller (Lauraceae), is an important fruit crop cultivated by small-holder farmers along Afrotropical highlands of Taita Hills in South-eastern Kenya and Mount Kilimanjaro in Northern Tanzania. The small-holder farmers in these East African regions generate substantial food and cash from avocado fruits. However, the avocado crop is faced with challenges of infestation by insect pests such as the common blossom thrips (Frankliniella schultzei Trybom) which feeds on pollen and floral tissue thereby reducing productivity of the trees. Moreover, there is no information describing distribution patterns of Frankliniella schultzei and associated weather in East African avocado orchards despite the fact that small-scale farming is dependent on rainfall. This article was, therefore, initiated to provide dataset on abundance of Frankliniella schultzei from the avocado plants that relates with monthly rainfall and air temperatures at Taita Hills and Mount Kilimanjaro. Frankliniella schultzei was collected using white coloured beating tray and camel brush whereas air temperatures (\u00b0C) and rainfall (mm) was recorded daily using automatic data loggers and rain gauge, respectively. The survey at the two transects commenced during peak flowering season of avocado crop in August up to end of harvesting period in July of the following year. Temporal datasets were generated by Kruskal-Wallis Chi-square test. Current temporal datasets presents strong baseline information specifically for Kenya and Tanzania government agencies to develop further agricultural strategies aimed at improving avocado farming within Taita Hills and Mount Kilimanjaro agro-ecosystems.Avocado, Specifications TableValue of the data\u2022Frankliniella schultzei presents baseline information specifically for Kenya and Tanzania government agencies, scientists and avocado farmers to enhance agricultural strategies.Abundance datasets of \u2022Weather datasets contributes to precise climate information of Taita Hills and Mount Kilimanjaro.\u2022The weather variables may be used to relate with avocado plant phenology and also seasonal abundance of pest or beneficial insect species.1Frankliniella schultzei in avocado orchards at Taita Hills and Mount Kilimanjaro, respectively. Frankliniella schultzei, rainfall, maximum temperature (Tmax), and minimum temperature (Tmin) in avocado orchards at Taita Hills and Mount Kilimanjaro, respectively. Frankliniella schultzei Trybom) specimen and 2This study was carried out in small-scale avocado farmlands at Taita Hills in South-eastern Kenya and at the South-eastern slopes of Mount Kilimanjaro in Northern Tanzania as described by Frankliniella schultzei Trybom, was sampled monthly from avocado trees using a white coloured beating tray and camel brush for two years as described by Palmer Air temperature (\u00b0C) of avocado orchards was recorded daily along the study areas using data loggers. The data loggers were hang on the lower canopy of avocado trees at a height of 2\u00a0m. Rainfall records was obtained from rain gauge for two years between August 2012 and July 2014. Geographical coordinates and elevation of study areas was verified using Geographical position system (GPS) Garmin model eTrex 30. The common blossom thrips,"} +{"text": "A 46-year-old woman had a delayed breast reconstruction using a free deep inferior epigastric perforator (DIEP) flap raised on a single medial row deep inferior epigastric perforator, complicated by intraoperative pedicle avulsion. Following a 1-cm excision of the intimally damaged vessel, the pedicle was repaired and the flap was salvaged using a supermicrosurgical technique.What is supermicrosurgery?What levels of pedicle injury can occur?What are the intraoperative strategies to salvage the free flap from pedicle avulsion?What scope is there for future advancements in free flap reconstruction using supermicrosurgery?Supermicrosurgery was first used in the 1980s, with successful replantation of distal fingertips.2Mishandling of the pedicle by the surgeon. This can result in intimal injury to an intact vessel.3Avulsion of the vascular pedicle by excessive traction. Single-vessel avulsion involves either arterial or venous supply to the flap.4Double-vessel avulsion of both arterial and venous supplies to the flap.5Diathermy injuries to the pedicle, from direct cautery or local thermal spread.6Anastomotic aneurysmal rupture, due to a pressure gradient created by mismatched donor and recipient vessels or a poorly constructed anastomosis.7A vascular pedicle injury is potentially disastrous in free flap surgery. Although uncommon, pedicle injury is an important surgical complication and understanding how it arises is essential to effective management. Different levels of pedicle injury are as follows:Before flap inset: If avulsion occurs while raising the flap, use an alternative perforator if available or repair the injured vessels if none available.During flap inset: If avulsion occurs during the flap transplant or microsurgical anastomosis with recipient vessels, reattempt a primary anastomosis. However, if the pedicle is now too short to reach the recipient vessel, use an interposition vein graft to lengthen the vascular pedicle and perform a tension-free anastomosis.3After flap inset: If avulsion occurs after the flap is inset, identify and perform an anastomosis with another shorter recipient vessel or repair and reanastomose the avulsed vessel.8Salvage of free flaps where smaller diameter vessel injury has occurred is now possible using supermicrosurgical techniques. Importantly, the surgeon must excise the zone of trauma prior to repair. Selecting the appropriate operative strategy to then repair the avulsed pedicle will depend on the nature of injury. We therefore propose an algorithm to support this selection:double-vessel avulsion, repairing the artery first allows the vein to fill and become more prominent for repair. In DIEP breast reconstruction specifically, repairing only the artery produces flap congestion and backpressure that expands the superficial inferior epigastric vein, which can then be used instead.For Free flap vascular pedicle injury remains uncommon but potentially devastating. However, free flap salvage is possible by use of innovative supermicrosurgical techniques and the operative strategies proposed. Supermicrosurgery has already brought a new frontier to free tissue transfer. Autologous transfer of tissue segments for congenital, oncological, and trauma-related defects is now possible. Perforator-to-perforator and free-style flaps, raised on anatomically variable vessels, have increased the diversity of reconstructive options, especially when smaller diameter vessels can be exploited using supermicrosurgical techniques. This will lead to spare-part surgery where disposable tissues with minimal donor morbidity can be used instead of locally destructive reconstructive options. Supermicrosurgical transfer of tissue and organ segments for facial allotransplantation and end-stage organ failure is being explored."} +{"text": "An enduring theme in microbial ecology is the interdependence of microbial community members. Interactions between community members include provision of cofactors, establishment of redox gradients, and turnover of key nutrients to drive biogeochemical cycles. An enduring theme in microbial ecology is the interdependence of microbial community members. Interactions between community members include provision of cofactors, establishment of redox gradients, and turnover of key nutrients to drive biogeochemical cycles. Pathways canonically conducted by isolated organisms in laboratory cultures are instead collective products of diverse and interchangeable microbes in the environment. Current sequence-based methods provide unprecedented access to uncultivated microorganisms, allowing prediction of previously cryptic roles in biogeochemical cycles and interactions within communities. A renewed focus on cultivation-based methods is required to test predictions derived from environmental sequence data sets and to address the exponential increase in genes lacking predicted functions. Characterization of enriched microbial consortia to annotate hypothetical proteins and identify previously unknown microbial functions can fundamentally change our understanding of biogeochemical cycles. As we gain understanding of microbial processes and interactions, our capacity to harness microbial activities to address anthropogenic impacts increases. Microorganisms represent the majority of life on earth, both in cell numbers and in diversity. They conduct critical ecosystem services, including biogeochemical cycling and contaminant transformations. Interactions between microbial community members are essential for maintenance of these ecosystem services. In most cases, microorganisms live within complex communities containing diverse populations, with key biogeochemical cycle steps distributed between community members. With significant heterogeneity across environments, characterization of microbial interactions is an ongoing endeavor within microbial ecology. High-throughput sequencing approaches, including total community DNA sequencing, or metagenomics, have provided a torrent of information on microbial distribution, diversity, and metabolic potential. This perspective argues that sequencing and enrichment cultivation together represent a powerful combination of new and old tools for examining microbial interactions and for identifying currently uncharacterized microbial activities.High-throughput sequencing combined with reconstruction of high-quality draft metagenome-associated genomes (MAGs) provides detailed information on taxonomy, metabolic potential, and organism abundance. Where initial metagenome studies were able to reconstruct genomes for the most abundant organisms in low-diversity environments, such as acid mine drainage or the oligotrophic ocean, genome binning from metagenome sequencing now routinely results in tens to hundreds, and even thousands, of MAGs for organisms within environments as complex as sediments and soils \u20134. This \u20132 . The majority of organisms implicated in denitrification contained a single pathway reaction encoded on their genomes, with the complete pathway dispersed across the microbial community. These trends held true for sulfur cycling as well, with the complete pathway from sulfide to sulfate present in only 3% of genomes for the organisms with predicted roles in sulfur oxidation, with single pathway reactions more commonly identified (2 formation is dependent on a functionally diverse community in many environments (With hundreds or thousands of MAGs available from a single environment, organismal roles in nutrient cycling can now be examined from a whole-community perspective, within the framework of partial genomes for the majority of populations. Deep metagenomic sequencing of a terrestrial sediment system identified a striking number of broken pathways within the thousands of reconstructed microbial genomes . The vas2 12 of 30, 3.6%.ronments . From thronments , alongsiThe current biggest challenge in environmental microbiology is annotating the thousands of hypothetical proteins identified from each new genome and metagenome\u2014the known unknowns. Reconstructed genomes can have upward of 40 to 50% of their genes as predicted open reading frames with no known function . The datHow best to identify unknown functions within organisms whose obligate interactions with community members preclude isolate cultivation? Enrichment cultures, originally developed by pioneering environmental microbiologist Martinus Beijerinck at the turn of the 19th century, remain a relevant and powerful tool. Enrichment cultures streamline the environmental community to a subset tractable for experimentation. The enriched consortia are frequently more robust than isolate cultures, as beneficial microbial interactions are maintained (Nitrospira species capable of conducting complete nitrification used enrichment cultures to simplify an environmental community without the need for isolation. Metagenome sequencing of the enrichments to reconstruct complete or high-quality draft genomes proved cooccurrence of ammonia oxidation genes with the nitrite oxidoreductase for nitrite oxidation (Candidatus Methylomirabilis oxyfera,\u201d the first genome for the NC10 phylum (Ca. Methylomirabilis oxyfera,\u201d where oxygen is produced intracellularly by metabolizing nitrite via nitric oxide into oxygen and dinitrogen gas (Combinations of metagenome sequencing and enrichment cultivation have already dramatically impacted our understanding of biogeochemical cycles. A major revision to the nitrogen cycle came with the discovery of comammox , 11. Botxidation , 11. Simxidation . Metagen0 phylum . Stable ogen gas . While togen gas , furtherParcubacteria, a CPR lineage of otherwise-uncultivated phyla (Parcubacteria in culture will allow experimentation to optimize further cultivation attempts. Enrichment cultures containing Dehalococcoides mccartyi sp. have been developed as bioremediation tools for chlorinated solvents, recalcitrant and common groundwater contaminants. Metagenome sequencing of D.\u00a0mccartyi enrichment cultures identified functionally conserved nondechlorinating microbes responsible for maintenance of a reducing environment, provision of cofactors including cobalamin, and carbon turnover (D.\u00a0mccartyi. Notably, the organisms conducting these roles within different consortia varied, preventing prediction of interactions from taxonomic information alone (Beyond explorations of biogeochemical cycles, enrichment cultivation coupled with metagenomics can identify interactions present within microbial consortia that contribute to a population\u2019s survival or that support a microbial activity of interest. An enrichment culture developed to examine benzene degradation contains the only known cultivated member of the ed phyla . Having turnover , activiton alone . EnrichmStudies connecting in-depth metagenomic characterization of environments with cultivation experiments to confirm predicted functions are the future of environmental microbiology . Bolster"} +{"text": "Radiation-induced alopecia after fluoroscopically guided procedures is becoming more common due to an increasing use of endovascular procedures. It is characterized by geometric shapes of nonscarring alopecia related to the area of radiation. We report a case of a 46-year-old man presenting with asymptomatic, sharply demarcated rectangular, nonscarring alopecic patch on the occipital scalp following cerebral angiography with fistula embolization under fluoroscopy. His presentations were compatible with radiation-induced alopecia. Herein, we also report a novel scalp dermoscopic finding of blue-grey dots in a target pattern around yellow dots and follicles, which we detected in the lesion of radiation-induced alopecia. Radiation-induced alopecia after fluoroscopically guided procedures, although infrequently reported in the dermatological literature, is possibly becoming more common due to an increasing use of endovascular procedures. It is characterized by geometric shapes of nonscarring alopecia confined to the area of radiation, usually asymptomatic without signs of scalp inflammation. We report a case of a 46-year-old man presenting with asymptomatic, sharply demarcated rectangular, nonscarring alopecic patch on the occipital scalp, 1 month after cerebral angiography with fistula embolization under fluoroscopy. His distinct clinical presentations together with a history of endovascular embolization under fluoroscopy were compatible with radiation-induced alopecia.A 46-year-old Thai man presented with asymptomatic sharply demarcated rectangular balding patch on the occipital scalp of 2 weeks' duration. Ten months earlier, he had a car accident and was diagnosed as having traumatic right carotid-cavernous fistula and optic neuropathy. Cerebral angiography revealed direct carotid-cavernous fistula from the C1 segment of cavernous part of the right internal carotid artery to the right cavernous sinus. Six months later, he was treated with transarterial balloon embolization without any complications. A month earlier, a follow-up magnetic resonance imaging and magnetic resonance angiography of the brain showed residual shunt. He underwent a cerebral angiogram with transvenous coil and glue embolization under fluoroscopy. The total procedure duration and the total radiation exposure time were 150 minutes and 67 minutes, respectively. The peak skin dose was 2.9\u2009Gy. Two weeks after the procedure, he presented at the outpatient clinic with asymptomatic balding patch on his occipital scalp. Dermatologic examination revealed a sharply demarcated rectangular nonscarring alopecic patch, measuring 10 \u00d7 12 centimeters in size, on the occipital scalp, without erythema or scaling Figures . A 4\u2009mm Fluoroscopically guided endovascular procedures are becoming more common in medical practice with an increasing use of minimally invasive techniques for various medical conditions. In general, radiation-induced alopecia is common and develops following radiation therapy of neoplasms. However, alopecia secondary to radiation exposure from fluoroscopically guided procedures is increasingly being reported due to an increasing use of endovascular procedures.Alopecia after fluoroscopically guided endovascular procedures is rarely reported in the dermatological literature, although this complication seems to be relatively common. Given that the procedures often require prolonged and repeated fluoroscopic imaging, doses above a deterministic threshold can potentially react with the skin and hair follicles , 2. The Pathogenesis of radiation-induced alopecia involves acute damage to actively dividing matrix cells of anagen follicles causing immediate loss of dystrophic anagen hairs (anagen effluvium) and premature entry of some anagen hair follicles into catagen and then into telogen phase, resulting in delayed onset of hair shedding (telogen effluvium) . RadiatiClinical presentation of radiation-induced alopecia includes geometric shapes of nonscarring alopecic patch confined to the area of radiation, usually asymptomatic without signs of scalp inflammation. Occipital, parietal, and temporal scalp are commonly affected. Occasionally, the alopecic area is clinically similar to other nonscarring alopecia cases such as alopecia areata. However, important clues to diagnosis are a history of fluoroscopically guided procedure and alopecic area which is confined to the radiation site. Hair loss mostly occurs within 1\u20133 weeks after radiation exposure with spontaneous regrowth of hair within 2\u20134 months \u201314. Cho Diagnosis of radiation-induced alopecia is primarily based on distinct clinical presentations and history of radiation exposure. Investigations including trichogram, dermoscopy, and histopathology are more likely to exclude other causes of nonscarring alopecia rather than confirming the diagnosis. Trichogram performed during an early phase usually shows dystrophic anagen hairs. However, in our patient, the presence of telogen hairs without dystrophic anagen in trichogram was a result of prolonged time from radiation exposure to the examination. All dystrophic anagen hairs shed off in the first few weeks after radiation exposure. A study of 10 patients with postangioembolization alopecia by Cho et al. reported that dermoscopic findings demonstrated both yellow dots and black dots (60%), short vellus hair (50%), peripilar sign (20%), broken hair (10%), coiled hair (10%), and white dots (10%), whereas histopathology showed increased numbers of catagen and telogen hairs without peribulbar inflammatory cell infiltrate, unlike alopecia areata, which usually shows peribulbar inflammation . AlthougOther possible mechanisms of alopecia after fluoroscopy-guided endovascular embolization including alopecia secondary to an impairment of the external carotid blood supply of the scalp and pressure-induced alopecia should be also considered. The impairment of the external carotid blood supply of the scalp may result from therapeutic embolization of blood vessels or radiation-induced luminal fibrosis . Owing tTreatment of radiation-induced alopecia is usually unnecessary due to its benign and self-limiting nature. Complete hair regrowth generally occurs within 2\u20134 months after irradiation \u201314. In aIn conclusion, we report the case of radiation-induced temporary alopecia after endovascular embolization under fluoroscopy. In addition to other nonscarring alopecia cases, physicians should be aware of and include this condition in the differential diagnosis when individuals presenting with nonscarring alopecia had a history of prolonged fluoroscopic endovascular procedures. Although the condition is benign and self-limiting, awareness, monitoring, and limitation of radiation exposure to the patient are the most important strategies to prevent hair loss."} +{"text": "Intracellular bacterial pathogens replicate within eukaryotic cells and display unique adaptations that support key infection events including invasion, replication, immune evasion, and dissemination. From invasion to dissemination, all stages of the intracellular bacterial life cycle share the same three-dimensional cytosolic space containing the host cytoskeleton. For successful infection and replication, many pathogens hijack the cytoskeleton using effector proteins introduced into the host cytosol by specialized secretion systems. A subset of effectors contains eukaryotic-like motifs that mimic host proteins to exploit signaling and modify specific cytoskeletal components such as actin and microtubules. Cytoskeletal rearrangement promotes numerous events that are beneficial to the pathogen, including internalization of bacteria, structural support for bacteria-containing vacuoles, altered vesicular trafficking, actin-dependent bacterial movement, and pathogen dissemination. This review highlights a diverse group of obligate intracellular bacterial pathogens that manipulate the host cytoskeleton to thrive within eukaryotic cells and discusses underlying molecular mechanisms that promote these dynamic host-pathogen interactions. Obligate intracellular bacteria comprise a group of highly infectious human pathogens that cause a spectrum of life threatening diseases. These bacteria demonstrate remarkable adaptations that support intracellular lifestyles comprised of unique challenges and advantages. To support diverse infection events, intracellular pathogens have evolved numerous methods to subvert host molecular signaling machinery that controls essential cellular functions. Intracellular pathogens display tropism for specific eukaryotic cell types and attach to these cells to initiate internalization, allowing intracellular growth using energy rich host metabolic products. Successful immune evasion is essential for productive infection, and the intracellular environment provides temporary cover from detection by immune cells and antibody/compliment-mediated immunity. Following replication, these pathogens exit the infected cell and disseminate to additional sites of infection.in vitro. These human pathogens include Chlamydia , Rickettsia , Anaplasma (human granulocytic anaplasmosis), and Ehrlichia (human monocytic ehrlichiosis) species. We also include the Q fever agent Coxiella burnetii, which replicates exclusively within host cells during natural infection, but can be cultured in specialized axenic media in vitro. The interaction of these pathogens with the host cytoskeletal network has been studied for many years, but detailed molecular mechanisms are lacking due to difficulty in genetically manipulating these bacteria. However, recent genetic breakthroughs provide tractable systems by which bacteria-actin interactions can now be defined for this intriguing group of pathogens -actin that hydrolyzes ATP to provide energy for F-actin polymerization Reisler, . Actin nHost cell entry is the first step in the intracellular pathogen invasion process. Bacterial cell wall components facilitate attachment to specific host cells via distinct receptors. Pathogens use the rearranging abilities of actin to facilitate rapid entry into the host cell, with phagocytic and non-phagocytic cells internalizing bacteria by different mechanisms Figure . BacteriC. burnetii preferentially infects phagocytic human macrophages via binding to CR3 receptors, triggering reorganization of filamentous actin at the attachment site is essential for invasion -anchored protein DNase X located on the cell surface. This interaction triggers cytoskeletal rearrangement and filopodia formation domain that binds to actin monomers and WASP proteins. RickA ultimately activates the Arp2/3 complex, promoting actin polymerization and intracellular motility in macrophages. F-actin assembles around the PV and is required for optimal vacuole formation signaling using a type IV secretion system, and this process is essential for PV formation observed in infected patients. Typhus group Rickettsia do not form actin tails (Heinzen et al., Spotted Fever group E. chaffeensis uses two different exit strategies during early and late stages of infection (Thomas et al., E. chaffeensis is transported into filopodia that extend into neighboring cells, providing a direct path for bacterial entry into nearby cells without immune detection. Actin rearrangement in infected cells is essential for filopodia formation and bacterial localization into filopodia. However, during late stages of infection, bacteria exit following host cell lysis (Thomas et al., Anaplasma, it has been suggested that A. phagocytophilum exits host granulocytes by exocytosis and host cell lysis. However, specific roles for cytoskeletal components during pathogen exit have not been characterized (Rikihisa, Chlamydia can exit host cells by host cell lysis or extrusion of the inclusion. Extrusion requires actin rearrangement and is considered an exocytosis-like process. Extrusion initiates with formation of inclusion-containing protrusions from infected cells. Extrusions are then pinched into separable compartments located at the cell periphery, allowing inclusion release without triggering cell death (Todd and Caldwell, Obligate intracellular bacteria include a unique group of human pathogens that have adapted to thrive within the host cell environment. These pathogens hijack host cell signaling by secreting bacterial effector proteins into the host cytosol to promote formation of a replication-permissive niche. Intracellular bacteria constantly encounter the dynamic host cytoskeletal network and have evolved methods to use actin and related proteins to facilitate infection. Intracellular pathogens rearrange the actin cytoskeleton during internalization by phagocytic and non-phagocytic host cells. Some intracellular bacteria replicate within a specialized membrane-bound vacuole, while others replicate free in the cytosol. Host cytoskeletal proteins often form a filamentous cage around bacteria-containing vacuoles, providing structural support and allowing vesicle fusion with the vacuole. Other intracellular bacteria stimulate actin polymerization and form actin tails that aid bacterial movement within the host cytosol and propulsion into neighboring cells. Intracellular bacteria further manipulate the actin cytoskeleton to exit host cells by lysis or vacuole extrusion. In conclusion, major events in bacterial lifecycles require host cytoskeletal components, and blocking these interactions negatively impacts bacterial replication. However, we clearly have more to learn about the molecular mechanisms controlling pathogen interaction with the host cytoskeleton. Targeting these interactions may provide novel approaches to develop antibacterial therapeutics targeting obligate intracellular bacterial pathogens.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Eutrophication and climate warming are profoundly affecting fish in many freshwater lakes. Understanding the specific effects of these stressors is critical for development of effective adaptation and remediation strategies for conserving fish populations in a changing environment. Ecological niche models that incorporated the individual effects of nutrient concentration and climate were developed for 25 species of fish sampled in standard gillnet surveys from 1,577 Minnesota lakes. Lake phosphorus concentrations and climates were hindcasted to a pre-disturbance period of 1896\u20131925 using existing land use models and historical temperature data. Then historical fish assemblages were reconstructed using the ecological niche models. Substantial changes were noted when reconstructed fish assemblages were compared to those from the contemporary period (1981\u20132010). Disentangling the sometimes opposing, sometimes compounding, effects of eutrophication and climate warming was critical for understanding changes in fish assemblages. Reconstructed abundances of eutrophication-tolerant, warmwater taxa increased in prairie lakes that experienced significant eutrophication and climate warming. Eutrophication-intolerant, warmwater taxa abundance increased in forest lakes where primarily climate warming was the stressor. Coolwater fish declined in abundance in both ecoregions. Large changes in modeled abundance occurred when the effects of both climate and eutrophication operated in the same direction for some species. Conversely, the effects of climate warming and eutrophication operated in opposing directions for other species and dampened net changes in abundance. Quantifying the specific effects of climate and eutrophication will allow water resource managers to better understand how lakes have changed and provide expectations for sustainable fish assemblages in the future. Climate change and eutrophication are potent environmental stressors that are altering the fundamental ecological processes that structure freshwater communities throughout the world ,2. SigniAs climate changes the thermal structure of lakes, fish are influenced through a number of pathways and processes ,9. EpiliEutrophication has substantially altered fish assemblages around the world and can Eutrophication and climate warming have affected many lakes in Minnesota ,26. NatiEcological niche modeling that incorporates specific effects of individual stressors has proven useful for disentangling multiple-stressor impacts on biotic communities ,33. EachUnderstanding the specific effects of eutrophication and climate warming is of critical importance for water resource managers and policy makers. Minnesota\u2019s lake fish taxa differ in their thermal and eutrophication tolerances ,29 and rEmpirical ecological niche models were developed for 25 species of fish commonly captured in Minnesota Department of Natural Resources (MDNR) lake netting assessments . The MinTaxa-specific ecological niche models were developed using generalized additive models (GAMs). The effects of several environmental and ecological stressor variables on the relative abundance of each species were quantified with the models. GAMs are particularly useful for modeling the ecological niche of biological organisms because they directly incorporate nonlinear smoothing to describe the effects of predictors on the response variable and are http://prism.oregonstate.edu, retrieved 3 Dec 2015). Air temperatures were estimated for the geographical center of each lake for the period from 1981\u20132010 using the geoknife package in R [Mean annual air temperature (MAT), which integrates a number of ecological effects across all seasons, was used as a proxy variable that captured the effects of climate on fish assemblages. Lake-specific air temperature data were developed from high resolution spatial interpolations of historic air temperatures available from the Oregon State University PRISM Climate Group .Phosphorus was selected as a proxy variable that captured the effects of eutrophication because it is the primary limiting nutrient in many lakes, including Minnesota ,30. Meanmgcv and by z-scores (subtracting the species-specific mean and dividing by the species-specific standard deviation) to allow for standardized comparisons among species. Lake size (ha) and depth (m) were log transformed and total alkalinity was square root transformed to normalize their distributions. Response surfaces of relative abundances were estimated from joint smooths of MAT and TP. The joint smooths allowed for the visualization of how responses of each variable changed as a function of the other variable. Individual responses can be visualized as slices through the response surface at specific values of the other variable. These interaction of MAT and TP can also be visualized as the shape of the slices change as a function of the other variable. Environmental variables were entered into the model as single variable smooth terms. A Gaussian family, with an identity link function, was used for each GAM and a dimension basis of k = 4, was used to limit the degrees of freedom for each smooth term [The package in the soth term .Pre-disturbance lake conditions were estimated for climate and eutrophication variables which provided inputs into species-specific ecological niche models. Pre-disturbance climate was calculated from historical air temperatures retrieved from the PRISM data set using identical methods as the contemporary climate data for comparison to present-day conditions. Annual lake-specific air temperatures from 1896\u20131925 (a thirty year period of the same duration as the contemporary period) were processed using the geoknife package in R , and meaTP = mean summer epilimnetic total phosphorus concentration (\u03bcg/l), depth = maximum lake depth (m), outwash = proportion of glacial outwash soils in watershed, disturbance = proportion of disturbed land uses in watershed. Assuming depth and proportion of outwash soils remained constant over both periods, estimation of pre-disturbance lake productivity collapses to:TPp = pre-disturbance mean summer epilimnetic phosphorus concentration (\u03bcg/l), TPc = contemporary, observed mean summer epilimnetic phosphorus concentration (\u03bcg/l), and disturbance = proportion disturbed land uses currently in watershed. Watershed delineations were available for 1,236 lakes in the analysis. Contemporary values of land uses were calculated with the 2001 National Land Cover Database [Pre-disturbance land use corresponded to the late 1800s when prairies were first converted to agriculture and urban areas started to develop in Minnesota. Pre-disturbance eutrophication status was estimated by hindcasting the lake phosphorus model developed by Cross and Jacobson to undisDatabase . Level 1Pre-disturbance fish assemblages were estimated by using the derived historical conditions as inputs to taxa-specific ecological niche models. Lake-specific CPEs were calculated from the fitted GAM models for each species to explore changes in abundance from pre-disturbance to contemporary conditions. The effects of climate warming and eutrophication on the relative abundance of each taxa were examined independently by using pre-disturbance conditions for one stressor while holding the other at contemporary levels, and then collectively by using pre-disturbance levels for both stressors.Generalized additive models described between 1.2 and 57.6% of deviance in fish relative abundance for the 25 species . Joint fResponse shapes of the joint effects of climate and productivity varied considerably between species . Some haMean annual air temperatures increased from pre-disturbance (1896\u20131925) to contemporary (1981\u20132010) times, although the magnitude of increase varied substantially between lakes and ecoregions . TemperaHindcasted total phosphorus concentrations indicated that lakes in the transition and prairie ecoregions have become more productive . Those eTrajectories of individual lakes within a 2-dimensional climate and productivity niche space illustraStressor-specific changes in modeled fish relative abundance varied considerably by species and ecoregion . The dirFor most taxa, hindcast changes in abundance were largest in prairie lakes, where both climate and productivity shifts were substantial. All nine eutrophication-tolerant warmwater species were estimated to have increased in abundance from increased phosphorus and temperature, while six intolerant species declined over the period. Stressors operated in opposite directions for a total of eight species, several of which experienced little change in abundance. Eutrophication-tolerant coolwater yellow perch benefited from increased total phosphorus, but warmer temperatures were detrimental. Conversely, intolerant warmwater bluegill benefited from warming temperatures, but gains in abundance were overwhelmed by detrimental effects of increased phosphorus. In general, eutrophication produced larger effects on relative abundance than climate warming for most taxa in the prairie ecoregion.Fish assemblages in the transition ecoregion also experienced significant changes after disturbance. Taxa-specific responses were similar to the prairie ecoregion with eutrophication-tolerant warmwater species benefitting most from increased temperatures and phosphorus concentrations. Increased phosphorus concentrations were detrimental to a number of eutrophication-intolerant species and increased temperatures were beneficial to warmwater taxa. Tolerant coolwater yellow perch also benefited from increased lake productivities, but increased temperatures were detrimental. Intolerant warmwater bluegill gains in abundance from increased temperatures were completely offset by losses from increased phosphorus concentrations and resulted in no net change. A total of 12 species in the transition ecoregion were affected by stressors that operated in opposite directions.Fishes in the forested ecoregion experienced changes primarily driven by temperature increases in the past century. Warmwater fishes such as black crappie, bluegill, largemouth bass, pumpkinseed, and yellow bullhead increased in abundance. The greatest abundance declines were seen within coolwater species such as white sucker, walleye, yellow perch, and smallmouth bass. The number of species affected by stressors that operated in opposite directions was large (15), but the net effect of increased phosphorus was very small in all cases.Grouping of taxa by thermal preference and eutrophication tolerance summarized fish assemblage changes that have occurred in the past century . WarmwatA century of eutrophication and climate warming profoundly affected lakes in Minnesota and consequently, their fish assemblages. Conversions of native prairies and forests to agricultural and urban uses increased nutrient concentrations in the prairie and transition ecoregions of the state. In response, abundances of eutrophication-tolerant fish likely increased. Climate also warmed in the past century throughout the entire state and reconstructed warmwater fish abundances increased accordingly. Trajectories of lake-specific changes spanned an extraordinary range of the 2-dimensional niche space represented by these two stressors in Minnesota. Together, eutrophication and climate warming likely drove an expansion of tolerant warmwater fish abundance at the expense of intolerant coolwater taxa. Conversely, climate and productivity shifts produced opposing effects on abundance of several species. For example, tolerant coolwater yellow perch likely benefitted from lake productivity increases, but climate warming was detrimental. Intolerant warmwater bluegill benefitted from climate warming, but gains in abundance were overwhelmed by negative effects of eutrophication. Disentangling the sometimes opposing, sometimes compounding, effects of these two important ecological stressors was critical for understanding changes in fish assemblages. Taxa-specific ecological niche models and explicit identification of stressor-specific tolerance guilds were valEutrophication drove changes in modeled lake fish assemblages in the prairie and transition ecoregions of Minnesota more than climate. Vegetated fish habitat in the many shallow lakes of the prairie was likely reduced by nutrient enrichment . Shifts Climate drove modeled fish assemblage change in forested ecoregion lakes more than eutrophication. Watersheds of these lakes remained largely undisturbed and forested resultinAlthough sequence and timing of individual stressor effects was not determined in this study, evidence exists that eutrophication was most important during the first part of the century and climate became more significant in recent years. Increases in mean annual temperatures in the state have accelerated since 1980 . Many laThe effects of climate warming on fish are expected to continue in all three ecoregions. Lakes in the forested ecoregion are likely to maintain suitable thermal habitat for cool- and warmwater species even under extreme warming scenarios ,55. ThusAlthough ecological niche modeling was useful for disentangling the effects of climate and eutrophication, significant uncertainty remains for predicting fish assemblage responses. Model errors propagated through the phosphorus hindcasting model and fish assemblage reconstruction were likely present. Modeled niches were assumed to remain unchanged from historic to contemporary conditions . PredictUnderstanding the specific effects of climate and land use change on lakes and fish assemblages is critical for developing management and adaptation strategies for effective conservation ,69. For S1 TableP-values and percent deviance explained for generalized additive models of the relative abundance of 25 fish species predicted by mean annual temperature (MAT) and mean summer epilimnetic total phosphorus concentrations (TP), depth, area, and alkalinity sampled in 1,577 Minnesota lakes.(XLSX)Click here for additional data file.S2 TableLake specific data used for ecological niche models developed from 1,577 Minnesota lakes. Metadata describing each data field are described in the first portion of the Table.(XLSX)Click here for additional data file.S1 FigGeneralized additive model responses of mean annual temperature (MAT \u00b0C) and mean summer epilimnetic total phosphorus concentrations (TP \u03bcg/l), depth (m), area (ha), and alkalinity on the relative abundance of 25 fish species sampled in 1,577 Minnesota lakes. Species codes are defined in (PDF)Click here for additional data file."} +{"text": "Bronchopulmonary dysplasia (BPD) is a chronic lung disease most commonly seen in premature infants who required mechanical ventilation and oxygen therapy for acute respiratory distress. While advances in neonatal care have resulted in improved survival rates of premature infants, limited progress has been made in reducing rates of BPD. Lack of progress may in part be attributed to the limited therapeutic options available for prevention and treatment of BPD. Several lung-protective strategies have been shown to reduce risks, including use of non-invasive support, as well as early extubation and volume ventilation when intubation is required. These approaches, along with optimal nutrition and medical therapy, decrease risk of BPD; however, impacts on long-term outcomes are poorly defined. Characterization of late outcomes remain a challenge as rapid advances in medical management result in current adult BPD survivors representing outdated neonatal care. While pulmonary disease improves with growth, long-term follow-up studies raise concerns for persistent pulmonary dysfunction; asthma-like symptoms and exercise intolerance in young adults after BPD. Abnormal ventilatory responses and pulmonary hypertension can further complicate disease. These pulmonary morbidities, combined with environmental and infectious exposures, may result in significant long-term pulmonary sequalae and represent a growing burden on health systems. Additional longitudinal studies are needed to determine outcomes beyond the second decade, and define risk factors and optimal treatment for late sequalae of disease. Bronchopulmonary dysplasia (BPD) is a chronic lung disease most commonly seen in premature infants who required mechanical ventilation and oxygen therapy for acute respiratory distress but can also occur in neonates that had a less severe respiratory course ,2,3. BPDThe incidence of BPD in surviving infants less than or equal to 28 weeks gestational age has been relatively stable at approximately 40% over the last few decades ,10,11,12Criteria to define BPD have historically lacked uniformity. The earliest clinical definition of BPD was limited to oxygen requirement at 28 days with consistent radiologic changes. These were originally modified to include continuing need for oxygen therapy at 36 weeks corrected gestational age (CGA). However, this definition inadequately addresses highly variable clinical practices as well as the wide range of disease, leading to further modification to include a severity assessment at 36 weeks gestational age . The defAt greatest risk of poor long-term outcome are the approximately 25% of infants with BPD who are identified to have elevated pulmonary pressures or BPD-associated pulmonary hypertension (PH), resulting in mortality rates as high as 14%\u201338% with one series noting only 25% survival at 2\u20133 years of age with severe BPD-associated PH ,22,23,24As the population of NICU survivors grow, long-term manifestations of chronic lung injury with BPD is likely to represent a greater burden to health systems. This paper seeks to review the pathophysiology of BPD, recent management strategies and what is currently known about long-term pulmonary outcomes in survivors.The phenotype seen with BPD is the end result of a complex multifactorial process in which various pre- and postnatal factors compromise normal development in the immature lung. The specBPD occurs almost exclusively in preterm infants that have received positive pressure ventilation suggesting that mechanical lung over-distension and alveolar stretch play a critical role in the pathogenesis of BPD. Ineffective pulmonary mechanics results in need for ventilatory assistance at birth. Recent data suggests that 65% of preterm infants born at 22 to 28 weeks gestational age are intubated in the delivery room, which has decreased since 1993 when 80% of this population was intubated immediately following birth . The preStudies in numerous animal models have identified that exposure to supraphysiologic oxygen alone induces a phenotype comparable to that seen with BPD, including compromised alveolar development and pulmonary vascular remodeling . ClinicaAnimal models suggest that even brief exposures to high concentrations of oxygen can result in long-term morphologic and functional changes in the lung . In addiEscherichia Coli endotoxin to pregnant ewes resulted in amplified inflammation with ventilation of the exposed preterm lambs including evidence of cellular apoptosis and compromised alveolar development [Controversy exists regarding the contribution of chorioamnionitis and prenatal inflammation to the risk of developing BPD . Clinicaelopment ,45. Whilelopment . This paelopment . Controvelopment .Less controversy exists regarding the contribution of postnatal inflammation or nosocomial infection to the increased risk of developing BPD ,48. NoviPreterm infants that are small for gestational age (SGA) at birth or with intrauterine growth restriction (IUGR) are at increased risk for adverse pulmonary outcomes ,54. StudExtremely premature infants are at additional risk for postnatal growth restriction secondary to challenges of delivering optimal nutrition. Despite significant advances in the content and use of both enteral and parental nutritional support, 55% of infants born less than 27 weeks gestation demonstrate growth failure with weight less than 10th percentile at 36 weeks postmenstrual age ,26,53. PWhile BPD results from cumulative exposures to both the pre- and postnatal factors noted above, there is a growing interest in the heritable contributions to development of BPD. Twin studies provide insight into genetic predispositions as monozygotic twins share 100% of their genetic information while dizygotic twins are 50% concordant . A totalMore recently, several genome-wide association studies (GWAS) have been conducted to identify candidate single nucleotide polymorphisms associated with BPD. The largest evaluated over 1700 infants and failed to identify genomic loci or pathways that accounted for the previously described heritability for BPD . A seconManagement strategies are aimed at protecting against lung injury and the development of BPD. As the pathogenesis of disease is multifactorial, diverse approaches have been adopted including both ventilation and medical strategies. Interestingly, both antenatal steroids and surfactant reduce rates of RDS and improve survival; however, neither has been shown to reduce incidence of BPD .2 targets (>52 versus <48 mmHg) [Evidence of lung injury induced by volutrauma has led to efforts to promote \u201cgentle ventilation,\u201d in part through the use of permissive hypercapnia. However, the data to support this strategy has been inconsistent and long-term neurodevelopmental outcomes remain unknown ,69. None48 mmHg) ,71. Gent48 mmHg) ,73,74. R48 mmHg) ,76; howe48 mmHg) . As manySignificant efforts have been made to move away from use of invasive ventilation over the past two decades . Meta-anUse of alternative non-invasive modalities including non-invasive positive pressure ventilation (NIPPV), bilevel nasal CPAP (biPAP) and high-flow nasal cannula (HFNC) is also increasing with some evidence to suggest these modes may also be effective in managing neonatal respiratory disease ,82,83. SAdditional controversy exists surrounding the use of non-synchronized NIPPV. Synchronization can be achieved and has been described in premature infants using an abdominal pneumatic (or Graseby) capsule to detect diaphragmatic descent. This approach has the theoretical advantage of ensuring glottis patency before flow is triggered. While randomized trials using SNIPPV have not been performed, a retrospective study suggested comparable clinical outcomes, including rates of BPD, in infants managed with synchronized as compared to non-synchronized NIPPV . More reFinally, for those infants who do require intubation, an early trial of extubation is encouraged to potentially reduce risks of ventilator-induced lung injury. Studies have identified that an early attempt at extubation alone may decrease the risk of BPD, regardless of need for reintubation or duration of ventilation ,89. ThesExtensive efforts have been made to define optimal saturation targets for premature infants with ongoing concerns for the quality of evidence available . A meta-Specific to the outcome of BPD, the Surfactant, Positive Pressure and Oxygenation Randomization Trial (SUPPORT) conducted in the US found slightly lower rates of BPD (38% vs. 41.7%) in the low-saturation group without statistical significance . The CanPostnatal glucocorticoids are recognized to reduce rates of BPD via reduced inflammation as well as the induction of lung maturational changes. However, the potential benefits of systemic steroids are often outweighed by concerns for long-term neurodevelopmental sequelae including increased risk of cerebral palsy (CP) ,99. RateIn attempt to more reliably deliver corticosteroids directly to alveoli of infants at risk of early lung injury, co-administration of budesonide with surfactant has been considered. Yeh, et al. have reported significant decrease in the incidence of BPD or death in ventilated infants with severe RDS who received endotracheal budesonide . AdditioIn the recent randomized, multicenter Caffeine for Apnea of Prematurity (CAP) trial, early initiation of caffeine was found to result in lower incidence of BPD as well as a shorter course of respiratory support as compared to controls . The speVitamin A deficiency may predispose to chronic lung disease as it plays a critical role in maintaining the integrity of respiratory tract epithelium and is a key regulator of normal lung growth ,111. WhiInhaled nitric oxide (iNO) for prevention of bronchopulmonary dysplasia deserves mention as it has been explored in numerous studies with inconsistent findings ,116. WhiLong-term outcomes of BPD remain difficult to characterize as adult populations currently available to study represent survivors of outdated care. While BPD tends to improve with ongoing lung development, data available from follow-up studies identify concerns for persistent pulmonary sequelae of disease. Notably, the impact on late pulmonary health as well as the consequences of additional infectious or environmental exposures remain poorly characterized.It is important to recognize the tremendous emotional, medical, and financial efforts invested into care of extremely premature infants. The mean length of hospitalization for those born under 1000 grams is approximately 60 days with high rates of need for additional medical support including rehospitalization after discharge . During Numerous studies have evaluated long-term pulmonary function after premature birth alone. A meta-analysis including 59 articles identified that percent of predicted forced expiratory volume in 1 second (FEV1) is decreased in preterm-born survivors, even in patients who did not have a history of BPD . EvaluatAdditional studies have raised concerns for the persistence of pulmonary disease in patients with BPD. Correlation between maximal flow at functional residual capacity in infancy and forced expiratory flow at 8 years raises concerns that limited recovery occurs during late stages of alveolarization . In addiExposure to environmental insults including respiratory infections, tobacco and pollution may complicate resolution of BPD and prolong risks of pulmonary morbidity ,142. PreBeyond environmental insults, pulmonary morbidity in ex-preterm infants can be complicated by chronic reflux and microaspiration with risk of aspiration pneumonia and/or chronic inflammation. While the evidence is variable, improvement of respiratory status has been reported after Nissen fundoplication of infants with severe chronic lung disease with some programs advocating for this intervention in severe cases ,147,148.Many survivors of BPD demonstrate a component of reactive airway disease. Long-term follow-up of infants born <26 weeks gestation identified that 25% had an asthma diagnosis at 11 years of age while over twice this percentage (56%) had evidence of abnormal spirometry . While c2 consistent with alveolar hypoventilation [Survivors of BPD may experience exacerbation of pulmonary morbidities with exercise or exposure to hypoxia. Significant risk of exercise-induced bronchoconstriction has been demonstrated in children with BPD consistent with concerns for reactive airway disease noted above . Howevertilation .Chemoreceptor function in preterm infants is dysmature, resulting in abnormal ventilatory responses to alterations of oxygen content in these patients. Specifically, normal responses of increased ventilation with hypoxia as well as decreased ventilation with hyperoxia may be altered. Persistent chemoreceptor dysfunction has been documented in survivors of BPD ,157. InaDysmorphic pulmonary vasculature and compromised angiogenesis with BPD results in risk of elevated pulmonary pressures or BPD-associated pulmonary hypertension (PH). Retrospective studies of infants with BPD suggested that 25%\u201337% of infants with BPD develop associated PH, but these data are limited by inconsistent definition and screening protocols ,22,23. EAs previously noted, patients with BPD and elevated pulmonary pressures are at high risk for PH crisis and early mortality. Those who survive may ultimately demonstrate resolution of disease with additional lung growth. However, recent data suggests that subclinical right ventricular dysfunction can be detected in children assumed to have recovered from BPD-associated PH . Longer-While severity of BPD does not predict likelihood of associated pulmonary hypertension, sicker infants with prolonged ventilator and oxygen requirements are at greatest risk ,161. AddHowever, the threshold for intervention and optimal treatment of BPD-associated PH remains elusive with limited evidence to guide care . While rSome guidance for treatment has been provided in the literature. However, none of these to date are evidence based ,167. KulWhile the past decade has been notable for increasing use of vasodilator therapy in the treatment of BPD-associated PH , randomiThe definition, pathophysiology, and management of bronchopulmonary dysplasia (BPD) has evolved significantly since first described by Northway almost 50 years ago. Advances in neonatal care have resulted in increased rates of survival of extremely premature infants leading to both a new set of management challenges as well as an emerging population of long-term survivors of BPD. Interdisciplinary care to address the complex pulmonary, nutritional and developmental needs of these patients is critical and may itself influence outcomes of severe BPD .Randomized therapeutic studies in addition to longitudinal evaluation of these patients remains essential to optimize care and further discern risk factors for morbidity. While these studies require significant resources, they are much in need as evidence for optimal treatment is lacking. In addition, little is known regarding pulmonary outcomes of BPD beyond the second decade of life. Of concern are data highlighting the potential for increased risk of subclinical right ventricular dysfunction, obstructive lung disease, exercise intolerance, and asthma-like symptoms in survivors. Abnormal response to hypoxia and central airway disease may further exacerbate illness with risks of sleep disordered breathing. These baseline morbidities, complicated by environmental and infectious exposures, may represent a significant challenge for the aging cohort of BPD survivors.As trends demonstrate increasing survival of extremely premature infants, nearly half of whom will be diagnosed with BPD, it is imperative that future studies investigate mechanisms and risk factors influencing long-term morbidity with an overall goal of reducing the burden of disease."} +{"text": "We administered neuropsychological measures considered sensitive to prefrontal dysfunction to obsessive-compulsive disorder (OCD) patients and control subjects. OCD subjects exhibited performance deficits, in comparison to community controls, on three measures sensitive to orbitofrontal neocortex dysfunction. Contrary to expectation, OCD patients also exhibited performance deficits on measures sensitive to dorsolateral prefrontal neocortex dysfunction. However, distinct neurocognitive profiles emerged when we examined the impact of comorbid schizotypal personality features on neuropsychological test performance. Primary OCD patients displayed impaired performance on measures sensitive to orbitofrontal dysfunction; however, they did not differ from control subjects on tests of dorsolateral function. OCD subjects presenting with schizotypal personality features performed poorly not only on tests sensitive to orbitofrontal dysfunction, but also on tests sensitive to dorsolateral dysfunction. Findings suggest that OCD can be subdivided into clinical subtypes, and distinct prefrontal subsystems may be differentially involved in these subtypes."} +{"text": "Abnormalities in GABA signaling in the forebrain at all stages - prenatal, postnatal and adult have been implicated with a wide range of neuropsychiatric illnesses ,2. AdditA receptors and GABA function with defective behaviors have been vital for understanding the pathobiology of neuropsychiatric illnesses, but all of these models were systemic or region-specific knockouts that could not serve to establish a cause - effect relationship between neuronal versus endothelial cells. Our observation of expression of GABAA receptor subunits and GAD65/67 in forebrain endothelial cells signified that forebrain angiogenesis has its own intrinsic GABA signaling mechanisms. To discover the functional significance of this endothelial GABA signaling pathway in vivo, we designed strategies to specifically turn off GABA release from endothelial cells or render endothelial GABAA receptors dysfunctional using cre-lox technology during early embryonic development. Both approaches first affected forebrain angiogenesis and in turn impaired neuronal migration. As endothelial GABA\u2019s roles were delineated individually for angiogenesis, neurogenesis, long distance GABAergic neuronal migration and radial migration of projection neurons, so too was the realization that neuronal GABA could not serve to compensate these roles. The data laid the foundation for a novel positive feedback signaling pathway in endothelial cells that functions via GABAA receptor mediated GABA release [Though there have been reports of GAD immunoreactivities in endothelial cells of cerebral arteries and GAD6A receptors, NKCC1-KCC2 expression, and chloride concentration in forebrain endothelial cells and alterations in disease scenarios. And most importantly, additional questions begin to emerge about the significance of this vascular GABA pathway and novel mechanisms specifically in the postnatal, adult and aging brain (As we now know that a common GABA pathway operates in both endothelial cells and GABAergic neurons of the embryonic telencephalon, it is essential to gain further mechanistic insights by segregating this pathway in individual cell types. It is important for future work to understand how the endothelial GABA signaling pathway specifically influences angiogenesis related genes and specific processes like tight junction formation, tip cell functions, vascular sprouting and migration. Also, it is important to see how components of the neuronal GABA pathway are affected in the absence of endothelial GABA signaling. For instance, how does endothelial GABA modulate interneuron migration - does it affect receptor-mediated signaling that transduces extracellular information or directly the transcription factors that provide interneurons with their intrinsic migratory ability or both? It also brings up several new questions with respect to roles of GABAng brain . New und"} +{"text": "BRCA1 or BRCA2 is recognized for its strong familial risk .Genome Wide Association Studies (GWAS) serve as a powerful approach for discovering common risk variants underlying disease etiology. Often these variants reside within the non-coding region of the genome making the determination of functional mechanisms driving susceptibility a challenging task . Differecis-associations (cis-eQTL) were interrogated for association with breast cancer risk. Three SNPs, rs11099601, rs656040 and rs738200 were significantly associated with an increased risk of breast cancer. The most significant association with increased risk for both ER-positive and ER-negative breast cancer was rs110099601 at 4q21, which constitutes a novel breast cancer susceptibility locus [In the study, Hamdi et al. evaluated 313 SNPs in 175 genes related to cancer for association with breast cancer risk in 46,451 breast cancer cancers and 42,599 controls of Caucasian ancestry participating in the Breast Cancer Association Consortium (BCAC) genotyped using the custom Illumina Infinium array iCOGS with rs11099601 were functionally annotated using ENCODE chromatin features such as overlapping with Histone epigenetic marks associated with promoters and enhancers or DNAse I hypersensitive sites , which may be particularly effective for tumor types with limited sample sets.In summary, Hamdi et al. reported a novel association to breast cancer risk likely to be related to changes in expression of multiple genes. Importantly, although the approach used by Hamdi et al. may exclude the discovery of genes not previously implicated in cancer, it provides an example of an approach likely to identify variants undetectable under stringent GWAS multiple testing threshold (typically"} +{"text": "Optical internal urethrotomy (OIU) is the most common procedure performed for short segment bulbar urethral stricture worldwide. This procedure most commonly performed using Sachse\u2019s cold knife. Various perioperative complications of internal urethrotomy have been described in literature including bleeding, urinary tract infection, extravasation of fluid, incontinence, impotence, and recurrence of stricture. Here we report a unique complication of breakage of Sachse knife blade intraoperatively and its endoscopic management. Optical internal urethrotomy (OIU) is the most common procedure performed for short segment bulbar urethral stricture worldwide . HoweverA 30 year-old male presented with complaint of lower urinary tract symptoms for the last six months. Uroflowmetry voiding pattern was suggestive of urethral stricture disease. Retrograde urethrography (RGU) revealed a short segment bulbar urethral stricture (<1.5cms). Optical internal urethrotomy was performed. Intraoperatively blade of Sachse\u2019s urethrotome accidently broken and fell proximal to the stricture which was confirmed on fluoroscopy . We compOptical internal urethrotomy became popularized after the work of Sachse in 1971 and now This complication should be kept in mind and instruments should be checked properly by the operative surgeon prior to start the procedure. Retained sharp objects like knife blade in urethra as a result of breakage of Sachse knife blade can be managed endoscopically."} +{"text": "Many real-world networks contain highly connected nodes called hubs. Hubs are often crucial for network function and spreading dynamics. However, classical models of how hubs originate during network development unrealistically assume that new nodes attain information about the connectivity (for example the degree) of existing nodes. Here, we introduce hub formation through nonlinear growth where the number of nodes generated at each stage increases over time and new nodes form connections independent of target node features. Our model reproduces variation in number of connections, hub occurrence time, and rich-club organization of networks ranging from protein\u2013protein, neuronal and fibre tract brain networks to airline networks. Moreover, nonlinear growth gives a more generic representation of these networks compared with previous preferential attachment or duplication\u2013divergence models. Overall, hub creation through nonlinear network expansion can serve as a benchmark model for studying the development of many real-world networks."} +{"text": "To present a method, alternative to penetrating keratoplasty, for the restoration of impaired corneal clarity with anterior stromal scarring following long-standing corneal graft failure.A 48-year old female who had previously underwent Descemet stripping automated endothelial keratoplasty (DSAEK) for the treatment of pseudophakic bullous keratopathy, presented with long-standing corneal oedema and anterior corneal scarring. A significant improvement in corrected distance visual acuity was demonstrated, as corneal clarity was restored following graft exchange and phototherapeutic keratectomy (PTK).The combination of corneal graft exchange and phototherapeutic keratectomy may represent an effective therapeutic option for long-standing corneal oedema with concomitant anterior corneal scarring after failure of a DSAEK graft. Descemet stripping automated endothelial keratoplasty (DSAEK) has become the modality of choice for the treatment of corneal oedema arising from corneal endothelial diseases including Fuchs endothelial dystrophy and pseudophakic bullous keratopathy .In cases of DSAEK graft failure or rejection, corneal graft exchange could be attempted. Nevertheless, when corneal oedema is left to ensue, the subsequent chronic corneal decompensation may result in anterior corneal fibrosis. The aforementioned complication limits the final visual outcome of a new DSAEK procedure and, thus, may alter the surgeon\u2019s plan in favour of penetrating keratoplasty (PK).A 48-year old female sought medical consultation due to decreased vision of the left eye. Her past medical history included no necessity for spectacle correction at a younger age and phacoemulsification surgery of the left eye 4\u00a0years ago. Following cataract surgery, no improvement of her visual acuity was noticed due to pseudophakic bullous keratopathy. Therefore, the patient underwent DSAEK procedure in the left eye six months post cataract extraction. Restoration of good visual acuity following DSAEK that lasted for the next year was noticed; upon the aforementioned period the patient reported gradual deterioration of vision. Gradual visual impairment was attributed to graft failure.The ophthalmic examination of the left eye revealed uncorrected distance visual acuity HM (hand movement) that could not be improved with spectacles. Slit-lamp biomicroscopy of the left eye showed corneal oedema accompanied by anterior corneal fibrosis.We proceeded with a second Descemet stripping endothelial keratoplasty in order to replace the non-functional graft with a healthy one. The procedure resulted in complete resolution of corneal oedema within the first postoperative month Fig\u00a0. NeverthIn the first postoperative month, anterior corneal fibrosis resolved Fig\u00a0 and the Corneal decompensation arising from a non-functional graft or from endothelial diseases such as Fuchs endothelial dystrophy and pseuIn our case, failure of DSAEK graft led to chronic corneal oedema with a central opacity that involved the anterior stroma. We decided against PK in an attempt to achieve not only satisfying post-keratoplasty visual acuity, as well as to obviate the increased morbidity of a full-thickness corneal graft. A two-step procedure that included DSAEK graft exchange and phototherapeutic keratectomy with adjunctive MMC was performed. To date, 6\u00a0months following PTK, no recurrence of the anterior corneal fibrosis has been observed.Manual debridement of the fibrosis would be an alternative in case of a superficial scar. However, in the case of scar extension into the anterior stroma, manual peeling may give rise to deep corneal defects that may, in turn, lead to uneven healing and an unpredictable visual outcome . In addiIn conclusion, DSAEK graft failure prompts consideration for timely restoration of subsequent corneal oedema, as chronic corneal decompensation can result in anterior corneal fibrosis. In the adverse event of graft failure with anterior corneal scarring, combined graft exchange and PTK should be considered in an effort to spare the patient from the increased morbidity of a PK graft and to achieve a greater visual outcome."} +{"text": "The book combines fields which experience increasing interest in recent years: optofluidics, microfluidics and fighting multiple drug resistance (MDR) seen as part of infectious diseases domain. Ther eported results are of interest for life sciences, environment quality control and biomedical basic and applied research. Biomedical specialists, chemists, physicists, public health experts and even outer space researchers may be among target readers, as well as students engaged in these fields.The book shows a convincing and useful connection between optofluidics and MDR studies. It is distributed along 18 chapters written by 40 authors from 9 countries and 12 laboratories.A set of chapters informs readers about selected non-antibiotic medicines which are exposed to UV pulsed laser beams for generating photoproducts with enhanced properties in fighting MDR. Such parent compounds are phenothiazines, quinazolines and hydantoin derivatives which do not have normally significant effects on bacteria or tumour tissues, but after being exposed to laser radiation in water (chosen as a biocompatible liquid) solutions, generate photoproducts with individual or synergistic effects on biological targets.The book shows the most recent results in the action of exposed chlorpromazine and thioridazine on Gram-positive and Gram-negative bacteria and their enhanced antibacterial and antibiofilm activity.Complementary data about the effects of two cytostatics, methotrexate and 5-Fluorouracil, exposed to optical radiation on eye pseudotumours are synthesised; showing that mixtures of photoproducts generated from them have higher anti-inflammatory effects then their parent compounds.These data are correlated with reports about microfluidic properties for microdroplets serving as vehicles for the transport of medicines to targets."} +{"text": "Mol. Biol. Cell. (2015)]we used the well-established yeast [PSI+]/Sup35 and[+PIN\u00ac]/Rnq1 prion models to show thatautophagy prevents sporadic prion formation. Importantly, we found thatspermidine, a polyamine that has been used to increase autophagic flux, acts asa protective agent which prevents spontaneous prion formation. Prions are self-perpetuating amyloid protein aggregates which underlie variousneurodegenerative diseases in mammals. The molecular basis underlying theirconversion from a normally soluble protein into the prion form remains largelyunknown. Studies aimed at uncovering these mechanism(s) are therefore essentialif we are to develop effective therapeutic strategies to counteract thesedisease-causing entities. Autophagy is a cellular degradation system which haspredominantly been considered as a non-selective bulk degradation process whichrecycles macromolecules in response to starvation conditions. We now know thatautophagy also serves as a protein quality control mechanism which selectivelydegrades protein aggregates and damaged organelles. These are commonlyaccumulated in various neurodegenerative disorders including prion diseases. Inour recent study [Speldewinde Oxidativelydamaged Sup35 was found to accumulate in mutants lacking core components of theautophagy pathway, and this was found to correlate with an increased frequency ofde novo [PSI+] prion formation. Weshowed that growth under anaerobic conditions in the absence of molecular oxygenprevented the accumulation of oxidized Sup35 and abrogated the high frequency of[PSI+] formation in an autophagy mutant. This suggeststhat autophagy normally functions to clear oxidatively damaged proteins prior to theirconversion to the prion form. A protective role for autophagy in preventing denovo prion formation was further confirmed by showing that increasingautophagic flux by treatment with spermidine abrogates the formation of prions inmutants which normally show high rates of de novo prion formation. Thisimportant new finding strongly implicates autophagy as a defense system which protectsagainst oxidative damage of the non-prion form of a protein. This is an importanttrigger for the formation of the heritable prion conformation, an event that has alsobeen implicated in the formation of mammalian prions.The molecular basis by which prions arise spontaneously is poorly understood. Our dataindicate that oxidative protein damage to Sup35, which is a known trigger for Our study highlights the potential use for autophagy-inducing agents such as spermidinein the prevention of the very early stages of spontaneous prion formation i.e.effectively acting as a prion prevention agent . By improving the clearance ofdamaged/misfolded proteins, there is less possibility for these abnormal proteins toaccumulate and to act as nucleation sites catalyzing the aggregation of other damagedproteins. Polyamines such as spermidine are polycations which play multiple roles incell growth, proliferation and longevity. Their beneficial effects in prolonginglifespan are thought to be mediated by increasing autophagic flux. Spermidine inhibitshistone acetylases and the resulting alterations in the acetylproteome increases thetranscription of different autophagy-related genes . More work will be requiredto determine whether the abrogation of prion formation by spermidine solely depends onincreasing autophagic flux, or whether spermidine additionally promotes other stressprotective pathways. For example, spermidine supplementation has been linked withincreased stress tolerance including heat and oxidative stress, which is not onlymediated by increasing autophagic flux. Whether spermidine modulates the expression ofother stress responsive genes, such as heat shock and antioxidant genes which are knownto influence protein misfolding and prion formation, has not been fully established.Hence, spermidine may amelioarte prion fomation via multiple mechnisms including theinduction of autophagy and other stress-related pathways. PSI+]-versions ofwild-type and atg1 mutant strains. Following short-term induction ofthe Sup35NM-GFP fusion construct, fluorescent foci can be detected due to thecoalescence of newly made Sup35NM-GFP with pre-existing Sup35 aggregates. FluorescentSup35 aggregates are normally visible in approximately 70% of[PSI+] cells examined . We found that spermidinetreatment reduced this number such that visible Sup35 aggregates are only detected inapproximately 25% of cells. This did not occur in an atg1 mutantconfirming the requirement for an active autophagy pathway to clear aggregates inresponse to spermidine treatment . This experiment suggests that increasingautophagic flux via spermidine treatment, not only promotes the removal of smallermisfolded/oxidized Sup35 proteins, but can also promote the removal of larger molecularweight Sup35 aggregates which are already formed within cells. It should be emphasizedthat visible Sup35-GFP aggregates do not necessarily correspond to the number of trueheritable [PSI+] aggregates in cells and more work will berequired to examine whether spermidine treatment can really cure cells of the[PSI+] prion. This may be unlikely though, since thepresence of only a few low molecular weight Sup35 propagons will be inherited bydaughter cells resulting in [PSI+] prion transmission.However spermidine may well be beneficial in the treatment of other non-heritable andamorphous protein aggregate diseases. Recent data from our lab, which was not included in the original pulication, demonstratesthat spermidine treatment can also promote the clearance of Sup35 aggregates from cellsin an autophagy-dependent manner . We used a Sup35NM-GFP fusion construct tovisualize Sup35 aggregate formation in [Polyamines, such as spermidine, are present in millimolar quantities within alleukaryotic cells. They play essential roles in a multitude of cellular processes relatedto cell growth, proliferation and metabolism. Spermidine is a naturally occurringpolyamine and rich dietary sources include soy products, legumes, corn, and whole graincereals. The cellular levels of polyamines, such as spermidine, decline with age andhave been linked to lifespan and age-related disorders. Supplementation of spermidineinto dietary regimes may therefore have added benefits for cellular health and healthyageing. Relative to other established pharmacological inducers of autophagy, such asrapamycin and resveratrol, spermidine can be readily obtained from dietary sources anddoes not exhibit deleterious side effects. This places spermidine as a promisingtherapeutic agent for the prevention and amelioration of protein homeostasis and relatedaggregation diseases."} +{"text": "Parvalbumin inhibitory interneurons (PVIs) are crucial for maintaining proper excitatory/inhibitory balance and high-frequency neuronal synchronization. Their activity supports critical developmental trajectories, sensory and cognitive processing, and social behavior. Despite heterogeneity in the etiology across schizophrenia and autism spectrum disorder, PVI circuits are altered in these psychiatric disorders. Identifying mechanism(s) underlying PVI deficits is essential to establish treatments targeting in particular cognition. Based on our previous publications and new data, we propose oxidative stress as a common pathological mechanism leading to PVI impairment in schizophrenia and some forms of autism.Using immunohistochemistry technique and confocal imaging analysis, we assessed the relationship between oxidative stress and PVI and their perineuronal net (PNN) in twelve established animal models relevant to autism and schizophrenia KO, GRIN2A KO, Gclm KO) with or without additional insult , methylazoxymethanol acetate developmental rodent model (MAM) and poly:IC).When PVI deficits in the anterior cingulate cortex were found in these animal models carrying genetic and/or environmental risks relevant to diverse etiological aspects of these disorders, oxidative stress was always present. Specifically, oxidative stress was negatively correlated with the integrity of PVIs and the extracellular perineuronal net enwrapping these interneurons. Oxidative stress may result from dysregulation of systems typically affected in schizophrenia, including glutamatergic, dopaminergic, immune, and antioxidant signaling. As convergent endpoint, redox dysregulation has successfully been targeted to protect PVIs with antioxidants/redox regulators across several animal models . D-serine, an allosteric modulator of brain NMDA receptor also protected PVIs and PNN against oxidative stress in SR KO mice.In view of the fact that the established pathophysiological processes dopamine excess, immune dysregulation and NMDA receptor hypofunction could all induce oxidative stress and are potentiated by additional oxidative insults, this mechanism could be central to damage of the highly metabolically active PVIs and the PNN surrounding them. Antioxidant systems are therefore potential therapeutic targets, assuming that redox regulators could be applied early, during environmental impacts, long before the clinical emergence of the disease."} +{"text": "Oral delivery is the most accepted and economical route for drug administration and leads to substantial reduction in dosing frequency. However, this route still remains a challenge for the pharmaceutical industry due to poorly soluble and permeable drugs leading to poor oral bioavailability. Incorporating bioactives into nanostructured lipid carriers (NLCs) has helped in boosting their therapeutic functionality and prolonged release from these carrier systems thus providing improved pharmacokinetic parameters. The present review provides an overview of noteworthy studies reporting impending benefits of NLCs in oral delivery and highlights recent advancements for developing engineered NLCs either by conjugating polymers over their surface or modifying their charge to overcome the mucosal barrier of GI tract for active transport across intestinal membrane. Lay abstract: Oral administration of drugs is considered to be a convenient route; however, various drugs that are insoluble in water or unable to permeate across GI tract membrane cannot be delivered by this route. To deliver them effectively, various lipid carriers have been widely explored by researchers. Lipid carriers encapsulate drug inside them and deliver them effectively via the oral route. Also, encapsulation of drug protects them from degradation inside GI tract and safely delivers them to the site of action. This review summarizes application of lipid carriers, in other words, nanostructured lipid carriers, in eradicating these problems, with suitable examples. It is also highly preferred for chronically administered agents, such as anti-tumor, antidiabetic and antihypertensive agents. Drug candidates, which are stable in gastric environment, possess adequate hydrophilic lipophilic balance to cross the intestinal epithelium membrane with the absence of the significant GI tract (GIT), irritation and toxicity signs are ideal candidates for oral delivery . Unfortu effects ,2. Thereet al. extensively worked on biocompatible and biodegradable solid lipids to develop solid lipid nanoparticles (SLNs) in early 1990 and thus resolved the stability and toxicity issues associated with the conventional lipid-based delivery systems [For bioavailability enhancement, the researchers have attempted various approaches to overcome the challenges associated with oral delivery, such as nanosizing of the drug molecules, salt formation, prodrug synthesis and encapsulation of drugs in nanosized carriers, such as polymeric micelles, nanoparticles, liposomes, emulsions, etc. ,3\u20134. Var systems . The dru systems . Modifie systems .NLCs possess unique characteristics and are formulated using a combination of solid and liquid lipids where less ordered structures are produced, which offer the firmer inclusion of the drug molecules within the matrix during the shelf life ,15. It hin vitro release patterns in both SLNs and NLCs were similar but NLCs displayed high-percent cumulative drug release in comparison to SLNs in 55 h. A lesser mobility of drug in SLNs in comparison to NLCs (disordered arrangement) was responsible for the slower release of drug. Differential scanning calorimetric analysis showed decreased recrystallization index of NLCs in comparison to solid lipids and physical mixture of solid lipid and liquid lipid favoring the formation of disordered arrangement and reduced capacity of solid lipids to recrystallize suggesting their higher long-term stability. The results of in vivo studies also suggested NLCs to be superior as they exhibited 2.29-fold increase in oral bioavailability when administered to mice. Similar results were also noted with lovastatin-loaded NLCs. Study of partitioning behavior of lovastatin in pure solid lipid and mixtures of solid lipid and liquid lipid also depicted higher partitioning of drug in the lipid phase consisting of a mixture of solid lipid (Precirol\u00ae ATO 5) and liquid lipid thus suggesting that higher solubility of drug was favored by the presence of liquid lipid [As mentioned previously NLCs overcome the disadvantages associated with SLNs, in other words, they provide higher drug loading, faster release rate and storage stability due to a use of blend of solid lipid and liquid lipid in their formulations. id lipid . Anotherid lipid and dompid lipid SLNs andNLCs are generally composed of solid lipid, liquid lipid, emulsifiers and water. They are fabricated using various methods, such as emulsification-sonication, solvent injection, high-pressure homogenization, microemulsion and solvent diffusion techniques that have been reviewed elsewhere ,13,22. Tet al. observed that small sized NLCs (200 nm) showed higher AUC values in comparison to higher sized NLCs (600 nm) when administered orally to rats, this was attributed to their higher mucoadhesion capability in the body [Literature reveals that composition and processing parameters employed for fabricating NLCs play a vital role in defining their particle size, percent entrapment efficiency and drug release profile and have been manipulated by various formulation scientists to obtain desired characteristics. Tailoring these properties can be advantageous for obtaining high therapeutic levels of drug in blood plasma. For instance, Muchow the body .et al. revealed that higher solubility of miconazole in lipid provided its better encapsulation in NLCs. In this study, the authors screened various solid lipids and liquid lipids for formulating miconazole-loaded NLCs. Gelucire 43/01 was selected as solid lipid because it presented highest solubility for miconazole. Among two liquid lipids, in other words, Migilol\u00ae 812 and Capryol\u00ae PGMC, short listed on the basis of solubility study, capryol PGMC was employed for the fabrication of NLCs as it had higher compatibility with solid lipid selected [et al. carried out 1H NMR analysis to determine any interaction between lipid and bicalutamide as it contains functional groups capable of accepting and donating protons that may interact with the lipids during the preparation of NLCs leading to incompatibility [Solid lipid and liquid lipids, the major constituents of NLCs, ideally should be biocompatible, biodegradable, chemically stable and not possess any toxic effects. The selection of lipids for formulating NLCs is usually done on the basis of solubility of the drug in the lipids as it has a direct impact on drug entrapment and loading efficiency of NLCs . For insselected . Similarselected . Hydrophselected . Kumbhartibility . FTIR antibility .et al. [et al. also reported that the particle size of NLCs was significantly affected by the presence of liquid lipid. Pure solid lipids generated higher sized particles, whereas continuous increment in liquid lipid content led to decrease in particle size due to decrease in viscosity and higher molecular mobility [et al. wherein the continuous addition of Labrafil M 1944CS to Compritol 888 ATO led to the formation of small-sized NLCs. Better entrapment efficiency was also obtained with the addition of liquid lipid due to enhanced solubility of drug facilitated by addition of liquid lipid [Amount of liquid lipid is another parameter that plays a significant role in tailoring particle size and release rate as it leads to reduction in viscosity and surface tension of the system that provides smaller sized NLCs, which in turn provides high surface area, promoting higher percent cumulative drug release as demonstrated by Tiwari et al. . Chen etmobility . A similid lipid .Various lipids/oils obtained from plants are also gaining popularity in the pharmaceutical field for formulating lipid nanoparticles. For instance, tripterine was encapsulated in lipid derived from an edible plant, in other words, broccoli by solvent diffusion method and enhanced oral bioavailability was achieved in comparison to Precirol ATO 5-based lipid nanoparticles and drug suspension suggesting the applicability of plant-based lipids . Also, sAmount of total lipid matrix is also known to affect particle size and entrapment efficiency of NLCs, in other words, an enhancement in both characteristics was observed with increasing the lipid matrix. The higher viscosity of the system is held responsible for growth in particle size, whereas reduction in drug escaping tendency due to higher lipid content results in higher entrapment efficiency. Thus, selection of optimal lipid content is crucial while formulating NLCs with desired properties .in vitro release study. Improved characteristics of myversol system resulted in higher bioavailability of lovastatin-loaded NLCs in orally administered rats to determine the in vivo fate and exact absorption mechanism employing water quenching fluorescent probes demonstrated no evidence of absorption of intact nanoparticles through the intestinal membrane after oral administration [in vivo studies on engineered NLCs are not satisfactory and there is necessity of detailed future studies to determine effects of composition, physiochemical properties and surface modification on the fate of lipid nanoparticles.During GIT passage, NLCs circumventing digestion process can be either conveyed to the portal blood via paracellular route bypassing metabolism due to enterocyte enzymes or can be captured by M cells of Payer's patches delivering NLCs to the lymphatic system . Extensistration . Howeverstration ,35. Alsostration . HoweverOwing to the poor bioavailability of most of the developed drugs, various research groups have worked on designing suitable oral delivery systems for such drugs. NLCs have gained high recognition as suggested by various research reports published so far for drugs, such as isoliquiritigenin, fenofibrate, baicalin, etc. ,43,47. VAppropriate solubility of drug at the absorption site is necessary for achieving acceptable oral bioavailability. However, more than 40% of new chemical entities coming out from combinatorial screening programs are poorly aqueous soluble, which is a subject of major concern to formulation scientists . NLCs haet al. developed NLCs of thymoquinone for oral delivery using high pressure homogenization technique as an aid to improve its gastroprotective activity. Rats pretreated with thymoquinone-loaded NLCs developed significantly reduced areas of ulcers in stomach in comparison to rats pretreated with plain NLCs against ethanol-induced ulcers via higher modulation of pH of gastric contents [Lercanidipine HCl is an antihypertensive agent that suffers from low solubility and presents poor oral bioavailability (10%). Lercanidipine HCl-loaded NLCs led to the enlargement in surface area, which resulted in an improved release rate to a receptor compartment (pH 7.4) across the rat stomach membrane in comparison to a drug suspension suggesting a higher dissolution rate of the drug. Moreover, drug-loaded NLCs showed superior antihypertensive activity for 24 h in comparison to drug suspension . Repaglicontents .50 values for drug-loaded NLCs were decreased up to five times in comparison to free drug due to the small size of NLCs that were highly absorbed by cells and released high concentration of drug within cells suggesting the applicability of this delivery vehicle for poorly soluble drugs.NLCs have also shown improvement in the pharmacokinetic profile of flavanoid drug; isoliquiritigenin having multiple health benefits, but presenting diminished therapeutic efficacy of its oral administration in suspension form due to its lipophillic nature. In this study, NLCs composed of glyceryl monostearate (solid lipid); Miglyol 812 (liquid lipid) and Tween 80 (surfactant) were developed. Higher diffusion of NLCs across the unstirred water layer of intestine epithelial cells facilitated by the presence of hydrophilic surfactant led to augmented values of AUC in comparison to drug solution. Moreover, the small size of NLCs facilitated bioadhesion to intestine membrane, which lead to higher absorption of NLCs . Also etAn orally ingested substance is exposed to varying conditions in different sections of GIT, which can adversely affect the stability of ingested bioactives. For instance, being a hydrophilic and acid labile compound, ifosfamide degrades at stomach pH and has a limited access to cancerous cells. Also, sintering of this compound on storage decreases its dissolution rate, which also presents problems in its delivery. More recently, ifosfamide was encapsulated inside NLCs having chitosan coating over their surface to provide sustained release of the drug. Formulated NLCs showed only 13% release at pH 1.2 for 6 h, suggesting suitability of NLCs in delivering ifosfamide effectively inside the body . PreviouIn vitro antioxidant study also suggested higher potential of lutein-loaded NLCs [The bioactives are susceptible to different environmental conditions and it is mandatory to protect them from such harsh conditions during storage to provide them better shelf life. For example, lipophillic nutraceuticals, such as luetin, \u03b2-carotene or quercetin are obligatory due to their multiple health benefits, but their low aqueous solubility and poor chemical stability during storage presents problems in their oral absorption. To trounce these difficulties, researchers have explored the capability of NLCs for accommodating great amounts of such poorly water soluble bioactives and prevent their premature decomposition . \u03b2-carotded NLCs . Thus, pet al. reported an increase in the plasma half life of biochanin A from 6 to 21 h after single oral administration in rats when encapsulated in NLCs [max (1.918-fold) and AUC values (3.2-fold) in comparison to a drug suspension after single administration in Wistar rats [Appropriately designed NLCs may act as a delivery vehicle capable of protecting drugs from premature degradation during their transport across GIT due to first pass metabolism. NLCs interact with bile salt in GIT to form mixed micelles, which undergo selective lymphatic uptake, thus bypassing the liver . Also, t in NLCs . In anot in NLCs . Flow cytar rats . In a sitar rats .1/2 (2 h), which restricts its clinical use due to need of frequent dosing. After encapsulation of simvastatin in NLCs, AUC values were improved up to 4.87-fold and t1/2 was almost doubled in comparison to a drug suspension [et al. combined two novel strategies in a single system, in other words, vinpocetine was incorporated in cyclodextrin complexes that were further incorporated in NLCs matrix and showed 39% higher in vitro release at pH 6.8 and 7.4 and superior bioavailability in male rabbits (92%) in comparison to conventional NLCs [Simvastatin is a drug of choice for treatment of hypercholesterolemia and is available as an immediate release formulation. It is poorly water soluble and highly metabolized in intestinal gut and liver and exhibits very short tspension . Furtherspension . In an anal NLCs .Ex vivo studies showed that formulation having 247-nm particle size (NLCs B) avoided P-gp efflux as it entered by both pathways, whereas other formulations entered only by caveolae pathway (NLCs A and NLCs C) as depicted in P-gp, is a 170 kDa protein belonging to the ATP-binding cassette family and is a well-studied protein, which mainly transports large, hydrophobic, cationic or electrically neutral molecules that can have remarkably dissimilar structures . P-gp isWhen a drug is administered orally, it enters the systemic circulation and gets distributed in different tissues of the body because of its physiochemical properties, which leads to decreased activity of drug than expected and in turn shows drug-associated toxicity. Therefore, it is a prerequisite for a delivery vehicle to deliver the drug at the site of action and at the same time be safe and should also minimize the adverse effects of drug for the effective treatment of any disease. NLCs have helped in improving treatment of various diseases via encapsulating drugs inside them and actively targeting disease area thus minimizing its potential toxicity. For example, tamoxifen is used to treat cancer and its use is accompanied by systemic and hepatic toxicity. Tamoxifen was integrated into NLCs composed of glyceryl monostearate of stearic acid and labrafil WL 2609 BS. On oral administration of 1.5-mg/kg dose of tamoxifen-loaded NLCs, the mice displayed slower clearance and did not show any increased levels of hepatotoxicity markers, whereas their levels were highly elevated with the same dose of tamoxifen suspension and its marketed formulation suggesting the potential of NLCs in circumventing its toxicity .et al. carried out in vitro cytotoxicity studies on Caco-2 cells for validating potential of NLCs in reducing toxicity of tripterine. Encapsulation of tripterine decreased cell killing with an IC50 value of 2.11 \u03bcg/ml, whereas cells treated with an equivalent concentration of drug solution exhibited higher cytotoxicity. Significant reduction in intestinal toxicity of the drug was also observed, this could be attributed to the controlled release of tripterine after its encapsulation in NLCs [Oral delivery of tripterine is also associated with adverse affects on GIT and kidneys. Chen in NLCs . Triptol in NLCs .max, mean residence time and AUC values in comparison to drug solution and marketed oral granules demonstrating the high therapeutic potential of NLCs in addition to overcoming its side effects.Metabolites of few drugs also lead to adverse affects in the body, which necessitates the development of sustained release system for them. For instance, metabolites of montelukast are known to cause hepatotoxicity during its conventional oral therapy. It is documented that long-chain lipids assure lymphatic uptake of NLCs and high drug concentration in mesenteric lymph nodes from NLCs composed with long-chain lipid, in other words, glycerylmonostearate of stearin has been observed . TherefoNLCs have also been employed for effective delivery of drugs in the oral cavity, especially with increasing their residence time in oral mucosa. The mucoadhesive properties of positively charged NLCs have promoted their interaction with negatively charged oral mucosa, thus providing optimal residence in the oral cavity. These systems have been studied to be employed for treatment of various bacterial and fungal infections of the oral cavity. However, considering the lower viscosity of NLCs dispersion, these systems are needed to be incorporated in semisolid preparations, such as hydrogels, to permit their better application in oral mucosa. Recently, miconazole-loaded NLCs have been studied to provide local delivery and controlled release to oral mucosa, which otherwise presents difficulty due to its poor solubility. In this study, the antifungal activity of drug-loaded NLCs was found to be more pronounced in comparison to its marketed formulation having 17-fold higher dose in comparison to NLCs . SimilarIn vitro studies revealed that thiomer (cysteine) conjugation onto the surface of docetaxel-loaded NLCs using postinsertion technique led to higher mucoadhesion (81.6%) with mucin in comparison to unconjugated NLCs (51.9%) [in situ intestinal perfusion investigation. Better pharmacokinetic parameters of modified NLCs in Sprague Dawley rats were also in concordance with results of intestinal perfusion study suggesting beneficial effects of engineered NLCs.The tight epithelial cells of the GIT are covered with a hydrophilic and negatively charged protective layer of mucus that restricts the passage of foreign particles across GIT. However, researchers have exploited mucus as a beneficial tool to increase plasma concentration and therapeutic efficacy of drugs via formulating engineered nanoparticles having the capability to anchorage with mucus. Binding of nanoparticles to mucus increases their residence time in GIT, which allows passive transport of drugs leading to their increased absorption. Two different approaches employing physiochemical properties of mucus have been documented to provide mucoadhesion property to nanoparticles A & B. Fi (51.9%) . Also, sIn vitro drug permeability study across mucus secreting cells (Caco-2/HT 29 MTX) depicted that coating of dextran-protamine to the surface of NLCs could remarkably (twofold) enhance the drug delivery across the cell in comparison to uncoated NLCs [It has been documented that customary rejuvenation of mucus layer by a turnover process hampers bioadhesion process . Therefoted NLCs .et al. observed prolonged-plasma concentration (24 h) in case of docetaxel-loaded PEGylated NLCs in comparison to drug solution, which was very low within 12 h postoral administration to rats as PEGylation prevented opsonin binding to intact NLCs in systemic circulation thus avoiding their macrophage uptake [et al. also incorporated an anticancer drug biochanin A in PEG-NLCs with the aim of achieving improved oral bioavailability [in vitro cytotoxicity study carried out over MCF-7 cell lines highlighted the superior performance of biochanin A loaded PEG-NLCs in comparison to drug suspension. Further, oral bioavailability of etoposide-loaded DSPE-PEG-NLCs in rats was also significantly improved when compared with conventional NLCs and drug suspension, which was attributed to their higher uptake due to opening of tight junctions of intestinal membrane by DSPE-PEG and reduced RES uptake [Hydrophilic moieties, such as poly(ethylene glycol) (PEG), also have the capability to penetrate the aqueous mucus layer of the GIT D. PEG coe uptake . Wang etlability . ResultsS uptake . Thus, Pin vivo. Thus, engineered NLCs have been used as a delivery vehicle for targeting drugs to specific tissues along with improving its pharmacokinetic profile encapsulating montelukast [\u03b6-potential is one of the fundamental parameters for assessing colloidal stability, in other words, values of \u03b6-potential above \u00b130 mV are the foremost requirement for the electrostatic stabilization due to repulsion between particles . In addi profile E. For ex . NLCs also showed concentration-dependent cytotoxic effects and hemolytic activity [Safety of nanomaterials employed for therapeutic or diagnostic purposes is one of the prime concerns in the modern arena. Numerous systems . Reportee nature . Similare nature or any ae nature . An oraldelivery . In a moactivity . In an iactivity . Thus, iex vivo potency, these candidates suffer from poor oral bioavailability and other issues, such as poor permeability, high first pass metabolism, toxicity concerns and instability in GIT. Increase in pubmed data since last decade indicated huge interest of researchers toward lipid-based nanoparticles. Successful NLCs based dermal products (Cutanova Nanorepair Q10 and FloraGlo\u00ae) introduced on the market have also directed formulation scientists to evaluate their potential in other routes. Researchers have explored the capability of these lipid nanoparticles for accommodating great amounts of bioactives, preventing their premature decomposition and enhancing their oral bioavailability. The various surfactants employed in NLCs formulations can overcome P-gp efflux and could also enhance permeability of drugs across the intestinal membrane by causing disruption in the membrane. Better pharmacokinetic parameters of drug-loaded NLCs obtained during different studies suggested that NLCs can serve as promising tool for enhancing therapeutic efficacy of drugs and also providing controlled release of encapsulated drugs. Different engineered NLCs investigated for further boosting their potential suggested that tuning of physical characteristics of NLCs via changing their composition/method of fabrication could provide fruitful results. Although the exact mechanism underlying behind enhanced absorption by NLCs needs to be addressed and solubility of drugs in different lipids needs to be determined as drugs show limited solubility in various lipids limiting their dose. Thus, further detailed in vivo studies are mandatory for taking them to clinics and considering the increased research on this system, it can be concluded that the NLCs based system intended for oral delivery will definitely reach clinical studies in near future.The poorly water soluble nature of drugs, resulting from drug discovery processes remains a major concern for pharmaceutical scientists despite their constant hard work. Besides their high Nanostructured lipid carriers (NLCs) are promising oral delivery vehicle due to their higher stability during storage and ease of scalability without any requirement of sterile conditions.These systems are capable in entraping both hydrophilic and lipophilic drugs.Biocompatible and biodegradable lipids employed in their fabrication minimize toxicity issues.Various studies have been reported based on NLCs for overcoming solubility, permeability, stability and toxicity issues of bioactives.Different engineered NLCs for generating mucus adhesive, mucus-penetrating particles or for better targeting have been explored.Peptidic ligands are also finding wider applicability in oral delivery as they facilitate active transport of the drugs loaded inside NLCs across the intestinal membrane.Better pharmacokinetic parameters of drug-loaded NLCs have been obtained during different studies.in vivo studies addressing their mechanism underlying enhanced oral bioavailability are needed for bringing these systems in clinics.Further, significant"} +{"text": "This study characterized regions of DNA which remained unassembled by either PacBio and Illumina sequencing technologies for seven bacterial genomes. Two genomes were manually finished using bioinformatics and PCR/Sanger sequencing approaches and regions not assembled by automated software were analyzed. Gaps present within Illumina assemblies mostly correspond to repetitive DNA regions such as multiple rRNA operon sequences. PacBio gap sequences were evaluated for several properties such as GC content, read coverage, gap length, ability to form strong secondary structures, and corresponding annotations. Our hypothesis that strong secondary DNA structures blocked DNA polymerases and contributed to gap sequences was not accepted. PacBio assemblies had few limitations overall and gaps were explained as cumulative effect of lower than average sequence coverage and repetitive sequences at contig termini. An important aspect of the present study is the compilation of biological features that interfered with assembly and included active transposons, multiple plasmid sequences, phage DNA integration, and large sequence duplication. Our targeted genome finishing approach and systematic evaluation of the unassembled DNA will be useful for others looking to close, finish, and polish microbial genome sequences. Since the first Next-Generation Sequencing (NGS) platform was released by 454 Life science is available and algorithm developments have facilitated improved genome assemblies. Progress in next-generation sequencing platforms, metrics, and performances has been reviewed PacBio sequence coverage and PacBio RS-II platforms. Clostridium pasteurianum ATCC 6013 to remove bases having PHRED quality score <30 and any reads shorter than 20 bp. Adapter trimming and filtering of raw PacBio data was performed through SMRT analysis software to obtain \u201cfiltered subreads\u201d with default parameters . Positional preference was determined using PerPlot and PerScan tools and B. cellulosolvens DSM 2933 (48X). Post-trimming and filtering statistics for Illumina and PacBio data including the number of reads, average read lengths and genome coverage and total bases are summarized in Tables Illumina sequence coverage for each genome is >200X, sufficient to derive high-quality draft genome assemblies values. Mfold analysis of PacBio gap sequences revealed the potential to form small stem-loop structures but large and/or strong secondary structural loops that might interfere with DNA polymerase and result in low sequence coverage were not identified. Significant differences were not observed between minimum free energies and secondary structures of PacBio gaps and 20 randomly selected regions from the AD2 and DSM 2933 genomes Table . In addiFor further characterization, we analyzed 1 kb DNA sequences flanking PacBio gaps from three near-finished genomes in this study. A self-blast was performed using 1 kb regions as a query against the entire genome using Geneious software with default parameters. The grade score from Geneious software for the top blast hits for gap termini regions are described in Table C. thermocellum LQRI (LQRI), and P. fermentans DSM 17108 genomes of 16S rRNA genome assemblies. Short reads from Illumina technology have limited power to resolve longer repetitive regions , but random errors in the PacBio platform can be corrected by using high (>100x) sequence coverage and/or Illumina data. However, uniform sequence coverage across the entire genome is not guaranteed and low coverage regions are prone to base-call errors. Assembly polishing is a crucial step to obtain accurate consensus sequence and facilitate downstream applications. Two assembly base-call correction algorithms applied in this study are Quiver (correction using PacBio reads) and Pilon (correction using Illumina reads) while iCORN . Therefore, for future projects, the application of circlator software followed by a careful inspection of the trimmed regions is recommended.Another important aspect of finished genome sequences is an accurate representation of a circular chromosome. Automatically finished assemblies generated through HGAP often have (duplicated) overlapping ends which need to be trimmed off for the final assembly. This could be achieved using the circulator (Hunt et al., de novo microbial genome assemblies. Our datasets and analyses will aid future efforts to better understand and overcome unassembled DNA from PacBio assemblies.In this study, we present an effective manual finishing approach targeted toward near-finished microbial genome assemblies. The importance of genome polishing steps is demonstrated through its positive influence on gene calling accuracy and improved protein coding potential, which will be useful to others looking to improve long-read assemblies. Assessment of Illumina gaps confirmed previous findings that repetitive rRNA operons are major contributors to fragmented short-read assemblies. For PacBio assemblies, our initial hypothesis that structural features of DNA might affect the PacBio sequence coverage leading to assembly gap was not accepted. However, we demonstrated that certain biological features such as presence of active transposons, plasmid sequences, and phage integration are possible reasons for assembly fragmentation. Additionally, DNA regions flanking the PacBio gap sequences showed high degrees of similarity with other loci and are likely contributors to incomplete PacBio assemblies in this dataset. The PacBio gap sequences in this study are attributed to a cumulative effect of various aspects of repetitive DNA content and biological features for specific genomes. Despite a few limitations, long reads from third-generation sequencing, in this case from the PacBio platform, are particularly advantageous for generating SU designed the study, performed, and contributed to all the experiments and analyses and wrote the manuscript draft; DK extracted genomic DNA, performed Illumina sequencing, and assisted with PCR and Sanger sequencing; RH contributed to study design and edited the manuscript; SB contributed to study design, assisted with draft writing, and editing. All authors reviewed and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In a policy forum, Daniel Schar and colleagues discuss the need for surveillance of antimicrobial consumption in animals in low- and middle-income countries and propose the establishment of antimicrobial consumption monitoring systems. Antimicrobial use in low- and middle-income country (LMIC) food animal production sectors is accelerating, commensurate with expanded intensive production to meet rapidly increasing demand for animal-source nutrition.However, antimicrobial consumption in animal production contexts of LMICs remains largely undocumented, limiting the ability to establish and monitor progress toward achieving consumption targets.We propose the establishment of antimicrobial consumption monitoring systems in a phased manner that will be responsive and adaptive to LMIC contexts, while directing a path toward incremental enhancement of monitoring structures.This phased approach enables implementation of systems yielding standardized, globally comparable antimicrobial consumption data, which could inform policies to optimize antimicrobial usage in food animal production.The approach should be complemented by efforts to strengthen animal production systems, eliminate medically important antimicrobial growth promoters, and reduce reliance upon prophylactic antimicrobial use.Global antimicrobial consumption in terrestrial and aquatic food animal production is accelerating, associated with expanded production to meet increasing demand for animal-source nutrition . In SoutEfforts to meet rising demand for animal-source nutrition in LMICs are driving a shift in animal production from small holder, mixed crop, and livestock operations to increasingly intensive, large-scale, and specialized commercialization ,3. IntenQuantitative volumes of AGP usage from LMICs are not available. However, studies from LMICs indicate substantial nontherapeutic use. In the Mekong Delta of Vietnam, 84% of poultry farms surveyed indicated that antimicrobials were used for prophylactic rather than therapeutic purposes, and nearly a third of overall usage involved antimicrobial classes on the WHO list of highest priority, critically important antimicrobials for human medicine . In the The discovery and commercialization of antimicrobials stands as a defining achievement of 20th century medicine. As usage patterns drive rising rates of antimicrobial resistance (AMR)-linked morbidity and mortality \u2014compoundAntimicrobial usage (AMU) in humans and animals exerts selection pressure potentiating AMR ,5\u20138; polFacilitates identification of trends and usage profiles,Permits establishment of time-bound consumption targets,Monitors progress toward achieving targets,Guides policy and targeted interventions optimizing antimicrobial use.Monitor consumption trends and benchmarking for optimization of antimicrobial consumption.Comparison of consumption data ultimately disaggregated by species and comparable across human and animal sectors,Antimicrobial consumption data become globally comparable,Contributes to international benchmarking,Creates a globally standardized monitoring architecture, upon which a future international agreement capping consumption could be developed.Comparison of antimicrobial consumption data across countries, species, farms, and with human consumption.Builds a platform for studying the association between antimicrobial consumption and AMR surveillance data.The measurement of AMU in human health and animal health and production settings is a central goal of the Global Action Plan on Antimicrobial Resistance and the The ecosystem in which veterinary antimicrobials are produced, distributed, and utilized in LMICs is complex and variable. A majority of LMICs currently lack structures capable of quantifying consumption at sufficient resolution to provide usage data by antimicrobial class, animal species, production context, purpose of usage, and route of administration, which are necessary to facilitate effective interventions to optimize use . Of the Patterns of antimicrobial use differ widely across animal production value chains, as evidenced by macrolide, fluoroquinolone, and tetracycline residue detection in animal products marketed for human consumption , but speDespite calls for establishing usage thresholds and targets ,7,17, inOther challenges frequently shared by LMICs are equaLow rates of AMR awareness and risk perception among farmers and veterinarians ,Inconsistent policies governing antimicrobial use in animal production,Absent AMU regulation and enforcement structures enabling wide accessibility to critically important antimicrobials without prescription,Where a legal veterinarian\u2013client\u2013patient relationship exists governing prescription use of antimicrobials in animals, the link between prescription and sales presents a sales volume profit incentive, andLack of systematic post-market quality surveillance that would enable recall of substandard and counterfeit veterinary antimicrobial products impacting therapeutic efficacy.Multiple methodologies for quantifying usage have been variously employed, hindering data comparability across countries and production sectors. The OIE terrestrial animal health code, the guiding framework for its 180 member nations, outlines the minimum standard as measuring gross usage by weight of active ingredient per year [Through the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) activity, European Union member states voluntarily report antimicrobial use by food animal\u2013producing species . The ESVvet) and defined course dose in animals (DCDvet) [vet and DCDvet\u2014proprietary ESVAC reporting nomenclature similar to animal defined daily dose (ADDD) and animal defined course dose (ADCD), respectively\u2014are not suited to contexts in which measurement must also capture continuous-use, subtherapeutic dosing, as in LMICs where policies governing AGP use vary significantly.Antimicrobial consumption in food animals can be crudely estimated by quantifying the total weight of the active ingredient adjusted for biomass eligible for treatment, usually expressed as mg/kg population correction unit (PCU), where PCU is defined as total live and slaughtered animal weight per year in a prescribed geographic area. While this measurement of total volume of active ingredient per biomass considers neither the concentration of administered product nor its pharmacokinetics in individual species, it is a readily calculated estimate of usage. ESVAC guidelines use the mg/PCU methodology and introduce both defined daily dose in animals (DDD(DCDvet) , serving(DCDvet) . HoweverAccurate accounting of antimicrobial consumption in food-producing animals of LMICs must capture both therapeutic and nontherapeutic use, including AGPs and mass administration of antimicrobials delivered in medicated, premixed feed. Antimicrobial consumption monitoring is particularly important in aquaculture, in which mass administration of antimicrobials in medicated feed for disease prevention and control is a standard practice .We propose a standardized, internationally-endorsed, phased approach that accounts for the context and currently available structures for collecting AMU data from food-producing animals\u2014both terrestrial and aquatic species\u2014in LMICs. The foundation is built upon the annual measurement of total sales of antimicrobials by class in mg/PCU, which can be derived from the total sales by class for member states reporting to the OIE divided by animal biomass data. Consistency in deriving the numerator\u2014active pharmaceutical ingredient (API)\u2014across multiple formulations of veterinary antimicrobials necessitates that products be managed through a standardized classification scheme, such as the Anatomical Therapeutic Chemical (ATCvet) system established for veterinary medical products . SimilarAs countries establish refined data collection structures , measureIn 2015, Thailand\u2019s International Health Policy Program and One Health partners established a human and animal national Surveillance for Antimicrobial Consumption (Thai SAC) system ,26. ThaiTechnical assistance could be housed within existing or newly established coordinating bodies and should prioritize intraregional LMIC exchanges and solutions relevant to unique regional capacities and contexts. An intergovernmental panel on AMR has been suggested , similarSalmonella enterica Serovar Heidelberg following elimination of third-generation cephalosporins from poultry hatcheries in Quebec, Canada [Documenting usage\u2014particularly for WHO-classified highest priority critically important antimicrobials\u2014permits trends monitoring and identification of animal production sectors in which targeted interventions hold promise of arresting drivers of resistance. Conceivably, a reversion to susceptibility is achievable, as noted in , Canada .Establishing antimicrobial consumption monitoring systems in animal production sectors should be a central, near-term goal of multisectoral national AMR action plans aligned with the WHO Global Action Plan and the focus of advocacy and support from the UN FAO, OIE, and WHO tripartite. Embedding this approach within national AMR action plans promotes monitoring capacities endorsed across ministries, including those vested with budget authority, and costed, resourced, and prioritized for implementation.In parallel, the WHO Joint External Evaluation (JEE) tool, which explicitly considers AMR and is increasingly being utilized by countries as an independent assessment of International Health Regulations (2005) capacity requirements , could dAntimicrobial consumption monitoring systems alone, however, will be insufficient to realize progress in directing prudent AMU in food-producing animals. Concurrently, support for strengthened farm and market chain biosecurity, enhanced livestock vaccination coverage, and improved uptake of good animal husbandry and nutrition practices will be necessary in achieving optimized usage, particularly in transitioning food animal production contexts of LMICs. New production facilities in LMICs should be designed to achieve high standards of husbandry and biosecurity, enabling more rapid phaseout of AGPs. Eliminating AGPs can be achieved at negligible cost to productivity, particularly in the context of such strengthened production systems .The framework presented here should provide LMIC policy makers with high-quality antimicrobial consumption data that can be used to establish usage targets, while building incrementally enhanced monitoring capacities. The analyses derived from this approach could steer targeted policies optimizing antimicrobial consumption and scale back selective pressures currently driving AMR in animal production, with benefits expected to extend broadly across animal and human health.The authors\u2019 views expressed in this publication do not necessarily reflect the views of the United States Agency for International Development or the United States Government."} +{"text": "Solanum lycopersicum) have not been extensively explored. In this study, we characterized the 13 SlGRF genes. In silico analysis of protein motif organization, intron\u2013exon distribution, and phylogenetic classification confirmed the presence of GRF proteins in tomato. The tissue-specific expression analysis revealed that most of the SlGRF genes were preferentially expressed in young and growing tissues such as flower buds and meristems, suggesting that SlGRFs are important during growth and development of these tissues. Some of the SlGRF genes were preferentially expressed in fruits at distinct developmental stages suggesting their involvement in fruit development and the ripening process. The strong and differential expression of different SlGRFs under NaCl, drought, heat, cold, abscisic acid (ABA), and jasmonic acid (JA) treatment, predict possible functions for these genes in stress responses in addition to their growth regulatory functions. Further, differential expression of SlGRF genes upon gibberellic acid (GA3) treatment indicates their probable function in flower development and stress responses through a gibberellic acid (GA)-mediated pathway. The results of this study provide a basis for further functional analysis and characterization of this important gene family in tomato.Growth regulating factors (GRFs) are plant-specific transcription factors that are involved in diverse biological and physiological processes, such as growth, development and stress and hormone responses. However, the roles of GRFs in vegetative and reproductive growth, development and stress responses in tomato ( GRF gene was identified in rice (Oryza sativa) where it mediates gibberellic acid (GA)-induced regulation of stem growth in deepwater rice . EF. EFhttp:GCAG-3\u2019) was usedeatments .Statistical significance of the differences in relative expression levels of each gene between treatments (control versus stress) and of the differences in expression levels between time points within a treatment was determined with one-way analysis of variance (ANOVA) using the MINITAB statistical software 17 . The mean separation of expression values was analyzed using Tukey\u2019s pairwise comparison test.SlGRF family genes using different bioinformatics approaches and transcript expression analysis. We analyzed their intron\u2013exon organizations, chromosomal distributions, gene structures, evolutionary relationships and expression profiles in different tissues and under different stress conditions to predict their possible biological functions. The SlGRF genes are variably expressed in different tissues and fruits at different developmental stages with particularly high expression in flower buds, and meristems. The increased expression of SlGRF genes in response to abiotic stress and phytohormone treatments implies their function in growth and development of tomato plants under different stress conditions. Together, our results obtained from gene structure, phylogenetic relationships and transcript expression profiles in different tissues and under different stresses facilitate the identification of tomato GRF genes that might play roles in specific developmental processes and/or environmental stress conditions.This study systematically characterized"} +{"text": "Negative symptoms (NSs) are more severe in Treatment Resistant Schizophrenia (TRS) than Antipsychotic Responder Schizophrenia (ARS) patients. NSs are predictors of outcomes of neurological soft signs and functional capacity in TRS but not in ARS patients. The scope of this work is to clarify whether NSs effects are integral to or independent from the TRS diagnosis in our sample of patients.70 out of 206 eligible putative TRS and ARS patients were included (enrollment still ongoing). Patients were tested by the Neurological Evaluation Scale (NES); the CGI-S; the PANSS; the Heinrichs\u2019 Quality of Life Scale (QLS); the UCSD Performance-Based Skills Assessment (UPSA); the Personal and Social Performance (PSP) scale and Specific Level of Functioning (SLOF). Patients were subdivided in NSHigh (severe NSs) and NSLow (mild NSs) based on ROC curve-derived cut-off.At the Student\u2019s t test, NSHigh had significantly lower scores than NSLow patients on: Verbal Fluency; QLS score; PSP score; UPSA Financial, Communication, and Family Skills; UPSA total score; all SLOF areas (except Area4). NSHigh patients had significantly higher scores than NSLow patients on CGI-S; PANSS Positive and General Psychopathology Subscale scores; and NES score.Distribution of NS patients was significantly different between TRS/ARS diagnostic groups, as NSHigh patients were significantly more frequent in the TRS group . Notably, mean PANSS Negative Subscale scores were significantly higher in TRS compared to ARS patients .Since multiple variables found to be significantly different in NSHigh vs. NSLow patients were also significantly different between TRS and ARS patients, the question arises whether the significant differences found between diagnostic groups may depend on the higher percentage of patients with more severe NSs in the TRS group. Therefore, a two-way ANOVA was carried out with dichotomous NS and Diagnosis variables as the independent variables. Outcomes on multiple clinical variables were significantly different among groups. A NS*Diagnosis interaction effect was found for NES score , Passive Social Withdrawal (N4), and Difficulty in Abstract Thinking (N5).These data suggest that NSs are both independent determinants and moderators of TRS/ARS diagnosis effect on multiple psychopathology, cognitive, and psychosocial factors. More impaired functions attributed to non-response to antipsychotics may depend on more severe NSs. However, only a subset of NSs appears to exert this action, possibly related to the multidimensional construct of these symptoms."} +{"text": "Malignant hypertension may be the first manifestation of systemic hypertension. We report a clinical case of a Caucasian 41-year-old man with no previous history of blood hypertension seen at casualty because of blurred vision. Fundus examination disclosed optic disk swelling, retinal hemorrhages and infarcts. The blood pressure was 220/130 mmHg. After the appropriate management of hypertension, optic disk and retinal edema resolved, leaving minor changes as mild optic disk pallor and hard exudates."} +{"text": "Atherosclerotic stenosis of the brachiocephalic artery sometimes occurs in patients with coronary artery disease, and can cause stroke during the perioperative period of coronary artery bypass grafting.We describe the case of a 77-year old male with severe stenosis of the brachiocephalic artery and severe coronary artery disease. He successfully underwent aorto-right subclavian artery bypass that was performed concomitantly with off-pump coronary artery bypass.Concomitant aorto-subclavian artery bypass with off-pump coronary artery bypass grafting is a therapeutic option that minimizes the risk of perioperative stroke in patients with brachiocephalic artery stenosis and coronary artery disease. Atherosclerotic stenosis of the brachiocephalic artery can be associated with coronary artery disease . StenosiA 77-year old male was referred to our hospital for known coronary artery disease and a history of antero-septal myocardial infarction and syncope. Coronary angiography showed severe triple vessel disease. Computed tomography revealed severe diffuse calcification from the aortic arch to the abdominal aorta. In particular, just proximal brachiocephalic artery was shown to be circumferentially calcified and 90% stenosed Fig.\u00a0. ProximaA median sternotomy was performed, and the bilateral internal thoracic arteries were dissected. At the same time, a saphenous vein graft was dissected. A direct ultrasonographic examination revealed severe atheromatous plaques inside the brachiocephalic artery; hence, we chose the right subclavian artery as the distal anastomosis site for the prosthetic bypass conduit. An 8-mm polytetrafluoroethylene graft was anastomosed to the right subclavian artery, and then the proximal end of this graft was anastomosed to the aorta with a side-biting clamp. Off-pump CABG was then performed using a method described previously . The lefPostoperatively, no neurological deficit was observed. The blood pressures of the bilateral upper extremities were identical. Computed tomography demonstrated the patency of the coronary bypass grafts and the aorto-right subclavian artery bypass graft Fig.\u00a0. PostopeAtherosclerotic stenosis of the subclavian artery or brachiocephalic trunk is sometimes associated with coronary artery disease . Many paPreoperative computed tomography revealed severe calcification just proximal brachiocephalic artery, and carotid ultra sound examination revealed subclavian steal phenomenon at right vertebral artery. But computed tomography revealed no significant stenosis from end of the brachiocephalic trunk to origin of right carotid artery and subclavian artery, and so we expected that the aorto-subclavian bypass provided a physiological brain perfusion and reduced the risk of stroke.Takach et al. reportedConcomitant aorto-subclavian artery bypass with off-pump CABG is a therapeutic option that minimizes the risk of perioperative stroke in patients with brachiocephalic artery stenosis and coronary artery disease."} +{"text": "Cyclosporin-A (CsA) and tacrolimus (FK-506) are immunomodulating agents used to prevent rejection in organ transplantation. They are both associated with several side effects, including nephrotoxicity and severe hypertension due to vascular injury, which often appears as a microvascular occlusive disorder . We report the first case of a microvascular occlusive disorder with the features of TMA in the small bowel of an orthotopic liver transplant (OLT) patient after immunosuppressive therapy with CsA and FK506. The patient presented with severe recurrent abdominal colics and distal subocclusion, requiring aggressive surgical treatment. Histological and ultrastructural analysis of the resected specimen disclosed intestinal TMA. Although rare, such a complication should be considered in the differential diagnosis of abdominal colics in patients undergoing immunosuppressant therapy after OLT."} +{"text": "Biotic and abiotic factors are increasingly acknowledged to synergistically shape broad-scale species distributions. However, the relative importance of biotic and abiotic factors in predicting species distributions is unclear. In particular, biotic factors, such as predation and vegetation, including those resulting from anthropogenic land-use change, are underrepresented in species distribution modeling, but could improve model predictions. Using generalized linear models and model selection techniques, we used 129 estimates of population density of wild pigs (Sus scrofa) from 5 continents to evaluate the relative importance, magnitude, and direction of biotic and abiotic factors in predicting population density of an invasive large mammal with a global distribution. Incorporating diverse biotic factors, including agriculture, vegetation cover, and large carnivore richness, into species distribution modeling substantially improved model fit and predictions. Abiotic factors, including precipitation and potential evapotranspiration, were also important predictors. The predictive map of population density revealed wide-ranging potential for an invasive large mammal to expand its distribution globally. This information can be used to proactively create conservation/management plans to control future invasions. Our study demonstrates that the ongoing paradigm shift, which recognizes that both biotic and abiotic factors shape species distributions across broad scales, can be advanced by incorporating diverse biotic factors. Predicting and mapping species distributions, including geographic range and variability in abundance, is fundamental to the conservation and management of biodiversity and landscapes23There is an ongoing paradigm shift in understanding how biotic and abiotic factors shape species distributions. Until recently, it was widely accepted that abiotic factors, such as temperature and precipitation, played the primary role in shaping distributions of species and biodiversity at broad scales and that biotic factors were most important at fine scales 9101213141515197In addition to species interactions, biotic factors related to vegetation can influence species distributions and abundance at broad scales. In particular, anthropogenic land-use change is rarely considered when evaluating species distributions at broad scales; however, given the human footprint globally23252613Invasive species are a primary driver of widespread and severe negative impacts to ecosystems, agriculture, and humans across local to global scalesMus musculus) and brown rat (Rattus norvegicus), wild pigs have one of the widest geographic distributions of any mammal; further, it exhibits the widest geographic range of any large mammal353940Few species exhibit a global distribution that extends across Europe, Asia, Africa, North and South America, Australia, and oceanic Islands. Besides naturalized animals, such as the house mouse evaluate how biotic and abiotic factors shape po2), which resulted in 129 estimates of density across their global distribution used in our analyses had\u2009>\u20091,000 times more support as the best approximating model than the top model considering only abiotic factors . The var\u00d7\u200910\u221217) . Density\u00d7\u200910\u221217) ; percentUsing the full model-averaged results of parameter estimates, we created a predictive map of global wild pig population density . Wild piPopulation density of an invasive large mammal was strongly influenced by both biotic and abiotic factors across its global distribution. Consistent with the prediction that abiotic factors drive broad-scale patterns of species distribution, potential evapotranspiration (PET) and precipitation variables were important predictors of population density on a global scale. In addition, contributing to growing evidence that biotic factors are also important determinants of broad-scale patterns of species distributions, both biotic interactions and vegetation played important roles in predicting the distribution of wild pig populations globally. Further, land-use change mediated by human activities strongly predicted the broad-scale distribution of an invasive large mammal. Consistent with previous studies evaluating how population density of ungulates varied across broad scales, both bottom-up (resource-related) and top-down (predation) factors influenced the distribution of wild pig populations1942Using both biotic and abiotic factors to evaluate broad-scale species distributions can create more realistic maps of range and density with better predictive ability16Abiotic factors, such as temperature and precipitation, are consistently found to be primary determinants of species distributions at broad scalesBiotic factors were among the most supported variables predicting population density across a global scale. Our results indicated that the presence of large carnivores can influence wild pig population density. Large carnivore richness was strongly supported in our models and exhibited a negative relationship with wild pig density; as the number of large carnivore species increased, wild pig density decreased, which is consistent with studies in Eurasia and Australia4247495052531718Although biotic interactions between animals are the primary biotic factors evaluated in species distribution models at broad scales, the role of plant communities has received less consideration. In particular, anthropogenic land-use change increasingly influences vegetation communities across continents and warrants a better understanding for how human activities are shaping broad-scale distributions of plant and animal populations22235758Forest is considered a key habitat type preferred by wild pigs59In some systems, abiotic factors can be stronger predictors of species distributions, than biotic factors, because of high correlations between these two factorsAdditional biotic factors that can influences species distributions on a broad scale, particularly invasive species, include the role of humans in distributing the founding individuals of new populations. For example, invasive wild pig populations have arisen across several continents recently through human activities. Illegal translocations by humans for hunting purposes can facilitate the long-distance expansion of wild pig populations into new areas646539676860Population density, compared to presence-absence occurrence, can provide more informative conclusions of species distributions in relation to biotic and abiotic factors77374Predicting species distributions provides critical information to the management and conservation of biodiversity, especially for controlling invasive species. Without intensive management actions, our study predicts that there is strong potential for wild pigs to expand their geographic range and further invade expansive areas of North America, South America, Africa, and Australia. Although wild pigs currently occupy broad regions of predicted habitat in their non-native range, many regions of predicted habitat are currently unoccupied and may be at high risk for future invasion. These areas might warrant increased surveillance by local, state, and federal agencies to counter the establishment of populations. Although attention in unoccupied areas that are predicted to support high densities of wild pigs might warrant priority for countering population introductions, wild pigs can persist in relatively low quality habitat and these areas also warrant attention to halt invasions. Given the potential for wild pig populations to rapidly expand once establishedet al.76To evaluate the population density of wild pigs throughout their global distribution, we compiled density estimates from the literature throughout its native and non-native ranges across each continent and island for which data were available . PreviouModels evaluating and predicting species distributions can be improved by including areas of absence or zero density to sample the full range of available landscape conditions73We considered a suite of biotic and abiotic landscape variables, which were divided into vegetation, predation, and climate factors that we The biotic factors that we evaluated included agriculture, broadleaf forest, enhanced vegetation index (EVI), forest canopy cover, difference in the proportion between forest and agriculture (to characterize landscape heterogeneity), normalized difference vegetation index (NDVI), large carnivore richness, and unvegetated area . We expeThe abiotic factors that we evaluated included two measures of ecological energy regimes, actual evapotranspiration and potential evapotranspiration , and calculated variable importance values93942 resolution). This map displays the maximal potential density of wild pigs in relation to the biotic and abiotic factors used in our modeling and reflects predicted densities that would be achieved if wild pigs had access to all landscapes, their movements were unrestricted, and management activities did not suppress populations. We validated our model using mean squared prediction error (MSPE)We used multiple linear regression to evaluate how population density was influenced by our final suite of biotic and abiotic factors . The disHow to cite this article: Lewis, J. S. et al. Biotic and abiotic factors predicting the global distribution and population density of an invasive large mammal. Sci. Rep.7, 44152; doi: 10.1038/srep44152 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."} +{"text": "In our recent updated studies, we found a significant association between periprocedural blood transfusion and acute kidney injury (AKI) following transcatheter aortic valve replacement (TAVR) with an overall 1.95-fold increased the risk of AKI. We also demonstrated that a transapical approach was significantly associated with increased AKI risk compared with a transfemoral approach. Nevertheless, the TAVR approach did not affect severe renal outcomes or long-term renal function. In addition, our meta-analysis demonstrated no significant association between contrast media volume and risk of AKI after TAVR. Thus, the dose of contrast media likely does not play a significant role in the pathogenesis of TAVR-related AKI. Growing knowledge of these risk factors of TAVR on kidney function will help improve preventive measures to improve patients\u2019 outcomes.We agree with Onuigbo and Agbasi that previous studies have attempted to identify effective interventions to prevent postoperative acute kidney injury (AKI) events including cardiac surgery-associated AKI and most of them failed to be successful ,2. In thAll authors have contributed equally to the preparation of the manuscript.The authors declare no conflict of interest.Ethical issues have been completely observed by the authors.None."} +{"text": "Oncorhynchus spp.) carcasses might yield suitable DNA quality for noninvasive monitoring of brown bears (Ursus arctos). We compared the efficiency of monitoring brown bear populations using both fecal DNA and salivary eDNA collected from partially-consumed salmon carcasses in Southeast Alaska. We swabbed a range of tissue types from 156 partially-consumed salmon carcasses from a midseason run of lakeshore-spawning sockeye (O. nerka) and a late season run of stream-spawning chum (O. keta) salmon in 2014. We also swabbed a total of 272 scats from the same locations. Saliva swabs collected from the braincases of salmon had the best amplification rate, followed by swabs taken from individual bite holes. Saliva collected from salmon carcasses identified unique individuals more quickly and required much less labor to locate than scat samples. Salmon carcass swabbing is a promising method to aid in efficient and affordable monitoring of bear populations, and suggests that the swabbing of food remains or consumed baits from other animals may be an additional cost-effective and valuable tool in the study of the ecology and population biology of many elusive and/or wide-ranging species.Noninvasive genetic sampling is an important tool in wildlife ecology and management, typically relying on hair snaring or scat sampling techniques, but hair snaring is labor and cost intensive, and scats yield relatively low quality DNA. New approaches utilizing environmental DNA (eDNA) may provide supplementary, cost-effective tools for noninvasive genetic sampling. We tested whether eDNA from residual saliva on partially-consumed Pacific salmon ( Environmental DNA, or eDNA, has proven to be a comprehensive, noninvasive means of monitoring biodiversity, providing rapid, cost-effective, and efficient insights on species\u2019 distribution and abundance ,2. As a et al. , marten [Martes americana], etc.), particularly if the microsatellites used are shared among species. For example, the sex marker we used, SRY, amplifies in multiple mammalian species. Where contamination is possible, researchers should consider utilizing species-specific markers. Studies utilizing markers that overlap among species should ensure that all PCR replicates give consistent results. These considerations aside, saliva is a promising new source for bear DNA in salmon ecosystems.Additionally, because of the nature of bear feeding behavior, it is possible for carcasses to become contaminated with DNA from a second individual bear if scavenging occurs following the initial consumption event. In populations with high allelic diversity and heterozygosity, however, mixed samples should be detectable . ContamiWe found residual saliva collected from partially-consumed salmon carcasses to be a successful, labor- and cost-effective way to sample brown bear populations. As far as we are aware, this study is the first to use noninvasively collected saliva to estimate the population density of any species of wildlife. As we focused primarily on the methodology of saliva sampling in this study, we recommend that researchers looking to implement this technique as a method to monitor bear populations take into account potential capture heterogeneity and violation of assumptions for mark-recapture models that may arise due to differing levels of fishing success or consumption behaviors among individual bears.Although salmon carcasses provide a readily available source of saliva to aid in the monitoring of bear populations, baited saliva sampling should be easily generalizable to systematic surveys of carnivores if appropriate baits can be identified and tested . As an eS1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S1 FigNumber of samples that successfully genotyped versus number of unique individuals identified across all samples collected, with trendlines.(TIF)Click here for additional data file.S1 File(DOCX)Click here for additional data file."} +{"text": "Wolbachia (Alphaproteobacteria) and Spiroplasma (Mollicutes), are discussed. Although several general patterns of genome reduction associated with the adoption of symbiotic relationships could be identified, extensive variation was found among these facultative symbionts. These findings are incorporated into the established conceptual frameworks to develop a more detailed evolutionary model for the discussion of possible trajectories. In summary, transitions from facultative to obligate symbiosis do not appear to be a universal one-way street; switches between hosts and lifestyles occur frequently and could be facilitated by horizontal gene transfer.Symbiosis between organisms is an important driving force in evolution. Among the diverse relationships described, extensive progress has been made in insect\u2013bacteria symbiosis, which improved our understanding of the genome evolution in host-associated bacteria. Particularly, investigations on several obligate mutualists have pushed the limits of what we know about the minimal genomes for sustaining cellular life. To bridge the gap between those obligate symbionts with extremely reduced genomes and their non-host-restricted ancestors, this review focuses on the recent progress in genome characterization of facultative insect symbionts. Notable cases representing various types and stages of host associations, including those from multiple genera in the family Enterobacteriaceae (class Gammaproteobacteria), This review synthesizes the recent progress in genome characterization of insect-symbiotic bacteria, the emphases include (i) patterns of genome organization, (ii) evolutionary models and trajectories, and (iii) comparisons between facultative and obligate symbionts. None declared."} +{"text": "Morphological responses of nonmammalian herbivores to external ecological drivers havenot been quantified over extended timescales. Herbivorous nonavian dinosaurs are an idealgroup to test for such responses, because they dominated terrestrial ecosystems for morethan 155 Myr and included the largest herbivores that ever existed. The radiation ofdinosaurs was punctuated by several ecologically important events, including extinctionsat the Triassic/Jurassic (Tr/J) and Jurassic/Cretaceous (J/K) boundaries, the decline ofcycadophytes, and the origin of angiosperms, all of which may have had profoundconsequences for herbivore communities. Here we present the first analysis ofmorphological and biomechanical disparity for sauropodomorph and ornithischian dinosaursin order to investigate patterns of jaw shape and function through time. We find thatmorphological and biomechanical mandibular disparity are decoupled: mandibular shapedisparity follows taxonomic diversity, with a steady increase through the Mesozoic. Bycontrast, biomechanical disparity builds to a peak in the Late Jurassic that correspondsto increased functional variation among sauropods. The reduction in biomechanicaldisparity following this peak coincides with the J/K extinction, the associated loss ofsauropod and stegosaur diversity, and the decline of cycadophytes. We find no specificcorrespondence between biomechanical disparity and the proliferation of angiosperms.Continual ecological and functional replacement of pre-existing taxa accounts fordisparity patterns through much of the Cretaceous, with the exception of several uniquegroups, such as psittacosaurids that are never replaced in their biomechanical ormorphological profiles. Sauropodomorph and ornithischian dinosaurs were the foremost herbivorous terrestrialvertebrates of the Mesozoic Era in terms of species richness, abundance, and functionaldiversity in herbivorous nonavian dinosaursthrough time. This approach complements previous attempts to examine these questions thoughspatiotemporal comparisons of species-richness patterns and provides the only rigorousbiomechanically and functionally based analysis of these issues attempted to date. Wehypothesize that ornithischians and sauropodomorphs will show distinct morphologies andbiomechanical profiles . Wealso hypothesize that the shift in plant community structure after the J/K boundary willtrigger a corresponding shift in dinosaurian jaw biomechanical profiles, due to thediffering physiognomies, digestibility, and mechanical properties of the varied potentialfood plant clades that were ecologically important at different times throughout theMesozoic Bakker . We use Data for 2D landmark and biomechanical trait analyses were compiled from 167 sauropodomorphand ornithischian dinosaur taxa . Herbivorousnonavian theropods were excluded from this data set, as complete mandibular material forthese animals is rare. A mandibular biomechanical profile represents a good proxy forcharacterizing the feeding system, as the mandible is primarily adapted for feeding, whereasthe cranium has multiple functional roles, some of which are unrelated to feeding, such ashousing the brain and sensory organs in Past, Version 3 , with the exception of Stegosaurus (twospecies). Regions of overlap are occupied by a wide range of both basal and derivedsauropodomorphs; these include: Plateosaurus gracilis,Lamplughsaura, mamenchisaurids, brachiosaurids, and two SouthAmerican titanosaurids (Antarctosaurus andBonitasaura). Sauropodomorphs occupy morphospace exclusively in the\u2212PC1 region: this region is characterized by dorsoventrally narrow jaws and the lack ofa prominent coronoid process. Noneusauropod sauropodomorphs , for the most part,account for sauropodomorph occupation of morphospace in +PC2: this region is typified byvery narrow anterior jaws. Macronarian and diplodocoid taxa (includingDiplodocus and Tapuiasaurus) primarily occupy \u2212PC2regions of morphospace . Jaws in this region exhibit a greater gap betweenlandmarks 1 and 2 than in sauropodomorph morphospace (due to the presence of thepredentary in iguanodontians). Disparate groups of nonthyreophoran ornithischians expandmorphospace occupation into +PC1 and +PC2 (hadrosaurids) and \u2212PC2 regions(leptoceratopsids and psittacosaurids). +PC1 and +PC2 regions typically contain jawswith prominent coronoid processes and downwardly deflected predentaries; \u2212PC2 regionscontain robust, dorsoventrally broad jaws. Nonceratopsid marginocephalian jawmorphologies, such as those of psittacosaurids and leptoceratopsids, contribute stronglyto the expansion of ornithischian shape morphospace, predominantly into +PC1/\u2212PC2. Taxaare absent in a region of morphospace around +0.05 PC1/\u22120.075 PC2.Our results demonstrate that sauropodomorph and ornithischian jaws occupy significantlydifferent regions of morphological morphospace p<0.01; ; Table2phospace . The cenp<0.01; Pisanosaurus, heterodontosaurids) and basal members of Thyreophora, Marginocephalia (Yinlong),and Ornithopoda .Sauropodomorphs occupy regions of +PCo1. Noneusauropod sauropodomorphs predominate in+PCo1/\u2212PCo2. This region is characterized by jaws with a high mechanical advantage and alarge adductor muscle attachment area. Diplodocids, nonneosauropods, andnontitanosaurian macronarians stretch sauropodomorph occupation into +PCo2. Jaws inthis region also display high mechanical advantages, coupled with high aspect ratios.Many iguanodontian, ceratopsid, and psittacosaurid jaw profiles occupy similar regionsof +PCo2 biomechanical morphospace (Montanoceratops). This region of functional space is characterized bydeep jaws with short adductor muscle attachment and a high posterior mechanicaladvantage. Expansion into \u2212PCo2 is accounted for by deep-jawed ankylosaurs, with low tooth:jawdepth ratios and high relative dental length share areas ofbiomechanical morphospace with iguanodontians but occupy very different regions of shapespace that plots between nonhadrosaurid ornithopods andankylosaurians extend biomechanical morphospace occupation into theregion of morphospace characterized by deep mandibles with short adductor muscleattachment and high posterior mechanical advantages . By contrast,biomechanical disparity undulates through the Mesozoic . Thereare no significant differences in disparity between successive time bins for eitherbiomechanical or morphological disparity curves (at p=0.05) and nomarginal-likelihood values exceed the threshold value of 8. There are a few instanceswhere disparity diverges markedly from sample size, suggesting that a trend, albeitnonsignificant, might be observed. For example, morphological disparity rises in theEarly Cretaceous, immediately after the J/K extinction, and in the early LateCretaceous, while sample size drops. Likewise, biomechanical disparity drops in theMiddle Jurassic while sample size rises slightly. Conversely, in the latest Cretaceous,sample size rises sharply while biomechanical disparity drops very slightly.Morphological (shape) and biomechanical disparity measures are decoupled through theMesozoic . MorpholMesozoic , a decoun=5). The lack of manydinosaur-bearing formations between the Berriasian and Albian may partially account forthe low species richness observed in this interval, although it could also be attributedto the J/K extinction event , despite the former existing around 10Myr earlier: this pattern supports theresults of another recent quantitative craniodental study . Perhapssurprisingly, we find minimal convergent occupation in biomechanical morphospace betweentitanosaurids and diplodocids and titanosaurids with longer snouts and pencil-liketeeth (such as Antarctosaurus), and diplodocids are outliers in thisbiomechanical morphospace. This pattern supports quantitative work on sauropodomorphcranial morphology related to feeding, with similar placement of the same taxa incranial and Manidens(Heterodontosauridae) share occupation of Late Jurassic sauropodomorph biomechanicalmorphospace . This suggests that mandibles withsimilar gross morphology were biomechanically and functionally differentiated by thistime. In general, sauropodomorphs and heterodontosaurids occupy similar regions of bothshape-based and biomechanical morphospace and do not extend their occupation ofmorphospace beyond regions already occupied by the end of the Early Jurassic (Camptosaurus), which is also reflected in the morphological disparitycurve occupy novel regions of morphological andbiomechanical morphospace: these taxa share regions of biomechanical morphospace withhadrosauroids until the disappearance of basal marginocephalians prior to the last 20Myr of the Mesozoic (Triceratops) and leptoceratopsids . The biomechanical profiles of ceratopsids show nooverlap with those of hadrosaurids. This supports the conclusions of Mallon and Anderson leads to an increase in biomechanical disparity levels fromthe early Late Cretaceous. Marginocephalian, ornithopod, and thyreophoran biomechanicalmorphospace occupation in the latest Cretaceous suggests that these groups, whilevarying from each other in mandibular shape, also share a variety of functional andbiomechanical traits relating to feeding. Late Cretaceous hadrosaurids and ankylosauridsfilled the biomechanical roles vacated by Early Cretaceous nonhadrosaurid iguanodontiansand nodosaurids, respectively. Individual occupation of morphospace by each taxon can beviewed in Supplementary Figures 2\u20136.Early Cretaceous marginocephalians . The exclusion of the Morrisontaxa removes the Late Jurassic peak in biomechanical disparity .A similar jackknifing of the taxa from the Dashanpu Formation (including the \u201cUpper andLower Shaximiao\u201d formations) yielded a trough in disparity in the Middle Jurassic butretained a strong peak in the latest Jurassic . These resultssuggest that the data may be sensitive to the inclusion or exclusion of particularlyrich fossil-bearing sites. In addition, the lack of available jaw material from Northand South American titanosaurs seriously underrepresents sauropodomorph diversity in theCretaceous. The addition of titanosaurid taxa to the analysis may increase both thedisparity and overall morphospace occupation of sauropodomorphs, although the titanosaurjaws sampled in this study already account for a broad range of morphologies.When disparity tracks sample diversity closely, as it does in this study forshape-based disparity, sampling bias cannot be ruled out. Morphological disparity inthis study partly tracks jaw sample size, suggesting a potential bias in the data setfor some features of the disparity curve when compared with mid-browsing taxa , and almost equal in disparity to very low-browsingsauropodomorphs . This pattern contrasts with sample diversity, with thelowest sample size found in the high-browsing feeding envelope (n=6). Unfortunately, low sample sizes within each feeding levelprevent any significant differences or definitive conclusions to be made. However, thispattern remains intriguing and the addition of more mandibular remains from high- andmid-browsing taxa to our sample (as and when they are discovered) would complement thisstudy. This is an avenue of study that requires more investigation in the future toenable deeper insights into niche partitioning between sauropod groups based on maximumbrowse height.Supplementary analyses of biomechanical and shape-based disparity withinsauropodomorphs in relation to maximum feeding height show higher levels of disparity inhigh-browsing sauropods .The dip in biomechanical disparity after the J/K recovered by our analyses may,therefore, be an artefact due to either geological biases or uneven collection effort,underrepresenting the true diversity of jaw biomechanical profiles at this time. Due tothe lack of complete mandibles from rebbachisaurids, dicraeosaurids, and other clades,it is possible that the latest Jurassic and earliest Cretaceous disparity levelsreported herein are currently undersampling the total diversity of mandible morphologyand potential function. Such exclusions cannot be corrected for by our analyses andrepresent a limitation of the fossil material currently available.Udanoceratops), a group that is also present in North America. LateCretaceous hadrosaurids and ankylosaurids filled the biomechanical roles vacated by EarlyCretaceous nonhadrosaurid iguanodontians and nodosaurids respectively. Our results implythat, after the establishment of peak overall biomechanical variation in the latestJurassic, only marginocephalians demonstrated widespread variation in biomechanical profilesover time, triggered by the isolated adaptive radiations of psittacosaurids andleptoceratopsians. The remainder of Cretaceous herbivorous dinosaurs underwent progressiveniche replacement, with successive replacement by related taxa with comparable biomechanicalprofiles.For the first time, we have quantified the morphological and biomechanical variation ofornithischian and sauropodomorph jaws throughout the Mesozoic and examined how diversityrelated to external extrinsic drivers such as extinction events and the rise of angiosperms.We find that herbivorous dinosaur clades have jaws that occupy different regions ofmorphospace throughout the Mesozoic. Furthermore, sauropodomorphs and ornithischians havejaws that also function in broadly different ways, yet there is some potentially convergentoverlap in biomechanical function between different ornithischian clades in the Cretaceous.Basal members of each clade tend to be more similar in form and function to each other,while derived taxa are more functionally and morphologically divergent. Herbivorous dinosaurjaws maintained a numerically steady diversity of biomechanical traits, with a peak observedin the Late Jurassic triggered by the diversification of high-browsing sauropods. This isconsistent with a rapid evolutionary radiation in biomechanical diversity among herbivorousdinosaurs followed by a plateau. The Tr/J extinction had no overall effect on biomechanicalvariation among herbivorous dinosaurs, despite fundamental changes in floral and faunalcomposition across the boundary. This consistency suggests that Early Jurassic dinosaursfilled the functional feeding niches vacated by the extinction of Late Triassic taxa.Similar successive replacement patterns are also seen in Devonian gnathostomes and Devonianto mid-Pennsylvanian tetrapodomorphs (Anderson et al."} +{"text": "The prognosis for children with high-risk neuroblastoma is often poor and survivors can suffer from severe side effects. Predictive preclinical models and novel therapeutic strategies for high-risk disease are therefore a clinical imperative. However, conventional cancer cell line-derived xenografts can deviate substantially from patient tumors in terms of their molecular and phenotypic features. Patient-derived xenografts (PDXs) recapitulate many biologically and clinically relevant features of human cancers. Importantly, PDXs can closely parallel clinical features and outcome and serve as excellent models for biomarker and preclinical drug development. Here, we review progress in and applications of neuroblastoma PDX models. Neuroblastoma orthotopic PDXs share the molecular characteristics, neuroblastoma markers, invasive properties and tumor stroma of aggressive patient tumors and retain spontaneous metastatic capacity to distant organs including bone marrow. The recent identification of genomic changes in relapsed neuroblastomas opens up opportunities to target treatment-resistant tumors in well-characterized neuroblastoma PDXs. We highlight and discuss the features and various sources of neuroblastoma PDXs, methodological considerations when establishing neuroblastoma PDXs, in vitro 3D models, current limitations of PDX models and their application to preclinical drug testing. One of the main reasons for the high attrition rate in oncology drug development is a lack of preclinical models that recapitulate the genotype and phenotype of the patient\u2019s disease. Xenografts based on conventional cancer cell lines have been used for decades and while this model system can provide valuable data, cultured cell lines that have adapted to the in vitro microenvironment often differ from the original tumor found in patients. Specifically, the addition of fetal calf serum to the culture medium can lead to cellular differentiation and significant genetic aberrations are generated from the subcutaneous or orthotopic implantation of intact patient tumor fragments directly into immunodeficient mice or rats, thereby avoiding in vitro adaptation. The concept of PDXs has been around for decades but interest in PDXs has recently increased due to greater insights into the limitations of classical xenografts and the development of personalized cancer medicines based on genomic profiling. Thus, PDXs have been established and characterized for various malignant tumor types including breast cancer, malignant melanoma, colorectal cancer, pancreatic adenocarcinoma, non-small cell lung cancer and more implemented the Pediatric Preclinical Testing Program (PPTP), which generated hundreds of pediatric subcutaneous tumor xenografts including neuroblastomas. Importantly, many of these xenografts were established at relapse following multi-modal chemotherapy. Several anti-cancer agents have been tested in the PPTP using in vivo and in vitro models and the effects of some of these agents are consistent with their known clinical activity , neuroblastoma protein markers , cellular differentiation status and proliferative index of their corresponding patient tumors. In contrast to many conventional cell-derived xenografts, PDOXs invade the surrounding tissues. Importantly, PDOXs spontaneously metastasize to the liver, lungs and bone marrow through implantation of either fresh or viably cryopreserved na\u00efve and relapsed high-risk neuroblastoma tumor fragments , the Targeting Of Resistance in PEDiatric Oncology program , the IMI2 ITCC-P4 program (http://cordis.europa.eu/project/rcn/210764_en.html) and the recently established NCI-funded Pediatric Preclinical Testing Consortium are other programs that aim to establish and characterize pediatric PDXs. In addition, The EuroPDX consortium, although mainly focused on adult cancers, has started to include pediatric PDXs (http://www.europdx.eu/).The Childhood Solid Tumor Network (CSTN) at St Jude Children\u2019s Research Hospital has established and characterized a number of pediatric cancer PDXs including neuroblastoma PDOXs. These PDOXs have undergone comprehensive molecular characterization including genomic and epigenomic analyses as well as drug sensitivity testing using short-term cultured cells , or tumor stroma, is critical for cancer progression, metastasis and treatment resistance tumor cells in serum-free medium requires more experience, patience and time compared to classical serum-cultured cell lines. However, in light of the aberrant changes seen in serum-cultured cells and the preservation of molecular features in cells cultured in 3D in serum-free medium, we believe that this is well worth the effort. Furthermore, 3D-cultured human tumor cells provide a means to implement the important principles of the 3Rs to minimize animal experimentation.Despite the promise of PDX models, they also have their limitations: (1) an abnormal immune system in the host mice, (2) the murine tumor microenvironment and (3) tumor heterogeneity. First, athymic nude mice lack functional T cells, NOD-scid mice lack functional T and B cells, while the NOD-scid-gamma (NSG) strain lack functional T, B and NK cells. The immunosuppressed status of these mice precludes immunotherapy testing until methods have been established to reconstitute the human immune system in the animals. It is conceivable that other therapeutic strategies also affect immune cells, a parameter not included in xenograft studies. Attempts are being made to reconstitute the human immune system in mice by injection of human hematopoietic stem cells contain various subclones with different genotypes resulting in intratumoral heterogeneity , MAPPYACTS , SMPaeds, iTHER and INFORM , the IMI2 ITCC-P4 program (http://cordis.europa.eu/project/rcn/210764_en.html) and the EU funded Targeting Of Resistance in PEDiatric Oncology program . Genomics analyses of relapsed neuroblastomas indicate that such treatments could include inhibition of ALK and the RAS-MAPK pathway, YAP inhibition and/or pathways involved in EMT are stored in ice-cold medium and cryopreserved through stepwise cooling in cryopreservation medium. These cryopreserved and viable samples can be stored and/or shipped on dry ice to another laboratory for implantation. We have previously shown that it is feasible to establish PDOXs from cryopreserved high-risk neuroblastoma samples (Braekeveldt et al. Clearly, establishing additional neuroblastoma PDXs from relapsed or post-mortem tumors would be very useful for testing therapies against treatment-resistant disease. Collection and injection of circulating tumor cells can also add value to the PDX model system (Girotti et al. Non-dissociated tumor fragments are commonly utilized to establish and serially propagate PDXs. As discussed above, cell culturing can lead to molecular and phenotypic deviations from the original patient tumor (Baysan et al. There is a possibility of contamination of tumor cells. First, patient tumor cell cultures can easily be contaminated with EBV-infected B lymphoblasts from the same patient tumor sample. Unfortunately, proliferative EBV lymphoblasts can, after prolonged culturing or in vivo growth, completely overgrow the tumor cells (Bondarenko et al. The site of implantation/injection will affect the features of established tumors. In experiments comparing subcutaneous injection of neuroblastoma cells versus orthotopic injection into the adrenal gland, orthotopic tumors retained a more relevant biological phenotype and spontaneous metastases to distant organs (Khanna et al. Not all patient tumor samples engraft in mice. The tumor engraftment rate using orthotopic implantations is around 50% (Braekeveldt et al. A final issue relates to the choice of mouse strain. Traditionally, patient samples have been implanted into athymic nude mice or scid mice to establish patient xenografts. We and others utilized severely immunodeficient NSG mice lacking T, B and NK cells, based on the assumption that these mice are more permissive to tumor engraftment due to their immunosuppressed status. Indeed, injection of patient-derived malignant melanoma cells results in much higher engraftment in NSG mice compared to NOD-scid mice (Quintana et al. There are a number of methodological issues regarding the establishment and use of PDXs as preclinical neuroblastoma models. Here, we discuss eight important issues that researchers using or intending to use these models might wish to consider.Subcutaneous and orthotopic neuroblastoma PDXs have been established at various institutions internationally and these PDXs retain the molecular and phenotypic features of patient tumors. Furthermore, neuroblastoma PDOXs retain robust spontaneous metastatic capacity and are therefore excellent models for targeting neuroblastoma metastasis. PDXs from various tumor types can predict clinical outcome, making them extremely good models for biomarker and preclinical drug development. Neuroblastoma PDXs might thus play an important role for personalized and precision medicine strategies against treatment-resistant disease, especially given our recent understanding of the genomic changes associated with relapsed neuroblastomas. However, establishing and characterizing additional PDXs from high-risk and relapsed tumors is crucial to cover the different biological subsets of high-risk neuroblastoma. Furthermore, initiation of a global clinical academic collaboration to include and share all existing neuroblastoma PDXs would increase the utility of these promising models. Despite their limitations, neuroblastoma PDXs hold promise to improve the treatment of children with high-risk metastatic neuroblastoma."} +{"text": "A 32-year-old female with a history of cholecystectomy three years prior, presented to the emergency department with epigastric pain. Liver function tests (LFTs) were abnormal , however ultrasound (US) imaging was negative for gallbladder pathology and the patient was discharged home with normal vital signs and instructed to follow up in two days if symptoms persisted. At her follow up visit, her LFTs worsened and the patient underwent a magnetic resonance cholangiopancreatography (MRCP) which showed a dilated common bile duct (CBD) with filling defect suspicious of stone . The patApproximately 5% of patients who have undergone cholecystectomy continue to have symptoms of abdominal pain, vomiting, dyspepsia, loose stool, and are thought to suffer from postcholecystectomy syndrome (PCS).1CBD stones are a serious complication after cholecystectomy, therefore the diagnosis of PCS must always be considered in patients status post cholecystectomy with upper abdominal pain.What do we already know about this clinical entity?Magnetic resonance cholangiopancreatography (MRCP) identifies retained stones in patients with prior gallbladder surgery, however MRCP is not a tool readily available to emergency physicians.What is the major impact of the image(s)?Given the wealth of information provided, perhaps MRCP imaging can be incorporated as part of a routine postcholecystectomy syndrome (PCS) workup and help to limit unnecessary hospital admissions.How might this improve emergency medicine practice?MRCP imaging can help to improve diagnostic capabilities for patients suffering from PCS presenting to the emergency department."} +{"text": "Autism spectrum disorder (ASD) is characterized by deficits in social functioning and language and communication, with restricted interests or stereotyped behaviors. Anatomical differences have been found in the parietal cortex in children with ASD, but parietal subregions and associations between Sylvian fissure (SF) and parietal anatomy have not been explored. In this study, SF length and anterior and posterior parietal volumes were measured on MRI in 30 right-handed boys with ASD and 30 right-handed typically developing boys (7\u201314 years), matched on age and non-verbal IQ. There was leftward SF and anterior parietal asymmetry, and rightward posterior parietal asymmetry, across groups. There were associations between SF and parietal asymmetries, with slight group differences. Typical SF asymmetry was associated with typical anterior and posterior parietal asymmetry, in both groups. In the atypical SF asymmetry group, controls had atypical parietal asymmetry, whereas in ASD there were more equal numbers of individuals with typical as atypical anterior parietal asymmetry. We did not find significant anatomical-behavioral associations. Our findings of more individuals in the ASD group having a dissociation between cortical asymmetries warrants further investigation of these subgroups and emphasizes the importance of investigating anatomical relationships in addition to group differences in individual regions."} +{"text": "Sunitinib, a multityrosine kinase inhibitor, is currently the standard first-line therapy in metastatic renal cell carcinoma (mRCC) and is also used in treating patients with pancreatic neuroendocrine and imatinib-resistant gastrointestinal stromal tumors (GIST). Nevertheless, most patients eventually relapse secondary to intrinsic or acquired sunitinib resistance. Autophagy has been reported to contribute to both chemo-sensitivity and -resistance. However, over the last few years, controversial regulatory effects of sunitinib on autophagy have been reported. Since gaining insights into the underlying molecular insights and clinical implications is indispensible for achieving optimum therapeutic response, this minireview article sheds light on the role of a network of prosurvival signaling pathways recently identified as key mediators of sunitinib resistance with established and emerging functions as autophagy regulators. Furthermore, we underscore putative prognostic biomarkers of sunitinib responsiveness that could guide clinicians toward patient stratification and more individualized therapy. Importantly, innovative therapeutic strategies/approaches to overcome sunitinib resistance both evaluated in preclinical studies and perspective clinical trials are discussed which could ultimately be translated to better clinical outcome. Following the initial breakthrough success of imatinib, the first FDA-approved tyrosine kinase inhibitor(TKI), TKIs were deemed to revolutionize cancer therapy. Nevertheless, emergence of imatinib-resistance prompted development of novel structurally distinct TKIs is a central player has been linked to tumorigenesis and Mcl-1 protein levels could serve as markers that predict sunitinib response. Additionally, elevated IncARSR levels in pre-treatment RCC patients significantly correlated with poor sunitinib response. In contrast, low IncARSR levels conferred improved progression-free survival and favorable prognosis following sunitinib therapy Ideally, though not easily achievable in clinical practice, tailoring sunitinib dose per each patient based on their response should select patients that need escalation of sunitinib dose to reach cytotoxic effects at tolerable doses. Rovithi et al. showed that an alternating schedule of high sunitinib efficiently impaired tumor growth (ii) Alternatively, pharmacological targeting of Mcl-1 and mTOR presents a promising strategy in combating/reversing sunitinib resistance. It is worth mentioning that FDA has already approved sequential treatment of sunitinib-resistant mRCC patients with everolimus, mTOR inhibitor. In addition, a phase I clinical trial aiming at determining the highest tolerable dose of \u201csunitinib and temsirolimus (mTOR inhibitor)\u201d combination that could be administered to mRCC patients has lately been completed. There are also parallel clinical trials testing the efficacy of sorafenib in treating sunitinib-resistant mRCC and GIST patients. Yet, the clinical outcome of combining sunitinib and Mcl-1 and/or mTOR inhibitor in sunitinib-resistant patients remains to be investigated. Consistent with the emerging role of MET and AXL signaling in mediating sunitinib resistance, combining a small molecule inhibitior of both MET and AXL, BMS777607, with sunitinib both suppressed the growth of sunitinib-resistant RCC xenografts and prevented the emergence of sunitinib resistance and lysosomal dysfunction (owing to sunitinib sequestration and hence inactivation). Both events acted as pro-survival adaptive responses that compromised the anticancer activity of sunitinib. Conversely, cytotoxic sunitinib levels destabilized Mcl-1, inhibited mTORC1 and activated autophagy. Hence, this may mechanistically resolve the previously described discrepancy in terms of \u201cON/OFF\u201d autophagy regulation by sunitinib. Gaining deeper mechanistic insights into sunitinib resistance would provide better prognostic biomarkers that could guide clinicians toward patient stratification and more individualized therapy. Importantly, this would offer more innovative therapeutic strategies/approaches to overcome sunitinib resistance which could ultimately be translated to a better clinical outcome.AKA conceived and wrote the manuscript. ABA, SS, SM, and ME revised the manuscript. SM and ME reviewed the outline and content of the manuscript. All authors have read and approved the submitted manuscript for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Reinforcement learning involves flexible adaptation towards a changing environment and is driven by dopaminergic reward prediction error \u2013 expectation (Q)) signaling in the midbrain and projecting regions, such as the ventral striatum . Schizophrenia patients show heightened dopamine levels in the striatum as well as deficits in reinforcement learning which may be mediated by disrupted prediction error signaling . Using model-based fMRI, the present study aims to assess these neural signals during a reversal learning paradigm in unmedicated schizophrenia patients and healthy individuals.In the current study, 19 schizophrenia patients and 23 age- and gender-matched healthy controls completed a reversal learning paradigm during fMRI scanning where subjects had to choose between two neutral stimuli to maximize their reward. A Rescorla Wagner learning model was fitted against the individual choice data using a softmax function. Individual RPE trajectories from the fitted Rescorla Wager learning model were correlated with the BOLD response during feedback onset. Parameter estimates of ventral striaral RPE trajectories were correlated with psychopathology scores from the PANSS .In the reversal learning task, schizophrenia patients chose the correct stimulus less often compared to healthy individuals . Across all participants, the RPE trajectories correlated with BOLD response in the bilateral ventral striatum . Schizophrenia patients displayed decreased RPE coding in the right ventral striatum compared to healthy individuals . In patients, extracted parameter estimates from the right ventral striatum correlated negatively with the PANSS total symptoms score .We found that unmedicated schizophrenia patients performed worse in the reversal learning task and displayed decreased striatal prediction error signaling. This neural deficit was increased in patients with overall higher symptom severity. While RPE coding seems to be intact in patients receiving antipsychotic medication , our findings are in line with previous studies in unmedicated schizophrenia patients . Therefore, deficient neural coding of this core reinforcement learning mechanism may reflect a characteristic of the disorder of schizophrenia and does not result from antipsychotic medication."} +{"text": "Following a stroke, the resulting lesion creates contralateral motor impairment and an interhemispheric imbalance involving hyperexcitability of the contralesional hemisphere. Neuronal reorganization may occur on both the ipsilesional and contralesional hemispheres during recovery to regain motor functionality and therefore bilateral activation for the hemiparetic side is often observed. Although ipsilesional hemispheric reorganization is traditionally thought to be most important for successful recovery, definitive conclusions into the role and importance of the contralesional motor cortex remain under debate. Through examining recent research in functional neuroimaging investigating motor cortex changes post-stroke, as well as brain-computer interface (BCI) and transcranial magnetic stimulation (TMS) therapies, this review attempts to clarify the contributions of each hemisphere toward recovery. Several functional magnetic resonance imaging studies suggest that continuation of contralesional hemisphere hyperexcitability correlates with lesser recovery, however a subset of well-recovered patients demonstrate contralesional motor activity and show decreased functional capability when the contralesional hemisphere is inhibited. BCI therapy may beneficially activate either the contralesional or ipsilesional hemisphere, depending on the study design, for chronic stroke patients who are otherwise at a functional plateau. Repetitive TMS used to excite the ipsilesional motor cortex or inhibit the contralesional hemisphere has shown promise in enhancing stroke patients' recovery. Stroke remains a leading cause of long-term disability , Action Research Arm Test (ARAT), and Stroke Impact Scale (SIS) ], saw significant motor gains associated with increased ipsilesional M1 recruitment with their experimental group as compared to control (Ramos-Murguialday et al., Reasons for the differences found in the BCI studies probably relate to the BCI/BMI designs and the patient exclusion criteria. For instance, Young and Song recruited patients with a greater range of severity of motor impairments than Ramos (Ramos-Murguialday et al., Overall, multiple BCI studies have found improved motor function for the severely impaired stroke patient correlated with contralesional M1 recruitment (Song et al., TMS therapy can inhibit or excite targeted brain regions, and applications of this technique may encourage stroke rehabilitation Hallett, without Another method to regain interhemispheric balance and improve recovery is to excite the ipsilesional side with TMS (Talelli et al., A few studies have compared inhibiting the contralesional hemisphere to exciting the ipsilesional side through rTMS although the results remain inconclusive. Khedr et al. comparedMajor factors influencing unilateral recovery post-stroke appear to include chronicity, as well as lesion size and location. Increases in unilateral ipsilesional M1 activation for movement on the affected side appears to positively correlate with chronicity, especially for well-recovered patients (Ward et al., BCI training demonstrates potential in assisting with motor recovery for stroke sufferers who have reached a functional plateau following traditional rehabilitation. Evidence suggests that this therapy, even for chronic stroke sufferers, may induce neuromodulatory changes that enhance motor function. Both BCI designs that demonstrate development of the contralesional M1, as well as designs that increase ipsilesional M1 activity, appear to enhance motor recovery. It is currently unclear if either type of BCI design is superior to the other for all, or certain subsets of, patients.Meanwhile, TMS is an effective and safe tool for research into this field and offers promising potential to be utilized for rehabilitation. TMS studies confirm that increased contralesional M1 activity as compared to the ipsilesional M1 is associated with lesser clinical outcome. Some TMS research suggests that for some well-recovered stroke patients contralesional corticomotor excitability does not decrease, but rather only the ipsilesional corticomotor excitability increases with recovery (Stinear et al., Both inhibition of the contralesional side and excitation of the ipsilesional side appear effective for motor recovery post-stroke. A few studies suggest that contralesional inhibition may be slightly more effective than ipsilesional M1 excitation although this is not seen throughout the literature. Initial degree of motor impairment and chronicity (Rose et al., Current evidence favors ipsilesional M1 excitation and development to be the most important for stroke recovery over contralesional hemispheric recruitment. However, the contralesional side does appear to play a significant role for at least a subset of stroke patients and some research suggests that certain BCI paradigms targeting the contralesional hemisphere may be beneficial for motor recovery. It is important to note the numerous confounding variables that require more research to completely understand their effects including lesion location and size, and chronicity.KD wrote the manuscript, VN and VP reviewed and edited it, and provided key guidance.VP has a pending US patent on the closed-loop neurofeedback used for BCI-facilitated intervention, application number 12/715090. The patent was filed jointly by VP and J. Williams. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Prehistoric human activities have contributed to the dispersal of many culturally important plants. The study of these traditional interactions can alter the way we perceive the natural distribution and dynamics of species and communities. Comprehensive research on native crops combining evolutionary and anthropological data is revealing how ancient human populations influenced their distribution. Although traditional diets also included a suite of non-cultivated plants that in some cases necessitated the development of culturally important technical advances such as the treatment of toxic seed, empirical evidence for their deliberate dispersal by prehistoric peoples remains limited. Here we integrate historic and biocultural research involving Aboriginal people, with chloroplast and nuclear genomic data to demonstrate Aboriginal-mediated dispersal of a non-cultivated rainforest tree.Castanospermum australe (Fabaceae), a non-cultivated culturally important riparian tree that produces toxic but highly nutritious water-dispersed seed. We validated cultural evidence of recent human-mediated dispersal by revealing genomic homogeneity across extensively dissected habitat, multiple catchments and uneven topography in the southern range of this species. We excluded the potential contribution of other dispersal mechanisms based on the absence of suitable vectors and current distributional patterns at higher elevations and away from water courses, and by analyzing a comparative sample from northern Australia.We assembled new anthropological evidence of use and deliberate dispersal of Innovative studies integrating evolutionary and anthropological data will continue to reveal the unexpected impact that prehistoric people have had on current vegetation patterns. A better understanding of how traditional practices shaped species\u2019 distribution and assembly will directly inform cultural heritage management strategies, challenge \u201cnatural\u201d species distribution assumptions, and provide innovative baseline data for pro-active biodiversity management. Studies of prehistoric human influences on the Australian vegetation have primarily centered around broad-scale change associated with the practice and cessation of Aboriginal burning , 2] and and2] anLivistona mariae in central Australia ..C. austrCastanospermum australe (black bean) is distributed along coastal eastern Australia, from Cape York to subtropical northern New South Wales . ). Castanredation . These credation , as wellredation .Our sampling strategy within the context of local Aboriginal dispersal focused on sites representing the species\u2019 southern distributional margin in northern New South Wales and was not intended to exhaustively represent all populations to explore continent-wide connectivity, or broader biogeographic questions. Sampling was undertaken under a Scientific Licence (#100569), Section 132c of the National Parks and Wildlife Services Act 1974 issued by the New South Wales Office of Environment and Heritage (sampling did not involve endangered or protected species). The objective was to ensure sufficient geographic representation across the main NNSW catchment areas in order to investigate genomic homogeneity vs. genomic heterogeneity hypotheses. Highly homogeneous maternally-inherited plastid genomes across the study area, would suggest rapid and recent dispersal from a small founder event, while plastid heterogeneity would suggest lengthier local persistence and / or multiple founder events. The focus on NNSW was influenced by the current paucity of local disperser fauna and absence of megafauna , and by Casuarius casuarius johsonii). This northern area also has an extended archaeological record of the use of C. australe\u2019s seeds de de26] de the AWT , 21], [, [C. aus the AWT includinRecent mitochondrial DNA studies revealed that Aboriginal people have inhabited Australia in consistent geographic arrangements for up to 50,000 years . ContinuC. australe in NNSW seeds as he journeyed inland from the east coast to the western Ranges . Common inheritance from the MRCA results in Bandjalangic vocabulary being inherited with only few sound changes [C. australe is uniformly bugam. This is in contrast with the rest of the distribution of C. australe where the terms exhibit little homology, even within members of the same low-level clade such as the Djirbalic languages from the AWT is likely to be close to 1,500 years old , catchments and regions. Analyses of sequence data across 96 individual trees from 12 distinct sites yielded 987 cpDNA SNPs and 29 nrDNA SNPs . None of these 12 sites yielded within-site cpDNA variability, suggesting that all eight individuals sampled within each population originated from a single maternal lineage. The nrDNA sequences produced between four and 12 heterozygotic variants across 5,813bp, confirming a pattern of low within-population diversity and 5,813bp of nuclear ribosomal DNA (nrDNA) were analysed and compared among iversity .C. australe [C. australe is unlikely to favor rapid water-mediated inland expansion and topographically complex area , and a single founder lineage would have rapidly expanded to its current distribution as habitat became increasingly available. Environmental niche models representing the availability of climatic conditions suitable to C. australe during the LGM suggest that available habitat is likely to have increased in the current interglacial period, and that environmental suitability in the south remains marginal compared to the north cannot be excluded. However oceanic currents, tidal processes, extreme weather events or river capture cannot explain the location of multiple sites inland and well above current and historical sea level . SecondaC. australe is therefore at odds with its large, toxic and reward-free seeds. Even within the AWT, where the highest diversity of frugivorous animals persists , the high genetic divergence measured between neighbouring catchments in collaboration with Aboriginal knowledge custodians.The new, combined evidence presented supports the deliberate dispersal of Cosgrove suggesteEvidence of prehistoric Australian Aboriginal people dispersing plant propagules for their direct need and benefit also significantly challenges assumptions of \u201cnatural\u201d plant distributions, requiring reassessment of distributional interpretations that omit the possible impact of prehistoric human intervention . CurrentC. australe, future studies can explore broader biogeographic questions including possible dispersal routes along eastern Australia and across the Pacific Islands. A scenario of long-distance dispersal by ancestors from the north was independently put forward by Aboriginal knowledge custodian Uncle Ron Heron Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file.S4 Appendix(DOCX)Click here for additional data file.S5 Appendix(DOCX)Click here for additional data file.S6 Appendix(MP4)Click here for additional data file."} +{"text": "The whole-genome sequences of eight fungal strains that were selected for exposure to microgravity at the International Space Station are presented here. These baseline sequences will help to understand the observed production of novel bioactive compounds. In a screening project of natural products, fungal strains isolated from environments associated with the Chernobyl nuclear power plant (ChNPP) accident have beeAspergillus niger, an industrially important filamentous fungus, contains a sequence resembling the fumonisin gene cluster, which suggests that the fungus has the genetic potential to produce carcinogenic fumonisins . Data frThis whole-genome shotgun project has been deposited in DDBJ/ENA/GenBank under the accession numbers given in"} +{"text": "Patients with intractable temporal lobe epilepsy (TLE) undergo surgical resection of the anterior temporal lobe. Preoperative assessment of TLE patients involves a multidisciplinary assessment and may involve the use of invasive electroencephalogram (EEG) recording for lateralization of seizure focus in ambiguous cases. Understanding the white matter fibre tracts affected in TLE may assist in preoperative lateralization and planning. We studied pre- and postoperative white matter fibre tract changes in six patients with TLE who underwent surgical resection. Our results indicate that changes in the corpus callosum are highly specific, with the ability to lateralize the epileptogenic side in 100% of our patients (six of six). Contralateral changes were found in all patients with variable involvement of white matter tracts. Postoperatively, most patients (five of six) exhibited further changes to the tracts on the\u00a0ipsilateral side, with three patients showing contralateral abnormalities. We provide a detailed assessment of pre- and postoperative white matter fibre tracts in patients with TLE\u00a0and confirm that abnormalities in the ipsilateral corpus callosum may aid in preoperative lateralization and obviate the need for invasive EEG monitoring. Approximately 20% of patients with temporal lobe epilepsy (TLE) are refractory, exhibiting no response to anti-epileptic drugs . A subseThis study was approved by our Human Resources Ethics Committee via Institutional Review Board. The study included six patients with a\u00a0history of epilepsy resistant to anti-seizure medication . Clinicopathological data are summarized in Table We performed whole-brain tractography using the BrightMatter\u2122 System neurosurgical planning system, which performs automated processing of T1-weighted anatomical images and diffusion-weighted images to perform skull-stripping, co-registration, diffusion tensor fitting, and whole brain tractography. Specific bundles were assessed through 1) modulating the tract filtering slide bars, 2) displaying tracts in specific orthogonal planes, and 3) filtering tracts according to the intersection with a surgical trajectory.Qualitative assessment was performed by the study author (FS) assessing reconstructed tracts on superimposed three-dimensional (3D) T1-weighted images and the methodology was verified by a neuroradiologist (MS). The anatomic course of each fibre was verified in axial, coronal, and sagittal planes. The healthy side was compared to the contralateral epileptogenic side. The preoperative and postoperative images and tracts were also evaluated for differences. In the postoperative patients, thinning was documented if there was additional thinning compared to the preoperative images only. Tract thinning between hemispheres was assessed by first isolating the tract using appropriate coronal or axial slices, then sweeping the tract reduction (thresholding) sliders across their extents, while assessing whether any asymmetries exist.\u00a0Assessment parameters included macroscopic white matter tract dislocation or thinning. The abnormalities were documented in the ipsilateral and contralateral sides in the preoperative and postoperative images\u00a0and compared.All patients underwent surgical resection following planning by a multidisciplinary team of epilepsy neurologists and neurosurgeons. Mesial temporal resection included the amygdala and anterior part of the hippocampus. Postoperative pathology was concordant with preoperative MRI findings in four patients with mesial temporal sclerosis (MTS). Two patients demonstrated non-specific gliosis.The white matter tracts evaluated for this study are the corpus callosum (CC), fornix (F), cingulum (C), superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), arcuate fasciculus (AF), uncinate fasciculus (UF), inferior fronto-orbital fasciculus (IFOF), optic radiations (OR), corona radiata (CR), and corticospinal tracts (CST). Abnormalities in preoperative studies included thinning of white matter tracts on the side ipsilateral to the epileptogenic side (six patients), the contralateral side (six patients), or bilateral abnormalities (six patients) were appreciated in some tracts as specified below. The details are recorded in Table All six patients exhibited thinning and disruption of the corpus callosum in the ipsilateral side\u00a0with no documented abnormalities in the contralateral side Figure . AdditioNew or further thinning and disruption of ipsilateral white matter tracts were present in four patients. Table Recent DTI studies have demonstrated abnormalities within several white matter tracts in patients with TLE . The curWe evaluated six patients with TLE who underwent resection of the mesial temporal lobe for drug-resistant epilepsy. Fiber tract thinning and asymmetry was found in both the ipsilateral and contralateral sides to the seizure focus. Assessment of pre- and post-surgical white matter fiber bundles by MR imaging tractography revealed abnormalities in all 11 tracts studied. Pre-surgically, all patients demonstrated asymmetry in the white matter tracts within their ipsilateral corpus callosum, with most patients (five of six) exhibiting ipsilateral changes in the fornix, cingulum, uncinate process, and the CSTs. The strong association of ipsilateral thinning of the corpus callosum fibers, mainly along with the described abnormalities, may provide further lateralizing information and aid in the\u00a0determination of the epileptogenic side. Tractography may serve as an additional tool in the\u00a0preoperative assessment of patients in whom the epileptogenic focus is indeterminate and may obviate the need for invasive EEG recording, including subdural and depth electrodes.Our findings are in keeping with previous studies that showed abnormalities in the cingulum, fornix, and corpus callosum to provide distinctive diffusion indices in patients with TLE with the ability to distinguish the pathological side . Nazem-ZPostoperative assessment of the white matter fiber tract showed the\u00a0progression of preoperative abnormalities or new fiber tract abnormalities, most prominently in the OR and CR, as expected. These fibers course through the temporal lobe\u00a0and surgical resection impacts the anatomy and function. Ipsilateral abnormalities in postoperative patients can be directly attributed to resection of the\u00a0surgical lesion. The abnormalities were not, however, limited to the ipsilateral temporal lobe, concordant with previous findings of widespread changes in TLE patients who undergo resection . DegradaInvestigators have found more widespread contralateral and bilateral abnormalities in patients with left TLE, with more ipsilateral abnormalities in patients with right TLE . We founThe corpus callosum is a major interhemispheric tract that is essential in cognitive functions, and previous DTI studies have reported a high specificity for asymmetrical interruption of ipsilateral corpus callosum for lateralization of epilepsy. In our series, only one patient demonstrated changes to the contralateral corpus callosum postoperatively. The connections that exist between the corpus callosum and the temporal lobe may contribute to these postoperative abnormalities. Fiber tracts that originate from hippocampal formation and amygdala, which are involved in epileptogenesis and connections to other ipsilateral and contralateral anatomical structures, play an essential role in spreading neuronal activity during seizures and are altered in patients with TLE. Recently, reorganization of language tracts in the contralateral non-dominant hemisphere following resection of the anterior temporal lobe has been demonstrated , in keepThis small case series suggests the potential for the specificity of corpus callosum thinning in the ipsilateral side to the epileptogenic focus in patients with TLE for lateralization. All patients exhibited ipsilateral thinning and disruption of the corpus callosum preoperatively compared to the contralateral side. Therefore, preoperative whole brain tractography may be considered as an additional tool to complement EEG and clinical assessment in cases with an ambiguous seizure side, potentially obviating the need for invasive EEG recordings. We also demonstrated bilateral changes in pre- and postoperative patients, in keeping with the diffuse connectivity network involved in temporal lobe epileptogenesis and propagation. Further studies are underway to include inter-rater reliability assessment and correlation with quantitative evaluation."} +{"text": "The electrocardiogram (ECG) is an essential investigation in the evaluation of chest pain in the emergency room (ER). Correct interpretation of the ECG findings, determines the diagnosis and management strategy. This ECG spot diagnosis will improve the skills of the residents and physicians working in ER. A 46-year-old man, who was earlier in sinus rhythm, presented with anginal type of chest pain of three hours duration. The electrocardiogram recorded in emergency room (ER) is shown in The electrocardiogram shows ST segment elevation in inferior leads suggesting inferior wall myocardial infarction. The underlying rhythm is atrial fibrillation. The irregularly, irregular R-R interval coupled with the continuously varying morphology of the fibrillatory waves establishes the diagnosis of atrial fibrillation. Though the rhythm appears like atrial flutter, this is unlikely due to the above mentioned reasons. Atrial flutter is characterized by undulating sawtooth like monomorphic flutter waves and the R-R interval is regularly, irregular due to fixed heart block. The varying atrioventricular block results in long-short cycle sequences that are followed by QRS complexes with increased width 130 msec) (indicated by * in 30 msec (Atrial fibrillation complicating inferior wall myocardial infarction with intermittent ventricular premature beats.As the fast, irregular ventricular response aggravates myocardial ischemia, reverting to sinus rhythm is mandatory. Since it is a new onset atrial fibrillation, electrical cardioversion can be done safely. The patient also requires reperfusion of the infarct related coronary artery at the earliest. He underwent successful fibrinolysis and electrical cardioversion to sinus rhythm. Post cardioversion he was started on oral beta-blocker therapy. The further in hospital course was uneventful and he continued to be in sinus rhythm at 4 months of follow-up.Atrial fibrillation complicating acute myocardial infarction is associated with increased morbidity and mortality. The proposed mechanism of atrial fibrillation in acute myocardial infarction includes congestive heart failure, ischemia and infarction of the conduction system, atrial infarction or ischemia, and vagal reflexes or increased sympathetic activity . ElectriIn conclusion, electrocardiographic recognition of atrial arrhythmias is important to risk stratify acute coronary syndrome patients. Identification and prompt treatment of atrial arrhythmias improve outcomes."} +{"text": "Arabidopsis, treating shoots with uniconazole can result in enhanced primary root elongation and bolting delay. Uniconazole spraying has become an important cultivation technique in controlling the flowering and improving the fruit-setting of litchi. However, the mechanism by which uniconazole regulates the complicated developmental processes in litchi remains unclear. This study aimed to determine which signal pathways and genes drive the responses of litchi inflorescences to uniconazole treatment. We monitored the transcriptional activity in inflorescences after uniconazole treatment by Illumina sequencing technology. The global expression profiles of uniconazole-treated litchi inflorescences were compared with those of the control, and 4051 differentially expressed genes were isolated. KEGG pathway enrichment analysis indicated that the plant hormone signal transduction pathway served key functions in the flower developmental stage under uniconazole treatment. Basing on the transcriptional analysis of genes involved in flower development, we hypothesized that uniconazole treatment increases the ratio of female flowers by activating the transcription of pistil-related genes. This phenomenon increases opportunities for pollination and fertilization, thereby enhancing the fruit-bearing rate. In addition, uniconazole treatment regulates the expression of unigenes involved in numerous transcription factor families, especially the bHLH and WRKY families. These findings suggest that the uniconazole-induced morphological changes in litchi inflorescences are related to the control of hormone signaling, the regulation of flowering genes, and the expression levels of various transcription factors. This study provides comprehensive inflorescence transcriptome data to elucidate the molecular mechanisms underlying the response of litchi flowers to uniconazole treatment and enumerates possible candidate genes that can be used to guide future research in controlling litchi flowering.In Litchi is an important tropical fruit widely cultivated in more than 20 countries in tropical and subtropical regions worldwide , 2. In CArabidopsis, treating shoots with uniconazole can result in enhanced primary root elongation and bolting delay , and flowering time ] .LUG, which is a critical regulator of gynoecium marginal tissue development [AGAMOUS expression in the first two whorls of the Arabidopsis flower [LUG genes were highly induced by uniconazole treatment controlling the development of flower have been cloned in Arabidopsis thaliana. SPT and ALC may be relevant to pistil development [AMS and DYT1 are closely related to the morphogenesis of anthers [The bHLH family includes genes regulating diverse processes of flower development. Four bHLH transcription factors Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S1 File(DOC)Click here for additional data file.S2 File(DOCX)Click here for additional data file."} +{"text": "We have described a myocardial infarct scar identified by a standard dual source CT coronary angiography (CTCA). We were able to detect the scar during the routine coronary assessment without contrast late enhancement and without additional radiation exposure. It is therefore feasible to assess chronic scar using a standard CTCA technique. CT coronary angiography (CTCA) has become a robust and accurate imaging modality for the non-invasive assessment of coronary vessels. It is now being widely used, particularly in the low to intermediate cardiovascular risk group for the diagnosis and assessment of coronary disease severity .It has been postulated that the data obtained from multi-detector CT (MDCT) during CTCA can also be used to quantify myocardial scar and viability but only by using delayed myocardial contrast enhancement, which involves a second, albeit low radiation dose , 3.Late gadolinium-enhanced cardiac magnetic resonance imaging (CMRI) is considered the gold standard for detection of myocardial scar and viability, and few pilot studies have reported favorable results when comparing CTCA with MRI , 3.Delayed enhancement studies usually offer more accurate information about the infarct size but at the cost of additional radiation exposure and more contrast. Cury et al demonstrated that patients with recent myocardial infarction (MI) could be detected using a standard MDCT dataset based on the presence of a perfusion defect (hypo-attenuation) with a sensitivity and specificity of 94% and 97% [We report the case of a 63-year-old gentleman presenting with chest pain who had previously undergone multi-vessel PCI in 2005. He underwent a CTCA in March 2013 for the evaluation of his coronary arteries as well assessment of his stents, which revealed an antero-apical, antero-lateral and infero-lateral myocardial scar and wall motion abnormalities in the same territories . The ste99mTc-sestamibi) was performed. SPECT slices and polar displays, illustrated on In view of proximal LAD lesion patient was referred for myocardial perfusion scan to assess ischemic burden. Stress (treadmill exercise + regadenoson) radionuclide myocardial perfusion imaging single photon emission CT (MPI SPECT) study with the 2 days protocol studies. Also it may be of prognostic importance in patients with previous silent infarction and in patients presenting with atypical chest pain in whom infarct size could influence the future management. However, we need to develop a technique to improve the accuracy of scar detection on the standard CTCA dataset without the need for further contrast and radiation exposure."} +{"text": "American Indians experience high rates of cardiovascular diseases (CVD). Environmental tobacco smoke (ETS) has been linked to CVD, possibly due to pro-inflammatory and oxidative stress pathways. We examined the relationship between self-reported exposure to ETS and fatal and nonfatal CVD incidence using Cox proportional hazards models among 1843 non-smoking American Indians participating in the Strong Heart Study. We also evaluated potential modifying effects of several dietary nutrients high in anti-inflammatory and anti-oxidant properties with ETS exposure on fatal and nonfatal CVD by creating interaction terms between ETS exposure and the dietary variable. Participants exposed to ETS had a higher hazard for developing CVD compared to persons not exposed. Interaction analyses suggested stronger effects of ETS on CVD incidence among those consuming diets lower in vitamin E as compared to those consuming higher amounts, particularly on the additive scale. Additional research is recommended to clarify whether public health prevention strategies should simultaneously target reductions in ETS exposures and improvements in diets that may exceed the expected benefits of targeting these risk factors separately. Exposure to environmental tobacco smoke (ETS) is one of the most important and common sources of indoor air pollution worldwide . ETS incIn general, American Indian populations experience higher rates of cardiovascular disease (CVD) and CVD-related risk factors as compared to the U.S. population as a whole . Eichner2.5 (particulate matter less than 2.5 microns in diameter), one of the constituents of ETS, has been implicated in CVD development , a sensitive and specific marker of ETS exposure with a half-life of about 3 weeks, and cotinine, the primary metabolite of nicotine are recommended. Furthermore, evaluation of subclinical cardiovascular disease endpoints could provide more detailed insight into mechanistic pathways. Finally, assessment of diet via a food-frequency questionnaire may allow for more accurate information on long-term nutrient intake patterns.These results are limited by the use of self-reported exposure to ETS, making it impossible to distinguish between secondhand and thirdhand smoke, as well as the use of a single 24-h recall to assess diet. ETS exposure may be confounded by socio economic factors that can also be related to CVD incidence rates. To determine ETS exposure more reliably, more accurate long-term measures such as NNAL [4-, as well as the widening ethnic/racial disparities in rates of both ETS exposure and CVD-related health outcomes, there is tremendous public health relevance in understanding how long-term exposure to ETS increases risk of developing CVD and whether or not certain subgroups of the population are more susceptible. Modifying factors, such as diets, may be important targets in future interventions to complement anti-smoking campaigns.The present analysis confirms the previously observed detrimental influence of ETS exposure on cardiovascular health. The Strong Heart Study population allows for the examination of a unique population with high smoking rates but typically low doses. Our results suggest that further research may be warranted to investigate whether consumption of diets high in certain nutrients may reduce these damaging effects. Further research is needed to clarify whether public health prevention strategies should simultaneously target both reductions in ETS exposures and improvements in diets to exceed the expected benefits of targeting these risk factors separately."} +{"text": "We investigated the evolution of the neurological and neuropsychological characteristics in a right-handed woman who was 53-years-old at the onset and who showed personality changes and behavioral disorders accompanied by progressive dysarthria. She had hypernasality and a slow rate of speech with distorted consonants and vowels, which progressed as motor disturbances affecting her speech apparatus increased; finally, she became mute two years post onset. Her dysarthria due to bilateral voluntary facio-velo-linguo-pharyngeal paralysis accompanied with automatic-voluntary dissociation fit the description of anterior opercular syndrome. She showed personality changes and behavioral abnormalities from the initial stage of the disease, as is generally observed in frontotemporal degeneration (FTD), and her magnetic resonance image showed progressive atrophy in the frontotemporal lobes; thus, she was clinically diagnosed with FTLD. This patient\u2019s symptoms suggest that FTLD, including bilateral anterior operculum degeneration, causes progressive pseudobulbar paretic dysarthria accompanied by clinical symptoms of FTD, which raises the possibility of a new clinical subtype in the FTLD spectrum."} +{"text": "Diabetic kidney disease is the leading cause of end-stage renal failure worldwide, however current treatments remain suboptimal. Recently various plants have shown beneficial effects not only on kidney function in diabetes mellitus, but also on kidney toxicities induced by some drugs or toxins. The active substances recognized in these plants include polysaccharides, flavonoids, xanthones and peptides.Panax quinquefolium, Vitis vinifera and glycosides from Stelechocarpus cauliflorus have also been shown to protect renal damage have been completely observed by the authors.None declared."} +{"text": "Bone marrow (BM) aspiration showed erythrocyte phagocytosis by macrophages (18F-fluorodeoxyglucose positron emission tomography (FDG-PET) performed for the staging showed splenic and multiple abdominal lymph node lesions and diffuse accumulation within the bones such as the vertebrae and pelvis , peripheral blood cytopaenia has become a standard tool for the initial staging and reassessment of Hodgkin lymphoma, which is generally characterised by contiguous lymph node involvement.Haemophagocytic lymphohistiocytosis, which is the uncontrolled activation of lymphocytes and macrophages caused by various diseases including malignant lymphoma, can induce diffuse hypermetabolism in the bone marrow reflecting a systemic cytokine storm.Recognition of false-positive findings on FDG-PET is necessary for the evaluation of bone marrow involvement in order to accurately determine the stage of Hodgkin lymphoma, which requires bone marrow examination.Patients with HLH with FDG-PET images indicating multiple lymphadenopathy and/or patchy multiple bone lesions may appear to be LA-HLH with BM involvement (BMI)."} +{"text": "Transcranial electrical stimulation (tES) uses low intensity current to alter neuronal activity in superficial cortical regions, and has gained popularity as a tool for modulating several aspects of perception and cognition. This mini-review article provides an overview of tES and its potential for modulating spatial processes underlying successful navigation, including spatial attention, spatial perception, mental rotation and visualization. Also considered are recent advances in empirical research and computational modeling elucidating several stable cortical-subcortical networks with dynamic involvement in spatial processing and navigation. Leveraging these advances may prove valuable for using tES, particularly transcranial direct and alternating current stimulation (tDCS/tACS), to indirectly target subcortical brain regions by altering neuronal activity in distant yet functionally connected cortical areas. We propose future research directions to leverage these advances in human neuroscience. Decades of empirical research have demonstrated involvement of diverse lateral and medial brain regions in spatial processing and navigation, including parietal, prefrontal and medial temporal areas using parietal object representations and a range of areas including retrosplenial cortex (RSC) and PCC, and secondarily to the hippocampus and parahippocampus , Figure Behavioral outcomes related to parieto-medial temporal pathway might be dissociated with outcomes of targeting the parieto-prefrontal pathway. Specifically, targeting lateral and ventral intraparietal areas might be expected to impact visuospatial spatial working memory performance, whereas targeting the cIPL may not. These types of dissociations between stimulation locations, stimulation conditions , and behavioral outcomes can help elucidate behavioral influences of each pathway, and reveal methods for altering spatial performance. Furthermore, as research reveals the oscillatory dynamics of the parieto-medial temporal pathway, frequency-specific tACS might also prove valuable for modulating network resonance and behavioral outcomes (Ali et al., People differ dramatically in spatial abilities (Hegarty and Waller, TTB conceived the review and prepared the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Cannabis use has repeatedly been associated with psychotic symptoms, with persistent risks beyond the direct effects of exogenous cannabinoids. However, it remains unknown whether cannabis use during pregnancy is a causal risk factor for psychotic symptoms in the offspring, or whether this relationship is explained by shared etiological factors, such as genetic and environmental vulnerabilities. More innovative study designs are needed to address this question. Here, we examined the adverse effects of cannabis exposure during pregnancy on psychotic symptoms in pre-adolescent offspring. Such a method would help causal inference as comparisons can be made between the observed associations of maternal versus paternal cannabis use during pregnancy and the risk of psychotic symptoms in the offspring. If the association between cannabis use and psychotic symptoms is causal, early intra-uterine exposure to cannabis could potentially affect neurodevelopment and, hence, contribute to the pathogenesis of psychotic phenomena in children who have not yet used cannabis themselves.This study used data from the Generation R Study, a prospective population-based birth cohort from Rotterdam, the Netherlands. Participants were included if data on maternal cannabis use during pregnancy of offspring psychotic-like symptoms at age ten years were available (N = 3692). To determine cannabis exposure, we used prospective maternal self-reports during pregnancy and cannabis metabolite levels from urine. Paternal cannabis use during pregnancy was obtained through maternal report. At age ten years, children were queried regarding psychotic symptoms. Ordinal logistic regression was conducted to investigate whether maternal and paternal cannabis use were associated with offspring psychotic symptoms. In a secondary analysis, a distinction was made between maternal cannabis use exclusively before versus continued maternal cannabis use during pregnancy. All models were adjusted for covariates that were previously associated with cannabis use in this cohort.Maternal cannabis use was associated with an increased risk for psychotic symptoms in their offspring . Estimates were comparable for cannabis use exclusively before pregnancy versus continued cannabis during pregnancy . Paternal cannabis use was significantly associated with offspring psychotic symptoms .Using data from a large population-based birth cohort, we demonstrated that maternal and paternal cannabis use were each associated with offspring psychotic symptoms at age ten years, well before the risk period of adolescent cannabis use initiation. Notably, estimates were similar for maternal cannabis use exclusively before pregnancy versus continued cannabis use during pregnancy. Moreover, estimates were comparable for maternal versus paternal cannabis use during pregnancy. This suggests that common etiologies, rather than solely causal intra-uterine mechanisms, underlie the association between parental cannabis use and offspring psychotic symptoms, shedding potential new light on the debated causal path from cannabis use to psychosis. Our findings indicate that diagnostic screening and preventative measures need to be adapted for young people at risk for severe mental illness, and that these programs need to offer a family-focused approach."} +{"text": "Mild cognitive impairment is considered as the first clinical manifestation ofAlzheimer's disease (AD), when the individual exhibits below performance onstandardized neuropsychological tests. However, some subjects before having alower performance on cognitive assessments already have a subjective memorycomplaint. A review about subjective cognitive decline, the association with AD biomarkersand risk of conversion to dementia. We performed a comprehensive non-systematic review on PubMed. The keywords usedin the search were terms related to subjective cognitive decline. Subjective cognitive decline is characterized by self-experience of deteriorationin cognitive performance not detected objectively through formalneuropsychological testing. However, various terms and definitions have been usedin the literature and the lack of a widely accepted concept hampers comparison ofstudies. Epidemiological data have shown that individuals with subjectivecognitive decline are at increased risk of progression to AD dementia. Inaddition, there is evidence that this group has a higher prevalence of positivebiomarkers for amyloidosis and neurodegeneration. However, Alzheimer's disease isnot the only cause of subjective cognitive decline and various other conditionscan be associated with subjective memory complaints, such as psychiatric disordersor normal aging. The features suggestive of a neurodegenerative disorder are:onset of decline within the last five years, age at onset above 60 years,associated concerns about decline and confirmation by an informant. These findings support the idea that subjective cognitive complaints may be anearly clinical marker that precedes mild cognitive impairment due to Alzheimer'sdisease. From the development of biomarkers that allow the detection ofb-amyloid peptide, tau protein and neuronal injury, it is known that the AD pathologyprecedes the onset of dementia by many years.,,The working group of the National Institute on Aging-Alzheimer's Association (NIA-AA)has produced new recommendations for the diagnosis of dementia due to Alzheimer'sdisease and proposed the concept of AD stages based on the model of the \"amyloidcascade\".,,,,This subtle cognitive decline is characterized by a self-experience of deterioration incognitive performance not detected objectively through formal neuropsychologicaltesting.We performed a comprehensive literature non-systematic review on PubMed for referencespublished between January 1990 and July 2016. The keywords used in the search were termsand words related to subjective cognitive decline: \"subjective memory complaint\",\"self-reported memory complaint\", \"subjective cognitive impairment\", \"subjectivecognitive concerns\" , \"Alzheimer's disease\", \"Alzheimer's biomarker\". The search wasrestricted to articles written in English, Spanish and Portuguese language.-,,Subjective cognitive decline: what is it and what is the risk? Various terms anddefinitions have been used in the literature, such as \"subjective memory complaint\",\"self-reported memory complaint\", \"subjective cognitive impairment\" and \"subjectivecognitive concerns\".-Several epidemiological studies have shown an increased risk of progression to ADdementia among individuals with subjective cognitive decline.Reisberg et al. followed 213 individuals for about seven years and found that 54.2% ofthe group with subjective cognitive impairment declined to mild cognitive impairment ordementia, compared to 14.9% among normal controls (hazard ratio 4.5).,,Some authors question whether the complaint of the individual would itself be sufficientto increase the risk of progression to dementia. This questioning arises from twoobservations: memory complaints are very prevalent in the elderly (and therefore can benonspecific) and a high prevalence of lack of insight among patients with dementiaexists. Consequently, some studies analyzed whether confirmation of cognitive decline byan informant increases the specificity and risk for progression to dementia.,However, akin to individuals with mild cognitive impairment, many with subjectivecomplaints may remain stable or even show improvement in cognition. Alzheimer's diseaseis not the only cause of subjective cognitive decline and various other conditions canbe associated with subjective memory complaints, such as normal aging, personalitytraits, psychiatric disorders and use of psychiatric drugs.,Subjective cognitive decline: how can it be identified? Although several studies haveevaluated subjective cognitive decline and its risk of progression to dementia, there isno standard on how the evaluation should be carried out. Ideally, the assessment ofsubjective cognitive decline in any study must provide balance and not be too sensitive or very specific (and therefore too restrictive).Several questionnaires and scales have been developed and applied in clinical andepidemiological studies. The most frequent self-reported measures include: QuestionnaireAgeCoDe Study,,,,As previously mentioned, not all subjective memory complaint is due to pre-clinicalAlzheimer's disease. Of other causes, mental disorders are among the most oftenassociated and therefore the evaluation of patients with subjective memory complaintmust include a neuropsychiatric inventory. However, even excluding patients who meetcriteria for a major psychiatric disorder, symptoms of depression and anxiety or morbidpersonality traits are fairly frequently observed in epidemiological studies.-Although subjective cognitive decline is defined as a complaint without detectableimpairment by standardized neuropsychological tests, a new generation of episodic memorytests has shown utility for the diagnosis of Alzheimer's preclinical disease with a goodcorrelation with subjective complaint.-Subjective cognitive decline studies in the Brazilian population. Although anincreasingly discussed topic in Cognitive Neurology, there are few studies involving theBrazilian population.In a community-based study, seventy-one healthy older adults were asked if they hadmemory complaints, filled out the Memory Complaint Questionnaire (MAC-Q) and underwent aformal test of episodic memory . Spontaneouscomplaints were associated with poor performance on the RAVLT, but not on theMAC-Q.,On the other hand, some studies have shown no correlation between worse performance oncognitive tests and the presence of subjective decline.in vivo of pathologic findings (using biomarkers) withclinical manifestations of Alzheimer's disease.,,,,-,--Alzheimer's disease biomarkers in subjective cognitive decline. In recent years, severalstudies have been investigating thecorrelation ,Perrotin et al. compared two groups of normal elderly, one with positive PiB PET-CT andanother with negative PiB PET-CT, for subjective cognition and performance on aneuropsychological evaluation.-,Evidence also points to a correlation between subjective cognitive decline and corticalatrophy on structural MRI, especially in commonly vulnerable regions for Alzheimerdisease.-Similarly to imaging methods, studies of b-amyloid peptide, total tau and phosphorylatedtau proteins in cerebrospinal fluid (CSF) are widely used in investigations ofsubjective cognitive decline.,In addition to the biomarkers, AD has many other risk factors, but none is betterestablished than the e4 allele of apolipoprotein E (APOE). There is ample evidence thatindividuals with subjective cognitive decline have a greater frequency of expression ofthe allele, especially among those with positive biomarkers.Several studies have shown that individuals with subjective cognitive decline are atincreased risk of progression to AD dementia. According to epidemiological data, thefeatures which increase the likelihood of conversion are: onset of decline within thelast five years, age at onset above 60 years, associated concerns about decline andconfirmation by an informant. In addition, there is evidence that this group has ahigher prevalence of positive biomarkers for amyloidosis and neurodegeneration.Consequently, these findings support the idea that subjective cognitive complaints maybe an early clinical marker of pathology and help further understanding on the naturalhistory of Alzheimer's disease from pre-dementia stages. However, due to lack ofconsensus on how to define and assess subjective cognitive decline, it is still unclearwhich characteristics of subjective cognitive decline suggest the preclinical ADstage."} +{"text": "Meta-analysis suggest that processing speed deficit is the largest single cognitive impairment in schizophrenia. Processing speed predicts functional outcome and indicates a vulnerability marker for schizophrenia. Several authors have proposed that abnormalities in white matter is related to reduced processing speed in schizophrenia. The purpose of this research was to investigate the relationship between processing speed and structural properties of white matter pathways in schizophrenia and healthy controls.The data using this study were from the SchizConnect. Participants included 64 patients with schizophrenia and 71 healthy controls. Diffusion tensor imaging(DTI) method was used to measure fractional anisotropy along white matter tracts. Group differences in white matter integrity-inferred from fractional anisotropy (FA), processing speed, verbal memory were examined. Mediation analysis were applied to inspect the relationship between FA and cognitive performance.Participants with schizophrenia had significantly reduced processing speed, verbal memory deficits, and whole-brain fractional anisotropy deficit. There were significant group differences in white matter integrity of the left thalamus occipital, right extreme capsule, and right thalamus occipital. FA in left thalamus occipital and right extreme capsule mediated group differences in processing speed, but not other cognitive domains.Study findings indicate that mediation effect of processing speed is regional tract-specific. These finding suggest that the structural integrity of white matter tracts associated with left thalamus occipital, right extreme capsule is closely related to reduced processing speed in schizophrenia, but not verbal memory and verbal learning."} +{"text": "Recently, Patrick Micke and colleagues from Uppsala University have contributed an outstanding publication on the limitations to predict prognosis in non-small cell lung cancer . For thThe authors discuss several possible reasons for the negative result, one of them that global gene expression profiles may have performed better. However, despite the availability of several non-small cell lung cancer cohorts with genome-wide data an improvement over clinicopathological parameters including performance status has not yet been demonstrated. A possible reason not discussed by the authors is that tumor tissue used for biomarker or genome-wide expression analysis was taken by surgery soon after diagnosis, while metastasis occurs usually years later. Eventually, biomarker expression undergoes changes during this period and the surgically obtained tumor tissue may no longer be sufficiently representative of the tumor that finally progresses and leads to death.Currently, numerous studies are performed in several tumor entities aimed to predict prognosis (Selinski et al., 2017; Hellwig"} +{"text": "Most retroperitoneal tumors such as renal cell carcinoma have been associated with tumor thrombus extending into the renal vein, inferior vena cava (IVC), and heart. The retroperitoneal metastatic potential of testicular tumors is well known. We report here the first instance of a cardiac murmur prompting diagnosis of metastatic testicular neoplasia in an 18-year-old patient. Chemotherapy was delayed and after successful surgical resection of the ventricular mass, the patient recovered uneventfully. This case underscores the need to pursue abnormal cardiac exams in newly diagnosed testicular cancer patients."} +{"text": "Phonologically similar items are more difficult to remember than dissimilar items , likely because of mutual interference of the items in the phonological store. Low-frequency transcranial magnetic stimulation (TMS), guided by functional magnetic resonance imaging (fMRI) was used to disrupt this phonological confusion by stimulation of the left inferior parietal (LIP) lobule. Subjects received TMS or placebo stimulation while remembering sets of phonologically similar or dissimilar pseudo-words. Consistent with behavioral performance of patients with neurological damage, memory for phonologically similar, but not dissimilar, items was enhanced following TMS relative to placebo stimulation. Stimulation of a control region of the brain did not produce any changes in memory performance. These results provide new insights into how the brain processes verbal information by establishing the necessity of the inferior parietal region for optimal phonological storage. A mechanism is proposed for how TMS reduces phonological confusion and leads to facilitation of phonological memory."} +{"text": "The field of therapeutic stem cell and oncolytic virotherapy for cancer treatment has rapidly expanded over the past decade. Oncolytic viruses constitute a promising new class of anticancer agent because of their ability to selectively infect and destroy tumor cells. Engineering of viruses to express anticancer genes and specific cancer targeting molecules has led to the use of these systems as a novel platform of metastatic cancer therapy. In addition, stem cells have a cancer specific migratory capacity, which is available for metastatic cancer targeting. Prodrug activating enzyme or anticancer cytokine expressing stem cells successfully inhibited the proliferation of cancer cells. Preclinical models have clearly demonstrated anticancer activity of these two platforms against a number of different cancer types and metastatic cancer. Several systems using therapeutic stem cells or oncolytic virus have entered clinical trials, and promising results have led to late stage clinical development. Consequently, metastatic cancer therapies using stem cells and oncolytic viruses are extremely promising. The following review will focus on the metastatic cancer targeting mechanism of therapeutic stem cells and oncolytic viruses, and potential challenges ahead for advancing the field. Cancer metastasis, which is a multiple process in which malignant cells spread from the primary site to colonize distant organs, is one of the greatest challenges in cancer treatment. Although metastasis is responsible for more than 90% of cancer associated mortality, it is difficult to diagnose and treat . For manConventional strategies of cancer therapy, including surgical resection, chemotherapy, radiotherapy and immunotherapy, have made significant contributions to cancer treatment. However, many people suffer from side-effects such as insufficient anti-cancer effects that involve drug resistance and systemic adverse reactions due to off target effects . For exaA mechanistic understanding of the metastatic process is important to development of anti-metastatic therapies that could reduce patient mortality. The metastatic process is initially derived from gene mutations that correlate with proliferative ability. Cells in normal tissues only divide when they receive growth stimulatory signals from other cells and stop dividing when they receive growth inhibitory signals; however, gene mutations providing the ability to be split ignore these signaling factors . AdditioIn this review, we will discuss recent strategies for the treatment of metastatic cancer based on stem cells and oncolytic viruses. Many stem cells have intrinsic tumor tropic properties that originate from chemokine interactions with cancer cells. Using this property, we can make a specific delivery system of anticancer molecules. Stem cells can migrate towards tumor microenvironments and eliminate tumors, enabling site specific delivery. Furthermore, stem cells can be modified to stably express various anticancer agents including cytokines and prodrug activating enzymes for induction of cancer apoptosis and removal of specific tumors. In addition, oncolytic viruses are a therapeutically useful system that can be used to selectively infect and damage tumor tissues without off target effects on normal tissues. Each virus has a specific cellular tropism that determines which tissues are preferentially infected. Viruses then increase in the tumors and destroy them, after which they infects another tumor cell. Viral oncotherapy can also be modified to increase tumor selectivity and enhance oncolytic activity. For example, some viruses have been modified to express capsid proteins that bind with specific cancer types and conditionally express the genes involved with the activation of host immune system. These two strategies will be able to complement the drawbacks of conventional cancer therapy.via stem cell engineering. Other signaling pathways have been found, including urokinase type plasminogen activator (uPA) - uPA receptor (uPAR) and vascular endothelial growth factor receptor 2 (VEGFR2) [Stem cells can trace cancer cells and tumor regions, which makes them very useful for tracing metastatic cancer and carrying anti-metastatic molecules. Various chemokine-chemokine receptor interactions are important to recognition of tumor cells and tumor tropism of stem cells. Stromal cell derived factor 1 alpha (SDF-1\u03b1) and its receptor, CSC chemokine receptor 4 (CXCR4), have been identified as key molecules responsible for the tropism of stem cells in many cancers . Accordi(VEGFR2) , 18. Thevia activation of JNK/activation protein-1 and stimulated the secretion of both tumor necrosis factor alpha and interferon gamma, which ultimately activated the caspase 3/7 pathway [Stem cells have intrinsic antitumor effects that occur through various factors secreted by stem cells and physical interactions of stem cells with tumor cells , 20. How pathway , 26. Neu pathway . In addi pathway . Using c pathway . Interfe pathway , 31. Sec pathway as shownvia the bystander effect. Cytosine deaminase (CD) and 5-fluorocytosine (5-FC) are well-known suicide gene systems. E. coli cytosine deaminase can convert a prodrug, 5-FC, into its active drug, 5-FU. The metabolite of 5-FU (fluorodeoxyuridine monophosphate) binds to the nucleotide binding site of the thymidylate synthase and dNTP in tumor cells becomes imbalanced, which can cause DNA damage and cell apoptosis [Stem cell mediated suicide gene therapy is another strategy for killing tumor cells. Stem cells are engineered to express an enzyme that converts a non-toxic prodrug into a cytotoxic drug that can efficiently kill tumor cells poptosis . In addipoptosis . The CD-poptosis , 36. In poptosis . Furtherpoptosis , which is one of the fusogenic membrane glycoproteins (FMGs) in neural stem cells, is a notable strategy for targeting tumor microenvironments . VSV-G eCancer treatments using stem cells have made improvements in regards to specific targeting of tumors, but a few obstacles must still be overcome prior to clinical application. The main concern is tumorigenicity of the stem cell and cell fate after systemic administration. To prevent therapeutic stem cells from forming tumors or aberrantly differentiating in the host, the tumorigenicity or differentiation potential should be tested in preclinical models. In addition, immortalized stem cells with therapeutic gene inserts may solve the difficulty of mass culture of stem cells and enable their stability in tumors. Therefore, it is important to develop a new strategy for mass culture of stem cells to ensure the ability of a suicide gene to perfectly eliminate stem cells after therapy. Therapeutic modifications could adversely affect the safety of stem cells. Therapeutic stem cells or secreted proteins interrupt host tolerance to self-antigens, which provokes additional complications in the patient and immune responses that might impair therapy. Improvement of stem cell specificity through detailed investigations of tumor tropism could relieve possible side effects.The idea of oncolytic virotherapy originates from clinical reports of cancer regression caused by viral infection and is currently being developed by genetically modifying viruses for the selective infection and destruction of cancer cells .The specificity of oncolytic viruses for tumors is very important to clinical trials. Many viruses have a natural specific tissue tropism for cell surface proteins that are overexpressed by cancer cells. This characteristic is very useful for metastatic cancer tracing. For example, measles virus recognizes the surface receptor CD46 (complement regulatory protein) for cell infection. CD46 is a cofactor for inactivation of complement components that is often overexpressed in cancer cells . Herpes in vitro by at least ten-fold. These data suggest an improved safety of Ad 5/3 in the setting of malignant glioma [Oncolytic viruses can be engineered to directly bind to unique surface molecules of cancer cells. This modification could assign additional specificity for metastasized tumor cells by improving infection of tumor tissues and decreasing infection of healthy tissues. This specificity can be achieved by modifying or combination protein of virus that require for cancer cell recognition. For example, glioma cells overexpress CD16 and CD80/86, which bind with adenovirus serotype 3 , 48. Bast glioma . The adet glioma . Other et glioma .Another strategy is a tumor specific transcriptional targeting using tumor specific promoters and microRNA target sequences. This strategy can restrict virus replication in off-target tissues. For example, adenovirus replication is correlated with their ability to promote cell cycle entry into the G1 phase through the viral immediate early protein E1A. Therefore, tumor specificity is achieved by placing the E1A gene under transcriptional regulation of a tumor specific promoter , CXCR4 iAfter oncolytic virus infection, cancer cells are destroyed by lysis. However, various strategies have been studied to achieve the maximum therapeutic efficacy for tumor cells. The therapeutic efficacy of oncolytic viruses can be enhanced using strategies that enable immunostimulatory factors to induce innate and adaptive immune responses against tumors. One successful strategy is the expression of granulocyte macrophage colony stimulating factor (GM-CSF), which stimulates stem cells to produce granulocytes and monocytes and stimulates adaptive immunity against tumor associated antigens . T-VEC iTransfer of metastatic suppressor genes or targeting metastasis related molecules is an effective strategy of targeting metastatic cancer. One of the tumor suppressor proteins, KAI1, plays a key role in downregulation of epidermal growth factor receptor (EGFR) signaling, which is associated with increased receptor desensitization and endocytosis . An adenSeveral studies have also explored the possibility of combining oncolytic viruses with stem cells to improve delivery . The theThe development of oncolytic viruses as therapeutic agents for metastatic cancer requires careful attention to establish appropriate clinical trial designs, as well as dosing regimens to minimize possible side effects. The most important technical challenge to overcome is the need to enhance tumor selectivity to decrease off target effects after systemic delivery of the oncolytic virus. The other major obstacle to successful application of viral therapy is neutralization of the virus by the host antibody. Many species of viruses are used in oncolytic virotherapy, and most people have already been exposed to the virus through previous vaccination or infection. Therefore, circulating antibodies can inhibit the oncolytic virus before it reaches the tumor site. Immune suppression agents and the aforementioned stem cell transport strategy is currently being investigated to solve this problem.Metastasis of cancer is one of the main factors leading to patient death. The unique properties of metastatic cancer, including their small size, high multiplicity and spread to multiple organs make it difficult to treat. Although conventional cancer treatment strategies have shown a lot of progress, they have been limited in metastatic cancer by recurrence of cancer, induction of drug resistance and systemic side effects after treatment. Accordingly, new strategies are needed to treat metastatic cancer.Stem cell based and oncolytic virus strategies have many potential benefits. Stem cell based therapies are emerging as promising strategies to treat metastatic cancer. Multiple types of stem cells have been shown to exhibit natural tropism towards tumors. In addition, when engineered to express therapeutic agents including prodrug activation enzymes, cytokines and oncolytic viruses, these vehicles can deliver treatments to target sites of metastasized tumor lesions and effectively kill the cancer cell. Many metastatic cancer models have shown therapeutic stem cells to be safe and effective. In addition, clinical trials using promising therapeutic stem cells are under investigation and summarized in Table via oncolytic virus particle modification, serotype changes and use of tumor specific activated promoters. Application of improved oncolytic viral constructs that can be delivered systemically or intratumorally will lead to effective treatments for metastatic cancer patients. Table Oncolytic virotherapy has rapidly advanced in a relatively short period through virological studies. In the early stage, oncolytic viruses destroyed tumors by their oncolysis ability alone; however, transduction of therapeutic transgenes and combination with other anti-tumor agents has enhanced the potency of the oncolytic virus platform. In addition, tumor selectivity has progressed Despite these advances, additional research is needed to develop safer strategies and a lot of validation is required before preclinical models can be applied to humans. By understanding of metastatic processes and biological mechanisms that specifically drive each step of metastasis, we can develop more advanced therapeutic stem cells and strategies of oncolytic virotherapy, which are highly promising approaches to the treatment of metastatic cancer."} +{"text": "Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment option for both malignant and some benign hematological diseases. During the last decade, many of the newer high-dose regimens in different intensity have been developed specifically for patients with hematologic malignancies and solid tumors. Today there are three main approaches used prior to allogeneic transplantation: Myeloablative (MA), Reduced Intensity Conditioning (RIC) and Non-MA (NMA) regimens. MA regimens cause irreversible cytopenia and there is a requirement for stem cell support. Patients who receive NMA regimen have minimal cytopenia and this type of regimen can be given without stem cell support. RIC regimens do not fit the criteria of MA and NMA: the cytopenia is reversible and the stem cell support is necessary. NMA/RIC for Allo-HSCT has opened a new era for treating elderly patients and those with comorbidities. The RIC conditioning was used for 40% of all Allo-HSCT and this trend continue to increase. In this paper, we will review these regimens in the setting of especially allogeneic HSCT and our aim is to describe the history, features and impact of these conditioning regimens on specific diseases. Treatment regimen used for hematopoietic stem cell transplantation (HSCT) must accomplish two goals depending on the patient\u2019s disease and the source of stem cells. Since the majority of allogeneic transplantations are performed for the treatment of malignant disease, the regimen must provide tumor cytoreduction and ideally disease eradication ,5,6,7,8.Several studies showing high doses of total body irridation (TBI) causes death from marrow failure and intravenous infusion of marrow or spleen cells after TBI prevents death in mice attracted many researchers to investigate human transplantations in mid-1950s (19). Early trials of human marrow grafting had been unsuccessful since patients failed to engraft or developed fatal graft-versus-host disease (GVHD) . In lateConventional ablative allo-HSCT depends on the tolerated doses of systemic chemo-radiotherapy in order to eradicate malignant tumor burden. This resulted with high regimen-related toxicities in elderly and patients with comorbidities. In considering that, most hematological diseases occur at ages from 65 to 70 , investiThe MA/NMA/RIC conditioning regimens currently in use summarized in It is well known that a complete donor T-cell chimerism is correlated with a low risk of relapse or progression. MA regimens leads to state of full chimerism rather earlier than RIC regimens. Mixed chimerism is detected initially after transplant in most RIC conditioning regimens and in fact graft rejection is more common in RIC Allo-HSCT patients compared to conventional regimens . MyeloabIn AML, several retrospective comparisons of RIC and MA conditioning regimens are difficult to evaluate due to different patient populations. Patients who received RIC regimens had more high risk features and comorbidities than those received MA conditioning but the survival rates were found to be similar between RIC and MA conditioning . SeveralIncreased NRM in elderly patients with comorbidities may worsen the outcome of MA allo-HSCT in acute lymphoblastic leukemia (ALL). Marks et al. had not Recently, the results of phase III multi-center randomized study of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901 have been released. This study compared outcomes on the basis of conditioning intensity in patients with Myelodysplastic syndrome (MDS) and AML. The study concluded that RIC results in higher relapse rates and lower TRM compared to MAC with a statistically significant advantage in RFS for patients receiving MAC. It has to be noted that inclusion of heterogeneous regimens in both RIC and MAC arms and lack of longer follow-up establishes the main weaknesses of the BMT CTN 0901 study .There are some controversies regarding the impact of conditioning intensity on disease control in MDS. Warlick et al. (55) reported improved disease control with MA regimens. High risk MDS patients (n=43) were treated with MA and T cell depleted alloHSCT resulted in EFS at 1 and 3 years as 47% and 34%, respectively. The overall toxicity was detected to be similar compared to multiple recorded series using RIC regimens. Martino et al. reportedMyeloproliferative neoplasms (MPNs) include a group of clonal and chronic hematologic disorders with similar features. Classical MPNs are chronic myeloid leukemia (CML), idiopathic/primary myelofibrosis (MF), polycythemia vera (PV), essential thrombocytopenia (ET), systemic mastocytosis, chronic neutrophilic leukemia and chronic eosinophilic leukemia . Today, In newly diagnosed severe acquired idiopatic aplastic anemia patients younger than 30-40 years, allo-HSCT is the first line treatment of choice . The staIn patients with Hodgkin\u2019s lymphoma (HL), allo-HSCT is generally performed in relapsed disease after autologous HSCT or refractory disease status but MAC followed by allo-HSCT with conventional preparative regimens had been associated with high toxicity rates and TRM in this group of patients. In the era of reduced intensity regimens, EBMT Lymhoma Working Party reported a lower NRM and improved OS with RIC allo-HSCT in patients with relapsed or refractory HL . In a reSeveral studies have evaluated the efficacy HSCT following RIC or NMA conditioning as a treatment option in relapse or refractory non-HL (NHL) after failure of autologous HSCT. The PFS rate at 3-year was 82% in 18 refractory mantle cell lymphoma (MCL) patients treated with NMA conditioning containing fludarabine, cyclophosphamide and rituximab . Maris eCLL has an indolent and prolonged clinical course and mostly patients are in older age group. Sorror et al. reportedBased on the growing knowledge on the immune system and T cell biology, allogeneic HSCT also represents a promising approach in some solid tumors. Several EMBT phase I and II studies which were conducted by Solid Tumors Working Party documented the presence of a graft-versus solid tumor effect in patients with various solid tumors such as renal, ovarian, colon and soft tissue sarcomas [27-78]. Aglietta et al. reportedIn conclusion, allogeneic stem cell transplantation is a curative approach in many diseases. The advantages of RIC regimens are lower toxicity profiles and lower NRM rates. RIC or NMA allo-HSCT can be a feasible option in geriatric patients and patients with comorbidities. Future studies are needed for a clear-cut understanding of the mechanisms of GVL and GVT effects of donor T cells and its subsets in order to optimize the efficacy of such treatment modalities as RIC or MAC in allo-HSCT ."} +{"text": "Memory deficits are a hallmark of psychotic disorders such as schizophrenia. However, whether neural dysfunction underlying these deficits is present prior to onset of illness and potentially predicts conversion to psychosis are unclear. This study aimed to investigate: 1) baseline brain functional alterations during memory processing in subjects at clinical high risk (CHR); 2) whether alterations are more severe in converters compared with non-converters and are thus predictive of psychosis; and 3) associations of these alterations with task performance, baseline symptoms and memory ability.A sample of 155 individuals at CHR and 137 subjects who did not convert ) and 108 healthy controls were drawn from the second phase of the North American Prodrome Longitudinal Study (NAPLS-2) consortium. All participants underwent functional magnetic resonance imaging (fMRI) with a paired-associate memory paradigm, which consisted of one run for encoding and another run for retrieval. During encoding, participants were presented a series of semantically unrelated word pairs and were asked to remember the presented word pair. During retrieval, a pair of words was presented on the screen on each trial and subjects were asked to indicate whether the given word pair had been presented during the encoding session. Active baseline conditions were included in the task for both encoding and retrieval runs.Data processing was performed for each run, following the standard procedures using the Statistical Parametric Mapping software (SPM12). At individual level, preprocessed images were entered into a general linear model (GLM), generating individual contrast maps (task vs baseline). These contrast maps were further used for a group-level GLM analysis, modeling group, sex, age and site as regressors. Significance was determined using family-wise error (FWE) correction across all voxels in the brain.The observed activation alterations were further tested for potential associations with task performance, clinical symptoms and/or general memory ability. Task performance was measured using the percentage of correct responses and the mean reaction time during retrieval. Clinical symptoms were evaluated by the summed scores of each domain in the Scale of Prodromal Symptoms (SOPS). Memory ability was quantified by the Brief Visuospatial Memory Test- Revised (BVMT-R) and the Hopkins Verbal Learning Test- Revised (HVLT-R) total recall scores.No significant group differences in activation were found during encoding. However, during retrieval, a significant group effect was observed in five brain regions: left dorsolateral prefrontal cortex , left ventrolateral prefrontal cortex , left inferior parietal lobule , left superior temporal gyrus , and right middle temporal gyrus . This effect was indicative of greater activation in converters than non-converters and controls and was particularly manifest in unmedicated subjects (P < 0.001). Baseline hyperactivation was correlated with retrieval reaction time during scan in converters , and with baseline positive, negative and disorganization symptoms and memory scores in the whole sample.These findings suggest that hyperactivation during memory retrieval may mark processes associated with conversion to psychosis; such measures have potential as biomarkers for psychosis prediction."} +{"text": "Functional brain networks are known to be affected by focal brain lesions. However, the clinical relevance of these changes remains unclear. This study assesses resting-state functional connectivity (FC) with electroencephalography (EEG) and relates observed topography of FC to cognitive and motor deficits in patients three months after ischemic stroke. Twenty patients and nineteen age-matched healthy participants underwent a ten-minute EEG-resting state examination. The neural oscillations at each grey matter voxel were reconstructed using an adaptive spatial filter and imaginary component of coherence (IC) was calculated as an index of FC. Maps representing mean connectivity value at each voxel were correlated with the clinical data. Compared to healthy controls, alpha band IC of stroke patients was locally reduced in brain regions critical to observed behavioral deficits. A voxel-wise Pearson correlation of clinical performances with FC yielded maps of the neural structures implicated in motor, language, and executive function. This correlation was again specific to alpha band coherence. Ischemic lesions decrease the synchrony of alpha band oscillations between affected brain regions and the rest of the brain. This decrease is linearly related to cognitive and motor deficits observed in the patients."} +{"text": "Malayopython reticulatus ssp.) are primarily harvested from the wild for their skins\u2014which are prized in the luxury leather goods industry. Trade dynamics of this CITES Appendix II listed species are complex and management approaches on the country or regional level appear obscure. Little is known about the actual geographic point-of-harvest of snakes, how genetic diversity is partitioned across the species range, how current harvest levels may affect the genetic viability of populations, and whether genetic structure could (or should) be accounted for when managing harvest quotas. As an initial survey, we use mitochondrial sequence data to define the broad-scale geographic structure of genetic diversity across a significant portion of the reticulated python\u2019s native range. Preliminary results reveal: (1) prominent phylogenetic structure across populations east and west of Huxley\u2019s modification of Wallace\u2019s line. Thirty-four haplotypes were apportioned across two geographically distinct groups, estimated to be moderately (5.2%); (2) Philippine, Bornean and Sulawesian populations appear to cluster distinctly; (3) individuals from Ambon Island suggest recent human introduction. Malayopython reticulatus is currently managed as a single taxonomic unit across Southeast Asia yet these initial results may justify special management considerations of the Philippine populations as a phylogenetically distinct unit, that warrants further examination. In Indonesia, genetic structure does not conform tightly to political boundaries and therefore we advocate the precautionary designation and use of Evolutionary Significant Units within Malayopython reticulatus, to inform and guide regional adaptive management plans.As an important economic natural resource in Southeast Asia, reticulated pythons ( Habitat loss and degradation as a result of unsustainable per capita consumption of natural resources and rising human population levels are haviMalayopython reticulatus ssp., Python bivittatus ssp., P. curtus, P. brongersmai and P. breitensteini) being heavily exploited for this purpose. Among these the reticulated python (M. reticulatus ssp.) is the most economically important species , the Philippine governments banned the export of M. reticulatus in 1986, and Viet Nam banned wild harvest of M. reticulatus in 1998 )Malayopython reticulatus across the species contemporary range, they offer an encouraging conservation genetics baseline that justifies implementing a precautionary approach [Although the results presented here offer a very provisional insight to the genetic structure of approach to populMalayopython reticulatus are to be continually exploited for the skin trade, management strategies should not solely be tailored to obtaining the maximum economic yield. Populations should instead be managed following an adaptive management scheme to ensure their long-term sustainability . Among ity , and maTo regulate trade dynamics, wild harvest rates and exploitation levels require regular monitoring of the status of resource population(s) to reduce uncertainties.Further fine scale genetic analysis is also warranted to delineate local genetic partitions, and the potential application of adaptive genetic markers to establish conservation units should be considered (see ).To encourage and foster scientific collaborative networks with the countries of origin to permit construction of comprehensive, reference sample databases on which to base the development of robust traceability protocols.S1 TableThe table contains information about samples included in this study along with the corresponding haplotypes inferred from sequence variation across a mitochondrial cytochrome b fragment.(PDF)Click here for additional data file."} +{"text": "Background: Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder which develops in approximately 10% of trauma-exposed individuals. Currently, there are few early preventive interventions available for PTSD. Intranasal oxytocin administration early posttrauma may prevent PTSD symptom development, as oxytocin administration was previously found to beneficially impact neurobiological and socio-emotional PTSD vulnerability factors.Objective: The overall aim of this dissertation was to investigate the potential of intranasal oxytocin administration as early preventive intervention for PTSD.Methods: We performed a functional magnetic resonance imaging (fMRI) study to assess the acute effects of a single administration of oxytocin on the functional fear neurocircuitry \u2013 consisting of the amygdala and (pre)frontal brain regions \u2013 in recently trauma-exposed emergency department patients (range n\u00a0=\u00a037\u201341). In addition, we performed a multicentre randomized double-blind placebo-controlled clinical trial (RCT) to assess the efficacy of repeated intranasal oxytocin administration early after trauma for preventing PTSD symptom development up to six\u00a0months posttrauma (n\u00a0=\u00a0107).Results: In our fMRI experiments we observed acutely increased amygdala reactivity to fearful faces and attenuated amygdala-ventromedial and ventrolateral prefrontal cortex functional connectivity after a single oxytocin administration in recently trauma-exposed individuals. However, in our RCT we found that repeated intranasal oxytocin administration early posttrauma reduced subsequent PTSD symptom development in recently trauma-exposed emergency department patients with high acute PTSD symptoms.Conclusions: These findings indicate that repeated intranasal oxytocin is a promising early preventive intervention for PTSD for individuals at increased risk for PTSD due to high acute symptom severity. Administration frequency dependent effects of oxytocin or the effects of oxytocin administration on salience processing may serve as explanatory frameworks for the contrasting oxytocin effects on anxiety-related measures in our clinical and neuroimaging studies. As trauma exposure constitutes an identifiable event of potential PTSD onset, the first hours to weeks posttrauma serve as a suitable time-period for the provision of early preventive interventions for PTSD, aimed to reduce subsequent PTSD symptom development. Previously, administration of benzodiazepines study to assess the acute effects of a single administration of oxytocin on the functional fear neurocircuitry \u2013 consisting of the amygdala and (pre)frontal brain regions \u2013 in recently trauma-exposed emergency department patients. In addition, we performed a randomized controlled clinical trial to assess the efficacy of repeated intranasal oxytocin administration early after trauma for preventing PTSD symptom development.3. 3.1. In chapter 2 . We observed that the effects of oxytocin administration on amygdala reactivity to emotional faces depended on stimulus valence and on sex. In all participants, oxytocin administration increased amygdala reactivity to fearful faces. Additionally, in women only, oxytocin administration increased amygdala reactivity to neutral faces. Our exploratory analysis showed that acute PTSD symptom severity was not associated with differential intranasal oxytocin administration effects on amygdala reactivity. Given these results we argued that a single intranasal administration of oxytocin may increase neural fear processing, possibly as a result of oxytocin-induced enhanced salience processing.We assessed the acute effects of a single administration of intranasal oxytocin on the fear neurocircuitry in a randomized double-blind placebo-controlled functional magnetic resonance imaging (fMRI) study in trauma-exposed emergency department patients within 11\u00a0days posttrauma. In chapter 4 . For each participant two resting-state fMRI scans were acquired: one after listening to a personal neutral script, and the second after listening to a personal trauma script which was based on the recent traumatic event. We observed that oxytocin-treated participants had diminished amygdala-left ventrolateral prefrontal cortex (vlPFC) functional connectivity in response to the trauma script compared to the neutral script, whereas an increase in amygdala-left vlPFC functional connectivity was observed in placebo-treated participants. In addition, irrespective of script condition, oxytocin administration enhanced amygdala-left (posterior) insula functional connectivity and decreased amygdala-ventromedial prefrontal cortex (vmPFC) functional connectivity. These neural oxytocin administration effects were accompanied by lower levels of sleepiness and higher flashback intensity after the trauma script in oxytocin-treated participants. Taken together, these observations indicate that that a single intranasal oxytocin administration may acutely impede emotion regulation in recently trauma-exposed individuals.In chapter 5 . However, the effects of oxytocin administration were moderated by acute PTSD symptom severity assessed prior to the intervention. Oxytocin administration reduced PTSD symptoms up to six\u00a0months posttrauma in trauma-exposed individuals with high acute PTSD symptoms only. These findings suggest that an eight-day intranasal oxytocin treatment regimen is a promising preventive early intervention for PTSD, specifically for individuals with high acute PTSD symptoms.In chapter 7 the results of our clinical trial are presented. We demonstrated that there was no overall effect of repeated oxytocin administration on PTSD, depression and anxiety symptoms up to six\u00a0months posttrauma . An administration frequency dependent effect on anxiety is a well-known phenomenon for selective serotonin reuptake inhibitors (SSRIs). A single SSRI administration acutely increased fear learning in rodents and may potentiate anxiety in humans socio-emotional functioning; there is no direct evidence that the salience theory also holds for repeated oxytocin administration effects. An alternative suggestion for previously observed differential effects of oxytocin administration between healthy individuals and patients with a psychiatric disorder is that oxytocin administration may only have beneficial effects in individuals who have something to gain with regard to social or emotional functioning oxytocin administration effects on reducing PTSD symptom development, (perception of) context factors should be explicitly assessed and tested as moderators of oxytocin effects in future studies.4.2. Although we were the first to study intranasal oxytocin effects in recently trauma-exposed individuals, meanwhile conducting the largest clinical RCT with intranasal oxytocin to date, some limitations of our studies need to be addressed. First, the statistical power of our clinical study was limited. We halted our study halfway, as our pre-planned interim analysis indicated low conditional power to detect a significant overall effect of oxytocin administration on PTSD symptoms at our primary outcome (1.5\u00a0month posttrauma follow-up). As results from studies with low statistical power are at increased risk for Type I error, replication of our findings is clearly warranted. In addition, the sample size of our imaging studies was also modest, therefore it was not possible to reliably test whether the effects of oxytocin administration on amygdala function were moderated by interindividual differences as we observed in our clinical study. We did explore whether acute PTSD symptom severity was differently associated with amygdala reactivity to fearful faces and found no differential effect , functional fear neurocircuitry and/or other socio-emotional processes (e.g. related to reward functioning).Furthermore, considering the potential future use of intranasal oxytocin in routine clinical practice \u2013 for PTSD prevention but for also other psychiatric indications \u2013 it is highly desirable to better understand when beneficial, null or even potentially non-beneficial effects of oxytocin administration can be expected. Particularly, oxytocin effects on fear memory consolidation and fear extinction should be studied, as there are indications that oxytocin-mediated enhanced fear and extinction memory consolidation may have either anxiolytic or anxiogenic effects, depending on administration frequency and timing in relation to fear conditioning (Janezic et al., In addition, a better understanding of the pharmacodynamics of intranasally administered oxytocin is needed. Oxytocin has a half-life of 3\u201320\u00a0min in blood, and the peptide is immediately degraded upon oral ingestion. There is no clear consensus on if and how intranasally administered oxytocin reaches the brain. Although intranasal oxytocin administration increased salivary (van IJzendoorn, Bhandari, van der Veen, Grewen, & Bakermans-Kranenburg, If our findings are replicated, intranasal oxytocin may be a safe and cheap preventive intervention for PTSD (MacDonald et al., Finally, there is only limited evidence linking functioning of the oxytocin system directly to PTSD risk (Lucas-Thompson & Holman, 5. We observed that repeated intranasal oxytocin administration early posttrauma reduced subsequent PTSD symptom development in recently trauma-exposed emergency department patients with high acute PTSD symptoms. Although replication is necessary, these findings indicate that intranasal oxytocin is a promising novel preventive intervention for individuals at increased risk for PTSD due to high acute symptom severity. However, we also observed acutely increased neural fear processing and impeded neural emotion regulation after a single oxytocin administration in recently trauma-exposed individuals. It remains unknown whether the positive clinical effects after repeated oxytocin administration are mediated by oxytocin effects on amygdala function, or whether the beneficial effects in our clinical study are mediated by other neurobiological and/or socio-emotional processes. Administration frequency dependent effects of oxytocin may be related to these seemingly contrasting effects on anxiety-related measures in our clinical and neuroimaging studies. In addition, the salience processing theory of oxytocin effects may serve as an explanatory framework for these seemingly contrasting results between the two study paradigms. Clinically relevant contextual and interindividual moderators of oxytocin effects should be investigated in the future, as well as underlying neurobiological and socio-emotional mechanisms that mediate oxytocin effects on anxiety-related outcomes and the development of PTSD symptoms. In all, our findings encourage further research into the clinical efficacy and feasibility of repeated oxytocin administration as early preventive intervention for PTSD, in order to try and reduce the high individual and societal burden associated with trauma exposure and PTSD."} +{"text": "Motor and vocal tics are the core symptom of Tourette syndrome (TS). Tic generation seems to develop throughout the known motor pathways. This review focuses on functional neuroimaging in order to check this assumption. Also it elucidates the alterations and interactions of motor networks in TS depending on different contexts and circumstances like resting state, spontaneous tic movements, suppression of tics and premonitory urges, voluntary goal-oriented movements as well as electrophysiological neuronal stimulation. In general, the primary tic generating motor network uses the basic motor pathways differently, interacts with secondary sensorimotor networks and neuronal systems of cognitive behavioural control in a merely hierarchical manner, changing during neurodevelopment."} +{"text": "Unfavorable left ventricular (LV) remodelling is associated with adverse prognosis after tetralogy of Fallot (TOF) repair. The aim of this study was to measure the extracellular volume (ECV) as a marker of diffuse LV myocardial fibrosis in children after TOF repair, and to understand its etiology and clinical significance.In this prospective, cross-sectional study ECV as a quantitative marker of diffuse fibrosis was measured in the LV myocardium using a modified look-locker inversion recovery (MOLLI) sequence. ECV was related to bypass and cross-clamp times at the time of surgery, to ventricular and myocardial function as well as to exercise tolerance.There was no difference in ECV between 31 TOF patients and 15 controls . ECV correlated with z-scores of LV end-diastolic volumes and of right ventricular (RV) end-diastolic and end-systolic volumes . LV ECV did not correlate with with LV or RV ejection fraction, indexed right and left ventricular enddiastolic volumes or pulmonary regurgitation fraction or regurgitant volumes. Female TOF patients had higher ECVs as compared to males . There were no gender differences in controls. Bypass-time during complete repair correlated with LV ECV . Patients who had undergone either a valve sparing repair or received a valved right ventricle to pulmonary artery conduit had a lower ECV than those after transannular patch repair .Maximum workload on exercise testing, as a percent of predicted based on reference populations, correlated inversely with ECV . There were no correlations between ECV and myocardial strain, strain rate or torsion.Although children after TOF repair did not present with higher ECV than controls in this pilot study the amount of diffuse myocardial fibrosis was associated with longer bypass-times at the time of initial repair. There is early evidence that increased fibrosis is associated with decreased exercise tolerance in young patients after TOF repair. Female patients appear to have more diffuse myocardial fibrosis than males consistent with their generally less favourable hemodynamics after TOF repair."} +{"text": "Human respiratory syncytial virus (RSV) remains the most common cause of severe lower respiratory tract disease amongst infants, and continues to cause annual epidemics of respiratory disease every winter worldwide. Demonstrating placental transmission of viable RSV in human samples is a major paradigm shift in respiratory routes considered likely for RSV transmission.Droplet digital PCR (ddPCR) was used to identify RSV present in cord blood mononucleocytes (CBM). CBMs testing positive for RSV were treated with phytohemagglutinin (PHA), PHA and nitric oxide (NO) or PHA, NO and palivizumab, and co-cultured with HeLa cell monolayers. Subsequent immuno-staining for RSV was used to visualize infective viral plaques.RSV was detected in 26 of 45 samples (57.7%) by ddPCR. CBM\u2019s collected in winter were more likely to test positive for RSV compared to non-winter months . RSV plaques were observed in non-treated and treated co-cultured HeLa monolayers.in utero transmission of infective virus to the fetus without causing overt disease. This is likely to have an important impact on immune development as well as future virus-host interactions, thereby warranting further investigation.Demonstrating active RSV in CBMs suggests Despite more than 50 years of research, human respiratory syncytial virus (RSV) continues to cause annual epidemics of respiratory disease every winter worldwide . RSV remRSV invades the epithelial cells of the lower respiratory tract following exposure to inhaled infective aerosolized droplets, or self-inoculation of the eyes and/or nose by contaminated fingers , 3. The RSV has also been shown to infect myeloid cells such as macrophages, dendritic cells (DCs), and cord blood monocytes \u201310; howein utero transmission, and activation of live virus in these cells to suggest a cellular reservoir. Findings from this study could be used to explain the prevalence of RSV bronchiolitis observed in infants every winter and inform novel targets for effective treatment of RSV induced airway disease.Based on observations from studies which have shown RSV persistence and replication reactivation in cells of monocyte lineage \u20139, we hyCord blood samples collected from 45 term infants from healthy mothers 18\u201345 years) recruited antenatally. Samples were collected from August 2002 until September 2003. Cord blood was collected immediately after delivery by means of venipuncture of placental vessels, as previously described [\u201345 yearsRNA purified from a pooled preparation of nasopharyngeal aspirates collected from patients diagnosed with RSV bronchiolitis were used as positive controls for RSVA and RSVB detection in cord blood samples by digital PCR analysis.De-identified cord and maternal blood samples used for this study were collected under institutional ethics approval with informed adult written consent Human Research Ethics Committee) to investigate developmental immunology. De-identified nasopharyngeal aspirates collected from patients testing positive for RSV were obtained with agreement from PathWest Laboratory Medicine to validate the presence of RSV by droplet digital PCR. According to the Human Tissue Acts of Australia, ethics approval was not required for use of these human samples as they were collected for therapeutic and/or diagnostic purposes and subsequently de-identified for pathology purposes, including assay validation . All resRSV gene expression was measured using a commercially available fluorescent probe real-time PCR kit designed to detect all species of RSV on a droplet digital PCR platform . Droplet digital PCR (ddPCR) is a next generation digital PCR with greater analytical sensitivity compared to conventional real-time PCR due to an enhanced ability to read nucleic acid at a single molecule level . Viral RImmuno-probing using an anti-RSV antibody was used to detect RSV plaques in order to demonstrate infective RSV detected by ddPCR in monocyte precursor cells contained in cord blood samples. Briefly, cryopreserved cord blood mononucleocytes (CBM) were thawed and allowed to rest for 3hrs at 37\u00b0C/5% CO2 in specialised dendritic cell media, X-VIVO . Following this, cultures were treated with one of the following: phytohaemagglutinin ; PHA with a soluble nitric oxide donor ; or PHA with NO and palivizumab . All cultures were incubated for 24hrs and then added to HeLa monolayers (American Tissue Culture Collection) grown to 70% confluence in Dulbecco\u2019s minimum essential medium (DMEM) supplemented with fetal calf serum (10% v/v). After 48 hours culture supernatants were removed and the remaining HeLa cell monolayers washed with PBS, and fixed with methanol containing hydrogen peroxide (1% v/v). These fixed HeLa cultures were then probed for RSV expression using anti-RSV HRP conjugated monoclonal antibody followed by incubation with Sigma-Fast Red to detect the presence of RSV as described previously . StainedA total of 45 samples were assessed for RSV expression and a minimum of 11 samples were used to compare RSV plaque assay formation in each treatment group. All samples were run in duplicate and all experiments completed at least twice to ensure reproducibility. Odd\u2019s ratios and relative risk for RSV detected in cord samples were calculated using cross-tabulations with Fishers exact analysis. Due to an absence of data regarding the prevalence of RSV in CBMs, post-hoc power analysis was used to assess if the study interpretations were feasible based on the sample size available. The observed power was calculated at 82% based on the relative risks of RSV detection and sample size used. In order to mitigate concerns surrounding use of observed power and demonstrate the precision of these findings, confidence intervals are reported for the effect sizes calculated. Due to the small sample size and skewed distribution of the dataset, Mann Whitney-U analysis was used to compare RSV expression between birth seasons, and to assess differences in RSV plaque numbers between non-treated and treated co-cultured cells. Stata software by StataCorp was used to complete graphs and statistical analysis for this study with significance taken as p = <0.05 for two-tailed tests. Graphs represent median values with interquartile ranges unless stated otherwise.in utero transmission of RSV to the human fetus. RSV could not be detected in a subset of 16 matched maternal bloods analysed by the same methods.Low level RSV expression was detected in human cord blood samples using droplet digital PCR , the amount of virus was not significantly different to those samples testing positive and collected in non-winter months.This is the first study to show evidence of low level RSV expression in human cord blood samples, suggesting We believe acute maternal respiratory infection acquired during annual RSV winter epidemics in late pregnancy may explain the greater number CBM samples testing positive for RSV in winter. RSV infections are common throughout adult life but generally cause mild symptoms in healthy adults, meaning presentations of RSV induced illness in healthy adults are unusual . TherefoOf the non-winter seasons RSV was most prevalent in spring. This may represent persistence following acquisition of RSV during winter months. DCs have been shown to harbor RSV with spoin utero. RSV release was significantly enhanced when CBMs were matured with phytohaemagglutinin (PHA) and treated with nitric oxide (NO), used as an environmental trigger of RSV replication. This effect was attenuated by treatment with the therapeutic anti-RSV antibody palivizumab, confirming RSV release from these cells. Therefore, this data suggests RSV is able to transmit from and between cells of monocyte lineage without inducing inflammatory symptoms usually associated with infection.Low level spontaneous release of RSV observed in epithelial cells co-cultured with CBMs suggest the fetus is exposed to low levels of infective RSV in utero during fetal immune system development may cause RSV immune tolerance [in utero exposure and the impact of viral exposure during fetal development is warranted due to maturing antigen-presenting precursor cell populations over the course of gestation [Importantly, exposure to infective RSV olerance , 27 explolerance \u201330. Dimiolerance , 3, 30. olerance . In ligholerance . Howeverestation .As this study was conducted retrospectively it was not possible to explore the impact of RSV detection on infant lung structure and function. An association between viral respiratory illness in asthmatic mothers and increased lower respiratory tract symptoms amongst their infants during the first year of life has been shown previously . The autin utero infection on host immune responses will have an important role in developing effective RSV vaccines and treatment in the future.The novel data generated in this study indicates RSV can cross the placenta and infect the fetus without causing overt disease. Trans-placental transmission of RSV appeared to be most common during the winter epidemic but was not limited to this period. While the implications of these findings remain confined to understanding the dynamics of RSV transmission, it is likely the effects of"} +{"text": "Control participants (n = 51) were recruited from the same region. Participants generated personal approach goals and avoidance goals and completed self-report measures of goal attainment likelihood and depressive symptoms. Participants also completed a measure of ease of disengagement from unattainable goals and re-engagement with new goals. Compared to controls, depressed participants reported fewer approach goals , rated their approach goal (rewarding) outcomes as less likely to happen and avoidance goal (threatening) outcomes as more likely to happen. Depressed participants also reported greater ease of disengagement from unattainable goals and more difficulty re-engaging with new goals than controls. Our findings extend current knowledge of the psychopathology of depression from a goal regulation perspective, suggesting that pessimism around goal pursuit accompanies fewer approach goal pursuits and a general tendency to disengage when difficulties are encountered.Despite the development of prominent theoretical models of goal motivation and its importance in daily life, research has rarely examined goal dysregulation processes in clinical depression. Here we aimed to investigate problematic aspects of goal regulation in clinically depressed adults, relative to controls. Depressed participants ( Prominent theories of motivation posit that dysfunctions in approach and avoidance systems underpin emotional susceptibility and affective disorders \u2013 2. Gray\u2018to run a marathon\u2019) whereas avoidance goals refer to representations of undesirable future outcomes ,,greater attempts . HoweverWe found that depressed individuals also reported struggling to engage in alternative goals when they have to stop pursuing unattainable goals, mirroring the apparent difficulty depressed persons had in generating idiographic approach goals relative to controls. The relative inability to engage with new goals among depressed persons may also reflect a generalized pessimism around goal attainment. Reduced goal re-engagement is consistent with the view that individuals who have difficulty developing new plans would be at a greater risk of depression . The resIn terms of clinical implications, our results suggest that depressed persons struggle to articulate positive goals to strive for and find it more difficult to engage in alternative goals when existing goals become unattainable. These findings also suggest that depressed people have reduced expectancies for attaining goal outcomes. Although these results are cross-sectional and do not in themselves identify treatment targets, they indicate that there may be value in helping depressed people to identify approach goals to strive for and challenge pessimistic reasons why participants think that goals cannot be achieved. In this respect, the results are consistent with behavioural activation, which encourages depressed persons to engage behaviourally with goals in the world, and cognitive-behaviour therapy, which may be useful in tackling hopelessness around goal attainment. Interventions that specifically address goal pursuit have shown promise in reducing depressive symptoms in clinical and non-clinical populations. Building confidence and self-efficacy around goal pursuit may also be a useful strategy in preventing depressive onset, but further research is needed.Some methodological considerations deserve comment. Diagnosis was determined via self-report (PHQ-9), clinical assessment and a brief structured interview. In contrast to the brief interview schedule designed for this study, the use of a validated interview schedule such as the SCID would provide a more comprehensive assessment. There were two 16-year-old participants in the otherwise adult sample, but the pattern of significant results was identical when these two participants were excluded. Furthermore, the cross-sectional design means that it is unclear whether depression causes dysregulation of goal processes or whether dysregulated goal processes cause depression, or whether goal dysregulation is epiphenomenal to the depressive episode. Longitudinal studies could usefully clarify whether dysregulated goal pursuit precedes depressive episodes. Future research would benefit from supplementing self-report measures of goal flexibility with behavioural measures that capture goal-directed effort among alternative pursuits.In conclusion, our findings illustrate altered goal processes in depression, characterized by blunted approach goal motivation, pessimistic goal expectancies, and increased goal disengagement and reduced goal re-engagement in the face of goal difficulties. Notably, effect sizes for group differences were large . AlthougS1 File(SAV)Click here for additional data file."} +{"text": "Haemophilus influenzae (NTHi)-associated ear and respiratory diseases (including pneumonia) represent a major health burden in many parts of the world. NTHi strains retrieved from the upper airways commonly reflect those found in the lower airways. Despite growing genomic and genotyping data on NTHi, there remains a limited understanding of global and regional NTHi population structures. The aim of this study was to determine whether nasopharyngeal carriage in four Australian paediatric groups at varying risk of NTHi colonisation was dominated by the same NTHi genotypes. Genotyping data generated by PCR-ribotyping were evaluated for 3070 NTHi isolates colonising the nasopharynges of Aboriginal and non-Aboriginal children enrolled in four longitudinal studies in three separate urban and remote regions of Australia. Several NTHi PCR-ribotypes dominated in nasopharyngeal carriage, irrespective of study setting. Principal coordinates analysis confirmed a cluster of common PCR-ribotypes among all cohorts. In conclusion, we identified dominant PCR-ribotypes common to geographically disparate Australian paediatric populations. Future genomic analyses will shed further light on the precise factors underlying the dominance of certain NTHi strains in nasopharyngeal carriage.Non-typeable Haemophilus influenzae (NTHi) represent a major health burden worldwide and chronic [e.g. bronchiectasis]) NTHi populations by whole genome sequencing or other genotyping means is necessary to determine the relevance of carriage versus disease genotype frequency, and may shed light on the factors supporting dominance of certain NTHi genotypes. Although the Australian experience may not necessarily apply elsewhere, whole genome sequence data from Australian and international NTHi isolates have (to date) demonstrated a level of core genome similarity between global and Australian NTHi populations . Thus, w"} +{"text": "Left ventricular pseudoaneurysm is a rare complication of myocardial infarction that carries a high mortality rate. Although conventional wisdom suggests prompt surgical repair in order to mitigate risk of expansion and rupture, there are some data to support non-operative management in asymptomatic individuals with likely chronic pseudoaneurysms, particularly when surgical candidacy is poor. We present a case of a medically managed left ventricular pseudoaneurysm subsequent to inferior ST-segment elevation myocardial infarction with 6-month follow-up data. Left ventricular pseudoaneurysm is a rare complication of myocardial infarction (MI) associated with serious morbidity and mortality . Unlike A 68-year-old man with history of chronic obstructive pulmonary disease and asbestos-related pneumoconiosis presented with chest pain and diaphoresis after a motor vehicle accident. Electrocardiogram revealed ST elevations in the inferior leads. The patient was promptly taken to the cardiac catheterization lab where he was found to have complete occlusion of the distal right coronary artery. The patient underwent successful percutaneous coronary intervention of the right coronary artery with placement of a drug eluding stent. One day after the coronary intervention, he remained asymptomatic when echocardiogram revealed a left ventricular pseudoaneurysm in the distal inferolateral wall . Left veA rare complication of either transmural MI or cardiac surgery, acquired pseudoaneurysm of the left ventricle, poses a difficult management dilemma, particularly among hemodynamically stable patients who are asymptomatic yet poor surgical candidates. The risk of expansion and eventual rupture must be balanced against a high surgical mortality, but the rarity of the condition has made understanding its natural history and identifying the highest risk patients challenging.Risk factors for development of left ventricular pseudoaneurysm include female sex, first occurrence of either lateral or anterior wall MI, age greater than 60 years and severe single-vessel coronary artery disease, the latter two of which were features in our patient . TransthConservative management of left ventricular pseudoaneurysms has been described in several case series (Our patient\u2019s severe underlying pulmonary disease precluded aggressive surgical management. Although possible, it is unlikely that his pseudoaneurysm was chronic and diagnosed incidentally on a routine post-infarct echocardiogram, which was not obtained under a high pre-test suspicion for pseudoaneurysm. As such, his clinical profile - an asymptomatic, acute and moderately sized pseudoaneurysm - reflects a slightly different demographic than captured by the aforementioned series, and makes application of a robust evidence-based management decision challenging. Development of a centralized registry of cases may help to better elucidate the true natural history of this rare entity, and should be the focus of future studies especially as advances in non-invasive diagnostic modalities are made and diagnostic awareness increases."} +{"text": "The creation of false memories within the Deese-Roediger-McDermott (DRM) paradigm has been shown to be sensitive to many factors such as task instructions, participant mood, or even presentation modality. However, do other simple perceptual differences also impact performance on the DRM and the creation of false memories? This study explores the potential impact of changes in perceptual disfluency on DRM performance. To test for a potential influence of disfluency on false memory creation, participants viewed lists under either perceptually disfluent conditions or not. Results indicated that disfluency did significantly impact performance in the DRM paradigm; more disfluent presentations significantly increased the recall and recognition of unpresented information, although they did not impact recall or recognition of presented information. Thus, although disfluency did impact performance, disfluency did not produce a positive benefit related to overall task performance. This finding instead suggests that more disfluent presentations can increase the likelihood that false memories are created, and provide little positive performance benefit. The creation of false memories within the Deese-Roediger-McDermott paradigincrease task performance )."} +{"text": "The left ventricular (LV) remodeling process associated with significant valvular heart disease (VHD) is characterized by an increase of myocardial interstitial space with deposition of collagen and loss of myofibers. These changes occur before LV systolic function deteriorates or the patient develops symptoms. Cardiovascular magnetic resonance (CMR) permits assessment of reactive fibrosis, with the use of T1 mapping techniques, and replacement fibrosis, with the use of late gadolinium contrast enhancement. In addition, functional consequences of these structural changes can be evaluated with myocardial tagging and feature tracking CMR, which assess the active deformation (strain) of the LV myocardium. Several studies have demonstrated that CMR techniques may be more sensitive than the conventional measures (LV ejection fraction or LV dimensions) to detect these structural and functional changes in patients with severe left-sided VHD and have shown that myocardial fibrosis may not be reversible after valve surgery. More important, the presence of myocardial fibrosis has been associated with lesser improvement in clinical symptoms and recovery of LV systolic function. Whether assessment of myocardial fibrosis may better select the patients with severe left-sided VHD who may benefit from surgery in terms of LV function and clinical symptoms improvement needs to be demonstrated in prospective studies. The present review article summarizes the current status of CMR techniques to assess myocardial fibrosis and appraises the current evidence on the use of these techniques for risk stratification of patients with severe aortic stenosis or regurgitation and mitral regurgitation. Valvular heart disease (VHD) is an important public-health problem with an increasing prevalence along with ageing of the population . ModeratChronic pressure and volume overload caused by severe left-sided VHD results in LV remodeling. Changes in the extracellular matrix with deposition of collagen I and loss of myofibers at a later stage result in myocardial fibrosis, the hallmark of LV remodeling , 6. CardLV remodeling in response to chronic pressure and volume overload caused by VHD is characterized by progressive increase of the interstitial space with increased collagen volume fraction (reactive fibrosis) and eventually apoptosis of myocardial cells which are replaced by firm fibrous tissue (replacement fibrosis or scar). T1 mapping and LGE CMR techniques are currently the most frequently used techniques to directly assess myocardial fibrosis . Although still not implemented in routine clinical practice, the measurement of myocardial ECV in patients with AS has important clinical implications [2) but without LGE (replacement fibrosis) showed significantly higher all-cause mortality and AS-related mortality rates (36 per 1000 patients-year for both) as compared to the patients with normal myocardium , pressure and volume overload induce growth of cardiomyocytes with addition of new sarcomeres in series and interstitial fibrosis, characterized by increased fibronectin and non-collagen components . SeveralMitral regurgitation (MR) is a heterogeneous disease, broadly classified as organic (primary) or functional (secondary) based on the underlying mechanism. Organic MR is due to intrinsic valvular disease whereas functional MR is caused by regional and/or global LV remodeling without structural abnormalities of the mitral valve . DegenerThese structural changes of the LV myocardium may be associated with subtle functional abnormalities. In 15 patients with chronic moderate and severe MR and preserved LV ejection fraction who underwent CMR with tissue tagging, Maniar et al. demonstrated preserved global longitudinal and circumferential strain but abnormal regional strain values: the septal LV segments exhibited impaired strain whereas the lateral segments showed compensatory hyper-contractility . SimilarTissue characterization and strain imaging with CMR have provided new insights into the pathophysiology of VHD. Current guidelines recommend valve surgery in severe symptomatic VHD or when LV function decreases , 3. HoweThe early valve replacement guided by biomarkers of left ventricular decompensation in asymptomatic patients with advanced aortic stenosis (EVOLVED) is the first multicenter randomized controlled clinical trial that will investigate whether the early valve intervention in patients with asymptomatic severe AS and midwall fibrosis on CMR improves patients\u2019 clinical outcomes compared to the standard care (NCT03094143). The results of this study may have an impact on future guidelines and recommendations on treatment of VHD."} +{"text": "However, most species used for epigenomic studies are annual herbaceous plants, and epigenome dynamics has been poorly investigated in perennial woody plants, including grapevine. In this context, we propose grape as an essential model for epigenetic and epigenomic studies in perennial woody plants of agricultural importance.Epigenetic marks include Histone Post-Translational Modifications and DNA methylation which are known to participate in the programming of gene expression in plants and animals. These epigenetic marks may be subjected to dynamic changes in response to endogenous and/or external stimuli and can have an impact on phenotypic plasticity. Studying how plant genomes can be epigenetically shaped under stressed conditions has become an essential issue in order to better understand the molecular mechanisms underlying plant stress responses and enabling epigenetic in addition to genetic factors to be considered when breeding crop plants. In this perspective, we discuss the contribution of epigenetic mechanisms to our understanding of plant responses to biotic and abiotic stresses. This regulation of gene expression in response to environment raises important biological questions for perennial species such as grapevine which is asexually propagated and grown worldwide in contrasting Epigenetic mechanisms regulate chromatin structure, gene expression, transposon mobility and DNA recombination . They ge5C) is found in all sequence context, including the CG and CHG symmetrical motives and the non-symmetrical CHH motif , the remodeling of chromatin organization and specific classes of small RNAs and long non-coding RNAs . BrieflyHistone PTMs are also essential epigenetic signals that can occur at the N-terminal tail of core histones through acetylation, methylation, phosphorylation and ubiquitination . Histone1). So far, histone PTM analysis relies on Chromatin Immunoprecipitation (ChIP) using specific antibodies followed by hybridization to tilling arrays , and analyzed with tilling arrays (MeDip-ChIP) or by Next Generation Sequencing (Medip Seq). Both approaches were used for methylome analysis for example in Arabidopsis, or poplar and HUB2 or non-CG methylation were markedly resistant to bacterial colonization.The profiling of the DNA methylomes of plants exposed to bacterial pathogen, avirulent bacteria, or salicylic acid revealed numerous stress-induced differentially methylated regions (DMRs) often coupled to differential gene expression . Mutant Arabidopsis since a triple mutant rdd (ros1 dml2 dml3), presents down-regulation of stress response genes and increased susceptibility to a fungal pathogen. Furthermore, these authors showed that DNA demethylases target promoter transposable elements in stress responsive genes to positively regulate them.DNA demethylation likely primes transposable elements as well as defense gene induction through the concomitant activation of their transactivators and/or the interference with other chromatin marks . Some imFigure 1; Natural epigenomic variation occurs during species evolution and togeArabidopsis by generating Epigenetic Recombinant Inbred Line (EpiRILs) populations derived from decrease in DNA methylation 1-2 (ddm1-2) or the met1 parents .Several studies have already emerged in crops, in particular, recent analyzes carried out in tomato fruits constituripening as reporripening . In thisChemical treatments that affect DNA methylation patterns could also be utilized to generate epimutations though tFigure 1). DNA methylation may generate multiple epialleles with various expression levels, thereby leading to continuous quantitative variation of a trait .In line with these ideas, the recent analysis of the transcriptomic changes associated with grape infection with the necrotrophic pathogen defense . Genes cV. vinifera. Comparing the epigenomes of wild and cultivated Vitis species with and without biotic and non-biotic stresses will bring insights on the epigenetic basis of grapevine resistance to adverse conditions with potential impact in breeding strategies. Moreover, epigenetic marks may participate in the priming mechanisms to better withstand biotic and abiotic stresses . Crop improvement via locus-specific epigenetic manipulation has become increasingly feasible with TALE- or CRISPR-based genome editing technologies (In a near future, epigenetic marker-assisted breeding strategies will be applied to select for agronomical desirable epigenetic quantitative traits (nologies . Such teAF and PG designed the perspective and wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Neurorehabilitation plays an important role for neural plasticity and functional recovery following neurological disease. Neurorehabilitation is based on rehabilitation medicine, neuroscience, and neurophysiology. This special issue focused on the efficacy and mechanism by which neurorehabilitation can induce neural plasticity and functional recovery.Articles published in this special issue covered neurorehabilitation following stroke, spinal cord injury, and other neurological disorders.T. Fujiwara et al. reviewed the neurorehabilitation using electromyography- (EMG-) controlled neuromuscular electrical stimulation for upper extremity motor function following stroke. This review showed that application of wearable EMG-controlled NMES for 8 hours in daytime improved both arm and hand function and can induce plastic change in intracortical interneuron and spinal reciprocal interneuron.J. Fu et al. reviewed the functional recovery induced by the exercise after spinal cord injury. Therapeutic exercise can induce reshaping of the skeletal muscle, physiological change of spinal motor neuron, and remodeling of the motor cortex.Neurophysiology and neuroimaging are great tools for revealing neural plasticity induced by neurorehabilitation.Neuroimaging studies in this special issue revealed novel findings of cortical reorganization following spinal cord injury, facial nerve palsy, hearing loss, and aerobic exercise in older adults.Neurophysiological studies in this special issue revealed neural activity related to reduction of gait speed in Parkinson's disease and functional recovery of hemiplegia following stroke.Advanced neurophysiological and neuroimaging techniques provided new insight into the functional recovery in neurological disorders.We hope this special issue provides further knowledge of neurorehabilitation.Toshiyuki FujiwaraNam-Jong PaikThomas Platz"} +{"text": "In patients with schizophrenia, distributed abnormalities are observed in grey matter volume. A recent hypothesis posits that these distributed changes are indicative of a plastic reorganization process occurring in response to a functional defect in neuronal information transmission. We investigated the structural covariance across various brain regions in early-stage schizophrenia to determine if indeed the observed patterns of volumetric loss conform to a coordinated pattern of structural reorganization.Structural MRI scans were obtained from 40 healthy adults and 41 age, gender and parental socioeconomic status matched patients with schizophrenia. Volumes of grey matter tissue was estimated at regional level across 90 atlas-based parcellations. Group level structural covariance was studied using a graph theoretical framework.Patients had distributed reduction in grey matter volume, with high degree of localized covariance (clustering) compared to controls. Patients with schizophrenia had reduced centrality of anterior cingulate and insula but increased centrality of the fusiform cortex, compared to controls. Simulating targeted removal of highly central nodes resulted in significant loss of the overall covariance patterns in patients compared to controls.Regional volumetric deficits in schizophrenia are not a result of random, mutually independent processes. Our observations support the occurrence of a spatially interconnected reorganization with systematic de-escalation of conventional \u2018hub\u2019 regions. The resulting morphological architecture may be primed for compensatory functions, albeit with a high risk of inefficiency."} +{"text": "Prenatal diagnosis of congenital heart disease is important to ensure both informed parental counselling before birth, and effective planning of potentially life-saving interventions after birth. MRI offers a safe, radiation-free adjunct to conventional diagnostic modalities, particularly in mothers with high BMI or at later gestations where ultrasound may be limited. However, cardiovascular imaging in the fetus presents several challenges, not least due to the small size and constant motion of the fetal heart, the lack of external cardiac gating, and gross fetal and maternal motion. We present our initial experience of 20 fetal cardiac MRI cases, each referred following fetal echocardiographic assessment to resolve specific points of diagnostic uncertainty.Referrals were based on the judgements of the attending fetal cardiologists between June 2014 and May 2015. A paediatric cardiologist with expertise in cardiac MR was present at every scan. Following a three-plan localiser, diagnostic sequences were generally limited to half-Fourier acquisition single-shot turbo spin-echo (HASTE) and balanced steady state free precession (bSSFP) gradient echo sequences. A large field of view bSSFP cine scan with low spatial resolution but higher temporal resolution (303 ms) was used following the localiser to demonstrate the degree of gross fetal movement. If needed, further shortened localiser sequences were also used, followed by bSSFP scans with higher spatial resolution for diagnostic purposes.Single-shot turbo spin-echo (HASTE) sequences produced T2 weighted images with black-blood like contrast which was particularly useful for assessing the extracardiac vascular anatomy. Balanced SSFP images gave good contrast between the blood pool and surrounding tissue and were useful for intracardiac structures; however these were more susceptible to motion artefacts. Real-time SSFP sequences allowed for dynamic imaging of the beating heart in assessing moving structures (e.g. cardiac masses and diverticulums); when used in combination with HASTE sequences, we were able to characterise rhabdomyomas in three patients.Our preliminary experience of fetal cardiac MRI suggests that it can provide safe, clinically useful complimentary imaging in the majority of selected cases within a tertiary fetal cardiac unit, particularly for extracardiac vascular anatomy and intracardiac masses. In the future, prenatal MRI may have a more prominent role in routine fetal cardiovascular assessment."} +{"text": "Volumetric brain differences between persons meeting criteria for a clinical high-risk state for psychosis (CHR) and healthy controls (HC) have been previously reported, yet little is known about potential abnormalities in surface-based morphological measures. Gyrification remains relatively stable across the lifespan and is minimally influenced by ubiquitous confounding factors . Recently, a multi-site analysis conducted in 104 CHR persons found global increases in cortical gyrification compared to HC . If replicated, gyrification abnormalities in CHR could potentially serve as early neuromarkers of elevated risk, and thus could eventually be used to identify objectively and efficiently the CHR state.www.pronia.eu), a large-scale international longitudinal study currently consisting of 10 European sites. Cortical surfaces were reconstructed from structural MRI images using a volume-based, newly introduced technique called the Projection-Based-Thickness (PBT) as available in the SPM-based-toolbox CAT12. Local gyrification was quantified automatically across the whole brain as absolute mean curvature for each vertex of the brain surface mesh consisting of thousands of individual measurement points. Vertex-wise differences of curvature values were calculated applying a General Linear Model, corrected for age, gender and site effects. Results were investigated at corrected and uncorrected levels.A total of 124 CHR and 264 HC subjects were recruited as part of the PRONIA consortium (We found no significant differences in vertex-wise gyrification between CHR and HC at either corrected or uncorrected levels (p>0.05). Further investigations of potential confounding site effects also did not reveal differences.Our preliminary findings suggest that CHR subjects do not show whole-brain gyrification abnormalities when compared with healthy subjects. These negative results agree with literature suggesting that cortical convolution might be more affected by neurodevelopmental or genetic factors, and thus deviations from normal patterns might not be detectable in heterogeneous samples of at-risk subjects wherein the etiology and ultimate prognosis is unknown. In order to better investigate differences in cortical folding and address the role of gyrification as neuroanatomical biomarker for psychosis, future investigations should focus on subgroups within CHR populations in addition to specific analyses of individuals with higher neurodevelopmental or genetic loadings."} +{"text": "Women with signs and symptoms of ischemia--but no obstructive coronary artery disease--often have coronary microvascular dysfunction (CMD), and are at increased risk of major cardiovascular events, including heart failure. Using cardiac magnetic resonance tissue tagging, we recently found subclinical diastolic dysfunction in these women, suggesting that ischemia-related diastolic dysfunction may be mechanistically linked to the development of heart failure. Tissue tagging involves specialized image acquisition and post processing, and thus is not typically suitable for large patient studies. We hypothesized that feature tracking of conventional cardiac cine images would provide similar information. We therefore compared feature tracking with gold-standard tissue tagging, and then, used feature tracking to assess left ventricular function in women with suspected CMD.We first conducted a validation study comparing feature tracking (applied to standard cine images) to the gold-standard tissue tagging approach (applied to tagged cine images). To this end, in n = 59 individuals, we measured circumferential strain and diastolic circumferential strain rate (CSdR) by tissue tagging and feature tracking . Following the validation study, we performed feature tracking on cine images from n = 116 women with suspected CMD (\"cases\") enrolled in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) Study, and n = 28 aged-matched healthy reference controls.In the validation study, feature tracking correlated with tissue tagging Fig. , providiFeature tracking applied to cine myocardial function images provides a convenient method to analyze wall motion in conventional CMR protocols. In this study, we used this technique to both confirm and extend previous observations in a cohort of women with suspected CMD, demonstrating subclinical diastolic and systolic dysfunction. Further analysis is warranted to better characterize the advantages and limitations of this approach in studies involving patients with suspected CMD and no obstructive disease."} +{"text": "Superior Longitudinal Fasciculus (SLF) differences are consistently reported in psychotic disorders. The SLF is a complex large bundle of association white matter fibers that bidirectionally connect caudal, temporal cortex and inferior parietal cortex to locations in the frontal lobe. Advances in tractography methodologies detail four discrete subdivisions ). Greater specificity of the SLF subdivisions and associated cognitive networks may clarify the mechanisms of divergent tract developmental and functional aspects associated with psychotic experience symptomology in population based samples of adolescents within the extended psychosis continuumA case-control sample of 25 adolescents reporting psychotic experiences versus 25 controls (mean age 13.7 years). We employed High Angular Resolution Diffusion Imaging (HARDI) based data with constrained spherical deconvolution (CSD) based fibre tractography to delineate the discrete subdivisions of the SLF including the arcuate fasciculous. Following tract identification, standard diffusion metrics, , and Diffusivity measures MD, AD and RD), were assessed. A secondary supportive \u201calong-tract\u201d analysis to ascertain more subtle patterns of variation of tract integrity over the tract length was applied. White matter nodal analysis exploring the structural connectivity was applied to investigate additional functional networks recruited by and interconnected via the SFL. We investigate the ability of tractography of the SLF subdivisions and nodal analysis to identify possible differences between adolescents experiencing subclinical psychotic like experiences and those who don\u2019t.Our results agree with recent studies of the SLF I and AF revealing a pattern of asymmetry of these tracts with more extensive tract bundles being consistently identified in the left hemisphere compared to the right. Along-tract analysis revealed subtle patterns of change in discrete subdivisions of the SLF while nodal analysis shows promise in its ability to define precise organisational networksDelineating the SLF subdivisions may clarify potential developmental trajectories between frontal and parieto-temporal speech-related areas contributing to the pathogenesis of psychotic like experiences. These results reveal the presence of aberrant structural connectivity in young adolescents with psychotic experiences."} +{"text": "Fourteen patients underwent surgery for benign intra-thoracic goitre many presented with respiratory distress due to tracheal compression, and in some desperately ill patients inoperable cancer of the lung was diagnosed. The plain chest X-ray revealed the goitre and once the true diagnosis was suggested, prompt surgical intervention followed."} +{"text": "A 76-year-old male presented for reverse total shoulder arthroplasty (TSA) in the beach chair position. A preoperative interscalene nerve catheter was placed under direct ultrasound-guidance utilizing a posterior in-plane approach. On POD 2, the catheter was removed. Three weeks postoperatively, the patient reported worsening dyspnea with a subsequent chest X-ray demonstrating an elevated right hemidiaphragm. Pulmonary function testing revealed worsening deficit from presurgical values consistent with phrenic nerve palsy. The patient decided to continue conservative management and declined further invasive testing or treatment. He was followed for one year postoperatively with moderate improvement of his exertional dyspnea over that period of time. The close proximity of the phrenic nerve to the brachial plexus in combination with its frequent anatomical variation can lead to unintentional mechanical trauma, intraneural injection, or chemical injury during performance of ISB. The only previously identified risk factor for PPNP is cervical degenerative disc disease. Although PPNP has been reported following TSA in the beach chair position without the presence of a nerve block, it is typically presumed as a complication of the interscalene block. Previously published case reports and case series of PPNP complicating ISBs all describe nerve blocks performed with either paresthesia technique or localization with nerve stimulation. We report a case of a patient experiencing PPNP following an ultrasound-guided placement of an interscalene nerve catheter. Interscalene blocks (ISB) are frequently used as an adjuvant therapy for shoulder surgery to optimize postoperative pain, decrease the length of hospitalization, and minimize the time in the postanesthesia care unit . Up to 1Prolonged phrenic nerve paresis (PPNP) resulting from interscalene catheters is rare. One previous investigation identified cervical degenerative disc disease as a potential risk factor for developing PPNP following ISB . OtherwiVerbal and written permission was obtained from the patient for the publication of this report. Written permission was obtained for the use of the patient's medical records.A 76-year-old male of average body habitus with history of hypertension, chronic obstructive pulmonary disease (COPD), coronary artery disease, and myocardial infarction status after three percutaneous coronary interventions presented for reverse TSA in the beach chair position under general anesthesia with an interscalene nerve catheter for postoperative pain management. After obtaining surgical and anesthetic consent, the patient was placed in a semirecumbent position with his head turned slightly toward the nonoperative shoulder with care to avoid neck discomfort. Intravenous midazolam and fentanyl were administered to achieve moderate sedation for the placement of an interscalene nerve catheter under direct ultrasound-guidance utilizing a lateral-to-medial in-plane approach as described by Antonakakis et al. . A 17-gaThree weeks postoperatively, the patient presented to his PCP with a complaint of worsening dyspnea. He was diagnosed with bronchitis and prescribed a course of antibiotics and inhalers. After completing his antibiotic regimen, the patient continued to experience dyspnea and was referred to a pulmonologist for consultation. Further investigation revealed that the patient had both orthopnea and worsened dyspnea on exertion. The physical exam revealed decreased breath sounds in the right lower lobe lung field and bilateral upper airway expiratory wheezing. A chest X-ray (CXR) demonstrated an elevated right hemidiaphragm with a small right-sided pleural effusion.A repeat CXR six weeks postoperatively continued to demonstrate an elevated right hemidiaphragm and right-sided pleural effusion, unchanged from his previous CXR . A diaphThe anatomical proximity of the brachial plexus and phrenic nerve leads to a nearly universal transient blockade of the phrenic nerve with large volume ISB; however, PPNP is a rare complication with a reported incidence to be 1 out of every 2069 single shot ISB or 0.048% . The cloAlthough decreasing the volume of local anesthetic utilized for interscalene blockade has been shown to decrease the incidence transient phrenic nerve palsy , total dProposed mechanisms for PPNP complicating an ISB include compression neuropathy from needle trauma, intraneural injection, chemical toxicity, or neuronal ischemia , 11. ShoPreviously published case reports and case series of PPNP complicating ISBs all describe nerve blocks performed with either paresthesia technique or localization with nerve stimulation (NS). Of note, this patient's interscalene catheter was performed with only US guidance and did not rely on NS or paresthesia techniques. Although the use of US guidance for regional anesthesia has not demonstrated a reduction in peripheral nerve injury, routine use of US guidance allows practitioners many practical advantages . A recenWe attempt to add to the body of literature describing the phenomenon of PPNP following ISB. The only previously identified risk factor for PPNP is cervical degenerative disc disease . Our pat"} +{"text": "De novo synthesis of folates in plants is tightly regulated through feedback-regulation of certain pathway catalysts. Recently, we investigated the prospects of incessant production of folates in an evolutionary conjunction, through the overexpression of feedback targeted and evolutionarily conserved heterologous E.coli dihydroneopterin aldolase (EcDHNA) in tobacco.EcDHNA surface having critical amino-acid differences as Ile 64 (His_63), Val 70 (Phe_69), His 75 (Arg_78) and Arg 79 (Glu_72). These structural characteristics are indicative of evolutionary signatures of the catalytic feedback-regulation of folate manufacturing. We exploited the biotechnological potential of such allosterically diverged trans-DHNA for improved folate production in plants. Nonetheless, genetic manipulation of single enzymes modulating complex pathways such as folate biosynthesis is often inadequate to achieve desired phenotypes; therefore, multi-gene integration with explicit genic-combination for folate enrichment in plants has also been projected for future folate agri-biofortification schemes. Also, the overexpressed bacterial DHNA protein was significantly correlated with the intracellular folate production in E. coli cells, assuming its potential usage for crop biofortification. Here, we provide additional data on the evolutionary characterization and homologies based allosteric site prediction at the surface of DHNA protein of bacterial and plant origins for the designing of genome engineering strategies, and also highlight the need of gene pyramiding for future crop biofortification programs.Recently, we reported the enhanced production of folates in tobacco leaves by the constitutive overexpression of recombinant i.e. bacteria, cyanobacteria and plants, the amino acid sequences were aligned using \u201cA la Carte\u201d mode of Phylogeny.fr online tool. In result, an unrooted phylogram was constructed having distinct clades of plants (both monocots and dicots), bacteria and cyanobacteria. Among bacterial DHNA sequences, E. coli and Xanthomans shared maximum sequence similarity whereas nodulating bacteria Rhizobium sp. showed prominent evolutionary relatedness with cyanobacteria members. On the contrary, selective bacterial representatives exhibited relatively more proximity to plants or algal species than other bacteria reported that ectopic overexpression of folA enzyme in folate biosynthetic pathway led to very high production of pterins in the cell, whereas little increase in the folate level was observed. Therefore, important enzymes such as DHNA and DHPS that are subjected to feedback regulation may be genetically manipulated in crop plants by the overexpression of heterologous proteins having divergent protein-regulation sites.The phylogenetic analysis of DHNA orthologs among bacterial, cyanobacterial and plants (monocot and dicot species) revealed certain degree of protein sequence conservation highlighting their functional conservation at evolutionary scale . As follEcDHNA protein in plants would lead to the independent and uninterrupted synthesis of tetrahydrofolate, in-silico predictions of allosteric regulatory sites at EcDHNA and AtDHNA surfaces were predicted using PARS, a server for the prediction of allosteric and regulatory sites on protein structures.EcDHNA and AtDHNA were extracted from the Protein Data Bank (PDB) with accession codes 2O90 and 1SQL, respectively. In silico prediction of allosteric sites in both EcDHNA and AtDHNA responsible for protein-regulation mechanism was performed. This prediction analysis has identified seven and eight surface allosteric regulatory cavities on EcDHNA and AtDHNA, respectively. One common cavity (CAV_5_Z) in both the proteins was identified as substrate binding site gene cassette as plant selection marker.EcDHNA to the cellular folate production under crucial metabolic constraints in cellular folate biosynthesis mainly through tight feedback regulation of native aldolases. The use of bacterial DHNA gene has definitely persuaded the turnover of end product in folate biosynthetic pathway that may have incredible impact on crop nutrigenomics programs.Could the folate levels be increased by ectopic over-expression of candidate folate biosynthetic pathway genes in plants? Based on the significant correlation between heterologous overexpression of DHNA gene and folate over-production, we assumed that the bacterial folE gene enhanced pterins biosynthesis up to 1250-fold without necessarily allaying with folate production in transgenic Arabidopsis,folE enzyme with aminodeoxychorismate synthase (ADCS) in p-ABA branch resulted into inadequate variation of the folate concentration in plants.p-ABA branch enzymes may not suffice for the ultimate genic-combination of folate vitamin enhancement in plants. If so, what genic-combination(s) should be preferred for improved folate production in the cell?Low amounts of folates in crop plants may be largely attributed to the tight feedback regulation of certain folate biosynthetic enzymes. Up to now, various plant species have been genetically modified with individual folate biosynthetic pathway genes for folate enhancement,folB) responsible for the formation of 6-hydroxymethyl-dihydropterin in folate biosynthesis pathway and DHPS (folKP) responsible for the formation of dihydropteroate are subjected to feedback regulation (EcDHNA gene potentially regulates folate biofortification in tobacco.EcDHNA has evolved with divergent allosteric sites at its surface which may avoid folate feedback regulation, it's pyramiding with other candidate genes of folate biosynthetic pathway such as folE and ADCS would be a promising experimental combination of genes for future folate metabolic engineering. As performed in our study,i.e. DHNA and DHPS genes and investigate their discrete impact on the folate production. Also, pyramiding of these two transgenes in the field through cross-pollination and analyze their collaborative impact on the folate production in F1 generation would be of tremendous scientific interest providing evidences for the genetics of folate agri-biofortification.Evidently, an aldolase enzyme DHNA (gulation . Recentl"} +{"text": "Wolbachia, Rickettsia and Spiroplasma) across 20 species of dance flies. We found evidence of widespread infection by all three symbionts and variation in sex-specific prevalence across the taxa sampled. However, there was no relationship between infection prevalence and adult sex ratio measures and no evidence that female ornaments are associated with high prevalences of sex-biased symbiont infections. We conclude that the current distribution of endosymbiont infections is unlikely to explain the diversity in mating systems among dance fly species.Maternally inherited bacterial endosymbionts are common in many arthropod species. Some endosymbionts cause female-biased sex ratio distortion in their hosts that can result in profound changes to a host\u2019s mating behaviour and reproductive biology. Dance flies (Diptera: Empidinae) are well known for their unusual reproductive biology, including species with female-specific ornamentation and female-biased lek-like swarming behaviour. The cause of the repeated evolution of female ornaments in these flies remains unknown, but is probably associated with female-biased sex ratios in individual species. In this study we assessed whether dance flies harbour sex ratio distorting endosymbionts that might have driven these mating system evolutionary changes. We measured the incidence and prevalence of infection by three endosymbionts that are known to cause female-biased sex ratios in other insect hosts ( Vertically transmitted symbiotic bacteria that are inherited from mother to offspring are common infections of arthropods \u20133. TheseA strong female bias in population sex ratio can profoundly alter the dynamics of sexual selection e.g. \u20138). When. When8])The dance flies (Diptera: Empididae: Empidinae) exhibit incredible interspecific mating system diversity . Dance fThe ultimate evolutionary causes of these interspecific mating system differences across the dance flies remain largely unknown. One possibility is that reproductive parasites have caused female-biased population primary sex ratios in some species. Such biases could conceivably lead to competition among females for access to males, which could in turn favour the evolution of elaborate female sexual ornaments. Such symbiont-induced skewed sex ratios may have altered mating behaviour (see ), triggeWolbachia )We tested for evidence that sex ratio distorting reproductive parasites have driven female-specific ornament evolution in the Empidinae. We found no evidence that reproductive parasites with strong impacts on host population sex ratio are common in this insect group. Furthermore, there was no association between the presence of putative sex ratio distorting endosymbionts and the presence of exaggerated female ornamentation. Further study with a focus on methods that allow for the primary or secondary sex ratio of the hosts to be measured would be helpful to more comprehensively measure sex ratio distortion in dance flies. In addition, research looking into spatial patterns of both the sex ratio of the dance fly hosts and the sex-specific prevalence of symbionts would be fruitful. While we cannot definitively rule out the possibility that historical infections by symbionts caused sex ratio distortion in ancestral populations, our data strongly suggest that female-biased OSRs and female-specific ornaments are being maintained in dance flies for some other reason than sex ratio distorting symbionts. Further research into sexual and natural selection within the mating swarms and reproductive behaviours of dance flies are important for fully understanding the diversity of reproductive phenotypes observed across this system."} +{"text": "Tissue damage derived from tumors, traumatic events, inflammatory diseases, or just aging causes life quality impairment. Thus, tissue regeneration not only represents the main goal of regenerative therapy but also is certainly one of the greatest challenges of modern medicine.Mesenchymal stem cells (MSCs) can be isolated from different source tissues in the adult organism. MSCs can differentiate in mature cells of different lineages; thus, if opportunely targeted, they have the potential to regenerate and heal the injured tissue. The scientific contributions which are part of this special issue present and analyzed these items both in the form of research articles and reviews.The bone marrow is still the gold standard tissue for harvesting MSCs: different clonal cells were analyzed showing heterogeneity; alkaline phosphatase assay could indicate the precursor's lineage . Dental tissues also contain MSCs: in particular, the dental follicle and dentA great challenge in regenerative therapy is the guidance of wound healing. MSCs promote wound healing, and human umbilical cord MSCs accelerate wound repair and hair follicle regeneration via Wnt overexpression . Interestingly, as shown by X. Liu et al., overexpression of semaphorin 3A in adipose-derived stem cells leads to a phenotype switch toward the osteoblastic lineage by upregulating the Wnt pathway as well. These studies on alternative sources of MSCs highlight the importance of molecular signals that might direct MSC fate and more specifically guide them to form mineralized tissue .\u03b2 signaling pathway and stimulating the expression of microRNA21 . Given that natural composition and structure of the extracellular environment has a profound impact on MSC osteogenic differentiation [To increase healing at bone fracture sites, several approaches that stimulate physically the differentiation of MSC have been developed. Pulsed electromagnetic fields promote bone marrow MSCs osteogenic differentiation by activating TGF-ntiation , a varieGiorgio MoriGiorgio MoriGiacomina BrunettiGiacomina BrunettiFiliberto MastrangeloFiliberto MastrangeloElisabetta A. Cavalcanti-AdamElisabetta A. Cavalcanti-Adam"} +{"text": "Hepatocellular Carcinoma (HCC) commonly develops in chronically damaged liver tissues. The resulting regenerative and inflammatory processes create an adverse milieu that promotes tumor-initiation and progression. A better understanding of the hepatic tumor-microenvironment interaction might infer profound therapeutic implications.Integrative whole genome and transcriptome analyses of different tumor regions, the invasive tumor border and tumor-surrounding liver (SL) were performed to identify associated molecular alterations and integrated with our existing HCC database. Expression levels and localization of established CSC markers were assessed in pre-neoplastic lesions and confirmed in two independent patient cohorts using qRT-PCR, immunohistochemistry and immunofluorescence.Our results indicate that genomic and transcriptomic profiles between SL and different tumor regions are quite distinct. Progressive increase in genetic alterations and activation of pathways related to proliferation as well as apoptosis were observed in the tumor tissue, while activation of stemness markers was present in cirrhotic SL and continuously decreased from pre-neoplastic lesions to HCC. Interestingly, the invasive tumor border was characterized by inflammatory and EMT-related gene sets as well as activation of pro-survival signaling. Consistently, integration of gene expression signatures with two independent HCC databases containing 300 HCCs revealed that border signatures are predictive of HCC patient survival.Prognostic significance of the permissive liver microenvironment might be a consequence of a pro-oncogenic field effect that is caused by chronic regenerative processes. Activation of key oncogenic features and immune-response signaling indicates that the cross-talk between tumor and microenvironment might be a promising therapeutic and/or preventive target. Hepatocellular carcinoma (HCC) ranks among the most common cancers worldwide . In the It is well recognized that acquisition of pre-neoplastic (epi-)genetic alterations in the hepatic microenvironment induces a continuum of morphologic changes from chronic inflammatory cell death over cirrhosis to dysplastic lesions which promotes malignant transformation . IntenseSeveral immune response-related and pro-oncogenic molecules induce opposing effects when activated in diverse parenchymal and non-parenchymal cell types (e.g. immune cells versus hepatocytes) and during different states of the chronic liver disease which underlines the critical importance of the interaction of signals from the microenvironment and the tumor cells for tumor initiation and progression , 12. OthThe importance of the chronic inflammatory liver diseases for HCC initiation and progression has been repeatedly demonstrated . To charWe next assessed the somatic genetic alterations present in the different regions by profiling the corresponding tissues using Illumina OmniExpress arrays followed by GISTIC 2.0 analyses. Overall, progression from SL to T showed a continuous increase in genetic alterations Figure . As expeOur molecular analyses indicated a predominant activation of proliferative signaling in the T region that might reflect tumor cell proliferation thereby potentially supporting tumor expansion. Extension of the GSEA for the T region confirmed this finding and demonstrated an enrichment of gene sets associated with deregulation of cellular genes particularly related to tumor cell proliferation in cervical cancer as well Since our molecular analyses indicated an activation of stemness in the SL region, we next assessed the gene expression levels of specific HCC/differentiation markers as well as the selected (cancer-) stemness markers and pluripotency genes (NANOG). As expected, a strong activation in expression levels of AFP and GPC3 as well as a concomitant downregulation of albumin levels were observed from SL to T Figure . NotablyTo confirm that the diseased hepatic tumor microenvironment is the critical determinant of stemness activation, we next assessed expression levels of the stemness genes in livers containing metastasis from different primaries (n = 5). Importantly, we found that these markers were not induced in the non-diseased liver tissue (i.e. in the absence of chronic liver damage) Figure . HoweverTo confirm the activation of inflammatory gene sets and dissect the corresponding immune cells reflected by the molecular changes, we limited our GSEA query to gene sets with association to immune-related properties. We observed a significant enrichment of gene sets related to alternative M2 macrophage activation that might exert pro-tumorigenic function Figure . FurtherFinally, we tested the clinical significance of our identified SL, B and T signatures and integrated all three signatures with our previously published gene expression dataset of 53 human HCC. SubsequeThe notion that HCC patients display two diseases that are inextricably linked to each other, i.e. a chronic liver disease and a malignant tumor, is increasingly recognized, whereby the diseased hepatic microenvironment significantly promotes cancer initiation and progression while concomitantly limiting aggressive therapeutic approaches . TherefoTo address the importance of distinct peritumoral and tumoral regions for hepatocarcinogenesis we analyzed the molecular profiles of tumor-surrounding liver tissue, the invasive tumor border and core tumor tissue by genome-wide approaches and at different molecular levels. The transcriptome analyses confirmed a distinct gene expression profile for each of the different regions Figure . As expeTissue from 28 patients with confirmed HCC undergoing resection at the Department of Surgery, University of Mainz, Germany were collected following patient informed consent and local ethics committee approval. Validation cohort of 20 patients was obtained from the Institute of Pathology, University of Basel, Switzerland. Clinicopatholigical details are provided in http://www.ncbi.nlm.nih.gov/geo, accession number: GSE84598). Details of the analyses are provided in the A total of 200 ng RNA was linearly amplified as recommended by the manufacturer and analyses were performed as described before . The micDiagnosis of HCC was established by expert pathologists. Tissue was either fixed in 4% formaldehyde and embedded in paraffin or preserved for cryosections and cut in 3-5 \u03bcm sections. Antibodies and conditions for fluorescence and immunohistochemical staining are listed in Statistical analysis was performed using Student's t-test, Friedman- test for multiple group comparisons followed by Dunns posthoc test as indicated. P-values \u22640.05 were considered statistically significant. Results are presented as means \u00b1 SD or means \u00b1 SEM as indicated. Survival analyses were performed using log rank (Mantel-Cox) tests."} +{"text": "The significant proportion of schizophrenia patients refractory to treatment targeting the dopamine system suggests that more than one mechanism may cause psychotic symptoms. Reinforcement learning tasks have frequently been employed in schizophrenia to assess dopaminergic functioning and reward processing, but studies have not directly compared groups of treatment-refractory and non-refractory patients.In the current functional magnetic resonance imaging study 21 patients with treatment resistant schizophrenia (TRS), 21 patients with non-treatment resistant schizophrenia (NTR), and 24 healthy controls (HC) performed a probabilistic reinforcement learning task, utilising emotionally valenced face stimuli which elicit a social bias toward happy faces. Behavior was characterized with a reinforcement learning model. Trial-wise reward prediction error (RPE) signaling and the differential impact of emotional bias on these reward signals were compared between groups.Patients showed impaired reinforcement learning relative to controls, while all groups demonstrated an emotional bias favouring selection of the happy faces. The pattern of RPE signaling was similar in HC and TRS groups, whereas NTR patients showed significant attenuation of RPE-related activation. The TRS patients differed from the NTR patients in the relationship between emotional bias and subcortical RPE signal during negative feedback.TRS can be dissociated from NTR on the basis of a different neural mechanism underlying their symptoms. The data support the hypothesis that a favourable response to antipsychotic treatment may be contingent on dopaminergic dysfunction, characterized by aberrant RPE signaling, whereas treatment resistance may be characterized by an abnormality in distinct cognitive mechanisms interacting with this response."} +{"text": "Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) are often comorbid and share similarities across some cognitive phenotypes, including certain aspects of attention. However, no functional magnetic resonance imaging studies have compared the underlying neural mechanisms contributing to these shared phenotypes.n = 20), boys with OCD (n = 20), and healthy control boys (n = 20) performed a parametrically modulated psychomotor vigilance functional magnetic resonance imaging task. Brain activation and performance were compared among adolescents with OCD, adolescents with ASD, and control adolescents.Age- and IQ-matched boys (11\u201317 years old) with ASD (Whereas boys with ASD and OCD were not impaired on task performance, there was a significant group by attention load interaction in several brain regions. With increasing attention load, left inferior frontal cortex/insula and left inferior parietal lobe/pre/post-central gyrus were progressively less activated in boys with OCD relative to the other two groups. In addition, boys with OCD showed progressively increased activation with increasing attention load in rostromedial prefrontal/anterior cingulate cortex relative to boys with ASD and control boys. Shared neurofunctional abnormalities between boys with ASD and boys with OCD included increased activation with increasing attention load in cerebellum and occipital regions, possibly reflecting increased default mode network activation.This first functional magnetic resonance imaging study to compare boys with ASD and OCD showed shared abnormalities in posterior cerebellar\u2013occipital brain regions. However, boys with OCD showed a disorder-specific pattern of reduced activation in left inferior frontal and temporo-parietal regions but increased activation of medial frontal regions, which may potentially be related to neurobiological mechanisms underlying cognitive and clinical phenotypes of OCD. Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social and communication difficulties and stereotyped repetitive behaviors with a pVigilance incorporates sustained attention, or the ability to maintain focus toward infrequently occurring stimuli , and focOn cognitive and symptom-based measures, ASD has been related to inattention. Thus, ASD can be characterized by short attention span, and impulsivity and inattention symptoms are common . FurtherClinical symptoms of inattention have been reported especially in pediatric patients with OCD , and patGiven diagnostic overlap and potential etiological links between ASD and OCD, it is critical to understand neurofunctional mechanisms that are shared or unique between these disorders. Work has begun to focus on delineating neural mechanisms between these disorders , but a cA total of 60 right-handed boys This study has several limitations. While patients with psychiatric comorbidities were excluded, we cannot rule out the presence of subthreshold symptoms of other disorders such as ADHD. This is in line with the debate around comorbidity versus overlapping phenotypes and their respective contribution to behavior and clinical presentation, particularly in the context of ASD and ADHD . It woulFuture work could compare ASD individuals with and without comorbid OCD with noncomorbid OCD individuals, building on this novel comparison to elucidate the mechanisms underlying clinical overlap of ASD and OCD. Moreover, it would be interesting to compare these patient groups with attention-related disorders such as ADHD to provide further insight into shared and/or disorder-specific neurofunctional attention mechanisms.This study provides the first evidence suggesting that adolescents with OCD have disorder-specific abnormalities in sustained attention networks, including left inferior and medial PFC and temporo-parietal regions, relative to adolescents with ASD, who had no frontal abnormalities. Findings suggest lateral inferior/medial fronto-temporo-parietal abnormalities during sustained attention may be a distinct neural signature of OCD but not of ASD. Individuals with ASD and OCD, however, shared abnormally enhanced activation in cerebellum/occipital lobe relative to healthy control individuals. These results provide promising evidence for identification of biomarkers that may clarify underlying mechanisms driving sustained attention and respective symptom profiles in autism and OCD."} +{"text": "Mechanical loading is the primary functional determinant of bone mass and architecture, and osteocytes play a key role in translating mechanical signals into (re)modelling responses. Although the precise mechanisms remain unclear, Wnt signalling pathway components, and the anti-osteogenic canonical Wnt inhibitor Sost/sclerostin in particular, play an important role in regulating bone's adaptive response to loading. Increases in loading-engendered strains down-regulate osteocyte sclerostin expression, whereas reduced strains, as in disuse, are associated with increased sclerostin production and bone loss. However, while sclerostin up-regulation appears to be necessary for the loss of bone with disuse, the role of sclerostin in the osteogenic response to loading is more complex. While mice unable to down-regulate sclerostin do not gain bone with loading, Sost knockout mice have an enhanced osteogenic response to loading. The molecular mechanisms by which osteocytes sense and transduce loading-related stimuli into changes in sclerostin expression remain unclear but include several, potentially interlinked, signalling cascades involving periostin/integrin, prostaglandin, estrogen receptor, calcium/NO and Igf signalling. Deciphering the mechanisms by which changes in the mechanical environment regulate sclerostin production may lead to the development of therapeutic strategies that can reverse the skeletal structural deterioration characteristic of disuse and age-related osteoporosis and enhance bones' functional adaptation to loading. By enhancing the osteogenic potential of the context in which individual therapies such as sclerostin antibodies act it may become possible to both prevent and reverse the age-related skeletal structural deterioration characteristic of osteoporosis. \u2022Loading-related changes in osteocyte sclerostin expression spatially predict subsequent osteogenic responses.\u2022Acute sclerostin down-regulation is not sufficient for maximal osteogenic responses to loading.\u2022Inability to suppress sclerostin precludes bone gain following loading. Lack of sclerostin prevents bone loss in disuse.\u2022Sclerostin influences the osteogenic context in which loading acts as its deletion enhances functional adaptation. Loading levels or distributions which engender strains beyond a habitual minimum effective strain (MES) trigger bone formation resulting in increased bone mass, improved bone architecture and thus re-establishment of habitual levels and distribution of strain Mechanical loading is the primary functional determinant of bone mass and architecture Sost/sclerostin is almost exclusively expressed by osteocytes in the adult skeleton e.g. apoptosing osteocytes around microcracks secrete Rankl via the expression of osteoprotogerin (Opg); mice lacking \u03b2-catenin in osteocytes have dramatically reduced bone mass due to reduced Opg levels Osteocytes are embedded in the mineralised matrix and were long thought to have little or no function, but are now known to play a particularly important role in coordinating local bone remodelling responses and have recently described as \u2018master-regulators\u2019 Given their location and morphology, with long interlinked dendritic processes forming a functional syncytium extending to the bone surfaces, osteocytes are ideally suited to sense load-associated strains, including shear strains across their membranes as fluid is displaced through their canalicular system. Osteocytes are now considered to be the primary mechanosensors which locally coordinate adaptive (re)modelling responses For many years after this, the mechanisms underlying the coordination of adaptive remodelling responses by osteocytes were largely unknown. Hypothesised mechanisms included direct cell-cell communication 2Sost RNA expression in the mouse tibia. However, protein level analysis of sclerostin expression by immunohistochemistry following tail suspension did not detect changes in the proportion of osteocytes stained positive for sclerostin around the level of the tibia/fibula junction The model presented in Sost despite having opposite effects on bone mass The lack of change in sclerostin expression around the mouse tibia/fibula junction during tail suspension is potentially consistent with the finding that this region appears to be the least affected by disuse, with the most significant bone loss occurring proximal and distal to this region Tg) were generated Sost expression in these mice. Further supporting evidence that sclerostin down-regulation is required for loading-induced bone formation, was the observation that loading induced significantly greater bone formation in wild type than SostTg mice. These independent studies specifically test the roles of sclerostin in bone's adaptation to loading and as such provide strong evidence that both loading-related bone gain and disuse-associated bone loss require changes in sclerostin expression, at least in young mice.Evidence that the spatial correlation between loading-related sclerostin regulation and changes in bone (re)modelling may be causal is provided by loading studies using different genetically modified mouse models. Sclerostin knockout mice do not show bone loss in response to disuse induced by hind limb unloading Sost down-regulation in bones' osteogenic response to loading also comes from studies utilising mice with genetic modifications in mechano-responsive pathways which result in altered Sost regulation following loading. For example, increased basal sclerostin expression, abrogation of sclerostin down-regulation with loading and reduced load-related bone formation is observed in periostin knockout (Postn\u2212/\u2212) mice Sost down-regulation and triggers a diminished osteogenic response to loading compared with wild type controls Evidence supporting the potential importance of 3in vivo studies describing altered basal sclerostin expression and changes in the load-related regulation of sclerostin in genetically modified mice, while informative, provide limited insight into the molecular mechanisms by which osteocytes regulate sclerostin expression. Instead in vitro studies using a variety of model systems have been required to address this. These studies have shown that the basal rate of sclerostin expression is under both transcriptional and broader epigenetic control enzymes such as Sirt1 and HDAC5 Sost RNA stability is influenced by micro-RNAs such as miR-218 The above control . Its resSost is down-regulated by PTH Sost regulation by strain have been hindered by the limited availability of cellular models. Primary osteoblasts do not express readily detectable levels of Sost until they form mineralised matrix, which precludes their use for in vitro strain studies. Mouse osteocytic MLO cell lines do not reliably produce readily detectable levels of SostSost after prolonged periods of differentiation Sost. However, rat UMR-106 osteosarcoma cells do respond to strain Sost in a manner akin to them having a constitutively active gene Sost RNA and sclerostin protein in vitro strain by four point bending increases their proliferation Sost over a time course which parallels that seen in rodent bones following in vivo mechanical loading SOST promoter activity is enhanced by Mef2 binding to a distal enhancer element and inhibition of this binding is one of the mechanisms by which Sost down-regulation by strain involves Cox2-initiated PGE2 signalling through an EP4/ERK pathway in vivoSost expression is further demonstrated by the recent report that Cox inhibition with carprofen prevents sclerostin down-regulation in the ulnae of mice subjected to axial loading Sost down-regulation in osteoblastic cells in vivo, produced higher levels of NO when subjected to fluid shear in vitroUsing the Saos-2 model we initially reported that Sost down-regulation by strain in Saos-2 cells, rather ER\u03b1 inhibition in vitro or global deletion in vivo reduces basal Sost levels Sost levels, but prevents strain-induced Sost down-regulation in Saos-2 cells in vitro models.AR, NO and PGE2 signalling pathways are all influenced by estrogen receptors (ERs), which also interact with canonical Wnt pathway components in mechanically strained osteoblastic cells Sost down-regulation following strain, although ER\u03b2 may also act down-stream of PGE2 signalling as PGE2 treatment increases estrogen response element activation in osteoblastic cells VV in the osteoblast lineage prevents Sost down-regulation in the ulnae of mice subjected to axial loading V directly interacts with and facilitates Igf1/Igf1R signalling Sost down-regulation V also facilitates opening of connexin (Cx)43 hemichannels and Cx43 facilitates the release of PGE2, which is involved in the rapid activation of \u03b2-catenin in osteoblastic cells subjected to mechanical stimulation in vitroV expression is not required for ERK activation in calvarial osteoblastic cells subjected to fluid shear Both these roles of ER\u03b2 are consistent with a down-stream Cox-2/PGE2/ERK pathway mediating in vivo studies have been published that have systematically investigated the roles of different mechano-responsive signalling pathways in sclerostin regulation following loading. The majority of available studies are based on in vitro observations in osteoblastic cell lines subjected to defined mechanical stimuli which cannot fully replicate the effects of in vivo loading on the heterogeneous cell populations residing in and on bone. Currently, only Cox2/prostaglandin signalling has been demonstrated to acutely regulate sclerostin expression in vitro, suggesting a direct effect, and to also facilitate sclerostin down-regulation following loading in vivo. Furthermore, the mechanisms by which unloading results in sclerostin up-regulation have not been investigated and cannot be assumed to be the same as those which result in its down-regulation following increased loading. Nonetheless, putting the available jigsaw pieces together it is possible to propose a linear pathway which links early strain-related signalling events to ultimate down-regulation of Sost expression as well as resumption of proliferation of cortical long bone derived osteoblastic cells This latter interpretation is consistent with the recent report that Sost knockout mice do not lose bone due to unloading, but still show osteogenic responses to increased loading in vitro is clearly demonstrated by their ability to very rapidly enter into the cell cycle after strain exposure in the absence of sclerostin In vivo, an increase in the number of osteoblasts on the periosteal surface is seen within 24\u00a0h following loading in vitro and the increase in the number of periosteal osteoblasts following loading in vivo were impaired. These deficiencies in osteoblast function that occur with age may not only limit bone's adaptive responses to loading but also the beneficial effect of sclerostin neutralising therapies The ability of osteoblasts to sense and respond to strain Sost has recently been independently replicated by Holguin et al. Sost in 5-month-old as well as 12-month-old and 22-month-old mice, although the bone formation response was blunted with age. A possible explanation is that Sost RNA down-regulation is more transient in bones from 22-month-old than 5-month-old mice and others have shown changes in Wnt pathway-related gene transcripts and blunting of \u03b2-catenin activity in the old Sost in young mice, only the first bout of loading results in Sost down-regulation in the old. This suggests that old bone cells become refractory to repeated bouts of increased loading. However, we have recently reported that prior and concurrent disuse enhances the osteogenic response to repeated bouts of axial tibial loading in aged mice The finding that osteocytes in tibiae of old mice remain able to sense changes in mechanical loading and acutely respond by down-regulating 6Numerous studies have demonstrated that sclerostin plays a role in the effective working of the mechanisms associated with regulation of bone mass and architecture in relation to mechanical loading (the mechanostat). Sclerostin expression increases following unloading with the consequent inhibition of Wnt signalling and associated bone loss. Down-regulation of sclerostin is permissive for osteogenesis in response to loading, at least in part by relieving inhibition of canonical Wnt signalling. This is consistent with the potently osteogenic responses observed in humans treated with sclerostin-inhibiting antibodies now in advanced stages of clinical development"} +{"text": "The glucocorticoid (GC) drugs are one of the most commonly prescribed and effective anti-inflammatory agents used for the treatment of many inflammatory disorders through their ability to attenuate phlogistic responses. The glucocorticoid receptor (GCR) primarily mediates GC actions via activation or repression of gene expression. GCs directly induce the expression of proteins displaying anti-inflammatory activities. However, the likely predominant effect of GCs is the repression of multiple inflammatory genes that invariably are overexpressed during nonresolving chronic inflammation. Although most GC actions are mediated through regulation of transcription, rapid nongenomic actions have also been reported. In addition, GCs modulate inflammatory cell survival, inducing apoptosis in immature thymocytes and eosinophils, while delaying constitutive neutrophil apoptosis. Importantly, GCs promote noninflammatory phagocytosis of apoptotic cell targets, a process important for the successful resolution of inflammation. Here, the effects and mechanisms of action of GC on inflammatory cell apoptosis and phagocytosis will be discussed."} +{"text": "A 90-year-old female presented after sudden collapse with a Glasgow Coma Score of 3, and profound hypotension. Shortly after endotracheal intubation, the patient developed significant hematemesis, and massive transfusion protocol was subsequently instituted. Computed tomography angiogram of the chest revealed active bleeding from an aortoesophageal fistula . During The most common causes of aortoesophageal fistulas are thoracic aortic aneurysm, foreign body ingestion, postoperative complications, and esophageal malignancy. The classic presentation of mid-thoracic chest pain and sentinel arterial hemorrhage followed by exsanguination is known as Chiari\u2019s triad.CPC-EM CapsuleWhat do we already know about this clinical entity?Aortoesophageal fistula is a rare and typically fatal pathology that presents as massive upper gastrointestinal hemorrhage.What is the major impact of the image(s)?This is a rarely seen image, given the degree of extremis and high mortality of patients with aortoesophageal fistula at emergency department presentation.How might this improve emergency medicine practice?Emergency medicine providers must be familiar with the presentation, diagnostics, rapid interruption of diagnostics and treatment of aortoesophageal fistulas."} +{"text": "Dear Editor,We appreciate Drs. Itkonen and Lamberg-Allardt\u2019s interest in our recent article \u201cDietary Sources of Phosphorus among Adults in the United States: Results from NHANES 2001\u20132014\u201d [Total bioavailable phosphorus intake is the sum of bioavailable phosphorus from each source. See Equation (1) , below. Note that total phosphorus intake from a specific source is the product of phosphorus content (mg/serving) and intake (servings/day).Identifying important dietary sources of total phosphorus intake is the first step in identifying important dietary sources of bioavailable phosphorus intake. Sources that contribute a small total amount of phosphorus (such as dark cola) necessarily contribute a small amount of bioavailable phosphorus, even if they have high bioavailability. Sources that contribute a large total amount of phosphorus (such as bread) may still contribute a large amount of bioavailable phosphorus with relatively low bioavailability. Our study highlights grain products as an increasingly important source of total dietary phosphorus intake.Drs. Itkonen and Lamberg-Allardt also note the importance of added phosphates to the diet. Many foods, including grain products, contain a combination of different types of phosphorus . Added phosphates are of special interest due to the potential for food manufactures to increase or decrease their use more readily than naturally-occurring phosphates. The Food and Nutrient Database for Dietary Studies (FNDDS) does not currently provide the phosphorus content of foods specifically from added phosphates . In the Research into dietary intake of bioavailable and added phosphorus will benefit from an increased focus on important dietary sources of total phosphorus intake, such as grain products, rather than dietary sources with the highest phosphorus bioavailability."} +{"text": "Although numerous studies have investigated the relationship between saccadic eye movements and spatial attention, one fundamental issue remains controversial. Some studies have suggested that spatial attention facilitates saccades, whereas others have claimed that eye movements are actually inhibited when spatial attention is engaged. However, these discrepancies may be because previous research has neglected to separate and specify the effects of attention for two distinct types of saccades, namely reflexive (stimulus-directed) and voluntary (antisaccades). The present study explored the effects of voluntary spatial attention on both voluntary and reflexive saccades. Results indicate that voluntary spatial attention has different effects on the two types of saccades. Antisaccades were always greatly facilitated following the engagement of spatial attention by symbolic cues (arrows) informing the subject where the upcoming saccade should be directed. Reflexive saccades showed little or no cueing effects and exhibited significant facilitation only when these cues were randomly intermixed with uncued trials. In addition, the present study tested the effects of fixation condition on attentional modulation. Cueing effects did not vary due to fixation condition. Thus, voluntary spatial attention consistently showed different effects on voluntary and reflexive saccades, and there was no evidence in these studies that voluntary cues inhibit reflexive saccades, even in a gap paradigm."} +{"text": "The importance to develop effective alternatives to known antibiotics due to increased microbial resistance is gaining momentum inrecent years. Therefore, it is of interest to predict, design and computationally model Antimicrobial Peptides (AMPs). AMPs are oligopeptideswith varying size (from 5 to over100 residues) having key role in innate immunity. Thus, the potential exploitation of AMPsas novel therapeutic agents is evident. They act by causing cell death either by disrupting the microbial membrane by inhibitingextracellular polymer synthesis or by altering intra cellular polymer functions. AMPs have broad spectrum activity and act as first lineof defense against all types of microorganisms including viruses, bacteria, parasites, fungi and as well as cancer (uncontrolled celldivision)progression. Large-scale identification and extraction of AMPs is often non-trivial, expensive and time consuming. Hence,there is a need to develop models to predict AMPs as therapeutics. We document recent trends and advancement in the prediction ofAMP. Machine learning is considerably applied in different areas ofbiological knowledge discovery for improved healthcare.Supervised, unsupervised and reinforcement learning are thethree major learning methods. Identification of AMPs using acombination of supervised and unsupervised learning techniquesis available. A set of experimentally annotated positive AMPpeptides collected from the databases is used for supervisedlearning. The negative data of short peptides collected from aspectrum of available non-secretary peptides is often used fortraining. A high performance machine learning model is built toclassify the data into AMPs and non-AMPs with domain featuressuch as amino acid frequencies and composition extracted fromknown data using the most suitable performance measures likeaccuracy, Mathew Correlation Coefficient, ROC etc. SupportVector Machines (SVM), Random Forests (RF) and ArtificialNeural networks have been used profusely for the identificationof AMPs. SVM employs a linear hyper plane in a higherdimensional feature space for separation. Random forestsclassifier combines a forest of decision tree models and builds aconsensus model. Artificial Neural Networks (ANN) usesinterconnected network of neurons.Thomas et al. 2009) , employe009 , empAMP's were also predicted elsewhere using muDatabases and prediction servers have a key role in the rationaldesign of novel AMPs as reviewed elsewhere . The wor"} +{"text": "Recent advances in the development of immunosensors using polymeric nanomaterials and nanoparticles have enabled a wide range of new functions and applications in diagnostic and prognostic research. One fundamental challenge that all immunosensors must overcome is to provide the specificity of target molecular recognition by immobilizing antibodies, antibody fragments, and/or other peptides or oligonucleotide molecules that are capable of antigen recognition on a compact device surface. This review presents progress in the application of immobilization strategies including the classical adsorption process, affinity attachment, random cross-linking and specific covalent linking. The choice of immobilization methods and its impact on biosensor performance in terms of capture molecule loading, orientation, stability and capture efficiency are also discussed in this review. Antibody (Ab) and antibody fragment-based biosensors or immunosensors are compact tools capable of providing sensitive and rapid detection or capture of a range of pathogens or cells of interests for further analysis. The history of biosensors dates back to 1956 when Leland C. Clark described the first biosensor which was developed to detect glucose levels in serum samples using a membrane bound biologically sensitive element [The fundamental basis of all immunosensors is to efficiently create stable linkages between desired capture molecules and the nanomaterial. Abs are the most extensively used antigen binding molecules due to their exquisite specificity and affinity. A vast selection of monoclonal Abs (mAbs) have been developed using hybridoma technology to provide excellent tools to detect, perturb, or enhance key components in biological systems. Recent efforts have been made to shrink Ab-based tools through the dissociation of full size Abs into smaller antigen binding fragments . InitialAbs or immunoglobulins (Igs) are highly soluble serum glycoproteins which can be divided into five main isotypes based on their heavy chain constant region sequences . PolycloE. coli expression. VHH binders with desired properties can be recombinantly expressed with tag sequences, protein fusion partners, or artificial amino acids through covalent modification [Although full-size Abs generated through immunization have been widely used for immunosensors since the beginning of biosensor development, recently developed recombinant molecules generated in vitro have many advantages over conventional Abs. The advantages of these alternative scaffolds include their compact sizes, excellent thermal and chemical stabilities, as well as low production costs ,15. For fication . Similarfication .Supporting materials of an immunosenor can be selected based on analytic needs . OpticalThe performance of an immnosensor depends upon three key factors: (1) the binding affinity and specificity of antigen binding molecules; (2) the accessibility and proportion of binding sites intact after immobilization; and (3) the density of binding molecules coated on the surface of immunosensor. Different strategies for immobilization may result in different outcomes and efficiencies . ImmobilPhysical adsorption of Abs onto hydrophobic surfaces such as polystyrene offers the simplest attachment. However, the process is uncontrollable in terms of orientation and stability, and often results in denaturation and detachment of protein on surface . ProteinVHHs, also known as nanobodies, are recombinant, antigen-specific, single-domain, variable fragments of camelid heavy chain-only antibodies. Compared to full size IgGs, VHHs can be expressed in high yield in bacterial systems. The small size (~14 kD) provides significant advantages in medical diagnostic and therapeutic applications . HoweverH) and light chains (VL) of Abs connected via a short peptide linker. Shen et al. optimized a 15-mer peptide linker (RGRGRGRGRSRGGGS) to increase the adsorption efficiency on anionic charged biosensor surface [E. coli which can display anti-cancer ScFvs and gold binding peptide on the surface of bacteria at the same time and highly soluble in aqueous solution. Deyev and others reported that DARPins can bind tightly to gold nanoparticles (GNPs) via adsorption . Aptamers are single-stranded DNA or RNA (ssDNA or ssRNA) oligonucleotides or peptides engineered through repeated in vitro selection or equivalent methods. However, aptamers have distinct limitations, especially for those composed of DNA or RNA. The rapid degradation of aptamers by nucleases in biological media is a serious problem. Such degradation causes instability which is unacceptable for biosensor application. Despite such limitations, many successful attempts have been made to create aptamer-based biosensors in relatively nuclease free systems. One approach employed terminally functionalized thiol group for gold surface binding . Other fThe performance of immunosensors is closely associated to the antigen binding molecules and immobilization approach. While Abs have been increasingly used as detection elements in immunosensors, recent development in antibody derivatives and other alternative binding molecules raise new opportunities and possibilities to create highly stable, efficient, and economically feasible diagnostic device. In this review, a wide range of immobilization strategies are presented for Ab and Ab alternatives and their applications on various nanomaterial surfaces are discussed. Pros and cons of each method are presented. The uniform orientation conferred by site-specific immobilization is essential for small Ab alternatives to retain their binding efficiency."} +{"text": "We report the sequential changes of retinal vessels observed by optical coherence tomography angiography (OCTA) in a case of nonischemic central retinal vein occlusion (CRVO) that converted to ischemic CRVO. An 81-year-old woman visited our Retina Clinic because of visual acuity loss in the left eye. Funduscopic examination showed venous tortuosity and intraretinal hemorrhage in all four quadrants of the fundus. OCT showed macular edema. Fluorescein angiography (FA) and OCTA showed loss of small capillaries. Nonischemic CRVO was diagnosed. Antivascular endothelial growth factor (VEGF) treatment resolved the edema and improved visual acuity. However, during follow-up, capillary dropout was observed on OCTA, which gradually enlarged. Eventually, FA confirmed the conversion to ischemic CRVO. In this case, sequential observations using OCTA showed that nonischemic CRVO did not convert to ischemic CRVO abruptly but occurred stepwise. Additionally, vascular changes began around the veins and blood flow changes were observed more clearly in deep capillary plexus than in superficial capillary plexus. Central retinal vein occlusion (CRVO) is a significant cause of acquired vision loss . CRVO waAn 81-year-old woman was referred to our Retina Clinic because of loss of visual acuity (VA) in the left eye 3 months ago. She had a history of uncontrolled hypertension, hyperlipidemia, and diabetes mellitus. Her best-corrected visual acuity (BCVA) was 20/20 in the right eye and 20/30 in the left eye. Funduscopic examination of the left eye showed typical features of nonischemic CRVO, including venous tortuosity and intraretinal hemorrhage in all four quadrants of the fundus. Fluorescein angiography (FA) and OCTA showed loss of small capillaries but nonperfusion areas were not observed, confirming a diagnosis of nonischemic CRVO. Optical coherence tomography (OCT) showed retinal thickening in the fovea with associated inner retinal cysts. drug aflibercept was initiated. One month later, visual acuity was improved to 20/25 along with gradual normalization of fundus findings associated with CRVO and macular cysts. After one more month OCTA revealed enlargement of the foveal avascular zone and broken foveal capillary ring in the superficial capillary plexus (SCP) and deep capillary plexus (DCP). Color fundus photograph demonstrated cotton wool spots located near the macula ; OCTA reWe performed sequential OCTA observations on a case initially presented with nonischemic CRVO which subsequently converted to ischemic CRVO. OCTA demonstrated capillary dropout occurring preferentially around the vein and these areas gradually enlarged forming avascular lesions. Moreover, OCTA revealed more extensive avascular zones in the DCP than in the SCP. Previous study has also reported that retinal vascular abnormalities in diseases of retinal veins develop more frequently in the DCP than in the SCP . GradualIn conclusion, the present case suggests that conversion to ischemic CRVO starts in the areas around the vein and progresses stepwise rather than abruptly. Moreover, in OCTA study, avascular zones are more readily recognized in the DCP than in the SCP. This is the first report of sequential observations of conversion from nonischemic CRVO to ischemic CRVO using OCTA. Further study of more cases may contribute to elucidation of the mechanism of conversion to ischemic CRVO."} +{"text": "Altered cellular metabolism is considered a hallmark of cancer and is fast becoming an avenue for therapeutic intervention. Mitochondria have recently been viewed as an important cellular compartment that fuels the metabolic demands of cancer cells. Mitochondria are the major source of ATP and metabolites necessary to fulfill the bioenergetics and biosynthetic demands of cancer cells. Furthermore, mitochondria are central to cell death and the main source for generation of reactive oxygen species (ROS). Overall, the growing evidence now suggests that mitochondrial bioenergetics, biogenesis, ROS production, and adaptation to intrinsic oxidative stress are elevated in chronic lymphocytic leukemia (CLL). Hence, recent studies have shown that mitochondrial metabolism could be targeted for cancer therapy. This review focuses the recent advancements in targeting mitochondrial metabolism for the treatment of CLL. A sactivity . CLL cel induce nonclassical cell death that is mitochondrial ROS dependent and facilitated by TCL1 oncogene overexpression [in vitro to therapeutic agents generally used in the treatment of CLL. This also enables a suitable model for mitochondrial targeting in CLL.Increased oxidative stress and altered mitochondrial metabolism in CLL cells are associated with the lymphoid oncogene TCL-1 (T cell leukemia 1). Prinz et al. demonstrated that organometallic nucleosides pression . MCNA inpression . These aDNA crosslinking agents are activated aromatic nitrogen mustards, the ability to crosslink DNA. DNA inter-strand crosslinks are identified as one of principle mechanisms for the cytotoxic effect of many antitumor drugs. These compounds exhibit very powerful crosslinking abilities in the presence of H2O2 and provide a novel strategy for tumor-specific damage. Primary CLL samples were more sensitive (40\u201380% apoptosis) than non-CLL lymphocytes from healthy donors [ROS inducible y donors . They fuMitochondrial metabolism has only now become of interest in the realm of cancer therapy. CLL is a disease that has many mitochondrial metabolic dependencies. However, the nature of metabolic networks that enable abhorrent cell proliferation, cell-cell communication, evasion of apoptosis, and drug resistance remains poorly understood. The list of therapeutic compounds described in this review implements a strong suggestion that targeting mitochondrial bioenergetics and metabolic alterations may provide a mechanistic explanation for the growth advantage and apoptotic resistance of tumor cells. In CLL patients, standard chemi-immunotherapy and novel targeted agents continue to lead to treatment failures. In order to best target this cancer, a multipronged treatment strategy such as combinations with mitochondrial targeting agents and currently approved treatments may enable a chance at cure for a currently incurable cancer."} +{"text": "Consciousness is often disrupted in epilepsy. This may involve altered responsiveness or changes in awareness of self and subjective experiences. Subcortical arousal systems and paralimbic fronto-parietal association cortices are thought to underpin current concepts of consciousness. The Network Inhibition Hypothesis proposes a common neuroanatomical substrate for impaired consciousness during absence, complex partial and tonic-clonic seizures.Neurostimulation in epilepsy remains in its infancy with vagal nerve stimulation (VNS) as the only firmly established techniqueand a series of other methods under investigation including deep brain stimulation (DBS), intracranial cortical stimulation andrepetitive transcranial magnetic stimulation (rTMS). Many of these systems impact on the neural systems thought to be involvedin consciousness as a continuous duty cycle although some adaptive (seizure triggered) techniques have been developed.Theoretically, fixed duty cycle neurostimulation could have profound effects on responsiveness, awareness of self and subjectiveexperience. Animal studies suggest vagal nerve stimulation positively influences hippocampal long term potentiation. In humans,a chronic effect of increased alertness in VNS implanted subjects and acute effect on memory consolidation have been reportedbut convincing data on either improvements or deterioration in attention and memory is lacking. Thalamic deep brain stimulation(DBS) is perhaps the most interesting neurostimulation technique in the context of consciousness. Neither bilateral anterioror centromedian thalamic nucleus DBS seem to affect cognition. Unilateral globus pallidus internus DBS caused transientwakefulness in an anaesthetised individual.As intracranial neurostimulation, particularly thalamic DBS, becomes more established as a clinical intervention, the effects onconsciousness and cognition with variations in stimulus parameters will need to be studied to understand whether these secondaryeffects of neurostimulation make a significant positive (or adverse) contribution to quality of life."} +{"text": "Since the Korean language has two distinct writing systems, phonogram (Hangul) and ideogram (Hanja: Chinese characters), alexia can present with dissociative disturbances in reading between the two systems. A 74-year-old right-handed man presented with a prominent reading impairment in Hangul with agraphia of both Hangul and Hanja after a left posterior occipital- parietal lesion. He could not recognize single syllable words and nonwords in Hangul, and visual errors were predominant in both Hanja reading and the Korean Boston Naming Test. In addition, he had difficulties in visuoperceptual tests including Judgment of Line Orientation, Hierarchical Navon figures, and complex picture scanning. These findings are consistent with the hypothesis that Hangul reading impairment results from a general visual perceptual deficit. However, this assumption cannot explain why performance on visually complex Hanja was better than performance on visually simple Hanja in our patient. In addition, the patient did not demonstrate higher accuracy on Hanja characters with fewer strokes than on words with more strokes. Thus, we speculate that the left posterior occipital area may be specialized for Hangul letter identification in this patient. This case demonstrates that Hangul-Hanja reading dissociation impairment can occur after occipital-parietal lesions."} +{"text": "Pulmonary vein stenosis is a well-established possible complication following an atrial fibrillation ablation of pulmonary veins. Symptoms of pulmonary vein stenosis range from asymptomatic to severe exertional dyspnea. The number of asymptomatic patients with pulmonary vein stenosis is greater than originally estimated; moreover, only about 22% of severe pulmonary vein stenosis requires intervention. We present a patient with severe postatrial fibrillation (AF) ablation pulmonary vein (PV) stenosis, which was seen on multiple imaging modalities including cardiac computed tomography (CT) angiogram, lung perfusion scan, and pulmonary angiogram. This patient did not have any pulmonary symptoms. Hemodynamic changes within a stenosed pulmonary vein might not reflect the clinical severity of the obstruction if redistribution of pulmonary artery flow occurs. Our patient had an abnormal lung perfusion and ventilation (V/Q) scan, suggesting pulmonary artery blood flow redistribution. The patient ultimately underwent safe repeat atrial fibrillation ablation with successful elimination of arrhythmia. Pulmonary vein stenosis, which occurs in 1% to 3% of cases, is a well-recognized potential complication after radiofrequency (RF) ablation of pulmonary veins. The clinical manifestations of pulmonary vein stenosis vary widely from asymptomatic to severe exertional dyspnea. While these symptoms are primarily affected by the severity and number of affected veins, pulmonary blood flow redistribution is thought to be one of the factors contributing to blunting clinical symptoms after RF ablation of atrial fibrillation (AF) [A 56-year-old male with history of AF, status after ablation, eight years ago at an outside hospital, presented with recurrent AF. Five years after his initial ablation, the patient developed symptomatic palpitations due to atrial fibrillation and he was prescribed flecainide and metoprolol. Despite antiarrhythmic therapy, the patient continued to have symptomatic atrial fibrillation with palpitations but no shortness of breath. The patient was taken for AF ablation. The preablation echocardiogram demonstrated normal ventricular function and pulmonary pressures. The preprocedural computed tomography (CT) scan along with the three-dimensional (3D) reconstruction was done on the procedural table prior to the transeptal puncture but did not pick up the pulmonary vein stenosis. Pulmonary vein potential mapping noted that there was a potential at the ostium of the left superior pulmonary vein. There was also difficulty advancing the catheter into the left superior pulmonary vein due to a possible obstruction. Direct angiography of the left superior pulmonary vein (LSPV) confirmed complete PV stenosis. The procedure was aborted in lieu of further diagnostic work up. A higher resolution cardiac CT angiogram and leftThe frequency of PV stenosis, a well-established possible complication following an AF ablation of pulmonary veins, has been declining due to the improvement of technique. However, depending on the technique and diagnostic modalities used, PV stenosis occurs as often as 40% of patients who underwent AF ablation . PV stenUltimately, the patient underwent successful repeat atrial fibrillation ablation employing a wide antral circumferential ablation technique with successful resolution of the left superior pulmonary vein. The patient's pacemaker was interrogated six months after ablation and demonstrated successful elimination of atrial fibrillation .We present a patient with severe post-AF ablation PV stenosis without pulmonary symptoms.Our patient's perfusion scan, which demonstrated no perfusion of the affected lung, is suggestive of pulmonary artery blood flow redistribution via pulmonary artery to systemic collaterals. The patient ultimately underwent safe repeat atrial fibrillation ablation with successful elimination of arrhythmia."} +{"text": "Comephorus spp.) represent a highly apomorphic taxon with unique skeletal morphology, soft anatomy, and reproductive ecology. Selection for novel behavior and life history may be evident in genes responsible for organismal energy balance, including those encoding subunits of the electron transport chain. Complete mitochondrial genomes were sequenced for the Big Baikal Oilfish and Little Baikal Oilfish (Comephorus dybowskii). Mitochondrial genomes encode genes essential for electron transport, and data provided here will complement ongoing investigations of genome-to-phenome maps for teleost respiration and metabolism. Phylogenetic analyses including oilfish mitogenomes and all publicly available cottoid representative sequences are largely concordant with previous studies.Sculpins are predominantly benthic sit-and-wait predators that inhabit marine and freshwaters of the Northern Hemisphere. In striking contrast to riverine relatives, sculpins endemic to Lake Baikal have diversified in both form and function, with multiple taxa having adaptations for pelagic and bathyal niches within the world\u2019s deepest lake. Baikal Oilfishes ( Comephorus baicalensis; Pallas Comephorus dybowskii; Korotneff Comephorus baicalensis is distinguished from C. dybowskii by having greater total length, greater proportional orbit length, shorter proportional pectoral fins, and smaller cephalic pore chambers was used as a reference sequence. A multiple alignment was conducted with MAFFT version 7 (Katoh and Standley Whole genomic DNA was isolated from fin clips collected from two specimens for each species, and voucher material was retained at the Sandel Laboratory of Aquatic Evolution at UWA. Mitochondrial genomes were generated using traditional Sanger sequencing at the Limnological Institute of the Russian Academy of Sciences and sequencing-by-synthesis on illumina HiSeq at the UAB Heflin Center for Genomic Sciences. Sanger reads were trimmed and aligned with Bioedit 7.0.0 Hall , and HiSCottus mitochondrial genomes (Balakirev et\u00a0al. MEGA 6 was used to select the optimum nucleotide substitution model and conduct a maximum-likelihood phylogenetic analysis (Tamura et\u00a0al."} +{"text": "The main goal of this analysis was prioritization of co-expressed genes and miRNAs that are thought to have important influences in the pathogenesis of colon and lung cancers.MicroRNAs (miRNAs) as small and endogenous noncoding RNAs which regulate gene expression by repressing mRNA translation or decreasing stability of mRNAs; they have proven pivotal roles in different types of cancers. Accumulating evidence indicates the role of miRNAs in a wide range of biological processes from oncogenesis and tumor suppressors to contribution to tumor progression. Colon and lung cancers are frequently encountered challenging types of cancers; therefore, exploring trade-off among underlying biological units such as miRNA with mRNAs will probably lead to identification of promising biomarkers involved in these malignancies. Colon cancer and lung cancer expression data were downloaded from Firehose and TCGA databases and varied genes extracted by DCGL software were subjected to build two gene regulatory networks by parmigene R package. Afterwards, a network-driven integrative analysis was performed to explore prognosticates genes, miRNAs and underlying pathways. A total of 192 differentially expressed miRNAs and their target genes within gene regulatory networks were derived by ARACNE algorithm. BTF3, TP53, MYC, CALR, NEM2, miR-29b-3p and miR-145 were identified as bottleneck nodes and enriched via biological gene ontology (GO) terms and pathways chiefly in biosynthesis and signaling pathways by further screening. Our study uncovered correlated alterations in gene expression that may relate with colon and lung cancers and highlighted the potent common biomarker candidates for the two diseases. The complex molecular interactions underlying cancers warrant identification of biological entities like miRNAs as well as the crosstalk between different cancers. Colon cancer is a fatal malignancy with estimated 1.4 million cases yearly that canData acquisition and pre-processing In the present article, colon cancer gene expression dataset generated by Illuminaga_RNASeqV2 containing 192 normal and cancer samples and 20532 genes was chosen from Firehose (https://confluence.broadinstitute.org/display/GDAC/Home). For the miRNA expression profiling data, lung cancer Illumina HiSeq included 231 normal and cancer samples and 1045 genes were retrieved from TCGA (https://www.synapse.org/#!Synapse:syn300013/wiki/27406). The expression values of miRNAs and mRNAs were subjected to expression Based filter and variance Based filter functions implemented in DCGL v2.0 R package to filteIn silico analysis and networking Predicted gene-miRNA interactions were collected from miRWalk 2.0 server based on miRBase database. Regarding the mRNAs, only the miRNAs target genes were retrieved by miRWalk from colon cancer transcripts. Afterwards, two independent gene regulatory networks were built using unique miRNAs and their target genes using arcana function with eps=0.05 implemented in parmigene R package . Next, gGene Ontology analysis and visualization To find the significantly over-represented biological GO terms and functions of gene products within regulatory network mRNAs, functional classification was performed using BINGO Cytoscape plugin running In order to study the functional roles of miRNA and their targets in biological pathways, pathway analysis was performed using PANTHER and mirPath v.3 (http://snf-515788.vm.okeanos.grnet.gr/), respectively. Building miRNA-mRNA interaction networksThe 192 most variable miRNAs and target transcripts extracted from lung and colon cancer data were subjected to build two independent interaction networks by ARACNE algorithm implemented in parmigene software (setting epsilon to 0.05). Information-theoretic approaches like ARACNE have beeAs shown in Exploring miRNA\u2013TF\u2013mRNA network The 192 miRNA variable transcripts of lung cancer data targeted 13711 validated genes based on miRWalk server. We then intersected between these 13711 targets and the most variable mRNAs in colon cancer data extracted from DCGL R package. As the parmigene method demands orthogonal matrices for inferring co-expression network, we then processed further with two matrices of miRNAs and mRNAs both including 192 samples and genes. Degree distribution and following motif discovery and receThe crossroads among the screened miRNAs, genes and TFs was illustrated in GO and pathway functional enrichment analysisAs shown in By representing the molecular interactions underlying biological processes, network biology paves the path to drug discovery, better understanding of diseases mechanism and cancer therapeutics -37. miRNWe aimed to explore biomarkers underlying both colon and lung cancers ;therefore, in the frame of network mining methods and topology feature analysis, a small number of putative genes, miRNAs and transcription factors were explored whose interplays are probably related to colon and lung cancers. An expected outcome of such a work would possibly identify crosstalk of miRNAs and genes in tumorigenesis in different tissues and more evidence for cancer diagnosis and treatment. In the present study, NGS data was chosen over microarray because: I) this technique provides more sensitive detection of transcripts, which is likely to be the reason for the ability of NGS data to detect low expressed genes while microarrays fail to differentiate between very low expressed and non-expressed genes ; II) accHowever, this analysis is challenged by some limitations. Firstly, despite well-demonstrated roles of miRNAs in regulating multiples target genes involved in different oncogenic pathways in cancers, we should be cautious about the fact that each miRNA could potentially target hundreds of genes. Therefore, we need a deeper understanding of miRNA biology and undeniable role of experimental practices to improve fidelity of bioinformatics results. Next, evidently from ontology analysis, target genes could barely provide a clear biological finding; therefore, research works addressing validating miRNA sites within mRNAs will decrease the ambiguity in defining regulatory interactions among miRNAs-targets. Furthermore, we inferred information-theoretic based undirected networks while connectivity between nodes does not mean the causal relationships; we then should be cautious about dynamic nature of cancers via strict analysis of statics networks. Additionally, it is essential to remove overestimated regulation dependencies by employing more sophisticated gene regulatory inference algorithms. Finally, network analysis at transcriptome level could be more intensified through merging studies with protein networks to draw more practical conclusions.It is concluded that utilizing dual information of miRNAs and mRNAs in cancers trade-off can help to discover important findings to identify underlying mechanisms and enlighten more molecular underpinnings of different cancers. We observed that the identified miRNAs-mRNA covered a wide range of known functions, mainly signaling pathways and biosynthesis implicated in colon and lung cancers.To summarize, conserved miRNAs and TFs like miR-195, miR-145, BTF3, Myc and TP53 with their targets could be considered as hallmark genes for future diagnosis and therapeutic researches where their rules could be confirmed by experiments.Utilizing dual information of miRNAs and mRNAs in cancers trade-off can help to discover important findings to identify underlying mechanisms and enlighten more molecular underpinnings of different cancers. We observed that the identified miRNAs-mRNA covered a wide range of known functions, mainly signaling pathways and biosynthesis implicated in colon and lung cancers.To summarize, conserved miRNAs and TFs like miR-195, miR-145, BTF3, Myc and TP53 with their targets could be considered as hallmark genes for future diagnosis and therapeutic researches where their rules could be confirmed by experiments."} +{"text": "Human learning and memory evaluation in real-life situations remains difficult due to uncontrolled variables. Buenos Aires waiters, who memorize all the orders without written support, were evaluated in situ. Waiters received either eight different orders and customers remained seated in their original locations (OL), or changed locations (CL). Match between orders, subjects and location was decreased only in CL. Waiters\u2019 feature/location strategy links client with position at the table and beverage later. The hypothesis we raise is that memory-schemas link working memory to long-term memory networks through rapid encoding, making the information resistant to interference and enabling its fast retrieval if necessary cues are present."} +{"text": "Lower extremity trauma during earthquakes accounts for the largest burden of geophysical disaster-related injuries. Insufficient pain management is common in disaster settings, and regional anesthesia (RA) has the potential to reduce pain in injured patients beyond current standards. To date, no prospective research has evaluated the use of RA in a disaster setting. This cross-sectional study assesses knowledge translation and skill acquisition outcomes for lower extremity RA performed with and without ultrasound guidance among a cohort of M\u00e9decins Sans Fronti\u00e8res (MSF) volunteers who will function as proceduralists in a planned randomized controlled trial evaluating the efficacy of RA for pain management in an earthquake setting.Background:Generalist humanitarian healthcare responders, including both physicians and nurses, were trained in ultrasound guided femoral nerve block (USGFNB) and landmark guided fascia iliaca compartment block (LGFICB) techniques using didactic sessions and interactive simulations during a one-day focused course. Outcome measures evaluated interval knowledge attainment and technical proficiency in performing the RA procedures. Knowledge attainment was assessed via pre- and post-test evaluations and procedural proficiency was evaluated through monitored simulations, with performance of critical actions graded by two independent observers.Methods:Twelve humanitarian response providers were enrolled and completed the trainings and assessments. Knowledge scores significantly increased from a mean pre-test score of 79% to post-test score of 88% (p<0.001). In practical evaluation of the LGFICB, participants correctly performed a median of 15.0 (Interquartile Range (IQR) 14.0-16.0) out of 16 critical actions. For the USGFNB, the median score was also 15.0 (IQR 14.0-16.0) out of 16 critical actions. Inter-rater reliability for completion of critical actions was excellent, with inter-rater agreement of 83.3% and 91.7% for the LGFICB and USGFNB evaluations, respectively.Results:Prior to conducting a trial of RA in a disaster setting, providers need to gain understanding and skills necessary to perform the interventions. This evaluation demonstrated attainment of high knowledge and technical skill scores in both physicians and nurses after a brief training in regional anesthesia techniques. This study demonstrates the feasibility of rapidly training generalist humanitarian responders to provide both LGFICB and USGFNB during humanitarian emergencies.Discussion: Among geophysical disasters, earthquakes result in high mortality rates and account for the largest burden of injuries,,,,,,,,Prior studies have demonstrated that regional anesthesia (RA) is a rapid and safe method for reducing pain caused by lower extremity trauma, and as such may have a role in improving pain management during the acute response phase of a major earthquake,,,,,The Regional Anesthesia for Painful Injuries after Disasters (RAPID) study is randomized controlled trial (RCT) that will be carried out in the immediate aftermath of a major earthquake to determine whether RA provided by generalist humanitarian medical responders, either with or without ultrasound-guidance, can improve pain treatment for lower limb injuries, above current standards of careEthicsThe RAPID study has received ethical approval from the M\u00e9decins Sans Fronti\u00e8res Ethical Review Board (Reference number: 1524) and has been preregistered at ClinicalTrials.gov (number: NCT02698228)Study Design Setting and PopulationThis cross-sectional study was designed to evaluate the efficacy of a focused training in regional anesthesia for lower extremity injuries provided to MSF volunteers who will serve as research proceduralists in a future RCT of RA for pain management in earthquake victimsThe study population was comprised of physician and nurse responders who had previously been deployed to humanitarian emergencies and were members of the MSF-USA association. Participants were made aware of the RAPID study and training prior to the meeting via digital correspondence with study investigators and were solicited to volunteer for participation.Participant Training and AssessmentTraining activities were designed to provide understanding of RA principles and competence in performing landmark guided fascia iliaca compartment blocks (LGFICB) and ultrasound-guided femoral nerve blocks (USGFNB). Study throughput is outlined in Following the initial assessment, participants took part in a three-hour interactive didactic session lead by study investigators using a semi-structured discussion platform that allowed for open-form content exchange between all participants. The educational information focused on RA principles and specific methodologies in performing LGFICB and USGFNBAfter completion of training activities, each participant was assessed through two observed simulation exams for performance of the LGFICB and the USGFNB. In each exam, participants were asked to perform the RA techniques using standard clinical equipment and a femoral regional anesthesia ultrasound model . During the simulation exams, two independent reviewers assessed each participant\u2019s technical competency using a preformed critical actions checklist with an objective scoring system. Assessed parameters evaluated appropriate positioning; identification of anatomic and ultrasonographic landmarks; use of sterile technique; provision of local superficial anesthetic; needle delivery; anesthetic injection; and proper procedural monitoring for possible adverse events.A post-training, fifteen question multiple-choice exam was performed to assess interval knowledge attainment. In the post-training assessment, participants were crossed-over to complete the alternative exam to the one they took at baseline .Data Collection Outcome MeasuresBaseline data on participants was collected using a structured questionnaire. Information on demographics, healthcare training, humanitarian response activities, ultrasound and RA experience was gathered. Knowledge assessment exams were scored with a single best answer for each question and participants were assigned a percent correct for both the pre-test and post-test. During observed simulation exams for the RA techniques, each rater provided a critical action completion score ranging from zero to sixteen based on eight assessment parameters. Accrued data was de-identified and entered into a password-protected database that was accessible only by study personnel.The primary outcome measures were the change in knowledge attainment based on mean pre- and post-test scores on the standardized exams and demonstration of technical competency in performing the LGFICB and USGFNB RA techniques. Technical competency was assessed based on adequate performance of critical actions during simulation assessments. Secondary outcome measures included the inter-rater reliability for the standardized critical action checklist and separate subgroup analyses of physician and nurses.Statistical AnalysisStatistical analyses were performed using STATA 13.0 . Characteristics of the cohort were evaluated using descriptive methods. Categorical variables were explored using frequencies with percentages, and continuous variables were analyzed using medians with corresponding interquartile ranges (IQR) or means with associated 95% confidence intervals (95% CI). Given the small sample size knowledge attainment data was analyzed using Shapiro-Wilks tests and frequency distributions to evaluate for normality. The results were found to satisfy criteria for normality and as such, one sample paired t-tests were used for the primary outcome of change in mean knowledge scores. A p value less than 0.05 was considered significant in primary outcome assessments.,Median scores with IQR for each rater were calculated for the LGFICB and USGFNB simulation assessments. Inter-rater reliability (IRR) was evaluated across all critical assessment variables based on rater agreement derived using Cohen\u2019s kappa calculation. Kappa values were interpreted according to previously utilized criteria with agreement classified as greater than 0.80 as representing excellent IRRTwelve MSF association members were enrolled and all participants completed the full study training and assessment procedures. The median age of the cohort was 41 years and the majority of participants were female. Half of participants reported their primary healthcare training as nurse and half as physician. The median years of healthcare practice and humanitarian response experience were eleven and five years respectively. Half of the cohort had prior experience with ultrasound use, though only a minority reported previous clinical application of RA techniques .The primary study outcomes are summarized in This study assessed knowledge translation and skill acquisition outcomes for simulated lower extremity RA performed both with and without ultrasound guidance among a small cohort of MSF volunteers who will function as proceduralists in a planned randomized controlled trial that will assess the efficacy of RA for pain management in the acute phase of a major earthquake,,,,,,,,,In the acute response phase to a natural disaster, where resources are often constrained, oligoanalgesia is common,,,Standardized assessment and training in research procedures is important in reducing error and deriving valid trial results,,,Although prior studies have assessed the performance of femoral never blockades after brief trainings in emergency department settings among physician and nurse trainees this study is the first to evaluate formal training of generalist humanitarian response providers in RA methodsThis work must be interpreted in the context of certain limitations. The presented results illustrate short-term acquisition of knowledge and skills among the MSF volunteers trained, but do not allow for assessment of application in actual disaster situations, nor for evaluation of skill retention over time. It is likely that similar to most technical skill sets, the study proceduralists will require refresher training prior to execution of the RAPID study, which has been built into the trial design. Although the population of humanitarian responders was drawn from a large pool of MSF volunteer personnel, the cohort was relatively small and not randomly selected, and as such the generalizability of these outcomes to the greater population of disaster healthcare personnel is not certain. During completion of the RAPID study this will be partially addressed, as there will be further onsite training for locally recruited healthcare providers, who will also serve as proceduralists during the later study phases. These later phase providers will be trained and assessed onsite using the same methods as described in this report.Prior to conducting a trial of RA in a disaster setting, providers need to gain the knowledge and skills necessary to perform the interventions. This study demonstrated high knowledge and technical skills scores with excellent inter-rater agreement between independent evaluators, illustrating the success of the focused training for generalist humanitarian response providers in the selected RA techniques. This work, in conjunction with the planned RAPID study, will contribute to the development of an enhanced evidence base to guide future care and improve health outcomes among high-risk patients injured in the settings of humanitarian emergencies.The data used for this analysis can be accessed via: https://figshare.com/s/1825267cbf21863b6cf4.All authors declare that they have no competing interests to disclose.Adam R. Aluisio, MD, MScWarren Alpert School of Medicine, Brown University, Department of Emergency Medicine55 Claverick Street, Room 274Providence, Rhode Island 02912, USAEmail: adam.aluisio@gmail.comCRED: Centre for Research on the Epidemiology of DisastersFICB: Fascia iliaca compartment blockFNB: Femoral nerve blockIQR: Interquartile RangeIRR: Inter-rater reliabilityLG: Landmark guidedLGFICB: Landmark guided fascia iliaca compartment blockLMIC: low- and middle-income countriesMoH: Ministry of HealthMSF: M\u00e9decins Sans Fronti\u00e8resRA: Regional anesthesiaRCT: Randomized Controlled TrialSAE: Serious Adverse EventsSD: Standard DeviationUS: UltrasoundUSG: Ultrasound guidedUSGFNB: Ultrasound guided femoral nerve blockWHO: World Health Organization"} +{"text": "The circadian clock underpins most physiological conditions and provides a temporal dimension to our understanding of body and tissue homeostasis. Disruptions of circadian rhythms have been associated with many diseases, including metabolic disorders and cancer. Recent literature highlights a role for the circadian clock to regulate innate and adaptive immune functions that may prime the host response to infectious organisms. Viruses are obligate parasites that rely on host cell synthesis machinery for their own replication, survival and dissemination. Here, we review key findings on how circadian rhythms impact viral infection and how viruses modulate molecular clocks to facilitate their own replication. This emerging area of viral-clock biology research provides a fertile ground for discovering novel anti-viral targets and optimizing immune-based therapies. Circadian rhythms are autonomous, self-sustaining, 24-h oscillations that synchronise physiological processes, such as sleep\u2013wake cycles, hormone release, cell regeneration, fluctuations in body temperature and metabolism, to external environmental cues. These rhythmic processes are controlled by the circadian timekeeping system that consists of a central circadian clock located in the suprachiasmatic nucleus (SCN) that links to a network of peripheral clocks located in every tissue Fig.\u00a0. The mamBMAL1 is a key component of the circadian clock ; mice deMany aspects of the innate and adaptive immune systems are under circadian control , 10. To Inflammatory lung diseases frequently show time-of-day variation in their severity, and a recent study from Gibbs and colleagues showed t. To assess the functional consequences of this observation, the authors immunised mice with ovalbumin and TLR9 ligand (CpG ODNs) adjuvant at various times of day. Vaccination at the time of increased TLR9 expression (ZT19) resulted in a greater immune response to ovalbumin, and this phenotype was lost in PER2 deficient mice. These observations are consistent with emerging evidence showing a role for the circadian clock to regulate host defences against bacterial pathogens [In addition to regulating host immunity to viral infections, the efficacy of viral vaccination has been reported to be under circadian control in rodents and humans. Silver et al. reported that expression of pattern recognition receptor Toll-like receptor 9 (TLR9) that recognises bacterial and viral DNA is circadian regulated . To asseathogens and suggPhillips et al. showed that patients immunised in the morning developed greater antibody responses to both hepatitis A and influenza vaccines . More reThe liver is one of the most circadian-regulated organs with 20% of genes showing circadian patterns of expression . Benegiabmal1-/- mice. Importantly, both studies confirmed an anti-viral role for BMAL1 using in vitro viral replication models that lack systemic circadian cues or host defenses, supporting a model where BMAL1 regulates cellular factors that are essential for viral replication. A comprehensive proteomic analysis of wild type and bmal1-/- primary cells revealed an enrichment of proteins involved in protein biosynthesis, endoplasmic reticulum function and intracellular vesicle trafficking [Bmal1 shows seasonal variation in human blood samples with the lowest levels observed during the winter months [Two recent studies report increased replication of herpes, influenza , respirafficking ; all patr months coincidir months .Herpes simplex virus (HSV) is a DNA virus whose gene expression is limited by histone deacetylation. CLOCK can function as a histone acetyltransferase, and Kalamkovi et al. reported that HSV hijacks this clock repressor to facilitate transcription of viral genes, where depletion or silencing CLOCK reduced viral protein expression , 31. TheGlucocorticoids (GCs) regulate carbohydrate, lipid and protein metabolism and are widely used as anti-inflammatory agents. GCs are secreted from the adrenal gland in a rhythmic circadian fashion, and their peak expression coincides with the onset of the active phase, suggesting a role in synchronizing signals between the SCN and peripheral tissues. GCs regulate gene transcription by activating the glucocorticoid receptor that binds GC response elements (GRE) in target gene promoters . Of noteWhile individual molecular circadian components have been reported to modulate viral infection, melatonin, a potent regulator of the circadian rhythm secreted by the pineal gland exhibitsA growing awareness of \u2018circadian disruption\u2019-associated pathologies, such as a high risk of cancer in shift workers, highlights the potential for this pathway to be deregulated in viral-associated cancers \u201344. Yang+ T-lymphocytes between the morning and evening coinciding with changes in the circadian pattern of serum cortisol levels [Human Immunodeficiency Virus (HIV) infection has been associated with the disruption of circadian-regulated physiological processes, including a blunting of systolic blood pressure decline from day to night . Malone l levels . To undel levels . Furtherl levels , 54.Studies with Simian Immunodeficiency Virus (SIV) reported perturbation of several circadian parameters of body temperature and activity parameters, where the amplitude of temperature and locomotor activity was significantly reduced . The autOther viral infections have been reported to influence circadian rhythms. Coxsackievirus A16 (CVA16) is one of the major causes of hand, foot and mouth disease, and transcriptomic analysis of infected human embryonic kidney cells identified differentially expressed miRNA target genes involved in circadian rhythm pathways, providing some insights into CAV16 induced pathogenesis . Human TAedes aegypti mosquito acts as a carrier for many viral infections such as dengue fever and Zika virus. Lima-Camara et al. reported that dengue virus infection increased the amplitude of rhythmic locomotor activity in the mosquito and speculated this would increase the vector\u2019s capacity to transmit virus [Culicoides biting midges that are vectors for African horse sickness and Bluetongue virus [A. aegypti, circadian regulators may provide new therapeutic targets [Circadian rhythms are likely to impact viral transmission especially if one considers zoonoses where multiple species can act as viral reservoirs Fig. . For patit virus . This ciue virus . Conside targets .Given the interplay between virus and the host circadian mechanism, host susceptibility to infection or disease is not only dependent on the infectivity of the viral inoculum, transmission route and length of exposure, but on the time of day when the pathogen is encountered. Understanding how viruses interact with host circadian rhythms has the potential to influence the treatment and clinical management of viral infections. In terms of circadian modulating therapies for treating or preventing viral infections, this could involve both pharmacotherapy and chronotherapy. Thus, it is possible that the efficacy of current anti-viral therapies could be improved by altering the time of drug administration. Recent advances in T cell engineering therapies show promising results using T cell receptor (TCR) or chimeric antigen receptor engineered T cells targeted against human viral antigens \u201367. InteHow do viruses engage with the molecular clockwork and modulate timekeeping? The discovery that the transcriptional clock mechanism is universal and exists in essentially every cell of the body highlights the potential of these TFs to regulate host susceptibility to viral infection directly via binding viral DNA genomes or indirectly via controlling host gene expression Fig. . The rep"} +{"text": "These data show that cigarette smoke exposure decreases in vivo MSC and HSC number and also increases pro-proliferative gene expression by cigarette smoke-exposed MSCs, which may stimulate HSPC expansion. These results of this investigation are clinically relevant to both bone marrow donors with a history of smoking and bone marrow transplant (BMT) recipients with a history of smoking.Effects of tobacco smoke on hematologic derangements have received little attention. This study employed a mouse model of cigarette smoke exposure to explore the effects on bone marrow niche function. While lung cancer is the most widely studied consequence of tobacco smoke exposure, other malignancies, including leukemia, are associated with tobacco smoke exposure. Animals received cigarette smoke exposure for 6 h/day, 5 days/week for 9 months. Results reveal that the hematopoietic stem and progenitor cell (HSPC) pool size is reduced by cigarette smoke exposure. We next examined the effect of cigarette smoke exposure on one supporting cell type of the niche, the mesenchymal stromal cells (MSCs). Smoke exposure decreased the number of MSCs. Transplantation of na\u00efve HSPCs into irradiated mice with cigarette smoke exposure yielded fewer numbers of engrafted HSPCs. This result suggests that smoke-exposed mice possess dysfunctional niches, resulting in abnormal hematopoiesis. Co-culture experiments using MSCs isolated from control or cigarette smoke-exposed mice with na\u00efve HSPCs While pulmonary disorders are the most obvious manifestation of cigarette smoke-induced disease, there is a growing appreciation that smoking and chronic lung disease are associated with significant systemic consequences and comorbidities. Distal organ and tissue injury, linked to systemic inflammation and oxidative stress, commonly result in skeletal myopathy, cardiovascular disease, osteoporosis, depression and metabolic derangement.Stem and progenitor cells play a pivotal role in tissue maintenance and repair in response to injury, and it has been proposed that resident and/or hematopoietic progenitor cell perturbations may be pathogenic in smoking-related emphysema . Further+ cytotoxic T cell lymphocytosis and neutrophilia. BrdU labeling studies show decreased transit time through the post-mitotic pool of the bone marrow, consistent with chronic stimulation of hematopoiesis .,33.18,33These data support our hypothesis that hematologic changes in cigarette smokers are caused by damage to niche cells, specifically MSCs and their progeny. We have shown that smoke exposure decreased HSPC pool size and concomitantly deceased MSC number. The decreased number of MSCs corresponded to a decrease in na\u00efve HSPC engraftment after bone marrow transplantation in smoke-exposed animals. In spite of this decrease in engraftment and number of HSPCs and MSCs, smoke exposure also altered MSC gene expression of pro-proliferative signaling proteins. Our data thus suggest that smoke exposure leads to dysregulation of hematopoiesis through disruption of MSC signaling pathways in addition to decreasing MSC number. This may serve as one mechanism by which smoke exposure promotes greater peripheral leukocyte production in cigarette smokers. These data also offer potential targets of therapeutic intervention with regards to both bone marrow donor and transplant recipient with a history of cigarette smoke exposure."} +{"text": "Aortic valve replacement is the second most common cardiothoracic procedure in the UK. With an ageing population, there are an increasing number of patients with prosthetic valves that require follow-up. Imaging of prosthetic valves is challenging with conventional echocardiographic techniques making early detection of valve dysfunction or complications difficult. CT has recently emerged as a complementary approach offering excellent spatial resolution and the ability to identify a range of aortic valve replacement complications including structural valve dysfunction, thrombus development, pannus formation and prosthetic valve infective endocarditis. This review discusses each and how CT might be incorporated into a multimodal cardiovascular imaging pathway for the assessment of aortic valve replacements and in guiding clinical management. The utility of cardiac CT for the assessment of possible aortic valve replacement dysfunction has risen rapidly over the past 10\u2005years following a similar, albeit delayed, trajectory to CT coronary imaging. It can be used to assess mechanical and bioprosthetic valves inserted surgically as well valves inserted using transcutaneous aortic valve implantation (TAVI). Clinicians familiar with both cardiac CT and valvular heart disease have identified a number of specific situations where CT can help in the assessment of possible aortic valve replacement dysfunction by providing complementary diagnostic information to transthoracic echocardiography, transoesophageal echocardiography and cardiac MR. These include the identification of pannus formation, thrombus, premature bioprosthetic leaflet degeneration, assessment of bileaflet mechanical valve leaflet motion and aortic root abscess formation. While the role of cardiac CT is relatively new in this setting, its use is steadily expanding across the world, with many experienced centres now using it routinely. This article evaluates the evidence in support of cardiac CT imaging for the detection of possible aortic valve replacement dysfunction and aims to prompt clinicians to consider it in specific clinical scenarios.Selecting the appropriate prosthetic heart valve has traditionally been a difficult decision for many patients undergoing surgical aortic valve replacement. However, recent advances in bioprosthetic valve design, coupled with an ageing population, have witnessed increasing use of these valves in preference to metallic valves. With the recent addition of TAVI, the number of patients with functioning bioprostheses is only set to expand further. Surveillance of bioprosthesis function, looking for evidence of valve degeneration, forms an integral part of the long-term management of patients with these valves and a substantial healthcare burden.Structural valve dysfunction can have catastrophic consequences, yet its underlying pathophysiology remains incompletely understood. The term structural valve dysfunction encompasses intrinsic functional changes to the valve leaflets including retraction or tearing, progressive stenosis and disruption of the annular housing or sewing ring. The principal pathological driver behind this degeneration and eventual failure appears to be leaflet calcification. This most commonly results in valvular regurgitation due to tearing of the leaflets but may also cause increasing valve stiffness, restenosis and peripheral embolism.The mechanisms driving prosthetic valve calcification are incompletely understood with several different processes having been implicated.While large-scale clinical trials are currently lacking, the requirement for improved assessment of bioprosthetic valve calcification was recently illustrated in the case of severe bioprosthetic valve obstruction in a 13-year-old girl who died suddenly just 23\u2005months after implantation of a bovine pericardial aortic bioprosthesis.et alOne of the major advantages biological prosthetic heart valves have over mechanical alternatives is the lack of a requirement for long-term anticoagulant use. During bioprosthesis endothelialisation, in the first 3\u2005months after implantation, thrombus formation can occur in 0.8\u20134.0% of cases.et alLeetmaa In light of the asymptomatic presentation of cusp thrombosis that occurs in spite of dual-antiplatelet therapy, important questions have been raised regarding the clinical relevance of hypoattenuated thickening and whether CT may more appropriately stratify antithrombotic therapy following transcatheter valve implantation. Importantly, the clinical significance of HALT has not been validated beyond these observational studies and the recent publication of low 30-day stroke rates following TAVI suggests that the presence of this finding does not always translate into significant thromboembolic events.Imaging of mechanical prosthetic valves has traditionally been performed using transthoracic echocardiography, transoesophageal echocardiography and fluoroscopy.Acquired mechanical prosthetic valve obstruction (PVO) is an uncommon but serious and potentially fatal complication of valve replacement.30Cardiac CT in suspected acquired mechanical PVO enables evaluation of leaflet opening and closing angles, dynamic leaflet motion and the composition of perivalvular masses valve helping to differentiate between valve thrombosis and pannus formation.33Prosthetic valve infective endocarditis carries a very high in-hospital mortality rate of 20\u201340%.37While the temporal resolution of echocardiography often means that highly mobile vegetations are better visualised on echocardiography, large prosthetic valve vegetations can be readily seen on CT as microlobulated, hypoattenuating lesions attached to the leaflets or sewing ring.35et alIn 2014, Ghersin 2.40Multiple factors can affect image quality when assessing mechanical aortic valve prostheses using CT, in particular the presence of cardiac arrhythmia and older prosthetic valve types.Based on current practice in experienced valve centres, we suggest that CT should be performed as an anatomical assessment following transthoracic echocardiography in patients with suspected prosthetic aortic valve dysfunction and 5. TThe diagnosis and management of aortic valve replacement dysfunction remains a significant clinical challenge. Cardiac CT provides complementary assessments of these valves allowing detection of structural dysfunction, leaflet calcification, thickening, thrombus and pannus formation. This can help to stratify downstream management and clinical decision-making as part of multimodality imaging approach."} +{"text": "In utero exposure to infections is associated with adverse neurocognitive outcomes in the offspring. Elevated maternal prenatal serum inflammatory markers, such as C-reactive protein (CRP), have been associated with increased risks of neurodevelopmental disorders, including schizophrenia, later in life. The objective of this study is to investigate the associations between elevated serum concentrations of CRP in early gestation, prospectively assayed in maternal sera, and adolescent psychotic experiences and academic performance. We hypothesised that elevated maternal CRP is associated with adolescent psychotic experiences and poorer academic performance.Using data from the Northern Finland Birth Cohort 1986 (NFBC1986), a prospective birth cohort including data since before birth, we examined the association between maternal CRP levels in early gestation and adolescent psychotic experiences and poorer academic performance , controlling for sex and maternal education level using multivariable regression analysis. Prior to analyses we determined there was sufficient power to detect small associations (OR>1.68) for these variables.After controlling for sex and maternal education, those in the highest tertile of prenatal maternal CRP had increased odds of auditory hallucinations (on the PROD-screen) at age 16 years , and poorer school academic performance .Maternal prenatal immune activation is associated with neurodevelopmental outcomes in adolescent offspring. This work extends previous findings regarding prenatal/childhood immune activation and clinical psychiatric diagnoses in adult offspring."} +{"text": "Salmonella enterica subsp. enterica serovar Poona strain ATCC BAA-1673. We employed in silico bioinformatics tools to subtract the strain-specific paralogous and host-specific homologous sequences from the bacterial proteome. The sorted proteome was further refined to identify the essential genes in the pathogenic bacterium using the database of essential genes (DEG). We carried out metabolic pathway and subcellular location analysis of the essential proteins of the pathogen to elucidate the involvement of these proteins in important cellular processes. We found 52 unique essential proteins in the target proteome that could be utilized as novel targets to design newer drugs. Further, we investigated these proteins in the DrugBank databases and 11 of the unique essential proteins showed druggability according to the FDA approved drug bank databases with diverse broad-spectrum property. Molecular docking analyses of the novel druggable targets with the drugs were carried out by AutoDock Vina option based on scoring functions. The results showed promising candidates for novel drugs against Salmonella infections. The emergence of novel pathogenic strains with increased antibacterial resistance patterns poses a significant threat to the management of infectious diseases. In this study, we aimed at utilizing the subtractive genomic approach to identify novel drug targets against Salmonella enterica subsp. enterica serovar Poona str. ATCC BAA-1673 using the subtractive genomics approach.Recent progress in the field of computational biology and bioinformatics has generated various in silico analysis and drug designing approaches, eliminating the time and cost involved in the trial and error experimentations that go into drug development . These mSalmonella enterica subsp. enterica serovar Poona str. ATCC BAA-1673 is a potent food-borne pathogen in humans N-acetyl-glucosamine-deacetylase and 3-deoxy-manno-octulosonate cytidylyltransferase (CMP-KDO synthetase) are associated with lipopolysaccharide biosynthesis pathway. Phosphate regulon response regulator OmpR, nitrogen regulation sensor histidine kinase GlnL, and response regulator CheB are associated with two-component system pathway. LPS is composed of a conserved core oligosaccharide, lipid A, linked to a variable O-antigen in the cell membrane of the Gram-negative bacteria, thus providing outer membrane stability [ Salmonella Poona have developed pathways that attribute resistance to CAMP [The proteins in tability . Drug th to CAMP , 20. Met to CAMP , 18. ThuThe current study was further reinforced by performing comparative docking studies of the novel druggable proteins with the ligands. Binding affinities from docking were compared between our target proteins and intended targets from other species against the corresponding drug. The shortlisted potential drug targets showed a pattern of similar binding characteristics, similar residues involved in the active site, and lower free energy \u20137. Thus, Salmonella Poona system. Among these, 11 proteins were already highly identical with the FDA approved drug targets. 6 proteins were proposed as novel drug targets to combat against Salmonella Poona which showed moderate similarity (65\u201330%) with the targets of FDA approved drugs that were used against other organisms. Furthermore, docking studies were used to predict the binding of existing FDA approved drugs to the novel targets within the proteome of the pathogen and also with the drug-specific FDA approved database target to compare the binding pattern between them.The vast array of information regarding the proteomes and genomes of various prokaryotic organisms and knowledge obtained from the human genome project can be manipulated to accelerate drug designing and gain further knowledge of pharmacogenomics in the treatment of bacterial infections. Subtractive genomics can aid in the identification of proteins targeted by existing FDA approved targets. A total of 52 potential targets were found within the"} +{"text": "Dear SirAlimentary tract duplications are epithelial-lined cystic or tubular structures attached to bowel wall and supplied by mesenteric vessels. Association between intestinal malrotation and duplication cyst, especially of jejunal location is rarely mentioned in literature[1-5]. We are reporting a rare coexistence of isolated jejunal duplication cyst and malrotation in a neonate with intestinal obstruction.A 15-day-old male neonate was brought to emergency for multiple episodes of bilious vomiting. The baby was born full-term by spontaneous vaginal delivery at home and antenatal ultrasonography(USG) was not done. At presentation, he was 2500 gm, moderately dehydrated, pulse 160/min and respiratory rate was 46/min. Resuscitation was started immediately and the nasogastric tube inserted. Abdomen was soft, non-tender and a mobile mass was palpable in left upper abdomen. Plain X-ray abdomen showed distended stomach and duodenum. Rest of the abdomen was gasless, but there was presence of rectal gas in pelvis . USG revealed a well defined thick walled cystic lesion in left mid abdomen measuring 42\u044537mm suggestive of duplication cyst . Doppler imaging showed \"Whirlpool sign\" in epigastric region with superior mesenteric vein (SMV) curving from right to left of superior mesenteric artery (SMA) suggesting midgut malrotation . At surgery, a non-communicating jejunal duplication cyst, intimately adherent to jejunal wall and compressing the intestinal lumen was found . Malrotation was also present which was corrected. Duplication cyst was excised along with a portion of adjoining jejunum. End-to-end jejunal anastomosis was done. Postoperative period was uneventful. Combination of enteric duplication and intestinal malrotation is a rare entity and may present as an acute surgical emergency [1-5]. Gastric and duodenal distension on plain X-ray of abdomen is suggestive of duodenal obstruction. The presence of rectal gas in addition to dilated stomach and duodenum will commonly point towards partial duodenal obstruction. This can occur in malrotation due to compression of distal duodenum by Ladd's bands [3]. Similarly our preoperative suspicion was malrotation on plain X-ray abdomen. Color Doppler imaging showing Whirlpool flow pattern of SMV around SMA is suggestive of midgut malrotation. Ultrasonography is very reliable in diagnosing duplication cysts.It will show an inner hyperechoic rim of mucosa-submucosa and an outer hypoechoic rim of muscular layer [2]. Duplication cysts are thick walled because it is composed of smooth muscle and mucosa as opposed to other types of cysts such as mesenteric and omental cysts. Our preoperative diagnosis coincided with operative findings.Surgical removal of duplication cyst preserving normal bowel is possible in some cases, but is extremely difficult [1]. Resection of duplication with the native bowel is the usual procedure due to common blood supply . This case represents a rare coexistence of two congenital malformations of GIT. Ultrasonography is very helpful in detecting both duplication cyst and malrotation.Source of Support: NilConflict of Interest: None"} +{"text": "Neurodegenerative disorders, such as Alzheimer\u2019s disease (AD), are associated with characteristic patterns of neuropathological spread in the brain. Disease progression is usually accompanied by regional atrophy that can be detected noninvasively using structural magnetic resonance imaging (MRI). A wealth of data has demonstrated the value of quantitative measurements of regional atrophy in AD, suggesting that volumetric MRI (vMRI) may be a useful clinical tool. vMRI provides biological evidence of neurodegenerative disease in patients with cognitive impairment. However, several hurdles impede implementation of vMRI in clinical practice. These include a lack of standardized MRI acquisition protocols, spatial distortions in MRI data, labor-intensive vMRI methods susceptible to interoperator variability, a lack of normative ranges for volume measures, and difficulty integrating vMRI in clinical workflow. Advances in vMRI have resulted from multi-institutional studies of brain imaging, such as the Alzheimer\u2019s Disease Neuroimaging Initiative (ADNI), and help address these challenges. New, fully-automated measures of brain structure volumes coupled with large, multi-center studies using standardized MRI protocols now allow the development of age-adjusted normative ranges for vMRI. Such advances are critical for providing physicians a framework for assessing the pattern and degree of regional atrophy in a patient's brain and applying vMRI in clinical practice."} +{"text": "Impairments in self-assessment are commonly found in people with schizophrenia and impairments in introspective accuracy (IA) predict impaired functional outcome. previous studies have suggested mis-estimation of cognitive and functional skills predict impairment in everyday functioning at least as much as ability scores. In this study, we examined self-assessment of social cognitive ability and related these self-assessments to assessments of social cognition from informants, to performance on tests of social cognitive ability, and to everyday outcomes. The difference between self-reported social cognitive abilities and informant ratings was our measure of IA.People with schizophrenia (n=135) performed 8 tests of social cognitive abilities. They also rated their social cognitive abilities on the Observable Social Cognition Rating Scale (OSCARs). High contact informants also rated social cognitive ability and everyday outcomes, while unaware of the patients\u2019 other scores. Social competence was also measured with a performance-based assessment and clinical ratings of negative symptoms were also performed.Patient reports of their social cognitive abilities were uncorrelated with performance on social cognitive tests and with three of the four domains of everyday functional outcomes. IA, in specific overestimation of performance compared to informant ratings, predicted impaired everyday functioning across all four functional domains. IA scores predicted functional outcomes even when the influences of social cognitive performance, social competence, and negative symptoms were considered in regression models. Thus, self-assessment of social cognition had a relatively specific impact social outcomes.Mis-estimation of social cognitive ability was a more important predictor of social and nonsocial outcomes in schizophrenia than performance on social cognitive tests. These results suggest that consideration of IA is critical when attempting to assess causes of everyday disability and when implementing interventions aimed at disability reduction."} +{"text": "Until now, no consensus is reached for the standardized assessment and quantification of extent and severity of myocardial ischemia and necrosis by cardiac magnetic resonance imaging (CMR). However, there is a good evidence base suggesting that these parameters might ameliorate established risk prediction models and thus might lead to an improved management of patients with stable coronary artery disease (CAD). Objective of this study therefore is to elaborate an easy-to-use algorithm for the quantification of ischemia and necrosis and to validate the obtained data in a large cohort of CAD patients.Patients with known or suspected CAD referred for adenosine-perfusion CMR were consecutively and prospectively enrolled. Examinations were conducted on a 1.5 Tesla whole-body scanner using a 5-element phased array surface receiver coil. All patients underwent standard first-pass perfusion imaging under adenosine infusion for the detection of myocardial ischemia and late gadolinium enhancement (LGE) imaging for the assessment of myocardial necrosis. Based on these sequences, ischemia and necrosis were quantified using a novel algorithm.Primary endpoint was defined as combination of cardiac death, non-fatal myocardial infarction and stroke. Several risk prediction models containing clinical and CMR parameters were built and analyzed with regard to correct risk stratification and endpoint prediction.The study cohort consisted of 845 patients. Median follow-up was 3.66 years. During this time, 61 primary endpoints occurred. Cutoff values for myocardial ischemia and LGE could be defined . A risk prediction model containing this information proved to be superior in comparison to models based on conventional CMR features .Myocardial ischemia and necrosis above the defined cutoff values are strongly associated with major clinical endpoints. Quantification of these parameters provides additive information and leads to improved risk stratification."} +{"text": "Cognitive impairments are a core feature in schizophrenia patients and are also observed in first-degree relatives of the schizophrenia patients. However, substantial variability in the impairments exists within and among schizophrenia patients, first-degree relatives and healthy controls. A cluster-analytic approach can group individuals based on profiles of traits and create more homogeneous groupings than predefined categories.Here, we investigated differences in the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery among 81 schizophrenia patients, 20 unaffected first-degree relatives and 25 healthy controls. To identify three homogeneous and meaningful cognitive groups regardless of categorical diagnoses , cognitive clustering was performed using a k-means clustering analysis approach, and differences in the BACS subscales among the cognitive cluster groups were investigated. Finally, the effects of diagnosis and cognition on brain volumes were examined.As expected, there were significant differences in the five BACS subscales among the diagnostic groups . The cluster-analytic approach generated three meaningful subgroups: (i) neuropsychologically normal , (ii) intermediate impaired and (iii) widespread impaired . The cognitive subgroups were mainly affected by the clinical diagnosis , and significant differences in all BACS subscales among clusters were found . The effects of the diagnosis (SCZ1 patient . We founmutation . MoreovepncA polymorphisms. Given the high likelihood of frameshift mutations resulting in resistance and the high specificity (94%\u201398%) of pncA SNPs for pyrazinamide resistance (pncA sequence, but its diagnostic accuracy has not yet been adequately tested (A diversity of \u2013A limitation of our study is that phenotypic pyrazinamide susceptibility testing was not performed on the sequenced isolates. Nonetheless, correlation with phenotypic testing has been previously reported in the literature for most polymorphisms, enabling us to estimate the proportion likely to be pyrazinamide resistant (pncA polymorphisms from geographically disparate countries suggests that guidelines to empirically use pyrazinamide in drug-resistant TB regimens, including shorter MDR TB regimens (The high prevalence of pncA gene mutations associated with pyrazinamide resistance in drug-resistant tuberculosis, South Africa and Georgia.Supplemental methods for study of"} +{"text": "The initiation and progression of malignant tumors is driven by distinct subsets of tumor-initiating or cancer stem-like cells (CSCs) which develop therapy/apoptosis resistance and self-renewal capacity. In order to be able to eradicate these CSCs with novel classes of anti-cancer therapeutics, a better understanding of their biology and clinically-relevant traits is mandatory.Several requirements and functions of a CSC niche physiology are combined with current concepts for CSC generation such as development in a hierarchical tumor model, by stochastic processes, or via a retrodifferentiation program. Moreover, progressive adaptation of endothelial cells and recruited immune and stromal cells to the tumor site substantially contribute to generate a tumor growth-permissive environment resembling a CSC niche. Particular emphasis is put on the pivotal role of multipotent mesenchymal stroma/stem cells (MSCs) in supporting CSC development by various kinds of interaction and cell fusion to form hybrid tumor cells.A better knowledge of CSC niche physiology may increase the chances that cancer stemness-depleting interventions ultimately result in arrest of tumor growth and metastasis. Various models are available for the generation of tumor initiating cells which subsequently give rise to neoplasias and malignant cancers including a hierarchical , 2 and aTumor initiation of the hierarchical model starts within a normal stem cell niche (SCN) which regulates proliferation, apoptosis resistance and maintains stemness whereby a normal stem cell evades regulation resulting in an aberrant/tumorigenic stem-like cell, also known as cancer stem-like cell (CSC) , 12. BesExamples of the hierarchical model have been shown in solid tumors such as breast cancer and in non-solid tumors such as acute myeloid leukemia , 2. For The stochastic model represents a second feasibility to circumstantiate tumor initiation. In comparison to the hierarchical model, every tumor cell within the stochastic model is biologically homogenous with an equal probability to initiate, maintain and promote tumor growth whereby functionalities depend on both, extrinsic factors originating from the tumor microenvironment and intrinsic factors such as signaling pathways and levels of transcription factors , 27. TumExamples of the stochastic model can also be found in solid and non-solid tumors such as colorectal cancer, lung adenocarcinoma and lymphoblastic leukemias \u201332.Whereas the stochastic model primarily addresses genetic heterogeneity without consideration of potential phenotypic variations within the genetically homogenous tumor cell population , the hieConsequently, both models of tumor initiation result in aberrant/tumorigenic stem-like cells which further promote tumor development and progression. However, little is known about the mechanism and the existence of a cancer stem cell niche (CSCN) for CSC generation and maintenance of tumor growth.Whereas tumor tissue harbors a variety of different cell populations including tumor cells in different states of development, one possibility of CSC development includes the hypothesis to be derived from neoplastic transformation during development or self-renewal of normal tissue-specific stem cells and to be primarily associated with solid tumors . AlternaMoreover, in a human myeloid leukemia model, phorbol ester-induced differentiation of U937 leukemia cells resulted in acquired adherence of cell cycle-arrested and differentiated monocyte/macrophage-like cells for several weeks. A decreasing threshold of phorbol ester or interference with the downstream signaling cascade of phorbol ester-activated protein kinase C interrupted transactivating processes via AP-1 (predominantly Jun/Fos) and NF\u03baB and induced retrodifferentiation , 42. ThiTogether, these findings suggest that certain stimuli which may include damage products and DAMPs within a tumor cell population can establish a CSCN and contribute to a retrodifferentiation process to rejuvenate tumor cells to a more stem-like phenotype with enhanced self-renewal capacity Fig.\u00a0. MoreoveA sensitive balance of timely available internal and external stimuli within a CSCN may also enable other modes of CSC development such as MSC-tumor cell fusion or entosis. Both types of interaction involve MSC as a potential cellular partner resulting in distinct functional hybrids. Although generally considered rare events, formation of hybrid cells via entosis or via fusion follow completely different mechanisms . EntosisThe normal SCN harbors stem cells and is responsible for regulating stem cell maintenance, in particular the balance between self-renewal and differentiation. Moreover, the normal SCN represents a dynamic and complex compartment whereby additional components including endothelial, immune and stromal cells, extracellular matrix, cell adhesion molecules, soluble factors and microvesicles/exosomes contribute to an environment necessary for enabling both, self-renewal and the capability to differentiate . Based oPrevious work described that stem cells reside in fixed compartments together with other cells determining stem cell behavior and regulating stem cell maintenance . Thus, tOne major prerequisite for tumor growth is the supply with nutrients and oxygen via blood vessels indicating the necessity of a CSCN localizing in the vicinity of vascular structures. Indeed, brain tumor stem cells have been reported to reside at perivascular regions . In variBesides neo-vascularization within the tumor microenvironment, the extracellular matrix (ECM) provides an important structural scaffold comprising fibrous proteins such as collagens, elastin, laminins, and fibronectin, globular proteins including the IgG superfamily integrins and cellular proteases, for instance MMPs, cathepsins and kallikreins for ECM remodeling . During When viewing a CSCN as a coordinated network of locally interacting cells cells, adipocytes, immune cells cells, dendritic cells (DC), macrophages) and mesenchymal cells ) together with dynamic thresholds and gradients of soluble factors in a specific ECM environment , then interference with this balanced homeostasis is predicted to alter CSC development Fig.\u00a0. Thus, EHuman tissue kallikreins also belong to the family of serine proteinases that are involved in degradation of ECM components such as fibronectin, laminin and collagen , 80. In Apart from distinct ECM components and appropriate restructure by distinct proteases that are required for a CSCN to promote CSC development, self-renewal and migration, adjacent cell types are also associated with a CSCN establishment via direct and indirect communication processes with tumor-derived cells to enable CSC development.An important cell population during tumorigenesis is represented by MSC. These multipotent stromal cells are located predominantly at perivascular niches of nearly all human tissues and organs and display a plethora of functions including tissue repair, immunomodulation and stem cell homeostasis \u201389. SubpRegulation of CSC generation also involves a diverse range of soluble factors including cytokines, chemokines, growth factors, hormones, metabolites and further trophic molecules. Breast cancer stem-like cells which are characterized by low levels of CD24, high levels of CD44, and aldehyde dehydrogenase expression , 103 havProduction and release of CCL5 by MSC has been suggested to activate corresponding receptors such as CCR5 on adjacent breast cancer cells thereby promoting altered breast cancer development and metastasis . MoreoveAccording to their recruitment to tumor sites associated with direct interactions of MSC with tumor cells, multipotent MSC may represent a major cellular component of a CSCN since various studies reported mutual acquisition of properties between both interaction partners which alter the original cell fate , 52.2+, small molecules such as microRNAs or second messenger are transported and exchanged via gap junctions allowing regulation of cell proliferation, differentiation and homeostasis maintenance [Gap junctions enable the direct interaction between two neighboring cells, also known as gap junctional intercellular communication (GJIC). Thereby, each cell contributes equally to gap junction formation. Gap junction channels consist of hemichannels/connexons which in turn are composed of six connexin protein subunits that form a pore through the plasma membrane , 112. Inntenance , 113. Duntenance . Furtherntenance . Moreoventenance . Dormancntenance Whereas GJIC proceeds between two tightly adjacent cells, nanotubes are characterized by thin, F-actin rich structures which link interacting cells over longer distances. These dynamic cytoplasmic protrusions facilitate communication via exchange of various biological cargo including small molecules and organelles . NotablyThe Notch signaling pathway plays a crucial role in cellular processes including tissue repair, stem cell maintenance and regulation of immune cell functions . There iTrogocytosis has been initially observed between immune cells as an active mechanism whereby lymphocytes extract surface molecules from antigen-presenting cells . More reDirect interaction and communication between MSC and tumor cells including GIJC, nanotube formation, Notch signaling, and trogocytosis may contribute to the generation of CSCs together with mutual exchange of distinct factors which alter properties of the involved cell populations. For example, cancer cell\u2013derived interleukin1 can stimulate prostaglandin E2 secretion by MSC operating in an autocrine manner to further induce expression of cytokines by the MSC which in turn activate \u03b2-catenin signaling in the cancer cells in a paracrine fashion and formation of CSCs .Together, these different types of direct interactions emphasize the importance and requirements of tumor-associated cells such as MSC within a CSCN to relay cellular properties that alter the original phenotype of tumor cells towards CSCs.In addition to direct interactions altering CSC phenotype and function, indirect communication plays a pivotal role within CSCN. It involves both the release of soluble molecules such as metabolites and hormones and the exchange of microvesicles and exosomes .In CSCN, metabolites including lactate, glutamine and keton bodies mutually reprogram metabolism of stromal stem cells and cancer cells favoring adaption of tumor cells to dynamic fluctuation of CSCN. Activation of CSCN homing CAFs by tumor cells leads to metabolic reprogramming of CAFs to a glycolytic phenotype meaning elevation of glucose uptake and elevation of lactate secretion serving as nutrient for adjacent cancer cells , 130. OnFurthermore, hormones as soluble agents have been demonstrated to influence CSCs. For instance, progesterone induced the expansion of breast cancer stem-like cells .Exosomes are characterized as homogeneous, 40 to 100\u00a0nm small endocytosed membrane particles which can be mutually exchanged by tumor cells and adjacent cell populations in the tumor microenvironment, particularly macrophages and MSC. These small particles contain a variety of proteins, lipids, functional RNAs and regulatory miRs , 136. AlAlthough knowledge about CSCs originating from a CSCN is limited, the tumor microenvironment in which CSCs reside, provides a structural scaffold with various resident cancer-associated aberrant cell types which contribute to tumor growth and exchange soluble factors by mutual intercellular communications. Due to progressively increasing tumor cell growth and impaired vascularization, some tumor cells within the center of a solid tumor have limited access to nutrients. An impaired nutrient availability during expansion of the tumor size leads to hypoxic and more acidic conditions with starvation of the inner tumor cells eventually resulting in autophagy and necrosis/necroptosis , a process required for metastasis, through activation of EMT transcription factors resulting in e.g. loss of E-cadherin , 157. InFollowing hypoxia and EMT, cancer cells can escape the primary tumor niche and migrate and disseminate to distant organs , 165.Besides the contribution of hypoxic conditions to metastasis, low pH/acidic conditions as a result of lactate release from increased anaerobic glycolysis of tumor cells may favor metastasis as well. Acidic conditions are proposed to activate proteases such as cathepsins which in turn degrade ECM for tumor invasion \u2013168. Alslow/CD44high breast cancer stem-like cells [Hypoxic and more acidic conditions in the inner part of a tumor are often accompanied by starvation and reduced tumor cell viability, Enhanced cell death of centrally located tumor cells by progressive nutrient deficiency, starvation and low oxygen levels can involve three main mechanisms: apoptosis, autophagy and necrosis/necroptosis. Apoptosis is a highly regulated cell death program that can be triggered by both extrinsic and intrinsic stimuli after induction in consequence of inevitable cell stress , 171. Hoke cells . Converske cells further Necrosis depicts another process of cell death characterized as random, accidental and unregulated . NonetheThe release of DAMPs initiates an innate and adaptive immune response attracting immune cells such as DC, NK cells, macrophages and regulatory T cells (Tregs) Fig.\u00a01)1). AlthoReduced immune response to tumor cells can also be mediated by MSC which are recruited to tumor sites due to the inflammatory microenvironment Fig.\u00a0. OverallMacrophages (M1) contribute to tumor destruction via IFN\u03b3 activation followed by production of type 1 cytokines and chemokines. Conversely, activation of M2 macrophages via MSC promotes tumorigenesis by production of type 2 cytokines and chemokines strengthening the dual role of macrophages depending on the phenotype and activation status. During progressive adaption to the tumor microenvironment, TAMs represent a further macrophage phenotype that triggers tumor development through support of angiogenesis and ECM remodeling . ConsequTogether, the cascade of hypoxic conditions and low nutrient supply accompanied by limited apoptosis, autophagy and necrosis/necroptosis followed by release of DAMPs evokes an inflammatory microenvironment which is modulated by interacting MSC. These mechanisms which are also influenced by protease activities and subsequent ECM modulation interfere with the dynamic and sensitive equilibrium of the CSCN which can critically alter the amount of CSCs affecting clinical outcomes and patient prognoses .The presence of a CSC population as part of a heterogeneous tumor entity is suggeAccording to metabolic alterations and functional interference with the requirements of a carefully balanced factor homeostasis for CSC generation, the sensitive maintenance of a CSCN is likely subject to changes. Such CSCN structures can be disabled at certain sites of the tumor and newly established at more favorable places within the tumor suggesting multiple and simultaneous possibilities for CSCNs with appropriate turnover. A potential CSCN turnover may depend on the stability of the environment. For example, CSCNs of tumor metastases in the bone marrow are more protected and stabilized in the spongy bone cavities as compared to CSCNs in more metabolically-exposed tissues such as primary organ-associated tumor tissues or lymph node metastases. Nevertheless, the dynamic generation and changes of CSCs within the plasticity of tumor tissues and the continuously functional alterations/adaptations of developing and metastasizing tumor cells by loss of distinct functions and/or acquisition of new properties represent the real challenge of a successful tumor therapy."} +{"text": "Our study aimed to present the distinctive correlates of formal thought disorder in patients with schizophrenia, using the Clinical Language Disorder Rating Scale (CLANG).We compared the formal thought disorder and other clinical characteristics between schizophrenia patients with (n = 82) and without (n = 80) formal thought disorder. Psychometric scales including the CLANG, Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMRS), Calgery Depression Scale for Schizophrenia (CDSS) and Word Fluency Test (WFT) were used.After adjusting the effects of age, sex and total scores on the BPRS, YMRS and WFT, the subjects with disorganized speech presented significantly higher score on the poverty of contents of abnormal syntax , lack of semantic association , disclosure failure , pragmatics disorder , dysarthria , and paraphasic error items than those without formal thought disorder. With defining the mentioned item scores as covariates, binary logistic regression model predicted that disclosure failure and pragmatics disorder were distinctive correlates of formal thought disorder in patients with schizophrenia.Disclosure failure and pragmatics disorder might be used as the distinctive indexes for formal thought disorder in patients with schizophrenia."} +{"text": "Deficits in social cognition and on social perception tasks are well studied and widely found in populations with schizophrenia. In addition, our work consistently replicates findings that individuals with schizophrenia report severe loneliness, significantly higher than healthy matches. Loneliness is a chronic, gnawing condition that induces distress and impedes life satisfaction and function across the spectrum of mental health. We also find social isolation impedes interpretation of social information and may lead to socio-perceptual deficits.The present study examines the effectiveness of a novel, adaptive virtual reality simulated social exposure training intervention in both decreasing feelings of loneliness and improving social cognitive function in individuals with schizophrenia. We investigate baseline relationships between social isolation, loneliness and social cognition abilities, as well as pre to post intervention changes in function and subjective social well-being.Fifteen medicated SZ outpatients completed 10 virtual reality social skills training sessions over the course of 5 weeks. Training sessions depicted three naturalistic social scenarios in which participants were instructed to complete 12 total social \u201cmissions\u201d to obtain information from VR avatar characters. Prior to training and following the final training session, participants were assessed using the CogState Brief Schizophrenia Battery Social Emotional cognition task and rated loneliness using the UCLA Loneliness Scale. Independent raters conducted pre- and post-training clinical interviews to assess changes in participants\u2019 levels of positive, negative, and overall psychiatric symptomsGreater overall psychiatric symptoms were significantly correlated with higher levels of experienced loneliness, consistent with previous findings. There was a significant improvement in social emotional cognition accuracy, and a trend-level reduction in loneliness from pre-training to post-testing following social VR training.Previous research indicates that individuals higher on the psychosis spectrum perform worse at social cognition and social perception tasks. Our own research indicates that individuals higher on the psychosis spectrum also endorse higher levels of social distress via social isolation and loneliness. The present study attempts to enhance social cognitive and interpersonal abilities of individuals with schizophrenia while decreasing loneliness by strengthening social bonds and skills using a virtual reality training game. We find that following 10 sessions of VR social training, accuracy on measures of social cognition is improved significantly, however loneliness is reduced non-significantly. These initial results demonstrate potential feasibility of a novel VR social skills training game for improving social experience for patients with schizophrenia."} +{"text": "Chromatin is a very long DNA\u2013protein complex that controls the expression and inheritance of the genetic information. Chromatin is stored within the nucleus in interphase and further compacted into chromosomes during mitosis. This process, known as chromosome condensation, is essential for faithful segregation of genomic DNA into daughter cells. Condensin and cohesin, members of the structural maintenance of chromosomes (SMC) family, are fundamental for chromosome architecture, both for establishment of chromatin structure in the interphase nucleus and for the formation of condensed chromosomes in mitosis. These ring-shaped SMC complexes are thought to regulate the interactions between DNA strands by topologically entrapping DNA. How this activity shapes chromosomes is not yet understood. Recent high throughput chromosome conformation capture studies revealed how chromatin is reorganized during the cell cycle and have started to explore the role of SMC complexes in mitotic chromatin architecture. Here, we summarize these findings and discuss the conserved nature of chromosome condensation in eukaryotes. We highlight the unexpected finding that condensin-dependent intra-chromosomal interactions in mitosis increase within a distinctive distance range that is characteristic for an organism, while longer and shorter-range interactions are suppressed. This reveals important molecular insight into chromosome architecture. How chromatin is spatially organized within the cell nucleus and within chromosomes is a fundamental question in cell biology. Centimeter-long DNA molecules change their spatial chromatin organization within micrometer-sized cells during cell cycle progression. In interphase, chromatin is distributed throughout the nucleus to express the genetic information. When cells enter mitosis, chromatin becomes compacted to form mitotic chromosomes. Chromosome condensation, the gross morphological change of spatial chromatin organization in mitosis, is indispensable for the faithful inheritance of genetic information. Structural maintenance of chromosomes (SMC) complexes are large proteinaceous rings that control spatial chromatin organization at various stages during cell growth and differentiation. By topologically entrapping more than one DNA strand within its ring, SMC complexes are thought to mediate interactions between DNA strands for the establishment of chromatin architecture Uhlmann . Two memChromosome conformation capture is a powerful technique to investigate spatial chromatin organization (Dekker et al. Recent Hi-C results have illustrated the dramatic alteration of chromatin organization during cell cycle progression in several species (Gibcus et al. A notable feature of mitotic chromosomes is a steep drop of contact probabilities at very large genomic distances, over 10\u00a0Mb in human cells (Naumova et al. The mitotic reduction of local chromatin contacts comes as a surprise, as one would expect that all DNA sequences come closer together in a condensed chromosome. However, new interactions at longer distances will restrict the freedom of movement of the chromatin chain, thereby reducing the probability of local interactions. Consistently, local chromatin motility becomes constrained in mitosis (Kakui et al. All the above described changes of chromatin contacts in fission yeast mitosis are dependent on condensin Fig.\u00a0 Kakui e. FurtherThe recent Hi-C experiments unveiled that SMC complexes drive a dramatic reorganization of chromatin contacts as cells enter mitosis. They did not elucidate the mechanism of how SMC complexes mediate chromatin interactions. Two proposed models how SMC rings modulate chromatin contacts are the stabilization of stochastic pairwise interactions and loop extrusion, two models that need not be mutually exclusive (Cheng et al."} +{"text": "Motivational deficits are prevalent feature of schizophrenia, which have been tightly linked to real-world outcomes. Abnormalities in effort cost computations have been proposed as a candidate mechanism underlying these deficits. In the present study, we sought to employ behavioural economic analyses to further understand cost-benefit decision making abnormalities in schizophrenia.58 young adults with schizophrenia and 58 matched controls participated in this study. Participants completed an effort-based decision-making task in which they made decisions to expend physical effort in exchange for monetary rewards. From participants choice behaviour, we computed indifference values for each individual participant. Other computational parameters were also computed such as choice consistency and subjective reward valuation.Patents and controls did not differ in their subjective valuation of reward. On the decision-making task, patients made more inconsistent choices relative to controls. In both univariate and multivariate analyses controlling for potential confounders, patients had higher indifference values meaning that patients required more money in the exchange of their effort. Among patients, higher indifference values were associated with more severe clinical motivational deficits.Patients had multiple abnormalities related to their decisions to expend effort for reward. Choices were more chaotic and reward value was discounted by effort at a steeper rate in patients. These results point toward an abnormality in the computation of effort costs or in the integration of these costs with value signals."} +{"text": "Intra-aortic balloon pump (IABP) counterpulsation is a catheter-based treatment for coronary artery disease and decompensated heart failure to increase coronary blood flow and improve cardiac output. IABP is generally well tolerated, and complications are usually related to peripheral vasculature or red blood cell and platelet consumption. The usual insertion site via femoral artery renders the patient bedbound. Recently, axillary artery has been used in patients with atherosclerotic peripheral vascular disease and documented small arteries or in those awaiting transplant to ensure ambulation and prevent deconditioning. We present a patient with ischemic cardiomyopathy and severe left ventricular dysfunction, awaiting Orthotropic Heart Transplant. His worsening intractable angina and dyspnea necessitated IABP placement via left axillary artery, significantly improving his condition. He subsequently experienced migraine-type persistent unilateral headache refractory to standard pain management. Multiple strategies were utilized to treat his pain, but the patient insisted that his pain commenced after IABP placement. Ultimately, the removal of the pump led to complete resolution with no recurrence. The authors hypothesize that the unilaterally directed blood flow and direct increase in cerebral perfusion from the intra-aortic balloon pump may have caused vasodilation of the extracranial arteries, leading to a persistent and debilitating headache in this susceptible patient. Intra-aortic balloon pump (IABP) is a cylindrical polyethylene device inserted into the descending thoracic aorta, which increases myocardial oxygen delivery and cardiac output . Its \u201ccoA 63-year-old male with ischemic cardiomyopathy and severe left ventricular dysfunction was admitted with chest pain and dyspnea at rest. He was on maximal medical therapy and had received multiple prior percutaneous coronary interventions and two previous coronary artery bypass surgeries. Recent coronary angiography revealed no possibility of further revascularization. He was evaluated for Orthotropic Heart Transplant (OHT) and listed as Status 1A-e (urgent need). His worsening intractable angina and dyspnea necessitated IABP placement via left axillary artery, which significantly improved his condition. Axillary artery was the chosen site of insertion in order to enable ambulation and prevent deconditioning, as the patient was awaiting transplant . The IABExamination revealed tender and bulging left temporal artery suspicious of temporal arteritis (TA); however, his normal erythrocyte sedimentation rate minimized TA as a likely diagnosis. Nonetheless, he was offered prophylactic prednisone, which he refused. Pain management service was consulted and multimodal treatment including acetaminophen, oxycodone, citalopram, and tizanidine was initiated, while nitrates were withheld . The patIn accordance with patient's wishes, the IABP was weaned and removed, and nitrates were initiated for angina prophylaxis. On postremoval assessment, the patient's headache had completely resolved with no future recurrence. He subsequently received OHT and was discharged with normal EF and no further headaches.Intra-aortic balloon pump (IABP) is a widely used circulatory assist device to improve coronary perfusion in acute coronary syndromes and improve cardiac output in acute decompensated heart failure. Coronary perfusion has often been compared to cerebral perfusion, drawing similarities in the pathophysiology and pharmacology of myocardial infarction and acute stroke , 8. AugmOne study showed that IABP augmentation causes a significantly higher increase in transcranial Doppler CBF velocity change in the middle cerebral artery with enhanced CBF especially in patients with preexisting left ventricular dysfunction . Data inFurther case reports suggest that IABP placement can increase proximal pressures and carotid blood flow above the IABP and decrease distal pressures and perfusion below it, leading to distal perfusion injuries (ischemia) , 18. The"} +{"text": "Swift and adequate fluid loading is a cornerstone of septic shock therapy. Yet, careful assessment of volume responsiveness and volume amount during the resuscitation process is a prerequisite. Both overzealous initial fluid administration and late fluid overload are harmful and may be associated with increased mortality.Static pressure readings are erroneous for monitoring fluid resuscitation and should be abandoned. Dynamic measurements better predict fluid responsiveness than static filling pressures but the conditions necessary for these parameters to correctly evaluate preload dependency are frequently not met. The passive leg raising maneuver as a means to alter biventricular preload in combination with real-time measurement of cardiac output changes is an easy-to-use, fast, relatively unbiased, and accurate bedside test to guide fluid management and to avoid fluid overload during early septic shock treatment. Moreover, PLR may also be particularly useful to assist various treatments that trigger fluid removal during the \u201cde-resuscitation\u201d phase of septic shock.The passive leg raising maneuver in combination with real-time measurement of cardiac output changes is an easy-to-use, fast, relatively unbiased, and accurate bedside test to guide fluid management during septic shock. The recently published Surviving Sepsis Campaign guidelines strongly recommend ample volume resuscitation during the first day of septic shock treatment . Such agJournal of Intensive Care, Krige et al. prospectively investigated the use of a novel generation Vigileo FloTrac\u2122 system during a PLR maneuver in medico-surgical patients with vasopressor-dependent circulatory shock [At the beginning of this millennium, several authors proposed to use physiologic heart-lung interactions during positive pressure ventilation as more reliable predictors of fluid responsiveness in septic shock . Variatiry shock . The stuThrough the years, awareness has risen that after initial aggressive fluid resuscitation the focus should shift towards obtaining a net and even negative fluid balance . Late liIn conclusion, PLR testing in combination with more sophisticated real-time hemodynamic monitoring actually seems to be the most appropriate method to guide a bedside \u201cdo not harm\u201d volume resuscitation strategy in septic shock. Future studies should assess the PLR maneuver using calibrated intermittent or continuous monitoring and evaluate whether this test could become pivotal in managing fluid removal during the \u201cde-resuscitation\u201d phase of septic shock."} +{"text": "Our understanding of the neurobiology of psychiatric disorders remains limited, and biomarker-based clinical management is yet to be developed. Induced pluripotent stem cell (iPSC) technology has revolutionized our capacity to generate patient-derived neurons to model psychiatric disorders. Here, we highlight advantages and caveats of iPSC disease modeling and outline strategies for addressing current challenges. Even as neuropsychiatric research has boomed, psychiatric disorders have remained a leading cause of global morbidity and disease burden . CurrentAs a result, definitive diagnoses and treatment strategies based on objective biomarkers continue to evade us. The development of human iPSC technology offers one approach to allow researchers to address the genetic complexity issue in psychiatric disorder research. Somatic cells such as skin fibroblasts from adult patients can be dedifferentiated to a pluripotent state by transient overexpression of the reprogramming transcription factors. Theoretically, iPSC clones can then be differentiated to any other cell type by exposure to an appropriate combination of patterning molecules. Parallel in vitro disease modeling efforts for studying the neural correlates of disease-associated genotypes may provide novel insights into the neurological underpinnings of psychiatric disorders . iPSCs aDISC1) gene altered synaptic activity and downstream signaling in iPSC-derived neurons, establishing a causal relationship between patient genetics and cellular phenotypes [A central goal of biological psychiatry is to understand how healthy and aberrant brain function may arise from the interaction of neural circuits. Crucial to this effort is generating relevant neural cell types from iPSCs, because studying the basic units of neural circuits in isolation enables the construction of in vitro model systems. Given the diversity of cell types in the mammalian brain, the field continues to develop protocols for generating relatively homogeneous populations of neuronal and glial subtypes, as well as genetic reporters to help label and identify specific cell types in mixed populations . This apenotypes . Furtherenotypes .While recent studies provide evidence for mechanisms that may contribute to disease pathology, excitement must be tempered by experimental knowledge addressing the caveats of in vitro disease modeling Fig.\u00a0. A downsAnother issue is that of variability between cell lines and across experimental batches, possibly due to somatic mosaicism in donor cells prior to reprogramming, accumulation of de novo mutations with selective advantages, stochastic events during differentiation, and heterogeneous patient genetics . HoweverOne such approach is the stratification of large patient cohorts based on factors such as genetic risk, pharmacological response profiles, distinctive and quantitative endophenotypes, or comorbidities with other diseases. Modeling genetic risk includes rare variants conferring large genetic risk, such as copy number variation, or higher frequency common variants, such as single nucleotide polymorphisms, conferring relatively lower risk . CellulaAnother strategy is to study iPSC-derived neurons from a subset of well-characterized patients from a larger cohort. Here, in vitro phenotypes can be correlated with multiple continuous variables such as clinical severity, behavioral/biological measures, brain activity, and blood metabolites. Obtaining such multidimensional data from even small patient cohorts could inform the predictive value of individual variables and lead to the discovery of biomarkers. The explosion of rich neuropsychiatric disease sequence databases coincides with the emergence of powerful and accessible predictive machine learning tools. In conjunction with large-scale genetic data, deep-learning models may enjoy improved performance by using intermediate cellular phenotypes from patient-derived cells to bridge the gap between molecular and circuit or clinical features .In addition to careful study design, picking appropriate in vitro models will be critical for discovering clinically relevant in vitro phenotypes. Three-dimensional iPSC-derived organoids may be able to recapitulate maturation-related signatures in developing circuits, as has been successfully done with autism spectrum disorder . SimilarIt is increasingly clear that gaining fresh insights into the biology of psychiatric disorders demands a multipronged approach, including but not limited to patient iPSC-based diseased modeling. Furthermore, concerted efforts across laboratories for tackling the inherent variability of in vitro systems may pave the way for establishing standardized in vitro parameters, which would be immensely helpful for moving toward high-throughput profiling and screening in the future . Despite"} +{"text": "Despite numerous medical advances in the care of at-risk preterm neonates, oral feeding still represents one of the first and most advanced neurological challenges facing this delicate population. Objective, quantitative, and noninvasive assessment tools, as well as neurotherapeutic strategies, are greatly needed in order to improve feeding and developmental outcomes. Pulsed pneumatic orocutaneous stimulation has been shown to improve nonnutritive sucking (NNS) skills in preterm infants who exhibit delayed or disordered nipple feeding behaviors. Separately, the study of the salivary transcriptome in neonates has helped identify biomarkers directly linked to successful neonatal oral feeding behavior. The combination of noninvasive treatment strategies and transcriptomic analysis represents an integrative approach to oral feeding in which rapid technological advances and personalized transcriptomics can safely and noninvasively be brought to the bedside to inform medical care decisions and improve care and outcomes.The study aimed to conduct a multicenter randomized control trial (RCT) to combine molecular and behavioral methods in an experimental conceptualization approach to map the effects of PULSED somatosensory stimulation on salivary gene expression in the context of the acquisition of oral feeding habits in high-risk human neonates. The aims of this study represent the first attempt to combine noninvasive treatment strategies and transcriptomic assessments of high-risk extremely preterm infants (EPI) to (1) improve oral feeding behavior and skills, (2) further our understanding of the gene ontology of biologically diverse pathways related to oral feeding, (3) use gene expression data to personalize neonatal care and individualize treatment strategies and timing interventions, and (4) improve long-term developmental outcomes.A total of 180 extremely preterm infants from three neonatal intensive care units (NICUs) will be randomized to receive either PULSED or SHAM (non-pulsing) orocutaneous intervention simultaneous with tube feedings 3 times per day for 4 weeks, beginning at 30 weeks postconceptional age. Infants will also be assessed 3 times per week for NNS performance, and multiple saliva samples will be obtained each week for transcriptomic analysis, until infants have achieved full oral feeding status. At 18 months corrected age (CA), infants will undergo neurodevelopmental follow-up testing, the results of which will be correlated with feeding outcomes in the neo-and post-natal period and with gene expression data and intervention status.The ongoing National Institutes of Health funded randomized controlled trial R01HD086088 is actively recruiting participants. The expected completion date of the study is 2021.Differential salivary gene expression profiles in response to orosensory entrainment intervention are expected to lead to the development of individualized interventions for the diagnosis and management of oral feeding in preterm infants.ClinicalTrials.gov NCT02696343; https://clinicaltrials.gov/ct2/show/NCT02696343 (Archived by WebCite at\u00a0http://www.webcitation.org/6r5NbJ9Ym) The biological complexities of oral feeding have made it the most advanced neurological milestone of the newborn and a predictor of both short- and long-term developmental outcomes in the at-risk premature neonatal population ,2. SucceThere is currently no objective and quantitative tool to assess oral feeding maturity in premature infants. The current standard of care to determine oral feeding readiness in the EPI population is to use largely subjective, qualitative, and unvalidated cue-based assessment tools -22. CareA new translational application, approved by the FDA in 2008, has been shown to promote ororhythmic motor patterning (nonnutritive suck) in preterm infants who exhibit delayed or disordered nipple feeding behaviors. This approach is based on mechanosensory entrainment of the suck central pattern generator using servo-controlled pulsed pneumatic stimuli to drive peri- and intra-oral afferents, which in turn modulate local reflex activity and produce nonnutritive suck rhythms -31. Sinc\u03bc L of saliva , and (3) Santa Clara Valley Medical Center . The research protocol has been approved by each site\u2019s Institutional Review Board (IRB). Participant recruitment began in July 2016, and NTrainer intervention is expected to be completed by 2020. Neurodevelopmental follow-up testing will begin in 2018.The primary outcome variables include salivary gene expression of a panel of genes previously identified as playing a role in oral feeding of preterm infants, time to transition to full oral feeding, and oromotor NNS pattern formation. Secondary outcome variables include: NICHD NRN 18-month Feeding-Growth-Nutrition Questionnaire, and Bayley III scores of cognitive, motor, and language skills at 18 months\u2019 corrected age (CA).Oral feeding is a complex neurological milestone that can pose a significant challenge for many preterm infants, particularly for those born extremely prematurely , as well as those with a compromised respiratory status. Persistent feeding difficulties can result in numerous short- and long-term medical complications, as well as place infants at risk for developmental disabilities. Currently, there is no objective method for treating delayed or disordered feeding skills, or for assessing oral feeding maturity. Therefore, there is a strong need for objective assessment tools and novel therapeutic interventions to identify the underlying mechanisms that delay and disrupt oral feeding success and provide evidence-based intervention strategies to help ameliorate outcomes. The current study aims to combine safe, noninvasive treatment strategies and salivary diagnostics in EPIs to improve oral feeding skills as well as long-term neurodevelopmental outcomes and to further our understanding of the gene ontology of biological pathways related to oral feeding, which may ultimately individualize the type and timing of interventions and personalize neonatal care."} +{"text": "To date, the oral cavity has yielded a diverse menagerie of adult stem cells that includes dental pulp stem cells (DPSCs), dental follicle stem cells (DFSCs), stem cells from apical papilla (SCAP), stem cells from human exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSCs), and gingival mesenchymal stem cells (GMSCs). These stem cells have various useful applications in clinical dentistry that is dental pulp regeneration after root canal treatment, osseous integration of titanium implants, and maxillofacial and periodontal regeneration. Stem cells-based approaches in clinical dentistry are reviewed by D. Hughes and B. Song, as well as S. Miran et al. within this special issue. in vitro culture, these dental and oral-derived adult stem cell populations exhibit much divergent characteristics and express variable cell surface markers and transcription factors. In this special issue, C.-M. Kang et al. compared the transcriptional profile of human DPSCs and umbilical cord stem cells (UCSCs) with microarray and qRT-PCR techniques and found similar expression levels of the various canonical mesenchymal stem cell markers. However, gene ontology analyses revealed significant differences in the expression of genes related to cell proliferation, angiogenesis, immune responses, growth factor activities, and signal transduction, between DPSCs and UCSCs, which could indicate divergent propensity to differentiate into various lineages.Despite their common embryonic origin from the cranial neural crest and their similar fibroblastic morphology within in vitro culture. Subsequently, L. Liu et al. demonstrated that transgenic expression of the human xeroderma pigmentosum group C (XPC) gene through a lentiviral vector could mitigate this age-related decline in pluripotency markers expression by DPSCs.Dental and oral-derived stem cells have a number of advantages over other more commonly utilized sources of adult stem cells. Compared to the invasive surgical procedure required for obtaining mesenchymal stem cells from bone marrow, these adult stem cells are readily isolated from biological waste produced during routine dental treatment . Several studies have reported that dental and oral stem cells such as SHED possess much more extensive multidifferentiation potential and proliferative capacity compared to other adult stem cells. This is extensively discussed in a review on SHED by V. Rosa et al. within this special issue. Even more surprising are reports of the expression of pluripotency markers such as OCT4, MYC, and SOX2 by some dental and oral-derived stem cells, which are not usually expressed in most other adult stem cell types. Expression of these markers might be indicative of the more extensive plasticity and multilineage differentiation potential of dental and oral-derived stem cells when compared to other sources of stem cells. In this special issue, the study of L. Liu et al. reported that these pluripotency markers were strongly expressed in DPSCs at early passage numbers but were gradually downregulated with extendedIt is possible that the relatively high baseline expression of pluripotency markers by dental and oral-derived stem cells such as DPSCs could render these adult stem cells more amenable to reprogramming into induced pluripotent stem cells (iPSCs). This is critically examined and discussed in a review by J.-H. Lee and S.-J. Seo within this special issue. The study of H. Okawa et al. utilized iPSCs derived from GMSCs to fabricate scaffold-free osteoinductive cellular constructs. Besides the derivation of iPSCs from dental and oral-derived stem cells, it may also be worthwhile to explore the reverse approach, which is the derivation of dental and oral adult stem cell-like lineages from pluripotent stem cells. This may allow us to recapitulate the developmental pathway of the various differentiated somatic lineages of the oral cavity, thus providing us with an extremely useful tool for studying the underlying genetic and developmental basis of various oral and maxillofacial disorders. In this special issue, Q. Zhu et al. reviewed the potential applications of pluripotent stem cell-derived neural crest stem cells, which resemble the various adult stem cell niches of the oral cavity. The study of G. Sriram et al. demonstrated that human embryonic stem cell-derived fibroblasts could be utilized as an alternative to GMSCs for studying the innate immune response to pathogens related to periodontitis (periodontopathogens).In view of the various promising biomedical applications of dental and oral-derived stem cells, we have organized this special issue as a platform to highlight some of the recent developments and cutting-edge research in this field. It is hoped that the comprehensive reviews and research articles presented in this special issue would stimulate greater interest amongst the scientific community to pursue this field of research, as well as facilitating the translation of research data into clinical therapy.Boon Chin HengBoon Chin HengChengfei ZhangChengfei ZhangXuliang DengXuliang DengYin XiaoYin XiaoAlessandra PisciottaAlessandra PisciottaFahad KidwaiFahad KidwaiThimios A. MitsiadisThimios A. Mitsiadis"} +{"text": "We describe a patient with right hemisphere damage affected by mild left visuo-spatial neglect and constructional apraxia. During the rehabilitation, he failed to draw a draught-board using horizontal and vertical trajectories, but he performed it successfully using oblique trajectories. These observations suggested an impairment of vertical/horizontal spatial coordinates system. In copying tasks including figure elements in different orientations he drew more accurately components in oblique orientation, whereas failed to reproduce components in horizontal orientation. The patient performed visuospatial perceptual and perceptual-imaginative tasks successfully. From these findings, it is possible to suggest that the oblique coordinate system of reference operates independently of vertical and horizontal coordinate systems in building a complex figure and that, therefore, cardinal orientation do not constitute a reference norm to define oblique orientation, as previously suggested."} +{"text": "To accurately predict atherosclerotic plaque progression, a detailed phenotype of the lesion at the molecular level is required. Here, we assess the respective merits and limitations of molecular imaging tools. Clinical imaging includes contrast-enhanced ultrasound, an inexpensive and non-toxic technique but with poor sensitivity. CT benefits from high spatial resolution but poor sensitivity coupled with an increasing radiation burden that limits multiplexing. Despite high sensitivity, positron emission tomography and single-photon emission tomography have disadvantages when applied to multiplex molecular imaging due to poor spatial resolution, signal cross talk and increasing radiation dose. In contrast, MRI is non-toxic, displays good spatial resolution but poor sensitivity. Preclinical techniques include near-infrared fluorescence (NIRF), which provides good spatial resolution and sensitivity; however, multiplexing with NIRF is limited, due to photobleaching and spectral overlap. Fourier transform infrared spectroscopy and Raman spectroscopy are label-free techniques that detect molecules based on the vibrations of chemical bonds. Both techniques offer fast acquisition times with Raman showing superior spatial resolution. Raman signals are inherently weak; however, leading to the development of surface-enhanced Raman spectroscopy (SERS) that offers greatly increased sensitivity due to using metallic nanoparticles that can be functionalised with biomolecules targeted against plaque ligands while offering high multiplexing potential. This asset combined with high spatial resolution makes SERS an exciting prospect as a diagnostic tool. The ongoing refinements of SERS technologies such as deep tissue imaging and portable systems making SERS a realistic prospect for translation to the clinic. Atherosclerosis is a complex multifactorial pathology that progresses over many decades. Immune-inflammatory responses play key roles in all phases of the pathology and inflammation contributes to plaque rupture resulting in clinical manifestations such as myocardial infarction (MI) and stroke.Multiple imaging techniques are available for both invasive and non-invasive imaging of the vasculature. These include contrast-enhanced ultrasound (CEUS), CT, MRI, positron emission tomography (PET), single-photon emission tomography (SPECT), near-infrared fluorescence (NIRF) microscopy and vibrational spectroscopy. MRI, CT and PET/SPECT are already in clinical use for diagnosing and monitoring atherosclerosis and can provide structural information such as quantifying stenosis and plaque size/location. In some instances, invasive imaging using intra-arterial probes employing one of the above modalities can reveal basic morphological information on plaque composition, yet there remains an urgent unmet requirement for non-invasive imaging tools that can provide information beyond the anatomic and functional level that are able to interrogate the cellular and molecular pathways driving local inflammatory responses that promote plaque vulnerability.Molecular imaging moves beyond anatomic and morphological detail to the level of cellular and molecular events. Activated endothelium offers a number of potential imaging targets, including adhesion molecules promoting leucocyte binding and transmigration into subendothelial locations. The complex inflammatory environment of a developing atherosclerotic plaque offers additional targets such as scavenger receptors present on macrophages/foam cells, and plaque destabilising proteases and peroxidases. True molecular imaging requires a targeting ligand , peptides, aptamers) to specific molecules/cells which are conjugated to a detection agent compatible with the imaging tool of choice, eg, microbubbles (CEUS), iodinated compounds (CT), radionucleotides (PET/SPECT), magnetic/superparamagnetic compounds (MRI) or fluorochromes (fluorescence imaging). Vibrational spectroscopy, such as Raman spectroscopy, offers the advantage of not requiring external imaging tracers owing to direct detection of endogenous biological molecules; however, Raman spectroscopy employing exogenous targeted nanoparticles\u00a0(NPs) (surface-enhanced Raman spectroscopy (SERS)) results in an imaging capability with remarkably increased sensitivity and ability to simultaneously detect multiple analytes (multiplexing), which may improve diagnostic specificity. Advantages and limitations of the described techniques are summarised in In this review, we will highlight recent advances in molecular imaging and their application in identifying vascular inflammation, with a particular focus on the potentialities of Raman and SERS.et alUltrasound-based molecular imaging relies on CEUS, which employs the use of microbubbles as a vascular wall targeting agent. Signals are generated through vibration/oscillation or release of free gas when the microbubbles are exposed to sonic energy. Kaufmann CT possesses relatively good temporal and spatial resolution which can further be improved on by multidetector spiral computed tomography and the concomitant use of iodinated contrast agents. This approach allowed the non-invasive identification of plaque location and sizeAs the current technology stands, clinical use of CT for cellular and molecular imaging of atherosclerosis may be restricted to the narrow use of identifying plaque mineral composition and cellular density. As with anatomic CT imaging, use in this area will be subject to careful review of the radioactive burden associated with CT X-ray exposure, especially in the context of repeated scans. To date, the low sensitivity of CT contrast agents combined with spatial resolution inadequate to detect vulnerable plaque componentsPET and SPECT are widespread imaging tools that rely on the administration of radionucleotides and subsequent detection of \u03b3-rays to construct three-dimensional images of biological tissue forming the cornerstone of nuclear imaging. PET/SPECT are attractive options for molecular imaging owing to their non-invasive nature and high sensitivity. Furthermore, the high sensitivity of nuclear imaging is frequently combined with CT or MRI, tools with superior spatial resolution to form hybrid imaging systems such as PET/CT, SPECT/CT and PET/MRI.18F]-Fluorodeoxyglucose (FDG) is a glucose analogue radiotracer commonly used in PET and uptake by tissues correlates with metabolic activity. Combined PET/CT imaging has shown that FDG accumulates more in symptomatic lesions than asymptomatic sites of stenosis, particularly in macrophage-rich regions.F-FluorodMRI is perhaps the most studied tool to date for molecular imaging in atherosclerosis, owing to excellent spatial and temporal resolution without requiring the administration of ionising radioactive nucleotides.-/- mice offering the potential for early intervention and monitoring.To overcome the major weakness of MRI (poor sensitivity), the use of paramagnetic agents such as gadolinium (Gd) chelates and superparamagnetic (iron oxide microparticles and nanoparticles) contrast agents have been employed to non-invasively image arterial diseases. MRI molecular imaging of atherosclerosis primarily employs ultrasmall paramagnetic iron oxide particles . The properties of USPIOs allow extravasation into vascular tissues enabling potential analysis of atherosclerotic lesions. This approach has been used as a tool for measuring plaque macrophage burden through MRI signal loss following phagocytic uptake of USPIOs in rabbits-/- mice.The use of microparticles of iron oxide (MPIO) offers several advantages over USPIOs. Their larger size (0.9\u20138\u2009\u00b5m) confines their location to endothelial surfaces, preventing cellular uptake and potential consequences of cellular toxicity and loss of molecular specificity. Furthermore, the greater iron payload carried by MIOPs improves signal detection. These attributes coupled with rapid clearance from the circulation can allow early imaging of vascular inflammation with a high degree of specificity.-/- mice.Fluorescence imaging is an optical imaging technique that detects the emission spectra from fluorescent probes excited by a light source. As with other imaging modalities, probes are either passively or actively targeted to a biological molecule or tissue of interest or can act as \u2018smart probes\u2019 that are activated at the target site, for example, enzymatic conversion from a non-fluorescent substrate to a fluorescent product allowing functional read outs of local enzyme activity.The wide optical imaging window available for NIRF imaging allows the use of multiple probes to be assessed in a single system owing to fluorochromes emitting in distinct spectral regions; however, the difficulty in resolving such spectra often requires multiple excitation wavelengths for optimal signal discrimination.Vibrational spectroscopy mainly encompasses two techniques: infrared (IR) and Raman spectroscopies, which create molecularly specific spectra based on the vibrational energies of chemical bonds.FTIR, the most refined modern form of IR spectroscopy gains information from the vibration of molecular bonds caused by absorbance of light; requiring no external labelling method. The ability to detect chemically specific IR spectra over a wide wavelength window allows FTIR to detect multiple classes of biological molecules. FTIR is especially useful for differentiating lipids and proteins and these have been the main focus of FTIR research in cardiovascular studies to date.FTIR has been employed to map the distribution of collagen I, collagen III and elastin in the fibrous cap region of human atheroma samples postmortemLike FTIR, Raman spectroscopy has been used to map the detailed composition of atherosclerotic plaques but improves on FTIR in terms of both spatial and spectral resolution.Raman spectroscopy is a particularly attractive molecular imaging tool for interrogation of atherosclerotic plaques and potential diagnostic agent due to its ability to non-destructively acquire biochemical data on the processes that drive plaque development. Although the non-invasive nature of Raman is an important advantage of the technique, the main disadvantage pertains to its low sensitivity due to the weakness of the Raman scattering effect leading to long imaging times and an inability to discriminate low-level target molecules from background \u2018noise\u2019. Furthermore, many biological molecules are spectrally similar requiring complex chemometric analysis to separate signals of interest.The shortcomings associated with Raman spectroscopy have led to the development of SERS, a highly sensitive advancement of conventional Raman spectroscopy. The enhancement of Raman signal is achieved when a molecule is adsorbed onto or in close proximity to a metal surface and is dependent on the nature of metal surface, the excitation frequency used, the attachment of the molecule to the surface and also the nature of the molecule itself.-/- mice with a superior signal-to-noise ratio compared with immunofluorescence.We have previously shown that intercellular adhesion molecule 1 (ICAM-1)-targeted NPs could detect ICAM-1 expression on aortic sinus tissue sections derived from apoEThe use of metallic NPs offers potential therapeutic applications to atherosclerosis, specifically through photothermal therapy in addition to acting as enhancers of Raman scattering. The photothermal effect arises when the plasmonic resonance wavelength of the NP matches the excitation wavelength of the laser and light is absorbed and converted to heat. If NPs are attached to or internalised by cells, the energy produced can be dissipated to the surrounding biological medium causing thermal destruction of the cell. Gold nanorods and single-walled carbon nanotubes are internalised by carotid artery resident macrophages in vivo following carotid ligation in mice and subsequent exposure of excised ligated vessels to NIR excitation-induced photothermal apoptosis of the macrophage population.https://clinicaltrials.gov/ct2/show/NCT01270139). This multicentre trial involved 180 patients aged 45\u201365 years\u00a0diagnosed as having coronary artery disease with flow-limiting lesions. The two treatment groups received either a surgical implanted \u2018on-artery\u2019 patch capable of transferring silica-gold NPs to the plaque (Nano group) or an intracoronary infusion of silica-gold iron-bearing NPs with CD68 targeted microbubbles and stem cells via a magnetic navigation system (Ferro group). A control group received a stent implantation void of any NP. Following \u2018detonation\u2019 of the NPs via intravascular or transcutaneous NIR laser excitation, no adverse events related to the procedure such as site-related thrombosis were recorded throughout the 1-year follow-up. Both treatments were associated with a reduction in total atheroma volume and the nano group displayed increased survival relative to control during follow-up.The first human trial using plasmonic phototherapy, as a technique for regressing atherosclerosis, was the Plasmonic Nanophotothermal Therapy of Atherosclerosis (NANOM-FIM: Despite risks associated with induced apoptosis in the atheroma, this approach highlights the range of options coupled with SERS/NP usage. Gold NPs are also amenable as carriers for drug delivery to the vessel wall owing to their low toxicity, versatile surface chemistry conjugation and efficient uptake by vascular endothelial cells.Looking forward, this review has summarised activities in the common molecular imaging approaches in atherosclerosis, focusing on Raman and SERS. Images showing typical findings with each modality are shown in"} +{"text": "Ectopic cardiac fatty images are not rarely detected incidentally by computed tomography and cardiac magnetic resonance, or by exams focused on the heart as in general thoracic imaging evaluations. A correct interpretation of these findings is essential in order to recognize their normal or pathological meaning, focusing on the eventually associated clinical implications. The development of techniques such as computed tomography and cardiac magnetic resonance allowed a detailed detection and evaluation of adipose tissue within the heart. This pictorial review illustrates the most common characteristics of cardiac fatty images by computed tomography and cardiac magnetic resonance, in a spectrum of normal and pathological conditions ranging from physiological adipose images to diseases presenting with cardiac fatty foci. Physiologic intramyocardial adipose tissue may normally be present in healthy adults, being not related to cardiac affections and without any clinical consequence. However cardiac fatty images may also be the expression of various diseases, comprehending arrhythmogenic right ventricular dysplasia, postmyocardial infarction lipomatous metaplasia, dilated cardiomyopathy, and lipomatous hypertrophy of the interatrial septum. Fatty neoplasms of the heart as lipoma and liposarcoma are also described. Ectopic intracardiac fatty images are not uncommon findings in thoracic imaging in both healthy and diseased patients. Development of diagnostic techniques with high spatial and contrast resolution as computed tomography (CT) and cardiac magnetic resonance (CMR) enabled detailed fat visualization within the heart. An incidental frequency of cardiac adipose images in about 11% of the patients performing cardiovascular CT examinations has been estimated .Physiologic ectopic cardiac adipose tissue may normally be present in healthy adults not affected by any cardiac disease, without clinical consequences . In factArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by structural and functional abnormalities that may lead to arrhythmias and sudden cardiac death . PatholoPostmyocardial infarction lipomatous metaplasia (PILM) is a tissue transformation process that may take place within the scar region after a healed myocardial infarction (MI). The prevalence of PILM at histology in the LV reached values of 68\u201384% of excised heart transplanted for ischemic heart disease . In imagIdiopathic or \u201cprimary\u201d dilated cardiomyopathy (DCM) is characterized by left or biventricular dilatation and impaired systolic function without significant coronary artery lesions, excluding other possible etiologic causes . PrimaryRegarding the differential diagnoses of this disease, left-dominant ARVC with fibrofatty replacement of the LV represents an affection hardly distinguishable from idiopathic DCM at CMR imaging: in this case a careful evaluation of the adipose tissue and of the LGE location is crucial, being both in ARVC predominantly represented in the subepicardium and not in the middle layer of the myocardium as in primary DCM.Besides the evidence of fatty intramyocardial tissue at imaging sparing the subendocardial layer and having no relationship with a coronary artery perfusion territory allows excluding a DCM secondary to a PILM.Finally fatty myocardial metaplasia phenomena in secondary DCM have also been described after an inflammatory process as chronic myocarditis 28]. In. In28]. Lipomatous hypertrophy of the interatrial septum (LHIAS) is an uncommon benign disorder with fatty accumulation into the interatrial septum that usually measures a transverse diameter > 2\u2009cm in this condition . LHIAS iTuberous sclerosis complex (TSC) represents a genetic multisystemic disorder with cardiac tumor-like manifestations such as rhabdomyomas that regress during childhood and intramyocardial fat-containing lesions in adults [n adults . Fatty in adults . A previn adults . Althougn adults . A possin adults . Notwithn adults . Howevern adults .Muscular dystrophies (MD) are X-linked recessive diseases characterized by cardiac involvement with replacement of the myocardium by connective and adipose tissue [e tissue . Particue tissue . Typicale tissue .Hypertrophic cardiomyopathy (HCM) has also been described to be related to the presence of intramyocardial fatty foci, with adipose tissue placed within the thickened myocardial segments involved by this disease [ disease . The rea disease .Although the presence of ectopic adipose tissue within the myocardium is often detectable in CT and CMR images, the \u201ccardiac steatosis\u201d defined as cardiomyocytes accumulation of lipids is not easily appreciable with these imaging techniques. Cardiomyopathies secondary to lipid metabolism disorders may have a heterogeneous clinical expression, mimic dilated or hypertrophic cardiomyopathy, and led to progressive heart failure.Fabry disease is a rare X-linked genetic lysosomal storage disease, resulting from dysfunctional metabolism of sphingolipids [golipids .Intramyocardial triglyceride deposition is linked to various pathological hereditary and acquired conditions .Triglyceride deposit cardiomyovasculopathy is a genetic disorder with accumulation of triglyceride in cardiomyocytes and smooth muscle cells due to abnormal intracellular deposit of triglyceride and its substrates [bstrates , 44.Usually in these conditions myocardial signal is not altered in the conventional T1- and T2-weighed sequences, whereas T1 mapping technique has emerged as a sensitive and specific CMR biomarker of tissue lipid accumulation irrespective of ventricular morphology and function .Moreover a case has been reported where the excessive production of fatty acids in subjects with high alcohol consumption caused an alcohol-related cardiomyopathy associated with left ventricular fatty infiltration .LP represent the second most common benign cardiac tumor after myxomas, accounting for about 10% of primary cardiac neoplasms . They arPrimary cardiac liposarcomas (LS) are extremely rare neoplasms, mostly originating from the right chambers of the heart, particularly from the right atrium . CardiacCardiac metastases from a primary LS located in other anatomical districts have also been reported, although rare . In factTypical features in CT imaging of cardiac primary LS or its metastatic lesions consist of large unencapsulated hypoattenuating inhomogeneous masses, mostly rounded shaped with thick septa and mild contrast enhancement, infiltrating the surrounding cardiac structures and the pericardium . Notably"} +{"text": "Transcranial Direct Current Stimulation (tDCS) is a non-invasive neuromodulation technique which uses a weak electric current from electrodes across the scalp to modulate targeted brain areas. It has been suggested that tDCS may be useful in reducing psychotic symptoms such as auditory hallucination. The aim of this study was to find alteration of key neurotransmitters in schizophrenia in temporo-parietal area (TPA) after tDCS intervention, using magnetic resonance spectroscopy (MRS) technique.Ten schizophrenia patients with auditory hallucination were recruited from the outpatient clinic of Seoul National University Hospital (SNUH). The anode was placed over the left dorsolateral prefrontal cortex (DLPFC), and the cathode was placed over the left TPA. Patients underwent MRS scan with the very short echo time phase rotation STEAM sequence before and after the tDCS sessions, respectively.Seven of the participants completed MRS scans before and after the tDCS sessions. Positive and Negative Symptom Scale (PANSS) total and general psychophathology scale showed a significant improvement after tDCS. There was no significant difference between glutamate/creatinine (Cr) level before and after tDCS sessions. However, a significant positive correlation between the pre-tDCS glutamate/Cr value in left TPA and the improvement in auditory hallucination measured by Auditory Hallucination Rating Scale (AHRS) after tDCS was found.The results of this investigation show that the schizophrenia patients whose auditory hallucination benefits the most from tDCS treatment had lower glutamate/Cr level in left TPA. Previous studies regarding the relationship between glutamatergic system and treatment response mostly have only focused on the frontal area and striatum. However, this study suggests a potential role of glutamatergic system in TPA in predicting treatment response of auditory hallucination."} +{"text": "Edema bullae typically forms at the site of skin swelling during acute states of volume overload, most commonly during renal or cardiac failure. Herpes zoster is a reactivation of latent varicella zoster virus that typically presents as painful vesicles in a dermatomal distribution. In immunocompromised individuals, disseminated herpes zoster skin manifestations\u00a0may occur with several lesions in multiple dermatomes or widespread individual lesions or both, even visceral organs can be involved. Additionally, many conditions are known to mimic the lesions and distribution of herpes zoster. A 53-year-old immunosuppressed male with a history of renal transplant presented with dermatomal and non-dermatomal, disseminated herpes zoster that was confirmed by polymerase chain reaction testing. After one week of intravenous antiviral therapy during which his virus infection-associated lesions were resolved, new blisters developed near the insertion site of a peripheral venous line located on a previously uninvolved yet swollen upper extremity. The varicella zoster virus disease was initially suspected, but lab studies and skin biopsy of a blister excluded progressive or persistent viral infection and established a diagnosis of acute edema bullae. The blisters resolved following removal of the peripheral catheter. Acute edema bullae should be added to the list of mimickers of\u00a0disseminated varicella zoster virus infection. Edema bullae are the blisters that occur following\u00a0the swelling at an affected site, most commonly in the lower extremities of the patients with acute exacerbation of fluid overload or chronic leg swelling . Herpes A 53-year-old immunosuppressed male with the history of the kidney transplant presented with two weeks of painful vesicles on his left forearm, left leg, and the abdomen. His past medical history was significant for kidney transplant four years prior and disseminated herpes zoster two years prior. His daily medications included 7.5 milligrams of prednisone, 6 milligrams of Tacrolimus, and 720 milligrams of mycophenolate sodium.The cutaneous examination showed individual and grouped, erythematous-based vesicles located in a dermatomal distribution on the left side of his abdomen, and more than 20 individual lesions in a diffuse, nondermatomal distribution on his body. Initial polymerase chain reaction testing of a lesional swab was positive for varicella zoster virus and negative for herpes simplex virus. He was started on 10 mg/kg of intravenous acyclovir three times per day for disseminated herpes zoster involving multiple dermatomes but without organ or central nervous system involvement.After seven days of intravenous antiviral therapy, his VZV-associated lesions had nearly resolved Figure . HoweverThe polymerase chain reaction testing of the new lesions was negative for varicella zoster virus and herpes simplex virus. Microscopic examination of a biopsy taken from the edge of a blister showed a paucicellular subepidermal vesicle with epithelial necrosis, focal ischemic alteration of the eccrine apparatus, and pronounced dermal edema Figure .Correlation of the laboratory studies and microscopic examination of the skin biopsy of the new, painless, polymerase chain reaction VZV-negative bullae in a patient with resolving disseminated herpes zoster following one week of antiviral therapy established a diagnosis of acute edema blister. These blisters were likely secondary to lymphedema from intravenous catheter-associated pressure or trauma since the new blisters were located in a limb previously uninvolved with VZV but associated with intravenous catheter access. The peripheral intravenous catheter was relocated to the left limb and lesions resolved.Edema bullae are the blisters that occur most commonly in the elderly and immobile during acute increases in interstitial fluid pressure . They prWhen capillary filtration develops too rapidly for compensatory lymphatic drainage, dermal edema may occur, leading to blister formation . This ocThe treatment of acute edema blisters is directed towards reducing fluid overload. The elevation of the dependent extremity may promote lymphatic drainage and lesions typically resolve once the fluid imbalance is corrected ,6. In ouThe herpes zoster classically manifests as grouped, painful vesicles in a dermatomal distribution. However, disseminated herpes zoster may present with skin lesions simultaneously involving multiple dermatomes (on one or both sides of the body) or with a widespread distribution of more than 20 lesions either alone or be accompanying lesions that are located in one or more dermatomes. The diagnosis is typically established clinically, but confirmation with polymerase chain reaction testing for VZV deoxyribonucleic acid (DNA) or direct fluorescent antibody testing can be performed . Ninety The treatment of uncomplicated herpes zoster involves oral antiviral therapy for seven to 10 days, while disseminated disease or visceral involvement warrants intravenous therapy. Immunosuppressed patients with uncomplicated herpes zoster may also be treated orally, although intravenous acyclovir is recommended in the severely immunocompromised in order to prevent disseminated disease . This poResolved areas of prior VZV infection may become \u201cimmunocompromised districts\u201d, areas of skin with increased susceptibility to other skin disorders, including malignancy (such as cutaneous metastases), opportunistic infections, and granulomatous disorders (such as granuloma annulare and sarcoidosis) . The preMany dermatological conditions are known to mimic VZV infection, including cellulitis, contact dermatitis, dermatitis herpetiformis, drug eruptions, herpes simplex infection, and tinea infection . Rarely,Edema bullae present as the medium to large-sized vesicles and typically manifest during states of volume overload causing acute swelling in the\u00a0affected site. Our patient\u2019s lesions occurred in the setting immediately following disseminated herpes zoster infection, and were initially misinterpreted as progressive disease. However, the viral studies were negative for VZV and herpes simplex virus, while a lesion biopsy showed a non-inflammatory subepidermal blister; correlation of these studies and the clinical history of recent intravenous therapy near the involved site established the correct diagnosis of acute edema bullae. In conclusion, the acute edema bullae may result from prolonged pressure or trauma from a peripheral venous line; in addition, acute edema bullae can be added to the list of dermatological conditions that may mimic varicella zoster virus infection."} +{"text": "We evaluated the impact of man-made conflict events and climate change impact in guiding evidence-based community \u201cOne Health\u201d epidemiology and emergency response practice against re-/emerging epidemics. Increasing evidence of emerging and re-emerging zoonotic diseases including recent Lassa fever outbreaks in almost 20 states in Nigeria led to 101 deaths and 175 suspected and confirmed cases since August 2015. Of the 75 laboratory confirmed cases, 90 deaths occurred representing 120% laboratory-confirmed case fatality. The outbreak has been imported into neighbouring country such as Benin, where 23 deaths out of 68 cases has also been reported. This study assesses the current trends in re-emerging Lassa fever outbreak in understanding spatio-geographical reservoir(s), risk factors pattern and Lassa virus incidence mapping, inherent gaps and raising challenges in health systems. It is shown that Lassa fever peak endemicity incidence and prevalence overlap the dry season (within January to March) and reduced during the wet season (of May to November) annually in Sierra Leone, Senegal to Eastern Nigeria. We documented a scarcity of consistent data on rodent (reservoirs)-linked Lassa fever outbreak, weak culturally and socio-behavioural effective prevention and control measures integration, weak or limited community knowledge and awareness to inadequate preparedness capacity and access to affordable case management in affected countries. Hence, robust sub/regional leadership commitment and investment in Lassa fever is urgently needed in building integrated and effective community \u201cOne Health\u201d surveillance and rapid response approach practice coupled with pest management and phytosanitation measures against Lassa fever epidemic. This offers new opportunities in understanding human-animal interactions in strengthening Lassa fever outbreak early detection and surveillance, warning alerts and rapid response implementation in vulnerable settings. Leveraging on Africa CDC centre, advances in cloud-sourcing and social media tools and solutions is core in developing and integrating evidence-based and timely risk communication, and reporting systems in improving contextual community-based immunization and control decision making policy to effectively defeat Lassa fever outbreak and other emerging pandemics public health emergencies in Africa and worldwide.The online version of this article (10.1186/s40249-018-0421-8) contains supplementary material, which is available to authorized users. Please see Additional file The increasing evidence of climate change and other man-made conflict events impacts on emerging and re-emerging zoonotic or vector-borne diseases such as Lassa fever outbreak direct risk-effect occurrence and burden worldwide and particularly in developing countries. Acute Haemorrhagic Fever Syndrome is a general term broadly attributable to diverse mild to severe group of animal and human illnesses that encompass: Lassa fever (arenaviridae), Rift Valley fever (RVF), Crimean-Congo haemorrhagic fever (CCHF) (bunyaviridae), yellow fever (flaviviridae), Ebola and Marburg viral diseases (filoviridae), dengue (dengue haemorrhagic fever (DHF) and other viral diseases such as rickettsial or bacterial diseases with ability to result in epidemics , 2.Mastomys natalensis is the rodent reservoir of the Arena spp. the virus responsible [Lassa fever a known endemic infectious disease of poverty has emerged as a severe outbreak of public health threat and burden in Nigeria in the recent past . Nigeriaponsible . Followiponsible , 3. Spatponsible , 2.nd week, 9.53% of suspected cases were confirmed by laboratory tests. However, of the 75 laboratory confirmed cases 90 deaths occurred i.e. 120% laboratory case fatality. That means 20% of observed Lassa fever related deaths were not confirmed as cases by laboratory tests hinting to a systems gap in the disease detection and surveillance. However, by 2017, this observed health systems gap in infectious disease and outbreak detection and surveillance was not appropriately addressed [Nigeria is no doubt now endemic for Lassa fever, there was an observed 21.3% seropositive prevalence in a countrywide study . A briefddressed . Of the The paper assesses the current trends in re-emerging Lassa fever geo-spatial distribution, inherent gaps and raising health system challenges towards improving interlinkage of laboratory and epidemiology surveillance to evidence for community towards one health approach and practice.M. natalensis and not M. erythroleucus correlates geographically with observed Lassa fever seropositivity prevalence in humans [Since the Lassa fever virus is transmitted to humans via contact with food or household items contaminated by rodent hosts, sexually or direct/indirect contact with body fluids such as the blood, urine, and saliva of an infected person , 5, an in humans . A studyn humans , similarn humans . Peak inn humans . Howevern humans . The endn humans , 14, 15.Hence, in absence of preventive medication or vaccine against Lassa fever, increasing community awareness and health education to avoid contact with reservoir sources mainly rats, prevention of food infestation rodent\u2019s and food safety practice to appropriate waste management coupled with improved water, sanitation and hygiene (WASH) program implementation is crucial. Since, sexual transmission of Lassa virus has also been reported, improved access to sexual and reproductive preventive measures is also important in line with WHO recommendations as well as shared traveller information support.Importantly, there is an urgent need to linking disease ecology with enhanced surveillance data garnered from 1969 across Sub-Saharan Africa , 16.Strengthening local and regional robust and sustainable integrated disease surveillance and response (ISDR) implementation into routine laboratory diagnostic and epidemiologic surveillance services, and surge resource capabilities is imperative. Scaling up adequate community social mobilization, nationwide enlightenment and health education outreach coverage using various social media and mass media outlets by various stakeholders is needed to prevent and respond promptly to potential epidemic events at each identified community health system level . LeveragLeveraging on digital, cloud-sourcing and social media in developing and integrating timely risk communication and reporting systems can be seen to start from the lowest administrative level at the community up to Central or Federal level while a feedback process flows from the development partners and Federal government back to the communities. Fostering key operational coordination, epidemiology and surveillance capacity building programs should ensure effective and concurrent trans-disciplinary outbreak response actions and Lassa fever clinical case management guidelines. Hence, strengthening community health centres and laboratory capacity, data sharing access and operational logistics for evidence operational research priorities and decision making policies, supply chain and timely risk communication and share livelihoods .st and 22nd of August, 2017, with the whole essence of building and strengthening robust and effective health system to achieve increasing access to universal health coverage (UHC) and sustainable development goals(SDGs). Noteworthy, was the technical support from the WHO Africa Regional Office (AFRO) and the National Lassa fever Steering Committee at the forum. The Nigeria Centre for Disease Control (NCDC) in partnership with the aforementioned as well as other supporting partners participants from State governments affected by Lassa fever endemicity and epidemics.The Federal Government of Nigeria has embarked on integrated infectious diseases prevention and control; however integration in primary healthcare is still seldom and unstructured at all levels nationwide. Integrating community-based \u201cOne Health\u201d surveillance and emergency response practice is crucial in addressing the persistent scourge of poverty-related Lassa fever outbreak and other emerging zoonotic disease pandemic threats amongst vulnerable populations across the region. In reviewing the 2016/2017 Lassa fever year, stakeholders hosted an interdisciplinary action review meeting in Abuja between 21Scaling up contextually diagnostic and care access at the point of need no matter the location and time without any encumbrances is critical to improving vulnerable population quality of life, productivity, reduction financial impoverishment and poverty alleviation , 19. TheContemporary increasing in consumer/provider-generated mhealth technology and application, social media penetration and acceptance, online disease data and information literacy and communication to emergency response or recovery to immunization scale coverage and effectiveness should exploited to optimize health benefits, wellbeing impacts and return of investment as coupled with traditional mass media in reachIn controlling the scourge of Lassa fever an early warning system and rapid response is important. Once one case of Lassa fever is suspected an alert should be made and once this is confirmed in the laboratory then the situation must be treated as an epidemic , 2. ThisBuilding early warning indicators and rapid response to adequately prevent or respond to Lassa fever medical care needs at the hospitals, scaling up access to medical supplies and vaccines stockpile are needed in preparedness and during potential epidemics. The following are usually supplied to Local Government Areas (LGAs) at risk in Nigeria , 17. MedIt is important to note that in effectively tackling this scourge, test kits and laboratory analysis to confirm suspected cases as soon as possible need to be readily accessible. Lassa virus and other emerging viral diseases detection and confirmation requires Biosafety level 4 (BSL-4) laboratories across the world, but very few exist in Africa . Some AfIt is alarming that the true incidence of Lassa fever is unknown as quoted incidences are extrapolations from 1980s studies. Thus the Lassa fever research field is in dire need of more accurate and recent studies on disease incidence, geographic distribution and virus seroprevalence , 30. RivAccelerating health systems strengthening and rebuilding transformations in affected West Ebola outbreak countries is important through improving ISDR system and scaling up access to routine immunization programs; while leveraging on community-based and vulnerable populations\u2019 empowerment and resilience activities in endemic regions to traveller medical information , 35. LikLassa fever virus outbreak, a poverty-related infectious diseases outbreak remains a public health threat and burden on vulnerable populations in West Africa and Nigeria in particular. Robust and sustainable leadership commitment and investment of all stakeholders and affected communities in Lassa fever outbreaks prevention and containment is crucial and requires strengthening integrated Lassa fever outbreak surveillance quality data gathering to support evidence data sharing, contextual local and regional outbreak early warning alert, preparedness and response systems. Collaborative \u2018One Health\u2019 approach operational research is needed in understanding spatio-geographical risk factors patterns, reservoir(s) mapping and phylogenetic in guiding evidence-based, appropriately tailored and timely integrated programs and strategic interventions implementation against the zoonotic disease epidemics and pandemics threats in Nigeria and the sub-Saharan Africa foci terrain. Furthermore, fast-tracking R&D for more sensitive diagnostic tools, safer and effective drugs and vaccine development is imperative in improving contextual community-based immunization decision making policy to effectively outwit Lassa fever outbreak and other emerging pandemics public health emergencies. Moreover, fostering local community to regional re-merging and emerging epidemics and pandemics data sharing and coordinated invasive pathogens epidemiology surveillance and early warning indicators metrics capacity building, monitoring and evaluation is crucial for timely and quality risk communication and operational research. Integrating community \u201cOne Health\u201d surveillance and rapid response approach practice against Lassa fever epidemic and other emerging pandemic threats offers new opportunities in understanding human-animal and environment interface and expanding zoonotic diseases public awareness and resilience strategies and mitigation measures in attaining national and global health security.Additional file 1:Multilingual abstracts in the five official working languages of the United Nations. (PDF 423 kb)"} +{"text": "This review focuses on the cognitive neuroscience of Attention Deficit Hyperactivity Disorder (ADHD) based on functional magnetic resonance imaging (fMRI) studies and on recent clinically relevant applications such as fMRI-based diagnostic classification or neuromodulation therapies targeting fMRI deficits with neurofeedback (NF) or brain stimulation. Meta-analyses of fMRI studies of executive functions (EFs) show that ADHD patients have cognitive-domain dissociated complex multisystem impairments in several right and left hemispheric dorsal, ventral and medial fronto-cingulo-striato-thalamic and fronto-parieto-cerebellar networks that mediate cognitive control, attention, timing and working memory (WM). There is furthermore emerging evidence for abnormalities in orbital and ventromedial prefrontal and limbic areas that mediate motivation and emotion control. In addition, poor deactivation of the default mode network (DMN) suggests an abnormal interrelationship between hypo-engaged task-positive and poorly \u201cswitched off\u201d hyper-engaged task-negative networks, both of which are related to impaired cognition. Translational cognitive neuroscience in ADHD is still in its infancy. Pattern recognition analyses have attempted to provide diagnostic classification of ADHD using fMRI data with respectable classification accuracies of over 80%. Necessary replication studies, however, are still outstanding. Brain stimulation has been tested in heterogeneously designed, small numbered proof of concept studies targeting key frontal functional impairments in ADHD. Transcranial direct current stimulation (tDCS) appears to be promising to improve ADHD symptoms and cognitive functions based on some studies, but larger clinical trials of repeated stimulation with and without cognitive training are needed to test clinical efficacy and potential costs on non-targeted functions. Only three studies have piloted NF of fMRI-based frontal dysfunctions in ADHD using fMRI or near-infrared spectroscopy, with the two larger ones finding some improvements in cognition and symptoms, which, however, were not superior to the active control conditions, suggesting potential placebo effects. Neurotherapeutics seems attractive for ADHD due to their safety and potential longer-term neuroplastic effects, which drugs cannot offer. However, they need to be thoroughly tested for short- and longer-term clinical and cognitive efficacy and their potential for individualized treatment. Attention Deficit Hyperactivity Disorder (ADHD) is characterized by symptoms of age-inappropriate inattention, hyperactivity and impulsivity , that are mediated by late developing fronto-striato-parietal and fronto-cerebellar networks Rubia, . The mosSince the advent of fMRI, several hundreds of fMRI studies have been published in ADHD children and adults over the last two decades, the majority of them targeting cognitive functions. The first fMRI studies conducted in very small numbers of ADHD patients found reduced inferior fronto-striatal activation in ADHD children relative to age-matched healthy controls during motor inhibition /anterior insula, the supplementary motor area (SMA), anterior cingulate cortex (ACC), left striatum and right thalamus . Thus, ADHD patients showed enhanced activation in typical regions of the DMN such as in rostromedial prefrontal cortex during interference inhibition or orbitofrontal cortex (OFC) and striato-limbic regions during tasks that tap into \u201chot\u201d EF such as reward-related decision making or temporal discounting tasks. One of the most consistent findings is reduced ventral striatum activation during reward anticipation, as shown in a recent meta-analysis of eight fMRI studies of a monetary reward anticipation task using region of interest analysis in 340 ADHD patients and healthy controls , which are hypothesis-driven and measure changes in interactions across brain activations. In children and adults with ADHD, reduced functional connectivity has been observed between task-relevant regions during cool EF tasks, suggesting dysfunction of entire networks and not just regions.In ADHD children, during motor response inhibition and WM tasks reduced functional connectivity has been reported relative to healthy controls between the right IFC and basal ganglia, parietal lobes and cerebellum, and between cerebellum, parietal and striatal brain regions during sustained attention and transcranial direct current stimulation (tDCS) have found successful applications in other psychiatric disorders. Pioneering applications of these techniques to ADHD over the past decade targeting IFC or DLPFC have been mixed, but revealed some promising findings of improving cognition and clinical behavior. The following sections will review these clinical applications of neuroimaging in ADHD.Despite the fact that ADHD is a neurodevelopmental disorder with consistent evidence for brain structure and function deficits, currently ADHD is diagnosed solely on the basis of subjective clinical and self-rating measures, which are often unreliable, leading to diagnostic variability between clinicians, cultures and countries and can make predictions for individual subjects as opposed to group-level inferences. These methods have been shown to provide sensitive and specific diagnostic indicators for individual patients with other pathologies in particular for neurological disorders such as Alzheimer\u2019s disease but also for autism and depression diagnosis or prognosis of individual patients and build the path for brain function (or brain structure)-based patient stratification and personalized medicine. Multimodal multivariate approaches including several imaging modalities, including functional and structural imaging data as well as non-imaging data such as cognitive and genetic measures are likely to achieve superior classification accuracy than univariate approaches rTMS promotes cortical excitability, while low frequency (1 Hz) rTMS inhibits cortical excitability or sham dTMS (N = 13). dTMS is a modification of standard TMS that enables deeper non-invasive cortical stimulation at an effective depth of approximately 3 cm depending on the coil\u2019s design and the stimulation intensity. Stimulation was applied over bilateral prefrontal cortex in 20 daily sessions over 4 weeks, each session consisting of 55 trains of pulses at 18 Hz . The study found an improvement in ADHD symptoms in both groups suggesting a placebo effect and no cognitive improvements in either group or decreasing the excitability of neurons via the generation of subthreshold (stimulation-polarity dependent) alterations of membrane potentials that modify spontaneous discharge rates, thus increasing/decreasing cortical function and synaptic strength relative to sham stimulation (N = 8); furthermore, all symptom improvements were still significant 2 weeks after stimulation, suggesting longer-term effects \u2014that has been shown to interact with physiological slow oscillatory activity, which is typically abnormal in ADHD\u2014over lateral prefrontal cortex during deep sleep in 12/14 ADHD adolescents compared to sham stimulation in a double-blind within patients design with 1 week break in between conditions. The outcome measures were slow oscillatory power during deep sleep in the non-stimulation periods and cognitive function improvements relative to sham tDCS in the next morning. Slow oscillatory power during deep sleep was increased, indicating an enhancement of endogenous oscillatory activity with the intervention. Cognitive improvements were in declarative memory had to learn to upregulate the rIFC, while the control group (N = 13) had to upregulate a control region, the left parahippocampal gyrus (lPHG). Both groups were tested before and after treatment in clinical and cognitive measures as well as in an fMRI Stop task and were followed up a mean of 11 months later in the main ADHD clinical outcome measure. Participants were trained to enhance activation of the target/control regions in 11 sessions of 8.5 min of rtfMRI-NF over four scan hours over 2 weeks. They were trained on a computer game where a rocket moved towards the sky, passing through clouds, and ultimately reaching some planets every time they managed to increase the activation of the target/control region. The fMRI data showed significantly enhanced activation as well as enhanced linear activation increase in two regions of the rIFC across all 11 sessions in the active relative to the control group and enhanced linear activation increase in three regions of the lPHG in the control relative to the active group and electromyography-NF (N = 9). Only NIRS-NF resulted in significant improvements in clinical ADHD symptoms and in cognitive inhibition and attention functions after 11 h sessions over 4 weeks, which was, however, not superior to EEG-NF or electromyography-NF of the left DLPFC in nine ADHD children, compared to EEG-NF neurobiological basis of different ADHD subtypes such as inattention without hyperactivity, or ADHD with emotional dysregulation. Furthermore, more understanding is needed on comorbid cases with other disorders such as autism, anxiety and affective disorders as well as on females with ADHD and gender differences. Future studies therefore ideally should be longitudinal, multimodal and tied to epidemiological samples.Clinical translation of neuroimaging is still in its infancy in the field of ADHD. Pattern recognition analyses applied to functional imaging data to make individual predictions on diagnostic status are promising, but more so for homogenous subtypes that likely share the same \u201cbiotype\u201d rather than heterogenous large groups of ADHD patients with different comorbidities or medication status. They will need to show replicability and clinical utility which will be the challenge over the next decades.Several brain stimulation studies with heterogeneous study designs have been conducted in small groups of ADHD children and adults, most of them using tDCS in either single or five sessions targeting mostly DLPFC or IFC based on the fMRI studies conducted in ADHD over the last two decades. The findings show some improvements on clinical symptoms or selective cognitive functions, with, however, also negative findings. Larger sham-controlled studies are needed to further test the efficacy of tDCS and potential costs on non-targeted cognitive or behavioral functions. In addition, far more knowledge is needed on the optimal stimulation protocols for different age and patient subpopulations . It is likely that brain stimulation combined with cognitive training has a larger potential to enhance brain plasticity in ADHD than brain stimulation alone. This will also require the development of good cognitive training tasks that target ADHD-relevant functions to be used in combination with brain stimulation techniques. Given minimal side effects, tDCS is a promising tool for the treatment of childhood onset psychiatric disorders, since it provides the opportunity to positively influence atypical brain development early and persistently , potential costs that may accompany the benefits, and their potential for individualized treatment (which ADHD subtype responds to which neurotherapy and why). It is likely that different subgroups of ADHD patients will benefit from either NF, brain stimulation or medication and establishing this knowledge will be crucial to the benefit of individual patients.The author confirms being the sole contributor of this work and approved it for publication.The author has received grants from Lilly and Shire and speaker\u2019s honoraria from Shire, Lilly and Medice."} +{"text": "Retinal artery occlusion is extremely rare in the pediatric population and most patients have risk factors. We report a case of a healthy child with segmental optic atrophy, complicated by incidental branch retinal artery occlusion (BRAO).A 10-year-old boy who had a history of his mother\u2019s gestational diabetes presented with an inferonasal visual field defect in the left eye. His best-corrected visual acuities were 20/20 in both eyes (OU). Fundoscopic examination revealed segmental pallor of the left optic disc, thinning of the superotemporal rim, a relative superior entrance of the central retinal artery and superior peripapillary scleral halo. Fluorescein angiography showed patchy filling delays in the corresponding disc area without retinal vascular abnormalities. Spectral domain optical coherence tomography (SD OCT) via automated segmentation analysis demonstrated sectoral absence of the ganglion cell layer and retinal nerve fiber layer with thinning of the inner plexiform layer, inner nuclear layer and outer plexiform layer in the corresponding retina. OCT angiography (OCTA) showed focal attenuation of superficial and intermediate/deep capillary plexuses in the corresponding areas. Systemic evaluation was unremarkable. The patient was diagnosed with segmental optic atrophy caused by incidental BRAO.Retinal vascular occlusions are rare in childhood, and may present as segmental optic atrophy mimicking congenital anomalies. OCTA allows the detection of previous microvascular abnormalities in the chronic phase. To the best of our knowledge, this is the first report of a child with segmental optic atrophy presumably caused by BRAO, which was documented by SD OCT and OCTA in detail. When segmental atrophy of the optic disc is found in children, benign conditions such as isolated superior segmental optic hypoplasia (SSOH) are mostly considered, particularly in healthy children of an insulin dependent diabetic mother . Rarely,A visually asymptomatic 10-year-old boy presented with an inferonasal visual field defect in the left eye Fig.\u00a0. He had Optic nerve atrophy is the secondary pathogenic endpoint of numerous diseases that cause intrinsic or extrinsic insult to the visual pathway. Although, partial optic atrophy with homonymous visual field defect is characteristic for cortical visual impairment, various congenital lesions involving the retina, optic nerve, chiasm, optic tract, or retrogeniculate pathways as well as acquired conditions such as periventricular leukomalacia also show segmental optic nerve changes , 7. HoweRetinal artery occlusion is an extremely rare condition in the pediatric population and most patients have some detectable risk factors . Surpris"} +{"text": "There are now several immunotherapy trials for ovarian cancer although the clinical benefits have been limited to a subset of patients . We receBRCA mutation (gBRCAm) associated platinum-sensitive recurrent disease [gBRCAm-associated platinum-sensitive recurrent ovarian cancer (NCT02734004) to examine how clinical benefits by immune checkpoint inhibitors are added to PARPi\u2019s activity in the background of gBRCAm. Interestingly, in our study, none of the women receiving durvalumab+olaparib >= 9 months had germline or somatic mutations in BRCA or other DNA repair genes [PARP inhibitors (PARPi) are intriguing combination therapy partners with other pathway inhibitors such as immune checkpoint blockade . The com disease . A phasegBRCAm, in which the role of neoantigen expression and changes in immune microenvironment induced by PARPi will be further examined. The optimal selection of patients for treatment with PARPi and immune checkpoint inhibitor in non-BRCA mutated settings and better understanding of the mechanisms of action will require further characterization and analysis.PARPi blocks DNA repair, resulting in DNA breaks . FragmenImmunotherapy manifests differently from traditional chemotherapy, eliciting delayed response kinetics . It has The overexpression of PD-L1 is an important and widely explored biomarker for response to immune checkpoint inhibitors. However, PD-L1 expression by immunohistochemistry fails to accurately select all patients suitable for PD-1/PD-L1 inhibitors . The preThe advent of immunotherapy combination therapy presents us with new approaches in ovarian cancer treatment with promising outcomes, preliminarily. Multiple clinical trials are currently being conducted to better define the role of PARPi and immunotherapy combinations, and further investigation is warranted to develop and identify predictive biomarkers. Assessing how immunotherapies should be incorporated with current standard-of-care treatments, such as PARPi is essential to make progress in the treatment of ovarian cancer."} +{"text": "The development of cardiac complications during or after endoscopic procedures is rare. However, mortality from myocardial ischemia, particularly in the elderly population, is elevated. We illustrate the rare case of a 79-year-old man with multiple cardiovascular risk factors who developed a non-ST elevation myocardial infarction (NSTEMI) after endoscopic removal of a foreign body. This case report summarizes a rare complication of a low-risk procedure and highlights the importance of considering this potential adverse event, particularly in patients with significant cardiovascular risk factors, to promote early diagnosis and proper treatment. Incidence of Acute Coronary Syndromes (ACS) following endoscopic procedures is low <1%), and usually these interventions do not require further preoperative testing [%, and usCardiac complications are 2\u20135 times more likely to occur during emergency procedures than with elective interventions , which cA 79-year-old man, former smoker and with type 2 diabetes, hypertension, and hyperlipidemia, presented to the hospital after swallowing a piece of denture while eating carrots. On arrival physical exam and laboratory tests were unremarkable. Computed tomography (CT) scan showed esophageal distention compatible with ingested foreign body, as well as aortic and coronary atherosclerosis. A flexible esophagogastroduodenoscopy was done attempting foreign body removal; however it was unsuccessful and during the procedure ST-segment elevation was noted on the cardiac monitor. An emergent rigid esophagoscopy was performed and the foreign object was removed. Electrocardiogram (ECG) showed a left bundle branch block (LBBB) that did not meet Sgarbossa criteria; however there was no prior ECG to compare with ; vital sRepeat ECG showed sCoronary angiography was attempted once but patient became very agitated during the procedure; the Interventional Cardiology team increased the sedation to try to finish the study but patient remained restless and kept moving all his extremities, so continuing the procedure under these circumstances would have been extremely dangerous.Transthoracic echocardiogram (TTE) revealed anteroseptum, apex, and distal-anterior wall akinesis; left ventricular ejection fraction was 30% . Troponin T peaked at 9.37\u2009ng/mL and then trended down. Before being discharged, the medical team discussed extensively the importance of having a coronary arteriogram done to evaluate the presence of obstructive lesions in the coronary vasculature. Despite the insistence of the team and the broad discussion with the patient regarding different methods of anesthesia, patient refused to undergo this procedure given his prior experience. He remained hemodynamically stable and was discharged in stable condition.This is, to the best of our knowledge, the first case report of NSTEMI associated with esophageal microperforation after endoscopy in the setting of foreign body ingestion. A few reports do exist; however, of myocardial ischemia following gastroscopy , suggestMyocardial ischemia results from imbalance between oxygen demand and supply. During endoscopy, catecholamine-induced tachycardia can trigger it in patients with high atheromatous burden and fixed coronary stenosis or with development of hypoxia during a difficult procedure. In our patient, the ACS could have been induced by stress of aspirated dentures and the intervention triggering any of these mechanisms; however we were unable to exclude other etiologies such as Takotsubo cardiomyopathy.Adverse cardiopulmonary events attributable to endoscopic procedures are rare \u20139 and raCurrent guidelines for preoperative cardiovascular evaluation do not recommend a preoperative 12-lead ECG or any other form of preprocedural cardiac assessment in asymptomatic patients undergoing low-risk interventions , and endECG is an inexpensive and very useful tool that could benefit some asymptomatic patients with multiple cardiovascular risk factors undergoing low-risk procedures and could be a cost-effective test to promote early diagnosis and treatment of cardiac complications. This case report summarizes an example of these adverse events aiming to increase awareness of this potentially fatal complication and highlight the relevance of prompt intervention and judicious use of preprocedural testing despite guideline statements to the contrary. This underscores that guidelines are just that and are not rigid, unbreakable rules with proper documented justification."} +{"text": "The Accreditation Council for Graduate Medical Education (ACGME) implemented revisions to resident duty hour requirements (DHRs) in 2011 to improve patient safety and resident well-being. Perceptions of DHRs have been reported to vary by training stage and specialty among internal medicine and general surgery residents. The authors explored perceptions of DHRs among all residents at a large academic medical center.medical and pediatric, surgery, or other.The authors administered an anonymous cross-sectional survey about DHRs to residents enrolled in all ACGME-accredited core residency programs at their institution. Residents were categorized as In total, 736 residents representing 24 core specialty residency programs were surveyed. The authors received responses from 495 residents (67%). A majority reported satisfaction (78%) with DHRs and believed DHRs positively affect their training (73%). Residents in surgical specialties and in advanced stages of training were significantly less likely to view DHRs favorably. Most respondents believed fatigue contributes to errors (89%) and DHRs reduce both fatigue (80%) and performance of clinical duties while fatigued (74%). A minority of respondents (37%) believed that DHRs decrease medical errors. This finding may reflect beliefs that handovers contribute more to errors than fatigue (41%). Negative perceived effects included diminished patient familiarity and continuity of care (62%) and diminished clinical educational experiences for residents (41%).A majority of residents reported satisfaction with the 2011 DHRs, although satisfaction was significantly less among residents in surgical specialties and those in advanced stages of training. TDespite the differences we observed between the surgical versus nonsurgical disciplines and senior versus junior residents, it is worth stating that a majority of these subgroups did ultimately report overall satisfaction with the DHRs. Most respondents also indicated that the DHRs were respected and enforced by their institution. While most indicated that situations do exist where violation of DHRs is justified, few reported more than sporadic violations within the past year.Although a majority of respondents believed the DHRs mitigate resident fatigue, only 37% believed that the requirements decreased medical errors. More than one-half of respondents believed that DHRs did not impact (44%) or increased (19%) medical errors. Our findings are congruent with a study using a grounded-theory analysis of resident comments, that found residents did not associate patient safety with DHR compliance , 25. ThiOnly 26% of residents perceived the DHRs to have a positive impact on their clinical educational experience. Prior studies have demonstrated findings of perceived reductions in bedside teaching, clinical educational experiences , and surStrengths of our study are the large sample size and high resident response rate. In addition, we surveyed residents currently enrolled in all ACGME-accredited core residency programs at a large academic institution, and included residents at all levels of training within those programs. We also endeavored to conduct a thorough evaluation of the survey instrument by piloting our survey among experienced medical educators prior to its implementation.Limitations of our study include a cross-sectional study design, single-institution sampling, and a subjective assessment by the study subject relating to Level 1 outcomes . BecauseIn this cross-sectional survey study of residents enrolled in all ACGME-accredited core residency programs at a large academic medical center, a majority of respondents were satisfied with the current ACGME DHRs and believed they affected their training in an overall positive manner. Residents in surgical specialties and those in advanced stages of training were significantly less likely to view DHRs favorably, although in these subgroups as well, a majority of the respondents did report overall satisfaction with the DHRs."} +{"text": "Epigenetic mechanisms have emerged as key players in cancer development which affect cellular states at multiple stages of the disease. During carcinogenesis, alterations in chromatin and DNA methylation resulting from genetic lesions unleash cellular plasticity and favor oncogenic cellular reprogramming. At later stages, during cancer growth and progression, additional epigenetic changes triggered by interaction with the microenvironment modulate cancer cell phenotypes and properties, and shape tumor architecture. We review here recent advances highlighting the interplay between epigenetics, genetics, and cell-to-cell signaling in cancer, with particular emphasis on mechanisms relevant for cancer stem cell formation (CSC) and function. Epigenetic regulators are one of the most commonly mutated classes of genes in cancer. During cancer initiation, mutated epigenetic regulators lead to oncogenic cellular reprogramming and promote the acquisition of uncontrolled self-renewal. The emergence of CSCs requires elaborate reorganization of the epigenome.During cancer growth, epigenetic mechanisms integrate the effect of cell-intrinsic and cell-extrinsic changes and establish intratumoral heterogeneity, either promoting or inhibiting the CSC state.\u2018Loose\u2019 epigenetic constraints in cancer cells enhance cellular plasticity and allow reversible transitions between different phenotypic states. Enhanced cellular plasticity favors cancer cell adaptability and resistance to therapy.Modulation of epigenetic processes allows targeting of the most downstream determinants of the CSC state. The molecular makeup of a cancer is the result of multiple changes occurring progressively during its lifetime. Early in the disease, alterations in key genes disrupt normal cell function and endow cells with the ability to initiate a tumor or a hematological malignancy. Subsequently, as a cancer grows, additional changes superimpose onto the initiating events and affect the biological properties of cells, either enhancing or inhibiting their malignant properties. As a result of this constant modulation of cell function, tumors comprise a remarkable collection of distinct cellular phenotypes which differentially contribute to disease progression.Intratumoral functional heterogeneity and cell-extrinsic mechanisms modulate the epigenome of cancer cells, and their combined effect determines which cells preserve the self-renewal capacity acquired during tumorigenesis. These cells, referred to as cancer stem cells (CSCs) or leukemic stem cells (LSCs), are those responsible for driving long-term cancer growth and disease progression cellular plasticity at various stages of the disease.Similarly, The recent identification of driver mutations affecting a wide range of epigenetic regulators in hierarchically organized cancers provides direct evidence for the importance of epigenetic dysregulation in the formation of CSCs. These mutations are typically clonal and promote the acquisition of uncontrolled self-renewal.KMT2A/MLL gene. KMT2A/MLL encodes a histone methyltransferase that orchestrates several essential cellular processes through modification of chromatin, mainly regulating accessibility to enhancer regions de novo self-renewal capacity Leukemias represent a paradigm of hierarchical cancers maintained by LSCs. Numerous studies have identified mutated epigenetic regulators that favor the acquisition of uncontrolled self-renewal ability and initiate the disease. A prominent example is offered by mixed lineage leukemia (MLL)-associated leukemia, which is characterized by chromosomal rearrangements involving the H3F3A, and a K27M substitution is the most common alteration Probably the most compelling evidence supporting a key role of chromatin in the acquisition of uncontrolled self-renewal comes from studies in glioblastoma (GBM), a highly aggressive form of brain cancer characterized by an undifferentiated phenotype and a high frequency of CSCs. Recent sequencing efforts have identified gain-of-function mutations in genes encoding histone H3 in about one third of pediatric GBMs. The gene mainly affected is Proteins involved in the establishment and maintenance of DNA methylation have also been identified as drivers of CSC formation. The methylation status of CpG dinucleotides depends on the action of DNA methyltransferases , which apply the methyl-group to cytosines, and methylcytosine dioxygenases (TET1 and TET2), which convert 5-methylcytosine to 5-hydroxymethylcytosine and initiate a demethylation process. DNMT3A is the DNMT most commonly affected by DNA lesions, being mutated in \u223c25% of AML patients de novo self-renewal capacity. In both cases, epigenetic constraints imposed during development to keep cellular plasticity under control are disrupted, and cells transform, losing their normal cellular identity in many cancers has been the basic observation supporting the hierarchical model of cancer development over the past two decades. Recent single-cell transcriptomic studies have extended our understanding of the gene expression programs that shape tumor architecture and have confirmed that aberrant differentiation programs establish cellular hierarchies within individual cancers. In a pioneering study, colon cancers were shown to contain multiple cell types with transcriptional profiles resembling those of the cellular lineages making up the normal epithelium. Importantly, single cancer cells could recapitulate the lineage diversity of the primary tumors in transplantation assays, demonstrating that multilineage differentiation represents a key source of intratumoral transcriptional heterogeneity The observation that IDH-induced oligodendrogliomas contain differentiated, non-self-renewing cells underscores the diverse, and at times antithetic, role of epigenetic mechanisms in cancer development. During tumorigenesis, mutations in IDH proteins drive CSC emergence partly through alteration of DNA methylation profiles and epigenetic reprogramming of committed oligodendrocytes. However, during tumor growth, additional epigenetic changes occur and establish developmental hierarchies that restrict the proliferative potential of some cells, counteracting the effect of the initiating mutations .Figure 2in vitroWhat are the mechanisms that generate distinct epigenetic states within tumors and confer distinct functional properties to CSCs and differentiated cells? Epigenetic regulators belonging to two distinct groups have so far been identified: those that inhibit cancer cell self-renewal and establish differentiation hierarchies, and those that are hijacked by CSCs to avoid differentiation and sustain their phenotype . Within Although many cancer cells succumb to differentiation during tumor growth, CSCs evade this process and preserve their self-renewal capacity acquired during transformation. Not surprisingly, considering the importance of epigenetic regulators in normal stem cell maintenance, many chromatin-related proteins and DNA-methylating enzymes are essential to maintaining the CSC state. Remarkably, most of the proteins implicated in CSC maintenance are typically not mutated but are co-opted in their wild-type state by CSCs to avoid differentiation and sustain their malignant properties. Prominent examples of hijacked proteins are Polycomb complex proteins. The PRC2 catalytic subunit EZH2 has a tumor-promoting role in many malignancies, and inhibition of its activity or genetically induced loss of the protein strongly impairs tumor growth A key feature of epigenetic mechanisms is their inherent reversibility. Thus, the dependence of CSCs on epigenetic regulators offers an opportunity to target their self-renewal capacity. The chromatin \u2018reader\u2019 BRD4 best illustrates this concept As with any therapeutic strategy, epigenetic modulation of CSCs faces challenges. Early concerns regarding targeting wild-type proteins that exert pleiotropic functions in normal cells have been mitigated by the observation that many tested inhibitors are not associated with major toxicity, suggesting that cancer cells exhibit a specific epigenetic vulnerability HOX oncogenes methylated in their promoter regions in particular AML cells and not in others A key question related to epigenetic regulation of the CSC state is: what determines epigenetic heterogeneity within tumors? For example, why do some cells express high levels of histone H1.0 and consequently differentiate, and others instead maintain low H1.0 levels and thus self-renewal capacity Variations in oxygen and nutrient concentrations are a likely source of phenotypic variation within tumors, and histone modifiers have been reported to act as sensors of hypoxia lo cells to CD44hi CSCs. Importantly, this cellular plasticity appears to be dependent on the chromatin status of the ZEB1 promoter because a poised, bivalent configuration allows reversion to CD44hi CSCs upon stimulation, while the presence of repressive marks renders CD44lo cells insensitive to TGF-\u03b2 et al. identified a subpopulation of cells that is required for continuous tumor growth and is marked by the expression of the histone demethylase JARID1B. However, instead of being a stable subpopulation, JARID1B+ cells are a dynamic subset whose composition changes over time as cells gain and lose JARID1B expression, and transiently acquire stemness properties depending on the tumor context A major difference between normal cellular hierarchies and cancer is that, although cell fate decisions triggered by environmental cues are generally stable and heritable in normal cells, cancer cells maintain an intrinsic plasticity that allows them to easily change their phenotype in response to new signals and possibly switch between cellular states. Evidence exists in some cancers that differentiated cells can reacquire self-renewal ability and revert to a CSC state . This ocet al. who reported the existence of a reversible drug-tolerant state in non-small cell lung cancer (NSCLC)-derived cell lines, and which can survive exposure to lethal concentrations of EGFR tyrosine kinase inhibitors. This drug-tolerant state does not involve drug efflux and is instead associated with an altered chromatin state and requires the histone demethylase KDM5A/JARID1A and IGF-1R signaling NOTCH1-driven T cell ALL, clinical trials using \u03b3-secretase inhibitors (GSI) have shown limited efficacy owing to the presence of a reversible subpopulation of GSI-tolerant cells characterized by BRD4-dependent transcriptional programs. Notably, combined treatment of patient-derived xenografts with NOTCH and BRD4 inhibitors showed greater efficacy than individual treatments Despite significant progress in the development of effective therapies against numerous cancer types, therapeutic resistance is still relatively common. CSCs are the likely source of resistant cells responsible for disease relapse because cells deprived of self-renewing potential are unable to reconstitute the cancer even if they survive treatment. While drug resistance primarily has a genetic basis, chromatin-related mechanisms have emerged as additional players in this context that are exploited by cancer cells to enhance their plasticity and adaptability . A paradEpigenetic alterations affecting chromatin and DNA methylation patterns are universal features of cancer. Historically, it has been difficult to distinguish whether these changes play a functional role in the disease or are a bystander phenomenon that merely reflects alterations in cell behavior. However, studies over the past 5\u201310 years have crystallized the importance of epigenetic mechanisms at various stages of cancer development and have uncovered unprecedented therapeutic opportunities . The reain vivo. The presence of cellular hierarchies in cancer clearly indicates that mechanisms inhibiting cell self-renewal ability exist, and can efficiently deprive cells of their malignant properties. Differentiation therapies that \u2018exaggerate\u2019 such mechanisms and restrict cellular plasticity may prove useful to exhaust CSCs and thus halt tumor maintenance, and also to impair cancer cell adaptability cells is established? Can cancer cell plasticity be modulated to reduce resistance to treatment? How prevalent are epigenetic mechanisms in the development of therapeutic resistance?Why do cancer cells, including CSCs, show specific sensitivity to epigenetic drugs that target wild-type proteins expressed in normal cells as well? Could epigenetic drugs be generally useful as agents to be administered in combination therapies?Considering the diverse role of epigenetics in cancer, and the possible interference with normal homeostasis, epigenetic modulation of CSCs clearly still faces many challenges, but at the same time offers unprecedented opportunities to hit the beating heart of the disease."} +{"text": "A 79-year-old female with no relevant past medical history was admitted in our emergencydepartment for dyspnea on minimal exertion and chest discomfort over 2 weeks. Blood gasanalysis showed severe hypoxemia and hypocapnia. Troponin was slightly positive. Despitea negative D-dimer assay, contrast-enhanced chest CT was performed to exclude pulmonaryembolism. It showed a large filling defect centered in the pulmonary valve plane (PanelsA and B). Bedside transthoracic echocardiogram showed a large echodense mass, apparentlymobile, extending across the right ventricle outflow tract, pulmonary valve, and themain pulmonary artery, with dilatation of the right sided chambers and transtricuspidpeak gradient of 70 mmHg (Panels C and D). Lower-limb venous compression ultrasound wasnegative for deep vein thrombosis. The patient remained stable, but required high oxygeninspiration fraction to maintain saturation above 90%. As pulmonary embolism was deemedunlikely given the clinical findings, the patient underwent cardiac surgery. Surgeryrevealed a pearly mass in the main pulmonary artery obliterating almost the entire lumenand with upstream extension to the pulmonary valve and right ventricle outflow tract(Panel E). The tumor was excised as much as possible and the pulmonary valve wasreplaced by a homograft. Pathological examination was compatible with angiosarcoma.Pulmonary artery angiosarcoma is exceedingly rare and carries a very poor prognosis. Itcan be clinical and radiologically indistinguishable from acute or chronic pulmonaryartery thromboembolism. Our clinical suspicion was heightened by a negative D-dimerassay and venous ultrasound and the apparent infiltration of pulmonary arterial walls onCT."} +{"text": "Analyses of covariance employed to partial out the influences of language and perceptual impairments, which frequently co-occur in these patients, provided evidence of different underlying cognitive mechanisms. These analyses revealed that language impairments explained the original poor scores obtained by the SD patients on the Ekman 60 and Emotion Selection tasks, which involve verbal labels. Perceptual deficits contributed to Emotion Matching performance in the bvFTD and AD patients. Importantly, all groups remained impaired on one task or more following these analyses, denoting a primary emotion processing disturbance in these dementia syndromes. These findings highlight the multifactorial nature of emotion processing deficits in patients with dementia. Patients with frontotemporal dementia as well as those with Alzheimer's disease (AD) show deficits on tests of face emotion processing, yet the mechanisms underlying these deficits have rarely been explored. We compared groups of patients with bvFTD ("} +{"text": "Fetal or prenatal programming, i.e. the process in which environmental events during pregnancy are shaping and determining the development of the embryo, can be embedded by epigenetic changes including DNA methylation. Apart from environment, also the genome plays an important role and a variety of studies which identified meQTLs have been published.Focusing on variably methylated regions (VMRs), we investigated if genotype (G), prenatal environment (E) or the combination of both best explain cordblood DNA methylation in sample of 817 Finnish neonates. Furthermore, we used an epigenetic clock predictor to evaluate if accelerated or decelerated epigenetic age was associated with prenatal environment or with childhood psychiatric problems at age 3.We found that SNP genotype alone best explained methylation status in 44%, SNP x environment in 32% and SNP and prenatal environment in 24% of all VMRs. While functionally relevant meQTLs were located in close proximity to the specific CpG-site, functionally relevant SNPs involved in interaction models showed much broader peaks.Concerning the epigenetic clock, lower gestational age was associated with maternal depression diagnosis and greater depressive symptoms throughout pregnancy. Epigenetic age deceleration was associated with pre-eclampsia. Furthermore, lower epigenetic gestational age was significantly associated with greater total and internalizing problems in boys.Not only environment but also genotype should be considered in epigenetic studies. Furthermore, our results suggest that long-distance effects are present in GxE interactions. The epigenetic clock which mirrors prenatal environment is partially predictive for future development of the child. Lower epigenetic gestational age seems to be developmentally disadvantageous for boys, who in early childhood show greater psychiatric problems."} +{"text": "A case of a renal artery stenosis and ipsilateral renal cell carcinoma with long term results is reported. A 65-year-old man with renovascular hypertension, renal insufficiency, and nephrotic range proteinuria presented with an incidental renal cell carcinoma. Concomitant in situ left partial nephrectomy and splenorenal arterial bypass was achieved. The patient is doing well without evidence of malignancy, stable renal function, markedly improved proteinuria and stable blood pressure more than three years later. The techniques of this procedure are detailed and underscore the possibility of successful removal of a renal cell carcinoma with preservation of renal function despite renal artery stenosis."} +{"text": "Based on the responses of 5,557 Chinese secondary students in Hong Kong, the relationships between perceived family functioning (systemic correlate), parent-adolescent communication (dyadic correlate), and suicidal ideation were examined in this study. Results showed that suicidal ideation was negatively related to global family functioning and parent-adolescent communication. Regression analyses indicated that the dyadic and systemic factors had similar importance in predicting suicidal ideation. Theoretical and practical implications of the findings are discussed."} +{"text": "Social cognition impairments are found in schizophrenia patients and hamper their ability to form social relationships. The biological underpinnings of this social cognition impairment are poorly investigated. We hypothesize that structural disconnectivity, which is replicated in schizophrenia, might has a relevant role in social cognition.The study we present here is under development. We have assessed social cognition using the Mayer, Salovey and Caruso emotional intelligence test (MSCEIT) in 30 patients with schizophrenia and 20 healthy controls. Structural connectivity is assessed with anatomical and Diffusion weighted (DWI) images acquired in a 3 Tesla MRI system. Anatomical and DWI images are processed to obtain fractional anisotropy (FA) values in the tracts connecting prefrontal cortex with anterior cingulate, superior temporal gyrus, insula and superior parietal cortex. The following statistics are assessed i) the differences in MSCEIT scores between patients and controls, ii) the differences in FA values between groups, iii) the relation between MSCEIT punctuation and FA values.In our preliminary analyses, patients show significantly lower MSCEIT scores. Furthermore, MSCEIT scores are directly related to FA values in the tracts connecting prefrontal cortex to anterior cingulate and superior temporal gyrus in the patients.Social cognition impairments seem to be associated with altered structural connectivity in the patients."} +{"text": "Arabidopsis have revealed the involvement of genes and proteins in the glycolytic and other metabolic pathways, particularly processes involved in dehydration tolerance, osmoprotection, and membrane transport. Furthermore, successful recovery appears to be dependent upon the presence of antioxidant protection from reactive oxygen species. Characterization of specific genes and proteins will lead to significant advances in plant cryobiology research.Plant cryobiology has primarily emerged from the classical fields of cryobiology and plant stress physiology. Cryopreservation tools are now available to geneticists for germplasm preservation and the field itself is advancing significantly through the use of molecular techniques. Long-term preservation of vegetatively propagated tissues can minimize the risks of long-term maintenance under tissue culture or field conditions. Cells can be successfully cryopreserved when the adverse affects of ice crystal formation are mitigated by the removal of water or procedures to limit ice formation and crystal growth. The addition of cryoprotectant solutions to hydrated cells may improve the survival of microdissected shoot tips or embryonic axes. Recent discoveries in the genetic pathways leading to cold acclimation and freezing tolerance suggest the involvement of key cold-regulated genes in the acquisition of cold tolerance in plant tissues. Model systems of banana and The field of plant cryobiology seeks to understand the physiological and molecular processes that allow plants to survive low temperatures. The focus of cryobiology is predominantly cryopreservation: the process and methods that permit long term survival of organisms at liquid nitrogen temperatures.Once cryopreserved, materials remain safe and available for a low annual cost. Novel, mutant, or transformed cell lines that can no longer be maintained in laboratory settings can be cryopreserved to prevent their loss . Clonal Successful cryogenic storage is dependent upon having a reliable source of coolant as well as a good documentation system. Once achieved, propagules often have extended storage longevity compared to conventional storage regimes (refrigerator or freezer conditions). Genetic drift and mutations are minimized compared to when materials are maintained in an actively growing state for extended intervals .Long term storage reduces the frequency of regenerations of accessions in genebanks and facilitates the use of specific individuals in breeding programs. Availability and transportability of cryopreserved pollen allows breeders to have access to materials that might otherwise be unavailable. Cryopreservation of embryo cultures lets breeding programs prolong the availability of juvenile materials while waiting for characterization of mature tree selections . CryothePlant cryobiology is a research discipline that is beginning to enter into the genomics arena. Traditionally, the discipline has been considered an extension of the cold hardiness and drought tolerance fields, centered primarily on long term preservation of seeds, shoot tips, dormant buds, pollen, embryos, cell lines, and other propagule types. A greater application of genomics techniques can increase our understanding of plant cryobiology. By combining physiological and genomic approaches, an array of methods are available to understand how cells are protected from freezing stress.One of the key issues in plant cryobiology is understanding why some genotypes are less tolerant of preservation stresses than other genotypes. Widescale adoption of cryopreservation technologies will likely depend on identifying universal cryoprotection protocols for each propagule type. A characterization of the genetic response to diverse cryoprotectants will determine if methods that rely on rapid cellular desiccation, permeable cryoprotectants, freeze desiccation, or air desiccation all result in similar cellular responses. Do cells sense and respond to the stresses differentially? Alternatively, do cells ultimately respond to either desiccation and/or temperature extremes? Careful analyses of gene expression responses will reveal which stress is perceived by cellular machinery and the pathways that are activated.Seeds and dormant buds can acquire an endogenous tolerance to desiccation and cryogenic temperature stresses. Dormant buds from temperate species collected mid-winter are more amenable to cryopreservation than those collected prior to acquiring cold tolerance or those which lose their cold-hardiness in the springtime . This acThe process of propagule recovery is poorly understood. Do cells acquire adequate protection from undesirable chemical effects that are generated during recovery? Is it possible to minimize production of free radicals while promoting cellular repair? Comparison of gene expression patterns will provide key information as to the timing and nature of the recovery pathways in systems that survive or fail to survive cryopreservation.Molecular marker technologies have already been applied to cryopreserved plant materials to ascertain if recovered explants are true-to-type. Generally, there is consensus that plant genotypes remain stable after cryopreservation when a single genotype is the conservation target -13. Key Both dehydration and low temperature affect water relations within the cell. Lethal ice forms when hydrated cells are cooled below their freezing point. Thus, for successful cryopreservation, cells must be desiccated to prevent ice propagation. Cells must also have intact membranes and stable proteins to tolerate the desiccation and cold stresses. The rich literatures of cold and desiccation tolerance have revealed that extraordinarily similar response pathways are triggered by these different stresses.It is not surprising that the regulatory mechanisms for desiccation and cold tolerance partially overlap. These stresses invoke second messengers such as calcium, reactive oxygen species, and inositol phosphates within minutes of stress signal perception . The casArabidopsis [Microarray chip methods have identified 299 drought inducible, 54 cold inducible, and 245 abscisic acid (ABA) inducible genes in bidopsis , 20. Of bidopsis . In thisCold treatments cause abrupt changes in the structure of cellular lipids and cytoplasm. Ice forms in hydrated cells and the plasma membrane undergoes an undesirable phase change that is induced by low temperatures. Formation of extracellular ice removes freezable cellular water, but also invokes a desiccation stress.Cold acclimation treatments can increase the levels of unsaturated fatty acids, alter lipid and protein composition, change the lipid/protein ratio, and increase the proportion of phospholipids to stabilize membranes and prevent phase changes , 23. LipoC [Genomic evaluations of cold acclimated and exposed plants have revealed complex response pathways. The DREB1 proteins are transcriptional activators of over 300 genes in the CBF cold response pathway . TranscroC . The coloC . The CBFoC .Desiccation tolerant seeds and pollen undergo extreme dehydration as part of the developmental maturation process. Orthodox seeds can lose most of their moisture during maturation, resulting in moisture contents of around 8%. At low moisture content, the cytoplasm enters a glassy state where molecular movement is minimal . GlassesVegetative cells can also tolerate desiccation. Tonoplast and plasma membrane specific aquaporins, water channels across membranes, may play critical roles in water movement during both desiccation and rehydration. Desiccation stresses may cause the plasma membrane to lose surface area. Sugars and other polyhydric solutes are believed to protect protein and membrane structures during desiccation, though the mode of action remains poorly understood , 32.LEA proteins accumulate in seeds when desiccation tolerance is acquired during seed maturation. LEA proteins are hydrophilic and remain soluble at boiling temperatures (e.g. ). They mA.The genetic response to drought or desiccation has been identified in several model systems. ABA independent pathways ultimately affect the pathways that regulate osmotic equilibrium and detoxification . The DRE/CRT cis-acting element associates with the desiccation-specific DREB2 transcription factor, found in the ABA independent pathway response to drought stress , 38. ERDB.Arabidopsis, several hundred genes were induced by exogenous ABA treatment [Exogenous ABA induces genes that are also activated by dehydration. In reatment . An exogreatment -46. Endogenous ABA is essential for some drought stress-responses , includiMAP kinases also play a role in the regulation of stress responses by affecting protein phosphorylation and dephosphorylation states . MAP kinAn alternative ABA dependent pathway involves the MYC and MYB transcription factors that bind to MYB and MYC recognition sequences and activate the drought inducible RD22 gene .Survival after desiccation is dependent upon cellular protection from the stress of water loss as well as the availability of functional repair mechanisms after rehydration. Desiccation tolerant seeds and pollen generally survive rehydration; whereas it is much more challenging to successfully regenerate less tolerant propagule types. Recovery is dependent upon having enough cells survive for successful propagule regeneration. In shoot tip systems, many of the larger cells in regions surrounding the meristem become extremely plasmolyzed and do not survive cryopreservation .Ribes accessions exhibited higher hydroxyl radical activity, antioxidant status, phenolic accumulation and anthocyanin pigments than Ribes accessions that were cryo-sensitive [The presence of reactive oxygen species within cells after stress can damage cells and generate lipid peroxides, aldehydic products and protein carbonyls , 51. Higensitive . The reaensitive . Reactivensitive . The cytensitive .Arabidopsis T87 suspension cells to facilitate conservation of transgenic lines. Arabidopsis can also be a good model to identify the gene expression responses to cryogenic stress [Arabidopsis shoot tips are easy to produce and readily survive diverse cryo-exposure protocols [et al. published methods for the cryopreservation of Arabidopsis shoot tips using three of the more common shoot tip cryoprotection protocols. Cryoprotectants serve to both dehydrate and promote the glassy state within cells [Arabidopsis methods employed the cryoprotectants Plant Vitrification Solution 2 or in solution-filled cryovials. In contrast, PGD-treated shoot tips are slowly cooled within cryovials to -30 or -35oC prior to LN exposure.Many plant cryobiologists have focused on finding methods to conserve horticultural species that are vegetatively propagated since seed storage does not maintain the genotype of interest. Recently, a cryopreservation protocol has been published for c stress . Arabidorotocols . In 2006in cells . Publishsucrose; ), Plant sucrose; ) and PGDArabidopsis system. Comparisons of gene expression patterns during cryoprotectant treatment, liquid nitrogen exposure, and recovery of Arabidopsis shoot tips using cDNA microarrays have revealed suites of genes up- and down-regulated in shoot tips that survive cryopreservation .Cryoprotectants vary in their toxicity as well as their protective mechanisms , 61, thuMusa shoot tips from multiple species are amenable to vitrification methods [Musa, proteomics approaches have proved advantageous [Musa proteomics efforts (http://www.pdata.ua.ac.be/musa/ modules/listview/?table=spot). These high sucrose treatments serve to decrease Musa meristem water content and increase the intracellular sucrose concentration [ methods , 64. Sinntageous -67. Merintageous . A websintration .Progress in genomic research in other kingdoms may reveal fundamental stress responses of cells to extreme conditions. Insects and microbes have adapted to polar environments . ReptileCryoptopygus antarcticus) from Antarctic regions upregulate structural and cuticle proteins. Furthermore, expression of genes involved in moulting supports a role of moulting in cold tolerance [Onychiurus arcticus) have also served as model to study desiccation and cold tolerance in insects [O. arcticus in various states of desiccation identified clones representing genes that fall into classes of aquaporins, dehydrins, heat shock proteins and those relating to antioxidant production that were upregulated [Desiccation and cold response pathways are interrelated in insects. Cold acclimated microarthopods (olerance . Arctic insects . As in p insects . Sequencegulated . Subtracegulated .The Storey laboratory at Carleton University has made remarkable progress identifying genomic responses in cold-tolerant vertebrates. Frogs and reptiles overwinter in a frozen state and use ice nucleators to initiate the freezing process extracellularly and use antifreeze proteins to inhibit recrystallization during freezing. High osmolyte contents limit cell volume reduction, membrane stabilizers such as trehalose and proline prevent lipid biolayer compression, and physiological adaptations regulate the cessation and reactivation of breathing and the heart . Novel gSuccessful cryoprotection in both animals and plants is dependent upon minimizing freezeable water within cells and the maintenance of sufficient cell volumes , 77. ColIt is clear that similar mechanisms have evolved in diverse kingdoms that enable organisms to tolerate extreme temperatures and desiccation. Cells have reduced biochemical reaction rates, increased cellular viscosities, alterations in membrane lipids and changes in protein conformation in response to extremely cold conditions . By miniPrevention of cellular ice formation and maintenance of intact membranes are critical for successful plant cryopreservation. Identification of the genomic responses to cold and desiccation stresses during the cryopreservation process will reveal how propagules respond to diverse cryoprotectants, extreme temperatures, and recover. Understanding plant acclimation is key to determining endogenous responses and more information about the recovery process is needed. Comparing the genetic responses to tolerance and longevity within and among plant species and propagules will guide conservation scientists in their quest to design improved preservation strategies."} +{"text": "Investigations were carried out on two lines of human melanomas xenografted in nude mice. The tumours were characterised by a similar vascular supply but showed a pronounced difference in the rate of volume growth and in the radiobiologically hypoxic fraction. The distribution of ATP, glucose and lactate in the tumours was investigated using quantitative bioluminescence and single photon imaging. Concentrations of the metabolites were obtained as global values for the entire tumour mass, in regions with densely packed, structurally intact tumour cells ('viable zones'), in areas with necrosis, stromal cells and fibrous material ('necrotic zones') and in adjacent normal tissue. In all melanomas investigated glucose concentrations were significantly lower and lactate concentrations were significantly higher than in normal tissue. In contrast, no significant differences for ATP were detected. ATP and glucose concentrations were significantly less in necrotic than in viable tumour zones, whereas lactate concentrations were nearly equal in these tumour parts. Corresponding results were obtained in central versus peripheral tumour zones. There was no dependency of global or regional metabolite concentrations on tumour size within the volume range 110-1470 mm3. Based on this lack of dependency, metabolic concentrations were averaged over the whole tumour size range. Metabolite concentrations were not significantly different either globally or regionally between the two tumour entities investigated, a finding which held true for all three metabolites registered. Thus, metabolite distributions apparently mirror the similarity in vascularity of MF and EE melanomas rather than reflecting intrinsic properties with regard to tumour growth rates or susceptibility to radiation."} +{"text": "Septic shock is a life-threatening clinical syndrome that, despite its rare occurrence in obstetrics,remains a leading cause of maternal mortality. Its pathophysiology is explained by a profoundsystemic response to a complex variety of host cellular and humoral mediators elaborated afterexposure to microbial toxins. Early recognition, prompt diagnostic workup, and immediate initiationof therapy improve outcomes. Therefore, recent publications have popularized the concept of the\u201csepsis syndrome,\u201d a preshock list of clinical criteria associated with progressive sepsis. Neededdiagnostic studies should never be withheld because of \u201cpregnancy concerns.\u201d With critically illpatients, the risk-to-benefit ratio supports the use of these diagnostic studies in almost all circumstances.Standard therapy is directed principally at restoring tissue perfusion by intravascularvolume expansion and in some instances vasoactive pharmacological intervention. Simultaneously,identification of the source of infection and commencement of appropriate empiric antibiotic treatmentare critical. In some cases, surgical abscess drainage or debridement of infected necrotic tissuewill need to be considered. Novel approaches to treatment that attempt to reduce the systemicresponse to microbial toxins are promising and under active investigation. Pregnancy-specific considerationsinclude the following: 1) initial signs or symptoms of septic shock may be masked bynormal physiologic alterations of pregnancy; 2) a mixed polymicrobial group of organisms, consistentwith lower genital tract flora, should be anticipated; and 3) initial therapy should be directedat maternal concerns since adverse fetal effects are most likely the result of maternal decompensation."} +{"text": "The prognosis of colorectal cancer has not significantly changed during the last 30 years. While evaluation of tumour cell proliferation may provide prognostic information, results obtained so far have been contradictory Heterogeneity in tumour cell proliferation may explain these contradictions. With in vivo injection of iododeoxyuridine (IdUrd), estimation of labelling index (LI), S-phase transit time (Ts) and potential doubling time (Tpot) may be performed from a single sample. A total of 109 colorectal cancers were studied after in vivo injection of IdUrd before surgical removal. From each cancer, four to eight samples were processed for both flow cytometrical (FCM) and immunohistochemical (IHC) visualization of IdUrd incorporation. LI/IHC was morphometrically quantified at both the luminal border and the invasive margin of these tumours. LI was significantly higher at the luminal border compared with the invasive margin, although they were correlated with each other. Using combined IHC and FCM methods, rapidly growing colorectal cancers (high LI and/or low Tpot) showed an increased survival in the entire unselected material and for radically removed Dukes' B tumours. FCM data alone did not discriminate for survival, with the exception of Ts in diploid and radically removed Dukes' B tumours."} +{"text": "The question of whether initial prognostic factors in small-cell lung cancer patients have a predictive value for patients' quality of life (QL) during chemotherapy is addressed in the context of a randomised clinical trial comparing early and late alternating chemotherapy (SAKK protocol 15/84). The relative impact of initial tumour stage and performance status, previous weight loss, sex and age on patient-rated QL was analysed over six chemotherapy cycles in 124-130 patients (according to available QL data) with more than 400 questionnaires. Fatigue/malaise, personal functioning, emotional and general well-being were prospectively selected as QL indicators. Predefined summary measures were analysed separately by scale in various patient groups. General linear models adjusted for treatment arm and response were used to confirm the univariate findings. Within the overall sample, the average QL scores over six cycles were predicted by initial prognostic factors. Patients with poor prognostic factors reported worse QL. Within a limited sample (with baseline QL), patients with poor prognostic factors reported worse QL at baseline and greater improvement under treatment. Graphical comparison of QL patterns over cycles showed permanent discrimination by levels of prognostic factors. The impact of initial prognostic factors was consistently confirmed in the three analyses. Levels of performance status and weight loss best discriminated QL. Initial tumour stage, performance status and previous weight loss can predict QL in small-cell lung cancer during chemotherapy, even after controlling for response to treatment. Our results may contribute to clinical decision-making with regard to the intensity of chemotherapy and QL outcome, especially in patients with extensive disease."} +{"text": "Among these chemicals is bisphenol A (BPA), a pervasive endocrine-disrupting compound used to make polycarbonate plastic and epoxy resins. Now researchers report evidence that exposure to environmentally relevant doses of BPA during pregnancy may alter insulin sensitivity and glucose homeostasis in mice, with potential disease-related consequences for both the mother and her male offspring The study evaluated the effects of two different doses of BPA (10 or 100 \u03bcg/kg/d) administered to pregnant mice during days 9\u201316 of gestation. Glucose metabolism experiments were performed on the mice during pregnancy and subsequently on their offspring.BPA exposure aggravated the insulin resistance that occurs during pregnancy, and four months postpartum, BPA-treated mice weighed more and had more severe insulin resistance than untreated females. The BPA-treated mice also showed elevated plasma levels of insulin, leptin, triglycerides, and glycerol (a breakdown product of triglycerides), as well as molecular changes indicating reduced insulin sensitivity in skeletal muscle and liver.Given that levels of the hormone leptin are normally increased during pregnancy, the authors propose that future research should seek to determine whether BPA directly regulates leptin release from fatty tissue or whether the observed hyperleptinemia is a consequence of the altered metabolic state of these animals.in utero had reduced glucose tolerance, increased insulin resistance, and altered blood parameters compared with offspring of untreated mothers. Moreover, studies of the male offspring\u2019s pancreases showed altered calcium signaling and insulin secretion.Previously the same research team had shown a relationship between BPA exposure and glucose intolerance and insulin resistance in adult male mice. In the present study, they further observed that, at 6 months of age, male offspring exposed to BPA The authors conclude that BPA exposure during pregnancy can alter the mother\u2019s glucose metabolism during pregnancy and later in life, and may contribute to metabolic disorders relevant to glucose homeostasis in the male offspring. The findings also suggest that BPA exposure should be further examined as a risk factor for diabetes."} +{"text": "Intrahepatic stones are difficult to manage, especially when they are associated with bile duct stricture,cholangitis and destruction of liver parenchyma. Suggested modes of treatment include surgical bile ductexploration, endoscopic procedures, transhepatic cholangiolithotomy and liver resection. This paper reports2 patients in whom liver resection was performed because of intrahepatic ductal stones, bile duct stricturesand repeated episodes of cholangitis. Liver resection was uncomplicated and long-term results were satisfactory.Our results support the view that liver resection is indicated in rare instances of intrahepatic bile ductstones associated with bile duct strictures."} +{"text": "The mechanism by which phagocytosed mast cell granules (MCGs) inhibit macrophage superoxide production has not been defined. In this study, rat peritoneal macrophages were co-incubated with either isolated intact MCGs or MCG-sonicate, and their respiratory burst capacity and morphology were studied. Co-incubation of macrophages with either intact MCGs or MCG-sonicate resulted in a dose-dependent inhibition of superoxide- mediated cytochrome c reduction. This inhibitory effect was evident within 5 min of incubation and with MCG-sonicate was completely reversed when macrophages were washed prior to activation with PMA. In the case of intact MCGs, the inhibitory effect was only partially reversed by washing after a prolonged co-incubation time. Electron microscopic analyses revealed that MCGs were rapidly phagocytosed by macrophages and were subsequently disintegrated within the phagolysosomes. Assay of MCGs for superoxide dismutase (SOD) revealed the presence of significant activity of this enzyme. A comparison of normal macrophages and those containing phagocytosed MCGs did not reveal a significant difference in total SOD activity. It is speculated that, although there was no significant increase in total SOD activity in macrophages containing phagocytosed MCGs, the phagocytosed MCGs might cause a transient increase in SOD activity within the phagolysosomes. This transient rise in SOD results in scavenging of the newly generated superoxide. Alternatively, MCG inhibition of NADPH oxidase would explain the reported observations."} +{"text": "A 26-year-old woman born with Tetralogy of Fallot initially underwent a left Blalock-Taussig shunt followed by a complete repair with a transannular patch at 2 years of age. She complained of non-sustained short episodes of palpitations. Her Holter monitor showed episodes of six beat run of non-sustained ventricular tachycardia. She was scheduled to undergo surgical pulmonary valve replacement. In view of her symptoms and Holter results she underwent an electrophysiology study to map any substrate of ventricular tachycardia for intra-operative ablation. Her baseline electrocardiogram demonstrated complete right bundle branch block pattern (RBBB) with QRS duration of 174 msec secondary to surgical interruption of the right bundle branch. During the electrophysiology study she was noted to have intermittent narrow QRS complexes .The QRS On initial assessment of the intracardiac tracings as well as the 12 lead electrocardiogram, there is evidence of baseline RBBB with intermittent appearance of normally conducted sinus activations with normal AH and slightly shortened HV. However on further analysis there seems to be a premature ventricular complex from the right ventricular apex that occurs immediately after the His deflection causing the apparent narrowing of the QRS complexes.Intermittent transition from wide to narrow QRS complex has been described with multiple mechanisms. These include change in heart rate, 'peel-back' refractoriness, rate dependent progressive shortening of bundle branch refractoriness, gap phenomena, supernormality, loss of pre-excitation, premature ventricular complex (PVC) ipsilateral to the bundle branch block and equal conduction delay in both the bundle branches . PresencThis physiological mechanism may have potential clinical applications for optimizing the timing of pacing intervals to obtain narrow QRS complexes as well to obtain interventricular synchrony."} +{"text": "Experiments conducted in vitro are described which indicate that a family of specifically substituted phosphoramides may share the carcinogenic properties displayed by the structurally novel carcinogen, hexamethylphosphoramide (HMPA). Most of the analogues tested only gave a positive response in vitro when using a substantially modified liver homogenate activation system (S-9 mix). The analogy drawn in our earlier paper between this new class of potential carcinogens and the nitrosamine carcinogens, has been strengthened. The following compounds gave a positive response in the cell transformation assay of Styles: hexamethylphosphoramide (HMPA), hexamethylphosphorous triamide, hexamethylphosphorothioic triamide, tripiperidinophosphine oxide, phosphorothioic trimorpholide and diethoxymorpholinophosphine oxide (DEMPA)."} +{"text": "Luminol-enhanced chemiluminescence was measured in fresh whole human blood, or human neutrophils isolated from heparinized blood, human alveolar macrophages and rat alveolar macrophages stimulated with bacterial endotoxin (LPS). Tetraacetate esters of rooperol, a dicatechol showing anticytokine activity, added to cells simultaneously with LPS inhibited the respiratory burst. The effective concentrations of rooperol were in the range of 1-10 \u03bcM depending on cell type and corresponded well with inhibition of nitric oxide production by rat alveolar macrophages. Thus rooperol may reduce some effects of excessive phagocytic activity and inflammatory reaction but by quenching free radicals production may also diminish the resistance to bacterial infections."} +{"text": "Endolaryngeal microscopic laryngosurgery (microlaryngosurgery) using a direct laryngoscopeis the preferred surgical method for treating laryngeal lesions under general anesthesia.However, this method does not provide a wide-angle view of the larynx and does not allowdetailed observations of the ventricle and subglottis of the laryngeal cavity, resulting in blindareas. Video-assisted endoscopic laryngosurgery using a direct laryngoscope and a longtransurethral rigid endoscope was therefore utilized to allow clear observations and completeresection of laryngeal lesions in these blind areas. This endoscopic surgical technique isintroduced, and clinical cases are presented."} +{"text": "Begomovirus (family Geminiviridae), with potential recombination hot- and cold-spots also having been identified. Nevertheless, because very little is understood about either the biochemical predispositions of different genomic regions to recombine or what makes some recombinants more viable than others, the sources of the evolutionary and biochemical forces shaping distinctive recombination patterns observed in nature remain obscure. Here we present a detailed analysis of unique recombination events detectable in the DNA-A and DNA-A-like genome components of bipartite and monopartite begomoviruses. We demonstrate both that recombination breakpoint hot- and cold-spots are conserved between the two groups of viruses, and that patterns of sequence exchange amongst the genomes are obviously non-random. Using a computational technique designed to predict structural perturbations in chimaeric proteins, we demonstrate that observed recombination events tend to be less disruptive than sets of simulated ones. Purifying selection acting against natural recombinants expressing improperly folded chimaeric proteins is therefore a major determinant of natural recombination patterns in begomoviruses.With the development of reliable recombination detection tools and an increasing number of available genome sequences, many studies have reported evidence of recombination in a wide range of virus genera. Recombination is apparently a major mechanism in virus evolution, allowing viruses to evolve more quickly by providing immediate direct access to many more areas of a sequence space than are accessible by mutation alone. Recombination has been widely described amongst the insect-transmitted plant viruses in the genus The exchange of genetic material between different virus species, called inter-species recombination, has the potential to generate, within a single genome replication cycle, an almost unimaginable number of genetically distinct virus strains, including many that might cause deadly new human, animal, or plant diseases. Many fear that inter-species recombination could provide viruses with quick access to evolutionary innovations such as broader host ranges, altered tissue tropisms, or increased severities. However, mounting evidence suggests that recombination is not an unconstrained process and that most inter-species recombinants that occur in nature are probably defective. It is suspected that networks of coevolved interactions between different parts of virus genomes and their encoded proteins must be kept intact for newly formed inter-species recombinants to have any chance of out-competing their parents. One category of coevolved interaction is that between contacting amino acids within the 3-D structures of folded proteins. Here we examine the distributions of recombination events across the genomes of a group of rampantly recombining plant viruses and find very good evidence that this class of interaction tends to be preserved amongst recombinant sequences sampled from nature. This indicates that selection against misfolded proteins strongly influences the survival of natural recombinants. Besides its vital cellular role in maintaining and repairing broken DNA molecules ,2, recomIn virology, two recombinational processes can be distinguished: genome reassortment and true recombination. Genome reassortment, also called pseudo-recombination, involves the exchange of intact genome components between viruses with multipartite genomes to yield viruses whose genomes are comprised of new combinations of components. True recombination, on the other hand, involves the exchange of genetic material between individual genomic molecules. The rearrangement of genetic information mediated by both true recombination and pseudo-recombination must yield fully functional and reasonably fit genomes for these processes to be easily detectable in nature. However, analysis of the functionality of recombinant genes ,9 and thWhile full accounts of experimentally verified intra-genome interactions are currently unavailable for any virus species, potential amino acid interactions within folded proteins can be inferred with reasonable accuracy given high resolution protein structural data. In the past five years, protein engineers have made substantial progress in the development of computational methods capable of accurately inferring degrees of recombination-induced fold disruption in experimentally generated chimaeras of proteins with known structures ,14,15. Arep) gene encoding a protein for which a high resolution crystal structure is available. In this paper we describe an expanded analysis of recombination amongst begomoviruses. We identify sets of unambiguously unique recombination events detectable in publicly available monopartite begomovirus DNA-A-like sequences and bipartite begomovirus DNA-A sequences. We then determine the distribution of recombination breakpoints across the analysed sequences and confirm the recombination hot- and cold-spots identified previously. We use a method called SCHEMA (AY795983), ToLCYTV-[Dem] (AJ865341), and TYLCSV (X61153). The Protein Data Bank (http://www.pdb.org/) ID number for TYLCSV N-terminal region structure is 1L2M.The National Center for Biotechnology Information ("} +{"text": "The principles and design of a Hadamard transform UV absorbance detector for liquid chromatography are outlined, and some spectra of aromatic compounds passing through its flow cell are presented. This approach could be valuable in providing alow-cost multi-wavelength detection method for liquid chromatography."} +{"text": "The occurrence of biliary stricutures in allografts following liver transplantation correlateswith the duration of preservation time. The correlation between preservation timeand biliary strictures suggests that anoxic or reperfusion injury of the bile duct epitheliumcauses stricture formation. However, the relative susceptibility of bile duct cells to anoxicor reoxygenation injury is unknown. Our aims were to determine the vulnerability of ratliver bile duct cells to anoxic and reoxygenation injury and to compare the results withhepatocytes. During anoxia, bile duct epithelial cells were significantly more resistant tocell killing than hepatocytes. Rates of cellular proteolysis were also 2.5-fold lower in bileduct cells than in hepatocytes during anoxia. In contrast to anoxia, reoxygenation ofanoxic cells increased cell killing of bile duct cells but improved viability of hepatocytes.The rate of toxic oxygen species formation by bile duct cells was 5-fold greater than inhepatocytes during reoxygenation. In addition, basal levels of glutathione are lower in bileduct cells than in hepatocytes. These data suggests that bile duct cells are more susceptibleto reoxygenation injury than to anoxia. These studies support the hypothesis thatreoxygenation injury during liver preservation leads to bile duct injury during livertransplantation."} +{"text": "Long term complications of laparoscopic cholecystectomy are uncommon. However, as experience with this procedure accumulates, sporadic reports of non-biliary complication have been published. We report a case of abdominal wall sinus formation secondary to gallbladder perforation and stone spillage occurring during laparoscopic cholecystectomy."} +{"text": "Ichthyosis uteri is a rare condition in which the entire surface of the endometrium is replaced by stratified squamous epithelium. Though the condition often is considered as benign, anaplastic and dysplastic changes have been reported. We describe herein a rare case of low-grade squamous cell carcinoma of endometrium associated with extensive ichthyosis uteri with dysplasia. The cervix showed moderate to severe dysplastic changes while the right fallopian tube showed extensive squamous metaplasia with dysplastic changes. We conclude that squamous cell carcinoma could develop into pre-existing ichthyosis uteri. A 65-year-old multi-gravida presented with complaints of abdominal pain and postmenopausal bleeding per vagina for seven months. Her past medical history was insignificant with no history of tuberculosis, inflammatory conditions of the uterus or iatrogenically introduced substances in uterus. She had attained menopause about 15 years back.Gynecological examination revealed atrophic ectocervix flushed with vagina. The vagina appeared normal. Uterus was bulky of around 12 weeks and adnexae were unremarkable. Colposcopy showed schiller's unstained areas on anterior lip of cervix. Ultrasound abdomen showed endometrial thickness of 2.6 cms. and fluid in the endometrial cavity. Ectocervical biopsy showed strips of moderate to severe dysplastic stratified squamous epithelium. Endometrial curetting revealed strips of stratified squamous epithelium showing moderate dysplastic changes. No normal endometrium was seen. The pyometra was drained, following which the patient underwent type-II radical hysterectomy. The procedure was well tolerated and the postoperative period was uneventful.The hysterectomy specimen revealed thickened and widened endometrial cavity with gray white nodule in the sub-adjacent myometrium. The cervix showed no obvious growth. The cut-section of the right fallopian tube showed thickened mucosa. Both the ovaries did not show any gross abnormality.The sections revealed entire endometrium replaced by stratified squamous epithelium showing areas of heavy keratinization, koilocytic changes, nuclear hyperchromasia and moderate increase in nuclear-cytoplasmic ratio indicating low grade dysplastic changes in underlying ichthyosis uteri Fig . ExtensiZeller coined the term \"ichthyosis uteri\" in the year 1885 to describe a condition of extensive squamous metaplasia of the surface endometrium following iatrogenically introduced caustic substances such as formalin or iodine [Ichthyosis is considered as benign condition. However, anaplastic and dysplastic changes have been reported by some authors -3. TheseBesides the dysplastic or anaplastic changes, a case of malignant degeneration has also been reported in ichthyosis uteri . This caIn summary, we describe a case of low-grade squamous cell carcinoma of endometrium developing in pre-existing extensive ichthyosis uteri with dysplasia. Though considered as benign condition, based on the present case report and that of Heckeroth et al , the posThe author(s) declare that they have no competing interests.KM, UM, VS drafted the manuscript. TR revised the draft critically for intellectual content. All authors read and approved the final manuscript."} +{"text": "This was performed under fresh (resting) conditions and after incubation for 6 h without (unstimulated) and with (stimulated) Escherichia coli endotoxin. The malignant groups showed higher mTF levels than each of the three controls for resting unstimulated and stimulated cells . Similarly, the benign inflammatory groups had higher mTF levels than controls for resting , unstimulated and stimulated cells . There was no significant difference between malignant and benign inflammatory groups in each organ. mTF levels showed an increase corresponding to that of histological tumour progression and were higher in non-surviving patients. In conclusion, mTF levels are raised in malignant and inflammatory disease compared to controls and patients with non-inflammatory conditions. Stimulated cells give better discrimination between the groups and may be of value in identifying high risk individuals. mTF levels showed an association with tumour grade or stage and the patients' survival time. \u00a9 1999 Cancer Research CampaignMonocytes express tissue factor (mTF) in several conditions including cancer where levels may be valuable in assessing tumour presence and progression. Using a two-stage kinetic chromogenic assay (KCA), mTF levels were measured in controls [normal subjects ("} +{"text": "Brassica genome structure and systematically relate it to the Arabidopsismodel. Hitherto, our view of the co-linearities between these closely related genomeshad been largely inferred from comparative RFLP data, necessitating substantialinterpolation and expert interpretation. Sequencing of the Brassica rapa genomeby the Multinational Brassica Genome Project will, however, enable an entirelycomputational approach to this problem. Meanwhile we have been developingdatabases and bioinformatics tools to support our work in Brassica comparativegenomics, including a recently completed draft physical map of B. rapa integratedwith anchor probes derived from the Arabidopsis genome sequence. We are alsoexploring new ways to display the emerging Brassica\u2013Arabidopsis sequence homologydata. We have mapped all publicly available Brassica sequences in silico to theArabidopsis TIGR v5 genome sequence and published this in the ATIDB databasethat uses Generic Genome Browser (GBrowse). This in silico approach potentiallyidentifies all paralogous sequences and so we colour-code the significance of themappings and offer an integrated, real-time multiple alignment tool to partition theminto paralogous groups. The MySQL database driving GBrowse can also be directlyinterrogated, using the powerful API offered by the Perl Bio\u2237DB\u2237GFF methods,facilitating a wide range of data-mining possibilities.Recent advances, such as the availability of extensive genome survey sequence (GSS)data and draft physical maps, are radically transforming the means by which wecan dissect"} +{"text": "A case report is presented of intra-mural gallbladder carcinoma discovered incidentally after laparoscopic cholecystectomy who subsequently developed abdominal wall recurrence at the epigastric exit port, and axillary lymph node metastases. Possible preventative steps for tumour dissemination and a management plan if incidental carcinoma is diagnosed is discussed. The use of a non-porous retrieval bag, early recognition of the carcinoma and excision of the exit wound are advocated."} +{"text": "Novel antiangiogenic agents currently being developed may ultimately be more effective against solid tumours and less toxic than cytotoxic chemotherapy. As a result of the early clinical trials of angiogenesis inhibitors, investigators are beginning to appreciate the complexity of targeting angiogenesis and the realisation that developing clinically useful antiangiogenic therapy will be more challenging than originally thought. It is now apparent that new methods and surrogate markers to assess these agents' biological activity are crucial for their successful development. This review summarises the currently available clinical data on the development of surrogate markers of angiogenesis inhibitors. Many anPreclinical studies suggested that angiogenesis inhibitors are cytostatic (growth-delaying) rather than cytotoxic. Traditionally, the maximum tolerated dose of a cytotoxic agent (determined by its dose-limiting toxicity) provided an estimation of the active dose range for subsequent clinical studies that are recruited from the bone marrow during tumour neovascularisation after initiation of treatment might provide an early indication of antiangiogenic activity before clinically demonstrable reductions in tumour size. Elevated levels of angiogenic growth factors, proteases, and endothelial adhesion molecules have been detected in sera of patients with malignant disease and the basement membrane during angiogenesis include the family of matrix metalloproteinases (MMPs) . Proteolvs those with stable disease of action of the angiogenesis inhibitor or the disease under study. In a Phase I study of tetrathiomolybdate can provide early proof of whether the biologic agent has successfully reached its hypothesised target. Some of the most compelling studies involved quantitative analysis by laser scanning cytometry (LSC) . In contrast, preclinical studies suggested that these small molecules had great potential, as they induced significant levels of apoptosis in endothelial cells, consequently inhibiting tumour growth . In addition, LSC-mediated analysis of additional surrogate markers hypothesised to be effected by endostatin including nuclear hypoxia-inducible factor-1\u03b1 and endothelial cell Bcl-2 levels peaked at similar doses of endostatin but failed to reach statistical significance. Importantly, two patients treated at intermediate doses of endostatin had minor antitumour responses and tumour metabolism [18F](FDG-fluorodeoxyglucose) 28 and 56 days after endostatin therapy . Importantly, the 95% confidence interval identified for blood flow overlapped the OBD (250\u2009mgm2d) determined from the tumour biopsy studies. Thus, integration of surrogate marker data along with imaging studies was crucial for assessing the OBD of recombinant human endostatin.Routine radiographic imaging techniques are useful for conventional measurement of disease and evaluating the effect of a biologic agent on tumour size after initiation of therapy may provide an assessment of optimal antivascular activity. Indeed, LSC-mediated analysis of apoptosis in tumour cells 48\u2009h after initiation of treatment has proven useful for predicting clinical response to cytotoxic therapies in breast cancer ("} +{"text": "Epidemiologic evidence has recently identified an association between an endemic outbreak of pleural and peritoneal mesothelioma in the Urgup region of Turkey and exposure to zeolite fibres. This malignancy is usually associated with exposure to asbestos dusts whose mineralogical characteristics differ from those of zeolites. The present study further defines the in vitro biologic activity of erionite, a common zeolite fibre found in the Urgup region of Turkey. Both erionite and crocidolite asbestos fibres were clastogenic in synchronous Chinese hamster ovary (CHO) fibroblasts. Both fibres also altered CHO ploidy. Erionite, unlike crocidolite or Min-U-Sil quartz, caused a slight increase in sister chromatid exchanges in synchronous CHO cells. Neither erionite nor crocidolite was mutagenic in a human lymphoblastoid cell line. Erionite fibres thus produced in vitro cytogenic changes similar to those caused by asbestiform mineral dusts and, like asbestos fibres, did not induce mutations in human lymphoblastoid cells."} +{"text": "We have addressed the question whether the epithelial stroma in the thymus is derivedfrom a common stem cell or whether cortical and medullary epithelial cells are derived fromdifferent embryonic stem cells emerging, for example, from endoderm and ectoderm. By theuse of rapidly expanding cultures of thymic epithelial cells (TEC) from 14 to 16 day-oldmurine fetuses and by specific antibodies against cortical and medullary epithelium,respectively, we were able to demonstrate a small subpopulation of double-labeled TEC inthe cultures. These cells were not present in TEC cultures initiated from thymuses ofneonatal mice. Double-labeled TEC were also found in tissue sections from fetal thymuses.These findings may indicate that TEC populations of the cortex and the medulla are derivedfrom a common stem cell, with potential for differentiation toward both cortical andmedullary TEC."} +{"text": "The heterogeneity evident among home care clients highlights the need for greater understanding of the clinical and social determinants of multi-dimensional health-related quality of life (HRQL) indices and of potential sex-differences in these determinants. We examined the relative contribution of social and clinical factors to HRQL among older home care clients and explored whether any of the observed associations varied by sex.The Canadian-US sample included 514 clients. Self-reported HRQL was measured during in-home interviews (2002-04) using the Health Utilities Index Mark 2 (HUI2). Data on clients' sociodemographic, health and clinical characteristics were obtained with the Minimum Data Set for Home Care. The relative associations between clients' characteristics and HUI2 scores were examined using multivariable linear regression models.Women had a significantly lower mean HUI2 score than men . Clients with distressed caregivers and poor self-rated health exhibited significantly lower HRQL scores after adjustment for a comprehensive list of clinical conditions. Several other factors remained statistically significant or clinically important correlates of lower HUI2 scores in adjusted analyses. These associations generally did not vary significantly by sex.For females and males, HRQL scores were negatively associated with conditions predictive or indicative of disability and with markers of psychosocial stress. Despite sex differences in the prevalence of social and clinical factors likely to affect HRQL, few varied significantly by sex in their relative impact on HUI2 scores. Further exploration of differences in the relative importance of clinical and psychosocial well-being to HRQL among female and male clients may help guide the development of sex-specific strategies for risk screening and care management. Health-related quality of life (HRQL) represents an important construct in understanding the health status and outcomes of older home care clients and ultiarthritis, heart failure, stroke, chronic obstructive pulmonary disease (COPD), urinary incontinence and mental health disorders. Despite some suggestion of sex differences in the strength of the associations between selected chronic diseases and HRQL indices ), cognitive and emotional status from MDS-HC items, we chose not to present the adjusted models including these scales because of interpretation difficulties due to collinearity between these measures (and other correlates of interest) and the single attributes comprising the HUI2 [As illustrated by the multivariable linear regression results, the strongest associations with overall HUI2 scores were observed for high caregiver stress and poor self-rated health. Several other factors remained statistically significant or clinically important correlates of lower HUI2 scores in the adjusted analyses displayed clinically important lower HUI2 scores. Some caution is warranted in the interpretation of the sex-differences observed for pressure ulcers and urinary tract infections given the relative low occurrence of these conditions and missing data (for pressure ulcers). A clinically important difference in HUI2 scores was observed for male clients reporting feelings of loneliness. None of the two-way interaction terms with sex were found to be statistically significant at p < 0.05 in the full model.and social factors to multi-dimensional HRQL indices such as the HUI2. Even less consideration has been paid to potential sex-differences in the relative importance of selected associations. In addition to highlighting the relative importance of the above disability-related conditions we found statistically significant and clinically important decrements in clients\u2019 HRQL associated with poor selfrated health, urinary infections and caregiver distress . Clients\u2019 HUI2 scores varied little with age, marital status, or the presence of several common disease diagnoses. HUI2 scores were clinically reduced for those with self-reported loneliness, congestive heart failure and pressure ulcers. Generally, the observed associations were not significantly modified by sex; however, the magnitude of score differences associated with selected factors did vary between females and males. Older home care clients often show considerable variability in physical, cognitive and social indices of vulnerability. The relative frailty of our client sample is reflected by their significantly lower overall mean HUI2 scores compared with published age-specific HUI2 norms . The lowThe relatively weak associations between individual disease diagnoses and clients' HRQL have also been reported by others ,7,37 andIn interpreting the relatively strong impact of poor self-rated health and caregiver distress on the HRQL of female and male clients it is important to acknowledge that these factors may serve as proxy measures for poorer clinical and functional status. Yet, both remained significantly associated with lower HUI2 scores after adjusting for clients' clinical and functional status including additional MDS-HC measures of ADL and cognitive impairment. Consequently, a broader interpretation might suggest that both factors provide unique information about clients' psychosocial well-being relevant to their overall HRQL ,39. AddiWidowhood and reported loneliness, although significantly more common among women, were not significantly associated with lower HRQL. Self-reported loneliness did, however, show a clinically important association with lower HUI2 scores among male clients. Others have reported weak to no associations between both marital status and living arrangements and HRQL in older populations ,21,22. AOur cross-sectional study precludes any clear discussion of the causal nature of selected observed associations . The absence of longitudinal data also limits our ability to detect and comment on relevant changes in clients' HRQL precipitated by expected fluctuations in their clinical and health conditions . ConsistWith our relatively select and small sample, some caution is warranted in generalizing our findings to other older populations and care settings including those in rural areas, in long-term care institutions and with moderate to severe cognitive impairment. Our relatively small number of male clients may also explain the relative absence of significant sex differences. As with other commonly used HRQL measures the HUI2 is particularly sensitive to physical impairment . Also, iAs expected, we observed important decrements in clients' HRQL for common health conditions predictive or indicative of disability, including arthritis, mental health disorders and incontinence. For both females and males, HUI2 scores varied little with the presence of several other prevalent clinical diagnoses. Most of the observed variation in clients' HRQL scores was accounted for by two factors, poor self-rated health and caregiver distress. Although the direction of these associations are unclear, both factors may serve as important markers of psychosocial frailty and increased risk for poor client outcomes including future declines in HRQL. Despite sex differences in the prevalence of social and clinical factors likely to affect HRQL, most did not vary significantly by sex in their relative impact on HUI2 scores. However, our findings highlight several areas worthy of further investigation with larger samples, including possible sex differences in the relative importance of arthritis, incontinence, mental health and self-reported loneliness. Further demonstration of a differential impact of these factors among female and male clients may assist in the identification of appropriate sex-specific strategies for risk screening and care management of vulnerable seniors in community care settings.DHF has a proprietary interest in Health Utilities Incorporated, Dundas, Ontario, Canada. HUInc. distributes copyrighted Health Utilities Index (HUI) materials and provides methodological advice on the use of HUI. All other authors declare that they have no competing interests.CJM developed the initial study, supervised data collection, directed data analyses and wrote and edited the manuscript. JK conducted the primary analyses. JW assisted with study design and implementation, data preparation and analyses. JZ assisted with data preparation and analyses. DBH assisted with study development and implementation. DHF assisted with study design and implementation. WW co-led the development of the initial study, supervised data collection and assisted with data analyses. All authors made meaningful contributions during the editing of the manuscript and approved the final version."} +{"text": "Ralstonia metallidurans (Rme) is better able to withstandhigh concentrations of heavy metals than any other well-studied organism. This factrenders it a potential agent of bioremediation as well as an ideal model organism forunderstanding metal resistance phenotypes. We have analysed the genome of Rmefor genes encoding homologues of established and putative transport proteins; 13%of all genes in Rme encode such homologues. Nearly one-third of the transportersidentified (32%) appear to function in inorganic ion transport with three-quartersof these acting on cations. Transporters specific for amino acids outnumber sugartransporters nearly 3 : 1, and this fact plus the large number of uptake systems fororganic acids indicates the heterotrophic preferences of these bacteria. Putative drugefflux pumps comprise 10% of the encoded transporters, but numerous efflux pumpsfor heavy metals, metabolites and macromolecules were also identified. The resultspresented should facilitate genetic manipulation and mechanistic studies of transportin this remarkable bacterium."} +{"text": "Occurrence of bioprosthetic valve thrombosis less than a year after replacement is very uncommon. Here, we describe a case of a 57 year old male, who presented 10 months after receiving a bioprosthetic mitral valve replacement with a two week history of dyspnea on exertion, worsening orthopnea and decreased exercise tolerance. Echocardiography revealed severe mitral regurgitation (MR), thrombosis of the posterior mitral leaflet, left atrial (LA) mural thrombus and a depressed left ventricular ejection fraction of twenty-five percent. Given severe clot burden and decompensated heart failure (New York Heart Association - NYHA class III) repeat sternotomy was done to replace the bioprosthetic mitral valve and remove LA mural thrombus. MR was resolved postoperatively. This brief report further reviews promoting factors, established guidelines and management strategies of bioprosthetic valve thrombosis. Bioprosthetic mitral valves are advantageous over mechanical valves as their incidence of thrombosis, pannus formation and embolic events are significantly lower. This disparity in thromboembolic events as compared to mechanical valves avoids a need for chronic anticoagulation in many patients receiving bioprosthetic valve replacement . HoweverA 57 year old male with a past medical history of chronic atrial fibrillation, a depressed ejection fraction of 25%, and severe MR underwent mitral valve replacement with a bioprosthetic Mosaic valve and a complete left and right sided MAZE procedure. Post operative transthoracic echocardiogram (TTE) showed a competent mitral valve tissue prosthesis and the patient was discharged on warfarin. Anticoagulation was discontinued three months after valve replacement and the patient remained in sinus rhythm on electrocardiography.Ten months following mitral valve replacement, the patient presented with a two week history of progressive dyspnea on exertion, orthopnea and weight gain. TTE revealed severe mitral valve stenosis and mitral regurgitation, with a mean gradient of 8.5 mmhg (max. gradient -- 25.5 mmhg) across the mitral valve, and restricted motion of mitral leaflets. On transesophageal echocardiogram (TEE), a mitral mass was observed on the posterior leaflet along with mural thrombus in a dilated left atrium measuring 4.90 cm in diameter figure . EjectioIntraoperatively, mural clot was debrided from the free and posterior left atrial walls. The mitral bioprosthesis was incompetent with pannus growing on the posterior leaflet. This valve was excised and replaced with a 25 mm On-X mechanical valve that functioned without leakage after placement. Postoperatively, the patient had improved exercise tolerance and was discharged on indefinite warfarin therapy.Clinically significant bioprosthetic valve thrombosis is considered uncommon, however, its incidence on routine echocardiographic surveillance is reported as high as six percent . Specifi2 score is greater or equal to 2 [Although freedom from long term anticoagulation is a feature of bioprosthetic valve replacement, this case calls for a brief review of current anticoagulation guidelines following bioprosthetic valve replacement and a radioablative MAZE procedure. The 2008 American Heart Association (AHA) and American College of Cardiology (ACC) guidelines state that high risk patients with any of the following risk factors including atrial fibrillation, LV dysfunction with EF < 30%, recurrent thromboembolic events or a hypercoagulable condition meet a class I indication for indefinite anticoagulation . To reduual to 2 . These gThis case also calls for frequent post operative echocardiographic monitoring in non- anticoagulated patients with risk factors promoting valve thrombosis. The 2007 European Society of Cardiology (ESC) guidelines recommenAccording to the 2007 ESC guidelines , once vaManagement of non-obstructive prosthetic valve thrombosis depends on the occurrence of thromboembolism (TE) and thrombus size . InitialIn the present case, obstructive valve thrombosis, large clot burden and critical illness made surgical replacement a reasonable and successful treatment option.Bioprosthetic mitral valve thrombosis is an under recognized complication in high risk patients that leads to rapid valve incompetence. Post-operatively, patients must be stratified in high or low risk categories, and anticoagulation should be maintained indefinitely for high risk patients. If anticoagulation is not maintained for individualized reasons then a semi-annual TTE within the first year and annually thereafter may detect subclinical bioprosthetic valve thrombosis in asymptomatic patients.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-n-Chief of this journal.OML discloses that he has served as a consultant and received research grants from Medtronic Corporation and On-X Life Technologies. The rest of the authors declare that they do not have any competing interests.OS: Resident physician, provided pre-operative care and primary author.BRW: Cardiologist, provided pre-operative care and advice during the manuscript writing process.MK: Assisted in writing and preparing manuscript.OL: Cardiothoracic Surgeon, performed the bioprosthetic valve repair and provided advice during the manuscript writing process.All authors have read and approve the final manuscript."} +{"text": "Hemangiomas and venous lymphatic malformations are the two most common orbital vascular lesions seen in pediatric patients. Orbital venous-lymphatic malformations (OVLMs) (previously referred to as \u2032lymphangiomas\u2032) are uncommon, benign cystic type I vascular malformations.OVLMs may remain clinically unapparent or might manifest in childhood with slowly progressive proptosis, periorbital swelling and displacement of globe. These malformations usually enlarge slowly. Spontaneous intraorbital hemorrhage or venous thrombosis may cause sudden acute proptosis, severe pain, compressive optic neuropathy or loss of vision, when intervention is indicated . Orbital2A 20-year-old girl presented with left-sided progressive painless orbital proptosis since birth . On examSystemic corticosteroids have been used as an adjuvant treatment to surgery, although their role is controversial. The diffuse form of orbital lymphangioma is well known for its difficult surgical treatment and frequent recurrences. Small, repeated excisions may be required. Surgical debulking with carbon dioxide laser through a lateral orbitotomy combined with three-wall orbital decompression is a preferred surgical technique and may be a useful alternative treatment in patients with severe proptosis.Ultrasonography of OVLMs show high amplitude echoes with a very wide separation due to large encapsulated fluid lakes. On CT scan, these are poorly defined slightly enhancing lesions that cross anatomic boundaries, such as the conal fascia and orbital septum. Areas of hemorrhage cause cyst-like masses with rim enhancement. In the last decade, role of MRI has been emphasized in the literature as it has the capability to precisely delineate and characterize these lesions. It is reWe conclude that imaging plays a crucial role in diagnosis of OVLMs and intracranial associations. However, atypical characteristics may be seen in a few pediatric patients and excision biopsy may be indicated to facilitate diagnosis."} +{"text": "Heterotransplantation of a human colonic neoplasm with classical morphologic characteristics of a carcinoid was sucessful in the cheek pouches of unconditioned, adult golden hamsters after a short sojourn in cell-impermeable chambers in rats. Although no mucin-secreting cells were detected in the donor carcinoid, the cheek pouch transplants exclusively exhibited mucinsecreting tumour cells of signet-ring type consistent with adenocarcinoma. This transplantable tumour, designated GW-77, has retained this appearance as well as expansive growth characteristics in xenogeneic hosts for a period of 4 years.These findings represent strong biological evidence consonant with views, based upon morphological findings, advocating a histogenetic relationship between colonic carcinoid and adenocarcinoma. It is believed that colonic adenocarcinoma has a selective advantage over carcinoid for serial propagation in an alien environment, indicating the less differentiated nature of its cellular components. Since the donor carcinoid cells failed to exhibit argentaffin reactions, these conclusions may be limited only to the nonreactive forms of carcinoid."} +{"text": "Several pathogens of humans and domestic animals depend on hematophagous arthropods to transmit them from one vertebrate reservoir host to another and maintain them in an environment. These pathogens use antigenic variation to prolong their circulation in the blood and thus increase the likelihood of transmission. By convergent evolution, bacterial and protozoal vector-borne pathogens have acquired similar genetic mechanisms for successful antigenic variation. Borrelia spp. and Anaplasma marginale (among bacteria) and African trypanosomes, Plasmodium falciparum, and Babesia bovis (among parasites) are examples of pathogens using these mechanisms. Antigenic variation poses a challenge in the development of vaccines against vector-borne pathogens."} +{"text": "Effects of neonatal androgenization or neonatal ovariectomy in female rats on endocrine functions and mammary tumourigenesis are examined. Pituitary gonadotrophin contents (both LH and FSH) are significantly lower in neonatally androgenized rats (TT) and significantly increased in neonatally ovariectomized rats (NO) when compared with controls of the same age. Plasma and pituitary prolactin levels are higher in TT rats than in the control rats of the same age, but the difference is not significant. Mammary tumours developing in TT rats after DMBA treatment are predominantly fibroadenomata, and lactogenesis in TT rats occurs almost entirely in those receiving DMBA treatment. Neonatal ovariectomy in female rats protects against subsequent induction of mammary cnacer by DMBA. The relationship between neonatal modification of endocrine functions and mammary tumourigenesis is discussed."} +{"text": "Myopotential oversensing in implantable defibrillators causing inhibition of pacing and inappropriate therapies is well described. Current literature is dominated by reports of diaphragmatic muscle as the source of such far-field oversensing. Those reporting pectoral muscle sources were invariably due to unipolar sensing circuits, incorrect DF-1 connections or inappropriate programming. We report an interesting case of pectoral muscle myopotential oversensing causing inhibition of bradycardia pacing leading to presyncope and syncope. Oversensing of skeletal muscle myopotentials is well described -3 and isA 60 year old female with hypertrophic cardiomyopathy had originally presented with syncope and documented ventricular tachycardia. A dual chamber cardioverter-defibrillator (Guidant VENTAK 1861) was implanted in June 2003 and an integrated bipolar right ventricular defibrillator lead was used (Guidant SN 0158). Electrogram amplitudes, pacing and defibrillation thresholds at the time of implantation were normal.After the procedure, the patient was without symptoms for two years. Device interrogation during routine follow-up demonstrated low levels of noise on ventricular electrograms. There were no appropriate or inappropriate therapies although three therapies were diverted.In Feb 2006 the patient developed persistent atrial fibrillation. Pharmacological attempts to maintain sinus rhythm were unsuccessful, she declined a left atrial ablation procedure and in May 2007 the patient underwent atrio-ventricular (AV) node ablation for ventricular rate control and was rendered pacemaker dependant. One month after AV node ablation the patient attended the cardiac device clinic complaining of recurrent episodes of dizziness and syncope during certain physical activities such as showering or washing dishes. At this time pacing thresholds, electrogram amplitudes and impedances were normal. A chest X-ray showed no radiographic evidence of loss of lead integrity.Device interrogation revealed 16 diverted therapies in the VF zone. One such episode is shown in At interrogation, these potentials were not reproducible with the usual provocative manoeuvres such as rapid, deep respiration and generator agitation, but were reproducible with isometric upper limb exercise and resulted in pacing inhibition and dizziness.Our immediate management was to reduce the sensitivity to the minimum programmable setting. This was deemed safe as a short term measure as VF detection at minimal sensitivity was confirmed at defibrillation threshold testing at implantation. We advised the patient to avoid driving and provocative manoeuvres. The patient was admitted electively for re-operation. At procedure the existing lead connections to the generator were found to be secure and appropriate. Invasive lead tests were satisfactory. We elected to leave the integrated lead in situ and implant a new dedicated bipolar pacing lead (Medtronic 5076) for ventricular sensing and pacing. The new pace/sense lead was connected to the ventricular IS-1 socket on the existing device and the old integrated defibrillator lead remained connected via the DF-1 sockets. The defibrillator lead IS-1 terminal was capped and secured within the prepectoral pocket. Subsequently, the patient's symptoms resolved and no further myopotentials were recordable.The case highlights a problem specific to integrated bipolar lead technology, that is, far-field myopotential oversensing due to distance between the lead tip and distal defibrillator coil.This patient only became symptomatic when rendered pacing dependant after AV node ablation when upper body muscular movement caused pacing inhibition through myopotential oversensing. Fortunately, this consistently caused dizziness or syncope which stopped physical activity thus terminating myopotential oversensing. As a result, therapies were always diverted and pacing resumed. It is therefore curious that no inappropriate therapies were delivered prior to AV node ablation. This may simply be explained by a dynamic ventricular sensing threshold facility available in most defibrillators, in this case, automatic gain control see . FollowiAtrial and T-wave oversensing, which have also been reported with integrated bipolar leads are usually easily overcome with re-programming. True myopotential oversensing however, invariably requires re-operation. Our solution in this case was to introduce a separate dedicated bipolar pace/sense lead and retain the integrated lead for defibrillation. An alternative solution would have been to replace the lead with a dedicated bipolar defibrillator lead and either extract the integrated lead or leave it redundant .The alternative to re-operation is to reduce ventricular lead sensitivity to exclude unwanted potentials. This particular device had three sensitivity settings - \"nominal\", \"less\" and \"least\". Although implant testing is done at \"least\" sensitivity, VF re-induction at \"least\" sensitivity to confirm VF sensing would have been a reasonable approach (though not without risk) as changes in sensing may have occurred with lead maturation. In this case, we employed this strategy only as an interim, particularly as \"least\" sensitivity would not have guaranteed a resolution to myopotential oversensing, because it could not be confidently reproduced in the setting of the device clinic as myopotential interference may change with patient position and activity.With dedicated bipolar (quadripolar) defibrillator leads available, the use of integrated leads may be questioned. Quadripolar leads are, however, not without problems. Increased pacing thresholds and sensing latency causing ventricular pseudofusion and unnecessary ventricular pacing are not uncommon . More prProgress in lead technology has not paralleled the rapid advances in generator design and technology. Newer quadripolar constructions with active fixation are gaining merit but longevity data is still anticipated. Hence, to date lead choice remains at the discretion of the implanter rather than guided by evidence."} +{"text": "Leucocyte interactions with the cremaster muscle microcirculation in vivo were investigated in response to culture medium conditioned with different cell types in 25 adult male Swiss mice. Animals were divided into five groups. Three groups received ex vivo fluorescently labelled lymphokine activated killer (LAK) cells systemically and had either tumour (murine melanoma K1735)-conditioned medium (TCM), fibroblast (murine 3T3)-conditioned medium (FCM) or fresh culture medium administered topically to the cremaster muscle. In the two remaining groups, the host leucocytes were labelled fluorescently by systemic administration of acridine red, and either TCM or FCM was applied topically to the cremaster muscle. There was an immediate but transient increase in the frequency of rolling and adherent LAK cells, and a subsequent (90-120 min later) increase in rolling and adherent host leucocytes, demonstrating temporal differences in the response to topical administration of TCM. These increases in contact with the vascular endothelium occurred in all vessel types, venules, arterioles and capillaries, with the greatest response observed in the venules. The FCM and normal culture medium did not affect the distribution and localization of either LAK cells or host leucocytes. These data suggest that there are one or more soluble tumour-specific chemoattractants for leucocytes present in the conditioned medium. The mouse cremaster muscle microcirculation is therefore a useful model to investigate the mechanism of leucocyte-endothelium interactions in tumour biology."} +{"text": "The patient had exertional chest pain and dyspnea prompting referral for cardiac evaluation. These symptoms were reproduced during intravenous adenosine infusion, and simultaneous first-pass perfusion imaging showed a significant subendocardial defect; both symptoms and perfusion deficit were absent at rest. Epicardial coronaries were free of disease by invasive angiography; together, these findings support the notion of impaired myocardial perfusion reserve in FA.We present the first This report describes myocardial perfusion reserve abnormality in Freidreich's ataxia (FA), a heritable disorder whose major manifestations are neurological and myocardial disease. In more than 90% of cases, this autosomal recessive condition results from excess of DNA triplet repeats (GAA) in the first intron at the end of exon 1 leading to suppression of FRDA (frataxin) gene expression. Around 5% of patients have a point mutation in the frataxin gene; both forms result in a deficiency of the protein frataxin that is located in the inner mitochondrial membrane, neitherA 26 year-old nonsmoking Middle Eastern woman presented for evaluation of exertional chest pain and shortness of breath. The past medical history was notable for genotype-proven Friedreich's ataxia (FA) diagnosed at age 19 that had produced ambulatory limitation with frequent falls due to her ataxia. Genotyping showed 846GAA repeats consistent with FA. Family history revealed extensive affected members and carriers with a 12-channel phased array coil. Resting steady-state free precession cine imaging showed normal left ventricular (LV) size and systolic function, with LV end-systolic volume 21 cc/mBased on the reproduction of chest pain with adenosine stress and accompanying perfusion abnormality, she was referred for invasive coronary angiography. This showed angiographically normal epicardial coronary arteries Figure and normIn summary, we identified impaired microcirculatory reserve in FA using CMR that occurred in the absence of epicardial coronary artery disease. Friedreich's ataxia is a neurodegenerative condition frequently accompanied by cardiomyopathy due to a mutation in the gene frataxin, resulting in intra-mitochondrial accumulation of iron. The predilection for neuromuscular and myocardial involvement in FA reflects the high energy demands of both systems.et al. using positron emission tomography; their work suggested that compensation for impaired energetics in FA occurs by increasing myocardial oxygen consumption rather than myocardial blood flow, though this study was conducted under resting conditions only[Prior magnetic resonance-based evaluation of FA cardiomyopathy has focused on cardiac magnetic resonance spectroscopy or quantions only.The detection of subendocardial perfusion abnormality afforded by adenosine CMR is similar to that described in other conditions such as syndrome X and coarctation of the aorta,7, thougThe author(s) declare that they have no competing interests."} +{"text": "Whole-blood caeruloplasmin measured by electron spin resonance was studied in 41 patients with chronic lymphocytic leukaemia. The levels were above normal at all stages of the disease, rose with increasing clinical involvement, and were higher in progressive than inactive disease. Whole-blood iron transferrin levels were more variable, and were significantly raised only in patients with marrow failure."} +{"text": "Patients with advanced idiopathic pulmonary artery hypertension have often a chronic pericardial effusion. It is the result of increased transudation and impaired re-absorption due to elevated venous pressure. These patients have pre-existent symptoms and signs of chronic right heart failure. High degree of suspicion is required to detect of development of an atypical form of tamponade with isolated compression of left heart chambers as shown in present case report. Transthoracic echocardiography provides a rapid access to the correct diagnosis, a prompt relief of symptoms following the ultrasound guided pericardiocentesis and important diagnostic tool for regular follow up of patients thereafter as shown in our case report. Circumferential pericardial effusion typically results in biventricular tamponade and equalization of intracardiac and pericardial pressure during diastole. In classic subacute tamponade the rising of pericardial pressure causes a progressive collapse of right atrium and ventricle preventing venous return to the right atrium. Symptoms and signs referable to increased filling pressure and diminished cardiac output ensue. Patients presents with dyspnea, orthopnea, peripheral edema, fatigability, hepatic engorgement. The three principal features: jugular venous distention, soft or absent heart sounds and hypotension (Beck's triad), tachycardia and pulsus paradoxus are present. However, tamponade may involve the right or left heart. While isolated left ventricular tamponade can occur as a postoperative complication form localized posterior pericardial effusions or hematoma, circumferential pericardial effusions leading to left heart tamponade are rare .We present a clinical course and echocardiographic examination in a patient with idiopathic pulmonary artery hypertension (IPAH) and chronic pericardial effusion who developed a subacute isolated left heart tamponade.A 57-year-old patient with IPAH and a previously known chronic pericardial effusion presented in an outpatient clinic with symptoms of dyspnea on exertion, in the last days even at rest, ortopnea and leg edema. During the past few months he was in good physical condition. He was on therapy with sildenafil, amlodipine, acenocoumarol and had a combination inhaler containing fluticasone propionate and salmeterol xinafoate. The clinical examination showed distended jugular veins, leg edema and an accentuated second heart sound. A chest radiogram showed an enlarged heart shadow. The echocardiographic examination showed a dilated right atrium and ventricle Figure with redAfter the normalisation of the haemosthasis with fresh frozen plasma echocardiographicly guided pericardiocentesis using a parsternal approach was performed. Immediately after removal of 250 ml of yellow fluid the patient became normopnoic. There was still 1.5 cm large pericardial effusion behind the left ventricular posterior wall without left heart collapse were negative. Rheumatic markers , angiotensin-convertyng enzyme and tumor markers were all in normal range. The function of the thyroid gland was normal.Patients with cor pulmonale and circumferential pericardial effusion develop an atypical form of cadiac tamponade with isolated left heart compression. Pre-existing pulmonary arterial hypertension can modify the classic presentation. Symptoms and signs of right heart failure could already be present, so a high index of suspicion for tamponade is required in every worsening of right heart failure symptoms. When the pericardial pressure starts to increase in a patent with cor pulmonale, elevated pressure in right heart chambers prevent right atrial and ventricular compression, but while the pericardial pressure rises to the point to exceed left chambers pressure, this results first in diastolic collapse of left atrium and later on in left ventricle collapse due to a transient reversal of the transmural pressure ,3. SignsThe most probable mechanism of accumulation of pericardial fluid in patients with IPAH is transudation and impaired re-absorption of pericardial fluid due to elevated venous hydrostatic pressure in the setting of cor pulmonale.In the setting of pulmonary arterial hypertension large hemodynamically significant pericardial effusions might be treated surgically and/or conservative and it is known that prognosis of patients with this complication is poor ,5. HowevThe right ventricle-to-right atrial pressure gradient may be difficult to estimate in the setting of severe tricuspid regurgitation, when there is a large color flow regurgitant jet. In this case, the peak velocity may not reflect the true pressure gradient.In conclusion, patients with advanced IPAH have often a chronic pericardial effusion. It is the result of increased transudation and impaired re-absorption due to elevated venous pressure. These patients have pre-existent symptoms and signs of chronic right heart failure. High degree of suspicion is required to detect of development of an atypical form of tamponade with isolated compression of left heart chambers. Transthoracic echocardiography provides a rapid access to the correct diagnosis, a prompt relief of symptoms following the ultrasound guided pericardiocentesis and important diagnostic tool for regular follow up of patients thereafter.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.TM: carried out interpretation and drafted the manuscriptHM: carried out interpretation and drafted the manuscriptBS: treated the patient, carried out interpretation and drafted the manuscriptMP: treated the patient, made acquisition of data, carried out interpretation and drafted the manuscriptAll authors read and approved the final manuscript.Transthoracic echocardiography from apical four chamber view shows enlarged right ventricle (RV) and right atrium (RA). There is pericardial effusion (PE) compressing left ventricle (LV) and left atrium (LA).Click here for fileTransthoracic echocardiography from short-axis plane at the papillary muscle level shows enlarged right ventricle (RV) with paradoxical movement of intraventricular septum. Left ventricle is compressed by RV and pericardial effusion (PE).Click here for fileTransthoracic echocardiography from apical four chamber view shows enlarged right ventricle (RV) and tricuspid regurgitation (TR).Click here for fileTransthoracic echocardiography from apical four chamber view after pericardiocentesis. Right ventricle (RV), right atrium (RA), left ventricle (LV), left atrium (LA).Click here for file"} +{"text": "Dear Sir,Communicable and nutritional eye diseases are declining in Oman while age-related and chronic eye diseases are on the rise. All stak2At present, there are three private hospitals with surgical eye care facilities in Oman. In addition, there are twelve private eye clinics with ophthalmologists, nearly 30 qualified contact lens practitioners, and 150 optical shops.[The private sector could assist national eye care services and contribute in policy making efforts within VISION 2020 initiative of Oman, in the following key areas:Refractive surgery and contact lens practice.Corneal transplant and collagen cross-linkage for keratoconus.Photo therapy and intravitreal management modalities for retinal diseases such as age-related macular degeneration and advanced cases of diabetic retinopathy.Individualized case management of rare eye conditions where multisystem care is needed.Low vision care to the adult population.Eye screening procedures in private schools for amblyopia and refractive error as per the recommendations of the National policies.Offering eye screening for driving licensing, insurance, and preemployment medical checkups.Provision of eye care through insurance and payment system to citizen of Oman, thereby reducing the workload of MOH institutions.Training Omani mid-level eye care people through collaboration with institutions of international standards.Keeping the ophthalmic fraternity knowledgeable through periodic meetings, where internationally renowned guest speakers could be invited."} +{"text": "Habitat use may lead to variation in diversity among evolutionary lineages because habitats differ in the variety of ways they allow for species to make a living. Here, we show that structural habitats contribute to differential diversification of limb and body form in dragon lizards (Agamidae). Based on phylogenetic analysis and ancestral state reconstructions for 90 species, we find that multiple lineages have independently adopted each of four habitat use types: rock-dwelling, terrestriality, semi-arboreality and arboreality. Given these reconstructions, we fit models of evolution to species\u2019 morphological trait values and find that rock-dwelling and arboreality limit diversification relative to terrestriality and semi-arboreality. Models preferred by Akaike information criterion infer slower rates of size and shape evolution in lineages inferred to occupy rocks and trees, and model-averaged rate estimates are slowest for these habitat types. These results suggest that ground-dwelling facilitates ecomorphological differentiation and that use of trees or rocks impedes diversification. Anolis lizards , Diporiphora [size]; see In addition, our sampling of agamid species likely influenced the pattern of evolutionary rate variation we document. Our data set represents approximately one-quarter of recognized agamid species diversity, though this proportion is not uniform across the major clades. The under-sampling of species from the southwest Asian/African clade may be the most problematic with respect to our conclusions because at least two primarily terrestrial genera, Our results provide compelling evidence that habitat use shapes diversification of limb and body form in Agamidae. The pattern of variation in rates of morphological evolution suggests that terrestrial habitats promote ecological differentiation whereas diversification is slower in rocky and arboreal habitats; however, the precise mechanism by which these habitats contribute differently to diversification remains speculative. We recommend that future research investigate the extent to which functional constraints, habitat complexity or biotic interactions within habitats influence the pattern we document. For example, locomotor performance tests could be applied across a range of agamid forms to determine whether arboreal and rocky surfaces impose more stringent functional demands than terrestrial surfaces. Also, comparisons of the number of co-occurring agamid species within each habitat type could assess whether these habitats present different numbers and types of species interactions. Application of such studies to Agamidae or other animal taxa has the potential to provide further insights into how habitat contributes to differential diversification among evolutionary lineages."} +{"text": "Biliary tract abnormalities occur in about one of every three people, usually being minor and of noclinical significance.Major abnormalities, however, may present in an unusual manner and provide amajor hazard to the unsuspecting surgeon.A patient presenting with cholangitis without jaundice or abnormal liver function tests is reported.Endoscopic retrograde cholangiography failed to demonstrate any bile ducts in the right postero-lateralsegments of the liver, the \u201cnaked segment sign\u201d. A percutaneous transhepatic cholangiogram demonstrateda stricture obstructing the right posterior segmental hepatic duct with hepatolithiasis above thestricture. At operation an anomalous vessel was found at the site of the stricture.This case highlights the unusual way in which biliary tract anomalies may present and the importanceof adequate pre-operative investigation."} +{"text": "Biliary tact carcinoids are extremely rare: only ten cases have been reported up to now. TheAuthors describe a successfully treated carcinoid tumour ofthe proximal bile duct and review theliterature about these rare malignancies.Despite extensive preoperative work-up, including ultrasound, CT scan and ERCP, a definitediagnosis is hardly possible prior to histologic examination of the operative or necropsyspecimen.Due to the slow-growing nature and the non-aggressive behaviour of these malignancies,surgical resection followed by biliodigestive anastomosis should be the treatment of choice."} +{"text": "Clinicopathologic correlation offive cases ofcystadenomas of the liver are reported. All patientswere female and radical surgical procedure, total excision or resection was performed four times,and partial excision once. In all patients the postoperative course was uneventful and they are allalive and well. Examined by conventional histological and special immuno-histochemical stainsthe tumors fulfilled diagnostic criteria for these rare cystic growths. The cyst wall was composedof three, histologically distinct layers. From the viewpoint of histogenesis and differentialdiagnosis immunohistochemical properties were analysed. CEA and EMA were demonstratedin epithelial cells and Vimentin in stromal cells."} +{"text": "We read with great interest the article by Xynos et al. reporting 2 cases of leishmaniasis in patients treated with biologic drugs infections occur more frequently than clinically apparent VL cases. An estimated 10%\u201320% of persons with asymptomatic infections develop clinically overt VL role in detecting Leishmania infection in this vulnerable patient population. Screening for leishmaniasis has been hampered by the lack of a standard test. Currently available serologic methods have variable sensitivities, specificities, and cross-reactivities, depending on the species being tested and the region where tests are performed. Many experts believe that serologic tests may complement other existing diagnostic tools, raising cost-efficiency concerns, especially in financially deprived countries result indicates exposure to Variations in specificities and sensitivities limit the diagnostic potential of available diagnostic tools. The context of immunosuppression further contributes to the diagnostic complications and increases the need for additional research in leishmaniasis diagnostics."} +{"text": "Prion diseases are fatal neurodegenerative disorders caused by accumulation of abnormalprion protein . PrPres accumulation is also detected in lymphoidorgans after peripheral infection. Several studies suggest that follicular dendritic cells(FDC) could be the site of PrPres retention and amplification. in situ and in vitro. When tonsillar cryosections were treated with anti-PrPantibody, the label was found on some very delicate cell extensions inside the lymphoid follicles,especially in the germinal centres. These extensions react with DRC1 antibody, used frequentlyto label FDC. Other structures labelled with anti-PrP antibody were the keratinocytes.Here we show that human follicular dendritic cells can express normal cellular prion protein(PrPc) both To confirm the ability of FDC to synthesise PrPc, we isolated FDC by a non-enzymaticprocedure and cultured them. By cytochemistry and flow cytometry it was clearly shown thatFDC do produce PrPc."} +{"text": "Stroke caused by brain ischemia is the third leading cause of adult disability. Active prevention and early treatment of stroke targeting the causes and risk factors may decrease its incidence, mortality and subsequent disability. Pien Tze Huang (PZH), a Chinese medicine formula, was found to have anti-edema, anti-inflammatory and anti-thrombotic effects that can prevent brain damage. This study aims to investigate the potential mechanisms of the preventive effects of Pien Tze Huang on brain damage caused by chronic ischemia and hypertensive stroke in rats.The effects of Pien Tze Huang on brain protein expression in spontaneously hypertensive rat (SHR) and stroke prone SHR (SHRsp) were studied with 2-D gel electrophoresis and mass spectrometric analysis with a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF)/TOF tandem mass spectrometer and on brain cell death with enzyme link immunosorbent assay (ELISA) and immunostaining.2 in the electron transfer chain of mitochondria preventing reactive oxygen species (ROS) damage and possibly subsequent cell death (caspase 3 assay) as caused by chronic ischemia or hypertensive stroke to hippocampus and cerebellum.Pien Tze Huang decreased cell death in hippocampus and cerebellum caused by chronic ischemia and hypertensive stroke. Immunostaining of caspase-3 results indicated that Pien Tze Huang prevents brain cells from apoptosis caused by ischemia. Brain protein expression results suggested that Pien Tze Huang downregulated QCRPien Tze Huang showed preventive effects on limiting the damage or injury caused by chronic ischemia and hypertensive stroke in rats. The effect of Pien Tze Huang was possibly related to prevention of cell death from apoptosis or ROS/oxidative damage in mitochondria. Cerebral ischemia and stroke are the major causes of mortality and morbidity worldwide -4. In thHypertension is the most important risk factor for ischemic stroke ,2,11 whicirca 1555 AD) in China, contains musk, Calculus Bovis , Shedan and Panax notoginseng (Tianqi or Sanqi) and is used to treat liver diseases, cancer and inflammation Click here for fileDirected acyclic graph of proteins. Expressed proteins in cerebellum. [Note: This graph should be read from top to bottom.]Click here for fileFunctional annotation by protein information resources (RIP). 3 most frequent gene ontology in hippocampus and cerebellum.Click here for file"} +{"text": "Myocardial MIBG scintigraphy is established in the diagnosis and differential diagnosis of Parkinson's disease (PD). Numerous studies address the pathophysiological impact of myocardial MIBG scintigraphy: the myocardial MIBG uptake correlates with the clinical phenotype of PD; the background of this phenomenon is unclear. Furthermore MIBG scintigraphy enables to study the extracranial Lewy body type-degeneration. In combination with cerebral dopamine transporter imaging, MIBG scintigraphy allows to correlate cerebral and extracranial Lewy body type-degeneration in PD. The accumulation of MIBG is visualized and measured by planar whole-body scintigraphy. In clinical practice, the MIBG scintigraphy is mainly used to detect (and sometimes to treat) neuroendocrine tumours, primarily pheochromocytomas and neuroblastomas /[counts per pixel in the upper mediastium] [The myocardial MIBG scintigraphy measures the postganglionic sympathetic cardiac innervation . In the iastium] , 18. PD iastium] \u201313. For iastium] , age, diiastium] \u201324.Coronary heart disease represents an exclusion criterion for myocardial MIBG scintigraphy, since a myocardial hypoperfusion due to coronary heart disease may influence myocardial MIBG scintigraphy. 99mTc-Metoxy-Isopropyl-Isonitril (MIBI) scintigraphy can detect a local myocardial hypoperfusion . TherefoPD is diagnosed clinically. The UK Brain Bank criteria represenPD and Lewy body dementia (LBD) share a common pathology with a Lewy body type-degeneration of the nervous system. The anatomical distribution of this Lewy body type-degeneration\u2014in PD primarily in the basal ganglia, in LBD primarily in cortical areas\u2014decides whether the patient shows clinical symptoms of PD or LBD. Both diseases, PD and LBD, are characterized by a remarkable Lewy body type-degeneration of postganglionic myocardial sympathetic neurons. Therefore MIBG scintigraphy discloses a pathologically reduced myocardial MIBG uptake in both PD and LBD patients , 39. MyoThere exist only small data to MIBG scintigraphy in hereditary Parkinsonism (HP): Quattrone et al. reportedIn multiple system atrophy (MSA), the autonomic nervous system is mainly affected in its preganglionic structures, whereas postganglionic involvement of the autonomic nervous system predominates in PD . FollowiOrimo et al. reportedSmall case series disclosed contradictory findings: Nagayama et al. observedPatients with essential tremor (ET) reveal a normal myocardial MIBG uptake, as reported by Lee et al. in 22 ETSince myocardial MIBG scintigraphy measures the sympathetic myocardial function, it is of interest whether myocardial MIBG uptake correlates with other autonomous functions. The autonomous nervous system can be investigated by means of several clinical tests such as orthostatic reaction, deep breathing, or Valsalva manoeuvre. During these clinical tests, the blood pressure (regulated mainly by the sympathetic nervous system), the heart rate, and variability of heart rate (regulated mainly by the parasympathetic nervous system) are measured . There aMyocardial MIBG uptake correlates with motor symptoms in PD; patients with tremor dominant PD reveal a significantly higher MIBG uptake than patPD is characterized by a cerebral as well as extracranial Lewy body type-degeneration. The cerebral\u2014predominantly nigrostriatal dopaminergic\u2014Lewy body degenerations is usually visualized by cerebral SPECT of the presynaptic dopamine transporters (DAT). As mentioned above, MIBG scintigraphy quantifies exactly the extent of extracranial myocardial sympathetic Lewy body degeneration. It is unclear whether cerebral nigrostriatal dopaminergic and extracranial sympathetic Lewy body degeneration occur independently from each other or not. \u201cExtreme\u201d cases might be possible in whom only the cerebral nigrostriatal system but not the extracranial sympathetic system degenerates or vice versa. The intraindividual comparison between cerebral nigrostriatal DAT SPECT and myocardial MIBG scintigraphy may clarify this aspect: Spiegel et al. and SpieMyocardial MIBG scintigraphy helps to differentiate between PD and other parkinsonian syndromes in clinically difficult cases. Furthermore, the myocardial MIBG scintigraphy allows insights into the pathophysiology of PD; myocardial MIBG uptake correlates significantly with the motor phenotype and with the nigrostriatal function (measured by DAT SPECT). These facts suggest that cerebral nigrostriatal dopaminergic degeneration and myocardial sympathetic degeneration are closely coupled in PD."} +{"text": "Prediction of optimal cytoreduction in patients with advanced epithelial ovarian caner preoperatively.Patients with advanced epithelial ovarian cancer who underwent surgery for the first time from Jan. to June 2008 at gynecologic oncology ward of TUMS were eligible for this study. The possibility of predicting primary optimal cytoreduction considering multiple variables was evaluated. Variables were peritoneal carcinomatosis, serum CA125, ascites, pleural effusion, physical status and imaging findings.Univariate comparisons of patients underwent suboptimal cytoreduction carried out using Fisher's exact test for each of the potential predictors. The wilcoxon rank sum test was used to compare variables between patients with optimal versus suboptimal cytoreduction.41 patients met study inclusion criteria. Statistically significant association was noted between peritoneal carcinomatosis and suboptimal cytoreduction. There were no statistically significant differences between physical status, pleural effusion, imaging findings, serum CA125 and ascites of individuals with optimal cytoreduction compared to those with suboptimal cytoreduction.Because of small populations in our study the results are not reproducible in alternate populations. Only the patient who is most unlikely to undergo optimal cytoreduction should be offered neoadjuvant chemotherapy, unless her medical condition renders her unsuitable for primary surgery. Ovarian cancer is the leading cause of morbidity and mortality among the gynecologic cancers . EpithelIt is not possible to do primary optimal debulking for all patients, in these cases primary surgery not only dose not have any benefit but also causes morbidity . The 30-Primary debulking in patients with advanced epithelial ovarian cancer has been compared with chemotherapy and interval debulking in different studies. Equal survival has been reported in patients undergoing primary surgery compared to patients undergoing debulking surgery after taking chemotherapy by Onnes et al. . They haIn 1999, Shwartz et al. demonstrated that women who underwent cytoreductive surgery after induction chemotherapy had statistically improved overall survival compared to women who did not undergo surgery.One randRegarding that residual tumor is more than 1 cm in many patients underwent primary surgiery, considering another method in this group of patients seems necessary. Although neoadjuvant chemotherapy and interval cytoreduction sounds to be good management but its indications have not yet determined.A critical point in order to define indications of neoadjuvant chemotherapy for advanced ovarian cancer is determination of uniform selection criteria that can consistently identify patients with surgically unresectable disease without depriving others from potential advantage associated with an optimal primary resection. Several studies have been done for determining markers which can reliably predict optimal resectability -18. CT-SApproval to conduct this study was obtained from research organization of gynecologic oncology department of Tehran University of Medical Sciences(TUMS). Patients with stage 3 and stage 4 epithelial ovarian cancer underwent primary surgery between Jan. to June 2008 at gynecologic oncology ward of Vali-e-Asr hospital of TUMS were eligible for entering the study.The possibility of predicting primary optimal cytoreduction considering multiple variables was assessed in this group. Variables were peritoneal carcinomatosis, serum CA125 level, ascites, pleural effusion, physical status and imaging findings.All surgeries were performed by gynecologic oncologists of TUMS. Optimal cytoreduction was defined as \u2264 1 cm residual disease. All imagings were reported by the professors of radiology of TUMS. Considered imaging parameters included: omental extention, liver involvement, peritoneal involvement and suprarenal adenopathy. Blood samples for measuring serum CA125 levels were taken at the morning.Physical statusesof patients were defined according to physical status classification of the American society of anesthesiology. In addition we considered optimal and suboptimal cytoreduction. Residual tumor less than 1 cm after surgery was considered as optimal cytoreduction.Univariate comparisons of the percentage of patients who underwent suboptimal cytoreduction carried out using Fisher's exact test for each of the potential predictors. The wilcoxon rank sum test was used to compare variables between patients with optimal versus suboptimal cytoreduction.Forty one patients from patients who were admitted at Vali-e-Asr hospital of TUMS from Jan. to June 2008 met study inclusion criteria. Demographic and clinical data are described in table Peritoneal carcinomatosis and suboptimal cytoreduction had statistically significant assosciation. There were no statistically significant differences between physical status, pleural effusion, imaging findings, CA125 serum levels and ascites in patients with optimal cytoreduction compared to those who underwent suboptimal debulking.Table Our current study identifies intraperitoneal carcinomatosis as being the only statistically significant predictor of suboptimal cytoreduction. Table There is no statistically significant difference between pleural effusions in individuals underwent optimal cytoreduction compared to those with suboptimal cytoreduction. It seems that low number of patients caused this result because the number of patients who were suboptimally cytoreduced is in confidence interval range of those who were optimally cytoreduced.The number of patients in our study is only 41. Considering small sample size of the study, proofing these results demands larger randomized study. We used imaging findings as predictive predictors of suboptimal debulking according to previous studies which had mentioned these factors have predictive value.To date, the predictive performance of clinical parameters, serum CA-125 threshold values, and radiographic imaging criteria have not demonstrated sufficient accuracy to achieve widespread applicability ,21-24.The most common criteria cited as justification for abandoning an up-front attempt at surgical cytoreduction are ascites volume greater than 1000 ml, peritoneal carcinomatosis, parenchymal liver disease, splenic metastasis or omental extension to the spleen, porta hepatitis disease, and bulky disease involving the diaphragm one of tOne of the principle difficulties in development of any reliable predictive model of surgical outcome for patients with advanced ovarian cancer is the challenge of factors in the significant impact of each institute surgeons' philosophy, effort and ability to utilize advanced surgical techniques to achieve maximal cytoreduction, in order to omit this factor, in this study all surgeries were performed by gynecologic oncology professors of TUMS.In summary, identification of risk factors for suboptimal cytoreduction in small populations such as ours is not reproducible in alternate populations. Until prospective randomized trials have demonstrated that neoadjuvant chemotherapy followed by interval cytoreduction is equivalent in terms of survival outcomes to primary optimal cytoreduction followed by chemotherapy, extreme caution should be used when applying preoperative predictors to decide between primary surgical exploration and neoadjuvant chemotherapy in the medically fit patient. Only the patient who is most unlikely to undergo optimal cytoreduction should be offered neoadjuvant chemotherapy, unless her medical condition renders her unsuitable for primary surgery.The authors declare that they have no competing interests.AM: supervised research project, carried out operations, supervised statistics. MMM: participated in operation as first aid, collect data, drafted the manuscript, and acted as corresponding author and did the revisions. MMG: carried out operations, she was head of the department. FG: carried out operations. NB: carried out operations. SA: participated in operation as first aid."} +{"text": "Immature teeth with necrotic pulp and large periapical lesion are difficult to treat via conventional endodontic therapy. The role of materials such as calcium hydroxide and mineral trioxide aggregate in apexification is indispensable. This case report presents the successful healing and apexification with combined use of white mineral trioxide aggregate and demineralized freeze-dried bone allograft. Complete asepsis and three-dimensional obturation of the root canal system are essential for long-term endodontic success. In certain cases such as immature teeth, the absence of natural apical constriction creates a challenge. Therefore, one of the aims of endodontic treatment is to produce an apical barrier or stop, against which one can place a root canal filling material avoiding overextrusion. This technique is termed apexification.Clinicians have tried several materials to form apical barrier in the past. These include: calcium hydroxide paste, calcium hydroxide powder; mixed with different vehicles,\u20133 tricalMineral trioxide aggregate (MTA) was developed at Loma Linda University for use as a root-end filling material. MTA has 13Bio-resorbable demineralized bone matrix (DMBM) is the protein component of bone and is widely used in various clinical conditions such as periodontal defects and oral and maxillofacial bone defects. Periodontal defects grafted with demineralized bone matrix allograft showed histologic evidence of regeneration of new bone and periodontium. ConsiderThe apical matrix of some resorbable and biocompatible material is essential to control extrusion of MTA. \u201cModified matrix concept\u201d for repair of perforation utilized resorbable collagen as a matrix followed by condensation of MTA. ConsiderTherefore, present case report highlights the nonsurgical management of symptomatic tooth with blunderbuss canal and large periapical radiolucency using bio-resorbable demineralized bone matrix and MTA.A 16-year-old male patient of south Indian origin reported to the department of conservative dentistry and endodontics, PMNM Dental College and Hospital, Bagalkot, Karnataka, India, with the complain of pain in right mandibular posterior teeth since 3 weeks. Careful intraoral examination revealed sinus opening in relation to the right lower second premolar. Hard tissue examination revealed the presence of \u201cdens evaginatus\u201d and a deep pit in right mandibular second premolar . ConcernDespite the higher success rate of apical barrier formation using calcium hydroxide, long-term follow-up is essential. Problems such as failure to control infection, recurrence of infection, and cervical root fracture may occur.18 ApexifMTA has superior biocompatibility and sealing ability and is less cytotoxic than other materials currently used in pulpal therapy. The 5-mmApexification using MTA lessens the treatment time between the patient\u2019s first appointment and the final restoration. The importance of this approach lies in the expedient cleaning and shaping of the root canal, followed by apical seal with a material that favors regeneration. In addition, there is reduced potential for fracture of immature teeth with thin roots, because of immediate placement of bonded core within the root canal.In the present case, combination of calcium hydroxide and iodoform was used as intracanal medicament for 15 days to make the canal dry and free from infection. Use of calcium hydroxide for such a short term does not adversely affect the fracture resistance of the tooth.The demineralized bone matrix acts as an osteoconductive and possibly as an osteoinductive material.26 Hence,Decalcified freeze-dried bone allograft material has been extensively used in the management of extensive periodontal defects. Its use results in significant probing depth reduction, clinical attachment gain, and bone fill. Definite evidence exists that sites grafted with DFDBA heal with regeneration of periodontium.28 Follow\u2018Dens evaginatus\u2019 or \u2018evaginated odontoma\u2019 is a developmental anomaly that occurs more often in mandibular premolars; however,This case report presents a novel approach to achieve single visit apexification of the cases with open apex and large periapical lesion. Present case also stresses the early detection and treatment of \u2018dens evaginatus\u2019 which if undetected can cause undue damage."} +{"text": "C. elegans and Drosophila), have contributed enormously to defining homology. The characteristics of specificity and memory and whether the antigen is pathogenic or nonpathogenic reveal considerable information on homology, thus deconstructing the more fundamentalist view. Senescence, cancer, and immunosuppression often associated with mammals that possess both innate and adaptive immunity also exist in invertebrates that only possess innate immunity. Strict definitions become blurred casting skepticism on the utility of creating rigid definitions of what innate and adaptive immunity are without considering overlaps.Adaptive immunity has often been considered the penultimate of immune capacities. That system is now being deconstructed to encompass less stringent rules that govern its initiation, actual effector activity, and ambivalent results. Expanding the repertoire of innate immunity found in all invertebrates has greatly facilitated the relaxation of convictions concerning what actually constitutes innate and adaptive immunity. Two animal models, incidentally not on the line of chordate evolution ( All multicellular animals (invertebrates and vertebrates) manage to keep self-integrity. Any attempt to answer questions concerning immune recognition must consider the universality of receptor-mediated responses. These may designate two forms: 1) rearranging clonally distributed antigen-specific receptors that distinguish between self and nonself according to classical Burnet hypothesis; and/or 2) pattern recognition receptors introduced by Janeway [ rearrang pattern With this in mind, we felt compelledto clarify and extend what seems to be the blurring or masking of certainimmunological characteristics of invertebrates and vertebrates \u20138. TodoAncient innate immunity-related functions like phagocytosis and cytokine production were already developed 700 million years ago in sponges and higher aquatic invertebrates . These fundamental functions remained unaltered during phylogenesis. A major evolutionary step happened 500 million years ago when fish developed jaws accompanied by evolution of the gut associated immune system. This system was fundamental to providing the genetic material required for recombination and mutation to produce variability and diversity of proteins . This system also enabled the occurrence of a wide spectrum of antigen-presenting proteins like the major histocompatibility complex (MHC). These MHC molecules developed from a primordial molecule over 300 million years ago .A genetically colorful background is generally considered to be advantageous for species in their constant adaptation to the neighboring environment. On the other hand, for a suddenly emerging costly macroscopic function like adaptive immunity, working with clonally distributed receptors, intraspecies genetic backcrosses can make survival difficult. Therefore, in such cases, interspecies borders may help the genetic solidification of evolutionarily novel characteristics. However, drawing interspecies borders is not always easy as often seen in cases of hybridogenesis with certain invertebrate arthropods or even with vertebrate fish and amphibian species \u201312.In the case of invertebrate organisms, species survival is maintained at the population level,which is risky for individuals. Whenever a new pathogen takes its toll, theremaining individuals are spared because they are more resistant than others.Such differences are genetically encoded . HoweverEcological immunology is a young but increasing science that examines causes and consequences of changes in immune function in the context of evolution and of ecology. Millions of invertebrate species depend exclusively on using innate immunity, in contrast to the only 45 000 vertebrate species that employ an additional acquired immune system. Regardless of this major distinction, most studies of ecological immunology discuss only vertebrates. Nevertheless, insect immunity might be more specific and similar to vertebrate immunity than previously thought \u201317.An explanation to why an anticipatory immune system employing clonally distributed receptors has not developed in invertebrates may be provided by immunological ecology. Highly developed organisms tend to be large in size. Since the size of individual cells does not show significant interspecies variances, being larger means having more cells. Adaptive immunity works with a huge number of recognition molecules distributed in a clonal pattern. Therefore, only highly developed organisms can afford to run such a costly immune system; otherwise costs would always outweigh benefits. It seems that having huge and complex communities of cells not only demands a highly effective adaptive immune system, but actually provides its basic framework in order to exist , 19.Senescence and age-related research isa promising approach that discovers revolutionary data. Immunological senescence of vertebrate adaptive immunity is a process widely accepted by most immunologists. This is, however, less evident when thinking in terms of invertebrate innate immunity. However, this will likely change in the near future as there is accumulating evidence of senescence and more specifically immunological senescence in invertebrate species.Morphological features of the aging process (senescence) have been recognized for many years in invertebrates. For example, when earthworms are maintained for long periods in the laboratory, a progressive decrease in size reminiscent of degeneration and a kind of wasting syndrome occur . Congo rDrosophila melanogaster expresses increasing levels of numerous antimicrobial peptides if exposed to septic bacterial infections, but not in response to bacterial extracts [Caenorhabditis elegans ortholog of the above MRG15) in the aging process has also been demonstrated [Caenorhabditis elegans and this function seems to be evolutionarily conserved: the DAF pathway also affects aging in Drosophila melanogaster and rodents [Caenorhabditis elegans are also regulated by the TGF\u03b2-like and the p38 MAPK pathways. The requirement of the DAF-2 cascade in regulating senescence and immunity raises molecular-level linkage of these processes [During senescence, extracts . Mortalinstrated . The DAF rodents . Innate ocesses .Cancer development has often been addressed in vertebrate species especially its relation with adaptive immunity. However, invertebrates also develop tumors in response to environmental carcinogens. Studying cancer development in species possessing innate immunity alone is a very promising field of research and may highlight adaptivelike functions present in invertebrates.Mytilus edulis homologue of vertebrate ras and p53 demonstrates extreme evolutionary conservatism in active domains, including four mutational hot spots [Mya arenaria have also been reported [Mussels are vulnerable to several environmental toxicants and carcinogens. DNA sequence alignment of the ot spots . Cases oreported \u201330.Drosophila offers a unique platform for the rapid identification and characterization of tumor suppressor genes, many of which have mammalian homologues. Genomewide microarray analysis of Drosophila brain tumor caused by the disfunction of the Brat tumor suppressor gene has identified over three hundred associated genes. Sixty of these sequences show homology to existing mammalian genes involved in tumor development [wts) sequence. The wts sequence was identified by the massive overgrowth of clones homozygous for wts deletion [elopment . As in deletion , 33. Sideletion .Cotesia congregata is a wasp thatinjects its eggs into the host caterpillar Manduca sexta. However, inthis particular host-parasite relation, the presence of a third partner isnecessary for successful parasitism: a bracovirus. The C. congregata bracovirus (CcBV) is injected simultaneously with the wasp eggs. Expression ofviral genes hijacks the caterpillar's immune defense responses, which favorsthe survival and development of adult parasitoid wasps [blurring of immunological functions [For those who believein the orthodox split between innate and adaptive immunities in terms of characteristics,it is perhaps difficult to accept the existence of viruses that specifically suppressthe cellular components of innate immunity. Nevertheless, as proved by experimentaldata, innate immunity-specific immunosuppressive viruses exist. id wasps , 64. Thid wasps . In inveunctions .C. elegans and Drosophila. In contrast, the lophotrochozoan systems share some distinct differences; mollusks may havemanaged immunological defense in a special manner similar to the annelidsincluding earthworms [Numerous examples have been presented of animal immune responses that may developfollowing challenge by pathogenic organisms or nonpathogenic stimuli . Here, rthworms [Sea urchins and seastars exhibit immune responses against grafted tissues similar to those foundin vertebrates , 50. Thed Fu/HC) , 75\u201378.Ciona intestinalis has been sequenced, it allows for the rapid identification ofearly evolutionary roots of adaptive immunity. In the hemocytes of C. intestinalis, certain adaptive-immunity homologous ESTs have been identified including vWF-like (von Willebrandfactor-like), distant homologues of type I interferon (IFN) receptors, and C6-like(complement 6-like) elements [Since the complete genome of the urochordate elements , 80. Moelements .The emergence of adaptive immunity was not a sudden event; its far-reaching evolutionary roots are currently under investigation by modern molecular biological methods. Genomewide sequence analysis of invertebrates has focused on the genes of innate immunity including complement components, Toll-like receptors, and those involved in intracellular signal transduction of immune responses. Assessment of extracellular C-type lectins, immunoglobulin domains, intracellular immunoreceptor tyrosine-based inhibitory motifs (ITIMs), and immunoreceptor tyrosine-based activation motifs (ITAMs) suggests that activating and inhibitory receptors have an early evolutionary origin .\u03b1\u22121, and GM-CSF. Malagoli et al.have identified a putative helical cytokine in Drosophila melanogaster by elaborate bioinformatics transcriptomeanalysis. It is very promising that transcription from this homologue isupregulated in parallel with the known antimicobial factors defensin andcecropin A1 following Gram\u2212 or Gram+ challenge [Pacifastacus leniusculus by mass spectrometry and PCR using degenerate primers. An astakine homologue has also been identified in the shrimp Penaeus monodon. In vertebrates, PK domains direct angiogenic growth. It has been demonstratedthat injections of recombinant astakine actively influencedifferentiation and growth of hemopoietic stem cells in vivo [After decades of anticipation, the ancestors of some cytokines\u2014soluble intercellular signaling moleculesthat form a complex network for the regulation of immunity\u2014have recently beenidentified. In vertebrates, helical cytokines inlude IL2, IL6, INF hallenge , 84. Si in vivo .14 unique VLR receptors [It is a notable observation that even our most distant vertebrate relatives, jawless fish, have an adaptivelike immune system. It operates by means ofclonally distributed leucine-rich repeat (LRR) receptors (similar to Toll-likereceptors) using a novel mechanism of gene rearrangement other than RAG. TheseLRR modules constitute the variable lymphocyte receptors (VLRs). Computer-assistedprediction suggests a repertoire of approximately 10ceptors \u201389. In rceptors . Recent ceptors .blurring and the strict distinction between innate and adaptive immunitiesmight need revision . Consequrevision ."} +{"text": "Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Klebsiella pneumonae. The activity data show the metal complexes to be more active than the parent freeligands against one or more bacterial species.Biologically active complexes of Co(II), Ni(II), Cu(II) and Zn(II) with novel ONO, NNO andSNO donor pyrazinoylhydrazine-derived compounds have been prepared and characterized on the basis ofanalytical data and various physicochemical studies. Distorted octahedral structures for all the complexeshave been proposed. The synthesized ligands and their complexes have been screened for their antibacterialactivity against bacterial species"} +{"text": "Members of the small multidrug resistance (SMR) protein family are integral membrane proteins characterized by four \u03b1-helical transmembrane strands that confer resistance to a broad range of antiseptics and lipophilic quaternary ammonium compounds (QAC) in bacteria. Due to their short length and broad substrate profile, SMR proteins are suggested to be the progenitors for larger \u03b1-helical transporters such as the major facilitator superfamily (MFS) and drug/metabolite transporter (DMT) superfamily. To explore their evolutionary association with larger multidrug transporters, an extensive bioinformatics analysis of SMR sequences (> 300 Bacteria taxa) was performed to expand upon previous evolutionary studies of the SMR protein family and its origins.groEL mutations (SUG), and paired small multidrug resistance (PSMR) using protein alignments and phylogenetic analysis. Examination of SMR subclass distribution within Bacteria and Archaea taxa identified specific Bacterial classes that uniquely encode for particular SMR subclass members. The extent of selective pressure acting upon each SMR subclass was determined by calculating the rate of synonymous to non-synonymous nucleotide substitutions using Syn-SCAN analysis. SUG and SMP subclasses are maintained under moderate selection pressure in comparison to integron and plasmid encoded SMR homologues. Conversely, PSMR sequences are maintained under lower levels of selection pressure, where one of the two PSMR pairs diverges in sequence more rapidly than the other. SMR genomic loci surveys identified potential SMR efflux substrates based on its gene association to putative operons that encode for genes regulating amino acid biogenesis and QAC-like metabolites. SMR subclass protein transmembrane domain alignments to Bacterial/Archaeal transporters (BAT), DMT, and MFS sequences supports SMR participation in multidrug transport evolution by identifying common TM domains.A thorough annotation of unidentified/putative SMR sequences was performed placing sequences into each of the three SMR protein subclass designations, namely small multidrug proteins (SMP), suppressor of Based on this study, PSMR sequences originated recently within both SUG and SMP clades through gene duplication events and it appears that SMR members may be evolving towards specific metabolite transport. Anthropogenic drug overuse combined with the rapid horizontal distribution of multidrug efflux genes encoded on mobile genetic elements has facilitated drug resistance in distant or unrelated microorganisms -3. One sgroEL mutations (SUG), and paired small multidrug resistance (PSMR) subclasses proteins from Archaea and Firmicutes, ethidium multidrug resistance protein E (EmrE) from Proteobacteria, and plasmid and/or integron encoded Qac proteins such as QacE, QacF and QacH (as reviewed by [Escherichia coli EmrE (Eco-EmrE) serve as the paradigm for all SMR members.The SMR protein family can be subdivided into three subclasses namely, small multidrug proteins (SMP), suppressor of iewed by ,12). Theiewed by ). ProteigroEL mutation phenotypes [qacC' [smr-2 [E. coli SugE (Eco-SugE) and Citrobacter freundii (Cfr-SugE) [SUG subclass members were initially identified based on their ability to suppress enotypes and thesenotypes ,12). Memenotypes ,15. To denotypes ,17 that s [qacC' and smr-' [smr-2 . Membersfr-SugE) ,15,20.B. subtilis YvdR/YvdS and YvaD only of the YvaD/YvaE pair [Members of the PSMR subclass are distinct from both SMP or SUG subclasses since they require co-expression of two SMR homologues to confer host resistance to QAC and toxic metabolites ,11,21-25vaE pair which suEach SMR subclass is thought to have a similar structural architecture based on hydropathy plot analysis and predicts that all SMR homologues adopt four TM strands connected by short loops of varying hydrophilicity ,28. One The short length and limited number of TM strands that comprise the SMR protein family have led to the proposal that they are the evolutionary building blocks of larger \u03b1-helical multidrug efflux proteins -31. AlthThe objective of this work is to explore the evolutionary origins of the SMR protein family by examining SMR diversity among Archaeal and Bacterial genomes. The specific goal is to gain insight into the evolutionary constraints exerted upon SMR subclass members to validate the notion that SMR proteins acted or are acting as the evolutionary starting points for larger transporters. We began these studies by surveying SMR sequences within Archaea and Bacteria from diverse taxonomic backgrounds using current genomic and plasmid sequence databases (as of March 2008). This effort identified 685 SMR amino acid sequences which were aligned to putatively classify SMR sequences into the three SMR protein subclasses. The evolutionary relatedness of assigned SMR protein sequences was refined by using phylogenetic analysis and assisted with SMR homologue classification. The degree of amino acid conservation and the selective pressures exerted upon selected taxonomic SMR representatives was determined by their rate of synonymous to non-synonymous nucleotide substitutions. Finally, the genomic loci of SMR homologues were surveyed within the currently sequenced Archaeal and Bacterial genomes to explore their functional association to metabolite transport and their affiliation with transposon and integron mediated inheritance among diverse microorganisms. The results from this bioinformatics exploration support the current models that SMR protein sequences act as genetic building blocks for much larger multidrug efflux proteins based on their diversity and rapid evolution.subtilis and E. coli as seed sequences. In total, 685 putative SMR protein sequences were retrieved from Archaea and Bacteria and a summary of their subclass distribution is presented in Table To understand and explore the extent of SMR subclass distribution and diversity, we surveyed the NCBI sequence database for chromosomally encoded SMR sequences among Archaea and Bacteria using characterised SMR homologues from B. -3). All three Crenarchaeal SMR sequences served as outgroups for subsequent phylogenetic analysis and will not be discussed further.The results from Archaeal genome surveys identified that SMR sequences are present within Euryarchaeal sub-phylum genomes Table . The lacB. subtilis YvaE (Bsu-YvaE). The presence of Methanomicrobia yvaE homologues could suggest that YvaE potentially represents a PSMR progenitor. This observation is supported upon closer examination of their genomic loci, where all of the Euryarchaeal yvaE homologues lacked the presence of yvaD a poorly conserved SMR that is commonly located in the same putative operon among Bacillus species [Overall, SMR homologues we identified from surveyed Euryarchaeal genomes belonged to SUG, SMP, and the PSMR (only YvaE) subclasses only Table . All Eur species .As expected from the wealth of bacterial genomic sequences available, SMR diversity among bacterial species far outnumbered Archaea Table . SurveysThe SUG subclass prevailed over all other subclasses in Bacteria since SUG homologues were found in nearly every class we examined Table . The preXanthomonas [Vibrio [SMP subclass sequences were identified within the genomes of particular Bacterial classes namely, Cyanobacteria, Chloroflexi, as well as \u03b1-, \u03b2- and \u03b3-proteobacteria Table . Unlike thomonas or Vibri [Vibrio -36 that yvaD in Bacilli and Lactobacilli only suggests that yvaD may be a rapidly diverging yvaE gene duplication product within Bacilli and Lactobacilli.PSMR subclass members have the most specific sequence distribution among the sequenced Bacterial genomes we surveyed strongly suggesting they are maintained under selective pressures different from either the SUG or SMP subclasses Table . ParticuTaken together, the unique distribution pattern of SUG, SMP and PSMR subclass members strongly supports SMR diversification that is tailored to particular genera.To explore the evolutionary relationships of SMR protein family members further, we analyzed a taxonomically diverse set of 338 SMR protein sequences. Previous phylogenetic analyses of SMR amino acid sequences using smaller taxonomic data sets ,12,26,37Our phylogenetic analysis demonstrated a division of SMR members into two major clades Figure , namely Since the greatest number of SMR homologues we identified are from Actinobacteria, Bacilli, and various Proteobacteria, it is not surprising that the phylogenetic groupings of SMR homologues within our dendrogram are strongly dominated by these Bacterial classes Figure . PreviouSimilar to the observations made from SMR sequence surveys Table , a trendPSMR subclass homologues grouped in distinct branches to either the SUG or SMP clades Figure . YvaD hoE. coli and B. subtilis, were selected for pairwise comparison to their respective putative homologues from Bacterial and Euryarchaeal class in our survey. Integron and plasmid encoded SMR homologues were included in this analysis to determine the extent of nucleotide changes within chromosomally encoded SMR sequences compared to the rate of divergence from their horizontally transferred counterparts. This comparison also served as a method to gauge differences that arise from the codon bias within the various host genomes.Since SMR subclass distribution is enriched within particular Bacteria, we wanted to compare the frequency of synonymous to non-synonymous changes occurring within SMR sequences at the nucleotide level. Examining the degree of nucleotide changes throughout the whole SMR sequence relative to the rate of change at each codon can identify regions of the protein that are actively evolving. Experimentally examined SMR sequences, specifically SMR homologues from The rate of synonymous to non-synonymous changes (dS/dN) in nucleotide sequences of SMP subclass homologues selected from various Euryarchaeal and Bacterial genera resulted in a mean value of 3.6 Table .Individual dS/dN values from pairwise SMP sequence comparisons indicated that the rate of synonymous and non-synonymous changes range from 1\u20136 among examined chromosomal SMP sequences Table . These vHalorubrum lacusprofundi sugE (Hla-sugE) sequence relative to the values of Eco-sugE compared to other PSMR members, reflecting its frequent diverse distribution in the genomes of both Archaea and Bacteria. Although the rate of synonymous to non-synonymous changes among comparisons of Bsu-yvaE to other yvaE homologues are in many cases indeterminable due to pS values exceeding the Jukes-Cantor threshold limits, those that could be calculated resulted in high overall dS/dN values suggesting that it is maintained under the least amount of selective pressure among all the PSMR members we examined.Members of the PSMR subclass appear to have very different selective constraints placed upon their sequences as reflected by the variable mean dS/dN values for each PSMR homologue in comparison to either SMP or SUG subclasses Table . B. subt to date ,22,25,26dN value .16 compaebrA/ebrB have a slightly lower mean dS/dN value (2.84) than the mean dS/dN values of yvaE, SMP, and SUG homologues , but not when compared to integron encoded Qac homologues than its counterpart ydgF (0.3\u20130.6) indicating that only ydgE is actively maintained. This trend is in good agreement with observations made by three dimensional cryo-electron microscopic structural studies of Eco-EmrE protein that support an asymmetrical arrangement of each protein monomer [E. coli has revealed its involvement in spermidine excretion and confirmed that only YdgE (MdtI) was essential for transport activity based on site-directed mutagenesis experiments of each active site Glu14 residue in the pair [ydgF and ydgE homologues to plasmid and integron encoded SMR homologues indicated that only ydgE members were maintained at similarly high levels.YdgE/YdgF homologues demonstrated a much lower mean dS/dN value (1.84) suggesting that these homologues are under far less selective pressure than the SMP or SUG members surveyed and yvdR/yvdS (2.0), revealed that each pair is maintained under moderately high selective pressures in comparison to all other PSMR members selective pressures on both pairs. Active maintenance of both homologues in the pair may reflect functional interdependency. More importantly, only ykkC demonstrated high dS/dN values when compared to plasmid/integron encoded SUG homologues suggesting that ykkC has closer association to horizontally transferred SUG counterparts. This contrasts our phylogenetic analysis of these sequences which suggest YkkD has greater evolutionary relationships to plasmid and integron encoded SUG homologues values were also calculated at each codon position in the SMR nucleotide alignment using Syn-SCAN analysis to determine the selective pressures exerted on each residue of the protein. Sd values were determined from pairwise comparisons of selected members (10\u201320 species/SMR subclass) and then averaged to generate the mean Sd at each codon. A summary of both analyses are shown in Figures Both SUG and SMP subclasses demonstrated a unique amino acid consensus in addition to the core SMR motif previously reported Figures and 3A. A striking feature within each panel of Figures Periodic \u03b1-helix conservation is also maintained in many PSMR subclass consensus maps but distinctly varies from TM strand to TM strand, where the least TM conservation is observed in the last strand TM4) Figures , and 4. Figures Amino acid sequence alignments for the PSMR subclass members EbrA and EbrB were difficult to distinguish from each other since they both had similar residue conservation patterns, especially when Actinobacterial EbrA and EbrB homologues were examined. The inability to reliably separate EbrA/EbrB homologues from each other forced an initial comparison of these PSMR members altogether. High amino acid conservation is observed for EbrA/EbrB homologues within the loop and C-terminus regions of the protein Figure . ConservDespite having a distinct amino acid consensus motif from SMP and SUG, YvaE demonstrated a similarly strong periodic amino acid conservation pattern, particularly within predicted loop and turn regions. As expected, YvaD homologues show low overall amino acid conservation throughout the entire protein with the exception of the three to four moderately conserved residues at the ends of the last two TM strands towards the C-terminus. This clearly indicates that YvaD has diverged dramatically from other PSMR members. An important feature of YvaD homologues to consider is loss of the highly conserved residue E14 (according to Eco-EmrE); yet conserved residues within the C-terminal residues are only partially maintained. These infrequently conserved residues are shared with both YvaE and SMP subclass members strongly supporting the idea that YvaD likely originated from YvaE but is maintained under very little selective pressure within the hosts.Examination of mean Sd values at each codon position within all SMR nucleotides demonstrated strong agreement to its corresponding amino acid consensus value within predicted loop and TM regions Figures , and 4. The mean Sd values observed for both SUG and SMP subclass sequences show a similar \u03b1-helical periodicity pattern to conserved amino acid residue positions strongly validating the observation that specific TM \u03b1-helix faces are highly conserved. However, it should be noted that there are also occasional amino acid positions in each SMR subclass consensus where codons corresponding to loop or TM strand regions have high mean Sd values but very low amino acid consensus value and vice versa. For example, numerous positions in TM4 of the SUG consensus map have high mean Sd values but low values for its conserved amino acid at the same position Figure . ConversA. nicotinovorans plasmid pAO1 encoding NepA and NepB have specifically demonstrated efflux of potentially toxic metabolites such as spermidine and nicotine intermediates, respectively [Experiments implicating SMR protein involvement in toxic metabolite transport suggest broader roles for this family of proteins during host metabolite regulation. Although members of the SMR protein family are known for conferring multidrug resistance to its host organism, very little is known about potential 'natural' substrates. PSMR members Eco-YdgE and Eco-YdgF and ectively ,11. In aectively ,14,48 anAfter completing our SMR genomic loci survey, many trends in SMR genomic arrangement were noted. The first common characteristic identified from these surveys was detection of horizontal gene transfer genes that encoded for integrases, transposons, insertion sequences (IS), plasmid maintenance genes, and bacteriophage replication and coat proteins downstream or upstream from the SMR sequence (within our 10 ORF radius cut-off), strengthening our arguments for horizontal SMR inheritance as shown in the phylogram Table . Mobile The second characteristic we observed upon examining SMR genomic loci was frequency of SMR subclass co-occurrence to various metabolite biosynthetic genes Table . In geneydgE/ydgF and ykkC/ykkD, were shown to frequently overlap (95%\u201398% surveyed respectively) in all proteobacterial genomic loci we surveyed. This contrasted the PSMR homologues ebrA/ebrB that did not frequently overlap and were often separated by other ORFs within their putative operons. In our survey EbrA/EbrB homologues were also found to correspond to a single gene only within species from Actinobacteria (32%), Clostridia (14%), Cyanophyceae (13%), Chloroflexi (25%) and Planctomycetacia (33%). This observation is similar to the situation we described for yvaE and yvaD pairing suggesting that some isogenic ebrA/ebrB homologues may possess functional activity alone or frequently undergo losses of either pair.The last final characteristic observed from the surveys of genomic loci showed that PSMR homologues had characteristic arrangements in gene pair at the locus. This observation may reflect their potential to act as predecessors of much larger transporters. To clarify this statement, the PSMR gene pairs, It is important to mention again that these surveys in no way prove the functional activities of the various SMR subclasses, but identify potential substrates or activities that could and should be examined experimentally. It also reaffirms that the distribution of particular SMR subclasses are focusing in on specific Archaeal and Bacterial groups, in addition to their shared proximity with other organisms enabling SMR mobile genetic element exchange.et al. 2001 was shown from alignments of SMR TM domains to portions of DME and BAT family proteins in either the N- or C-terminus region of the protein. According to these alignments SMR proteins shared the greatest amount of sequence identity to the C-terminus regions of BAT or DME families [SMR proteins are one of the 14 families that encompass the DMT superfamily and inclfamilies . Hence, E. coli and B. subtilis homologues) in both heterogeneous (e.g. Eco-EmrE to Eco-SugE) and homogenous (Eco-EmrE to Eco-EmrE) protein combinations to serve as seed sequences for phi-BLAST analyses of genomic databases. These searches identified numerous TM domain regions within SMR fusions that had similarity to various DMT superfamily members in addition to members of MFS but not E. coli YdgE-YdgF (10%) alignment to DMT superfamily member RarD and Escherichia coli [-4 and served as the cut-off value for positive SMR identification. The 685 putative SMR protein sequences were aligned using ClustalW [SMR sequences used for this study were obtained from NCBI genomic blast surveys (tBLASTn and BLASTp) using SMR sequences functionally characterized for transport activity ,22,26,58_416117) . As a reClustalW ,61 and TClustalW . SMR suSMR proteins alignments to BAT, DMT and MFS transporters were performed using ClustalW and manual alignment using the editing program GeneDoc (v 2.5.010 ). BAT, DemrE codon 3 (W3) to codon 107 (L107). The distribution of point mutations from SMR sequences was examined spanning a 300 bp region which included nucleotides that encoded each of the four predicted transmembrane strands as well as loop/turn regions and truncated poorly conserved codons from the encoded N- and C-termini. For yvdR/yvdS and ebrA/ebrB sequences, poor alignment of three codons within the region encoding the first putative loop1 had to be removed. The rate of synonymous to non-synonymous changes (dS/dN) was determined using the online Syn-SCAN program website [SMR nucleotide sequences used for Syn-SCAN analysis were sel website -69 and t-3 and each sequence produced highly similar tree arrangements and bootstrap values (data not shown). Therefore, Archaeoglobus fulgidus QacE sequence was selected arbitrarily as the outgroup for the final tree. The results of these analyses are presented in Figure To examine the evolutionary relatedness of the all SMR subclass members assigned from the original 685 SMR protein alignment, a smaller alignment of 338 SMR protein sequences was prepared to adequately represent the taxonomic diversity of sequence origin ; TM: (transmembrane); QAC: (quaternary ammonium compounds).The following abbreviations used in the manuscript are listed here in alphabetical order: BAT: ; DME: (drug metabolite exporter); DMT: (drug metabolite transporter); dS/dN: (rate of synonymous to non-synonymous mutations); MFS: (Major facilitator superfamily); PSMR: ; Sd: (number of synonymous nucleotide substitutions); SMP: ; SMR: ; SUG: are listed beside their respective nodes above 59%. Plasmid and integron encoded SMR proteins are underlined. SMR sequence accession numbers are indicated adjacent to its genus and species name.Click here for fileSummary of synonymous to non-synonymous nucleotide substitution patterns within PSMR subclass members.Click here for fileAn alignment of 338 SMR protein sequences identified from BLAST surveys of completed Archaeal and Bacterial genomes. The 338 SMR protein sequence alignment was truncated from a larger alignment of 685 SMR sequences that was generated using a manually edited ClustalW alignment. It is important to note that this alignment may contain truncated versions of some SMR sequences.Click here for file"} +{"text": "A case of 49-year-old woman with a retroperitoneal undifferentiated foregut cyst attachedto the right adrenal gland is reported. The bronchogenic cyst is a type of foregut cyst witha cartilage component, but in this case the multicystic tumor lacked both cartilage andgland. It is quite rare among retroperitoneal tumors and has not been reported so far tohave malignant potential. The preoperative diagnosis was an adrenal benign incidentaloma, and the patient successfully underwent laparoscopic resection of the cystic tumor togetherwith the right adrenal gland by lateral transabdominal approach. Laparoscopic surgery for a retroperitoneal tumor is problematic, however, since benignancy cannot be predicted. In laparoscopic adrenalectomy for non-functioning adrenal tumor, therefore, a differential diagnosis from retroperitoneal tumor should be given serious consideration."} +{"text": "Aiming to discern the mechanisms by which circulatingglycated albumin alters the glomerular filtration propertiesthat lead to glomerular dysfunction in diabetes, the authorsstudied the distribution and densities of anionic chargesthrough the rat glomerular wall upon intravascular infusionof Amadori products, as well as in various conditions ofincreased glomerular permselectivity. Polylysine-gold wasused as the probe to reveal the anionic charges. The studywas carried on renal tissue sections of bovine serum albumin(BSA)- and glycated BSA\u2013injected, normoglycemicanimals. Results were generated through morphometricalevaluations of the gold labeling. Changes in glomerular anionicdistribution were corroborated on renal tissue sectionsof short- and long-term diabetic rats and of normal newbornrats, situations known for abnormal glomerular filtration.Altered renal function in these conditions was clearlyassociated with changes in glomerular anionic charges. Onthe other hand, the infusion of glycated albumin in the circulationof normal rats, though altering glomerular filtrationproperties, did not modify the distribution and density ofthe polylysine-gold labeling through the glomerular basementmembrane. Thus, anionic charges seem not to be thefactor involved in the early changes of glomerular permeabilityinduced by circulating glycated albumin."} +{"text": "More optimistic perceptions of cardiovascular disease risk are associated with substantively lower rates of cardiovascular death among men. It remains unknown whether this association represents causality (i.e. perception leads to actions/conditions that influence cardiovascular disease occurrence) or residual confounding by unmeasured factors that associate with risk perceptions and with physiological processes that promote cardiovascular disease .To evaluate whether previously unmeasured biological markers of inflammation or endothelial dysregulation confound the observed association between cardiovascular disease risk perceptions and cardiovascular disease outcomes;We conducted a nested case-cohort study among community-dwelling men from Southeastern New England (USA) who were interviewed between 1989 and 1990 as part of the Pawtucket Heart Health Program. We measured C-reactive protein (CRP) and Vascular Endothelial Growth Factor (VEGF) levels from stored sera for a random sample of the parent cohort and all cases of cardiovascular death observed through 2005 . We evaluated potential confounding using stratified analyses and logistic regression modeling.Optimistic ratings of risk associated with lower odds of dying from cardiovascular causes among men . Neither CRP nor VEGF confounded these findings.The strong cardio-protective association between optimistic ratings of cardiovascular disease risk and lower rates of cardiovascular mortality among men is not confounded by baseline biomarkers of systemic inflammation or endothelial dysfunction. Risk perceptions are plausibly influenced by psychological conditions that influence inflammatory status and endothelial reactivity. Since biomarkers of systemic inflammation (C-reactive protein) and endothelial dysregulation also predict CVD events [Considering plausible causal mechanisms D events -16, thesD events .We conducted a case-cohort study nested within a community-based sample of men from southeastern New England (USA). A case-cohort study is an efficient epidemiologic design similar to a case-control study, except that the control group is chosen without regard to the outcome (i.e. a random sample of the base population), thus allowing comparison to multiple \"case\" groups . This strategy averts the time and financial cost of analyzing frozen sera from a full cohort.All participants completed household interviews between 1990 and 1993. Serum samples were obtained during household interviews and frozen per standard protocol. Death record information was obtained from the National Death Index through December 2005 to identify cases. In depth description of this nested case-cohort study and the All participants were enrolled during the post-intervention period of the Pawtucket Heart Health Program (PHHP), a controlled community intervention designed to lower prevalence of CVD risk factors . One thoParticipants were asked at the beginning of the household interview, \"Compared with persons of your own age and sex, how would you rate your risk of having a heart attack or stroke within the next 5 years?\" Participants rated their CVD risk as \"high\", \"average\", \"low\", or \"don't know\". Endorsing one's risk to be lower than average we refer to as an optimistic rating.We obtained the date of death and underlying cause of death by linking personal identifiers for each participant to the Center for Disease Control National Death Index (NDI) for the years 1990-2005. Linkage and cause of death were established using NDI-standardized protocols. Cases were those participants whose primary or contributing cause of death was due to cardiovascular disease, as defined by International Classification of Disease (ICD) codes for coronary heart disease or stroke .Using thawed sera, the concentrations of CRP and VEGF were measured using immunoturbidimetric and ELISA assays, respectively. Prior epidemiologic research has verified the validity of these samples and measurement procedures .st degree family history of early-onset coronary heart disease, current use of lipid or blood pressure lowering medications, current aspirin use, physical inactivity, alcohol, and psychotropic medications.We considered the following as potential confounders or effect measure modifiers of the association between comparably optimistic self-rated CVD risk and CVD mortality: CRP, VEGF, age, race/ethnicity, income, education, foreign birth, city, Framingham Risk Score, total/HDL cholesterol ratio, hypertension, smoking status, body mass index, 1We evaluated the frequency and distribution of key study variables. For univariate comparisons shown in Table Since more elaborate adjustment for potential social, biologic and behavioral confounders for all statistical analyses. Where p-values are reported, we used a statistical significance threshold of 0.05.The institutional research review boards at Memorial Hospital of Rhode Island and the University of Rochester School of Medicine and Dentistry approved this study.i.e. optimistic ratings). Forty-four participants died of cardiovascular causes during the 15-year surveillance period. Higher levels of CRP and VEGF were associated with higher risk of CVD mortality and CRP for comparative optimists compared to others were small and statistically insignificant.Thirty one percent of the participants endorsed their risk of having a cardiovascular event in the next five years as lower than average for their age and sex . Adjusting for CRP alone, VEGF alone, or in combination with age, income and Framingham Risk Score did not substantially change these findings [see Table i.e. inflammation and endothelial dysregulation) would confound these provocative observations. We observed that controlling for baseline CRP and VEGF did not weaken the protective association between optimistic ratings of CVD risk and CVD mortality.Following previous findings of an independent association between optimistic perceptions of CVD risk and substantially lower rates of CVD mortality among men, we evaluated whether biomarkers of stress that will shape our society's understanding of cardiovascular risk.CRP: C-reactive protein; VEGF: vascular endothelial growth factor; ICD: International Classification of Disease; NDI: National Death IndexThe authors declare that they have no competing interests.All authors participated in the interpretation of these findings, contributed substantively to the writing of this manuscript and approved this submission. RG, MR, and CB participated in data collection and initial analyses. WK, LZ, and KH participated in subsequent revised analyses."} +{"text": "The present study set out to evaluate perceptions of risk, psychological morbidity and health behaviours in women with a family history of breast cancer who have attended genetic counselling and determine how these differ from general population risk women. Data were collected from 62 genetic counselees (cases) attending the Royal Marsden and Mayday University Hospital genetic counselling services and 62 matched GP attenders (controls). Levels of general psychological morbidity were found to be similar between cases and controls; however, cases reported significantly higher breast cancer-specific distress despite clinic attendance . Although cases perceived themselves to be more susceptible to breast cancer, many women failed correctly to recall risk figures provided by the clinic; 66% could not accurately recall their own lifetime chance. Clinics appeared to have a positive impact on preventive behaviours and cases tended to engage more regularly in breast self-examination , although few differences were found between groups in terms of health beliefs. We conclude that counselees and GP controls showed considerable similarities on many of the outcome measures, and risk of breast cancer was not predictive of greater psychological morbidity; although cases were more vulnerable to cancer-specific distress. Despite genetic counselling, many cases continued to perceive their risk of breast cancer inaccurately."} +{"text": "Previous investigators have noted that certain ovarian cancer cell lines secrete and respond to transforming growth factor-alpha , suggesting that endogenous activation of the epidermal growth factor (EGF) receptor through autocrine or paracrine mechanisms might contribute to the proliferative response. In order to determine whether autocrine stimulation was partly responsible for the proliferative response in ovarian cancer, we investigated whether the EGF receptor expressed by ovarian cancer cell lines was constitutively activated as assessed by the presence of tyrosine phosphorylation. A specific anti-phosphotyrosine antibody was used in conjunction with an immunoblotting technique in order to detect EGF receptor phosphorylation in ovarian cancer cell lines in the absence and presence of exogenous EGF. The effects of neutralising anti-EGF receptor antibody on the proliferation of ovarian cancer cell lines was also examined. We found no evidence for constitutive tyrosine phosphorylation of the p170 EGF receptor in eight epithelial ovarian cancer cell lines tested, although each line demonstrated inducible phosphorylation in response to exogenous EGF. The absence of constitutive EGF receptor activation was also noted when cells were grown under high density conditions, thus excluding a role for membrane-bound EGF or TGF-alpha in this process. Media conditioned by five ovarian cancer cell lines, as well as malignant ascites obtained from 12 different ovarian cancer patients, were not capable of stimulating EGF receptor phosphorylation. Finally, the proliferation of ovarian cancer cell lines was not significantly inhibited in the presence of neutralising anti-EGF receptor antibody. These data suggest that EGF receptor activation through autocrine pathways is not a major mechanism for the growth of many ovarian cancer cell lines. Other pathways of signal transduction which bypass the requirement for EGF receptor activation may be important in the proliferation for ovarian cancer cells. Such EGF receptor-independent pathways may limit the effectiveness of strategies designed to inhibit ovarian cancer cell growth through disruption of EGF receptor function."} +{"text": "Tubularized incised plate repair is based on an old principle of urethral plate tubularization, also known as the Thiersch-Duplay procedure. Although a good concept, its main drawback was the limitation imposed by the width of the urethral plate. Snodgrass popularized the concept of urethral plate incision with subsequent tubularization and secondary dorsal healing for primary hypospadias repair. This relatively simple yet elegant and effective procedure has gained widespread acceptance, currently being recognized as the surgical technique of choice for distal and other types of hypospadias repair.\u20103 In theDecision making in hypospadias repair is no longer determined by meatal location, as in the past, but by severity of penile curvature and appearance of the incised urethral plate. Severe curvature, requiring plate transection or an \"unhealthy\" incised plate are uncommonly encountered.A treatment Algorithm must consider the following:Differentiation between functionally necessary and aesthetically feasible operative proceduresEstablishing therapeutic objectivesPre-operative hormonal treatmentAge at surgeryPenile curvaturePreservation of the well-vascularised urethral plateRe-do hypospadias repairsUrethral reconstructionUrine drainage and wound dressingAdolescent satisfaction with penis sizeRate of fistula formationThe second thing is the rate of fistulae. Although it is comparable to the literature, they do not favour use of a two-layer coverage and deny that Snodgrass has recommended two-layer neourethra closure to decrease fistula formation in all types of hypospadias defects. Several factors may influence fistula formation, such as surgical technique, delicate tissue handling, patient age, type of hypospadias defect, surgeon's experience, water-proof urethroplasty coverage and concomitant foreskin reconstruction.The meatal stenosis rate varies from 0 to 17%, and Snodgrass has reported meatal stenosis rates below 1%. This has been a controversial topic and considered to be possibly related to the surgical technique. In the present study, meatal stenosis was high (8.8%), with no explanation for this high rate."} +{"text": "The presence or absence of venousinvasion did not influence lymph node metastasis. Laparoscopic surgery involving lymph nodedissection should be indicated for sm1 carcinoma lesions with unfavorable histological factors.In lesions diagnosed as sm2 or sm3 prior to resection, intestinal resection involving lymph nodedissection by laparoscopic surgery should be directly performed without endoscopic resection.We investigated the relationship between histological factors and lymph node metastasis in77 lesions with submucosally invasive colorectal carcinomas to establish useful criteria forlesions in which endoscopic treatment alone results in cure of malignancy. There were positivecorrelations between histological factors, including the level of invasion, the histologic grade,presence or absence of lymphatic invasion, presence or absence of budding, and lymph nodemetastasis or II (moderately-differentiated), andthe absence of lymphatic invasion and budding, endoscopic treatment alone is sufficient."} +{"text": "Major heart diseases such as ischemia and hypertrophic myocardiopathy are accompanied with significant changes in the passive mechanical properties and active contractility of myocardium. Identification of these changes helps diagnose heart diseases, monitor therapy, and design surgery. A dynamic cardiac elastography (DCE) framework is developed to assess the anisotropic viscoelastic passive properties and active contractility of myocardial tissues, based on the chamber pressure and dynamic displacement measured with cardiac imaging techniques. A dynamic adjoint method is derived to enhance the numerical efficiency and stability of DCE. Model-based simulations are conducted using a numerical left ventricle (LV) phantom with an ischemic region. The passive material parameters of normal and ischemic tissues are identified during LV rapid/reduced filling and artery contraction, and those of active contractility are quantified during isovolumetric contraction and rapid/reduced ejection. It is found that quasistatic simplification in the previous cardiac elastography studies may yield inaccurate material parameters."} +{"text": "Experiments were conducted to determine whether the histological pattern of tumour growth of hormone-responsive MCF-7 human mammary adenocarcinoma varied in different tissues of athymic mice. Tumours in the uterus following intrauterine injection were rapidly proliferating and highly invasive. Tumours injected intracerebrally were also highly invasive. In contrast, s.c. tumours and those which arose in the lung following intrapleural injection, grew as small localized nodules without evidence of aggressive invasion of surrounding tissues. These findings indicate that selective implantation of human tumours in athymic mice can be used to develop different models of tumour growth and aggressiveness."} +{"text": "Borna disease virus, a newly classified nonsegmented negative-strand RNA virus with international distribution, infects a broad range of warm-blooded animals from birds to primates. Infection causes movement and behavioral disturbances reminiscent of some neuropsychiatric syndromes. The virus has not been clearly linked to any human disease; however, an association between infection with the virus and selected neuropsychiatric disorders has been suggested. We reviewed recent advances in Borna disease virus research, focusing on evidence of infection in humans."} +{"text": "DNA fingerprinting has demonstrated predominance of the Beijing genotype among Mycobacterium tuberculosis strains isolated in Southeast Asia. We prospectively examined the occurrence of Beijing genotype strains in tuberculosis patients in Indonesia. Early in treatment, patients infected with Beijing genotype strains more often had fever unrelated to disease severity, toxicity, or drug resistance, indicating that Beijing genotype strains may have specific pathogenic properties."} +{"text": "Metabolite ratios (phosphocreatine (PCr)/beta nucleoside triphosphate (beta NTP), PCr/Pi, beta NTP/Pi) calculated from the NMR spectra were compared with ratios obtained from acid extracts of tumours of similar size. Measurements of creatine and ADP were also made. Three of the tumours showed positive correlations between increasing tumour size and decreasing metabolite ratios measured both by NMR and in extracts, whereas the Walker carcinosarcoma showed no correlation between size and any parameters measured. Phosphorus metabolite ratios, measured in extracts of skin overlying the tumours, indicated a fall in high energy phosphate when there was histological evidence of skin invasion by the tumour. Surface coil 31P-NMR spectra of subcutaneously grown or induced tumours in the rat represent a slowly changing steady state as the tumour increases in size. We conclude that increasing numbers of hypoxic tumour cells, rather than large areas of necrotic tissue, contribute largely to the NMR spectrum."} +{"text": "Twelve mongrel dogs were randomly allocated into two groups using matched paired-design. Catheterswere inserted into the hepatic artery, hepatic vein and the femoral vein, respectively. In the first group,gelfoam supplemented with mitomycin C (MMC) was injected into the hepatic artery, whereas thesecond group received a hepatic arterial injection of MMC solution alone. Simultaneous blood samplingfrom the hepatic and femoral veins at regular intervals was performed. MMC concentrations in plasmawas determined using high performance liquid chromatography (HPLC) and the pharmacokinetics ofMMC were determined.MMC concentrations in hepatic and femoral veins did not differ and no significant difference inpharmacokinetics was found when comparing MMC administration into the hepatic artery with orwithout gelfoam supplementation. Thus, our results revealed that gelfoam could not delay the clearanceof MMC from the liver."} +{"text": "It was demonstrated previously that mice undergoing an inflammatory reaction induced by subcutaneous (SC) implantation of copper rods, produce humoral factors that initially enhance, but subsequently inhibit, diffusion chamber (DC) granulopoiesis. This provided evidence that granulopoiesis is under the control of both humoral stimulators and inhibitors. In order to test the granulopoietic regulatory mechanism in leukaemic mice, we investigated the regulatory role of granulopoietic humoral inhibitors during in vivo granulopoiesis. We noticed that mice suffering from acute myeloid leukaemia (AML) are unable to augment the production of these humoral inhibitory factors when acute inflammation is induced, since no change in DC cell content was observed with or without prior inflammation. Moreover, unlike healthy mice, the serum of leukaemic mice withdrawn during the inhibition phase of acute inflammation did not show any inhibitory activity toward granulocyte\u2014monocyte (GM) colony growth in vitro. Our results also show that increased levels of normal humoral inhibitors do not influence the proliferation and/or differentiation of leukaemic cells implanted in diffusion chamber cultures."} +{"text": "The major histocompatibility complex (MHC) class II is involved both in thymocyte maturationand peptide presentation and might thus play a key role in the pathogenesis of paraneoplasticmyasthenia gravis (MG) in thymomas. To further investigate this issue, we analyzedand scored the expression of epithelial class II expression in 35 thymomas and correlatedit with the histological tumor subtype, prevalence of MG and thymocyte maturation, whichwas analyzed by flow cytometry and RT-PCR. Our results show that both MHC class IIexpression and thymocyte maturation are highly dependent on the histological tumor subtype.CT / WDTC retain features of the normal outer thymic cortex, namely substantial MHC classII expression together with normal early thymocyte maturation until late phases of positiveselection, but disturbed terminal thymopoiesis. By contrast, MDT and MXT retain features ofthe normal inner cortex and the medulla with low to absent class II expression and highlyabnormal early thymocyte maturation including impaired positive selection, while terminal Tcell maturation in MXT appeared undisturbed. There was no correlation between MHC classII expression and MG status for a given tumor subtype. In conclusion, our results provide evidencefor a different histogenesis of cortical thymomas and well differentiated carcinomas onthe one hand and mixed and medullary thymomas on the other.Decreased expression levels of MHC class II, although of crucial importance for abnormalintratumorous maturation, are not sufficient to explain the emergence of paraneoplastic MG."} +{"text": "The total N-acetyl neuraminic acid (NANA) content of lymphocytes, erythrocytes and plasma obtained from normal and lymphatic leukaemic patients was measured by the Warren thiobarbiturate technique. Lymphocytes from patients with chronic lymphatic leukaemia and lymphoblasts from patients with acute leukaemia had decreased levels."} +{"text": "Miniature spectrometers incorporating array detectors are becoming a viable, low-cost option for field and process deployments. The performance characteristics of one such instrument are reported and compared with those of a conventional benchtop instrument. The parameters investigated were wavelength repeatability, photometric linearity, instrumental noise (photometric precision) and instrumental drift."} +{"text": "Background: Resection of hepatocellular carcinoma is associated with high rates of morbidity and mortality. Since intensive nutritional support can reduce the catabolic response and improve protein synthesis and liver regeneration, we performed a prospective study to investigate whether perioperative nutritional support could improve outcome in patients undergoing hepatectomy for hepatocellular carcinoma. Methods: We studied 124 patients undergoing resection of hepatocellular carcinoma. Sixty-four patients were randomly assigned to receive perioperative intravenous nutritional support in addition to their oral diet, and 60 patients were randomly assigned to a control group. The perioperative nutritional therapy consisted of a solution enriched with 35 percent branched chain amino acids, dextrose, and lipid emulsion (50 percent medium-chain trigylcerides) given intravenously for 14 days perioperatively). Results: There was a reduction in the overall postoperative morbidity rate in the perioperative-nutrition group as compared with the control group , predominantly because of fewer septic complications . There were also a reduction in the requirement for diuretic agents to control ascites , less weight loss after hepatectomy , and less deterioration of liver function as measured by the change in the rate of clearance of indocyanine green . These benefits were seen predominantly in the patients with underlying cirrhosis who underwent major hepatechtomy. There were five deaths during hospitalization in the perioperativenutrition group, and nine in the control group (P not significant). Conclusions: Perioperative nutritional support can reduce complications after major hepatectomy for hepatocellular carcinoma associated with cirrhosis."} +{"text": "Two proprietary semi-permanent hair dyes were tested for carcinogenicity in A and DBAf mice by repeated topical applications in aqueous acetone. Mice of both strains developed lymphoid tumours but experimental differences were marked only in DBAf mice. A number of tumours of the ovary and uterus, and some skin papillomas near the penis, occured in dye-treated but not in control DBAf mice. As many hair-dye constituents are known mutagens, adequate carcinogenicity testing of these substances, and epidemiological study of exposed human populations, are needed for evaluating possible health hazard from hair dyeing."} +{"text": "Streptococcus pneumoniae is a major cause of acute otitis media, pneumonia, bacteremia, and meningitis. Because in recent years antibiotic-resistant pneumococcal strains have been emerging throughout the world, vaccination against pneumococcal infections has become more urgent. The capsular polysaccharide vaccine that has been available is neither immunogenic nor protective in young children and other immunocompromised patients. Several pneumococcal proteins have been proposed as candidate vaccines, but no human studies associated with them have been reported. Clinical trials of first-generation pneumococcal conjugate vaccines have shown that covalent coupling of pneumococcal capsular polysaccharides to protein carriers improves the immunogenicity of the polysaccharides. The protective efficacy of the conjugate vaccines against carriage, acute otitis media, and invasive infections is being studied."} +{"text": "In patient tumour samples the activity in vitro of Taxol corresponded fairly well to the known clinical activity and Taxol showed low cross-resistance to standard cytotoxic drugs. However, the Taxol solvent Cremophor EL--ethanol was considerably active alone, whereas paclitaxel formulated in ethanol was less active. Taxol thus seems to contain two components active against patient tumour cells in vitro."} +{"text": "In accordance with the suggested adenoma\u2013carcinoma sequence of the colon, four patients reflected the progressive accumulation of genetic defects in synchronously appearing tumours during carcinogenesis. However, two patients with non-hereditary malignomas presented different genetic instabilities in different but synchronously appearing tumours suggesting non-clonal growth under almost identical conditions of the environment. Thus, sporadically manifesting multiple lesions of the colon were not necessarily driven by similar genetic mechanisms. Premalignant lesions may transform into malignant tumours starting from different types of genetic instability, which indicates independent and simultaneous tumorigenesis within the same organ. \u00a9 2000 Cancer Research CampaignThe colorectal adenoma\u2013carcinoma sequence represents a well-known paradigm for the sequential development of cancer driven by the accumulation of genomic defects. Although the colorectal adenoma\u2013carcinoma sequence is well investigated, studies about tumours of different dignity co-existent in the same patient are seldom. In order to address the distribution of genetic alterations in different lesions of the same patient, we coincidently investigated carcinomas, adenomas and aberrant crypt foci in patients with sporadic colon cancer. By utilizing polymerase chain reaction, single-strand conformation polymorphism, heteroduplex-analysis, restriction fragment length polymorphism, protein truncation test and sequencing techniques we looked for mutations and microsatellite instability of APC, H-"} +{"text": "Human ovarian carcinoma cells obtained from ascites were tested for susceptibility to lysis by peripheral blood NK cells, alpha-interferon-activated NK cells, and interleukin 2-activated killer cells. Cryopreserved tumour cell preparations were used to allow repeated testing of the same target, and the tumour cells were fractionated using albumin density gradients to determine if fractions containing clonogenic (stem) cells were killed. Four tumour cell donors were studied and each showed a different pattern of susceptibility of unfractionated tumour to lysis by different effector cells. Using fractionated tumour cells, we found that NK and interferon-activated NK cells did not always lyse cells in the clonogenic fractions and that interferon activation could in some cases shift killing away from the clonogenic fractions and towards the peak of proliferating (but not self-renewing) colony forming cells. Interleukin 2-activated killer cells (LAK) however, killed the fractions containing clonogenic cells in all 4 cases. The magnitude of killing seen when fractions of the original tumour were tested were often striking when compared to lysis of the unfractionated cells. Apparent heterogeneity between patients and stem cell susceptibility to effector cells may be important determinants of the efficacy of treatment of patients with biologic response modifiers such as interferon and interleukin 2."} +{"text": "Damage of laryngeal mask airway and other supraglottic airway devices has always been a matter of concern. Although manufacturer recommends maximum 40 uses of LMA (and its congeners) but damage before 40 uses needs to be evaluated. We hereby, describe a novel method of repair of supraglottic devices when damage occurs at mask inflation line or pilot balloon valve assembly. Various supraglottic airway devices like laryngeal mask airway (LMA), Proseal LMA, laryngeal tube etc. are novel innovative devices for upper airway management.Laryngeal mask airway and its variants are most often used in elective surgical procedures, emergency difficult airway management and in fields or camp surgeries. The currently manufactured model is made of silicone rubber and needs special care for its longitivity . The devBiting of airway tube or LMA damage often occurs at cuff portion or airway tube shaft. The junction where airway tube is attached to the cuff may break while inserting laryngeal cuff in oral cavity and this may cause an irreparable loss of the equipment. The mask inflation line or valve assembly of supraglottic airway devices like LMA (and its congeners ) etc. can also damage while handling, washing or cleaning of expensive equipment. We hereby, recommend novel indigenous method of securing various supraglottic airways when damaged at mask inflation line or valve assembly.LMA and its variants contain mainly 4 parts- cuff, connector, airway tube and mask inflation line to the mask inflation line.The steps of repairing the supraglottic devices (LMA or its congeners) are as follows:1. Expose and clear the damaged part of pilot balloon assembly Fig. 2. Attach mask inflation line to 'Threeway Stopcock and closed leur access split septum port' assembly by inserting inflation line (teared end) inside End A of Threeway stopcock)Fig. .3. End B of Threeway stopcock is attached to closed leur access split septum port4. Completely repaired LMA assembly is ready in 1981, it has been successfully used as a ventilatory device in both predicted and unpredicted difficult airway. In certain situations, such as cardiac arrest, there is no time to predict and/or act on the prediction of a difficult airway and supraglottic airway devices act as rescue airway management devices . The othDuring training period of residents, the probability of tearing of mask inflation line of any supraglottic devices is very high and consequently it leads to irrepairable loss of equipment. Further, the mask inflation line may get damaged during extubation phase and this can occur most often in patients with surgeries in psychiatric patients. In situations like cardiac arrest or unanticipated difficult airway if SAD is damaged from inflation line or valve assembly then it may create panic in anaesthesiologist's mind.The present supraglottic equipment repairing technique is a novel indigenous method and can be useful for anaesthesiologists working in developing countries and working in fields/camps. This repairing can also be utilized in cases of patients with trauma and in emergency airway management when LMA or such expansive equipments may damage. This indigenous method can be applicable to expansive equipments like LMA proseal, LMA C-trach, Laryngeal Tube, Laryngeal Tube Suction, ILMA, ETT of ILMA etc. and the cost-effectiveness of equipment can be maintained by this simple, cheap and easier repair technique."} +{"text": "Multiple sclerosis (MS) is a central nervous system disease in which activated autoreactive T-cells invade the blood brain barrier and initiate an inflammatory response that leads to myelin destruction and axonal loss. The etiology of MS, as well as the mechanisms associated with its unexpected onset, the unpredictable clinical course spanning decades, and the different rates of progression leading to disability over time, remains an enigma. We have applied gene expression microarrays technology in peripheral blood mononuclear cells (PBMC) to better understand MS pathogenesis and better target treatment approaches. A signature of 535 genes were found to distinguish immunomodulatory treatment effects between 13 treated and 13 untreated MS patients. In addition, the expression pattern of 1109 gene transcripts that were previously reported to significantly differentiate between MS patients and healthy subjects were further analyzed to study the effect of cytokine-related pathways on disease pathogenesis. When relative gene expression for 26 MS patients was compared to 18 healthy controls, 30 genes related to various cytokine-associated pathways were identified. These genes belong to a variety of families such as interleukins, small inducible cytokine subfamily and tumor necrosis factor ligand and receptor. Further analysis disclosed seven cytokine-associated genes within the immunomodulatory treatment signature, and two cytokine-associated genes SCYA4 and FCAR that were common to both the MS gene expression signature and the immunomodulatory treatment gene expression signature. Our results indicate that cytokine-associated genes are involved in various pathogenic pathways in MS and also related to immunomodulatory treatment effects."} +{"text": "Most lumbar artificial discs are still composed of stainless steel alloys, which prevents adequate postoperative diagnostic imaging of the operated region when using magnetic resonance imaging (MRI). Thus patients with postoperative radicular symptoms or claudication after stainless steel implants often require alternative diagnostic procedures.Possible complications of lumbar total disc replacement (TDR) are reviewed from the available literature and imaging recommendations given with regard to implant type. Two illustrative cases are presented in figures.Access-related complications, infections, implant wear, loosening or fracture, polyethylene inlay dislodgement, facet joint hypertrophy, central stenosis, and ankylosis of the operated segment can be visualised both in titanium and stainless steel implants, but require different imaging modalities due to magnetic artifacts in MRI.Alternative radiographic procedures should be considered when evaluating patients following TDR. Postoperative complications following lumbar TDR including spinal stenosis causing radiculopathy and implant loosening can be visualised by myelography and radionucleotide techniques as an adjunct to plain film radiographs. Even in the presence of massive stainless steel TDR implants lumbar radicular stenosis and implant loosening can be visualised if myelography and radionuclide techniques are applied. Total disc replacement (TDR) is an evolving surgical option for patients with degenerative disc disease ,2. The aIt is widely accepted that lumbar disc arthroplasty is associated with several access- and implant-associated complications. Unfortunately imaging modalities after TDR cannot simply be transferred from fusion patients. In this review the complications following total disc replacement are discussed and guidelines for imaging following lumbar disc arthroplasty are provided.All commercially available lumbar artifical discs are composed of a stainless steel core with titanium surfacing Table . This haMyelography alone and later combined with CT has for many years been the primary diagnostic means in suspected lumbar spinal stenosis. Myelographic findings in central canal stenosis include complete or partial block to the contrast column, appearing as an hour-glass constriction on the AP view. There appears to be poor correlation between clinical symptoms and findings at myelography, with myelography commonly showing more abnormalities than would be expected ,7, althoScintigraphy with 99mTc radionuclide tagged white blood cells can be a helpful means in diagnosing suspicious infections . 99mTc-HPostoperative low-grade-infection or implant loosening can be hard to visualise. As in hip or knee arthroplasty radionuclide scintigraphy has some value with regard to sensitivity, but has lower specificity with regard to loosening or low-grade infection. Gallium 67 scans have a sensitivity and specificity of 89% and 85% .In the last years the increased availability of positron emission tomography (PET) enabled postoperative diagnostics with greater specificity for infection. Gratz et al found flDespite the biomechanically appealing concept of motion preservation, lumbar disc arthroplasty is associated with access-related and implant-specific complications. Access and implant related complications can be due to technical errors or may be due to abnormal anatomy . ImplantAll commercially available FDA-approved lumbar total disc replacements require an anterior access for the implantation of artificial discs. Lumbar discs can be implanted via a transperitoneal or a retroperitoneal approach, of which the latter is favoured by most surgeons. Complications with regard to these accesses are well known and differ not from those of anterior fusion, even though TDR-implantation requires a wider exposure of the disc, which often requires more traction and pressure of retractors on the surrounding tissue . EspeciaMost access-related complications can be visualised by sonography and abdominal CT with intravenous contrast. In few cases an angiography or an uretherography may be necessary.There is no specific data on the occurrence of infection of artificial discs, but early and mid-term infections may occur as likely as in anterior fusion with 0 and 12% in lumbar instrumented fusion . NeverthPostoperative infections of the spine can optimally be visualised by MR with contrast. A sensitivity and specificity of 93% and 97% makes the MRI superior to all other radiological imaging modalities . If MRI-Daly et al presented a case series of five anterior dislocations of the Charit\u00e9 (Link) or the AcroDisc (DePuy) disc prosthesis causing compression and erosion of vascular structures. In figure Mobile polyethylene cores can dislocate, too, and can cause compression to anterior abdominal or pelvic structures. This is especially true in non-constrained PE inlays (i.e. Charit\u00e9 TDR) Mathew et al presenteImplant dislocation can easily be diagnosed with plain radiographs figure . This isThe long-term investigation of the first implanted lumbar discs by Putzier et al includedImplant fractures are mostly visible on plain radiographs.Since implant wear has for decades been a major issue in hip and knee-arthroplasty it is not surprising that other weight-bearing implants with articulating surfaces \u2013 as in lumbar disc prostheses \u2013 will have to deal with implant wear and loosening, too. Punt et al retrieveMetal-metal articulations are known to cause metallosis with chronic inflammation leading to implant loosening . Fran\u00e7oiDiagnostics of implant loosening range from standard plain radiographs \u2013 revealing radiolucencies around the implant \u2013 to scintigraphy and PET, showing increased metabolism in the bone-implant interface.The case in figure MR diagnostics are the gold-standard for investigation of spinal canal pathologies. In cases where this is not possible \u2013 i.e. stainless steel TDR \u2013 other modalities as CT and myelography have to be considered.Bendo et al found thTo control implant positioning plain radiographs are usually sufficient.Long-term investigations failed to present preservation of motion of the operated segment. Putzier et al found thTo diagnose fusion either a CT-scan showing ankylosis or dynamic radiographs excluding remaining segmental mobility are required.In osteoporosis or poor bone quality, years after the original implantation, the artificial disc can subside into the endplates, causing secondary implant dislocation and increasing pain. To avoid this complication the choice of the largest possible implant and a placement close to the rim of the endplates is recommended .To visualise implant subsidence plain radiographs are sufficient. If an osteoporotic vertebral endplate fracture is suspected, radionuclide scans may show increased uptake of the fractured vertebra.Postoperative imaging of lumbar total disc replacement requires alternative imaging techniques to conventional MRI-diagnostics. All currently available lumbar artificial discs contain stainless steel alloys, and, therefore, generate major artefacts on MRI. Alternative imaging modalities include plain film radiographs, myelography and radionucleotide imaging. These imaging modalities should be utilised in cases with suspected postoperative complications after lumbar TDR.The appearance of artificial discs on the implant market meant a drawback in postoperative radiological transparency with regard to MR-diagnostics, since all lumbar disc prostheses are still based on stainless steel alloys, thus causing major artefacts. Other imaging modalities are available and are in the first line of choice in cases with suspected postoperative complications after lumbar TDR. Until lumbar titanium artificial discs are available postoperative imaging of the operated segment requires altered radiological strategies.The authors have no competing interests with regard to the publication of this manuscript.YR wrote the manuscript and BS critically revised it. Both authors read and approved the final version of the manuscript"} +{"text": "Serum bone alkaline phosphatase (BALP), serum carboxy-terminal propeptide of type I procollagen (PICP) and serum bone gla protein (BGP) as markers of bone formation, serum carboxy-terminal telopeptide of type I collagen (ICTP) as a marker of collagen resorption and fasting molar ratio of urinary calcium to creatinine (CaCr) and serum parathyroid hormone (PTH) were determined in two groups of cancer patients: 48 with advanced or metastatic disease with negative bone scan and 174 with bone metastases categorised as having lytic, mixed or blastic lesions and with more or fewer than or equal to three sites involved. In patients without apparent bone involvement, bone formation markers were rarely elevated. Conversely, serum ICTP was frequently found to be supranormal, showing it to be a non-specific marker for early detection of bone metastases. As expected, values of bone formation markers progressively increased in patients with lytic, mixed and blastic lesions, but ICTP levels did not show any differences according to the types of bone appearances, confirming previous reports of elevated osteoclast activity also in patients with apparent blastic lesions. Serum PTH increased significantly in patients with lytic compared with patients with mixed and blastic appearances, paralleling the bone formation markers, but CaCr showed the opposite pattern. These data are compatible with calcium entrapment in the bone in patients with increased osteoblast activity. This so called 'bone hunger syndrome' is further confirmed by the finding that in the subgroup of blastic appearances CaCr diminished whereas both ICTP and PTH increased according to the extent of tumour load in the bone."} +{"text": "Epidemiologic and pathologic features of prostate cancer have given rise to an interestin focal treatment for carefully selected patients. Prostate cancer remains highlyprevalent, particularly in the U.S. and Europe. As screening programs have become moreaggressive and widespread, a substantial proportion of men diagnosed with localizedprostate cancer have disease characteristics associated with a low risk of progression. Treatments such as radical prostatectomy and radiation therapy can lead to durable recurrence-free survival in most patients, but carry variable risks of bowel, urinary, andsexual side effects. Few men and few urologists are comfortable leaving a potentiallycurable prostate cancer untreated. Focal therapy offers an attractive alternative for thepatient faced with a choice between aggressive local intervention (radiation or surgery)and watchful waiting. Contemporary diagnostic biopsy strategies and imaging tools, andthe development of predictive statistical models (nomograms), have led to improvementsin tumor characterization and risk stratification, making focal therapy a viable treatmentoption for specific men. This article reviews the rationale and indications for focaltherapy and highlights vascular-targeted photodynamic therapy (PDT) as one of manypromising focal therapy techniques."} +{"text": "Accurate amino acid insertion during peptide elongation requires tRNAs loaded by cognate amino acids and that anticodons match codons. However, tRNA misloading does not necessarily cause misinsertions: misinsertion is avoided when anticodons mismatch codons coding for misloaded amino acids.Occasional compensation of misacylation by codon-anticodon mismatch necessarily occurs. Putatively, occasional error compensation may be enhanced beyond the random combination of independent errors in tRNA loading and codon-anticodon interactions: tRNA misacylation might alter potentials for codon-anticodon mismatches, perhaps specifically increasing potentials for mismatching those codons coding for the misacylated non-cognate amino acid. This hypothetical phenomenon is called 'error coordination', in distinction from 'error compensation' that assumes independence between misacylation and mismatch.Eventually, the hypothesis should be tested for each combination of amino acid misacylation and codon-anticodon mismatch, by comparing stabilities or frequencies of mismatched codon-anticodon duplexes formed by tRNAs loaded by their cognate amino acid with stabilities formed by that tRNA when misloaded with the amino acid coded by the mismatched codon. Competitive mismatching experiments between misloaded and correctly loaded tRNAs could also be useful, yet more sophisticated experiments.Detecting error coordination implies estimating error compensation, which also promotes protein synthesis accuracy. Hence even in the absence of evidence for error coordination, experiments would yield very useful insights into misacylation and mismatch processes. In case experiments consider post-transcriptional RNA modifications , results on codon-anticodon mismatches would enable significant improvements and sophistications of secondary structure prediction softwares. Positive results would show that protein translation enhances accuracies of products, not of single steps in the production. Ancient translational machineries putatively optimized error coordination, especially before tRNA editing by tRNA synthetases evolved: few primitive, but functionally versatile tRNA species perhaps executed low accuracy translation. Systems artificially designed/selected for low complexity and high efficiency could make use of this property for anticodons with high levels of error compensation and coordination. The two major groups of tRNA synthetases, class I and II, seem to minimize impacts of misinserted amino acids in protein sequences by tRNAs that were misloaded by these tRNA synthetases ,2. AccurDespite editing, misinsertion sometimes occurs. However, misinsertion is avoided if the misloaded tRNA's anticodon mismatches a codon coding for the misloaded amino acid, a phenomenon potentially meaningful for organisms. If mismatch is unaffected by misacylation, combinatorial probabilities predict their joint occurrence. This phenomenon is called here error compensation. The hypothesis suggested here is that misacylation affects mismatch potentials and hence joint occurrences of misacylations and mismatches do not match combinatorial probabilities, called error coordination. Error compensation is an unavoidable phenomenon whose potential effects are explored elsewhere. Here I focus on error coordination, which is a more readily testable phenomenon because it can be compared to a null hypothesis, that defined by error compensation, hence its detection implies estimating error compensation.The tRNA's acceptor stem and the anticodon are not adjacent. Hence properties of amino acids may have little impact on anticodon potentials for interactions with codons. It is nevertheless plausible that such effects exist, even if subtle. These may be larger when the tRNA molecule has relatively low molecular weight , and/or is relatively small. Sometimes, small tRNA-like molecules might transfer amino acids, as suggested by the observation of aminoacylated RNA corresponding to the mitochondrial light strand replication origin and hypoAnother amino acid property potentially affecting error coordination is its charge. Charge differences between cognate and misloaded amino acid could affect the tRNA's electro-magnetic properties, including of its anticodon. Codon-anticodon interactions depend on electro-magnetic properties of the interacting atoms . Misacylations altering amino acid charges could affect codon-anticodon interactions: positive charges might enhance positive partial dipole moments, decrease negative ones; the opposite would occur for negative charges (aspartic and glutamic acids). These effects would alter codon-anticodon duplex stabilities, including for mismatches. Such effects on anticodons are difficult to predict, because tRNA acceptor stems are not adjacent to anticodons. Charge effects on anticodon interactions may be buffered as well as enhanced by particular RNA sequences connecting amino acid and anticodon. Perhaps RNA rich in pyrimidines (which have high dipole moments) functions as conductor of effects of amino acid charge on anticodons. Softwares predicting dipole moments of proteins exist ,18, hencEscherichia coli and Homo sapiens).Other amino acid properties might also affect codon-anticodon interactions. This suggests that experimental observations on effects of misacylations on mismatches should be made for all combinations of misacylations and codon-anticodon mismatches, because effects of swapping one amino acid with another may be unpredictable, as different amino acid properties may be relevant. As noted above, specific tRNA sequences may also influence. If this is the case, models predicting these influences would be particularly important for predicting error coordination, because tRNA sequences frequently vary between species and individuals, and it is unrealistic that experimental data will be produced for more than a few model species , so as to test for associations between that quantity and its assumed effects on protein metabolism and related phenomena at higher organismic levels . Error compensation is a case where a null hypothesis is in itself biologically interesting, similar to the neutral theory of evolution. Error coordination is more adequate in relation to designing classical manipulative experimental tests. It expects that misacylated tRNAs form more stable (or more frequently) mismatched codon-anticodon duplexes with codons coding for the misloaded amino acid than the same tRNA when it is correctly aminoacylated. This can be tested by comparing results from different, independent experiments. Experiments designed to estimate 'competition' between molecules can also be designed. For example, matching and mismatching codons are put in presence of either correctly or incorrectly loaded tRNAs, and duplex stabilities/frequencies of correctly matched and mismatched anticodons are compared (one way competition between codons). Mixing correctly and incorrectly loaded tRNAs with either matching or mismatching codons would estimate one way competition between correctly and incorrectly loaded tRNAs. Two-way competition could also be considered. Ideally, such experiments should be done for all combinations of codons, anticodons and amino acids.Recent observations suggest that ribosomes select against misacylated tRNAs . Error cPrecisely estimating error coordination would imply producing data that include effects of posttranscriptional tRNA modifications -22, in pError compensation and coordination suggest that accurate translation has probabilistic properties. Design of artificial translational systems might take advantage of error compensation and coordination. Primordial systems at the origins of life perhaps used few versatile, yet accurate tRNAs (or tRNA-like molecules), thanks to high error compensation and coordination. Various editing mechanisms ,26 existThe author declares that he has no competing interests.HS is the sole author of this publication."} +{"text": "The lengthof time the recipient remained euglycemic was used to measurethe ability of the transgenes to protect the graft fromautoimmune destruction. Although the results of these cotransfectionsgave little evidence of a synergistic relationship,they were useful to show that gene combinations can be used to more efficiently protect islet grafts from diabetogenicT cells.Islet transplantation therapy would be applicable to awider range of diabetic patients if donor islet acceptanceand protection were possible without systemic immunosuppressionof the recipient. To this aim, gene transferto isolated donor islets ex vivo is one method that hasshown promise. This study examines the combined effect ofselected immunomodulatory and anti-inflammatory genesknown to extend the functional viability of pancreatic isletgrafts in an autoimmune system. These genes, indoleamine2,3-dioxygenase (IDO), manganese superoxide dismutase(MnSOD), and interleukin (IL)-1 receptor antagonist protein(IRAP), were transferred to isolated NOD donor isletsex vivo then transplanted to NOD"} +{"text": "Xenopus thymustumor-derived lymphoid cell lines undergoing apoptosis and also in apoptotic, nontransformedsplenocytes. Cultured Xenopus tumor lymphoid cells induced to undergo, apoptosis by serumdeprivation or treatment with the calcium ionophore, ionomycin, displayed altered morphologytypical of apoptotic cells, as judged by flow cytometric light-scatter characteristics and byfluorescence microscopy of acridine-orange-stained cells. Flow cytometry of permeabilized cellsand fluorescence microscopy of acetone-fixed cytospins revealed that apoptotic Xenopus tumorcells, especially those displaying loss or condensation of DNA, displayed increased expressionof epitopes recognized by a rabbit polyclonal antibody against ASP. Flow cytometry confirmedthat ASP is also expressed in splenocytes induced to apoptose by culture in ionomycin orfollowing concanavalin A stimulation. No increased expression of ASP was seen when lymphoidtumor cells or splenocytes were induced into necrosis by overdose with the antifungal agentamphotericin B. Western blotting with antibody against ASP identified the emergence of severalprotein bands in cell lysates from apoptotic, but not necrotic, Xenopus tumor cells. The new andsimple methodology for identifying apoptotic cells described here is likely to be of value to thosestudying immune system development and associated programmed cell death in Xenopus.A novel apoptosis-specific protein (ASP) has recently been identified in the cytoplasm ofapoptotic mammalian cells. This paper investigates whether ASP is found in"} +{"text": "Despite previous advances on miRNA regulation of gene expression, little has been investigated from a genome scale.To gain new insight into miRNA regulation in humans, we used large scale data and carried out a series of studies to compare various features of miRNA target genes to that of non-miRNA target genes. We observed significant differences between miRNA and non-miRNA target genes for a number of characteristics, including higher and broader mRNA expression, faster mRNA decay rate, longer protein half-life, and longer gene structures. Based on these features and by analyzing their relationships we found that miRNA target genes, other than having miRNA repression, were most likely under more complex regulation than non-miRNA target genes, which was evidenced by their higher and broader gene expression but longer gene structures. Our results of higher and broader gene expression but fast mRNA decay rates also provide evidence that miRNA dampening of the output of preexisting transcripts facilitates a more rapid and robust transition to new expression programs. This could be achieved by enhancing mRNA degradation through an additive effect from multiple miRNA targeting.Genome-scale analysis on the nature of miRNA target genes has revealed a general mechanism for miRNA regulation of human gene expression. The results of this study also indicate that miRNA target genes, other than having miRNA repression, are under more complex gene regulation than non-miRNA target genes. These findings provide novel insight into miRNA regulation of human gene expression. Caenorhabditis elegans as post-transcriptional regulators of genes involved in developmental timing , were then subjected to the prediction of miRNA binding sites through the RNA22 web server Supplemental Figure 1. Shows the expression differences between non-miRNA and miRNA target genes predicted from TargetScanS and RNA22.Click here for fileSupplemental Figure 2. Shows the expression breadth differences between non-miRNA and miRNA target genes predicted from TargetScanS and RNA22.Click here for fileSupplemental figure 3. Shows the correlation between mRNA expression and decay rate for miRNA target genes predicted from TargetScanS.Click here for fileShows the correlation between mRNA expression and decay rate for miRNA target genes predicted from RNA22.Click here for fileShows the correlation between gene expression and protein stability for miRNA target genes predicted from TargetScanS.Click here for fileShows the correlation between gene expression and protein stability for miRNA target genes predicted from RNA22.Click here for file"} +{"text": "Specialized cells found near the dermal-epidermal junction, characterized by numerous membrane-bound granules with dense cores. The cells were named after German anatomy professor Friedrich Sigmund Merkel, who experimented with osmium tetroxide staining and described these cells in 1875. First identified in the skin of a mole, they were later found in human skin. The cells are responsible for the highly malignant skin tumor known as Merkel cell carcinoma. An infectious cause for Merkel cell carcinoma has been proposed."} +{"text": "A middle aged chronic alcoholic presented with deep jaundice, markedly enlarged and tender spleen with leukoerythroblasticblood picture and bone marrow biopsy showing mild fibrosis. He was tested negative for HIV, hepatitis B and C viruses.Besides very high serum bilirubin, alkaline phosphatase was raised four times the normal value. Contrast enhanced CTshowed enlarged spleen and liver with multiple heterogenous lesions in spleen and tiny hypo-dense lesions in liver. Inhospital, he developed haemolytic uraemic syndrome and succumed to his illness. At autopsy spleen weighed 5200 gms andvariegated in appearance due to large areas of necrosis and whitish tumour nodules. Histology revealed morphology of anangiosarcoma. Liver was also infiltrated by the tumour mainly in and around portal tract areas."} +{"text": "To assess regional systolic function and global contractile function in patients with WPW Syndrome.pRS) or range (difference between maximum and minimum peak RS i.e. RangepRS). Spectral Doppler (continuous wave) measurements were acquired through the left ventricular outflow tract to determine Pre Ejection Period (PEP), Left Ventricular Ejection Time (LVET) and measures of left ventricular systolic performance.Eleven cases with manifest Wolff-Parkinson-White (WPW) syndrome in sinus rhythm were compared to 11 age matched controls. 2D strain analysis was performed and peak segmental radial strain (pRS) values obtained from basal ventricular parasternal short-axis images (70 \u00b1 5 frames/sec) using a dedicated software package. Heterogeneity of radial strain pattern in six circumferential basal left ventricular segments was measured in terms of standard deviations of peak RS and corrected PEP were significantly longer in WPW patients compared to controls. The PEP/LVET ratio was also significantly greater in WPW cohort suggesting global systolic dysfunction.LV segmental radial strain was profoundly heterogeneous in WPW cases in contrast to fairly homogenous strain pattern in normal subjects. Wide SDPatients with manifest preexcitation (predominantly those with right-sided pathways) have regional and global contractile dysfunction resulting from aberrant impulse propagation inherent to the preexcited state. Abnormal electrical activation of the accessory pathway results in characteristic electrocardiographic abnormalities and clinical symptoms manifesting as WPW syndrome . Data oTraditionally, regional left ventricular function has been evaluated using visual wall-motion analysis as well as by other quantitative methods such as integrated backscatter, automatic border detection and tissue Doppler imaging (TDI) -9. HowevIt has recently become evident that chronic right ventricular apical pacing induced dyssynchrony leads to deleterious effects on left ventricular systolic function ,13. AccTo the best of our knowledge, no data on the prevalence of left ventricular dysfunction in patients with accessory pathway conduction exists in the literature. We sought to characterize regional left ventricular function in patients with manifest WPW syndrome by examining radial myocardial strain patterns. We also attempted to investigate the presence of global dysfunction using systolic time intervals.The study included 11 cases with manifest pre-excitation on surface ECG and an equal number of age-matched controls . None oAll accessory pathways were localized using the algorithm proposed by Milstein and colleagues on a staContinuous wave Doppler measurements were acquired through the left ventricular outflow tract. PEP was defined as the time from the beginning of the QRS complex to the onset of ventricular ejection (opening click). LVET was measured from the onset of ventricular ejection (opening click) to the closure of the aortic valve (closure click) . CorrectAll patients and controls were in sinus rhythm and image acquisition was performed in the resting state in the left lateral position. Standard short axis views at the level of mitral valve were obtained from the left ventricle (LV) at a frame rate of 70 \u00b1 5 frames/second during end-expiratory apnea and stored in cine-loop format for subsequent offline analysis . The endocardial border was then traced using the built-in software at end-systole by a 'point-and-click' approach with care taken to adjust tracking of all endocardial segments. Upon defining this endocardial circle, a larger concentric circle was automatically generated outlining the epicardium with a default width of 11 mm and perimeter adjusted manually as needed to track the myocardium. Strain tracings were then generated using a dedicated software package from a six segment LV model . Radial strain values at peak systolic period were obtained for each individual LV segments using online calipers .pRS): One standard deviation of six pRS in each case. Range of pRS (RangepRS): Arithmetic difference between maximum and minimum of six pRS values in each case.For descriptive purpose, following parameters were calculated: Global LV Peak radial strain = Arithmetic mean of pRS of six individual segments for each case as a surrogate marker of overall LV peak systolic radial strain. To measure heterogeneity, following dispersion indices were calculated ): Standard Deviation of pRS . Data are presented as mean \u00b1 SD unless stated otherwise. Non-parametric Wilcoxon's signed rank and the Mann-Whitney U test were used to compare the continuous variables in WPW patients and controls. All measurements were done by two independent observers with a minimal degree of variability. Intraclass correlation coefficients (ICC), commonly used as a measure of reliability, with a value of 1 representing a perfect correlation was used to quantify the intraexaminer and interexaminer variation. The ICC was calculated from mean values according to Portney ,19. TwoThe study cohort consisted of eleven cases and age-matched eleven controls . Baseline characteristics of the study population and accessory pathway location are shown in pRS as well as RangepRS) were profoundly greater for WPW cases compared to healthy controls (p<0.001) . This siAs shown in pRS and RangeSDpRS although the average global LV radial strain was similar to the healthy subjects (mean of pRS)}. Moreover, global systolic contractile function appeared to be depressed as well, as evident from systolic time interval analysis.Our findings suggest that patients with manifest WPW have evidence of regional contractile dysfunction. This is evidenced from a wide dispersion of pRS {higher SDEjection fraction (EF), the most frequently used index to assess global cardiac function is the LV stroke volume expressed as a percentage of the end-diastolic volume. This measure has gained popularity largely because it is widely available, easily obtainable and also because no other alternative optimal measures of myocardial contractility have emerged despite extensive investigation. Nevertheless, accurate EF calculation using the recommended Simpsons biplane method requires precise measurement of LV end-diastolic and end-systolic volumes in multiple views with special attention to avoid foreshortening of the LV cavity. Averaged values from both 4-chamber and 2-chamber views, preferably from 2 or 3 beats are recommended for more reliable estimation of ventricular volumes and EF. However, this technique is predicated on geometric assumptions and although it is fairly accurate in ventricles with symmetric contractility, it is less reliable in ventricles with overt/subtle regional wall motion abnormalities or geometrically deformed ventricles such as ventricular aneurysms. This limitation of the Simpsons method to reflect regional asymmetry of LV function is the reason why EF was not selected as the preferred metric to assess global systolic function in the present study.Systolic and diastolic 'wall motion' abnormalities have been well described in patients with WPW Syndrome -3,5,20. In our study, WPW cases exhibited a wide dispersion in pRS values of LV segments during systole suggesting markedly heterogenous strain pattern and contractility. It has to be emphasized that wall motion abnormalities are not necessarily always associated with altered contractility. Toyoda et al studied interventricular septal (IVS) contractile patterns in patients post coronary artery bypass surgery (CABG) and reported that peak tissue Doppler velocities in the IVS were attenuated . HoweverRadial strain data obtained in our patients extends the well-recognized observations of pre-excitation on wall motion and unequivocally demonstrates its detrimental effects on regional left ventricular function.The transmural arrangement of myocardial fibers is not uniform across the wall of the LV. Subendocardial and subepicardial muscle bundles are aligned longitudinally (long axis contraction), with a slight spiral arrangement, and midwall fibers are aligned circumferentially . Although the precise mechanism for abnormal contractile function in the pre-excited state remains speculative, we believe that accessory pathway conduction leads to ventricular depolarization via myocyte-myocyte conduction as opposed to the normal orderly propagation of the impulse via the His-Purkinje system. Depending on the degree of pre-excitation, ventricular insertion site of bypass tract and/or layer of muscle fibers/bundles being recruited, further heterogeneity of depolarization may ensue. As observed with dependent right ventricular apical pacing it is plSystolic time intervals have been reported as reliable surrogate parameters of left ventricular systolic function. Electromechanical systole comprises the PEP and LVET. LVET is the effective contraction phase during electromechanical systole. Weissler and co-workers -18 have During the cardiac cycle, regional deformation of the myocardium occurs in three major directions: longitudinally, circumferentially and radially, all of which can be quantified using 2-dimensional strain techniques providing real-time automatic assessment of regional cardiac function. This technique analyzes myocardial motion objectively by tracking natural acoustic markers in grey scale ultrasonic images in two dimensions (speckle tracking) and is a validated Doppler-independent method of quantifying regional cardiac deformation ,11,27. TWe found the dispersion indices like standard deviation or range segmental radial strain to be superior estimate of heterogeneity of regional contractility compared to mean radial strain. Interestingly, we also observed hypercontractility in segments diametrically opposite to those with impaired radial strain probably accounting for the lack of difference in mean radial strain values and ejection fraction between groups.Abnormal motion does not always imply contractile dysfunction. With 2D strain imaging, an angle-independent quantification of regional cardiac deformation, relatively independent of wall motion is possible. Our data suggests that the preexcited state is associated with an impairment of regional and global left ventricular contractility. In some respects, the mechanism by which RV apical pacing or left bundle branch block adversely influence LV contractility in the setting of congestive heart failure appear to be similar to those responsible for impaired contractility in the pre-excited state; both essentially mediated by electromechanical delay. The extent, progression and reversibility of left ventricular dysfunction in the setting of chronic preexcitation however, is unknown but certainly merits further study.The number of patients enrolled was limited and they predominantly appeared to have right-sided pathways, even though we enrolled consecutive patients; whether or not patients with left sided pathways have disordered contractility is uncertain. The accuracy of pathway localization using the surface ECG has inherent drawbacks; clearly localization of pathways by electrophysiological studies would be desirable. Speckle Tracking Imaging is very image quality dependent and short axis images cannot eliminate longitudinal motion entirely. We found frame rates in the range of 65 Hz to be most suitable for speckle-tracking analysis and the algorithm performed poorly with frame-rates of > 100 Hz.We used a modified method for systolic time interval assessment using Doppler-based data but had a control group for comparison; however, direct comparison of normative values with established techniques would have to be done with caution. Controversy exists regarding 'rate' correction for systolic time intervals; it is also not clear whether the prolonged PEP intervals ought to be corrected in the setting of LV conduction blocks. No specific recommendations relating to PEP adjustments in patients with pre-excitation could be found in the literature.Our observations indicate that patients with manifest WPW (predominantly right-sided pathways) have impairment of regional contractility as ascertained by radial strain dispersion parameters, resulting from the abnormal temporal sequence of activation in the pre-excited state. Differences in surrogate measures of global contractility such as PEP/LVET seem to indicate global LV dysfunction in this cohort of patients. Our findings will need to be validated in a larger group of patients that includes left-sided pathways."} +{"text": "Patients with head and neck cancer were treated with synchronous radiotherapy and chemotherapy . Before treatment, mucositis was absent and low amounts of prostaglandin-like material were extracted from peripheral plasma. As treatment proceeded mucositis occurred, and its degree correlated with the amount of prostaglandin-like material extracted from the plasma. Some patients were given moderate doses of drugs which inhibit prostaglandin synthesis, but mucositis still occurred."} +{"text": "Steven Opal reviews the phenomenon of bacterial communities and discusses the role played by bacterial communication and cooperation in host-pathogen interactions, particularly in urinary tract infection. PLoS Medicine, Rosen and colleagues [Escherichia coli commonly exist and are likely of to be of clinical significance in uncomplicated bacterial cystitis. This novel finding is remarkable in many respects, not the least of which is the circuitous route by which our understanding about bacterial communities has evolved in the pathogenesis of infectious diseases.In this issue of lleagues present Since the inception of the germ theory of disease over 150 years ago, it has generally been assumed that potential pathogens invade the host essentially as solitary microorganisms (\u201clone soldiers\u201d). Successful pathogens must find a susceptible host and then gain access to host tissues through a defect in epithelial barriers. The pathogen must replicate rapidly, and either overwhelms the host's innate and adaptive immune system, or successfully evades antimicrobial defenses by avoiding host recognition and clearance mechanisms .Vibrio fischeri, which forms an unusual symbiotic relationship with the Hawaiian bobtail squid (Euprymna scolopes). The bioluminescent V. fischeri is taken up by light organs along the body of the squid and, when high concentrations of bacteria are attained, the bacterium induces its luciferase genes to generate visible light.This traditional view of microbial pathogenesis was turned on its head about 30 years ago when three microbiologists, Nealson, Platt, and Hastings [PLoS Medicine:This Research in Translation article discusses the following new study published in 10.1371/journal.pmed.0040329Rosen DA, Hooton TM, Stamm WE, Humphrey PA, Hultgren SJ (2007) Detection of intracellular bacterial communities in human urinary tract infection. PLoS Med 4(12): e329. doi:Analyzing urine specimens from women with bladder infections, David Rosen and colleagues find evidence for intracellular bacterial communities, which have been associated with recurrent urinary tract infections in mice.V. fischeri.The bacteria benefit from this mutualistic relationship, as the squid provides a source of nutrients for the bacteria. Meanwhile, the squid benefits from the microbial light source, which provides a unique form of camouflage for the squid during nighttime mating rituals. The adult squid populations congregate in large numbers along the water's surface for mating. On moonlit nights, the squid's body is silhouetted against a starlit sky and is thus readily detectable from below by predatory fish. Light organs on the underside of the squid provide a \u201cstarry sky camouflage\u201d by their association with the light-generating clusters of Vibrio species is only activated with high bacterial densities. But how do individual bacterial cells know their relative concentration within the light organ of the squid? The answer was discovered when V. fischeri was found to produce a soluble \u201cquorum sensing\u201d molecule that co-activates the operon for luciferase production in neighboring bacteria when the organisms are in high concentration [The bioluminescent potential of this ntration .E. coli, use quorum sensing genes to regulate critically important virulence genes during microbial invasion.This observation was initially viewed as a mere curiosity unique to marine microbiology until genome searches revealed homologous quorum sensing genes among many clinically relevant microbial pathogens . RemarkaV. fischeri and uses acyl homoserine lactone (acyl HSL) molecules for signaling. This system is widely used by medically important gram-negative bacterial pathogens. The second system, found in gram-positive bacteria, is a functionally homologous version of quorum sensing that uses a series of short cyclic peptides and a two-component receptor\u2013kinase signaling pathway. A third hybrid system, found in both gram-positive and gram-negative bacterial species, uses some elements similar to the acyl HSL system of gram-negative bacteria and the receptor\u2013kinase system of gram-positive bacteria [At least three separate systems of quorum sensing and auto-induction molecules exist in bacteria. The first is highly homologous to the system found in bacteria ,6.What is now clear is that bacterial communication and cooperation is a ubiquitous phenomenon and that these communications systems are control elements in host\u2013pathogen interactions . The entPseudomonas aeruginosa can sense human gamma interferon, alerting the bacterial pathogen to physiologic stress within the infected host [Recent evidence now reveals that these communication pathways can cross kingdom boundaries . Bacterited host .Quorum sensing is essential to the production of healthy and fully developed biofilms. These palisade-like complex multicellular structures are relatively stable communities of bacterial populations living in a sessile, protected environment . Their sBiofilm communities develop rapidly on catheter surfaces and on mucous membranes along epithelial surfaces. Bacterial communities residing on urinary catheter surfaces are relatively refractory to the lytic action of many antibiotics. This resistance undermines the capacity of antimicrobial agents to eradicate infections on biofilmladen foreign bodies within the genitourinary system .Qazi et al., 2006 [S. aureus; this pathway could favor the quorum sensing gram-negative pathogens over S. aureus when in competition for limited resources during microbial invasion of the host.l., 2006 The sameShiner et al., 2005 [l., 2005 This manWu et al., 2005 [P. aeruginosa uses its quorum sensing apparatus to detect and signal transcriptional programs for virulence expression in response to human interferon gamma. This interferon marker signals an inflammatory stress in the host during microbial invasion by the microbial pathogen.l., 2005 P. aerugNovick et al., 2003 [l., 2003 An excelSmith et al., 2003 [P. aeruginosa and their respective roles in biofilm formation and bacterial pathogenesis.l., 2003 This papE. coli cystitis. Up to 41% of urine specimens in women with cystitis have evidence of filamentous bacterial forms, a morphologic hallmark of recent residence among sessile bacterial communities. Similar findings have previously been reported in the murine model of cystitis [Rosen and colleagues now go ocystitis . CytologAcyl homoserine lactone: a highly soluble, cyclic homoserine moiety covalently linked to short fatty acids that functions as a quorum sensing signal molecule for many gram-negative bacteriaAuto-induction molecule: diffusible low-molecular weight signal molecule recognized by the microorganism that produced the molecule and capable of inducing changes in the transcription of specific genesHalophilic: capable of living in a salty environmentOpen reading frames: Sequences of DNA that include the start codon AUG and appropriate translation sequences that generate a functional protein productOperon: a series of adjacent open reading frames transcribed from a single promoter site that generates gene products working on the same metabolic pathwayQuorum sensing: ability to detect the density of a bacterial population and alter genetic programs in response to that population densityReceptor\u2013kinase signaling pathway: two-component system consisting of a membrane receptor to detect extracellular ligands, linked to an intracellular phosphorylating enzyme, which alters the transcriptional programs of the bacterial cellToll-like receptor: Pattern recognition receptor used by the innate immune system to detect and respond to highly conserved microbial mediators such as bacterial lipopolysaccharide or bacterial flagellinE. coli have the capacity to invade epithelial lining cells, where they find sanctuary from immune surveillance and urinary clearance mechanisms [Uropathogenic chanisms ,16. The There are numerous implications of these findings for the pathogenesis of urinary tract infections, and for the possible treatment options available to prevent recurrent infection in UTI-prone women. These sessile bacterial communities might easily provide a sequestered site from antimicrobial defenses, allowing for repopulation of the urinary tract after a seemingly appropriate course of antimicrobial agents for bacterial cystitis. The formation of IBCs is a Toll-like receptor (TLR4)-dependent process in the murine system and is lE. coli? Staphylococcus aureus regulates many of its virulome invasion genes through its auto-inducing peptides and quorum sensing system [S. aureus or other gram-positive bacterial pathogens use communal intracellular invasion strategies.The current study was performed in young, sexually active women. Many women had a history of recurrent bacterial cystitis. What is the prevalence of IBCs in children, the elderly, or men or women experiencing their first episode of UTI? Does the presence of IBCs in first episodes of UTI indicate a greater propensity for treatment failure or relapsing urinary tract infection? What is the prevalence of IBCs in patients with upper urinary tract infections or complicated urinary tract infections associated with urinary obstruction or foreign bodies? Are similar IBCs identifiable with pathogens other than g system ,5. It woThe findings of Rosen et al. raise th"} +{"text": "Earlier studies on the kinetics, glucosedependenceand sensitivity to metabolic inhibitorsof the interaction between NAT and KATP channelssuggested a distinct signaling pathways with NATcompared to REP, glyburide (GLY) or glimepiride(GLI). To obtain further evidence for this concept,the present study compared the insulin secretion invitro from rat islets stimulated acutely by NAT, GLY,GLI or REP at equipotent concentrations during 1-hrstatic incubation following overnight treatmentwith GLY or tolbutamide (TOL). The islets fullyretained the responsiveness to NAT stimulationafter prolonged pretreatment with both SUs, whiletheir acute response to REP, GLY, and GLI wasmarkedly attenuated, confirming the desensitizationof islets. The insulinotropic efficacy of NAT in isletsdesensitized to SUs may result from a distinctreceptor/effector mechanism, which contributes tothe unique pharmacological profile of NAT.Chronic exposure of pancreatic islets to sulfonylureas(SUs) is known to impair the ability of isletsto respond to subsequent acute stimulation bySUs or glucose. Nateglinide (NAT) is a novelinsulinotropic agent with a primarily site of actionat"} +{"text": "Here we report the unusual case of a patient who suffered from acute optic neuropathy following hemispherical subdural hematoma. Although confirmed up to now only through necropsy studies, our case strongly suggests a local, microcirculatory deficit identified through magnetic resonance imaging A 70-year-old Caucasian German who developed a massive left hemispheric subdural hematoma under oral anticoagulation presented with acute, severe visual impairment on his left eye, which was noticed after surgical decompression. Neurologic and ophthalmologic examinations indicated sinistral optic neuropathy with visual acuity reduced nearly to amaurosis. Ocular pathology such as vitreous body hemorrhage, papilledema, and central retinal artery occlusion were excluded. An orbital lesion was ruled out by means of orbital magnetic resonance imaging. However, cerebral diffusion-weighted imaging and T2 maps of magnetic resonance imaging revealed a circumscribed ischemic lesion within the edematous, slightly herniated temporomesial lobe within the immediate vicinity of the affected optic nerve. Thus, the clinical course and morphologic magnetic resonance imaging findings suggest the occurrence of pressure-induced posterior ischemic optic neuropathy due to microcirculatory compromise.in vivo magnetic resonance imaging diagnostics which may remain unconsidered by computed tomography.Although lesions of the second cranial nerve following subdural hematoma have been reported individually, their pathogenesis was preferentially proposed from autopsy studies. Here we discuss a dual, pressure-induced and secondarily ischemic pathomechanism on the base of In these studies, microcirculatory compromise of the optic nerve was proven as a pathogenic mechanism . In thisA 70-year-old Caucasian man of German nationality receiving warfarin therapy for the primary prevention of chronic atrial fibrillation was admitted to our hospital due to symptoms of a coronary syndrome. An initial international normalized ratio (INR) of 1.7 was elevated to therapeutic ranges (INR = 2.5). Three days later, the patient was found comatose after a first-ever generalized seizure. Cerebral computed tomography (CT) revealed a subdural hematoma measuring 16 mm at its maximum thickness and covering almost the entire left convexity which caused a massive midline shift Figure . Rapid cTwo days after extubation and recovery from anaesthesia, the patient complained of severe sinistral visual loss. Neurologic and ophthalmologic examinations confirmed a severely reduced visual acuity on his left eye with concomitant afferent pupillary defect. A normal vascular fundoscopy and the lack of papilledema led to the working diagnosis of posterior ON. Four days after the surgery, a follow-up DWI of the cerebral MRI Figure showed aThe corresponding hyperintensity of T2-weighted images indicated focal brain edema in line with regional hypoperfusion and the preceding uncal shift Figure . Thus, pin vivo findings do not at all elucidate its aetiology. Generally, reports do not present the existence of papilledema or of radiologic in vivo evidence of optic nerve compression by mass effects [To date, only a few cases of ON following subdural hematoma are presented, and their pathomorphologic effects . In cont effects .The pathophysiology of ON has been discussed in the context of diverse aetiological events, and adequate diagnostic approaches have already been proposed. Table At present, only a few cases refer to the diagnostic value of MRI in ON. By means of MRI, unilateral and simuin vivo. Radiological signs of herniation were discrete, although highly sensitive MRI revealed a mechanic, pressure-induced brain lesion of the mesiobasal temporal lobe in proximity to the affected optic nerve. However, focal ischemic injury was missed in detecting basal brain shift by CT. Since MRI pathologies fulfilled the criteria of ischemic compromise, we suggest that the local increase in intracranial pressure (ICP) exceeded the perfusion pressure of both structures, namely the formation of the uncus and the nearby passing optic nerve. Consistent with this notion of a microcirculatory deficit, the lesion did not follow the characteristic extent of a vascular territory.Using the MRI technique, we now provide a pathophysiologic insight on ON following space occupying subdural hematoma early We suggest that rare cases of acute ON following subdural hematoma are due to local pressure-induced optic nerve infarction. This pathomechanism may remain neglected when massive brain shift is lacking or when CT is the only diagnostic means. The use of serial MRI may help balance the discrepancy between the paucity of clinical reports and frequent neuropathological findings of anterior visual pathway damage in space-occupying brain injury .ADC: apparent diffusion coefficient; AION: anterior ischemic optic neuropathy; CT: computed tomography; DWI: diffusion-weighted imaging; FLAIR: fluid attenuated inverse recovery; ICP: intracranial pressure; INR: international normalized ratio; MRI: magnetic resonance imaging; ON: optic neuropathy; PION: posterior ischemic optic neuropathy.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.AK and CP interpreted the patient data and clinical course regarding the neurological disease. HF, OW and CT were major contributors in conceiving and writing the manuscript. All authors read and approved the final manuscript."} +{"text": "Helix pomatia (HPA), is associated with metastatic competence and poor patient prognosis in a range of human adenocarcinomas. These glycoproteins remain poorly characterised, and their functional role has yet to be elucidated. This study describes characterisation of a range of human breast/breast cancer cell lines for the expression of the N-acetylgalactosaminylated glycoproteins of interest, and their comparison with normal breast epithelium and a range of clinical breast carcinoma samples. Confocal and light microscopy studies revealed cytochemical HPA-binding patterns consistent with a fundamental disruption in normal glycobiosynthetic pathways attending increasing metastatic potential. We report the most complete comparative analysis of HPA-binding ligands from cultured breast cells, clinical breast carcinoma samples and normal breast epithelium to date. Lectin blotting identified 11 major HPA-binding glycoprotein bands common to both clinical tumour samples and breast cell lines and 6 of these bands were also expressed by samples of normal breast epithelium, albeit at much lower levels. Moreover, very marked quantitative but not qualitative differences in levels of expression consistent with metastatic capability were noted. \u00a9 2001 Cancer Research Campaignhttp://www.bjcancer.comOver-expression of N-acetylgalactosamine glycoproteins as detected by binding of the lectin from"} +{"text": "We have previously documented the development and subsequent disappearance of cytolytic activity mediated by lymphocytes from lymph nodes draining Moloney sarcomas destined either to regress or grow progressively. We now report that these tumour-draining lymphnode cells (LNC) that were no longer cytotoxic, spontaneously regenerated peak levels of killing after culture in vitro for 4 days in the absence of exogenous tumour antigen. Cytolytic activity, which was antigenically specific, was mediated by T lymphocytes. Resurgence of cytolytic activity in vitro was accompanied by proliferative changes which peaked on the 3rd day of culture. Although normal, nonimmune LNC underwent quantitatively similar proliferative changes in culture, the killing that developed was weak and antigenically nonspecific. Transfer of cultured, tumour-draining LNC to immunologically compromised, syngeneic mice conferred complete protection from Moloney sarcoma progression. Adoptive transfer could be delayed for 6 days after tumour induction without loss of protection. These results suggest that there exists in Moloney sarcoma-bearing mice a mechanism that limits the differentiation of pre-killer cells into cytolytically active T lymphocytes, and that such inhibition is eliminated when LNC are explanted into culture."} +{"text": "This report presents histopathological evidence of mycotic infection of the gingival epithelium followed by inverted verrucous giant cell epitheliomata of the gingiva. Sections from biopsy tissue revealed intercellular spaces of the parabasal squamous epithelium parasitized by Periodic Acid Schiff stain positive branching septate hyphae and conidia of morphological appearance of Trichophyton. Epithelial cells presented epitheliomatous proliferation with formation of giant cells showing phagocytosed fragments of mold. Some fungi are known for carcinogenic metabolites and signaling. Dermatop13, differential leucocyte count - P68L29E2M1, fasting blood sugar 95 mg/dL, serum urea 29 mg/dL and serum creatinine 1.1 mg/dL. Screening tests for human immunodeficiency virus, hepatitis and syphilis were negative.A 52-year-old goldsmith's ash washerman with a history of extraction of aching right upper second molar tooth 2 years back followed by painful on-and-off swelling, managed by the patient by frequenting dentists' prescriptions and consumption of countryside liquor a bottle a day, was referred to this hospital. Gingival biopsy with clinical diagnosis of leukoplakia/squamous carcinoma was submitted for histopathological diagnosis. The patient had no history of fungal infection of the skin or nails. The total leucocyte count was 8,000 cells/mmSections from the biopsy tissue revealed surface dyskeratosis with underlying keratinocytic hyperplasia of the gingival epithelium. Basal and parabasal layers presented with epitheliomatous proliferation of cells with formation of giant cells. Retepegs were broadened and elongated with keratinocytes in a pearl arrangement forming the core and hyperplastic cells dotted by giant cells at the periphery . At placPeriodic Acid Schiff (PAS) stained sections revealed septate branching fungal hyphae of mold parasitizing intercellular clefts in basal and parabasal squamous layers, with the cells around undergoing immunoactive and giant cell transformations . Some ofLow-mitotic basal\u2013parabasal epitheliomatous proliferation with dyskeratotic\u2013acanthocytic hyperplasia, pearl formation and papillary clubbing and elongation of retepegs are the features diagnostic of epitheliomatous-inverted papilloma or verrucous\u2013hyperplastic leukoplakia, which di4th century. Oral mycosis, particularly periodontal infection caused by dermatophytosis, and host-defensive activity of human cells in response to trichophyton have also been reported,[Histopathological evidence in the present case was diagnostic of mycotic giant cell epitheliomatous inverted papilloma of the gingiva. Oropharyngeal proliferative verrucous leukoplakia and its related lesions, like invreported,7 besidesreported,2 TrichopDermatophytes are known for cutaneous infections and for invading and parasitizing superficial keratinocytic layers, while keratin is believed to be the source of nourishment for the mold. In the pDermatophytes are rarely known to infect the wet epithelium of the gum, except through periodontal mycosis leading to gingival hyperplasia. History Trichophyton mold can infest and parasitize the basal and parabasal layers of the gingival squamous epithelium. The portal of entry may be periodontal.Acanthocytes around the hyphae of the mold may respond by giant cell epitheliomatous response and verrucous keratinocytosis.Intercellularly parasitizing PAS-positive hyphae, phagocytosed segments of hyphae and conidia may be demonstrable in the giant cell epitheliomatous areas.No fungal hyphae or identifiable fragments of mold may be visible in areas of the gingival epithelium undergoing advanced keratinocytic change.Giant cells in the epithelioma call for detailed meticulous histopathological examination for the pathogenic organism."} +{"text": "Current Neuropharmacology devoted to the theme of AED conversions and related issues. In this series of articles, we reviewed the role of AED monotherapy in newly diagnosed epilepsy, the practice of transitional polytherapy during AED monotherapy conversions in patients experiencing breakthrough seizures or adverse effects, chronic maintenance polytherapy for refractory epilepsy, and the related topics of strategies for minimizing adverse effects, appropriate blood level monitoring, and patient-related factors in AED conversions. Successful conversion between AED monotherapies and polytherapy drug sequencing requires that practitioners possess and apply a thorough knowledge of epilepsy, AED pharmacology, and clinical reasoning, while being sensitive and reactive to patient reported adverse effects of treatment.The process of conversion between AED monotherapies is frequently necessary in epilepsy care, yet little practical guidance is available to practitioners. This article introduces an issue of That which grows fast, withers as rapidly. That which grows slowly, endures.\u201dDr. Josiah Gilbert Holland, Founder of Scribner\u2019s Monthly\u201cWhen the music changes, so does the dance.\u201dAfrican ProverbThe first antiepileptic drug (AED) monotherapy utilized successfully manages nearly half of epilepsy patients; however, conversion to a second monotherapy is necessary for those who fail to become seizure-free or who do not tolerate an initially chosen AED, and chronic polytherapy is necessary in many patients who develop refractory epilepsy . Over thMonotherapy is widely favored over polytherapy by neurologists in the treatment of newly diagnosed epilepsy, limited evidence for this \u201cmonotherapy maxim\u201d notwithstanding. Abundant evidence is available when initiating adjunctive AED therapy in refractory epilepsy, on practical grounds an important setting for use of newer AEDs since when a new AED becomes available, it is generally first limited to use in refractory patients having the greatest need for improved seizure control, until its safety and tolerability profile and expanded evidence for use in other settings is well established. While it is probable that all AEDs proven effective in adjunctive polytherapy settings are also efficacious for use as monotherapy, available evidence guiding AED monotherapy remains somewhat limited, leading to relatively narrow FDA indications in United States practice. Several newer AEDs have randomized controlled trial evidence for monotherapy application, while clinical experience and lesser evidence lead to FDA \u201cgrandfathering\u201d of older AEDs for monotherapy indication in newly diagnosed epilepsy. However, relatively little evidence is available to guide clinicians as they implement changes between monotherapy or polytherapy AED regimens for patients with epilepsy. A panel of epilepsy neurologists and clinical pharmacologists was recently convened to address this important topic. The goal of the SPECTRA panel (Study by a Panel of Experts: Considerations for Therapy Replacement in Antiepileptics) was to develop consensus regarding practical issues in AED monotherapy conversions. This panel developed consensus on a key overriding treatment principle: to fully titrate an adjunctive drug prior to tapering a baseline drug when possible. The panel also developed drug-specific consensus recommendations that expand and complement available prescribing information that is useful in planning AED monotherapy conversions as well as AED sequencing in chronic polytherapy regimens .Current Neuropharmacology focuses on the topic of AED conversions in epilepsy care. This series of articles begins with a practical review of AED monotherapy in newly diagnosed epilepsy, next examines factors involved in monotherapy conversions during the process of transitional polytherapy, then outlines important considerations in ensuring successful chronic polytherapy. A discussion of the rationale and strategies for minimizing adverse effects in epilepsy care is then followed by a review of principles for appropriate blood level monitoring. Finally, this issue considers important patient-related factors in AED conversions. The above-referenced motivational sentiment of 19th century physician, author, and poet Josiah Holland well anticipated the approach to epilepsy treatment favored herein: initiate AED treatment as monotherapy, sequence medications as needed to achieve seizure control or improve a patient\u2019s acceptance and tolerability of therapy, and titrate most medications slowly and carefully to ensure maximal success. However, as the ensuing proverb reminds us, conversion between different AEDs may require specific modifications to ensure treatment success. The SPECTRA data summarized herein provides clinicians with a helpful new approach to guide conversions between AED therapies, and the accompanying review articles offer further relevant guidance for clinicians implementing AED conversions in epilepsy care.This issue of"} +{"text": "Respiratory papilloma is a rare lesion that arises in the larynx, trachea and bronchus.We describe a patient with laryngeal papilloma that spread to the trachea and whichwas effectively treated by Nd-YAG laser. Two years after the initial treatments of thelaryngeal and tracheal papillomas, a recurrent lesion (solitary papilloma) was observedon the membranous portion of the trachea. We examined the recurrent lesion by bronchoscopyincluding bronchoscopic ultrasound (US), helical computed tomography (CT)and tracheal biopsies. Respiratory papillomatosis sometimes shows either malignanttransformation or invasion to tracheal wall without displaying cytohistological atypia.Therefore, we concluded that bronchoscopic US and helical CT were useful for decidingon therapeutic strategy in cases of recurrence of tracheal papilloma."} +{"text": "Circumscribed choroidal hemangiomas are vascular tumors associated with secondary changes in the overlying retinal pigment epithelium and neuro-sensory retina. Spectral-domain optical coherence tomography, a recent advancement in fundus imaging techniques provides high resolution images of the retina. We describe spectral domain Optical coherence tomography findings in a case of circumscribed choroidal hemangioma which was successfully treated with photodynamic therapy.A 41-year-old white male presented with decreased vision in his right eye. Fundus evaluation showed findings consistent with circumscribed choroidal hemangioma. Spectral-domain optical coherence tomography revealed a large serous retinal detachment overlying the tumor with an intact photoreceptor layer. The patient underwent photodynamic therapy and a repeat tomography scan confirmed the resolution of serous detachment with return of normal foveal contour.Spectral domain optical coherence tomography is an emerging modality in imaging of the retina and reveals ultrastructural changes occurring in various retina pathologies. In this case report we illustrate the use of spectral domain optical coherence tomography for the first time to document retinal changes overlying a choroidal hemangioma and its role as a non-invasive tool in planning the treatment and prognosticating the final visual outcome following treatment for circumscribed subfoveal choroidal hemangiomas. Choroidal hemangiomas are vascular hamartomas of the choroid and can cause visual loss due to subfoveal location, associated exudative retinal detachment, cystoid macular edema or subretinal fibrosis ,2. A numSpectral domain OCT, in recent times, has been an important advancement in OCT technology, having enhanced speed and sensitivity in acquiring retinal images. It acquires upto 40000 scans in a short period of time and renders a 3-dimensional image with cross-sectional sections providing detailed ultrastructural changes within the retina . PDT. PDT8]. In conclusion, SD OCT is an emerging tool in the imaging of retina and provides high definition ultrastructural changes associated with vitreo-retinal disorders. In this case report we illustrate the use of SD OCT for the first time to document retinal changes overlying a choroidal hemangioma and its role as a non-invasive tool in planning the treatment and prognosticating the final visual outcome following treatment for circumscribed subfoveal choroidal hemangiomas.CCH: circumscribed choroidal hemagioma; ICG: indocyanine green; PDT: photodynamic therapy; RPE: retinal pigment epithelium; SD OCT: spectral domain optical coherence tomography.Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.KC and SG identified the case and directly participated in management. They also revised the manuscript and verified its intellectual content. VB and RM worked in collaboration to collect data, acquire clinical photographs, and draft, revise, and reference the manuscript."} +{"text": "In these patients, the number of apoptotic lymphocytes was significantly increased within tumour and peripheral blood. Furthermore, sFasL was present in the corresponding supernatants and induced apoptosis of Jurkat cells in a dose-dependent manner. These findings suggest that mFasL-positive colon cancer cells release sFasL, and thus may induce apoptosis of host lymphocytes as a potential mechanism for immune evasion. \u00a9 2001 Cancer Research Campaignhttp://www.bjcancer.comExpression of membrane-bound Fas ligand (mFasL) on colon cancer cells serves as a potential mechanism to inhibit host immune function by inducing apoptosis of host lymphocytes. Membrane-bound FasL can be cleaved and released as a soluble mediator (sFasL), which may spread the apoptosis induction effect. Our study examined whether colon adenocarcinoma cells release sFasL, and induce apoptosis of host lymphocytes without direct cell\u2013cell contact. In 12 consecutive patients with colon adenocarcinoma mFasL was identified in the tumours, sFasL was measured in the sera and apoptosis identified in tumour-infiltrating and peripheral blood lymphocytes. To analyse the function of sFasL, colon cancer cells were primarily cultured; sFasL was isolated from supernatants, measured, incubated with Fas-bearing Jurkat cells, and the resulting apoptosis was analysed. Serum levels of sFasL were significantly elevated in all colon cancer patients with mFasL expression in tumour tissues ("} +{"text": "Five species of sigmodontine rodents have been identified in Argentina as the putative reservoirs of six circulating hantavirus genotypes. Two species of Oligoryzomys are associated with the genotypes causing hantavirus pulmonary syndrome, Oligoryzomys flavescens for Lechiguanas and O. longicaudatus for Andes and Oran genotypes. Reports of human cases of hantavirus pulmonary syndrome prompted rodent trapping at potential exposure sites in three disease-endemic areas. Antibody reactive to Sin Nombre virus was found in six species, including the known hantavirus reservoir species. Risk for peridomestic exposure to host species that carry recognized human pathogens was high in all three major disease-endemic areas."} +{"text": "We present a case of a man admitted to our Hospital for right acute scrotum that six months before had undergone a right hernioplasty with mesh implantation. Clinical history and testicular color Doppler sonography (CDS) patterns suggested an orchiepididymitis following acute prostatitis. After 48h the clinical picture worsened and testicular CDS showed a decreased telediastolic velocity that suggested testicular ischemia. The patient underwent surgical exploration: spermatic cord appeared stretched by an inflammatory tissue in absence of torsion and releasing of spermatic cord was performed.In patients with genitourinary infection who previously underwent inguinal mesh implantation, testicular CDS follow-up is mandatory. The acute scrotum constitutes the most common urological emergency and color Doppler sonography (CDS), along with the physical exam, represents the imaging modality more frequently employed in the clinical assessment of acute scrotum.The two most important entities that must be ruled out in every case of acute scrotal pain are torsion of spermatic cord and orchiepididymitis, while other causes occur more rarely. In case of inguinal hernia repair using mesh techniques the spermatic cord is potentially affected by chronic inflammatory tissue remodeling that may impair testicular perfusion inducing acute scrotum.A rare case of testicular ischemia following mesh hernia repair and acute prostatitis that presented as acute scrotum is reported herein.A 23-year-old man was admitted for right orchialgia arising 24h before admission; although he referred urinary symptoms and fever of five days\u2019 duration, no therapy was previously administered. Six months before, the patient underwent a mesh implantation to treat a recurrent right inguinal hernia. At admission, history, genitourinary exam, blood and urine test and transrectal CDS suggested an acute prostatitis; testicular CDS revealed normal signal in correspondence of the testis and epididymis. The patient was hospitalized and submitted to antibiotic therapy. After 48h the clinical picture worsened: testicular pain and fever increased, CDS showed a decreased TDV (telediastolic velocity) on intratesticular artery and a hiSpermatic cord torsion, orchiepididymitis and trauma constitute the main causes of acute scrotum, although the differential diagnosis refers essentially to the torsion of spermatic cord vs. inflammatory lesions. A careful physical exam and anamnesis combined with CDS parameters often address toward the diagnosis of testicular ischemia that, more rarely, can be secondary to severe epididymitis, inguinal hernia repair, spontaneet al. performed an experimental study in 15 adult male pigs that underwent transinguinal preperitoneal implantation of polypropylene mesh and shouldice repair on the contralateral side. The authors reported that mesh repair led to a decrease of arterial perfusion, testicular temperature and seminiferous tubules.[et al.[et al.[The use of mesh during hernia repair is associated with a relative reduction in the risk of hernia recurrence of around 30-50%; however, there is no apparent difference in recurrence between laparoscopic and open mesh methods of hernia repair. Experime tubules. Dilek ets.[et al. reportedl.[et al. showed tl.[et al. reportedIn our case report testicular ischemia was secondary to spermatic cord compression by an inflammatory and scar tissue in absence of torsion and only after releasing of spermatic cord the patient became asymptomatic.In conclusion, in patients with genitourinary infection who previously had an inguinal mesh implantation, clinical observation and CDS follow-up is mandatory to treat in time this unusual complication."} +{"text": "An assay system is described in which effector cells added along with suitable target cells inhibit, in a quantitative fashion, the subsequent uptake of 3H-thymidine by those target cells. Effector cells active in this assay, using embryonic fibroblast cells as targets, develop spontaneously in cultures of mouse lymphoid cells, but are apparently different from those described earlier by investigators of activity in cytotoxic assays. Further evidence is presented to show the development of spleen-derived effector cells with cytostatic activity (for embryonic fibroblast target cells) in mice during the course of normal pregnancy, or growth of spontaneously appearing mammary adenocarcinomas. Indeed, such effector cells can also be found within the growing solid mass itself. Different populations of tumour cells isolated from a solid tumour apparently differ in their susceptibility to growth inhibition by tumour-bearer-derived cytostatic effector cells, a phenomenon which may be related to metastatic spread of tumour cells."} +{"text": "Symptomatic prostatic cyst presenting as obstructive lower urinary tract symptoms (LUTS) is an infrequent diagnosis in males. Midline cysts are much more likely to obstruct the bladder outlet. We report our experience with four such cases in the last one year, along with a short review of the literature. Two of these cases had additional presenting symptoms besides LUTS - febrile Urinary tract infection (UTI) with perinephric abscess and primary infertility. One case had an anterior midline prostatic cyst which is an extremely rare entity. The remaining three had midline posterior cysts. All cases were treated with transurethral marsupialization, had good relief of symptoms and no adverse effects. Prostatic cysts, an erstwhile infrequent diagnosis in males, are usually asymptomatic and mostly detected incidentally during abdominal or trans-rectal ultrasonography (TRUS). Etiological factors include chronic prostatitis as a predominant cause of lateral prostatic cysts and congenital causes for midline cysts. Existent literature on midline prostatic cysts is mostly in the form of isolated case reports, which highlights their uncommon occurrence and even lower propensity for causing symptoms. We report our experience with managing symptomatic benign midline prostatic cysts, including a rare variant of an anterior midline prostatic cyst for which only three cases have been reported so far.Four young males presented to us with lower urinary tract symptoms (LUTS) and/or other associated symptoms . ObstrucInitial evaluation included a urine microscopic analysis and culture, uroflowmetry and a screening abdominal ultrasonography which documented the presence of a prostatic cyst . AdditioAll patients underwent cystoscopy and transurethral incision of the prostatic cyst ; Case 4 The widespread use of TRUS for evaluating bladder outlet obstruction, infertility, UTI, hemospermia, ejaculatory pain, chronic pelvic pain, prostatic carcinoma or guiding prostatic biopsy has resulted in more frequent identification of prostatic cysts. Most proSymptomatic prostatic cysts are reported to be associated with prostatic abscess, chronic/recurrent prostatitis; as a cause of chronic pelvic pain, upper or lower UTI, infertility, hemospermia and rarely malignancy.4Lower urinary tract symptoms surprisingly are uncommon presenting symptoms, though midline cysts more frequently present with LUTS than laterally placed cysts. The large intraprostatic cyst may compress the prostatic urethral lumen, cause ejaculatory duct obstruction or stretch the prostatic capsule causing pelvic pain.Etiologically, prostatic cysts include the utricle, mullerian duct cyst, hemorrhagic prostatic cyst, hydatid cyst and cysts associated with prostatitis. Midline cysts, located posteriorly at the prostatic floor, are mostly developmental in origin and arise from remnants of fetal tissue \u2013 utricle or m\u00fcllerian duct. Utricular cysts are endodermal in origin, contain no spermatozoa and are located near the verumontanum, whereas m\u00fcllerian cysts are mesodermal in origin, contain spermatozoa and are located more posterior and nearer the prostate base. Some cysts are primarily prostatic glandular in origin and are acquired later in life. Most lateral prostatic cysts are related to chronic prostatitis, where they may play a causative role or may be consequent to it. Anterior midline cysts of prostatic origin are extremely rare with only three cases reported in the literature so far.\u20137 Case 1In some cases it may be fairly easy to directly relate the presence of the prostatic cyst as the etiology behind the patient's clinical symptoms. Though the diagnosis of a midline prostatic cyst can be made on TRUS examination, the functional implication of the midline prostatic cyst cannot be determined by TRUS alone. Thus, inet al., reported durable, recurrence-free results in a series of patients with medial prostatic cyst treated with transurethral incision.[et al., reported excellent outcome with transurethral resection of midline prostatic cyst projecting into the prostatic urethra and presenting as obstructive LUTS.[Various therapeutic options for managing midline prostatic cysts described include transrectal aspiration with or without sclerotherapy, transurethral marsupialization and open surgery. Dik et aincision. Similarlive LUTS."} +{"text": "Mycobacterium ulcerans is an infection of the subcutaneous tissue leading to chronic necrotising skin ulcers. The pathogenesis is associated with the cytocidal and immunosuppressive activities of a macrolide toxin. Histopathological hallmark of progressing disease is a poor inflammatory response despite of clusters of extracellular bacilli. While traditionally wide excision of the infected tissue was the standard treatment, provisional WHO guidelines now recommend an eight week pre-treatment with streptomycin and rifampicin.Buruli ulcer caused by We conducted a detailed immunohistochemical analysis of tissue samples from Buruli patients who received antibiotic treatment. Cellular immune response along with bacterial load and distribution were monitored. We demonstrate that this treatment leads to the development of highly organized cellular infiltration surrounding areas of coagulative necrosis. Diffuse infiltrates, granulomas and dense lymphocyte aggregation close to vessels were observed. Mycobacterial material was primarily located inside mononuclear phagocytes and microcolonies consisting of extracellular rod-shaped mycobacteria were no longer found. In observational studies some patients showed no clinical response to antibiotic treatment. Corresponding to that, one of five lesions analysed presented with huge clusters of rod-shaped bacilli but no signs of infiltration.M. ulcerans, lacking patient compliance or poor drug quality are responsible for the absent clinical responses in some patients. In future, analysis of local immune responses could serve as a suitable surrogate marker for the efficacy of alternative treatment strategies.Results signify that eight weeks of antibiotic treatment reverses local immunosuppression and leads to an active inflammatory process in different compartments of the skin. Structured leukocyte infiltrates with unique signatures indicative for healing processes developed at the margins of the lesions. It remains to be analysed whether antibiotic resistance of certain strains of Buruli ulcer (BU) is a debilitating disease of the skin presenting with extensive tissue destruction and suppression of local host defence mechanisms. Surgical removal of the affected area has been the standard therapy until in 2004 WHO recommended eight weeks' treatment with the anti-mycobacterial drugs rifampicin and streptomycin. We performed a detailed histological analysis of the local immune response in biopsies from five children medicated according to WHO provisional guidelines. One patient still revealed all histopathological signatures of an active BU lesion with huge bacterial clusters in areas of fatty tissue necrosis. Different factors can contribute to treatment failure, such as poor patient compliance and resistant bacterial strains. In four patients, different compartments of the skin presented active immune processes with only limited residues of bacterial material persisting. We demonstrated that antibiotic treatment not only directly controls the infectious agent but is also associated with fulminant host immune responses. Characterization of the healing process in BU due to therapy is highly relevant to increase our knowledge of the impact of treatment strategies to fight the disease. Mycobacterium ulcerans is a chronic necrotizing skin disease mainly affecting subcutaneous and adipose tissue M. ulcerans bacteria Buruli ulcer (BU) caused by BU is considered to be the third most common mycobacterial infection after tuberculosis and leprosy. Clinical lesions usually start as painless subcutaneous nodules that may develop into plaques or oedema. If left untreated, extensive ulcerations with typical undermined edges of the dermis develop. Spontaneous healing can occur, often leaving the patient behind with extensive scarring, retractions and deformities Until recently, surgery has been the only WHO recommended treatment for BU M. ulcerans strains indicate that infiltrating cells are killed due to the cytotoxic and apoptosis inducing activity of mycolactone M. ulcerans may be captured by phagocytes during different stages of infection, it appears to persist only transiently inside these host cells Histopathological hallmarks of progressing BU are a poor inflammatory response and growing regions of necrosis of the dermal and adipose tissue eventually leading to the collapse of the overlying epidermis . ClusterMycobacterium ulcerans disease, WHO, 2001), IS2404 PCR, microscopic detection of acid-fast bacilli and observation of characteristic histopathological changes. After receiving informed consent the immunologically non responding patient was tested for HIV positivity. Ethical approval for analysing patient specimens was obtained from the ethical review board of the Noguchi Memorial Institute for Medical Research and the National Ethics Committee of Cameroon.Surgical specimens from five patients aged between six and 11 years with ulcerative lesions were obtained from the Amasaman Health Centre in Ghana and the Ayos district hospital in Cameroon . Lesions3 were collected from different areas of the excised lesions to characterize the gradient of histopathological changes from necrotic areas to healthy appearing tissue at the excision margins and Haematoxylin/Eosin (HE) was performed on all collected tissue specimen. Staining for acid-fast bacteria was performed according to WHO standard protocol (WHO Diagnostic booklet). In brief, sections were deparaffinized and rehydrated followed by incubation with ZN carbolfuchsin for 30 min at RT. Subsequently slides were washed in cool tap water for 5\u201310 min and individually differentiated with acid-alcohol. Counterstain was completed with haematoxylin and slides were mounted with Eukitt mounting medium.Pictures taken with a Nikon optiphot-2 microscope were saved using analySIS soft imaging system and processed with Adobe Photoshop CS.M. leprae and highly cross-reactive with other mycobacteria, was used to stain M. ulcerans for confirmation of ZN staining results. Staining of common mycobacterial antigens with polyclonal anti-leprae antibody (pAbLep) antiserum and haematoxylin counterstain revealed an accumulation of mycobacteria highly organized epithelioid granulomas of different size and state of differentiation, primarily located in deeper dermal tissue ; (ii) leHistopathological characteristics of BU were still found in all four patients. These included psoriasiform and pseudoepitheliomatous epidermal hyperplasia and depigmentation with excThe distribution of mycobacterial material was assessed by ZN staining and immu+ T lymphocytes (+ B cells appeared at the outer margins of the T lymphocyte layer (+ antigen-presenting cells (APCs) in particular Langhans' giant cells (+ phenotype (+ (proliferating) cells (+ polymorphonuclear neutrophilic leucocytes (PMNL) nor CD56+ natural killer (NK) cells could be detected in granuloma formations.A panel of antibodies specific for leukocyte markers were usephocytes with CD4 T cells always o T cells . These ls (dDCs) . Occasiote layer . Cytoplant cells insert ant cells . Staininnt cells , arrow. henotype . Variablg) cells presenteg) cells insert. + PMNL (+ NK cells showed a similar distribution with even lower cell counts (not shown). Foci of PMNL and NK cells with signs of apoptosis were located within necrotic tissue . Small clusters of CD20+ B lymphocytes were scattered within infiltrates Click here for additional data file.Table S1Main data of enrolled patients(0.03 MB DOC)Click here for additional data file."} +{"text": "Patients with pre-existing neurological disease present a unique challenge to the anaesthesiologist. The cause of postoperative neurological deficits is difficult to evaluate, because neural injury may occur as a result of surgical trauma, tourniquet pressure, prolonged labour, or improper patient positioning or anaesthetic technique. Progressive neurological diseases such as multiple sclerosis may coincidentally worsen perioperatively, independently of the anaesthetic method. The most conservative legal approach is to avoid regional anaesthesia in these patients. However, high-risk patients, including those with significant cardiopulmonary disease, may benefit medically from regional anaesthesia and analgesia. The decision to proceed with regional anaesthesia in these patients should be made on a case-by-case basis. Meticulous regional anaesthetic technique should be observed to minimise further neurological injury.Neurological injury directly related to regional anaesthesia may be caused by trauma, neurotoxicity and ischaemia. Direct needle- or catheter-induced trauma rarely results in permanent neurological injury. The overall incidence of persistent paraesthesias has been estimated at 0.08% after spinal anaesthesia and at 2% after brachial plexus block1The needle-bevel configuration may influence the frequency and severity of peripheral nerve damage during regional anaesthesia. In an in vitro study, Selander et alNeurological deficits after regional anaesthesia may be a direct result of local anaesthetic toxicity. Clinical and laboratory findings indicate that anaesthetic solutions are potentially neurotoxicNeural ischaemia may occur as a result of systemic or local vascular insufficiency. Systemic hypotension with or without a spinal anaesthetic may produce spinal cord ischaemia in the watershed areas between radicular vessels, resulting in flaccid paralysis of the lower extremities . The use of local anaesthetic solutions containing epinephrine or phenylephrine may theoretically result in local ischaemia, especially in patients with microvascular disease, but clinical data are lacking8Previous spinal surgery has been considered to represent a relative contraindication to the use of regional anaesthesia. Many of these patients experience chronic back pain and are reluctant to undergo epidural or spinal anaesthesia, fearing exacerbation of their pre-existing back complaints. Several postoperative anatomical changes make needle or catheter placement more difficult and complicated after major spinal surgery. In a study 105 of 48 patients with chronic low back pain after spinal fusion, 8 showed significant spinal stenosis on computed tomographic scans and requited surgical decompressionThe guidelines for epidural anaesthesia after spinal surgery are unclear. Daley et alCrosby and HalpernHubbertThus, historically it was concluded that epidural anaesthesia may be successfully performed in patients who have had previous spinal surgery, but successful catheter placement may be possible on the first attempt in only 50% of patients, even by an experienced anaesthesiologist. Although adequate epidural anaesthesia is eventually produced in 40-95% of patients, there appears to be a higher incidence of traumatic needle placement, unintentional dural puncture and unsuccessful epidural needle or catheter placement, especially if spinal fusion extends to between L-5 and S-1.A more recent investigation examined the overall success and neurological complication rates among 937 patients with spinal stenosis or lumbar disc disease undergoing neuraxial block between 1988 and 2000Success rates did not differ between patients who had previous surgery and those who had undergone a spinal procedure. Ten patients experienced new or progressive neurological deficits compared with preoperative findings. Although the majority of the deficits were related to surgical trauma or tourniquet ischaemia, the neuraxial block was the primary aetiology in 4 patients.The preliminary nature of these data warrants care in their interpretation. However, overall, patients with spinal stenosis or lumbar disc disease may undergo successful neuraxial block without a significant increase in neurological complications. Importantly, this includes patients who have undergone prior (minor) spinal surgery.Progressive neurological disease is considered by some to be a relative contraindication to regional anaesthesia, because of the difficulty in determining the cause of new neurological deficits that appear perioperatively. There are no controlled clinical studies identifying regional anaesthesia as a significant factor in increased risk of neurological injury, only anecdotal reports are available. The medicolegal issue, however, remains, and if regional anaesthesia is indicated for other pre-existing medical conditions or by patient request, the patient should be informed of the risk of neurological complications, including coincidental progression of preoperative deficits, associated with anaesthesia and surgery. This discussion, along with preoperative neurological status, should be fully documented in the patient's record.Patients with preoperative neurological deficits may undergo further nerve damage more readily from needle or catheter placement, local anaesthetic systemic toxicity, and vasopressor-induced neural ischaemia. Although the use of paraesthesia techniques is not contraindicated, care should be taken to minimize needle trauma and intraneuronal injection. Dilute local anaesthetic solutions should be used whenever feasible to decrease the risk of local anaesthetic systemic toxicity.The use of epinephrine-containing solutions is controversial. The potential risk of vasopressor-induced nerve ischaemia must be weighed against the advantages of predicting local anaesthetic intravascular injections, improved quality of block, and decreased blood levels of local anaesthetics. Because epinephrine also prolongs and block and therefore neural exposure to local anaesthetics, the appropriate concentration and dose of local anaesthetic solutions must be considered. Patients with microvascular disease in combination with an underlying peripheral neuropathy, such as those with diabetes, may be most sensitive to the vasoconstrictive effects of epinephrine.Efforts should also be made to decrease neural injury in the operating room through careful patient positioning. Postoperatively, these patients must be followed closely to detect potentially treatable sources of neurological injury, including constrictive dressings, improperly applied casts and increased pressure on neurologically vulnerable sites. New neurological deficits should be evaluated promptly by a neurologist for formal documentation of the patient's evolving neurological status and the arrangement of further testing and long-term follow-up."} +{"text": "In brain mapping studies of sensory, cognitive, and motor operations, specific waveforms of dynamic neural activity are predicted based on theoretical models of human information processing. For example in event-related functional MRI (fMRI), the general linear model (GLM) is employed in mass-univariate analyses to identify the regions whose dynamic activity closely matches the expected waveforms. By comparison multivariate analyses based on PCA or ICA provide greater flexibility in detecting spatiotemporal properties of experimental data that may strongly support alternative neuroscientific explanations. We investigated conjoint multivariate and mass-univariate analyses that combine the capabilities to (1) verify activation of neural machinery we already understand and (2) discover reliable signatures of new neural machinery. We examined combinations of GLM and PCA that recover latent neural signals (waveforms and footprints) with greater accuracy than either method alone. Comparative results are illustrated with analyses of real fMRI data, adding to Monte Carlo simulation support."} +{"text": "Avery and Avery, who find comparing conventional Japanese and organic Swedish beef production misleading, propose relying on \u201ccomprehensive life cycle analyses\u201d (LCAs) to quantify emissions from conventional U.S. beef production. However, neither study they cite appears These results indicate that the intensification of beef production systems may be counterproductive because net emissions of carbon dioxide as well as nitrogen and other pollutants would increase.For a more comprehensive analysis, additional production aspects must be considered. A better comparison of conventional versus organic beef production may be an LCA of greenhouse gas (GHG) emissions from three Irish systems reported by In contrast to conventional production, organic farming can reduce nitrous oxide emissions by avoiding excessive amounts of manure, as stocking densities are limited to land available for manure application. Organic agriculture typically also uses less fossil-fuel energy, in part because thousands of feed transport miles may be reduced .2O in pasture soil organic matter , the Intergovernmental Panel on Climate Change concludeMost of the observed increase in global average temperatures since the mid-20th century is very likely due to the observed increase in anthropogenic GHG concentrations.The link between GHG mitigation and organic or extensive animal agriculture systems is well established, as are the other environmental and public health benefits of less-intensive production systems. Understanding the efficacy of less technology-dependent mitigation strategies is critical as the effects of global warming become more evident."} +{"text": "Studies on the zebrafish model have contributed to our understanding of severalimportant developmental processes, especially those that can be easily studied in theembryo. However, our knowledge on late events such as gonad differentiation in thezebrafish is still limited. Here we provide an analysis on the gene sets expressed inthe adult zebrafish testis and ovary in an attempt to identify genes with potentialrole in (zebra)fish gonad development and function. We produced 10 533 expressedsequence tags (ESTs) from zebrafish testis or ovary and downloaded an additional23 642 gonad-derived sequences from the zebrafish EST database. We clustered thesesequences together with over 13 000 kidney-derived zebrafish ESTs to study partialtranscriptomes for these three organs. We searched for genes with gonad-specificexpression by screening macroarrays containing at least 2600 unique cDNA insertswith testis-, ovary- and kidney-derived cDNA probes. Clones hybridizing to only oneof the two gonad probes were selected, and subsequently screened with computationaltools to identify 72 genes with potentially testis-specific and 97 genes with potentiallyovary-specific expression, respectively. PCR-amplification confirmed gonad-specificityfor 21 of the 45 clones tested . Our study, which involvesover 47 000 EST sequences and specialized cDNA arrays, is the first analysis of adultorgan transcriptomes of zebrafish at such a scale. The study of genes expressed inadult zebrafish testis and ovary will provide useful information on regulation of geneexpression in teleost gonads and might also contribute to our understanding of thedevelopment and differentiation of reproductive organs in vertebrates."} +{"text": "Cardiac surgery is associated with excessive bleeding as compared to non-cardiovascular surgery. In many situations excessive bleeding is expected but unexpected bleeding may pose problem during and, or after surgery. Studies have found certain predictors for bleeding like, increased age, emergency surgery, low body surface area, prolonged cardiopulmonary bypass (CPB) time > 150 minutes, combined intracardiac and bypass surgery, number of bypass grafts (> 4), reoperative surgery and preoperative antiplatelets agent. Between 3% to 14% of patients with significant bleeding require re-exploration.3Liberal use of red blood cells transfusion is associated with increased nosocomial infection and mortality in critically ill patients.5Current blood conservation practice guidelines suggest that institutions strategy should start with preoperative evaluation to identify high risk patients and appropriate management of antiplatelet therapy. In all planned surgery thienopyridines (clopidogrel) should be stopped 5 to 7 days prior to surgery except in patients with drug eluting stents, in whom sudden withdrawal of antiplatelets can result in sudden stent thrombosis. Aspirin should only be discontinued in purely elective cases without acute coronary syndrome. The addition of clopidogrel to aspirin increases postoperative haemorrhage. Yende and Wunderink demonstrated that aspirin and clopidogrel increase postoperative bleeding sevenfold.Evidence for transfusion trigger recommends use of haemoglobin level and platelets count for red cells and platelets transfusion respectively. More advanced measurements such as whole body oxygen-carrying capacity, oxygen consumption, oxygen extraction ratios, and oxygen delivery provide more accurate means to estimate the need for red blood cell transfusions.9Intraoperative techniques in blood conservation cannot be underemphasized. Meticulous haemostasis and operative technique can play an important role in reducing blood loss. Acute normovolaemic haemodilution (ANH) has not only been shown to be more cost effective than preoperative autologous donation but also is not limited by time restraints preoperatively. The strategy behind ANH is to lower the red blood cell mass loss during surgery while preserving clotting factors. However, the efficacy of ANH is controversial. Segal et at showed that ANH was only moderately effective in reducing transfusions by 10% or 1 to 2 units less than the control group.11To limit blood transfusions, The Society of Thoracic Surgeons(STS) and The Society of Cardiovascular Anesthesiologists(SCA) guidelines recommend use of aprotinin and lysine analogues epsilon am inocaproic acid (EACA) and tranexamic acid (Cyclokapron) in high risk patients. Aprotinin (Trasylol) and the lysine analogues have very different modes and scope of action but ultimately inhibit fibrinolysis by limiting the action of plasmin. A metaanalysis on aprotinin concluded significant reduction in blood transfusion in patients undergoing CABG, redo CABG and valve replacement.13Factor VIIa is recommended for intractable bleeding, unresponsive to usual hemostatics and non surgical means.Some intervention and modification during CPB are useful in blood conservation. Open reservoir membrane oxygenator system during CPB may reduce blood utilization and improve safety. Similarly activated clotting time (ACT) guided heparin dosing during prolonged CPB not only reduce blood transfusion but also haemostatic system activation, and platelets and proteins consumption as compare to fixed dose heparin supplements. Retrograde autologous priming of the CPB circuit, intraoperative autotransfusion, either with blood directly from cardiotomy suction or recycled using a cell-saving device, shortly after the completion of CPB, salvage of pump blood, either administered without washing or after washing with a cell-saving device should be used for blood conservation.8Lastly, one cannot ignore importance ofa multimodality approach involving multiple stakeholders, institutional support and enforceable transfusion algorithms supplemented with point-of-care testing to prevent blood loss and blood transfusion.8This becomes particularly important in a developing country like India with limited resources, variable quality of blood banking and surgical expertise with exponential growth of cardiac surgical centres. The role of anaesthesiologist is vital for implementing evidence based transfusion practices in cardiac surgery."} +{"text": "Mucobilia is a rare condition characterized by theaccumulation of abundant mucus within the intra- orextrahepatic biliary tree. A variety of hepatobiliaryand pancreatic neoplasms are mucin producingand have been associated with the development ofmucobilia including biliary mucinosis, biliary papillomatosis,mucin-producing cholangiocarcinoma(MPCC), or cystic neoplasms of the pancreas orbiliary tree (cystadenoma or cystadenocarcinoma).We report the case of 46 year-old male with a biliarycystadenocarcinoma of the caudate lobe which resultedin chronic biliary obstruction and relapsingcholangitis. A review of the literature for both mucobiliaand biliary cystadenocarcinoma is providedalong with a discussion addressing the clinical presentation,diagnosis, treatment, and prognosis forthis rare entity."} +{"text": "Vascular abnormalities are uncommon causes of uterine bleeding. Laparoscopic surgeries, however, require expertise and improper techniques can lead to major vascular complications. We report an unusual case of utero-adenexal arterio- venous fistula with arterio - venous malformation due to pelvic trauma caused during laparoscopic sterilisation procedure, which was treated by percutaneous embolisation technique. To the best of our knowledge, this is the first documentation of such a complex vascular injury caused by laparoscopic sterilisation and its endovascular management. Vascular abnormalities are rare but potentially life-threatening causes of uterine bleeding in women of reproductive age, especialA 35-year-old female presented with profuse, irregular, intermittent vaginal bleeding for the past six months. One month prior to onset of the symptoms she underwent a laparoscopic tubal ligation at a peripheral centre. Her past obstetric history was non-contributory. General, systemic and gynaecological examinations were unremarkable except for the presence of significant pallor. Abdominal and transvaginal sonography showed presence of multiple vascular channels in the parametrium and myometrium with a bulky uterus and fluid in the endometrial cavity. Color Doppler imaging, suggested presence of arterio-venous shunting. Pelvic magnetic resonance imaging (MRI) revealedDurreil and Loubat first described uterine AVM in 1926 and clasUltrasound with Color Doppler remains the primary imaging modality, which shows many hypoechoic or anechoic spaces, with evidence of flow on colour Doppler. Angiography is the gold standard for diagnosing these lesions and is essential to landmark the pattern of blood supply to the lesion pre-operatively. In addition, percutaneous endovascular embolisation preceding surgery can help contain the per-operative blood loss. Angiographic features consist of a complex tangle of vessels supplied by enlarged feeders from the uterine arteries. Early venous drainage indicated an associated AVF as was sAlthough laparoscopy is a relatively safe procedure occasionally serious complications such as major vascular injury (0.1 per 1000) arise. Such casEndovascular embolotherapy may serve as a viable option for management of vascular complications secondary to surgical trauma. The present report highlights a rare vascular complication due to a minimally invasive technique which was managed by another minimally invasive endovascular approach."} +{"text": "Bacterial pathogens have evolved extraordinary mechanisms to efficiently infect host organisms. A majority of these pathogens do so by delivering virulence factors into host cells, which act to dampen host defenses or utilize the host as a niche for replication. Although regulation of virulence factor expression by bacterial pathogens is a well known pathogenic mechanism Yersinia spp., Shigella flexneri, Helicobacter pylori, and diarrheagenic Escherichia coli are well known for their ability to kill host cells. For Yersinia, death of infected macrophages dampens cytokine release and enables the pathogen to propagate with minimal challenges from the immune system Yersinia species is tightly regulated. Yersinia pestis, the etiologic agent of plague, and gastroenteritis-inducing Yersinia pseudotuberculosis and Yersinia enterocolitica all encode a cytotoxic virulence factor called YopJ/P (YopJ in the two former species and YopP in the latter), which are translocated into infected cells via a type III secretion system (T3SS) Y. pseudotuberculosis affects its virulence. Decreased secretion of YopJ was shown to enhance Y. pseudotuberculosis pathogenesis in vivo Y. pestis, enhanced cytotoxicity results in decreased incidence of pneumonic plague in vivo Yersinia is an efficient virulence strategy. Increased apoptosis of infected immune cells decreases production of proinflammatory cytokines; however, some inflammation at the early stages of infection is thought to facilitate tissue damage necessary for movement of bacteria and infected cells to other sites of replication within the host Escherichia coli, enterohaemorrhagic E. coli , and Citrobacter rodentium are attaching and effacing (A/E) pathogens that cause severe diarrheagenic disease espZ mutant (\u0394espZ) caused enhanced cytotoxicity in host cells when compared to the wild-type strain espZ strain is severely attenuated for virulence in vivo Enteropathogenic H. pylori causes apoptosis of infected gastric epithelial cells H. pylori has been linked to a secreted toxin called VacA, which induces cytochrome c release from mitochondria by which S. flexneri enhances NF\u03baB-mediated pro-survival signals are unknown.All of the above pathogens have evolved strategies to attenuate their own host-damaging virulence factors. In many of these scenarios, removal of host-protective mediators actually reduces pathogenicity of the bacteria. The observation that EPEC encodes a host-protective virulence factor that is essential for its pathogenesis suggests that protecting host cells may be a key to the pathogenic strategies of other bacterial pathogens. The concept of host-protective virulence factors is only just emerging, and we believe host-protective virulence factors will become more apparent in other pathogenic strategies and may become interesting targets to combat bacterial disease. Importantly, virulence phenotypes that appear counterintuitive should not be ignored. Future studies into pathogenic mechanisms of virulent bacteria will likely reveal important roles for effectors or regulatory mechanisms that help the host cell and promote bacterial pathogenesis."} +{"text": "Background: Disseminated herpetic infections during pregnancy have been reported in the literature. Case: This case presentation describes a pregnant patient who presented with fever, elevated liver enzymes, and upper abdominal tenderness and succumbed from fulminant herpetic hepatitis. Conclusion: Early diagnosis and treatment are essential because of the high mortality rate."} +{"text": "The authors have determined that epineurial arteriolesof the sciatic nerve are innervated by nonadrenergic,noncholinergic nerves that contribute to the regulation ofvasodilation. Using immunohistochemistry, the authorsdetermined that nerves innervating epineurial arteriolescontain the neuropeptide calcitonin gene\u2013related peptide(CGRP). Using streptozotocin-induced diabetic rats, the authorsdemonstrated that CGRP content in sensory nervesinnervating epineurial arterioles and vasodilation in responseto exogenous CGRP was decreased. In summary,epineurial arterioles of the sciatic nerve are innervated bysensory nerves containing the neuropeptide CGRP. Thediabetes-like condition induced by streptozotocin reducesthe content of CGRP in these nerves and exogenous CGRPmediatedvasodilation. CGRP is likely an important regulatorof vascular tone and compromising its function couldcontribute to nerve ischemia and diabetic neuropathy."} +{"text": "This prompted us to examine the 3D vascular network of normal colon mucosa, adenomas and invasive carcinomas by means of quantitative microvascular corrosion casting. Fresh hemicolectomy specimens from 20 patients undergoing cancer or polyposis coli surgery were used for corrosion casting, factor VIII and VEGF immunostaining. In addition, immunostaining was done on colorectal tissue from 33 patients with metastatic and non-metastatic carcinomas, polyposis coli and adenomas. This first quantitative analysis of intervessel and interbranching distances, branching angles and vessel diameters in human cancer specimens revealed distinct patterns of the microvascular unit in the tumour centre and periphery. Irrespective of the tumour localization and grading all individual tumours displayed qualitatively and quantitatively the same vascular architecture. This gives further evidence for the existence of a tumour type-specific vascular architecture as recently demonstrated for experimental tumours. Metastatic tumours displayed different vascular architectures only within hot spots, in terms of smaller intervascular distances than in non-metastatic tumours. Pre-cancerous lesions have in part virtually the same vascular architecture like invasive carcinomas. Comparison of VEGF immunostaining also suggests that angiogenesis sets in long before the progress towards invasive phenotypes and that the so-called angiogenic switch is more likely a sequence of events. \u00a9 2001 Cancer Research Campaign"} +{"text": "Previously we have demonstrated that diabetescauses impairment in vascular function ofepineurial vessels, which precedes the slowingof motor nerve conduction velocity. Treatmentof diabetic rats with aldose reductaseinhibitors, aminoguanidine or myo-inositolsupplementation have been shown to improvemotor nerve conduction velocity and/ordecreased endoneurial blood flow. However,the effect these treatments have on vascularreactivity of epineurial vessels of the sciaticnerve is unknown. In these studies we examinedthe effect of treating streptozotocininducedrats with sorbinil, aminoguanidine ormyo-inositol on motor nerve conduction velocity,endoneurial blood flow and endothelium dependentvascular relaxation of arterioles thatprovide circulation to the region of the sciaticnerve. Treating diabetic rats with sorbinil,aminoguanidine or myo-inositol improved thereduction of endoneurial blood flow and motornerve conduction velocity. However, onlysorbinil treatment significantly improved thediabetes-induced impairment of acetylcholinemediatedvasodilation of epineurial vessels ofthe sciatic nerve. All three treatments were efficaciousin preventing the appropriate metabolicderangements associated with either activationof the polyol pathway or increased nonenzymaticglycation. In addition, sorbinil wasshown to prevent the diabetes-induced decreasein lens glutathione level. However, other markers of oxidative stress were not vividlyimproved by these treatments. These studiessuggest that sorbinil treatment may be moreeffective in preventing neural dysfunction indiabetes than either aminoguanidine or myoinositol."} +{"text": "Photofrin accumulation in malignant and host cell populations of various tumours was studied by flow cytometry analysis of cells dissociated from the tumour tissue. The transplantable mouse tumour models included in this analysis were sarcomas EMT6, RIF, KHT and FsaN, Lewis lung carcinoma, SCCVII squamous cell carcinoma (SCC) and slowly growing moderately differentiated AT17 SCC. An example of spontaneous mouse adenocarcinoma was also examined. Staining with specific monoclonal antibodies was used to identify the various cell populations present in these tumours. The main characteristic of Photofrin cellular accumulation was a very high photosensitiser content found exclusively in a subpopulation of tumour-associated macrophages (TAMs). Photosensitiser levels similar to or lower than in malignant cells were observed in the remaining TAMs and other tumour-infiltrating host cells. Photofrin accumulation in malignant cells was not equal in all tumour models, but may have been affected by tumour blood perfusion/vascularisation. Results consistent with the above findings were obtained with SCC of buccal mucosa induced by 9,10-dimethyl-1,2-benzanthracene in Syrian hamsters. The TAM subpopulation that accumulates by far the highest cellular Photofrin levels in tumours is suggested to be responsible for the tumour-localised photosensitiser fluorescence."} +{"text": "Research on the evolution of reproductive isolation in African cichlid fishes has largely focussed on the role of male colours and female mate choice. Here, we tested predictions from the hypothesis that allopatric divergence in male colour is associated with corresponding divergence in preference.Pseudotropheus zebra complex. We predicted that more distantly-related populations that independently evolved similar colours would interbreed freely while more closely-related populations with different colours mate assortatively. We used microsatellite genotypes or mesh false-floors to assign paternity. Fisher's exact tests as well as Binomial and Wilcoxon tests were used to detect if mating departed from random expectations.We studied four populations of the Lake Malawi P. emmiltos observed under control conditions. By contrast, assortative mating broke down when direct contact between female and male was prevented.Surprisingly, laboratory mate choice experiments revealed significant assortative mating not only between population pairs with differently coloured males, but between population pairs with similarly-coloured males too. This suggested that assortative mating could be based on non-visual cues, so we further examined the sensory basis of assortative mating between two populations with different male colour. Conducting trials under monochromatic (orange) light, intended to mask the distinctive male dorsal fin hues (blue v orange) of these populations, did not significantly affect the assortative mating by female We suggest that non-visual cues, such as olfactory signals, may play an important role in mate choice and behavioural isolation in these and perhaps other African cichlid fish. Future speciation models aimed at explaining African cichlid radiations may therefore consider incorporating such mating cues in mate choice scenarios. Drosophila . Theosophila , the breosophila , and theosophila providedCichlid fishes specialised to live on rocky shores are known to be philopatric and poor dispersers, with significant genetic structure among populations isolated by habitat discontinuities ,18. It hGasterosteus spp.) in North American lakes that have adapted to different ecological conditions and and P. eklebacks ,54,55. THaplochromine cichlids are usually strongly sexually dimorphic in colour. We do not yet know whether olfactory signals involved in mate choice are expressed by both sexes. If so, it would greatly increase the likelihood that mate preferences may be learned by imprinting on the mother during mouthbrooding, a situation that may enhance the probability of speciation . Sexual The three principal implications of the findings presented here are that: (i) behavioural mating preferences in cichlid fish depend, in some populations, not on colour, but on other forms of sensory communication, which in some cases is not visual; (ii) between-population divergence in male colour does not necessarily imply divergent female preferences, so parallel evolution of male colour is not necessarily coupled with parallel evolution of female mating preference; (iii) sensory cues involved in behavioural isolation among haplochromine cichlids may vary among species and lakes and so speciation models based on one particular mate choice scenario may not apply to whole or all radiations of cichlids. This last point is worth bearing in mind because the type of trait involved in species isolation might provide important clues about which evolutionary force has driven population divergence and speciation.JB performed microsatellite genotyping, statistical analyses, and drafted the manuscript. MP performed behavioural experiments. CR provided critical review and discussion of draft versions. MIT performed microsatellite genotyping and contributed to preparation of the final manuscript. OS provided critical review and discussion of draft versions and supervised the data collection for experiment 1. CVO contributed with critical discussion of draft versions. GFT coordinated the study and was involved throughout the design, analysis, interpretation and writing of the work. All authors have read and approved the final manuscript.Pseudotropheus zebra and related species populations.Results of mate choice trials involving The data presented are statistical analyses of the full data set, including female multiple spawnings and male multiple sirings, in mate choice trials involving either geographically and phylogenetically distant or proximal Pseudotropheus zebra and related species populations.Click here for file"} +{"text": "The concept of endotoxin-mediated rather than direct liver injury in biliary obsruction wasinvestigated using the experimental rat model of bile duct ligation (BDL) and small bowelbacterial overgrowth (SBBO). Small identical doses of intravenous endotoxin caused a significantly more severe liver injury in rats with BDL, compared with sham-operatedrats, suggesting the possible contribution of LPS in this type of liver damage. BDL was thencombined with surgically created jejunal self-filling blind loops, which resulted in SBBO. PlasmaLPS level increased significantly, and once again a more severe liver injury, determined by liverhistology and serum gamma-glutamyl transpeptidase levels, was observed compared with thecontrol group of rats with BDL+self-emptying blind loops. The data presented suggest thatsmall amounts of exogenous LPS and/or the ordinarily innocous amounts of LPS constantlyabsorbed from the intestinal tract may be critical in the hepatic damage caused by obstructionof the biliary tract."} +{"text": "Immunofluorescence studies of sera from mice with induced enhancement of tumour growth demonstrated that these sera contained factors (\"interfering factors\") which in an apparently competitive manner interfered with the subsequent binding of specific antibodies to antigenic sites on the tumour-cell membrane. The factors were tumour-specific but lacked some of the immunoglobulin determinants. They could not be detected by polyvalent FITC-antimouse gamma-globulin. Interfering factors did not seem to be related to IgA or IgE. They were demonstrable in sera from tumour-free animals without growing tumours, thus differing from the tumour-specific \"blocking factors\"."} +{"text": "The value of neuron specific enolase (NSE) immunoreactivity as a marker for small cell lung cancer (SLC) has been assessed using a monoclonal antibody (MCAB) against NSE, MCAB specificity was confirmed using purified enolase isoenzymes, sections of human brain, a panel of lung tumours, neuroendocrine and non-neuroendocrine tumours and normal tissues. Using this MCAB in radioimmunoassay and immunohistochemistry, NSE immunoreactivity was detected in all SCLC material examined. However, considerable reactivity was also observed in a number of non-small cell lung cancer cell lines and tumour biopsy specimens. Furthermore, intratumoral heterogeneity with respect to NSE immunostaining was observed in several cases. Factors which may underlie such intratumoral phenotypic diversity were assessed using flow cytometry together with MCABs directed against both NSE and non-neuronal enolase. Such studies revealed that enolase expression in cells which were no longer actively proliferating differed markedly from that of cells in exponential growth. Furthermore, cells grown under conditions of increasing hypoxia exhibited increased enolase expression relative to those grown under oxygenated conditions. It is concluded from these studies that NSE immunoreactivity per se is an unreliable marker for the SCLC phenotype."} +{"text": "ELISAs for pesticides and herbicides in environmental andagricultural samples are becoming very important in screeningapplications [1-3]. Traditional chromatographic methods areexpensive and results need long turnaround times, making themincompatible with rapid on-site decision making. ELISA methodshave been shown to meet or exceed the performance of gaschromatography\u2014they offer rapid low-cost analysis, therebyincreasing the frequency of sampling and enhancing data quality.Automated ELISA workstations allow the full benefit of these kitsto be realized. Sample preparation, reagent pipetting, incubation,and photometric evaluation can be performed without userintervention. Reliability is increased through the elimination ofoperator error, better accuracy and precision, and often higher speed.Much larger batch sizes are possible and these systems can providesample tracking with report generation for documentationrequirements. In this paper the manual procedures and ELISAmethods are compared and some critical aspects of automating theseELISA kits are discussed."} +{"text": "A 41-year-old female patient was admitted with streptococcal meningitis on a background of 5-month history of CSF rhinorrhoea. Imaging revealed an extensive skull base lesion involving the sphenoid and ethmoid sinuses, the pituitary fossa with suprasellar extension and bony destruction. Histological examination of an endonasal transethmoidal biopsy suggested a diagnosis of olfactory neuroblastoma. A profuse CSF leak occurred and the patient developed coliform meningitis. A second endonasal endoscopic biopsy was undertaken which demonstrated the tumour to be a prolactinoma. Following endonasal repair of the CSF leak and lumbar drainage, she developed profound pneumocephalus. The patient underwent three further unsuccessful CSF leak repairs. Definitive control of the CSF leak was finally achieved through a transcranial approach with prolonged lumbar drainage. This case illustrates some of the potentially devastating complications which can occur as a consequence of complex skull base lesions. A multidisciplinary approach may be required to successfully manage such cases. Traditionally, complex paranasal and anterior skull base lesions have been managed with either transcranial or transphenoidal microsurgical approaches. The application of endoscopy to neurological surgery and advances in neuronavigation have provided further options to skull base surgeons. One of the commonest complications of skull base lesions and their management is the occurrence of CSF leakage, which can result in the potentially fatal consequences of pneumocephalus and meningitis. Despite advances in microsurgical and endoscopic technology and expertise, definitive management of complex lesions and their resultant complications may require multidisciplinary team management and open transcranial neurosurgery. A 41-year-old female patient was referred to the ENT outpatient clinic with 5-month history of clear fluid discharging from the nose. Fluid samples were sent for tau protein analysis and outpatient imaging was requested. Prior to completion of skull base imaging, the patient was admitted in an acute confusional state, with a nonblanching rash, pyrexia, and signs of meningism. A diagnosis of streptococcal meningitis was made following lumbar puncture and she was commenced on appropriate antibiotics. Magnetic resonance imaging demonstrated an extensive skull base lesion involving the sphenoid and ethmoid sinuses, pituitary fossa, and suprasellar region . ComputeAn endonasal transethmoidal biopsy was undertaken, following which there was profuse CSF rhinorrhoea. Subsequently, the patient developed clinical signs of meningism with pyrexia, neck stiffness, photophobia, and deterioration in neurological status. CSF analysis revealed gram-negative coliforms and antibiotic treatment was commenced.The patient was transferred to the regional neuroscience centre for joint neurosurgical and ENT management. On recovery from the second episode of meningitis, she underwent an endoscopic endonasal biopsy and repair of the anterior pituitary fossa and planum sphenoidale using layered fat graft and artificial dural substitute sealed with Tisseel fibrin sealant . Histological analysis of this biopsy specimen confirmed the tumour to be a prolactinoma. Although her initial serum prolactin level was only 451\u2009miu/mL , it did rise to 953\u2009miu/mL in the immediate postbiopsy period. Following endocrine review, she was commenced on cabergoline.Despite satisfactory intraoperative appearances, CSF rhinorrhoea recurred. A CT cisternogram was undertaken to further characterise the site of CSF leakage . ThroughBoth attempts were unsuccessful and lumbar CSF drainage resulted in profound pneumocephalus . The patOnce sufficient neurological recovery had occurred, a second CT cisternogram was undeFollowing the fourth unsuccessful attempt, the patient underwent a transcranial repair of the CSF leak through a right-sided pterional craniotomy. Intraoperatively, no dural defect was visible; however, bony defects in the anterior pituitary fossa floor were palpable and therefore sealed with layers of temporalis fascia and muscle grafts secured with Tisseel sealant. A prolonged post-operative period of lumbar CSF drainage (7 days) was also undertaken which resulted in a successful control of CSF rhinorrhoea. The initial and subsequent biopsies were reviewed and showed an identical tumour consisting of sheets of cells with mildly pleomorphic round to oval nuclei and moderate amounts of eosinophilic cytoplasm . MitoticThe difficulties encountered in definitive occlusion of the bony defects resulting in CSF rhinorrhoea in this case are likely to have resulted from a number of causes. Whilst bony destruction is a recognised feature of aggressive prolactinomas, the extensive infrasellar growth pattern seen in this case is unusual . Once thThe potential pitfalls in differentiating olfactory neuroblastoma from prolactinoma and other paranasal tumours on histological examination have previously been described . The hisComplex paranasal and skull base lesions can result in bony defects and problematic CSF leaks. Although dopamine receptor agonists are the treatment of choice for prolactinomas, tumour shrinkage can take several weeks and residual tumour may contribute to recurrence of CSF leakage. Consequently, tumour debulking might be considered in patients with recurrent CSF rhinorrhoea in whom a histological diagnosis of prolactinoma has been confirmed. This case illustrates some of the potentially devastating complications of untreated CSF rhinorrhoea including recurrent meningitis and consequent raised CSF pressure, and pneumocephalus resulting in seizures and reduced conscious level. Management of these lesions requires a multidisciplinary approach involving ENT surgeons, neurosurgeons, neuroradiologists, and endocrinologists. The time at which endoscopic or transphenoidal approaches are abandoned in favour of transcranial surgery will depend on the surgical experience of the team and the anatomy of the site of CSF leakage. Despite advances in neuro-navigation and endoscopic surgery, transcranial repair maybe the only successful solution."} +{"text": "New computational tools were used to find a robust set of DNA oligomers that can distinguish artificial vector sequences from all available background viral and bacterial genomes. Using newly designed computational tools we show that, despite substantial shared sequences between natural plasmids and artificial vector sequences, a robust set of DNA oligomers can be identified that can differentiate artificial vector sequences from all available background viral and bacterial genomes and natural plasmids. We predict that these tools can achieve very high sensitivity and specificity rates for detecting new unsequenced vectors in microarray-based bioassays. Such DNA signatures could be important in detecting genetically engineered bacteria in environmental samples. Synthetic vector sequences are of fundamental importance in molecular biology. Cloning and expression vectors are among a multitude of synthetic sequence types commonly used as part of a basic tool set for DNA amplification and protein production . As the Large-scale computational pipelines have advanced bio-defense by efficiently finding polymerase chain reaction (PCR) assay-based primers that are able to accurately identify dangerous bacterial and viral pathogens -10. The A computational analysis was performed on the available synthetic vector sequences, which form an important basis for current tools in genetic engineering . One of k-mer matching (a k-mer is a nucleic acid sequence of length k). This alignment-free comparative sequence approach and [GenBank:4323404].The vector sequences with the greatest number of he graph with theCDS, coding sequence; MCS, multiple cloning site; PCR, polymerase chain reaction, RAM, random access memory.JEA, SNG and TRS conceived and designed experiments. JEA implemented experiments and drafted the manuscript. All authors read and approved the final manuscript.The following additional data are available with the online version of this paper. Additional data file The list of artificial vector identifiers.Click here for additional data fileThe list of natural plasmid identifiersClick here for additional data fileThe complete set of 30-mer signatures used in the cross-validation setClick here for additional data fileThe complete set of 60-mer signatures used in the cross-validation setClick here for additional data file"} +{"text": "Metering liquid reagents into reaction mixtures in a controlled andreproducible manner has often been a problem in syntheticchemistry. Carrying out the real simultaneous addition of two ormore liquid reagents (concurrent additions) is even more inconvenient.Difficulties increase when addition volumes become small,when addition times become long, or when the reagents are corrosiveor air-sensitive. We have constructed and tested an inexpensive,automated device for the slow, precise delivery of liquid reagentsinto laboratory-scale reaction mixtures. Controlled by a standardpersonal computer, this slow adder can accommodate liquidvolumes from hundreds of microlitres to litres and addition timesfrom minutes to days. Its glass and Teflon construction makes ituseful for nearly all reagents. By using multiple slow adders, trueconcurrent addition of several liquids can be easily achieved."} +{"text": "Cryostat sections and established in vitro cultures of dimethylnitrosamine(DMN)-induced renal mesenchymal tumours and monolayer cultures of transformed kidney cells derived from rats treated with a carcinogenic dose of DMN were examined by indirect immunofluorescence with human serum containing smooth muscle antibody. Eight mesenchymal tumours examined showed filamentous cytoplasmic staining of spindle cells infiltrating between renal tubules, whilst in normal kidneys interstitial cells were only weakly positive. In established in vitro cultures from 6 mesenchymal tumours, different patterns of staining were observed in morphologically different cell forms, ranging from fine filamentous staining in giant cells to diffuse cytoplasmic fluorescence in small bipolar cells, and cell outline staining in polygonal cells. In addition filamentous staining of microvillous projections and nucleolar staining were observed in some tumour cells. Monolayer cultures of transformed kidney cells showed strong staining of coarse, randomly-orientated cytoplasmic filaments, whilst fibroblasts cultured from normal rat kidney demonstrated an ordered array of fine, parallel filaments. Specificity of the immunofluorescent staining reaction was established by failure to obtain staining with normal serum, with smooth muscle antibody serum neutralized by homogenates of smooth muscle or extracts containing actin derived from smooth muscle. These results indicate that there is an apparent increase of actin-like contractile microfilaments in transformed cells and in renal mesenchymal tumours. The cytoplasmic contracile microfilaments in these cells may play a role in tumour cell mobility and invasion."} +{"text": "Plasmodium falciparum can induce immunity in patients from which further inhibits fertilization of gametes, and consequently oocyst production in the mosquito midgut [P. falciparum-infected blood fed to female Anopheles mosquitoes showed no oocyst production. Twenty-six percent of these oocyst inhibitory plasma distorted morphology and hampered maturity of the gametocytes (Fig.Gametocyte antigens of o midgut . Here, wytes Fig.. A possiAnti-gametocyte antibodies were elicited during natural malaria infection. The oocyst inhibitory antibodies diffused to and interacted with developing intraerythrocytic gametocytes and reduced number of stage II to V gametocytes, and hampered their maturation. Therefore the alternative development of transmission blocking vaccine in the high transmission area should focus on the identification of the gametocyte antigens inducing inhibitory antibodies to reduce gametocytemia."} +{"text": "A series of intensive, longitudinal, mark-recapture studies of hantavirus infection dynamics in reservoir populations in the southwestern United States indicates consistent patterns as well as important differences among sites and host-virus associations. All studies found a higher prevalence of infection in older mice; one study associated wounds with seropositivity. These findings are consistent with horizontal transmission and transmission through fighting between adult male rodents. Despite very low rodent densities at some sites, low-level hantavirus infection continued, perhaps because of persistent infection in a few long-lived rodents or periodic reintroduction of virus from neighboring populations. Prevalence of hantavirus antibody showed seasonal and multiyear patterns that suggested a delayed density-dependent relationship between prevalence and population density. Clear differences in population dynamics and patterns of infection among sites, sampling periods, and host species underscore the importance of replication and continuity of long-term reservoir studies. Nevertheless, the measurable associations between environmental variables, reservoir population density, rates of virus transmission, and prevalence of infection in host populations may improve our capacity to model processes influencing infection and predict increased risk for hantavirus transmission to humans."} +{"text": "Although basic mechanisms of bronchial hyper-responsiveness (BHR)are still incompletely understood, inflammation of airways is likelyto play a fundamental role in modulating BHR in patients withasthma. The involvement of several inflammatory cells andof bioactive mediators secreted by these cells in the pathogenesisof asthma is well documented. Sodium cromoglycate and nedocromilsodium are two pharmacological agents which have anti-allergic andanti-inflammatory properties. Their clinical effectiveness in mildto moderate asthma, and the capacity to reduce BHR under differentnatural and experimental conditions, make them valuable drugs formaintenance therapy in patients with asthma."} +{"text": "Beyond the classic Normal Pressure Hydrocephalus (NPH) triad of gait disturbance, incontinence, and dementia are characteristic signs of motor dysfunction in NPH patients. We used highly sensitive and objective methods to characterize upper limb extrapyramidal signs in a series of NPH subjects compared with controls. Concentrated evaluation of these profound, yet underappreciated movement disorders of NPH before and after techniques of therapeutic intervention may lead to improved diagnosis, insight into pathophysiology, and targeted treatment.Twenty-two (22) consecutive NPH patients and 17 controls performed an upper limb motor task battery where highly sensitive and objective measures of akinesia/bradykinesia, tone, and tremor were conducted. NPH subjects performed this test battery before and more than 36 h after continuous CSF drainage via a spinal catheter over 72 h and, in those subjects undergoing permanent ventriculo-peritoneal shunt placement, at least 12 weeks later. Control subjects performed the task battery at the same dates as the NPH subjects. Statistical analyses were applied to group populations of NPH and control subjects and repeated measures for within subject performance.Twenty (20) NPH subjects remained in the study following CSF drainage as did 14 controls. NPH subjects demonstrated akinesia/bradykinesia (prolonged reaction and movement times) and increased resting tone compared with controls. Furthermore, the NPH group demonstrated increased difficulty with self-initiated tasks compared with stimulus-initiated tasks. Following CSF drainage, some NPH subjects demonstrated reduced movement times with greater improvement in self- versus stimulus-initiated tasks. Group reaction time was unchanged. Resting tremor present in one NPH subject resolved following shunt placement. Tone measures were consistent for all subjects throughout the study.Clinical motor signs of NPH subjects extend beyond gait deficits and include extrapyramidal manifestations of bradykinesia, akinesia, rigidity, and propensity to perform more poorly when external cues to move are absent. Objective improvement of some but not all of these features was seen following temporary or permanent CSF diversion. The classic clinical triad of Normal Pressure Hydrocephalus (NPH) includes gait disturbance, incontinence, and dementia though most patients exhibit less than three of these signs early in the progressive clinical course ,2. In adThat ventriculo-peritoneal shunting reverses each of the classic signs in some NPH patients suggests a causative role in CSF dynamics, but the mechanisms underlying the neuronal and glial pathophysiology of NPH remain obscure. During the course of NPH, periods of elevated intracranial CSF pressure are hypothesized to result in dysfunction of white and gray matter of the brain . These hFew investigations of NPH patients have included objective and sensitive analysis of extrapyramidal motor signs, and examination of these signs outside of gait dysfunction are rarer still ,10-12. WThis study, together with patient recruitment, was approved by the Johns Hopkins University Institutional Review Board. Signed, informed consent was obtained from each subject. Twenty-two (22) consecutive subjects above the age of 50 referred for evaluation of possible NPH were recruited from the Johns Hopkins University Outpatient Center, with no enrollment restrictions based on race or ethnic origin. Requirements for inclusion were radiographic evidence of ventriculomegaly by CT scan or conventional MRI, and clinical signs of NPH that included gait impairment, urinary incontinence, or cognitive impairment. Subjects were excluded if they had undergone prior shunt or intracranial surgery, were unable to undergo lumbar puncture for CSF drainage or had other active neurologic disease . Controls (n = 17) were partners of eligible NPH subjects and were required to be free from clinical signs of NPH.NPH subjects were tested with the entire battery of tasks at 1) baseline, 2) within 36 h following removal of approximately 10 ml CSF/h for 72 h via a temporary spinal catheter and 3) approximately 12 weeks following ventriculo-peritoneal shunt insertion (Medtronic). Control subjects were tested with the entire battery of tasks on the same days of testing as NPH subjects. Two NPH subjects demonstrated signs of infection following CSF drainage via spinal catheter and were excluded from further testing and analysis. One subject withdrew consent to participate in the study after baseline testing such that subsequent data were not collected.Subjects performed ballistic movements using their dominant hand by moving a manipulandum that constrained two-dimensional movement about the wrist. Targets, 10\u00b0 wide and unbounded , were separated by 50\u00b0. Practice trials were performed for this simple task to avoid any potential learning curve barriers. Subjects reacted and moved in response to an auditory \"GO\" signal (stimulus-initiated tasks) or performed the identical movement task in the absence of a \"GO\" signal (self-initiated tasks). All subjects were informed ahead of time if they were to perform stimulus- or self-initiated tasks, and in both cases received preparatory auditory cues of \"ready\" and \"set\" in the initial stages of the task. In stimulus-initiated tasks, these preparatory cues preceded randomly delivered \"GO\" signals, and in self-initiated tasks, where no \"GO\" signal was delivered, a minimum time of 2 s of hold time was required after the \"set\" cue before initiating movement. Errors were recorded and the task discarded if movement occurred prior to 150 ms more than \"GO\" signal, more than 1 s after the \"GO\" signal, or if final target was overshot. An electronic goniometer continuously recorded manipulandum position during the task and was fed into an online recording computerized system along with auditory cues and electromyographic recordings of agonist and antagonist wrist muscles performing the task. Forty-five correctly performed trials were performed by each of the subjects. Reaction time (RT) was measured as time between \"GO\" signal and first significant change of the agonist electromyographic record (EMG) over baseline (RT/EMG) and between \"GO\" signal and movement onset (MO) (RT/MO). Electromechanical delay (EMD) was determined as the time between first agonist EMG and movement onset. Movement time (MT) was defined as the time between movement onset (MO) and achieving final target.k = the slope of force over displacement), or active EMG activity in primary agonists or antagonists about the elbow [Muscle tone was measured by an apparatus that quantifies tone about the elbow. Subjects rested their dominant forearm in a molded and padded cradle mounted on a metal beam. The cradle rotated on low-friction ball bearings and an electronic goniometer measured angular displacement. A load cell located at the side of the metal beam measured the torque applied by the examiner. The torque plotted against the angle (degrees) represented muscle stiffness, and post-hoc least squares fit analysis was then performed to determine the slope of the contour representing tone about the elbow . The tonhe elbow . Three dhe elbow .Tremor was analyzed using triaxial solid-state accelerometers that detect frequency (Hz) and amplitude in \u03bcm. Triaxial accelerometers were placed on the distal hand while the subjects' hands were at repose for a period of 120 s. Subjects were then asked to hold their arms outstretched, and tremor analysis was repeated during the next 60 s. All data were fed online to a Pentium based computer and analyzed using Fast Fourier Transforms. Mean tremor amplitude and dominant frequency were recorded while at rest and with outstretched arms.Group statistical analyses for parametric measures were compared using ANOVA tests with Fisher's Least Square Difference Post-Hoc analysis when F scores were significant or Kruskal-Wallis comparisons for non-parametric measures of reaction time. Analyses within individuals were compared using Repeated-measures ANOVA with Fisher's Least Square Difference or Friedman's analysis with Mann-Whitney Post-Hoc analysis.p < 0.01), or as RT/MO when compared with the control group . Mean movement times for stimulus-initiated and self-initiated tasks are plotted for each NPH subject at baseline in Figure As a group, NPH subjects demonstrated prolonged MT versus controls Table . At baseThose NPH subjects with fastest movement times (least bradykinetic) were least apt to exhibit discrepancies between self- and stimulus-initiated movements. Furthermore, those NPH subjects with fastest movement times were least apt to exhibit wide intertrial movement time variability as reflected by size of error bars Figure .p < 0.05), but this did not hold true for the group analysis comparing NPH subjects before and after continuous CSF drainage . Those subjects demonstrating significant differences of movement times from baseline following CSF drainage maintained this difference following shunt placement. Furthermore, selective improvement of self- versus stimulus-initiated movement times persisted with shunt placement Figure . Controlp < 0.02, Table p < 0.02, R2 = 0.79). Following CSF drainage and following shunt placement, there were also no significant changes in slope (representing rigidity at the elbow) for the NPH subjects. However, there were qualitative differences in tone hysteresis loops following CSF drainage in NPH subjects including greater incidence in EMG activity and sudden tone perturbations in the NPH group not seen in control subjects.Tone measures at baseline demonstrate increased passive tone about the elbow in NPH subjects compared with control cohorts . Although some subjects improved in both gait and upper extremity measures, this was not uniformly so \u2013 such that substantial improvement in gait measures did not always coincide with improvement in ballistic measures. Since none of the subjects improved in measures of tone, improvement in gait did not correlate with this measure. Interestingly, some of those subjects that demonstrated increased upper extremity bradykinesia following CSF drainage also demonstrated worsening bradykinesia in gait testing.In a parallel study, these same subjects underwent formal gait analysis in NPH subjects. This implies that different pathophysiological substrates underlie each of these motor signs in NPH, and/or that these signs emerge independently. Of these extrapyramidal signs, not all respond equally to CSF drainage. Why would only some symptoms respond to CSF drainage? It is plausible that some structures revert to normal function with reduction of direct shearing forces, while others are irreversible or require time for tissue recovery or compensatory pathways to develop. In addition, there is always a potential for multiple etiologies to confound the presentation and responsiveness of clinical signs related to NPH, but our selection criteria sought to minimize these factors.It is an interesting finding that some NPH patients demonstrated the classic Parkinsonian motor characteristic of improved movement execution in the presence of external cues. Others have seen a less dramatic benefit of external cues when studying NPH patients during gait analysis ,18. Our NPH subjects demonstrate increased tone compared with controls. This tone is unrelated to spasticity and independent of movement speed. Our measures of tone are highly sensitive, and even a significant increase in tone compared with controls may be subclinical. From what is known of NPH, one would expect a supraspinal mechanism underlying increased tone. Such mechanisms have been proposed for the increased tone seen in Parkinsonism . There wThe underlying motor pathophysiology of NPH signs extends beyond gait and bladder dysfunction with prevalence of extrapyramidal signs. These include even complex Parkinsonian signs of reliance upon external cues for improved motor performance. That NPH subjects demonstrated improvement of some signs in short order following CSF drainage suggests reversible pathophysiologic mechanisms that can improve activities of daily living. However, sensitive and objective motor measures in this sample suggest other motor dysfunction is resistant to immediate correction by CSF drainage and may be recalcitrant or require chronic treatment to see improvement.Dr. Michael A. Williams and Dr. Daniele Rigamonti have received honoraria in the past from Medtronic, Inc. Dr. George Thomas worked at the Adult Hydrocephalus Center at Johns Hopkins when this study was conducted. His salary was supported by a grant from Medtronic, Inc.ASM provided study design, oversight of data acquisition, data analysis, and drafting the manuscript. JH tested each subject, performed data collection and first stage data analysis. GT provided subject recruitment, scheduling and evaluation. REM participated in critical review of the manuscript and in evaluation of study design. TOC participated in provided testing environment and critical analysis on data collection and interpretation. MAW contributed in patient evaluation and categorization and critical manuscript review. DR contributed to study design, patient evaluation and critical manuscript review. All authors have read and approved the final manuscript."} +{"text": "Recent advances in genomics provide genetic information from humans and othermammals traditionally used as models as wellas new candidates (pigs and cattle). In addition, linked enabling technologies,such as transgenesis and animal cloning, provide innovative ways to design andperform experiments to dissect complex biological systems. Exploitation of genomicinformation overcomes the traditional need to choose naturally occurring models.Thus, investigators can utilize emerging genomic knowledge and tools to createrelevant animal models. This approach is referred to as reverse genetics. In contrastto \u2018forward genetics\u2019, in which gene(s) responsible for a particular phenotypeare identified by positional cloning (phenotype to genotype), the \u2018reverse genetics\u2019approach determines the function of a gene and predicts the phenotype of acell, tissue, or organism (genotype to phenotype). The convergence of classicaland reverse genetics, along with genomics, provides a working definition of a\u2018genetic model\u2019 organism (3). The recent construction of phenotypic maps definingquantitative trait loci (QTL) in various domesticated species provides insights intohow allelic variations contribute to phenotypic diversity. Targeted chromosomalregions are characterized by the construction of bacterial artificial chromosome(BAC) contigs to isolate and characterize genes contributing towards phenotypicvariation. Recombineering provides a powerful methodology to harvest geneticinformation responsible for phenotype. Linking recombineering with gene-targetedhomologous recombination, coupled with nuclear transfer (NT) technology canprovide \u2018clones\u2019 of genetically modified animals."} +{"text": "Repeated treatment with streptozotocin selected toxin resistant subpopulation of insulin producing tumor RINmS cells, characterized increased level of insulin content and secretion. In the present study RINmS cells were found to have higher glucose sensitivity and insulin response compared with parental RINm cells. In addition, compounds known to induce elevated level of cAMP beta-cells, such as isobutyl methyl xanthine, and forskolin, potentiated glucose-induced insulin secretion of RINmS, but had no effect on the naive parental RINm cells. These experiments suggest that differentiation therapy can be utilized for engineering insulin producing cells with improved defense and secretory mechanisms.Differentiation therapy has been proposed as a new approach to selectively engage the process of tumor cell differentiation during chemotherapy of cancer. Our recent"} +{"text": "Molecular epidemiologic studies of infectious diseases rely on pathogen genotype comparisons, which usually yield patterns comprising sets of DNA fragments (DNA fingerprints). We use a highly developed genotyping system, IS6110-based restriction fragment length polymorphism analysis of Mycobacterium tuberculosis, to develop a computational method that automates comparison of large numbers of fingerprints. Because error in fragment length measurements is proportional to fragment length and is positively correlated for fragments within a lane, an align-and-count method that compensates for relative scaling of lanes reliably counts matching fragments between lanes. Results of a two-step method we developed to cluster identical fingerprints agree closely with 5 years of computer-assisted visual matching among 1,335 M. tuberculosis fingerprints. Fully documented and validated methods of automated comparison and clustering will greatly expand the scope of molecular epidemiology."} +{"text": "Tissue sections of frozen biopsy specimens obtained from normal and hyperplastic human lymphoid tissues, 33 cases of non-Hodgkin lymphomas as well as various forms of immunoregulatory disorders (angioimmunoblastic and dermatopathic lymphadenopathy) were analysed in immunofluorescence tests (using red TRITC and green FITC double-labelling). A panel of antisera including well-characterized conventional reagents to immunoglobulin classes, T lymphoid and Ia-like antigens, and monoclonal antibodies was used. In selected cases the results were compared with the observations of membrane-marker staining on viable cells in suspension. the findings show that the immunological methods can give a very accurate analysis of the normal and malignant lymphoid cells, and can provide complementary information to conventional histology. The investigator can choose the reagent combinations which give answers to various specific questions: e.g. antisera to light chains establish the monoclonality of lymphomas, whilst staining combinations for human T and Ia-like antigens are particularly useful in various immunoregulatory disorders. Monoclonal antibodies will be particularly useful in various immunoregulatory disorders. Monoclonal antibodies will be particularly useful reagents for analysing the tissue distribution of lymphoid subpopulations and ancillary cells in tissue biopsy specimens."} +{"text": "Mycobacterium ulcerans infection, all of whom received rifampicin-based oral antibiotic therapy followed by surgical resection (three patients) or oral antibiotics alone (one patient). Following oral antibiotics for between 4 and 8 weeks, viable M. ulcerans was not detectable by culture in three of the patients, or by histology in a fourth patient from whom no specimen for culture was obtained. All cases spent time in a BU-endemic area in coastal Victoria, Australia. Baseline characteristics, diagnosis, treatment received, and histopathology of resected specimens are detailed in Buruli ulcer (BU) was treated primarily with wide surgical excision until recent studies confirmed the efficacy of oral rifampicin combined with intramuscular streptomycin. Whether all-oral antibiotic regimens will be equally effective is unknown. This report describes four patients with M. ulcerans was confirmed by positive polymerase chain reaction (PCR) and isolation of M. ulcerans by culture from swabs obtained prior to treatment. Three patients had ulcerative lesions suggest that shorter periods may be effective as suggested for the combination of rifampicin and streptomycin In the four patients we have described here, combination oral antibiotic therapy prior to excision led to the inability to recover Treatment of patients with limited BU prior to surgery using rifampicin-based oral antibiotics resulted in culture-negative resection specimens.Clinical healing is slow despite the microbiological activity of oral antibiotics.Apparent relapses that occur during or after treatment may be due to immunologically driven paradoxical reactions rather than primary treatment failure.M. ulcerans infection followed by delayed surgery appears to simplify management by allowing excision and closure in one step without relapse.Rifampicin-based oral antibiotic therapy for the treatment of"} +{"text": "Iodised oil (lipiodol) administered via the hepatic artery localises selectively in primary liver cell cancers (hepatocellular carcinomas or HCCs) for prolonged periods and has been used as a vehicle for cytotoxic agents. Despite clinical use, the mechanism of lipiodol retention by tumours has remained unclear, embolisation of oil droplets in the tumour vasculature being the prevailing hypothesis. We have investigated the role of tumour and endothelial cells in lipiodol retention. Human liver tumour (Hep G2) cells and human umbilical vein endothelial cells in culture were exposed to lipiodol. Light microscopy using selective silver impregnation stains and transmission electron microscopy revealed lipiodol incorporation by both cell types, probably by pinocytosis. This was not associated with cellular injury in terms of cell lysis, cell replication or radio-labelled leucine uptake. Histological analysis of 24 HCCs either surgically resected or discovered incidentally at liver transplantation revealed vesicles of lipiodol in the cytoplasm of tumour cells and endothelial cells lining tumour vessels. Thus, lipiodol is likely to deliver cytotoxic agents directly into tumour cells and endothelial cells, both in vitro and in vivo. This may also apply to other lipids and to other human tumours. These findings have significant therapeutic implications."} +{"text": "Progressive night blindness and constriction of the visual fields are features of Bietti crystalline corneoretinal dystrophy, but here we report a case with the most probable diagnosis of Bietti crystalline dystrophy and good central visual acuity and severely decreased electroretinogram.The patient was a 28-year-old woman with complaint of decreased vision without night blindness. Her both eyes visual acuity were 20/25 with plano refraction. Fundus examination showed intraretinal crystals distributed in the posterior pole and also midperiphery. Fullfield electroretinogram showed decreased scotopic a and b-wave amplitudes.In our patient central foveal region was relatively intact; and this can explain subnormal visual acuity. Although visual acuity was nearly spared, electroretinogram was extremely affected. Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive disorder of retinal degeneration characterized by numerous tiny sparkling yellow-white spots at the posterior pole of the fundus. The small glistering crystals can also occur in the corneal limbus and circulating lymphocytes ,2. CliniA 28-year-old Iranian Caucasian woman referred to our clinic with complaints of decreased vision without night blindness and visual acuity of both eyes was 20/25 with plano refraction. Her slit lamp examination revealed clear cornea and clear lens, and 1+ pigment in vitreous. Intraocular pressure was 18 mmHg for right eye and 17 mmHg for left eye. She did not have any history of associated other medical conditions or drug usage.Fundus examination showed intraretinal crystals distributed in the posterior pole and also midperiphery. There was midperipheral RPE and choriocapillaris atrophy, peripheral pigment clumping and retinal scarring . FlouresFullfield ERG showed severely decreased scotopic a and b-wave amplitudes. Moreover, the photopic a and b wave amplitudes were both severely attenuated . Visual Bietti first reported cases of tapetoretinal degeneration characterized by yellow glistering retinal crystals, choroidal sclerosis, and marginal crystalline dystrophy of the cornea. Similar cases with no limbal crystalline deposits have been reported and called Bietti crystalline fundus dystrophy or crystalline retinopathy -8. The pAffected patients presented with visual symptoms from the third decade onward. The most common presenting symptom is a decrease in visual acuity, often accompanied by nyctalopia. In the presented patient, visual acuity was good and central vision had not been affected. This sparing of the central vision until late in the disease is also recently described in European patients with BCD .Patient with RPE atrophy and intraretinal crystals confined to the posterior pole tend to show lesser disturbances in the full-field electroretinogram (ERG) . This isHistologically, BCD shows evidence of advanced panchorioretinal atrophy characterized by generalized loss and sclerosis of the choriocapillaris with crystals and complex lipid inclusions within the choroidal fibroblasts. The abnormal inclusions are similar to those found in circulating lymphocytes, keratocytes, and conjunctival and skin fibroblasts ,2. AccorBietti initially noted similarities with retinitis punctata albescens and fundus albipunctatus. These conditions are considered flecked retina syndromes and do not have the distinctive crystalline deposits in patients with Bietti\u2019s crystalline dystrophy. Several advanced cases of Bietti\u2019s crystalline dystrophy have been misdiagnosed as retinitis pigmentosa, since advanced cases may have severe visual loss, extensive chorioretinal atrophy, pigment deposition, minimal crystals, and nonrecordable ERG. The diagnosis of BCD is based on clinical findings; biomicroscopic and ophthalmoscopic appearance are usually sufficient to make diagnosis . We can"} +{"text": "The regulation of cholesterol esterification during cell proliferation was studied. The serum free cholesterol, cholesterol esters and lecithin: cholesterol acyltransferase (LCAT) activity of nude mice with and without pancreatic acinar cell tumours and rats with proliferating tissues were determined. In addition, the apparent activity of acyl-CoA: cholesterol acyltransferase (ACAT) in homogenates of nude mouse tumours and proliferating rat tissues were determined and compared with those of normal nude mouse and rat tissues. Serum cholesterol ester levels were significantly lower in host nude mice with tumours and in rats with regenerating liver, and increased significantly in pregnant rats when compared with respective controls. Circulating LCAT activity levels decreased in host nude mice, in pregnant rats, and in rats with regenerating pancreas and regenerating liver. Apparent ACAT activity levels increased significantly in nude mouse tumours and in foetal and postnatal rat pancreata and also in postnatal liver. At the same time, apparent ACAT activity levels decreased in foetal and regenerating rat livers when compared with respective control tissues. These results suggest that serum cholesterol esters, circulating LCAT and cellular ACAT levels are modulated during cell proliferation."} +{"text": "We describe a novel, testable theory of autoimmunity, outline novel predictions made by the theory, and illustrate its application to unravelling the possible causes of idiopathic thrombocytopenia purpura (ITP). Pairs of stereochemically complementary antigens induce complementary immune responses (antibody or T-cell) that create loss of regulation and civil war within the immune system itself. Antibodies attack antibodies creating circulating immune complexes; T-cells attack T-cells creating perivascular cuffing. This immunological civil war abrogates the self-nonself distinction. If at least one of the complementary antigens mimics a self antigen, then this unregulated immune response will target host tissues as well. Data demonstrating that complementary antigens are found in some animal models of autoimmunity and may be present in various human diseases, especially ITP, are reviewed. Specific mechanisms for preventing autoimmunity or suppressing existing autoimmunity are derived from the theory, and critical tests proposed. Finally, we argue that Koch's postulates are inadequate for establishing disease causation for multiple-antigen diseases and discuss the possibility that current research has failed to elucidate the causes of human autoimmune diseases because we are using the wrong criteria."} +{"text": "High-throughput custom designed genotyping arrays are a valuable resource for biologically focused research studies and increasingly for validation of variation predicted by next-generation sequencing (NGS) technologies. We investigate the Illumina GoldenGate chemistry using custom designed VeraCode and sentrix array matrix (SAM) assays for each of these applications, respectively. We highlight applications for interpretation of Illumina generated genotype cluster plots to maximise data inclusion and reduce genotyping errors.We illustrate the dramatic effect of outliers in genotype calling and data interpretation, as well as suggest simple means to avoid genotyping errors. Furthermore we present this platform as a successful method for two-cluster rare or non-autosomal variant calling. The success of high-throughput technologies to accurately call rare variants will become an essential feature for future association studies. Finally, we highlight additional advantages of the Illumina GoldenGate chemistry in generating unusually segregated cluster plots that identify potential NGS generated sequencing error resulting from minimal coverage.We demonstrate the importance of visually inspecting genotype cluster plots generated by the Illumina software and issue warnings regarding commonly accepted quality control parameters. In addition to suggesting applications to minimise data exclusion, we propose that the Illumina cluster plots may be helpful in identifying potential in-put sequence errors, particularly important for studies to validate NGS generated variation. The generation of next-generation sequencing (NGS) quencies ,2. For cThe Illumina platform has proven reliable and efficient for a number of high-throughput genotyping applications using DNA extracted from several sources, -9. VeraCIn this study, we assess genotype information generated on custom-designed Illumina 96-SNP VeraCode and BeadArray Sentrix Array Matrix (SAM) assays, for optimal generation of accurate genotyping and NGS generated variant validation. Application of strict analysis parameters may lead to valuable genetic information being lost. Alternatively, limited QC may result in the addition of incorrect genotype calls confounding data analysis. The SNP assays described in this study have the potential of being disregarded or falsely included during analysis based on the current QC selection criteria. We discuss the importance of visually inspecting each cluster plot, particularly for custom designed genotype arrays, and suggest strategies for interpreting data in plots that would normally be discarded during the QC process.Sarcophilus harrisii). DNA was genotyped as part of a validation of sequence variation determined from minimal coverage (0.3\u00d7 versus 0.5\u00d7) of NGS de novo sequencing data of two animals using the Roche/454 Titanium chemistry (unpublished data). Genotype analysis was performed using a custom 96-plex SAM array for 96 samples. For both studies, the GoldenGate genotyping procedure was performed as outlined by Illumina [Two sample data sets were used to assess and interpret Illumina-generated genotype cluster plots. The first was part of a gene/pathway targeted human prostate cancer association study. In brief, DNA was extracted from dried blood spots (Guthrie card) and genotyped using a custom 96-plex VeraCode SNP array for 768 samples (unpublished data). In the second study, DNA was extracted from ear clippings of Tasmanian devils , the eight VeraCode runs were assessed individually. The genotype cluster plots generated by each VeraCode and SAM assays were visually inspected for quality of calls. Plots that appeared to be \"unusually\" clustered ) were further investigated by selecting samples to assess by direct Sanger sequencing for genotype confirmation. Samples were sequenced using Big Dye Terminator v3.1 chemistry according to manufacturer's guidelines and sequenced on an AB 3730 genetic analyzer (AB).Using the VeraCode technology we observed several consistent examples of SNP cluster plots that appeared to be incorrectly genotyped due to a combination of a short \u03b8 and the presence of outlier DNA samples. In the two examples discussed in this study Figure , the previce versa for the X-linked variants , genotyping technologies must accurately perform two-cluster calling. In this study successful two-cluster calling was observed for both rare autosomal , direct Sanger sequencing revealed a single nucleotide error in the NGS generated data surrounding the putative SNP. In the examples highlighted in this study Large-scale custom-designed genotyping studies have been made feasible by the development of high-throughput technologies and improvements of automated genotype calling software. In this study we demonstrate how simple applications for interpreting automatically generated Illumina cluster plots can be used to avoid spurious genetic associations as well as optimising data inclusion and interpretation, particularly for custom designed target arrays.Variation in quality and quantity of DNA input, is largely unavoidable in large-scale studies. In order to limit the effect potential outlier DNA samples may have on genotype calls, it is important to visually inspect the genotype plots and exclude outliers as demonstrated in this study Figure . In addiInvestigating the disease-causing potential of rare variants , can prde novo generated NGS data, we observed several examples of individual clusters being partially segregated within the one genotype group which lead to the identification of NGS-generated sequencing error. We therefore suggest that visual inspection and closer investigation of unusually clustered scatter plots, may provide information that exceeds the initial goal of SNP validation and is a complimentary tool for NGS data validation.A growing number of laboratories are employing the use of NGS technology to sequence as yet unclassified genomes, as well as resequencing of human and human disease-associated genomes. From the predicted sequence variants generated by these projects, custom-designed arrays are being employed for validation and frequency determination. Although the optimal coverage required to distinguish true sequence variation is highly debatable, and dependent on the type of NGS platform used, high-throughput genotyping platforms allow for rapid, cost-effective validation at even minimal coverage. The SAM array discussed in this study was developed from long-read NGS information generated from minimal coverage of two samples of an as yet unsequenced species (unpublished data). In both the VeraCode assay, custom designed to genotype 96 confirmed human variants, and the SAM array, designed to verify newly identified variants from p Figure and 4. Ap Figure , the unuWe demonstrate in this study, applications to optimise and improve the efficiency of data analysis generated using the Illumina GoldenGate chemistry using logical interpretation of both rare and common genotyping data. We also present this platform as a successful tool for NGS variant validation, which is applicable to even limited sequence coverage.The authors declare that they have no competing interests.WM and SCS provided analysis of NGS data, EAT, DCP and SN performed genotyping and Sanger sequencing analysis; EAT, DCP, SN and VMH were involved in data analysis; and EAT and VMH participated in study design and manuscript drafting. All authors read and approved the final manuscript."} +{"text": "Many growth factors are implicated in the pathogenesisof proliferative diabetic retinopathy. Alteration of growthfactors and their receptors in diabetes has been shown inboth experimental and clinical studies. Sustained hyperglycemiaresulting from long-standing diabetes leads to severalbiochemical abnormalities that consequently result inretinal hypoxia. Retinal oxygenation state regulates variousgrowth factors that promote angiogenesis in order to meetthe oxygen demands of the tissue. However, unregulated expressionof these growth factors and induction of complexcascades leading to augmentation of other proangiogenicfactors, which may not be regulated by tissue oxygenation,leads to uncontrolled retinal neovascularization and blindnessin diabetic patients."} +{"text": "Complete mitochondrial genome sequences have become important tools for the study of genome architecture, phylogeny, and molecular evolution. Despite the rapid increase in available mitogenomes, the taxonomic sampling often poorly reflects phylogenetic diversity and is often also biased to represent deeper (family-level) evolutionary relationships.Solenopsis, which represent various evolutionary depths. Overall, ant mitogenomes appear to be typical of hymenopteran mitogenomes, displaying a general A+T-bias. The Solenopsis mitogenomes are slightly more compact than other hymentoperan mitogenomes (~15.5 kb), retaining all protein coding genes, ribosomal, and transfer RNAs. We also present evidence of recombination between the mitogenomes of the two conspecific Solenopsis mitogenomes. Finally, we discuss potential ways to improve the estimation of phylogenies using complete mitochondrial genome sequences.We present the first fully sequenced ant (Hymenoptera: Formicidae) mitochondrial genomes. We sampled four mitogenomes from three species of fire ants, genus The ant mitogenome presents an important addition to the continued efforts in studying hymenopteran mitogenome architecture, evolution, and phylogenetics. We provide further evidence that the sampling across many taxonomic levels (including conspecifics and congeners) is useful and important to gain detailed insights into mitogenome evolution. We also discuss ways that may help improve the use of mitogenomes in phylogenetic analyses by accounting for non-stationary and non-homogeneous evolution among branches. There has been a rapid proliferation of whole mitochondrial genomes (mitogenomes) sequenced in recent years, no doubt driven in part by the increasing speed and decreasing cost of sequencing technologies. Whole mitogenomes are increasingly used in phylogenetic studies -6 and inHowever, the utility of these datasets for these purposes greatly depends on taxon sampling. Currently, 237 insect mitogenomes have been fully sequenced , yet the taxa utilized for these sequencing studies often do not reflect the distribution of species diversity. For example, Hymenoptera is one of the most species-rich insect orders , yet onNasonia and Drosophila yakuba [GenBank: NC001322]. We subsequently designed additional primers spanning other regions with no or low coverage using sequence data generated for fire ants. All primers developed and used for this study are presented in Additional file Complete mitochondrial genomes were generated for four individuals from three closely related Brazil) . We sequ Brazil) as well Several lines of evidence suggest that our sequences generated specifically represent mitochondrial genomic DNA rather than nuclear mitochondrial-like sequences (numts), which appear to be common and are generally short and highly fragmented in ants and other Hymenoptera -83: The HQ215537, HQ215538, HQ215539, HQ215540].All PCR amplicons were sequenced in both directions and each strand was assembled into single contigs with overlapping ends, indicating that our mitogenome sequences contained no gaps. Leading and lagging strand for each mitogenome were then aligned and manually checked for indels or ambiguous base calls. Mitogenomes were deposited in the NCBI GenBank database , 3 beetles , and 3 moths ). jModeltest and sub-tree pruning and regrafting [SPR]) on five random starting trees. In addition to running one hundred bootstrap replicates to estimate levels of branch support, we also implemented the SH-like aLRT, which assesses the likelihood gain of the presence of that branch [Maximum likelihood analyses were implemented on the PhyML 3.0 webserver http://wwt branch . To accot branch using deThe evolution of tRNA-N was studied using phylogenetic analyses as suggested by Saks et al. and DowtJC and DDS carried out all aspects of the molecular lab work. DG and DDS performed all analyses of the data and wrote the manuscript. All authors read and approved the final manuscript.Primers used for PCR amplification and sequencing of fire ant genomes. Primers names and sequences used in this study. J and N within primer names refer to heavy and light strands, respectively, and indicate the orientation of the primers. Primer names beginning with \"Gem\" were designed specifically to amplify the mitogenome of S. geminata.Click here for file"} +{"text": "Lindbergh.Pacemakers have evolved over a period of time trying to mimic the normal response rates, conduction and activation characteristics, though are still far from what nature has bestowed upon us. Better understanding of cardiac physiology and hemodynamics has led to current available pacing technology and we do recognize now that to achieve physiological pacing we should have an appropriate heart rate response, ventriculo-ventricular (VV) synchronization and atrio-ventricular (AV) synchronization.Patients receiving rate responsive pacemakers for sinus node dysfunction, in spite of using various sensors and rate response algorithms -5, stillRight ventricular (RV) pacing represents a non-physiological activation of the heart causing wide QRS (left bundle branch block) with electrical and mechanical VV dyssynchrony . Higher Optimal AV interval at rest ranges from 100 to 150 milliseconds. In normal individuals the AV interval shortens with increased heart rate during exercise in a predictable and linear fashion. Most pacemakers have a programmable shortening of AV delay at higher rates, the hemodynamic benefits of which have not yet been shown . Device An electrocardiogram based method to determine optimal AV interval is described by Sorajja et al in this Based on echocardiographic parameters and natriuretic peptide levels, AV delay optimization is found to be beneficial in patients with normal LV function in short term small studies -25. TherAdopt the pace of nature: her secret is patience - Ralph Waldo EmersonLook deep into nature, and then you will understand everything better - Albert Einstein"} +{"text": "Tibialis posterior has a vital role during gait as the primary dynamic stabiliser of the medial longitudinal arch; however, the muscle and tendon are prone to dysfunction with several conditions. We present an overview of tibialis posterior muscle and tendon anatomy with images from cadaveric work on fresh frozen limbs and a review of current evidence that define normal and abnormal tibialis posterior muscle activation during gait. A video is available that demonstrates ultrasound guided intra-muscular insertion techniques for tibialis posterior electromyography.Current electromyography literature indicates tibialis posterior intensity and timing during walking is variable in healthy adults and has a disease-specific activation profile among different pathologies. Flat-arched foot posture and tibialis posterior tendon dysfunction are associated with greater tibialis posterior muscle activity during stance phase, compared to normal or healthy participants, respectively. Cerebral palsy is associated with four potentially abnormal profiles during the entire gait cycle; however it is unclear how these profiles are defined as these studies lack control groups that characterise electromyographic activity from developmentally normal children. Intervention studies show antipronation taping to significantly decrease tibialis posterior muscle activation during walking compared to barefoot, although this research is based on only four participants. However, other interventions such as foot orthoses and footwear do not appear to systematically effect muscle activation during walking or running, respectively. This review highlights deficits in current evidence and provides suggestions for the future research agenda. The tibialis posterior (TP) muscle has a vital role during gait; via multiple insertion points into the tarsal bones it acts as the primary dynamic stabiliser of the rearfoot and medial longitudinal arch (MLA) ,2. The sThe TP muscle is contained within the deep posterior compartment of the lower limb, arising from the adjacent posterior surfaces of the tibia, fibula and interosseus membrane Figure . The tenThe TP tendon has multiple insertions within the foot, dividing into three main components: (i) anterior; (ii) middle; and (iii) posterior -23. The The most common modality used to quantify TP muscle activation is via EMG recorded with intramuscular electrodes. The advantage of using EMG over other modalities (such as MRI and ultrasound) is the ability to investigate muscle activation simultaneously with dynamic weightbearing tasks such as walking. However, due to the deep location of the muscle within the posterior compartment of the leg, surface electrodes cannot record TP EMG activity without signal cross-talk from various superficial muscles Figure . Therefo(i) the posterior-medial; and (ii) the anterior insertion. A video demonstration of both approaches can be viewed via downloadable supplements with the use of ultrasound guidance. All five electrodes were correctly located in the muscle belly of TP; figure Experience gained (GSM) in performing more than 150 intramuscular EMG electrode insertions into TP has led to some important practical insights. Participants usually describe low to mild discomfort during the insertion procedure with approximately 1 in 20 describing severe pain, although this has not been quantified using a validated pain scale. When participants experience severe pain, the wires are removed and a second attempt at relocating new wire electrodes is undertaken; rarely is a third attempt required. During walking, participants usually describe 'mild' pain for the first couple of minutes, which frequently subsides to 'no' or 'low' pain after this period. Mild calf pain is often experienced for 24 hours following the insertion procedure. There were no reported cases of serious complications such as infection. The use of wire electrodes is generally a safe and effective method of investigating tibialis posterior EMG during walking.Current literature has characterised TP EMG during gait among normal and pathological populations and with various interventions including antipronation taping, foot orthoses and athletic footwear. Figure Normative EMG for TP during walking is based on studies with typically small sample sizes (ranging from 5 to 12) and with participants' age ranging from 18 to 76 years ,12,27-29TP EMG activity during running was characterised by Reber and colleagues when theOverall, the availability of normative EMG for TP during walking is based on relatively small sample sizes and is limited to only adult and older adult participants. Despite the absence of normative data, other studies have investigated TP EMG activation with pathological conditions including rheumatological and neurogenic diseases. With the high variability seen in healthy people, it is difficult to conclude whether the findings from studies investigating abnormal muscle activity are meaningful.Tibialis posterior tendon dysfunction (TPTD) has been reported as the most common cause of adult acquired flatfoot ,22,31,32It has been suggested that certain rheumatological conditions may predispose to TPTD including rheumatoid arthritis (RA) ,39 and sDespite the uncertainty regarding the pathogenesis of pes plano valgus, gait analysis has been shown to improve our understanding of this condition in RA ,45. Yet TP muscle dysfunction is likely to occur with many neurogenic conditions, however little is known about how many of these conditions affect TP muscle activity during walking. Cerebral palsy is one neurogenic condition where TP muscle activation has been investigated as part of several laboratory-based clinical assessments -53. CereIntramuscular electrodes have been utilised to assess TP muscle activation among infants, children and young adult patients (age range: 4\u201324 years) \u2013 often as part of a surgical planning procedure Figure 46-50].-50.46-50A further study by Michlitsch and colleagues involvedWhile there is consensus among these investigations that both TP and tibialis anterior contribute to varus or equinovarus foot deformity with cerebral palsy, one major shortcoming is that none of these investigations have directly compared TP EMG profiles to age matched control groups within the same study. This may account for the different and potentially invalid classifications among these studies of TP dysfunction with cerebral palsy. Further normative EMG from TP is required to inform studies investigating pathological sub-types of TP muscle dysfunction in children with cerebral palsy.Only one study has investigated the effect of foot orthoses on TP activation during walking despite These findings contrast another investigation on the effect of anti-pronation taping on TP EMG during walking in four young- to middle-aged adults with flat-arched feet . FranettA number of studies investigating TP EMG activation in health and disease have been undertaken with small sample sizes providing preliminary evidence of either abnormal function or response to intervention. Accordingly, further EMG studies, recruiting larger sample sizes and representation from the younger and older populations, are required to investigate both the effect of interventions on TP muscle activity and to establish a reference database. Whilst it has been recognised that TP plays a vital role during gait, further work is required to more fully understand the role of TP in the development of pathology and in disease-specific populations including RA, cerebral palsy and TPTD.In summary, TP EMG remains a specialist investigation undertaken in relatively few centres internationally; however, this technique has multiple applications both in research and in planning interventions and evaluating outcomes. Recent advances in technology, including imaging, represent an opportunity to employ this technique more frequently and advance our understanding in a variety of areas.The authors declare that they have no competing interests.DET and JW conceived the idea for the review, RS and GSM drafted the manuscript and the figures, GSM prepared the video supplement, JW and DET critically revised the manuscript. All authors read and approved the final manuscript.Posterior approach. A video demonstration of the posterior approach of intramuscular electrode insertion. Additional files 1 and 2 can only be viewed using the latest version of QuickTime Player which can be downloaded via the following link: http://www.apple.com/downloads/Click here for fileAnterior approach. A video demonstration of the anterior approach of intramuscular electrode insertion.Click here for file"} +{"text": "We report a case of a rapid renal deterioration due to ureteropelvic junction obstruction (UPJO) in an asymptomatic woman with prior normal diuretic renography. This case illustrates \u201csilent\u201d renal obstruction and the inability of diuretic renography in detecting significant renal obstruction. This case may favor close surveillance of any adult patient with potential UPJO, especially those with underlying renal disease or solitary kidney. Ureteropelvic junction obstruction (UPJO) is an uncommon condition in adults. UPJO is most commonly diagnosed during childhood with treatment required for any patient demonstrating renal deterioration, stone formation, infection, or pain. Not all patients with hydronephrosis require intervention, although the natural history of untreated UPJO is better understood in children than adults. We describe a woman who rapidly developed renal deterioration due to UPJO despite lacking symptoms and previous normal evaluation by diuretic renography.A 62-year-old woman was referred for a brief episode of left flank pain and imaging demonstrating fullness of the left renal pelvis . She hadAt the request of her primary care physician, the patient underwent repeat computed tomography (CT) imaging 12 months later despite being asymptomatic. Repeat imaging demonstrated severe left-sided hydronephrosis . Repeat The natural history of UPJO in adulthood is poorly understood but believed to be related to intrinsic narrowing of the upper ureter or extrinsic pressure on the ureter caused by aberrant vessels or fibrous bands. As prenaAlthough there is evidence that not all pediatric patients demonstrating hydronephrosis require intervention, the natural history of untreated UPJO in adults is less well documented. Most studies document preservation or improvement of renal function following treatment for adult UPJO.\u20135 A smalThe case presented documents rapid renal deterioration from UPJO in an asymptomatic adult patient with prior normal evaluation for presence of obstruction. Although undoubtedly rare, this case illustrates that diuretic renography may not detect significant renal obstruction, and that renal deterioration may occur in an otherwise asymptomatic patient. The sensitivities of current standards for the diagnosis of UPJO, namely diuretic renography and CT scanning, are imperfect. There remains room for improvement in the diagnosis, perhaps at a functional imaging level or at a molecular level, of UPJO.Nonetheless, serial imaging in all asymptomatic patients who have a normal evaluation for the presence of UPJO cannot be recommended, however repeat imaging (ultrasound or CT scanning) may be prudent in patients at risk for renal compromise . Patients and physicians need be aware of silent renal obstruction and the potential for diuretic renography and CT scanning to, at least transiently, miss the diagnosis."} +{"text": "The streptococcal preparation OK432 was studied for its effects on natural killer (NK) activity of peripheral blood lymphocytes (PBL) from normal donors and from ovarian cancer patients, and of tumour-associated lymphocytes (TAL) from peritoneal effusions. OK432 augmented NK activity against the susceptible K562 line and induced killing of the relatively resistant Raji line. Freshly isolated ovarian carcinoma cells were relatively resistant to killing by unstimulated PBL and TAL. OK432 induced significant, though low, levels of cytotoxicity against 51Cr-labelled ovarian carcinoma cells. Augmentation of killing of fresh tumour cells by OK432 was best observed in a 20 h assay and both autologous and allogeneic targets were lysed. PBL were separated on discontinuous Percoll gradients. Unstimulated and OK432-boosted activity were enriched in the lower density fractions where large granular lymphocytes (LGL) and activity against K562 were found. Thus, OK432 augments NK activity of PBL and TAL in human ovarian carcinomas and induces low, but significant, levels of killing of fresh tumour cells. Effector cells involved in killing of fresh ovarian tumours copurify with LGL on discontinuous gradients of Percoll."} +{"text": "A new imaging modality framework, calledelasto-mammography, is proposed to generate the elastograms ofbreast tissues based on conventional X-ray mammography. Thedisplacement information is extracted from mammography projectionsbefore and after breast compression. Incorporating thedisplacement measurement, an elastography reconstruction algorithmis specifically developed to estimate the elastic moduli ofheterogeneous breast tissues. Case studies with numerical breastphantoms are conducted to demonstrate the capability of theproposed elasto-mammography. Effects of noise with measurement,geometric mismatch, and elastic contrast ratio are evaluated inthe numerical simulations. It is shown that the proposedmethodology is stable and robust for characterization of theelastic moduli of breast tissues from the projective displacementmeasurement."} +{"text": "Recent preclinical work investigating the role of progenitor cell therapies for central nervous system (CNS) injuries has shown potential neuroprotection in the setting of traumatic brain injury (TBI), spinal cord injury (SCI), and ischemic stroke. Mechanisms currently under investigation include engraftment and transdifferentiation, modulation of the locoregional inflammatory milieu, and modulation of the systemic immunologic/inflammatory response. While the exact mechanism of action remains controversial, the growing amount of preclinical data demonstrating the potential benefit associated with progenitor cell therapy for neurological injury warrants the development of well-controlled clinical trials to investigate therapeutic safety and efficacy. In this paper, we review the currently active or recently completed clinical trials investigating the safety and potential efficacy of bone marrow-derived progenitor cell therapies for the treatment of TBI, SCI, and ischemic stroke. Our review of the literature shows that while the preliminary clinical trials reviewed in this paper offer novel data supporting the potential efficacy of stem/progenitor cell therapies for CNS injury, a great deal of additional work is needed to ensure the safety, efficacy, and mechanisms of progenitor cell therapy prior to widespread clinical trials. Central nervous system (CNS) insults including ischemic stroke, traumatic brain injury (TBI), and traumatic spinal cord injury (SCI) represent a major burden to the healthcare system worldwide. Approximately 5 million people are burdened by the long-term physical, cognitive, and psychosocial deficits associated with TBI in the United States with 40% of patients reporting unmet needs 1 year post injury . OverallPreliminary research is currently underway to evaluate the potential efficacy of adult tissue progenitor (stem) cell therapies for the treatment of CNS injury. Adult tissue progenitor cells are located in select microenvironments (niches) which protect against overproliferation and depletion as well as regulate progenitor cell involvement in resident tissue repair and regeneration . By defiRecent preclinical work investigating bone marrow derived-progenitor cell therapies for CNS injury has shown potential neuroprotection after TBI , ischemiin vitro with subsequent implantation into rodent cortex after focal ischemic injury. The implanted progenitor cells were found to display neural cell markers and engraft up to 100 days after injury with associated behavioral recovery ..46].Geron Corporation has started a United States Food and Drug Administration (FDA) approved trial using embryonically derived oligodendroglial precursor cells to replace myelin-forming cells within injured spinal cords. The cell preparations are injected directly into the spinal cords at the lesion site. The treatment population is restricted to adults with complete thoracic (T3\u2013T9) level SCI. Patients must undergo treatment within 7 to14 days following injury. Preclinical data showing that SCI animals treated with Geron's cell line developed cysts at the level of treatment caused the FDA to put a hold on the clinical trial. Geron and the FDA have reached an agreement to allow the trail to move forward if subsequent preclinical studies provide satisfactory outcome.in vivo cell tracking need to be completed to ensure the safety of potential trials while affording them the best possible chance at success. Additional preclinical work to more clearly delineate the progenitor cell mechanism of action would also aid in the planning of quality-controlled clinical studies. Overall, while the very preliminary clinical trials reviewed in this paper offer novel data supporting the potential efficacy of cell therapeutics for CNS injury, a great deal of additional work is needed to ensure the safety and efficacy of progenitor cell therapy prior to widespread clinical trials.Prior to large, multicenter clinical trials investigating the potential efficacy of progenitor cell therapies for CNS insults, a number of issues need to be addressed. Further research into optimal cell dosing, cell delivery method, and techniques for"} +{"text": "Fungal diseases are increasing among patients infected with human immunodeficiency virus (HIV) type 1. Infections due to Candida and Cryptococcus are the most common. Although mucocutaneous candidiasis can be treated with oral antifungal agents, increasing evidence suggests that prolonged use of these drugs results in both clinical and microbiologic resistance. The optimal therapy for cryptococcal meningitis remains unresolved, although initial treatment with amphotericin B, followed by life-long maintenance therapy with fluconazole, appears promising. Most cases of histoplasmosis, coccidioidomycosis, and blastomycosis occur in regions where their causative organisms are endemic, and increasing data suggest that a significant proportion of disease is due to recent infection. Aspergillosis is increasing dramatically as an opportunistic infection in HIV-infected patients, in part because of the increased incidence of neutropenia and corticosteroid use in these patients. Infection due to Penicillium marneffei is a rapidly growing problem among HIV-infected patients living in Southeast Asia. Although the advent of oral azole antifungal drugs has made primary prophylaxis against fungal diseases in HIV-infected patients feasible, many questions remain to be answered before the preventive use of antifungal drugs can be advocated."} +{"text": "A(PDPK FA) was overexpressed in various cancerous tissues relative to normal controls. However, the functional role of overexpressed PDPK FAin cancer remains to be established. In this report, we explore the potential role of PDPK FAin leukaemia cell growth by investigating the effects of partial inhibition of this kinase on the malignant phenotype of human chronic myeloid leukaemia cells (K562). Cloning of PDPK FAcDNA and its recombinant antisense expression vector and PDPK FA-specific antibody were successfully developed. Two stable antisense clones of K562 cells were subcloned which expressed 70% and 45% of PDPK FArespectively, compared with control-transfected clone in both immunoprecipitate activity assay and immunoblot analysis. In sharp contrast, these two antisense clones expressed no significant suppression of any other related PDPK family members, indicating the specificity of these two antisense clones. Moreover, these antisense clones proportionally and potentially exhibited cell growth retardation, poor clonogenic growth in soft agar and loss of serum independence. The results demonstrate that specific antisense suppression of PDPK FAis sufficient to interfere with the growth of K562 cells, indicating that PDPK FAis essential for human chronic myeloid leukaemia cell growth. \u00a9 2000 Cancer Research CampaignInitial studies revealed that proline-directed protein kinase F"} +{"text": "The importance of the applications of lanthanides, as an excellent diagnosticand prognostic probe in clinical diagnostics, and an anticancer material, is remarkably increasing. Lanthanidecomplexes based X-ray contrast imaging and lanthanide chelates based contrast enhancing agents formagnetic resonance imaging (MRI) are being excessively used in radiological analysis in our body systems.The most important property of the chelating agents, in lanthanide chelate complex, is its ability to alter thebehaviour of lanthanide ion with which it binds in biological systems, and the chelation markedly modifiesthe biodistribution and excretion profile of the lanthanide ions. The chelating agents, especially aminopolycarboxylic acids, being hydrophilic, increase the proportion of their complex excreted from complexedlanthanide ion form biological systems. Lanthanide polyamino carboxylate-chelate complexes are used ascontrast enhancing agents for Magnetic Resonance Imaging. Conjugation of antibodies and other tissuespecific molecules to lanthanide chelates has led to a new type of specific MRI contrast agents and theirconjugated MRI contrast agents with improved relaxivity, functioning in the body similar to drugs. Manyspecific features of contrast agent assisted MRI make it particularly effective for musculoskeletal andcerebrospinal imaging. Lanthanide-chelate contrast agents are effectively used in clinical diagnosticinvestigations involving cerebrospinal diseases and in evaluation of central nervous system. Chelatedlanthanide complexes shift reagent aided"} +{"text": "Peripheral-blood monocytes from normal individuals and from patients with malignant melanoma reduce nitroblue tetrazolium (NBT). A quantitative assay for dye reduction was applied to 25 healthy donors and 31 patients with malignant melanoma. NBT reduction expressed as dye reduction per monocyte was significantly impaired in patients with disseminated disease, and they responded poorly to a phagocytic stimulus. Monocytes from patients with micrometastatic disease, however, showed normal resting NBT reduction but, following exposure to a suspension of latex-polystyrene, showed significantly greater NBT reduction than those from normal individuals. Since NBT reduction is an indirect measure of intracellular hexose-monophosphate-shunt activity we conclude that the monocytes from patients with minimal disease are in some way activated."} +{"text": "The STAR-VA training program in Veterans Health Administration Community Living Centers (CLCs) has been helping interdisciplinary care teams understand and manage dementia-related behaviors in the nursing home setting, with promising clinical outcomes. However, sustaining a new care approach in a health care system poses multiple challenges. This presentation will discuss facilitators and barriers to STAR-VA sustainability based on CLC team and nurse leader feedback. Findings are informing development of a new site coaching program and a sustainability toolkit. Feedback to date suggests that critical STAR-VA implementation and sustainability strategies include: regularly scheduled team meetings to discuss behavioral assessment and care plans; ongoing staff training ; communicating care plans across shifts and in the health record; multiple nurse/shift champions; impromptu huddles; acknowledging staff successes; leadership engagement. The coaching program engages teams in setting and tracking site sustainability goals. Lessons learned will be discussed."} +{"text": "Persons with dementia frequently demonstrate behavior symptoms of dementia (BSD), associated with poorer outcomes. A measure of BSD was created for routine use in VA Community Living Centers (CLCs). Reliability and validity of Minimum Data Set (MDS 3.0) behavior items was established using exploratory factor analysis and a multitrait, multimethod correlation matrix. 385 CLC residents with BSD were assessed using validated measures of BSD, depression, and anxiety, and team ratings of the frequency and severity of target behaviors identified for intervention. Factor analysis on MDS items closest to baseline resulted in two stable factors. MDS behavior factors related to validated clinical measures in predicted ways at baseline and post-intervention. MDS distress behavior factor sensitivity to change was evaluated by using change score correlations with validated clinical measures. The MDS distress behavior factor can be used routinely, evaluate the impact of intervention effectiveness, and provide quality improvement feedback."} +{"text": "Primary immunodeficiencies (PID) are a heterogeneous group of disorders with a variable clinical spectrum of manifestations. The central nervous system may be involved in PID with symptoms which may present initially or develop at later stages. The purpose of this study was to review the neurological manifestations of different PID syndromes.We focused on 104 selected studies on PID with certain neurological abnormalities which may accompany these disorders or may later signify a PID in their course.Diverse neurological deficits accompanying certain PIDs may be mild or they may greatly influence the course of the disease with major impacts on the quality of life of these patients.Early recognition and treatment is important to prevent or reduce future irreversible neurological sequelae. Therefore physicians should be aware of the neurological features accompanying PID. Primary immunodeficiencies (PID) are a heterogeneous group of 354 distinct disorders with 344 different gene defects with a vPIDs have been classified practically according to the affected immune function to the following groups: immunodeficiencies affecting cellular and humoral immunity, combined immunodeficiencies with associated or syndromic features, antibody deficiencies, diseases of immune dysregulation, congenital defects of phagocytes, defects in intrinsic and innate immunity, autoinflammatory disorders, complement deficiencies and phenocopies of PIDs . The cenNeurological manifestations will be discussed in detail according to the specific classification of primary immunodeficiencies to assist the treating physicians\u2019 timely diagnosis and prompt treatment in order to avoid irreversible neurologic sequelae. The categorization of the inborn errors of immunity is based on the International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity ADA is a ubiquitous enzyme in purine salvage pathway which is also expressed in both the peripheral and central nervous systems . ADA defDNA Ligase IV deficiencyThis autosomal recessive form of SCID is caused by an impairment of the DNA damage repair process with a pronounced radiosensitivity . DNA douCernunnos deficiencyThis is another rare autosomal recessive form of SCID with severe T and B lymphopenia and dysgammaglobulinemia in addition to radiosensitivity caused by mutations in the CERNUNNOS or XRCC4-like factor (XLF). Microcephaly and developmental delay are the prominent neurological features . CID with associated or syndromic featuresAtaxia-TelengiectasiaThis autosomal recessive complex disorder with substantial severity in affected individuals is charaThere are also Ataxia Telengiectasia-Like Disorders (ATLD) which are clinically similar to ataxia telengiectasia although without telangiectasia and a slower progression of neurologic manifestations. These patients remain ambulatory until their third decades of lives , 20.Nijmegan Breakage SyndromeThis is a rare autosomal recessive, multisystemic disease of chromosomal instability presenting at birth with microcephaly but no additional neurologic manifestation . The mutImmunodeficiency, Centromeric Region Instability and Facial Anomalies SyndromeThis genetic disease is due to a mutation in DNA methylteransferase gene which caRiddle SyndromeThis syndrome is characterized by a defect in DNA damage response causing immunodeficiency and increased radiosensitivity accompanied by neurologic symptoms and growth delay due to an increased apoptosis and reduced proliferative capacity during brain development presenting as mild motor control and learning difficulties . DiGeorge SyndromeIn addition to the characterizing triad of cardiac defects, hypocalcemia and cellular immune deficiency, there may be neurological manifestations which present with developmental delay in motor, language and speech areas, neuropsychiatric problems and epilepsy . Most paHyper-immunoglobulin E syndromeThese syndromes are characterized by recurrent skin and pulmonary infections in the presence of elevated IgE concentrations and usually eosinophilia. The hyper-IgE syndromes have four distinct genetic causes including mutations in signal transducer and activator of transcription 3 (STAT3), dedicator of cytokinesis 8 (DOCK8), tyrosine kinase2 (TYK2) and phosphoglucomutase 3 (PGM3) , 34. VasSchimke Immuno-osseous DysplasiaThis autosomal recessive disorder is caused by mutation in the SMARCAL1 gene which encodes a chromatin remodeling protein. Defective cellular immunity causes recurrent bacterial, fungal and viral infections which in association with short stature and progressive renal insufficiency characterizes the disorder . NeuroloHoyeraal-Hreidarsson syndromeThis is an X-linked recessive disorder of telomere dysfunction which represents a severe form of dyskeratosis congenita characterized by a classic triad of reticular skin pigmentation, dysplastic nails and oral leukoplakia . PancytoPurine Nucleoside Phosphorylase DeficiencyThis rare autosomal recessive metabolic disorder, similar to ADA deficiency, results from impaired purine salvage pathway which causes combined immunodeficiency in association with prominent neurological abnormalities . \u201cMutatiHepatic Veno-Occlusive Disease with ImmunodeficiencyThis is caused by homozygous mutation in the autosomal SP110 gene. The onset of clinical features usually occurs before the age of six months with hepatic sinusoidal obstruction. Serum Ig levels are low. T cell subsets and B-cell numbers are reduced. Neurological abnormalities include leukodystrophy and extensive cerebral necrosis on postmortem examination are found in one third of the patients .VICI Syndrome This rare autosomal recessive disorder is caused by mutation in the EPG5 gene which results in defective autophagy . ClinicaPredominantly Antibody deficiencyCommon variable immunodeficiencies and agammaglobulinemia are the most frequent forms of presentations of antibody deficiency. Symptoms mainly consist of respiratory or gastrointestinal involvement. However, neurologic manifestations may also occur. Common Variable ImmunodeficiencyNeurologic manifestations are a complex of diverse and rare complications of CVID including brain or spinal cord infections (meningitis as the most common neurologic manifestation), autoimmune involvements , transveAgammaglobulinemiaIn patients with agammaglobulinemia symptoms mainly consist of recurrent respiratory or gastrointestinal infections. Serum immunoglobulins are severely decreased and usually undetectable . CNS comDisorders of Immune RegulationChediac Higashi SyndromePatients with this autosomal recessive lethal disorder present with recurrent respiratory and bacterial skin infections due to severe immunodeficiency, partial oculocutaneous albinism, bleeding tendency and progressive neurological features . This syHermansky-Pudlak syndrome type 2Among Hermansky Pudlak syndromes, this type is characterized by an immunodeficiency due to neutropenia and T lymphocyte dysfunction which differentiates it from other types of this syndrome . These pFamilial Hemophagocytic LymphohistiocytosisFHL comprises a group of autosomal recessive life-threatening disorders characterized by uncontrolled proliferation of activated lymphocytes and macrophages associated with massive secretion of cytokines infiltrating into organs including lymph nodes, bone marrow, liver, spleen and central nervous system , 71. CNSCongenital defects of phagocytic number or functionChronic Granulomatous DiseaseChronic granulomatous disease is the most common inherited disorder of phagocytic cells. It results from an inability of phagocytes to produce bactericidal superoxide anions due to defects of the NADPH oxidase system and it leads to the defect in killing of a specific spectrum of bacteria and fungi resulting in concomitant hyper-inflammation and tissue granuloma formation . NeuroloSevere Congenital NeutropeniaThis term is used for a heterogeneous group of primary immunodeficiencies including sporadic autosomal recessive, autosomal dominant and x-linked types of whichSchwachman-Diamond SyndromeThis is a multisystem disorder characterized by bone marrow failure, exocrine pancreatic insufficiency and metaphyseal chondrodysplasia. These features are attributed to mutation in SBDS gene . HoweverLeukocyte Adhesion Deficiency type 2LAD syndromes consist of rare autosomal recessive disorders among which only LAD type 2 presents with neurologic abnormalities. These patients are characterized by recurrent bacterial infections without pus formation in the first years of life and severe mental retardation later . Other n\u03b2-Actin deficiencyThis autosomal dominant immunodeficiency disorder caused by a non-lethal mutation, characterized by defects in neutrophil migration, mental retardation, short stature, thrombocytopenia and photosensitivity . The halAutoinflammatory DisordersMevalonate Kinase Deficiency (MKD)This is a term used for a wide clinical spectrum of autosomal recessive disorders due to a congenital error in cholesterol biosynthesis, with hyperimmunoglobulinemia D syndrome as the benign variant of the disorder and Mevalonic aciduria as the more severe form of MKD . MevalonNeonatal Onset Multisystem Inflammatory DisorderThe disease results from mutations in the CIAS-1 gene which encodes cryopyrin . CryopyrBlau syndrometh nerve palsy, cerebral vasculitis and cerebral infarction (This rare autosomal dominant syndrome clinically resembles early onset sarcoidosis characterized by granulomatous inflammation mostly involving joints, eyes and skin -97 and ifarction , 101.Aicardi-Goutieres syndromeThis is a genetically determined encephalopathy caused by mutations in TREX1 genes encoding RNAs involved in removing RNA, leading to the accumulation of endogenous RNA, triggering Toll-like receptor-dependent interferon-\u03b1 production in the brain with the resultant activation of neurotoxic lymphocytes and immune system in addition to the inhibition of angiogenesis , 103. NeIn conclusion, neurological manifestations of primary immunodeficiencies are common with diverse pathologic mechanisms. Neurological deficits may be mild or they may greatly influence the course of the disease with major impacts on the quality of life of the patients. Some of these complications may even cause death. Neurological manifestations may have an early onset, beginning at birth or they may appear later which in both situations may lead to misdiagnosis and delayed therapy. Therefore a high suspicion of an underlying primary immunodeficiency is important in any type of neurological problems occurring with recurrent infections. All three authors were involved in data collection, and writing the article.The authors declare that there is no Conflict of Interest."} +{"text": "Previous studies highlighted the destructive effects of neurotoxin on integrity of nigral dopamine system, accompanying series of changes in motor regulating network relate to striatal pathways. The fact that L-Dopa or deep brain stimulation (DBS) improves motor gaits in Parkinson's disease (PD) further strengthened the potential importance of subcortical circuits in motor ability control. A recent study highlighted the contribution of cortical inhibition in the process, and therefore might imply the cortical targeting strategy in motor disorder management , which might contribute to the decreased ability of motor learning. This rapid turnover correlates to enhanced apical dendrite Ca2+ spike generation, which is dependent on local NMDA receptors, the major source of calcium permeable glutamate receptors.Somatostatin (SST) interneuron provides important sources to dendritic inhibition, while Parvalbumin (PV) preferably targets somatic region of cortical pyramidal neurons . Indeed, several studies reported aberrant neuronal activity at cortex and GABA deficits in PD patients or animal models of PD. In addition, L-dopa administration enhanced GABA efflux at primary motor cortex, which might be relate to partly the motor improvement, and sometimes the dyskinesia as well . TMS pulses evoke cortical oscillation changes and dis-inhibit cortical dendrites by modulation cortical inhibition (Murphy et al., Taken together, many lines of evidences co-suggest the importance of motor cortical inhibition in motor learning ability, and potentially other aspects of motor functioning. Targeting cortical inhibition with drugs, exercise, and TMS stimulation are feasible approaches for motor rehabilitation.All authors designed the study together and wrote the manuscript together.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The goal of cancer eradication has been overshadowed despite the continuous improvement in research and generation of novel cancer therapeutic drugs. One of the undeniable existing problems is drug resistance due to which the paradigm of killing all cancer cells is ineffective. Tumor microenvironment plays a crucial role in inducing drug resistance besides cancer development and progression. Recently, many efforts have been devoted to understand the role of tumor microenvironment in cancer drug resistance as it provides the shelter, nutrition, and paracrine niche for cancer cells. Cancer-associated fibroblasts (CAFs), one major component of tumor microenvironment, reside in symbiotic relationship with cancer cells, supporting them to survive from cancer drugs. The present review summarizes the recent understandings in the role of CAFs in drug resistance in various tumors. Acknowledging the fact that drug resistance depends not only upon cancer cells but also upon the microenvironment niche could guide us to formulate novel cancer drugs and provide the optimal cancer treatment. Various studies have already identified that the nature of tumor does depend not only upon the malignant cancerous cells themselves but also to their microenvironment components Kalluri . The conCAFs constitute major proportion of non-neoplastic stromal compartment in various human tumors. Various researches have suggested that they are capable of modulating tumor cells by forming the communication network with cancer cells or with other elements and hence susceptible to cancer drug resistance inhibitor in genetically engineered pancreatic ductal adenocarcinoma (PDAC) and chemically induced bladder cancer mice model showed reduction in stromal contents consequently promoting tumor growth and malignancy, which indicated stromal cells function as tumor suppression and myofibroblast (myCAFs), where they observed that myCAFs lack tumor-promoting chemokines and cytokines , which is regulated by NF-\u03ba\u03b2 after DNA damage, activates the canonical Wnt program in tumor cells and induces cytotoxic chemotherapy resistance in prostate cancer breast cancers. A research performed in ER+ MCF-7 cells showed that CAF was the source of tamoxifen and fulvestrant resistance and also protected cancer cells from doxorubicin and PARP inhibitor was decreased in breast CAFs and promoted cancer invasion by overexpression of thrombospondin type 1 , poor prognostic marker in pancreatic cancer cells, did not inhibit tumor growth and they verified two subtypes: saa3-competent and saa3-null CAFs, which showed pro-tumorigenic and anti-tumorigenic effect, respectively was blocked by CXCL12 receptor inhibitor unable to identify its specific origin (Fujiwara et al. One previous study showed that despite the heterogeneity of CAFs, they are genetically more stable than cancer cells. Therefore, targeting CAFs in cancer treatment would have smaller possibilities to develop drug resistance Kerbel ]. RecentIn conclusions, CAFs, the building block of microenvironment, have a crucial role in modulating cancer drug sensitivity and understanding in detail could minimize the existing challenge of drug resistance and direct the future innovation of cancer drug by avoiding or overcoming the drug resistance."} +{"text": "The adult mammalian central nervous system (CNS) is generally considered as repair restricted organ with limited capacities to regenerate lost cells and to successfully integrate them into damaged nerve tracts. Despite the presence of endogenous immature cell types that can be activated upon injury or in disease cell replacement generally remains insufficient, undirected, or lost cell types are not properly generated. This limitation also accounts for the myelin repair capacity that still constitutes the default regenerative activity at least in inflammatory demyelinating conditions. Ever since the discovery of endogenous neural stem cells (NSCs) residing within specific niches of the adult brain, as well as the description of procedures to either isolate and propagate or artificially induce NSCs from various origins ex vivo, the field has been rejuvenated. Various sources of NSCs have been investigated and applied in current neuropathological paradigms aiming at the replacement of lost cells and the restoration of functionality based on successful integration. Whereas directing and supporting stem cells residing in brain niches constitutes one possible approach many investigations addressed their potential upon transplantation. Given the heterogeneity of these studies related to the nature of grafted cells, the local CNS environment, and applied implantation procedures we here set out to review and compare their applied protocols in order to evaluate rate-limiting parameters. Based on our compilation, we conclude that in healthy CNS tissue region specific cues dominate cell fate decisions. However, although increasing evidence points to the capacity of transplanted NSCs to reflect the regenerative need of an injury environment, a still heterogenic picture emerges when analyzing transplantation outcomes in injury or disease models. These are likely due to methodological differences despite preserved injury environments. Based on this meta-analysis, we suggest future NSC transplantation experiments to be conducted in a more comparable way to previous studies and that subsequent analyses must emphasize regional heterogeneity such as accounting for differences in gray versus white matter. Ever since the discovery of naturally occurring neural stem cells (NSCs) residing in discrete niches of the adult mammalian central nervous system (CNS) ,2,3,4,5,While screening the publicly available literature, it became evident that there is a large degree of heterogeneity when it comes to the NSC transplantation procedure itself, related for example to age and species of donor- as well as host tissues, the question whether sorted/enriched cell populations versus mixed cell grafts were applied or concerning time-points at which host tissue and grafted cells were analyzed. Likewise, the localization and type of an injury prior to engraftment of stem cells, as well as their positioning within lesion zones additionally influence cellular integration and differentiation. It would therefore be important to define rate limiting and dominating parameters to ensure a larger degree of comparability across different investigations and to promote the development of protocols that will eventually lead to a successful clinical translation.Clinical research depends on animal models, which mimic human disease or injury. For neuropathological studies of the CNS various animal models such as acute and chronic spinal cord injury (SCI); traumatic brain injury (TBI); inflammatory-, genetically-, or chemically induced demyelination/neurodegeneration have been used to assess the impact of NSC transplantation on either lesion amelioration or tissue regeneration. The outcome of these studies shows a surprising degree of variability in terms of cell fate acquisition, migration within the host tissue as well as the implanted cell\u2019s potential to fully mature 5 or P75 old mice for transplantation into the striatum, motor cortex, and lateral posterior thalamic nucleus, Seidenfaden and colleagues showed that transplanted cell survival is independent of the donor animal age\u2014at least when comparing immature postnatal- to young adult brains . FurtherA related transplantation study used rats instead of mice for both donor cells as well as host animals . HoweverFurther support for the assumption that exogenous factors influence the fate of transplanted NSCs resultedFor a successful treatment of neurological conditions such as multiple sclerosis (MS) or adrenoleukodystrophies transplanted NSCs would have to distribute well within diseased brains in order to access multiple and irregularly dispersed lesions. Active migration within the brain parenchyma appears indeed to be a rare feature of implanted NSCs as for example transplantation of SVZ-derived NSCs into neighboring SVZ regions of adult healthy mice did not result in any observable migration activities . TransplSupporting evidence that brain region specific cues act across different species arose from a subsequent study in which embryonic human NSCs (huNSCs) were applied to injury-free models . Here, dThe astonishing impact especially the RMS exerts on transplanted NSCs was corroborated by yet another study . This inComparing outcomes of NSC transplantation in different neuropathological or injury inflicted models is important in order to understand the adaptability NSCs are capable of and also for the development of CNS repair strategies. Nevertheless, due to the high degree of variation and heterogeneity across the different model systems this section will focus on selected models representing both common and rare as well as global and focal pathologies. Working out the details between different injury models, and taking into account heterogenic responses of different brain regions depends on comparable starting conditions. This includes information on donor age, on the particular donor stem cell niche, on isolated cell types and whether they were propagated in culture or whether genetic manipulation was applied prior to transplantation. Moreover, variations deriving from different model systems will also be considered.Treatment of hereditary white matter disorders characterized by abnormal or complete absence of myelin due to mutations in genes encoding for myelin proteins (such as in Pelizaeus-Merzbacher disease) will most likely depend on engraftment of healthy cells giving rise to functionally unimpaired myelin forming oligodendrocytes. In shiverer mice (shi) homozygous mutations in the myelin basic protein (MBP) gene lead to the absence of MBP expression and consequently to low levels of compact and functional myelin ,21 and ishi/shi) were used as host animals, which in terms of methodology makes these studies highly comparable. Therefore, the reason for such differential fate outcome remains obscure.However, intracerebroventricular transplantation of the same NSC cell line (C17.2) into shi mice of comparable age (P1-P3) resulted in mainly neuronal differentiation . While tStudies in which transplantation experiments were performed using different stem cell types but exclusively applying a single neuropathological model are of special value since methodological differences can be ruled out. When adult forebrain SVZ neural precursor cells (aNPCs) were grafted into the dysmyelinated spinal cord of shiverer rats, the majority differentiated into oligodendroglial cells and even into mature myelinating OLs . In contTraumatic brain injury (TBI) results from forced impact to the skull and brain, which leads to a primary- (direct negative influence on tissue architecture and homeostasis) as well as a secondary injury . Due to The study by Koutsoudaki and colleagues elegantly demonstrated the non-necessity of NSC modulation prior to transplantation into injured adult mouse brains. Upon TBI to the hippocampus by stabbing multiple times 2 mm deep through the cortex, corpus callosum, and hippocampus, non-modified (reporter-gene expression only) and insulin like growth factor 1 (IGF1) overexpressing NSCs were transplanted close to the lesion site. Considering fate outcome as well as functional improvement , no differences between IGF1 producing and reporter gene only expressing NSCs were observed. Both cell populations ameliorated injury-induced spatial learning deficits and in both cases transplanted NSCs mainly differentiated into oligodendroglial cells . As in sIn contrast to the TBI wound induced by a blunt-end needle, which also disrupts WM structures , the modIn a comparable experimental set up (modified Feeney method) neonatal mouse hippocampus-derived NSCs were transplanted 24 h after injury into the pericontusional region . SimilarTemporal lobe epilepsy (TLE) is a common form seen in about 30% of epileptic patients. By injecting kainic acid (KA) into the rodent hippocampus or the SVZ, neurodegeneration is induced and neuronal cell death and functional impairments similar to TLE patients can be mimicked. While NSC transplantation has also been investigated in terms of trophic support these NSCs can confer to the damaged environment, this section will focus on the aspect of NSC mediated cell replacement and fate choice.Since kainate induced hippocampal degeneration represents a focal CNS injury, transplantation of P5 mouse SVZ-derived NSCs into the hippocampus close to the injection site resulted in only minor migration towards the lesion area . Stem ceWhile transplantation of NSCs into the kainate-induced neurodegenerative hippocampus resulted in mostly neuronal differentiation and ameliorated cognitive function , anotherA further TLE study also reported primarily astroglial fate choices although NSCs were transplanted into an acute TLE model . A changAnother interesting finding is that SVZ-derived NSCs transplanted into healthy non-injured hippocampi were also located close to the SVZ several weeks after transplantation \u2014a distriSly disease is a rare hereditary lysosomal storage disorder, characterized by the deficiency in \u03b2-glucuronidase (GUSB) and subsequent accumulation of glycosaminglycans in many organs including the brain leading to mental retardation. Applying NSCs as early as technically feasible might provide a potential therapeutic approach in order to restore global dysfunction of the developing brain. The mucopolysaccharidosis VII (MPS VII) mouse strain mimics human sly disease pathological features. Upon transplantation of GUSB-expressing C17.2 NSCs into lateral ventricles of neonatal MPS VII mice, cells distributed and integrated in the whole brain and no tumorigenesis was observed . WidesprThe lack of oxygen supply in the brain results in ischemic stroke, leading to irreversible neuronal damage . IschemiTransplantation of neurosphere-derived cells from neonatal mice hence containing NSCs, various progenitors and more differentiated cells into theRegarding differences in the microenvironment of ischemic brain regions over time, Darsalia and colleagues compared the differential outcome of intrastriatally transplanted human fetal striatal NSCs 48 h and six weeks after stroke. Transplantation after 48 h following stroke resulted in a higher NSC survival rate as compared to transplantation at the later time-point. However, different time-points did not affect the extent of migration, differentiation and proliferation. Interestingly, analysis of neuronal fate acquisition revealed no change in the percentage of Dcx-positive neuroblasts but for both transplantation time-points the percentage was lower as compared to injury-free animals . Such ob35\u201355) peptide induced EAE, which leads to a T-cell mediated autoimmune response towards oligodendrocytes with the first symptoms appearing ten days after initial immunization.Multiple sclerosis (MS) is an autoimmune disease characterized by oligodendrocyte and myelin loss, which ultimately leads to axonal degeneration and subsequent sensory, motor, and cognitive dysfunction . The mosIntracerebroventricular transplantation of human embryonic stem cell-derived early multipotent neural precursor cells (hESC-NPCs) demonstrated robust migration into the host WM, which led to significantly reduced clinical sings of EAE in host mice . The benFurther evidence for a high migratory activity of implanted cells in the EAE brain derived from a report on human induced pluripotent stem cell-derived NSCs (iPSC-NSCs) having migrated into the dentate gyrus one month following intraventricular transplantation in EAE mice . Co-locaMinor regeneration promoting effects using allogenic NSCs were also reported for a chronic EAE model, into which transplantation was performed 40 days post-immunization. Here, treatment with non-modified bone marrow-derived (BM) NSCs (derived from six- to eight-week-old mice) blocked While the two previous studies report minor regeneration promoting effects using allogenic or na\u00efve NSCs in EAE mice, Einstein and colleagues could show that intraventricularly transplanted striatal newborn rat multipotential NSCs migrated into inflamed WM tracts and subsequently differentiated into glial cells in EAE rats. This transplantation strategy resulted in a reduced inflammation of the host brain and ameliorated the disease course. Whether beneficial effects were due to additional processes attributed to particularly the rat system remains open.Intraventricular transplantation of both, glial-derived neurotrophic factor (GDNF) overexpressing- (GDNF-NSCs) or na\u00efve newborn rat cerebrum-derived NSCs ten days following EAE induction led to a delayed disease onset and significant reduction of clinical EAE signs . More spwww.alzforum.org) [Neurodegeneration in Alzheimer\u00b4s disease (AD) results in learning deficits and dementia. In a murine AD model (APP/PS1 mice), neuron-specific Thy1 promotor driving the co-expression of KM670/671NL mutated amyloid precursor protein (APP) and of L166P mutated presenilin-1 (PS1) leads to human amyloid depositions and local neuronal loss in the dentate gyrus ,50. The rum.org) ,53,54,55rum.org) ,60,61,62rum.org) ,57,61,62rum.org) . Using arum.org) . The obsInterestingly, most of the compiled studies report that transplanted NSCs showed high migratory behavior leaving injection sites ,63,64,65Using a chemical model to mimic AD related neuropathological features by okadaic acid injection into the lateral ventricles only traHuntington\u00b4s disease (HD) is an inherited neurodegenerative disease caused by the progressive loss of GABAergic medium spiny neurons (MSNs) in the striatum. Injection of 3-nitropropionic acid (3-NP) into the striatum serves as an animal model to mimic HD symptoms and related neurodegenerative aspects. Transplantation of human NSCs into the injured striatum one week prior to the injury resulted in decreased loss of striatal neurons as well as the appearance of calbindin-expressing donor cell-derived neurons . Upon imSpinal cord injury (SCI) is a devastating neurological condition, which is caused by a traumatic impact to the spinal cord. It results in permanent impairment of motor- and sensory functions due to the interruption of descending and ascending nerve fiber tracts. Local cell loss at sites of injury is followed by glial scar formation and accompanied by inflammation which prevent regeneration of transected axons and exert an additional negative impact on functionality and survival of remote neurons ,75. StemIn this regard, we compared data on fate acquisition of transplanted NSCs from two methodologically different SCI models. Compression or contusion used to induce broader and probably medically more relevant spinal cord lesions is compared to more defined injuries resulting from spinal cord hemisection or complete transection. Both models affect spinal cord integrity and lead to motor and sensory dysfunction while differing in terms of lesion volume and extent of secondary damage. Transplantation of various NSCs indeed led to the generation of different cell fates correlating with the type of evoked injury.Interestingly, rodent and human NSCs transplanted into a compression or a contusion lesion preferentially differentiated into oligodendrocytes ,89,90,91While most NSC transplantation based SCI studies focused on rodent models, Iwanami and colleagues used a primate contusion model. Upon cervical contusion in marmosets and subsequent transplantation of human NSCs, assessment of fate acquisition of the engrafted NSCs showed the following distribution: 46% GFAP-positive astrocytes, 25% nestin-positive stem cells, 21% \u03b2-III-Tub-positive neurons, and 5% Olig2-positive oligodendroglial cells . Since iMigration of transplanted NSCs towards an injury site, into lesion zones or close to demyelinated axonal fibers is key for a potential beneficial role of transplanted NSCs in terms of local neurotrophic factor secretion or remyelination. Considering the migratory potential of transplanted NSCs, it was found that migration exclusively occurs in spinal cords with a contusion or compression injury ,99,103. Despite the well described self-renewing potential of stem cells in vitro as well as in their discrete niches in vivo, transplanted stem cells showed little or no proliferation activities within host tissues in all SCI studies considered here ,91,95,98The aforementioned studies revealing differences and similarities in different SCI models all used subacute or acute application conditions, in that NSC transplantation was performed immediately or shortly after injury. However, this does not necessarily reflect a patient\u2019s situation who will first receive emergency surgery in order to stabilize general conditions and to avoid secondary damage preceding possible regeneration directed therapies. Moreover, for autologous stem cell transplantation a timely application of appropriate cell numbers is not feasible. Investigating chronic SCI models in which cells are transplanted several weeks after SCI might therefore be more relevant in terms of clinical translation and feasibility. In this regard, not only the type of induced injury (pressure or cut) appears to be important but also the disease process seems to account for the NSC fate. This particular question was addressed by several groups comparing chronic to a subacute (days after injury) transplantation approaches. In two studies, a lower survival rate of NSCs transplanted after four and eight weeks into contusion lesions compared to a subacute transplantation process was observed ,86. WhilOf note, given that at least for transplanted OPCs heterogenic responses in gray vs. white matter have been described , a systeThe high complexity of adult mammalian central nervous systems and the low degree of intrinsic repair capacity results in devastating functional impairments and persisting disabilities in most neuropathologies. The discovery of neural stem cells and their potential to give rise to all cell lineages of the CNS has revived the field in terms of functional cell replacement. Initial concerns related to exogenously applied NSCs and possible adverse effects were refuted as the majority of NSC transplantation studies revealed no tumor formation. Interestingly, studies investigating the outcome of NSC transplantations into healthy CNS tissue revealed dominant region-specific cues instructing the grafts. Despite a great heterogeneity among different CNS lesion models, transplanted NSC migration towards lesion sites and subsequent differentiation into to be replenished cell types are common observations in the majority of neuropathological models. These observations raise hope for the development of NSC-mediated CNS regeneration therapies as most neural stem cell types seem to be sensible to injury environments and their requirements and since even delayed NSC applications can confer functional benefits."} +{"text": "Angina with no obstructive coronary artery disease (ANOCA) is a common syndrome with unmet clinical needs. Microvascular and vasospastic angina are relevant but may not be diagnosed without measuring coronary vascular function. The relationship between cardiovascular magnetic resonance (CMR)-derived myocardial blood flow (MBF) and reference invasive coronary function tests is uncertain. We hypothesise that multiparametric CMR assessment will be clinically useful in the ANOCA diagnostic pathway.The Stratified Medical Therapy Using Invasive Coronary Function Testing In Angina (CorMicA) trial is a prospective, blinded, randomised, sham-controlled study comparing two management approaches in patients with ANOCA. We aim to recruit consecutive patients with stable angina undergoing elective invasive coronary angiography. Eligible patients with ANOCA (n=150) will be randomised to invasive coronary artery function-guided diagnosis and treatment (intervention group) or not (control group). Based on these test results, patients will be stratified into disease endotypes: microvascular angina, vasospastic angina, mixed microvascular/vasospastic angina, obstructive epicardial coronary artery disease and non-cardiac chest pain. After randomisation in CorMicA, subjects will be invited to participate in the Coronary Microvascular Angina Cardiac Magnetic Resonance Imaging (CorCMR) substudy. Patients will undergo multiparametric CMR and have assessments of MBF (using a novel pixel-wise fully quantitative method), left ventricular function and mass, and tissue characterisation (T1 mapping and late gadolinium enhancement imaging). Abnormalities of myocardial perfusion and associations between MBF and invasive coronary artery function tests will be assessed. The CorCMR substudy represents the largest cohort of ANOCA patients with paired multiparametric CMR and comprehensive invasive coronary vascular function tests.The CorMicA trial and CorCMR substudy have UK REC approval (ref.16/WS/0192).NCT03193294. Angina with no obstructive coronary artery disease (ANOCA) is a common syndrome with unmet clinical needs.A significant proportion of these patients may suffer from microvascular and vasospastic angina.Diagnosis in this patients may be challending, are there are uncertain associations between the results of reference invasive diagnostic tests and the non-invasive ischaemia test results.Novel CMR methods for measuring myocardial blood flow have not been validated in patients with ANOCA and underlying microvascular and vasospastic angina.The CorCMR substudy represents the largest cohort of ANOCA patients with paired multiparametric CMR and comprehensive invasive coronary vascular function tests. CorCMR will provide information on the diagnostic value of quantitative pixel-wise mapping of myocardial perfusion in patients with ANOCA.In contrast to the reference standard invasive tests of coronary artery function, non-invasive imaging is safer and more acceptable to patients.The CorCMR sub-study presents a unique opportunity to assess and validate the diagnostic accuracy of fully-quantitative stress perfusion CMR in patients with ANOCA and comprehensive invasive coronary artery function testing.Ischaemic heart disease is the leading cause of mortality standardised by age and sex.Patients with angina and no obstructive coronary artery disease (ANOCA) present a diagnostic conundrum.The underlying pathogenesis in patients with ANOCA is unclear, as specific disease endotypes are not routinely tested for. CMD may result from coronary structural abnormalities, whereby decreased capillary luminal size and number result in increased microvascular resistance to myocardial blood flow (MBF) and reduced vasodilatory capacity.Abnormalities of coronary vascular function portend a worse prognosis in patients with both obstructive epicardial CAD and ANOCA.Diagnosis of coronary microvascular and vasomotor dysfunction is challenging due to the heterogeneity of underlying disease mechanisms, the potentially patchy distribution of disease throughout the myocardium, and limited spatial resolution of existing diagnostic tests.There is no accepted guideline-directed diagnostic algorithm for coronary vascular dysfunction in routine clinical practice.The available non-invasive ischaemia tests were all validated for the detection of obstructive epicardial CAD. There has been a low yield of inducible myocardial ischaemia in ANOCA patients with traditional non-invasive ischaemia tests .Coronary microvascular disease may be revealed by a deficit in MBF during stress CMR. The spatial distribution of this abnormality typically involves the subendocardium, which is the location of the microvascular plexus.There are uncertain associations between the results of invasive diagnostic tests and the non-invasive ischaemia test results in patients with ANOCA. There is no accepted objective diagnostic threshold for the diagnosis of coronary vascular dysfunction , with either PET or perfusion CMR. Recent studies have investigated the relationships between invasive tests of coronary artery function and semiquantitative perfusion CMR analysis.The Stratified Medical Therapy Using Invasive Coronary Function Testing In Angina (CorMicA) clinical trial is a proof-of-concept, prospective, blinded, randomised, sham-controlled study comparing two management approaches to the clinical problem of patients with ANOCA.The IDP consists of coronary artery function testing using a dual pressure-sensitive and temperature-sensitive guidewire and adenosine followed by intracoronary acetylcholine provocation testing. Assessment of microvascular resistance (IMR), microvascular vasodilatory capacity (resistance reserve ratio (RRR)), epicardial and microvascular vasodilatory capacity (CFR), endothelial function (acetylcholine provocation testing) and epicardial CAD ) will be performed. Following these invasive tests of coronary artery function, patients will be classified into the following ANOCA disease endotypes : (1) micPatients in the control group will receive standard care based on the interpretation of the invasive coronary angiogram alone. Patients in the intervention group will have care based on the disease endotypes disclosed by invasive tests of artery function, and pharmacotherapy linked to the underlying disease endotype will be commenced.Novel CMR methods for measuring MBF have not been validated in patients with ANOCA and underlying microvascular and vasospastic angina. The CorCMR substudy of the CorMicA clinical trial presents a unique opportunity to assess and validate the diagnostic accuracy of fully quantitative stress perfusion CMR in patients with ANOCA and comprehensive invasive coronary artery function testing.We hypothesise that abnormal myocardial perfusion, as revealed by a novel fully quantitative pixel-wise CMR perfusion sequence, will be prevalent in a contemporary UK cohort of patients presenting with ANOCA and that multiparametric CMR imaging will be clinically useful in the diagnostic pathway of patients with ANOCA.We aim to assess the diagnostic validity of quantitative stress perfusion CMR in patients with ANOCA and specific disease endotypes of coronary vascular dysfunction. Our specific aims are to assess:The proportion of ANOCA patients with abnormal myocardial perfusion. There is no accepted threshold for abnormal MPR. Thresholds for reduced CFR of 1.5\u20132.6 have been described, however <2.0 is commonly used.The diagnostic accuracy of the perfusion CMR metrics for abnormal invasive tests of coronary artery function and the associations between specific disease endotypes and myocardial perfusion in patients with ANOCA. We also aim to assess the correlation between abnormal CMR-derived perfusion and invasive tests of coronary artery function, of qualitative versus quantitative perfusion methods.The proportion of patients with ANOCA and abnormal myocardial tissue characterisation derived from CMR imaging) and its association with abnormal myocardial perfusion.The associations between baseline patient characteristics and abnormal myocardial perfusion.The proportion of patients with a change in diagnosis based on quantitative CMR findings, as compared with the initial diagnosis by the attending cardiologist based on the coronary angiogram.Prespecified substudy of the CorMicA stratified medical therapy clinical trial.Patients referred from 14 acute hospitals to two large regional UK hospitals providing invasive care to all patients in the West of Scotland (population 2.5 million). All CMR studies will be performed at the Golden Jubilee National Hospital.Consecutive outpatients undergoing clinically indicated elective diagnostic angiography for investigation of suspected angina will be screened and invited to participate in the CorMicA trial. Informed consent is obtained before the invasive coronary angiogram. A minimum of 400 consecutive patients undergoing elective invasive coronary angiography is expected to be screened to enrol 150 subjects with ANOCA within 24 months. Consenting patients who are not randomised will enter a registry. Only patients randomised in the CorMicA trial (both in the intervention and control groups) are eligible to participate in the CorCMR substudy.Age \u226518 years, a clinically indicated plan for invasive coronary angiography and symptoms of angina (according to the Rose angina questionnaire).A non-coronary indication for invasive angiography , obstructive epicardial CAD disease evident in a main coronary artery (diameter >2.5 mm) (defined as diameter stenosis >50% or FFR \u22640.80) and contraindication to contrast-enhanced CMR .Patients will undergo perfusion CMR within 42 days of the CorMicA trial invasive coronary artery function testing. CMR studies will be performed at 1.5 Tesla , and patients will undergo a standardised CMR protocol. All patients will be asked to abstain from caffeine-containing beverages or foodstuffs for 24 hours and vasoactive medications for 48 hours prior to the CMR examination. All scan acquisitions will be spatially coregistered. All CMR analyses will be performed by analysts blinded to the invasive coronary artery function test results. The standardised CMR protocol is demonstrated in Stress and rest first-pass perfusion imaging will be performed using an echo planar imaging dual-sequence investigational perfusion method, which consists of a low resolution arterial input function image, followed by three short axis myocardial images during each R\u2013R interval.The raw stress and rest perfusion images will be qualitatively assessed for inducible or fixed perfusion defects. Perfusion defects will be reported on a segmental basis according to the American Heart Association 16-segment model.Pixel-wise perfusion maps will be generated and analysed to derive fully quantitative MBF estimates on a pixel-wise basis in mL/g/min of myocardium. The pixel-wise perfusion method uses a series of automated postprocessing steps on the raw Digital Imaging and Communications in Medicine images to generate fully quantitative pixel maps.2] and percentage coefficient of variation of time to maximum signal intensity upslope and time to peak myocardial signal intensity enhancement.The myocardial perfusion dyssynchrony index is a novel perfusion metric that assesses temporal differences in the distribution of gadolinium-based contrast media myocardial wash-in. This index has the potential to increase the diagnostic sensitivity and specificity of perfusion CMR for abnormalities of myocardial perfusion in patients with ANOCA.Fast gradient echo images in the axial, coronal and sagittal planes will be qualitatively assessed for extra cardiac anatomy and pathology and clinically relevant incidental findings.Steady-state free procession \u2018cine\u2019 imaging using a trueFISP sequence (multislice single-shot breath-hold true fast imaging) will be performed in the three long-axis and short-axis planes for assessment of LV volumes, function and mass.Native T1 mapping will be performed using a modified look-locker inversion recovery investigational prototype sequence. Images will be obtained in three short-axis images . T1 mapping will be performed pre- and post-gadolinium contrast to assess the myocardial native T1 relaxation time and estimate the myocardial extracellular volume (ECV) in both the mid-septum and globally.LGE imaging will be performed using a segmented phase-sensitive inversion recovery turbo fast low-angle shot imaging sequence.Abnormal myocardial perfusion reserve .A summary of the secondary outcomes is shown in Box 2.LV EFLVEDVLV EDV indexLV ESVLV ESV indexLV massLV mass indexLV COLV CO index2)Left atrial area (cmLeft atria dilated (Y/N)2)Right atrial area (cmRight atria dilated (Y/N)Abnormal perfusion (Y/N)Number of abnormal segments (n)Transmurality of perfusion defects (%)Pattern Global MPR <2.0 (Y/N)Segmental/AHA MPRGlobal stress and rest MBFSegmental/AHA territory stress and rest MBFGlobal stress endocardial:epicardial MPR ratioSegmental/AHA territory endocardial:epicardial MPR ratioMyocardial perfusion dyssynchrony index Splenic switch-off (Y/N)HR and BPchangeRate-pressure product at rest and stressAbnormal LGE (Y/N).Number of affected AHA segments (n)Pattern of abnormal LGE (ischaemic and non-ischaemic)Myocardial infarct scar burden Native T1 ECV Feature-tracking and DENSE (two methods)Longitudinal strain Circumferential strain Radial strain Present (Y/N)Clinically significant (Y/N)Sex, age and traditional CAD risk factorsCAD risk scores (JBS3 and ASSIGN)Gensini score of epicardial plaque burdenAssociation of myocardial perfusion with IMR, CFR, RRR and endothelial function testing (continuous and binary)Subset of patients with multivessel invasive coronary artery function measurementsAssociation with clinical diagnosis (ANOCA disease endotype)LV volumes and massMyocardial strainNative T1 relaxation time and ECVPresence of LGEDiagnostic accuracy of quantitative perfusion CMR to detect abnormal IMR, CFR, RRR and endothelial dysfunctionAHA, American Heart Association; ANOCA, angina with no obstructive coronary artery disease; BP, blood pressure; CFR, coronary flow reserve; CAD, coronary artery disease; CO, cardiac output; CorCMR, Coronary Microvascular Angina Cardiac MRI; EF, ejection fraction; EDV, end-diastolic volume; ESV, end-systolic volume; ECV, extracellular volume; HR, heart rate; IMR, index of microcirculatory resistance; LV, left ventricular; LGE, late gadolinium enhancement; MBF, myocardial blood flow; MPR, myocardial perfusion reserve; RRR, relative resistance ratio,The CorMicA trial has a comprehensive statistical analysis plan that governs all statistical aspects of the study authored by the trial statistician. The statistical analysis plan includes the prespecified CorCMR substudy that is designed to assess for associations between CMR measures and invasive measures and endotypes (reference dataset). Continuous outcomes will be analysed using linear regression with adjustment for baseline levels where available. Where continuous data are clearly not normally distributed, standard transformations will be applied to achieve approximate normality prior to analysis. Appropriate alternative regression methods will be applied to other types of data .The primary outcome is the proportion of patients with an MPR<2.0. The proportion of patients with microvascular angina defined by invasive endotyping will be assessed. We will further assess the MPR ratio with the highest AUC for microvascular angina classified invasively.Considering the correlation between CFR measured invasively and MPR measured non-invasively within the common territory of a major epicardial coronary artery, then a sample size of 110 subjects would enable a minimum clinically significant correlation of 0.3 to be detected with 90% power at a 5% significance level. If only 60 subjects have available data, then 80% power would be available to detect a correlation of 0.37 at the 5% level.The British Heart Foundation CorMicA trial will assess a routine stratified medicine strategy in a large cohort of prospectively enrolled patients with ANOCA. The prespecified CorCMR substudy will involve comprehensive invasive tests of coronary artery function paired with multiparametric perfusion CMR studies. The analysis will provide information on the diagnostic value of quantitative pixel-wise mapping of myocardial perfusion in this population.Contemporary guidelines recommend functional testing, including with CMR, to assess for myocardial ischaemia in patients in whom multidetector CT coronary angiography has shown CAD of uncertain functional significance or is non-diagnostic.The CorCMR substudy will be performed on a 1.5 Tesla MRI scanner. In comparison, 3.0 Tesla imaging permits improved signal-to-noise ratio and provides higher in-plane spatial resolution perfusion imaging.et alet alPatients with confirmed microvascular or vasospastic angina have a precise diagnosis of the underlying disease endotype, and pharmacotherapy may be commenced as appropriate. Conversely, patients with normal invasive coronary artery function tests may have antianginal therapy appropriately discontinued, and alternative causes of chest pain investigated. In comparison with invasive tests of coronary artery function, non-invasive CMR imaging may be more attractive to patients, but at present, the role of CMR in the diagnostic work-up of patients is uncertain. CorCMR will provide data on the role of CMR in the diagnosis of patients with ANOCA. Traditional non-invasive ischaemia testing in patients with ANOCA has provided mixed results. Panza et al compared semiquantitative perfusion CMR against IMR measurement in 50 patients with ANOCA and 20 age-matched healthy control subjects.et alCorCMR will inform the nascent evidence on the presence and magnitude of associations between invasive and non-invasive assessments of coronary vascular function. Liu et alCMR permits the reference-standard non-invasive assessment of myocardial tissue characterisation. CorCMR will provide data on diffuse interstitial fibrosis, ECV and myocardial scar. The role of T1 mapping and ECV analysis in patients with ANOCA is uncertain. In a substudy of the iPOWER natural history study, 54 women with ANOCA underwent native T1 mapping and ECV analysis, PET-derived MBF measurement, and transthoracic Doppler echocardiography CFR assessment.http://www.equator-network.org/reporting-guidelines/stard/) and Consolidated Standards of Reporting Trials (http://www.consort-statement.org/) guidelines.Progress in the trial will be monitored by the trial anager (KB) and sponsor. The study will be subject to internal and external audit that is routinely coordinated by the sponsor. An annual report will be submitted to the Research Ethics Committee on a 12-month basis. The flow diagram illustrates conservative estimates of patient enrolment and activity on a single site. The study will follow Standards for Reporting of Diagnostic Accuracy (STARD) (The CorCMR data will be presented at conferences and/or published in peer-reviewed journals."} +{"text": "Coarctation of aorta (CoA) is a discrete narrowing in aorta causing obstruction to the flow of blood. It accounts for 6\u20138% of all congenital heart diseases. With advances in fetal echocardiography rate of prenatal diagnosis of coarctation of aorta has improved but it still remains a challenging diagnosis to make prenatally. Transthoracic echocardiography is mainstay of making initial diagnosis and routine follow-up. Cardiac magnetic resonance imaging (MRI) and computed tomography (CT) are great advanced imaging tools for two-dimensional and three-dimensional imaging of aortic arch in complex cases. Based on type of coarctation, size of patient, severity of lesion, and associated abnormalities various management options like surgical treatment, transcatheter balloon angioplasty and transcatheter stent implantation are available. There is significant improvement in long-term survival from pre-surgical era to post-surgical era. But, among the postsurgical era patients, the long-term survival has not significantly changed between older and contemporary cohort. Patients with coarctation of aorta need lifelong follow-up event after successful initial intervention. Coarctation of aorta (CoA) can be simply defined as cardiac abnormality resulting in obstruction to the blood flow in the aorta. CoA can occur at any region in the thoracic and abdominal aorta. Most common location for CoA is just distal to the left subclavian artery at the point where ductus arteriosus connects to the aorta. Typically there is presence of medial thickening with \u201cshelf like\u201d tissue protruding in the lumen of aorta from the posterior aortic wall , 2. CoA EpidemiologyCongenital heart disease (CHD) accounts for nearly 28% of all major congenital anomalies . The birPathogenesisDuring embryonic period aorta develops from pharyngeal arches and its arterial system. Development of aortic arch starts in third week of gestation and the primordial pharyngeal arch arterial pattern is transformed into the final fetal arterial arrangement during eighth week of gestation. Ventral primitive aorta forms the aortic sac and dorsal primitive aorta forms the descending aorta. Developing pharyngeal arch arterial system connects these two portions. There are six sets of pharyngeal arches that contribute towards development of aortic arch and its branches. It should be noted that all the arches are not present at the same time during fetal period. Primary portion of the aortic arch develops from fourth pharyngeal arch and other arches contribute to development of branch pulmonary arteries, ductus arteriosus and aortic arch branches , 13. AnyThere are three leading developmental theories regarding formation of CoA. First, during development of aortic arch the tissue from ductus arteriosus may get incorporated in the aortic wall where it connects to the descending aorta. As the ductus arteriosus constricts after birth, this tissue in isthmus area constricts causing development of CoA , 14. SecClinical presentationThe clinical presentation and exam findings are variable based on patient\u2019s age. Typically earlier presentation corresponds to severe disease.Younger ChildrenNewborns and neonates are usually asymptomatic right after birth as patent ductus arteriosus (PDA) helps perfuse lower body irrespective of severity of CoA. Neonates with severe/critical CoA develop\u00a0signs and symptoms of cardiogenic shock as the ductus arteriosus closes after birth. Clinically, babies may show absent/feeble femoral pulse, delayed capillary refill, feeding problems, decreased responsiveness, metabolic acidosis, mesenteric ischemia, myocardial depression, etc. It is empirical to keep ductus arteriosus open with prostaglandin E1 infusion as soon as the diagnosis of severe/critical CoA is made and further definitive intervention can be performed. Beyond the neonatal period, cardiogenic shock is an unusual presentation but still a possibility during early infancy. Older pediatric patients are usually diagnosed due to weak femoral pulse, upper extremity hypertension, a systolic murmur over upper sternal border with radiation to the back, and upper-lower extremity systolic blood pressure gradient. Newborn pulse oximetry screening is a great tool in detecting cases of critical congenital heart disease in newborns. Although, its utility is limited in patients with pure CoA without presence of PDA (due to lack of mixing/shunting). Newborns with severe/critical coarctation with presence of PDA may have positive results on pulse oximetry screening due to right to left shunting at PDA .Adolescent and AdultsAlmost always these patients are diagnosed with CoA during workup of systemic hypertension or heart murmur. Clinical signs may include upper extremity hypertension, weak femoral pulse, arm-leg blood pressure gradient (>20 mmHg is significant), a systolic murmur on the back from flow through the coarctation segment or a continuous murmur from the collateral flow around the coarctation site. Patients may also complain of frequent headaches resulting from systemic hypertension and lower limb claudication from chronic hypoperfusion. If the collateral circulation around the coarctation site is significant then distal pulses may be adequate and arm-leg blood pressure gradient may not be significant.HypertensionSystolic hypertension improves and need for antihypertensive medications decreases in almost all patients after successful intervention, but chronic hypertension remains a significant issue in large proportion of patients with CoA. Prevalence of hypertension is lower in patients who are treated during neonatal period and infancy. Overall prevalence of long-term hypertension is noted at 25\u201368% .\u00a0PreoperDiagnostic imagingTransthoracic echocardiography (TTE) is the preferred diagnostic modality for diagnosis and follow-up of CoA. Fetal echocardiography (FE) has advanced significantly over past couple of decades to allow us to make prenatal diagnosis of CoA and avoid cardiovascular catastrophe after birth. Cardiac MRI (cMRI) and cardiac computed tomography (CT) have emerged as a sophisticated second line of advanced imaging that provides excellent image resolution and anatomical details. Prior to advances in echocardiography, cardiac catheterization was the mainstay for making the diagnosis of CoA. In current era, it is primarily used for interventional purpose.Fetal EchocardiographyPrenatal diagnosis of CoA helps with parental counselling, delivery planning, avoids postnatal cardiac emergencies, and guides timely management . PrenataTransthoracic EchocardiographyTTE remains the mainstay of postnatal diagnosis and follow-up for aortic arch anomalies. Goal of TTE is to identify arch anatomy, site of coarctation, determine severity, and assess for associated intracardiac abnormalities , 25. SupTransesophageal EchocardiographyTransesophageal echocardiography is seldom used for primary diagnosis of CoA due to its invasive nature and limited views for arch imaging . It is uComputed TomographyCT angiography uses intravenous contrast and ionizing radiation to obtain intracardiac and extracardiac structural data with very high spatial resolution . CT alloMagnetic Resonance ImagingcMRI is a preferred non-invasive advanced imaging for patients with CoA . cMRI doElectrocardiogramElectrocardiogram is a typical initial screening test for heart rhythm evaluation and to assess for possible cardiac chamber enlargement. This can be normal or show evidence of left ventricular hypertrophy in patients with CoA. Newborns may show presence of right ventricular hypertrophy on electrocardiogram.Chest X-RayChest X-ray is helpful at looking for aortic arch sidedness on most patients. Classic \u201cfigure of three\u201d sign can be seen on some patients with CoA. This is formed by patent pre-stenotic aortic nob, indentation from stenotic segment, and post-stenotic dilated segment. Patients with long standing unrepaired coarctation develop extensive collateral circulation through dilatation of intercostal arteries. These arteries run on the inferior aspect of the ribs. These patients can show inferior rib notching bilaterally from third to eighth ribs on chest X-ray .TreatmentSurgical repair, transcatheter balloon angioplasty and transcatheter stent implantation are treatment modalities available for management of CoA . Preferr- Non-invasive systolic blood pressure gradient of >20 mmHg between upper and lower limbs- Peak-to-peak transcatheter gradient of >/= 20 mmHg across the coarctation site- Peak-to-peak transcatheter gradient of <20 mmHg in the setting of extensive collateral circulation around the coarctation site- Significant left ventricular hypertrophy- Left ventricular systolic dysfunction- Uncontrolled systemic hypertension in the setting of coarctation of aorta- Abnormal blood pressure response during exercise stress testSurgerySince the first surgical repair of CoA in early 1940s by Dr. Crafoord, surgery remains a major treatment option for patients of all age group with CoA . In neonTranscatheter Balloon AngioplastyTranscatheter balloon angioplasty for native CoA was first introduced in the early 1980s . During Transcatheter Stent ImplantationTranscatheter stent implantation was introduced in the late 1980s and was widely accepted as a therapeutic measure for patients with CoA in the early 1990s . This isForbes et al. compared safety and efficacy of surgical and transcatheter treatment options for native coarctation at acute interval and at follow-up for patients between the years 2002 and 2009 from 36 institutions . They noCoA remains most common aortic arch abnormality in children. Key to optimum management of these patients is early detection and timely intervention. Various surgical and transcatheter options are available for management of CoA. Treatment option should be individualized for each patient based on associated factors. Lifelong follow-up is mandatory for these patients to monitor for any late complications."} +{"text": "Pseudomonas aeruginosa is known to tolerate antibiotic therapy during infection. This prevents clearance of infection and negatively impacts patient outcomes. Pseudomonas aeruginosa is known to tolerate antibiotic therapy during infection. This prevents clearance of infection and negatively impacts patient outcomes. Here, we report the transcriptome sequence of antibiotic-treated and untreated P. aeruginosa cultures and the differential gene expression observed when treated cells are compared to untreated cells. Pseudomonas aeruginosa is a Gram-negative bacterium which causes various human infections using a suite of virulence factors reached 0.5, at which point the cells were collected and preserved in RNAprotect. Biofilms were formed in LB broth on borosilicate glass discs as described previously and preserved in RNAprotect (NC_002516) using Bowtie, allowing 2 mismatches in a default seed length of 28 nucleotides to prevent the mapping of low-quality reads may be involved in antibiotic tolerance, these data will provide a starting point for investigating the mechanisms of tolerance in GSE120602.The RNA-seq reads and the DESeq results have been deposited in the NCBI Gene Expression Omnibus (GEO) and are"} +{"text": "Life on earth is sustained by oxygenic photosynthesis, a process that converts solar energy, carbon dioxide, and water into chemical energy and biomass. Sunlight is essential for growth and productivity of photosynthetic organisms. However, exposure to an excessive amount of light adversely affects fitness due to photooxidative damage to the photosynthetic machinery, primarily to the reaction center of the oxygen-evolving photosystem II (PSII). Photosynthetic organisms have evolved diverse photoprotective and adaptive strategies to avoid, alleviate, and repair PSII damage caused by high-irradiance or fluctuating light. Rapid and harmless dissipation of excess absorbed light within antenna as heat, which is measured by chlorophyll fluorescence as non-photochemical quenching (NPQ), constitutes one of the most efficient protective strategies. In parallel, an elaborate repair system represents another efficient strategy to maintain PSII reaction centers in active states. This article reviews both the reaction center-based strategy for robust repair of photodamaged PSII and the antenna-based strategy for swift control of PSII light-harvesting (NPQ). We discuss evolutionarily and mechanistically diverse strategies used by photosynthetic organisms to maintain PSII function for growth and productivity under static high-irradiance light or fluctuating light environments. Knowledge of mechanisms underlying PSII maintenance would facilitate bioengineering photosynthesis to enhance agricultural productivity and sustainability to feed a growing world population amidst climate change. Cyanobacteria, algae, and plants convert sunlight into chemical energy through photosynthesis to provide oxygen and food building blocks that are essential for most life forms on earth. Photosynthesis starts with capture of light by light-harvesting antenna, which drives photosynthetic electron flow through photosynthetic machinery comprising several large protein complexes embedded in the thylakoid membranes of prokaryotic cyanobacteria and eukaryotic chloroplasts. Oxygen-evolving photosystem II (PSII) is a highly conserved multi-subunit pigment-containing membrane complex that functions as a light-driven water:plastoquinone oxidoreductase during photosynthetic electron transport LQY1 (LOW QUANTUM YIELD OF PHOTOSYSTEM II 1) protein\u2014interacting with HHL1\u2014regulates repair of damaged core complexes to sustain high PSII efficiency upon exposure to excessive light and diatom Phaeodactylum tricornutum both need the LHCSR (LHC STRESS-RELATED PROTEIN) family protein for NPQ formation. Synthesis of the Chlamydomonas LHCSR protein is dramatically induced by high light, and it is responsible for the majority of flexible NPQ protein in higher plants plays a similar role to the algal type LHCSR. It senses the pH of the chloroplast thylakoid lumen when there is excess light and induces flexible NPQ . Short-lin, LCNP . Intriguin, LCNP . These din, LCNP . The impin, LCNP .The wide distribution of NPQ across photosynthetic prokaryotes and eukaryotes highlights its crucial role in PSII photoprotection. Notably, different NPQ systems have evolved in these diverse photosynthetic organisms. Flexible NPQ (qE), the major and also best-studied component of photoprotective excess energy dissipation, constitutes three systems, which are classified based on their associations with the diversification of the light-harvesting equipment in photosynthetic organisms: the OCP (ORANGE CAROTENOID PROTEIN)-dependent system in cyanobacteria, the LHCSR-dependent system in algae and mosses, and the PsbS-dependent system in mosses and vascular plants . Therefolhcsr mutant . Althougvia an ancient endosymbiotic event protein is reported to have a crucial role in adjusting Arabidopsis photosynthesis to fluctuating light and MET1 (MESOPHYLL-ENRICHED THYLAKOID PROTEIN 1) caused stunted phenotypes when exposed to fluctuating light intensities is that NPQ relaxation lags behind fluctuations in sunlight during sudden transitions from high to low light. This happens when passing clouds or movement of neighboring leaves/plant species shade sunlit leaves. The slow NPQ response could cost up to 30% of carbon gain , suggestnditions . Much moIn oxygenic photosynthesis, it is important to (1) safely handle excess absorbed light energy that would otherwise cause massive ROS production and damage the photosynthetic machinery and (2) efficiently convert solar energy into chemical bond energy. Tight regulation of these two aspects may contribute to an increase in productivity in agriculture and natural ecosystems. Understanding the elaborate NPQ mechanisms and the robust PSII repair systems may help identify targets to optimize photosynthetic efficiency. This would facilitate translational work toward exploring yield potential to sustainably meet the global rising demands for food, fuel, and fiber in the future climate change. Prior to accomplishing these grand goals, multiple outstanding questions await to be addressed:Do antenna-based photoprotection and reaction center-based repair operate in concert or in parallel to regulate PSII efficiency and photosynthetic capacity under photoinhibitory light and other environmental stresses? How does evolution of NPQ in the oxygenic organisms contribute to that of repair and vice versa?How do ROS regulate PSII activity under fluctuating light environments or field conditions?Are the molecular mechanisms of PSII repair under changing light different or similar to those under high-light irradiance? Can photosynthetic species discern PSII damage caused by these two types of light conditions and initiate distinct repair strategies?JL and RL conceived the project. JL, YL, WH, and RL wrote and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Alcohol-related problems affect increasing numbers of older adults. Recent studies have begun to investigate problem drinking among older adults based on a conceptual model proposing correlations between personal characteristics, life context , treatment, and drinking-related outcomes. In a community sample of older problem and nonproblem drinkers, alcohol consumption, life stressors, social resources, and coping responses differed between the two groups, although these factors did not directly and uniformly affect late-life drinking behavior. Furthermore, drinking behavior did not always have the expected effects on older drinkers\u2019 life contexts. Findings from a sample of treated alcohol and other drug-abusing older patients demonstrated the importance of providing mental health aftercare for this group. Historically, most efforts to understand and treat problem drinkingThis heightened interest in the alcohol-related problems of older adults has inspired studies yielding considerable information about the scope and correlates of alcohol consumption and problem drinking in late adulthood. The current prevalence of alcohol abuse and dependence in the general population of older adults is between 2 and 4 percent; it is considerably higher\u20145 to 30 percent\u2014in clinical populations . Most stRecent research highlights the importance of distinguishing between two groups of older problem drinkers: late onset and early onset. Late onset problem drinkers, of whom a significant proportion are women, first develop drinking problems later in life . Early onset problem drinkers, in contrast, develop drinking problems earlier during adolescence or adulthood and maintain them into late life. Compared with early onset problem drinkers, late onset problem drinkers generally are in better health , have better social relations , and are less likely to have been treated for alcohol and other drug (AOD) abuse , preventing inferences about the direction of causality between variables . Moreover, most studies have focused on correlations between personal characteristics and late-life drinking behavior; few have considered the influence of the drinkers\u2019 environmental contexts . Finally, little is known about either the factors that prompt older adults to seek help for their alcohol-related problems or the treatment efficacy for this group. This article presents a model for conceptualizing late-life drinking behavior. Based on this research model, the article also describes the findings of two long-term research studies aimed at elucidating predictors of alcohol consumption, drinking problems, treatment seeking, and treatment outcome in older adults.The conceptual framework presented in The late-life drinking behavior model posits several relationships between these four domains :Both personal characteristics and life context affect treatment seeking as well as drinking behavior and outcomes.Drinking behavior, in turn, influences a person\u2019s life context and certain personal characteristics.Some personal characteristics moderate the relationship between life context and outcomes.Treatment, including specific aspects of treatment programs, influences drinking-related outcomes.The validity of these assumptions was tested using a sample of older community residents as well as a sample of treated older AOD-abuse patients. The findings obtained with these two samples are described in the following sections.To examine the relationships between personal characteristics, life context, treatment seeking, and late-life drinking behavior, Brennan, Moos, and colleagues studied Focusing on the latter two groups, the investigators addressed four questions: (1) Do the personal characteristics, life contexts, and coping responses of older problem drinkers differ from those of older nonproblem drinkers? (2) Do personal and life context factors at the beginning of the study predict drinking behavior 1 and 4 years later? (3) How does initial alcohol use in older problem drinkers affect their subsequent life context and psychological well-being? (4) What factors prompt older community residents to seek treatment for alcohol-related problems?Older problem and nonproblem drinkers differed with respect to several personal characteristics . As expeProblem drinkers also had more stressful life contexts than did nonproblem drinkers . Thus, tFinally, problem drinkers and nonproblem drinkers differed in their coping responses to stressful situations. Two broad categories of coping responses are approach coping and avoidance coping. Approach coping involves attempts to master or resolve a stressful situation; avoidance coping consists of efforts to avoid thinking about a stressor and its implications and includes the expression of stress-related emotions without attempting a resolution. A comparison of older problem and nonproblem drinkers showed that although both groups used comparable levels of approach-coping strategies to manage stressors, problem drinkers were more likely to use avoidance-coping strategies Moos et.Consistent with earlier research several Overall, these results implied that experiencing more stressors, having fewer social resources, and relying more heavily on avoidance coping could lead to late-life drinking problems. The results also suggested that drinking problems might harm the life contexts and psychological well-being of older adults. To learn more about these causal relationships, the participants were reassessed over extended periods of time.reduced alcohol consumption over intervals ranging from 1 to 10 years tends to determine how social resources influence drinking behavior . Thus, iThe study\u2019s findings also illustrate the influence of an older person\u2019s drinking history on the relationship between life context and drinking behavior: The more alcohol the older drinkers consumed at the beginning of the study, the more likely were certain stressful life events, such as a relative\u2019s sickness or injury, to cause an increase or a smaller-than-expected decrease in alcohol consumption at followup . SimilarThe use of certain coping responses also appears to moderate the effects of life context on late-life drinking behavior. For instance, more non-health-related negative life events predicted elevated drinking problems among older drinkers who relied heavily on avoidance coping. In contrast, among drinkers who used fewer avoidance-coping strategies, negative life events prompted a decline in drinking problems . SimilarTaken together, these observations belie the idea that life context directly and uniformly affects drinking behavior in later life. Whether and how stressors and social resources influence late-life drinking appear to depend on several factors, including (1) the specific type of stressors , (2) the type of drinking behavior being assessed , and (3) personal risk factors .Although several studies have analyzed the effects of life context on late-life drinking, few have considered the effects of older adults\u2019 drinking behavior on their subsequent life contexts and personal well-being. Contrary to intuitive expectations, these studies indicate that ongoing drinking problems generally do not adversely affect the life contexts of older drinkers. For example, at the 1-year followup in the community study of older adults, problem-drinking women experienced a decline in spouse stressors, and problem-drinking men reported a reduction in conflicts with friends . MoreoveSimilarly, older adults\u2019 drinking behavior affected their psychological well-being in unexpected ways. For example, heavier initial alcohol consumption among women predicted fewer subsequent depressive symptoms; among men, more initial drinking problems predicted reduced depression .Finally, one would expect remission from drinking problems to improve the life contexts of older men and women. However, remission had little influence on the life contexts of male problem drinkers. Moreover, women who remitted experienced a loss of support from extended family members and reported more family stressors at followup than did remitted men . Thus, fLonger term followups are needed to determine the permanence of these effects as well as their consequences. For example, do ongoing drinking problems eventually lead to increased interpersonal stressors? And do adverse family contexts or self-medication with alcohol to avoid depression pose relapse risks for older, remitted women? The answers to these questions might have treatment implications; older women in early remission, for example, may need enhanced support to cope with family conflict and depressive symptoms.Older adults rarely seek formal treatment . ConsistSeveral factors predicted whether these community residents sought treatment. The most important predictors were prior treatment seeking and a greater number of health problems compared with the rest of the group. Frequently using avoidance-coping responses, experiencing more negative life events, and having fewer friends who approved of drinking also predicted more treatment seeking . FinallyThese findings suggest that older adults in the community are reluctant to identify themselves as having drinking problems and therefore delay treatment until their health problems and stressful life contexts require it. This result highlights the importance of identifying and treating older adults\u2019 drinking problems early. In addition, more information is needed about the personal characteristics, life contexts, and treatment features that deter older adults from seeking help for alcohol-related problems.Despite their reluctance to seek treatment, older adults constitute at least 20 percent of the AOD-abuse population in inpatient settings . Yet litBased on this information, the researchers addressed two broad sets of questions: (1) What are the extent and the predictors of health service use by older AOD-abuse patients? (2) To what extent is AOD-abuse treatment effective for older patients, and which specific treatment program characteristics predict better outcome?The VA AOD-abuse patients used health care services heavily. They received more than 920,000 days of care for AOD abuse or psychiatric disorders in the 4 years before their index episodes of care as well as 1.2 million days of care in the 4 years afterwards b. MoreovOlder and younger AOD-abuse patients received different types of treatment. Compared with younger patients, older patients received care focused more on their medical needs than on their AOD-abuse and psychiatric treatment needs . MoreoveThe readmission rates of older patients depended in part on their AOD-abuse histories. First-time AOD-abuse patients had lower readmission rates than the total sample b. This fCo-occurring psychiatric disorders also affected the frequency of health service use and complicated the treatment of older AOD abusers. At the index episode of care, almost 30 percent of the patients suffered from concomitant psychiatric disorders, most commonly depressive disorders, personality disorders, and schizophrenia . These dIn addition to AOD-abuse history and the presence of psychiatric disorders, the study identified several other predictors of higher readmission rates for older AOD-abuse patients at both the 1- and 4-year followups. These predictors included being unmarried, more prior service use, more severe and complex psychiatric diagnoses, disrupted or shorter length of treatment, and insufficient mental health aftercare b, 1995.The question of treatment effectiveness among older AOD-abuse patients usually is framed as a comparison: Do older patients respond as well to AOD-abuse treatment as younger patients do? No definitive answer exists for this question (for reviews, see Some recent investigations have begun to clarify this issue by examining the match between age and specific treatment modalities. For example, Although the studies reviewed here have contributed new data about late-life drinking behavior, many questions remain. For example, further information is needed on the relationships between life context and drinking behavior in later life. Moreover, longitudinal studies should investigate the predictors of late onset problem drinking and its remission. Researchers must identify factors that deter older adults from seeking assistance for their alcohol-related problems and devise new screening and referral methods that facilitate earlier recognition and treatment of late-life drinking problems.The study of VA patients has demonstrated that older, treated AOD-abuse patients\u2014especially those with long histories of alcohol abuse and psychiatric comorbidity\u2014place a heavy burden on the health care system. Consequently, researchers and other professionals must work to evaluate and improve the treatment effectiveness in this patient population. Factors such as continuity of care and followup mental health care appear to promote better outcomes among older patients and may be especially important for patients who have fewer informal social resources from which to draw. Accordingly, researchers must determine how much and what kind of mental health aftercare is optimal for maintaining successful treatment outcomes among older patients.Future research also should address the match between the treatment needs of older AOD-abuse patients and particular treatment program characteristics. Currently, the data more clearly indicate which treatment approaches do not work well for older patients than which ones do. More broadly, a need exists for further theory development in the study of late-life drinking behavior and for more longitudinal investigations of older adults\u2019 drinking behavior, especially among understudied populations, such as older women and older adults in racial minority groups. Such work should enhance our understanding of the course and predictors of late-life drinking behavior and assist clinicians in treating older adults\u2019 alcohol-related problems."} +{"text": "Background: Given findings that generally support the benefits of information and communication technology (ICT) for older adults\u2019 psychosocial adjustment, one might surmise that lonely older adults, who have a stronger need for psychological support, would reap more psychosocial benefits from ICT use. However, scant research has examined this view, much less the likelihood that ICT use might worsen the psychological well-being of lonely older adults, as has been shown to be the case in younger adults. Objective: To examine whether the association between ICT use and psychological adjustment among older adults depends on their loneliness levels. Methods: A representative sample of 738 Hong Kong SAR Chinese older adults aged 60 years or older was interviewed in 2017 on loneliness, frequency of ICT use , psychological distress , and SOC. Results: Regression analyses showed that loneliness significantly moderated the relationship between ICT use frequency and psychological adjustment ; more frequent ICT use was associated with more psychological distress and less SOC, with higher levels of loneliness. Conclusion: These findings suggest that ICT use may be a mixed blessing for older adults, i.e., using more ICT might predict worse psychological adjustment among lonelier older adults. Efforts that promote ICT use among older adults should take their loneliness levels into account."} +{"text": "Early recognition of VATS-related complications is crucial for early interventions, treatments and better outcomesPatient presented with post-obstructive pneumonia like symptoms 1 week after VATS pulmonary resection.CT scan chest showed evidence of complete consolidation of the lobe where the pulmonary segmentectomy resection took place.Diagnostic bronchoscopy confirmed the erroneous transection of the Superior Segment (SS) of Right Lower Lobe (RLL). Patient was then taken back for completion lobectomy and found with necrotic SS of RLL. This finding potentially could have caused significant complication if not recognized and treated earlyPatient recovered well after completion lobectomy and was discharged home several days laterErroneous bronchial transection should be suspected early in patients presenting with post-obstructive pneumonia after VATS pulmonary resection. CT scan chest and diagnostic bronchoscopy are the 2 main diagnostic tests This minimally invasive approach is currently employed for diagnostic and therapeutic lung surgery, as well as other procedures involving the mediastinum, chest wall, pericardium, esophagus and diaphragm. In general, VATS procedures are well tolerated and the prevalence of major intraoperative complications is around 1.5%.2We present a 65 year old woman, with a history of prior left upper lobectomy for early stage non-small cell lung cancer, who underwent elective VATS for a highly suspicious right lower lobe lung nodule Fig. . The nod3In this case, diagnostic bronchoscopy led to an early recognition of erroneous bronchial transection which ultimately was treated with completion lobectomy and saved this patient significant morbidity. Had the bronchoscopy not been performed, her clinical and radiographic findings would have been blamed on severe pneumonia and broad-spectrum antibiotics would have been administered hoping for clinical improvement.\u20135 In all cases, the fissure-last technique has been identified as a potential cause of this complication. In this technique, the surgeon dissects and transects the hilar structure first then proceeds to complete the fissure with a stapling device last.,7 The fissure-last lobectomy requires advanced expertise and recognition of anatomical structures prior to attempting transection of the hilar structures. A ventilation test after clamping the targeted bronchus could also be helpful. The fissure-last technique could be challenging especially in right-lower lobectomy and when a ventilation test is neglected or not performed.,7The erroneous bronchial transection has been reported as a major complication of VATS pulmonary resection ranging from 0.9 to 1.8%.Just like in this case, the evaluation of pneumonia early after VATS lung surgery should include a CT scan of the chest. Careful review of the operative report, identification and visualization of ipsilateral remaining proximal airways, and localization of surgical clips on imaging are crucial in diagnosing an erroneous bronchial transection of remaining neighboring lobes or segments to the resected part of the lung. If the CT scan shows an unexplained complete consolidation of any lobe or segment and bronchus cut-off sign with presence of proximal surgical clips, a diagnostic bronchoscopy is warranted with careful examination of the airways looking for erroneous transection. Discussion with the surgical team and aggressive surgical resection of the affected segment or lobe are the mainstay of treatment approach.In summary, in patients presenting early after VATS pulmonary resection with signs and symptoms of pneumonia, CT scan chest with careful focus on airway patency is an important diagnostic test. Suspicious findings should be futher investigated with a diagnostic bronchoscopy to rule out an erroneous bronchial transection followed with surgical intervention if applicablePatient has provided informed consent for publication of the case and accompanying imagesWriting \u2013 original draft: Amit Borah, Steven Cocciardi, Ziad Boujaoude, Wissam Abouzgheib.Writing \u2013 review & editing: Amit Borah, Steven Cocciardi, Ziad Boujaoude, Wissam Abouzgheib."} +{"text": "This study examined the trajectories of pain, insomnia, and depression during a four-year period in community-dwelling participants aged 65 or older from the National Health and Aging Trends Study. Self-reported pain, insomnia, and depressive symptoms were collected at each wave. Dementia status was determined using a modified previously validated algorithm. We analyzed retrospective trajectories of each symptom using mix-effect models and a backward timescale. We also tested for differences in each symptom trajectory between those with and without dementia. Results showed that the trajectory of depression significantly differed by dementia status . Participants with dementia had persistently higher depression level than those without dementia, particularly during the year before dementia onset. Trajectories of pain and insomnia did not differ before dementia onset. Depression increases risks of dementia and studies with longer length of follow-up are needed to detect significant trajectories of pain and insomnia before dementia onset."} +{"text": "Retroviruses have invaded vertebrate hosts for millions of years and left an extensive endogenous retrovirus (ERV) record in the host genomes, which provides a remarkable source for an evolutionary perspective on retrovirus-host associations. Here we identified ERV variation across whole-genomes from two chicken lines, derived from a common founder population subjected to 50 years of bi-directional selection on body weight, and a distantly related domestic chicken line as a comparison outgroup. Candidate ERV loci, where at least one of the chicken lines indicated distinct differences, were analyzed for adjacent host genomic landscapes, selective sweeps, and compared by sequence associations to reference assembly ERVs in phylogenetic analyses. Current data does not support selection acting on specific ERV loci in the domestic chicken lines, as determined by presence inside selective sweeps or composition of adjacent host genes. The varying ERV records among the domestic chicken lines associated broadly across the assembly ERV phylogeny, indicating that the observed insertion differences result from pre-existing and segregating ERV loci in the host populations. Thus, data suggest that the observed differences between the host lineages are best explained by substantial standing ERV variation within host populations, and indicates that even truncated, presumably old, ERVs have not yet become fixed in the host population. Retroviruses have infiltrated vertebrate germline for millions of years by integrating as proviruses in host DNA, which have then passed down to the offspring through generations as inherited endogenous retroviruses (ERVs). The genomic ERV record represents retroviruses that were replicating at the time of integration and constitutes large fractions of contemporary vertebrate genomes, for example about 7\u20138% of human DNA ,2 and abgag, pol, and env genes [Diverse sets of ERVs can be identified across all studied vertebrate genome assemblies by screenv genes . Over tinv genes . ERV connv genes , modificnv genes ,7. On thnv genes ,8,9. ERVnv genes ,11,12,13It is desirable to identify orthologous ERV loci across the compared host lineages in order to evaluate potential effects of retroviruses and ERVs on host biology because it allows for connecting ERV integrations to host phenotypic differences and evolutionary history. ERV studies have benefited from recent advancements in sequencing technology and a growing catalogue of reference host genome assemblies, where much focus has been placed on comparing ERV records across related host species reference genome assemblies, an approach that suffers from undersampling of the diversity within vertebrate species, and thus presents challenges for reaching a better understanding of potential factors that contribute to the long-term retrovirus-host associations . More reIn an attempt to further explore ERV-host associations in a hitherto un-examined system, we make use of an artificial selection system where selection lines of domestic chicken that have been undergoing strong bi-directional selection on body weight at eight weeks of age for more than 50 years . This seDomestic animals provide rare possibilities, currently not feasible in human biomedicine, to study connections between genes, phenotypes, and biological function . CrossbrThe rationale for utilizing chicken as a model dates back more than 100 years to pioneering studies of retroviruses and ERVs, reviewed in ,20, and Here, we identify ERV insertion differences across available re-sequenced genomes derived from the two bi-directionally growth-selected chicken lines and compare candidate ERV loci with a commercial layer chicken outgroup. We map insertions and deletions to establish their positions relative to the adjacent host genomic landscape and compare candidate loci associated by sequence similarity to ERVs identified in the Red junglefowl reference assembly along with reference retroviral sequences within a phylogenetic framework.http://genome.ucsc.edu) by Rubin et al. [Whole-genome re-sequenced DNA from domestic chicken selection lines was analyzed for differences in ERV makeups as potential markers for effects of ERVs on host genome function and evolution, see n et al. .Briefly, to allow identification of reference as well as non-reference assembly ERVs using mate-pair short reads sequencing technology, we applied a strategy where reads were mapped to an independent ERV library and then located along host chromosomes by anchoring their mate-pair reads to positions in the flanking host DNA. The RetroTector software was usedp < 4 \u00d7 10\u22126) after Bonferroni correction for multiple testing.Candidate ERV loci were tested for read mapping differences across the re-sequenced chicken lines using Fisher\u2019s exact test if the minimum observed read counts at the locus were fewer than 15 and otherwise by comparison to the Chi distribution. Loci where short reads were missing in one or two of the three chicken lines were kept for further analyses if p-values for ERV-associated read counts passed the conservative threshold (http://genome.ucsc.edu) and intersected with positions for candidate ERV loci in order to explore biological significance of genes located adjacent to ERVs and their potential associations with the chicken selection line phenotypes. Associations among chromosomal genes and ERVs, intragenic as well as intergenic positions covering 150 kb up- and downstream of reference gene transcription start sites were analyzed. Candidate ERV loci were intersected with sweep regions previously determined for the H and L chicken selection lines [https://david.ncifcrf.gov/) to explore biological impact of differences in ERV integrations across the H and L chicken selection lines.The Red junglefowl reference gene dataset was downloaded from the UCSC genome browser , and visualized using FigTree v1.4.2 (http://tree.bio.ed.ac.uk/software/figtree/).Phylogenetic analyses of ERVs identified in the reference assembly together with reference retrovirus sequences were performed as previously described ,25,26. BastTree2 . The resWhole-genomes from domestic High-Growth (H), Low-Growth (L), and White Leghorn (W) chicken selection lines were previously sequenced using high throughput SOLiD technology and mapped to the chicken reference assembly by Rubin et al. , see TabGallus gallus, which was separated from the investigated chicken lines about 8000 years ago when chicken was first domesticated, see The bi-directionally growth-selected chicken lines (H and L) diverged from a single broiler founder population about 60 years ago and were separated more than 100 years ago from the branch leading to the comparison outgroup represented here by the commercial White Leghorn (layer) chicken. For reference, the compared chicken lines share a relatively recent common ancestry, compared to the reference genome assembly, generated from the Red junglefowl, http://genome.ucsc.edu) and previously determined selective sweeps for the H and L chicken selection lines [p = 0.1, binomial test), given the size of the sweep areas and the number of detected ERV insertions elsewhere in the host genomes. In addition, gene ontology searches were inconclusive and could not establish links between ERVs and adjacent host genes that could help explain the distinct phenotypes. We, therefore, analyzed candidate ERV insertion orientations and distances relative to host genes. Candidate ERV loci within host gene transcripts show a clear bias in antisense orientation relative to the host gene transcript, which could be explained by purifying selection due to potential splice interference from canonical splice signals as previously discussed [To explore potential connections between the observed divergent ERV loci across the domestic chicken lines, we intersected chromosomal positions with the reference assembly host genes , divergent ERV loci in the domestic H, L, and W chicken lines located across the phylogenetic tree that was rooted on a distant outgroup, rather than being found inside any specific retroviral clade, which is what could be expected if variation was due to retroviral expansion after the last common ancestor. Instead, the result indicates that the observed candidate ERV insertion differences do not result from recent retrovirus replication and integrations as ERVs in one or two of the chicken lineages, but rather it is consistent with standing variation of segregating ERV loci present at the onset of the bi-directional selection experiment as well as during breed formation since the domestication of chicken. Multiple radiations involving candidate ERV loci associated with assembly ERVs showing short terminal branch lengths indicate relatively recent expansions occurring within several retroviral genera across the phylogeny. It seems plausible that these radiations have generated a substantial number of segregating ERV insertions in the domestic chicken lines, thus providing the standing variation that explains the observed differences in ERV makeups, and that the number of divergent ERV loci is largely a product of the accelerated genomic divergence caused by the strong selection imposed on the H and L lines specifically, as well as directed selection of host features during domestication, which has affected all three studied chicken lines.The known breeding history and well-studied phenotypic traits among domestic animals make them first-rate model organisms to identify potential ERV contributions to biological functions and dynamics of complex genetic traits. Rare genomic changes resulting in host phenotypes that would require thousands of years to establish, or become lost, in wild host populations may be selected for in domestic settings during fewer generations ,21,29. THere, we utilized whole-genome sequences from two bi-directionally growth-selected domestic broiler chicken lines and a distantly related domestic layer chicken line for idenAs high-throughput parallel sequencing technologies generate short reads and limited coverage into the ERV loci depending on mate-pair insert sizes for reliable chromosomal anchoring, we utilized ERVs identified in the Red junglefowl reference assembly to generate an independent ERV search library and anchored loci to chromosomal positions by ERV-associated short reads mate-pair mapping. Despite limited ERV sequence coverage, it is thus possible to associate the best fit for candidate ERV loci reads with assembly ERV sequences, which could be used to construct phylogenetic frameworks and to determine associations between ERV loci and host genomic landscapes.The whole-genome sequences were generated from pooled individual DNA, see However, although gene ontology searches for genes adjacent to divergent candidate ERV loci could not explain host phenotypic variation, which could be due to the known highly polygenic nature of the trait under selection ,29, inteSimilar observations have also recently been made in other vertebrate host populations , demonstWhile it can be informative to study ERV variation from host species assemblies covering multiple species over long evolutionary time scales ,25, analIn summary, it appears increasingly important to employ careful experimental design to control the occurrence of artifacts and incorrect inferences due to unbalanced sampling in analyses aimed at evaluating host species ERV makeups. In order to obtain valid comparisons from population and distantly related genomes, it is valuable to focus on well-known pedigrees like those offered by domestic animal selection lines, where the prior knowledge makes it possible to compare observed patterns with expectations that are based on the evolutionary context of the specific case with higher precision than is generally achievable in natural populations. Sequencing and analyses of domestic animal populations and single genomes from known selection pedigrees facilitated by improved sequencing technologies that provide depth and coverage over long insertion sizes together with newly developed and fine-tuned analysis methods will facilitate mapping of ERVs previously not feasible and thereby generate new knowledge about contributions from retroviruses and ERVs to host genome function and evolution."} +{"text": "The literature is mixed with respect to how stress reactivity changes with age. Previous studies have overlooked contexts, ignoring whether stressors occurred in the laboratory or in daily life. The Health and Daily Experiences (HEADE) study includes 126 younger and older adults who completed both laboratory stressors and ecological momentary assessments (EMA) of affect and stressor experiences in daily life. We found that the laboratory stressor elicited the greatest levels of negative affect reactivity and positive affect reactivity compared to the two types of daily life stressors. Interpersonal stressors were associated with greater negative and positive affect reactivity compared to non-interpersonal stressors in daily life. Younger adults exhibited greater stress reactivity than older adults. Together, these findings support age-related reductions in stress reactivity. Implications for understanding stressor-health links are discussed."} +{"text": "Background Serum tumor markers are ubiquitously used in the clinic for cancer screening. However, the mechanisms accounting for the elevated levels of the serum tumor markers remain to be explored.Methods We performed a pan-cancer analysis of serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA). The relation between concentration of serum tumor markers and the expression of their coding genes was assessed. Then the expression of AFP and its genomic background in hepatocellular carcinoma (liver cancer) was studied.Results High expression of AFP mRNA was found mainly in liver cancer. In gastric cancer, breast cancer and lung cancer, high AFP mRNA expression was also discovered occasionally. In liver cancer patients, serum AFP levels correlated significantly with AFP mRNA expression in cancer tissues . Whole transcriptome analysis revealed that serum AFP levels clearly separated liver cancer into two classes with distinct expression profiles according to PCA analysis. Gene co-expression analysis revealed that AFP expression was connected to a module enriched with genes accounting for cell cycle and cell proliferation regulation. In addition, high AFP expression was associated with the molecular classification of liver cancer, including iCluster . Methylation analysis revealed de-methylation of AFP promoter occurred in some liver cancer tissues, which was significantly related to AFP mRNA expression. Survival analysis indicated high serum AFP levels was prognostic of poorer survival of the liver cancer patients (Log-rank test: p = 0.046). This was confirmed by an independent dataset in which liver cancer patients with high serum AFP also had poorer survival (Log-rank test: p = 0.024).Conclusion High expression of AFP defined a subtype of liver cancer with distinct gene expression profiles and clinical features. De-methylation of cytosine from CpG di-nucleotides in AFP promoter may be the cause of AFP re-expression in adult human liver cancer tissue. Serum tumor markers are essential noninvasive tools for the screening and diagnosis of various cancer types. Many serum tumor markers have been studied and approved for use in the clinic. For example, alpha-fetoprotein (AFP) is widely used for the diagnosis of hepatocellular carcinoma (liver cancer). In addition, positive AFP could also be encountered in other cancer typesAFP is the main component of mammalian fetal serum. It is synthesized by visceral endoderm of the yolk sac and by fetal liver. After birth AFP level decreases dramatically in blood. However, AFP synthesis can be reactivated in liver tumors and germinogeneous teratoblastomas. As a result, serum AFP is an important marker for liver tumors and is widely used in clinical practice Carcinoembryonic antigen (CEA) is a glycoprotein of about 200,000 Daltons in molecular weight. It is expressed in significant amounts during embryonic life, especially by the large intestine, and postnatally by carcinomas arising from this site. Many tumors of epithelial origin at other sites may also express CEA and are associated with elevated CEA levels in blood circulation PSA is most frequently detected in prostate cancer. Positive correlation has been confirmed between the PSA level and tumor stage and volumeAlthough serum tumor markers like AFP, CEA and PSA have been extensively studied and used in the clinic, questions regarding the mechanisms leading to their expression in cancer have not been well answered. This is exemplified by AFP, for which the molecular mechanisms leading to re-expression of AFP in adult human liver cancer and other tumor types is still unclearIn this study, we tried to address the questions mentioned above using genomic data from large cohort of cancer patients. We compared the expression of the coding genes of AFP, CEA and PSA, and found that only AFP expression correlated with its serum levels in liver cancer patients. Further analysis revealed aberrant AFP re-expression actually represented a shift of cell transcriptome that involved many genes, especially those related to cell proliferation regulation. We then identified de-methylation of a CpG locus located at the promoter of AFP that may be accountable for the AFP re-activation.Totally 4,666 tumor samples were included in the pan-cancer gene expression analysis of tumor markers. There were 421 liver cancer samples, 326 colon cancer samples and 549 prostate cancer samples. The details of patient and sample information could be found in the publications associated with each studyFor hepatocellular carcinoma dataset from TCGA (The Cancer Genome Atlas) study, all patients received surgical resection of their tumors. No other treatment, for example ablation, chemotherapy, or radiotherapy had been given to the patients before surgery. Surgical specimens of primary hepatocellular carcinoma and matched blood samples were collected for each patient. Totally 371 patients with full genomic data were included in this study. For clinical data analysis, patient information from the TCGA hepatocellular carcinoma publication was used, which contained 196 samplesGenomics data from TCGA project were downloaded using RTCGA package in R. The most recent version of RTCGA dataset was used (2016-01-28). For mRNA sequencing analysis, the RNASeq v2 data was used. For methylation analysis of TCGA data, the beta values of each CpG locus derived from Human Methylation 450 array platform was used. For survival analysis, a recently updated follow-up data processed by Liu J et.al. was usedGene co-expression network analyses was performed using Co-Expression Modules identification Tool (CEMiTool), an R package that can identify and analyze co-expression modules in a fully automated manner. CEMiTool is featured by unsupervised gene filtering, automated parameter selection for identifying modules, enrichment and module functional analyses, as well as integration with interactome data to generate molecular interactionsThe whole genome methylation analysis was performed using Human Methylation 450 array platform. There are 4 probes targeting AFP gene, including one probe mapped onto the promoter region (cg10778295), two probes mapped onto around -5,000 from the transcription start site , and another probe mapped onto the interior of the gene (cg02387745). However, the probe inside AFP has no readings. Pearson correlation analysis was performed to assess relationship between methylation status of each probe with AFP expression.Statistical analysis was performed using R software. Human genome assembly hg19 was used as the reference genome. Liver cancer patients were separated into three groups based on serum AFP levels: high (>= 300 ng/ml), middle , low (< 6 ng/ml). Survival plot was estimated using Kaplan-Meier method and groups were compared with log-rank test. For correlation analysis between the levels of markers in serum and tumor, serum marker levels were added by 1 and then log2 transformed. Pearson correlation analysis was then performed. For comparison of means of gene expression or methylation between two groups, t test was used.To unveil the roots of serum tumor markers, we selected AFP, CEA (encoded by CEACAM5)Next, we asked whether the presence of tumor markers in the bloodstream was resulted from high expression of these markers by tumors. We compared the expression of CEA, AFP and PSA in tumor tissue with their serum levels. In liver cancer, a strong correlation between AFP gene expression and serum levels was observed . In addiPrincipal component analysis (PCA) was performed to assess the inner structure of liver cancer expression data. The distribution of liver cancer samples was plotted using the top three principal components and patients are colored by their serum AFP levels. A clear separation between high and low serum AFP patients could be seen Figure A. This dTo identify key genomic modules co-regulated with AFP, we performed gene co-expression analysis using mRNA sequencing data of liver cancer. Five gene modules were revealed for liver cancer and AFP belonged to M4 module. M4 and M5 module were significantly related to AFP high expressing liver cancer Figure . To furtRecent high throughput genomic studies classified liver cancer into several molecularly distinct subtypes. We thus asked whether AFP activation is related to the molecular classification of liver cancer. Higher serum AFP level was significantly associated with iCluster of liver cancer. The iCluster clustering of liver cancer was derived by integrating multiple whole genome platforms, which is supposed to be the most comprehensive and unbiased classification of cancer Aiming at identifying the molecular mechanisms underlying the elevated levels of the serum tumor markers, we performed a pan-cancer analysis of AFP, CEA and PSA to assess the relationship between concentration of serum tumor markers and the expression of their coding genes. Only AFP expression in tumor tissue correlated with its serum levels. In addition, high expression of AFP defined a subtype of liver cancer with distinct gene expression profiles and clinical features. Methylation analysis revealed de-methylation of AFP promoter occurred in some liver cancer tissues, and was significantly related to AFP mRNA expression.Previous studies suggested that serum AFP levels are mainly controlled at transcriptional level in fetal liver. For example, in normal development of mouse liver, a parallel accumulation of both AFP and albumin mRNAs before birth, followed by a selective nonreciprocal decrease in AFP mRNA after birth, was observedLiver cancer is a heterogeneous disease. Many molecular subtypes have been proposed for liver cancer Most previous studies investigated AFP alone. What we found in this study suggested aberrant activation of AFP was not an isolated event. It was actually part of the systematic diversion of the transcriptome in the liver cancer cells. More importantly, this diversion in transcription also has clinical significance. The most obvious features of AFP high tumors is its poorer prognosis compared with serum AFP normal tumors. Actually, the inferior prognosis in serum AFP positive tumors has been reported by many other studies alreadyIn vivo experimental using mouse models revealed that a 7 kb regulatory region upstream of AFP gene was related to the regulation of AFP expression Although the transcriptional control of AFP expression is evident, it's unclear how liver cell cease expressing AFP after birth, and how AFP expression is re-activated in liver cancer. 2+ influx, prompting DNA synthesis and enhancing tumor cell proliferation Evidence suggests that AFP may not only be a biomarker for cancer diagnosis, but also play functional roles in tumorigenesis. AFP can promote cancer cell proliferation through binding AFP receptor (AFPR), activating PI3K/AKT and many other cancer related genes In conclusion, this study indicates that AFP re-activation is a result of the systematic transcriptome change, which collectively define a molecular subtype of liver cancer. More importantly, high AFP expression is associated with over activation of cell growth or cell cycle control genes. In addition, high AFP expression is related to poor survival in the patients. These data highlights AFP as a biomarker for both liver cancer classification and prognosis.Supplementary figures and tables.Click here for additional data file."} +{"text": "Empirical evidence supports positive associations between social support, interpersonal connections, and health as people age. This symposium addresses how human-animal interaction may facilitate connection throughout later life. Each talk presents unique ways pets: fit into social networks; expand interpersonal connections; and thereby, impact health and wellbeing. The first talk presents longitudinal associations of a history of pet ownership and marital status on health, in particular cognitive functioning, over time. The second talk presents qualitative evidence for how pets fit into older adults\u2019 social network and quantitative evidence for the impact of animal and interpersonal companionship on overall and functional health. The third talk builds upon the literature linking dog walking with older adults\u2019 physical health, by providing evidence for the positive impact of dog walking improving interpersonal connections with neighbors. The fourth talk discusses the influence of a unique intergenerational human-animal interaction service-learning course on university students\u2019 attitudes towards older adults and those with disabilities. Enrolled students provide pet care to low-income pet owners ages 60 and older and disabled adults. Students reported decreased biases towards older adults and those with disabilities after completing the course. The final talk is the first study to focus on the influence of pets in LGBTQ older adults living in rural southern Appalachia. Identifying as a LGBTQ person and living in a rural environment can present unique challenges and these qualitative results provide insight into pets\u2019 influence on aging in this understudied population."} +{"text": "For older adults living with dementia, social network quality influences health outcomes. However, current social network measurement methods are time consuming and mentally draining for people living with dementia. This study aimed to accurately measure social networks using sensor technology. Bluetooth and radio-frequency identification (RFID) sensors were used to collect social network data in a simulation of a falling nursing home resident living with dementia. Participants wore sensors on their clothing, and video recordings were compared to sensor data. Bluetooth data reflected general direction of movement and instances of idling but were neither precise or accurate. RFID data was accurate after applying data filters. Both systems detected multiple sensors simultaneously. The Bluetooth system is not feasible for clinical use, but the RFID system shows potential for clinical application and accurate measurement of social network factors as interaction frequency and duration."} +{"text": "Following stroke, the leading cause of disability in the United States, muscle alterations commonly occur. These alterations include gross atrophy and shift in fiber type, particularly in the paretic limb, which have lasting implications on gait ability. We will discuss the current evidence supporting a mechanism for these changes and how these factors differ between the paretic and non-paretic limbs. Further, we will discuss how various therapeutic exercise modalities can be used to modify or reverse skeletal muscle abnormalities and alter physical functioning post-stroke."} +{"text": "Mycobacterium tuberculosis - a global threat, the recent breakout in MDR-TB and XDR-TB has challenged researchers in diagnosis to provideeffective treatment. The main objective to combat drug resistance is to provide rapid, reliable and sensitive diagnostic methods in healthcare centres. This study focuses on development of an effective pipeline to identify drug resistance mutations in whole genome data ofMycobacterium tuberculosis utilizing the Next Generation Sequencing approach and classification of drug resistance strains based on geneticmarkers obtained from TGS-TB, tbvar and TBDReamDB. 74 isolates are characterized into 20 DR-TB, 16 MDR-TB, 16 XDR-TB and 6 nonresistantstrains based on known drug resistance genetic markers. Results provide mutation pattern for each of the classified strains andprofiling of drug resistance to the group of anti-TB drugs. The presence of specific mutation causing resistance to a drug will help set thedosage levels which play an important role in the treatment. Findings on amino acid changes and its respective codon positions incandidate genes will provide insights in drug sensitivity and a way for discovery of potent drugs. The implementation of these approachesin clinical setting provides rapid and sensitive diagnostics to combat the emerging drug resistance. Mycobacteriumtuberculosis and has plagued humans since antiquity. The discoveryof antibiotics brought a revolution in Tuberculosis Chemotherapy,which started, in 1943with Streptomycin, followed by advent ofmany potent anti-TB drugs. The implementation of these drugs intuberculosis therapy immediately resulted in a drastic reduction ofTB incidence all over the world. TB was considered to be no longera public health concern in many developed countries until theoutbreaks of multidrug resistant strains in 1980s Tuberculosis (TB) is an infectious disease caused by M. tuberculosis has evolved to emerge as drug resistant strain thathas resulted in the restriction of TB chemotherapy which pose anurgent public health problem and requires rapid intervention. Thestrains were initially resistant to single drugs, have now evolvedwith sequential accumulation of resistance mutations which hasled to the emergence of Multi-Drug Resistance strain (MDR-TB),Extensively Drug Resistance (XDR-TB) and most recently, totallydrug resistant (TDR) strains. First-line drugs, which are commonlyused for treating tuberculosis such as Rifampicin, Isoniazid,Pyrazinamide and Ethambutol, are becoming ineffective due tomutations in certain genes. These genetic markers are essential forthe identification and classification of drug-resistant strains andmost importantly give scientists an opportunity to design drugs,which counteract the effects of these mutations. MDR-TB showsresistance to at least one of the two most potent drugs: isoniazid(INH) and rifampicin (RIF). The emergence of XDR-TB resistanceis due to having developed resistance to both rifampicin andisoniazid, as well as to fluoroquinolones and at least one of thesecond-line drugs The NGS whole genome sequencing paired-end data ofMycobacterium tuberculosis was procured from NCBI-SRA database.The data isfreely accessible, and the datasets accession numbers arelisted in the supplementary data. The reference genome sequenceH37Rv was retrieved from Genbank database.NGS data may encompass sequence artefacts which include poorquality reads, read errors, duplication and adapter/primercontamination which will have an impact on downstream analysis.Therefore, the quality of the data is crucial in distinguishing thetrue mutations from the sequencing errors otherwise they may leadto wrong conclusions. Pre-Processing of the data was executedusing FastQC tool kit to assess the read quality For mapping of raw reads versus Mycobacterium tuberculosis h37rvcomplete genome, BWA-MEM algorithm was used The variants were identified using Genome Analysis Toolkitvariant calling best practice workflow including indel realignmentand base recalibration The annotated VCF files generated from SNPeff were combinedusing VCFcombine tool from Galaxy web-based platform, whichcombines all the VCF, files positionally when sites and alleles areidentical Out of screening 480 entries in the SRA database search formycobacterium whole genome data, 74 isolates were selected basedon quality control and genome coverage. These samples werefurther processed for variant calling and the generated VCF fileswere combined to obtain the union list of mutations positionally.This resulted in identification of 11,130 variants of which 8554(76.85%) were SNPs, 776 (6.97%) were insertions and 1024 (9.2%)were deletions. These mutations were mapped to the known drugresistant mutations obtained from various databases includingTGS-TB, tbvar and TBDReamDB to generate the resistance profilingof each isolate. Further annotation was performed using SNPefftopredict the effects of variants, gene annotation, codon change andits impact for all the variants called. The number of SNPs annotatedfrom various databases arelisted in the Antimicrobial resistance pattern was determined based onmutations conferring drug resistance to anti-TB drugs. Thedetermined resistance pattern for XDR, MDR and DR strains areillustrated in The annotated SNPs of the predicted resistant types were combinedto obtain the list of mutations specific to each resistant type. Pythonscript was written to read the annotated VCF files and to count thefrequency of synonymous and missense mutation across thegenome to derive the mutation pattern which is represented inIdentification of amino acid changes is crucial to understand theassociation of resistance with drugs. Python script was written togenerate the pattern of codon variations in 25 candidate drugresistant genes The present study explains the classification of drug resistant strains basedon the known drug resistance mutations obtained from various TB mutationdatabases. The mutation pattern generated for the classified strains helps tounderstand the distribution of the SNPs in certain genomic regions resultingfrom the drug selection pressures, thus providing the information onevolutionary targets of drug resistance mechanism. Profiling resistance tovarious TB drugs is important to decide the drug regimen. Otherwise, afaulty diagnosis leading to the ineffective regimen will further increase thedevelopment of Antimicrobial Resistance. The schematic representation ofcodon variations gives overall picture of resistance regions in the candidategenes. The hot spot regions will serve as diagnostic tool for screeningresistance and non-drug resistant regions can be alternative drug targets tocombat resistance. Rapid and accurate prediction of drug resistance throughmolecular diagnostics promise to improve patient's treatment outcome. Infuture directions, implementation of molecular based diagnosis in theclinical setting will help in timely diagnosis and efficient treatment of TBpatients will reduce the development of AMR.Authors declare no conflict of interest."} +{"text": "Until recently, consumers have had limited resources to assess quality of hospices agencies, contributing to growing numbers of consumers turning to online review sites, such as Yelp. Yet little is known about the content of hospice Yelp reviews and how these relate to recently available Center for Medicare and Medicaid Services\u2019 Hospice Compare site data. No study has examined Yelp hospice reviews and compared the themes identified in Yelp reviews to the topics addressed by CMS\u2019s HC measures. To better understand how consumers perceive hospice care, we drew a purposeful sample of 67 hospices in California. Researchers used grounded theory to identify themes and categories within the hospice reviews. Each of two teams of two researchers independently coded the reviews and then met to compare coding and reconcile discrepancies until 100% consensus was reached. We coded a total of 692 consumer Yelp reviews, identifying 15 themes and grouping them under five overarching thematic categories: patient/caregiver-provider relationship; clinical care; agency competency; staff professionalism; and medical equipment and supplies. We found that overall Yelp comments were positive. The most frequently mentioned Yelp themes in hospice reviews were compassionate, caring staff; patient/family gratitude; and staff responsiveness. There was considerable overlap between the themes captured in HC caregivers survey items and Yelp. However, Yelp reviews cover a greater number and more diverse themes than those measures reported on the CMS Hospice Compare site. We recommend that consumers consider both HC and online review sites such as Yelp when evaluating a hospice."} +{"text": "Globally, neonatal mortality rates remain relatively stagnant despite overall progress in reducing under-5 mortality . In regiSignificant gaps exist in infection prevention and control (IPC) practices in maternal-neonatal care settings, resulting in increased risk of health care-associated infections (HAI) for both mother and baby . HealthcAcinetobacter species (spp) and Klebsiella spp [In many resource-limited settings, neonatal sepsis is predominantly caused by Gram-negative organisms, with high prevalence of antimicrobial resistance ,5. A recella spp .As contributors to HAI risk are variable and IPC resources are limited, standardized assessments linked to improvement strategies are essential to guide health care facilities in LMIC to prioritize high-impact strategies to reduce neonatal HAI and death. The WHO has designed several tools to assess hospital-wide IPC practices, including the Hand Hygiene Self-Assessment Framework and the Infection Prevention and Control Assessment Framework at the Facility Level (IPCAF) ,8. StrenThe United States Agency for International Development (USAID) sponsored Infection Control Assessment Tool (ICAT) is a more comprehensive tool designed to assess IPC practices across acute care hospitals. It includes 22 modules as well as checklists for direct observation of several key practices . StrengtThese findings suggest that an assessment tool targeting facility-based maternal and neonatal IPC practices is needed and should address several key factors. First, an assessment tool must cover the wide spectrum of care provided for mothers and neonates in LMICs. Fundamental elements of IPC practice, such as hand hygiene, must be incorporated, but advanced care content, such as IPC related to the use of invasive devices and prolonged supportive care in neonates, should also be included for use by sites where these interventions are provided. Components of the tool focusing on antibiotic administration should also embrace antimicrobial stewardship principals targeting areas with high endemic rates of antimicrobial resistance. While self-assessment would facilitate broad uptake in LMICs, direct observation of key IPC practices by a trained assessor, whether internal or external, would ensure observations made had a high probability of guiding true gaps in IPC practice. An assessment tool should highlight strengths and opportunities for improvement, guiding facilities to plan and implement interventions with the ultimate aim of creating a sustained improvement in IPC practices. Linkage to educational materials and implementation tools would strengthen such a tool, providing key recommendations to health care facilities seeking to improve IPC in maternal and neonatal care. Ultimately, a comprehensive assessment tool designed specifically for maternal and neonatal care will allow facilities to most effectively reduce morbidity and mortality due to HAI in this vulnerable population."} +{"text": "Antibody-based therapy has revitalized the world of cancer therapeutics since rituximab was first approved for the treatment of Non-Hodgkin\u2019s Lymphoma. Monoclonal antibodies against cancer antigens have been successful strategies for only a handful of cancer types due to many reasons including lack of antibody specificity and complex nature of tumor milieu which interfere with antibody efficacy. Polyspecific antibodies are promising class of anti-cancer agents which can be directed at multiple tumor antigens to eradicate tumor cells more precisely and effectively. They may overcome some of these limitations and have already changed treatment landscape for some malignancies such as B cell acute lymphoblastic leukemia. Pre-clinical studies and early phase clinical trials have demonstrated that this approach may be an effective strategy even for solid tumors. This review focuses on the development of bispecific and trispecific antibody therapy for the treatment of solid tumor malignancies and highlights the potential they hold for future therapies to come. Cancer remains the second leading cause of death in the United States, with lung cancer being the leading cause of cancer deaths, followed by breast cancer in women and prostate cancer in men Siegel . Over th. Although some of these primitive formats showed appreciable activity against certain malignancies, the vast majority had a dismal therapeutic-risk index. With rapid advances in genetic engineering, the past two decades have seen a dramatic increase in the production of polyspecific antibodies with more than 120 described formats now in clinical use or undergoing evaluation in clinical trials are genetically engineered proteins that can simultaneously engage two or more different types of epitopes Figs.\u00a0 and 2 F. They shBispecific antibodies with ability to engage two different antigens are the most commonly used PsMabs. Since the initial experiments to produce BsMabs , tandem single chain variable fragments (taFvs), diabodies (Dbs), single chain diabodies (scDbs), and triplebodies. Due to their small size, these scFV based antibody fragments have high tumor specificity and tumor penetration. However, their small size also limits serum half-lives which could potentially limit efficacy and increase cost by requiring repetitive dosing into the proximity of the tumor cell to enhance antitumor effect Fig.\u00a0. This fu. DART bispecific antibodies, created by engineering two Fv fragments with the variable heavy chain portion exchanged with one another, are larger than BITEs and show better serum stability antibodies, tandem diabodies appear to potently eliminate targets expressing their tumor associated antigen (TAA) in the absence of costimulatory models or IL-2 pre-activated T cells . Blinatumomab is a novel bi-specific T cell engager which binds sites for both CD19 and CD3 T cell receptor complex, leading to T cell proliferation and activation resulting in target cell (lymphoblast) apoptosis. Unlike catumaxomab, which uses large IgG-like bi-specific antibodies with Fc regions, blinatumomab was created by the fusion of two single chain variable fragments (scFv) connected in a flexible manner through a peptide linker , which first allows tumor specific antibodies to distribute to the tumor antigen site followed by the administration of a small radioactive agent with high affinity for the tumor antibody, limits the accumulation of radiation in non-target sites and histamine- succinyl-glycine (HSG), when used with lutetium-177 labeled peptide for PRIT in prostate cancer demonstrated effective targeting and permeability in mice pre-clinical studies and radioimmunotherapy (RIT) use the antibody specificity of tumor-based antigens in conjunction with emitted radiation from suitable radioisotopes to image malignancies (RIS) for diagnostic and treatment purposes. The radioantibody is injected intravenously and distributes to the antigen binding site on tumor cells where the radionuclide delivers the tumoricidal dose to the tumor mass for detection of colonic liver lesions in an orthotopic murine model , breast cancer, uterine, and bladder cancers [NCT02324257], [NCT01284231] and met gene amplification has been shown to be a major mechanism in which cancers develop resistance to EGFR inhibitors , and also found in breast and lung carcinoma, was recently found to be expressed in glioma stem cell lines , which binds CD3 and targets EpCAM, increased the sensitivity of tumor cells to cytotoxic T cell death in multiple EpCAM positive ovarian and endometrial cancer cell lines including ovarian carcinosarcoma and primary uterine serous papillary carcinoma or programmed death-1 (PD-1) or its ligand (PD-L1) and transforming growth factor-\u03b2 (TGF-\u03b2), which mediates immune tolerance using a bifunctional antibody-ligand trap was recently reported and tri-specific killer cell engagers (TriKEs). BiKEs are created by the fusion of a single chain variable fragment (Fv) against CD 16 and a single-chain Fv against a tumor associated antigen and targets the death receptor 5 , can selectively and potently kill melanoma cells. This approach may prove beneficial in those patients resistant to monoclonal antibody therapy directed against HER1, HER3, c-MET and IGF1R with enhanced antitumor effects in a preclinical model , there are many new molecules with three or four binding sites. For example, Castoldi et al.Another example of how novel approaches may simplify treatment is a recent preclinical study demonstrating elimination of large tumors by in-vivo production of bispecific antibodies induced by parenterally administered engineered mRNA (Holzinger et al. Advances in antibody directed therapy have simultaneously fostered the development of another form of immunotherapy, CAR-T cell therapy. While an in-depth discussion on this exciting topic is out of scope for this review article which is focused on polyspecific antibodies, we present a brief review on the topic here and compare the two forms of immunotherapy. CAR-T cell therapy consists on removing T cells from patients and modifying ex vivo using gene transfer to enable expression of specific receptors targeting tumor cells through an antibody-derived binding domain. Once the T cells are genetically modified to express the chimeric antigen receptor, they are infused back into the patients to directly kill the cancer cells Fig.\u00a0 Caruana. CurrentWhile both monoclonal antibody therapy and CAR T-cells are antigen specific immunotherapies, CAR T cells, at present, have to be individually manufactured for each patient resulting in high cost of production. Despite this, CAR T-cells exhibit several qualities that could make them more advantageous than antibody directed tumor therapy. The genetically engineered receptors allow CAR T-cells to recognize tumor cells with low antigen expression and cause direct lysis of tumor cells whereas classical monoclonal antibodies need a high density of tumor antigens to trigger the ADCC or complement cascade (Caruana et al. Antibody-based cancer directed therapy is an exciting and rapidly advancing field. The introduction of monoclonal antibodies such as rituximab revolutionized cancer therapy and have given way to the creation of bi-specific and tri-specific antibodies which work with more precision and efficacy than their predecessors. The one currently approved bi-specific antibody therapy, blinatumomab and catumaxomab, have shown improved survival rates and quality of life for subsets of cancer patients. Multiple agents are currently being evaluated in clinical trials while optimal structures and treatment algorithms are being defined to maximize benefit-risk ratio. Newer approaches concurrently targeting checkpoint molecules and cancer-specific antigens seem promising in preclinical models and may change the landscape of cancer therapeutics (Junttila et al. Several biological parameters are still missing in the understanding of the tumor biology and its complex microenvironment. Engineered polyspecific antibodies will likely play a major role in oncotherapeutics as cancer research continues to climb to new heights."} +{"text": "Dual-plating of the distal femur is required in some cases to achieve stable fixation. The indications of a medial plate in addition to the lateral plate are medial supracondylar bone loss, low trans-condylar bicondylar fractures, medial Hoffa fracture, peri-prosthetic distal femur fractures, non-union after failed fixation with single lateral plate, poor bone quality and comminuted distal femur fractures (AO type C3). We recommend orthogonal plate configuration with locked plates by a single incision or dual incision approach as per surgeon choice. Supracondylar femur fractures are commonly associated with severe comminution and significant soft tissue injury. Distal femoral fractures are mostly caused by high-energy injuries, such as falling injury and traffic accidents, and fractures are often severely comminuted. Despite the recent advances in techniques and implants, the treatment of intra-articular multi-fragmentary distal femoral fractures remains a challenge. Long-term disability can occur in patients with extensive articular cartilage damage and marked comminution. Distal femur fractures in the elderly are complicated by poor bone quality (severe osteoporosis), a distal segment that is too short for adequate fixation, blood loss, malunion and non-union, and increased mortality -4.Locked plating is one of the best and modern options for treating supracondylar femur fractures with relatively low failure rates. Single lateral plating of distal femur fractures was often found to have a relatively higher failure rate .A medial plate in addition to lateral plating reduces the chances of failure of fixation . This arPre-operative planningDecision making before surgical stabilization is important. The treating surgeon should examine the injured limb to check for the soft tissue status and any distal neurovascular deficit. Also, other injuries should be ruled out. Good quality radiographs in two planes are necessary. Computed tomography of the distal femur with coronal and sagittal reformations helps in delineating fracture patterns. Proper pre-operative planning will guide towards the need for dual plating of distal femur fractures .Indications for dual platingSupracondylar femur fractures were previously treated with condylar buttress plates . SubsequMedial Supracondylar Bone LossIn distal femur fractures with extensive metaphyseal comminution, osteopenic bone and in high-energy or open fractures, there is functional loss of medial cortical buttress. In these situations, there is less chance of healing of the medial column. The addition of a medial plate helps in giving additional stability and reduces the chances of implant failure ,14. RajaLow Trans-condylar Bicondylar FracturesHigh energy injuries sometimes lead to a low horizontal trans-condylar fracture pattern which is associated with an intercondylar split. In this fracture pattern, fixation with a single lateral plate may not achieve stable fixation as sufficient screw purchase will not be possible because of the intercondylar notch. A medial buttress plate in addition to the lateral plate is helpful in this situation ,16.Medial Hoffa FractureAnatomical restoration of the articular surface is necessary for comminuted distal femur fractures. In fractures with a large medial Hoffa fragment, the application of a medial neutralization plate is necessary to achieve stable fixation. This fixation provides stability in addition to interfragmentary lag screws .Peri-prosthetic Distal Femur FracturesIn peri-prosthetic fractures of the distal femur, dual plating offers stable fixation, especially in osteoporotic bone. This allows for early mobilization and rehabilitation. Stable fixation of peri-prosthetic fractures is necessary to avoid failures of fixation. Cicek et al. advocated dual locked plate fixation of peri-prosthetic distal femur fractures with osteoporotic bones .Non-union after Failed Fixation with Single Lateral PlateThere is an increased risk of non-union in patients with comminuted distal femur fractures treated with single lateral locking plate . In thesPoor Bone QualityIn patients with distal femur fracture with osteoporotic bone, there is a high incidence of failure of fixation with a single lateral plate due to poor purchase of screw in osteoporotic bone. Metwaly and\u00a0Zakaria demonstrated that dual plating in osteoporotic distal femur fractures by a single incision offers the stability of fixation with resultant early mobility and accelerated rehabilitation . In the Comminuted Distal Femur Fractures (AO type C3)In patients with AO type C3 distal femoral fractures, dual plating offers a more stable construct. Imam et al. demonstrated that dual plating fixation using anterior approach for type C3 distal femoral fractures is an efficient and safe method of management. It has several advantages such as precise exposure, easy manipulation, anatomical reduction, and stable fixation . SteinbeSurgical techniquePositionThe patient is positioned supine on a radiolucent operating table with the knee flexed at 30 degrees. Tourniquet use depends on the surgeon and may be used in very distal fractures. The use of a lateral femoral distractor with pins placed in the femoral diaphysis and proximal tibia metaphysis facilitates fracture alignment and disimpacts intra-articular fragments. Intra-operative use of C-arm is necessary for proper plate placement and fracture reduction and alignment .ApproachThe choice of approach depends on the surgeon. There are two approaches, the dual incision approach\u00a0and the single incision approach. The dual incision approach involves placing a medial and lateral incision for exposure of fracture and articular surface . The sinPrecautionsSoft tissue attachments to bone fragments should be preserved to prevent any devascularisation of bone fragments. Soft tissue retractors should be used with care .Choice of ImplantDual 4.5 anatomically contoured locking plates are generally used. The T-buttress plate can also be used for medial condyle fixation. Cancellous screws of 6.5 mm are preferred for intercondylar fragment fixation .Plate ConfigurationOrthogonal dual plate configuration provides more stable fixation and is biomechanically superior to dual adjacent plating for constructs fixed with either standard compression or locking plates .Post-operative careEarly mobilization in a protected hinged knee brace should be done. Weight-bearing is to be allowed according to radiographic and clinical examination findings at the subsequent follow-up visits. Radiographic healing is established by the union of three cortices of the bone on the anteroposterior (AP) and lateral radiographic views of the bone. Clinical healing is confirmed by the absence of pain either with weight-bearing or with the application of stress over the injured area on examination. Malrotation is detected clinically by comparing the injured side to the normal side. Follow-up is to be continued until fracture healing and full weight-bearing .Dual plating of distal femur fractures offers a reliable stable fixation in cases with medial supracondylar bone loss, low trans-condylar bicondylar fractures, medial Hoffa fracture, peri-prosthetic distal femur fractures, non-union after failed fixation with single lateral plate, poor bone quality and comminuted distal femur fractures (AO type C3). Single-incision or dual incision approach may be used. Orthogonal plate configuration with locked plates provides stable fixation and allows for early rehabilitation. Early mobilization is necessary to prevent joint stiffness."} +{"text": "However, recent studies demonstrate the existence of a novel, centrally-derived peripheral glial population called motor exit point (MEP) glia, which myelinate spinal motor root axons in the periphery. Until recently, the boundaries that exist between the CNS and PNS, and the cells permitted to cross them, were mostly described based on fixed histological collections and static lineage tracing. Recent work in zebrafish using Myelin is a unique plasma membrane extension produced by specialized glial cells that is wrapped around axons and facilitates rapid transmission of electrical impulses over long distances. Although myelin appeared 430 million years ago in the vertebrate lineage consists of the brain and the spinal cord, while the peripheral nervous system (PNS) consists of neural tissue outside of the CNS, including motor and sensory axons and sensory neurons clustered in ganglia. While many neurons establish circuits within the CNS, some of these cells send their axons freely across specialized CNS boundaries known as transition zones (TZs) and travel long distances throughout the organism and ultimately make synapses on peripheral tissues, including muscle. By associating tightly with axons to ultimately ensheath and insulate them with fatty membranes called myelin, myelinating cells increase nerve impulse conduction speed and strengthen the function and efficiency of the whole nervous system.In the CNS, oligodendrocytes (OLs), which are derived from neural tube precursors, make myelin in the brain and spinal cord, while Schwann cells (SCs), which originate from the neural crest (NC), myelinate axons of the PNS and OL lineage cells. After exiting the CNS, MEP glia reside just outside of the ventral spinal cord along spinal motor nerve root axons, occupying axonal territory between SCs in the periphery and OLs in the spinal cord. The pMN domain constitutes the major site of expression of the basic helix-loop-helix (bHLH) transcription factor Olig2. In zebrafish, olig2 mutants, which harbor a mutation in sox10 and lack SCs, have peripheral OPCs that differentiate and myelinate spinal motor nerves, suggesting that sox10 may be required for MEP glial function or survival transgenic line that faithfully mimics the endogenous expression of foxd3 , a transcription factor expressed by boundary cap (BC) cells that is also required for SC myelination and MEP TZs, where axons enter and exit the spinal cord, respectively that are not found all together in any other myelinating glial cell type and both mbp and transcript and MBP protein can be detected along motor nerve root axons as early as 4 dpf mutants, where SCs are arrested at the pro-myelinating stage and fail to myelinate peripheral axons, Monk et al. (gpr126 mutants are, in fact, MEP glial myelin sheaths (Figures gpr126 to initiate myelination. And as previously mentioned, these glial cells also do not express Krox20. Therefore, they are a CNS-derived, peripheral glial cell that myelinates peripheral axons, but uses a distinct molecular mechanism to initiate myelination.Fascinatingly, in k et al. describe Figures . These d+Krox20 BC cells project membrane processes across the MEP TZ into the ventral spinal cord (Radomska and Topilko, + cells residing within the mouse spinal cord give rise to SCs, which are usually NC-derived (Zawadzka et al., Drosophila, zebrafish and mouse (Sepp et al., For years, mammalian BC cells were thought to constrain MN cell bodies to the spinal cord by repulsion from outside the spinal cord (Bron et al., MEP glial development and function raise many new questions. What are the signals mediating OPC-MEP glial interactions across the MEP TZ? Do MEP glia also interact with SCs and via which molecular mechanisms? Does this novel, centrally-derived glial cell population adopt a central-like myelination pattern, involving the extension of multiple membrane processes to wrap more than one axonal segment? Or does it behave more like a Schwann cell, ensheathing a single axonal segment in a truly peripheral-like fashion? Or alternatively, is MEP glial myelin a kind of hybrid myelin featuring both central and peripheral characteristics? How do MEP glia myelinate if they do not require Krox20 or Gpr126? Electron microscopy of the MEP TZ will be needed to examine MEP glial development at the ultrastructural level to characterize their myelin sheaths that connect the CNS and PNS. RNA-sequencing coupled to genome editing tools such as CRISPR/Cas9 will shed light on the molecular mechanisms that drive MEP glial development, their gating function and differentiation into peripheral myelinating glia. Recent studies in zebrafish have uncovered the existence of novel centrally-derived myelinating glia that function in the PNS and are required for nervous system TZ integrity, and future work may change our way of thinking about mammalian myelinating glia as well.LF wrote the manuscript with input from SK.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Although a number of new systemic therapeutic options in patients with advanced solid cancers have emerged due to the improved knowledge of molecular dysregulation in cancers, the durable, long-term, objective responses infrequently occur. This editorial article highlights the major limitation of current systemic therapy due to an inefficient drug delivery. While several mechanisms contributing to cancer drug resistance have been described, the common key barrier among solid cancers is the unique tumor microenvironment that causes the high interstitial fluid pressure (IFP). We discussed the mechanism causing an elevated IFP and how it interferes with drug delivery. To target the high IFP, we demonstrated the novel approach using gold nanoparticle carrying recombinant human tumor necrosis factor (TNF), a vascular disrupting agent, that preferentially and specifically targets tumors while the systemic toxicity is markedly reduced. The addition of cytotoxic agent by either directly conjugating to the gold nanoparticle or by systemic administration following gold nanoparticle carrying TNF resulted in significantly reduced tumor burden and increased survival in multiple mouse models with primary and metastatic endocrine cancer and pancreatic ductal carcinoma. A clinical trial in patients with advanced solid cancers is warranted based on the promising results in preclinical studies. In the era of \u201cprecision medicine\u201d for cancer, efforts have been made to identify agents that preferentially target expressed molecular pathways specific to the cancer cells. Despite the potential of these new targeted therapies, durable long-term responses rarely occur. A major limitation of current systemically delivered cancer therapies is the failure of these drugs to effectively reach their target, the cancer cells. Because of inefficient systemic drug delivery, high doses of systemically-administered cancer drugs are usually given, which inevitably cause off-target toxicity, to achieve anti-tumor efficacy. Several factors contribute to the failure of systemic cancer treatments to effectively kill cancer cells. These include the ATP-binding cassette (ABC) transporters that can actively pump cytotoxic drugs out of cancer cells and the Normally, water and molecules transported through convection flow out of capillaries, flow through the interstitial space, and into the lymphatic system and/or the venous drainage system. This transcapillary flow, created by the gradients of hydrostatic and colloid osmotic pressures in capillaries and in the interstitium, is typically outward (capillaries to lymphatic and/or venous system) because of the slightly negative pressure gradients in the normal interstitium . The eleTumor necrosis factor alpha (TNF) is a cytokine involved in systemic inflammatory response. This cytokine also has a potent effect on vascular endothelium, causing vascular leakage. Because of the severe systemic toxicity, the EU-approved clinical role for TNF in cancer treatment is currently limited to a cumbersome but effective surgical procedure that regionally delivers the combination of TNF and a high dose cytotoxic agent to the affected limb for locally advanced melanoma (isolated limb perfusion). To mitigate the systemic toxicity associated with TNF, our group demonstrated in a phase I clinical trial in patients with advanced solid cancers that CYT-6091, a PEGylated colloidal gold nanoparticle carrying recombinant human TNF, preferentially targets tumor tissue and had no dose-limiting toxicity at a dose 3-times higher than previous clinical trials in cancer patients treated with systemically administered recombinant human TNF. Although CYT-6091 was safe, the anti-tumor activity was minimal as only one patient of 27 achieved a partial response . Thus, Cand a paclitaxel prodrug. We studied the effect of CYT-21625 and CYT-6091 in 3 mouse models of thyroid cancer and neuroendocrine tumors. In this recent publication, we performed CT scan, FDG-PET, and histologic analyses showing that CYT-6091 and CYT-21625 specifically and preferentially target tumor tissue without histologic or clinical evidence of toxicity to normal organs. In addition, both nanomedicines caused intratumoral vascular damage and leakage only in tumor tissue. CYT-21625 treatment resulted in statistically significant lower tumor burden in mice with metastatic anaplastic thyroid cancer, poorly differentiated thyroid cancer (PDTC) and in genetically engineered mice that naturally develop pancreatic neuroendocrine tumors. The survival benefit was observed in mice with metastatic PDTC. Histologic analysis showed that CYT-21625 treated xenografts had lower tumor cell proliferation and increased caspase-dependent apoptosis [all mice that received CYT-6091 pretreatment followed by protein-bound paclitaxel survived. None of the mice receiving vehicle control survived at day 42 support this approach as the treatments induced tumor vascular leakage, increased cytotoxic drug accumulation, and improved animal survival. Because tumor vascular architecture in these mice resembles that seen in patients, such promising responses in preclinical studies of nanomedicine targeting tumor microenvironment need to be expanded to patients with advanced solid cancers in clinical trials."} +{"text": "Physical examination revealed a back abrasion, stupor, and spasmodic laughter is rare.What do we already know about this clinical entity?Malignant catatonia (MC) often leads to fatal consequences. Administration of low-dose lorazepam typically leads to rapid resolution of symptoms; thus, definite diagnosis is crucial.What is the major impact of the image?Because MC resembles tetanus, diagnosis is often difficult and delayed.How might this improve emergency medicine practice?Administration of low-dose benzodiazepines may be warranted when patients presenting with MC symptoms have a history of psychological disorders and normal blood, urine, cerebrospinal fluid testing and imaging.Documented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report."} +{"text": "Post-traumatic Stress Disorder (PTSD) is a stress related syndrome. Chronic PTSD has increasingly been associated with poor health outcomes, neurodegeneration and risk for cognitive impairment (CI). However, the biological mechanisms underlying the development and maintenance of symptoms and potential associations in accelerating aging are not well understood. The aim of this study was to evaluate whether specific biomarkers influence functional limitations and cognitive impairment in rescue and recovery workers (i.e. responders) from the attacks on the World Trade Center (WTC) in New York. Plasma biomarkers were collected during annual health and wellness visits at the WTC responder clinic between 2012 and 2014. Short Physical Performance Battery (SPPB) and clinical data were examined with prospective PTSD symptom scores collected during participant\u2019s initial enrollment into the parent study as early as 2002. We examined the relationship between cardiovascular , metabolic and inflammation markers with Post-traumatic Stress Disorder (PTSD), cognitive functioning and frailty in responders from the World Trade Center (WTC). We first examined correlations between biomarkers, PTSD symptom severity, PTSD dimensions, cognitive functioning and frailty. We then conducted multivariate regression analyses. In models adjusted for potential confounders, among N=1,045 responders, elevated PTSD was strongly associated with increased frailty, cardiovascular dysregulation and mild cognitive impairment. Current work is ongoing to identify trajectories of change in cognition with frailty and biological factors."} +{"text": "We sought to extend recent research that explored model-based approaches for combining clinical and gait measures to determine the most sensitive grouping for retrospectively classifying fallers from non-fallers which resulted in a model with 92% sensitivity and 66% specificity and an overall model of 83%. In the present study, the clinical assessment battery was augmented by incorporating more challenging balance items while removing clinical measures characterized by ceiling effects and restricted range. Thirty-two community-dwelling older adults completed a battery comprising 76 measures of more challenging clinical measures of mobility and balance, and retained gait (GaitRITE), postural sway and physiological measures. Within each domain, highly collinear and theoretically-redundant measures were removed. Next, a Principal Component Analysis (PCA) identified those clinical and gait variables that accounted for the most unique variance. Finally, a backward stepwise logistic regression was performed on the reduced set of variables from the PCA to develop predictive equations. The current analysis yielded improved specificity of 75%, but slightly lower sensitivity 81%. Interestingly, when the results for the PCA from the previous study were used with the current data, the model classified fallers with 87% sensitivity and 86% specificity and an overall model of 86%. Notably, in all analyses, gait variables were central in identifying fall risk, with single- vs. dual-task difference scores of particular predictive importance. The differences observed between the best-fitting models across the two cohorts implies that modelling methods should accommodate and harness individual differences ."} +{"text": "Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. Activating mutations in KIT or PDGFRA receptor tyrosine kinases (RTKs) are central to GIST biology and drive GIST growth and progression . This onKIT exon 14 T670I gatekeeper mutation was also suppressed by regorafenib, but not KIT exon 13 V654A resistance mutation, the most common secondary mutation present at the onset of imatinib failure. These results were further corroborated in biopsies from GIST patients treated with regorafenib in the phase II trial, underscoring V654A mutation as the main vulnerability for regorafenib treatment. Remarkably, we found that all TKIs, either approved or investigated in clinical trials, had activity profiles targeting only a subset of KIT secondary mutations and growth. Together, we established the rationale for a phase I clinical trial that tested, for the first time in cancer, a rapid alternation treatment-schedule using agents with complementary activity against resistant subclones (NCT02164240).In the absence of approved drugs with pan-KIT inhibitory activity, novel therapeutic strategies are urgently needed in order to overcome the inter- and intra-tumor heterogeneity of subclones harboring different KIT secondary mutations. Interestingly, several TKIs had complementary profiles against secondary resistant mutations, including second- and third-line approved agents for advanced GIST, sunitinib and regorafenib, respectively. Combination of these two drugs widens the spectrum of secondary-resistant clones effectively targeted and may augment the magnitude and/or duration of clinical response. However, dose reduction due to overlapping effects might preclude activity in patients. We first established co-cultures of barcoded GIST cell lines containing clinically relevant KIT primary and secondary mutations, thus representing the polyclonal imatinib-resistance heterogeneity observed in many GIST patients. We subsequently modeled preclinically a rapid alternation treatment schedule of sunitinib and regorafenib, to maintain selective pressure against polyclonal secondary-resistance GIST cells, thereby impeding the regrowth of targeted subclones when the relevant drug for those subclones is withheld. Alternation of three days of sunitinib followed by four days of regorafenib was more effective than either drug alone inhibiting cell proliferation of these polyclonal populations and preventing emergence of a single dominant clone. The intrinsic heterogeneity of resistant subpopulations challenges standard management of cancer patients based on the sequential use of single-agent therapies that are discontinued upon progression or unbearable toxicities. Further, although combinations of kinase inhibitors have a biologic rationale highly needed, clinical development has encountered difficulties due to enhanced and/or overlapping toxicities . In this"} +{"text": "The discovery of a fossil survival strategy in modern corals explains unexpected recoveries after warming-induced mortalities. Climate change is affecting reef-building corals worldwide, with little hope for recovery. However, coral fossils hint at the existence of environmental stress\u2013triggered survival strategies unreported in extant colonial corals. We document the living evidence and long-term ecological role of such a survival strategy in which isolated polyps from coral colonies affected by warming adopt a transitory resistance phase, in turn expressing a high recovery capacity in dead colony areas. Such processes have been described in fossil corals as rejuvenescence but were previously unknown in extant reef-builder corals. Our results based on 16 years of monitoring show the significance of this process for unexpected recoveries of coral colonies severely affected by warming. These findings provide a link between rejuvenescence in fossil and extant corals and reveal that beyond adaptation and acclimatization processes, modern scleractinian corals show yet undiscovered and highly effective survival strategies that help them withstand and recover from rapid environmental changes. Corals are subjected to climate change\u2013related impacts worldwide, with overwhelming evidence of mass mortalities affecting vast geographical areas in tropical Mediterranean Sea, Spain] Red List . Near-full recoveries are located 30 nautical miles off the nearest coast . A marine reserve encircles the archipelago, covering an area of 5500 hectares. Illa Grossa , the largest of the islets in the Columbretes, is a C-shaped, drowned, Quaternary volcanic caldera. The monitored C. caespitosa colonies was annually monitored in the Columbretes Islands from 2002 to 2017. Each colony was examined after the summer, when mortality-triggering thermal anomalies occur, and the extent of the necrosed surface was recorded with photographs and sketches recovered from the last major mortality event suffered by each colony to the last annual monitoring.n = 21) from the Columbretes Islands, previously cleared of organic matter, and a corallite sample from a Holocene fossil reef in Menorca (Samples of rejuvenated corallites ("} +{"text": "Despite research documenting gender differences in numerous outcomes in later life, we know little about gender differences in quality of life (QoL) for older adults who receive institutional long-term care. To address this gap, this study examines the relationship between gender and nursing home (NH) residents\u2019 QoL, including possible reasons for differences observed. We used a mixed methods design including surveys with a random sample of Minnesota NH residents using a multidimensional measure of QoL , resident clinical data, facility-level characteristics, and qualitative interviews with NH residents (n=64). We used mixed models and thematic analysis of resident interviews to examine possible differences in resident QoL based on gender. After controlling for individual and facility characteristics, women reported higher overall QoL than men, with men reporting significantly lower QoL in 4 of 8 QoL domains. In interviews, men noted being especially dissatisfied with facility activities, whereas women more frequently described having friends in the facility and relying on family for support. Some women viewed the NH as a place of respite and described wanting to stay long-term, even though their families asked them to return home. In contrast, men more often described the NH as necessary due to physical needs, but undesirable for long-term living. Our findings provide preliminary evidence that men and women experience QoL differently, with men reporting lower QoL in several domains. Tailoring more activities for men and finding ways to strengthen relationships for men within the facility may help reduce the gender disparities in QoL we observed."} +{"text": "Iatrogenic aortocoronary arteriovenous fistula is a very rare complication of coronary artery bypass grafting in which one of the arterial grafts inadvertently forms a fistulous tract with a cardiac vein, shunting blood from the anastomosed coronary artery. We report a patient with an iatrogenic left internal mammary artery graft to cardiac vein fistula presenting with recurrent angina three years after a three-vessel coronary artery bypass grafting. This case of iatrogenic aortocoronary arteriovenous fistula (ACAVF) is interesting because it is a rare but important complication of coronary artery bypass grafting (CABG) which can result in significant clinical consequences like heart failure, tamponade, and death. To the best of our knowledge, only 38 similar cases of ACAVF have been reported in the literature. We have included a brief review of the literature on this rare complication and the various available treatment options.A 61-year-old woman with diabetes mellitus, hypertension, and hyperlipidemia initially presented with unstable angina; a regadenoson stress nuclear myocardial perfusion imaging (MPI) revealed anterolateral wall ischemia. Subsequent coronary angiography demonstrated severe stenoses of the left anterior descending (LAD) artery, left circumflex artery, and right coronary artery. She underwent CABG with a left internal mammary artery (LIMA) graft to the LAD artery and saphenous venous grafts (SVG) to the right posterior descending (RPDA) and obtuse marginal 4 (OM4) arteries. After CABG, the patient was doing well on guideline-directed medical therapy. Three years later, she presented with acute onset of chest pain suggestive of unstable angina. On admission, her heart rate was 80/min, blood pressure was 140/86\u2009mmHg, and her physical exam was unremarkable.Electrocardiogram showed normal sinus rhythm without any evidence of ischemia. Serially monitored cardiac enzymes were within normal limits, and transthoracic echocardiography revealed normal ejection fraction with no distinct regional wall motion abnormalities. Regadenoson stress nuclear MPI showed anterolateral ischemia, a territory which should have been supplied by the LIMA to LAD graft. Diagnostic coronary angiography revealed known severe native, three-vessel coronary artery disease. The native LAD vessel was very small. Proximal LAD was medium sized. Mid LAD had 100% stenosis at the origin of diagonal branch. Distal LAD was not visualized . Graft aThe case was discussed with the cardiac surgical team as well as in a multicenter interventional conference to explore both surgical and percutaneous options. A percutaneous approach of coiling of the fistula is anatomically complex; a surgical approach which would involve ligation of ACAVF and redo CABG, would put the patient at higher risk of perioperative cardiac morbidity and mortality. Because of the coronary arterio-venous fistula with steal, it was unclear whether revascularization of the native LAD would be of any significant benefit to the patient. After full discussion about the risks versus benefits of treatment options with the heart team, the patient elected for medical management and intervention only if she has escalating symptoms. The patient's anti-anginal therapy was optimized with Metoprolol 50\u2009mg daily, which she tolerated well with gradual improvement in her exercise tolerance and resolution of her anginal symptoms. The patient is currently asymptomatic at 1 year follow-up. Repeat cardiac stress testing may be pursued if she has recurrent symptoms. The tentative plan is to offer her interventional coil closure or surgical closure of the ACAVF if she has recurrent angina or heart failure symptoms.Iatrogenic ACAVF is a rare complication of CABG causing significant morbidity. To the best of our knowledge, only 38 cases have been reported . ACAVF c"} +{"text": "Gametocyte density and sex ratio can predict the proportion of mosquitoes that will become infected after feeding on blood of patients receiving nongametocytocidal drugs. Because primaquine and methylene blue sterilize gametocytes before affecting their density and sex ratio, mosquito feeding experiments are required to demonstrate their early transmission-blocking effects. Anopheles mosquitoes must ingest at least 1 male and 1 female gametocyte to become infected. The formation of Plasmodium oocysts on the mosquito midgut wall is commonly used as evidence for successful transmission. These oocysts enlarge over time to rupture and release sporozoites that render mosquitoes infectious. In the absence of treatment, infectivity of malaria-infected individuals can be reasonably well predicted by the density of male and female gametocytes in their peripheral blood = 1.08 ; density or sex r density . Infecti density . There wWe found that measures of mRNA gametocyte density do not correlate with infectivity shortly after treatment with gametocytocidal drugs. The major implication of this finding is that studies that examine transmission-blocking effects of drugs and potentially vaccines require mosquito-feeding assays to measure infectivity. Gametocytocidal drugs rapidly clear gametocytes, distort the gametocyte sex ratio , 11, andHere, we present evidence that gametocyte density and sex ratio are unaffected in the first 48 hours after initiation of treatment, despite a near complete prevention of onward transmission to mosquitoes. Nongametocytocidal drugs did not alter the shape of the associations between gametocyte density, sex ratio, and mosquito infection prevalence; gametocytes appeared equally infectious before and after treatment. In contrast, gametocyte density and sex ratio no longer explained transmission after treatment with DP-MB or SP/AQ-PQ; gametocytes persisted with sex ratios similar to those before treatment, but mosquito infections were nearly completely prevented.The mechanism that underlies the early sterilizing effect despite continued presence of gametocyte mRNA transcripts is unclear. While mRNA is unlikely to survive in free-floating form and, also by microscopy, gametocyte densities remain unaffected shortly after treatment , it is pThe molecular mechanisms that underlie the apparent male-biased clearance of gametocytes after MB treatment and female-biased clearance after PQ treatment are currently unclear; however, they likely reflect the sexual dimorphism of gametocyte proteomes. Our findings thus provide evidence for an early sterilizing effect of MB and PQ. Molecular tools to quantify male and female gametocytes cannot replace mosquito-feeding experiments to assess transmission-blocking properties of antimalarials."} +{"text": "Mobility impairments are prevalent in older adults. Whereas walking had traditionally been viewed as an autonomous process, evidence over the last decade has shown that cognitive processes such as attention and executive function have a significant impact on gait function in older adults. However, the exact neural mechanisms underlying difficulties in the control of mobility in older adults remains an open question. We examine the changes in the executive control of mobility in older adults with mobility impairments using functional near-infrared spectroscopy, as operationalized by performance in the community balance and mobility scale (CB&M). We hypothesized that prefrontal cortical (PFC) activity increases would be higher in older adults with mobility impairments, compared with older adults without mobility impairment, as dual-task walking difficulty increased. Older adults with and without mobility impairment were recruited from the local community. Dual-task walking was performed at a comfortable pace, while the difficulty of the concurrent cognitive task was increased using the modified Stroop test. PFC activity was measured using measures of oxygenated hemoglobin across the PFC. Older adults with mobility impairments demonstrated disproportionate increases in PFC activity, in comparison to those without mobility impairments, as the difficulty of the concurrent cognitive task increased (P<.001), even after controlling for age. In conclusion, these data suggest that older adults with mobility impairments may require greater attentional resources than those without mobility impairments when concurrently performing thinking and walking tasks."} +{"text": "The effect was not dependent on the method of immortalization as it was seen in both SV40 and E6 KO cell lines. sAC activity was not directly proportional to expression suggesting that additional regulatory pathways exist. Interestingly, targeted delivery of sAC to the mitochondria was not as effective in rescuing glucose sensitivity as untargeted delivery of sAC into all possible microdomains. Therefore, even though mitochondrial sAC is known to influence metabolism, our data suggests that the nonmitochondrial isoform is most important for cancer cell metabolism. Although metabolomics analysis suggested that serine synthetic pathways are activated in sAC null cells, there is no evidence to suggest that serine is required for sAC null cell growth. Neither inhibition of serine synthesis nor serine starvation differentially affected the growth of sAC null cells compared with WT sAC. DISCUSSION/SIGNIFICANCE OF IMPACT: These data suggest that the Warburg metabolic phenotype in sAC null cells is regulated by specific sAC microdomains. By targeting sAC to specific microdomains, we can further distinguish the role of sAC localization in cellular metabolism. Cancer cells have been shown to exhibit altered metabolic circuitry of pathways like glycolysis, which allow them to adapt to increased metabolic demands of cellular proliferation and waning environmental resources. Beyond helping us improve the use of sAC immunolocalization as a cancer diagnostic, a better understanding of sAC microdomains in transformed cells will help us understand how this signaling pathway is important in cancer. Pharmacologic manipulation of sAC signaling may represent a new cancer therapeutic strategy.OBJECTIVES/SPECIFIC AIMS: The soluble adenylyl cyclase (sAC) is a noncanonical source of cAMP in mammalian cells. sAC is an ATP/bicarbonate ion sensor, whose activity responds to intracellular signals such as pH changes and metabolism. Unlike the more traditionally studied transmembrane adenylyl cyclase, sAC is not tethered to the cell membrane and instead is found in subcellular microdomains like the mitochondria and nucleus. In particular, sAC localization in the mitochondria has been implicated in oxidative phosphorylation and mitochondrial metabolism. Specific changes in sAC microdomain localization have diagnostic utility in a wide variety of cancers, namely melanoma. We have recently found that loss of sAC leads to tumorigenesis and a Warburg/cancer-like metabolic phenotype, consisting of an activated flux through glycolysis, increased lactate production, and dependence on glucose metabolism. In addition, computational analysis of the metabolomics profile of sAC null cells suggests an increased flux through serine synthetic pathways. We hypothesized that specific sAC microdomains are responsible for this cancer-like metabolic state. METHODS/STUDY POPULATION: We have established oncogenic SV40 large T antigen and HPV16-E6 expressing mouse embryonic fibroblasts lacking sAC expression . Using these parental lines, we reintroduced sAC by targeting the protein to specific microdomains. sAC was either driven into the mitochondria (mito-sAC) or was driven into all possible microdomains (WT sAC). Single clones were generated and sAC expression was confirmed by Western analysis. Stable cell lines were evaluated for mitochondrial metabolism, glucose sensitivity, and serine sensitivity. RESULTS/ANTICIPATED RESULTS: We found that reintroduction of WT sAC into sAC null cells rescued sensitivity to glycolytic inhibition compared with control cells ("} +{"text": "The comorbidity between alcoholism and eating disorders, especially in young women, is well documented. Alcohol and other drug (AOD)-use disorders are particularly common in women with bulimia nervosa. Although the mechanisms underlying the coexistence of these disorders remain unknown, recent family epidemiology studies suggest that bulimia nervosa and AOD dependence are transmitted independently in families. Furthermore, bulimia nervosa generally develops before the onset of AOD dependence. Thus, factors other than addictive behavior may contribute to the development of bulimia nervosa in a substantial proportion of women. The comorbidity of AOD-use disorders with eating disorders has implications for the treatment of the affected patients. Clinicians working with either alcoholic patients or patients with eating disorders have observed that both types of disorders frequently co-occur. Only recently, however, have researchers begun to investigate the reasons for this comorbidity. This article describes some characteristics of the most common eating disorders and reviews studies examining their comorbidity with alcoholism and other drug-use disorders.The two most common eating disorders are bulimia nervosa and anorexia nervosa. Both disorders primarily affect young women, with the usual ages of onset being between early and late adolescence for anorexia nervosa and between adolescence and early adulthood for bulimia nervosa. Only approximately 10 percent of all eating disorder cases occur in men. Because of this gender distribution, the vast majority of studies have investigated eating disorders only in women. Therefore, this review also focuses mainly on studies of women with eating disorders. Clinically diagnosable eating disorders are relatively rare in the general population. The lifetime prevalence rates are 1 to 3 percent for bulimia nervosa and 0.1 to 1 percent for anorexia nervosa .Bulimia nervosa is characterized by lack of control over food intake, leading to the recurrent consumption of large amounts of food in short periods of time . These binge-eating episodes are interspersed with recurrent compensatory purging behavior(s), such as vomiting or laxative abuse, to prevent weight gain. In addition, the patients\u2019 self-evaluations are unduly influenced by their body shape and weight .Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM\u2013IV), two types of anorexia nervosa exist: a restricting type and a binge-eating/purging type. Patients with restricting anorexia nervosa lose weight primarily by extremely restricting their food intake. Patients with binge-eating/purging anorexia nervosa achieve or maintain a subnormal weight by regularly engaging in binge-eating and purging behavior in addition to restricting their food intake. Thus, binge-eating/ purging anorexia nervosa differs from bulimia nervosa in that the anorexic is severely underweight and amenorrheic, whereas the bulimic typically is of normal weight. These distinctions are important, because the rates of alcohol-use disorders vary among women with different eating disorders.Anorexia nervosa is characterized by the relentless pursuit of thinness, intense fears of becoming fat, and a distorted body image. People with anorexia nervosa experience substantial weight loss. In female patients, the resulting changes in the hormonal system also lead to the absence of menstruation . AccordiAnother eating disorder described provisionally in the DSM\u2013IV is binge-eating disorder . Like buThe causes and mechanisms underlying eating disorders remain unknown but most likely include genetic and environmental factors. Twin studies suggest that for bulimia nervosa, approximately 50 percent of the risk is attributable to genetic factors and 50 percent is attributable to the environment . MoreoveNumerous studies have investigated the prevalence of AOD-use disorders among women with eating disorders. A recent review of 51 studies suggestsA recent survey of AOD-use disorders among women in the general population showed rates of 12 percent for alcohol abuse or dependence and 10 percent for other drug abuse or dependence . TherefoWomen with different eating disorders also differ in their rates of regular alcohol use : These rates were substantially higher among bulimics and binge-eating/purging anorexics (45 percent) than among restricting anorexics (11 percent) . These vThe frequency of eating disorders among alcoholic women has been studied less extensively than the frequency of alcohol-use disorders among eating-disordered women. Several studies have found, however, that the lifetime rates of any comorbid eating disorder among AOD-abusing women are significantly higher than in the general population, ranging from 15 to 32 percent . With reOne study of eating disorders among female and male Japanese alcoholics in inpatient treatment found that 11 percent of the female alcoholics and 0.2 percent of the male alcoholics had lifetime histories of eating disorders . The verA striking finding emerged when the researchers analyzed different age groups of female alcoholics: Seventy-two percent of all the female alcoholics under the age of 30 had lifetime histories of comorbid eating disorders, compared with 11 percent in the entire sample. Again, the majority of these patients (89 percent) suffered from either bulimia nervosa or binge-eating/ purging anorexia nervosa. Thus, the association between eating disorders with bulimic features and alcohol-use disorders appears to be particularly strong among young women. The reasons for this concentration of eating disorders among young women are unclear. Although bulimia nervosa has been defined only relatively recently , its ratAnother study that examined the rates of eating disorders among female alcohol-dependent inpatients found that 30 percent of these women had lifetime histories of eating disorders . One-thiIn summary, the literature on both eating disorders and AOD-use disorders supports clinical observations of the frequent co-occurrence of both types of disorders. Furthermore, bulimia nervosa and the bulimic subtype of anorexia nervosa are much more commonly associated with alcohol-use disorders than restricting anorexia nervosa. These findings are consistent with past research that determined behavioral and personality trait differences among patients with different eating disorders. For example, binge-eating/purging anorexics and bulimics share certain traits characteristic of impulsive behavior and mood swings, whereas restricting anorexics consistently have been described as behaviorally restrained and compulsive . Based oAlthough studies have confirmed that eating disorders and AOD-use disorders frequently coexist, the mechanisms underlying this comorbidity have not been elucidated. At least four potential explanations exist for the high rates of co-morbidity :Both disorders are different manifestations of a shared underlying etiology.The two disorders have different causes, but the presence of one disorder may increase a person\u2019s chances of developing the other.An independent disorder causes both disorders.The two disorders have some risk factors in common, whereas other risk factors are specific to each disorder.The first hypothesis of a common etiology has been studied most extensively. Supporters of this hypothesis believe that both eating disorders and AOD-use disorders may be manifestations of an underlying predisposition toward impulsivity or may result from a common mechanism involving endogenous opioids . EndogenVery few studies have investigated the possible roles of transmissible genetic or environmental familial factors in the comorbidity of eating disorders and alcohol-use disorders. In a recent family study, Accordingly, the researchers divided the bulimic subjects into two groups: those with and those without lifetime histories of comorbid AOD dependence. When the rates of AOD dependence were examined in the first-degree relatives of both groups, the prevalence was elevated only among the relatives of bulimics with comorbid AOD dependence but not among the relatives of non-AOD-dependent bulimics. The analyses produced similar, though less robust, results when the rates of not only AOD dependence but also AOD abuse and dependence were evaluated. These findings refute the hypothesis that eating disorders and AOD-use disorders are different manifestations of a shared underlying etiology and indicate instead that both disorders are attributable to independent transmissible factors.not exhibit familial vulnerability to AOD-use problems, factors other than addictions may contribute to the development of bulimia nervosa in a substantial proportion of women. These findings raise the possibility that two bulimic subtypes exist. The first type would represent a \u201cmulti-impulsive\u201d subtype, with a familial and personal history of AOD-use problems. The second type may best be described as an \u201canorexic-like\u201d subtype, with personality and behavioral traits similar to restricting anorexics . Similar to restricting anorexics, these bulimics have no extensive personal or family histories of AOD-use problems.If many bulimic women do Other recently published studies also suggest that alcoholism and bulimia nervosa do not share a common etiology. For example, Genetic analyses of six major psychiatric disorders in women, including bulimia nervosa and alcoholism, supported the existence of separate genetic liabilities for eating disorders and alcoholism . The stuThus, the three epidemiological studies described here suggest that although bulimia nervosa and alcoholism frequently coexist, they apparently do not share an underlying familial or genetic liability. Instead, the two disorders are likely to result from independent causal factors.The other three potential explanations for the high rates of comorbidity between alcoholism and eating disorders have been examined less thoroughly. Most studies investigating the hypothesis that the presence of one disorder may increase the chances of developing the other disorder found that the onset of bulimia nervosa generally preceded the onset of alcohol dependence see . AlthougThe theory that an independent disorder can cause both eating disorders and alcoholism also has not been well studied. One potentially fruitful line of research would be to examine the relationship among anxiety disorders, bulimia nervosa, and alcoholism, because anxiety disorders frequently co-occur with both of the other disorders .The most likely\u2014although also not well-investigated\u2014explanation of the frequent comorbidity of eating disorders, particularly bulimia nervosa, and AOD-use disorders may be that people with both types of disorders share some underlying traits, such as periodic behavior disinhibition and difficulty modulating feelings or emotions . In addition to these shared traits, other etiologic factors likely exist that are specific to each disorder. Clearly, more research is needed to further evaluate this hypothesis.Over the past decade, several researchers have hypothesized that bulimia nervosa, like alcoholism, is a type of addictive disorder . Both alThe addiction model of eating disorders has contIn contrast, other therapies, such as cognitive-behavioral therapy (CBT) and antidepressant medication, have proven useful in treating eating disorders . CBT focThe most effective treatment approaches for alcoholism and eating disorders also will likely differ, because different behaviors must be addressed for both types of disorders. The primary focus in alcoholism treatment is to avoid consuming the substance, whereas the focus in bulimia nervosa treatment is to change the manner in which the substance is consumed. Many bulimics and binge-eating/purging anorexics have difficulty modulating food intake and often alternate between periods of imposed food restriction and overconsumption combined with purging behaviors. Treatment must take into consideration both these consumption patterns as well as a disturbed body image. Accordingly, cognitive-behavioral approaches addressing all these issues differ greatly from the 12-step programs commonly used to treat alcoholics.Few empirical data exist to help identify and treat patients with coexisting eating disorders and AOD-use disorders. Still, the frequent comorbidity of these disorders underscores the necessity of determining whether eating disorders are present, especially among young, AOD-abusing women entering treatment. Adequate assessment is even more important, because alcoholic, eating-disordered patients also are likely to engage in other behaviors common among \u201cmulti-impulsive bulimics,\u201d such as shoplifting, suicide attempts, or self-mutilating behavior . These cAOD-abusing patients with coexisting eating disorders should receive thorough medical assessments and nutritional consultations. The management of these patients should include monitoring their weight, food intake, and purging behavior as well as assessing their cardiac, fluid, and mineral statuses. The patients should be observed during and after each meal, with supervised bathroom use to minimize purging opportunities. Although monitoring eating-disordered patients in an AOD-abuse treatment facility may be challenging and labor intensive, it is necessary for treatment.Patients with comorbid AOD-use and eating disorders can pose a particular challenge for the individual clinician or the staff of a treatment facility. These patients may represent a group distinct from patients who only have an AOD-use disorder or an eating disorder. They may require different, more varied, and more intensive assessment and treatment approaches. Researchers and clinicians still have not identified the most beneficial treatment approaches for these patients, and future treatment outcome studies must address this difficult patient population."} +{"text": "Chronic sterile inflammation is a pathological feature of Alzheimer\u2019s disease (AD) and other neurodegenerative diseases. The mechanisms that drive neuroinflammation and its impact on AD progression are still incompletely understood. The accumulation of molecular damage in somatic cells can trigger cellular senescence, an irreversible state of cell cycle arrest accompanied by the expression of proinflammatory mediators known collectively as the \u201csenescence-associated secretory phenotype\u201d (SASP). Misfolded tau forms pathogenic soluble aggregates that are released extracellularly and are transmitted trans-neuronally, promoting native tau phosphorylation and aggregation in target cells. We recently showed that, in addition to neurons, pathogenic soluble extracellular tau aggregates propagate to brain microvascular endothelial cells, where microtubule destabilization triggers senescence/SASP. Because astrocytes have a critical role in the regulation of both synaptic function and cerebral blood flow and are directly exposed to tau at its site of release at the tripartite synapse, we conducted studies to define whether soluble aggregated tau propagates to astrocytes, inducing astrocyte senescence/SASP and neuronal dysfunction/damage. Our studies indicate that tau can be propagated transcellularly to astrocytes, triggering cellular senescence/SASP. Our studies suggest that astrocyte senescence is detrimental to dendritic and synaptic structure and density, suggesting that pathogenic soluble tau-induced astrocyte senescence may contribute to synaptic dysfunction and loss in AD. Drugs that eliminate senescent cells are FDA-approved and antibody-based approaches to remove tau from brain are already in clinical trials. Our studies suggest that these interventions could be effective in the treatment of AD and other tauopathies."} +{"text": "Nationally, there is a shortage of geriatric trained healthcare providers caring for older adults. As the population of older adults grows, health care systems and primary care providers struggle to provide high quality, cost effective care for older adults. Time for training is also limited in busy community health centers. The CATCH-ON Learning Communities (LCs) are telehealth educational interventions based on the ECHO model, modified to be less time intensive, thus decreasing cost to participating clinics. In the LC, geriatric specialists provide evidence-based, best practice training utilizing case discussions to illustrate pertinent learning points via monthly one hour video conferences. Practical, specific behavioral recommendations are offered for immediate implementation in each session. LCs are provided to interprofessional primary care teams. The first LC with a federally-qualified health center (FQHC) yielded consistently high satisfaction from participants, along with a 17% decrease in high risk medication prescriptions and 22% increase in falls screenings. Training the primary care workforce in evidence based geriatric interventions can improve the care of all older adults within each health system, improving healthcare access to help mitigate healthcare inequalities, slow adoption of best practices and rising costs of caring for complex older adults. The CATCH-ON Learning Community is an effective, low cost model of training the primary care work force without geographical or financial constraints that frequently limit access to specialized care."} +{"text": "Financial exploitation (FE) in older adults is a significant public health problem linked to outcomes including depression, financial ruin and early mortality. This study applied exploratory data science techniques to a multi-year statewide protective services dataset of over 8,000 elder abuse cases. The goal was to derive data-driven psychosocial profiles of abuse with an emphasis on determining which factors, commonly shared across abuse cases, were most important for determining when elder FE was occurring and whether it was occurring alone or in conjunction with other types of abuse. We found that pronounced psychological distress was most important for indicating when abuse had occurred and predicted non-FE related abuse. Drug paraphernalia in the home and perpetrator drug/alcohol use were important predictors of FE-related abuse. When differentiating pure FE from hybrid FE, factors indicative of long-term FE occurrence and substantial financial loss were most important . The findings parallel some existing work characterizing pure and hybrid FE, but also highlight new profile factors that may help determine when FE is occurring and when it is less likely. Applying data science approaches to other large protective service datasets and national datasets such as the National Adult Maltreatment Registry could help improve characterization of abuse types such as pure and hybrid FE resulting in better detection, response and prevention."} +{"text": "Hepatitis C virus (HCV)-induced cirrhosis is a major cause of hepatocellular carcinoma (HCC) worldwide. HCC is an aggressive malignancy in which tumor thrombus can invade portal vein, hepatic veins and inferior vena cava (IVC) in the later stages. Our case brings to attention, HCV patient population who might need long-term follow-up to ensure HCV clearance. Physicians should ensure appropriate follow-up after treatment of HCV and should emphasize on the ongoing screening for HCC in patients with cirrhosis or advanced fibrosis, regardless of antiviral treatment outcome. Hepatocellular carcinoma (HCC) is the fourth most common cancer and the third leading cause of cancer-related deaths in the world . HCC is A 58-year-old male presented to the\u00a0hospital with chief complaints of dyspnea on exertion associated with pleuritic chest pain and fatigue for two weeks prior to presentation. Medical history was significant for hypertension and hepatitis C genotype 1 treated with ledipasvir/sofosbuvir four years ago. HCV was successfully treated with achievement of sustained virologic response four years ago. The patient did not follow-up after treatment completion. On physical examination, mildly distended, non-tender abdomen was noted. Computed tomography (CT) angiogram of chest was done due to an elevated D-Dimer of 1878 ng/ml and the patient was found to have a segmental pulmonary embolism in the right lower lobe of the lung Figure . Tumor tHCV-induced cirrhosis is a major cause of HCC worldwide. The redetection of HCV RNA in our patient can either be explained by ledipasvir-sofosbuvir treatment failure with HCV reactivation, HCV relapse or HCV reinfection. The preferred antiviral regimen for the vast majority of patients with chronic HCV infection was ledipasvir-sofosbuvir when our patient was treated . HCV NS5The diagnosis of HCC is typically made by radiological liver imaging in combination with serum AFP without the need for biopsy especially in patients with cirrhosis . TherefoExtension of IVC thrombus into right atrium (RA) can present as RA mass . Primary.Definitive therapy of pulmonary tumor emboli is directed at treating the primary tumor . SurgicaThe prognosis of HCC patients with tumor thrombi is extremely poor, with median survival of about three months from diagnosis without treatment . The oneIn conclusion, our case is unique as advanced HCC presented as pulmonary tumor embolism after successful treatment of HCV. In patients with HCC, who present with respiratory distress and chest pain, clinicians should have a high index of suspicion for pulmonary tumor embolism. Our case emphasizes the importance of HCC screening in patients treated for hepatitis C and have advanced fibrosis or cirrhosis for early detection and management of hepatocellular carcinoma."} +{"text": "Plasmodium falciparum genetic diversity typing and resistance monitoring and proposes how the different tools could be employed in resource-poor settings. Advanced approaches enabling targeted deep sequencing is valued as a sensitive method for assessing drug resistance and parasite diversity but remains out of the reach of most laboratories in sSA due to the high cost of development and maintenance. It is, however, feasible to equip a limited number of laboratories as Centres of Excellence in Africa (CEA), which will receive and process samples from a network of peripheral laboratories in the continent. Cheaper, sensitive and portable real-time PCR methods can be used in peripheral laboratories to pre-screen and select samples for targeted deep sequence or genome wide analyses at these CEAs.The intensification of malaria control interventions has resulted in its global decline, but it remains a significant public health burden especially in sub-Saharan Africa (sSA). Knowledge on the parasite diversity, its transmission dynamics, mechanisms of adaptation to environmental and interventional pressures could help refine or develop new control and elimination strategies. Critical to this is the accurate assessment of the parasite\u2019s genetic diversity and monitoring of genetic markers of anti-malarial resistance across all susceptible populations. Such wide molecular surveillance will require selected tools and approaches from a variety of ever evolving advancements in technology and the changing epidemiology of malaria. The choice of an effective approach for specific endemic settings remains challenging, particularly for countries in sSA with limited access to advanced technologies. This article examines the current strategies and tools for Malaria continues to cause significant morbidity and mortality across Africa, despite the intensification of control interventions . A worldPlasmodium falciparum as a parasite has been attributed partly to its enormous genetic diversity n, [T]n, and [TAA]n repeats [P. falciparum drug-resistance markers and flanking microsatellite loci can be employed to assess the genetic diversity and evolution of selective signatures around drug resistance genes [Microsatellites are tandem repeats of one to six base pairs (bp) that are highly polymorphic. They are abundant in the repeats . Anderso repeats . These t repeats \u201379. Alsoce genes .msp/glurp typing, microsatellite typing depends on accurate DNA fragment amplification by PCR, which can result in artefacts. Accurate allele sizing requires expensive capillary electrophoresis equipment that are largely unavailable. Moreover, there are no methods for phase resolution of parasite haplotypes in mixed infections. However, thousands of P. falciparum genome sequences are now available for mining new microsatellite loci which can be developed into new assays for population diversity analyses. Low cost thermocyclers combined with HRM for determining sizes of DNA fragments can improve the availability of microsatellite typing to less specialized laboratories [Similar to ratories .P. falciparum isolates [I.A 96 genome-wide SNP panel used to assess the impact of decreased transmission on parasite diversity in Senegal and at the Thai-Burma border , 86. TheII.A 384-SNP custom GoldenGate Illumina Mass array that clearly resolved global patterns of genetic diversity and the structure of geographically distinct populations across global endemic populations .III.P. falciparum containing five mitochondrial and 18 SNPs of the apicoplast genomes thought to offer a higher resolution between isolates from different endemic blocs [P. falciparum isolates. This can identify imported cases of P. falciparum into elimination settings.23-SNP panel for ic blocs . The facIV.A recent malaria Taqman Array with 87 loci that enable both species classification and typing of markers across drug resistance and neutral loci . DeploymV.https://www.malariagen.net/projects/spotmalaria).The Spot malaria project currently provides a large panel of loci including targets for drug resistance and neutral sites for population diversity analysis. This has been constituted into a \u2018Genetic Report Card\u2019 (GenRE). This will become increasingly useful as the genotyping methods applied are sensitive enough to detect parasites genomes and alleles in very low-density infections and the Human Hereditary and disease in Africa (H3Africa) Pan-African Genetic Epidemiology Network (PAMGEN). These programmes will expand access and application of WGS/GVA approaches to malaria elimination research in sSA. Effective deployment and translation could be further facilitated by sample pooling and employing cheaper but sensitive Real time PCR genotyping methods to pre-screen and select samples in peripheral laboratories prior to genome wide analyses at CEAs. Pre-screening could prioritize loci for diversity, drug or vaccine resistance most relevant to the local control and intervention strategies.Unlike the analysis of individual loci, which may be the target of strong natural selection, inferences from genome-wide diversity are less subject to target biases and, therefore, more accurately reflect overall patterns of Genetic epidemiology of malaria can improve understanding of parasite origins, flow rates between populations , drug resistance and potential susceptibility to candidate anti-malarial drugs and vaccines , 95, 96.Targeted deep and whole genome sequencing are sensitive and specific for detecting patterns of malaria parasite diversity and critical for \u2018drug resistant intelligence\u2019. Though they required significant investment in equipment and trained personnel, it is feasible to equip genomic Centres of Excellence in Africa, which will receive and process samples from a network of smaller laboratories with PCR capabilities. These centres will be hubs for developing field deployable genotyping assays for PCR and portable next-Generation sequencing technologies such as the Nanopore to boost genomic surveillance for malaria elimination in Africa. Centres of excellence and molecular surveillance nodes will need computational infrastructure to combine novel approaches for ancestry, relatedness, transmission models and machine learning to resolve spatial\u2013temporal parasite flow, population structure and drug resistance , 99. Thu"} +{"text": "With the rise in global older adult populations, university programs need to produce an effective, gerontology-trained workforce . Career decision-making involves interactive learning , as adults explore career options, engage in career learning, and understand curriculum integration within professional settings . Gerontology faculty can utilize career planning models that integrate intergenerational engagement within the curriculum to aid student career decisions . This paper provides an overview of a career planning model and highlights the ways intergenerational programs can be intentionally staged in research, service, and extracurricular domains to promote career planning and success in post-graduate employment. Data from our recent gerontology alumni survey including graduates since the program inception will be outlined to support the importance and success of developing strong applied intergenerational career programs in gerontology."} +{"text": "Two transport pathways have long been proposed for entry of nanoparticles from the blood circulation into solid tumors. We examine and discuss available evidence supporting interendothelial and transendothelial transport processes and suggest new avenues for re-evaluating these pathways. Understanding of integrative mechanisms controlling nanoparticle extravasation into tumors is important for improving engineering and performance of anti-cancer nanopharmaceuticals. The enhanced permeability and retention effect (EPR) has become an equivocal concept in the targeting and development of anti-cancer nanomedicines. This concept has been recently scrutinized due to disappointing therapeutic efficacy and limited clinical success with anti-cancer nanomedicines compared with excellent results in small animal xenograft models as well as many pathophysiological factors such as size heterogeneity seen in tumor vessel fenestrae (100\u20131200\u00a0nm), pore frequency/density, other architectural abnormalities, and stochastic intratumoral pressure has contributed to ambiguity in transport pathways across tumor endothelium. Furthermore, the interaction between nanoparticles and vessel walls (and subsequent extravasation processes) might be controlled by the perfusing concentration of nanoparticles as well as capillary architecture, and integrated mechanical and fluid dynamic factors that modulate local blood cell stretching. Here, nanoparticle physicochemical properties such as size, shape, deformability, and surface characteristics all play important roles in establishing nanoparticle impaction with blood cells, contact with endothelium, and rolling on vessel walls. Recent developments in nanoparticle engineering include precision control of particle shape, mechanical stiffness, and surface properties (Moghimi et al."} +{"text": "Participation in risky health behaviors can increase the potential for cognitive decline. Smoking, alcohol consumption, and minimal physical activity are modifiable risk factors associated with worse performance on cognitive assessments; however, the relationship between subjective cognitive decline (SCD) and risky practices has not been assessed. As a potential early indicator of cognitive impairment, SCD may serve as a screening measure for dementia. The Behavioral Risk Factor Surveillance System is an annual, self-reported telephone survey of Americans that includes fifteen core and twenty-five optional sections. The present study included Behavioral Risk Factor Surveillance System participants age 45 or older who completed the core and cognitive decline modules in 2015 . Roughly 11% of participants endorsed worsening memory in the previous year. Logistic regression examined the impact of smoking, drinking, and inactivity on self-reported cognitive decline. Current or former smokers had greater odds of endorsing cognitive decline compared to those who never smoked . Individuals who consumed at least one alcoholic beverage in the previous month had lower SCD odds compared to non-drinkers . Respondents who engaged in little to no physical activity had greater odds of endorsing cognitive decline compared to active respondents . Individuals who endorsed cognitive decline engaged in unhealthy habits such as smoking or inactive lifestyles; however, low to moderate alcohol consumption may be beneficial for cognitive functioning."} +{"text": "Birds are a diverse and agile lineage of vertebrates that all use bipedal locomotion for at least part of their life. Thus birds provide a valuable opportunity to investigate how biomechanics and sensorimotor control are integrated for agile bipedal locomotion. This review summarizes recent work using terrain perturbations to reveal neuromechanical control strategies used by ground birds to achieve robust, stable, and agile running. Early experiments in running guinea fowl aimed to reveal the immediate intrinsic mechanical response to an unexpected drop (\u201cpothole\u201d) in terrain. When navigating the pothole, guinea fowl experience large changes in leg posture in the perturbed step, which correlates strongly with leg loading and perturbation recovery. Analysis of simple theoretical models of running has further confirmed the crucial role of swing-leg trajectory control for regulating foot contact timing and leg loading in uneven terrain. Coupling between body and leg dynamics results in an inherent trade-off in swing leg retraction rate for fall avoidance versus injury avoidance. Fast leg retraction minimizes injury risk, but slow leg retraction minimizes fall risk. Subsequent experiments have investigated how birds optimize their control strategies depending on the type of perturbation , visibility of terrain, and with ample practice negotiating terrain features. Birds use several control strategies consistently across terrain contexts: (1) independent control of leg angular cycling and leg length actuation, which facilitates dynamic stability through simple control mechanisms, (2) feedforward regulation of leg cycling rate, which tunes foot-contact timing to maintain consistent leg loading in uneven terrain , (3) load-dependent muscle actuation, which rapidly adjusts stance push-off and stabilizes body mechanical energy, and (4) multi-step recovery strategies that allow body dynamics to transiently vary while tightly regulating leg loading to minimize risks of fall and injury. In future work, it will be interesting to investigate the learning and adaptation processes that allow animals to adjust neuromechanical control mechanisms over short and long timescales. Birds are diverse and agile vertebrates capable of many combinations of aerial, terrestrial, and aquatic locomotion. Living birds vary in size from hummingbirds to ostriches, and exhibit diversity in the length and mass proportions of the wings and legs, reflecting adaptation for different locomotor ecologies . While wLegged locomotion is complex and dynamic, involving abrupt foot-contact transitions and uncertainty due to variable terrain and sensorimotor errors. Animals must precisely control limb dynamics to move effectively over varied and uncertain terrain while avoiding falls, collisions, and injury . It remaAvoiding slip, fall, and injury requires precise regulation of foot-contact timing and leg-substrate interaction forces . Yet, inOne inherent challenge of animal systems is sensorimotor delay that limits feedback response times ; 2013. SNerve transmission delays increase with the anatomical distances of neural pathways. This physical constraint creates a direct link between neuroanatomy and temporal scaling of control processes . ConsideThe phrase \u201cpassive-dynamics\u201d has often been used to refer to the intrinsic mechanical response of the locomotor system. However, this phrase can be somewhat misleading, because the intrinsic mechanical response is actively tuned by the selection of a specific muscle activation pattern from the possible solutions that could meet the mechanical requirements of the task . Each muTerrain perturbations are ubiquitous in nature and disrupt the predictability and timing of foot\u2013substrate interactions, requiring transient locomotor responses to recover from disturbances. Understanding transient locomotor dynamics is important for revealing natural locomotor behaviors, and for understanding the specific mechanical demands and constraints that have shaped animal locomotor control.in vivo muscle force\u2013length dynamics, body dynamics, leg\u2013substrate interaction forces, and joint mechanics during locomotion , and with ample practice negotiating visible terrain features. In comparing locomotor control strategies between hidden and visible potholes, guinea fowl slow down in anticipation of visible potholes when they encounter them for the first time, and actually stumble more when negotiating the visible drop . AlthougBlum and colleagues (2014) explored how animals manage the trade-off between terrain robustness and injury avoidance in leg angular control when given ample practice negotiating a visible drop in terrain. Under these conditions, guinea fowl converge upon a strategy similar to the hidden pothole strategy\u2014they maintain high speeds and allow intrinsic leg mechanics to mediate the perturbation response . The autBlum et\u00a0al. 2011In another series of experiments, Birn-Jeffery and colleagues investigated control strategies used by ground birds when negotiating visible obstacles, to investigate potential trade-offs in stance leg function . SimilarRegulation of leg cycling rate can be viewed as a combined feedforward plus \u2018preflexive\u2019 control strategy that minimizes the need for reactive adjustments by exploiting the intrinsic mechanical coupling between leg contact angle and leg loading. Experimental evidence from both humans and birds running over a range of terrain perturbations are consistent with leg angular trajectory as a key target of neural control . Humans Whereas leg angular trajectory appears insensitive to perturbations and adjusted over longer timescales, leg-length actuation shows high stride-to-stride variance, suggesting both predictive (feedforward) and reactive (feedback) adjustment in uneven terrain . Leg lenWhile modular control of leg angular trajectory and leg-length actuation have emerged as consistent control strategies for robustly stable running, it remains less clear whether, and under what circumstances, leg stiffness serves as a direct target of control. Research on humans running over soft and hard surfaces suggests that humans regulate leg stiffness to maintain steady body trajectory . HoweverDifferences between birds and humans in stiffness regulation could also relate to leg morphology. Birds have a more crouched leg posture with four segments, in contrast to the vertically oriented three-segment leg configuration of humans. The limb morphology of birds may allow more flexible adjustment of leg posture to accommodate terrain variation, minimizing the need for active regulation of leg stiffness. This idea is supported by evidence from a study that directly compared control strategies in humans and birds from a model-based perspective . Birds eIn vivo recordings of muscle force, length, and activation dynamics during perturbed locomotion can help reveal the relative contributions of intrinsic mechanical, feedback, and feedforward control mechanisms. These studies also help reveal how neuromechanics of locomotion are integrated across levels of organization, from individual muscle\u2013tendon dynamics to joint, whole limb, and body dynamics. The relationship between muscle activation and mechanical output is known to be nonlinear and dynamically variable, depending on instantaneous fascicle length, velocity and recent strain history during stance decreases by 81% during perturbed steps compared to steady strides, despite maintaining the same electromyography (EMG) activation levels investigated context dependent shifts in sensorimotor control by comparing muscle activation patterns during obstacle negotiation at low and high speeds, and with low and high-contrast obstacles. In slower speed obstacle negotiation, anticipatory increases in muscle activity are apparent in the steps preceding obstacles. At higher running speeds, the neuromuscular response is largely reactive, occurring after foot contact with the obstacle . AnticipWhile neuromechanical control of locomotion involves a complex interplay of mechanical and sensorimotor mechanisms, studies of running birds have revealed several strategies for robust, stable, and agile bipedal locomotion that are consistent across terrain contexts: (1) independent control of leg angular cycling and leg length actuation, which facilitates dynamic stability through simple control mechanisms, (2) feedforward regulation of leg cycling rate to maintain consistent leg loading in uneven terrain, (3) load-dependent muscle actuation to stabilize body mechanical energy in response to disturbances, and (4) multi-step recovery strategies that allow body dynamics to transiently vary while tightly regulating leg loading to minimize risks of fall and injury. Muscle proprioceptive feedback arising from non-steady force\u2013length dynamics likely plays important roles in effective tuning of perturbation responses over time, as well as maintaining accurate state estimates for internal models, path planning, and navigation in higher brain centers. However, it remains unclear how sensory feedback is integrated with spinal neural circuits and higher brain centers to adjust locomotor control over short and long time-scales. In future work, it will be interesting to investigate the learning and adaptation of neuromechanical control mechanisms through repeated exposure to perturbations in controlled conditions."} +{"text": "Most older adults prefer to \u201cage in place\u201d and maintain independent regarding activities of daily living (ADL). Dependency in ADL might be caused by frailty. This study explored the relationship between multidimensional frailty and ADL dependency, and if protective factors, derived from a systematic literature review, moderate this relationship. A longitudinal study with a 24-month follow-up was performed among 1,027 community-dwelling older adults. Multidimensional frailty was assessed with the Tilburg Frailty Indicator, and ADL dependency with the Groningen Activity Restriction Scale. Other measures included socio-demographic characteristics and seven protective factors against ADL dependency, such as physical activity and non-smoking. Logistic regression analyses showed that frail older people had a twofold risk of developing ADL dependency in comparison to non-frail older people after 24 months . Analyses with interaction terms indicated that the selected protective factors against ADL dependency did not signi\ufb01cantly moderate this relationship. Nonetheless, higher levels of physical activity and having su\ufb03cient \ufb01nancial resources decreased the risk of becoming ADL dependent in the overall sample . In conclusion, multidimensional frail older people are at higher risk of developing ADL dependency and the studied factors against ADL dependency did not signi\ufb01cantly moderate this relationship. To develop prevention strategies for ADL dependency and facilitate aging in place, future studies might explore the relationship between each specific frailty domain and ADL dependency, and the role of (other) moderating factors."} +{"text": "O-glycans serve as attachment sites and metabolic substrates to the gut commensal bacteria, which have adapted to the mucosal environment. Technology progress has advanced our understanding of mucin biosynthesis, glycosylation and organization. However, the molecular mechanisms underpinning gut bacteria-mucin glycan interactions remain poorly defined. The mucus layer covering the gastrointestinal tract plays a critical role in maintaining a homeostatic relationship with our gut microbiota. The large intestine, which is home to most microbial species constituting the gut microbiota, is lined by a bi-layer of mucus. The outer layer provides a habitat for bacteria, whereas the inner layer maintains them at a safe distance from the epithelial surface. The terminal mucin Lactobacillus acidophilus [Helicobacter pylori [Akkermansia muciniphila, revealing its occurrence in other anatomical regions of the gastrointestinal tract although its optimal ecological niche remains the mucus layer in the colon [This issue gathers eight articles covering various mechanistic aspects of gut bacteria-mucus interactions and impact on health and disease. These include comprehensive overviews of the role of mucus in the interaction with the gut microbiota in humans or in hodophilus or pathor pylori highlighr pylori . This adr pylori . Two artr pylori , food adr pylori influenche colon . It is c"} +{"text": "Post-surgical complications are most common in older adults. While a number of factors contribute, one key determinant is malnutrition. Malnutrition is seen in up to 86% of older adults at hospital admission. Malnutrition and post-surgical complications are linked through two critical observations: 1) malnutrition dramatically reduces the ability of older adults to overcome postsurgical health stressors, and 2) nutritional status is likely to deteriorate further during hospitalization and after discharge. Despite convincing evidence that perioperative nutrition intervention can improve surgical outcomes, nutrition screening and assessment in the preoperative period is not required or standardized. We will review issues surrounding screening and assessment of malnutrition in older adults preparing for elective surgery and present data on screening (NRS-2002) and assessment tools used in this high-risk population. Finally, we will discuss best practices for identifying and intervening with malnourished older adults in the preoperative setting."} +{"text": "Lung cancer is among the most prevalent cancers and a leading cause of malignancy-related death . For a lThis morphological ITH goes along with multiple molecular alterations within primary and metastatic lesions of the same individual: Whole-exome sequencing of spatially separated tumor regions demonstrated extensive genetic and genomic ITH Figure 3]. App. App3]. EGFR and KRAS alterations with tumor cell content and the predominant morphological growth pattern, we recently analyzed central sections of 19 ADCs subdivided into 467 5\u00d75 mm segments. We demonstrated that EGFR and KRAS driver mutations were present in all malignant segments, suggesting a clonal origin. Despite high levels of inter-and intratumor heterogeneity, we found a significant correlation between variant allele frequencies (VAFs) and morphological growth patterns, but not with tumor sizes [Despite this considerable ITH, only few studies performed an integrative analysis of molecular and morphological markers in NSCLC. To comprehensively compare the spatial distribution of In addition to genomic ITH we addressed somatic mutations of the mitochondrial genome (mtDNA), which were either ubiquitously distributed throughout a tumor section or restricted to specific regions . SpatialTo analyze tumor heterogeneity on the epigenomic level, we recently used a similar segmentation approach and deteTo infer the phylogenetic relationships between the segments, we calculated distance matrices based on DNA methylation and CNVs. In line with a previous publication , methylaIncreasing evidence suggests a crucial role of ITH as a driver of tumor progression and therapy failure. Hence, ITH poses a major challenge for the treatment and prognosis of patients. However, only little is known about epigenomic ITH to date. Our results suggest that extensive inter-as well as intra-tumor variation shape the molecular and phenotypic heterogeneity of ADCs. The challenge of future research will be to understand the interplay between these multiple genomic and epigenomic layers Figure . While aTo overcome the limitations of single tissue biopsies and to avoid repeated multiregional tissue sampling, novel approaches are required. To this end, tumor DNA circulating in the blood might depict tumor heterogeneity and clonal evolution under therapy more comprehensively , 10. How"} +{"text": "The gut microbiota is a central regulator of host metabolism. The composition and function of the gut microbiota is dynamic and affected by diet properties such as the amount and composition of lipids. Hence, dietary lipids may influence host physiology through interaction with the gut microbiota. Lipids affect the gut microbiota both as substrates for bacterial metabolic processes, and by inhibiting bacterial growth by toxic influence. The gut microbiota has been shown to affect lipid metabolism and lipid levels in blood and tissues, both in mice and humans. Furthermore, diseases linked to dyslipidemia, such as non-alcoholic liver disease and atherosclerosis, are associated with changes in gut microbiota profile. The influence of the gut microbiota on host lipid metabolism may be mediated through metabolites produced by the gut microbiota such as short-chain fatty acids, secondary bile acids and trimethylamine and by pro-inflammatory bacterially derived factors such as lipopolysaccharide. Here we will review the association between gut microbiota, dietary lipids and lipid metabolism The gut microbiota regulates many metabolic processes in the host including energy homeostasis, glucose metabolism and lipid metabolism . MicrobiLipid metabolism includes the biosynthesis and degradation of lipids such as fatty acids, triglycerides and cholesterol. Specialized lipoproteins facilitate the transport of lipids from the gut to the liver (the site of most lipid transformations) and between the liver and peripheral tissues. Obesity is linked to dysregulation of lipid metabolism, which may result in abnormal levels of blood lipids, ectopic lipid deposition and associated metabolic diseases such as non-alcoholic liver disease (NAFLD) and atheThe gut microbiota has the capacity to perform many processes that cannot be carried out by the host. These processes can give rise to microbially produced or modulated metabolites that function as metabolic substrates and signaling molecules in the host, with major implications for host metabolism and health. Dietary composition is central to the metabolic output of the gut microbiota because: (1) the gut microbiota processes dietary nutrients into metabolites and (2) the diet affects the gut microbiota composition and thereby its metabolic potential and impact on the host. In particular, the importance of dietary fibers for gut microbiota composition and function has been extensively studied. In addition, several studies have reported an important role for dietary lipids.In this review, we will discuss interactions between lipids, the gut microbiota and the host. We will describe the current knowledge on how dietary lipids affect the gut microbiota, how interactions between dietary lipids and the gut microbiota influence host physiology and health, and how the gut microbiota affects host lipid metabolism.n-6 PUFA or n-3 PUFA) showed that diets with saturated fat or n-6 PUFA induced weight gain, but only saturated fat increased insulin resistance, colonic permeability, and mesenteric fat inflammation [n-3 PUFA diet differed from the other groups, whereas the gut microbiota of mice fed a saturated fat diet and a n-6 PUFA diet were similar. In another study where mice fed a high-fat diet containing lard, rich in saturated fat, were compared to mice fed a isocaloric high-fat diet containing fish oil, rich in n-3 PUFA, it was found that phylogenetic diversity and abundance of the beneficial bacteria Akkermansia muciniphila, Lactobacillus and Bifidobacterium were lower in mice on a lard diet [The gut microbiota has been shown to differ between mice fed diets that are high or low in fat and between diets that contain equal amounts of fat but from different sources \u201313 but not in GF mice when compared to palm oil [Not only fat sources with major differences in lipid composition, such as lard and fish oil, but also fat sources that are more similar, may give rise to different gut microbiota composition and function. Devkota et al showed that a diet with milk fat, but not diets with lard or safflower oil, increased expansion of in mice . Milk fapalm oil . The larThe mechanisms by which dietary fatty acids affect gut microbiota are not well defined. Although most of the fatty acids consumed are absorbed in the small intestine, a minority will pass through the gastrointestinal tract and may therefore directly modulate colonic microbiota composition. Fatty acids have a broad spectrum of antibacterial activity including lysis and solubilization of bacterial cell membranes , 15 and Intestinal bacteria can also react with fatty acid double bonds to produce metabolites that cannot be synthesized by mammalian hosts. Bacterial processing of linoleic acid, for example, has been shown to produce metabolites that may influence host physiology and health. Conjugated linoleic acid (CLA) can be produced by several gut bacteria including Lactobacillus, Butyrivibrio, and Megasphaera , 20. DifBacterial production of CLAs is a multistep process involving several metabolic intermediates. These metabolites include several hydroxy fatty acids that affect processes related to host health. 10-hydroxy-cis-12-octadecenoic acid (HYA) enhances intestinal barrier function and suppresses the development of colitis in mice in a free fatty acids 1 (FFR1/GPR40)-dependent manner . AnotherStudies in gnotobiotic mice have shown that the gut microbiota affects host lipid metabolism. Importantly, GF mice are protected against diet-induced obesity through a combination of several mechanisms including increased fatty acid oxidation and decreased deposition of triglycerides in adipocytes compared to CONV-R mice . FurtherThe gut microbiota affects host lipid metabolism and lipid composition through interaction with the diet. In a recent study by Just et al, CONV-R and GF mice were fed palm oil or lard diet (both rich in saturated lipids) supplemented with bile acids . They foLactobacillus curvatus alone or together with Lactobacillus plantarum reduced cholesterol in plasma and liver and the two strains had a synergistic effect on hepatic triglycerides [Studies in mice treated with probiotics provide further evidence for a role of the gut microbiota in regulation of host lipid homeostasis. In mice fed a high-fat high-cholesterol diet, ycerides . Similarycerides .Overall, studies in mouse models show that the gut microbiota, in concert with the diet, regulates host lipid metabolism and lipid levels in serum and tissues.The fecal microbiota has also been linked to lipid metabolism in humans. Taxonomy and functional profiles of the bacteria differ between obese and lean subjects, but results from different studies are inconsistent, in part because of the complex nature of obesity but also because different methods have been used to analyze the microbiota . A numbeChanges in fecal microbiota composition are also present in individuals with pathophysiological conditions associated with dyslipidemia and ectopic fat deposition such as atherosclerosis and fatty liver. By analyzing the microbial composition of atherosclerotic plaques, fecal samples and the oral cavity in patients with symptomatic carotid artery stenosis , Koren eBacteroidetes in patients with fibrosis or NASH is the most consistent finding in these studies.Several studies have shown that the fecal microbiota composition in subjects with NAFLD differs from that of healthy controls and obese patients without fatty liver disease \u201345. HoylShort-chain fatty acids (SCFAs) such as acetate, propionate and butyrate are bacterial metabolites derived from fermentation of fibers in the colon Fig. . Both buGpr41 knockout mice are leaner and weigh less than their wild-type littermates, while these differences are not found in GF mice. Furthermore, the microbiota increases peptide YY (PYY) production through GPR41 [In addition to being metabolic substrates, SCFAs act as signaling molecules, notably through the G-protein coupled receptors GPR43/FFAR2 and GPR41/FFAR3. GPR43 protects against diet-induced-obesity in mice \u201355. Actigh GPR41 . Butyratgh GPR41 , and SCFgh GPR41 , reducedgh GPR41 .Overall, SCFAs have been shown to have a positive impact on metabolic health . Supplemde novo synthesis from cholesterol [Primary bile acids are synthesized from cholesterol and conjugated to taurine or glycine in the liver. The bile acids are stored in the gallbladder and excreted into the duodenum after food ingestion to aid emulsification of dietary lipids. Most of the bile acids are reabsorbed and recirculated to the liver, but bacterially mediated deconjugation of the glycine or taurine group reduces reabsorption. Deconjugated bile acids can be further metabolized to secondary bile acids through dehydrogenation, dehydroxylation and epimerization by colonic bacteria . Microbilesterol .In addition to their role in lipid digestion, bile acids can act as signaling molecules that regulate host metabolism by binding to the nuclear receptor farnesoid X receptor (FXR) and the Takeda G-protein coupled bile acid receptor TGR5. Microbial processing of bile acids increases the diversity of the bile acid pool and the different bile acids vary in their affinity to the receptors and can act as agonists or antagonists. Both of the primary bile acids cholic acid (CA) and chenodeoxycholic acid (CDCA) and the secondary bile acids lithocholic acid (LCA) and deoxycholic acid (DCA) are FXR agonists, but with different affinities . In humaFxr knockout mice with or without bacteria a high-fat diet, Pars\u00e9us et al showed that microbiota-induced weight gain, steatosis and inflammation were dependent on FXR signaling [Fxr knockout donor mice, demonstrating that FXR may contribute to increased adiposity by altering the microbiota composition. Comparison of whole body and tissue-specific Fxr knockout mice have revealed that activation of the liver and intestinal FXR result in distinct metabolic outcomes in obesity models [FXR is involved in the regulation of lipid metabolism, especially triglyceride trafficking, synthesis and utilization . Microbiignaling . FXR alsy models \u201377. Sevey models , 77 but Bile acids have also been shown to influence host lipid metabolism through TGR5. TGR5 activation in skeletal muscle and brown adipose tissue promotes energy expenditure . In addiBile acids have been implicated in the pathogenesis of fatty liver disease. Patients with NASH have been shown to have altered fecal bile acid composition . In addiLipopolysaccharides (LPS), also known as endotoxins, are structural compounds in the outer membrane of Gram-negative bacteria. LPS induces inflammation through activation of TLR4, which is expressed on immune cells such as macrophages as well as on many other cell types including hepatocytes and adipocytes. The intestinal epithelium works as a barrier to prevent translocation of bacterially derived factors. However, weight gain, high-fat diet and incrLPS interacts with blood lipids in various ways. First, it increases the concentration of blood triglycerides by multiple mechanisms. In rats, low-dose LPS increases hepatic synthesis of VLDL, whereas high-dose LPS decreases lipoprotein catabolism . Mice laLPS has been shown to promote atherosclerosis and cardiovascular disease. LPS-treated hypercholesterolemic rabbits have increased atherosclerosis compared with controls and miceMouse studies have shown that hepatic steatosis is induced by a high-fat diet and associated with dysbiosis and increased intestinal permeability . MoreoveApoe knockout mice show that increased microbial capacity for TMA production increases aortic lesions[The gut microbiota metabolizes methylamine-containing nutrients such as choline, lecithin and L-carnitine to generate trimethylamine (TMA), which is further processed to trimethylamine N-oxide (TMAO) by flavin monooxygenases (FMO) in the liver. TMAO levels have been correlated with risk of cardiovascular events and prevc lesions.Fmo3 results in reduced atherosclerotic lesion areas, altered lipid and cholesterol metabolism, and decreased TMAO plasma levels [FMO3 is the primary enzyme converting TMA into TMAO. Knockdown of a levels , 120. FMa levels . Gut micThe mechanisms by which TMAO contributes to atherosclerosis appears to be complex and not fully understood. Antibiotic treatment reduces production of TMA and has been shown to suppress foam cell formation. TMAO can also contribute to atherosclerosis by inhibiting reverse cholesterol transport and by iApoe knockout mice fed diets with or without choline supplementation found no effect of choline enrichment on aortic root atherosclerosis in mice[Although many studies have reported associations between plasma levels of choline, TMAO, and cardiovascular disease , 125 thes in mice. TMAO prs in mice. Similars in mice, 127.The gut microbiota has been targeted for treatment of diseases related to dyslipidemia. Strategies include supplementing the diet with fibers to enhance the growth or activity of beneficial bacteria (prebiotics), live bacteria (probiotics) or a combination of pre- and probiotics (symbiotics).A meta-analysis of 11 minor clinical trials using fermented milk and probiotics show beneficial effects on serum lipid profiles. AnotherStatins lower cholesterol levels by inhibiting HMG-CoA reductase, but may also exert a lipid-lowering effect through interaction with the gut microbiota. Liu et al demonstrated that the cholesterol-lowering effect of rosuvastatin was reflected in microbial alpha diversity measured after eight weeks of treatment . StudiesThe studies performed on microbiota-targeted therapy against dyslipidemia and NAFLD are heterogeneous, the cohorts small and the intervention periods short. Therefore, long-term benefits remain uncertain. Prevention of atherosclerosis by modulation of the gut microbiota has not been studied in humans and data in mice are conflicting\u2013137.An intricate crosstalk links the gut microbiota, dietary lipids and host lipid metabolism. The microbiota processes lipids and other nutrient factors to produce metabolites with impacts on host lipid homeostasis and putative effects on pathophysiological processes. Studies in gnotobiotic and genetic mouse models have identified mechanisms behind these interactions, and studies in humans have found associations between microbial composition, lipid profiles and prevalence of metabolic diseases. However, although it is evident that fat from different sources has different effects on the gut microbiota, the role of specific fatty acids is not known. It also remains to be investigated how the combination of lipids with other nutrients - such as dietary fibers \u2013 affects the gut microbiota. Even though efforts have been made to understand how dietary pattern affect the gut microbiota, 139, th"} +{"text": "Inflammaging is the chronic low-grade inflammation that occurs with age that contributes to the pathology of age-related diseases. Monocytes are innate immune cells that become dysregulated with age and which can contribute to inflammaging. Metabolism plays a key role in determining immune cell functions, with anti-inflammatory cells primarily relying on fatty acid oxidation and pro-inflammatory cells primarily relying on glycolysis. It was recently shown that lipopolysaccharide (LPS)-stimulated monocytes can compensate for a lack of glucose by utilizing fatty acid oxidation. Given that mitochondrial function decreases with age, we hypothesized that monocytes taken from aged individuals would have an impaired ability to upregulate oxidative metabolism and would have impaired effector functions. Aging did not impair LPS-induced oxygen consumption rate during glucose starvation as measured on a Seahorse XFp system. Additionally, aged monocytes maintained inflammatory gene expression responses and phagocytic capacity during LPS stimulation in the absence of glucose. In conclusion, aged monocytes maintain effector and metabolic functions during glucose starvation, at least in an ex vivo context."} +{"text": "Leaves are initiated as lateral outgrowths from shoot apical meristems throughout the vegetative life of the plant. To achieve proper developmental patterning, cell-type specification and growth must occur in an organized fashion along the proximodistal (base-to-tip), mediolateral , and adaxial\u2013abaxial (top-bottom) axes of the developing leaf. Early studies of mutants with defects in patterning along multiple leaf axes suggested that patterning must be coordinated across developmental axes. Decades later, we now recognize that a highly complex and interconnected transcriptional network of patterning genes and hormones underlies leaf development. Here, we review the molecular genetic mechanisms by which leaf development is coordinated across leaf axes. Such coordination likely plays an important role in ensuring the reproducible phenotypic outcomes of leaf morphogenesis. Arabidopsis, the leaf is subdivided into the proximal petiole and distal lamina. Leaf development also involves specialization of the upper and lower leaf surfaces, defining an adaxial\u2013abaxial (top-bottom) axis of asymmetry. At its inception, the leaf primordium possesses inherent asymmetry along this axis due to the proximity of the adaxial leaf surface to the SAM relative to the abaxial leaf surface ) and barley (NARROW LEAF DWARF1 [NLD1]), and yield comparable phenotypes when disrupted, although defects in margin patterning extend well into the leaf blade in these species ), petunia (MAEWEST [MAW]), and Medicago (STENEFOLIA [STF]) and have conserved roles in promoting the mediolateral outgrowth of the leaf blade . . miR319 YAB genes were linked to the control of abaxial cell identity in the leaf . . BOP gened light C 140]. . BOP genactivity ,142,143.KNOX genes by factors regulating development along all three axes. Clearly, KNOX repression is an essential and tightly regulated developmental program of the leaf. Additionally, coordinating factors frequently cross-regulate multiple patterning modules, as well as interact with a host of co-regulatory proteins to carry out their functions. Looking forward, advances in live imaging methods will allow for enhanced analysis of leaf development and its associated spatiotemporal gene expression patterns in real time. This, coupled with rapdily advancing genomics technologies, will provide a major boon to understanding the complex and interwoven leaf axial patterning pathways. Through such work, we will come closer to understanding the remarkable consistency of leaf patterning in three dimensions.Plants are capable of producing consistently patterned leaves throughout their lifespan, a feat that requires highly robust control of underlying genetic patterning factors. One way that such robustness may be achieved is through the close coordination of factors patterning the three growth axes of leaves, a prediction realized by the work of Waites and Hudson almost twenty five years ago. Here, we have described several genetic and hormonal factors that simultaneously regulate developmental patterning along multiple leaf axes simultaneously. Such control mechanisms likely ensure that growth along these axes proceeds in a synchronized and organized fashion. Perhaps most striking is the highly redundant repression of Class I"} +{"text": "OBJECTIVES/SPECIFIC AIMS: Brown adipose tissue (BAT) increases energy expenditure by dissipating chemical energy as heat. The combustion of glucose and lipids produces beneficial metabolic effects and renders BAT an attractive target to battle obesity and associated diseases. The majority of adults do not display active BAT on positron emission tomography (PET) without prior cold exposure. Interestingly, a fraction of individuals with BAT positive PET scans exhibits excessive BAT (eBAT) activity, indicating a possible underlying genetic contributor. We aim to identify genetic determinants of BAT activity by studying individuals with eBAT activity using next-generation sequencing. A cellular model will be used to validate variants and perform in-depth pathway analysis. METHODS/STUDY POPULATION: We performed a retrospective review of PET scans over a period of 12 months in patients presenting with suspected or diagnosed cancer . The distribution of BAT positive individuals (n=1251) was used to implement a threshold to define eBAT activity. Samples from prospectively recruited individuals with BAT activity above the threshold will undergo whole exome sequencing. Variants associated with eBAT activity will be engineered into an immortalized BAT cell line using CRISPR to validate results and perform in-depth pathway analysis. RESULTS/ANTICIPATED RESULTS: We expect to identify genetic variants associated with eBAT. Studying the effects of these variants on thermogenesis followed by in-depth pathway analysis in genetically engineered cellular and mouse models may enable us to find new regulators of BAT activity. These findings may eventually contribute to the development of new drugs targeting obesity and its sequelae. DISCUSSION/SIGNIFICANCE OF IMPACT: The contribution of genetic factors to individual BAT activity is currently unknown. Identifying individuals with eBAT on PET scans and studying the underlying genetic determinants may provide the foundation for the discovery of new pathways for BAT activation."} +{"text": "Background: Both hearing loss and mobility decline are well-known risk factors of cognitive impairment among older adults. However, the effects of the accumulation of these functional impairments are still unclear. Thus, the present study examined whether the interactive effects of hearing loss and poor gait performance contribute to cognitive impairments. Methods: Hearing loss and gait performance were assessed in 716 community-dwelling older adults at baseline. Pure-tone audiometry was conducted to determine hearing loss at 1 and 4 kHz . Poor gait performance was defined as the lowest quartile (fourth quartile) of age- and sex-appropriate mean gait velocity. Participants were then classified into four groups according to the presence of hearing loss and poor gait performance. Cognitive function was assessed using MMSE and MoCA at baseline and four years later. Results: Older adults who had either hearing loss (low or high tone) or poor gait performance showed lower MMSE and MoCA scores at baseline. Multiple regression models showed that hearing loss and poor gait performance at baseline were significantly associated with decreased cognitive function at follow-up. Among older adults with low tone hearing loss, absence of slow gait was not associated with decreased cognitive function. Conclusions: Our results indicate the possibility that hearing loss and slow gait synergistically increase the risk of cognitive impairment. The results also suggest that the effect of slow gait on cognition exceeds the effects of hearing loss, indicating the importance of maintaining mobility in late life."} +{"text": "Vector-borne disease control relies on efficient vector surveillance, mostly carried out using traps whose number and locations are often determined by expert opinion rather than a rigorous quantitative sampling design. In this work we propose a framework for ecological sampling design which in its preliminary stages can take into account environmental conditions obtained from open data not necessarily designed for ecological analysis. These environmental data are used to delimit the area into ecologically homogeneous strata. By employing Bayesian statistics within a model-based sampling design, the traps are deployed among the strata using a mixture of random and grid locations which allows balancing predictions and model-fitting accuracies. Sample sizes and the effect of ecological strata on sample sizes are estimated from previous mosquito sampling campaigns open data. Notably, we found that a configuration of 30 locations with four households each (120 samples) will have a similar accuracy in the predictions of mosquito abundance as 200 random samples. In addition, we show that random sampling independently from ecological strata, produces biased estimates of the mosquito abundance. Finally, we propose standardizing reporting of sampling designs to allow transparency and repetition/re-use in subsequent sampling campaigns. SamplinGenomic technologies are radically transforming our understanding of vector-borne disease transmission dynamics due to tAnopheles, Culex and Aedes) a priori Finally, our framework can be applied to other ecological studies. For example, Wang and colleagues includedIn conclusion, big and open data and research outputs could enhance the power of ecological and genomic studies , facilit"} +{"text": "In most patients, epilepsy arises due to various initial precipitating injuries during the developmental stages. A major challenge in the neuroscience and neuroclinical fields is understanding how this precipitating injury produces a persistent reorganization of the brain's neural network, thereby transforming the normal brain into epileptogenesis. Identifying the pathological basis of epileptic seizure may lay the foundation for the development of new anti-epileptic drugs, benefiting 60 million people with epilepsy worldwide. This is why our editors chose the theme \u201cThe Developmental Seizure-Induced Hippocampal Mossy Fiber Sprouting: Target for Epilepsy Therapies?\u201dCavarsan et al.]. The development of mossy fiber sprouting may be associated with epilepsy comorbidities rather than with seizure incidence. For example, people with mesial temporal lobe epilepsy (mTLE) and depression show more sprouting than those with only mTLE . A 4-week zinc-deficient diet exacerbated MFS caused by developmental seizures, accompanied by cognitive deficits and reduced seizure thresholds. In contrast, zinc supplementation for 4 weeks significantly reduced MFS and improved the above-mentioned damage-related changes. Mitophagy-mediated zinc homeostasis via mitochondrial activation may be a potential mechanism [ and three reviews. With respect to the demographics of this Research Topic collection, the corresponding authors are from Japan, the United States, Canada, Brazil, South Korea, and China. We hope that the information gathered from this topic will help promote post-epilepsy MFS study and help promote clinical translational medical research to better prevent and treat these injuries in the near future.This Research Topic collects seven articles: four animal studies (including one HN wrote the draft. TK, BN, and CH reviewed the manuscript.BN was employed by the company Expesicor Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Heart failure (HF) with either reduced or preserved ejection fraction is an increasingly prevalent condition. Cardiac imaging plays a central role in trying to identify the underlying cause of the underlying systolic and diastolic dysfunction, as the imaging findings have implications for patient\u2019s management and individualised treatment. The imaging modalities used more frequently in patients with heart failure in clinical routine are echocardiography and cardiac magnetic resonance. Both techniques keep some strengths and weakness due to their spatial and temporal resolution. Notably, several features in the diagnostic algorithm of heart failure with preserved systolic function (HFpEF) may be improved by an integrated approach. This review focuses on the role of each modality in characterising cardiac anatomy, systolic and diastolic function as well as myocardial tissue characterisation in the most common phenotypes of dilated and hypertrophied hearts. Cardiac imaging plays a central role in trying to phenotype the underlying cause of heart failure (HF) which has implications for patient\u2019s management and individualised treatment. Heart failure has recently been classified as heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF) ; althougTwo-dimensional transthoracic echocardiography is the first line imaging tool providing information on function, cavity size, relative wall thickness (RWT) and myocardial mass which are used for classification of typical geometric phenotypes\u2014concentric or eccentric hypertrophy and remodelling , 5. MoreCardiac magnetic resonance (CMR) is the gold standard for cardiac anatomical and functional quantification, with unique capabilities of non-invasive tissue characterisation \u20139, complNovel CMR tissue characterisation techniques are called CMR relaxometry (T1 and T2 mapping and extracellular volume fraction (ECV)) which allow a more detailed and quantitative approach to tissue characterisation and 4D-Flow which provides quantitative information on intracavitary flows. Current applications appear particularly useful for diastolic dysfunction detection although they deserve a specific comparison with traditional Doppler and Tissue Doppler analysis in order to confirm the applicability in clinical practice.The most common cardiomyopathic processes underpinning HFpEF (hypertrophied phenotypes) and HFrEF (dilated phenotypes) are discussed below.Left ventricular (LV) hypertrophy (LVH) is a consequence of an underlying genetic or acquired condition and it is accompanied by alterations in cardiac function and haemodynamics. The differential diagnosis between LVH due to physiological adaptation or underlying pathology can be challenging.Non-physiological left ventricular hypertrophy (LVH) regardless to the underlying cause leads to important cardiovascular complications such as atrial fibrillation, diastolic and systolic heart failure , and it Systemic blood pressure elevation is the most common cause of the increment in ventricular mass with a high RWT, which results in concentric or eccentric hypertrophy and concentric remodelling . These sGlobal longitudinal strain (GLS) is an emerging parameter currently available with both methods. GLS is typically reduced in advanced stages of HHD, and it is strongly associated with diastolic dysfunction, it is less dependent on afterload changes and degree of LVH compared with EF, and it has a role in differentiating HHD from other hypertrophic phenotypes , 22. CMRe\u2032 velocity associated with increased E/e\u2032 ratio. Myocardial deformation parameters or patterns of regional strain values such as relative apical sparing or septal apical-base longitudinal strain gradient may have a better differentiating capacity in detecting and differentiating cardiac amyloidosis from other hypertrophic substrates, including HCM, hypertrophy in aortic stenosis or metabolic cardiomyopathies [Infiltrative myocardial disease particularly cardiac amyloidosis can present with very heterogenous hypertrophic phenotypes with wide ranges of wall thicknesses including normal . Granulaopathies . Using dopathies . Howeveropathies . These nopathies .Dilated phenotypes are a heterogenous group characterised by large LV cavities with eccentric remodelling or hypertrophy and impaired contractility. Such phenotypes can be a response to abnormal loading conditions typically in valvular disease or hypertension, severe coronary or congenital disease or predoReflecting perfusion contraction matching and mismatching, ischaemic heart failure (IHF) consists of a spectrum of pathophysiological states, from early remodelling characterised by wall thinning and dilatation to irreversible late remodelling resulting from myocardial fibrosis and scar . EchocarMutations in over 50 genes have been associated with dilated cardiomyopathy . MultiplThe longitudinal trajectories of LV ejection fraction vary between the two conditions in a very sensitive way. When adequate follow-up is available, repeat echocardiograms in HFpEF can detect a maximum of 2\u20135% fell in EF over 5 years, with a larger fall in the presence of coexisting coronary artery disease , 62. A sMore similarities, than discrepancies, instead, can be detected when looking at diastolic dysfunction in HFpEF vs. HFrEF patients. Diastolic dysfunction contributes to exercise intolerance, both in systolic and primary diastolic dysfunction. In both conditions, in fact, diastolic impairment limits exercise tolerance before resulting in symptoms at rest .E/e\u2032 ratio have been debated. In theory, the occurrence of the above-mentioned picture is typical of a restrictive pattern and along with increased LA volume and increased pulmonary pressure, reflects high filling pressure in either HFrEF and HFpEF [E/e\u2032 ratio in relation to wedge pressure, but a complete measurement of left chambers pressure is lacking [E/e\u2032 ratio and LVEDP in a recent metanalysis appears modest and patients with atrial fibrillation (AF) were excluded [In the absence of mitral stenosis, the two major factors that determine the early diastolic mitral valve pressure gradient and the rate of LV filling are the rate of LV relaxation and the LA pressure at the time of mitral valve opening . With exnd HFpEF . However lacking , 72. Theexcluded . All theexcluded . We thinexcluded . Thus, fDiastolic dysfunction is a dominant feature in many HF patients. LV diastolic dysfunction causes LA dilatation, which can lead to AF . DespiteRecently, in characterising the governing role of the four-chamber (near) constant-volume pump physiology, wherein the atrial and ventricular volumes simultaneously reciprocate throughout the cardiac cycle, CMR has elucidated and characterised LA and LV phasic function, thereby quantifying the conduit contribution to ventricular filling as the integral of net, diastolic, instantaneous difference between synchronised atrial and ventricular volume curves . BecauseUsing single-beat simultaneous left atrial and ventricular full-volume 3D dataset, it was demonstrated that the atrial conduit contribution to ventricular filling has a direct relationship with the degree of underlying ventricular diastolic impairment in HF patients . More reIn addition to LA and LV volume curves, CMR can provide further information on myocardial tissue characteristics. Myocardial fibrosis have been implicated in the pathophysiology of HFpEF by promoting adverse ventricular remodelling, increasing myocardial stiffness, and in turn, causing diastolic dysfunction . DiffuseHeart failure is disease with large phenotypic variations in morphology, function and natural history. Such a heterogeneity in presentation is perhaps a reason why despite different clustering approaches, many interventions in clinical trials have not shown efficacy. Cardiac imaging provides diverse insights, but the ability to distinguish between overlapping phenotypes remains a challenging proposition. The evaluation of diastolic function by echocardiography and CMR with their traditional and novel techniques deserves specific analysis and a comparison with haemodynamic measurement before to be universally accepted. Diastolic function parameters derived by CMR may be applied in routine clinical care and matched with more feasible echo analysis in order to increase our awareness in the HFpEF mechanisms and reduces the current diagnostic gap. New parameters studying both radial and circumferential relaxation together with identification of extracellular collagen volume could facilitate the diagnosis and will play a central role in the identification of underlying pathophysiological mechanisms. Comparative imaging trials should be encouraged in order to discern which technique(s) alone, or in combination, could provide additional prognostic value."} +{"text": "Imaging plays a central role in evaluating responses to therapy in neuro-oncology patients. The advancing clinical use of immunotherapies has demonstrated that treatment-related inflammatory responses mimic tumor growth via conventional imaging, thus spurring the development of new imaging approaches to adequately distinguish between pseudoprogression and progressive disease. To this end, an increasing number of advanced imaging techniques are being evaluated in preclinical and clinical studies. These novel molecular imaging approaches will serve to complement conventional response assessments during immunotherapy. The goal of these techniques is to provide definitive metrics of tumor response at earlier time points to inform treatment decisions, which has the potential to improve patient outcomes. This review summarizes the available immunotherapy regimens, clinical response criteria, current state-of-the-art imaging approaches, and groundbreaking strategies for future implementation to evaluate the anti-tumor and immune responses to immunotherapy in neuro-oncology applications. Central nervous system (CNS) malignancies are associated with significant morbidity and mortality. In adults, the extremely aggressive glioblastoma (GBM) has the highest incidence of all gliomas and causes more deaths than all other primary CNS malignancies combined. GBM is associated with a median overall survival of less than two years despite surgery and chemo-radiotherapy Cancer immunotherapy strategies aim to stimulate innate or adaptive immune responses against malignant cells. During the last decade, immunotherapy regimens have made remarkable clinical progress in cancer patients, particularly those with recalcitrant solid tumors, by overcoming immune-suppressive signals present in the tumor microenvironment Non-invasive, longitudinal imaging is central to measuring the progression of disease and the efficacy of treatment in neuro-oncology. Historically, response criteria based on conventional imaging through computed tomography (CT) or magnetic resonance imaging (MRI) techniques were used to monitor changes in tumor morphology and responses to tumoricidal chemo-radiotherapy regimens, where shrinkage corresponded with malignant cell death and therapeutic response, while enlargement or appearance of new foci corresponded to therapeutic failure and progressive disease. Studies over the last two decades with emerging biologic or immunotherapy regimens, which are predominantly tumoristatic, have shown the failure of traditional morphologic response criteria and conventional imaging techniques to predict therapeutic outcomes. Inflammatory responses and related effects from immunotherapy are often indistinguishable from progressive disease during conventional imaging, particularly at early stages of treatment An expanding effort is being mounted to address these challenges through modified response criteria and advanced imaging techniques in research and clinical settings Non-invasive imaging in neuro-oncology aims to define widely applicable clinical response criteria for evaluating disease progression and comparing response outcomes across studies. However, distinguishing between tumor response, pseudoprogression, and progressive disease is a significant challenge in neuro-oncology patients treated with immunotherapy. Pseudoresponse is an alternative imaging pattern where the malignancy falsely appears to have responded to a particular therapy regimen The Macdonald criteria, proposed in 1990 The response assessment in neuro-oncology (RANO) criteria were introduced in 2010 There are currently hundreds of concurrent clinical trials investigating various immunotherapy strategies in neuro-oncology. These studies have shown ongoing challenges to monitor therapeutic efficacy due to variations in response patterns observed during immunotherapy as opposed to traditional chemo-radiotherapy. The immunotherapy RANO (iRANO) criteria were published in 2015 to guide response assessment specifically in neuro-oncology patients treated with immunotherapy The RANO and iRANO criteria were developed primarily for patients with GBM, with the understanding that separate criteria would be required to most effectively define responses to therapy in patients with low grade glioma or with metastases from non-CNS malignancies. RANO characterizes low grade glioma tumor burden by FLAIR signal area rather than by contrast enhancing area, but is otherwise homologous to high grade glioma criteria 18F]fluoro-D-glucose [FDG] or radiolabeled amino acids) in clinical care and in trials that monitor outcomes to therapy, with the expectation that PET parameters could be incorporated into future response criteria in neuro-oncology Non-invasive imaging techniques for neuro-oncology can be grouped into the following categories: 1) structural imaging through conventional CT or MRI, 2) physiological imaging through advanced MRI, positron emission tomography (PET), or single photon emission computed tomography (SPECT) and 3) molecular imaging through advanced MRI, PET, or SPECT based on the expression of biomarkers that correspond to the therapeutic regimen. While biopsy or surgical tissue samples can provide information for tumor progression or biomarker expression, tissue sample analyses are subject to sampling error, may not be representative of spatial-temporal tumor heterogeneity, and are not always available from essential CNS regions or serial time points. Conversely, non-invasive advanced imaging strategies allow global, serial assessment to predict response to treatment or identify biomarker expression 1T MRI and/or extent of 2T hyperintense areas observed on FLAIR MRI sequences are currently standard parameters used to monitor tumor progression in neuro-oncology. However, enlargement of MRI contrast enhancing components and/or enlargement of FLAIR hyperintense areas can be seen both in tumor progression and in inflammatory responses associated with immunotherapy metric is used in clinical practice and in clinical trials to evaluate response. This parameter is an indication of water diffusivity, which is inversely proportional to cellularity + cell densities at the interface between the brain and secondary brain metastases in a cohort of 26 patients, suggesting that DTI could be a surrogate marker for immune cell response + cells, suggesting that immune cell localization can be detected by low fractional anisotropy values in peritumoral regions. While the effects of immunotherapy were not investigated, these findings support future studies to determine if similar fractional anisotropy patterns occur during immunotherapy in patients with brain metastases or with GBM.i. Diffusion tensor imaging (DTI) MRI adds directionality to DWI and has been used as an anatomic tool to map white matter tracts . DTI is also useful in functional MRI assessment ii. Diffusion kurtosis imaging (DKI) MRI enables quantification of non-random diffusion of water due to structural features present in tissues. This metric is more sensitive to structural abnormalities in gray matter compared to DTI q-space imaging MRI uses Fourier transformation of water diffusivity at high b values to quantify non-Gaussian mean water displacement, thus providing structural information about tissues. Theoretical calculations indicate q-space imaging MRI can detect tissue-restricted water diffusion in white matter with high sensitivity, although the sequences require relatively long acquisition times compared to alternative DWI methods q-space imaging MRI in patients with low-grade glioma iii. iv. Neurite orientation dispersion and density index MRI differentiates water diffusion within linear cell structures (axons), free fluid , and constricted water flow in cells or extracellular spaces PWI MRI monitors time-intensity parameters of fluid flow through tissues of interest to assess vascularity in the tissues. Various PWI parameters have also been used to monitor response in several immunotherapy trials in neuro-oncology patients. Through these imaging techniques, progressive disease is identified by increased fluid flow due to neovascularization to support tumor growth. Early stages of immunotherapy may also show increased fluid movement due to inflammatory responses, subsequent stabilization of vascularity and permeability during continued response to therapy is anticipated to show lower perfusion values relative to progressive disease.i. Dynamic susceptibility-weighted contrast-enhanced (DSC) MRI is the most common PWI technique in clinical practice. DSC MRI monitors contrast agent dynamics during the first pass of the contrast material through the brain to determine relative cerebral blood volume as a surrogate for microvessel density, relative cerebral blood flow, mean transit time of the contrast agent, and time to peak for contrast agent accumulation at a location of interest, which are all useful parameters for tumor grading and assessing response to chemo-radiotherapy. Confounders include artifacts from disruption of the BBB (accumulation of contrast agent) or from signal susceptibility at bone interfaces 1T-weighted sequence acquired before, during, and after the injection of a Gd-based contrast agent and then fit to a two-compartment model to assess the rate of transfer from plasma to extravascular extracellular space (Ktrans), the extravascular extracellular volume (ev), the volume plasma (pv), and the \u201cwash-out\u201d, or the transfer from the extravascular extracellular space to the plasma (*epk) ii. Dynamic contrast-enhanced (DCE) MRI is a iii. Arterial spin label MRI utilizes endogenous signaling of water molecules within moving blood (compared to static parenchyma) before entering the brain to provide contrast for perfusion analyses. Compared to other techniques, arterial spin label MRI provides poor signal due to relaxation and to the low amount of \u201clabeled\u201d blood relative to \u201cunlabeled\u201d blood in the region of interest during the scan. This technique has not yet been widely explored in neuro-oncology patients treated with immunotherapy 18F]-fluoromisonidazole for imaging hypoxia, have favorable properties for imaging because they can access all CNS tissues and are selectively retained in hypoxic malignant regions Advanced imaging of hypoxic or acidic tumor microenvironments, which are commonly observed in GBM, is an alternative strategy for physiological imaging in neuro-oncology. BBB-permeable small compounds, such as the PET agent methionine -L-tyrosine ([18F]FET), and 3,4,-dihydroxy-6-[18F]fluoro-l-phenylalanine ([18F]FDOPA). System L amino acid transporters are overexpressed in malignant glioma and CNS metastases relative to normal cells Amino acid PET imaging is increasingly being recognized for its potential clinical utility in neuro-oncology Antibodies or antibody derivatives that bind to prognostic or therapeutically relevant proteins or receptors overexpressed on tumor cells or immune cells are gaining use in oncology applications. Attaching a PET radionuclide or MRI contrast agent to these macromolecules provides a diagnostic companion for \u201cantibody-based\u201d molecular imaging of the target cells or tissues 18F]fluorothymidine, [18F]FLT) have been used in clinical neuro-oncology studies. As normal astrocytes are not significantly proliferative, proliferation PET imaging has shown encouraging results in monitoring GBM progression in pilot human studies PET compounds that indirectly monitor cell proliferation spectra are the most commonly used MRS parameters, although other nuclei, including 31P or metal ions, have also been measured by MRS and have demonstrated potential utility to monitor malignant growth during pilot studies in neuro-oncology patients 1H MRS, myoinositol, choline, creatine, amino acids, N-acetylaspartate, and lipid/lactate picks are captured. The choline peak is a marker of cell membrane turnover, the creatine peak indicates cellular energy reserves, and N-acetylaspartate is for normal neurons. High tissue concentration of lipid/ lactate or specific amino acids can be measured using MRS. Classically, gliomas show a reverse of the normal ratio of choline to N-acetylaspartate or creatine by MRS analyses when compared to normal brain parenchyma due to loss of normal neurons and high cell membrane turnover associated with tumor cell proliferation. The myoinositol peak is a marker of tissue inflammation N-acetylaspartate would remain high due to continued malignant cell proliferation.MRS techniques evaluate characteristic signals in the magnetic spectrum of a tissue to determine the relative amounts of specific molecules within the tissue. Similar to the boom in immunotherapy trials for non-CNS malignancies, a growing number of pilot studies and phase I, II, or III clinical trials have tested the efficacy of various types of immunotherapy to impact patient survival in neuro-oncology. The majority of these studies are beyond the scope of this review and will not be discussed. The following sections briefly discuss four main classes of immunotherapy regimens that are under investigation in neuro-oncology and how advanced physiological or molecular imaging techniques have contributed to assessing or predicting patient responses to these treatment regimens in human patients: 1) vaccine immunotherapy, 2) cell-based immunotherapy, 3) checkpoint inhibitor immunotherapy, and 4) virus immunotherapy T-cells (and their variants), lymphokine-activated killer cells, T-cell receptor-transduced T-cells, and activated tumor infiltrating lymphocytes, among others In cell-based immunotherapy strategies Figure B, precurAdvanced imaging has also been used to monitor tumor responses during cell-based immunotherapy Checkpoint inhibitor immunotherapies Figure C were deA study of 10 patients with recurrent GBM treated with anti-PD-1 and/or anti-CTLA-4 checkpoint inhibitor immunotherapy used intermediate ADC DWI volume changes within FLAIR regions of relatively high cellularity to correlate imaging parameters with response to immunotherapy Figure 105. The18F]FET at initial assessment. Only one of the five patients had both pre- and post-immunotherapy assessment by [18F]FLT, so no definitive conclusions could be made regarding changes in PET signal and therapeutic outcome. This patient was evaluated by PET with [18F]FLT upon entrance to the study and one month after treatment with nivolumab and ipilimumab. The second PET/MRI scan showed a mixed partial response in the five evaluable CNS lesions, where three lesions decreased in size and showed lower uptake of [18F]FLT relative to the baseline image. New, small lesions (less than 1 cm diameter) were also observed on the post-immunotherapy MRI scan, although these lesions did not show appreciable accumulation of [18F]FLT. The patient was switched to an alternative therapy and not further evaluated by PET in the reported study. The results from this study warrant future work to determine correlations between [18F]FLT signals in the tumor and outcomes to immunotherapy in neuro-oncology patients.A pilot study used fluoro-3-(hydroxymethyl)butyl]guanine. A recent publication demonstrated the results of this strategy in six additional patients with recurrent GBM butyl]guanine increased in all brain lesions after injection of the transformed CAR cells relative to the pre-treatment PET scan with the tracer. The pattern of the increase in the PET signal intensity and volume of distribution varied among patients, thus precluding the definitive assessment of CAR cell trafficking to the tumors in the small cohort of patients. These studies highlight the importance of distinguishing between non-specific pooling of PET imaging agents and specific immune cell trafficking within GBM tumors to assess immunotherapeutic efficacy through transgene PET imaging.b. Transgene/reporter gene studies with immune cells. Imaging of transgene expression through a PET reporter has been used in clinical research to monitor immune cell trafficking and response to therapy. An initial case report published in 2009 18F]fluoro-9-\u03b2-D-arabinofuranosyl-adenine and imaged by PET prior to and following treatment with a dendritic cell vaccine in combination with pembrolizumab or bevacizumab correlate with clinical outcomes during therapy. Future trials incorporating larger cohorts of patients and their long-term outcomes to therapy will be needed to discern the most reliable metrics for monitoring responses to immunotherapy regimens.Besides the approaches discussed above, additional imaging agents and analytical techniques are being developed to define prognostic parameters for immunotherapy responses Expansions in advanced imaging have catalyzed the emergence of research and clinical strategies defining patterns of response to immunotherapy for neuro-oncology patients. However, significant obstacles must be overcome prior to routine clinical adoption of experimental imaging strategies. As the incidence of GBM is low and patients with secondary CNS metastases often have confounding clinical factors , a main hurdle has been implementing prospective clinical trials with sufficient numbers of neuro-oncology patients to demonstrate statistically reliable correlates between imaging parameters and therapeutic outcomes during immunotherapy. Most patients in these trials have received multiple, varying courses of therapy before enrollment in immunotherapy trials, further complicating the assignment of defined imaging response patterns to a specific therapeutic regimen. An additional challenge is in implementing standardized terminology and response criteria across neuro-oncology studies, as a recent report found that 63% of neuro-oncology publications after 2010 did not use the RANO criteria 18F]-FDG are available from the European Organization for Research and Treatment of Cancer (EORTC) for glioma and brain metastases, and from PET Response Criteria in Solid Tumors (PERCIST) guidelines for brain metastases. While recommended guidelines to compare multi-modality imaging parameters have not yet been established, integrating imaging parameters from various modalities has been shown in previous studies to increase diagnostic specificity and sensitivity relative to separate, single-modality imaging in neuro-oncology patients Most advanced imaging approaches to evaluate response to immunotherapy are still in initial, exploratory stages in neuro-oncology research. For the field to make rapid, meaningful advancement, it will be important to reach consensus across studies and institutions regarding acquisition parameters and reported findings for a particular imaging technique Imaging scientists should work closely with referring physicians, neuro-oncologists, and the clinical research team to best integrate advanced imaging into trial design and patient care. Considering the limited patient population and the poor prognosis associated with primary or metastatic CNS malignancies, simultaneously enrolling the same patients into both immunotherapy and imaging trials would enable streamlined evaluation of non-invasive imaging methods and responses to immunotherapy. Incorporating advanced imaging sessions into large cohorts of patients in phase II or III immunotherapy trials would aid accumulation of sufficient patient data to yield statistically meaningful results for both therapeutic outcome and matched imaging parameters.As addressed above, distinguishing tumor progression from inflammation and other treatment-related effects is a significant clinical challenge in neuro-oncology. Utilizing multi-modality imaging to differentiate between these separate biological processes is an attractive strategy to address this challenge. One way to potentially identify responses to immunotherapy regimens is to specifically monitor trafficking and activity of effector immune cells across serial imaging time points, and to correlate these changes to a biological outcome While much progress has been made in the fields of advanced molecular imaging and immunotherapy during the last decade, further developments are needed to determine how they can best be merged to improve the outcomes for neuro-oncology patients. No single agent or imaging technique has yet been clinically validated as a satisfactory prognostic indicator for response to immunotherapy regimens. The clinical and imaging communities eagerly await emerging results from ongoing neuro-oncology clinical trials that utilize investigational immunotherapy regimens, novel imaging strategies, and improved response criteria. As these forthcoming data become available, it is anticipated that prognostic patterns will be realized and incorporated into future practice to improve the outcomes of neuro-oncology patients."} +{"text": "Objective. To report a rare presentation of solitary retinal capillary hemangioma manifesting with combined retinal detachment as initial presentation and its successful management.Methods. A 35-year-old healthy Indian male presented with combined retinal detachment associated with solitary retinal capillary hemangioma as initial presentation; a clinical entity still not reported in literature. Patient was managed with pars plana vitrectomy combined with retinectomy, endolaser, & silicon oil tamponade with good visual & anatomical recovery.Results. Patient had good clinical outcome with final best-corrected visual acuity (BCVA) of 6/ 24 and well attached retina at last follow-up.Conclusion. Solitary retinal capillary hemangiomas can rarely present with advanced vitreo-retinal complications like combined retinal detachment as initial manifestation that can be effectively managed with skilled & appropriate surgical intervention. Retinal hemangiomas are mainly asymptomatic but can present with vision loss that occurs due to exudation at the macular region or secondary tractional retinal detachment, which occurs due to development of gliotic tissue involving the macula [4]. Different treatment modalities undertaken for treatment of retinal hemangiomas include laser photocoagulation, cryotherapy, photodynamic therapy (PDT), anti-VEGF, and vitreo-retinal surgery depending on clinical presentation with variable outcome in these patients [5-9]. Retinal capillary hemangiomas are benign vascular tumors of the retina either occurring as isolated tumors or in association with tumors in other systems, especially central nervous system hemangioblastomas and renal cell carcinomas as part of von Hippel-Lindau (VHL) disease [We report a case of solitary retinal hemangioma that manifested with combined retinal detachment, a rare presenting feature of retinal hemangioma, and its successful management. To the best of our knowledge, this rare presentation has not been reported in published literature until now.Fig. 1) and examination of the left eye fundus was normal. We initially considered the differential diagnosis of retinal hemangioma and vasoproliferative tumors of the retina (VPRT). Fundus fluorescein angiography confirmed the diagnosis of retinal capillary hemangioma, showing typical feeder vessel with early hyperfluorescence of vascular mass and draining vein in the right eye, with no evidence of hemangioma in the left eye.A 35-year-old, serving military soldier presented with diminution of vision in his right eye for the past 3 months, which has rapidly worsened over the last month. His systemic parameters were within normal limits. Ocular examination revealed a best-corrected visual acuity (BCVA) of hand movement close to face (HMCF) with accurate projection of rays in the right eye and 6/ 6 in the left eye. Examination of the anterior segment was normal in both eyes. Fundus examination in the right eye revealed total retinal detachment with about 6 Disc Diameter (DD) size reddish orange mass with two large stretch breaks stretching in the inferotemporal quadrant with surrounding fibrous tractions , thus showing a successful outcome in unusual presentation. Since the patient had already reached a stage in which the treatment modalities like laser photocoagulation, cryotherapy, photodynamic therapy (PDT), anti-VEGF, did not have any role due to total retinal detachment, he underwent combined surgery with sclera band buckle (240 size) with pars plana vitrectomy and endoresection of tumor with high viscosity silicon oil tamponade. There were no intra-operative complications with stable course post surgery and attached retina. Silicon oil was removed 5 months after the initial surgery, as soon as the emulsification was noted. At 9 months post surgery, BCVA in right eye had improved to 6/ 24 with attached retina, no evidence of remnant of tumor/ reproliferation and healthy well laser retinectomy site in temporal periphery with pars plana vitrectomy, endoresection of tumor with high viscosity silicon oil tamponade. Patient had stable post-operative period with good visual recovery. He underwent silicon oil removal 5 months post initial surgery with good anatomical and visual outcome and no evidence of tumor proliferation/ redetachment at last follow-up, which was 9 months post vitrectomy.Thus, combined retinal detachment can be an unusual or atypical presentation of rare etiology like retinal capillary hemangiomas but appropriate and skilled vitreo-retinal surgical intervention can lead to successful visual and anatomical outcomes in these patients. Availability of Data & materialFreely available on request.Competing InterestNil.Conflict of InterestNo conflict of interest was declared by the authors.Financial DisclosureThe authors declared that this study received no financial support.AcknowledgementNil."} +{"text": "Upon sub-stratification, the prognostic value remained highly significant in the adenocarcinoma subtype (p = 0.002) but not in the squamous carcinoma subtype (p = 0.578). This finding highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. Elucidation of the underlying pathways regulating Cx43 localization may provide for novel therapeutic opportunities.Direct intercellular communication, mediated by gap junctions formed by the connexin transmembrane protein family, is frequently dysregulated in cancer. Connexins have been described as tumour suppressors, but emerging evidence suggests that they can also act as tumour promoters. This feature is connexin- and tissue-specific and may be mediated by complex signalling pathways through gap junctions or hemichannels or by completely junction-independent events. Lung cancer is the number one cancer in terms of mortality worldwide, and novel biomarkers and therapeutic targets are urgently needed. Our objective was to gain a better understanding of connexins in this setting. We used several in silico tools to analyse TCGA data in order to compare connexin mRNA expression between healthy lung tissue and lung tumours and correlated these results with gene methylation patterns. Using Kaplan-Meier plotter tools, we analysed a microarray dataset and an RNA-seq dataset of non-small cell lung tumours in order to correlate connexin expression with patient prognosis. We found that connexin mRNA expression is frequently either upregulated or downregulated in lung tumours. This correlated with both good and poor prognosis in a clear connexin isoform-dependent manner. These associations were strongly influenced by the histological subtype (adenocarcinoma versus squamous cell carcinoma). We present an overview of all connexins but particularly focus on four isoforms implicated in lung cancer: Cx26, Cx30.3, Cx32 and Cx43. We further analysed the protein expression and localization of Cx43 in a series of 73 human lung tumours. We identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival ( The World Health Organization (WHO) currently estimates that 1.69 million deaths per year worldwide are due to lung cancer, far more than any other cancer type. Non-small cell lung cancer (NSCLC), which includes the two major subtypes of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), accounts for about 85% of lung cancers. In terms of the biology of lung cancer, significant advances have been made ) contains correlation analyses based on mRNA expression levels with respect to clinical outcome for 17 major cancer types and almost 8000 cancer patients [Kaplan-Meier survival curves (mRNA expression): Overall survival (OS) was derived both from TCGA array data of lung cancer and from pan-cancer RNA-seq data. All analyses were performed online analysis tool [http://maplab.imppc.org/wanderer/) [Methylation analysis: We used an online (sis tool to gain nderer/) to analyIn conclusion we have found that major changes in some specific connexin mRNAs often occur in lung tumours but in general this do not correlate well in relation to changes in promoter methylation. Connexin mRNA expression can however correlate with both good and poor prognosis, which depends on the connexin isoform analysed and the histological subtype (LUAD versus LUSC). In addition to changes in mRNA expression, it is clear that protein location and functionality is critical. In this study, we identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival. The prognostic value was highly significant in LUAD, and larger cohorts will be needed to definitively assess the correlation in LUSC. This study highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. It also proposes that modulation of Cx43 trafficking may be a useful therapeutic strategy."} +{"text": "Epidemiology & Infection while also discussing advances in emerging infectious diseases.This invited editorial introduces a special issue of World Health Organization (WHO) recently enumerated 10 threats to global health for 2019, notably emphasising Ebola and other high-threat emerging pathogens as growing priorities [annualised financial impact of a global pandemic has been estimated to be as high as US$80 billion, severely burdening already constrained national budgets and healthcare systems [The systems . Outbrea systems . These fEpidemiology & Infection highlights new insights into many of the emerging infectious diseases mentioned in the WHO report, as well as re-emerging diseases that are gaining global prominence. They address a variety of diagnostic, therapeutic and epidemiological advances in outbreak preparedness. Several papers review data on priority pathogens with a focus on resource-limited settings. For example, Sikkema et al. present a systematic review on Middle East Respiratory Syndrome Coronavirus with the aim of characterising the distribution and spread of infection in dromedary camels [et al. review the recent Nipah virus outbreaks in Bangladesh and India, shedding light on transmission patterns of this emerging pathogen while also highlighting the importance of ongoing surveillance [et al. discusses genetic variations among avian influenza viruses circulating in Bangladesh and the impact of accumulating mutations noted in poultry. Lessons learned from the WHO response to the recent 2017 pneumonic plague outbreak in Madagascar are presented by Heitzinger et al., who highlight specifically the challenges of implementing rapid infection prevention and control measures in epidemic settings [This edition of y camels . Aditi eeillance . A reviesettings . These, Outbreaks of re-emerging infectious diseases in high-income countries are also discussed, often implicating products imported across borders as well as trans-national spread due to as yet unknown causes. Other papers discuss zoonotic and vector-borne disease epidemiology and present opportunities for predictive modelling. Several diagnostic advances are also mentioned, elucidating changing epidemiological trends in recently recognised re-emerging pathogens.Epidemiology & Infection represents a diverse overview of current concerns surrounding emerging infectious diseases globally. All highlight the importance of supporting ongoing surveillance efforts as the cornerstone of disease prevention. Early recognition of an outbreak allows control measures to be initiated in a timely way that can shift the epidemic curve, reducing its impact and possibly its geographic spread. Enhanced surveillance measures with an emphasis on innovation, transparency and incorporation of the One Health model are critical to epidemic preparedness measures in the future. It is also crucial to encourage research during outbreaks through rapid data sharing to facilitate rapid response efforts, as is promoted through organisations such as the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) [This issue of (ISARIC) . Vaccina(ISARIC) . These e(ISARIC) . Emergin"} +{"text": "Writing and publication in an academic setting is vital for advancing careers and knowledge. Attempting to increase scholarly productivity, our division created a physician-writing group, led by a prolific humanities expert to hone our writing skills. An unexpected outcome was realized. Using a mix of reflective, intent-driven, impromptu writing exercises and group sharing we discovered new opportunities for personal and professional growth through empathy. During these 1-hour sessions, several organic themes emerged. These included gaining greater inner-personal insight and recognizing inter-personal similarities in career paths and provider benevolence as motivation to continue when experiencing emotional fatigue and burnout. Ultimately, while honing our professional writing skills we also stimulated compassion to ourselves and our colleagues, opening new sources of resilience. We plan to continue these sessions exploring the potential multifaceted impacts on professional/academic growth these sorts of writing groups can have for geriatric and palliative medicine professionals and other healthcare providers."} +{"text": "Mesothelioma is an incurable cancer caused by exposure to asbestos. Several countries have witnessed a growth in incidence of epidemic proportions over the last two decades, and approved treatment is limited to front-line chemotherapy . The recCOMMAND was negative, despite hopes of recapitulating preclinically observed synthetic lethality in the context of NF2 mutation , as wellSince the initiation of the COMMAND trial, comprehensive genomic studies have revealed extensive genetic disruption of hippo signaling in mesothelioma involving multiple components of this tumor suppressor pathway , 8. In tA phase II window of opportunity trial involving defactinib monotherapy in patients prior to surgical resection demonstrated a promising 80% disease control and 13% response rate . InteresAfter the initiation of the COMMAND trial, another important insight into FAK biology came to light. FAK plays a crucial role in regulating the tumour microenvironment via augmentation of Treg abundance . Inhibithippo defective biomarkers, or directly antagonizing YAP/TEAD transcription may provide next-generation approaches to phenocopying this important tumor suppressor pathway in mesothelioma.In summary, targeting the Hippo pathway remains a potentially promising strategy for controlling mesothelioma. Widening the net to capture more hippo deficient phenotypes through the use of comprehensive"} +{"text": "We recently identified pathogenic soluble aggregated tau (tau oligomers) in the cerebral microvasculature of human patients with tauopathies, including Alzheimer\u2019s disease (AD). The functional consequences of cerebrovascular tau accumulation are not yet understood. The aim of the present study was to determine whether pathogenic tau accumulation leads to cerebrovascular dysfunction. To this end, we measured neurovascular coupling (NVC), a highly regulated process that synchronizes cerebral blood flow to neuronal activation, using the PS19(P301S) mouse model of tauopathy. The change in cerebral blood flow evoked by whisker stimulation was measured using Laser Doppler flowmetry in PS19 and wildtype control mice and the functional contribution of neuronal and endothelial nitric oxide synthase was calculated. Vascular reactivity was assessed using topical acetylcholine to evoke endothelium-dependent vasodilation. To assess the direct impact of pathogenic tau on cell-specific NOS function, we treated N2a neuroblastoma cells or mouse brain vascular endothelial cells with soluble tau aggregates and measured activity of nNOS and eNOS. Our data indicate isolated overexpression of mutant tau impairs NVC responses, and this deficit is mediated by a reduction in nNOS activity in vivo. Further, our studies suggest tauopathy also impairs endothelium-dependent vasoreactivity in the cortex. Additionally, soluble tau aggregates inhibit the phosphorylation of NOS in primary cultured cells. Therefore, inhibition of NOS phosphorylation by pathogenic soluble tau aggregates may underlie cerebrovascular dysfunction in tauopathies. Thus, therapeutic modulation of pathogenic tau may mitigate brain microvascular deficits, which occur prior to clinical onset in Alzheimer\u2019s disease and potentially other tauopathies."} +{"text": "Patient portals are popular health care tools. Few portals target caregiving families and few use predictive modeling to assist caregiving families make decisions about elder care options. Our goal is to incorporate the algorithms being developed for predicting tipping points in elder care to assist caregiving families visualize changes in older adults\u2019 activity patterns, understand possible implications for continued in-home safety, and access educational information and consultation. While many patients use portals, use is restricted among persons in racial and ethnic minorities, with lower educational levels and poorer health literacy, and with fewer economic resources. The following strategies help us address these issues. Our portal archives data from affordable, wearable technology. Portal access uses similarly technology. Our educational materials use techniques known to be appealing and effective with older individuals in unique groups, e.g., results displays; fotonovelas. Input from community members/users helps maintain sensitivity to cultural appropriateness and health literacy."} +{"text": "Culture change represents an organizational transformational process to become person-centered, through staff and resident empowerment. Culture change initiatives have been associated with fewer health-related deficiency citations and better psychosocial outcomes. Knowledge management, defined as the process of creating or locating knowledge, and managing the dissemination of knowledge within and between organizations, has been shown to be associated with the adoption of innovations such as culture change initiatives. This study examines the relationship between knowledge management activities of high Medicaid census (70% or higher) nursing homes (NHs) and the adoption of culture change initiatives. This study used facility survey data from approximately 324 nursing home administrators (30% response rate) from 2017- 2018, merged with data from LTCFocus, Area Health Resource File, and Medicare Cost Reports. Binary logistic regression models revealed that the probability of adopting a culture change initiative was 0.12 higher for facilities reporting a one-unit higher level of knowledge management activities. Additional interaction analysis revealed that knowledge management activities were associated with a greater likelihood of adopting a culture change initiative for NHs where the director had been in his/her position fewer years. Similarly, higher levels of overall knowledge management activities were significantly associated with greater adoption of culture change initiatives at intermediate levels of nurse retention. Results suggest that knowledge management activities may help high Medicaid NHs acquire and mobilize informational resources in ways that can support the adoption of patient-centered initiatives. These activities may be particularly effective in nursing homes with leadership and nursing staff instability."} +{"text": "Circulating microRNAs offer attractive potential as epigenetic disease biomarkers by virtue of their biological stability and ready accessibility in liquid biopsies. Numerous clinical cohort studies have revealed unique microRNA profiles in different disease settings, suggesting utility as markers with diagnostic and prognostic applications. Given the complex network of microRNA functions in modulating gene expression and post-transcriptional modifications, the circulating microRNA landscape in disease may reflect pathophysiological status, providing valuable information for delineating distinct subtypes and/or stages of complex diseases. Heart failure (HF) is an increasingly significant global health challenge, imposing major economic liability and health care burden due to high hospitalization, morbidity, and mortality rates. Although HF is defined as a syndrome characterized by symptoms and findings on physical examination, it may be further differentiated based on left ventricular ejection fraction (LVEF) and categorized as HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). The presenting clinical syndromes in HFpEF and HFrEF are similar but mortality differs, being somewhat lower in HFpEF than in HFrEF. However, while HFrEF is responsive to an array of therapies, none has been shown to improve survival in HFpEF. Herein, we review recent HF cohort studies focusing on the distinct microRNA profiles associated with HF subtypes to reveal new insights to underlying mechanisms and explore the possibility of exploiting these differences for diagnostic/prognostic applications. Heart failure (HF) is a complex clinical syndrome arising from deficient cardiac output that is unable to meet the metabolic needs of the organs and tissues in the body. HF evolves from systolic and/or diastolic contractile dysfunction caused by progressive structural and functional alterations of the heart . MultiplThe overall prevalence of HF is about 1\u20132% worldwide with an estimated 37.7 million people affected globally ,8. In thSymptoms of HF include breathlessness, cough, interrupted sleep, exercise intolerance, edema, and fatigue. However, the nonspecificity of these symptoms can confound the diagnosis of HF as they also occur in noncardiac conditions including renal impairment and chronic obstructive pulmonary disease. More specific signs of HF include elevated jugular venous pressure and the displacement of the apical cardiac impulse. However, these signs may be hard to detect and difficult to interpret in patients with comorbidities such as obesity or airway diseases . Thus, tLeft ventricular ejection fraction (LVEF) is a widely adopted phenotypic parameter to define HF. HF with reduced ejection fraction and HF with preserved ejection fraction are two major HF subtypes that differ in terms of pathophysiology and etiology, as well as treatment responses . The twoThe poor prognosis in HF, despite advances in treatment, mandates efforts to enhance management and improve patient outcomes. HF is underpinned by multiple risk factors, comorbidities, and pre-existing conditions which have an adverse impact on cardiac structure and function. The first line of HF drugs were directed towards improving quality of life by attenuating symptoms and slowing down disease progression, as well as reducing morbidity and mortality in HFrEF. However, to date, no HF therapeutics have consistently and permanently halted progression of structural and functional cardiac deterioration. Drugs targeting the renin-angiotensin-aldosterone system (RAAS) including angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), \u03b2-adrenergic receptor blockers, and mineralocorticoid receptor antagonists (MRAs) have been shown to ameliorate the symptoms of HF and improve outcomes including HF re-admissions and mortality ,35. ReceTo facilitate the development of next generation HF therapeutics, key knowledge gaps in the underlying mechanisms and pathophysiology of HF must be addressed. The current lack of circulating biomarkers that could provide definitive diagnosis, prognosis, risk stratification, and subtype categorization of HF remains an ongoing challenge. The detailed molecular mechanisms underlying HF pathogenesis and how pathological pathways differ between subtypes and their translation to phenotype-specific therapeutic strategies remain elusive. Unravelling the relationship between biomarkers and HF pathogenesis may shed the light for developing precision medicine for HF in the near future. MicroRNAs comprise a cluster of noncoding RNA species that are known to play important roles in modulating the expression of most protein coding genes at the post-transcriptional level . MicroRNWith increasing understanding of the characteristic differences between HFrEF and HFpEF, there has been active interest in finding signature microRNA profiles to facilitate HF subtype categorization. Ellis et al. pioneered early work on HFrEF and HFpEF microRNA profiling and reported a set of differentially expressed microRNAs in a dyspnea cohort comprising 16 HFrEF and 16 HFpEF with high NT-proBNP plasma concentrations . HoweverIt is noteworthy that each study reported a unique set of differentially dysregulated microRNAs and no overlap of microRNAs was observed across all four cohort studies. This discrepancy is not totally unexpected and may be attributed to the heterogenous comorbidities of HF and sample size of cohorts, as well as the different criteria used for patient enrollment. Profiling reported in the five studies highlighted in http://www.microrna.gr/miRPathv3), an online pathway analysis software [In addition to potential diagnostic applications, the discovery of microRNA clusters that are differentially expressed in HFrEF and HFpEF patients provides an approach to delineate the different pathobiological pathways underlying HFrEF and HFrEF. software . Based osoftware . The sigChanges in plasma concentrations of free fatty acids across three different HF subtypes have been reported previously . ResultsInterestingly, predicted targets analysis (microT-CDs) revealed that transforming growth factor beta (TGF-\u03b2) signaling and Forkhead box O (FoxO) transcription factors signaling are among the top pathways predicted to be affected by the eight HF signature microRNAs. TGF-\u03b2 signaling is known to play pivotal roles in the pathogenesis of cardiac remodeling and fibrosis. The putative roles of microRNAs in TGF-\u03b2 signaling have been reported and tested in various diseased models. For instances, miR-101a was shown to target the TGF-\u03b21 receptor, subsequently attenuating fibrogenesis and improving cardiac function in a rodent transverse aortic constriction (TAC) model . FoxOs aThe discovery of microRNAs and their roles in post-transcriptional modification have led to further advances in understanding the complexity of gene regulation. However, translating findings of distinct circulating microRNA compositions and their pathophysiological implications in different disease states to decipher underlying mechanisms with a view towards therapeutic exploitation remains challenging. MicroRNA-3\u2019UTR interactions do not require perfect Watson\u2013Crick pairing and this significantly increases the functional flexibility of microRNA. It is now known that one microRNA can have multiple 3\u2019UTR targets, and one 3\u2019UTR can be recognized by more than one microRNA so that biological homeostasis could be tightly controlled in the normal state while dynamic biochemical responses could also be triggered upon stimulation. Although it has been established that microRNAs play important roles in post-transcriptional modification, scientists have yet to fully understand the operating rhythm of microRNAs. The traditional approach of deciphering the regulatory effect of one microRNA on one gene is manifestly inadequate in bringing together the influence of the microRNA landscape on gene expression regulatory networks. Dysregulated microRNAs can be viewed as functional clusters that variously contribute to HF pathogenesis. This concept was supported by our previous study where data from microRNA/3\u2019UTR binding and gain-of-function assays demonstrated putative regulatory effects of HF-related microRNAs upon key molecules involved in neurohormonal signaling . Given the potential application of signature microRNAs in HF diagnosis, further independent verification of our findings by other reputable investigators is needed. Furthermore, the diagnostic performance of microRNAs may require further refinement according to comorbidities and clinical background. Further studies to clarify the association between HF-related microRNAs and pathogenesis will be essential to translate these epigenetic alterations into therapeutic applications. It is conceivable that linear algorithms will not be adequate to describe the interaction networks between transactivation and post-transcriptional regulation of microRNAs with their target genes. Hence, large scale international multi-disciplinary collaborative research integrating expertise in biomedicine, clinical practice, bioinformatics, artificial intelligence, and machine learning will be pivotal to advancing progress in HF research."} +{"text": "The human hair follicle is a neuroendocrine mini-organ that can be used to study aging processes in vitro. Neurotrophins maintain homeostasis in hair biology via the Trk-family of receptors. TrkA, the high affinity receptor for nerve growth factor (NGF), is expressed in hair follicle melanocytes and keratinocytes, where it regulates proliferation, differentiation and apoptosis and may thereby play a role in hair pigmentation and growth. We investigated TrkA expression during the human hair cycle and the effects of a selective high affinity TrkA agonist, Gambogic Amide, on hair pigmentation and hair growth in human hair follicles in vitro. In human scalp skin, TrkA expression was strongest in proliferating melanocytes re-establishing the pigmentary unit in the hair bulb during the early hair growth phase, anagen. During high anagen and in the de-composing pigmentary-unit of the regression phase, catagen, bulb-melanocytes lost TrkA expression and only undifferentiated outer root sheath melanocytes maintained it. In cultured human anagen hair follicles, Gambogic Amide was able to prevent gradual pigment loss, while it stimulated hair shaft elongation. This was achieved by increased melanocyte activation, migration and dendricity, highlighted by distinct c-KIT-expression in melanocyte sub-populations. Our results suggest that Gambogic Amide can maintain hair follicle pigmentation by acting on undifferentiated melanocytes residing in the outer root sheath and making them migrate to establish the pigmentary-unit. This suggests that the selective TrkA agonist Gambogic Amide acts as an anti-hair greying and hair growth promoting molecule in vitro. In today\u2019s society healthy aging is crucial for well-being. One of the clinically visible signs of aging is greying hair . This isHair follicle pigmentation involves exact temporal and spatial regulation of the cells that produce the pigment, the melanocytes. Melanocyte turnover within the hair follicle, meaning renewal , maturation (differentiation) and removal (senescence and apoptosis) is highly regulated to prevent melanoma development and spontaneously occurring primary hair follicle melanoma is in fact rarely reported . To prevTo identify safe intervention strategies, it is therefore necessary to monitor melanocyte dynamics during hair growth. Hair shaft pigmentation, also called follicular melanogenesis, in both mice and humans is tightly linked to the growth phase (anagen) of the hair cycle \u20138, whichIdeally, the mechanisms allowing hair pigmentation to be reestablished with each hair cycle are in a state of homeostasis. This homeostasis works optimally for the first 10\u201315 hair follicle growth cycles (until about 40 years of age). Thereafter, the mechanisms that maintain pigmentation seem to exhaust and the regeneration potential of the pigmentary-unit diminishes, leading to grey or white hair .An agent stimulating hair follicle pigmentation should improve homeostasis but not interfere with it. One of the main routes studied to improve hair pigmentation focusses on melanin synthesis in hair follicle melanocytes and the gradual loss of factors maintaining it, such as alpha-melanocytes stimulating hormone . In addiSkin has documented neuroendocrine properties , 21, andGarcinia hanburryi tree in South-eastern Asia [The question therefor arises, if expression and manipulation of TrkA plays a role in hair follicle pigmentation homeostasis . Gambogiern Asia , was ideern Asia . In addiern Asia . Based oTissue collection was essentially done as previously described . In brieAnagen VI HF were cultured for seven days in supplemented Williams\u2019 E medium as published before , 37. On 8-\u03bcm-thick longitudinal cryosections through full thickness human scalp skin and cultured HF were processed and analyzed using a digital image analysis system as previously described . For NKIStatistical analysis was performed as previously described . Means wNative human scalp skin was investigated for TrkA expression of distinct sub-populations of hair follicle melanocytes during the hair cycle and showed a staining of keratinocytes in the outer root sheath throughout. In addition, in early anagen hair follicles round undifferentiated melanocytes in the re-establishing pigmentary-unit strongly expressed TrkA . In highNext the capacity of the TrkA agonist nerve growth factor (NGF) to modulate pigmentation in cultured human hair follicles was tested. 5 ng/ml NGF maintained pigmentation in cultured human anagen hair follicles over theBased on the findings in Figs To analyze target melanocyte subpopulations of Gambogic Amide we investigated c-KIT-expression of hair follicle melanocytes in response to Gambogic Amide in various compartments of the hair bulb after 7 days of culture . While cFurthermore, we observed a slight increase in melanocyte dendricity in response to Gambogic Amide (50\u20131000 nM) . No signTo control, if these effects occurred within the anagen phase or were associated with premature catagen development in cultured anagen hair follicles, hair follicles exposed to Gambogic Amide were subjected to hair cycle progression analysis. By histomorphometry, Gambogic Amide at all tested concentrations did not significantly alter hair cycle progression compared to control samples . In factConcerning melanocyte turnover and cellular homeostasis, we found here an increased p16 expression at all tested concentrations with a peak at 500 nM of Gambogic Amide in melanocytes of all follicular compartments . HoweverFinally, growth of hair follicles exposed to Gambogic Amide was analyzed and revealed that in addition to hair pigmentation maintenance, Gambogic Amide was able to increase hair shaft elongation at all concentrations tested . This fuIn this study we investigated the expression of TrkA in human hair follicles and studied the effects of a selective, plant derived TrkA agonist Gambogic Amide on the pigmentation of hair follicles in vitro to investigate its potential as an anti-aging ointment. We found TrkA expression during the human hair cycle in distinct melanocyte subpopulations suggestive of its expression primarily in undifferentiated melanocytes and potentially melanoblasts Figs and 2. AIn the human scalp skin, we found that TrkA was strongly expressed in hair follicle melanocytes in the outer root sheath and in the developing pigmentary-unit at the beginning of anagen as well as in the outer root sheath of fully developed anagen hair follicles. This is in line with previous findings showing that TrkA is mainly expressed in melanocytes and keratinocytes in anagen hair follicles . HoweverIn addition, TrkA-positive melanocytes were round-shaped and expressed the melanocyte migration marker c-KIT. In mice, c-KIT was previously shown to be predominantly expressed in migrating melanoblasts in the developing hair follicle and it iIn line with c-KIT being also a melanocyte differentiation marker, the melanocytes in hair follicle treated with Gambogic Amide also displayed slightly enhanced dendricity. Since melanocytes are derived from the neural crest it resembled the capability of Gambogic Amide to induce neurite outgrowth in various neuronal cell lines , 34. In Looking at hair follicle pigmentation we found that Gambogic Amide showed a similar activity as nerve growth factor NGF, which is the natural high affinity agonist of TrkA. In contrast to NGF however, we found that Gambogic Amide showed pro-pigmenting activity dose-dependently at higher concentrations, whereas NGF showed a maximum at 5 ng/ml. High concentrations of NGF like 50 ng/ml decreased hair follicle pigmentation in vitro . NotablyWe used here the Philpott model of hair follicles which are truncated below the bulge region. This means Gambogic Amide acted on undifferentiated melanoblasts released from the bulge already, and as such was able to sustain pigmentation in vitro more efficiently without In summary, we provide evidence that it is possible to halt the hair aging process represented by hair greying in vitro with Gambogic amide. An important mechanism how Gambogic Amide stimulates pigmentation in hair follicle melanocytes is via induction of c-KIT expression . GambogiThe potential of Gambogic Amide or other molecules activating TrkA signaling in human hair follicle as a remedy to reverse signs of aging hair like greying is further corroborated by the finding that Gambogic Amide is able to induce hair follicle growth in vitro . In addiThe notion that Gambogic Amide recruits melanocytes of the outer root sheath while the hair continues or even improves its growth activity is evidenced by the maintenance of anagen morphology and increased hair shaft elongation. This is intriguing, as it was shown previously that without treatment, in vitro pigmentation correlated negatively with hair shaft elongation in cultured human anagen hair follicles and vice-versa and that this links with up-regulated gene-expression of keratins involved in active hair growth , 51. OurIn conclusion, we provide evidence that the TrkA agonist Gambogic Amide is a promising molecule able to protect hair follicle pigmentation in vitro by mobilizing TrkA and c-KIT-positive hair follicle melanocytes. Furthermore, Gambogic Amide has a growth promoting activity on hair follicles in vitro, further highlighting its potential as a hair health or hair anti-aging active."} +{"text": "Pulmonary arteriovenous malformations (PAVM) are rare pulmonary vascular anomalies and hemothorax as a presenting feature of PAVM is a very rare occurrence.A 45-year old woman presented with chest pain and breathlessness. A chest x-ray showed left-sided pleural effusion. An emergency MSCT scan with contrast showed no signs of pulmonary embolism but instead a probable AV malformation was shown. Diagnostic thoracocentesis revealed hemorrhagic exudate with negative cytology and microbiology findings. Thoracic drainage was performed resulting with complete regression of hemothorax. Three months later, patient was treated with transcatheter embolization of PAVM with good clinical outcome.We have shown that management of PAVM related hemothorax initially by thoracic drainage followed by later on performed catheter embolization of the PAVM could lead to a successful outcome. Pulmonary arteriovenous malformations (PAVMs) are abnormal direct communications between pulmonary arteries and veins . They arA non-smoker 45-year old woman presented with left-sided chest pain and breathlessness over 7-day duration, with no history of chest trauma. She had no signs of hemodynamic instability and did not appear to be in significant respiratory distress with only mild partial respiratory insufficiency.Laboratory findings were within normal limits apart from mild normocytic anemia (Hgb 106 g/L) and elevated D dimers (2.06 mg/L). Accordant to clinical examination of the chest, chest x-ray confirmed left-sided pleural effusion. An emergency MSCT scan with contrast showed no signs of pulmonary embolism but instead a probable AV malformation 17 mm in diameter was shown in anterior segment of left upper lobe . DiagnosMSCT scan with contrast performed three months later then confirmed a simple PAVM in the peripheral lingular area supplied from superior left pulmonary artery, and with a drainage vein entering the pulmonary veins and left atrium . The fee During further treatment, the patient participated in pulmonary rehabilitation program because of persistent dyspnea on exertion and since then has been attending regular follow-ups with normal radiological and pulmonary function test findings without recurrence of pleural effusion .Pulmonary arteriovenous malformations (PAVMs) are rare abnormal communications between the branches of pulmonary arteries and veins , 3. TheyThe clinical manifestations and complications of idiopathic PAVMs are also similar to those associated with HHT . More thPotentially life-threatening complications that occur in less than 10-20 percent of patients with PAVMs are hemothorax and hemoptysis . HemothoWhile hemoptysis is likely due to rupture of either parenchymal PAVM or an endobronchial teleangiectasia, hemothorax results from rupture of a subpleural PAVM. As seen in our patient, probable rupture of PAVM in peripheral area led to this rare complication. Massive hemoptysis and massive hemothorax from rupture of PAVM into the pleural space have been reported, with fatal outcomes , but hem Contrast-enhanced pulmonary angiography remains the gold standard for defining the anatomy of PAVMs that are considered potentially suitable for embolotherapy, which has largely replaced surgical intervention. PAVMs were historically treated with surgical resection. As endovascular techniques developed, embolization became the mainstay of treatment. Initial management with therapeutic embolization may well be appropriate in most patients who present with symptomatic PAVM. In patients who are hemodynamically unstable or in whom embolization has failed, open surgical resection of the PAVM has been successful . Treatme Transcatheter embolotherapy has proven to be a safe and effective treatment for sporadic PAVMs providing excellent functional and radiological improvement , 4, as sIn reviewed cases, which included mostly acute onset of PAVM associated with hemothorax, primary treatment was surgical or urgent embolization interventions, or combination of both , 12, 13.In conclusion PAVMs are relatively rare disorders with very common presentations and they are an important part of the differential diagnosis of pulmonary problems like hemoptysis, pulmonary nodule and hypoxemia. Although rarely seen, a PAVM as underlying cause of a spontaneous hemothorax should also be considered. \u00a0Contrast-enhanced computed tomography is a valuable and widely available diagnostic tool for patients with abnormal chest radiography suspicious of PAVM. There is little data on idiopathic PAVMs in the literature, especially presenting with hemothorax, and hopefully this case could benefit treatment of some of PAVM patients, which is why we consider our case worthy of reporting.We have shown that management of PAVM-related hemothorax initially by thoracic drainage followed by later on performed catheter embolization of the PAVM in a low risk patient could lead to a successful outcome."} +{"text": "Cancer cells accelerate glycolysis to maintain ATP and other metabolites which are necessary to maintain their survival and chemoresistance. Glutathione (GSH) is the major antioxidant in living organisms and has multiple functions including maintenance of intracellular redox homeostasis. Cancer cells produce reactive oxygen species (ROS) that results from mitochondrial dysfunction, aberrant metabolism, and frequent genetic mutations. Such circumstances cause accumulation of large amounts of oxidized molecules including proteins, DNA and lipids. Therefore, cancer cells require active synthesis and recycling of GSH under regulating the balance of glucose utilization between glycolysis and pentose phosphate pathway which is necessary to synthesize NADPH and nucleic acid precursors . Excess Ferroptosis has recently been identified as a novel type of regulated cell death caused by severe oxidative stress and subsequent lipid peroxidation against which GSH-dependent antioxidant system protects. Inhibition of xCT cystine transporter or the GSH-dependent enzyme glutathione peroxidase 4 has been shown to induce ferroptosis in cancer cells . Since mOncotarget, Okazaki et al. performed a synthetic lethal screen of a drug library to identify agents that sensitize the GSH deficiency-resistant cancer cells to the xCT inhibitor sulfasalazine and identified the oral anesthetic dyclonine. Dyclonine possesses a unique structure responsible for covalent inhibition of aldehyde dehydrogenase enzymes (ALDHs) [In this issue of (ALDHs) . Treatme (ALDHs) . They al (ALDHs) . Further (ALDHs) .In this context, of importance is that an engineered human enzyme cyst(e)inase which can degrade cystine/cysteine systemically has been developed . The cli"} +{"text": "Due to an editorial error, the Data Availability Statement containing the raw sequences was erroneously omitted from the article. The publisher apologizes for the mistake.MG242652-MG243345.Raw sequences have been deposited in Sequence Read Archive SRR6187016 and BioProject PRJNA414535; the 694 OTUs (representative sequences) under GenBank accession #"} +{"text": "Simultaneous cerebral and myocardial infarction is called cardiocerebral infarction (CCI), and is rarely encountered. Because of the narrow time window and complex pathophysiology, CCI is challenging to immediately diagnose and treat.A 73-year-old woman suddenly developed right hemiplegia and severe aphasia. Twelve-lead electrocardiography showed tachycardic atrial fibrillation without any significant ST-T change. Magnetic resonance imaging revealed a proximal middle cerebral artery occlusion. She was immediately treated with alteplase at the dosage approved for ischemic stroke followed by mechanical thrombectomy as bridging therapy, and complete recanalization was achieved. Aphasia improved and she began to complain of chest pain, and reported that she had experienced chest discomfort just prior to right limb weakness. Coronary angiography showed a partial filling defect in the right coronary artery with rapid and adequate distal flow, for which percutaneous coronary intervention was not required. Alteplase was suggested to have effectively resolved the coronary emboli. The occlusions of the cerebral and coronary arteries were assumed to have occurred nearly simultaneously and cardiogenic embolism due to atrial fibrillation was considered as the most likely etiology.As seen in the present case, CCI may benefit from immediate treatment with intravenous tissue plasminogen activator (IV-tPA). Although which of percutaneous coronary intervention or cerebral thrombectomy should be performed first remains unclear, we must decide whether to rescue the brain or heart first in each patient within a limited window of time. This dilemma has recently become evident in this era with mechanical thrombectomy strongly established as an effective intervention for acute ischemic stroke. Close cooperation between stroke physicians and cardiologists is becoming more important. Simultaneous cerebral and myocardial infarction is called cardiocerebral infarction (CCI), and is rarely encountered . Because4/\u03bcL. No abnormalities were evident on chest roentgenogram.A 73-year-old woman suddenly developed right hemiplegia and severe aphasia and was transported to our emergency service 47\u2009min after onset. Her medical history included hypertension and paroxysmal atrial fibrillation. Anticoagulants have been discontinued because of a few episodes of falls although she had previously received oral anticoagulation. Blood pressure was 105/75\u2009mmHg without any significant difference between right and left limbs. No cardiac murmurs were audible. Twelve-lead electrocardiography (ECG) showed tachycardic atrial fibrillation with a heart rate of 150 beats/min but no significant ST-T changes, although the baseline was undulating due to patient movement and mechanical thrombectomy, followed by coronary angiography, which did not suggest any requirement for PCI. Coronary angiography suggested that alteplase at the dosage approved for ischemic stroke had resolved the coronary emboli. Because IV-tPA is effective for both cerebral and myocardial infarction, CCI is likely to benefit from immediate treatment with IV-tPA prior to endovascular therapy. Although the recommended dosages of IV-tPA differ between cerebral and myocardial ischemia, in 6 previously reported cases of CCI treated with IV-tPA therapy, the dosage of IV-tPA applied was that used for acute ischemic stroke , 10, 11 A dilemma exists regarding endovascular therapy: although the occluded cerebral and coronary arteries have to be recanalized as soon as possible in the case of CCI, prioritizing one therapy leads to delays in the other. In previous studies, four patients were treated with both PCI and cerebral thrombectomy , 14, witIn conclusion, simultaneous cerebral and coronary embolism is rare and its prompt and appropriate management is difficult. Coexistence of coronary embolization should be considered when planning the treatment strategy for acute cerebral embolism. Further cases need to be studied to resolve the dilemma inherent in the recanalization strategy for CCI."} +{"text": "Intrauterine growth restriction (IUGR) continues to be a global epidemic that is associated with high early-life mortality rates and greater risk for developing metabolic disorders that lower length and quality of life in affected individuals.Fetal programming of muscle growth and metabolic function associated with IUGR is often comparable among nonlitter bearing mammalian species, which allows much of the information learned in domestic animal models to be applicable to humans .Recent studies in sheep models of IUGR have begun to uncover the molecular mechanisms linking adaptive fetal programming and metabolic dysfunction.Targets of adaptive fetal programming indicated by sheep studies include adrenergic and inflammatory pathways that regulate skeletal muscle growth and glucose metabolism. Adaptive changes in these pathways represent potential focus areas for prenatal interventions or postnatal treatments to improve outcomes in IUGR-born offspring.Low birthweight due to intrauterine growth restriction (IUGR) encumbers United States and global livestock production by increasing neonatal mortality, reducing growth efficiency, and diminishing carcass yield and quality. Low birthweight food animals that survive typically exhibit impaired muscle growth and metabolic dysfunction that leads to poor feed conversion, lighter carcasses, and reduced carcass merit . The endThe above models create placental stunting indirectly by imposing maternal conditions that disrupt uteroplacental blood flow during placental development. However, techniques described in this section impair placental function by directly diminishing structural components of the placenta. In one model, 150-\u03bcm microspheres are embedded into placental capillaries by infusing them into the surgically catheterized descending aorta of the fetus . This teFetal growth restriction can be achieved through restriction of maternal nutrients, although it is unclear whether it is mediated by placental insufficiency . The resAG- , and y+ . A collerginine) as the frginine) .fetal adrenal gland and primary skeletal muscle (ex vivo) was substantially reduced in MI-IUGR fetal sheep myoblasts and a ~10% reduction in late differentiating (desmin+) myoblasts after 72 hr in differentiation media . The fact that both proliferation and differentiation capacities were reduced in PI-IUGR fetal myoblasts (The \u03b22 adrenergic receptor is the predominant isoform in skeletal muscle, although \u03b21 and \u03b23 receptors are also present. However, we found that skeletal muscle and myoblasts from PI-IUGR fetal sheep as well as skeletal muscle from PI-IUGR neonatal lambs express less mRNA for the \u03b22 adrenergic receptor than controls . Conversyoblasts shows thyoblasts .enhanced by muscle adaptations in MI-IUGR fetal sheep (Like the \u03b22 adrenergic signaling pathway, inflammatory cytokine pathways appear to be altered in muscle and myoblasts of PI-IUGR and MI-IUGR fetal sheep . Unlike al sheep . In addial sheep . Sustainal sheep . Moreoveal sheep . We specIntrauterine growth restriction is a leading cause of perinatal mortality worldwide and leaves individuals at 18-fold greater risk for metabolic disorders that reduce length and quality of life. Unlike other major maternofetal pathologies, the prevalence of IUGR in the United States has not fallen over the last two decades. The fetal conditions and postnatal outcomes of IUGR are consistent among most mammalian species, which makes observations in animal models translatable to humans. A number of models developed in pregnant sheep have drastically improved our knowledge of IUGR fetal programming, which provides the fundamental basis for improving health outcomes in IUGR-born individuals."} +{"text": "Although bioturbation is commonly recognized in contourites, only a few studies have analyzed the ichnological content of these deposits in detail. These studies have mainly focused on meso-scale bigradational sequence (a coarsening upward followed by a fining-upward sequence resulting from variations in current velocity). Here we present data from gravitational cores collected along the NW Iberian Margin showing systematic variation in ichnological content across proximal to distal depocenters within a large-scale elongated contourite drift. Data demonstrate that tracemakers\u2019 behavior varies depending on the distance relative to the bottom current core. Trace fossils are already known to be a useful tool for studying of contouritic deposits and are even used as criterion for differentiating associated facies , though not without controversy. We propose a mechanism by which the distance to the bottom current core exerts tangible influence on specific macro-benthic tracemaker communities in contourite deposits. This parameter itself reflects other bottom current features, such as hydrodynamic energy, grain size, nutrient transport, etc. Ichnological analysis can thus resolve cryptic features of contourite drift depositional settings. Due to their implications for reconstruction of depositional conditions, contourite deposits have become a critical topic of investigation within the sub-disciplines of paleoceanography, slope-stability, and petroleum exploration. Due to their relative inaccessibility, however, contourites remain somewhat enigmatic. Only few studies have managed to investigate bioturbation and ichnofabrics in contour current settings6. Despite ongoing controversies8, trace fossil content is considered both a criterion for characterizing contouritic deposits and also a proxy for paleoenvironmental conditions7. These records are typically overprinted by bottom current activity9. In recent years, detailed ichnological studies conducted on contourite deposits in outcrops and core material have provided new insights into depositional processes, environmental conditions and the influence of bottom currents on tracemakers11. Due to lack of detailed records, the ichnological paradigm for contourites remains somewhat tentative. Here we describe unequivocal trace fossils in contouritic deposits from deep-sea gravity cores. Comparison of features reveals distinctive lateral variation with relative to bottom current cores.The role of bottom currents in shaping deep-sea deposits is currently a matter of debate in the scientific community12 during the ForSaGal 09 research cruise around the Galicia Interior Basin exhibit a clear pattern with contouritic intervals dominated by Thalassinoides and Planolites experienced relatively low sedimentation rate and low organic matter flux. Organic matter at the sediment surface may be rapidly oxidized, preventing the development of shallow/middle tier structures. Under these conditions, only deep tier structures are produced, by organisms able to store organic matter deeper in the sediment as in the case of the Zoophycos tracemaker. Sediments from site FSG09-07 indicate higher sedimentation rate and organic matter flux. Under these conditions, organic matter burial prevents oxidation and allows the development of shallow/middle tier dwelling structures, e.g. Palaeophycus . In distal settings, sedimentation rate and organic matter availability is lower. Organic matter is rapidly oxidized at the surface, favoring development of middle and deep tier tracemakers, which transport organic matter to deeper layers of the sediment . Systematic lateral variation in ichnological content of contourite drifts demonstrates an impactful role for ichnological analysis in contourite research. Trace fossils not only could differentiate contourites from turbidites and associated deposits, they also record proximal to distal deposition within a contourite drift relative to core bottom current features.Sedimentation rate, oxygen conditions, and organic matter availability influence the macrobenthic tracemaker communities and resulting trace fossil assemblage in actively forming contourite drifts. This report provides novel evidence of systematic proximal, to core bottom current, versus distal variation in ichnological features from muddy contourites. Varying depositional conditions are interpreted to reflect distance from the bottom current core. Sedimentation rate and organic matter availability are higher in proximal areas where organic matter is rapidly buried. This prevents oxidation and makes organic matter available for shallow tier tracemakers were previously characterized based on grain size, composition, sedimentary features and Computed Tomography (CT) scanning17. Contourite deposits, concretely muddy contourites, were identified in three cores. Only cores FSG09-07 and FSG09-17 along the NW Iberian margin36, then calculated according to the Bioturbation Index scale38. These values reflect the spatial extent of discrete trace fossils identified over a common mottled background.Ichnological analysis identified ichnotaxa based on ichnotaxabases , tiering , crosscutting relations, and degree of bioturbation. The degree of bioturbation was determined by calculating the percentage of bioturbated surface using a quantification method based on high resolution digital images14C ages for the cores material analyzed12.Age was calculated using the age model based on XRF data and AMS-"} +{"text": "Therefore, this microbial ecosystem is intertwined with host physiology at multiple levels. While it is evident that microbes that reach the blood stream can trigger thrombus formation, it remains poorly explored if the wealth of microbes that colonize the body surfaces of the mammalian host can be regarded as a modifier of cardiovascular disease (CVD) development. To experimentally address the microbiota's role in the development of atherosclerotic lesions and arterial thrombosis, we generated a germ-free (GF) low-density lipoprotein receptor-deficient ( From a perspective of cultural evolution, during the past decades Western societies have faced an enormous shift from traditional fibre-rich nutrition to the consumption of industrial foods that severely affects the diversity and function of the gut microbiota. To a large extent, the mutualistic nature of this microbial ecosystem with its host relies on intact barriers that are typically are formed by the mucus layer, the integrity of epithelial cell layers and by a tightly regulated and multifaceted immune vigilance but is also determined by nutritional factors shaping the diversity of the commensal microbiota. These efficient barriers are disrupted by infectious pathogens and in case of injury. Related to infection, the concept of immunothrombosis views blood clotting as an intravascular effector pathway of innate immunity, constituting a physiologic response that prevents the invasion and dissemination of microbes but becoming detrimental to the host if exceeding, e.g. in sepsis. These microorganisms produce foreign products that, dependent on dietary habits, constitute a continuous stimulus of low-grade inflammation and at the same time possess an enormous metabolic capacity interfering with host metabolism. This is particularly relevant, as, in addition to the nutrition-dependent formation of microbiota-derived metabolites that can cross the intestinal barrier (e.g. the choline metabolite trimethylamine), cholesterol metabolism, a major pathway that drives atherogenesis, is strongly influenced by the gut microbiota. In recent years, numerous studies have identified the gut microbiota as a relevant source of microbial-associated molecular patterns in plasma. These microbial signatures retain their biologic activity and promote chronic low-grade inflammation, influencing for instance steady-state myelopoiesis and turn-over of myeloid cells but also acting on host metabolic pathways that influence atherogenesis.\u2212/\u2212Ldlr) atherosclerosis mouse model, we tested the microbiota's role in the development of atherosclerotic lesions and arterial thrombosis. Given the complexity of the gut microbial ecosystem, it is evident that such gnotobiotic approaches are invaluable to causally pinpoint the influence of the gut microbiota on plasma cholesterol levels and the size and cellular composition of atherosclerotic lesions at defined diets and standardized feeding regimes. Hence, we fed GF \u2212/\u2212Ldlr mice with Western diet and compared them to conventionally raised (CONV-R) \u2212/\u2212Ldlr control mice, which were colonized by a microbiota from birth. Furthermore, these gnotobiotic mouse models are especially interesting to experimentally address whether the absence of microbiota impacts on arterial thrombus growth, the lethal complication arising from the rupture of atherosclerotic lesions.Using a germ-free (GF) low-density lipoprotein receptor-deficient , could in principle result in an extended phenotype of the gut microbial ecosystem that enhances cardiovascular risk.. Due to the non-absorbable properties of coprostanol in the small intestine, an inverse relationship exists between serum cholesterol levels and the coprostanol/cholesterol ratio in feces. It is known for many years that the conversion of cholesterol to coprostanol via biohydrogenation is mediated by cholesterol-reducing enzymatic activities of Eubacterium, Bifidobacterium, Lactobacillus and Peptostreptococcus strains, promoting cholesterol excretion. Furthermore, in the small intestine, the bile salt hydrolases from different gut bacterial genera deconjugate bile salts and reduce their solubility and reabsorption . By studying GF \u2212/\u2212Ldlr mice relative to their CONV-R \u2212/\u2212Ldlr counterparts, our study confirmed increased plasma cholesterol levels and elevated very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels in this GF \u2212/\u2212Ldlr hyperlipidemia model when mice were kept on chow diet. However, this difference was abolished when the \u2212/\u2212Ldlr mice were fed a 0.2% cholesterol-rich diet for 16 weeks. This result was in line with earlier studies on GF apolipoprotein E-deficient (\u2212/\u2212Apoe) mice that also showed increased plasma cholesterol levels at chow diet conditions, but not at Western diet feeding, when compared to CONV-R controls, demonstrating unequivocally the cholesterol lowering impact of the gut microbiota. Hence, the targeted modulation of gut microbial communities towards communities with enhanced cholesterol biohydrogenation capacity and bile salt hydrolase activity could in the future hold promise for new cholesterol-lowering therapies.Atherogenesis is primarily driven by elevated plasma cholesterol levels and an altered lipoprotein profile. Cholesterol absorption takes place in the upper small intestine. Various experimental and analytical approaches have comprehensively shown that the conversion of cholesterol to the more hydrophilic coprostanol essentially depends on established gut microbial communities \u2212/\u2212Ldlr mouse model addressed whether the presence of gut microbiota affects the development of carotid artery lesions. Although we found myeloid blood cell counts significantly reduced in hyperlipidemic GF \u2212/\u2212Ldlr mice and lower counts of adherent leukocytes to the vessel wall of carotid artery plaques, relative carotid artery plaque areas did not differ between late atherosclerotic GF \u2212/\u2212Ldlr mice and their CONV-R \u2212/\u2212Ldlr counterparts. This could be explained by the relatively late time point of our atherothrombosis study (16 weeks of Western diet). Alternatively, the unchanged plasma cholesterol levels and lipoprotein profile of late atherosclerotic GF and CONV-R \u2212/\u2212Ldlr mice might be due to the relatively high cholesterol content (0.2%) of the Western diet. Future studies should therefore test standardized diets with lower cholesterol content and analyze whether the absence of the gut microbiota affects the time course of atherogenesis in the \u2212/\u2212Ldlr mouse model. Based on our results, further in-depth analyses of gnotobiotic mouse models on atherosclerotic lesion size and plaque composition are required to pinpoint whether the cholesterol-lowering impact of the gut microbiota or the pro-inflammatory roles of gut-resident commensals can influence the onset and time course of atherogenesis.As elevated plasma cholesterol levels are a critical determinant for the progression of atherosclerotic lesions, our study on the GF \u2212/\u2212Ldlr mice relative to CONV-R \u2212/\u2212Ldlr mice in standardized flow chamber experiments with anticoagulated whole blood . Interestingly, we observed a diminished exposure of the platelet activation marker phosphatidylserine on the outer leaflet of the platelet membrane of GF \u2212/\u2212Ldlr mice in this standardized flow chamber model. Thus, our data indicate that at Western diet feeding conditions, the presence of gut microbiota promotes adhesion-dependent platelet activation. This observation is largely coherent with recent studies from other laboratories that have linked the gut microbiota with diet-dependent platelet hyperreactivity and demonstrated that fecal microbiota transplantation potentially can influence procoagulant function.As atherosclerotic lesions in the carotid arteries are a frequent cause of stroke, our study put focus on atherothrombosis, the lethal complication of atherosclerosis. In our previous work, we have shown that the gut microbiota promotes carotid artery thrombosis even at chow diet conditions. In addition to the carotid artery ligation model that has revealed reduced platelet deposition to exposed subendothelial matrix in GF relative to CONV-R C57BL/6J mice at chow diet conditions, our recent study demonstrated that GF C57BL/6J mice kept on chow diet also show significantly reduced occlusion times in the ferric chloride injury model of carotid artery thrombosis. At chow diet conditions, pattern recognition of microbiota-derived ligands by hepatic endothelial cells influenced arterial thrombus growth through modulation of hepatic endothelial von Willebrand factor (VWF) synthesis and VWF plasma levels. In contrast, at Western diet conditions, the adhesion-dependent platelet deposition to type III collagen, a major constituent of atherosclerotic lesions, was significantly reduced in GF \u2212/\u2212Ldlr mice and results in a platelet phenotype of increased phosphatidylserine exposure . A number of recent studies have linked the microbiota with metabolic functions that promote platelet reactivity and arterial thrombosis, e.g. by the microbiota's positive impact on the host serotonin biosynthesis pathway or the conversion of choline to trimethylamine. Our study provides an alternative role of the gut microbiota in the modulation of platelet function, as we could show in a standardized flow chamber model that the extent of phosphatidylserine exposure in the platelets of hyperlipidemic \u2212/\u2212Ldlr mice was dependent on the presence of the commensal microbiota. Since at low cholesterol nutrition the gut microbiota protects the host from high blood cholesterol levels, mechanistic insights on how the metabolic capacity of specific community members affects arterial thrombosis might in the future turn out instrumental to develop new therapeutic interventions based on nutrition, prebiotics or the selective inhibition of metabolic functions of gut microbes to prevent cardiovascular risk.Collectively, our study argues for a prothrombotic role of the microbiota under hyperlipidemic Western diet conditions that is due to enhanced adhesion-dependent platelet activation on type III collagen in colonized"} +{"text": "Home-delivered meals (HDMs) provided through the Older Americans Act (OAA) are intended to reduce hunger, promote socialization, and maximize wellness. However, HDM recipients are at increased likelihood of being hospitalized due to their complex health needs and risk for social isolation and depression. Drawing data from the OAA-HDM National Survey, we evaluated the predictors of hospitalization among HDM recipients in 2017. From our sample (n = 578), we conducted random forest classification analyses to identify the most important risk factors related to HDM recipient hospitalization. Our random forest model yielded an accuracy rate of 66.3% with risk factors most indicative of hospitalization being attributed to number of co-morbidities, depressive symptoms, and feelings of social isolation. These findings indicate that although HDMs may help alleviate hunger among older adults, innovate strategies are warranted to address the unmet mental health needs of HDM recipients."} +{"text": "Senescent cells drive aging. Preclinical studies suggest that targeted elimination of senescent cells offers a unique therapeutic approach to counter numerous chronic diseases and geriatric syndromes. To foster the translation of basic science discoveries to clinical application, we have sought to identify circulating biomarkers that reflect systemic senescent cell burden. We first analyzed the secretome of multiple senescent human cell-types and developed a candidate panel of proteins that could be reliably measured in human blood. Multiple proteins demonstrated significant associations with chronological age in a community-based cohort of adults aged 20-to-90 years. Impressively, in two distinct surgical cohorts (severe aortic stenosis and ovarian cancer), candidate protein concentrations were associated with biological age indices, including frailty and adverse outcomes. Our data suggest senescence biomarkers may have utility for clinical practice as indicators of risk, and for clinical research as surrogate endpoints in trials of interventions targeting senescent cells."} +{"text": "Throughout a marriage, couples will share countless ordinary moments together, such as laughing together or engaging in leisure activities. Although these moments may seem trivial in isolation, research suggests that accumulating small positive moments together helps couples build emotional capital, which serves as an essential resource for protecting marriages from the harmful consequences of relationship challenges. This study explored whether emotional capital may buffer couples not only from the negative effects of relational stressors, but also from the negative effects of life stressors encountered outside the relationship in a sample of younger (age 30-45) and older (age 60+) married couples. Drawing from theories of socioemotional expertise, we also examined whether the buffering effects of emotional capital may be stronger for older adults. One hundred forty-five couples completed a 21-day daily diary task assessing shared positive experiences with the partner, negative partner behaviors, marital satisfaction, life stress, and mood. Spouses who generally accrued more shared positive moments with their partner across the diary days maintained greater marital satisfaction on days of greater partner negativity compared to spouses who accrued fewer positive moments. Moreover, spouses who generally accrued more shared positive moments with their partner across the diary days also reported lower levels of negative mood on days in which they experienced more life stress compared to spouses who accrued fewer shared positive moments; in both cases, the buffering role of emotional capital was significantly stronger for older adults. All results held when adjusting for relationship length and general marital happiness."} +{"text": "Prediction of transcription factor (TF) binding from epigenetics data and integrative analysis thereof are challenging. Here, we present TEPIC 2 a framework allowing for fast, accurate and versatile prediction, and analysis of TF binding from epigenetics data: it supports 30 species with binding motifs, computes TF gene and scores up to two orders of magnitude faster than before due to improved implementation, and offers easy-to-use machine learning pipelines for integrated analysis of TF binding predictions with gene expression data allowing the identification of important TFs.https://github.com/SchulzLab/TEPIC and can be used on Linux based systems.TEPIC is implemented in C++, R, and Python. It is freely available at Bioinformatics online. TEPIC 2 builds upon and extends the functionality of existing TFBS prediction tools. Among other features, TEPIC 2 allows the direct aggregation of TFBS predictions on the gene level and uses these scores to gain novel insights on cell type specific functions of TFs via several machine learning analysis. This is a unique feature not supported by competitive TFBS prediction approaches are key players of transcriptional regulation. Prediction of TF binding is essential to gain a deeper understanding of their function. While experimental identification of TF binding is possible through laborious and expensive ChIP-seq assays, several computational approaches have been proposed to identify TF binding sites (TFBSs) . DYNAMITE has been successfully applied to discover regulators of CD4+ T cell differentiation (EPIC-DREM), which was used to analyze mesenchymal stem-cell differentiation of osteoblasts and adipocytes . DetailsTEPIC 2 is a fast and easy-to-use tool for TFBS prediction combined with integrative analysis capabilities for gene expression and epigenomic data. TFBS prediction and downstream machine learning pipelines for various analysis settings allow a deep, seamless exploration of epigenomic datasets supporting data driven hypothesis generation about the role of individual TFs in complex regulatory landscapes.Supplementary MaterialClick here for additional data file."} +{"text": "Transcranial magnetic stimulation (TMS) is among a growing family of noninvasive brain stimulation techniques being developed to treat multiple neurocognitive disorders, including Alzheimer\u2019s disease (AD). Although small clinical trials in AD have reported positive effects on cognitive outcome measures, significant knowledge gaps remain, and little attention has been directed at examining the potential influence of TMS on AD pathogenesis. Transcranial magnetic stimulation (TMS) is among a growing family of noninvasive brain stimulation techniques being developed to treat multiple neurocognitive disorders, including Alzheimer\u2019s disease (AD). Although small clinical trials in AD have reported positive effects on cognitive outcome measures, significant knowledge gaps remain, and little attention has been directed at examining the potential influence of TMS on AD pathogenesis. Our review briefly outlines some of the proposed neurobiological mechanisms of TMS benefits in AD, with particular emphasis on the modulatory effects on excitatory/inhibitory balance. On the basis of converging evidence from multiple fields, we caution that TMS therapeutic protocols established in young adults may have unexpected detrimental effects in older individuals or in the brain compromised by AD pathology. Our review surveys clinical studies of TMS in AD alongside basic research as a guide for moving this important area of work forward toward effective treatment development. There is an urgent need for the development of new, effective strategies in the battle against Alzheimer\u2019s disease (AD). Transcranial magnetic stimulation (TMS) has emerged as a promising possibility, but evidence regarding long-term efficacy and mechanism of action is limited. Among the major unresolved issues, findings linking the effects of TMS on excitatory/inhibitory balance with mechanisms of AD pathogenesis merit careful consideration. Our survey of clinical TMS studies in AD alongside basic research aims to move the area forward toward effective treatment development using noninvasive brain stimulation.Alzheimer\u2019s disease (AD), the most common form of dementia, is characterized by progressive memory impairment and associated decline in multiple cognitive domains, ultimately leaving patients incapacitated. Inexorably eroding the lifetime of memories that defines us, AD robs patients of their unique identity. The neuropathological hallmarks of AD prominently include microscopic foci of degenerating neurites and extracellular amyloid \u03b2-protein (A\u03b2) deposition, together with intracellular aggregates of hyperphosphorylated tau protein that disrupt microtubule organization . The sinCurrently approved pharmacological treatments for AD offer limited symptomatic relief for some patients, and none alter the underlying progression of disease. While the search for new drugs with improved clinical efficacy is ongoing, increasing attention is focused on disease-modifying strategies aimed at bending the trajectory of aging toward healthy neurocognitive outcomes. Ideally, intervention would be initiated in at-risk individuals before the clinical expression of disease, during the decades-long prodromal phase thought to precede AD diagnosis. Noninvasive brain stimulation (NIBS) has generated considerable interest in this context. Prominently including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation, this family of related technologies shares a generally well tolerated safety profile in healthy young adults and is currently under investigation for treating a growing list of potential indications .Among the various types of NIBS, TMS has received the greatest attention in clinical research on neuropsychiatric disorders. The mechanistic basis of TMS benefits is poorly understood, but there is general agreement that cortical excitability can be persistently modified by the repetitive delivery of a high-intensity magnetic field, generated by passing electrical current through an inductive coil. Repetitive TMS (rTMS), delivered in daily hour-long sessions over the course of several weeks was approved by the US Food and Drug Administration (FDA) for the treatment of pharmacologically refractory depression in 2008. In general, trials of rTMS treatment versus sham showed significant improvement in depression scores and lower rates of remission with rTMS , benefitDeveloping NIBS as a potential intervention for any clinical indication critically involves the choice of an appropriate stimulation protocol. Generally, rTMS protocols are operationally classified as \u201clow frequency\u201d or \u201chigh frequency,\u201d and \u201cconventional\u201d or \u201cpatterned.\u201d Low-frequency typically refers to stimulation rates \u22641 Hz, whereas rates \u22653 Hz are considered high frequency . In conventional protocols, single TMS pulses are applied in a regular rhythm; in patterned rTMS, short, high-frequency bursts are interleaved with brief periods of no stimulation. Some examples of patterned rTMS include stimulation mimicking theta activity, wherein short bursts of high-frequency pulses repeated at 5 Hz [theta burst stimulation (TBS)] are delivered as continuous TBS or intermittent TBS (iTBS) pulses. Perhaps most important with respect to the clinical effects of stimulation, low-frequency rTMS protocols are understood to result in cortical suppression and inhibition, whereas high-frequency stimulation increases cortical facilitation and excitability . Beyond Initial studies of rTMS effects in AD focused on high-frequency protocols almost exclusively , 2008. OStudies directly comparing cognitive outcomes following high-frequency versus low-frequency stimulation in patients with AD were first reported in 2012. In one investigation, 20 or 1 Hz rTMS was delivered bilaterally over the dlPFC in participants with mild or severe dementia . High-frEncouraged by this background, together with the much larger literature of experimental studies in normal participants , stimulaComplementing these findings, rTMS-COG in a group of probable AD case patients reportedly produced statistically significant or numerical improvement relative to baseline, as assessed by a variety of standard measures , either immediately or 6 weeks after the intervention protocol . Effectswww.fda.gov, March 21, 2019, Neurological Devices Panel of the Medical Devices Advisory Committee: De Novo DEN160053). The following sections briefly consider some of the experimental design challenges in this area of research, and then turn to evidence concerning the neurobiological mechanisms that might mediate the effects of TMS. A comprehensive mechanistic review is available elsewhere were not considered. Studies examining rTMS-COG protocols have generally lacked groups receiving either rTMS alone or cognitive assessment without stimulation . However, the available evidence regarding clinical efficacy and mechanism of action is limited. The view developed here is that defining the neurobiological substrates responsible for the effects of TMS and other NIBS modalities will be critical for maximizing their efficacy and safety. We encourage a constructive, dispassionate evaluation of the evidence, aimed at establishing an informed platform for moving TMS and related strategies forward toward clinical application in AD.The possibility that a safe, noninvasive, and relatively low-cost treatment such as TMS might prove effective in the battle against AD has generated understandable excitement (The evidence summarized in this review highlights at least three conceptually distinct targets for TMS intervention in AD. in vivo imaging in patients receiving TMS are also needed. Efficacy in appropriately controlled, well powered trials remains to be confirmed, and longer-term cognitive outcomes established. At what stage in the progression of AD pathology will TMS be most effective? If TMS is used to target excitatory/inhibitory balance, at what frequency and in which brain regions, recognizing that such effects may be brain region specific (The need for effective strategies in the battle against AD grows ever more urgent. The disappointing outcome of recent clinical trials encourages the consideration of fresh perspectives, and in this context, NIBS has emerged as a novel alternative to pharmacological therapeutics and other interventions. The exciting potential of this approach, however, should not overshadow the important questions that remain unanswered. Among them, the safety profile established for other indications merits reconsideration in the context of neurobiological changes associated with AD, including hyperexcitability and epileptic activity, consistent with current safety guidelines . Studiesspecific ? Indeed,specific . The cha"} +{"text": "Hypomesus transpacificus) and Chinook Salmon (Oncorhynchus tshawytscha). Since many tidal wetland restoration projects are planned or have recently been constructed in the Delta, understanding the diversity and variability of wetland invertebrates that are fish prey items is of increasing importance. During this study, two different invertebrate sampling techniques were tested (leaf packs and sweep nets) in four habitat types within three different wetland areas to evaluate which sampling technique provided the most reliable metric of invertebrate abundance and community composition. Sweep nets provided a better measure of fish food availability than leaf packs and were better able to differentiate between habitat types. Generalized linear models showed submerged and floating vegetation had higher abundance and taxa richness than channel habitats or emergent vegetation. Permutational multivariate analysis of variance showed significantly different communities of invertebrates in different habitat types and in different wetlands, and point-biserial correlation coefficients found a greater number of mobile taxa associated with sweep nets. There were more taxa associated with vegetated habitats than channel habitats, and one area had more taxa associated with it than the other two areas. These results suggest that restoration sites that contain multiple habitat types may enhance fish invertebrate prey diversity and resilience. However, the effect of habitat diversity must be monitored as restoration sites develop to assess actual benefits to at-risk fish species.Restored tidal wetlands may provide important food web support for at-risk fish species in the Sacramento-San Joaquin Delta (Delta) of California, including Delta Smelt ( Tidal wetlands provide an important source of productivity to many estuaries worldwide, subsidizing the surrounding open-water areas with vascular plant detritus, phytoplankton, zooplankton, and nekton biomass \u20135. ProduOncorhynchus tshawytscha) and Delta Smelt (Hypomesus transpacificus) . Thi. Thi73].We found significant differences in macroinvertebrate communities that may be traced to habitat heterogeneity. This implies that constructing a diverse range of habitats, including emergent vegetation, floating vegetation, submerged vegetation, and open water, during tidal wetland restoration may increase the variety of invertebrates produced on the site. The difference in invertebrates between habitats is not surprising, as research in this and other systems have found large differences between habitats , 30, 71,A wider range of invertebrate prey may increase resiliency of at-risk fishes and the ecosystem as a whole. There are multiple ways a diverse ecosystem may respond to changes in taxon composition , but theSurprisingly, we found no significant differences in invertebrate catch between the two time periods (March versus May). This suggests that invertebrate abundance may remain somewhat constant throughout the spring, however further sample points are required before any conclusions can be drawn. Due to strong seasonal patterns in invertebrate communities found by other studies , 40, 85,Invertebrate community composition was highly variable within and between Delta wetlands. Sweep nets provided a simple, efficient way to sample the invertebrate community, and demonstrated that different areas and habitat types supported different groups of organisms. Measuring invertebrate abundance across all habitat types within a wetland will allow managers to evaluate the effectiveness of their restoration projects in providing food for at-risk fishes. Wetland restoration can benefit from incorporating multiple habitat types in each project to develop a diverse community of invertebrates. Furthermore, restoration projects in different areas may have different benefits, and a variety of restoration projects may provide greatest resilience for the aquatic food web and the at-risk fishes it supports.S1 Data(CSV)Click here for additional data file."} +{"text": "In the accompanying article, Horiuchi et al. (Biosci. Rep. (2019) 39(4), BSR20190213) evaluate the availability of apolipoprotein B-depleted serum for CEC assays. Using their recently developed immobilized liposome-bound gel beads (ILG) method, Horiuchi et al. demonstrate that apolipoprotein B-depleted serum obtained with poly ethylene glycol precipitation enables CEC assays to be easily and accurately introduced into laboratory medicine.Cholesterol efflux capacity (CEC), an important functional step in reverse cholesterol transport, is the main anti-atherosclerotic function of high-density lipoprotein (HDL). Assays that improve the determination of CEC Lack of symptoms for the risk prediction is one of the leading causes of death by cardio vascular disease (CVD). Serum HDL cholesterol (HDL-C) levels have long been shown to be a biomarker of CVD risk and is a powerful inverse predictor of CVD. Regular blood work estimating the HDL levels in addition to lipid metabolic profile is a guideline by American Heart Association and the National Cholesterol Education Program before administering drug therapies for coronary heart disease in United States. However, recent studies suggest that despite elevated HDL-C levels being consistent with atheroprotection, the causal relation between HDL levels and cardiovascular disease is not clear . Two cliin vitro measure of an individual\u2019s ability to efflux cholesterol [., macrophages in an ex vivo system that involves apolipoprotein B-depleted serum from the study participants, the assay acts as a good predictor of cardiovascular risk [Cholesterol efflux capacity is an lesterol . When aplar risk . CEC is lar risk ,7. This lar risk . The varviz., macrophages. The ex vivo system in a clinical set-up is not ideal as some clinical laboratories, especially in developing countries might lack cell culture, radioisotope handling or ultracentrifugation equipment and facilities. To address this dependency on infrastructure, authors developed a variation of CEC assay using immobilized liposome-bound gel beads whole serum/plasma; (ii) Apo B depleted serum (BDS); and (iii) pure HDL. Isolation of serum HDL by ultracentrifugation is the most prevalent method. However, the method demands special equipment and is time consuming. In addition, HDL fraction concentrated by ultracentrifugation may not always reflect the concentration of HDL in the serum . The conTo circumvent the ultracentrifugation step for preparation of apolipoprotein B (ApoB)-100 depleted serum, as the cholesterol acceptor, assay developed by Horiuchi et al., use polyethylene glycol (PEG) precipitation. HDL fraction obtained from PEG method (BDS) is indeed an effective alternative instead of using laborious ultracentrifugation method in a clinical setting. Human plasma lipoproteins are routinely fractionated using PEG-6000 ,13 and wTypically, CEC assay requires cells loaded with excess of radiolabeled cholesterol and a cholesterol acceptor (HDL). Instead of radioisotope labeling the assay developed by Horiuchi et al., employs fluorescently labeled cholesterol using boron-dipyrromethene (BODIPY) dye. Fluorescent intensity is measured by using microplate reader, which is routinely available in a clinical setting, to measure the CEC. Use of fluorescently labeled cholesterol instead of radiolabeled one can be a great choice for working in safe laboratory environment. However, testing the effect of BODIPY-cholesterol concentrations during ILG preparation methodology would be a good option.One of the limitations of the Horiuchi et al. study isBy changing three steps of CEC assay viz., (i) ILGs for cultured cells; (ii) fluorescently labeled cholesterol; (iii) PEG precipitated HDL, authors demonstrate that it sufficient to estimate CEC with a significant correlation with a conventional assay using foam cells derived from THP-1 macrophages. Here is a holistic approach in which an observation arising from using HDL fraction obtained from the simple PEG method as a cholesterol acceptor in CEC assay. Although there is change in cholesterol safe labeling and the quick method of isolation of HDL fraction, the cultured cells are the only choice for CEC assay until recently. Having artificial cells that is liposome containing fluorescent BODIPY-labeled cholesterol as a substitute for the cultured cells is an effective method in clinical laboratories."} +{"text": "Very few studies have compared oral health status between the US-born and foreign-born immigrant older adults. Using data collected among 430 Chinese older adults age 55+ residing in Hawai\u2019i, we examined the association between immigrant status and oral health related quality of life (OHQoL) and the moderating role of resilience in linking the association. Controlling for some key covariates, our study results show that US-born Chinese immigrant older adults had better OHQoL than their foreign born counterparts. Factors such as higher level of education (graduate degree or higher), better self-reported health status and no significant tooth loss were related to better OHQoL. The association between immigrant status and OHQoL was moderated by resilience. Specially, resilience was positively and significantly associated with OHQoL among U.S.-born older adults but not among the foreign-born ones. Our findings indicate the importance of immigration and resilience in shaping oral health outcomes among older Chinese Americans."} +{"text": "Chronic subdural hematoma (CSDH) is one of the most common neurological diseases, which mainly occurs among elderly people and usually develop after minor head injuries. Over the years, a simple burr hole evacuation of the hematoma has been accepted as the widespread method for most cases of CSDH, but acute parenchymal hemorrhage is a rare and deadly complication after surgery. We report three elderly cases of post-operative parenchymal hemorrhage and analyse the underlying factors and formulate relevant strategies in this article. Three advanced age patients had been admitted to our department with gradually increasing headache and limb activity disorder urgently and underwent an emergency operation of burr hole drainage of CSDH in frontal-temporal region after preoperative evaluations and examinations. Unfortunately, acute post-operative parenchymal hemorrhage occurred in three advanced age patients. Ultimately, the patients achieved satisfying outcome with no significant neurological deficit through conservative treatment. The exact mechanism of such uncommon complications are difficult to explain and remain poorly understood. Advanced age, hypertension, amyloidosis, high perfusion triggered by rapid hematoma release, cerebrospinal fluid (CSF) loss, oral anticoagulant, primary disease aggravation were the main mechanisms which were speculated in our report. Simultaneously, positive measures could be adopt to prevent this rare complication. Chronic subdural haematoma (CSDH) is one of the most common neurosurgical conditions and is especially prevalent among elderly individuals . BehavioCase 1: An 71-year-old male patient had been admitted to our department with two-week history of gradually increasing headache and slight limb activity disorder and a 2-month history of minor head trauma as a result of fall to the ground. Cranial CT revealed bilateral CSDH. There was hypertension and multiple lacunar infarction were the systemic diseases which were under normal control and asthma. Neurological assessment confirmed mental confusion and gait imbalance without focal deficits. The CT scan revealed a sizeable right chronic subdural hematoma which caused midline left shift loss, oral anticoagulant, primary disease aggravation. Although CSDH drainage is considered as a minimally invasive surgical approach, neurosurgeons must be aware of this rare and deadly event. Correction of coagulation function, control of blood pressure and treatment of primary diseases are essential in order to prevent such complications before operation. Careful and gentle evacuation of the subdural hematoma without excessive head rotation is suggested to avoid rapid shift of intracranial contents and local hyper transfusion during operation. Continuous electrocardiograph monitoring, repeated evaluation of neurologic conditions, prompt radiological assessment, positive therapy of primary disease, volume of drainage control strictly and the height of drainage tube adjustment are mandatory after operation. Above all, when the uncommon complication occurs, conservative treatment is recommended intensively unless enormous intracranial hematoma make the patients unconsciousness, even brain hernia. Unfortunately, evacuation of hematoma and decompressing craniotomy were only adopted to save lives accompanied by poor prognosis.The authors declare no competing interests."} +{"text": "Following publication of the original article , the autEnzyme adsorption comparison on lignin materials derived from acid and alkali pre-treated corn stover.To further understand the role of lignin materials in enzyme adsorption, we enzymatically hydrolyzed dilute acid pre-treated and dilute alkali pre-treated corn stover excessively to remove all the carbohydrates that are hydrolyzable by the enzyme cocktail applied. The obtained cellulolytic enzyme lignin (CEL) materials were used to investigate their enzyme adsorption kinetics Fig. , and theFurther to this, the authors reported an error in Fig. The corrected Fig."} +{"text": "Gaucher disease is an inherited metabolic disorder resulting in deficiency of lysosomal enzyme \u03b2-glucocerebrosidase causing the accumulation of abnormal macrophages (\u201cGaucher cells\u201d) within multiple organs, most conspicuously affecting the liver, spleen, and bone marrow. As the most common glycolipid metabolism disorder, it is important for radiologists encountering these patients to be familiar with advances in imaging of organ and bone marrow involvement and understand the role of imaging in clinical decision-making. The recent advent of commercially available, reliable, and reproducible quantitative MRI acquisitions to measure fat fractions prompts revisiting the role of quantitative assessment of bone marrow involvement. This manuscript reviews the diverse imaging manifestations of Gaucher disease and discusses more optimal quantitative approaches to ascertain solid organ and bone marrow involvement with an emphasis on future applications of other quantitative methods including elastography. Non-neuronopathic Gaucher disease most conspicuously involves bone marrow, liver, and spleen.Organ volumes are commonly used for disease severity and treatment response.Anatomic imaging is relatively insensitive to marrow infiltration in Gaucher disease.Quantitative marrow fat-fractions indicate musculoskeletal severity and show early treatment response.Elastography may aid in assessing fibrosis in Gaucher disease.GBA) gene identified to-date , 6522, 6Marrow infiltration manifests with low signal on T1-weighted imaging Fig.\u00a0. Early qNumerous semi-quantitative scoring methods have been developed to report overall extent of bone marrow involvement based on signal intensity alterations on MRI, each with specific objectives and limitations summarized in Table\u00a0Multiple quantitative factors have been proposed to objectively assess marrow involvement in Gaucher disease and are supported by histopathologic evidence of an inverse relationship between marrow glucocerebroside and triglyceride concentrations . Some ofCurrently, quantitative MRI-based fat fraction measurements have been applied to objectively assess marrow involvement in Gaucher disease. Quantitative chemical-shift imaging (QCSI) using Dixon-based techniques and MRS are both capable of reliably measuring bone marrow fat fraction \u201390. WorkThe importance of understanding developmental increases in marrow fat over the lifespan beginning first in the peripheral skeleton as well as normal variation in bone marrow fat fractions cannot be understated. Patient age, sex, and body mass index should be considered in the interpretation of these values, ideally in the context of normative data relevant to the measurement method , 96\u201398. DWI may also hold promise with some evidence of decreased vertebral marrow ADC reflecting increased cellularity corresponding with disease status . Last, iNuclear medicine studies are not routinely used for routine follow-up assessment of Gaucher disease at most institutions, although 99\u2009m-Tc-Sestamibi scintigraphy has been studied as an alternative means of quantifying bone marrow involvement with good agreement with MRI-based semi-quantitative scoring , 102. TrOne of the earliest skeletal manifestations of Gaucher disease type 1 in children is osteopenia . The devProgressive osseous involvement in type 1 Gaucher disease may begin with painful bone crises that may eventually result in osteonecrosis in about half of patients that may be attributed to packing of the marrow with Gaucher cells leading to thrombosis in situ within the marrow , 110. OsRadiographic detection of early osseous complications such as osteonecrosis and bone infarct may be difficult, often being occult on initial imaging with subsequent development periosteal reaction that may be confused with osteomyelitis (\u201cpseudo-osteomyelitis\u201d) , 67. FocGiven these limitations, assessment of acute osseous complications is best performed with initial radiographs followed by prompt MRI assessment . Bone crBone-related malignancies may be slightly more common in Gaucher disease, perhaps related to osteonecrosis as a predisposing factor. MRI may often be warranted for evaluation of discrete lytic lesions given the incidence of malignant bone lesions such as multiple myeloma, osseous lymphoma, sarcomas, and malignant epithelioid hemangioendothelioma \u2013120. ParAs with the liver, spleen, and bone marrow, Gaucher cells can infiltrate in the lungs, typically depositing within interstitial spaces. Such lung involvement is quite rare, more common in the neuronopathic type, nd not likely to occur as an initial manifestation of this disease . ReticulThere are multiple proposed etiologies for pulmonary hypertension in Gaucher patients. Pulmonary hypertension is attributable to perivascular infiltration of Gaucher cells or secondary to hepatic disease . An earlThe extent of cardiac involvement in Gaucher disease is uncertain with small numbers of mitral valve prolapse and valvular calcifications reported in a few patients with homozygous D409H mutations . Given tThere is a clear need for an objective and reproducible scoring system capable of assessing disease severity to standardize patient monitoring. While clinical scoring methods (PGS3 and GD-DS3) are useful tools for estimating disease severity, these scoring methods do not assess diffuse hepatic disease such as fibrosis, iron accumulation, fat infiltration, and portal hypertension, nor do they assess the full extent of asymptomatic marrow involvement with inclusion of only subjective imaging assessment of marrow involvement.While ultrasound is affordable and may be sufficient for the assessment of organ volumes and liver lesion screening, there is increasing use of MRI in Gaucher disease with most authorities considering MRI the standard of care , 45. As Diagnostic imaging of hepatic and splenic involvement should consist of sequences tailored for volumetric organ measurement and screening for focal lesions. In conjunction with these conventional acquisitions, MR elastography should be considered, when available, to provide non-invasive assessment of liver and splenic stiffness. While the role of elastography in the clinical management of hepatic fibrosis in Gaucher disease is not yet established, acquisition of organ stiffness measurements may afford insights into disease and treatment effects in the future with wider clinical adoption. It is important to note that elastography results should be interpreted in the context of known limitations including inaccuracy of gradient recalled echo(GRE)-based elastography in patients with iron deposition and massive ascites ; as suchNewer proton density fat fraction (PDFF) sequences allow for single breath-hold acquisition of the entire liver to provide triglyceride fat fractions, R2* mapping, and some also provide automated liver volumes \u2013128. TheSingle-voxel MRS for fat fraction measurement may also be considered as a supplement or alternative if PDFF sequences are not available. DWI is included in our protocol as it may also be provide indirect assessment of organ cellularity with ADC as a possible quantitative marker of disease severity .If suspicious focal lesions are noted on this surveillance evaluation, dedicated lesion work-up with dynamic hepatocyte-specific contrast-enhanced MRI, multiphase contrast-enhanced CT, or contrast-enhanced ultrasound should be recommended, depending on institutional resources , 130.Qualitative imaging of both the axial (lumbar spine) and appendicular skeleton is important for assessment of global marrow involvement, as these sites may respond differently to treatment . While aDiscrete parameters for the frequency of follow-up of Gaucher disease patients with imaging are informed by consensus recommendations and institution-specific practices , 133. CoAs part of clinical severity scoring and recommended care for patients, bone mineral density measurement is recommended beginning at 6\u00a0years of age with follow-up obtained every 1 to 2\u00a0years , 18, 31.Regional radiographic assessment of acute bone pain should be the first-line examination to assess for the presence of pathologic fracture . HoweverDecisions regarding routine imaging assessment of cardiac abnormalities with echocardiography and cardiac MRI are beyond the scope of this review with some authors recommending baseline echocardiographic screening in all ages at diagnosis and follow-up evaluation in adults on treatment , 122. ThConventional imaging of non-neuronopathic Gaucher disease underestimates multisystem organ involvement in Gaucher disease, and recent clinical and experimental evidence shows a significant role of multifaceted processes of inflammation, chemotaxis, iron deposition, and fibrosis, even in treated patients. Quantitative bone marrow fat fraction measurements have been touted as a reliable marker of skeletal involvement for treatment response assessment but have been relegated to selected academic medical centers previously. Newer commercially available quantitative MRI methods enable efficient quantification of liver, spleen, and bone marrow fat fraction values and a comprehensive imaging protocol is introduced in this article to take advantage of this opportunity to better characterize this complex disease and guide personalized therapy."} +{"text": "Social and behavior change approaches have shown promise for addressing the demand- and supply-side challenges in postabortion care. As implementers seek to improve the quality of postabortion care, systematically integrating long-standing models and emerging approaches, including behavioral economics, human-centered design, and attribute-based models of behavior change, can promote positive health outcomes. Social and behavior change approaches have shown promise for addressing the demand- and supply-side challenges in postabortion care. As implementers seek to improve the quality of postabortion care, systematically integrating long-standing models and emerging approaches, including behavioral economics, human-centered design, and attribute-based models of behavior change, can promote positive health outcomes. Unsafe abortion is the fifth leading direct cause of maternal deaths globally and in developing countries.Programmatic experience suggests that key behavior-related challenges in the delivery of high-quality PAC services arise before the PAC client reaches a facility, during her visit to a facility, and after she leaves a facility. These challenges include the followingBefore:Ensuring timely care seeking by women and their partnersDuring:Promoting respectful treatment of PAC clients by providers and addressing the stigma that specific client groups may experience in interactions with providersEnsuring that during counseling, providers address client needs for clear information about return to fertility and family planning options and acknowledge barriers to postabortion family planningEnsuring providers offer a full range of voluntary family planning methods prior to discharging the client, including long-acting reversible contraceptives and permanent methodsAfter:Supporting clients in returning to services to facilitate both voluntary contraceptive continuation and follow-up for clients whose treatment requires return visitsKey challenges in the delivery of high-quality PAC services arise before, during, and after a PAC client\u2019s visit to a facility.While additional formal evaluation of social and behavior change in the context of PAC is needed, lessons learned from programmatic experience in this and other areas of reproductive health suggest that intentional use of behavior change principles and approaches is necessary to address common challenges in PAC programming.,,Seeking care at the first sign of complication is essential to effective treatment of spontaneous and induced abortions. Facilitating timely care seeking requires attention to barriers to accessing services, which may be specific to a given context or client group. Lack of information about the warning signs of spontaneous abortion, dangerous complications of spontaneous and induced abortion, and where to seek PAC prevents women from seeking help.\u2013\u2013PAC programs have successfully intervened at the community level to address barriers to care seeking and reinforce supportive norms. In Kenya and Somalia, community education, training of community health workers and community preparedness have effectively increased awareness, acceptance, and utilization of PAC, including voluntary use of postabortion family planning.PAC programs have successfully intervened to address community-level barriers to care seeking and reinforce supportive norms.\u2013before emergency care is required. PAC programs must consistently apply proven practices in behavioral design, including systematic diagnosis of barriers to service utilization among key client groups. In addition to addressing the common barriers cited above, implementers should employ formative research approaches used in behavioral programming as a means to generate insights about client perceptions and motivations. In particular, immersive and participatory approaches grounded in human-centered design show promise as a means to better understand and address barriers to care seeking. Human-centered design is an iterative process that includes developing a deep understanding of the people affected by a problem, identifying opportunities for design to address that problem, prototyping potential solutions, and repeatedly testing and refining those prototypes.providers may treat clients with disrespect or restrict care due to norms or attitudes associated with abortion, sexuality, and sexual health among specific client groups; circumstances such as a subsequent abortion or failure to use family planning; and/or use of family planning after pregnancy loss.,\u2013providers may not adequately explain healthy spacing of pregnancy. The World Health Organization recommends women delay pregnancy for at least 6 months after an abortionproviders may not adequately explain return to fertility, which can occur within 2 weeks after a first trimester spontaneous or induced abortion.providers may fail to counsel PAC clients on the full range of family planning methods available to them and fail to offer these methods prior to discharging the client.,\u2013The client-provider interaction during health care provision represents a critical opportunity to build trust and establish healthy behaviors pertaining to family planning and reproductive health care seeking. Four distinct but interrelated challenges may influence the quality of care offered during a PAC client\u2019s visit to a health facility. Failing to prevent these challenges can ultimately hinder adoption of voluntary family planning methods that enable women and their partners to achieve their desired fertility. First, ,,,To prevent these challenges, PAC programming has successfully employed a range of approaches to influence provider behaviors pertaining to counseling PAC clients, particularly about postabortion family planning. Many PAC programs have integrated discussions of provider attitudes and values into trainings that seek to reduce stigma toward women and adolescents who need reproductive health services, dispel misconceptions about contraceptive methods, and build effective counseling skills. These discussions offer opportunities for providers to reflect on how their own values and beliefs influence their interactions with clients.PAC programming has successfully employed several approaches to influence provider behaviors in counseling PAC clients.PAC programs can build on the rapidly growing evidence base for provider behavior change as a means to improve not only the knowledge and skills that underpin effective counseling, but the full range of motivational and normative influences affecting providers. To do so, implementers must use formative research to analyze specific drivers of provider behavior. As with programs targeting PAC clients themselves, the insights derived from this research can inform segmentationBehavioral design may deepen the impact of traditional knowledge- and skills-based interventions to improve client-provider interaction.PAC programs can further improve the quality of client-provider interaction through continued attention to the drivers of client behavior, specificity in behavior change messaging, and promotion of client engagement during care and counseling. Counseling and other communication approaches should acknowledge and address barriers to postabortion family planning, including social norms regarding fertility and couples\u2019 communication.PAC programming must address challenges relating to support for voluntary contraceptive initiation or continuation and care for clients who require follow-up treatment. Clients who receive counseling and choose a voluntary family planning method may require assistance with accessing ongoing supplies of short-acting methods,Social and behavior change interventions within PAC programs enhance a client\u2019s follow-up care, including family planning, and reinforce linkages between the client\u2019s home and health care workers. Client communication materials facilitate follow-up care. Several international professional associations and development partners recommend that PAC clients should receive simple written instructions for the use of their method, along with concise information about common side effects and benefits.Social and behavior change interventions within PAC programs enhance a client\u2019s follow-up care.Mobile phone-based communication has shown promise to facilitate access to health information and services in low-resource settings. A randomized control trial in Cambodia found that follow-up communication through mobile phones supports postabortion contraceptive use. It helped women retain family planning information provided during PAC and prompted women who wanted a long-acting method but did not receive one during the initial PAC visit to return for an implant or intrauterine device.,,Evidence suggests that engaging the male partners of PAC clients in counseling, when acceptable to clients themselves, can improve health outcomes. PAC programs in Bolivia and Tanzania found that engaging partners by informing them of the client\u2019s condition and providing both with family planning counseling helped to ensure safe recovery and increased voluntary family planning continuation.In general, promotion of voluntary contraceptive continuation or return to services remains less understood than either creation of initial demand for services or improvement of client-provider interaction. Improved design and measurement of activities addressing behavioral initiation or maintenance after a client leaves a facility is an area of increasing collaboration between social and behavior change and service delivery professionals. The concerns of PAC program implementers constitute an important component of this discourse. The rapidly evolving thinking in this area affords PAC program implementers an opportunity to build upon emerging practices and develop innovative solutions to the challenges they face. For example, a growing body of gray literature pertaining to understanding and grouping similar behaviors and the attributes of those behaviors,We should build our understanding of how to address behavioral initiation or maintenance after a client leaves a facility.PAC programs have successfully used community-based social and behavior change approaches and provider behavior change interventions to support clients in accessing postabortion services and adopting voluntary family planning. To ensure that all women have access to high-quality PAC, implementers must build upon this important foundation through continued application of proven practices in behavior change, including formative research, audience segmentation, and the use of iterative, multichannel communication approaches that target clients, providers, and community members. Concomitantly, implementers should seize the opportunity to play a leading role in the application of social and behavior change approaches for PAC by leveraging new trends in behavioral economics, human-centered design, and attribute-based models of behavior change and increasing alignment between demand-side and supply-side programming."} +{"text": "Plant growth dynamics are shaped by the diversity of associating pathogenic, saprotrophic, and mutualistic soil fungi. Feedbacks between plants and soil microbial communities play an important role in vegetation dynamics, but the underlying mechanisms remain unresolved. Here, we show that the diversity of putative pathogenic, mycorrhizal, and saprotrophic fungi is a primary regulator of plant-soil feedbacks across a broad range of temperate grassland plant species. We show that plant species with resource-acquisitive traits, such as high shoot nitrogen concentrations and thin roots, attract diverse communities of putative fungal pathogens and specialist saprotrophs, and a lower diversity of mycorrhizal fungi, resulting in strong plant growth suppression on soil occupied by the same species. Moreover, soil properties modulate feedbacks with fertile soils, promoting antagonistic relationships between soil fungi and plants. This study advances our capacity to predict plant-soil feedbacks and vegetation dynamics by revealing fundamental links between soil properties, plant resource acquisition strategies, and the diversity of fungal guilds in soil. The accumulation of host-specific pathogenic fungi in plant rhizospheres has been identified as an important driver of negative density dependence in plant populations. These negative plant-soil feedbacks underlie plant species coexistence and positive diversity-productivity relationships . Physicochemical properties, such as cation exchange capacity, pH, and soil carbon (C), nitrogen (N), and phosphorus (P) concentrations, formed another axis of variation reflecting inherent soil fertility that was not significantly affected by conditioning with different plant species . Therefore, the experiment captured variation in soil abiotic properties resulting from both plant species conditioning and inherent variability in soil fertility at the site of soil collection. This enabled us to gauge the relative importance of both biotic and abiotic drivers of plant-soil feedbacks.Replicated monocultures of 14 common temperate grassland species, encompassing a broad spectrum of functional traits . After tR2 = 0.32, F13,41 = 2.9, P = 0.004) but not in the accumulation of specialist AM and saprotrophic fungi . Plant species identity had little influence on soil bacterial communities, which were primarily determined by soil abiotic conditions (fig. S1). The distinct effects of plant species on soil fungal communities became more pronounced when fungi were split into putative plant pathogens and saprotrophs released into the soil , but the effect was considerably weaker than that of the richness of putative pathogens and AM fungi . In support of this conclusion, variation in biotic feedback was more correlated with differences in the richness of putative pathogenic and AM fungi than with differences in the composition of these fungal groups . These findings provide compelling evidence that plant-soil feedback is regulated by the diversity of soil fungi and indicate that diversity effects of soil organisms are not only positive . Soil collected from the grassland site exhibited natural spatial heterogeneity in soil properties, and this variation was preserved when filling the mesocosms with soil collected randomly from across the grassland. Plant traits, soil abiotic properties, and microbial communities were measured for each mesocosm at the end of the conditioning stage were polymerase chain reaction amplified and used to characterize the microbial communities. The amplicons were sequenced on an Illumina MiSeq instrument with 2 \u00d7 151 base pair kits.Microbial community structure was determined as in . AM fungi were represented with 126 ESVs . Saprotrophs were represented by 338 ESVs . Detailed functional data are not currently available for soil bacteria and protists. We therefore only assessed the composition of bacterial and protist communities, and the relative abundance and richness of well-known pathogenic oomycete ESVs (Pythium and Phytophthora genera), as predictors of plant-soil feedbacks. We found that the composition of bacterial and protist communities was strongly correlated with that of saprotrophic fungi (table S2). Only the latter was included in the subsequent path analysis as a representative characteristic of overall microbial community composition.Exact sequence variant counts were determined from raw sequence data using the DADA2 pipeline . For each soil sample, the relative abundance, ESV richness, and exponential Shannon diversity (effective species number) were calculated for each fungal functional group and specialist and generalist sequences within each functional group. Asymptotic exponential Shannon diversity was calculated for each fungal group using the package iNEXT in R was characterized using principal coordinate analysis (using Bray-Curtis distances and Hellinger transformation of read abundance data). The first two principal coordinates for each fungal group and the first two principal component axes of plant traits and soil abiotic properties were used as predictors of plant-soil feedback in the analysis described below. The importance of plant species identity and the first principal component of abiotic soil properties in explaining variation in plant traits and soil microbial properties was analyzed using variance partitioning for univariate traits (comparison of linear fixed-effects models) and redundancy analysis for multivariate data [package vegan, function dbrda in R 3.4.0 (The best predictors of soil feedback were selected on the basis of Akaike information criterion (AIC) from five groups of variables: plant traits, soil abiotic properties, and soil fungal community properties . Each variable was tested in a separate linear model as a predictor of soil feedback, and predictors yielding the lowest AIC scores within each variable set were retained for use in the path analysis to explore possible paths by which plant traits and soil properties jointly affect soil feedback (table S1). Additional variables explaining more than 10% of variation in the feedback index, and not strongly correlated with the best predictor within each variable group, were also included in the path analysis. Within the set of abiotic soil properties, many variables were highly correlated and aligned closely with the first principal component. Hence, the latter was included in the path analysis to reflect the major axis of variation in abiotic soil properties. For the analysis of specific feedback, AIC scores with a sample size of 55 were calculated, as our dataset contained 55 mesocosms in the conditioning stage, representing true replicates in plant trait and soil measurements.P values higher than 0.1 were sequentially dropped (table S4).Path analysis was used to test whether fungal communities in conspecific and heterospecific soil affected plant-soil feedback and whether soil abiotic properties and plant traits have a direct or microbially mediated indirect effect on plant-soil feedback. Plant traits could be affected by soil abiotic conditions [i.e., phenotypic plasticity . For conspecific soil properties, paths significant at To confirm that the diversity of putative pathogens and AM fungi were better predictors of biotic feedback than differences in fungal composition, Mantel tests were performed to assess the correlation between biotic feedback and fungal composition (based on Bray-Curtis distances and Hellinger-transformed data). The strength of this correlation was compared to the correlation between biotic feedback and fungal diversity obtained from the analogous Mantel test.To test for the sensitivity of specific soil feedback to variation in soil fungal composition, pairwise dissimilarities between individuals of each species grown in conspecific versus heterospecific soils were calculated using log-transformed biomass and fungal sequencing data. Microbial dissimilarity was calculated as the Bray-Curtis distance based on the relative abundance data with Hellinger transformation [package vegan, function vegdist in R 3.4.0 ("} +{"text": "Habitat contamination can alter numerous biological processes in individual organisms. Examining multiple individual-level responses in an integrative fashion is necessary to understand how individual health or fitness reflects environmental contamination. Here we provide an example of such an integrated perspective based upon recent studies of an amphibian that experiences several, disparate changes when larval development occurs in a trace element\u2013contaminated habitat. First, we present an overview of studies focused on specific responses of individuals collected from, or transplanted into, a habitat contaminated by coal combustion residues (CCR). These studies have reported morphological, behavioral, and physiological modifications to individuals chronically interacting with sediments in the CCR-contaminated site. Morphological abnormalities in the oral and tail regions in contaminant-exposed individuals influenced other properties such as grazing, growth, and swimming performance. Behavioral changes in swimming activities and responses to stimuli appear to influence predation risk in the contaminant-exposed population. Significant changes in bioenergetics in the contaminated habitat, evident as abnormally high energetic expenditures for survival (maintenance) costs, may ultimately influence production pathways in individuals. We then present a conceptual model to examine how interactions among the affected systems may ultimately bring about more severe effects than would be predicted if the responses were considered in isolation. A complex interplay among simultaneously occurring biological changes emerges in which multiple, sublethal effects ultimately can translate into reductions in larval or juvenile survival, and thus reduced recruitment of juveniles into the population. In systems where individuals are exposed to low concentrations of contaminants for long periods of time, research focused on one or few sublethal responses could substantially underestimate overall effects on individuals. We suggest that investigators adopt a more integrated perspective on contaminant-induced biological changes so that studies of individual-based effects can be better integrated into analyses of mechanisms of population change."} +{"text": "Relationships with adult children play an important role in older adults\u2019 well-being. However, little is known about the association between parent-child relations and aging parents\u2019 sleep quality, which is an emerging health issue that is closely related to individuals\u2019 physical and mental well-being in later life. With the largest aging population, China has experienced rapid changes of family structure and traditional norms regarding parent-child ties. This study focused on different dimensions of parent-child relationships in Chinese aging families. This study examined the association between parent-child relationships and older parents\u2019 sleep quality, comparing one-child and multiple-children Chinese families. Utilizing the 2014 wave of the Chinese Longitudinal Aging and Social Survey, we analyze data from 8,450 respondents (aged 60+) who had at least one living child. Descriptive analysis showed that parents with multiple children engaged in more intense financial exchanges, less frequent instrumental support, and lower levels of emotional closeness with their adult children compared to their counterparts with only one child. Logistic regression models revealed that older parents who received more instrumental support were more likely to report sleep difficulty in both one-child and multiple-children families. For parents with multiple children, the overall level of financial transfers from children was negatively associated with having sleep difficulties, while the variability of financial transfers across multiple children was positively associated with having sleep difficulty. Findings highlight the importance of considering family dynamics in studying sleep quality among Chinese older adults."} +{"text": "To review recent studies investigating hypothalamic-pituitary-adrenal axis function in children and adolescents with disruptive behavior disorders (DBDs) and adults with antisocial personality disorder. We consider key concepts and methodological issues in cortisol assessment and review studies investigating basal cortisol secretion and stress reactivity in antisocial populations. Lastly, we consider whether cortisol abnormalities predict prognosis or treatment outcomes and the impact of exposure to adversity on hypothalamic-pituitary-adrena (HPA) axis activity.Studies tracking cortisol levels across the day and assessing cortisol awakening responses (CARs) have reported broadly intact, but flatter, diurnal rhythms and lower CARs in children and adolescents with DBDs, whereas findings in antisocial adults have been mixed. Cortisol hyporeactivity to stress is consistently reported in male antisocial populations, whereas no comparable data exist in females.Severe antisocial behavior is associated with cortisol hyporeactivity to stress, and such hyporeactivity predicts poor treatment outcomes. Further research investigating sex differences and the impact of adversity is needed. Harmonization of methods for assessing hypothalamic-pituitary-adrenal axis function and antisocial behavior would enhance progress in this area. In this article, we review recent research on hypothalamic-pituitary-adrenal (HPA) axis function in child and adult antisocial populations, focusing particularly on conduct disorder (CD) in children and antisocial personality disorder (ASPD) and psychopathy in adults. To test theories proposing that low physiological arousal or hyporeactivity is causally related to the etiology of antisocial behavior, researchers have investigated whether CD or ASPD is associated with lower basal cortisol levels or blunted cortisol responses to stress. We start by providing an overview of the HPA axis and its functions, and outline key methodological developments in this area. We then review evidence for disturbances in basal cortisol secretion and cortisol hyporeactivity in children and adolescents with CD and disruptive behavior disorders (DBDs) more generally . We subsequently consider studies on cortisol secretion under basal conditions and stress reactivity in adults with ASPD or psychopathy. Finally, we discuss whether HPA axis abnormalities predict treatment outcomes or normalize following successful treatment, and also whether such abnormalities reflect the consequences of exposure to early adversity which is frequently present in these individual backgrounds.The HPA axis is the main physiological system which mediates the body\u2019s stress response. The paraventricular nucleus of the hypothalamus releases corticotrophin-releasing hormone in response to threat signals from brain regions such as the amygdala . CorticoGiven this rhythmicity and physiological response to waking, it is important to assess patterns of cortisol secretion across the day (including the CAR) when assessing whether individuals with psychiatric disorders display HPA axis abnormalities. However, relatively few studies on antisocial behavior have adopted such methodological approaches, instead largely relying on single-point determinations of cortisol levels . In fact, rather than just assessing cortisol several times within the same day, some researchers have argued that cortisol should be measured over multiple days to yield robust findings . It is aIn the following sections, we consider recent studies investigating diurnal cortisol secretion and the CAR, as well as cortisol reactivity to stress, in children and adolescents with DBDs and adults with ASPD or psychopathy. Given that the ASPD diagnostic criteria require the individual to have had CD prior to age 15 , substanIn an important early study, Popma et al. (2007) investigated diurnal cortisol secretion and the CAR in adolescent boys attending a delinquency diversion program, comparing those with and without DBD diagnoses with healthy controls \u2022. AlthouFairchild et al. (2008) adopted a similar design, investigating diurnal cortisol rhythms and the CAR over three consecutive days in males with either childhood-onset or adolescence-onset CD and healthy controls. The aim was to assess whether cortisol abnormalities were specific to childhood-onset CD . There were no significant group differences in morning cortisol levels or CAR magnitudes, although evening cortisol levels were elevated in both CD subgroups, consistent with a flatter diurnal rhythm overall \u2022.n\u2009=\u200936) and typically developing boys (n\u2009=\u200936). Although broadly similar cortisol diurnal rhythms were observed in both groups, there was some evidence for an attenuated CAR and lower cortisol levels at 12:00\u00a0h in the CD group. When the childhood-onset CD group was split into those with versus without callous-unemotional (CU traits), the CD/CU+ group showed a smaller CAR than the controls, although there were no group differences in diurnal cortisol secretion [Extending this work, von Polier et al. (2013) investigated the CAR and diurnal rhythm in boys with childhood-onset CD of detained adolescents and healthy controls . The authors assessed the impact of CU traits and impulsivity to examine whether low cortisol was specifically associated with CU traits. There were no group differences in overall cortisol secretion or diurnal slope, and no significant associations between CU traits or impulsivity and cortisol levels. However, the study relied on self-report measures of CU traits and impulsivity did not assess the CAR, and the \u2018healthy control\u2019 group included participants with subclinical levels of CD symptoms.Another recent study investigAlthough they did not use categorical CD/ODD diagnoses, Ruttle et al. (2011) and Salis et al. (2016) examined concurrent and longitudinal associations between externalizing behavior and cortisol secretion in children. Ruttle et al. (2011) found that externalizing behavior was related to blunted cortisol rhythms, both concurrently and longitudinally, but the longitudinal associations with cortisol were stronger \u2022. This iIn another important study, Platje et al. (2013) examined longitudinal relationships between the CAR and aggressive and rule-breaking behavior in a large community sample of adolescents. Persistently elevated aggression was associated with smaller CARs over a 3-year period, whereas there was no association between rule-breaking behavior and CAR magnitudes \u2022\u2022, suggecortisol reactivity to stress in children and adolescents with DBDs. These studies have yielded a more consistent pattern of results\u2014particularly those using effective stressors such as the trier social stress test for children Trier Social Stress Test for Children (TSST-C) or the frustration/provocation task.Having reviewed recent work investigating basal cortisol secretion, we now consider studies examining Van Goozen and colleagues , 21 condPopma et al. (2006) investigated cortisol and subjective responses to stress in adolescents referred to a delinquency diversion program, with versus without DBD diagnoses, and a healthy control group. The DBD+ group again showed lower cortisol responses to stress than the controls, despite displaying the expected increase in negative mood . On the n\u2009=\u2009165), but was limited by relying on retrospective reports regarding the age-of-onset of CD (thus some participants may have been misclassified), and did not investigate the impact of CU traits on cortisol reactivity.Fairchild et al. (2008) extended this work by examining whether cortisol hyporeactivity to stress was specific to childhood-onset CD. The authors compared male adolescents with childhood-onset and adolescence-onset forms of CD and a healthy control group. Both CD subgroups showed attenuated cortisol (and cardiovascular) responses to stress compared with controls, despite reporting strong increases in negative feelings during the experiment, which used the frustration/provocation task \u2022. This sStadler et al. (2011) addressed the latter issue when examining cortisol reactivity to stress in a sample of children with a primary diagnosis of ADHD, many of whom had comorbid DBDs, by splitting their sample into those with high versus low levels of CU traits. The participants with elevated CU traits showed weaker cortisol responses to the TSST-C than the low CU traits subgroup, even though these subgroups did not differ in subjective mood responses . Unfortucortisol recovery following stress. Lower basal cortisol levels were observed in the pure ODD/CD group alone. No differences in cortisol reactivity were observed between the ODD/CD and control groups, although CD symptoms were inversely related to reactivity on a dimensional level and ODD/CD + ANX participants tended to show higher cortisol reactivity than their pure ODD/CD counterparts [cortisol recovery following stress, and distinguishing between those with and without comorbid anxiety disorders. It suggests that failing to take account of internalizing comorbidity might explain some of the inconsistent findings in the DBD literature. Hartman et al. (2013) provided further evidence to support this notion by studying a large, mixed-sex sample of adolescents with preadolescent externalizing or internalizing diagnoses. Self-reported internalizing symptoms predicted greater cortisol secretion, whereas self-reported externalizing symptoms predicted lower cortisol secretion under stressful conditions [Recent studies have examined the impact of common comorbidities on cortisol reactivity to stress in CD. Schoorl et al. (2016) compared boys with ODD/CD alone and ODD/CD plus comorbid anxiety disorders (ODD/CD + ANX) in terms of basal cortisol, cortisol reactivity to stress, and terparts \u2022. Finallnditions . Associan\u2009=\u200995) and those with ADHD+CD (n\u2009=\u2009107) in terms of basal cortisol levels and cortisol reactivity to stress. There were no differences between these groups in basal cortisol, whereas the ADHD+CD group showed blunted cortisol reactivity to stress relative to the ADHD-only group [positively related to baseline cortisol, but negatively related to cortisol reactivity to stress. CU traits were not significantly related to either cortisol measures. This study provides further evidence that ADHD is not associated with cortisol reactivity in its own right, rather, it is CD/ODD that leads to cortisol hyporeactivity.In another interesting study, Northover et al. (2016) compared male children and adolescents with pure ADHD are associated with cortisol hyporeactivity to stress . Such hyporeactivity is observed in children and adolescents and appears to be present in both childhood-onset and adolescence-onset forms of CD. As some studies have indicated that CU traits may be an important determinant of cortisol hyporeactivity, whereas others have shown no impact of CU traits, an important issue for future research is whether CD symptoms or CU traits are more influential in determining cortisol reactivity. This should be addressed in both clinical samples in which the full range of CD symptoms and CU traits are observed and in high-risk and community samples. The statistical analyses should also test whether CD symptoms and CU traits exert effects in opposite directions . Furthermore, as previous studies focused largely on males, cortisol diurnal rhythms and stress reactivity should be investigated in females with DBDs and varying levels of CU traits.Cima and colleagues (2008) investigated morning and afternoon cortisol secretion in male psychopathic and nonpsychopathic prisoners and a healthy control group . All three groups showed a normal diurnal profile, with cortisol levels being significantly higher in the morning than in the afternoon. Neither prisoner group differed from controls at any time-point, but the nonpsychopathic prisoners had higher cortisol levels than the psychopathic prisoners at two of the four time-points (8:00 and 14:00\u00a0h), suggesting hyperarousal in the former group \u2022. HoweveSimilarly to Cima, Loomans et al. (2016) measured the CAR and afternoon and evening cortisol levels in male psychiatric inpatients and two healthy comparison groups . The authors investigated whether diurnal cortisol rhythms could differentiate between ASPD and psychopathic patients, and also between those with personality disorders and the general population. No differences in cortisol secretion between the personality-disordered groups were found, whereas both the ASPD and psychopathic groups tended to show higher cortisol levels than the general population sample . This wan\u2009=\u200949) [A few studies have investigated relationships between psychopathic traits and cortisol reactivity to stress. For example, Johnson et al. (2015) assessed baseline cortisol levels and cortisol responses to the TSST in young adult male offenders (n\u2009=\u200949) . There wn\u2009=\u200949) , whereasn\u2009=\u200949) . A limitpositive associations. Nevertheless, studies with stronger methodological designs (including measurements of the CAR) are needed to draw firmer conclusions and investigate which aspects of the diurnal profile are affected.The majority of the studies described above investigated HPA axis activity in males alone. However, both sexes may display severe antisocial behavior and it is therefore important to consider similarities and differences between the sexes. Studies examining relationships between basal cortisol and CD symptoms in community samples have yielded mixed results, with Young et al. (2012) finding a positive association between CD symptoms and salivary cortisol levels in females, whereas a nonsignificant negative association was observed in males . SimilarIn terms of cortisol reactivity to stress, Kobak et al. (2009) found that sex moderated associations between antisocial behavior and cortisol responses to conflict discussions with caregivers in a community sample of adolescents . SpecifiAn early study by van der Wiel et al. (2004) investigated this important issue, examining whether cortisol reactivity to stress predicted treatment response in boys with oppositional defiant disorder. Lower cortisol reactivity at baseline predicted higher posttreatment aggression levels , suggestMore recently, Schoorl et al. (2017) investigated whether cortisol reactivity to stress or recovery after stress predicted outcomes in boys with DBDs who were treated using a parent training intervention. Boys who showed higher reactivity and more pronounced recovery following stress at baseline showed greater reductions in aggression over a 1-year period . Althougadaptation to early life stress or chronic adversity that would otherwise overwhelm the HPA axis and lead to neurotoxic effects of elevated stress hormones on the developing brain [An important question is whether cortisol hyporeactivity to stress or lower CARs in those with antisocial behavior are genetically determined or whether such abnormalities represent an ng brain \u2022\u2022. Exposng brain , 41, andng brain \u2022. It theng brain , may undng brain \u2022. A corosubjective responses to stress or lower basal cortisol, is difficult to reconcile with existing theoretical models, such as the sensation-seeking, underarousal, or fearlessness models of antisocial behavior [The finding that severe antisocial behavior is associated with cortisol hyporeactivity to stress, but not attenuated behavior , 45. Thebehavior , it seembehavior . Blair hbehavior . In contbehavior . HoweverIn summary, recent research using state-of-the-art methods to characterize the cortisol diurnal rhythm and CAR in children, adolescents, and adults with severe antisocial behavior has yielded mixed findings. Overall, the diurnal rhythm appears to be intact in antisocial populations, although flatter diurnal slopes and smaller CARs have been reported\u2014especially in adolescents with DBDs. In contrast to these mixed, but mostly negative, findings for basal cortisol, studies investigating cortisol reactivity to stress have yielded consistent evidence for hyporeactivity in children and adolescents with DBDs and adults with ASPD or psychopathy. Nevertheless, heterogeneity within antisocial behavior and psychiatric comorbidity both appear to influence cortisol reactivity, as CU traits appear to be associated with a more pronounced pattern of hyporeactivity whereas comorbid internalizing disorders predict heightened cortisol reactivity and impaired recovery following stress. As most research has focused on males, an important direction for future research is to investigate diurnal cortisol rhythms and stress reactivity in girls with DBDs and women with APSD. Researchers should also move away from using single-point determinations of cortisol, instead tracking cortisol levels across the day and the CAR to deepen our understanding of HPA axis-antisocial behavior relationships. Finally, longitudinal research designs that allow researchers to examine whether cortisol abnormalities predict the emergence or escalation of antisocial behavior over time, and also whether cortisol secretion normalizes in those who desist from antisocial behavior, will be important in understanding causal relationships between these constructs and identifying intervention targets."} +{"text": "Although life longevity has increased across the world, evidence suggests some heterogeneity of the ageing process across individuals. To investigate different ageing patterns, the ATHLOS project harmonised data from 411,000 individuals across 17 existing cohort studies. The harmonised dataset provides comparable information on functioning measures, cognition, mental health, sociodemographic and lifestyle behaviours. To measure the process of healthy ageing across time and cohorts, we employed a Bayesian Multilevel Item Response Theory(IRT) and created a common metric of health status by using items of functioning. The IRT measurement model includes parameters describing the difficulty and discriminatory power of each item. We adopted the Bayesian Multilevel framework as it allows item parameters to vary among studies and the simultaneous estimation of all parameters under a Markov Chain Monte Carlo(MCMC) method. Finally, we assessed the predictive validity of the metric against mortality by performing a Receiver Operating Characteristic(ROC) curve analysis."} +{"text": "Factor V Leiden (FVL) is the most common inherited hypercoagulable condition. It is a genetic disorder caused by a missense mutation that prevents inactivation of Factor V in the clotting cascade, leading to overproduction of thrombin and excess clotting. This pathophysiological process is especially unfavorable in patients undergoing free tissue transfer. Many authors have noted a propensity for both venous and arterial thrombosis leading to partial or complete flap loss. To date, there have been no published reports of patients with FVL undergoing deep inferior epigastric perforator flap reconstruction without flap complications. Here, the authors present two cases of successful free tissue transfer for breast reconstruction in patients with diagnosed FVL. The perioperative thromboelastography lab values are evaluated to help guide anticoagulation regimen for these high-risk procedures. Microsurgical procedures performed by skilled surgeons have shown a relatively low complication rate. In those rare instances of adverse events, the most common indication for reoperation in microvascular surgery is pedicle thrombosis . Most miThe first case describes a 48-year-old female who had an established diagnosis of heterozygous FVL with a positive family history and was diagnosed with left breast cancer in October 2010. She presented to our institution in November 2013 with painful capsular contracture from prior implant-based reconstruction and a desire for bilateral autologous reconstruction. After detailed counseling regarding her operative risks, she underwent bilateral implant removal, capsulectomy and bilateral sensate DIEP flaps. There were no significant perioperative adverse events. The patient received 3000 IU of intravenous unfractionated heparin (UFH) after both sets of anastomoses were performed. At her 2-year follow-up at our institution in early 2016, the patient was in good health with her flaps sensate and well-perfused . The authors adhered to the Declaration of Helsinki at all times."} +{"text": "OBJECTIVES/SPECIFIC AIMS: Incomplete spinal cord injury (iSCI) is a life-long disability that typically results in a profound loss of locomotion capability. Current rehabilitation methods rarely restore full community ambulation, which in turn limits quality of life. Most individuals with iSCI exhibit persistent deficits in eccentric muscle control and reach recovery plateaus below the levels necessary for independent community ambulation. Eccentric motor control is essential during the weight acceptance phase of gait, which is emphasized during downhill walking. METHODS/STUDY POPULATION: The overground locomotion of subjects with chronic iSCI was analyzed both prior to and following a 12-week downhill body-weight-supported treadmill training regimen and compared to that of matched healthy controls in terms of kinematics, kinetics, and EMG activation. RESULTS/ANTICIPATED RESULTS: We expect to find significant differences between the controls and subjects with iSCI, with deficits in eccentric motor control accounting for some of these differences. In addition, we expect the downhill training to yield significant improvement in eccentric muscle control that translates into improvements in functional, overground walking for the subjects with iSCI. DISCUSSION/SIGNIFICANCE OF IMPACT: The goal is to determine if downhill training can improve eccentric motor control and extend recovery beyond established plateaus. OpenSim modeling of the experimental data will help quantify changes in eccentric control of individual muscles to clarify where specific gains are made."} +{"text": "Transcranial Doppler (TCD) is a bedside, low-cost, and non-invasive technique able to evaluate cerebral hemodynamics ; the impWe discussed herein on how we use TCD in neuro-critically ill patients for hemodynamic indications; some of these proposals could also be used in non-brain injured critically ill patients at a high risk of cerebral complications.When the indications for invasive intracranial pressure (ICP) monitoring are met, we recommend intraparenchymal or intraventricular probes, as TCD cannot substitute invasive ICP measurement . HoweverAlthough the diagnosis of brain death is based on neurological examination, we use routinely TCD as an ancillary test to demonstrate the absence of cerebral blood flow (CBF) . We use We assess cerebral autoregulation (CA) at the bedside as altered CA is related with a poor outcome in many diseases and may increase the risk of cerebral damage . In caseDetection of cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH) is crucial as this is one of the main determinants of delayed cerebral ischemia and poor neurological outcome in this setting . AlthougWe often use TCD to monitor brain hemodynamics in critically ill patients. Future TCD development, such as the assessment of the compliance of arterial and cerebrospinal fluid compartment as well as critical capillary closing pressure, will further expand its use in this setting .Additional file 1: Table S1. Factors that may influence pulsatility index (PI) and flow velocities. (DOCX 13 kb)"} +{"text": "Tribulus terrestris were more prominent in raising LH and Testosterone levels whileThe mechanisms of action of these phytotherapics are poorly understood, especially for the less-studied Anacyclus pyrethrum. This herb has been proposed for different conditions , althprimum non nocere which should be always applied when proposing any therapy, including herbal therapies. When studying any treatment for a specific condition, is important to have a more global perspective, evaluating potential side-effects of the proposed medication. Specifically, for Tribulus terrestris, our group recently showed this herb leads to arterial blood pressure increase and renal morphology alteration with glomerular loss (Since the ancient Greece Hippocrates advocated the principle of lar loss . This ki"} +{"text": "Dear Editor,Organophosphate insecticides (OPI), derived from phosphoric, phosphonic or phosphinic acids, find application as agents for controlling insect pest populations. OPIs elicit their characteristic toxicity by phosphorylating and inhibiting the enzyme, acetylcholinesterase (AChE). Cholinergic stress resulting from overstimulation of nicotinic- and muscarinic acetylcholine receptors is the chief mechanism of acute toxicity of OPI (Fukuto, 1990; Abou-DoA large number of animal studies explicitly demonstrate that OPIs have the propensity to cause hyperglycemia, perturbations in carbohydrate metabolism and endocrine dysregulations. Repeated exposure to OPI precipitates insulin resistance (studies listed in Table 1Authors are thankful to Jain University, Bangalore for the support.The authors declare no conflict of interest."} +{"text": "This research examined the relation between physical activity, pain, and mood among older adults with osteoarthritis (OA). Physical activity is associated with long-term maintenance of function in persons with chronic pain , but less is known about the association between objective measures of activity and transient mood states. Therefore, we captured the activity and mood levels of 218 older adults with knee OA over a seven-day period. Wrist and waist accelerometers captured small and large motor movements. Self-reported momentary pain and affect were collected through phone calls four times daily. We examined average and peak activity levels over the 4-hour windows between self-reports. Cross-sectionally, there was no association between momentary pain and activity. Average large motor movement was positively associated with positive affect and negatively associated with negative affect. Analyses revealed one association between affect and average previous activity; small motor movements predicted greater positive affect. Peak levels of both movements predicted greater positive affect, but only peak wrist activity predicted negative affect. Peak small motor movement at the previous call was associated with both positive and negative affect. These results provide insight into the unique contributions of small and large motor activity to mood and pain states. It appears that average large motor movements and prior small motor activity may have the greatest impact on momentary affect. Further study of distinct activity types and mood will be important for understanding and improving the quality of life among individuals diagnosed with OA (Supported by R01-AG041655)."} +{"text": "Individuals who identify as lesbian, gay, bisexual, transgender or other non-heterosexual or binary gender identifiers (LGBTQ) face tremendous obstacles in search of quality healthcare. Older LGBTQ adults face these obstacles in the setting of more complex health problems with few social services and support. Negative treatment from healthcare professionals has proven to be one of the most pervasive barriers to care faced by older LGBTQ adults. Sensitization training with the film, Gen Silent, is one way knowledge gaps and biases of healthcare professionals has been addressed. By utilizing the survey previously validated by Porter et al., health professionals\u2019 knowledge, perceptions, and attitudes toward LGBTQ older adults before and after viewing Gen Silent were assessed in Lehigh Valley Health Network (LVHN)-affiliated primary care practices. The principle outcome of this study was a statistically significant change in responses. Primary care practices were recruited for 45-minute sessions that included the showing of an educational, abbreviated version of Gen Silent to available staff. It was preceded by administration of a pretest survey and followed by a posttest survey and discussion. A paired t-test was conducted to determine significance of differences between pre- and posttest responses. Seventeen individuals (N=17) viewed the film and finished pre- and posttest surveys. Nearly all questions exhibited changes between pre- and posttests. Significantly, respondents indicated increased awareness of additional barriers to care faced by LGBTQ older adults compared to heterosexual peers. While limited, these results indicate that primary care professionals would benefit from training specific to the aging LGBT population."} +{"text": "This study operationalized the third dimension of Rowe & Khan\u2019s Successful Aging model, social engagement, as neighborhood connectedness. We examined 2820 older adults in the MIDUS III dataset to assess the impact of neighborhood connectedness on life satisfaction and daily spiritual experiences. A composite scale for neighborhood connectedness (Cronbach = .745) was created. Linear regression analysis was undertaken for life satisfaction on daily spiritual experience, neighborhood connectedness, neighborhood environment and age controlling for gender, co-habitation, income, and disability. Regression analysis was also conducted for daily spiritual experience on the same variables. Analysis for each outcome variable was run three times to explore changes across three age groups of older adults . Results of regression analysis found frequency of daily spiritual experience was a substantial and significant predictor of life satisfaction for all age groups Additionally, regression analysis revealed a higher level of neighborhood connectedness was the most powerful predictor of daily spiritual experience across all age groups This study demonstrates the applicability of operationalizing the Successful Aging model\u2019s social engagement dimension as neighborhood connectedness. This study also contributes evidence of the impact of daily spiritual experience on life satisfaction. Finally, the study supplies promising new evidence linking neighborhood connectedness with spiritual well-being."} +{"text": "The benefits of mobility devices for knee Osteoarthritis Patients include reducing burden of knee joint, enhancing confidence and increasing autonomy, yet many who might benefit from using mobility devices do not use them. The purpose of this study is to explore the cognition and using experiences about mobility devices use in patients with knee osteoarthritis of China. Naturalistic inquiry research was adopted, 15 patients with knee osteoarthritis were recruited and Semi-structured interviews were conducted. Data were analyzed based on conventional content analysis methodology. Two themes of using experiences about mobility devices were extracted, including positive feelings, negative feelings. Cognition about mobility devices use included light consciousness, incorrect attitude. Mobility devices have a positive effect on knee osteoarthritis patients, but some patients lack sufficient understanding and face many problems in the use of mobility devices. Policy Support, greater physician involvement, positive peer modules, and safe, visually appealing devices would promote greater acceptance and satisfaction of mobility devices with knee osteoarthritis patients."} +{"text": "Transcranial Direct Current Stimulation (tDCS) is a potentially useful tool to improve upper limb rehabilitation outcomes after stroke, although its effects in this regard have shown to be limited so far. Additional increases in effectiveness of tDCS in upper limb rehabilitation after stroke may for example be achieved by (1) applying a more focal stimulation approach like high definition tDCS (HD-tDCS), (2) involving functional imaging techniques during stimulation to identify target areas more exactly, (3) applying tDCS during Electroencephalography (EEG) (EEG-tDCS), (4) focusing on an effective upper limb rehabilitation strategy as an effective base treatment after stroke. Perhaps going even beyond the application of tDCS and applying alternative stimulation techniques such as transcranial Alternating Current Stimulation (tACS) or transcranial Random Noise Stimulation (tRNS) will further increase effectiveness of upper limb rehabilitation after stroke. Impaired arm function after stroke is both frequent and a considerable burden for people with stroke and their caregivers. An emerging approach for enhancing neural plasticity after acute and chronic brain damage, thus enhancing rehabilitation outcomes in the upper limb rehabilitation after stroke, is non-invasive brain stimulation (NIBS), for example delivered by transcranial direct current stimulation (tDCS) . tDCS isMany small trials regarding the effects of tDCS on arm motor function poststroke were undertaken in the past with partly promising but not conclusive results , 3. BaseThe problem of limited focal specificity of tDCS may lead to an ineffective stimulation and in turn may be reduced by the application of HD-tDCS, which involves up to five small electrodes, arranged in a ring, instead of two big conventional sponge electrodes for delivering direct current. The positioning of HD-tDCS for improving arm motor function after stroke has been described elsewhere. On the oTDCS during fMRI has already successfully been applied in language production tasks in healthy people and in people with stroke . MeinzerBased on EEG data, it is possible to measure cortical activity after or even during tDCS with superior temporal resolution . There aSince tDCS enhances neuroplasticity by modulating cortical activity, the application of an efficient base therapy, resulting in sufficient cortical activity, is still crucial. Therefore is has to be kept in mind that tDCS has to be applied in combination with an appropriate and individually selected and effective arm training: For instance in people with severe arm paresis it makes sense to apply electromechanically-assisted arm training whereas in people with only minor arm paresis a forced use paradigm seems to be promising to improve arm function and to overcome learned non use. There is a considerable evidence base regarding effective base treatments during tDCS for improving upper limb rehabilitation outcomes poststroke.An alternative to tDCS could be the application of transcranial Alternating Current Stimulation (tACS) to increase excitability . tACS aiAnother recent non-invasive approach to brain stimulation is transcranial Random Noise Stimulation (tRNS) . tRNS deThe mode of action of tDCS is not fully understood yet, which has implications for its clinical application: for example, tDCS suffers from a lack of focality of stimulation, and attaining neurophysiological data in adequate spatial and temporal resolution for further exploration of its mode of action remains challenging. HD-tDCS may be a one tool for reducing variability in future tDCS trials in upper limb rehabilitation after stroke by increasing focality of stimulation. Together with tDCS during fMRI, which allows for superior spatial resolution, online EEG-tDCS delivering superior temporal resolution could give valuable insights into tDCS mechanisms. Hopefully, this will improve our understanding of tDCS in upper limb rehabilitation in people with stroke and corollary also its clinical application. However, with tDCS being rather a facilitatory intervention thus needing an effective base treatment resulting in sufficient neuroplasticity, it requires efficient interventions delivered by therapists .Particularly from the perspective of clinicians, it eventually should be kept in mind that despite the currently considerable research interest in tDCS, it is still likely that tDCS reveals only small or even no additional benefits to arm rehabilitation after stroke."} +{"text": "There is solid epidemiological evidence demonstrating that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing colorectal cancer, and to a lesser extent gastric and esophageal cancers[1]. Importantly, NSAIDs suppress colon polyp formation and progression in patients diagnosed with familial adenomatous polyposis coli (APC)[2]. In many animal studies, NSAIDs have been shown to prevent tumor formation and slow tumor progression, thus confirming and extending the clinical observations. Recent findings have demonstrated that NSAIDs inhibit angiogenesis, suggesting that the tumor suppressive activity of these drugs may be due, at least in part, to their ability to inhibit tumor angiogenesis[6]. The study of the mechanism by which NSAIDs suppress tumor angiogenesis, is matter of intense research."} +{"text": "Cognitive health, physical function, and chronic disease represent interdependent health outcomes that may exert influence on the course of each other\u2019s development. To investigate the association between baseline health in each domain and developmental change across domains, we estimated trajectories of working memory, mobility limitations, and comorbidity among US adults age 65 and older over 18 years. We drew observations from the nationally-representative Health and Retirement Study with an analytic sample consisting of 5,963 adults age 65 and over in 1998. Immediate word recall, an 11-item Nagi scale of mobility limitations, and a summary count of eight doctor-diagnosed chronic conditions were measured biennially from 1998 to 2016. Parallel-process quadratic growth models with individually-varying time scores were used to estimate non-linear trajectories of each health measure, allowing identification of associations between baseline health and developmental change in each health process at both earlier and later stages of older adulthood. All estimates adjusted for covariates, complex survey design, and missing data. Greater baseline immediate word recall was associated with less rapid increase in mobility limitations at earlier ages. More baseline mobility limitations were associated with faster increase in comorbidity at earlier ages. Greater baseline chronic conditions were associated with more rapid increase in mobility limitations at later ages. These results highlight the importance of conceptualizing health among older adults as an interdependent and developmental process and should help clinicians recognize that single-domain health status may influence the progression of other health outcomes at different stages of older adulthood."} +{"text": "Background: Thoracic Aortic Injury (TAI) due to penetrating or blunt chest trauma is a critical life-threatening aortic injury. Its diagnosis and treatment always is challenging.mmHg despite multiple anti-hypertensive drugs. Trans-Thoracic Echocardiography (TTE) revealed abnormal Doppler flow pattern in proximal descending thoracic aorta suggestive for probable coarctation of aorta. Chest CT scan revealed pseudoaneurysm of the descending thoracic aorta just below the isthmus. Due to uncontrolled hypertension, persistent hemothorax and probable aortic pseudoaneurysm presenting as aortic luminal narrowing, surgical resection of the aneurysm was planned.An 18-year-old male was admitted due to blunt chest trauma after a high-impact road traffic collision. According to presenting dyspnea, an emergency chest-x-ray revealed left hemothorax for which chest tube was inserted. Hemodynamic monitoring demonstrated uncontrolled hypertension with systolic blood pressure of 200\u2013220 The postoperative course was uneventful and blood pressure normalized without any drugs. Patient is normotensive after 8 years follow up. Thoracic Aortic Injury (TAI) due to penetrating or blunt (more common) chest trauma is the most frequent type of traumatic aortic injury and is a catastrophic and also final scenario in most circumstances . Blunt TAs aortic dissection may be associated with a hypertensive crisis, the patients must be ICU admitted and dedicated control of blood pressure is very important to reduce the progressive process of dissection.Once the clinical suspicion of acute aortic dissection is suggested, intravenous (IV) antihypertensive regimen should be started as soon as possible in emergency department in all non-hypotensive patients and continued in the intensive care unit or the operation room. Systemic blood pressures, urine output, consciousness, and focal neurologic signs should be regularly checked for any derangement owing to complications.Surgical techniques can be open surgery with a clamp-and-sew technique, surgery with the use of a vascular graft, and using heparin-less partial cardiopulmonary bypass. Recently new endovascular techniques have been largely introduced as a therapeutic choice in traumatic and non-traumatic aortic injury in descending and abdominal aorta.mmHg despite multiple anti-hypertensive drugs. Another CT scan revealed pseudoaneurysm of the descending thoracic aorta.An 18-year-old man with shortness of breath and left sided bloody pleural effusion was admitted in this center. The patient did not have any underlying disease. The patient was pale and bilateral lower extremity pulses were not palpable. There was history of blunt chest trauma after an acceleration- deceleration traffic collision 12 days ago. After resuscitation and stabilization of the patient, because of dyspnea and hemothorax, an emergency chest-x-ray showed left hemothorax and chest tube was inserted. Patient referred to tertiary lung disease center due to persistent dyspnea and admitted to ICU because of low O2 saturation. Hemodynamic monitoring in ICU demonstrated severe refractory uncontrolled hypertension with systolic blood pressure of 200\u2013220 Bedside Trans-Thoracic Echocardiography (TTE) from suprasternal notch revealed abnormal continuous Doppler flow pattern in proximal descending thoracic aorta suggestive for probable coarctation of aorta and aortThe patient underwent left sided thoracotomy and a transection of aorta in the posterior surface of aorta just after the isthmus was found which resulted in pseudoaneurysm formation. After excision, the aorta was repaired with a 16 mm Gore-Tex interposing graft .th post-operative day. Follow up imaging with Magnetic Resonance Imaging (MRI) revealed normal anatomy of the aorta without luminal narrowing two weeks after operation. No complication occurred and patient had normal blood pressure after 8 years follow up.The postoperative course was uneventful and blood pressure normalized without any drugs and the patient had full recovery on the 7Traumatic damages to aorta are accomplished with wide range of aortic damages including minimal aortic injury, aortic laceration or transverse aortic tearing. Aortic transection is also known as aortic rupture, aortic pseudoaneurysm and aortic intramural hematoma.Supine chest-x-ray is the initial screening test in the traumatic patient. A large autopsy survey reported that 97% of victims of aortic injury had additional traumatic damages in other regions. Indirect signs suggestive for aortic injury are mediastinal hematoma and widening or concomitant multiple rib fractures. Other imaging tests such as contrast enhanced-CT scan, Magnetic Resonance Angiogram (MRA), or aortic angiogram may be used to determine if aortic tear is present. Another noninvasive diagnostic test that may be used is bedside echocardiography that had been conducted for this patient and demonstrated TAI.Regarding the mechanism of refractory hypertension in this case, aortic luminal narrowing or kinking just after aortic injury site in isthmus with a pseudocoarctation physiology presenting as continuous Doppler flow pattern in descending aorta was completely normalized after successful surgical aortic repair.There are different guidelines for medical treatment of hypertension in these patients . Over thThe striking aspects of the case were new-onset refractory hypertension in previously normotensive young man and echocardiographic findings mimicking aortic coarctation as result of traumatic transection of aorta and amenability of lesion to surgery and complete correction of hypertension after surgical repair.Blunt traumatic TAI is a deadly catastrophe with disappointing survival rates, as confirmed by previous studies and immediate death rate of more than 75% , 12. In"} +{"text": "Active citizenship is romanticized in policy for its role in keeping older adults healthy, and rural communities sustainable. However, as proportions of older adults resident in rural communities continue to increase, the gerontological literature has begun to highlight challenges associated with both the capacity and desire of rural older adults to be active citizens. Through an integrative review of the international literature, this paper interrogates how active citizenship trends among rural older adults support or hinder healthy aging in rural settings. Findings indicate that active citizenship among older adults can increase rural age-friendliness and facilitate individual wellbeing. However, practices associated with active citizenship among this cohort can disenfranchise certain groups of older adults, through reshaping societal norms relating to citizenship, age-friendliness and rurality. These findings indicate that programs designed to promote active citizenship must both consider, and account for, diverse capacities and desires for active citizenship among rural older adults."} +{"text": "Resting-state functional connectivity (FC), which measures the temporal correlation of spontaneous hemodynamic activity between distant brain areas, is a widely accepted method in functional magnetic resonance imaging (fMRI) to assess the connectome of healthy and diseased human brains. A common assumption underlying FC is that it reflects the temporal structure of large-scale neuronal activity that is converted into large-scale hemodynamic activity. However, direct observation of such relationship has been difficult. In this commentary, we describe our recent progress regarding this topic. Recently, transgenic mice that express a genetically encoded calcium indicator (GCaMP) in neocortical neurons are enabling the optical recording of neuronal activity in large-scale with high spatiotemporal resolution. Using these mice, we devised a method to simultaneously monitor neuronal and hemodynamic activity and addressed some key issues related to the neuronal basis of FC. We propose that many important questions about human resting-state fMRI can be answered using GCaMP expressing transgenic mice as a model system. Temporal correlation of spontaneous hemodynamic signals, commonly referred to as FC , is one Several groups have recently used transgenic mice expressing a genetically encoded calcium indicator (GCaMP) in neocortical neurons to simulUsing this method, we examined the relationship between fast spatiotemporal patterns of neuronal calcium activity and the spatial pattern of FC. We found a significant relationship between two seemingly different types of large-scale spontaneous neuronal activities \u2013 namely, global waves propagating across the neocortex and transient coactivations among cortical areas sharing high FC. Different sets of cortical areas, sharing high FC within each set, were coactivated at different timings of the propagating global waves, suggesting that spatial information of cortical network characterized by FC was embedded in the phase of the global waves . FurtherThe proposed method also allows us to ask questions related to newly developed analyses methods for FC in human fMRI . In contThe temporal fluctuation of FC across short time-windows does not necessarily indicate non-stationary FC. Indeed, recent studies using resting-state fMRI in humans reported that the temporal fluctuation of FC cannot be distinguished from that in a model assuming stationary FC and statistical sampling error ,24. ApplThere are several future applications of the proposed method. For example, resting-state FC in mouse models of mental diseases can be used to examine the possibility of diagnosis based on resting-state FC . Genetic"} +{"text": "Gerardo Ferbeyre , Francis Rodier, and Daohong Zhou . In his welcoming speech, Dr. Ferbeyre summarized the key aspects that have attracted so much interest in cellular senescence including its ability to act as a tumor suppressor mechanism but also to promote aging and age-linked diseases , ICSA president Manuel Serrano and NCI director Ned Sharpless . Dr. Sharpless presented in his keynote lecture how the key senescence gene and tumor suppressor p16INK4A acts as a double-edged sword to regulate aging, health span and cancer incidence.More than two hundred scientists gathered in Montreal on July 8, 2018 for the International Cellular Senescence Association (ICSA) Meeting to discuss the biological and medical impact of cellular senescence. The meeting was organized by diseases . The duaFrederic Lessard from the Ferbeyre laboratory , described the senescence-associated ribosome biogenesis defects and how they are linked to the inhibition of CDK4 via accumulation of ribosome-free RPS14. This work expands the extraribosomal functions of ribosomal proteins, which are now linked to both the p53 and the RB tumor suppressor pathways [Guadalupe-Elizabeth Jimenez showed an intriguing connection between B-distroglycan and the nucleolus in senescent cells. Jiri Bartek , delivered the EMBO Keynote lecture summarizing the role of replication stress and the DNA damage response in cellular senescence [Fred Dick , presented novel roles of RB suppressing the expression of satellite repeats and regulating chromosome condensation [Karl Riabowol presented a link between senescence and endocytosis via RB in cells that express the ING1a epigenetic regulator. Jesus Gil and Mathieu Desch\u00eanes presented data linking the control of alternative splicing to cellular senescence.nescence . Recent Xiaolu Yang explained how p53 represses major forms of NADPH generation via distinct mechanisms, clarifying why reactive oxygen species and oxidative damage accumulate in senescent cells. Talks form Eiji Hara , Maria Grazia Vizioli and Andrea Ablasser , provided links between DNA metabolism, the activation of the cGAS-STING pathway and the regulation of the senescence-associated secretory phenotype (SASP). Masashi Narita summarized the dual role of autophagy in cancer and presented a mouse model where conditional inactivation of ATG5 altered cancer susceptibility. Fr\u00e9d\u00e9rick A. Mallette presented an intriguing connection between cholesterol 25-hydroxylase (CH25H) and cellular senescence. In a mouse model of retinopathy [Ch25h mRNA levels increased and correlated with induction of features of cellular senescence in the retina. Perhaps, related to this discovery, Dr. Hara presented evidence that another cholesterol metabolite, deoxycholic acid (DCA), induced senescence in liver cells; interestingly, DCA is produced by the gut microbiota during obesity in mice and facilitates the development of hepatocellular carcinoma [Several talks described a clear connection between senescence and metabolism. arcinoma .Andrei Gudkov challenged several existing views of senescence from the analysis of the transcriptome of senescent cells and cells arrested by contact inhibition. Using principal component analysis he proposed that the gene expression pattern of senescent cells is a superposition of two components: one, which depends on the time cells are in culture without dividing, and the other one, which depends on the type of treatment. Oliver Bishof also presented a kinetic transcriptome analysis of cells rendered senescent by oncogenic ras. He described an intriguing dynamic gene expression program driven by a hierarchical network of transcription factors reminiscent of a developmental process. Along the same lines, Judith Campisi discussed how multiple functional senescence-associated phenotypes are interlaced and dynamic in the senescence program, particularly in different cells types and tissue contexts, and presented a new effort to globally identify senescent cells surface molecules.Scott Lowe , who together with Manuel Serrano discovered the process of oncogene induced senescence, presented data explaining how cancer cells can be forced into an RB-dependent but p53-independent senescence using a combination of a MEK inhibitor with the CDK4 inhibitor palbociclib. Intriguingly, this treatment also engages NK cells to kill senescent tumor cells, underscoring the view that pro-senescence cancer therapies benefit from immune surveillance mechanisms. Regarding immune clearance of senescent cells, Christian Beausejour revealed his efforts to develop novel humanized mouse models to better mimic interactions between senescent cells and immune cells. He showed that senescent human cells are not always immunogenic in this context, suggesting strong context-dependent effects and the importance of using relevant models. The importance of the elimination of senescent cells after treatment was highlighted in several talks. Clemens Schmitt was the first keynote speaker of the meeting. He presented evidence for an underlying stemness gene expression signature in senescent cells. Cells that managed to escape from senescence, take advantage of this stemness program to form aggressive cancers [Konstantinos Evangelou also focused on cells that escaped from senescence as demonstrated with a novel senescence biomarker (SenTraGorTM) [Corinne Abbadie characterized the senescence response to irradiation in fibroblasts at the margin of an irradiated field. She explained that these cells accumulate single- stranded breaks but not double-stranded DNA breaks and they were able to escape from senescence giving rise to a progeny of mutated cells. From a more clinical angle, Francis Rodier explored the occurrence of therapy-induced senescence in human cancer patients particularly demonstrating that senescence occurs in response to ovarian cancer chemotherapy. Interestingly, the presence of senescence hallmarks in treated ovarian tumors predicted beneficial outcomes in patients, suggesting that senescence biomarkers could help inform cancer treatment strategies and that senescence becomes a target for pharmacological manipulation in human ovarian cancer therapy. Olivier Coqueret presented data on TSP1 acting as a cytokine that prevents escape from senescence and described how its receptor CD47 regulates escape from the senescent arrest. Dr. Serrano presented data indicating that palbociclib, a CDK4 inhibitor approved for the treatment of some cancers, accumulates in lysosomes and this prolongs its biochemical effects explaining the induction of senescence even after a short period of exposure to the drug. The storage of palbociclib into lysosomes also accounts for its delayed and long-term release to the external milieu and the efficient induction of paracrine senescence, which in this case is mostly due to the drug and not to the SASP. Marco Demaria further expanded on the use of CDKi to induce a potentially less inflammatory senescence response in normal and cancer cells, as he demonstrated the lack of a typical SASP in this context. He suggested that this could be beneficial in some therapeutic contexts, but harmful in others, as SASP-less senescence might alter normal immune clearance of senescent cancer cells. In summary, a theme emerged that any therapy that aims to induce or reinforce senescence in tumors should also be combined with strategies to prevent escape from senescence or to stimulate the elimination of senescent cells.A number of talks solidified the view that senescence is a powerful tumor suppressor mechanism. cancers . KonstanraGorTM) . EscapedraGorTM) ,10. CoriJan Van Deursen presented recent evidence that the elimination of senescent cells can induce regression of advanced atherosclerosis without any detectable side effects. Jennifer Hartt Elisseeff showed that clearance of senescent cells using senolytics attenuates osteoarthritis development. The connection between senescent cells and immune responses to injury and repair was presented. Darren Baker presented experimental evidence that senescent cells promote neurodegeneration in mutant tau mice [James Kirkland , showed that transplanting senescent cells to young mice caused frailty, diabetes and osteoporosis accelerating death from all causes. A cocktail of quercetin and dasatinib, a SRC-family kinase inhibitor, can kill senescent cells and revert their pathological effects both in senescent-cells transplanted young mice or in naturally aged mice, extending median life span up to 36% [Salvador Macip found another kinase, BTK, which activates the tumor suppressor p53 inducing senescence [Irina Conboy used parabiosis to demonstrate the presence of factors in the serum of old mice that can induce senescence in young mice suggesting that some senescent cells in vivo may originate from extrinsic factors. She also presented interesting data on enhanced myogenesis and reduced liver adiposity, but no improvement in hippocampal neurogenesis in the old 3MR mice, when p16-high cells were experimentally ablated. Albert Davalos (Buck Institute for Research on Aging) followed-up on his earlier discovery that the alarmin HMGB1 is a key regulator of the proinflammatory SASP [Myriam Gorospe, identified proteins expressed at the surface of senescent cells. SCAMP4 was found to favor the SASP [Mei Wang presented her work showing that mesenchymal stem/progenitor cells (MSPCs) in primary spongiosa of long bone during late puberty undergo a normal programed senescence. MSPC senescence is epigenetically controlled by the polycomb histone methyltransferase Ezh2 and its H3K27me3 mark. Loss of Ezh2-H3K27me3 in young mice leads to premature cellular senescence followed by impaired osteogenesis and bone loss, and antagonizing cellular senescence by manipulating epigenetic factors may be a potential approach to treat pediatric or juvenile osteoporosis. Maria Almeida discussed the role of senescent osteocytes in age-related bone loss via production of increased levels of RANKL and the therapeutic potential of senolytic agents in preventing and treating osteoporosis by targeting senescent cells in the bones [Claude LeSaux reported some new interesting findings that eicosanoids such as prostaglandins and leukotrienes may function as new SASP factors and play an important role in the pathogenesis of pulmonary fibrosis. Together these studies show the tremendous potential of senolytics to improve health at old ages.One of the most exiting trends in senescence research is the concept of senolysis or the specific elimination of senescent cells . Jan Vantau mice and theip to 36% . Salvadonescence . Ibrutinory SASP by showithe SASP . Mei Wanhe bones . Claude Daohong Zhou presented some new development of Bcl-xl-targeted senolytic agents using proteolysis targeting chimera (PROTAC) technology. These Bcl-xl PROTACs that target Bcl-xl to an E3 ligase for ubiquitination and degradation exhibit an improved potency against senescent cells but reduced toxicity to normal cells and platelets compared to navitoclax or ABT-263 and thus have the potential to be developed as a safer senolytic agent. John Lewis described a clinically viable gene therapy consisting of a suicide gene under a senescent cell promoter delivered in vivo with fusogenic lipid nanoparticles (LNPs) to deplete senescent cells. This approach represents a first-in-class therapeutic that targets cells based on transcriptional activity, rather than surface markers or metabolism. Guangrong Zheng identified a dietary natural product, piperlongumine, as a novel senolytic agent. It can selectively kill senescent cells by targeting oxidation resistance 1 (OXR1), an important oxidative stress sensor that regulates the expression of a variety of antioxidant enzymes. His finding may lead to the development of better senolytic agents [Daniel Munoz-Espin described the design of a new targeted-drug delivery system to senescent cells using the technology of the encapsulation of drugs with galacto-oligosaccharides because of the high lysosomal \u03b2-galactosidase activity of senescent cells. He showed that gal-encapsulated cytotoxic drugs can selectively target senescent cells in a tumor xenograft mouse model to improve tumor regression and toxicity. This senescent cell selective drug delivery method opens new diagnostic and therapeutic applications for senescence-associated disorders. At the end of the meeting Ned David delivered a talk summarizing how his company is translating basic research on senescence into clinical trials using several senolytics. Senescence is undoubtedly at the forefront of biomedical research. The next ICSA meeting in Athens 2019 will reveal additional exiting research: stay tuned!The promise that clearance of senescent cells with a therapeutic agent may prolong the health span and treat age-related diseases stimulates the research in finding new senolytic agents, therapeutic strategies, and delivery methods. c agents . Daniel"} +{"text": "Aging of the vasculature is the leading risk factor for cardiovascular and cerebrovascular disease . As suchThe healthy artery comprises endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and the extracellular matrix (ECM), all of which are susceptible to damage or disruption during aging . The intRapid advances in geroscience have identified a \u2018Molecular Signature\u2019 for the aged vessel that represents distinct underlying intracellular and extracellular molecular processes . IntraceAlthough all of these processes are associated with vascular aging, it is unclear whether they are a cause or consequence of aging, how they are inter-related, and whether targeting one or more is sufficient to prevent or delay vascular aging. For example, we recently reported that mitochondrial function progressively deteriorates with aging of mouse arteries, associated with reduced mitochondrial DNA copy number (mtCN) and expression of enzymes that regulate mitochondrial DNA synthesis; we showed that increasing mtCN enhanced mitochondrial function and delayed the onset of multiple structural and functional parameters of vascular aging . Althoug+) booster nicotinamide mononucleotide (NMN) promoted angiogenesis and recapitulated the benefits of exercise via sirtuin 1-mediated inhibition of Notch signalling in aged exercised mice [In contrast, the ability of enhanced mitochondrial function since birth to delay vascular decline suggests that preventative and early intervention are key to delay vascular aging. Indeed, several studies have demonstrated beneficial effects of long-standing lifestyle changes such as caloric restriction (CR) and exercise, and compounds that mimic these processes. For example, \u03b2-hydroxybutyrate, a ketone released naturally during CR, enhances cell division and protects against DNA damage and cellular senescence in ECs and VSMCs in older fasted mice via the Oct4-mediated LaminB1 pathway [sed mice .Vascular stiffness is a major link between normal vascular aging and development of vascular complications. Although the marked changes in ECM content and structure in aging influence vascular mechanical properties directly, aging also affects cell-ECM interactions, and the stiffness of VSMCs themselves. For example, VSMCs can take on a stiffness phenotype dependenIn summary, identification of the distinct molecular pathways involved in vascular aging provides great potential for therapeutics. Research efforts should focus on disentangling the complex interactions between the molecular processes involved, and testing the feasibility and timing of administration of potential therapeutics that can limit the effects of oxidative stress, mitochondrial dysfunction, cellular senescence, and DNA damage. Arterial stiffness and central blood pressure (cBP) are excellent predictors of age-related complications and can"} +{"text": "Older adults are increasingly occupying multiple life roles, including working, caregiving, and volunteering, creating the opportunity for role conflict. Such conflict occurs when stress and strain created by the demands of multiple life roles outstrips an individual\u2019s resources to successfully manage such demands. A two-phase research study was recently completed with 1,697 RSVP volunteers drawn from 55 RSVP program sites across the country (Phase I) with a follow-up survey of RSVP programs conducted with 17 sites (Phase II). Grounded in role theory, the Phase I volunteer survey explored role conflict in addition to self-reported strategies used to mitigate the experience of role conflict. The Phase II program survey gathered responses from volunteer managers and staff about the strategies used by their older adult volunteers to avoid and address role conflict. Based on findings from both surveys, caregivers engaged the following strategies in order to minimize role conflict: obtaining respite care, and volunteering alongside their care recipient. Worker-specific strategies focused largely on time management and included volunteering during off-work hours and completing time-limited volunteer assignments. While a high level of convergence was noted between volunteer manager and volunteer perspectives, two themes emerged from the volunteer survey that were not identified in program survey responses: seeking volunteer opportunities that leverage similar skills and experiences across roles and seeking volunteer opportunities that provide a different experience from that of other roles. Implications for future research and volunteer management strategies will be discussed."} +{"text": "This presentation will review the design, methods, and early lessons learned from the Making Engagement Meaningful through Organized Routine Interaction (MEMORI) Corps trial recently funded by NIA. This trial is evaluating the feasibility and efficacy of the MEMORI Corps program, a novel 12-week activity-based companion care model designed to mobilize and equip senior volunteers to deliver individualized, evidence-based activity programming to persons with dementia PWD living at home and offer family CGs needed respite. The intervention synthesizes and adapts prior evidence-based work from the Tailored Activities Program\u00ae (an activity-based intervention persons with dementia), Experience Corps\u00ae , and MIND at Home\u00ae (a home-based dementia care coordination program) to simultaneously address unmet respite care needs of family CGs, provide PWD structured meaningful activities and social engagement, and provide meaningful engagement and peer support opportunities for senior volunteers."} +{"text": "The Florida Department of Elder Affairs (DOEA) provides programs and services for over 65,300 older people and adults with disabilities. These individuals are uniquely vulnerable and may be displaced, and/or disoriented during natural disasters. DOEA clients are dependent upon community-based services to provide supervision or assistance to perform basic self-care, which often makes sheltering in place alone a danger to their health and well-being. During Hurricane Michael (2018) many older adults who previously were independent sought help for many issues including property damage, utility interruption, food and medicine scarcity, and physical or mental health problems associated with the storm and its aftermath. In normal conditions, DOEA identifies older populations via Census tracts and then conducts outreach events to inform the public how to access social services. However, after the widespread displacement post-storm, traditional outreach approaches were insufficient. A method was needed to remove areas that were rendered uninhabitable and find who remained in place. DOEA identified viable neighborhoods by overlaying property damage locations on base layers of Census tracts with concentrations of older adults and polling places with high percentage of age 60+ voter participation in the subsequent November election. Then in partnership with Feeding Florida, we provided information and registration assistance via local food distribution sites in those areas. This methodology of overlaying Division of Emergency Management property damage records and voter participation records against publicly available Census tract files is a strategy that could be replicated by other disaster and flood-prone communities or organizations that have similar needs."} +{"text": "Caring relationships between older residents and nurse aides are fundamental in terms of service delivery in nursing homes. However, little is known for the nuanced dynamics of this relationship in China. The purpose of this study is to explore how caring relationships develop between older residents and nurse aides in the nursing home setting in urban China. Informed by the dyadic perspective, this study illustrates the development process and relational nuances by simultaneously eliciting residents\u2019 and nurse aides\u2019 perceptions. This qualitative study purposively sampled 20 matched resident-nurse aide dyads (N= 40) in a government-sponsored nursing home in Shanghai. Participants participated in semi-structured, in-depth interviews from January to June 2017. Thematic analysis was performed. The findings reveal that the caring relationship began with nursing home assignment and primarily focused on instrumental assistance. Gradually, emotional involvement grew within dyads and reciprocity emerged. Based on different dyadic perceptions, this study conceptualized four types of caring relationships: (a) parent-child alike, (b) mutually respectful, (c) solo performance, and (d) reasonably detached. The findings suggest that residents and nurse aides could have different views on caring relationships, which further influenced the relationship development. The four types of caring relationships shared some similar traits while differentiating from some of the common types of interactions found in the existing nursing evidence across the world. Chinese filial tradition also influenced the relationship dynamics."} +{"text": "Purpose. to report malignant glaucoma and infectious crystalline keratopathy as complications after an uneventful Descemet Membrane Endothelial Keratoplasty (DMEK), and corneal clearance despite graft detachment after the surgery in a patient with pseudophakic bullous keratopathy. Method. A 81-year-old patient with high Intraocular Pressure (IOP) and flat anterior chamber with patent iridotomies after DMEK was diagnosed of malignant glaucoma. The medical approach being insufficient, the patient required a pars-plana vitrectomy, capsulo-hyaloidectomy, and surgical iridectomy. Results. The IOP was reduced and anterior chamber was repositioned after surgical management. Corneal clearance was observed despite graft detachment. The patient developed an infectious crystalline keratopathy after the resolution of malignant glaucoma. Conclusions. malignant glaucoma is a rare complication following DMEK. Corneal clearance can be attained despite graft detachment after DMEK probably due to an unintentional Descemet Membrane Endothelial Transfer (DMET). However, in low dosage, steroid treatment remains a risk factor for developing ICK. Abbreviations: PBK = Pseudophakic Bullous Keratopathy, DMEK = Descemet Membrane Endothelial Keratoplasty, DMET = Descemet Membrane Endothelial Transfer, IOP = Intraocular Pressure, BCVA = Best Corrected Visual Acuity, AC = Anterior Chamber, MG = Malignant Glaucoma, ICK = Infectious Crystalline Keratopathy Nevertheless, DMEK is not without complications [2], graft detachment being the most common complication. Either air or expandable gas is used both in the straightforward surgery and in the \u201cre-bubbling\u201d procedure to treat graft detachment. The main cause of raised Intraocular Pressure (IOP) in the early postoperative period is usually a reverse pupillary block secondary to a full air or gas fill that pushes the iris backwards .Pseudophakic Bullous Keratopathy (PBK) is a common indication of corneal transplantation. Descemet Membrane Endothelial Keratoplasty (DMEK) is increasingly performed due to its excellent results, low graft rejection rate and reduced need of steroids . A careful differential diagnosis of MG should be undergone. Pupillary block presents a moderate depth of the central AC and iris bomb\u00e9e. Choroidal detachments and effusions are typically hypotonic. Suprachoroidal haemorrhage usually presents severe pain and is often preceded by hypotony [5]. Medical approach of MG is recommended during the first five days using mydriatic and cycloplegic agents in order to relax the ciliary muscle and retracting the lens-iris diaphragm. This can also be achieved by dehydrating the vitreous using hyperosmotics. Aqueous suppressants are used to decrease posterior pooling of aqueous humour. In refractory cases, Nd:YAG anterior hyaloidotomy should be considered in pseudophakic and aphakic eyes, allowing movement of fluid between the posterior and anterior segments of the eye. If ineffective, pars plana vitrectomy with capsulo-hyaloidectomy and lensectomy should be considered [5]. MG is defined as a uniform flattening of the AC in an eye with raised IOP in the presence of a patent iridotomy. It is thought that the cause is a misdirection of the aqueous humour towards the vitreous cavity, shifting the lens-iris diaphragm forward. MG is described as a complication of most intraocular surgeries, especially glaucoma surgery in patients with prior angle closure, being more frequent in hyperopic eyes . In the case we presented, we hypothesized that the irido-corneal contact, in the context of MG after DMEK, caused an almost fully detached graft, hence, the procedure ended up being an unintentional DMET. Interestingly, the corneal oedema improved in the following months. Several cases of corneal oedema resolution in presence of DMEK graft detachment, or even descemetorhexis with no posterior graft transplant have been reported. Dirisamer et al. proposed that contact between donor and host cornea is required to achieve corneal clearance as they reported successful results in patients with partial or large detachments, but not in eyes with a \u201cfree-floating graft roll\u201d in the anterior chamber . Our case matched these findings, as the graft was not completely detached. Descemet Membrane Endothelial Transfer (DMET) is performed by injecting the donor graft consisting in Descemet Membrane and endothelium into the anterior chamber after descemetorhexis, without fully unfolding it, but with some contact area between graft and host cornea [8]. Shah et al. reported an increase in endothelial population despite the extraction of the graft and in descematorrhexis-alone procedures, suggesting a possible mechanism of host endothelial cell migration [9]. Dirisamer also had similar results and hypothesized that the recipient endothelium must be primarily involved due to the difference in clinical outcome of DMET in PBK and FED. Hence, DMET is ineffective in eyes with total deficiency of endothelial cells (PBK), yet if performed after descematorrhexis in patients with a pathologically altered subcellular matrix (FED) results in re-endothelialization and corneal clearance [9]. However, in our patient with severe PBK the corneal oedema improvement was evident despite the graft being detached. Although the mechanism is uncertain, we reason that DMET might have contributed to recover partially the corneal transparency [6].Birbal et al. reported unsuccessful long-term results in eight patients receiving DMET. They experienced corneal clearance in eyes with Fuchs endothelial dystrophy (FED) but not PBK, suggesting that the mechanism of DMET might be to stimulate host endothelial migratory response rather than to supply functional cells .One year after the surgery, our patient developed ICK, probably because of the combination of topical corticosteroids and bandage contact lens, as ICK typically occurs after an epithelial defect from a surgical procedure and is potentiated by localized immunosuppression, commonly steroids. Many pathogens can cause ICK although Although rare, malignant glaucoma can be a complication after DMEK surgery, and we must suspect it in postoperative patients with high IOP and flat AC in the presence of a patent iridotomy. Although steroid dosage is usually lower after DMEK compared to other keratoplasty techniques, it remains a risk factor for the growth of stromal biofilm that could ultimately lead to ICK, especially if bandage contact lens is worn.DisclosuresPatient informed consent was obtained.Conflict of interestConflicts of interest and source of funding: none.AcknowledgementsNone."} +{"text": "This Forum article synthesizes the current evidence on the links between predator-prey interactions, protected areas and spatial variations in Lyme disease risk in Fennoscandia. I suggest key research directions to better understand the role of protected areas in promoting the persistence of diverse predator guilds. Conserving predators could help reducing host populations and Lyme disease risk in northern Europe. There is an urgent need to find possible win-win solutions for biodiversity conservation and human health in ecosystems facing rapid global environmental change. Borrelia burgdorferi sensu lato (s.l.) species complex, carried and transmitted by several species of Ixodes ticks, the most common in Europe being Ixodes ricinus , which take a single blood meal from a wide range of hosts before molting to the next stage , or reproducing and dying is the most common tick-borne disease in temperate forested regions of North America and Eurasia, with increased number of reported cases worldwide Increasing incidence of LD cases have been reported in Finland host population trends in the study area; (2) how trophic interactions could affect these main host species; finally (3) how PAs may impact predator abundance, host species and thus tick abundance and LD risk.Sorex araneus) and small rodents (Microtus and Myodes voles and Apodemus mice) are the most important hosts of larval I. ricinus in Fennoscandia , see Ecke et al. Insectivores and lagomorphs (Lepus timidus and L. Europaeus) are important feeding hosts for adult Ixodes ticks are known to be key hosts for nymphal ticks in Europe are still present, offering a unique opportunity to study intra-guild relationships between these species, their potential impact on mesocarnivore abundance reducing the most important host species abundance or changing the host community composition and (2) inducing fear-mediated changes in habitat use of the main host species, which could decrease LD transmission risks is a common prey of the lynx influence the trophic pathways identified above and impact LD risk at various scales and combining empirical, experimental and modeling approaches at local and global scales. Existing nation-wide datasets of LD incidence and wildlife community composition can be used in several northern European countries to assess the environmental drivers of LD incidence. Comparative designs inside and outside PAs, where host abundance, predator community structure, tick density and infection prevalence in ticks and hosts are sampled, would help determine how multi-level trophic cascades influence LD risk in boreal ecosystems.In conclusion, it is time for research to strive to understand the top-down processes regulating LD transmission in Fennoscandia. Such research could improve public attitude toward predators and provide powerful motivation for society to preserve complex ecological networks in boreal ecosystems currently facing the combined effects of land cover change and climate change."} +{"text": "We developed SNPnexus to meet this need by assessing the potential significance of known and novel SNPs on the major transcriptome, proteome, regulatory and structural variation models. Since its previous release in 2012, we have made significant improvements to the annotation categories and updated the query and data viewing systems. The most notable changes include broader functional annotation of noncoding variants and expanding annotations to the most recent human genome assembly GRCh38/hg38. SNPnexus has now integrated rich resources from ENCODE and Roadmap Epigenomics Consortium to map and annotate the noncoding variants onto different classes of regulatory regions and noncoding RNAs as well as providing their predicted functional impact from eight popular non-coding variant scoring algorithms and computational methods. A novel functionality offered now is the support for neo-epitope predictions from leading tools to facilitate its use in immunotherapeutic applications. These updates to SNPnexus are in preparation for its future expansion towards a fully comprehensive computational workflow for disease-associated variant prioritization from sequencing data, placing its users at the forefront of translational research. SNPnexus is freely available at SNPnexus is a popular analytical tool that was designed to meet this need and neo-epitope prediction for the immunotherapeutic application (for hg38). These will be added to other assemblies as soon as the primary datasets are made available from their respective sources. A complete list of the annotation categories is provided in http://www.roadmapepigenomics.org/) and the FANTOM project , Roadmap project have beeThe vast majority of germline and somatic variations occur in the noncoding part of the genome, only a small fraction of which are believed to be functional. From the tens of thousands of noncoding variations detectable in each genome, distinguishing the potential functional variants from non-functional ones is a challenge. Going beyond SIFT and PolyPhen predictions for deleterious effect of coding variants on protein functions, SNPnexus users can now obtain the predicted functional impact of noncoding variants from eight popular noncoding variant scoring algorithms, namely CADD , DeepSEAhttp://hapmap.ncbi.nlm.nih.gov/), the new release also provides minor allele frequency (MAF) data generated from the 1000 Genomes (1KG) Project . 1KG data covers 26 different populations around the globe grouped together in 5 super populations: AFR (African), AMR (Ad Mixed American), EAS (East Asian), EUR (European) and SAS (South Asian). Since the release of Phase 3 data in 2013 with information on over 84 million genetic variants (MAF > 1%), the 1KG project has overshadowed the utility of HapMap data and established itself as a research standard for population genetics. SNPnexus also provides MAF data generated as part of the Exome Aggregation Consortium (ExAC) . ExAC coWith ever-increasing number of association studies identifying new relationships among genetic variation and phenotypes, SNPnexus has added another resource ClinVar along wihttps://doi.org/10.1101/174243) and NetTepi molecule is considered as the essential factor for determining the viability of a peptide as neo-epitope. For user-specified human leukocyte antigen (HLA) allele type corresponding to MHC-I protein, SNPnexus employs NetMHCpan and MHCflurry to report the predicted peptide-MHC (pMHC) binding affinity of each n-mer mutated and wild-type peptide pair in nanoMolar (nM) unit. SNPnexus also reports prediction scores from NetTepi, which integrates pMHC binding affinity with pMHC stability and T-cell propensity in its calculations. By reporting scores from multiple immunogenicity prediction methods, SNPnexus enables users to make a better-informed decision on subsequent wet-lab investigations.It has now become well established that somatic variation within a tumour gives rise to neo-epitopes that may make strong candidates for personalized cancer immunotherapy vaccines . Assumin NetTepi . For eacSNPnexus utilizes primary annotation datasets from different sources to instantly calculate and report variant-centric functional annotations. Currently, we maintain three separate databases for GRCh38/hg38, GRCh37/hg19 and NCBI36/hg18 assemblies. The primary datasets for annotation categories present in the previous release remain unchanged. Most of the primary datasets for hg38 assembly are downloaded from either UCSC genome annotation database or Ensembl 90 data dumps. Among others, the 1KG Project datasets are downloaded from the International Genome Sample Resource (IGSR) FTP site. ExAC, COSMIC and miRBase data are downloaded from their respective FTP sites. The most recent ClinVar data are extracted from the NCBI ClinVar FTP site. Most of the non-coding variant scoring tools except DeepSEA provide pre-computed genome-wide scores, which are downloaded. No such pre-computed scores are available for DeepSEA, for which the respective standalone tool is installed in SNPnexus server and executed for each submission. Similarly, the standalone versions of the three neo-epitope prediction tools are installed and executed from the SNPnexus server. The complete list of data sources for SNPnexus annotation categories is provided in About section with an overview of the available annotation categories. The User Guide compiles the sources of primary annotation data, followed by exhaustive descriptions of query format and output data types. An Example section is available, with practical demonstrations of how to use SNPnexus.The query interface has been redesigned with dedicated navigation tabs for different sequence assemblies. It allows users to analyse variants mapped on different assemblies with greater ease. The results are presented with easier navigation facility and in an interactive tabular format with filtering, pagination and sorting options, and are available for download in multiple formats. Where appropriate, results are also summarized in graphical format using the open source visualization library Google Charts. The website contains an SNPnexus and other similar resources work on the principle of aggregating/calculating variant annotation information from disparate sources, which would be otherwise laborious for researchers to explore individually. As such, users need to apply their own discretion when interpreting findings reported in SNPnexus, notably those from the prediction algorithms with varying efficiency. Users should consult the individual resources and related peer-reviewed publications to check the reliability of the results generated by these algorithms.http://wannovar.wglab.org), the freely accessible web version of ANNOVAR, doesn\u2019t provide all the functionalities provided by its command line version. With the provision of predicted functional impact of noncoding variants and putative neo-antigen detection, SNPnexus also surpasses the functionalities offered by the Ensembl VEP Web (http://www.ensembl.org/vep).To the best of our knowledge, no single tool, or combinations thereof, available in the public domain provides the range of functionalities offered by SNPnexus. A few command-line-based tools such as ANNOVAR ,\u00a0EnsemblThe enhancements made in the current release of SNPnexus ensure that it remains a cutting-edge tool and continues to contribute toward maximizing the knowledge extracted from sequence variation data. Looking forward, the analytical focus of SNPnexus will expand toward multi-sample cohort study. This will allow users to build genetic variation profiles within and between samples, highlighting the shared variants and significantly mutated genes contributing to the phenotype studied. Based on the fully annotated variant results in one individual and/or across multiple samples, SNPnexus could then derive a prioritized list of putative disease-associated variants and genes for further investigation of clinical utility. At the same time, the addition of neoepitope prediction feature has propelled SNPnexus to the forefront of personalized medicine with the potential to intersect genomics and immunology. We are planning further useful expansions, for example, mining a candidate neoepitope in known antigen databases and assessing the expression pattern of the corresponding mutated gene, to grow SNPnexus\u2019 application in personalized immunotherapy.Supplementary DataClick here for additional data file."} +{"text": "Recent genomic studies identified a putative rdh gene in an uncultured deltaproteobacterial genome that was not accompanied by an rdhB gene, but contained transmembrane helixes in N-terminus. Therefore, rather than having a separate membrane anchor protein, this putative RDase is likely a hybrid of RdhA and RdhB, and directly connected to the membrane with transmembrane helixes. However, functionality of the hybrid putative RDase remains unknown. Further analysis showed that the hybrid putative rdh genes are present in the genomes of pure cultures and uncultured members of Bacteriodetes and Deltaproteobacteria, but also in the genomes of the candidate divisions. The encoded hybrid putative RDases have cytoplasmic or exoplasmic C-terminus localization, and cluster phylogenetically separately from the existing RDase groups. With increasing availability of (meta)genomes, more diverse and likely novel rdh genes are expected, but questions regarding their functionality and ecological roles remain open.Attempts for bioremediation of toxic organohalogens resulted in the identification of organohalide-respiring bacteria harbouring reductive dehalogenases (RDases) enzymes. RDases consist of the catalytic subunit (RdhA, encoded by Recent genomic analysis revealed putative reductive dehalogenase genes from extreme subsurface environments that unlike known reductive dehalogenases have membrane integral domains. With the advent of the Industrial Revolution, human impacts on the environment increased dramatically. Hazardous halogenated organic compounds, organohalogens, were widely distributed in the natural environment through careless use and indiscriminate disposal, and caused major public concerns due to possible effects on human and environmental health H\u00e4ggblom . In atteet al. rdh) have a conserved operon structure that consists of rdhA, coding for the catalytic subunit (RdhA); rdhB, coding for a small putative membrane anchor (RdhB) that (presumably) locates the A subunit to the outside of the cytoplasmic membrane; and a variable set of accessory genes (e.g. rdhCTKZED) in the N-terminus. Whereas the known respiratory RDases do not have membrane-integral domains, most RdhBs have three TMHs . Although the existence of rdh genes lacking the TAT motif and rdhB were reported in the genomes of strain NaphS2 and D. sandiegensis by reoxidation of respiratory cofactors for membrane-bound RDases, and catabolic reductive dehalogenation for cytoplasmic RDases RDases? Detoxification of organohalogens and thereby securing a hospitable environments for themselves and the nearby organisms? Providing carbon sources for themselves (catabolic RDase) or others (respiratory RDase)?et al. rdh genes RDases be involved in the production of halogenated bioactive compounds as was shown for biosynthesis of marine bacterial pyrroles mediated by a reductive debrominase that utilizes a redox thiol mechanism (El Gamal Genomics and allied technologies have greatly increased the diversity of putative ce Table\u00a0, Antarct"} +{"text": "Hepatic arterioportal fistulae are frequent vascular complications due to neoplasm, trauma and iatrogenic injury. On the other hand, fistulae between the hepatic arteries and hepatic veins (arteriohepatic venous fistula) are rare. We report the case of a 45-year-old male who suffered from a blunt abdominal trauma with abdominal distension. Initial cross-sectional imaging revealed laceration of the right lobe of liver with an arteriovenous fistula and hemoperitoneum. The diagnosis of arteriohepatic venous fistulae was confirmed on digital subtraction angiography (DSA) and treated angiographically with superselective coil embolization. Post-embolization angiogram showed complete occlusion of arteriovenous fistulae. We emphasis on the management part of the fistulae and endovascular treatment. We emphasis on the management part of the fistulae and endovascular treatment.Hepatic arterioportal fistulae are frequent vascular complications due to neoplasm, trauma and iatrogenic injury. On the other hand, fistulae between the hepatic arteries and hepatic veins (arteriohepatic venous fistula) are rare. We report the case of a 45-year-old male who suffered from a blunt abdominal trauma with abdominal distension. Initial cross-sectional imaging revealed laceration of the right lobe of liver with an arteriovenous fistula and hemoperitoneum. The diagnosis of arteriohepatic venous fistulae was confirmed on digital substraction angiography (DSA) and treated angiographically with superselective coil embolization. Post-embolization angiogram showed complete occlusion of arteriovenous fistulae. Hung et alA 45-year-old male with history of blunt abdominal trauma was brought to casualty with abdominal distension and drop in haemoglobin levels. Initial ultrasound imaging revealed free fluid in the abdomen. Exploratory laprotomy was done that show hemoperitoneum, and liver laceration in the right lobe. Perihepatic packing was done to achieve hemostasis.CT imaging done on day two revealed replaced right hepatic artery arising from superior mesenteric artery (SMA) with hepatic laceration involving segment VI and VII. Arterial phase CT images showed a prominent segmental branch of the right hepatic artery with a fistulous track communicating with the right hepatic vein \u20132. Two dFrom a transfemoral approach, the superior mesenteric artery was catheterized with 6F catheter (Chuang-William Cook Europe APS). Selective angiogram showed two prominent hepatic artery segmental branches leading to the lacerated liver parenchyma with early filling of the right hepatic vein suggesting post-traumatic arteriovenous fistulae . The rep2 congenital anomaly,3 trauma and iatrogenic injuries like needle biopsy and percutaneous drainage.4The most common cause of liver injury is blunt abdominal trauma. The incidence of hepatic vascular injuries after blunt trauma is much lower than that after penetrating injury. Traumatic intrahepatic arteriovenous fistulae are rarely encountered which generally involve arterial to portal venous connection and rarely result in arterial to hepatic vein connection. The leading cause of arteriovenous fistulae are neoplasm,4 in his series of patients after needle biopsy and percutaneous biliary drainage demonstrated arterioportal fistula in eight patients and arteriohepatic venous fistula in one patient on angiography. Fistulae of systemic venous system can lead to cardiovascular compromise with high output cardiac failure.5 Infrequent cause of arteriohepatic venous fistulas may be attributed to the larger distance between artery and hepatic vein. Post-traumatic arterioportal shunts are more frequent as these vessel systems are in close proximity at the portal tract. Dessousky et al6 in his series of patients with intrahepatic vascular shunts proposed a strategy for early identification, classification and management of shunts.Okuda et al7 Congestive cardiac failure, portal hypertension, portosystemic encephalopathy, cholangitis and atypical cirrhosis have been reported as possible serious complications related to this condition. Thus, a correct diagnosis is important and diagnostic imaging has a fundamental role in the evaluation of shunts and determination of the appropriate management.8 Two types of shunts were identified- arteriovenous (72%) and venovenous (28%). Arteriovenous shunts can be further classified into arterioportal and arteriohepatic shunts, whereas venovenous shunts can be further classified into portovenous, portoportal and venovenous shunts.6Intrahepatic vascular shunts (IHVSs) are abnormal communications between intrahepatic vasculature involving the arterial, portal or hepatic venous systems. The etiology of these shunts is controversial and may be either acquired, as those associated with cirrhosis or hepatocellular carcinoma, those that occur after traumatic injuries to the liver or interventional transhepatic procedures , or they may appear in the form of congenital and idiopathic vascular malformations, as in Rendu\u2013Osler\u2013Weber syndrome (hereditary hemorrhagic telangiectasia).6 proposed a practical strategy with therapeutic implication based on both imaging and clinical findings and categorized patients into three groups as follows: Group I included asymptomatic patients with small non-neoplastic shunts (3\u20136\u2009mm) and with shunt ratio <\u200930%. They were followed by Doppler and clinical examination at 3 to 6 months interval. If the shunt did not change or regressed, and no signs or symptoms developed, then conservative management was applied according to the type of shunt.Dessousky et alGroup II included patients with symptomatic shunts, large (15\u201323\u2009mm) or aneurysmal shunt (28\u201345\u2009mm), those with shunt ratio >30% or neoplastic shunt. These shunts are usually managed by interventional technique.Group III included patents with diffuse shunts or with shunt ratio >60%, and were planned directly for surgery.In our case, as the patient was symptomatic and as the size of the fistulae were >15\u2009mm, management with embolization was considered.9 Early angiographic embolization decreases the incidence of blood transfusion and number of liver-related operations.8 Transcatheter arterial embolization has proved to be effective in treatment of arterioportal shunts, and its associated complications are rare.103D post-processing of CT angiography with multiplanar reformation (MPR), maximal intensity projection (MIP) and volume rendering technique (VRT) is especially helpful in detection of vascular injuries. In this case, CT promptly showed the hypertrophic segmental branches leading to the fistulae. Interventional techniques, especially angiographic embolization, are well-known as useful adjunct in non-operative management of blunt liver trauma.Arteriovenous shunts are rare complication of blunt trauma. Arteriohepatic shunts are rarer than arterioportal shunts. Multiphasic MDCT can be very helpful in proper planning before an interventional procedure. Angiographic embolization can decrease the incidence of transfusion and surgical procedures. Intrahepatic vascular shunts can be managed by interventional technique, and surgery depending on clinical presentation and shunt ratio.Arteriohepatic venous shunts can occur rarely when compared with arterioportal shunts in abdominal trauma.Management of arteriohepatic venous shunts is similar to arterioportal shunts by interventional technique like micro coil embolization depending on the shunt ratio and clinical presentation.Written informed consent was obtained from the patient(s) for publication of this case report, including accompanying images."} +{"text": "Social relationships are a well-established correlate of late-life well-being. Extensive research finds social support is associated with fewer depressive symptoms, yet few studies distinguish fine-grained types of support from spouse, children, other family and friends, nor whether these linkages differ by gender and marital status. Studies exploring coarse associations between support and well-being may conceal gender and marital status differences. We use data from two waves of the Health and Retirement Study to study fine-grained linkages between diverse types of relationship strain and support and depressive symptoms (CESD) among adults aged 51+. The results show that the association between support/strain and depressive symptoms varies based on the source of support. For instance, among married/partnered older adults, spousal support is negatively associated with depressive symptoms whereas friend strain is positively associated with depressive symptoms. Among widowed respondents, friend support is negatively associated with depressive symptoms. These marital status patterns differed by gender however, such that the impact of friend strain on depressive symptoms was especially large for divorced men. Our results suggest that no single form of social support (or strain) is uniformly protective (or distressing), so services and interventions to enhance late-life mental health should more fully consider older adults\u2019 social location, including gender and marital status. For current cohorts of older adults, who have lower rates of marriage and childbearing than their predecessors, it is critically important to understand both the levels and impacts of alternative sources of support from other kin and friends."} +{"text": "Cardiac resynchronization therapy (CRT) is an effective treatment for patients with heart failure (HF) and conduction abnormalities. Conceptually, CRT works by improving myocardial contraction synchrony and performance with a parallel left ventricular (LV) reverse remodeling and subsequent improvement in morbidity and mortality -3. CurreCRT mechanically ameliorates the activation delay between opposing contracting walls of LV by an extra lead implanted into LV free wall. Echocardiography can provide the additional necessary improvement in selection of patients by identifying more precisely the asymmetry in contraction and activation delay between the opposing contracting walls of LV. Over the years, a number of echocardiographic techniques have been introduced to identify this asymmetry more commonly known as mechanical dyssynchrony . DespiteRecent studies applied some new echocardiographic techniques focusing on the physiology of a how a CRT works which have shown promising results in small-scale studies , 3. One This editorial focusses on the sub-study performed on the Echocardiography guided cardiac resynchronization therapy (EchoCRT) trial data by Tayal et al. . In EchoThis study highlights the limitation of time-to-peak dyssynchrony methods, bringing forward the discussion on the role of dyssynchrony in patients treated with CRT and its physiology. Future trials applying these newer echocardiographic techniques in selection of patients with wide QRS (> 130ms) for CRT in multicenter randomized settings can provide more convincing evidence. Specifically focusing on groups where the guidelines are still ambiguous, such as LBBB patients with intermediate QRS duration (130-149 ms) and non-LBBB morphology (> 130ms) would be of benefit by reducing unnecessary implants."} +{"text": "Dually eligible individuals often have worse health and greater functional limitations than patients eligible for Medicare only. For dually eligible patients receiving inpatient rehabilitation services following a major illness or injury, improvement in function may be lower than for Medicare-only patients. To our knowledge, this is the first study to examine the relationship of dual eligibility on improvement in mobility for inpatient rehabilitation facility (IRF) patients by 13 primary diagnosis groups . Data was collected on the IRF-Patient Assessment Instrument at admission and discharge for all IRF patients discharged during 2017 . A generalized linear model was run for each primary diagnosis group to examine the effect of dual eligibility on change in mobility during an IRF stay, adjusting for sociodemographic factors, clinical factors, and comorbidities. The proportion of patients who were dually eligible varied among primary diagnosis groups . Compared to patients who were non-dually eligible, dually eligible patients had lower improvement in mobility across all 13 diagnostic groups. The strongest effect of dual eligibility on lower improvement in mobility was among patients with hip and/or knee replacements and patients with non-traumatic spinal cord dysfunction . This research indicates that dually eligible patients may have worse functional mobility outcomes than non-dually eligible patients for some IRF primary diagnosis groups, and these patients may need additional support after discharge."} +{"text": "Eucalyptus nitens breeding population focused on improvement for solid wood production. A high-density SNP chip (EUChip60K) was used to genotype 691 individuals in the breeding population, which represented two seed orchards with different selection histories. Phenotypic records for growth and form traits at age six, and for wood quality traits at age seven were available to build genomic prediction models using GBLUP, which were compared to the traditional pedigree-based alternative using BLUP. GBLUP demonstrated that breeding value accuracy would be improved and substantial increases in genetic gains towards solid wood production would be achieved. Cross-validation within and across two different seed orchards indicated that genomic predictions would likely benefit in terms of higher predictive accuracy from increasing the size of the training data sets through higher relatedness and better utilization of LDGenomic selection is expected to enhance the genetic improvement of forest tree species by providing more accurate estimates of breeding values through marker-based relationship matrices compared with pedigree-based methodologies. When adequately robust genomic prediction models are available, an additional increase in genetic gains can be made possible with the shortening of the breeding cycle through elimination of the progeny testing phase and early selection of parental candidates. The potential of genomic selection was investigated in an advanced Eucalyptus nitens (Deane & Maiden), is the most important commercial eucalypt species in New Zealand, with an advanced breeding programme moving towards its fourth generation breeding population, therefore, some inaccuracy in breeding values is expected due to unknown paternal contribution and plausible pedigree errors. Precisely recorded pedigrees and known ancestors of the breeding population individuals are prerequisites for accurate genetic evaluation and consequently, efficient breeding programme management and boosted genetic gain in forest tree species.Shining gum, Genomic selection was proposed as a tool to predict individual breeding values on the basis of information from high-density genetic marker panels through multiple regression models was estimated in terms of status number as following \u019f is group co-ancestry of individuals individuals per family used for genomic prediction analysis for which genomic information and phenotypic trait records were available. The Waiouru seed orchard was represented by 431 genotyped individuals with effective population size of 133.2, while the Tinkers seed orchard was represented by 236 genotyped individuals with effective population size of 64.7. The effective population size . The marker data were filtered for genTrain score\u2009>\u20090.5, GenCall\u2009>\u20090.15, minor allele frequency\u2009>\u20090.01, SNP call rate\u2009>\u20090.6 and pairwise LD in terms of a composite estimate (r2\u2009<\u20090.9), with 12,236 SNPs selected to train genomic prediction models. The missing data were imputed through expectation-maximisation algorithm implemented in \u201crrBLUP\u201d package following A is the average numerator relationship matrix is set nested within replication following e following X and Z1, Z2 and Z3 are incidence matrices assigning fixed and random effects to measurements in vector y from breeding cycles and selections based only on genetic markers. It was estimated as follows:The full efficiency of genomic selection was investigated by comparing genetic gains per generation using pedigree-based estimated breeding values (BLUP) with genetic gains using genomic marker-based estimated breeding values (GBLUP). Both of these individual based estimated genetic gains included the availability of phenotypic records for all traits. The mean value of BLUP and GBLUP breeding values of the 20% of selected individuals was the measurement for the estimated genetic gain.Pedigree-based analysis showed low to moderate within seed orchard heritabilities in both seed orchards Table . PedigreAcross seed orchard heritability estimates were generally higher using marker-based breeding values than pedigree-based with only a few exceptions Table . RecondiMarker-based breeding values had consistently higher accuracies than pedigree-based breeding values. Generally, accuracies of breeding values were higher for both seed orchards when using marker-based rather than pedigree-based estimated breeding values. However, there were some inconsistencies, with the Tinkers seed orchard showing lower genomic breeding value accuracies for radial wood shrinkage, DBH and height than for the same traits using pedigree-based models, reflecting the pattern in heritability.The cross-validation analysis showed no, or very low, predictive accuracy for breeding values for one seed orchard when based on a model trained in an alternative seed orchard, using pedigree-based or marker-based models Table . Within Generally estimated absolute genetic gains per generation were as expected higher when using GBLUP breeding values rather than BLUP breeding values Table . The estThe benefits of using information from genomic markers in the genetic evaluation were apparent in the current study, where both within seed orchard and across seed orchard estimations supported the use of GBLUP over BLUP predictions. The reduced number of SNPs after filtering still provided sufficient genomic information to perform efficient marker-based predictions, which improved breeding value accuracies when compared with pedigree-based evaluations. A gain in accuracy of breeding values would likely be even more substantial when increasing the size of training population by additional genotyping. Grattapaglia and Resende estimateForest tree breeding programmes are generally in the very early stages compared to animal and crop breeding programmes with faster generation turnover plays a significant role in forestry tree breeding (Li et al. Estimated absolute genetic gains based on GBLUP breeding values per generation indicate that genomic selection would significantly improve the efficiency of selection for solid wood properties. The major benefit of genomic selection in accelerating the rate of genetic improvement would be derived from the ability to shorten the generation interval through the very early selection at the seedling stage (Resende et al. E. nitens breeding population. A question remains as to how well prediction models perform after several breeding cycles (Resende et al. E. nitens breeding population is required to find the best possible methodology, including additional data infusions of wider breeding population that will reflect better the future selection population than in the current study. We expect further data infusions to result in considerably higher predictive accuracy of genomic breeding values compared to pedigree-based methods. Increasing the training population size as well as applying different statistical methods that can account efficiently for the accuracy due to LD may give further confidence in implementing GEBVs in the breeding programme (Habier et al. The potential to make faster selections by skipping progeny testing should be pursued in this E. nitens was possible by implementing genomic marker-based prediction compared to pedigree-based prediction. The greatest improvement in genetic parameters was obtained for tangential air-dry wood shrinkage and growth strain, which are the key traits in selection for solid wood production in eucalypts. Wood shrinkage traits had moderate heritabilities, which mainly increased further with genomic prediction.This study showed that a significant improvement in breeding value accuracy and genetic gains for selection of wood properties in Results from cross-validation analysis implied that further infusions of additional seed-orchard material into the training data would be useful to increase the efficiency of genomics in the selection, regarding breeding value accuracy and predictive accuracy. Further analysis, including more progeny trial sites to investigate the transferability of these models across generations and environments is recommended.Data available from Dryad: 10.5061/dryad.pf58510."} +{"text": "OBJECTIVES/SPECIFIC AIMS: To develop a robust spatial normalization pipeline for brains of individuals with focal cortical lesions. METHODS/STUDY POPULATION: Individuals with chronic focal cortical lesions from stroke. RESULTS/ANTICIPATED RESULTS: We have developed a robust spatial normalization pipeline for brains of individuals with focal cortical lesions, and demonstrate how the pipeline overcomes obfuscated neuroanatomy to yield both consistent and excellent results. DISCUSSION/SIGNIFICANCE OF IMPACT: Our robust normalization pipeline will enable group analyses of individuals with cortical lesions with greater spatial precision. This greater spatial precision will improve answers to questions about functional localization in the brain, and ultimately allow translation of findings from neuroimaging studies in individuals with cortical lesions to the clinic."} +{"text": "The two branches of the autonomic nervous system (ANS) have been individually linked to age-related changes in cognitive functioning: The parasympathetic nervous system (PNS) is thought to support healthy cognitive aging, whereas the sympathetic nervous system (SNS) has been linked to heightened cognitive decline. Despite these separate findings and despite the integrative nature of the ANS, little work has examined the two branches simultaneously to better understand their interactive effects on age-related cognitive changes. We examined cognitive change in two waves of the MIDUS cognitive project and indexed PNS and SNS activity from heart rate variability and epinephrine levels (respectively) from the MIDUS biomarker project . Our findings indicate that higher PNS levels attenuate cognitive decline, but only among individuals with low SNS levels; at higher SNS levels, the beneficial effects of the PNS are blocked. Further, lower PNS levels can be somewhat compensated for by increased SNS levels. This pattern was most robust among individuals transitioning to mid-life . These results suggest that interventions targeting the ANS as a modifiable factor in cognitive aging should consider both ANS branch\u2019s effects simultaneously, particularly in the early stages of midlife."} +{"text": "Cancer cell dormancy is an important source of treatment failure. We studied the molecular characteristics and functional behaviour of dormant colorectal cancer cells finding them to be a differentiated yet plastic population. Organoid drug screening identified itraconazole perturbs dormancy through non-canonical hedgehog signalling effects on the WNT pathway. Functional heterogeneity can be defined as differences in both the identity and phenotype of cancer cells and has been shown to poorly correlate with mutational background.3 Studies seeking to understand functional heterogeneity have tended to focus on understanding the nature of highly clonogenic so-called cancer stem cell populations. Efforts to explore cell cycle-defined functional heterogeneity have been limited despite the well-established connection between cell cycle progression and clonogenic status.Heterogeneity exists at multiple levels in colorectal cancer (CRC) and over the last decade, major progress has been made cataloguing and quantifying inter-tumoral genetic differences.4 The study of tumour dormancy is technically difficult as there are only a small number of suitable experimental assays that can be used to identify dormant cells. The most common technique used to identify and isolate dormant cells is through label-retention. Label-retaining assays involve initially marking all cells of interest with a visible label. Following labelling, proliferative cells will gradually dilute out the marker with subsequent divisions whereas dormant cells will retain a visible label (label-retaining cells).Adjuvant CRC therapy relies on s-phase cytotoxics, which target exclusively dividing cells. Therefore, it is of vital clinical importance to effectively identify and target dormant CRC cell populations as potential drivers of disease recurrence. Prevalent prolonged intermission between primary disease treatment and representation with metastases in CRC patients indicates that reactivation of chemotherapy-resistant quiescent cancer cells may indeed be key in disease relapse. Having previously defined the nature of quiescent cells in the normal murine intestinal epithelium we sought to apply insights from normal stem cell biology to aid the identification of dormant CRC cells.5 Cells were grown in spheroid culture to permit the simultaneous culture of both clonogenic and differentiated cells thereby mirroring primary CRC cellular heterogeneity. In other cancers dormant cells have commonly been found to possess cancer stem cell features, however we unexpectedly found dormant CRC cells to reside in a differentiated state. Furthermore, upon re-culture in a permissive environment, we found dormant cells readily re-entered the cell cycle and acquired a cancer stem cell identity. These surprising results are consistent with a recent report from Toshiro Sato\u2019s group who lineage-traced LGR5+ (leucine-rich repeat-containing G-protein coupled receptor 5) cancer stem cells and KRT20+ (keratin 20) differentiated cells in murine CRC xenografts.6 In agreement with our findings, Sato and colleagues observed that following elimination of LGR5+ cancer stem cells, KRT20+ cells de-differentiated and acquired cancer stem cell features. This plasticity of cancer cell identity and functionality demonstrated by ourselves and the Sato group resembles the previously described reversion of partially differentiated intestinal progenitors to a stem cell state upon perturbation of homeostasis.7To define the molecular landscape of CRC cell dormancy we applied a label-retaining approach, to a panel of cell lines representing the molecular diversity found in CRC, in combination with transcriptomic profiling.We hypothesised that perturbing dormancy would render the tumour, as a whole, more sensitive to conventional chemotherapy. Therefore, to identify compounds that could alter the dormant state of label-retaining cells we carried out a functional murine organoid drug screen. The most striking phenotype identified from our drug screen was found with the anti-fungal itraconazole. Itraconazole generated profound organoid collapse, almost complete loss of dormant cells followed by global senescence. We validated our murine organoid findings in human CRC cell lines, human primary and metastatic patient-derived organoids, and performed transcriptomic analysis to examine the mechanism of the itraconazole derived phenotype.8 Itraconazole has previously been shown to inhibit canonical hedgehog signalling by binding smoothened (SMO).9 Unexpectedly, we found hedgehog pathway inhibition was inconsistently associated with itraconazole responsiveness. Conversely, WNT pathway inhibition was uniformly correlated with the itraconazole response and phenotype. We hypothesised that suppressor of fused (SUFU) may link an apparent hedgehog pathway inhibitor with WNT inhibition. Indeed, siRNA knockdown of SUFU rescued the itraconazole phenotype and WNT signalling thereby confirming the novel effect of itraconazole on the key regulatory pathway of CRC development (in vivo pre-clinical validation studies indicating that itraconazole causes irreversible tumour growth arrest, WNT pathway inhibition and synergistic activity with classical s-phase cytotoxics.Canonical hedgehog signalling in CRC is predominantly paracrine with pathway activation found in the stromal microenvironment alone.elopment . Finally10 Our findings and that of Lange and colleagues are highly compatible with the exception that Regan et al. propose that the non-canonical hedgehog derived effect is Patched-1 dependent. However, our data show this to be SMO and SUFU mediated. Interestingly, we found that another classical smoothened inhibitor, cyclopamine failed to reproduce the findings found with itraconazole. This suggests that SMO inhibitors may induce distinctive structural changes which may differentially alter the subsequent interaction between SMO and SUFU and potentially explain the difference between Lange\u2019s findings and ours.Autocrine non-canonical hedgehog effects on WNT signalling and differentiation status in CRC has been recently described by Martin Lange\u2019s group.High CRC and also renders dormant cells temporarily vulnerable to cytotoxic therapy prior to entering permanent senescence paving the way for future clinical studies.Cumulatively, our study provides evidence that a safe FDA-approved compound generates profound growth retardation in WNT"} +{"text": "Recent Zika virus (ZIKV) epidemics necessitate the urgent development of effective drugs and vaccines, which can be accelerated by an enhanced understanding of ZIKV biology. One of the ZIKV structural proteins, precursor membrane (prM), plays an important role in the assembly of mature virions through cleavage of prM into M protein. Recent studies have suggested that prM protein might be implicated in the neurovirulence of ZIKV. Most vaccines targeting ZIKV include prM as the immunogen. Here, we review progress in our understanding of ZIKV prM protein and its application in ZIKV vaccine development. Zika virus (ZIKV) was first isolated in 1947 from a rhesus monkey taken from the Zika Forest in Uganda . Prior tZika virus outbreaks from 2015 onward have been of major public health concern due to their associated clinical complications, such as Guillain-Barre syndrome in adults and neonatal microcephaly, suggesting mother to child transmission of the virus . Owing tZika virus is mainly transmitted to humans through mosquito-borne vectors , though trans-Golgi network before release of mature virions and dengue virus. ZIKV has an approximately 11 kb positive-stranded RNA genome, with untranslated regions flanking the 5\u2032 and 3\u2032 ends of its open reading frame. The genome is translated into structural proteins and non-structural (NS) proteins [reviewed in ]. The NS virions . The prMiviruses . A conseiviruses . Therefoiviruses . This shTable 1). These genomic variations might have been driven by ZIKV adopting an urban-based transmission cycle targeting humans as hosts rather than the original sylvatic mode of transmission that normally involves Aedes mosquitoes and non-human primates . These sroteins) .pr peptide of prM protein might not be present in the final vaccine formulation.The ZIKV vaccines currently under development are mainly based on purified inactivated viruses, plasmid DNA, or mRNA platforms . ImportaA vaccine produced by immunizing mice with VLPs that incorporates full-length ZIKV structural proteins (C-prM-E) can also endow full protection against ZIKV and induces production of more ZIKV-neutralizing antibodies than DNA vaccines . A chimeSuccessful immunization and neutralizing antibody production in C57BL/6 mice has been demonstrated for an RNA nanoparticle vaccine based on prM-E . This vaModified mRNA vaccines based on ZIKV prM-E proteins have also been developed . These mZika virus has become a major public health concern, with outbreaks of the disease spreading across the globe and resulting in congenital birth defects in some instances. Evolutionary and purifying selection pressures might have facilitated modifications of the ZIKV genome that enhance its replication efficiency and reduce host immune efficiency as it adapted to new hosts in urban environments. This has led to virus strains being categorized as either pre-epidemic or epidemic, with the latter being associated with recent infection outbreaks. Thus far, the S139N amino acid substitution of prM protein has been linked to increased neurovirulence, suggesting that alterations of ZIKV prM protein may enhance viral virulence. Further studies on other observed amino acid substitutions in all viral proteins should be carried out to establish their roles in viral replication efficiency.Various platforms have been employed to generate vaccines against ZIKV infections, including purified inactivated virus, plasmid DNA, and mRNA nanoparticles. Despite these platforms having been adapted from studies of other flaviviruses, the resulting vaccines have exhibited experimental success when a combination of both prM and E proteins are utilized. In contrast, sole use of ZIKV prM protein in vaccines against ZIKV has not yet proven as effective as prM-E combinations.It remains unclear if future epidemics will have the same clinical implications as the most recent epidemic or which viral protein modifications are more likely to result in another epidemic. Furthermore, whether the ZIKV vaccines currently under development can be effective against future epidemics is uncertain. These basic questions should guide research efforts for the prevention, control and therapeutic strategies of ZIKV. Additional focused studies on the molecular and structural biology of ZIKV prM may accelerate our ability to tackle this emerging public health concern.PN wrote the manuscript. W-CS contributed to the framework and the editing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Oxidative stress has a role in the initiation and progression of breastcancer .OxidatiBy damaging DNA, activating oncogenes, and producing genomic instability,reactive oxygen species can initiate carcinogenesis . ReactivBreast cancer tumors with enhanced proliferative capacity produce high levelsof reactive oxygen species during their chronic cycles of ischemia, reperfusion, andangiogenesis, resulting in growth signaling . Cancer Many chemotherapeutic drugs and radiation treatments eliminate tumors throughthe induction of reactive oxygen species in cancer cells . HoweverEndogenous antioxidants, including non-enzyme and enzyme antioxidant defensesystems act to prevent or limit tissue damage by scavenging free radicals incells . SuperoxExogenous antioxidants from dietary intake such as vitamin A, vitamin E, andVitamin C, may also have a role in the alleviation of oxidative stress, which couldreduce risk of breast cancer or slow progression of the disease . HoweverResults from observational epidemiologic studies conducted over the pastseveral decades demonstrate that physical activity and weight control are importantdeterminants of breast cancer risk and progression . OxidatiIn order to inform future studies of antioxidant chemo-preventive agents thatmay reduce risk of breast cancer initiation or progression, the complexities of howredox imbalance contributes to cancer and other chronic diseases should beconsidered. This includes the observation that although high levels of reactiveoxygen species disrupt cellular processes, lower levels of reactive oxygen speciescan act as cell signaling messengers by reversibly oxidizing protein thiol groupsand modifying protein structure . Thus, t"} +{"text": "A 76-year-old male with a small bowel neuroendocrine tumor with hepatic metastases presented with new onset lower extremity swelling, bloating, and weight gain which ultimately lead to cardiac magnetic resonance (CMR) to evaluate for cardiac involvement of disease. CMR showed right and left ventricular myocardial metastases along with findings suggestive of carcinoid heart disease. The patient had severe tricuspid valve regurgitation necessitating surgical valve repair. The patient underwent bioprosthetic tricuspid valve replacement and debulking of the metastases with surgical pathology confirming neuroendocrine tumor metastases. Follow-up clinical evaluations at 3, 6, and 9 months postoperatively showed improvement in cardiac function and stable hepatic tumor burden. This case demonstrates the utility of CMR to diagnose myocardial metastases and carcinoid heart disease complicated by severe tricuspid regurgitation, which guided surgical management. Neuroendocrine tumors (NETs) are a diverse group of tumors arising from neuroendocrine cells, and they can cause primary tumors in many different organs including the lungs, small intestine, rectum, pancreas, and other organs . Within NETs of the midgut commonly release vasoactive substances including 5-hydroxytryptamine (serotonin), histamine, tachykinins, and prostaglandins . When thIn rare cases, NETs can metastasize to the heart , 11. CarA 76-year-old male with stage IV, small bowel NET metastatic to the liver had been followed by our institution for 4 years with stable hepatic metastatic disease on octreotide long-acting release (LAR) therapy. Originally, the tumor Ki-67 index was 5% and 24-hour urine 5-hydroxyindole acetic acid (5-HIAA) was 105\u2009mg. The patient presented with mild progression of disease on abdominal magnetic resonance imaging (MRI) after apCMR showed aThe patient underwent bioprosthetic tricuspid valve replacement and biopsy and debulking of the myocardial tumors. The myocardial tumors were histologically confirmed as NET metastases. The patient recovered well from surgery, and follow-up clinical visits demonstrated significant improvement in his carcinoid heart disease. As of the latest visit, the patient has excellent cardiac function with resolution of tricuspid regurgitation. His 9-month postoperative follow-up CT scan showed relatively stable disease, and his urine 5-HIAA was improving. The patient is continuing on octreotide LAR 30\u2009mg.We present a unique case of carcinoid heart disease and myocardial metastases both contributing to this patient's severe symptomatic tricuspid regurgitation. The tricuspid valve thickening is a specific finding of carcinoid heart disease, and well-defined lesions with arterial perfusion in the RV and LV walls are specific for metastases. Previous authors have suggested that vasoactive mediators associated with myocardial metastases may accelerate the onset of carcinoid heart disease, which could explain the case described here , 16.Carcinoid heart disease manifests via the accumulation of carcinoid plaque composed of smooth muscle, myofibroblasts, and elastic tissue . Plaque Echocardiography serves as first line screening for cardiac involvement in patients with carcinoid syndrome. Common echocardiographic features of carcinoid heart disease include morphologic changes to the tricuspid valve causing a thick retracted appearance with decreased mobility and enlargement of the right atrium and ventricle related to valvular insufficiency . SurgicaCMR offers more specific evaluation of cardiac lesions to help differentiate benign lesions from metastases compared to echocardiography evaluation which is based on lesion intrinsic signal and perfusion characteristics . While eThis case demonstrates the importance of CMR to evaluate for carcinoid heart disease and cardiac metastases. The results of the CMR exam in our case lead to characterization of myocardial metastases and allowed for planning of metastasis resection during the tricuspid valve bioprosthetic surgery. The case also serves as a reminder for providers that while echocardiography may offer first line screening for cardiac involvement when carcinoid heart disease is suspected, CMR may be useful when myocardial metastases are suspected for potential surgical planning."} +{"text": "Seven enterprises that have had recent Cleaner Production (CP) audits in Beijing were interviewed to identify whether these enterprises implemented the audit recommendations. If enterprises did implement the recommendations, their reasons and the results were analyzed. Finally, some suggestions on how to promote enterprise-wide CP were given."} +{"text": "Utilizing two-photon fluorescence lifetime imaging microscopy and the phasor analysis method, we have observed AD-related variations of endogenous fluorescence of reduced nicotinamide adenine dinucleotide (NADH) in vivo. We collected NADH FLIM images from the cerebral cortices of both APPswe:PS1dE9 mice to model amyloid Disruptions and alterations to cerebral energy metabolism play a vital role in the onset and progression of many neurodegenerative disorders and cerebral pathologies. In order to precisely understand the complex alterations underlying Alzheimer\u2019s disease (AD) progression, Current estimates indicate that AD accounts for 60% to 80% of dementia cases,\u2013in vitro conditions, oxygen levels can be adjusted and metabolic substrates can be added such that the sample\u2019s NADH can reversibly be adjusted between its fully oxidized and fully reduced states, therefore providing calibration for the minimal and maximal detectable NADH fluorescence signal. Confounds arising from toxicity prevent calibration and absolute quantitation in living organisms; however, evaluating relative changes of in vivo NADH fluorescence intensity still provides a useful indication of pathology-induced variations of mitochondrial function and intracellular oxygen requirements.in vivo measurement techniques\u2019 utility was greatly extended by coupling NADH fluorescence with 2-photon microscopy (2PM),,,,\u2013in vivo FLIM measurements can resolve disruptions to the TCA cycle, electron transport chain, and oxidative phosphorylation.\u2013For several decades, measurements of reduced nicotinamide adenine dinucleotide (NADH) have been utilized as a nondestructive tool to characterize mitochondrial respiratory chain activities. NADH is an electron carrier molecule residing in almost all eukaryotic cells both in cytosol and mitochondria, and it performs vital roles in both anaerobic glycolysis and aerobic oxidative metabolism.In this report, we apply two-photon fluorescence lifetime imaging microscopy (2P-FLIM) of endogenous cortical NADH for minimally invasive characterization of AD-induced variations in cerebral metabolism in a mouse model of AD. We utilized phasor analysis to show that amyloid 2,Our imaging experiments were performed under a protocol approved by the Institutional Animal Care and Use Committee at Massachusetts General Hospital. For our studies, we utilized female transgenic APPswe:PS1dE9 mice . By integrating the photon count matrices along the time axis, intensity images were generated and used for preprocessing. First, to isolate parenchymal NADH fluorescence, features such as blood vessels were masked out manually, as well as constituents displaying endogenous fluorescence such as lipofuscin granules. The boundaries for ,The coordinates, 3We sought to evaluate AD-related alterations to mitochondrial function by measuring NADH in the living cortex of AD mouse models. Similar to flavin adenine dinucleotide (FAD), NADH is endogenous and ubiquitous within most eukaryotic cells, and it participates in multiple steps of glucose breakdown and ATP synthesis. Monitoring the fluorescence of these electron carriers uniquely enables nondisruptive assessment of energy metabolism within living biological tissue.,in vivo and in vitro. Conversely, lipofuscin phasor clusters were broad and dispersed over a range of short lifetimes. For both endogenous fluorophores, phasor clusters corresponding to measurements taken from regions near After masking, phasor computations were performed on all measurements and grouped using our custom software. ,To evaluate the spatial extent of metabolic variations around in vitro observations of impaired respiration and mitochondrial toxicity induced by intracellular Although further validation is required, the present, phasor-based observations of endogenous NADH fluorescence from living cortices of AD mouse models strongly indicate a pronounced influence of ,,Conversely, our observations of plaque-induced variations in lipofuscin fluorescence lifetime were unanticipated and raise intriguing questions regarding the nature and mechanisms of plaque-related toxicity. Often regarded as an aging-related pigment, lipofuscin granules are chemically and morphologically hetereogeneous masses primarily comprised of oxidatively modified protein and lipid residues that resist degradation by lysosomes. Lipofuscin is considered \u201cbiological garbage\u201d that progressively accumulates within several tissues with age, but the rate of accumulation can be accelerated in the presence of higher oxygen or reduced by administration of antioxidants.in vivo measurements of endogenous fluorescence are useful for characterizing distinct variations in mitochondrial metabolism and lipofuscin accumulation in the presence of Our study shows that phasor-based"} +{"text": "Background: According to the notion of maturational dualism, the link between mind and body weakens with age and this weakening has important consequences for emotional experiences. Specifically, it is hypothesized that age-related decline in interoceptive awareness and physiological reactivity reduce the ability to use bodily states to guide judgments about emotions. If this hypothesis is valid, then age may moderate the association between explicit measures and implicit measures of affective reactivity. Purpose: To investigate whether age moderates the association between explicit and implicit measures of negative affective reactivity. Methods: A sample of 275 participants (age range=20-78) viewed 25 pictures validated to induce negative emotions. Participants filled in the PANAS assessing explicit affect and the IPANAT assessing implicit affect before and after viewing the pictures. Emotional reactivity was operationalized as residualized gain scores derived from regressions of baseline affect on affect following picture viewing. Results: Age moderated the association between implicit negative affective reactivity and explicit negative affective reactivity (B=60). Discussion: The results showed a reduced association between explicit and implicit negative affective reactivity with age. This finding is consistent with the notion of maturational dualism and may indicate that older adults use affective processes that are not represented consciously less than young adults when judging their emotional state."} +{"text": "Breast cancer may affect young women who have not yet completed childbearing.Assisted reproductive technology (ART) provides alternatives for fertilitypreservation such as oocyte, embryo or ovarian tissue cryopreservation. Wereviewed the published literature on fertility-preserving management in breastcancer, aiming at finding evidence to answer the following questions: (1) Whatare the fertility sparing options available?; (2) How do these women respond toIVF? and (3) Can pregnancy influence breast cancer recurrence? There is apaucity of publications describing clinical experience and outcome data whichlimits accessibility to fertility preservation in this setting. Presently,oocyte or embryo cryopreservation are the main options for fertilitypreservation. IVF success rates are comparable to the ones of non-oncologicalpopulations according to the woman's age but current published studies lack dataon definitive success rates following embryo banking for cancer patients. Theperception that IVF and pregnancy may worsen cancer prognosis remains, despitethe lack of scientific evidence to support this notion. Published studies showreassuring results for pregnancies occurring >2 years after breast cancerdiagnosis. The best published evidence suggests pregnancy after breast cancerdoes not increase the risk of disease recurrence, thus pregnancy should not beforbidden once treatment is completed. Decision making for women diagnosed withcancer requires up-to-date knowledge of the efficacy and safety of availableoptions. Providing consultation with a reproductive specialist and appropriateinformation on fertility preservation for these women should be an essentialaspect of their supportive care. Cancer still represents an enormous global health burden, and published data revealedabout 14.1 million new cases and 8.2 million deaths in 2012 worldwide estimates that there will be 252,710 cases of invasive breast cancerdiagnosed in US women and 40,610 deaths. Data also shows that breast cancer isresponsible for 30% of new cancer cases, and 1 in 8 women will develop breast cancerduring their lifetime ,but only a small part of the patients (10%) used fertility preservation is achieved by subcutaneousinjection of gonadotropins for 8 to 14 days, along with pituitary blockagewith GnRH analogues. Follicular growth is monitored by transvaginalultrasound and final oocyte maturation can be triggered by hCG or GnRH-a.However, due to the concerns pertaining to the effects of supraphysiologicalhormonal concentrations, several different protocols have been studied in anattempt to minimize possible worsening in oncological prognosis and embryoor oocyte cryopreservation is the most effective option for fertilitypreservation in breast cancer. Ovarian stimulation significantly increasesestradiol levels, which raises concerns regarding safety of such a procedure aswell as the possible role of malignancy and BRCA mutation in reducing ovarianresponse to stimulation , as wellas comparable live-birth-rates in comparison to the electivecryopreservation group considers that evidence on anydifference in prognosis between pregnant and nonpregnant women with breastcancer is lacking, and it does not recommend pregnancy termination regardless oftumor status (Overall, the literature is reassuring and does not show a worse outcome for womenwith previously diagnosed and treated breast cancer who seek to become pregnantafterwards. Some data even suggest a better survival outcome. Those findingsshould bring comfort to physicians and to women with a previous breast cancerdiagnosis.In summary, the best available published evidence so far suggests that pregnancyafter breast cancer does not increase a woman's risk of disease recurrence.Pregnancy should not be forbidden after breast cancer treatment solely becauseof concerns on cancer recurrence and death, since current available data israther reassuring. If pregnancy is an option, these women must receive carefullycoordinated multidisciplinary approach. More large randomized prospective trialsare nedded to develop appropriate protocols in this setting.Hundreds of thousands of women in their reproductive years are diagnosed with cancereach year. Advances in breast cancer treatment result in increased numbers of femalepatients who survive cancer raising the demand for effective and individualizedfertility preservation options. Unfortunately fertility counseling remains asecondary issue for many breast cancer specialists. The perception that IVF andpregnancy may worsen cancer prognosis remains, despite the lack of scientificevidence to support this notion. Currently there are limited clinical options forfertility preservation, and the paucity of publications describing clinicalexperience and outcome data has limited accessibility to these options. Decisionmaking for patients diagnosed with cancer requires up-to-date knowledge of theefficacy and safety of available techniques. Providing consultation with areproductive specialist and appropriate information on fertility preservation forwomen with breast cancer should be an essential aspect of their supportive care."} +{"text": "Current research must utilize nationally-representative samples of older adults and their family caregivers to accurately reflect the growing diversity of the United States. This study aims to use a stress process model to examine potential racial differences in caregiving in a population-based sample of 844 White and 389 Black family caregivers in the United States. We conducted 3 x 2 x 2 (relationship type x race x dementia care status) factorial ANOVAs to examine potential differences in caregiving stressors, appraisals, resources, and mental and physical health outcomes among primary family caregivers. Results indicated significant racial differences in caregiving on several stress process measures. Although Black caregivers reported more caregiving stressors, compared to White caregivers, they tended to report more positive appraisals of caregiving and more caregiving resources. Dementia caregivers tended to report greater caregiving stressors and worse measures of appraisal compared to non-dementia caregivers. There was a significant two-way interaction among relationship type and dementia care status for the caregiving stressor, hours of care. A stress process model can allow researchers to investigate various factors associated with racial differences in caregiving."} +{"text": "South African adolescents experience high levels of trauma, including various types of childhood maltreatment. Different types of maltreatment often co-occur. Previous research suggests that childhood maltreatment provokes a latent liability to internalising and externalising dimensions of psychopathology. Our objective was to examine the effects of childhood maltreatment on internalising and externalising disorders in trauma-exposed adolescents and to assess the mediating effect of post-traumatic stress disorder (PTSD) on these associations.A cross-sectional study was conducted with 262 trauma exposed adolescents (aged 12\u201318 years) in South Africa. Childhood maltreatment and PTSD severity were assessed using the Childhood Trauma Questionnaire and the Child PTSD Checklist, respectively. Psychiatric disorders were diagnosed utilising the Kiddie Schedule for Affective Disorders and Schizophrenia \u2013 Present and Lifetime version \u2013 and were grouped into internalising and externalising disorders. Hierarchal logistic regression was used to assess the association between childhood maltreatment types and internalising and externalising disorders, controlling for statistically significant socio-demographic characteristics, with PTSD severity added to the final model as a potential mediator.B = 0.07, p = 0.011), although this effect was mediated by PTSD severity . In contrast, physical abuse and gender were associated with externalising disorders, but the addition of PTSD severity did not significantly alter these associations.Sexual abuse was significantly associated with internalising disorders (The association between sexual abuse and internalising disorders was fully mediated by PTSD symptom severity. Gender and physical abuse severity, but not PTSD severity, was associated with the presence of externalising disorders. Adolescents displaying internalising or externalising psychopathology need to be assessed for exposure to childhood physical and sexual abuse and PTSD comorbidity."} +{"text": "Aspergillus spp. spores found ubiquitously in the ambient environment is uncommon in immunocompetent patients. Previous reports of invasive upper airway aspergillosis in immunocompetent patients have generally demonstrated the efficacy of treatment regimens utilizing antifungal agents in combination with periodic endoscopic debridement, with symptoms typically resolving within months of initiating therapy.The development of respiratory infections secondary to Aspergillus fumigatus was isolated on tissue culture. Several months of oral voriconazole monotherapy failed to resolve her symptoms and she underwent mechanical debridement for symptom control. Following transient improvement, her symptoms subsequently returned and failed to fully resolve in spite of increased voriconazole dosing and multiple additional tissue debridements over the course of many years.A 43-year-old previously healthy female presented with worsening respiratory symptoms after failing to respond to long-term antibiotic treatment of bacterial sinusitis. Biopsy of her nasopharynx and trachea revealed extensive fungal infiltration and Invasive upper airway aspergillosis is exceedingly uncommon in immunocompetent patients. In the rare instances that such infections do occur, combinatorial voriconazole and endoscopic debridement is typically an efficacious treatment approach. However, some patients may continue to experience refractory symptoms. In such cases, continued aggressive treatment may potentially slow disease progression even if complete disease resolution cannot be achieved. Invasivpatients \u20137.Immunocompetent patients suffering from invasive upper airway aspergillosis can be particularly challenging to diagnose given that many initially present with indolent sinus symptoms easily mistaken for bacterial sinusitis , 8. WithA 43-year-old female with no significant past medical history presented with a chief complaint of worsening respiratory symptoms that included purulent nasal secretions, dysphagia, mild dysphonia and dyspnea with chronic cough. The symptoms had begun approximately 2 years previously and had failed to completely resolve in spite of multiple rounds of empiric antibiotic therapy for a presumed bacterial upper respiratory infection. She denied previous tobacco use and had no pertinent family history. Her physical exam was notable for erythematous nasal mucosa and a small anterior septal perforation. Blood work demonstrated a white blood cell count (WBC) of 11,400/uL (neutrophils 93.8%) and an erythrocyte sedimentation rate (ESR) of 11\u2009mm/h. Electrolytes were all within normal limits and a random glucose was 96\u2009mg/dL. Head and chest computed tomography (CT) showed air-fluid levels in the bilateral maxillary sinuses and irregular thickening along the left lateral and posterior tracheal wall just above the level of the medial clavicles but was negative for lung parenchymal changes.Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa but showed no fungal growth. As such, the patient was treated with intravenous vancomycin and cefepime in addition to steroids and nebulized treatments. Her breathing significantly improved during the course of her hospitalization and she was subsequently discharged with plans to continue outpatient intravenous antibiotics for an additional 2 months.Given these imaging findings in the setting of worsening dyspnea, the patient underwent a laryngoscopic examination, which revealed subglottic crusting with diffuse purulent secretions, anterolateral cricoid inflammation, and vocal cord inflammation. Her nasal cavity also demonstrated thick purulent secretions in the middle meatus bilaterally extending to the nasopharynx. Biopsies of the trachea, subglottis, and nasal septum demonstrated purulent, atypical squamous epithelium and necrotic tissue with bacterial colonies. Cultures from these sites were positive for methicillin-resistant Aspergillus fumigatus. Given a new diagnosis of invasive pseudomembranous aspergillosis, the patient was started on oral voriconazole with close outpatient follow-up.Several months later, the patient returned for follow-up and was found to have similar upper airway symptoms despite completing her antibiotic regimen. She again underwent endoscopic examination that revealed multiple regions of white, friable pseudomembranous patches spanning her mid-trachea, subglottis, and nasopharynx Fig.\u00a0. BiopsieAspergillus fumigatus. A formal immunological workup during this time was non-revealing with normal immunoglobulin levels, CD4+ T cell counts, absolute neutrophil counts, and complement levels. HIV testing was negative. Given her poor response to antifungal monotherapy, she was initiated on topical amphotericin B (100 mcg/ml) and budesonide (10 mcg/ml) nasopharyngeal rinses twice daily for symptomatic flares in addition to an increased dose of oral voriconazole .Over the following year, despite continuous antifungal treatment, the patient continued to experience tenacious, mucoid secretions, worsening dysphonia, nighttime pharyngitis, and frequent low-grade fevers. She required two separate inpatient admissions due to symptom escalation requiring endoscopic debridement of her trachea, pharynx, and nasal passages. Repeat tissue biopsies during this time period continued to demonstrate necrotic exudates in the presence of fungal hyphae with cultures continuing to grow pan-sensitive The patient continued on this regimen for 2 months and was found to have marked improvement on repeat endoscopic examination, at this point 18\u2009months after her initial diagnosis of invasive aspergillosis. Her larynx and subglottis had near normal appearance; her nasal cavities were dry bilaterally; her nasopharynx demonstrated mild scarring but otherwise demonstrated significantly less mucopurulence than on previous exams. However, in spite of this transient improvement, the patient again began developing upper airway symptoms over the following year, correlating with increased purulence in the nasal cavities along with the reformation of pseudomembranous, brown-mucoid layering in the nasopharynx seen on endoscopic exam. Increases in her voriconazole dosing to as high as 300\u2009mg, twice daily were attempted but did not result in significant improvement and were further complicated by vision changes attributed to supratherapeutic voriconazole trough drug levels. Additionally, while the frequency of mechanical debridement had previously averaged once every four to 6 months, the patient began requiring nearly monthly endoscopic suctioning of her nasal passage and pharynx for symptom control.Approximately 6 years after her initial diagnosis of invasive aspergillosis the patient continued to experience chronic symptoms including dysphagia, persistent dysphonia, and purulent secretions. Erosive changes to her posterior nasopharynx resulted in velopharyngeal insufficiency. Of note, serial chest x-rays during the course of her treatment never demonstrated abnormal parenchymal findings suggesting long-standing upper airway disease without progression to lower airway involvement. In the setting of persistently positive fungal hyphae seen on upper airway tissue biopsy, she was continued on oral antifungal therapy in combination with oral rinses and periodic mechanical debridement for symptomatic relief.Invasive aspergillosis of the respiratory tract is a rare but serious airway disease typically seen in immunocompromised patients. However, it is becoming increasingly clear that these infections can also occur in patients lacking the classic risk factors normally associated with underlying immunodeficiency. In the preceding case report, we presented the clinical course of an immunocompetent patient with clinical, microbiological, and histopathologic evidence of invasive pseudomembranous upper airway and tracheal aspergillosis persisting for many years in spite of longstanding treatment efforts. In our reading of the literature, this appears to be one of the most chronic cases of respiratory aspergillosis reported in an immunocompetent patient.aspergillus-related respiratory infections typically should have a formal immunological evaluation to rule-out primary and secondary causes of immunodeficiency. While different screening studies can be performed, enumeration of T cells and neutrophil counts are particularly important given their essential role in clearing fungal infections [Patients found to have invasive fections . Given tfections , more adfections .aspergillus-related respiratory infections develop in immunocompetent patients is poorly understood and difficult to study given the infrequency with which such cases occur and are reported. Interestingly, many of the comorbidities previously reported in immunocompetent patients diagnosed with invasive upper airway and tracheobronchial disease were notably absent in the case of our patient. D\u2019Anza et al. [The mechanism by which a et al. identifia et al. identifiaspergillus invasion in the absence of any other overt systemic predisposing risk factors. This is also potentially hinted at by the anatomical distribution of fungal disease seen in this case which appears to have mirrored the involvement of pre-existing invasive bacterial infection both histologically and on culture from the patient\u2019s trachea and nasopharynx during her initial course. We also note that concurrent infection of the upper airway and tracheobronchial tree appears to be a particularly rare anatomic distribution for invasive respiratory aspergillosis, with infection of these sites typically occurring in isolation of one another or in combination with lung parenchymal involvement when the disease becomes particularly widespread and aggressive [Given the absence of these previously described comorbidities, the question as to what initially predisposed our patient to her longstanding infection still remains. It does seem noteworthy that prior to presenting to our care, the patient was treated for mixed MRSA/pseudomonal bacterial sinusitis for approximately 2 years before developing evidence of aspergillosis on biopsy and culture data. Several case reports seem to suggest that chronic invasive aspergillosis may develop as a secondary infection following initial respiratory infections in immunocompetent patients. While these cases seem to be associated more often with viral etiologies such as influenza or even dengue , 12, it gressive , 13.Aside from the challenges in identifying the source of our patient\u2019s infection, understanding her poor response to combinatorial systemic antifungal therapy and mechanical debridement has proven equally challenging. In accordance with current treatment guidelines for invasive aspergillosis, oral voriconazole was started and continued for the duration of her disease course \u201316. HoweWhen used in combination, voriconazole and endoscopic debridement of infected tissue typically results in excellent outcomes in immunocompetent patients. Looking specifically at cases of upper airway aspergillosis, the patients described by D\u2019Anza et al. all requBased on this previous work, the expectation at the outset of our patient\u2019s treatment was that this combinatorial approach would be efficacious, particularly given her benign past medical history. However, it is notable that after years of active invasive infection, the patient had no radiographic involvement of the lung parenchyma on serial imaging, suggesting that while unable to completely resolve her disease, her treatment appears to have at least slowed her disease progression. The use of topical amphotericin B and steroid rinses, while more conventionally used for treatment of allergic fungal rhinosinusitis , 18 rathAlthough invasive upper airway aspergillosis is exceedingly uncommon in immunocompetent patients, such patients with chronic sinusitis and respiratory symptoms should be evaluated for the possibility of secondary invasive fungal infections, particularly those who fail to improve with appropriate antibiotic therapy. Although combinatorial voriconazole and endoscopic debridement is typically an efficacious treatment approach, some patients may continue to experience refractory symptoms, in which case continued aggressive treatment may potentially slow disease progression even if complete disease resolution cannot be achieved. Ultimately, this case highlights the possibility of refractory invasive aspergillosis in an immunocompetent patient and demonstrates the importance of further investigation into the pathogenesis of invasive fungal disease in the absence of overt systemic immunosuppression."} +{"text": "Traditional approaches aimed at delaying or preventing age-dependent diseases view each disease as a distinct entity, resulting from separate pathophysiological chains of events. However, it is becoming increasing clear that even in adult animals there remains significant plasticity in terms of ageing trajectories and lifespan, suggesting that targeting ageing processes directly may be a promising alternative strategy. However, to date effects of even the most efficacious pharmacological interventions are smaller than those of ageing mutations, even when targeting the same ageing pathways. Interestingly, it has been shown that simultaneously targeting multiple ageing pathways can result in lifespan benefits that are synergistic (more than additive). We have recently shown that dramatic lifespan and healthspan extension can also be archived by leveraging interactions between drugs targeting distinct subsets of the gene-regulatory network controlling ageing of C. elegans. These interventions were highly efficacious, even when animals were treated only as adults."} +{"text": "OBJECTIVES/SPECIFIC AIMS: To describe how Michigan Institute for Clinical & Health Research (MICHR) has engaged communities in its leadership and governance structure. This presentation will describe these practices, how they are being evaluated, and future plans for institute-wide engagement of communities in translational research. METHODS/STUDY POPULATION: Engaged partners from various communities across Michigan in various ways within MICHR\u2019s Community Engagement Program. RESULTS/ANTICIPATED RESULTS: MICHR has utilized participatory practices in the development of the CAB to strengthen existing relationships and build new ones with potential partners. DISCUSSION/SIGNIFICANCE OF IMPACT: MICHR-wide Community Advisory Board (CAB) will ensure community voices are heard and utilized in leadership and strategic decisions for CTSA activities."} +{"text": "Cardiac lipomas are rare benign primary cardiac tumours primarily composed of mature adipocytes. They are usually well defined, encapsulated masses, but rarely demonstrate malignant characteristics by infiltrating the myocardium. This causes diagnostic uncertainty as it becomes a priority to rule out primary malignant cardiac tumours such as sarcoma which often carry a poor prognosis.A 61\u2009year old female presenting with chest pain was found to have an infiltrating right atrial hypertrophic mass. Mutli-disciplinary team (MDT) discussions along with the presence of symptoms and likelihood of malignancy led to the recommendations for surgery.Intraoperatively this involved the right pulmonary veins and superior vena cava (SVC). The mass was resected with good margins and reconstruction of the right atrium, pulmonary veins and SVC was done using porcine pericardial patch. The patient made a good postoperative recovery and was discharged home in sinus rhythm with no significant valvular lesions. This was further confirmed at 6\u2009month follow up. Final histology was that of infiltrating lipoma.In this rare case of infiltrating cardiac lipoma in a relatively young patient, the diagnostic uncertainty despite multimodal imaging meant surgery was indicated due to the high suspicion of cancer. Even in benign cases, fatty infiltration can lead to conduction defects and embolisation. Technical difficulties in sectioning these specimens is caused by intra-tumour variability and current recommendations are for excision biopsy, for best characterisation.The management of these patients requires an MDT with Cardiac surgery being a safe approach providing definitive management. Primary cardiac neoplasms are rare with post-mortem incidence estimates ranging from 0.001% to 0.03% . CardiacFurthermore, myocardial infiltration can result in conduction defects causing rhythm disturbances .A 61 year old female with a background of asthma, hypertension and previous smoking, presented with chest pain and was found to have an infiltrating right atrial hypertrophic mass suspicious for sarcoma on transthoracic echocardiography and cardiac MRI.Coronary angiogram showed no flow-limiting lesions and cardiac echocardiogram showed restrictive changes with epicardial thickening in the right atrium and around the superior vena cava (SVC). Cardiac computed tomography (CT)Fig. and magnFollowing multi-disciplinary team (MDT), patient and family discussions, the patient consented to surgery.Intraoperatively, there was a fatty infiltrating mass involving the right atrium, right superior pulmonary vein and SVC. The patient was placed onto cardiopulmonary bypass using bicaval cannulation with the SVC cannulated as distal as possible. The mass was resected with good margins. Right atrium, pulmonary veins and proximal SVC were reconstructed using porcine pericardium.Tissue was sent for histology, Sections showed lipomatous tumour entrapping myocardial cells, composed of lobules of mature adipocytes and very thin fibro-vascular septa. No significant cytological atypia was observed. On molecular genetic testing, MDM2 gene amplification was negative by interphase FISH ruling out a malignant liposarcoma. A diagnosis of infiltrating lipoma involving the right atrium was established.The patient made a good postoperative recovery and was discharged in sinus rhythm with no significant valvular lesions. This was confirmed at six months review.Infiltrating cardiac lipoma provides a diagnostic challenge. It cannot be distinguished from primary malignant cardiac lesions such as liposarcoma based on clinical presentation or non- invasive diagnostic modalities. Cardiac liposarcomas are aggressive malignant mesenchymal neoplasms which carry poor prognosis and hence represent important differentials to be ruled out . Intra-cIn a literature review, we found seven cases of infiltrating cardiac lipoma. Three of these cases describe lipomas originating on the epicardial aspect infiltrating into the underlying ventricular myocardium one of which reported multiple infiltrating lipomas \u201313. The Due to the rarity of cardiac lipomas, there have been no large cohort studies or randomised trials to produce guidelines on treatment. Prompt surgical management can however lead to complete cure resulting in excellent long-term prognosis. Even if benign, infiltrating cardiac lipomas can manifest in fatal clinical sequelae such as arrythmias and heart failure. The management of infiltrating lipomas provides for diagnostic challenges and hence requires an MDT approach and comprehensive patient counselling. We have demonstrated cardiac surgery in this setting is safe and provides good medium to long-term results."} +{"text": "Mice that overexpress mutant human tau in forebrain neurons develop many features of Alzheimer\u2019s disease (AD), including behavioral impairments and neurodegeneration by 5 months of age. While an appropriate model to study AD-like pathology, the transgene\u2019s high neurotoxicity makes it difficult to investigate how aging impacts AD onset and progression. The removal of endogenous mouse tau decreases the transgene\u2019s neurotoxicity in young mice, which has allowed us to age mice to 20 months of age and investigate behavior at a more AD-relevant stage of life. Interestingly, the tau transgenic mice show increased discrimination between familiar and unfamiliar objects than non-transgenic littermates (p = 0.02) suggesting tau transgenic mice have better memory. The transgenic mice also displayed increased physical activity in the Open Field Test than non-transgenic littermates . Their improved behavioral performance occurred despite significant forebrain atrophy . Interestingly, the non-transgenic control mice lacking endogenous mouse tau developed insulin resistance and obesity, and had significantly smaller cerebellum than transgenic mice . These data suggest that insulin resistance and obesity contribute more profoundly to poor behavioral performance than forebrain neurodegeneration. Moreover our study suggests that the cerebellum, recognized primarily for its role in coordination and motor function, may be an important mediator of late life cognitive function, especially in the presence of insulin resistance and obesity."} +{"text": "Although functional mobility limitations are associated with increased healthcare needs in later life, little research explores how older adults with varying functional mobility trajectories experience healthcare quality. To this end, we explore the effects of functional mobility trajectories on differences in healthcare treatment satisfaction, perceived disability discrimination in healthcare settings, and perceived everyday disability discrimination. We analyzed 9 waves of the Health and Retirement Study . First, we estimate age-specific group-based trajectories of functional mobility across age using finite mixture models. Second, we use multinomial logistic regression to identify sociodemographic factors that place individuals at elevated risk of membership in each group. Third, we explore how membership in one disability trajectory group over another affects healthcare satisfaction, perceptions of everyday discrimination in the context of healthcare treatment settings, and perceived discrimination in everyday life. Regression models include clustered standard errors to account for heteroscedasticity across repeated observations of individuals over time. We identify six group-based trajectories of functional mobility limitation among aging Americans. Black, female, and less-educated Americans are at higher risk of membership in disadvantaged trajectories, characterized by more rapidly increasing counts of functional mobility limitations, than their counterparts. Disadvantaged functional limitation trajectories are associated with lower levels of healthcare satisfaction, higher levels of perceived physical disability discrimination in healthcare treatment settings, and higher levels of perceived physical discrimination in other contexts of everyday life. The present study advances our knowledge of how older adults experience healthcare settings and discrimination across functional mobility status trajectories."} +{"text": "Biases against older adults and people with disabilities can lead to discriminatory behaviors. One way to better understand attitudes towards these populations is through the examination of implicit (unconscious) factors. This paper utilizes The Implicit Association Test, a computer-based categorization task designed to assess implicit or unconscious attitudes, to assess the impact of an intergenerational service-learning course created to support the human animal bond between vulnerable pet owners and their companion animals. This study, using the Wilcoxon signed-rank test, assessed the impact of college students\u2019 interactions with older pet owners on these students\u2019 implicit attitudes. Pre- and post-assessment of participating students found statistically significant decreased biases towards older people and people with disabilities after completing the course (p=.032). Results from this study suggest that participating in an intergenerational service-learning course centered around the human animal bond can positively affect implicit attitudes towards older adults or people with disabilities."} +{"text": "STimulator of INterferon Gene (STING), canonically known for initiating a type I IFN production and innate immune response to cytosolic DNA, is required for host defense against neurotropic RNA viruses. We evaluated the role of STING in host defense to control WNV infection and pathology in a murine model of infection. When challenged with WNV, STING knock out (-/-) mice displayed increased morbidity and mortality compared to wild type (WT) mice. Virologic analysis and assessment of STING activation revealed that STING signaling was not required for control of WNV in the spleen nor was WNV sufficient to mediate canonical STING activation in vitro. However, STING-/- mice exhibited a clear trend of increased viral load and virus dissemination in the CNS. We found that STING-/- mice exhibited increased and prolonged neurological signs compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the CNS of STING-/- mice, with sustained pathology after viral clearance. We found that STING was required in bone marrow derived macrophages for early control of WNV replication and innate immune activation. In vivo, STING-/- mice developed an aberrant T cell response in both the spleen and brain during WNV infection that linked with increased and sustained CNS pathology compared to WT mice. Our findings demonstrate that STING plays a critical role in immune programming for the control of neurotropic WNV infection and CNS disease.West Nile Virus (WNV), an emerging and re-emerging RNA virus, is the leading source of arboviral encephalitic morbidity and mortality in the United States. WNV infections are acutely controlled by innate immunity in peripheral tissues outside of the central nervous system (CNS) but WNV can evade the actions of interferon (IFN) to facilitate CNS invasion, causing encephalitis, encephalomyelitis, and death. Recent studies indicate that Stimulator of Interferon Genes (STING) in conferring host defense during WNV infection in a murine model. Our studies revealed that STING is essential for restricting pathology in the CNS during WNV infection. Further, STING is required for effective programming of the innate and adaptive immune response to WNV. In the absence of STING, aberrant immune development leads to ineffective viral clearance and immunopathology in the CNS. These studies uncover a critical and previously unidentified role for STING in the restriction of WNV that may have broader implications for a role in conferring host defense against RNA viruses.In recent years, outbreaks of emerging and re-emerging neuroinvasive West Nile virus (WNV) infection have brought about a critical need to understand host factors that restrict neuropathology and disease. WNV infection in humans typically is either asymptomatic or results in a mild febrile illness, but in some cases virus spreads to the central nervous (CNS) causing a more severe form of neuropathological disease. Previous studies established that both innate and adaptive immune responses are essential for controlling WNV disease and restricting the virus from the CNS. In this study, we examined the role of Flavivirus infections, including West Nile virus (WNV), are ongoing or emerging threats to global health BME and [40ng/mL] murine MCSF (mMCSF). Cells were cultured for 7 days in non-TC coated plates, then scraped, washed with PBS and seeded at 1E6 cells/well in 12-well TC coated plates with cDMEM+BME+mMCSF. Cells were infected or transfected the next day.in vivo work, while WNV-TX ic (infectious clone) stocks were utilized for cell culture (in vitro) studies. Working stocks were propagated in Vero-E6 and titered by standard plaque assay on VeroWHO and BHK21 cells as previously described . Images acquired using [Allen Brain Institute Brain Explorer 2]. Available from: [http://mouse.brain-map.org/static/brainexplorer].STING localization in the brain is centralized to the hind/mid-brain, hippocampus, primary motor-cortex and olfactory bulb in the brain. Square: midbrain/thalamus region. Oval: hindbrain (cerebellum and brain-stem). Image is from the Allen Institute for Brain Science. [Allen Mouse Brain Atlas]. Available from: [(TIF)Click here for additional data file."} +{"text": "Summary: Today\u2019s American elders are increasingly being seen as an asset to society through civic engagement. A new challenge facing America now and in the years ahead is how to tap such asset. Formal organizations should play a leading role in institutionalizing American elders\u2019 civic engagement. Due to a structural lag between social changes and organizational practices, however, many organizations are not ready to engage the large number of American elders. To address this issue, formal organizations first need to know which factors affect American elders\u2019 civic engagement and then are able to come up with effective solutions. Although some studies have investigated the contributing factors of American elders\u2019 civic engagement, there are very few systematic syntheses of these factors from various different studies. To fill this gap, the authors conducted a mixed methods systematic literature review using meta-summary. Through electronic search of five databases and hand search of bibliographies, 22 articles were used in final analysis based on eligibility criteria, including 19 quantitative studies, two qualitative studies and one mixed methods study. Findings: The review identified six themes and 28 factors related to American elders\u2019 civic engagement. These themes encompassed socio-demographic factors (eight factors), health status (four factors), program characteristics (four factors), engagement opportunities (three factors), engagement outcomes (five factors) and social capital (four factors). Applications: Formal organizations are advised to develop relevant competencies to capture the influences of identified factors. Social workers are also required to develop multilevel competencies to better engage American elders with the organizational settings."} +{"text": "Pain and depression, two of the common symptoms among chronically ill older adults, have been found to be related in various populations; however, further knowledge is needed about their relationships and moderating factors among community-dwelling, chronically ill older adults, particularly in lower-income, rural areas with limited healthcare resources. Therefore, this study aimed to examine the association between pain level and depression among chronically ill older adults in rural areas. A total of 100 residents of a rural county in West Alabama, who are 55+ and have chronic illnesses and pain, were recruited from four community senior centers and were interviewed using a structured questionnaire. Pain levels were assessed by the Philadelphia Geriatric Center (PGC) Pain Scale, and depression by an abbreviated version of the Center for Epidemiologic Studies Depression Scale (CES-D). Bivariate correlation and multivariate analysis were conducted. The correlation between pain and depression was significantly positive . The results of the model indicated that pain scores and other control variables explained approximately 18 percent of the variance in depression. The multivariate analysis results confirmed that those who had higher pain scores were significantly likely to have increased depression scores . Education marginally significantly moderated the relationship between pain and depression (p = .059). The previously reported positive pain-depression relationship exists among chronically ill older adults in rural areas, calling for tailored interventions to reduce their pain and its impact on depression."} +{"text": "This study aimed to understand the movement behaviour and utilization distributions of Kori bustards in space and time in the Serengeti ecosystem. A total of 14 individuals were tracked with the aid of GPS satellite transmitters, and their sexes were identified using DNA analysis. A species utilization distribution was estimated using the Brownian bridge movement model (hereafter dBBMM) in which the probability of being in an area is conditioned by starting and ending (GPS) relocations. Resource selections were analysed by comparing the GPS relocations with locations randomly placed within each individual\u2019s region of utilization in a spatio-temporal approach. Vegetation information was derived from a Serengeti GIS vegetation map and Data Centre and was reclassified as Open grassland, Dense grassland, Shrubbed grassland, Treed grassland, Shrubland, and Woodland. The Shannon diversity index for vegetation was calculated based on the original vegetation classification. Used versus non-used habitats were contrasted using a generalized linear mixed-effects model with a binomial distribution. The results indicated that males were 21.5% more mobile than females, and movements were 6.3% more diffuse during the non-breeding period compared to the breeding period . Contrasting models indicated that males preferred more open grasslands during the non-breeding period and also preferred closed and shrubbed grassland during the breeding period. Females preferred more woody vegetation during the non-breeding season compared to the breeding season. The most parsimonious model indicated that females preferred to stay closer to rivers and diverse areas during the non-breeding period whereas males preferred areas that were farther from rivers and homogenous. Homogeneous areas were preferred during the breeding period, and heterogeneous areas were preferred during the non-breeding period. We conclude that the movement behaviours of Kori bustards changes with the season and habitat. Further research is needed to understand the factors driving the seasonal movement of Kori bustards in the Serengeti ecosystem. Habitat selection in animals helps maximize their fitness \u20134. HowevPeriods of reproduction may affect both the home range size and habitat selection. In birds, breeding pairs with chicks may have smaller home ranges because breeding birds require habitats with abundant food and safety for their young. Similarly, incubating females may have relatively small home ranges because their nests depend on incubation and protection . HoweverThe Kori bustard is the heaviest flying bird that is indigenous to the grasslands and lightly wooded savannahs of southern and east Africa ; howeverArdeotis kori struthiunculus is listed as near threatened by the IUCN and is included in Appendix II of the list of CITES species ). Whereas males preferred more open grasslands, females preferred to use more woody vegetation . Females preferred to stay closer to rivers, even more so during the non-breeding period . Females preferred more diverse areas contrary to males, who preferred more homogenous areas in different seasons may be due to the tendencies of some individuals to have strong movements, while these tendencies may be absent in other individuals. According to , Kori bu [Tetrax tetrax) showed similar differences in habitat preferences between males and females [The spatial configuration of the habitats available within the Kori bustard minimum convex polygons and contrasting models based on AIC showed a species preference to woody vegetation, which is more heterogeneous and closer to rivers. The most parsimonious model explained the sexual differentiation in response to seasonal habitat/vegetation preferences wherein males preferred more open grasslands, and females preferred to use more woody vegetation. These preferences may reflect the species\u2019 breeding system, where males and females require different microhabitats, as also observed in the Bengal florican alensis) . Males ralensis) , 47, 48. females , 49. TheArdeotis kori kori, female home ranges are confined by environmental conditions and the accessibility of resources [The most parsimonious model explaining the selection for distance to rivers indicated sexual differentiation in the seasonal responses to habitat preference . Femalesesources .Our study highlights how spatial use and habitat preferences shape the movements of Kori bustards in the Serengeti ecosystem. Overall, our results note the presence of distinct movement patterns related to breeding (December-June) and non-breeding (July-November) periods. We conclude that different movement patterns exist among individual Kori bustards during breeding and non-breeding periods, as females perform partial movements in their habitat of preference, whereas males migrate from one habitat to another. The Kori bustard habitat preferences in the Serengeti ecosystem are sex-specific and differ during different periods of the year, with males utilizing mostly shrubbed grassland and open grassland and females utilizing mostly woody vegetation with increasing habitat diversity. Finally, we recommend further studies on the factors that influence habitat preferences and differential movements of the Kori bustard in their ecosystem during different seasonal periods.S1 Fig6 km2) over Julian days from capture for six male (blue) and eight female (red) Kori bustards in the Serengeti Ecosystem during the breeding and non-breeding period .Net-squared displacement (in 10(TIFF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file."} +{"text": "This report describes the first case of extensive macular atrophy with pseudodrusen (EMAP) imaged with optical coherence tomography angiography (OCTA). A 58-year-old Caucasian man presented with decreased central vision in both eyes. Fundus examination showed large areas of macular atrophy centered on the fovea surrounded by diffuse reticular pseudodrusen. Spectral domain OCT (SDOCT) revealed outer retinal and choriocapillaris atrophy. OCTA demonstrated marked absence of choriocapillaris flow. Extensive macular atrophy with pseudodrusen is a rare clinical entity and a new extreme phenotype of macular degenerations that could shed more light on the role of pseudodrusen and choriocapillaris compromise in the pathogenesis of AMD. Extensive macular atrophy with pseudodrusen (EMAP) is a rare clinical entity that was first described by Hamel et al. in 18 patients with bilateral well-delineated chorioretinal atrophy extending to the temporal arcades without sparing the fovea and widespread pseudodrusen throughout the posterior pole and peripheral retina. Earlier onset, more rapid progression of atrophy, and severe visual loss were noted in contrast to age-related macular degeneration (AMD) .Optical coherence tomography angiography (OCTA) is a relatively new, fast, noninvasive imaging modality that analyzes high-speed OCT images, measures changing reflectance, and reconstructs high-resolution blood flow maps of the retina, allowing en face imaging of the retinal capillary plexuses and choroidal vasculature.The author describes the first case of EMAP imaged with optical coherence tomography angiography (OCTA).A 58-year-old Caucasian male presented with progressively decreasing central vision in both eyes over the past five years. He also complained of mild night blindness. There was no significant medical history and no family history of retinal disease. Best-corrected visual acuity was 20/60 in the right eye and 20/200 in the left eye with mild nuclear sclerotic cataracts. Fundoscopic examination revealed large areas of macular atrophy centered on the fovea surrounded by reticular pseudodrusen. Peripapillary atrophy was also present along with scattered areas of peripheral pavingstone degeneration OU Figures . There wExtensive macular atrophy with pseudodrusen (EMAP) is a retinal dystrophy that affects patients in their sixth decade and is defined by bilateral symmetric widespread macular atrophy centered on the fovea surrounded by diffuse macular and midperipheral pseudodrusen. Pavingstone lesions can also be found peripherally . An assoExtensive macular atrophy with pseudodrusen may be a new extreme phenotype of macular degenerations that could shed more light on the role of pseudodrusen and choriocapillaris compromise in the pathogenesis and progression of AMD. An association between pseudodrusen and decreased choroidal thickness has been documented as has a"} +{"text": "An abundance of research involving adults who care for family members with dementia has guided the creation of supportive programs/services. Much less is known about adolescents who are dementia caregivers. This descriptive secondary analysis utilized data collected during a qualitative examination into the psychological well-being of adolescent dementia caregivers. Eleven adolescent/adult dyads who provided dementia care for a family member completed surveys prior to the adolescents\u2019 participation in focus groups. Five male and six female adolescents ages 12 to 17 and eleven female adults were asked similar questions about caregiving tasks, education resources, and demographic information. Using descriptive statistics, the results of the surveys provide a snapshot of caregiving among a group of adolescents living in northwest Ohio and highlight differences reported by the dyads. Adult accounts of adolescent preparatory education were incongruent with the adolescents\u2019 and did not report their use of books or online caregiving resources. Conversely, three adults (27%), but no adolescents, identified hands-on and observational opportunities as education resources. Adults reported greater adolescent involvement in ten activities of daily living (71%), especially related to bathing, shopping, transportation, and managing medication and finances. Adolescents reported helping with tasks such as eating and laundry more often than adults. While the sample size was small, these findings suggest a need for triangulation when seeking knowledge about adolescent caregiving. These results may inform researchers wishing to investigate the role of adolescent caregivers, as well as guide supportive agencies who provide education materials to families caring for individuals with dementia."} +{"text": "Humic substances are breakdown products of decaying organic matter that co-extract with proteins from fossils. These substances are difficult to separate from proteins in solution and interfere with analyses of fossil proteomes. We introduce a method combining multiple recent advances in extraction protocols to both concentrate proteins from fossil specimens with high humic content and remove humics, producing clean samples easily analysed by mass spectrometry (MS). This method includes: (i) a non-demineralizing extraction buffer that eliminates protein loss during the demineralization step in routine methods; (ii) filter-aided sample preparation (FASP) of peptides, which concentrates and digests extracts in one filter, allowing the separation of large humics after digestion; (iii) centrifugal stage tipping, which further clarifies and concentrates samples in a uniform process performed simultaneously on multiple samples. We apply this method to a moa fossil (approx. 800\u20131000 years) dark with humic content, generating colourless samples and enabling the detection of more proteins with greater sequence coverage than previous MS analyses on this same specimen. This workflow allows analyses of low-abundance proteins in fossils containing humics and thus may widen the range of extinct organisms and regions of their proteomes we can explore with MS."} +{"text": "Lack of positive attitudes towards aging has shown to cause challenges within intergenerational networks in employment situations. These can include job satisfaction, intrinsic motivation to work, and ageism subjectivity as underlying determinants and consequences. The collaborative intervention pilot training program goals were two-fold: 1) To expose and understand ageism as a discriminatory action. 2) To create a more positive social dynamic network in a diverse workplace in regard to general expectations of ageism. Two team-based learning intervention programs were created in order to increase collaborative awareness of ageism and were presented to a medium size intergenerational department staff (N=64) as part of a professional development series on equity, diversity and inclusion. Through three multidimensional self-help training activities, learning was done individually, within similar age employee groups, and within intergenerational employee groups. Participants were able to discuss and express general understandings and expectations of aging and learning tools such as intergenerational reactivity and emotion regulation strategies were presented. Within survey responses at the completion of the trainings, key findings showed that respondents had a better understanding of ageism (76%) and felt better equipped to work within an employment team of diverse ages (71%). Additionally, the subject matter of this pilot training program resulted in re-conceptualized positive aging (61%). Future implications and goals for the program include interventions to further increase positive intergenerational understanding and workplace generational inclusiveness."} +{"text": "OBJECTIVES/SPECIFIC AIMS: The objectives of this study are to determine whether high-frequency ipsi-lesion or low-frequency contra-lesion ECS improves forelimb function following experimental stroke in aged animals with focal and large strokes. We also want to investigate whether ECS-induced improvements in motor function are related to an enhancement of neural structural plasticity (dendrites and synapses) and changes in growth promoting (BDNF) and growth inhibiting (NOGO-A) expression in the infarcted motor cortex in young and aged animals. METHODS/STUDY POPULATION: We will investigate whether excitatory ECS of the infarcted cortex or inhibition of the noninfarcted cortex combined with daily impaired-forelimb rehabilitative training (RT) results in greater motor functional recovery compared to RT alone. Immunohistochemical (IHC) analyses and unbiased stereological techniques will be performed to investigate changes in proteins associated with dendritic restructuring (MAP2), synaptic plasticity (PSD95 and synaptophysin), and alteration in the expression of BDNF and NOGO-A. RESULTS/ANTICIPATED RESULTS: We expect that inhibitory ECS of the noninfarcted motor cortex will improve behavioral outcomes in moderate to severe stroke animals compared with excitatory ECS or no stimulation animals. We predict that the ECS condition that improves motor performance most significantly compared with RT alone will have a corresponding greater increase in remaining ipsi-infarct motor cortical dendritic and synaptic plasticity , and greater expression of BDNF. It is unknown, but also expected that better behavioral recovery will coincide with a greater reduction in NOGO-A in the injured motor cortex. DISCUSSION/SIGNIFICANCE OF IMPACT: These studies will aid in creating a model that will allow for a better understanding of the relationship between brain stimulation, severity of injury and, in future studies, aging. These studies will also help clarify previous conflicting brain stimulation results."} +{"text": "Aerobic training has been shown to be effective at improving cognitive and brain outcomes in older adults with mild subcortical ischemic vascular cognitive impairment (SIVCI). However, uncertainty remains regarding the underlying neurobiological mechanisms by which exercise elicits these improvements in cognition. Increased aberrant functional connectivity of the default mode network has been highlighted as a factor contributing to cognitive decline in older adults with cognitive impairment. Greater connectivity of the DMN at rest is associated with poorer performance on attention-demanding tasks, indicative of a lack of ability to deactivate the network on task. Our previous work on a randomized controlled trial of participants with mild SIVCI, demonstrated that 6-months of thrice weekly aerobic training led to improved global cognitive function, as measured by Alzheimer\u2019s disease Assessment Scale-Cognitive subscale (ADAS-Cog), compared with a health education program. Thus, we conducted secondary analyses to investigate whether these changes in global cognitive function were associated with changes in resting state DMN connectivity. A subsample of 21 participants underwent a resting state functional magnetic resonance imaging (fMRI) scan before and after trial completion. Change in resting state DMN connectivity was found to significantly predict change in ADAS-Cog score after controlling for age, intervention group, and baseline functional capacity = 3.507, p=.031). These findings suggest that functional connectivity of the DMN may underlie changes in global cognitive function. Furthermore, aerobic exercise is a promising intervention by which to elicit these changes in older adults with mild SIVCI."} +{"text": "The causes of chronic cough in children are mainly dependent on the setting and age of the child. Protracted bacterial bronchitis is a frequent cause of morbidity in childhood, and antibiotic treatment is beneficial. Prompt recognition and early treatment is important both to prevent inappropriate use of asthma medications and also progression to bronchiectasis, but the diagnosis should not be made uncritically, because chronic wet cough is not necessarily due to lower airway disease. Upper Airway Cough Syndrome (UACS) is considered by some to cause chronic cough in childhood. Underlying UACS are many common conditions, including allergic rhinitis, adenoiditis and rhinosinusitis. Diagnosis relies on a combination of clinical criteria that are relatively sensitive but non-specific. The role of nasal endoscopy in children with chronic cough and signs suggesting UACS is unclear. Nasal saline solution irrigation is commonly used in UACS, but most studies have methodological biases, and efficacy data are scanty. Randomized controlled trials are urgently required. However, if saline washes, rather than oral antibiotics, can effectively treat some children with wet cough associated with upper airway conditions, antibiotic resistance could potentially be reduced. There is a need to further study wet cough and not to assume it to be equivalent to lower airway infection in all children. All that coughs is not bronchitisCough is common in childhood . SpontanThis article aims to suggest a practical approach in children with wet cough and concomitant nasal symptoms through a vignette describing \u201ca child\u201d typical of those referred to outpatient services of two tertiary level Italian hospitals by primary care pediatricians. The diagnostic work-up and the treatment options in this clinical setting are critically discussed.A preschool boy presented with a 3-weeks history of a troublesome cough that had developed after an acute respiratory infection (ARI). Cough was initially dry, but gradually became wet. A runny nose, nasal obstruction and snoring at night were other features. He had received a 10-days course of oral amoxicillin-clavulanate with minimal effect. The family history was unremarkable. The personal history revealed frequent episodes of ARI during winter since starting attending day care. There was no history of wheeze. Parents were concerned about the frequency of respiratory episodes and had wished for \u201csome tests\u201d over the previous year. Routine laboratory tests including full blood count, erythrocyte sedimentation rate and C-reactive protein, were normal. Pharyngeal swab was also normal. Skin prick testing revealed minor sensitization to house dust mites. Physical examination revealed only a moist cough. A \u201crattle\u201d sound was audible over the chest. The ear/nose/throat (ENT) examination revealed yellowish mucus dripping down into the oropharynx, a cobblestone pharyngeal mucosa and swollen turbinates. Nasal endoscopy revealed mild adenoidal hypertrophy with no evidence of sinus involvement. A diagnosis of adenoiditis was made and a 7-days course of nasal douching with hypertonic solution was prescribed. At 2-weeks follow-up, his cough had completely disappeared and physical examination was unremarkable. He remained well with no antibiotic therapy until a new ARI recurred after 2 months.(PPB-micro) and new definitions were introduced comprised a history of chronic wet cough, importantly a positive bronchoalveolar lavage (BAL) culture for a respiratory pathogen, and response to a 2-weeks course of oral amoxicillin-clavulanate . Since utroduced . PBB-cliPBB-clinical definition lacks specificity and inherently has limitations. First, many cases of PBB may be \u201cprolonged acute cough\u201d lasting 4\u20138 weeks, which most commonly follows a viral ARI and typically resolves without intervention and quality (wet or productive) of cough, and excluding other causes of wet cough. The proposed rvention . Second,rvention . Differervention . In chilrvention . Interesrvention ; neverthrvention . Fourth,rvention . FinallyPBB-clinical definition may lead to substantial over-diagnosis and increased prescription of antibiotics if not meticulously verified. The evidence-base for benefits of antibiotic therapy in children with PBB mainly rely on a single randomized controlled study (RCT) involving children with chronic cough in Australia , the optPost-nasal drip (PND) is the drainage of secretions from the nose or paranasal sinuses into the pharynx. The suspicion of PND rests on the patient recognizing that something is dripping down into the throat and/or is suffering from frequent throat clearing. The finding of mucoid secretions in the pharynx or a cobblestone aspect of pharyngeal mucosa is suggestive.The causal role of PND in chronic cough is a controversial issue both in adults and in cThe reported incidence of UACS in children with chronic cough varies widely. Asilsoy et al. used theThe ACCP guidelines for adults explicitly state that the treatment options for UACS-induced cough are somewhat dependent on the subcategory of disease that is present . AntihisNasal saline solution irrigation (NSSI) has recently gained popularity in selected settings . An ItalThe exact mechanism of action of NSSI is not known , but mechanical cleaning of the nasal mucosa, which leads to the removal of inflammatory mediators and temporary improvement of mucociliary clearance, may be important. This may favor to resolve inflammation/infection spontaneously or with drugs.Despite being used in daily practice, NSSI is only briefly mentioned in the guidelines for the treatment of RS , 39. SysAll children cough, but most of them are \u201cexpected\u201d or merely a normal part of common childhood respiratory infections. Isolated dry cough in a community setting in an otherwise well child is unlikely to betoken any serious underlying condition. On the other hand, children with chronic wet cough often pose a diagnostic and management dilemma to the physician. Children similar to the one described in the vignette are frequently seen in primary care.The clinical presentation of the case described does not fulfill the diagnostic criteria for PBB since the cough lasted only 3 weeks. Therefore, the prescription of antibiotics was inappropriate. Parents are often disturbed by cough and ask that \u201csomething is done.\u201d In a prospective study in Australian children, a high proportion of parents thought antibiotics should be given for post-infectious cough (34%) or were unsure (24%); surprisingly, antibiotics were prescribed in 14% of episodes characterized by isolated dry cough with no fever . Post-inThe patient presented with a clinical history and physical signs consistent with UACS. There is no mention of nasal symptoms and/or signs in the recently extended list of cough pointers for the management of children with chronic wet cough . Some spIn the vignette, the diagnosis of adenoiditis was made by nasal endoscopy. The inflammatory involvement of adenoids is common in children, especially those attending day care , as uppeCough in the above child had not disappeared after antibiotic therapy but did a few days after treatment with NSSI; however, spontaneous resolution cannot be excluded. In a prospective study, most children with suspected UACS had cough which resolved after treatment with NSSI . Cough ibefore prescribing an antibiotic; and this includes making the diagnosis of \u201cnormal child\u201d and reassuring the family. Unfortunately, available data demonstrate that is difficult not to give in to this temptation. Respiratory diseases are the most common reason for the prescription of antibiotics in primary care, but many of them are unnecessary , Amoroso Angelo (Pescara), Andreozzi Americo (Macerata), Basile Lucio (Pescara), Beghella Massimo (Ancona), Bellucci Nazareno (Todi), Bernacchi Stefania (Perugia), Bosco Fiorella (Pescara), Brachelente Linda (Perugia), Cappellucci Domenico (Pescara), Carnevale Maurizio (Pescara), Castiglione Giovanni Battista (Pescara), Chioccoloni Roberta (Marsciano), Coronati Valeria (Ancona), Della Vedova Giacomo (Spello), Di Filippo Antonella (Giulianova), Di Florio Rossana (Pescara), Di Giampietro Tiziana (Pescara), Di Girolamo Franca (San Benedetto del Tronto), Gabbanelli Gianna (Ancona), Gabriele Piera (Pescara), Gobbi Costantino (Macerata), Gonnellini Rita (Deruta), Guerrieri Arcangela (Ancona), Laguardia Luigi (Montesilvano), Liberati Marina (Ascoli Piceno), Martello Cecilia (Perugia), Merluzzi Angela (Citt\u00e0 di Castello), Migliori Cesare (Ancona), Minucci Maria Giovanna (Foligno), Mora Marina (Ancona), Nuzzaci Roberto (Castelfidardo), Passali Maria Grazia (Pescara), Piermattei Loredana (Tolentino), Rossi Laura (Foligno), Ruggeri Anna Grazia (Matelica), Sardo Infirri Margherita (Spoleto), Solinas Lucia (Foligno), Truffarelli Francesca (Foligno).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Felton Institute has been working to eliminate isolation and loneliness in San Francisco since its inception as a community social service agency 130 years ago. Felton offers culturally and linguistically appropriate programs and services that foster community and social connections among socially isolated, low income older adults, including those living with serious mental illness and those residing in local long-term care facilities. Examples include workforce programs for older adults; the foster grandparent program; and the senior companion program which includes friendly visiting, senior counseling, and peer escort services. This session will highlight lessons learned from these successful programs as well as how they have led to the development of new initiatives focused on conducting outreach, providing trauma-informed services, offering wellness classes, and organizing meaningful activities including a choir, intergenerational gardening, arts and dance classes, and cultural exchange opportunities to isolated older adults living in poverty in San Francisco\u2019s Visitacion Valley."} +{"text": "Fundamental watershed-scale processes governing chemical flux to neighboring ecosystems are so poorly understood that effective strategies for mitigating chemical contamination cannot be formulated. Characterization of evapotranspiration, surface runoff, plant uptake, subsurface preferential flow, behavior of the chemicals in neighboring ecosystems, and an understanding of how crop management practices influence these processes are needed. Adequate characterization of subsurface flow has been especially difficult because conventional sampling methods are ineffective for measuring preferential flow of water and solutes. A sampling strategy based on ground-penetrating radar (GPR) mapping of subsurface structures coupled with near real-time soil moisture data, surface topography, remotely sensed imagery, and a geographic information system (GIS) appears to offer a means of accurately identifying subsurface preferential flow pathways. Four small adjacent watersheds draining into a riparian wetland and first-order stream at the USDA-ARS Beltsville Agricultural Research Center, Beltsville, MD are being studied with this protocol. The spatial location of some preferential flow pathways for chemicals exiting these agricultural watersheds to the neighboring ecosystems have been identified. Confirmation of the pathways is via examination of patterns in yield monitor data and remote sensing imagery."} +{"text": "Regulated hemostasis, inflammation and innate immunity entail extensive interactions between platelets and neutrophils. Under physiological conditions, vascular inflammation offers a template for the establishment of effective intravascular immunity, with platelets providing neutrophils with an array of signals that increase their activation threshold, thus limiting collateral damage to tissues and promoting termination of the inflammatory response. By contrast, persistent systemic inflammation as observed in immune-mediated diseases, such as systemic vasculitides, systemic sclerosis, systemic lupus erythematosus or rheumatoid arthritis is characterized by platelet and neutrophil reciprocal activation, which ultimately culminates in the generation of thrombo-inflammatory lesions, fostering vascular injury and organ damage. Here, we discuss recent evidence regarding the multifaceted aspects of platelet-neutrophil interactions from bone marrow precursors to shed microparticles. Moreover, we analyse shared and disease-specific events due to an aberrant deployment of these interactions in human diseases. To restore communications between the pillars of the immune-hemostatic continuum constitutes a fascinating challenge for the near future. The circulatory system provides functional integration to tissues throughout the body and constitutes a dynamic platform for tasks, such as immune patrolling and defense against threats \u20133. ConsiCellular membranes allow the segregation of selected information in compartments and modulate their subsequent effects on the environment by integrating multiple stimuli. Circulating membrane-endowed players in the immuno-hemostatic network encompass leukocytes, platelets and microparticles, with the endothelium as a fourth static counterpart , 13. PlaHemostasis and inflammation counterbalance the effect of injuring external stimuli. Selective regulation and polarization of these pathways enhance homeostatic responses at sites of tissue or vascular injury and minimize the detrimental effects to the host. Multiple mechanisms have developed, including variability in the lifespan of players involved in the immune-hemostatic balance and availability of soluble or membrane-bound moieties. Emission of membrane-endowed subcellular particles fine-tunes cellular activation and converts locally concentrated high-intensity responses into a sum of smaller but widespread and reciprocally independent biological events. Generation of extracellular vesicles enables the extension of the total membrane area interacting with the environment as well as of the range of potential cellular targets. In addition, segregation of information in multiple signaling quanta discloses the possibility of independent interactions with distinct cellular counterparts according to the differential needs of target tissues. Platelets are anucleate cell fragments released by megakaryocytes. After a multi-stage process of cytoplasm compartmentalisation and concentration of bioactive compounds into granules taking place over the course of days, platelets are released as elongated precursors (proplatelets), which undergo multiple iterative fission events to reach their final size. Preplatelets are round-shaped precursors constituting a reversible intermediate stage in the transition from proplatelets to platelets . Small vIncreased platelet demand and/or consumption during acute systemic inflammation warrants adaptation of megakaryocytes. Inflammatory cytokines, such as IL6 promote megakaryocyte increase in ploidy and prompt thrombocytopoiesis through increased liver synthesis of thrombopoietin as part of the acute phase response . PlateleControlled exocytosis or integration of bioactive compounds into platelet membrane is crucial for these tasks. Platelets are endowed with three classes of granules: alpha-granules; dense granules and few lysosomes. Some authors also described \u201cT granules\u201d equipped with Toll-like receptor 9 as a potential fourth platelet compartment \u201328. BesiNeutrophils constitute the most abundant leukocyte population in the blood and are in charge of the early innate effector response to noxious stimuli . NeutropPhagocytosis and digestion of invading pathogens constitutes the default-mode defensive task performed by neutrophils. However, frustrated microbial phagocytosis promotes the generation of extracellular traps (NETs) , i.e., tNeutrophils also account for tissue and vascular damage in immune-mediated diseases including inflammatory bowel diseases, systemic lupus erythematosus (SLE) rheumatoid arthritis (RA) and vasculitides either directly or through NET-induced facilitation of thrombosis , 74\u201376. Platelets interact productively with multiple cells types , althougVital neutrophil internalization (emperilopolesis) into megakaryocytes occurs in the bone marrow. Engulfed neutrophils provide megakaryocytes with activating stimuli (causing a rise in platelet production) and donate membrane segments causing enhanced phosphatidylserine expression by chimeric daughter platelets . It is tPlatelets and megakaryocytes communicate long-range with neutrophils through exocytosed mediators and microparticles with enhancing actions on neutrophil activation , 95. TheThe interaction between platelets and neutrophils impacts on multiple stereotyped pathological manifestations . A firstPatients with inflammatory diseases of the blood vessels , 131, coAberrant coagulation is detectable in immune mediated diseases , 119. AlThrombotic microangiopathy, consisting in diffuse deposition of thrombi along small vessels due to widespread endothelial activation with hemolysis and platelet consumption, might complicate SLE, SSc, antiphospholipid syndrome and other immune-mediated diseases \u2013185. UndThe lung is a major inflammatory target . NeutropSystemic vasculitides encompass a very large set of immune-mediated diseases characterized by vascular injury and downstream organ ischemia as the core pathophysiological event . They caNeutrophils cause vascular damage in small-vessel vasculitis, possibly reflected by the accumulation of leukocyte cellular debris in peri-vasculitic lesions (leukocytoclasia). In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), neutrophil mediated vascular injury is part of a vicious circle linking exposure of myeloperoxidase (MPO) and/or proteinase-3 from granules to neutrophil surface or into the setting of NETs to the dIn large vessel-vasculitides, activation of platelets may contribute to promote vascular remodeling through the release of signals, such as VEGF . Platelevasa vasorum and entailing aberrant platelet-neutrophil cross-talk.Little is known on platelet-leukocyte interactions in large vessel vasculitides, although relative depletion of neutrophil granule content has been reported in giant cell arteritis in association with platelet activation , 132. NoSLE is a multi-organ autoimmune disease with a wide spectrum of clinical manifestations and pathogenic mechanisms . FailureCardiovascular manifestations are frequent in patients with SLE and a cause of morbidity and mortality . AccelerEndothelial derived microparticles constitute the most abundant microparticle subset in patients with SLE and correlate with endothelial dysfunction and interferon-\u03b1 signature , 232. HoMechanistically, platelet activation in SLE might depend on circulating immunocomplexes, which are abundant in SLE patients biological fluids and are recognized on platelet surface by Fc\u03b3RIIA and Toll-like receptor 4,7 . PD\u03bcP thSSc is a systemic autoimmune disease, characterized by unrelenting inflammation with a wound repair response consisting in mesenchymal extracellular matrix deposition leading to fibrosis, and by microvascular dysfunction and aberrant neoangiogenesis , 238. PlActivated platelets in SSc contribute to impaired vascular tone anRheumatoid arthritis is a relatively frequent autoimmune disease characterized by prominent involvement of the synovial joints. Although extra-skeletal manifestations are relatively less frequent compared to other immune-mediated diseases, patients with RA show an increased ischemic risk, pointing to the existence of a core pathophysiological event linking inflammatory manifestations to vascular dysfunction .Neutrophils undergoing NET generation might provide autoantigens in RA. Patients in fact frequently develop antibodies against citrullinated peptides (ACPA). Citrullination occurs thanks to the activity of deiminating enzymes, such as protein-arginine deiminase 4 (PAD4), abundantly expressed in neutrophils . CitrullPlatelets can be activated by collagen through the megakaryocyte lineage-specific glycoprotein VI and thus prompted to generate microparticles. Boilard and colleagues showed tPlatelets and neutrophils are major determinants of the immune-hemostatic continuum and extensively interact based on cell-cell contact and/or exchange of soluble signals and microparticles to synergise in contrasting the noxious effects of endogenous or environmental stimuli toward vessel and tissue integrity and to promote physiological tissue renewal and homeostasis. These events, part of a set of simple, innate, but evolutionarily preserved stereotyped responses, are disproportionately active and self-sustained in patients with immune-mediated diseases, such as systemic vasculitides, SLE, SSc, RA and possibly allergic disorders and might account for the development of either some inflammatory manifestations and of cardiovascular complications. Patients with immune-mediated diseases consistently show signs of platelet (and/or PD\u03bcP) activation, possibly prompting either the formation of heterotypic aggregates with neutrophils (as in giant cell arteritis) or neutrophil activation toward enhanced survival and eventually NET generation . Diagnostic and therapeutic strategies currently employed in the setting of autoimmune diseases to prevent disease progression and the occurrence of secondary complications are generally not targeted on these pathogenic mechanisms, suggesting the existence of a largely unexplored window of opportunity to improve survival and quality of life for patients by dampening sustained neutrophil-platelet interactions.GR and NM collected the literature data, drafted, and revised the manuscript. AM revised the manuscript and provided critical analysis of intellectual content. All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work will appropriately be investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Exercise/therapy interventions). Six of the seven training studies were concerned with upper limb function , and one examined the effect of foot drop stimulator training. The six upper limb studies used a variety of training modalities including Wii-based upper limb therapy (two papers from one group), EMG-driven robotic devices with or without neuromuscular electrical stimulation (NMES) (three papers), and traditional physical/occupational therapy (one paper).The nineteen papers of the research topic Electromyography (EMG) Techniques for the Assessment and Rehabilitation of Motor Impairment Following Stroke highlight a variety of ways that EMG may be used to better understand and treat stroke-induced brain damage. Seven papers addressed the impact of weekly training on EMG properties and function post-stroke, and one paper examined the effect of a robotic exoskeleton on gait during a single training session (Mechanisms of motor impairment). These included one study that addressed coupling between the index finger and thumb, whereas another addressed upper limb synergies during reaching. One paper examined EMG co-contraction during gait, and one addressed gait EMG during obstacle crossing. One group examined reticulospinal pathways during elbow flexor activity using startling acoustic stimulation. Another studied masticatory muscle activity following brainstem stroke. Finally, one group addressed coupling between the electroencephalogram (EEG) and EMG signals during upper limb movements.Another seven papers were focused on using EMG to examine motor impairment after stroke ((Novel EMG processing techniques). These included new approaches to intramuscular EMG decomposition, coherence of motor unit firing patterns from surface EMG, clustering index analysis of surface EMG, and pattern recognition from high density surface EMG.Four studies used novel EMG processing techniques to study motor control and impairment post-stroke A number of studies examined the effects of an exercise/therapy program, or a single exercise session, on EMG and motor function. Some also addressed the associated cortical plasticity.Hesam-Shariati et al. examined changes in upper limb EMG activity resulting from the standardized 14-day Wii-based Movement Therapy program in chronic stroke survivors. They found that training lead to different patterns of EMG changes that were related to the level of motor deficit. In their companion paper Hesam-Shariati et al. they quantified muscle synergies during therapy based on EMG activity of the affected arm muscles using a non-negative matrix factorization algorithm. They were able to identify differences in the number of muscle synergies used by patients as a function of the level of motor deficit.Many addressed the effect of exercise/therapy on upper limb muscle activation properties. Lu et al. used forearm EMG signals to detect a stroke survivor's motion intent, and then used the EMG to drive a hand exoskeleton to assist with finger motion in real time. After 10-weeks of robot-assisted hand therapy, the patient showed improved grip strength and hand function. The results demonstrate the feasibility of robot-assisted training driven by myoelectric pattern recognition in chronic stroke survivors.Device-assisted interventions offer a way to study and train patients with more severe limb impairment. In a case study, Qian et al. evaluated the effects of 1 month (20 sessions) of EMG-driven NMES combined with robotic assistance, targeting the elbow, wrist, and fingers of subacute stroke survivors. EMG parameters, including the co-contraction index and the activation level of targeted muscles were used to monitor the muscle coordination patterns. They found that the NMES combined with robotic training could achieve higher motor outcomes at the distal joints and more effective reduction in muscle tone than traditional therapy.After a stroke, it is critically important to start rehabilitation early to take advantage of the highly plastic period of the neural system. In a pilot randomized control trial, Wilkins et al. found EMG-driven NMES task-specific arm/hand training (7 weeks) improved hand opening and functional use in chronic stroke survivors with moderate to severe motor impairments. Functional improvement was paralleled with functional reorganization in the ipsilesional primary sensorimotor cortex. The neural plastic reorganization after functional improvement was also seen with strengthened corticomuscular coupling. In a case study of a subacute stroke subject, Zheng et al. evaluated corticomuscular coupling between EEG and EMG (biceps) signals during elbow flexion before and after 1 month of regular physical and occupational therapy. Corticomuscular coherence was increased in the affected limb with functional improvement, but not in the non-affected limb. These results exemplify that stroke survivors with severe motor impairments may still have the potential to improve hand function if appropriate interventions are used to induce neural plasticity.Some investigators also addressed training-related cortical plasticity and corticomuscular coupling. Pilkar et al. used different EMG-based indices to quantify the effects of a foot drop stimulator on muscle activation during gait over a 6 month period of community walking. A wavelet-based time-frequency analysis approach was used to quantify activation changes of multiple ankle muscles in chronic stroke survivors. The findings suggest alterations in motor unit recruitment strategies after foot drop stimulator use. The outcomes establish the efficacy of a foot drop stimulator as a rehabilitation intervention that may promote motor recovery in addition to reducing foot drop.Androwis et al. used novel EMG analysis (Burst Duration Similarity Index) to quantify the intensity and timing of muscle activation during a single session of robotic gait therapy in acute stroke survivors. The authors showed that a robotic exoskeleton can reduce the soleus and rectus femoris muscle activity in the affected limb during stance phase, and can also improve the timing of muscle activation in the affected limb.Quantitative and continuous monitoring of muscle activation is necessary to adjust training protocols in a timely manner. Jones and Kamper studied the coupling of the index finger and thumb during close-open pinching motions in chronic stroke survivors. A Cable-Actuated Finger Exoskeleton was used to perturb joints of the index finger during pinching motions, while finger/thumb muscle surface EMG and finger kinematics were recorded. They found that involuntary finger-thumb coupling was present during the dynamic pinching task, with perturbation of the index finger impacting thumb activity. This finding reveals a potential mechanism to improve hand mobility following stroke. Li et al. analyzed motor synergies during arm reaching based on surface EMG recordings from multiple muscles and correlated with reaching kinematics. They were able to detect task-specific deficits in reaching movements after strokeSurface EMG together with other signals recorded peripherally or centrally provides a means to assess mechanisms of motor impairment. Ma et al. studied lower limb muscle activity during obstacle crossing using surface EMG in chronic stroke survivors. EMG activity of the leading limb during the swing phase was larger in all muscles in the stroke compared to the control group, and TA activity increased with obstacle height in both groups. Co-contraction between agonist-antagonist muscle pairs was larger in the stroke group in the leading/ trailing limb during certain phases. The authors suggested that the greater muscle activation during obstacle crossing following stroke may have a negative impact on balance.Banks et al. quantified surface EMG co-contraction of agonist-antagonist muscle pairs in three ways and determined their association with gait impairment during treadmill walking. Co-contraction during the terminal stance phase was not different between healthy controls and the stroke subjects, regardless of the normalization method. Normalization also did not impact the ability to resolve group differences. Furthermore, the correlation between stance phase co-contraction and walking speed was modest. Pathological co-contraction may not be a primary factor contributing to impaired gait in most stroke survivors. The authors suggest other approaches that account for timing and amplitude components of the EMG may better capture the relevant deficits.It remains unclear whether co-contraction of agonist-antagonist muscles is excessive and impacts gait significantly following stroke. In chronic stroke survivors, Gao et al. studied subacute stroke patients completing tasks such as hand gripping and elbow bending. Stroke subjects demonstrated greater strength in the bi-directional corticomuscular coupling between the EEG and EMG signals. Such changes suggest a compensational strategy after the brain lesion.The coupling strength between the EEG and EMG signals during motion is instructive in assessing motor function. in vivo even with the most advanced neuroimaging techniques. Startling acoustic stimulation is known to stimulate the reticulospinal pathways, thus allowing the opportunity to assess the role of brainstem motor system indirectly. Li et al. analyzed changes in EMG and force in response to startling acoustic stimulation during isometric elbow flexion in stroke survivors and healthy controls. They reported that the sound-induced force and EMG increase in stroke survivors was not significantly different from those in healthy controls. As such, there results suggest that the reticulospinal projections do not increase their contributions to muscle strength in stroke. Jian et al. analyzed surface EMG signals of bilateral masticatory muscles in stroke survivors after brainstem stroke using multiple EMG parameters. In addition to expected differences between muscles and sides, they did not observe the head position effect on muscle activation on both sides. These are valuable information as the results could advance the understanding whether head positions alter chewing and swallowing activities in stroke survivors.It is difficult to assess activities of brainstem nuclei Ren et al. developed a new intramuscular EMG decomposition technique to improve the accuracy of EMG decomposition with interference patterns. The technique was implemented by using six stages of analysis including feature extraction, clustering, refinement of the classification, and splitting of the superimposed MUAPs. A high accuracy of MUAP detection was reported in 8 subacute stroke survivors (88%) and 20 healthy control participants (94%).Examining motor unit discharge and recruitment patterns post-stroke can disclose valuable information pertaining to impaired spinal versus supraspinal motor control. EMG decomposition into constituent motor unit action potential (MUAP) trains, however, is challenging with severe superposition of multiple MUAPs. Dai et al. quantified the different types of connectivity in the spinal networks and changes in their relative contributions after a stroke. By comparing the coherence of motor unit firing pattern across different isometric contractions, they identified significant changes in coherence in three frequency bands: delta (1\u20134 Hz), alpha (8\u201312 Hz), and beta (15\u201330 Hz) in the paretic hand muscles. These changes reflect increased common synaptic inputs in the subcortical pathway and provide evidence on different origins of impaired muscle activation in stroke.Tang et al. applied clustering index analysis to examine surface EMG in the distal and proximal muscles of the upper limb from 12 stroke survivors. They observed abnormally high or low clustering index values in the paretic muscles compared to healthy controls. This finding may indicate that both neurogenic and myopathic changes may occur in paretic muscles.To further differentiate neurogenic and myopathic changes in the muscle, Wang et al. developed a novel pattern recognition technique for precise discrimination of 20 hand/upper limb functional movements in stroke survivors. Specifically, they applied wavelet packet to extract the neural control features and used the Fisher's class separability index and the sequential feedforward selection analyses to select appropriate channels in high density surface EMG. Such implementation can facilitate use of surface EMG control in stroke rehabilitation.Selection of appropriate features from surface EMG is essential for development of highly effective pattern recognition algorithms in the EMG-controlled devices. All authors made an equal contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The hypothalamic-pituitary-ovarian (HPO) axis is a tightly regulated system controlling female reproduction. HPO axis dysfunction leading to ovulation disorders can be classified into three categories defined by the World Health Organization (WHO). Group I ovulation disorders involve hypothalamic failure characterized as hypogonadotropic hypogonadism. Group II disorders display a eugonadal state commonly associated with a wide range of endocrinopathies. Finally, group III constitutes hypergonadotropic hypogonadism secondary to depleted ovarian function. Optimal evaluation and management of these disorders is based on a careful analysis tailored to each patient. This article reviews ovulation disorders based on pathophysiologic mechanisms, evaluation principles, and currently available management options. The hypothalamic-pituitary-ovarian (HPO) axis must be viewed as an entity that works in concert to allow for procreation by means of cyclic production of gonadotropic and steroid hormones. This cycle is tightly regulated to select a dominant follicle for ovulation, meanwhile priming the endometrium for implantation. The ovary plays a pivotal role in the production of steroid hormones necessary for follicular development and oocyte maturation. It contains a finite number of oocytes that a woman will have for the span of her reproductive life and influences the hormonal milieu required for oocyte maturation and fertilization. This complex regulation can be negatively impacted when pathologies occur within any juncture of the HPO axis.Ovulatory disorders are the leading cause of infertility classified into three categories according to the World Health Organization (WHO ). Group Here, we provide an overview of ovulation disorders categorized by pathophysiologic mechanism from recent literature, along with guidance on evaluation and currently available management options.Group I ovulation disorders, hypothalamic-pituitary failure (HPF) manifests as hypogonadotropic hypogonadism. Females with HPF typically present with delayed or impaired pubertal development, primary or secondary amenorrhea, and infertility. Idiopathic hypogonadotropic hypogonadism (IHH) due to a congenital absence of gonadotropic releasing hormone (GnRH) is the most common cause of HPF. IHH associated with anosmia is termed Kallmann syndrome, which results from failure of GnRH neuronal migration from the olfactory placode during embryonic development. This disorder has a multimodal genetic inheritance pattern and can be transmitted in an X- linked, autosomal dominant, autosomal recessive, or oligogenic fashion with variable penetrance. Several gene mutations in association with this disorder have been identified, most notably ANOS1 . The nasAcquired causes include panhypopituitarism, characterized by >50% deficiency of one or more tropic hormones secreted by the pituitary gland. Etiologies leading to panhypopituitarism involve tissue necrosis (secondary to acute ischemia or pituitary gland apoplexy), autoimmune or infectious hypophysitis and compression by pituitary adenomas or adjacent brain tumors. Postpartum hemorrhage and significant head trauma may temporarily or permanently impact hormone production from the anterior pituitary. Similarly, intracranial tumors may compress the anterior pituitary stalk disrupting axonal communication between the hypothalamus and pituitary gland. Craniopharyngioma, a benign brain tumor deriving from a Rathke\u2019s pouch, is the most common brain tumor causing delayed puberty and primary amenorrhea. In addition to dysregulation of the HPO axis, bitemporal hemianopsia and chronic headaches may be observed if the optic nerve is compressed . AdditioLangerhans cell histiocytosis should be considered when more common causes of HPF are ruled out. This condition is marked by uncontrolled proliferation of dendritic cells associated with the monocyte-macrophage system . When LaA patient\u2019s medical history can help delineate between the various etiologies, to tailor evaluation and management. Basic evaluation includes follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2). In some instances, further evaluation is advisable to exclude central hypothyroidism (low TSH), hypocortisolism (low ACTH) and low growth hormone, which are a hallmark of panhypopituitarism.Commonly, a head MRI is indicated to rule out morphologic pituitary anomalies or presence of a tumor . OverallGroup II, eugonadal ovulatory dysfunction, accounts for the majority of ovulation disorders and comprises a wide spectrum of disorders. Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive aged women with a prevalence of 6\u201310% . It is tExtremes of weight and body fat distribution, influences the regulation of ovulation. Obesity, particularly central type, interferes with endocrine and paracrine mechanisms involved in reproductive cycle regulation. Loss of normal GnRH pulsatility is commonly due to excessive aromatization of androgen precursors, DHEA and testosterone, to estrone in adipose tissue, decreased levels of sex hormone binding globulin (SHBG) and elevated production leptin by adipocytes . FurtherIn contrary, in underweight patients, GnRH pulsatility is affected by depletion of circulating leptin, excessive cortisol and neuropeptide Y production, in addition to elevated centrogenic opioid and endorphin secretion. Hyperprolactinemia is a common cause for ovulatory dysfunction. There are many known causes of hyperprolactinemia including anterior pituitary adenomas, prolactinomas, primary hypothyroidism with thyrotropin releasing hormone (TRH) stimulation of prolactin, renal failure with abnormal clearance of prolactin, and psychotropic medications altering dopamine release. Primary hypothyroidism hinders regulation of the HPO axis since excessive TRH secretion will interfere with GnRH pulsatility. Furthermore, abnormal thyroid function affects folliculogenesis and oocyte quality. Some studies have suggested thyroid stimulation hormone (TSH) > 2.5 \u03bcIU/mL may be enough to lead to disordered ovulation; however additional studies have presented conflicting data. The literature has demonstrated that during controlled ovarian hyperstimulation, TSH is noted to increase and if baseline TSH exceeds 3 \u03bcIU/mL, patients will experience clinical hypothyroidism ,17,18. AThe ultimate goal for anovulation caused by eugonadal hypothalamic-pituitary dysfunction is to correct the underlying etiology. The majority of endocrinopathy related infertility is reversible and can be managed medically. Patients who present with menstrual dyscrasias should undergo initial evaluation with AMH, TSH and total T4, and prolactin level. If clinical signs of hyperandrogenism are apparent, 17-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulfate (DHEA-S) and total testosterone should be measured to rule out presence of ovarian or adrenal androgen secreting tumors. It is important to consider that multiple endocrinopathies may co-exist and must be treated concurrently. Prior to medical management, preconceptual counseling and lifestyle optimization should be emphasized, particularly weight loss and exercise. Thyroid deficiency and hyperprolactinemia, when corrected often will lead to successful ovulation and pregnancy. Patients suffering with PCOS commonly require ovarian suppression with combined oral contraceptive pills (OCPs), unless conception is desired. Multiple non-contraceptive benefits exist with the use of OCPs in this setting including reversing hyperandrogenism with shrinkage of exaggerated ovarian stroma, regulation of menses and reducing the risk of ovarian and endometrial cancer . Those dGroup III ovulatory disorders is defined as ovarian insufficiency or failure with a hypergonadotrophic-hypogonadic profile that affects 5% of women with ovulatory dysfunction . Women pDespite a low incidence, the most common genetic form of POI remains Turner syndrome, 45 XO, with either complete or partial X chromosome deletions. These patients commonly present with primary amenorrhea due to accelerated oocyte depletion. The second most common cause of POI is chromosomal aberrations. Approximately 10\u201330% of cases appear to be familial, primarily exhibiting an x-linked inheritance pattern with varying penetrance ,24. SeveNOBOX) and factor in germline alpha (FIGLA) that are responsible for gonadal differentiation and folliculogenesis [Additional candidate genes have been proposed to be causative, however lack sufficient evidence. New headways illustrating causes for POI includes mutations in transcription factors such as nuclear receptor subfamily five group A member 1 (NR5A1), newborn ovary homeobox , type I and II, associated with endocrine gland and extra-glandular tissue destruction reported to cause POI. APS type I affects younger children, with 60% of girls affected experiencing primary amenorrhea and POI. Type II causes gonadal failure in 4% of affected individuals . AssociaCommon gynecologic disorders may also contribute to accelerated reproductive aging. Endometriosis affects 10% of reproductive aged women. In addition to structural pathologies, ovarian endometriosis may lead to ovarian destruction and consequently a hypoestrogenic state. A study performed by Cahill et al. described endometriosis related diminished LH levels in serum and follicular fluid impacting ovulation . InevitaA number of environmental toxins may lead to POI. Effects of cigarette smoking have been extensively investigated. Smoking is associated with accelerated follicular atresia, displayed by significant lower AMH and earlier onset of menopause . EnvironAs oncologic treatments continue to improve, and the number of cancer survivors continue to increase, so does the rate of iatrogenic ovarian insufficiency. Cancer therapy causes oocyte depletion in several ways, the most common being inhibiting growth and proliferation of cells that support oocytes. How chemotherapeutic drugs affect immature oocytes is still unclear, however commonly used toxins including alkylating agents, work by interlinking DNA causing breaks that damage the cell . AdditioPelvic and total body irradiation has significant ramifications on ovarian function. Radiation doses as low as 4\u20135 Gy results in permanent loss of ovarian function. Knowing these treatment modalities confer poor prognosis for post-therapy gonadal and uterine function, careful consideration can be made in planning for future fertility. The field of onco-fertility is ever growing, with fertility preservation becoming increasingly available. Both the quantity and quality of available oocytes significantly diminishes once a woman reaches 35 years of age with exponential decline until menopause. Ovarian insufficiency can be diagnosed by measuring AMH, estradiol, FSH levels and antral follicle count. Though spontaneous pregnancy is not impossible, it is certainly much more difficult to achieve without intervention. Patients faced with such a diagnosis should be provided reassurance and guidance to the alternate reproductive options currently available. Evaluation approach is dependent on medical history and physical examination. Reproductive aged women less than 35 years old with rapidly declining ovarian reserve warrant genetic and infectious disease testing. If genetic testing is abnormal, genetic counseling is prudent.Patients with Turner syndrome may present with lack of pubertal milestone or primary amenorrhea. Mosaic Turner syndrome patients may be aware of their diagnosis prior to complete follicular atresia and can salvage their fertility by means of oocyte and/or embryo cryopreservation. With newer vitrification techniques, oocyte cryopreservation has become a reliable and available method for fertility preservation . In factOnco-fertility patients also greatly benefit from oocyte or embryo preservation prior to gonadotoxic therapy. In recent years, random start ovarian hyperstimulation in preparation for egg retrieval allows physicians to shorten treatment duration to proceed with chemoradiotherapy . In a spIVF with donor oocytes currently remains the most successful treatment modality for women with POI or age related diminished ovarian reserve. Currently available options of fresh or frozen or known vs. unknown donors provides patients with more options. Furthermore, women may opt to have their young relatives, with abundant ovarian reserve, to donate oocytes to them . The use of mesenchymal stem cells (MSCs) has been emerging as a treatment option for patients with POI. Stem cell therapy has particularly been studied in the setting of iatrogenic ovarian destruction and shown great promise. Various sources of stem cells under investigation for this purpose include umbilical cord MSCs (UCMSCs), induced pluripotent adult stem cells (iPSCs), and embryonic stem cells. Mouse models with chemotherapy induced ovarian insufficiency undergoing subsequent treatment with UCMSCs have demonstrated improved ovarian function with recovery of sex steroid levels and decreased cumulus cell apoptosis ,46. The More novel therapeutic options are beginning to make strides for age related oocyte quality improvement. One suggested mechanism responsible for depleted ovarian reserve involves mitochondrial dysfunction . Though Those affected by POI have health implications if they remain in a chronic hypoestrogenic state including as cardiovascular risk, sexual function and bone health. Hormone replacement therapy (HRT) should be encouraged through use of estrogen therapy with cyclic progestin if a woman still has her uterus. Those who no longer have a uterus, estrogen replacement alone is recommended. HRT is important to reduce the risk of morbidity and mortality as it mimics normal ovarian function until the natural age of menopause . Dose tiIn summary, this review outlines an up to date classification of ovulatory disorders to serve as a guide for its evaluation and management. As ongoing research in etiology and pathogenesis emerges, novel treatment approaches continue to develop. Familiarity with ovulatory disorders will enable practitioners to provide high quality medical care and be a beacon of hope to a wide array of patients."} +{"text": "A dearth of research investigates socio-environmental mechanisms of health disparities. Therefore, this paper tests the association between neighborhood characteristics and telomere length (TL), a biomarker of cellular age, and examines if this relationship differs by race and urban residence. Data from US-born, non-Hispanic Black and White midlife and older adults in the 2008 Health and Retirement Study was analyzed to test the relationship between TL and perceived neighborhood safety, cleanliness, and social cohesion. Linear regression models stratified by race included interaction terms between neighborhood characteristics and urban residence. Negative perceptions of neighborhood characteristics were associated with shorter TL in Blacks, with urban-dwelling Blacks having shorter TL than Blacks in less urban areas. Findings suggest that negatively perceived neighborhoods may be more detrimental to TL for urban compared to rural Blacks. Future research should elucidate the biobehavioral consequences of socially disadvantaged urban neighborhoods on healthy aging among Black adults."} +{"text": "Ochotona curzoniae) populations distributed along an altitudinal gradient of the Tibetan Plateau. We predicted that high-altitude pika would be more docile and less active.Animals inhabiting high altitudes consistently show slow life-histories. The pace-of-life syndrome (POLS) hypothesis posits behavioural, physiological and/or morphological traits that mediate the trade-off between current and future reproduction or survival, which have coevolved along a slow-fast life history continuum. Previous studies have shown that the life histories of plateau pikas varied across altitude, high-altitude individuals showed slow pace of life which were characterized by few litters per year with small litter sizes. Thus, we hypothesized that pikas populations at higher altitudes would also express personalities characteristic associated with slow life history, such as high sociability, low activity or aggressiveness. We tested this hypothesis by comparing the activity and docility of three plateau pika (The behaviour of 556 pikas, from which 120 individuals were measured at least twice, was quantified. We observed that plateau pikas at high altitudes were less active and more docile than pika at lower altitudes. Activity and docility were significantly and negatively correlated in populations from high altitudes but not in populations from low altitudes.Our results support the POLS hypothesis, highlight the existence of personality variation among populations distributed along an altitudinal gradient and emphasise the importance of environmental selection on personality divergence. Species with wide ranges usually exhibit geographic variation in life history traits, such as growth and reproduction \u20133. GeogrJunco hyemalis) bred at high elevations showed delayed development of structures necessary for reproduction, reduced duration of reproductive period and fewer broods than low-elevation conspecifics ) and moderately repeatable, respectively, indicating that variation in these two personality traits varies consistently among individuals over time.Activity and docility were highly and ZK populations but showed no correlation with docility in the GN population.Three populations at different altitudes showed our predicted differences in activity and docility Table\u00a0. ActivitWe investigated the phenotypic divergence of personality traits among plateau pika populations along an altitudinal gradient. Previous work on plateau pika populations indicates that the life-histories of high-altitude populations are slow. In support of the POLS hypothesis, we observed that higher-altitude populations also possessed personality traits that have been characterized as slow, i.e., less active and more docile, compared with the lower-altitude populations.The differences in activity and docility among plateau pika altitude-associated populations can be attributed to the differing life history strategies that have evolved in response to different climates and environments Table . Low-altOur findings indicate that differences in environmental conditions resulted in specific associations between behavioural traits of plateau pikas. These results indicate that behavioural syndromes could be adaptive, such that associations between behaviour may vary substantially in accordance with prevailing environmental conditions. Activity and docility were negatively associated in pikas from high- and medium-altitude sites. Correlations between these traits may corroborate the POLS hypothesis . In the We analysed behavioural differences among populations at the phenotypic level. As a result, we cannot rule out whether phenotypic differences reflect genetic differences or developmental plasticity . RegardlWe were unable to conclusively identify the precise divergences in the personality of pika populations distributed at higher altitudes, given that we focused on the traits of pika populations distributed within a limited altitude range. Nevertheless, our data reveal that the personality of pikas differs across altitudinal sites. Our study also provides valuable information regarding the effects of ecological conditions on the behavioural traits of animals at the population levels . AlthougPlateau pikas exhibit significant differences in activity and docility along the altitudinal gradient, supporting the POLS hypothesis. Future studies are needed to explore the mechanism and ecological consequences of personality divergences at large spatial-temporal scales and combine the animal personality with global climate changes."} +{"text": "Declining stem cell function during aging leads to impaired tissue function and contributes to delayed tissue repair following damage. In adult skeletal muscle, loss of myofiber integrity caused by mechanical injuries or diseases are repaired by resident muscle stem cells (MuSCs), called satellite cells, which promptly exit from quiescence after disruption of muscle architecture to expand, differentiate and drive tissue regeneration. The fate of MuSCs fundamentally depends on the \u201cniche\u201d, their local environment, which is orchestrated by diverse cellular and acellular elements. Aging causes cell-extrinsic changes to the MuSC niche and dysregulates signaling pathways, which collectively alter the regenerative function of MuSCs . The lowFibro/adipogenic progenitors (FAPs) constitute a population of interstitial mesenchymal cells in skeletal muscle which are devoid of myogenic potential, but support muscle stem cell commitment and can differentiate to the adipogenic or fibrotic lineages drives the perturbed support of aged FAPs to MuSCs. Genetic invalidation of WISP1 disrupts the communication between FAPs and MuSCs and leads to abnormal regeneration of skeletal muscle. Mechanistically, WISP-1 controls MuSC asymmetric expansion by activating Akt signaling. Importantly, this new paracrine mechanism can be targeted therapeutically by administering recombinant WISP-1 systemically. Altogether, our work reveals that loss of WISP1 from FAPs directly contributes to MuSC dysfunction in aged muscle and demonstrates that adipogenic progenitors are not just quiescent precursors waiting for pathological cues to elicit pathological conversions, but actually constitute bona fide elements of the stem cell niche, which regulate an active cross-talk with stem cells via paracrine signaling [The decline of MuSC function and muscle regenerative capacity during aging is under the control of a wide range of signals, out of which many arise from extrinsic cues coming from the local or systemic environment . In a reignaling .Along similar lines, a subpopulation of stromal progenitors in adipose tissue has recently been identified using single-cell RNA sequencing as a negative regulator of adipogenesis which represses the differentiation of adipocytes and keeps fat expansion in check . FAPs ar"} +{"text": "OBJECTIVES/SPECIFIC AIMS: (i) Digitally quantify pathologically relevant glomerular microcompartmental structures in murine renal tissue histopathology images. (ii) Digitally model disease trajectory in a mouse model of diabetic nephropathy (DN). METHODS/STUDY POPULATION: We have developed a computational pipeline for glomerular structural compartmentalization based on Gabor filtering and multiresolution community detection (MCD). The MCD method employs improved, efficient optimization of a Potts model Hamiltonian, adopted from theoretical physics, modeling interacting electron spins. The method is parameter-free and capable of simultaneously selecting relevant structure at all biologically relevant scales. It can segment glomerular compartments from a large image containing hundreds of glomeruli in seconds for quantification\u2014which is not possible manually. We will analyze the performance of our computational pipeline in healthy and streptozotocin induced DN mice using renal tissue images, and model the structural distributions of automatically quantified glomerular features as a function of DN progression. The performance of this structural-disease model will be compared with existing visual quantification methods used by pathologists in the clinic. RESULTS/ANTICIPATED RESULTS: Computational modeling will reveal digital biomarkers for early proteinuria in DN, able to predict disease trajectory with greater precision and accuracy than manual inspection alone. DISCUSSION/SIGNIFICANCE OF IMPACT: Automated detection of microscopic structural changes in renal tissue will eventually lead to objective, standardized diagnosis, reflecting cost savings for DN through discovery of digital biomarkers hidden within numerical structural distributions. This computational study will pave the path for the creation of new digital tools which provide clinicians invaluable quantitative information about expected patient disease trajectory, enabling earlier clinical predictions and development of early therapeutic interventions for kidney diseases."} +{"text": "Following presentation with abnormal liver function enzymes, confusion and fatigue, a 65-year-old male with alcoholic cirrhosis underwent spectral Doppler sonography that showed tardus parvus-like morphology in the main and left hepatic arteries, although peak systolic velocities and resistive indices remained normal. The patient\u2019s continuing clinical symptoms prompted CT angiography, which demonstrated an unexpected, haemodynamically significant stenosis of the celiac artery. Although the stenosis was successfully stented and the hepatic arterial waveforms normalized, the transplanted liver had already undergone ischaemic necrosis, with resulting failure and the need for retransplantation. Recognition of abnormal waveforms, despite normal peak systolic velocities and resistive indices, with prompt definitive imaging evaluation of the arterial tree beyond just the main hepatic artery, may lead to the diagnosis of unexpected flow-limiting lesions in time to allow revascularization and thus prevent ischaemic transplant failure. CT angiography 2 days thereafter revealed not only a normal main hepatic artery and patent surgical arterial anastomosis, but also an unexpected, haemodynamically significant stenosis (exceeding 50% diameter2) at the origin of the celiac artery should be pursued promptly when an abnormal hepatic arterial waveform is recognized in the setting of graft dysfunction.9 Some authors have noted that celiac artery compression by the arcuate ligament occurs in as many as 10% of patients undergoing liver transplantation.7 It is rarely symptomatic, owing to efficient arterial collateralization from the superior mesenteric and the gastroduodenal arteries; however, in patients without sufficient collateralization, symptomatic hepatic arterial insufficiency and/or thrombosis may result. Fortunately, the stenting procedure for our patient restored flow such that, for either possible cause, the patient\u2019s retransplantation can proceed with adequate arterial inflow.It is essential to consider feeding vessels in addition to the main hepatic artery itself, such as the celiac artery, when searching for flow-limiting lesions. In the present case, the haemodynamically significant celiac stenosis undoubtedly developed after the patient\u2019s original, successful transplant surgery. Because no calcifications were demonstrated at the site of the celiac stenosis by CT angiography, the differential diagnosis would include non-calcified atherosclerotic plaque as well as the median arcuate ligament syndrome.In summary, abnormal hepatic arterial waveforms following hepatic transplantation, even when other values such as RIs and peak systolic velocities are not abnormal, should elicit a prompt search for flow-limiting lesions using definitive imaging modalities such as CT angiography, with careful evaluation for lesions not only at the arterial anastomosis but also at other sites within the arterial tree supplying the transplanted liver.Abnormal hepatic arterial waveforms in hepatic transplant patients, despite normal peak systolic values and normal RIs, should elicit a search for flow-limiting arterial lesions.Definitive imaging, such as CT angiography, should be pursued promptly in the search for flow-limiting arterial lesions.Severe complications following liver transplantation may result from unexpected flow-limiting arterial lesions at sites other than the typical location at the donor/recipient anastomosis.Our institutional review board approved this study and waived informed consent in view of its retrospective nature. All procedures were conducted in compliance with the Health Insurance Portability and Accountability Act."} +{"text": "When patients develop destructive osteomyelitis, clinicians must always consider the possibility of SAPHO syndrome because even extremely destructive osteomyelitis can be cured by NSAIDs. YT: involved in manuscript drafting and clinical care of the patient. SY: involved in study conception and manuscript revision."} +{"text": "Sociedade Portuguesa de CuidadosIntensivos summarizes the current evidence and gives six clinicalstatements and an algorithm aiming to provide a standardized prescribing policyfor the use of stress ulcer prophylaxis in the intensive care unit.Critically ill patients are at risk of developing stress ulcers in the upperdigestive tract. Agents that suppress gastric acid are commonly prescribed toreduce the incidence of clinically important stress ulcer-relatedgastrointestinal bleeding. However, the indiscriminate use of stress ulcerprophylaxis in all patients admitted to the intensive care unit is not warrantedand can have potential adverse clinical effects and cost implications. Thepresent guidelines from the Systemic hemodynamic andlocal alterations result in gastric mucosal blood flow impairment with subsequentischemic mucosal injury. However, the crucial factor for the development ofulceration and gastric bleeding is the high gastric intraluminal acidity, which ispotentiated by fasting.(3) less than 50% ofpatients will have occult bleeding (defined as guaiac-positive gastric aspirate orguaiac-positive stool) and approximately 5%(5)will have overt bleeding . However, this does not necessarily translate into clinicallysignificant gastrointestinal bleeding ,(6) whose incidence seems to have decreased over theyears. In studies published before 1999, the incidence of clinically significantgastrointestinal bleeding was between 2% and 6% in patients not receivingprophylaxis.(6) However, in studies published since 2001, theincidence has been reported to range between 0.1% and 4% with or withoutprophylaxis,(7) which is related to better overall critical care,including the increased use of early enteral feeding. This, along with concernsrelated to the reported increasing frequency of infectious complications ,(9) has challenged thetraditional cornerstone of pharmacological prophylaxis with agents that suppressgastric acid for stress ulcer prophylaxis.(10)Endoscopically evident upper gastrointestinal lesions may be found in up to 90% ofcritically ill patients within 3 days of admission;Sociedade Portuguesa de Cuidados Intensivosaims to summarize current evidence and give clinical recommendations for the use ofstress ulcer prophylaxis in the intensive care unit (ICU) to provide a standardizedprescribing policy and avoid injudicious use.This guideline from the A multidisciplinary task force was assembled. The task force comprised physicians, nurses, pharmacistsand economists with special interest and expertise in stress ulcer prophylaxisand/or evidence-based medicine. All members of the task force declared that noconflict of interest influenced the development of the guidelines.(11) The availability of a Cochranereview(12) relevant to the clinical questions was confirmed bysearching the Cochrane Database of Systematic Reviews. A further complementaryliterature search of PubMed\u00ae was performed. Trial data identifiedby the search strategies were considered to represent the best-quality evidence. TheGrading of Recommendations Assessment, Development, and Evaluation (GRADE) systemprinciples(13) was used to assess the quality of evidence fromhigh to very low and to determine the strength of recommendations.Task force members participated in a discussion via e-mail, and six clinicalquestions were built for evidence evaluation. Each working member took charge of oneclinical question and built search queries in the PICO format.(14) This was done according to the GRADE system andconsidered the following factors: evidence quality, certainty in the balance betweenadvantages and disadvantages, certainty or similarity in values and preferences, andresource implications. Arriving at a consensus required an average level ofagreement of \u2265 80%. When the agreement level was < 80%, furtherdiscussions and voting were conducted.Finally, the task force determined the direction (for or against) and strength(strong or weak) of the recommendations using a two-round (self-administeredquestionnaire with no meetings among the participants) simple Delphimethod.A strong recommendation was worded as \"we recommend\" and a weak recommendation as \"wesuggest\".Sociedade Portuguesa de Cuidados Intensivos in Oporto anddiscussed by the panel and audience members.The key recommendations were presented at the annual symposium of theWe recommend maintaining (or initiating) agents that suppressgastric acid in patients with compellingindications for acid suppression. Strong recommendation, moderate qualityof evidence.Several clinical situations require gastric acid suppression , and indications should be respected, both in the ambulatory andhospital (including intensive care) settings.Patients with compelling indications include the following:Helicobacter pylori-negative ulcers; need tocontinue NSAID or failure to eradicate Helicobacterpylori; ulcers complicated at the outset; and giant(> 2cm), refractory or recurrentulcers].(15)- Known peptic ulcer disease in the healing phase and maintenancephase in selected circumstances is comparingproton-pump inhibitors and histamine-2-receptor antagonists, and the results areexpected to provide more relevant data.(27)The efficacy of proton-pump inhibitors and histamine-2-receptor antagonists inpreventing stress-ulcer bleeding in critically ill patients has been compared inseveral randomized control trials and meta-analyses.(51) focused on the comparison betweenhistamine-2-receptor antagonists and proton pump inhibitors for the prophylaxisof stress ulcerrelated gastrointestinal bleeding. The results are contradictory,mainly due to the use of different clinical inputs, and there is no strongevidence regarding which is the most effective alternative. Data from the mostrecent meta-analysis of clinical trials indicate that proton pump inhibitorsshould be used. However, if one relies on a propensity score-matchedobservational cohort study, histamine-2-receptor antagonists are the preferredoption.(51) The only clear conclusion is that, as the costof prophylaxis is small when compared to the costs of complications, the mosteffective alternative will constitute a dominantalternative.(51)There are multiple pharmacoeconomic analyses(53) It is acknowledgedthat the published literature on this issue derives from heterogeneouspopulations of critically ill patients who may differ from the populations atrisk identified by the previous recommendation.Although the quality of evidence is suboptimal, proton-pump inhibitors have beenthe preferred regimen in intensive care units across Europe, the United Statesand Canada.(54) provided evidenceof an increase in pneumonia with proton-pump inhibitor use; however, this studywas related only to cardiac surgery patients, and confidence intervals werewide. Small randomized trials (55)) and a case-control study showed anincreased adjusted risk for Clostridium difficile infectionsduring treatment with proton-pump inhibitors, but this was more related to theduration of exposure.(56)Additionally, the expected adverse effects of proton-pump inhibitors are aconcern and must be taken into account. A cohort studyUltimately, the desirable consequences of stress ulcer prophylaxis withproton-pump inhibitors are expected to outweigh the undesirable consequencesamong the population at risk.We make no recommendation regarding specific proton-pump inhibitorregimens.The ideal drug regimen should be effective in reducing the risk of ulceration,with a low potential for adverse effects and drug interactions andpharmacokinetic characteristics that facilitate its use in patients with organdysfunction; it should also be cost-effective.a prioridefined subgroup analysis of at least one meta-analysis suggests that the routeof administration and dosing (onceversus twice a day) do not affect theresults.(45)There is no direct comparison between different proton-pump inhibitor-basedregimens , and heterogeneity across studies (comparing proton-pump inhibitorsto other regimens) impairs the comparison of effects between the individualproton-pump inhibitor regimens tested to date. An e.g., vasopressor use, altered gastric emptying andmotility, feeding tube and nutrient interactions) may influence enteralabsorption in critically ill patients, and the intravenous route is generallypreferred.(57) This is disputed by a study showing that,despite a lower bioavailability, enteral lansoprazole suppressed acid inintensive care unit patients better than the intravenousformulation.(58) However, this has not been confirmed by furtherstudies, and lansoprazole requires a complex and labor-intensive galenicformulation for feeding tube administration.In relation to the route of administration, multiple factors(qd) may be a reasonable choice.(59) However, thedefinitive choice of the specific proton-pump inhibitor regimen should be basedon individual patient and medical values, experience, product labeling,cost-benefit analyses, anticipated risks of drug-drug interactions and adverseeffects.Due to its safety in (at least moderate) organ dysfunction, lower probability ofdrug-drug interactions, and available formulations, intravenous pantoprazoleThe most recent and comprehensive meta-analysis(61) found that therapywith agents that suppress gastric acid was associated with a significant risk ofClostridium difficile infections but that the risk waslower for histamine-2-receptor antagonists than with proton-pump inhibitors.Accumulating evidence suggests that the use of agents that suppress gastric acidmay increase the frequency of infectious complications.Clostridiumdifficile infections is still controversial because meta-analysisis weak in detecting a modest increase in these events.(62) Nevertheless, therisk of Clostridium difficile infections remains higher inpatients receiving proton-pump inhibitors compared with patients receivinghistamine-2-receptor antagonists.(8) Moreover, observationalstudies(64) have shown thatcontinued proton-pump inhibitor use during incident Clostridiumdifficile infections increases the risk of recurrence.In the critically ill population, the increased risk for Clostridium difficile infections, proton-pumpinhibitors should be avoided, and histamine-2-receptor antagonists should be thepreferred therapy when stress ulcer prophylaxis isindicated.(62)Based on available data and given the significant disease burden and mortalityassociated with We recommend stopping prophylaxis with agents that suppress gastricacid when risk factors are no longer present and the patient is receivingenteral nutrition. Strong recommendation, low quality ofevidence.(65) This is inagreement with studies that have concluded that 88.5% of stress ulcerprophylaxis in nonintensive care unit patients isinappropriate(66) and that a relatively restrictive stress ulcerprophylaxis program not only reduces inappropriate use without increasing therates of hospital-related gastrointestinal bleeding but also results in anestimated annualized cost savings of more than US$200.000.(67)Acid suppressants are inappropriately continued in a large proportion of patientsafter the resolution of risk factors and even after intensive care unit orhospital discharge, thus extending the potential risks and costs associated withstress ulcer prophylaxis beyond the intensive care unit.(26) there is some evidence to suggest that inpatients receiving enteral feeding, pharmacologic stress ulcer prophylaxis isnot beneficial, and combined interventions may even increase the risk of someinfectious complications. However, the evidence is still insufficient to justifywithholding stress ulcer prophylaxis from patients who are at high risk forgastrointestinal bleeding. It is sufficiently compelling to support thecessation of prophylaxis when risk factors are no longer present and the patientis receiving enteral nutrition.As previously described,(68) As one of the more common indications forstress ulcer prophylaxis is mechanical ventilation, extubation is crucial toidentify and possibly discontinue acid suppressiontherapy.(62)Patients should thus be evaluated daily during multidisciplinary care rounds forthe continued need for prophylaxis, and once the patient is receiving enteralnutrition and risk factors are no longer present, stress ulcer prophylaxisshould be discontinued. This strategy will reduce the overuse and unnecessarycontinuation of agents that suppress gastric acid upon discharge and in theoutpatient setting.Clostridiumdifficile infection, for which histamine-2-receptor antagonists arepreferred (Statement 5). Once the patient is receiving enteral nutrition andrisk factors are no longer present, stress ulcer prophylaxis should bediscontinued (Statement 6). The general algorithm for the prophylaxis of stress ulcer bleeding in theintensive care unit is presented in The authors suggest that the practices recommended in this guideline arecontinuously evaluated and monitored and that this guideline is updated as newevidence becomes available."} +{"text": "Housing coordination, a central component of the Money Follows the Person program, allows older adults and people with disabilities to experience greater independence and sense of well-being . This study was part of the 2017 Money Follows the Person (MFP) Process Evaluation involving 26 key informants (KIs) who completed telephone interviews sharing their experiences about program implementation. Of these, 13 KIs providing housing coordination services to the MFP transition team were asked about the housing coordination training they received and suggestions to improve the training. They were also asked about housing resources, how they develop their housing inventory, and recommendations for a \u201cHousing Best Practices Report.\u201d Interviews were audio-taped and transcribed. Data were analyzed using ATLAS.ti. Results demonstrate a need for more training and assistance to enable housing coordinators to expand their knowledge of housing alternatives, increase their awareness of housing policy/process changes, and further inform consumers about housing choices. Suggestions to improve housing coordination included offering more creative solutions during monthly housing coordination phone calls. Housing inventory challenges mentioned by KIs included time constraints, limited staff, administrative delays, and lack of affordable housing. Suggestions for housing inventory development focused on improving the management/maintenance of housing inventories. Best housing practices underscored the importance of communicating, teaming, building relationships with landlords and management companies, and standardizing housing policies and procedures. Overall recommendations included strengthening collaboration among housing coordinators to identify and implement best practices and improving housing inventory development to widen housing options for consumers."} +{"text": "In conclusion, even under deep propofol sedation, apneas and hypopneas can be terminated without cortical arousal. However, extensive suppression of the arousal threshold can lead to critical hypoxemia suggesting careful respiratory monitoring.Recent evidences suggest that non-arousal mechanisms can restore and stabilize breathing in sleeping patients with obstructive sleep apnea. This possibility can be examined under deep sedation which increases the cortical arousal threshold. We examined incidences of cortical arousal at termination of apneas and hypopneas in elderly patients receiving propofol sedation which increases the cortical arousal threshold. Ten elderly patients undergoing advanced endoscopic procedures under propofol-sedation were recruited. Standard polysomnographic measurements were performed to assess nature of breathing, consciousness, and occurrence of arousal at recovery from apneas and hypopneas. A total of 245 periodic apneas and hypopneas were identified during propofol-induced sleep state. Cortical arousal only occurred in 55 apneas and hypopneas (22.5%), and apneas and hypopneas without arousal and desaturation were most commonly observed (65.7%) regardless of the types of disordered breathing. Chi-square test indicated that incidence of no cortical arousal was significantly associated with occurrence of no desaturation. Higher dose of propofol was associated with a higher apnea hypopnea index ( Patency of the pharyngeal airway is state-dependent in patients with obstructive sleep apnea (OSA). Reduction of upper airway (UA) dilating muscle activity during loss of consciousness appears to account for UA obstruction during sleep . Burst o2-mediated genioglossus muscle activity [Younes, however, recently proposed that cortical arousals are coincidental events that occur just prior to arousal-independent airway opening through analysis of the breathing and cortical activity in experimentally-induced apneas or hypopneas ,5,6. In activity and to dactivity . Furtheractivity .Despite physiological evidence suggesting advantages of arousal threshold reduction, cortical arousal was observed to occur at apnea termination even under light sedation . ConsequWe performed a prospective observational study after obtaining approval from the institutional Ethics Committee and written informed consent from each subject. Ten adult patients undergoing ESD surgery for early gastric cancer under propofol sedation participated in the study. Relatively higher incidence of obstructive apneas and hypopneas was found in the elderly patients under propofol sedation as the primary result of the study , this seThe patient lying on the left side received 2 L/min oxygen through a nasal prong. In order to minimize body movements during the endoscopic submucosal dissection (ESD), relatively deep sedation maintaining Ramsey score 5 to 6 was achi2), and snoring over a microphone were recorded and stored in a computer for later analyses. For research purposes, a standard polysomnography was performed . Bilateral central and occipital electroencephalograms (EEG), bilateral electrooculograms (EOG), submental electromyogram (EMG), electrocardiogram, airflow measurement with a nasal pressure prong and an oro-nasal thermistor, thoraco-abdominal wall motions with piezo respiratory effort sensors, oxygen saturation , presence or absence of thoraco-abdominal respiratory movements , and presence or absence of cortical arousal evidenced by the electroencephalograms upon restoration from apneas and hypopneas . Apnea hypopnea index (AHI) was determined as the frequencies of apneas and hypopneas per hour of sleep for each of the category combinations with and without the 3 features of apneas and hypopneas [Polysomnography data were manually reanalyzed for this secondary analysis by a certified sleep technician (RK) and an investigator (SI) using a dedicated computer software . Consciousness states (awake or sleep) were determined for each 30 s polysomnography recordings by using the criteria of Rechtschaffen and Kales , and breypopneas .p < 0.05 was considered statistically significant, and all p-values were two sided. All statistical analyses were performed by using a computer software . Arousal rate defined as the ratio between the incidence of respiratory disturbances with cortical arousal and total incidence of the respiratory disturbances occurring in all participants was calculated for each of the categories. Comparison of the arousal rates with and without desaturation was performed by using Chi-square test. Values were presented as frequencies and proportions for categorical data, and means and standard deviations (SD) for continuous variables. A value of \u22121. Thirty-eight more apneas and hypopneas were identified in this secondary analysis than in the primary analysis [r = 0.673, p = 0.033, n = 10). AHI without desaturation was significantly greater than AHI with desaturation (p = 0.024).Patients\u2019 characteristics and details of the sedation are presented in analysis . Total AThis is the first study which assessed the occurrence of cortical arousal in response to apneas and hypopneas during propofol-induced sleep in elderly patients undergoing endoscopic surgery. Cortical arousal only occurred in 55 of 245 apneas and hypopneas (22.5%) during propofol-induced sleep. Apneas and hypopneas without arousal and desaturation was most commonly observed (65.7%) regardless of types of disordered breathing. The results strongly suggest that cortical arousal is possibly a coincidental event to the non-arousal recovery from respiratory disturbances and is not always necessary to restore breathing even in the elderly.Propofol is a potent GABA agonist and used as a general anesthetic as well as a sedative depending on the administration dose . It doseAccording to recent accumulated knowledge of arousal and obstructive sleep apnea , interacIn contrast, propofol increases arousal threshold over the UA opening threshold and decreases respiratory drives to the diaphragm and UA muscles B. It is Despite common UA obstruction episodes under propofol sedation, few critical respiratory events occurred in this study, which may reflect few reports of fatal complications under propofol sedation for endoscopic procedures ,20. HoweThere are several limitations in this study. Firstly, the sample size is very small and the patient population is severely limited to non-obese elderly without previous OSA diagnosis. Only few respiratory disturbances occurred during propofol sedation resulting in severe hypoxemia commonly observed in patients with severe OSA. Obviously, our study design does not allow generalization of the findings. However, we believe that incidences and natures of respiratory disturbances and restorative capacity without cortical arousals were objectively assessed by polysomnographies during the sedation. Certainly, four electroencephalograms used in this study were probably not able to cover the whole brain activities and undetected cortical arousal may have occurred during recovery from the respiratory disturbance. However, we consider this possibility unlikely due to the propofol dose used in this study ,21. SecoEffects of various types of hypnotics and sedatives on OSA have been assessed in many previous studies, but the results are diverse; some studies demonstrated an increase of AHI and apnea duration, but clinically meaningful AHI reduction without increase of apnea duration was reported particularly in studies using nonmyorelaxant sedatives such as eszopiclone ,24. JordPharmacological sedation is becoming frequently used in various clinical situations such as invasive endoscopy, minor surgery, radiological examinations for children, and mechanical ventilation in ICU ,25,26,27Obstructive apneas and hypopneas during propofol sedation were spontaneously terminated without cortical arousal while repeated periodically. The appropriative depth of propofol sedation appears to reduce both the UA dilating muscle activity and its oscillation, possibly stabilizing respiration and decreasing frequency of respiratory disturbances. However, extensive suppression of the arousal threshold with higher doses of propofol can lead to prolonged apnea and critical hypoxemia suggesting careful respiratory monitoring with both pulse oximetry and nasal pressure monitor during advanced GI endoscopy under propofol sedation."} +{"text": "This synthetic method features a silane-driven catalytic intramolecular Wittig reaction as a key annulation step and represents the first successful application of catalytic Wittig reaction in multicomponent cascade reaction.Tri- or tetrasubstituted furans have been prepared from terminal activated olefins and acyl chlorides or anhydrides by a multicomponental convergent synthesis mode. Instead of stoichiometric A broad scope of substrates, bearing various reducible functional groups including ketone, acyl chloride, olefin, nitro, cyano, and ester, are all well tolerated in the presence of reducing agent silane. This synthetic method features a silane-driven catalytic intramolecular Wittig reaction as a key step and represents the first successful application of catalytic Wittig reaction in a multicomponent cascade reaction. Future efforts in our laboratory will be directed toward exploring the asymmetric reactions involving catalytic chiral phosphine mediated Wittig reaction, the results of which will be reported in due course.In conclusion, a convergent synthetic method for tri- or tetra-substituted furans has been developed by catalytic phosphine mediated multicomponental cascade reactions. Instead of stoichiometric"} +{"text": "Orbital emphysema occurs when air enters the soft tissue surrounding the orbit. Although orbital blowout fractures are often caused by face trauma, nontraumatic orbital fractures can also occur but have been rarely described. Here, a case of orbital and palpebral emphysema caused by forceful nose-blowing is presented. Examination uncovered gross swelling of the right eye and discernable subcutaneous emphysema. The patient had normal eye movement and visual acuity. Orbital computed tomography (CT) revealed orbital emphysema secondary to an orbit floor fracture into the maxillary sinus, resulting from high intranasal pressure upon blowing her nose. The patient received conservative management with antibiotics and was given instructions not to sneeze or blow her nose. She fully recovered and all her symptoms completely resolved. Orbital emphysema is a somewhat rare clinical event. A collection of air within the orbits or eyelids is most commonly associated with fracture and trauma of an orbital bone. Although trauma is the most common etiology of orbital emphysema, nontraumatic spontaneous orbital emphysema due to coughing, sneezing, nose blowing, or any type of straining as a result of iatrogenic otolaryngeal and dental procedures and infectious gas-producing microorganisms have been described \u20135.We describe a patient with orbital emphysema presenting swelling surrounding the left eye several hours after blowing her nose. Most cases of orbital emphysema resolve spontaneously; however, emergency physicians should be aware that early recognition of orbital emphysema is crucial to prevent possible vision-threatening complications if unrecognized . Since oA 59-year-old healthy Japanese female with chronic rhinitis was taken to our emergency department due to a sudden and painless left periorbital swelling following forceful nose-blowing. Examination revealed a gross swelling of the left eye. There was painless palpable emphysema around her left eye; she had normal eyeball movement and visual activity. By ophthalmic consultation, the intraocular pressure was found to be slightly higher in her left eye (20\u2009mmHg) compared to the right (13\u2009mmHg). Noncontrast CT revealed orbital subcutaneous and subconjunctival emphysema and fracture of the median orbital wall of the left eye. Focal herniation of extraconal fat into the ethmoid air cells was noted . OtherwiThis case highlights spontaneous orbital emphysema caused by forceful nose-blowing, which may pose a diagnostic challenge. In our patient, orbital emphysema developed when the patient blew her nose by air transfer from the paranasal sinuses into the orbit along a pressure gradient, causing a one-way valve forcing air into the orbit. Orbital fat may function like a ball-valve, becoming displaced from the fracture site during insufflation but falling back to seal the opening under the pressure of trapped air.Gwaltney et al. measured intranasal pressure during coughing, sneezing, and nose-blowing using fluid dynamic modeling with sinus CT. They reported a mean maximal intranasal pressure of 66\u2009mm Hg during nose-blowing, 4.6\u2009mmHg during sneezing, and 6.6\u2009mmHg during coughing. Intranasal pressures greater than 190\u2009mmHg have been measured during nose blowing with maximal expiratory efforts, offering evidence that air can be introduced into the orbit under substantial pressure . Old traIn our patient, chronic inflammation in the maxillary sinus associated with chronic rhinitis may have caused weakening of the orbital floor, making it more susceptible to fracture with high pressure with forceful nose-blowing.Most orbital emphysema cases require no treatment. However, with progressive emphysema, urgent decompression of the trapped air and acute orbital compartment syndrome is necessary to avoid irreversible vision loss because of mechanical optic nerve stretching or vascular compromise. Extraocular muscle motility and visual acuity are the two most important ophthalmologic functions that should be evaluated emergently in patients with acute orbital trauma. Assessing these abilities may be challenging at times due to head injury severity, level of periorbital soft tissue edema, lack of complete cooperation in alert patients, and reduced consciousness.Reduced vision after trauma may be caused by intraorbital emphysema, retrobulbar hemorrhage, optic nerve thickening presumably secondary to edema, ruptured globe, detached retina, and optic nerve impingement. These complications are ophthalmic emergencies requiring immediate intervention. Therefore, differentiating benign orbital emphysema from an ophthalmic emergency is critical to avoid adverse sequelae. In nontraumatic cases, the most important differential diagnosis to exclude in acute unilateral eye swelling is orbital cellulitis, which may present with pain on eye movement, visual loss, chemosis, and fever .The diagnosis can be easily made by palpation of the pathognomonic cracking and crepitation on the eyelids. CT plays a crucial role in assessing the intraorbital contents of patients with orbital trauma. Most patients with compromised visual acuity or decreased extraocular muscle motility caused by trauma have abnormalities shown by orbital CT.Most cases of orbital emphysema resolve spontaneously, and no treatment is needed. Experts generally recommend prophylactic oral antibiotics to treat sinus pathogens for patients with orbital fracture into a sinus . A 23-gaIn conclusion, clinicians should investigate all suspected orbital blowout fractures with imaging and full ophthalmological examination regardless of trauma history to avoid possible complications like vision loss because of infection and pressure."} +{"text": "Images were parcellated into 278 regions of interest (ROI) based on Shen et al. (2013). Connectivity between each ROI pair was described by Pearson correlation coefficient. Brain regions were grouped into 7 canonical RSNs as described by Yeo et al. (2015). Pearson correlation values were then averaged across pairs of ROIs in each network and averaged across individuals in each group. These values were used to determine relative expression of FC in each RSN (intranetwork) and create RSN profiles for each group. RESULTS/ANTICIPATED RESULTS: Our findings support previous literature which shows that limbic networks are disrupted in FTLD participants compared with AD and age-matched controls. In addition, interactions between different RSNs was also examined and a significant difference between controls and AD subjects was found between FP and DMN RSNs. Similarly, previous literature has reported a disruption between executive network and default mode network in AD compared with controls. DISCUSSION/SIGNIFICANCE OF IMPACT: Our approach allows us to create profiles that could help compare intranetwork FC in different neurodegenerative diseases. Future work with expanded samples will help us to draw more substantial conclusions regarding differences, if any, in the connectivity patterns between RSNs in various neurodegenerative diseases.OBJECTIVES/SPECIFIC AIMS: Recent evidence from resting-state fMRI studies have shown that brain network connectivity is altered in patients with neurodegenerative disorders. However, few studies have examined the complete connectivity patterns of these well-reported RSNs using a whole brain approach and how they compare between dementias. Here, we used advanced connectomic approaches to examine the connectivity of RSNs in Alzheimer disease (AD), Frontotemporal dementia (FTD), and age-matched control participants. METHODS/STUDY POPULATION: In total, 44 participants from an ongoing study at Indiana University School of Medicine were used. Resting-state fMRI data was processed using an in-house pipeline modeled after Power"} +{"text": "Traumatic spinal cord injury (SCI) leads to disruption of sensory, motor and autonomic function, and triggers structural, physiological and biochemical changes that cause reorganization of existing circuits that affect functional recovery. Propriospinal neurons (PN) appear to be very plastic within the inhibitory microenvironment of the injured spinal cord by forming compensatory circuits that aid in relaying information across the lesion site and, thus, are being investigated for their potential to promote locomotor recovery after experimental SCI. Yet the role of PN plasticity in autonomic dysfunction is not well characterized, notably, the disruption of supraspinal modulatory signals to spinal sympathetic neurons after SCI at the sixth thoracic spinal segment or above resulting in autonomic dysreflexia (AD). This condition is characterized by unmodulated sympathetic reflexes triggering sporadic hypertension associated with baroreflex mediated bradycardia in response to noxious yet unperceived stimuli below the injury to reduce blood pressure. AD is frequently triggered by pelvic visceral distension (bowel and bladder), and there are documented structural relationships between injury-induced sprouting of pelvic visceral afferent C-fibers. Their excitation of lumbosacral PN, in turn, sprout and relay noxious visceral sensory stimuli to rostral disinhibited thoracic sympathetic preganglionic neurons (SPN) that manifest hypertension. Herein, we review evidence for maladaptive plasticity of PN in neural circuits mediating heightened sympathetic reflexes after complete high thoracic SCI that manifest cardiovascular dysfunction, as well as contemporary research methodologies being employed to unveil the precise contribution of PN plasticity to the pathophysiology underlying AD development. Propriospinal neurons (PN) have intraspinal origins and project to interneurons in other spinal cord segments as reported in electrophysiological and tract-tracing studies in feline and rodent models SCI, in which transcutaneous electrical stimulation of lower limb nerves evoke motor responses in distal forearms in the thoracolumbar intermediolateral cell column (IML), which results in the loss of sympathetic modulation from the caudal and rostral ventrolateral medulla in the brainstem that then modulates the sympathetic response, accordingly. Supraspinal denervation results in the sudden depletion of descending excitatory signals resulting in a 50\u201370% loss of innervation to SPN neutralizing antibody or trkA-IgG fusion protein in T4 spinal transected rats decreases CGRP-fiber density in association with reduced AD symptoms in experimental rats undergoing experimental colorectal distension (CRD; Christensen and Hulsebosch, via interneurons that may be excitatory or inhibitory in nature depending on the type and location of the stimuli (Chau et al., Autonomic PN are pre-sympathetic as they innervate the SPN to control their level of excitation (Gebber and McCall, de novo by visceral stimuli following SCI.BDA anterograde tracer injected into the central gray matter at rat L6-S2 spinal levels shows that ascending PN extend projections up to cervical levels through lamina X, and retrograde labeling using wheat germ agglutinin-horseradish peroxidase show projections to laminae VII and VIII at lumbar and thoracic levels indicating the anatomical locations of ascending PN (Matsushita, Ascending PN plasticity is believed to contribute to the development of AD. These neurons relay visceral sensory information towards the SPN in the thoracic cord (Rabchevsky, via intraspinal projection neurons (Pascual et al., via interneurons. After SCI, the supraspinal control is lost but the SPN are activated by peripheral afferent stimuli whose signal is relayed via ascending PN to trigger a sympathetic response, resulting in hypertension (Accordingly, BDA tracers injected into the lumbosacral cord following T4 transection show more labeling of ascending lumbosacral PN fibers that originate at the DGC and terminate proximal to Fluorogold-labeled thoracic SPN (Hou et al., rtension .Excitatory interneuron connectivity with SPN preferentially increases after T3 spinal transection in mice, and repeated CRD induces an increase in these excitatory interneurons co-labeled with vGlut2 (Ueno et al., Electrophysiology and retrograde tract-tracing are the most common tools used to identify the tracts involved in autonomic function. Although several studies labeling long descending PN and short tract PN exist, it is still highly challenging to specifically target and label ascending propriospinal tracts after injury due to unintended labeling of fibers en passage. Moreover, it is reported that transsynaptic labeling by pseudorabies virus is significantly reduced in the T4 transected spinal cord (Duale et al., In this regard, Kinoshita et al. reversibPN plasticity after traumatic SCI plays a critical role in improving not only spontaneous motor function but also potentially aggravating autonomic dysfunction. In addition to afferent C-fiber sprouting and loss of supraspinal regulation of the IML, maladaptive plasticity of PN below the level of high thoracic SCI appears essential for manifesting chronic autonomic dysfunction. Thus, while selectively promoting PN sprouting might serve as a promising therapeutic target for specific motor functional recovery, it may also be prevented selectively to combat AD development and/or severity, and the advancement of strategies to reversibly silence these interneurons will help further our understanding on their role in AD.FM wrote the first draft of the manuscript. SP reviewed the manuscript. AR critically evaluated the manuscript and wrote the final revised version. All authors contributing to the manuscript have read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Metastatic dissemination of epithelial ovarian cancer (EOC) predominantly occurs through direct cell shedding from the primary tumor into the intra-abdominal cavity that is filled with malignant ascitic effusions. Facilitated by the fluid flow, cells distribute throughout the cavity, broadly seed and invade through peritoneal lining, and resume secondary tumor growth in abdominal and pelvic organs. At all steps of this unique metastatic process, cancer cells exist within a multidimensional tumor microenvironment consisting of intraperitoneally residing cancer-reprogramed fibroblasts, adipose, immune, mesenchymal stem, mesothelial, and vascular cells that exert miscellaneous bioactive molecules into malignant ascites and contribute to EOC progression and metastasis via distinct molecular mechanisms and epigenetic dysregulation. This review outlines basic epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulators, and summarizes current knowledge on reciprocal interactions between each participant of the EOC cellular milieu and tumor cells in the context of aberrant epigenetic crosstalk. Promising research directions and potential therapeutic strategies that may encompass epigenetic tailoring as a component of complex EOC treatment are discussed. Epithelial ovarian cancer (EOC), a histopathologically, morphologically, and molecularly heterogeneous group of neoplasms , is the EOC initiation results from accumulation of genetic mutations and epigenetic changes resulting in malicious transformation of epithelial cells, stem cells, or transient metaplastic regions at the primary site, either ovary or the fallopian tube fimbriae ,16,17,18DNA methylation\u2014addition of methyl groups to DNA CpG sites without altering DNA nucleotide sequence. Methylation occurs by means of enzymes called DNA methyltransferases (DNMTs), which place methyl groups on symmetric cytosine residues in double-stranded CpG sites ,47. HypeHistone modifications\u2014various posttranslational modifications (PTMs) at histone protein N-terminal tails, which impair proper interactions between adjacent nucleosomes to affect the compact packing of the chromatin and impede the binding ability of other factors/enzymes that are involved in gene transcription ,58. The Chromatin remodeling\u2014rearrangement of chromatin organization through complete or partial nucleosome repositioning and altering gene access for transcription. Chromatin remodeling can occur via nucleosome sliding (movement of the core histone octamer nexus across DNA segment with no evident disintegration of the octamer itself), nucleosome ejection (nucleosome segregation from the chromatin chain), or histone eviction ,66,67. TAltogether, the three epigenetic mechanisms that are described above work closely to mediate DNA (un)coiling around the core histones and ensure dynamic chromatin reassembly between heterochromatin and euchromatin states.9 methylation with RNA interference machinery, followed by DNA methylation and gene transcription repression) and heterochromatic silencing . . 155]. DWhile the overwhelming majority of research work is focused on the elucidation of cell signaling pathway implications, the epigenetic interplay between MSCs and EOC remains largely unexplored. While considering the well accepted role of epigenetic aberrations in CSC reprogramming (comprehensively outlined in ), emergiTECs refer to endothelial cells that line the inner walls of newly formed blood vessels in tumors. TECs support blood flow, tumor tissue trophics, and accelerate tumor progression. TECs are genetically non-malignant cells, however, they differ from normal endothelial cells by exhibiting cytogenetic abnormalities , distortTECs exhibit considerable heterogeneity (reviewed in ), and di4 methylation was reported, and re-expression of ICAM-1 in TECs by DNMT and HDAC inhibitors successfully restored leukocyte-TEC adhesion and leukocyte infiltration of vessel walls in vitro and in vivo, respectively . . 247]. IEpigenetic regulation of hematopoietic stem cell lineage commitment and subsequent differentiation of dendritic cell precursors into specific dendritic subtypes (including PDCs) and interferon response in the context of chromatin remodeling, miRNA and lncRNAs interference are well documented ,259,260 MCs are simple squamous epithelial cells that line the intra-abdominal cavity as an upper single layer (mesothelium) of the peritoneum, immediately supported by the basal membrane, underneath which is the collagen-rich extracellular matrix A. MCs fuThe bidirectional interplay between EOC cells and MCs has been recently assessed in a study by Matte et al. , who repThe growing body of information on epigenetic control of ovarian cancer metastatic advancement and acquisition of resistance to standard-of-care chemotherapy make epigenomic alterations attractive prognostic markers and druggable targets to improve therapeutic outcomes in EOC patients especially with platinum-resistant and recurrent disease. Our group and others are actively exploiting DNA hypermethylation, modifications of histone marks, and aberrant expression of non-coding RNAs in malignant EOC cells in an attempt to treat EOC, re-sensitize ovarian tumors to conventional chemotherapy, and prevent/delay disease recurrence A. We andContinuous accumulation of knowledge on epigenomic perturbations in ovarian TME cellular compartments in the context of their communication with EOC cells holds great translational promise. The fact that non-malignant stromal cells lack genetic mutations and acquire potentially reversible tumor-specific molecular traits and cancer-indulgent functions via epigenetic reprogramming by EOC cells suggests the epigenetic tailoring of ovarian TME as a promising strategy in ovarian cancer management. Given the varying stroma representation in ovarian malignancies and higTreatment of different stromal components with HMAs demonstrated tumor-restrictive potential. In particular, the exposure of adipocytes to guadecitabine attenuated HGSOC cells metastasis-associated behaviors . HMA decAlternatively, similarly to an improved anticancer effect of a DNMT/HDAC inhibitor combination on ovarian tumors and otheGiven that CAF reprogramming is shown to repress ovarian tumor advancement , preventExploiting host immune system in managing ovarian cancer growth and metastatic spread has emerged as another key research and therapeutic direction ,295,296.To summarize, a deeper understanding of epigenomic involvement in reciprocal EOC tumor-stroma interrelationship is essential and it will help to determine pharmacological routes to alter the TME, which in turn could inhibit EOC metastatic progression and the development of chemoresistance and tumor recurrence. Furthermore, we believe epigenetically-mediated pharmacological engagement of certain TME players, such as immune cells, to boost immune responses towards complete malignant cell elimination has tremendous potential."} +{"text": "Subjective tinnitus is an auditory phantom perceptual disorder without an objective biomarker. Bothersome tinnitus in single-sided deafness (SSD) is particularly challenging to treat because the deaf ear can no longer be stimulated by acoustic means. We contrasted an SSD cohort with bothersome tinnitus against an SSD cohort with no or non-bothersome tinnitus using resting-state functional magnetic resonance imaging (fMRI). All study participants had normal hearing in one ear and severe or profound hearing loss in the other. We evaluated corticostriatal functional connectivity differences by placing seeds in the caudate nucleus and Heschl\u2019s Gyrus (HG) of both hemispheres. The TIN cohort showed increased functional connectivity between the left caudate and left HG, and left and right HG and the left caudate. Within the TIN cohort, functional connectivity between the right caudate and cuneus was correlated with the Tinnitus Functional Index (TFI) relaxation subscale. And, functional connectivity between the right caudate and superior lateral occipital cortex, and the right caudate and anterior supramarginal gyrus were correlated with the TFI control subscale. These findings support a striatal gating model of tinnitus and suggest tinnitus biomarkers to monitor treatment response and to target specific brain areas for innovative neuromodulation therapies. The search for physiological substrates that account for tinnitus persistence and tinnitus severity has led investigators to evaluate the central nervous system (CNS) using a variety of techniques. Some documented CNS changes are synchronous hyperactivity5, tonotopic map cortical plasticity8, thalamocortical dysrhythmia10, and gamma band oscillations13.Tinnitus is a common auditory phantom perceptual disorder where conventional audiometric hearing loss profiles alone cannot help clinicians to distinguish between patients who merely experience tinnitus from those who are troubled by tinnitus15, case reports17, and an early clinical trial18 focused on the caudate nucleus of the basal ganglia support a striatal gating model15 of tinnitus awareness. This model delineates modulators of tinnitus persistence and tinnitus severity, where corticostriatal connections between the striatum and auditory cortex act to gate auditory phantom representations to reach perceptual awareness and connections between the striatum and limbic structures act to modulate auditory phantom distress.Human physiological studies20 or is driven by abnormal auditory-limbic interactions23. Neuroimaging studies in support of abnormal striatal connectivity as a potential biomarker of chronic tinnitus25 have been reported in cohorts with inhomogeneous hearing loss profiles. Those studies used post-hoc statistical techniques to address the possible confound of hearing loss levels on neural correlates of tinnitus. However, there is not yet a neuroimaging investigation that incorporates a specific hearing loss pattern in a cohort contrast study design that could isolate differential network connectivity findings to chronic tinnitus.A striatal gating model of phantom percept awareness is complementary to other CNS hypotheses, including those that posit tinnitus is primarily an expectation mismatch within the auditory system26, although this is not necessarily the case in congenital SSD27. Tinnitus localized to the deaf ear eliminates the treatment option of masking sound delivery to the defective sensory end organ, as it is unresponsive to acoustic stimulation. Moreover, acoustic therapies directed to the better hearing ear are of minimal to no benefit30. Behavioral therapies may be beneficial in modulating tinnitus distress, but without effective sound therapy to the deaf ear, have little to no effect on tinnitus loudness32. Neuromodulation of the auditory periphery by cochlear implantation of the deaf ear, an alternative method of auditory system stimulation, often reduces tinnitus severity similar to acoustic therapies in an ear with hearing loss36. However, this intervention requires surgical implantation of hardware to the skull and complicates future head magnetic resonance imaging (MRI) examinations.Patients with bothersome tinnitus in single-sided deafness (SSD) or unilateral severe to profound hearing loss and normal or nearly normal thresholds in the only hearing ear represent an exceptional opportunity to study tinnitus not confounded by hearing loss variations. Bothersome tinnitus in adult acquired SSD is expected to be localized to the deaf ear37 within the TIN cohort.The goal of this study was to identify candidate biomarkers to monitor tinnitus treatment response and targets for brain-based neuromodulation approaches. We evaluated basal ganglia and cortical connectivity patterns by contrasting an SSD cohort with bothersome tinnitus (TIN) against an SSD cohort no or non-bothersome tinnitus (NO TIN). We used resting-state functional magnetic resonance imaging (fMRI) to define whole-brain connectivity patterns of the caudate nucleus and auditory cortex. We report on connectivity differences between TIN and NO TIN cohorts, and voxelwise connectivity strength correlations with subscale scores of the validated Tinnitus Functional Index (TFI)Data on TFI score, age, sex, deafness duration, diagnosis of vestibular schwannoma, and deaf ear laterality for SSD TIN and SSD NO TIN cohorts are shown in Table\u00a0Resting-state functional connectivity maps were reconstructed for TIN and NO TIN cohorts for the four seed regions (Heschl\u2019s gyrus (HG), and caudate, bilaterally). Functional connectivity seeded from the left caudate was significant with the right caudate, and with multiple regions of pre-frontal cortex (PFC) in both TIN and NO TIN cohorts Fig.\u00a0. The TINWithin the TIN cohort, voxelwise correlations with TFI subscales showed increased connectivity between the right caudate and cuneus for the relaxation subscale, where increased connectivity was correlated with higher interference with the ability to relax Fig.\u00a0. Voxelwi18. The striatum is believed to be normally restrictive, blocking out phantom percepts, but becomes dysfunctionally permissive in chronic tinnitus. Initial evidence in support of this model stems from results of acute direct stimulation of the striatum at the junction of the head and body subdivisions (area LC) during deep brain stimulation (DBS) surgery in movement disorders patients with chronic tinnitus, where auditory phantom loudness can be modulated14. In those without tinnitus, caudate DBS can trigger auditory phantom percepts15 and vascular infarction of the dorsal striatum results in enduring tinnitus loudness reduction16. Furthermore, chronic caudate DBS has been shown to significantly improve TFI in some patients with severe, chronic tinnitus18. Although the exact physiological mechanisms are not clear, alteration of excitation and inhibition balance either within the caudate nucleus or in its connections to auditory cortex may be modulating phantom percept gating permissiveness39. Findings from this study extend generalizability of results from human neurophysiological18 and resting-state fMRI25 studies in binaural patients.The key finding of this study is increased connectivity between the caudate nucleus and auditory cortex in the SSD cohort with chronic, bothersome tinnitus. All patients relied on monaural hearing with normal audiometric thresholds, thereby removing hearing loss variation as a possible confound and isolating abnormal striatal functional connectivity to chronic tinnitus. This independent replication of the critical finding in our prior studies, where tinnitus cohorts had variable hearing loss profiles, further supports a striatal gating model of tinnitus awareness where the limbic system may be driving tinnitus severity40, as measured by the Tinnitus Handicap Inventory41 (THI) score, is positively correlated with pre-treatment activities of the left insula42. Increased functional connectivity between the caudate and the insula observed in this study suggests that the left insula may be an important structure within corticostriatal loops that link the auditory system with language networks and the limbic system44. Tinnitus awareness burden is negatively correlated with delta band activity of rostral and dorsal anterior cingulate cortices. Those areas are considered to be at the core of a descending noise cancellation system whose dysfunction may contribute to the percentage of daytime tinnitus awareness45. Increased striatal functional connectivity between the left caudate and the right supplementary motor area (SMA) observed in this study may possibly include neighboring dorso-rostral anterior cingulate cortices, thereby contributing to overall tinnitus distress.Other tinnitus neuroimaging studies using EEG methodologies have yielded interesting insights that are relevant to our findings. Tinnitus severity response to Tinnitus Retraining Therapy24. Increased connectivity with the superior lateral occipital cortex and anterior supramarginal gyrus is correlated with reduced sense of control over the phantom percept, regions that are part of task-positive visual and dorsal attention networks, suggesting enhanced attentional engagement for control of tinnitus46. Although the right caudate connectivity shows significant correlation with TFI subscale scores, it did not survive across cohort differences in functional connectivity, most likely due to the underlying small sample size. Nevertheless, the highest connectivity of the right caudate is with the left caudate , constant, non-pulsatile tinnitus to collect both high-resolution structural T1-weighted fast spoiled gradient echo brain volume images and to collect spontaneous fMRI data using a resting-state echo planar imaging (EPI) sequence . Foam earplugs with a 32\u2009dB noise reduction rating were inserted into both ears during data acquisition.https://www.nitrc.org/projects/artifact_detect/), tissue segmentation, spatial normalization to the Montreal Neurological Institute (MNI) template, and spatial smoothing (using a 8\u2009mm FWHM kernel). Prior to functional connectivity analyses, resting-state data were temporally filtered (0.008Hz-0.09\u2009Hz bandpass) and denoised by applying a regression model using 12 realignment parameters and the global mean signal of the white matter.Resting-state fMRI data were spatially preprocessed using a standardized pipeline implemented in the CONN toolbox. Imaging data preprocessing steps were as follows: functional realignment and unwarping, translation to center, outlier detection using Artifact Detection Tools as implemented in the CONN toolbox. Correlation coefficients were computed across all voxels of these pre-defined regions of interest (ROIs) with the rest of the brain. Voxelwise regression analyses were performed only within the TIN cohort (n\u2009=\u200915) between functional connectivity and TFI subscale scores. Voxelwise analyses within and between groups (TIN versus NO TIN) were performed using parametric one-tailed t-tests for determining regions with increased and decreased connectivity separately for each of the four seeds. We report on within and across-group whole-brain analyses that survived a threshold of p\u2009<\u20090.05 following a false discovery rate based cluster-mass correction for multiple comparisons59.All functional connectivity and group analyses were performed using the CONN toolbox. For resting-state functional connectivity, four seed regions (right/left Heschl\u2019s gyrus (HG); right/left caudate) were anatomically defined using AAL labelled regions ("} +{"text": "As populations age, identifying factors that foster the maintenance of health is crucial for improving the health and well-being of older adults. Yet, most psychological, biomedical, and public health efforts have focused on reducing harmful risk factors. While the risk management approach has contributed greatly to prevention and treatment programs, our aging society continues to grapple with the steadily rising tide of chronic conditions. Expanding the focus to include upstream, health-promoting psychosocial assets may help inform a more comprehensive response effort. Mounting research suggests that different dimensions of psychological well-being are uniquely associated with reduced risk of chronic conditions. However, the mechanisms underlying these associations remain understudied. This symposium presents 4 studies evaluating potential mechanisms. The first talk presents research evaluating how a spouse\u2019s level of optimism may be uniquely associated with an individual\u2019s cognitive health over time . A second talk, draws upon a multi-burst daily diary study and focuses on affective stress response as a potentially modifiable target that could explain the health benefits of optimism. A third talk evaluates how baseline levels purpose in life might be associated with repeated measures of five key health behaviors over time. A fourth talk discusses results from a longitudinal-burst daily diary study determining the reciprocal relationships among optimism, pain interference, and goal-directed activity among older women who experience pain. Overall, these studies add to the growing research on psychological well-being and physical health by providing evidence around potential biobehavioral pathways."} +{"text": "An 8-year-old male patient presented after suffering blunt trauma to the left side of the face during a football game. On initial evaluation, the patient denied malocclusion or chin deviation. Computed tomography (CT) identified a displaced intracapsular left-sided mandibular condylar fracture , and conWhat is the etiology of pediatric mandibular fractures?How are pediatric patients affected by condylar fractures?What are the different methods of treatment of pediatric condylar fractures?What are the benefits of closed reduction with dynamic elastic therapy?Several types of traumatic mandibular injury are seen in the pediatric population. According to one recent study, the most common events leading to mandibular fractures were sports injuries, falls, and road traffic accidents.Several differences exist between pediatric and adult condylar fractures. Pediatric bones are more likely to remodel, which can partially compensate for malunion unlike mandibular fractures in adolescents and adults.,Treatment modalities for pediatric condylar fractures include conservative management with liquid diet, jaw rest, and careful clinical follow-up, closed reduction with maxillomandibular fixation (MMF), or open reduction with internal fixation (ORIF). Most authors advocate for closed management due to the lack of outcomes data on open surgery and due to the risks of damaging growth centers with open treatment. Remodeling and dental evolution can also overcome malocclusion in closed treatment, especially in patients with primary/deciduous dentition, as there will be more dental evolution compared with patients with secondary teeth.6Closed reduction of pediatric condylar fractures with MMF may be accomplished through several methods but can be difficult in pediatric patients when attaching arch bars, brackets, or screws to primary or deciduous dentition. Prior work discusses risks of tooth avulsion and damage to developing dentition.Dynamic elastic therapy is suitable for the management of condylar fractures with any degree of displacement or dislocation in pediatric patients and offers superior or similar results compared with rigid maxillomandibular fixation while minimizing patient discomfort."} +{"text": "The high mortality rate associated with pancreatic cancer necessitates accurate and early detection methods. Computed tomography currently is the primary diagnostic modality used; however, subtle imaging features in concert with novel clinical presentations may obscure the initial diagnosis. Here, we describe a unique initial presentation of pancreatic cancer as a pancreatic leak, with subtle initial CT evidence of malignancy. An 83-year-old female with prior surgical history of open splenectomy and ventral hernia repair presented with two weeks of vague abdominal pain and leukocytosis. Initial CT revealed abdominal peripancreatic fluid collections. Interventional radiology-guided drain placement was performed, which revealed amylase-rich pancreatic fluid within the collections. Repeat CT scan revealed subtle pancreatic duct dilation with slow resolution of the fluid collections. Ultimately, endoscopic ultrasound identified an ill-defined pancreatic mass, revealed to be pancreatic adenocarcinoma. The patient subsequently underwent an open distal pancreatectomy. Diagnosis of pancreatic cancer relies heavily on cross-sectional imaging, with no screening tests currently available. However, subtle radiographic features and unique clinical presentations may delay accurate diagnosis and staging. EUS may be a useful tool for initial evaluation of high-risk individuals. Pancreatic cancer has one of the lowest five-year survival rate of all malignancies 8.5%), accounting for 10.9 out of 100,000 deaths in the US \u20134. When %, accounHere, we describe an unusual case of pancreatic adenocarcinoma initially presenting as pancreatic duct disruption in a patient with a prior splenectomy. Initial CT did not suggest pancreatic cancer; however, EUS was eventually used to evaluate subtle pancreatic duct dilation and revealed the presence of pancreatic adenocarcinoma. Our experience demonstrates that EUS is an accurate modality for detecting pancreatic cancer with both an initial negative CT and a complex clinical presentation.An 83-year-old female presented to the emergency department with two weeks of vague abdominal pain. Her past medical history was significant for open splenectomy for spontaneous rupture three years prior to presentation and subsequent ventral hernia repair with mesh. She denied history of pancreatitis, diabetes mellitus, nor family history of gastrointestinal disease or malignancy. She was found to have a UTI and leukocytosis of 20,000, with LFTs and lipase within normal limits. Initial CT demonstrated abdominal fluid collections around the stomach and pancreatic tail, extending to segment two of the liver Figures . She wasHere, we describe a diagnosis of pancreatic cancer in an 83-year-old female patient characterized by a unique clinical presentation and equivocal initial radiologic findings. EUS revealed the ill-defined pancreatic mass, and EUS-guided biopsy confirmed pancreatic adenocarcinoma. Given the high morbidity and mortality of this disease, evaluation and improvement of current diagnostic techniques is crucial.Initial clinical symptoms of pancreatic cancer are vague and nonspecific, and patients typically present with abdominal pain and weight loss . PainlesCT, the recommended first line imaging modality for pancreatic cancer evaluation, has high sensitivity for large lesions and is useful in disease staging . Recent As demonstrated in this case of pancreatic cancer presenting initially as peripancreatic fluid collection, an atypical clinical presentation coupled with negative initial imaging studies may obscure the underlying diagnosis of pancreatic cancer. EUS has high diagnostic accuracy and allows for immediate tissue biopsy. Thus, EUS should be rigorously evaluated to determine its potential use in the initial screening of patients with high clinical suspicion for pancreatic cancer."} +{"text": "Research efforts in these areas have already yielded critical insights into pathophysiological mechanisms and will continue to stimulate innovation in this promising area of translational research.Neural circuits are the underlying functional units of the human brain that govern complex behavior and higher-order cognitive processes. Disruptions in neural circuit development have been implicated in the pathogenesis of multiple neurodevelopmental disorders such as autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and schizophrenia. Until recently, major efforts utilizing neurological disease modeling platforms based on human induced pluripotent stem cells (hiPSCs), investigated disease phenotypes primarily at the single cell level. However, recent advances in brain organoid systems, microfluidic devices, and advanced optical and electrical interfaces, now allow more complex hiPSC-based systems to model neuronal connectivity and investigate the specific brain circuitry implicated in neurodevelopmental disorders. Here we review emerging research advances in studying brain circuitry using Neural circuits can be detected as early as 18\u201322 weeks gestational age (GA) during human brain development. Transient circuitries in the brain are initially established in the subplate, formed by afferent inputs from multiple brain regions, including the basal forebrain, brainstem, and somatosensory thalamus . Then thin vitro are emerging to complement these animal models. Since hiPSCs were first generated \u201321, patiin vitro disease modeling has significantly accelerated following the generation of hiPSCs in 2007. The ability to harness patient-specific somatic cells and reprogram them into pluripotent stem cells indistinguishable from human embryonic stem cells (hESCs) has opened a novel area of research for modeling neurodevelopmental disorders. Development of robust hiPSC reprogramming methodologies has been an area of intense research with more than a dozen methods currently available the ability to physically segregate cell bodies of different neural subtypes while still allowing axonal growth between compartments (ii) compatibility with high-resolution video microscopy to investigate morphological and functional connectivity (iii) the ability to control axonal growth and monitor stages from early synaptic formation through late synaptic maturation. Thus, microfluidic chip platforms provide compelling systems to investigate neural circuit dysfunction in neurodevelopmental disorders.The development of compartmentalized microfluidic devices has further enabled innovative methods to model human brain circuitry with an unmatched level of control. Microfluidic chip devices provide several novel features as platforms to model circuit-level connectivity As a proof of concept, a five-compartment microfluidic device was developed to model a mid-brain neural circuit composed of GABAergic, glutamatergic, and dopaminergic (DA) neurons . Using dIn another study, a microfluidic chip platform modeled the hippocampal dentate gyrus (hDG)-Cornu Ammonis region 3 (CA3) circuit of schizophrenic patients . An effiA similar two-compartment microfluidic device reconstructed cortico-striatal circuits using primary neurons from a mouse model of Huntington's disease (HD). Though the main focus of this review is based on hiPSCs, this innovative system was included to emphasize the value of microfluidic systems in modeling brain circuitry. Data from this study suggested that presynaptic cortical dysfunction was both necessary and sufficient to induce pathogenic properties within post-synaptic striatal neurons, thus highlighting the critical value of these systems in providing mechanistic insights into disease pathogenesis . Throughin vivo conditions , assays could be developed to record the electrophysiological properties of brain organoids in the context of normal development or exposure to environmental factors. Further, MEAs could be utilized as functional readout tools to phenotypically profile abnormal electrical activity arising from diseased brain organoids, thereby allowing for drug screening approaches to identify potential therapies that rescue electrophysiological deficits. Additional applications for MEAs include analysis of network topological properties and functional connectivity graphs within brain organoids based on spike train data, which could be derived using information-theory based network analysis \u201369. AddiIn conjunction with neural circuit analysis within single brain organoids, regionally diverse brain organoids could be combined into assembloids to model long-range circuits such as those implicated in neurodevelopmental disorders and drug addiction. The same optical and electrical interface tools could then also be applied to these long-range circuit models. To further enhance the fidelity and reproducibility of assembloid-based platforms in modeling long-range circuits, microfluidic devices could segregate organoids into different compartments, while still allowing inter-compartmental projections and synaptic contacts between the separated organoids . Thus, cin vitro platforms for modeling human brain circuitry, it is critical to remember the developmental context of many neurological disorders. Some neurodevelopmental disorders may be triggered early, potentially resulting from environmental exposures in combination with a susceptible genetic makeup; common examples are cases of parenteral heavy metal or intranganese) \u201378. Othenganese) \u201381 or thnganese) \u201384. New AH and MH conceived the main ideas and developed the structure of the paper. AH, MH, NM, and CM wrote the manuscript. AH prepared the figure and the table. All authors critically reviewed and approved the final manuscript for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with one of the authors MH."} +{"text": "Within California, older adults living in rural counties have reported higher rates of falls than urban dwelling older adults. Although many Indigenous people live in rural areas, it is unclear whether the rate of falls among Indigenous older adults is similar to that of non-indigenous older adults living in rural areas. Thus, the purpose of this study was to examine fall risk behaviors and intrinsic risk factors for falls in rural dwelling Indigenous (N = 89), and non-Indigenous (N = 68) older adults 60-95 years of age living in California. Results showed that both Indigenous and non-Indigenous older adults share similarly high fall rates, but there are a much greater number of Indigenous older adults falling multiple times a year. Moreover, fall risk behaviors and intrinsic fall risk factors were significantly different between Indigenous and non-Indigenous rural-dwelling older adults. Future studies should investigate falls and fall risk factors in different tribes/locations of Indigenous older adults to better understand whether these risk factors differ among tribes. Moreover, it would be beneficial for future studies to assess the effectiveness of fall prevention exercises on fall risk in these communities. Information gained from this study helps to inform clinicians and researchers alike about the prevalence of falls and factors contributing to falls among Indigenous older adults living in rural communities; and helps to influence decisions in the future of programs for reducing fall risk in this often neglected population."} +{"text": "While considerable progress has been made in studying genetic and cellular aspects of metastasis with in vitro cell culture and in vivo animal models, the driving mechanisms of each step of metastasis are still relatively unclear due to their complexity. Moreover, little progress has been made in understanding how cellular fitness in one step of the metastatic cascade correlates with ability to survive other subsequent steps. Engineered models incorporate tools such as tailored biomaterials and microfabrication to mimic human disease progression, which when coupled with advanced quantification methods permit comparisons to human patient samples and in vivo studies. Here, we review novel tools and techniques that have been recently developed to dissect key features of the metastatic cascade using primary patient samples and highly representative microenvironments for the purposes of advancing personalized medicine and precision oncology. Although improvements are needed to increase tractability and accessibility while faithfully simulating the in vivo microenvironment, these models are powerful experimental platforms for understanding cancer biology, furthering drug screening, and facilitating development of therapeutics. Metastatic progression of solid tumors can be divided into five major steps: (1) invasion of the basement membrane and cell migration; (2) intravasation into the surrounding vasculature or lymphatic system; (3) survival in the circulation; (4) extravasation from vasculature to secondary tissue; and finally, (5) colonization at secondary tumor sites .5 PDXs and primary cells obtained directly from patients are more rigorous predictors of clinical outcomes by incorporating patient-specific genomics absent from cell lines. Notably, PDXs can accurately predict clinical response to targeted cancer therapeutics.6 Although these must be maintained in immunocompromised mice long term and can be only used for a limited number of passages in vitro, the ability to assimilate primary human samples into engineered models is a significant advance over traditional animal models and microfabricated platforms.Numerous cell lines have been isolated from human or murine tumors to provide homogeneous samples that possess genomic alterations consistent with their native tissue sources.7 Tissue specimens from diagnostic surgery can be procured and manipulated to obtain primary human cells which can be immortalized for long term use by treating with human telomerase.8 Immortalized primary cells retain many traits from the primary tissue specimen while still undergoing multiple passages, and they can recapitulate cancer cell signaling and extracellular matrix (ECM) remodeling.8 The ability to incorporate primary samples into in vitro models of each metastatic stage has the potential to transform these devices into more precise and impactful predictors of clinical outcomes.With tissue banks becoming more readily available for research use, both normal and cancerous tissue samples from patients can be obtained.9 Invasion through the basement membrane is considered the differentiating step between pre-cancerous neoplasia and malignant cancer in which increased collagen deposition, fiber thickness, and linearized fiber architecture contribute to a stiffer environment.11 Cells mechanically remodel ECM through a cycle of cell protrusion and contraction, and chemically degrade the matrix using metalloproteinases as they migrate.12 In addition, cancer cell contractility and matrix stiffness create a positive feedback loop causing downstream effects on cell behavior during metastatic progression.13 As such, accurate invasion and migration models must incorporate ECM with tunable stiffness, adjustable pore size, and measurable and/or controllable degradability.Metastasis is initiated during invasion and migration where cancer cells penetrate the basement membrane and navigate as single cells or via collective means through the stromal microenvironment, respectively., in vitro tumor models rarely capture the full complexity of spatiotemporal heterogeneities inherent in tumor progression due to cell culture time scales and construct size limits. The use of organoids partly overcomes these limitations by better representing genotypic and phenotypic diversity in a structured in vitro microenvironment. These structures, derived directly from human tumor tissue samples, preserve three-dimensional architecture and patient-specific phenotypes while in culture posts modeling various levels of substrate rigidity, and synthesized networks of tunable porosity mimic features in tumor architecture during disease progression.32 To observe confined migration in a more physiologically relevant system, collagen can be micro-molded to create tracks of tunable geometries recapitulating in vivo collagen structures differentiation into endothelial cells which assembled into perfusable, capillary-like networks, and capturing endothelial response to different environmental biochemical and biophysical cues.43 Incorporation of patient-derived hiPSCs in platforms such as these lays the foundation for personalized characterization of tumor angiogenesis and endothelial cell response to cancer therapeutics. In addition, the hyaluronic hydrogel used in this platform has been shown to induce cell migration, and thus further modifications to this design could potentially be used to simultaneously investigate invasion and migration in a defined microenvironment.Since blood flow and interstitial pressure influence tumor angiogenesis, most microfluidic systems focus on recapitulating these in vitro. Models utilizing micromolding and bioprinting techniques have been used to fabricate endothelialized tissue constructs to visualize real-time endothelial cord formation during tubulogenesis.44 In addition, tremendous inter-tumor heterogeneity in angiogenic activity depends partly on the organ of origin and cancer subtype, due to organ-specific differences in the pro- and anti-angiogenic molecule secretion profiles of stromal cell populations.35 Thus, the development of more specific, personalized experimental systems will enable characterization of angiogenic behavior within different tumor types and for individual patients, leading to improvements in drug-screening models.Although current in vitro models contain essential features of angiogenesis, further work should be aimed at incorporating tissue-specific cell types and ECM features found at organ-specific primary tumors sites, such as recapitulating low permeability vascular beds present at the blood\u2013brain barrier or highly permeable vascular beds of liver sinusoids.45 The tumor microenvironment provides both chemical and physical cues to induce tumor cell intravasation. For example, stiffened ECM has been correlated with increased endothelial permeability which potentially promotes tumor cell intravasation.47 Although tumor cells secrete pro-angiogenic factors influencing the vascular phenotype, vascular cells actively regulate invasion.49 Thus, co-culture models representing the complex interactions between cancer cells, endothelium, and surrounding stroma are necessary to characterize intravasation.In addition to providing nutrients, tumor vasculature also facilitates intravasation, the process by which cells infiltrate the vasculature.50 For example, one of these systems incorporating cancer, endothelial, and immune cells supports the role of macrophage-assisted intravasation correlating with clinical results.48 Thus, these platforms serve as models to examine potential immune cell involvement in intravasation.Microfluidic systems allow for the incorporation of fluid flow and are amenable to real-time imaging capability. Recently, commercially available microchannel systems were used to observe intravasation events after vascular network formation.51 Circulating tumor cells (CTC) arrest in a vessel and extravasate through two primary mechanisms: physical occlusion and adhesion after rolling (Fig. Although few cancer cells reach the circulation, even fewer survive the hemodynamic shear forces, immune stresses, and red blood cell collisions they encounter once there.ing Fig. . During 55 These platforms often employ surfaces functionalized with CTC-specific adhesion proteins or antibodies to optimize adhesion dynamics for CTCs while minimizing that of leukocytes also present in whole blood.55 Physical entrapment under flow can also be utilized to isolate CTC clusters that have been suggested to have increased metastatic potential compared to single CTCs.54 Recent work has shown that single-cell encapsulation of CTCs into microdroplets can be utilized to profile enzyme secretion.56 In addition, single-cell RNA sequencing of human patient CTCs has been optimized to assess inter- and intra-patient heterogeneity and identify potential therapeutic targets using a microfluidic platform and barcoding technique.57 As the methods to capture viable CTCs become more tractable, further probing of later stages of metastasis using isolated CTCs could provide insight into the properties of these rare but crucial cells. Engineered platforms have the potential to elucidate the changes CTCs may undergo as they transition from solid tissue to the circulation, as well as determine the properties of CTCs best suited for extravasation and colonization.Microfluidic and microtubing systems enabling the collection of both single and clustered CTCs from patient blood have contributed greatly to understanding cancer metastasis.59 and study the interactions of CTCs with neutrophils, platelets, and endothelial monolayers.62 Efforts to increase throughput have led to the development of a cone viscometer platform that interfaces with standard 96-well plates to enable more streamlined testing.63 Although cone and plate viscometers facilitate highly controlled, reproducible exposure to shear conditions, they lack relevant vessel-like architecture and do not allow for real-time imaging during shear exposure.Cone and plate viscometers are often used to expose cancer cells to physiological shear forces in cell culture medium or whole blood65 Parallel plate flow chambers can be used to assess rolling-adhesion interactions between circulating cells perfused over a substrate coated with ECM, ligands, or endothelial monolayers.67 Others assess the rolling and adhesion of cancer cells to physiologically relevant proteins using controlled perfusion through functionalized microtubing.70Numerous commercially available, relatively inexpensive platforms are used to produce shear stresses in vitro. Motorized expulsion through a needle has been used to assess cancer cell viability and conditioning after shear stress exposure.71 More complete microfluidic models can incorporate spatially defined chemokine gradients and or organ-specific cells, such as primary lung endothelial cells or osteo-differentiated bone marrow derived stem cells.74 Although numerous microfluidic platforms mimic the vasculature, CTCs can also travel through the lymphatic system. Notably, it was observed that low shear stresses mimicking lymphatic flow induced cancer cell motility while high shear stresses mimicking arterial and venous flows inhibited cell motility in a YAP1-dependent manner, highlighting the importance of selecting physiologically relevant shear stresses since different ranges can elicit divergent cell behaviors.75Microfluidic systems provide an immense degree of customization, with the ability to incorporate complex structures and dynamic flow patterns in perfused channels that can be coated with ECM or endothelial monolayers.76 For example, a microfluidic device with capillary-sized channels was used to show that CTC clusters isolated from patient blood can traverse these constrictions while remaining intact.77Tumor cell arrest during extravasation can also occur through cancer cell occlusion in capillary networks. Serial deformation and transmigration chambers in microfluidic devices have been designed to mimic constrictions in capillaries and relevant endothelial/ECM barriers that cells must bypass to transmigrate after arresting.78 To stabilize self-assembled networks, co-culturing fibroblasts segregated from endothelial cells provides the necessary paracrine signaling for network stabilization, while co-seeding with pericytes regulates vessel diameter and decreases vessel permeability.79 Although self-assembled microvascular networks do not necessarily require specialized equipment, control over network formation is limited.Recently, self-assembled perfusable microvascular networks have been developed to investigate physical occlusion and rolling-adhesion events leading to extravasation.80 Although geared towards improving tissue engineering designs, this platform could be adapted to study extravasation in capillary networks. Live-cell lithography was developed to better control cell placement for in vitro vascular network assembly.81 In this system, multiple optical tweezers are used to manipulate placement of cells in three dimensions allowing the controlled addition of pericytes, smooth muscle cells, and fibroblasts outside of the vessel. Advances like these lay the foundation for systems that better recapitulate the complexity of the tumor microenvironment. As patient CTC capture platforms improve, further incorporation of these precious clinical samples into downstream assays will be crucial towards investigation of CTC performance during subsequent stages of metastasis. If assays can be streamlined and correlated with clinical data, theranostic platforms with CTCs isolated from patient blood have the potential to improve clinical outcomes.Three-dimensional printing of carbohydrate glass sacrificial fibers can create highly controlled, multiscale, and perfusable vascular networks.82 After extravasation, cancer cells have one final task to complete: colonization of secondary sites. This process is thought to be extremely inefficient with only a minute percentage of CTCs growing into lesions.83 Metastatic niches possess cell types and ECM compatible for tumor cell survival and growth,83 including perivascular niches, spaces around blood capillaries where cancer cells can seed. Extravasation and colonization models require tissue-specific cell types, microenvironmental cues, and vascularization. Leveraging tissue engineering advancements to model metastatic sites may be key in understanding factors driving colonization as it is possible to tailor the site to isolate roles of cells types, growth factors, and ECM architectures.Following arrest within the vessel, cancer cells must extravasate from the vessel to colonize new sites. This process differs from intravasation, where cancer cells navigate tumor-modified stroma via chemotactic and durotactic gradients toward leaky, nascent vasculature without experiencing hemodynamic stressors; rather, during extravasation, the vasculature that is breached by cancer cells is healthier, and cancer cells actively experience fluid shear stresses due to blood flow.84 Osteo-differentiated mesenchymal stem cells, mineralized hydroxyapatite-incorporated ECM, and ex vivo bone scaffolds have all been shown to elicit relevant cell behavior in in vitro bone tissue models.88 Incorporation of perfusable vascular networks in these models allows for cancer cells to be flowed though, recapitulating extravasation events at the metastatic site. Bioreactors can be used to create complex, mature tissue constructs for seeding as well as to expose seeded scaffolds to tunable, physiological compressive forces to observe colonization behavior.90As bone metastasis occurs frequently in breast and prostate cancers and correlates with shortened patient prognoses, many models of metastatic colonization in bone have been created.91 Moreover, decellularization provides a scaffold that can then be re-seeded with cancer cells to examine colonization in a simplified yet physiological setting.92 Decellularization proves a powerful technique to enhance and inform tissue-engineered constructs of metastatic colonization sites and assess cancer cell-ECM interactions. LiverChip\u00ae is a commercialized microfluidic model of the hepatic niche used to observe interactions between cancer cells, hepatocytes, and non-parenchymal cells.93 Infiltration of the brain\u2013blood barrier has been modeled by adding cancer cells to numerous permutations of co-cultures containing endothelial cells, pericytes, glial cells, astrocytes, and cancer-associated fibroblasts.98 As lung, liver, brain, and lymph node are all extremely common metastatic sites, further work should be directed towards developing more complex, physiologically relevant in vitro models for assessment of cancer cell metastatic colonization at these distinct locations.Several different models have been exploited to assess colonization in various organ systems. Decellularization of tissues including mammary fat pad, lymph node, and lungs has been used to three-dimensionally map the spatial distribution of ECM components of these tissues in health and disease.Currently, metastatic colonization assays are in their infancy relative to assays focusing on earlier stages. As colonization is the stage where metastasis gains its lethality and where confounding events like drug-resistance and dormancy often occur, it is promising as a key point of intervention. While much emphasis is placed on the personalized side of patient-specific cancer cells, understanding patient-specific, non-tumor cells in metastatic sites may help explain drug-resistance and dormancy.While in vivo models can be used to study the entirety of the cascade, the complexity and timescale of metastasis limits their utility. In vitro models successfully recapitulate individual steps in metastasis, yet few encompass more than one stage in the process.99 Specifically, microfluidic chambers containing a gut tissue-like \u2018source\u2019 seeded with colon cancer cells and a liver tissue-like \u2018sink\u2019 are connected by a perfused flow channel. In this model, cancer cells can exit the gut chamber and spread to the liver chamber. This three-dimensional construct facilitates drug-screening and visualization of metastasis, though it still lacks important features like endothelial barrier function, intravasation, and extravasation. Despite limitations, it marks one of the first steps toward an in vitro model distilling the key components representing the diverse microenvironments cancer cells encounter during metastasis.Recent work to develop a more complete metastatic platform has resulted in a microfluidic metastasis-on-a-chip model where hydrogels embedded with host tissue cells are combined with microfluidics to represent the spread of metastatic cells from primary to secondary tissue.100 However, metastasis is a dynamic, multi-step process and by simplifying models to exclude parts of the cascade, we are only gaining insight as to how well cancer cells perform specific steps out of context. Thus, it is critical that more complete models be developed so that metastasis can be observed in the correct series of events.Although there are still limitations hindering in vitro recapitulation of the full metastatic cascade, approaches that stitch together multiple sequential steps into a single assay have fewer impediments. Reductionist models that incorporate a primary tumor site and a metastatic niche site separated by ECM serve as a simplified approach to assessing metastatic potential.Engineered in vitro models have greatly expanded our understanding of cancer metastasis. Incorporation of primary cells and tissue within metastatic models provides more physiologically relevant and clinically applicable findings that often correlate with patient outcomes, aiding in drug-screening and personalized medicine to advance precision oncology. As tissue banks become more common and access to primary human samples increases, metastatic models are moving towards more faithful representations of native in vivo cell interactions and behaviors Fig. .Fig. 4Pr15With the addition of primary patient blood or tumor tissue samples into established in vitro models of the metastatic cascade, personalized characterization of metastatic cancer cell behavior is gaining tractability. Further, coupling these patient-specific assays with high-throughput drug-screening approaches could aid in optimizing patient treatment plans as well as facilitate drug discovery. For example, patient-derived organoids can serve as effective preclinical models for rapidly assessing therapeutics, shown to exhibit similar responses to chemotherapeutic drugs such as topotecan and melphalan consistent with clinical outcomes.99 Moving forward on the path towards personalized cancer theranostics, ameliorations to existing in vitro models, including the addition of patient-derived samples and integration of multiple steps of the metastatic cascade into one platform, will be essential.As microfabrication techniques and biomaterials advance, models are gaining the ability to recapitulate multiple tissue-specific microenvironments connected in a physiologically relevant manner as pioneered primarily for pharmaceutical toxicity studies. Adaptation of these systems to simulate key elements of multiple metastatic stages in sequence could provide novel insight. In addition, more comprehensive models such as the metastasis-on-a-chip model that elegantly incorporates multiple steps still lack essential components in their design, such as endothelial barriers to study intravasation and extravasation effects.Further information on research design is available in the Reporting Summary"} +{"text": "Tasks of increasing difficulty require increasing levels of cognitive engagement from participants. The costs associated with cognitive engagement rise with age in response to normative cognitive decline. Additionally, previous studies have shown an interaction between age and task difficulty, with age differences in effort expenditure increasing along with task demands. Motivational accounts of effort allocation predict the opposite relationship, where increased task difficulty in the face of declining cognitive abilities result in disengagement among older adults, comparatively lowering their effort expenditure relative to younger adults that remain committed to the task. The current study quantitatively reviews the available literature on age and effort expenditure across tasks of increasing difficulty. An initial meta-analysis found no age differences in effort across task difficulty, but inspection of the significantly heterogeneous effect sizes indicated that measurement domain might account for some of the variance found between the effect sizes. A second, post-hoc meta-analysis was conducted, recoding effect sizes giving preference to subjective measures. Subsequent moderator variable analyses found that the combined effect of age and domain of effort measurement explained a sufficient portion of the variance across effect sizes. When using physiological measures, effort was not found to differ across task difficulty for either age group. Alternatively, when measured subjectively, effort was reported to greatly increase (>1 standard deviation) with difficulty, with a larger increase in younger adults. Results are discussed in terms of effort mobilization across adulthood and the importance of measurement domain in the interpretation of results."} +{"text": "Sitophilus zeamais (Motschulsky) and Prostephanus truncatus (Horn). Other insects of lesser economic importance also were observed in the visual surveys, including Sitotroga cerealella (Olivier) (Lepidoptera: Gelechiidae), and Tribolium castaneum (Herbst). This study demonstrated that the use of acoustic technology with visual surveys and pitfall traps can help managers to identify and target infestations within their warehouses, enabling them to reduce postharvest losses. With most warehouses being located in relatively noisy urban or peri-urban areas, background noise considerations are being incorporated into the design of future acoustic detectors for stored pest infestations. Kenya must import grain yearly to meet consumption needs; however, if the current yearly postharvest losses of 20\u201330% in warehouses decreased, import costs could be reduced considerably.Grain production is an important component of food security in Kenya but due to environmental conditions that favor rapid growth of insect populations, farmers and other agricultural stakeholders face ongoing and novel challenges from crop and stored product pest insects. To assist development of methods to reduce economic losses from stored product insect pests in Kenya, acoustic, visual, and pitfall trap surveys were conducted in five grain storage warehouses. Two commercially available acoustic systems successfully detected the pests of greatest economic importance, Spodoptera frugiperda (J.E. Smith) (Lepidoptera: Noctuidae) [fall armyworm] into sub-Saharan Africa will lead to 20\u201350% maize yield loss , Sitophilus zeamais (Motschulsky) (Coleoptera: Curculionidae) [maize weevil], Tribolium castaneum (Herbst) (Coleoptera: Tenebrionidae) [red flour beetle] and Sitotroga cerealella (Olivier) (Lepidoptera: Gelechiidae) [Angoumois grain moth] are the major maize pests in sub-Saharan Africa , T. castaneum, and possibly other postharvest pests have been developing resistance to phosphine and Oryzaephilus surinamensis (Linnaeus) [sawtoothed grain beetle].Pitfall trap counts provide sampling information about local insect populations that can be useful for pest management programs . Two of also in . Though AEC and IMC systems provided consistent quantitative measurements. Previous research has shown, however, that among the commercially available detection systems, piezoelectric sensors have greater sensitivity to insect-produced sounds because the signals encounter less attenuation as signals traverse from the insects to the sensors across different media [The results of the visual and acoustic assessments of infestation of the 50 kg storage bags suggest that both the nt media . In addiAEC probe system than for the IMC system. Such results were in agreement with Leblanc et al. [Proximity of the insects to the sensors is known to be another important factor contributing to the sensitivity of an acoustic system to detect insect infestation. The use of waveguide probes can improve the detection range by increasing the volume of grain close enough to the sensor for detection, thus improving the accuracy of detection. In this study, the rates of insect sound bursts detected and the rate of burst impulses, were consistently greater for the c et al. , who comTo improve the sensitivity and accuracy of detection in the presence of background noise, efforts have been directed towards constructing sound-attenuating boxes lined with foam and fitted with piezoelectric sensors, an example of which is shown in . These iP. truncatus and S. zeamais pest species, which provides earlier detection. However, the effects of distance between insect and sensor on detectability noted above, as well as the considerable variation of an insect\u2019s level of activity over time [The statistically significant correspondence between the magnitude of insect sound burst rates and counts of insects captured in the probe traps confirms that acoustic detection is a useful tool for detecting and monitoring infestations in Kenyan grain warehouses. An important benefit of acoustic systems is their identification of hidden as well as visible infestations of important ver time , and thever time , combinever time ,24 in inver time and hermver time .It is worth noting that several cell phone sound detection apps have been developed, e.g., , some ofExperience gained from the Kenyan stored product insect acoustic detection study indicates that acoustic, visual, and pitfall trap surveys all contribute information useful for early detection and management of visible and hidden pest infestations but suggests that challenges remain in designing user-friendly acoustic systems that automatically discriminate out background noise often present in warehouses. Efforts are in progress to incorporate additional spectral and temporal pattern features of sounds produced by target insects into cost-effective acoustic detection systems. Knowledge of early infestation can assist warehouse managers in maintaining strategic grain reserves with scarce resources. Improved monitoring combined with innovations such as hermetic storage bags may enable reduced reliance on grain imports."} +{"text": "Facial appearance served great function in social interactions, especially for older adults in making trustworthiness judgements. Previous literatures have consistently shown that when making trustworthiness judgements older adults tended to rely more on facial cues rather than behaviors, due to declines in cognition. However, one question remains unsolved, whether older adults could make accurate trustworthiness judgements if evaluative information is easily accessible. Sixty younger adults (YAs) and sixty older adults (OAs) were recruited, and asked to make investment decisions for different brokers in ninety-six trials. In each trial, brokers\u2019 facial appearance (trustworthy and untrustworthy looking) and different behavioral evaluative information were displayed simultaneously on screen to facilitate investment decisions. Brokers\u2019 facial appearances and behaviors were set to be independent to each other. The results indicated that YAs\u2019 and the majority of OAs\u2019 proportions of correct investment increase, gradually reaching a stable high correction rate, although OAs needed more trials than did YAs. The findings extended prior work by suggesting that both OAs and YAs had similar abilities to distinguish different brokers according to easily accessible evaluative information. However, and surprisingly, a small subgroup of OAs (with low economic status) still had a lower correction rate even after ninety-six trials, suggesting that they could not distinguish brokers based on their evaluations at all, who might be at risk for fraud."} +{"text": "Second, Lindsey will introduce technological innovations used in the I-CONECT project including development of user-friendly video-chat devices, recording of audio and video data and innovative recruitment efforts. Third, Asgari will share results on how speech utterance and characteristics collected through the project could distinguish those with mild cognitive impairment from those with normal cognition using machine learning modelling approaches. Finally, Cerino and his team will show results of the study which examined whether cognitive improvements through conversation-based intervention depend on an individual\u2019s personality, laying the groundwork for a personalized intervention trial in the future. The symposium is of interest for those who study social isolation and its prevention, the link among cognition, social isolation and personality, as well as those who focus on technology as a tool for improving well-being of older adults.Epidemiological studies have demonstrated that larger social networks or more frequent social interactions may have protective effects against cognitive decline and the incidence of dementia. Therefore, increasing social interaction could be a promising intervention for improving cognitive well-being in socially isolated older adults. We have conducted multiple NIH-funded randomized controlled trials (RCT) over 10 years, examining whether conversational interactions through webcam and internet can improve cognitive functions and enhance cognitive reserve. In this symposium, we will introduce this series of behavioral intervention trials through 4 presentations. First, Dodge will provide background and results of their previous RCT where they showed efficacy of conversational intervention on domain-specific cognitive functions and introduce the ongoing larger project called I-CONECT ("} +{"text": "Mammalian guts harbor indigenous microbes that are integral to host health. Microbiome research using sophisticated model organisms has provided insights into intricate interactions between microbiota and host animals. However, it remains unclear how these animal-microbe associations developed. We have recently addressed this question via comparative analyses of chordates, given that complex biological systems can be resolved into ancestral and derived elements when examined in an evolutionary framework (Nat Commun 9: 3402). Results support the view that microbial colonization of the mucus layer that overlies mammalian gastrointestinal epithelium was established upon loss of ancestral chitin-based barrier immunity. Comparative approaches enable us to arrange ongoing biological processes into host natural history for better understanding of intestinal animal-microbe associations. Mammalian intestines are home to indigenous microbial communities. High-throughput sequencing approaches revealed that these microbes are taxonomically diverse and distinct from those of the surrounding environment. Omics analyses of germ-free animals, combined with manipulation of gut flora, provided growing evidence for complex cellular and molecular mechanisms that underlie reciprocal interactions between microbiota and hosts. Nonetheless, we know little about how these intimate animal-microbe associations developed. Biological systems result from a series of evolutionary processes. Thus, in principle, regardless of their complexity, they can be discriminated into ancestral and derived elements when examined in a proper biological setting. Accordingly, we have conducted comparative analyses of chordates.In animal phylogeny, chordates form a branch of deuterostomes and consist of two invertebrate groups, lancelets and tunicates, as well as vertebrates. Gill slits are a key anatomical feature of deuterostomes, which enable water flow from the mouth to the gill slits. This water flow through the pharynx was prerequisite for their particulate feeding. Invertebrate chordates further employ unique net-like structures secreted from the endostyle, a chordate-specific pharyngeal glandular organ, to establish efficient filter-feeding. Using tunicates, we addressed if this chordate lineage that feeds on environmental microbes harbors indigenous microbes in their gut space similarly to mammals.Ciona intestinalis Type A revealed that the gut space was radially compartmentalized by an unknown membranous structure. Microbes captured by filtration were confined to a luminal space enclosed by this membrane, while a peripheral space over the gut epithelium appeared almost free of bacteria. A combination of chemical and physical analyses demonstrated that the membrane was formed of multilayered, meshed chitin nanofibers embedded in a proteinaceous matrix. The chitinous membranes were secreted and delaminated from the gut epithelium. When chitin synthesis was chemically inhibited, the membrane and axenic space disappeared and food microbes directly contacted with the enterocytes, thereby causing an increased death rate of Ciona. These data showed that the endogenous chitinous membranes are essential for formation of the axenic space and contribute to gut homeostasis by acting as a physical barrier .Transmission electron microscopy of gut sections of the tunicate Ciona membrane, as these structures are framed with meshed chitin nanofibers produced by homologous chitin synthases. On the other hand, these structures have distinct matrix protein compositions. While invertebrate peritrophic matrix consists of protein with chitin-binding and/or proline-threonine-serine-domains, Ciona membranes are comprised of anti-bacterial proteins and gel-forming mucin, which is the main constituent of the mammalian mucus layer that covers the gut epithelium. Briefly, the Ciona membrane provides molecular evidence for a possible link between the invertebrate peritrophic matrix and the mammalian mucus layer, which are considered analogous, i.e. with no common descent . To test this idea, we have examined the following chordate lineages that occupy phylogenetic positions between invertebrates and mammals: a basal chordate Branchiostoma floridae (lancelet), a jawless vertebrate Eptatretus atami (hagfish), and a jawed vertebrate Oreochromis mossambicus (ray-finned fish). All these organisms possessed intestinal chitinous membranes.Similar chitinous barrier membranes have been well studied in several invertebrate lineages. So-called invertebrate peritrophic matrices structurally resemble the O. mossambicus, seemingly contradicts the common view that gut mucosal surfaces of ray-finned fish are covered with a mucus layer that is colonized by indigenous microbes as in mammals. Actually, 16S ribosomal RNA gene analysis showed the presence of indigenous microbes in the gut of O. mossambicus, but this microbial community was enclosed by chitinous membranes and was segregated from the surrounding mucus layer secreted by crypt goblet cells. In contrast, we were unable to detect chitin in the guts of mice, where gut microbiota directly interact with goblet cell-derived mucus.The finding of chitinous membranes in the ray-finned fish, In conclusion, this comparative study provides a glimpse of evolutionary changes in the intestinal mucosal surfaces of chordates. We proposed a transition from a chitin-based ancestral condition to a mucin-based derived state . Radial compartmentalization of the gut space by chitinous membrane seems to be an ancestral feature of chordates. In tunicates, filter-fed microbes transiently pass through the intestine, while being confined to the luminal space by the chitinous barrier. Ray-finned fishes retain this chitin-based barrier immunity, but viable passage of ingested microbes was prevented by bactericidal gastric juice, an invention of jawed vertebrates. This would have offered the subsequent gut space as a new ecological niche for surviving microbes. Because mammals lack the chitinous barrier, gut microbes interact directly with the surrounding goblet cell-derived mucus. Thus, it seems that chitin-based barrier immunity and its loss predated mucus colonization by indigenous gut microbiota.There are considerable variations in intestinal mucus-microbe interactions. In mice, ileum mucus is loose, yet it limits microbial access to host tissues through joint actions with diffusible molecules like RegIII\u03b3. Colon mucus forms two layers with the outer layer extensively colonized by microbes and the densely packed inner layer devoid of microbes. The degree of mucus penetrability varies among bacterial species. These variations can be explained in the context of regional adaptation driven by local functional demands since the onset of direct mucus-microbe interaction. Accordingly, comparative approaches enable us to arrange ongoing biological processes into host natural history to decipher the complex animal-microbe association."} +{"text": "This symposium examines how social and psychological factors including formal schooling, subjective memory, and neuropsychological symptoms impact cognitive function among older adults in China and the U.S. The first paper used the WHO\u2019s Study on global AGEing and adult health Wave-1 data to examine the relationship between subjective cognitive function, perceived memory decline, and objective cognitive function among older adults in China. The results showed worse subjective cognitive function was associated with poorer working memory and verbal fluency, whereas greater perceived memory decline was associated only with poorer working memory. Furthermore, using data from the Health and Retirement Study, the second paper applied group-based trajectory modeling to assess dual trajectories of subjective memory impairment and objective cognitive decline. Four distinct dual-trajectory typologies were identified, suggesting complex co-occurring changes in subjective memory and objective cognition in older adults. The third paper characterized the trajectories of three neuropsychological symptoms prior to dementia onset. Using data from the National Health and Aging Trends Study, the study found older adults with dementia exhibit distinct trajectory of depression before dementia onset than those without dementia. Trajectories of pain and insomnia did not differ before dementia onset. The last paper examined the effect of education on cognitive decline among lower educated older adults using data from the Longitudinal Study of Older Adults in Anhui Province, China. Results suggest that older adults with some formal schooling had slower cognitive decline; the gap in cognition between the literate and illiterate widened with age."} +{"text": "Interventions to improve nursing home care have been developed and tested. However readily disseminated interventions are lacking. Barriers include low staffing levels contributing to limited time for education and high turnover of direct care and administrative staff. Educational interventions must be accessible to accommodate busy staff. Meaningful outcome measures are needed and interventions must fit varied nursing home sizes, ownership, resident population, and regions. Changing Talk Online (CHATO) was adapted from the effective, yet time-intensive, Changing Talk program addressing nursing home staff communication. The original classroom-based program significantly improved staff communication with residents and resulted in subsequent reductions in resident behavioral and psychological symptoms of dementia. Strategies for marketing and recruiting nursing homes and to engage administrators and staff will be discussed as implemented in the Changing Talk Online (CHATO) R61 trial. Approaches addressing unique nursing home challenges to implementation are essential for successful dissemination to improve care."} +{"text": "Collectivism refers to the social practice of investing in and relying on one\u2019s social network, rather than formal institutions, to ensure personal security. Using the re-engineered 2014 Survey of Income and Pension Participation (SIPP), we investigate how collectivist practices affect life course health disparities at older ages in the US. Indicators of Collectivism include measures of caregiving, inter and intrahousehold financial and material support and help from charities, friends and family members. Regression results indicate that increased collectivist interactions are associated with improved self-reported health status outcomes. Government support for collectivist behaviors can thus yield a low cost means of improving health outcomes among the elderly."} +{"text": "Falls are common, costly, and the leading cause of fatal and nonfatal injuries for older Americans. Reports show that fall death rates are increasing. Healthcare providers play an important role in fall prevention but few talk to their patients about falls. This lack of communication demonstrates the need for more physician-initiated fall prevention. The Centers for Disease Control and Prevention (CDC) created the Stopping Elderly Accidents, Deaths, and Injuries (STEADI) initiative to help providers talk to their patients about falls. Specifically, CDC\u2019s new STEADI-based fall prevention program, the Coordinated Care Plan to Prevent Older Adult Falls (CCP) and Evaluation Guide for Older Adult Clinical Fall Prevention Programs can assist healthcare providers in integrating and evaluating new fall prevention programs that screen older adults for fall risk, assess patients\u2019 modifiable fall risk factors, and implement evidenced-based fall prevention interventions . The CCP offers guidance for incorporating a STEADI-based fall prevention program including how to engage leadership, integrate with existing clinic workflow and electronic health records, and strategies on how to obtain reimbursement for fall prevention. The Evaluation Plan offers details on how to engage stakeholders, collect data, interpret findings and how to share results for maximum impact. Both documents were based on lessons learned from successful implementation of STEADI-based programs in primary care. A STEADI-based program in New York found fewer fall-related hospitalizations among at-risk patients who received a fall prevention care plan compared to at-risk patients who did not receive a care plan."} +{"text": "Undernutrition affects millions of children in low- and middle-income countries (LMIC) and underlies almost half of all deaths among children under 5 years old. The growth deficits that characterize childhood undernutrition (stunting and wasting) result from simultaneous underlying defects in multiple physiological processes, and current treatment regimens do not completely normalize these pathways. Most deaths among undernourished children are due to infections, indicating that their anti-pathogen immune responses are impaired. Defects in the body's first-line-of-defense against pathogens, the innate immune system, is a plausible yet understudied pathway that could contribute to this increased infection risk. In this review, we discuss the evidence for innate immune cell dysfunction from cohort studies of childhood undernutrition in LMIC, highlighting knowledge gaps in almost all innate immune cell types. We supplement these gaps with insights from relevant experimental models and make recommendations for how human and animal studies could be improved. A better understanding of innate immune function could inform future tractable immune-targeted interventions for childhood undernutrition to reduce mortality and improve long-term health, growth and development. In low- and middle-income countries (LMIC) childhood undernutrition manifests as growth deficits which can result in a child being too short for their age score <-2), and/or too thin for their height score <-2), which are both associated with a greater risk of all-cause mortality . Severe Stunting and wasting are the most readily measurable indicators of undernutrition, but these anthropometric deficits result from underlying defects in multiple physiological processes . The mosIn this review we will discuss the current evidence for the role of innate immune cell dysfunction in undernutrition, focusing on children living in LMIC. We will draw on population studies and supplement knowledge gaps from existing undernutrition research with insights from experimental models. Our goal is to highlight the potential for innate immune cell dysfunction to shape clinical outcomes of undernutrition and outline how future studies could be used to improve our understanding of these pathways.in utero: a principal predictor of postnatal growth is maternal nutritional status during pregnancy, and length and weight at birth recurrent symptomatic infections and sub-clinical pathogen carriage; (2) chronic systemic inflammation and immune activation; (3) impaired gut function, enteropathy and dysbiosis of the gut microbiome , 13; (4)at birth . These iat birth . The resat birth . Immune at birth . For exaat birth . Micronuat birth . The comat birth .In the past decade, substantial advances in experimental approaches to study the microbiome have been used to demonstrate a causal association between dysbiosis in the gut and malnutrition . Hoin vitro. Addition of Vitamin A to monocyte cultures treated with BCG led to an inhibitory histone methylation mark (H3K9me3) that suppressed monocyte cytokine responses upon re-stimulation relative to monocytes treated with BCG alone is present and associated with colonization with pathogenic microorganisms, dysbiosis, innate leukocyte recruitment, and reduced gut functional capacity . Not allStudies among children hospitalized with SAM suggest that systemic and intestinal inflammation independently contribute to mortality , 43, 44.Inclusion of functional analysis of immune cells in cohort studies of children in LMIC is uncommon. Of the studies conducted, many demonstrate innate and adaptive immune cell dysfunction during undernutrition [summarized in a systematic review by Rytter et al. ]. HowevePlasmodium parasites has shaped a distinct myelopoietic niche in the bone marrow resulting in a characteristic neutropenia among the majority of people of African ancestry . The interaction between HIV, inflammation and undernutrition was demonstrated in a recent study of children starting antiretroviral therapy in Uganda and Zimbabwe . A propory alone . CarefulNo studies to our knowledge have assessed innate immune cell function in stunting in LMIC beyond soluble inflammatory biomarkers (discussed above). There has also been limited assessment of innate immune cell function in undernourished tissues, with an understandable majority of studies focusing on more readily accessible innate immune cells in peripheral blood. Despite the limitations of existing studies, a number demonstrate innate immune cell dysfunction in undernutrition and basal (from the lamina propria) signaling via polarized expression of receptors and tight regulation of membrane permeability. Immunohistochemical analysis of intestinal biopsy specimens indicates that this regulation by epithelial cells is disrupted in children with SAM in gut biopsy specimens from severely undernourished Gambian children compared to adequately-nourished controls from the same community . Epithelsphatase \u2014a mechansphatase . Murine nfection . Intestinfection . After enfection . Defectsnfection . Thus, bDisrupted epithelial cell responses have also been observed in enteropathy associated with other health conditions. For example, diabetic enteropathy in adults causes defects in colonic epithelial stem cell mobilization due to reduced levels of circulating IGF-1 and IGFBP3 , both ofper se . In a sin vitro ; both dein vitro . Interfein vitro . The assin vitro , 8 and din vitro , suggestin vitro, even when NK-to-tumor cell ratios were high or antibody ligation of NK1.1 surface antigens relative to NK cells isolated from ad libitum-fed controls share some of the functions of adaptive T cells, but respond to challenges with the rapid kinetics of innate immune cells [reviewed by Eberl et al. ]. NK celIn this review we have outlined knowledge gaps in the function of all innate immune cell types during childhood undernutrition. A concerted effort is needed to translate immunological paradigms from animal models into human cohort studies. Furthermore, whilst assays of soluble immune biomarkers, proteome, transcriptome, epigenome, and metabolome profiling in peripheral samples provide insights into immune and immune-metabolic derangement, direct measurements of immune function will rely on cell- and tissue-based assays. In the long-term, developing high-quality assays of innate immune cell function for well-powered population studies in LMIC will rely on leveraging existing laboratory capacity for immunology research and developing capacity where it is not currently available. Such efforts would be accelerated by adaptation of existing technologies for assessing immune cell function in high-income settings to affordable standardized field-deployable formats. Cohort studies of innate immune function should be: (i) powered adequately to detect differences in highly heterogeneous immune responses; (ii) longitudinal in design to distinguish short-term fluctuations from persistent functional defects; and, (iii) ideally nested within studies that also characterize concurrent immunological stimuli , which are necessary to accurately interpret immune cell behavior. To identify localized changes in innate immune cells and learn more about the function of tissue-resident cells during undernutrition, sampling from a more diverse range of anatomical sites will be necessary. For example, despite respiratory tract infections being a frequent cause of mortality among undernourished children , we knowBeyond understanding the basic immunology of childhood undernutrition, developing novel therapies targeting innate immune dysfunction will require cohort studies to assess whether innate immune cell function is associated with clinical outcomes, and identify the pathways that lead to dysfunction. Identifying immune biomarkers of prognostic value for stunting, wasting and infectious mortality has proven challenging to-date due to the multiple mediators that are simultaneously altered , 10, 12.vice versa has been bolstered by studies of nutrient deprivation in animals Environmental toxin exposure, such as exposure to mycotoxins derived from molds that contaminate staple crops, which is extremely common amongst pregnant mothers and children in some settings . SeveralExisting studies have been critical to our understanding of innate immune cell function in childhood undernutrition, but considerable knowledge gaps remain. Studies among undernourished children demonstrate impairments in a range of innate immune responses, but the pathways underlying these defects are unclear. Experimental animal models provide a clearer picture of how individual features of the undernourished state can drive changes in innate immune cell function, but do not recapitulate the multiple simultaneous immune challenges that are typical during childhood undernutrition in LMIC. It is increasingly apparent that novel therapeutic approaches are required to improve health outcomes for children with undernutrition, given the complex pathology that underlies wasting and stunting. Since infections are the leading cause of death , a betteCB wrote the manuscript with input and critical commentary from KJ and AP.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Family caregivers of persons with dementia experience guilt for various reasons when placing their family member into residential long-term care (RLTC). Research has shown a relationship between guilt and overall caregiver burden; however, literature on predictors of guilt related to caregiving following RLTC placement is limited. The Residential Care Transition Module (RCTM) provides counseling and psychoeducation to family caregivers who have recently moved their family member with Alzheimer\u2019s disease or a related dementias into RLTC. This semi-structured intervention provides counseling on various topics including guilt, grief, and family dynamics. Using treatment group data (N=87) from the parent RCTM randomized controlled trial, we identified the impact of caregiver status , sense of caregiver competence, and relationship closeness on baseline measures of guilt status and magnitude. Preliminary analyses showed that adult child status was associated with greater prevalence of guilt (37.5%) compared to spousal caregivers (26.7%). In addition, qualitative case notes were coded to identify common themes of experiences of guilt to inform practice. Examples include: Guilt related to no longer being able to care for the family member at home; not meeting self-dictated expectations ; and feeling guilted into being a caregiver in the first place. The current analyses aim to help practitioners better predict risk for placement-related guilt and highlight specific issues practitioners should consider to help mitigate such feelings. Specific opportunities for intervention are discussed."} +{"text": "Modifying neighborhood environments to target well-established risk factors for cardiovascular disease may reduce health disparities by complementing clinical services. Prior research, however, includes limited measures of neighborhoods and does not adequately account for individual-level processes known to mediate health outcomes. We combine baseline data from the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) dataset with neighborhood-level data to yield a diverse sample of Black and white middle-aged and older residents of Baltimore City (N=2707). We use structural equation modeling to examine associations between neighborhood environments and obesity (BMI>=30), focusing on individual-level mediators. Initial direct associations between neighborhoods and obesity are mediated by healthcare access and health behaviors. Additional indirect pathways exist through health behaviors . These findings highlight the importance of considering indirect pathways to cardiovascular health promotion among aging adults in different neighborhood contexts."} +{"text": "OBJECTIVES/SPECIFIC AIMS: Incomplete spinal cord injury typically results in life-long disability, often in the form of profound loss of locomotion capability. Individuals who have experienced incomplete spinal cord injury exhibit persistent eccentric motor deficits, which are particularly prevalent in the weight acceptance phase of gait and emphasized in sagittal plane knee motion and frontal plane hip motion. METHODS/STUDY POPULATION: Motion analysis can capture the kinematic and joint-level deficits of these individuals, but it is impossible to directly calculate the contributions of individual muscles to weight acceptance due to the complexity of the musculoskeletal system. Instead, those muscle contributions must be simulated in order to approximate muscle power during locomotion. RESULTS/ANTICIPATED RESULTS: The traditional method for driving these simulations with electromyography readings is unavailable for individuals who have neuromuscular deficits , due to the need to generate reliable maximum voluntary isometric contractions for baseline purposes. Instead, this research develops a novel method for using resting electromyography data to drive musculoskeletal simulations using a muscle activation threshold paradigm. DISCUSSION/SIGNIFICANCE OF IMPACT: The simulation results of this method more closely resemble experimental results, but further simulation refinement is needed to fully capture the true muscle activity."} +{"text": "A 69-year-old man presented with precordial pain and a dilated ascending aorta with the suspicion of an intramural hematoma. At emergency operation, the aorta appeared grossly thickened with diffuse intimal scarring. Retrospectively, the patient tested positive to serologic screening for syphilis with histologic findings also compatible with a syphilitic aortitis. A 69-year-old man, previously asymptomatic and with an unremarkable clinical history, presented with dyspnea and precordial pain at our emergency unit. He denied any risky sexual behavior and did not show any signs or symptoms related to secondary syphilis. An angio computed tomographic (CT) scan showed a fusiform aneurysm of the ascending aorta with a maximum diameter of 65\u2009mm, with a thickened wall raising the suspicion of an intramural hematoma . Other Histology of the aortic wall showed full-thickness infiltrates involving all layers with adventitial fibrosis surrounding thickened vasa vasorum ,B witAortitis is the main manifestation of a syphilitic cardiovascular infection, but aortic aneurysms due to tertiary infection are substantially uncommon in the modern era;Syphilitic aortitis is usually diagnosed combining histologic and laboratory data, although cases of negative laboratory testing have been reported.Our experience demonstrates that luetic infection still remains a potential cause of ascending aortic aneurysms."} +{"text": "One consequence of modern longevity is the growing number of older adults with very old parents. While family members are often interdependent in their development and aging, less is known about how intergenerational relationships may influence individuals\u2019 attitudes toward their own aging in later life. Using 70 dyads of oldest-old parents (Mage = 93) and their children (Mage = 67) from the Boston Aging Together Study, we examined the dyadic concordance in positive attitudes toward own aging, and how perceptions of giving and receiving care are associated with attitudes toward own aging for parents and children. On average, parents reported more negative attitudes toward own aging than did children. In less than half of all dyads (46%), both parents and children reported positive attitudes toward own aging. T-test results showed that the dyads with positive attitudes toward own aging had more within-dyad age difference, better average self-rated health, fewer depressive symptoms and less loneliness than others. For children, higher level of caregiver\u2019s burden was associated with more negative attitudes toward own aging. For parents, perception of received support was not associated with their attitudes toward own aging. This study sheds light on how both individual and family characteristics may influence individuals\u2019 aging perceptions. Findings suggest the context of parent-child ties may particularly be relevant to those older adults who may have to deal with their own aging- related challenges as well as those of their parents."} +{"text": "When students from two or more professions learn about, from, and with one another in joint learning activities, interdisciplinary perceptions and attitudes improve and collaborative knowledge and skills increase.3 Most, more or less, hinge on the development of competencies deemed necessary for effective collaborative practice, such as communication and ethical values.The contribution of these skill sets to the positive and productive function of patient care teams is both apparent and universal. For example, abilities to listen and constructively consult, discuss, and debate are obvious elements for collegial interactions. Respecting patient dignity and maintaining confidentiality reflects a commitment to professional conduct and engenders trusting relationships. Such behaviours and attitudes are further recognized as collective competencies given they have been adopted by many North American health professional training programs as discipline-specific educational outcomes. By both accounts, these principles also apply to the scholar competency role.Different frameworks exist to guide integration of IPE programming into health professional curricula worldwide.4Similarly, the American Association of Medical Colleges outlines an entrustable professional activity milestone whereby trainees \u2018form clinical questions and retrieve evidence to advance patient care\u2019.5Albarqouni et al recently enlisted over 200 multidiscipline clinicians and academics from 28 countries to agree upon a set of evidence-based practice competencies for health professional teaching and learning.6 Through Delphi survey and consensus processes,they arrived at a set of 68 core competencies further organized into introductory concepts and five main evidence-based practicesteps including: ask, acquire, appraise and interpret, apply, and evaluate.While the authors acknowledge somecompetencies likely require modification to suit specific needs of any given discipline, most are indeed fundamental skills broadly applicable across professions. Examples include converting clinical questions into structured, answerable formats; constructing and carrying out an appropriate search strategy; distinguishing evidence-based from opinion-based clinical practice guidelines; explaining the evidence to patients and integrating their preferences into decision-making processes; and managing clinical decision-making uncertainty in practice. The consensus statement represents an important step towards unifying expectations of evidence-based practice. The details can guide instructional and assessment design and delivery in health professional curricula and for a number of programs, these may fall within the scholar competency role .From 50 years agowhen McMaster University launched a novel medical program where students first learned about patient problems concurrent with epidemiology and biostatistics, Canadian physicians-in-training today are meant to \u2018identify pertinent evidence, evaluate it using specific criteria, and apply it in their practice\u2019 as part of the scholar competency role.nt care) .7 That is, how are these competencies truly interprofessional in nature and not simply common skills expected by many different professions? First, this set of competencies is an acknowledgement that a majority of professionals employ evidence-based practice in patient care. Although decision-making may occur within the discrete scope of a profession\u2019s practice, we can be assured of a common language when this care is informed by reported literature, such as randomized controlled trials, meta-analyses, or clinical practice guidelines. Like the fundamental aspects of interprofessional communication these competencies represent an opportunity for standardization of practice principles across patient care providers. Furthermore, when teams of various disciplines convene to develop treatment protocols or care pathways, there is a shared understanding of how the evidence under consideration may be interpreted.Clinicians may enlist similar approaches to navigate incomplete available data or ambiguous study findings to make treatment choices.If as Nandiwada&Kormos further contend, this work substantiates the existence and importance of evidence-based practice competencies across health professions, howdo they expressly promote shared or collaborative care?Interprofessional competencies are meant to promote collaborative care that ultimately improves patient outcomes. Integration of evidence-based competencies into shared decision-making clearly has the potential to do so. Patient adherence may be enhanced when care providers can clearly explain the data underpinning the rationale for the selected treatment and offer realistic estimates of potential risk. Clinicians who can interpret and synthesize a wide array of literature may have greater abilities to individualize care while also incorporating patient preferences. In this regard, optimal evidence-based practice must be enabled by the communication and collaboration skills endorsed by both profession-specific and interprofessional competency frameworks. Just as effective team-based care must draw upon the collective contributions of its diverse members, quality healthcare also relies on this complement of a clinician\u2019s knowledge, skills, and behaviors."} +{"text": "Aortic dissection is the most devastating sequelae of aortopathy other than aortic rupture. However, aortic dissection can be asymptomatic in the acute phase with delayed symptomatic presentation or incidental diagnosis upon chest imaging. We report a case of a 63-year-old male who was diagnosed with pericardial effusion upon preoperative workup for elective cholecystectomy. Further investigations confirmed hemorrhagic pericardial effusion secondary to a chronic dissecting ascending aortic aneurysm. The patient condition was successfully managed with open surgical repair with an uneventful postoperative course. This case demonstrates an extremely rare presentation of incidental hemorrhagic pericardial effusion caused by a chronic dissecting ascending aortic aneurysm. A 63-year-old male with a history of hypertension, 20 pack-years of smoking, thyroid cancer in remission with partial thyroidectomy, and chronic obstructive lung disease (COPD) presented to the emergency department (ED) with acute abdominal pain. Abdominal ultrasound showed gallstones with no evidence of cholecystitis or biliary obstruction. The patient was diagnosed with biliary colic and discharged home with a plan to perform an elective cholecystectomy. Computed tomography (CT) scan of the abdomen was performed as an outpatient as part of the preoperative workup which showed evidence of gallstones, small bilateral pleural effusions, and moderate pericardial effusion with high density suggestive of hemorrhage . ConsequAcute Stanford type A aortic dissection (AD) is a life-threatening condition that serves as an impetus to immediate surgical repair aiming to prevent dissection-associated complications such as acute aortic regurgitation, aortic rupture, myocardial or cerebral ischemia, and pericardial tamponade . HoweverThe first clue for CTAD diagnosis was the detection of high-density pericardial effusion note on abdominal CT scan before elective cholecystectomy. Given the lake of symptoms, transudation of fluid across the wall of the false lumen into the pericardial cavity is the most plausible mechanisms. Also, hemopericardium in our case could be a sign of silent contained rupture.All patients with aortic dissections will need immediate surgical evaluation independent of location . PatientOur patient had an aorta diameter of 7.5 cm; furthermore, his dissection was complicated by hemorrhagic pericardial effusion and moderate aortic regurgitation. Thus, the open surgical repair was the chosen approach. According to a recent review of a 696 type A patients, following open repair, patients with CTAD had lower in-hospital mortality and longer five- and ten-year survival compared to the acute type A dissection patients [Chronic type A aortic dissection is a challenging diagnosis with a wide range of clinical presentations including incidental hemorrhagic pericardial effusion. Pericardial puncture in pericarial effusion complicating type A dissection can result in the propagation of the rupture. Accordingly, obtaining a CT scan of the chest prior to any diagnostic pericardial puncture is highly recommended. Surgical repair is the treatment of choice for complicated chronic type A aortic dissection."} +{"text": "Promoting healthy aging does not end when people enter skilled nursing facilities (SNF) where the demands for clinical and psychosocial care are likely to be greatest. Many chronic conditions present opportunities for better SNF care and thus, healthier aging. Such conditions cannot wait for the often-long path to discovery that is typical of most traditional randomized controlled clinical trials. Conversely, pragmatic clinical trials are real-world investigations that offer the possibility of immediate benefit while answering important research questions. Depression and disrupted sleep are two examples of treatable conditions with opportunities for immediate benefit through pragmatic trials and applied best practices. How best to support best-practice integration has received increasing attention but identifying the most effective strategies continues to evolve. We report two different SNF-mentorship models utilizing Minimum Data Set (MDS) data for depression and environmental (noise-level) data for disrupted sleep, which have supported better SNF practices and presumably, healthier aging."} +{"text": "Although CGRP has been implicated in numerous physiological processes , the precise physiological roles of CGRP remain to be elucidated. To provide a better understanding of the physiological role(s) mediated by this peptide neurotransmitter, we have generated aCGRP-null mice by targeted modification in embryonic stem cells."} +{"text": "A 54-year-old man presented to the emergency department with confusion and Parkinsonian features after suspected heroin snorting. He had magnetic resonance imaging of the brain demonstrating isolated symmetric bilateral globus pallidus (GP) restricted diffusion and edema consistent with hypoxic ischemic encephalopathy. In contrast to other anoxic/ischemic insults, where the GP is preferentially spared, autopsy reports on intravenous heroin users have found the GP to be specifically affected, often demonstrating symmetric bilateral lesions. Opioid toxicity should be considered in patients presenting with Parkinsonian features on examination or pallidal lesions on imaging, especially in younger adults where infarction is less common. On arrival to the ED he was awake but confused and noted to have bilateral upper and lower extremity rigidity along with sustained clonus, hyperreflexia in upper and lower extremities, and complained of \u201cfoot cramping.\u201d A non-contrast computed tomography of the brain was normal (A 54-year-old man presented to the emergency department (ED) after receiving naloxone for a suspected opioid overdose. He was found in bed unresponsive, hypoxemic to SpOs normal . Brain ms normal .In autopsies on patients with heroin use disorder, bilateral GP lesions were noted to be frequently encountered.The patient was admitted to the hospital where he admitted to snorting heroin powder. He had resolution of his symptoms by hospital day five. Hypoxic ischemic insult, including opioid toxicity, should be considered in patients with Parkinsonian features on exam and/or isolated pallidal lesions on imaging without history of overt cardiorespiratory arrest, especially in adolescents and younger adults where infarction is less common.What do we already know about this clinical entity?Bilateral Globus Pallidus (GP) lesions have been noted in autopsies of patients with heroin use disorder. The etiology is unclear as anoxic-ischemic insults typically affects other brain areas.What is the major impact of the image(s)?Toxin induced Globus pallidus injury is a recognized finding in carbon monoxide, methanol, and cyanide poisoning. This magnetic resonance imaging finding should prompt a differential that includes opioid use.How might this improve emergency medicine practice?Recognition of GP lesions may identify a patient at high risk of future opioid related injury or death; who would benefit from counseling, substance use referral, and other resources."} +{"text": "RESULTS/ANTICIPATED RESULTS: Results: The symptom of auditory hallucination was significantly more endorsed in AA bipolar patients than EA bipolar patients . Conversely, the symptom of elevated or euphoric mood was significantly less endorsed in AA bipolar patients than in EA patients . AA, in comparison to EA bipolar patients, had a significantly higher prevalence of lifetime exposure to haloperidol and fluphenazine . In contrast, AA, in comparison to EA bipolar patients, had a significantly lower prevalence rate of lifetime exposure to lithium , and lamotrigine . DISCUSSION/SIGNIFICANCE OF IMPACT: Conclusion: The higher rate of psychotic symptom endorsement and lower rate of core manic symptom endorsement represent differential illness presentation that may contribute to misdiagnosis in African-American bipolar patients. The higher rate of high potency typical antipsychotic treatment and lower rate of classic mood stabilizing treatment may also contribute poorer bipolar treatment outcome. While structured diagnostic interviews are the gold standard in diagnostic confirmation, this study is limited by lack of knowledge of clinician/expert interviewer interpretation of symptom endorsement which may contribute to symptom misattribution and misdiagnosis. Incorporation of additional African American participants in research is a critical future direction to further delineate symptom presentation and diagnosis to serve as validation for these results.OBJECTIVES/SPECIFIC AIMS: Learning Objectives of this session: Identify possible reasons for misdiagnosis of bipolar patients of African ancestry by reviewing differences in symptom presentation between African American (AA) and European American (EA) bipolar individuals. Introduction: Bipolar disorder is a chronic mental illness with a prevalence rate up to 5.5% of the US population and is associated with substantial personal and economic morbidity/mortality. Misdiagnosis is common in bipolar disorder, which can impact treatment and outcome. Misdiagnosis disproportionally affects racial/ethnic minorities; in particular, AAs are often misdiagnosed with schizophrenia. There is interest in better understanding the contribution of differential illness presentation and/or racial bias to misdiagnosis. METHODS/STUDY POPULATION: Patients and Methods Utilizing the Genetic Association Information Network (GAIN) public database, this study compared clinical phenomenology between bipolar patients of African Versus European ancestry (AA=415 vs. EA=1001). The semi-structured Diagnostic Interview for Genetic Studies (DIGS) was utilized to evaluate individual symptom endorsement contributing to diagnostic confirmation. A \u03c7"} +{"text": "OBJECTIVES/SPECIFIC AIMS: Modulation of autophagy has the potential to treat inflammatory bowel disease (IBD). IBD is characterized by dysregulated inflammatory pathways and a defective intestinal epithelial barrier. We sought to better understand how autophagy can be utilized to regulate both inflammation and the intestinal barrier. METHODS/STUDY POPULATION: We examined mice with an autophagy defect in only macrophages in an animal model of IBD. To understand the phenotype, we utilized macrophages to investigate the mechanism behind autophagy and proinflammatory cytokine secretion. In addition, we analyzed the development of colonoids in a co-culture system with macrophages with or without a functional autophagy pathway. Lastly, pharmacological modulation of autophagy to control inflammation was assessed. RESULTS/ANTICIPATED RESULTS: Mice with autophagy-deficient macrophages were highly susceptible to intestinal barrier disruption. Susceptibility was due to enhanced proinflammatory cytokine secretion and intestinal permeability. Furthermore, proinflammatory macrophages (due to an autophagy defect) co-cultured with colonoids, significantly decreased the number of mucus producing goblet cells. Finally, pharmacologically modulation of autophagy reduced the secretion of proinflammatory cytokine by macrophages and reduced intestinal permeability. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results strongly suggest autophagy modulation can dampen inflammation and enhance the intestinal epithelial barrier."} +{"text": "Older adults are at risk for altered nutritional status and functional impairment due to physiological and psychosocial factors . Those with alterations in nutritional and/or functional status are at risk for poor health outcomes-including delayed healing of chronic wounds. We will discuss our lessons learned when devising nutrition assessment protocols from our ongoing double-blind randomized control clinical trial testing the effectiveness of ultrasound treatment on healing chronic leg wounds. The discussion will focus on the following measures: the Mini-Nutritional Assessment, hand-grip strength assessment, and inflammatory biomarkers."} +{"text": "Oral history narratives of nine childless centenarians from the Oklahoma 100 Year Life Project were reviewed to investigate loneliness. Oral history narratives were assessed qualitatively, using content analysis to determine themes. We predicted that childless centenarians would feel lonely due to \u201celder orphanhood.\u201d Findings revealed little indication of loneliness. Centenarians admitted they voluntarily chose to remain childless due to raising siblings earlier in life or delaying marriage. However, most remained socially well-adjusted and connected to extended family, particularly nieces. When confronted by social network losses due to death or relocation, most adapted by actively seeking and forming new relationships. In some cases, childless centenarians remained gainfully employed and working. Childlessness does not appear to make centenarians lonely. Rather, purposeful pursuit of intrapersonal and interpersonal sources of lifelong emotional contentment may render childless centenarians immune from conditions of loneliness."} +{"text": "Foreign body ingestion is an important problem in adult with psychological disorders. In literature ingestion such as fish bone, fork and several metallic elements were reported. The first attempt, after diagnosis, is endoscopic removalA 25-year-old male deaf patient was admitted in emergency department with complaint of abdominal pain and unable to communicate anything of his clinical history. Physical examination was normal except an epigastric tenderness. Laboratory results were normal. Direct radiography revealed a circular shaped metallic object in stomach and other several metallic objects in gastrointestinal tract A. An emeA delay in the diagnosis an dextraction of sharp or large sized foreign objects can lead to severe complications including mucosal laceration, obstruction, hemorrhage, and perforation. Therapeutic esophagogastroduodenoscopy with an esophageal overtube should be the first choice retrieval of large sized foreign bodies to avoid mucosal laceration, perforation and the surgical treatment."} +{"text": "Negative affect (NA) and positive affect (PA) vary from moment-to-moment and these variations are associated with cognitive health. Past work has primarily focused on valence (negative/positive), however, largely ignoring the potential import of arousal (high/low). We address this gap by assessing the impact of high and low arousal NA and PA on daily cognition. A sample of 238 older adults completed mobile surveys up to four times daily for 14 days. Participants reported current levels of high and low arousal NA and PA and performed processing speed and working memory tasks. For processing speed, there were significant within-person affect by age interactions. Moments when low arousal NA was higher than usual were associated with slower processing speed , and this effect was amplified in older participants . Moments when high arousal PA was higher than usual were associated with faster processing speed , and this effect was amplified in younger participants . For working memory, a significant within-person high arousal PA by age interaction emerged such that moments when high arousal PA was higher than usual were marginally associated with worse working memory performance only among older participants . Results suggest momentary increases in low arousal NA and high arousal PA may confer greatest risk to daily cognitive health among older adults with more limited capacity and/or cognitive resources, whereas affective influences may be more facilitative among comparatively younger adults."} +{"text": "Carpopedal spasm have various causes ranging from dsyselecrolytemia, syndromic, metabolic or endocrine causes. Any of these could cause a decrease in ionized calcium and tetany. Excessive vomiting leading to alkalosis, hypokaleamia and decreased ionised calcium should be kept in mind for early etiological diagnosis of carpopedal spasm. We report a case of 4-year-old boy presenting with a history of recurrent painful spasm and flexion of bilateral hands following excessive vomiting and electrolyte derangement. Carpopedalspasms are frequent and involuntary muscle contractions in the hands and feet with associated pain. Hypocalcemia, low calcium levels can cause carpopedal spasms as a warning sign . It occu2. Abdomen is flat, soft and moves with respiration. Vital signs are normal and physical examination revealed mild dehydration as evidenced by dry oral mucosa, and tender bilateral carpopedal spasm (A 4-year-old boy was brought to the children emergency department of Wesley Guild Hospital Ilesa with painful spasm and flexion of bilateral hands . He had al spasm . LaboratIonized calcium was the active form responsible for tetany . AlkalosExcessive vomiting leads to alkalosis, hypokaleamia and decreased ionised calcium and carpopedal spasm. Hence, serum electrolyte including serum calcium, magnesium, potassium and bicarbonate should be done promptly in all patients with persistent vomiting from any cause to detect dyselectrolytemia early and forestall late complication such as carpopedal spasm and tetany.The authors declare no competing interests."} +{"text": "The term, ageism, refers to any form of personal or institutional prejudice or discrimination based on chronological age. Ageism may encompass attitudes and prejudices, as well as behaviors, highlighting the complex nature of ageist behaviors observed among students and professionals alike . We examined the prevalence of self-reported ageist behaviors in a sample of college students who ranged in age from 18 to 44 years to test the hypothesis that aging knowledge would be associated with self-reported ageist behaviors (positive and negative). The study sample was comprised of adults who were enrolled in classes at Louisiana State University (n = 110). Most of these students were traditional aged college students (18-25 years old). Participants completed the Relating to Older People Evaluation , the Facts on Aging Quiz , and the Knowledge of Memory Aging Questionnaire . Results indicated that positive ageist behaviors were more frequent than negative ageist behaviors. Men endorsed positive and negative ageism items more than women reported. Follow-up analyses on participants\u2019 responses to the two aging knowledge questionnaires showed that increased knowledge of aging was significantly correlated with diminished reports of negative ageist behaviors, after controlling for age and gender. These results imply that self-reported ageist behaviors are associated with aging knowledge. Strengthening college curricula by including course offerings in adult development and aging may improve self-reported ageist behaviors among college students."} +{"text": "Receptor-mediated gene delivery capitalises on the presence of specific cell surface molecules for DNA uptake into cells and represents a particularly appealing approach for targeting vector DNA to specific cell types in vivo and in vitro. Various ligand/DNA and antibody/DNA transfer complexes were generated that, following binding to cells, are internalised and reach the endosomal compartment. Vector complexes contain endosomolytic components that ensure vector release from the endosome and translocation of vector DNA into the nucleus where transcription occurs. Thus, receptor-mediated gene delivery encompasses several critical steps that must be considered when designing and applying such vector systems."} +{"text": "Magnetotactic bacteria biomineralize intracellular magnetic nanocrystals surrounded by a lipid bilayer called magnetosomes. Due to their unique characteristics, magnetite magnetosomes are promising tools in Biomedicine. However, the uptake, persistence, and accumulation of magnetosomes within mammalian cells have not been well studied. Here, the endocytic pathway of magnetite magnetosomes and their effects on human cervix epithelial (HeLa) cells were studied by electron microscopy and high spatial resolution nano-analysis techniques. Transmission electron microscopy of HeLa cells after incubation with purified magnetosomes showed the presence of magnetic nanoparticles inside or outside endosomes within the cell, which suggests different modes of internalization, and that these structures persisted beyond 120 h after internalization. High-resolution transmission electron microscopy and electron energy loss spectra of internalized magnetosome crystals showed no structural or chemical changes in these structures. Although crystal morphology was preserved, iron oxide crystalline particles of approximately 5 nm near internalized magnetosomes suggests that minor degradation of the original mineral structures might occur. Cytotoxicity and microscopy analysis showed that magnetosomes did not result in any apparent effect on HeLa cells viability or morphology. Based on our results, magnetosomes have significant biocompatibility with mammalian cells and thus have great potential in medical, biotechnological applications. C) STEM-HAADF image of magnetosomes inside endosome, showing crystalline structures near the magnetosome (white square) displayed with greater exposure on the inset. D) Higher magnification of the region indicated by the square in (C) showing a crystalline structure near the magnetosome; inset shows FFT corresponding to the white square area, with a plane lattice distance of (TIF)Click here for additional data file."} +{"text": "Aging the detrimental molecular changes that occur in lymphatics with age [The diverse etiologies of age-related diseases, from osteoarthritis to Alzheimer\u2019s disease, all share an impairment, or slow loss, of tissue function. Aging tissue homeostasis shifts towards progressive, low-grade inflammation and a dampened immune response. The lymphatic vasculature is the key regulator of tissue homeostasis in health and disease. Lymphatics transport antigens and other macromolecules, excess interstitial fluid, and activated immune cells during inflammation. Shang and colleagues recently reviewed for with age . Here weAging review \u201cPathophysiology of aged lymphatic vessels\u201d, Shang and authors have summarized research focused on lymphatic collecting vessels finding that lymphatic muscle contractions are reduced in amplitude and frequency and can become irregular with age [Lymphatic vessels are structurally quite different from blood vessels, beginning with blind-ended capillaries possessing leaf-like cell junctions that lead to large, unidirectionally-valved collecting vessels. These larger vessels are surrounded by lymphatic muscle cells that provide intrinsic pumping to maintain lymph flow. In their with age . The Gaswith age ,2. They Chronic tissue degeneration is a common feature of age-associated disorders like osteoarthritis (OA). A series of collaborative studies from the Schwarz and Xing groups have extensively detailed lymphatic involvement in several models of arthritis. They have demonstrated that inflammatory lymphangiogenesis and increased pumping initially facilitate the removal of immune cells and fluid to the draining lymph nodes, but that over time lymphatics regress and collecting lymphatic vessels lose contractility . In theiRecently mapped pathways by which fluid and immune cells enter lymphatic vessels may play important roles in neurological decline, notably in Alzheimer\u2019s disease (AD). The Proulx laboratory used near infrared dynamic imaging of macromolecule transport to identify several outflow pathways for the egress of cerebral spinal fluid (CSF) to lymphatics . FurtherCardiovascular (CV) disease and diabetes are progressive pathologies whose diagnoses increase with age, and the side effects, treatment, and recovery are more difficult to manage in older patients. Lymphatic vessels have demonstrated a critical role and therapeutic potential in several CV pathologies including atherosclerosis, myocardial infarction, hypertension, and diabetes . AtherosIn conclusion, the pathophysiology of aging lymphatic vessels reviewed by Shang and colleagues reduces lymphatic fluid clearance, immune migration, and inflammatory responsiveness. Research in several disease models including osteoarthritis, Alzheimer\u2019s disease, and CV disease has identified that enhancing lymphatic function may provide therapeutic benefit. Understanding the mechanisms of lymphatic decline and identifying maintenance or therapeutic regimens targeting lymphatic physiology is therefore important in addressing age-related disease."} +{"text": "Pinus ponderosa) forests. However, the extent, characteristics, and predictability of ponderosa pine fire refugia are largely unknown. Within 23 fires in ponderosa pine-dominated forests of the Colorado Front Range (1996\u20132013), we evaluated the spatial characteristics and predictability of refugia: first using Monitoring Trends in Burn Severity (MTBS) burn severity metrics, then using landscape variables . Using 1-m resolution aerial imagery, we created a binary variable of post-fire conifer presence (\u2018Conifer Refugia\u2019) and absence (\u2018Conifer Absence\u2019) within 30-m grid cells. We found that maximum patch size of Conifer Absence was positively correlated with fire size, and 38% of the burned area was \u2265 50m from a conifer seed source, revealing a management challenge as fire sizes increase with warming further limiting conifer recovery. In predicting Conifer Refugia with two MTBS-produced databases, thematic burn severity classes (TBSC) and continuous Relative differenced Normalized Burn Ratio (RdNBR) values, Conifer Absence was high in previously forested areas of Low and Moderate burn severity classes in TBSC. RdNBR more accurately identified post-fire conifer survivorship. In predicting Conifer Refugia with landscape variables, Conifer Refugia were less likely during burn days with high maximum temperatures: while Conifer Refugia were more likely on moister soils and closer to higher order streams, homes, and roads; and on less rugged, valley topography. Importantly, pre-fire forest canopy cover was not strongly associated with Conifer Refugia. This study further informs forest management by mapping post-fire patches lacking conifer seed sources, validating the use of RdNBR for fire refugia, and detecting abiotic and topographic variables that may promote conifer refugia.Forested fire refugia (trees that survive fires) are important disturbance legacies that provide seed sources for post-fire regeneration. Conifer regeneration has been limited following some recent western fires, particularly in ponderosa pine ( We determined connectivity of Conifer Refugia and Conifer Absence patches by grouping contiguous pixels of the same classification using an eight-cell neighborhood . To determine whether the proportion of Conifer Refugia within fires changed over the study period, we analyzed the percent area of Conifer Refugia in each fire and used ordinary least squares regression to test the significance of a temporal trend 1996\u20132014 (\u03b1 = 0.05) . To deteTo inform local management plans for potential post-fire recovery programs, we evaluated the reliability of two readily available MTBS databases to represent the locations of post-fire surviving conifers. We calculated the TBSC and RdNBR values for pixels of Conifer Refugia and Conifer Absence across all fires. We graphed the percent of Conifer Refugia and Conifer Absence in different thematic burn severity classes. We assessed the power of TBSC and RdNBR to predict Conifer Refugia and Conifer Absence in a Classification and Regression Tree model (CART) in R ,70. CARTTo examine factors influencing patterns of Conifer Refugia and Conifer Absence, we first constructed spatial overlays with Pre-fire Forest Cover and daily fire weather variables and compared the distributions in the two classes across equal interval bins of each predictor variable. These descriptive statistics aided in interpretation of subsequent predictive models and associated predictor importance.To assess how well weather, anthropogenic, abiotic, and biotic factors predict the locations of Conifer Refugia and Conifer Absence, we used Random Forests in R R ,73. We tOver 147,000 ha were mapped within the 23 fire perimeters in ponderosa pine-dominated forests of the CFR from 1996\u20132013 . For all2 = 0.85, p \u22640.0001, The proportion of Conifer Refugia within fire perimeters did not significantly decrease or increase over time between 1996 and 2013 p \u22650.05, . We founBoth TBSC and RdNBR maps showed relationships with the locations of Conifer Refugia and Conifer Absence across the study area . Within Overlays of fires with Pre-fire Forest Cover reveal that 95% of the total burned area had pre-fire forest cover (>1%), with over half (55%) of the total area having dense pre-fire forests aerial imagery to map post-fire Conifer Refugia within 23 fires that burned ponderosa pine-dominated forests of the CFR from 1996\u20132013 allowed us to thoroughly examine the spatial characteristics and predictability of Conifer Refugia in this region. Our study of post-fire surviving trees found that over one-third of the area burned in the CFR resulted in large contiguous patches without surviving trees at distances greater than the common dispersal distance of ponderosa pine seeds, presenting a potential forest recovery challenge. We generally found that abiotic and topographic landscape variables, many indicative of moister microsites, were the most important predictors of conifer refugia, except under high maximum temperatures and the most extreme fire weather, in which case conifers were generally less likely to survive. The lack of a strong relationship between pre-fire forest cover and post-fire Conifer Refugia may have strong implications for forest management aimed at increasing the resilience of ponderosa pine to wildfire through tree thinning. We recommend prioritizing RdNBR over TBSC as a management tool to more accurately identify post-fire conifer refugia, evaluate patch metrics of surviving post-fire conifers, and plan for post-fire recovery.Post-fire forested refugia are important disturbance legacies providing seed sources and microsites for recovery of ponderosa pine forests ,22,24,75Evaluating both the spatial and temporal trends in Conifer Refugia proved critical to understanding the potential effectiveness of these legacies in promoting post-fire recovery. We found a consistent proportion of Conifer Refugia across time in the CFR, similar to findings during the last two decades in the northern Rockies . AlthougIn the Southern Rockies, from 1984 to 2006 there was a trend of increasing area burned , which mLimited long-distance dispersal into high-severity patches has been documented . Such diThe use of high-resolution imagery allowed us to accurately map conifers at very low densities and thoroughly evaluate the ability of coarser scale burn severity indices to detect these conifer refugia. We found that post-fire conifer refugia are not consistently detected by MTBS TBSC and that these classes generally under-estimated conifer loss in the ponderosa pine cover type in our region. Although thematic burn severity metrics typically capture changes in all organic matter above and below ground, such as soil, understory vegetation, and canopy mortality , we focuRdNBR provided a more robust method for detecting post-fire surviving conifers and we recommend its use in post-fire recovery planning in ponderosa pine-dominated forests. RdNBR is more consistent in classifying burn severity in areas with low forest cover and has identified fire refugia in other regions ,78. Our Conifer refugia were least likely to survive wildfires occurring under the highest temperatures, highest wind speeds, and driest conditions. Higher daily maximum temperature was the highest ranked variable in the primary random forest model predicting higher tree mortality. Our findings generally corroborate other studies showing the decreased importance of topographic variables in predicting fire severity and fire refugia under warmer, drier, and more extreme burning conditions ,30,31,78Our hypothesis that abiotic factors have an influential role in providing post-fire refugia across the CFR was generally supported. The most important landscape variables in predicting Conifer Refugia were related to soil characteristics, proximity to higher order streams, less rugged terrain, valley landforms, and lower elevation in drainages. The partial dependence plots of the Random Forest model suggest that post-fire conifer survivorship in ponderosa pine dominated forests is generally predicted in moister or less steep sites. Conifer survivorship in locations near the floodplain or watershed drainage is most likely influenced by soil properties, microclimates, and topography. Wetlands, stream confluences, riparian areas, valley bottoms and cold air drainages can have decreased fire severities ,89\u201392. ASoil properties in the top five centimeters heavily influenced the presence of Conifer Refugia. Quantitative studies of ponderosa pine densities and soil texture in the Southwest have shown that soils with a high clay content are less favorable for ponderosa pine and more favorable for competing grasses ,94,95. AAnthropogenic influences also promoted conifer survivorship within our study area. Both proximate distance to homes and distance to roads were consistently ranked in the top ten predictors of Conifer Refugia. Roads may serve as natural fuel breaks or be used to strategically locate active fire suppression efforts, both promoting survivorship of trees in the area. Homes are also actively protected from oncoming wildfires with wildfire suppression tactics and numerous private land owners in the CFR treat fuels adjacent to their homes ,97. TreeBiotic variables, distance to savanna and pre-fire forest cover, were not strong predictors of Conifer Refugia. Overlays showed that forest cover under 60% was only slightly more likely to survive these wildfires and half of the area with forest cover between 20% and 50% had no surviving conifers. Although forest cover overall had a very weak relationship with tree survivorship, the proximate distance to savannas (open areas and forest cover \u2264 20%) had a stronger influence. While elevation is historically the single most important predictor of low-severity fire within the CFR , forestsThe importance and decline of small meadows in ponderosa pine has been documented in Colorado . BetweenIn addition to the decline in area of meadows along the CFR, there appears to be a surprising lack of resistance to recent fire in the remaining savannas. Nearly half of the canopy cover of the savannas within the fire perimeters did not survive. The maintenance and protection of large, old trees is important for both ecosystem services and carbon storage . The higOur analysis highlights specific opportunities regarding forest management to enhance forest resilience in the face of increased wildfires under a warming climate \u2013109: 1) Although 42% of the total burned area contained surviving post-fire conifers in our study of 23 fires, mechanisms of resilience of ponderosa pine systems to wildfire may be declining along the CFR. We highlight four general findings that underscore the potential declining resilience of ponderosa pine forests in Colorado with a continued trend of increasing area burned under a warming climate: 1) large fires are expected to have large patches approximately a third the size of the fire area that lack surviving conifers and therefore seed sources for regeneration; 2) wetter areas and topographic low points generally have a higher likelihood of conifer presence following wildfires; 3) forest cover was not a strong predictor of conifers surviving wildfire; and 4) conifers are less likely to survive under extreme fire weather and burning conditions. Research in the CFR and elsewhere has reported decreased ponderosa pine regeneration in response to warmer drier climates following wildfires. These same climate conditions are promoting large wildfires with extensive treeless patches, further compromising post-fire resilience to wildfire. For ponderosa pine forests in the CFR, the combination of larger fires and warmer-drier burning conditions poses a potentially great threat of forest loss with a lack of post-fire recovery due to lack of seed sources alone. Even patches of the lowest tree cover in ponderosa pine forests suffered high mortality in recent fires along the CFR. Our results suggest numerous management implications including: the preference of RdNBR over TBSC to evaluate post-fire surviving seed sources, the importance of including soil and topographic variables into management planning to promote post-fire conifer refugia, the increased use of prescribed fire in existing meadows and woodlands to potentially increase the survivorship of conifer trees, and a reprioritization that may include wide-scale planting of seedlings for this forest type in areas lacking seed sources but at sites where they are more likely to survive future fires.S1 TablePercent cover of forest and woodlands in the 2001 LANDFIRE Existing Vegetation Types within 23 fires that burned ponderosa pine-dominated forests along Colorado\u2019s Front Range 1996\u20132013.(DOCX)Click here for additional data file.S2 TableTotal percent cover and area of forest and woodlands in the 2001 LANDFIRE Existing Vegetation Types across 23 fires that burned ponderosa pine-dominated forests along Colorado\u2019s Front Range 1996\u20132013.(DOCX)Click here for additional data file.S3 TableImportance and data sources for landscape variables generated for the random forest model meant to classify Conifer Refugia and Conifer Absence. Selected variables in more than six of 11 Random forest models are indicated by *. An expected positive relationship between the variable and Conifer Refugia is denoted with (+) and an expected negative relationship with (-). All variables are at 30-m resolution.(DOCX)Click here for additional data file.S4 TableMaximum, mean, and standard deviation of distance to potential pre- and post-fire seed source for the 23 fires that burned ponderosa pine-dominated forests along Colorado\u2019s Front Range 1996\u20132013.(DOCX)Click here for additional data file.S1 FigThree examples of Conifer Refugia within 23 fires that burned ponderosa pine-dominated forests along Colorado\u2019s Front Range 1996\u20132013 as shown by 2015 NAIP aerial imagery.(TIF)Click here for additional data file.S1 Text(DOCX)Click here for additional data file."} +{"text": "Immune checkpoint blockade (ICB) has elicited durable therapeutic responses across a number of cancer types. However, the impact of ICB on mCRPC has been disappointing, which may signal the need to combine mechanistically-distinct ICB agents and/or override immunosuppression in the tumor microenvironment. Our objective is to determine if robust immunotherapy responses in mCRPC may be elicited by the combined actions of ICB agents together with targeted agents that neutralize MDSCs yet preserve T cell function. METHODS/STUDY POPULATION: We created a novel embryonic stem cell-based chimeric mouse model of mCRPC engineered with signature mutations to study the response to single and combination immunotherapy. The efficacy studies were followed with detailed mechanistic investigation and clinical validation. RESULTS/ANTICIPATED RESULTS: Consonant with early stage clinical trials experience, anti-CTLA4 or anti-PD1 monotherapy failed to impact disease progression. Similarly, modest anti-tumor activity was observed with combination ICB as well as monotherapy with targeted agents including Cabozantinib (tyrosine kinase inhibitor), Dactolisib (PI3K/mTOR inhibitor), and Dasatinib (tyrosine kinase inhibitor). In contrast, mCRPC primary and metastatic disease showed robust responses to dual ICB treatment together with either Cabozantinib or Dactolisib, but not with Dasatinib which impaired T cell infiltration in the tumor. Detailed intratumoral immune profiling with mass cytometry (CyTOF) showed that combined ICB and Cabozantinib or Dactolisib was associated with significant depletion of MDSCs. Cabozantinib and Dactolisib blocked the PI3K signaling activity in MDSCs and reduced their immunosupppresive activity. Mechanistically, the combination efficacy was due to the upregulation of IL-1RA and suppression of MDSC-promoting cytokines secreted by mCRPC cells. DISCUSSION/SIGNIFICANCE OF IMPACT: We demonstrated that an antibody cocktail targeting CTLA4 and PD1 was insufficient to generate effective anti-tumor response, but combination of ICB with targeted therapy that inactivates PI3K signaling displayed superior synergistic efficacy through impairing MDSCs in the tumor microenvironment. These observations illuminate a clinical path hypothesis for combining ICB with MDSC-targeted therapies in the treatment of mCRPC. Importantly, conclusions from the study on PCa may have implications in combination immunotherapy for aggressive breast cancer which is also largely resistant to immune checkpoint blockade and replete with immunosuppressive myeloid cells.OBJECTIVES/SPECIFIC AIMS: Prostate cancer (PCa) is the most common noncutaneous malignancy in men in the United States. A significant fraction of advanced PCa treated with androgen deprivation therapy experience relentless progression to lethal metastatic castration-resistant prostate cancer (mCRPC). The PCa tumor microenvironment is comprised of a complex mixture of epithelial and stroma cell types engaged in multifaceted heterotypic interactions functioning to maintain tumor growth and immune evasion. We recently uncovered the important role played by myeloid-derived suppressor cells (MDSCs) to mediate tumor immune evasion in aggressive PCa (Wang, Lu"} +{"text": "Cicatricial organizing pneumonia is an uncommon form of organizing pneumonia, which may manifest as persisting linear opacities on computerized tomography (CT) scan mimicking a fibrosing interstitial pneumonia. It may also manifest with pulmonary ossification, which is a metaplastic bone formation within the lung tissue. The latter presentation could be either nodular or dendriform, both secondary to underlying lung disease and rarely idiopathic. Dendriform pulmonary ossification (DPO) has rarely been described as a cause of spontaneous pneumothorax. We present a case of a 55-year-old male with history of recurrent pneumothoraces and worsening dyspnea on exertion. A CT of the chest revealed progressive bilateral sub-pleural and peribronchovascular reticular opacities associated with densely ossified branching and nodular opacities. Video-assisted thoracoscopic biopsy of the lung demonstrated cicatricial organizing pneumonia with areas of marked diffuse DPO. The case highlights that dendriform pulmonary ossification arising from cicatricial organizing pneumonia should be considered in the differential diagnosis of recurrent pneumonias among patients with lower lobe sub-pleural reticular opacities. The case highlights that dendriform pulmonary ossification rarely can cause spontaneous pneumothorax and can be associated with cicatricial organizing pneumonia and reticular opacities on imaging. Organizing pneumonia (OP) is characterized by the presence of organizing fibromyxoid proliferations within the lumens of respiratory bronchioles and alveolar ducts. Peripheral and /or peribronchiolar consolidations are the most frequent findings of OP on a computerized tomography (CT) scan. These opacities could be migratory in nature. OP is often steroid-responsive and reversible with total resolution of radiological opacities, but occasionally may recur , 2.Cicatricial OP (OPc) is a newly described entity in the pathology literature , 4 and dA 55 year-old, nonsmoker male presented with a recurrent large left pneumothorax requiring a chest tube placement. He had a same side pneumothorax three and six years earlier, also requiring a chest tube placement. The patient also reported dyspnea on exertion with stairs and inclines, which had progressed over last three years along with a dry cough.He had a remote exposure to quails while training hunting dogs. He was known to have hypertension and suffered with symptoms of gastroesophageal reflux disorder (GERD). His physical examination was unremarkable. A review of his pulmonary function revealed gradual decline in his FEV1, FVC and diffusion capacity over the past seven years .Review of serial chest CT imaging revealed progressive bilateral sub-pleural and peribronchovascular branching dense opacities suggestive of DPO . He undeOrganizing pneumonia is usually steroid-responsive and pathologically characterized by presence of loose fibromyxoid plugs within the lumens of the respiratory bronchioles and alveolar ducts , 2. CicaOn CT, conventional OP presents as patchy bilateral peribronchial and subpleural consolidations \u201319, whicPulmonary ossification is a metaplastic process where mature bone is present in the alveolar interstitium and/or alveolar spaces. Pulmonary ossification is classified into DPO and NPO. NPO is usually a localized process of lamellar bone and can occur in the setting of chronic congestion as seen in mitral valve stenosis. Unlike DPO, NPO usually does not contain bone marrow (fat or hematopoietic cells) . On CT, DPO manifests on CT as small nodules, which are seen predominantly in the peripheral interstitium . These nodules form contiguous and branching pattern resembling tree branches. In most instances these nodules are of high attenuation, reflecting the underlying ossification. The detection of small high-attenuation foci is improved using thin slices and maximum-intensity-projection images. DPO has tendency to affect lower lobes and posterior aspect of upper lobes. Association with recurrent aspiration and DPO has been suggested . The preSpontaneous pneumothorax has been reported in several cases of DPO \u201314 incluThe case we present showed evidence of radiographic progression and worsening restrictive pattern on PFT over several years. The reported cases of cicatricial OP by Churg and his colleagues have beeIn summary, we present a case of cicatricial OP with DPO presenting with recurrent pneumothoraces and slow progressive pulmonary physiologic restrictive impairment. Cicatricial OP should be considered in the differential diagnosis of peribronchial or subpleural reticular opacities with DPO. Radiologists and clinicians alike should be aware of this newly described entity as distinct from other classical fibrosing processes, its potential association with DPO, and the presumed association between subpleural DPO and spontaneous pneumothorax."} +{"text": "Rapid changes in family structures have expanded caregiving boundaries beyond the level of lineal kin to include extended and fictive kin. Guided by stress process and health behavior models, we analyzed semi-structured interviews with 120 family caregivers of persons with dementia (PWD) in rural Appalachia to explore personal/family circumstances that influence the responsibilities nonlineal kin assumed to meet the needs of PwD. Compared to spouse and adult children caregivers, nonlineal caregivers reported that PWD had similar behavioral problems, but greater ADL limitations. They also expressed greater burden, overload and role captivity; yet, they reported higher personal mastery, and perseverance. Although sisters and nieces did not report using any paid services to care for PwD, grandchildren and fictive kin used paid services such as meal delivery, personal care, and respite services. Findings provide new insights into a more elaborated conception of caregiving that considers the transformations occurring in family life today."} +{"text": "Correction to: Antimicrob Resist Infect Control (2019) 8:77https://doi.org/10.1186/s13756-019-0524-4The original article containsAs such, the authors would like to clarify that in the context of this manuscript, LCMV needlestick injuries may only lead to life-threatening infections in immunosuppressed persons.The Conclusions sub-section of the Abstract should instead state:\u201cThis is the first case report of a PCR-documented LCMV meningitis, coupled with seroconversion, following needlestick injury. It highlights the importance of infection prevention practices that comprise particularly well established safety precaution protocols in research laboratories handling this pathogenic virus, because exposure to LCMV can lead to a severe infection.\u201dThe latter part of the penultimate paragraph of the Background section should instead state:\u201cTherefore, prevention of stab wounds with contaminated sharp objects, bite of infected mice and inhalation of contagious droplets, is indispensable to protect laboratory worker from occupational infection.\u201dThe final paragraph of the Background section should instead state:\u201cThis highlights the importance of infect prevention strategies that comprise particularly well established safety precaution protocols in research laboratories handling this pathogenic virus, because exposure to LCMV can lead to a severe infection.\u201dA middle sentence in the Discussion and conclusion section should instead only state:\u201cPrevention of stab wounds with contaminated sharp objects, bite of infected mice and inhalation of contagious droplets, is crucial to protect laboratory worker from iatrogenic infection.\u201dThe latter half of the penultimate paragraph of the Discussion and conclusion section should instead state the following:\u201cWhen working with LCMV in research laboratories, standard biosafety 2 laboratory practices are mandatory. This includes an appropriate ventilation system as well as wearing high quality gloves and protective gowns when working with LCMV. Surfaces should be routinely disinfected using a registered compound active against LCMV. In addition, a standard operating procedure should be available for the management of unintentional exposure to the virus. Pregnant women and immunosuppressed persons must be taught that exposure to this virus can lead to a severe, life-threatening infection.\u201dThe final paragraph of the Discussion and conclusion section should instead only state:\u201cIn conclusion, this well-documented case of LCMV-meningitis after needlestick injury highlights the importance of infection prevention practices in research laboratories and the need of safe handling of this virus.\u201dThe affected statements in the manuscript and their corrected version can be viewed ahead:"} +{"text": "The dentate gyrus continually produces new neurons throughout life. Behavioral studies in rodents and network models show that new neurons contribute to normal dentate functions, but there are many unanswered questions about how the relatively small population of new neurons alters network activity. Here we discuss experimental evidence that supports multiple cellular mechanisms by which adult-born neurons contribute to circuit function. Whereas past work focused on the unique intrinsic properties of young neurons, more recent studies also suggest that adult-born neurons alter the excitability of the mature neuronal population via unexpected circuit interactions. Thus, GCs integrate sensory and spatial information to help generate a neural representation of a context5. Interestingly, resident neural stem cells produce new GCs throughout adulthood, and these adult-born GCs receive synapses from cortical neurons via the perforant path and form output synapses with downstream neurons to participate in hippocampal network activity. Although the majority of neuroblasts undergo programmed cell death, surviving neurons are permanently incorporated into the DG and acquire properties similar to GCs generated early in development8. While adult-born GCs may replace a fraction of the developmentally generated population that is lost over time10, their continuous addition accounts for the substantial increase in GC number across the first year of life in rodents12. How this process contributes to hippocampal learning and memory is an intriguing neurobiological question. Current insight into this question relies on experimentally tractable rodent models, but evidence of DG neurogenesis in healthy humans across the lifespan14 suggests that it could have implications for human cognition.The dentate gyrus (DG) is viewed as the main entry point for neural activity into the hippocampus, a brain region essential for learning and memory. The principal neurons, the dentate granule cells (GCs), are innervated by neurons of the entorhinal cortex that encode information about objects, spatial location, and details of the environment16. Brain regions involved in associative learning, such as the cerebellum and hippocampus, use circuits that perform pattern separation as a \u201cpre-processing\u201d step to help discriminate input patterns carrying sensory or contextual cues17. Sparse population activity, wherein only a small fraction of principal neurons are active at a given time, is thought to be a critical component of pattern separation17. In the DG, sparse activity is predicted to allow distinct GC ensembles to encode similar patterns of afferent activity, with a large capacity to transform overlapping patterns in the cortex into non-overlapping patterns in CA319. Interestingly, selective manipulations of adult-born GCs are sufficient to alter behavior paradigms thought to rely on DG pattern separation ergic interneurons that inhibit mature GCs, a circuit motif called feedback inhibition. Consistent with this idea, reducing neurogenesis with focal X-irradiation generated bursts of GC activityin vivo35 and hypersensitivity to a chemoconvulsant52. While these studies assayed excitability across the population of GCs, subsequent work acutely silencing young GCsin vivo andex vivo using designer receptors exclusively activated by designer drugs (DREADDs) also revealed enhanced excitability of individual mature GCs consistent with feedback inhibition53.Some of the first evidence that adult-born GCs alter the excitability of mature GCs came from voltage-sensitive dye imaging of hippocampal slices from mice with enhanced or ablated neurogenesis56 58. Whereas feedback inhibition generated by 8-week-old GCs suppressed perforant path-induced spiking, inhibition evoked by the same number of 4-week-old GCs had little effect -mediated currents in mature GCs even when polysynaptic activity was blocked by \u03b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonists. Such recurrent connectivity contrasts sharply with the conventional view that GCs provide a unidirectional glutamatergic projection, except in pathological conditions like epilepsy62. Yet the possibility that young GCs release both GABA and glutamate is consistent with a long-standing literature showing a transient dual-neurotransmitter phenotype, although the nature and prevalence of GABAergic signaling from young GCs has been controversial65.The plot thickened as subsequent work proposed that ChR2 activation of adult-born GCs younger than 7 weeks old provides strong inhibitory responses in neighboring GCs66 first showed that silencing adult-born GCs increased mature GC responses evoked by stimulation of the lateral perforant path (LPP), whereas it reduced mature GC responses evoked by stimulation of the medial perforant path (MPP). Since the LPP carries sensory information and the MPP carries spatial information3, adult-born GCs might selectively gate different forms of information during the creation of DG contextual representations in mature GCs. This unexpected pathway-specific regulation was attributed to activation of postsynaptic glutamate receptors on mature GCs rather than feedback inhibition. In fact, blocking GABAA receptors did not block the responses evoked by new GCs, suggesting that feedback inhibition generated by young GCs is not a major circuit function in this paradigm.Even as the efficacy of GABAergic feedback inhibition recruited by young GCs remains debated, a recent study further expands the potential repertoire of adult-born GC circuit functions by focusing on the direct glutamatergic signaling from young GCs to mature GCs . Luna an68. Luna and colleagues showed that optogenetic activation of young GCs evoked NMDAR-mediated excitatory postsynaptic potentials (EPSPs) in mature GCs as well as slow inhibitory postsynaptic potentials (IPSPs) driven by mGluRs. Such NMDAR- and mGluR-driven responses are characteristic of spillover signaling, wherein receptors located outside of synapses are activated by glutamate acting at a distance from the release site. Spillover transmission can occur in the absence of anatomically defined synaptic junctions or in addition to conventional point-to-point synaptic transmission71. The authors suggest that when a small number of young GCs are activated by LPP stimulation, the relatively low level of glutamate spillover favors mGluR-mediated inhibition, whereas a larger population of young GCs activated by MPP stimulation recruit stronger NMDAR-mediated depolarization that overrides mGluR inhibition. Thus, the number of young GCs recruited will affect their circuit function coupled to potassium channels that cause hyperpolarizationunction . In thiset al.66 described circuit interactions that enable adult-born GCs to rapidly modify mature GC excitability in response to network activity, neurogenesis also changes synaptic structure and function of existing GCs over a longer time window as young GCs integrate into the circuit. The possibility that newborn GCs compete for synaptic input with existing GCs was implied by evidence that the survival of newborn GCs is competitively regulated by NMDAR activation72. Subsequent anatomical analysis showed that immature dendritic spines transiently receive a high proportion of synapses from multiple-synapse boutons that could represent an intermediate structure in the transfer of cortical synapses from old to new GCs74 (but see77. In accordance with a redistribution of available presynaptic and postsynaptic elements, ablating GCs enhances the density of GABAergic somatic synapses on remaining GCs78 and increasing the number of new GCs does not appear to alter the density of spines and synapses in the molecular layer79. Recent support for the hypothesis that new GCs integrate into the circuit by competing for pre-existing synapses was provided by complementary studies showing that reducing the spine density of mature GCs enhanced the integration of new GCs80 and that manipulating the number of newborn GCs inversely regulated synaptic connectivity of mature GCs81. Thus, synaptic competition and subsequent redistribution of cortical connectivity may provide an additional mechanism for neurogenesis to contribute to sparsity and decorrelation of mature GC activity20.Whereas Luna but see. Whetheret al.66 propose that dual signaling allows young GCs to differentially regulate mature GC excitability depending on the strength of LPP versus MPP activity that differs between behavioral states and in the superior and inferior blade. Another possibility is that direct excitation/inhibition exerts local effects on neighboring GCs, whereas feedback influences GCs over a larger spatial domain as dictated by the extensive axonal arbors of GABAergic interneurons. Untangling the consequences of these multifaceted circuit interactions on hippocampal encoding and behavior will be an interesting challenge.The possibility that young GCs influence mature GC excitability by direct glutamatergic excitation and inhibition suggests an unexpectedly complex regulation layered upon additional secondary influences including feedback inhibition and synaptic competition. On the surface, it is difficult to envision the purpose of simultaneous direct excitation and inhibition. Luna82? Finally, what is the temporal relationship and relative efficacy of direct glutamatergic signaling in comparison with feedback inhibition and synaptic competition at each stage of new GC maturation? While the existing evidence indicates that the integration of new GCs has complex consequences for the local circuit, there is still a long way to go to understand how a few cells affect the many. The multi-layered complexity of the circuit interactions, in combination with activity-dependent regulation of adult neurogenesis, implies that continual neurogenesis provides extraordinary flexibility for adaptation to environmental changes and cognitive demands. Further exploring the cellular mechanisms by which adult-born GCs modify DG excitability and downstream hippocampal activity, along with cell-type-specific manipulations in behaving rodents to test their influence on behavior (reviewed inMany questions also remain about the mechanisms of these interactions at the cellular and synaptic level. For example, how is glutamate released from young GCs in a manner that generates receptor activation reminiscent of spillover signaling and where does this signaling occur? What is the efficiency of this novel signaling mechanism in controlling mature GC spiking, especially considering the stimulation of a single or small number of young GCs is insufficient to engage these interactions? How does the MPP recruit a larger population of young GCs than the LPP in light of evidence that the LPP preferentially innervates young GCsAMPAR, \u03b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; ChR2, channelrhodopsin-2; DG, dentate gyrus; EPSP, excitatory postsynaptic potential; GABA, gamma-aminobutyric acid; GC, granule cell; IPSP, inhibitory postsynaptic potential; LPP, lateral perforant path; mGluR, metabotropic glutamate receptor; MPP, medial perforant path; NMDAR, N-methyl-D-aspartate receptor."} +{"text": "Gastric outlet obstruction can be caused by various pathologies, including peptic ulcer disease, gastric polyps, and malignancies. The incidence rate of breast cancer metastasis to the stomach is only 0.3%. We describe a rare case of an 83-year-old female with a remote history of breast cancer who presented with symptoms of nausea and vomiting. She underwent an upper endoscopy, and biopsies revealed chronic gastritis. However, when she presented for the second time with similar symptoms, she underwent endoscopic ultrasound (EUS)-guided biopsies, which clinched the diagnosis of breast cancer metastasis causing gastric outlet obstruction. This case describes the importance of keeping a wide differential diagnosis for the causes of gastric outlet obstruction and the significance of deeper EUS-guided biopsies if initial endoscopic biopsies are inconclusive. Gastric outlet obstruction (GOO) has multiple etiologies, including peptic ulcer disease, malignancies, and gastric polyps. With the identification of Helicobacter pylori and the use of proton pump inhibitors, the etiology of gastric outlet obstructions has changed over the years with malignancy now being the most common cause . The mosAn 83-year-old female presented to our emergency department with complaints of nausea and vomiting for four days. She had been diagnosed with right-sided, multicentric, infiltrating lobular carcinoma of the breast , progesterone receptor positive (PR+), human epidermal growth factor receptor 2 negative (HER2-) 10 years ago. She had undergone a right mastectomy, and her sentinel lymph nodes, which were sampled during surgery, were negative for metastases. Previously, she had been treated with adjuvant anastrozole for five years, and yearly mammograms had been negative for recurrence.One year prior to this presentation, she was evaluated at our hospital for similar complaints of nausea and vomiting. A computed tomography (CT) scan of her abdomen and pelvis on admission revealed a mass-like thickening of the gastric antrum and distension of the proximal stomach, as illustrated in Figure An upper endoscopy (EGD) was performed, which revealed esophagitis and gastric stenosis. This was dilated using a through-the-scope controlled radial expansion (CRE) balloon to a maximum balloon size of 12 mm without fluoroscopic guidance. Biopsy of the gastric stenosis revealed gastric mucosa of antral type with minimal chronic inactive gastritis. No morphologic evidence of a Helicobacter pylori infection was detected. The patients\u2019 symptoms of nausea and vomiting improved following balloon dilation. She was subsequently discharged on a daily proton pump inhibitor.The patient underwent endoscopic ultrasound (EUS) 12 weeks later. Gastric stenosis was found at the pylorus and duodenal bulb, which was dilated again with a CRE balloon to a maximum dilation of 13.5 mm. Diffuse wall thickening of the antrum of the stomach was visualized endosonographically. The gastric wall measured up to 11 mm in thickness. Thickening within the deep mucosa, submucosa, and muscularis propria was noted. EUS-guided biopsies were taken, which revealed invasive poorly differentiated metastatic breast adenocarcinoma, as shown in Figure Tumor immunohistochemistry and morphology revealed ER+, PR+, and HER2- negative lobular breast adenocarcinoma as demonstrated in Figure This case highlights the importance of keeping a broad differential diagnosis for cases presenting with gastric outlet obstruction, especially in patients with a history of cancer. A diagnosis of breast cancer metastases to the gastrointestinal tract is often challenging because of its low incidence. Distinguishing between metastatic breast carcinoma and primary gastric adenocarcinoma cannot always be done using histological examination alone, and superficial biopsies may not be sufficient. Invasive lobular breast carcinoma and primary gastric cancer can have similar histopathology, as both can show signet ring cells. Immunohistochemistry is needed to make a distinction between the two, based on staining for estrogen and progesterone receptors . As in oAn important differential diagnosis for patients with concurrent gastric and breast adenocarcinoma includes hereditary diffuse gastric cancer (HDGC), which is an inherited cancer syndrome associated with an increased risk for primary gastric cancer and lobular breast carcinoma and is characterized by a poor prognosis. CDH1 gene mutations are frequently associated with HDGC and patients with this syndrome may benefit from genetic counseling.Ulmer et al. described a similar case to ours where previous gastric mucosal biopsies had been negative; however, a EUS-guided fine needle aspiration clinched the final diagnosis of metastatic lobular breast carcinoma causing gastric outlet obstruction . Of noteAlthough case reports of breast cancer metastasis causing GOO do exist in the literature, our case emphasizes the need to be diligent and thorough with a low threshold for EUS-guided biopsies if the initial endoscopic biopsy is inconclusive. This is critical in order to avoid delay in care for a patient with metastatic carcinoma."} +{"text": "Nursing homes that fostered open communication and teamwork were more likely to change their practices and adopt the \u201cIt\u2019s Not OK to Fall\u201d program. This pilot study evaluated the feasibility and acceptance of a team-building approach for developing leadership skills to three groups of coworkers: Administrators/Directors of Nursing, charge nurses, and certified nursing assistants (CNA) employed by nursing homes in Oklahoma. Each coworker group received one day of job specific leadership training, with another one half-day session where all levels engaged in team-building exercises. Participant satisfaction with course content ranged from agree-to-strongly agree. All stated that they could apply the leadership strategies at their facility. Administrators/Directors of Nursing found tools for tracking turnover/retention and strategies for improving staff communication helpful. Charge nurses and certified nursing assistants seldom viewed themselves as leaders, found coworker group communication very fragmented, and felt least knowledgeable about nursing home care best practices."} +{"text": "Widespread changes to the epigenome occur with aging. DNA methylation is one of the most commonly studied epigenetic mechanisms, reflects lifetime exposures that impact aging, and is associated with age-related disease risk. Many longitudinal cohort studies have existing cross-sectional or longitudinal DNA methylation data along with genotype and expression data permitting investigation of relationships between DNA methylation markers, exposures, and disease. The data can be leveraged to conduct large epigenome-wide association studies (EWAS) of aging and age-related disease to identify DNA methylation biomarkers and lead to insights into novel biologic pathways for development of interventions to delay aging. DNA methylation age measures robustly predict chronologic age and associate with both healthspan and lifespan. During the workshop, examples from cohort studies and the CHARGE consortium will be presented."} +{"text": "The Diverse Elders Coalition, in partnership with its six member organizations and the Benjamin Rose Institute on Aging, completed a national survey of 840 family and friend caregivers from diverse racial, ethnic, and sexual orientation communities to understand their unique caregiving issues and challenges. Data from a subsample of 404 caregivers identifying as Hispanic/Latino, Asian, Southeast Asian or from multiple ethnicities were examined to determine the relationship between difficulties performing culture-related care tasks and a variety of caregiver outcomes. Regression analysis controlling for background and context characteristics showed caregivers experiencing more culture-related task difficulties had significantly higher levels of several negative caregiving consequences, including health strain , relationship strain , work strain, isolation , and symptoms of depression . Moreover, higher levels of strain and depression among caregivers who reported high levels of culture-related task difficulties ranged from 26%-54%. More difficulties with culture-related tasks also were significantly related to dissatisfaction with support resources, including lower ratings of the quality of care receivers\u2019 healthcare , and lower satisfaction with support they and their care receivers received from family and friends . Results suggest caregivers from diverse communities struggling with culture-related tasks experience more negative consequences of caregiving and less helpful social support. Service providers working with caregivers from diverse communities should assess for culture-related task difficulties, recognizing these problems may be a window into a variety of adverse caregiving effects."} +{"text": "The 1.7 million older adults receiving long-term services often do not receive end of life care consistent with their wishes. Advance directives (ADs) can help, yet only one-third of Americans have completed ADs. The limited effectiveness of traditional interventions to increase AD completion may be because they do not address the behavioral aspects of advance care planning. Behavioral Design is an innovative approach that combines design thinking and behavioral economics to identify predictable behavioral bottlenecks and create real-time solutions. This study used Behavioral Design to address low AD completion rates of long-term care residents. Consistent with the Behavioral Design process, an interdisciplinary team compiled evidence from 10 diverse data sources to identify behavioral bottlenecks to AD completion. These barriers were analyzed using the cognitive bias codex to determine behavioral levers for intervention. Informed by these findings, the study team designed multicomponent interventions to address behavioral aspects of AD completion. Four behavioral bottlenecks incorporating ten behaviorally mediated causes for lack of AD completion were identified. For example, AD completion is affected by complexity mediated by hassle factor, choice overload, and ambiguity effect. Three interventions were designed to address these behaviorally mediated causes. For example, the intervention HeAD Start would provide a simple, easy to read AD (addressing choice overload) to residents upon admission (addressing hassle factor) with scheduled follow-up by trained staff (addressing ambiguity effect). Behavioral Design incorporates design thinking and leverages behavioral economic principles to create behaviorally mediated AD interventions. Next steps include testing behaviorally informed designs in practice."} +{"text": "Background and Objectives: The relationship between objective and subjective cognitive function and depressive symptoms is complex and potentially multidirectional. This longitudinal prospective study examined the directionality of their relationship among a community sample of older people with no known diagnosis or treatment for dementia or depression. Research Design and Methods: We examined the temporal relationship between objective cognitive functioning, subjective cognitive complaints, and depressive symptoms in 1,814 community-dwelling older people at baseline and one-year follow-up using regression and two-wave cross-lagged panel analyses, after controlling for demographic and health confounders. Results: Cross-lagged analysis showed that depressive symptoms at follow-up were directly predicted by baseline subjective cognitive complaints, but not baseline objective cognitive functioning. The effect differed across objective cognitive functioning levels. In people with clinically significant cognitive impairment at baseline, objective cognitive decline but not baseline subjective cognitive complaints predicted depressive symptoms. In people with mild objective cognitive impairment at baseline, baseline subjective complaints but not objective cognitive decline predicted depressive symptoms. Discussion and Implications: The effects of objective and subjective cognitive decline on depressive symptoms varied across older people with different levels of cognitive impairment. Awareness and insight of one\u2019s cognitive status may contribute to the development/progression in depressive symptom in people with mild cognitive impairment. Mechanisms unrelated to appraisal may be involved in increased depressive symptoms among older persons with significant objective cognitive impairment."} +{"text": "Background: Substance Use Disorder (SUD) and behavioral addictions are common and require a multidisciplinary approach. New technologies like Virtual Reality could have the potential to improve assessment and treatment of these disorders.Objective: In the present paper, we therefore present an overview of Virtual Reality (Head Mounted Devices) in the field of addiction medicine for craving assessment and treatment.Method: We conducted a systematic review by querying PubMed database for the titles of articles published up to March 2019 with the terms [virtual] AND [addictive] OR [addiction] OR [substance] OR [alcohol] OR [cocaine] OR [cannabis] OR [opioid] OR [tobacco] OR [nicotine] OR [methamphetamine] OR [gaming] OR [gambling].Results: We screened 319 abstracts and analyzed 37 articles, dividing them into two categories, the first for assessment of cue reactivity and the second for intervention, each drug being detailed within each category.Conclusions: This overview suggest that VR provide benefits in the assessment and treatment of substance use disorders and behavior addictions and achieve high levels of ecological validity. While, craving provocation in VR is effective across addiction disorders, treatments based exclusively on virtual exposure to drug related cues as shown heterogenous results. Substance Use Disorder (SUD) and behavioral addictions are prevalent in many countries , attention bias and drug seeking behaviors triggered by stimuli previously associated with drug use or cognitive behavioral therapy (CBT)-driven techniques applied in real time. VR may also facilitate the link between clinician and patients and improve our understanding of addictive behavior.Until recently, VR was limited by its cost and by the quality of the multimedia content. There has been a recent democratization of these systems concomitant with the video game industry's growing interest in this technology. Decreasing costs and increasing power are making it useful for performing an ecological assessment of cognition, emotions, and behavior in real-time.The purpose of this systematic review is to evaluate the usefulness and efficacy of immersive VR in cue reactivity assessment and craving management for patients undergoing SUD or behavioral addictions. To this end, the proposed systematic review will answer the following questions:- When compared to VR neutral stimuli, are VR cues able to elicit cue reactivity in adult patients suffering from addictive disorders? Is there an advantage of using VR cue reactivity over traditional cue reactivity methods?- Can VR be used as an effective tool for craving reduction compared to standard therapy in this aforementioned population?To identify appropriate resources and search for relevant evidence. We used a PICOS framework, to form a well-focused question and facilitate the literature search and the second for treatment, each drug being detailed within each category.See PRISMA diagram .A brief description of the concepts underlying virtual reality (VR) and cue features in the field of addiction is summarized in Studies and results described below are summarized in n = 465) assessed cue reactivity after virtual nicotine-related cues in adult smokers. Nicotine addiction criteria were reported in 13 studies, using DSM 4 in VR showed craving induction in adult smokers. Various cues were associated with craving induction.All studies investigating craving , complex cues were evaluated and often compared to other types of cues . All studies reported a significant increase of attentional bias compared to virtual neutral environments. Adding olfactory nicotine cues were surprisingly not associated with greater attention to cue in Traylor et al. or the Smoking Attention Scale (SAS) assessed cue reactivity after presentation of virtual alcohol-related cues in adults suffering from alcohol use disorder showed its induction after VR cue exposure suffering from cocaine use disorder (DSM-IV) Guze, assessedCraving induction through virtual cues has been demonstrated with contextual and complex environments compared to neutral virtual environments in cocaine-dependent subjects. Craving assessment was performed using single-item VAS. Situations triggering highest craving are those related to cocaine use and interactions with a dealer.Physiological reactivity was also measured. Heart rate increased in a manner comparable to craving in scenes of cocaine use and interaction with a dealer compared to neutral scenes. Besides, there was no change in skin conductance measurements between virtual neutral exposure or virtual cocaine-related exposure.n = 20) suffering from cannabis use disorder (DSM-IV) Guze, assessedBordnick et al. showed cIn this study were induced after exposure to a virtual and real slot machine environments in Bouchard et al. . Cravingn = 34) suffering from internet gaming disorder [DSM-5 . One VET trial was effective on craving and cigarette consumption reduction after 5 weekly sessions on 48 subjects with low to moderate nicotine dependence in association with a tobacco education group studied VCBT in nicotine addiction reduction in Korea evaluated virtual exposure therapy, including aversive exposure situations on alcohol craving reduction suggest that greater craving can be triggered by complex environments. Moreover, recent interest in proximal stimuli has emerged and new studies on other substance consumption behavior in virtual reality could further enrich the exposition realism.Social interaction with avatars can efficiently induce cravings for multiple substances, mainly assessed in cigarette smoking and alcohol studies. However, difficulties persist in separating social craving from context craving. Indeed, several questions remain regarding stimuli specification assessment in VR craving induction. A significant number of studies were exposed to carry over effect while a better understanding of craving stimuli characteristics could be obtained by using a two by two comparison protocols or by an effective carry over effect control .The lack of stimuli comparability resulting from the craving ceiling effect may have been increased by VAS widespread use by limiting the measurement to its intensity level, while a dimensional analysis of scales such as QSU could have revealed interesting qualitative differences (Rosenberg, in vivo scenarios. However, metanalyses report disappointing results (Mellentin et al., Traditional Cue Exposure Therapy studies' designs are mainly on substance-related cues detached from social environmental or In the future, attention to potential limits should be considered:Cost-effective studies are needed.Access to VR and therapists training need to be evaluated.Ethical considerations remain regarding the use of aversive exposures.Cybersickness could represent a threat to virtual reality usability and effectiveness and would also require integration in future studies (Gallagher and Ferr\u00e8, Patient's adherence should be accurately assessed before implementing aversion therapy in routine practice.Both positive and negative studies show numerous methodological biases: confusion bias due to the absence of control groups, selection bias due to the absence of randomization, attrition bias due to little intent to treat analysis, altogether indicating low internal validity and limiting the possibility of drawing clear conclusions.Future studies appear necessary and should evaluate dependence and abstinence maintenance as primary endpoint, offer more long-term follow-up, and include more control treatment groups to limit confusion bias.Efficacy of treatment based exclusively on virtual exposure to drug related cues appears to be limited, but interesting results point the great potential of implementing VR in CBT. Pericot-Valverde et al. shows hoDespite these limitations, VR has the potential to offer new opportunities for treatment through its ability to provide a more ecological environment with more control and safety over exposition. The ability to fine-tune environments composition according to patient's preferences and most relevant data makes it a future tool for personalized medicine.Because VR has the potential to be disruptive [for review (Freeman et al., Besides its acceptability, its accessibility also raises questions. It could be limited due to the lack of financial support. The populations suffering from substance disorders being frequently in situation of social precariousness. The question of the cost of VR will also have to be evaluated in order to consider its wide implementation in health centers.The studies presented in this review suggest that VR provide benefits in the assessment and treatment of substance use disorders, behavior addictions and achieve high levels of ecological validity. While, craving provocation in VR is effective across addiction disorders, treatments based exclusively on virtual exposure to drug related cues as shown heterogenous result. The addition of learning coping strategies in VRCBT studies are promising, however more rigorous methodological studies are warranted.The datasets generated for this study are available on request to the corresponding author.TS and TB screening and abstract analysis, both authors contributed equally to the writing. AB, SM, and FF conceptual framework, supervised development of work, helped in data interpretation and manuscript evaluation. C-SP and J-VB helped to evaluate and edit the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "To date, there is a dearth of interdisciplinary simulation education and research that involves LGBT older adults within schools of social work and nursing. The purpose of this mixed method study was to examine the use of an intervention among social work and nursing students to determine if lecture and simulations impacted their health-related knowledge and cultural sensitivity/awareness of health provisions with LGBT older adults. Interprofessional faculty created lecture and interdisciplinary simulations with actual members of the older LGBT communities using simulation clinic/lab and health care scenarios. An adapted survey with permission from Grubb et al (2013) was used to include quantitative and qualitative measures of cultural awareness with LGBT populations. Pre-Post test data were analyzed using Generalized Linear Models in SAS software. Results indicated that the intervention positively changed perceptions and increased knowledge among allied health students. Statistically significant change experiences in their work with LGBT individuals were noted to positively alter their beliefs about sexuality, gender identity, and sexual development =26.51, p<0.001). Qualitative findings include four primary themes about how gender identity and sexual orientation influences health: (a) bias of health care providers, (b) access to quality care, (c) specific health care needs, and (d) health risks of LGBT older adults. As older adults continue to be the largest population needing health care, it is imperative that professionals are trained to give culturally sensitive health care and demonstrate this competency in their practice and interpersonal interactions with clients."} +{"text": "Here we highlight two areas of research where multiple talks provided new insights. POLE/POLD1 mutations resulting in hypermutation and response to immune therapy. Imielinski\u2019s group presented 10 signatures that were based on the pattern of structural variation within tumors. The method utilized to generate SV signatures combined features derived from classic as well as motif-based patterns of structural variation. The expectation is that these patterns may also subsequently allow recognition of patterns that will implicate specific cancer treatments e.g. homology-directed repair deficiency and response to polyADP ribose polymerase (PARP) inhibition.In the Cancer and Medical Genomics session, Marcin Imielinski of the New York Genome Center highlighted the enormous complexity of structural rearrangements that can be found in individual cancer genomes. This complexity has challenged current genome presentations and Imielinksi described new tools for the generation of cancer genome graphs (gGraphs) and analysis of complex structural variation . Somatic mutation signatures based on single nucleotide variants (SNVs) have been previously described. Specific SNV signature patterns has provided insight to underlying genetic variation and, in some cases, these signatures identify tumors that may be responsive to specific cancer treatments, e.g. Similar to the focus on structural variation as opposed to SNV\u2019s in protein coding genes, there were a number of excellent talks defining variation in non-coding regions from genome sequencing datasets of different patient populations. Patrick Short from Matthew Hurles\u2019 group at the Wellcome Sanger Institute investigated the de novo mutation rate in regulatory elements using over 10,000 whole genome sequencing samples from the Deciphering Developmental Disorders (DDD) study and found that de novo mutations (DNMs) in these individuals are enriched within the ultra-conserved elements and these variants may contribute to 1\u20133% of subjects without a diagnostic finding. There was substantial overlap between DNMs identified in cohorts diagnosed with developmental delay and autism-spectrum disorders. To facilitate analysis of this type of non-coding variation dataset, the group is now developing a non-coding constraint metric .Taking a different approach based on gene expression, Pejman Mohammadi presented work utilizing allele-specific gene expression data to identify genetic regulatory outliers in a cohort of patients with muscular dystrophy using Analysis of Expression Variance- Dosage Outlier Test (ANEVA-DOT). These talks and a number of posters at the meeting illustrate our need to develop consistent ways to describe clinically relevant regulatory \u201cgrammar\u201d.The two keynote addresses provided new insights into chromosomal and chromatin regulation in normal and disease states. Wendy Bickmore (University of Edinburgh) described the role of regulatory variation in developmental genes in Mendelian diseases. Bickmore highlighted the central role of chromosomal decompaction in transcriptional regulation as mediated by PARP through phase separation or by Lmbr1 through chromosomal looping.In the second keynote address, David Page (Whitehead Institute) investigated overlapping sets of genes retained on sex chromosomes over the course of evolution from autosomes see Fig. . InteresWith regard to the \u201cBiology\u201d of genomes, several talks provided early results of elegant, yet massive, screens to better understand the biological and functional consequence of variation seen in either genomic disorders or cancer. Parisa Razaz from Michael Talkowski\u2019s lab at Massachusetts General Hospital modeled isogenic 16p11.2 reciprocal gene disorder using CRISPR mediated deletions and duplications in induced pluripotent stem cells (iPSCs) and mouse models. These models were then used to investigate gene expression differences and the genes which altered expression due to copy number change were enriched in genes expressed at early and late developmental stages and for genes within autism spectrum disorder risk pathways.Trey Ideker of University of California San Diego described findings from the Cancer Cell Map Initiative (CCMI) designed to generate large protein interaction maps of tumor cells. By integration of somatic RNA expression, whole genome sequencing, and enhancer-gene networks, his group identified 193 somatic eQTLs. Additionally, using hierarchical structured data from yeast, the team developed a deep neural network model (DCell) to predict mechanistic genotype-phenotype relationships giving useful insights into cell structure and function.BRCA1 based on CRISPR mediated saturation genome editing. The functional screen identified pathogenic missense variants in BRCA1 with high accuracy. The increasing use of CRISPR methodologies to facilitate large-scale genetic screens or assist functional assessment of thousands of possible variants within clinically relevant genes is expected to have a high impact on clinical interpretation of variants identified through genetic testing, particularly for rare variants where there is not sufficient patient and/or population related data to determine the pathogenicity of the variant.Sidi Chen of Yale University presented work from functional cancer genome atlas project that used in vivo AAV-CRISPR screen to reveal a functional map of frequently mutated driver genes in hepatocellular carcinoma and glioblastomas. Gregory Findlay from Jay Shendure\u2019s laboratory at the University of Washington described functional classification of nearly all possible SNVs in functional domains of"} +{"text": "Most individuals with dementia are undiagnosed or they/their families are unaware of the diagnosis. Implications of dementia diagnosis and awareness are poorly understood. Our objective was to determine whether undiagnosed dementia or unawareness increases risk of hospitalization or emergency department (ED) visits, outcomes with recognized risk in diagnosed dementia. We linked National Health and Aging Trends Study (NHATS) data to fee-for-service Medicare claims for 4,311 community-living participants in the nationally representative cohort. We assessed probable versus no dementia using validated NHATS dementia criteria, undiagnosed versus diagnosed using Medicare claims, and aware versus unaware using NHATS self or proxy report of diagnosis. Cox proportional hazards models evaluated hospitalization and ED visit risk by time-varying dementia diagnosis and awareness status, adjusting for sociodemographic characteristics, functional impairment, medical comorbidities, and prior hospitalization. Compared to no dementia, persons with dementia who were unaware but diagnosed had greater risk of hospitalization and ED visits . Persons unaware but diagnosed also had greater risk compared to persons aware and diagnosed . Persons with undiagnosed dementia demonstrated hospitalization risk similar to persons with no dementia and similar or potentially lower than persons aware and diagnosed ; ED visit findings were similar. Results suggest that being unaware of dementia diagnosis may affect healthcare utilization. Strategies to improve communication and understanding of dementia could potentially reduce hospitalizations and ED visits."} +{"text": "Persons living with dementia-related disorders (PwD) can experience challenging behavioural and psychological symptoms (BPSD) as their illness progresses. There is a continued reliance on antipsychotic drugs (APD) in long-term care to manage this issue despite the well-documented risks of adverse events and increased morbidity and mortality. This study examines the role of culture of care in relation to efforts at reducing inappropriate APD use in managing BPSD within long-term care. Culture of care consists of shared norms, beliefs, and cognitive frames which guide clinical practice and inform the development and implementation of care strategies. Findings were obtained from three Canadian long-term care facilities working on reducing inappropriate use of APD. Data came from interviews with 6 nurses, 18 licenced practical nurses, 14 health care assistants, 4 activity leaders, 4 directors of care, 1 chaplain, and 10 physicians. We found that direct care providers initially varied in their perceived ability to develop and use alternate care strategies with health care assistants being most concerned about safety and exposure to violence. Change involved detective work and innovative thinking in assessing possible causes of BPSD beyond psychosis, including pain and feelings of confusion. Informal reciprocal patterns of communication emerged among health care assistants to identify effective non-pharmaceutical strategies to manage BPSD. Overall, the study shows how shared beliefs in the need for and value of alternate care practices among direct care providers along with the existence of effective informal communication can contribute to successful reduction in APD use when managing BPSD in PwD."} +{"text": "In a post hoc study of the multicenter FINNAKI trial, Tverring et al. recently reported that measuring heparin-binding protein (HBP) on admission in the intensive care unit (ICU) improved prediction of sepsis-induced acute kidney injury (AKI). In addition, high plasma HBP levels were associated with a significantly higher fluid balance within 24\u00a0h, more organ failure within the first week, and increased 28-day mortality . These oHBP is stored in azurophilic granules and secretory vesicles of neutrophils and is quickly and abundantly secreted when neutrophils are activated and mobilized. Once released, HBP displays a strong proinflammatory activity. In the blood stream, HBP chemoattracts and activates more neutrophils but also T-lymphocytes and monocytes. Binding of HBP to \u03b22-integrins of monocytic cells initiates intracellular signaling processes which evoke a release of chemokines and proinflammatory mediators . SheddinHBP proved to be a valuable diagnostic marker in suspected sepsis and demoDevelopment and progression of sepsis-related AKI are determined by endothelial leakage, renal tubular cell inflammation, and an adaptive cell-cycle shutdown effect . These iTargeting HBP modulatory effects in sepsis could prove therapeutically useful. Either preventing HBP receptor binding or HBP release from neutrophils are theoretically attractive options. However, evidence that decreasing HBP plasma levels would improve global or renal outcome is still scarce. Moreover, a specific receptor for HBP has not been identified and unselective blocking of crucial immunologic effects of frontline neutrophils may expose patients to unexpected or unwanted side effects. HBP is highly positively charged and thus can be neutralized by negatively charged molecules such as heparin and colloid solutions. Unfractionated and low molecular weight heparin block HBP-induced endothelial cell permeability and rena"} +{"text": "Ficedula hypoleuca, collects information about nest predation risk from indirect cues of predators visiting nests of heterospecific birds. Furthermore, we investigated whether the migratory birds can associate such information with a specific nest site characteristic and generalize the information to their own nest site choice.Breeding site choice constitutes an important part of the species niche. Nest predation affects breeding site choice, and has been suggested to drive niche segregation and local coexistence of species. Interspecific social information use may, in turn, result in copying or rejection of heterospecific niche characteristics and thus affect realized niche overlap between species. We tested experimentally whether a migratory bird, the pied flycatcher Our results demonstrate that flycatchers can use the fate of heterospecific nesting attempts in their own nest site choice, but do so selectively. Young flycatcher females, when making the decision quickly, associated the fate of an artificial nest with nest-site characteristics and avoided the characteristic associated with higher nest predation risk.Copying nest site choices of successful heterospecifics, and avoiding choices which led to failed attempts, may amplify or counter effects of nest predation on niche overlap, with important consequences for between-species niche divergence-convergence dynamics, species coexistence and predator-prey interactions.The online version of this article (10.1186/s12862-018-1301-3) contains supplementary material, which is available to authorized users. The niche concept is a central tenet in the theory of species coexistence and community ecology, stating that two species cannot coexist without adequate niche differences \u20134. One iBreeding site choice driven by varying nest predation pressure has been shown to be an important mechanism affecting species coexistence \u20137. This Direct observations of often stealthy, widely ranging and quickly moving nest predators are relatively rare events for an observer, and therefore offer little information for decision-making. Encounters with nest predators may also threaten the observer itself e.g. , 15). Ye. Ye15]).and convergence of realized niches, and both could conceivably be amplified by social information use. Resulting dynamics can be complex, scale-sensitive, and highly dependent on local conditions and community composition.Heterospecific social information use is expected to be most useful between ecologically similar species , in thisFicedula hypoleuca), collects information about nest predation risk from indirect cues of predators visiting nests of a heterospecific resident bird, the great tit (Parus major). We then investigated whether the migratory bird can associate such information with a specific nest site characteristic, are able to generalize the perceived information and use it in guiding their own nest-site choice. Great tits and flycatchers are putative competitors )This study demonstrates that birds i) can detect indirect cues of predation risk from observing heterospecifics nesting attempts and ii) can associate nesting site characteristics with that predation risk infromation and iii) can \u2013 but only conditionally do \u2013 develop preference for \u201csafer\u201d characteristics in their own nest site choice. Such interspecific social information use in relation to nest predation risk may affect realized niche dynamics among coexisting species with important implications for species coexistence and community dynamics. These findings also add to the accumulating evidence of between-individual variation in social information use patterns; both due to age-related differences and also due to within-age-group variation. Given the substantial potential of individual level variation in behaviour to affect key ecological and demographic processes, also including species coexistence and community ecology and evolution \u201357, we sAdditional file 1:The data set supporting the article. (XLSX 16 kb)"} +{"text": "Cigarette smoking and nicotine dependence commonly co-occur with alcohol dependence. However, treatment for tobacco dependence is not routinely included in alcohol treatment programs, largely because of concerns that addressing both addictions concurrently would be too difficult for patients and would adversely affect recovery from alcoholism. To the contrary, research shows that smoking cessation does not disrupt alcohol abstinence and may actually enhance the likelihood of longer-term sobriety. Smokers in alcohol treatment or recovery face particular challenges regarding smoking cessation. Researchers and clinicians should take these circumstances into account when determining how best to treat these patients\u2019 tobacco dependence. Cigarette smoking and alcohol dependence co-occur at high rates. Research indicates that approximately 80 percent of people with alcoholism smoke cigarettes and that most of these smokers are nicotine dependent . ConversDespite the fact that 60 to 75 percent of patients in alcoholism treatment are tobacco dependent and about 40 to 50 percent are heavy smokers , treatmeSmoking is more benign than alcoholism. The short-term effects of alcoholism may appear more dangerous than those of cigarette smoking. However, mortality statistics suggest that more people with alcoholism die from smoking-related diseases than from alcohol- related diseases . In addicf.cf.Smokers with comorbid alcoholism have either no interest or no ability to quit smoking. It is interesting to note that although addiction treatment programs routinely address multiple substances of addiction , tobacco is frequently the sole excluded substance. The scientific literature also frequently describes treatment of multiple nontobacco substances simultaneously, making it difficult to evaluate the impact of smoking cessation on alcoholism treatment per se cf.. Still, Inclusion of smoking as a target for intervention does not appear to reduce patients\u2019 commitment to broader addiction treatment. For example, incorporating smoking cessation treatment into inpatient addiction treatment centers has not substantially reduced longterm treatment completion . In addicf.Evidence suggests that a history of alcohol use difficulties may not impede a specific smoking cessation attempt, though it does seem to reduce the likelihood of quitting smoking during one\u2019s lifetime . ResearcMyth: Smoking is more benign than alcoholism.More people with alcoholism die from smoking-related diseases than from alcohol-related illness .Comorbid smoking and alcoholism result in synergistic exacerbation of health risks .Myth: Smokers with comorbid alcoholism have either no interest or no ability to quit smoking.cf.The majority (up to 80 percent) of individuals in addiction treatment are interested in quitting smoking cf..Inclusion of smoking cessation treatment into other addiction programs does not negatively affect rates of treatment completion or motivation for abstinence that patients must choose between abstinence from cigarettes and abstinence from alcohol. In contrast to this concern, research suggests that treating tobacco dependence within broader addiction programs does not adversely influence recovery from alcoholism (or illicit substances). Although not universal e.g., , the majThe mechanisms of action responsible for the potential benefits of smoking cessation interventions provided during alcoholism treatment remain largely unexplored. However, possible explanatory factors may include greater clinical contact time, reduced exposure to substance use cues, relapse prevention and/or coping skills practice, increased mastery or self-efficacy, and broader healthy lifestyle choices . Self-inAlcohol-dependent patients who quit smoking while in recovery from alcohol problems also do so without negative consequences to their alcohol or drug abstinence . Data suNot only does the preponderance of evidence suggest that smoking cessation does not compromise alcohol abstinence, but multiple studies indirectly suggest that continued smoking may place alcohol-dependent smokers at risk for alcohol relapse . These dUnfortunately, even with today\u2019s best interventions for tobacco cessation, smokers in alcohol treatment or recovery face particular challenges to their cessation efforts. On average, compared with smokers who do not abuse substances, alcoholic smokers are more addicted to nicotine, smoke higher nicotine cigarettes, smoke more per day, and score higher on nicotine dependence measures and on carbon monoxide assessment . Many smDespite concerns to the contrary, the majority of empirical evidence indicates that smoking cessation does not pose a risk to successful alcoholism treatment. Not only does smoking cessation not disrupt alcohol abstinence, it actually may enhance the likelihood of longer-term sobriety. Although research has yet to determine the extent to which smoking cessation is impeded by active alcohol use difficulties, the presence of these difficulties does not prohibit achievement of tobacco abstinence. Given the substantial negative health consequences of co-occurring cigarette smoking and alcoholism, smoking cessation efforts in the context of treatment for alcoholism are likely to yield important benefits to patients physically, emotionally, socially, and economically."} +{"text": "Radiofrequency (RF) wire recanalization of short segments of central venous obstruction has been considered safe; however its use for recanalization of long segments of inferior vena cava (IVC) has not been reported.A 55-year-old female with recurrent massive hematemesis was found to have systemic venous upper esophageal varices on endoscopy and an extensive chronic IVC occlusion on CT. Using both a percutaneous transhepatic and transfemoral approach IVC recanalization was performed. A snare was advanced to the cavo-atrial junction via transhepatic venous access. From the groin utilizing RF wire steerable guide sheaths, endovascular reconstruction of the IVC was performed. Post recanalization venography demonstrated patent stented IVC and marked decrease in the intraabdominal-pelvic collaterals. No recurrence of hematemesis was noted. After 6 months, patient remained asymptomatic and had functioning right femoral arteriovenous hemodialysis graft.Using appropriate techniques, Power wire recanalization of long occlusive segments of IVC can be safe and effective. Recanalization of central venous obstruction with RF wire has been considered safe and effective based on outcomes of prior reports (Guimaraes et al., The patient is a 55-yo-female with past medical history of end stage renal failure on hemodialysis with chronic SVC and IVC occlusions from prior hemodialysis accesses. She also had a history of chronic pancreatitis, coronary artery disease. She presented with recurrent massive episodes of hematemesis. Upper GI endoscopy 3showed varices only in the upper esophagus but none in the lower esophagus. The patient did not have liver disease. Cross sectional imaging at that time revealed extensive IVC occlusion Fig. and multOne month later, the patient returned for follow up venography, which demonstrated widely patent stented IVC and removal of the transhepatic permcath Fig. . NephrolRF wire recanalization has been successfully used to treat pulmonary atresia, to create atrial septal perforation, to recanalize completely occluded thoracic aorta and to recanalize chronic or malignant central venous obstructions after failure of conventional endovascular techniques (Guimaraes et al., In order to safeguard neighboring critical structures, we used following techniques. We placed indicator VCF-1 catheter in the aorta and constantly monitored Power wire tip to avoid deviation towards periaortic area. Unpredictable movement of the RF wire tip was a major concern while crossing long occlusive segment in caudal to cranial direction, especially when the flexible tip moves away from the power generator towards the beating heart. Use of steerable sheath allowed us to have better control of RF wire tip. Also by placing a 25\u00a0mm snare tip at the IVC-atrial junction, Power wire trajectory was given a precise target.Due to easy penetrability of heated tip of RF wire, prior studies used techniques such as short duration of RF energy delivery and very small advancements of RF wire tip (Guimaraes et al., Multiple cranial and/or femoral access approaches have been reported in the literature to treat chronic complex central venous occlusions (Massmann et al.,"} +{"text": "The choices we make can have long-lasting effects on our health. Repetitive stress; diet; use of cigarettes, drugs, or alcohol; and work-related exposure to environmental toxins often exhibit no immediate effects. Symptoms can appear later on, sometimes many decades later, making it challenging to assign specific blame to behaviors that occurred in the past.Drosophila melanogaster males is caused by an early spermatogenesis arrest. Instead of proceeding through development normally, precursor germline and somatic cells accumulate as immature progenitors, causing a nearly complete block in spermatogenesis. Through careful investigation, the authors discovered that continuous mating causes developmental arrest indirectly, via induction of inflammation signals in the muscle sheath that surrounds the testes. Thus, it appears that muscle exhaustion or mating-associated muscle damage impacts cell fate determination nonautonomously.Most impactful are behaviors that cause irreversible changes to impair tissue function. The paper by Yi-Chieh Chang and colleagues describeGamete quality is paramount for maintenance of species, with multiple mechanisms contributing to age-associated fertility arrest . The besChang and colleagues focus on the effects of aging on the non-self-renewing daughters of GSCs and CySCs . Reciprodpp by poorly differentiated cyst cells blocks germ cell differentiation. However, reducing dpp expression has no effect on accumulation of poorly differentiated cyst cells, indicating that a previously undiscovered mechanism must regulate cyst cell differentiation.Numerous studies have demonstrated the critical role of transforming growth factor beta (TGF\u03b2) signaling in promoting GSC and CySC self-renewal by blocking differentiation . The autUsing clever deductive reasoning, Chang and colleagues determined that c-Jun N-terminal kinase (JNK) activity within cyst cells blocks their differentiation. They narrowed down the source of the JNK activating ligand to the muscle sheath surrounding the testes, finding that the tumor necrosis factor (TNF) ligand Eiger is both necessary and sufficient to inhibit cyst cell differentiation via JNK activation. The data support the model that excess muscle use leads to increasing Eiger production with age, with receipt of the signal by the TNF receptor Grindelwald on the cyst cell surface triggering JNK activity and the resulting differentiation block.For years, scientists have noted the inverse impact of reproduction on fertility. This study defines a novel mechanism in which inflammatory signals in tissue-associated muscle prevent gamete production, resulting in fertility arrest. The results are congruous with the disposable soma theory, in which the germline is protected at the expense of the soma . In thisWhy does this mechanism exist? One idea is that fertility arrest occurs because of increasing genetic mutations over time, resulting in gamete defects and unsuccessful reproduction. However, Chang and colleagues show that aged, never-mated males produce differentiated sperm and can productively mate to produce progeny. This calls into question the idea that passive mutation accumulation over time is the key mechanism driving fertility arrest. Perhaps TNF produced by damaged muscle induces mutations in developing germ cells. Eiger is expressed throughout the entire muscle sheath surrounding the testes in continuously mated males , suggest"} +{"text": "Recently published article by Pieri\u2019s group suggested that follicle-stimulating hormone (FSH) activates canine testicular spermatogonial stem cells (SSCs) and results in increased expression of pluripotent markers and formation of germ cell clumps possibly via indirect paracrine effect of Sertoli cells. We disagree with their interpretations and herewith provide a better explanation to their findings. We have earlier reported the presence of pluripotent, very small embryonic-like stem cells (VSELs) as a sub-group among the SSCs in human and mouse testes and that both VSELs and SSCs express FSH receptors. Thus, FSH exerts a direct stimulatory action on the testicular stem/progenitor cells whereby VSELs undergo asymmetrical cell divisions to self-renew (result in upregulation of pluripotent markers) and give rise to slightly bigger SSCs which undergo symmetrical cell divisions and \u201cclonal expansion\u201d (rapid proliferation with incomplete cytokinesis) which was noted by the authors as \u201cclump\u201d formation. This action of FSH is mediated via alternately spliced FSHR3 rather than the canonical FSHR1 receptor isoform, and FSH exerts similar action on ovarian and uterine stem/progenitor cells also. Being quiescent by nature, VSELs survive chemotherapy. Transplanted germ cells colonize chemoablated tubules but do not differentiate into sperm since the testicular stem cell niche comprising Sertoli cells gets functionally compromised by chemotherapy. Transplanting healthy niche cells can restore spermatogenesis in chemoablated testes. Pieri et al. have pubTestis harbors OCT-4-positive pluripotent stem cells in addition to SSCs: We have reported that both adult human and mouse testicular stem cells include a sub-group of pluripotent stem cells termed very small embryonic-like stem cells (VSELs) along with SSCs [ith SSCs \u20134. VSELsith SSCs , 5 and aith SSCs and endoith SSCs similar Effect of FSH on stem cells in adult mammalian testis: FSH treatment upregulated pluripotent markers in the testis. We have reported an increase in pluripotent OCT-4-positive stem cells after FSH treatment in mouse testis, ovaries, and uterus [d uterus \u20134, 7. InFSH stimulates SSCs to expand and form clumps or \u201ccolonies\u201d: FSH activated the SSCs to undergo proliferation resulting in a clump formation, with paracrine influence by the Sertoli cells as suggested by the authors. Rather, the testicular stem cells including VSELs and SSCs express FSHR, and FSH has a direct effect as reported for the first time in the literature by our group for both the testis [e testis and ovare testis . We havee testis . Similare testis . Pluripoe testis , 8, 9.Transplanted SSCs colonize and expand in response to FSH but fail to differentiate in chemoablated mouse testis: This needs to be clearly understood. We have reported that VSELs survive chemotherapy whereas the Sertoli cells get functionally compromised. The authors observed long-term survival and colonization of cSSCs in chemoablated mouse testis, but they did not differentiate since Sertoli cells become non-functional as a result of chemotherapy. Transplantation of mesenchymal cells directly in the chemoablated testis (not intratubular route through the rete testis) helped to achieve differentiation since they provided an improved paracrine support to the surviving VSELs to restore spermatogenesis [ogenesis , 10.Both bone marrow and testicular VSELs when cultured on a Sertoli cell bed and in the presence of Sertoli cell-conditioned medium differentiate into germ cells and sperm .The purpose to write this commentary is because major interpretations and conclusions reported by Pieri\u2019s group need to be re-examined. Their findings are correct but still lack clarity on the role of FSH in adult testis that needs to be understood in proper perspective. We would like to discuss several facets of our findings to provide a novel understanding of the role of FSH on adult testicular stem cells.To conclude, FSH action is not limited to only the ovary and testis, and besides Sertoli and granulosa cells, it exerts a direct action on the stem cells to undergo self-renewal and clonal expansion. Alternately spliced FSH receptor isoform biology needs to be studied in greater details, and one needs to acknowledge both the stem cells and their niche to ensure regeneration of chemoablated testis."} +{"text": "Adenocarcinomas account for approximately 40% of small bowel cancers. They are typically mucosal lesions with distinctive features on endoscopy. We describe a rare case of duodenal adenocarcinoma presenting as a subepithelial lesion which posed a diagnostic challenge. An 85-year-old male patient presented for investigation of iron deficiency anaemia. Initial upper endoscopy found a subepithelial duodenal lesion with central depression but otherwise normal appearing mucosa. Superficial biopsies of the duodenal lesion were unremarkable. Subsequent antegrade single balloon enteroscopy revealed active bleeding from the lesion which was refractory to endoscopic treatment. A complete local excision of the lesion via laparotomy was necessary to achieve haemostasis. Histopathology from the lesion showed a moderately differentiated duodenal adenocarcinoma with invasion into the submucosa but no evidence of lymphovascular spread. Duodenal adenocarcinomas are rare gastrointestinal tumours associated with a poor prognosis. This case report outlines a rare presentation of duodenal adenocarcinoma and highlights the importance of judicious assessment of lesions found on endoscopy. Advances in endoscopic diagnostic modalities could facilitate early diagnosis and improve therapeutic outcomes. Adenocarcinomas account for 40% of cancers in the small intestine and the most common site of involvement is the duodenum . They arAn 85-year-old male patient was referred for investigation of iron deficiency anaemia. His comorbidities included ischemic heart disease and localized prostate cancer with previous transurethral resection (TURP) and external beam radiotherapy (EBRT). Gastroscopy found the presence of two Forrest grade III antral ulcers which were biopsied. Histopathology from the gastric antral biopsies showed moderate chronic gastritis and focal intestinal metaplasia. His colonoscopy was unremarkable. CT abdomen pelvis with oral and intravenous contrast did not find a source of bleeding, evidence bowel obstruction or mural thickening suspicious for malignancy. He subsequently underwent capsule endoscopy for investigation of occult gastrointestinal bleeding which found a non-bleeding lesion in the duodenum. Antegrade single balloon enteroscopy again identified the 1.5\u2009cm polypoid, subepithelial lesion in the lateral wall of the second part of the duodenum, distal to the major papilla. The lesion had central depression and minor ulceration but otherwise normal appearing mucosa on endoscopy . Initialth edition, Stage I, T1bN0M0) has demonstrated utility in the assessment of subepithelial lesions found on endoscopy. It provides a minimally invasive method of acquiring tumour characteristics such as size, layer of infiltration, and the presence of local lymphadenopathy which holds prognostic value and guides the use of biopsy techniques. EUS itself can be combined with fine needle aspiration (EUS-FNA) and fine needle biopsy (EUS-FNB) techniques for the sampling of lesions arising from the submucosa and muscularis propria . EUS-FNBThe treatment approach for duodenal adenocarcinoma differs from that of other subepithelial lesions in the small bowel. The American Society of Gastrointestinal Endoscopy (ASGE) outlines an approach for the management of subepithelial lesions, which takes into account histological features, size, layers involved, distal spread, symptomatology, and other patient factors . EndoscoAlthough rare, there have been previous reports of duodenal adenocarcinoma presenting as a subepithelial lesion. Kojima et al. reported this presentation in a 63-year-old female patient undergoing investigation for epigastric pain . The lesThis case report describes an unusual presentation of duodenal adenocarcinoma as a subepithelial lesion with initially unremarkable superficial biopsies. The diagnosis was only made retrospectively following complete excision of the lesion. The failure of initial biopsies to successfully diagnose the underlying lesion exposes the limitations of current techniques in the sampling of subepithelial lesions not accessible via endoscopic ultrasound. Improvements in endoscopic modalities for the assessment of subepithelial lesions could facilitate early diagnosis and improve therapeutic outcomes."} +{"text": "Although metabolic alterations are one of the hallmarks of cancer, there is a lack of understanding of how metabolic landscape is reconstituted according to cancer progression and which genetic alterations underlie its heterogeneity within cancer cells. Here, the configuration of the metabolic landscape according to genetic alteration is examined across 7648 subjects representing 29 cancers. The metabolic landscape and its reconfiguration according to the accumulated mutation maintained characteristics of their tissue of origin. However, there were some common patterns across cancers in terms of the association with cancer progression. Carbohydrate and pyrimidine metabolism showed the highest positive correlation with tumor metabolic burden and they were also common poor prognostic pathways in several cancer types. We additionally examined whether genetic alterations associated with the heterogeneity of metabolic landscape. Genetic alterations associated with each metabolic pathway differed between cancers, however, they were a part of cancer drivers in most cancer types.The online version of this article (10.1186/s12943-018-0895-9) contains supplementary material, which is available to authorized users. Cancer cells reorganize their metabolism to fulfill their biosynthetic requirements for tumor growth and proliferation . BesidesHere, we aim to investigate the metabolic landscape of multiple cancer types and its configuration according to the progression. We also aim to find answers for whether there are common features in genetic alterations related to the metabolic landscape across cancer types. An integrated analysis of genomic and transcriptomic profiles of 29 different solid cancers was performed. We demonstrate that some common metabolic pathways exhibit the close relationship with TMB and clinical outcome across several cancer types. We also show that genetic alterations associated with cancer metabolic heterogeneity were a part of cancer drivers in most cancer types.We compared the median values of metabolic signatures manually curated considering cancer-related pathways for each cancer type . Of note, glycolysis, the well-known cancer metabolic feature, showed relatively weak correlation with TMB. LUSC showed the highest carbohydrate metabolism and TMB among 29 cancer types . In general, carbohydrate and nucleotide metabolism were associated with poor prognosis. Specifically, poor prognostic metabolic signatures include carbohydrate metabolism, ribonucleotide synthesis, pyrimidine metabolism, purine metabolism, and glycolysis, whereas good prognostic signatures include peroxisomal lipid metabolism, fatty acid oxidation, and biological oxidation.Several metabolic signatures were associated with overall survival across all cancer samples were included in cancer drivers Fig. . In otheAccording to the results, cancer transcripts and protein networks consisting of metabolic pathways may be changed by cancer drivers instead of alterations of genes participated in the networks. It corresponds to the Darwinian selection of cancer cells which carry driver mutations facilitate cellular survival and growth by changing a favorable metabolic landscape . The reshttps://choih.shinyapps.io/metabolicsignatures) according to cancer type and its reconstitution according to cancer progression can contribute to developing appropriate diagnostics and therapeutics targeting metabolism for cancer subtypes.Among several metabolic signatures, carbohydrate metabolism representing overall nutrient demand and nucleotide metabolism showed the closest association with TMB and clinical outcome. Genetic alterations closely associated with metabolic heterogeneity were a part of cancer drivers in most cancers rather than genes affiliated to metabolic pathways. It supports the role of cancer drivers in the evolution process in constituting metabolic landscape appropriate for tumor growth. Our database of the metabolic landscape"} +{"text": "Television viewing is a risk factor for poor physical and cognitive health. Yet, we know little about associations between current health and frequency of television viewing throughout the day. This study examined associations between multiple assessments of physical and cognitive well-being and television viewing. Participants (N = 313) from the Daily Experiences and Well-being Study completed an initial interview assessing their health and well-being. They also wore an Electronically Activated Recorders (EAR) to capture sound in the environment and an Actical to measure physical activity for 5 days. Coders rated the audiofiles for television viewing. Multilevel models revealed that participants who spent a greater proportion of time tuned into television had: higher BMI, poorer health, expended less energy, were more sedentary, and reported drinking more alcohol and eating more junk food. We discuss findings with regard to potential reciprocal influences between television viewing and poor health."} +{"text": "Reperfusion injury follows ischemia/reperfusion events occurring during myocardial infarction, stroke, embolism, and other peripheral vascular diseases. Decreased blood flow and reduced oxygen tension during ischemic episodes activate cellular pathways that upregulate pro-inflammatory signaling and promote oxidant generation. Reperfusion after ischemia recruits inflammatory cells to the vascular wall, further exacerbating oxidant production and ultimately resulting in cell death, tissue injury, and organ dysfunction. Diving mammals tolerate repetitive episodes of peripheral ischemia/reperfusion as part of the cardiovascular adjustments supporting long duration dives. These adjustments allow marine mammals to optimize the use of their body oxygen stores while diving but can result in selectively reduced perfusion to peripheral tissues. Remarkably, diving mammals show no apparent detrimental effects associated with these ischemia/reperfusion events. Here, we review the current knowledge regarding the strategies marine mammals use to suppress inflammation and cope with oxidant generation potentially derived from diving-induced ischemia/reperfusion. The ability to manage body oxygen stores in the face of environmental hypoxia constrains the life history of many vertebrate taxa. In humans, oxygen management is critically important in clinical settings where both acute and chronic conditions such as organ transplantation and intermittent hypoxia contribute to ischemic injuries. Diving mammals, however, experience fluctuations in blood flow and oxygen saturation without sustaining such injuries. A range of physiological mechanisms for coping with finite oxygen availability has been identified to date is considered the master regulator of the molecular response to hypoxia across taxa . Functiop apneas . MoreoveRecent phylogenomic studies have begun to uncover additional molecular mechanisms underpinning ischemia/reperfusion tolerance in marine mammals, including the expansion and positive selection of several gene families related to oxidative stress tolerance and oxygen management. Most work has considered cetacean species; pinniped genomes have generally been less available. In strong agreement with the current physiological understanding of antioxidants in both cetaceans and pinnipeds, several genes in the glutathione system \u2013 including glutathione reductase, glutathione peroxidases, and \u03b3-glutamylcysteine ligase \u2013 are expanded, under positive selection, and/or have amino acid changes in cetaceans . Two perManaging body oxygen stores and tissue oxygen supply while diving is of paramount importance for marine mammals. Hemoglobin and myoglobin are central to this process; both are under positive selection in cetaceans . In the ex vivo systems that are amenable to physiological manipulation and molecular perturbation in an effort to provide the missing link between genomic- and organismal-level investigations. Identifying the drivers of ischemic and hypoxemic tolerance in marine mammals can provide a mechanistic understanding of natural tolerance to such conditions while aiding in translation to clinical applications.Marine mammals experience diving-induced hypoxemia and ischemia/reperfusion events without apparent detrimental effects. Physiological, biochemical, and genomic studies have begun to uncover the mechanisms underlying such extreme tolerance. Among those mechanisms, coordinated body-wide responses to delay the onset of tissue hypoxia, counteract oxidant generation and prevent inflammation are critical. Convergent genomic changes across marine mammal lineages hint at the evolutionary underpinnings of the physiological adaptations supporting mammalian diving . The incKA and JV-M wrote and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Adults who remain cognitively active may be protected from age-associated changes in white matter (WM) and cognitive decline. To determine if cognitive activity is a precursor for WM plasticity, the available literature was systematically searched for Region of Interest (ROI) and whole-brain studies assessing the efficacy of cognitive training (CT) on WM microstructure using Diffusion Tensor Imaging (DTI) in healthy adults (> 40 years). Seven studies were identified and included in this review. Results suggest there are beneficial effects to WM microstructure after CT in frontal and medial brain regions, with some studies showing improved performance in cognitive outcomes. Benefits of CT were shown to be protective against age-related WM microstructure decline by either maintaining or improving WM after training. These results have implications for determining the capacity for training-dependent WM plasticity in older adults and whether CT can be utilised to prevent age-associated cognitive decline. Additional studies with standardised training and imaging protocols are needed to confirm these outcomes."} +{"text": "Papio ursinus) and assesses their relative importance. Our results show that oestrous females initiate fewer copulations in the presence of adult male bystanders, irrespective of whether they are mate-guarded or not. This inhibitory effect probably reflects a response to indirect sexual coercion by males, whose close proximity may dissuade females to initiate copulations with rival males to avoid punishment and/or aggressive mating interference. By contrast, females initiate more matings with their mate-guard in the presence of higher-ranking female bystanders, which may reflect an attempt to secure bodyguard services from their mate when they feel threatened. These results emphasize the importance of intra- and intersexual conflicts in shaping female sexual behaviour in this promiscuous society.In social species, female mating strategies can be constrained by both male and female groupmates through sexual conflict and reproductive competition, respectively. This study tests if females adjust their sexual behaviour according to the presence of male and female bystanders in wild chacma baboons ( For example, dominant females often harass other females and interfere with their mating attempts, and monopolize resources that are necessary to breed, such as shelters, mates or offspring care . SimilarTheropithecus gelada) )"} +{"text": "The combination of aging and losing an only adult child challenges an increasing number of older adults in China. Current literature primarily focuses on older parents\u2019 bereavement but seldom examines how they restore their lives. Guided by the Dual Process Model, this study explores how older parents who lost their only adult child restore their lives and prepare for future care in Shanghai. Twenty-four older adults were purposively sampled and participated in face-to-face, in-depth interviews. The findings suggest that participants tried to restore their lives by rationalizing grief and expanding their social networks. Despite their losses, participants remained in favor of family caregiving and reluctantly prepared for future care. They showed ambivalent attitudes toward current government support while proposing their preferred services. This study informs social work practice to incorporate caregiving plan services and emotional support for this vulnerable group."} +{"text": "The current achievements in treating glioblastoma (GBM) patients are not sufficient because many challenges exist, such as tumor heterogeneity, the blood brain barrier, glioma stem cells, drug efflux pumps and DNA damage repair mechanisms. Drug combination therapies have shown increasing benefits against those challenges. With the help of nanocarriers, enhancement of the efficacy and safety could be gained using synergistic combinations of different therapeutic agents. In this review, we will discuss the major issues for GBM treatment, the rationales of drug combinations with or without nanocarriers and the principle of enhanced permeability and retention effect involved in nanomedicine-based tumor targeting and promising nanodiagnostics or -therapeutics. We will also summarize the recent progress and discuss the clinical perspectives of nanocarrier-based combination therapies. The goal of this article was to provide better understanding and key considerations to develop new nanomedicine combinations and nanotheranostics options to fight against GBM. GBM therapeutics need to be able to cross this barrier and penetrate the brain to reach the tumor. However, only small lipophilic chemotherapeutic agents with a molecular weight less 400 Da and 8 hydrogen bonds can passively pass through the BBB The blood brain barrier (BBB) is a particularly formidable challenge in developing therapeutics for brain tumors. Brain microvascular endothelial cells, pericytes, astrocytes, tight junctions, neurons and the basement membrane together form a physical barrier to protect the brain and maintain a well-defined intracranial environment Another difficulty is found in the heterogeneity of GBM. Genomic research has shown that GBM contains many different cell types depending on their origin or subsequent genetic and epigenetic conversions in vitro and in vivo. Consequently, populations of glioma stem cells remain alive after initial treatment and reinitiate tumor recurrence This genetic drift can result in self-renewing, tumorigenic glioblastoma stem cells (GSCs) that contribute to tumor initiation and therapeutic resistance MDR1 gene has been mostly considered as the cause of anti-cancer drug resistance. MDR1 P-gp is present in the brain capillaries of the BBB, as well as in many other tissues. Many drugs exhibit significantly improved brain penetration when drug efflux transporters are inhibited Multidrug resistance (MDR) presents another major barrier for chemotherapeutic drugs to get access to brain tumor cells effectively. Among the different mechanisms of MDR, ATP-binding cassette (ABC) transporter-mediated exocytosis was mostly noticed. The P-glycoprotein (P-gp) which is encoded by the human Because of these challenges, combining drugs with different working mechanisms has gained great attention in recent years. The right combination of compounds could enhance efficacy by targeting these issues in a synergistic or additive manner. However, the efficiency of many chemotherapeutic agents is also limited by their dose-related toxicities. As the BBB shields the brain from most systemically administrated compounds, high doses are given to achieve intracranial therapeutic drug levels. Increasing the dose of a specific anticancer drug will inevitably lead to significant toxicity. Many GBM chemotherapeutic drugs have demonstrated off-target toxicity at the doses needed to reach an intracranial effect. For example, TMZ is associated with lymphopenia, thrombocytopenia and neutropenia With growing investigation of the tumor microenvironment and by unravelling biological and molecular pathways, increasingly more potential drug combinations are emerging. However, just combining cytotoxic compounds does not address the problems associated with poor drug distribution at the desired tumor site. Different approaches have been raised to defeat unfavorable drug distribution in the brain In this review, we will discuss and address the advantages of drug combinations with or without nanocarriers, nanomedicine-based tumor targeting strategies, current preclinical drug combinations, and promising nanotherapeutics and nanodiagnostics. The aim of this review was to highlight the importance and potential of drug combinations and give a comprehensive understanding of different combination strategies for GBM therapy.Poor drug delivery, tumor heterogeneity and drug resistance pathways have prevented single compound therapies to show significant benefits for GBM patients Drug delivery to GBM is notoriously difficult due to the inability of most drugs to cross the BBB and penetrate the tumor tissue. Only few systemically administrated drugs reach the tumor site in a therapeutic dose. Various approaches, such as chemical modification of chemotherapeutic drugs, BBB altering strategies and efflux transporter inhibitors, are being investigated to enhance the systemic delivery of potential anti-GBM drugs. For instance, drugs can be modified to a more lipophilic form by adding lipid groups to the polar ends of therapeutic molecules. A log P (octanol-water) value ranging from 1.5 to 2.5 of lipophilic analogs has better brain permeability Alternatively, hyperosmotic agents, bioactive molecules, surfactants and ultrasound or electromagnetic waves have been used to alter the permeability of the BBB. Yet, such approaches are often associated with risks such as possible tumor diffusion to the periphery, and exposure of the brain to neurotoxins.In addition, inhibition of ABC efflux gene families can increase drug penetration into the brain without compromising the integrity of the tight junctions and endothelial layers. However, this approach will also reduce the efflux of potential neurotoxic compounds. In fact, many of these efflux pumps transporters could not be fully inhibited due to various reasons, including multifactorial multidrug resistance and genomically unstable tumor cells via convection enhanced delivery. The Ommaya reservoir is a reservoir capsule connected to a catheter located in the lateral ventricle. The capsule is embedded under the scalp and is easily accessible for cerebrospinal fluid (CSF) aspiration or drug delivery directly into the ventricular CSF and relies on the flow of CSF to distribute chemotherapeutics, radioactive compounds, antibodies, viruses or cells throughout the brain Local intracranial delivery not only overcomes BBB-associated drug delivery issues but also prevents systemic compound clearance and/or degradation and reduces systemic side effects. As such, much lower dosages are needed. Local drug delivery to the brain and further distribution within the brain can be mediated by simple diffusion using a reservoir-catheter system or positive pressure bulk flow via convection-enhanced delivery (CED). The positive pressure drives convective local transport of therapeutic concentrations of anti-tumor drugs into the interstitial tumor space. This technique achieved higher drug concentrations in the targeted tumor tissue compared with diffusion-limited delivery Alternatively, drugs are administered to the brain continuously with a positive pressure bulk flow \u00ae wafer for newly diagnosed malignant and recurrent GBM. However, the success of Gliadel\u00ae wafers is restricted by the limited penetration of the active compound, carmustine, into the brain tumor tissue. Moreover, use of the wafers has been associated with several adverse events, including intracranial infections, wafer migration, cerebral edema, CSF leakage and seizures Locally implanted (biodegradable) drug delivery depots have increasingly gained interest. Currently, the only FDA-approved biodegradable implant is the GliadelNevertheless, the concept of local delivery by implanting drug-releasing depots in the tumor resection cavity remains intriguing for the treatment of GBM. Films, foams and gels have been investigated for their use in local drug delivery. Particularly hydrogels have gained much attention in recent years. In general, hydrogels are injectable, biocompatible, biodegradable and mechanically comparable to soft tissue, making them attractive for intracranial implantation. They provide a versatile drug delivery system because they can be loaded with small-molecule drugs, biomacromolecules (such as DNA or protein) or cells. The gels can be engineered to tune the release of their contents in a timeframe ranging from hours up to several months Different drug combination strategies have been explored in clinical trials to tackle known drawbacks of GBM treatment. A non-exhaustive summary of combination therapy trials is presented in table 6-methylguanine-DNA methyltransferase (MGMT inhibitor) O6-benzylguanine (O6-BG) to rebuild drug sensitivity in TMZ-resistant anaplastic glioma. Indeed, O6-BG was able to restore TMZ sensitivity in TMZ-resistant anaplastic glioma, but not in TMZ-resistant GBM Another phase II clinical trial combined TMZ with an OMore often than not, promising preclinical anti-tumor strategies disappoint in clinical trials due to various reasons. For example, a phase I/II trial to determine the efficacy of vorinostat + erlotinib versus vorinostat + erlotinib + TMZ in patients with recurrent GBM multiforme was terminated because of unanticipated toxicities (NCT01110876). A trial that combined the histone deacetylase inhibitor vorinostat and proteasome inhibitor bortezomib to treat recurrent GBM, reported that no patient achieved 6-month PFS and only one patient showed a partial response according to the Macdonald Criteria, probably due to brain delivery issues in vitro results can be explained by several factors therapeutics, which has led to disappointing clinical outcomes table . For GBM\u00ae, Doxil\u00ae, DaunoXome\u00ae) mainly reduce toxicity of the parent compound and thereby improve its therapeutic index. Small interfering RNAs (siRNA) show great therapeutic promise but have disappointing clinical relevance due to stability and delivery issues. The only currently FDA approved siRNA therapeutic is Patisiran\u00ae, which is based on a lipid NP formulation that improves siRNA stability.Depending on the materials, nanoformulations are able to load hydrophilic and hydrophobic drugs, ensure sustained drug release and enhance the half-life of the drug in the circulation. For example, the half-life of TMZ was enhanced to 13.4 h compared to 1.8 h of the free drug by encapsulation in a chitosan-based nanoparticle Two decades have passed since the first NP-based cancer treatment was approved by the FDA, with an increasing number of clinical trials now ongoing, including many for GBM. A variety of systems based on polymers , inorganic materials and/or lipids have been investigated for drug delivery to the brain. The therapeutic drugs can be loaded in these particles by encapsulation, covalent linking or surface adsorption Passive tumor targeting is based on the observation that certain sized particles tend to accumulate in tumor tissue much more than they do in healthy tissues. This is known as the enhanced permeability and retention effect (EPR) effect, which was first described by Matsumura and Maeda in 1986 i) heterogeneity or lack of fenestrations in the tumor endothelium, (ii) presence of acidic and hypoxic areas (iii) lower or heterogeneous pericyte and basement membrane coverage, (iv) and high interstitial fluid pressure (IFP) induced by dense extracellular matrix, explaining the difficulty in translating the EPR effect from bench to bedside However, within the last couple of years, more and more researchers have realized that the EPR effect is highly heterogeneous both intra- and intertumorally, varies during tumor development and does not always hold up in clinical settings Figure . MoreoveInterestingly, GBM is characterized by robust endothelial proliferation resulting in tortuous, disorganized and highly permeable vasculature First of all, when comparing different imaging modalities, it becomes clear that T1-weighted MRI alone does not visualize the entire tumor. Beyond the contrast-enhancing region, essentially all of GBM show non-enhancing edema on T2-weighted or fluid attenuation inversion recovery imaging Other key pathological features of GBM are hypoxic areas surrounded by hypercellular rings of actively migrating tumor cells Due to the differences in EPR effect between and within tumors, approaches to still take advantage of it may vary. In certain situations, one might benefit from tumor vasculature normalization 64Cu-labeled long-circulating particles of different size were systemically administered and tracked via MRI and positron-emission tomography (PET) in an intracranial rat GBM model. It was demonstrated that 7 hours after systemic injection, the uptake of 20 nm NPs is significantly greater than those of 110 nm. It also showed that PET/MRI co-registration of brain images may contribute to the monitoring of disease progression and determining what drug delivery approach is feasible The extent of EPR in a tumor could be tested prior to treatment using imaging modalities. In a preclinical study, the relative blood volume was found to correlate with the tumor accumulation of polymeric drug carriers. With the help of contrast-enhanced ultrasound imaging, this vascular parameter proved useful in predicting EPR-mediated tumor accumulation of NPs and could possibly be used to preselect patients eligible for nanotherapeutic treatment The high variability of the EPR effect is considered as one of the major challenges for translating nanomedicine into the clinic. This issue can be addressed by indirect EPR imaging, utilizing companion diagnostics or developing systems with both diagnostic and therapeutic properties (theranostics). Indirect EPR imaging can non-invasively visualize and quantify the key EPR-determining parameters of the tumor vasculature, while theranostics or companion diagnostics can give insight in NPs distribution and tumor responses.via the secretion of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and CXC-chemokine ligand 2, paving the way for hypervascularity as seen in GBM et al. developed an albumin-based biomimetic NPs with transferrin receptor-binding peptide T12 and mannose as targeting ligands for codelivery of the disulfiram/copper complex and the macrophage modulator regorafenib. The T12 peptide can enhance BBB permeability and glioma cell uptake. The mannose ligand can bind to mannose receptors on TAM2. This system efficiently inhibited the glioma cell proliferation, successfully induced the protumor TAM2 towards antitumor TAM1 and triggered macrophage-directed anti-glioma immunotherapy via TAM, regulatory T cells, CD8+ T cells and cytokines Many cancers are preceded by infections or (chronic) inflammation and it is increasingly clear that the immune system plays a central role not only in cancer development but also in tumor progression et al. show that NPs predominantly accumulate in tumor associated immune cells rather than tumor cells. They used fluorescently labeled polymeric NP (100 nm) together with magnetic NP (20 nm) in several tumor mouse models to predict NP tumor accumulation and treatment outcome. It appeared that NP distribution was mainly determined by vascularization and permeability at early time points, but at later time points by cellular uptake. Both NPs were mostly taken up by host phagocytes (> 90%). High local TAM counts correlated with increased NP accumulation and as such proved an important component of the EPR effect In vitro studies show monocyte mediated transfer of NP over an endothelial monolayer In vivo, TAM with ingested NPs has been observed to cross the BBB and migrate to (distant) tumors. As such, NPs were shuttled between contralateral CNS tumors via migrating TAMs via these cells.The inflammatory response observed in GBM results in increased vascular permeability as well. In turn, this will not only allow for extravasation of immune cells, but also of therapeutics including NPs. Furthermore, extracellular matrix (ECM) remodeling can influence NPs transport through the interstitial space e.g. ATP, calreticulin, high-mobility group box 1(HMGB1) and chemokine ligand 10 (CL10), allowing dendritic cells to recognize the dying cell and initiate an anti-tumor immune response to clear tumor cells Another point that might influence the immune microenvironment-based therapy for GBM is the immunosuppressive effects of chemotherapy. Indeed, systemic chemotherapy might suppress the bone marrow and consequently impact the amount and activation state of immune cells When passive targeting is insufficient, active targeting of NPs can facilitate their transport over the BBB. With polymeric NPs this is often achieved by modifying their surface with surfactants or BBB- or glioma-specific ligands. For example, doxorubicin (DOX) loaded poly butyl-cyanoacrylate NPs were more effective when coated with the surfactant P80 and increased the survival time of GBM tumor bearing rats compared to the non-coated group \u00ae) resulted in a significantly higher intratumoral concentration of DOX than normal brain tissue in GBM patients via RME and promote tumor specific uptake. Transferrin conjugated liposomes increased brain delivery of 5-fluorouracil by 13 times compared to non-conjugated liposomes Lipid NPs, liposomes in particular, are also widely investigated in the drug delivery field. Liposomes can encapsulate hydrophilic compounds in the aqueous compartment and hydrophobic compounds in the bilayer making it a versatile delivery vehicle. Covering the surface of these particles with polyethylene glycol (PEG) neutralizes surface charge but thereby ensures prolonged circulation and increases the EPR effect. Radiotherapy supplemented with PEGylated liposomal DOX (CaelyxLipid nanocarriers (LNCs) are also able to load both hydrophilic and hydrophobic molecules in an aqueous core by formation of reversed micelles 131I-labeded CTX-functionalized polyethylenimine-entrapped gold nanoparticles as a multifunctional glioma-targeting nanoprobe was generated. After incubation with the NPs, C6 cells displayed much stronger fluorescence intensities than those treated with negative controls under the same conditions by confocal imaging. This CTX-loaded NP could also act as a nanoprobe for the targeted single photon emission computed tomography (SPECT)/ computed tomography (CT) imaging of glioma cells and in a subcutaneous tumor model Sometimes NPs are made by organic-inorganic hybrid materials as the magnetic and optical features of metallic NPs can be used to actively target to tumor site and monitor delivery non-invasively. In an U87MG orthotopic tumor model, magnetic targeting treatment with superparamagnetic iron oxide (SPIO) and PTX coloaded PLGA NPs significantly enhanced the median survival time compared with the passive targeting treatment group via passive targeting, while active targeting might be employed to increase this accumulation in hard to reach tumors such as GBM. Imaging (whether direct or indirect) can give an indication of the potential of certain tumors to be treated with NP formulations, thereby preselecting patients and possibly improving treatment success.Overall, NPs show great potential in preclinical studies. They often improve accumulation of therapeutic compounds Nanocarrier formulations additionally offer the opportunity to incorporate imaging features facilitating diagnostic as well as monitoring features. Accurate diagnosis is essential for adequate cancer treatment. For GBM, imaging is pivotal as the alternative diagnostics (e.g. biopsies or surgery) are highly invasive. As such, imaging is crucial for (preliminary) tumor characterization and localization, planning of surgical strategies and monitoring of treatment response.Generally, maximal gross resection is correlated with increased survival via compromised and leaky vasculature, amino acid linked PET tracers can transverse the intact BBB Where conventional contrast enhancers and tracers can only enter the brain Coupling the integrin targeting ligand RGD to PET tracers increased their tumor specificity in mouse models via fluorescence imaging ex vivoet al. designed a carbon-based QD that could emit red light. Intravenously injected dots accumulated in xenograft HeLa tumors via EPR and allowed in vivo fluorescent as well as PA imaging. Moreover, the dots could be used as photothermal inducers, as a large percentage of the absorbed energy is converted to heat, facilitating thermal ablation of tumor tissue Preclinically, novel materials and approaches are being investigated such as quantum dots (QDs), metallic NPs, protein conjugates and polymeric particles 64CuCl2. These particles could be imaged using PET scans in a xenograft GBM mouse model. The dots were self-luminescent via cerenkov resonance energy transfer, making it possible to visualize tumors via luminescence imaging as the EPR effect resulted in tumor accumulation of the PEGylated particles via PET imaging and showed promising fluorescence imaging opportunities in an earlier mouse study Alternatively, QDs can be coupled to other imaging agents such as radioactive tracers to allow deeper tissue imaging. PEGylated radioactive QDs were made using metal chlorides and via MRI allowing tracking of the particles and simultaneously present a way of directing the particles toward their goal via magnetic fields. A second biocompatible layer reduces toxicity and extends circulation via magnetic targeting, assisted by ultrasound-targeted microbubble destruction of the BBB. They were visualized by MRI (SPION) and fluorescent imaging (using the QD). The fluorescent signal was able to improve gross resection while the loaded cinglitide could inhibit tumor growth \u00ae for hyperthermal treatment of primary and recurrent GBM. The particles are injected intratumorally, followed by applying alternating magnetic fields to produce cell killing heat. Combined with radiotherapy, NanoTherm\u00ae prolonged survival in 66 patients with recurrent GBM As mentioned in the section of active targeting, superparamagnetic iron oxide nanoparticles (SPIONs) are extensively investigated as standalone theranostic particles as well. The magnetic iron core can be visualized As more and more information is gathered on the presence of different cellular compositions in different tumor regions, subtype specific diagnostic/ theranostic NPs might be used to elucidate the tumor make up and provide tailored therapy e.g. Bortezomib and HDAC; O6-BG and TMZ) in vitro. Intravenous administration of NPs encapsulating the compounds in their optimal ratio significantly inhibited tumor growth in a U87 subcutaneous model in vivoDue to differences in BBB permeability, drug stability and pharmacokinetics, therapeutic efficacy may be disappointing when simply administering two or more theoretically synergistic compounds in several tumor models Besides the optimal ratios, the timing and order in which drugs are administered can have significant effects on the treatment outcome. For instance, the complex tumor microenvironment can greatly impair drug distribution within the tumor p53 gene plasmid was loaded in a transferrin targeted liposome (SGT-53) which could sensitize human glioma cells to TMZ. Moreover, pretreatment of TMZ resistant tumors with SGT-53 reversed TMZ resistance, while co-delivery of SGT-53 and TMZ postponed the development of TMZ resistance in an intracranial mouse GBM model p53 inhibitors MDMX and MDM2 which was loaded in an RGD-targeted micelle. The micelles could reach an intracranial tumor and exert potent p53-dependent anti-proliferative activity. In addition, activating p53 sensitized the tumors for subsequent TMZ treatment The timing and order of treatments can also significantly affect the way tumors respond to certain insults on a cellular level, a factor that often seems overlooked. Knocking down epidermal growth factor receptor (EGFR) signaling in triple-negative breast cancer cells markedly increased their sensitivity to subsequent DOX treatment. Reverse order or simultaneous administration had no such effect and could even be inhibitory, emphasizing the importance of timing rather than just co-administration Intelligent designs of NPs As single drug therapies often seem insufficient for the treatment GBM, the focus has shifted to combination therapies. It is important to find combinations that act synergistically and preferably on different targets as tumor heterogeneity and emergence of resistance pathways need to be considered. Genetic profiling of tumors can help in finding the most promising approach. Incorporating established therapies in combination approaches will ensure faster translation to the clinic while adding compounds for novel targets such as the tumor immune microenvironment has shown promising results. However, simply administering two compounds systemically will most likely result in underwhelming results. Brain delivery of most compounds has proven challenging and seems to be insufficiently acknowledged as few clinical trials investigate or report brain concentrations of the used compounds.in vivo studies, results fail to translate to the clinic. This is partly due to too simplistic (murine) models that don't represent the complex human tumor heterogeneity.Intracranial delivery of therapeutics is promising but still needs significant optimization before it is sufficiently practical to be implemented in standard care. Systemic delivery is predominantly hampered by the BBB. There is increasing interest in nanoformulations for the delivery of drugs to the brain and has shown promising results in preclinical animal studies. The ideal design of a nanosized delivery system depends predominantly on the encapsulated molecules, the preferred release profile of each compound (simultaneous or time staggered) and which cells are targeted. Nevertheless, certain characteristics seem to be universally beneficial. PEGylating the particle and keeping the size around 20-75nm ensures prolonged circulation and at the same time allows sufficient tissue penetration. Factors such as the partition coefficient, the molecular weight and the synergistic ratio of the payloads have to be considered as well. Although nanocarrier based brain delivery shows promising results in preclinical p53 and/or Rb knock-down and the activation of pro-survival RTK and Ras signaling to allow for de novo tumor formation. With GEMMs, it could be possible to investigate the function of tight junction proteins, transporters, or ECM components in BBB development and biology as well. On the other hand, GEMMs also failed to recapitulate the intratumoral heterogeneity seen in patients. Other limitations like expensive breeding and low tumor penetrance have to be considered In order to have a more accurate prediction of clinical outcome of novel therapeutic strategies, an ideal mouse glioma model should be orthotopic and highly reproducible with predictable tumor growth, bear a genetic similarity to human glioma, show cellular heterogeneity and angiogenic-like growth Additionally, EPR based passive brain targeting of NPs as seen in animal models fails to translate to the clinic. Active targeting is often suggested to improve tumor accumulation yet it is most likely more favorable to pre-select for patients that are suited for NP based treatment. Novel imaging modalities as well as the rise of nanotheranostics will provide the opportunity to pre-select patients with appropriate tumor characteristics such as high tumor perfusion and large relative blood volumes. Additionally, nanotheranostics will provide a way to monitor drug delivery and possibly visualize treatment outcome.The preclinical success of immunotherapy of GBM has not been replicated in human clinical trials. Both vaccines as single therapy and immune check point inhibitors have led to disappointing clinical results GBM is a complicated cancer that involves various sophisticated molecular pathways, gene mutations, and tumor microenvironments. Despite plentiful investigations, an unmet medical need persists for the treatment of invasive GBM. Here we have described the current strategies for nanomedicine-based drug combination therapies. With increasing knowledge of GBM molecular pathways, increasingly more intelligent drug combination strategies will be developed. Nanocarriers will be designed to improve delivery and allow targeting of different pathways within the tumor microenvironment. Future approaches will exploit different nanocarrier-based combinations, the most promising being immunotherapy and nanotheranostics, to enhance the therapeutic benefits for GBM. With the broad knowledge and efforts of researchers, nanocarrier-based combination therapies are expanding the way for success in the battle for GBM treatment."} +{"text": "Cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) improve survival of patients with colorectal peritoneal metastases (PM).,Therefore, identification of practical clinicopathologic prognostic variables is key to optimize treatment for patients with PM. Patients who experience PM despite previous adjuvant chemotherapy after primary tumor resection are thought to benefit less from cytoreduction and HIPEC, and several studies and guidelines exclude these patients from a potentially curative HIPEC treatment.3This study evaluated all relevant clinicopathologic variables potentially associated with oncologic outcome in a large prospectively obtained cohort of 175 patients who had colorectal PM and were treated with cytoreduction and HIPEC.Future guidelines should incorporate the identified clinicopathologic prognosticators into clinical practice. Before clinical implementation, however, these variables require further prospective validation. A combined effort, with prospectively collected consecutive data from patients with PM, is key for this purpose. Currently, ongoing clinical trials with patients who have colorectal PM are addressing perioperative systematic chemotherapy, the additional value of HIPEC versus cytoreduction alone, and novel chemotherapeutic HIPEC agents. Future research to optimize treatment of patients with PM should focus on identification of molecular tumor characteristics that could improve patient selection. In addition, the substantial progress regarding the use of blood samples as liquid biopsies could provide prognostic (epi-)genetic information. Knowledge of tumor biology not only could help in selecting the right patients, but also could provide guidance regarding the optimal chemotherapeutic drug for the HIPEC treatment. Ultimately, a personalized profile consisting of both clinical and molecular characteristics will provide a way toward tailored treatment for patients with colorectal PM."} +{"text": "Extrachromosomal gene amplification refers to copy number gains of DNA fragments that are not contiguous with the twenty-three canonical chromosomes. Unlike typical chromosomes, they are composed of circular DNA fragments without centromeric sequences . They arEGFR) is, by far, the most commonly altered oncogene in glioblastomas, the most common form of primary brain cancer. It is mutated or amplified in 60% of glioblastomas [EGFR gene. EGFRvIII-positive glioblastomas exhibit unique molecular physiologies associated with distinct therapeutic response profiles and an overall tumor aggressiveness [Epidermal growth factor receptor gene (lastomas . OncogenEGFR deletion variants.Breakpoint junctions in EGFRvIII are highly variable between tumor samples due to 120-kb-long intron one of this gene where one of the breaks take place. Breakpoint sequence analyses implicate contribution by multiple DNA strand-break repair mechanisms, including non-homologous end joining, micro-homology mediated end joining, and other forms of replication mediated repair . These fEGFRvIII is that a single tumor can harbor multiple, independent EGFRvIII variants -- each with distinct breakpoint junctions. These variants as well as the accompanied amplified full-length EGFR share common allelic profiles, suggesting that the deleted variants arose from a common ancestral amplified EGFR. A corollary of this hypothesis is that distinct additional genomic rearrangements of amplified full-length EGFR in glioblastoma subpopulations gave rise to polyclonal EGFRvIII breakpoint species (Figure Another interesting observation pertaining to s Figure .EGFR variant formation and EGFR amplification. Is extrachromosomal EGFR amplification a requisite precursor of EGFRvIII? For instance, this acquisition of glioblastoma specific EGFR deletion mutation might be associated with the fact that amplified EGFR in glioblastoma mostly resides in extrachromosomal DNA that is selectively captured in micronuclei [EGFRvIII.An important mechanistic question in this context involves the sequence of events that led to ronuclei , where cronuclei . In thisEGFRvIII is formed, not only do cells expressing this mutant transform to a more aggressive phenotype as mentioned above, but surrounding tumor cells without mutant EGFR are also benefited in terms of growth and cell survival by paracrine effects through cytokines such as interleukin-6 [EGFR yielding EGFRvIII that establishes an ecosystem supportive of aggressive tumor growth. Elucidation of this mechanisms of further rearrangements of extrachromosomal amplicons should yield opportunities for future therapeutic development and mechanistic insight.Once leukin-6 , or throleukin-6 (Figure"} +{"text": "Drug targeting has opened a new paradigm in therapeutics with development of delivery vectors like liposomes and polymeric nanoparticles. Although their clinical application is crippled by limited biological adaptability. Off-target toxicity and biocompatibility still remains one of the critical problems in anticancer therapeutics that can be life-threatening. Here we report a quick, simple and facile method of engineering human platelets to generate drug loaded platelet-derived microparticles (PMPs) by top-down approach, which are biocompatible and naturally target leukemia cells. Drug loaded PMPs and cancer cell uptake were characterized by flow cytometry, confocal microscopy, Nanoparticle Tracking Analysis and fluorimetry. Effective drug delivery was tested in cancer cell lines as well as in clinical samples from leukemia patients. We explored that PMPs are capable of carrying multiple drug payloads, have long shelf life and can be harvested in large quantity in short period. Importantly, PMPs exhibited remarkably higher toxicity towards cancer cells than free drug and had lower escape into extravascular spaces. Transfer of drug to cancer cells of leukemia patients was significantly higher than free drug, when delivered through PMPs. Our experiments validated therapeutic application of PMPs as biocompatible drug delivery vector against cancer cells with minimal off-target delivery. Off-target toxicity is presently one of the main issues associated with drug administration, especially anticancer therapy . Being pTargeting drugs to specific sites of action through nano-sized vehicles has opened new paradigm in therapeutics . Despitein vivo, as well as overcoming biological barriers such as the blood-brain barrier under informed consent. Leukemia diagnosis was confirmed by presence of >90% blast cells with high nuclear-cytoplasmic ratio in peripheral blood and bone marrow examinations. Aliquots (100 \u03bcl) of whole blood from each sample were treated either with vehicle (buffer without Dox), or free drug (0.15\u20130.2 \u03bcg/ml DoX), or equivalent PMPDox for 1 h. WBCs were separated using RBC lysis reagent (Puregene), fixed with 2% paraformaldehyde and Dox uptake was evaluated by flow cytometry. Comparison with normal leukocytes was carried out with blood obtained from healthy donors following similar procedure.t-test was used for evaluation of significance and values of p < 0.05 were considered significant. This study was approved by ethical committee of Institute of Medical Sciences, Banaras Hindu University.All data are representative of at least three independent experiments. Two-tailed Student\u2019s In this report we discussed a quick and facile top-down approach of generating drug-loaded PMPs that behave as natural vectors targeted against leukemia and other cancers. PMPDox engineered from autologous human platelets are physiological, biocompatible, non-immunogenic and inherently targeted towards cancer cells, thus obviating the need for implantation of exogenous targeting molecules on the particle surface. PMPDox is also capable of carrying multiple therapeutic payloads. Platelets can be easily accessed from blood and harvested in large quantity. PMPDox can be generated in huge number from donor platelets, stored for several days without loss of stability and exhibit targeted delivery and higher toxicity against leukemia cells than free drug. Successful drug delivery and compatibility in whole blood samples from leukemia patients confirmed potential practical application of this approach. Multimodality is also feasible in our approach as multiple anticancer drugs and/or contrasting agent can be loaded into PMP. Reduced extravascular escape of drug from PMPDox would minimize off-target adverse effects including cardiac and hepato- toxicity, making it far safer approach for anticancer therapy."} +{"text": "V600E can be targeted with selective inhibitors, such as vemurafenib. Despite initial positive tumor responses of regression and decreased viability, both single agent or combination agent drug treatments provide a selective pressure for drug resistant evolving clones within the overall heterogeneous tumor. Also, there are evidences suggesting that sequential monotherapy is ineffective and selects for resistant and ultimately lethal tumor clones. Reconstructing both clonal and subclonal thyroid tumor heterogeneous cell clusters for somatic mutations and epigenetic profile, copy number variation, cytogenetic alterations, and non-coding RNA expression becomes increasingly critical as different clonal enrichments implicate how the tumor may respond to drug treatment and dictate its invasive, metastatic, and progressive abilities, and predict prognosis. Therefore, development of novel preclinical and clinical empirical models supported by mathematical assessment will be the tools required for estimating the parameters of clonal and subclonal evolution, and unraveling the dormant vs. non-dormant state of thyroid cancer. In sum, novel experimental models performing the reconstruction both pre- and post-drug treatment of the thyroid tumor will enhance our understanding of clonal and sub-clonal reconstruction and tumor evolution exposed to treatments during ultra-precision targeted therapies. This approach will improve drug development strategies in thyroid oncology and identification of disease-specific biomarkers.The introduction of ultra-precision targeted therapy has become a significant advancement in cancer therapeutics by creating treatments with less off target effects. Specifically with papillary thyroid carcinoma (PTC), the cancer's hallmark genetic mutation BRAF V600E mutation. Constitutive activation of the BRAF proto-oncogene leads to activation of ERK1/2 pathway and other intracellular pathways associated with abnormal cell proliferation and growth (Papillary thyroid carcinoma (PTC) is the most frequent type of thyroid cancer, accounting for almost 80% of thyroid cancer cases. The genetic hallmark of human PTC is the somatic BRAFd growth .V600E can be targeted with selective inhibitors such as vemurafenib, the first FDA approved orally administered inhibitor and suppression of growth signals. Part of a cell's evolution to evade these signals involves genetic mutations, which predisposes the cells to being able to survive with mutations that would otherwise not survive in non-cancerous or malignant cells. Tumorigenesis requires increased mutability in order for tumor cells to bypass regulatory and apoptotic pathways and signals. Increased mutability of cells is achieved through down regulation of genomic maintenance mechanisms, including P53 gene inactivation . The dowV600E in PTC resistant subclones , some tumor cells will respond to the treatment and die gene, targeted drug treatment therapy positively selected for a number of drug resistant clones and drove tumor clonal evolution gene family mutations . In . In V600t cancer . Single Combination therapy is seen as the best treatment option for overcoming resistance to single agent targeted therapy . HoweverV600E, Tg mutations were more likely passenger mutations that are advantageous in the malignant evolution of PTC as opposed to the actual drivers of PTC. Since Tg mutations are associated with mutations in genes encoding components of the MAPK signaling pathway, it is possible that some subclones harboring both driver and maybe passenger mutations, such as RBM gene family mutations gene were associated with poorer clinical prognosis . Additio0, RBMX) , could s0, RBMX) .Another experimental model focusing on tumor heterogeneity in breast cancers identified a subclonal genetic marker associated with CD44+ breast cancer stem cells. Previous studies had demonstrated that CD44+ cells displayed increased tumorigenesis compared to CD44\u2013 cells . Given tV600E and CDKN2A\u2212/\u2212 mutant PTC's and for overcoming both innate/primary and secondary tumor resistance mechanisms.In the PTC experimental model, an understanding of the subclonal construction of the tumor having chromosome 5 amplifications and RBM gene family mutations, revealed potential pathways for secondary resistance. This knowledge of both the clonal and subclonal configuration of the tumor, allowed for a more effective solution to treating BRAFBeyond elucidating better understandings of potential cellular pathways and genes involved in drug therapy resistance, clonal and subclonal reconstructions of tumors can also reveal biomarkers for early detection of aggressive thyroid cancer that could dictate future tumor behavior. With regard to thyroid cancers, PTC is classified as a differentiated thyroid cancer, and other types of thyroid carcinomas, such as anaplastic thyroid carcinoma (ATC), are classified as undifferentiated thyroid cancer. The transition from PTC to undifferentiated thyroid carcinoma is still poorly understood and furthermore effective treatments of ATC represent a large unmet clinical need. Clonal and subclonal reconstructions of both heterogeneous PTC and ATC Importantly, ATC show increased mutational burden compared to PTC. In one study examining the genetic profile of 196 ATC samples, only 41% (81 tumors) harbored BRAF mutations . If ATC In sum, some bioinformatics models have been designed and are being used to reconstruct the clonal and subclonal heterogeneity of tumors. However, we need novel experimental models performing the clonal and subclonal reconstruction both pre- and post-drug treatment(s) of the thyroid tumor for somatic mutational and epigenetic profile, copy number variation, cytogenetic alterations, and non-coding RNA expression. Clonal and subclonal evolution of tumor cell clusters is also driven by the selective pressure of targeted drug therapy, therefore the pre-treatment reconstruction and the post-treatment reconstruction would identify all clones and subclones that drug treatments positively select, those that are responsive to drug treatments and die, and clones containing passenger genetic alterations conferring secondary tumor resistance.CN: design. CN and EM: editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Abstract Global new-born mortality has shown steady decline over the last two decades, but this decline has been slowest in Sub-Saharan Africa (SSA). Perinatal asphyxia (PA) is a major cause of new-born deaths in this region and as such SSA now contributes a disproportionate large percentage of global asphyxia-related deaths. In this paper, we examine regional challenges affecting primary, secondary and tertiary prevention of PA and proffers locally adaptable solutions to these identified challenges. Global newborn mortality has shown steady decline over the preceding two decades, but this has been slowest in Sub-Saharan Africa (SSA), where newborn deaths now accounts for 38 percent of global neonatal mortality . In thisEnding preventable newborn deaths currently feature prominently in the global health agenda and this is reflective in the Sustainable Development Goals, specifically Goal 3 . To achiIn this paper, we examine challenges faced in the prevention and management of perinatal asphyxia by countries within this region, and we suggest possible solutions to the current issues.These challenges relate to identifying and limiting the risk of pregnant women who without intervention might deliver asphyxiated babies. They hinder effective demand and supply of obstetric services within the region.In SSA, attendance of ante-natal care, which should connect the \u2018at-risk pregnant woman\u2019 with the formal health system, is poor, as under 40 percent of women attend at least four visits . Within Despite widespread regional poverty, 40 to 54 percent of people access healthcare primarily out-of-pocket which hinders health service demand . In instRegional sociocultural norms such as child marriages also negatively affect antenatal care attendance. A recent review of demographic and health survey data in 31 SSA countries documented a third of girls were married by age 18 in more than half of the studied countries . In thesThese relate to three service delivery gaps: coverage, equity and quality gaps. The coverage gap connotes insufficient manpower to address regional obstetric needs. The global health worker shortage is greatest in SSA, where the majority of countries have health worker to population densities below 2.5 per 1000 population, starkly contrasting developed country estimates which are between two and ten times this number . The ine15Additionally, existing quality gaps affect obstetric supply. In a review of data from 20 SSA countries, 71 percent of women did not have intermittent preventive treatment for malaria in pregnancy despite attending at least 4 antenatal care visits . SimilarSecondary prevention of asphyxia involves resuscitation of newborn infants with breathing problems who are at risk of developing perinatal asphyxia. One major challenge to this is the large proportion of out-of-hospital births occurring in the presence of unskilled birth attendants who lack knowledge and skill of neonatal resuscitation . More thWhen births occur in-facility, obstetric service providers frequently do not have the basic skills or equipment necessary to provide quality neonatal resuscitation . A regioTertiary prevention of asphyxia involves treating acute complications and mitigating their progression to long-term disabling morbidities. This requires functional multidisciplinary rehabilitative care teams which are lacking in SSA. Countries within the region have rehabilitative worker densities below 0.01 per 10,000 population, contrasting developed countries where these figures are almost a thousand times this number . AdditioFocusing on primary prevention within the region is most likely to have the greatest impact on asphyxia burden and this would entail stimulating a demand for obstetric services while improving supply. Infrastructural and human capacity development are key to improving regional obstetric demand. Road networks, transportation, referral, communication and information systems, all of which have direct effects on service demand would need to be upgraded . Additio8Community engagement is also fundamental to stimulating demand and should entail changing community perceptions regarding orthodox obstetric services through health education, local media and provision of holistic, culturally acceptable and easily accessible obstetric services. In these settings, the buy-in of prominent local community, traditional and religious leaders is crucial to programmatic success.From a supply perspective, an obvious solution to tackle the existing coverage gaps would be to attract skilled birth attendants through competitive remuneration. However, this is not feasible in the short term, as many SSA countries are currently economically challenged. Task-shifting, a practice which involves delegating roles and responsibilities otherwise carried out by senior health staff to lower and mid-health care workers can serve as a short term measure . Local r27Equitable distribution of obstetric human resources across geographical divides needs to be ensured through health worker tax rebates and provision of rural allowances to encourage their retention in these areas. Nigeria and Zambia have instituted rural midwives\u2019 and rural health worker retention schemes which have shown modest successes 30. Rural31Regional governments need to increase budgetary allocations to the health sector to improve quality of obstetric care. Local services would also need to be more effectively organized by developing strong bottom-up referral systems which centralize high-risk pregnancies to tertiary obstetric health centers and those considered low-risk to primary healthcare. In addition, proper supervision and monitoring of existing obstetric facilities using methods such as perinatal audits, obstetric checklists, regular in-house staff training and drills will also improve quality of care .Despite being controversial among policy makers , traininTo improve tertiary prevention of asphyxia, capacity building for rehabilitative service providers is essential. Local health facilities would need to establish collaborative links with international agencies and centers with specialized rehabilitative care that can offer voluntary services and develop local capacity. Vital registration of all births and deaths in SSA needs to be improved for accurate data on local asphyxia burden and for managing regional government development plans.Challenges to successfully preventing perinatal asphyxia in SSA might seem herculean. The key to solving these would be the institution of pragmatic locally adapted solutions that take into cognizance existing realities in the region. These would need to target safer pregnancy and delivery outcomes with a focus on accessible quality neonatal resuscitation and human capacity development."} +{"text": "Here we report optimization, expression and binding of DMAbs based on anti-PD1 CPI and discuss the potential of DMAbs in checkpoint immunotherapy.Checkpoint inhibitors (CPI) have revolutionized the treatment of many solid tumors. However, difficulties in production, stability, the requirement of frequent high doses for antibody administration and long intravenous administration are recurring issues. Synthetically designed DNA-encoded monoclonal antibodies (DMAbs) are a novel delivery method for antibody therapy which could potentially address many of these issues, simplifying design and implementation of MAb-based therapies. DMAbs delivered through plasmid DNA injection and electroporation have been used in preclinical models for the treatment or prophylaxis of infectious diseases, cancer and cardiovascular disease. Our group has recently reported that immune checkpoint blockers can be optimized and delivered Checkpoint inhibitors (CPI) have revolutionized the treatment of many solid tumors. These therapies have generated an increase in the percentage of cancer long-term survivors by \u2018releasing the brakes\u2019 of the immune system to potentiate its antitumor effect in those patients who respond . HoweverSynthetically designed DNA-encoded monoclonal antibodies (DMAbs) are a novel delivery method for antibody therapy which could potentially address many of these issues, as well as open up novel approaches for design and implementation of MAb based therapies. DMAbs represent a simple, scalable development system, with the additional benefit of higher stability and simpler storage than protein biologicals. DMAbs are administered locally by intramuscular injection and allow simple coformulation, permitting the generation of CPI with a unique profile of expression and potency, suggesting they could be considered as a new tool for study in this important therapeutic arena.DMAbs delivered through plasmid DNA injection and electroporation (EP) have been used in pre-clinical models for the treatment or prophylaxis of infectious diseases , 5, cancin vivo advancing further DMAb technology [in vivo expression for several months. These first studies in mice, while encouraging, require additional examination in other models, including additional optimization in other species to further understand the implications with an eye towards subsequent clinical evaluation. Furthermore, studies in combinations and with additional genetic modifications for functional enhancement by the Fc portion of the Ig heavy chain can be much more easily developed and studied as DMAbs than as protein biologicals to advance new CPI-like forms with improved functions resulting in improved tumor impact advancing clinical benefit. Under this concept the development of additional CPI targets as DMAbs appears important.In support, Duperret et al., recently reported that immune checkpoint blockers can be optimized and delivered chnology . In the chnology or tremechnology . These sThe PD-1-PD-L1 signaling pathway was first discovered in 1992 and monoclonal antibodies targeting this suppressive pathway were moved towards clinical testing in 2006. These MAb have made a major positive impact in the clinic resulting in FDA approvals for treating a variety of different tumor types due to exciting clinical benefit for treatment of diverse cancer types including melanoma, non-small cell lung carcinoma, renal cell carcinoma, high microsatellite instability cancers, Hodgkin\u2019s disease, hepatocellular carcinoma, urothelial carcinoma, bladder carcinoma, Merkel cell carcinoma and gastroesophageal junction [in vivo expression while retaining their required binding ability and functionality. These DMAbs expressed for several months and exhibited the specificity and cell binding of the parental antibodies. The recent development of DMAbs encoding anti-CTLA4 [in vivo production is likely to provide unique research and ultimately clinical benefit in the cancer arena.Accordingly, the development of forms of DMAbs encoding anti-PD-1 like antibodies are important. Engineered DMAb forms mimicking highly impactful anti-PD-1 monoclonal antibodies were studied in an effort to optimize direct DMAb ti-CTLA4 and for ti-CTLA4 , 12 or DIn summary, DMAbs are a new tool that conceptually simplifies antibody therapies and their combinations, including checkpoint blockade, which if successful would likely expand their applications bringing CPI therapies to a much larger patient population. Further translational study of the DMAb platform for impacting cancer is worthy of consideration."} +{"text": "Recent breakthroughs in cancer immunotherapy have led to curative efficacy and significantly prolonged survival in a subset of patients of multiple cancer types; and immunotherapy has become the newest pillar of cancer treatment in addition to surgery, chemotherapy, radiotherapy and precision targeted therapies. In the metastatic disease setting, responses to immunotherapy are heterogeneous depending on the metastatic organ sites. The tissue-specific immuno-biology in the tumor microenvironments (TMEs) contributes to the differential therapeutic responses. Herein, we review the impact of tissue-specific tumor microenvironment on the efficacy of immunotherapy, with a focus on historically under-represented central nervous system (CNS) metastasis, which was excluded from most clinical trials. Retrospective examination of patient specimens and prospective clinical studies with immune checkpoint blockade (ICB) have established that brain can harbor an \u201cactive\u201d immune microenvironment for effective immunotherapy. Regulation by the innate immune microglial cells and remodeling of the blood\u2013brain barrier (BBB) may contribute to immunotherapeutic responses mediated by T lymphocytes. How to convert an \u201cinactive\u201d (cold) brain microenvironment into an \u201cactive\u201d (hot) brain TME should be the focus of future efforts. Thus, procurement and complete examination of clinical specimens from brain metastases as well as development of appropriate preclinical brain metastasis models susceptible to external manipulation of the TME are critical steps towards that goal. A deeper understanding of the immuno-biology in distinct organ microenvironments will help to expand the benefits of immunotherapy to more needed patients. The idea of immunotherapy was conceptualized more than 100\u00a0years ago when German pathologist Rudolf Virchow first described the involvement of immune cells in human tumors . Even thBeginning in the 1980s, therapeutic monoclonal antibodies, a bioengineered version of the naturally secreted immune molecule, emerged as a versatile platform of therapeutic agents against cancer , 5. AfteIt has long been known that CD8+ effector T cells have cytolytic capability that kills cancer cells . In-deptDifferent cancer types tend to colonize specific organ sites, as depicted by the \u201cseed and soil\u201d hypothesis of metastasis . Many ofA common clinical observation with advanced cancer patients is the differential responses to systemic treatments where some metastatic lesions may be less or more responsive to therapy compared to lesions located at other anatomical sites. Such frequently encountered clinical phenomenon strongly suggests that the local TME plays crucial roles in modulating therapeutic responses. For example, in a retrospective study of 371 metastatic melanoma patients treated with the first FDA-approved \u201cmodern\u201d immunotherapy high-dose IL-2, the response rate in patients with cutaneous or subcutaneous metastasis was\u2009~\u200950% whereas with visceral metastases it was only 13%; more strikingly, in individual patients harboring both cutaneous/subcutaneous and visceral metastases, tumor regression took place only at cutaneous/subcutaneous lesions whereas visceral metastases progressed upon the same systemic IL-2 therapy . FurtherDespite the clear relevance derived from multiple clinical studies, further in-depth mechanistic investigations that require procuring clinical specimens from multiple metastatic organ sites can be logistically challenging. To that end, an exceptional case study reported a single patient with high-grade serous ovarian cancer who was treated with multiple chemotherapy regimens and exhibited regression of some metastatic lesions with concomitant progression of other lesions . After cTo broadly elucidate the underlying biological mechanisms of the organ specific TME impact on immunotherapy responses, multiple studies have used preclinical murine models harboring metastases at multiple anatomical sites and having treatments by various immunotherapy agents. For example, implanting murine 4T1 mammary cancer cells at subcutaneous or intratibial sites and FACS profiling of isolated tumor-associated immune cells revealed significant differences in the immune composition depending on the sites of tumor growth . AdditioUnfortunately, despite fair amount of effort by the research community to compare differential anatomic responses to cancer therapies, the brain, one common metastasis organ site, has been adversely neglected , 34. WitWhile the primary regulatory and cognitive functions of the central nervous system (CNS) are conducted by neuronal circuitry, it is also essential to maintain a homeostatic environment of stable metabolism and inflammation, which tasks fall on the large number of stromal cells in the brain, including astrocytes and microglia cells . To thatIntracranial malignant neoplasms can arise either from primary brain tumors (mainly glioma) or from secondary cancers metastatic to the CNS. Lung cancer, breast cancer and melanoma are the major sources of brain metastases, which collectively outnumber primary malignant brain tumors by\u2009~\u200910:1 , 47. WhiIntriguingly, infiltration with adaptive immune T lymphocytes is highly heterogenous in brain metastasis lesions, varying from total absence to very dense infiltration , 59. A sLastly, how do adaptive immune T cells infiltrate brain metastatic lesions in the presence of blood\u2013brain barrier (BBB)? Pharmacodynamic studies in preclinical murine models of breast cancer brain metastasis showed that BBB permeability could be compromised, and vascular leakiness became highly heterogeneous depending on the progression of brain metastatic outgrowth . FurtherBrain is conventionally regarded a major organ site of metastasis with sanctuary immune status; hence, up till recently, most clinical trials exclude patients with CNS metastases , 38. WitBased on these clinical studies showing early signals of positive intracranial activity, a landmark trial of treating melanoma brain metastasis with ICB combination of anti-PD-1 nivolumab and anti-CTLA-4 ipilimumab has been conducted . It was Despite these promising results, the advances are still in the early stage and most patients with CNS metastases remain difficult to treat; the benefit must also be extended to brain metastases from other primary cancer types in addition to melanoma. Additionally, the underlying mechanism of resistance versus response of the intracranial tumors to systemically administered ICB remains a fundamentally unanswered question. Because immune cells are highly dynamic in response to physiological alterations, their biological functions must be tightly coupled to the cellular metabolism that provides the underlying material and energetic support. From in vitro studies, it was believed that activation of T cells shifts cellular metabolism towards glycolysis which takes place in the cytosol and produces more biological building blocks in preparation of cell proliferation and clonal expansion, and that na\u00efve and memory T cells are more dependent on mitochondrion-dependent oxidative phosphorylation (OXPHOS) which yields more ATP to confer higher spare respiratory capacity . HoweverCurrently, immunotherapy benefits a small number of patients across multiple cancer types, and the immuno-biological microenvironments at distinct metastatic organ sites are important determinants for differences in efficacy. In particular, the local immuno-biological TME at metastatic organ sites, partly mediated by the tissue-resident innate immune cells, interacts with the systemic adaptive immune system to determine responses to immunotherapy. Therefore, the major goal of future efforts should be deepening the understanding of underlying immuno-biological mechanisms responsible for the organ-specific anti-tumor immune responses and based on such knowledge developing strategies to expand the benefits of immunotherapy to more patients with advanced metastatic cancer. To that end, it is important to analyze clinical specimens of immunotherapy treated metastases of all cancer types to examine immune cell infiltration and composition, as well as local stromal cell alterations, which will reveal novel insight into the response mechanism of immunotherapy in distinctive metastatic TMEs. Additionally, it is necessary to perform mechanistic studies and functional validations using appropriate animal models in order to better understand the immuno-biology underlying effective immunotherapy.In the CNS, it has been convincingly established, by retrospective examinations of brain metastasis specimens and prospective clinical studies of ICB treatment of patients with brain metastases, that in some patients the brain can harbor an \u201cactive\u201d immune microenvironment that respond to immunotherapy. Enrichment of mitochondrion mediated OXPHOS is a unique metabolic trait of brain metastasis; modulating the OXPHOS activity in the brain TME may impact efficacy of ICB treatments. To overcome the immunosuppressive TME in the CNS, future efforts should also include combining checkpoint inhibitors with other treatments . The rapid progress in clinical investigations and preclinical studies will pave the way for effective modulation of the brain metastasis tumor microenvironment that allows effective T cell-mediated responses and enables more brain metastasis patients to benefit from immunotherapy.In summary, persistent endeavor in clinical investigations and preclinical studies to explore effective ways of manipulating the local immuno-biological microenvironment will likely enhance and expand the efficacy of immunotherapy to more metastatic diseases."} +{"text": "The STOMP trial is a multicenter, randomized, phase II trial that incClinicalTrials.gov: NCT02680587), comparing observation versus SBRT in oligometastatic hormone-sensitive prostate cancer, are comparable to those observed in the STOMP trial, validating the safety and efficacy of SBRT in this setting.Despite some inherent limitations such as the small patient cohort and the use of a treatment-related primary endpoint, the STOMP trial represents the first randomized study exploring the role of MDT compared to standard of care in oligorecurrent patients. Of note, preliminary results of the phase II randomized Baltimore ORIOLE trial [It is noteworthy that the optimal treatment of oligorecurrent patients remains a challenging and open question, based mainly on, even if promising, retrospective and heterogeneous data. The possibility to treat a metastatic disease with a potentially curative intent collects an increasing interest, with expert panels considering MDT a valid treatment option for these patients . Of noteent ADT) . Some poFirst, although oligorecurrent prostate cancer with exclusive nodal involvement is a common clinical situation and the 68Ga prostate-specific membrane antigen (PSMA) PET-CT [Second, improvements in the diagnostic procedures such as use of ) PET-CT will surLastly, implementation in trials of translational analysis of leading-edge laboratory measuring circulating tumor cells, circulating tumor DNA, and circulating T-cell receptor repertoires will surely help to better characterize the oligomestatic status by identifying patients with potentially curable metastatic disease and evaluating the effects of MDT on disease response .ClinicalTrials.gov: NCT03569241), a randomized phase II trial for the Salvage Treatment of OligoRecurrent nodal prostate cancer Metastases, will surely help to answer some of these open questions. By randomizing patients between MDT (SBRT or sLND) versus MDT combined with WPRT (adjuvant WPRT after sLND or WPRT with boost to the positive nodes), and implementing modern imaging techniques and liquid biopsies, the study aims at finding the better treatment strategy in terms of extrapelvic metastasis-free survival as primary endpoint for this subset of patients.The recently opened Belgian-Swiss PEACE V STORM trial and European Society for Radiotherapy and Oncology (ESTRO) OligoCare observational basket study should be encouraged."} +{"text": "Fructans are fructose-based oligo- and polymers that serve as reserve carbohydrates in many plant species. The biochemistry of fructan biosynthesis in dicots has been resolved, and the respective cDNAs have been cloned. Recent progress has now succeeded in elucidating the biochemistry and molecular biology of fructan biodegradation in chicory, an economically important species used for commercial inulin extraction. Unlike fructan biosynthetic genes that originated from vacuolar-type invertase, fructan exohydrolases (FEHs) seem to have evolved from a cell-wall invertase ancestor gene that later obtained a low iso-electric point and a vacuolar targeting signal. Expression analysis reveals that fructan enzymes are controlled mainly at the transcriptional level. Using chicory as a model system, northern analysis was consistent with enzymatic activity measurements and observed carbohydrate changes throughout its development."} +{"text": "Siphoviridae, Myoviridae and Podoviridae), where members of the same family were generally far more divergent and often not detectably homologous to each other. Analysis of the 20 currently classified prokaryotic virus families indeed split them into 70 separate clusters of tailed phages genetically equivalent to family-level assignments of eukaryotic viruses. It further divided several bacterial and archaeal (Lipothrixviridae) families. We also found that the subfamily-level groupings of tailed phages were generally more consistent with the family assignments of eukaryotic viruses, and this supports ongoing reclassifications, including Spounavirinae and Vi1virus taxa as new virus families. The current study applied a common benchmark with which to compare taxonomies of eukaryotic and prokaryotic viruses. The findings support the planned shift away from traditional morphology-based classifications of prokaryotic viruses towards a genome-based taxonomy. They demonstrate the feasibility of a unified taxonomy of viruses into which the vast body of metagenomic viral sequences may be consistently assigned.Genome Relationship Applied to Virus Taxonomy (GRAViTy) is a genetics-based tool that computes sequence relatedness between viruses. Composite generalized Jaccard (CGJ) distances combine measures of homology between encoded viral genes and similarities in genome organizational features (gene orders and orientations). This scoring framework effectively recapitulates the current, largely morphology and phenotypic-based, family-level classification of eukaryotic viruses. Eukaryotic virus families typically formed monophyletic groups with consistent CGJ distance cut-off dividing between and within family divergence ranges. In the current study, a parallel analysis of prokaryotic virus families revealed quite different sequence relationships, particularly those of tailed phage families ( Currently, 4404 species are assigned to 735 genera, which in turn are assigned to 122 families ]. Similarly, the list of unclassified archaeal viruses with complete genomes was retrieved using the search terms . Only those from the GenBank database were collected. In total, the list comprised 576 whole genomes of unclassified bacterial viruses, and eight unclassified archaeal viruses (Table S4). The search was performed in February 2018. The genome of unclassified bacteriophages and archaeal viruses were run through the GRAViTy pipeline to identify which virus groups they might belong to. Our results (Table S5) show that 580 of the unclassified bacteriophages (573 viruses) and archaeal viruses (seven viruses) exhibit some similarity to group I dsDNA. A bootstrapped dendrogram depicting relationship among these unclassified viruses and the classified dsDNA viruses is shown in The list of unclassified bacteriophages with complete genomes was compiled from the NCBI database using the search terms [Click here for additional data file.Click here for additional data file."} +{"text": "Research on bile acids has increased dramatically due to recent studies demonstrating their ability to significantly impact the host, microbiome, and various disease states \u20133. AlthoMembers of the gastrointestinal tract (GIT) microbiota initiate bile acid metabolism via a critical first step catalyzed by bile salt hydrolases (BSHs) . These eA recent review by Dong and colleagues has reported in depth on many of the biochemical and structural features of BSHs that are summarized here . BSHs beClostridium perfringens BSH (Protein Data Bank ID 2BJF) has been captured with a hydrolyzed taurodeoxycholic acid (TDCA) substrate in its active site [Despite the conservation of their active sites and the similarity of their overall topology , BSHs haive site . Even wiLactobacillus and Bifidobacterium because these species are associated with deconjugation in the small intestine and harboring a BSH is thought to be a beneficial feature of probiotics [Clostridium and Enterococcus similarly display a high occurrence of BSH-positive strains. Recent work characterizing BSH encoding members of the Bacteroidetes phylum has begun to elucidate the phenotypes of gram-negative BSH activity [The broad distribution and abundance of BSHs in the GIT suggests that bile acid deconjugation is a selected adaptive trait of several bacterial species for symbiosis or pathogenesis within the host , 18. Theobiotics , 18, 19.activity , 21.Despite their single hydrolytic function, BSHs can be advantageous in various ways. Because some bile acids are toxic molecules due to their acidic nature and detergent-like properties , 23, BSHBrucella abortus BSH activity leads to membrane modifications resisting phagocytosis [Listeria monocytogenes exploits its BSH for survival in the bile acid-rich liver and gall bladder [Clostridioides difficile, which can use taurocholate (TCA) as a spore germinant, but vegetative cells are sensitive to most secondary bile acids [Lactobacillus johnsonii BSH activity has been shown to limit the eukaryotic pathogen Giardia duodenalis in vivo [Bacterial pathogens, like some commensals, use BSHs to persist and survive during host infection. ocytosis . Listeri bladder , 29. Altle acids . Similar in vivo . The varThe bile acid pool, influenced in part by microbial-encoded BSHs, in turn shapes the microbiome composition and function . This biDuring enterohepatic recirculation, circulating bile acids interact with BARs in all major organs to impart signals that regulate metabolic and homeostatic processes inside and outside of the gut, in which their transformations originate . The nucEscherichia coli engineered to express Lactobacillus BSHs were able to mimic these effects by modifying the bile acid pool, curbing lipid and cholesterol metabolism, and protecting mice from weight gain [Bacteroides thetaiotaomicron native BSH to modify the germfree mouse bile acid pool in a manner that reflects the BSH\u2019s in vitro substrate preferences, further supporting the notion that these enzymes can be delivered in a targeted manner to selectively manipulate the bile acid pool [Several studies have used mouse models to bridge the gaps between weight gain and/or obesity, the microbiota, and bile acids through the FXR signaling. Mouse models of diet-induced obesity have demonstrated that both the microbiome and FXR signaling are necessary for weight gain, implicating deconjugated primary and secondary bile acids as regulators of host metabolism , 36. Furght gain . Similarcid pool .Bile acid dysregulation has also been implicated in other diseases, though the role of BSHs in their etiology is not well understood. A mouse model of nonalcoholic fatty liver disease (NAFLD) demonstrated that symptoms could be relieved by inhibiting bile acid reabsorption, leading to a reduction in conjugated bile acids, and a reduction in FXR antagonism . BSH actCan BSHs be used to alter the bile acid pool to rationally alter the gut microbiota and shape host physiology?Are BSHs required for general bacterial fitness and competition for nutrients? Is this context dependent? What happens in the face of inflammation and other disease states?Can BSHs be engineered with increased activity and substrate specificity for certain bile acids? What amino acid residues are important for determining bile acid substrate specificity?How do BSHs with different activity and substrate specificity alter the bile acid pool, microbiota, and host response in different regions of the GIT? How will BSHs be delivered to the different regions of the GIT?"} +{"text": "Cumulative Dis/Advantage (CDA) theory concerns how societal structure influences individual developmental and health trajectory across the life span, but few studies have applied CDA in the international setting with gender comparisons. This study provides a cross-national perspective to test CDA in explaining health inequality between developing and developed countries. Cross-sectional harmonized data from the international Health Retirement Study-series in 2013-2014 were used . Four health indicators were included: self-reported health, depressive symptoms, functional ability, and memory. Sociodemographic information and health behaviors were used as covariates. Regression models were fitted to examine the moderation roles of country and gender in health trajectory in later life. Results indicate self-reported health and mental health remained steady while functional ability and memory declined across late life span. Older Chinese and Mexican respondents had poorer health status than their British and American counterparts consistently except for memory in the Mexican data. Cumulative health gaps between developing and developed countries existed only for functional ability. Females in the four countries had poorer health than their male counterparts except their memory status. We conclude that CDA explains only the temporal decline of functional ability and its increasing gaps in later life between countries. Health inequality between countries could be attributed to the limited availability of healthcare and social resources in developing countries. However, other health status, including general health and mental health, depend more on individuals\u2019 intrinsic capacity and human agency."} +{"text": "CareSearch is an Australian Government Department of Health funded repository of evidence-based palliative care information and resources. The CareSearch Allied Health Hub was developed in 2013 to support all allied health professionals working with palliative care clients in all clinical settings. This cross-sectional online survey sought to elicit allied health professionals palliative care experiences and subsequent considerations for educational and clinical practice needs. The survey was disseminated nationally via a range of organisations. Data was collected about palliative care knowledge, experience working with palliative care clients and professional development needs. Data were evaluated by profession, experience and practice setting. In total, 217 respondents answered one or more survey questions (94%). Respondents (65%) reported seeing >15 palliative care clients per month with 84% seen in hospital and community settings. Undergraduate education underprepared or partially prepared allied health professionals to work with these clients (96%) and 67% identified the need for further education. Access to postgraduate professional development was limited by available backfill and funding. Study findings support the importance of free, accessible, relevant educational and professional development resources to support clinical practice. This is particularly relevant for allied health professionals who have limited opportunities to attend formal professional development sessions. The World Health Assembly Resolution 2014) recommends palliative care be considered as a component of comprehensive care throughout the life course due to rapidly increasing numbers of people with palliative care needs [4 recommeAllied health professionals play a key role in the care of people with palliative care needs in all health care settings . They bring profession-specific knowledge and skills that can be essential in addressing the person\u2019s individual care needs. They can provide non-pharmacological symptom control options alongside pharmacological interventions. Their care approaches enable continuing participation in essential and valued daily activities ,4. AllieAllied health professionals can make important contributions in the treatment and non-pharmacological management of symptoms, alongside improving the quality of life for palliative care patients and caregivers. Increasing numbers of allied health professionals employ a rehabilitative approach to optimise function of palliative care patients . ManagemLittle research considers the type of end-of-life care interventions being provided outside of specialist palliative care settings, the experiences of allied health professionals and their education and practice needs in these non-specialist settings. The purpose of this study was to survey allied health professionals across Australia on their understanding and views about palliative care, of its relevance to practice, their knowledge, and their clinical information education needs. The aim of this paper is to present survey results pertaining to palliative care training and continuing educational needs. Qualitative survey results presenting allied health professionals\u2019 knowledge and views about palliative care are presented elsewhere .This study was a purpose-designed cross-sectional survey of Australian Allied Health Professionals. For the purposes of this survey, allied health professionals included were those most likely to work with palliative care clients in specialist or generalist settings. Survey functionality and face validity was determined by piloting the questions with the Executive Officer of Allied Health Professions Australia (AHPA) and representatives of the CareSearch Allied Health Hub advisory group prior to distribution (available from authors on request). The survey design and conduct were reviewed against the CHERRIES checklist . Ethics approval for this study was provided by the Flinders University Social and Behavioural Research Ethics Committee (Project 7014). Participant consent was implied through commencement of the online questionnaire. Allied health professionals were recruited to complete the survey through member newsletters of the Allied Health Professions of Australia and through social media channels such as CareSearch, LinkedIn and Twitter. Allied health professionals approached to participate in the survey included occupational therapists, physiotherapists, speech pathologists, social workers, dietitians, psychologists and music therapists. These allied health disciplines were represented in the CareSearch Allied Health Hub. It is not possible to determine how many people were offered the opportunity to participate in the survey due to the variety of approaches via member networks and social media but it is estimated that the networks alone represented more than 120,000 allied health professionals.Participants accessed the participant information sheet and the online survey through embedded hyperlinks within newsletters or social media posts. Data were collected from 1 November 2015 to 30 April 2016, and included 42 items on palliative care education and professional development, practice, and attitude.n) and proportion (%). As it was not compulsory to respond to each survey item, there are varying levels of missing data for every question. Individual n values are presented for each item to indicate completeness of responses. Differences in proportions between groups were evaluated using Chi-square statistics. Statistical analyses were conducted using IBM SPSS version 23.0 (IBM Corp) and statistically significant differences (p < 0.05) are highlighted in bold.This paper reports on demographic data and descriptive statistics. Categorical data are reported as number of respondents were incomplete. Sociodemographic characteristics are reported in Occupational therapists, social workers, physiotherapists and dietitians comprised 86% of the sample . Fifty sOver half of allied health professionals felt their undergraduate training did not prepare (54%), or only partially prepared them (42%) to care for palliative care patients and/or their families. Many allied health professionals had previously undertaken professional development in palliative care, most frequently by reading and short in-service training sessions within their workplace. Palliative care educational opportunities appeared to be frequent, with 68% reporting their most recent opportunity was within the last year. Over one-third (39%) had completed online learning modules. While approximately 10% had specific qualifications in palliative care, 67% indicated that they needed additional education to better inform their clinical practice when working with palliative care patients. However, respondents reported barriers to accessing education, most frequently citing time (41%) and funding (33%) as primary limitations. Lack of available leave or backfill to cover clinical caseloads and limited knowledge about specialised or relevant educational opportunities also prevented access to education .There were no significant differences in palliative care qualifications or need to access palliative care education by allied health discipline. However, speech pathologists (70%) and physiotherapists (75%) felt the least prepared by undergraduate education and reported needing higher levels of postgraduate training in order to work effectively with palliative care patients (data not shown).Further training in grief and loss (56%) and symptom management (54%) were identified as priorities by the majority of disciplines . HoweverWhen asked to reflect on difficulties encountered in their most recent palliative care experience, most allied health professionals reported caseload or time demands as limiting (57%), while some reported feeling overwhelmed discussing non-medical topics (15%), and at their inability to take time out (14%). The proportion of allied health professionals who reported changing mindsets about working with palliative care patients differed by years of experience post-training. Those with the least experience reported this to be a greater problem at more than double the number of professionals overall (46% versus 23%). Additionally, the proportion citing a lack of palliative care knowledge or skills making their palliative care experiences difficult was significantly higher for those with less experience and those working outside of specialist palliative care settings. Forty-three percent of all respondents noted that access to postgraduate professional development was limited by available time, cost/funding, workload pressures and backfill. Further, allied health professionals working outside of a palliative care service were far more likely to report feeling overwhelmed discussing non-medical topics compared with medical topics than those working within this setting.A diverse allied health workforce delivers patient care in metropolitan, regional, rural, and remote settings. Each setting brings with it specific workforce issues and needs. Given lower life expectancies and high levels of chronic disease in lower socioeconomic areas, existing allied health models of care need to take into consideration ways to best support patients and caregivers at the end-of-life . For exaA recent study of occupational groups working in long-term care settings highlighted the differences in palliative care-specific educational needs and the intensity of inter-professional collaboration . UnderstOnline resources targeting context-specific needs have been found to build confidence of allied health professionals who work with palliative care patients and were accessed by survey respondents. Australian palliative care resources that specifically address the allied health context such as the Allied Health section on the CareSearch website and the This study had some limitations. Respondents were a self-selecting sample of allied health professionals, some of whom already worked in palliative care. This may have led to under-representation of generalist clinician professional development needs. Numbers of respondents are small and not equal for all disciplines, hence their responses may not be representative of individual discipline educational needs.Allied health professionals have an active role to play in the physical, social, emotional and spiritual care of palliative care patients and their caregivers. However, in order to do this allied health professionals require access to evidence-based education to enable better support of patients and their caregivers as deterioration ensues. Allied health professionals working in rural and remote locations often take on specialist generalist roles but require adequate support to provide quality care to patients with complex palliative care needs. Generalist allied health professionals in particular require targeted post-graduate education, particularly around grief and loss and non-pharmacological symptom management. Online resources such as CareSearch and End-of-Life Essentials and clinical placements such as those offered through PEPA can support all allied health professionals in non-specialist palliative care settings to develop and sustain clinical skills through best available evidence and clinical networking."} +{"text": "Patients\u2019 survival for most cancer types is slightly improving due to progress in faster diagnosis and advances in treatment. However, median period of survival time of patients with pancreatic cancer, glioblastoma, metastatic melanoma, metastatic lung tumors, high-grade serous subtype epithelial ovarian cancer, abdominal bowel and esophagus tumors treated with standard therapies is extremely low. There are several reasons for this therapeutic failure. Tumor initiating cells are resistant to drugs, have the ability of self-renewal and can be source of metastatic spread. Other additional major drawbacks of standard therapies lie in a lack of tumor specificity of anti-cancer drugs and the emergence of drug-resistant cell subpopulations after radio and/or chemotherapy. Further progress in cancer therapy requires novel therapeutic modalities.HSV-MSC/GCV system [Physiological role of human mesenchymal/stromal stem cells (MSCs) is to regenerate damaged and used tissues in the body. MSCs possess the ability to migrate to the site of injury and secrete a variety of soluble factors and extra-cellular nanovesicles \u2013 exosomes capable of a number of functions inducing and supporting regenerative processes in the damaged tissue. MSCs recognize tumor as an injury, home in the tumor and, together with other cells, form the tumor stroma. Based on our experience with virus mediated cancer gene therapy, the tumor-specific tropism of MSCs inspired us to develop a targeted prodrug gene therapy mediated by MSCs engineered to express the yeast cytosine deaminase::uracil phosphoribosyl transferase fusion gene (yCD::UPRT), yCD::UPRT-MSC/5-FC system and MSCsV system . Both syV system . SpecifiV system melanomaV system and prosV system . In all HSV-MSC/GCV system. Tumor specificity of MSC suicide gene exosomes is rather broad, but tissue origin of MSCs can influence the tumor cell targeting and augment the suicide gene therapeutic effect. Exosomes secreted by MSCs derived from placenta selectively inhibit growth of prostate cancer cells. Generally, MSC-exosomes display a unique anti-tumor effect thanks to a variety of molecular species such as micro-RNAs within their cargo and the capability to activate multiple gene pathways [The explanation came when we found release of extracellular vesicles - exosomes from yCD::UPRT gene transduced MSCs. Exosomes incorporated mRNA of suicide gene in their cargo. Such exosomes we call MSC suicide gene exosomes. Size-exclusion chromatography of the secretome released from yCD::UPRT-MSCs revealed that the biological activity was clearly localized in the exosome fractions. These exosomes migrate to tumor similarly like MSCs, internalized tumor cells, therefore they kill tumor cells by intracellular conversion of prodrug 5-FC to cytostatic drug 5-FU and to 5-FUMP . Similarpathways . Since Mpathways .Exosomes from suicide gene modified MSCs have the potential to be a new class of highly selective cancer-targeted therapeutics. Composition of exosomes released from MSCs might be purposely modified to create therapeutically interesting exosomes for cancer treatment. Recently we reported a dual action of MSCs-yCD-UPRT-MSCs exosomes possessing beside mRNA of suicide gene also iron oxide nanoparticles. These nanoparticles were able to act both as a prodrug dependent therapeutic and hyperthermia inducing factor when tumor cells were exposed to alternating magnetic field .Our present research direction is headed to development of suicide gene exosomes for metastases. Human tumor cell specific exosomes with suicide gene we found to induce tumor cell death in a similar way as MSC exosomes (article in preparation). It was reported that aggressive tumor cells release exosomes creating pre-metastatic niche in body organs. Integrins of tumor exosomes determine organotropic metastasis. Therefore suicide gene exosomes prepared from primary human tumor might be used in future as a therapeutic tool for the patient-tailored therapy of metastases. The usefulness of prodrug gene therapy for cancer mediated by MSC suicide gene exosomes is now validated by animal studies.Described findings open new exciting possibilities for cancer gene therapy of human tumors that do not respond to standard therapies such as grade IV glioblastoma multiform. MSC suicide gene exosomes carry mRNA of suicide gene protected by the plasma membrane. They can travel long distances in the body, when administered intravenously might execute their therapeutic effect at a distant location. Accumulating evidence indicates that cancer therapy using MSC exosomes has multiple advantages over cell therapy. CM or exosomes are stable after intravenous administration and exhibit a superior safety profile.To be innovative cancer therapy curative; it must differ from standard therapies. The therapy should be targeted not only to tumor mass, but also specifically to tumor cells, drugs should be able to internalize both cancer stem cells and cancer cells and act intracellular. In this way it could be possible to avoid side effects, to prevent development of resistance and even kill already resistant tumor cells . Suicide"} +{"text": "Gorilla g. gorilla) from Dzanga Sangha Protected Areas, Central African Republic. We examined 43 fecal samples for GIPs and quantified strongylid nematodes. We characterized fecal microbiome composition through 454 pyrosequencing of the V1-V3 region of the bacterial 16S rRNA gene. Entamoeba spp. infections were associated with significant differences in abundances of bacterial taxa that likely play important roles in nutrition and metabolism for the host, besides being characteristic members of the gorilla gut microbiome. We did not observe any relationships between relative abundances of several bacterial taxa and strongylid egg counts. Based on our findings, we suggest that there is a significant relationship between fecal microbiome and Entamoeba infection in wild gorillas. This study contributes to the overall knowledge about factors involved in modulating GIM communities in great apes.Relationships between gastrointestinal parasites (GIPs) and the gastrointestinal microbiome (GIM) are widely discussed topics across mammalian species due to their possible impact on the host's health. GIPs may change the environment determining alterations in GIM composition. We evaluated the associations between GIP infections and fecal microbiome composition in two habituated and two unhabituated groups of wild western lowland gorillas ( The mammalian gastrointestinal microbiome (GIM) is essential in providing access to nutrients, regulating epithelial development, and shaping immunity Berg, . Thus, dGorilla gorilla gorilla showed that feeding behavior, geographical range and increased anthropogenic pressure may be important modulators of the gorilla GIM. Moreover, the GIMs of two gorilla species G. gorilla and G. beringei exhibit significantly different patterns, but the GIMs converge when hosts face similar dietary constraints, associated with low fruit availability in their habitats suggesting that in primates dietary constraints triggered during their adaptive radiation were potential factors behind the species-specific GIM patterns observed today infections on the composition and activity of the GIM has received increasing attention and several studies have been conducted in humans and animals that may change the gut environment, potentially leading to alterations in GIM composition proteins, which may function as proteases or pore-forming proteins that could affect epithelial integrity) can suppress innate and adaptive pro-inflammatory immune responses has been hypothesized to decrease gluten sensitivity and could serve as a potential treatment for celiac disease in Dzanga Sangha Protected Areas (DSPA), Central African Republic , which are highly prevalent in studied gorillas Does the fecal microbial diversity differ between individuals positive and negative for particular GIP? (ii) Does the abundance of specific bacterial taxa differ between individuals positive and negative for particular GIP? (iii) Is there a relationship between fecal microbial diversity and surrogate measures of intensity of parasite strongylid infection (egg counts)? (iv) Is there a relationship between abundances of specific bacterial taxa and surrogate measures of intensity of parasite strongylid infection (egg counts)?As a part of the long-term non-invasive monitoring of GIP infections and fecal microbiome/GIM of western lowland gorillas (G. g. gorilla) were collected at two research sites: Mongambe and Bai Hokou in the Dzanga sector of the Dzanga-Ndoki National Park (part of the DSPA complex), Central African Republic . Samples were diluted with water up to 50 ml volume and centrifuged for 5 min at 2,000 rpm. The sediment was weighed and re-suspended to 10 ml with 4% formaldehyde. For coprological examinations, Sheather's flotation with modified sugar solution was used (specific gravity 1.33) , Hasegawa et al. (Oesophagostomum or Necator. Therefore we divided the strongylid eggs found in gorilla samples into two categories: (i) Necator/Oesophagostomum and (ii) Mammomonogamus.We reported parasite presence/absence and for strongylid nematodes, also the intensity of infection expressed as EPG. Although the number of parasite eggs shed in feces may not be linearly correlated with the intensity of infection and 534r . Amplicon purification was done using the QIAquick PCR Purification Kit . Amplicons were multiplexed and pyrosequenced using 454 FLX-Titanium technology as described previously according to the manufacturer's protocol. The V1-V3 region of the 16S rRNA gene was PCR amplified using primers 27f with Entamoeba status as a predictor variable and gorilla social group as a covariate was fitted using MASS package ; eggs of Strongyloides, Necator/Oesophagostomum, Mammomonogamus, Bertiella, and Spirurida fam. gen and 3.13 EPG , respectively (see Table We detected: trophozoites of en Table . The medEntamoeba positive (Ent+) and Entamoeba negative (Ent-) individuals , weighted UniFrac , and unweighted UniFrac .We obtained a median sampling depth of 6,458 reads per gorilla fecal sample after sequence quality control with Entamoeba status as a predictor variable and gorilla social group as a covariate reached higher levels in Ent+ individuals. At the family level, Peptostreptococcaceae reached significantly higher levels in Ent\u2212 individuals , while unknown Selenomonadales , Erysipelotrichaceae , unknown Mollicutes , and Anaeroplasmataceae reached higher levels in Ent+ individuals. At the genus level, unknown Selenomonadales , unknown Erysipelotrichaceae , unknown Molicutes , unknown Deltaproteobacteria , Olsenella , and Dorea reached significantly higher levels in Ent+ individuals. Three out of six indicator taxa on genus level belonged among the 26 most abundant bacterial genera . We did not find significant differences in relative abundances of any other bacterial taxa between individuals positive or negative for other detected parasites (data not shown).We detected significant differences in relative abundances of indicator taxa, detected by Species indicator analysis and Random forest classifier, in te Table . Specifia Figure . AlthougEnt+ and Ent- individuals, even though they reached higher values in Ent+ individuals . Analyses of multivariate dispersion of communities or inter-individual variation within groups also did not show differences between Ent+ and Ent- individuals did not significantly differ between Necator/Oesophagostomum and Mammomonogamus (EPG) and overall fecal microbiome composition, as described by the first NMDS axis, NMDS1 . We found weak relationships only between relative abundances of members of phylum Verrucomicrobia, family Verrucomicrobia subdivision 5 and Necator/Oesophagostomum egg counts based on Spearman's rank correlations and linear regression models . We did not find any significant relationship between relative abundances of any bacterial taxa and Mammomonogamus egg counts using Spearmans rank correlation analyses and linear regression model (data not shown).Using linear regression models we found no relationships between egg counts of Figures , but wheNecator/Oesophagostomum and egg count of Entamoeba spp. is associated with the abundance of specific bacterial taxa in the gorilla gastrointestinal tract. The mechanism behind these observations is unknown, however, this may be a reflection of either direct or indirect interaction between entamoebas, the GIM, and the host immune system. The genus Entamoeba contains both pathogenic and commensal species and taxa that seem to be a signature of the fecal microbiome of gorillas even if they belong among minor taxa in gorillas must be tested molecularly, by specifically targeting the presence and expression of known parasite-associated virulence factors. Since large diversity of Entamoeba spp. has been observed in wild great apes that are not reflected in the fecal microbiome composition , the host immune machinery, and the other microbiota. To gain further insight into the specific nature of these interactions, it will be necessary to apply additional molecular approaches to assess GIP diversity and function at the mucosal level to understand how the host immune system reacts to the GIPs and their virulence factors, with subsequent consequences for gut bacterial communities. Likewise, the role of diet in this interaction should be clarified from a molecular perspective in terms of metabolic impact on the GIPs and the other microbiota. For more complex analyses adding other factors affecting fecal microbiome of great apes, e.g., sex and age would be also beneficial, nevertheless, it would require studying captive or larger number of habituated animals. Moreover, future work may be directed into analyzing the evolutionary correlates of GIP infections for health and disease in humans and great apes. Our results can have implications for understanding host-microbe interactions and gorilla welfare in both wild and captive conditions. Absence of GIP in captive apes may be responsible for particular health or digestive problems (together with other factors like diet), on the other hand, it is well-known that particular GIP in captive apes can reach higher intensities than in the wild and infected animals suffer from clinical outcomes which are rarely observed in the wild.Here, we examined the associations between GIP infections and the GIM composition of wild lowland gorillas. Although we did not observe notable changes in global bacterial community profiles in connection with GIP infections, we found significant relationships between KV and AG conceived the initial project design, with inputs from KP; BP KP and AT designed the field study and collected the samples; KV, AG, MT performed the microbial community analyses; BP performed parasitological analyses; KV analyzed the data with significant contributions from AG; KP, DM, KN, BreW, BryW, CY, RS, SL provided the financial support; KV wrote the initial manuscript with significant contributions from AG and KP. All authors reviewed the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer AK and handling Editor declared their shared affiliation."} +{"text": "Family caregivers play a crucial role in supporting older adults through home health (HH) episodes; yet no prior research examines factors affecting the adequacy of caregiver support during HH. We use a novel dataset linking nationally-representative survey data with HH assessment data for community-dwelling older adults to identify older adult characteristics associated with adequate caregiver support in four task categories during a subsequent HH episode. Weighted, multivariable logistic regression is used to model the likelihood of adequate caregiver support in each category. Multiple older adult characteristics prior to the HH episode were associated with greater likelihood of adequate caregiver support during HH, including: prior caregiver assistance with mobility, self-care, and health care tasks, living with others, and cognitive impairment. These findings reveal new risk factors for consideration in risk assessment and payment adjustments related to social determinants of health."} +{"text": "Obesity has been linked to multiple conditions including cardiovascular disease, cancer, and metabolic syndrome. While the relationship between obesity and these diseases is well-established, the relationship between obesity and changes in cognitive function is less clear. This study examined the effects of overweight and obese status on performance in tests of executive function and memory. It was hypothesized that overweight and obese individuals would perform worse than normal weight individuals. Data from 547 individuals who participated in the Midlife in the United States Refresher cohort were used. Body mass index (BMI) and waist circumference (WC) were employed as measures of obesity. Both variables were examined continuously and categorically (from NHBLI-defined cutoffs). Z-scores were computed for each cognitive test and averaged together to create separate composite scores for executive function and memory. When measuring BMI and WC continuously, higher BMI was significantly associated with lower executive function ; no significant association between executive function and WC was found (p=.162). When measuring BMI and WC with clinical thresholds, participants with overweight or obese WC had significantly lower executive function (p=.030). No overall association between BMI-based thresholds and executive function was found (p=.682). Memory did not differ between overweight/obese participants and healthy weight controls with continuous or clinical threshold specifications. These findings suggest that: 1) obesity may relate to poorer executive function but not worse memory, and 2) the way in which obesity is measured reflects saliently in the results. Future researchers should consider conducting sensitivity analyses with different obesity criteria."} +{"text": "Self-neglect includes persistent inattention to personal hygiene and the conditions of one\u2019s immediate living environment and is known to be associated with an increased risk of mortality among older adults. Although previous studies have shown that many individual factors predict self-neglect, neighborhood characteristics have received much less attention. Extant research has yet to consider connections between the conditions of one\u2019s neighborhood and self care over time. Using nationally representative longitudinal data from the National Social Life, Health, and Aging Project (NSHAP), we consider several features of neighborhood context in later life, including self-reported perceptions of neighborhood cohesion and neighborhood danger, neighborhood disorder (measured by interviewer ratings), and concentrated neighborhood disadvantage (using census data). Adjusting for individual-level factors , results from both lagged dependent variable and cross-lagged panel models find higher levels of neighborhood disorder to be associated with higher self-neglect scores (measured by interviewer ratings) over time. Social cohesion, perceived neighborhood danger, and collective efficacy were not associated with self-neglect when controlling for neighborhood disorder. These findings suggest that improving neighborhood disorder may be an effective approach for self-neglect prevention in later life"} +{"text": "The potential life-threatening consequences of catecholamine use for emergency circulatory support in Takotsubo cardiomyopathy-related acute heart failure is a major challenge in cardiovascular emergences. In their recent work in BMC Cardiovascular Disorders Ansari U. et al. demonstrated the harmful effects of catecholamines on the outcome of patients with Takotsubo cardiomyopathy. Concerning this matter we emphasize the usefulness of speckle-tracking-derived echocardiography for early recognition of an acute phase of a Takotsubo syndrome in order to avoid the deleterious effects of a catecholamine therapy in patients with Takotsubo-associated acute heart failure. We read with great interest the publication by Ansari U. et al. , in whicAlthough the etiopathogenesis of TTS is still under debate, the role of catecholamines appears central to the pathophysiology of TTS. There is increasing evidence that the reversible change in left ventricular (LV) shape associated with potentially life-threatening LV dysfunction, which characterize the acute phase of TTS reflect an uncommon myocardial response to sympathetic stimulation \u20134 PatienCatecholamines are still the first-line therapeutics in cardiogenic shock following acute myocardial infarction (MI), but are absolutely contraindicated in TTS patients, regardless of the severity of hemodynamic compromise. The potentially life-threatening consequences of catecholamine use for emergency circulatory support if the underlying cause of acute LV dysfunction is unrecognized TTS are therefore the main problem that can derive from diagnostic errors , 4, 5.c) reached up to 7 times higher value in the apex than in basal regions [c can be high enough to oppose circumferential myocardial fiber shortening which mainly generates the visible inward movement in this region and thus could explain the visually akinetic appearance of the apical regions in spite of the unequivocal prove of myocardial viability provided by the longitudinal strain data [Transthoracic echocardiography can be useful for early distinction between TTS and acute apical MI if attention is focused on regional myocardial function using the advantages of strain imaging.In patients with life-threatening acute HF, before coronary angiography becomes possible, echocardiography including also STE can identify a highly probable acute phase of TTS and in such patients, if absolutely necessary, any administration of cathecholamines should be continuously monitored by echocardiography and immediately stopped if the signs for TTS become more evident.Clinically (including laboratory tests), electrocardiographically, and even echocardiographically using only conventional echocardiographic techniques, TTS-related acute LV disorders closely mimic acute apical MI and without coronary angiography data these two etiopathogenically different diseases are almost indistinguishable. The only helpful conventional echocardiography signs which indicate that any sympathomimetic treatment can be deleterious are the detection of mitral valve systolic anterior movement (SAM) and high LV outflow tract (LVOT) pressure gradients. However, even during acute stress-induced LV dysfunction, LVOT obstruction because of mitral valve SAM is not evident in all patients with TTS . On the regions . Such anain data , 5. Suchain data . All the"} +{"text": "Choir interventions confer psychological benefits for persons with dementia (PwD) and their caregivers. However, less is known about whether physiological function also exhibits improvements pursuant to such social-cognitive interventions. The present study, based upon a subsample of the Voices in Motion (ViM) project, explored whether participation in an intergenerational choir results in systematic improvements in gait velocity for both informal caregivers and PwD . Longitudinal burst data from the first of three cohorts spanning 4 assessments over 3.5 months was analysed using multilevel modeling. Whereas caregivers exhibited significant improvements (p<.05) in gait velocity, PwD showed no improvement. Ongoing analyses are exploring additional cohorts, and whether improvements in gait dynamically covary with reductions in comorbidities . These results underscore the potential of choir for facilitating both psychosocial and physiological function for caregivers and PwD."} +{"text": "Traumatic lesions of the wrist occur frequently and may give rise to underdiagnosed secondary abutment syndromes. The latter are a common cause of incapacitating pain and limited range of motion, despite minimal or even absent alterations on radiographs. Moreover, the complex wrist anatomy often results in ignorance or underappreciation of these syndromes.This paper presents a pictorial review of frequent and rare secondary abutment syndromes at the wrist joint, which \u2013 in contrast to primary abutment syndromes \u2013 are not based on anatomical variants or congenital deformations. The merit of each imaging modality is briefly mentioned. Traumatic wrist lesions occur frequently. Subsequently, secondary abutment syndromes (SAS), a common cause of incapacitating pain and limited range of motion in spite of minimal or absent alterations on radiographs, may arise. They are often underappreciated due to the complex wrist anatomy and call for a thorough analysis of all wrist components.The aim of this pictorial review is to present an overview of SAS and to highlight the role of imaging.The wrist is a complex structure of cartilaginous joints with little intrinsic stability, but mainly relies on soft tissue constraints from various ligaments. The three-dimensional motion is very susceptible to disturbances of their complex surfaces and to ligamentous lesions .Wrist fractures are frequently missed on radiographs . LigamenThe secondary repetitive bony impaction may result in contusion with theSAS may give rise to complaints, sometimes appearing years after trauma. The predominant symptoms are restricted motion and incapacitating pain, exacerbated by activity. SAS may have a negative impact on the three-dimensional hand positioning during daily activities .Intra-articular fractures of the radius may heal with a residual step-off , seen onLunate bone impaction on its articular fossa may cause SAS. Parasagittal radial fractures Figure need carDistal radioulnar joint (DRUJ) fractures are difficult to evaluate on radiographs, particularly coronal sigmoid notch fractures Figure and B. BA relative ulnar shortening may appear after trauma, causing a DRUJ impingement Figure and F. EStyloid process fractures may fail to heal, resulting into fragmentation and collision during ulnar deviation. MRI highlights neo-articulation and BMO Figure . The tri9Due to styloid process length increase, impaction with the triquetral bone may appear Figure . As in tIn secondary positive ulnar variance, the latter abuts the lunate and/or triquetral bone and eventually leads to ulnar head deformation Figure . It may Extensive destruction of extrinsic ligaments leads to a proximal-ulnar carpal shift , creatinFractures appear most frequently at the scaphoid waist . Radial Avascular necrosis \u2013 probably due to chronic microtraumata \u2013 with deformation starts at the radial side . Due to On radiographs Figure , a widenMRI may also show this ligamentous tear Figure and the Hamatolunar abutment is related to lunate bony variants (Viegas type II). However, a posttraumatic disturbance of the carpal row alignment (Gilula) may induQuadrangular joint traumata may result in bony carpal boss . AlthougA large variety of pathologies may cause SAS. This underscores the need for a thorough posttraumatic joint evaluation. Follow-up radiographs and MRI are mandatory in the presence of clinical symptoms. Concerns about the prognosis \u2013 certainly in expert or insurance-related files \u2013 should encourage detailed assessment, as even small lesions may be very functionally disabling.Posttraumatic SAS may interfere with a large variety of normal daily activities, as the wrist is a crucial structure in the three-dimensional positioning of the hand. Some are fairly unknown and, due the complex anatomy of the wrist, a SAS is also often ignored or underappreciated."} +{"text": "Thousands of physicians attend scientific conferences each year. While recent data indicate that variation in staffing during such meetings impacts survival of non-surgical patients, the association between treatment during conferences and outcomes of a surgical population remain unknown. The purpose of this study was to examine mortality resulting from traumatic injuries and the influence of hospital admission during national surgery meetings.Retrospective analysis of in-hospital mortality using data from the Trauma Quality Improvement Program (2010\u20132011). Identified patients admitted during four annual meetings and compared their mortality with that of patients admitted during non-conference periods. Analysis included 155 hospitals with 12,256 patients admitted on 42 conference days and 82,399 patients admitted on 270 non-conference days. Multivariate analysis performed separately for hospitals with different levels of trauma center verification by state and American College of Surgeons (ACS) criteria.Patient characteristics were similar between meeting and non-meeting dates. At ACS level I and level II trauma centers during conference versus non-conference dates, adjusted mortality was not significantly different. However, adjusted mortality increased significantly for patients admitted to trauma centers that lacked ACS trauma verification during conferences versus non-conference days , particularly for patients with penetrating injuries, whose mortality rose from 11.6% to 15.9% (p = 0.006).Trauma mortality increased during surgery conferences compared to non-conference dates for patients admitted to hospitals that lacked ACS trauma level verification. The mortality difference at those hospitals was greatest for patients who presented with penetrating injuries. Variation in hospital staffing has been associated with increases in risk of patient morbidity and mortality. Mortality for both critically ill patients and those requiring emergent surgical intervention, for example, has been found to increase during nights and weekends, the so-called \u201cweekend effect.\u201d , 2 SimilDespite efforts to maintain high levels of quality healthcare delivery at all times, trauma centers continue to experience regular fluctuations in staffing, and the potential risks associated with those periods remains largely unclear. Multiple times each year, thousands of surgeons leave their respective institutions to travel to academic conferences. A recent study found that during national cardiology meetings, mortality decreased for high-risk patients hospitalized with heart failure and cardiac arrest. As the aIn this study, we examine the association between national surgery conferences and in-hospital trauma mortality. We also perform subgroup analysis on specific trauma populations and hospitals according to their different forms of trauma center accreditation. We hypothesize that mortality resulting from traumatic injuries increases during national surgery conferences, presumably due to fluctuations in staffing.We conducted a retrospective cohort study of trauma patients treated at hospitals participating in the American College of Surgeons Trauma Quality Improvement Program (ACS TQIP). The primThe study population consisted of patients meeting inclusion criteria for the ACS TQIP. TQIP is We included injured patients admitted to TQIP participating centers between January 2010 and December 2011. The data excludes children (age less than 16 years) and patients who lacked records for date and time of admission to the Emergency Department. We excluded patients who presented to emergency departments without signs of life, defined as an initial systolic blood pressure of zero, heart rate of zero, and Glasgow Coma Scale motor score of one. Rates ofa priori and obtained meeting dates from publicly available conference announcements. After identifying dates of each individual meeting, we created a composite \u201cmeeting\u201d variable that consisted of all surgery conference periods combined. The control group consisted of patients admitted three weeks before and after each meeting.The primary exposure variable was hospital admission during national surgery conferences that are consistently well attended by trauma surgeons. Conferences included annual meetings of the American College of Surgeons, the Eastern Association for the Surgery of Trauma, the Western Trauma Association, and the American Association for the Surgery of Trauma. We selected these conferences When modeling the influence of conference periods on mortality, we adjusted the probability of death for patients using the ISS, the motor component of the Glasgow Coma Scale, age, gender, race, initial systolic blood pressure in the Emergency Department, mechanism of injury, inter-hospital transfer status, payer type, and hospital teaching status.We first performed descriptive statistics using chi-square and Student t tests to compare patient characteristics in both cohorts. All tests were two tailed with \u03b1 = 0.05. We then performed risk adjustment of patient level factors and hospital teaching status using multivariable logistic regression models, clustering at the hospital level. We constructed the mortality model using forward selection, and the order of variable entry was determined by the c-index, a measure of the ability of a parameter to discriminate outcome. Continuous data (systolic blood pressure) exhibited a right-skewed distribution and was natural log-transformed in a manner consistent with the TQIP mortality model. We testeWe performed several sensitivity analyses. We first conducted falsification analyses to assess for potential confounding in the relationship between surgery meeting and non-meeting periods.\u201317 SpeciThe ACS TQIP registry included a total of 94,566 trauma patient admissions reported from 156 hospitals during the study period. Of those patients, 12,256 patients (13%) presented during national surgical conferences. Patients in both cohorts, those admitted during meeting compared with non-meeting periods, were similar with respect to their demographic and injury characteristics. The majority of patients were male and white, and falls were the most common mechanism of injury. The majority of patients in each cohort were treated at ACS level I university hospitals, and approximately one third of the patients in each cohort were transferred from other facilities, suggesting that patients were not diverted away from academic centers during surgical conferences. Patient and injury characteristics of each cohort are summarized in The study included data collected from 145 hospitals (2010\u20132011), with an addition ten hospitals included in 2011. The majority of participating hospitals had an ACS trauma verification level (I or II), however, a considerable number of hospitals without ACS trauma verification contributed data as well . We provided a summary of hospital characteristics in Overall risk-adjusted in-patient mortality was similar for trauma patients admitted during meetings compared with non-meeting periods (approximately 6%). Also, when we stratified patients by injury type (blunt and penetrating), patient mortality exhibited no difference between meeting and non-meeting cohorts. However, we found that when stratified by ACS trauma verification level, mortality increased significantly during meetings among trauma patients admitted to hospitals that lacked ACS trauma verification . That association was particularly pronounced at non-ACS verified trauma centers among patients with penetrating injuries, whose predicted mortality increased from 12% to 16%. We found in subgroup analysis by state verification level that the conference effect in non-ACS trauma centers was entirely driven by state verified level I trauma centers. In contrast, mortality remained unchanged during meetings compared with non-meeting periods for injured patients who presented to ACS verified trauma centers.When stratified by injury acuity (ISS\u226415 and ISS>15), we found no evidence in the overall patient cohort of conference effect among low-acuity patients and high-acuity patients . At trauma centers that lacked ACS trauma verification, we found statistically insignificant trends towards increased mortality during meetings among both low- and high-acuity patients . The association only reached statistical significance among high-acuity patients with penetrating injuries . We found no evidence of interaction effects between number of trauma surgeons and meetings, meaning the number of trauma surgeons did not contribute to mortality differences during meetings, so we did not include that variable in the final mortality model. Additionally, we found no evidence of interaction between patient characteristics and surgery meetings with regards to mortality risk. Odds ratios and predicted probability of risk-adjusted in-patient mortality during meetings compared with non-meeting periods are summarized for each patient cohort in We tested the robustness of our model and found no evidence that unmeasured confounding contributed to differences in in-patient mortality between national surgical meetings and non-meeting periods. Risk-adjusted mortality of trauma patients was similar during national meetings for oncology and health services research when compared with the three weeks before and after those meetings. That analysis included 114,918 patients, 17,154 patients admitted during meetings and 97,764 patients admitted during non-meeting periods. Subgroup analysis, stratifying patients by hospital ACS trauma verification level and injury type, produced no difference in mortality between cohorts (meeting and non-meeting) for non-surgery conferences. Results of those tests are summarized in We found substantial increases in mortality among trauma patients admitted to hospitals that lack trauma center verification by the ACS during national surgery conferences, particularly for patients who presented with penetrating injuries. Since typical risk factors such as ISS, age, and transfer status did not differ significantly between patients admitted during meeting and non-meeting periods, it is unlikely that high-risk patients were directed to or from particular hospitals during meetings. The increased mortality during meetings is most likely attributable to the selective decline of surgeons and changes in hospital staff composition that occur, potentially leaving hospitals with decreased capacity and/or capability to effectively treat injured patients. The finding that mortality increased among patients with penetrating injuries, in particular, supports this explanation, since those patients often require surgical intervention compared with patients whose injuries result from blunt mechanisms.Study of the conference effect phenomenon is limited. Cardiology conferences have been associated with decreases in both percutaneous coronary interventions (PCI) and cardiovascular mortality, whereas we found surgery conferences were associated with increased mortality for trauma patients. These diIt is also noteworthy that we found no such association between surgery meetings and increased mortality for patients admitted to ACS verified trauma centers. This finding may be due to trauma center adherence to the ACS guidelines. The American College of Surgeons Committee on Trauma (ACS-COT) has maintained guidelines for regionalized trauma systems since 1979, and the a priori for the purposes of this study. The study does not include a comprehensive assessment of all surgery, trauma, and critical care conferences. Inclusion of both additional specialty conferences and more granular attendance data, including the clinical experience of the attendees, may clarify the relationship between fluctuations in staffing during surgery conferences and trauma patient mortality.The primary limitation of our study was the inability to establish specific mechanisms by which patients admitted during national surgery conferences to hospitals lacking ACS verification had increased risk of mortality. Further study of variation in processes of care such as resuscitation practices and procedures may explain the influence of surgical meetings on clinical outcomes. Another limitation is that we selected four surgery conferences In this study, we identified a \u201cconference effect\u201d for trauma patients treated at non-ACS verified trauma centers, and we identified patients with penetrating injuries as particularly at-risk of increased mortality during national surgery meetings. Staffing criteria of trauma center verification by the American College of Surgeons appears to protect against the conference effect. These findings have important implications for both how hospitals prepare for conferences with regards to staffing and, potentially, how conferences themselves are structured to allow for increased remote participation.S1 TableAppendix A and Appendix B.(DOCX)Click here for additional data file.S1 File(DTA)Click here for additional data file."} +{"text": "Ductal adenocarcinoma is the most common pancreatic neoplasm. A variety of pancreatic lesions mimic pancreas ductal adenocarcinoma (PDAC), such as high-grade neuroendocrine tumors, small solid pseudopapillary tumors, metastases, focal autoimmune pancreatitis, and groove pancreatitis. These occasionally look similar in images, but they have differential diagnosis points. Familiarity with the imaging features of PDAC and its mimics is paramount for correct diagnosis and management of patients. In this essay, we describe imaging findings of PDAC and its mimics for differential diagnosis. Pancreas ductal adenocarcinoma (PDAC) accounts for 85\u201390% of all pancreatic neoplasms and is one of the leading causes of death worldwide 2. Variou3438Computed tomography (CT) is a useful modality for detecting and staging PDACs . PDACs u12Pancreatic NETs originate from the islet cells of Langerhans and are divided into low-, intermediate-, and high-grade according to the World Health Organization classification . High-gr71417SPTs are uncommon neoplasms with low malignancy potential, occurring predominantly in young women 19. Calci202222A previous study reported24Autoimmune pancreatitis (AIP) is an uncommon form of chronic pancreatitis caused by an autoimmune mechanism . It is a282930Groove pancreatitis is an uncommon type of pancreatitis affecting the pancreaticoduodenal groove, defined as the potential space between the pancreatic head, common bile duct, and duodenum . This in9259Neoplastic lesions such as high-grade NETs, small SPTs, and metastases and inflammatory lesions including focal AIP and groove pancreatitis can mimic PDAC. Abrupt narrowing of a dilated pancreatic duct is a usual imaging finding of PDAC. Although some mimics occasionally accompany pancreatic duct dilatation, they have points of differential diagnosis: presence of tumor thrombus and hypervascular liver metastases, absence of adjacent vascular invasion, and delayed enhancement pattern. In addition to these imaging findings, the shape of the narrowed pancreatic duct is a key imaging feature for discrimination of PDAC from other disease entities. Familiarity with the imaging features of PDAC and its mimics is paramount for managing patients in daily practice."} +{"text": "Research suggests that older adults with neurodegenerative diseases are at increased risk of developing a subsequent neurodegenerative or comorbid psychiatric disorder or both. Depression and other psychiatric conditions, though prevalent, are often under-diagnosed and under-treated among those with neurodegenerative conditions potentially leading to more rapid disease progression, poorer health outcomes and increased health care use. Few population-based studies have comprehensively examined the risk and temporal ordering of common neurodegenerative and psychiatric conditions, including whether these associations differ by age or sex. Initial findings regarding the incidence of ordered pairs of neurological conditions and psychiatric disorders will be summarized. This population-based retrospective cohort study will provide essential data to allow policymakers, planners and providers to better anticipate the prognosis and care needs of older adults with comorbid neurodegenerative and psychiatric conditions."} +{"text": "Hosts must recognize pathogen invasion and respond rapidly. The need for speed requires a low threshold for triggering a response, causing occasional false alarms. Host immune systems therefore require strong negative regulators to shut down unnecessary responses. The evolutionary consequences of rapid trigger dynamics balanced by negative regulators have received little attention. Here, we emphasize four aspects that influence the evolutionary genetics of immunity: diverse gene families of rapidly acting triggers opposed by slower-acting negative regulators, pathogen attack against negative regulators, diversifying selection of negative regulators by pathogen pressure, and heritability of immune-related disease from imbalance between triggers and negative regulators.Acropora digitifera has around 500 genes, sea urchins have approximately 200, and zebrafish have about 385 [A broad sensor array of receptors, located on the cell surface or in the cytosol, recognize pathogen-associated molecular patterns and trigger innate immunity. Common triggers include the peptidoglycan recognition proteins, gram-negative binding proteins, Toll-like receptors (TLRs), nucleotide-binding domain leucin-rich repeats (NLRs), and the cyclic GMP-AMP synthase (cGAS) system that detects double-stranded DNA (dsDNA) , 2. In tbout 385 . SpongesThese receptors trigger immune cascades that are often evolutionarily ancient within groups or across broad domains of life. Key components of such cascades include nuclear factor-\u03baB (NF-\u03baB) transcription factors, interferons (IFNs), interleukins, and Toll and immune deficiency (IMD) pathways \u20139. The pThe need for speed in immune response demands All organisms have an impressive array of negative regulators. Post-transcriptional modification of innate sensors and downstream molecules suppress the effect of the pattern recognition receptor triggers , 14. TriDifferent organisms will tune the tradeoff between faster response and lower error rates in different ways. A focus on the tuning of that tradeoff may lead to interesting comparative insights about the design of immune regulation.Leishmania exploits a negative TLR regulator to suppress production of key proinflammatory cytokines [Attackers use diverse mechanisms to block the expression of host innate immunity , 25\u201327. ytokines , virusesytokines , and manytokines .Invaders of insects alter the expression of an impressive variety of miRNAs, including negative regulators. Some pathogens express their own miRNAs to alter host immunity. The function of most miRNAs remains unknown, providing a rich topic for further study .Tumors also evolve to down-regulate immunity against cancer cells and often manipulate the normal repressors of immunity. For example, Vinay and colleagues note thaHosts gain by altering the specific sequences of their negative regulators to avoid recognition or mimicking by pathogen effectors. Negative immune regulators that are under attack may form diverse gene families and evolve relatively rapidly. Few prior studies have focused explicitly on the diversity and evolutionary rate of negative regulators.Drosophila, Lee and Ferrandon [Drosophila, genes involved in the response signaling cascade tended to be more conserved than recognition proteins, but those that functioned primarily in modulating the immune response showed evidence for positive selection far above the genomic average [In errandon note tha average .The nature of diversifying selection depends on the specificity of mechanisms by which attackers manipulate host immunity. In human immunity, attack against negative immune regulators may be relatively nonspecific, in the sense that the attackers may not be differentially targeting molecules based on sequence variability. By contrast, for the small RNAs that regulate immunity in plants, insects, and other organisms, the RNA sequences and the mechanisms of manipulation are likely to be highly specific. The more sequence-specific the mechanisms that attackers use to manipulate negative immune regulators, the stronger the diversifying selection will be.Regulation by strongly opposed triggers and repressors is prone to failure ( discussePlants may use miRNAs to tune the threshold for the triggering of immunity by the NLR pattern recognition receptors. Canto-Pastor and colleagues found thSimilarly, constitutively expressed inhibitors of the type I IFN response in human immunity may \u201cdetermine a threshold of activation of an antiviral response\u201d . A quantGenetic variability in triggers and negative regulators can lead to mismatches in the opposing regulatory components of innate immunity and various types of immune-related disease. One possibility concerns the various immune-related disorders associated with misexpression of type I IFN . AnotherOur hypothesis and these preliminary examples suggest that further study of genetic variability in the positive and negative regulators of immune cascades may lead to interesting insights about the heritability of immune misregulation."} +{"text": "Social capital is essential for healthy living in later life, and evidence indicates the importance of neighborhood context in facilitating access to this resource. However, additional research is needed to compare how objective and subjective indicators of context shape this association. We examine links between objective (census tract-level population density and composition) and subjective (perceived safety and quiet) indicators of neighborhoods and social capital . Data include participants age 65+ (N=259) from Wave 3 (2015) of the longitudinal Social Relations Study based in Detroit, Michigan. Multivariate analyses indicate respondents living in more densely populated neighborhoods reported more frequent contact with network members. Those perceiving their neighborhood as safe reported larger networks, more trust in and greater support exchanged among neighbors. Findings suggest both objective and subjective indicators of neighborhood context shape access to social capital, but perceptions play a larger role."} +{"text": "OBJECTIVES/SPECIFIC AIMS: The objective of this project is the application of complex fusion models, which combine observed and modeled data, to areas with sparse monitoring networks with multiple chemical components is under-developed. Such models could provide improved accuracy and coverage for air quality measurement predictions, an area greatly limited by the amount of missing data. METHODS/STUDY POPULATION: This project focuses on the development of methods for improved estimation of pollutant concentrations when only sparse monitor networks are found. Sparse monitoring networks are defined as areas where fewer than three criteria air pollutants (based on EPA standards) are monitored. Particularly, a multivariate air pollutant statistical model to predict spatio-temporally resolved concentration fields for multiple pollutants simultaneously is developed and evaluated. The multivariate predictions allow monitored pollutants to inform the prediction of nonmonitored pollutants in sparse networks. RESULTS/ANTICIPATED RESULTS: Daily, ZIP code level pollutant concentration estimates will be provided for 8 pollutants across South Carolina, and goodness of fit metrics for model variants and previously established methods will be compared. DISCUSSION/SIGNIFICANCE OF IMPACT: These methods utilize only widely available data resources, meaning that the improved predictive accuracy of sparsely monitored pollutant concentrations can benefit future studies in any US area by improving estimation of health effects and saving resources needed for supplemental air pollutant monitoring campaigns. Our method for estimation attempts to improve predictive accuracy and data availability for sparsely monitored pollutants and areas."} +{"text": "A 78-year old male presented to the emergency department after accidental dislodgement of his chronic gastrostomy tube. A replacement gastrostomy tube was passed easily through the existing stoma and flushed without difficulty. Confirmatory abdominal radiography demonstrated contrast in the proximal small bowel, but the patient subsequently developed epigastric pain and refractory vomiting. Computed tomography revealed the tip of the gastrostomy tube terminating in the pylorus or proximal duodenum. This case highlights gastric outlet obstruction complicating the replacement of a gastrostomy tube and the associated radiographic findings. A 78-year-old male with a history of stroke presented to the emergency department after accidental dislodgement of his chronic gastrostomy tube approximately five hours prior. The patient offered no other complaints and denied abdominal pain, nausea, or vomiting. On examination, he appeared comfortable with unremarkable vital signs. His abdomen was non-tender and demonstrated a patent, mature gastrostomy stoma. A replacement gastrostomy tube was passed easily through the existing stoma and flushed without difficulty. Confirmatory abdominal radiography revealed contrast in the duodenum and proximal jejunum, but no portion of the stomach was outlined . ShortlyGastric outlet obstruction related to gastrostomy tubes is rare.4What do we already know about this clinical entity?Dislodged gastrostomy tubes are commonly repositioned or replaced in the emergency department. Gastric outlet obstruction is a potential, albeit rare, complication.What is the major impact of the image(s)?Emergency physicians should be familiar with the appearance of gastric outlet obstruction due to gastrostomy tube malposition on contrast-enhanced plain radiography.How might this improve emergency medicine practice?Early identification of gastric outlet obstruction on plain radiography can prevent patient discomfort and the need for additional advanced imaging."} +{"text": "Notopteridae represents an old fish lineage with ten currently recognized species distributed in African and Southeastern Asian rivers. Their karyotype structures and diploid numbers remained conserved over long evolutionary periods, since African and Asian lineages diverged approximately 120 Mya. However, a significant genetic diversity was already identified for these species using molecular data. Thus, why the evolutionary relationships within Notopteridae are so diverse at the genomic level but so conserved in terms of their karyotypes? In an attempt to develop a more comprehensive picture of the karyotype and genome evolution in Notopteridae, we performed comparative genomic hybridization (CGH) and cross-species (Zoo-FISH) whole chromosome painting experiments to explore chromosome-scale intergenomic divergence among seven notopterid species, collected in different African and Southeast Asian river basins. CGH demonstrated an advanced stage of sequence divergence among the species and Zoo-FISH experiments showed diffuse and limited homology on inter-generic level, showing a temporal reduction of evolutionarily conserved syntenic regions. The sharing of a conserved chromosomal region revealed by Zoo-FISH in these species provides perspectives that several other homologous syntenic regions have remained conserved among their genomes despite long temporal isolation. In summary, Notopteridae is an interesting model for tracking the chromosome evolution as it is (i) ancestral vertebrate group with Gondwanan distribution and (ii) an example of animal group exhibiting karyotype stasis. The present study brings new insights into degree of genome divergence vs. conservation at chromosomal and sub-chromosomal level in representative sampling of this group. This ancestral teleost lineage retained primitive anatomical features 4 and, considering their very ancient origin (200 Mya), their current distribution pattern could reflect the vicariance events occurring after the Gondwana\u2019s break-up6. While some osteoglossiform families are restricted to Africa, other ones exhibit a patchy distribution, with species endemic to different continents7.The monophyletic fish order Osteoglossiformes represents an ancient teleost group with a geographic distribution restricted to the freshwater river basins13]. This lack of data is probably due to the worldwide distribution of the whole group and, on the other hand, the endemic status of majority of its species, thus hindering integrative studies that allow a globalized view of its evolutionary process.Their wide geographic distribution and basal position in the teleost phylogeny, qualifies this group as an excellent model for systematic, genomic, cytogenetic and evolutionary studies. However, only few cytogenetic and genomic studies have been undertaken so far, covering a limited number of osteoglossiform species , and CGH homology (intraclade genomic similarity). The groups/species relationships followed phylogenetic hypothesis based on DNA molecular markers available for family"} +{"text": "We highlight a range of strategies for establishment of three dimensional (3-D) airway and intestinal organoid models and evaluate the limitations and potential improvements in each system, focusing on their application in CF. The in vitro CFTR functional assays in patient-derived organoids allow for preclinical pharmacotherapy screening to identify responsive patients. It is likely that organoids will be an invaluable preclinical tool to unravel disease mechanisms, design novel treatments, and enable clinicians to provide personalized management for patients with CF.Cystic fibrosis (CF) is an inherited disorder where individual disease etiology and response to therapeutic intervention is impacted by CF transmembrane regulator (CFTR) mutations and other genetic modifiers. CFTR regulates multiple mechanisms in a diverse range of epithelial tissues. In this Review, we consolidate the latest updates in the development of primary epithelial cellular model systems relevant for CF. We discuss conventional two-dimensional (2-D) airway epithelial cell cultures, the backbone of It is cMajor advances in symptom management have been instrumental in delaying disease progression in CF. Administration of enzyme replacement therapy, nutritional support, mucolytic agents airway clearance techniques, and antibiotics for bacterial lung infection, along with early detection of disease has dramatically improved life expectancy in CF patients over the last 4 decades. The median age of death is now above 40 years airway and rectal organoids. We also discuss their emerging use as More than 2,000 CFTR mutations have been identified so far and at least 336 of these are reported to lead to symptoms characteristic of CF , reduced episodes of pulmonary exacerbations and improved body mass index (BMI) restored F508del-CFTR channel activity to 15% of wild-type CFTR in in vitro epithelial cell lines. It is thus not surprising that this model has a higher propensity of false-positive and false-negative \u201chits\u201d compared to that performed in primary human bronchial epithelial (HBE) cells.One of the major hurdles to the development of novel treatment regimens in CF is the bench-to-bedside translation of scientific knowledge. Many drugs that perform well in a laboratory setting fail to advance in clinical trials, largely due to inappropriate selection of Although CF is a monogenic disease, the diverse mutation variants identified within the CFTR gene as well as the presence of modifier genes (known and unknown), warrants adoption of new technologies to extend research capabilities. There is a clear unmet need for a representative library of patient-specific epithelial cell models for disease modeling, preclinical testing of drug response, and biobanking for future drug discovery. The cell models can be derived from embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), or tissue-resident adult stem cells. Whereas, ethical concerns pertaining the source of human ESC, limit their use in research, generation of CFTR gene corrected iPSC lines enable disease modeling, drug discovery and toxicology studies [reviewed in fluid and induced sputum samples usually do not provide sufficient cell counts to initiate culture. Therefore, supply of CF patient-derived HBE cells are often limited and hard to come by.The pulmonary epithelium is divided into three regions; upper , lower (trachea and primary bronchi), and distal small airway epithelia . Persistent inflammation, bacterial colonization, and airway structural changes in CF occur in the lower respiratory tract. Primary HBE cells are therefore the gold standard for studying CF disease pathogenesis and evaluating CFTR functional response cells are increasingly used as surrogates for the lower airway epithelium in CF research values . Expansion of epithelial cells is often necessary in the initial passages for biobanking purposes and to generate enough cell numbers needed to differentiate cells under air-liquid interface (ALI) conditions. HBE cells are most \u201c\u2212 transport in these cells is also preserved.Conditionally reprogrammed cells (CRCs) are generated by co-culturing patient-derived airway epithelial cells with irradiated fibroblast feeder cells. Specialized conditioned media (termed F-Media) which contains Rho-associated protein kinase (ROCK) inhibitor, promotes serial passages of airway epithelial cells and enhances population doubling without compromising the characteristic epithelial cell morphology. Both ROCK inhibitor and the feeder layer are essential in maintaining the stem cell-like phenotype evident in CRCs demonstrated some advantage over the standard CRCs. The modified CRCs could support airway epithelial cell growth up to passage 10 with robust formation of pseudostratified epithelium at the extended passage, although a modest decrease in CFTR-dependent Cl+ currents and Cl\u2212 conductance declined fairly rapidly after serial passage 6 and bone morphogenic protein (BMP), showed airway epithelial cells could be expanded up to 18\u201325 passages without loss of proliferative potential or are cultured in such a manner that they develop ECM-like scaffolds between them, thus mimicking the in vivo phenotype more faithfully. While cell-derived ECMs such as Matrigel have been most commonly used for development of organoids, their undefined components introduce inconsistency in replicating the native 3-D culture environment , which establishes intercellular cues or network in the Different methods for generating organoids (or spheroids) from human lung cells have been described to date, each producing organoids with distinct definitive structure and cellular compositions. Barkauskas and colleagues have elegantly reviewed the different lung organoids (airway organoids inclusive) established from varying lung progenitor cell populations, including basal cells in the proximal airways, secretory club Clara cells in bronchioles and alveolar type II cells in the alveoli, as well as those from embryonic and iPSCs , patient-derived intestinal epithelial cells also present an invaluable resource in characterizing the relationship between the CFTR gene mutation and the disease phenotype. More recently, they play an important role in the development of HTS strategies to elucidate novel drugs for the treatment of CF.ex vivo conditions. Other limitations to the use of rectal biopsies include the small number of biopsies collected (4\u20138 biopsies) and the need for all biopsies to be tested on collection day i.e., the biopsies cannot be preserved for further testing.Compared to human airway tissue, colon tissue damage in CF patients is minimal and the rectal epithelium is accessible in a less invasive manner. The abundant expression of CFTR in the distal colon makes rectal biopsies an attractive cellular source for interrogating CFTR function , inhibitors of TGF-\u03b2 and BMP signaling and the basement membrane matrix (matrigel). Intestinal organoids can be indefinitely cultured and remain genetically and phenotypically stable upon repeated passaging and long term culture overcome these limitations by extending the use of rectal biopsies in cultures. Intestinal organoids can be grown from crypts isolated from freshly isolated rectal biopsies. Crypts are rich in Lgr5The primary functional assay to assess CFTR activity in organoids, the forskolin-induced swelling (FIS) assay is CFTR dependent. This approach does not measure the net transepithelial ionic transport. Rather, forskolin is used to stimulate intracellular cAMP production which then activates CFTR at the plasma membrane. CFTR activation drives chloride and fluid flux to the organoid lumen , causing rapid swelling of organoids with functional CFTR or those derived from non-CF subjects. This swelling effect is significantly reduced or absent in organoids derived from CF subjects who exhibit differing rates of FIS with different classes of CFTR mutations and also between individuals with the same CFTR mutation , are either absent or present in negligible amounts in the gut to be functional (Rajendran et al., SAW, NTA, and SLW wrote the manuscript with critical input from CKH, LKF, AK and AJ.AK is a scientific advisor for Unizyme Laboratories A/S. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Acute traumatic patellar dislocations are encountered with relative frequency, making up 3% of all knee injuries. Typically witnessed in younger patients following sporting injuries, this injury can be debilitating, potentially leading to recurrent dislocation, pain, reduction in activity and patellofemoral osteoarthritis.Management of this injury remains controversial, and as such detailed magnetic resonance imaging (MRI) is increasingly recommended to help illustrate the exact nature of osteochondral and soft tissue injury, with a view to assessing the anatomical sequelae of patellar dislocation as well as the potential of recurrence and dictating the need for either conservative or surgical management in the acute setting. As such, awareness of the typical MRI findings in traumatic patellar dislocations may potentially aid in pursuing appropriate intervention for this pathology.This case describes a 33-year-old gentleman presenting to the emergency department following patellar dislocation. After failed departmental closed reduction, this patient progressed on to definitive anatomical MRI assessment followed by acute surgical intervention in the form of\u00a0medial patellofemoral ligament (MPFL) repair. This case allows for both illustration and discussion of typical radiological features associated with traumatic patellar dislocation. Acute traumatic patellar dislocations are encountered with relative frequency, making up 3% of all knee injuries . TypicalAssessment of a primary traumatic patellar dislocation is multifaceted, involving initial clinical history and examination followed by initial plain radiographic evaluation involving anteroposterior, lateral and axial views . While pThe following case report allows for illustration and discussion of some of the typical MRI findings one may encounter following acute patellar dislocation that may potentially precipitate subsequent definitive surgical intervention.A 33-year-old gentleman presented to the emergency department describing substantial right knee pain and swelling following a rotational injury. Inspection indicated significant joint effusion and subsequent examination showed absence of straight leg raise on the affected side. Plain radiographic evaluation of the knee showed lateral displacement of the patella Figure confirmiRadiological investigations displayed evidence of lateral patellar dislocation on plain radiograph Figure , as wellIn the context of failed closed reduction as well as confirmation of the diagnosis, associated soft-tissue injuries and presence of risk factors for recurrent dislocation, this patient subsequently proceeded to definitive surgical treatment in the form of MPFL repair, with excellent postoperative function and no further dislocation at 46 months postoperatively.Acute patellar dislocations are debilitating, with up to 58% of patients noting persistent limitation to strenuous activity and 55% failing to return to sport at six months following index injury ,4. WhileDetailed anatomical illustration of the patellofemoral joint and surrounding structures at time of injury has thus become increasingly important aspect of initial evaluation following this injury -8. This Given both the increased diagnostic role of MRI and the relative frequency in which this injury is encountered, particularly in the adult population, awareness of both the plain radiographic features and more importantly the MRI findings associated with acute traumatic patellar dislocation as\u00a0discussed above may aid in improved detection, earlier management and prevention of recurrent dislocations, hence reducing the potential debilitating effect of this injury ,2.Traumatic patellar dislocations most commonly occur laterally and are associated with injury to both the medial patellofemoral ligament and medial patellar retinaculum. MRI is becoming an increasingly important diagnostic tool in assessment of traumatic patellar dislocations, useful in both detecting associated cartilage and soft tissue disruption as well as risk factors for recurrent dislocation. As such, awareness of the typical MRI findings in traumatic patellar dislocations outlined in the above case may potentially aid in pursuing either definitive conservative or surgical treatment in this pathology."} +{"text": "Innate immune cells trigger sophisticated intracellular signaling pathways via innate immune receptors, including membrane-bound or cytosolic receptors3. Host innate immune activation results in the production of multiple effector molecules, including cytokines and chemokines as well as antimicrobial proteins, to combat invading pathogens and parasites4. In addition, innate immune cells, such as macrophages and dendritic cells, are the principal antigen-presenting cells that activate T cells, which are involved in more specific and delicate immune responses6. In particular, Th1 cell-mediated interferon (IFN)-\u03b3 can efficiently promote cell-autonomous host defenses against intracellular parasitic and mycobacterial infections through various effectors, including IFN-inducible GTPases, inducible nitric oxide synthase, and autophagy proteins8.Host\u2013pathogen interaction is considered a highly dynamic process between diverse microbial pathogens and hosts in all stages of pathogenic infection, from invasion to dissemination. Upon pathogenic infection, innate immune systems respond to pathogen-associated molecular patterns and activate immediate host inflammatory and antimicrobial responsesHere, a special issue of articles presents recent findings on how host immune and pathological responses are generated by intracellular signaling machinery, which can be activated at various stages of host\u2013pathogen interaction, and further describes how pathogens subvert host protective responses to establish an infection in the harsh environment inside host cells. In addition, this special issue includes invited reviews that discuss current knowledge of host defensive components and pathways, i.e., immune receptors, cytokines, signaling molecules, autophagy, and the microbiota. We further describe recent innovative trials based on studies of the host\u2013pathogen interface involving the therapeutic utilization of bacteria in the context of anticancer treatments. A comprehensive understanding of host\u2013pathogen interaction will provide new insights into the identification of novel targets for both host effectors and microbial factors and will lead to new therapeutic treatments for infections and other human diseases.9. Lee and coworkers provide a comprehensive summary of viral strategies that evade host cytosolic sensing to facilitate intracellular infection and replication of viruses. Although innate immune responses are essential for combating viral infections, they should be tightly regulated to prevent harmful host responses. Lee and coworkers also review recent findings on the positive and negative regulatory mechanisms for intracellular sensors in-host cells. Recent studies have uncovered key signaling molecules that participate in the recognition of cytosolic pathogen-associated molecular patterns (PAMPs) and the activation of innate immune responses against viral infection11. Ahn and Barber highlight the immune regulatory functions of stimulators of interferon genes and cyclic dinucleotides that can recognize microbial DNA from various pathogens, including bacteria, viruses, and parasites, as well as cytosolic DNA of self-origin from host cells. Investigations on the abundance of in-host effector mechanisms and pathogenic strategies will provide an ideal opportunity to develop innovative tools that can be utilized to modulate microbial pathogenesis.When encountering the host defense system, numerous intracellular pathogens employ a variety of evolved strategies to escape, modulate, and hijack host immunity during infection14. Jo and coworkers summarize the function of autophagy and xenophagy in mycobacterial infection and how to manipulate autophagy pathways to promote host-targeted therapeutics against mycobacterial infection. A more comprehensive understanding of the elaborate mechanisms by which host autophagy pathways overcome bacterial pathogenesis strategies may lead to more efficient antimicrobial defense strategies against numerous intracellular pathogens that can reside and replicate within the host cell cytoplasm16.Autophagy, a cell-autonomous catabolic pathway involving lysosomal degradation of cargos, is becoming recognized as an innate effector mechanism to enhance pathogen control and resolution of tissue pathology associated with infection18. Recent studies have also revealed the function of cytokines, including type I IFNs, IL-15, and IL-18, in the bystander activation of CD8\u2009+\u2009T cells, which are responsible for tissue injury in viral infections20. Shin and Kim will present a new concept of bystander response, which leads to pathological or protective outcomes, depending on the context. An understanding of the IFN-inducible responses in various aspects of host\u2013pathogen interactions will be essential for the development of effective therapeutics that also minimize tissue damage.When considering the role of type I and II interferons (IFNs) in the activation of antiviral and Th1 immune responses, respectively, it is generally accepted that IFN actions are typically required for protective immune responses against viruses and intracellular bacteria. Yamamoto and Sasai discuss recent progress on the cell-intrinsic defense mechanisms by which IFN-inducible GTPase-dependent host defenses exhibit antiparasitic and antibacterial responses. IFN-\u03b3-inducible GTPases, including guanylate binding proteins (GBPs) and immunity-related GTPases (IRGs), are essential in various aspects of immune protective functions, including the release of bacterial components, production of reactive nitrogen species, inflammasome activation, and autophagy21. To date, the majority of studies on host\u2013pathogen interactions have focused on comprehensive elucidation of the innate and adaptive immune responses during infection. Recently, several efforts have been made to manipulate genetically modified bacteria for utilization as a new form of therapeutic agent for the treatment of cancer22. Min and coworkers review the current trials, perspectives, and limitations of therapeutic approaches using live bacteria with tumor-targeting ability and discuss recent advances in our understanding of bacterium-tumor cell interactions.Accumulating evidence supports the importance of the gut microbiota in human health and diseases. Takeda and Maeda summarize the recent findings of molecular details in-host-microbe interactions in rheumatoid arthritis and how alterations at the interface between the host and microbes result in excessive inflammation and infection. In addition, this review will introduce multiple metabolic and immunological mechanisms by which the gut and oral microbiota induce the development of arthritisIn revealing a vast array of strategies adopted by host cells and pathogens during various stages of infection, paradigms are shifting. Accumulating evidence indicates a more diverse impact of pathogenic manipulations of host cells than previously known. This special issue highlights recent advances in studies that extend traditional concepts of host\u2013pathogen interactions toward new insights on innate and adaptive immune signaling, molecular pathogenesis, host-directed therapy, and manipulation of bacteria for anticancer therapy. We believe that the cutting-edge reviews presented here will provide novel insights into the growing area of host\u2013pathogen interface signaling, thereby expanding basic knowledge for use in clinical applications. Studying the basic and applied fields relating to this topic will promote our knowledge of highly complex host\u2013pathogen relationships and facilitate future investigations in this area for the development of improved therapies against infections."} +{"text": "PARKIN gene cause early-onset Parkinson\u2019s disease (PD). Despite the high proportion of still missing phenotyping data in the literature devoted to early-onset PD, studies suggest that, as compared with late-onset PD, PARKIN patients show dystonia at onset and extremely dose-sensitive levodopa-induced dyskinesia (LID). What pathophysiological mechanisms underpin such early and atypical dyskinesia in patients with PARKIN mutations? Though the precise mechanisms underlying dystonia and LID are still unclear, evidence suggests that hyperkinetic disorders in PD are a behavioral expression of maladaptive functional and morphological changes at corticostriatal synapses induced by long-term dopamine (DA) depletion. However, since the dyskinesia in PARKIN patients can also be present at onset, other mechanisms beside the well-established DA depletion may play a role in the development of dyskinesia in these patients. Because cortical and striatal neurons express parkin protein, and parkin modulates the function of ionotropic glutamatergic receptors (iGluRs), an intriguing explanation may rest on the potential role of parkin in directly controlling the glutamatergic corticostriatal synapse transmission. We discuss the novel theory that loss of parkin function can dysregulate transmission at the corticostriatal synapses where they cause early maladaptive changes that co-occur with the changes stemming from DA loss. This hypothesis suggests an early striatal synaptopathy; it could lay the groundwork for pharmacological treatment of dyskinesias and LID in patients with PARKIN mutations.Mutations in the PARKIN gene cause autosomal recessive juvenile parkinsonism (ARJP) (PARKIN mutations differ from those observed in idiopathic Parkinson\u2019s disease (iPD). Unlike iPD, neuronal loss is greater in the substantia nigra pars compacta (SNpc) than in the locus coeruleus in most parkin cases. Also, Lewy bodies are not detected in the majority of parkin cases, suggesting a difference in the pathogenic processes between PARKIN-related disease and iPD . Autopsy and iPD . Also, Pfeatures , 2018. Efeatures . Early d and DJ1 . Since PPARKIN mutations and the recent evidence that parkin modulates glutamatergic neurotransmission. We discuss the hypothesis that early hyperkinetic symptoms of PD patients with PARKIN mutation may be considered manifestations of corticostriatal synaptopathy. These features can be linked to dopamine depletion, a well-recognized mechanism in the literature, but they also may be related to a potential direct effect of parkin on the corticostriatal synapse.Here, we review the clinical evidence for early hyperkinetic symptoms in patients with PARKIN gene in two families , prompts screening for PARKIN mutations along with GTP cyclohydrolase 1 and tyrosine hydroxylase in clinically diagnosed DRD patients . MSNs arThe molecular signatures that have recently emerged as key signals in LIDs are ERK1/2 phosphorylation , abnormaPARKIN patients. Clinical studies with [18F] Dopa as a marker of the functional integrity of pre-synaptic dopamine nerve terminals have shown that Parkin mutated patients have widespread pre-synaptic dopaminergic deficits and thus regulates its function: loss of parkin increases KAR levels in the human cortex and KAR function in glutamatergic hippocampal neurons in vitro (in vitro study showing that parkin-deficient hippocampal neurons exhibit significantly reduced AMPA receptor-mediated currents (PARKIN mutations disturb glutamatergic synaptic transmission by directly changing NMDAR, AMPAR, and KAR receptor function. Since parkin is widely expressed in various brain regions and neuron types, including cortical neurons and MSNs, (in vitro . At the in vitro . The rolcurrents . The sugcurrents . Hence, nd MSNs, it is coParkin gene. Unfortunately, studies on the nigrostriatal pathway revealed many discrepancies probably deriving from different experimental conditions and/or from in vivo age-dependent compensatory mechanisms. Increased spontaneous DA release from SNc DA neurons was found in Parkin-knockout mice aged 8 to 9 months (Parkin knockout mice (Parkin-knockout mice, DA levels were reported to be indistinguishable (Parkin-knockout mice (Parkin-knockout mice. Studies on corticostriatal synapses performed by intracellular recordings of MSNs revealed impairment in long-term depression and long-term potentiation in Parkin-knockout mice (Parkin-knockout mice do not show DA neuron loss, motor impairment, dystonic phenotype or hypersensitivity to levodopa (PARKIN mutations were observed to potentiate glutamatergic transmission by modifying synaptic vesicle function at the pre-synaptic site of the corticostriatal synapse (PARKIN mutations. In particular, as compared with control neurons, the parkin-deficient neurons had a stronger response to the activation of D1-class dopamine receptors (These studies on the localization of parkin and its capacity to directly regulate excitatory transmission constitute an important step toward understanding the functions of parkin at the synapses . The com9 months . Decreasout mice . In the uishable . DA overout mice . Indeed,out mice . These rlevodopa . The autlevodopa ; nonethe synapse . Moreoveeceptors .This raises the possibility that parkin could be involved in D1 receptor hypersensitization after dopaminergic denervation, an important mechanism underlying the dyskinesia in iPD . AccordiTaken together, these findings suggest that parkin orchestrates a complex remodeling of corticostriatal synapses through multiple mechanisms. These mechanisms are likely to include changes due to DA depletion as well as those due to loss of parkin function at these synapses: alterations in the trafficking of glutamate vesicles at the glutamatergic pre-synapse and/or dysregulation of glutamate receptor levels on MSNs and/or dysregulation of D1-signaling. These mechanisms may be responsible for the precocious maladaptive plasticity of the corticostriatal synapses that leads to early dyskinesia .PARKIN mutation affects corticostriatal transmission, leading to early maladaptive changes in this glutamatergic synapse. This alteration could produce changes due to corticostriatal-induced depletion of DA at the synapses. What does this scenario imply for the development of specific and effective treatments? The only currently available drug for symptomatic treatment of dyskinesia is amantadine, an antiviral agent introduced in the early 1970s that also displays NMDA receptor antagonism (PARKIN patients and late-onset PD patients could be relevant for devising precision medicine strategies for parkin patients. The recent discovery that LID is caused by a distinct and stable group of striatal neurons (Since the parkin protein modulates glutamatergic receptor function and possibly glutamate release as well, it is conceivable that tagonism . With a tagonism . Moreove neurons paves thPARKIN mutation.In conclusion, published data support the hypothesis of an early corticostriatal synaptopathy in parkin patients caused by parkin modulating the glutamatergic synapse. This hypothesis could provide a biological basis for studying the disease phenotype and lay the groundwork for the pharmacological treatment of PD patients with JS wrote first draft of the manuscript. FV and AC reviewed and critically revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Background: The current study examines the cross-sectional association between everyday discrimination and kidney function among older adults. Methods: We use cross-sectional data from a nationally representative sample of older adults to examine this relationship. Our measure of kidney function derives from the estimated glomerular filtration rate (eGFR) obtained by the Chronic Kidney Disease Epidemiology Collaboration equation, while our indicator of everyday discrimination is drawn from self-reports. Results: Results from our ordinary least squared regression models reveals that, after adjusting for demographic characteristics, everyday discrimination was associated with lower mean eGFR . The relationship between everyday discrimination and kidney function was not explained by cardiovascular, metabolic, or economic factors. Conclusions: Findings suggest this study suggest that everyday discrimination may be a unique risk factor for poorer kidney function among older adults. Because these findings are cross-sectional, additional research is needed to determine whether the observed associations persist over time."} +{"text": "Molecular Cancer, Wang and colleagues\u2019 work revealed the common and histopathological subtype-specific circular RNA (circRNA) expression patterns between LUAD and LUSC and highlighted the important diagnostic potential of circRNAs in lung cancer [Few studies have used high-throughput RNA sequencing for functional characterization of patients with non-small cell lung cancer (NSCLC) including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). In a study recently published in g cancer .p-value \u22640.05 and fold change \u22652), differential expression of 50 and 172 circRNAs was identified in tumor tissues of LUAD and LUSC, respectively. In addition, 26 circRNAs were commonly deregulated in both tumors. Moreover, another independent cohort of 67 lung cancer patients\u2019 samples were subjected to experimentally validation of RNA-sequencing data. Results were consistent and validated the accuracy and robustness of the circRNA analysis pipeline.To obtain a comprehensive and accurate quantification of circRNAs, the authors analyzed high-throughput RNA sequencing data from 10 pairs of lung tumors and their adjacent normal tissues using five computational tools. Results revealed 17,952 circRNAs including 2593 previously unidentified circRNAs. Using stringent criteria curve analysis of several selected circRNAs and revealed high diagnostic potential of hsa_circ_0077837 and hsa_circ_0001821 in discriminating NSCLC from normal tissues. Authors\u2019 results also highlighted the potential application of hsa_circ_0001073 and hsa_circ_0001495 for diagnostic in the histopathological subtyping of NSCLC. Collectively, this study demonstrated that LUAD and LUSC as the major subtype of NSCLC share a common differential expression pattern, but also have their unique circRNA expression signatures. Identified circRNAs may serve as and new clinical tools for diagnosis of pathological subtypes of NSCLC and therapeutic intervention."} +{"text": "Dear Editor,The study by Terregino et al , outlineThe ECRS scale was tested with videos of students participating in objective structured clinical examinations (OSCEs) . CompariThe ECRS could also be used for a wide range of scenarios, including those appearing acutely medical. For example, a case about anaphylaxis allows the student to communicate with the patient and their family whilst prioritising acute management of the life-threatening condition. Additional notes could be added to the ECRS about how students balance emergency medical management with their communication towards the patient and family. This would allow students to act like physicians who manage medical problems alongside patient ideas, concerns and expectations. Focusing training on empathy ensures students display empathy in real-life scenarios as future doctors .Additionally, a modified ECRS could be used to practice other realistic clinical encounters including consultations across a language barrier. Although interpreters should be available for consultations, issues including administrative errors mean this may not happen. Non-native speakers may not pick up on empathetic phrases and therefore rely on nonverbal, compassionate behaviours that cross-cultural boundaries .To conclude, the ECRS appears to be a useful tool to assess medical student empathy in OSCEs to ensure students develop patient-centred communication skills . Whilst"} +{"text": "Circulating tumor cells (CTCs) slough off primary tumor tissues and are swept away by the circulatory system. These CTCs can remain in circulation or colonize new sites, forming metastatic clones in distant organs. Recently, CTC analyses have been successfully used as effective clinical tools to monitor tumor progression and prognosis. With advances in next-generation sequencing (NGS) and single-cell sequencing (SCS) technologies, scientists can obtain the complete genome of a CTC and compare it with corresponding primary and metastatic tumors. CTC sequencing has been successfully applied to monitor genomic variations in metastatic and recurrent tumors, infer tumor evolution during treatment, and examine gene expression as well as the mechanism of the epithelial-mesenchymal transition. However, compared with cancer biopsy sequencing and circulating tumor DNA sequencing, the sequencing of CTC genomes and transcriptomes is more complex and technically difficult. Challenges include enriching pure tumor cells from a background of white blood cells, isolating and collecting cells without damaging or losing DNA and RNA, obtaining unbiased and even whole-genome and transcriptome amplification material, and accurately analyzing CTC sequencing data. Here, we review and summarize recent studies using NGS on CTCs. We mainly focus on CTC genome and transcriptome sequencing and the biological and potential clinical applications of these methodologies. Finally, we discuss challenges and future perspectives of CTC sequencing. Circulating tumor cell (CTC) studies began in 1869 Ashworth , which hPrevious CTC studies have mainly focused on the development of CTC enrichment technology technology in NCBI PUBMED and found 19 CTC publications or to delete immune cells (CD45\u2212) , genome or transcriptome amplification, and sequencing and analysis Fig.\u00a0. SeveralAfter CTC enrichment from the blood, zero to several hundred CTCs may be retained in a thousand to ten thousand background cells, resulting in a low efficiency for sequencing and analysis of these cell pools CTC variation detection rate in a mean depth of 1500X of 14 CTCs. These authors concluded that there exists a high inter- and intra-patient heterogeneity in CTC mutational status is also frequently altered during cancer evolution. Ni et al. surveyed the CTC CNVs from a small-cell lung cancer (SCLC) patient during sequential chemotherapy treatment and observed that the evolution of CNV was consistent along the therapeutic stage, indicating that the reproducible CNV pattern was not affected by drug treatment (Ni et al. Previous studies have highlighted particular molecular pathways involved with cancer metastasis, such as TGF-\u03b2 signaling (Akhurst and Derynck WNT2 gene mediated the metastasis-associated survival signal, consistent with observations of the upregulation of multiple Wnt genes in pancreatic patients (Yu et al. Yu et al. first utilized single-molecule RNA sequencing and a mouse pancreatic cancer model and found that the The EMT of adherent epithelial cells to a migratory mesenchymal state has been implicated in tumor metastasis in pre-clinical models. Yu et al. characterized the dynamic cell fates in breast cancer CTCs and found an association of mesenchymal CTCs with disease progression (Yu et al. As shown in this review, CTC sequencing can now be used as an efficient liquid biopsy tool to investigate the spectrum of somatic variation and gene expression changes in primary, metastatic, and recurrent cancer patient tumors non-invasively. The somatic alterations could either be used to understand the origin, ITH, and evolution of tumors or to monitor disease progression during cancer treatment. The most important clinical implication of CTC sequencing is for personalized medicine, or so-called precision medicine, according to the variation spectrum detected, which indicates the selection of target therapy based on the CTC variation spectrum. With the development of CTC capture and SCS technologies, we can expect the establishment of more comprehensive cancer origins and evolution models in the near future. Moreover, more novel biomarkers or potential drug targets for cancer metastasis or drug resistance prevention or treatment can be identified through CTC sequencing.However, as mentioned above, sequencing a CTC genome or transcriptome faces technical challenges. Obtaining enough cells for library preparation and sequencing is the first critical step in CTC sequencing. However, various conclusions can be drawn from different studies based on different isolation method and cancer types. Some cancer types tend to generate more CTCs than other cancer types (Allard et al. More importantly, bioinformatics analyses of CTC sequencing data require additional quality evaluation and assessment, particularly the biases introduced during sample and sequencing library preparation Fig.\u00a0. Allele Despite the development of advanced microfluidics approaches, several novel sequencing technologies show promise for solving the technological hurdles to CTC sequencing. For example, scientists can now perform in situ DNA or RNA sequencing, even on samples fixed on slides (Lee et al."} +{"text": "Both affective and blood pressure (BP) reactivity are associated with long term risk of chronic disease and mortality. Thus, understanding age-related changes in negative affect and BP responses to everyday demands is vital for promoting healthy aging. However, few studies have examined both psychological and BP reactivity simultaneously, which would provide more comprehensive understanding of regulatory processes at play. For the present study, 232 adults aged 50-70 years were assessed at baseline and 6 years later with ambulatory BP monitoring and momentary electronic diaries. Reactivity coefficients were output from multilevel models and used to test changes in negative affective and ambulatory BP reactivity to task demand, longitudinally. Results indicate that both systolic and diastolic BP reactivity increase with age, while negative affect reactivity does not change with age. Results are discussed in the context of life course theories of role strain and role changes and socioemotional theories of aging."} +{"text": "Microbial consortia execute collaborative molecular processes with contributions from individual species, on such basis enabling optimized molecular function. Such collaboration and synergies benefit metabolic flux specifically in extreme environmental conditions as seen in acid mine drainage, with biofilms as relevant microenvironment. However, knowledge about community species composition is not sufficient for deducing presence and efficiency of composite molecular function. For this task molecular resolution of the consortium interactome is to be retrieved, with molecular biomarkers particularly suited for characterizing composite molecular processes involved in biofilm formation and maintenance. A microbial species set identified in 18 copper environmental sites provides a data matrix for deriving a cross-species molecular process model of biofilm formation composed of 191 protein coding genes contributed from 25 microbial species. Computing degree and stress centrality of biofilm molecular process nodes allows selection of network hubs and central connectors, with the top ranking molecular features proposed as biomarker candidates for characterizing biofilm homeostasis. Functional classes represented in the biomarker panel include quorum sensing, chemotaxis, motility and extracellular polysaccharide biosynthesis, complemented by chaperones. Abundance of biomarker candidates identified in experimental data sets monitoring different biofilm conditions provides evidence for the selected biomarkers as sensitive and specific molecular process proxies for capturing biofilm microenvironments. Topological criteria of process networks covering an aggregate function of interest support the selection of biomarker candidates independent of specific community species composition. Such panels promise efficient screening of environmental samples for presence of microbial community composite molecular function. Microbial communities display cooperation and leverage on synergies, all embedded on the level of entangled molecular processes across individual species. Occurrence of such traits is tightly controlled via given species genotypes and environmental conditions, and centers on cost and benefit . ExtremeCooperation displays as higher order function, i.e. molecular processes executed by the community being not reducible to any of its individual species alone. Higher order molecular functions may alter local environmental parameters, in turn imposing a feedback on cooperation mechanisms, individual species abundance and specific involvement. Examples for such community properties include occupation of sites lacking viable conditions for individual species, division of labor, and fostering significant increase in metabolic flux .Microbial communities hold profound relevance in industrial processes. One example is bioleaching, i.e. extraction of base metals from sulfide ores . A seconRational design and optimization of community function was recently demonstrated for copper bioleaching . HoweverExtrapolation from a species inventory to capabilities of embedded community molecular function is limited, as resolution of species interaction on a molecular function level is needed. Next to allowing optimization of given consortia properties such knowledge promises particular utility in molecular function prospecting. Such scenario focuses on identification of communities in environmental samples exhibiting specific aggregate molecular function of interest .Recalling that increased efficiency in bioleaching resembles a composite molecular process in the sense of a microbial community aggregate function, a relevant proxy for such molecular configuration is given as molecular biomarkers. Use of molecular biomarkers is further supported by recently identified evidence that function and underlying molecular processes of a community may be preserved while the species composition of a community exhibits a dynamic flux . FurtherBiomarker identification approaches include explorative methods, involving comprehensive functional gene arrays as well as various omics tools. For example, Roume et al. integrated omics profiling results on molecular interaction networks for characterizing the impact of environmental conditions on microbial communities relevant in biological waste water treatment . On the M composed of n individual microbial species mi, mj, \u2026 mn which together constitute the community. A higher order function results out of a composite molecular process pi, principally grounded on the set of protein coding genes gi, gj of all community species, hence the community genome G.Analysis of molecular context is of particular value when aiming at characterizing composite function. Microbial community representation has to focus on the species set G for deriving the specific set of cross-species processes pi, pj responsible for triggering phenotypic community characteristics. A biomarker in its definition serves as proxy for the status of a molecular process. Having identified candidate processes pi, pj responsible for a molecular function of interest in turn allows selecting corresponding candidate biomarkers bi, bj, where bi monitors the state of process pi, and bj of pj, respectively. Recalling the finding of community stability in terms of composite function but not in terms of species composition, such a biomarker panel may offer generalization in prospecting of environmental samples. Further, such biomarker panel approach realized as multiplexed assay may prove efficient for high throughput analysis of environmental samples.The composite molecular process sees involvement of molecular functionality (gene products) from different species, needing modeling of the microbial community on the level of in silico workflow for identifying biomarker candidate panels aimed at reflecting aggregate microbial community properties. Starting with a reference inventory of a functionally relevant subset of G further combined with interaction information allows deriving a molecular process graph. On the graph level, topological parameters aiming at resembling molecular process proxies as well as species coverage considerations are used for biomarker candidate selection. The resulting candidate biomarker panel is thus specific for the function in focus but to some degree agnostic regarding actual species composition. Such candidate panel promises generic applicability in bioprospecting regarding a composite molecular function of interest.On this basis we propose an While the workflow is applicable for studying various instances of microbial community aggregate function we in the following focus on community cooperation in forming a biofilm microenvironment in copper bioleaching/AMD. Biofilms can be instantiated by certain individual microbial species, however, in most environmental settings multiple species contribute molecular function to this microenvironment. In selected scenarios such environment provides grounds for emergent community phenotypes, including significant increase in bioleaching efficiency or initiation of AMD \u201315.The workflow illustrated in In a first step scientific literature is screened for microbial communities reported as relevant in a given focus (as copper bioleaching/AMD) for cataloguing constituent species genomes. In addition, biological community aggregate molecular functions reported as relevant are extracted. In a second step, catalogued genes are assigned to community molecular functions. Third, an all-against-all ortholog map is created for the gene set assigned to the biological function term in focus (e.g. biofilm formation), followed by consolidating protein-protein interaction information for the set of orthologs (step 4). With a gene set and respective interaction data at hand a molecular process model approximating the function term is retrieved (step 5), on this basis deriving topological parameters of the interaction network for guiding biomarker candidate selection (step 6). Finally, candidate biomarkers are forwarded to experimental evaluation (step 7).A list of natural acid mine drainage sites, major industrial bioleaching operations as well as suitable laboratory scale experiments, in the following referred to as \u2018sites\u2019, was compiled by mining the National Library of Medicine (NCBI) PubMed scientific literature repository in publication title and abstract for the terms \u2018bioleaching\u2019 and \u2018acid mine drainage\u2019. For all identified sites respective mineral endowment was extracted. For industrial mining sites additional mineral composition data were sourced from the Mindat database . AltogetNext, scientific literature covering the sites was screened for inventorying involved microbial species. 133 microbial species could be retrieved, of which 42 are specifically associated with one or more of the 18 copper sites.For each of the copper site-associated microbial species gene-centric annotation was retrieved from public databases as described previously . BrieflyEach copper site-associated species was evaluated for availability of annotation data for assigning protein coding genes to functional groups (COG) , and forA matrix of biological function terms and genes of relevance in copper bioleaching was obtained by manual data extraction from scientific publications reporting species given in Leptospirillum ssp. Group IV \u2018UBA BS\u2019 and T. arsenitoxydans) were sourced from the NCBI RefSeq database.A comprehensive all-against-all ortholog screening of the 25 species holding COG annotation was executed using the InParanoid pipeline (version 4.1) with default settings . As inpuProtein interaction information was retrieved from STRING and subsequently aggregated across all 25 species using ortholog screening results to obtain an interactome on the ortholog level. This procedure allowed inclusion of protein coding genes of species as such not represented in the STRING database on the level of identified ortholog sequences from respective species being covered in STRING. The resulting interaction matrix was used to derive an ortholog network.Topological parameters of the ortholog graph were calculated using the NetworkAnalyzer application of Cytoscape version 3.2.1 , networkFor evaluation of candidate biomarkers selected on the ortholog graph level resembling the composite process of biofilm formation available omics profiles were used. A scientific literature review identified omics profiles in scope of bioleaching/AMD providing a resolution on the level of protein coding gene products. Data sets of specific interest needed to resemble meta-transcriptomics or -proteomics profiles covering microbial communities exhibiting biofilms in various environmental or laboratory conditions.Leptospirillum and Ferroplasma species. To assess biofilm functional traits quantitative proteomics comparison of natural versus laboratory settings was conducted, complemented by determining biomass to estimate in situ chemoautotrophic production. Productivity in the laboratory biofilm community was nearly five times lower compared to its natural equivalent, being reflected in differential abundance of a range of metabolic proteins. The authors concluded that the differences in both production as well as protein expression profiles reflect metabolic stress in the laboratory biofilm. After optimization of laboratory culture conditions , community proteomics profiles resembled the environmental setting particularly in respect to expression of stress response proteins and community growth rates.Two data sets appeared particularly suitable with respect to biofilm formation serving as surrogate of bioleaching/AMD. The first study conducted by Belnap et al. covers proteomics profiling . The autFor calculation of differences in expression in the proteomics data the respective log2-ratios of abundance when comparing the optimized laboratory culture with a natural biofilm sample were subtracted from the respective abundance values comparing a standard laboratory culture with a natural biofilm. Respective fold changes are therefore indicative for the level of biofilm formation and are used in biomarker candidate evaluation with respect to prospecting the capacity of forming a composite biofilm microenvironment.A. ferrooxidans as well as L. ferriphilum and L. ferrooxidans, respectively. Further community members worth noting include Acidimicrobium ferrooxidans as well as several Acidiphilum, Ferroplasma and Sulfobacillus species, respectively. The study compared transcriptional profiles of natural planktonic and biofilm-associated consortia to gain insights into physiological differences between free and the sessile community fractions. This approach allowed a precise assessment of biofilm physiology determined on a genomic array of L. ferrooxidans, identifying as main contributors to the biofilm situation genes coding for quorum sensing, motility and chemotaxis, as well as matrix component production and transport.A second data source originates from a transcriptomics profiling study on bacterial communities isolated from the Rio Tinto acid mine drainage system published by Moreno-Paz et al. . The comIn biomarker evaluation the fold changes (log2-ratios) are used contrasting planktonic and biofilm status in focus of biofilm formation capacity.L. ferriphilum in continuous vs. bioleaching conditions, the latter being grown on 2% (wt/vol) chalcopyrite [A third study conducted by Christel et al. compared a culture of copyrite . The autThis study serves as negative control experiment for candidate biomarker evaluation, utilizing fold changes (log2-ratios) comparing cultures in absence and presence of chalcopyrite.Protein coding genes addressed in the three experimental studies were assigned to the ortholog graph via Basic Local Alignment Search Tool 2 (BLAST2) , selectiA. ferrooxidans (identified in 11 sites), L. ferrooxidans (9 sites), L. ferriphilum (7 sites) and A. cryptum, A. ferrivorans, A. thiooxidans and F. myxofaciens (4 sites each). Each site further reports a diverse and distinctive array of less frequent species.An important prerequisite for candidate biomarkers to be used in microbial community screening is applicability in absence of prior information about specific community species composition. Therefore a meta-analysis approach is applied starting with an inventory of microbial communities being involved in either bioleaching or acid mine drainage. Consortia retrieved from 70 environmental sites in focus of bioleaching/AMD provide 133 individual species. 18 sites report on copper sulfite ores with in total 42 individual microbial species. The majority (32) is comprised of Bacteria, complemented by Archaea. The four most prevalent species are Manual literature curation of molecular features involved in molecular processes relevant in acid mine drainage and/or bioleaching together with their molecular functional annotation identifies 14 molecular function categories holding 1,696 protein coding genes . The Clu20 of the 26 COG terms are addressed in the AMD/bioleaching context, with specific function terms seeing varying assignment to COG terms. For instance, chemotaxis is associated with 5 COG terms, on a gene count level mainly involving cell motility (N) and signal transduction (T). Other terms are considerably more complex, specifically the function term biofilm formation involving 19 COG terms. Main contributions come from cell wall/membrane/envelope biogenesis (M), cell motility (N), signal transduction (T), intracellular trafficking and secretion (U) as well as extracellular structures (W). Other complex functions with diverse COG term involvement include quorum sensing together with toxicant and copper resistance. Genes lacking COG annotation or being assigned to the unspecific COG terms R and S (Function Unknown) are not further considered.Related function terms map to similar COG term combinations. For biofilm formation, COG terms include cell wall biogenesis, signal transduction and trafficking/secretion categories. Comparable patterns of COG category involvement are found for quorum sensing and chemotaxis, reflecting close biological relationship.For deriving a biomarker candidate panel capturing major molecular aspects of relevance in both AMD and copper bioleaching, function terms covering a broad set of COG terms appear preferential, ideally further seeing broad involvement of microbial species. Of the 14 function terms, biofilm formation exhibits particularly broad COG term assignment as well as species coverage across the original catalogue of 25 copper mineral associated microbes, providing all ingredients for establishment of higher order molecular function. Furthermore, from a biological function perspective, establishment of biofilms is relevant in both acid mine drainage as well as bioleaching. As demonstrated, enrichment of consortia with microbes particularly competent in formation of biofilms significantly boosts bioleaching process efficiency . BiofilmAccordingly, the set of genes assigned to the aggregate function of biofilm formation is used as basis for deriving a protein coding gene interaction network, subsequently serving for biomarker panel selection.According to data retrieval and functional category assignment 272 protein coding genes are identified in the molecular context of biofilm formation. Ortholog screening of this set in the genomes of the 25 species provides 3,106 orthologs, identifying at least one ortholog for all but 23 genes. 57 of the 272 genes hold orthology to other members of the biofilm gene set and are removed to avoid biases from multiple sequence representation in subsequent molecular network retrieval.Ortholog information allows utilizing interaction information across species to derive an ortholog graph, thereby complementing interaction data by aggregation. This procedure enables inclusion of interaction information for finally 191 unique molecular features of the biofilm gene set in a sinL. ferrodiazotrophum, a diazotrophic mesophilic bacterium also found in AMD biofilms [L. ferrodiazotrophum efficiently fixes nitrogen, but its genome lacks annotation including COG term assignment and interaction data in STRING. The nitrogenase cassette is highly homolog to features found in other diazotrophic bacteria such as L. ferrooxidans and Acidithiobacillus ssp., i.e. the cassette is considered at the ortholog level.The ortholog network allows capturing molecular function of species as such not included in a species set. Representative for such an organism is biofilms . L. ferrThe ortholog graph serves as basis for identifying biomarker candidates according to network topology. Topological parameters characterizing the centrality of a given node capture properties related to the functional importance within its network context. Specifically, node degree and stress centrality resemble properties prone to biomarker candidate selection. Both centrality measures reflect affectedness of state changes in molecular processes, hence serving as proxies for molecular process status. Nodes with high degree centrality establish a large number of interactions, i.e. serve as network hubs . Nodes eThe relevance of degree and stress becomes apparent from Accordingly, biomarker candidates from the ortholog graph of biofilm formation showing high degree and stress centrality are deemed to serve as relevant proxy for the entire process, and promise sensitivity in monitoring the presence of biofilm formation.Relevance of network topology aspects is evaluated using proteomics profiles published by Belnap et al., contrasting a generic and an optimized laboratory setting with environmental samples in focus of biofilm formation efficiency . ProteomAnnotation of nodes of the ortholog graph with fold change values assigned to biofilm formation in combination with computation of the topological parameters degree as well as stress centrality allow determining significance in difference of graph measure distributions. Degree as well as stress centrality are found to be different for nodes holding a significant fold change compared to nodes not found to be affected according to the proteomics data positive correlation is identified , aside lBased on the observed association of degree and stress centrality with a probability of abundance change under varying biofilm conditions, a rank score of both graph measures and species coverage is determined. Each individual parameter is ranked starting with the maximum value, with the rank score reflecting the mean of the sum of each individual parameter rank for a given protein. L. ferrooxidans, significant orthology of sequences selected in the biomarker panel render fold changes as indicative for biomarker expression on the background of the ortholog network.For evaluation of the biomarker candidate panel two omics studies appear particularly useful due to providing i) substantial coverage of the entire molecular feature space represented in the biofilm network, and ii) showing differential readout for biofilm formation under varying conditions. The first study conducted by Moreno-Paz et al. resembles a prospecting situation and reports transcriptomics profiling comparing planktonic versus biofilm associated bacterial consortia in a natural AMD site . The stuA monitoring/process optimization situation can be approximated via comparing proteomics data of the generic and the optimized laboratory condition as provided in Belnap et al. . With opL. ferrooxidans cultivated in an agitated-tank bioreactor [The third data set prepared by Christel et al. compared gene expression of a continuous and a bioleaching culture of oreactor . This sporeactor and Moreoreactor ), and isA. ferrooxidans on pyrite [A further data set provided by Vera et al. implemented shotgun proteomics for characterizing early biofilm formation of n pyrite . In thisThe most prominent function category involved in the biomarker set is chaperones with four protein-coding genes. High ranking in degree centrality reflects broad involvement in folding and arrangement of macromolecular structures as well as their propensity to associate with hub proteins. This property meets with the processes of biofilm formation, but questions specificity, as activity of these proteins is supposedly relevant in a variety of molecular processes beyond the aggregate function in focus.Still, given chaperones hold specific evidence in the biofilm context in an acidic environment. GroEL chaperones are generally known as stress response proteins and are frequently found in acidophilic bacteria when grown on elementary sulfur. A more specific role of the protein family is modulation of fatty acid components of bacterial cell walls deemed essential during biofilm maturation . The putA second prominent function term covers central biofilm components involved in the synthesis of extracellular polymeric substances. Members include a uridine diphosphate (UDP)-glucose 4-epimerase converting uridine diphosphate galactose to UDP-glucose, a precursor for the osmoprotectant trehalose, as well as several exopolysaccharides , 39. FurThe third term set covers chemotaxis, sensing and motility, of apparent relevance in structuring the community microenvironment in a biofilm. For dimethyladenosine transferase a more specific function in quorum sensing was discovered and involves environmental adaptation through cross-species synchronization . As secoTaken together, the panel members represent core functional elements required in establishing a biofilm microenvironment, covering chemotaxis, motility, quorum sensing as well as the production of extracellular matrix components. The prominent representation of chaperones of the GroEL-Dnak-GrpE system not only points to adaptation processes allowing communities to establish in the extreme environments, but also reflects the need for a proper orchestration of the biofilm formation processes . Genes fStill, the exposed network topology of the panel members being hubs and connectors and on top being encoded in a wide range of species, in various instances covering more than 20 of the in total 25 microbial species involved, may in part be driven by annotation biases of network nodes and interactions, at present not allowing for evidence-based correction. Aside this aspect the need for specialist species for driving aggregate molecular processes is to be addressed. Analyzing species coverage of nodes in the network neighborhood of degree and stress centrality hubs sees more sparse species coverage, indicating the need for marginal consortia members on the molecular process level . As examMolecular features involved in biofilm formation are identified in a range of organisms commonly isolated in AMD and bioleaching sites. For a subset of organisms a sufficient depth of annotation is available both on functional as well as on protein interaction level. Lack of annotation per design removes a subset of protein coding genes from integrative analysis, although eventually resembling excellent biomarker candidates. However, coding regions displaying no orthology to annotated sequences of an extended species set retrieved in a meta-analysis approach may be fairly specific for certain species. In consequence, biomarkers from such subset may lack generalization capacity, in turn limiting sensitivity in a species-agnostic prospecting approach.Available interaction data allow deriving an ortholog network to approximate the community molecular process of biofilm formation. By integrating orthology information in the network some major limitations, given by unknown or incompletely characterized genes, lack of functional annotation as well as of interaction data can be addressed to some extent. The interaction data source used in this work provides interactions holding experimental evidence and candidate interactions resting on computational inference. With lack of completeness of experimentally derived interactomes together with biases introduced by experimental protocols, inference of interactions from heterogeneous data sources in part addresses given limitations and biases. This approach at the same time introduces probabilistic assignments. In consequence, resulting networks primarily serve hypothesis generation, demanding subsequent experimental evaluation. On the other hand, correlation of abundance of sequences with unknown function and annotated nodes of a mechanistic network model may support candidate function assignment .Combining various functionalities deemed necessary for effective biofilm formation in a multimarker panel promises improved sensitivity as well as specificity. The functional diversity of the process of forming a biofilm microenvironment, specifically beyond enzymes, points to an important aspect for selecting a comprehensive network model. For example, approaches restricted to metabolic networks by e.g. utilizing KEGG orthology (KO) terms of enzymes (nodes) connected by metabolites (edges) cover less than half of the network nodes included in the biofilm orthology graph . In addiThe workflow discusses candidate biomarker retrieval for prospecting of an aggregate biological function executed by microbial consortia in environmental samples. The approach leverages on cross-species interaction consolidated as ortholog network, and utilizes topological properties of network nodes for molecular feature selection.Identification of candidate panel members is based on a molecular process model tailored at representing the molecular context of biofilm formation. The candidate biomarkers are selected according to a rank score of degree and stress centrality as well as species coverage, thus focusing on prevalent proteins being deemed essential for establishing a biofilm microenvironment. Evaluating candidate biomarkers via utilizing public domain omics profiles indicates relevance in biofilm formation. Applicability of the method is not restricted to biofilm prospecting in copper mineral decomposition, but is expandable to alternative microbial community functions including as examples biofertilization in agriculture or microbial communities serving in oil spill bioremediation.de novo functional characterization of unknown species.Practical implementation on the mRNA level, e.g. via quantitative polymerase chain reaction (qPCR)-based methods, demands conserved sequence regions as probes. The approach of defining a set of biomarkers designed to screen for a given molecular function being at least to some extent independent of the executing microbes bears the promise to significantly facilitate prospecting of novel bacterial consortia. The precise composition of consortia is in most cases unknown at the point of screening. A species-robust screening tool supersedes the need for any prior knowledge on likely species occurrence. In line with prospecting goals a biomarker panel allows a first evaluation of samples, and in case of positive biomarker readout providing grounds towards a more detailed molecular analysis e.g. via metagenomics. This is particularly useful in cases where potential prospecting areas are large and diverse, or where a fast and frequent read-out, e.g. in a monitoring situation, is needed. Further, the approach facilitates the targeted discovery of new species in a functional context in focus, particularly if combined with novel techniques such as methods for In conclusion, interaction networks offer a methodology for characterization of community aggregate molecular functions via integrating individual species contributions into a molecular process network. Next to adding to our understanding of molecular mechanisms of aggregate function such networks allow selecting candidate biomarkers grounded on network topology characteristics. Such biomarkers promise support in microbial function prospecting as well as in industrial process monitoring in a range of application areas, with bioleaching and bioremediation as examples.S1 TableSpreadsheet \u201csites\u201d: Copper site-specific scientific references; spreadsheet \u201cspecies\u201d: Microbial species-specific scientific references; spreadsheet \u201cfunctions\u201d: key scientific references covering molecular function terms.(XLSX)Click here for additional data file.S2 TableProvided is the protein name together with identifiers from database references of UniProt, PATRIC and IMG.(XLSX)Click here for additional data file.S3 TableThe listing holds genes assigned to the functional term biofilm formation embedded in the ortholog network, respective topology measures of degree and stress centrality, species coverage, and ranked sum of topological parameters and species coverage.(XLSX)Click here for additional data file."} +{"text": "In Sub-Saharan Africa, there is an increase in trypanosome non-susceptibility to multiple trypanocides, but limited information on judicious trypanocide use is accessible to smallholder farmers and agricultural stakeholders in disease endemic regions, resulting in widespread multi-drug resistance. Huge economic expenses and the laborious nature of extensive field studies have hindered collection of the requisite large-scale prospective datasets required to inform disease management. We examined the efficacy of community-led data collection strategies using smartphones by smallholder farmers to acquire robust datasets from the trypanosomiasis endemic Shimba hills region in Kenya. We used Open Data Kit, an open-source smartphone application development software, to create a data collection App.Our study provides proof of concept for the viability of using smartphone Apps to remotely collect reliable large-scale information from smallholder farmers and veterinary health care givers in resource poor settings. We show that these datasets can be reliably collated remotely, analysed, and the findings can inform policies that improve farming practices and economic wellbeing while restricting widespread multi-drug resistance. Moreover, this strategy can be used to monitor and manage other infectious diseases in other rural, resource poor settings.The online version of this article (10.1186/s13104-019-4198-z) contains supplementary material, which is available to authorized users. Trypanosoma congolense, Trypanosoma brucei, and Trypanosoma vivax) is endemic to Shimba hills, in Kwale County, Kenya, a resource poor setting inhabited by smallholder farmers [2 (23% of the country), putting livestock and people at risk of infection [Animal African trypanosomiasis (AAT), a life-threatening neglected tropical disease that affects cattle, goats and sheep, caused by trypanosomes parasites , 22. IntAlthough performing financial transactions using mobile phones is predominant , there iCommunity engagement when implementing mobile phone-based strategies is important for gaining trust, educating on use and importance of data collected, and easy reporting of feedback . Kwale CThis pilot study was part of a larger study evaluating evolutionary markers of trypanocide non-susceptibility conducted among two smallholder livestock farming communities of different ethnicities from Mbegani and Kizibe in Shimba hills, Kwale County, Kenya . We obtaWe used Open Data Kit (ODK) an open-source smartphone App development software to create a data collection App . ODK hasWe used multiple correspondence analysis (MCA), a data reduction technique which permits the identification of complex patterns in a dataset of categorical variables , to deteWe conducted a pilot study on the efficacy of a community-led data collection approach by conveniently sampling from two communities of smallholder farmers (n\u2009=\u200947) from: Kizibe (n\u2009=\u200923) and Mbegani (n\u2009=\u200924) to acquire information on trypanocide non-susceptibility and perceptions of smallholder farmers on trypanosomiasis. There was a disproportionately lower number of female smallholder farmers , who also had less cattle ownership compared to their male counterparts Fig.\u00a0a. These A large proportion of smallholder farmers and veterinary health care givers interviewed welcomed the smartphone App developed on the ODK platform as a method of trypanosomiasis data collection. The farmers with dissenting views about using the App were illiterate. Our multiple correspondence analysis results show variation between the two communities from the overall mean, which would not be detected if knowledge on community ethnicity was not considered.Kwale is one of the most resource poor Counties in Kenya. Kizibe and Mbegani, in Shimba hills, Kwale, are trypanosomiasis endemic regions with varying economic capacities and different farming practices, which have made understanding temporal trends in trypanocide non-susceptibility challenging. Previous studies have used generalised cross-sectional survey approaches that lumped together findings from different communities in Kwale making it challenging to pinpoint subtle differences in farmers perceptions and disease management practices . We estaWe used multiple correspondence analysis (MCA) to highlight subtle variation in farming practices by the smallholder farmers in Kizibe and Mbegani, which could be used to inform trypanosomiasis management. Similar approaches have been used to assess animal African trypanosomiasis (AAT) vulnerability in cattle-owning communities of sub-Saharan Africa . Our resMobile phone affordability and technology uptake has increased tremendously in Kenya , suggestThe limitation in this pilot study was focus on a restricted set of questions to establish proof of concept, but other pertinent research questions based on study design can be included for prospective research. We also anticipate some recall bias during data collection. We currently underpowered to estimate the extent of this bias, but anticipate that a much larger dataset from prospective data collection will reduce confounding during analysis. This study was conducted using datasets from smallholder farmers due to insufficient data from the small number of veterinary healthcare workers. Another setback was the intermittent mobile network coverage by some mobile service providers. We were able to circumvent this challenge by transmitting information to the central database once connected to a strong network.Additional file 1. Questionnaire used to develop the ODK-based mobile App. The App questions were divided into two: (i) questions to animal health care workers (ii) questions to smallholder farmers."} +{"text": "The addictive brain undergoes dramatic changes as a result of drug exposure. A growing body of evidence suggests a wide range of brain areas, including ventromedial prefrontal cortex (VMPFC), orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DLPFC) and other subcortical regions, namely anterior cingulate cortex (ACC), striatum, and anterior insula, are involved in drug-related cue processing over left VMPFC could change the cue-related FC, which was examined by fMRI scans before and after cTBS (Kearney-Ramos et al., These understandings were addressed in a recent study published on the journal of Another extensive line of research has demonstrated VMPFC-limbic connections are altered in addicts (Ma et al., In conclusion, the current study demonstrated that cTBS of VMPFC-limbic circuits could change drug cue reactivity. Their results are likely to inspire more therapeutic interventions targeting drug-bias attention and self-awareness to modify previously inappropriate rewarded behavior for this chronic repeated relapsing disease. The approach combining fMRI with rTMS will be widely used to understand the underlying pathophysiologic neural circuits, and to design individualized treatment intervention. Nevertheless, although such evidence seems to be informative to us, it cannot effectively reduce drug-induced craving or relieve addiction syndrome. Our previous results indicated more participants respond to five repeated sessions with a better effect on craving in comparison to those who only receive a single session (Shen et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Middle-age and older adults vary widely in their physical health. This symposium describes studies that identify diverse daily experiences that account variation in health using multiple indicators of well-being . Fingerman et al. assessed daily TV viewing among older adults and found that more frequent television watching was associated with poorer physical health, worse health behaviors, and less energy expenditure . Leger et al., examined links between daily affect and sleep. Greater variability in daily positive affect is associated with fewer hours of sleep and greater morning tiredness even after adjusting for mean levels of affect. Luong et al. examined links between daily stress and affect. Interpersonal stressors were associated with greater affect reactivity than non-interpersonal stressors and links were reduced among older adults. Birditt et al. assessed links between daily social interactions and cardiovascular reactivity. More frequent social interactions and negative social interactions were associated with increased heart rate and links varied by gender and race. Polenick et al. examined links between daily social interactions and salivary DHEA-S (a marker of the stress response). Positive interactions predicted greater DHEA-S over the course of the day and links between negative interactions and DHEA-S varied by age group such that younger individuals appeared to be more reactive. These studies offer important clues regarding how daily experiences get under the skin to influence health and well-being."} +{"text": "OBJECTIVES/SPECIFIC AIMS: Listening effort is needed to understand speech that is degraded by hearing loss and/or a noisy environment. Effortful listening reduces cognitive spare capacity (CSC). Predictive contexts aid speech perception accuracy, but it is not known whether the use of context reduces or preserves CSC. Here, we compare the impact of predictive context and cognitive load on behavioral indices of CSC in elderly, hearing-impaired adults. METHODS/STUDY POPULATION: Elderly, hearing-impaired adults listened in a noisy background to spoken sentences in which sentence-final words were either predictable or not predictable based on the sentence context. Cognitive load was manipulated by asking participants to remember either short or long sequences of visually presented digits. Participants were divided into low or high cognitive capacity groups based on a pretest of working memory. Accuracy and response times were examined for report of both sentence-final words and digit sequences. RESULTS/ANTICIPATED RESULTS: Preliminary results indicate that accuracy and response times for both words and digits were facilitated by sentence predictability, suggesting that the use of predictive sentence context preserves CSC. Response times for both words and digits and accuracy for digits were impaired under cognitive load. Trends were similar across high and low cognitive capacity groups. The preliminary results support the idea that habilitation strategies involving context use could potentially support CSC in elderly, hearing-impaired adults. DISCUSSION/SIGNIFICANCE OF IMPACT: These preliminary results support the concept that habilitation strategies involving context use could potentially support CSC in elderly, hearing-impaired adults."} +{"text": "While caloric restriction (CR) provides highly robust improvements to longevity and health, dietary restriction of the essential amino acid methionine can provide similar benefits including improved metabolic function and increased longevity. Despite these similarities between CR and methionine restriction (MR), there is growing evidence to suggest they may be mediated by different mechanisms that require further elucidation. The sulfur side-chain of methionine is highly prone to oxidation, even in vivo, with redox changes of these residues potentially altering protein function and interfering with its use as a substrate. An entire family of enzymes, methionine sulfoxide reductases, have evolved in aerobic organisms to regulate the redox status of methionine. We tested the role of methionine sulfoxide reductase A (MsrA) in the physiological and metabolic benefits of MR. After three months of MR, mice lacking MsrA (MsrA KO) showed significant loss of weight, including both fat and lean mass, in comparison to wild-type mice under MR. Both MsrA KO and wild-type mice responded to MR with improvements to both glucose and insulin tolerance. However, MR MsrA KO mice showed lower HbA1c and reduced leptin compared to MR wild-type mice. Overall, our results show mice lacking MsrA have a stronger response to MR suggesting that methionine redox may play an important role in some of the mechanisms responsible for these metabolic outcomes. Further studies clarify whether MsrA could also be a potential regulator of the longevity benefits of MR."} +{"text": "In meiosis, DNA break formation and repair are essential for the formation of crossovers between homologous chromosomes. Without crossover formation, faithful meiotic chromosome segregation and sexual reproduction cannot occur. Crossover formation is initiated by the programmed, meiosis\u2010specific introduction of numerous DNA double\u2010strand breaks, after which specific repair pathways promote recombination between homologous chromosomes. Despite its crucial nature, meiotic recombination is fraud with danger: When positioned or repaired inappropriately, DNA breaks can have catastrophic consequences on genome stability of the resulting gametes. As such, DNA break formation and repair needs to be carefully controlled. Within centromeres and surrounding regions , meiotic crossover recombination is repressed in organisms ranging from yeast to humans, and a failure to do so is implicated in chromosome missegregation and developmental aneuploidy. (Peri)centromere sequence identity and organization diverge considerably across eukaryotes, yet suppression of meiotic DNA break formation and repair appear universal. Here, we discuss emerging work that has used budding and fission yeast systems to study the mechanisms underlying pericentromeric suppression of DNA break formation and repair. We particularly highlight a role for the kinetochore, a universally conserved, centromere\u2010associated structure essential for chromosome segregation, in suppressing (peri)centromeric DNA break formation and repair. We discuss the current understanding of kinetochore\u2010associated and chromosomal factors involved in this regulation and suggest future avenues of research. Fusion of two gametes upon fertilization reconstitutes the diploid genome of the zygote. Meiosis relies on the same basic molecular machinery as mitosis but requires additional dedicated events \u2010sized regions directly adjacent to centromeres pericentromeres prevented? Ectopic targeting experiments by Robine et al. revealedTaken together, a localized regulation of Red1 function within budding yeast pericentromeres could play a role in controlling DSB formation, in a manner that might share foundational principles within the fission yeast system. However, clear differences between fission and budding yeast regulation of DSB formation and repair exist. Most importantly, whereas in fission yeast, DSB regulation involves cohesin (Nambiar & Smith, 4As discussed here, fascinating new aspects of localized control of meiotic DSB formation and repair have recently been revealed. Despite structural differences within pericentromeres, a common thread is a key role for cohesin in controlling local DSB formation and repair (Nambiar & Smith,"} +{"text": "Pluripotent stem cells (PSCs) such as embryonic stem cells (ESCs), ESCs derived by somatic cell nuclear transfer (ntESCs), and induced pluripotent stem cells (iPSCs) have unlimited capacity for self-renewal and pluripotency and can give rise to all types of somatic cells. In order to maintain their self-renewal and pluripotency, PSCs need to preserve their telomere length and homeostasis. In recent years, increasing studies have shown that telomere reprogramming is essential for stem cell pluripotency maintenance and its induced pluripotency process. Telomere-associated proteins are not only required for telomere maintenance in both stem cells, their extra-telomeric functions have also been found to be critical as well. Here, we will discuss how telomeres and telomere-associated factors participate and regulate the maintenance of stem cell pluripotency. Telomeres are ends of linear chromosomes that are bound by a host of protein factors and form a complex nucleoprotein structure. In mammalian cells, telomeres are consisted of repetitive [TTAGGG]n sequences and protected by the core six-protein shelterin/telosome complex , including embryonic stem cells (ESCs), nuclear transfer ESCs (ntESCs) and induced pluripotent stem cells (iPSCs), have the potential of unlimited-proliferation and the capacity to differentiate into any cell type. Therefore, PSCs can be used for any cell type replacement and have great value for regenerative medical. Proper regulation of telomere length and telomere-binding proteins is critical for telomere function and genomic stability, both in somatic cells and PSCs. Mouse ESCs and/or iPSCs with short telomeres exhibited unsuccessful teratoma formation and chimera production and failed to produce ES/iPS mice capable of completely counteracting normal telomere shortening. PSCs can proliferate indefinitely while maintaining pluripotency and avoid telomere attrition and genome instability by elongating and protecting their telomeres. Short telomeres in ESCs lead to reduced pluripotency and unstable differentiation , could activate telomerase genes during reprogramming. For example, OCT3/4 and NANOG could bind to the TERC promoter and activate TERC transcription and three proteins with no demonstrable DNA-binding activities , increased TRF1 expression was observed before the onset of telomere elongation was initially discovered as a protein that could interact with TRF1 (Kim et al., Repressor/activator protein 1 or RAP1 localizes to telomere via its interaction with TRF2 (Li et al., Multiple links have been established between telomere homeostasis and stem cell pluripotency maintenance. Sufficient telomere length is critical for unlimited self-renewal of PSCs. Telomere length and integrity may serve as general signatures to evaluate the quantity of ESCs and iPSCs. Longer telomeres would be advantageous for human ESCs and iPSCs in the application of PSCs in regenerative medicine. However, excessive telomere elongation heightens sensitivity of hESCs to replication stress at overly long telomeres, and causes the formation of C-circles (Rivera et al., Telomere length maintenance in ESCs and iPSCs is regulated by telomere-binding modulators and epigenetic modifications. Additionally, higher level of the shelterin/telosome component TRF1 also correlates with higher pluripotency of stem cells. Numerous studies have elucidated the roles of these telomere-binding proteins in telomere homeostasis. In the future, more focused effort should be made to delineate how stem cell pluripotency is regulated by telomere-binding modulators. Epigenetic changes at telomeres are acquired during reprogramming and ESC differentiation, these epigenetic modifications may provide a more flexible and efficient system to control of telomere length regulation in pluripotent cells. Future studies into how these telomeric chromatin status is regulated and contributes to the telomere homeostasis would provide insights to understand the mechanism of pluripotency maintenance and aging.In vivo studies will be necessary to fully understand the molecular functions of telomere-binding proteins in somatic stem cells and tissue development.Mutations in telomere proteins have been identified in many human diseases including DC. Our previous systematic analysis of human shelterin/telosome knockout cells has revealed functional differences between human and mouse telomeric proteins in telomere length homeostasis and end-protection (Kim et al., The role of telomere binding proteins in the stem cell self-renewal and pluripotency maintenance has been well discussed. However, the functions of these binding proteins in stem cell differentiation are still rarely studied. During the differentiation process, the gradually shorter telomeres may release some of the telomere binding proteins from telomeres or recruit some new factors to telomeres, which may affect the process of differentiation. Future studies should focus on the specific role of these telomere binding modulators in stem cell differentiation. In addition, telomere shortening or uncapping in stem cells leads to cell senescence and aging. However, previous studies usually focus on cellular level, but rarely mention individual level. What are the differences of telomere binding proteins in stem cells between young and elder individuals? How these differences contribute to individual stem cell therapy? Further studies are needed."} +{"text": "Here we present an inexpensive widefield ratiometric fibred OEM system capable of enhancing the contrast between similar spectra of pathologically relevant fluorescent signals without the burden of complex spectral unmixing. As an exemplar, we demonstrate the potential of the platform to detect fluorescently labelled Gram-negative bacteria in the challenging environment of highly autofluorescent lung tissue in whole ex vivo human lungs.Fibre-based optical endomicroscopy (OEM) permits high resolution fluorescence microscopy in endoscopically accessible tissues. Fibred OEM has the potential to visualise pathologies targeted with fluorescent imaging probes and provide an Future work will include assessing performance in lung tissue with existing infection, in exploiting the capability to unmix multiple targets over multiple wavelengths, and in a label-free imaging regime of lung and other tissues, see appendix, and"} +{"text": "Pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis and is expected to become the second leading cause of cancer mortality in the United States by 2030 . The disPtf1aCreERTM; KrasG12D/+) [in vitro and in vivo, highlighting the significant role of smoking in both tumor formation and progression. In addition to direct effects on PDAC tumor cells, NNK exposure also exerts significant changes in the tumor microenvironment (TME). This includes enhanced infiltration of immunosuppressive cell populations into the TME, including regulatory T-cells (Tregs) and tumor-associated macrophages (TAMs). Additionally, the progression of stromal fibrosis, a major contributor of therapeutic resistance in PDAC, is also heavily influenced by smoking carcinogens, as NNK exposure in vivo results in a marked increase in tumor desmoplasia. Through mechanistic studies, we have demonstrated that the oncogenic effects of NNK exposure are mediated through the activation of CREB through downstream stimulation of the AKT/PI3K pathway. Moreover, inhibition of CREB has shown both direct and indirect influences on PDAC tumor growth, wherein it has directly impeded NNK-induced tumor cell proliferation and indirectly reduced immunosuppressive cell infiltration into TME and stromal fibrosis in PDAC [Cigarette smoking has been extensively described as a major risk factor in the development of numerous solid organ malignancies including pancreatic cancer. Our findings show that exposure to a nicotine-derived nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), significantly accelerates pancreatic precancerous lesion (PanIN) formation in a genetically engineered mouse model of PDAC (sG12D/+) . Further in PDAC .in vivo through activation of the AKT/PI3K pathway [Chronic alcohol consumption is implicated in the pathogenesis of multiple pancreatic disorders through the induction of acinar cell injury. Chronic alcohol exposure prompts a profound inflammatory response through repeated cellular damage in the pancreas, eventually leading to neoplastic transformation and the subsequent development of PDAC. Recent reports have shown that alcohol exerts its pro-tumorigenic effects by initiating a cellular reprogramming event known as acinar-to-ductal metaplasia, eventually advancing to PanIN formation and invasive cancer pathway . We have pathway . Further pathway . TherefoObesity is another well-established risk factor in PDAC development. Obesity is known to induce a pro-inflammatory state that differentially regulates pro-oncogenic cytokines and growth factors that are key mediators of PDAC progression. We have previously reported that the IL-6/STAT3 pathway is the critical regulator of obesity-induced PDAC growth . There iThe association among multiple modifiable risk factors on the initiation and progression of PDAC is well described; however, our understanding of the diverse cellular mechanisms that are affected by these pathologic states remains unclear. It is apparent that smoking, alcohol exposure, and morbid obesity induce oncogenic effects through direct interaction with PDAC cells, but additionally they seem to exert profound effects on the immune cell population and architecture of the microenvironment that may mediate disease progression and resistance to therapy. Our studies have provided fundamental insights into PDAC carcinogenesis induced by these risk factors and suggest CREB as a key oncogenic driver and therapeutic target in these processes. Further investigations into the central role of CREB in risk factor-associated PDAC are needed to promote our understanding and expand the treatment options available for this deadly malignancy."} +{"text": "Additionally, students whose interviewees experienced intense physical suffering or physical limitations or students who were enrolled in a course with intensive VPD and vaccine curriculum had significantly increased vaccine attitudes. This suggests that introducing students to VPDs can decrease vaccine hesitancy.In 2019, the World Health Organization (WHO) listed vaccine hesitancy in its top ten threats to global health. Vaccine hesitancy is a \u201cdelay in acceptance or refusal to vaccinate despite availability of vaccination services\u201d. Urban areas with large amounts of vaccine hesitancy are at risk for the resurgence of vaccine-preventable diseases (VPDs). Many vaccine-hesitant (VH) parents may be unfamiliar with the consequences of VPDs, and thus might be swayed when confronted with the symptoms and dangers of VPDs. As such, we sought to educate college students (future parents) in an urban vaccine-hesitant hotspot by assigning them to interview family or community members who had experienced a VPD. Student vaccine attitudes were assessed by surveys before and after the interviews. Vaccine-hesitant students who conducted a VPD interview but received no additional vaccine educational materials were significantly more likely (interaction term For months she couldn\u2019t leave the house.\u201d This interview led the student to explain having students interview individuals who had experienced a VPD or (2) providing intensive vaccine- and VPD-related course material. Combining intervention styles allowed us to assess the strength of each intervention. VPD interviews (intervention group) were most successful at swaying student vaccine attitudes when the coursework did not discuss vaccines or if the interviews had strong themes of physical suffering and limitations. The majority of students in the intervention group who became pro-vaccine and the resulting increase in vaccine attitude scores mirrored those achieved through intensive education (MMBio 261). Thus, encouraging students to conduct VPD interviews may be an easy and effective intervention when the course has little to do with VPDs or lacks vaccine-related content.In courses that do address vaccines, it may be advantageous to first rigorously introduce students to VPD consequences before addressing, lightly, vaccine safety and societal implications. While Bio 100 introduces vaccines through a homework assignment that seeks to correct misconceptions about vaccine safety and societal implications, MMBio 261 begins with rigorous weeks-long sections on immunity and VPDs but only briefly discusses vaccine safety and herd immunity. This may explain why Bio 100 VH students did not have significantly increased post-intervention VASs, only a suggestive upward trend, whereas MMBio 261 VH students had significantly improved post-intervention VASs. The comparison between Bio 100 and MMBio 261 students mirrors earlier research that discussing VPD ramifications has a greater impact on combating vaccine hesitancy than correcting flawed assumptions or asserting an absence of risk about vaccines ,13,14,15This study does have limitations. We did not examine whether an interview-based intervention would be successful in a non-science course. Any biological instruction discussing vaccines might provide some boost to vaccine attitudes. Additionally, for logistical reasons, we did not assess whether the increase in VAS is meaningful by following whether students vaccinate their current and future children. Furthermore, this study focuses on college students and may not be expandable to the general population. Nonetheless, despite these limitations, interview-based interventions and intensive VPD-dependent vaccine education does significantly increase vaccine attitudes, in a population susceptible to anti-vaccine attitudes. Vaccine hesitancy is a complex, situation-dependent problem, and requires unique and tailored interventions. Interview-based interventions are easy to implement and can supplement courses or even community outreach programs seeking to address vaccine hesitancy. Predisposing students to think more favorably about vaccinations by openly discussing the consequences of vaccine-preventable diseases may improve their prospective individual and familial vaccine uptake. Future research should tease apart the contributions of science education and personal familiarity with VPDs towards improving vaccine attitudes in diverse populations.There are two major conclusions of this work. First, an interview-based intervention, where students discuss vaccine-preventable diseases with people who have actually experienced these diseases, can significantly improve attitudes towards vaccination. Second, the subject matter used while teaching about vaccine-preventable diseases matters. In the class with extensive discussion of the diseases themselves, there was a strong increase in vaccine attitudes among vaccine-hesitant students, while this effect was not seen in the class that discussed mostly vaccine safety. Taken together, these findings indicate that increasing familiarity with vaccine-preventable diseases leads to improved attitudes towards vaccination. This should help to create solutions to the worldwide problem of vaccine hesitancy or denial, by indicating aspects of education that are important for affecting those attitudes."} +{"text": "In this study, we examine the association between perceived age discrimination at the workplace and job stress, with depressive symptoms among currently working late-middle-aged adults. In particular, we investigate whether the association between these work-related factors and depression varies by the strength of their social networks. We use data from the Panel on Ageing and Transitions in Health Survey (PATHS) a national study of 1654 Singaporean citizens and permanent residents aged 50 to 59 years, conducted in 2016-2017. We account for age and other sociodemographic characteristics, measures of economic status, occupation, early retirement intentions, personality traits, as well as multiple physical health measures. Our findings indicate that age discrimination at work and job stress are both positively associated with higher depressive symptom scores. The relationship between age discrimination and depressive symptoms however varies by social networks, with age discrimination negatively associated with depressive symptom scores among those with larger friends-based social networks. Our findings indicate that while psychological wellbeing of late middle-aged workers is adversely affected by age discrimination and job stress, these workers benefit from wider and deeper social connections with friends. Our results provide empirical support to previous research that suggests that friends-based social networks yield distinct benefits in terms of subjective well-being and increased self-worth."} +{"text": "Recent technological developments provide individuals with vision impairment the transformative ability to upload pictures they take and promptly receive descriptions from remote workers. This study aimed to: identify challenges for visually impaired individuals to use such technology to obtain health-related information and provide recommendations for crowd-workers and the future development of assistive artificial intelligence (AI) design. In spring and summer of 2019, we analyzed 265 images of medication packages submitted by users of a visual question answering (VQA) application called VizWiz -- a smartphone application that provides near realtime assistance to visually impaired users by employing crowd-workers. We developed a 4-category coding scheme to analyze image quality, with two independent coders achieving excellent intercoder reliability (85%-95%). Of the 265 images, we found less than half were legible (46%), contained clear indicators for information sought (40%), or had minimum background noise (40%); while only a small percentage contained complete information (6%). Through thematic analysis of the data, we also highlight seven challenges with queries submitted by vision impaired users . Based on our findings, we make recommendations for the future design of VQA technologies, such as VizWiz, for visually impaired users. We also suggest that there is both great need and potential for user-centered design research to significantly enhance such assistive technologies. While this study did not focus exclusively on data submitted by aging adults, many VizWiz users are, in fact, aging adults, and such assistive technologies have strong implications for the design of assistive technology for this age group."} +{"text": "This paper explores how perceptions of unfair treatment shape healthcare satisfaction across race/ethnicity. We investigate the overall impact of life course exposure to healthcare discrimination on current healthcare satisfaction across race/ethnicity among a sample of midlife and older Black, Latinx, and White Americans age 50+ in the Health and Retirement Study. We then test whether everyday healthcare discrimination mediates the impact of major medical discrimination on healthcare satisfaction, controlling for sociodemographic factors, mental and physical health characteristics, functional status, life course stress exposure, and lifetime and everyday discrimination in contexts beyond healthcare settings. Black Americans had poorer healthcare satisfaction than White Americans. Everyday discrimination in healthcare settings mediated a modest amount of the relationship between lifetime healthcare discrimination and healthcare satisfaction, and this association varied in strength across White, Black, and Latinx Americans. Results underscore the need for future work identifying and addressing mechanisms shaping healthcare satisfaction."} diff --git a/PMC_clustering_624.jsonl b/PMC_clustering_624.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..5eaca1e1ee9dab0c96271d79d2a31a2ab593d33f --- /dev/null +++ b/PMC_clustering_624.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:3c786c82235d4a2d1136a9609c66e8912c9786c848305135f79afee9a6c5976c +size 86228277 diff --git a/PMC_clustering_625.jsonl b/PMC_clustering_625.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..988f0bca8661948611dd3e4f7615c4f5c1e9b0ef --- /dev/null +++ b/PMC_clustering_625.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:ae5e6319a4e4ef1fc7cd738cfe83f1a4e6945bc9a3f83cbb7c9c17a255267a27 +size 20616371 diff --git a/PMC_clustering_626.jsonl b/PMC_clustering_626.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..ac4c0b147e7d6ab51ca30785648d3a5ca5934455 --- /dev/null +++ b/PMC_clustering_626.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:9d1297a9b109bee29ec70c77186198bf7e9cf7764404131c87a4a1d8c6313d3c +size 14711113 diff --git a/PMC_clustering_627.jsonl b/PMC_clustering_627.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..5a60e8fcdea192eb1ebb29ec4e190bfbee9c2088 --- /dev/null +++ b/PMC_clustering_627.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:9cd80b9e72dd852ccc8e8a6f7df38b208cb1bd39dd516d5bdec6c3523a2c9f3b +size 26564594 diff --git a/PMC_clustering_628.jsonl b/PMC_clustering_628.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..c065db5d69a63aa9100de2b1a55cc38ec7408d37 --- /dev/null +++ b/PMC_clustering_628.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:dbf2bde74ab7c6ba30143e82f23d0311ea91e671d5311cc47464ed3f17429146 +size 38294840 diff --git a/PMC_clustering_629.jsonl b/PMC_clustering_629.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..b80d9e1c365aa9b8ae43960fb5037d2f5bfc8784 --- /dev/null +++ b/PMC_clustering_629.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:04697b49a4285e22d71e69edc67ce6a0b061981d872d423933538e3cdf71c18a +size 74380395 diff --git a/PMC_clustering_630.jsonl b/PMC_clustering_630.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..d52f269694714ed5e5db63f86259c6cb7a96a289 --- /dev/null +++ b/PMC_clustering_630.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:d073aca3ad1931d1a2017eef38e7a304519b1b3c1bc7eb1183455c4acbf58c0b +size 61241446 diff --git a/PMC_clustering_631.jsonl b/PMC_clustering_631.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..ecf14c36c93e2bddb3c0bc5a83fe27bdd78f887d --- /dev/null +++ b/PMC_clustering_631.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:5bdfe71a45c3324350b4809989b2f4a8fafd67a5dc04cfc9b2b6a1dd15b0f070 +size 79897250 diff --git a/PMC_clustering_632.jsonl b/PMC_clustering_632.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..1a66d1f80b567c13c1855654586957b448f61c25 --- /dev/null +++ b/PMC_clustering_632.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:bceb3d2b7ef4239416397555f460ea84232e483ca2b955cd14f43267559b0d31 +size 47387256 diff --git a/PMC_clustering_633.jsonl b/PMC_clustering_633.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..6019dc6b9291725e0a7b8a69ece93ef674945e6f --- /dev/null +++ b/PMC_clustering_633.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:26476ed621a54c94d14a7b03c9ecc302557a5da57bf7c092c58612dd0dce5a7b +size 37146850 diff --git a/PMC_clustering_634.jsonl b/PMC_clustering_634.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..59795e2c39d81d5b362943e5a2c8178c20a8576e --- /dev/null +++ b/PMC_clustering_634.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:a9352da9b421bc548e2a4405859b29bd8f30908fd0887c6b95c6f352c8af38b0 +size 37921218 diff --git a/PMC_clustering_635.jsonl b/PMC_clustering_635.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..ffae5405aa7ce3c05cba7dfb890b91575820a2a7 --- /dev/null +++ b/PMC_clustering_635.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:a687cc17aba443da46354dafaefc3b49203fccd253847a32d90a4fc98edbacc3 +size 20576773 diff --git a/PMC_clustering_636.jsonl b/PMC_clustering_636.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..16e7612e364415267149efdb6500dc6552e970ce --- /dev/null +++ b/PMC_clustering_636.jsonl @@ -0,0 +1,522 @@ +{"text": "The second corresponding author is Brahim Belhaouari Samir. Dr. Samir\u2019s email address is: Additionally, the following information is missing from the Funding statement: Support for this study was provided by the Qatar National Library to BBS."} +{"text": "Erratum to: The PROFID project .Upon the original publication of this article, the Funding section has been updated as follows online:Previous version:FundingThis project has received funding from the European Union\u2019s Horizon 2020 research and innovation programme under grant agreement No 847999.Corrected version:FundingThis project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 847999.The publisher apologises for this error."} +{"text": "The following information is missing from the Funding statement: Dr. Liangliang Cheng received the funding from Dalian Science and Technology Innovation Fund Project (grant number: 2020JJ27SN077). The publisher apologizes for the error."} +{"text": "The correct licence for the paper is CC-BY."} +{"text": "Following publication of the original article , the autThe incorrect author name is: Tao Qing Liu.The correct author name is: Qing Tao Liu.The author group has been updated above and the original article has been"} +{"text": "Following publication of the original article , the autThe incorrect author name is: M. Bilal.The correct author name is: Muhammad Bilal.The author group has been updated above and the original article has been"} +{"text": "Following publication of the original article , the autThe incorrect author name is: Jianhui Niu.The correct author name is: Jiahui Niu.The author group has been updated above and the original article has been"} +{"text": "The Funding statement is incorrect. The correct Funding statement is as follows: This research is supported by the National Natural Science Fund of China (No.81874349)."} +{"text": "Funding: The study was funded by King Saud University through the Researchers Supporting Project number (RSP-2019/118).Acknowledgments: The authors thank King Saud University through the Researchers Supporting Project number (RSP-2019/118).The authors wish to make the following corrections to their paper . The numThese changes do not affect the conclusion of the paper. The authors would like to apologize for any inconvenience this might have caused."} +{"text": "The Funding statement is incorrect. The correct Funding statement is as follows: Open Access funding provided by the Qatar National Library."} +{"text": "The corrected author list appears here and with the article online.The authors regret the error."} +{"text": "The author list and Author Contributions section of the online article have been updated. All co-authors have approved the changes. We apologize for the omission."} +{"text": "In the Funding section, the grant number from the funder National Institutes of Health is listed incorrectly. The correct grant number is: R01GM102262."} +{"text": "Following publication of the original article , the autThe incorrect author name is: Martin Wagemann.The correct author name is: Martin Wagenmann.The author group has been updated above and the original article has been"} +{"text": "The publisher apologizes for the error.The Data Availability statement for this paper is incorrect. The correct statement is: An anonymized version of the dataset and the corresponding R-Code are uploaded to GitHub ("} +{"text": "The original version of this article unfortunately contained a mistake. The Collaborator name Joukje van der Naalt is incorrectly tagged. Therefore, author name is cited incorrectly in PubMed. The given name and family name should be as follows:Given name: Joukje.Family name: van der Naalt."} +{"text": "In the original version of the article, the pretreatment TMJ images demonstrated in Fig. The revised Fig."} +{"text": "The correct statement is: All optical mapping, CAGE and RNA-seq data used in the study are available using the following DOI:"} +{"text": "Following publication of the original article , the autThe incorrect author name is: E Xiaofei.The correct author name is: Xiaofei E.The author group has been updated above and the original article has been"} +{"text": "Following publication of the original article , the autThe incorrect author name is: Shaiq uz Zaman.The correct author name is: Shahiq uz Zaman.The author group has been updated above and the original article has been"} +{"text": "The author wishes to make the following correction to this paper . After cwith the following:The correction of"} +{"text": "In the original article , there wThe original Figure 1E is:and should be replaced with the following version:The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated."} +{"text": "The author would like to correct the names for the below co-authors in the online published article.The correct author names are given below:Fawaz AbomarayMohamed Abumaree"} +{"text": "The Funding statement is incorrect. The correct Funding statement is as follows: This study was supported by the Klaus Tschira Foundation, Heidelberg, Germany."} +{"text": "The authors wish to make the following erratum to their paper :The Funding information has now been corrected (see the corrected version below):"} +{"text": "Following publication of the original article , the autThe incorrect author name is: Hiroaki Fukazawa.The correct author name is: Hiroaki Fukuzawa.The author group has been updated above."} +{"text": "Following the publication of the original article , the autIncorrect funding note:A part of this research was funded partially by NIMAD [no. 971130].Correct funding note:This research was funded by NIMAD , Project no. 971130.The author group has been updated above and the original article has been"} +{"text": "In the funding statement, the grant number from the funder Spanish JCyL cofinanced with the European Union FEDER funds 2017 is listed incorrectly. The correct grant number is: SA070P17."} +{"text": "The following information is missing from the Funding statement: This work was also supported by the European Research Council (ERC) (ADG 741781 GLOWSOME to E.H.)."} +{"text": "The authors wish to make the following corrections to this paper :The authors apologize for not giving sufficient credit to the involvement of Prof. C.R. Jimenez and her research group in this paper. Therefore, the following section is corrected: The \u201cAcknowledgements\u201d statement should be changed to:Acknowledgements: The authors acknowledge Marloes Zoetemelk for the preparation of RNAseq material and Tse Wong for the expert technical support. The authors thank the iGE3 Genomics Platform (UNIGE) for preforming RNAseq experiments. The authors acknowledge Connie R. Jimenez and her team for generating the phosphoproteomics data included in Figure 3.The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "In the original publication of this article , the autThe incorrect author name is: Bertram Brening.The correct author name is: Bertram Brenig."} +{"text": "Following publication of the original article, we were notified that three of the names of the MeHAEMO working group were incorrectly reported. The correct names are: Marco La Torre, Stefano Mancini and Giovanni De Palma.The original article has been corrected."} +{"text": "In the Funding statement, the grant number from the funder Fundamental Research Funds for the Central Universities is listed incorrectly. The correct grant number is: SWU118004.The ISI score values in"} +{"text": "The authors wish to make the following correction to this paper :Change in Funding.The authors wish to change the funding part from:Funding: This research was supported by Russian Science Foundation grant (project No 19-79-30002).toFunding: This research received no external funding.The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "In the Funding section, the grant numbers from the funder Natural Science Foundation of Hunan Province of China are listed incorrectly. The correct grant numbers are: 2021JJ30326 and 2021JJ30336."} +{"text": "Cell Death Dis 10: 717, 2019. The authors regret that the data in question featured in the original"} +{"text": "Funding section was not complete.This should have read:Funding: This study was supported by the Italian Ministry of Health (Ricerca Corrente) 20/1819.The affected articles are listed in the reference list.In addition in Riccardi et al,We apologize for this error."} +{"text": "The above abstract was published with the incorrect title. The title should be as follows:Preliminary Validation of the Arabic Global Neuropsychological Assessment (GNA)Additionally, John Gillies should have been listed as an author.The original abstract has been corrected online to rectify these errors."} +{"text": "The corresponding author is Arunima Sengupta, email: The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "This should read:instead of:This error has been corrected in the article."} +{"text": "There are errors in the Funding section. The correct Funding statement is: Funded by the Deutsche Forschungsgemeinschaft \u2013Projektnummer 491466077."} +{"text": "There are errors in the Funding section. The correct Funding statement is: Open Access funding provided by the Qatar National Library."} +{"text": "Saidul Islam The authors regret that the affiliation of the author Terumasa Ikeda was incorrectly listed in the original manuscript. The correct affiliation is listed above. The affiliation 'e' was incompletely listed in the original manuscript. The correct affiliation is given below. The authors also regret that the following funding grants were not attributed to the correct funders. The correct funders are listed below:JPMJTM20SL: Japan Science and Technology Agency (JST)JP17H01200 and 22K07103: Japan Society for the Promotion of Science (JSPS)The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The correct sentence is: We applied the same methods to develop a web-based application ("} +{"text": "There are errors in the Funding statement. The correct Funding statement is as follows: The study was funded by Chinese Academy of Sciences President\u2019s International Fellowship Initiative (CAS PIFI: Grant No. 2019PB0105). The Higher Education Commission (HEC), Pakistan, also provided a travel grant for visit to USA to improve the data analyzing skills.["} +{"text": "The cover image is based on the Themed Section of this issue: Usage of different tumor models in cancer research. The research on the mechanism of cancer occurrence and metastasis has always been an international hotspot. This section focuses on the progress in tumor research using animal models and organoids.The source of the background of the cover image: Adobe Stock Number: 535775715 \u00a9 auntspray/Adobe"} +{"text": "The published version of this paper listed onlyRobert Freer asthe corresponding author. The purpose of this correction is to identifyboth David J. Lewis and Robert Freer as corresponding authors.The conclusions of the work have not been affected by this correction."} +{"text": "The section Factors associated with the COVID-19 fear and in table 2 were incorrect.The authors apologise that a number of numerical values within The correct section and tables are below:The article has been updated."} +{"text": "The correct version of funding information can be found below:In the original published version of this article, the authors have not provided the complete funding information. The funding information has now been updated. 10.13039/501100012650TU Wien Bibliothek for financial support through its Open Access Funding Program.The authors acknowledge The authors apologize for the errors. Both the HTML and PDF versions of the article have been updated to correct the errors.The authors declare no conflict of interest."} +{"text": "Following publication of the original article , due to The incorrect Fig.\u00a03 is:The correct Fig."} +{"text": "Eq 5 is incorrect. The correct equation is:The publisher apologizes for the error."} +{"text": "This article has been corrected: The authors found an error in Figure 3A: the magnification used for the images of Hoechst 33342-stained cells shown is not uniform. The authors corrected the error with representative images from the original experiments. The presented correction does not affect the results or conclusions of this article.Figure 3 is presented below.Corrected"} +{"text": "The correct affiliation list is: The publisher apologizes for this mistake.The original article has been updated."} +{"text": "Following publication of the original article , the autThe sentences currently read:Similar results were obtained by Goh et al. for the The sentences should read:Similar results were obtained by Goh et al. for the The indicated sentences in the Discussion section have been updated above and the original article has been"} +{"text": "In the Funding section, the grant number from the funder The National Science Foundation is listed incorrectly. The correct grant number is: 31871911."} +{"text": "There is an error in the article title. The correct title is: Prevalence of anemia among people with diabetes mellitus in South Asia: A systematic review and meta-analysis."} +{"text": "In the published article, there was an error in the Funding statement. This study has been funded by the Natural Science Foundation of Beijing Municipality (Grant Number: 9222993). The correct Funding statement appears below."} +{"text": "Nearly a century has passed since the first studies of life in the subsurface . Ricardo Amils: Conceptualization .The authors declare that they do not have any conflict of interest."} +{"text": "This document summarizes the recommendations that are included within each section of \u201cA Compendium of Strategies to Prevent Healthcare-Associated Infections in Acute-Care Hospitals: 2022 Updates.\u201d which also provides a summary of the background and the methods used to develop the Compendium: 2022 Updates. The individual Compendium 2022 sections summarize the major changes to the recommendations from the Compendium: 2014 Updates.Appendix Tables Compendium: 2022 Updates.Appendix Table"} +{"text": "There are errors in the Funding section. The correct Funding statement is: Open Access funding provided by the Qatar National Library."} +{"text": "Dear Editor,It is with great interest that I read the research article by Dr. Mogadam and colleagues: Comparison of Analgesic Effect between Gabapentin and Diclofenac on Post-Operative Pain in Patients Undergoing Tonsillectomy . This ra"} +{"text": "The names of two authors were given incorrectly. The correct names of the ninth and tenth authors are, respectively: Alberto Ortiz and Maria D Sanchez-Ni\u00f1o. The correct abbreviation of the tenth author in Contributions is: MDSN"} +{"text": "There is an error in the funding section. The grant FONDECYT number 1070444 should be: 1100176."} +{"text": "The name of the eighth author was spelled incorrectly. The correct name is: Houda Tahiri."} +{"text": "The two equations in the Materials and Methods section are incorrect. The corrected versions are provided here."} +{"text": "In the list of authors, the second author's name is incorrectly spelled. The correct spelling is Pesach Lubinsky."} +{"text": "There was an error in the second sentence of the Funding statement. The correct second sentence is: \"The publication charges have been funded by institutional project BSC-0111.\""} +{"text": "The name of the last author is incorrect. The correct name is: Dawn A Skelton."} +{"text": "The name of the ninth author is spelled incorrectly. The correct name is: Lingjian Wang"} +{"text": "The World Allergy Organization Journal on pages 224-232, the author degrees were listed incorrectly. The correct author list is as follows:In the article \"Mast Cell Regulation of the Immune Response\", which appeared in volume 2 of"} +{"text": "In the published articleCorrespondence to: Ji-Min ZhangEmail: jimin0820@163.comThe authors and the journal apologize for the error and for any confusion it may have caused."} +{"text": "The name of the 12th author was spelled incorrectly. The correct name is: Franck Prugnolle."} +{"text": "There was an error in the name of the sixth author.The correct author name is: Young-chul Kim"} +{"text": "The name of the tenth author was given incompletely. The correct name is: Vera Maria Cury Salemi. The correct abbreviation in Contributions is: VMCS."} +{"text": "The name of the seventh author in the article byline and the author contributions contained an error. The correct name is: Maria Grazia Spillantini. In the author contributions, the correction should be to the last contribution: \"Wrote the paper: AB MGS CM PS.\""} +{"text": "The following information was missing from the Funding section: This work was granted access to HPC resources at the French National Computing Center CINES under grant no. 2011-c2011076723 funded by the GENCI ."} +{"text": "A second grant from the National Institutes of Health to the twelfth author was incorrectly omitted from the funding statement. The number of this grant is: R21 AI073230-01."} +{"text": "A funding source is missing from the financial disclosure section. The authors wish to add the following to their funding information: \"The research of ISK and VIV was supported by a grant from National Library of Medicine (ARRA) R01 LM010125.\""} +{"text": "The name of the fourth author contained an error in the byline of the PDF version. The correct name is Hung-Wen Li."} +{"text": "The number of the National Science Foundation grant is incorrect. The correct grant number is: NSF MCB 0743448."} +{"text": "The name of the fifteenth author was incorrect.The correct name is: Dominique Valeyre."} +{"text": "A funding organization was incorrectly omitted from the Funding statement. The FundingStatement should read: \"This study was prepared with partial support from the Bill andMelinda Gates Foundation through the Disease Control Priorities Network at theUniversity of Washington. The funders had no role in study design, data collection andanalysis, decision to publish, or preparation of the manuscript.\""} +{"text": "The second accession number given in the first sentence of the section \"Nucleotide Sequence Accession Numbers\" in Materials and Methods is incorrect. The correct accession number is: SRA059295."} +{"text": "A word was dropped from the title. The full title of this article is:Cell cycle checkpoint abnormalities during dementia: A plausible association with the loss of protection against oxidative stress in Alzheimer's disease"} +{"text": "The following information was missing from the Funding section: Bioacoustic examination was supported by a research grant of the Hungarian Scientific Research Fund (OTKA K81929)."} +{"text": "The funding information for PB is incorrect. The correct funding information for PB is: \"P. Bejon is supported by the NIHR Biomedical Research Centre Oxford.\""} +{"text": "The following information is missing from the funding section: The charge for this publication was covered by the German Research Foundation (DFG) sponsorship \"open access publication\"."} +{"text": "The name of the first author was spelled incorrectly. The correct name is: Zhenxing Zhang."} +{"text": "The name of the fourth author was spelled incorrectly. The correct name is: Yunxing Li."} +{"text": "The name of the 14th author was spelled incorrectly. The correct name is: Kei Sakamoto."} +{"text": "The Competing interests statement should read: Dr. Sanjiv Sam Gambhir serves on the board of Endra Inc., is a founding member, and has stock options. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials."} +{"text": "There was an error in the oxygen consumption rate (OCR) unit of measurement. The correct unit of measurement is pmol."} +{"text": "The name of an employer of the second and fourth authors was incorrectly given in the Competing Interests Statement. The Competing Interests Statement should read: \"The authors Daniel P. Bradley and Jennifer Terkelsen are employees of Millennium: The Takeda Oncology Company. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.\""} +{"text": "The name of the 14th author is incorrect. The correct name is: Viacheslav Iu Zhuravlev."} +{"text": "The name of the 27th author was spelled incorrectly. The correct name is Takashi Morihara."} +{"text": "The name of the eighth author was given incorrectly. The correct name is: Marjan Askarian-Amiri."} +{"text": "The corresponding author's last name was cut off in the online version of the article. The corresponding author's full name is Christopher J. Lord."} +{"text": "The name of the eighth author was given incorrectly. The correct name is: Mohammed Afzal. The correct abbreviation of the eighth author's name in the Author Contributions Statement is: MA."} +{"text": "There is an error in the number of the first author's (JFP) NIH grant. The correct grant number is: GM086416."} +{"text": "The hippocampus has a critical role in processing context during the acquisition and retrieval of memories. The contextual-dependence of Pavlovian fear extinction is closely associated with the hippocampus . The con"} +{"text": "The name of the 17th author is incorrect. The correct name is: Kohei Takeuchi."} +{"text": "The name of the second author was spelled incorrectly. The correct name is Xin Fang."} +{"text": "A funding organization was incorrectly omitted from the Funding Statement. The following sentence should be included with the Funding Statement: \"We would like to thank the Robert-Pfleger-Foundation for giving a fund to support the present study.\""} +{"text": "The name of the ninth author is spelled incorrectly. The correct name is: Hans-Reimer Rodewald."} +{"text": "The name of the first author was spelled incorrectly. The correct name is: Dominik Sebastian Sieh."} +{"text": "The name of the ninth author is spelled incorrectly. The correct name is: Kyriaki Michailidou."} +{"text": "Two funding organizations were incorrectly omitted from the Funding Statement. The following sentence should be included with the Funding Statement: \"The article processing charge was funded by the German Research Foundation (DFG) and the Albert-Ludwigs-University Freiburg through the funding programme 'Open Access Publishing'.\""} +{"text": "Dear Editor,Regarding the article of Leonardi and La Rosa: \"Are hepatitis B virus and celiac disease linked?\", published in the 2010 issue of Hepatitis Monthly . Several"} +{"text": "Some information was missing from the Funding section. The missing information is: BBK and BGN are funded by NIH R01 DK060838."} +{"text": "The name of the second author was spelled incorrectly. The correct name is: Nam-Kyong Choi."} +{"text": "The name of the last author is incorrect. The correct name is: Liang Yi Si."} +{"text": "The name of the seventh author was spelled incorrectly. The correct name is: An Do."} +{"text": "There was an error in the the second to last sentence of the Abstract: The key word \"no\" is missing. The correct sentence should be: \"The common disease mutations associated with increased susceptibility to PD show no differences in activity or iron (II) levels.\""} +{"text": "There was an error in the name of the 32nd author.The correct name is: Pierre Verrelle"} +{"text": "There is an error in the following Author Contributions designation: Conceived and designed the experiments: MZY LJB XEZ."} +{"text": "In the byline, the name of the fifth author is incorrect. The correct name is: Julian Little."} +{"text": "The name of the eighth author is spelled incorrectly. The correct name is: Koji Uchino."} +{"text": "The following information was missing from the Funding section: The present study was also supported by the National Institutes of Health Grant R01HD057446 to T.E.C."} +{"text": "J Antimicrob Chemother 2013; 68: 697\u2013707The name of the second author was incorrectly spelled in the published version of this article. The correct version is shown above. The authors apologize for this error."} +{"text": "The name of the 12th author was spelled incorrectly. The correct name is: Jonathan M. Gershoni."} +{"text": "The following information is missing from the Funding Statement:The Mexican CONACyT funded this project (CB--2008-01 106003) and provided the doctoral fellowship to MC Ruiz de la Torre."} +{"text": "The name of the second author is incorrect. The correct name is: Tania D. Stafinski."} +{"text": "The accession number listed in the Phylogenetic Analysis section of Methods is incorrect. The correct accession number is KC807984."} +{"text": "The name of the seventh author is spelled incorrectly. The correct author name is: Mohamad Habes."} +{"text": "The name of the second author is spelled incorrectly. The correct name is: Frank Giton."} +{"text": "The name of the last author was given incorrectly. The correct name is: Philip C. Stevenson."} +{"text": "There was an error in the name of the fourth author.The correct name is: Curt H. Hagedorn"} +{"text": "The published Funding and Competing interests statements were incorrect. The correct statements are:Funding: No current external funding was received for this study.Competing interests: One or more of the authors are employed by Laboratoire Chelles surdit\u00e9. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials."} +{"text": "The name of the second author was spelled incorrectly. The correct name is: Jinsong Hu"} +{"text": "There is an error in the Competing interests statement. The correct statement is: The SA NHLS is the sole owner of the PLG CD4 patent, and receives royalties related to licensing agreement with BC Miami."} +{"text": "The ninth author is listed as Tom B. Smith. His name should instead read Thomas B. Smith.The following information was missing from the Funding section: \"This study was also made possible by the generous support of the American people through the United States Agency for International Development (USAID) Emerging Pandemic Threats PREDICT.\""} +{"text": "The name of the ninth author was spelled incorrectly. The correct name is: Huangxing Su."} +{"text": "A funding organization and grant were incorrectly omitted from the Funding Statement. The following sentence should be included in the Funding Statement:\"The collection of data in the field was supported also by Wellcome Trust grant 088862/Z/09/Z.\""} +{"text": "The name of the fourth author was spelled incorrectly. The correct name is: Cornelis Jan de Vries."} +{"text": "The grant number from National Research Foundation of Korea is incorrect. The correct grant number is: \"2009-0067910\""} +{"text": "The Funding statement was incorrect. The correct Funding section should read: \"This study was funded by the United States Department of Agriculture. The manuscript was reviewed for general policy statements committing the USDA to action, but otherwise the findings were independently developed by the authors.\""} +{"text": "The number of samples quoted in the BC and EC rows are incorrect. Please view the correct Table 1 here: ."} +{"text": "The published table represents an earlier generation of this file. The most recent generation of this data can be found at the following link: Click here for additional data file."} +{"text": "The name of the 12th author was given incorrectly. The correct name is: Charles J. Sailey."} +{"text": "There was an error in the name of the fifth author.The correct name is: Maximilian von Fragstein."} +{"text": "The name of the 10th author was incorrectly given. The correct name is: Joonas H. Kauppila. The correct abbreviation in the Author Contributions Statement is: JHK."} +{"text": "The authors would like to add the following to the Competing Interests statement: \"A patent application concerning part of the results of this study has been filed by the University Maastricht (Application no. 10172846.7-2401).\""} +{"text": "The accession number was omitted from the Results. The following sentence belongs after the sixth sentence of the first paragraph in the section: \"The nucleotide sequence data reported for PlatAMP are available in the Third Party Annotation Section of the DDBJ/EMBL/GenBank databases under the accession number TPA: BK008723.\""} +{"text": "The name of the second author was spelled incorrectly. The correct name is: Shubhra Srivastava."} +{"text": "There is an error in the financial disclosure. The correct funding for Philip Bejon is: \"P. Bejon is supported by the NIHR Biomedical Research Centre Oxford.\""} +{"text": "The name of the first author was spelled incorrectly. The correct name is: Ching-Wei Lee."} +{"text": "The authors would like to add the following sentence to the Funding section: \"L. Fadiga was supported by the EU project SIEMPRE.\""} +{"text": "There was an error in the oxygen consumption rate (OCR) unit of measurement. The correct unit of measurement is pmol."} +{"text": "The name of the seventh author was given incorrectly. The correct name is: Jeffrey J. Rade."} +{"text": "The name of the fourth author is incorrect. The correct name is: Mahendra Pal Singh Negi."} +{"text": "The method employed for the evaluation of publication bias in this meta-analysis is incorrectly referred to as \"Beggar's funnel plot\" in the article . The method should have been cited as Begg's funnel plot. The authors apologize for this error."} +{"text": "The name of the eighth author was spelled incorrectly. The correct name is: Amar Abderrahmani."} +{"text": "The name of the third author was spelled incorrectly. The correct name is: Shougang Zhuang."} +{"text": "The following information was missing from the Funding section: AIS laboratory is partially funded by the SepiAs project from the Italian Ministry of Health. AL is supported by the CARIPLO grant n. 2010-0253."} +{"text": "The name of the eighth author was spelled incorrectly. The correct name is: El Moukhtar Aliouat."} +{"text": "There was an error in the author contributions section. The corrected author list for the category \"Conceived and designed the experiments\" is: \"GDF GRB JFR IS DMK.\""} +{"text": "There is a funder and grant number missing from the Funding Statement. The following is the missing information:This work was also supported by the the National Institute of Aging (NIA), with the Grant #1R03AG042860-01."} +{"text": "The number of the third listed grant in the Funding statement is incorrect. The correct grant number is: 201207007."} +{"text": "The name of the sixth author was given incorrectly. The correct name is: Shivaprakash Jagalur Mutt. The correct abbreviation in the Author Contributions Statement is: SJM."} +{"text": "The name of the second author was given incorrectly. The correct name is: Geoffrey Legault."} +{"text": "The name of the last author is incorrect. The correct name is: Ivan J. Perry. The correct abbreviation in the Author Contributions Statement is: IJP."} +{"text": "There was an error in the name of the 13th author. The correct name is Florence Nguyen-Khac."} +{"text": "The first sentence of the funding section is incorrect. It should read: \"Philip Bejon is supported by the NIHR Biomedical Research Centre Oxford.\""} +{"text": "The lower panels in Figure 4 are out of focus. Please see the corrected figure at the following link: ."} +{"text": "The name of the last author is incorrect. The correct name is: Dean R. Artis. The correct abbreviation in Contributions is: DRA."} +{"text": "An NIH grant to the last three authors was incorrectly omitted from the Funding Statement. The number of the grant is: EY022063-01."} +{"text": "In the author byline, the name of the sixth author is given incorrectly. The correct name is: Mario D\u2019Andrea"} +{"text": "In the author byline, the name of the first author is given incorrectly. The correct name is: Katy M Roach."} +{"text": "There was an error in the penultimate sentence of the Abstract. The correct sentence is: Species with larger body mass (for hosts of Lyme disease and WNE) or smaller clutch size (for hosts of EEE) had a lower reservoir competence."} +{"text": "An additional grant from the National Cancer Institute was incorrectly omitted from the Funding Statement. The number of the grant is: R01 CA151979."} +{"text": "The name of the 7th author was misspelled. The correct spelling is Stuart Sims."} +{"text": "There was an error in the title of the article. The correct title is: Pleiotrophin (PTN) Expression and Function in the Mouse Mammary Gland and Mammary Epithelial Cells"} +{"text": "A grant from the NIH that funded the last author's work for the article is incorrect. The grant number is: R01-EY19304."} +{"text": "The Supporting Information was incorrectly omitted from the article. Please view the Supporting Information here: Click here for additional data file."} +{"text": "The name of the eighth author was given incorrectly. The correct name is: Yu Yang."} +{"text": "A contribution of the sixth author (MAP) to the study was incorrectly omitted from the Contributions Statement. The following should be included with the Author Contributions Statement: \"Contributed to the follow up data collection: MAP.\""} +{"text": "The following information is missing from the Funding section: This study was supported by National Institutes of Health, P50 DK096415: to NK."} +{"text": "The following information is missing from the Funding section: PB was supported by the program CONICYT PAI/Academia (grant 79130005)."} +{"text": "The original version of this article unfortunately contained some mistakes. The presentation of Table"} +{"text": "In the Funding section, the grant number from the funder the UK Medical Research Council was omitted. The correct grant number is: MC_UU_12014."} +{"text": "Scientific Reports5: Article number: 1615810.1038/srep16158; published online 11092015; updated on 01122016The original version of this Article contained a typographical error in the spelling of the author Hongping Yin, which was incorrectly given as Honging Yin. This has now been corrected in the PDF and HTML versions of the Article."} +{"text": "Lars A. Bach is affiliated with: The Data Availability statement for this paper is incorrect. The correct statement is: All relevant data are within the paper and Supporting Information files."} +{"text": "In the Funding section, the grant number from the funder Zhejiang Provincial Natural Science Foundation of China is listed incorrectly. The correct grant number is: LQ13H160015."} +{"text": "The Funding section is incorrect. The correct Funding information is: This study was supported by the research grant from Marie Sk\u0142odowska-Curie Fund, European Commission (268184)."} +{"text": "There is an error in the final sentence of the Apparatus and Measurements subsection of the Experimental section. The correct sentence is: Scanning electron microscopy (SEM) images were taken using a Hitachi S-4800 scanning electron microscope."} +{"text": "In the Funding section, the grant number from the funder Research Centre of Excellence is listed incorrectly. The correct grant number is: 9878/2015/FEKUT project."} +{"text": "The correct sentence is: A complete dataset of all original and filtered images is available at the Harvard Dataverse, URL:"} +{"text": "The following information is missing from the Funding section: This study was co-financed by the European Union through the Fondo Europeo de Desarrollo Regional ."} +{"text": "In the Funding section, the grant number from the funder National Science Foundation is missing. The correct grant number is: 1239889."} +{"text": "IJERPH [The authors wish to add the following amendments and corrections to their paper published in IJERPH .Page 2460, Table 9: The data in last two columns are reversed. The correct The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "There was an error with one Author name (Number 3). Name and surname were inverted. The correct one is: NAME: Elidon and SURNAME: Mici."} +{"text": "Several of the equations in this article are incorrect.In the Determinant of A Matrix: A Brief Review section under the subheading \u201cEvaluation of determinant by row reduction\u201d, the seventh expression is incorrect. The correct expression is:In The New Approach Based on Dictionary Notation section, the example matrices under Step 6 are incorrect. The correct matrices are:In The New Approach Based on Dictionary Notation section, the dictionary in Iteration 4 is incorrect. The correct dictionary is"} +{"text": "The following information is missing from the Funding section: In addition, this work was supported by the Brain Korea 21 PLUS program."} +{"text": "The Data Availability statement does not appear on the paper. The correct Data Availability statement is: The authors confirm that all data underlying the findings are freely available without restriction. All data are included within the paper and its Supporting Information files.The publisher apologizes for this error."} +{"text": "The name of the second to last author in the authorship listing is spelled incorrectly. The correct spelling of the name is: Stefan P\u00f6hlmann. The citation from the original article remains the same."} +{"text": "Reason for Erratum:The first sentence of Figure"} +{"text": "There is an error in the third sentence of the Abstract. The name of the tool is incorrect. The correct sentence is: The Carer Support Needs Assessment Tool (CSNAT) is a validated instrument designed to systematically identify and address caregiver needs."} +{"text": "In the Funding section, the grant number for the Fujian Province University grant is incorrect. The correct grant number is: JA14095."} +{"text": "There is an error in the spelling of the eleventh author\u2019s name. The correct name is: Ariadne Runte-Geidel."} +{"text": "In the Funding section, the funder Tiffany Foundation should be listed as The Tiffany & Co. Foundation."} +{"text": "The correct statement is: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are deposited in the Harvard Dataverse Network, with the DOI:"} +{"text": "The affiliation for the fourth author is improperly abbreviated. The correct affiliation for Ahmed Mandil is: King Saud University\u2013College of Medicine, Riyadh, Kingdom of Saudi Arabia."} +{"text": "The original version of this article unfortunately contained some mistakes. The presentation of Figs."} +{"text": "The authors wish to update the Acknowledgments section in their paper published in Sensors , doi:10."} +{"text": "Ha equation in the second paragraph of the Methods section. The inequality symbol within this equation should read >. Please view the correct, complete equation here:There is an error in the The publisher apologizes for this error."} +{"text": "The Y-axes for the three graphs in"} +{"text": "There is an error in affiliation for Editor Gang Fang. The affiliation should be:Icahn School of Medicine at Mount Sinai, UNITED STATES"} +{"text": "Nature Communications 7: Article number: 1170010.1038/ncomms11700 (2016); Published: 05242016; Updated: 06232016.The financial support for this Article was not fully acknowledged. The Acknowledgements should have also included the following:The Hoglund Brain Imaging Center is supported by a generous gift from Forrest and Sally Hoglund and funding from the National Institutes of Health . The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies."} +{"text": "Nature Communications 6: Article number: 1008110.1038/ncomms10081 (2015); Published: 12012015; Updated: 01072016The original version of this Article contained an error in the spelling of \u2018theranostic' in the title of the paper. This has now been corrected in both the PDF and HTML versions of the Article."} +{"text": "The following information is missing from the Acknowledgements section: TCCON data were obtained from the TCCON Data Archive, hosted by the Carbon Dioxide Information Analysis Center (CDIAC)\u2014tccon.onrl.gov."} +{"text": "The Publisher apologizes for this error.The Data Availability statement for this paper is incorrect. The correct statement is: Data are available from Dryad Digital Repository:"} +{"text": "Scientific Reports5: Article number: 1623910.1038/srep16239; published online: 11092015; updated: 01292016In the HTML version of this Article, the references cited in the text from the Discussion section onwards are incorrect; the PDF version of the paper was correct from the time of publication."} +{"text": "The text from the Funding section is incorrectly included in the Competing Interests section. The correct Competing Interests information is as follows: The authors have declared that no competing interests exist. The publisher apologizes for this error, which was introduced during the typesetting process."} +{"text": "Some of the funders listed in the Funding statement did not contribute financially to this study. The publisher apologizes for the error. The correct funding information is as follows: This work was supported by a grant from Kyung Hee University 2013 [KHU-20130438]."} +{"text": "In the Funding section, one of the grant numbers from the funder the National Institutes of Health is listed incorrectly. The correct grant number is: U19 AI089672."} +{"text": "The following information is missing from the Funding section: This study was also supported by the NSF of China, Grant No. 11275003."} +{"text": "The following information is missing from the Funding section: Funding for this work was provided by the NSF-Couple Natural Human Systems Program (DEB-1211797)."} +{"text": "In the Data Availability statement, the accession number is listed incorrectly. The correct accession number is: GSE 59517."} +{"text": "Scientific Reports5: Article number: 1620710.1038/srep16207; published online 11092015; updated: 02092016The original version of this Article contained a typographical error in the spelling of the author Alessandro Ciattoni which was incorrectly given as Alessardro Ciattoni. This has now been corrected in the PDF and HTML versions of the Article."} +{"text": "To The Editor:I read with interest the recent published article in your The prevalence of HAV infection differs in various parts of the world based on the geographic area, sanitary conditions and socioeconomic levels . There a"} +{"text": "The date this article was received is listed incorrectly. The correct date received is the following: October 26, 2014."} +{"text": "In the Funding section, the grant number from the funder FONDECYT is listed incorrectly. The correct grant number is: FONDECYT 1090742."} +{"text": "Nature Communications7: Article number: 11520 10.1038/ncomms11520 (2016); Published: 0592016; Updated: 06072016The HTML version of this Correspondence was previously published with an incomplete title and incorrect Article number. This has now been corrected in the HTML; the PDF version of the paper was correct from the time of publication."} +{"text": "The Funding section is incorrect. The publisher apologizes for the error. The correct funding information is as follows: The study was funded by the German Bundesministerium f\u00fcr Bildung und Forschung (Grant number: 01ER0810). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."} +{"text": "The affiliation for the second author is incomplete. Louise Locock should have the following added to her affiliation: Health Experiences Fellow, NIHR Oxford Biomedical Research Centre."} +{"text": "The competing interests statement is incorrect; the publisher apologizes for the error. The correct statement is: The authors confirm that co-author Aldo Rustichini is an academic editor of PLOS ONE. This does not alter the authors\u2019 adherence to PLOS ONE Editorial policies and criteria."} +{"text": "The publisher apologizes for the error. The correct email address is:"} +{"text": "The original version of this article unfortunately contained a mistake. The presentation of Figs."} +{"text": "The correct statement is: All relevant data are within the paper, its Supporting Information files and from Zenodo:"} +{"text": "The following information is missing from the Funding section: This study was supported by the research project JA TEP-1136 from Junta de Andaluc\u00eda and MAT2013-43946R from the Spanish Ministry of Economy and Competitiveness."} +{"text": "The publisher apologizes for the error. The correct sentence is: Furthermore, our"} +{"text": "Critical Care[We read with great interest the article by Scales and Cutherbertson on percutaneous dilatational tracheostomy in a previous issue of ical Care. In partical Care. For theGCE: Global cerebral edema; ICP: Intracranial pressure; NeuroICU: Neurosciences intensive care unit.The authors declare that they have no competing interests."} +{"text": "There is an error in the Funding section. The first sentence should read: The work was supported by 16230 Associazione Italiana per la ricerca sul cancro, Marie Curie Actions European Union to GDC."} +{"text": "The publisher apologizes for the error.The Data Availability statement for this paper is incorrect. The correct statement is: Data have been deposited to Figshare:"} +{"text": "Scientific Reports5: Article number: 11933; 10.1038/srep11933published online: 07072015; updated: 11042015The original version of this Article contained a typographical error in the spelling of the author Sung Hee Chun which was incorrectly given as Sung He Chun.In addition, the original version of the Article did not indicate that Myung Hwa Kim and Jeong Min Baik jointly supervised the work.These errors have been corrected in both the PDF and HTML versions of the paper."} +{"text": "This error was introduced during the preparation of this manuscript for publication. The publisher apologizes for this error. Please see the complete, correct equation here: The 20"} +{"text": "Unfortunately, the original version of this article contained an error. The name of one author Jay Gopal Ray was included incorrectly. The correct name can be found below:Jay Gopal Ray"} +{"text": "Dear Sir:The article by Arce and others was helpful."} +{"text": "The publisher apologizes for the error.The Data Availability Statement is incorrect. The correct statement should read as follows: Data are available from the Edinburgh DataShare repository ("} +{"text": "Scientific Reports5: Article number: 1302110.1038/srep13021; published online: 08172015; updated: 10232015The original HTML version of this Article contained a typographical error in the spelling of the author Azadeh HajiHosseini which was incorrectly given as Azadeh Haji Hosseini. This has now been corrected in the HTML version of the Article.In addition, the original version of this Article quoted an incorrect abbreviation for Azadeh HajiHosseini in the \u2018How to cite this article\u2019 section. This has now been corrected in both the PDF and HTML versions of the paper."} +{"text": "In the Funding section, the grant number from the funder National Institute on Alcohol Abuse and Alcoholism is listed incorrectly. The correct grant number is: T32 AA013527."} +{"text": "In the Funding section, the grant number from the funder Agricultural Science and Technology Innovation Program is listed incorrectly. The correct grant number is: ASTIP-IAS10."} +{"text": "The correct statement is: Data are available from the NCBI Short Read Archive (SRA) ("} +{"text": "The publisher apologizes for the error.The eighth and ninth authors, Qin Hong and Xia Chi, should be noted as corresponding authors. The contact email for Qin Hong is"} +{"text": "The names of the eighth and nineteenth authors are incorrect. The correct name for the eighth author is: Adriana Zeevi. The correct name for the nineteenth author is: Elaine F. Reed."} +{"text": "Scientific Reports6: Article number: 2639510.1038/srep26395; published online: 05202016; updated: 07182016The original version of this Article contained an error in the spelling of the author Maria Luisa Scattoni which was incorrectly given as Scattoni Maria Luisa. These errors have now been corrected in the PDF and HTML versions of the Article."} +{"text": "We congratulate Yu et al. for their successful results where they evaluated the pattern distribution and the changes of strabismus surgery in pediatric population . The autIntermittent exotropia (X(T)) is the most common form of childhood exotropia . It has"} +{"text": "The Funding section appears incorrectly. Please view the complete, correct Funding statement here: The publication of this manuscript has been funded by the Jagiellonian University Medical College, Faculty of Medicine KNOW funds.The publisher apologizes for the error."} +{"text": "There are errors in the Funding section. The correct funding information is as follows: This is a new analysis of data from a Defra-funded research project . The research project was quality assured and independently peer reviewed. University of Lincoln provided financial support for the additional analysis presented in this paper."} +{"text": "In the Funding section, the catalogue number from the EDENext Steering Committee is listed incorrectly. The correct number is: EDENext320."} +{"text": "The following information is missing from the Funding section: This work was partially funded by the European Union Programs Regional Potential/Translational Potential Grant 285948 (to GN and EC)."} +{"text": "The second author\u2019s name is spelled incorrectly in the original article and in the correction published on September 3, 2015. The correct name is: Sung Eun Kim."} +{"text": "Casuarina equisetifolia and Acacia sp. are misspelled in the Discussion section.The species names for The last row of"} +{"text": "The Data Availability statement does not appear on the paper. The correct Data Availability statement is: The authors confirm that all data underlying the findings are freely available without restriction. All data are included within the paper.The publisher apologizes for this error."} +{"text": "In the Funding section, the grant number from the funder EMBO is listed incorrectly. The correct grant number is: 2138."} +{"text": "The data are available from Open Science Framework instead of Dataverse. The correct sentence is: The questionnaire programmed in Qualtrics was offered in Dutch and took on average 15 minutes to complete (on a notebook (Acer) or an iPad; the exact questionnaire in Dutch are available via"} +{"text": "The Data Availability statement for this paper is incorrect. The correct statement is: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.Please see the S1 Data(RAR)Click here for additional data file."} +{"text": "The Acknowledgments section is incomplete. The correct Acknowledgments should appear as follows: We thank Aaron Darling and Hatch Stokes for their comments on an early draft of this manuscript.The image for"} +{"text": "The SNP array data are available from NBDC website under controlled access (http://biosciencedbc.jp/en/). The NBDC number is hum0030, and the JGA (Japanese Genotype-phenotype Archive) accession number is JGA00000000022.There are errors in the Data Availability statement. The correct statement is: The expression array data are freely available in the GEO website (The accession number is GSE65986 in GEO website ("} +{"text": "The following information is missing from the Funding section: KL-T was also supported by the European Research Council (ERC)."} +{"text": "Corrected publisher error in data availability statement. The correct data availability information is as follows: Data from the EPIC Norfolk Study cannot be deposited publicly due to ethics and consent issues. The EPIC-Norfolk data access committee can be contacted at The publisher apologizes for the error."} +{"text": "The tenth author\u2019s name is spelled incorrectly. The correct name is: Alvaro Moreno-Aspitia.The Academic Editor field is missing from the published paper. The name of the Academic Editor is: Aamir Ahmad, Wayne State University School of Medicine, United States."} +{"text": "In the Funding section, the second grant number from the funder NIH is listed incorrectly. The correct grant number is: U54 GM111274."} +{"text": "The following information is missing from the Funding section: Funding was also received from the Anton Betz Foundation of the Rheinische Post, Duesseldorf, Germany."} +{"text": "The authors would like to acknowledge the use of the Bi-directional dual promoter complex with enhanced promoter activity for transgene expression in eukaryotes in this study . The aut"} +{"text": "The third author\u2019s name is spelled incorrectly. The first and last names of this author have been swapped. The correct name is: Corona Alonso."} +{"text": "The following information is missing from the Funding section: This work was supported by NIH NM-INBRE grant P20 GM103451 (CEM) and by start-up funds from University of New Mexico (CEM).There are errors in the legend for"} +{"text": "There is an error in the first sentence of the Introduction. The publisher apologizes for the error. The correct sentence is: Although alcoholism is a worldwide problem resulting in millions of deaths, only a small percentage of alcohol users become addicted [1]."} +{"text": "The Data Availability statement for this paper is incorrect. The correct statement is: The unigenes information was deposited in the Sequence Read Archive (SRA) database in NCBI .In the subsection Analysis of transcriptome sequencing results of the Materials and Methods section, the final sentence of the first paragraph references the incorrect accession number. The complete, correct sentence is: The unigenes information was deposited in the Sequence Read Archive (SRA) database in NCBI ."} +{"text": "The publisher apologises for this error.The published version of this article states an incorrect publication year of 2015. The correct date of publication is 19"} +{"text": "The following information is missing from the Funding section: This study was funded in part by a National Institutes of Health grant (HD-042311) to JPL."} +{"text": "The publisher apologizes for the error.The following information is missing from the Funding section: This study was supported by grant BIO2014-53029 from the Ministerio de Econom\u00eda y Competitividad ("} +{"text": "The footnotes for each table were removed during the typesetting process of this article. The publisher apologizes for this error. Please see the corrected tables here."} +{"text": "There is an error in the author list of this manuscript. The eighth author's name is spelled incorrectly. The correct name is: Annika C. Karlsson."} +{"text": "Scientific Reports6: Article number: 2591710.1038/srep25917; published online: 05202016; updated: 07042016The original version of this Article contained a typographical error in the spelling of the author Maria Iliut which was incorrectly given as Maria Iluit. This has now been corrected in the PDF and HTML versions of the Article."} +{"text": "The Data Availability statement does not appear on the paper. The correct Data Availability statement is: The authors confirm that all data underlying the findings are freely available without restriction. All data are included within the paper.The publisher apologizes for this error."} +{"text": "Erratum of \"In time: averting the legacy of kidney disease \u2212 focus on childhood\" , in the In the editorial It should read:"} +{"text": "Dear Editor,Regarding the article: Application of queuing theory to decrease waiting times in emergency department: Does it make sense? published in Archives of Trauma Research , I would"} +{"text": "The third author's name is spelled incorrectly. The correct name is: Michaela Faulstich. The citation from the original article remains the same."} +{"text": "In the Funding section, the grant number from the NIH is listed incorrectly. The correct grant number is: R01DC014479."} +{"text": "In the Funding section, the grant number from the funder Ministry of Food and Drug Safety in 2019 is listed incorrectly. The correct grant number is: 19162MFDS021."} +{"text": "The authors regret a mistake in the author names of ref. 44. The correct reference is shown below as ref. The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Following publication of the original article , the autThe incorrect author name is: Geetha Ahuja.The correct author name is: Geeta Ahuja.The author group has been updated above and the original article has been"} +{"text": "The virus isolate UG09615 is incorrectly reported throughout the article as isolated in 2010 in Uganda. The correct date of isolation in Uganda is 2012. The date of isolate collection has been updated in the reference GenBank sequence with accession #MN813491."} +{"text": "In the original publication , Scheme The correct schemes should be as follows:The authors state that the scientific conclusions are unaffected. The original publication has also been updated."} +{"text": "The original version of this article unfortunately contained an error regarding the order of authors. Given here is the corrected list of authors.The original article has been corrected."} +{"text": "Following publication of the original article , the autThe incorrect author name is: Fabian Temorshuizen.The correct author name is: Fabian Termorshuizen.The author group has been updated above and the original article has been"} +{"text": "Duygu Kocyigit. The affiliation is available via this correction article. The original article [The original publication of this article was missing the affiliation of article has been"} +{"text": "The incorrect author name is: Michelle PoimbouefThe correct author name is: Michelle PoimboeufFollowing publication of the original article , the autThe author group has been updated above and the original article has been"} +{"text": "Following publication of the original article , the autThe incorrect author name is: Abbas Adams.The correct author name is: Abass Adams.The author group has been updated above and the original article has been"} +{"text": "The Authors wish to make the following corrections to this paper : In the original article, there were mistakes in The mistakes were caused during copy-editing. The caption in"} +{"text": "Following publication of the original article , the autThe updated paragraph 4 in the Future Delirium Monitoring section is given below which now indicates the correct reference number 89 and the reference is included within this correction article.Future Delirium MonitoringOne exception is the DeltaScan monitor, with fair (69%) sensitivity and fair (69%) specificity, meaning that further improvement is necessary .The incorrect author name is: Given Name: Shawniqua Given Name: Williams Family Name: Roberson.The correct author name is: Given Name: Shawniqua Family Name: Williams Roberson.The citation and reference and author group has been updated in this correction article and the original article has been"} +{"text": "The raw non-aggregate data underlying the results of this article are misshttps://osf.io/st8jc/.The previous Data Availability statement is therefore incorrect. The correct statement is: The data that support the findings of this study are openly available in Open Science Framework (OSF) at With this correction, all relevant data are now provided."} +{"text": "This article has been corrected: The authors corrected the FUNDING section. The correct section is presented below."} +{"text": "The information listed in the Funding statement is incorrect. The correct Funding statement is as follows: This study was supported by the \"Regional Initiative of Excellence\" in 2019\u20132022 in the form of funds to MP [project no. 002 / RID / 2018/19]."} +{"text": "Following publication of the original article , the autThe incorrect author name is: Hazem Abdelkalel.The correct author name is: Hazem Abdelkhalek.The author group has been updated above, and the original article has been"} +{"text": "In the original article , there wOriginal Scheme 1:This should be replaced with the following:Original Scheme 2:This should be replaced with the following:"} +{"text": "Following publication of the original article , the autThe incorrect author names: Liu Meimei and Ma Zenghui.The correct author names: Meimei Liu and Zenghui Ma.The author group has been updated above and the original article has been"} +{"text": "The correct statement is: The authors confirm that all data underlying the findings are fully available without restriction. The source code and original data are available here: The processed data is available in the Supporting Information."} +{"text": "In the Funding statement, the grant number from the funder Outstanding Youth of the natural science foundation of Inner Mongolia is listed incorrectly. The correct grant number is: No.2018JQ01."} +{"text": "In the original publication of the article, the author name has been incorrectly published as Maria C. Santagati in the Review (2022). The correct name is Maria Santagati.The original article has been corrected."} +{"text": "The correct email is: The Publisher apologises for the error."} +{"text": "The author's name and affiliation have been corrected. The original published version of this article featured the incorrect spelling of the author's name (as entered by the author) and an incorrect author affiliation . The name and affiliation have now been corrected. The author deeply regrets these errors."} +{"text": "The original version of this article unfortunately contained a mistake. The footnotes in Table The original article has been corrected."} +{"text": "In the article by Abedi et al. (2022), the name of the third author was incorrect. The article has been corrected online, so author byline now reads as:Vrya Hosseini | Khadijeh Bahalkeh | Nicolas GrossMehdi Abedi | Reza Omidipour | Seyed The authors apologize for the error."} +{"text": "In the original publication, the name of fourth and seventh authors were incorrectly published as: Takashi Sangai and Hidetoshi Kawagichi. The correct version of names are: Takafumi Sangai and Hidetoshi Kawaguchi as given in this Correction.The original publication has been corrected."} +{"text": "The authors have not stated any conflicts of interest.In the Notes section (page 20), the conflicts of interest statement was missing. The following statement should be added:"} +{"text": "The Fig.\u00a01 in the original published version of the above article was incorrect. The corrected Figure is shown as follows:The original article has been corrected."} +{"text": "The following note was missing from the original online version of this article:Soo kyung Ahn and Sohee Oh contributed equally to this work.The original article was corrected."} +{"text": "Andreas Bayer Eur J Radiol. 2021 Sep;142:109885The removal of pelvic lymph nodes is a important point during the radical prostatectomy and radical cystectomy. The extension of lymph node dissection is controversial and associated with more complications in post-operative period . In this"} +{"text": "An author's name was misspelled in the above paper: Yohanes Mirekena Lemu should be Yohanes Mirkena Lemu. This has now been corrected in the online PDF and HTML copies of the article.The authors apologise for the error."} +{"text": "The Acknowledgements section was missing from this article and should have read:The present work was performed in fulfillment of the requirements for obtaining the degree \"Dr. med.\"/\"Dr. med. dent.The original article has been corrected."} +{"text": "In the Funding statement, the grant number from the funder Ratchadapisek Somphot Fund for Postdoctoral Fellowship is missing. The grant number is: RA62/013."} +{"text": "A funding acknowledgement was missing from the original publication of this article. The below acknowledgement should have been includedFund Name: Key Project of Hunan Provincial Science and technology innovation [No. 2020SK1015-3]This has now been added to the original version of record."} +{"text": "In the Funding section, the grant number from the funder NIH to author DHH is listed incorrectly. The correct grant number is: OD010943."} +{"text": "There are errors in the Correction published on April 8, 2021. The corrected figures are incorrect. The correct figures are:The publisher apologizes for the errors."} +{"text": "The authors wish to make the following corrections to this paper :Data Availability Statement: Reads will be available upon acceptance of the manuscript.To the correct version, as follows:Data Availability Statement: The data presented in this study are openly available in the European Nucleotide Archive (ENA), project PRJEB48225.The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "The following information is missing from the Funding statement: This work was supported by CAPES/Fapeam."} +{"text": "Following publication of the original article , the autThe incorrect author name is: Giovanna Paglietti.The correct author name is: Maria Giovanna Paglietti.The original article has been"} +{"text": "The authors regret that the start date of the study was published incorrectly (Pages 671and 672). The start date must be changed from August 2018 to May 2018. The authorswould like to apologize for any inconvenience caused. The online version of article hasbeen updated on July 14, 2021."} +{"text": "The eighth author\u2019s name is spelled incorrectly in the byline and in the Resources subsection of the Author Contributions. The correct name is: Ikyon Kim.The eighth author\u2019s initials are listed incorrectly after their email address. The correct initials are: IK."} +{"text": "Following publication of the original article , the autThe incorrect author name is: Vasilis Vasilou.The correct author names is: Vasilis Vasiliou.The author group has been updated above and the original article has been"} +{"text": "Following publication of the original article , the autThe incorrect author name is: Masahiro Hiyashita.The correct author names is: Masahiro Miyashita.The author group has been updated above and the original article has been corrected in the author list and Authors\u2019 contributions section."} +{"text": "There are errors in the Funding statement. The correct Funding statement is as follows: This work was supported by JST SPRING, Grant Number JPMJSP2124."} +{"text": "This article : 404-414) has been retracted due to concerns on multiple image duplications as identified by PubPeer users. This raises concerns about the integrity of the data presented in the paper."} +{"text": "The incorrect author name is: Iresha AyatilakebandaThe correct author name is: Iresha JayatilakebandaFollowing publication of the original article [1], the author identified an error in the author name of Iresha Jayatilakebanda.The author group has been updated above and the original article has been"} +{"text": "In the original publication of the article, the first name of the eighth author was incorrect. The correct name of the author should be as given below:First Name: Johan F.Last Name: Langenhuijsen.The original article has been updated accordingly."} +{"text": "Following publication of the original article , the autThe incorrect author names are: Meareg Wolde and Simegniew Handebo.The correct author names are: Maereg Wolde, Simegnew Handebo.The author group has been updated above and the original article has been"} +{"text": "Following publication of the original article , the autThe incorrect author name is: Kouji Tsuta.The correct author name is: Koji Tsuta.The author group has been updated above and the original article has been"} +{"text": "There is a typographical error in the article title. The correct title is: Testing the potential of streamflow data to predict spring migration of ungulate herds. The publisher apologizes for the error."} +{"text": "The Editors decided to retract this paper to avoid further damage to the scientific community.The Brazilian Journal of Medical and Biological Research remains vigilant to prevent misconduct and reinforces the Journal\u2019s commitment to good scientific practices. We regret the unprofessional behavior of the authors involved.zhangweiwei3832@126.com>Correspondence: Weiwei Zhang: <"} +{"text": "The Genome Sequence Archive for Human accession number for the RNA-seq data has been corrected to HRA001985. The HTML and PDF versions of the Article have been corrected."} +{"text": "The authors wish to make the following erratum to this paper : the sumThe corrected Equations (11) and (12) appear below:The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated."} +{"text": "The Editor-in-Chief has retracted this article at the request of Fei Xu. The article contains substantial overlap with another article previously published in Chinese by different authors .All authors agree with this retraction."} +{"text": "The attribution of the image used in this article is incorrect. The correct attribution is: (Image: Henri Mouy)."} +{"text": "The following information is missing from the Acknowledgments: This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-Track research funding program.This information is also missing from the Funding statement. The correct Funding statement is as follows: This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Fast-Track research funding program."} +{"text": "Following publication of the original article , the autThe incorrect author name is: Rafiqul Islam.The correct author name is: Mohammad Rafiqul Islam.The author group has been updated above and the original article has been"} +{"text": "The incorrect author name is: Xiuiyng WangThe correct author name is: Xiuying WangFollowing publication of the original article , the autThe author group has been updated above and the original article has been"} +{"text": "Following the publication of the original article , the autThe incorrect corresponding author is: Linyu Wang.The correct corresponding author is: Yuanning Liu.The original article has been"} +{"text": "Following the publication of the original article , the autThe incorrect indicator function:The correct indicator function:The original article has been"} +{"text": "In the Original version of the article, the first two author names were incorrect.The Correct names are given below:Ziyu Sun, Jianyu Ye."} +{"text": "African Health Sciences. The supplement epitomizes successful completion of training of African fellows in Global leadership. The fellows have authored diverse manuscripts in three themes: HIV, reproductive and child health.Welcome to this Afya Bora supplement of This is a welcome break from the COVID-19 pandemic. The HIV papers are basically on antiretroviral therapy (ART), with special emphasis on outcome"} +{"text": "In the Funding section, the grant number from the funder King Saud University is listed incorrectly. The correct grant number is: RSP-2021/193. The publisher apologizes for the error."} +{"text": "The Funding statement is incorrect. The correct statement is: Funding to support open access publication of this manuscript was provided by The Society for Companion Animal Studies (SCAS)."} +{"text": "Psychological Medicine with the some conflicts of interest information missing. The correct conflict of interest statement is written below:The above mentioned article was published in H. Lundbeck A/S provided the study drug.The authors apologise for this error."} +{"text": "Originally published table:Corrected table:Following the publication of the original article (Trollip et al. The original article has been corrected."} +{"text": "Following publication of the original article , the autThe incorrect author name is: Paria Fadari Dehcheshmeh.The correct author name is: Paria Fadaei Dehcheshmeh.The author group has been updated above and the original article has been"} +{"text": "The authors would like to make the following corrections about the published paper .Replacing the Data Availability Statement from: Not applicable.Data Availability Statement: The data presented in this study are available on request from the corresponding author."} +{"text": "The first author\u2019s name is spelled incorrectly. The correct name is: Gyung Doek Han.In the Funding statement, the grant number from the funder Rural Development Administration, Republic of Korea is listed incorrectly. The correct grant number is: PJ01562003."} +{"text": "Following the publication of the original article , the autThe incorrect equation:The correct equation:The original article has been"} +{"text": "In the original article, there was an error. The analyses accession number in the DATA AVAILABILITY STATEMENT section was wrong.DATA AVAILABILITY STATEMENT:A correction has been made to The detailed information of SNP2 can be found in the European Variation Archive database. Project: PRJEB33081; Analysis Accession: ERZ3224744.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Following publication of the original article , the autThe incorrect author name is: Vindy Wing Sun Chan.The correct author name is: Vindy Wing Sum Chan.The author group has been updated above and the original article has been"} +{"text": "Authors would like to correct the typo in author name of the co-author. The author name is corrected from \"Ann Karin Olson\" to \"Ann Karin Olsen\" in the original publication.The original article has been corrected."} +{"text": "The original version of this article unfortunately contained some mistakes. Some figures were incorrect and interchanged respectively. The correct assignment of figures is as follows: Figs. The original article has been corrected."} +{"text": "The incorrect author name is: Stefania Brozetti.The correct author name is: Stefania Brozzetti.Following publication of the original article , the autThe author group has been updated above and the original article has been"} +{"text": "The information has been updated in the article.Authors of the above-mentioned article DOI:"} +{"text": "There are errors in the Funding statement. The correct Funding statement is as follows: The authors received no specific funding for this work."} +{"text": "Following publication of the original article , the autThe incorrect author name is: Linda Abicher.The correct author name is: Lynda Abicher.The original article has been"} +{"text": "In the aforementioned article, the figures have been incorrectly inverted. The correct figures and their corresponding captions are as follows:The publisher regrets this error."} +{"text": "Following publication of the original article , the autThe incorrect author name is: Maryam Daneshpoor.The correct author name is: Maryam Daneshpour."} +{"text": "The following information is missing from the Funding statement: This study was supported by the NIH in the form of a grant awarded to AL (R03-HD101765)."} +{"text": "In the Funding section, the grant number from the funder University of South Bohemia Ceske Budejovice is missing. The correct grant number is: 62972."} +{"text": "This article has been corrected: The authors neglected to include the funding of Changsha City Technology Program for Zhe-Yu Hu. The authors state that this correction does not change the scientific conclusions of the article. The updated Funding information is provided below."} +{"text": "Following publication of the original article , the autThe incorrect author name is: David Carvalho.The correct author name is: Davide Carvalho.The author group has been updated above and the original article has been"} +{"text": "The following information is missing from the Funding section: This study is part of a research program funded by Breast Cancer Research Trust, UK."} +{"text": "The following information is missing from the Funding section: The page charge of this paper has been paid by PROEX-CAPES agreement."} +{"text": "There are errors in the Subclass and Order information presented in the ciliate classification table in the Results section. Please see the corrected ciliate classification table here. The publisher apologizes for the errors.The ciliate classification follows Lynn [38]."} +{"text": "In the abstract, the trial number is incorrect. Please see the corrected trial number here: NCT00564967."} +{"text": "InThe mean ages of the groups were not statistically significantly different.The text was incorrect and should have read:The mean ages of the groups were statistically significantly different.The authors apologize for this error."} +{"text": "There is an error in the first sentence of the Abstract. The correct sentence is as follows: The central 5-hydroxytryptamine deficiency impairs sociosexual behaviors and olfaction preferences in sexually naive mice."} +{"text": "The following information is missing from the Funding section: This work has been supported by iNEXT, grant number 653706, funded by the Horizon 2020 programme of the European Union."} +{"text": "The following information is missing from the Funding section: This work was supported by a grant from the Natural Science Foundation of Shandong Province (grant No. ZR2015PC020)."} +{"text": "The Funding section is incorrect. The correct funding information is: Published with a contribution from 5 x 1000 IRPEF funds in favor of the University of Foggia, in memory of Gianluca Montel."} +{"text": "The following information is missing from the Funding section: The authors greatly acknowledge the financial support from Jawaharlal Nehru University, New Delhi, India towards the publication charges of this article."} +{"text": "The byline designation for the Visigen Consortium is incorrect. The correct name is: International Visible Trait Genetics (Visigen) Consortium, and the members can be found in the Acknowledgments section. The publisher apologizes for the error."} +{"text": "After publication of the original article the authThe authors name should be presented in the original article as:First name: B. Kim.Surname: Humphreys.This has been corrected in the authorship list and reference of this Correction."} +{"text": "The total heat of the electron gas per volume was taken as )+P.The simul"} +{"text": "The first sentence in the Material and Methods section under the subheading \"Off-target search\" is incorrect. The correct sentence is: For each off-target site of any sgRNA a score is computed that indicates the likelihood of an unstable sgRNA/DNA heteroduplex."} +{"text": "The correct funding information is as follows: This study was supported by Sun Yat-Sen University (no. 2014005,"} +{"text": "The Competing interests statement for this paper is incorrect. The correct statement is: The research generated in this manuscript was used to file a provisional patent application in Australia to protect any possible intellectual property arising from this work. Provisional patent application number: 2017901487. Title: SIMPLE DNA EXTRACTION. Applicant: The University of Queensland. Filing date: April 24, 2017. The authors have not licensed or sold their technology to any company and it is not being commercialized by them."} +{"text": "In the original version of this article , publishDarquy SylvianeOriginally the author name has been published as:Sylviane DarquyThe correct author name is:The original publication of this article has been corrected."} +{"text": "The original version of this article (Diaz-Cardenas et al. The original article has been corrected."} +{"text": "The title of the original publication had an eIncorrect title:Reduced nicotine content cigarettes in smokers of low socioeconomic status: study protocol for a randomized control trialCorrect title:Reduced nicotine content cigarettes in smokers of low socioeconomic status: study protocol for a randomized controlled trialError in Fig.\u00a02:The study week and study day numbers at the top of the figure should match up with the numbers at the bottom of the figure."} +{"text": "To the Editor: I read with interest the article by Khan et al. (Orientia tsutsugamushi infection) ("} +{"text": "The following information is missing from the Funding section: This project was supported by a Sinergia-grant from the Swiss National Research Foundation (CRSII3 160704). The publisher apologizes for the error."} +{"text": "Nature Communications8: Article number: 15908; DOI: 10.1038/ncomms15908 (2017); Published 06262017; Updated 03302018The original version of this Article omitted the following from the Acknowledgements:\u2018The work was also supported by a grant to Y.H. from the Cancer Prevention Research Institute of Texas CPRIT RP170126.\u2019This has been corrected in both the PDF and HTML versions of the Article."} +{"text": "The correct statement is: Data are available from the figshare repository: ("} +{"text": "The original version of this article unfortunately contained a mistake: The spelling of the Ebrahim Gafar-Zadehs\u2019 name was incorrect. The corrected name is given above."} +{"text": "In the original publication was an eIncorrect name: Young-June LeeCorrect name: Young-Jun LeeThe original article has been updated to rectify this error."} +{"text": "The following grant is missing from the Funding section: Gates Foundation (OPP1066118).The publisher apologizes for the error."} +{"text": "The correct sentence is: Carbonate dissolution and soil COThere is an error in the sixth sentence of the Conclusions section: The correct sentence is: In addition, the involvement of sulfuric acid from coal related industries had a significant impact on the carbon evolution along the Beipan River."} +{"text": "Nature Communications8: Article number: 15235; DOI: 10.1038/ncomms15235 (2017); Published online: 05112017; Updated: 04102018The financial support for this Article was not correctly acknowledged. The Acknowledgements incorrectly stated that the study was funded in part by Research Foundation Flanders for project GN005212.The Acknowledgements should have stated that the study was funded in part by Research Foundation Flanders for projects G005312N and G005915N.This error has been corrected in both the PDF and the HTML versions of the Article."} +{"text": "The correct primers and PCR product size are as below:After publication of the original article , it came"} +{"text": "The following information is missing from the Funding section: This work was supported by the Andalusian Health Service (reference project CTS 2482)."} +{"text": "In the Funding section, the grant number from the funder Hort Frontiers Fruit Fly Fund is listed incorrectly. The correct grant number is: HG14033."} +{"text": "Nature Communications7 Article number: 1234210.1038/ncomms12342 (2016); Published 08092016; Updated 09132016The HTML version of this Article incorrectly listed the authors of the UK IBD Genetics Consortium and the NIDDK IBD Genetics Consortium individually in the main author list. This has now been corrected in the HTML; the PDF version of the paper was correct from the time of publication."} +{"text": "The Funding information is incorrect. The correct funding information is as follows: This work was supported by a grant from the National Nature Fund Project (Screening of molecular markers for early diagnosis of acute aortic dissection based on proteomic techniques) awarded to XM (grant number 81660085)."} +{"text": "The following information is missing from the Funding section: This study was supported by the European Union Horizon 2020 Research and Innovation Programme (Grant No. 692195)."} +{"text": "Upon publication, the following error was introduced to the title of this article : The \u2018UKThe correct title should read: 'Developing a mHealth intervention to promote uptake of HIV testing among African communities in the UK: a qualitative study'.The correct title has been included in this erratum and has also been updated in the original article."} +{"text": "The author\u2019s name was corrected from: Paolo Savalaggio to: Paolo Salvalaggio. This error appeared only in the print form of the journal and not in the PubMed database."} +{"text": "In the Funding section, the grant number from the funder Lundbeck Foundation is listed incorrectly. The correct grant number is: R105-9813."} +{"text": "In the original publication was the Old name: SightSimCorrect name: PeekSim"} +{"text": "In the Author Contributions section, Jin Wang (JW) should be listed as one of the persons responsible for writing\u2014reviewing & editing.The following information is missing from the Funding Disclosure: This study was supported by National Science Foundation (grant no. PHY-76066).The publisher apologizes for these errors."} +{"text": "Scientific Reports6: Article number: 2663910.1038/srep26639; published online: 05242016; updated: 06012018Scientific Reports at the request of Nanyang Technological University. An investigation at Nanyang Technological University found that ethical approval for the reported experiments was not sought from their Internal Review Board.This Article has been retracted by The Authors do not agree with the Retraction."} +{"text": "In the Funding section, the grant number from the funder Asan Institute for Life Sciences is listed incorrectly. The correct grant number is: 2016\u2013307."} +{"text": "In the Funding section, the grant number from the National Science Foundation Dimensions in Biodiversity awards for KMO is listed incorrectly. The correct grant number is: 1240892."} +{"text": "The Competing Interests statement is incorrect. The correct statement is: The corresponding author Chih-Horng Kuo is an Academic Editor for PLOS ONE. This does not alter the authors\u2019 adherence to PLOS ONE Editorial policies and criteria."} +{"text": "The challenge of AAA: unusual case of obstructive jaundice). We would like to apologise for any inconvenience caused.Following publication of the original article , it was"} +{"text": "Scientific Reports5: Article number: 1358310.1038/srep13583; published online: 08282015; updated: 06012018Scientific Reports at the request of Nanyang Technological University. An investigation at Nanyang Technological University found that ethical approval for the reported experiments was not sought from their Internal Review Board.This Article has been retracted by The Authors do not agree with the Retraction."} +{"text": "The Data Availability statement for this paper is incorrect. The correct statement is: All relevant data are available within the paper and its Supporting Information files. RNA sequence data are available from the NCBI Gene Expression Omnibus (GEO) repository under the following accession numbers: GSE93023, GSE93021, and GSE93022."} +{"text": "The original publication of this article exhibits an error with respect to an introduced patient value found in the first paragraph of the Results section. The correct version can be found below.Incorrect sentence:Twelve patients needed the intraoperative transfusion.Correct sentence:Seven patients needed the intraoperative transfusion."} +{"text": "The title contains an error in the original publication . The cor"} +{"text": "The authors wish to make the following corrections to this paper :jcm-05-The authors apologize for any inconvenience caused to the readers by these changes."} +{"text": "There is an error in the last sentence of the first paragraph in the Results section. The correct sentence is: Sequences were deposited in the GenBank database under the accession numbers KY696790-KY696837."} +{"text": "The Competing Interests statement is incorrect. The correct statement is: YW owns equity in PhenoSys. The other authors have declared that no competing interests exist. This does not alter our adherence to PLOS ONE policies on sharing data and materials.https://zenodo.org/record/400271.The following information is missing from the Data Availability statement: Data are available from"} +{"text": "Scientific Reports7: Article number: 4514110.1038/srep45141; published online: 03222017; updated: 05162017One of the Supplementary Information files that accompany this study was inadvertently omitted in the original version of this Article. The link to this Supplementary Information file has now been added to the HTML version of the Article."} +{"text": "The correct author name should read: on behalf of the Cognitive Function Ageing Studies (CFAS) collaboration. The publisher apologizes for the error.There is an error in the byline for the 7"} +{"text": "The Competing Interest Statement for this paper is incorrect. The correct Statement is: The authors have declared that no competing interests exist. The publisher apologizes for the error."} +{"text": "The name of the author [Zhixin Wan] was not completely displayed in the original publication . The ori"} +{"text": "Nature Communications4: Article number: 2674; DOI: 10.1038/ncomms3674 (2013); Published online 10242013; Updated 03302018The original HTML version of this Article had an incorrect article number of 2578; it should have been 2674. This has now been corrected in the HTML; the PDF version of the Article was correct from the time of publication."} +{"text": "Scientific Reports6: Article number: 2705910.1038/srep27059; published online: 06012016; updated: 01082018In the original version of this Article, the Supplementary Information file containing the supplementary figures and tables was omitted. This has been corrected in the HTML version of the Article; the PDF version was correct at the time of publication."} +{"text": "In the Funding section, the grant number from the funder Jiangsu Natural Science Foundation is listed incorrectly. The correct grant number is: No. BK20161474."} +{"text": "The following information is missing from the Funding section: Additional funding was provided to FCK by the UK Natural Environment Research Council within the framework of the Oceans 2025 program / WP 4.5.The images for Figs"} +{"text": "The publisher apologizes for this error. The correct statement is: Data are available within the paper and the Supporting Information files. The associated raster files to create the threat maps are available on Harvard Dataverse:"} +{"text": "Nature Communications5: Article number: 3524; DOI: 10.1038/ncomms4524 (2014); Published 04082014; Updated 03292018The original HTML version of this Article had an incorrect article number of 3424; it should have been 3524. This has now been corrected in the HTML; the PDF version of the Article was correct from the time of publication."} +{"text": "In the Funding section, the second grant number from the funder National Institutes of Health is listed incorrectly. The correct grant number is: AR067739."} +{"text": "The corrected author name is Diego Miranda-Saavedra. The spelling is now correct in the online version of the study. The authors apologize for the inconvenience."} +{"text": "Scientific Reports6: Article number: 2694810.1038/srep26948; published online: 05312016; updated: 06012018Scientific Reports at the request of Nanyang Technological University. An investigation at Nanyang Technological University found that ethical approval for the reported experiments was not sought from their Internal Review Board.This Article has been retracted by The Authors do not agree with the Retraction."} +{"text": "The large-scale organization of shape processing in the ventral and dorsal pathways. Published 5, October 2017In We have corrected the error by replacing The corrected figure is shown here:The originally published The article has been corrected accordingly."} +{"text": "The Funding statement is incorrect. The publisher apologizes for this error. The correct statement is: This work was supported by the Federal Ministry of Education and Research, Germany (grant number 03ZZ0904A)."} +{"text": "The original version of this article unfortunately contained a mistake: the spelling of the Ebrahim Gafar-Zadehs\u2019 name was incorrect. The corrected name is given above."} +{"text": "There are errors in the Funding section. The correct funding information is as follows: The authors have no support or funding to report."} +{"text": "The following information is missing from the Funding section: This study was supported by the ERC Starting Grant Malares (Grant No. 260918)."} +{"text": "The first row of Table 2 is missing. Please view the corrected table below. The publisher apologizes for the error."} +{"text": "Scientific Reports6: Article number: 3878910.1038/srep38789; published online: 12122016; updated: 01232017The original version of this Article contained an error in the spelling of the author Sadhan Das which was incorrectly given as Das Sadhan. These errors have now been corrected in the PDF and HTML versions of the Article."} +{"text": "The publisher apologizes for the error.The Data Availability statement for this paper is incorrect. The correct statement is: The data have been deposited with figshare:"} +{"text": "The name of the author group is incorrect. The correct author group is Cognitive Function andAgeing Studies (CFAS) collaboration. The publisher apologizes for the error."} +{"text": "In the Funding and Acknowledgments section, the grant number from the funder Global Center of Excellence in Clinical Trials is listed incorrectly. The correct grant number is: HI14C1062."} +{"text": "Scientific Reports6: Article number: 3855510.1038/srep38555; published online: 12082016; updated: 06012018Scientific Reports at the request of Nanyang Technological University. An investigation at Nanyang Technological University found that ethical approval for the reported experiments was not sought from their Internal Review Board.This Article has been retracted by The Authors do not agree with the Retraction."} +{"text": "In the original version of this article , publishIrjala HeikkiOriginally the author name has been published as:Heikki IrjalaThe correct author name is:The original publication of this article has been corrected."} +{"text": "All other relevant data are within the article and its Supporting Information files.The Data Availability Statement for this article is incomplete. The statement should read: Raw data files are available from the SRA database,"} +{"text": "The ninth author's name appears incorrectly in the XML of the article. The ninth author's name should be indexed as: van Wijngaarden E. The publisher apologizes for the error."} +{"text": "To the Editor: The recent etymologia article on Creutzfeldt-Jakob disease by Henry and Murphy ("} +{"text": "The following information is missing from the Funding section: This study was supported by a European Research Council (ERC) grant (no: 637752)."} +{"text": "The word \"in\" was omitted from the article title, and the title appears incorrectly in the citation as well. The correct title is: \"A Novel Strategy Involved in Anti-Oxidative Defense: The Conversion of NADH into NADPH by a Metabolic Network\""} +{"text": "The grant number from the funder University of South Bohemia Ceske Budejovice was listed incorrectly. The correct grant number is: MSM6007665801."} +{"text": "The incorrect deposition number of RB-1 was showed in the section Materials and Methods. The correct deposition number is JCM13870."} +{"text": "The first name and middle initial of the 13th author were switched. The correct name is A. Rod Merrill. In the Author Contributions section, Igor Stagljar (IS) should be listed as one of the persons who wrote the paper."} +{"text": "The last line of the Author Contributions is incorrect. It should read: Wrote the paper: BYS JZ AC."} +{"text": "The Supplementary Tables do not appear in the manuscript. They can be viewed here:Click here for additional data file."} +{"text": "To the Editor: I read with keen interest the article published by Soldo-Juresa et al in the last issue of the journal.4"} +{"text": "To the Editor: Brundage and Shanks (Streptococcus pneumoniae (The major bacterial pathogen associated with influenza-related pneumonia in 1918 was"} +{"text": "The last name of the second author in the Hopital de Limoges collaborators in the SIMA study group was misspelled. The correct spelling is: D.Ajzenberg."} +{"text": "The word \"Neovascularization\" is misspelled in the article title and the citation. The correct title is: Augmentation of Neovascularization in Hindlimb Ischemia by Combined Transplantation of Human Embryonic Stem Cells-Derived Endothelial and Mural Cells."} +{"text": "The following information was missing from the Funding section: The authors are grateful to the UK Department for International Development (DFID) for funding this work through the HPAI risk reduction project (GCP/UK/804/INT)."} +{"text": "There was an error in the title of the article, which omitted the word \"in.\" The correct title should read: ACC2 Is Expressed at High Levels in Human White Adipose and Has an Isoform with a Novel N-Terminus. This also affects the article's citation."} +{"text": "In the Funding section, the full name of the funding agency (FACETS) was listed incorrectly. The correct name is: Fast Analog Computing with Emergent Transient States."} +{"text": "Patient: A case of Turner's syndrome developing a leiomyosarcoma of the oropharynx and metachronous neurogenictumors is described. Discussion: To our knowledge, this case is the second reported leiomyosarcoma in a patient with Turner's syndrome. Alsothe site of involvement is particularly unusual for the already rare leiomyosarcomas in the young age."} +{"text": "The following information is missing from the Funding statement: We thank the European Research Council for funding (grant no. 322620 to FMA)."} +{"text": "The funding section is incorrect. The correct funding information is as follows: Open access funding provided by University of Vienna."} +{"text": "In the Materials and methods section, the access number for the electron microscopy data bank is incorrect. The correct access number is: EMD-20055."} +{"text": "The following information is missing from the Funding statement: This study was co-funded by European Regional Development Fund (FEDER)."} +{"text": "To the Editor:We thank Dr. Ye and colleagues for thei"} +{"text": "The Author Contributions for Minli Chen are incorrect. The correct contributions for Minli Chen are: Investigation, Software. The publisher apologizes for the error."} +{"text": "In the original publication of this article there waWatanabe M. MakotoIncorrect name upon publication:Makoto M. WatanabeCorrected name:The original publication has been updated. The publisher apologizes to the readers and authors for the inconvenience."} +{"text": "The following information is missing from the Funding statement: The publication of this article was funded by the Qatar National Library. No additional external funding was received for this study.The histograms are partially hidden in Figs"} +{"text": "It is essential to include abdominal CT and AY and MT: involved in editing the manuscript. FO: involved in supervision of all procedures."} +{"text": "Please view the complete, correct equation here:In the Introduction section, there is an error in the first equation. The variable"} +{"text": "The Funding statement is incorrect. The correct funding statement is as follows: This work was supported by the Swiss National Science Foundation (SNF 205321_175978).The captions for"} +{"text": "The author reported an error in an equation in the article .The incorrect formula shown is the following:The correct formula should be:"} +{"text": "Two errors occurred in the References part of our paper : One forWe would like to apologize for any inconvenience caused. The change does not affect the scientific results."} +{"text": "The affiliation for the sixth author is incorrect. Zehra Zaidi is affiliated with theEuro-Mediterranean Center on Climate Change and Ca' Foscari University ofVenice.The following information is missing from the Funding section: ZZ was supported bythe SMALLDIS project, which received funding from the European Union's Horizon 2020research and innovation programme under the Marie Sklodowska-Curie grant agreementNo. 707683."} +{"text": "The authors wish to make the following correction to their paper . The conThe concentrations of aurantio-obtusin in"} +{"text": "In the Funding section, the grant number from the funder the Zhejiang Provincial Natural Science Funds is listed incorrectly. The correct grant number is: LR15C060001."} +{"text": "The publisher apologizes for the error.The Data Availability statement is incorrect. The correct statement is: Data are available at"} +{"text": "The authors regret that in the original version of their paper, Laura Santambrogio and Mary Sue Brady were inadvertently omitted from the author list. The corrected author list appears above.All versions of this article have been corrected."} +{"text": "The third author's name is spelled incorrectly. The correct name is: Tasawar Hayat.There are errors in Eqs There are errors in the last four columns of"} +{"text": "The original version of this article unfortunately contained a mistake. The presentation of Equation was incorrect. The corrected equation is given below.The original article has been corrected."} +{"text": "In the Funding section, the reference for the funder Center of Biological Engineering is listed incorrectly. The correct reference is: UID/BIO/04469."} +{"text": "In the Funding section, the second grant number from the funder Ministry of Health & Welfare, Republic of Korea is listed incorrectly. The correct grant number is: HC17C0133."} +{"text": "The publisher apologizes for the error. The correct statement is: All relevant data are available at DOI:"} +{"text": "Following publication of the original article , the autAntonin MorillionOriginally the author name was published as:The correct author name is:Antonin Morillon"} +{"text": "Following publication of the original article , the autFigure 1 published is:The incorrect Figure 1 is:The correct"} +{"text": "The following information is missing from the Funding section: This research was supported by the 17896-4/2018/FEKUTSTRAT grant of the Hungarian Ministry of Human Capacities."} +{"text": "The correct statement is: The data underlying this study have been uploaded to the Open Science Framework and are accessible using the following link: The following information is missing from the Acknowledgments section: The primer sequences contained in S3 Appendix were provided to the authors by Dr. Christian Roos."} +{"text": "The eleventh author's name is spelled incorrectly in the PDF version of this paper. The correct name is: Eugenia Ofondu. The publisher apologizes for the error."} +{"text": "The following information is missing from the Funding statement: This study was supported by Claude D. Pepper Older Americans Independence Center at Yale University School of Medicine ."} +{"text": "The are errors in the Funding statement. The correct Funding statement is as follows: The funding was provided by the Fundamental Research Funds for the Central Universities (Grant No. 2019RC027). The publisher apologizes for the errors."} +{"text": "The correct sentence is: The genes in this group included genes in the pyruvate dehydrogenase complex and malate synthase .In the Results section, under the \u201cTnSeq reveals differences in the genetic requirements for"} +{"text": "In the Funding section, the grant number from the funder Ministry of Health & Welfare, Republic of Korea is listed incorrectly. The correct grant number is: HC17C0133."} +{"text": "The following information is missing from the Funding section: This work was supported by European Union\u2019s Horizon 2020 Research and Innovation Programme, Grant agreement No.700326. The publisher apologizes for the error."} +{"text": "The correct, complete Data Availability statement with updated MetaboLights repository information is: The minimal data set for this study has been uploaded to public repositories. The trait data is stored in the TRY Plant Trait Database: DOI:"} +{"text": "The publisher apologizes for the error. The correct statement is: Data underlying the study is available in the Dataverse repository ("} +{"text": "In the original publication the corresponding author appeared incorrectly as Xin-Wen Zhang.The corrected text is given below:The corresponding author of the article is Gang Xu."} +{"text": "The following information is missing from the Funding statement: This study was also supported by the New York Sea Grant project R/XG-22."} +{"text": "The Data Availability statement for this paper contains an incorrect accession number. The correct statement is: All relevant data are within the paper and its Supporting Information files. Additional data from microarray studies are available from the Gene Expression Omnibus (GEO) database, under accession number GSE72517."} +{"text": "The BioProject accession number in the Data Availability statement is incorrect. The correct accession number is: PRJNA344071."} +{"text": "The authors wish to make the following corrections to this paper : the autFunding: Grant Cariplo 2016-0919 (Serena Mazzucchelli).Acknowledgments: The authors thank Fabio Corsi and Serena Mazzucchelli for biological material and the University of Milan for financial support.In the original version of our article , insuffi"} +{"text": "In the Funding section, the grant number from the funder National Project is listed incorrectly. The correct grant number is: AWS14J011."} +{"text": "The following information is missing from the Funding statement: This project was supported by the European Research Council (ERC) Synergy Grant no. 319818."} +{"text": "In the Funding section, the grant number from the funder National Project is listed incorrectly. The correct grant number is: AWS14J011."} +{"text": "There are errors in the Funding and Competing interests sections. The following information is missing from the Funding section: The study was funded by the Laerdal Foundation.The correct Competing interests information is as follows: The authors have declared that no competing interests exist."} +{"text": "The following information is missing from the Funding statement: This project was supported by the CAPES-PrInt program."} +{"text": "In the original publication, the corresponding author field has been omitted. The correct corresponding author name is: Bogdan Mastalier. The original article is now corrected."} +{"text": "The author wishes to make the following correction to this paper :The correct author\u2019s name is: Danuta Drozdowska."} +{"text": "In the Funding section, the first grant number from the funder National Institutes of Health is listed incorrectly. The correct grant number is: #R01 AI130058."} +{"text": "Molecules [The authors wish to make the following corrections to the paper published in olecules : The aut"} +{"text": "The Data Availability statement for this paper is incorrect. The correct statement is: The data underlying this study have been uploaded to the Sequence Read Archive and are available using the following accession number: SRP131701."} +{"text": "In the Funding section, the grant number from the funder Excellent Youth Foundation of He\u2019nan Scientific Committee is listed incorrectly. The correct grant number is: 174100510003. The publisher apologizes for the error."} +{"text": "The following information is missing from the Funding statement: Funding was provided by the European Research Council (ERC Advanced grant MeSSI)."} +{"text": "The corrected equation is:The authors regret that there was a typo in Eq. Eq."} +{"text": "Nature Communications ; 10.1038/ncomms15659; published online 06 June 2017Correction to: The original version of the Supplementary Information associated with this Article contained an error in Supplementary Figure 4 in which the colours on the maps rendered incorrectly. The correct version of Supplementary Fig. 4 is:The HTML has been updated to include a corrected version of the Supplementary Information.which replaces the previous incorrect version:"} +{"text": "The following information is missing from the Funding section: This study was supported by the Binational US-Israel Foundation grant 2016555 to AS."} +{"text": "Nature Communications 10.1038/ncomms5750; published online 01 September 2014Correction to: This Article contains errors in Supplementary Table 3. The sixth equation in the table should read:The simulation results in the Article were based on the correct formula and thus the results are not affected by this correction. The errors have not been fixed in the original Article."} +{"text": "The Data Availability statement for this paper is incorrect. The correct statement is: Data are available from Openfmri at: ds000220."} +{"text": "In the original publication, the corresponding author name has been incorrectly typeset as: Robabeh Soleimani. The correct corresponding author name is: Somayeh Shokrgozar. The original article is now corrected."} +{"text": "The following information is missing from the Funding section: This research was supported by the 17896-4/2018/FEKUTSTRAT grant of the Hungarian Ministry of Human Capacities."} +{"text": "The following information is missing from the Funding section: The authors received funding from the Department of Science and Technology, India, under the DST PURSE-II grant towards publication charges."} +{"text": "M. Please view the complete, correct equation here:In the Procedure section there is an error in equation six in the bottom row of the matrix"} +{"text": "In the Funding section, the grant number from the funder National Institutes of Health to EMD is listed incorrectly. The correct grant number is: T32 HL082610."} +{"text": "The original version of this article unfortunately contained a mistake: the spelling of the Shadi Hassanajili\u2019s name was incorrect. The corrected name is given above."} +{"text": "In the original publication, the author name and the corresponding author field have been omitted. The author name is: Marta Licata. The original article is now corrected."} diff --git a/PMC_clustering_637.jsonl b/PMC_clustering_637.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..ca57d43cf2a3a2d965427ad95a81b96885d518a3 --- /dev/null +++ b/PMC_clustering_637.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:61d82075a3484203db698a0d57fb1eb856919d04fc7c280fb3829e22de63a038 +size 75151748 diff --git a/PMC_clustering_638.jsonl b/PMC_clustering_638.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..05ecdb621b81d3407e10ca4141529ef597d554a1 --- /dev/null +++ b/PMC_clustering_638.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:e7040d8916f9ba570e784df13fb77285149375cf4a8db95ef388863b789efd36 +size 22869040 diff --git a/PMC_clustering_639.jsonl b/PMC_clustering_639.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..649ee6b6e877a84dad0b80d530fa1ed17bddddfa --- /dev/null +++ b/PMC_clustering_639.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:314eac8ee3f81fc7dcab3b4deedbd1716c0a0aafc3e026219286faef5366c055 +size 94339548 diff --git a/PMC_clustering_640.jsonl b/PMC_clustering_640.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..2a89c660e028daf3377178175b1151beffa6a536 --- /dev/null +++ b/PMC_clustering_640.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:4621d365d3981e61620a507a287d5ee8adde779e9618cd26ed6802cca2d971af +size 43064292 diff --git a/PMC_clustering_641.jsonl b/PMC_clustering_641.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..ac65ec2b946dd68ab15a594bb4b3a385b5c93354 --- /dev/null +++ b/PMC_clustering_641.jsonl @@ -0,0 +1,937 @@ +{"text": "Journal of the Medical Library Association (JMLA) sincerely thanks the 220 peer reviewers in 2019 who helped vet and improve the quality of work published in our journal.The Journal of the Medical Library Association (JMLA) sincerely thanks the 220 peer reviewers in 2019 who helped vet and improve the quality of work published in our journal.The JMLA is always looking to expand our pool of reviewers who can critically comment on any topic of research or practice in health sciences librarianship. If you are interested in serving as a peer reviewer for JMLA, please send your CV to the editor-in-chief at jmla@journals.pitt.edu.Elizabeth AitkenKristine M. Alpi, AHIPKatherine AndersonKatelyn AngellMarilia Y. Antunez, AHIPThea AtwoodCaitlin Bakker, AHIPMichael BalesJill Barr-WalkerMichelle B. Bass, AHIPDanielle BeckerChristopher William BelterSkye Bickett, AHIPBrooke L. Billman, AHIPLindsay E. Blake, AHIPCatherine BodenSarah BonatoJill Boruff, AHIPAlexandria Leigh Brackett, AHIPWichor BramerMarci BrandenburgEllen Brassil, AHIPEmily BrennanTara BrighamAdrienne BrodieStewart Brower, AHIPHeather BrownRoy Eugene Brown, AHIPKrystal Bullers, AHIPJohn BullionChristopher BurnsNicole Capdarest-Arest, AHIPAlexander J. Carroll, AHIPTallie CasucciSusan CavanaughThane ChambersRobin ChampieuxLiza ChanMarina ChilovNatalie ClairouxHeather CoatesKeith W. Cogdill, AHIPJamie ConklinNicole ContaxisMarisa Conte, AHIPJean-Paul CourneyaJill Crawley-LowAndrew CreamerJohn W. CyrusSandy De Groote, AHIPAriel DeardorffDiana Delgado, AHIPMichelle DemetresRobin DesmeulesJennifer DinaloDaniel DollarKathel DunnMartha Earl, AHIPErin RB EldermireJonathan Eldredge, AHIPMarina EnglesakisKeith Engwall, AHIPElectra EnslowLisa Federer, AHIPRita Fleming-CastaldyDavid FlynnMargaret Jane Foster, AHIPJacqueline FreemanMelissa C. FunaroEmily J. GlennAbigail GobenAlexandra Gomes, AHIPKelsey Grabeel, AHIPAdelia GrabowskyVera GranikovJean Gudenas, AHIPGale G. Hannigan, AHIPArdis HansonSusan Maria Harnett, AHIPTeresa HartmanR. Brian HaynesMargaret Henderson, AHIPRachel Hinrichs, AHIPElizabeth G. Hinton, AHIPCarmen HowardCarol L. HoweMatt Hoy, AHIPShanda HuntEmily J. Hurst, AHIPHolly JacksonRebecca JacobSarah T. JewellPhill Jo, AHIPEmily M. Johnson, AHIPTimothy JohnsonEllen Justice, AHIPKellie N. Kaneshiro, AHIPJill R. Kavanaugh, AHIPSusan KellerAndrea KetchumSujin KimMichele Klein-Fedyshin, AHIPLorie Andrea Kloda, AHIPMolly Knapp, AHIPRachel Amelia Santose KoenigLaura KoppenLaura Kuo, AHIPErica Lake, AHIPMariana LapidusFred Willie Zametkin LaPollaDeborah L. LausengJanna C. Lawrence, AHIPGregory LaynorAnne M. Linton, AHIPElizabeth R. Lorbeer, AHIPDiane LorenzettiYa-Ling LuIrene (Rena) Machowa Lubker, AHIPJinxuan MaMark MacEachernTara R. MaloneDerek MarshallHeather J. Martin, AHIPLisa MastinKaren McElfresh, AHIPBethany S. McGowanLisa McGuireDina J. McKelvy, AHIPSandra McKeownMisa Mi, AHIPElizabeth MoretonWhitney MortensenBethany Myers, AHIPSawyer NewmanAnnie Nickum, AHIPTyler NixHannah Friggle Norton, AHIPMelanie J. NortonKelly O\u2019BrienMarilyn OermannEugenia OpudaRob O\u2019ReillyLisa Palmer, AHIPJanet PapadakosRobin ParkerMelanie Parlette-StewartEmily Patridge, AHIPDonald Pearson, AHIPRobert PerretGerald J. Perry, AHIP, FMLAKeith PickettT. Scott Plutchak, AHIP, FMLAAriel FitzGerald PomputiusKimberly R. PowellSusan PowelsonZahra PremjiKatie Prentice, AHIPLivia PuljakAlexandria QuesenberryBart RagonGurpreet Kaur RanaMarcia RapchakRebecca Raszewski, AHIPMelissa Ratajeski, AHIPRebecca RaworthRobyn Reed, AHIPMelissa L. Rethlefsen, AHIPMegan Rosenbloom, AHIPAmanda Ross-White, AHIPStephanie Roth, AHIPAlexandra SarkozyCathy Sarli, AHIPKate SaylorCarolyn SchubertStephanie SchulteApril Joy Schweikhard, AHIPAmanda ScullBarbara SenRobert Shapiro IIClaire SharifiTracy C. Shields, AHIPMary ShultzJohn Siegel, AHIPErin M. SmithJudith SmithEdwin Vincent Sperr Jr., AHIPStuart SporeSusan Steelman, AHIPElizabeth StellrechtSean StoneJudy Carol Stribling, AHIPAlisa SurkisStephanie M. Swanberg, AHIPNatalie TaggeMichele R. Tennant, AHIPNicole Theis-Mahon, AHIPAnnie ThompsonHolly ThompsonLorraine ToewsLauren TopperEfren Macanlalay Torres Jr.Ivana TruccoloRose L. TurnerAndrea Twiss-BrooksAna UgazMarcy VanaEmily VardellKimberly VardemanMegan von Isenburg, AHIPStacey Elizabeth WahlAmanda Wanner, AHIPTerrie R. WheelerJudith Ann WienerJeff D. Williams, AHIPGloria WillsonJoe WuLin Wu, AHIPJingfeng XiaLauren M. Young, AHIPKatherine G. Akers, PhD, JMLA@journals.pitt.edu, http://orcid.org/0000-0002-4578-6575, Editor-in-Chief, Journal of the Medical Library Association"} +{"text": "In the Author Contributions, Manuel Garcia Herranz (MGH) should be listed as having the following contributions: Conceptualization, Formal Analysis, Investigation, Methodology, Validation, Writing\u2013Original Draft, Writing\u2013Review & Editing."} +{"text": "Tauritermes Krishna, 1961 species, Tauritermesbandeiraisp. nov. are described. It is the fourth species of Tauritermes and occurs from the Caatinga and Atlantic Forest of Brazil. Unlike its congeners, the soldier of T.bandeirai has prominent frontal horns.The imago and soldier castes of a new Calcaritermes, Cryptotermes, Eucryptotermes, Glyptotermes, Proneotermes, and Tauritermes . Most recently, Tauritermes from Bolivia and Paraguay.In South America, six kalotermitid genera have soldiers with partial to robust head capsule phragmosis: ritermes . Accordie region . DambrosTauritermes, as other kalotermitid genera, is best characterized by venation of the winged imago and soldier head capsule morphology. For Kalotermitidae, most diagnostic characters at the intrageneric level are attributed to head capsule characters. Rugitermes, Marginitermes, and Tauritermes, respectively. They found that differentiation of the gut morphology of kalotermitids remains elusive at both the generic and specific levels.Tauritermes species, T.bandeirai sp. nov. from samples collected by Tauritermes to be described based on external imago and soldier characters.Herein, we report on a new University of Florida Termite Collectio (UFTC) records are available online are more angular but much smaller, barely elevated above the frons in oblique view , the dorsal horn is more elevated and angular, while the frontal horn is also absent ; 659 meters A.S.L., 17AUG2000, A. Vasconcellos (AV); one soldier no. SA499, subsample from Universidade Federal da Para\u00edba Termite Collection (UPTC) no. 3160.-14.2840, -39.8428), 194 m, 18MAR1994, Jan K\u0159e\u010dek; one soldier, pseudergates; UFTC SA444. Bahia, Morro do Chap\u00e9u , 974 m, 5NOV2015, AV; four soldiers, four imagos, pseudergates; SA504, 7309 (UFTC and UPTC accession numbers respectively). Bahia, Milagres , 700 m, 16MAR2012, AV; four soldiers, pseudergates; 4362. Para\u00edba, Matur\u00e9ia ; 700 m, 20MAY2000, AV; three soldiers, pseudergates; SA497, 1255. Para\u00edba, Mamanguape ; 33 m, 24JUN2000, AV; two soldiers, pseudergates; SA498, 1799. Para\u00edba, Jo\u00e3o Pessoa ; 53 m, 20DEC2012, AV; three soldiers, five imagos; SA502, 4747. Para\u00edba, S\u00e3o Jos\u00e9 dos Cordeiros, RPPN Faz. Almas , 523 m, 07MAR2003, AV; three soldiers, pseudergates; 4746. Pernambuco, Bu\u00edque ; 705 m, 16APR2009, AV; two soldiers, one imago, pseudergates; SA500, 3307. Pernambuco, Floresta Tacaratu ; 924 m, 29JUN2010, A. A. V. O. Couto; one soldier, two imagos, pseudergates; SA503, 5014. Pernambuco, Igarassu ; 129 m, 10MAR2016, A. A. V. O. Couto; two soldiers, pseudergates; SA505, 8512.Brazil: Bahia, Itagiba, Fa. Conjunto S. Luis and in dead terminal branches still attached to the trunks, both in areas of Caatinga and Atlantic Forest. In the Caatinga, colonies of T.bandeirai were relatively easy to extract from dead terminal branches of Commiphoraleptophloeos (Mart.) J.B. Gillett (Burseraceae). This tree is also a \u201chot spot\u201d for collecting other kalotermitids, such as Cryptotermes, Neotermes, and Rugitermes.The colonies of T.bandeirai were collected five times; once in December, thrice in January, and once in February. This period represents a transition between the dry and rainy season in the area. For the Atlantic Forest, alates were recorded in wood in March, June, and December.Using light traps over a year (December 2017 to November 2018) in a Caatinga area located in the municipality of S\u00e3o Jos\u00e9 dos Cordeiros, Para\u00edba-Brazil, the alates of Tauritermesbandeirai infestations in buildings, either in urban or agricultural environments. Other Tauritermes species infest sound, dry wood and are even structural pests , Ruptitermesreconditus , Nasutitermesmacrocephalus , Microcerotemesindistinctus Mathews, 1977, among others.The Caatinga and the Atlantic Forest are neighboring domains Fig. , but dra"} +{"text": "Nature Communications 10.1038/s41467-020-17552-3, published online 29 July 2020.Correction to: The original version of this Article contained errors in the author affiliations.Giulia Pavani, Marine Laurent, Anna Fabiano, Erika Cantelli, Aboud Sakkal, Guillaume Corre and Mario Amendola were incorrectly associated with \u2018INTEGRARE, Genethon, UMR_S951 Inserm, Univ Evry, Univ Paris-Saclay, 91002 Evry, France\u2019 instead of the correct \u2018Genethon, 91000, Evry, France\u2019 and \u2018Universit\u00e9 Paris-Saclay, Univ Evry, Inserm, Genethon, Integrare Research Unit UMR_S951, 91000, Evry, France\u2019.Magali Toueille was incorrectly associated with \u2018INTEGRARE, Genethon, UMR_S951 Inserm, Univ Evry, Univ Paris-Saclay, 91002 Evry, France\u2019 instead of the correct \u2018Genethon, 91000, Evry, France\u2019.Annarita Miccio was incorrectly associated with \u2018Imagine Institute, UMR_163 INSERM, Paris, France\u2019 and \u2018Paris Descartes Univ Sorbonne Paris Cit\u00e9, Paris, France\u2019 instead of the correct \u2018Universit\u00e9 de Paris, Imagine Institute, Laboratory of chromatin and gene regulation during development, INSERM UMR 1163, F-75015, Paris, France.\u2019This has now been corrected in both the PDF and HTML versions of the Article."} +{"text": "Scientific Reports 10.1038/s41598-019-57042-1, published online 13 January 2020Correction to: In the original version of this Article, Figure\u00a01 contained an error where Northeastern Australia was omitted.In addition, there was a typographical error in Affiliation 5, which was incorrectly given as \u2018MARBEC, Univ Montpellier, IRD, Ifremer, CNRS, Montpellier, France\u2019. The correct affiliation is listed below:MARBEC, Univ Montpellier, CNRS, Ifremer, IRD, Montpellier, FranceThese errors have now been corrected in the HTML and PDF versions of the Article."} +{"text": "Scientific Reports 10.1038/s41598-020-74577-w, published online 15 October 2020Correction to: The original version of this Article contained an error in the order of author names, which was incorrectly given as Sung-chan Gwark, Jisun Kim, Cham Han Lee, Young Hun Kim, Myoung Shin Kim, Sung Woo Hong, Mi Young Choi, Byung Hee Jeon, Nak\u2011Jung Kwon, Kyoung\u2011Yeon Kim, Yongnam Kim, Suhwan Chang, Jong\u2011Han Yu, Ji Yeon Park, Jin-Hee Ahn, Kyung Hae Jung, Sung\u2011Bae Kim, Hee Jin Lee, Gyung\u2011Yub Gong, Sae Byul Lee, Il Yong Chung, Beom Seok Ko, Hee Jeong Kim, Jong Won Lee, Byung Ho Son & Sei Hyun Ahn.Furthermore, the original version of this Article contained errors in the spelling of the authors Sungchan Gwark, YongNam Kim and Jonghan Yu, which were incorrectly given as Sung-chan Gwark, Yongnam Kim and Jong\u2011Han Yu respectively.These errors have now been corrected in the HTML and PDF versions of the Article, and in the accompanying Supplementary Information files."} +{"text": "Editor-in-ChiefTibor F\u00fcl\u00f6p, MD, PhD; Medical University of South Carolina, Charleston, South Carolina, USADeputy EditorMih\u00e1ly Tapolyai, MD, PhD; FMC Hungary, Hatvan, HungaryAssociate EditorsBasic SciencesIstv\u00e1n Arany, PhD, CSc; University of Mississippi Medical Center (ret.), Jackson, Mississippi, USAClinical SciencesSohail Abdul Salim, MD; University of Mississippi Medical Center, Jackson, Mississippi, USALajos Zsom, MD; FMC Hungary, Cegl\u00e9d, HungaryBiostatistics and Clinical EpidemiologyWisit Cheungpasitporn, MD; University of Mississippi Medical Center, Jackson, Mississippi, USAEditorial Board Members:Anand Achanti, MD; Medical University of South Carolina, Charleston, South Carolina, USAAysen Akalin, MD; Eskisehir Osmangazi University, Eskisehir, TurkeyAndrea Angioi, MD; Azienda Ospedaliera G. Brotzu, Cagliari, ItalySebastjan Bevc, MD; University of Maribor, Maribor, SloveniaAna de Lurdes Agostinho Cabrita, MD; Faro, PortugalJorge Castaneda, MD; University of Mississippi Medical Center, Jackson, Mississippi, USAOrsolya Cseprekal, MD, PhD; Semmelweis University, Budapest, HungaryErsin Fad\u0131ll\u0131o\u011flu, MD; Ankara, TurkeyAbduzhappar Gaipov, MD, PhD; Nazarbayev University School of Medicine, Nur-Sultan City, KazakhstanMehul P. Dixit, MD; University of Mississippi Medical Center, Jackson, Mississippi, USANeville R. Dossabhoy, MD; Louisiana State University, Shreveport, LA, USAChristian A. Koch, MD, PhD; Fox-Chase Cancer Institute, Temple University, Philadelphia, PA, USAS. Mehrdad Hamrahian, MD; Thomas Jefferson University, Philadelphia, Pennsylvania, USACsaba Kopitko, MD, PhD; Uzsoki Utcai K\u00f3rh\u00e1z, Budapest, HungaryNicolas Hanset, MD; University Hospital Saint-Luc, Brussels, BelgiumJolanta Malyszko, MD, PhD, Medical University of Warsaw, Warsaw, PolandMiklos Z. Molnar, MD, PhD; University of Tennessee Health Science Center, Memphis, TN, USALovelesh Nigam, MD; Dr. H.L. Trivedi Institute of Transplantation Sciences, Asarwa, Ahmedabad, IndiaKen Sakai, MD, PhD; Toho University Faculty Medicine, Tokyo, JapanKarim M. Soliman, MD, MSc; Cairo University, Cairo, EgyptBlaithin A. McMahon, MD, PhD; Medical University of South Carolina, Charleston, South Carolina, USADaniela Ponce, MD, University of Sao Paulo State, UNESP \u2013 Botucatu, BrazilVinaya Rao, MD; Medical University of South Carolina, Charleston, South Carolina, USAL\u00e1szl\u00f3 Rosiv\u00e1ll, MD, PhD, DSc Med, Medhabil.; Semmelweis University, Budapest, HungaryMichael E. Ullian, MD; Medical University of South Carolina, Charleston, South Carolina, USAWisit Kaewput, MD; Phramongkutklao Hospital, Bangkok, ThailandStatistical Consultant Advisor:Zsolt Lengv\u00e1rszky, PhD; Louisiana State University Shreveport; Shreveport, LA, USAPrevious Editor:William F. Finn, MD - University of North Carolina, USA"} +{"text": "Hernandez Moura Silva should be included in the author byline. Hernandez Moura Silva should be listed as the sixth author, and his affiliation, which is not indicated, is 7: Kimmel Center for Biology and Medicine at the Skirball Institute, New York University Grossman School of Medicine, New York, 10016, United States of America. The contributions of this author are as follows: Conceptualization, data curation, formal analysis, investigation, methodology, project administration, software, supervision, validation, visualization, writing\u2014review & editing.https://doi.org/10.1371/journal.pone.0237773The correct citation is: Ledo JH, Zhang R, Mesin L, Mour\u00e3o-S\u00e1 D, Azevedo EP, Silva HM, et al. (2020) Lack of a site-specific phosphorylation of Presenilin 1 disrupts microglial gene networks and progenitors during development. PLoS ONE 15(8): e0237773."} +{"text": "Siddell, Peter J. Walker, Elliot J. Lefkowitz, Arcady R. Mushegian, Bas E. Dutilh, Bal\u00e1zs Harrach, Robert L. Harrison, Sandra Junglen, Nick J. Knowles, Andrew M. Kropinski, Mart Krupovic, Jens H. Kuhn, Max L. Nibert, Luisa Rubino, Sead Sabanadzovic, Peter Simmonds, Arvind Varsani, Francisco Murilo Zerbini, Andrew J. Davison, was originally published Online First without Open Access. After publication in volume 165, issue 2, page 519-525 the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to \u00a9 The Author(s) 2020 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License ("} +{"text": "The names of Thomas Eiwegger, Julia Upton, Gordon Sussman and Thomas Poder were inadvertently omitted from the authorship of the original article . Thomas The full and correct authorship has been updated in the original article and included in the author list of this Correction article.The \u2018Competing interests\u2019 section is also corrected here to read: The authors declare no conflict of interest related to the study. KS reports personal fees from Novartis outside the submitted work. TE reports grants from DBV technologies, Innovation fund Denmark, CIHR, and Regeneron and personal fees from ALK ourside the submitted work. He serves as associate editor for Allergy. JU reports personal fees from Food Allergy Canada, ALK-Abell\u00f3, Kaleo, and grants from Toronto SickKids Foundation, DBV technologies, Regeneron, and ALK-Abell\u00f3 outside the submitted work. GS reports personal fees from Novartis, Aralez, CSL Behring, Sanofi, Pediapharm, GSK, Genentech, DBV technologies, Aimmune, Astrazeneca, Stallergenes, Merck, Pfizer, Dyax, Biocryst, Greencross, Kendrion, Shire, Leopharma, Regeneron, mdBriefCase and grants from Novartis, GSK, Genentech, DBV technologies, Aimmune, CSL Behring, Astrazeneca, Stallergenes, Merck, Pfizer, Dyax, Biocryst, Greencross, Kendrion, Leo Pharma, Regeneron, Sanofi, Blueprint, ALK, Amgen, Cliantha outside the submitted work. ADR reports grants from Merk and ALK outside the submitted work. PB reports personal fees from Novartis, Pfizer, Sanofi, ALK and Aralez, as well as grants from DBV technologies, Regeneron and Sanofi outside the submitted work."} +{"text": "RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the This process requires multiple attempts of different keyword combinations and manual examination of numerous citations. A long list of both relevant and irrelevant articles is often encountered requiring manual curation after further reading, yet not all of the important relevant articles are necessarily included after this long and tedious process. The task of finding truly relevant articles becomes increasingly time-consuming and challenging as the number of scientific articles published every year expands at a rapid pace. For example, the PubMed descriptors . Most imhttp://www.ncbi.nlm.nih.gov/pubmed), ResearchGate (http://www.researchgate.net) and CiteULike (http://www.citeulike.org). Numerous newly developed methods are not yet translated into practice because it is unclear whether they have improved over existing methods consortium of 1500+ scientists from 84 countries around the world. The consortium annotated over 180,000 document\u2013document pairs indexed by PubMed, nearly 400 times larger than the single other human annotated data collection we could find with just 460 annotations by 90 authors for recommending articles (\u2018candidate-articles\u2019) potentially relevant to an input article (\u2018seed-article\u2019) given by, or assigned to, a user. The APSE allowed users to assess and annotate recommended candidate articles regarding their degree of relevance to a respective seed article and facilitated submission of these annotations. Then, we established the RELISH consortium of scientific authors (\u2018participants\u2019) and invited them to the APSE to evaluate 60 candidate articles for one or more seed articles that they are interested in or, preferably, they have authored. Finally, annotations submitted by participants were compiled and organized into the RELISH database. A participant\u2019s \u2018contribution\u2019 was defined as the submission of annotations for all 60 candidate articles with respect to a seed article.The overall procedure for establishing the RELISH database was as follows. First, we established the article-based PubMed search engine , followed by incremental synchronization with daily update releases. Only articles with available title and abstract metadata were included in the corpus, no other selection criteria were imposed. As of 3 July 2018, this collection contained 18,345,070 articles, from which participants selected seed articles.The seed article corpus used by the APSE server was extracted from the biomedical literature database hosted by PubMed. The corpus database was constructed using the 2017 baseline downloaded from PubMed\u2019s public FTP server by the following pipeline. We first applied Lucene\u2019s \u2018UAX29URLEmailTokenizer\u2019, which follows Unicode Text Segmentation rules to dividThe APSE recommendation system is built on three baseline methods: PMRA , BM25 3, 40 and For the individual method evaluations presented in this study, the original method-specific list of results were used (in this case the same candidate article may be shared by multiple methods). Each method\u2019s list of candidate articles was sorted by descending score. To generate the list of recommendations presented to the user for annotation, we took the individual method-specific result lists and combined them into a unified list. We set a maximum of 60 articles per seed article so as to include at least the top 20 highest-scoring non-redundant candidate articles per method.The unified list assembly procedure is as follows: in a round-robin fashion between all methods, consider the current top-scoring article from a method. If the article is not already in the unified list, add it. Otherwise, disregard this article and continue with the next best-scoring article until an addition to the unified list has been made. Essentially, this procedure is performing a three-way merge while ensuring an equal selection of non-redundant recommended articles from each method. This unified list of recommendations was not presented in the order of predicted similarity. Instead, before presentation to users, it was shuffled randomly to reduce the possibility of a systematic bias in annotation.To achieve the goal of a large dataset facilitating future deep machine learning-based method development, we established the RELISH consortium of biomedical researchers who have annotated studies potentially related to one or more seed articles that they had authored or were interested in. To maximize the quality and efficiency of annotation, we encouraged participants to use articles that they had authored as the seed articles. All participants contributed voluntarily. Only submissions with annotations completed for all 60 recommended candidate articles per seed article were accepted.Our recruitment strategy involved two major phases: the first was internal referrals, personal invitations, social media posts and a correspondence letter ; the secA total of 129,190 unique authors were contacted regarding 72,764 unique PubMed articles. Of these articles, 54,071 (74.3%) had contact information for a single author only (assumed to be the corresponding author), 7452 (10.2%) had contact information for two authors (assumed to be first and corresponding authors), while the remainder had contact information for more than two authors. In any case, all available contacts per article were invited, as to encourage multiple annotators of the same article for consistency analysis.Finally, of the 1570 total unique participants, we had 342 (21.8%) participants join by the initial recruitment phase. During the secondary recruitment stage, 1228 (78.2%) authors accepted our invitation yielding an overall response rate of 0.95%, thus the majority of contributions resulted from this phase.Relevant: an article topically relevant to the seed article; within the same specific sub-field of research, i.e. an article that would be interesting to read further or could have been cited within the original work.Somewhat-relevant: an article missing some key topical details of the seed article; within the broader area of research but does not specifically fit into the sub-field, i.e. unlikely to be considered for a citation within the original work.Irrelevant: an article unrelated to the seed article and obviously does not fit inside the specific sub-field of research.An overview of the annotation procedure is shown in Although definitions of \u2018relevance\u2019 are subjective, we aimed to make the choice as simple as possible by using this three-point system of document pair \u2018closeness\u2019, as opposed to a higher number of relevance degrees, like the 5-point or 10-point scales . AdditioBefore submitting annotations, contributors were asked to provide their level of experience from the following options: PhD student, years of experience after PhD studies and other .The expert-annotated document pairs provided the opportunity to evaluate the performance of the three baseline methods for the first time. To simplify the evaluation, we collapsed our three-state label classes to fit a two-state classification in which, unless stated otherwise, \u2018relevant\u2019 seed candidate article pairs were assigned to the \u2018positive\u2019 class, while \u2018somewhat-relevant\u2019 or \u2018irrelevant\u2019 article pairs were assigned to the \u2018negative\u2019 class. Using this stratification, we assessed method\u2019s performances using both binary classification and information-retrieval metrics.For binary classification metrics, we used Matthews correlation coefficient (MCC) and area under the [receiver operating characteristic (ROC)] curve (AUC). Metrics used for information-retrieval are precision of top-N ranked results (P@N) and mean reciprocal rank (MRR). MCC and AUC emphasize good discrimination between \u2018positive\u2019 and \u2018negative\u2019 classes, whereas P@N and MRR metrics emphasize highly ranked \u2018positive\u2019 class results.MCC is the eAUC is deterP@N is the pMRR measureshttps://github.com/elastic/elasticsearch; using Apache Lucene (https://github.com/apache/lucene-solr)]. The web interface was designed using React (https://github.com/facebook/react), web services were built using Apache (https://github.com/apache/httpd) and Python (https://github.com/channelcat/sanic) and data were organized using MongoDB (https://github.com/mongodb/mongo).The database search infrastructure was powered by Elasticsearch [Here we introduce RELISH-DB, the database that resulted from the annotation work of the RELISH consortium. All annotations submitted by participants before 27 July 2018 were consolidated into the initial revision of RELISH-DB.The remainder of this section presents statistics of database content and consortium participation, and the results for annotation consistency analyses and method performance evaluations.The distribution of the three possible relevance labels across all contributions per seed article is shown in Our definition of relevance, partial relevance and irrelevance is subject to different interpretations by different individuals. The perceived efficacy of document recommendation systems depends on the expected agreement between the subjective opinions of different individuals. To examine if such agreement exists, we compared the performance of the three baseline methods on annotations made by scientists of different experience levels, annotations of the same articles by different individuals, annotations across different research fields and durations of time spent annotating.To carry out these comparisons, seed articles for the benchmark datasets were selected from RELISH-DB according to the following conditions. First, we removed 44 seed articles that PMRA provided fewer than 20 article recommendations for; this was to ensure a fair comparison with the other baseline methods that will always have 20 recommendations per seed article. Next, 186 seed articles without any positive or negative samples were removed as assessment of discrimination is impossible when all candidate articles belong to either the positive or negative class. Finally, we set aside 154 duplicate annotations of the same seed article by different participants (\u2018D154\u2019), and 400 randomly selected seed articles as an independent test set (\u2018T400\u2019), to be analyzed separately.This led to a total of 2233 seed articles (\u2018ALL2233\u2019) available for evaluation. From this set we derived an \u2018NR\u2019 (non-redundant) set, comprised of a single seed article from each unique participant to avoid potential bias against specific annotators. In this dataset, for participants with multiple seed article contributions, a seed article was selected at random. This \u2018NR\u2019 set had 1220 seed articles (\u2018NR1220\u2019) in total, less than the total number of unique participants due to aforementioned exclusions.Here, we have collectively defined candidate articles marked as \u2018somewhat-relevant\u2019 or \u2018irrelevant\u2019 as negative samples, with those marked as \u2018relevant\u2019 defined as positive samples. This was to challenge the three baseline methods and allow the measurement of their performance according to binary classification. For all statistical testing we used the Wilcoxon signed-rank test implemenTable P-values from Wilcoxon signed-rank tests are given in P-values less than 0.05 for MCC, AUC, MRR and P@5. For the \u2018ALL2233\u2019 set, BM25 was also significantly higher than PMRA in terms of MCC and AUC; however, in the \u2018NR1220\u2019 only MCC is significant. In all cases there was no significant difference in either MCC or AUC between BM25 and TF-IDF. However TF-IDF did significantly outperform BM25 in terms of P@5. These results suggest that out of the three baseline methods, TF-IDF was most effective at ranking relevant candidate articles highly.Statistical As previously mentioned, according to author name matches, the majority (91%) of our annotated seed articles were provided by one of the respective authors. Here we investigate whether method performance is affected considering annotations given by non-authors. These non-author annotators may have more general knowledge and not be biased by a close-up view of their given field like an author could be, potentially providing a more objective assessment.A total of 181 seed articles were identified to have been annotated by a non-author (anonymous annotations were not included), submitted by 73 unique annotators. These articles were split into respective \u2018ALL\u2019 and \u2018NR\u2019 subsets accordingly. Table P-values of the distribution comparison using Wilcoxon signed-rank tests presented in Table Figure Finally, although the overall average was nearly identical among annotators with different experience levels, fluctuations around the average (standard deviations around 0.2) were quite substantial. This large fluctuation, however, may not have been caused by individuals\u2019 subjective opinions. This is explored further with the assessment of single participants who annotated many seed articles in the next section.As some dedicated contributors had annotated a large number of seed articles, we were able to assess method performance within these groups. Table Additionally, as method performance is again quite close overall, some noise appeared to exist regarding the preferred method within these individual annotator groups. It could be argued that \u2018A1\u2019 prefers BM25, \u2018A2\u2019 prefers TF-IDF and \u2018A3\u2019 prefers PMRA. Furthermore, precision-based metrics for \u2018A1\u2019 demonstrated fluctuation of \u2018difficulty\u2019, compared to the \u2018A2\u2019 and \u2018A3\u2019 groups, with regard to the number of \u2018positive\u2019 annotations per seed article. For example, a P@20 of around 0.1 means that on average each method was trying to rank 2 relevant articles higher than 18 irrelevant articles that must have also had large content-based similarity of some form allowing their initial detection by the baseline methods. In contrast, \u2018A2\u2019 and \u2018A3\u2019 were relatively easier, especially considering the MRR value close to 1, meaning that on average the top result was actually relevant.Here, we assessed performance consistency across different research topics, defined by MeSH descriptors associated with each seed article (if any). Articles that shared a MeSH descriptor were clustered accordingly. The eight largest clusters were evaluated, Figure A more direct assessment of consistency is to examine the same document pairs annotated by different contributors, using the \u2018D154\u2019 set. These contributions covered a total of 74 unique articles. However, 32 articles were removed due to duplicate submitted annotations from a single participant (i.e. the same participant contributed annotations more than once for the same seed article). Subsequently excluded were two articles that were annotated by three participants. In total, 40 unique articles remained in this consistency set .We measured the agreement by first collapsing ternary class annotations into their binary class equivalents. Next the Jaccard index was calcThe duration of time a participant spent annotating seed articles was an additional aspect we tested for consistency. This duration was estimated from the time of loading the first page of results to the time of submission. As this time was estimated and is likely to contain a small degree of error due to noise in the logs, we restricted the duration of time spent to between 2 and 120 min.Figure Distinguishing positives from negatives requires a threshold for the similarity score calculated by PMRA, BM25 or TF-IDF. An ideal method should have the same threshold for different seed articles regardless of research field and abstract/title length. This would be beneficial to real-world recommender systems by enabling a dynamic number of articles deemed as relevant to be presented to the user rather than the traditional approach of delivering a fixed number of recommendations.We analyzed the distribution of method score thresholds in Figure Figure https://figshare.com/projects/RELISH-DB/60095, under the CC0 license. All data records were stripped of personally identifiable information and then converted to JSON format on our data server. These include the complete versions of the \u2018ALL2233\u2019 and \u2018NR1220\u2019 sets, as well as copies of these sets broken down by annotator experience level. In addition, the three single-annotator sets are also available. Furthermore, we also provided an option to allow users to generate a dataset according to various pre-defined parameters .As shown in Figure Method testing: to facilitate comparison and avoid overtraining, we set aside a blind-test set for critical assessment of method performance. This selection of 400 randomly selected NR seed articles have their annotation data withheld from the rest of the database. The dataset has two variants . Baseline method performances for this set are shown in Table To make RELISH collections useful for future method developers, we have established a data server at Many users, both expert and non-expert, require literature searching for various purposes. Generally, the information need revolves around knowledge expansion of a topic; whether the goal is to find pertinent supporting material to solidify insight or to broaden their vision by locating different aspects, of a particular claim, idea or field of research.Users most commonly rely on manual keyword searching methods to serve their needs , 37, 70.Here, the use case of our work falls into the \u2018recommendation\u2019 sub-field of literature search. Specifically, we focus on pairwise similarity detection between documents. Considering the rate of literature growth and the associated \u2018information overload\u2019 for users, remedial approaches like recommender systems have been proposed to tackle the difficulty and time burden of keeping track of the most promising and relevant studies , 30. WhiThis work is not the first to propose the use of a seed article (manuscript) as a query instead of keywords , 55, 71.Finally, we must stress that the basis of our use case here is a complementary alternative to keyword search, it is not intended as a replacement. An accurate keyword-less recommendation system is sure to benefit both expert and non-expert users, especially in this era of information overload. In addition, this is more than a database exclusively for seed article-based search. It can be used to train keywords or sentence-based search by examining if keywords or the title from one article would automatically lead to the other articles. That is, a method can be trained for title/sentence-based and title/abstract based search on this benchmark.Our work represents a community-wide effort to establish a database of document relevance that is suitable for machine learning. It should be noted that our APSE system facilitating the annotation process was not intended as a stand-alone search engine. Rather, it was developed and employed exclusively for data collection. Nevertheless, using three different methods appeared to provide a more complete search compared to systems powered by a single technique such as TF-IDF in JANE or PMRA More than 1500 scientists around the world participated in the RELISH consortium and annotated the relevance for over 180,000 document pairs that represent diverse research fields, covering 76% of all PubMed MeSH descriptors without clear bias Figure . These aA number of potential systematic biases were considered during the construction of this database. Potentially affected aspects of our methodology primarily include how the documents presented to annotators were selected and how annotators themselves were selected. We discuss here the biases we were able to identify and explain the rationale behind how they were dealt with.Inherent selection biases could be argued regarding the baseline methods used to generate the sets of documents for annotation. Firstly, since only the top 20 non-redundant documents from each method were presented to annotators, we have necessarily excluded potentially related articles with lower similarity scores from this pool. We could have taken more results from a single method, but then bias towards that single method would have been introduced. Additionally, we chose to take this number of results from each method to reduce the burden on annotator\u2019s participation time, as we appreciate that volunteered time to contribute is valuable. Secondly, as the baseline methods rely exclusively on exact term matches to generate respective similarity scores, it is possible that semantically related documents are missing from this pool. Although there was no scalable solution present to circumvent this, we feel it should be mentioned here.Potentially subjective bias is a major concern affecting document relevance manually annotated by such a diverse group of scientists. This could be in terms of a biased consideration of recommended documents according to the annotator\u2019s close-up view of their given field as opposed to the more objective consideration annotators with general knowledge could have. We opted to use authors of their own papers as relevance judges to increase participation rate, the effort required from participants was again considered here. This is because our goal for this benchmark was to capture sub-field similarity such that articles marked as relevant could have been suitable for citation by the originating seed article. This task requires highly specialized experts in respective sub-fields to make that determination. In other words, the more sub-field experience of an annotator, the more accurate annotations will be made. Although non-PhD researchers are underrepresented in their participation of database construction, it will not affect the overall accuracy of annotations as we have demonstrated that there is no bias according to the experience level of annotators and across different fields of researchers. In fact, using expert annotations will ensure the production of relevant articles for all non-PhD researchers, clinicians and the general public in their searches.If a subjective bias exists, one would expect that the performance of the three baseline methods would have certain systematic trends. We showed that method performances were nearly the same across different annotator experience levels Figure and diffHigh-quality data collected by the RELISH consortium offered an unprecedented opportunity to compare the three baseline methods . Somewhat surprisingly, all three methods performed similarly, with TF-IDF presenting a slight edge. Our finding is somewhat different from previous studies , 51, 68 https://relishdb.ict.griffith.edu.au.Encouraging method development was the principal motivation behind the assembly of this database. A recent survey of research paper recommendation systems revealed the urgent need for a common evaluation framework , as currWe expect that dissemination of this manuscript will attract more scientists to contribute more annotations. A major struggle for us was participant recruitment, the first phase of our recruitment strategy ultimately failed to attract enough contributions to establish a meaningful dataset. Because of this failure we reluctantly decided to proceed with the second phase of sending direct emails. Although the response rate was low (around 1%), it was good enough to achieve the sizeable database we have now. Our server will continue to collect annotations. We hope to publish the next version of the database with at least double the number of present annotations.None declared.P.B. participated in the design, carried out the study, implemented the websites and search systems and wrote the manuscript. RELISH consortium annotated the articles. Y.Z. conceived the study, participated in the initial design, assisted in analyzing data and wrote the manuscript. All authors read, contributed to the discussion and approved the manuscript.3,Aik-Choon Tan4,Mohamed A. El-Esawi5,Thomas Liehr6,Oliver Blanck7,Douglas P. Gladue8,Gabriel M. F. Almeida9,Tomislav Cernava10,Carlos O. Sorzano11,Andy W. K. Yeung12,Michael S. Engel13,Arun Richard Chandrasekaran14,Thilo Muth15,Martin S. Staege16,Swapna V. Daulatabad17,Darius Widera18,Junpeng Zhang19,Adrian Meule20,Ken Honjo21,Olivier Pourret22,Cong-Cong Yin23,Zhongheng Zhang24,Marco Cascella25,Willy A. Flegel26,Carl S. Goodyear10,Mark J. van Raaij27,Zuzanna Bukowy-Bieryllo28,Luca G. Campana29,Nicholas A. Kurniawan30,David Lalaouna31,Felix J. H\u00fcttner32,Brooke A. Ammerman33,Felix Ehret34,Paul A. Cobine35,Ene-Choo Tan36,Hyemin Han37,Wenfeng Xia38,Christopher McCrum39,Ruud P. M. Dings40,Francesco Marinello41,Henrik Nilsson42,Brett Nixon43,Konstantinos Voskarides44,Long Yang45,Vincent D. Costa46,Johan Bengtsson-Palme47,William Bradshaw48,Dominik G. Grimm49,Nitin Kumar50,Elvis Martis51,Daniel Prieto52,Sandeep C. Sabnis53,Said E. D. R. Amer1,Alan W. C. Liew54,Paul Perco55,Farid Rahimi56,Giuseppe Riva57,Chongxing Zhang58,Hari P. Devkota59,Koichi Ogami60,Zarrin Basharat61,Walter Fierz62,Robert Siebers63,Kok-Hian Tan64,Karen A. Boehme65,Peter Brenneisen66,James A. L. Brown67,Brian P. Dalrymple68,David J. Harvey69,Grace Ng70,Sebastiaan Werten71,Mark Bleackley72,Zhanwu Dai73,Raman Dhariwal74,Yael Gelfer75,Marcus D. Hartmann76,Pawel Miotla77,Radu Tamaian78,Pragashnie Govender79,Oliver J. Gurney-Champion80,Joonas H. Kauppila81,Xiaolei Zhang82,Natalia Echeverr\u00eda83,Santhilal Subhash84,Hannes Sallmon85,Marco Tofani86,Taeok Bae87,Oliver Bosch88,P\u00e1raic O. Cu\u00edv89,Antoine Danchin90,Barthelemy Diouf91,Tuomas Eerola92,Evangelos Evangelou93,Fabian V. Filipp94,Hannes Klump95,Lukasz Kurgan96,Simon S. Smith97,Olivier Terrier98,Neil Tuttle99,David B. Ascher100,Sarath C. Janga101,Leon N. Schulte102,Daniel Becker103,Christopher Browngardt68,Stephen J. Bush104,Guillaume Gaullier105,Kazuki Ide106,Clement Meseko107,Gijsbert D. A. Werner108,Jan Zaucha109,Abd A. Al-Farha110,Noah F. Greenwald111,Segun I. Popoola112,Md Shaifur Rahman113,Jialin Xu113,Sunny Y. Yang114,Noboru Hiroi115,Ozgul M. Alper116,Chris I. Baker117,Michael Bitzer118,George Chacko119,Birgit Debrabant120,Ray Dixon72,Evelyne Forano121,Matthew Gilliham122,Sarah Kelly123,Karl-Heinz Klempnauer124,Brett A. Lidbury125,Michael Z. Lin126,Iseult Lynch127,Wujun Ma128,Edward W. Maibach129,Diane E. Mather130,Kutty S. Nandakumar131,Robert S. Ohgami132,Piero Parchi133,Patrizio Tressoldi134,Yu Xue135,Charles Armitage136,Pierre Barraud137,Stella Chatzitheochari138,Luis P. Coelho139,Jiajie Diao140,Andrew C. Doxey141,Ang\u00e9lique Gobet142,Pingzhao Hu143,Stefan Kaiser144,Kate M. Mitchell145,Mohamed F. Salama146,Ivan G. Shabalin147,Haijun Song148,Dejan Stevanovic149,Ali Yadollahpour150,Erliang Zeng151,Katharina Zinke152,C. G. Alimba153,Tariku J. Beyene154,Zehong Cao155,Sherwin S. Chan156,Michael Gatchell157,Andreas Kleppe158,Marcin Piotrowski159,Gonzalo Torga160,Adugna A. Woldesemayat161,Mehmet I. Cosacak162,Scott Haston163,Stephanie A. Ross164,Richard Williams165,Alvin Wong166,Matthew K. Abramowitz167,Andem Effiong168,Senhong Lee169,Muhammad Bilal Abid170,Cyrus Agarabi370,Cedric Alaux171,Dirk R. Albrecht172,Gerald J. Atkins173,Charles R. Beck174,A. M. J. J. Bonvin175,Emer Bourke176,Thomas Brand177,Ralf J. Braun178,James A. Bull179,Pedro Cardoso180,Dee Carter181,Robin M. Delahay182,Bernard Ducommun183,Pascal H. G. Duijf184,Trevor Epp185,Eeva-Liisa Eskelinen186,Mazyar Fallah187,Debora B. Farber188,Jose Fernandez-Triana189,Frank Feyerabend190,Tullio Florio191,Michael Friebe192,Saori Furuta193,Mads Gabrielsen194,Jens Gruber195,Malgorzata Grybos196,Qian Han197,Michael Heinrich198,Heikki Helanter\u00e4199,Michael Huber200,Albert Jeltsch201,Fan Jiang202,Claire Josse203,Giuseppe Jurman204,Haruyuki Kamiya205,Kim de Keersmaecker206,Erik Kristiansson207,Frank-Erik de Leeuw208,Jiuyong Li209,Shide Liang210,Jose A. Lopez-Escamez211,Francisco J. Lopez-Ruiz212,Kevin J. Marchbank213,Rolf Marschalek10,Carmen S. Mart\u00edn214,Adriana E. Miele215,Xavier Montagutelli216,Esteban Morcillo217,Rosario Nicoletti218,Monika Niehof219,Ronan O\u2019Toole220,Toshihiko Ohtomo221,Henrik Oster222,Jose-Alberto Palma223,Russell Paterson224,Mark Peifer7,Maribel Portilla225,M. C. Portillo226,Antonia L. Pritchard227,Stefan Pusch228,Gajendra P. S. Raghava229,Nicola J. Roberts230,Kehinde Ross231,Birgitt Schuele232,Kjell Sergeant233,Jun Shen234,Alessandro Stella235,Olga Sukocheva236,Vladimir N. Uversky237,Sven Vanneste238,Martin H. Villet239,Miguel Viveiros240,Julia A. Vorholt241,Christof Weinstock242,Masayuki Yamato243,Ioannis Zabetakis244,Xin Zhao245,Andreas Ziegler246,Wan M. Aizat247,Lauren Atlas248,Kristina M. Bridges249,Sayan Chakraborty250,Mieke Deschodt251,Helena S. Domingues252,Shabnam S. Esfahlani253,Sebastian Falk254,J. L. Guisado255,Nolan C. Kane256,Gray Kueberuwa257,Colleen L. Lau258,Dai Liang259,Enwu Liu260,Andreas M. Luu261,Chuang Ma262,Lisong Ma263,Robert Moyer264,Adam D. Norris265,Suresh Panthee266,Jerod R. Parsons267,Yousong Peng251,In\u00eas Mendes Pinto269,Cristina R. Reschke270,Elina Sillanp\u00e4\u00e4212,Christopher J. Stewart271,Florian Uhle272,Hui Yang273,Kai Zhou274,Shu Zhu275,Mohamed Ashry276,Niels Bergsland277,Maximilian Berthold278,Chang-Er Chen279,Vito Colella280,Maarten Cuypers281,Evan A. Eskew282,Xiao Fan283,Maksymilian Gajda284,Rayner Gonz\u00e1lezlez-Prendes285,Amie Goodin286,Emily B. Graham287,Ewout J. N. Groen288,Alba Guti\u00e9rrez-Sacrist\u00e1n289,Mohamad Habes290,Enrico Heffler291,Daniel B. Higginbottom292,Thijs Janzen293,Jayakumar Jayaraman294,Lindsay A. Jibb295,Stefan Jongen296,Timothy Kinyanjui297,Rositsa G. Koleva-Kolarova298,Zhixiu Li299,Yu-Peng Liu300,Bjarte A. Lund301,Alexandre A. Lussier302,Liping Ma303,Pablo Mier304,Matthew D. Moore305,Katja Nagler306,Mark W. Orme307,James A. Pearson308,Anilkumar S. Prajapati309,Yu Saito310,Simon E. Tr\u00f6der311,Florence Uchendu312,Niklas Verloh313,Denitza D. Voutchkova314,Ahmed Abu-Zaid315,Joaira Bakkach316,Philipp Baumert317,Marcos Dono318,Jack Hanson319,Sandrine Herbelet320,Emma Hobbs321,Ameya Kulkarni322,Narendra Kumar323,Siqi Liu324,Nikolai D. Loft325,Tristan Reddan326,Thomas Senghore327,Howard Vindin328,Haotian Xu329,Ross Bannon330,Branson Chen331,Johnny T. K. Cheung332,Jeffrey Cooper333,Ashwini K. Esnakula334,Karine A. Feghali335,Emilia Ghelardi336,Agostino Gnasso337,Jeffrey Horbar89,Hei M. Lai338,Jian Li339,Lan Ma340,Ruiyan Ma341,Zihang Pan342,Marco A. Peres343,Raymond Pranata344,Esmond Seow345,Matthew Sydes346,Ines Testoni347,Anna L. Westermair348,Yongliang Yang349,Masoud Afnan350,Joan Albiol351,Lucia G. Albuquerque353,Eisuke Amiya354,Rogerio M. Amorim355,Qianli An356,Stig U. Andersen357,John D. Aplin358,Christos Argyropoulos359,Yan W. Asmann360,Abdulaziz M. Assaeed361,Atanas G. Atanasov362,David A. Atchison363,Simon V. Avery288,Paul Avillach364,Peter D. Baade365,Lars Backman366,Christophe Badie367,Alfonso Baldi368,Elizabeth Ball369,Olivier Bardot371,Adrian G. Barnett372,Mathias Basner298,Jyotsna Batra373,O. M. Bazanova374,Andrew Beale375,Travis Beddoe376,Melanie L. Bell377,Eugene Berezikov2,Sue Berners-Price378,Peter Bernhardt379,Edward Berry380,Theolis B. Bessa381,Craig Billington382,John Birch383,Randy D. Blakely384,Mark A. T. Blaskovich385,Robert Blum386,Marleen Boelaert387,Dimitrios Bogdanos388,Carles Bosch389,Thierry Bourgoin390,Daniel Bouvard391,Laura M. Boykin392,Graeme Bradley393,Daniel Braun394,Jeremy Brownlie395,Albert Br\u00fchl396,Austin Burt397,Lisa M. Butler398,Siddappa N. Byrareddy399,Hugh J. Byrne400,Stephanie Cabantous216,Sara Calatayud401,Eva Candal402,Kimberly Carlson403,S\u00f2nia Casillas404,Valter Castelvetro405,Patrick T. Caswell406,Giacomo Cavalli407,Vaclav Cerovsky408,Monica Chagoyen409,Chang-Shi Chen410,Dong F. Chen411,Hao Chen412,Hui Chen413,Jui-Tung Chen414,Yinglong Chen415,Changxiu Cheng416,Jianlin Cheng417,Mai Chinapaw418,Christos Chinopoulos419,William C. S. Cho420,Lillian Chong421,Debashish Chowdhury422,Andre Chwalibog423,A. Ciresi424,Shamshad Cockcroft425,Ana Conesa426,Penny A. Cook427,David N. Cooper428,Olivier Coqueret429,Enoka M. Corea431,Elisio Costa432,Carol Coupland433,Stephanie Y. Crawford434,Aparecido D. Cruz435,Huijuan Cui436,Qiang Cui437,David C. Culver438,Amedeo D\u2019Angiulli439,Tanya E. S. Dahms440,France Daigle441,Raymond Dalgleish157,H\u00e5vard E. Danielsen443,S\u00e9bastien Darras444,Sean M. Davidson445,David A. Day446,Volkan Degirmenci72,Luc Demaison447,Koenraad Devriendt448,Jiandong Ding449,Yunus Dogan450,X. C. Dong451,Claudio F. Donner452,Walter Dressick453,Christian A. Drevon454,Huiling Duan455,Christian Ducho456,Nicolas Dumaz457,Bilikere S. Dwarakanath458,Mark H. Ebell459,Steffen Eisenhardt460,Naser Elkum461,Nadja Engel462,Timothy B. Erickson47,Michael Fairhead463,Marty J. Faville464,Marlena S. Fejzo465,Fernanda Festa466,Antonio Feteira467,Patrick Flood-Page468,John Forsayeth469,Simon A. Fox470,Steven J. Franks135,Francesca D. Frentiu471,Mikko J. Frilander472,Xinmiao Fu473,Satoshi Fujita474,Ian Galea475,Luca Galluzzi476,Federica Gani477,Arvind P. Ganpule478,Antonio Garc\u00eda-Alix479,Kristene Gedye480,Maurizio Giordano481,Cecilia Giunta482,Paul A. Gleeson483,Cyrille Goarant484,Haipeng Gong485,Diop Gora486,Michael J. Gough487,Ravinder Goyal488,Kathryn E. Graham489,Ana Grande-P\u00e9rez490,Patricia M. Graves491,Harm Greidanus2,Darren Grice492,Christoph Grunau493,Yosephine Gumulya494,Yabin Guo495,Vsevolod V. Gurevich496,Oleg Gusev298,Elke Hacker497,Steffen R. Hage498,Guy Hagen499,Steven Hahn500,Dagmar M. Haller501,Sven Hammerschmidt502,Jianwei Han503,Renzhi Han504,Martin Handfield505,Hapuarachchige C. Hapuarachchi506,Timm Harder507,Jennifer E. Hardingham508,Michelle Heck509,Marcel Heers510,Khe F. Hew511,Yohei Higuchi512,Cynthia St. Hilaire513,Rachel Hilton514,Enisa Hodzic515,Andrew Hone516,Yuichi Hongoh398,Guoku Hu517,Heinz P. Huber518,Luis E. Hueso519,Judith Huirne520,Lisa Hurt521,Helena Idborg522,Kazuho Ikeo523,Evan Ingley524,Philip M. Jakeman525,Arne Jensen526,Hong Jia2,Husen Jia527,Shuqin Jia528,Jianping Jiang529,Xingyu Jiang530,Yi Jin531,Daehyun Jo532,Andrew M. Johnson533,Marie Johnston534,Karen R. Jonscher535,Philippe G. Jorens536,Jens O. L. Jorgensen537,Johan W. Joubert538,Sin-Ho Jung539,Antonio M. Junior540,Thomas Kahan541,Sunjeev K. Kamboj542,Yong-Kook Kang543,Yannis Karamanos544,Natasha A. Karp545,Ryan Kelly546,Ralph Kenna547,Jonathan Kennedy548,Birgit Kersten549,Roy A. Khalaf550,Javaria M. Khalid551,T. Khatlani552,Tarig Khider553,Gregor S. Kijanka554,Sarah R. B. King555,Tomasz Kluz556,Paul Knox557,Tatsuya Kobayashi558,Karl-Wilhelm Koch559,Maija R. J. Kohonen-Corish560,Xiangpeng Kong561,Deborah Konkle-Parker562,Kalevi M. Korpela563,Leondios G. Kostrikis564,Peter Kraiczy565,Harald Kratz566,G\u00fcnter Krause567,Paul H. Krebsbach568,S\u00f8ren R. Kristensen569,Prerna Kumari570,Akira Kunimatsu571,Hatice Kurdak572,Young D. Kwon573,Carl Lachat574,Malgorzata Lagisz575,Brenda Laky576,Jan Lammerding577,Matthias Lange578,Mar Larrosa579,Andrew L. Laslett581,Elizabeth E. LeClair582,Kyung-Woo Lee583,Ming-Yih Lee584,Moon-Soo Lee585,Genyuan Li586,Jiansheng Li587,Klaus Lieb588,Yau Y. Lim589,Merry L. Lindsey590,Paul-Dag Line591,Dengcai Liu592,Fengbin Liu274,Haiyan Liu593,Hongde Liu594,Vett K. Lloyd595,Te-Wen Lo596,Emanuela Locci597,Josef Loidl598,Johan Lorenzen599,Stefan Lorkowski600,Nigel H. Lovell601,Hua Lu602,Wei Lu603,Zhiyong Lu604,Gustavo S. Luengo605,Lars-Gunnar Lundh606,Philippe A. Lysy607,Angela Mabb608,Heather G. Mack609,David A. Mackey610,S. R. Mahdavi611,Pamela Maher612,Toby Maher613,Sankar N. Maity614,Brigitte Malgrange615,Charalampos Mamoulakis616,Arduino A. Mangoni617,Thomas Manke618,Antony S. R. Manstead619,Athanasios Mantalaris620,Jan Marsal621,Hanns-Ulrich Marschall622,Francis L. Martin623,Jose Martinez-Raga624,Encarnacion Martinez-Salas625,Daniel Mathieu626,Yoichi Matsui627,Elie Maza628,James E. McCutcheon629,Gareth J. McKay630,Brian McMillan631,Nigel McMillan632,Catherine Meads633,Loreta Medina634,B. Alex Merrick635,Dennis W. Metzger636,Frederic A. Meunier637,Martin Michaelis638,Olivier Micheau639,Hisaaki Mihara640,Eric M. Mintz641,Takuo Mizukami642,Yann Moalic643,D. P. Mohapatra644,Antonia Monteiro645,Matthieu Montes646,John V. Moran647,Sergey Y. Morozov427,Matthew Mort648,Noriyuki Murai649,Denis J. Murphy650,Susan K. Murphy651,Shauna A. Murray652,Shinji Naganawa653,Srinivas Nammi654,Grigorios Nasios655,Roman M. Natoli656,Frederique Nguyen657,Christine Nicol658,Filip van Nieuwerburgh659,Erlend B. Nilsen660,Clarissa J. Nobile661,Margaret O\u2019Mahony662,Sophie Ohlsson663,Oluremi Olatunbosun664,Per Olofsson665,Alberto Ortiz666,Kostya Ostrikov667,Siegmar Otto668,Tiago F. Outeiro472,Songying Ouyang669,Sabrina Paganoni670,Andrew Page671,Christoph Palm672,Yin Paradies470,Michael H. Parsons673,Nick Parsons674,Pigny Pascal675,Elisabeth Paul676,Michelle Peckham677,Nicoletta Pedemonte678,Michael A. Pellizzon679,M. Petrelli680,Alexander Pichugin681,Carlos J. C. Pinto682,John N. Plevris683,Piero Pollesello684,Martin Polz685,Giovanna Ponti686,Piero Porcelli297,Martin Prince687,Gwendolyn P. Quinn688,Terence J. Quinn689,Satu Ramula690,Juri Rappsilber691,Florian Rehfeldt692,Jan H. Reiling693,Claire Remacle694,Mohsen Rezaei695,Eric W. Riddick696,Uwe Ritter697,Neil W. Roach698,David D. Roberts699,Guillermo Robles700,Tiago Rodrigues701,Cesar Rodriguez702,Jo Roislien703,Monique J. Roobol704,J. Alexandra Rowe705,Andreas Ruepp706,Jan van Ruitenbeek707,Petra Rust708,Sonia Saad709,George H. Sack710,Manuela Santos711,Aurore Saudemont712,Gianni Sava713,Simone Schrading714,Alexander Schramm715,Martin Schreiber716,Sidney Schuler717,Joost Schymkowitz718,Alexander Sczyrba2,Kate L. Seib719,Han-Ping Shi720,Tomohiro Shimada721,Jeon-Soo Shin722,Colette Shortt723,Patricia Silveyra724,Debra Skinner725,Ian Small726,Paul A. M. Smeets727,Po-Wah So728,Francisco Solano729,Daniel E. Sonenshine730,Jiangning Song396,Tony Southall731,John R. Speakman636,Mandyam V. Srinivasan732,Laura P. Stabile733,Andrzej Stasiak734,Kathryn J. Steadman735,Nils Stein736,Andrew W. Stephens737,Douglas I. Stewart738,Keith Stine739,Curt Storlazzi740,Nataliya V. Stoynova741,Wojciech Strzalka742,Oscar M. Suarez743,Taranum Sultana744,Anirudha V. Sumant745,Mathew J. Summers746,Gang Sun747,Paul Tacon748,Kozo Tanaka749,Haixu Tang750,Yoshinori Tanino751,Paul Targett-Adams752,Mourad Tayebi753,Reema Tayyem754,Christoph C. Tebbe755,Evelyn E. Telfer756,Wolfram Tempel757,Julita A. Teodorczyk-Injeyan758,Gert Thijs759,Sally Thorne760,Amanda G. Thrift761,Celine Tiffon762,Philip Tinnefeld763,Daryono H. Tjahjono764,Fabrice Tolle765,Ervin Toth766,Andria L. del Tredici767,Apostolos Tsapas768,Konstantinos Tsirigotis769,Ayse Turak770,George Tzotzos771,Edet E. Udo772,Toshiaki Utsumi773,Subramanian Vaidyanathan774,Michel Vaillant775,Armand Valsesia776,Roosmarijn E. Vandenbroucke777,Feliciano H. Veiga778,Marc Vendrell779,Peter A. Vesk780,Paul Vickers781,Victor M. Victor782,Richard Villemur783,Marie-Claude Vohl784,Christian R. Voolstra785,Anne Vuillemin786,Steven Wakelin787,Levi Waldron788,Laurence J. Walsh789,Amanda Y. Wang790,Fuan Wang791,Yun Wang792,Yoichi Watanabe793,Andreas Weigert794,Jet-Chau Wen795,Carol Wham796,Ethan P. White797,Jan Wiener798,Gottfried Wilharm799,Simon Wilkinson800,Raffaella Willmann801,Coralie Wilson802,Brunhilde Wirth803,Timothy R. Wojan804,Mathieu Wolff805,Bryan M. Wong806,Tzu-Wei Wu807,Hanno Wuerbel808,Xiangshu Xiao416,Dong Xu809,J. W. Xu810,Jianping Xu811,Bin Xue812,Suayib Yalcin813,Hong Yan814,En-Cheng Yang815,Shiqi Yang816,Wei Yang749,Yuzhen Ye817,Zhi-Qiang Ye818,Jari Yli-Kauhaluoma819,Hiroshi Yoneyama820,Ying Yu821,Guo-Cheng Yuan822,Chiou-Hwa Yuh823,Manuela Zaccolo824,Chen Zeng310,Branko Zevnik825,Chi Zhang826,Li Zhang827,Li Zhang828,Yingkai Zhang829,Yusen Zhang830,Zhiyong Zhang831,Zhong-Yin Zhang832,Yuan Zhao833,Min Zhou834,Torsten Zuberbier835,Carmen M. Aanei836,Rafi Ahmad837,Manar Al-Lawama838,Alexandre Alanio839,Judith Allardyce362,David Alonso-Caneiro2,John M. Atack840,Dirk Baier841,Abhisheka Bansal842,Yannick Benezeth843,Colette Berbesque844,Frederik Berrevoet845,Peter H. W. Biedermann846,Erik Bijleveld847,Florian Bittner848,Fabian Blombach849,Wouter van den Bos850,Shellie A. Boudreau851,Adam D. Bramoweth852,Oliver Braubach853,Yufeng Cai2,Matthew Campbell854,Zanxia Cao855,Thibault Catry856,Xin Chen857,Shuiqin Cheng858,Hee-Jung Chung859,Miguel A. Ch\u00e1vez-Fumagalli298,Aaron Conway860,Bruno M. Costa861,Normand Cyr862,Lorraine T. Dean863,Martin S. Denzel864,S. V. Dlamini865,Kevin J. Dudley866,Maeva Dufies867,Thorsten Ecke868,Denitsa Eckweiler869,Elisenda Eixarch870,Hosny El-Adawy871,Julius V. Emmrich872,Alex J. Eustace19,Christine M. Falter-Wagner875,Johannes Fuss876,Jianzhao Gao877,Martin R. Gill878,Liz Gloyn879,Robert Goggs880,Usha Govinden881,Garrett Greene882,Victor Greiff883,D. S. Grundle884,Patrick Gr\u00fcneberg885,Nicksy Gumede886,Gbaguidi Haore887,Pille Harrison888,Xavier Hoenner889,Diego Hojsgaard890,Hikaru Hori891,Maria P. Ikonomopoulou892,Patrick Jeurissen893,Daniel M. Johnson894,Dhiraj Kabra895,Koji Kamagata896,Chandan Karmakar897,Olga Kasian898,Linda K. Kaye899,Murad M. Khan900,Yong-Min Kim901,J. K. Kish902,Sebastian Kobold903,Gary Kohanbash904,Gregor Kohls905,Jan-Michael Kugler906,Gyanendra Kumar907,Jon Lacy-Colson908,Asam Latif909,Volker M. Lauschke910,Bingling Li911,Chinten J. Lim912,Fang Liu913,Xiaodong Liu914,Jin-Jian Lu915,Qiang Lu916,Poornima Mahavadi917,Ugo Marzocchi918,Christine A. McGarrigle919,Tom van Meerten920,Rogier Min921,Iain Moal922,Massimiliano Molari923,Lucas Molleman924,Saiful R. Mondal925,Thea van de Mortel926,W. N. Moss927,Othonas A. Moultos928,Maheswari Mukherjee929,Kazuhiko Nakayama442,Edward Narayan930,Navaratnarajah931,Philipp-Alexander Neumann932,Jiyun Nie933,Yingjiu Nie934,Frank Niemeyer935,Fiona Nolan936,Ogueri Nwaiwu937,Wendy H. Oldenmenger938,Emmanuel Olumayede939,Jianhong Ou940,Menuka Pallebage-Gamarallage941,Simon P. Pearce942,Tuula Pelkonen132,Maria C. Pelleri943,Joana L. Pereira944,Mpho Pheko945,Karina A. Pinto132,Allison Piovesan946,Michael Pluess947,Illya M. Podolsky948,Julie Prescott949,Dongchen Qi950,Xingshun Qi951,Vaia D. Raikou952,Andreas Ranft953,Johanna Rhodes954,Jean-Yves Rotge955,Anna D. Rowe956,Manish Saggar957,Robert A. Schuon958,Shaouli Shahid959,Vahid Shalchyan960,Prasad Shirvalkar961,Oleg Shiryayev962,Jugpreet Singh963,Michael J. Smout964,Ant\u00f3nio Soares965,Chunjiao Song966,Kshitij Srivastava967,Rupesh K. Srivastava968,Jim Sun969,Attila Szabo970,Wiktor Szymanski971,Chan N. P. Tai972,Hisashi Takeuchi973,S. Tanadini-Lang974,Fei Tang274,Wanyin Tao975,G. Theron976,Chang F. Tian977,Yu-Shi Tian978,Lisa M. Tuttle979,Anna Valenti980,Pierre Verlot981,Mirella Walker982,Jun Wang983,Danielle Welter984,Matthew Winslade985,Dalei Wu986,Yi-Rui Wu987,Han Xiao988,Beisi Xu989,Juan Xu990,Ziyue Xu991,Dongdong Yang992,Mingjun Yang993,Patricio Yankilevich994,Yuyi You995,Chenglong Yu2,Jian Zhan996,Gong Zhang997,Kai Zhang998,Tuo Zhang999,Yi Zhang1000,Guoyan Zhao1001,Jing Zhao1002,Xiaofan Zhou1003,Zhenxing Zhu651,Penelope A. Ajani1004,Udunna C. Anazodo1005,Saeed A. Bagloee1006,Kasia Bail394,Ido Bar1007,Joe Bathelt1008,David Benkeser1009,Meghan L. Bernier1010,Adam M. Blanchard1011,Dominic W. Boakye1012,Vasileios Bonatsos1013,Michele H. Boon1014,George Bouboulis1015,Elizabeth Bromfield285,Joshua Brown1016,Kim C. M. Bul1017,Kathryn J. Burton1018,Eugene G. Butkowski1019,Grace Carroll1020,Fengqing Chao1021,Elisabeth E. Charrier1022,Xiaoyin Chen1023,Yu-Chih Chen484,Chenguang1024,Jane R. Choi1025,Tore Christoffersen1026,Jo\u00e3o C. Comel1027,Cyril Cosse1028,Yanru Cui1029,Pieter van Dessel1030,Dhaval1031,Daria Diodato1032,Maelle Duffey1033,Avik Dutt1034,Luis G. Egea1035,Mohammed El-Said1036,Martin Faye665,Beatriz Fernandez-Fernandez1037,Kieran G. Foley1038,Luria L. Founou1039,Fan Fu1040,Rabea A. Gadelkareem1041,Evgeny Galimov1042,Gulcan Garip1043,Alison Gemmill1044,Quentin Gouil1045,James Grey391,Zoya Gridneva1046,Michel J. Grothe1047,Th\u00e9ophile Gr\u00e9bert1048,Fabricio Guerrero1049,L\u00e9o Guignard1050,Marco J. Haenssgen1051,David Hasler1052,Joan Y. Holgate1053,Ancheng Huang1054,Amanda M. Hulse-Kemp1055,Claire Jean-Quartier1056,Sang-Min Jeon1057,Yangyang Jia1058,Catherine Jutzeler1059,Panagiotis Kalatzis208,Masud Karim1060,Kathrin Karsay1061,Anne Keitel1062,Andreas Kempe1063,Jeremy R. Keown1064,Chin M. Khoo1065,Nyil Khwaja1007,Rogier A. Kievit784,Aleksandra Kosanic1067,Dimitrios A. Koutoukidis1068,Paul Kramer1069,Dilip Kumar1070,N\u00fckhet K\u0131ra\u011f1071,Giuseppe Lanza208,Thuc D. Le1072,Jung W. Leem1073,Daniel Leightley1074,Andreia Leite1075,Lukas Lercher1076,Ying Li1077,Renly Lim1078,Luiz R. A. Lima1079,Li Lin1080,Tong Ling1081,Yuchen Liu1082,Zhonghua Liu1083,Yao Lu1084,Fok M. Lum1085,Hang Luo398,Jatin Machhi1086,Angus Macleod1087,Isaac Macwan1088,Hanumantha R. Madala1089,Nima Madani921,Nicola de Maio1090,Kalina Makowiecki1091,Daniel J. Mallinson1092,Ruta Margelyte132,Maria Caracausi1093,Y. Markonis1094,Luca Marsili1095,Suzanne Mavoa1096,Lorna McWilliams1097,Moa Megersa1098,Caetano S. M. Mendes1099,Julia Menichetti1100,Rebecca Mercieca-Bebber1101,Jack J. Miller1102,David-Paul M. Minde1103,Alexander Minges1104,Eleanor Mishra1105,Virendra R. Mishra1106,Carly Moores1107,Nicola Morrice1108,Alexander E. Moskalensky1109,Nicol\u00f2 Navarin1110,Edessa Negera1111,Philippe Nolet1112,Ana Nordberg1113,Rickard Nord\u00e9n1114,Jessica P. Nowicki799,Nelly Olova1115,Pawe\u0142 Olszewski1116,Robert Onzima1117,Chih-Long Pan1118,Charny Park1119,Dong Ik Park1120,Seyoung Park1121,Chandrashekhar D. Patil1122,Sansoa A. Pedro2,Samuel R. Perry1123,Jessica Peter1124,Brent M. Peterson40,Andrea Pezzuolo1126,Ilya Pozdnyakov1127,Siyu Qian1128,Lei Qin1129,Ali Rafe1130,Ishier Raote1131,Ali Raza1132,Henrike Rebl383,Osama Refai1133,Tim Regan1134,Tambi Richa1135,Mark F. Richardson1136,K. R. Robinson1137,Luca Rossoni1138,Romain Rouet1139,Soroush Safaei1140,Pierre H. H. Schneeberger1141,Daniela Schwotzer1142,Agata Sebastian375,Jennifer Selinski1143,Stefanie Seltmann1144,Feng Sha1145,Nir Shalev1146,Jin-Long Shang1147,Josef Singer1148,Mandeep Singh1149,Taylor Smith1150,Emma Solomon-Moore1151,Lijuan Song1152,Samuele Soraggi1153,Ryan Stanley1154,Nico Steckhan1155,Frederic Strobl1156,Lorenzo Subissi1157,Irwan Supriyanto1158,Chinmay R. Surve1159,Tomo Suzuki1160,Caitlin Syme1161,Karl S\u00f6relius1162,Young Tang1163,Marwa Tantawy1164,Sumudu Tennakoon1165,Serafino Teseo1166,Christine Toelzer1167,Nikola Tomov1168,Miguel Tovar1169,Linh Tran1170,Sushil Tripathi207,Anil M. Tuladhar1171,Azubuike C. Ukubuiwe1172,Carolina O. L. Ung1173,Kaspar Valgepea1174,Hamid Vatanparast1175,Arnau Vidal1176,Fang Wang1177,Qing Wang1178,Ricky Watari1179,Rebecca Webster1180,Ruth Webster1181,Junnian Wei1182,David Wibowo1183,Tanja S. H. Wingenbach1184,Rose M. Xavier1185,Shumin Xiao1,Peng Xiong1186,Shicai Xu1187,Shilin Xu484,Ruifeng Yao1188,Wen Yao1189,Qinan Yin1190,Yongbo Yu1191,Masayoshi Zaitsu1192,Zian Zeineb1193,Xiao-Yong Zhan1194,Jilei Zhang1195,Rongqiang Zhang1196,Wei Zhang1197,Xianglilan Zhang1198,Shan Zheng1199,Bailing Zhou1200,Xiaoyan Zhou2,Haroon Ahmad1201,Sayo A. Akinwumi1202,Gregory F. Albery1203,Ahmed Alhowimel1204,Junaid Ali1205,Mansour Alshehri1206,Mohammed Alsuhaibani1207,Andrey Anikin1208,Samuel O. Azubuike1209,Anders Bach-Mortensen1210,Lior Baltiansky1211,Martin Bartas1212,Kiflemariam Y. Belachew1213,Vivek Bhardwaj1214,Karin Binder636,Nicholas S. Bland1215,Michael Boah1216,Benjamin Bullen1217,Giovanna E. Calabr\u00f21218,Tiffany J. Callahan1219,Bing Cao1220,Kelsey Chalmers1221,Wei Chang1222,Zhengping Che1223,Andrew T. Y. Chen1224,Haimin Chen233,Huaming Chen1225,Youning Chen1226,Zhao Chen1227,YoungRok Choi1228,Mohiuddin A. K. Chowdhury1229,Martin R. Christensen1230,Robert S. C. Cooke1231,Marzia Cottini1232,Natalie V. Covington1233,Catriona Cunningham1234,Julien Delarocque1235,Lucie Devos1236,Aurup R. Dhar1237,Ke-Feng Ding1238,Kexian Dong1239,Zheng Dong1240,Niklas Dreyer1241,Chelsea Ekstrand1242,Tanguy Fardet1243,Berhanu E. Feleke1039,Thomas Feurer1244,Angela Freitas1245,Tian Gao1246,N.G. Asefa1247,Francesco Giganti690,Piotr Grabowski1248,Jos\u00e9 R. Guerra-Mora1249,Chengying Guo1250,Xinyi Guo1251,Himanshu Gupta1252,Shuonan He1253,Marloes Heijne1254,Stephanie Heinemann1255,Alexander Hogrebe1256,Zhengping Huang1257,Sophinese Iskander-Rizk1258,Lavanya M. Iyer1259,Yasmin Jahan1260,Ameh S. James1201,Emmanuel Joel1261,Bastian Joffroy1262,Clara J\u00e9gousse1263,George Kambondo1264,Priyanka Karnati1265,Cihan Kaya1266,An Ke1267,Daniel Kelly1268,Rob Kickert1269,Peter E. Kidibule1270,Jennifer P. Kieselmann1271,Hyeon J. Kim1272,Takeshi Kitazawa1273,Aniek Lamberts1274,You Li1275,Huakang Liang1276,Sabrina N. Linn1,Thomas Litfin1277,Wang Liusuo1278,Vasiliki Lygirou1279,Ajay K. Mahato1280,Zhi-Ming Mai1281,Rupert W. Major1282,Samira Mali1283,Panagiotis Mallis484,Wenzhi Mao1284,Wenzhi Mao1285,Katie Marvin-Dowle211,Leanda D. Mason1286,Ben Merideth1287,Maria J. Merino-Plaza1288,Britt Merlaen1289,Rossella Messina1290,Anand K. Mishra1291,Junaid Muhammad1292,Conrad Musinguzi1293,Afroditi Nanou1294,Amreen Naqash1295,Joe T. Nguyen1296,Thi T. H. Nguyen1297,Duan Ni1298,Nida1299,Shirli Notcovich1300,Barnabas Ohst1301,Quinn R. Ollivier703,Dani\u00ebl F. Osses1302,Xiangda Peng1303,Arnoud Plantinga1304,Michael Pulia1305,Muhammad Rafiq1306,Ayush Raman1307,Delphine Raucher-Ch\u00e9n\u00e91308,Rafa\u0142 Rawski1309,Asit Ray1310,Lubna A. Razak1311,Kevin Rudolf1312,Peter Rusch1313,Margaux L. Sadoine1314,Axel Schmidt1315,Roey Schurr1316,Stephen Searles1317,Saurab Sharma1318,Barry Sheehan1319,Chunhu Shi1320,Belal Shohayeb1321,Andrew Sommerlad1322,Jan Strehlow1323,Xianbao Sun1324,Raghav Sundar1,Ghazaleh Taherzadeh1325,Nur D. M. Tahir1326,Jun Tang1327,Jean Testa139,Zhiqi Tian1328,Qian Tingting846,Geert P. Verheijen1329,Casey Vickstrom1330,Teng Wang1331,Xiaomin Wang1332,Zhenxing Wang1333,Pan Wei1145,Alex Wilson1334,Wyart1335,Abdul-Amir Yassine1336,Abbas Yousefzadeh1337,Asma Zare1338,Zhen Zeng1339,Chengrong Zhang1340,Haowen Zhang1341,Linxing Zhang2,Tongchuan Zhang208,Weijia Zhang2,Zhe Zhang1342,Jianyu Zhou1343,Dongjie Zhu1344,Vincenzo Adamo1345,Adebolajo A. Adeyemo1346,Maria Aggelidou1347,Adi M. Al-Owaifeer1348,Arwa Z. Al-Riyami1349,Saeed K. Alzghari1350,Vibeke Andersen1351,Kathryn Angus1352,Muhammad Asaduzzaman1353,Hadi Asady1354,Dai Ato1355,Xiaoyong Bai1356,Rebecca L. Baines1357,Maghan Ballantyne1358,Bo Ban1359,Jill Beck426,Walid Ben-Nafa1360,Emma Black1361,Antoine Blancher1362,Ron Blankstein1363,Neil Bodagh1364,Paulo A. V. Borges1320,Anastasia Brooks1365,Josue Brox-Ponce1366,Arturo Brunetti1367,Colin D. Canham1368,Piero Carninci1369,Richard Carvajal1370,Shun C. Chang1371,Jie Chao1372,Pranab Chatterjee1373,He Chen1375,Yi-Chun Chen1376,Adnan K. Chhatriwalla1377,Ibrahim Chikowe1378,Trees-Juen Chuang1379,Rosane G. Collevatti1380,Diego A. Valera-Cornejo1381,Ana Cuenda1382,Myriam Dao1383,Delphine Dauga1384,Zaian Deng1385,Kiran Devkota1386,Lisa V. Doan1387,Yaser H. A. Elewa1388,Dongsheng Fan1389,Mohammed Faruk1390,Shi Feifei1391,Trevor S. Ferguson1392,Francesco Fleres1393,Emma J. Foster1394,C. Stephen Foster1395,Tzvi Furer1396,Yibo Gao1397,Enid J. Garcia-Rivera1398,Adi Gazdar1399,Ronald B. George1400,Sayantan Ghosh1401,Elena Gianchecchi1402,Joshua M. Gleason1403,Allan Hackshaw1404,Adam Hall1405,Richard Hall1406,Paul Harper1407,William E. Hogg1408,Guangqun Huang1409,Kylie E. Hunter1410,Adriaan P. IJzerman1411,Carlos Jesus1412,Gao Jian1413,James S. Lewis Jr.1414,Souha S. Kanj1415,Harsheen Kaur1416,Shona Kelly1417,Fayez Kheir1418,V. S. Kichatova1419,Musa Kiyani1420,Reinhild Klein1421,Tom Kovesi1422,Jennifer L. Kraschnewski1423,Addanki P. Kumar1424,Dmitry Labutin1425,Alejandro Lazo-Langner1426,Guy Leclercq1427,Maoteng Li1428,Qingchun Li1429,Tangliang Li1430,Yongzhe Li1431,Wei-Ting Liao1432,Zheng-yin Liao1433,Jessica Lin1434,J. Lizer1435,Giambattista Lobreglio1436,Cher Lowies1437,Cheng Lu1438,Haroon Majeed1439,Adam Martin1440,Luis Martinez-Sobrido1441,Edwin Meresh1442,Marianne Middelveen1443,Alireza Mohebbi1444,Jorge Mota1445,Zahra Mozaheb1446,Ley Muyaya1447,Amar Nandhakumar1448,Sheryl H. X. Ng1449,Monther Obeidat1450,Deog-Hwan Oh1451,Mohammed Owais1452,Pia Pace-Asciak1453,Ajay Panwar341,Caroline Park1013,Chris Patterson1454,Felipe Penagos-Tabaree1455,Paolo T. Pianosi1456,Valentina Pinzi778,Clare Pridans1458,Anna Psaroulaki1459,Ravi Kumar Pujala1460,Leonardo Pulido-Arjona591,Peng-Fei Qi1461,Proton Rahman1462,Nayanjot K. Rai1463,Tienush Rassaf1464,Julie Refardt1217,Walter Ricciardi1465,Olaf Riess1466,Alexandros Rovas1467,Frank M. Sacks1468,Sherif Saleh1469,Christopher Sampson1470,Axel Schmutz1471,Robert Sepanski1472,Neeraj Sharma1473,Manisha Singh1474,Paul Spearman1475,Mehala Subramaniapillai1476,Ritu Swali1477,Cher M. Tan1478,Juan I. Tellechea1479,Lisa-Marie Thomas1408,Xin Tong1480,Demetrios G. Vavvas1481,Ralf Veys1482,Veronica Vitriol1483,Horng-Dar Wang1484,Jinhui Wang1239,Jiucun Wang1485,Jason Waugh1486,S. A. Webb1487,Brendan A. Williams1488,Alan D. Workman1489,Tingxiu Xiang1490,Li-Xin Xie1491,Jun Xu1492,Taosheng Xu1493,Chongjun Yang1494,Jihoon G. Yoon1495,Christina M. Yuan1496,Arno Zaritsky1497,Yao Zhang1498,Haochen Zhao1499,Hannah Zuckerman1,Ran Lyu1Wayne Pullan3. Department of Medicine / Medical Oncology, University of Colorado Anschutz Medical Campus, CO, USA;4. Botany Department, Faculty of Science, Tanta University, Tanta, Egypt;5. Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany;6. Department of Radiation Oncology, University Medical Center Schleswig-Holstein, Campus Kiel, Germany;7. Agricultural Research Service, U.S. Department of Agriculture, Plum Island Animal Disease Center, Greenport, NY 11944, USA;8. Department of Biological and Environmental Science, University of Jyvaskyla, Finland;9. Institute of Environmental Biotechnology, Graz University of Technology, Graz, Austria;10. Department of Macromolecular Structures, National Center for Biotechnology (CNB-CSIC), Madrid, Spain;11.Oral and Maxillofacial Radiology, Applied Oral Sciences and Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China;12. Biodiversity Institute, Division of Entomology, University of Kansas, KS, USA;13. The RNA Institute, University at Albany, State University of New York, Albany, NY, USA;14. Department for Methods Development and Research Infrastructure, Robert Koch Institute, Berlin, Germany;15. Department of Surgical and Conservative Pediatrics and Adolescent Medicine, Martin Luther University of Halle-Wittenberg, Halle, Germany;16. Department of BioHealth Informatics, IU School of Informatics and Computing, Indiana University-Purdue University, IN, USA;17. School of Pharmacy, Stem Cell Biology and Regenerative Medicine, University of Reading, UK;18. School of Engineering, Dali University, Dali City, Yunnan Province, China;19. Department of Psychiatry and Psychotherapy, University Hospital Munich (LMU), Munich, Germany;20. Faculty of Life and Environmental Sciences, University of Tsukuba, Ibaraki, Japan;21. Aghyle, UniLaSalle, Beauvais, France;22. Department of Immunology, Henry Ford Health System, Michigan, US;23. Department of Emergency Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China;24. Anesthesia and Pain Medicine, Istituto Nazionale Tumori. Fondazione Pascale. IRCCS, Napoli, Italy;25. Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD, USA;26. Institute of Infection, Immunity & Inflammation, University of Glasgow, UK;27. Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland;28. Department of Surgery, Oncology and Gastroenterology (DISCOG), University of Padua, Padova, Italy;29. Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Netherlands;30. Institut de Biologie Mol\u00e9culaire et Cellulaire (IBMC), University of Strasbourg, France;31. Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany;32. Psychology, University of Notre Dame, Notre Dame, IN, USA;33. Radiology and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA;34. Department of Biological Sciences, Auburn University, AL, USA;35. KK Research Centre, KK Women\u2019s And Children\u2019s Hospital, Singapore;36. Educational Psychology, University of Alabama, Tuscaloosa, AL, USA;37. Wellcome/EPSRC Centre for Interventional & Surgical Sciences, University College London, UK;38. Department of Nutrition and Movement Sciences, Maastricht University, Maastricht, Netherlands;39. Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA;40. Department of Land, Environment, Agriculture and Forestry, University of Padua, Padova, Italy;41. Department of Biological and Environmental Sciences, University of Gothenburg, Sweden;42. Priority Research Centre for Reproductive Science, The University of Newcastle, Callaghan, NSW, Australia;43. Medical School, University of Cyprus, Nicosia, Cyprus;44. Agricultural Big-Data Research Center, College of Plant Protection, Shandong Agricultural University, Taian, Shandong, China;45. Laboratory of Neuropsychology, National Institute of Mental Health, Bethesda, MD, USA;46. Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI, USA;47. Structural Genomics Consortium, University of Oxford, UK;48. Bioinformatics, TUM Campus Straubing for Biotechnology and Sustainability, Weihenstephan-Triesdorf University of Applied Sciences, Straubing, Germany;49. Cardiovascular Research, University of Michigan, MI, USA;50. Pharmaceutical Chemistry, Bombay College of Pharmacy, Mumbai, India;51. Developmental Neurobiology, Instituto de Investigaciones Biologicas Clemente Estable, Uruguay;52. Surgical Gastroenterology and HPB Surgery, Gem Hospital & Research Centre, Coimbatore, India;53. Department of Zoology, Faculty of Science, Kafr El Sheikh University, Kafr El Sheikh, Egypt;54. Deparment of Internal Medicine IV, Medical University of Innsbruck, Austria;55. Division of Biomedical Science and Biochemistry, The Australian National University, Canberra, ACT, Australia;56. Applied Technology for Neuro-Psychology Lab., Catholic University of the Sacred Heart, Milan, Italy;57. Medical Entomology, Shandong Institute of Parasitic Diseases, Shandong, China;58. School of Pharmacy, Kumamoto University, Kumamoto, Japan;59. Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan;60. Jamil-ur-Rahman Center for Genome Research, PCMD, ICCBS, University of Karachi, 75270-Karachi, Pakistan;61. labormedizinisches zentrum Dr Risch, Vaduz, Liechtenstein;62. Medicine, University of Otago, Dunedin, New Zealand;63. Maternal Fetal Medicine, KK Women\u2019s And Children\u2019s Hospital, Singapore;64. G.E.R.N. Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Medical Center - Albert-Ludwigs-University of Freiburg, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Germany;65. Institute of Biochemistry & Molecular Biology, Heinrich Heine University, Duesseldorf, Germany;66. Surgery, National University of Ireland Galway, Ireland;67. Institute of Agriculture, The University of Western Australia, Perth, WA, Australia;68. Nuffield Department of Medicine, University of Oxford, UK;69. Punggol Polyclinic, SingHealth Polyclinics, Singapore;70. Division of Biological Chemistry, Biocenter, Medical University of Innsbruck, Austria;71. Biochemistry and Genetics, La Trobe Institute for Molecular Sciences, La Trobe University, Melbourne, VIC, Australia;72. INRA, University of Bordeaux, France;73. Agriculture and Agri-Food Canada, Lethbridge Research and Development Centre, Lethbridge, Canada;74. Trauma and Orthopaedics, St George\u2019s Hospital, London, UK;75. Department of Protein Evolution, Max Planck Institute for Developmental Biology, T\u00fcbingen, Germany;76. 2nd Department of Gynaecology, Medical University of Lublin, Poland;77. ICSI Analytics, National Research and Development Institute for Cryogenics and Isotopic Technologies \u2013 I.C.I.T. Ramnicu Valcea, VL, Romania;78. Occupational Therapy, University of KwaZulu-Natal, Westville Campus, Durban, South Africa;79. Joint Department of Physics, The Institute of Cancer Research, London, UK;80. Department of Molecular Medicine and Surgery, Karolinska Institute, Solna, Sweden;81. Orthopaedics, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China;82. Laboratorio de Virolog\u00eda Molecular, Centro de Investigaciones Nucleares, Facultad de Ciencias, Universidad de la Rep\u00fablica, Uruguay;83. Department of Medical Biochemistry & Cell Biology, University of Gothenburg, Sweden;84. Pediatric Cardiology, Charit\u00e9 Medical University of Berlin, Germany;85. Neurorehabilitation Unit, Department of Neurosciences and Neurorehabilitation, Bambino Ges\u00f9 Children's Hospital, Rome, Italy;86. Microbiology and Immunology, Indiana University School of Medicine-Northwest, Gary, IN, USA;87. Department of Behavioural and Molecular Neurobiology, University of Regensburg, Germany;88. The University of Queensland Diamantina Institute, The University of Queensland & Translational Research Institute, Brisbane, QLD, Australia;89. School of Biomedical Sciences, The University of Hong Kong, Hong Kong, China;90. Pharmaceutical Sciences Department, St. Jude Children\u2019s Research Hospital, Memphis, TN, USA;91. Music, Durham University, Durham, UK;92. Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece;93. School of Life Sciences Weihenstephan, Technical University M\u00fcnchen, Maximus-von-Imhof-Forum 3, D-85354, Freising, Germany;94. Institute for Transfusion Medicine, University Hospital Essen, Germany;95. Computer Science, Virginia Commonwealth University, Richmond, VA, USA;96. Institute for Social Science Research, The University of Queensland, Brisbane, QLD, Australia;97. Centre International de Recherche en Infectiologie, Universit\u00e9 de Lyon, France;98. School of Allied Health Sciences, Griffith University, Gold Coast, QLD, Australia;99. Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, Australia;100. Department of Biohealth Informatics, School of Informatics and Computing, Indiana University-Purdue University, IN, USA;101. Institute for Lung Research, Philipps-University Marburg, Germany;102. Department of Biology, Indiana University, Bloomington, IN, USA;103. Oral Biology, University of Florida, Gainesville, FL, USA;104. Department of Biochemistry, University of Colorado, Boulder, CO, USA;105. Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan;106. Institute for Virus Diagnostics, Friedrich Loeffler Institute, Insel Riems, Greifswald, Germany;107. Department of Zoology, University of Oxford, UK;108. Department of Bioinformatics, Technical University of Munich, M\u00fcnchen, Germany;109. School of Animal and Veterinary Sciences, University of Adelaide, SA, Australia;110. Cancer Biology, Stanford University, Palo Alto, CA, USA;111. Department of Electrical and Information Engineering, Covenant University, Ota, Nigeria;112. Institute for Stem Cell Research and Regenerative Medicine, Heinrich Heine University, D\u00fcsseldorf, Germany;113. Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, BC, Canada;114. Psychiatry, Albert Einstein College of Medicine, New York City, NY, USA;115. Medical Biology and Genetics, Akdeniz University, Antalya, Turkey;116. National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA;117. Internal Medicine I, Medical University Hospital, T\u00fcbingen, Germany;118. Netelabs, NET ESolutions, McLean, VA, USA;119. Institute of Public Health, University of Southern Denmark, Odense, Denmark;120. Molecular Microbiology, John Innes Centre, Norwich, UK;121. Australian Research Council Centre of Excellence in Plant Energy Biology, Waite Research Precinct, University of Adelaide, SA, Australia;122. Cambridge Institute of Public Health, University of Cambridge, UK;123. Institute for Biochemistry, University of Muenster, Germany;124. National Centre for Epidemiology and Population Health (RSPH), The Australian National University, Canberra, ACT, Australia;125. Neurobiology and Bioengineering, Stanford University, Palo Alto, CA, USA;126. Geography, Earth and Environmental Sciences, University of Birmingham, UK;127. School of Veterinary & Life Sciences, Murdoch University, Perth, WA, Australia;128. Center for Climate Change Communication, George Mason University, Fairfax, VA, USA;129. School of Agriculture, Food and Wine, University of Adelaide, SA, Australia;130. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China;131. Pathology, Stanford University, Palo Alto, CA, USA;132. Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Italy;133. Department of General Psychology, University of Padua, Padova, Italy;134. Department of Bioinformatics & Systems Biology, Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, and the Collaborative Innovation Center for Biomedical Engineering, Huazhong University of Science and Technology, Wuhan, Hubei, China;135. School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia;136. Institut de Biologie Physico-Chimique, French National Center for Scientific Research (CNRS), Paris, France;137. Department of Sociology, University of Warwick, Coventry, UK;138. Structural and Computational Biology, European Molecular Biology Laboratory, Heidelberg, Germany;139. Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA;140. Biology, University of Waterloo, ON, Canada;141. Sorbonne Universit\u00e9, CNRS, Integrative Biology of Marine Models (LBI2M), Station Biologique de Roscoff (SBR), Roscoff, France;142. Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada;143. Ultrafast Solid State Spectroscopy, Max Planck Institute for Solid State Research, Stuttgart, Germany;144. Department of Infectious Disease Epidemiology, School of Public Health, Imperial College London, UK;145. Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt;146. Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA;147. State Key Laboratory of Biogeology and Environmental Geology, China University of Geosciences, Wuhan, China;148. Child Psychiatry, Clinic for Neurology and Psychiatry for Children and Youth, Belgrade, Serbia, Belgrade;149. Medical Physics, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran;150. Division of Biostatistics and Computational Biology of College of Dentistry, Departments of Preventive & Community Dentistry, Biomedical Engineering, and Biostatistics, University of Iowa City, IA, USA;151. Institute of Medical Psychology and Behavioural Neurobiology, University T\u00fcbingen, Germany;152. Department of Zoology, University of Ibadan, Nigeria;153. College of Veterinary Medicine, Kansas State University, Manhattan, KS, USA;154. Discipline of ICT, School of Technology, Environments and Design, University of Tasmania, Hobart, Australia;155. Radiology, Children\u2019s Mercy Hospital, Kansas City, MO, USA;156. Department of Physics, Stockholm University, Stockholm, Sweden;157. Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway;158. CSIRO Manufacturing, CSIRO, Pullenvale, QLD, Australia;159. Urology, Johns Hopkins School of Medicine, Baltimore, MD, USA;160. Life and Consumer Sciences, University of South Africa, Johannesburg, South Africa;161. Mechanisms of Induced Plasticity of the Brain, German Center for Neurodegenerative Diseases, Bonn, Germany;162. Developmental Biology and Cancer, Institute of Child Health, University College London, UK;163. Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada;164. Centre for Health Informatics, University of Manchester, UK;165. School of Human Movement and Nutrition Sciences, The University of Queensland, Brisbane, QLD, Australia;166. Department of Medicine, Albert Einstein College of Medicine, New York City, NY, USA;167. Kennedy Institute of Ethics, Georgetown University, Washington, DC, USA;168. Dermatology, Skin and Cancer Foundation, Carlton, VIC, Australia;169. Divisions of Hematology/Oncology & Infectious Disease, Medical College of Wisconsin, Milwaukee, WI, USA;170. Office of Biotechnology Products, U.S. Food and Drug Administration, Washington, DC, USA;171. Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA, USA;172. Centre for Orthopaedic and Trauma Research, University of Adelaide, SA, Australia;173. National Infection Service, Public Health England, Bristol, UK;174. Faculty of Science - Chemistry, Utrecht University, Netherlands;175. Pathology, National University of Ireland Galway, Ireland;176. National Heart and Lung Institute (NHLI), Imperial College London, UK;177. Neurodegeneration, Danube Private University, Krems/Donau, Austria;178. Department of Chemistry, Imperial College London, UK;179. Finnish Museum of Natural History, University of Helsinki, Finland;180. School of Life and Environmental Sciences, University of Sydney, NSW, Australia;181. Nottingham Digestive Diseases Centre, University of Nottingham, UK;182. ITAV USR3505 CNRS, University of Toulouse, France;183. University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia;184. CZ-Openscreen, Institute of Molecular Genetics of the ASCR, Prague, Czech Republic;185. Institute of Biomedicine, University of Turku, Finland;186. School of Kinesiology and Health Science, York University, Toronto, ON, Canada;187. Ophthalmology, Stein Eye Institute, University of California Los Angeles, CA, USA;188. Agriculture and Agri-Food Canada, Ottawa Research and Development Center, Ottawa, ON, Canada;189. Material Design and Characterization, Helmholtz-Zentrum Geesthacht, Germany;190. Internal Medicine, Unversity of Genova, Italy;191. Intelligent Catheter \u2013 INKS, Otto-von-Guericke-University, Magdeburg, Germany;192. Cancer Biology, University of Toledo Health Science Campus, OH, USA;193. Structural Biology, CRUK Beatson Institute, Glasgow, UK;194. Medical RNA Biology, Leibniz Institute for Primate Research, G\u00f6ttingen, Germany;195. PEIRENE EA 7500, University of Limoges, France;196. Veterinary Medicine, Hainan University, Haikou, Hainan, China;197. Pharmacognosy and Phytotherapy, School of Pharmacy, University College London, UK;198. Ecology and Genetics Research Unit, University of Oulu, Finland;199. Institute of Biochemistry and Molecular Immunology, RWTH Aachen University, Aachen, Germany;200. Institute of Biochemistry and Technical Biochemistry, University Stuttgart, Germany;201. School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China;202. Medical Oncology, GIGA-Research Institute & CHULi\u00e8ge, Li\u00e8ge, Belgium;203. MPBA, Fondazione Bruno Kessler, Trento, Italy;204. Department of Neurobiology, Hokkaido University Graduate School of Medicine, Sapporo, Japan;205. Oncology, University of Leuven, Belgium;206. Department of Mathematical Sciences, Chalmers University of Technology, G\u00f6teborg, Sweden;207. Department of Neurology, Radboud University Medical Center, Nijmegen, Netherlands;208. School of Information Technology and Mathematical Sciences, University of South Australia, Adelaide, SA, Australia;209. Department of Computational Biology, Bio-Thera Solutions Ltd., Guangzhou, China;210. Otolaryngology, Instituto de Investigaci\u00f3n Biosanitario de Granada IBS.Granada, Spain;211. School of Molecular and Life Sciences, Curtin University, Perth, WA, Australia;212. Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK;213. Institute of Pharm. Biology/DCAL, Goethe University, Frankfurt, Germany;214. UMR 5246 Institut de Chimie et Biochimie Mol\u00e9culaires et Supramol\u00e9culaires (ICBMS), Universit\u00e9 de Lyon, France;215. Department of Genomes and Genetics, Institut Pasteur, Paris, France;216. Pharmacology, University of Valencia, Spain;217. Research Centre for Olive, Citrus and Tree Fruit, Council for Agricultural Research and Economics, Caserta, Italy;218. Preclinical Pharmacology and In Vitro Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany;219. School of Medicine, University of Tasmania, Hobart, TAS, Australia;220. Oncology Lifecycle Management Department, Chugai Pharmaceutical Co. Ltd, Tokyo, Japan;221. Institute of Neurobiology, University of L\u00fcbeck, Germany;222. Neurology, New York University School of Medicine, New York, NY, USA;223. Department of Plant Pathology, University Putra Malaysia, Seri Kembangan, Malaysia;224. Biology, University of North Carolina at Chapel Hill, NC, USA;225. Faculty of Health Sciences, University of Southampton, UK;226. Genetics and Immunology Research Group, University of the Highlands and Islands, Inverness, UK;227. Institute of Pathology, University of Heidelberg, Germany;228. Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India;229. School of Health and Life Sciences, Glasgow Caledonian University, Glasgow, UK;230. Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK;231. Basic Research, Parkinson\u2019s Institute and Clinical Center, Sunnyvale, CA, USA;232. Environmental Research and Innovation, Luxembourg Institute of Science and Technology, Luxembourg;233. School of Computing and Information Technology, University of Wollongong, Wollongong, NSW, Australia;234. Department of Biomedical Sciences and Human Oncology, Universit\u00e0 degli Studi di Bari Aldo Moro, Bari-Italy;235. College of Nursing and Health Sciences, Flinders University, Adelaide, SA, Australia;236. Molecular Medicine, University of South Florida, Tampa, FL, USA;237. Behavioral & Brain Sciences, The University of Texas at Dallas, Richardson, TX, USA;238. Zoology & Entomology, Rhodes University, Grahamstown, South Africa;239. Instituto de Higiene e Medicina Tropical, Universidade NOVA de Lisboa, Portugal;240. Institute of Microbiology, ETH Zurich, Switzerland;241. Immunohaematology, German Red Cross Blood Service, Institute Ulm, Germany;242. Institute of Advanced Biomedical Engineering and Science, Tokyo Women\u2019s Medical University, Tokyo, Japan;243. Biological Sciences, University of Limerick, Ireland;244. Department of Animal Science, McGill University, Montreal, QC, Canada;245. StatSol, L\u00fcbeck, Germany and School of Mathematics, Statistics and Computer Science, University of KwaZulu-Natal, Pietermaritzburg, South Africa;246. Institute of Systems Biology (INBIOSIS), Universiti Kebangsaan Malaysia (UKM);247. National Center for Complementary and Integrative Health, National Institutes of Health, Bethesda, MD, USA;248. Family Medicine Research Division, University of Kansas Medical Center, Kansas City, KS, USA;249. Multimodal Molecular Biology, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore;250. Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Belgium;251. International Iberian Nanotechnology Laboratory (INL), Braga, Portugal;252. Computing and Technology, Anglia Ruskin, Cambridge, UK;253. Structural Cell Biology, Max Planck Institute of Biochemistry, Planegg, Germany;254. Department of Computer Architecture and Technology, Universidad de Sevilla, Spain;255. EBIO, University of Colorado, Boulder, CO, USA;256. Cancer Sciences, University of Manchester, UK;257. Research School of Population Health, The Australian National University, Canberra, ACT, Australia;258. Bio-systems, Singapore-MIT Alliance for Research and Technology, Singapore;259. Musculoskeletal Health and Ageing Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, VIC, Australia;260. General Surgery, St. Josef Hospital - Ruhr University Bochum, Germany;261. College of Life Sciences, Northwest A&F University, Shaanxi, China;262. Division of Plant Science, Research School of Biology, The Australian National University, Canberra, ACT, Australia;263. Clinical and Nonclinical Research, Battelle, Columbus, OH, USA;264. Biological Sciences, Southern Methodist University, Dallas, TX, USA;265. Institute of Medical Mycology, Teikyo University, Tokyo, Japan;266. Bioinformatics, Tempus Labs, Chicago, IL, USA;267. College of Biology, Hunan University, Changsha, China;269. FutureNeuro Research Centre, Physiology & Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland;270. Gerontology Research Center, University of Jyvaskyla, Finland;271. Department of Anesthesiology, University of Heidelberg, Germany;272. Biology, Pennsylvania State University, PA, USA;273. State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China;274. School of Life Sciences, University of Science and Technology of China, Anhui, China;275. Animal Science, Michigan State University, East Lansing, MI, USA;276. Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, NY, USA;277. Institute for Biological Sciences, University of Rostock, Germany;278. Environmental Research Institute, School of Environment, South China Normal University, Guangzhou, China;279. Department of Veterinary Medicine, University of Bari, Italy;280. Primary and Community Care, Radboud University Medical Center, Nijmegen, Netherlands;281. EcoHealth Alliance, New York, NY, USA;282. Cardiovascular Department, Mayo Clinic, Rochester, MN, USA;283. Department of Epidemiology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland;284. Animal Science, University of Lleida, Spain;285. Pharmaceutical Outcomes & Policy, University of Florida College of Pharmacy, Gainesville, FL, USA;286. Earth and Biological Science Directorate, Pacific Northwest National Laboratory, Richland, WA, USA;287. Centre for Discovery Brain Sciences, University of Edinburgh, UK;288. Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA;289. Radiology, University of Pennsylvania, Philadelphia, PA, USA;290. Biomedical Sciences - Personalized Medicine, Asthma and Allergy unit, Humanitas University and Research Hospital, Rozzano, Italy;291. Department of Quantum Science, The Australian National University, Canberra, ACT, Australia;292. Ecological Genomics, University of Oldenburg, Germany;293. Paediatric Dentistry & Orthodontics, International Medical University, Kuala Lumpur, Malaysia;294. School of Nursing, University of Ottawa, ON, Canada;295. Department of Education Support, Maastricht University, Maastricht, Netherlands;296. Mathematics, University of Manchester, UK;297. School of Population Health Sciences, Faculty of Life Sciences and Medicine, King\u2019s College London, UK;298. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia;299. Epidemiology, Public Health School, Harbin Medical University, Heilongjiang, China;300. Department of Chemistry, UiT - The Arctic University of Norway, Troms\u00f8, Norway;301. Biological Statistics and Computational Biology, Cornell University, Ithaca, NY, USA;302. Shanghai Key Lab for Urban Ecological Process and Eco-restoration, School of Ecological and Environmental Sciences, East China Normal University, Shanghai, China;303. Faculty of Biology, Johannes Gutenberg University, Mainz, Germany;304. Food Science, University of Massachusetts Amherst, MA, USA;305. Complex Adaptive Traits Research Group, Max Planck Institute for Terrestrial Microbiology, Marburg, Germany;306. Centre for Exercise and Rehabilitation Science, NIHR Biomedical Research Centre - Respiratory, Leicester, UK;307. Section of Endocrinology, Department of Internal Medicine, Yale University, New Haven, CT, USA;308. Department of Biosciences, Sardar Patel University, Gujarat, India;309. Department of Applied Physics, The University of Tokyo, Japan;310. Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), in vivo Research Facility (ivRF), University of Cologne,Germany;311. Department of Public Health Science, National Open University of Nigeria, Lagos, Nigeria;312. Department of Radiology, University Hospital Regensburg, Germany;313. Geography, National University of Singapore;314. College of Medicine, Alfaisal University, Riyadh, Saudi Arabia;315. Biomedical Genomics and Oncogenetics Research Laboratory, Faculty of Sciences and Techniques of Tangier, Abdelmalek Essaadi University, Morocco;316. Exercise Biology Group, Faculty of Sport and Health Sciences, Technical University of Munich, Germany;317. Departamento de Psicolox\u00eda Social, B\u00e1sica e Metodolox\u00eda, Universidade de Santiago de Compostela, Galiza, Spain;318. Signal Processing Laboratory, Griffith University, Brisbane, QLD, Australia;319. Department of Neurology, Ghent University and Ghent University Hospital, Belgium;320. Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium;321. Institute for Clinical and Translational Research, Albert Einstein College of Medicine, New York City, NY, USA;322. Faculty of Medical Science, Anglia Ruskin University, Cambridge, UK;323. College of Chemistry and Molecular Engineering, Peking University, Beijing, China;324. Department of Dermatology and Allergy, Herlev and Gentofte Hospital, Hellerup, Denmark;325. Medical Imaging and Nuclear Medicine, Lady Cilento Children\u2019s Hospital, Brisbane, QLD, Australia;326. Nursing and Reproductive Health, School of Medicine and Allied Health Sciences, University of The Gambia, Brikama, Gambia;327. Woolcock Institute of Medical Research, University of Sydney, NSW, Australia;328. Computer Science, Wayne State University, Detroit, MI, USA;329. Otolaryngology, Aberdeen Royal Infirmary, Aberdeen, Scotland;330. Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada;331. Institute of Ageing, The Chinese University of Hong Kong, Hong Kong, China;332. Emergency Medicine, University of Nebraska Medical Center, Omaha, NE, USA;333. Pathology, University of Florida College of Medicine, Gainesville, FL, USA;334. Radiation Oncology, MD Anderson Cancer Center, Houston, TX, USA;335. Translational Research NTMS, University of Pisa, Italy;336. Clinical and Experimental Medicine, Magna Grecia University, Catanzaro, Italy;337. Pediatrics, Larner College of Medicine University of Vermont, Burlington, VT, USA;338. Diagnostic and Interventional Ultrasound, Sun Yat-sen University Cancer Center, Guangzhou, China;339. Institutes of Brain Science, Fudan University, Shanghai, China;340. College of Agronomy, Shanxi Agricultural University, Shanxi, China;341. Institute of Medical Science, University of Toronto, ON, Canada;342. ARCPOH, University of Adelaide, SA, Australia;343. Cardiology and Vascular Medicine, Faculty of Medicine, Pelita Harapan University, Tangerang, Indonesia;344. Research Division, Institute of Mental Health, Singapore;345. MRC Clinical Trials Unit, University College London, UK;346. Department of Philosophy, Sociology, Education and Applied Psychology (FISPPA), University of Padua, Padova, Italy;347. Department of Psychiatry and Psychotherapy, University of L\u00fcbeck, L\u00fcbeck, Germany;348. Center for Molecular Medicine, Dalian University of Technology, Liaoning, China;349. Reproductive Medicine, Tianjin United Family Healthcare, Tianjin, China;350. Departament d\u2019Enginyeria Qu\u00edmica Biol\u00f2gica i Ambiental, Universitat Aut\u00f2noma de Barcelona, Spain;351. Department of Animal Science, Sao Paulo State University (UNESP), Sao Paulo, Brazil;353. Department of Cardiovascular Medicine, The University of Tokyo, Japan;354. Veterinary Clinical, Sao Paulo State University, Paulo, Brazil;355. Institute of Biotechnology, Zhejiang University, Hangzhou, Zhejiang, China;356. Department of Molecular Biology and Genetics, Aarhus University, Denmark;357. Maternal and Fetal Health, St. Mary\u2019s Hospital, University of Manchester, UK;358. Internal Medicine, University of New Mexico, Albuquerque, NM, USA;359. Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA;360. Plant Production, King Saud University, Riyadh, Saudi Arabia;361. Department of Molecular Biology, Institute of Genetics and Animal Breeding of the Polish Academy of Sciences;362. Optometry and Vision Science, Queensland University of Technology, Brisbane, QLD, Australia;363. School of Life Sciences, University of Nottingham, UK;364. Cancer Research Centre, Cancer Council Queensland, Brisbane, QLD, Australia;365. Department of Chemistry, Ume\u00e5 University, Ume\u00e5 Sweden;366. Centre for Radiation, Chemical & Environmental Hazards, Public Health England, Bristol, UK;367. DISTABIF, Universit\u00e0 della Campania \u201dL. Vanvitelli\u201d, Caserta, Italy;368. Obstetrics and Gyanecology, Bartshealth, London, UK;369. GReD Laboratory, Universit\u00e9 Clermont Auvergne, Clermont-Ferrand, France;370. INRA, Abeilles et Environnement, Avignon, France;371. School of Public Health and Social Work, Queensland University of Technology, Brisbane, QLD, Australia;372. Psychiatry, University of Pennsylvania, Philadelphia, PA, USA;373. Research Institute of Physiology and Basic Medicine, Novosibirsk State University, Russia;374. Department of Chemistry, University College London, UK;375. Animal, Plant and Soil Sciences, La Trobe University, Melbourne, VIC, Australia;376. Epidemiology and Biostatistics, University of Arizona, Tucson, AZ, USA;377. ERIBA, University Medical Center Groningen, University of Groningen, Netherlands;378. Department of Radiation Physics, Institution of Clinical Science, University of Gothenburg, Sweden;379. Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, USA;380. Centro de Pesquisas Goncalo Moniz, Fundacao Oswaldo Cruz, Bahia, Brazil;381. Food, Water and Environmental Microbiology, Institute of Environmental Science & Research (ESR), Christchurch, New Zealand;382. Food Science, University of Otago, Dunedin, New Zealand;383. Biomedical Science, Florida Atlantic University, Boca Raton, FL, USA;384. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia;385. Institute of Clinical Neurobiology, University Hospital W\u00fcrzburg, Germany;386. Public Health, Institute of Tropical Medicine, Antwerpen, Belgium;387. Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece;388. Department of Orthodontics and Pediatric Dentistry, UZB University Center for Dental Medicine, University of Basel, Switzerland;389. Institut Syst\u00e9matique, Evolution, Biodiversit\u00e9 (ISYEB), UMR 7205 MNHN-CNRS-Sorbonne Universit\u00e9-EPHE, Museum National d\u2019Histoire Naturelle, Paris, France;390. Institute for Advanced Bioscience, CNRS, France;391. School of Molecular Sciences, The University of Western Australia, Perth, WA, Australia;392. Biochemistry and Microbiology, University of Fort Hare, South Africa;393. Physics, University T\u00fcbingen, Germany;394. School of Environment and Science, Griffith University, Brisbane, QLD, Australia;395. Statistics and Standardised Methods, Philosophisch-Theologische Hochschule Vallendar, Germany;396. Life Sciences, Imperial College London, UK;397. Adelaide Medical School, University of Adelaide, SA, Australia;398. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA;399. FOCAS Research Institute, Technological University Dublin, Ireland;400. Cancer Research Center of Toulouse, National Institute for Health and Medical Research (INSERM), Paris, France;401. Grupo BRAINSHARK, Departamento de Biolox\u00eda Funcional, Universidade de Santiago de Compostela, Galiza, Spain;402. Biology, University of Nebraska at Kearney, NE, USA;403. Departament de Gen\u00e8tica i Microbiologia, Universitat Aut\u00f2noma de Barcelona, Spain;404. Chemistry and Industrial Chemistry, University of Pisa, Italy;405. Wellcome Trust Centre for Cell-Matrix Research, University of Manchester, UK;406. Institute of Human Genetics, CNRS, University of Montpellier, France;407. Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Prague, Czech Republic;408. Computational Systems Biology Group, National Center for Biotechnology (CNB-CSIC), Madrid, Spain;409. Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan, Taiwan;410. Ophthalmology, Schepens Eye Research Institute, Harvard Medical School, Boston, MA, USA;411. Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, China;412. School of Life Sciences, University of Technology Sydney, NSW, Australia;413. Gynecology, JT Chen Clinic, Tokyo, Japan;414. Institute of Agriculture, and School of Agriculture and Environment, The University of Western Australia, Perth, WA, Australia;415. Faculty of Geographical Science, Beijing Normal University, Beijing, China;416. Electrical Engineering and Computer Science, University of Missouri, Columbia, MO, USA;417. Department of Public and Occupational Health, Amsterdam Public Health Research Institute, VU University Medical Center, Amsterdam, Netherlands;418. Medical Biochemistry, Semmelweis University, Budapest, Hungary;419. Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong, China;420. Chemistry, University of Pittsburgh, PA, USA;421. Neurology, G B Pant Institute of Post Graduate Medical Education and Research, New Delhi, India;422. Veterinary and Animal Sciences, University of Copenhagen, Denmark;423. Section of Endocrinology, Biomedical Department of Internal and Specialist Medicine (DIBIMIS), University of Palermo, Italy;424. Neuroscience, Physiology, and Pharmacology (NPP), University College London, UK;425. Microbiology and Cell Science, University of Florida, Gainesville, FL, USA;426. School of Health Sciences, University of Salford, Manchester, UK;427. Institute of Medical Genetics, Cardiff University, UK;428. ICO Cancer Center, Inserm, Angers, France;429. Microbiology, Faculty of Medicine, University of Colombo, Sri Lanka;431. Faculty of Pharmacy, University of Porto, Portugal;432. Division of Primary Care, University of Nottingham, UK;433. Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago, IL, USA;434. Escola de Ci\u00eancias Agr\u00e1rias e Biol\u00f3gicas, Pontif\u00edcia Universidade Cat\u00f3lica de Goi\u00e1s, Brazil;435. Department of Oncology, China-Japan Friendship Hospital, Beijing, China;436. Chemistry, Boston University, MA, USA;437. Environmental Science, American University, Washington, DC, USA;438. Neuroscience, Carleton University, Ottawa, ON, Canada;439. Chemistry and Biochemistry, University of Regina, SK, Canada;440. Microbiolgy, Universite de Montreal, Montreal, QC, Canada;441. Department of Genetics and Genome Biology, University of Leicester, UK;442. School of Agriculture and Food Sciences, The University of Queensland, Gatton, QLD, Australia;443. BIOM, CNRS, France;444. The Hatter Cardiovascular Institute, University College London, UK;445. Science and Engineering, Flinders University, Adelaide, SA, Australia;446. Engineering, University of Warwick, Coventry, UK;447. Center for Human Genetics, KU Leuven, Belgium;448. Department of Macromolecular Science, Fudan University, Shanghai, China;449. Biology Education, Dokuz Eylul University, Izmir, Turkey;450. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA;451. Pulmonary Disease, Mondo Medico, Borgomanero, Italy;452. U.S. Naval Research Laboratory, Center for Bio/Molecular Science & Engineering, Washington, DC, USA;453. Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Norway;454. Department of Mechanics and Engineering Science, Peking University, Beijing, China;455. Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbr\u00fccken, Germany;456. Skin Research Institute, National Institute for Health and Medical Research (INSERM), Paris, France;457. Research & Development, Shanghai Proton and Heavy Ion Center, Shanghai, China;458. Epidemiology, University of Georgia, Athens, GA, USA;459. Department of Plastic and Hand Surgery, Medical Center, University of Freiburg, Germany;460. Research, Sidra Medicine, Doha, Qatar;461. Department of Oral, Maxillofacial and Plastic Surgery, Rostock University Medical Center, Germany;462. Emergency Medicine, Brigham & Women\u2019s Hospital / Harvard Medical School, Boston, MA, USA;463. Forage Science, AgResearch, Palmerston North, New Zealand;464. Medicine, University of California Los Angeles, CA, USA;465. Virginia G. Piper Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, AZ, USA;466. Materials and Engineering Research Institute, Sheffield Hallam University, Sheffield, UK;467. respiratory medicine, Aneurin Bevan University Healthboard, Newport, UK;468. Neurological Surgery, University of California San Francisco, CA, USA;469. UWA Dental School, The University of Western Australia, Perth, WA, Australia;470. Biological Sciences, Fordham University, Bronx, NY, USA;471. Institute of Biotechnology, University of Helsinki, Finland;472. College of Life Sciences, Fujian Normal University, Fujian, China;473. Department of Frontier Fiber Technology and Science, University of Fukui, Japan;474. Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, UK;475. Department of Biomolecular Sciences, University of Urbino, Italy;476. Allergology Unit, Ospedale San Luigi, Torino, Italy;477. Department of Urology, Muljibhai Patel Urological Hospital, Gujarat, India;478. Stratigraphy and Paleontology, University of Granada, Spain;479. School of Veterinary Sciences, Massey University, Auckland, New Zealand;480. High Performance Computing and Networking Institute, National Research Council, Naples, Italy;481. Division of Metabolism and Children\u2019s Research Center, University Children\u2019s Hospital Z\u00fcrich, Switzerland;482. Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, Australia;483. Leptospirosis Research and Expertise Unit, Institut Pasteur, Noumea, New Caledonia;484. School of Life Sciences, Tsinghua University, Beijing, China;485. Biology Animal Department, Sciences Faculty, Cheikh Anta Diop University (UCAD), Dakar, Senegal;486. Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA;487. Agriculture and Agri-Food Canada, Lacombe Research and Development Centre, Lacombe, Canada;488. Performance Management and Evaluation, Alberta Innovates, Edmonton, AB, Canada;489. Instituto de Hortofruticultura Subtropical y Mediterr\u00e1nea \u201dLa Mayora\u201d (IHSM-UMA-CSIC), Universidad de M\u00e1laga-Consejo Superior de Investigaciones Cient\u00edficas, Spain;490. College of Public Health, Medical and Veterinary Sciences, James Cook University, Cairns, QLD, Australia;491. Joint Research Centre, European Commission, Ispra, Italy;492. University of Montpellier, France;493. Commonwealth Scientific and Industrial Research Organisation (CSIRO), Floreat, WA, Australia;494. Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China;495. Pharmacology, Vanderbilt University, Nashville, TN, USA;496. KFU-RIKEN Translational Genomics Unit, RIKEN, Yokohama, Japan;497. Neurobiology of Vocal Communication, University T\u00fcbingen, Germany;498. UCCS center for the Biofrontiers Institute, University of Colorado at Colorado Springs, CO, USA;499. Division of Basic Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA;500. Primary Care Unit, Faculty of Medicine, University of Geneva, Switzerland;501. Department of Molecular Genetics and Infection Biology, Universit\u00e4t Greifswald, Germany;502. Department of Fine Chemistry, East China University of Science and Technology, Shanghai, China;503. Surgery, The Ohio State University, Columbus, OH, USA;504. R&D, Oragenics, Tampa, FL, USA;505. Environmental Health Institute, National Environment Agency, Singapore;506. Institute of Diagnostic Virology, Friedrich Loeffler Institute, Insel Riems, Greifswald, Germany;507. Oncology, The Queen Elizabeth Hosptal, Woodville, SA, Australia;508. Emerging Pests and Pathogens Research Unit, USDA, NY, USA;509. Epilepsy Center, Department of Neurosurgery, Medical Center, University of Freiburg, Germany;510. Information and Technology Studies, Faculty of Education, The University of Hong Kong, Hong Kong, China;511. Agricultural and Environmental Biology, Graduate School of Agricultural and life Sciences, The University of Tokyo, Japan;512. Department of Medicine, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, PA, USA;513. Directorate of Transplant, Renal and Urology, Guy\u2019s & St Thomas\u2019 NHS Foundation Trust, London, UK;514. Clinic for Heart, Blood Vessel and Rheumatic Diseases, Clinical Center, University of Sarajevo, Sarajevo;515. School of Mathematics, Statistics and Actuarial Science, University of Kent, UK;516. Department of Life Science and Technology, Tokyo Institute of Technology, Japan;517. Laser Center Department of Applied Sciences and Mechatronics, University of Applied Sciences Munich, Germany;518. Nanodevices, CIC nanoGUNE, San Sebastian, Spain;519. Gynaecology, VU University Medical Center, Amsterdam, Netherlands;520. Division of Population Medicine, Cardiff University Medical School, UK;521. Department of Medicine, Karolinska Institute, Solna, Sweden;522. Center for Information Biology, National Institute of Genetics, Mishima, Japan;523. Harry Perkins Institute of Medical Research, Murdoch University, Perth, WA, Australia;524. Physical Education & Sport Sciences, University of Limerick, Ireland;525. Campus Clinic Gynecology, Ruhr-University Bochum Universit\u00e4tsstr, Bochum, Germany;526. Epidemiology and Biostatistics, School of Public Health, Southwest Medical University, Sichuan, China;527. Center for Molecular Diagnostics, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing Cancer Hospital, Beijing, China;528. Herpetological Department, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, China;529. Key Laboratory of Nano Biological Effects and Safety, Beijing, China;530. PK Sciences, Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland;531. Pain Center, Daejeon St. Mary\u2019s Hospital, Daejeon, Korea;532. School of Health Studies, The University of Western Ontario, London, ON, Canada;533. Health Psychology Group, University of Aberdeen, UK;534. Anesthesiology, University of Colorado Anschutz Medical Campus, CO, USA;535. Critical Care Medicine, UZA , University of Antwerp, Edegem, Belgium;536. Endocrinology, Aarhus University Hospital, Denmark;537. Industrial and Systems Engineering, Centre for Transport Development, University of Pretoria, South Africa;538. Department of Biostatistics and Bioinformatics, Duke University, NC, USA;539. Medical, Pharmaceutical and Biomedical Sciences School, Pontif\u00edcia Universidade Cat\u00f3lica de Goi\u00e1s, Brazil;540. Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden;541. Clinical, Educational and Health Psychology, University College London, UK;542. Development and Differentiation Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB);543. Laboratoire de la Barri\u00e8re H\u00e9mato-enc\u00e9phalique, Universit\u00e9 d\u2019Artois, Arras, France;544. Quantitative Biology, Discovery Sciences, IMED Biotech Unit, AstraZeneca, Cambridge, UK;545. Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA, USA;546. Statistical Physics Group, Applied Maths Research Centre, Coventry University, UK;547. Invista Performance Technologies, The Wilton Centre, Cleveland, UK;548. Genome Research, Th\u00fcnen Institute of Forest Genetics, Gro\u00dfhansdorf, Germany;549. Natural Sciences, Lebanese American University, Byblos, Lebanon;550. Evidence and Value Generation, Takeda, Osaka, Japan;551. Stem Cell and Regenerative Medicine, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia;552. Industries - Pulp and Paper, University of Bahri, Khartoum, Sudan;553. Mater Research Institute-The University of Queensland, Mater Medical Research Institute, Brisbane, QLD, Australia;554. NREL, Colorado State University, Fort Collins, CO, USA;555. Ob/Gyn Department, Rzeszow University Hospital, Rzeszow, Poland;556. Faculty of Biological Sciences, University of Leeds, UK;557. Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA;558. Neuroscience, University of Oldenburg, Germany;559. Microbiome Research Centre, St George & Sutherland Clinical School, UNSW Sydney, NSW,z Australia;560. Departments of Biochemistry & Molecular Pharmacology, New York University School of Medicine, NY, USA;561. Medicine/Infectious Diseases, University of Mississippi Medical Center, Jackson, MS, USA;562. Faculty of Social Sciences / Psychology, Tampere University, Finland;563. Department of Biological Sciences, University of Cyprus, Nicosia, Cyprus;564. Institute of Medical Microbiology and Infection Control, Goethe University, Frankfurt, Germany;565. Institute for Radiology, Charit\u00e9 Medical University of Berlin, Germany;566. Internal Medicine I, University Hospital Cologne, University of Cologne, Germany;567. Section of Periodontics, School of Dentistry, University of California Los Angeles, CA, USA;568. Department of Clinical Biochemistry, Aalborg University Hospital, Denmark;569. Pharmacy Practice, Manipal Academy of Higher Education, India;570. Department of Radiology, Institute of Medical Science, The University of Tokyo, Japan;571. Family Medicine, Faculty of Medicine, \u00c7ukurova University, Adana, Turkey;572. Department of Humanities and Social Medicine, College of Medicine, The Catholic University of Korea;573. Food Technology, Safety and Health, Ghent University, Belgium;574. School of Biological, Earth and Environmental Sciences (BEES), UNSW Sydney, NSW, Australia;575. Research Unit, St. Vincent Shoulder & Sports Clinic Vienna, Austria;576. Biomedical Engineering, Cornell University, Ithaca, NY, USA;577. Research Group Bioinformatics And Information Technology, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Germany;578. School of Doctoral Studies, Universidad Europea de Madrid, Spain;579. Biomedical Manufacturing, CSIRO Manufacturing, Melbourne, VIC, Australia;581. Biological Sciences, DePaul University, Chicago, IL, USA;582. Department of Animal Science and Technology, Konkuk University, Seoul, Korea;583. Graduate Institute of Medical Mechatronics, Chang Gung University, Taoyuan, Taiwan;584. Psychiatry, College of Medicine, Korea University, Seoul, Korea;585. Chemistry, Princeton University, NJ, USA;586. Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Henan University of Chinese Medicine, Henan, China;587. Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Germany;588. School of Science, Monash University Malaysia, Selangor, Malaysia;589. Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA;590. Department of Transplantation Medicine, University of Oslo, Norway;591. Triticeae Research Institute, Sichuan Agricultural University, Sichuan, China;592. Gastroenterology, Guangzhou University of Chinese Medicine, Guangzhou, China;593. School of Biological Science & Medical Engineering, Southeast University, Jiangsu, China;594. Biology, Mount Allison University, Sackville, NB, Canada;595. Biology, Ithaca College, Ithaca, NY, USA;596. Department of medical Sciences and Public Health, University of Cagliari, Monserrato, Italy;597. Chromosome Biology, University of Vienna, Austria;598. Nephrology, University of Z\u00fcrich, Switzerland;599. Institute of Nutritional Sciences, Friedrich Schiller University, Jena, Germany;600. Graduate School of Biomedical Engineering, UNSW Sydney, NSW, Australia;601. Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA, USA;602. National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA;603. NCBI, NLM, National Institutes of Health, Bethesda, MD, USA;604. L'Or\u00e9al Research and Innovation, Aulnay sous Bois, France;605. Department of Psychology, Lund University, Malm\u00f6, Sweden;606. Institut de Recherche Exp\u00e9rimentale et Clinique, Universit\u00e9 Catholique de Louvain, Brussels, Belgium;607. Neuroscience Institute, Georgia State University, Atlanta, GA, USA;608. Surgery, Ophthalmology, University of Melbourne, Parkville, VIC, Australia;609. Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, WA, Australia;610. Medical Physics, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran;611. Cellular Neurobiology, Salk Institute, La Jolla, CA, USA;612. Fibrosis Research Group, Imperial College London, UK;613. Genitourinary Medical Oncology, University of Texas MD Andersson Cancer Center, Houston, TX, USA;614. GIGA-Neurosciences, University of Liege, Belgium;615. Urology, School of Medicine, University of Crete, Greece;616. Department of Clinical Pharmacology, Flinders Medical Centre, Flinders University, Adelaide, SA, Australia;617. Bioinformatics, Max Planck Institute of Immunobiology and Epigenetics, Breisgau, Germany;618. School of Psychology, Cardiff University, UK;619. Chemical Engineering, Imperial College London, UK;620. Clinical Sciences, Skane University Hospital, Lund University, Malm\u00f6, Sweden;621. Department of Molecular and Clinical Medicine, Sahlgrenska Academy, Institution of Clinical Science;622. School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston, UK;623. Psychiatry & Clinical Psychology, Hospital Universitario Doctor Peset, Valencia, Spain;624. Genome Dynamics and Function, Centro de Biologia Molecular Severo Ochoa, Madrid, Spain;625. Department of Intensive Care, Unviversity Hospital of Lille, France;626. Surgery, Kansai Medical University, Osaka, Japan;627. Laboratory of Genomics and Biotechnology of Fruit, \u00c9cole Nationale Sup\u00e9rieure Agronomique de Toulouse, Institut National Polytechnique de Toulouse, Universit\u00e9 de Toulouse, France;628. Institute for Psychology, UiT - The Arctic University of Norway, Tromst\u00f8, Norway;629. Centre for Public Health, Queen\u2019s University Belfast, UK;630. Centre for Primary Care and Health Services Research, University of Manchester, UK;631. Menzies Health Institute, Griffith University, Gold Coast, QLD, Australia;632. FHSCE, Anglia Ruskin University, Cambridge, UK;633. Department of Experimental Medicine, Universitat de Lleida, Spain;634. Biomolecular Screening Branch, Division National Toxicology Program, National Institute of Environmental Health Sciences, NC, USA;635. Immunology and Microbial Disease, Albany Medical College, NY, USA;636. Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia;637. School of Biosciences, University of Kent, UK;638. LNC, UMR 1231, Inserm, Universit\u00e9 Bourgogne Franche-Comt\u00e9, Cedex, France;639. Department of Biotechnology, College of Life Sciences, Ritsumeikan University, Shiga, Japan;640. Biological Sciences, Kent State University, OH, USA;641. Department of Safety Research on Blood and Biological Product, National Institute of Infectious Diseases, Tokyo, Japan;642. Laboratory of Microbiology of Extreme Environments, European Institute for Marine Studies, Plouzan\u00e9, France;643. Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, USA;644. Biological Sciences, National University of Singapore;645. Laboratoire GBA, EA4627, Conservatoire National des Arts et M\u00e9tiers, Paris, France;646. Department of Human Genetics, University of Michigan, MI, USA;647. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Russia;648. Department of Molecular Biology, The Jikei University School of Medicine, Tokyo, Japan;649. Genomics & Computational Biology, University of South Wales, Treforest, UK;650. Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA;651. Climate Change Cluster, University of Technology Sydney, NSW, Australia;652. Department of Radiology, Nagoya University Graduate School of Medicine, Aichi Prefecture, Japan;653. School of Science and Health, Western Sydney University, NSW, Australia;654. Department of Speech and Language Therapy, TEI of Epirus, Ioannina, Greece;655. Orthopaedic Surgery, Indiana University-Purdue University, IN, USA;656. Veterinary Pathology, Oniris, Nantes, France;657. Pathobiology and Population Sciences, Royal Veterinary College, Hertfordshire, UK;658. Lab of Pharmaceutical Biotechnology, Ghent University, Belgium;659. Terrestrial Ecology, Norwegian Institute for Nature Research, Trondheim, Norway;660. Molecular and Cell Biology, University of California Merced, CA, USA;661. Centre for Transport Research, School of Engineering, Trinity College Dublin, The University of Dublin, Ireland;662. Nephrology, Institution of Clinical Sciences, Lund University, Malm\u00f6, Sweden;663. Mechanical Engineering, University of Birmingham, UK;664. OB/GYN, Institution of Clinical Sciences, Lund University, Lund, Sweden;665. Nephrology and Hypertension, Fundaci\u00f3n Jim\u00e9nez Diaz Hospital, Madrid, Spain;666. School of Chemistry, Physics and Mechanical Engineering, Queensland University of Technology, Brisbane, QLD, Australia;667. Psychology, Otto-von-Guericke-University, Magdeburg, Germany;668. Department of Experimental Neurodegeneration, University Medical Center G\u00f6ttingen, Germany;669. Physical Medicine and Rehabilitation, Harvard Medical School, Spaulding Rehabilitation Hospital, Boston, MA, USA;670. Scientific Operations, Quadram Institute Bioscience, Norwich, UK;671. Regensburg Medical Image Computing (ReMIC), Ostbayerische Technische Hochschule Regensburg (OTH Regensburg), Germany;672. Faculty of Arts and Education, Deakin University, Melbourne, VIC, Australia;673. Warwick Medical School, University of Warwick, Coventry, UK;674. Biochemistry & Molecular Biology, National Institute for Health and Medical Research (INSERM), Paris, France;675. Tax Institute, Universit\u00e9 de Li\u00e8ge, Belgium;676. School of Molecular and Cellular Biology, University of Leeds, UK;677. UOC Genetica Medica, IRCCS Istituto Giannina Gaslini, Genova, Italy;678. Science, Research Diets, Inc., New Brunswick, NJ, USA;679. Department of Physics and Geology, University of Perugia, Italy;680. Cellular Immunology, Walter Reed National Military Medical Center, Bethesda, MD, USA;681. Microbiology, Immunology and Parasitology Departament, Biological Science Center, Federal University of Santa Catarina, Brazil;682. Centre for Liver and Digestive Disorders, The Royal Infirmary, University of Edinburgh, UK;683. Critical Care Proprietary Products Division, Orion Pharma, Espoo, Finland;684. Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA;685. Department of Veterinary Sciences, University of Turin, Italy;686. Dept. Psychological, Health and Territorial Sciences, University of Chieti, Italy;687. OB-GYN, New York University School of Medicine, New York, NY, USA;688. Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK;689. Department of Biology, University of Turku, Finland;690. Bioanalytics, Technische Universitaet Berlin, Germany;691. University of Goettingen, Third Institute of Physics - Biophysics, Germany;692. Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION), Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;693. Life Sciences, University of Li\u00e8ge, Belgium;694. Department of Toxicology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran;695. Agricultural Research Service, USDA, Stoneville, MS, USA;696. RCI Regensburg Center of Interventional Immunology, University of Regensburg, Germany;697. School of Psychology, University of Nottingham, UK;698. Laboratory of Pathology, National Institutes of Health, Bethesda, MD, USA;699. Electrical Engineering, Universidad Carlos III de Madrid, Spain;700. Chemical Biology, Instituto de Medicina Molecular, Lisbon, Portugal;701. CIET, University of Costa Rica;702. Faculty of Health Sciences, University of Stavanger, Norway;703. Urology, Erasmus University Medical Center, Rotterdam, Netherlands;704. School of Biological Sciences, University of Edinburgh, UK;705. Institute for Bioinformatics and Systems Biology (IBIS), Helmholtz Zentrum M\u00fcnchen-German Research Center for Environmental Health (GmbH), Ingolst\u00e4dter Landstra\u00dfe 1, D-85764 Neuherberg, Germany;706. Huygens-Kamerlingh Onnes Laboratory, Leiden University, Netherlands;707. Nutritional Sciences, University of Vienna, Austria;708. Medicine, Kolling Institute of Medical Research, St Leonards, NSW, Australia;709. Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, MD, USA;710. Medicine / Nutrition and Microbiome Laboratory, Universite de Montreal, Montreal, QC, Canada;711. Cell and Gene Therapy, GlaxoSmithKline, Stevenage, UK;712. Life Sciences, University of Trieste, Italy;713. Department of Radiology, RWTH Aachen University, Aachen, Germany;714. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Germany;715. Obstetrics & Gynecology, Medical University of Vienna, Austria;716. Social and Behavioral Health Sciences Division, FHI 360, Washington, DC, USA;717. VIB Switch Laboratory, VIB-KU Leuven, Belgium;718. Faculty of Technology, Bielefeld University, Germany;719. Department of Gastrointestinal Surgery, Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China;720. Department of Agricultural Chemistry, Meiji University, Kawasakishi, Japan;721. Microbiology, Yonsei University College of Medicine, Seoul, Korea;722. Johnson & Johnson EAME, Maidenhead, UK;723. Pediatrics, Penn State College of Medicine, PA, USA;724. Department of Social Medicine, University of North Carolina at Chapel Hill, NC, USA;725. ARC CoE Plant Energy Biology, The University of Western Australia, Perth, WA, Australia;726. Division of Human Nutrition and Health, Wageningen University, Wageningen, Netherlands;727. Department of Neuroimaging, King\u2019s College London, UK;728. Biochemistry & Molecular Biology, University of Murcia, Spain;729. Department of Biological Sciences, Old Dominion University, Norfolk, VA, USA;730. Biochemistry and Molecular Biology, Monash Univerity, Melbourne, VIC, Australia;731. Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China;732. Pharmacology & Chemical Biology, University of Pittsburgh, PA, USA;733. Center for Integrative Genomics, University of Lausanne, Switzerland;734. School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia;735. Genebank, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Germany;736. Research and Development, Piramal Imaging, Berlin, Germany;737. Civil Engineering, University of Leeds, UK;738. Chemistry and Biochemistry, University of Missouri St. Louis, MO, USA;739. Coastal and Marine Geology Program, US Geological Survey, USGS Pacific Coastal and Marine Science Center, Santa Cruz, CA, USA;740. Ajinomoto-Genetika Research Institute, Moscow, Russia;741. Department of Plant Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krak\u00f3w, Poland;742. Engineering Science and Materials, University of Puerto Rico, Mayag\u00fcez, PR, USA;743. Department of Chemistry and Biochemistry, University of Regina, SK, Canada;744. Center for Nanoscale Materiaals, Argonne National Laboratory, IL, USA;745. Sunshine Coast Mind & Neuroscience - Thompson Institute, University of the Sunshine Coast, QLD, Australia;746. Department of Gastroenterology and Hepatology, The Chinese PLA General Hospital, Beijing, China;747. Griffith Centre for Social and Cultural Research, Griffith University, Gold Coast, QLD, Australia;748. Department of Molecular Oncology, Inst Dev Aging Cancer, Tohoku University, Sendai, Japan;749. Computer Science, Indiana University, Bloomington, IN, USA;750. Department of Pulmonary Medicine, Fukushima Medical University School of Medicine, Fukushima, Japan;751. Biology, MEDIVIR AB, Huddinge, Sweden;752. Neuroimmunology, Western Sydney University, NSW, Australia;753. Nutrition and Food Technology, The University of Jordan;754. Institute of Biodiversity, Federal Research Center for Rura Areas, Forestry and Fisheries, Th\u00fcnen Institute of Forest Genetics, Gro\u00dfhansdorf, Germany;755. Institute of Cell Biology and the Centre for Integrative Physiology, University of Edinburgh, UK;756. Structural Genomics Consortium, University of Toronto, ON, Canada;757. Graduate Education and Research, Canadian Memorial Chiropractic College, Toronto, ON, Canada;758. R&D, Agilent Technologies, Leuven, Belgium;759. School of Nursing, The University of British Columbia, Vancouver, BC, Canada;760. Stroke and Ageing Research, Department of Medicine, School of Clinical Sciences at Monash Health, Monash Univerity, Melbourne, VIC, Australia;761. Biology, Transfer, Innovations, French National Cancer Institute, Boulogne-Billancourt, France;762. NanoBioSciences, Physical Chemistry, Ludwig Maximilians-Universit\u00e4t M\u00fcnchen, Germany;763. Medicinal Chemistry, School of Pharmacy, Bandung Institute of Technology, Indonesia;764. Life Sciences Research Unit, University of Luxembourg;765. Department of Gastroenterology, Skane University Hospital, Lund University, Malm\u00f6, Sweden;766. Translational Genetics, Millennium Health, San Diego, CA, USA;767. Clinical Research and Evidence-Based Medicine Unit, Second Medical Department, Aristotle University Thessaloniki, Greece;768. Department of Psychology, The Jan Kochanowski University in Kielce, Piotrk\u00f3w Trybunalski Branch, Poland;769. Engineering Physics, McMaster University, Hamilton, ON, Canada;770. Department of Agriculture, Food and Environmental Sciences, Marche Polytechnic University, Ancona, Italy;771. Microbiology, Faculty of Medicine, Kuwait University;772. Department of Breast Surgery, Fujita Health University, Aich, Japan;773. Spinal Injuries Centre, North West Regional Spinal Injuries Centre, Merseyside, UK;774. Competence Centre in Methodology and Statistics, Luxembourg Institute of Health;775. Metabolic Health, Nestle Institute of Health Sciences SA, \u00c9cublens, Vaud, Switzerland;776. VIB Center for Inflammation Research, Ghent, Belgium and Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium;777. Curr\u00edculo, forma\u00c7\u00e3o de professores e tecnologia, Instituto de Educa\u00c7\u00e3o da Universidade de Lisboa, Portugal;778. Centre for Inflammation Research, University of Edinburgh, UK;779. School of BioSciences, University of Melbourne, Parkville, VIC, Australia;780. Computer and Information Sciences, Northumbria University, Newcastle upon Tyne, UK;781. Endocrinology, University of Valencia, Spain;782. INRS-Institut Armand-Frappier, INRS, Laval, QC, Canada;783. School of Nutrition, INAF, Universit\u00e9 Laval, Qu\u00e9bec City, QC, Canada;784. Department of Biology, University of Konstanz, Konstanz, Germany;785. Universit\u00e9 C\u00f4te d\u2019Azur, LAMHESS, France;786. Systems Ecology, Scion, Christchurch, New Zealand;787. Epidemiology and Biostatistics, CUNY Graduate School of Public Health and Health Policy, NY, USA;788. School of Dentistry, The University of Queensland, Brisbane, QLD, Australia;789. The Renal and Metabolic Division, The George Institute for Global Health, Sydney, NSW, Australia;790. College of Chemistry & Molecular Sciences, Wuhan University, Hubei, China;791. School of Environment and Science, Griffith University, Gold Coast, QLD, Australia;792. Radiation Oncology, University of Minnesota, Minneapolis, MN, USA;793. Faculty of Medicine, Goethe University, Frankfurt, Germany;794. Department and Graduate School of Safety and Environment Engineering, National Yunlin University of Science & Technology, Taiwan;795. School of Sport, Exercise and Nutrition, Massey University, Auckland, New Zealand;796. Wildlife Ecology and Conservation, University of Florida, Gainesville, FL, USA;797. Department of Psychology, Bournemouth University, Poole, UK;798. Project Group P2, Robert Koch Institute, Berlin, Germany;799. MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, UK;800. Biozentrum, University of Basel, Switzerland;801. School of Medicine, University of Wollongong, Wollongong, NSW, Australia;802. Institute of Human Genetics, University of Cologne, Germany;803. Rural Economics Branch, Economic Reserach Service, Washington, DC, USA;804. Institut de Neurosciences Cognitives et Int\u00e9gratives d\u2019Aquitaine, CNRS, Uiversity of Bordeaux, France;805. Department of Chemical & Environmental Engineering and Materials Science & Engineering Program, University of California Riverside, CA, USA;806. Department of Medicine, Mackay Medical College, New Taipei City, Taiwan;807. Division of Animal Welfare, University of Bern, Switzerland;808. Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR, USA;809. Institute of Interdisciplinary Medical Science, Shanghai University of Traditional Chinese Medicine, Shanghai, China;810. Biology, McMaster University, Hamilton, ON, Canada;811. Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, Tampa, FL, USA;812. Medical Oncology, Hacettepe University Institute of Cancer, Ankara, Turkey;813. Department of Electronic Engineering, City University of Hong Kong, Hong Kong, China;814. Department of Entomology, National Taiwan University, Taipei, Taiwan;815. Ecological Security, Institute of Environment and Sustainable Development in Agriculture, Chinese Academy of Agricultural Sciences, Beijing, China;816. Chemistry and Biochemistry, Institute of Molecular Biophysics, Florida State University, Tallahasse, FL, USA;817. Lab of Computational Chemistry and Drug Design, State Key Laboratory of Chemical Oncogenomics, Peking University Shenzhen Graduate School, Shenzhen,China;818. Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Finland;819. Microbial Biotechnology, Tohoku University, Sendai, Japan;820. Department of Pharmacology, School of Basical Medical Sciences, Tianjin Medical University, Tianjin, China;821. Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, MA, USA;822. Institute of Molecular and Genomic Medicine, National Health Research Institutes, Taiwan;823. Physiology Anatomy and Genetics, University of Oxford, UK;824. Physics, George Washington University, Washington, DC, USA;825. School of Biological Sciences, University of Nebraska-Lincoln, NE, USA;826. Department of Laboratory Medicine and Pathobiology, Toronto General Hospital Research Institute, ON, Canada;827. Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA;828. Department of Chemistry, New York University, NY, USA;829. School of Mathematics and Statistics, Shandong University, Shandong, China;830. Hefei National Laboratory for Physical Science at Microscale and School of Life Sciences, University of Science and Technology of China, Anhui, China;831. Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, USA;832. Advanced Therapies, National Institute for Biological Standards and Control (NIBSC), Herts, UK;833. Department of Pulmonary & Critical Care Medicine, Ruijin Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China;834. Dermatology and Allergy, Charit\u00e9Medical University of Berlin, Germany;835. Hematology, University Hospital of Saint-Etienne, France;836. Institute of Biotechnology, Inland Norway University of Applied Sciences;837. Pediatrics, The University of Jordan;838. Molecular mycology unit, Institut Pasteur, Paris, France;839. Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, UK;840. Social Work, Zurich University of Applied Sciences, Switzerland;841. School of Life Sciences, Jawaharlal Nehru University, New Delhi, India;842. LE2I, University of Burgundy - Franche-Comt\u00e9, Dijon, France;843. Life Sciences, University of Roehampton, London, England;844. General and HPB Surgery, Ghent University Hospital, Belgium;845. Insect-Fungus Symbiosis lab, University of Wuerzburg, Germany;846. Behavioural Science Institute, Radboud University, Nijmegen, Netherlands;847. Application center HOFZET, Fraunhofer WKI, Hannover, Germany;848. Structural and Molecular Biology, University College London, UK;849. Developmental Psychology, University of Amsterdam, Netherlands;850. CNAP, SMI, Health Science and Technology, Aalborg University, Denmark;851. Center for Health Equity Research and Promotion, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA;852. Neurosurgery, Cedars Sinai Medical Center, Los Angeles, CA, USA;853. School of Data and Computer Science, Sun Yat-sen University, Guangzhou, Guangdong, China;854. Shandong Provincial Key Laboratory of Biophysics, Dezhou University, Shandong, China;855. UMR Espace-DEv, Institut de Recherche pour le D\u00e9veloppement, Maison de la T\u00e9l\u00e9d\u00e9tection, Montpellier, France;856. School of Life Sciences, Xiamen University, Fujian, China;857. Department of Medical Imaging, National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China;858. School of Social Policy, Sociology and Social Research, University of Kent, UK;859. Infectious Diseases and Tropical Medicine, Federal University of Minas Gerais, Brazil;860. Life and Health Sciences Research Institute (ICVS) - School of Medicine, University of Minho, Braga, Portugal;861. Biochimie et M\u00e9decine Mol\u00e9culaire, Universite de Montreal, Montreal, QC, Canada;862. Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA;863. Metabolic and Genetic Regulation of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany;864. Health Sciences, University of Swaziland;865. Institute for Future Environments, Queensland University of Technology, Brisbane, QLD, Australia;866. D\u00e9partement de Biologie M\u00e9dicale, Centre Scientifique de Monaco;867. Urology, HELIOS Hospital, Bad Saarow, Germany;868. Institute of Microbiology, Technische Universit\u00e4t Braunschweig, Germany;869. Fetal i+D Fetal Medicine Research Center, IDIBAPS BCNatal \u2014 Barcelona Center for Maternal Fetal and Neonatal Medicine, Hospital Cl\u00ednic and Hospital Sant Joan de D\u00e9u, Universitat de Barcelona, Spain;870. Institute of Bacterial Infections and Zoonoses, Friedrich Loeffler Institut, Jena, Germany;871. Neurology, Charit\u00e9Medical University of Berlin, Germany;872. Molecular Therapeutics for Cancer in Ireland, National Institute for Cellular Biotechnology, Dublin City University, Ireland;875. Institute for Sex Research and Forensic Psychiatry, University Medical Center Hamburg Eppendorf, Germany;876. School of Mathematical Sciences and LPMC, Nankai University, Tianjin, China;877. Oncology, University of Oxford, UK;878. Classics, Royal Holloway, Egham, UK;879. Clinical Sciences, Cornell University, Ithaca, NY, USA;880. Pharmaceutical Chemistry, University of KwaZulu-Natal, Westville Campus, Durban, South Africa;881. Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland;882. Department of Immunology, University of Oslo, Norway;883. Marine Nitrogen Cycling Lab, Bermuda Institute of Ocean Sciences, St. George\u2019s, Bermuda;884. Institute of Liberal Arts and Sciences, Kanazawa University, Japan;885. World Health Organization Regional Office for Africa, Brazzaville, Congo;886. Infection Control Department, University Hospital of Besan\u00c7on, France;887. Clinical Development, Galapagos NV, Mechelen, Belgium;888. Integrated Marine Observing System, University of Tasmania, Hobart, TAS, Australia;889. Department of Systematics, Biodiversity and Evolution of Plants, Albrecht-von-Haller Institute for Plant Sciences, Georg August University of G\u00f6ttingen, Germany;890. Department of Psychiatry, University of Occupational and Environmental Health, Fukuoka, Japan;891. Program of Precision Nutrition and Aging, IMDEA-Food, Madrid, Spain;892. IQHealthcare, Radboud University Medical School, Netherlands;893. Department of Cardiovascular Surgery, Maastricht University, Maastricht, Netherlands;894. Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, D\u00fcsseldorf, Germany;895. Department of Radiology, Juntendo University Graduate School of Medicine, Tokyo, Japan;896. School of Information Technology, Deakin University, Melbourne, VIC, Australia;897. Department of Interface Chemistry and Surface Science, Max-Planck-Institut fur Eusenforschung, Dusseldorf, Germany;898. Department of Psychology, Edge Hill University, Ormskirk, UK;899. Psychiatry, Aga Khan University, Karachi, Pakistan;900. Korean Bioinformation Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB);901. Health Economics and Outcomes Research, Cardinal Health Specialty Solutions, Dallas, TX, USA;902. Division of Clinical Pharmacology, Klinikum der Universit\u00e4t M\u00fcnchen, Germany;903. Neurological Surgery, University of Pittsburgh, PA, USA;904. Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, RWTH Aachen University, Aachen, Germany;905. Institute of Molecular and Cellular Biology, University of Copenhagen, Denmark;906. Structural Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, USA;907. Colorectal Surgery, Royal Shrewsbury Hospital, UK;908. Faculty of Medicine & Health Sciences, University of Nottingham, UK;909. Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden;910. State Key Lab of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Jilin, China;911. Pediatrics, The University of British Columbia, Vancouver, BC, Canada;912. Cotton Germplasm Resources, Research Base in Anyang Institute of Technology, State Key Laboratory of Cotton Biology/Institute of Cotton Research, Chinese Academy of Agricultural Sciences, Beijing, China;913. Anaesthesia and Intensive care, The Chinese University of Hong Kong, Hong Kong, China;914. ICMS, University of Macau, Guangdong, China;915. School of Renewable Energy, North China Electric Power University, Beijing, China;916. Department of Internal Medicine, Justus-Liegbig University, Giessen, Germany;917. Bioscience, Aarhus University, Denmark;918. The Irish Longitudinal Study on Ageing (TILDA), Trinity College Dublin, The University of Dublin, Ireland;919. Hematology, University Medical Center Groningen, University of Groningen, Netherlands;920. Child Neurology, VU University Medical Center, Amsterdam, Netherlands;921. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK;922. HGF MPG Joint Research Group for Deep-Sea Ecology and Technology, Max Planck Institute for Marine Microbiology, Bremen, Germany;923. Center for Adaptive Rationality, Max Planck Institute for Human Development, Berlin, Germany;924. Mathematics, King Faisal University, Hofuf, Saudi Arabia;925. School of Nursing & Midwifery, Griffith University, Gold Coast, QLD, Australia;926. The Roy J. Carver Department of Biochemsitry, Biophysics and Molecular Biology, Iowa State University, Ames, IA, USA;927. Engineering Thermodynamics, Process & Energy Department, Faculty of Mechanical, Maritime and Materials Engineering, Delft University of Technology, Leeghwaterstraat 39, 2628CB, Delft, The Netherlands;928. Cytotechnology Education, College of Allied Health Professions, University of Nebraska Medical Center, Omaha, Nebraska, USA;929. Department of Cardiovascular Medicine, Shinko Memorial Hospital, Kobe, Japan;930. Materials, Imperial College London, UK;931. Department of Surgery, Technical University of Munich, M\u00fcnchen, Germany;932. Laboratory of Quality and Safety Risk Assessment for Fruit (Xingcheng), Ministry of Agriculture, Research Institute of Pomology, Chinese Academy of Agricultural Sciences, Liaoning, China;933. Communication Sciences and Disorders, James Madison University, Harrisonburg, VA, USA;934. Institute for Orthopaedic Research and Biomechanics, University Hospital Ulm, Germany;935. School of Health and Social Care, University of Essex, UK;936. Research Services, Alpha-Altis, Nottingham, UK;937. Medical Oncology, Erasmus University Medical Center, Rotterdam, Netherlands;938. Department of Industrial Chemistry, Federal University Oye, Ekiti, Nigeria;939. Cell Biology, Duke University Medical Center, Durham, NC, USA;940. Nuffield Department of Clinical Neurosciences, University of Oxford, UK;941. Cancer Research UK Manchester Institute, University of Manchester, UK;942. Children\u2019s Hospital, Helsinki University Hospital, Finland;943. Department of Biology, CESAM - Centre for Environmental and Marine Studies, University of Aveiro, Portugal;944. Psychology, University of Botswana, Gaborone, Botswana;945. Nursing School, Federal University of Bahia, Canela, Salvador-Bahia;946. Biological and Experimental Psychology, Queen Mary University of London, UK;947. Medicinal Chemistry Department, National University of Pharmacy, Kharkiv, Ukraine;948. Department of Education and Psychology, University of Bolton, UK;949. Department of Chemistry and Physics, La Trobe University, Melbourne, VIC, Australia;950. Department of Gastroenterology, General Hospital of Northern Theater Command, Liaoning, China;951. Department of Nephrology, Doctors Hospital Athens, Greece;952. Pediatrics III, University Hospital Essen, Germany;953. Infectious Disease Epidemiology, Imperial College London, UK;954. Department of Psychiatry, Sorbonne Universite, Paris France;955. Education, UNSW Sydney, NSW, Australia;956. Department of Psychiatry & Behavioral Sciences, Stanford University, Palo Alto, CA, USA;957. Clinic for Laryngology, Rhinology and Otology, Hannover Medical School, Germany;958. Centre for Aboriginal Studies, Curtin University, Perth, WA, Australia;959. Biomedical Engineering Department, Iran University of Science and Technology, Tehran, Iran;960. Anesthesiology, University of California San Francisco, CA, USA;961. Mechanical Engineering, Khalifa University of Science and Technology, Abu Dhabi, UAE;962. Horticultural Sciences, University of Florida, Gainesville, FL, USA;963. Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, QLD, Australia;964. CINTESIS, Faculty of Medicine, University of Porto, Portugal;965. Medical Research Center, Shaoxing People\u2019s Hospital, Zhejiang, China;966. Department Transfusion Medicine, National Institutes of Health, Bethesda, MD, USA;967. Department of Biotechnology, All India Institute of Medical Sciences (AIIMS), New Delhi, India;968. Biochemistry, Microbiology and Immunology, University of Ottawa, ON, Canada;969. Division of Mental Health and Addiction, Institute of Clinical Medicine, University of Oslo, Norway;970. Department of Radiology, University Medical Center Groningen, University of Groningen, Netherlands;971. School of Nursing, The University of Hong Kong, Hong Kong, China;972. Urology, Tokyo Medical University Ibaraki Medical Center, Japan;973. Department of Radiation Oncology, University Hospital Z\u00fcrich, Switzerland;974. Division of Immunotherapy, Institute of Human Virology and Department of Surgery, University of Maryland, Baltimore, MD, USA;975. Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, South Africa;976. College of Biological Sciences, China Agricultural University, Beijing, China;977. Graduate School of Pharmaceutical Sciences, Osaka University, Japan;978. Biochemistry, University of Washington, Seattle, WA, USA;979. Institute of Bioscience and BioResources, National Research Council of Italy, Naples, Italy;980. Physics, Universit\u00e9 de Lyon, France;981. Center for Social Psychology, Faculty of Psychology, University of Basel, Switzerland;982. Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK;983. Samples, Phenotypes & Ontologies Team, European Bioinformatics Institute (EMBL-EBI), Cambridge, UK;984. Faculty of Arts and Education, Charles Sturt University, Bathurst, NSW, Australia;985. Helmholtz Institute of Biotechnology, State Key Laboratory of Microbial Technology, School of Life Sciences, Shandong University, Shandong, China;986. Department of Biology, Shantou University, Guangdong, China;987. Institute of Biomedical Sciences, Shanxi University, Shanxi, China;988. Computational Biology, St. Jude Children\u2019s Research Hospital, Memphis, TN, USA;989. College of Bioinformatics Science and Technology, Harbin Medical University, Heilongjiang, China;990. Radiology and Imaging Sciences, National Institutes of Health, Bethesda, MD, USA;991. Department of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA;992. XtalPi Inc., Cambridge, MA, USA;993. Bioinformatics, Instituto de Investigaci\u00f3n en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina;994. Save Sight Institute, University of Sydney, NSW, Australia;995. Australian Centre for Precision Health, University of South Australia Cancer Research Institute, University of South Australia, Adelaide, SA, Australia;996. Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, Jinan University, Guangdong, China;997. Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at Houston, TX, USA;998. Department of Microbiology and Immunology, Weill Cornell Medicine, NY, USA;999. Biotechnology Laborary, Guangdong Institute of Applied Biological Resources, Guangdong, China;1000. College of Life Science, Shandong Normal University, Jinan, China;1001. Life Sciences Department, Shandong University, Shandong, China;1002. Integrative Microbiology Research Centre, South China Agriculture University, Guangzhou, Guangdong, China;1003. Crop Molecular Improving Laboratory, Liaoning Academy of Agricultural Sciences, Liaoning, China;1004. Medical Biophysics, Lawson Health Research Institute, London, ON, Canada;1005. Infrastructure Engineering, University of Melbourne, Parkville, VIC, Australia;1006. Faculty of Health, University of Canberra, ACT, Australia;1007. MRC Cognition & Brain Sciences Unit, University of Cambridge, UK;1008. Biostatistics and Bioinformatics, Emory University, Atlanta, GA, USA;1009. Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA;1010. The School of Animal Rural and Environmental Sciences, Nottingham Trent University, Nottingham, UK;1011. Biosciences, University of Exeter, UK;1012. Hillingdon Hospitals NHS Foundation Trust, London, UK;1013. MRC/CSO Social and Public Health Sciences Unit, University of Glasgow, UK;1014. ICU Evaggelismos Athens Hospital, National and Kapodistrian University of Athens, Greece;1015. Biological Sciences, The University of Newcastle, Callaghan, NSW, Australia;1016. Centre for Innovative Research Across the Life Course, Faculty of Health and Life Sciences, Coventry University, UK;1017. Service of Endocrinology, Diabetes and Metabolism, Lausanne University Hospital, Switzerland;1018. School of Community Health, Charles Sturt University, Bathurst, NSW, Australia;1019. Institute for Global Food Security, Queen\u2019s University Belfast, UK;1020. Institute of Policy Studies, National University of Singapore;1021. Intitute doe Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, USA;1022. Cold Spring Harbor Laboratory, NY, USA;1023. EECS, University of Michigan, MI, USA;1024. Centre for Blood Research, The University of British Columbia, Vancouver, BC, Canada;1025. Faculty of Health Sciences, Department of Health and Care Sciences, UiT - The Arctic University of Norway, Troms\u00f8, Norway;1026. Physiotherapy, Hospital of Clinics of Porto Alegre, Brazil;1027. Medical school, University Paris Descartes, Paris, France;1028. Institute of Crop Sciences, National Key Facility for Crop Gene Resources and Genetic Improvement, Chinese Academy of Agricultural Sciences, Beijing, China;1029. Experimental-Clinical and Health Psychology, Ghent University, Belgium;1030. Bioinformatics & Structural Biology, Indian Institute of Advanced Research, Gujart, India;1031. Laboratory of Molecular Medicine, Bambino Ges. Children\u2019s Research Hospital, Rome, Italy;1032. Center of Infectious Disease - Parasitology, University of Heidelberg, Germany;1033. Electrical Engineering, Stanford University, Palo Alto, CA, USA;1034. Biology, University of C\u00e1diz, Andalusia, Spain;1035. general surgery, Mansoura University Hospital, Egypt;1036. Virology pole, Institut Pasteur de Dakar, Senegal;1037. Division of Cancer & Genetics, Cardiff University, UK;1038. Food Safety and Environmental Microbiology, Centre of Expertise and Biological Diagnostic of Cameroon, Yaound\u00e9, Cameroon;1039. Laboratory of Thin Films and Photovoltaics, Swiss Federal Laboratories for Materials Science and Technology, D\u00fcbendorf, Switzerland;1040. Assiut Urology and Nephrology Hospital, Faculty of Medicine, Assiut University, Assiut, Egypt;1041. GEE and IHA, University College London, UK;1042. University of Derby Online Learning, University of Derby, UK;1043. Family, Population and Preventive Medicine, Stony Brook University, NY, USA;1044. Molecular Medicine Division, Walter and Eliza Hall Institute, Melbourne, VIC, Australia;1045. Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK;1046. Clinical Dementia Research, German Center for Neurodegenerative Diseases, Bonn, Germany;1047. UMR 7144, Station Biologique, Sorbonne Universit\u00e9, CNRS, France;1048. Odontoestomatologia, University of Barcelona, Spain;1049. Computer Science, Janelia Research Campus, Ashburn, VA, USA;1050. Centre for Tropical Medicine and Global Health, University of Oxford, UK;1051. ARTORG Center for Biomedical Engineering Research, University of Bern, Switzerland;1052. Eccles Institute of Neuroscience, John Curtain School of Medical Research, The Australian National University, Canberra, ACT, Australia;1053. Metabolic Biology, John Innes Centre, Norwich, UK;1054. Genomics and Bioinformatics Research Unit, USDA Agricultural Research Service, Raleigh, NC, USA;1055. Holzinger Group, Institute for Medical Informatics, Statistics and Documentation, Medical University Graz, Austria;1056. Pharmacy, Ajou University, Suwon, Korea;1057. School of Energy and Environment, City University of Hong Kong, Hong Kong, China;1058. School of Kinseiology, The University of British Columbia, Vancouver, BC, Canada;1059. Department of Biology, Marine Biology Section / University of Copenhagen, Denmark;1060. Department of Communication, University of Vienna, Austria;1061. School of Social Sciences, University of Dundee, UK;1062. Institute of Botany, Technische Universitat Dresden, Germany;1063. Division of Structural Biology, University of Oxford, UK;1064. Medicine, National University Health System, Singapore;1065. School of Biological Sciences, University of Canterbury, Christchurch, New Zealand;1067. Primary Care Health Sciences, University of Oxford, UK;1068. National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Bethesda, MD, USA;1069. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA;1070. Department of Public Health Nursing, Faculty of Nursing, Adnan Menderes University Aydin, Turkey;1071. Department of Neurology IC, Oasi Research Institute - IRCCS, Troina, Italy;1072. Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA;1073. King\u2019s Centre for Military Health Research, King\u2019s College London, UK;1074. Department of Infectious Diseases Epidemiology, LSHTM, London, UK;1075. BMWZ - Organic chemistry, University Hannover, Germany;1076. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi\u2019an Jiaotong University, Shaanxi, China;1077. School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia;1078. Department of Physical Education, Federal University of Santa Catarina, Florian\u00f3polis, Brazil;1079. Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China;1080. Hansen Experimental Physics Laboratory, Stanford University, Palo Alto, CA, USA;1081. Institute of Translational Medicine, Shenzhen Second People\u2019s Hospital, The First Affiliated Hospital of Shenzhen University, Guangdong, China;1082. Department of Statistics and Actuarial Science, The University of Hong Kong, Hong Kong, China;1083. Department of Mechanical Engineering, University College London, UK;1084. Laboratory of Microbial Immunity, Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore;1085. State Key Laboratory of Powder Metallurgy, Central South University, Hunan, China;1086. Institute of Applied Health Sciences, University of Aberdeen, UK;1087. Biomedical Engineering, University of Bridgeport, CT, USA;1088. Pharmaceutical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, USA;1089. Ecosystem and Conservation Sciences, University of Montana, Missoula, MT, USA;1090. Department of Systems Neuroscience, University of Goettingen, Germany;1091. School of Public Affairs, Penn State Harrisburg, PA, USA;1092. Bristol Medical School, University of Bristol, UK;1093. Water Resources and Environmental Modeling, Czech University of Life Sciences, Prague, Czech Republic;1094. Neurology, Gardner Family Center for Parkinson\u2019s Disease and Movement Disorders, University of Cincinnati, OH, USA;1095. Melbourne School of Population and Global Health, University of Melbourne, Parkville, VIC, Australia;1096. Christie Patient Centred Research, The Christie NHS Foundation Trust, Manchester, UK;1097. Environmental Health Science and Engineering, Jimma University;1098. Laboratory of Systems Genetics, National Heart, Lung, and Blood Institute, Bethesda, MD, USA;1099. Department of Medicine, University of Oslo, Norway;1100. Medicine, University of Sydney, NSW, Australia;1101. Clarendon Laboratory, Department of Physics, University of Oxford, UK;1102. Biochemistry, University of Cambridge, UK;1103. Biochemical Plant Physiology, Heinrich Heine University, Duesseldorf, Germany;1104. Department of Respiratory Medicine, Norfolk and Norwich University Hospital NHS Foundation Trust, UK;1105. Imaging, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA;1106. Nutrition and Dietetics, College of Nursing and Health Sciences, Flinders University, Adelaide, SA, Australia;1107. School of Medicine, University of Dundee, UK;1108. Laboratory of Optics and Dynamics of Biological Systems, Novosibirsk State University, Russia;1109. Department of Mathematics, University of Padova, Italy;1110. Clinical Research, London School of Tropical Medicine, UK;1111. Sciences naturelles, UQO, Ripon, QC, Canada;1112. Faculty of Law, Lund University, Lund, Sweden;1113. Department of Microbiology and Immunology, University of Gothenburg, Sweden;1114. Biology Department, Stanford University, Palo Alto, CA, USA;1115. Department of Genetics and Biosystematics, University of Gdansk, Poland;1116. Kachwekano Zardi, National Agricultural Research Organization (NARO), Entebbe, Uganda;1117. Bachelor Program in Interdisciplinary Studies, National Yunlin University of Science &Technology, Yunlin County, Taiwan;1118. Clinical Genome Analysis Branch, National Cancer Center, Goyang, Korea;1119. Danish Research Institute of Translational Neuroscience (DANDRITE), Department of Biomedicine, Aarhus University, Aarhus, Denmark;1120. Biostatistics, Yale University, New Haven, CT, USA;1121. Centre de Recherches Insulaires et Observatoire de l\u2019Environnement (CRIOBE), PSL University Paris: EPHE-UPVD-CNRS USR 3278 CRIOBE, University of Perpignan via Domitia, France;1122. Mathematics and Computer Sciences, Eduardo Mondlane University, Maputo, Mozambique;1123. Department of Old Age Psychiatry and Psychotherapy, University of Bern, Switzerland;1124. Kinesiology and Health Science, Biola University, La Mirada, CA, USA;1126. Laboratory of Cytology of Unicellular Organisms, Institute of Cytology RAS, Saint Petersburg, Russia;1127. Faculty of Engineering and Information Technology, University of Wollongong, Wollongong, NSW, Australia;1128. School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing, China;1129. Food Processing, Research Institute of Food Science and Technology (RIFST), Mashhad, Iran;1130. Cell and Developmental Biology, Centre for Genomic Regulation, Barcelona, Spain;1131. Queensland Alliance for Agriculture and Food Innovation, The University of Queensland, Brisbane, QLD, Australia;1132. Cell Biology, Rostock University Medical Center, Germany;1133. Genetics and Genomics, The Roslin Institute, University of Edinburgh, UK;1134. Biochemistry, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE;1135. Genomics Centre & Centre for Integrative Ecology, Deakin University, Geelong, VIC, Australia;1136. Division of Rehabilitation and Agein, University of Nottingham, UK;1137. Engineering, University of Nottingham, UK;1138. Immunology, Garvan Institute, Sydney, NSW, Australia;1139. Auckland Bioengineering Institute, University of Auckland, New Zealand;1140. Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, University of Basel, Switzerland;1141. Inhalation Toxicology, Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover, Germany;1142. Department of Rheumatology and Internal Medicine, Wroclaw Medical University, Poland;1143. BCRT, Charit\u00e9 Medical University of Berlin, Germany;1144. Public Health, The University of Hong Kong, Hong Kong, China;1145. Experimental Psychology, University of Oxford, UK;1146. School of Life Sciences, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, Central China Normal University, Hubei, China;1147. Department for Internal Medicine II, University Clinic Krems, Karl Landsteiner University for Health Sciences;1148. Anesthesia and Pain Medicine, University Health Network and University of Toronto, ON, Canada;1149. Institute of Earth and Environmental Science, University of Potsdam, Germany;1150. Department for Health, University of Bath, UK;1151. Institute of Organic Chemistry, Justus-Liegbig University, Giessen, Germany;1152. Computational and RNA Biology, University of Copenhagen, Denmark;1153. Bedford Institute of Oceanography, Fisheries and Oceans Canada, Dartmouth, NS, Canada;1154. Integrative Medicine & Clinical Naturopathy, Institute for Social Medicine, Epidemiology and Health Economics, Charit\u00e9 Medical University of Berlin, Germany;1155. Physical Biology, BMLS, CEF-MC, Goethe Universit\u00e4t, Frankfurt am Main, Germany;1156. Viral Diseases, Sciensano, Ixelles, Belgium;1157. Department of Psychiatry, Faculty of Medicine, Public Health and Nursing, Gadjah Mada University, Yogyakarta, Indonesia;1158. Anatomy and Structural Biology, Albert Einstein College of Medicine, New York City, NY, USA;1159. Nephrology and Hypertension, St. Marianna University, Kanagawa, Japan;1160. Office of the Queensland Chief Scientist, Department of Environment and Science, Queensland Government, Brisbane, QLD, Australia;1161. Department of Surgical Sciences, Section of Vascular Surgery, Uppsala University, Uppsala, Sweden;1162. Animal Science, University of Connecticut, Storrs, CT, USA;1163. Research, Children\u2019s Cancer Hospital, Cairo, Egypt;1164. Department of Earth, Ocean, and Atmospheric Science, Florida State University, Tallahasse, FL, USA;1165. Unit\u00e9 Biologie Fonctionnelle et Adaptative (BFA) CNRS UMR8251, Universit\u00e9 Paris Diderot, Paris, France;1166. School of Biochemistry, University of Bristol, UK;1167. Department of Anatomy, Faculty of Medicine, Trakia University, Stara Zagora, Bulgaria;1168. Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany;1169. Institute of Research and Development, Duy Tan University, Da Nang, Vietnam;1170. Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Finland;1171. Department of Animal Biology, Federal University of Technology Minna, Nigeria;1172. Institute of Chinese Medical Sciences, University of Macau, Guangdong, China;1173. Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia;1174. Research Institute of Petroleum Industry (RIPI), NIOC, Tehran, Iran;1175. Bioanalysis, Ghent University, Belgium;1176. Department of Dermatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China;1177. School of Business, Dalian University of Technology, Liaoning, China;1178. Faculty of Kinesiology, University of Calgary, AB, Canada;1179. Department of Psychological Medicine, Weston Education Centre, King\u2019s College London, UK;1180. Chief Scientist, The George Institute for Global Health, Sydney, NSW, Australia;1181. Radiology and Chemistry, UCSF, San Francisco, CA, USA;1182. Griffith Institute for Drug Discovery, Griffith University, Brisbane, QLD, Australia;1183. Centre of Biology and Health Sciences, Mackenzie Presbyterian University, S\u00e3o Paulo, Brazil;1184. Neuropsychiatry, University of Pennsylvania, Philadelphia, PA, USA;1185. School of Environmental and Municipal Engineering, Tianjin Chengjian University, Tianjin, China;1186. Shandong Provincial Key Laboratory of Biophysics, College of Physics and Electronic Information, Dezhou University, Dezhou, China;1187. Int Med-Hematology/Oncology, University of Michigan, MI, USA;1188. College of Life Sciences, Henan Agricultural University, Zhengzhou, China;1189. Department of Transufusion Medicine, National Institutes of Health, Bethesda, MD, USA;1190. Beijing Children\u2019s Hospital, Capital Medical University, Beijing, China;1191. Public health, The University of Tokyo, Japan;1192. Biomedical Genomics and Oncogenetics Research Laboratory, Faculty of Sciences and Techniques of Tangier, Abdelmalek Essaadi University, Morocco;1193. The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China;1194. Department of Medicine, University of Illinois at Chicago, IL, USA;1195. Department of Occupational Health, School of Public Health, Shaanxi University of Chinese Medcine, Shaanxi, China;1196. Department of Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Guizhou, China;1197. State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China;1198. Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China;1199. Institute of Biophysics, Dezhou University, Shandong, China;1200. Pathology, Fudan University Shanghai Cancer Center, Shanghai, China;1201. Department of Physics, Covenant University, Ota, Nigeria;1202. Institute of Evolutionary Biology, University of Edinburgh, UK;1203. Department of Physical Therapy and Health Rehabilitation, Prince Sattam Bin Abdulaziz University, Al Kharj, Saudi Arabia;1204. Chemical Engineering, Loughborough University, UK;1205. Physiotherapy, Umm Al-Qura University, Mecca, Saudi Arabia;1206. Department of Computer Science, University of Liverpool, UK;1207. Cognitive Science, Lund University, Malm\u00f6, Sweden;1208. Department of Public and Environmental Health, National Open University of Nigeria, Abuja, Nigeria;1209. Department of Social Policy and Intervention, University of Oxford, UK;1210. Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel;1211. Department of Biology and Ecology, Faculty of Science, University of Ostrava, Czech Republic;1212. Agricultural Sciences, University of Helsinki, Finland;1213. Bioinformatics Unit, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany;1214. Mathematics Education, University of Regensburg, Germany;1215. Public Health, Ghana Health Services;1216. The Wales Centre for Podiatric Studies, Cardiff Metropolitan University, Cardiff, UK;1217. Institute of Public Health - Section of Hygiene, Catholic University of the Sacred Heart, Rome, Italy;1218. Computational Bioscience Program, University of Colorado Anschutz Medical Campus, CO, USA;1219. Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, China;1220. Menzies Centre for Health Policy, School of Public Health, University of Sydney, NSW, Australia;1221. College of Life Sciences, Heilongjiang University, Harbin, China;1222. Department of Computer Science, University of Southern California, Los Angeles, CA, USA;1223. Department of Electrical and Computer Engineering, University of Auckland, New Zealand;1224. College of Life Sciences, Zhejiang Sci-Tech University, Zhejiang, China;1225. College of Chemistry and Chemical Engineering, Xianyang Normal College, Shannxi, China;1226. Research Center of TCM Information Engineering, Beijing University of Chinese Medicine, Beijing, China;1227. Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea;1228. Maternal and Child Health Division, International Centre for Diarrhoeal Diseases Research, Bangladesh;1229. Department of Forensic Medicine, University of Copenhagen, Denmark;1230. Biological Sciences, University of Southampton, UK;1231. Cardiac surgery, Niguarda Hospital, Milan, Italy;1232. Hearing and Speech Sciences, Vanderbilt University, Nashville, TN, USA;1233. Faculty of Biology, Medicine and Health, University of Manchester, UK;1234. Clinic for Horses, University of Veterinary Medicine Hannover, Germany;1235. NeuroPSI - UMR9197, CNRS, France;1236. Agricultural Economics, Bangladesh Agricultural University;1237. Department of Surgical Oncology, The Second Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, Zhejiang, China;1238. Laboratory of Medical Genetics, Harbin Medical University, Heilongjiang, China;1239. State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China;1240. Biology, Natural History Museum of Denmark;1241. Department of Psychology, University of Saskatchewan, Saskatoon, SK, Canada;1242. Laboratoire Mati\u00e8re et Syst\u00e8mes Complexes, Universit\u00e9 Paris Diderot, France;1243. Epidemiology and Biostatistics, Bahir Dar University, Ethiopia;1244. Centre of Studies in Geography and Spatial Planning (CEGOT), University of Coimbra, Portugal;1245. Computer Science and Engineering, University of Nebraska-Lincoln, NE, USA;1246. Epidemiology, University Medical Center Groningen, University of Groningen, Netherlands;1247. Department of Radiology, University College London Hospital NHS Foundation Trust, and Division of Surgery & Interventional Science, University College London, London, UK;1248. Department of Neurology and Neurosurgery, South Central High Specialty Hospital, Pemex, Mexico;1249. College of Information Science and Engineering, Shandong Agricultural University, Taian, Shandong, China;1250. College of Life Sciences, Sichuan University, Sichuan, China;1251. National drug Research Institute, Curtin University, Perth, WA, Australia;1252. Gibson Lab, Stowers Institute for Medical Research, Kansas City, MO, USA;1253. Bacteriology and Epidemiology, Wageningen Bioveterinary Research, Lelystad, Netherlands;1254. General Practice, University Medical Center G\u00f6ttingen, Germany;1255. Novo Nordisk Foundation Center for Protein Research, Proteomics Program, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark;1256. Department of Rheumatology and Immunology, Guangdong Second Provincial General Hospital, Guangzhou, China;1257. Biomedical Rngineering, Erasmus University Medical Center, Rotterdam, Netherlands;1258. Pharmacology and Toxicology, University Medical Center Goettingen, Goettingen, Germany;1259. Graduate School of Biomedical & Health Sciences, Hiroshima University, Japan;1260. Science and Engineering, University of the Sunshine Coast, QLD, Australia;1261. Center for Advancing Electronics Dresden, Technische Universitat Dresden, Germany;1262. School of Health Sciences, University of Iceland, Reykjav\u00edk, Iceland;1263. Health Promotion, Ministry of Health and Child Care, Zimbabwe;1264. Material Science and Engineering, The Ohio State University, Columbus, OH, USA;1265. Computational and Systems Biology, University of Pittsburgh, PA, USA;1266. School of Chemical Biology & Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China;1267. School of Materials, University of Manchester, UK;1268. DPECS, Erasmus University Rotterdam, Netherlands;1269. Molecular Biology, Centro de Biologia Molecular Severo Ochoa, Madrid, Spain;1270. Radiotherapy and Imaging, The Institute of Cancer Research, London, UK;1271. Neurology, Ewha Womans University School of Medicine and Ewha Medical Research Institute, Seoul, Korea;1272. Plastic and Reconstructive Surgery, Matsunami General Hospital, Kasamatsu, Japan;1273. Department of Dermatology, University Medical Center Groningen, University of Groningen, Netherlands;1274. Centre for Global Health Research, University of Edinburgh, UK;1275. Department of Construction Management, Harbin Institute of Technology, Heilongjiang, China;1276. Institute of Zoology, University of Veterinary Medicine Hannover, Germany;1277. National Laboratory of Solid State Microstructures, Department of Physics, and Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, China;1278. Proteomics, Biomedical Research Foundation, Academy of Athens, Greece;1279. Genomics, ICAR-National Research Centre on Plant Biotechnology, New Delhi, India;1280. School of Public Health, The University of Hong Kong, Hong Kong, China;1281. Health Sciences, George Davies Centre for Medicine, University of Leicester, UK;1282. Bioengineering, University of Illinois at Chicago, IL, USA;1283. Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Greece;1284. Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, China;1285. Faculty of Health and Wellbeing, Sheffield Hallam University, Sheffield, UK;1286. Bioinformatics Institute, University of Missouri, Columbia, MO, USA;1287. Quality Functional Unit, Hospital Doctor Moliner, Valencia, Spain;1288. Plants and Crops, Ghent University, Belgium;1289. Department of Biomedical and Neuromotor Sciences, University of Bologna, Italy;1290. Center for Micro-Biorobotics, Istituto Italiano di Tecnologia, Genoa, Italy;1291. Department of Bioinformtaics and Biostatistics, Shanghai Jiao Tong University, Shanghai, China;1292. Health System Strengthening, Baylor College of Medicine Children\u2019s Foundation - Uganda;1293. Medical Cell BioPhysics, University of Twente, Enschede, Netherlands;1294. Department of Pharmaceutical Sciences, University of Kashmir;1295. Biologic and Materials Sciences, University of Michigan, MI, USA;1296. Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia;1297. School of Medicine, Shanghai Jiao Tong University, Shanghai, China;1298. Surgery, Aga Khan University, Karachi, Pakistan;1299. School of Veterinary Science, Massey University, Auckland, New Zealand;1300. Department of Clinical Psychology and Psychotherapy, Institute of Psychology, University of Freiburg, Germany;1301. Centre for Integrative Ecology, Deakin University, Melbourne, VIC, Australia;1302. State Key Laboratory Of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Liaoning, China;1303. Social Psychology, Tilburg University, Netherlands;1304. Emergency Medicine, University of Wisconsin-Madison, WI, USA;1305. Learning Informatics Management and Ethics (LIME), Karolinska Institute, Solna, Sweden;1306. Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX, USA;1307. Department of Psychiatry, University Hospital of Reims, France;1308. Department of Inorganic and Analytical Chemistry, Rzeszow University of Technology, Poland;1309. Centre for Biotechnology, Siksha O Anusandhan Universityr, Odisha, India;1310. School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia;1311. Institute of Health Promotion and Clinical Movement Science, German Sport University Cologne, Germany;1312. Department for Gynecology and Obstetrics, University Hospital Essen, Germany;1313. M\u00e9decine Sociale et Pr\u00e9ventive, Universite de Montreal, Montreal, QC, Canada;1314. Intitute for Separation and Process Technology, University of Technology Clausthal, Germany;1315. Edmond & Lily Safra Center for Brain Sciences, Hebrew University of Jerusalem, Israel;1316. Department of Pathology, University of California San Diego, CA, USA;1317. Department of Physiotherapy, Kathmandu University School of Medical Sciences, Dhulikhel, Nepal;1318. Accounting and Finance, University of Limerick, Ireland;1319. Division of Nursing, Midwifery and Social Work, School of Health Sciences, Faculty of Biology, Medicine and Health, University of Manchester, UK;1320. School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia;1321. Division of Psychiatry, University College London, UK;1322. Image Guided Therapies, Fraunhofer MEVIS, Bremen, Germany;1323. Polymer Science and Engineering, University of Science and Technology of China, Anhui, China;1324. Haematology-Oncology, National University Health System, Singapore;1325. Laboratory of Marine Biotechnology, Institute of Bioscience, Universiti Putra Malaysia, Selangor, Malaysia;1326. Breast Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China;1327. Unit of Bacteriology-Virology, Centre de Recherche Medicale et Sanitaire, Niamey, Niger;1328. Laboratory Animal Centre, Bengbu Medical College, Anhui, China;1329. Pharmacology and Toxicology, Medical College of Wisconsin, Wauwatosa, WI, USA;1330. School of Chemistry, Physics and Mechanical Engineering, Science and Engineering Faculty, Queensland University of Technology, Brisbane, QLD, Australia;1331. Institution for Social Medicine and Family Medicine, School of Public Health, Zhejiang University, Hangzhou, Zhejiang, China;1332. School of Computer Science and Technology, Harbin Institute of Technology, Heilongjiang, China;1333. Electrical and Computer Engineering, Mississippi State University, Mississippi State, MS, USA;1334. Department of Molecular Biotechnology and Health Sciences, University of Turin, Italy;1335. Electrical and Computer Engineering, University of Toronto, ON, Canada;1336. Physiotherapy Department, School of Rehabilitation, Tehran University of Medical Sciences, Iran;1337. Department of Occupational Health, School of Health, Shiraz University of Medical Sciences, Iran;1338. Department of Forest Sciences, University of Helsinki, Finland;1339. Department of Surgery, Weifang Medical University, Weifang, China;1340. School of Computational Science and Engineering, Georgia Institute of Technology, Atlanta, GA, USA;1341. Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, China;1342. Computer Science and Technology, Tsinghua University, Beijing, China;1343. Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China;1344. Human Pathology, University of Messina &AO Papardo Hospital Messina, Italy;1345. Institute of Child Health, College of Medicine, University of Ibadan, Nigeria;1346. Paediatric Surgery, University Hospital of Alexandroupolis, Dragana, Greece;1347. Faculty of Ophthalmology, College of Medicine, King Faisal University, Al-Hasa, Saudi Arabia;1348. Department of Hematology. Sultan Qaboos University Hospital, Al Khod, Oman;1349. Gulfstream Genomics, Gulfstream Diagnostics, Dallas, TX, USA;1350. Institute of Molecular Medicine, University of Southern Denmark, Denmark;1351. Institute for Social Marketing, University of Stirling, UK;1352. Laboratory Sciences & Services Division, International Centre for Diarrhoeal Diseases Research, Bangladesh;1353. Social Determinants of Health Research Center, Saveh University of Medical Sciences, Saveh, Iran;1354. Gakujutsu Shien Co. Ltd., Tokyo, Japan;1355. Institute of Geochemistry, Chinese Academy of Sciences, Guiyang, China;1356. Medical School, University of Plymouth, UK;1357. CDER/OPQ/OBP/DBRRII, U.S. Food and Drug Administration, Silver Spring, MD, USA;1358. Department of Endocrinology, Affiliated Hospital of Jining Medical University, Shandong, China;1359. Pediatric Hematology/Oncology, Children\u2019s Hospital &Medical Center, Omaha, NE, USA;1360. PWMHU, SJOG Burwood Hospital and UNSW Sydney, NSW, Australia;1361. immunology, CHU de Toulouse, France;1362. Medicine, Harvard Medical School, Boston, MA, USA;1363. Cardiology, Barts Health NHS Trust, London, UK;1364. Centre for Ecology, Evolution and Environmental Changes, Azorean Biodiversity Group and Universidade dos A\u00e7ores, Azores, Portugal;1365. Social Psychology, University of Valencia, Spain;1366. Department of Advanced Biomedical Sciences, University of Naples \u201dFederico II\u201d, Italy;1367. Orthopaedic Surgery, Rochester General Hospital, Pittsford, NY, USA;1368. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan;1369. Medicine, Columbia University Medical Center, New York, NY, USA;1370. Holistic Education Center, Mackay Medical College, New Taipei City, Taiwan;1371. Physiology, Southeast University, Jiangsu, China;1372. Division of Epidemiology, Indian Council of Medical Research, National Institute of Cholera and Enteric Diseases, India;1373. Department of Global Health, School of Public Health, Peking University, Beijing, China;1375. Department of Neurology, Chang Gung Memorial Hospital Linkou Medical Center and College of Medicine, Chang-Gung University, Taoyuan, Taiwan;1376. Cardiology, Saint Luke\u2019s Mid America Heart Institute, Kansas City, MO, USA;1377. Biomedical Sciences and Pharmacy Departments, College of Medicine, University of Malawi, Blantyre, Malawi;1378. Genomics Research Center, Academia Sinica, Taipei, Taiwan;1379. Instituto de Ciencias Biologicas, Universidade Federal de Goias, Goi\u00e2nia, Brazil;1380. Retina department, Cl\u00ednica Vista, Lima, Per\u00fa1381. Department of Immunology and Oncology, National Center for Biotechnology (CNB-CSIC), Madrid, Spain;1382. Pathology Department, CHU Bic\u00eatre, France;1383. Biocuration, Bioself Communication, Marseille, France;1384. School of Biomedical Engineering, School of Ophthalmology &Optometry and Eye Hospital, Wenzhou Medical University, Zhejiang, China;1385. Pediatrics I, Renmin Hospital, Hubei University of Medicine, Hubei, China;1386. Anesthesiology, Perioperative Care and Pain Medicine, New York University School of Medicine, New York, NY, USA;1387. Histology, Zagazig University, Egypt;1388. Department of Neurology, Peking University Third Hospital, Beijing, China;1389. Department of Pathology, College of Health Sciences, Faculty of Basic Clinical Sciences, Ahmadu Bello University, Zaria, Nigeria;1390. School of Computer and Communication Engineering, University of Science and Technology, Beijing, China;1391. Caribbean Institute for Health Research, The University of the West Indies, Jamaica;1392. Human Pathology of the Adult and Evolutive Age \u201dGaetano Barresi\u201d, Section of General Surgery, University of Messina, Italy;1393. Ageing Clinical and Experimental Research (ACER) Team, University of Aberdeen, UK;1394. Ophthalmology, Massachusetts Eye Research and Surgery Institution, Waltham, MA, USA;1395. Child & Adolescent Psychiatry, Child Study Center at Hassenfeld Children\u2019s Hospital of New York at NYU Langone, NY, USA;1396. Department of Thoracic Surgery, National Cancer Center / Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China;1397. Endowed Health Services Research, School of Medicine, University of Puerto Rico, Mayag\u00fcez, PR, USA;1398. Pathology and Hamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA;1399. Department of Anesthesia, Pain Management, and Perioperative Medicine, Dalhousie University, Halifax, NS, Canada;1400. Faculty of Mathematics & Technology, Koblenz University of Applied Sciences, Germany;1401. VisMederi srl, Siena, Italy;1402. Medicine, Ross University School of Medicine, Miramar, FL, USA;1403. Cancer Research UK and UCL Cancer Trials Centre, University College London, UK;1404. Department of Critical Care, University of Alberta, Edmonton, AB, Canada;1405. Critical Care Medicine, Dalhousie University, Halifax, NS, Canada;1406. Clinical Haematology, Palmerston North Hospital, New Zealand;1407. Family Medicine, University of Ottawa, ON, Canada;1408. College of Engineering, China Agricultural University, Beijing, China;1409. NHMRC Clinical Trials Centre, University of Sydney, NSW, Australia;1410. Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Netherlands;1411. Biomedical Sciences Department of ESTESC - Coimbra Health School, Polytechnic Institute of Coimbra, Portugal;1412. Department of Interventional Radiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China;1413. Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, TN, USA;1414. Infectious Diseases, American University of Beirut Medical Center, Beirut, Lebanon;1415. Pediatrics, University of New Mexico, Albuquerque, NM, USA;1416. Department of Social Work, Social Care and Community Studies, Sheffield Hallam University, Sheffield, UK;1417. Pulmonary Diseases, Critical Care & Environmental Medicine, Tulane University School of Medicine, New Orleans, LA, USA;1418. Viral Hepatitis, Mechnikov Research Institute for Vaccines and Sera, Moscow, Russia;1419. Neurosurgery, Duke University Medical Center, Durham, NC, USA;1420. Internal Medicine, University T\u00fcbingen, Germany;1421. Pediatrics, University of Ottawa, ON, Canada;1422. Medicine, Penn State College of Medicine, Hershey, PA, USA;1423. Urology, University of Texas Health Science Center at San Antonio, TX, USA;1424. Department for Wound Infection Treatment and Prevention, Vreden Russian Research Institute of Traumatology and Orthopaedics, St. Petersburg, Russia;1425. Medicine, Western University, London, ON, Canada;1426. Laboratoire Canc\u00e9rologie Mammaire / Institut J. Bordet, Universit\u00e9Libre de Bruxelles (ULB), Brussels, Belgium;1427. College of Life Science and Technology, Huazhong University of Science and Technology, Hubei, China;1428. Department for TB Control and Prevention, Hangzhou Center for Disease Control and Prevention, Zhejiang, China;1429. Institute of Aging Research, School of Medicine, Hangzhou Normal University, Zhejiang, China;1430. Department of Rheumatology and Clinical Immunology, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China;1431. Department of Biotechnology, Kaohsiung Medical University, Taiwan;1432. Oncology, West China Hospital, Sichuan, China;1433. School of Medicine, University of California Irvine, CA, USA;1434. Diagnostics, Zoetis, Kalamazoo, MI, USA;1435. Clinical Pathology Laboratory, Vito Fazzi General Hospital, Lecce, Italy;1436. Head and Neck Oncology Research, Aintree University Hospital NHS Trust, Liverpool, UK;1437. Department of Otolaryngology, Head Neck Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China;1438. Trauma & Orthopaedics, Wrightington Hospital, Wigan, Greater Manchester, UK;1439. Physical and Environmental Sciences, University of Toronto, Scarborough, ON, Canada;1440. Microbiology and Immunology, University of Rochester, NY, USA;1441. Department of Psychiatry, Loyola University Medical Center, Maywood, IL, USA;1442. Microbiology, Atkins Veterinary Services, Calgary, AB, Canada;1443. Microbiology, Golestan University of Medical Sciences, Iran;1444. CIAFEL, FADEUP, University of Porto, Portugal;1445. Hematology-Oncology, Mashhad University of Medical Science, Iran;1446. Global Health, Stellenbosch University, South Africa;1447. Anaesthesiology, Kovai Medical Center and Hospital, Tamilnadu, India;1448. Saw Swee Hock School of Public Health, National University of Singapore;1449. Pediatric cardiology, Queen Alia Heart Institute, Royal Medical Services, Amman;1450. Department of Food Science and Biotechnology, College of Biotechnology and Bioscience, Kangwon National University, Chuncheon, Korea;1451. Internal Medicine, Kakatiya Medical College, Telangana, India;1452. Otolaryngology, St. Paul\u2019s Hospital, Vancouver, Canada;1453. Neurology, Kakatiya Medical College and Mahatma Gandhi Memorial Hospital, Warangal, India;1454. CIBAV Research Group, Veterinary Medicine School, University of Antioquia, Medellin, Colombia;1455. Paediatrics, King\u2019s College Hospital NHS Trust, London, UK;1456. Neurosurgery, Carlo Besta Neurological Institute Milan, Italy;1458. Department of Clinical Microbiology and Microbial Pathogenesis, School of Medicine, University of Crete, Greece;1459. Soft and Active Matter Group, Department of Physics, Indian Institute of Science Education and Research (IISER) Tirupati, Andhra Pradesh 517507,India;1460. Center of Studies in Physical Activity Measurements, School of Medicine and Health Sciences, Universidad del Rosario, Bogota D.C, Colombia;1461. Medicine, Rheumatology, St. Clares Mercy Hospital, St. Johns, NL, Canada;1462. Department of Community Dentistry and Population Health, University of Colorado Anschutz Medical Campus, CO, USA;1463. Cardiology and Vascular Medicine, University Hospital Essen, Germany;1464. Endocrinology, University Hospital Basel, Switzerland;1465. Institute of Medical Genetics and Applied Genomics, University T\u00fcbingen, Germany;1466. Department of Medicine D, Division of General Internal Medicine, Nephrology, and Rheumatolog, University Hospital M\u00fcnster, Germany;1467. Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA;1468. Department of Nephrology, University of Kentucky, Lexington, KY, USA;1469. Emergency Medicine, University of Missouri, Columbia, MO, USA;1470. Department of Anaesthesiology and Critical Care, Medical Centre, University of Freiburg, Germany;1471. Quality and Safety, Children\u2019s Hospital of The King\u2019s Daughters, Norfolk, VA, USA;1472. Research, IIHMR University, Rajasthan, India;1473. Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA;1474. Infectious Diseases, Cincinnati Children\u2019s Hospital Medical Center, OH, USA;1475. Mood Disorders Psychopharmacology Unit, University Health Network, Toronto, ON, Canada;1476. Department of Medicine, University of California Irvine, Orange, CA, USA;1477. Center for Reliability Science and Technology, Chang Gung University, Taoyuan, Taiwan;1478. Gastroenterology, Profensa, La Pampa, Argentina;1479. Centre for Global Development and Institute of Applied Health Sciences, University of Aberdeen, UK;1480. Ophthalmology, Harvard Medical School, Boston, MA, USA;1481. Department of Urology, University Hospitals Leuven, Belgium;1482. Medical School, University of Talca, Chile;1483. Institute of Biotechnology and Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan;1484. College of Life Sciences, Chinese Academy of Sciences, Beijing, China;1485. Department of Obstetrics and Gynaecology, Medical and Health Sciences, University of Auckland, New Zealand;1486. School of Clinical Medicine, University of Cambridge, UK;1487. Orthopaedics & Rehabilitation, University of Florida, Gainesville, FL, USA;1488. Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA;1489. Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China;1490. Department of Pulmonary &Critical Care Medicine, Chinese PLA General Hospital, Beijing, China;1491. Department of Chemical Engineering, Tsinghua University, Beijing, China;1492. Institute of Intelligent Machines, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Anhui, China;1493. Department of Instrumental and Electrical Engineering, Xiamen University, Fujian, China;1494. Department of Pharmacology, Yonsei University College of Medicine, Seoul, Korea;1495. Nephrology, Walter Reed National Military Medical Center, Bethesda, MD, USA;1496. Department of Pediatrics, Eastern Virginia Medical School, Children\u2019s Hospital of The King\u2019s Daughters, Norfolk, VA, USA;1497. Department of Mathematics, College of Science, China Three Gorges University, Yichang, China;1498. College of Information Engineering, Xiangtan University, Hunan, China;1499. Mood Disorders and Psychopharmacology, University Health Network, Toronto, ON, Canada"} +{"text": "Correction to: Arthritis Res Ther (2021) 23:5https://doi.org/10.1186/s13075-020-02372-zSujatha Muralidharan: Kiniksa Pharmaceuticals Corp, Lexington, MA 02421, USANatalia V. Giltiay: Division of Rheumatology, Department of Medicine, School of Medicine, University of Washington, 750 Republican St, Seattle, WA 98109, USAFollowing publication of the original article , a typesThe original article has been"} +{"text": "The affiliation for the forty-fourth author is incorrect. Tao Ai is not affiliated with #23 but with #24: Chengdu Women\u2019s & Children\u2019s Central Hospital, Chengdu, China.Additionally, Tao Ai should be noted as having also contributed equally to this work with: Lina Chen, Mingfang Shi, Quanmin Deng, Wenjun Liu, Qin Li, Piao Ye, Xiahui Yu, Benjin Zhang, Yuxia Xu, Xiaolan Li, Yao Yang, Min Li, Yi Yan, Zhe Xu, Jing Yu, Long Xiang, Xiaojun Tang, Guangping Wan, Qiang Cai, Li Wang, Bo Hu, Tao Ai."} +{"text": "J Clin Endocrinol Metab. 2020; doi: 10.1210/clinem/dgaa653), the following transcriptional error occurred in the Advance Article version of the published paper: \u201cTorben Hansen\u2019s name was misspelled in the author list.\u201dIn the above-named article by Deshmukh HA, Madsen AL, Vi\u00f1uela A, Have CT, Grarup N, Tura A, Mahajan A, Heggie AJ, Koivula RW, De Masi F, Tsirigos KK, Linneberg A, Drivsholm T, Pedersen O, S\u00f8rensen TIA, Astrup A, Gjesing AAP, Pavo I, Wood AR, Ruetten H, Jones AG, Koopman ADM, Cederberg H, Rutters F, Ridderstrale M, Laakso M, McCarthy MI, Frayling TM, Ferrannini E, Franks PW, Pearson ER, Mari A, Hansen T, and Walker M (The spelling of Torben Hansen\u2019s name has been corrected in the final published version.10.1210/clinem/dgaa653Doi:"} +{"text": "Scientists have created the most detailed map of the fruit fly brain to date, identifying over 25,000 neurons and 20 million synapses. Related research article Scheffer LK, Xu CS, Januszewski M, Lu Z, Takemura SY, Hayworth KJ, Huang GB, Shinomiya K, Maitlin-Shepard J, Berg S, Clements J, Hubbard PM, Katz WT, Umayam L, Zhao T, Ackerman D, Blakely T, Bogovic J, Dolafi T, Kainmueller D, Kawase T, Khairy KA, Leavitt L, Li PH, Lindsey L, Neubarth N, Olbris DJ, Otsuna H, Trautman ET, Ito M, Bates AS, Goldammer J, Wolff T, Svirskas R, Schlegel P, Neace E, Knecht CJ, Alvarado CX, Bailey DA, Ballinger S, Borycz JA, Canino BS, Cheatham N, Cook M, Dreher M, Duclos O, Eubanks B, Fairbanks K, Finley S, Forknall N, Francis A, Hopkins GP, Joyce EM, Kim S, Kirk NA, Kovalyak J, Lauchie S, Lohff A, Maldonado C, Manley EA, McLin S, Mooney C, Ndama M, Ogundeyi O, Okeoma N, Ordish C, Padilla N, Patrick CM, Paterson T, Phillips EE, Phillips EM, Rampally N, Ribeiro C, Robertson MK, Rymer JT, Ryan SM, Sammons M, Scott AK, Scott AL, Shinomiya A, Smith C, Smith K, Smith NL, Sobeski MA, Suleiman A, Swift J, Takemura S, Talebi I, Tarnogorska D, Tenshaw E, Tokhi T, Walsh JJ, Yang T, Horne JA, Li F, Parekh R, Rivlin PK, Jayaraman V, Costa M, Jefferis GS, Ito K, Saalfeld S, George R, Meinertzhagen I, Rubin GM, Hess HF, Jain V, Plaza SM. 2020. A connectome and analysis of the adult Drosophila central brain. eLife9:e57443. doi: 10.7554/eLife.57443Every thought, feeling and action emerges from the electrical interplay of billions of neurons in the brain \u2013 wired together by an intricate network of cables that connect through hundreds of billions of synapses. Therefore, to fully understand how the brain works we need to consider all parts of the brain and the connections between them.A connectome is a comprehensive map of the structural and functional neural connections in the brain that enables scientists to explore and compare different pathways, circuits and regions. Creating such a map is a difficult endeavor: neurons are minuscule, and their extensive branches are even smaller .Caenorhabditis elegans (whose brain only consists of 302 neurons), it took the better part of a decade to generate a comprehensive connectome generated a connectome for one half of the largely symmetrical fly brain, comprising over 25,000 neurons and 20 million synapses . To achiNeuprint\u2019,\u00a0and anyone can search the database for a neuron of interest, observe the images it was traced from, plot it in 3D and see which brain regions it interacts with is low \u2013 three quarters of neurons were linked by three or fewer interneurons. Moreover, they demonstrated that the different neuropils are indeed segregated electrically, suggesting that the same neuron can perform separate computations in different regions at the same time.Of course, no map is perfect. Most branches traced belong to yet unidentified neurons (presumably the ones that reside outside the borders of the sequenced brain). Many of the tiniest twigs that are difficult for both human and machine eyes to trace may have been missed or lie \u2018disconnected\u2019 from their true parent neuron, which may reside in the other unmapped half of the brain. This could potentially reduce the number of synapses between two cells.C. elegans and will undoubtedly help unravel the neurological basis underlying a fly\u2019s behavior. And it may bring us one step closer to creating connectomes of larger animals, including vertebrates.Scheffer et al. have pledged to improve and update their connectome over time \u2013 after all, another half of the fly brain remains to be analyzed. Nevertheless, the current map marks a significant increase in scale over the one of"} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-64115-z, published online 30 April 2020Correction to: In the original version of this Article, Nhung Thi Trang Trinh was incorrectly affiliated with \u201cInstitute of Biotechnology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Ha Noi, Vietnam\u201d and \u201cUniversity of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Ha Noi, Vietnam\u201d.The correct affiliations for Nhung Thi Trang Trinh are listed below.Architecture et Fonction des Macromol\u00e9cules Biologiques, Aix-Marseille Universit\u00e9, UMR 7257, 163 Avenue de Luminy, Case 932, 13009, Marseille, France.Architecture et Fonction des Macromol\u00e9cules Biologiques, Centre National de la Recherche Scientifique, UMR 7257, 163 Avenue de Luminy, Case 932, 13009, Marseille, France.Faculty of Medical Technology, PHENIKAA University, Yen Nghia, Ha Dong, Hanoi 12116, Vietnam.PHENIKAA Research and Technology Institute (PRATI), A&A Green Phoenix Group JSC, No. 167 Hoang Ngan, Trung Hoa, Cau Giay, Hanoi 11313, VietNam.This has now been corrected in the PDF and HTML versions of the Article."} +{"text": "In the following article,The correct list of author names is listed below:Nadine Kerr, W. Dalton Dietrich, Helen M. Bramlett, Ami P. Raval."} +{"text": "Acer cinnamomifolium (Aceraceae) is a plant species endemic to China. In our present study, the complete chloroplast (cp) genome sequence of Acer cinnamomifolium was assembled from Illumina pair-end sequencing data. The complete cp genome sequence of A. cinnamomifolium was 156,227\u2009bp in size. Totally, 139 genes were identified, including 88 protein-coding genes, 40 transfer RNAs, 8 ribosomal RNA genes, and 3 pseudogenes . Phylogenetic analysis results showed that A. cinnamomifolium is sister to Acer sino-oblongum, with a support rate of 100%. Acer cinnamomifolium is an evergreen tree species endemic to China. It is mainly distributed in Zhejiang, Fujiang, Jiangxi, Hubei, Hunan, Guangdong, and Guangxi province. It features grey to blackish-grey bark, leathery leaves, yellowish-green petals, and brownish-yellow fruit. Acer cinnamomifolium mainly grows in broadleaf forests at altitudes of 300\u20131200\u2009m and this tree species can be used as a promising ornamental garden plant. The chloroplast (cp) genome of A. cinnamomifolium has not been reported. In this study, we assembled the complete cp genome of A. cinnamomifolium and generated a phylogenetic tree to understand its relationship with other Acer species.de novo assembled by NOVOPlasty , Yueqing City, Wenzhou, Zhejiang province, China. The sample was sealed in a plastic bag and taken to the laboratory. The voucher CHS2017085) is stored at the Molecular Biology Laboratory at Taizhou University. Leaf DNA was extracted following Doyle and Doyle . A 150\u2009b085 is stA. cinnamomifolium cp genome (GenBank accession: MN414240) is 156,227\u2009bp, and its overall GC content is 37.9%. The genome is comprised of two inverted repeats (IRs), a large single copy (LSC), and a small single copy (SSC), and their sizes are 26,079, 85,928, and 18,121\u2009bp, respectively. There are 89 protein-coding genes, 40 tRNAs, 8 rRNAs, and 3 pseudogenes in the plastome genome. Most genes occur as single-copy, while 22 genes contain two copies, these include ndhB, orf42, rpl2, rpl32, rps7, rps12, rrn4.5, rrn5, rrn16, rrn23, trnA-UGC, trnI-CAU, trnI-GAU, trnL-CAA, trnM-CAU, trnN-GUU, trnR-ACG, trnT-GGU, trnV-GAC, ycf1, ycf2, and ycf15. Three genes, infA, ycf1, and rps2, are proved to be pseudogenes.The plastome sequence was annotated using Dual Organellar GenoMe Annotator (DOGMA), tRNAscan-SE, and ARAGORN as the outgroup. The Acer plant species for ML tree construction were Acer laevigatum, Acer palmatum, Acer wilsonii, Acer buergerianum, Acer truncatum, Acer miaotaiense, Acer catalpifolium, Acer davidii, Acer morrisonense, Acer griseum, and Acer sino-oblongum. Our results indicated that A. cinnamomifolium grouped with A. sino-oblongum, and the bootstrap support value was 100%, revealing their close phylogenetic relationship (A maximum-likelihood (ML) phylogenetic tree including tionship ."} +{"text": "Ahmad, ShaadLiu, KarenAtukorallaya, DeviLorenz, BirgitBlaner, William S.Lu, LinchaoBraendle, ChristianMarcoli, ManuelaBrand, ThomasMaves, LisaCampione, MarinaMu\u00f1oz-Ch\u00e1puli, Ram\u00f3nCoultas, LeighNarayanan, S. PriyaCrawford, Bryan D.Noelle, DwyerDamjanovski, SashkoOsna, NataliaDu, ShaojunOs\u00f3rio, DanielDurand, B\u00e9atrice C.Oxford, JuliaDworkin, SebastianPal, KasturiErskine, LyndaPettitt, JonathanEsteve-Altava, BorjaPiekny, AlisaFantin, AlessandroPons, SebastianFay, DavidPopoff, StevenFlaherty, KevinPruyne, DavidFrancis, MichaelRasskin-Gutman, DiegoFrand, AlisonRichtsmeier, JoanGerhardt, ChristophSchneider-Maunoury, SylvieGreen, RebeccaShaham, ShaiGritli-Linde, AmelShlizerman, EliHall, David H.Sommer, Ralf J.Henry, ClarissaSucov, HenryIshizaki, YasukiTaghibiglou, ChangizIwata, JunichiTolwinski, NicholasJaurand, Marie-ClaudeTylzanowski, PrzemkoJohnston, ChristopherVadigepalli, RajanikanthKelly, RobertWingert, RebeccaKugler, Matthias ChristianZiermann, JanineLe Guellec, DominiqueThe editorial team greatly appreciates the reviewers who have dedicated their considerable time and expertise to the journal\u2019s rigorous editorial process over the past 12 months, regardless of whether the papers are finally published or not. In 2019, a total of 20 papers were published in the journal, with a median time to first decision of 22 days and a median time from submission to publication of 51 days. The editors would like to express their sincere gratitude to the following reviewers for their generous contribution in 2019:"} +{"text": "Abarca, CarlaJiang, Xiao-TaoAchim, CristinaJones, MelissaAli, AliJu\u00e1rez-Maldonado, AntonioAlShamrani, NouraKananavi\u010di\u016bt\u0117, R\u016btaAnaya-L\u00f3pez, Jose LuisKarlsson, IsabellaAshour, Mohamed LotfyKato, RyujiBec, KrzysztofKhalilia, Walid MahmoudBhattacharya, AnannyaLeung, IvanhoeBobko, NaraLong, YichengBorges, Alisson CarraroLuo, PingpingBurgos-Aceves, Mario AlbertoMr\u00e1z, JaroslavBussadori, Sandra KalilNagai, KouheiCaldeira, MichaelPham, Thang V.Carlsson, Henrik (Sweden)Philip, NebuCarlsson, Henrik (USA)Qualley, DominicCastiglia, MartaRezvani, EhsanChan, Ka LungRodr\u00edguez-Ruano, Sonia Mar\u00edaChan, WanRouleau, EtienneChen, SimingR\u00f3\u017cycki, BartoszChen, XunSalawu, EmmanuelCieplik, FabianSantos, ClesivanColeman, JonathanSchmitz, KatjaDe Rond, TristanSchneiderhan-Marra, NicoleDemertzis, KonstantinosShin, Dong-SikDeshpande, GauraviSignorini, CinziaElaiw, Ahmed M.Smyth, Gordon K.Font, RafaelSzostak, RomanGallo, GiovanniTan, Bertrand Chin-MingGarner, AngieTsoukalas, DimitrisGuo, JingshuUchida, ShizukaHu, GangVan Campen, Julia C.Hu, QiwenVladimirov, Vladimir I.Huang, DongweiWrenger, SabineHuang, Ruo-PanXia, TianHuang, XiaohuZhang, JinyangHufert, Frank T.Zheng, Yongqi Ji, ShaofeiThe editorial team greatly appreciates the reviewers who have dedicated their considerable time and expertise to the journal\u2019s rigorous editorial process over the past 12 months, regardless of whether the papers are finally published or not. In 2019, a total of 18 papers were published in the journal, with a median time to first decision of 16.5 days and a median time from submission to publication of 48 days. The editors would like to express their sincere gratitude to the following reviewers for their generous contribution in 2019:"} +{"text": "Author Contributions section. The wording used to declare the contribution of Elisabeth Zechendorf was not clear.In the original article, there was an error in the Author Contributions section appears below.The new In vitro experiments and data analyses: EZ, LM, TS, T-PS, AM, GM-N, OK, GM, and PV. Medical in silico experiments and data analyses: EZ, PV, JZ, GD, AS, LM, AH, and GA. EZ wrote the manuscript. Correction of the manuscript: EZ, PV, LM, CT, GM, GD, T-PS, and AS. All the authors reviewed and finally approved the manuscript.Conception and design: EZ, LM, GD, AS, and CT. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The authors\u2019 first and last names are incorrectly switched throughout the article. The publisher apologizes for the error. Please view the correct author byline, citation, and author contributions here:Andrea Moglia, Francesco Elia Florio, Sergio Iacopino, Alessandra Guerrieri, Anna Maria Milani, Cinzia Comino, Lorenzo Barchi, Arianna Marengo, Cecilia Cagliero, Patrizia Rubiolo, Laura Toppino, Giuseppe Leonardo Rotino, Sergio Lanteri, Laura BassolinoS. melongena L.). PLoS ONE 15(5): e0232986. https://doi.org/10.1371/journal.pone.0232986Moglia A, Florio FE, Iacopino S, Guerrieri A, Milani AM, Comino C, et al. (2020) Identification of a new R3 MYB type repressor and functional characterization of the members of the MBW transcriptional complex involved in anthocyanin biosynthesis in eggplant (Conceptualization: Andrea Moglia, Cinzia Comino, Laura Bassolino.Data curation: Andrea Moglia, Sergio Iacopino, Lorenzo Barchi, Arianna Marengo, Cecilia Cagliero, Patrizia Rubiolo, Laura Bassolino.Investigation: Andrea Moglia, Francesco Elia Florio, Sergio Iacopino, Alessandra Guerrieri,Anna Maria Milani, Lorenzo Barchi, Arianna Marengo, Laura Toppino, Laura Bassolino.Supervision: Andrea Moglia, Laura Bassolino.Writing\u2013original draft: Andrea Moglia, Laura Bassolino.Writing\u2013review & editing: Andrea Moglia, Francesco Elia Florio, Cinzia Comino, Lorenzo Barchi, Laura Toppino, Giuseppe Leonardo Rotino, Sergio Lanteri, Laura Bassolino."} +{"text": "Mencacci, Regina Reynolds, Sonia Garcia Ruiz, Jana Vandrovcova, Paola Forabosco, Alvaro S\u00e1nchez-Ferrer, Viola Volpato, UK Brain Expression Consortium, International Parkinson\u2019s Disease Genomics Consortium, Michael E. Weale, Kailash P. Bhatia, Caleb Webber, John Hardy, Juan A. Bot\u00eda, Mina Ryten. Dystonia genes functionally converge in specific neurons and share neurobiology with psychiatric disorders. Brain 2020; 143: 2771\u20132787. doi:The publisher apologizes for erroneously publishing an incorrect version of this manuscript. This has been corrected."} +{"text": "Correction to: BMC Womens Health (2020) 21:46https://doi.org/10.1186/s12905-020-01010-9Following publication of the original article , we wereAssistant Professor, Vir Chandra Singh Garhwali Government Institute of Medical Science and Research, Srinagar, Pauri Garhwal, Uttarakhand, IndiaIncorrect affiliation:MD, Senior Resident, Department of Community & Family Medicine, All India Institute of Medical Sciences, Bhopal, MP, India.Correct affiliation:"} +{"text": "Environmental enteric dysfunction (EED) may be an important modifiable cause of child stunting. We described the evolution of EED biomarkers from birth to 18 months in rural Zimbabwe and tested the independent and combined effects of improved water, sanitation, and hygiene (WASH), and improved infant and young child feeding (IYCF), on EED.The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial was a 2x2 factorial cluster-randomised trial of improved IYCF and improved WASH on child stunting and anaemia at 18 months of age. 1169 infants born to HIV-negative mothers provided plasma and faecal specimens at 1, 3, 6, 12, and 18 months of age. We measured EED biomarkers that reflect all domains of the hypothesized pathological pathway. Markers of intestinal permeability and intestinal inflammation declined over time, while markers of microbial translocation and systemic inflammation increased between 1\u201318 months. Markers of intestinal damage (I-FABP) and repair (REG-1\u03b2) mirrored each other, and citrulline increased from 6 months of age, suggesting dynamic epithelial turnover and regeneration in response to enteric insults. We observed few effects of IYCF and WASH on EED after adjustment for multiple comparisons. The WASH intervention decreased plasma IGF-1 at 3 months and plasma kynurenine at 12 months , and increased plasma IGF-1 at 18 months , but these small WASH effects did not translate into improved growth.Overall, we observed dynamic trends in EED but few effects of IYCF or WASH on biomarkers during the first 18 months after birth, suggesting that these interventions did not impact EED. Transformative WASH interventions are required to prevent or ameliorate EED in low-income settings. Child stunting remains a global health challenge rooted in an intergenerational cycle of poor health, reduced neurodevelopment and poverty. Environmental enteric dysfunction (EED) is an acquired condition of the small intestine likely resulting from frequent faecal-oral microbial exposure, which is hypothesized to underlie stunting. We found dynamic changes in EED biomarkers between 1 and 18 months of age in a cohort of rural Zimbabwean infants, suggesting a complex developmental period of intestinal maturation, adaptation and response to environmental insults. Randomized improved infant and young child feeding, and improved water, sanitation and hygiene (WASH) interventions had no meaningful impact on EED. Greater investment in transformative WASH is needed to prevent EED in low-income countries. Child stunting, defined as an attained length or height >2 standard deviations below the age- and sex-matched standard population median , is a peThree decades ago, tropical enteropathy was proposed as an important factor in undernutrition ,11. ThisThere is no agreed case definition for EED. Differential urinary excretion of two sugars, typically lactulose and mannitol, has most often been used to characterize abnormalities in gut permeability and absorption, but this test has substantial limitations ,18 and oThe Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial was a clhttps://osf.io/w93hy. SHINE was a 2x2 factorial cluster-randomised trial assessing the individual and combined effects of improved IYCF and improved WASH on child stunting and anaemia at 18 months of age . A total of 211 clusters, defined as the catchment area of 1\u20134 Village Health Workers (VHWs) employed by the Ministry of Health and Child Care (MoHCC), were allocated to one of four intervention groups using highly constrained randomization: standard-of-care (SOC); IYCF; WASH; or IYCF+WASH. Between 22 November 2012 and 27 March 2015, pregnant women living in these clusters were enrolled following written informed consent. VHWs delivered treatment group-specific behavior change interventions and commodities during 15 home visits, between enrolment and 12 months postnatal. Between 13\u201317 months, VHWs made monthly visits to provide routine care, deliver intervention commodities in active groups, and encourage participants to practice behaviors relevant to their study arm. At 18 months a review module, which reiterated key messages, was implemented in all arms. Commodities and behavior change communication messages delivered in the four treatment groups were:A detailed description of the SHINE trial design and methods has been published , and theSOC: promotion of exclusive breastfeeding to 6 months [6 months , and uptWASH: SOC interventions plus a ventilated improved pit (VIP) latrine, two handwashing stations, plastic mat and play yard ; monthly delivery of soap and chlorine solution with promotion of safe disposal of feces, handwashing with soap, protection of infants from geophagia, chlorination of drinking water, and hygienic preparation of complementary food.IYCF: SOC interventions plus 20g small-quantity lipid-based nutrient supplement (SQ-LNS) to be fed to the infant daily from 6\u201318 months; education and counseling to feed the infant nutrient-dense locally available food, feeding during illness, and dietary diversity.WASH+IYCF: All SOC, WASH, and IYCF interventions.A latrine was constructed in SOC and IYCF arms after completion of the trial. Due to the nature of the interventions, masking was not possible.Research nurses made two home visits during pregnancy and five postnatal visits at infant ages 1, 3, 6, 12, and 18 months. At baseline, maternal education and age, household wealth, access to water and sanitation, and food insecurity were assessed; mothers were tested for HIV via rapid test algorithm and HIV-positive women were urged to seek immediate care for prevention of mother-to-child transmission. Infant birth date, weight, and delivery details were transcribed from health facility records; the trial provided Tanita BD-590 infant scales to all health institutions in the study area and trained facility staff. Gestational age at delivery was calculated from the date of the mother\u2019s last menstrual period.Given the household-based trial interventions, visits were not conducted if the mother had moved from the household where she consented, except for the 18-month visit when follow-up was conducted anywhere within Zimbabwe. Indicators of uptake of the interventions were collected at all visits and reported here for the 12-month postpartum visit.Part-way through the trial (from mid-2014 onwards) mother-infant pairs were invited to join a substudy to investigate biomarkers of EED. Women were informed about the EED substudy at their 32-week gestation visit and those with live births were enrolled at the 1 month postnatal visit, or as soon as possible thereafter. We pre-specified that primary trial inferences would be based on findings among infants born to mothers who were HIV-negative during pregnancy, because of the likely impact of HIV exposure and infant cotrimoxazole prophylaxis on underlying causal pathways . ResultsFrom children in the EED substudy, additional specimens were collected at each postnatal visit, including stool (passed on the morning of the research visit and collected by the mother into a plain container) and blood, collected by venepuncture into an EDTA tube. In the field laboratory, EDTA tubes were centrifuged to collect plasma, which was stored at -80\u00b0C. Stool specimens were transported in a cold box to the field laboratory, aliquoted into plain tubes and stored at -80\u00b0C. Samples were subsequently transferred to the Zvitambo Laboratory in Harare for long-term storage at -80\u00b0C until analysis.We selected a range of biomarkers that would characterize the domains of EED. These were previously described, together with the rationale for each , with thet al. [All assays were undertaken by laboratory scientists masked to the trial intervention arm. Plasma samples were tested at the Zvitambo laboratory by Enzyme Linked Immunosorbent Assay (ELISA) according to manufacturers\u2019 instructions for CRP (limit of detection (LOD) 0.01ng/mL), soluble CD14 (LOD 125pg/mL), IGF-1 (LOD 0.026ng/mL) ; and I-FABP (LOD 47pg/mL); Hycult Biotechnology, Uden, The Netherlands. Stool samples were tested at the Zvitambo laboratory by ELISA according to manufacturers\u2019 instructions for neopterin , myeloperoxidase , A1AT , and REG\u20101\u03b2 . Plasma citrulline (LOD 100ng/mL), kynurenine (LOD 40ng/mL), and tryptophan (200ng/mL) were assayed by ultrahigh-performance liquid chromatography tandem mass spectrometry with electrospray ionization at Imperial College, London. Urine samples were tested on a Shimadzu Prominence liquid chromatograph with a Restek Ultra Amino 3\u03bcm 150/2.1mm column and tandem Sciex QTRAP5500 mass spectrometer with a Turbo V ion source and TurboIonSpray probe at Pain Care Specialists of Oregon, USA. Both analytes were quantified against lab-made calibrators at ng/mL levels of 3250, 2500, 1250, 750, 350, 100, 10, and 1. The calibrator was confirmed each day by lab-made quality control samples at 150 and 750ng/mL. Lactulose for calibrators and control were obtained from Spectrum Chemical (LOD 1ng/mL). Mannitol was obtained from Tokyo Chemical Industry (LOD 1ng/mL). Both internal standards were obtained from Sigma-Aldrich. Citrulline and KTR were not measured at 18 months (no funding for samples). We also calculated the environmental enteropathy score (EE score) proposed by Kosek et al. , as a coThe substudy was based on a sample size of 250 children per trial arm with longitudinal assessments of EED, after allowing for missed samples and loss to follow-up. Assuming an average of 2\u20133 infants per cluster, type I error of 5%, and a coefficient of variation across clusters of 0.25 provides >80% power to detect a difference of at least 0.18 standard deviations between WASH and non-WASH arms, or between IYCF and non-IYCF arms.AER [sandwich package [geepack package [All analyses were intention-to-treat at the child level. Independent intervention effects of IYCF and WASH, as well as IYCF-by-WASH interaction effects, were evaluated by fitting separate regression models with each biomarker as the dependent variable. Independent variables included IYCF and WASH coded as dummy variables and an IYCF-by-WASH interaction term. If the interaction was not significant (p>0.05) and if the interaction term was <0.25 standard deviations in absolute magnitude, main intervention effects were tested to compare IYCF to non-IYCF and WASH to non-WASH groups in separate models. Except for citrulline and EE score, tobit regression was used to account for unobserved biomarker values below the LOD using the package AER , and san package , both in package . All bio package . RegressWomen gave written informed consent to join the trial and additional consent for their infant to join this substudy. Both the SHINE trial and this substudy were approved by the Medical Research Council of Zimbabwe and the Institutional Review Board of the Johns Hopkins Bloomberg School of Public Health.Of 5280 women enrolled in the SHINE trial, there were 3989 live births to 3937 HIV-negative mothers; of these, 1169 (29%) infants were enrolled in the EED substudy. Of the 1169 enrolled infants, 33 (2.8%) died and 31 (2.7%) were lost to follow-up or exited before the 18-month visit . A furthBaseline characteristics of mother-infant pairs who were enrolled versus not enrolled in the EED substudy are shown in At the 12-month study visit, among EED households in the WASH arms, 97% received ventilated improved pit latrines, almost all received handwashing stations and play mats, more than 96% received play yards, and >80% received 80% or more of the planned deliveries of soap and chlorine solution . Among hChanges over time in each biomarker between 1\u201318 months of age, by randomized treatment arm, are shown in Figs Myeloperoxidase was quite stable around geometric mean of 7518ng/mL (95%CI:7014\u20138059) between 1 and 6 months, then rapidly declined thereafter to 2825ng/mL (95%CI:2669\u20132991) at 18 months. Neopterin showed a minor increase from 1 to 6 months of age (from 980nmol/L (95%CI:908\u20131057) to 1283nmol/L (95%CI:1230\u20131337)), followed by a steep decline to 383nmol/L (95%CI:362\u2013407) at 18 months.Biomarkers of intestinal damage showed more variable patterns .Stool REG-1\u03b2, a marker of epithelial regeneration, increased linearly from 40.6\u03bcg/mL (95%CI:36.4\u201345.1) at 1 month to 154.6\u03bcg/mL (95%CI:145.5\u2013164.2) at 12 months, with a small decrease to 132.9\u03bcg/mL (95%CI:123.1\u2013143.6) at 18 months. Plasma citrulline, a marker of small intestinal epithelial mass, was approximately 2744ng/ml (95%CI:2658\u20132834) from 1 to 6 months, but increased to 3150ng/mL (95%CI:3075\u20133227) by 12 months. Plasma I-FABP, which reflects small intestinal villous damage, showed a U-shaped pattern, declining from 1031pg/mL (95%CI:993\u20131021) at 1 month to 913pg/mL (95%CI:892\u2013934) at 6 months, followed by an increase to 1198pg/mL (95%CI:1160\u20131237) at 18 months.Markers of intestinal permeability decreased during the 18 month follow-up period. Stool A1AT decreased linearly from 0.47mg/mL (95%CI:0.44\u20130.51) at 1 month to 0.24mg/mL (95%CI:0.22\u20130.25) at 18 months . UrinaryCRP increased between 1 and 18 months, from 0.63mg/L (95%CI:0.55\u20130.71) to 1.28mg/L (95%CI:1.14\u20131.43). However, KTR declined from 64.8 at 1 month to approximately 44.9 between 6\u201312 months.Soluble CD14, a marker of microbial translocation, showed a pronounced increase from 769,192pg/mL at 1 month to 1,334,175 pg/mL at 18 months. Finally, IGF-1, which is produced by the liver in response to growth hormone, declined rapidly from 27.1 ng/mL (26.0\u201328.2) at 1 month to a fairly stable minimum around 17.9ng/mL at 12 months (17.4\u201318.5) .There was no consistent evidence of interaction between IYCF and WASH for any biomarker based on our prespecified criteria, so inteRelative to the non-WASH group, stool A1AT was 1.17 times higher and stooIn this substudy of over 1000 HIV-unexposed infants from the SHINE birth cohort in rural Zimbabwe, we investigated the evolution of EED during infancy and evaluated the impact of improved water, sanitation and hygiene, and improved infant feeding on biomarkers of EED. We measured biomarkers that reflect different aspects of intestinal structure and function, microbial translocation, systemic inflammation and growth hormone activity at 1, 3, 6, 12, and 18 months of age, to capture the entire hypothesized pathway from the gut to growth . OverallWe report changes over time for the largest number of EED biomarkers in infants to date. Biomarker trends were similar within EED structural and functional domains but varied between domains. In general, markers of intestinal permeability and intestinal inflammation declined over time, whilst markers of microbial translocation and systemic inflammation increased between 1\u201318 months of age. Markers of intestinal damage (I-FABP) and repair (REG-1\u03b2) generally mirrored each other, and citrulline increased from around 6 months of age, suggesting a dynamic process of epithelial turnover and regeneration in response to enteric insults during infancy. The increase in citrulline at 6 months may also be attributable to the introduction of solid foods around that time, since dietary supplementation can increase plasma citrulline . The higOverall, we found few effects of the randomized interventions on biomarkers in this large cohort of infants. Compared to the non-IYCF group, we observed a decrease in neopterin at 18 months in the IYCF group after adjusting for multiple testing. Neopterin is a marker of monocyte and macrophage activation by T-helper 1 (TH1) cells in response to infection. An improved nutrient supply can reduce Th1 cell cytokine production to achieve a more balanced inflammatory response \u201375. CompE.coli contamination of water, and Giardia duodenalis prevalence were also reduced in this trial [Overall, the lack of consistent change in any intestinal biomarker suggests that the WASH intervention did not prevent or ameliorate EED, at least as measured by the best currently available biomarkers. This reinforces our previous report that WASH also had very limited effect on enteropathogen carriage . By contis trial ,78, whicis trial . This stis trial ,27,30,80We have recently asserted that the elementary WASH interventions implemented in SHINE did not reduce faecal exposure sufficiently to improve growth ,81. Our This is the largest cohort to date in which such an extensive range of EED biomarkers has been measured during a crucial period of growth and development in a sub-Saharan African setting. Embedding this substudy in a randomized trial has allowed us to ascertain the effects of WASH and IYCF on these biomarkers during this period, with laboratory analysts who were masked to intervention arm. Some limitations of our analyses are notable. First, this was a substudy from a larger cluster-randomized controlled trial. Although baseline variables were largely balanced across trial arms for the infants included in this analysis, increasing confidence in the internal validity of our findings, there were more mothers from households with a more diverse diet and slightly better coping strategy index, meaning the external validity of these substudy results is unclear. Second, there was less frequent specimen collection at the earliest study visits (1 and 3 months), due to the practice of mothers moving from their homestead in the perinatal period, which may have limited the power to detect statistically significant differences between intervention groups at the youngest ages. Third, EED is a difficult condition to identify. There is no accepted case definition, and available biomarkers have limitations. For example, methods used to undertake and analyse the lactulose-mannitol test differ between studies, as reviewed extensively elsewhere . BiomarkOur analyses illustrate that WASH and nutritional interventions did not prevent EED during infancy in an environment with high levels of faecal contamination , where bJean H. Humphrey, Andrew D. Jones, Amee Manges, Goldberg Mangwadu, John A. Maluccio, Mduduzi N. N. Mbuya, Lawrence H. Moulton, Robert Ntozini, Andrew J. Prendergast, Rebecca J. Stoltzfus, James M. Tielsch, Cynthia Chasokela, Ancikaria Chigumira, William Heylar, Preston Hwena, George Kembo, Florence D. Majo, Batsirai Mutasa, Kuda Mutasa, Philippa Rambanepasi, Virginia Sauramba, Naume V. Tavengwa, Franne Van Der Keilen, Chipo Zambezi, Dzivaidzo Chidhanguro, Dorcas Chigodora, Joseph F. Chipanga, Grace Gerema, Tawanda Magara, Mandava Mandava, Tafadzwa Mavhudzi, Clever Mazhanga, Grace Muzaradope, Marian T. Mwapaura, Simon Phiri, Alice Tengende, Cynthia Banda, Bernard Chasekwa, Leah Chidamba, Theodore Chidawanyika, Elisha Chikwindi, Lovemore K. Chingaona, Courage K. Chiorera, Adlight Dandadzi, Margaret Govha, Hlanai Gumbo, Karen T. Gwanzura, Sarudzai Kasaru, Rachel Makasi, Alois M. Matsika, Diana Maunze, Exevia Mazarura, Eddington Mpofu, Johnson Mushonga, Tafadzwa E. Mushore, Tracey Muzira, Netsai Nembaware, Sibongile Nkiwane, Penias Nyamwino, Sandra D. Rukobo, Thompson Runodamoto, Shepherd Seremwe, Pururudzai Simango, Joice Tome, Blessing Tsenesa, Umali Amadu, Beauty Bangira, Daniel Chiveza, Priscilla Hove, Horaiti A Jombe, Didymus Kujenga, Lenin Madhuyu, Prince Mandina-Makoni, Naume Maramba, Betty Maregere, Ellen Marumani, Elisha Masakadze, Phathisiwe Mazula, Caroline Munyanyi, Grace Musanhu, Raymond C. Mushanawani, Sibongile Mutsando, Felicia Nazare, Moses Nyarambi, Wellington Nzuda, Trylife Sigauke, Monica Solomon, Tendai Tavengwa, Farisai Biri, Misheck Chafanza, Cloud Chaitezvi, Tsundukani Chauke, Collen Chidzomba, Tawanda Dadirai, Clemence Fundira, Athanasios C. Gambiza, Tatenda Godzongere, Maria Kuona, Tariro Mafuratidze, Idah Mapurisa, Tsitsi Mashedze, Nokuthula Moyo, Charles Musariri, Matambudzo Mushambadope, Tawanda R. Mutsonziwa, Augustine Muzondo, Rudo Mwareka, Juleika Nyamupfukudza, Baven Saidi, Tambudzai Sakuhwehwe, Gerald Sikalima, Jenneth Tembe, Tapiwanashe E. Chekera, Owen Chihombe, Muchaneta Chikombingo, Tichaona Chirinda, Admire Chivizhe, Ratidzai Hove, Rudo Kufa, Tatenda F. Machikopa, Wilbert Mandaza, Liberty Mandongwe, Farirai Manhiyo, Emmanuel Manyaga, Peter Mapuranga, Farai S. Matimba, Patience Matonhodze, Sarah Mhuri, Joice Mike, Bekezela Ncube, Walter T. S. Nderecha, Munyaradzi Noah, Charles Nyamadzawo, Jonathan Penda, Asinje Saidi, Sarudzai Shonhayi, Clemence Simon, Monica Tichagwa, Rachael Chamakono, Annie Chauke, Andrew F. Gatsi, Blessing Hwena, Hillary Jawi, Benjamin Kaisa, Sithembile Kamutanho, Tapiwa Kaswa, Paradhi Kayeruza, Juliet Lunga, Nomatter Magogo, Daniel Manyeruke, Patricia Mazani, Fungai Mhuriyengwe, Farisai Mlambo, Stephen Moyo, Tawanda Mpofu, Mishelle Mugava, Yvonne Mukungwa, Fungai Muroyiwa, Eddington Mushonga, Selestino Nyekete, Tendai Rinashe, Kundai Sibanda, Milton Chemhuru, Jeffrey Chikunya, Vimbai F. Chikwavaire, Charity Chikwiriro, Anderson Chimusoro, Jotam Chinyama, Gerald Gwinji, Nokuthula Hoko-Sibanda, Rutendo Kandawasvika, Tendai Madzimure, Brian Maponga, Antonella Mapuranga, Joana Marembo, Luckmore Matsunge, Simbarashe Maunga, Mary Muchekeza, Monica Muti, Marvin Nyamana, Efa Azhuda, Urayai Bhoroma, Ailleen Biriyadi, Elizabeth Chafota, Angelline Chakwizira, Agness Chamhamiwa, Tavengwa Champion, Stella Chazuza, Beauty Chikwira, Chengeto Chingozho, Abigail Chitabwa, Annamary Dhurumba, Albert Furidzirai, Andrew Gandanga, Chipo Gukuta, Beauty Macheche, Bongani Marihwi, Barbara Masike, Eunice Mutangandura, Beatrice Mutodza, Angeline Mutsindikwa, Alice Mwale, Rebecca Ndhlovu, Norah Nduna, Cathrine Nyamandi, Elias Ruvata, Babra Sithole, Rofina Urayai, Bigboy Vengesa, Micheal Zorounye, Memory Bamule, Michael Bande, Kumbirai Chahuruva, Lilian Chidumba, Zvisinei Chigove, Kefas Chiguri, Susan Chikuni, Ruvarashe Chikwanda, Tarisai Chimbi, Micheal Chingozho, Olinia Chinhamo, Regina Chinokuramba, Chiratidzo Chinyoka, Xaviour Chipenzi, Raviro Chipute, Godfrey Chiribhani, Mary Chitsinga, Charles Chiwanga, Anamaria Chiza, Faith Chombe, Memory Denhere, Ephania Dhamba, Miriam Dhamba, Joyas Dube, Florence Dzimbanhete, Godfrey Dzingai, Sikhutele Fusira, Major Gonese, Johnson Gota, Kresencia Gumure, Phinias Gwaidza, Margret Gwangwava, Winnet Gwara, Melania Gwauya, Maidei Gwiba, Joyce Hamauswa, Sarah Hlasera, Eustina Hlukani, Joseph Hotera, Lovemore Jakwa, Gilbert Jangara, Micheal Janyure, Christopher Jari, Duvai Juru, Tabeth Kapuma, Paschalina Konzai, Moly Mabhodha, Susan Maburutse, Chipo Macheka, Tawanda Machigaya, Florence Machingauta, Eucaria Machokoto, Evelyn Madhumba, Learnard Madziise, Clipps Madziva, Mavis Madzivire, Mistake Mafukise, Marceline Maganga, Senzeni Maganga, Emmanuel Mageja, Miriam Mahanya, Evelyn Mahaso, Sanelisiwe Mahleka, Pauline Makanhiwa, Mavis Makarudze, Constant Makeche, Nickson Makopa, Ranganai Makumbe, Mascline Mandire, Eunice Mandiyanike, Eunice Mangena, Farai Mangiro, Alice Mangwadu, Tambudzai Mangwengwe, Juliet Manhidza, Farai Manhovo, Irene Manono, Shylet Mapako, Evangelista Mapfumo, Timothy Mapfumo, Jane Mapuka, Douglas Masama, Getrude Masenge, Margreth Mashasha, Veronica Mashivire, Moses Matunhu, Pazvichaenda Mavhoro, Godfrey Mawuka, Ireen Mazango, Netsai Mazhata, David Mazuva, Mary Mazuva, Filomina Mbinda, John Mborera, Upenyu Mfiri, Florence Mhandu, Chrispen Mhike, Tambudzai Mhike, Artwell Mhuka, Judith Midzi, Siqondeni Moyo, Michael Mpundu, Nicholas Msekiwa Msindo, Dominic Msindo, Choice Mtisi, Gladys Muchemwa, Nyadziso Mujere, Ellison Mukaro, Kilvera Muketiwa, Silvia Mungoi, Esline Munzava, Rosewita Muoki, Harugumi Mupura, Evelyn Murerwa, Clarieta Murisi, Letwin Muroyiwa, Musara Muruvi, Nelson Musemwa, Christina Mushure, Judith Mutero, Philipa Mutero, Patrick Mutumbu, Cleopatra Mutya, Lucia Muzanango, Martin Muzembi, Dorcus Muzungunye, Valeliah Mwazha, Thembeni Ncube, Takunda Ndava, Nomvuyo Ndlovu, Pauline Nehowa, Dorothy Ngara, Leonard Nguruve, Petronella Nhigo, Samukeliso Nkiwane, Luckson Nyanyai, Judith Nzombe, Evelyn Office, Beatrice Paul, Shambadzirai Pavari, Sylvia Ranganai, Stella Ratisai, Martha Rugara, Peter Rusere, Joyce Sakala, Prosper Sango, Sibancengani Shava, Margaret Shekede, Cornellious Shizha, Tedla Sibanda, Neria Tapambwa, John Tembo, Netsai Tinago, Violet Tinago, Theresa Toindepi, John Tovigepi, Modesta Tuhwe, Kundai Tumbo, Tinashe Zaranyika, Tongai Zaru, Kamurayi Zimidzi, Matilda Zindo, Maria Zindonda, Nyaradzai Zinhumwe, Loveness Zishiri, Emerly Ziyambi, James Zvinowanda, Ekenia Bepete, Christine Chiwira, Naume Chuma, Abiegirl Fari, Samson Gavi, Violet Gunha, Fadzai Hakunandava, Constance Huku, Given Hungwe, Grace Maduke, Elliot Manyewe, Tecla Mapfumo, Innocent Marufu, Chenesai Mashiri, Shellie Mazenge, Euphrasia Mbinda, Abigail Mhuri, Charity Muguti, Lucy Munemo, Loveness Musindo, Laina Ngada, Dambudzo Nyembe, Rachel Taruvinga, Emma Tobaiwa, Selina Banda, Jesca Chaipa, Patricia Chakaza, Macdonald Chandigere, Annie Changunduma, Chenesai Chibi, Otilia Chidyagwai, Elika Chidza, Nora Chigatse, Lennard Chikoto, Vongai Chingware, Jaison Chinhamo, Marko Chinhoro, Answer Chiripamberi, Esther Chitavati, Rita Chitiga, Nancy Chivanga, Tracy Chivese, Flora Chizema, Sinikiwe Dera, Annacolleta Dhliwayo, Pauline Dhononga, Ennia Dimingo, Memory Dziyani, Tecla Fambi, Lylian Gambagamba, Sikangela Gandiyari, Charity Gomo, Sarah Gore, Jullin Gundani, Rosemary Gundani, Lazarus Gwarima, Cathrine Gwaringa, Samuel Gwenya, Rebecca Hamilton, Agnes Hlabano, Ennie Hofisi, Florence Hofisi, Stanley Hungwe, Sharai Hwacha, Aquiiline Hwara, Ruth Jogwe, Atanus Kanikani, Lydia Kuchicha, Mitshel Kutsira, Kumbulani Kuziyamisa, Mercy Kuziyamisa, Benjamin Kwangware, Portia Lozani, Joseph Mabuto, Vimbai Mabuto, Loveness Mabvurwa, Rebecca Machacha, Cresenzia Machaya, Roswitha Madembo, Susan Madya, Sheneterai Madzingira, Lloyd Mafa, Fungai Mafuta, Jane Mafuta, Alfred Mahara, Sarudzai Mahonye, Admire Maisva, Admire Makara, Margreth Makover, Ennie Mambongo, Murenga Mambure, Edith Mandizvidza, Gladys Mangena, Elliot Manjengwa, Julius Manomano, Maria Mapfumo, Alice Mapfurire, Letwin Maphosa, Jester Mapundo, Dorcas Mare, Farai Marecha, Selina Marecha, Christine Mashiri, Medina Masiya, Thembinkosi Masuku, Priviledge Masvimbo, Saliwe Matambo, Getrude Matarise, Loveness Matinanga, John Matizanadzo, Margret Maunganidze, Belinda Mawere, Chipiwa Mawire, Yulliana Mazvanya, Maudy Mbasera, Magret Mbono, Cynthia Mhakayakora, Nompumelelo Mhlanga, Bester Mhosva, Nomuhle Moyo, Over Moyo, Robert Moyo, Charity Mpakami, Rudo Mpedzisi, Elizabeth Mpofu, Estery Mpofu, Mavis Mtetwa, Juliet Muchakachi, Tsitsi Mudadada, Kudakwashe Mudzingwa, Mejury Mugwira, Tarsisio Mukarati, Anna Munana, Juliet Munazo, Otilia Munyeki, Patience Mupfeka, Gashirai Murangandi, Maria Muranganwa, Josphine Murenjekwa, Nothando Muringo, Tichafara Mushaninga, Florence Mutaja, Dorah Mutanha, Peregia Mutemeri, Beauty Mutero, Edina Muteya, Sophia Muvembi, Tandiwe Muzenda, Agnes Mwenjota, Sithembisiwe Ncube, Tendai Ndabambi, Nomsa Ndava, Elija Ndlovu, Eveln Nene, Enniah Ngazimbi, Atalia Ngwalati, Tafirenyika Nyama, Agnes Nzembe, Eunica Pabwaungana, Sekai Phiri, Ruwiza Pukuta, Melody Rambanapasi, Tambudzai Rera, Violet Samanga, Sinanzeni Shirichena, Chipiwa Shoko, More Shonhe, Cathrine Shuro, Juliah Sibanda, Edna Sibangani, Nikisi Sibangani, Norman Sibindi, Mercy Sitotombe, Pearson Siwawa, Magret Tagwirei, Pretty Taruvinga, Antony Tavagwisa, Esther Tete, Yeukai Tete, Elliot Thandiwe, Amonilla Tibugari, Stella Timothy, Rumbidzai Tongogara, Lancy Tshuma, Mirirayi Tsikira, Constance Tumba, Rumbidzayi Watinaye, Ethel Zhiradzango, Esther Zimunya, Leanmary Zinengwa, Magret Ziupfu, Job Ziyambe, James A. Church, Amy Desai, Dadirai Fundira, Ethan Gough, Rukundo A. Kambarami, Cynthia R. Matare, Thokozile R. Malaba, Tatenda Mupfudze, Francis Ngure, Laura E. Smith, Val Curtis, Katherine L. Dickin, Jean-Pierre Habicht, Collen Masimirembwa, Peter Morgan, Gretel H. Pelto, Corinne Sheffner-Rogers, Roslyn Thelingwani, Paul Turner, Lindiwe Zungu, Tariro Makadzange, Hilda A. Mujuru.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.S4 Table(XLSX)Click here for additional data file.S5 Table(XLSX)Click here for additional data file.S6 Table(XLSX)Click here for additional data file.S7 Table(XLSX)Click here for additional data file.S8 Table(XLSX)Click here for additional data file.S9 Table(XLSX)Click here for additional data file.S10 Table(XLSX)Click here for additional data file.S11 Table(XLSX)Click here for additional data file.S12 Table(XLSX)Click here for additional data file.S13 Table(XLSX)Click here for additional data file.S14 Table(XLSX)Click here for additional data file.S15 Table(XLSX)Click here for additional data file.S16 Table(XLSX)Click here for additional data file.S17 Table(XLSX)Click here for additional data file."} +{"text": "The first two authors, H.M. Bhamare and R.Z. Sayyed, are listed out of order. The first two authors should also be noted as having contributed equally to this work. The third author, Sapna, and the eighth author, Daniel J. Dailin, should be noted as having contributed equally to this work with: Najat Marraiki, Abdallah M. Elgorban, Asad Syed, and Hesham Ali El-Enshasy. Please view the correct author order, affiliations, and citation here:1, R. Z. Sayyed2, Sapna3, Najat Marraiki4, Abdallah M. Elgorban4,5, Asad Syed4, Hesham Ali El-Enshasy6,7,8, Daniel J. Dailin6,7H. M. Bhamare1 Department of Biotechnology, SSVP Sansth\u2019s Late Karmveer Dr. P. R. Ghogrey Science College, Dhule, India, 2 Department of Microbiology, PSGVP Mandal\u2019s Arts, Science and Commerce College, Shahada, India, 3 ICAR-National Bureau of Plant Genetic Resources, New Delhi, India, 4 Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia, 5 Centre of Excellence in Biotechnology Research, King Saud University, Riyadh, Saudi Arabia, 6 Institute of Bioproduct Development, Universiti Teknologi Malaysia (UTM), Skudai, Johor Bahru, Malaysia, 7 School of Chemical and Energy Engineering, Faculty of Engineering, Universiti Teknologi Malaysia (UTM), Skudai, Johor Bahru, Malaysia, 8 City of Scientific Research and Technology Applications, New Burg Al Arab, Alexandria, Egypthttps://doi.org/10.1371/journal.pone.0229968Bhamare HM, Sayyed RZ, Sapna, Marraiki N, Elgorban AM, Syed A, et al. (2020) Tree bark scrape fungus: A potential source of laccase for application in bioremediation of non-textile dyes. PLoS ONE 15(6): e0229968."} +{"text": "Correction to: Animal Microbiome (2019) 1:3https://doi.org/10.1186/s42523-019-0004-4Robert Kinley was not listed among the authors in the original article . The corBreanna Michell Roque, Charles Garrett Brooke, Joshua Ladau, Tamsen Polley, Lyndsey Jean Marsh, Negeen Najafi, Pramod Pandey, Latika Singh, Robert Kinley, Joan King Salwen, Emiley Eloe-Fadrosh, Ermias Kebreab and Matthias Hess*.The original article has been corrected."} +{"text": "The neutrophil-to-lymphocyte ratio (NLR) has been investigated in many autoimmune conditions as a biomarker of inflammation and/or disease activity. The role of NLR in AQP4-IgG-positive neuromyelitis optica spectrum disorders (NMOSD) is far from clear. In this study, NLR was evaluated in patients with AQP4-IgG-positive NMOSD at disease onset and its prognostic impact was subsequently assessed.In this multicenter study, we retrospectively included all recent/newly diagnosed treatment-na\u00efve patients with AQP4-IgG-positive NMOSD (n=90) from three different countries in Latin America (LATAM): Argentina, Ecuador, and Mexico. NLR was compared between AQP4-IgG-positive NMOSD and healthy controls . Demographic, clinical, paraclinical (including imaging), and prognostic data at 12 and 24 months were also evaluated. Multivariate regression analysis was used to describe and identify independent associations between the log-transformed NLR and clinical (relapses and EDSS) and imaging (new/enlarging and/or contrast-enhancing MRI lesions) outcomes.NLR was higher in NMOSD patients during the first attack compared with HC . Regardless of immunosuppressant\u2019s initiation at disease onset, NLR remained higher in NMOSD patients at 12 and 24 months. No association was found at 12 and 24 months between the log-transformed NLR and the presence of relapses, new/enlarging and/or contrast-enhancing MRI lesions, and/or physical disability.In this cohort of LATAM patients with AQP4-IgG-positive NMOSD, NLR was abnormally high in attacks but also during follow-up. However, a high NLR was not an independent predictor of clinical or imaging outcomes in our models. Neuromyelitis optica spectrum disorder (NMOSD) is a rare and disabling condition characterized by inflammatory attacks, especially involving the optic nerves and spinal cord . NMOSD iWhite blood cells (WBC) and their subtypes has been proposed as biomarkers for inflammation and/or disease activity. Neutrophil-to-lymphocyte ratio (NLR) represents a combination of two of these markers, and is superior to other WBC-derived parameters, due to its stability , 4. NLR NLR is an easily obtained parameter that could act as a biomarker of inflammation and/or disease activity in NMOSD. Therefore, the aim of this study was to evaluate NLR in a Latin American (LATAM) cohort of patients with AQP4-ab-positive NMOSD at disease onset and then to assess the prognostic role of this potential biomarker at two years.In this multicenter study, we retrospectively included patients with a first NMOSD attack who fulfilled the 2015 diagnostic criteria lesions on MRI were assessed at onset, 12 and 24 months. The frequency of clinical relapses was evaluated at 12 and 24 months. In LATAM reference centers, it is a standard practice to perform annual MRIs as a complementary evaluation during follow-up . Thus, MBlood samples were obtained and recorded within 24\u00a0h of admission at disease onset. Data containing laboratory results such as complete blood count (CBC) were included. NLR at baseline, 12 months and 24 months was evaluated in both patients with NMOSD and healthy controls (HC). After the first attack, all patients were started on immunosuppressant treatment (IST). For those started on azathioprine (AZA) or mycophenolate mofetil (MMF), a concomitant oral steroid was used for 3\u20136 months while steroid-sparing therapy reached full efficacy. As they were on IST, follow-up routine lab tests were requested. These tests (including a CBC) were reviewed approximately at 12 and 24 months after the first attack. HC [median age 40 (range: 18\u201365) years] were recruited in Argentina (2012\u20132017) among healthy subjects who underwent a routine physical examination and general blood tests for their annual physicals. This is part of a preventive healthcare program in Argentina. These medical records were retrieved in an anonymized manner using only filters for age and reason for visit . Therefore, gender is unknown. NLR was calculated as the absolute count of neutrophils divided by the absolute count of lymphocytes from peripheral blood samples before any treatment has been started. Serum AQP4-ab was tested by cell-based assay and only patients with positive results were included.NMOSD typical lesions on brain MRI were classified as follows , 22: optStatistical analysis was performed using STATA 13.0 . Categorical variables are reported as absolute count/frequency (percentage), while continuous variables are summarized as mean \u00b1 standard deviation (SD) or median (IQR), according to their distribution. Distribution was assessed using a combination of the following: visual inspection of histogram and normal probability plot, median, mean, skewness, kurtosis and the Shapiro-Wilk test. NRL was natural log (base e) transformed to fit the normal distribution.Neutrophil and lymphocyte counts, as well as NLR, were compared using the t-test or Mann-Whitney U test, as appropriate. Regression analysis was used to describe and identify independent associations between log-transformed NLR and clinical (relapses and EDSS change) as well as MRI activity (new/enlarging and/or contrast-enhancing MRI lesions). To account for multiple observations on each subject, we used a lineal mixed-effects model with a subject specific random intercept. First, we analyzed the association between NLR and the described outcomes, and then we evaluated separate models with different adjustments . We further explored the association of NLR and EDSS assuming a Poisson distribution and dichotomizing it. For all the analyses, significance level (p) was set at less than 0.05.Ninety AQP4-ab-positive patients and 365 HC were included. Twelve AQP4-ab-positive NMOSD patients were excluded due to diabetes mellitus (n = 3), arterial hypertension (n = 2), and concomitant autoimmune conditions (n = 7). General characteristics of this LATAM cohort are summarized in NLR was higher in NMOSD patients during the first attack compared to HC (versus others) was not identified as an effect modifier of the relationship between the log-transformed NLR and NMOSD outcomes in the mixed-effects regression model.No association was found at 1 and 2 years between the log-transformed NLR and relapses, new/enlarging and/or contrast-enhancing MRI lesions, or physical disability when considering multiple observations was obtained from all participants before data collection.Hesham Abboud, MD, PhD, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, OH, USA; Raed Alroughani, MD, FRCPC, FAAN, Amiri Hospital Kuwait City, Kuwait; Metha Apiwattanakul, MD, Prasat Neurological Institute, Bangkok, Thailand; Jeffrey Cohen, MD, Cleveland Clinic, Cleveland, OH, USA; Joachim Havla, MD, LMU Hospital, Munich, Germany; Jyh Yung Hor, MD, Penang General Hospital, Penang, Malaysia; Raffaele Iorio, MD, PhD, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Anu Jacob, MD, Cleveland Clinic Abudhabhi, Abu Dhabi, United Arab Emirates; Najib Kissani, MD, Marrakech Medical School, Cadi Ayyad University, Marrakech, Morocco; Michael Levy, MD, PhD, Massachusetts General Hospital, Boston, MA, USA; Sara Mariotto, MD, PhD, University of Verona, Italy; Marcelo Matiello, MD, MSc, Harvard Medical School, Boston, MA, USA; Esther Melamed, MD, PhD, Dell Medical School, UT Austin, Austin, TX, USA; Veronika E. Neubrand, PhD, University of Granada, Granada, Spain; Celia Oreja-Guevara, MD, PhD, Hospital Clinico San Carlos, Madrid, Spain; Friedemann Paul, MD, Charit\u00e9 University, Berlin, Germany; Anne-Katrin Pr\u00f6bstel, MD, PhD, University Hospital Basel, Switzerland; Peiqing Qian, MD, Swedish Medical Center, Seattle, WA, USA; Sasitorn Siritho, MD, Siriraj Hospital, Mahidol University, Bangkok, Thailand; Terry J. Smith, MD, University of Michigan Medical School, Ann Arbor, MI, USA; Pablo Villoslada, MD, Stanford University School of Medicine, Stanford, CA, USA; Dean Wingerchuk, MD, Mayo Clinic, Scottsdale, AZ, USA; Michael R. Yeaman, PhD, 1) Los Angeles Biomedical Research Institute at Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance, CA, USA, 2) David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.\u2020Affiliated members of The Guthy-Jackson Charitable Foundation International Clinical Consortium (GJCF-ICC) who revised the manuscript for intellectual content: ECC and JR: designed/conceptualized the study, analyzed the data, interpreted the data, and drafted and revised the manuscript for intellectual content. GD-G: collected and interpreted the data and drafted and revised the manuscript for intellectual content. JC: collected and interpreted the data, analyzed the data, and revised the manuscript for intellectual content. PL, JP, EC, JM, EC-D, M\u00c1, JMZ, EG-F, VR-A, JF-R, VT, and AC: collected and interpreted the data, and revised the manuscript for intellectual content. All authors contributed to the article and approved the submitted version.The Article Processing Charge was funded by The Guthy-Jackson Charitable Foundation.ECC has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Biogen, Bayer, Genzyme, Merck, Novartis, Roche, Raffo, and Teva. GD-G has received research grants/salary support from the Consejo Nacional de Ciencia y Tecnolog\u00eda (Mexico), Universidad Nacional Aut\u00f3noma de M\u00e9xico, and Fundaci\u00f3n Carlos Slim. JC serves as a Health outcomes manager for GlaxoSmithKline. PL has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Biogen, Bayer, Genzyme, Merck, Novartis, Roche, Raffo, and Teva. JP has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Biogen, Bayer, Genzyme, Merck, Novartis, Roche, Raffo, and Teva. EC has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Biogen, Bayer, Genzyme, Merck, Novartis, Roche, and Teva. JM has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Bayer, Merck, and Novartis. VR-A has received reimbursement for developing educational presentations, educational and research grants, consultation fees,and/or travel stipends from Roche, Sanofi, Merck, Stendhal, Biogen, Novartis, and Allergan. JF-R has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Roche, Sanofi, Merck, Stendhal, Biogen, Novartis, Terumo BCT, Bayer, and Teva. VT has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Biogen, Bayer, Genzyme, Merck, Novartis, Roche, Raffo, and Teva. AC has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Biogen, Bayer, Genzyme, Merck, Novartis, Roche, Raffo, and Teva. JR has received reimbursement for developing educational presentations, educational and research grants, consultation fees, and/or travel stipends from Biogen, Bayer, Genzyme, Merck, Novartis, Roche, and Teva.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Microcystis aeruginosa is a bloom-forming cyanobacterium found in freshwater environments. The draft genomes of the M. aeruginosa strains NIES-3787, NIES-3804, NIES-3806, and NIES-3807, which were isolated from Lake Kasumigaura, Japan, were sequenced. The genome sizes of NIES-3787, NIES-3804, NIES-3806, and NIES-3807 were 4,524,637, 4,522,701, 4,370,004, and 4,378,226\u2009bp, respectively. Microcystis aeruginosa is a bloom-forming cyanobacterium found in freshwater environments. The draft genomes of the M. aeruginosa strains NIES-3787, NIES-3804, NIES-3806, and NIES-3807, which were isolated from Lake Kasumigaura, Japan, were sequenced. The genome sizes of NIES-3787, NIES-3804, NIES-3806, and NIES-3807 were 4,524,637, 4,522,701, 4,370,004, and 4,378,226\u2009bp, respectively. Microcystis aeruginosa is the most well-known bloom-forming cyanobacterium, and it is distributed in eutrophic freshwater environments. The most serious problem associated with this species is the production of hepatotoxic cyanotoxins called microcystins based on multilocus phylogenetic analyses . These strains were established by using a micropipette under an inverted microscope. The strains were cultured in 10\u2009ml of Microcystis aeruginosa medium at 22\u00b0C under light at 25\u2009\u03bcmol photons m\u22122 s\u22121 with a 12:12-h light/dark cycle. Genomic DNA was extracted from 10-ml cultures of these strains using Agencourt Chloropure (Beckman Coulter) following the manufacturer\u2019s protocol. The resultant DNAs were fragmented to approximately 550\u2009bp using an M220 ultrasonicator (Covaris). Genomic libraries of paired-end reads were constructed using a NEBNext Ultra II DNA library prep kit for Illumina (New England Biolabs). Next-generation sequencing was performed with the MiSeq platform (Illumina) using a 500-cycle MiSeq reagent kit version 2. The resultant paired-end reads for NIES-3787, NIES-3804, NIES-3806, and NIES-3807 were 151,461,029\u2009bp, 643,439,906\u2009bp, 395,828,445\u2009bp, and 197,435,680\u2009bp, respectively. The raw reads were trimmed using Trimmomatic version 0.38 (de novo assembly was performed using SPAdes version 3.11.1 (https://github.com/tseemann/shovill). Next, the assembled scaffolds were polished using Pilon version 1.22 (ftsZ, one of seven multilocus sequence typing loci (Axenic cultures of M. aeruginosa would be useful for monitoring algal blooms and managing freshwater ecosystems.The genome assembly results are detailed in Microcystis aeruginosa NIES-3787, NIES-3804, NIES-3806, and NIES-3807 have been deposited in DDBJ/EMBL/GenBank under the accession numbers BJCH01000001 to BJCH01000214, BJCI01000001 to BJCI01000238, BJCJ01000001 to BJCJ01000235, and BJCK01000001 to BJCK01000228, respectively. The raw genomic reads of the strains are available in DDBJ/EMBL/GenBank under the accession numbers DRR205020, DRR205021, DRR205022, and DRR205023, respectively.The draft genomic sequences of"} +{"text": "Scientific Reports 10.1038/s41598-019-45060-y, published online 20 June 2019Correction to: The original version of this Article contained a typographical error in the spelling of the author Luis Mart\u00ednez-Mart\u00ednez, which was incorrectly given as Luis Mart\u00ednez.In addition, this Article contained a typographical error in the following affiliation.Infectiuos Diseases Unit, Hospital Universitario Cruces, Plaza de Cruces, S/N, 48903, Baracaldo, Vizcaya,Spainnow reads:Infectious Diseases Unit, Hospital Universitario Cruces, Plaza de Cruces, S/N, 48903, Baracaldo, Vizcaya, SpainThese errors have now been corrected in the PDF and HTML versions of the Article, and in the accompanying Supplementary Material File."} +{"text": "Styrax agrestis (Lour.) G. Don, is a deciduous species of Styracaceae with beautiful shape, drooping flowers, and blooming like snow. Here, we characterized the complete chloroplast (cp) genome of S. agrestis using next generation sequencing. The circular complete cp genome of S. agrestis is 157,893\u2009bp in length, containing a large single-copy (LSC) region of 87,512\u2009bp, and a small single-copy (SSC) region of 18,285\u2009bp. It comprises 136 genes, including eight rRNA genes, 37 tRNAs genes, 90 protein-coding genes, and one pseudo gene. The GC content of S. agrestis cp genome is 36.96%. The phylogenetic analysis suggests that S. agrestis is a sister species to Styrax faberi in Styracaceae. Styrax agrestis (Lour.) G. Don is mainly distributed in tropical and subtropical lowland areas in Southeast Asia. Currently, S. agrestis possesses high value for ornamental, timber, and medicinal purposes based on Illumina pair-end sequencing to provide a valuable complete cp genomic resource.agrestis grown in Jianfengling, Ledong County , Hainan, China. The voucher specimen was deposited at the herbarium of Nanjing Forestry University (accession number: NF2020090). The whole genome sequencing was carried out on Illumina Hiseq platform by Nanjing Genepioneer Biotechnology Inc. . The original reads were filtered by CLC Genomics Workbench v9, and the clean reading was assembled into chloroplast (cp) genome with SPAdes regions of 26,048\u2009bp, which were separated by a large single-copy (LSC) region of 87,512\u2009bp, and a small single-copy (SSC) region of 18,285\u2009bp. A total of 136 genes are encoded, including 90 protein-coding genes (82 CDS species), 37 tRNAs gene (30 tRNA species), eight rRNA genes (four rRNA species), and one pseudo gene. Most of genes occurred in a single copy; however, eight protein-coding genes , seven tRNA genes , and four rRNA genes are totally duplicated. A total of nine protein-coding genes contained one intron while the other three genes had two intron each. The rest of the 70 protein-coding genes are psaA, psaB, psaC, psaI, psaJ, psbA, psbB, psbC, psbD, psbE, psbF, psbH, psbI, psbJ, psbK, psbL, psbM, psbN, psbT, ndhC, ndhD, ndhE, ndhF, ndhG, ndhH, ndhI, ndhJ, ndhK, petA, petG, petL, petN, atpA, atpB, atpE, atpH, atpI, rbcL, rpl14, rpl20, rpl22, rpl23, rpl32, rpl33, rpl36, rps11, rps14, rps15, rps18, rps19, rps2, rps3, rps4, rps7, rps8, rpoA, rpoB, rpoC2, matK, cemA, accD, ccsA, infA, lhbA, orf188, orf42, ycf1, ycf15, ycf2, and ycf4. The overall GC content of S. agrestis genome is 36.96%, and the corresponding values in LSC, SSC, and IR regions are 34.81%, 30.29%, and 42.92%, respectively.The circular genome of S. agrestis was clustered with other families of Styracaceae with 100% bootstrap values as outgroups with sequenced cp genomes. We found that p values . In addi"} +{"text": "The novel coronavirus COVID-19) has spread rapidly and become a severe global threat, with a reported acute respiratory distress syndrome (ARDS) incidence up to 40% 9 has spr.p\u2009=\u20090.033), especially in patients who received Chinese herbal therapy during the whole disease course. Further, these patients were also divided into two groups according to whether they had used Chinese herbal; a decreased trend of mortality was also observed .Here we presented the data from a single ICU of Tianyou hospital in Wuhan, and according our experience, the overall mortality decreased in patients receiving Chinese herb therapy. From January 11, 2020, to March 17, 2020, a total of 37 patients confirmed with COVID-19 infection were admitted to ICU (Table\u00a0Formula 1: Xinren, Shigao, Gualuo, Dahuang, Mahuang, Tinglizi, Taoren, Caoguo, Binglang, Cangshu, Jinyinhua, Lianqiao, Hongjingtian.Formula 2: Fuzhi, Shengjiang, Huangqi, Renshen, Xinren, Shigao, Gualuo, Dahuang, Mahuang, Tinglizi, Taoren, Caoguo, Binglang, Cangshu, Gancao.We understand our finding is unstable due to the limited sample size and potential cofounders. However, in China, Chinese herbal therapy has been fully applied to patients with COVID-19 infection in the middle stage of this epidemic and the effect is positive. The following content is the main Chinese herbal formulas for these nine patients:"} +{"text": "Manuscript: Induction of selective liver hypothermia prevents significant ischemia/reperfusion injury in Wistar rats after 24 hoursPublication: Acta Cir Bras. 2020;35(2):e202000205Doi:http://dx.doi.org/10.1590/s0102-865020200020000005On the first page of the original publication, instead of this authors names:I, Larisse LongoII, Jorge Luiz dos SantosIII, Gemerson GabiattiIV, Carlos BoffilV, Emanuel Bendo dos SantosVI, Carlos Thadeu Schmidt CerskiVII, Marcio Fernandes ChedidVIII, Carlos Otavio CorsoIXTomaz de Jesus Maria Grezzana-FilhoConsider this names:I, Larisse LongoII, Jorge Luiz dos SantosIII, Gemerson GabiattiIV, Carlos BoffilV, Emanuel Burck dos SantosVI, Carlos Thadeu Schmidt CerskiVII, Marcio Fernandes ChedidVIII, Carlos Otavio CorsoIXTomaz de Jesus Maria Grezzana-Filho"} +{"text": "When writing the \u201c2019 State of the Journal Report\u201d at this same time last year, we could not have predicted the global changes that would beset us with so many challenges from the emergence of the COVID-19 pandemic. Some of us lost loved ones, friends, and colleagues, while the entire world adapted to working from home, participating in remote classrooms, and adopting safety precautions as a new means of daily life. The research community was also affected, with the cessation of travel leading to virtual conferences. Thanks to the heroic efforts of many conference chairsYet, in the presence of a global pandemic, scientific contributions continued in the software and systems modeling community. The number of SoSyM submissions over the past year saw an increase, while the general health of the journal remains strong. Measures put in place recently, such as the second year of moving to six issues per year, have helped to reduce the time to publication significantly. The Open Access movement is also progressing, with Springer announcing new initiatives to make SoSyM publications more accessible to a broader community of researchers. The rest of this editorial summarizes the progress made by the journal during this unprecedented situation.Our hope is that you remain safe and have a productive 2021!The six SoSyM issues published in 2020 contained 17 Regular papers, 33 Special Section papers, 6 Theme Section papers, 4 Expert Voices, and 9 Guest Editorials. In total, 1587 pages were published in volume 19.We are very happy to report that the 2-year Impact Factor (IF) for SoSyM continues to be very respectable at 1.876 (previously at 2.66 in 2019 and 1.722 in 2018), with the 5-year IF holding at 1.915. Furthermore, the h-5 Google Scholar ranking places SoSyM at #12 among all conferences and journals related to software engineering and programming languages.There are two new positive \u201crecords\u201d set for SoSyM in 2020 related to submissions and downloads. Over the past year, SoSyM received 372 submissions\u2014the largest number for any year in our history (over 100 submissions over the average of the past three years). Furthermore, at the time of this writing, there were over 164,316 downloads from January through the end of November 2020. This is well beyond the 2019 download numbers of 136,378. These two observations suggest the growing interest in SoSyM among the research community.The acceptance rate in 2020 was 19%, which is a respectable rate for a high-quality journal such as SoSyM. The average time from submission to the final decision (accept or reject) has slightly increased to 146\u00a0days (128\u00a0days in 2019 and 138\u00a0days in 2018).http://www.sosym.org/awards/.MODELS 2020 was originally planned to be held in Montreal, Canada, but due to the safety concerns with COVID-19, the conference was held virtually in October 2020. We thank the MODELS 2020 organizers (Eugene Syriani and Houari Sahraoui) and the PC co-Chairs (Silvia Abrah\u00e3o and Juan de Lara) for collaborating with SoSyM. We were able to host another awards session with paper presentations of the Best SoSyM Papers over the past 10\u00a0years during a special virtual session of MODELS 2020. The selection was based on the ISI citation index among papers published in SoSyM since 2010. More information about the awards can be found at: SoSyM 2020 \"Ten-year most influential Regular paper award\" was given to:Journal on Software and Systems Modeling (SoSyM), Volume 9, Issue 2, pp. 257\u2013280, Springer, April 2010.Jeff Offutt and Ye Wu, \"Modeling presentation layers of web applications for testing,\" In: https://doi.org/10.1007/s10270-009-0125-4The SoSyM 2020 \"Ten-year most influential Theme Section paper award\" was given to:Journal on Software and Systems Modeling (SoSyM), Volume 9, Issue 4, pp. 427\u2013451, Springer, September 2010.Nicolas Anquetil, Uira Kulesza, Ralf Mitschke, Ana Moreira, Jean-Claude Royer, Andreas Rummler, and Andre Sousa, \"A model-driven traceability framework for software product lines,\" In: https://doi.org/10.1007/s10270-009-0120-9The Journal on Software and Systems Modeling (SoSyM), Springer, in press, 2020. https://doi.org/10.1007/s10270-020-00807-4Yinling Liu, Tao Wang, Haiqing Zhang, and Vincent Cheutet. \u201cAn improved approach on the model checking for an agent-based simulation system.\u201d In: Journal on Software and Systems Modeling (SoSyM), Springer, in press, 2020. https://doi.org/10.1007/s10270-020-00819-0Simin Cai, Barbara Gallina, Dag Nystr\u00f6m, and Cristina Seceleanu. \u201cSpecification and automated verification of atomic concurrent real-time transactions.\u201d In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 1, Springer, January 2021. https://doi.org/10.1007/s10270-020-00804-7Karim Jahed, Mojtaba Bagherzadeh, and Juergen Dingel. \u201cOn the benefits of file-level modularity for EMF models.\u201d In: Journal on Software and Systems Modeling (SoSyM), Springer, in press, 2020. https://doi.org/10.1007/s10270-020-00815-4Stefan G\u00f6tz, Matthias Tichy, and Raffaela Groner. \u201cClaimed Advantages and Disadvantages of (dedicated) Model Transformation languages: A Systematic Literature Review.\u201d In: Journal on Software and Systems Modeling (SoSyM), Volume 19, Issue 3, pp. 647\u2013691, Springer, May 2020. https://doi.org/10.1007/s10270-019-00752-xAnthony Anjorin, Thomas Buchmann, Bernhard Westfechtel, Zinovy Diskin, Zinovy, Hsiang-Shang Ko, Romina Eramo, Georg Hinkel, Leila Samimi-Dehkordi, and Albert Zuendorf. \u201cBenchmarking bidirectional transformations: theory, implementation, application, and assessment.\u201d In: Journal on Software and Systems Modeling (SoSyM), Volume 19, Issue 3, pp. 741\u2013762, Springer, May 2020. https://doi.org/10.1007/s10270-019-00764-7Milena Guessi, Flavio Oquendo, and Elisa Yumi Nakagawa. \u201cArk: A constraint-based method for architectural synthesis of smart systems.\u201d In: Journal on Software and Systems Modeling (SoSyM), Volume 19, Issue 3, pp. 763\u2013784, Springer, May 2020. https://doi.org/10.1007/s10270-019-00770-9Enyo Gon\u00e7alves, Camilo Almendra, Miguel Goul\u00e3o, Jo\u00e3o Ara\u00fajo, and Jaelson Castro. \u201cUsing empirical studies to mitigate symbol overload in iStar extensions.\u201d In: Journal on Software and Systems Modeling (SoSyM), Volume 19, Issue 4, pp. 959\u2013981, Springer, July 2020. https://doi.org/10.1007/s10270-020-00780-yNicolas Hili, Mojtaba Bagherzadeh, Karim Jahed, and Juergen Dingel. \u201cA model-based architecture for interactive run-time monitoring.\u201d In: Journal on Software and Systems Modeling (SoSyM), Volume 19, Issue 3, pp. 625\u2013646, Springer, May 2020. https://doi.org/10.1007/s10270-019-00755-8Juan C. Vidal, Paulo Carreira, Vasco Amaral, Joao Aguiam, and Jo\u00e3o Sousa. \u201cTowards high-level fuzzy control specifications for building automation systems.\u201d In: Journal on Software and Systems Modeling (SoSyM), Volume 19, Issue 6, pp. 1483\u20131587, Springer, November2020. https://doi.org/10.1007/s10270-020-00806-5Bence Graics, Vince Moln\u00e1r, Andr\u00e1s V\u00f6r\u00f6s, Istv\u00e1n Majzik, and D\u00e1niel Varr\u00f3. \u201cMixed-semantics composition of statecharts for the component-based design of reactive systems.\u201d In: The continuous collaboration between SoSyM and the MODELS conference in organizing the SoSyM \u201cJournal-First\u201d was successfully continued. This enables authors of recent SoSyM papers to present their work across the core conference sessions at MODELS. Through this collaboration, SoSyM authors have the opportunity to reach a broader audience to present their work. This also benefits the MODELS conference program by including research talks that explore more depth through analytical and empirical evidence than can be presented in a traditional conference submission. The virtual nature of MODELS 2020 allowed for more SoSyM papers to be selected for presentation. At MODELS 2018, four articles were presented. At MODELS 2019, we increased this number to seven articles and at MODELS 2020 to ten articles (papers that were accepted from July 2019 through June 2020). The SoSyM \u201cJournal-First\u201d papers presented at MODELS 2020 were the following (note: Some of the papers are available online but have not yet received an assignment to an issue):Each year, Editors who served the SoSyM community for many years retire from the SoSyM Editorship with distinction of service and our deep appreciation. In 2020, Dorina Petriu announced that she desired to step down as an Editor after many years of service. Thanks Dorina for all of your contributions to SoSyM! As mentioned earlier in this report, SoSyM received a record number of submissions this year (372), which requires us to grow the Editorial Board. We are very happy to welcome the following new SoSyM Editors and look forward to working with them in the future.Juergen Dingel, Antonio Garc\u00eda-Dom\u00ednguez (twice!), Marcus Gerhold, Mario Gleirscher, Sylvain Hall\u00e9, Stefan Klikovits, Thomas K\u00fchne, Hugo A. L\u00f3pez, Florian Matthes, Libero Nigro, Bentley Oakes, Stefan Sauer, Harald St\u00f6rrle, Valent\u00edn Valero, Steven van Kervel, and Simon Van Mierlo.A strong research community depends on the efforts of volunteers who help serve as reviewers.The software and systems modeling community has always risen to the request for help from SoSyM. We appreciate all of the help that the reviewers provided in service to the modeling community! We would also like to offer special recognition to the following reviewers, who were recommended as the SoSyM Best Reviewers of 2020, based on the technical depth and feedback provided to authors over the past year\u2014congratulations! We will send a certificate of recognition to each of the following reviewers:http://www.sosym.org/people/.Rasmus Adler, Paulo Alencar, Ian Alexander, Joao Paulo Almeida, Ahmad Salim Al-Sibahi, Juliana Alves Pereira, Vasco Amaral, Elske Ammenwerth, Moussa Amrani, Daniel Amyot, Kelly Androutsopoulos, Anthony Anjorin, Muhammad Anwar, Vincent Aranega, Joao Araujo, Paolo Arcaini, Chetan Arora, Cyrille Artho, Wesley K. G. Assuncao, Colin Atkinson, Vanessa Ayala-Rivera, Thomas Baar, Onder Babur, Mojtaba Bagherzadeh, Mira Balaban, Torsten Bandyszak, Luciano Baresi, Kamel Barkaoui, Jiri Barnat, Angela Barriga, Francesco Basciani, Mar\u00eda Bastarrica, Dinesh Batra, Steffen Becker, Mitra Tabaei Befrouei, David Benavides, Luca Berardinelli, Gabor Bergmann, Simona Bernardi, Ilia Bider, Robert Bill, Olivier Biot, Karsten Boehm, Francis Bordeleau, Dominik Bork, Artur Boronat, Saida Boukhedouma, Frederic Boulanger, Erwan Bousse, Drazen Brdjanin, Uwe Breitenbuecher, Ruth Breu, Jean-Michel Bruel, Davide Brugali, Hugo Bruneliere, Andrea Burattin, Erik Burger, Loli Burgue\u00f1o, Arvid Butting, Cristina Cabanillas, Jos\u00e8 Campos, Laurent Capocchi, Jan Carlson, Victorio Carvalho, Roberto Casadei, Ana Cavalcanti, Graziana Cavone, Moharram Challenger, Mohammad Chami, Michel Chaudron, Franck Chauvel, Stanislav Chren, Antonio Cicchetti, Federico Ciccozzi, Robert Claris\u00f3, Tony Clark, Peter Clarke, Manuel Clavel, Rolland Colette, Nelly Condori-Fern\u00e1ndez, Maxime Cordy, Carl Corea, Mario Cortes-Cornax, Jes\u00fas S\u00e1nchez Cuadrado, Alberto da Silva, Fabiano Dalpiaz, Marian Daun, Nancy Day, Alfonso de la Vega, Juan de Lara, Romulo De Oliveira, Julien DeAntoni, Patrick Delfmann, Romain Demangeon, Joerg Desel, Xavier Devroey, Juri Di Rocco, Davide Di Ruscio, Marcos Didonet Del Fabro, Aleksandar Dimovski, Crystal Din, Juergen Dingel, Zinovy Diskin, Lydie Du Bousquet, Francisco Duran, Alexander Egyed, Maged Elaasar, Eduard Enoiu, Romina Eramo, Huseyin Ergin, Maria Escalona, Lorenz Esch, Elisabet Estevez, Bedilia Estrada, Dirk Fahland, Michalis Famelis, Anna Rita Fasolino, Andreas Fellner, Peter Fettke, Barabara Fila, Hans-Georg Fill, John Fitzgerald, Ulrich Frank, Martin Fr\u00e4nzle, Agn\u00e8s Front, Frederik Gailly, Antonio Garc\u00eda-Dom\u00ednguez, Gregory Gay, Sebastien Gerard, Marcus Gerhold, Mario Gleirscher, Martin Gogolla, Aniruddha Gokhale, Thomas Goldschmidt, Claudio Gomes, Cesar Gonzalez-Perez, Catarina Gralha, Peter Green, Joel Greenyer, Paul Grefen, Raffaela Groner, Georg Grossmann, Lars Grunske, Esther Guerra, Renata Guizzardi, Jens Gulden, Jin Guo, Simon Hacks, Sylvain Hall\u00e9, Stefan Hallerstede, Oystein Haugen, Jane Hayes, Xiao He, Regina Hebig, Reiko Heckel, Constance Heitmeyer, Loic Helouet, Martin Henkel, James Hill, Georg Hinkel, Nico Hochgeschwender, Jennifer Horkoff, Christopher Hoyle, Ludovico Iovino, Muhammad Zohaib Iqbal, Karim Jahed, Amin Jalali, Phillip James, Cyrille Jegourel, Manfred A. Jeusfeld, Christian Johansen, Monika Kaczmarek, Bernhard Kaiser, Sungwon Kang, Dimitris Karagiannis, Gabor Karsai, Evangelia Kavakli, Timo Kehrer, Udo Kelter, Wael Kessentini, Djamel Eddine Khelladi, Ferhat Khendek, Marite Kirikova, Stefan Klikovits, Alexander Knapp, Jan Kofron, Shekoufeh Kolahdouz-Rahimi, Dimitrios Kolovos, Dimitris Kolovos, Harald K\u00f6nig, Nikolai Kosmatov, Stefan Kugele, Thomas K\u00fchne, Akhil Kumar, Katsiaryna Labunets, Yngve Lamo, Kevin Lano, Xavier Le Pallec, Choonhwa Lee, Henrik Leopold, Shuai Li, Sotirios Liaskos, Crescencio Lima, Lukas Linsbauer, Guanjun Liu, Malte Lochau, Hugo A. L\u00f3pez, Ernesto L\u00f3pez-Mellado, Florian Lorber, Mass Soldal Lund, Fernando Mac\u00edas, Fr\u00e9d\u00e9ric Mallet, Beatriz Mar\u00edn, Andrea Marrella, Florian Matthes, Raimundas Matulevicius, Claudio Menghi, Gergely Mezei, Faida Mhenni, Judith Michael, Miguel Mira da Silva, Raffaela Mirandola, Michael M\u00f6hring, Brice Morin, Sebastien Mosser, Christian Moya, Seyyedeh Atefeh Musavi, Gunter Mussbacher, Andreas Naderlinger, Pascal N\u00e9gros, Bernd Neumayr, Phu Nguyen, Phuong Nguyen, Libero Nigro, Alexander Nolte, Arne Nordmann, Markus N\u00fcttgens, Bentley Oakes, Peter \u00d6lveczky, Andreas Opdahl, Mert Ozkaya, Richard Freeman Paige, Marc Pantel, Jovanka Pantovic, Nick Papoulias, Raul Pardo, Chris Partridge, Oscar Pastor, Patrizio Pelliccione, David Pereira, Diego Perez-Palacin, Barbara Pernici, Justyna Petke, Alfonso Pierantonio, Ingo Pill, Elias Pimenidis, Geert Poels, Pascal Poizat, Fiona Polack, Gregor Polan\u010di\u010d, Luigi Pomante, Saheed Popoola, Sam Procter, Luise Pufahl, Ahsan Qamar, Truong Ho Quang, Ansgar Radermacher, Akshay Rajhans, Alexander Raschke, Muhammad Rashid, Daniel Ratiu, Gil Regev, Gianna Reggio, Manfred Reichert, Hajo Reijers, Wolfgang Reisig, Guizzardi Renata, Jan Oliver Ringert, Roberto Rodr\u00edguez-Echeverr\u00eda, Marcela Ruiz, Adrian Rutle, Renaud Rwemalika, Aymen Saied, Gwen Salaun, Cesar Sanchez, Jes\u00fas S\u00e1nchez Cuadrado, Kurt Sandkuhl, Alceste Scalas, Axel Scheithauer, Johannes Schobel, Stefan Sch\u00f6nig, Ulrik Schultz, Christoph Sch\u00fctz, Cristina Seceleanu, Ed Seidewitz, Lionel Seinturier, Bran Selic, Sagar Sen, Eltefaat Shokri, Natalia Sidorova, Anthony Simons, Monique Snoeck, Stefan Sobernig, Pnina Soffer, Hui Song, Wei Song, Matthew Stephan, Janis Stirna, Volker Stolz, Harald St\u00f6rrle, Eleni Stroulia, Daniel Str\u00fcber, Patrick St\u00fcnkel, Arnon Sturm, Andreas Symeonidis, Eugene Syriani, Gabor Szarnyas, J\u00e9r\u00e9mie Tatibouet, Michael Tautschnig, Ramin Tavakoli Kolagari, Martin Thibault, Matthias Tichy, Ulyana Tikhonova, Massimo Tisi, Saurabh Tiwari, Jake Tom, Hanh Nhi Tran, Javier Troya, Christos Tsigkanos, Valent\u00edn Valero, Antonio Vallecillo, Han van der Aa, Steven van Kervel, Simon Van Mierlo, Irene Vanderfeesten, Juan Manuel Vara, Tullio Vardanega, Daniel Varro, Gabriel Wainer, Pengyuan Wang, Barbara Weber, Ron Weber, Heike Wehrheim, Marco Wehrmeister, Jun Wei, Andrew Weinert, Georg Weissenbacher, Bernhard Westfechtel, Anton Wijs, Manuel Wimmer, Karsten Wolf, Uwe Wolter, Murray Woodside, Andreas Wortmann, Franz Wotawa, Jin-Long Wu, Sobhan Yassipour-Tehrani, Sira Yongchareon, Shin Yoo, Bahman Zamani, Anna Zamansky, Jelena Zdravkovic, Bernard P. Zeigler, Man Zhang, Alois Zoitl, Athanasios Zolotas, Steffen Zschaler, and Albert Zuendorf.Below is a list of those who reviewed one or more papers for the journal in the last year. The complete list of reviewers can also be found on our website Expert's Voice\u201cThe triptych of conceptual modeling\u2014A framework for a better understanding of conceptual modeling\u201d by Heinrich C. Mayr and Bernhard ThalheimEMMSAD 2019 Special SectionGuest Editors: Iris Reinhartz-Berger and Jelena ZdravkovicRegular Papers\"Generation of hazard relation diagrams: Formalization and tool support\" by Bastian Tenbergen and Thorsten Weyer\"A framework for automated multi-stage and multi-step product configuration of cyber-physical systems\" by Safdar Aqeel Safdar, Hong Lu, Tao Yue, Shaukat Ali, and Kunming Nie\"On the benefits of file-level modularity for EMF models\u201d by Karim Jahed, Mojtaba Bagherzadeh, and J\u00fcrgen DingelThe contents of this issue are as follows:We wish you a Happy New Year with the hope that you enjoy reading the papers in this issue!Huseyin Ergin, Jeff Gray, Bernhard Rumpe, and Martin Schindler"} +{"text": "Manuscript: Differences in lipidomics may be potential biomarkers for early diagnosis of pancreatic cancerPublication: Acta Cir Bras. 2020;35(5):e202000508Doi:http://dx.doi.org/10.1590/s0102-865020200050000008On the first page of the original publication, instead to this presentation by the authors:I, Di MuII, Ming ChengIII, Yuting DouIV, Xianwei ZhangV, Zhensheng FengVI, Guangting QiuVII, Hua YuVII, Yang ChenVIII, Hong XuVIII*, Jian SunVIII*, Ling ZhouIX*Dehua ZhouConsider this:I*, Di MuII*, Ming ChengIII, Yuting DouIV, Xianwei ZhangV, Zhensheng FengVI, Guangting QiVII, Hua YuVII, Yang ChenVIII, Hong XuVIII, Jian SunVIII, Ling ZhouIXDehua Zhou"} +{"text": "Scientific Reports 10.1038/s41598-020-59342-3, published online 12 February 2020Correction to: The original version of this Article contained errors in the affiliation list.Yanbo Song was incorrectly affiliated with \u2018Life Science College, Shanxi Agricultural University, Taigu, Shanxi, 030801, PR China\u2019.Furthermore, Guoliang Wu was incorrectly affiliated with \u2018Horticulture College, Henan Agricultural University, Zhengzhou, Henan, 450002, PR China\u2019.The correct author affiliations are listed below.Affiliation 1Horticulture College, Shanxi Agricultural University, Taigu, Shanxi, 030801, PR China.Yanbo Song, Guoliang WuAffiliation 2Life Science College, Shanxi Agricultural University, Taigu, Shanxi, 030801, PR China.Xiaojing Shi, Yanli Zou, Juanru Guo, Nan Huo, Chengping Zhao and Hong LiAffiliation 3Institute of Pomology, Shanxi Academy of Agricultural Sciences, Taigu, Shanxi, 030801, PR China.Shuangjian ChenAffiliation 4Shanghai Applied Protein Technology Co., Ltd, Shanghai, 201100, PR China.Yong PengThese errors have now been corrected in the PDF and HTML versions of the article."} +{"text": "PLOS ONE 2] are tXZ and AQ agreed with the retraction. LD, YY, HL, JL, LW, YL, ZD, XJ, HW, ZL, and GZ either did not respond directly or could not be reached. CW did not agree with the retraction."} +{"text": "Correction to: Modern Pathology10.1038/s41379-019-0279-8Since the publication of this paper, the authors noticed that the affiliation information for Francesco Bertolini, Giovanna Motta, Federica Melle, Valentina Tabanelli and Angelica Calleri was not complete. The correct affiliation is shown below:Division of Haematopathology, IEO European Institute of Oncology IRCCS, Milan, ItalyGiovanna Motta, Federica Melle, Valentina Tabanelli, Angelica Calleri and Stefano A. Pileri."} +{"text": "Synsepalum dulcificum D. belongs to the Sapotaceae family, which is an evergreen shrub native to tropical West Africa. It is a kind of magical plant that has the unique characteristic of modifying sour flavors to sweet. In this study, the chloroplast genome of S. dulcificum was sequenced, assembled, and annotated firstly. Chloroplast genome size of S. dulcificum is 158,463\u2009bp, the circular chloroplast genome consists of four regions: a large single-copy region of 88,256\u2009bp, two inverted repeat regions of 25,958\u2009bp, and a small single-copy region of 18,669\u2009bp, with the GC content of 36.87%. A total of 133 genes were annotated in the S. dulcificum chloroplast genome, of which 88 were protein-coding genes (PCGs), 37 were transfer RNA (tRNA) genes, and eight were ribosomal RNA (rRNA) genes. Phylogenetic analysis showed that Pouteria campechiana was most closely related to S. dulcificum. The study provides important genomic data for further utilization and breeding of S. dulcificum. Synsepalum dulcificum D. belongs to the Sapotaceae family and frozen in liquid nitrogen. The genomic DNA was extracted using the Dneasy Plant Mini Kit (Qiagen) and then stored in the ultra-low temperature specimen library at YITC (specimen accession number: YITC-2020-FZ-S-013). DNA was sequenced using the Illumina Hiseq 2500 Platform . The complete chloroplast genome was assembled with CLC Genomics Workbench v3.6 (http://www.clcbio.com) and annotated with Dual Organelle GenoMe Annotator under the accession number MT723946, and a physical map was generated by OGDRAW (http://ogdraw.mpimp-golm.mpg.de/) , eight ribosomal RNA (rRNA) genes, and 37 transfer RNA (tRNA) genes, with a total number of 133 genes that were annotated in the S. dulcificum chloroplast genome.Chloroplast genome size of S. dulcificum and other 23 plant species was constructed to verify its phylogenetic relationship. The names of 70 genes common to all species which were used to construct the phylogenetic tree are as follows: Ndhb, Rps12, Rps11, Petn, Ndhf, Rps16, Ndhd, Rps14, Ndhj, Ndhk, Rps18, Rpl2, Ycf3, Rps7, Psab, Rps4, Rps3, Rps2, Rpl22, Rps8, Petd, Petg, Peta, Rps15, Petb, Rpoc1, Petl, Ycf4, Rpoc2, Ycf2, Rpl20, Rpl23, Rpob, Atpi, Atph, Atpb, Atpa, Ndhg, Atpf, Atpe, Psbd, Psba, Psaj, Psbc, Psbb, Psbm, Ndhc, Psbn, Psbi, Psbh, Psbk, Clpp, Psbt, Rpl16, Ndhh, Rpoa, Rpl14, Rpl36, Rpl33, Infa, Psaa, Ndhi, Psai, Ndha, Rbcl, Ndhe, Ccsa, Matk, Cema, and Psac. Multiple sequence alignment was done with MAFFT (Katoh and Standley Hydrangea petiolaris which belongs to Hydrangeaceae family and was used as the out group. The result showed that S. dulcificum was most closely related to Pouteria campechiana (S. dulcificum.A maximum-likelihood (ML) tree based on the sequences of protein-coding genes of pechiana . The stu"} +{"text": "Dekkers, Jean-Paul Vallee, Katja Derlin, Mike Notohamiprodjo, Ruth P. Lim, Stefano Palmucci, Suraj D. Serai, Joao Periquito, Zhen Jane Wang, Martijn Froeling, Harriet C. Thoeny, Pottumarthi Prasad, Moritz Schneider, Thoralf Niendorf, Pim Pullens, Steven Sourbron and Eric E. Sigmund, was originally published electronically on the publisher\u2019s internet portal on 01 November 2019 without open access. With the author(s)\u2019 decision to opt for Open Choice the copyright of the article changed on 10 January 2020 to \u00a9 The Author(s) 2020 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License ("} +{"text": "The following article was originally published in issue 9(1). It has now been added to issue 9(S2) :Posttraumatic stress and depressive symptoms in children after the Wenchuan earthquakea,b, YiMing Lianga,b, Lin Fua,b and ZhengKui LiuaJin ChengaCAS Key Laboratory of Mental Health, Institute of Psychology, Beijing, China; bDepartment of Psychology, University of Chinese Academy of Sciences, Beijing, ChinaDOI:10.1080/20008198.2018.1472992https://tandfonline.com/toc/zept20/9/sup2?nav=tocListSpecial Issue URL: The following article was originally published in issue 9(1). It has now been added to issue 8(S7) :Training the next generation of psychotraumatologists: Collaborative Network for Training and EXcellence in psychoTraumatology (CONTEXT)a, Philip Hylanda,b, Jamie Murphyc, Maj Hansend, Mark Shevlinc, Ask Elklitd, Ruth Ceannta, Cherie Armourc, Nana Wiedemanne, Mette Munke, Cecilie Dinesene, Geraldine O\u2019Haref, Twylla Cunninghamf, Ditte Askerodg, Pernille Spitzg, Noeline Blackwellh, Angela McCarthyh, Leonie O\u2019Dowdh, Shirley Scotth, Tracey Reidi, Andreas Mokakej, Rory Halpinj, Camila Pereraa,e, Christina Gleesonc,j, Rachel Frostc,h, Natalie Flanagand,j, Kinan Aldammana,e, Trina Tamrakard,i, Maria Louison Vangc,g, Larissa Sherwooda,i, \u00c1ine Traversd,f, Ida Haahr-Pedersena,g, Catherine Walshec,h, Tracey McDonaghd,f and Rikke Holm BramsendFr\u00e9d\u00e9rique Valli\u00e8resaCentre for Global Health, School of Psychology, Trinity College Dublin, Dublin, Ireland; bNational College of Ireland, Dublin, Ireland; cDepartment of Psychology, Psychology Research Institute, Ulster University, Northern Ireland; dDepartment of Psychology, University of Southern Denmark, Odense, Denmark; eInternational Federation of the Red Cross Centre for Psychosocial Support hosted by Danish Red Cross, Copenhagen, Denmark; fProbation Board of Northern Ireland, Belfast, Northern Ireland; gDanish Children\u2019s Centres, Odense, Denmark; hDublin Rape Crisis Centre, Dublin, Ireland; iPolice Service of Northern Ireland, Belfast, Northern Ireland; jSpirasi, Dublin, Ireland10.1080/20008198.2017.1421001DOI: https://tandfonline.com/toc/zept20/8/sup7?nav=tocListSpecial Issue URL:"} +{"text": "Yue Hu, Lin Zheng, Deng Pan, Lei Shao, Xianfa Xu, Yiming Yu, Qidong Zhuang, Zaichun Deng, and Zhongbo Chen should have read:\u2009 Yue Hu, Lin Zheng, Deng Pan, Lei Shao, Xianfa Xu, Yiming Yu, Qidong Zhuang, Zhongbo Chen, and Zaichun DengIn the article titled \u201cSpecial Staining of the Liquid-Based Cytopathology Test in Bronchoalveolar Lavage Fluid for Diagnosis of Invasive Pulmonary Aspergillosis with Nonneutropenic Patients\u201d , the autThe correct author order is also shown above in the author information."} +{"text": "The authors would like to correct the names and surnames of the following authors of their previous paper , Umile GInt. J. Environ. Res. Public Health2020, 17, 2974.Longo, U.G.; Risi Ambrogioni, L.; Berton, A.; Candela, V.; Massaroni, C.; Carnevale, A.; Stelitano, G.; Schena, E.; Nazarian, A.; DeAngelis, J.; et al. Scapular Dyskinesis: From Basic Science to Ultimate Treatment. Therefore, to cite this paper please use the correct reference as follows:"} +{"text": "Thunia alba (Lindley) H. G. Reichenbach is a wild ornamental orchid, and it is a rare plant species with small populations. In this study, the complete chloroplast genome sequence of T. alba was assembled using short reads produced by high-throughput sequencing technologies. The whole chloroplast genome was 159,948\u2009bp in length with a typical quadripartite structure, which consisted of a large single-copy (LSC), a small single-copy (SSC), and two inverted repeats (IRs). The sizes of LSC, SSC, and IR were 87,532, 18,852, and 26781\u2009bp, with GC contents of 35.0%, 30.3%, and 43.2%, respectively. There were a total of 135 genes, which included 88 protein-coding genes, 8 rDNA genes, 38 tRNA genes, and a pseudogene. A phylogenetic tree was generated using the maximum-likelihood method, and the results revealed that T. alba was sister to Pleione bulbocodioides and Pleione formosana, with a support rate of 100%. Thunia alba H. G. Reichenbach is a small genus belonging to family Orchidaceae, and it is composed of about six species. Thunia plants are distributed in Indonesia, Malaysia, Myanmar, Nepal, Thailand, Vietnam, India, Bhutan, and China, and T. alba is the only species found in China , Taizhou, Zhejiang, China. The CTAB method was applied to extract leaf DNA following the protocol , four rRNA genes , and seven tRNA genes were present in two copies. One copy of ycf1 locating at the border of IR/SSC was identified as a pseudogene with a size of 1035\u2009bp, while the normal ycf1 was 5568\u2009bp in length, encoding 1856 amino acids. Among the protein-coding genes, both clpP and rps12 possessed two introns, and the other 11 genes, rpl2, ndhB, ndhA, ndhB, rpl2, rpl16, petD, petB, rpoC1, atpF, and rps16, each contained one intron. Moreover, six tRNA genes, trnA-UGC, trnG-GCC, trnI-GAU, trnK-UUU, trnL-UAA, and trnV-UAC, also contained a single intron.The plastome was predicted to contain 135 genes, of which included 88 protein-coding genes, eight rDNA genes, 38 tRNA genes, and a pseudogene. Nine protein-coding genes as an outgroup. The results revealed that T. alba was sister to Pleione bulbocodioides and P. formosana, with a support value of 100% (A total of 13 chloroplast genome sequences of of 100% ."} +{"text": "European Journal of General Practice (EJGP) would like to express their gratitude to all reviewers who have advised us during the year 2019. To acknowledge their essential contribution to the European Journal of General Practice, we have listed the names of all referees who completed at least one review report in 2019.The Editors of the Aarendonk, Diederik; Abecain, Francisco; Adab, Peymane; Adam, Rosalind; Adams, Margo; Adriaenssens, Niels; Afonso, Luis; Agyeman-Yeboah, Joana; Akman, Mehmet; Albasri, Ali; Alvarez, Isabel; Anthierens, Sibyl; Aragon\u00e9s, Enric; Archibald, Lennox K.; Augustine, Erin M.; Avinadav, Efrat; Bak, Marieke; Bayona, Carol; Begum, Aysha; Belbasis, Lazaros; Berenguera, Anna; Best, James D.; Bethell, Christina D.; Bickel, Horst; Ble, Alessandro; Blozik, Eva; Boeckxstaens, Pauline; B\u00f8gelund, Mette; Boogaard, Jannie A.; Borrell, Francisco; Bosmans, Jan; Brandenbarg, Daan; Brandt, C.; Brayne, Carol; Broekema, Susanne; Brown, Stepahnie; Buchanan, Jo; Bucher, Heiner C.; Bullock, Laurna; Buntinx, Frank; Busschers, Wim; Cabral, Christie; Cals, Jochen; Campbell, Paul; Campi\u00f1ez, Manuel; Carbonnel, Fran\u00e7ois; Carrasquillo, Olveen; Cartwright, Claire; Chen, Meixuan; Chung, Paul J.; Clark, Christopher E.; Clark-Grill, Monika; Cohen, Debbie L.; Cohen, Jordana; Coker, Tumaini R.; Colliers, Annelies; Cooper, Jason; Cordoba, Gloria Correia de Sousa, Jaime; Cots, Josep Maria; Cottrell, Lizzie; Cutler, Lizl Dal Bianco, Peter Davis, Ann de la Flor, Josep; De Smedt, Delphine; de Sutter, An; Deasy, C.; Denekens; Joke; Digby, Robin; Dijkland, Simone; Dinant, Geert-Jan; Dinnes, Jacqueline; Discigil; Guzel; Doherty, Sarah; Dreno, Brigitte; Duggleby, Wendy; Duimel-Peeters, Inge; Bell, Mark H.; Eichler, Tilly; Eldin, Carole; Elfstr\u00f6m, K.Miriam; Ellbrant, Julia A.; Endacott, Ruth; Falger, Paul; Fasset, Rob; Fernandes, Susana; Finney, Andrew; Firet, Lotte; Fischer, Gabriele; Fletcher, Benjamin; Fouche, Pieter; Fox, Larry A.; Freund, Tobias; Gallagher, Joe; Geersing, Geert-Jan; Gerber, Jeffrey; Gertig, Dorota M.; Godycki-Cwirko, Maciek; Goicolea, Isabel; Goodloe, Jeffrey; Grand, Johannes; Grassi, Guido; Greer, Joy A.; Griebling, Thomas; Griffin, Tania; Gross, D.; Gryglewska, Barbara; Gucek, Nena; Guedj, Romain; Gunvar, Tolga; Guenoer, Ken; Haidinger, Gerald; Hallberg, Ingalill Rahm; Hamashima, Chisato; Hansmann, Yves; Harskamp, Ralf; Hay, Alastair; Hayward, Gail Nicola; Hedin, Katarina; Helliwell, Toby; Helsper, Charles; Hernandez Santiago; Virginia; Heron, Neil; Herrmann, Wolfram; Hinrichs, Timo; Holm, Maja; Hopstaken, Rogier; Huesing, Paul; Hughes, Lloyd; Huibers, Linda; Iacob, Mihai; Ingram, Jenny; Janne Fangel, Jensen; Jardim, Thiago Veiga; Jensen, Henry; Jensen, Martin; Jeyashree, Kathiresan; Junius-Walker, Ulrike; Kanabar, Dipak; Keiren, Suzanne; Kendir, Candar; Keohane, David; Kern, Jean-Baptiste; Kluetz, Paul; Knottnerus, Bart; Koes, Bart; Koshiaris, Constantinos; Kostev, Karel; Kotseva, Kornelia; Kraaijvanger, Nicole; Krist, Alex H.; Ku\u015fkonmaz, \u015eerife; Lagro-Jansen, Toine; Lamarre-Cliche; Maxime; Lan, Patrick G.; LeBlanc, Constance; Leeflang, Mariska; Legido-Quigley, Helena; Legrand, Deplphine; Leysen, Bert; Lieb, Klaus; Liira, Helena; Lim, Anita; Lischka, Martin; Llor, Carl; Lloyd-Williams, Mari; Loehr, Laura; Lofters, Aisha; Lowres, Nicole; Maarsingh, Otto; Madurell, Jordi; Maertens, H.; Maerz, Richard; Magin, Parker; Mahabee-Gittens, E. Melinda; Mahajan, Preetam; Maier, Manfred; Mallen, Christian; Marshall, Sara; Martin Lesende, I\u00f1aki; Martinez-Gonzalez, Nahara; Marzuillo, Pierluigi; Mathes, Erin F. D.; Mathhys, Jan; Mazaheri, Monir; McCabe, Marita; McGorrian, Catherine; McManus, Richard J.; McWhannell, Nicola; Melbye, Hasse; Merianos, Ashley L.; Missiou, Aristea; Moberg, Anna; Moragas-Moreno, Ana; Morato, M. Lluisa; Morita; Tatsuya; Moser, Albine; Moth, Grete; Murphy, Marie; Muth, Christiane; Naouri, Diane; Nekhliyudov, Larrissa; Neri, Emanuele; Ntzani, Evangelia; Nygaard, Peter; O\u2019Caoimh, R.; Olsman, Erik; Onakpoya, Igho; Pallan, Miranda; Park, Young-Jae; Parry, Emma; Perez Cachafeiro, Santiago; Peteiro, Jesus; Petek Ster, Marija; Petek, Davorina; Polomeni, Pierre; Prasad, Ramakrishna; Pujol, Jesus; Qaseem, Amir; Raman, Gowri; Rat, C\u00e9dric; Rattray, Nicholas A.; Rebnord, Ingrid; Reid, Jim; Rimoin, Anne; Roodbol; Petrie; Rouge-Bugat, Marie-Eve; Rubio P\u00e9rez, Francisco; Rubio-Guerra, Alberto; Rustoen, Tone; Sachs, Alfred; Sancho-Garnier, Helene; Schmidt, Morten; Schuers, Matthieu; Schwartz, Claire; Scolnik, Dennis; San Sebastian, Miguel; Senan Sanz, M. Rosa; Shepherd, Tom; Shewade, Hemant Deepak; Silina, Vija; Siontis, George; Siontis; Konstantinos; Spooner, Sharon; Staessen, Jan A.; Standage, Martyn; Stewart, Robert; Stoffers, Jelle; Sturman, N; Sultana, Farhana; Svab, Igor; Szecsenyi, Joachim; Tatsioni, Ath\u00edna; Taylor, Elizabeth Johnston; Taylor, Leslie; Thompson, Paul; Thomsen, Janus; Thulesius, Hans; Thyrian, Jochen Rene; Tiro, Jasmin A.; Tomasik, Tomasz; Tonkin-Crine, Sarah; Topsever, Pinar; Trolle, Laura; Troncoso, Amelia; Twigg, Diane E.; Valderas, Jose M; van der Steen, Jenny T.; van Doorn, Sander; van Lieshout, Jan; van Marwijk, Harm; Van Royen, Paul; van Schayck, Constant; Vankrunkelsven, Patrick; Varva, Olimpia-Maria; Vaughan Sarrazin, Mary; V\u00e1zquez-L\u00f3pez, Esther; Verbakel, Jan; Verhoeven, Veronique; Visca, Modesta; Vorspan, Florence; Wallace, Paul; Wancata, Johannes; Watzke, Herbert; van Weert, Henk; Weinzimer, Stuart A.; Wensing, Michel; Whited, John D.; Windak, Adam; Winer, Rachel L.; Wong, Eliza; Wu, Ann Chen; Wucherer, Diana; Young, Richard; Yuguero Torres, Oriol; Zhu, Dingliang; Zittleman, Linda; Zwakhalen, Sandra MG.European Journal of General Practice accepts around 20% of all submitted manuscripts.We want to thank you all for your appreciated assistance! Your review reports were very valuable feedback to the authors and helped us to make our editorial decisions. Currently, the http://mc.manuscript-central.com/ejgp and log in to modify your profile.Although our database of authors and reviewers steadily increases, the Editors do not always find it easy to find referees within the journal\u2019s deadlines. Therefore, we sincerely hope that all reviewers want to continue their review work in the future. If you would like to update your reviewer account, e.g. to specify your expertise, please visit European Journal of General Practice who would like to review manuscripts for this journal, to visit http://mc.manuscriptcentral.com/ejgp and to register as \u2018new user\u2019, i.e. to complete the details of their expertise. We provide a format to facilitate the review.In addition, we invite all readers of the ejgp-agermeraad@maastrichtuniversity.nl).If you have comments regarding the journal or its peer review process, we invite you to contact the editorial office ejgp-jstoffers@maastrichtuniversity.nlJelle Stoffers"} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-62150-4, published online 23 March 2020.Correction to: The original version of this Article contained errors in the author affiliations.Otto Miettinen was incorrectly affiliated with \u2018Department of Plant and Microbial Biology, University of California Berkeley, Berkeley, CA, 94,720, USA.\u2019 The correct affiliation is listed below.Mycology Unit, Botanical Museum, Finnish Museum of Natural History, University of Helsinki, P.O. Box 7, Helsinki, Finland.Fei Ren was incorrectly affiliated with \u2018Mycology Unit, Botanical Museum, Finnish Museum of Natural History, University of Helsinki, P.O. Box 7, Helsinki, Finland\u2019. The correct affiliations are listed below.Faculty of Agriculture and Forestry, Department of Forest Sciences, University of Helsinki, P.O. Box 27, FIN-00014, Helsinki, Finland.Forestry experiment center of north China, Chinese Academy of Forestry, 102300, Beijing, China.Michael R. Thon was incorrectly affiliated with \u2018Forestry experiment center of north China, Chinese Academy of Forestry, 102300, Beijing, China\u2019. The correct affiliation is listed below.Universidad de Salamanca, Instituto Hispano-Luso de Investigaciones Agrarias (CIALE), Villamayor, Spain.Igor V. Grigoriev was incorrectly affiliated with \u2018Universidad de Salamanca, Instituto Hispano-Luso de Investigaciones Agrarias (CIALE), Villamayor, Spain\u2019. The correct affiliations are listed below.US Department of Energy Joint Genome Institute, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA, 94720, USA.Department of Plant and Microbial Biology, University of California Berkeley, Berkeley, CA, 94720, USA.These errors have now been corrected in the PDF and HTML versions of the Article."} +{"text": "Scientific Reportshttp://doi.org/10.1038/s41598-020-75760-9, published online 29 October 2020Correction to: In the original version of this Article, authors Siok Fong Chin and Rahman Jamal were incorrectly affiliated with \u201cDepartment of Community Health, Faculty of Medicine, UKM Medical Center, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000, Cheras, W. Persekutuan, Malaysia.\u201dThe correct affiliation for Siok Fong Chin and Rahman Jamal is listed below.Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Jalan Yaacob Latif, Bandar Tun Razak, 56000, Cheras, W. Persekutuan, MalaysiaThis error has now been corrected in the PDF and HTML versions of the Article."} +{"text": "Genetics in Medicine 2020; 10.1038/s41436-020-0766-9, published online 03 March 2020Correction to: In the original version of this Article, the contribution of the Splicing and Disease Working Group was not acknowledged. The PDF and HTML versions of the Article have now been corrected to include the following clinical collaborators:Swati Naik, Nicola Ragge, Helen Cox, Jenny Morton, Mary O'Driscoll, Derek Lim, Deborah Osio, Frances Elmslie, Camilla Huber, Julie Hewitt; Heidy Brandon, Meriel McEntagart, Sahar Mansour, Nayana Lahiri, Esther Dempsey, Merrie Manalo, Tessa Homfray, Anand Saggar; Jin Li, Julian Barwell; Kate Chandler, Tracy Briggs, Sofia Douzgou, Julian Adlard, Alison Kraus; Sarju Mehta; Amy Watford, Alan Donaldson, Karen Low; Gabriela Jones, Abhijit Dixit, Elizabeth King, Nora Shannon; Marios Kaliakatsos; Merrie Manalo; Shelagh Joss; Meena Balasubramanian, Diana Johnson; Sarah Everest; Claire Salter, Victoria Harrison, Gillian Wise, Audrey Torokwa, Victoria Sands, Esther Pyle, Tessy Thomas, Katherine Lachlan, Nicola Foulds, Andrew Lotery, Andrew Douglas, Simon Hammans, Emily Pond, Rachel Horton, Mira Kharbanda, David Hunt, Charlene Thomas, Lucy Side, Catherine Willis, Stephanie Greville-Heygate, Rebecca Mawby, Catherine Mercer, Karen Temple, Esther Kinning; Ognjen Bojovic; L. Archer."} +{"text": "Liu YJ, Chen MJ, Guo C, Zhong W, Ye QY, Zhao J, Zhou Q, Gao XX, Liu XY, Liang HG, Shi YQ, Jiang DLN, Liu HS, Xu Y, Li SQ and Wang MZ contributed data collection. Liu YJ, Chen MJ, Guo C, Xu Y, Li SQ and Wang MZ provided critical inputs on design, analysis, and interpretation of the study. Liu YJ, Chen MJ, Guo C, Xu Y, Li SQ and Wang MZ contributed manuscript writing. All the authors had access to the data. All authors read and approved the final manuscript as submitted."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-73788-5, published online 14 October 2020Correction to: The original version of this Article contained errors in the spelling of the authors Roberto Grassi, Roberta Fusco, Maria Paola Belfiore, Alessandro Montanelli, Gianluigi Patelli, Fabrizio Urraro, Antonella Petrillo, Vincenza Granata, Palmino Sacco, Maria Antonietta Mazzei, Beatrice Feragalli, Alfonso Reginelli & Salvatore Cappabianca which were incorrectly given as Grassi Roberto, Fusco Roberta, Belfiore Maria Paola, Montanelli Alessandro, Patelli Gianluigi, Urraro Fabrizio, Petrillo Antonella, Granata Vincenza, Sacco Palmino, Mazzei Maria Antonietta, Feragalli Beatrice, Reginelli Alfonso & Cappabianca Salvatore.These errors have now been corrected in the PDF and HTML versions of the Article."} +{"text": "Harpegnathosvenator, Monomoriumpharaonis, Nylanderiabourbonica, Odontoponeradenticulata, Polyrhachistyrannica and Pseudoneoponerabispinosa. The checklist presents distribution records for Nepalese ant species and provides comparisons with the neighboring countries of China and India.The location of Nepal in the Central Himalaya promotes high habitat and species diversity. Ant diversity is likely high, but there have been few studies of the diversity and distribution of ants in Nepal. Here we present an updated checklist list of Nepalese ants that includes 128 named species in 48 genera and eight subfamilies. Among these species, 21 species have a type locality from Nepal, nine species are endemic to Nepal, and three are introduced species. We add six new ant records for Nepal, namely Formicidae) are one of the most successful groups of organisms on the planet is the first comprehensive global database with ant species records in available publications and existing databases ;MCZCMuseum of Comparative Zoology, Harvard University, Cambridge, Massachusetts, USA;MHNGMus\u00e9um d\u2019Histoire Naturelle, Geneva, Switzerland;MSNGMuseo Civico di Storia Naturale \u201cGiacomo Doria\u201d, Genoa, Italy;NHMBNaturhistorisches Museum, Basel, Switzerland;NHMUKThe Natural History Museum, London, United Kingdom;NHMWThe Natural History Museum Vienna, Austria;PSWC Philip S Ward collection, California, USA;SCHULZ Ted Schulz private collection, Washington DC, USA;SIZKSchmalhausen Institute of Zoology of the Ukrainian National Academy of Sciences, Kiev;UCDCBohart Museum of Entomology, University of California, Davis;USNMUnited States National Museum of Natural History, Washington DC.The checklist of the ants of Nepal includes 128 valid species. These ant species represent ca. 0.9% of the global ant diversity . The lisAmblyoponinae, Dolichoderinae, Dorylinae, Formicinae, Leptanillinae, Myrmicinae, Ponerinae, and Pseudomyrmecinae. The ant species and genus level richness for each subfamily is given in Table The presented checklist is comprised of 128 named ant species belonging to 48 genera and eight subfamilies (see checklist below). The eight recorded subfamilies are Myrmicinae is the most diverse subfamily in the region with 19 genera and 63 species, followed by Formicinae (11 genera and 36 species), Ponerinae (8 genera and 13 species), Dolichoderinae (4 genera and 6 species), Dorylinae (3 genera and 4 species), Pseudomyrmecinae (1 genus and 4 species), Leptanillinae (1 genus and 1 species) and Amblyoponinae (1 genus and 1 species). Over 87% of all described ant species of the world are from four main subfamilies, Myrmicinae, Formicinae, Ponerinae and Dolichoderinae , Strumigenys (8), Cardiocondyla (7), Prenolepis (6), Polyrhachis (7), Pheidole (5) and Tetraponera (4), Lasius (4). Eighteen other genera contain two or three species: Formica (3), Nylanderia (2) Lepisiota (2), Tetramorium (3), Aphaenogaster (3), Meranoplus (3), Carebara (3), Dorylus (2), Brachyponera (2), Leptogenys (2), Crematogaster (3), Lordomyrma (2), Technomyrmex (2), Dolichoderus (2), Monomorium (3), Diacamma (2), Odontoponera (2) and Pseudoneoponera (2). Twenty-two genera are represented in Nepal by a single species. The most speciose ant genus in India is Camponotus with 83 species in the neighboring countries of China are new records for Nepal. The ant genus Harpegnathos is recorded for the first time for Nepal. The most speciose subfamily and genus in Nepal are Myrmicinae and Myrmica respectively. Overall, 21 species were first described from Nepalese specimens, nine species are endemic to Nepal, and three ant species are introduced species. No ant genera are known to be endemic to Nepal. Nepal shares over half of the listed ant species with its neighboring countries.An updated checklist of the ants of Nepal contains 128 valid ant species belonging to 48 genera and eight subfamilies. Six ant species .Stigmatommapertinax Distribution in Nepal. Taplejung: Maewakhola (= Maiwakhola), Sanghu, KH Hyatt leg., NHMUK Distribution in Nepal. Solukhumbu: Tate, 2900 m Distribution in Nepal. Sankhuwasabha: 16 km NE Tumlingtar, 740 m, C Carpenter leg., PSWC Distribution in Nepal. Gorkha, AR Sthapit leg. .Ooceraeabiroi Distribution in Nepal. Bara: Amlekhgunj, EI Coher leg (Sysciasylvestrii); Nepal ; Nepal .Type-species.Acropygaacutiventris Roger, 1862: 243, Type locality. Sri Lanka.Acropygayaeyamensis Terayama & Hashimoto, 1996Distribution in Nepal. Lalitpur: Godavari (= Godawari), C Baroni Urbani leg., MCZC, NHMB Distribution in Nepal. Dolakha: Jarsa, 2000 m Distribution in Nepal. Kavrepalanchok: Chyaubas, 2000 m; Dolakha: Sikris, 2300 m, J Quinlan leg.; Kaski: Phewa lake, Pokhara, 830 m., J Quinlan leg. Distribution in Nepal. Kaski: Pokhara, 1000 m, J Quinlan leg. Distribution in Nepal. Kaski: Phewa lake, Pokhara, 830 m, J Quinlan leg. Distribution in Nepal. Specific locality unknown , 4800 m (Mani and Singh 1862).Type-species.Formicanigra Linnaeus, 1758: 580, Type locality. Europe.Lasiusalienoflavus Bingham, 1903Distribution in Nepal. Jumla: Talphi, H Franz leg., NHMB Distribution in Nepal. Solukhumbu: Junbesi, 2700 m Distribution in Nepal. Myagdi: Bakhri Kharka, 1830 m, J Quinlan leg. Distribution in Nepal. Dolakha: Jiri Khola valley, 1900 m; Solukhumbu: Ringmo\u2013Junbesi, 2800 m; Ghai, 2700 m; Tate, 2900 m; Nare Ghat, 2700 m; Ramechhap, Likhu Khola, 1690 m Distribution in Nepal. Dolakha: Jiri Khola Valley, 1900 m; Solukhumbu: Ringmo\u2013Junbesi, 2800 m Distribution in Nepal. Kavrepalanchok/Sindhupalanchok: Charnawati/Zharange Khola to Kiratechap, 1160\u20131800 m, Bhotekoshi, 1150 m; Tamba Kosi, 1150\u20131450 m, Dhading: Dhunibesi, KC Sharma, J Hanstek and others leg. Distribution in Nepal. Nagarjun forest, Shivapuri-Nagarjun National Park, 1660 m, IP Subedi leg., CDZMTU.Nylanderiaindica Distribution in Nepal. Solukhumbu: Thaksindhu, 3500 m, Ringmo\u2013Junbesi, 2800 m, Tate, 2900 m; Ramechhap: Likhu khola, 1690 m Distribution in Nepal. Region del Terai: Ratnanagar, 200 m, M Granados leg., KGAC Distribution in Nepal. Nagarjun forest, Shivapuri-Nagarjun National Park, 1650 m, IP Subedi leg., CDZMTU.Polyrhachisthompsoni Bingham, 1903Distribution in Nepal. Makawanpur: 14.5 km W. Hetauda, 400 m, ES Ross and DQ Cavagnaro leg., CASC , 1450 m, C Baroni Urbani, leg., NHMB Distribution in Nepal. Taplejung: Tseram, NE Nepal, 3600 m, Pache leg., MHNG Distribution in Nepal. Solukhumbu: Tate, 2900 m, Sikris, 2333 m, KM Hyatt leg. Distribution in Nepal. Dolakha: Sikris \u2013 Jarsa, 1950\u20132300 m; Bakhri Kharka, 1833 m, J Quinlan leg. .Cardiocondylakagutsuchi Terayama, 1999Distribution in Nepal. Kaski: Pokhara vic., 27 km NW Distribution in Nepal. Specific locality unknown Distribution in Nepal. Bhaktapur Distribution in Nepal. Kaski: Lumle Distribution in Nepal. Baredamar, EI Coher leg Distribution in Nepal. Specific locality unknown, MCZC Distribution in Nepal. Specific locality unknown, MCZC , 250 m, C Baroni Urbani leg., NHMB, NHMUK Distribution in Nepal. Kathmandu, 1350 m, Allen leg., NHMUK; Makawanpur: Hetaura (= Hetauda), Franz leg., NHMB; 9 miles (= 14.5 km) W Hitaura (= Hetauda), 400 m, Ross and Cavagnaro leg., CASC, Bara: Amlekhgunj, Franz leg.; Goropani, W Pokhara, NHMB .Monomoriumdichroum Forel, 1902Distribution in Nepal. Makawanpur: 9 miles (= 14.5 km) W Hitaura (= Hetauda), 400 m, ES Ross and DQ Cavagnaro leg., CASC Distribution in Nepal. Tanahun: Jamune, 530 m, IP Subedi leg., S Yamane det., CDZMTU.Monomoriumsahlbergi Emery, 1898Distribution in Nepal. Makawanpur: 9 mi (= 14.5 km) W Hitaura (= Hetauda), 400 m, ES Ross and DQ Canvagnaro leg., CASC , 3900 m, Tate, 2900 m; Sindhupalchok: Hoxe (= Hokse), 1000\u20132000 m Pati, Gosaikunda, H Franz leg.; Sankhuwasabha: Maghang Kharka, Makalu Barun Conservation Area, 2548 m, D Emmett and Subedi leg. Sankhuwasabha: Maghang Kharka, Makalu Barun Conservation Area, 2634 m, Alpert, Alonso and Subedi leg., NHMB, SIZK, ELMES .Perissomyrmexmonticola Baroni Urbani & De Andrade, 1993Distribution in Nepal. Kosi, Chauki, 2600\u20133000 m, NHMB , Type locality. Malakka, West Malaysia.Pristomyrmexsulcatus Emery, 1895Distribution in Nepal. Likhu Khola, 1700 m; Tate, 2900 m Distribution in Nepal. Kathmandu, MG Allen leg. Distribution in Nepal. Taplejung: Maiwa Khola, Sanghu, 1981 m, KH Hyatt leg., NHMUK , 250 m, 5 km E of Manhari, 350 m, NHMB Nepal Exped., NHMB Distribution in Nepal. Lalitpur: Godawari, 1700 m, M Brendell, NHMUK, MCZ Distribution in Nepal. Kathmandu, MG Allen leg., NHMUK Distribution in Nepal. Taplejung, RL Coe leg., NHMUK luteipescroceicornis Emery, 1900: 315, Type locality. New Guinea.Brachyponerachinensis Distribution in Nepal. Sankhuwasabha: Makalu Barun National Park, 2400 m, G Alpert et al. leg., MCZ Distribution in Nepal. Dolakha: Jiri Khola, 1900 m; Kavrepalanchok, 1750 m Distribution in Nepal. Specific locality unknown Distribution in Nepal. Specific locality unknown Distribution in Nepal. Kaski: Pokhara e Goropani, H Franz leg., NHMB Distribution in Nepal. Tanahun: Jamune, 530 m, IP Subedi leg., S Yamane det., CDZMTU.Type-species.Leptogenysfalcigera Roger, 1861: 42, Type locality. Sri Lanka.Leptogenysdiminuta Distribution in Nepal. Locality unknown, 830\u20131900 m , 1400 m; Kaski: Phewa lake (Pokhara), 830 m, J Quinlan leg. Distribution in Nepal. Tanahun: Jamune, 530 m, IP Subedi leg., S Yamane det., CDZMTU.Odontoponeratransversa Distribution in Nepal. Kaski: Pokhara, 800 m, D Little leg. , New Guinea.Pseudoneoponerabispinosa Distribution in Nepal. Tanahun: Jamune, 530 m, IP Subedi leg., CDZMTU.Pseudoneoponerarufipes Distribution in Nepal. Dolakha: Namdu, 1450 m, Jarsa, 2000 m, Kavrepalanchok, 1750 m , Type locality. Maharashtra, India.Tetraponeraallaborans Distribution in Nepal. Dolakha: Namdu, 1450 m Distribution in Nepal. Bara: Amlekhgunj, 520 m, EI Coher leg., PSWC Distribution in Nepal. Bara: Amlekhgunj, 520 m, EI Coher leg. Distribution in Nepal. Kavrepalanchok: Cha Khola valley, 1000 m; Kaski: Pokhara, 1000 m; J Quinlan leg. (UCDC, Janakpur, Sunkoshi river, near Khurko, L Morrison leg., PSWC, Kosi, 12 km ENE Tumlingtar, 1150 m, C Carpenter leg., Chitwan National Park, 600 m, A Hacklander leg., PSWC, Kosi, Arun valley, 610 m, L Swan leg, CASC (CDZMTU.lan leg. , Bagmatieg, CASC . Tanahunantmaps.org are not substantiated by specimens, or literature records and/or are with references unverified. These species are marked as dubious and have been excluded from the main species list. We present them below with explanation of their exclusion (Table Thirty-seven ant species reported in on Table ."} +{"text": "The first, third, and fourth authors, Jakob D. Wikstrom, Margareta Frohm-Nilsson, and Ada Girnita, should be noted as contributing equally to this work."} +{"text": "Mushrooms are used in their natural form as a food supplement and food additive. In addition, several bioactive compounds beneficial for human health have been derived from mushrooms. Among them, polysaccharides, carbohydrate-binding protein, peptides, proteins, enzymes, polyphenols, triterpenes, triterpenoids, and several other compounds exert antiviral activity against DNA and RNA viruses. Their antiviral targets were mostly virus entry, viral genome replication, viral proteins, and cellular proteins and influenced immune modulation, which was evaluated through pre-, simultaneous-, co-, and post-treatment in vitro and in vivo studies. In particular, they treated and relieved the viral diseases caused by herpes simplex virus, influenza virus, and human immunodeficiency virus (HIV). Some mushroom compounds that act against HIV, influenza A virus, and hepatitis C virus showed antiviral effects comparable to those of antiviral drugs. Therefore, bioactive compounds from mushrooms could be candidates for treating viral infections. Lentinus (Lentinula), Auricularia, Hericium, Grifola, Flammulina, Pleurotus, Lactarius, Pisolithus, Tremella, Russula, Agaricus, and Cordyceps are well-known edible mushroom species .,35.P. osCaliciviridae .,37.CalicI. obliquus significantly decreased MNV-1 titers by 91.67 \u00b1 3.36% when pretreated in RAW 264.7 cells .,39.38,39G. lucidum reduced the viral RNA level by pre- and cotreatment in human rhabdomyosarcoma (RD) cells [Triterpenoids from D) cells . The intA. brasiliensis and L. edodes exerted antiviral activity against PV-1 (P. pini showed the reduction of the coxsackievirus B3 (CVB3) titer when it was simultaneously treated with CVB3 in HeLa cells , proteins , peptides, enzymes (laccase and tyrosinase), polyphenols, triterpenes, triterpenoids, and several other compounds. They reportedly inhibit viral entry, replication, viral enzyme, the expression of viral proteins, and cellular proteins, and enhance immunity against HSV-1, HSV-2, influenza A virus, HIV, HCV, FCV, and EV71. In addition, polysaccharide, sulfated polysaccharide, acidic polysaccharide, peptidomannan, and peptide relieved viral diseases caused by HSV, influenza virus, and HIV. Antiviral mechanisms of mushroom compounds were well defined against enveloped viruses; however, that still needs to be evaluated against non-enveloped viruses such as NoV and enteroviruses. Bioactive metabolites derived from mushrooms could be considered as potential antiviral candidates against DNA and RNA viruses."} +{"text": "The Editor has retracted this article because Authors Chuncheng Zhang, Jing Yue, Mingyue Li, Wei Jiang, Yu Pan, Zhimin Song, Cailian Shi, Weixuan Fan and Zhenxiang Pan all agree to this retraction."} +{"text": "Editor-in-ChiefRob DeSalle - American Museum of Natural History, 79th Street at Central Park W, New York, NY 10024, USA. http://desalle.amnh.orgAssociate EditorMikhail Alexeyev - University of South Alabama, Dept. Physiology and Cell Biology, 5851 USA Dr. North, MSB3074, Mobile, AL 36688, USAManaging & Handling EditorSergios-Orestis Kolokotronis - SUNY Downstate Medical Center, School of Public Health, 450 Clarkson Avenue, Mail Stop Code 43, Brooklyn, NY 11203-2098, USA"} +{"text": "Correction to: BMC Emerg Med 20, 16 (2020)https://doi.org/10.1186/s12873-020-00308-zThe original article containsAcknowledgementsMembers of the ICPP also include Yael Errera-Ankri, Sarah Freedman, Jessie Frijling, J Carel Goslings, Jan Luitse, Alexander McFarlane, Derrick Silove, Hanspeter Moergeli, Joanne Mouthaan, Daisuke Nishi, Meaghan O\u2019Donnell, Mark Rusch, Marit Sijbrandij, Sharain Suliman, and Mirjam van Zuiden. We are grateful for the contributions of Paul O\u2019Connor at the Nathan Kline Institute for his invaluable assistance in data management and quality assurance."} +{"text": "In the title of Mixed-effects cumulative logistic regression models were run separately. The random effects were the 18 administrative districts.Analysis adjusted for sex, age, household size, educational attainment, equivalent income, history of cancer, hospitalization during the past year, fall during the past year, alcohol drinking status, and TMIG-IC score."} +{"text": "In this paper,Therefore, the correct author list is:Caroline Tuchmann\u2010Durand, Eloise Thevenet, Florence Moulin, Fabrice Lesage, Juliette Bouchereau, Mehdi Oualha, Diala Khraiche, Ana\u00efs Brassier, Camille Wicker, St\u00e9phanie Gobin\u2010Limballe, Jean\u2010Baptiste Arnoux, Florence Lacaille, Clotilde Wicart, Bruno Coat, Joel Schlatter, Salvatore Cisternino, Sylvain Renolleau, Philippe\u2010Henri Secretan, Pascale De Lonlay."} +{"text": "Scientific Reports 10.1038/s41598-017-12412-5, published online 25 October 2017Correction to: The original version of this Article omitted an affiliation for Thibaut Pollina and Wenche Eikrem. The correct affiliations are listed below:Thibaut Pollina:Sorbonne Universit\u00e9s, UPMC Universit\u00e9 Paris 06, CNRS, UMR7144, Station Biologique de Roscoff, Roscoff, FranceNorwegian Institute for Water Research, Gaustadall\u00e9en 21, 0349, Oslo, NorwayDepartment of Biosciences, University of Oslo, PO Box 1066, Blindern, 0316, Oslo, NorwayWenche Eikrem:Norwegian Institute for Water Research, Gaustadall\u00e9en 21, 0349, Oslo, NorwayNatural History Museum, University of Oslo, PO Box 1069, Blindern, 0316, Oslo, NorwayDepartment of Biosciences, University of Oslo, PO Box 1066, Blindern, 0316, Oslo, NorwayThis has now been corrected in the HTML and PDF versions of this Article, and in the accompanying Supplemental Material."} +{"text": "Robinson, Maximillian Pietsch, Thomas Wolfers, Paul Aljabar, Lucilio Cordero Grande, Rui P.A.G. Teixeira, Jelena Bozek, Andreas Schuh, Antonios Makropoulos, Dafnis Batalle, Jana Hutter, Katy Vecchiato, Johannes K. Steinweg, Sean Fitzgibbon, Emer Hughes, Anthony N. Price, Andre Marquand, Daniel Reuckert, Mary Rutherford, Joseph V. Hajnal, Serena J. Counsell, A. David Edwards. Modelling brain development to detect white matter injury in term and preterm born neonates. Brain 2020; 143: 467\u2013479. doi:The authors apologize for misspelling the name of the authors Emma C. Robinson, Joseph V. Hajnal, Anthony N. Price and A. David Edwards. These have now been corrected."} +{"text": "Paenibacillus alvei and its utilization in lactic acid production by simultaneous saccharification and fermentation. Open Life Sci. 2020;15:185\u201397. doi: 10.1515/biol-2020-0019\u201d the affiliations of authors Kamal A. M. Abo-Elyousr and Zakaria A. Mohamed are incorrect.In the published article \u201cMostafa YS, Alamri SA, Hashem M, Nafady NA, Abo-Elyousr KAM, Mohamed ZA. Thermostable cellulase biosynthesis from The correct affiliations of Kamal A. M. Abo-Elyousr and Zakaria A. Mohamed are as follows:Kamal A. M. Abo-Elyousr, Assiut University, Faculty of Agriculture, Plant pathology Department, Assiut, Egypt; King Abdulaziz University, Faculty of Meteorology, Environmental and Arid Land Agriculture, Department of Arid Land Agriculture, Saudi ArabiaZakaria A. Mohamed, Department of Botany & Microbiology, Faculty of Science, Sohag University, Sohag, 82524, Egypt"} +{"text": "The following article was originally published in issue 9(S3) . It has now been moved to standard issue 10(1):Fear extinction learning improvement in PTSD after EMDR therapy: an fMRI studya, Myriam El Khoury-Malhameb, Emmanuelle Reynaudc, Sarah Boukezzic, A\u00efda Cancelc, Xavier Zendjidjiand, Val\u00e9rie Guyond, Jean-Claude Samueliand, Eric Guedje, Thierry Chaminadec and Stephanie KhalfaaPierre-Fran\u00e7ois RousseauaLaboratoire de Neurosciences Sensorielles et Cognitives, UMR 7260 CNRS, Marseille, France; bSchool of Arts and Sciences, Neurosciences, Neuropsychology, Lebanese American University, Beirut, Lebanon; cTimone Institute of Neuroscience, UMR 7289 CNRS, Marseille, France; dDepartment of Psychiatry, La Conception University Hospital, Marseille, France; eBiophysics and Nuclear Medicine Department, Timone Hospital, Marseille, France10.1080/20008198.2019.1568132DOI:"} +{"text": "Scientific Reports 10.1038/s41598-017-09783-0, published online 25 August 2017Correction to: G\u00e9nesis Vega was omitted from the author list in the original version of this Article. This has been corrected in the PDF and HTML versions of the Article, and in the accompanying Electronic Supplementary Material.The updated Author List now reads:Sebasti\u00e1n Alarc\u00f3n, Wallys Garrido, G\u00e9nesis Vega, Claudio Cappelli, Raibel Su\u00e1rez, Carlos Oyarz\u00fan, Claudia Quezada, Rody San Mart\u00ednThe Author Contributions section now reads:Conceived and designed the experiments: SA, CO, CQ, RSM. Performed the experiments: SA, WG, GV, CC, RS, CO. Analyzed the data: SA, WG, GV, CC, RS, CO, CQ, RSM. Contributed reagents/materials/analysis tools: SA, WG, CC, RS, CO, CQ, RSM. Wrote the paper: SA, CQ, RSM."} +{"text": "Correction to: BMC Med Educ 20, 341 (2020)https://doi.org/10.1186/s12909-020-02257-4Following publication of the original article , the corIncorrect: General and Breast Surgery, Department of General and Special Surgery, Faculty of Medicine, Hashemite University, Irbid-Amman Street, Al Husn, P.O.Box 3, Irbid 21510, JordanCorrect: Department of General and Special Surgery, Faculty of Medicine, Hashemite University, Zarqa, Jordan.The original article has been corrected."} +{"text": "Nature Communications 10.1038/s41467-019-14026-z, published online 09 January 2020.Correction to The original version of this Article contained errors in the author affiliations. Affiliation 2 incorrectly read Laboratory of Integrative Neuroscience, Institute of Biology, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. This has been corrected to Leibniz Institute for Neurobiology, Magdeburg, Brenneckestr. 6, 39118 Magdeburg, Germany. Also, the affiliation of Kentaroh Takagaki with Laboratory in Sensory Physiology, Institute of Biology, Otto-von-Guericke University Magdeburg, Leipziger Strasse 44, 39120, Magdeburg, Germany was inadvertently omitted.These have now been corrected in both the PDF and HTML versions of the Article."} +{"text": "Huang HY, Fang Y, Fang H, Wu DW, Wang SH,Bai Y, Yu AQ, Wang H, Sun C, Yu Y, Fan Y, Yang C, Shi JF,Li N performed the experiments. Huang HY, Fang Y, Shi JF,Li N analyzed the data. Huang HY, Yang C, Shi JF, Shi JFcontributed analysis tools. Huang HY, Fang Y, Shi JF, Li Nprovided critical inputs on design, analysis, and interpretationof the study. All the authors had access to the data. All authorsread and approved the final manuscript as submitted."} +{"text": "J Clin Endocrinol Metab. 2020;105(4):1847\u20131861; doi: 10.1210/clinem/dgz310) the following omission occurred in the published paper: \u201cThe name of T\u00fclay G\u00fcran was omitted from the list of Turkish investigators acknowledged as members of the REAL 3 Study Group.\u201d The correct group membership section should read as follows:In the above-named article by S\u00e4vendahl L, Battelino T, Brod M, H\u00f8jby Rasmussen M, Horikawa R, Vestergaard Juul R, Saenger P, on behalf of the REAL 3 Study Group (\u201c*Members of the REAL 3 Study Group:Austria: Dieter Furthner, Bettina Piringer, Lorenz Auer-Hackenberg, Klaus Schmitt, Marlene ReitmayrBrazil: Marcello Delano Bronstein, Francisco Samuel Magalh\u00e3es LimaGermany: Martin Wabitsch, Carsten Posovszky, Volker B\u00f6ttcher, Alexander MannIsrael: Eli Hershkovitz, Alon Haim, Neta Lowenthal, Orit Hamiel, Sharon Sheinvald Levin, Kineret Mazor-Aronovitch, Michal Ben-Ami, Yael Levy Shraga, Dalit Modan, Noah Gruber, Moshe Phillip, Yael Lebenthal, Ariel Tenenbaum, Alon Eliakim, Nitzan Dror, Ruby Haviv, Nehama Zuckerman-Levin, Naim Shehadeh, Liav Givon, Ameer Elemy, Miriam Marji, Vardit GepsteinIndia: Praveen V.P., Aswin P, Nithiya Abraham, Rajesh Khadgawat, Yashdeep Gupta, Vaman Khadilkar, Anuradha Khadilkar, Sagar LadJapan: Reiko Horikawa, Yasuhiro Naiki, Yasuko Ogiwara, Yuta Chiba, Yusuke Fujisawa, Yumiko Terada, Tomoko Yoshida, Kenichi Kinjo, Atsushi Tsukamura, Shinobu Ida, Yuri Etani, Yasuko Shoji, Masanobu Kawai, Hisakazu Nakajima, Jun Mori, Shota Fukuhara, Keiichi Shigehara, Hidechika Morimoto, Yusuke Tsuma, Yasuhiro Kawabe, Takeshi Ota, Kenichi Kashimada, Ryuichi Nakagawa, Atsumi Tsuji, Risa Nomura, Kei Takasawa, Takeru Yamauchi, Kanako Ishii, Naoko Toda, Kazuhiro Ohkubo, Tohru Yorifuji, Yuki Hosokawa, Rie Kawakita, Yukiko Hashimoto, Azumi Sakakibara, Shinji Higuchi, Shun Soneda, Kenichiro Ogushi, Shuichi Yatsuga, Yasutoshi Koga, Takako Matsumoto, Miyuki KitamuraSweden: Lars S\u00e4vendahl, Ricard Nerg\u00e5rdhSlovenia: Tadej Battelino, Mojca Zerjav TansekTurkey: Serap Turan, Abdullah Bereket, Zeynep Atay, Azad Akbarzade, T\u00fclay G\u00fcranUkraine: Olena Bolshova, Mykola Tronko, Olga Vyshnevskaya, Natalia Sprynchuk, Iryna Lukashuk, Natalia Muz, Tatyana Marchenko, Nataliya Chorna, Mar\u0456ana Konovalova, Liliya ZelinskaUSA: Lawrence Silverman, Barbara Cerame, Sunita Cheruvu, Daisy Chin, Laurie Ebner-Lyon, Marie Fox, Marianna Nicolette-Gentile, Kristin Sabanosh, Harold Starkman, Ian Marshall, Mariam Gangat, Sadana Balachandar, Philippe Backeljauw, Andrew Dauber, Leah Tyzinski, Paul H. Saenger, Luis Zamora Siliezar, Jacqueline P. Velasco, Judith L. Ross, Martha Bardsley, Karen Kowal, Gad B. Kletter, Britney G. Frazier, Kathryn Garrison\u201d10.1210/clinem/dgz310doi:"} +{"text": "Correction to: Mol Cancer 19, 57 (2020)https://doi.org/10.1186/s12943-020-01175-9Following the publication of the original article , authorsAuthors\u2019 contributionsConceptualization, AAB, SYN, MH and SU; writing\u2014original draft preparation, AAB, SN, IA, RM, SKS, LZ, IE, SK, KSP, AQ, SK and SU; writing\u2014review and editing, AAB, SN, MH, MK, WER, HZ, MAZ\u00a0and SU; Revision of manuscript, AAB, SSR, SN, IA, RM, SKS, LZ, IE, SK, KSP, AQ,\u00a0SK, SKY and SU; supervision, AAB, SU, MH, SN, MK, WER and SU. AAB, SSR and LZ \u2014Preparation of Illustrations. All authors have read and approved the final version of the manuscript."} +{"text": "Hospital-acquired infections, particularly in the critical care setting, have become increasingly common during the last decade, with Gram-negative bacterial infections presenting the highest incidence among them. Multi-drug-resistant (MDR) Gram-negative infections are associated with high morbidity and mortality with significant direct and indirect costs resulting from long hospitalization due to antibiotic failure. Time is critical to identifying bacteria and their resistance to antibiotics due to the critical health status of patients in the intensive care unit (ICU). As common antibiotic resistance tests require more than 24 h after the sample is collected to determine sensitivity in specific antibiotics, we suggest applying machine learning (ML) techniques to assist the clinician in determining whether bacteria are resistant to individual antimicrobials by knowing only a sample\u2019s Gram stain, site of infection, and patient demographics. In our single center study, we compared the performance of eight machine learning algorithms to assess antibiotic susceptibility predictions. The demographic characteristics of the patients are considered for this study, as well as data from cultures and susceptibility testing. Applying machine learning algorithms to patient antimicrobial susceptibility data, readily available, solely from the Microbiology Laboratory without any of the patient\u2019s clinical data, even in resource-limited hospital settings, can provide informative antibiotic susceptibility predictions to aid clinicians in selecting appropriate empirical antibiotic therapy. These strategies, when used as a decision support tool, have the potential to improve empiric therapy selection and reduce the antimicrobial resistance burden. The rapid emergence of antibiotic-resistant infections during the last decade constitutes a worldwide problem with increasing health and economic costs . As statData from the European Antimicrobial Resistance Surveillance Network (EARS-Net) suggest that in 2015, Greece was among the countries with the greatest burden of infections due to antibiotic-resistant bacteria in the EU and European Economic Area (EEA) , with caPseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae isolates between the intensive care unit (ICU) and other facilities in two consecutive years (2017 and 2018), in one of the largest public tertiary hospitals in Greece, to implement more effective strategies for the reduction of multidrug resistance. By using the same antimicrobial susceptibility dataset from the Microbiology Laboratory, we proposed a methodology .K. pneumoniae was measured based on the following antibiotics: amikacin, amoxicillin/clavulanic acid, ampicillin/sulbactam, cefepime, cefotaxime, cefoxitin, ceftazidime, cefuroxime, ciprofloxacin, colistin, ertapenem, gentamicin, imipenem, meropenem, piperacillin/tazobactam, tetracycline, tobramycin, trimethoprim/sulfamethoxazole, levofloxacin, moxifloxacin, and tigecycline. The highest resistance rate was reported to older beta lactams/beta lactamase inhibitors (amp/sulb 85.98%), fluoroquinolones (up to 83.04%), carbapenems (up to 81.44%) and third generation cephalosporins (up to 81.61%) [The resistance for 81.61%) . Achromobacter xylosoxidans was measured based on the following antibiotics: amikacin, aztreonam, ceftazidime, gentamicin, imipenem, meropenem, minocycline, piperacillin/tazobactam, tobramycin, levofloxacin, and trimethoprim/sulfamethoxazole. The resistance for Enterobacter aerogenes was measured based on the following antibiotics: amikacin, amoxicillin/ clavulanic acid, ampicillin/sulbactam, cefepime, cefotaxime, cefoxitin, ceftazidime, cefuroxime, ciprofloxacin, colistin, ertapenem, gentamicin, imipenem, levofloxacin, meropenem, moxifloxacin, piperacillin/tazobactam, tetracycline, tobramycin, and trimethoprim/sulfamethoxazole. The resistance for Enterobacter cloacae was measured based on the following antibiotics: amikacin, amoxicillin/ clavulanic acid, ampicillin/sulbactam, aztreonam, cefepime, cefotaxime, cefoxitin, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, colistin, ertapenem, gentamicin, imipenem, levofloxacin, meropenem, moxifloxacin, piperacillin/tazobactam, tetracycline, tobramycin, and trimethoprim/sulfamethoxazole.The resistance for E. coli was measured based on the following antibiotics: amikacin, amoxicillin/clavulanic acid, ampicillin, ampicillin/sulbactam, aztreonam, cefepime, cefotaxime, cefoxitin, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, colistin, ertapenem, gentamicin, imipenem, levofloxacin, meropenem, moxifloxacin, piperacillin/tazobactam, tetracycline, tobramycin, and trimethoprim/sulfamethoxazole. The resistance for Proteus mirabilis was measured based on the following antibiotics: amikacin, amoxicillin/clavulanic acid, ampicillin, ampicillin/sulbactam, aztreonam, cefepime, cefotaxime, cefoxitin, ceftazidime, ceftriaxone, cefuroxime, ciprofloxacin, ertapenem, gentamicin, imipenem, levofloxacin, meropenem, moxifloxacin, piperacillin/tazobactam, tobramycin, and trimethoprim/sulfamethoxazole. The resistance for Stenotrophomonas maltophilia was measured based on the following antibiotics: ceftazidime, levofloxacin, minocycline, and trimethoprim/sulfamethoxazole.The resistance for Enterococcus faecalis was measured based on the following antibiotics: amoxicillin/clavulanic acid, ampicillin, ciprofloxacin, daptomycin, gentamicin500, levofloxacin, linezolid, pristinamycin, quinupristin/dalfopristin, rifampin, streptomycin 1000, teicoplanin, tetracycline, and vancomycin. The resistance for Enterococcus faecium was measured based on the following antibiotics: amoxicillin/clavulanic acid, ampicillin, ciprofloxacin, daptomycin, gentamicin 500, levofloxacin, linezolid, pristinamycin, quinupristin/dalfopristin, rifampin, streptomycin 1000, teicoplanin, tetracycline, and vancomycin. The resistance for S. aureus was measured based on the following antibiotics: ceftaroline, ciprofloxacin, clindamycin, daptomycin, erythromycin, fusidic acid, gentamicin, levofloxacin, linezolid, oxacillin, penicillin, pristinamycin, quinupristin/dalfopristin, rifampin, teicoplanin, tetracycline, tobramycin, trimethoprim/sulfamethoxazole, and vancomycin. Methicillin-resistance (MRSA) was found in 21.12% of the total S. aureus isolates.The resistance for Our research focuses only on the antibiotics mentioned above since there is an adequate number of samples for these for deducing reliable conclusions for the models that were examined. The incidence of multidrug (MDR) or extensively drug resistant (XDR) bacteria was not examined in the present study. In the present study, bacteria were assigned as sensitive or resistant against each antibiotic tested. As mentioned in In this paper, we evaluated a collection of very popular learning classifiers on an ICU antimicrobial susceptibility dataset. The best results achieve an F-measure of 0.678 with the RIPPER algorithm and an ROC area of 0.726, with the Multilayer perceptron classifier. The experimental results demonstrate that, especially, the Multilayer perceptron and J48 (C4.5) algorithms are suitable models for ICU antimicrobial susceptibility data sets with the evaluation of ROC Area results. The decision to use one of these techniques as an assistant depends mainly on whether the ICU places a premium on the accuracy or explainability, though there do exist approaches that attempt to bridge these preferences. Given the fact that the algorithms presented contain only a few variables, retrieved solely from the Microbiology Department without adjuvant clinical data, the best performances achieved were not high enough to characterize our techniques widely applicable. Despite limitations of the study, our primary goal was to take advantage of these data using ML techniques and possibly create an inexpensive ancillary tool to aid the clinician in identifying patients carrying antibiotic-resistant bacteria and guide proper therapy with greater confidence in situations where there is significant uncertainty and a crucial decision needs to be taken.In future work, we will focus on enriching our datasets with clinical attributes as well as investigating the configurations, which would improve the algorithms\u2019 performances."} +{"text": "The data obtained in rock slabs, fragments, anhydrous nuclei, flaked and ground stone from Sonora, Mexico, were used to select certain analysed elements that help to formulate geochemical variation diagrams to identify chemical trends and correlations between the samples. It proves to be an excellent analytical method for the provenance studies of archaeological artifacts. Subsequently, the integration of the obtained data here and their arrangement with the existing chemical analysis of obsidians for different localities of NW Mexico and the SW of the United States will allow for better knowledge of the primary sources of obsidian in the extraction and manufacture of archaeological artifacts Geological primary obsidian sources localities comprise Vidrios Viejos and La Sierra Batamote at El Pinacate Region, Cerro Izabal at Hermosillo, Arroyo El Cajete and Arroyo El Galindro at Sierra Libre, and Arroyo San Jos\u00e9 de Robinson of the Ejido Francisco Villa at Sierra El Aguaje. The characteristics of these obsidian geological deposits and other new localities are described in The analysed samples come from 13 archaeological sites: 22.1The initial stage in the obsidian analysis consisted of the petrological study of about 500 obsidian samples, both archaeological and geological, describing the physical parameters and appearance, the colour, the texture and the mineralogy to get the 133 obsidian specimens analysed 2.2Niton Thermo Scientific, XL3t 500, include: Mo, Zr, Sr, U, Rb, Th, Pb, Se, As, Hg, Au, Al, W, Cu, Ni, Co, Fe, Mn, Sb, Sn, Cd, Ag, Nb, Y, Bi, Cr, V, Ti, Pd, Sc, Ca, K, S, Ba, Cs y Te. The raw data of X-Ray analyses are presented in the supplementary material at Mendeley Data [https://data.mendeley.com/datasets/24kkg2hctg/5].At the end of the experimental stage of the chemical detection of archaeological and geological obsidian samples, it was possible to establish an analysis protocol that was supported by the reliability values of the reference materials obtained by the portable analyser X-Ray Fluorescence XL3t . The anaSubsequently, data processing was performed in Excel, which consisted of evaluating values obtained and its relationship whit the analytical error for each element concerning the reference standard. Elements with a low detection limit and those with high errors were discarded. The study obtained reliable detection values for Zr, Sr, Rb, Th, Pb, Zn, Fe, Mn, Nb and Y . Based oDoes not apply to this data.Jes\u00fas Roberto Vidal-Solano: Conceptualization, Methodology, Investigation, Writing - original draft, Writing - review & editing, Supervision. Alejandra Marisela G\u00f3mez-Valencia: Validation, Formal analysis, Data curation, Writing - original draft, Writing - review & editing, Visualization, Project administration. Adriana Hinojo-Hinojo: Validation, Formal analysis, Resources, Data curation, Writing - original draft, Writing - review & editing, Visualization. Rufino Lozano-Santa Cruz: Validation, Investigation, Resources, Writing - review & editing.The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article."} +{"text": "J Clin Endocrinol Metab. 2020;105(12);1\u201313. doi: 10.1210/clinem/dgaa551), the following typographical error occurred in the published paper:In the above-named article by Koscinski I, Mark M, Messaddeq N, Braun J, Celebi C, Muller J, Zinetti-Bertschy A, Goetz N, Dollfus H, and Rossignol S (The order of the first and second name of each author was reversed. The author names should be listed as follows:Isabelle Koscinski, Manuel Mark, Nadia Messaddeq, Jean Jacques Braun, Catherine Celebi, Jean Muller, Anna Zinetti-Bertschy, Nathalie Goetz, H\u00e9l\u00e8ne Dollfus, and Sylvie Rossignol.The names have been corrected in the publication online.10.1210/clinem/dgaa551doi:"} +{"text": "Correction to: BMC Cancer 21, 158 (2021)https://doi.org/10.1186/s12885-021-07825-5Following publication of the original article , the autThe corrected affiliation is: Department of Cardiothoracic Surgery, Chongqing Emergency Medical Center, Chongqing University Center Hospital, School of Medicine, Chongqing University, No.1 Healthy Road, Yuzhong District, Chongqing, 400014 ChinaThe original article has been"} +{"text": "MYC or other oncogenes, or throughout oncogenic rearrangements, such as the BRD4-NUMT1 translocation, which drive NUT\u2013midline carcinoma (NMC), an extremely aggressive undifferentiated squamous cell carcinoma family of readers, which includes BRD2, BRD3, BRD4, and BRDT, recognize acetylated lysine on histones\u2014a mark associated with active transcription at promotors, enhancers, and super-enhancers\u2014and recruit transcription factors . BET proarcinoma .MYC\u2013driven diseases and clinical activity in NMC has generated great enthusiasm, with the perspective of \u201cdrugging the undruggable,\u201d Following very encouraging initial preclinical activity in y in NMC ,6, multiHere, Piha-Paul et al. report the results of the phase I dose-escalation study of molibresib (GSK525762) in 65 patients with NMC and other solid tumors . Once-daBRD3-NUTM1 fusion; the limited size of the series precluded from correlating fusion gene status with treatment duration. BETi antitumor activity has been observed in NMC patients with both BRD4-NUT and the less common non\u2013BRD4-NUT fusions, such as BRD3-NUT and NSD3-NUT fusions. For example, responses to birabresib were mostly observed in patients with BRD4-NUT fusions . In this context, targeted drug delivery strategies might allow an increase of the therapeutic window. Heterobifunctional small molecule BET protein degraders, such as the proteolysis-targeting chimera (PROTAC) ARV-771, ARV-825, BETd-260/ZBC260, dBET6, or QCA570 , or to reverse or delay acquired resistance (reviewed in Affiliations of authors: DITEP (D\u00e9partement d\u2019Innovations Th\u00e9rapeutiques et Essais Pr\u00e9coces), Gustave Roussy, Villejuif, France ; Universit\u00e9 Paris Saclay, Universit\u00e9 Paris-Sud, Facult\u00e9 de m\u00e9dicine, Le Kremlin Bic\u00eatre, France (SP-Y); ATIP-Avenir group, Inserm Unit U981, Gustave Roussy, Villejuif, France (SP-Y).SPV INSERM laboratory is funded by the INSERM ATIP-Avenir grant and Integrated Cancer Research Site (SIRIC) SOCRATE-2 INCa-DGOS-INSERM_12551.Conflict of interest statement: As part of the Drug Development Department (DITEP), PMR, CB, and SPV are principal investigator or sub investigator of clinical trials from Abbvie, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Eli Lilly, Exelixis, Forma, Gamamabs, Genentech, Inc., Glaxosmithkline, H3 Biomedicine, Inc., Hoffmann La Roche Ag, Innate Pharma, Iris Servier, Janssen Cilag, Kyowa Kirin Pharm. Dev., Inc., Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre, Roche, Sanofi Aventis, Taiho Pharma, Tesaro Inc, and Xencor. SPV has participated in advisory boards for Merck KGaA; has benefited from reimbursement for attending symposia from AstraZeneca; and has received laboratory research funding from Fondation Roche France, Boehringher Ingelheim, and Merck KGaA. CB received personal fees from BMS, Sanofi, Abbvie, and Astra Zeneca."} +{"text": "Scientific Reports 10.1038/s41598-020-70881-7, published online 19 November 2020Correction to: The original version of this Article contained errors in the spelling of the authors Christophe Clesse, Jonathan Cottenet, Joelle Lighezzolo-Alnot, Karine Goueslard, Michele Scheffler, Paul Sagot and Catherine Quantin, which were incorrectly given as Clesse Christophe, Cottenet Jonathan, Lighezzolo-Alnot Joelle, Goueslard Karine, Scheffler Michele, Sagot Paul and Quantin Catherine.These errors have now been corrected in the PDF and HTML versions of the Article."} +{"text": "There is an error in affiliation 1 for authors Ikuko Takahara, Yuko Akazawa, Maiko Tabuchi, Hisamitsu Miyaaki, Youko Kido, Yasuko Kanda, Naota Taura, Ken Ohnita, Fuminao Takeshima, and Kazuhiko Nakao. The correct affiliation 1 is: Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan."} +{"text": "Scientific Reports 10.1038/s41598-020-78366-3, Published online 16 December 2020Correction to: The original version of this Article contained errors in the spelling of the authors Osnat Cohen-Zontag, Rotem Gershon, Orit Harari-Steinberg, Itamar Kanter, Dorit Omer, Oren Pleniceanu, Gal Tam, Sarit Oriel, Herzl Ben-Hur, Guy Katz, Zohar Dotan, Tomer Kalisky, Benjamin Dekel, and Naomi Pode-Shakked, which were incorrectly given as Cohen-Zontag Osnat, Gershon Rotem, Harari-Steinberg Orit, Kanter Itamar, Omer Dorit, Pleniceanu Oren, Tam Gal, Oriel Sarit, Ben Hur Herzel, Katz Guy, Zohar Dotan, Kalisky Tomer, Dekel Benjamin, and Pode-Shakked Naomi.These errors have now been corrected in the PDF and HTML versions of the Article, and in the accompanying Supplementary Information file."} +{"text": "A list of 40 species is presented of the rodents and insectivores collected during a 15-year period from the Republic of Mordovia. The dataset contains more than 24,000 records of rodent and insectivore species from 23 districts, including Saransk. A major part of the data set was obtained during expedition research and at the biological station. The work is based on the materials of our surveys of rodents and insectivorous mammals conducted in Mordovia using both trap lines and pitfall arrays using traditional methods. Over this period, not only has the species composition of the region changed but also the status of many species.There is a need to review the species composition of rodents and insectivores in all regions of Russia, and the work by The Mordovian fauna is heterogeneous and consists of four different ecological and faunal complexes of species\u2013taiga, coniferous and broad-leaved forests, and steppe\u2013which are widely distributed in several natural areas .Here, we publish a checklist of rodent and insectivore records across the Republic of Mordovia. This checklist was based on comprehensive surveys of small mammals carried out from 2006 to 2020.Insectivores are represented in Mordovia by 12 species belonging to three families.Erinaceidae Fischer, 1814Family Northern white-breasted hedgehog, Erinaceus roumanicus Barrett-Hamilton, 1900West European hedgehog, Erinaceus europaeus Linnaeus, 1758Talpidae Fischer, 1814Family European mole, Talpa europaea Linnaeus, 1758Russian desman, Desmana moschata Soricidae Fischer, 1814Family Eurasian common shrew, Sorex araneus Linnaeus, 1758Laxmann\u2019s shrew, Sorex caecutiens Laxmann, 1788Least shrew, Sorex minutissimus Zimmermann, 1780Taiga shrew, Sorex isodon Turov, 1924Eurasian pygmy shrew, Sorex minutus Linnaeus, 1766Eurasian water shrew, Neomys fodiens Southern water shrew, Neomys anomalus Cabrera, 1907Lesser white-toothed shrew, Crocidura suaveolens Rodents are represented by 29 species belonging to eight families.Sciuridae Fischer, 1817Family Red squirrel, Sciurus vulgaris Linnaeus, 1758Spotted suslik, Spermophilus suslicus G\u00fcldenstaedt, 1770Bobak marmot, Marmota bobak Castoridae Hemprich, 1820Family Eurasian beaver, Castor fiber Linnaeus, 1758Gliridae Thomas, 1897Family Forest dormouse, Dryomys nitedula Garden dormouse, Eliomys quercinus Fat dormouse, Glis glis Hazel dormouse, Muscardinus avellanarius Sminthidae Brandt, 1855Family Northern birch mouse, Sicista betulina Allactagidae Vinogradov, 1925Family Great jerboa, Allactaga major Spalacidae Gray, 1821Family Greater mole rat, Spalax microphthalmus G\u00fcldenstaedt, 1770Family Cricetidae Fischer, 1817Bank vole, Myodes glareolus Northern red-backed vole, Myodes rutilus European water vole, Arvicola amphibius Root vole, Microtus oeconomus Gray dwarf hamster, Cricetulus migratorius Common hamster, Cricetus cricetus Muskrat, Ondatra zibethicus Steppe lemming, Lagurus lagurus Pallas, 1773Common vole, Microtus arvalis East European vole, Microtus rossiaemeridionalis Ognev, 1924Field vole, Microtus agrestis European pine vole, Microtus subterraneus Muridae Illiger, 1811Family Striped field mouse, Apodemus agrarius Pygmy wood mouse, Apodemus uralensis Yellow-necked wood mouse, Apodemus flavicollis Harvest mouse, Micromys minutus House mouse, Mus musculus Linnaeus, 1758Norway rat, Rattus norvegicus Microtusarvalis and M.rossiaemeridionalis, have not been conducted in the region. Approaches and criteria for differentiation of two similar species, Erinaceusroumanicus and E.europaeus, have been applied for a number of specific morphological and craniometric characteristics , the length of the premaxillary-nasal suture does not exceed 9.0 mm (in E.europaeus >9.0 mm), and the maximum length of the nasal bones in their back part is greater than or equal to 3.0 mm (E.europaeus <3.0 mm) reported from the Republic of Mordovia were not detected during our surveys. However, these species were captured by our colleagues, either long ago or even in the last year, and most of them were recorded in the Mordovian state nature reserve, Temnikovsky district . The coldistrict . MicrotuMordovia . This reMordovia . In addiow known .M.bobak, Sp.suslicus, Al.major, Sp.microphthalmus, Cr.migratorius, Cr.cricetus, L.lagurus, and M.minutus) occur only in steppe habitats. Only in the steppe areas of Mordovia are there concentrated populations of S.microphthalmus ; Penza region - Spermophilusmajor Pallas, 1778, Sicistastrandi , Tamiassibiricus , Pteromysvolans , Myodesrufocanus , Pteromysvolans (Red Book 2010); and Ryazan region - Rattusrattus , Pteromysvolans (Red Book 2011). Thus, seven species of rodents and insectivores present in adjacent regions are absent from the fauna of Mordovia.The rodent and insectivore fauna of Mordovia is in general large, as it includes both steppe and taiga species. The largest rodent of Mordovia is r bodies . The rodv, 1931) ; Nizhny l, 1846) ; ChuvashThe dataset contains more than 24,000 registrations of rodent and insectivore species from the districts of the Republic of Mordovia, including Saransk Table .Kingdom: AnimaliaPhylum: ChordataClass: MammaliaOrder: Eulipotyphla, RodentiaFamily: Erinaceidae, Talpidae, Soricidae, Sciuridae, Castoridae, Gliridae, Sminthidae, Allactagidae, Spalacidae, Cricetidae, MuridaeGenus: Talpa, Desmana, Sorex, Neomys, Crocidura, Sciurus, Spermophilus, Marmota, Castor, Dryomys, Eliomys, Glis, Muscardinus, Sicista, Allactaga, Spalax, Myodes, Arvicola, Microtus, Cricetulus, Cricetus, Ondatra, Lagurus, Microtus, Apodemus, Micromys, Mus, RattusSpecies: Erinaceusroumanicus, Erinaceuseuropaeus, Talpaeuropaea, Desmanamoschata, Sorexaraneus, Sorexcaecutiens, Sorexminutissimus, Sorexisodon, Sorexminutus, Neomysfodiens, Neomysanomalus, Crocidurasuaveolens, Sciurusvulgaris, Spermophilussuslicus, Marmotabobak, Castorfiber, Dryomysnitedula, Eliomysquercinus, Glisglis, Muscardinusavellanarius, Sicistabetulina, Allactagamajor, Spalaxmicrophthalmus, Myodesglareolus, Myodesrutilus, Arvicolaamphibius, Microtusoeconomus, Cricetulusmigratorius, Cricetuscricetus, Ondatrazibethicus, Laguruslagurus, Microtusarvalis, Microtusrossiaemeridionalis, Microtusagrestis, Microtussubterraneus, Apodemusagrarius, Apodemusuralensis, Apodemusflavicollis, Micromysminutus, Musmusculus, RattusnorvegicusThe dataset covers the entire Republic of Mordovia within 53\u00b038'N to 55\u00b011'N and 42\u00b011'E to 46\u00b045'E.The data were collected from 2006 to 2020.Erinaceusroumanicus, Erinaceuseuropaeus, Talpaeuropaea, Desmanamoschata, Sciurusvulgaris, Spermophilussuslicus, Marmotabobak, Castorfiber, Allactagamajor, Spalaxmicrophthalmus, Cricetuscricetus, and Ondatrazibethicus were obtained via direct observations, recording and/or detection of the traces of their activities . Latin names of species are given according to the classical nomenclature left over night in lines of from 50 to 100 traps with a distance of 5 m between them and baited with bread and sunflower oil. We also used live traps baited with salami and apple to catch dormice. Voucher specimens are stored in the personal collection A. Andreychev, Saransk (teriomordovia@bk.ru). Data on nclature ."} +{"text": "VOLUME 107107(3) July, pages 439\u201340http://dx.doi.org/10.5195/jmla.2019.545.Read KB, Koos J, Miller RS, Miller CF, Phillips GA, Scheinfeld L, Surkis A. A model for initiating research data management services at academic libraries. J Med Libr Assoc. 2019 Jul;107(3):432\u201341. DOI: Pages 439\u201340: Acknowledgments of pilot program participants Deborah Chiarella, Pamela M. Rose, Aletia Morgan, and Gretchen Sneff are missing. The \u201cAcknowledgments\u201d should be:This program was supported by the National Library of Medicine (NLM), National Institutes of Health (NIH), under cooperative agreement number UG4LM012342 with the University of Pittsburgh, Health Sciences Library System, and NIH R25LM012283. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. We acknowledge pilot participants of this program, specifically those from University at Buffalo: Nell Aronoff, Donna R. Berryman, AHIP, Deborah Chiarella, Amy Gische Lyons, AHIP, FMLA, Pamela M. Rose, Michelle L. Zafron, Elizabeth Stellrecht, and Linda Lohr; University of Delaware: Sarah E. Katz, Tom Melvin, Natalia Lopez, Sandra Millard, and Aletia Morgan; Drexel University: Abby L. Adamczyk, AHIP, Elizabeth Ten Have, Kathleen Turner, Janice Masud-Paul, and Deborah Morley; and Temple University: Jenny Pierce, Natalie Tagge, Gretchen Sneff, and Nancy Turner. The authors also thank Richard McGowan for discussion and comment on the manuscript."} +{"text": "On request received from the corresponding author, the following article is retracted because the authors noted problems in the statistical analysis of the data, so the conclusions drawn in this study cannot be sustained:Shi, Lixin, Zhang, Lei, Wang, Chunyang, Sun, Shengkun, Cao, Xiyuan, & Zhang, Xu. (2017). Expression of serum microRNA-378 and its clinical significance in renal cell carcinoma. Genetics and Molecular Biology, 40(2), 525-529.10.1590/1678-4685-gmb-2016-0121Prof. Dr. Carlos Frederico Martins MenckEditor in chief"} +{"text": "In the article titled \u201cAlcoholic and Nonalcoholic Liver Disease: Diagnostic Assessment and Therapeutic Perspectives\u201d , the affCIBER-EHD, Instituto de Salud Carlos III, Madrid, SpainHepatology and Liver Transplantation Unit, IIS La Fe, Hospital Universitario y Polit\u00e9cnico La Fe, Valencia, SpainFaculty of Medicine, University of Valencia, Valencia, Spain"} +{"text": "Nature 10.1038/s41586-023-06480-z Published online 13 September 2023Correction to: In the version of the article initially published, the author list for The Ki Child Growth Consortium was incorrect. Rina Das, Subhasish Das and Najeeb Rahman have been added to The Ki Child Growth Consortium author list, while Souheila Abbeddou, Linda S. Adair, Hasmot Ali, Per Ashorn, Rajiv Bahl, Mauricio L. Barreto, Maharaj Kishan Bhan, Nita Bhandari, Santosh K. Bhargava, Delia Carba, Ines Gonzales Casanova, Kathryn G. Dewey, Caroline H. D. Fall, Sonja Y. Hess, Jean H. Humphrey, Elizabeth Yakes Jimenez, Michael S. Kramer, Alain Labrique, Nanette R. Lee, Mustafa Mahfuz, Kenneth Maleta, Reynaldo Martorell, Sarmila Mazumder, Ishita Mostafa, Robert Ntozini, Harshpal Singh Sachdev, Saijuddin Shaikh, Alberto Melo Soares, Aryeh D. Stein, Keith P. West Jr, Lee Shu Fune Wu and Seungmi Yang have been removed. This has been updated in the PDF and HTML versions of the article."} +{"text": "Proc. R. Soc. B290, 20222500. (Published online 15 February 2023). (https://doi.org/10.1098/rspb.2022.2500)Palaeoneurorthus Wichard, 2009 [After publication of the article , it was Girafficervix, nomen novumPalaeoneurorthus Du, Niu & Baoin substitution for Type species: Girafficervix baii Du, Niu & Bao, typification by monotypy.Diagnosis: as species.Gender: feminine.Etymology: the name is compounded from the genus name Giraffa, meaning giraffe, and cervix, Latin meaning neck, in reference to the specimen's long neck.Girafficervix baii, nomen novum, holotype YLNHM01098, paratype NIGP201165 in substitution for Palaeoneurorthus baii Du, Niu & BaoRefer to Du, Niu & Bao (2023) for deta"} +{"text": "Nature Medicine 10.1038/s41591-023-02317-4. Published online 24 April 2023.Correction to: In the version of this article initially published, the STRATIFY data also included cohort data from the ESTRA consortium, though this was not acknowledged in the author list and the section in Methods on the Stratify dataset. The Methods are now updated, and the author list is amended to combine the STRATIFY and ESTRA consortium names and to include the following authors: Marina Bobou, M. John Broulidakis, Betteke Maria van Noort, Zuo Zhang, Lauren Robinson, Nilakshi Vaidya, Jeanne Winterer, Yuning Zhang, Sinead King, Herv\u00e9 Lema\u00eetre, Ulrike Schmidt, Julia Sinclair, Argyris Stringaris and Sylvane Desrivi\u00e8res. The STRATIFY and ESTRA consortia are now combined to list Marina Bobou, M. John Broulidakis, Betteke Maria van Noort, Zuo Zhang, Lauren Robinson, Nilakshi Vaidya, Jeanne Winterer, Yuning Zhang, Sinead King, Gareth J. Barker, Arun L. W. Bokde, Herv\u00e9 Lema\u00eetre, Frauke Nees, Dimitri Papadopoulos Orfanos, Ulrike Schmidt, Julia Sinclair, Argyris Stringaris, Henrik Walter, Robert Whelan, Sylvane Desrivi\u00e8res and Gunter Schumann as members, and the IMAGEN consortium is updated to also include Sylvane Desrivi\u00e8res. Affiliations, author contributions and acknowledgements have been updated to reflect the new authorship, and all changes have been made in the HTML and PDF versions of the article."} +{"text": "Correction: Eating and Weight Disorders\u2014Studies on Anorexia, Bulimia and Obesity (2022) 27:3695\u20133711https://doi.org/10.1007/s40519-022-01512-5In this article Rebecca C. Reynolds was missing from the author list. The complete correct author group is given below.Lorenzo M. Donini, Juan Ram\u00f3n Barrada, Friederike Barthels, Thomas M. Dunn, Camille Babeau, Anna Brytek-Matera, Hellas Cena, Silvia Cerolini, Hye-hyun Cho, Maria Coimbra, Massimo Cuzzolaro, Claudia Ferreira, Valeria Galfano, Maria G. Grammatikopoulou, Souheil Hallit, Linn H\u00e5man, Phillipa Hay, Masahito Jimbo, Clotilde Lasson, Eva-Carin Lindgren, Renee McGregor, Marianna Minnetti, Edoardo Mocini, Sahar Obeid, Crystal D. Oberle, Maria-Dolores Onieva-Zafra, Marie-Christine Opitz, Mar\u00eda-Laura Parra-Fern\u00e1ndez, Reinhard Pietrowsky, Natalija Plasonja, Eleonora Poggiogalle, Adrien Rig\u00f3, Rachel F. Rodgers, Maria Roncero, Carmina Salda\u00f1a, Cristina Segura-Garcia, Jessica Setnick, Ji-Yeon Shin, Grazia Spitoni, Jana Strahler, Nanette Stroebele-Benschop, Patrizia Todisco, Mariacarolina Vacca, Martina Valente, M\u00e0rta Varga, Andrea Zagaria, Hana Flynn Zickgraf, Rebecca C. Reynolds & Caterina Lombardo.The original article has been"} +{"text": "Scientific Reports 10.1038/s41598-023-33127-w, published online 20 April 2023Correction to: The original version of this Article contained errors in the names of authors Davide Esposito, Jenifer Miehlbradt, Alessia Tonelli, Alberto Mazzoni, and Monica Gori, which were incorrectly given as Esposito Davide, Miehlbradt Jenifer, Tonelli Alessia, Mazzoni Alberto and Gori Monica.The original Article has been corrected."} +{"text": "The corrected section appears below:In the published article, there was an error in the 1, 2\u2020, Jin Wei3, 4\u2020, Ning Wang3, 4\u2020, Yisheng Chen5\u2020, Cheng Fang6, Minwen Zhou3, 4, Xinrong Zhou3, 4*, Jianfeng Luo6, 7, 8*, Xiaodong Wang9*, Qing Peng1*Yifan Zhoucitation section. The citation was incorrectly written as: Zhou Y, Wei J, Wang N, Chen Y, Fang C, Zhou M, Zhou X, Peng Q, Wang X and Luo J (2023) The prevalence, incidence, and persistence of self-reported visual impairment among Chinese population with diabetes mellitus: evaluation from a nationally representative survey, 2015\u20132018. Front. Public Health. 11:978457. doi: 10.3389/fpubh.2023.978457.In the published article, there was an error in the The corrected section appears below:Front. Public Health. 11:978457. doi: 10.3389/fpubh.2023.978457.Zhou Y, Wei J, Wang N, Chen Y, Fang C, Zhou M, Zhou X, Luo J, Wang X and Peng Q (2023) The prevalence, incidence, and persistence of self-reported visual impairment among Chinese population with diabetes mellitus: evaluation from a nationally representative survey, 2015\u20132018. copyright section. The copyright section was incorrectly written as: \u00a9 2023 Zhou, Wei, Wang, Chen, Fang, Zhou, Zhou, Peng, Wang and Luo.In the published article, there was an error in the The corrected section appears below:\u00a9 2023 Zhou, Wei, Wang, Chen, Fang, Zhou, Zhou, Luo, Wang, PengThe authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The Oncologist, Volume 26, Issue 10, October 2021, Pages e1862\u2013e1869, https://doi.org/10.1002/onco.13879This is a correction notice for: Anna Ozaki, Takaomi Kessoku, Yuki Kasai, Yuma Takeda, Naoki Okubo, Michihiro Iwaki, Takashi Kobayashi, Tsutomu Yoshihara, Yasushi Honda, Akiko Fuyuki, Takuma Higurashi, Hiroto Ishiki, Masataka Taguri, Shunsuke Oyamada, Noritoshi Kobayashi, Atsushi Nakajima, Yasushi Ichikawa, Elobixibat Effectively Relieves Chronic Constipation in Patients with Cancer Regardless of the Amount of Food Intake, In the originally published version of this article, the Disclosures section was incorrect and should have read as follows:This study was conducted without company funding; however, three co-authors have financial relationships to disclose. Takaomi Kessoku received lecture honoraria and research funding from EA Pharma Co. Ltd. and Mochida Pharmaceutical Co., Hiroto Ishiki received lecture honoraria from EA Pharma Co. Ltd., and Atsushi Nakajima received scholarship fee, lecture honoraria, and research funding from EA Pharma Co. Ltd. and Mochida Pharmaceutical Co.These details have been amended only in this correction notice to preserve the published version of record."} +{"text": "Communications Medicine 10.1038/s43856-022-00163-y, published online 29 August 2022.Correction to: An author, Luciana Madeira da Silva (LMdS), had inadvertently been omitted from the author list of this article. This author has now been added and the author list is as follows: \u2018Rodney P. Rocconi, Laura Stanbery, Min Tang, Luciana Madeira da Silva, Adam Walter, Bradley J. Monk, Thomas J. Herzog, Robert L. Coleman, Luisa Manning, Gladice Wallraven, Staci Horvath, Ernest Bognar, Neil Senzer, Scott Brun, John Nemunaitis\u2019.LMdS is affiliated with the Mitchell Cancer Institute, Division of Gynecologic Oncology, University of South Alabama, Mobile, USA.The Author Contributions section has been updated to include LMdS and is now as follows: \u2018RPR was responsible for conceptualization, methodology, investigation, resources, writing \u2013 review and editing. LS and MT were responsible for conceptualization, methodology, validation, formal analysis, investigation, resources, writing \u2013 original draft, review and editing. LMdS was responsible for methodology, data generation, investigation, writing \u2013 editing. AW was responsible for methodology, supervision, and writing \u2013 review and editing. BJM, TJH, RLC, NS and SB were responsible for supervision and writing \u2013 review and editing. LM, GW, SH and EB contributed to investigation, resources and writing \u2013 review and editing. JN was responsible for conceptualization, investigation, formal analysis and writing \u2013 original draft, review and editing.\u2019These changes have been made in the HTML and PDF versions of the article."} +{"text": "BRCA) 1 and 2 genes has been widely demonstrated in high grade serous ovarian carcinoma (HGSOC) represent one of the most common causes of mortality in women . The mai (HGSOC) , and a c (HGSOC) .In this Special Topic of Frontiers in Oncology, we would like to discuss the methods, findings and prospects of evidence from molecular pathology that will help in the early diagnosis, treatment decision-making, and drug resistance prediction in gynecological malignancies.Jiang et\u00a0al, Tang and Hu) In particular, Jiang et\u00a0al reported that almost all analyzed patients (94.57%) harbored at least one mutation within TP53, PIK3CA, PTEN, KRAS, BRCA1, BRCA2, ARID1A, KMT2C, FGFR2, and FGFR3 genes. Interestingly, patients with ovarian cancer showed a high rate of BRCA1/2 mutations. Of note, patients harboring TP53, PIK3CA, PTEN, and FGFR3 mutations showed a high tumor mutational burden.Overall, the role of molecular pathology in the management of advanced stage gynecological malignancies has rapidly evolved during the last years. In particular, a number of different genomic alterations have been reported, and may be potential target for personalized therapies From a prognostic point of view, it has been highlighted the role of RPL24 as a potential biomarker to predict the prognosis of cervical cancer patients and assess chemotherapy efficacy.Molecular pathology may play a crucial role in the diagnostic process, in particular in those morphological trouble cases. In the experience by Wang et\u00a0al.; Kong et\u00a0al.)Finally, an emerging tool for molecular purposes is represented by extracellular vesicles, that have demonstrated their utility as a novel biomarker and therapeutic target. (Overall, this Research Topic has highlighted the recent evidences from molecular pathology that will help in the early diagnosis, treatment decision-making and drug resistance prediction in gynecological malignancies.Ongoing research is warranted to improve the clinical outcome of these patients.UM: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing \u2013 original draft, Writing \u2013 review & editing. SU: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing \u2013 original draft, Writing \u2013 review & editing. SC: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing \u2013 original draft, Writing \u2013 review & editing. CA: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing \u2013 original draft, Writing \u2013 review & editing. PG: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing \u2013 original draft, Writing \u2013 review & editing."} +{"text": "Article title: Pneumococcal surface adhesion A protein (PsaA) interacts with human Annexin A2 on airway epithelial cellsAuthors: Yoonsung Hu, Nogi Park, Keun Seok Seo, Joo Youn Park, Radha P. Somarathne, Alicia K. Olivier, Nicholas C. Fitzkee, and Justin A. ThorntonJournal: VirulenceDOI: https://doi.org/10.1080/21505594.2021.1947176It has been noted by the corresponding author that, two undergraduates significantly contributed to the research by helping to construct knockout strains which were included in the final publication. They were mistakenly left off as authors and as both have continued in professional programs, their inclusion on this published work is important to their future careers. An updated author list has been placed below:a, Nogi Parkb, Keun Seok Seob, Joo Youn Parkb, Radha P. Somarathnec, Natalene Vonkchaleea,Yoonsung Hua, Alicia K. Olivierd, Nicholas C. Fitzkeec, and Justin A. ThorntonaKatelyn JacksonaDepartment of Biological Sciences, Mississippi State University, Mississippi State, USA; bDepartment of Basic Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, USA; cDepartment of Chemistry, Mississippi State University, Mississippi State, USA; dDepartment of Population and Pathobiology, College of Veterinary Medicine, Mississippi State University, MS, USA"} +{"text": "Ecology and Evolution, 13, e10593. https://doi.org/10.1002/ece3.10593Geng, X., Zuo,J., Meng, Y., Zhuge, Y., Zhu, P., Wu, N., Bai, X., Ni, G., & Hou, Y. (2023). Changes in nitrogen and phosphorus availability driven by secondary succession in temperate forests shape soil fungal communities and function. The current affiliation mentioned for authors Yunhao Meng, Yanhui Zhuge, Ping Zhu, Xinfu Bai as \u201cSchool of Resources and Environmental Engineering, Ludong University, Yantai, China\u201d is wrong.The correct affiliation should be \u201cCollege of Life Sciences, Ludong University, Yantai, China\u201d.We apologize for this error."} +{"text": "PLOS ONE Editors retract this article [The article , 2 becauAA, ZA, AR, HMA, MHS, MZMS, and CH did not agree with the retraction. MN, SH, TJ, SA, RS, SA, TS, and MAJ either did not respond directly or could not be reached."} +{"text": "In the author list, an author\u2019s name was spelled incorrectly. The correct name is: JP Armstrong.https://doi.org/10.1371/journal.pgph.0001380The correct citation is: Brennan DJ, Armstrong J, Kesler M, Bekele T, Lachowsky NJ, Grace D, et al. (2023) Willingness and eligibility to donate blood under 12-month and 3-month deferral policies among gay, bisexual, and other men who have sex with men in Ontario, Canada. PLOS Glob Public Health 3(1): e0001380. Additionally, there are errors with this author\u2019s contributions. JP Armstrong\u2019s full contributions are: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Software, Supervision, Writing\u2013original draft, and Writing\u2013review & editing.The publisher apologizes for the errors."} +{"text": "CYP6A14 and CYP6N6 Participation in Deltamethrin Metabolic Resistance in Aedes albopictus. AM J Trop Med Hyg 108(3): 609\u2013618. doi: 10.4269/ajtmh.22-0524. PMID: 36746656; PMCID: 9978559.Peng H, Wang H, Guo X, Lv W, Liu L, Wang H, Cheng P, Liu H, Gong M, 2023. In Vitro and In Vivo Validation of American Journal of Tropical Medicine and Hygiene, has been retracted by the Journal.The above article, published in the After publication, an expert in the field identified numerous problems with this manuscript, including questions regarding appropriate methodology, inaccuracy of reported results, and, specifically, implausibility regarding the reported identification of deltamethrin metabolites. A second expert concurred with these impressions. Therefore, with serious questions about the methodology used, results presented, and conclusions made, the manuscript has been retracted after publication."} +{"text": "Each year hundreds of reviewers contribute their expertise to peer review, a process that contributes critically to the quality of the Brain Pathology. The editors at Brain Pathology would like to extend their gratitude to those who have provided their time and energy to review manuscripts for our journal over the last year. We are well aware that our journal can only exist thanks to your concerted efforts to provide concise, accurate, and thoughtful reviews. Below is a list of all of you who completed at least one review, and agreed to have your name published. We also thank those reviewers who choose not to have their names published.Ahrendsen, JaredAlexandrescu, SandaAuer, RolandAyton, ScottBattini, Jean\u2010LucBieniek, KevinBockmayr, MichaelCai, JinquanCarare, RoxanaCullell, NDel Bigio, MarcDudek, EdEnglert, BenjaminEvelson, PabloFalkenburger, Bj\u00f6rnFerrer, IsidreGilani, AhmedGiustetto, MaurizioGlatzel, MarkusGu, YanGuo, JifengGuzman, SamuelHan, LeiHawkins, CynthiaHerms, JochenHighley, RobinHorbinski, CraigIrwin, DavidJoseph, JeffreyJoutel, AnneKovacs, GaborLammens, MartinLangdon, KristopherLeske, HenningLevine, AdrianLi, JianrongLiu, YingMarklund, NiklasMechtler, KarlMeinhardt, JennyMunoz, DavidNasrallah, MacLeanNicolas, GaelNordin, AngelicaPiao, YueshanPittella, Jos\u00e9Popa\u2010Wagner, AurelPriller, JosefPuig, BertaReimann, JensRosi, SusannaRozemuller, AnnemiekeRushing, ElisabethSaleeb, RolaSatomi, KaishiSchulz\u2010Schaeffer, Walter JSepulveda\u2010Falla, DiegoShelkovnikova, Tatyana ASpringer, WolfdieterTan, JieqiongTroakes, ClaireVazquez\u2010Manrique, RafaelVinters, HarryWakabayashi, KoichiWang, YanjiangWang, YuXu, YuqiaoYao, YuZhao, JunliZheng, DanfengZimmermann, Marina"} +{"text": "There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis.Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism.Excess mortality was 4185 per 100\u2009000 cases of appendicitis using approach 1 and 3448 per 100\u2009000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92\u2009492 million using approach 1 and $73\u2009141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95\u2009004 million using approach 1 and $75\u2009666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality.For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially. The economic burden due to loss of income from deaths and days off sick of not meeting need for appendicitis surgery. This is estimated by considering the losses from not providing care to the \u201clocal standard\u201d or not providing care to the \u201chighest standard\u201d (based on high income country standards). Improving access to care whilst keeping the local standard of care would overcome most of the economic losses; improving quality to the highest standard has marginal additional benefits. The associated loss of economic productivity has been estimated at $12.3 trillion for the interval 2015\u201320301. In addition to insufficient access to surgery, it has been recognized that outcomes of surgery can be suboptimal for many patients in low- and middle-income countries. This is reflected in the higher rate of perioperative mortality and surgical-site infections experienced by patients undergoing surgery in low- and middle-income countries compared with those in high-income countries3. This high-level evidence has been insufficient to prompt large-scale policy change and substantial investment in surgery. The cost to a given society of not providing adequate surgical care for specific conditions might provide direct evidence that more targeted investment in surgical services could be cost-effective.It has been estimated that, each year, 143 million additional surgical procedures need to be done in low- and middle-income countries to prevent disability and reduce mortality4. Although the magnitude of lack of access to quality surgical care has been estimated, developing a health service to provide such holistic surgical care for all conditions may not currently be attainable. It should, however, be within the reach of many countries to provide services to treat some conditions that are otherwise fatal and require a fairly simple procedure5.Surgery is a treatment for many diverse conditions6. Although it leads to death or disability if not treated, timely surgical treatment results in a rapid return to normal function. It disproportionally affects younger populations, who are generally economically productive. Hence, lack of access to surgical treatment for appendicitis is likely to have substantial economic consequences for individuals and societies.Appendicitis is a common condition, with an incidence of around 17\u2009700\u2009000 in 20197, unlike planned procedures that can be referred to a tertiary centre. Appendicitis can vary in severity from self-limiting infection to life-threatening peritonitis, depending on the development of irreversible, but unpredictable, gangrene. The safest treatment is, therefore, early surgery. Effective surgery for appendicitis is also reflective of local and district surgical services8, and improved delivery is likely to have additional benefits for other common surgical conditions.Effective treatment of appendicitis requires appropriate and timely surgery, necessitating ready access to acute services6, the unmet need for surgery1, and of harm from lack of access to quality surgery, including procedures for appendicitis2. However, there has been no previous estimation of the global economic burden associated with failure to provide access to quality care for appendicitis. Given that access to surgical treatment for appendicitis reflects local surgical care provision, such information is needed to inform discussions on the investment case for provision of surgical care at country, regional, and international levels9.Estimates are available for the global incidence of appendicitisThis study assessed the economic burden (from loss of income) associated with unmet or delayed or substandard surgical care in low- and middle-income countries. The study focused on two types of indirect cost: lost income owing to premature death and lost income due to absenteeism and/or sick days.3, was assumed to reflect optimal care. The economic burden attributed to scenario 1 could be avoided by increasing the coverage of operations to all who require them while keeping the standard of care in each country the same as it is currently. Scenario 2 involves increasing the coverage of operations to all who require them while increasing the standard of care in each country to be equivalent to that seen in high-income countries. Additionally, the study estimated the total economic burden experienced owing to the current state of care across countries, that is the consequences of providing surgical care of local standard to the proportions of people who currently receive care, and providing no surgical care to those who do not. Supplementary material S.2 provides a detailed description of the method, and details of the data sources and indicator construction can be found in supplementary material S.3. The main analysis was conducted at country level, although some data inputs were available only at the level of country-income groups. The results are presented aggregated to WHO region in the main text. The estimates are presented for the year 2015 as this was the latest year for which data from most sources were available.This study calculated the economic burden in two scenarios: that resulting from not providing surgery at local standards in low- and middle-income countries; and that resulting from not providing surgical care in these countries at the standard available in high-income countries, which, based on the literature6. Data on numbers of appendicectomies performed (or the shortage of appendicectomies) were not available for most countries. Thus, the unmet need was estimated using the following two approaches. The first approach assumed a need for surgical volume of 5000 operations per 100\u2009000 people, for all conditions that should be treated surgically, following the Lancet Commission on Global Surgery1. Using data on a country\u2019s total surgical volume delivered from Holmer et al.10, the gap between surgical need and volume was defined as the unmet need. It was assumed that the proportion of unmet need for appendicitis is equivalent to that for all conditions requiring surgery.All scenarios required information on the number of individuals with appendicitis who do not receive any surgical care. For this, estimates of the incidence of appendicitis for a given country and 5-year age group in 2015 from the Global Burden of Disease project were used11. Given that data on volume of appendicectomies to surgical volume were not available for most countries, several steps were taken to derive these estimates. First, information on the ratio of appendicectomies to gastrointestinal surgery from 116 countries was taken from the COVIDSurg Collaborative, GlobalSurg Collaborative database12. Second, information on the share of gastrointestinal surgery relative to total surgical volume in low- and middle-income countries was taken from multiple publications identified in a systematic search of the literature, as listed in the supplementary material Table S2. Data from England\u2019s Hospital Episode Statistics were used as a proxy for data from high-income countries. Data from low-, middle-, and high-income countries are shown in the Supplementary material to illustrate how the ratio of gastrointestinal surgery to total surgery varies between World Bank income groups. Although these data were used to calculate the predicted number of appendicectomies for high-income countries, it was assumed that there is no unmet need in such countries; thus, the resulting figures were not included in the estimation. Third, a combination of these sources was used to predict the number of appendicectomies for each country based on its surgical volume from Holmer et al.10. The gap between a country\u2019s incidence of appendicitis and the predicted number of appendicectomies was then defined as the unmet need.The second approach assumed that appendicectomies comprise a certain share of surgical volume, with that share varying depending on characteristics of the country. This approach was taken based on the knowledge that lower-income countries perform a larger volume of emergency and gastrointestinal procedures (such as appendicectomy), relative to total surgical volume, than high-income countries14.For both approaches, it was assumed that all patients with appendicitis in high-income countries receive surgical treatment. Organisation for Economic Co-operation and Development (OECD) data for 25 high-income countries in 2015 showed that, for most countries, the number of cases of appendicitis was very close to the number of appendicectomies performedthe supplementary material Section S2). Estimates of the probabilities and mortality or absenteeism (days lost) outcomes were based on adverse events of surgically treated appendicitis from the GlobalSurg Collaborative database15 . The outcomes of not surgically treating appendicitis in low- and middle-income countries rely on the literature summarized in the supplementary material Table S6. Multiplied by the share of unmet surgical need, this gave the expected mortality risk and the number of days absent from employment resulting from not providing surgery to the local or highest standard to an individual with appendicitis .This study focused on two types of income loss: that resulting from early death and that associated with absenteeism. In the first step, the mortality and absenteeism outcomes of surgical treatment in low- and middle-income countries were estimated using surgical treatment at a standard received in low- and middle-income countries and that in high-income countries (as highest available standard), and outcomes of no surgical treatment at all , deflated to the year 2015. All costs were aggregated by WHO region to display the main results. Country-level results are available in the supplementary material Fig. S16, Table S11.In the next step, the expected mortality risk was multiplied by the age-specific incidence of appendicitis to obtain the total number of expected deaths for a given country and age group. The associated income losses were calculated by multiplying the number of expected deaths by the earnings the individuals were expected to have received if they had not died. Similarly, the expected number of absent days was multiplied by the share of unmet surgical need and the incidence of appendicitis to obtain the total number of expected lost working days for a given country. Absenteeism-related income losses were calculated by multiplying the lost working days by the average daily wage. Estimates of the average annual wage for each country were extracted from the International Labour Organization shows the key statistics used to calculate the economic burden of unmet surgical need by WHO region. The estimated share of unmet need was higher using the first approach than the second for all regions except the Americas. This was also evident at country level .Fig. 2, which allows a more detailed comparison of the two approaches. For most countries, approach 1 yielded a higher unmet need than approach 2, whereas the reverse applied mostly to Latin American countries .Country-specific shares of unmet need are shown in supplementary material Table S10). The rate was highest in Africa (8299 per 100\u2009000 for approach 1 and 6522 per 100\u2009000 for approach 2) and South-East Asia . The mortality rate from not providing surgery at the highest standard was slightly higher, on average 4237 per 100\u2009000 (approach 1) and 3500 per 100\u2009000 (approach 2) across the sample.As an intermediate outcome, excess mortality resulting from not providing surgery to local standards was estimated at 4185 per 100\u2009000 patients with appendicitis using approach 1 and 3448 per 100\u2009000 using approach 2 across the whole sample for all countries using approach 1, ranging from $1415 million for Europe and $36\u2009637 million for Western Pacific. Using approach 2, the mortality-related income losses totalled $71\u2009984 million, ranging from $889 million in Europe to $24\u2009040 million for South-East Asia. Expressed as a percentage of gross domestic product (GDP), the economic burden ranged from 0.0050 per cent of GDP in Europe to 0.2602 per cent of GDP in South-East Asia using approach 1, and from 0.0031 per cent of GDP in Europe to 0.2144 per cent in South-East Asia using approach 2. The mortality-related income losses associated with not providing surgery to the highest standard of care were slightly higher, but very similar to the income losses of not providing surgery to local standards.The resulting income loss estimates are shown in versus highest standards was much larger than for the mortality estimates. For South-East Asia, the economic burden increased by about 50 per cent, for all other regions except Europe between 75 and 120 per cent, and for Europe it increased 8-fold (approach 1) or 13-fold (approach 2).Similar to the mortality-related income losses, absenteeism-related income losses associated with not providing surgery to local standards were lowest in Europe and highest in Western Pacific when estimated using either approach. In Europe, income losses were $23 million for approach 1 and $14 million for approach 2; in Western Pacific, losses were $622 million and $389 million respectively. However, the difference between income losses of not providing surgery to local supplementary material Fig. S15).Combining mortality and absenteeism-related income losses, the global economic burden of not providing surgery to local standards amounted to $92\u2009492 million using approach 1 and $73\u2009141 million using approach 2. The additional economic burden of not providing surgery to the highest standard was $2512 million for approach 1 and $2525 million USD for approach 2. The economic burden of unmet access to surgical care at local standards comprised between 87 and 97 per cent of the total economic burden in all regions except Europe . The absolute economic burden was highest in South-East Asia and Western Pacific, but the difference between the two approaches was large for both regions. However, even the lower estimates for both regions yielded some 1.5\u20132-fold higher absolute costs than most other regions.Absenteeism-related income losses contributed to a small fraction of the economic burden of unmet surgical need for appendicitis, irrespective of the approach employed or benchmark . It was found that 45 per cent of the current surgically avertable burden in terms of DALYs could be avoided with scaled up access to higher-quality surgical care . This may be explained in part by differences in methodology, but most likely relates to the impact of surgery on mortality from different digestive diseases. Simple emergency surgery for appendicitis has a substantial effect on mortality, maximizing the impact of reduced access.Reduction in mortality and morbidity, and thus reduction in patient\u2019s income losses, through provision of surgery requires that surgical care can be accessed and that care, once accessed, is of high quality. The Lancet Global Health Commission on High Quality Health Systemsversus lack of quality, other studies22 have shown that lack of access to surgical care is a huge issue in low- and middle-income countries, particularly for emergency conditions7. Access is a multidimensional problem, encompassing service availability, and geospatial, financial, and sociocultural considerations. Solutions therefore require engagement of multiple stakeholders24. Although dimensions of geospatial, financial, and sociocultural considerations certainly need to be addressed, they offer complex challenges25. However, given the relative simplicity of surgery for appendicitis, it may be that service availability issues can be addressed more readily by task-shifting or sharing, to compensate for the worldwide shortage of surgeons10. Task shifting or sharing has been applied successfully to caesarean section and inguinal hernia in some contexts27. Increasing the availability of technicians could grow surgical services more rapidly than can possibly be achieved through traditional training. This solution could enable out-of-hours surgery in local hospitals and also release surgeons to provide increased diagnostic and perioperative care (which is particularly important in the emergency setting). It could also enable increased efficiency of theatre utilization. Improved access to emergency appendicectomy will thereby provide benefits in surgical care that reach beyond the treatment of appendicitis.Appendicectomy was selected because it is an emergency procedure required worldwide, and for which every surgeon receives training. Unlike specialist procedures, accessing any surgically ready facility should enable appropriate care. For more complex procedures, lack of appropriate surgical expertise is more likely to influence outcomes adversely. The present study found that improving access to appendicectomy at current local standards of care can substantially decrease mortality. This shows that, despite calls for improved quality, access should not be neglected, especially for the most common emergency procedures. Although they did not compare outcomes resulting from lack of access 28, this could easily cover the costs of training. These findings can be put into perspective by taking India as an example. According to Global Burden of Disease data, India had an incidence rate of appendicitis of 121 per 100\u2009000 in 2015 (world median 240 per 100\u2009000), or about 765\u2009000 cases in the age group 20\u201364 years, for which the economic burden was calculated. The present study estimated an unmet need for 653\u2009000 people (85 per cent) in approach 1, and 418\u2009000 people (55 per cent) in approach 2. Total costs for not providing surgery to a local standard amounted to $14\u2009086 million in approach 1 and $9017 million in approach 2. In contrast, total care costs were 3616 rupees or $69.5 for an appendicectomy at a tertiary care hospital in India in 2010\u2013201129. If India could invest 5 per cent of the foregone earnings in surgical care, this would free up resources to provide 10.1 million (approach 1) or 6.5 million (approach 2) additional appendicectomies, thus closing the gap in surgical need. Such service development would inevitably provide wider benefits, particularly in emergency surgical care, as no service is provided in isolation. Measuring the societal impact of such an investment would be expected to demonstrate substantial additional improvements in care and associated societal benefits.Although training surgical providers comes at a cost, if countries can raise revenue from earnings forgone as a result of morbidity or mortality associated with lack of access to quality care for appendicitis, and invest 5 per cent of this into improving services, as a recommended minimum share of public spending on healthAlthough the results as a whole are striking, there are some nuances within the findings that are worthy of explanation. The economic burden, relative to GDP, of unmet surgical need was highest in South-East Asia, followed by Africa. Africa and South-East Asia had the greatest economic burden as both had a comparatively high share of unmet surgical need according to the estimates. For South-East Asia, a large contributor to the economic burden was the high incidence rate in Nepal, Bhutan, and Bangladesh according to the Global Burden of Disease data. Without these outliers, South-East Asia would have ranked second after Africa. The ranking differed between economic burden relative to GDP and absolute economic burden of unmet surgical need. The absolute economic burden was highest in Western Pacific and South-East Asia, followed by the Americas, Eastern Mediterranean, and Africa. For Western Pacific, relatively high wages led to higher income losses, whereas the high unmet need and the extreme incidence rates contributed further to the high economic burden for South-East Asia. For most regions, the income losses were higher using approach 1 compared with approach 2; the reverse was, however, true for the Americas, and was also evident at the country level. This seemed to be driven by a combination of comparatively high surgical volume with an even higher incidence rate. For the first approach, the gap between actual surgical volume and the need to achieve a surgical volume of 5000 per 100\u2009000 was considered to estimate the unmet need. As the surgical volume was quite high in the Americas, this resulted in a reasonably low unmet need when using approach 1. Still, the surgical volume was not high enough to counterbalance the very high incidence rate, such that the estimate of unmet need in approach 2 exceeded the estimate of approach 1.appendix S.3). Still, the Global Burden of Disease data are the only nationally comparable and comprehensive incidence data available. Additionally, there are large gaps in the surgical outcomes data, particularly in the emergency setting. Uniquely, this study benefited from accessing the raw data in the COVIDSurg Collaborative and GlobalSurg Collaborative studies which provided global prospectively collected outcomes data. The extrapolation to all low- and middle-income countries might not be accurate for the context of every country, and might obscure variations between certain countries. Similarly, there are no reliable global data to distinguish outcomes by age or sex. As the extrapolation is based on comparable data from several low- and middle-income countries, the results should yield reasonable estimates. Furthermore, because of uncertain and conflicting data on appendicectomies, two analyses were provided in an attempt to provide two different angles on unmet need. The assumption is that the approaches give a reasonable second-best option in the absence of data on appendicectomies performed. Finally, the models are static, in the sense that feedback mechanisms were not incorporated. For example, the models do not account for changes in surgical quality if the access to surgical care increases. Yet, the direction of such feedback mechanisms is likely to depend on many different factors, so any assumptions regarding such mechanisms would be highly debatable.There are limitations to this study. The main constraint is the availability of data on appendicitis incidence, outcomes, and appendicectomies in low- and middle-income countries. The Global Burden of Disease project provides country-level estimates of the incidence of appendicitis, but these diverge from administrative data in high-income countries, probably owing to different data sources Global Surgery Collaboration: AA Essam, Abd Elkhalek Sallam, Abd Elrahman Elshafay, Abd El-Rahman Hegazy Khedr, Abdalla Gamal Saad, Abdalla Gharib, Abdalla Kenibar, Abdallah Salah Elsherbiny, Abdalrahman Adel, Abdelaziz Abdelaal, Abdelaziz Osman Abdelaziz Elhendawy, Abdelfatah Hussein, Abdelkader Belkouchi, Abdelmalek Hrora, Abdelrahman Adelshone, Abdelrahman Alkammash, Abdelrahman Assal, Abdelrahman Geuoshy, Abdelrahman Haroun, Abdelrahman Mohammed, Abdelrahman Sayed, Abdelrahman Soliman, Abdelrhman Essam Elnemr, Abdelrhman KZ Darwish, Abdelrhman Osama Elsebaaye, Abdul Khalique, Abdul Rehman Alvi, Abdul Wahid Anwar, Abdulaziz Altwijri, Abdullah Al-Mallah, Abdullah Almoflihi, Abdullah Altamimi, Abdullah Daqeeq, Abdullah Dwydar, Abdullah Gouda, Abdullah Hashim, Abdulmalik Altaf, Abdulmalik Huwait, Abdulrahman Abdel-Aty, Abdulrahman M. Altwigry, Abdulrahman Sheshe, Abdulrasheed A Nasir, AbdulRazzaq Oluwagbemiga Lawal, Abdulshafi Khaled Abdrabou, Abdurrahaman Sheshe, Abdussemiu Abdurrazzaaq, Abebe Bekele Zerihun, Abeer Al-shammari, Abeer El Gendy, Abeer Esam, Abeer Marey, Abhishek Mittal, Abiboye Yifieyeh, Abid Bin Mahamood, Abidemi Adesuyi, Abouelatta Khairy Aly, Abrar Nawawi, Adam Gyedu, Ade Waterman, Adedapo Osinowo, Adedeji Fatuga, Adel Albiety, Adel B Hassanein, Adel Denewar, Adeleke Adekoya, Ademola Adebanjo, Ademola Adeyeye, Ademola Popoola, Adesina Adedeji, Adesoji O Ademuyiwa, Adesoji Tade, Adewale Adeniyi, Adewale O Adisa, Adham Tarek, Adomas Ladukas, Adrian F. Palma, Afifatun Hasanah, Afizah Salleh, Afnan Abdelfatah, Afnan Altamimi, Afnan Altamini, Agazi Fitsum, Agboola Taiwo, Ahamed Hassan, Ahed Ghaben, Ahmad Abdel Fattah, Ahmad Abdel Razaq Al Rafati, Ahmad Aboelkassem Ibrahem, Ahmad Aldalaq, Ahmad Ali, Ahmad Almallah, Ahmad Alrifaie, Ahmad Ashour, Ahmad Bakr, Ahmad Bani-Sadar, Ahmad Bin Adnan, Ahmad Elbatahgy, Ahmad Faraz, Ahmad Gudal, Ahmad Hasan, Ahmad Khaled Sabe, Ahmad Khoja, Ahmad Nashaat, Ahmad Qaissieh, Ahmad Sabe, Ahmad Saber Sleem, Ahmad Sakr, Ahmad Shalabi, Ahmad Uzair Qureshi, Ahmed Aamer, Ahmed Abd El Galeel, Ahmed Abd Elmoen Elhusseiny, Ahmed Abd Elsameea, Ahmed Abdelkareem, Ahmed Abdelmotaleb Ghazy, Ahmed Abo El Magd, Ahmed Abo Elazayem, Ahmed Adamu, Ahmed Adel, Ahmed Afandy, Ahmed Ahmed, Ahmed Alghamdi, Ahmed Ali, Ahmed Al-khatib, Ahmed Altibi, Ahmed Alzahrani, Ahmed Ata, Ahmed Badr, Ahmed Dahy, Ahmed Diab, Ahmed El Kashash, Ahmed El Kholy, Ahmed Elgaili Khalid Musa, Ahmed Elgebaly, Ahmed Elkelany, Ahmed Elkholy, Ahmed El-Sehily, Ahmed Essam, Ahmed Fahiem, Ahmed Farag, Ahmed Fawzy, Ahmed Fouad, Ahmed Gad, Ahmed Ghanem, Ahmed Gheith, Ahmed Gomaa, Ahmed Hafez El-Badri Kotb, Ahmed Hammad, Ahmed Hassan, Ahmed Hossam Eldin Fouad Rida, Ahmed Ismail, Ahmed Karim, Ahmed Khyrallh, Ahmed Lasheen, Ahmed M. Rashed, Ahmed Magdy, Ahmed Mahmoud Abdelraouf, Ahmed Menshawy, Ahmed Meshref, Ahmed Mohamed Afifi, Ahmed mohamed Ibrahim, Ahmed Mohameden, Ahmed Mohammed, Ahmed Mokhtar, Ahmed Mosad, Ahmed Moustafa, Ahmed Moustafa Saeed, Ahmed Negida, Ahmed Rabeih Mohammed, Ahmed Rabie Mohamed, Ahmed Ragab Nayel, Ahmed Ragab Soliman, Ahmed Raslan, Ahmed Raza, Ahmed Refaat, Ahmed Rslan, Ahmed Sabry, Ahmed Sabry El-Hamouly, Ahmed Safwan Marey, Ahmed Saidbadr, Ahmed Sakr, Ahmed Samir, Ahmed Shahine, Ahmed Sheta, Ahmed Soliman, Ahmed Tammam, Ahmed Tarek Abdelbaset Hassan, Ahmed W. Shamsedine, Ahmed Zaki, Ahmed Zaki Eldeeb, Ahmed Zohair, Ahmedali M Kandil, Ahmedglal Elnagar, Ahsan Zil-E-Ali, Aijaz Jabbar, Ailsa Claire Snaith, Ainhoa Costas-Chavarri, Aiste Austraite, Ajayesh Mistry, Akin Olaolorun, Akinlabi E Ajao, Al Faifi Jubran, Ala Shamasneh, Alaa Abouelnasr, Alaa Al-Buhaisi, Alaa Bowabsak, Alaa El Jamassi, Alaa Elazab, Alaa Elhadad, Alaa Fergany, Alaa Habeebullah, Alaa Hassan, Alaa Shabkah, Alaa Shaheen, Alaba Adesina, Alan Baird, Alan Grant, Alasdair Ball, Alban Cacurri, Albert Mohale Mphatsoe, Alberto Realis Luc, Alejandro Matheu, Alejandro Munera, Alemayehu Ginbo Bedada, Alessandro Favero, Alessio Maniscalco, Alexander Canta Calua, Alexander J Fowler, Alexandra Gerosa, Alexandre Horobjowsky, Alexandre Venancio De Sousa, Alexia Farrugia, Alexis Pierre Arnaud, Alfio Alessandro Russo, Alfredo Gulielmi, Ali Ababneh, Ali Abo El Dahab, Ali Amin Ahmed Ata, Ali Khan Niazi, Ali Kiasat, Ali Mohamed Hammad, Ali Zardab, Ali Zeynel Abidin Balkan, Aliaa Gamal Toeema, Aliaa Sadek, Aliaksandr Filatau, Aliang Latif, Alibeth Andres Baquero Suarez, Alice Faure, Alice Niragire, Alina Robledo-Rabanal, Aline Broch, Alireza Hasheminia, Alisdair Macdonald, Aliyu Ndajiwo, Allan Novak, Alphonse Zeta Mutabazi, Alvaro Enrique Mendoza Bele\u00f1o, Alvin Ee Zhiun Cheah, Aly Abd Elrazek, Aly Nasr, Aly Sanad, Alyaa Halim Elgendy, Alyne Daltri Lazzarini Cury, Amal Ibrahim, Amandine Martin, Amani Althwainy, Amany Abouzahra, Amany Eldosouky Mohammed, Amar Kourdouli, Amel Hashish, Amerdip Birring, Amgad Al Meligy, Amina Abdelhamid, Aminah Hanum Haji Abdul Majid, Aminu Mohammad, Amir Ait Kaci, Amira Atef Omar, Amira Elsawy, Amira Hassan Bekhet, Amira Reda, Amjad Abu Qumbos, Amjad Elmashala, Ammar Gado, Amna Mamdouh Mohamed, Amna Mohamed, Amoudtha Rasendran, Amr Ahmed Saleh, Amr Fadel, Amr Hasan, Amr Hassaan, Amr Hossameldin, Amr Muhammad Elkorashy, Amr Tarek Hafez, Amreen Faruq, Amro Aglan, Ana Cecilia Manchego Bautista, Ana Lucia Contreras-Vergara, Ana Maria Sandoval Barrantes, Ana Vega Carreiro De Freitas, Ana Vega Freitas, Anam Rashid, Anan Rady Abdelazeam, Anand Kirishnan, Anass Majbar, Anastasia Bamicha, Anastasios Stefanopoulos, Anders Thorell, Andre Das, Andre Dubois, Andre L Mihaljevic, Andre Navarro, Andrea Allegri, Andrea Armellini, Andrea Belli, Andrea Bondurri, Andrea Echevarria Rosas Moran, Andrea Natili, Andrea Ruzzenente, Andrea Simioni, Andreass Haloho, Andrei Tanase, Andrej Kolosov, Andrejus Subocius, Andrew G N Robertson, Andrew Kirby, Andrew Mcguigan, Andrew Spina, Andrey Litvin, Andrius Burmistrovas, Andrius Strazdas, Andy Arenas, Aneel Bhangu, Anele Rudzenskaite, Angel David P\u00e9rez Rojas, Angela Dell, Angelica Genoveva Vergara Mejia, Angeline Charles, Angelo Antoniozzi, Angelo Benevento, Angelos Tselos, Angham Solaiman El-Ma'doul, Anjana Sreedharan, Ankur Bhatnagar, Ann Kjellin, Anna Lasek, Anna Maffioli, Anna Powell, Anna Rinaldi, Anna Watts, Annalisa lo Conte, Annamaria Bigaran, Annelisse Ashton, Annisa Dewi Fitriana Mukin, Antanas Gulbinas, Antanas Zadoroznas, Anthonius Santoso Rulie, Anthony Ajiboye, Anthony Avoka, Anthony Chuk-Him Lai, Anthony Davor, Anthony Sander, Antje Oosterkamp, Antoinette Bediako-Bowan, Antonella La Brocca, Ant\u00f4nio Leal, Antonio Nocito, Antonio Ramos-De La Medina, Antonio Taddei, Anwar Atiyeh, Anyomih Theophilus Teddy Kojo, Aoife Driscoll, Apar Shah, Apostolos Vlachogiorgos, April Camilla Roslani, Aram Abdelhaq, Arazzelly del Pilar Paucar, Arcangelo Picciariello, Areej Tarek, Arezo Kanani, Ari Lepp\u00e4niemi, Arianna Birindelli, Arij Ibrahim, Arjun Nesaratnam, Arlindawati Suyadi, Armando Jos\u00e9 Rom\u00e1n Vel\u00e1squez, Arnaud Bonnard, Arnav Agarwal, Aroub Alkaaki, Arturas Vaicius, Arvin Khamajeet, Arvo Reinsoo, Arwa Abouzaid, Arwa Elfarargy, Arwa Ibrahim, Arwa Mohamed, Asaf Kedar, Asdaq Ahmed, Ased Ali, Aseel Alnusairat, Aseel Hamarshi, Aseel Musleh, Ash Prabhudesai, Ashraf A. Maghrabi, Ashraf Morsi, Ashrarur Rahman Mitul, Asmaa Abdelgelil, Asmaa Abdel-Rahman Al-Aarag, Asmaa Rezq, Asmaa Salah, Aspasia Papailia, Assmaa Badwy, Astrid Leusink, Ata Khan, Ataa Ahmed, Athanasia Bamicha, Athar Eysa, Athirah Zulkifli, Atif Mahdi, Attia Attia, Attia Mohamed Attia, Audrey Clarissa, Audrius Dulskas, Audrius Parseliunas, Augusto Zani, Aung Kyaw Tun, Aurel Mironescu, Aurel Sandu Mironescu, Aurelien Scalabre, Aurora Mariani, Aurore Haffreingue, Aurore Thollot, Ausrine Usaityte, Aust\u0117 Skard\u017eiukait\u0117, Awais Raza, Aya Abdel Fatah Ibraheem, Aya Aboarab, Aya Adel Elsharkawy, Aya El-Sawy, Aya Elwaey, Aya Firwana, Aya Hagar, Aya Hammad, Aya Mohamed Fathy, Aya Reda, Aya Yehia Ata, Ayah Hamdan, Ayat Hassaan, Ayman And Taher, Ayman Elwan, Ayman Nabawi, Ayman Salman, Ayman Shwky, Ayokunle Ogunyemi, Azher Herebat, Azmina Verjee, Babajide Adenekan, Babatunde Odeyemi, Badr Eldin Adel, Badreldin Adel Tawfik, Bahar Busra Ozkan, Bakeer Mohamed, Bakhtiar Nighat, Bandar Albeladi, B\u00e1rbara M\u00e1laga, Barbara Mijuskovic, Barbara Pereira Silvestre, Basant Kumar, Basem Sieda, Bashir Bello, Basim Alghamdi, Basma Magdy, Basma Mahmoud, Basmah Alhassan, Bassant Mowafy, Beatrice Brunoni, Beatrix Weber, Belen Sanchez, Ben Thompson, Beno\u00eet Parmentier, Bernard Limoges, Bernard Van Duren, Bernhard Wolf, Bertrand Dousset, Besmir Grizhja, Bettina Lieske, Betty Maillot, Billal Mansour, Bjorn Frisk, Bogdan Diaconescu, Bogdan-Valeriu Martian, Boris Marinkovic, Brendan Skelly, Brian Cameron, Britta Dedekind, Bruno Noukpozounkou, Bryon Frankie Hon Khi Chong, Bylapudi Seshu Kumar, Caio Vin\u00edcius Barroso de Lima, Calogero Iacono, Cameron Fairfield, Camila Sanchez Samaniego, Camilla Cona, Camilo Lopez-Arevalo, Caoimhe Normile, Caranj Venugopal, Carla Cecilia Ram\u00e3\u00adrez Cabrera, Carla Pierina Garc\u00eda Torres, Carlo Corbellini, Carlos Alejandro Arroyo Basto, Carlos Iv\u00e1n P\u00e9rez Vel\u00e1squez, Carlos Morales, Carlos Nsengiyumva, Carlos Paz Galvez, Carmen Capito, Carmen Fern\u00e1ndez, Carmina Diaz-Zorrilla, Carolina Guzm\u00e1n Due\u00f1as, Carolina Oliveira Felipe, Caroline Clifford, Caroluce K Musyoka, Catherine A Shaw, Cathy Magee, Cecile Muller, Cecilia Costa, Cecilia Tolg, Cecilia Wredberg, Celeste Del Basso, C\u00e9line Grosos, Cesar Augusto Azmitia Mendizabal, Cesar Miranda, Cesar Razuri, Cezar Ciubotaru, Chali Chibuye, Challine Alexandre, Charing Cheuk Ling Szeto, Charles Dally, Charlotte Jane Mcintyre, Chaymae Benyaiche, Chean Leung Chong, Chee Siong Wong, Cheewei Gan, Chelise Currow, Chelsea Deane, Cheng Chun Goh, Cherry Koh, Cheryl Ou Yong, Chetan Khatri, Chi Chung Foo, Chi Ying Jacquelyn Fok, Chia Kong, Chiara Ceriani, Chimwemwe Kwatiwani, Chingwan Yip, Chintya Tedjaatmadja, Choon Seng Chong, Chouikh Taieb, Choy Ling Tan, Chris Bode, Chris Lee, Christel Leanne Almanon, Christian Hinojosa, Christian Lari Coompson, Christin Schoewe, Christina Neophytou, Christina P Major, Christina Panteli, Christine Mizzi, Christoforos Ferousis, Christopher Bode, Christos Agalianos, Christos Anthoulakis, Christos Barkolias, Christos Dervenis, Chu-Ann Chai, Chui Yee Wong, Ciara Fahy, Cicilia Viany Evajelista, Cirugia De Emergencia, Ciskje Zarb, Citra Dewi Mohd Ali, Claire Sharpin, Clara Milagros Herrera Puma, Clare M Rees, Clare Morgan, Claudia Reali, Claudio Arcudi, Claudio Fermani, Claudio Gabriel Fermani, Clemens Nawara, Clement Onuoha, Clodagh Mangan, Colleen Sampson, Collins Nwokoro, Colombani Jean-Francois, Constantinos Marinos, Cornelius Mukuzunga, Corrado Bottini, Craig Gouldthorpe, Crislee Elizabeth Lopez, Cristina Fernandes, Crystal Yern Nee Chow, Cutting Edge Manipal, Dale Vimalachandran, Dalia Alkhabbaz, Dalia Hemeda, Damien Brown, Damir Ljuhar, Dan L Deckelbaum, Dana Jaradat, Danelo Du Plessis, Daniel Ardian Soeselo, Daniel Cox, Daniel Dabessa, Daniel Estuardo Marroqu\u00edn Rodr\u00edguez, Daniel Hamill, Daniel Nel, Daniel Youssef, Daniela Magri, Daniele Angelieri, Daniele Gui, Danilo Herrera Cruz, Danjuma Sale, Dansou Gaspard Gbessi, Dario Andreotti, Darius Kazanavicius, Darragh McCullagh, David Mcnish, David Merlini, David Monterroso Cohen, Davide De Boni, Davide Rossi, Dayang Nita Abdul Aziz, DC Grobler, Debora Schivo, Deborah Chiesa, Deimante Mikuckyte, Deividas Dragatas, Demi Gray, Diaa Eldin Abdelazeem Amin Elsorogy, Diaa Moustafa Elbendary Elsawahly, Diaaaldin Zahran, Diana Duarte Cadogan, Diana Sanchez, Dickson Bandoh, Diego Alonso Romani Pozo, Diego Antezana, Diego Coletta, Diego Romani, Diego Sasia, Dietmar \u00d6fner, Dieudonne Duhoranenayo, Dimitri Aristotle Raptis, Dimitrios Balalis, Dimitrios K Manatakis, Dimitrios Karousos, Dimitrios Korkolis, Dimitrios Kyziridis, Dimitrios Lytras, Dimitrios Papageorgiou, Dimitrios Sfougaris, Dimitris-Christos Zachariades, Dina Al-Marakby, Dina Faizatur Rahmah, Dina Gamal, Dina Tarek, Dineshwary Periasammy, Diogo Vinicius dos Santos, Dion Morton, Diya Mirghani, Djifid Morel Seto, DM Cocker, Dmitri A Raptis, Dmitri Nepogodiev, Dmitri Raptis, Doaa Emadeldin, Doaa Gamil, Doaa Hasan, Doaa Hasanain, Doaa Maher Abdelrouf, Domenica Pata, Domingos Mapasse, Dominic Charles Marshall, Donal B O\u2019Connor, Donatas Danys, Donatas Venskutonis, Dorota Radkowiak, Doug Bowley, Dovil\u00e8 Majauskyt\u00e9, Dulan Irusha Samaraweera, Durvesh Lacthman Jethwani, Dush Iyer, Dushyant Iyer, Dzianis Khokha, Dzmitry Paulouski, Ebenezer Takyi Atkins, Echaieb Anis, Edgar Domini, Edilberto Temoche, Eduardo Huaman, Edvard Grisin, Edvinas Dainius, Efeson Thomas, Egle Preckailaite, Ehab Alnawam, Ehab Mamdouh, Eirik Kjus Aahlin, Eirini Kefalidi, Ekow Mensah, Elaine Borg, Eldaa Prisca Refianti Sutanto, Eleanor Marks, Elena Goldin, Elena Muzio, Elena Vendramin, Elena Zdanyte Sruogiene, Eleonora Ciccioli, Elio Jovine, Elisa Francone, Elisabeth Jensen, Elissa Rifhan Mohd Basir, Elizabeth Snyder, Ella Teasdale, Elliot Akoto, Elodie Gaignard, Elodie Haraux, Elsa Robert, Elsayed Ali, Elsayed Gamaly, Emad Abdallah, Emad Al-Dakka, Emad Ali Ahmed, Emad Aljohani, Emad Mohamed Saeed Taha, Eman Abd Al Raouf, Eman Abdelmageed, Eman Abuqwaider, Eman Adel Sayma, Eman Elwy, Eman Emara, Eman Hashad, Eman Ibrahim, Eman Magdy, Eman Magdy Hegazy, Eman Mahmoud Abdulhakeem, Eman Mohamed Ibrahim, Eman Mohamed Morshedy, Eman Nofal, Eman Rashad, Eman Yahya Mansor, Emanuel Barrios, Emanuele Rausa, Emeka Nwabuoku, Emilia De Luca, Emilie Eyssartier, Emilio Dijan, Emma Blower, Emma Jurdell, Emma Upchurch, Emmanuel Acquah, Emmanuel Akatibo, Emmanuel Barrios, Emmy Runigamugabo, Enas Alaloul, Enas Alqahtani, Enoch Dagoe, Enoch Tackie, Eriberto Farinella, Eric Ackom, Eric Kofi Appiah, Erick Samuel Florez Farfan, Erik Hervieux, Erik Schadde, Erika Vicario, Erikas Laugzemys, Ernest Yemalin Stephane Ahounou, Eslam Elbanby, Eslam Ezzat, Esraa Abd Elkhalek, Esraa Abdalmageed Kasem, Esraa Alm Eldeen, Esraa El-Gizawy, Esraa Elhalawany, Esraa El-Taher, Esraa Gamal, Esraa Ghanem, Esraa Kasem, Esraa Samir Elbanby, Esraay Zakaria, Ethar Hany, Etienne Courboin, Eu Xian Lee, Euan Macdonald, Eugene Niyirera, Eugenio Grasset, Eugenio Morandi, Eugenio Panieri, Eva Borin, Evangelos Voulgaris, Evelina Slapelyte, Evelina Woin, Ewan Macdermid, Ewen M Harrison, Eyad Khalifah, Ezio Veronese, Fabian Deichsel, Fabrizio Aquilino, Fahd Abdel Sabour, Faisal Idris, Faith Qi Hui Leong, Fanjandrainy Rasoaherinomenjanahary, Farah Mahmoud Ali, Farhana Iftekhar, Farrag Sayed, Fatai Balogun, Fatema Al Bastawis, Fatema Asi, Fathee Nada, Fathi Elzowawi, Fathia Abd El-Salam, Fathy Sroor, Fatima Baluch, Fatimah I Elgendy, Fatma Elkady, Faustin Ntirenganya, Fawzia Abdellatif Elsherif, Fawzy Mohamed, Fayez Elian Al Barrawi, Fazlin Noor, Federica Bianco, Federica Falaschi, Federico Coccolini, Fei Zheng, Felipe Zapata, Felix Alakaloko, Felix Lee, Feng Yih Chai, Ferdy Iskandar, Fernanda Altoe, Fernanda Frade, Fernande Djivoh, Fernando Espinoza, Fernando Fernandez-Bueno, Fernando Tale, Ferry Fitriya Ayu Andika, Fidelis Jacklyn Adella, Filippo Di Franco, Finaritra Casimir Fleur Prudence Rahantasoa, Fitjerald Henry, Fitriana Nur Rahmawati, Florence Dedey, Florian Primavesi, Florin-Mihail Iordache, Fong Yee Lam, Foteini Koumpa, Francesca Steccanella, Francesco Pata, Francesco Riente, Francesco Ruben Giardino, Francesco Selvaggi, Francis Abantanga, Francis Dossou, Francisco Fujii, Francisco Regalado, Francois-Coridon Helene, Fran\u00e7oise Schmitt, Frank Enoch Gyamfi, Frank Owusu, Fred Alexander Naranjo Aristiz\u00e3\u00a1bal, Fred Hodonou, Frederick Du Toit, Frederique Sauvat, Fredrik Wogensen, Frehun Ayele Asele, Fridiz Saravia, Gabriel Pardo, Gabriela Elisa Nita, Gaetano Gallo, Gaetano Luglio, Gaetano Tessera, Galaleldin Abdelazim, Gamal Shimy, Gandau Naa Barnabas, Garba Samson, Gareth Irwin, Gehad El Ashal, Gehad Samir El Sayed, Gehad Tawfik, Gemma Humm, Genoveffa Balducci, George Christian Manrique Sila, George Ihediwa, George Manrique Sila, Georges Azzie, Georgette Marie Camilleri, Georgios Gemenetzis, Georgios Gkiokas, Georgios Karabelias, Georgios Kyrou, Georgios Tzikos, Gerardo Perrotta, Gerfried Teufelberger, Germain Ahlonsou, German Minguez, Geta Maharaj, Gezim Galiqi, Ghada Elhoseny, Ghada Saied Nagy, Ghiath Al Saied, Ghina Shamim Shamsi, Giacomo Nastri, Giacomo Pata, Gianfranco Cocorullo, Gianluca Curletti, Gianluca Pagano, Gianluca Pellino, Gianmaria Confalonieri, Gianpiero Gravante, Giedrius Lauzikas, Giles Dawnay, Gintaras Simutis, Giorgio Vasquez, Giovanni Landolfo, Giovanni Lazzari, Giovanni Luca Lamanna, Giovanni Pascale, Giovanni Pesenti, Giovanni Sgroi, Giridhar H Devadasar, Gisele Moreira, Giuliano Borda-Luque, Giuseppe Clerico, Giuseppe Rotunno, Giuseppe Salamone, Giuseppe Sammarco, Gokhan Lap, Greg Padmore, Gregorio Tugnoli, Gregory Kouraklis, Greta Mclachlan, Greta Wood, Greta \u017diubryt\u0117, Guillaume Podevin, Guillermo Sanchez Rosenberg, Guo Liang Yong, Gurdeep Singh Mannu, Gurpreet Singh Banipal, Gustavo Miguel Machain Vega, Gustavo Peixoto Soares Miguel, Gustavo Pereira Fraga, Gustavo Recinos, Gustavo Rodolfo Pertersen Servin, Haaris A. Shiwani, Hadeel Al-farram, Hafiz Hakim, Hagar Zidan, Hager Abdul Aziz Amin, Hager Abdulaziz, Hager Ahmed El-badawy, Hager Elwakil, Hager Tolba, Hagir Zain Elabdin, Haidar Hajeh, Hala Ahmed, Hala Saad, Halima Aliyu, Hamdi Ebdewi, Hamza Asumah, Hamza Waleed, Hanan Adel Saad, Haney Youssef, Hani Natalie, Hanna Royson, Hannah Anderson-Knight, Hannah Burns, Hannah S Thomas, Hans-Ivar Pahlsson, Harish Neelamraju Lakshmi, Harriet Jordan, Hasan Ismael Ibraheem, Hasan Ismael Ibraheem Al-Hameedi, Hasbi Maulana Arsyad, Hasnain Abbas Dharamshi, Hassan Ali Mostafa, Hatem El-Sheemy, Haya Tahboub, Hayam Ahmed, Hayden Kretzmann, Hayssam Rashwan, Haytham Abudeeb, Hazem Khaled, Hazmi Dwinanda Nurqistan, Heather Bougard, Heba Baraka, Heba Gamal, Heba Shaker, Hector Shibao Miyasato, Helen Mohan, Helen Woodward, Helena Franco, Helene Francois-Coridon, Helmut Alfredo Segovia Lohse, Hend Adel Gawad Shakshouk, Hend Kandil, Hend Mahmoud, Henri Kotobi, Henry Mendel, Henry Nnaj, Herlin Karismaningtyas, Herman Cruz, Hesham Magdy, Hesham Mohammed Bakry, Hian Ee Heng, Hildur Thorarinsdottir, Hisham Safa, Hisham Samih, Hogea Mircea, Hong Kong SAR, Hong Yee Wong, Hoong-Yin Chong, Hope Edem Kofi Kordorwu, Hope Glover-Addy, Horacio Paredes Decoud, Hosni Khairy Salem, Hossam Dawoud, Hossam Elfeki, Hossam Emadeldin, Houda Bachri, Hunain Shiwani, Hussein Ali, Hussein El-Kashef, Hussein Mohammed, Hussien Ahmed, Iason-Antonios Papaskarlatos, Ibrahem Abdelmotaleb, Ibrahim AbdelFattah, Ibrahim Alhabli, Ibrahim Al-Slaibi, Ibrahim AlYoussef, Ibrahim Elzayat, Ibrahim Elzayyat, Ibrahim N. Alomar, Ibrahim Rakha, Ibrahim Raza, Ida Bj\u00f6rklund, Idelso Vasquez, Ignas Rakita, Ihab Hassan, Ihdaa Adawi, Iloba Njokanma, Iman Elkadsh, Immacolata Iannone, Ingemar Havemann, Ioannis Kyriazanos, Ioannis Patoulias, Ioannis Valioulis, Ionasc Dan, Ionut Negoi, Ionut-Bogdan Diaconescu, Irene Montes, Irene Ortega-Vazquez, Isaac Amole, Isaac Bertuello, Isaac Hanley, Isam Bsisu, Islam Magdy El Sayed, Ismael Isaac Zelada Alvarez, Ismail Lawani, Israa Abdullah Aziz Al-Azraqi, Israa Adel, Israa Awad, Israa Qawasmi, Ivan Mendoza Restrepo, J Edward Fitzgerald, Jack Almy, Jacqueline Sheehan, Jaime Andres Montoya Botero, Jaime Herrera-Matta, Jakeline Restrepo, Jakov Mihanovic, James Adeniran, James Brown, James Davies, James Giles, James Glasbey, James Olivier, James Pape, James Richards, James Wheeler, James Yang, Jamie Shah, Janet Pagnozzi, Jannin Salcedo, Jasim Amin, Jason Brown, Javier Pastora, Javier Rosales, Jazmin Coronel, Jean Br\u00e9aud, Jean De La Croix Allen Ingabire, Jean-Baptiste Marret, Jean-Francois Colombani, Jean-Fran\u00e7ois Lecompte, Jeffrey Dalli, Jehad Hassan Youssif, Jehad Meqbil, Jemina Onimowo, Jen Cornick, Jenifa Jeyakumar, Jennifer Nowers, Jennifer Rickard, Jennifer Skehan, Jerry Makama, Jesse Ron Swire Ting, Jessica Juliana Tan, Jessica Patricia Gonzales Stuva, Jessica Roth, Jessica Souza Luiz, Jia Hao Law, Jia Yng Siaw, Jian Er Saw, Jibran Abbasy, Jiheon Song, Jimy Harold Jara Quezada, Joachim Amoako, Joachim Wiborg, Joanna Swann, Jo-Anne Carreira, Joanne Edwards, Joe Vincent, Joel Kin Tan, Joe-Nat Clegg-Lamptey, Johanna Joosten, Johanna Nyberg, Johannes Kurt Schultz, Johannes Wiik Larsen, John Bondin, John F. Camilleri-Brennan, John Jemuel V. Mora, John Lee Y Allen, John Whitaker, Jolanta Gribauskaite, Jon Arne S\u00f8reide, Jon Kristian Narvestad, Jonathan Ajah, Jonathan Dakubo, Jonathan Heath, Jonathan R L Wild, Jonny Setiawan, Jorge Armando Chungui Bravo, Jorge Torres Cardozo, Jose Aguilar-Jimenez, Jose Andres Garcia-Marin, Jose Antonio Cabala Chiong, Jose Costa-Maia, Jos\u00e9 Hamasaki, Jos\u00e9 Luis Hamasaki Hamaguchi, Jose Luis Rodicio, Jose Mar\u00eda Vergara Celis, Jos\u00e9 Ren\u00e9 Ar\u00e9valo Azmitia, Joselyn Ye, Joseph Awuku-Asabre, Josephine Psaila, Joshua Luck, Joshua Michael Clements, Joyeta Razzaque, Juan Camilo Correa, Juan Carpio, Juan Gouws, Juan Jaime Herrera Matta, Juan Manuel Carmona, Juan Marcelo Delgado, Juana Kabba, Jubran J Al-Faifi, Julia Guasti Pinto Vianna, Julian Camilleri-Brennan, Juliana Menegussi, Julien Leroux, Julien Rod, Juliette Hascoet, Julio Jimenez, Junyeong Oh, Juozas Kutkevicius, Justas Kuliavas, Justas \u017dilinskas, Justin Chak Yiu Lam, Justus Lando, Ka Hin Gabriel Li, Ka Wai Leung, Kai Yin Lee, Kalangu Kabongo, Kalitha Pinnagoda, Kalon Hewage, Kamau Kinandu, Kamran Faisal Bhopal, Kandasami Palayan, Kareem Dabbour, Kareem Elshaer, Karen Bailey, Karim Hilal, Karl Bonavia, Karolis Lagunavicius, Karolis Varkalys, Kate Cross, Kate Yu-Ching Chang, Katharina Beate Reinisch, Katharine Whitehurst, Katherine Gash, Kathryn Chu, Kathryn Lee, Katie Connor, Katrin Gudlaugsdottir, Kaustuv Das, Kazeem Atobatele, KC Janardha, Kean Leong Koay, Keat-Seong Poh, Keiran David Clement, Keith Sammut, Keith Say Kwang Tan, Kenneth Aaniana, Kenneth Johnson, Kenneth Mealy, Kenneth Thorsen, Kenny Turpo Espinoza, Kent Pluke, Kestutis Strupas, Kevin C. Conlon, Kevin Turpo Espinoza, Khaled Abozeid, Khaled Alhady, Khaled Aljboor, Khaled Dawood, Khaled Hesham Elbisomy, Khaled Ibrahim, Khaled Khattab, Khaled Naser El Deen, Khalid Mahmud, Khalid Qurie, Khalid Salah El-Dien, Khalil Abdul Bassit, Khaoula Boukhal, Khlood Ashour, Kholod Tarek Lasheen, Kholoud Abdelbadeai, Khurram Khan, Khuzaimah Zahid Syibrah, Kieran Atkinson, Kieran Ka Kei Li, Kirsten Lafferty, Kjetil S\u00f8reide, Knut Magne Augestad, Kolonia Konstantina, Konstantinos Farmakis, Konstantinos Gasteratos, Kornelija Maceviciute, Kp\u00e8mahouton Ren\u00e9 Keke, Kresimir Zamarin, Kristian Styles, Kristijonas Jasaitis, Kristijonas Jokubonis, Kristina Cassar, Kuet Jun Chung, Kuhaendran Gunaseelan, Kuok Chung Lee, Kurt Carabott, Kwabena Agbedinu, Kwaku Boakye-Yiadom, Kwame Maison, Kwasi Asare-Bediako, Kwasi Kusi, Kyaw Phyo Aung, Kylie Joan-yi Szeto, Kyriakos Psarianos, Laimonas U\u0161\u010dinas, Lalith Asanka Jayasooriya Jayasooriya Arachchige, Lana Abusalem, Larissa Ines P\u00e1ez Lopez, Lau Wen Liang Joel, Laura Gavagna, Laura Koskenvuo, Laura Lorenzon, Laura Luque, Laurent Fourcade, Lawal Abdullahi, Lawani Isma\u00efl, Lawrence Bongani Khulu, Layza-Alejandra Mercado Rodriguez, Lee Shi Yeo, Leif Israelsson, Lemuel Davies Bray, Lenin Pe\u00f1a, Leo Licari, Leonardo Solaini, Li Jing Yeang, Liam Henderson, Liam Richardson, Liana Roodt, Lillian Reza, Linas Urbanavicius, Linas Venclauskas, Linda Alvi Madrid Barrientos, Linda Andersson, Ling Wilson, Linn Nymo, Linnea Mauro, Liviu Iuliu Muntean, Liviu Muntean, Ljiljana Jeremic, Lofty-John Anyanwu, Lopna Ahmed Mohamed Ahmed, Lorena Fuentes-Rivera, Lorena Rodriguez, Lorena Solar Garc\u00eda, Lorraine Sproule, Lotfy Eldamaty, Luai Jamal, Luana Ayres Da Silva, Lubna Sabeeh, Luc Herv\u00e9 Samison, Luca Ansaloni, Luca Bortolasi, Luca Turati, Lucia Duinhouwer, Lucian Corneliu Vida, Lucile Fievet, Lucio Selvaggi, Ludwing Alexander Zeta Solis, Luen Shaun Chew, Luigi Bonavina, Luigi Bucci, Luigi Maria Cloro, Luis Alberto Valente Laufer, Luis Barneo, Luis Joaqu\u00edn Garc\u00eda Florez, Luis M. Helguero-Santin, Luis Miguel Alvarez Barreda, Luis Tale, Luisa Giavarini, Luiz Carlos Barros De Castro Segundo, Luiza Sarmento Tatagiba, Lukas Eisner, Lusi Padma Sulistianingsih Mata, Maarten Vermaas, Mabel Amoako-Boateng, Maciej Wal\u0119dziak, Madan Jha, Madelaine Gimzewska, Mads Gran, Maeve O'neill, Magdalini Mitroudi, Magnus Boijsen, Maha Al-faqawi, Maha Elmasry, Maha Gamal Mohamad Hamad, Maha Nasr, Mahadevan Deva Tata, Mahitab Essam, Mahitab Morsy Farahat, Mahmoud A. Elnajjar, Mahmoud Abdelshafy, Mahmoud Abdelshakour, Mahmoud Abdulgawad, Mahmoud Ahmed Fathi Abozyed, Mahmoud Alrahawy, Mahmoud Amreia, Mahmoud Badawy, Mahmoud Eldafrawy, Mahmoud Elfiky, Mahmoud Elkhadragy Maher, Mahmoud Elkhadrawi, Mahmoud Elsayed Moghazy, Mahmoud Gomah, Mahmoud M. Saad, Mahmoud Mohamed Metwally, Mahmoud Morsi, Mahmoud Saad, Mahmoud Saami, Mahmoud Salama, Mahmoud Salma, Mahmoud Shalaby, Mahmoud Warda, Mahmoud Zakaria, Mahmut Arif Yuksek, Mahnoor Javaid, Mahnuma Mahfuz Estee, Mai Ebidy, Mai Mohamed Ebidy, Mai Salama, Ma\u00edra Cassa Careta, Maja Marcus, Majd Dabboor, Majed Aboelella, Makafui Dayie, Makki Elsayed, Malcolm Falzon, Maleeha Hassan, Malin Sund, Man Fung Leung, Man Hon Andrew Yeung, Manar Abd-Elmawla, Manar Saeed, Mantas Drungilas, Mantas Jokubauskas, Mantas Vil\u010dinskas, Manuel Francisco Roxas, Manuel Hache-Marliere, Manuel Lopez, Manuel Rodriguez Castro, Manuela Mendez, Manzoor Dar, Maram Abu-toyour, Maram Salah, Marcelo O\u00b4Higgins Roche, Marco Catani, Marco Maria Pascale, Marco Migliore, Mardelangel Zapata Ponze De Leon, Margaret O'Shea, Margarita Montrimaite, Margherita Notarnicola, Margub Hussain, Maria Clara Mendoza Arango, Maria Giovanna Grella, Maria Hjertberg, Maria Isabel Villegas Lanau, Maria Jesusa B. Ma\u00f1o, Maria Lorena Aguilera, Maria Marta Modolo, Maria Mayasari, Maria Novella Ringressi, Maria Soledad Gonzales Montejo, Maria Soledad Merlo, Maria Utter, Mar\u00eda Valcarcel-Salda\u00f1a, Maria-Lorena Aguilera-Arevalo, Mariam Darweesh, Mariam O. Gad, Mariam Saad Aboul-Naga, Mariano Cesare Giglio, Mariastella Malavenda, Marie Carmela Lapitan, Marie Dione Parreno-Sacdalan, Marie Paul, Mariette Renaux-Petel, Marija Agius, Marilia Del Carmen Escalante Salas, Marilla Dickfos, Marina Luiza Pimenta, Mario Contreras Urquizu, Mario Corbellino, M\u00e1rio Jacobe, Mario Lopez, Mario Pasini, Mario Trompetto, Marisa Leal, Marisol Manriquez-Reyes, Mariuca Popa, Mark Ian Hampton, Mark Sykes, Mark Wagener, Markus Zuber, Marte Bliks\u00f8en, Martha Glynn, Martin Jarmin, Martin Kyereh, Martina Perino, Martina Yusuf Shawky, Martinique Vella-Baldacchino, Marvin Vargas, Marwa Altarayra, Marwa Elashmawy, Marwa Elshobary, Marwa Hamdan, Marwa Sayed, Marwan Abubakr, Marwan Fahim, Marwan Shawki, Maryam Ali Khan, Maryna Shubianok, Mashael Al-Mousa, Masood Alghamdi, Masood Jawaid, Massiell Machaca, Massimiliano Dal Canto, Massimo Coletti, Matas Pa\u017euskis, Matei Bratu, Matei Razvan Bratu, Mateusz Rubinkiewicz, Matteo Papandrea, Matteo Ripa, Mattew Ekow, Matthew Baldacchino, Matthew Billy, Matthew Young-Han Kim, Matthieu Peycelon, Matti Tolonen, Maureen Bezzina, Maurizio Foco, Mawaddah Alrajraji, Max D\u00e9nakpo, Max Rath, Mayaba Maimbo, Mazed Mohamed, Mazen Hassanain, Megan Turner, Mehmet Ali Yavuz, Mehmet Gumar, Mehmet Ulu\u015fahin, Melanie Castro Mollo, Melanie Zapata Ponze De Leon, Menatalla Salem, Mengistu Worku, Menna Tallah Ramadan, Mennaallah Hafez, Mennat-Allah Mustafa, Menold Archee P. Redota, Meran Allam, Meric Mericliler, Merna Mostafa, Meryem Abbouch, Metwally Aboraya, Michael Amoah, Michael Cox, Michael Edye, Michael Gillespie, Michael Hanrahan, Michael Livingston, Michael Puttick, Michael Stoddart, Michael Van Niekerk, Michael Walsh, Michael Wilson, Michail Kontos, Michail Margaritis, Micha\u0142 Janik, Micheal Ohene-Yeboah, Michela Monteleone, Michele Carlucci, Michele Sacco, Michelle Mccarthy, Midhun Mohan, Miguel Angel Paludi, Miguel Siguantay, Mihael Radic, Mihaela Vartic, Miklosh Bala, Milaksh Kumar Nirumal, Milan Radojkovic, Milica Nestorovic, Millika Ghetia, Mindaugas Kiudelis, Mircea Beuran, Mircea Hogea, Mirko Mangiapane, Mitchelle Solange De F\u00e3 Tima Linares Delgado, Moayad Othman, Mobolaji Oludara, Modise Zacharia Koto, Mohamad Baheeg, Mohamad Bakhaidar, Mohamad Jeffrey Bin Ismail, Mohamed A Abdelaziz, Mohamed A Amer, Mohamed A Baky Fahmy, Mohamed Abbas, Mohamed Abd El Slam, Mohamed Abdelaty, Mohamed Abdelaty Mohamed, Mohamed Abdelkhalek, Mohamed Abdelraheim, Mohamed Abozaid, Mohamed Abozed Abdullah, Mohamed Abuseif, Mohamed Adel Badenjki, Mohamed Ali Ghonaim, Mohamed Ali Mahmoud, Mohamed Ameen, Mohamed Ammar, Mohamed Asal, Mohamed Awad Elkarim Hamad Mohamed, Mohamed Dablouk, Mohamed El Halawany, Mohamed Elazoul, Mohamed Elbermawy, Mohamed Elfil, Mohamed Elsehimy, Mohamed Elzayat, Mohamed Etman, Mohamed F Zalabia, Mohamed Fares, Mohamed Fawzy Mahrous Badr, Mohamed Fouad Hamed, Mohamed Gadelkarim, Mohamed Ghoneem, Mohamed Gulamhussein, Mohamed Hafez, Mohamed Hashish, Mohamed Hassab Alnaby, Mohamed Husseini, Mohamed Ibrahim, Mohamed Ismail, Mohamed Karkeet, Mohamed Kelany, Mohamed Mabrouk, Mohamed Magdy, Mohamed Mahmoud, Mohamed Moamen Mohamed, Mohamed Moaty, Mohamed Mostafa, Mohamed Mustafa, Mohamed Nashat, Mohamed Nazir, Mohamed Reda loaloa, Mohamed Rezal Abdul Aziz, Mohamed Sabry Ammar, Mohamed Salah, Mohamed Salah Elhelbawy, Mohamed Seisa, Mohamed Shaalan, Mohamed Sleem, Mohamed Sobhi Jabal, Mohamed Youssef, Mohamed Zidan, Mohamedraed Elshami, Mohammad Abdulkhalek Habeeb, Mohammad Aboraya, Mohammad Adawi, Mohammad Alherz, Mohammad Aliyu, Mohammad Elsayed Omar, Mohammad Ghannam, Mohammad Ghassan Alwafai, Mohammad Mohsin Arshad, Mohammad Rashid, Mohammadasim Amjad, Mohammed Alamoudi, Mohammed Alhendy, Mohammed AlRowais, Mohammed Alsaggaf, Mohammed Alzahrani, Mohammed Bukari, Mohammed Deputy, Mohammed Elgheriany, Mohammed Elsayed, Mohammed Elshaar, Mohammed Elsiddig, Mohammed Firdouse, Mohammed G. Azizeldine, Mohammed Hanafy, Mohammed Ismail, Mohammed Kamal Ismail, Mohammed Mousa, Mohammed Mousa Salem, Mohammed Mustafa Hassan Mohammed, Mohammed Mustafa Mohammed, Mohammed Najjar, Mohammed Nasr, Mohammed Osman, Mohammed Osman Dablouk, Mohammed Saeed, Mohammed Saleh A. Alghamdi, Mohammed Ubaid Alsaggaf, Mohammed Yahia Mohamed Aly, Mohannad Aledrisy, Mojolaoluwa Olugbemi, Mona Hamdy Madkor, Mona Hosh, Mona Rashad, Monica Bassem, Monique Moron Munhoz, Monty Khajanchi, Morgan Haines, Morvarid Ashtari, Mostada Samy, Mostafa Abdelkader, Mostafa Ahmed Bahaa Eldin, Mostafa Allam, Mostafa Gemeah, Mostafa Mahmoud Eid, Mostafa Qenawy, Mostafa Samy, Mostafa Seif, Mostafa Shalaby, Mousa Mustafa, Moustafa Ibrahim Mahmoud, Moustafa R. Aboelsoud, Msafiri Kimaro, Muayad Ahmed Alfarsi, Muhamed M H Farhan-Alanie, Muhammad Adil, Muhammad Alkelani, Muhammad Amsyar Auni Lokman, Muhammad Bin Hasnan, Muhammad Daniyan, Muhammad El-Saied Ahmad Muhammad Gohar, Muhammad Fathi Waleed Omar, Muhammad Habib Ibrahim, Muhammad Mohsin Furqan, Muhammad Rashid Minhas Qadir, Muhammad Saqlain, Muhammad Shawqi, Muhammad Talha Butt, Muhammad Taqiyuddin Yahaya, Muhammad Waqar, Muhammed Masood Riaz, Muhammed Talaat, Muhtarima Haque, Muna Rommaneh, Murad Aljiffry, Murat Karakahya, Musah Yakubu, Muslimat Alada, Mustafa Farhad, Mustafa Mohammed Taher, Muthukumaran Rangarajan, Muwaffaq Mezeil Telfah, Myint Tun, Myranda Attard, Nada Ahmed Reda Elsayed, Nada El-Sagheer, Nada Elzahed, Nada Mohamed Bekhet, Nader Abd El Hamid, Nadia Khalid Abd El-Latif, Nadia Ortiz, Nadin Elsayed, Nadya Johanna, Nahilia Carrasco, Najwa Nadeem, Naomi J Wright, Napoleon Mendez, Narimantas E. Samalavicius, Nashat Ghandora, Nasir Bustangi, Natale Di Martino, Natalie Blencowe, Natalie Redgrave, Nathalie Botto, Nathania Sutandi, Nawal Sadig, Nazmie Kariem, Nebil Behar, Nebiyou Seyoum Abebe, Nebyou Seyoum, Nebyou Seyoum Abebe, Neel Gobin, Neel Limaye, Neerav Aruldas, Nehal Yosri Elsayed Abdel-Wahab, Neil Smart, Nelson Manuel Urbina Rojas, Nelson Msiska, Nerijus Kaselis, Nermeen Soubhy El-Shahat, Nermin M Badwi, Nermin Mohamed Badwi, Nesma Elfouly, Nicholas Phillips, Nichole Starr, Nicola Chetta, Nicola Zanini, Nicolas Henric, Nicole D'aguzan, Nicole Grech, Nicoleta Panait, Nicoletta Leone, Nicol\u00f2 Falco, Nidhi Gyanchandani, Nigel J Hall, Nihaal Shaikh, Niiarmah Adu-Aryee, Nik Azim Nik Abdullah, Nik Ritza Kosai, Nikica Pezelj, Nikki Green, Nikolaos Gouvas, Nikolaos Ivros, Nikolaos Mitroudis, Nikolaos Nikoloudis, Nikolaos Zampitis, Nithya Niranjan, Niveshni Maistry, Noha Abdullah, Noha Abdullah Soliman, Noha Maraie, Noha Wael, Nohad Osman, Noman Shahzad, Nora Abdul Aziz, Norah Al Subaie, Noran Abdel-Hameed, Noran Halim El Gendy, Norbert Uzabumwana, Norberto Herrera, Norma Depalma, Nosisa Sishuba, Nouf Akeel, Noura A. Attallah, Nourhan Adam, Nourhan Anwar, Nourhan Elsabbagh, Nourhan Medhat Elhadary, Nourhan Mesbah, Nourhan Semeda, Nourhan Soliman, Novia Adhitama, Nowrin F. Aman, Nuno Muralha, Nur Zulaika Riswan, Nurlaila Ayu Purwaningsih, Nyawira Ngayu, Octavio Garaycochea, Oday Halhouli, Ogechukwu Taiwo, Ola Sherief Abd El Hameed, Olabisi Osagie, Olabode Oshodi, Olajide Abiola, Olalekan Ajai, Oliver Warren, Oliver Ziff, Olivier Abbo, Olivier Azzis, Olivier Rosello, Olubukola Faturoti, Olufemi Habeeb, Olumide Elebute, Oluseyi Ogunsua, Oluwaseyi Adebola, Oluwatomi Odutola, Omar Abdelkader, Omar Abdulbagi, Omar Aguilera, Omar Alahmady, Omar Arafa, Omar Ghoneim, Omar Hesham, Omar Mattar, Omar Moussa, Omar Osman, Omar Salah, Omar Saleh, Omnia Aboelmagd, Omnia Mosalum, Omobolaji O Ayandipo, Omolara Faboya, Omolara Williams, Opeoluwa Adesanya, Orestis Ioannidis, Osaid H. Alser, Osama Algohary, Osama Mohamed, Osama Mohamed Salah, Osama Mokhtar Mohamed Hassan, Osama Saadeldeen Ebrahim, Osama Seifelnasr, Osman Imoro, Ossama Al-Obaedi, Otto Coyoy-Gaitan, Ourdia Bouali, Owusu Emmanuel Abem, Oyediran Kehinde Timothy, Oyindamola Oshati, Pablo Ramazzini, P\u00e5l Aksel N\u00e6ss, Pamphile A Assouto, Panchali Sarmah, Pandi Eduard, Panu Mentula, Paola Salusso, Paola Violi, Paolino De Marco, Paolo Aonzo, Paolo Silvani, Paolo Ubiali, Patrizio Mao, Paul Kielty, Paul Sutton, Paul Ugalde, Paul Witherspoon, Paul Wondoh, Pauline Gastaldi, Paulius Karumnas, Paulius Kondrotas, Paulo Alves Bezerra Morais, Pedro Angel Toribio Orbegozo, Peep Talving, Pei Ying Koh, Per Weber, Per-Olof Lundgren, Peter Deutschmann, Peter Labib, Peter Wiel Monrad-Hansen, Petras Vi\u0161inskas, Phebe Anggita Gultom, Philip Alexander, Philip Choi, Philip Mshelbwala, Philip Taah Amoako, Philippe Buisson, Phoebe De Bono, Phumudzo Ndwambi, Pier Paolo Grandinetti, Piergiorgio Danelli, Pierpaolo Sileri, Pietra Ligure, Pietro Mingrone, Pigeneswaren Yoganathan, Piotr Major, Poddevin Francois, Povilas Ignatavicius, Povilas Mazrimas, Prasad Pitigala Arachchi, Pratik Jain, Prince Kwakyeafriyie, Prisca A.L. Har, Pui Xin Chin, Puneet Malik, Puyearashid Nashidengo, Qinyang Liu, Quentin Alimi, Quentin Ballouhey, Quinn Ellison, R. Goh Ern Tze, Rachel King, Rachel Moore, Radhian Amandito, Radin Mohd Nurrahman Radin Dorani, Rafael Araujo, Rafael Soley, Rafa\u0142 Roszkowski, Raffaele Galleano, Ragavan Narayanan, Ragnar Herikstad, Rahma Kamil, Rajeev Satoskar, Rakan Kabariti, Ralph F Staerkle, Ram Nataraja, Ramadan Oumer, Ramadan Shaker, Ramdan Shaker, Ramesh Jonnalagadda, Ramon Alvarado Jaramillo, Ram\u00f3n Augusto Melo Cardozo, Rana Mamdouh, Rana Saadeh, Raquel Rodr\u00edguez-Ur\u00eda, Raquillet Claire, Rasha Abdelhamed, Razvan-Matei Bratu, Reda \u017dilinskien\u0117, Redouane Mammar Bennai, Reem Alyahya, Reem Fakher, Reem Husseiny, Reem Khreishi, Reem Mohammed Hassan Balila, Rehab Elashry, Reham Alaa El-Din, Reham Alshareef, Reham Saad, Renato Melo, Reuban D'cruz, Reuben Goh Ern Tze, Reynu Rajan, Rezaul Karim, Ricardo Velasquez, Richard Gilbert, Richard Lilford, Richard Opoku-Agyeman, Richard Spence, Richard William Gilbert, Richmond Hagan, Rifan Alyami, Riinu Ots, Ritauras Rakauskas, Roaa Khan, Robert George, Robert Karlo, Robert Kerley, Robert Mcintyre, Robert Morton, Robert Parker, Robert Tyler, Roberta Bugeja, Roberta Tutino, Roberta Villa, Robertas Baltrunas, Robertas Pranevicius, Roberto Cautiero, Roberto Cirocchi, Roberto Faccincani, Roberto Klappenbach, Roberto Macchiavello, Roberto Peltrini, Roberto Schiavone, Robinson Mas, Roel Matos-Puig, Rofida Elsemelawy, Roger Lawther, Roger Schmid, Rohan Ardley, Rohi Shah, Rokas Rackauskas, Rokayah Julaihi, Rokia Sakr, Roland Osuoji, Romeo Guevara, Romeo Lages Simoes, Romualdas Riauka, Ronald Coasaca Huaraya, Ronald Renato Barrionuevo Ojeda, Ronan Cahill, Rony Camacho, Rory Callan, Rosario Sacco, Rose Khreishi, Rosie Mcdonald, Ross Bowe, Ross Coomber, Rowida Elmelegy, Roxanne Chenn, Roy Quek, Rub\u00e9n Balmaceda, Rub\u00e9n Dar\u00edo Arias Pacheco, Ruben Rivas, Ruben Santiago Restrepo Giraldo, Rudy Gunawan, Rula Zaa'treh, Ruqaya Kadhim Mohammed Jawad Al-Hasani, Ruta Mazelyte, Ruth Blanco, Ruth Gratton, Ruth Scicluna, Ryan Adams, Ryan Choon Kiat Tan, Ryan Mcintosh, S.V. Kinnera, Saad Al Awwad, Sabbir Karim, Sabine Irtan, Sabrina Asturias, Sabrina Dardenne, Sabry Mohy Eldeen Mahmoud, Safia Ali, Safwat Al-Nahrawi, Saged Elsherbiney, Sahar Abdoun Ishag Idris, Sahar Jaber, Sahlu Wondimu, Saiba Abdul-Latif, Said Alyacoubi, Sakhaa Hanoun, Saleem El-Rabaa, Saleh A. Alnuqaydan, Saleh Alqahtani, Salim Anderson Khouri Ferreira, Sally Elshanwany, Sally Hallam, Salma Magdy, Salma Mansour, Salma Said Elkolaly, Salman Aldhafeeri, Salomone Di Saverio, Salwa Khallaf, Sam Arman, Sam Debrah, Sam Seisay, Samaa Mahmoud Al Attar, Samah Afana, Samantha Corro-Diaz Gonzalez, Samar Abdelhady, Samar Adel Ismail, Samar Saad, Samar Soliman, Sameer Kushwaha, Sameh Emile, Sameh Sarsik, Sami Martin Sundstrom, Samson Olori, Samuel Essoun, Samuel Nigo, Samuel Osei-Nketiah, Samuel S. Y. Sii, Samuel Sani Ali, Sandip Kumar, Sandra Ahlqvist, Sandrine Kwizera, Sandro Pasquali, Sani Ali Samuel, Sanju Sobnach, Santiago Villalobos, Sara Abd Elmageed Barakat, Sara Ahmed, Sara Al-saqqa, Sara Amr Mohamed Farouk, Sara Arafa, Sara Ayad, Sara Elhamouly, Sara Etienne, Sara Ghanem, Sara Kharsa, Sara Mahmoud Abdel-Kader, Sara Mamdouh Matter, Sara Mar\u00eda Contreras M\u00e9rida, Sara Mehrez, Sara Mohammed, Sara W Al-Saqqa, Sarah Abdelghany, Sarah Antar, Sarah Benammi, Sarah Braungart, Sarah Hafez, Sarah Rayne, Sarah Sahel, Sarah Samy, Saraibrahim Ahmed, Saskia Highcock, Saud Aljohani, Saulius Bradulskis, Saulius Mikalauskas, Savino Occhionorelli, Savni Satoskar, Sawsan Adel Awad, Sayed Sarwary, Sayeda Nazmum Nahar, Sayeeda Aktar Tori, Sayinthen Vivekanantham, Scott K D'amours, Sean Mizzi, Sebastian Bernardo Shu Yip, Sebastian King, Sebastian Shu, Sebastian Sierra, Sebastien Gaujoux, Sebestian Shu, Sefeldin Mahdi, Selina Chiu, Selina Man Yeng Chiu, Semay Desta, Serena Manfreda, Serge Kapenda Tshisola, Sergio Estupinian, Sergio Ribaldi, Sergio Zegarra, Servio Tulio Torres Rodriguez, Shadid Al Amin, Shadid Alamin, Shady Elhadry, Shady Hussein, Shady Mahmoud, Shagorika Talukder, Shahadatul Shaharuddin, Shahinaz Alaa El-Din, Shaimaa Aql, Shalon Guevara Torres, Shamsudeen Aliyu, Sharad Karandikar, Sharon Koh, Shaza Rabie Mohamed, Shereen Elsheikh, Sherif Shehata, Sherif Tariq, Shimaa Gamal, Shimaa Said Elkholy, Shireen Gaafar, Shirish Tewari, Shiva Dindyal, Shivanee Tharmalingam, Shorouk El Mesery, Shpetim Ymeri, Shravan Nadkarni, Shruti Ayyar, Shu Ning Kong, Shuang Yi Teo, Shyam Gokani, Shyang Yee Lim, Silje Holte, Silvia Basilic\u00f2, Silvia Boni, Silvia De Franciscis, Simon George Gosling, Simon Gosling, Simon Ng, Simon Stock, Simona Juciute, Simona Kasputyte, Simone Conci, Simone Sandler, Simone Targa, Sir Young Yam, Siti Mohd Desa Asilah, Siti Nur Alia Kamarulzamil, Sivasuriya Sivaganesh, Siyaka Itopa Suleiman, Siyi Chung, Soaad Elsobky, Sofia Mouttalib, Soha Abushamleh, Sohaila Elmihy, Soliman Magdy Ahmed, Sondos Turkustani, Sophian Hmila, South Africa, Srinivas Pai, Sriram Bhat, SS Prasad, Stassen Paul, Stavros Parasyris, Stefan Botes, Stefan Breitenstein, Stefan Zammit, Stefano Berti, Stefano Cucumazzo, Stefano M.M Basso, Stefano Roncali, Stella Binna Kim, Sten Saar, Stephanie Hiu-wai Kwok, Stephanie Van Straten, Stephen Dias, Stephen J Chapman, Stephen Kache, Stephen Mcaleer, Stephen R Knight, Stephen Tabiri, Steponas Petrikenas, Stuart J Fergusson, Styliani Parpoudi, Stylianos Germanos, Sudipta Roy, Sukrit Suresh, Sule Burger, Suleiman Baba, Sultan Almuallem, Sung-Hee Kim, Sunil Kumar, Suparna Das, Suraya Bahar, Susan Aviles, Susan Limache, Susan Wndy Mathew, Susana Yrma Aranzabal Durand, Svetlana Doris Brincat, Swantje Kruspi, Swapnil Roy, Syed Abdul Wahhab Eusoffee Wan Ali, Syed Altaf Naqvi, Syed Asaat ul Razi, Sylvia Batista Lemaire, Sylvie Mochet, Syrine Rekhis, T Ariani Widiastini, Tagang Ebogo Ngwa, Taha Yusufali, Taher Al-taher, Tahir Muhammad Yaseen, Tahir Yaseen, Tahira Naqvi, Taiwo Akeem Lawal, Taiwo Lawal, Tan Arulampalam, Tanzeela Gala, Tapan Kumar, Tara Grima, Tarek Ezzat, Tarek Razek, Tasneem Idress, Tasnia Hamid Kanta, Tatsiana Shachykava, Taufiq Khan, Tebian Hassanein Ahmed Ali, Tessa Fautz, Tewodros Worku, Thamer Nouh, Thays Brunelli Pugliesi, Thea Dimech, Thelma Tembo, Thelma Xerri, Theodore Pezas, Theodosios Theodosopoulos, Thiago Fernandes Giuriato, Thierry Alihonou, Thomas Feidantsis, Thomas Fozard, Thomas G Weiser, Thomas M Drake, Thomas Olagboyega Olajide, Thomas Pinkney, Thomas Prudhomme, Thomas Sherman, Thomas Tetens Moe, Thuraya Alzayat, Thusitha Sampath Hettiarachchi, Tien Seng Bryan Lee, Timothy White, Tina Gaarder, Tobias Schuetz, Todisoa Emmanuella Christina Tolotra, Tolg Cecilia, Tom AM Malik, Tom Arthur, Tom Falconer Hall, Tomas Abaliksta, Tomas Jankus, Tomas Po\u0161kus, Tommaso Bocchetti, Tommaso Campagnaro, Tommaso Fontana, Tony Mak, Toqa Khafagy, Torhild Veen, Trude Beate Wold, Tsz-Yan Katie Chan, Tuan Nur'Azmah Tuan Mat, Tunde Sholadoye, TWC Mak, Tyler Rouse, Tzu-Ling Chen, Uday Muddebihal, Ufuk Karabacak, Ulf Gunnarsson, Ulf Gustafsson, Umar Muktar, Umberto Tedeschi, Umme Salma, Usama Hantour, Uthman Alamoudi, Valdemaras Jotautas, Valentine Parent, Vanessa Dina Palomino Castillo, Vanessa Msosa, Vania Guglielmo, Vania Silvestri, Vasileios Despotidis, Vasileios Kalles, Vasiliki Soulou, Vassilis Kalles, Veereanna Shatkar, Venerand Barendegere, Veronica Grassi, Veronica Lazzari, Vicky Jennings, Victor Dassah, Victor Etwire, Victor Kong, Victor Manuel Quintero Riaza, Victor Nwinee, Victoria K Proctor, Vijaid Upadhyaya, Vijay Gadhvi, Viktorija Ambrozeviciute, Viktorija Nevieraite, Ville Sallinen, Vimalakanthan Thanusan, Vincas Jonas Banaitis, Virgilijus Beisa, Viviana Sollazzo, Vivien Graffieille, Vizir Jean Paul Nsengimana, Vladimir Khokha, Vu Thanh Hien Le, Vytautas Gai\u017eauskas, Vytautas Lipnickas, Wahid Anwer, Wai Cheong Soon, Wai Him Lam, Wairimu Ndegwa, Waleed Thabet, Walid Adham, Walter Forno, Walter Ruiz Panez, Wan Nurul \u2018Ain Wan Mohd Nasir, Wanigasekara Senanayake Mudiyanselage Kithsiri Janakantha Senanayake, Ward Hamsho, Wasim Dar, Wedyan Alhazmi, Wei Guo, Weiguang Ho, Weihei Dao, Wendy Leslie Messa Aguilar, Wennweoi Goh, Wifanto Saditya Jeo, Wilfredo Pino, William Appeadu-Mensah, William Beasley, William Bonney, William Hutch, William J. Lossius, William Milligan, Willy Alcca Ticona, Wing Sum Li, Witold Chachulski, Xavier Delforge, Xianelle Rodriguez, Xinwei Low, Xue Wei Chan, Ya Theng Neo, Yacoubou Imorou Souaibou, Yahaya Ukwenya, Yahya Salama, Yaseen Rajjoub, Yasmein Ibrahim, Yasmin Abd-Elrasoul, Yasmin Elfouly, Yasmin Hegazy, Yasmin Soliman, Yasser Abd El Salam, Yee Wen Tan, Yehia Zakaria, Yella Reddy, Yi Koon Tan, Yi Ting Mok, Yih Jeng Cheong, Yiing Yee Gan, Yishan Der, Yogendra Praveen Mogan, Yomna Allam, Yomna Hosny Asar, Yong Yong Tew, Yousef Abuowda, Yousra El Shoura, Ysabel Esthefany Alejos Berm\u00fadez, Y\u00fccel Cengiz, Yuk Hong Eric Cheung, Yuksel Altinel, Yung Kok Ng, Yuri Macchitella, Yves Aigrain, Zaher Mikwar, Zahra Jaffry, Zain Ali Khan, Zainab Iftikhar, Zaynab M Elsayed, Zhongtao Zhang, Zi Hao Sam, Zigmantas Urnie\u017eius, Zilvinas Dambrauskas, Zineb Bentounsi, Zygimantas Tverskis.znac195_Supplementary_DataClick here for additional data file."} +{"text": "Nature Communications 10.1038/s41467-023-43835-6, published 30 November 2023Correction to: In this article the affiliation \u2018Department of Geography, Planning, and Sustainability, Rowan University, Glassboro, NJ, USA\u2019 was incorrectly assigned to Kelsea Best. The original article has been corrected."} +{"text": "Stem Cells Translational Medicine, Volume 11, Issue 6, June 2022, Pages 597\u2013603, https://doi.org/10.1093/stcltm/szac019This is a correction to: Huangfan Xie, Zhongjie Sun, Xiong Xiao, Defang Liu, Hailong Qi, Guoxiong Tian, Miao Chen, Ligong Chen, XunCheng Su, Transient Inhibition of the JNK Pathway Promotes Human Hematopoietic Stem Cell Quiescence and Engraftment, In the originally published version of this article, the institutional affiliations labeled 1 and 2 were presented in the wrong order. These should have been presented as follows:1. State Key Laboratory of Elemento-organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China2. School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, ChinaThis error has been corrected."} +{"text": "Scientific Reports 10.1038/s41598-023-31771-w, published online 22 March 2023Correction to: The original version of this Article omitted an affiliation for Hijaz Ahmad. The correct affiliations are listed below.Section of Mathematics, International Telematic University Uninettuno, Corso Vittorio Emanuele II, 39, 00186 Roma, ItalyNear East University, Operational Research Center in Healthcare, Near East Boulevard, PC: 99138 Nicosia/Mersin 10, TurkeyThe original Article has been corrected."} +{"text": "PLOS ONE Editors retract this article [The article because article and Figs article , 3. ThesYM and JY agreed with the retraction. HJ, ZZ, DZ, BW, YY, ML, LD, HY, BG, ZL, FW, WS, CL, JZ, HZ, and JL either did not respond directly or could not be reached."} +{"text": "A magnetic resonance imaging (MRI) scan showed hydrocephalus (Cryptococcusmay exhibit unique clinical manifestations, such as gelatinous pseudocysts in the basal ganglia, cerebral cryptococcomas, leptomeningitis, cranial neuropathies, adhesive arachnoiditis, and obstructive hydrocephalus.A 37-year-old male patient presented with subacute paraparesis, urinary incontinence, and a sensory level of T8. An analysis of the cerebrospinal fluid revealed lymphocytic pleocytosis (5 white blood cells/mmephalus , myelopephalus , and adephalus . Meningephalus , withouprotein 73 mg/dL, glucose 5 mg/dL, tic acid .7 mmol/L"} +{"text": "Depressive symptoms are a common feature of schizophrenia (SCH) and define bipolar disorder and major depressive disorder (MDD). Their emergence is related to altered neurotransmission at the serotonin receptors and potentially at dopamine D3 receptors.The aim of this analysis was to examine the efficacy of cariprazine (CAR) in treating depressive symptoms in SCH, bipolar depression (BD) and MDD.Clinical trials with randomised, double-blind, placebo (PLB)-controlled designs were included in these analyses. Data from 3 SCH and 3 BD studies were pooled. In MDD, add-on CAR to antidepressant treatment was evaluated against PLB in two studies and Week 8 [NCT01469377] in MADRS total score (major depressive disorder).Altogether, 1466 SCH patients were included in the pooled analysis. In the BD analysis, data from 1383 patients were pooled. In the MDD trials, there were 502 CAR and 249 PLB-treated patients [NCT03738215], and 544 CAR and 264 PLB patients in the other study [NCT01469377]. In SCH, CAR achieved significantly greater reductions than PLB on the Marder anxiety/depression factor domain : the effect was driven by 3 out of 4 items. In BD, CAR yielded significantly greater improvement on the MADRS compared to PLB , which was driven by 9 out of 10 items. In MDD [NCT03738215], CAR 1.5 mg/d add-on significantly alleviated depressive symptoms compared to PLB , while in the other MDD trial [NCT01469377], CAR 2-4.5 mg/d add-on produced significantly greater reductions than PLB .These findings indicate that CAR is an effective treatment option for the treatment of depressive symptoms independent of disease , being a transdiagnostic broad-spectrum treatment option.R. McIntyre Grant / Research support from: CIHR/GACD/National Natural Science Foundation of China (NSFC), the Milken Institute, Consultant of: Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Gedeon Richter, Recordati, Atai Life Sciences, Speakers bureau of: Lundbeck, Janssen, Alkermes, Neumora Therapeutics, Boehringer Ingelheim, Sage, Biogen, Mitsubishi Tanabe, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Axsome, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Viatris, Abbvie, Gedeon Richter, Recordati, Atai Life Sciences, R. Csehi Employee of: Gedeon Richter Plc., G. N\u00e9meth Employee of: Gedeon Richter Plc."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-42702-0, published online 23 September 2023Correction to: In the original version of this Article Mahmoud Ashry was incorrectly affiliated with \u2018Medical Physiology Department, National Research Centre, Giza, Egypt\u2019. Additionally, Khaled G. Abdel-Wahhab was incorrectly affiliated with \u2018Pathology Department, National Research Centre, Giza, Egypt.\u2019 Their correct affiliations are listed below.Mahmoud Ashry:Zoology Department, Faculty of Science, Al-Azhar University, Assuit, Egypt.Khaled G. Abdel-Wahhab:Medical Physiology Department, National Research Centre, Giza, Egypt.The original Article has been corrected."} +{"text": "Scientific Reports 10.1038/s41598-023-42429-y, published online 21 September 2023Correction to: The original version of this Article contained an error, where the given names were not spelled out for the authors Filip De Ridder, Elisabeth De Waele, Nicole Hoornaert, Patrick Lacor, Rembert Mertens, Anne-Marie Vanbinst, Romain Meeusen, Guy Nagels, and Johan De Mey.The original Article has been corrected."} +{"text": "Remote assessment of disease and relapse\u2014Alzheimer\u2019s disease), IDEA-FAST and Mobilise-D aim to identify digital endpoints relevant for neurodegenerative diseases that provide reliable, objective, and sensitive evaluation of disability and health-related quality of life. In this article, we will draw from the findings and experiences of the different IMI projects in discussing (1) the value of remote technologies to assess neurodegenerative diseases; (2) feasibility, acceptability and usability of digital assessments; (3) challenges related to the use of digital tools; (4) public involvement and the implementation of patient advisory boards; (5) regulatory learnings; and (6) the significance of inter-project exchange and data- and algorithm-sharing.Alzheimer\u2019s disease (AD) and other neurodegenerative diseases such as Parkinson\u2019s disease (PD) and Huntington\u2019s disease (HD) are associated with progressive cognitive, motor, affective and consequently functional decline considerably affecting Activities of Daily Living (ADL) and quality of life. Standard assessments, such as questionnaires and interviews, cognitive testing, and mobility assessments, lack sensitivity, especially in early stages of neurodegenerative diseases and in the disease progression, and have therefore a limited utility as outcome measurements in clinical trials. Major advances in the last decade in digital technologies have opened a window of opportunity to introduce digital endpoints into clinical trials that can reform the assessment and tracking of neurodegenerative symptoms. The Innovative Health Initiative (IMI)-funded projects RADAR-AD ( The rapid advancement of technological developments allows entirely new approaches to assessing activities of daily living (ADL), sleep and fatigue, motor, cognitive, social, neuropsychiatric, and autonomous body functions with potential for both trials and clinical practice. The appeal lies in the objective, immediate and continuous measurement in both clinical and home settings, the reduction of visits to research or clinic facilities, the accessibility for under-served populations, the potential for better stratification and more personalised therapies, and the possibility to support otherwise time-intense clinical decisions with Artificial Intelligence (AI). This is of specific importance for Alzheimer\u2019s disease (AD), but also other neurodegenerative diseases, such as Parkinson\u2019s disease (PD) and Huntington\u2019s disease (HD), with a predominantly slow progression over years as well as cognitive impairment and fluctuations, which reduce the validity of data from self-rated or one-time assessments.Functional decline is a significant indicator of progression of neurodegenerative diseases. A range of questionnaires have been developed to assess ADL . HoweverRADAR-AD aims to identify and validate remote monitoring technologies (RMTs) to assess functional impairment in all stages of Alzheimer\u2019s disease. The study includes wearables and smartphone apps in the main study (n =\u2009232) and passive at-home sensors in a sub-study (n =\u200945). The RMTs measure a wide range of cognitive and functional domains, including spatial navigation, activity, sleep, speech, driving behaviour, and gait aims to identify digital parameters in patients with PD and HD, and immune-mediated disorders, which are related to fatigue, sleepiness, and sleep quality. A pilot study will be recruited at up to 24 sites across Europe.ot study , 7 has iMobilise-D (n =\u2009600) and other diseases associated with mobility impairment (racture) , 10.In this article, we will draw from the findings and experiences of these different IMI projects in discussing (1) the value of remote technologies to assess neurodegenerative diseases; (2) feasibility, acceptability and usability of digital assessments; (3) challenges related to the use of digital tools; (4) public involvement and the implementation of patient advisory boards to guide clinical trials in terms of protocol design, ethical issues, and selection and applicability of digital tools; (5) regulatory learnings; and (6) the significance of inter-project exchange and data- and algorithm-sharing .2.Technological advances in the last decade opened a window of opportunity to introduce digital endpoints into clinical trials. RMTs could provide a useful, objective way to measure decline by collecting data that correspond to various functional domains that are clinically relevant. They assess functional ability either passively or interactively . The benefit of RMTs as compared to standard assessments, is that they are objective and can collect data in the real world continuously. They are ideally placed to potentially measure subtle functional changes that are prevalent among individuals in the early, preclinical stages of neurodegenerative diseases, where current methods of cognitive assessments lack the necessary sensitivity and to cIn the three consortia, different functional domains were measured. Mobility, for example, was evaluated in various ways within the IMI projects. Mobilise-D applied both supervised (in the presence of study staff) and unsupervised testing using a standardised protocol. In addition to that, home mobility was evaluated using an inertial measurement unit (IMU) for 7 days at different time points. In RADAR-AD, mobility was evaluated using a supervised standardised protocol as well, and home mobility using a wrist-worn IMU for 8 consecutive weeks. In both RADAR-AD and IDEA-FAST, heart rate was measured using a wearable. Another functional domain assessed was sleep. IDEA-FAST and RADAR-AD both made use of an app to actively collect data on sleep, asking the participants daily about their fatigue, sleep pattern and quality. Moreover, sleep was measured passively: RADAR-AD made use of a portable EEG device, which a subset of participants wore every night for a month, while IDEA-FAST used a bed sensor with a force-sensitive piezo-electric film, placed under the mattress. Cognition has been addressed in a supervised standardised way in all consortia. Cognitive data was evaluated remotely using several smartphone apps in RADAR-AD and a web-based application of CANTAB in IDEA-FAST and both consortia collected passive information on smartphone use, including keyboard metrics and GPS location tracking.Future clinical trials will profit from these recent technological developments, which promise improved sensitivity and specificity of endpoint measures, better external validity, and the need of fewer visits to research or clinical facilities and smaller sample sizes due to more detailed datasets per participant.3.The use of RMTs can present challenges with respect to a range of aspects including the validity of measurements, related to sensitivity and specificity , data quality, e.g., choosing the right time granularity , data mi4.It becomes increasingly important to consider the feasibility, acceptance, usability, and ecological validity of digital endpoints in real-world settings. Few studies report on these factors and ageing populations are not well represented in RMT research , but areSome of these barriers became apparent in RADAR-AD. For example, engaging with RMTs led to some participants feeling discouraged, as they acted as a reminder for their declining cognition. Cognitive impairment also led to missing data, e.g., participants removed their wearables before going to bed, meaning sleep hygiene could not be tracked. Study partners are essential when it comes to reducing or overcoming (cognitive) barriers\u2014they help with charging/handling RMTs, provide emotional support, and remind participants to keep wearing/using RMTs. Overall, study partners are vital in the adherence and usability of digital tools in neurodegenerative diseases 5.Public Involvement (PI) is about involving people affected by the condition in all aspects of the research process as partners rather than as research participants , 34. PI All three consortia involved patients and, in the case of RADAR-AD, also carers in special advisory boards. They provided strategic input to various aspects of consortium activities throughout the projects, including: study protocols and participant-facing documents; digital health technology in general and digital assessments and outcomes in particular; feasibility, usability and acceptability of digital outcome assessment and how it can contribute to improved care; consultation around health technology assessment and regulatory acceptance of digital outcomes; ethical considerations, recruitment and retention strategies; and involvement in promotion activities about the impact and benefits of results. RADAR-AD and IDEA-FAST also collaborated with patient organisations and in IDEA-FAST, two additional groups consisting of patients, consortium members and representatives from patient organisations were formed to develop and review the project activities and to support the design of the two clinical studies.6.If digital endpoints are to be used in clinical trials aimed to achieve a market authorisation for medicinal products, it is of paramount importance that the endpoints are accepted by the regulatory authorities. In recent years, the use of RMT-based assessments has increased dramatically . HoweverIt is highly recommended for similar consortia to develop a regulatory strategy early on, to ensure that what is being developed will also be accepted in drug trials. It is important to plan for multiple Health Authority meetings utilising Innovation Task Force and EMA Qualification advice meetings as well as meetings with other major Health Authorities, as appropriate. Early advice on study design prior to protocol finalisation/study initiation would be highly desirable. Further development of clear guidance for the use of digital technologies in registration trials could remove some of the regulatory hurdles that currently complicate the development and use of novel improved endpoints .7.To extend and generalise individual project findings and foster deeper understanding of digital outcomes across neurodegenerative diseases, inter-project exchange and data sharing has gained significance. The full value of data collected in large research programmes can only be realised by enabling a wider set of analytics than is possible through individual consortia. This need is only heightened by the current rapidly expanding popularity in AI and Machine Learning research which relies on large datasets. Sharing resources allows for more rapid research to be undertaken, leading to greater efficacy in terms of advancing state-of-the-art than could be otherwise be achieved working on the data in isolation. For example, the sharing of speech data through DementiaBank has enabwww.epnd.org) aims to accelerate the discovery of diagnostics and treatments for neurodegenerative diseases by removing barriers to data and sample sharing , which is in line with the FAIR principlesWe argue that sustainability should be plannable and funded beyond the duration of a project, ideally via IMI-funded platforms, to guarantee a lasting impact and allow following projects to profit from the large data volumes produced by RMTs, previous experiences, including cross-learning about device selection and barriers/facilitators of using digital health technology, especially for studies that are targeting similar demographics and conditions.8.Technological advances and collaboration between IMI-funded and other consortia bring new opportunities to develop and introduce digital endpoints into clinical trials that can revolutionise the assessment and tracking of neurodegenerative symptoms. The digitalization of endpoints allows for objective, immediate and continuous measurement in both clinical and home settings, the reduction of visits to research or clinic facilities, greater accessibility for under-served populations, better stratification and more personalised interventions, and AI-supported clinical decisions.Dag Aarsland, Halil Agin, Vasilis Alepopoulos, Alankar Atreya, Sudipta Bhattacharya, Virginie Biou, Joris Borgdorff, Anna-Katharine Brem, Neva Coello, Pauline Conde, Nick Cummins, Jelena Curcic, Casper de Boer, Yoanna de Geus, Paul de Vries, Ana Diaz, Richard Dobson, Aidan Doherty, Andre Durudas, Gul Erdemli, Amos Folarin, Suzanne Foy, Holger Froehlich, Jean Georges, Dianne Gove, Margarita Grammatikopoulou, Kristin Hannesdottir, Robbert Harms, Mohammad Hattab, Keyvan Hedayati, Chris Hinds, Adam Huffman, Dzmitry Kaliukhovich, Irene Kanter-Schlifke, Ivan Koychev, Rouba Kozak, Julia Kurps, Sajini Kuruppu, Claire Lancaster, Robert Latzman, Ioulietta Lazarou, Manuel Lentzen, Federica Lucivero, Florencia Lulita, Nivethika Mahasivam, Nikolay Manyakov, Emilio Merlo Pich, Peyman Mohtashami, Marijn Muurling, Vaibhav Narayan, Vera Nies, Spiros Nikolopoulos, Andrew Owens, Marjon Pasmooij, Dorota Religa, Gaetano Scebba, Emilia Schwertner, Rohini Sen, Niraj Shanbhag, Laura Smith, Meemansa Sood, Thanos Stavropoulos, Pieter Stolk, Ioannis Tarnanas, Srinivasan Vairavan, Nick van Damme, Natasja van Velthogen, Herman Verheij, Pieter Jelle Visser, Bert Wagner, Gayle Wittenberg, and Yuhao Wu.http://mobilise-d.eu/wp-content/uploads/2023/06/v9-logos_06.17.2022_Mobilise-D-consortium-members-names.pdf.Full membership of the Mobilise-D consortium is available on the website Wan-Fai Ng, Christopher Bull, John Isaacs, Chris Lamb, Alison Yarnall, Lynn Rochester, Silvia Del Din, Chloe Hinchliffe, David Halliday, Ashur Rafiev, Bing Zhai, Dan Jackson, Peter Gallagher, Victoria MacRa, Leigh Denley, Ellen Silva, Philip Brown, Helen Gallon, Sean Scott, Phillip McGrouther, Dean Miller, Darren Storey, Lee Briton, Walter Maetzler, Kirsten Emmert, Robert Goeder, Jennifer Kudelka, Corina Maetzler, Hanna Kaduszkiewicz, Tanja Lange, Marie Bornhorst, Hanna Grasshoff, Stefan Schreiber, Sophia Hinz, Friso Muijsers, Kristina Brandt, Tina Hagen-Hurley, Robbin Romijnders, Clint Hansen, Linda Pialek, Kirstin Hansen, Johanna Graeber, Susanna Nikolaus, Florian Schrinner, Pia G\u00f6rrissen, Paula Cullen, Maren Williams, Andrea Pilotto, Alessandro Padovani, Sabrina Denardi, Giulio Bonzi, Marcello Catania, Valentina Chirico, Fiorenza Cavagnini, Christen Janneke van de Woude, Nynke Borren, Monique Devillers, Nicole Larmonie, Denise Schenk, Hans van Leeuwen, Jorina van der Salm, Iain McInnes, Neil Basu, Joe Galloway, Norelee Kennedy, Alexander Fraser, Hayley Connolly, Sadhbh Ni Mhidigh, Imelda Doolan, Cathal Linnane, Jacques Demotes-Mainard, Linda St\u00f6hr, Neshat Chareh, Hanna Schrinner-Fenske, Martina Esdaile, Alicja Szofer-Araya, Costantino Pitzalis, Michele Bombardieri, Louise Warren, Myles Lewis, Paul Giuliani, Sharon Palmer, Vicky Byers, Yi-Ke Guo, Kai Sun, Danilo Mandic, Mary Morrell, Siyao Wang, Florian Guitton, Yifeng Mao, Ailsa Hart, Shaun Power, Guanyu Tao, Benjamin Vandendriessche, Arno Bossaert, Rebeca Munoz, Hans De Clercq, Pierrick Arnal, Bertrand Fatus, Evgeniia Kurash, Maya Dorsey, Miles Parkes, Sree Subramanian, Louise Stockley, Rona Smith, Renata Schaeffer, J\u00e9r\u00f4me Kalifa, Jonathan Chauvin, Cl\u00e9mence Pinaud, Adrien Bennetot, Alexandra Belfiore, Laura Carrasco Marin, Mayca Mar\u00edn, Jennifer Jimenez, Miriam Grande, Susana Donate, Evert-Ben van Veen, Daniel Groos, Martin Boeckhout, Beatrice van der Velden, Olenka van Ardenne, Denis Groot, Nebo Savic, Irene Schluende, Franziska Klepka, Simon Beniston, Veli Stroetmann, Rainer Thiel, Daniel Schmidtmann, Karin Breuer, Jessica Paul, Shahan Tariq, Alexandra Prodan, Griselda Marku, Tiago Guerreiro, Andr\u00e9 Rodrigues, Diogo Branco, Livia Moreira, Carla Marques, H\u00e9lia Rodrigues, Fabio Roli, Davide Ariu, Stefania Casula, Battista Biggio, Luca Piras, Luca Didaci, Matteo Mauri, Joaquim Ferreira, Leonor Correia Guedes, In\u00eas Dias, Ana Teresa, Joana Costa, Mariana Matos, Teemu Ahmaniemi, Luc Cluitmans, Jani M\u00e4ntyj\u00e4rvi, Juha Kortelainen, Rajdeep Nath, Emmi Antikainen, Kinga Koski, Francesca Cormack, Michele Veldsman, Laura Keylock, James Dobson, Janet Griffiths, Nick Taptiklis, Julian Fierrez, Aythami Morales, Ruben Tolosana, Alejandro Pena, Luis Gomez, Rafael Oliveros, Ruben Vera-Rodriguez, DaQing Zhang, Xujun Ma, Mossaab Hariz, Pei Wang, Djamal Zeghlache, Jordi Evers, Laura Siepman, Martijn Niessen, Ralf Reilmann, Robin Schubert, Atbin Djamshidian-Tehrani, Grzegorz Witkowski, Halina Sienkiewicz-Jarosz, Malgorzata Dusza-Rowinska, Klaus Seppi, Katarina Schwarzova, Corinne Horlings, Samuel Labrecque, Anita Malik, Wolfram Rieneck, Maria B. Lauvsnes, Roald Omdal, Katrine Norheim, Svein Skeie, Anne Hjelle, Hilde Norvik, Dave Wenn, Mike Jackson, Luisa Avedano, Bella Haaf, Tatiana Negurita, Susanne de Bot, Carola Buitelaar, Kasper van der Zwaan, Laura Kuijper, Adrie van Weeghel, Ian Bruce, John McBeth, Liz Fay, Joanna Jozefiak, James Prior, Denise Faulkner, Ioannis Pandis, Nikolay Manyakov, Stefan Avey, Meenakshi Chatterjee, Kenneth Mosca, Cesar Calderon, Rana Rehman, Melissa Mendez-Nguyen, Lori Warring, Marc Walton, Bethany Paxson, Diana Koletzki, Shyla Jagannatha, Zhi (Carrie) Li, Drew Elias, Kai Langel, Dario Masullo, Matthew Roche, Victoria Zolfaghari, Sarah Weingast, Maurizio Facheris, Tony Bannon, Matt Czech, Jie Shen, Shiv Patel, Michelle Crouthamel, Josh Cosman, Sean Turner, Magnus J\u00f6rnt\u00e9n-Karlsson, Tim Ruckh, Folke Folkvaljon, J\u00f6rgen Jensen, Neil Newman, Susan Forda, Birgit Steckel-Hamann, David Dexter, Nikul Bakshi, Joe Mather, Seleen Ong, Carla Cox, Yiorgos Christakis, Hao Zhang, Carrie Nothcott, Elaine Borthwick, David Nobbs, Jens Schjodt-Eriksen, Sebastian Holst, Florian Lipsmeier, Jason Hannon, Nadir Ammour, Haneen Njoum, Hillol Sarker, Imane Brigui, Raolat Abdulai, Xavier Benain, Jimena Diaz DeLeon, Manon Cariou, Fabrice Bonche, Vincent Mittoux, Sheila Thomas, Caroline Zutterling, Juliette Muszka, Frederique Guilbert, Xavier Brusson, Gwenaelle Corre, Babak Boroojerdi, Coralie Domange, Phil Scordis, Kasper Claes, Valentina Ticcinelli, Chengliang Dai, Giovanni Campana, Sarah Bilali, Oliver Stumpp, Mireille Delval, David Marquet, Gwenaelle de Keyser, Claudia Mazza, Alexandra Auffret, Jeremy Edgerton, Juha Rouru,Minna Korolainen, Sammeli Liikkanen, Mikko Kuoppam\u00e4ki, Marina Lindford, Anssi M\u00e4kiniemi, Toni Sarapohja, Olavi Kilkku, Antonella Chiucchiuini, Brian Tracey, Dimitri Volfson, Tairmae Kangarloo, Francesco Onorati, Wojtek Piwko, Geert van Gassen, Todd Swick, Armella Escher, Pietro Artoni, Robert Latzman, Mike Chambers, Elizabeth Amstutz, Nick Bott, Laura Rosen, Ieuan Clay, Aiden Doherty, Sara Riggare, Dina de Sousa, Cate Titterton, Heather Hunter, Ulli Funken, Jill Shutt, Werner Rammele, Jean Heather, Paul Howard.A-KB and DA conceived the idea. A-KB wrote the initial draft. All authors contributed to the article and revised it critically for important intellectual content and approved the submitted version.RADAR-AD project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 806999. This Joint Undertaking receives support from the European Union\u2019s Horizon 2020 research and innovation programme and EFPIA and Software AG. See www.imi.europa.eu for more details. This communication reflects the views of the RADAR-AD consortium and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein. Research of Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting Steun Alzheimercentrum Amsterdam. The MOBILISE-D project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 820820. This Joint Undertaking receives support from the European Union\u2019s Horizon 2020 research and innovation programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). The IDEA-FAST project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 853981. This Joint Undertaking receives support from the European Union\u2019s Horizon 2020 research and innovation programme and EFPIA and associated partners.The AP received grant support from Ministry of Health (MINSAL) and Ministry of Education, Research and University (MIUR), from Airalzh Foundation, LIMPE-DSIMOV society and MI H2020 initiative (MI2-2018-15-06); he received speaker honoraria from Abbvie, Bial, Biomarin, Roche and Zambon Pharmaceuticals. W-FN has consulted for Novartis, GlaxoSmithKline, Abbvie, BMS, Sanofi, MedImmune, Janssen, Resolve Therapeutics and UCB. LR receives consultancy from MJ Fox Foundation and grant support from the EU, NIHR, MRC, PDUK, Dunhill Medical Trust, Cure Parkinson\u2019s Trust, EPSRC, MJ Fox Foundation. DA has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, Evonik, Roche Diagnostics, and GE Health, and served as paid consultant for H. Lundbeck, Eisai, Heptares, Mentis Cura, Eli Lilly, Cognetivity, Enterin, Acadia, EIP Pharma, and Biogen. JC was employed by Novartis Institutes for Biomedical Research (NIBR), Basel, Switzerland and GE was employed by Novartis Pharmaceuticals Corporations, Cambridge, MA, United States.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "The Bluebelle Wound Healing Questionnaire (WHQ) is a universal-reporter outcome measure developed in the UK for remote detection of surgical-site infection after abdominal surgery. This study aimed to explore cross-cultural equivalence, acceptability, and content validity of the WHQ for use across low- and middle-income countries, and to make recommendations for its adaptation.This was a mixed-methods study within a trial (SWAT) embedded in an international randomized trial, conducted according to best practice guidelines, and co-produced with community and patient partners (TALON-1). Structured interviews and focus groups were used to gather data regarding cross-cultural, cross-contextual equivalence of the individual items and scale, and conduct a translatability assessment. Translation was completed into five languages in accordance with Mapi recommendations. Next, data from a prospective cohort (SWAT) were interpreted using Rasch analysis to explore scaling and measurement properties of the WHQ. Finally, qualitative and quantitative data were triangulated using a modified, exploratory, instrumental design model.In the qualitative phase, 10 structured interviews and six focus groups took place with a total of 47 investigators across six countries. Themes related to comprehension, response mapping, retrieval, and judgement were identified with rich cross-cultural insights. In the quantitative phase, an exploratory Rasch model was fitted to data from 537 patients (369 excluding extremes). Owing to the number of extreme (floor) values, the overall level of power was low. The single WHQ scale satisfied tests of unidimensionality, indicating validity of the ordinal total WHQ score. There was significant overall model misfit of five items and local dependency in 11 item pairs. The person separation index was estimated as 0.48 suggesting weak discrimination between classes, whereas Cronbach\u2019s \u03b1 was high at 0.86. Triangulation of qualitative data with the Rasch analysis supported recommendations for cross-cultural adaptation of the WHQ items 1 (redness), 3 (clear fluid), 7 (deep wound opening), 10 (pain), 11 (fever), 15 (antibiotics), 16 (debridement), 18 (drainage), and 19 (reoperation). Changes to three item response categories were adopted for symptom items 1 to 10, and two categories for item 11 (fever).This study made recommendations for cross-cultural adaptation of the WHQ for use in global surgical research and practice, using co-produced mixed-methods data from three continents. Translations are now available for implementation into remote wound assessment pathways. BJS in 2019) to detect wound infections remotely after abdominal surgery over the telephone in global surgery research and practice. This tool can help to upscale telemedicine safely in low-resource environments.This mixed-methods study within the FALCON trial across six low-and middle-income countries used qualitative and state-of-the-art psychometric methods with Rasch analysis. The authors make recommendations for adaptation of a Wound Healing Questionnaire (originally published in Delayed return to work, readmission or reoperation leads to substantial effects on quality of life during recovery, and has spill-over effects on mental, economic, and social well-being for patients6. This is particularly relevant in low-resource settings, where patients are more likely to suffer catastrophic expenditure around the time of surgery7. Consequently, research in SSI prevention has been prioritized by patients, researchers, and clinicians in low- and middle-income countries (LMICs)8.Surgical-site infection (SSI) is the most common complication of abdominal surgery, and has a cross-societal, global impact on patients and their families9: directly, through delayed intervention for patients with active infection, and indirectly, by introducing bias to randomized studies that feed into best practice guidelines10. Postdischarge surveillance is therefore considered to be a key quality marker in SSI research and is an important component of postoperative care pathways10.Timely identification of SSI is essential in maintaining patient safety after hospital discharge. Missed SSI diagnoses or misclassification of SSI can directly and indirectly affect patient safety12. This instrument has, however, not yet been adapted for cross-cultural and cross-language implementation in LMICs. High-quality, contextually relevant tools for remote wound evaluation are urgently needed to build resilient and sustainable surgical systems and support safe upscaling of capacity during pandemic recovery14. They are also needed to reduce loss to follow-up and risk of attrition bias in randomized trials by developing contextually relevant pathways for remote assessment9.The Bluebelle Wound Healing Questionnaire (WHQ) was developed and validated in the UK in the English language to support postdischarge surveillance for SSI after abdominal surgeryThe aims of this mixed-methods study (TALON-1) were: to explore cross-cultural and cross-language equivalence, acceptability, and content validity of the WHQ across several LMICs; to assess the scaling and psychometric properties of the WHQ when used across different patient populations and subgroups using Rasch analysis; and to consolidate recommendations for adaptation of the WHQ for use in global surgical research by triangulating qualitative and quantitative data.15\u201317. The study used qualitative and quantitative data to explore the extent to which the WHQ measured SSI as a concept, and the parameters of the latent trait in the target (low-resource context) and source cultures. It then aimed to assess how accurately items could transfer meaning across languages18. Some adaptation of standard methodology was required to enable the qualitative phase to progress during the SARS-CoV-2 pandemic (Appendix S2). An overview of the study methodology is shown in Fig. 1 and detailed in Table 1.TALON-1 was a mixed-methods study embedded in an international randomized trial, conducted according to best practice guidelines, and co-produced with community and patient partners21, and PCORI recommendations16 for best practice in mixed-methods adaptation of outcome measures (PCORI checklist is available in Appendix S3). Primary data from FALCON were published in The Lancet in 202122. The protocol for TALON-1 was preregistered on the MRC Hubs for Trial Methodology Research database23 (Queen\u2019s University Belfast) (SWAT ID126) and published in Trials20.This study was reported with reference to recommendations from the Global Health Network for qualitative research in LMICs, the COREQ framework24, hosted at the University of Birmingham, UK, and held in line with General Data Protection Regulation principles.This study within a trial (SWAT) was first approved within the pragmatic multicentre factorial RCT testing measures to reduce SSI in LMICs protocol by a University of Birmingham Research Ethics Committee (v1_0_substudies_v1_0. Reference: ERN_18-0230A). Additional approvals were then obtained from national, regional, and/or hospital-level ethics committees for selected centres in all participating countries, in accordance with local protocols. Written (or fingerprint) informed consent to participate was obtained from all participants. In the qualitative phase, an information sheet for was provided to all participants. Verbal consent was taken and recorded. Participant data were pseudonymized for storage securely within a password-protected NVivo\u00ae V12 data management system. In the quantitative phase, written (or fingerprint) informed consent to participate was obtained from all participants. Quantitative data were stored in a secure REDCap server1. FALCON provided a platform for this study both to identify eligible site investigators for interviews and focus groups, and for co-recruitment of patients to the embedded prospective cohort study.FALCON was a stratified, pragmatic, multicentre, 2 \u00d7 2 factorial trial testing two measures to reduce superficial or deep skin infection after abdominal surgery in seven LMICs (NCT03700749)Appendix S426. The WHQ includes 19 items (18 items and 1 subitem) related to the construct of surgical wound healing, with 11 items related to symptoms of SSI, and 8 items related to interaction with the treatment pathway for SSI. It was designed so that it could either be administered by a healthcare professional, or self-reported by patients27 . Two developers of the WHQ were collaborating members of the Study Management Group.The WHQ was developed with the aim of detecting postdischarge SSI after abdominal surgery, and validated in a large feasibility study within a pilot RCT (Bluebelle) in the UK, as summarized in 29. Participants were purposefully sampled from sites participating in the FALCON trial , with a view to including an information-rich mix of participants by sex, country, patient population , and experience in face-to-face and telephone follow-up assessments. These interviews aimed to explore the universality of the construct of SSI, cross-cultural relevance of concepts, and construct validity of the questionnaire18.Owing to the number of target languages for questionnaire in the host trial, cross-cultural adaptation was initially performed in English language. Structured interviews were conducted with two to three research staff in each country, according to a template from the Social Research Association based on WillisAppendix S5): item comprehension (patients\u2019 understanding of the idea and item), response mapping , retrieval , and judgement 29. Unstructured interview notes and a reflexive diary were also maintained as an additional data source. Coding was performed using a pragmatic qualitative approach informed by cognitive theory, by a clinician with training in relevant qualitative research methods and with 10 years\u2019 experience of working in international multicentre trials (Appendix S6). The reflexive diary supported interpretation of the interviewer\u2019s role as a questionnaire developer and the potential impact on data collection. To ensure credibility, member checking was undertaken with the final summary themes with representative participants and in-country consultants to ensure that meaning was correctly interpreted and maintained30.The topic guide was structured around four predefined categories . A new sample of participants (separate from those participating in interviews) was approached for the focus group phase. Where required, iterative adaptation of the WHQ was made until a point of saturation was reached according to accepted best practice principles for adaptation of instruments34. Recommendations from the qualitative phase were either made overall, specific to an individual item, or related to questionnaire administration. The focus group also included several investigators who were fluent in both the source and target language to serve as a baseline translatability assessment. Together, the process produced an English language questionnaire which had been adapted to broadly ensure cross-cultural equivalence across the participating countries, was acceptable to all national principal investigators, and highlighting potential translatability issues during cross-language adaptation. The procedures for remote, telephone administration of the WHQ were also explored using targeted questions based on investigators\u2019 experience within the FALCON trial.To check trustworthiness, one or two focus groups were then held with investigators from each country to review and discuss the thematic coding. The focus groups were held after the interviews had been completed to explore consensus and contrasting opinions between different stakeholders around themes emerging in the semistructured interviews. The overall objective was to obtain a single cross-culturally adapted questionnaire to move into cross-language adaptation34\u201336. This involved a seven-step process alongside clinicians directly involved in wound assessment recruited to the FALCON trial were eligible. These included a broad range of abdominal operations with a predicted clean-contaminated, contaminated or dirty operating field, and a planned skin incision of greater than 5 cm. Operations could be performed for benign, malignant, trauma, or obstetric indications. Consent for an additional telephone follow-up call to administer the WHQ was taken at the same time as trial consent, using a targeted Informed Consent Form and Patient Information Sheet. Patient and community partners supported co-production of these resources to ensure culturally attuned language and delivery.Appendix S8. No minimum sample size was set, but a target of 100 patients per country was discussed with each of the national principal investigators for use in Rasch unidimensional measurement modelling, based on published recommendations37.Telephone administration of the translated WHQ was undertaken 28\u201330 days after surgery (in the 72 h before in-person follow-up) integrated into the host trial pathway. The telephone WHQ was administered by a researcher, doctor, or research nurse (non-consultant or attending grade), who was independent of the assessment for the trial primary outcome at 30 days after surgery. Optimization and quality assurance of WHQ administration is described in Appendix S9.A simple summary of Rasch methodology for the general reader is provided in 39. Individual items were assessed for excessive misfit and response dependency (where items are related by more than just the underlying trait). Additionally, appropriate use of item response categories was checked using category probability curves and threshold mapping. Where probability curves were disordered, response categories were rescored and item fit was then re-examined. Where residual correlations between items were high, subtesting was carried out with re-evaluation of item and model fit. Differential item functioning (DIF) was examined for each item by country, language, and patient home location . Exploration of DIF was undertaken only where a subgroup included at least 50 complete WHQ responses.The Rasch unidimensional measurement model was fitted to examine the psychometric properties of the WHQ, identify anomalies in the data, and evaluate the extent to which the WHQ items are measuring the latent trait of wound infection40\u201343. Finally, there was a phase of proofreading, before completion of a final report of the adapted WHQ, and adoption of this version for further prospective validation. Data were also triangulated regarding measurement procedures to optimize future implementation of remote follow-up pathways.Qualitative and quantitative data were triangulated using data (between countries) and methodological triangulation, adopting a modified, exploratory, instrumental design model. Triangulation was performed item by item to enable a final version of the instrument in both source (English) and target languages to be finalized and consolidated44.Patients and community members from LMICs were engaged in all phases of the design and delivery of this study. The interview topic guide was co-designed with input from a representative global surgery patient forum. Practicable methods for conducting interviews, and patient compensation for time in participation, were determined with the support of local community leaders. The Guidance for Reporting Involvement of Patients and the Public (GRIPP-2) short form was used to track and report the impact of CEITable S1 and treatment items in Table S2. Themes emerged relating to comprehension, response mapping, retrieval, judgement, and novel cross-cultural insights.In total, 10 structured interviews and six focus groups were arranged with a total of 47 investigators across six countries. They included 34 surgeons, five anaesthetists, and eight research staff caring for patients in both urban and rural populations, and across a range of abdominal surgery disciplines. Interview duration ranged from 34 to 112 min, and focus groups lasted from 92 to 126 min. There was a median of 11 (range 6\u201316) participants involved in the focus groups. Interview and focus group data from site investigators confirmed that the assumption of a universalist approach to SSI was acceptable, and that symptomology and treatment paradigms were shared across settings. No divergence from this was identified during thematic analysis. This was also explored with the CEI partners; together, they confirmed content validity across settings. No new domains or concepts related to symptoms or treatment of SSI arose, suggesting content validity across contexts. A summary of qualitative data are presented for symptom items in Translation was successfully completed in five target languages after the qualitative phase: French (Benin), Hindi (India), Kinyarwanda (Rwanda), Punjabi (India), and Tamil (India). For some potential languages of delivery, there was no written version of the dialect , and, on rare occasions, patients would travel a very long distance for treatment and spoke a language that was uncommon to the local area . Here, the questionnaire was translated ad hoc from English (source language) by the assessor in the cohort study.Table 2.An attempt was made to contact 655 patients in the cohort study across five countries, of whom five had died by 30 days (15 missing status). Of the 635 confirmed to be alive, 537 (84.5 per cent) were contactable for WHQ completion. Features of included patients are summarized in Table S3). Both analysis of principal components between positively and negatively loading items and symptom and pathway items suggested unidimensionality of the WHQ instrument in detection of SSI.The exploratory Rasch model was fitted using these data from 537 patients (369 excluding extremes) across five class intervals and a poor person separation index . Conversely, Cronbach\u2019s \u03b1 (with missing data excluded) demonstrated acceptable internal consistency, with a value of 0.86. There was a strong positive skew of person location values, with a mean(s.d.) person location of \u22122.91(1.05), demonstrating some mistargeting of the WHQ, as may be expected in a diagnostic or screening tool . The item location map reflected clinical severity, with 168 of 537 participants (31.3 per cent) at the floor of the scale (no signs or symptoms of SSI), and item locations reflecting degrees of infection at the ceiling .Overall, the model did not fit well, with a high probability of item\u2013trait interaction (\u03c7Table S4), but the person fit was acceptable (mean(s.d.) person fit residual \u22120.52(0.69)). Examination of individual-person fit did not reveal any significant misfit . There was a high degree of correlation and dependence between items with local dependency in 11 item pairs (Table S5).Five items displayed significant misfit to the model (mean(s.d.) item fit residual \u22121.61(1.75)) by country in items 1, 3, 5, 8, 10, and 13, and non-uniform DIF by country in items 4, 10, 13, 16, 17, and 19 (Appendix S10). Where deductive cognitive themes or inductive cross-cultural themes arose, they were explored against individual item fit, dependency, and DIF in the Rasch model . Recommendations were made for cross-cultural adaptation for WHQ items 1 (redness), 3 (clear fluid), 7 (deep wound opening), 10 (pain), 11 (fever), 15 (antibiotics), 16 (debridement), 18 (drainage), and 19 (reoperation). When triangulating disordered threshold probabilities with corroborating or conflicting qualitative data, a recommendation was made to move to three item response categories for symptom items 1 to 10, and to two categories for item 11 (fever). A summary of recommendations is displayed in Table 3, and the final adapted questionnaire in Appendix S11. Translated versions of the adapted WHQ are provided in Appendix S12.Triangulation of qualitative and quantitative data was performed item by item for the 11 symptom items (10 items and 1 subitem) and eight pathway items with high data completeness .\u2018People were very impressed that I was calling them and still following up on the surgeries and were willing to talk very happily.\u2019 A summary of measurement procedures is shown in \u2018Early feedback that the questionnaire is highly acceptable to patients. Patients say they are receiving a \u2018VIP\u2019 treatment.\u2019 In total, 533 of 537 patients (99.2 per cent) reported the telephone WHQ pathway to be very satisfactory or satisfactory:Appendix S13.Often the telephone owner was a friend or relative (who was then able to connect the researcher directly to the patient) rather than the patient themselves , and commonly this was a mobile phone . In total, 154 of 537 (28.7 per cent) had a mobile phone with video capability. Feedback from CEI partners alongside interview data supported optimization of the telephone follow-up pathway for future implementation; this is presented in a toolkit available in Pathways for remote assessment of common complications after surgery in low-resource settings are essential in improving the safety and resilience of surgical care systems. This mixed-methods study made recommendations for cross-cultural and cross-language adaptation of the WHQ for use in LMICs, and improved its relevance across cultures and for patients with lower levels of health literacy. Conceptual equivalence, and content and construct validity was confirmed across languages using qualitative and translation methods. Unidimensionality, measurement properties, and use of the total WHQ score were seen to be valid within the Rasch framework, although the overall power of fit was low. The telephone pathway was demonstrated to be feasible and highly acceptable. Working with CEI partners, recommendations were made for optimization of telephone follow-up in research and postoperative surveillance programmes. This study provides a large, international, high-quality proof of concept for rapid adaptation and implementation of patient-reported measures in emerging global health arenas such as surgery.The use of mixed methods here added strength and depth. The qualitative data were used primarily to inform cross-cultural adaptation ahead of translation. Although this was based on cognitive theory, data were collected indirectly about patient experience from frontline clinicians involved in wound assessment. The Rasch analysis supplemented this, and allowed patient-level data to enrich and inform final recommendations for adaptation. In a majority of instances, the qualitative and quantitative data were supportive of one another, demonstrating coherence during triangulation. Where conflict arose, qualitative findings were softened and/or caveated .46. Here, its principal value was in confirming the validity of use of the total WHQ score as an ordinal scale and in enhancing understanding of the response structure and local dependency. Properties of the WHQ, however, make it a rather unusual application of the Rasch model. First, it is principally a diagnostic tool for SSI rather than an interval-level tool measuring a spectrum of severity of a latent trial. This was best seen in mistargeting of the WHQ to the study population, with many patients at the \u2018floor\u2019 adding low information value to the model, as would be expected in a screening tool (where many patients are asymptomatic). This reduced the overall power of fit as many participants contributed little information about item locations. Second, as expected in a diagnostic test, many items had high levels of local dependency, which may have contributed to the overall model misfit. Third, several items misfit the Rasch model and the person separation index was poor, with a conversely high Cronbach\u2019s \u03b1 value. Again, this is highly likely to be due to the extreme \u2018floor\u2019 of respondents in the setting of a diagnostic tool. It was not the overall aim to fit this diagnostic tool closely to the Rasch model, and it would not be required to be valid for use if it demonstrated a satisfactory psychometric structure, unidimensionality, and sufficient sensitivity and specificity upon clinical application. This highlights the importance of further work to validate the tool externally in a diagnostic test accuracy study.Rasch analysis is an established method for instrument development and cross-cultural refinementExploring complex relationships between items and optimizing the measurement properties using subtesting and adjusting for DIF was not the aim here, but warrants further investigation. It is feasible that the instrument could be simplified, or its diagnostic accuracy could be improved using Rasch by better accounting for differences in the symptomology and health-seeking behaviours of patients with SSI across countries. DIF by country observed for several items here supports methods to ensure balance in randomized trials, such as stratification or minimization of randomization by country.29. Sampling of researchers directly involved in the same portfolio of trials was a pragmatic decision, but may have reduced the transferability of themes across other hospital types , resource settings or differing populations . Thematic saturation overall was aimed for when ending recruitment to the qualitative phase, but this is unlikely to have been reached at an individual-country level47. It is, therefore, possible that important insights were missed during adaptation, although recommendations were strengthened by triangulation with quantitative data to reduce over-reliance on qualitative data alone40. Second, related to analysis, as the WHQ did not meet all the Rasch assumptions for model fit, a logit-adjusted scale was not developed. Further development could improve the measurement properties of the questionnaire to allow direct patient-to-patient comparisons in future research. Complex patterns of DIF in measurement that could lead to differences in point score equivalence across different patients with differing characteristics when applied clinically were not taken into account. Finally, related to interpretation, the most important metric of clinical utility in a screening tool such as this would be diagnostic test accuracy. A formal external validation study comparing the WHQ to a standard reference test for SSI is now required48. A choice of cut-off score for the adapted WHQ is likely to favour sensitivity to triage all patients with a likelihood of SSI to seek medical care.This study has several limitations. Owing to safety and ethical concerns during the SARS-CoV-2 pandemic, cognitive interviewing could not be undertaken directly with patients. Instead, aggregate perspectives of frontline clinicians involved in the care of surgical patients were explored. This meant that the data represented clinicians\u2019 impressions of patients\u2019 responses, and challenges in retrieval and judgement, rather than direct exploration with patients in typical cognitive interviewing49\u201351. Health technology assessments thus neglect important insights into quality of recovery and health utility that could affect policy decisions52. This study provides a proof of concept for rapid, pragmatic adaptation of instruments in the surgical setting that can be used across other measures and emerging contexts. Developing culturally attuned, remote follow-up pathways is particularly important during pandemic recovery in building resilience in resource-poor health systems54. The co-produced pathway for telephone follow-up in LMICs described here is ready for wider adoption. Recommendations from this mixed-methods study can now to be used for further exploration of the diagnostic accuracy of the adapted WHQ in low-resource contexts.The use of patient-reported outcome measures (PROMs) in low-income settings is complex; many instruments have not yet undergone cross-cultural and cross-language adaptation, and there is uncertainty about the feasibility of remote, digital methods. Although examples exist from established global health fields, such cardiovascular disease, few studies in global surgery have adopted PROMs to dateP Anachy, Amy Mathew, Josy Thomas, Philip V Alexander, Pradeep Zechariah, Neerav D Aruldas, Asif Mehraj, Hafsa Imtiyaz Ahmed, Rauf A Wani, Fazl Q Parray, Nisar A Chowdri, Antonio Ramos De la Medina*, Laura Martinez Perez Maldonado, Diana S Gonzalez Vazquez, Iran I Dur\u00e1n S\u00e1nchez, Maria J Mart\u00ednez Lara, Alejandra Nayen Sainz de la Fuente, Ana O Cortes Flores, Mariana E Barreto Gallo, Alejandro Gonzalez Ojeda, Monica E Jimenez Velasco, Luis Hern\u00e1ndez Miguelena, Reyes J Cervantes Ortiz, Gonzalo I Hernandez Gonzalez, Marco Hurtado Romero, Rosa I Hernandez Krauss, Luis A Dominguez Sansores, Alejandro Cuevas Avenda\u00f1o, Celina Cuellar Aguirre, Isaac Baltazar Gomez, Hector Ortiz Mejia, Alejandro Gonz\u00e1lez Ojeda, Oscar E Olvera Flores, Erick A Gonz\u00e1lez Garc\u00eda de Rojas, Kevin J Pintor Belmontes, Francisco J Barbosa Camacho, Aldo Bernal Hern\u00e1ndez, Laura Reyes Aguirre, Rub\u00e9n E Mor\u00e1n Galaviz, Clotilde Fuentes Orozco, Wenceslao G \u00c1ngeles Bueno, Fernando S Ramirez Marbello, Diego E Luna Acevedo, Michel Hern\u00e1ndez Valadez, Ana L Bogurin Arellano, Luis R Ram\u00edrez-Gonz\u00e1lez, Bertha G Guzm\u00e1n Ram\u00edrez, Eduardo Valtierra Robles, Ramona I Rojas Garc\u00eda, Jos\u00e9 V P\u00e9rez Navarro, Edgar J Cortes Torres, David R Dominguez Solano, Alberto N Pe\u00f3n, Roque D Lincona Menindez, Rozana Reyes Gamez, Maria C Paz Mu\u00f1oz, Orimisan Belie, Victoria Adeleye, Adesoji Ademuyiwa, Oluwafunmilayo Adeniyi, Opeyemi Akinajo, David Akinboyewa, Felix Alakaloko, Oluwole Atoyebi, Olanrewaju Balogun, Christopher Bode, Olumide Elebute, Francis Ezenwankwo, Adesiyakan Adedotun, George Ihediwa, Jubril Kuku, Oluwaseun Ladipo-Ajayi, Ayomide Makanjuola, Samuel Nwokocha, Olubunmi Ogein, Rufus Ojewola, Abraham Oladimeji, Thomas Olajide, Iyabo Alasi, Oluwaseun Oluseye, Justina Seyi-Olajide, Adaiah Soibi-Harry, Emmanuel Williams, Agbulu Moses Vincent, Nnamdi Jonathan Duru, Kenneth Uche Onyekachi, Christiana Ashley, Chinelo Victoria Mgbemena, Moyosoluwa Ojo, Olowu Oluyemisi, Iyabode Ikuewunmi, Adeoluwa Adebunmi, Edet Glory Bassey, Ephraim Okwudiri Ohazurike, Olayide Michael Amao, Osunwusi Benedetto Oluwaseun, Emily Doris, Olutola Stephen, Christianah Gbenga-Oke, Olawunmi Olayioye, Olowu Oluyemisi, Kayode Oluremi, Esther Abunimye, Christianah Oyegbola, Olayade Kayode, Adeola Ayoola Orowale, Omolara M Williams, Olufunmilade A Omisanjo, Omolara M Faboya, Zainab O Imam, Olabode A Oshodi, Yusuf A Oshodi, Ayokunle A Ogunyemi, Olalekan T Ajai, Francisca C Nwaenyi, Adewale O Adisa, Adewale A Aderounmu, Funmilola O Wuraola, Oludayo Sowande, Lukman Olajide Abdur-Rahman, Jibril Oyekunle Bello, Hadijat Olaide Raji, Nurudeen Abiola Adeleke, Saheed Abolade Lawal, Rafiat Tinuola Afolabi, Abdulwahab Lawal, Okechukwu Hyginus Ekwunife, Ochomma Amobi Egwuonwu, Chisom Faith Uche, Abubakar Bala AB Muhammad, Saminu S Muhammad, Idris Usman IU Takai, Mohammed AS Aliyu Salele, Onyekachi G Ukata, Mahmoud Kawu MK Magashi, Lawal Barau LB Abdullahi, Bello Abodunde BA Muideen, Khadija A Ado, Lofty-John Chukwuemeka LJC Anyawu, Samson Olori*, Samuel A Sani, Olabisi O Osagie, Ndubuisi Mbajiekwe, Oseremen Aisuodionoe-Shadrach, Godwin O Akaba, Lazarus Ameh, Lazarus Ameh, Francis o Adebayo, Martins Uanikhoba, Felix O Ogbo, Nancy O Tabuanu, Taiwo A Lawal, Rukiyat A Abdus-Salam, Akinlabi E Ajao, Augustine O Takure, Omobolaji O Ayandipo, Hyginus O Ekwuazi, Olukayode Abayomi, Olatunji O Lawal, Solomon Olagunju, Kelvin I Egbuchulem, Sikiru Adekola Adebayo, Peter Elemile, Usang E Usang, Joseph E Udosen, Expo E Edet, Akan W Inyang, Edima M Olory, Gabriel U Udie, Godwin O Chiejina, Adams D Marwa, Faith J Iseh, Sunday A Ogbeche, Mary O Isa, Uchechukwu O Ezomike, Sebastian O Ekenze, Matthew I Eze, Emmanuel O Izuka, Jude K Ede, Vincent C Enemuo, Okezie M Mbadiwe, Ngozi G Mbah, Alphonsine Imanishimwe, Sosthene Habumuremyi, Faustin Ntirenganya, JC Allen Ingabire, Isaie Ncogoza, Emmanuel Munyaneza, Jean de Dieu Haragirimana, Christian Jean Urimubabo, Violette Mukanyange, Jeannette Nyirahabimana, Emmanuel Mutabazi, Christophe Mpirimbanyi, Olivier Mwenedata, Hope Lydia Maniraguha, Emelyne Izabiriza, Moses Dusabe, Job Zirikana, Francine Uwizeyimana, Josiane Mutuyimana, Elisee Rwagahirima, Alphonsine Imanishimwe, Ronald Tubasiime, Aphrodis Munyaneza, Sosthene Habumuremyi, Salathiel Kanyarukiko, Gibert Ndegamiye, Francine Mukaneza, Jean Claude Uwimana, Pierrine Nyirangeri, Deborah Mukantibaziyaremye, Aime Dieudonne Hirwa*, Salomee Mbonimpaye, Piolette Muroruhirwe, Christine Mukakomite, Elysee Kabanda, Rachel Moore, Ncamsile Anthea Nhlabathi, Maria Fourtounas, Mary Augusta Adams, Gabriella Hyman, Hlengiwe Samkelisiwe Nxumalo, Nnosa Sentholang, Mmule Evelyn Sethoana, Mpho Nosipho Mathe,NIHR Global Health Research Unit on Global Surgery: James Glasbey, Adesoji Ademuyiwa, Alisha Bhatt, Bruce Biccard, Jane Blazeby, Peter Brocklehurst, Sohini Chakrabortee, JC Allen Ingabire, Francis Mo\u00efse Dossou, Irani Dur\u00e1n, Rohini Dutta, Dhruva Ghosh, Frank Gyamfi, Parvez Haque, Pollyanna Hardy, Mike Horton, Gabriella Hyman, Ritu Jain, Oluwaseun Ladipo-Ajayi, Ismail Lawani, Souliath Lawani, Mwayi Kachapila, Rachel Lillywhite, Rhiannon Macefield, Laura Magill, Janet Martin, Jonathan Mathers, Kenneth McLean, Punam Mistry, Rohin Mittal, Mark Monahan, Rachel Moore, Dion Morton, Moyo Ojo, Faustin Ntirenganya, Emmanuel Ofori, Rupert Pearse, Alberto Pe\u00f3n, Thomas Pinkney, Antonio Ramos de la Medina, Tubasiime Ronald, David Roman, Emmy Runingamugabo, Alice Sitch, Anita Slade, Donna Smith, Stephen Tabiri, Aneel Bhangu, James Glasbey, Anita Slade, Mike Horton, Rhiannon Macefield, Aneel Bhangu, Pollyanna Hardy, Adesoji O Ademuyiwa, Lawani Ismail, Dhruva Ghosh, Antonio Ramos de la Medina, Rachel Moore, Faustin Ntirenganya, Stephen Tabiri, Emmy Runingamugabo, Simin Patrawala, Angela Prah, Christian Oko, Karolin Kroese, Isma\u00efl Lawani, Francis Mo\u00efse Dossou, Corinne Dzemta, Covalic Melic Bokossa Kandokponou, Souliath Lawani, Hulrich Behanzin, Cyrile Kpangon, Bernard Appiah Ofori, Stephen Tabiri, Abdul-Hafiz Saba, Gbana Limann, Daniel Kwesi Acquah, Shamudeen Mohammed Alhassan, Sheriff Mohammed, Owusu Abem Emmanuel, Yakubu Musah, Yenli Edwin, Sheba Kunfah, Yakubu Mustapha, Abantanga Atindaana Francis, Emmanuel Ayingayure, Gbana Limann, Forster Amponsah-Manu, Eric Agyemang, Vera Agyekum, Esther Adjei-Acquah, Emmanuel Yaw Twerefour, Barbra Koomson, Ruby Acheampong Boateng, Ato Oppong Acquah, Richard Ofosu-Akromah, Leslie Issa Adam-Zakariah, Nii Armah Adu-Aryee, Theodore Wordui, Coomson Christian Larbi, Akosa Appiah Enoch, Mensah Elijah, Kyeremeh Christian, Addo Gyambibi Kwame, Boakye Percy, Kontor Effah Bismark, Gyamfi Brian, Manu Ruth, Romeo Hussey, Samuel Dadzie, Akosua Dwamena Appiah, Grace Yeboah, Cynthia Yeboah, James Amoako, Regina Acquah, Naa Anyekaa Sowah, Atta Kusiwaa, Esther Asabre, Cletus Ballu, Charles Gyamfi Barimah, Frank Owusu, Clement Sie-Broni, Vivian Adobea, Prince Yeboah Owusu, Marshall Zume, Abdul-Hamid Labaran, Raphael Adu-Brobbey, Martin Tangnaa Morna, Samuel A. Debrah, Patrick Opoku Manu Maison, Michael Nortey, Donald Enti, Mabel Pokuah Amoako-Boateng, Anthony Baffour Appiah, Emmanuel Owusu Ofori, Richard Kpankpari, Benedict Boakye, Elizabert Mercy Quartson, Patience Koggoh, Anita Eseenam Agbeko, Frank Enoch Gyamfi, Joshua Arthur, Joseph Yorke, Christian Kofi Gyasi-Sarpong, Charles Dally, Agbenya Kobla Lovi, Michael Amoah, Boateng Nimako, Robert Sagoe, Anthony Davor, Fareeda Galley, Michael Adinku, Jonathan Boakye-Yiadom, Jane Acquaye, Juliana Appiah, Dorcas Otuo Acheampong, Iddrisu Haruna, Edward Amoah Boateng, Emmanuel Kafui Ayodeji, Samuel Tuffuor, Naa Kwarley, Yaa Tufuor, Ramatu Darling Abdulai, Fred Dankwah, Ralph Armah, Doris Ofosuhene, Dorcas Osei-Poku, Arkorful Ebenezer Temitope, Delali Akosua Gakpetor, Victoria Sena Gawu, Christopher Asare, Enoch Tackie, James Ankomah, Isaac Omane Nyarko, Zelda Robertson, Serbeh Godwin, Appiah Anthony Boakye, Godfred Fosu, Frank Assah-Adjei, Parvez Haque, Ritu Jain, Alisha Bhatt, Jyoti Dhiman, Rohini Dutta, Dhruva Ghosh, Esther Daniel, Priyadarshini K, Latha Madankumar, Rohin Mittal, Ida Nagomy, Soosan Prasad, Arpit Jacob Mathew, Danita Prakash, Priya Jacob, Jeremiah Zain Ally*, Margot Flint, Bruce Biccard, Adesoji O Ademuyiwa, Adewale O. Adisa, Aneel Bhangu, Peter Brocklehurst, Sohini Chakrabortee, Pollyanna Hardy, Ewen Harrison, JC Allen Ingabire, Parvez D Haque, Lawani Ismail, James Glasbey, Dhruva Ghosh, Frank Enoch Gyamfi, Elizabeth Li, Rachel Lillywhite, Antonio Ramos de la Medina, Rachel Moore, Laura Magill, Dion Morton, Dmitri Nepogodiev, Faustin Ntirenganya, Thomas Pinkney, Omar Omar, Joana Simoes, Donna Smith, Stephen Tabiri, Adesoji O Ademuyiwa, Lawani Ismail, Dhruva Ghosh, Antonio Ramos de la Medina, Rachel Moore, Faustin Ntirenganya, Stephen Tabiri, Adesoji Ademuyiwa, Aneel Bhangu, Felicity Brant, Peter Brocklehurst, Sohini Chakrabortee, Dhruva Ghosh, James Glasbey, Pollyanna Hardy, Ewen Harrison, Emily Heritage, Lawani Ismail, Karolin Kroese, Carmela Lapitan, Rachel Lillywhite, David Lissauer, Laura Magill, Antonio Ramos de la Medina, Punam Mistry, Mark Monahan, Rachel Moore, Dion Morton, Dmitri Nepogodiev, Faustin Ntirenganya, Omar Omar, Thomas Pinkney, Tracy Roberts, Donna Smith, Stephen Tabiri, Neil Winkles, Pollyanna Hardy, Omar Omar, Emmy Runigamugabo, Azmina Verjee, Pierre Sodonougbo, Pamphile Assouto, Michel Fiogbe, Houenoukpo Koco, Serge Metchinhoungbe, Hodonou Sogbo, Hulrich Behanzin, Djifid Morel Seto, Yannick Tandje, Sosth\u00e8ne Kangni, Cyrile Kpangon*, Marcelin Akpla, Hugues Herve Chobli, Blaise Kovohouande, G\u00e9rard Agboton, Rene Ahossi, Raoul Baderha Ngabo, Nathan Bisimwa, Covalic Melic Bokossa Kandokponou, Mireille Dokponou, Francis Mo\u00efse Dossou, Corinne Dzemta, Antoine Gaou, Roland Goudou, Emmanuel Hedefoun, Sunday Houtoukpe, Felix Kamga, Eric Kiki-Migan, Souliath Lawani, Isma\u00efl Lawani, Ren\u00e9 Loko, Afissatou Mouta\u00efrou, Pencome Ogouyemi, Fouad Soumanou, Pia Tamadaho, Mack-Arthur Zounon, Luke Aniakwo Adagrah, Bin Baaba Alhaji Alhassan, Mabel Pokuah Amoako-Boateng, Anthony Baffour Appiah, Alvin Asante-Asamani, Benedict Boakye, Samuel A Debrah. Donald Enti, Rahman Adebisi Ganiyu, Patience Koggoh, Richard Kpankpari, Isabella Naa M. Opandoh, Meshach Agyemang Manu, Maison Patrick Opoku Manu, Samuel Mensah, Martin Tangnaa Morna, John Nkrumah, Michael Nortey, Emmanuel Owusu Ofori, Elizaberth Mercy Quartson, Esther Adjei-Acquah, Vera Agyekum, Eric Agyemang, Rebecca Adjeibah Akesseh, Forster Amponsah-Manu, Richard Ofosu-Akromah, Ato Oppong Acquah, Leslie Issa Adam-Zakariah, Esther Asabre, Ruby Acheampong Boateng, Barbara Koomson, Ataa Kusiwaa, Emmanuel Yaw Twerefour, James Ankomah, Frank Assah-Adjei, Anthony Appiah Boakye, Godfred Fosu, Godwin Serbeh, Kofi Yeboah Gyan, Isaac Omane Nyarko, Zelda Robertson, Ralph Armah, Christopher Asare, Delali Akosua Gakpetor, Victoria Sena Gawu, Ambe Obbeng, Doris Ofosuhene, Dorcas Osei-Poku, Diana Puozaa, Enoch Tackie, Arkorful Ebenezer Temitope, Regina Acquah, James Amoako, Akosua Dwamena Appiah, Mark Aseti, Charles Banka, Samuel Dadzie, Derick Essien, Frank Enoch Gyamfi, Romeo Hussey, Jemima Kwarteng, Naa Anyekaa Sowah, Grace Yeboah, Cynthia Yeboah, Kwame Gyambibi Addo, Enoch Appiah Akosa, Percy Boakye, Christian Larbi Coompson, Brian Gyamfi, Bismark Effah Kontor, Christian Kyeremeh, Ruth Manu, Elijah Mensah, Friko Ibrahim Solae, Gideon Kwasi Toffah, Dorcas Otuo Acheampong, Jane Acquaye, Michael Adinku, Kwabena Agbedinu, Anita Eseenam Agbeko, Emmanuel Gyimah Amankwa, Michael Amoah, George Amoah, Juliana Appiah, Joshua Arthur, Alex Ayim, Emmanuel Kafui Ayodeji, Jonathan Boakye-Yiadom, Edward Amoah Boateng, Charles Dally, Anthony Davor, Christian Kofi Gyasi-Sarpong, Naabo Nuhu Noel Hamidu, Iddrisu Haruna, Naa Kwarley, Agbenya Kobla Lovi, Boateng Nimako, Bertina Beauty Nyadu, Dominic Opoku, Anita Osabutey, Robert Sagoe, Samuel Tuffour, Yaa Tufour, Francis Akwaw Yamoah, Abiboye Cheduko Yefieye, Joseph Yorke, Nii Armah Adu-Aryee, Faisal Adjei, Erica Akoto, Elikem Ametefe, Joachim Kwaku Amoako, Godsway Solomon Attepor, George Darko Brown, Benjamin Fenu, Philemon Kwame Kumassah, David Olatayo Olayiwola, Theodore Wordui, Nelson Agboadoh, Fatao Abubakari, Cletus Ballu, Charles Gyamfi Barimah, Guy Casskey Boateng, Prosper Tonwisi Luri, Abraham Titigah, Frank Owusu, Raphael Adu-Brobbey, Christian Larbi Coompson, Abdul-Hamid Labaran, Junior Atta Owusu, Vivian Adobea, Amos Bennin, Fred Dankwah, Stanley Doe, Ruth Sarfo Kantanka, Ephraim Kobby, Kennedy Kofi Korankye Hanson Larnyor, Edwin Osei, Prince Yeboah Owusu, Clement Ayum Sie-Broni, Marshall Zume, Francis Atindaana Abantanga, Darling Ramatu Abdulai, Daniel Kwesi Acquah, Emmanuel Ayingayure, Imoro Osman, Sheba Kunfah, Gbana Limann, Shamudeen Alhassan Mohammed, Sheriff Mohammed, Yakubu Musah, Bernard Ofori, Emmanuel Abem Owusu, Abdul-Hafiz Saba, Anwar Sadat Seidu, Stephen Tabiri, Mustapha Yakubu, Edwin Mwintiereh Taang Yenli, Arun Gautham, Alice Hepzibah, Grace Mary, Deepak Singh, Dimple Bhatti, William Bhatti, Karan Bir, Swati Daniel, Tapasya Dhar, Jyoti Dhiman, Dhruva Ghosh, Sunita Goyal, Ankush, Goyal, Monika Hans, Parvez Haque, Samuel Konda, Anil Luther, Amit Mahajan, Shalini Makkar, Kavita Mandrelle, Vishal Michael, Partho Mukherjee, Reuben Rajappa, Prashant Singh, Atul Suroy, Ravinder Thind, Alen Thomas, Arti Tuli, Sreejith Veetil, Esther Daniel Mark Jesudason, Priyadarshini K, Latha Madankumar, Rohin Mittal, Ida Nagomy, Rajesh Selvakumar, Bharat Shankar, Moonish Sivakumar, Rajeevan Sridhar, Cecil Thomas, Devabalan Titus, Manisha Aggarwal, Parth Dhamija, Himani Gupta, Vinoth Kanna, Ashwani Kumar, Gurtaj Singh, Philip Alexander, Josy Thomas, Pradeep Zechariah, Amos Dasari, Priya Jacob, Elizabeth Kurien, Arpit Mathew, Danita Prakash, Anju Susan, Rose Varghese, Rahul Alpheus, Ashish Choudhrie, Hemanth Kumar, Nitin Peters, Subrat Raul, Rajeev Sharma, Rakesh Vakil, Wenceslao \u00c1ngeles Bueno, Francisco Barbosa Camacho, Aldo Bernal Hern\u00e1ndez, Ana Bogurin Arellano, Edgar Cortes Torres, Clotilde Fuentes Orozco, Erick Gonz\u00e1lez Garc\u00eda de Rojas, Alejandro Gonz\u00e1lez Ojeda, Bertha Guzm\u00e1n Ram\u00edrez, Michel Hern\u00e1ndez Valadez, Diego Luna Acevedo, Rub\u00e9n Mor\u00e1n Galaviz, Oscar Olvera Flores, Jos\u00e9 P\u00e9rez Navarro, Kevin Pintor Belmontes, Fernando Ramirez Marbello, Luis Ram\u00edrez-Gonz\u00e1lez, Laura Reyes Aguirre, Ramona Rojas Garc\u00eda, Eduardo Valtierra Robles, Reyes Cervantes Ortiz, Gonzalo Hernandez Gonzalez, Rosa Hernandez Krauss, Luis Hern\u00e1ndez Miguelena, Marco Hurtado Romero, Isaac Baltazar Gomez, Celina Cuellar Aguirre, Alejandro Cuevas Avenda\u00f1o, Luis Dominguez Sansores, Hector Ortiz Mejia, Laura Urdapilleta Gomez del Campo, Claudia Caballero Cerdan, David Dominguez Solano, Rafael Toriz Garcia, Mariana Barreto Gallo, Ana Cortes Flores, Alejandro Gonzalez Ojeda, Monica Jimenez Velasco, Rozana Reyes Gamez, Roque Lincona Menindez, Alberto Navarrete Pe\u00f3n, Maria Paz Mu\u00f1oz, Ir\u00e1n Irani Dur\u00e1n S\u00e1nchez, Diana Samantha Gonz\u00e1lez V\u00e1zquez, Mar\u00eda Jos\u00e9 Mart\u00ednez Lara, Laura Martinez Perez Maldonado, Alejandra Nayen Sainz de la Fuente, Antonio Ramos De la Medina, Lawal Abdullahi, Khadija Ado, Mohammed Aliyu, Lofty-John Anyanwu, Mahmoud Magashi, Abubakar Muhammad, Saminu Muhammad, Bello Muideen, Idris Takai, Onyekachi Ukata, Opeoluwa Adesanya, David Awonuga, Olushola Fasiku, Chidiebere Ogo, Moruf Abdulsalam, Abimbola Adeniran, Olalekan Ajai, Olukemi Akande, Kazeem Atobatele, Grace Eke, Omolara Faboya, Zainab Imam, Esther Momson, Francisca Nwaenyi, Ayokunle Ogunyemi, Mobolaji Oludara, Olufunmilade Omisanjo, Olabode Oshodi, Yusuf Oshodi, Yemisi Oyewole, Omotade Salami, Omolara Williams, Victoria Adeleye, Adesoji Ademuyiwa, Oluwafunmilayo Adeniyi, Opeyemi Akinajo, David Akinboyewa, Iyabo Alasi, Felix Alakaloko, Oluwole Atoyebi, Olanrewaju Balogun, Orimisan Belie, Christopher Bode, Andrew Ekwesianya, Olumide Elebute, Francis Ezenwankwo, Adedeji Fatuga, George Ihediwa, Adesola Jimoh, Jubril Kuku, Oluwaseun LadipoAjayi, Ayomide Makanjuola, Olayanju Mokwenyei, Samuel Nwokocha, Olubunmi Ogein, Rufus Ojewola, Abraham Oladimeji, Thomas Olajide, Oluwaseun Oluseye, Justina Seyi-Olajide, Adaiah Soibi-Harry, Aloy Ugwu, Emmanuel Williams, Ochomma Egwuonwu, Okechukwu Ekwunife, Victor Modekwe, Chukwuemeka Okoro, Chisom Uche, Kenneth Ugwuanyi, Chuka Ugwunne, Akeem Adeleke, Wilson Adenikinju, Olumide Adeniyi, Akinfolarin Adepiti, Adewale Aderounmu, Abdulhafiz Adesunkanmi, Adewale Adisa*, Samuel Ajekwu, Olusegun Ajenjfuja, Jerrie Akindojutimi, Akinbolaji Akinkuolie, Olusegun Alatise, Olubukola Allen, Lukmon Amosu, Micheal Archibong, Olukayode Arowolo, Deborah Ayantona, Ademola Ayinde, Olusegun Badejoko, Tajudeen Badmus, Amarachukwu Etonyeaku, Emeka Igbodike, Omotade Ijarotimi, Adedayo Lawal, Fayowole Nana, Tunde Oduanafolabi, Olalekan Olasehinde, Olaniyi Olayemi, Stephen Omitinde, Owolabi Oni, Chigozie Onyeze, Ernest Orji, Adewale Rotimi, Abdulkadir Salako, Olufemi Solaja, Oluwaseun Sowemimo, Ademola Talabi, Mohammed Tajudeen, Funmilola Wuraola, Francis Adebayo, Oseremen Aisuodionoe-Shadrach, Godwin Akaba, Lazarus Ameh, Ndubuisi Mbajiekwe, Felix Ogbo, Samson Olori, Olabisi Osagie, Abu Sadiq, Samuel Sani, Nancy Tabuanu, Martins Uanikhoba, Godwin Chiejina, Ekpo Edet, Akan Inyang, Mary Isa, Faith Iseh, Adams Marwa, Sunday Ogbeche, Edima Olory, Gabriel Udie, Joseph Udosen, Usang Usang, Olukayode Abayomi, Rukiyat Abdus-Salam, Sikiru Adebayo, Akinlabi Ajao, Olanrewaju Amusat, Omobolaji Ayandipo, Kelvin Egbuchulem, Hyginus Ekwuazi, Peter Elemile, Taiwo Lawal, Olatunji Lawal, Solomon Olagunju, Peter Osuala, Bamidele Suleman, Augustine Takure, Lukman Abdur-Rahman, Nurudeen Adeleke, Muideen Adesola, Rafiat Afolabi, Sulaiman Agodirin, Isiaka Aremu, Jibril Bello, Saheed Lawal, Abdulwahab Lawal, Hadijat Raji, Olayinka Sayomi, Asimiyu Shittu, Jude Ede, Sebastian Ekenze, Vincent Enemuo, Matthew Eze, Uchechukwu Ezomike, Emmanuel Izuka, Okezie Mbadiwe, Ngozi Mbah, Uba Ezinne, Matthew Francis, Iweha Ikechukwu, Okoi Nnyonno, Philemon Okoro, Igwe Patrick, John Raphael, Oriji Vaduneme, Abhulimen Victor, Salathiel Kanyarukiko, Francine Mukaneza, Deborah Mukantibaziyaremye, Aphrodis Munyaneza, Gibert Ndegamiye, Ronald Tubasiime, Moses Dusabe, Emelyne Izabiriza, Hope Lydia Maniraguha, Christophe Mpirimbanyi, Josiane Mutuyimana, Olivier Mwenedata, Elisee Rwagahirima, Francine Uwizeyimana, Job Zirikana, Aime Dieudonne Hirwa, Elysee Kabanda, Salomee Mbonimpaye, Christine Mukakomite, Piolette Muroruhirwe, Georges Bucyibaruta, Gisele Juru Bunogerane, Sosthene Habumuremyi, Jean de Dieu Haragirimana, Alphonsine Imanishimwe, JC Allen Ingabire, Violette Mukanyange, Emmanuel Munyaneza, Emmanuel Mutabazi, Isaie Ncogoza, Faustin Ntirenganya, Jeannette Nyirahabimana, Christian Urimubabo, Mary Augusta Adams, Richard Crawford, Chikwendu Jeffrey Ede, Maria Fourtounas, Gabriella Hyman, Zafar Khan, Morapedi Kwati, Mpho Nosipho Mathe, Rachel Moore, Ncamsile Anthea Nhlabathi, Hlengiwe Samkelisiwe Nxumalo, Paddy Pattinson, Nnosa Sentholang, Mmule Evelyn Sethoana, Maria Elizabeth Stassen, Laura Thornley, Paul Wondoh Edenvale Hospital, Johannesburg: Cheryl Birtles, Mathete Ivy, Cynthia Mbavhalelo, Zain Ally, Abdus-sami Adewunmi, Jonathan Cook, David Jayne, Soren Laurberg, Julia Brown, Simon Cousens, Neil Smartznad058_Supplementary_DataClick here for additional data file."} +{"text": "Journal of Surgical Case Reports, Volume 2023, Issue 3, March 2023, rjad093, https://doi.org/10.1093/jscr/rjad093This is a correction to: Abdulmajeed Ali Alkhathami, Zuhair Babiker Ahmed, Abdullah Mohammed A. Khushayl, Faiz Alsaffar, Abdullah M. Alshahrani, Acute pancreatitis after intragastric balloon insertion: case report, In the originally published version of this manuscript, Abdullah Mohammed A. Khushayl's name was incorrectly written as Abdullah M. Alkhushayl.This error has now been corrected."} +{"text": "Dear Editor,In a recent meta-analysis , Dr.Cao First, a literature search was conducted in PubMed, Web of Science, Cochrane, Embase, and Scopus databases, from December 1, 2019 to November 1, 2022. However, one trial [Second, the efficacy of prone positioning in COVID-19 has been investigated in dozens of studies . The maj"} +{"text": "Enterococcus faecalis BAU_Ef01 isolated from a shrimp in Bangladesh. The whole genome of the strain had a length of 2,862,301 bp, 38 contigs, an average G+C content of 37.36%, 80.0\u00d7 genome coverage, and 35 predicted antibiotic resistance and virulence genes each.Here, we sequence and analyze a biofilm-forming strain of Enterococcus faecalis, that can be transferred to humans through the food chain. E. faecalis is well known for forming biofilms to endure its challenging surrounding conditions samples were collected from Cox\u2019s Bazar and transferred to our laboratory . Subsequently, samples were processed following the previously described procedure , with a cumulative length of 2,862,301 bp and an average G+C content of 37.36%. In the PATRIC annotation, the genome contained 2,728 protein-coding sequences, 48 transfer RNA genes, and three ribosomal RNA genes. This genome corresponds to sequence type ST862 based on MLST and exhibits a probability of 89.6% for being a human pathogen based on PathogenFinder. The E. faecalis BAU_EF01 genome had 35 ARGs under different antimicrobial classes, including glycopeptides, tetracyclines, macrolides, fluoroquinolones, rifamycins, diaminopyrimidine, lincosamides, streptogramins, etc. Our assembled genome harbored 35 predicted VFGs under various virulence factors, including biofilm formation, toxin, adherence, antiphagocytosis, enzyme, immune evasion, and others. Moreover, our genome contained 779 subsystems with 29% coverage and harbored 1,075 genes for different subsystem features, such as virulence, disease, and defense, carbohydrates, amino acids and derivatives, nucleosides and nucleotides, cofactors, vitamins, prosthetic groups, pigments, iron acquisition and metabolism, etc.The assembled draft"} +{"text": "In this special edition (closed on 31 October 2022), 4 reviews, 13 original papers, 1 communication, and 1 case report are published. These papers were published by scientific teams from 24 countries, including China, Tunisia, Canada, France, Serbia, Portugal, Spain, Chile, Singapore, Australia, USA, Mexico, Czech Republic, Germany, Sweden, Finland, United Kingdom, Norway, Poland, Greece, Japan, Italy, Switzerland, and Israel, which is a really great achievement.In the review of Chen et al. , the autThe review of Benkhalifa et al. was dediThe review of Viloti\u0107 et al. provided\u00c2ngelo-Dias et al. performeOrtega et al. demonstrPe\u00f1ailillo et al. describeMartinez-Fierro et al. present Our research group introducCzamara et al. showed tHuang et al. demonstrLynch et al. reportedMisan et al. describeMavreli et al. introducSzala-Po\u017adziej et al. reportedKedziora et al. studied Kadife et al. demonstrDymara-Konopka et al. evaluateChighine et al. presenteFinally, Sammar et al. showed o"} +{"text": "PLOS ONE Editors retract this article [The article because article and Fig article respectiYM, CL, and JY agreed with the retraction. HL, ZL, ML, and YL disagreed with the retraction. DZ, LD, BW, HY, FW, and JZ either did not respond directly or could not be reached."} +{"text": "Yun Shan Goh, Siew\u2010Wai Fong, Angeline Rouers, Zi Wei Chang, Matthew Zirui Tay, Jean\u2010Marc Chavatte, Nicole Ziyi Zhuo, Pei Xiang Hor, Chiew Yee Loh, Yuling Huang, Joel Xu En Wong, Yong Jie Tan, Daniel Rui Xiang Lim, Bei Wang, Eve Zi Xian Ngoh, Siti Nazihah Mohd Salleh, Raphael Tze Chuen Lee, Surinder Pada, Louisa Jin Sun, Desmond Luan Seng Ong, Jyoti Somani, Eng Sing Lee, NCID Study Group, COVID\u201019 Study Group, Sebastian Maurer\u2010Stroh, Cheng\u2010I Wang, Yee\u2010Sin Leo, Raymond TP Lin, Ee Chee Ren, David C Lye, Barnaby Edward Young, Poh Lian Lim, Lisa FP Ng & Laurent ReniaClinical & Translational Immunology 2023; 12: e1449.Correction to: Clin Trans Immunol 2022; 11: e1043. https://doi.org/10.1002/cti2.1403. Published online 23 August 2022The authors inadvertently excluded a funding body in the Acknowledgments section. The corrected version appears below:"} +{"text": "PLOS ONE Editors retract this article [The article because KM, AW, HuR, OF, RMI, FZ, MHuR, MAhmad, MAlam, MuAli, MaAli, AK, MIshtiaq, and MMW did not agree with the retraction. All other authors either did not respond directly or could not be reached."} +{"text": "In \u201cDigital Phenotyping for Differential Diagnosis of Major Depressive Episode: Narrative Review\u201d the authors made three additions to the authorship list.The authorship is currently listed as:Eric Ettore, Philipp M\u00fcller, Jonas Hinze, Michel Benoit, Bruno Giordana, Danilo Postin, Amandine Lecomte, Hali Lindsay, Philippe Robert, Alexandra K\u00f6nigAnd will be changed to read as follows:Eric Ettore, Philipp M\u00fcller, Jonas Hinze, Matthias Riemenschneider, Michel Benoit, Bruno Giordana, Danilo Postin, Rene Hurlemann, Amandine Lecomte, Michel Musiol, Hali Lindsay, Philippe Robert, Alexandra K\u00f6nigThe authors who have been recently added are affiliated with the following institutions, which are already correctly presented in the affiliation list:3:Matthias RiemenschneiderDepartment of Psychiatry and Psychotherapy, Saarland University Medical Center, Hombourg, Germany.5:Rene HurlemannDepartment of Psychiatry, School of Medicine and Health Sciences, Carl von Ossietzky University of Oldenburg, Bad Zwischenahn, Germany.6:Michel MusiolResearch Department S\u00e9magramme Team, Institut national de recherche en informatique et en automatique, Nancy, France.The correction will appear in the online version of the paper on the JMIR Publications website on April 12, 2023, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories."} +{"text": "PNAS Nexus, Volume 2, Issue 4, April 2023, pgad104, https://doi.org/10.1093/pnasnexus/pgad104This is a correction to: Fumiaki Sakura, Kosuke Noma, Takaki Asano, Kay Tanita, Etsushi Toyofuku, Kentaro Kato, Miyuki Tsumura, Hiroshi Nihira, Kazushi Izawa, Kanako Mitsui-Sekinaka, Ryo Konno, Yusuke Kawashima, Yoko Mizoguchi, Shuhei Karakawa, Seiichi Hayakawa, Hiroshi Kawaguchi, Kohsuke Imai, Shigeaki Nonoyama, Takahiro Yasumi, Hidenori Ohnishi, Hirokazu Kanegane, Osamu Ohara, Satoshi Okada, A complementary approach for genetic diagnosis of inborn errors of immunity using proteogenomic analysis, PNAS Nexus, it was discovered that this paper was missing a statement acknowledging compliance with the PNAS Nexus Human and Animal Participants and Clinical Trials policy:During a retroactive audit conducted by The local ethics boards at Hiroshima University, Tokyo Medical and Dental University, National Defense Medical College, Gifu University, Kyoto University, and Kazusa DNA Research Institute approved this study. Informed consent was obtained from all participants.This error has been corrected in the original article."} +{"text": "Bioinformatics, Volume 38, Issue 22, 15 November 2022, Pages 5144\u20135148, https://doi.org/10.1093/bioinformatics/btac654This is a correction to: Nayang Shan, Yao Lu, Hao Guo, Dongyu Li, Jitong Jiang, Linlin Yan, Jiudong Gao, Yong Ren, Xingming Zhao, Lin Hou, CITEdb: a manually curated database of cell\u2013cell interactions in human, In the originally published version of this manuscript, author Xingming Zhao\u2019s affiliation was incorrect.The author\u2019s affiliation has been corrected online to:\u201cKey Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education, Fudan University, Shanghai, China.\u201d"} +{"text": "Scientific Reports 10.1038/s41598-023-40099-4, published online 16 August 2023Correction to: The original version of this Article omitted affiliations for Tara Chand. The correct affiliations are listed below.Department of Psychiatry and Psychotherapy, Jena University Hospital, Philosophenweg 3, 07743, Jena, GermanyClinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, GermanyDepartment of Clinical Psychology, Friedrich Schiller University Jena, Am Steiger 3-1, 07743, Jena, GermanyJindal Institute of Behavioural Sciences, O. P. Jindal Global University (Sonipat), Haryana, IndiaThe original Article has been corrected."} +{"text": "The correct reference is: Winding M, Pedigo BD, Barnes CL, Patsolic HG, Park Y, Kazimiers T, et al. The connectome of an insect brain. Science. 2023; 379(6636)."} +{"text": "The corrected author list appears below.In the published article, there was an error in the *\u201d\u201cYing Ding\u2020, Nannan Chu\u2020, Linling Que, Kai Huang, Yuanxing Chen, Wei Qin, Zhenzhong Qian, Yunfei Shi, Zhen Xu, and Qing HeAuthor contributions. This sentence previously stated:A correction has been made to \u201cYD and QH designed the study. NC, YD, LQ, KH, YC, WQ, ZQ, YS, and ZX performed the clinical study. NC wrote and revised the manuscript.\u201dThe corrected sentence appears below:\u201cQH and YD designed the study. YD, LQ, KH, YC, WQ, ZQ, YS, and ZX performed the clinical study. NC wrote and revised the manuscript.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Public Health Reviews would like to thank all Reviewers in 2022 for the time they have spent and the valuable contributions they have made to ensure the scientific quality of the journal.The Editors of Carla AbouZahr, SwitzerlandAna Johnson, CanadaGabriela Albuquerque, PortugalVishaldeep Kaur Sekhon, United StatesSaleh Alessy, Saudi ArabiaJune Kloubec, United StatesDiogo Almeida, PortugalMark Kroese, United KingdomIsabel Alvarado-Cruz, United StatesThao Minh Lam, NetherlandsAlain Amstutz, SwitzerlandElizabeth Lee, United StatesDaniela Anker, SwitzerlandJonathon Leider, United StatesSaeed Anwar, CanadaMayara Lima, BrazilJoao Araujo, BrazilCosima Lisi, PortugalMark Avery, AustraliaLaura Maga\u00f1a, United StatesSuzanne Babich, United StatesCarlos Matos, PortugalBarbara B\u00fcrkin, SwitzerlandMiroslaw Mazurek, PolandSimon Capewell, United KingdomSinenhlanhla Memela, South AfricaLuisa Concei\u00e7\u00e3o, PortugalElina Miteniece, NetherlandsAna Rute Costa, SwitzerlandSamantha Morais, CanadaAna Cruz, PortugalJessica Neicun, NetherlandsValeria Carolina Cuenca Cuenca, SpainVasileios Nittas, United StatesKatherine Curry, United StatesNgoy Nsenga, SwitzerlandKatarzyna Czabanowska, NetherlandsVicka Oktaria, IndonesiaNicole Geovana Dias, BrazilOyeladun Okunromade, NigeriaRita Dias, PortugalRasaq Oladapo, NigeriaAbeer Elshater, EgyptLaura Orlando, CanadaMarta Fadda, SwitzerlandMartina Paric, NetherlandsRebecca Forman, United KingdomDavid Patterson, NetherlandsCassiano Franco, BrazilElizabeth Peacocke, NorwayXing Gao, United StatesMargarida Pereira, SwitzerlandMark Green, United KingdomPriyanka Priyanka, United StatesMohammad Mehedi Hasan, BangladeshAna Catarina Queiroga, PortugalElena Isaevska, SwitzerlandRajesh Kumar Rai, IndiaKunihiro Iwamoto, JapanJes\u00fas Rivera Navarro, SpainCl\u00e1udia Raquel Jardim Santos, SwitzerlandPablo Rodr\u00edguez-Feria, NetherlandsNeusa Jessen, MozambiqueAnkur Saxena, IndiaVivi Schlunssen, DenmarkFlorence Secula, SwitzerlandKenbon Seyoum, EthiopiaDawa Sherpa, IndiaAvaneesh Singh, IndiaPrashant Kumar Singh, IndiaAsha Soletti, IndiaMaoyi Tian, ChinaCecilia Tinonin, ThailandYu-Chuan Tsai, TaiwanKaspar Wyss, Switzerland"} +{"text": "Haemophilus influenzae type b. In practice, switching between HCVs during the childhood vaccination series is sometimes necessary due to vaccine availability, health care provider preference, tender awards, or other reasons. The various HCVs differ in the types of antigens used, which may affect immunogenicity and reactogenicity. The use of Vaxelis\u2122 as a booster dose after another HCV has not previously been studied in a clinical trial. The purpose of this study was to describe the safety, tolerability, and immunogenicity of a booster dose of Vaxelis\u2122 in toddlers who previously received a primary infant series of either Vaxelis\u2122 or Hexyon\u2122.Vaxelis\u2122 is a hexavalent combination vaccine (HCV) indicated in infants and toddlers for the prevention of diphtheria, tetanus, pertussis, hepatitis B, poliomyelitis, and invasive disease due to Healthy participants approximately 11 to 13 months of age who previously received a two-dose primary series of Vaxelis\u2122 (VVV group) or Hexyon\u2122 (HHV group) at approximately 2 and 4 months of age all received a Vaxelis\u2122 booster dose. Safety was evaluated as the proportion of participants with adverse events (AEs). Immunogenicity was evaluated by measuring antibody levels to individual vaccine antigens approximately 30 days following booster vaccination.Participant characteristics were comparable between groups . The overall proportions of participants with AEs\u00ad\u2500including injection-site, systemic, vaccine-related, and serious AEs\u2500were generally comparable between groups. The proportions of participants with antibody-specific responses for antigens contained in both Vaxelis\u2122 and Hexyon\u2122 at 30 days postvaccination with Vaxelis\u2122 were comparable between groups and higher in the VVV group for antigens FIM2/3 and PRN found only in Vaxelis\u2122 (Table 1).A booster dose of Vaxelis\u2122 was well tolerated following a primary series of Hexyon\u2122 with a safety profile similar to a 3-dose series of Vaxelis\u2122. Immune responses were comparable for all shared antigens and higher for those found only in Vaxelis\u2122. These data support the use of Vaxelis\u2122 as a booster in mixed HCV regimens.Andrea Guerra, MD, Merck Sharp & Dohme LLC - United Kingdom: employee|Merck Sharp & Dohme LLC - United Kingdom: Stocks/Bonds Federico Martinon-Torres, MD, PhD, Assoc. Prof, Ablynx, Gilead, Regeneron, Roche, Abbott and MedImmune: Honoraria|Ablynx, Gilead, Regeneron, Roche, Abbott and MedImmune: principal investigator|Astra Zeneca, GSK, Pfizer Inc, Sanofi, MSD, Seqirus, Moderna, Novavax, Biofabri, and Janssen: Advisor/Consultant|Astra Zeneca, GSK, Pfizer Inc, Sanofi, MSD, Seqirus, Moderna, Novavax, Biofabri, and Janssen: Board Member|Astra Zeneca, GSK, Pfizer Inc, Sanofi, MSD, Seqirus, Moderna, Novavax, Biofabri, and Janssen: Honoraria|Astra Zeneca, GSK, Pfizer Inc, Sanofi, MSD, Seqirus, Moderna, Novavax, Biofabri, and Janssen: speaker and investigator Courtney Lambeth, BS, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: employee|Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Stocks/Bonds Ziqiang Chen, PhD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: employee|Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Stocks/Bonds Jessie Lumley, MA, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: employee|Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Stocks/Bonds David Johnson, MD, MPH, Sanofi: employee Marissa B. Wilck, MD, Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: employee|Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA: Stocks/Bonds"} +{"text": "E. coli) BSI.To assess the long-term survival of patients with enterococcal bloodstream infections (BSI), encompassing various species and resistance patterns, in comparison to Escherichia coli BSI were included. Enterococcus faecalis (ECFA), vancomycin/Linezolid-susceptible ECFM, and E. coli BSI were randomly assigned. Cox-regression models were used to assess survival as the primary endpoint and were adjusted for limiting prognostic factors, which were measured for their importance using a random forest model (RFM).Between 2010 and 2019, 3,290 enterococcal and 3,415 E. coli BSI were retrospectively screened in seven hospitals in Munich, Germany. All vancomycin (VRE), vancomycin/linezolid (LVRE), and linezolid (LRE) resistant E. coli BSI . This difference remained significant in the Cox-regression analysis after adjusting for 17 prognostic factors and excluding patients with limited life expectancy . Adjusted 5-year survival between E. coli and ECFA was similar but significantly different between ECFA and ECFM BSI . The analysis conducted on monomicrobial ECFM and VRE BSI indicated that their respective 5-year survival was similar .952 patients with 916 episodes of enterococcal BSI and 193 E. coli BSI episodes were analysed. RFM identified multimorbidity and markers for disease severity as most indicative of low survival in enterococcal BSI. The 5-year survival was significantly lower for enterococcal BSI than for ECFM BSI seems to be an independent risk factor for poor long-term survival. However, additional vancomycin resistance does not appear to be a contributing factor.Jochen Schneider, MD, JS reports grants, personal fees, and nonfinancial support from AbbVie, Gilead Sciences, Janssen-Cilag, GSK/ViiV Healthcare, and MSD, Dr. Falk Pharma: Grant/Research Support Karl Dichtl, MD, KD reports grants from Euroimmun Medizinische Labordiagnostika and Fujifilm Wako Chemicals Europe outside of this study.: Advisor/Consultant Ulrich Seybold, MD, reports personal fees and nonfinancial support from Gilead Sciences, ViiV Healthcare, Janssen-Cilag, Falk Foundation, Sanofi-Aventis.: Advisor/Consultant Christoph Spinner, MD, AbbVie, Gilead Sciences, Janssen-C,MSD, Cepheid, GSK, ViiV Healthcare, AstraZeneca, Apeiron, Braun, Pfizer, Novartis, Lilly, Biontech\u2026: Advisor/Consultant|AbbVie, Gilead Sciences, Janssen-C,MSD, Cepheid, GSK, ViiV Healthcare, AstraZeneca, Apeiron, Braun, Pfizer, Novartis, Lilly, Biontech\u2026: Board Member|AbbVie, Gilead Sciences, Janssen-C,MSD, Cepheid, GSK, ViiV Healthcare, AstraZeneca, Apeiron, Braun, Pfizer, Novartis, Lilly, Biontech\u2026: Grant/Research Support|CDS reports grants and personal fees from AbbVie, grants, fees and non-financial support from Gilead Sciences, grants and personal fees from Janssen-C: Advisor/Consultant|CDS reports grants and personal fees from AbbVie, grants, fees and non-financial support from Gilead Sciences, grants and personal fees from Janssen-C: Board Member|CDS reports grants and personal fees from AbbVie, grants, fees and non-financial support from Gilead Sciences, grants and personal fees from Janssen-C: Grant/Research Support"} +{"text": "Correction: BMC Pregnancy Childbirth 23, 500 (2023)https://doi.org/10.1186/s12884-023-05812-1Following publication of the original article , the autThe incorrect author names are: Hruban Lukas, Jouzova Anna, Janku Petr, Weinberger Vit, Seidlova Dagmar, Juren Tomas, Senkyrik Jan, Kadlecova Jana, Hausnerova Jitka, Jandakova EvaThe correct author names are: Lukas Hruban, Anna Jouzova, Petr Janku, Vit Weinberger, Dagmar Seidlova, Tomas Juren, Jan Senkyrik, Jana Kadlecova, Jitka Hausnerova, Eva JandakovaThe author group has been updated above and the original article has been corrected."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-29519-7, published online 13 February 2023Correction to: The original version of this Article contained errors in the name of authors Annamaria D'Alessandro, Domenico Ciavardelli, Anna Pastore, Santina Lupisella, Rosa Carmela Cristofaro, Giovina Di Felice, Roberta Salierno, Marco Infante, Alberto De Stefano, Andrea Onetti Muda, Maria Morello, Ottavia Porzio which were incorrectly given as D\u2019Alessandro Annamaria, Ciavardelli Domenico, Pastore Anna, Lupisella Santina, Cristofaro Rosa Carmela, Di Felice Giovina, Roberta Salierno, Infante Marco, De Stefano Alberto, Onetti Muda Andrea, Morello Maria and Porzio Ottavia.The original Article has been corrected."} +{"text": "Scientific Reports 10.1038/s41598-023-44297-y, published online 10 October 2023Correction to: The original version of this Article contained an error in Affiliation 1, which was incorrectly given as \u2018Xiangya Hospital, Changsha, China\u2019.The correct affiliation is listed below.Department of Clinical Laboratory, Xiangya Hospital, Central South University, No.87 Xiangya Road, Kaifu District, Changsha, 410008, Hunan, China.The original Article has been corrected."} +{"text": "International Journal of Epidemiology, dyac158, https://doi.org/10.1093/ije/dyac158.This is a correction to: Kevin Wing, Daniel J Grint, Rohini Mathur, Hamish P Gibbs, George Hickman, Emily Nightingale, Anna Schultze, Harriet Forbes, Vah\u00e9 Nafilyan, Krishnan Bhaskaran, Elizabeth Williamson, Thomas House, Lorenzo Pellis, Emily Herrett, Nileesa Gautam, Helen J Curtis, Christopher T Rentsch, Angel Y S Wong, Brian MacKenna, Amir Mehrkar, Seb Bacon, Ian J Douglas, Stephen J W Evans, Laurie Tomlinson, Ben Goldacre, Rosalind M Eggo; on behalf of the OpenSAFELY consortium, In the Results, \u201cFor South Asian people, as for Wave 1, multigenerational living was associated with severe COVID-19 but not COVID-19 death\u2009\u2026\u201d should have read \u201cFor South Asian people, as for Wave 1, multigenerational living was associated with severe COVID-19 but not non-COVID-19 death\u2009\u2026\u201d.The paper has been corrected."} +{"text": "In contrast, this was not observed for nAb responses. When measuring SARS-CoV-2 RNA transcripts in nasal swabs at recruitment, we saw no significant differences by sex or disease severity status. However, we have shown higher antibody levels associated with low nasal viral RNA indicating a role of antibody responses in controlling viral replication and shedding in the upper airway. In this study, we have shown discernible differences in the humoral immune responses between males and females and these differences associate with age as well as with resultant disease severity.The SARS-CoV-2 pandemic enables the analysis of immune responses induced against a novel coronavirus infecting immunologically na\u00efve individuals. This provides an opportunity for analysis of immune responses and associations with age, sex and disease severity. Here we measured an array of solid-phase binding antibody and viral neutralising Ab (nAb) responses in participants (n=337) of the ISARIC4C cohort and characterised their correlation with peak disease severity during acute infection and early convalescence. Overall, the responses in a Double Antigen Binding Assay (DABA) for antibody to the receptor binding domain (anti-RBD) correlated well with IgM as well as IgG responses against viral spike, S1 and nucleocapsid protein (NP) antigens. DABA reactivity also correlated with nAb. As we and others reported previously, there is greater risk of severe disease and death in older men, whilst the sex ratio was found to be equal within each severity grouping in younger people. In older males with severe disease (mean age 68 years), peak antibody levels were found to be delayed by one to two weeks compared with women, and nAb responses were delayed further. Additionally, we demonstrated that solid-phase binding antibody responses reached higher levels in males as measured The mosDisease outcome may also be determined by the timing and magnitude of humoral immune responses \u201319. GeneUsing serum samples from patients hospitalised during the first wave of the COVID-19 pandemic in the United Kingdom (UK), we have performed an extensive analysis of the serological responses generated to SARS-CoV-2 in an immune-na\u00efve population. Anti-RBD reactivity, neutralising function and class specific antibodies to S and N proteins were measured using a hybrid double antigen binding assay (DABA) , a pseud22.1This analysis included sera from 337 patients admitted to UK hospitals with COVID-19 between February and June 2020 before vaccines were made available and therefore describing a new infection in a na\u00efve human population. The patients were enrolled in the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study. Study participants were confirmed SARS-CoV-2 positive by reverse transcription polymerase chain (PCR) reaction or were highly suspected cases based on clinical presentation and providing a serological response in one or more of the described assays being recorded. Acute infection samples were collected within 21 days of the onset of symptoms and convalescent samples were collected when SARS-CoV-2 PCR showed undetectable viral burden. A number of patients underwent serial sampling , with not all follow up specimens tested in every assay implemented. Samples with repeated measures were included in a mixed effect regression model to analyse the antibody responses over time (section 3.5).Patients were stratified into five categories of peak illness severity based on the World Health Organization (WHO) COVID-19 ordinal scale : 1) no o2.2Escherichia coli with N-terminal hexahistidine-SUMO and C-terminal Twin Strep tags and purified by tandem immobilised metal and StrepTactin\u00ae affinity chromatography. The IgM and IgG capture ELISAs for the detection of antibody to S1, Spike and NP were undertaken as described previously lineage were tested. The SARS-CoV-2 full length spike glycoprotein and the nucleoprotein (NP) conjugated to Horseradish peroxidase (HRP) were purchased from The Native Antigen Company . The SARS-CoV-2 S1 antigen , 42 was eviously .2.3SARS-CoV-2 RNA was quantified using a NEB Luna Universal Probe One-Step RT-qPCR Kit and 2019-nCoV CDC N1 primers and probes ). Genome copy numbers were quantified using a standard curve generated from serial dilutions of a plasmid containing the target N protein gene fragment. The standard was quantified and quality controlled using QX600 droplet digital PCR system .2.4Antibodies targeting SARS-CoV-2 were measured using a hybrid double antigen bridging assay (DABA) that was previously developed to detect Ebola virus (EBOV) glycoprotein targeting antibodies and rece2.52.5.1\u00ae CRL-3216\u2122) cells were cultivated in Dulbecco\u2019s modified eagle medium (Invitrogen) and supplemented with 10% heat-treated FCS (Sigma), 2mM/ml L-glutamine (Invitrogen), 100 U/ml penicillin (Invitrogen) and 100 mg/ml streptomycin (Invitrogen), termed complete DMEM (Thermofisher). HEK293T/ACE-2 cells were used to monitor PVP infectivity and in performing serum neutralisation assays. All cells were cultured at 37\u00b0C and at 5% CO2.HEK293T (Corning) were grown in 2.0\u00a0ml of complete DMEM overnight. Cells were transfected with 750 ng of the lentiviral luciferase reporter construct, pCSFLW, along with 450 ng of the SARS-CoV-2 S expression plasmid and 500 ng of the lentiviral backbone, p8.91, using cationic polymer transfection reagent (Polyethylenimine) (Polysciences) and in the presence of OptiMEM (Invitrogen). OptiMEM/plasmid mix was removed 16\u00a0h post transfection and 2.0\u00a0ml complete DMEM added with the single-cycle infectious SARS-CoV-2 stock harvested 48\u00a0h later, passed through a 0.45\u00b5M filter, aliquoted and stored at \u221280\u00b0C. PVP infection was monitored on HEK293T/ACE-2 cells through measuring luciferase activity (expressed from the HIV-1 LTR promoter) under control of Tat expression from the HIV-1 backbone. 100 \u00b5l of virus stock was used to infect 1.5x104 cells/well for 6\u00a0h in a white 96 well plate (Corning). Following infection 100 \u00b5l DMEM complete medium was added to each well. 48\u00a0h post infection, media was discarded from the wells and the cells washed with PBS (Thermofisher), lysed with 30 \u00b5l cell lysis buffer (Promega) and luciferase activity determined utilising the commercially available luciferase assay (Promega) and measured using a BMGLabtech FluoroStar Omega luminometer.The ancestral SARS-CoV-2 S glycoprotein (Accession MN908947) was cloned into the pCDNA3.1 expression plasmid (produced by GeneArt Gene Synthesis) and was used in generating PVP stocks escribed , 46. HEK2.5.350, IC70 or IC90, respectively).SARS-CoV-2 enveloped PVP was thawed and pooled and subsequently diluted 1/20 in complete DMEM. Serum samples from SARS-CoV-2 individuals were serially diluted 2-fold with complete DMEM; 28 \u00b5l serum dilution was incubated with 420 \u00b5l diluted SARS-CoV-2 PVP for 30\u00a0min at RT. 200 \u00b5l of virus/serum dilution mix was used to infect HEK293T/ACE-2 cells. Luciferase activity readings of neutralised virus were analysed i) by considering 0% inhibition as the infection values of the virus in the absence of convalescent plasma included in each experiment, ii) by considering 0% inhibition as the infection values of two consecutive high dilutions not inhibiting virus entry. The neutralisation activity defined as the serum dilution that reduced viral infectivity by 50%, 70% or 90% and non-parametric ANOVA . Significant P values < 0.05 were depicted by * or a horizontal line above the groups compared. Repeated measures linear regression was used to model antibody levels over time, including a random intercept term to account for within-individual correlation, age and a time-sex interaction to predict trajectories for males and females separately, adjusted for age.33.1We analysed the patient demograhics of individuals within our cohort, specifically age and sex, to determine the risk of severe disease across these groups. A higher proportion of the 337 study participants were male . Median age was 57 years (range: 15\u201394) with no age difference observed between sexes . As this was a hospital study, no asymptomatic individuals were enrolled. Participants were grouped into categories S1-S5 according to disease severity . The ratWe next anlysed the time between the onset of symptoms and hospital presentation to compare the rate of deteriation across different patient groupings. No difference was found between males and females in the time between symptom onset and hospital presentation , measured using the PVP neutralisation assay, revealed a similar serological profile to anti-RBD with a sharp initial increase reaching the peak at around day 26 post symptom onset (70) a correlation was observed during the first 21-day period . This correlation remained but was lower in magnitude after 21 days following disease onset high antibody levels were measured within one week following onset of symptoms and were maintained at high levels for 3 to 4 weeks (70) than those aged 20-49 or those >70 years old. or nAb responses . The S1 region of spike that includes the RBD was was also studied individually considering it is the primary target of nuetralising antibodies. In samples taken at recruitment, which represents a range of days between patients since the onset of symptoms and hospital presentation, IgM and IgG antibody binding responses to spike, S1 and NP were not significantly different between males and females for most age groupings, except for the IgM responses to S1, which were higher in men aged 60-70 at recruitment no differences were found between males and females within age categories but differences were observed between the different age categories. Individuals in age categories 20-40 and >70 had lower antibody titres than those in the intermediate age categories.3.3We next analysed the relationship between the antibody classes IgM and IgG against different virus antigens, comparing acute infection with convalescence. During acute infection, IgG responses against Spike protein correlated with IgM antibody levels (P<0.0001), whereas this correlation disappeared during convalescence and both IgM and IgG to total spike and S1 (70) directed against the same antigens. We observed similar profiles during both acute infection and convalescence with disease severity responses over the same period , . There were no differences in viral RNA levels by sex , using several measurements of host responses and viral RNA, has enabled the identification of differences in antibody profiles in an immunologically na\u00efve population. Very early in the SARS-CoV-2 pandemic it was reported that a number of factors such as age, sex, co-morbidities, obesity and ethnicity were associated with the risk of severe disease \u20137. In ouMany other studies have measured antibody responses following acute infection with SARS-CoV-2 , 48\u201350. We sought to identify how the timing of antibody responses associates with disease severity. Our data supports previous findings that antibody seroconversion occurs 10-19 days post symptom onset , 49, 54 When comparing antibody responses between sexes, we observed a more rapid induction of antibody responses in females than was observed in male participants and have associated this with differences in disease severity. Therefore, it is possible that a contributing factor to sex-associated differences in disease severity is the timing of antibody responses, whereby a delay in antibody production may account for increased risk of severe disease outcome. This association between age, sex and disease outcome with antibody kinetics has been previously reported, where females demonstrated more rapid increases in protective IgG responses than males and thatThrough measuring upper respiratory tract viral RNA transcripts, indicative of localised viral shedding and therefore a surrogate measure for viral load, we observed an inverse correlation between nAb levels which may indicate a critical role of effective serological responses limiting viral replication and leading to clearance of the infection. Nevertheless, our samples were obtained a median of 2 weeks post symptom onset and therefore viral RNA has been predominantly measured during the decline phase of infection . AdditioIn this study, immunological linkages with disease outcome have been deciphered independently in a na\u00efve host population and with a homogenous viral strain. The analyses of patients early in the pandemic has been vital in enabling description of the associations we have identified. Subsequent multiple exposures to different types of vaccines, natural infections and the emergence of diverse viral variants makes unravelling further host genetic and immune factors associated with disease challenging, meaning that the data presented here are unique, and are unlikely to be obtained as the pandemic evolves.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This analysis included sera from 337 patients admitted to UK hospitals with COVID-19 between February and June 2020 and enrolled in the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) World Health Organization (WHO) Clinical Characterisation Protocol UK (CCP-UK) study. The patients/participants provided their written informed consent to participate in this study.Co-Investigator: Beatrice Alex, Petros Andrikopoulos, Benjamin Bach, Wendy S Barclay, Debby Bogaert, Meera Chand, Kanta Chechi, Graham S Cooke, Ana da Silva Filipe, Thushan de Silva, Annemarie B Docherty, Gon\u00e7alo dos Santos Correia, Marc-Emmanuel Dumas, Jake Dunning, Tom Fletcher, Christoper A Green, William Greenhalf, Julian L Griffin, Rishi K Gupta, Ewen M Harrison, Julian A Hiscox, Antonia Ying Wai Ho, Peter W Horby, Samreen Ijaz, Saye Khoo, Paul Klenerman, Andrew Law, Matthew R Lewis, Sonia Liggi, Wei Shen Lim, Lynn Maslen, Alexander J Mentzer, Laura Merson, Alison M Meynert, Shona C Moore, Mahdad Noursadeghi, Michael Olanipekun, Anthonia Osagie, Massimo Palmarini, Carlo Palmieri, William A Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L Robertson, Clark D Russell, Vanessa Sancho-Shimizu, Caroline J Sands, Janet T Scott, Louise Sigfrid, Tom Solomon, Shiranee Sriskandan, David Stuart, Charlotte Summers, Olivia V Swann, Zoltan Takats, Panteleimon Takis, Richard S Tedder, AA Roger Thompson, Emma C Thomson, Ryan S Thwaites, Lance CW Turtle, Maria Zambon; Project Manager: Hayley Hardwick, Chloe Donohue, Fiona Griffiths, Wilna Oosthuyzen; Project Administrator: Cara Donegan, Rebecca G. Spencer; Data Analyst: Lisa Norman, Riinu Pius, Thomas M Drake, Cameron J Fairfield, Stephen R Knight, Kenneth A Mclean, Derek Murphy, Catherine A Shaw; Data and Information System Manager: Jo Dalton, Michelle Girvan, Egle Saviciute, Stephanie Roberts, Janet Harrison, Laura Marsh, Marie Connor, Sophie Halpin, Clare Jackson, Carrol Gamble, Daniel Plotkin, James Lee; Data Integration and Presentation: Gary Leeming, Andrew Law, Murray Wham, Sara Clohisey, Ross Hendry, James Scott-Brown; Material Management: Victoria Shaw, Sarah E McDonald. Patient Engagement: Se\u00e1n Keating; Outbreak Laboratory Staff and Volunteers: Katie A. Ahmed, Jane A Armstrong, Milton Ashworth, Innocent G Asiimwe, Siddharth Bakshi, Samantha L Barlow, Laura Booth, Benjamin Brennan, Katie Bullock, Benjamin WA Catterall, Jordan J Clark, Emily A Clarke, Sarah Cole, Louise Cooper, Helen Cox, Christopher Davis, Oslem Dincarslan, Chris Dunn, Philip Dyer, Angela Elliott, Anthony Evans, Lorna Finch, Lewis WS Fisher, Terry Foster, Isabel Garcia-Dorival, Philip Gunning, Catherine Hartley, Rebecca L Jensen, Christopher B Jones, Trevor R Jones, Shadia Khandaker, Katharine King, Robyn T. Kiy, Chrysa Koukorava, Annette Lake, Suzannah Lant, Diane Latawiec, Lara Lavelle-Langham, Daniella Lefteri, Lauren Lett, Lucia A Livoti, Maria Mancini, Sarah McDonald, Laurence McEvoy, John McLauchlan, Soeren Metelmann, Nahida S Miah, Joanna Middleton, Joyce Mitchell, Shona C Moore, Ellen G Murphy, Rebekah Penrice-Randal, Jack Pilgrim, Tessa Prince, Will Reynolds, P. Matthew Ridley, Debby Sales, Victoria E Shaw, Rebecca K Shears, Benjamin Small, Krishanthi S Subramaniam, Agnieska Szemiel, Aislynn Taggart, Jolanta Tanianis-Hughes, Jordan Thomas, Erwan Trochu, Libby van Tonder, Eve Wilcock, J. Eunice Zhang, Lisa Flaherty, Nicole Maziere, Emily Cass, Alejandra Doce Carracedo, Nicola Carlucci, Anthony Holmes, Hannah Massey; Edinburgh Laboratory Staff and Volunteers: Lee Murphy, Sarah McCafferty, Richard Clark, Angie Fawkes, Kirstie Morrice, Alan Maclean, Nicola Wrobel, Lorna Donnelly, Audrey Coutts, Katarzyna Hafezi, Louise MacGillivray, Tammy Gilchrist; Local Principal Investigators: Kayode Adeniji, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Erin L. Aldera, Ana Alegria, Sam Allen, Brian Angus, Abdul Ashish, Dougal Atkinson, Shahedal Bari, Gavin Barlow, Stella Barnass, Nicholas Barrett, Christopher Bassford, Sneha Basude, David Baxter, Michael Beadsworth, Jolanta Bernatoniene, John Berridge, Colin Berry, Nicola Best, Pieter Bothma, David Chadwick, Robin Brittain-Long, Naomi Bulteel, Tom Burden, Andrew Burtenshaw, Vikki Caruth, David Chadwick, Duncan Chambler, Nigel Chee, Jenny Child, Srikanth Chukkambotla, Tom Clark, Paul Collini, Catherine Cosgrove, Jason Cupitt, Maria-Teresa Cutino-Moguel, Paul Dark, Chris Dawson, Samir Dervisevic, Phil Donnison, Sam Douthwaite, Andrew Drummond, Ingrid DuRand, Ahilanadan Dushianthan, Tristan Dyer, Cariad Evans, Chi Eziefula, Chrisopher Fegan, Adam Finn, Duncan Fullerton, Sanjeev Garg, Sanjeev Garg, Atul Garg, Effrossyni Gkrania-Klotsas, Jo Godden, Arthur Goldsmith, Clive Graham, Elaine Hardy, Stuart Hartshorn, Daniel Harvey, Peter Havalda, Daniel B Hawcutt, Maria Hobrok, Luke Hodgson, Anil Hormis, Michael Jacobs, Susan Jain, Paul Jennings, Agilan Kaliappan, Vidya Kasipandian, Stephen Kegg, Michael Kelsey, Jason Kendall, Caroline Kerrison, Ian Kerslake, Oliver Koch, Gouri Koduri, George Koshy, Shondipon Laha, Steven Laird, Susan Larkin, Tamas Leiner, Patrick Lillie, James Limb, Vanessa Linnett, Jeff Little, Mark Lyttle, Michael MacMahon, Emily MacNaughton, Ravish Mankregod, Huw Masson, Elijah Matovu, Katherine McCullough, Ruth McEwen, Manjula Meda, Gary Mills, Jane Minton, Mariyam Mirfenderesky, Kavya Mohandas, Quen Mok, James Moon, Elinoor Moore, Patrick Morgan, Craig Morris, Katherine Mortimore, Samuel Moses, Mbiye Mpenge, Rohinton Mulla, Michael Murphy, Megan Nagel, Thapas Nagarajan, Mark Nelson, Lillian Norris, Matthew K. O\u2019Shea, Igor Otahal, Marlies Ostermann, Mark Pais, Carlo Palmieri, Selva Panchatsharam, Danai Papakonstantinou, Hassan Paraiso, Brij Patel, Natalie Pattison, Justin Pepperell, Mark Peters, Mandeep Phull, Stefania Pintus, Jagtur Singh Pooni, Tim Planche, Frank Post, David Price, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Tim Reynolds, Neil Richardson, Mark Roberts, Devender Roberts, Alistair Rose, Guy Rousseau, Bobby Ruge, Brendan Ryan, Taranprit Saluja, Matthias L Schmid, Aarti Shah, Prad Shanmuga, Anil Sharma, Anna Shawcross, Jeremy Sizer, Manu Shankar-Hari, Richard Smith, Catherine Snelson, Nick Spittle, Nikki Staines, Tom Stambach, Richard Stewart, Pradeep Subudhi, Tamas Szakmany, Kate Tatham, Jo Thomas, Chris Thompson, Robert Thompson, Ascanio Tridente, Darell Tupper-Carey, Mary Twagira, Nick Vallotton, Rama Vancheeswaran, Lisa Vincent-Smith, Shico Visuvanathan, Alan Vuylsteke, Sam Waddy, Rachel Wake, Andrew Walden, Ingeborg Welters, Tony Whitehouse, Paul Whittaker, Ashley Whittington, Padmasayee Papineni, Meme Wijesinghe, Martin Williams, Lawrence Wilson, Sarah Cole, Stephen Winchester, Martin Wiselka, Adam Wolverson, Daniel G Wootton, Andrew Workman, Bryan Yates, Peter Young.Consortium Lead Investigator: J Kenneth Baillie; Chief Investigator: Malcolm G Semple; Co-Lead Investigator: Peter JM Openshaw; ISARIC Clinical Coordinator: Gail Carson EP, JT, KJR, SI, FM, KK, CD, EV, SD, KJ, and NJC performed experiments. EP, JT, KJR, SI, TE, LL, EV, SCM, SD, WP and GP analyzed laboratory and clinical data. NC, JH and PC designed, produced and donated key reagents. LL, CJ, HH, EV, SEM and SCM administered patient specimens and curated clinical data. MS, JB and PO designed and delivered the ISARIC4C consortium project. The study was designed by SI, MM, JB, PO, MS, WP, RT, and GP. The manuscript was written by EP, JT, KJR, SI, TE, LT, AH, MS, WP, RT. and GP. All authors contributed to the article and approved the submitted version."} +{"text": "Recently, an increasing number of tau tracers have become available. There is a need to standardize quantitative tau measures across tracers, supporting a universal scale. We developed several cortical tau masks and applied them to generate a tau imaging universal scale.18F\u2010flortaucipir, 18F\u2010MK6240, 18F\u2010PI2620, 18F\u2010PM\u2010PBB3, 18F\u2010GTP1, or 18F\u2010RO948. The universal mask was generated from cognitively unimpaired amyloid beta (A\u03b2)\u2212 subjects and Alzheimer's disease (AD) patients with A\u03b2+. Four additional regional cortical masks were defined within the constraints of the universal mask. A universal scale, the CenTauRz, was constructed.One thousand forty\u2010five participants underwent tau scans with either z allows robust discrimination between low and high levels of tau deposits.None of the regions known to display off\u2010target signal were included in the masks. The CenTauRhttps://www.gaain.org/centaur\u2010project.We constructed several tau\u2010specific cortical masks for the AD continuum and a universal standard scale designed to capture the location and degree of abnormality that can be applied across tracers and across centers. The masks are freely available at Prior to this development, the presence and extent of aggregated tau in the brain could only be characterized using In addition to the idiosyncratic characteristics of tau aggregates, and their asymmetric and heterogeneous brain distribution, a major obstacle to the widespread implementation of tau imaging in therapeutic trials or comparing the findings of investigational imaging studies across cohorts and institutions is that tau tracers differ in their molecular structures and display a range of tau binding affinities, in vivo kinetics, and degree of non\u2010specific binding, as well as distinct regional patterns of \u201coff\u2010target\u201d and non\u2010specific binding. Such differences lead to disparities in PET\u2010derived standardized uptake value ratio (SUVR) measurements between tracers, as highlighted by several head\u2010to\u2010head studies comparing different tau tracers.11C\u2010Pittsburgh compound B, the idiosyncratic binding properties of these A\u03b2 tracers remain unaccounted for so they might be more or less sensitive or accurate for making a statement about a similar index of cerebral A\u03b2 burden. Furthermore, while the pattern of A\u03b2 deposition throughout the brain is relatively uniform across subjects, and thus a single universal target mask provides reproducible statements of A\u03b2 in the brain, the deposition of tau, especially at the early stages, tends to be more heterogeneous,In response to similar challenges faced earlier with A\u03b2 PET,18F\u2010flortaucipir, 18F\u2010MK6240, 18F\u2010PI2620, 18F\u2010PM\u2010PBB3, 18F\u2010RO948, and 18F\u2010GTP1) and an approach similar to the one used in the Centiloid project.In the present study, we aimed to standardize tau PET results by establishing the location and amount of abnormality of tau aggregates in the brain, and expressing them in a universal standard scale, the unit of which are termed \u201cCenTauR\u201d\u2014using tau PET data from the six most commonly used tracers , academic institutions , as well as industry . All participants underwent a tau PET scan and a structural magnetic resonance imaging , and Statistical Parametric Mapping using the standard pipeline for the Centiloid method (CL\u2010SPM) described in Klunk et\u00a0al.Tau scans were spatially normalized using principal component analysis (PCA) based on Computational Analysis of PET by AIBL (CapAIBL),Systematic review: The authors reviewed the literature using traditional sources and meeting abstracts and presentations. While the use of tau positron emission tomography (PET) imaging rapidly increased in research and in clinical trials over the past few years, there is no standardization pipeline for the quantification of tau imaging across tau tracers and quantification software.Interpretation: We built a global and several regional universal masks for the sampling of tau PET scans based on the most commonly used tau PET tracers. We then derived a universal scale across tracers, the CenTauRz, to measure the tau signal.Future directions: Standardized quantification will facilitate the derivation of universal cut\u2010off values, merging of large cohorts, and comparison of longitudinal changes across tracers and cohorts both in clinical studies and therapeutic trials.z scores in each of the five ROIs, similar to what was previously proposed by Vemuri et\u00a0al.For each tracer and normalization approach , we averaged all CU A\u03b2\u2212 and AD A\u03b2+ scans separately, generating mean CU A\u03b2\u2212 and AD A\u03b2+ images. We then subtracted the CU A\u03b2\u2212 mean image from the AD A\u03b2+ mean image to generate a difference image. After exploring several thresholds, the resultant difference\u2010image was thresholded at one third of the difference in the inferior temporal lobe. This threshold produced large and consistent volumes of interest across tracers of areas of the brain with the greatest tau load. We then constructed a \u201cuniversal\u201d tau mask from the intersection of the six tracer\u2010specific masks. An MRI\u2010derived gray matter mask obtained from the FreeSurfer segmentation of 100 MRIs (independent dataset) at PET resolution was then applied to the universal mask to only sample cortical regions. The resulting mask was then mirrored and fused to remove the hemispherical asymmetry of tau pathology. Last, an additional four subregions were defined within the constraints of the universal mask: Mesial Temporal, Meta Temporal, Temporo\u2010Parietal, and Frontal ROIs , blind to participant characteristics, resulting in consensus visual reads, as previously described.Seventy\u2010eight 318F\u2010GTP1 and 18F\u2010PM\u2010PBB3 cohorts were significantly younger compared to participants from the other cohorts. Compared to the MCI and AD dementia groups, CU A\u03b2+ participants were significantly older and had fewer males . No significant differences in age, sex, Mini\u2010Mental State Examination or Clinical Dementia Rating were found between the AD A\u03b2+ patients from the different cohorts .Participant characteristics by tau PET tracer are summarized in Table 3.118F\u2010RO948, one 18F\u2010GTP1, five 18F\u2010PI2620, one 18F\u2010FTP, eight 18F\u2010PM\u2010PBB3) did not pass visual QC using the CL\u2010SPM pipeline or did not have an MRI of sufficient quality while only one scan did not pass visual QC using both CapAIBL and CL\u2010SPM. A further six CU A\u03b2\u2013 were visually excluded due to the presence of tracer uptake in the MTL. These 29 scans were excluded from further analysis.Twenty\u2010three scans for each of the six tau tracers included in the study. Figure\u00a0z for CU A\u03b2\u2212 and AD A\u03b2+ individuals. CTRz for the other four ROIs are presented in Figure z are displayed in Figure z in the Meta Temporal ROI, all tracers showed high discriminative accuracy for the separation of AD A\u03b2+ from CU A\u03b2\u2212 individuals with mean CTRz scores for the six different AD cohorts ranging from 8.1 to 22 . CU A\u03b2+ had significantly higher CTRz compared to CU A\u03b2\u2212 and MCI A\u03b2\u2212 in all regions with the strongest effect size in the Mesial Temporal ROI (Welch's T > 6) and the lowest in the Frontal ROI (Welch's T \u2248 3). Among the CU A\u03b2+, 36% had a CTRz higher than 2 in the Mesial Temporal, 29% in the Meta Temporal, 21% in the Temporo\u2010Parietal, 12% in the Frontal, and 23% in the universal mask, while these prevalences were, respectively, 77%, 63%, 58%, 41%, 60% for the MCI A\u03b2+ group, and 91%, 90%, 87%, 73%, and 88% for the AD A\u03b2+ and around 4% and 2.5% in all regions for the MCI A\u03b2\u2212 and CU A\u03b2\u2212, respectively.Figure\u00a03.3z scores are presented in Table 18F\u2010PM\u2010PBB3, due to the slightly higher standard deviation of the CapAIBL SUVRs in the CU A\u03b2\u2212 group. The correlation between CTRz scores from CL\u2010SPM and CapAIBL was 0.99 in the Meta Temporal ROI; 0.98 in the Mesial, Temporo\u2010Parietal, and universal ROIs; and 0.89 in the Frontal ROI , with mean CTRz for the different AD cohorts ranging from 7.6 to 20.6 ; applying a threshold of 2 CTRz in the Mesial Temporal and in the Meta Temporal together slightly increased the accuracy of detecting tau negative scans . Using CTRz > 2 in Mesial Temporal ROI and <2 in the Meta Temporal ROI, yielded an accuracy of 0.92 to detect limbic\u2010predominant individuals. Using CapAIBL the specificities and accuracies were slightly improved generated consistent results in quantifying tau scans in all ROIs, with high discriminative power in distinguishing AD A\u03b2+ from CU A\u03b2\u2212 and tau negative scans from limbic predominant, hippocampal sparing, and typical AD tau scans when using a threshold of > 2 CTRz in different ROIs.In the present work we described the CenTauRz level is considered high tau.18F\u2010FTP,z accuracy.An important aspect, both for clinical interpretation and for therapeutic trials, is the selection of brain regions sampled to capture the distribution of tau, how this index of tau load changes over time, and what CTR18F\u2010MK6240 and 18F\u2010FTP comparing young adult controls with elderly controls show no significant differences in the tau signalz could be subtracted from the meta temporal CTRz; (3) similar to what was proposed with the Centiloid method, it allows to resample a CTRz parametric image, either with a different atlas template, using SPM or with a different image analysis pipeline or software, once all voxels are transformed into CTRz parametric images using one of the provided equations ; and , the Aging Mind Foundation (DAF2255207) and NIH (2P01AG025204\u201016) and is and has been a consultant or paid speaker at sponsored conference sessions for Eli Lilly, Life Molecular Imaging, ACE Barcelona, and IXICO. Sandra Sanabria Bohorquez and Robby Weimer are a full\u2010time employees and stock owners of Roche. Santiago Bullich and Andrew Stephen are full\u2010time employees of Life Molecular Imaging GmbH. Hitoshi Shimada and Makoto Higuchi hold patents on compounds related to the present report (JP 5422782/EP 12 884 742.3/CA2894994/HK1208672). Christopher C. Rowe has received research grants from NHMRC, Enigma Australia, Biogen, Eisai, and Abbvie. He is on the scientific advisory board for Cerveau Technologies and consulted for Prothena, Eisai, Roche, and Biogen Australia. Oskar Hansson has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Genentech, Merck, Novartis, Novo Nordisk, Roche, Sanofi, and Siemens. The other authors did not report any conflict of interest.All participants gave written consent for publication of de\u2010identified data.The following are the published list of collaborators associated with ADNI:Michael Weiner, MD ; Paul Aisen, MD ; Ronald Petersen, MD, PhD ; Clifford R. Jack, Jr., MD ; William Jagust, MD ; John Q. Trojanowki, MD, PhD ; Arthur W. Toga, PhD ; Laurel Beckett, PhD ; Robert C. Green, MD, MPH ; Andrew J. Saykin, PsyD ; John Morris, MD ; Leslie M. Shaw ; Enchi Liu, PhD ; Tom Montine, MD, PhD (University of Washington); Ronald G. Thomas, PhD (UC San Diego); Michael Donohue, PhD (UC San Diego); Sarah Walter, MSc (UC San Diego); Devon Gessert (UC San Diego); Tamie Sather, MS (UC San Diego); Gus Jiminez, MBS (UC San Diego); Danielle Harvey, PhD (UC Davis); Michael Donohue, PhD (UC San Diego); Matthew Bernstein, PhD ; Nick Fox, MD (University of London); Paul Thompson, PhD (USC School of Medicine); Norbert Schuff, PhD (UCSF MRI); Charles DeCArli, MD (UC Davis); Bret Borowski, RT (Mayo Clinic); Jeff Gunter, PhD (Mayo Clinic); Matt Senjem, MS (Mayo Clinic); Prashanthi Vemuri, PhD (Mayo Clinic); David Jones, MD (Mayo Clinic); Kejal Kantarci (Mayo Clinic); Chad Ward (Mayo Clinic); Robert A. Koeppe, PhD ; Norm Foster, MD (University of Utah); Eric M. Reiman, MD (Banner Alzheimer's Institute); Kewei Chen, PhD (Banner Alzheimer's Institute); Chet Mathis, MD (University of Pittsburgh); Susan Landau, PhD (UC Berkeley); Nigel J. Cairns, PhD, MRCPath (Washington University St. Louis); Erin Householder (Washington University St. Louis); Lisa Taylor Reinwald, BA, HTL (Washington University St. Louis); Virginia Lee, PhD, MBA (UPenn School of Medicine); Magdalena Korecka, PhD (UPenn School of Medicine); Michal Figurski, PhD (UPenn School of Medicine); Karen Crawford (USC); Scott Neu, PhD (USC); Tatiana M. Foroud, PhD (Indiana University); Steven Potkin, MD UC (UC Irvine); Li Shen, PhD (Indiana University); Faber Kelley, MS, CCRC (Indiana University); Sungeun Kim, PhD (Indiana University); Kwangsik Nho, PhD (Indiana University); Zaven Kachaturian, PhD ; Richard Frank, MD, PhD ; Peter J. Snyder, PhD (Brown University); Susan Molchan, PhD ; Jeffrey Kaye, MD ; Joseph Quinn, MD ; Betty Lind, BS ; Raina Carter, BA ; Sara Dolen, BS ; Lon S. Schneider, MD ; Sonia Pawluczyk, MD ; Mauricio Beccera, BS ; Liberty Teodoro, RN ; Bryan M. Spann, DO, PhD ; James Brewer, MD, PhD ; Helen Vanderswag, RN ; Adam Fleisher, MD ; Judith L. Heidebrink, MD, MS (University of Michigan); Joanne L. Lord, LPN, BA, CCRC (University of Michigan); Ronald Petersen, MD, PhD ; Sara S. Mason, RN ; Colleen S. Albers, RN ; David Knopman, MD ; Kris Johnson, RN ; Rachelle S. Doody, MD, PhD (Baylor College of Medicine); Javier Villanueva Meyer, MD (Baylor College of Medicine); Munir Chowdhury, MBBS, MS (Baylor College of Medicine); Susan Rountree, MD (Baylor College of Medicine); Mimi Dang, MD (Baylor College of Medicine); Yaakov Stern, PhD ; Lawrence S. Honig, MD, PhD ; Karen L. Bell, MD ; Beau Ances, MD ; John C. Morris, MD ; Maria Carroll, RN, MSN ; Sue Leon, RN, MSN ; Erin Householder, MS, CCRP ; Mark A. Mintun, MD ; Stacy Schneider, APRN, BC, GNP ; Angela Oliver, RN, BSN, MSG ; Daniel Marson, JD, PhD (University of Alabama Birmingham); Randall Griffith, PhD, ABPP (University of Alabama Birmingham); David Clark, MD (University of Alabama Birmingham); David Geldmacher, MD (University of Alabama Birmingham); John Brockington, MD (University of Alabama Birmingham); Erik Roberson, MD (University of Alabama Birmingham); Hillel Grossman, MD (Mount Sinai School of Medicine); Effie Mitsis, PhD (Mount Sinai School of Medicine); Leyla deToledo\u2010Morrell, PhD ; Raj C. Shah, MD ; Ranjan Duara, MD (Wien Center); Daniel Varon, MD (Wien Center); Maria T. Greig, HP (Wien Center); Peggy Roberts, CNA (Wien Center); Marilyn Albert, PhD (Johns Hopkins University); Chiadi Onyike, MD (Johns Hopkins University); Daniel D'Agostino II, BS (Johns Hopkins University); Stephanie Kielb, BS (Johns Hopkins University); James E. Galvin, MD, MPH (New York University); Dana M. Pogorelec (New York University); Brittany Cerbone (New York University); Christina A. Michel (New York University); Henry Rusinek, PhD (New York University); Mony J. de Leon, EdD (New York University); Lidia Glodzik, MD, PhD (New York University); Susan De Santi, PhD (New York University); P. Murali Doraiswamy, MD ; Jeffrey R. Petrella, MD ; Terence Z. Wong, MD ; Steven E. Arnold, MD (University of Pennsylvania); Jason H. Karlawish, MD (University of Pennsylvania); David Wolk, MD (University of Pennsylvania); Charles D. Smith, MD (University of Kentucky); Greg Jicha, MD (University of Kentucky); Peter Hardy, PhD (University of Kentucky); Partha Sinha, PhD (University of Kentucky); Elizabeth Oates, MD (University of Kentucky); Gary Conrad, MD (University of Kentucky); Oscar L. Lopez, MD (University of Pittsburgh); MaryAnn Oakley, MA (University of Pittsburgh); Donna M. Simpson, CRNP, MPH (University of Pittsburgh); Anton P. Porsteinsson, MD ; Bonnie S. Goldstein, MS, NP ; Kim Martin, RN ; Kelly M. Makino, BS ; M. Saleem Ismail, MD ; Connie Brand, RN ; Ruth A. Mulnard, DNSc, RN, FAAN ; Gaby Thai, MD ; Catherine Mc Adams Ortiz, MSN, RN, A/GNP ; Kyle Womack, MD ; Dana Mathews, MD, PhD ; Mary Quiceno, MD ; Ramon Diaz Arrastia, MD, PhD ; Richard King, MD ; Myron Weiner, MD ; Kristen Martin Cook, MA ; Michael DeVous, PhD ; Allan I. Levey, MD, PhD (Emory University); James J. Lah, MD, PhD (Emory University); Janet S. Cellar, DNP, PMHCNS BC (Emory University); Jeffrey M. Burns, MD ; Heather S. Anderson, MD ; Russell H. Swerdlow, MD ; Liana Apostolova, MD ; Kathleen Tingus, PhD ; Ellen Woo, PhD ; Daniel H.S. Silverman, MD, PhD ; Po H. Lu, PsyD ; George Bartzokis, MD ; Neill R. Graff Radford, MBBCH, FRCP (London) ; Francine Parfitt, MSH, CCRC ; Tracy Kendall, BA, CCRP ; Heather Johnson, MLS, CCRP ; Martin R. Farlow, MD (Indiana University); Ann Marie Hake, MD (Indiana University); Brandy R. Matthews, MD (Indiana University); Scott Herring, RN, CCRC (Indiana University); Cynthia Hunt, BS, CCRP (Indiana University); Christopher H. van Dyck, MD ; Richard E. Carson, PhD ; Martha G. MacAvoy, PhD ; Howard Chertkow, MD ; Howard Bergman, MD ; Chris Hosein, Med ; Sandra Black, MD, FRCPC ; Dr Bojana Stefanovic ; Curtis Caldwell, PhD ; Ging Yuek Robin Hsiung, MD, MHSc, FRCPC (U.B.C. Clinic for AD & Related Disorders); Howard Feldman, MD, FRCPC (U.B.C. Clinic for AD & Related Disorders); Benita Mudge, BS (U.B.C. Clinic for AD & Related Disorders); Michele Assaly, MA Past (U.B.C. Clinic for AD & Related Disorders); Andrew Kertesz, MD ; John Rogers, MD ; Dick Trost, PhD ; Charles Bernick, MD ; Donna Munic, PhD ; Diana Kerwin, MD (Northwestern University); Marek Marsel Mesulam, MD (Northwestern University); Kristine Lipowski, BA (Northwestern University); Chuang Kuo Wu, MD, PhD (Northwestern University); Nancy Johnson, PhD (Northwestern University); Carl Sadowsky, MD ; Walter Martinez, MD ; Teresa Villena, MD ; Raymond Scott Turner, MD, PhD ; Kathleen Johnson, NP ; Brigid Reynolds, NP ; Reisa A. Sperling, MD ; Keith A. Johnson, MD ; Gad Marshall, MD ; Meghan Frey ; Jerome Yesavage, MD (Stanford University); Joy L. Taylor, PhD (Stanford University); Barton Lane, MD (Stanford University); Allyson Rosen, PhD (Stanford University); Jared Tinklenberg, MD (Stanford University); Marwan N. Sabbagh, MD ; Christine M. Belden, PsyD ; Sandra A. Jacobson, MD ; Sherye A. Sirrel, MS ; Neil Kowall, MD (Boston University); Ronald Killiany, PhD (Boston University); Andrew E. Budson, MD (Boston University); Alexander Norbash, MD (Boston University); Patricia Lynn Johnson, BA (Boston University); Thomas O. Obisesan, MD, MPH (Howard University); Saba Wolday, MSc (Howard University); Joanne Allard, PhD (Howard University); Alan Lerner, MD (Case Western Reserve University); Paula Ogrocki, PhD (Case Western Reserve University); Leon Hudson, MPH (Case Western Reserve University); Evan Fletcher, PhD ; Owen Carmichael, PhD ; John Olichney, MD ; Charles DeCarli, MD ; Smita Kittur, MD ; Michael Borrie, MB ChB ; T. Y. Lee, PhD ; Dr Rob Bartha, PhD ; Sterling Johnson, PhD (University of Wisconsin); Sanjay Asthana, MD (University of Wisconsin); Cynthia M. Carlsson, MD (University of Wisconsin); Steven G. Potkin, MD ; Adrian Preda, MD ; Dana Nguyen, PhD ; Pierre Tariot, MD (Banner Alzheimer's Institute); Adam Fleisher, MD (Banner Alzheimer's Institute); Stephanie Reeder, BA (Banner Alzheimer's Institute); Vernice Bates, MD (Dent Neurologic Institute); Horacio Capote, MD (Dent Neurologic Institute); Michelle Rainka, PharmD, CCRP (Dent Neurologic Institute); Douglas W. Scharre, MD (Ohio State University); Maria Kataki, MD, PhD (Ohio State University); Anahita Adeli, MD (Ohio State University); Earl A. Zimmerman, MD ; Dzintra Celmins, MD ; Alice D. Brown, FNP ; Godfrey D. Pearlson, MD ; Karen Blank, MD ; Karen Anderson, RN ; Robert B. Santulli, MD ; Tamar J. Kitzmiller ; Eben S. Schwartz, PhD ; Kaycee M. Sink, MD, MAS ; Jeff D. Williamson, MD, MHS ; Pradeep Garg, PhD ; Franklin Watkins, MD ; Brian R. Ott, MD ; Henry Querfurth, MD ; Geoffrey Tremont, PhD ; Stephen Salloway, MD, MS ; Paul Malloy, PhD ; Stephen Correia, PhD ; Howard J. Rosen, MD (UC San Francisco); Bruce L. Miller, MD (UC San Francisco); Jacobo Mintzer, MD, MBA ; Kenneth Spicer, MD, PhD ; David Bachman, MD ; Elizabeth Finger, MD ; Stephen Pasternak, MD ; Irina Rachinsky, MD ; John Rogers, MD ; Andrew Kertesz, MD ; Dick Drost, MD ; Nunzio Pomara, MD (Nathan Kline Institute); Raymundo Hernando, MD (Nathan Kline Institute); Antero Sarrael, MD (Nathan Kline Institute); Susan K. Schultz, MD ; Laura L. Boles Ponto, PhD ; Hyungsub Shim, MD ; Karen Elizabeth Smith, RN ; Norman Relkin, MD, PhD (Cornell University); Gloria Chaing, MD (Cornell University); Lisa Raudin, PhD (Cornell University); Amanda Smith, MD ; Kristin Fargher, MD ; Balebail Ashok Raj, MD AIBL's large, multidisciplinary research team includes the following active members.Arti Appannah, Mary Barnes, Kevin Barnham, Justin Bedo, Shayne Bellingham, Lynette Bon, Pierrick Bourgeat, Belinda Brown, Rachel Buckley, Samantha Burnham, Ashley Bush, Graeme Chandler, Karren Chen, Roger Clarnette, Steven Collins, Ian Cooke, Tiffany Cowie, Kay Cox, Emily Cuningham, Elizabeth Cyarto, Phuong Anh Vu Dang, David Darby, Patricia Desmond, James Doecke, Vincent Dore, Harriet Downing, Belinda Dridan, Konsta Duesing, Michael Fahey, Maree Farrow, Noel Faux, Michael Fenech, Shane Fernandez, Binosha Fernando, Chris Fowler, Maxime Francois, Jurgen Fripp, Shaun Frost, Samantha Gardener, Simon Gibson, Petra Graham, Veer Gupta, David Hansen, Karra Harrington, Andy Hill, Eugene Hone, Maryam Hor, Malcolm Horne, Brenda Huckstepp, Andrew Jones, Gareth Jones, Adrian Kamer, Yogi Kanagasingam, Lisa Keam, Adam Kowalczyk, Betty Krivdic, Chiou Peng Lam, Fiona Lamb, Nicola Lautenschlager, Simon Laws, Wayne Leifert, Nat Lenzo, Hugo Leroux, Falak Lftikhar, Qiao\u2010Xin Li, Florence Lim, Lucy Lim, Linda Lockett, Kathy Lucas, Mark Mano, Caroline Marczak, Georgia Martins, Paul Maruff, Yumiko Matsumoto, Sabine Bird,Rachel McKay, Rachel Mulligan, Tabitha Nash, Julie Nigro, Graeme O'Keefe, Kevin Ong, Bernadette Parker, Steve Pedrini, Jeremiah Peiffer, Sveltana Pejoska, Lisa Penny, Keyla Perez, Kelly Pertile, Pramit Phal, Tenielle Porter, Stephanie Rainey\u2010Smith, Parnesh Raniga, Alan Rembach, Carolina Restrepo, Malcolm Riley, Blaine Roberts, Jo Robertson, Mark Rodrigues, Alicia Rooney, Rebecca Rumble, Tim Ryan, Mather Samuel, Ian Saunders, Greg Savage, Brendan Silbert, Hamid Sohrabi, Julie Syrette, Cassandra Szoeke, Kevin Taddei, Tania Taddei, Sherilyn Tan, Michelle Tegg, Philip Thomas, Darshan Trivedi, Brett Trounson, Robyn Veljanovski, Giuseppe Verdile, Victor Villemagne, Irene Volitakis, Cassandra Vockler, Michael Vovos, Freda Vrantsidis, Stacey Walker, Andrew Watt, Mike Weinborn, Bill Wilson, Michael Woodward, Olga Yastrubetskaya, Paul Yates, Ping Zhang.Supporting InformationClick here for additional data file.Supporting InformationClick here for additional data file."} +{"text": "Early detection and intervention are critical for improved outcomes in mental disorders, and this is particularly true for bipolar disorders. Understanding the risk factors involved in the onset of the disease and the subsequent relapses and recurrences may lead to better results as regards to functional outcomes, which are the most relevant for patients and their significant others. This presentation will review those factors and discuss which ones can be used as targets for early intervention. It has been argued that, most often, early intervention comes late, and it is therefore paramount to build on strategies aimed at effective detection of people at risk and situations that may lead to recurring episodes of illness. Treatments not only aimed at treating symptoms, but at improving illness trajectories are necessary, and pharmacological formulations and interventions improving treatment adherence are particularly relevant to avoid interruptions of effective therapies.E. Vieta Grant / Research support from: Boehringer-ingelheim, Compass, Janssen, Lundbeck, Novartis, Consultant of: AB-Biotics, AbbVie, Adamed, Angelini, Biogen, Boehringer-Ingelheim, Celon Pharma, Compass, Dainippon Sumitomo Pharma, Ethypharm, Ferrer, Gedeon Richter, GH Research, Glaxo-Smith Kline, Janssen, Lundbeck, Medincell, Merck, Novartis, Orion Corporation, Organon, Otsuka, Roche, Rovi, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris"} +{"text": "BJS Open, Volume 7, Issue 5, October 2023, zrad079,This is an erratum to: Anne G Lincoln, Sally C Benton, Carolyn Piggott, Shama Riaz Sheikh, Andrew D Beggs, Leah Buckley, Bianca DeSouza, James E East, Pete Sanders, Michael Lim, Donal Sheehan, Katie Snape, Helen Hanson, John R Greenaway, John Burn, David Nylander, Menna Hawkins, Fiona Lalloo, Kate Green, Thomas J Lee, Julie Walker, Gillian Matthews, Terry Rutherford, Peter Sasieni, Kevin J Monahan, Risk-stratified faecal immunochemical testing (FIT) for urgent colonoscopy in Lynch syndrome during the COVID-19 pandemic, In the originally published version of this manuscript, there were errors in section a of Figure\u00a03a/b.Figure\u00a03a should read:instead of:The errors have been emended in the article."} +{"text": "Pemphigoid gestationis (PG) is a rare blistering disorder that usually develops during the second and third trimesters of pregnancy, but can present at any stage, including postpartum.,Traditional treatment of PG includes topical and oral corticosteroids, antihistamines, and intravenous immunoglobulins.A 36-year-old woman with a prior history of PG was referred to our Dermatology clinic by her obstetrician for an itchy rash on her legs that had been present for 1 to 2\u00a0weeks . Her iniclinicaltrial.gov NCT04206553.,PG is a rare pruritic blistering disease that occurs surrounding pregnancy. Treatment primarily relies on oral corticosteroids, which can elicit many undesirable systemic symptoms.Dr Anadkat has served as a Consultant and/or Advisor for ImClone, Bristol Myers Squibb, Astra Zeneca, Therakos, Aspire Bariatrics, Biogen, Amgen, Veloce, Adgero, Eli Lilly, Abbvie, UCB Biopharma, Innovaderm, Boehringer-Ingelheim, OnQuality, Novocure, Springworks, BioLinq, and Protagonist. MJA has served as a Principal Investigator for Novartis, Boehringer-Ingelheim, Lutris, OnQuality, UCB Biopharma, InflamRx, Eli Lilly, InCyte, Abbvie, Moonlake, AnaptysBio, Hana Biosciences, Xoma, Veloce, Biogen, Xbiotech, and Chemocentryx. Author Chen and Dr Yokoyama have no conflicts of interest to declare."} +{"text": "Pretreatment predictors of finite nucleo(s)tide analogue (NUC) therapy remain elusive. We studied the association between pretreatment HBV DNA levels and outcomes after therapy cessation.Patients with chronic hepatitis B who were HBeAg negative at the start of NUC treatment were enrolled from sites in Asia and Europe. We studied the association between pretreatment HBV DNA levels and (1) clinical relapse and (2) HBsAg loss after NUC withdrawal.vs. 60% among patients with pretreatment HBV DNA levels >20,000 IU/ml, whereas the cumulative probabilities of HBsAg loss were 17.5% vs. 5% (p <0.001). In multivariable analysis, pretreatment HBV DNA levels <20,000 IU/ml were independently associated with a reduced likelihood of clinical relapse and with an increased chance of HBsAg loss .We enrolled 757 patients, 88% Asian, 57% treated with entecavir, with a median duration of treatment of 159 (IQR 156\u2013262) weeks. Mean pretreatment HBV DNA levels were 5.70 (SD 1.5) log IU/ml and were low in 150 (20%) and high in 607 (80%). The cumulative risk of clinical relapse at 144 weeks after therapy cessation was 22% among patients with pretreatment HBV DNA levels <20,000 IU/ml Lower pretreatment HBV DNA levels are associated with a lower risk of clinical relapse and a higher chance of HBsAg loss after cessation of NUC therapy, independent of end-of-treatment viral antigen levels. Further studies are needed to confirm these findings in non-Asian populations.A subgroup of patients with chronic hepatitis B may not require retreatment after stopping antiviral therapy. In this study, comprising 757 patients with chronic hepatitis B from Europe and Asia, we found that higher viral load before initiation of treatment was a risk factor for relapse after stopping treatment. Patients with a low HBV DNA level before starting antiviral therapy had the lowest risk of relapse, and a high chance of HBsAg loss, after stopping treatment. These findings can help select patients for treatment withdrawal and guide intensity of off-treatment monitoring. \u2022A subset of patients may achieve sustained remission and even HBsAg loss after cessation of nucleo(s)tide analogue therapy.\u2022Higher pretreatment HBV DNA levels were associated with a higher risk of clinical relapse, and a lower chance of HBsAg loss, after cessation of treatment.\u2022A pretreatment HBV DNA level <20,000 IU/ml was associated with favourable outcomes after cessation of antiviral therapy.\u2022The association between pretreatment HBV DNA levels and off-treatment outcomes was independent of other established predictors, including end-of-treatment HBsAg and HBcrAg levels. Interestingly, recent studies indicate that a subset of patients may achieve persistently low HBV DNA levels and even HBsAg clearance after cessation of NUC therapy. Such favourable outcomes are more likely to be achieved in non-Asian patients, and in those with low end-of-treatment (EOT) viral antigen and/or HBV RNA levels.e.g. alanine aminotransferase [ALT] and viral antigen levels). These findings can therefore not be used to counsel currently untreated patients who are considering antiviral therapy regarding their chances of finite therapy. The association between low EOT viral antigen levels and low relapse rates suggests that patients with low replicative CHB are more likely to achieve successful therapy withdrawal. Indeed, previous small studies indicate that low pretreatment HBV DNA levels may also be associated with favourable outcomes after therapy cessation, although findings are conflicting.,Long-term treatment with nucleo(s)tide analogues (NUCs) results in HBV DNA suppression in the vast majority of patients with chronic hepatitis B (CHB). Suppression of HBV DNA is associated with histological improvement and a reduced risk of hepatocellular carcinoma.The aim of the current study was therefore to assess the relationship between pretreatment HBV DNA levels and off-treatment outcomes after cessation of NUC therapy.,,The current study used data from a pooled dataset comprising patients with CHB who discontinued NUC therapy as part of studies or clinical practice in centres in Europe and Asia.HBV DNA was measured using local PCR methods. HBsAg was measured using various standardised methods. HBcrAg was quantified with the Lumipulse G HBcrAg assay on a LUMIPULSE G1200 analyser . The assay\u2019s lower limit of quantification is 3 log U/ml, and the lower limit of detection is 2 log U/ml. HBV genotyping was performed using various methods including line-probe assays, restriction fragment length polymorphism, and/or sequencing. Other biochemical tests were performed using local laboratory facilities. Stage of liver disease was assessed based on liver stiffness or biopsy (when available). Cirrhosis could also be ruled in based on compatible imaging findings.vs. >20,000 IU/ml), and stratified by EOT HBsAg (<100 and >100 IU/ml) or HBcrAg levels (undetectable and detectable) and compared using log-rank tests. We also performed multivariable Cox regression analyses, which were adjusted for previously reported predictors of outcome after therapy withdrawal, including antiviral agent, patient ethnicity (or HBV genotype), age, sex, EOT viral antigen levels, and baseline and EOT ALT levels.The association between pretreatment HBV DNA levels and EOT HBcrAg and HBsAg levels was explored using Pearson correlation and multivariable linear regression adjusting for patient age and duration of antiviral therapy. Clinical relapse was defined as the occurrence of either HBV DNA >2,000 IU/ml with ALT >2\u00a0\u00d7\u00a0the upper limit of normal or re-initiation of antiviral therapy (for any reason). Patients achieving HBsAg loss were considered to remain free from clinical relapse. HBsAg loss was defined as undetectable HBsAg at any time during off-treatment follow-up. Retreated patients were considered persistently HBsAg positive. Cumulative probabilities of either endpoint were estimated using the Kaplan\u2013Meier estimator in the overall population, across HBV DNA level categories . All statistical tests were two-sided and were evaluated at the 0.05 level of significance.p <0.001). Information on the presence of cirrhosis was unavailable for 309 patients; among the remaining 448 patients, 23 (5.1%) had cirrhosis. Cohort characteristics are shown according to pretreatment HBV DNA level in We enrolled 757 patients, the majority of whom were treated with entecavir 56.5%; . The medp <0.001) and EOT HBsAg levels . These associations were consistent in multivariable linear regression adjusted for age and duration of therapy .Mean pretreatment HBV DNA was 5.70 (SD 1.5) log IU/ml; pretreatment HBV DNA levels were <20,000 IU/ml in 150 (20%) and >20,000 IU/ml in 607 (80%). Mean HBsAg levels at EOT were 2.46 (SD 0.9) log IU/ml, and mean HBcrAg levels at EOT were 3.11 (SD 1.0) log U/ml. We observed a positive, albeit weak, correlation between pretreatment HBV DNA and EOT HBcrAg .Patients with low pretreatment HBV DNA levels had significantly lower rates of clinical relapse and significantly higher chances of HBsAg clearance after therapy withdrawal A and B. Pretreatment HBV DNA levels <20,000 IU/ml were associated with a lower cumulative probability of clinical relapse and a higher cumulative probability of HBsAg loss among patients with detectable and patients with undetectable EOT HBcrAg levels . Similarp <0.001), undetectable HBcrAg, HBsAg levels <100 IU/ml, younger age, lower ALT levels, non-tenofovir therapy, and non-Asian ethnicity were associated with a reduced risk of clinical relapse after therapy cessation (p <0.001), undetectable HBcrAg, HBsAg levels <100 IU/ml, and non-Asian ethnicity were also independently associated with an increased chance of HBsAg loss after treatment cessation fashion, as there remains a risk of post-therapy relapse.Finally, our findings are also important for the interpretation of studies conducted with novel antiviral compounds. As pretreatment viraemia appears to predict disease remission after therapy withdrawal, it will be of major importance to present the outcomes of future studies on finite therapy stratified by pretreatment HBV DNA levels to allow for comparisons across studies, cohorts, and compounds.Although our study is relatively large and enrolled patients from centres in Europe and Asia, it does have several limitations. First, we limited our analysis to patients with HBeAg-negative CHB, and our findings therefore cannot be applied to patients with HBeAg-positive disease who achieved seroconversion during treatment. Furthermore, it is important to note that the patients with pretreatment HBV DNA <20,000 IU/ml enrolled in this study likely reflect a select subgroup of such patients with an indication for antiviral therapy, based on either ALT levels (73% had elevated ALT) or otherwise. In addition, HBV DNA levels may fluctuate over time, and patients with HBV DNA <20,000 IU/ml at the time of therapy initiation may have had higher levels during previous assessments. Of note, pretreatment ALT levels were not associated with off-treatment outcomes in the overall population or in the subset of patients with low pretreatment HBV DNA levels. Another potential limitation of this dataset is the relatively low number of non-Asian patients. Although we observed consistent results among Asian and Caucasian patients, with superior outcomes observed for patients with a baseline HBV DNA level <20,000 IU/ml, findings were non-significant in the relatively limited number of Caucasian patients, and the group of non-Asian/non-Caucasian patients was too small to analyse separately. Finally, the current cohort lacks detailed information on pretreatment stage of liver disease (information was missing in 309 cases), and we were therefore unable to analyse the association between stage of liver fibrosis and outcomes after therapy cessation.In conclusion, our multicentre study shows that low pretreatment HBV DNA levels are associated with favourable outcomes after NUC cessation. Further studies are required to confirm these results in non-Asian populations. Our findings can be used to select patients for, and counsel patients about, their chances of successful finite NUC therapy.Fujirebio. Materials for HBcrAg testing were provided free of charge to several participating centres. Fujirebio had no influence on CREATE study design, data collection, data analysis, writing of the current manuscript, or the decision to submit for publication.The CREATE study was supported by Study design: MJS, SMC, CHC, BM, JYP, AK, WKS, YT, IC, MP, FvB, TB, FZ, SHA, GND, HW, MC, MFY, KA, AB, MB, TP, GP, BM, PC, MB, NSE. Collection of data: MJS, SMC, CHC, BM, JYP, AK, WKS, YT, IC, MP, FvB, TB, FZ, SHA, GND, HW, MC, MFY, KA, AB, MB, TP, GP, BM, PC, MB, NSE. Data analysis: MJS, SMC, CHC, BM, JYP, AK, WKS, YT, IC, MP, FvB, TB, FZ, SHA, GND, HW, MC, MFY, KA, AB, MB, TP, GP, PC, MB, NSE. Writing of the manuscript: MJS, SMC, CHC, BM. Critical review of the manuscript: JYP, AK, WKS, YT, IC, MP, FvB, TB, FZ, SHA, GND, HW, MC, MFY, KA, AB, MB, TP, GP, BM, PC, MB, NSE. Approval of the final version: all authors. Approval of the submission of the manuscript: all authors.The data used for the current analysis were derived from previously published cohorts and clinical datasets. The data cannot be shared.MJS has received speaker\u2019s fees and research support from Roche, Gilead, BMS, and Fujirebio. SMC has nothing to disclose. JYP is an investigator in clinical trials sponsored by AbbVie, Gilead Sciences, Hanmi, and Norvatis. WKS has received speaker\u2019s fees from Mylan and AstraZeneca; has provided consultancy for Abbott; has received speaker\u2019s fees and provided consultancy for AbbVie; and has received speaker\u2019s fees from, provided consultancy for, and received research funding from Gilead Sciences. YT reports lecture fees from Fujirebio, GlaxoSmithKline Pharmaceuticals Ltd, and Gilead Sciences, and research fees from Fujifilm Corp, Janssen Pharmaceutical K.K., Gilead Sciences, GlaxoSmithKline Pharmaceuticals Ltd, Sysmex, and Stanford Junior University. FvB has received research support from and provided consultancy for Roche. TB currently acts as an advisor to AbbVie, Alexion, Bayer, BMS, Gilead, Intercept, Janssen, MSD/Merck, Merz, Novartis, and Sequana Medical. He has received speaking honoraria from AbbVie, Alexion, Bayer, BMS, Eisai, Gilead, Intercept, Ipsen, Janssen, MSD/Merck, Merz, Novartis, Sirtex, and Sequana Medical in the past 2 years. He has received grant support from AbbVie, BMS, Gilead, Humedics, Intercept, Janssen, MSD/Merck, Merz, Novartis, and Sequana Medical. FZ is an advisor for Aicuris, Aligos, Antios, Assembly, Blue Jay, Evotec, Gilead, and GSK, and has received research grants from Assembly, Beam, Janssen, and Viravaxx. SHA has acted as an advisor and investigator for Gilead, Janssen, AbbVie, Roche, Assembly Biosciences, Arbutus, Brii, Vaccitech, GSK, Inovio, Aligos, Vir Biotechnology, SL Vaxigen, GeneOne Life Science, GreenCross, Yuhan, Samil, and Ildong. GND is an advisor or lecturer for Ipsen, Pfizer, Genkyotex, Novartis, and Sobi; has received research grants from AbbVie and Gilead; and has served as PI in studies for AbbVie, Novartis, Gilead, Novo Nordisk, Genkyotex, Regulus Therapeutics Inc, Tiziana Life Sciences, Bayer, Astellas, Pfizer, Amyndas Pharmaceuticals, CymaBay Therapeutics Inc, Sobi, and Intercept Pharmaceuticals. MB has received fees for consultancy/speakers bureau from AbbVie, Gilead, Janssen, EISAI-MSD, and Roche. HW has received research grants from Abbott, AbbVie, BMS, Gilead, Merck, Novartis, Roche, Roche Diagnostics, and Siemens; consultant fees from Abbott, AbbVie, BMS, Boehringer Ingelheim, Gilead, JJ/Janssen-Cilag, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, and ViiV; and speaker fees from Abbott, AbbVie, BMS, Boehringer Ingelheim, Gilead, JJ/Janssen-Cilag, Merck/Schering-Plough, Novartis, Roche, Roche Diagnostics, Siemens, Transgene, and ViiV. MC has received personal fees from AbbVie, Bristol Myers Squibb, Gilead Sciences, Janssen-Cilag, Merck (MSD), Biogen, Falk Foundation, Boehringer Ingelheim, Siemens, and Spring Bank as well as grants and personal fees from Roche. MFY has provided consultancy for and/or received research funding from AbbVie, Arbutus Biopharma, Assembly Biosciences, Bristol Myers Squibb, Dicerna Pharmaceuticals, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp and Dohme, Clear B Therapeutics, and Spring Bank Pharmaceuticals, and has received research funding from Arrowhead Pharmaceuticals, Fujirebio Incorporation, and Sysmex Corporation. KA has received fees for consultancy/speakers bureau from Assembly, Aligos, Arbutus, Gilead, Immunocore, Janssen, Roche, Sobi, Spring Bank, and Vir, and research support from Abbott, Gilead, and MSD. AB has received research fees from Fujirebio, Gilead Sciences, and Janssen Pharma. MB reports consultancy and lecture honoraria from AbbVie, Arbutus, Gilead, Janssen, Merck/MSD, and Spring Bank. GP has served as an advisor/lecturer for AbbVie, Albireo, Dicerna, Gilead, GSK, Janssen, Ipsen, MSD, Novo Nordisk, Roche, and Takeda, and has received research grants from AbbVie and Gilead. CHC has nothing to disclose. BM has received speaker and/or consulting fees from Abbott Molecular, Astellas, Intercept, Falk, AbbVie, Norgine, Bristol Myers Squibb, Fujirebio, Janssen-Cilag, Merck (MSD), and Roche. He has also received research support from Abbott Molecular, Altona Diagnostics, Fujirebio, and Roche.Please refer to the accompanying ICMJE disclosure forms for further details."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-40712-6, published online 22 August 2023Correction to: In the original version of this Article, Montaser M. Hassan was incorrectly affiliated with \u2018Plant Protection Department, College of Food and Agriculture Sciences, King Saud University, P.O. Box 2460, 11451, Riyadh, Saudi Arabia.\u2019The correct affiliations are as follows:Department of Entomology, Faculty of Basic and Applied Sciences, The University of Haripur, Haripur, Khyber Pakhtunkhwa, 22062, Pakistan.Department of Biology, College of Science, Taif University, P.O. Box11099 Taif 21944, Saudi Arabia.The original Article has been corrected."} +{"text": "Sexual Medicine, Volume 11, Issue 2, April 2023, qfad005, https://doi.org/10.1093/sexmed/qfad005This is a correction to: Kowsar Qaderi, Mansoureh Yazdkhasti, Sanaz Zangeneh, PhD, Bahar Morshed Behbahani, Mehri Kalhor, Ahmadreza Shamsabadi, Younes Jesmani, MD, Solmaz Norouzi, PhD, Mehrnaz Kajbafvala, Rasa Khodavirdilou, PhD, Nahid Rahmani, Masoumeh Namadian, Sajjad Ghane Ezabadi, MD, Ibrahim Alkatout, Esmaeel Mehraeen, Dara Rasoal, PhD, Changes in sexual activities, function, and satisfaction during the COVID-19 pandemic era: a systematic review and meta-analysis, In the originally published version of this manuscript, Esmaeil Mehraeen's name and affiliation were incorrectly presented. The correct information for this author is:Esmaeil MehraeenDepartment of Health Information Technology, Khalkhal University of Medical Sciences, Khalkhal, Iran.This error has been corrected online."} +{"text": "Strocov, Mo\u00efra Hocevar, Chris Palmstr\u00f8m,and Noa Marom. These errors are misprints made by the publisher. Theydo not affect the scientific content of the paper. The correct affiliationsare provided here:The original version of thisarticle (An-Hsi Chen: Universit\u00e9 Grenoble Alpes,CNRS, Grenoble INP,Institut N\u00e9el, 38000 Grenoble, France.Yu-Hao Chang:Materials Department, University of California-SantaBarbara, Santa Barbara, California 93106, United States.AaronEngel: Materials Department, University of California-SantaBarbara, Santa Barbara, California 93106, United States.VladimirN. Strocov: Paul Scherrer Institut, Swiss Light Source,CH-5232 Villigen PSI, Switzerland.Mo\u00efra Hocevar: Universit\u00e9Grenoble Alpes, CNRS, GrenobleINP, Institut N\u00e9el, 38000 Grenoble, France.Chris Palmstr\u00f8m:Materials Department and Department of Electricaland Computer Engineering, University of California-Santa Barbara,Santa Barbara, California 93106, United States.Noa Marom: Departmentof Materials Science and Engineering, Departmentof Physics, and Department of Chemistry, Carnegie Mellon University,Pittsburgh, Pennsylvania 15213, United States."} +{"text": "Despite COVID-19 vaccination, individuals who are immunocompromised due to underlying conditions, such as cancer and organ transplant, are at a greater risk of severe COVID-19 outcomes compared with the general population that is vaccinated. However, there are limited data quantifying this risk during the omicron-predominant period, particularly for important sub-groups that may have variable risk for severe COVID-19 outcomes. We report initial findings from the INFORM study describing the clinical burden and severe COVID-19 outcomes in patients with immunocompromised conditions (IC) in England, UK in 2022.Table 1. Severe COVID-19 outcomes were defined as COVID-19\u2013related hospitalization, COVID-19\u2013related intensive care unit (ICU) admission, and/or COVID-related death.This retrospective cohort study utilized National Health Service database in England. The study period was from Jan 1\u2013Dec 31, 2022 and the baseline period for assessment of patient characteristics, including IC, was from Jan 1, 2017\u2013Dec 31, 2021. Definitions of IC sub-groups are provided in Table 2). The risk of severe COVID-19 outcomes was higher in well-recognized IC conditions across all the sub-groups compared with the overall population (Table 2).Of the 11,990,730 individuals in the general population sample aged \u2265 12 years, 468,745 (3.9%) were immunocompromised and accounted for approximately one-quarter of severe COVID-19\u2013related outcomes (22% of hospitalizations, 28% of ICU admissions, and 23% of deaths; There is an increased burden in the prevalence of severe COVID-19 outcomes among all individuals with IC, highlighting the need for additional protection to target this population.Richard McNulty, MD, AstraZeneca: Employee Sabada Dube, PhD, AstraZeneca: Employee Yi Lu, PhD, Evidera: Employee Sophie Graham, MSc, Evidera: Employee Sofie Arnetorp, MS, AstraZeneca: Employee Nahila Justo, PhD, MBA, Evidera: Employee|Karolinska Institute: Employee Renata Yokota, PhD, AstraZeneca: Employee Kathryn Evans, MPH, Evidera: Employee Sudhir Venkatesan, MPH, PhD, AstraZeneca: Employee Mark Yates, PhD, Evidera: Employee Sylvia Taylor, PhD, MPH, MBA, AstraZeneca: Stocks/Bonds Jennifer Quint, PhD, AstraZeneca: Grant/Research Support|Evidera: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Insmed: Grant/Research Support Rachael A. Evans, PhD FRCP, AstraZeneca: Advisor/Consultant|Boehringer: Advisor/Consultant|Evidera: Advisor/Consultant"} +{"text": "PLOS ONE Editors retract this article [The article because SUR, QX, US, MAB, and AR did not agree with the retraction. LR, GY, ANS, MSJ, AD, and ZD either did not respond directly or could not be reached."} +{"text": "Sparsentan is a novel single-molecule dual endothelin angiotensin receptor antagonist with hemodynamic and anti-inflammatory properties and is not an immunosuppressant. The ongoing phase 3 PROTECT trial examines sparsentan in adults with IgA nephropathy (IgAN).The PROTECT trial (NCT03762850) is a multicenter, international, randomized, double-blind, parallel-group, active-controlled study. The efficacy and safety of sparsentan versus the active control irbesartan is being evaluated in adults with biopsy-proven IgAN and proteinuria\u00a0\u22651.0 g/d despite maximized treatment with an angiotensin-converting enzyme inhibitor (ACEi) and/or angiotensin receptor blocker (ARB) for at least 12 weeks. Blinded and aggregated baseline characteristics are reported descriptively and compared to contemporary phase 3 trials with patients with IgAN.The primary analysis population includes 404 patients who were randomized and received study drug . Enrolled patients were from Europe (53%), Asia Pacific (27%), and North America (20%). Baseline median urinary protein excretion was 1.8 g/d. The range of estimated glomerular filtration rate (eGFR) was broad with the largest proportion of patients (35%) in chronic kidney disease (CKD) stage 3B. Before transitioning to study medication, mean systolic/diastolic blood pressure was 129/82 mm\u00a0Hg, with the majority of patients (63.4%) receiving the maximum labeled ACEi or ARB dose. Patients in Asian versus non-Asian regions included a higher percentage of females, had lower blood pressures, and included lower proportions of patients with a history of hypertension and baseline antihypertensive treatment.Patient enrollment in PROTECT, with differing racial backgrounds and across CKD stages, will allow for important characterization of the treatment effect of sparsentan in patients with IgAN with proteinuria at high risk of kidney failure. Details of the study methods have been previously reportedThe PROTECT trial ; and systolic blood pressure\u00a0\u2264150 mm\u00a0Hg, and diastolic blood pressure\u00a0\u2264100 mm\u00a0Hg. Key exclusion criteria were as follows: IgAN secondary to another condition or IgA vasculitis; cellular glomerular crescents present in >25% of glomeruli on kidney biopsy within 6 months before screening; a cause of CKD in addition to IgAN; administration of any systemic immunosuppressive medications (including corticosteroids) for >2 weeks within 3 months before screening; and significant cerebrovascular, cardiovascular (including New York Heart Association Class II\u2013IV heart failure), or hepatic conditions.The study duration of 270 weeks includes a double-blind period of 114 weeks followed by an open-label extension period of up to 156 weeks. Eligible patients met the following key inclusion criteria at screening: male or female aged\u00a0\u226518 years; biopsy-proven IgAN (the biopsy may have been performed at any time in the past); 24-hour urine protein excretion value\u00a0\u22651.0 g/d; eGFR\u00a0\u226530 ml/min per 1.73 mEnrolled patients discontinued RAASi and any other prohibited concomitant medications before the randomization (day 1) visit and completed comprehensive baseline evaluations and clinical laboratory tests. Routine blood and urine samples for laboratory assessments were analyzed at a central laboratory . eGFR was determined using the Chronic Kidney Disease Epidemiology formula.The primary efficacy end point of the PROTECT trial is the change from baseline (day 1) in urine protein-to-creatinine ratio on the basis of a 24-hour urine sample at week 36. Key secondary efficacy endpoints include chronic eGFR slope over 1 and 2 years and total eGFR slope over the full double-blind treatment period of 110 weeks, as well as a variety of proteinuria variables up to week\u00a0114.In this report of the baseline characteristics of patients enrolled in the PROTECT trial, the blinded and aggregated data of the enrolled patients in the primary analysis population are summarized descriptively. The primary analysis population includes the patients who at the time of data extraction were randomized and had taken at least 1 dose of the assigned treatment. Baseline is defined as the last nonmissing observation on or before the start of dosing. Mean and SD are used for normally distributed characteristics; median and interquartile range (IQR) are used for characteristics with a skewed distribution.,,,,We compared the baseline characteristics of participants enrolled in PROTECT to those of participants enrolled in other contemporary phase 3 trials with patients with IgAN. We identified the following 4 such studies: (i) Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy ,A total of 671 patients were screened; 406 patients from clinical sites in 18 countries met eligibility criteria and were enrolled and randomized into PROTECT. Two randomized patients withdrew from the study before initiating study treatment. The 404 randomized patients who received study drug were included in the primary analysis population, and their baseline characteristics are described here. Approximately half of the enrolled patients were from Europe (53%), followed by Asia Pacific (27%) and North America (20%). Patients had a median age of 46 years and were primarily male, White, and non-Hispanic; 28.5% of patients were Asian . The iniBaseline assessments showed median urine protein-to-creatinine ratio of 1.2 g/g, median urinary protein excretion of 1.8 g/d, and 12.1% of patients had nephrotic-range proteinuria . Median Before transitioning from ACEi and/or ARB treatment to study medication, mean systolic and diastolic blood pressure were 129.0 and 82.4 mm\u00a0Hg, respectively. Of the 404 randomized patients that received study medication, 403 patients (99.8%) were receiving ACEi and/or ARB treatment at screening and during the screening period . A highen\u00a0= 74) and non-Asian geographic regions .2, shifted the target population to those with more progressed disease. Low eGFR is a strong predictor of kidney failure,2 at screening, 20 patients (5%) experienced eGFR\u00a0<30 ml/min per 1.73 m2 at baseline (minimum eGFR was 24 ml/min per 1.73 m2). The benefit of this broad approach will be the ability to evaluate the treatment effects of sparsentan versus irbesartan from early to later stages of disease progression.In contrast to these dedicated IgAN studies, phase 3 trials enrolling a broad spectrum of patients with diabetic and nondiabetic CKD have been initiated. These studies, such as DAPA-CKD,,,,,As noted previously, phase 3 studies have varied greatly in the geographic region in which they were conducted, which may be reflected in some of the differences in certain patient baseline characteristics. PROTECT, DAPA-CKD, and NefIgArd are global studies enrolling patients across multiple continents. In contrast, STOP-IGAN recruited patients from 32 centers in Germany and TESTING was predominantly in sites in China.,,,A final consideration when comparing the phase 3 IgAN trials is the choice of comparator. Unlike the other phase 3 studies and other ongoing phase 2 and phase 3 trials in IgAN, PROTECT is unique in the double-blind randomized application of an active control, irbesartan, to compare to the investigational drug, sparsentan. Each of the IgAN-dedicated studies relies on the investigators to use their best judgment as to whether a patient is on a maximum tolerated dose if the patient is on less than the MLD of an unblinded RAASi at study entry.A limitation of the PROTECT trial is that the assessment of microscopic hematuria was not possible given the use of a central laboratory for analyses. This would have resulted in an unreliable analysis of microhematuria because of the transport time and analysis delays. In addition, there was no systematic collection of history of macroscopic hematuria from patients at study entry. The MLD of ACEis and ARBs may be defined differently in different geographic regions. To minimize heterogeneity for assessment of eligibility and reporting, a strength of the PROTECT trial is the use of a standardized daily doses table that was applied on the basis of a consensus of the majority of participating countries .Sparsentan is a novel single-molecule dual endothelin angiotensin receptor antagonist that is not an immunosuppressant agent. It is being evaluated in PROTECT as a promising new therapeutic in IgAN, an entity with unmet need for novel therapies. The patients enrolled in PROTECT were adults with biopsy-confirmed IgAN (excluding IgAN secondary to another condition or IgA vasculitis) and at high risk of progression to kidney failure requiring dialysis or kidney transplantation based on urinary protein excretion\u00a0\u22651.0 g/d despite maximum standard-of-care treatment with ACEi and ARB at screening. The enrollment of patients across both (i) Asian and non-Asian geographic regions with differing racial backgrounds, and (ii) a full range of CKD stages will enable characterization of the treatment effect of sparsentan in high-risk patients with IgAN across geographic regions and levels of kidney function, respectively.Bhadran Bose, Muralikrishna Gangadharan, Stephen McDonald, Chen Peh, Sadia Jahan, Chii Yeap, Philip Clayton, Georgina Irish, Nikhil Thyagarajan, Peter Hollett, Rathika Krishnasamy, Robert Carroll, Shilpanjali Jesudason, Susan Crail, Toby Coates, Jane Waugh, Euan Noble, Kumaradevan Mahadevan, Victoria Campbell, Tania Salehi, Wai Lim, Neil Boudville, Aron Chakera, Doris Chan, Anoushka Krishnan, Yusuf Eqbal, Alastair Gillies, Eswari Vilayur, Thida Maung Maung Myint, Nicholas Gray, Jane Waugh, Euan Noble, Melissa Cheetham, Yusuf Eqbal, Peter Hollett, Rathika Krishnasamy, Kumaradevan Mahadevan, Victoria Campbell, Carol Pollock, Bruce Cooper, Amanda Mather, Sarah Roxburgh, Yvonne Shen, Stefanie Stangenberg, Amanda Siriwardana, Muh Geot Wong, Emma O\u2019Lone, Susan Wan, Brendon Neuen, Jeffrey Tsun Kit Ha, Dana Kim, Lauren Heath, Arunima Jain, Elaine Phua, Yan Li, Martin Gallagher, Meg Jardine, Angus Ritchie, Mona Razavian, Celine Foote, Roger Wyndham, Shaundeep Sen, Zoltan Endre, Jonathan Erlich, Mangalee Fernando, Kenneth Yong, Grant Luxton, Sradha Kotwal, Simon Roger, Vidu Wijeratne, David Packham, and Ian Fraser.Bert Vandewiele, Margo Laute, Wim Lemahieu, Sofie Jamar, Sara Ombelet, Gert Meeus, Marc Decupere, Olivier Schockaert, Peter Doubel, Liesbeth Viaene, Luc Radermacher, Catherine Masset, Martial Moonen, Eric Firre, Martina Milicevic, Xavier Warling, Bart Maes, An Vanacker, and Thomas Malfait.Ivan Durlen, Ivica Horvatic, Ana Savuk, Lana Gellineo, Sandra Karanovic, Zivka Dika, Bojan Jelakovic, Djuro Plavljanic, Ivana Mikacic, Dubravka Trajbar Kentric, Dunja Barisic, Marija Stankovic, Karolina Majstorovic Barac, Ivan Kruljac, Drasko Pavlovic, Martin Drinkovic, Ingrid Prkacin, Jerko Barbic, Zvonimir Sitas, and Dunja Vujcic.Ivan Rychlik, Anna Benesova, Klara Drinovska, Karolina Kratka, Vladimir Tesar, and Dita Maixnerova.Madis Ilmoja, Kristin Unt, Kadri Lilienthal, Asta Auerbach, Liisi Leis, Julia Piel, Annika Adoberg, Mai Rosenberg, Kulli Kolvald, Kristi Veermae, Kadri Telling, Elviira Seppet, and Jana Uhlinova.Philippe Zaoui, Pierre-Louis Carron, Ingrid Masson, Miriana Dinic, Damien Thibaudin, Christian Broyet, Nicolas Maillard, Hesham Mohey, Christophe Mariat, Guillaume Claisse, Eric Alamartine, Bertrand Dussol, Stephane Burtey, Noemie Chiche-Jourde, Jean-Emmanuel Serre, Guillaume Jeantet, Leila Chenine, Anne Blanchard, Stephane Roueff, Eric Thervet, David Fouassier, Alexandre Buffet, Marine Livrozet, Roxane Gaisset, Alexandre Karras, Anne-Elisabeth Heng, Cyril Garrouste, Carole Philipponnet, Clementine Nicolo, Alba Atenza, Camille Lanaret, Clarisse Greze, Valentin Mayet, Clement Dumond, Yahsou Delmas, Christian Combe, Claire Rigothier, Laure Burguet, Aurore Labat, Simon Mucha, and Val\u00e9rie de Pr\u00e9cigout.Thomas Weinreich, Helmut Reichel, Diliana Draganova, Lothar Wolf, Bernd Hohenstein, Sven Heinrichs, Simone Kulka, Sebahat Sat, Lea Weiland, Thilo Krueger, Gunter Wolf, Christiane Kettner, Mandy Schlosser, Johann Konstantin Herfurth, Annegret Koch, Martin Busch, Stephan Christian Werth, Martin Nitschke, Figen Cakiroglu, Franziska Sarnow, Lisa Schulz, Stefan Weiner, Nikolaus Wirtz, Eric Koester, Marcus Moeller, Juergen Floege, Eleni Stamellou, Silja Sanden, Hans Schmidt-Guertler, Wanja Bernhardt, Margret Patecki, Georg Schlieper, Kevin Schulte, Annette Girardet, and Ulrich Kunzendorf.Sydney Chi Wai Tang, Lorraine Pui Yuen Kwan, Maggie Ming Yee Mok, Gary Chi Wang Chan, Mingyao Ma, Davina Ngoi Wah Lie, Anthony Ting Pong Chan, Cheuk Chun Szeto, Kit Chung Jack Ng, Siu Fai Cheung, Tak Tai Andrew Yue, Ka Shun Samuel Fung, Hon Tang, Ka Fai Yim, Wai Ping Law, Yick Hei Wong, Chi Kwan Darwin Lam, and Sze Ho Sunny Wong.Carmelita Marcantoni, Roberta Aliotta, Francesca Deodato, Gemma Patella, Nicolino Comi, Caterina Vita, Nazareno Carullo, Davide Bolignano, Michela Musolino, Matias Trillini, Norberto Perico, Giuseppe Remuzzi, Erica Daina, Luigi Biancone, Loredana Colla, Manuel Burdese, Chiara Cogno, Elena Boaglio, Isabella Abbasciano, Carlotta Federica Zizzi, Paolo Randone, Pietro Napodano, Anna Ricchiuto, Matthias Cassia, Simone Accarino, Mario Cozzolino, Rocco Baccaro, Stefano Costanzi, Federica Di Maio, Maria Arena, Federica Urciuolo, Sara Vigano, Andrea Cavalli, Monica Limardo, Monica Bordoli, Serena Ponti, Selena Longhi, Andrea Solazzo, Francesco Giaroni, Gabriele Donati, Massimo Torreggiani, Davide Catucci, Marco Colucci, Vittoria Esposito, Ciro Esposito, Loreto Gesualdo, Flavia Capaccio, Emma Diletta Stea, Carmen Sivo, Francesca Annese, Federica Papadia, Mirco Belingheri, Patrizia Passerini, Silvia Malvica, and Piergiorgio Messa.Marius Miglinas, Alvita Vickiene, Urte Zakauskiene, Egle Asakiene, Inga Arune Bumblyte', Asta Stankuviene, and Lina Santockiene.Ashik Hayat, Allister Williams, Peter Sizeland, Kannaiyan Rabindranath, Eddie Tan, Gerald Waters, Lai Wan Chan, Andrew Henderson, Angus Turnbull, Andrew McNally, Annie Reynolds, Helen Pilmore, Ian Dittmer, Paul Manley, Elizabeth Stallworthy, Tze Goh, David Semple, Michael Collins, Elizabeth Curry, Jafar Ahmed, and Thu Nguyen.Agata Winiarska, Justyna Zbrzezniak, Tomasz Stompor, Magdalena Krajewska, Hanna Augustyniak-Bartosik, Dorota Zielinska, Anna Jander, Malgorzata Stanczyk, Marcin Tkaczyk, Przemyslaw Miarka, Dariusz Aksamit, Piotr Jaskowski, Wladyslaw Sulowicz, Dominik Cieniawski, Julita Gontarek-Kacprzak, Robert Malecki, Elzbieta Felicjanczuk, Norbert Kwella, Bogna Kwella, and Ewa Satora.Jo\u00e3o Carlos Fernandes, Ana Marta Gomes, Marina Reis, Daniela Lopes, Catarina Almeida, Helena S\u00e1, Ana Carolina Figueiredo, Clara Pardinhas, Edgar Almeida, Mario Raimundo, Ana Cortes\u00e3o Costa, Luis Pedro Falcao Goncalves, Sara Fernandes, S\u00f3nia Silva, Catarina Teixeira, Adriana Fernandes, Fernando Nolasco, Patricia Alves, Mario Gois, Nuno Fonseca, Ana Messias, Maria Menezes, Filipa Cardoso, Helena Sousa, Joana Marques, Rui Barata, Jose Antonio Lopes, Sofia Jorge, Joana Gameiro, Jose Nuno de Almeida Agapito Fonseca, Sara Goncalves, Ana Farinha, Patricia Valerio Santos, Ana Natario, Jose Carlos de Jesus Barreto, Catarina Abrantes, Elsa Sofia Quadrado Soares, Joana de Sousa Soares Felgueiras, Liliana Cunha, Lucia Parreira, Teresa Furtado, and Alvaro Vaz.Kook-Hwan Oh, Hajeong Lee, Se Joong Kim, Dong-Wan Chae, Jong Cheol Jeong, Yeong Hoon Kim, Yunmi Kim, Hyeong Cheon Park, Hoon Young Choi, Hyung Wook Kim, Moon Hyoung Lee, Songuk Yoon, Kyu-Beck Lee, Young Youl Hyun, Tae-Hyun Yoo, Seung Hyeok Han, Jung Tak Park, Sunggyun Kim, Young Rim Song, Jwa-Kyung Kim, Hyung-seok Lee, Narae Joo, JungEun Lee, Hye Ryoun Jang, Junseok Jeon, Wookyung Chung, Hyun Hee Lee, Jae Hyun Chang, Ka Yeong Chun, JiYong Jung, Han Ro, Aejin Kim, Sang-Kyung Jo, Jihyun Yang, Myung-Gyu Kim, and SeWon Oh.Caridad Martinez Villanueva, Ana Vilar Gimeno, Gustavo Andres Useche Bonilla, Esther Tamarit, Antonio Galan Serrano, Eduardo Verde Moreno, Jose Lu\u00f1o Fernandez, Maria Angeles Goicoechea Diezhandino, Ursula Verdalles Guzman, Ana Perez de Jose, Alberto Ortiz Arduan, Mar\u00eda Vanessa P\u00e9rez G\u00f3mez, Catalina Mart\u00edn Cleary, Raul Fernandez Prado, Elena Goma, Jose Ballarin, Montserrat Diaz Encarnacion, Iara Da Silva Santos, Helena Marco Rusinol, Monica Furlano, Carlos Arias, Clara Barrios, Eva Rodriguez Garcia, Adriana Sierra Ochoa, Belen Vizcaino Castillo, Jonay Pantoja Perez, Mercedes Gonzalez Moya, Mari Sargsyan, Emma Calatayud Aristoy, Ana Avila Bernabeu, Leticia Perez Lluna, Tamara Malek Marin, Maria Antonia Munar Vila, Ivon Maritza Bobadilla Rico, Natalia Allende Burgos, Eduardo Gutierrez Martinez, Elena Gutierrez Solis, Angel Sevillano, Evangelina Merida Herrero, Josep Miquel Blasco Pelicano, Lida Maria Rodas Marin, Luis F Quintana, Maria Antonieta Azancot Rivero, Natalia Ramos Terrades, Clara Garcia Carro, Irene Agraz Pamplona, Mercedes Salgueira Lazo, Francisco de la Prada Alvarez, Fabiola Alonso Garcia, Wenceslao Adrian Aguilera Morales, Salia Virxinia Pol Heres, Angel Forcen, Eduardo Parra Moncasi, Cristina Medrano Villarroya, Alejandro Soria Villen, Olga Gracia Garcia, Mercedes Velo Plaza, Maria Dolores S\u00e1nchez de la Nieta, Marta Calvo Arevalo, Antolina Moreno, Secundino Cigarran Guldris, Manuel Pereira de Vicente, Maria Antonia Munar Vila, Ivon Maritza Bobadilla Rico, and Natalia Allende BurgosBang-Gee Hsu, Chih-Hsien Wang, Cheng-Hsu Chen, Tung-Min Yu, Ming-Ju Wu, Shang-Feng Tsai, Chia-Tien Hsu, Hsien-Fu Chiu, Kang-Ju Chou, Hua-Chang Fang, Po-Tsang Lee, Hsin-Yu Chen, Chien-Liang Chen, Chien-Wei Huang, Shih-Hsiang Ou, Tzung-Yo Ho, Chih-Yang Hsu, Ming-Shan Chang, Yen-Ling Chiu, Yu-Sen Peng, Kai-Hsiang Shu, Szu-Yu Pan, Shih-Ping Hsu, Ju-Yeh Yang, Mei-Fen Pai, Po-Yu Tseng, Hon-Yen Wu, Wan-Chuan Tsai, Kuei-Ting Tung, Hung-Yuan Chen, Hung-Chun Chen, Shang-Jyh Hwang, Mei-Chuan Kuo, Daw-Yang Hwang, Yi-Wen Chiu, Chi-Chih Hung, Hung-Tien Kuo, and Jer-Chia Tsai.Kieran McCafferty, Suzanne Forbes, Indranil Dasgupta, Mark Thomas, Amar Mahdi, Bamidele Ajayi, Paramit Chowdhury, Theodoros Kasimatis, Dimitrios Moutzouris, Caroline Dudreuilh, Rishi Pruthi, Nick Mansfield, Gabriel Doctor, Sapna Shah, Sui Kon, Priscilla Smith, Patrick Hamilton, Durga Kanigicherla, Omar Sherin Ibrahim Ragy, Bassam Alchi, Oliver Flossmann, Farid Ghalli, Sarah Lawman, Smeeta Sinha, Constantina Chrysochou, Chukwuma Chukwu, Aine Maire De Bhailis, Saif Al Chalabi, Amy Hudson, Arun Gopu, Olivia Wickens, Joshua Storrar, Mona Wahba, Nathan Lorde, Mohammad Rony, Sian Griffin, Farah Latif, Mohammad Ali, Louise DaSilva, Jonathan Ayling-Smith, Eamon Mahdi, Lisa Willcocks, Rachel Jones, Jonathan Barratt, Chee Kay Cheung, Haresh Selvaskandan, Dan Pugh, Matthew Sayer, Neeraj Dhaun, Fiona Chapman, Patrick Mark, Colin Geddes, Emily McQuarrie, Rajan Patel, Laurence Solomon, Arvind Ponnusamy, Adam Morris, Pedro Okoh, Lauren Floyd, Ajay Dhaygude, Janson Leung, Christopher Goldsmith, Bhavna Pandya, Didem Tez, Ashraf Mikhail, Karen Brown, Thomas Bucknall, and Mark Lambie.Roderick Comunale, Donald Brandon, Stacy Martinez, Amanda Hall, Amy Henderson, Aaron Fearday, Nicole Douthit, Brian Snow, Arnold Silva, Cathylee Sly, Christopher Keller, Robert Davidson, Jerry Meng, Robert Haws, Siddhartha Kattamanchi, Javad Mojarrab, Unnikrishnan Pillai, Richard Lafayette, Michelle O'Shaughnessy, Fahameedah Kamal, Kshama Mehta, Bruce Baker, Mario Ruiz, Praveena Jyothinagaram, Usha Peri, William Paxton, James Tumlin, Kerri McGreal, Ellen McCarthy, Cassandra Kimber, Archana Gautam, Kassem Khalil, Viet Nguyen, Viet Nguyen, Raffi Minasian, Dariush Arfaania, Sam Daneshvari, Michel Zakari, Artashes Patrikyan, Rouzbeh Afsari, Christine Ayvazyan, Faisal Fakih, Mark Lagatta, Faisal Fakih, Alfred Rodriguez, Jorge Enrique Monroy Avella, Ramachandra Patak, Jigar Kadakia, Jai Radhakrishnan, Gerald Appel, Wooin Ahn, Bradley Nelson, Allyson Medina, Syeda Ahmad, Yonatan Peleg, Nisha Clement, Ian Chiu, Elizabeth Hendren, Andrew Bomback, Pietro Canetta, Bruce Spinowitz, Chaim Charytan, Nishita Parikh, Sheng Kuo, Ritesh Raichoudhury, Mirela Dobre, Lavinia Negrea, Aparna Padiyar, Arksarapuk Jittirat, Nishigandha Pradhan, Ranjit Dhelaria, Saravanan Balamuthusamy, Machaiah Madhrira, Thomas Powell, Howard Lifland, Asha Bailey, Sarah Ashley Ford Sightler, Meera Patel Suthar, Heather Green, Samir Parikh, Isabelle Ayoub, Brad Rovin, Salem Almaani, Gabriel Contreras, Alessia Fornoni, Yelena Drexler, Abdallah Geara, Brittany Sheridan, Gaia Coppock, Jonathan Hogan, Carlos Gonzalez, Shamik Bhadra, Pradip Chowdhury, Kay Kyaw, May Tan, Lathika Raakesh, Elder Mendoza, Veronica Viramontes, Asghar Chaudhry, Juan Carbonell, Rajdeep Gadh, Victor Fernandez, Mohamad Kassem, Radu Jacob, Karen Wilder, Britt Newsome, Kathryn Klamm, Irina Suyumova, Laura Ann Kooienga, Catherine Janko, Dana Rizk, Bruce Julian, Dawn Caster, Erika Perez, Gunjan Garg, Nayan Gowda, Suneel Udani, Sreedhar Mandayam, Biruh Workeneh, Roderick Comunale, Donald Brandon, Unnikrishnan Pillai, Ali Assefi, Barbara Greco, Michael Germain, Jusmin Patel, Sarah Quinn, James Sullivan, Jeffrey Glaze, Phillip Madonia, Kellyn McMahon, Harold Giles, Sharon Adler, and Tiane Dai.JB has received research grants from Argenx, Calliditas Therapeutics, Chinook Therapeutics, Galapagos NV, GlaxoSmithKline, Novartis, and Travere Therapeutics Inc.; and is a medical/scientific advisor to Alnylam Pharmaceuticals, Argenx, Astellas Pharma, BioCryst Pharmaceuticals, Calliditas Therapeutics, Chinook Therapeutics, Dimerix, Galapagos NV, GlaxoSmithKline, Novartis, Travere Therapeutics Inc., UCB, Vera Therapeutics, and Visterra. BR is a consultant to Calliditas, Novartis, Omeros, Travere Therapeutics Inc., and Vera. MGW received honorarium from Alpine, Amgen, AstraZeneca, Baxter, Chinook, CSL Behring, Dimerix, Eledon, George Clinical, Horizon, Otsuka, and Travere Therapeutics Inc. for scientific presentation. CEA is a consultant to AstraZeneca and Mantra Bio; and received grant support from Sana. SB is an employee and stockholder of Travere Therapeutics Inc. PH is an employee and stockholder of Travere Therapeutics Inc. JI is an employee and stockholder of Travere Therapeutics Inc. RK is an employee and stockholder of Travere Therapeutics Inc. HJLH is a consultant to AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Behring, Dimerix, Eli Lilly, Gilead, Janssen, Merck, Novo Nordisk, and Travere Therapeutics Inc.; research support for clinical trials from AstraZeneca, Boehringer Ingelheim, Janssen, and Novo Nordisk; and The George Institute for Global Health and George Clinical hold research contracts for trials in kidney disease. AM is a consultant to Travere Therapeutics Inc. through contract with JAMCO Pharma Consulting AB. ILN received honorarium for scientific presentation from\u00a0AstraZeneca, Bayer, Novartis, and The George Institute for Global Health holds research contracts for trials in kidney disease. JR received consulting fees and grant support from Travere Therapeutics Inc. MNR is a clinical trial site PI for Chinook, Kaneka, Reata, River 3 Renal Corp., Sanofi, and Travere Therapeutics Inc.; is a consultant to Visterra; and is a data and safety monitoring board member for Advicenne. WR is an employee and stockholder of Travere Therapeutics Inc. HTra has served as a consultant to and/or a member of a data monitoring committee for Akebia, ChemoCentryx, Goldfinch Bio, Inc., Natera, Otsuka, Travere Therapeutics Inc., and Walden. HTri received honorarium for scientific work from AstraZeneca, Bayer, Calliditas, Chinook, Dimerix, GlaxoSmithKline, Novartis, Omeros, Roche, Travere Therapeutics Inc., and Visterra Otsuka; and The George Institute for Global Health holds research contracts for trials in kidney disease. VP received grants from Pfizer, which provided study drug and initial seed funding, during the conduct of the study; received grants from AbbVie for a clinical trial steering committee; received personal fees from Amgen for serving on an advisory board; serving on a clinical trial steering committee for Astellas; received personal fees from AstraZeneca, Boehringer, Ingelheim, Janssen, Novo Nordisk, and Novartis for serving on a steering committee, advisory committee, and scientific presentations; serves on a trial steering committee and advisory committee for Bayer; received personal fees from Chinook Therapeutics for serving on an advisory committee; serving on a data and safety monitoring committee for Dimerix; serving on the board of directors for George Clinical; serving on a steering committee and advisory committee for Gilead, GlaxoSmithKline, and Travere Therapeutics, Inc.; serving on an advisory committee for Medimmune; receiving personal fees from Mitsubishi Tanabe for scientific presentations; receiving personal fees from Mundipharma for advisory committee and scientific presentations; and serving on an advisory committee for Vifor Pharma; and holds research contracts with The George Institute for Global Health for trials in kidney disease."} +{"text": "Systematic Biology, Volume 71, Issue 3, May 2022, Pages 610\u2013629, https://doi.org/10.1093/sysbio/syab070This is a correction to: James Willson, Mrinmoy Saha Roddur, Baqiao Liu, Paul Zaharias, Tandy Warnow, DISCO: Species Tree Inference using Multicopy Gene Family Tree Decomposition, In the originally published version of this manuscript the supplementary material file providing more information on the study was inadvertently omitted. This error has been corrected online."} +{"text": "Telemedicine emerged as an alternative care delivery system used to offer effective long-term management to patients with chronic, inflammatory conditions such as psoriatic disease. Teledermatology can provide reliable clinical information through thorough history-taking and virtual evaluations that include patient-provided images and disease activity assessment tools that may help accurately diagnose and manage patients with psoriasis. The integration of validated screening tools for psoriatic arthritis and effective teledermatology practices may improve access to specialists, thus avoiding preventable delays in the diagnosis and treatment of patients with psoriatic arthritis. Although the provision of telehealthcare should not completely replace high quality, in-person dermatologic or rheumatologic visits, the convenience and collaborative nature of teledermatology may lead to expanded access and expedited care in the appropriate setting, whether it be in a virtual or in-person visit. Physicians have since continued to leverage emerging technologies to deliver quality care from remote locations.,,Teledermatology emerged as an alternative care delivery system used to offer effective long-term management to patients with chronic, inflammatory skin conditions such as psoriasis. Unlike conventional in-person care, accurate diagnosis and management by virtual visits rely partly on the quality of live video images and photographs provided by patients. When properly collected, these images can be of appropriate quality for physicians to make accurate assessments of disease severity using Psoriasis Area and Severity Index (PASI) scores in patients of different skin phototypes.,,As compared with in-person care, collaborative and efficient teledermatology models equivalently improve PASI scores, BSA, and dermatology life quality index.,,Teledermatology expands the ability to deliver patient care. Distance, incapacity, and transportation costs are barriers to in-person care for many patients with psoriasis.Similarly, teledermatology allows physicians to reach patients with psoriasis in institutions with restricted access. Patients with psoriasis who are institutionalized for psychiatric reasons face uncommon difficulties in setting up external appointments and have a high patient turn-around time, in other words, the total time needed for patient transport and completion of an in-patient encounter.Despite achieving comparable improvements in disease severity, the estimation of areas of involvement and induration of psoriatic lesions are different between teledermatology and in-person evaluations.,https://www.psoriasis.org/psoriatic-arthritis-screening-test/), wherein patients can answer 5 simple questions and quickly receive their results for presentation at a virtual evaluation.It is critical to determine if teledermatology is suitable for addressing comorbid conditions that affect patients with psoriasis. Up\u00a0to 30% of patients with psoriasis develop psoriatic arthritis (PsA); undertreatment and diagnostic delay of PsA lead to irreversible joint damage and significant functional impairment.Following the identification of suspected PsA, an in-depth discussion and evaluation of joint involvement are warranted. Teledermatology applications using physician-guided palpation, photos of involved joints, and thorough history-taking allow physicians to accurately diagnose active arthritis, dactylitis, or enthesitis; evaluate pain through a visual analog scale; and manage therapeutics for PsA.,,Despite the development of virtual evaluation techniques, the accurate determinations of disease activity may be limited, in some cases of complex joint disease, without an in-person physical examination.Teledermatology is a valuable tool that can be used to supplement other care modalities for patients with psoriatic disease. Although it is not a direct replacement for in-person care, when utilized appropriately, it can be used as a tool to achieve numerous goals of care, such as identifying patients who need a rheumatology referral and increasing access to care. Teledermatology can provide reliable clinical information through thorough history-taking and virtual evaluations that include patient-provided images and disease activity assessment tools that may help accurately diagnose and manage patients with psoriasis. The use of objective measures, including PASI and dermatology life quality index scores, is helpful to quantitively measure patient disease activity but is not necessary for routine clinical care, treatment selection, or assessing treatment response in nonresearch settings. The integration of validated screening tools for PsA and effective teledermatology practices may improve access to specialists, thus avoiding preventable delays in the diagnosis and treatment of patients with PsA. Although the provision of telehealthcare should not completely replace high quality, in-person dermatologic or rheumatologic visits, the convenience and collaborative nature of teledermatology may lead to expanded access and expedited care in the appropriate setting, whether it be in a virtual or in-person visit.1.Teledermatology is a reasonable alternative for providing long-term management of patients with psoriasis. Teledermatology may be an option for initial visits, especially when incapacity, distance, and circumstances prevent the realization of an in-person evaluation.2.It is important to guarantee the accessibility of in-person care for patients with psoriasis and ensure that telemedicine does not supplant such availability.3.A discussion about the available virtual evaluation tools should be undertaken to determine what form of teledermatology is best suited for a patient-physician encounter. This decision should consider patient familiarity with the virtual evaluation platform used, access to stable internet connection, and skillfulness with taking photos and video with electronic devices. Counseling on how to provide high quality images for the encounter should be performed prior to the telehealth visit.4.Developing better technology\u2014allowing for reliable, high quality image capture and appropriate workflows that emulate a dermatology in-person practice\u2014is important in helping to expand the applicability and utility of teledermatology. Standardized, accessible, and objective modalities to assess BSA/PASI may be helpful in having objective measures to monitor for treatment response. The PEST should be provided to patients every 6\u00a0months to screen for PsA to help mitigate the undertreatment and delay in the diagnosis of this common comorbidity in patients with psoriasis.5.A flexible approach to teledermatology for PsA proposes the efficient utilization of in-person and virtual care based on the severity and complexity of the appreciated joint disease. Thorough history-taking and collaborative evaluation techniques are useful in assessing for joint involvement in patients with suspect PsA. Simpler and established cases may be suitable for virtual evaluations, whereas complex or severe cases may warrant an in-person evaluation and referral to a rheumatologist.6.Telemedicine has the potential to allow for collaborative connected-health models to expand the reach of experienced dermatologists to help comanage patients with primary care physicians and community dermatologists who are not comfortable with newer systemic treatments for psoriasis.www.DrScore.com and the founder and part owner of Causa Research. Abby Van Voorhees is consultant for Novartis, Celgene, Novartis, Merck, Dermira, UCB, BMS, Amgen, and Boehringer Ingelheim and conducts research for AbbVie, Novartis, and Allergan. Lawrence Green is investigator, speaker, and/or consultant for AbbVie, Amgen Inc, Arcutis, Dermavant, MC2, Novartis, Lilly, OrthoDerm, SunPharma, and UCB. Sergio Schwartzman has received consulting fees, research grants, speakers\u2019 bureau activity, or ownership or partnership from 10.13039/100006483AbbVie, 10.13039/100002429Amgen, Boston Scientifc, Crescendo Bioscience, Dermtech, Eli Lilly, 10.13039/100004328Genentech, 10.13039/100005564Gilead Sciences, Janssen, 10.13039/100004374Medtronic, Myriad Genetics, 10.13039/100003185National Psoriasis Foundation, 10.13039/100004336Novartis, Pfzer, 10.13039/100009857Regeneron, 10.13039/100004358Samsung, Sanof, and UCB and has participated in the advisory boards of Jubilant, Myriad, and Stelexis. Evan Siegel has received research grants, consulting fees, and speaker fees from 10.13039/100006483AbbVie, BMS, Eli Lilly, 10.13039/100004336Novartis, Janssen, and UCB. Kelly M. Cordoro is a founding member of the Psoriasis Investigator Group of the Pediatric Dermatology Research Alliance, a counselor for the International Psoriasis Council, and contributor of psoriasis educational materials to the American Academy of Dermatology. Leon Kircik has received research grants from 10.13039/100006483AbbVie, 10.13039/100007819Allergan, Almirall, 10.13039/100002429Amgen, Arcutis, 10.13039/100001003Boehringer Ingelheim, Breckinridge Pharma, Bristol Myers Squibb, 10.13039/100006436Celgene, Cellceutix, Centocor, Combinatrix, Connetics, Coria, Dermavant, 10.13039/100013988Dermira, Dow Pharma, Dr Reddy\u2019s Laboratories, Eli Lilly, 10.13039/501100009754Galderma, 10.13039/100004328Genentech, 10.13039/100004330GlaxoSmithKline, Idera, 10.13039/100004331Johnson & Johnson, Leo Pharma, Maruho, 10.13039/100004334Merck, Medicis, 10.13039/100004336Novartis AG, 10.13039/100004319Pfizer, PharmaDerm, Promis, Stiefel, 10.13039/501100013671Sun Pharma, UCB, 10.13039/100011284Valeant, and XenoPort and has received honoraria from 10.13039/100006483AbbVie, 10.13039/100007819Allergan, Almirall, 10.13039/100002429Amgen, Arcutis, 10.13039/100006314Biogen Idec, Bristol Myers Squibb, 10.13039/100006436Celgene, Cipher, Connetics, Dermavant, 10.13039/100013988Dermira, Dr Reddy\u2019s Laboratories, Eli Lilly, 10.13039/501100009754Galderma, 10.13039/100004328Genentech, 10.13039/100004330GlaxoSmithKline, 10.13039/100004331Johnson & Johnson, Leo Pharma, 10.13039/100004334Merck, 10.13039/100004336Novartis AG, PharmaDerm, Promis, Serono , Stiefel, 10.13039/501100013671Sun Pharma, Taro, UCB, and 10.13039/100011284Valeant. Wilson Liao has received research grant funding from 10.13039/100006483AbbVie, 10.13039/100002429Amgen, Janssen, Leo, 10.13039/100004336Novartis, 10.13039/100004319Pfizer, 10.13039/100009857Regeneron, and TRex Bio. Jason E. Hawkes has received personal fees/honoraria from 10.13039/100006483AbbVie, Janssen, LearnSkin, LEO Pharma, 10.13039/100004336Novartis, 10.13039/100004319Pfizer, 10.13039/100004339Sanofi, UpToDate, and VisualDx. Jeffrey Weinberg is a speaker for AbbVie, Amgen, Eli Lilly, Novartis, Sun, Leo Pharma, and Pfizer and an investigator for Dermavant, AbbVie, Corrona Psoriasis Registry, Dermira, Lilly, Novartis, and Pfizer. John Koo has served as an advisor for AbbVie, Amgen, Celgene, Janssen, Eli Lilly, Leo Pharma, EPI, Novartis, Pfizer, Sun Pharma, and Ortho Dermatologics, Regeneron/Sanofi, and UCB. Elizabeth Brezinski Wallace serves as an investigator for Pfizer and Target Real World Evidence. April Armstrong is investigator for Sanofi Genzyme, Bristol Myers Squibb, Dermavant, Dermira, Eli Lily, Galderma, Janssen\u2013Ortho, Inc, Kyowa Hakko Kirin, AbbVie, Janssen Pharmaceuticals Inc, Leo Pharma, Modernizing Medicine, Novartis Pharmaceuticals Corp, Ortho Dermatologics, Pfizer Inc, Regeneron Pharmaceuticals, Sun Pharma, and UCB Pharma; a speaker for AbbVie, Regeneron Pharmaceuticals, and Sanofi Genzyme; and on the data safety monitoring board for Boehringer Ingelheim/ Parexel. George Han is investigator, consultant/advisor, or speaker for AbbVie, Amgen, Arcutis, Athenex, Bausch Health, Boehringer Ingelheim, Bond Avillion, Bristol Myers Squibb, Celgene Corporation, Dermavant, DermTech, Eli Lilly and Company, EPI Health, Janssen Pharmaceuticals, LEO Pharma, MC2 Therapeutics, Novartis, Ortho Dermatologics, PellePharm, Pfizer, Regeneron Pharmaceuticals, Sanofi Genzyme, SUN Pharmaceutical Industries Ltd, and UCB and conducts research for Bausch Health, Eli Lilly and Company, Janssen Pharmaceuticals, and Novartis. Natalia Pelet del Toro, Rayan Yahia, Seemal R. Desai, and Leah M. Howard have no conflicts to declare.Steve R. Feldman received compensation from AbbVie, Accordant, Advance Medical, Almirall, Alovtech, Amgen, Arcutis, Arena, Argenx, Biocon, Boehringer Ingelheim, Bristol Myers Squibb, Caremark, Celgene, Dermavant, Eli Lilly, Galderma, GlaxoSmithKline/Stiefel, Helsinn, Informa, Janssen, Leo Pharma, Menlo, Merck, Mylan, National Biological Corporation, National Psoriasis Foundation Novan, Novartis, Pfizer, Qurient Forte, Regeneron, Samsung, Sanofi, Sun Pharma, Suncare Research, UCB, UpToDate, Valeant, and vTv Therapeutics and is the founder and majority owner of"} +{"text": "PLOS ONE Editors retract this article [The article because MIsrar and FMA-Z did not agree with the retraction. FA, SUR, AA, HG, MIdrees, RI, AK, and MH either did not respond directly or could not be reached."} +{"text": "Rheumatology, Volume 61, Issue 2, February 2022, Pages 679\u2013687, https://doi.org/10.1093/rheumatology/keab388This is a correction to: Toby O Smith, Celia Clarke, Jacob Wells, Jack R Dainty, Laura Watts, Max Yates, Valerie M Pomeroy, Emma Stanmore, Terence W O\u2019Neill, Alexander J Macgregor, Clinical and biomechanical factors associated with falls and rheumatoid arthritis: baseline cohort with longitudinal nested case\u2013control study, The author list has been updated to add Jacob Wells as third author."} +{"text": "The authors regret this error.In the original publication of this article, [Ni Y, Zhong H, Gu Y et al. Clinical Features, Treatment, and Outcome of Psittacosis Pneumonia: A Multicenter Study, Open Forum Infectious Diseases, Volume 10, Issue 2, February 2023, ofac518,"} +{"text": "Few prospective studies have documented the seropositivity among those children infected with severe acute respiratory syndrome coronavirus 2. From 2 April 2021 to 24 June 2021, we prospectively enrolled children between the ages of 2 and 17\u00a0years at three North Carolina healthcare systems. Participants received at least four at-home serological tests detecting the presence of antibodies against, but not differentiating between, the nucleocapsid or spike antigen. A total of 1,058 participants were enrolled in the study, completing 2,709 tests between 1 May 2021 and 31 October 2021. Using multilevel regression with poststratification techniques and considering our assay sensitivity and sensitivity, we estimated that the seroprevalence of infection-induced antibodies among unvaccinated children and adolescents aged 2\u201317\u00a0years in North Carolina increased from 15.2% in May 2021 to 54.1% (95% CrI 46.7\u201361.1) by October 2021, indicating an average infection-to-reported-case ratio of 5. A rapid rise in seropositivity was most pronounced in those unvaccinated children aged 12\u201317\u00a0years, based on our estimates. This study underlines the utility of serial, serological testing to inform a broader understanding of the regional immune landscape and spread of infection. The mortality rate of acute coronavirus disease 2019 (COVID-19) has typically followed a strong age gradient with children being at lower risk of severe clinical outcomes . HoweverThe United States National Commercial Laboratory Seroprevalence Survey has monitored infection-induced seroprevalence in all age groups since August 2020, with a recent focus on children aged \u226417\u00a0years , 13. TheWe describe trends in prevalence of infection-induced antibodies using serial at-home serological testing in a cohort of 2- to 17-year-old children enrolled in a prospective, syndromic surveillance study in North Carolina. We used seroprevalence estimates to calculate infection-to-reported case ratios for a better understanding of the local burden of SARS-CoV-2 infections.The COVID-19 Community Research Partnership (CCRP) is a multi-site, prospective cohort study combining electronic symptom surveillance with serological surveillance , 15. FroThis study was approved by the institutional revenue board for Wake Forest University School of Medicine (IRB00064912).An Innovita Biological Technology SARS-CoV-2 lateral flow assay was used to detect SARS-CoV-2 immunoglobulin G (IgG) with a sensitivity of 84.5% and a specificity of 99%; the assay detected but did not differentiate between anti-spike and anti-nucleocapsid IgG. Infection-induced antibodies were defined as the presence of a positive IgG prior to any reported vaccine dose.To estimate seroprevalence from infection over time, a Bayesian framework was employed accounting for assay sensitivity and specificity. Participants from North Carolina and South Carolina were pooled for the analysis. The proportion of respondents with infection-induced antibodies was estimated for each study month. To estimate the North Carolina seroprevalence from infection using the cohort data, multilevel regression with poststratification (MRP) was performed. A multilevel logistic regression was fitted with an intercept and random effects for age group in years , 12\u201317, All analyses were conducted with R version 4.1.3 (2022-03-10) and Stan version 2.28.1 .A total of 1,058 participants from 35 and 6 counties in North Carolina and South Carolina, respectively, consented to both syndromic and serological surveillance. Participants were predominately White and non-Hispanic and returned a median of serology two tests (IQR 1\u20134) within a median of 32\u00a0days (IQR 27\u201338) . During Our findings support the mounting evidence of a high seroprevalence of SARS-CoV-2 infection among children and adolescents . By OctoThe seroprevalence of infection-induced antibodies among children has exceeded that of adult age groups in the United States since November 2020 . As of SWe found that those unvaccinated adolescents aged 12\u201317 had the highest prevalence of infection-induced antibodies and further had several periods of large increases in seroprevalence. The estimated higher prevalence may be a product of differing contact patterns amongst this age group when compared with the younger age groups. Prior studies of contact patterns conducted in European countries have indicated that those aged 10\u201319\u00a0years have the highest number of reported contacts when compared to other age groups \u2013 a pattLikely the most profound change in contact patterns in children and adolescents during the study period was the widespread return to in-person education . Due to Our study highlights the opportunity to use Bayesian techniques with a relatively small number of prospectively enrolled participants conducting at-home testing, even among children and adolescents, to make small area inferences and better capture local disease dynamics for infections other than SARS-CoV-2. While traditional national sentinel-based frameworks leverage existing networks of healthcare providers, studies have shown that these frameworks may under-ascertain the disease dynamics in lower socio-economic populations who do not have access to these resources . MinoritOur study has a few limitations. The surveillance was limited to North Carolina and South Carolina, limiting generalisability of results. However, this geographic focus is important because public health measures may need to be deployed given local transmission dynamics, underlying comorbidities, and probability of adverse outcomes. For example, individuals in the Southeast United States are often disproportionately affected by many chronic diseases and infection , 44. OurUnlike prior national surveys , 7, 13, Although children have milder illness compared to adults with COVID-19, they play a major role in transmission, even if asymptomatic , 15. AccWake Forest School of Medicine: Thomas F. Wierzba, PhD, MPH, MS, John Walton Sanders, MD, MPH, David Herrington, MD, MHS, Mark A. Espeland, PhD, MA, John Williamson, PharmD, Morgana Mongraw-Chaffin, PhD, MPH, Alain Bertoni, MD, MPH, Martha A. Alexander-Miller, PhD, Paola Castri, MD, PhD, Allison Mathews, PhD, MA, Iqra Munawar, MS, Austin Lyles Seals, MS, Brian Ostasiewski, Christine Ann Pittman Ballard, MPH, Metin Gurcan, PhD, MS, Alexander Ivanov, MD, Giselle Melendez Zapata, MD, Marlena Westcott, PhD, Karen Blinson, Laura Blinson, Mark Mistysyn, Donna Davis, Lynda Doomy, Perrin Henderson, MS, Alicia Jessup, Kimberly Lane, Beverly Levine, PhD, Jessica McCanless, MS, Sharon McDaniel, Kathryn Melius, MS, Christine O\u2019Neill, Angelina Pack, RN, Ritu Rathee, RN, Scott Rushing, Jennifer Sheets, Sandra Soots, RN, Michele Wall, Samantha Wheeler, John White, Lisa Wilkerson, Rebekah Wilson, Kenneth Wilson, Deb Burcombe, Georgia Saylor, Megan Lunn, Karina Ordonez, Ashley O\u2019Steen, MS, Leigh Wagner.Atrium Health: Michael S. Runyon, MD, MPH, Lewis H. McCurdy, MD, Yhenneko J. Taylor, PhD, Lydia Calamari, MD, Hazel Tapp, PhD, Michael Brennan, DDS, Lindsay Munn, PhD RN, Timothy Hetherington, MS, Lauren C. Lu, Connell Dunn, Melanie Hogg, MS, CCRA, Andrea Price, Marina Leonidas, Melinda Manning, Frank X. Gohs, MS, Anna Harris, MPH, Jennifer S. Priem, PhD, MA, Pilar Tochiki, Nicole Wellinsky, Crystal Silva, Tom Ludden, PhD, Jackeline Hernandez, MD, Kennisha Spencer, Laura McAlister.Wake Med Health and Hospitals: William H. Lagarde, MD, LaMonica Daniel, BSCR.George Washington University Data Coordinating Center: Sharon L. Edelstein, ScM, Michele Santacatterina, PhD, Greg Strylewicz, PhD, Brian Burke, MS, Mihili Gunaratne, MPH, Meghan Turney, MA, Shirley Qin Zhou, MS, Ashley H. Tjaden, MPH, Lida Fette, MS, Asare Buahin, Matthew Bott, Sophia Graziani, Ashvi Soni, MS, Guoqing Diao, PhD, Jone Renteria, MS.George Washington University Mores Lab: Christopher Mores, PhD, Abigail Porzucek, MS.Oracle Corporation: Rebecca Laborde, Pranav Acharya.Vysnova Partners: Anne McKeague, PhD, Johnathan Ward, MS, Diana P. Naranjo, MA, Nana Darko, MPH, Kimberly Castellon, BS, Ryan Brink, MSCM, Haris Shehzad, MS, Derek Kuprianov, Douglas McGlasson, MBA, Devin Hayes, BS, Sierra Edwards, MS, Stephane Daphnis, MBA, Britnee Todd, BS."} +{"text": "There are limited data on the safety profile of the severe acute respiratory syndrome coronavirus-2 vaccine among patients taking immunosuppressive medications. Our aim was to evaluate the adverse events related to the vaccines in a nationwide cohort of patients with inflammatory bowel disease on diverse immunosuppressive medications.This was a retrospective cohort study using data from the Veterans Health Administration. The primary outcome was any adverse event of special interest within 90 days of vaccination.A total of 17,201 patients were included, and 12,351 patients (71.8%) received at least 1 vaccine dose. The most common adverse events were acute myocardial infarction and venous thromboembolism. In inverse probability treatment weighting-adjusted logistic regression, full vaccination was not significantly associated with increased adverse events through 90 days, relative to unvaccinated patients.Full severe acute respiratory syndrome coronavirus-2 vaccination was not associated with an increased rate of key adverse events relative to unvaccinated individuals among patients with inflammatory bowel disease. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has affected over 596 million people worldwide as of August 24, 2022 . To prevInflammatory bowel disease (IBD), comprising ulcerative colitis (UC), and Crohn's disease (CD), is a chronic inflammatory disorder of the gastrointestinal tract. Vaccination is strongly recommended to prevent the development of SARS-CoV-2 among patients with IBD. The vaccines have been shown to be effective among patients with IBD . A possiThis was a retrospective cohort study using data from an established national IBD cohort in the VHA. We used a previously validated algorithm based on administrative codes and pharmacy data to identify patients with UC or CD before December 18, 2020, the start date of the VHA COVID-19 vaccination campaign (index date) ,4. PatieThe primary exposure in this study was SARS-CoV-2 vaccination . Vaccine administration events were identified using Current Procedural Terminology codes. For each patient, we additionally obtained baseline demographics , alcohol use history, tobacco use history, geographic region, IBD type (UC or CD), and Charlson Comorbidity Index. IBD medication groups in the 3 months before the index date were categorized as 5-ASA alone, thiopurines , with or without 5-aminosalicylic acid medications), antitumor necrosis factor (anti-TNF) agents alone, anti-TNF + TPs, vedolizumab, ustekinumab, and tofacitinib. Steroid use was also ascertained in a 3-month window before the index date using prescriptions for budesonide, methylprednisolone, prednisolone, or prednisone.International Classification of Diseases 9/10 codes to ascertain the first occurrence of the following composite events identified as adverse events of special interest (AESIs), which were commonly reported in the Pfizer and Moderna trials: cerebrovascular accident, venous thromboembolism (VTE), acute myocardial infarction, and Bell palsy. AESIs were identified within 90 days of first or second vaccination doses. As a reference group, AESIs for unvaccinated patients were evaluated relative to an index date set to the median time to first vaccination in patients who were vaccinated . Importantly, every adverse event was manually adjudicated for confirmation through detailed chart review. For statistical analysis, refer supplementary material.The primary outcome was development of any adverse event of interest after SARS-CoV-2 vaccination, with follow-up data obtained through February 2, 2022. Based on observed adverse events in clinical trials, we used incident After application of selection criteria and exclusion of 387 patients who received the Janssen vaccine, we identified a total of 17,201 patients with IBD. Of these, 12,351 (71.8%) received at least 1 vaccine dose and 4,850 (28.2%) remained unvaccinated (Table A summary of postvaccination AESIs is provided in Table http://links.lww.com/CTG/A895). In unadjusted models, first-dose vaccination was associated with reduced odds of AESIs vs unvaccinated patients , and there was no significant difference in AESIs between second-dose vaccination and unvaccinated patients .After creation of propensity scores and application of inverse probability weights, excellent covariate balance was achieved between unvaccinated and vaccinated groups, demonstrated by standardized mean differences reduced to within \u00b1 0.1 for each exposure variable and by the National Institute of Diabetes and Digestive and Kidney Diseases (K08-DK124577). There was no designated funding received for this study.Potential competing interests: N.K. has received an unrestricted research grant from Pfizer, Luitpold, and Takeda Pharmaceuticals as well as Samsung BioEpis. He has served on the advisory board of Pharmacosmos. N.M., M.P., and R.S. have nothing to disclose regarding conflicts of interest. W.R. (i) has served as a speaker for Abbott Laboratories, AbbVie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, and Yakult; (ii) has served as a consultant for Abbott Laboratories, AbbVie, Aesca, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena Pharmaceuticals, Astellas, AstraZeneca, Avaxia, Roland Berger GmBH, Bioclinica, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernst & Young, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Gr\u00fcnenthal, ICON, Index Pharma, Inova, Intrinsic Imaging, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Medahead, MedImmune, Millennium, Mitsubishi Tanabe Pharma Corporation, MSD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, OMass, Otsuka, Parexel, PDL, Periconsulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Quell Tx, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Therakos, Theravance, Tigenix, UCB, Vifor, Zealand, Zyngenia, and 4SC; (iii) has served as an advisory board member for Abbott Laboratories, AbbVie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, DSM, Elan, Ferring, Galapagos, Genentech, Gr\u00fcnenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millennium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Zealand, Zyngenia, and 4SC; and (iv) has received research funding from Abbott Laboratories, AbbVie, Aesca, Centocor, Falk Pharma GmbH, Immundiagnostik, and MSD.Data Availability Statement: The data for this manuscript cannot be made available in accordance with the HIPAA rules. However, deidentified data (without patient name and SSN) can be made available upon reasonable request.IRB Approval Statement: Data were collected using preexisting electronic patient records in the VISTA CAPRI database after an institutional review board (IRB) approval from the Corporal Michael J Crescenz VA Medical Center, Philadelphia, PA."} +{"text": "European Heart Journal, Volume 43, Issue 29, 1 August 2022, Pages 2770\u20132780, https://doi.org/10.1093/eurheartj/ehac307This is a corrigendum to: William K F Kong, Antonio Salsano, Daniele Roberto Giacobbe, Bogdan A Popescu, C\u00e9cile Laroche, Xavier Duval, Robert Schueler, Antonella Moreo, Paolo Colonna, Cornelia Piper, Francisco Calvo-Iglesias, Luigi P Badano, Ilija Srdanovic, David Boutoille, Olivier Huttin, Elisabeth St\u00f6hr, Ana Teresa Tim\u00f3teo, Jolanta Justina Vaskelyte, Anita Sadeghpour, Pilar Tornos, Leila Abid, Kian Keong Poh, Gilbert Habib, Patrizio Lancellotti, on behalf of the EURO-ENDO Investigators, Outcomes of culture-negative vs. culture-positive infective endocarditis: the ESC-EORP EURO-ENDO registry, EURO-ENDO Investigators were mistakenly included in the supplementary data section, rather than the main body of the manuscript.In the originally published version, named members of the This has now been corrected online."} +{"text": "Schizophrenia Bulletin, Volume 48, Issue 5, September 2022, Pages 967\u2013980, https://doi.org/10.1093/schbul/sbac049This is a correction to: Grace E Woolway, Sophie E Smart, Amy J Lynham, Jennifer L Lloyd, Michael J Owen, Ian R Jones, James T R Walters, Sophie E Legge, Schizophrenia Polygenic Risk and Experiences of Childhood Adversity: A Systematic Review and Meta-analysis, Referencing errors were identified in the original published version of this manuscript. These errors have now been corrected."} +{"text": "Correction: BMC Pregnancy Childbirth 23, 20 (2023)10.1186/s12884-022-05204-xFollowing publication of the original article , the autThe incorrect author names are: Ungureanu Anda, Marcu Andreea-Sorina, Patru Ciprian Laurentiu, Ruican Dan, Nagy Rodica, Stoean Ruxandra, Stoean Catalin, Iliescu Dominic Gabriel.The correct author names are: Anda Ungureanu, Andreea-Sorina Marcu, Ciprian Laurentiu Patru, Dan Ruican, Rodica Nagy, Ruxandra Stoean, Catalin Stoean, Dominic Gabriel Iliescu.The author group has been updated above and the original article has been"} +{"text": "R. China2Department of Anesthesiology, Peking University Third Hospital, Beijing, P. R. China3Obstetrics and Gynecology, Jiaozuo Women and Children Hospital, Jiaozuo, Henan Province, China4Department of Hepatobiliary Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, P. R. China5Department of Liver Transplantation, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China#Co\u2010first authors: Shipeng Li and Jindan He*Correspondence Author:Shipeng Li, Department of Hepatobiliary Surgery, First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan Province, 453100, P. R. China. Email: shipengli2010@163.comBingbing Qiao, Department of Hepatobiliary Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450000, P. R. China. Email: popzxcbb@126.comHaiming Zhang, Department of Liver Transplantation, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, PR China. Email: mdzhanghaiming@qq.comhttps://doi.org/10.1002/mco2.58First published: 11 February 2021, In the process of checking the raw dataAbbreviations: IRI, ischemia\u2010reperfusion injury; ALT, alanine transaminase; AST, aspartate transaminase; TUNEL, Terminal Deoxynucleotidyl Transferase Mediated dUTP Nick End Labeling; PCNA, proliferating cell nuclear antigen; IRF, Interferon Regulatory Factor; JNK, c\u2010Jun N\u2010terminal kinase; GAPDH, glyceraldehyde\u20103\u2010phosphate dehydrogenase; GFP, green fluorescent protein; TEM, Transmission Electron Microscope."} +{"text": "The correct author names are: Kadio Jean-Jacques Olivier Kadio, Amadou Ciss\u00e9, Thierno Saidou Diallo, Foromo Guilavogui, Adrien Fapeingou Tounkara, Damey Pe, Alhassane Sow, Fatoumata Fily Bah, Souleymane S\u00e9kou Youla, Ibrahima Diallo, Niouma Nestor Leno, Lazare Mboungou, Nyawotope Koffi Arnold Ahiatsi, Laye Kaba, Sy Zeynabou, Ignasi Vall\u00e8s-Casanova, Alison Wringe, Sarah Hoibak, Youssouf Ko\u00efta, Xavier Vall\u00e8s. The correct citation is: Kadio KJ-JO, Ciss\u00e9 A, Diallo TS, Guilavogui F, Tounkara AF, Pe D, et al. (2023) Retention in care among people living with HIV in the national antiretroviral therapy programme in Guinea: A retrospective cohort analysis. PLOS Glob Public Health 3(5): e0000970. There are also errors in the Funding information. The correct Funding information is: This work was funded by the Global Fund to fight against AIDS, Malaria and Tuberculosis in the form of a grant (GIN-H-MOH) awarded to KJJOK, AC, TSD, FG, AFT, DPD, AS, FFB, SSY, ID, NNL, LM, NKAA, LK and YK. This work was also funded by Instiuto de Salud Carlos III, Ministry of Science and Innovation (Spain) through the study CLIMATE-COVID19 in the form of a grant (PIM-E-202030E222) awarded to IVC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."} +{"text": "Accordi stages) ,16. Sinc stages) ,18. Chem stages) ,20,21 an stages) . Because stages) ,24. A fe stages) ,26. The ly 1960s . Since ts et al. . At thats et al. . Beyond s et al. . Howevers et al. . Pharmacs et al. ,33. Thisidazoles ,35. In pchanisms ,37. Howechanisms . Some ofchanisms ,40, focuotection . Furtherotection . Anotherotection and rumiflagrans . This spflagrans ,46 mixedflagrans or in anflagrans . Once chflagrans ,50,51,52flagrans ,54 and fflagrans ,56,57,58flagrans ,60,61. Eflagrans ,63. Tropflagrans ,65. The flagrans ,67. Seveflagrans ,67,68,69flagrans . Among oflagrans . Such suflagrans , facilitflagrans ,74, enabdy score ,76. Othedy score . The useer alone or in coontortus .In recent years, the number of studies on novel approaches for parasite control has increased, with focus on viable tools to design an efficient integrated program for GIPN control. The inevitable new era of anthelmintic resistance in livestock, along with consumer awareness of animal welfare and environmental health, calls for in-depth scientific work to offer solutions to the livestock industry. In the pursuit of a chemically synthesized anthelmintic drug independency, parasite control, in the near future, will rely on prevention and on the combined use of strategies. The present Pathogens Special Issue aims to describe for the readers some of the novel approaches for GIPN control in ruminants, developed based on animal welfare awareness to tackle this group of pathogens in an environmentally friendly manner."} +{"text": "Medical Assistance in Dying, Palliative Care, Safety, and Structural Vulnerability. That report attempted to argue that structural vulnerability was not a concern in the provision of assisted dying (AD) by a selective review of evidence in medical literature and population studies. It claimed that palliative care has its own safety concerns, and that \u201cmisuse\u201d of palliative care led to reports of wrongful death. We and our signatories do not feel that the conclusions reached are supported by the evidence provided in the contested report. The latter concluded that the logical policy response would be to address the root causes of structural vulnerability rather than restrict access to AD. Our report, endorsed by an international community of palliative care professionals, believes that public policy should aim to reduce structural vulnerability and, at the same time, respond to evidence-based cautions about AD given the potential harm.This report, signed by >170 scholars, clinicians, and researchers in palliative care and related fields, refutes the claims made by the previously published The interpretation and faithfulness to the original text and how a piece of evidence applies to an argument can generate what has increasingly been called \u201cspin.\u201dMedical Assistance in Dying, Palliative Care, Safety, and Structural Vulnerability by Downar et al.3We wish to express our deep concern about the flawed scholarship in the report on We recognize that Medical Assistance in Dying (MAiD) is a fiercely contentious and polarizing issue. We believe individuals should be allowed to voice their opinions, no matter what they are. However, we take exception to seeing those opinions presented as if they were evidence based when the conclusions appear to be reached by ignoring critical information within cited sources and engaging in speculation without basis. The resultant conclusions can only be described as spurious ones. Given its potential to affect future research, medical practice, policies, and public health, this special report cannot enter the public record without it being strongly contested.The authors point out that assisted death (AD) is more common in people with higher income and education, with the implication being that these people are not structurally vulnerable. Of the four articles referenced, two are Canadian studies conducted before AD was available to people who did not have a reasonably foreseeable death and who were more likely to be structurally vulnerable. The American study consists of 114 patients over the first two years of AD in a system where applicants must be within six months of death. The Swiss population-based study is from 2003 to 2008, with only 20 of the 1301 ADs being for mental illness.4 This statistic parallels the 2:1 ratio of females to males in attempting suicide during vulnerable times, most of whom do not attempt suicide again. The obvious concern is whether AD for mental illness is providing a lethal means for women to die, during times of vulnerability, who would otherwise recover and regain the desire to live.Studies of patients whose death is not reasonably foreseeable reveal a different picture. A Dutch review of the publicly available information on 66 ADs for mental illness between 2011 and 2014 reported the ratio of women to men as 2.3:1.Most of the disorders were depression (55%), but 12% had psychotic features, and 52% of the 66 cases had personality problems, some without an official diagnosis. The majority of patients (56%) reported unresolved social suffering including social isolation or loneliness. The majority of patients had long histories with mental illness and had tried multiple therapies, though 56% had refused some therapies making the judgment of treatment futility challenging. It must be noted that Canadian law does not require any treatments be tried or accessible before providing AD.5 examines the association of functional decline comparing cancer deaths with those caused by heart failure, stroke, and diabetes.The authors state that people with frailty and organ failure, whom they describe as more vulnerable and dependent than patients with cancer, receive less palliative care and do not make up nearly as many patients receiving AD. Hence, they conclude that AD is not targeting those with structural vulnerability. The article they reference by Teno et al.Although people with noncancer illnesses started their last year of life with more disability than those with cancer, the latter experienced a more precipitous decline in activities of daily living (ADL) starting approximately five months before death, leading to functional impairment exceeding that of noncancer illnesses in the final months. This rapid decline was associated with where the person died and whether palliative care was involved in their last months of life.6 of cancer as opposed to the unpredictable course for organ failure and frailty.8 Hence, cancer is the most prevalent diagnosis for AD because its terminal course is predictable, and it is the most common cause of death in Canada.9Studies show that people with cancer receive more palliative care relative to frailty or organ failure in multiple countries, because of the \u201cdecline predictability\u201d10 Early childhood deaths have had the most impact over the centuries, with the impact of AD in adults being minimal. It is not logical to make conclusions about one factor in complex systems in different countries.The authors note that life expectancy has grown in countries that permit AD as opposed to those that do not. Life expectancy in a country depends on public health outcomes resulting from policies in health care and beyond, which affect the social determinants of health.11 As such, in the Netherlands, Belgium, and parts of Canada, it would be impossible to sort these deaths out from others to characterize them as excess mortality. Excess mortality is difficult to detect even with the best design, but especially during a pandemic, when there is another source of excess deaths that was much more common.The authors state that during COVID-19, which targeted structurally vulnerable people, AD increased even further in Canada, Belgium, and the Netherlands, yet these countries had substantially lower excess mortality during this time. Tracking excess mortality requires researchers to know the cause of death, and only some provinces in Canada mandate that AD be noted on the death certificate.The authors state that the importance of these population studies \u201ccannot be overstated.\u201d They even double down by suggesting that a rise in life expectancy in countries allowing AD suggests vulnerability may offer protection. The evidence they provide does not support this.The authors imply that, like AD, palliative care is culpable for unintended deaths.The first claim notes that palliative care providers regularly advocate for improved access to opioids for people with advanced illness, and \u201cIncreased opioid availability is a key facilitator of good PC, but it is also a contributor to the opioid crisis in many countries.\u201d They state, \u201cRoughly 8000 Canadians died of an opioid overdose in 2021 alone; a substantial proportion of these overdoses involved a pharmaceutical opioid that was either prescribed or diverted.\u201d They reference a Health Canada website publication that is no longer directly available, as it is updated yearly.12 a large headline proclaims, \u201ctoxicity of supply continues to be a major driver of the crisis\u201d and notes, \u201cOf all accidental apparent opioid toxicity deaths in 2022 (January\u2013December), 79% involved opioids that were only non-pharmaceutical.\u201d More studies are reporting an increase in overdoses from illegal opioids, even as the use of prescription opioids is declining.13 Implying that palliative care is partly responsible for the opioid crisis is a misreading of the evidence and disregards the complex nature of the problem.In the version accessible now,14The second claim involves the Liverpool Care Pathway (LCP). Downar et al. state there were \u201cnumerous complaints of widespread abuse and hastened deaths, particularly among the structurally vulnerable.\u201d The LCP independent review reported that \u201csome relatives and carers have reached the conclusion that \u2018the pathway\u2019 represents a decision on the part of clinicians, in effect, to kill their dying patients, when that is clearly not the case.\u201d15The authors cast doubt on media stories showing that vulnerable people have been approved for AD. They review only two of the numerous media-reported cases that have surfaced in Canada. The first is a woman with multiple chemical sensitivities who requested and received AD. Downar et al. state her situation was incorrectly portrayed in the media as poverty and a lack of adequate housing rather than intolerable suffering related to her underlying condition. They reference testimony from her AD provider, reading a note from the woman thanking her for believing in her suffering and granting her AD.16 quotes the letter saying, \u201cWe physicians find it UNCONSCIONABLE that no other solution is proposed to this situation other than medical assistance in dying.\u201dThis same AD provider signed a letter to federal housing and disability government officials confirming that her symptoms improved in cleaner air environments and asked for help to find or build a chemical-free residence. MediaThe second case is a man whose request for AD was because of impending homelessness. They quote a twitter post from the man saying the story was \u201chijacked by the right trying to spin it into their own agenda.\u201d The full quote says: \u201cIt seems my story has been hijacked by the right trying to spin it into their own agenda. I hope people don't get distracted by this. The real issue isn't whether or not someone like me should be able to access MAiD. It's making life bearable enough that they won't need to.\u201d We agree people should receive adequate support to live, and we desire adequate safeguards to prevent life termination when structurally vulnerable people are despairing from a social failure of society.In both these cases, the authors edited the patient's stories and words to affirm their argument that there are no concerns of structural vulnerability driving AD.17\u201319There are some credible well-investigated cases in the media that should concern everyone.20 They did this study the same year that Canada first approved AD for persons without a foreseeable death, so few cases would be expected. Although the article says unmet needs were rare, it reports \u201cThere were some cases in which the provider was worried that unmet needs were driving the request for MAiD. These situations included poor quality or inappropriate housing, inadequate home care in someone who refuses to go into long term care, long waitlists for publicly funded multidisciplinary chronic pain clinics and no local care available requiring unacceptable travel.\u201dA 2021 Canadian academic study questioning whether unmet needs were driving requests for AD interviewed 20 of 120 clinicians of the national association of AD assessors and providers.The same study quoted an AD provider's take on the conflict of an applicant with structural vulnerability requesting AD from them: \u201cI think we've become\u2014I don't know if comfort is the right word, but we've become more accepting that there are patients that have unmet needs that if they were met may change their request or their timeline, but that those needs are not meetable under the current system, and therefore, we go ahead and approve the patient and sometimes provide MAiD.\u201d21 that structural vulnerability may be driving some cases of AD. Yet, in a report from 2022 testimony to a parliamentary committee reviewing AD,22 the lead author of the article we contest stated: \u201cthere is absolutely no data suggesting that the practice of MAiD at this point is driven to any degree by poor access to palliative care, socio-economic deprivation or any isolation.\u201d Independent of the total numbers of confirmed cases of Canadians receiving AD for structural vulnerability, which may be under-reported given current data reporting requirements that are based on provider self-reported data rather than prospective oversight, we are concerned by the blanket dismissal and minimization of any deaths by AD for unmet social needs.There is evidence in scholarly publications3 It references the Quebec oversight body that publishes a yearly report. No details about cases who did not comply with legislation, nor what was done about it are provided. Dr. Michel Bureau, head of the oversight body, recently sent a memo to doctors that was published online,23 reminding them to stay within the limits of the law.The article states: \u201cAny concerning cases are referred to the appropriate regulatory body for further investigation. Although we do not have reports from all jurisdictions\u2026\u201d.24 that 15 out of 3663 doctor-ADs in Quebec between spring 2021 and spring 2022 did not comply with the law. The physician's regulatory body declined to take any disciplinary action.Two notes from the memo stand out: \u201cAdvanced age and aging-related problems are not a serious illness and incurable and do not warrant MAiD\u201d; and \u201cShopping around\u201d for a favorable second opinion is not an acceptable practice.\u201d Dr. Bureau stated during an interview25 Thus, it is not surprising that no cases related to AD have yet to appear in the Ontario College's case outcomes. The chief coroner of Ontario recently announced a Medical Assistance in Dying Death Review Committee (MDRC)26 in response to increasing health, social, and intersectional complexities arising from current and pending legislative changes. The MDRC will provide an independent expert review of MAiD deaths to assist in evaluating public safety concerns.In Ontario, Canada's most populous province, the Ontario coroner reviews AD deaths, and the only public document that appears is their framework of notification of assessors/providers if they are not following regulations. It appears to require ongoing violations before any reporting to a regulatory body or police occurs.27 The report noted regional variations in the provision of AD and a lack of a framework for case review. In 2018, the coroner's office announced that the only AD cases they would be reviewing were those where the underlying condition leading to the request for MAiD relates to an accident, violence, or self-inflicted injury; or if the death was provided in a mental health or correctional facility.28British Columbia (BC) has a MAiD Oversight Unit that lies within the ministry of health, but it has no publications or public facing website. There is only one BC coroner's death review panel on AD and that covers only the year 2016.The memo from the Quebec oversight body and the formation of the Ontario MDRC have happened since the publication of the article we are contesting. These changes counter the article's assertions that all is well and that we should trust the current oversight.The article closes by restating the major argument that the data show no evidence of structural vulnerability in the provision of AD and that controversies in palliative care are the mirror image of those with AD. The evidence, however, simply does not support the many claims and conclusions.There is evidence of people receiving AD when they are structurally vulnerable, and providing death to people for those situations was never intended by the legislation and should be rigorously and transparently investigated. We believe that public policy should aim to reduce structural vulnerability in all people and, at the same time, be responsive to evidence-based cautions about AD given the potential harm. We take no pleasure in writing this rebuttal but feel compelled to expose what appears to be spin that is harmful to future scholarship, clinical practice, health policy, and public education focused on the practice of assisted dying.Tristan Anderson, MD, FRCPC, Psychiatrist, Manitoba, Canada; Jeremy Bannon, MD, CCFP, Hospitalist, Hotel Dieu Shaver, Associate Clinical Professor (Adjunct), Michael G. DeGroote School of Medicine, McMaster University, MA Candidate , Pellegrino Center for Clinical Bioethics, Georgetown University, Ontario, Canada; Samia Barakat, MD, Professor Emeritus, Psychiatry, University of Manitoba, Manitoba, Canada; Paul Barr\u00e9, MD, FRCP(C), Quebec, Canada; Sasha Bernatsky, MD, FRCPC, PhD, Quebec, Canada; Eileen Biggs, MD, Ontario, Canada; Thomas Bouchard, MD, FCFP, Alberta, Canada; Eduardo Bruera, MD, FT McGraw Chair in the Treatment of Cancer, Chair, Department of Palliative, Rehabilitation, & Integrative Medicine, MD Anderson Cancer Center, Texas, USA; Althea Burrell, BASc, MD, FRCPC, Adult Respirology, Ontario, Canada; Ira Byock, MD, FAAHPM, Emeritus Professor of Medicine and Community & Family Medicine Dartmouth Geisel School of Medicine, Montana, USA; Casimiro Cabrera Abreu, Associate Professor of Psychiatry, Department of Psychiatry, Providence Care Hospital, Queen's University, Kingston, Ontario, Canada; Luigi A. Castagna, MD, FRCP(C), Paediatric Neurology, Developmental Paediatrics, Ontario, Canada; David Chan, MD, MSc, Professor Emeritus, Family Medicine, McMaster University, Ontario, Canada; David Chen, MD, MS-Bioethics DFAPA, Maryland, USA; Maria Cigolini, MBBS (USyd), FRACGP, FAChPM, Grad.DipPallMed(UMelb), Senior Palliative Medicine Physician, Board Member, International Association of Hospice and Palliative Care, Associate Professor, New South Wales, Australia; Stephen R Connor, PhD, LP, Executive Director, Worldwide Hospice Palliative Care Alliance, London, United Kingdom; Margaret M Cottle, MD, CCFP (PC), LM, Clinical Assistant Professor, Division of Palliative Care, Faculty of Medicine, University of British Columbia, British Columbia, Canada; Paul Dagg, MD, FRCPC, Clinical Professor UBC, British Columbia, Canada; Douglass Dalton, FCFP, Quebec, Canada; Jane Dobson, MD, FCFP, Ontario, Canada; Sinead Donnelly, MD, FRCPI, FRACP, Associate Professor, Aotearoa New Zealand and Ireland; P. Drijber, MD, PhD, CCFP (F), CBOM (A), Ontario, Canada; David D'Souza, MD, CCFP, DTM&H, DCAPM, Pain, Addictions, Care of the Elderly, Assistant Professor, Queen's University, Ontario, Canada; David Paul D'Souza, MD, FRCPC, Ontario, Canada; Mark D'Souza, MD, CCFP(EM), FCFP, Assistant Professor, Queen's University, Ontario, Canada; Roy Eappen, MDCM, FACE, FRCP(C), FACP, CD, FACE, Quebec, Canada; Timothy Ehmann, MD, FRCPC, Child & Adolescent Psychiatrist, Alberta, Canada; Joel N. Eisen, MD, FRCP, Psychiatrist, Ontario, Canada; James M. Ellison, MD, MPH, Pennsylvania, USA; E. Wesley Ely, MD, MPH, Grant W. Liddle Professor of Medicine and Critical Care, CIBS Center, Vanderbilt University Medical Center, TN Valley VA GRECC, Tennessee, USA; Sherif Emil, MDCM, FRCSC, FACS, FAAP, Mirella & Lino Saputo Foundation Chair in Pediatric Surgical Education & Patient and Family-Centred Care Professor of Pediatric Surgery, Surgery, and Pediatrics, Associate Chair for Education & Departmental Citizenship, Department of Pediatric Surgery, McGill University Faculty of Medicine, Director; Harvey E. Beardmore, Division of Pediatric Surgery, Senior Investigator, The Research Institute of the McGill University Health Centre, Quebec, Canada; Karen Ethans, MD, FRCPC, Associate Professor, Internal Medicine, Section of Physical Medicine and Rehabilitation, University of Manitoba, Manitoba, Canada; Adrian J Farrell, BScHons, MBChB, MD, FRCP, Consultant Rheumatology, WAHT , Worcestershire, United Kingdom; Natasha Fernandes, MD, FRCPC (Psychiatry), Ontario, Canada; Nisha Fernandes, MD, FRCPC, Ontario, Canada; Catherine Ferrier, MD, CCFP (COE), FCFP, Division of Geriatric Medicine, McGill University Health Centre, Quebec, Canada; Baroness Finlay of Llandaff, FRCGP, FRCP, FMedSci, FHEA, FLSW, London, United Kingdom; Timothy Foggin, MD, BSc, MDCM, MPH, CCFP, FCFP, FRCPC, FACHE, British Columbia, Canada; Sarah Garside, MD, PhD, FRCPc, Associate Professor, McMaster University, Ontario, Canada; Sheenagh George, MD, FRCPC, Nova Scotia, Canada; Roger Ghoche, MDCM, CCFP-PC, MTS, Rehabilitation and Palliative Care Medicine, Professeur Adjoint, Directeur de Cours de M\u00e9thode Clinique II, Universit\u00e9 McGill, Assistant Professor, Course Director of Clinical Method II, McGill University, Mount Sinai Hospital, Montr\u00e9al, Quebec, Canada; Judy Glass, MD, FRCPC, DLFAPA, Director, Emergency Psychiatry, Jewish General Hospital, Assistant Professor, McGill University, Department of Psychiatry, Qu\u00e9bec, Canada; John Good, MB, BCh, LM , DRCOG (UK), MICGP (Ireland), Past Medical Delegate for the International Committee of the Red Cross , Ontario, Canada; Randolph B Goossen, MD, CCFP, FCFP, FRCPC, Psychiatry, Manitoba, Canada; Michael Grasic, MD, Family Medicine, Ontario, Canada; Salvador M. Guinjoan, MD, PhD, Oklahoma, USA; Jack Haggarty, MD, FRCPC, CCPE, Senior Medical Director, St. Joseph's Care Group, Professor and Chair, Section of Psychiatry, Northern Ont. School Medicine University, Ontario, Canada; Lila Haj-Ahmad, MDCM, Ontario, Canada; Sheila Rutledge Harding, MD, MA, FRCPC, Saskatchewan, Canada; Margaret J. Hart, DO, FAAFP, Family Medicine/Geriatric Medicine, Arizona, USA; Philippa H. Hawley, FRCPC, Clinical Professor Medical Director, Pain & Symptom Management/Palliative Care, BC, Cancer, British Columbia, Canada; Kevin Hay, MRCPI, CCFP, FCFP, Alberta, Canada; J. David Henderson, MD, CCFP (PC), Senior Medical Director Integrated Palliative Care Nova Scotia Health, Associate Professor Department of Family Medicine Dalhousie University, Nova Scotia, Canada; Leonie Herx, MD, PhD, CCFP (PC), FCFP, Palliative Medicine Consultant, Clinical Professor, Cumming School of Medicine, University of Calgary, Alberta, Canada; Angela O Ho, HBSc, MD, FRCPC, Assistant Professor, Dept of Psychiatry, Faculty of Medicine, University of Toronto, Ontario, Canada; Sheila C Hollins, Professor the Baroness Hollins FRCPsych, FRCPCH, FRCP, FHEA, Independent Life Peer, House of Lords, Westminster, UK, Emeritus Professor of Psychiatry, St George's, University of London, Past President, Royal College of Psychiatrists, Past President, British Medical Association, President, Royal College of Occupational Therapists, President, Royal Medical Benevolent Fund, London, United Kingdom; Tae Young (Peter) Hong, MD, CFPC, Ontario, Canada; Philip Howard, MA, MD, GDL, LLM, FRCP, Consultant Gastroenterologist, London, United Kingdom; Trevor A. Hurwitz, MBChB, MRCP (UK), FRCP (C), Psychiatry FRCP (C) Neurology, Diplomate in Psychiatry - American Board of Psychiatry and Neurology, Diplomate in Neurology - American Board of Psychiatry and Neurology, Diplomate Behavioral Neurology & Neuropsychiatry - United Council of Neurologic Subspecialties. Department of Psychiatry, University of British Columbia, British Columbia, Canada; Lauren Jackson, BSc, MD, FCFP, British Columbia, Canada; Laila Jamal, MD, FRCPC, Ontario, Canada; Lawrence F. Jardine, BA, BMedSci, MD, FRCPC, Honorary Consultant, Division of Pediatric Hematology Oncology, Children's Hospital (LHSC), Professor Emeritus (Pediatrics), Schulich School of Medicine and Dentistry, University of Western Ontario, Ontario, Canada; Anna Jasinska, MD, FRCPC (psychiatry), Pennsylvania, USA; Will Johnston, MD, Clinical assistant professor, Department of family practice, University of British Columbia, British Columbia, Canada; Pamela Joseph, MD, FRCPC, Ontario, Canada; Stephanie Kafie, MD, CCFP (COE), BHsc, Ontario, Canada; Gurnaam Singh Kasbia, MD, BSc, FRCPC, Psychiatrist, Ontario, Canada; Ebru Kaya, MBBS, MRCP(UK), Rose Family Chair in Palliative Medicine and Complex Care at University Health Network, Palliative Care Site Lead, Toronto General Hospital, Director, Division of Palliative Medicine, and Associate Professor, Department of Medicine, Temerty Faculty of Medicine, University of Toronto, President, Canadian Society of Palliative Care Physicians; Eric Kelleher, MB, PhD, MRCP, MRCPsych, Consultant Liaison Psychiatrist, Cork University Hospital & Mercy University Hospital, Honorary Clinical Senior Lecturer, University College Cork, Munster, Ireland; Sister Nuala Kenny, OC, MD, FRCP(C), Emeritus Professor Dalhousie University School of Medicine, Nova Scotia, Canada; Laurence J. Kirmayer, MD, FRCPC, FCAHS, FRSC, James McGill Professor & Director, Division of Social & Transcultural Psychiatry, McGill University, Quebec, Canada; Leah Koetting, MD, CCFP, Manitoba, Canada; Mark S Komrad, MD, DFAPA, Faculty of Psychiatry, Johns Hopkins, Tulane, and University of Maryland, Maryland, USA; Jaro Kotalik, MD, FRCPC, Ontario, Canada; Jessica Kreviazuk, MD, FRCPC, Assistant Professor University of Manitoba, Community Psychiatrist, Manitoba, Canada; Emeritus Professor Linda Kristjanson, AO, PhD, FAICD, FTSE, Victoria, Australia; Mark Kristjanson, MD, CCFP, Assistant Professor, Department of Family Medicine, Rady Faculty of Health Sciences, University of Manitoba, Manitoba, Canada; Charles Lakusta, MD, Alberta, Canada; Karen Lam, MD, FRCPC, Ontario, Canada; Tim Lau, MD, FRCPC, Associate Professor, University of Ottawa, Ontario, Canada; Alejandro Lazo-Langner, MD, MSc, FRCPC, Professor of Medicine, Oncology, and Epidemiology and Biostatistics, Chair/Chief, Division of Hematology, Department of Medicine, Western University, Hematology Division, London Health Sciences Centre, Ontario, Canada; Mark Leakos, MD, Saskatchewan, Canada; Cassandra Lin-Pepe, MD, CCFP, Dip P Derm, Ontario, Canada; Jeffrey H Lipton, PhD, MD, FRCPC, Clinician Investigator, Princess Margaret Cancer Centre, Cancer Clinical Research Unit (CCRU), Princess Margaret Cancer Centre, Professor of Medicine, University of Toronto, Ontario, Canada; Iris Liu, MD, British Columbia, Canada; Matthew Loscalzo, LCSW, APOS Fellow, Executive Director, People & Enterprise Transformation, Emeritus Professor Supportive Care Medicine, Professor Population Sciences, California, USA; Joyce Lui, MD, CCFP, Alberta, Canada; Patrick MacGillivray, MD, CCFP, Ontario, Canada; James MacMillan, MD, CCFP, Palliative Care, Saskatoon & Integrated North, Saskatchewan, Canada; John Maher, MD, FRCPC, President, Ontario Association for ACT & FACT, Editor-in-Chief, Journal of Ethics in Mental Health, Ontario, Canada; Lauren Mai, MD, FRCPC, Neurologist, Assistant Professor, Western University, Ontario, Canada; Katalin Margittai, MD, FRCPC DABPN, DLFAPA, Assistant Professor of Psychiatry, University of Toronto, Ontario, Canada; Stephen Martin, MD, FCFP, FCBOM, ABPM(OM), Quebec, Canada; Karen Mason, MD, Retired family physician, Ontario, Canada; Paul McArthur, BSc, MD, CCFP, Adjunct Professor of Family Medicine, University of Western Ontario, Ontario, Canada; Annette McCarthy, MD, CCFP, Family Physician, Newfoundland, Canada; Gordon McDonald, MD, CCFP, Department of Family Medicine, Dalhousie University, Fredericton, Canada; C. Ann McKenzie, MD, Manitoba, Canada; Diane E. Meier, MD, FACP, FAAHPM, Founder, Director Emerita and Strategic Medical Advisor, Center to Advance Palliative Care, Co-director, Patty and Jay Baker National Palliative Care Center, Professor, Department of Geriatrics and Palliative Medicine, Catherine Gaisman Professor of Medical Ethics, Icahn School of Medicine at Mount Sinai, New York, USA; Tim Millea, MD, Fellow, American Board of Orthopedic Surgeons, Iowa, USA; Alisha Montes, MD, MPH, FRCP, Pediatrician, Newfoundland, Canada; Jos\u00e9 A. Morais, MD, FRCPC, Director, Division of Geriatric Medicine, McGill University, Quebec, Canada; Marie Angelle Moreau, MD, General Internist, Alberta, Canada; Louis Morissette, MD, FRCP, Forensic Psychiatrist, UM, Institiut national de psychiatrie l\u00e9gale Philippe-Pinel, Quebec, Canada; R. Sean Morrison, MD, Ellen and Howard C. Katz Professor and Chair, Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, USA; Michael E. Mrozek, MD, FRCP(C), Toronto, Ontario; Christopher Newcombe, CCFP (EM), British Columbia, Canada; Nicholas Newman, MD, FRCSC, Associate Professor, Department of Surgery, Universit\u00e9 de Quebec, Quebec, Canada; Laurence Normand-Rivest, MD, Quebec, Canada; Natalia Novosedlik, MD, CCFP(PC), Ontario, Canada; Kevin O'Kane, BSc(Hons), MB, ChB, LLM, FRCP, FRCPE, Consultant in General & Acute Internal Medicine, London, United Kingdom; F\u00e9lix Pageau, MD, FRCPC, MA, Philosophy, Geriatrician, Ethicist, Assistant Medicine Professor (Professeur adjoint m\u00e9decin enseignant sous octoi), Department of Medicine, Faculty of Medicine, Laval University, Full researcher, VITAM - Research Center on Sustainable Health and the Centre d'excellence en vieillissement de Qu\u00e9bec, Laval University and CIUSSS Capitale-National, Quebec, Canada; Michael J. Passmore, MD, FRCPC, British Columbia, Canada; M. Jill Peacock, MD, FCFP (retired), British Columbia, Canada; Jos\u00e9 Pereira, MBChB, CCFP (PC), MSc, FCFP, PhD, Professor, Division of Palliative Care, Department of Family Medicine, McMaster University, Ontario, Canada; Donald J. Peters, MD, FRCPC (retired), Manitoba, Canada; Robin Pierucci, MD, MA, Clinical Neonatologist, Michigan, USA; Liette Pilon, MD, Retired Family Practice, Quebec, Canada; Ivan Poukhovski-Sheremetyev, MD, FRCPC, Ontario, Canada; Fran\u00e7ois Primeau, MD, FRCPC, Full Clinical Professor, Psychiatry and Neurosciences, Laval University, Qu\u00e9bec, Canada; Lukas Radbruch, MD, PHD, Professor, Department of Palliative Medicine, University Hospital Bonn, Chair of the board of directors of IAHPC, North Rhine-Westphalia, Germany; Larry Rados, MD, CCFP, Manitoba, Canada; Shirley Reddoch, MD, FAAP, Pediatric Hematology/Oncology, Maryland, USA; Claud Regnard, FRCP, Honorary consultant in Palliative Care Medicine, St. Oswald's Hospice, Newcastle-upon-Tyne, United Kingdom; Karen Reimers, MD, FRCPC, Assistant Professor, University of Central Florida, Florida, USA; Jean-Marie M. Ribeyre, MD, PhD, FRCPC, Associate Professor/Professeur Agrege, St. Lawrence Valley Correctional and Treatment Centre - Secure Treatment Unit, Ontario, Canada; Evan Ritchie, MD, PGY-4, Anesthesiology & Pain Medicine, Alberta, Canada; Roger Roberge, MD, PhD, Quebec, Canada; Anne Rose, MD, Ontario, Canada; Skye Rousseau, MD, FRCPC, Assistant Professor, University of Manitoba, Dept. of Psychiatry, Manitoba, Canada; Edward J Rzadki, BA, MD, FRCPC, Assistant Professor Psychiatry U of T 1969 (retired), Past President, Ontario Psychiatric Association, Past Chief of Psychiatry, Etobicoke General Hospital, Past Chief of Staff, Etobicoke General Hospital, William Osler Health Centre, Past Corporate Chief of Psychiatry and Past Medical Director, Mental Health and Addictions, 1999-2007, Ontario, Canada; Paul Saba, M.D. C.M. M.Sc., Family Physician & Author of Made to Live, Quebec, Canada; Richard H. Sandler, MD, Professor of Pediatrics, Professor of Mechanical and Aerospace Engineering, University of Central Florida, Florida, USA; Jitender Sareen, MD, Department Head, Psychiatry, University of Manitoba, Provincial Specialty Lead, Mental Health and Addictions, Shared Health, Manitoba, Canada; Luke Savage, BKin(Hons), MD, CCFP, FCFP, Alberta, Canada; Anton Scamvougeras, MBChB, FRCPC, Neuropsychiatrist, UBC Neuropsychiatry Program, Department of Psychiatry, University of British Columbia, British Columbia, Canada; H. Schipper, BASc, MD, FRCP(C), Professor of Medicine, Adjunct Professor of Law, University of Toronto, MindenSchipper & Associates Inc., Ontario, Canada; Valerie Schulz, MD, FRCPC, MPH, CPC(HC), Ontario, Canada; John F Scott, MD, Associate Professor, Palliative Medicine, University of Ottawa, Ontario, Canada; Nathan Schaffer, MD, FRCPC, Clinical Assistant Professor, Dept of Psychiatry, University of British Columbia; Mary V. Seeman, OC, MDCM, Department of Psychiatry, University of Toronto, Ontario, Canada; Antonia Seli, BSc(Hons), MD, FRCPC, Staff Psychiatrist, Adult Outpatient Services, Halton Healthcare - Oakville Trafalgar Memorial Hospital, Medical Lead - One Link, Assistant Clinical Professor - McMaster University, Ontario, Canada; Keith Sequeira, MD, FRCPC, Associate Professor, Schulich School of Medicine and Dentistry, Western University, Department of Physical Medicine and Rehabilitation, Ontario, Canada; Amir Shamlou, MD, FRCPC, Manitoba, Canada; Alexander Simpson, MBChB, BMedSci, FRANZCP, FCPA, Chair in Forensic Psychiatry, CAMH + University of Toronto, Senior Scientist, Research Program, CAMH, Professor, Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health - University of Toronto, Ontario, Canada; Richard R. J. Smyth, MBBS, LRCP, FRCS, FRCSC - retired, Adjunct Professor in Faculty of Science, Thompson Rivers University, BC, Clinical Instructor in Otolaryngology - Head and Neck Surgery, University of British Columbia, British Columbia, Canada; Allan B. Steingart, MD, FRCPC, Ontario, Canada; Theresa Szezepaniak, MB ChB, DRCOG, Dip IMC(RCSEd), LMCC, Hospitalist, Family Medicine, British Columbia, Canada; Matthew David Swatski, MD, University of Pittsburgh School of Medicine, SUNY at Buffalo Pediatrics Chief Resident, Pennsylvania, USA; Sanasi Swatski, MD, PGY2, Family Medicine, McMaster University, Ontario, Canada; Sephora Tang, MD, FRCPC, Assistant Professor, University of Ottawa, Ontario, Canada; Agnes Tanguay, MD, CCFP, Ontario, Canada; Robert Twycross, DM, FRCP, FRCR, Emeritus Clinical Reader in Palliative Medicine, Oxford University, Oxford, United Kingdom; Stephen Vander Klippe, Family Physician., Ontario, Canada; Lilian Lee Yan Vivas, BSc, MD, FRCPC, CSCN, Dip. (EMG), Physical Medicine and Rehabilitation, Ontario, Canada; Lucas Vivas, CD, MD, MHSc (Bioethics), FRCPC, Active Staff, General Internal Medicine, William Osler Health System, Assistant Clinical Professor (Adjunct), Department of Medicine, McMaster University, Ontario, Canada; Declan Walsh, MD, MSc, FACP, FRCP(Edin), Chair, Department of Supportive Oncology, Atrium Health Levine Cancer, Clinical Professor, Department of Internal Medicine, Wake Forest University School of Medicine, The Hemby Family Endowed Chair in Supportive Oncology, Editor-in-Chief, BMJ Supportive and Palliative Care, Fellow Emeritus, Trinity College, The University of Dublin, North Carolina, USA; Ellen Warner, MD, MSc, FRCPC, FACP, Division of Medical Oncology, Sunnybrook Odette Cancer Centre, Professor of Medicine, University of Toronto, Ontario, Canada; Eric Wasylenko, MD, CCFP, (PC), MHSc (bioethics), Adjunct, Division of Palliative Medicine, Department of Oncology, Cumming School of Medicine, University of Calgary; and Adjunct, John Dossetor Health Ethics Centre, University of Alberta, Alberta, Canada; Shawn Whatley, MD, FCFP(EM), Munk Senior Fellow in Health Policy, Macdonald-Laurier Institute, Past President, Ontario Medical Association, Ontario, Canada; Frederick J. White, MD, FACC, FCCP, HEC-C, Louisiana, USA; DP Whitehouse, MB, ChB, MSc, PG Dip Pall Med, Diploma Tropical Med and Hygiene, PG Cert International Development & Conflict, FRCP, AFOM., Consultant in Palliative, Respiratory and General Medicine., Bosham, United Kingdom; James Wheeler, MD, MSC, CCFP, FCFP, Ontario, Canada; Kiely Williams, MD, CCFP, FCFP, Alberta, Canada; Maria Wolfs, MD, MHSc, FRCPC, Ontario, Canada; Jerome Yang, MD, MHSc, CCFP(AM), British Columbia, Canada; Jonathan Yang, MD, CCFP, British Columbia, Canada; Stanley Yaren, MD, FRCPC (psychiatry), Associate Professor, University of Manitoba, Manitoba, Canada; John W. S. Yun, MD, FRCPC, Oncology, British Columbia, Canada; Joel Zivot, MD, FRCPC, Emory University, Georgia, USA; Alexandra Zyla, MD, PGY-2 Anatomical Pathology, University of Toronto, Ontario, Canada.No funding was received for this article."} +{"text": "A scientific journal exists only because of the good will and assistance of its reviewers. We can only publish approximately a fifth of the papers we receive and, in order to publish really high-quality papers, we depend on the expertise of many people. During 2021 a total of 480 reviewers have helped us to decide about the papers that we should publish. Their names are listed below and we would like to take this opportunity to thank them. The list refers to reviewers completing their task until 1st of December 2021. Merita Berisha, AlbaniaEdward A. Ruiz-Narv\u00b4aez, United StatesMette Aadahl, DenmarkMari Aaltonen, FinlandMuhammad Abbas, ChinaMichelle Addison, United Kingdom of Great Britain and Northern IrelandKees Ahaus, NetherlandsMarion Aichberger, GermanyEva Aizpurua, United StatesYannis Alamanos, GreeceTit Albreht, SloveniaDjordje Alempijevic, SerbiaDenise Alexander, IrelandGianfranco Alicandro, ItalyMirjam Allik, United Kingdom of Great Britain and Northern IrelandJordi Alonso, SpainCarlos Alves, PortugalTarik Amer, United Kingdom of Great Britain and Northern IrelandC. Ananth, United StatesIngelise Andersen, DenmarkTatiana Andreeva, UkrainePeter Angelopoulos, GreeceAhti Anttila, FinlandCigdem Apaydin Kaya, TurkeyFranklin Apfel, United Kingdom of Great Britain and Northern IrelandRamiz Arabaci, TurkeyNimmathota Arlappa, IndiaHector Arolas, SpainLucia Artazcoz, SpainBarbara Artnik, SloveniaHila Axelrad, IsraelAli Babij, United StatesThomas Babor, United StatesEva Bacsne Baba, HungarySekene Badiaga, FranceChristine Baldwin, United Kingdom of Great Britain and Northern IrelandTom Baranowski, United StatesAngelo Barbato, ItalyLiad Bareket-Bojmel, IsraelPepita Barlow, United Kingdom of Great Britain and Northern IrelandOrna Baron-Epel, IsraelSarah Basharat, PakistanAlessandra Battisti, ItalyC\u00e9dric Baumann, FranceLinda Bell, United Kingdom of Great Britain and Northern IrelandNadia Benahmed, BelgiumFernando Benavides, SpainNetta Bentur, IsraelPatrick Bergman, SwedenClaudia Berlin, GermanyMarriot Bernadette, United StatesMatthias Bethge, GermanyMaria Augusta, Bezerra, BrazilStuart Biddle, Australia\u00c9va B\u00edr\u00f3, HungaryAlexandre Bisdorff, LuxembourgIngunn Bjornsdottir, DenmarkCecilia Bj\u00f6rkelund, SwedenJohan Bj\u00f8rngaard, NorwayJenni Blomgren, FinlandKim Bloomfield, DenmarkMartin Bobak, United Kingdom of Great Britain and Northern IrelandStefania Boccia, ItalyEdwin Boezeman, NetherlandsPaolo Boffetta, ItalyAnette Ella, Boklund, DenmarkAnne Brabers, NetherlandsHenry Brandon, United StatesSven Bremberg, SwedenBronwyn Brew, SwedenOve Bring, Sweden\u00d3scar Brito Fernandes, NetherlandsJoanna Broad, New ZealandTimothy Broady, AustraliaDenise Brown, United Kingdom of Great Britain and Northern IrelandLaura Brunelli, ItalyMartin Brussig, GermanyBernd Br\u00fcggenj\u00fcrgen, GermanyRichard Br\u00e4nstr\u00f6m, SwedenHenrik Br\u00f8nnum-Hansen, DenmarkAlex Burdorf, NetherlandsJeni Burnette, United StatesBo Burstr\u00f6m, SwedenSusan Buskin, United StatesHenrik B\u00f8ggild, DenmarkChiara Cadeddu, ItalyYutong Cai, United Kingdom of Great Britain and Northern IrelandToma\u017e \u010cak\u0161, SloveniaAdele Caldarella, ItalyIn\u00eas Campos-Matos, United Kingdom of Great Britain and Northern IrelandJaume Canela, SpainMayilee Canizares, CanadaLorenzo Capasso, ItalySimon Capewell, United Kingdom of Great Britain and Northern IrelandMabel Carabali, CanadaMartin Caraher, United Kingdom of Great Britain and Northern IrelandMargarida Cardoso, PortugalMargherita Caroli, ItalyEwan Carr, United Kingdom of Great Britain and Northern IrelandElena Carrillo \u00c1lvarez, SpainDayan Carvalho Ramos Salles de Oliveira, BrazilJose Castillo, SpainR. Catalano, United StatesNicolo Cavalli, United Kingdom of Great Britain and Northern IrelandJeremy Chancellor, United Kingdom of Great Britain and Northern IrelandJustin Chapman, United StatesHaohao Chen, ChinaKong-Tong Chen, TaiwanLan Cheng, GermanyPalma Chill\u00f3n, SpainMaria-Dolores Chirlaque, SpainEun Choi, United StatesAnne Christensen, DenmarkNain-Feng Chu, TaiwanBronwyn Clark, AustraliaMiriam Colombo, United StatesGiuseppe Costa, ItalyClaudia Costa, PortugalJen Coury, United StatesMatty Crone, NetherlandsPaolo Crosignani, ItalyYuehua Cui, ChinaSarah Cuschieri, MaltaBruno da Costa, BrazilEspen Dahl, NorwayAnna-Karin Danielsson, SwedenZuzana Dankulincova, SlovakiaJean-Francois Daoust, United Kingdom of Great Britain and Northern IrelandRituparna Das, IndiaMike Daube, AustraliaBarbara D'Avanzo, ItalyA. Davis, United Kingdom of Great Britain and Northern IrelandGuy De Backer, BelgiumSascha de Breij, NetherlandsAstrid de Wind, NetherlandsPatricia M. Dekkers-S\u00e1nchez, NetherlandsAnnarosa del Mistro, ItalyLanfranco D'Elia, ItalyMichael Deml, SwitzerlandEvangelia Demou, United Kingdom of Great Britain and Northern IrelandZelalem Destaw, EthiopiaGiorgio Di Gessa, United Kingdom of Great Britain and Northern IrelandGiuseppe Di Martino, ItalySara Dias, PortugalJulio Diaz, SpainFinn Diderichsen, DenmarkJennifer Dixon, United Kingdom of Great Britain and Northern IrelandFel\u0131citas Dom\u0131nguez-Berjon, SpainYanghui Dong, ChinaDanny Dorling, United Kingdom of Great Britain and Northern IrelandGerardine Doyle, IrelandDunja Dreesens, NetherlandsSven Drefahl, SwedenGertjan Driessen, NetherlandsKatarzyna Dubas-Jak\u00f3bczyk, PolandNathalie Duchange, FranceXavier Duran, SpainMagdalena Durda-Masny, PolandRaika Durusoy, TurkeyMarion Duval, FranceHans Duvekot, NetherlandsChristina Edwards, NorwayFrida Eek, SwedenBoris Ehrenstein, GermanyPeter Eibich, GermanyMarion Eisele, GermanyMikael Ekblad, FinlandAnna Mia Ekstr\u00f6m, SwedenNuha El Sharif, Palestine, State of Eric Emerson, United Kingdom of Great Britain and Northern IrelandCornelia Enzenbach, GermanySaffet Erdo\u011fan, TurkeyErdem Erkoyun, TurkeySofija Ernesta, AustraliaJohn Fanourgiakis, GreeceAlan Farrier, United Kingdom of Great Britain and Northern IrelandPaula Feder-Bubis, IsraelGracia Fellmeth, United Kingdom of Great Britain and Northern IrelandJoao Ferreira-Pinto, United StatesWies\u0142aw Fidecki, PolandFlorian Fischer, GermanyClaudia Fischer, NetherlandsPatricia Fitzpatrick, IrelandMaria Elena Flacco, ItalyMaria Fleischmann, NetherlandsP\u00e4r Flodin, SwedenMari-Ann Flyvholm, DenmarkAnders Foldspang, DenmarkCarla Fornari, ItalyEmma Fransson, SwedenIn\u00eas Fronteira, PortugalThomas Fr\u00f6hlich, GermanySari Fr\u00f6jd, FinlandJudith Fuchs, GermanySonsoles Fuentes, SpainSilvano Gallus, ItalyM\u00aa Victoria Galvez, SpainThomas Gamsj\u00e4ger, AustriaKristin Ganahl, AustriaInmaculada Garc\u00eda Mart\u00ednez, SpainHeike Garritsen, NetherlandsTony Gatrell, United Kingdom of Great Britain and Northern IrelandVijay Gc, United Kingdom of Great Britain and Northern IrelandLaurence Geebelen, BelgiumDelaram Ghodsi, IranMonica Giancotti, ItalyTheodoros Giannouchos, United StatesKatja Gillander G\u00e5din, SwedenFelix Gille, SwitzerlandAlejandro Gil-Salmer\u00f3n, United Kingdom of Great Britain and Northern IrelandPaolo Giorgi Rossi, ItalyRoberto Gnavi, ItalyPere Godoy, SpainRosa Gofin, IsraelBernard Gonik, United StatesAngelina Gonzalez Viana, SpainFrancisco-Javier Gonzalez-Barcala, SpainNick Goodwin, United Kingdom of Great Britain and Northern IrelandUnni Gopinathan, NorwayGiuseppe Gorini, United StatesIgor Grabovac, AustriaGuendalina Graffigna, ItalyIrina Grafova, United StatesEleanor Grieve, United Kingdom of Great Britain and Northern IrelandAnne Griffin, IrelandEva Grill, GermanyPeter Groenewegen, NetherlandsLaurence Gruer, United Kingdom of Great Britain and Northern IrelandMaria Gualano, ItalyPedro Gullon, SpainMaria Guzman-Castillo, FinlandIsabel Hach, GermanyFaisal Hakeem, United Kingdom of Great Britain and Northern IrelandTorleif Halkjelsvik, NorwayVirginie Halley des Fontaines, FranceLiping Hao, ChinaBeatrijs Haverkamp, NetherlandsLouise Hawkley, United StatesSamah Hayek, IsraelK\u00e8ne Henkens, NetherlandsGunnel Hensing, SwedenAnders Hjern, SwedenSarah Hoeck, BelgiumTheodore Holford, United StatesChristine Holmberg, GermanyC. Homer, AustraliaH. Hoven, GermanyChang-Ming Hsieh, United StatesMin Hu, ChinaKuo-Cherh Huang, TaiwanJuliette Hussey, IrelandLena H\u00fcnefeld, GermanyM. Ishikane, JapanNazrul Islam, United Kingdom of Great Britain and Northern IrelandRachel Jackson-Leach, United Kingdom of Great Britain and Northern IrelandTeresa Janevic, United StatesJanko Jankovic, SerbiaDomantas Jasilionis, GermanyMelanie Jones, United Kingdom of Great Britain and Northern IrelandJoshua Winston Joseph, United StatesChristian Jung, GermanyKarsten J\u00f8rgensen, DenmarkM. Kakizaki, JapanRainer Kaluscha, GermanyDaiga Kamer\u0101de, United Kingdom of Great Britain and Northern IrelandSamuli Kangaslampi, FinlandBrystana Kaufman, United StatesLars Kayser, DenmarkCarl Kendall, United StatesErin Kenzie, United StatesEvert Ketting, NetherlandsMyriam Khlat, FranceKatarzyna Kissimova-Skarbek, PolandNiek Klazinga, NetherlandsA.K. Knudsen, NorwayTetsuro Kobayashi, JapanStefan Kohler, GermanyNatasja Koitzsch Jensen, DenmarkNaoru Koizumi, United StatesMargarita Kokkorou, United Kingdom of Great Britain and Northern IrelandRudolf Kool, NetherlandsKarolina K\u00f3sa, HungaryKaroline Kragelund Nielsen, DenmarkMargareta Kristenson, SwedenAlfgeir Kristjansson, IcelandTove Kristoffersen, NorwayAnton Kunst, NetherlandsOliver Kurzai, GermanyY. Kusama, JapanThomas K\u00fchlein, GermanyCarlo La Vecchia, ItalyJeremy Labrecque, NetherlandsNathalie Lahoud, LebanonTaavi Lai, EstoniaTea Lallukka, FinlandGiovanni Lamura, ItalyPeter Lansberg, NetherlandsOlga Laosa, SpainAndrea Lavazza, ItalyStephen Lawoko, SwedenTeresa Leao, PortugalWonkyong Lee, CanadaSeo Yoon Lee, Korea, the Republic of Hans Lehrach, GermanyLijian Lei, ChinaLiliya Leopold, NetherlandsPeter Lepping, United Kingdom of Great Britain and Northern IrelandJie Li, United StatesYige Li, United StatesYajun Liang, SwedenLaura Lindberg, DenmarkHedda Lippus, EstoniaEmily Long, United Kingdom of Great Britain and Northern IrelandFrancesco Longo, ItalyE. Lothian, United Kingdom of Great Britain and Northern IrelandRikke Lund, DenmarkUlf Lundberg, SwedenTorkild Lyngstad, NorwayMhairi Mackenzie, United Kingdom of Great Britain and Northern IrelandIgnacio Madero-Cabib, ChileManfred Maier, AustriaElena Manescu, RomaniaM. Marti, SpainLeslie Martin, United StatesJolanda Mathijssen, NetherlandsT. Matsubayashi, JapanXi\u00e1n Mayo, SpainJoanna Mazur, PolandJim McCambridge, United Kingdom of Great Britain and Northern IrelandMary McEniry, United StatesPhilip McLoone, United Kingdom of Great Britain and Northern IrelandErik Mel\u00e9n, SwedenAziz Mensah, GermanyEmmanouil Mentzakis, United Kingdom of Great Britain and Northern IrelandGwenn Menvielle, FranceChristian Meyer, GermanyQun Miao, CanadaDusanka Micetic-Turk, SloveniaReyaj Mikrani, ChinaPilar Modamio, SpainS. Modrek, United StatesSusanne Moebus, GermanyAnders Moellekaer, DenmarkBishav Mohan, IndiaJill-Marit Moholt, NorwayAnu Molarius, SwedenLinda Montanari, PortugalSimon Moore, United Kingdom of Great Britain and Northern IrelandBritt Morthorst, DenmarkShayan Mostafaei, IranMaria Mour\u00e3o-Carvalhal, PortugalMassimo Mucciardi, ItalyMadhuri Mulekar, United StatesYuichi Muraki, JapanAkinori Nakata, JapanCathrine Nakken, DenmarkElin Naurin, SwedenLuciana Neamtiu, ItalyDavide Negrini, ItalyGeorgios Nikolopoulos, CyprusPeter Nilsson, SwedenThor Norstr\u00f6m, SwedenLeslie Ogilvie, GermanyAtte Oksanen, FinlandAnna Oksuzyan, GermanyVal\u00e9rie Oli\u00e9, FranceJacques Orvain, FranceAndrea Padoan, ItalyDemosthenes Panagiotakos, GreeceKelly Parsons, United Kingdom of Great Britain and Northern IrelandAnna Pearce, United Kingdom of Great Britain and Northern IrelandSergio Perelman, BelgiumJulian Perelman, PortugalPamela Pereyra-Zamora, SpainIvan Perry, IrelandArmando Peruga, SwitzerlandT. Petitte, United StatesPaola Piccolo, ItalySylvain Pichetti, FranceMatthias Pierce, United Kingdom of Great Britain and Northern IrelandPeter Piko, HungaryStefan Pilcher, SwitzerlandPaul Pinsky, United StatesSami Pirkola, FinlandPrisco Piscitelli, ItalyCarme Planas-Campmany, SpainSabine Plancoulaine, FranceThomas Pl\u00fcmper, AustriaAndrea Poscia, ItalyAlejandro Prieto Ayuso, SpainTina Purnat, SwedenOssi Rahkonen, FinlandFrancesco Ramponi, SpainSarah Reed, United Kingdom of Great Britain and Northern IrelandSijmen Reijneveld, NetherlandsSofia Ribeiro, PortugalMargret Rihs, SwitzerlandArja Rimpel\u00e4, FinlandKaaja Risto, United StatesRenne Rodrigues, BrazilFernando Rodriguez-Artalejo, SpainVladimir Rogalewicz, Czech RepublicManuel Romero-Gomez, SpainJ\u00e9r\u00f4me Ronchetti, FranceSam Rowlands, United Kingdom of Great Britain and Northern IrelandSarah Rozenblum, United StatesReiner Rugulies, DenmarkAbigail Emma Russell, United Kingdom of Great Britain and Northern IrelandKeith Sabin, SwitzerlandLu\u00eds Saboga Nunes, PortugalMuhammad Saeed, PakistanEdgar Samarasundera, United Kingdom of Great Britain and Northern IrelandLaura Samuel, United StatesJo\u00e3o Santos, PortugalTugce Schmitt, NetherlandsClaudia Schoenborn, BelgiumNaomi Schwartz, CanadaDavid Seal, United StatesChris Segrin, United StatesVida Sheikh, United StatesWensong Shen, Hong KongMary Shilalukey Ngoma, ZambiaColin Shore, United Kingdom of Great Britain and Northern IrelandKarri Silventoinen, FinlandErika Siu, United StatesSara Souza, CanadaPinar Soysal, TurkeyJacob Spallek, GermanyDomonic Sparkes, United Kingdom of Great Britain and Northern IrelandAdina Stan, RomaniaDenes Stefler, United Kingdom of Great Britain and Northern IrelandRobert Stein, United StatesTimo St\u00e5hl, FinlandHarry Sumnall, United Kingdom of Great Britain and Northern IrelandAlma S\u00f6rberg Wallin, SwedenJennifer Taber, United Kingdom of Great Britain and Northern IrelandM. Tallarek, GermanyDavid Taylor-Robinson, United Kingdom of Great Britain and Northern IrelandLiesbeth Temme, NetherlandsJ\u00fcrgen Thelen, GermanyIoannis Theodossiou, United Kingdom of Great Britain and Northern IrelandBetsy Thom, United Kingdom of Great Britain and Northern IrelandSiri Thor, United StatesMaija Toivakka, FinlandHanna Tolonen, FinlandP. Tyrer, United Kingdom of Great Britain and Northern IrelandSven T\u00f6rnberg, SwedenEmre Umucu, United StatesAntonis Valachis, GreeceMaria Valenzuela, United Kingdom of Great Britain and Northern IrelandDavid Walsh, United Kingdom of Great Britain and Northern IrelandJ. van der Velden, NetherlandsHans van der Wouden, NetherlandsFrank van Lenthe, NetherlandsHanna van Solinge, NetherlandsIrene van Valkengoed, NetherlandsCarine Vande Voorde, BelgiumP. Vanella, GermanyRakhi Vashishtha, AustraliaH. Gilbert Welch, United StatesJacques Wels, BelgiumUno Wennergren, SwedenRobert Verheij, NetherlandsMargaret Whitehead, United Kingdom of Great Britain and Northern IrelandFrancesco Violante, ItalyMarianna Virtanen, SwedenDirk Witteveen, United Kingdom of Great Britain and Northern IrelandAlejandra Vives, ChileSabine Vogler, AustriaG Zagury, ChinaJennifer Zeitlin, FranceCaixia Zhang, ChinaDong Zhang, United StatesPengxiang Zhao, SwedenBin Zhou, United Kingdom of Great Britain and Northern IrelandCorina-Aurelia Zugravu, RomaniaGunnar \u00c5gren, SwedenJohan \u00c5hl\u00e9n, SwedenPer-Olof \u00d6stergren, SwedenHilal \u00d6zcebe, Turkey"} +{"text": "Scientific Reports 10.1038/s41598-023-38980-3, published online 20 July 2023Correction to: The original version of this Article contained errors in affiliations 6, 7, 9 and 10. The correct affiliations are listed below.6 International Maize and Wheat Improvement Center (CIMMYT), ICRAF House, UN Avenue, Nairobi, P.O. Box 1041-00621, Kenya.7 Department of Molecular Biology, College of Biotechnology, CCS Haryana Agricultural University, Hisar 125004, Haryana, India.9 Handong Global University, Pohang, Republic of Korea.10 International Corn Foundation, Pohang, Republic of Korea.The original Article has been corrected."} +{"text": "To the Editor: The benefit of switching between biologics is being documented by a growing body of evidence in the plaque psoriasis literature.,We conducted a multicenter retrospective study of patients aged \u226518\u00a0years with moderate-to-severe plaque psoriasis who received risankizumab following an inadequate response to guselkumab. Responders were those who achieved 90% improvement in baseline Psoriasis Area and Severity Index (PASI90) or Physician Global Assessment scores of 0 (clear) or 1 .,The baseline demographics and clinical outcomes are summarized in Among primary guselkumab nonresponders, 60% (9/15) of patients responded to risankizumab at week 16 and 46.7Adverse events (AEs) to risankizumab were uncommon, with 1 AE reported in each of the 16- and 52-week cohorts. Injection-site reaction led to discontinuation of risankizumab in 1 patient prior to 16\u00a0weeks; in another patient, a non\u2013life-threatening venous thromboembolism developed between 16 and 52\u00a0weeks, with risankizumab being subsequently discontinued because of an unsatisfactory response. Neither of the 2 aforementioned patients reported AEs while on guselkumab.In summary, we present the largest cohort of patients with long-term follow-up, highlighting the favorable real-world effectiveness and safety of risankizumab for plaque psoriasis in guselkumab-failure patients. The results of our study support the growing body of literature regarding the promising effectiveness and safety profiles of risankizumab, with the added perspective of switching from guselkumab.Dr Yeung has been an advisor, consultant, speaker, and/or investigator for AbbVie, Allergan, Amgen, Arcutis, Astellas, Bausch Health, Boehringer Ingelheim, Bristol Meyers Squibb, Celgene, Centocor, Coherus, Dermavant, Dermira, Forward, Galderma, GlaxoSmithKline, Incyte, Janssen, Kyowa, Leo Pharma, Lilly, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sandoz, Sanofi Genzyme, SunPharma, Takeda, UCB, Valeant , and Xenon. Dr Prajapati has served as an investigator for AbbVie, Amgen, Arcutis, Arena, Asana, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Concert, Dermavant, Dermira, Eli Lilly, Galderma, Incyte, Janssen, LEO Pharma, Nimbus Lakshmi, Novartis, Pfizer, Regeneron, Reistone, Sanofi Genzyme, UCB, and Valeant and has served as a consultant, advisor, and/or speaker for AbbVie, Actelion, Amgen, Aralez, Arcutis, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Eli Lilly, Galderma, GlaxoSmithKline, Homeocan, Janssen, LEO Pharma, L'Oreal, Medexus, Novartis, Pediapharm, Pfizer, Sanofi Genzyme, SunPharma, Tribute, UCB, and Valeant. Dr Vender received grants/research support from Abbvie, Amgen, Bausch Health, Centocor, Dermira, Dermavant, Galderma, GSK, Leo, Lilly, Takeda, Novartis, Merck, Pfizer, Regeneron, UCB; received honoraria as a speaker for AbbVie, Amgen, Janssen, Galderma, GSK, Leo, Lilly, Merck, Novartis, Pfizer, Bausch-Health, Actelion, Celgene, Cipher, and UCB; and was a consultant for Abbvie, Amgen, BMS, Janssen, Galderma, GSK, Leo, Lilly, Merck, Novartis, Paladin Labs Inc., Pfizer, Bausch-Health, Actelion, Celgene, Cipher, and UCB. Drs Mufti, Maliyar, and Georgakopoulos and Authors Bagit, Rankin, Le, and Rimke have no conflicts of interest to declare."} +{"text": "Please note that my affiliation has to be corrected as mentioned below and disregard my previous affiliation:A. Corrected Affiliation:11\u2010Team Erevnites, Trivandrum, India.2Virgen Milagrosa University Foundation College of Medicine, San Carlos City, Pangasinan, Philippines.B. Previous wrong Affiliation:1Team Erevnites, Trivandrum, India.2Computational Cardiovascular Simulations Center, University of Miami, Coral Gables, Florida, USA.Regards,Prakash Gupta.drprakashgupta1993@gmail.com"} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-39884-y, published online 30 August 2023Correction to: The original version of this Article omitted an affiliation for Sudhanshu Kumar. Their correct affiliations are listed below.Centre for Ocean, River, Atmosphere and Land Sciences (CORAL), Indian Institute of Technology Kharagpur, Kharagpur, 721302, India.Department of Crop, Soil, and Environmental Sciences, Auburn University, Auburn, AL, USA.The original Article has been corrected."} +{"text": "Corrigendum on:Impact of a tobacco sales ban on the frequency of tobacco consumption in India during the COVID-19 pandemicBy Nitika Sharma, Mansi Chopra, Linda Bauld, Gaurang P. Nazar, Nishigandha Joshi, Aastha Chugh, Sailesh Mohan, Deepa Mohan, Mohammed K. Ali, Vishwanathan Mohan, Nikhil Tandon, K. M. Venkat Narayan, K. Srinath Reddy, Dorairaj Prabhakaran, Monika AroraTobacco Induced Diseases, Volume 21, Issue April, Pages 1\u20136, Publish date: 28 April 2023https://doi.org/10.18332/tid/161855DOI: In the originally published version of the article, the name of the 12th author was given as Venkat K. M. Narayan and is now changed to K. M. Venkat Narayan. Furthermore, in the authors\u2019 contributions section, the initials VKMN are now changed to KMVN. The mentioned changes are corrected also online."} +{"text": "PLOS ONE Editors retract this article [The article because MI, IH, TH, and MA did not agree with the retraction. HK, AP, MM, ST, FS, and HOE either did not respond directly or could not be reached."} +{"text": "Neuro-Oncology, Volume 22, Issue Supplement_3, December 2020, Page iii287, https://doi.org/10.1093/neuonc/noaa222.052This is a corrigendum to: Grace Lau, Julie Drummond, Nataliya Zhukova, Paul Wood, Lisa Janson, DDEL-17. TRIPLE INTRAVENTRICULAR CHEMOTHERAPY FOR TREATMENT OF RELAPSED CHOROID PLEXUS CARCINOMA, In the originally published online version of this manuscript, Paul Wood was inadvertently omitted from the list of authors.This error has now been corrected."} +{"text": "Correction: Acta Neuropathologica 10.1007/s00401-023-02571-3In the original publication, Dr Ghazaleh Tabatabai\u2019s affiliation was incorrectly published as Department of Neurosurgery, Center for Neuro-Oncology, Comprehensive Cancer Center, Eberhard Karls University T\u00fcbingen, T\u00fcbingen, Germany.The correct affiliation should read asDepartment of Neurology and Interdisciplinary Neuro-Oncology, Center for Neuro-Oncology, Comprehensive Cancer Center, Hertie Institute for Clinical Brain Research, Eberhard Karls University T\u00fcbingen, T\u00fcbingen, Germany."} +{"text": "Journal of the American Medical Informatics Association, Volume 30, Issue 1, January 2023, Pages 103\u2013111, https://doi.org/10.1093/jamia/ocac203This is a correction to: Vaclav Papez, Maxim Moinat, Erica A Voss, Sofia Bazakou, Anne Van Winzum, Alessia Peviani, Stefan Payralbe, Elena Garcia Lara, Michael Kallfelz, Folkert W Asselbergs, Daniel Prieto-Alhambra, Richard J B Dobson, Spiros Denaxas, Transforming and evaluating the UK Biobank to the OMOP Common Data Model for COVID-19 research and beyond, In the originally published version of this manuscript, Elena Garcia Lara was erroneously omitted from the list of authors.This error has now been corrected."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-33094-2, published online 20 April 2023Correction to: The original version of this Article contained errors in the names of authors Sara Cerasi, Davide Leardini, Nunzia Lisanti, Tamara Belotti, Luca Pierantoni, Daniele Zama, Marcello Lanari, Arcangelo Prete and Riccardo Masetti, which were incorrectly given as Cerasi Sara, Leardini Davide, Lisanti Nunzia, Belotti Tamara, Pierantoni Luca, Zama Daniele, Lanari Marcello, Prete Arcangelo and Masetti Riccardo.The original Article and accompanying Supplementary Information file have been corrected."} +{"text": "Correction to: BMC Public Health 23, 1824 (2023).10.1186/s12889-023-16761-xThe original publication of this article contained an affiliation error, the correct and incorrect information is listed in this correction article. The original article has been updated.Incorrect3Bich Ha Pham3Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, 100 South Los Robles Avenue, Pasadena, CA 91101, USA.Correct2Bich Ha Pham2Healthcare Anchor Network, 2202 18th St. NW, Suite 317, Washington, DC 20009, USA."} +{"text": "Journal of Surgical Case Reports, Volume 2023, Issue 3, March 2023, rjad106, https://doi.org/10.1093/jscr/rjad106This is a correction to: Wajiha Arshad, Shahzaib Maqbool, Javeria A Kiany, Ali Raza, Umer Farooq, Qasim Ali, Ka Y Lee, A rare case of retropharyngeal liposarcoma: a rare location of a rare diagnosis, In the originally published version of this manuscript, author Ka Y Lee's affiliation, Department of Health Sciences, Mid Sweden University, Ostersund 83125, Sweden, was inadvertently omitted.This error has been corrected."} +{"text": "Scientific Reports 10.1038/s41598-023-33769-w, published online 24 April 2023Correction to: The original version of this Article contained errors in the names of the authors Nattapon Rotpenpian, Aree Wanasuntronwong, Sompol Tapechum, Anchalee Vattarakorn, Chit Care, Wongsathit Chindasri, Kanokwan Tilokskulchai, Mayuree H. Tantisira & Narawut Pakaprot, which were incorrectly given as Rotpenpian Nattapon, Wanasuntronwong Aree, Tapechum Sompol, Vattarakorn Anchalee, Care Chit, Chindasri Wongsathit, Tilokskulchai Kanokwan, Tantisira H. Mayuree & Pakaprot Narawut.The original Article has been corrected."} +{"text": "PLOS ONE Editors retract this article [The article because TY, NL, JL, QH, YL, and HZ did not agree with the retraction. RL, YY, WC, and QW either did not respond directly or could not be reached."} +{"text": "Brain Communications, Volume 5, Issue 1, 2023, fcac255, https://doi.org/10.1093/braincomms/fcac255This is a correction to: Sara Baldini, Maria Elisa Morelli, Arianna Sartori, Fulvio Pasquin, Alessandro Dinoto, Alessio Bratina, Antonio Bosco, Paolo Manganotti, Microstates in multiple sclerosis: an electrophysiological signature of altered large-scale networks functioning?, In the originally published version of this manuscript, in Figure\u00a03, the colours included in the key for HCs and RRMS values were transposed; HCs was incorrectly labelled blue and RRMS red.This error has been corrected."} +{"text": "In \u201cUnassisted Clinicians Versus Deep Learning\u2013Assisted Clinicians in Image-Based Cancer Diagnostics: Systematic Review With Meta-analysis\u201d , the authors noted one error.In the originally published article, the highest academic degrees for thirteen of the authors were erroneously displayed in the authorship list as follows:Peng Xue, PhD; Mingyu Si, PhD; Dongxu Qin, MD; Bingrui Wei, MD; Zichen Ye, MD; Mingyang Chen, PhD; Sumeng Wang, PhD; Cheng Song, PhD; Bo Zhang, MD; Ming Ding, MD; Wenling Zhang, MD; Anying Bai, PhD; Huijiao Yan, PhD.These have been corrected to:Peng Xue, MPH; Mingyu Si, MPH; Dongxu Qin, BM; Bingrui Wei, BS; Zichen Ye, BM; Mingyang Chen, BM; Sumeng Wang, BM; Cheng Song, MPhil; Bo Zhang, BM; Ming Ding, BM; Wenling Zhang, BM; Anying Bai, BM; Huijiao Yan, MPH.The correction will appear in the online version of the paper on the JMIR Publications website on June 2, 2023, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories."} +{"text": "British Journal of Surgery, 2022; znac301, https://doi.org/10.1093/bjs/znac301This is an erratum to: Michelle R de Graaff, Rianne N M Hogenbirk, Yester F Janssen, Arthur K E Elfrink, Ronald S L Liem, Simon W Nienhuijs, Jean Paul P M de Vries, Jan Willem Elshof, Emiel Verdaasdonk, Jarno Melenhorst, H L van Westreenen, Marc G H Besselink, Jelle P Ruurda, Mark I van Berge Henegouwen, Joost M Klaase, Marcel den Dulk, Mark van Heijl, Johannes H Hegeman, Jerry Braun, Daan M Voeten, Franka S W\u00fcrdemann, Anne Loes K Warps, Anna J Alberga, J Annelie Suurmeijer, Erman O Akpinar, Nienke Wolfhagen, Anne Loes van den Boom, Marieke J Bolster-van Eenennaam, Peter van Duijvendijk, David J Heineman, Michel W J M Wouters, Schelto Kruijff, the Dutch CovidSurg Collaborative Study Group, Impact of the COVID-19 pandemic on surgical care in the Netherlands, In the originally published version of this article, Rianne N M Hogenbirk was erroneously not recognized as one of the first authors.This error has been corrected."} +{"text": "BioScience, Volume 73, Issue 3, March 2023, Pages 168\u2013181, https://doi.org/10.1093/biosci/biac100This is a correction to: Sofie Meeus, Iolanda Silva-Rocha, Tim Adriaens, Peter M J Brown, Niki Chartosia, Bernat Claramunt-L\u00f3pez, Angeliki F Martinou, Michael J O Pocock, Cristina Preda, Helen E Roy, Elena Tricarico, Quentin J Groom, More than a Bit of Fun: The Multiple Outcomes of a Bioblitz, In the originally published HTML version of this manuscript, figures 4 and 5 were transposed.This error has now been corrected."} +{"text": "Bioinformatics, Volume 39, Issue 9, September 2023, btad548, https://doi.org/10.1093/bioinformatics/btad548This is a correction to: Seong-Joon Park, Sunghwan Kim, Jaeho Jeong, Albert No, Jong-Seon No, Hosung Park, Reducing cost in DNA-based data storage by sequence analysis-aided soft information decoding of variable-length reads, In the originally published version of this manuscript, author Sunghwan Kim\u2019s affiliation was incomplete.This has been corrected."} +{"text": "Culicoides of Mexico is presented. It includes 86 species with their regional distribution and corresponding record references, known immature stages and associated pathogens. In addition, a taxonomic key for subgenera and species groups for Mexico is presented and an index of species by state is included.An updated catalogue of Culicoides Latreille, 1809 are tiny hematophagous dipterans, between 1 to 3 millimeters of length, and are known as \u201cjejenes\u201d, \u201cpolvorines\u201d, \u201cpurrujas\u201d, or \u201cchaquistes\u201d in Spanish, and as \u201cbiting midges\u201d, \u201cno-see-ums\u201d, or \u201cpunkies\u201d in English . Type species: Culicoidesdendrophilus Amosova, by original designation.Culicoides (Amossovia) cochisensis Wirth & Blanton, 1967Culicoidescochisensis Wirth & Blanton, 1967: 216. Type locality: United States, Arizona, Santa Cruz, Sycamore Canyon. Additional references: Distribution in Mexico. Baja California Sur oklahomensis Khalaf, 1952Culicoidesoklahomensis Khalaf, 1952: 355 (as subspecies of villosipennis Root and Hoffman). Type locality: United States, Oklahoma, Wichita Refuge. Additional references: Distribution in Mexico. Baja California, Sonora ousairani Khalaf, 1952Culicoidesousairani Khalaf, 1952: 354. Type locality: United States, Oklahoma, Wichita Refuge. Additional references: Distribution in Mexico. Nuevo Le\u00f3n . Type species: Culicoidescovagarciai Ortiz, by original designation.Culicoides (Anilomyia) hayesi Matta, 1967Culicoideshayesi Matta, 1967: 75. Type locality: Honduras, Distrito Central, La Tigra. Additional references: Distribution in Mexico. Tamaulipas nigrigenus Wirth & Blanton, 1956Culicoidesnigrigenus Wirth & Blanton, 1956b: 222. Type locality: Panama, Boca del Toro, Almirante. Additional references: Distribution in Mexico. Veracruz pseudodecor Spinelli & Huerta, 2015Culicoidespseudodecor Spinelli & Huerta, 2015: 818. Type locality: Mexico, Morelos, El Salto Falls.Distribution in Mexico. Morelos, Veracruz . Type species: Ceratopogonobsoletus Meigen, by original designation.Culicoides (Avaritia) boydi Wirth & Mullens, 1992Culicoidesboydi Wirth & Mullens, 1992: 1006. Type locality: United States, California Riverside County, Deep Canyon, Santa Rosa Mountains. Additional references: Distribution in Mexico. Baja California pusilloides Wirth & Blanton, 1955Culicoidespusilloides Wirth & Blanton, 1955a: 104. Type locality: Panama, Boca del Toro Province, Almirante. Additional references: Distribution in Mexico. Chiapas pusillus Lutz, 1913Culicoidespusillus Lutz, 1913: 52. Type locality: Brazil, Rio de Janeiro, Manguinhos. Additional references: Distribution in Mexico. Chiapas . Type species: Culicoidescrepuscularis Malloch, by original designation.Culicoides (Beltranmyia) crepuscularis Malloch, 1915Culicoidescrepuscularis Malloch, 1915: 303. Type locality: United States, Illinois, Du Bois. Additional references: Distribution in Mexico. Mexico City , H.velans . Type species: Culicoidesgrisescens Edwards, by original designation.Culicoides (Culicoides) elutus Macfie, 1948Culicoideselutus Macfie, 1948: 75. Type locality: Mexico, Chiapas, El Carrizal. Additional references: Distribution in Mexico. Oaxaca fortinensis Spinelli & Huerta, 2015Culicoidesfortinensis Spinelli & Huerta, 2015: 812. Type locality: Mexico, Veracruz, Fort\u00edn de la Flores.Distribution in Mexico. Veracruz luteovenus Root & Hoffman, 1937Culicoidesluteovenus Root & Hoffman, 1937: 156. Type locality: Mexico, Mexico City, San Jacinto. Additional references: Distribution in Mexico. Mexico City neopulicaris Wirth, 1955Culicoidesneopulicaris Wirth, 1955: 355. Type locality: United States, Texas, Kerrville. Additional references: Distribution in Mexico. San Luis Potos\u00ed, Guerrero rulfoi Spinelli & Huerta, 2015Culicoidesrulfoi Spinelli & Huerta, 2015: 816. Type locality: Mexico, Michoac\u00e1n, Puerto Garnica.Distribution in Mexico: Michoac\u00e1n . Type species: Culicoidesbaueri Hoffman, by original designation.Culicoides (Diphaomyia) baueri Hoffman, 1925Culicoidesbaueri Hoffman, 1925: 297. Type locality: United States, Maryland, Baltimore. Additional references: Distribution in Mexico. Puebla blantoni Vargas & Wirth, 1955Culicoidesblantoni Vargas & Wirth, 1955: 33. Type locality: Mexico, Tamaulipas, Ciudad Mante. Additional references: Distribution in Mexico. Guerrero, Puebla, San Luis Potos\u00ed, Tamaulipas haematopotus Malloch, 1915Culicoideshaematopotus Malloch, 1915: 302. Type locality: United States, Illinois. Additional references: Distribution in Mexico. Mexico City , Bluetongue virus iriartei Fox, 1952Culicoidesiriartei Fox, 1952: 368. Type locality: Venezuela, Zulia, La Salina. Additional references: Culicoidesvargasi Wirth & Blanton, 1953: 74, syn. Type locality: Panama.Distribution in Mexico. Chiapas, Veracruz . Type species: Culicoidescopiosus Root and Hoffman, by original designation.Culicoides (Drymodesmyia) arizonensis Wirth & Hubert, 1960Culicoidesarizonensis Wirth & Hubert, 1960: 655. Type locality: United States, Arizona, Maricopa. Additional references: Distribution in Mexico. Baja California bakeri Vargas, 1954Culicoidesbakeri Vargas, 1954: 27. Type locality: Mexico, Mexico City , Chapultepec. Additional references: Distribution in Mexico. Mexico City butleri Wirth & Hubert, 1960Culicoidesbutleri Wirth & Hubert, 1960: 650. Type locality: United States, Arizona, Baboquivari, Brown Canyon. Additional references: Distribution in Mexico. Nuevo Le\u00f3n cacticola Wirth & Hubert, 1960Culicoidescacticola Wirth & Hubert, 1960: 653. Type locality: United States, California, Los Angeles, San Dimas Canyon. Additional references: Distribution in Mexico. Baja California Sur, Sonora copiosus Root & Hoffman, 1937Culicoidescopiosus Root & Hoffman, 1937: 171. Type locality: Mexico, Mexico City , San Jacinto. Additional references: Distribution in Mexico. Mexico City insolatus Wirth & Hubert, 1960Culicoidesinsolatus Wirth & Hubert, 1960: 654. Type locality: Mexico, Baja California, San Felipe. Additional references: Distribution in Mexico. Baja California jamaicensis Edwards, 1922Culicoidesjamaicensis Edwards, 1922: 165 (as var.loughnani Edwards). Type locality: Jamaica, Kingston. Additional references: Distribution in Mexico. Chiapas loughnani Edwards, 1922Culicoidesloughnani Edwards, 1922: 165. Type locality: Jamaica, Kingston. Additional references: Distribution in Mexico. Yucat\u00e1n panamensis Barbosa, 1947Culicoidespanamensis Barbosa, 1947: 22. Type locality: Panama, Barro Colorado. Additional references: Culicoidesalambiculorum Macfie, 1948: 81, syn. Type locality: Mexico, Chiapas.Distribution in Mexico. Chiapas poikilonotus Macfie, 1948Culicoidespoikilonotus Macfie, 1948: 82. Type locality: Mexico, Chiapas, El Vergel. Additional references: Culicoidescacozelus Macfie, 1948: 85, syn. Type locality: Mexico, Chiapas.Culicoideshertigi Wirth & Blanton, 1953: 229, syn. Type locality: Panama.Distribution in Mexico. Chiapas ryckmani Wirth & Hubert, 1960Culicoidesryckmani Wirth & Hubert, 1960: 656. Type locality: United States, California, Los Angeles, San Dimas Canyon. Additional references: Distribution in Mexico. Baja California sitiens Wirth & Hubert, 1960Culicoidessitiens Wirth & Hubert, 1960: 652. Type locality: United States, California, Los Angeles, San Dimas Canyon. Additional references: Distribution in Mexico. Baja California torridus Wirth & Hubert, 1960Culicoidestorridus Wirth & Hubert, 1960: 654. Type locality: Mexico, Baja California, San Felipe. Additional references: Distribution in Mexico. Baja California wirthomyia Vargas, 1953Culicoideswirthomyia Vargas, 1953: 227. Type locality: Mexico, Guerrero, Iguala. Additional references: Distribution in Mexico. Guerrero . Type species: Culicoidesscopus Root and Hoffman, by original designation.Culicoides (Glaphiromyia) dampfi Root & Hoffman, 1937Culicoidesdampfi Root & Hoffman, 1937: 169. Type locality: Mexico, Mexico City , San Jacinto. Additional references: Distribution in Mexico. Mexico City parascopus Wirth & Blanton, 1978Culicoidesparascopus Wirth & Blanton, 1978: 238. Type locality: Mexico, Michoac\u00e1n, Puerto Garnica. Additional references: Distribution in Mexico. Michoac\u00e1n scopus Root & Hoffman, 1937Culicoidesscopus Root & Hoffman, 1937: 170. Type locality: Mexico, Mexico City , San Jacinto. Additional references: Distribution in Mexico. Mexico City debilipalpis Lutz, 1913Culicoidesdebilipalpis Lutz, 1913: 60. Type locality: Brazil, S\u00e3o Paulo, Serra da Bocaina. Additional references: Culicoideskhalafi Beck, 1957: 104, syn. Type locality: United States, Florida.Culicoidesichesi Ronderos & Spinelli, 1995: 77, syn. Type locality: Argentina, Misiones.Distribution in Mexico. Veracruz, Yucat\u00e1n eadsi Wirth & Blanton, 1971Culicoideseadsi Wirth & Blanton, 1971a: 37. Type locality: United States, Texas, Cameron County. Additional references: Distribution in Mexico. Nayarit, San Luis Potos\u00ed, Sonora, Yucat\u00e1n ginesi Ortiz, 1951Culicoidesginesi Ortiz, 1951: 586. Type locality. Venezuela, San Felipe, Yaracuy. Additional references: Distribution in Mexico. Oaxaca kettlei Breidenbaugh & Mullens, 1999Culicoideskettlei Breidenbaugh & Mullens, 1999a: 150. Type locality: United States, California, Riverside County. Additional references: Distribution in Mexico. Baja California paraensis Culicoidesparaensis : 137 (as Haematomyidiumparaensis). Type locality: Brazil, Par\u00e1. Additional references: Culicoidesundecimpunctatus Kieffer, 1917: 307, syn. Type locality: Argentina, San Pablo.Distribution in Mexico. Quintana Roo, San Luis Potos\u00ed . Type species: Culicoidesinamollae Fox and Hoffman (= Culicoidesinsignis Lutz), by original designation.Culicoides (Hoffmania) diabolicus Hoffman, 1925Culicoidesdiabolicus Hoffman, 1925: 294. Type locality: Panama, Cabima. Additional references: Distribution in Mexico. Chiapas, Veracruz filariferus Hoffman, 1939Culicoidesfilariferus Hoffman, 1939: 172. Type locality: Mexico, Chiapas, El Vergel. Additional references: Distribution in Mexico. Chiapas foxi Ortiz, 1950Culicoidesfoxi Ortiz, 1950c: 461. Type locality: Puerto Rico, Campo Tortuguero. Additional references: Distribution in Mexico. Veracruz hylas Macfie, 1940Culicoideshylas Macfie, 1940: 26. Type locality: Guyana, New River. Additional references: Distribution in Mexico. Veracruz insignis Lutz, 1913Culicoidesinsignis Lutz, 1913: 51. Type locality: Brazil, Rio de Janeiro. Additional references: Culicoidesinamollae Fox & Hoffman, 1944: 110, syn. Type locality: Puerto Rico.Culicoidespainteri Fox, 1946: 257, syn. Type locality: Honduras.Distribution in Mexico. Chiapas ocumarensis Ortiz, 1950Culicoidesocumarensis Ortiz, 1950b: 455. Type locality: Venezuela, Miranda, Ocumare del Tuy. Additional references: Distribution in Mexico. Oaxaca, Tabasco palpalis Macfie, 1948Culicoidespalpalis Macfie, 1948: 78. Type locality: Mexico, Chiapas, San Cristobal. Additional references: Distribution in Mexico. Chiapas pseudodiabolicus Fox, 1946Culicoidespseudodiabolicus Fox, 1946: 256. Type locality: Trinidad and Tobago, Cumuto Village. Additional references: Distribution in Mexico. Veracruz verecundus Macfie, 1948Culicoidesverecundus Macfie, 1948: 76. Type locality: Mexico, Chiapas, El Vergel. Additional references: Distribution in Mexico. Chiapas . Type species: Ceratopogonphlebotomus Williston, by original designation.Culicoides (Macfiella) phlebotomus Culicoidesphlebotomus : 281 (as Ceratopogon). Type locality: St. Vincent. Additional references: Culicoidesamozonius Macfie, 1935: 52, syn. Type locality: Brazil, Par\u00e1.Distribution in Mexico. Oaxaca willistoni Wirth & Blanton, 1953Culicoideswillistoni Wirth & Blanton, 1953: 116. Type locality: Panama, Cocl\u00e9, Rio Hato. Additional references: Distribution in Mexico. Sonora . Type species: Culicoidesmojingaensis Wirth and Blanton, by original designation.Culicoides (Mataemyia) dicrourus Wirth & Blanton, 1955Culicoidesdicrourus Wirth & Blanton, 1955b: 123. Type locality: Panama, Canal Zone, Loma Borracho. Additional references: Distribution in Mexico. Tabasco . Type species: Ceratopogonnubeculosus Meigen, by original designation.Stigmoculicoides Isaev, 1988: 15 (as subgenus of Culicoides). Type species: Culicoidesstigma (Meigen), by original designation.Culicoides (Monoculicoides) occidentalis Wirth & Jones, 1957Culicoidesoccidentalis Wirth & Jones, 1957: 21 (as subspecies of variipennis). Type locality: United States, California, Lake County. Additional references: Distribution in Mexico. Baja California, Puebla (ipennis) , pupa (Sipennis) .Associated pathogens. Unknown.Culicoides (Monoculicoides) sonorensis Wirth & Jones, 1957Culicoidessonorensis Wirth & Jones, 1957: 18 (as subspecies of variipennis). Type locality: United States, Arizona, Cochise County. Additional references: Culicoidesvariipennisalbertensis Wirth & Jones, 1957: 17, syn. Type locality: Canada.Culicoidesvariipennisaustralis Wirth & Jones, 1957: 15, syn. Type locality: United States, Louisiana.Distribution in Mexico. Estado de Mexico, Guerrero, Mexico City, Nuevo Le\u00f3n, Nuevo Le\u00f3n, Puebla, Sonora (variipennis) (ipennis) , larva (ipennis) , pupa variipennis Culicoidesvariipennis : 602 (as Ceratopogon). Type locality: United States, Virginia, Richmond. Additional references: Distribution in Mexico. Mexico City barbosai Wirth & Blanton, 1956Culicoidesbarbosai Wirth &Blanton, 1956a: 161. Type locality: Panama, Canal Zone, Mojinga Swamp. Additional references: Distribution in Mexico. Quintana Roo cancer Hogue & Wirth, l968Culicoidescancer Hogue & Wirth, 1968: 2. Type locality: Costa Rica, Puntarenas, Golfo de Nicoya, Boca de Barranca. Additional references: Distribution in Mexico. Sinaloa furens Poey, 1853Culicoidesfurens : 236. Type locality: Cuba. Additional references: Ceratopogonmaculithorax : 277, syn. Type locality: St. Vincent.Culicoidesdovei Hall, 1932: 88, syn. Type locality: United States, Georgia.Culicoidesbirabeni Cavalieri, 1966: 59, syn. Type locality: Venezuela.Distribution in Mexico. Veracruz . Type species: Culicoideshieroglyphicus Malloch, by original designation.Culicoides (Selfia) hieroglyphicus Malloch, 1915Culicoideshieroglyphicus Malloch, 1915: 297. Type locality: United States, Arizona, Graham Mountains, Ash Creek. Additional references: Distribution in Mexico. Baja California, Sonora multipunctatus Malloch, 1915Culicoidesmultipunctatus Malloch, 1915: 296. Type locality: United States, Illinois, Urbana. Additional references: Distribution in Mexico. Tamaulipas .Distribution in Mexico. Mexico City .General distribution. Neotropical. Mexico, Honduras, Panama, Venezuela, Trinidad and Tobago, Surinam, Brazil , Culicoidesdonajii Vargas, 1954: 28, syn. Type locality: Mexico, Oaxaca.Culicoidespatupalpis Wirth & Blanton, 1959: 421, syn. Type locality: Panama.Distribution in Mexico. Oaxaca (donajii).General distribution. Neotropical. Mexico, Central America, Colombia, Ecuador, Bolivia, Venezuela, Trinidad and Tobago, Brazil Culicoidesmelleus : 604 (as Ceratopogon). Type locality: United States, Florida, Lake Worth. Additional references: Distribution in Mexico. Baja California : 164. Type locality: Mexico, Mexico City, San Jacinto. Additional references: Distribution in Mexico. Mexico City and C. (Monoculicoides) are predominant in the Nearctic Region, while C. (Drimodesmyia) has a significant presence in both the Neotropical and Nearctic Regions.The distribution of C. (Anilomyia), C. (Avaritia), C. (Culicoides) and C. (Diphaomyia) have a predominant distribution in the Neotropical Region. Although C. (Hoffmania) is also common in this Region, the presence of C.insignis has been recorded in the Nearctic and represents an important health risk. In addition, C. (Glaphiromyia) is a subgenus mainly endemic to Mexico, which makes it of special interest from a biogeographical perspective since species of this subgenus have been described in the transition zone of central Mexico.On the other hand, the subgenera Culicoides species have been recorded in only 25. Veracruz and Chiapas had the highest richness of biting midges. The subgenus Drymodesmyia is the best represented in the country with 14 species recorded, followed by the subgenus Hoffmania, represented by nine species. It should be noted that most of the records made in the country are the result of collection events more than half a century old and few records have been made in recent years; in addition, there are species that have not been collected since they were recorded; thus, the occurrence and distribution of several species should be reevaluated.Of Mexico\u2019s 32 states, Culicoides species are largely unknown and represent an important potential area of study. The immature stages of 30% of species present in Mexico are known. The egg stage is known for 5.8% of the species, while both larval and pupal stages for 27%. On the other hand, 15 species (17.4%) have been associated with different pathogens and therefore represent a potential risk as vectors in the country. Of these, eight species were associated with viruses, among which C.sonorensis, C.insignis and C.paraensis stand out for their greatest impact on human and animal health. The presence of these species in the country poses a greater health risk; therefore, it is vital to increase surveillance efforts to prevent possible disease outbreaks, especially in regions of high susceptibility, such as those with high livestock production. In addition, six species were associated with the transmission of nematodes and six species with protozoa, particularly Haemosporida.In general, the immature stages of Culicoides fauna of Mexico. Previously, it was necessary to consult several studies to identify the species present in the country. However, since the current subgeneric classification of Culicoides species could include inconsistencies and is in urgent need of revision, it is likely that these keys should help update the knowledge of the genus in the country.The dichotomous keys presented in this work are the first to specifically focus on the Culicoides in the country is far from being elucidated.Lastly, it is important to note that due to the physiographic, climatic, and topographic characteristics of the country, the great variety of ecosystems with conditions like those of other neotropical countries, as well as the lack of systematic and faunistic studies that address the spatial and temporal changes of the group, it can be inferred that the species richness of"} +{"text": "PNAS Nexus, Volume 1, Issue 4, September 2022, pgac173, https://doi.org/10.1093/pnasnexus/pgac173This is a correction to: Sho Watanabe, Yuri Sudo, Takumi Makino, Satoshi Kimura, Kenji Tomita, Makoto Noguchi, Hidetoshi Sakurai, Makoto Shimizu, Yu Takahashi, Ryuichiro Sato, Yoshio Yamauchi, Skeletal muscle releases extracellular vesicles with distinct protein and microRNA signatures that function in the muscle microenvironment, In the originally published version of this manuscript, the image for Calnexin was duplicated in Figure\u00a04E's right panel (CD81-isolation) from the left panel.The figure has now been corrected in the article."} +{"text": "JAC-Antimicrobial Resistance, Volume 5, Issue 2, April 2023, dlad030, https://doi.org/10.1093/jacamr/dlad030This is a correction to: Hala Kandil, Robert M Gray, Rakan El-Hamad, Madhuri Vidwans, Tejal Vaghela, Omar Naji, Sebastien Van De Velde, Empirical use of temocillin in hospitalized patients: results from a retrospective audit, In the originally published version of this manuscript, the affiliations of authors Rakan El-Hamad and Tejal Vaghela were incorrect.Rakan El-Hamad's affiliation was given as \u2018Microbiology Department, West Hertfordshire Teaching Hospitals NHS Trust, Vicarage Road, Watford, Hertfordshire WD18 0HB, UK\u2019 instead of \u2018Department of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan\u2019.Tejal Vaghela's affiliations were given as \u2018Microbiology Department, West Hertfordshire Teaching Hospitals NHS Trust, Vicarage Road, Watford, Hertfordshire WD18 0HB, UK\u2019 and \u2018Department of Pathology and Microbiology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan\u2019, instead of just \u2018Microbiology Department, West Hertfordshire Teaching Hospitals NHS Trust, Vicarage Road, Watford, Hertfordshire WD18 0HB, UK\u2019.These errors have been corrected."} +{"text": "Brain Communications, Volume 5, Issue 2, 2023, https://doi.org/10.1093/braincomms/fcad048This is a correction to: William J Scotton, Cameron Shand, Emily Todd, Martina Bocchetta, David M Cash, Lawren VandeVrede, Hilary Heuer, PROSPECT Consortium, 4RTNI Consortium, Alexandra L Young, Neil Oxtoby, Daniel C Alexander, James B Rowe, Huw R Morris, Adam L Boxer, Jonathan D Rohrer, Peter A Wijeratne, Uncovering spatiotemporal patterns of atrophy in progressive supranuclear palsy using unsupervised machine learning, In the originally published version of this manuscript, there was an error within Figure\u00a02. The significance bar should be across columns marked PSP-RS and PSP-SC, rather than across those marked PSP-C and PSP-SC. Figure\u00a02 should thus read:instead of:The figure has been emended in the article."} +{"text": "Correction to: Nano-Micro Letters (2022) 14:192https://doi.org/10.1007/s40820-022-00925-2In this article Florian Puchtler at affiliation \u2018University of Bayreuth\u2019, Josef Breu at affiliation \u2018University of Bayreuth\u2019, and Ziliang Wu at affiliation \u2018Zhejiang University\u2019 was missing from the author Min Cao, Senping Liu, Qingli Zhu, Ya Wang, Jingyu Ma, Zeshen Li, Dan Chang, Enhui Zhu, Xin Ming, Florian Puchtler, Josef Breu, Ziliang Wu, Yingjun Liu, Yanqiu Jiang, Zhen Xu, Chao Gao list.The original article has been corrected."} +{"text": "British Journal of Surgery, Volume 110, Issue 1, January 2023, Pages 92\u201397, https://doi.org/10.1093/bjs/znac371This is an erratum to: Carmel Conefrey, Cynthia Ochieng, Christin Hoffmann, Daisy Elliott, Kerry Avery, Joanne Bennett, Natalie Blencowe, Sarah Duff, James Kinross, Angus McNair, David Messenger, Anne Pullyblank, Baljit Singh, Anni King, Sarah E Squire, Jane Blazeby, Barry Main, Leila Rooshenas, Managing surgical demand when needs outstrip resource: qualitative investigation of colorectal cancer surgery provision in the first wave of the COVID-19 pandemic, In the originally published version, the third and twelfth authors\u2019 names were mis-spelled.These have been corrected online."} +{"text": "PLOS ONE Editors retract this article [The article because KSA, MAA, FN, and RWB did not agree with the retraction. MSI, MA, AM, SAH, NA, SM, HA, and KS either did not respond directly or could not be reached."} +{"text": "Author list, whereby author \u201cAnna-Maria Liphardt\u201d was erroneously listed as the second author. The corrected Author list appears below.In the published article there was an error in the \u201cAlina Saveko, Takuro Washio, Lonnie G. Petersen, Marc-Antoine Custaud and Anna-Maria Liphardt\u201d.In the published article, there was an error in affiliation for Marc-Antoine Custaud. Instead of \u201cUniversity Angers, CRC, CHU Angers, Inser, CNRS, MITOVASC, SFR CAT, Angers, France\u201d, it should be \u201cCRC, CHU Angers, Inserm, CNRS, MITOVASC, SFR ICAT, University of Angers, Angers, France\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "We show the ability of LACTB to function as a tumor suppressor in ovarian cancer through down-regulation of Slug and induction of differentiation. PMID: 36375842.Article: Cutano V, Ferreira Mendes JM, Escudeiro-Lopes S, Machado S, Vinaixa Forner J, Gonzales-Morena JM, Prevorovsky M, Zemlianski V, Feng Y, Kralova Viziova P, Hartmanova A, Malcekova B, Jakoube P, Iyer S, Keckesova Z (2022 Nov 14) LACTB exerts tumor suppressor properties in epithelial ovarian cancer through regulation of Slug. Life Science Alliance 6(1): e202201510. doi: Correction"} +{"text": "Plant Physiology, Volume 192, Issue 1, May 2023, Pages 119\u2013132, https://doi.org/10.1093/plphys/kiad097This is a correction to: Yingxuan Ma, Thomas Shafee, Asha M Mudiyanselage, Julian Ratcliffe, Colleen P MacMillan, Shawn D Mansfield, Antony Bacic, Kim L Johnson, Distinct functions of FASCICLIN-LIKE ARABINOGALACTAN PROTEINS relate to domain structure, In the originally published version of this manuscript, there was a typographical error in the title, whereby \u2018FASCICLIN-LIKE\u2019 was given as \u2018FASCILIN-LIKE\u2019.This error has been corrected."} +{"text": "Correction to: Surgical Endoscopy (2022) 37:977-988 10.1007/s00464-022-09547-6The original online version of this article was revised to correct the affiliations of author Antonino Spinelli. The correct affiliations are Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy.The original article has been corrected."} +{"text": "In the published article, the surname of the fourth author was incorrectly written in the article's citation as \u201cMumbua Nzioka B\u201d and copyright statement as \u201cMumbua Nzioka\u201d. It should read \u201cNzioka BM\u201d and \u201cNzioka\u201d, respectively.The author's name was also incorrectly abbreviated in the Author contributions statement as BN, while it should read BMN. This sentence previously stated:\u201cAA, CS, and EN-M: conceptualization and methodology. SO, BN, RO, AA, CS, and EN-M: investigation. RO, PM, and SO: data management. SO, PM, and AA: formal analysis. SO, BN, AA, CS, and EN-M: project administration and supervision. SO and PM: writing-original draft preparation. SO, PM, BN, RO, CS, EN-M, and AA: writing-review and editing. All authors read, provided feedback, approved, and agreed to the published version of the manuscript.\u201dThe correct statement appears below:\u201cAA, CS, and EN-M: conceptualization and methodology. SO, BMN, RO, AA, CS, and EN-M: investigation. RO, PM, and SO: data management. SO, PM, and AA: formal analysis. SO, BMN, AA, CS, and EN-M: project administration and supervision. SO and PM: writing-original draft preparation. SO, PM, BMN, RO, CS, EN-M, and AA: writing-review and editing. All authors read, provided feedback, approved, and agreed to the published version of the manuscript.\u201dIn the published article, there was an error. The authors stated that PHQ-9 and GAD-7 were significantly positively correlated with resilience and work engagement instead of negatively correlated in the results section of the abstract.Results, Lines 97\u201399. This sentence previously stated:A correction has been made to Abstract, \u201cThe PHQ-9 and GAD-7 were also significantly positively correlated with resilience and work engagement, supporting divergent validity.\u201dThe corrected sentence appears below:\u201cThe PHQ-9 and GAD-7 were significantly negatively correlated with resilience and work engagement, supporting divergent validity.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "PLOS ONE Editors retract this article [The article because MI, KHB, IH, TH, SHA-H, and SS did not agree with the retraction. HK, MA, MMaqbool, WM, ST, RB, and MMuzamil either did not respond directly or could not be reached."} +{"text": "In the published article, there was an error regarding the Conflict of Interest for Patrick D. Mahar, Christopher Schuster, Imre Pavo, and Isabella Yali Wang. The Conflict of Interest statement should be:AE has honoraria as consultant and/or speaker from AbbVie, Almirall, Bristol-Meyers Squibb, Leo Pharma, Samsung Bioepis Co., Ltd., Pfizer, Eli Lilly, Novartis, Galderma, and Janssen Pharmaceuticals. LP has received honoraria/consultation fees from Abbvie, Almirall, Amgen, Baxalta, Boehringer Inglheim, Celgene, Gebro, Janssen, Leo-Pharma, Lilly, Merck-Serono, MSD, Mylan, Norvartis, Pfizer, Regeneron, Roche, Sandoz, Samsung-Bioepis, Sanofi and UCB. LP has participated in company sponsored speaker's bureau for Celgene, Janssen, Lilly, MSD, Norvartis and Pfizer. KS is a consultant, investigator, speaker and has received grants from: AbbVie, Amgen, Almirall, Biogen, Bristol-Myers Squibb Boehringer Ingelheim, Celgene, Chugai, Galderma, Janssen-Cilag, Leo-Pharma, Lilly, Merck Sharp & Dohme Corp., Morphosys, Novartis, Pfizer, Regeneron, UCB Pharma. JM is a consultant and/or investigator for Amgen, Bristol-Myers Squibb, Abbvie, Dermavant, Eli Lilly, Novartis, Janssen, UCB, Sanofi-Regeneron, Sun Pharma, Biogen, Pfizer and Leo Pharma. CG has received honoraria or research grants from AbbVie, Almirall, Anaptysbio Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, GSK, Janssen, LEO Pharma, Pfizer, Novartis ONO Pharmaceuticals, UCB Pharma and Walgreens Boots Alliance, and is supported in part by the Manchester NIHR Biomedical Research Centre. PM has served as a consultant, investigator, speaker and/or advisor for Novartis, AstraZeneca, Abbvie, Pfizer, Bristol-Meyers Squibb, Eli Lilly and Company and Boehringer Ingelheim. PM, CS, IP, and IW are employees of Eli Lilly and Company. PM owns equity in Eli Lilly and Company. CS, IP, and IW are minor shareholders of Eli Lilly and Company.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Values in bold means the summarized values.\u2019The correct footnote appears below. The publisher apologizes for this mistake.aSince/at diagnosis of PTLD, respectively. bWhere applicable .\u2018 Abbreviations: 7\u00a0+\u00a03=cytarabine and daunorubicin. (s)AML=(secondary) acute myeloid leukemia. assoc.=associated. sAA=severe aplastic anemia. CAD=cyclophosphamide, doxorubicin, and dexamethasone. cALL=common acute lymphoblastic leukemia. cHL=classic Hodgkin lymphoma. CKD=chronic kidney disease. CNL=Chronic neutrophilic leukemia. DLBCL=diffuse large B-cell lymphoma. GMALL07/2003=study protocol containing daunorubicin and doxorubicin. HCC=Hepatocellular carcinoma. IDA-FLAG=idarubicin, fludarabine, cytarabine, G-CSF. Mito-FLAG=mitoxantrone, fludarabine, cytarabine, G-CSF. monom.=monomorphic. PBL=Plasmablastic lymphoma. PCL=plasma cell leukemia. PD=Progressive disease. Pola=Polatuzumab-Vedotin. PSC=Primary sclerosing cholangitis. T-LBL=T-lymphoblastic lymphoma. T1D=Type 1 diabetes. TAD=thalidomide, doxorubicin, Dexa. T-ALL=T-acute lymphoblastic leukemia.\u2019The original version of this article has been updated.aSince/at diagnosis of PTLD, respectively. bWhere applicable .Additionally, due to a production error, there was a mistake in the footnote for Table\u00a02 as published. The abbreviations were written as \u2018 AVD, adriamycin, vinblastine, dacarbazine; Benda, Bendamustine; BV, brentuximab-vedotin; CAD, cyclophosphamide, doxorubicin, and dexamethasone; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; DLBCL, diffuse large B-cell lymphoma; DLI, Donor lymphocyte infusion; GMALL07/2003, study protocol containing daunorubicin and doxorubicin; GMALL-B-NHL 2002, protocol containing R, Dexa, vincristine, MTX, ifosfamide, cytarabine, etoposide, cyclophosphamide, doxorubicin; HCC, Hepatocellular carcinoma; IDA-FLAG, idarubicin, fludarabine, cytarabine, G-CSF; IS, immunosuppression; Mito-FLAG, mitoxantrone, fludarabine, cytarabine, G-CSF; monom;, monomorphic; MTX, Methotrexate; PD, Progressive disease; Pola, Polatuzumab-Vedotin; PSC, Primary sclerosing cholangitis; R, Rituximab; RIS, Reduction of immunosuppression; RTx, Radiotherapy; thalidomide, doxorubicin, Dexa; VST, Virusspecific T cells. Values in bold means the summarized values.\u2019The correct footnote appears below. The publisher apologizes for this mistake.\u2018aSince/at diagnosis of PTLD, respectively. bWhere applicable .AVD, adriamycin, vinblastine, dacarbazine; Benda, Bendamustine; BV, brentuximab-vedotin; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisolone; DLI, Donor lymphocyte infusion; GMALL-B-NHL 2002, protocol containing R, Dexa, vincristine, MTX, ifosfamide, cytarabine, etoposide, cyclophosphamide, doxorubicin; IS, immunosuppression; Mito-FLAG, mitoxantrone, fludarabine, cytarabine, G-CSF; monom, monomorphic; MTX, Methotrexate; PD, Progressive disease; Pola, Polatuzumab-Vedotin; R, Rituximab; RIS, Reduction of immunosuppression; RTx, Radiotherapy; VST, Virus-specific T cells.\u2019Due to a production error, there was a mistake in"} +{"text": "The safety and efficacy of balloon-expandable versus self-expanding trans-catheter aortic valve replacement in high-risk patients with severe symptomatic aortic stenosis By Senguttuvan NB, Bhatt H, Balakrishnan VK, et al. (2023) Front. Cardiovasc. Med. 10:1130354. doi: 10.3389/fcvm.2023.1130354A Corrigendum on Error in Author ListIn the published article, there was an error in the author list. The previously-named author Gilbert H. L. Tang needs to be removed. The corrected author list appears below.1,2, Hemal Bhatt2,3, Vinod Kumar Balakrishnan1, Parasuram Krishnamoorthy3, Sunny Goel3, Pothireddy M K Reddy1, Vinodhini Subramanian1, Bimmer E Claessen2,4, Ashish Kumar5, Monil Majmundar6, Richard Ro2, Stamatios Lerakis2, Ramamoorthi Jayaraj7, Ankur Kalra5,8, Marcus Flather9, George Dangas2Nagendra Boopathy SenguttuvanThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.Text CorrectionIn the published article, there was an error. The Author Contribution section stated that Gilbert H. L. Tang's (GT) made a contribution to the article.A correction has been made to the Author contribution section. This section previously stated:\u201cNS: planning, execution, data extraction, statistics, reporting, writing the first manuscript, review and editing. HB: planning, execution, data extraction, statistics. VB, PK, SG, RR, SL, AKu, MM, RJ, Aka, MF, GD, and VS: review and editing. PR: data extraction, review and editing. BC: planning, execution, review and editing. GT: senior author, guarantor.\u201dThe corrected section appears below.\u201cNS: planning, execution, data extraction, statistics, reporting, writing the first manuscript, review and editing. HB: planning, execution, data extraction, statistics. VB, PK, SG, RR, SL, AKu, MM, RJ, Aka, MF, GD, and VS: review and editing. PR: data extraction, review and editing. BC: planning, execution, review and editing.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Correction to: BMC Public Health (2023) 23:108210.1186/s12889-023-16023-wThe original publication of this article contained an incorrect author contribution section.The incorrect and correct information is listed in this correction article, the original article has been updated.IncorrectCheah WL, Poh BK, Ruzita AT, Koh D, Reeves S, Essau C, Summerbell C, Gibson EL developed the concept and study design. Cheah WL, Noor Hafzah Y, Anchang GNJ, Gibson EL provided the administrative support. Cheah WL, Noor Hafzah Y and Achang GNJ analyzed and interpreted the data. All authors contributed to the writing of the manuscript and approved.Correct(i) Conception and design: Cheah WL, Poh BK, Ruzita AT, Lee JAC, Koh D, Reeves S, Essau C, Summerbell C, Gibson EL; (ii) Administrative support: Cheah WL, Noor Hafizah Y, Anchang GNJ, Gibson EL; (iii) Data analysis and interpretation: Cheah WL, Noor Hafizah Y, Anchang FNJ; Manuscript writing: All authors; (vi) Final approval of manuscripts: all authors."} +{"text": "QJM: An International Journal of Medicine, Volume 116, Issue 6, June 2023, Pages 429\u2013435, https://doi.org/10.1093/qjmed/hcad050This is a correction to: G M Massen and others, on behalf of the DEMISTIFI Consortium, Classifying the unclassifiable\u2014a Delphi study to reach consensus on the fibrotic nature of diseases, Acknowledgements section was omitted. The text there should read: \u201cWe are grateful to everyone who took part in survey development as well as responding to the survey, including Ralf Weiskirchen, Nazia Chaudhuri, Gavin Murphy, Gabriela C Tabaj, Claude Jourdan le Saux, Robert Scott, Diego Moriconi, Peter Boor, Bibek Gooptu, Timothy Kendall, Christopher Fry, Elisabeth Bendstrup, Dean Sheppard, Jesper R\u00f8mhild Davidsen, Scott Friedman, Kerri Johannson, John Greenland, Christine Fiddler, Eduardo Martin-Nares, Ole Hilberg, Alastair Moss, Guruprasad Aithal, Jonathan A Fallowfield, Joseph Jacob, Alberto Ortiz, Hilary Longhurst, Liz Lightstone, Vincent Cottin, Ivette Buendia-Roldan, Helen Parfrey, Giulio Marchesini.\u201dIn the originally published version of this manuscript, the This has been emended in the article."} +{"text": "In Ghafoor, Ali, and Goldust.,Syeda Mahanum Ali, MCPS"} +{"text": "Innovation in Aging, Volume 7, Issue 3, 2023, igad017, https://doi.org/10.1093/geroni/igad017This is a correction to: Nathan Louras, MD, Meghan Reading Turchioe, PhD, MPH, RN, Leah Shafran Topaz, MSc, BPT, Michelle R. Demetres, MLIS, Melani Ellison, BS, Jamie Abudu-Solo, BS, Erik Blutinger, MD, MSc, Kevin G Munjal, MD, MPH, Brock Daniels, MD, MPH, Ruth M Masterson Creber, PhD, MSc, RN, Mobile Integrated Health Interventions for Older Adults: A Systematic Review, In the article, \u201cMobile Integrated Health Interventions for Older Adults: A Systematic Review,\u201d the following author was omitted from the author list in error: Michelle R. Demetres, MLIS. This error has been corrected."} +{"text": "PLOS ONE Editors retract this article [The article because SUR, AI, and ZA did not agree with the retraction. GQ, MHNT, SF, FA, MSajjad, MShees, MU, and ZG either did not respond directly or could not be reached."} +{"text": "In: Geldsetzer P, Tan MM, Dewi FST, Quyen BTT, Juvekar S, Hanifi SMA, et al. Hypertension care in demographic surveillance sites: a cross-sectional study in Bangladesh, India, Indonesia, Malaysia, Viet Nam. Bull World Health Organ. 2022 Oct 1;100(10):601\u2013609, On page 601, the affiliation of Sayed MA Hanifi should be: Health Systems and Population Studies Division, icddr,b, Dhaka, Bangladesh."} +{"text": "LIPIGEN Paediatric Group was erroneously excluded. The corrected author list appears below.In the published article, there was an error in the author list, and 1, Manuela Casula2,3, Stefano Bertolini4, Maria Elena Capra5, Elena Olmastroni3, Alberico Luigi Catapano2,3, Cristina Pederiva6 and the LIPIGEN Paediatric Group\u201cMarta Gazzotti1SISA Foundation, Milan, Italy2IRCCS MultiMedica, Sesto San Giovanni (Milan), Italy3Department of Pharmacological and Biomolecular Sciences, Epidemiology and Preventive Pharmacology Service (SEFAP), University of Milan, Milan, Italy4Department of Internal Medicine, University of Genova, Genova, Italy5Centre for Paediatric Dyslipidaemias, Paediatrics and Neonatology Unit, Guglielmo da Saliceto Hospital, Piacenza, Italy6Clinical Service for Dyslipidaemias, Study and Prevention of Atherosclerosis in Childhood, Paediatrics Unit, ASST-Santi Paolo e Carlo, Milan, Italy\u201dMassimiliano Allevi, Internal Medicine and Geriatrics, Department of Clinical and Molecular Sciences, University \u201cPolitecnica delle Marche\u201d and IRCCS-INRCA, Ancona, Italy; Marcello Arca, Dipartimento di Medicina Traslazionale e di Precisione, Sapienza Universit\u00e0 di Roma\u2014A. U. O Policlinico Umberto I, Rome, Italy; Renata Auricchio, Dipartimento di Scienze Mediche Traslazionali, AOU Policlinico Federico II, Naples, Italy; Maurizio Averna, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza, Universit\u00e0 degli Studi di Palermo, Palermo, Italy; Davide Baldera, Dipartimento di Scienze Biomediche, Universit\u00e0 degli Studi di Cagliari and Centro per le Malattie Dismetaboliche e l\u2019Arteriosclerosi, Associazione ME.DI.CO. Onlus Cagliari, Cagliari, Italy; Giuseppe Banderali, U.O. Clinica Pediatrica, Servizio Clinico Dislipidemie per lo Studio e la Prevenzione dell\u2019Aterosclerosi in et\u00e0 Pediatrica, ASST-Santi Paolo e Carlo, Milan, Italy; Andrea Bartuli, UOC Malattie Rare e Genetica Medica, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, Rome, Italy; Stefano Bertolini, Department of Internal Medicine, University of Genova, Genova, Italy; Giacomo Biasucci, Centro Dislipidemie in Et\u00e0 Evolutiva, U.O. Pediatria e Neonatologia, Ospedale Guglielmo da Saliceto, Piacenza, Italy; Claudio Borghi, U.O. di Medicina Interna Cardiovascolare, Centro Aterosclerosi, Ambulatorio Dislipidemie, IRCCS S. Orsola Ospedale Policlinico S. Orsola-Malpighi, Bologna, Italy; Patrizia Bruzzi, U.O.C. Pediatria, Azienda Ospedaliero Universitaria di Modena, Modena, Italy; Raffaele Buganza, Paediatric Endocrinology, Department of Public Health and Paediatric Sciences, Turin University, Turin, Italy; Paola Sabrina Buonuomo, UOC Malattie Rare e Genetica Medica, Ospedale Pediatrico Bambino Ges\u00f9, IRCCS, Rome, Italy; Paolo Calabr\u00f2, U.O.C. Cardiologia Clinica a Direzione Universitaria e U.T.I.C., A.O.R.N. \u201cSant'Anna e San Sebastiano\u201d, Caserta, Italy and Dipartimento di Scienze Mediche Traslazionali, Universit\u00e0 degli Studi della Campania \"Luigi Vanvitelli\u201d, Naples, Italy; Sebastiano Calandra, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; Maria Elena Capra, Centro Dislipidemie in Et\u00e0 Evolutiva, U.O. Pediatria e Neonatologia, Ospedale Guglielmo da Saliceto, Piacenza, Italy; Francesca Carubbi, U.O. Medicina interna metabolica, Centro dislipidemie e malattie metaboliche rare, Ospedale Civile Baggiovara, AOU di Modena, Modena, Italy; Manuela Casula, Dipartimento di Scienze Farmacologiche e Biomolecolari, Universit\u00e0 degli Studi di Milano, and IRCCS MultiMedica, Sesto San Giovanni (Milan), Italy; Alberico Luigi Catapano, Dipartimento di Scienze Farmacologiche e Biomolecolari, Universit\u00e0 degli Studi di Milano, and IRCCS MultiMedica, Sesto San Giovanni (Milan), Italy; Arturo Cesaro, U.O.C. Cardiologia Clinica a Direzione Universitaria e U.T.I.C., A.O.R.N. \u201cSant'Anna e San Sebastiano\u201d, Caserta, Italy and Dipartimento di Scienze Mediche Traslazionali, Universit\u00e0 degli Studi della Campania \u201cLuigi Vanvitelli\u201d, Naples, Italy; Francesco Cipollone, Clinica Medica, Centro di riferimento regionale per le Dislipidemie, Ospedale Policlinico S.S. Annunziata, Chieti, Italy; Nadia Citroni, Centro Dislipidemie e Aterosclerosi, UOC Medicina Interna, Ospedale di Trento, Trento, Italy; Giuseppe Covetti, U.O. Medicina Interna 2, Centro per le malattie da arteriosclerosi, AORN Cardarelli, Naples, Italy; Annalaura Cremonini, IRCCS Ospedale policlinico San Martino UOSD Dietetica e Nutrizione Clinica and Dipartimento di Medicina Interna, Universit\u00e0 di Genova, Genova, Italy; Sergio D\u2019Addato, U.O. di Medicina Interna Cardiovascolare, Centro Aterosclerosi, Ambulatorio Dislipidemie, IRCCS S. Orsola Ospedale Policlinico S. Orsola-Malpighi, Bologna, Italy; Maria Del Ben, Dipartimento Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari - Sapienza Universit\u00e0, A.O. Policlinico Umberto I, Rome, Italy; Maria Donata Di Taranto, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli studi di Napoli Federico II and CEINGE Biotecnologie Avanzate s.c.a.r.l., Naples, Italy; Giuliana Fortunato, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universit\u00e0 degli studi di Napoli Federico II and CEINGE Biotecnologie Avanzate s.c.a.r.l., Naples, Italy; Roberto Franceschi, UOC Pediatria, Ospedale di Trento, Trento, Italy; Federica Galimberti, IRCCS MultiMedica, Sesto San Giovanni (Milan), Italy; Marta Gazzotti, Fondazione SISA , Milan, Italy; Simonetta Genovesi, IRCCS Istituto Auxologico Italiano and Dipartimento di Medicina e Chirurgia, Universit\u00e0 di Milano-Bicocca, Milan, Italy; Antonina Giammanco, Dipartimento di Promozione della Salute, Materno-Infantile, di Medicina Interna e Specialistica di Eccellenza, Universit\u00e0 degli Studi di Palermo, Palermo, Italy; Liliana Grigore, Centro per lo Studio dell'Aterosclerosi, IRCCS MultiMedica, Sesto San Giovanni (Milan), Italy and Centro per lo Studio dell\u2019Aterosclerosi, Ospedale E. Bassini, Cinisello Balsamo, Milan, Italy; Ornella Guardamagna, Paediatric Endocrinology, Department of Public Health and Paediatric Sciences, Turin University, Turin, Italy; Arcangelo Iannuzzi, U.O. Medicina Interna 2, Centro per le malattie da arteriosclerosi, AORN Cardarelli, Naples, Italy; Gabriella Iannuzzo, Dipartimento di Medicina Clinica e Chirurgia, Centro Coordinamento regionale per le Iperlipidemie, AOU Policlinico Federico II, Naples, Italy; Lidia Lascala, AOU Mater Domini, Catanzaro; Fabiana Locatelli, Ambulatorio ipertensione dislipidemie rischio cardiovascolare, ASST Valle Olona, Ospedale di Gallarate, Gallarate, Italy, Ospedale di Busto Arsizio, Busto Arsizio, Italy; Lorenzo Iughetti, U.O.C. Pediatria, Azienda Ospedaliero Universitaria di Modena, Modena, Italy; Sara Madaghiele, U.O. di Medicina Interna e Geriatria \u201cC. Frugoni\u201d and Centro di Assistenza e Ricerca Malattie Rare, A.O. Universitaria Policlinico Consorziale, Universit\u00e0 degli Studi di Bari \u201cAldo Moro\u201d, Bari, Italy; Giuseppe Mandraffino, Department of Clinical and Experimental Medicine\u2014Lipid Center\u2014University Hospital G. Martino, Messina, Italy; Massimo Raffaele Mannarino, Internal Medicine, Angiology and Arteriosclerosis Diseases. Department of Medicine and Surgery. University of Perugia, Perugia, Italy; Bucci Marco, Clinica Medica, Centro di riferimento regionale per le Dislipidemie, Ospedale Policlinico S.S. Annunziata, Chieti, Italy; Lorenzo Maroni, Ambulatorio ipertensione dislipidemie rischio cardiovascolare, ASST Valle Olona, Ospedale di Gallarate, Gallarate, Italy, Ospedale di Busto Arsizio, Busto Arsizio, Italy; Ilenia Minicocci, Dipartimento di Medicina Traslazionale e di Precisione, Sapienza Universit\u00e0 di Roma\u2014A. U. O Policlinico Umberto I, Rome, Italy; Giuliana Mombelli, Centro Dislipidemie ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Sandro Muntoni, Dipartimento di Scienze Biomediche, Universit\u00e0 degli Studi di Cagliari and Centro per le Malattie Dismetaboliche e l\u2019Arteriosclerosi, Associazione ME.DI.CO. Onlus Cagliari, Cagliari, Italy; Fabio Nascimbeni, U.O. Medicina interna metabolica, Centro dislipidemie e malattie metaboliche rare, Ospedale Civile Baggiovara, AOU di Modena, Modena, Italy; Elena Olmastroni, Servizio di Epidemiologia e Farmacologia Preventiva (SEFAP), Dipartimento di Science Farmacologiche e Biomolecolari, Universit\u00e0 degli Studi di Milano, Milan, Italy; Gianfranco Parati, IRCCS Istituto Auxologico Italiano and Dipartimento di Medicina e Chirurgia, Universit\u00e0 di Milano-Bicocca, Milan, Italy; Angelina Passaro, Department of Translational Medicine, University of Ferrara, Ferrara, Italy and Research and Innovation Section, University Hospital of Ferrara Arcispedale Sant'Anna, Ferrara, Italy; Chiara Pavanello, Centro Dislipidemie ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy and Centro Grossi Paoletti, Dipartimento di Scienze Farmacologiche e Biomolecolari, Universit\u00e0 degli Studi di Milano, Milano, Italy; Cristina Pederiva, U.O. Clinica Pediatrica, Servizio Clinico Dislipidemie per lo Studio e la Prevenzione dell\u2019Aterosclerosi in et\u00e0 Pediatrica, ASST-Santi Paolo e Carlo, Milan, Italy; Fabio Pellegatta, Centro per lo Studio dell'Aterosclerosi, IRCCS MultiMedica, Sesto San Giovanni (Milan), Italy and Centro per lo Studio dell\u2019Aterosclerosi, Ospedale E. Bassini, Cinisello Balsamo, Milan, Italy; Francesco Massimo Perla, Dipartimento Materno Infantile e Scienze Urologiche\u2014Sapienza Universit\u00e0, A.O. Policlinico Umberto I, Rome, Italy; Medicina Generale, Ospedale di Trecenta, Trecenta, Rovigo, Italy; Matteo Pirro, Internal Medicine, Angiology and Arteriosclerosis Diseases. Department of Medicine and Surgery. University of Perugia, Perugia, Italy; Livia Pisciotta, IRCCS Ospedale policlinico San Martino UOSD Dietetica e Nutrizione Clinica and Dipartimento di Medicina Interna, Universit\u00e0 di Genova, Genova, Italy; Arturo Pujia, A.O.U. Mater Domini, Catanzaro, UOC di Nutrizione Clinica, Ambulatorio Dislipidemie, Catanzaro, Italy; Francesco Purrello, Department of Clinical and Experimental Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy; Elisabetta Rinaldi, U.O. Endocrinologia, Diabetologia e Malattie del Metabolismo, Centro regionale specializzato per la diagnosi e terapia delle dislipidemie e aferesi terapeutica and A.O. Universitaria Integrata di Verona, Verona, Italy; Riccardo Sarzani, Internal Medicine and Geriatrics, Department of Clinical and Molecular Sciences, University \u201cPolitecnica delle Marche\u201d and IRCCS-INRCA, Ancona, Italy; Roberto Scicali, Department of Clinical and Experimental Medicine, University of Catania, Ospedale Garibaldi, Catania, Italy; Patrizia Suppressa, U.O. di Medicina Interna e Geriatria \u201cC. Frugoni\u201d and Centro di Assistenza e Ricerca Malattie Rare, A.O. Universitaria Policlinico Consorziale, Universit\u00e0 degli Studi di Bari \u201cAldo Moro\u201d, Bari, Italy; Patrizia Tarugi, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy; Sabrina Verachtert, Department of Clinical and Experimental Medicine\u2014Lipid Center\u2014University Hospital G. Martino, Messina, Italy; Giovanni Battista Vigna, Medicina Generale, Ospedale di Trecenta, Trecenta, Rovigo, Italy; Jos\u00e8 Pablo Werba, U.O. Ambulatorio Prevenzione Aterosclerosi, IRCCS Centro Cardiologico Monzino, Milan, Italy; Alberto Zambon, Dipartimento di Medicina, Universit\u00e0 di Padova, Padua, Italy; Sabina Zambon, Dipartimento di Medicina, Universit\u00e0 di Padova, Padua, Italy; Maria Grazia Zenti, Servizio di Diabetologia e Malattie Metaboliche, Ospedale P. Pederzoli, Peschiera del Garda, Verona, Italy.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Viviana A. Cavieres and Gonzalo A. Mardones were not included as authors in the original publication . Due to Fernando M. Ruggiero: conceptualization, methodology, data curation, formal analysis, writing\u2014original draft, writing\u2014review and editing, supervision, project administration, and investigation. Natalia Mart\u00ednez-Koteski: methodology, data curation, formal analysis, writing\u2014review and editing, and investigation. Viviana A. Cavieres: methodology and validation. Gonzalo A. Mardones: conceptualization, funding acquisition, project administration, resources, and supervision. Gerardo D. Fidelio: resources, writing\u2014review and editing, and project administration. Aldo A. Vilcaes: conceptualization, methodology, resources, data curation, formal analysis, writing\u2014review and editing, supervision, project administration, and investigation. Jose L. Daniotti: conceptualization, resources, supervision, and funding acquisition."} +{"text": "Many surgeons routinely place intraperitoneal drains after elective colorectal surgery. However, enhanced recovery after surgery guidelines recommend against their routine use owing to a lack of clear clinical benefit. This study aimed to describe international variation in intraperitoneal drain placement and the safety of this practice.COMPASS was a prospective, international, cohort study which enrolled consecutive adults undergoing elective colorectal surgery (February to March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis of postoperative intraperitoneal collections; rate of surgical site infections (SSIs); time to discharge; and 30-day major postoperative complications (Clavien\u2013Dindo grade at least III). After propensity score matching, multivariable logistic regression and Cox proportional hazards regression were used to estimate the independent association of the secondary outcomes with drain placement.P = 0.287) or earlier detection (hazard ratio (HR) 0.87, 0.33 to 2.31; P = 0.780) of collections. Although not associated with worse major postoperative complications , drains were associated with delayed hospital discharge and an increased risk of SSIs .Overall, 1805 patients from 22 countries were included . The drain insertion rate was 51.9 per cent (937 patients). After matching, drains were not associated with reduced rates (odds ratio (OR) 1.33, 95 per cent c.i. 0.79 to 2.23; Intraperitoneal drain placement after elective colorectal surgery is not associated with earlier detection of postoperative collections, but prolongs hospital stay and increases SSI risk. Despite current guidelines, intraperitoneal drain placement after elective colorectal surgery remains widespread. Drains were not associated with earlier detection of intraperitoneal collections, but were associated with prolonged hospital stay and increased risk of surgical-site infections. However, recent evidence suggests that drains can stimulate serous fluid production, and may lead to an increased risk of surgical-site infection (SSI) and adhesions, which in turn can result in poorer postoperative pain control and mobility4. Furthermore, drains may have an impact on patient well-being owing to increased discomfort and postoperative anxiety5.Peritoneal drains are placed after elective colorectal surgery in the historical belief that they can provide diagnostic and therapeutic benefit through prevention and early detection of anastomotic leak or other intraperitoneal collections6\u20139. Based on these findings, current enhanced recovery after surgery (ERAS) guidelines strongly recommend against the routine use of peritoneal drains after elective colorectal surgery10. Despite these recommendations, the use of prophylactic drains remains widespread, with data from the 2018 EuroSurg Collaborative IMAGINE study showing that 35 per cent of participating centres routinely used intraperitoneal drains for the majority of elective colorectal procedures11.Recent evidence has shown no effect on measured clinical outcomes associated with drain placement after elective colorectal surgeryThe COMPASS study aimed to describe international variation in practice regarding intraperitoneal drain placement in elective colorectal surgery, and the associated effects on postoperative outcomes.Appendix S1)12. This analysis was performed according to STROBE reporting guidelines for observational studies13.COMPASS was a prospective, international, multicentre, cohort study describing international variation in intraperitoneal drain placement after colorectal surgery and the safety of this practice. The protocol was developed by an international study management group, with input from patient representatives , and the later ones cancelled because of the COVID-19 pandemic15. To determine the accuracy and completeness of data, an independent validation exercise was preplanned. Data accuracy was determined by assessing the accuracy of 10 planned data points ; case ascertainment was determined by assessing the accuracy of participant eligibility.COMPASS was delivered by a student- and trainee-led collaborative group using a collaborative model12.Consecutive adults (aged at least 18 years) undergoing elective colorectal surgery for any indication were eligible. However, this excluded: operations without colorectal resection, or appendicectomies without more extensive colorectal resection; operations that were not primarily colorectal procedures ; and operations without an abdominal incision . The full list of included procedures can be found in the study protocol16. Any patients diagnosed with postoperative SARS-CoV-2 infection were still included.In response to the COVID-19 pandemic, retrospective validation of the SARS-CoV-2 infection status of patients was conducted by a collaborator independent of the original data collection team at each site. All patients noted to have been diagnosed with a preoperative SARS-CoV-2 infection (within 7 days) were also excluded based on a positive laboratory test or chest CT, or clinical diagnosis (no laboratory test or CT chest performed)17; rate of 30-day drain-specific complications including SSI (Centers for Disease Control and Prevention definition18), cutaneous irritation at the drain site , small bowel evisceration and herniation of omentum , and bowel injury (defined by intraoperative identification or CT-proven drain-related iatrogenic bowel perforation); overall 30-day adverse event rates defined by the highest Clavien\u2013Dindo grade19; and duration of postoperative hospital stay.The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis (measured in whole days) of intraperitoneal postoperative collections, defined as collections that altered the normal postoperative course 20, excessive intraoperative blood loss or fluid collections , poor vascularization of the anastomosis, or a positive air leak test; or prophylactic, with the reason for insertion recorded as \u2018surgeon preference\u2019, \u2018prophylaxis for anastomosis\u2019, or no reason identified.The main explanatory variable of interest was intraperitoneal drain insertion. Inserted drains were classified as either: indicated, because of a record of contaminated or dirty surgery2)\u2013normal (18.5\u201324.9\u2005kg/m2), overweight (25.0\u201330.0\u2005kg/m2) or obese (more than 30.0\u2005kg/m2)); ASA classification (grade I\u2013V); cardiovascular and metabolic diseases ; previous abdominal surgery; immunosuppression status ; anticoagulation therapy (defined as the use of any known antiplatelet or antithrombotic agent); operative approach and indication ; transfusion of red cells; operative contamination ; and intraoperative complications (vascular or organ injury).Additional variables were collected to risk-adjust outcomes for the following potential confounding factors: age; sex (M or F); smoking status ; BMI . Categorical variables were cross-tabulated and compared using \u03c7Mixed-effects multivariable regression was performed to derive risk-adjusted drain insertion rates, and to determine whether drain placement (prophylactic or with indication) was associated independently with the occurrence or timing of postoperative complications. Logistic regression was used for binary outcomes and Cox proportional hazards regression was used for time-to-event data . For all models, clinically plausible preoperative and perioperative factors associated with drain insertion and clinical outcomes were incorporated into the modelling approach as fixed effects, and hospital was used as a random effect. Patients who had incomplete data for explanatory variables were excluded from the analysis. First-order interactions were checked and included in the model if found to be influential, with final model selection performed through minimization of the Akaike information criterion.21. The balance in the preoperative and perioperative factors between groups was assessed before and after using the absolute standardized mean difference, and a value below 0.2 was considered to indicate that a variable was well balanced between groups. Subsequent doubly robust estimation22 was performed through risk adjustment using multivariable regression models, based on the same variables as used to generate the propensity score.To investigate the association between drain placement (for any indication) and clinical outcomes, propensity score matching was used to minimize selection bias in terms of who did or did not receive intraperitoneal drains. The propensity score was defined as the probability that a patient would receive a drain based on the same model as used to determine risk-adjusted drain insertion rates. Unlike nearest-neighbour propensity score matching approaches, which can lead to inappropriate discarding of patient data, full matching was used to allow multiple patients from each group to be matched together (if appropriate) and weighted to achieve balancea priori as P < 0.050. All analyses were undertaken using R version 3.4.4 with the tidyverse, finalfit, and finalpsm packages.All effect estimates are presented as odds ratios (ORs) for binary outcome data and hazard ratios (HRs) for time-to-event data, with 95 per cent confidence intervals. The threshold for statistical significance was set Fig. 1 and Table 1). The most common underlying indication for surgery was malignancy (69.1 per cent), and colonic resections comprised 49.4 per cent of the cohort; rectal resections accounted for 29.8 per cent and stoma formation/closure for 20.7 per cent (Table 2). A full breakdown of operative procedures and indications is provided in Tables S1 and S2. Overall, 937 patients (51.9 per cent) received a drain, of whom 635 (67.8 per cent) had a prophylactic drain and 302 (32.2 per cent) a drain with a defined indication. The reasons indicated for drain placement were (inserted drains could have more than 1 indication): excessive intraoperative fluid collection ; contaminated or dirty surgery ; excessive intraoperative blood loss ; poor vascularization of the anastomosis ; and a positive air leak test . Data validation was performed using information on 1470 patients (81.4 per cent of the cohort), with 95.1 per cent data accuracy and 98.3 per cent case ascertainment. Propensity score matching produced balanced, well matched treatment groups (Table S3).Of 2673 eligible patients from 22 countries, 1805 undergoing elective colorectal surgery were included in the analysis (Table 1). Some differences in baseline co-morbidities were noted; patients receiving a drain with a defined indication had higher ASA grades and were more frequently immunocompromised. A primary anastomosis was created in 71.0 per cent of the cohort, with comparable rates across drain groups (Table 2). Patients with drains more frequently had a rectal resection, malignant pathology, an open surgical approach, contaminated or dirty operations, and more frequently had intraoperative complications.Patients who did not receive a drain and those who received either a prophylactic or indicated drain were comparable in terms of age, sex, smoking status, BMI, diabetes mellitus, and history of previous abdominal procedures . This substantial variation in practice could not be explained based on case mix following adjustment using a mixed-effects logistic regression model (median 62.0 (27.2\u201386.4) per cent) .Among all 937 intraperitoneal drains placed at 188 centres over the study interval, the median rate of drain placement was 67.0 (i.q.r. 37.2\u2013100) per cent , and this persisted on Cox proportional hazard regression, which demonstrated a lower hazard of discharge for those with prophylactic drains . This association was even more pronounced following propensity score matching as patients with a drain were almost half as likely to be discharged on a given day than those without (Table S5).On univariable analysis, the overall 30-day mortality and postoperative SARS-CoV-2 infection rates were comparable between groups. However, those who received drains had a longer postoperative hospital stay , major postoperative complications , and intraperitoneal collections among patients who received drains. However, there was no difference in time to diagnosis of collections . After adjustment using mixed-effects models, none demonstrated significant differences between those who did or did not receive a drain for either prophylactic or indicated reasons . After confounding by indication had been accounted for in the propensity score-matched model, drain insertion was associated with 2.5-fold higher odds of SSI (Table S10). No differences were shown for major postoperative complications, postoperative intraperitoneal collections, or time to diagnosis of collections (Tables S11\u2013S13).Before risk adjustment, there was a higher rate of SSI . Similarly, there was no difference in the time to diagnosis of intraperitoneal collections. Previous studies25 reached similar conclusions, and showed that drains did not decrease anastomotic leakage, morbidity, reoperation rates, and mortality after elective colorectal surgery. Therefore, COMPASS strengthens the evidence for lack of clinical benefit from routine drain placement after elective colorectal surgery.Intraperitoneal drain placement after elective colorectal surgery has historically been thought to prevent and improve detection of intraperitoneal complications3. Although the occurrence of SSI in those who receive intraperitoneal drains is often heavily confounded by indication, following propensity score matching, drain insertion was associated with a 2.5-fold increased risk of SSI. In the literature, there is mixed evidence, with older studies27 suggesting no difference in SSI rates with use of drains, but more recent evidence29 pointing to an associated increase. Furthermore, particularly with the advent of ERAS guidance10, it has been recognized that the presence of drains is associated with increased pain and reduced mobility, potentially leading to increased respiratory complications30. In the present cohort, patients receiving drains had a longer hospital stay. This outcome is rarely reported in the literature; older evidence31 suggested that drain placement has no significant effect on duration of hospital stay, but more recent data32 suggest it can be associated with delayed hospital discharge. Although not directly assessed in this study, the use of drains could suggest overall low compliance with an ERAS protocol. Therefore, it is unclear whether the association between drain placement and longer hospital stay in this study was directly related to drain placement alone, or confounded by decreased compliance with other non-drain-related ERAS recommendations. High-quality randomized data in an ERAS context may provide definite answers to this question.The potential for harm from intraperitoneal drain insertion cannot be disregarded given that this remains an invasive procedure. There is evidence to suggest that drains may disrupt wound healing and even promote infection16. The impact on the present results was minimized by undertaking a validation of the included data, with assessment of SARS-CoV-2 infection rates. There were minimal recorded postoperative cases with no difference across the drain groups (Table 3).This study represents a large prospective, international data set on the topic of intraperitoneal drain insertion in elective colorectal surgery. It provides insight into the outcomes associated with both prophylactic and indication drain insertion, and provides robust adjustment for confounding by indication through propensity score matching. However, there are also several important limitations to this work. This was an observational study, with drain placement being at the discretion of the surgeon. Therefore, although selection bias regarding who received drains was accounted for, this was limited to the variables measured and so there is a persistent risk that unobserved factors may still be confounding the results. Data on decision to insert a drain were collected predominantly from clinical notes according to documentation by the surgical team. Different surgeons may have different thresholds as regards indications for drain insertion, other indications not specified in COMPASS, and also may not routinely document the specific indication in hospital records. To mitigate potential heterogeneity and disclosure bias in indication, the propensity score-matched cohort was analysed as naive to the recorded indication. Finally, it must be recognized that COMPASS overlapped with the onset of the COVID-19 pandemic outbreak. This not only limited the intended period of data collection, but also potentially introduced an unanticipated confounding factor for postoperative morbidity and mortality24, this large multicentre, international, prospective, cohort study has found that intraperitoneal drain insertion continues to remain common practice internationally in elective colorectal surgery. In the absence of clear evidence of clinical benefit, yet evidence of potential harm to patients, surgeons should ensure that any drain placed is specifically indicated . 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Gressmann K, Cullen N, Graham A, Nasehi A, Montano King C, Gaule L, Martin B, Stokell C, Crone L, Sanderson N, Farnan R, jassim S, Arnold A, Chan B, Chua Vi Long K, Kaka N, Pandey S, Neo WX, Chitul A, Bezede C, Grama F, Beuca A, Cincilei D, David A, Blaga M, Blaga SN, Fagarasan V, Tulina I, Khetagurova M, Rodimov S, Kapustina A, Mekhralyzade A, Zabiyaka M, Juloski J, Jankovi\u0107 U, Cuk V, Panyko A, H\u00e1jska M, Dubovsk\u00fd M, Hro\u0161ov\u00e1 M, Ferancikova N, Camarero Rodr\u00edguez E, Laguna Alc\u00e1ntara F, Adarraga J, Jezieniecki C, Ruiz Soriano M, G\u00f3mez Sanz T, Suarez A, S\u00e1nchez Garc\u00eda C, Mar\u00edn Santos JM, Alonso Batanero E, Cifrian Canales I, Llosa P\u00e9rez J, Merayo M, Urbieta A, Geg\u00fandez Sim\u00f3n A, Tone JF, Gazo Mart\u00ednez J, Vicario Bravo M, Chavarrias N, Gil Catal\u00e1n A, Oseira A, Villalonga B, Soldevila Verdeguer C, Jeri S, Col\u00e1s-Ruiz E, Perez Calvo J, Nogu\u00e9s A, Cros B, Y\u00e1nez C, Talal El-Abur I, Blas Laina JL, Utrilla Fornals A, Rold\u00f3n Golet M, Garc\u00eda Dom\u00ednguez M, Colsa P, Gimenez Maurel T, Delorme M, Buchwald P, Axmarker T, Gialamas E, Chevallay M, Pham TV, Ozmen BB, Sel EK, Ozben V, Atar C, Aktas MK, Aba M, Ozkan BB, Sarkin M, Akkaya YM, Durmaz AG, Calikoglu F, Gullu HF, Bo\u011fa A, Akta\u015f A, Bakar B, Demirel MT, Kural S, Hysejni X, Zafer F, Taser M, Guzel OR, Bozbiyik O, Isik A, \u00d6zen D, \u00d6lmez M, Kaya Y, Uyar B, G\u00fcl\u00e7ek E, Kayacan GS, At\u0131c\u0131 N, Gul OF, Altiner S, Ibis B, Altunsu S, Banaz T, Diler C, Demirbas I, Usta MA, Erkul O, Orman R, Salih S, Utkan NZ, Tatar OC, G\u00fcler SA, Acil C, Ozgur E, Maddahali M, Turhan AB, Eskici AB, Ular B, Do\u011fru M, \u00d6zt\u00fcrk OU, Arslan ER, Panahi Sharif A, Hurmuzlu D, Dikmen E, Ates J, Bircan R, Cavus T, Sever AE, Balak B, Duman E, Korkmaz K, Altay L, Emanet O, Cullen F, Tan JY, Sharma P, Nathan A, Rottenberg A, Williams CY, Mitrofan CG, Xu D, Bawa JH, Morris P, Troller R, Gordon D, Richmond G, Hui JC, Hagan N, Ighomereho O, Rocks R, McCabe S, Fitzpatrick A, Mooney J, Nicoletti J, Hui JC, Auterson L, Darrah N, Soh VWY, Light A, Ong CS, Utukuri M, Gallagher C, Stuart LM, Hipolito M, Douglas N, Ghazal R, Parris G, Catchpole J, Tansey M, Bryden M, Jamal S, Karim Z, Lyon-Dean C, Bhojwani D, Rowley G, Lee KS, Whitehurst O, Mirza A, Sheikh F, Yousaf H, Bilbao J, Sinclair R, Takar S, Kressel H, McGing RM, Chan V, Mallon A, Schack K, Osborne R, Baldemor S, Smyth S, Gilmour S, Ting A, Bozonelou I, Saunders P, Qhaireel Anwar QA, Tirimanna R, Jauhari S, Gardener A, Walker B, Spilsbury C, Wenban C, Reddy H, Conway-Jones R, Loganathan S, Clynch A, James C, Matey E, Cameron F, James R, Roberts W, Gicquel A, Milliken C, Forbes J, Rubinchik P, O\u2019Brien S, Isaac A, Azmi A, Hawkes C, Cornett L, Adarkwah P, McConville R, O'Hara S, Tijare C, Parkes J, Yao L, Ahmad R, Balasubramanya S, Shafiq U, Mhaisalkar A, Gurung A, Sadik H, de Stadler K, Elias S, Thomas T, Madras A, Jani A, Daler HK, Tong KS, Sundaralingam SS, Nowinka Z, Szal A, Khan A, O'Sullivan C, Baker E, Joseph-Gubral J, Gala T, Chen JY, Turner B, Hadley E, Trivedi R, Igwelaezoh E, Goh E, Barton H, Allison W, Hurst W, Alam F, Parkes I, Hassan K, Jamshaid M, Azizan N, Burgher T, Afzal A, Eltilib I, Zahid M, Sadiq O, Lloyd A, Mason P, Ho R, Brazukas A, Li CH, Kamdar M, Mohamed Nazeer MN, Tzoumas N, Mighiu A, Kim D, Wilkins L, Kuo L, Conway-Jones R, Rafe T, Noton T, Maduka D, Cheema H, Farag K, Mirza M, Abdellatif M, Nzewi R, Kruczynska A, Grasselli H, Yousuff M, Ahmed N, Bassi R, Mann AK, Chopra J, Shaikh M, Sharma P, D Sa S, Tsimplis V, Ghanchi A, Skene E, Asim K, Zaheer M, Chan S, Dalton H, Gibbons K, Adderley O, Chukwujindu I, Jayasuriya I, Sivanu K, Borumand M, Bylapudi SK, Chick G, Bridges I, Tomlin J, McKenna J, Nandra N, Grace N, Grieco C, Quek FF, Mercer R, Latif S, Brankin-Frisby T, Sattar A, Aslam A, Edelsten E, Shafi S, Kouli T, Ford V, Gurung F, Kiam JS, Fernandes M, Deader N, Ponniah R, Jamieson S, Davies A, Taubwurcel J, Aung MT, Desai R, Begum S, Jamadar T, Kangatharan A, Rzeszowski B, Ho C, Yap SHK, Prendergast M, Sethi R, Duku A, Lowe C, Bray J, Elsamani K, Ghobrial M, Nichita V, Wagstaff A, Hughes C, Rengasamy E, Abu Hassan F, Mahmood H, Savill N, Shah S, Almeida T, Sinan LOH, Edwards A, Antypas A, Catchpole B, El-Dalil D, Halford Z, Carmichael A, Khoo EJM, Alsusa H, Salim EE, Boyd M, Reid C, Stark D, Williams J, Feyi-Waboso J, Patel M, Zeidan Z, Bailey E, Bapty J, Brazkiewicz M, Minhas N, Tremlett A, Fowler G, Pringle H, Mankal S, Kaminskaite V, Chung W, Rees E, Parry-Jones E, Anderson K, Mcforrester A, Stanley A, Hoather A, Wise H, Laid I, Giudiceandrea I, Scriven J, Braniste A, Wilson A, Le Blevec L, Pakunwanich N, Evans N, Chong HL, White C, Hunter J, Haque M, Vanalia P, Murdoch S, Choudhary T, McCann A, Harun A, Shah H, Dieseru N, Hunt S, Shafiq Y, Murphy A, Bickley-Morris E, Emms L, Dare M, Patel M, Akula Y, Yates C, Deliyannis E, Mayes F, Ellacott M, Zagorac Z, Farren A, Manning C, Hughed C, Stewart EG, Lim KH, Chohan N, Thaker A, Thompson B, Ziolkowska K, Ahari D, Burdekin E, Okwu U, Akintunde A, Lhaf F, Khoda F, Douthwaite J, Govindan R, Leelamanthep S, Gull E, Wright F, Dundas L, Okocha M, Mackdermott N, Burchi-Khairy T, Campbell I, Walsh J, Yeo JY, Meehan S, Banerjee D, Fu M, Kawka M, Ali T, Hussain Z, Thomas C, Ahmad H, Moroney J, Yick C, Risquet R, Ntuiabane D, Shimato M, Khan M, Ilangovan S, Vaselli NM, Smithers R, Uhanowita Marage R, Valnarov-Boulter A, Kayran J, Banerjee M, Parekh-Hill N, Hooper A, Bowen J, Jagdish R, Mcquoid C, Khan N, O Hare R, Jeffery S, Devine A, Zahid A, Elsworth C, Walter L, Dhillon S, Rao S, Anthony A, Ashaye A, Phillips N, Faderani R, Pengelly S, Choi S, Kwak SY, Lau YHL, Bagheri K, Pancharatnam R, McDonnell S, Ong DYC, Kerr E, Falconer K, Clancy N, Douglas S, Zhang Y, Greenfield F, Mutanga I, McAlinden J, Olivier J, Willis L, Adefolaju A, Agarwal H, Barter R, Harris G, Spencer G, Lim HJ, Lee MW, V Vadiveloo T, Herbert G, Moroney J, Yick C, Patel R, Risquet R, Shah M, Slim N, El Falaha S, Wong C, Soare C, Akram J, Elsayeh K, Bozhkova L, Ma Y, Vo UG, Tan HWN, Leto L, Kamal MA, Hadzhieva E, Krastev P, Tonchev P, Kokkinos G, Pozotou I, Sabbagh D, Votava J, Koci\u00e1n P, St F, Koliakos N, Tsaparas P, Zografos G, Mantas D, Tsourouflis G, Fradelos E, Castaldi A, Trigiante G, Labellarte G, Resta G, Capelli G, D'Amore A, Verlingieri V, Campagnaro T, Maffioli A, Viscosi F, De Lucia C, Poillucci G, Meneghini S, Fancellu A, Colella M, Biondi A, De Peppo V, Pace U, Albino V, Gattulli D, Piangerelli A, Kalivaci D, Sisto G, Mazzola M, Caneparo A, Grassia M, Lunghi EG, Andolfi E, Nespoli LC, Angrisani M, Sinibaldi G, Langone A, Galleano R, Gelarda E, Virgilio E, Angelini E, Fornasier C, Asero S, Venturelli P, Filippone E, Frongia F, Cal\u00f2 PG, Bellato V, Panaccio P, Sagnotta A, Loponte M, Ipponi P, D'Amico S, Gili S, Giuliani A, Lisi G, Braccio B, Tiesi V, Stolcers K, Kokaine L, Novikovs V, Farrugia M, Capel L, Bastiaenen V, Heijmans H, Ribeiro da Silva B, Silva A, Botelho P, Henriques S, Gan SZ, Ramanayake H, Nolan M, Kakodkar P, Temperley H, Kakodkar P, Ciofic E, Beuca A, Pop BA, Kurtenkov M, Jovanovi\u0107 M, Vician M, Egea Arias P, Beltr\u00e1n de Heredia J, Labalde Martinez M, De Santiago Alvarez I, Alvarez-Gallego M, Col\u00e1s-Ruiz E, Talal El-Abur I, Rodriguez Artigas JM, Dwidar O, Korkmaz HK, Eray IC, Meri\u00e7 S, Aydin R, \u00c7etin B, \u00d6zen D, Yalcinkaya A, Karaca BE, Kuyumcu OF, Baki BE, Y\u00fcksel E, Uprak TK, Ugur M, Karabulut K, Kavuk\u00e7u E, Mansor A, Troller R, Hackett R, Zammit-Maempel M, Sabaratnam R, Nicoletti J, Maan A, Ferarrio I, Dixon L, Halai H, Sethi S, Nelson L, Grassam-rowe A, Krishnan E, Deeny D, McKeever M, George Pandeth A, Dhavala P, Sreenivasan S, Sundaram Venkatesan G, Zhu L, Atiyah Z, Gregory J, Morey T, Seymour Z, Holdsworth L, Abdelmahmoud S, Bourhill J, Bisheet G, Shaw J, Kulkarni K, Kumarakulasingam P, Pillay S, Al-Habsi R, Kungwengwe G, Richards J, Davoudi K, Ibrahim B, Tailor B, Zayed M, Chen F, Bailey S, Sheefat S, Nawaz G, Pawar R, Marsh S, Sam ZH, Roy Bentley S, Simpson C, Hughes J, Lim Y, Ooi R, Toh WH, Mannion P, Lovett A, Kin\u010dius A, Hussein S, Kirby E, Beckett RG, Salmon J, Rafie A, Glynn T, Choo SY, Lyons S, Browne D, Ravindran W, Ahmad S, Erotocritou M, Zhu X, Erotocritou M, Bradbury M, McNulty J, McCarthy L, Ng J, Karmally Z, McTeir K, Hanna M, Tan E, Namdeo S, Schembri R, Pusey E.znac069_Supplementary_DataClick here for additional data file."} +{"text": "Correction: Trials 24, 507 (2023)https://doi.org/10.1186/s13063-023-07465-zFollowing publication of the original article , we haveCorrect affiliations are below:Youhua Li, Southeast UniversityShuai Tian, Liaoning Police CollegeLu Jin, Central University of Finance and EconomicsJixin Li, Suzhou Vocational UniversityXianfa Liu, Henan University of TechnologyJingjing(CA) Ji, Southeast University"} +{"text": "Scientific Reports 10.1038/s41598-023-42065-6, published online 08 September 2023Correction to: In the original version of this Article Gauri Misra was incorrectly affiliated with \u2018Molecular Diagnostics and COVD-19 Kit Testing Laboratory, Ministry of Health and Family Welfare, Noida, U.P., 201309, India\u2019. Additionally, Affiliation 1 was incorrectly stated as \u2018A-32, Sector-62, Institutional Area, National Institute of Biologicals, Noida, UP, 201309, India.\u2019 The correct Affiliation 1 is listed below.Molecular Diagnostics and COVID-19 Kit Testing Laboratory,\u00a0National Institute of Biologicals ,\u00a0A-32, Sector-62, Institutional Area, Noida, UP, 201309, India.The original Article has been corrected."} +{"text": "Initial adaptation of the OnTrack coordinated specialty care model in Chile: An application of the Dynamic Adaptation Process Le PD, Choe K, Burrone MS, Bello I, Velasco P, Arratia T, Tal D, Mascayano F, Jorquera MJ, Schilling S, Ram\u00edrez J, Arancibia D, Fader K, Conover S, Susser E, Dixon L, Alvarado R, Yang LH and Cabassa LJ. (2022) Front. Health Serv. 2:958743. doi: 10.3389/frhs.2022.958743A Corrigendum on Incorrect AffiliationIn the published article, there was an error in the affiliations. Author Diego Arancibia was incorrectly given the affiliation \u2018Escuela de Salud P\u00fablica, Facultad de Medicina, Universidad de Chile, Santiago, Chile', instead of the correct \u2018Instituto de Investigaci\u00f3n y Postgrados, Facultdad de Salud, Universidad Central de Chile, Santiago, Chile'. Author Rub\u00e9n Alvarado was incorrectly given the affiliation \u2018Escuela de Medicina, Facultad de Medicina, Universidad de Chile, Santiago, Chile', instead of the correct \u2018Department of Public Health, School of Medicine, Faculty of Medicine, Universidad de Valparaiso, Valparaiso, Chile'.The authors apologise for these errors and state that they do not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Bioinformatics, Volume 38, Issue 10, May 2022, Pages 2963\u20132964,\u00a0https://doi.org/10.1093/bioinformatics/btac204This is a correction to: Nicolas Captier, Jane Merlevede, Askhat Molkenov, Ainur Ashenova, Altynbek Zhubanchaliyev, Petr V Nazarov, Emmanuel Barillot, Ulykbek Kairov, Andrei Zinovyev, BIODICA: a computational environment for Independent Component Analysis of omics data, A change has been made to the author list."} +{"text": "Bioinformatics, Volume 39, Issue 6, June 2023, btad328, https://doi.org/10.1093/bioinformatics/btad328This is a correction to: Nicholas Mateyko, Omar Tariq, Xinyi E Chen, Will Cheney, Asfar Lathif Salaudeen, Ishika Luthra, Najmeh Nikpour, Abdul Muntakim Rafi, Hadis Kamali Deghan, Cassandra Jensen, Carl de Boer, GIL: a python package for designing custom indexing primers, In the originally published version of this manuscript, a co-author\u2019s name was incorrect. The name was incorrectly spelt Hadis Kamali Deghan instead of the correct version \u201cHadis Kamali Dehghan\u201d.This error has been corrected online."} +{"text": "Bioinformatics, Volume 39, Issue 6, June 2023, btad345, https://doi.org/10.1093/bioinformatics/btad345This is a correction to: Suryadipto Sarkar, Marta Lucchetta, Andreas Maier, Mohamed M Abdrabbou, Jan Baumbach, Markus List, Martin H Schaefer, David B Blumenthal, Online bias-aware disease module mining with ROBUST-Web, The originally published version of this manuscript was incorrectly assigned to vol. 35, issue 6, and has now been correctly placed in volume 39, issue 6. Please note the updated citation information.This error has been corrected online."} +{"text": "The correct names are: Nambusi Kyegombe, Gbolahan Ajibola, Maureen Sakoi-Mosetlhi, Tsholofelo Rebatenne, Motswedi Anderson, Simani Gaseitsiwe, Joseph Makhema, Una Ngwenya, Sikhulile Moyo, Odile Sauzet, Lucy Mupfumi. The correct citation is: Kyegombe N, Ajibola G, Sakoi-Mosetlhi M, Rebatenne T, Anderson M, Gaseitsiwe S, et al. (2023) Youth and healthcare workers\u2019 perspectives on the feasibility and acceptability of self-testing for HIV, Hepatitis and Syphilis among young people: Qualitative findings from a pilot study in Gaborone, Botswana. PloS ONE 18(7): e0288971."} +{"text": "Picromerus Amyot & Serville, 1843 comprises 11 species found in the Northern Hemisphere. In Japan, two species have been recorded to date. However, an easy-to-understand identification method, such as an illustrated key, is lacking. Currently, Picromerusgriseus has been recorded in Bangladesh, Bhutan, China, Indonesia, Myanmar, Pakistan and Taiwan, but not in Japan.The predatory stink bug genus Picromerusgriseus was recorded in Japan for the first time, based on a single individual collected from grasslands around the fields of Ishigaki Island of the Ryukyu Islands, which belong to the Oriental Region. This discovery represents the easternmost record of the species. An illustrated key to the species of Picromerus occurring in Japan is also provided. Asopinae Spinola, 1850 comprises 303 species in 63 genera worldwide and all species for which their biology is known are predacious ; Armacustos ; Dinorhynchusdybowski Jakovlev, 1876; Eocantheconafurcellata ; E.japonica ; E.kyushuensis ; E.shikokuensis ; Picromerusbidens ; P.lewisi Scott, 1874; Pinthaeussanguinipes ; Rhacognathuscorniger Hsiao & Cheng, 1977; and Zicronacaerulea . Two Japervation .Picromerus Amyot & Serville, 1843 (Asopinae) comprises 11 species from the Northern Hemisphere: P.bidens; P.brachypterus Ahmad & \u00d6nder, 1990; P.conformis Herrich-Sch\u00e4ffer, 1841; P.elevatus Zhao, Liu & Bu, 2013; P.fasciaticeps Zheng & Liu, 1987; P.griseus ; P.lewisi; P.nigridens ; P.orientalis Rishi & Abbasi, 1973; P.pseudobidens Ahmad & \u00d6nder, 1990; and P.viridipunctatus Yang, 1934 . After the first author examined its morphological characteristics, we concluded that it belonged to P.griseus, which is currently known to occur in Bangladesh, Bhutan, China, Indonesia, Myanmar, Pakistan and Taiwan . To examine the genital characteristics, the male terminalia were removed from the body after softening the specimens in hot water. The removed genital capsule was immersed in hot 15% potassium hydroxide (KOH) solution for 5 min. For further observations, parameres were removed from the genital capsule soaked in 99% ethanol. Male genitalia were preserved in small polyethylene vials containing a 50% glycerine and 50% water solution. A polyethylene vial was mounted on the pin with the specimens. The specimens were photographed using a digital microscope and a compact digital camera and image stacks were processed using Adobe Photoshop 2021 ver. 22.5.1 when using the digital microscope. Measurements were obtained using a stereoscopic microscope equipped with an ocular grid and a digital microscope. Morphological terms were assigned as described by Picromerusgriseus examined in the present study was deposited at the Laboratory of Entomology, Faculty of Agriculture, Tokyo University of Agriculture, Kanagawa, Japan (TUA). Specimens of the Japanese species of Picromerus that were used for creating the identification key and for comparison with P.griseus were deposited in the Entomological Laboratory, Faculty of Agriculture, Kyushu University, Fukuoka, Japan (ELKU) and TUA.The single specimen of 77EEBAC0-304E-5F94-8CDF-CE8E4A7B3777Cantheconagrisea Dallas, 1851 - Picromerusobtusus Walker, 1867 - Picromerusgriseus.Picromerusnigrivitta Walker, 1867 - Picromerusobtusus.Picromerussundanus Breddin, 1902 - Picromerusgriseus. Picromerusgriseus Schouteden, 1907 - Type status:Other material. Occurrence: recordedBy: Akihiro Utagawa; individualCount: 1; sex: male; lifeStage: adult; occurrenceID: B9C40A18-594B-59E7-BCA1-4AB46599AC3E; Taxon: scientificName: Picromerusgriseus ; namePublishedIn: 1851; kingdom: Animalia; phylum: Arthropoda; class: Insecta; order: Hemiptera; family: Pentatomidae; genus: Picromerus; specificEpithet: griseus; scientificNameAuthorship: Dallas; Location: islandGroup: Ryukyu Islands; island: Ishigaki Island; country: Japan; countryCode: Okinawa; municipality: Ishigaki-shi; locality: Sakieda; decimalLatitude: 24.438250; decimalLongitude: 124.102167; geodeticDatum: WGS84; Identification: identifiedBy: Jun Souma; dateIdentified: 2023; Event: samplingProtocol: none specified; eventDate: 08-11-2022; Record Level: institutionCode: TUA; basisOfRecord: PreservedSpecimenPicromerusgriseus can be distinguished from other species of the genus using a combination of the following characteristics: head, pronotum, scutellum and femora uniformly brown , Bangladesh, Bhutan, China, Indonesia, Myanmar, Pakistan, Taiwan Figs 1. In conc446F3361-8AD0-525D-9221-AEDDD875210BAfghanistan, Albania, Algeria, Armenia, Austria, Azerbaijan, Belgium, Bosnia Herzegovina, Bulgaria, Byelorussia, Canada, China, Croatia, Czech Republic, Denmark, Estonia, Finland, France, Georgia, Germany, Greece, Hungary, Iran, Ireland, Italy, Japan , Kazakhstan, Kirgizia, Korea, Latvia, Liechtenstein, Lithuania, Luxemburg, Macedonia, Moldavia, Mongolia, Montenegro, Netherlands, Norway, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Tajikistan, Turkey, Ukraine, United Kingdom, USA, Uzbekistan .193F1E3C-A7F4-5123-9FA6-6231EDC725B0http://en.wikipedia.org/wiki/Atypus_affinisBangladesh, Bhutan, China, Indonesia, Japan (Ishigaki Island), Myanmar, Pakistan, Taiwan , Kazakhstan, Korea, Russia, Taiwan ."} +{"text": "Communications Biology 10.1038/s42003-023-04889-w, published online 11 May 2023.Correction to: In the original version of the article, the Competing Interests statement read as:\u2018J.A.R. reports receiving a commercial research grant from The University of Texas MD Anderson Cancer Center, sponsored research agreement from Genprex, Inc, has ownership interest in Genprex, Inc., and is a consultant/advisory boardmember for Genprex, Inc. T.G.B. is an advisor to Array/Pfizer, Revolution Medicines, Springworks, Jazz Pharmaceuticals, Relay Therapeutics, Rain Therapeutics, Engine Biosciences, and receives research funding from Novartis, Strategia, Kinnate, and Revolution Medicines. J.W.R. is an advisor to Blueprint, Beigene, Daiichi Sankyo, EMD Serono, Janssen, Turning Point, Regeneron, Sanofi Aventis and a consultant to Blueprint, Novartis, Boehringer Ingelheim. He also receives research funding from Merck, Novartis, Spectrum, Revolution Medicine, AstraZeneca.The other authors disclosed no potential conflicts of interest or competing interests.\u2019This has now been changed to:\u2018Jack A. Roth reports receiving a commercial research grant from The University of Texas MD Anderson Cancer Center, sponsored research agreement from Genprex, Inc, has ownership interest in Genprex, Inc., and is a consultant/advisory board member for Genprex, Inc. Trever G Bivona is an advisor to Array/Pfizer, Revolution Medicines, Springworks, Jazz Pharmaceuticals, Relay Therapeutics, Rain Therapeutics, Engine Biosciences, and receives research funding from Novartis, Strategia, Kinnate, and Revolution Medicines. Jonathan Wesley Riess is an advisor to Blueprint, Beigene, Daiichi Sankyo, EMD Serono, Janssen, Turning Point, Regeneron, Sanofi Aventis and a consultant to Blueprint, Novartis, Boehringer Ingelheim. He also receives research funding from Merck, Novartis, Spectrum, Revolution Medicine, AstraZeneca. Elizabeth Shpall is involved in consulting/Scientific advisory board/Speaking in Adaptimmune, Navan, Celaid Therapeutics, Zelluna Immunotherapy, FibroBiologics and Axio. She has also license agreement with Takeda, Affimed and Syena. The other authors disclosed no potential conflicts of interest or competing interests.\u2019This has been updated in the PDF and HTML versions."} +{"text": "Journal of the American Medical Informatics Association, Volume 28, Issue 8, August 2021, Pages 1765\u20131776, https://doi.org/10.1093/jamia/ocab054This is a correction to: Jihoon Kim, Larissa Neumann, Paulina Paul, Michele E Day, Michael Aratow, Douglas S Bell, Jason N Doctor, Ludwig C Hinske, Xiaoqian Jiang, Katherine K Kim, Michael E Matheny, Daniella Meeker, Mark J Pletcher, Lisa M Schilling, Spencer SooHoo, Hua Xu, Kai Zheng, Lucila Ohno-Machado, for the R2D2 Consortium, Privacy-protecting, reliable response data discovery using COVID-19 patient observations, The originally published version of this manuscript inadvertently omitted listing the members of the R2D2 Consortium.This error has been corrected."} +{"text": "Scientific Reports 10.1038/s41598-023-39592-7, published online 31 July 2023Correction to: The original version of this Article contained errors in the name of authors Filippo Trentini, Oriana Ciani, Elena Vanni, Simone Ghislandi, Aleksandra Ghislandi, Elena Azzolini and Alessia Melegaro which were incorrectly given as Trentini Filippo, Ciani Oriana, Vanni Elena, Ghislandi Simone, Torbica Aleksandra, Azzolini Elena and Melegaro Alessia.The original Article has been corrected."} +{"text": "Brain Communications, Volume 5, Issue 2, 2023, fcad035, https://doi.org/10.1093/braincomms/fcad035This is a correction to: Gabriel Gonzalez-Escamilla, Venkata C Chirumamilla, Nabin Koirala, Abdul R Anwar, Oliver T\u00fcscher, Johannes Vogt, Phillip Horstmann, Benjamin Meyer, George A Bonanno, Sergiu Groppa, Muthuraman Muthuraman, Modular segregation drives causality of the dynamic oscillatory network responses during threat processing, In the originally published version of this manuscript, the affiliation of one of the authors, Prof. Johannes Vogt, was incorrect. The correct affiliation for Prof. Vogt is as follows:Department of Molecular and Translational Neuroscience, Institute of Anatomy II, Cluster of Excellence-Cellular Stress Response in Aging-Associated Diseases (CECAD), Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, GermanyThis error has been corrected online."} +{"text": "British Journal of Surgery, 2022;, znac302, https://doi.org/10.1093/bjs/znac302This is an erratum to: Eva B Deerenberg, Nadia A Henriksen, George A Antoniou, Stavros A Antoniou, Wichor M Bramer, John P Fischer, Rene H Fortelny, Hakan G\u00f6k, Hobart W Harris, William Hope, Charlotte M Horne, Thomas K Jensen, Ferdinand K\u00f6ckerling, Alexander Kretschmer, Manuel L\u00f3pez-Cano, Flavio Malcher, Jenny M Shao, Juliette C Slieker, Gijs H J de Smet, Cesare Stabilini, Jared Torkington, Filip E Muysoms, Updated guideline for closure of abdominal wall incisions from the European and American Hernia Societies, In the originally published version, affiliations of some of the authors were incorrect in the HTML version. All affiliations in the PDF version were correct.These errors have now been corrected."} +{"text": "Rhodomyrtus tomentosa, Horticulture Research, Volume 10, Issue 3, March 2023, uhad005, https://doi.org/10.1093/hr/uhad005This is a correction to: Fangping Li, Shiqiang Xu, Zitong Xiao, Jingming Wang, Yu Mei, Haifei Hu, Jingyu Li, Jieying Liu, Zhuangwei Hou, Junliang Zhao, Shaohai Yang, Jihua Wang, Gap-free genome assembly and comparative analysis reveal the evolution and anthocyanin accumulation mechanism of In the originally published version of this manuscript, in Figure 4, panels B and C were erroneously transposed.In addition, in Figure 5B, \u2018TJN-4-TJN-gene-131.252\u2019 in the GST-F section was incorrectly rendered in black.The Publisher apologizes for not correcting these errors at an earlier production stage."} +{"text": "Journal of Occupational Health from October 1, 2022 to September 28, 2023.The Japan Society for Occupational Health expresses its sincere appreciation to the following volunteers for reviewing manuscripts for Adi, Nuri Purwito (Japan)Anderson, Amanda (United States)Ando, Hajime (Japan)Antao, Helena Sofia Arakawa, Ritsuko (Japan)Aung, Myo (Japan)Azuma, Kenichi (Japan)Bazazan, Ahmad (Iran)Cheng, Wan\u2010Ju (China)Cheng, Yawen (Taiwan)Choi, Byungjoo Cruz, Alex Junio Silva (Brazil)Deepreecha, Kathawoot (Thailand)Del Razo, Luz Mar\u00eda (Mexico)Dollard, Maureen Dragano, Nico (Germany)Du, Tanghuizi (Japan)Dugdale, Zoe (United States)Ebara, Takeshi (Japan)Eguchi, Hisashi (Japan)Eguchi, Yasumasa (Japan)Ely Zarina, Samsudin Ernawati, Ernawati (Indonesia)Fink, Anne (United States)Formazin, Maren (Germany)Franke, Warren (United States)Fujino, Yoshihisa (Japan)Fujiyoshi, Akira (Japan)Fukai, Kota (Japan)Fukushima, Noritoshi (Japan)Fukutani, Naoto (Japan)Furuta, Michiko (Japan)Fushimi, Atsushi (Japan)Gi, Min (Japan)Gillespie, Gordon L (United States)Hanners, Audra (United States)Hara, Kunio (Japan)Hara, Megumi (Japan)Harada, Arisa (Japan)Harmer, Bonnie (United States)He, Yupeng (Japan)Hidaka, Tomoo (Japan)Higashi, Hidenori (Japan)Higuchi, Yoshiyuki (Japan)Hikichi, Hiroyuki (Japan)Hino, Ayako (Japan)Hiraku, Yusuke (Japan)Hirokawa, Kumi (Japan)Honda, Takanori (Japan)Horie, Seichi (Japan)Horiguchi, Hyogo (Japan)Ichihara, Gaku (Japan)Idris, Mohd Igarashi, Yu (Japan)Iida, Mako (Japan)Ikeda, Atsuko (Japan)Ikeda, Hiroki (Japan)Ikegami, Kazunori (Japan)Imai, Teppei (Japan)Inoue, Akiomi (Japan)Inoue, Koki (Japan)Irigoyen\u2010Oti\u00f1ano, Mar\u00eda (Spain)Ishimaru, Tomohiro (Japan)Ishitake, Tatsuya (Japan)Itani, Osamu (Japan)Ito, Akiyoshi (Japan)Ito, Yuki (Japan)Iwakiri, Kazuyuki (Japan)Iwasaki, Akio (Japan)Iwasaki, Shinichi (Japan)Iwasawa, Satoko (Japan)Iwata, Hiroko (Japan)Izumi, Hiroyuki (Japan)Janwantanakul, Prawit (Thailand)Jurisic, Vladimir (Serbia)Kakamu, Takeyasu (Japan)Kanamori, Satoru (Japan)Kanda, Kanae (Japan)Kang, Mo\u2010Yeol Kang, Young\u2010Joong Katayama, Akihiko (Japan)Kawada, Michiko (Japan)Kawakami, Tsuyoshi (Thailand)Kawanami, Shoko (Japan)Kawashima, Masatoshi (Japan)Khalili, Arash (Iran)Kido, Takamasa (Japan)Kishi, Taro (Japan)Kitamura, Hiroko (Japan)Kodithuwakku Arachchige, Sachini (United States)Kojima, Reiji (Japan)Kojin, Hiroyuki (Japan)Kostelac, Deni (Croatia)Kozaki, Tomoaki (Japan)Kubo, Tomohide (Japan)Kubo, Yoshiko (Japan)Kurosawa, Hajime (Japan)Kuwahara, Keisuke (Japan)Lee, Jihye Leff, Todd (United States)Leocadio\u2010Miguel, Mario (United Kingdom)Lin, Ro\u2010Ting (Taiwan)Liu, Xinxin (Japan)Loh, Ping Yeap (Japan)L\u00f3pez G\u00f3mez, Mar\u00eda Andr\u00e9e (Spain)Lu, Dasheng (China)Lu, Ming\u2010Lun (Taiwan)Macabulos, Edmyr (Philippines)Maeda, Eri (Japan)Maeda, Shunta (Japan)Mafune, Kosuke (Japan)Maruyama, Takashi (Japan)Massimi, Azzurra Masuda, Masashi (Japan)Matsugaki, Ryutaro (Japan)Matsumoto, Junko (Japan)Matsumoto, Shun (Japan)Matsuo, Tomoaki (Japan)Mbare, Benta (Finland)Meucci, Rodrigo (Brazil)Michishita, Ryoma (Japan)Miki, Akiko (Japan)Minami, Kouichiro (Japan)Miyamoto,Toshiaki (Japan)Mori, Koji (Japan)Mori, Mihoko (Japan)Mori, Takahiro (Japan)Morimoto, Yasuo (Japan)Morioka, Ikuharu (Japan)Morita, Yusaku (Japan)Murakami, Haruka (Japan)Murakami, Takahisa (Japan)Muto, Go (Japan)Nagano, Chikage (Japan)Nagata, Masako (Japan)Nagata, Tomohisa (Japan)Naif, Moath (Cyprus)Nakamura, Mieko (Japan)Nakata, Yoshio (Japan)Neupane, Subas (Finland)Nishi, Kenichiro (Japan)Nishihama, Yukiko (Japan)Nogawa, Kazuhiro (Japan)Nomura, Kyoko (Japan)Ogami, Akira (Japan)Ogata, Toru (Japan)Ogawa, Masanori (Japan)Ohta, Masanori (Japan)Okawara, Makoto (Japan)Ono\u2010Ogasawara, Mariko (Japan)Ose, Solveig (Norway)Ota, Atsuhiko (Japan)Otsuka, Toshiaki (Japan)Otsuka, Yasumasa (Japan)Otsuka, Yuichiro (Japan)Park, Chang (United States)Pic\u00f3\u2010Monllor, Jos\u00e9 Antonio (Spain)Puttonen, Sampsa (Finland)Ramacciati, Nicola Riediker, Michael (Switzerland)Ruseski, Jane (United States)Saijo, Yasuaki (Japan)Sakai, Kosuke (Japan)Sakakibara, Keiko (Japan)Sakuraya, Asuka (Japan)Sasaki, Minako (Japan)Sasaki, Natsu (Japan)Sato, Yukihiro (Japan)Sawada, Shinichi (Japan)Sawada, Susumu (Japan)Schleupner, Ricarda (Austria)Shibata, Eiji (Japan)Shimazu, Akihito (Japan)Shimura, Akiyoshi (Japan)Shinada, Kayoko (Japan)Sieber, W. Karl (United States)Smith, Todd (United States)So, Rina (Japan)Song, Fujian (United Kingdom)Sriram, Krishnan (United States)Sugai, Toshiki (Japan)Sugama, Atsushi (Japan)Sugano, Ryosuke (Japan)Sukadarin, Ezrin Hani Suzuki, Ayako (Japan)Svensson, Thomas (Sweden)Tachi, Norihide (Japan)Tahara, Hiroyuki (Japan)Takahara, Ryuji (Japan)Takahashi, Toru (Japan)Takahashi, Yukio (Japan)Talapatra, Subrata (Bangladesh)Tamakoshi, Koji (Japan)Tani, Naomichi (Japan)Tatsumi, Yukako (Japan)Tokizawa, Ken (Japan)Tominaga, Maki (Japan)Tomita, Yoshihito (Japan)Toyama, Hiroyuki (Finland)Tsai, Feng\u2010jen (Taiwan)Tse, Lap Ah (Hong Kong)Tsuchiya, Masao (Japan)Tsuda, Yoko (Japan)Tsuji, Masayoshi (Japan)Tsujimura, Hiroji (Japan)Tsukinoki, Rumi (Japan)Tsuno, Kanami (Japan)Uchida, Mitsuo (Japan)Ueta, Ikuo (Japan)Ukawa, Shigekazu (Japan)Van Wijk, Charles (South Africa)Wada, Keiko (Japan)Wada, Koji (Japan)Watanabe, Kazuhiro (Japan)Yamamoto, Makoto (Japan)Yamauchi, Takenori (Japan)Yatera, Kazuhiro (Japan)Yokouchi, Nobutada (Japan)Yoon, Jin\u2010Ha Yoshikawa, Etsuko (Japan)Zaitsu, Masayoshi (Japan)"} +{"text": "Scientific Reports 10.1038/s41598-023-41884-x, published online 29 September 2023Correction to: In the original version of this Article Guang Sheng Zhao was incorrectly affiliated with \u2018Heart Center, Affiliated Zhongshan Hospital of Dalian University, No.6 Jie Fang Street, Zhongshan District, Dalian 116001, Liaoning Province, China\u2019. The correct affiliation is listed below.Minimally invasive interventional diagnosis and treatment center, Affiliated Zhongshan Hospital of Dalian University, No.6 Jie Fang Street, Zhongshan District, Dalian 116001, Liaoning Province, China.The original Article has been corrected."} +{"text": "Caplan, Keri Cavanaugh, Bertrand Perroud, Tadeusz Wroblewski, Richard W. Michelmore, Blake C. Meyers, The Role of TIR-NBS and TIR-X Proteins in Plant Basal Defense Responses, Plant Physiology, Volume 162, Issue 3, July 2013, Pages 1459\u20131472, The authors were made aware of the image duplicated in This correction does not otherwise affect the results nor alter any of the original conclusions. We apologize for any inconvenience to the readers."} +{"text": "G3 Genes|Genomes|Genetics, Volume 13, Issue 7, July 2023, jkad059, https://doi.org/10.1093/g3journal/jkad059This is a correction to: Gerson Ascencio, Matthew A de Cruz, Judy Abuel, Sydney Alvarado, Yuma Arriaga, Emily Conrad, Alonso Castro, Katharine Eichelberger, Laura Galvan, Grace Gundy, Jorge Alberto Inojoza Garcia, Alyssa Jimenez, Nhein Tuyet Lu, Catharine Lugar, Ronald Marania, Tserendavaa Mendsaikhan, Jose Ortega, Natasha Nand, Nicole S Rodrigues, Khayla Shabazz, Cynnie Tam, Emmanuel Valenciano, Clive Hayzelden, Anthony S Eritano, Blake Riggs, A deficiency screen of the 3rd chromosome for dominant modifiers of the Drosophila ER integral membrane protein, Jagunal, In the originally published version of this manuscript, a student co-author\u2019s name was misspelled. Nhein Tuyet Lu should be correctly spelled Nhien Tuyet Lu.This error has been corrected online."} +{"text": "To the Editor,Chronic Spontaneous Urticaria (CSU) is caused by the activation of skin mast cells (MCs) by various signals including IgG and IgE autoantibodies in autoimmune (type IIb) and autoallergic CSU, respectively.Upon IgE\u2010mediated activation, MCs release the soluble isoform of the high affinity IgE receptor (sFc\u025bRI), which results in increased serum levels.p\u00a0<\u00a00.0001; Figure\u00a0Patients with CSU had significantly higher sFc\u03b5RI serum levels (median\u00a0\u00b1\u00a0IQR: 1.9\u00a0\u00b1\u00a062.9\u00a0ng/mL) than HCs and significantly correlated with sFc\u03b5RI levels, albeit weakly . Chronic Spontaneous Urticaria patients with normal and elevated IgE (>40\u00a0IU/mL) versus low IgE (<40\u00a0IU/mL) had significantly higher sFc\u03b5RI levels or chronic inducible urticaria from Novartis, Menarini, Uriach, FAES, Pfizer. MSD and has received a research Grant from GSK and Novartis. AGA or recently was a speaker and/or advisor for and/or has received research funding from Almirall, Amgen, AstraZeneca, Avene, Celldex, Escient Pharmaceuticals, Genentech, GSK, Instituto Carlos III\u2010 FEDER, Leo Pharma, Menarini, Novartis, Sanofi\u2013Regeneron, Thermo Fisher Scientific, Uriach Pharma/Neucor. CEHG has done consultancy work recently for Celltrion and Sanofi. TJ or recently was a speaker and/or advisor for and/or has received research funding from ALK\u2010Abello, Allergy Therapeutics/Bencard, Novartis and Thermo\u2010Fisher Scientific. GNK or recently was a speaker and/or advisor for and/or has received research funding from AstraZeneca, Chiesi, GSK, Menarinin, Novartis, Pfizer, Sanofi, Vianex. UR is or recently was a speaker and/or advisor for Almirall, Abbvie, Janssen, Sanofi, Novartis and UCB. PS is or recently was a speaker and/or advisor for and/or has received research funding from AbbVie, Allergika, Almirall\u2010Hermal, Amgen, Beiersdorf, Biocryst, BMS, Boehringer\u2010Ingelheim, Celgene, CSL\u2010Behring, Eli\u2010Lilly, Galderma, Hexal, Janssen, Klinge, Klosterfrau, LEO\u2010Pharma, LETI\u2010Pharma, L\u00b4Oreal, Novartis, Octapharma, Pfizer, Pfl\u00fcger, Pharming, Regeneron, Shire, Takeda, Regeneron, Sanofi\u2010Genzyme and UCB Pharma. TK, Tamar Kinaciyan is or recently was a speaker and/or advisor for and/or has received research funding from ALK, Sanofi/Regeneron, Novartis, CSL Behring, Biocryst, Takeda and KalVista. MMakris is or recently was a speaker and/or advisor for and/or has received research funding from Astra Zeneca, Chiesi, GSK, Novartis, Pfizer, Sanofi, Menarini, Elpen, Vianex. PSG or recently was a speaker and/or advisor for and/or has received research funding from AbbVie, Aimmune, ALK\u2010Abello, Amgen, AstraZeneca, Bencard, Biomed, B\u00fchlmann Diagnostics, Galderma, GlaxoSmithKline, Jansen, LEO, Lilly, L`Or\u00e9al, Menarini, Novartis, Pfizer, Pierre Fabre, Roche Pharma, Sanofi Regerenon, Stallergenes and Thermo Fisher. GS is also a medical advisor and/or has received payment for lectures from Novartis, CSL Behring, Pfizer, Abvie, Astra\u2010Zeneca, Nuvo Pharmaceuticals, and the Allergy Asthma and Immunology Society of Ontario. MMaurer is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Amgen, Aralez, ArgenX, AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, GIInnovation, GSK, Innate Pharma, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Pfizer, Roche, Sanofi/Regeneron, Third Harmonic Bio, UCB, and Uriach. SA or recently was a speaker and/or advisor for and/or has received research funding from AstraZeneca, Allakos, Biocryst, CSL Behring, Sanofi, Takeda, ThermoFisher, Moxie and Novartis.Deutsche Forschungsgemeinschaft, Grant/Award Number: RA\u20101026/3\u20102Supporting Information S1Click here for additional data file."} +{"text": "Staphylococcus aureus Network Adaptive Platform Trial Protocol: New Tools for an Old Foe.\u201d Clin Infect Dis; https://doi.org/10.1093/cid/ciac476). The list of members of the Staphylococcus aureus Network Adaptive Platform (SNAP) Study Group was incomplete. An amended list of study group members appears below; names of collaborators who were initially left off the list appear in bold. Additionally, two researchers initially included in the study group, Kevin Brown and Nan Vasilunas, have been removed from the list of contributors.An error appeared in the corrected proof publication of this article (Tong et al. \u201cThe Lauren Barina, Emma Best, Max Bloomfield, Jennifer Bostock, Carly Botheras, Asha Bowen, Philip Britton, Hannah Burden, Anita Campbell, Hannah Carter, Matthew Cheng, Ka Lip Chew, Ivor Russel Lee Ming Chong, Geoffrey Coombs, Peter Daley, Nick Daneman, Jane Davies, Joshua Davis, Yael Dishon-Benattar, Ravindra Dotel, Adrian Dunlop, Felicity Flack, Katie Flanagan, Hong Foo, Nesrin Ghanem-Zoubi, Stefano Giulieri, Anna Goodman, Jennifer Grant, Daniel Gregson, Stephen Guy, Amanda Gwee, Erica Hardy, Andrew Henderson, George Heriot, Benjamin Howden, Fleur Hudson, Jennie Johnstone, Shirin Kalimuddin, Dana de Kretser, Andrea Kwa, Todd Lee, Amy Legg, Roger Lewis, Martin Llewelyn, Thomas Lumley, David Lye, Derek MacFadden, Robert Mahar, Isabelle Malham\u00e9, Michael Marks, Julie Marsh, Marianne Martinello, Gail Matthews, Colin McArthur, Anna McGlothlin, Genevieve McKew, Brendan McMullan, Zoe McQuilten, Eliza Milliken, Jocelyn Mora, Susan Morpeth, Srinivas Murthy, Clare Nourse, Matthew O'Sullivan, David Paterson, Mical Paul, Neta Petersiel, Lina Petrella, Sarah Pett, David Price, Jason Roberts, James Owen Robinson, Benjamin Rogers, Benjamin Saville, Matthew Scarborough, Marc Scheetz, Oded Scheuerman, Kevin Schwartz, Simon Smith, Thomas Snelling, Marta Soares, Christine Sommerville, Andrew Stewardson, Neil Stone, Archana Sud, Robert Tilley, Steven Tong, Rebecca Turner, Jonathan Underwood, Sebastiaan van Hal, Lesley Voss, Genevieve Walls, Rachel Webb, Steve Webb, Lynda Whiteway, Heather Wilson, Terence Wuerz, Dafna YahavNick Anagnostou, Sophia Archuleta, Eugene Athan, The authors regret the error."} +{"text": "To the Editor:Chronic hand eczema (CHE) is a debilitating heterogeneous condition characterized by pruritus secondary to hyperkeratosis, vesicles, or fissures.https://data.mendeley.com/datasets/vtkgpr7c2m/1). Quality of evidence was assessed based on the Oxford center for evidence-based medicine 2011 levels of evidence. After independent screening by 2 reviewers, 33 articles (publication date: 2018-2023) reflecting 550 patients and 560 treatments with reported outcomes were included (https://data.mendeley.com/datasets/vtkgpr7c2m/1). The mean age of the patients was 45\u00a0years , with 218 males (39.6%), 321 females (58.4%), and 11 (2%) patients with unreported sex. The frequently reported clinical subtypes of CHE were as follows: atopic , irritant , hyperkeratotic , dyshidrotic , and allergic . CHE was refractory to nonbiologic or non\u2013small molecule systemic or topical therapy in 94% (517/550) of patients.Following preferred reporting items for systematic reviews and meta-analyses guidelines, Embase and MEDLINE databases were searched using specific keywords . Complete resolution was observed commonly with dupilumab , followed by crisaborole , gusacitinib , delgocitinib , upadacitinib , and baricitinib . Conversely, no resolution was documented often with apremilast . The studies used Hand Eczema Severity Index (HECSI) as a validated outcome measure wherein >41-point reduction from baseline may represent a meaningful improvement.Mean treatment duration was 153.8\u00a0days in 524 of 560 patients. Concomitant medications were used in 23% (127/550) of patients, with topical corticosteroids being the most frequent (Supplementary Table II). The most common biologic or small-molecule classes utilized were topical delgocitinib , dupilumab , gusacitinib , upadacitinib , topical crisaborole , baricitinib , and apremilast (Supplementary Table III, available via Mendeley at ,,Although the pathogenesis of CHE remains unclear, increased systemic Th1/Th2 activation along with upregulated interleukin-4 transcripts have been implicated in patients with several disease subtypes.Study limitations include incomplete follow-up data and potential selection bias. Moreover, data heterogeneity prevented meta-analysis. Nonetheless, we highlight evidence that supports the use of biologics and small molecules such as dupilumab, delgocitinib, upadacitinib, and gusacitinib for CHE. Further larger-scale studies are warranted.Dr Asfandyar Mufti has been a speaker for AbbVie and Janssen. Dr Jensen Yeung has been an advisor, consultant, speaker, and/or investigator for AbbVie, Allergan, Amgen, Astellas, Bausche, Baxalta, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Fresnius Kabi, Galderma, Incyte, Janssen, LEO Pharma, Lilly, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, and Xenon.\u00a0The remaining authors Mr Sood, Mr Akuffo-Addo, Dr Georgakopoulos, and Dr Maliyar have no relevant disclosures."} +{"text": "CRLS1 lead to cardiolipin deficiency and cause an autosomal recessive multi-system mitochondrial disease, Human Molecular Genetics, Volume 31, Issue 21, 1 November 2022, Pages 3597\u20133612, https://doi.org/10.1093/hmg/ddac040This is a correction to: Richard G Lee, Shanti Balasubramaniam, Maike Stentenbach, Tom Kralj, Tim McCubbin, Benjamin Padman, Janine Smith, Lisa G Riley, Archana Priyadarshi, Liuyu Peng, Madison R Nuske, Richard Webster, Ken Peacock, Philip Roberts, Zornitza Stark, Gabrielle Lemire, Yoko A Ito, Care4Rare Canada Consortium, Kym M Boycott, Michael T Geraghty, Jan Bert van Klinken, Sacha Ferdinandusse, Ying Zhu, Rebecca Walsh, Esteban Marcellin, David R Thorburn, Tony Roscioli, Janice Fletcher, Oliver Rackham, Fr\u00e9d\u00e9ric M Vaz, Gavin E Reid, Aleksandra Filipovska, Deleterious variants in In the originally published version of this manuscript, the names of authors Tony Roscioli and Ying Zhu were inadvertently misspelled.These errors have been corrected online."} +{"text": "Human Molecular Genetics, Volume 32, Issue 9, 1 May 2023, Pages 1466\u20131482, https://doi.org/10.1093/hmg/ddac297This is a correction to: Willcyn Tang, John Thundyil, Grace Gui Yin Lim, Teddy J W Tng, Sean Qing Zhang Yeow, Aditya Nair, Chou Chai, Tso-Pang Yao, Kah-Leong Lim, Parkin regulates neuronal lipid homeostasis through SREBP2-lipoprotein lipase pathway\u2013implications for Parkinson's disease, In the originally published version of this manuscript, in Figure 4A, panels in the bottom row (Rot200nM (48 hrs), Parkin O/E) inadvertently duplicated the panels in the top row .The Figure has now been corrected."} +{"text": "Dear Editor1. As health systems plan post-COVID recovery of elective surgical services, they should identify potential future external risks to surgical services2. Extreme weather events resulting from climate change could present an increasing challenge to healthcare systems3; surges in injuries and cardiorespiratory complications during heatwaves could reduce capacity to deliver elective care4. The aim of this study was to determine the impact of summer pressures on the delivery of elective surgery in the UK.The COVID-19 pandemic exposed the fragility of elective surgical and anaesthesia services, resulting in millions of operations being cancelled across the worldFig. 1).The authors conducted a cross-sectional survey of surgeons, anaesthetists, and critical care doctors who worked during the UK heatwave of 16\u201319 July 2022. A total of 271 responses were received from across 20 specialties in 140 UK hospitals. One in five respondents reported that the heatwave directly resulted in the cancellation of elective surgery. A further third anticipated that cancellations were likely in the event of a prolonged heatwave. Factors contributing to heatwave-related cancellations included staff shortages (reported by 35.8 per cent of 271 respondents), unsafe theatre environments (30.3 per cent), and bed shortages (22.1 per cent) (Table S1).Surgical services were poorly prepared for heatwaves. Ambient temperature could not be controlled in 41.0 per cent of operating theatres. Most hospitals lacked summer pressure plans to maintain elective surgical safety and capacity. Some 96 respondents (35.4 per cent) reported making adaptations to maintain the routine surgical activity during the heatwave (5, they must consider how to safeguard against further climate change-related disruption to the delivery of surgical services. This should be included in the preparation of summer pressure plans to improve the resilience of elective surgery services.These data demonstrate that even short heatwaves may result in widespread disruption to surgical services. As hospitals tackle post-COVID surgery backlogsGreenSurg Collaborative: Maria Picciochi, James C Glasbey, Elizabeth Li, Sivesh K Kamarajah, Dmitri Nepogodiev, Joana FF Simoes, Aneel Bhangu, Arjun Nathan, Nizar S M Ismail, Amer J Durrani, Fanourios Georgiades, Ignatius Liew, Mamun D Dornseifer, Chetan D Parmar, Angelos G Kolias, Efstratia A Baili, Ashwani Kumar Nugur, Erminia Albanese, Marios Ghobrial, Andreas K Demetriades, Joseph P Attwood, Baljit Singh, Ciaran M Barlow, Sheila M Fraser, Manas K Dube, Avinash Aujayeb, Dinesh K Thekkinkattil, Abraham J Botha, Tosin O Akinyemi, W K E Peng, Salah A Hammouche, Muyed K A Mohamed, Mahmoud K A Elmesalmi, Maria G Cannoletta, Kai Yuen Wong, Hassan MT Fawi, Suk F Cheng, Funlayo O Odejinmi, Hugo RM Layard Horsfall, Nikolaos Machairas, Rory C Cuthbert, Shahbaz S Malik, Rory G Callan, Richard J Egan, Nader N Moawad, David W Ferguson, Nathan Grundy, Michelle L Collins, Jonathan BT Herron, Chetan Khatri, Sophia E Lewis, Tariq Alhammali, Andrew J Beamish, Kiran K Singisetti, Joseph Shalhoub, Chung S Chean, Rajesh Sivaprakasam, Sreekar Devarakonda, Miles W Benjamin, Sivesh K Kamarajah, James Ashcroft, Pierfrancesco Lapolla, Christin Henein, Baljit Singh, Cillian T Forde, Mohammad Zain Sohail, Rachael J Clegg, Zoe M Seymour, Stavros V Parasyris, Nikolaos Dimitrokallis, Benjamin J Davies, Waleed F A Fahmy, Obafemi K Wuraola, Athanasios Serlis, Binay Gurung, Andrew J Kelly, Rishi Talwar, Paul S Cullis, Dale J Gracie, Markus P Baker, George WV Cross, Wai Wai Win Mar, Raashad Hasan, Dimitri J Pournaras, Cho Ee Ng, Ashok R Ramasamy, Amir N A Iskandar, James C Glasbey, Haaris A Shiwani, Sujesh Bansal, Stephen F McAleer, Omar Ahmed, Nader N Moawad, Umakanth R Kempanna, John-Joe Reilly, Richard J Davies, Sibtain Anwar, Grant A Harris, Usama Ahmed, Kareem T Elsanhoury, Wen Jie Chin, Nikhil Kumar Ponugoti, Javaria Faiz, Amer J Durrani, Mohit Bhatia, Jonathon RC Sheen, Imran H Yusuf, Ziyan Sheng, Grant D Stewart, Shafquat Zaman, Aloka S Danwaththa Liyanage, Karthikeyan P Iyengar, Ravi Aggarwal, Setthasorn Z Y Ooi, Ayesha Mahmud, Mingzheng Aaron Goh, James M D Wheeler, Nicola J Eardley, Michael El Boghdady, Delvene Soares, Alexander D O'Connor, Ankur D Kariya, Filip Fryderyk Brzeszczy\u0144ski, Joshua L Moreau, Abdel Saed, Isobel Pilkington, Devaraj M Navaratnam, Neil A Ryan, Hooman Soleymani Majd, Lamiese Ismail, Hemina B Shah, Akib M Khan, Paul C Nankivell, Waleed Fayez Ali Fahmy, Robert W Tyler, Leandro Siragusa, Syed S Mannan, Giorgio Bogani, Jibran Abbasy, Piergiorgio Solli, Nadine Di Donato, Josh R Burke, Abdul Hakeem, Firas Aljanadi, Alexander J Baldwin, Mohamed Bekheit, Peter P Bobak, Matyas Fehervari, Fabio Barra, Mohamed A Thaha, Nadir Syed, James B Olivier, Khaled A K Mohammed, Kate J Williams, Tatiana Martin, Aman S Coonar, Michael W S Ho, Mark W Yao, Alexandros Konstantinos Charalabopoulos, Porfyrios G Korompelis, Kay Anne Mak, Abdelrahman AA Elsayed, Eve R Hawley, Ahmed Y Azzam, Alan JB Kirk, Ahmed E Sherif, Mostafa K.A Hussein, James A Blair, Yirupaiahgari KS Viswanath, Simon J Cole, Dheeraj S Attarde, Anna Y Allan, Ioannis N Gerogiannis, Shiva Dindyal, Muhammad H Siddique, Saidah Sahid, Jonathan J Neville, David N Naumann, Matthew H V Byrne, Sean MA Garcia, Ali Yasen Y Mohamedahmed, Alan A Askari, Joerg M Pollok, Hani J Marcus, Kapil Sahnan, Mohamed A Thaha, Qamar Mustafa, Ruben P Thumbadoo, Angelos G Kolias, Ketan Agarwal, Sean Khedar Ramcharan, Mehran Lashari, Mostafa EA Abdelkarim, Toby M Noton, Bilal H Kirmani, Robert D J Whitham, Sofia Anastasiadou, Rute S S Castelhano, Sanad Saad, Gakul Dr Bhatta, Chetan D Parmar, Antonio Leyte Golpe, Rucira Ooi, Emily C M McKenzie, Kenneth N Linton, Khalid M Bhatti, Shyama S Chadha, Liam N Phelan, Alvaro Bedoya Ronga, Vladislav Kutuzov, Mohammed Jibreel Mohammed, Sharan H Sambhwani, Catrin Sohrabi, Raghavan Vidya, Jaskiran K Gill, Lisa S Rampersad, Bincy Merin Zacharia, Waheeb A K Al-Azzani, Omar Pathmanaban N Pathmanaban, Rachel Sarah Olive, Fahad S Hossain, Jessica Harvey, Naren K Kumaran, Annamaria Minicozzi, Andrew Neil Wheelton, Victoria A Evans, Andrew D Beggs, Omar M Ismail, Chandra Shekhar Biyani, Shaikh S Seraj, Mohammed Deputy, Eltayeb B E Shammeseldin, Wafi Mohammed W M Mohammed, Mohamed Onsa, Yizhe Lim, Ahmad Riyadh Abdulsaheb Al-Shaye, Mujahid Gasemelseed Fadlallah, Hash Al-Musawi, Umar B J Yousuf, Safia Zahir Ahmed, Alexandros Laios, Aliabbas Moosa, Zoe Li, Peter J Hutchinson, Abdalla Hassan Abdalla Hassan, Shreya M Kulkarni, Shihab A Chowdhury, Ahmed Y Ammar, Tarig Hassan Ahmed, Raimundas A Lunevicius, Dimitrios Angelou, Edward J Caruana, Panna K Patel, Stephen J Bromage, Panagiotis Kapsampelis, Khaled M Sarraf, Antonios Nicolaos Athanasiou, Jai Relwani, James E Tomlinson, Amarkumar D Rajgor, Pedram Panahi, Rachael V Collins.znad033_Supplementary_DataClick here for additional data file."} +{"text": "AZD7442 is a combination of two half-life extended monoclonal antibodies, tixagevimab and cilgavimab. A population pharmacokinetic (popPK) model for AZD7442 included interim data from phase 3 trials in pre-exposure prophylaxis , post-exposure prophylaxis (STORMCHASER), and treatment of mild-to-moderate COVID-19 (TACKLE) in adults. This popPK model facilitated inclusion of adolescents in the AZD7442 label, the decision to increase the recommended PreP dose of AZD7442 in response to evolving SARS-CoV-2 variants, and selection of doses for a pediatric study (TRUST). Upon completion of the adult phase 3 studies, the popPK model was updated to include data from eight studies.The final popPK analysis included 4940 adult participants from North and South America, Europe, and Asia. To predict the PK of AZD7442 in pediatric patients, the effect of post-menstrual age on clearance was incorporated into the model.The PK of AZD7442, tixagevimab, and cilgavimab were very similar and dose-proportional. PopPK analyses found no difference in AZD7442 PK between PreP and treatment . The final AZD7442, tixagevimab, and cilgavimab models included body weight, sex, age, BMI, Black race, and site of intramuscular administration as covariates; none of these were clinically relevant nor required dose adjustment. When interim TRUST (pediatric) data became available, popPK predictions were compared to observed serum PK data . Good agreement was observed, confirming appropriateness of dosing adolescents \u226540kg with the same dosing regimen as adults, and adequate characterization of AZD7442 PK in pediatric participants. Safety data from TRUST and adult studies were comparable.The PK of AZD7442, cilgavimab, and tixagevimab are comparable and follow linear kinetics with an extended half-life, allowing for prolonged duration of protection. AZD7442 PK is comparable across indications and between adults and pediatric populations. PopPK analyses facilitated rapid decision-making during the COVID-19 pandemic, including accelerating access to AZD7442 by adolescent patients ahead of the availability of pediatric clinical data.Lindsay E. Clegg, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Oleg Stepanov, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Henning Schmidt, PhD, AstraZeneca: Employed by IntiQuan, which received payment from AstraZeneca for work involved in this analysis Ventakesh Pilla Reddy, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Weifeng Tang, MD, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Michael Gibbs, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Sangeeta Sedani, MSc, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Antonella Nadia Tuillio, MD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Sam Sadow, MA, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Nuria Martinez-Alier, PhD, AstraZeneca: Employee|AstraZeneca: Employement|AstraZeneca: Stocks/Bonds|AstraZeneca: Stocks/Bonds Taylor Cohen, PhD, AstraZeneca: Employement|AstraZeneca: Stocks/Bonds Saul N. Faust, FRCPCH PhD, AstraZeneca, Janssen, Pfizer, Moderna, GlaxoSmithKline, Novavax, Sanofi, Seqirus, Medimmune, Merck, MSD, Iliad and Valneva: Advisor/Consultant|AstraZeneca, Janssen, Pfizer, Moderna, GlaxoSmithKline, Novavax, Sanofi, Seqirus, Medimmune, Merck, MSD, Iliad and Valneva: Investigator Mark T. Esser, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Mats N\u00e5g\u00e5rd, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds"} +{"text": "Scientific Reports 10.1038/s41598-023-43267-8, published online 26 September 2023Correction to: In the original version of this Article Hanan B. Ahmed was incorrectly affiliated with \u2018Dyeing, Printing and Auxiliaries Department, Textile Research and Technology Institute, National Research Centre, 33 EL Buhouth St., Dokki, Giza, 12311, Egypt\u2019. The correct affiliation is listed below.Chemistry Department, Faculty of Science, Helwan University, Ain-Helwan, Cairo 11795, EgyptThe original Article has been corrected."} +{"text": "Correction: BMC Neurol 22, 186 (2022)10.1186/s12883-022-02707-0Following publication of the original article , an erroThe updated conclusion is given below and the changes have been highlighted in bold.Authors\u2019 contributionsLP, RC and KG designed and conceptualized the study; AD, LP, MM, TK, IK, BP and KG acquired data; AD, LP, MM, TK, IK, BP, RF, RC and KG analyzed data; RF, LP and KG conducted the statistical analysis, AD, LP and KG drafted the manuscript for intellectual content; AD, LP, MM, TK, IK, KL, SP, HUK, BP, RM, BP, RF, MM, RC and KG revised the manuscript for intellectual content. The author(s) read and approved the final manuscript.AD, The original article has been"} +{"text": "Regenerative Biomaterials, Volume 8, Issue 6, December 2021, rbab045, https://doi.org/10.1093/rb/rbab045This is a correction to: Dingsu Bao, Jiacheng Sun, Min Gong, Jie Shi, Bo Qin, Kai Deng, Gang Liu, Shengqiang Zeng, Zhou Xiang, Shijie Fu, Combination of graphene oxide and platelet-rich plasma improves tendon\u2013bone healing in a rabbit model of supraspinatus tendon reconstruction, In the article titled \u201cCombination of graphene oxide and platelet-rich plasma improves tendon-bone healing in a rabbit model of supraspinatus tendon reconstruction\u201d, we notice this following error:(i) The image in The corrected figure is shown herein."} +{"text": "Wasmannia auropunctata, commonly known as the electric ant or little fire ant. Because viruses can be effective biological control agents against many insect pests, including ants, a metagenomics/next-generation sequencing approach was used to facilitate discovery of virus sequences from the transcriptomes of W. auropunctata. Five new and complete positive sense, single-stranded RNA virus genomes, and one new negative sense, single-stranded RNA virus genome were identified, sequenced, and characterized from W. auropunctata collected in Argentina by this approach, including a dicistrovirus (Electric ant dicistrovirus), two polycipiviruses , a solinvivirus (Electric ant solinvivirus), a divergent genome with similarity to an unclassified group in the Picornavirales (Electric ant virus 1), and a rhabdovirus (Electric ant rhabdovirus). An additional virus genome was detected that is likely Solenopsis invicta virus 10 (MH727527). The virus genome sequences were absent from the transcriptomes of W. auropunctata collected in the USA (Hawaii and Florida). Additional limited field surveys corroborated the absence of these viruses in regions where the electric ant is invasive . The replicative genome strand of four of the viruses was detected in Argentinean-collected W. auropunctata indicating that the ant is a host for these viruses. These are the first virus discoveries to be made from W. auropunctata.Despite being one of the most destructive invasive species of ants, only two natural enemies are known currently for The online version contains supplementary material available at 10.1007/s11262-023-01969-1. Wasmannia auropunctata is an invasive myrmicine tramp ant species native to Central and South America that is now well established throughout tropical and sub-tropical regions of the world, including the USA ) indicative of helicase function and an RdRp motif characteristic of viruses in this order . Key to virus abbreviations, family, and accession numbers: AhV, Atkinsonella hypxylon virus, Partitivirdae, L39126; ALSV, Apple latent spherical virus, Secoviridae, NC030941.1; ANV, avian nephritis virus, Astroviridae, AB033998; APV, Acyrthosiphon pisum virus, Unassigned, NC003780.1; BaYMV, Barley yellow mosaic virus, Potyviridae, NC002990; BBWV 1, Broad bean wilt virus 1, Secoviridae, NC005289.1; BDRC, Bryopsis cinicola chloroplast replicon, Unclassified; BDRM, Bryopsis mitochondria-associated dsRNA; BWYV, Beet western yellows virus, Solemoviridae, NC004756; CHV1, Cryphonectria hypovirus 1, Hypoviridae, NC001492; CHV2, Cryphonectria hypovirus 2, Hypoviridae, NC003534; CHV3, Cryphonectria hypovirus 3, Hypoviridae, NC000960; CHV4, Cryphonectria hypovirus 4, NC006431; CPMV, Cowpea mosaic virus, Secoviridae/Comovirinae, NC003549.1; CPV, Cryptosporidium parvum virus-1, Partiviridae, GCA002868475; CRLV, Cherry rasp leaf virus, Secoviridae, NC006271.1;CrPV, Cricket paralysis virus, Dicistroviridae, NC003924.1; CtRLV, Carrot red leaf virus, Solemoviridae, NC006265; DCV, Drosophila C virus, Dicistroviridae, NC001834.1; DWV, Deformed wing virus, Iflaviridae, NC004830.2; EADS, Electric ant dicistrovirus, Dicistroviridae, OP518023; EAPV1, Electric ant polycipivirus 1, Polycipiviridae, OP518021; EAPV2, Electric ant polycipivirus 2, Polycipiviridae, OP518022; EASV, Electric ant solinvivirus, Solinviviridae, OP518024; EAV1, Electric ant virus 1, Unclassified, OP518025; EMCV, encephalomyocarditis virus, Picornaviridae, NC001479; FCCV, Fragaria chiloensis cryptic virus, Partitiviridae, NC009519; FCV, Feline calicivirus, Caliciviridae, GCA008767155; FGMV, Fusarium graminearum mycovirus, Unassigned, LC006128; FHV, felid herpesvirus 1, Nodaviridae, NC013590; FMDV, Foot-and-mouth disease virus, Picornaviridae, GCA008799075; GFLV, Grapevine fanleaf virus, Secoviridae/Comovirinae, NC003615.1; GGNNV, Greasy grouper nervous necrosis virus, Nodaviridae, AF318942; GLV, Giardia lamblia virus, Totiviridae, NC003555; HaRNAV, Heterosigma akashiwo RNA virus, Marnaviridae, NC005281.1; HAstV1, human astrovirus 1, Astroviridae, Z25771; HAV, Hepatitis A virus, Picornaviridae, KT229611; HcRNAV, Heterocapsa circularisquama RNA virus, Unclassified, NC007518; HRV1A, Heterocapsa circularisquama RNA virus, Picornaviridae, NC007518; IFV, infectious flacherie virus, NC003781.1; JP A, marine RNA virus JP-A, Unassigned, NC009757.1; JP B, Marine RNA virus JP-B, Unassigned, NC009758.1; KFV, Kelp fly virus, Unassigned, NC007619.1; LRV1, Leishmania RNA virus 1, Totiviridae, NC003601; LTSV, Lucerne transient streak virus, Solemoviridae, GCA000861405; MBV, Mushroom bacilliform virus, Barnaviridae, NC001633; NoV, Nodamura virus, GCA000847805; NrV, Neckar River virus, Unassigned, NC038927.1; NwV, Newbury virus, Caliciviridae, GCA000851625; OAstV1, ovine astrovirus 1, Astroviridae, Y15937, SmVB, Sclerophtora macrospora virus A, Unclassified, Go0081047; OPV, Ophiostoma partitivirus 1, Partitiviridae, NC038918; PLRV, Potato leafroll virus, GCA021461725; PnPV, Perina nuda virus, Iflaviridae, NC003113.1; PYFV, Parsnip yellow fleck virus, Secoviridae, NC003628.1; RasR1, Raphanus sativus cryptic virus 2, Partitiviridae, NC010343; RHDV, Rabbit hemorrhagic disease virus, Caliciviridae, NC001543; RiPV, Riptortus pedestris virus 1, Unassigned, NC031750.1; RsRNAV01, Rhizosolenia setigera RNA virus 01, Unassigned, NC018613.1; RTSV, Rice tungro spherical virus, Secoviridae, NC001632.1; SBMV, Southern bean mosaic virus, Solemoviridae, GCA000860745; SCPMV, Southern cowpea mosaic virus, Solemoviridae, NC001625; ScVL A, Saccharomyces cerevisiae virus L-A, Totiviridae, NC003745; SDV, satsuma dwarf virus-S58, Secoviridae, AB009958; SINV10 in EA, Solenopsis invicta virus 10 in electric ant, Unassigned, OP518026; SJNNV, striped jack nervous necrosis virus, Nodaviridae, NC003448; SmVA, Sclerophtora macrospora virus A, Unclassified, AB083060; SPMMV, sweet potato mild mottle virus, Potyviridae, NC003797; SssRNAV, Aurantiochytrium single-stranded RNA virus 01, Unassigned, NC007522.1; SV, Sapporo virus, Caliciviridae, GCA000849945; TAstV1, Astroviridae, Y15936; TEV, Tobacco etch virus, Potyviridae, NC001555; TRSV, Tobacco ringspot virus, Secoviridae/Comovirinae, NC005096.1; TrV, Triatomoa virus, Dicistroviridae, NC003783.1; TSV, Taura syndrome virus, Dicistroviridae, NC003005.1; TVV, Trichomonas vaginalis virus, Totiviridae, NC003824; WSMV, Wheat Streak Mosaic Virus, Potyviridae, NC001886. Supplementary file1 (TIF 1377 KB)Supplementary Figure 2. Mapping of RNA-Seq reads from four groups of electric ant samples collected in Argentina to seven virus genomes. The X-axis presents virus genome length in kilobases (kb) and the Y-axis represents sequencing coverage. Arrows indicate libraries with genome-wide sequencing coverage.Supplementary file2 (TIF 2911 KB)Supplementary file3 (DOCX 23 KB)Supplementary file4 (DOCX 42 KB)Supplementary file5 (DOCX 15 KB)Supplementary file6 (DOCX 23 KB)Below is the link to the electronic supplementary material."} +{"text": "Journal of Burn Care & Research, Volume 44, Issue Supplement_2, May/June 2023, Page S140, https://doi.org/10.1093/jbcr/irad045.197This is a correction to: Kathryn King-Shier, RN, PhD, FESC and others, 723 Provincial Burn Mass Casualty Incident Planning: Preliminary Results, In the originally published version of this manuscript, the incorrect author information was provided. The correct order of the authors of this abstract is as follows: Danielle Fuchko, RN BN, Kathryn King-Shier, RN PhD, Vincent Gabriel, MD FRCPCThis error has been corrected online."} +{"text": "Retraction Note: BMC Cancer 18, 641 (2018)https://doi.org/10.1186/s12885-018-4559-3The Editor has retracted this article. After publication, concerns were raised about the apparent overlap between panels H1975/shNC and H1993/shNC in Fig.\u00a02D. The authors sent raw data on request, where additional irregularities have been found, and the images for Fig.\u00a02D were different. The authors did not provide a sufficient explanation of the irregularities. The Editor has, therefore, lost confidence in the integrity of the findings. Xue Hou, Haoxian Yang and Li Zhang agree to this retraction. The Editor has been unable to obtain the current email addresses for Run Gong, Jianhua Zhan, Ting Zhou, Yuxiang Ma, Yuanyuan Zhao, Yaxiong Zhang, Gang Chen, Zhonghan Zhang, Shuxiang Ma, Xi Chen, Fangfang Gao, Shaodong Hong, Fan Luo, Wenfeng Fang, Yunpeng Yang, Yan Huang, and Likun Chen."} +{"text": "In the above published articleGabriel Birgand, Caroline Landelle, James R. Price, Nico T. Mutters, Daniel J. Morgan, Jean-Christophe Lucet, Solen Kerneis and Walter Zingg"} +{"text": "We also studied the efficacy and safety of empagliflozin in people with coexistent HF and PAD.While it is well established that peripheral artery disease (PAD) is associated with worsening major adverse cardiovascular events and major adverse limb events,2), and a higher proportion of albuminuria . With respect to background therapies, patients in both groups had similar rates of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor/neprilysin inhibitor (82.1% versus 83.7%) and \u03b2-blocker (90.5% versus 89.4%) use; however, mineralocorticoid receptor antagonist use was lower in the PAD group (43.1% versus 51.2%). Use of other antihypertensives including calcium channel blockers and renin inhibitors (30.1% versus 20.9%), lipid-lowering medications (86.0% versus 69.1%), and antiplatelet therapies (64.7% versus 48.3%) were higher among patients with PAD.In EMPEROR-Pooled (n=9718), a total of 821 (8.4%) patients had PAD and 8897 patients did not (3469 in EMPEROR-Reduced and 5428 in EMPEROR-Preserved). Patients with PAD were more likely to be men (70.5% versus 62.6%), White (83.9% versus 72.9%), and older (72.2\u00b18.3 versus 69.7\u00b110.5 years). Patients with PAD were more symptomatic and were more likely to have ischemic HF (60.5% versus 39.9%), be previous/current smokers (65.0% versus 48.8%), as well as have diabetes (65.2% versus 47.9%), hypertension (90.6% versus 82.9%), and hypercholesterolemia (84.8% versus 62.9%). Left ventricular ejection fraction was similar in patients with and without PAD (45.6\u00b114.5% versus 43.9\u00b115.3%). Patients with PAD had higher systolic blood pressure (131.1\u00b117.1 versus 127.8\u00b116.3 mm\u2009Hg), lower eGFR . Renal outcomes, including slope of eGFR and the composite renal end point, were similar in both PAD and no-PAD patients randomized to placebo in the EMPEROR-Pooled, EMPEROR-Reduced, and EMPEROR-Preserved populations (not shown).In the pooled analyses, patients randomized to placebo with a history of PAD had an elevated risk of HF outcomes and mortality compared with people without PAD. Specifically, the hazard ratios for total hospitalizations for HF (HHF), cardiovascular death, all-cause mortality, and the composite of cardiovascular death and time to first HHF were higher in people with PAD . Since patients with PAD were at higher absolute risk, the associated absolute risk reductions for total HHF events was 6.0% amongst patients with PAD and 3.2% amongst those without PAD. The efficacy of empagliflozin was consistent across all other cardiovascular outcomes and concordant in both the EMPEROR-Reduced and EMPEROR-Preserved populations individually. In terms of patient-reported outcomes, empagliflozin increased the Kansas City Cardiomyopathy Questionnaire clinical summary scores by a similar magnitude irrespective of PAD status .The efficacy of empagliflozin on cardiorenal outcomes in EMPEROR-Pooled was consistent regardless of PAD history . Rates of lower limb amputations were higher in people with PAD; however, rates were comparable in empagliflozin- versus placebo-treated patients .5 were similar. These data underscore an important and previously underappreciated association of PAD with HF events.In this large, contemporary cohort of patients with HF (with either reduced or preserved ejection fraction), we report a significantly elevated risk of HF outcomes among patients with PAD compared with those without PAD, including a \u224850% increase in total HHF and \u224840% increase in cardiovascular and all-cause mortality. While empagliflozin was efficacious in both populations, people with PAD had a higher absolute risk reduction on total HHF events compared with those without PAD. There was no excess in adverse events with empagliflozin in people with PAD, and specifically rates of lower limb amputations, which have been a previous concern with canagliflozin,https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information.To ensure independent interpretation of clinical study results and enable authors to fulfill their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data after publication of the primary manuscript and secondary analyses in peer-reviewed journals and regulatory and reimbursement activities are completed, normally within 1 year after the marketing application has been granted by major regulatory authorities. Researchers should use the The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors.This study was supported by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance.S. Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and reports receiving research grants and speaking honoraria from Amarin, Amgen, AstraZeneca (AZ), Bayer, Boehringer Ingelheim (BI), Bristol-Myers Squibb (BMS), Eli Lilly, EOCI Pharmacomm, Ltd, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk (NN), Sanofi, Sun Pharmaceuticals, PhaseBio, and the Toronto Knowledge Translation Working Group. He is a member of the Scientific Excellence Committee of the EMPEROR-Reduced trial and served as a national lead investigator of the DAPA-HF and EMPEROR-Reduced trials. The salary of M.P. Bonaca is partially supported through funds from CPC\u2014a nonprofit academic research organization affiliated with the University of Colorado that receives research grant/consulting funding from Abbott, Agios, Alexion Pharma, Alnylam, Amgen, Angionetics, ARCA Biopharma, Array, AZ, Atentiv, Audentes, Bayer, Better Therapeutics, Brigham and Women\u2019s Hospital, BMS, Cardiol Therapeutics, CellResearch, Cook Medical, Cook, CSL Behring, Eidos Therapeutics, EP Trading Co, Esperion Therapeutics, EverlyWell, Faraday, Fortress Biotech, HDL Therapeutics, Heartflow, Hummingbird Bioscience, Insmed, Janssen, Kowa Research, Lexicon, Merck, Medtronic, Moderna, Novate Medical, NN, Pfizer, PhaseBio, PPD Development, Prairie Education and Research, Prothena Biosciences, Regeneron, Regio Biosciences, Sanifit Therapeutics, Sanofi, Smith and Nephew, Stealth BioTherapeutics, University of Colorado, Worldwide Clinical Trials, Wraser, and Yale Cardiovascular Research Group. He also reports stock in Medtronic and Pfizer and consulting fees from Audentes. J. Butler reports research support from the National Institutes of Health, Patient Centered Outcomes Research, and the European Union. He serves on the speakers\u2019 bureau for Novartis, Janssen, and NN. He serves as a consultant and serves on the Steering Committee, Clinical Events Committee, or data safety monitoring boards for Abbott, Adrenomed, Amgen, Array, AZ, Bayer, Berlin-Cures, BI, BMS, Cardiocell, CVRx, G3 Pharmaceutical, Innolife, Janssen, Lantheus, LinaNova, Luitpold, Medscape, Medtronic, Merck, Novartis, NN, Relypsa, Roche, Sanofi, Stealth-Peptide, SC Pharma, V-Wave, Ltd, Vifor, and ZS Pharma. S.D. Anker reports grants and personal fees from Vifor International and Abbott Vascular and personal fees from AZ, Bayer, Brahms, BI, Cardiac Dimensions, Novartis, Occlutech, Servier, and Vifor International. J. Pedro Ferreira is a consultant for BI. G. Filippatos reports lecture fees and committee member contributions in trials sponsored by Bayer, Medtronic, Vifor, Servier, Novartis, Amgen, and BI and research support from the European Union. J.L. Januzzi is a Trustee of the American College of Cardiology; a board member of Imbria Pharmaceuticals; has received grant support from Applied Therapeutics, Innolife, Novartis Pharmaceuticals, and Abbott Diagnostics; has received consulting income from Abbott, Janssen, Novartis, and Roche Diagnostics; and participates in clinical end point committees/data safety monitoring boards for Abbott, AbbVie, Amgen, Bayer, CVRx, Janssen, MyoKardia, and Takeda. C.S.P. Lam reports research support from Bayer, NN, and Roche Diagnostics; fees as consultant or on the Advisory Board/Steering Committee/Executive Committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AZ, Bayer, BI, Boston Scientific, Cytokinetics, Darma, Inc, EchoNous, Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, NN, Prosciento, Inc, Radcliffe Group, Ltd, Recardio, Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and position as cofounder and nonexecutive director at Us2.ai. N. Sattar reports personal fees from Abbott Laboratories, Afimmune, Amgen, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, NN, Pfizer, and Sanofi and grants and personal fees from AZ, BI, Novartis, and Roche Diagnostics. T. Iwata, M. Nordaby, and M. Brueckmann are employees of BI. S.J. Pocock is a consultant for BI. M. Packer reports personal fees from Abbvie, Actavis, Amarin, Amgen, AZ, BI, Caladrius, Casana, CSL Behring, Cytokinetics, Imara, Lilly, Moderna, Novartis, Reata, Relypsa, and Salamandra. The other authors report no conflicts."} +{"text": "Scientific Reports 10.1038/s41598-023-34716-5, published online 05 June 2023Correction to: The original version of this Article contained errors in the names of the authors Matheus Araujo, Samer Ghosn, Lu Wang, Nengah Hariadi, Samantha Wells, Carl Y. Saab & Reena Mehra, which were incorrectly given as Araujo Matheus, Ghosn Samer, Wang Lu, Hariadi Nengah, Wells Samantha, Saab Y. Carl & Mehra Reena.The original Article has been corrected."} +{"text": "The authors would like to add Dr. LindaValmorriat to the authors' list. Thus, the authors' list will be:Laura Ridolfi, Massimiliano Petrini, Laura Fiammenghi, AnnaMaria Granato,Valentina Ancarani, Elena Pancisi, Emanuela Scarpi, Massimo Guidoboni,Giuseppe Migliori, Stefano Sanna, Francesca Tauceri, Giorgio Maria Verdecchia,Angela Riccobon, Linda Valmorriat, and Ruggero Ridolfi."} +{"text": "Rhopalopsole. The new species is named R. tricuspis Qian and Du, sp. nov. A redescription of R. basinigra Yang and Yang 1995 is supplemented. A key is provided for the adult males of Leuctridae from the Qinling Mountains.Plecopteran species (Leuctridae) were collected from the Qinling Mountains in southern Shaanxi Province, China. This mountain range is home to nine species of Leuctridae belonging to two genera, and the species identified in this work include one new species and three new records for the Qinling Mountains, all belonging to the genus Leuctridae is one of the families of Plecoptera distributed in the Nearctic, Palearctic, and Oriental Regions, established by Klapalek in 1905. Due to their small size and general absence from light traps, the number of known Chinese leuctrids is far less than in other regions. Thus far, eight leuctrid species have been recorded from China by early workers such as Klapalek (1912), Chu , Wu 193, 1949, C2 . Tergum 10 with posterior notch, cerci with a small bulge on dorsal arm1. Anal field of hind-wing large. Presternum of prothorax partially separated from basisternum Rhopalopsole)Anal field of hind-wing very small. Presternum of prothorax completely separated from basisternum : Illies, 1966,Das Tierreich 82: 118.Paraleuctra orientalis (Chu): Paraleuctra orientalis (Chu): Paraleuctra orientalis (Chu): Paraleuctra orientalis (Chu): Material examined. 1 \u2642, China: Shaanxi Province, Qinling Mountain Range, Mt. Tiantai, Source of Jialing River, 1750 m, 10 June 1998, Leg. Du Yu-Zhou. 1 \u2640, China: Shaanxi Province, Qinling Mountain Range, Zhouzhi County, Houzhenzi, Hougou, 1300 m, 26 May 1995, Leg. Du Yu-Zhou. 4 \u2640\u2640, China: Shaanxi Province, Qinling Mountain Range, Railway Station of Qinling, 16 May 1995, Leg. Du Yu-Zhou.Remarks.Paraleuctra orientalis (P. cercia (Okamoto 1922). They have deeply forked cerci with long ventral arms; paraproct without an expansion, male subgenital plate with a deeply excavated hind margin and the female subgenital plate is strongly sclerotized and divided in the middle of the hind margin. We also have found a small projection on the ventral arm of the cerci.ientalis . Our exaRhopalopsole basinigra Yang and Yang, 1995 (new record) Rhopalopsole basinigra Yang and Yang, 1995, Plecoptera: Leuctridae. In: Insects and Macrofungi of Gutianshan, Zhejiang, 20.Rhopalopsole basinigra Yang and Yang, 1995, Plecoptera: Perlidae. In: Insects of Baishanzu Mountain, Eastern China, 61.Rhopalopsole basinigra Yang and Yang: Material examined. 3 \u2642\u2642, China: Shaanxi Province, Qinling Mountain Range, Mt. Tiantai, Source of Jialing River, 1800 m, 10 June 1998, Leg. Du Yu-Zhou. 23 \u2642\u2642, China: Shaanxi Province, Qinling Mountain Range, Zhouzhi County, Hougou, Houzhenzi, 500 m, 24\u201326 May 1995, Leg. Du Yu-Zhou. 1 \u2642, China: Shaanxi Province, Qinling Mountain Range, Railway Station of Qinling, 15 May 1995, Leg. Du Yu-Zhou.Adult habitus. Head dark brown, wider than prothorax, three ocelli, hind ocelli much closer to the eyes than to each other, antennae yellowish brown, palpi light brown. Prothorax light brown, quadrate, longer than wide, angles rounded and some brown stripes on it. Legs light brown. Wings hyaline, veins light brown.Male. Body length 6.0 mm, length of forewing 5 mm. Ventral lamella on tergum 9 rounded did not describe in detail R. basinigra. We checked the types of R. basinigra in the Insect Collection of Beijing Agricultural University. It has a ridge that juts out before the mid-posterior margin of tergum 9; with long lateral processes reaching beyond the mid-line of tergum 10; apex of epiproct flattened, with a trilobed tip and a downcast spine in the middle lobe at a short distance to the tip. Epiproct of some species like in Rhopalopsole emeishanMaterial examined. 14 \u2642\u2642, China: Shaanxi Province, Qinling Mountain Range, Huoditang, 5 Jun. 1998, Leg. John C. Morse and Du Yu-Zhou. 11 \u2642\u2642, China: Shaanxi Province, Qinling Mountain Range, Mt. Tiantai, Source of Jialing River, 1800 m, 10 June 1998, Leg. Du Yu-Zhou.Remarks. Recently described species from Sichuan Province, China. Epiproct curved hook-like, its tip narrowing and turned forward. Distal ends of cerci with a little macula.Rhopalopsole furcataRhopalopsole furcata Yang and Yang: Rhopalopsole furcata Yang and Yang: Material examined. 10 \u2642\u2642, China: Shaanxi Province, Qinling Mountain Range, Mt. Tiantai, Source of Jialing River, 1800 m, 9 June 1998, Leg. Du Yu-Zhou. 2 \u2642\u2642, China: Shaanxi Province, Qinling Mountain Range, Zhouzhi County, Angou, Houzhenzi, 1250 m, 2 June 1998, Leg. Du Yu-Zhou.Remarks. We checked the types of R. furcata and R. sinensis Yang and Yang 1995, deposited in the Insect Collection of China Agricultural University, R. furcospina , 1400 m, 8 June 1998, Leg. Du Yu-Zhou.Remarks. Recently described species from Sichuan Province, China.Rhopalopsole jialingensisMaterial examined. 39 \u2642\u2642, China: Shaanxi Province, Qinling Mountain Range, Mt. Tiantai, Source of Jialing River, 1750\u20131800 m, 8\u201310 June 1998, Leg. Du Yu-Zhou. 4 \u2642\u2642, China: Shaanxi Province, Qinling Mountain Range, Zhouzhi County, Houzhenzi, Hougou, 1300 m, 3 June 1995, Leg. Du Yu-Zhou.Remarks. Recently described species from Shaanxi Province, China.Rhopalopsole qinlingaet al., Scopolia 64: 77.Material examined. 3 \u2642\u2642, China: Shaanxi Province, Qinling Mountain Range, Liuba County, Miaotaizi (Zhangliang Temple), 1400 m, 8 June 1998, Leg. Du Yu-Zhou.Remarks. Recently described species from Shaanxi Province, China.Rhopalopsole shaanxiensisMaterial examined. 11 \u2642\u2642, China: Shaanxi Province, Qinling Mountain Range, Huoditang, 5 June 1998, Leg. Du Yu-Zhou. 3 \u2642\u2642 , same data, Leg. John C. Morse. 6 \u2642\u2642, same data, Leg. Sun Chang-Hai and Yang Lian-Fang. 1 \u2642, same data, Leg. Ma Yun.Remarks. Recently described species from Shaanxi Province, China.Material examined. Holotype \u2642, China: Shaanxi Province, Qinling Mountain Range, Liuba County, Miaotaizi (Zhangliang Temple), 1400 m, 8 June 1998, Leg. Du YuZhou. Paratype 5 \u2642\u2642, same data as holotype. All type material deposited in the Insect Collection of Yangzhou University, Jiangsu, China.Adult habitus. Head brown, wider than prothorax, three ocelli and hind ocelli much closer to the eyes than to each other, antennae and palpi light brown. Prothorax light brown, subquadrate, angles rounded and some faintly brown stripes on it. Legs light brown. Wings hyaline, veins light brown.Male. Body length 5.0 mm, forewing length 5.5 mm. On tergum 9, the ventral lamella somewhat large and rounded ( rounded , a scler rounded , two sma rounded . Tergum rounded . Postero rounded . Epiproc rounded , an L-li rounded . Subanal rounded separate rounded . Cerci s rounded .Female. Unknown.Etymology. The species name is derived from the shape of the epiproct in dorsal view.Remarks. This new species seems similar to R. shaanxiensis group (R. qinlingaR. qinlinga by the outline of tergum 9, epiproct distal ends and subanal lobe. In R. qinlinga, no ridge juts out before the mid-posterior margin of tergum 9, epiproct distal ends blunt rounded and no split, subanal lobes separated into a basal lobe and an upper distal lobes in ventral view, each with strong dark sclerotized stripes on it.is group . It seem"} +{"text": "AbstractSymmorphus Wesmael from China. We also provide a key to these species. Three new species are described and illustrated, namely Symmorphus (Symmorphus) tianchiensis Li & Chen, sp. n., S. (S.) cavatus Li & Chen, sp. n., and S. (S.) nigriclypeus Li & Chen, sp. n. The following four species are newly recorded from China: Symmorphus (S.) fuscipes (Herrich-Schaeffer), S. (S.) lucens (Kostylev), S. (S.) sublaevis Kostylev, and S. (S.) violaceipennis Giordani Soika. In addition, we map the species geographical distributions in China of these 19 species. Type specimens of these three new species are deposited in Chongqing Normal University and Yunnan Agricultural University.In this study, we recognize and review a total of 19 species of the genus Symmorphus Wesmael contains 44 species with two subspecies, and is distributed in the Palearctic, Oriental, Nearctic regions and the northernmost Neotropical region. These species are usually slender and easily recognized by the combination of the following characters: mesoscutum with well-developed notaulices; metasomal tergum 1 distinctly narrower than tergum 2, but not petiolate, with a basal transverse carina and a median longitudinal furrow; and antennal apex in male simple, not forming a recurved hook. The known species of the genus were described or revised in detail by Symmorphus is absent. Twelve species were already recorded from China and Department of Entomology, College of Plant Protection, Yunnan Agricultural University, Kunming (YNAU), respectively. Descriptions and measurements were made under a stereomicroscope (Nikon SMZ1500), and all figures were taken with a stereomicroscope (LEICA EZ4HD) attached to a computer using Leica Application Suite version 2.1.0 software. The ratios used throughout the descriptions were measured in the same amplifying multiple of stereomicroscope. All measurements were taken as the maximal length of body parts measured. Body length was measured from the anterior margin of head to the posterior margin of metasomal tergum 2. For the density description of punctures, the phrase widely spaced means that the intervals between are larger than diameter, moderately spaced means equal to diameter, and whereas closedly spaced means less than diameter. The abbreviations used in the text are shown as follows: PageBreakWesmael, 1836SymmorphusOdynerus Latreille; Wesmael, 1836: 45, subgenus of Odynerus elegans Wesmael, 1833, designated by Li & Chensp. n.http://zoobank.org/FCA23B0A-F2DB-499B-B1B6-15D75C34CBABhttp://species-id.net/wiki/Symmorphus_tianchiensis25\u00b052'13.05\"N, 99\u00b017'14.33\"E, 2579 m, 9.VII.2011, Tingjing Li, No. 1001516 (CQNU); Paratypes: 1\u26401\u2642, the same as holotype, Nos. 1001524, 1001517 (CQNU); 1\u2640, China, Yunnan Prov., Nujiang City, Lanping County, Jinding Town, Xinshengqiao National Forest Park, 26\u00b026'56.36\"N, 99\u00b023'04.69\"E, 2412 m, 12. VII.2011, Tingjing Li, No. 1004036 (CQNU).Holotype. \u2640, China, Yunnan Prov., Dali City, Yunlong County, Tianchi National Nature Reserve, Female : body leHead. Clypeus sparsely punctate-puncticulate to foveolate-puncticulate, apex broadly and moderately emarginated, evenly convex, with apical teeth, and slightly reflexed anteriorly ; frons aPageBreakmesepimeron sparsely foveolate, space between punctures smooth and polish, ventral mesepimeron dull, and coarsely alutaceous. Metanotum foveolate-puncticulate dorsally, obscurely puncticulate ventrally, metanotum nearly vertical, dorsal surface narrow. Propodeal dorsum and posterior face coarse, areolate-rugose, propodeal superior shelf moderately long , lateral face of propodeum striately rugose ventrally, areolate-rugose dorsally, propodeal submedian carina present ventrally, faint and irregular dorsally .Symmorphus (Symmorphus) sichuanensis by S1 without basal carina, T1 with transverse carina laterally faint to obsolete, and mesepisternum with epicnemial carina dorsally obsolete; but can be easily distinguished from the similar species and other members of the genus by the combination of the following characters: body moderately long; in both female and male, dorsal pronotal spot orange-red .Holotype. \u2640, China, Yunnan Prov., Xishuangbanna, Jinghong City, Jinuo mountain, Female : body leHead. Clypeus moderately punctate-puncticulate to foveolate-puncticulate, punctures sparse medioapically, space between punctures smooth and polish; clypeal apex truncated, clypeus evenly convex, without apical teeth . Frons aPageBreakPageBreakpropodeal superior shelf short, 2 times trans-scutal sulcus; propodeal submedian carina entirely absent, propodeal valvula short posteriorly, fused distally to posterior margin; propodeal orifice small and indistinct.Mesosoma. Pronotum, except anterior face, foveolate-puncticulate, with major punctures closely spaced, more or less costate laterally; anterior face distinctly imbricate; pronotal carina dorsally obsolete; humeral angle slightly projected. Mesoscutum foveolate-puncticulate, major punctures closely spaced anteriorly and posteriorly, widely spaced laterally; notaulus complete; epicnemial carina complete; pseudosternum anterior margin without high reflexed margin. Mesoscutellum foveolate-puncticulate, major punctures closely spaced, with shallowly medial furrow. Mesepisternum with complete epicnemial carina , dorsallMetasoma. Metasomal tergum 1 with postcarinal area foveolate-puncticulate, major punctures densely spaced, postcarinal length short, postcarinal length/apical width=0.68, carinal width/apical width=0.85, postcarinal sides barely convergent toward base, transverse carina complete, longitudinal furrow narrowly and shallowly depressed, with deeper narrow medial sulcus, apical margin indistinctly depressed ; S1 rugoMale. Unknown.Symmorphus by the combination of the following characters: propodeal posterior face deeply hollowed .cavatus (= hollow), which refers to propodeal posterior face of the species deeply hollowed.The specific name is the Latin Li & Chensp. n.http://zoobank.org/C5EFD701-81FE-44EA-B533-E1531BA283FDhttp://species-id.net/wiki/Symmorphus_nigriclypeus29\u00b071'N, 95\u00b063'E, 3026 m, 13.VII.2013, Yong Zhou, No. 1004038 (CQNU).Holotype. \u2642, China, Tibet, Nyingchi, Medog County, Male : body leHead. Clypeus moderately punctate-puncticulate, clypeal apex deeply emarginated and with acute apical toothed laterally . Frons pPageBreakpunctures evenly and closely spaced; anterior face obscurely imbricate; pronotal carina complete; humeral angle moderately projected. Mesoscutum punctate-puncticulate to foveolate-puncticulate, primarily punctate-puncticulate, minor punctures evenly and densely spaced, major punctures great widely spaced; notaulus complete and distinctly deep .nigriclypeus is the Latin nigr (= black) + clypeus (=clypeus), which refers to the clypeus in male of the species black.The specific name Cumming, 1989http://species-id.net/wiki/Symmorphus_ambotretusSymmorphus ambotretus1\u2640, China, Yunnan Prov., Dali, North Gucheng, 9.V.2007, Rui Zhang; 1\u2640, China, Yunnan Prov., Dali, Yunlong, Luodun Town, 10.VII.2011, Tingjing Li; 1\u2640, China, Yunnan Prov., Nujiang, Lanping, Yingpan Town, 13.VII.2011, Zhenhu Wu; 1\u2640, China, Yunnan Prov., Lijiang, Ninglang, Daxing Town, 25.VII.2011, Tingjing Li; 6\u2642\u2642, China, Yunnan Prov., Dehong, Yingjiang, Tongbiguan Natural reserve, 3.V.2013; 1\u2640, China, Chongqing, Wansheng, Heishangu, 4.V.2011, Zhenhu Wu.China ; Nepal; Korea.http://species-id.net/wiki/Symmorphus_angustatusOdynerus angustatus Zetterstedt, 1838: 457.Odynerus suecicus de Saussure, 1855: 187 (key), 190, pl. X fig. 3.Odynerus laeviventris Thomson, 1874: 86; Symmorphus angustatus (Zetterstedt): Symmorphus hakutozanus Tsuneki, 1986: 23\u201324, 26; Symmorphus nansetsurei Tsuneki, 1986: 26, 27; Symmorphus iwatai Yamane, 1990: 115 (key), 127\u2013128, synonymized by 1\u2640, China, Jilin Prov., Tonghua, Mehekou, 22.VIII.1993, Zhihong Li.China (Jilin); Norway; Sweden; Finland; Denmark; France; Germany; Austria; Greece; Turkey; Belarus; Russia (to Primorskij Krai); Kazahkstan; Mongolia; the Korean Peninsula; Japan.PageBreakhttp://species-id.net/wiki/Symmorphus_apiciornatusAncistrocerus apiciornatus Cameron, 1911: 288.Odynerus (Ancistrocerus) apiciornatus (Cameron): Symmorphus apiciornatus (Cameron): Symmorphus seoulensis Tsuneki, 1986: 22, figs 66-67, female; 1\u2640, China, Beijing, Haidian, 29.IV.1952. Jikun Yang; 1\u2640, China, Beijing, Gongzhufen, 12.V.1952. Jikun Yang; 1\u2642, China, Shaanxi Prov., Baoji, Fengxian, Jialing River, 26.V.2007, Xiaoyu, Jiang.China ; Russia; South Korea; Japan.Giordani Soika, 1986http://species-id.net/wiki/Symmorphus_aurantiopictusSymmorphus aurantiopictus Giordani Soika, 1986: 154, fig. 47; No specimens examined.China (Jiangsu).http://species-id.net/wiki/Symmorphus_bifasciatusVespa bifasciata Linnaeus, 1761: 419; Symmorphus bifasciatus (Linnaeus): Vespa sinuata Fabricius, 1793: 270; Odynerus sinuatusmutinensis Baldini, 1894: 78, pl. III fig. 6; var. Symmorphus sparsus Morawitz, 1895: 490; Symmorphus sinuatissimus Richards, 1935: 162; PageBreakSymmorphus mutinensis Baldamus: Symmorphus mutinensis auster Giordani Soika, 1975: 150, 160; Symmorphus mutinensis yezoanus Tsuneki, 1977: 16; 1\u2642, China, Chongqing, Jiangjin, Simianshan National Nature Reserve, 6.V.2012, Ju You.China ; Europe, eastward to northeastern Siberia and Far Eastern Russia; Kyrgyzstan; Kazahkstan; Korea; Japan.Gussakovskii, 1932http://species-id.net/wiki/Symmorphus_foveolatusSymmorphus foveolatus Gussakovskii, 1932: 55; Odynerus captivus Smith: 6\u2640\u26402\u2642\u2642, China, Sichuan Prov., Panzhihua, Renhe Town, 28.VII.2011, Tingjing Li.China (Sichuan); Russia; the Korean Peninsula; Japan.new recordhttp://species-id.net/wiki/Symmorphus_fuscipesOdynerus fuscipes Herrich-Schaeffer, 1838: 18, pl. 18; Symmorphus karelicus Morawitz, 1895: 490.Symmorphus fuscipes (Herrich-Schaeffer): 2\u2640\u2640, China, Liaoning Prov., Liaoyang, Gongchangling, Anping, 7.VII.2012.Ju You; 1\u2640, China, Jilin Prov., Changchun, Dehui, Xiajiadian, 28.VI.2012, Ju You; 1\u2640, China, Jilin Prov., Baishan, Linjiang, Naozhi Town, 7.VII.2012, Ju You.China ; Norway; Sweden; Finland; Netherlands; Germany; Austria; Belarus; Mongolia; Russia.PageBreakhttp://species-id.net/wiki/Symmorphus_hoozanensisOdynerus hoozanensis von Schulthess, 1934: 67.Symmorphus hoozanensis (von Schulthess): Cumming, 1989: 3, 5, 21 (key), 26.No specimens examined.China (Taiwan).http://species-id.net/wiki/Symmorphus_lucensOdynerus lucens Kostylev, 1938: 304; Symmorphus lucens (Kostylev): Symmorphus ishikawai Giordani Soika, 1975: 151, 159; 2\u2640\u2640, China, Inner Mongolia, Helan Mountain, Gulamuxiaosong Hill, 30.VII.2010, Jian Li & Junzhe Xue; 1\u2640, China, Inner Mongolia, Helan Mountain, Halawu Ravine, 20.VII.2006, Ming Luo; 1\u2640, China, Inner Mongolia, Helan Mountain, Yushuwan, 27.VII.2010, Fangzhou Ma.China (new record: Inner Mongolia), Russia: southern Siberia to Sakhalin; Korea; Japan.Tsuneki, 1977http://species-id.net/wiki/Symmorphus_mizuhonisSymmorphus mizuhonis Tsuneki, 1977: 15-20; Symmorphus kurentzovi Kurzenko, 1981: 104, figs 111-116; Symmorphus iiyamai Tsuneki, 1986: 26 (key), fig. 70, male; Symmorphus shiroyamai Tsuneki, 1986: 26 (key), 27, fig. 71, male; Symmorphus piceanus Tsuneki, 1986: 26 (key), 27, fig. 72; Symmorphus sassai Tsuneki, 1986: 26 (key), 27, fig. 73; 2\u2640\u26404\u2642\u2642, China, Yunnan Prov., Diqing, Deqin, Near the county, 19.VII.2011, Tingjing Li; 4\u2640\u2640, China, Yunnan Prov., Dali, Yunlong, Tianchi, 9.VII.2011, Tingjing Li.China ; Russia: Irkutsk, Primorskij Krai; Kazahkstan; North Korea; Japan.PageBreakGusenleitner, 2000http://species-id.net/wiki/Symmorphus_ornatusSymmorphus ornatus Gusenleitner, 2000: 939, 945.No specimens examined.China (Taiwan).Lee, 1981http://species-id.net/wiki/Symmorphus_sichuanensisSymmorphus sichuanensis Lee, 1981: 423, fig. 1; 3\u2640\u2640: China, Sichuan Prov., Leshan City, Emeishan, Gaoqiao Town, Yanshi Village, 11.VIII.2011, Tingjing Li.China (Sichuan); Thailand.Kostylev, 1940new recordhttp://species-id.net/wiki/Symmorphus_sublaevisOdynerus sublaevis Kostylev, 1940: 40.Symmorphus sparsus Morawitz: Symmorphus sublaevis (Kostylev): 5\u2642\u2642, China, Ningxia, Jingyuan, Xixia Forest, 15\u201316.VII.2008, Xiumin Li; 1\u2642, China, Ningxia, Longde, Sutai Forest, 1\u20132,VII.2008, Xinpu Wang; 1\u2642, China, Ningxia, Guyuan, Lvyan Forest, 9\u201310.VII.2008, Guodong Ren.China (new record: Ningxia); Kyrgyzstan; Kazahkstan.Giordani Soika, 1966new recordhttp://species-id.net/wiki/Symmorphus_violaceipennisSymmorphus violaceipennis Giordani Soika, 1966: 102; 10\u2640\u2640, China, Yunnan Prov., Dali, Yunlong, Tianchi, 9.VII.2011, Tingjing Li; 9\u2640\u2640, China, Yunnan Prov., Nujiang, Lanping, Yingpan Town, 12.VII.2011, Zhenhu Wu; 1\u2640, China, Sichuan Prov., Kangding, Paoma Mountain, 7.VII.2005, Hu Zhou.China ; India; Nepal.PageBreakGusenleitner, 2002http://species-id.net/wiki/Symmorphus_yananensisSymmorphus yananensis Gusenleitner, 2002: 345.No specimens examined.China (Shaanxi).Gusenleitner, 2002http://species-id.net/wiki/Symmorphus_yunnanensisSymmorphus yunnanensis Gusenleitner, 2002: 345; 5\u2640\u264011\u2642\u2642, China, Yunnan Prov., Diqing, Deqin, Near the county, 19.VII.2011, Tingjing Li; 1\u2642, China, Tibet, Changdu, Mangkang, 3508 m, 5.VII.2013, Yong Zhou.China .PageBreak"} +{"text": "Fingerprint-based structure representation has a broad range of applications including, but not limited to, diversity analysis, compound classification, chemical space visualization , activit"} +{"text": "AbstractOsmia (Melanosmia) found in North America, including the description of two new species found in Canada and the northern United States: Osmia (Melanosmia) aquilonaria sp. n., and Osmia (Melanosmia) nearctica sp. n., respectively belonging to the inermis and xanthomelana species groups. We additionally provide keys to the non-metallic Melanosmia found in North America, and update keys to the palearctic Melanosmia based on study of the type specimens of Osmia disjuncta Tkalc\u016f, Osmia ephippiata Smith, Osmia ishikawai Hirashima, and Osmia pamirensis Gussakovskij.We review the six species of non-metallic Melanosmia females of Osmia(Melanosmia) tersula Melanosmia below.As currently understood, the \u201cdark Melanosmia, there is a possibility that the two new North American species described herein are already known from the Palearctic. In order to avoid producing new junior synonyms, it is necessary to understand the 20 species of Melanosmia known from the Palearctic are unknown to us although we attempted to borrow the holotype material.Given the holarctic distribution of many non-metallic learctic , and upon examination of the female holotype we conclude that it also belongs to the inermis species group.PageBreakPageBreakOf the remaining 18 species of palearctic es group , 2010 ar inermis ; Osmia lOsmia nigriventris . These unusual features are shared with the North American species Osmia bucephala, a species that has further apomorphies that have obscured its taxonomic placement within Osmia.iventris into a tMelanosmia have received less treatment in recent revisions and are thus considerably less well-known. They are Osmia ephippiata Smith, 1879, Osmia ishikawai Hirashima, 1973, Osmia melanota Morawitz, 1888, Osmia pamirensis Gussakovskij 1930, Osmia recta P\u00e9rez, 1902, and Osmia thoracica Radoszkowski, 1874. Of these, we were able to exclude Osmia melanota from consideration as a possible component of the North American fauna due to the original description of the type material as dark metallic blue has additionally seen the type series of two males and nine females of Osmia pamirensis at the Russian Academy, St. Petersburg in 1984 . Osmia laticeps (as Osmia hyperborea) in his revision of palearctic Melanosmia; the female of this species was diagnosed by Osmia laticeps and include it in an updated key to palearctic Melanosmia based on Of the palearctic The morphological terminology used herein follows that proposed by The following morphological abbreviations are used: flagellar segment (F), metasomal tergum (T), metasomal sternum (S), and ocellar diameter (OD). Measurements are given for the holotype specimen, with the observed range from other specimens following in parentheses.PageBreakFull label data are given for all specimens of new species.\u00a0 Label data of examined material for the remaining species were summarized at the county level or its equivalent, along with date, floral record, and altitude (if given). The following abbreviations are used for specimen repositories, with individuals associated with those repositories following in parentheses:University of Colorado, Boulder CO (V. Scott)BoulderOregon State University, Corvallis OR CorvallisUniversity of California, Davis CA (S. Heydon)DavisUSDA Bee Biology and Systematics Laboratory, Logan UT LoganPersonal collection of T. Griswold, Logan UTLogan-TGUniversity of Idaho, Moscow ID MoscowAmerican Museum of Natural History, New York NY New YorkCanadian National Collection, Ottawa OttawaCalifornia Academy of Sciences, San Francisco CA San FranciscoMissouri Department of Conservation, St. Charles MO (M. Arduser)St. CharlesRoyal Ontario Museum, Toronto Ontario (B. Hubley)TorontoUppsala University, Sweden (B. G. Svensson)UppsalaRoyal British Columbia Museum, Victoria B. C. (R. Cannings)VictoriaSpecimens were examined and measured using a Leica MZ12 dissection microscope and ocular micrometer. Photomicrographs were taken using a Keyence Digital Imaging System. N.W.T. [Northwest Territories] km 491, Dempster Hwy, 26.VI.80 [26 June 1980], 1000 m, Wood & Lafontaine//CANADA: NORTHWEST TERRITORIES, Inuvik Region, Aklavik, 25 June 1931, O. Bryant , 25 July 1931, 1600 ft ; Black Mountain, SW of Aklavik, 1 August 1931, O. Bryant ; Holman, Victoria Island, 25 June 1952, B. A. Gibbard ; NOVA SCOTIA, Cape Breton Highlands National Park, 60\u02da50'W 46\u02da47'N, 22 June 1983, Birch ; NUNAVUT, Kitikmeot Region, Coppermine, 3 August 1951, S. D. Hicks ; ONTARIO, Cochrane District, Low Bush, Lake Abitibi, 5 June 1925, N. K. Bigelow , 18 June 1925, N. K. Bigelow ; Thunder Bay District, Silver Island, Sibley Peninsula, 18 July 1961, Rubus sp., H. E. Milliron ; QUEBEC, Nord-du-Qu\u00e9bec Region, Highway to James Bay km 66, 50\u02da03'N 77\u02da07'W, 12 June\u20138 August 1987, Malaise-FIT Salix bushes, L. Leblanc ; YUKON, Dempster Highway km 465, 23\u201325 June 1980, 800 m, Wood & Lafontaine ; USA: ALASKA, North Slope Borough, Cape Thompson, 29 June 1961, B. S. Heming ; Yukon-Koyukuk Census Area, Kathul Mountain, Yukon River, Steppe, 4 June 1991, Arnica alpina, J. A. Bishop , 5 June 1991, Lupinus arcticus ; Kathul Mountain, Yukon River, 110 km NW Eagle, Tundra, 16 June 1992, Lupinus arcticus, J. A. Bishop ; WYOMING, Fremont Co., Roaring Fork Mountain, Wind River Range, 29 June 1990, 11000\u20131200 ft, E. A. Sugden .The name \u201caquilonaria\u201d is Latin, meaning northern or northerly, and is in reference to the northern distribution of the species in North America.(Zetterstedt)Anthophora (Osmia) inermis Osmia globosaApis globosa Osmia vulpecula Osmia globosiformis Osmia (Melanosmia) inermis (Zetterstedt); Osmia (Chenosmia) inermis (Zetterstedt); PageBreakFemales are known by the slightly acute angle or tooth midway on the ventral margin of the mandible . Males cOsmia inermis is found from Spain, Italy, and Greece north to the United Kingdom, Norway, Sweden, and Finland, and east through Russia and northern China . The related, if not synonymous, species Osmia ishikawai is found in Japan.In the Nearctic, from Sierra Nevada of California north to British Columbia and Alaska, east through Canada to Nova Scotia and Newfoundland south in the United States to Massachusetts, Michigan, the Black Hills of South Dakota, and mountainous areas of Nevada, Utah, and Colorado. In the Palearctic, PageBreakOsmia inermis has been recorded nesting under stone or in preexisting cavities in rocks and stones, with cells composed of chewed leaves , 25 May 1892 , 29 May 1922 , 6 July 1955 ; Northern Alberta Region, 29 May 1977 ; BRITISH COLUMBIA, Central Kootenay, 3 June 1906 , 9 June ; Stikine Region, 6 June 1955, 2200 ft , 17 June 1955, 2200 ft ; Okanagan-Similkameen District, 21 May 1958 ; MANITOBA, Northern Region, 1 July 1927 , 11 July 1950 , 29 July 1949 ; Parkland Region, 26 June 1961, 2000 ft ; NEW BRUNSWICK, St. John Co., 9 June 1901 , 23 June 1901 ; York Co., 29 May 1918 ; NEWFOUNDLAND AND LABRADOR, Twillingate Islands, 30 May 1951 ; NOVA SCOTIA, Halifax Co., 2 July 1914 ; Hants Co., 4 June 1931, Cornus sp. , 22 June 1931 ; ONTARIO, Kawartha Lakes, 25 May 1964, Viola adunca ; Lennox and Addington Co., 12 May 1962, Chamaedaphne sp. ; Rainy River District, 2 July 1960 ; QUEBEC, Capitale-Nationale Region, 17 May 1914 , 28 May 1916, Vaccinium sp. ; Nord-du-Qu\u00e9bec Region, 4\u201312 June 1987 , 12 June\u20138 July 1987 , 18 June 1949 , 14 August 1949 , 18 August 1949 , 23 August 1949 , 2 September 1949 , 3 September 1949 ; Outaouais Region, 14 May 1916, Vaccinium sp. ; YUKON, 26 May 1951 , 31 May 1951 , 5 June 1951 , 12 June 1960, 3500 ft , 21 June 1949, 5200 ft , 2 July 1962, 3500 ft , 10 July 1985 ; RUSSIA, Siberia, 3 July 1992 , 5 July 1992 ; SWEDEN: , 12\u201319 June 1972 , J\u00f6nk\u00f6ping Co., 12 July 1932 ; Norrbotten Co., , 25 August 1975 ; USA: ALASKA, Fairbanks North Star Borough, 19 May 1987 ; Kenai Peninsula, 20 June 1951 ; CALIFORNIA, Madera Co., 19 July 2004, 3315 m, Phyllodoce breweri ; Mariposa Co., 15 June 2004, 3024 m , Phyllodoce breweri , 3215 m , 23 June 2004, 3112 m , 4 July 2004, 2860 m , 2847 m, Horkelia tridentata , 14 July 2005, 3112 m, , Phyllodoce breweri , 16 July 2004, 2944 m, Phyllodoce breweri , 14 August 2004, 3189 m, , 1 August 2005,PageBreak 3189 m, ; Shasta Co., 30 July 1947, 7000 ft , Tuolumne Co., 14 July 2004, 3049 m , 3114 m , Phyllodoce breweri , 15 July 2004, 3215 m, , Phyllodoce breweri , 17 July 2005, 3215 m , 28 July 2006, 3215 m, Arenaria kingii var. glabrescens , Eriogonum incanum , Phyllodoce breweri ; COLORADO, Boulder Co., 18 June 1940 , 20 June 1940 , 27 June 1939 , 8 July 1940 ; Grand Co.PageBreak, 22 June 1976 ; Larimer Co., 19 June , 25 July ; Mesa Co., 10 July 1938 ; Routt Co., 21 May 1964, 8500 ft, Erythronuim sp. ; Summit Co., 29 July 1961, 11700 ; IDAHO, Bear Lake Co., 10 August 1972 ; Lemhi Co., 20 July 1963 ; MAINE, Knox Co., 28 May 1962, Vaccinium angustifolium ; MASSACHUSETTS, Barnstable Co., 16 May 1914 ; MICHIGAN, Alger Co., 23 May 1982, Vaccinium sp. , 29 May 1991, Vaccinium angustifolium ; Marquette Co., 25 May 1983, Vaccinium angustifolium , 9 June 1985, Gaylussacia sp. , 21 June 1984 ; MONTANA, Carbon Co., 10 July 1963, 5900 ft, Melilotus sp. , 12 July 1963, 5900 ft, Melilotus sp. , 28 July 1975 ; Gallatin Co., 1 May 1927 , 24 June 2008 ; NEVADA, Elko Co., 9 July 1979 , 19 July 1975, 9500 ft , 21 July 1976, 9600 ft ; OREGON, Baker Co., 15 July 1930, 7100 ft ; Wallowa Co., 26 July 1929, 7500 ft ; SOUTH DAKOTA, Custer Co., 20 June 1955, Trifolium repens ; UTAH, Cache Co., 7 June 1962, , 18 June 1948, Wyethia sp , 30 June 1976, Penstemon leonardi , 4 July 1947, Ranunculus acriformis var. montanensis , 5 July 1981, 8500 ft , 17 July 1995, 8200\u20138600 ft, Penstemon sp. , 25 July 1971 , 28 July 1975, Penstemon cyananthus ; 1 August 1965 , 4 August 1975, Potentilla fruticosa ; Grand Co., 8 June 1963 ; Sanpete Co., 25 June 1990, 10760 ft, Astragalus montii ; Weber Co., 13 July 1950 ; WASHINGTON, King Co. ; WYOMING, Big Horn Co., 6 August 2000, 8975 ft, Machaeranthera sp. ; Carbon Co., 31 May 1972 ; Fremont Co., 10 June 1955 , 29 June 1990, 11000\u201312000 ft ; Johnson Co., 22 July 1998 ; Sheridan Co., 26 June 1986 ; Sublette Co., 20 July 1959 ; Teton Co., July 1937 , 4 July 1983, 6700 ft, Hedysarum boreale , 13 July 1983, 6700 ft, Hedysarum boreale ; 17 July 1983, 6700 ft, Hedysarum boreale .23 April , 30 July 1955 ; ThomsonOsmia laticepsOsmia uncinata Gerst\u00e4cker]; Osmia uncinata Gerst\u00e4cker]. Osmia (Melanosmia) hyperboreaOsmia parietina Curtis]; Osmia parietina Curtis, diagnosis of female]; Osmia laticeps Thomson]. PageBreakOsmia laticeps are distinguished from all other North American non-metallic Osmia by the following characters of the mandible , the following characters can be used to distinguish females of the two species , and the relatively unmodified S4 : the apiDark brown to brown-black, sometimes with reddish overtones especially on mouthparts, labrum, mandible, flagellar segments, legs, and apical margins of T1\u2013T5. Wings mostly clear to weakly infuscate, except moderately infuscate along dorsal half of marginal cell.Clypeus below apical margin with lateral tuft of golden, medially directed hairs. White to golden, minutely branched hairs on most of body except as follows: brown, simple hairs interspersed with pale, branched hairs on clypeus, sometimes interantennal area and near ocelli, gena ventrally and along compound eye, outer surfaces of femora and tibiae ; dark-brown, simple hairs only (no branched hairs) on mouthparts, labrum, inner surfaces of legs (golden on tarsi), outer surfaces of hind tibia and all tarsi, T2\u2013T6, and scopa; brown, short, simple hairs evenly covering forewing. Galea and basal two labial palpal segments with hairs on lateral margins straight, 0.2\u20130.3 OD in length. Labrum with long hairs arranged in two curved, transverse rows, along subapical margin and approximately at midpoint, with additional fringe of minute hairs at apical margin. Clypeus with hairs about as dense as on frons, midapically with some hairs slightly curved at apical tips. Hypostomal area with straight hairs evenly distributed across most of area, 2.0\u20133.0 OD in length.PageBreakctures separated by about half a puncture diameter; metepisternum with punctures less distinct, separated by up to a puncture diameter; hypostomal area anteriorly near angle, posterior half of gena, and legs with punctures shallowly impressed, sometimes elongated into oval shape; tegula with punctures minute, sparse medially and posteriorly, separated by up to four puncture diameters (up to six puncture diameters in some specimens); PageBreakpronotum, metanotum, and lateral and posterior surfaces of propodeum with punctures less distinctly impressed and background integument weakly shagreened; propodeal triangle with dorsal fourth reticulate to lineate, lower three fourths strongly shagreened, dull. T1 anterior surface moderately shagreened, weakly shining, with scattered, sparse, minute punctures throughout; T1\u2013T3 dorsal surfaces weakly shagreened, shining, with small punctures nearly contiguous to separated by 2.0 puncture diameters on basal three-fourths, minute and much more sparsely spaced on apical fourth (4.0\u20136.0 puncture diameters apart), apical margins with narrow region entirely impunctate (PageBreakicaceae) .CANADA: MANITOBA, Northern Region, 12 June 1952 , 20 June 1930 ; NOVA SCOTIA, Kings Co., 24 May 1932, apple ; ONTARIO, Kenora District, 10 June 1964, Viola adunca ; Ottawa, 22 May 1973 ; QUEBEC, Abitibi-T\u00e9miscamingue Region, 24 May 1934 ; Nord-du-Qu\u00e9bec Region, 9 PageBreakJune 1956 ; Bas-Saint-Laurent Region, 22 June 1916 ; YUKON, 22 May 1951 , 28 May 1951 , 2 June 1951 , 12 June 1960, 3500 ft , 17 July 1981 ; RUSSIA: Siberia, 11\u201315 July ; SWEDEN: Norrbotten Co., 6 July 1975 ; USA: MAINE, 15 June 1982 ; MICHIGAN, Alger Co., 3\u201311 June 1982, sand pit , 28 June 1982, Vaccinium myrtilloides ; Marquette Co., 10 June 1985, Gaylussacia sp. , 18 June 1983 .FrieseOsmia maritima Osmia maritima is one of two currently known species of the xanthomelana species group in North America . Females of Osmia maritima are distinguished from the other North American xanthomelana species group member, Osmia nearctica, by characteristics of the mandible, outer hind tibial spur, and clypeus: the mandible has a third tooth that is recessed below a distinct carina between the second and fourth teeth , and the apical truncation of the clypeus is not distinctly set apart from the lateral apical margin of the clypeus, Osmia nearctica with the apical truncation forming a 90 degree angle with the lateral apical margin of the clypeus, Osmia maritima also have almost entirely black pubescence on the clypeus (significant amounts of light hairs throughout the clypeus in Osmia nearctica) and longer hair on the galea in dorsal view.th teeth and weakly emarginate S2 .Males of Osmia maritima is known only from the Northwest Territories and Alaska. In the Palearctic, Osmia maritima is known from the Netherlands, Germany, Denmark, Norway, Sweden, and Finland east to Mongolia and through Russia to Far Eastern Siberia ;PageBreak however, since a holarctic distribution is well established for other Osmia species , until proven otherwise we conservatively retain the name Osmia maritima for this species. Interestingly, there appear to be two female morphs of Osmia maritima. Specimens from Alaska and the Russian Far East share pale hair on the paraocular area and mesepisternum and scarcely sculptured apical areas on T2 and T3; females from the Northwest Territories and western Europe have dark hair on the paraocular area and mesepisternum and microsculptured apical areas of T2 and T3.We have not found any male specimens of PageBreakOsmia maritima from the Palearctic is known to be polylectic and nests in sandy soil with cells composed of chewed leaves and sand grains , 20\u201325 June 1971 , 28\u201330 June 1971 , 11 July 1948 ; NETHERLANDS: Terschelling, 2 June 1969 ; RUSSIA: Siberia, 5 July 1992 , 12 July 1992 ; USA: ALASKA, Fairbanks North Star Borough, 31 July 1985 ; Southeast Fairbanks Census Area, 21 June 1984, Oxytropis campestris ; Yukon-Koyukuk Census Area, 17 May 1991, Dodecatheon frigidum , 19 June 1992, Penstemon gormanii .Rightmyer, Griswold, & Arduser sp. n.urn:lsid:zoobank.org:act:E8E24354-14D3-463C-8505-F6E2002F401EOsmia nearctica is one of two members of the xanthomelana species group in North America; characters to distinguish it from the other member of that group, Osmia maritima, are given under that species (see above).Osmia nearctica is most similar to Osmia xanthomelana, but can be differentiated from that species by the following characters: In females, the propodeal triangle is shining but weakly shagreened throughout , the outer hind tibial spur is only about half the length of the hind basitarsal segment , and the lower margin of the mandible has a distinct, translucent flange that curves away from the condylar ridge . The hairs of the mesepisternum tend to be dark brown in Osmia nearctica, while in Osmia xanthomelana the hairs tend to be pale yellow to white, and the hairs of the hypostomal area tend to be denser in Osmia nearctica than in Osmia xanthomelana.In the Palearctic, roughout ; the lower tooth of the mandible is only slightly longer than the upper tooth in Osmia nearctica ; T7 midapically has a shallower emargination in Osmia nearctica ; and the apical tip of the gonoforceps is more rounded in Osmia nearctica . Osmia nearctica can be differentiated from Osmia maritima and Osmia alticola by the microscopic hairs on the underside of thePageBreak flagellar segments .In males, the propodeal triangle is weakly shagreened throughout in earctica , and dorsal surfaces of T2, T5, T6; almost entirely white to yellow, minutely branched hairs on vertex (sometimes), mesoscutum, mesoscutellum, metanotum, dorsally on propodeum (excluding triangle), pronotal lobe, and dorsal surface of T1; brown, simple hairs interspersed with minutely branched hairs on most of body, except simple hairs lacking on dorsal mesosoma; simple hairs only (no branched hairs), golden on all tarsi and brown on scopa; brown, short, simple hairs evenly covering forewing. Galea and basal two labial palpal segments with hairs on lateral margins straight, 0.2\u20130.5 OD in length. Labrum with long hairs arranged in two curved, transverse rows, along subapical margin and approximately at midpoint, with additional fringe of shorter hairs at apical margin. Clypeus with hairs about as dense as on frons. Hypostomal area with hairs densely distributed across area, straight to weakly incurved at apical tips, 3.0\u20134.0 OD in length.Head and mesosoma with punctures nearly contiguous, more or less round, and moderately impressed except as follows: labrum mostly impunctate except near fringes of hairs; clypeus with impunctate midapical truncation about length of F2 or little longer ; mesoscuPageBreak margin of third tooth forming distinct V-shape with adjacent margin of second and slightly smaller V-shape with adjacent margin of fourth, third tooth more or less on same plane as second and fourth , golden on all tarsi and brown on scopa; brown, short, simple hairs evenly covering forewing. Galea and basal two labial palpal segments with hairs on lateral margins straight, 0.2\u20130.5 OD in length. Labrum with long hairs arranged in two curved, transverse rows, along subapical margin and approximately at midpoint, with additional fringe of shorter hairs at apical margin. Clypeus with hairs about as dense as on frons. Hypostomal area with hairs densely distributed across area, straight to weakly incurved at apical tips, 3.0\u20134.0 OD in length.Head and mesosoma with punctures nearly contiguous, more or less round, and moderately impressed except as follows: labrum mostly impunctate except near fringes of hairs; clypeus with impunctate midapical truncation about length of F2 or little longer ; mesoscuPageBreak margin of third tooth forming distinct V-shape with adjacent margin of second and slightly smaller V-shape with adjacent margin of fourth, third tooth more or less on same plane as second and fourth \u201c[Canada] Norman Wells, N.W.T. [Northwest Territories], 13-VII-1949, W.R.M. Mason// Holotype male CANADA: MANITOBA, Winnipeg Capitol Region, Kettle Rapid, near Winnipeg, 14 July 1917 ; NORTHWEST TERRITORIES, Dehcho Region, Hay River, 5 June 1951, P. R. Ehrlich ; Inuvik Region, Reindeer Depot, MacKenzie Delta, 23 June 1948, W. J. Brown , 16 July 1948, J. R. Vockeroth ; Sahtu Region, Norman Wells, 19 May 1953, C. D. Bird , 27 May 1953, C. D. Bird , 12 June 1949, W.R.M. Mason , 3 July 1949, W.R.M. Mason , 4 July 1949, W.R.M. Mason ; NUNAVUT, Kitikmeot Region, Coppermine, 3 August 1951, S. D. Hicks ; ONTARIO, Thunder Bay District, Black Sturgeon Lake, 13 June 1961 ; QUEBEC, Nord-du-Qu\u00e9bec Region, Rupert River, 10 July 1956, J. R. Lonsway ; YUKON, Dempster Highway km 465, 15 July 1982, D. Wood .The name \u201cnearctica\u201d is derived from the Greek arktikous, meaning northern or arctic, and is in reference to the known distribution of this species in northern regions of the New World .(Zetterstedt)Anthophora nigriventris Osmia nigriventris (Zetterstedt); Osmia baicalensisOsmia dimidiata Morawitz]; Osmia dimidiata Morawitz, synonymy with Osmia nigriventris (Zetterstedt)]. Osmia frigida PageBreakOsmia hudsonica Osmia corticalis Osmia (Melanosmia) nigriventris (Zetterstedt); Osmia (Centrosmia) nigriventris (Zetterstedt); Osmia (Centrosmia) nigriventris frigida Smith; Osmia bucephala, but unlike in that species, there is no metallic coloration in the integument of the meso- and metasomata). Males are known by the strongly reflexed apicolateral angles of T5 and T6 .Females of this species are known by the swollen clypeal margin ; it nests in old insect burrows in dead wood and constructs cell partitions and nest plugs with chewed leaves , 21 May 1915 , 25 May 1922 , 3 July 1968, Dryas drummondii , 8 July 1968, Hedysarum sulphurescens , 23 August 1955, 4500 ft ; Central Alberta, 8 June 1921 BRITISH COLUMBIA, Stikine District, 6 June 1955, 2200 ft , 9 June 1955, 2200 ft , 26 July 1955, 2200 ft ; Columbia-Shuswap District, 1 August 1950 , 1 August 1952, 6000 ft , 2 August 1952, 6000 ft ; Peace River District, 11 June 1948 , Thompson-Nicola District, 8 August 1943 ; MANITOBA, Eastman Region, June 1966 ; Northern Region, 31 May 1949 , 3 June 1952 , 12 June 1952 , 19 June 1949 , 26 June 1950 , 29 June 1949 , 5 July 1950 , 10 July 1952 , 13 July 1937 , 15 July 1949 , 17 July 1937 ; NEWFOUNDLAND AND LABRADOR, Great Northern Peninsula, 12 June 1951 ; NORTHWEST TERRITORIES, Dehcho Region, 31 May 1969 , 5 June 1951 , 5 JunePageBreak 1969 ; Inuvik Region, 13 June 1956 , 16 June 1956 , 18 June 1956 , 21 June 1910 , 22 June 1948 , 22 June 1956 , 25 June 1948 , 26 June 1948 , 27 June 1948 , 28 June 1956 , 29 June 1956 , 2 July 1948 , 3 July 1956 , 7 July 1948 , 10 July 1948 , 18 July 1948 , 25 July 1957 ; North Slave Region, 9 July 1949 ; Sahtu Region, 9 June 1949 , 12 June 1949 , 18 June 1948 , 3 July 1972 ; ONTARIO, 17 May 1962, Chamaedaphne sp. ; Kawartha Lakes, 24 May 1964, Taraxacum officinale , 10 June 1964, Taraxacum officinale ; QUEBEC, Nord-du-Qu\u00e9bec Region, 12 June\u20138 August 1987 , 19 June 1956 , 25 June 1956 , 25 July 1954 ; C\u00f4te-Nord Region, 7 July 1948 ; YUKON, 22 May 1951 , 28 May 1951 , 29 May 1951 , 1 June 1951 , 2 June 1951 , 5 June 1951 , 15 June 1960 , 15 June 1980 , 17 June 1960, 3200 ft , 19 June 1960, 3000 ft , 22 June 1982 , 23\u201325 June 1980, 800 m , 27 June 1960, 3300 ft , 27 June 1984 , 29 June 1984 , 1 July 1949 , 1\u20134 July 1973 , 1\u20135 July 1987, 720 m , 9 July 1983, 2300 ft , 9 August 1981 ; RUSSIA: Siberia, 3 July 1992, Vaccinium vitis-idea ; USA: ALASKA, Fairbanks North Star Borough, 5\u201313 May 2009 , 7 May 1982, Pulsatilla patens , 5 June 1987, Hedysarum mackenziei , 28 June 1987, Hedysarum sp. ; Southeast Fairbanks Census Area, 22 May 1985, Arctostaphylos uva-ursi , 27 July 1982, Aster sibiricus ; Yukon-Koyukuk Census Area, 30 June 1991, Hedysarum boreale ; IDAHO, Lemhi Co., 20 July 1963 ; MICHIGAN, Marquette Co., 18 May 1982, Amelanchier bartramiana , 19 May 1982, Amelanchier bartramiana ; MONTANA, Carbon Co., 22 June 1981, 6200 ft , 11 July 1963, 5200 ft ; OREGON, Deschutes Co., 19 July 1927, 5500 ft ; WASHINGTON, Okanogan Co., 2 July 2004 ; WYOMING, Fremont Co., 28 June 1990, 10400 ft, Arctostaphylos uva-ursi , 30 June 1990, 10500 ft ; Johnson Co., 22 July 1998 ; Teton Co., 14 July 1930 .19 July 1955 , 28 July 1955 ;"} +{"text": "There were errors in the author affiliations. The affiliations should appear as shown here: 1 Department of Genetics, Biological faculty, M.V. Lomonosov Moscow State University, Moscow, Russia, 2 Evolutionary Genomics Laboratory, Faculty of Bioengineering and Bioinformatics, M.V. Lomonosov Moscow State University, Moscow, Russia, 3 A.A. Kharkevich Institute for Information Transmission Problems, Russian Academy of Science, Moscow, Russia"} +{"text": "Cronobacter helveticus, Cronobacter pulveris, and Cronobacter zurichensis are newly described species in the Cronobacter genus, which is associated with serious infections of neonates. This is the first report of draft genome sequences for these species. Cronobacter genus until recently consisted of seven species, C. sakazakii, C. malonaticus, C. turicensis, C. universalis, C. muytjensii, C. dublinensis, and C. condimenti . Therefore, the genome sequencing of these newly described species is warranted for better understanding of the genus diversity and improved detection methodology. This was undertaken using C. helveticus strain LMG23732T, C. zurichensis strain LMG23730T, and C. pulveris strain LMG24059 isolated from powdered infant formula.The ndimenti . In 2013De novo assembly was performed using Velvet and sequenced using an Illumina HiSeq 2500 sequencing system. g Velvet . For furg Velvet .C. helveticus LMG23732T, C. pulveris LMG24059, and C. zurichensis LMG23730T generated 8,351,512, 5,000,582, and 6,613,368 high-quality paired-end reads of 150 bp in length, respectively. The genome sizes were 4,530,369 bp, 4,900,556 bp, and 4,246,797 bp with G+C contents of 56%, 56.6%, and 57.8%, respectively. These were in 79, 125, and 103 contigs with 4,315, 4,630, and 3,883 coding sequences (CDS), respectively, and 30-fold coverage. The CDS include traits previously described in Cronobacter (C. helveticus, C. pulveris, and C. zurichensis have been deposited in GenBank under the accession numbers AWFX00000000, AWFY00000000, and AWFZ00000000, respectively.The genome sequences of"} +{"text": "AbstractXantholinus in North America. Xantholinus elegans (Olivier 1795) (= X. jarrigei Coiffait 1956)is recorded from North America for the first time, based on specimens collected in Ontario, Canada from 2007-2010. The armature of the internal sac of the aedeagus in situ is illustrated to aid in identification. Xantholinus linearis (Olivier 1795), known previously from the Maritime Provinces of Canada and the eastern United States, is newly recorded from Ontario. Xantholinus longiventris Heer 1839 is still only known from western North America. A key is provided to allow recognition of all three species.New distributional and bionomic data are provided for species of the genus Xantholinus Dejean (Staphylininae: Xantholinini) is a diverse, mainly Palearctic group and contains several species that prefer open, disturbed areas, where they often dominate the staphylinid assemblage (PageBreaksubsequent establishment of Xantholinus species into North America. Xantholinus linearis (Olivier 1795) from both eastern and western portions of the North America and Xantholinus longiventris (Olivier 1795) only from western regions. Since then, several publications have presented either new provincial and state records, or additional locality data for these two species was prepared for examination as in Xantholinus elegans was taken with the same system. Maps were created using ARC-GIS and Abode Photoshop software. The institutions (and their abbreviations) from which material was examined are as follows:The aedeagus of Agriculture and Agri-Food Canada, Prince Edward Island, Canada (Christine Noronha)ACPECape Breton University, Sydney, Nova Scotia, Canada CBUChristopher G. Majka Collection, Halifax, Nova Scotia, Canada (Christopher G. Majka)CGMCUniversity of Guelph, Guelph, Ontario DEBUUniversity of New Hampshire, Durham, New Hampshire, USA DENHDavid H. Webster Collection, Kentville, Nova Scotia, Canada (David. H. Webster)DHWCNew Brunswick Museum, Saint John, New Brunswick, Canada NBMNova Scotia Museum, Halifax, Nova Scotia, Canada (Christopher G. Majka)NSMCNova Scotia Department of Natural Resources, Shubenacadie, Nova Scotia, Canada (Jeffrey Ogden)NSNRSaint Mary\u2019s University, Halifax, Nova Scotia, Canada (Doug Stongman)SMUPageBreakUniversit\u00e9 de Moncton, Moncton, New Brunswick, Canada (Pauline Duerr)UMNB(Olivier 1795)Staphylinus elegansXantholinus elegans: All specimens studied are deposited in DEBUCANADA: ONTARIO: Peterborough County: 5 Km SW of Marmora, under fresh horse dung, 31-VII-2010, A. Brunke (1).Waterloo Region: Blair, Rare Charitable Research Reserve, near Whistlebare Rd., soybean field, pitfall trap, 27-VII-2010, A. Brunke (1); Wellington County: Arkell, Arkell Research Station, under loose sod beside canola field, 20-VII-2007, A. Brunke (1); Eramosa, Eramosa Rd. and Wellington Rd. 29, soil in agricultural field, corn in previous year, 8-VI-2010, A. Brunke (1); Eramosa, Eramosa Rd. and Wellington Rd. 29, soybean field, pitfall trap, 13-VII-2010, A. Brunke (1); Eramosa, Eramosa Rd. and Wellington Rd. 29, soybean field, pitfall trap, 10-VIII-2010, A. Brunke (1); Guelph, Gordon St. and Wellington Ave, on sidewalk near dry field, 23-VIII-2008, A. Brunke and D.K.B. Cheung (1); Guelph, Arboretum, woods edge in leaf litter, 11-IX-2008, M. Bergeron, S. Paeiro and D.K.B. Cheung, (1); Guelph. University of Guelph campus, under rocks, 22-VII-2009, C. Ho and S.P.L. Luk, (2); Guelph, Victoria Rd. and Conservation Line, soybean field, pitfall trap, 4-VIII-2009, A. Brunke, (1). Guelph, Stone Rd., heavily disturbed forest edge under rock, coll. as larva 10-IV-2010, emerged 15-V-2010, A. Brunke (1).Xantholinus elegans is newly recorded from North America based on the above specimens collected near Guelph and near Marmora, Ontario, Canada (Xantholinus jarrigei Coiffait in Xantholinus elegans (Olivier) by Oniscus asellus, although the larva was never observed to feed., Canada . Dissect(Olivier 1795)Staphylinus linearisXantholinus linearis: CANADA: ONTARIO: Huron County: Auburn, 1km NE of Baseline Rd. and Londesboro Rd., wooded hedgerow, pitfall trap, 23-XI-2009, A. Brunke (1); AuPageBreakburn, Hullett-McKillop Rd. nr. Limekiln Rd., soybean field, pitfall trap, 4-VIII-2010, A. Brunke (1); Goderich, Sharpes Creek Line, wooded hedgerow, pitfall trap, 19-X-2009 (1), 16-XI-2009 (1), A. Brunke. Waterloo Region: Blair, Dickie Settlement Rd. nr. Whistlebear Golf Club, pitfall trap, soybean field, 15-XI-2009, A. Brunke (1); wooded hedgerow, 10-XI-2009, (1), 24-XI-2009 (15), A. Brunke; Blair: rare charitable research reserve, Fountain St. and Limerick Rd., pitfall trap, soybean field, 15-IX-2009, A. Brunke (1), wooded hedgerow, 27-X-2009 (2), 10-XI-2009 (6), 24-XI-2009 (14), A. Brunke; Blair, nr. Whistlebare Rd., soybean field, pitfall trap, 29-VI-2010 (2), 13-VII-2010 (6), 27-VII-2010 (2), A. Brunke; Wellington County: Eramosa, Eramosa Rd. and Wellington Rd. 29, agricultural hedgerow, pitfall trap, 18-V-2010, A. Brunke (1); Guelph, University of Guelph, debris under dead hawk, 27-VI-2008, A. Brunke (1), under patio stone, 2-IV-2009, S.P.L Luk (1), leaf litter in woodlot, 2-IV-2009, A. Brunke (1), on brick wall, 9-XI-2009, S.P.L Luk (1); Guelph, Victoria Rd. and Conservation Line, wooded hedgerow, pitfall trap, 20-X-2009 (2), 17-XI-2009 (2), A. Brunke.Xantholinus linearis is newly recorded from Ontario based on numerous recent collections from the southern portion of the province. Specimens were collected mainly in agricultural or urban settings in open or forest edge habitat. The earliest Canadian records are from 1949 (in Nova Scotia and Newfoundland) and the earliest NorthPageBreak American ones are from 1930 (in Washington state) (Xantholinus linearis is summarized in n state) . The curHeer 1839Xantholinus longiventrisXantholinus longiventris: Xantholinus longiventris is summarized in The current distribution of Xantholinus elegans is certainly a recent accidental introduction to North America as it was not included in Xantholinus elegans is distributed widely in the western Palearctic region and recorded from Austria, Belgium, Bosnia Herzegovina, Czech Republic, France, Great Britain, Germany, Hungary, Ireland, Italy, Luxembourg, The Netherlands, Poland, Slovakia and Spain (nd Spain . In Eurond Spain . While mMarmora) represenXantholinus linearis was intercepted twice in soil with primrose and moss shipments from Europe in the 1930\u2019s . Further survey work is needed to fully delimit the eastern range of this species.Xanthlinus longiventris is still known only from the western United States and has not been reported from additional states or any provinces since it was treated in Xantholinus longiventris, while it often co-occurs with Xantholinus linearis, prefers a higher level of moisture as it has not been collected from drier urbanized places where the latter species is often found. This species\u2019 range in North America is probably confined by the Rocky Mountain system and will likely remain stable in the absence of secondary introductions.Xantholinus are now known to have established themselves in North America via human activity. Of these, at least Xantholinus linearis is apparently continuing to expand its distribution towards the centre of the continent and may be detected in additional provinces and states in the future. This paper provides a current synthesis of distributional information and facilitates the identification of a previously unrecognized species for the North American fauna. A complete review and identification manual for the entire Xantholinini in eastern North America is currently in preparation.Three species of"} +{"text": "The authors wish to add the following to the Competing Interests Section: \"Dr. Wiendl has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec/Elan Corporation, Sanofi-Aventis, Merck Serono, and Teva Pharmaceutical Industries Ltd.; has served/serves as a consultant for Merck Serono, Medac, Inc., Sanofi-Aventis/Teva Pharmaceutical Industries Ltd., Biogen Idec, Bayer Schering Pharma, Novartis, and Novo Nordisk; and receives research support from Bayer Schering Pharma, Biogen Idec/Elan Corporation, Sanofi-Aventis, Merck Serono, and Novo Nordisk.\""} +{"text": "J Neuroinflammation 2010, 7:3.Correction to Dirscherl K, Karlstetter M, Ebert S, Kraus D, Hlawatsch J, Walczak Y, Moehle C, Fuchshofer R, Langmann T. Luteolin triggers global changes in the microglial transcriptome leading to a unique anti-inflammatory and neuroprotective phenotype. The authors observed that the original study contains"} +{"text": "After publication of this work , we noteThe authors declare that they have no competing interests.Conceived and designed the experiments: LMB, MLB, KGA, RFG. Performed the experiments: LMB, MLB, KGA, EMZ. Analyzed the data/critical review of manuscript: LMB, MLB, KGA, JNG, JSS, JER, DSG, VNR, PCS, RFG. Contributed reagents/materials: IJM, LAH. Provided medical/outreach/case investigation support in Sierra Leone: LMM, JJB, DSG, VNR, MF. Wrote the manuscript: LMB, MLB, KGA, JNG, RFG. All authors have read and approved the final manuscript."} +{"text": "Lichen planus (LP) is a common T-cell-mediated chronic inflammatory disease of the stratified squamous epithelium, with unknown etiology. It can affect oral mucosa, the skin, genitalia, hair follicles, nails, esophagus, urinary tract, nasal mucosa, larynx and even the eyes . Local c"} +{"text": "AbstractStaphylinidae (Rove Beetles) from northeastern North America deposited in the University of Guelph Insect Collection were curated from 2008\u20132010 by the first author. The identification of this material has resulted in the recognition of thirty-five new provincial or state records, six new Canadian records, one new record for the United States and two new records for eastern Canada. All records are for subfamilies other than Aleocharinae and Pselaphinae, which will be treated in future publications as collaborative projects. Range expansions of ten exotic species to additional provinces and states are reported. The known distributions of each species in northeastern North America are summarized and presented as maps, and those species with a distinctive habitus are illustrated with color photographs. Genitalia and/or secondary sexual characters are illustrated for those species currently only identifiable on the basis of dissected males. The majority of the new records are in groups that have been recently revised, demonstrating the importance of curation and local insect surveys to the understanding of biodiversity, even for taxa and areas considered \u2018relatively well-known\u2019. Staphylininae, Tachyporinae, Steninae, Pselaphinae and to some degree Omaliinae, modern monographs by in early 2010 further augmented this material. Previously deposited at the University of Waterloo, this collection of mostly Coleoptera has strengths in the subarctic, boreal and eastern deciduous fauna of Canada. Most Staphylinidae at DEBU were inadequately curated and mostly unidentified prior to recent curatorial work by the senior author, but now all rove beetles in the collection are identified at least to the genus level (except the Aleocharinae and Pselaphinae) and a large proportion of identified specimens are now entered into the central database. We here report on the faunistic discoveries made in the process of curating this material and discuss their importance in the context of previous knowledge. Known distributions are summarized for each species and those species with a distinctive habitus are illustrated to aid in their identification. Where necessary, the aedeagi and/or secondary sexual characters of species are illustrated. Identification of the Pselaphinae and Aleocharinae at DEBU is in progress and future publications on these subfamilies are planned.Although the University of Guelph Insect Collection (DEBU) is Canada\u2019s third or fourth largest collection of invertebrates, relatively few of its staphylinid specimens were considered in the course of the above-mentioned revisions. We assume this oversight was due to the collection\u2019s reputation for its coverage of Nearctic and Neotropical PageBreak water after preparation following Specimens were examined with a WILD Heerbrugg M5A stereomicroscope and dissections of male genitalia and genital segments of both sexes were performed in distilledErichson, 1840CANADA: ON: Chatam-Kent Co., Tilbury, pitfall trap, 9-VI-1994 (2), T. Sawinksi; Essex Co., Leamington, pitfall trap, 15 to 22-V-1992 (1), 22-V-1992 (1), 9-VI-1993 (1), Palichuck; Point Pelee Natl. Pk., Visitor Centre, malaise and pans, 22 to 29-V-2000, (2), 26-IX to 10-sX-2000 (1) O. Lonsdale. Huron Co., Auburn, Londesboro Rd. nr. Hwy 8, 43.728, -81.529, hedgerow, pitfall, 26-X-2009, A. Brunke (1); Benmiller, Sharpes Creek Line, 43.691, -81.608, hedgerow nr. creek, pitfall, 2-XI-2009, A. Brunke (1); Brucefield, London Rd. nr. Centennial Rd., 43.509, -81.516, hedgrerow nr. creek, pitfall, 27-IX-2009 (1), 12-X-2009 (4) A. Brunke; Waterloo Reg., Blair, Dickie Settlement Rd. nr. WhistleBear golf course, 43.373, -80.400, hedgerow, pitfall, 28-IX-2009 (6), 13-X-2009 (2) A. Brunke; Blair, Dickie Settlement Rd. nr. WhistleBear golf course, 43.373, -80.400, hedgerow, canopy trap in buckthorn, 10-XI-2009, A. Brunke (1); Blair, Fountain St. S. nr Speed River, 43.391, -80.373, hedgerow, pitfall, 24-XI-2009, A. Brunke (1); Blair, Whistlebare Rd. and Township Rd.1, 43.372, -80.362, hedgerow, canopy trap in buckthorn, 18-V-2010, A. Brunke (2); Blair, Whistlebare Rd. and Township Rd.1, 43.372, -80.362, hedgerow, pitfall, 1-VI-2010, A. Brunke (1); Blair, Whistlebare Rd. and Township Rd. 1, 43.367, -80.358, hedgerow, canopy trap in buckthorn, 18-V-2010 (1), 21-IX-2010 (1), A. Brunke; Blair, Whistlebare Rd. and Township Rd. 1, 43.367, -80.358, hedgerow, pitfall, 5-X-2010, A. Brunke (1); St. Jacobs, \u2018Stuart pitfall\u2019, 3-VI-1993 (1), 14-VI-1994 (1), T. Sawinksi.Omalium currently lacks a rigorous definition and consists of a heterogeneous assemblage of species CANADA: ON: Thunder Bay Distr. Pukaskwa Natl. Pk. beach trail, dunes, 30-VII-2003, S.M. Paiero (1).Porrhodites inflatus (Hatch), the only other member of the genus in North America, by the combination of: pronotal margins evenly arcuate; metasternum without microsculpture; antennomere two distinctly longer than segment three (Campbell 1984) (This species can be readily distinguished from ll 1984) .Porrhodites fenestralis is a holarctic, boreal to subarctic species known in the Nearctic region from Alberta, British Columbia, Manitoba, Newfoundland, Northwest Territories, Quebec, Yukon Territory, and Alaska, with a relict population in the Rocky Mountains of Montana and Wyoming (Campbell 1984).In the Palaearctic PageBreakit is known from Austria, Czech Republic, Finland, Germany, Italy, Norway, Russia , Sweden, and Switzerland tree (Campbell 1984). Another specimen was found in a deer mouse (Pteromyscus) nest (Campbell 1984).tzerland . Ganglbatzerland . The newCANADA: ON: Bruce Co., Dorcas Bay, dunes, pans under malaise, 5 to 13-VI-1999, S.A. Marshall (1).Ischnosoma flavicolle is easily distinguished from others of the genus by the distinctly bicolored elytra that each lack a humeral spot IschnosomIschnosoma flavicolle is frequently collected from sifted litter in a variety of forest types, and hammocks in the southern extremes; it has also been found in grasslands, carrion, under bark .Sepedophilus campbelli is distinguished from other species of the genus in northeastern North America by the combination of: pronotum and elytra withoutPageBreak microsculpture and without pale or reddish markings; small size ; middle-tibia with two apical spines; basal abdominal segments with long lateral bristles.Sepedophilus micans), eight specimens were known from scattered localities in Alabama, Maryland, District of Columbia, and North Carolina. Recently, five specimens of Sepedophilus campbelli were found in Cuivre River State Park, Missouri, at blacklight and under bark UNITED STATES: NH: Coos Co., Jefferson, under bark, 20-IV-2010, T. Murray (1).CANADA: ON: Essex Co., Kingsville, 14-V-1973, R. Roughly (1); Waterloo Reg., Blair, RARE, Cruickston Creek, yellow pan traps, 15 to 20-VI-2006, S.A. Marshall and M. Bergeron (1); Blair, Dickie Settlement Rd. nr. WhistleBear golf course, 43.373, -80.400, hedgerow, pitfall, 13-X-2009 (1), 10-XI-2009 (1), A. Brunke;Blair, Fountain St. S. nr Speed River, 43.391, -80.373, hedgerow, pitfall, 13-X-2009 (1), 10-XI-2009 (1);Blair, Whistlebare Rd. and Township Rd.1, 43.372, -80.362, hedgerow near soybean field, pitfall trap, 2-XI-2010 (2); Wellington Co., Arkell, 27-IX-1986, L. Work (1); Belwood Lake, lake margin, fallen log overhang, 3-VI-2008, S.A. Marshall (1); Eramosa, Wellington County Rds. 124 and 29, 43.615, -80.215, hedgerow, pitfall, 4-V-2010, A. Brunke (1); Guelph, 19-V-1981, G.M. Grant (1); Guelph, in rotten wood, 20-IV-2007, S.P.L. Luk (1); Guelph, Preservation Park, under bark, 21-IX-2010, S.P.L. Luk (1).Sepedophilus marshami may be distinguished from all other members of the genus in eastern North America except Sepedophilus testaceus by the following combination of characters: body size large ; tergite seven with a white, apical, palisade fringe and at least one pair of bristles; elytra reddish but without distinct, reddish basal markings; middle-tibia with two apical spines . This species is widespread in the Palaearctic region CANADA: ON: Huron Co., Benmiller, Sharpes Creek Line, 43.691, -81.608, hedgerow nr. creek, canopy trap in buckthorn, 22-VI-2009, A. Brunke (1); Elgin Co., Orwell, 15-VI-1978, D. Morris (1); Essex Co., Point Pelee Natl. Pk., wood area by W beach, malaise/pan traps, 10 to 23-IX-1999, O. Lonsdale (1); Hald.-Norfolk Reg.,Turkey Point Provincial Park, malaise trap, 3 to 28-VIII-2009, S. Paiero (1); Kent Co., Rondeau Prov. Park, spicebush trail, 42\u00b018'9N, 81\u00b051'6W, Carolinian forest, WPT, 16to17-VI-2003, Paiero and Carscadden (1); Wellington Co., Guelph, University arboretum nature reserve, ex. Beech litter, 3-V-2009, Brunke and Cheung (1); Guelph, Victoria Rd. and Conservation Line, 43.580, -80.275, hedgerow, pitfall, 2-VI-2009, A. Brunke (1).Sepedophilus occultus can be distinguished from other northeastern Sepedophilus with a reddish area at the base of each elytron by the combination of: basal abdominal segments with short bristles only; elytral epipleuron with few or no setae on its basal half; pronotum uniformly colored; elytra without coarse bristles laterally; apical ctenidium of mesotibia restricted to the apex CANADA: ON: Hald.-Norfolk Reg., Backus Tract Woods, sifting leaf litter under mushrooms, 7-VI-2009, A. Brunke and L. DesMarteaux (5); Backus Tract Woods, sifted litter in sugar maple-dominated, mesic forest, 2-IV-2010, A. Brunke (1); Kent Co., Rondeau Prov. Pk., spicebush trail, carolinian forest, malaise, 16 to 29-VII-2003, S. Marshall et al. (1); Rondeau Prov. Pk., south point trail, slough forest, sifting leaf litter, 27-IX-2009, A. Brunke and D.K.B. Cheung (1). Lambton Co., Pinery Prov. Pk., Carolinian Trail, hardwood forest, litter around white pines, 17-IV-2010, A. Brunke (3).Sepedophilus opicus can be distinguished from other members of genus in northeastern North America by a combination of: base of elytra with reddish markingsPageBreak extending laterally to the margin; basal abdominal segments with long bristles; elytral epipleuron uniformly setose; pronotal microsculpture distinct in Backus Tract Woods, Ontario and this may be a preferred microhabitat.This widely distributed species is known from Alabama, Florida, Illinois, Indiana, Iowa, Maryland, Massachusetts, Michigan, Missouri, New Jersey, New York, North Carolina, Pennsylvania, Qu\u00e9bec, Texas, and Virginia . Herein CANADA: ON: Kent Co., Rondeau Prov. Pk., spicebush trail, Carolinian forest, malaise, 3 to 16-VII-2003 (1), 15-VIII to 7-IX-2003 (1), Marshall et al., 16 to 29-VII-2003, S.A. Marshall (1).Sepedophilus versicolor can be easily separated from others of the genus except Sepedophilus crassus and Sepedophilus ctenidialis by the apical ctenidium of the mesotibia, which extends upwards along the lateral edge .ral edge . It is bSepedophilus crassus and in a \u2018rotten stump with a small nest\u2019 UNITED STATES: MA: Middlesex Co., Groton, 22-IV-2010, T. Murray (1).Tachinus corticinus is easily distinguished from congeners in northeastern North America by the combination of: pronotum and elytra lacking microsculpture; pronotum with at least borders paler than head; female tergite eight with all lobes of similar size; male sternite seven without apical lobes; small size (3.00\u20133.75 mm from clypeus to apex of elytra).PageBreak, New Brunswick, Prince Edward Island .This exotic species was first collected in North America in St. Cyrville, Qu\u00e9bec in 1967 and was first recognized in North America by d Island and Ontad Island . Herein d Island . Tachinuc region and has c region , LevesquPageBreakCampbell, 1979CANADA: ON: Huron Co., Benmiller, Sharpes Creek Line, 43.691, -81.608, soybean field, pitfall, 18-IX-2009, A. Brunke (1).UNITED STATES: NH: Coos Co., Dixville, leaf litter, 6-IV-2010, T. Murray (1); Jefferson, leaf litter, grassy area near stream, 20-IV-2010, T. Murray (1); Dixville, 4-V-2010, T. Murray (4). MA: Middlesex Co., Groton, sifting hay, flood debris in farm field nr. drainage ditch, 30-IV-2010, T. Murray (1). VT: Orange Co., Topsham, sweeping low vegetation, 22-VI-2010, T. Murray (1).Tachyporus browni can be easily recognized amongst other northeastern Tachyporus by the combination of a bicolored abdomen and elytra without black discal markings .Tachyporus ornatus can be distinguished from all other large northeastern members of the genus except Tachinus lecontei, by the combination of a non-bicolored abdomen and the crisp, dark markings on the elytra. From Tachinus lecontei it is most easily identified by the fine microsculpture of the elytra which produces a strong metallic sheen (the former species completely lacks microsculpture).Alnus\u201d, and the lakeside habitat of the Ontario specimen recorded here suggest an affinity for decaying organic matter near water, but further collecting is necessary to confirm this.PageBreakThis species is transcontinental in North America with a disjunct population in the Rocky Mountains of Colorado. It was previously known from the following states and provinces: Alberta, Colorado, Manitoba, Massachusetts, New Hampshire, New Jersey, New York, North Dakota, Pennsylvania, Qu\u00e9bec, Saskatchewan, and Vermont. Herein we newly record it from Ontario . The onlCasey, 1889CANADA: PEI: Stanhope Beach, National Park, d\u00e9bris v\u00e9g. sur plage (=beach debris), 23-VII-1979 (2) R. Sexton.Bledius neglectus can be identified to the Bledius basalis group of species by the combination of the complete elytral epipleuron, the undivided labrum and the lack of a suture on the epipleuron UNITED STATES: MA: Middlesex Co., Groton, 30-IV-2010, T. Murray, (1).CANADA: ON: Halton Reg., Milton, Derry Rd. and 4th line, grass field, yellow pans, 23 to 24-VI-2001, S. Paiero, (1); Huron Co., Auburn, Hullett-McKillop Rd. nr. Limekiln Line, 43.744, -81.507, soybean field, pitfall, 4-VIII-2010 (1), A. Brunke; Auburn, Limekiln Line, 43.736, -81.506, hedgerow, pitfall, 26-V-2010 (1), A. Brunke; Benmiller, Sharpes Creek Line, 43.691, -81.608, hedgerow nr. creek, canopy trap in buckthorn, 11-V-2009 (2), A. Brunke;Brucefield, London Rd. nr. Centennial Rd., 43.509, -81.516, hedgrerow nr. creek, pitfall, 11-V-2009 (1), A. Brunke; Ottawa, Carleton Place, 12-IX-1992, W. Bennett, (1); Peel Reg., Cooksville, pond margin, 30-V-1993, C. Krupke, (1); Waterloo Reg., Blair, Whistlebare Rd. and Township Rd.1, 43.372, -80.362, hedgerow, pitfall, 18-V-2010 (1), A. Brunke; Wellington Co., Guelph, 10-IX-1980, Y. Deedat; Guelph, 17-IX-1980, Y. Deedat; Guelph, University Arboretum, 1-X-2005, M. Bergeron, (1); Guelph, Victoria Rd. and Conservation Line, 43.580, -80.275, soybean field, canopy trap, 23-VI-2009 (1), A. Brunke; York Reg., Stouffville, V-1982, Brian Brown, (1);PageBreakStenus clavicornis is, at present, only reliably distinguished from congeners in North America by its characteristic aedeagus United States: VA: Giles Co., Ripplemead, Rte. 460 at bridge, flood debris, 11 to 25-V-2008 (6) A. Brunke.Eustilicus tristis is the only northeastern member of the genus and its distinct habitus will readily identify it as a Eustilicus CANADA: ON: Huron Co., Auburn, Hullett-McKillop Rd. nr. Limekiln Line, 43.742, -81.514, hedgerow, pitfall, 26-V-2010 (1) A. Brunke; Auburn, Limekiln Line, 43.736, -81.506, hedgerow, canopy trap in buckthorn, 26-V-2010 (2) A. Brunke; Benmiller, Sharpes Creek Line, 43.691, -81.608, hedgerow nr. creek, pitfall, 11-V-2009 (1) A. Brunke; Muskoka Reg., S. Waseosa Rd., 8-VII-1996 (1)W. J. Crins; Wellington Co., Guelph, 26-V-1978 (1) Ron O. Kreazer; Guelph, under rock, 16PageBreak-III-1983 (1) Brian Brown; Guelph, University Arboretum nature reserve, sifting beech litter, 3-V-2009 (4) A. Brunke and D.K.B. Cheung, sifting litter, 6-VI-2009 (1) A. Brunke; York Co., Toronto, 2-V-1959 (2) R. J. Pilfrey.Medon is in need of revision in North America, and Medon fusculus is currently recognizable in North America only from the characteristic modifications of the male seventh sternite and aedeagus , 7-VII-2010 (6), 21-VII-2010 (4), 1-IX-2010 (1), A. Brunke; Benmiller, Sharpes Creek Line, 43.691, -81.608, hedgerow nr. creek, canopy trap in buckthorn, 22-VI-2009 (1) A. Brunke; Brucefield, London Rd. nr. Centennial Rd., 43.509, -81.516, soybean field, canopy trap, 22-VI-2009 (1) A. Brunke; Waterloo Reg., Blair, Dickie Settlement Rd. nr. WhistleBear golf course, 43.373, -80.400, soybean field, pitfall, 23-VI-2009 (1), 7-VII-2009 (2), 21-VII-2009 (1), A. Brunke; Blair, Fountain St. S. nr Speed River, 43.391, -80.373, soybean field, pitfall, 23-VI-2009 (3),7-VII-2009 (1) A. Brunke; Blair, Whistlebare Rd. and Township Rd.1, 43.372, -80.362, soybean field, pitfall, 13-VII-2010 (4), A. Brunke; Blair, Whistlebare Rd. and Township Rd. 1, 43.367, -80.358, soybean field, pitfall trap, 15-VI-2010 (3), 27-VII-2010 (1), A. Brunke. Wellington Co., Eramosa, Wellington County Rds. 124 and 29, 43.615, -80.215, soybean field, pitfall, 13-VII-2010 (2); Guelph, Victoria Rd. and Conservation Line, 43.580, -80.275, soybean field, pitfall trap, 23-VI-2009 (23), 7-VII-2009 (4), 21-VII-2009 (11), 4-VIII-2009 (1), 18-VIII-2009 (2), 1-IX-2009 (1), 15-IX-2009 (4); Guelph, Victoria Rd. and Conservation Line, 43.580, -80.275, soybean field, vacuum sampled from soybean foliage at 8pm, 16-VII-2009.Scopaeus is greatly in need of revision in North America and thus, Scopaeus minutus can only be recognized currently by the form of the aedeagus CANADA: ON: Huron Co., Auburn, Hullett-McKillop Rd. nr. Limekiln Line, 43.742, -81.514, hedgerow, canopy trap in buckthorn, 26-V-2010 (1); Waterloo Reg., Blair, Whistlebare Rd. and Township Rd. 1, 43.367, -80.358, hedgerow, pitfall, 4-V-2010 (1); Wellington Co., Eramosa, Wellington County Rds. 124 and 29, 43.615, -80.215, hedgerow, pitfall, 4-V-2010 (1).Sunius melanocephalus may be easily recognized among other northeastern members of the genus by the combination of the non-serrate lateral margins of the pronotum and the bicolored body.Sunius melanocephalus is widely distributed ; Simcoe Co., Noisy River, Prov. Nature Res., beaver lodge, 28-IX-2008, S.A. Marshall (1).Acylophorus agilis is reliably separated from others in the diverse Acylophorus pronus - group only by the characteristically shaped paramere of the aedeagus CANADA: ON: Cochrane Dist., N. Moosonee, sandy beach, ridge along coastal marsh, Picea, Populus, Alnus and herbs, pitfall trap, 23-VI-1990, J. Pilny, (1).Bisnius cephalicus is readily distinguished from others of the genus in the northeast by the combination of: body bicolored with orange elytra; pronotum with five punctures in each dorsal row; eyes small, with the space behind them about three times longer UNITED STATES: VA: Giles Co., Mountain Lake, on dead fox squirrel, 11 to 25-V-2008, A. Brunke (3).CANADA: PEI: Long Pond, National Park, milieu mar\u00e9cageux (=marshy environment), 30-VII-1979, R. Sexton (2); West Covehead, d\u00e9bris sur la plage (=beach debris), 25-VII-1979, R. Sexton, (3).Bisnius siegwaldii is easily recognized among other species of the genus in the northeast by the combination of: body not bicolored; elytra dark; pronotum with at least five punctures in each dorsal row; head with punctures arranged to form a \u2018V\u2019 Bisnius sBisnius siegwaldii is a common species found in carrion, dung, rotting fungi, decaying plant matter and wood, moss, and in vegetation near water ; QC: La Valle\u00e9-de-la-Gatinaeu,Martindale, hutte \u00e0 castor (=beaver lodge), 19-IX-1976, R. Sexton (26).This species is easily recognized among others of the genus with a sparsely punctate forebody by its large size and transverse head with slightly converging temples .Erichsonius brachycephalus was previously known from Illinois, Maine, Massachusetts, New Jersey, Texas (PageBreakand Qu\u00e9bec) and suggest that this species is broadly distributed in northeastern North America, reaching its northern limit in southernmost Canada CANADA: PEI: Long Pond National Park, milieu mar\u00e9cageux (=marshy environment), 30-VII-1979, R. Sexton (2).PageBreakErichsonius nanus can be recognized among the other densely punctate species in northeastern North America by its larger size , and the apical portion of the median lobe of the aedeagus, which is distinctly thin and sinuate in lateral view CANADA: ON: Kent Co., Rondeau Prov. Pk., spicebush trail, Carolinian forest, yellow pans, 25-V-2003, M. Buck and S. Paiero (1); Rondeau Prov. Pk., spicebush trail, Carolinian forest, yellow pans, 16 to 17-VI-2003, Buck and Carscadden (1); Wainfleet bog, 8km S of Welland, DIE pt. 1 \u2013north ditch (control), 10 to 24-V-1988, A. Stirling (1); 7 to 13-VI-1988, all collected by A. Stirling: D2H pt. 2 \u2013 \u20181962 zone\u2019(1), D4H pt. 4 \u2013 \u20181980 zone\u2019 (1), D5H pt. 5 \u2013 \u20181985 zone\u2019(1), D5E pt. 5 \u2013 \u20181985 zone\u2019 (1).Erichsonius parcus can be easily distinguished from other northeastern species of the genus with a sparsely punctate forebody, with the exception of Erichsonius pusio, by its small size . Erichsonius parcus could be separated from Erichsonius pusio by the paler coloration, the smaller eyes and the head broader behind the eyes. Head shape was found to be highly variable in both males and females of Erichsonius parcus and this character should not be used to identify this species. However, the length of the pronotum appears to be a reliable character and is subequal to that of the elytra in Erichsonius parcus , District of Columbia, Massachusetts, Louisiana, Virginia , and New \u2018drift\u2019 and at l \u2018drift\u2019 ; all CanSmetana, 1995CANADA: ON: Simcoe Co. Midhurst, forest nr. Neretva St., under bark of large beech trunk, 4-IX-2009, A. Brunke and K. Brunke (1).Gabrius amulius may be recognized by the combination of: large size ; eyes large, with temple that is distinctly less than twice as long as the eye; forebody without a greenish metallic lustre; elytra with sparsely distributed punctures that are separated by two to three times their diameter; area between basal lines on tergites two and three punctatePageBreak in Missouri by Gabrius amulius is almost certainly an uncommon specialist of deciduous or mixed forests.This apparently rare species was known from only five specimens at the time of its description from locCANADA: ON: Huron Co., Auburn, Hullett-McKillop Rd. nr. Limekiln Line, 43.744, -81.507, soybean field, pitfall, 23-VI-2010 (1), 7-VII-2010 (2), A. Brunke; Auburn, Limekiln Line, 43.736, -81.506, soybean field, pitfall, 23-VI-2010 (1), 7-VII-2010 (1), 4-VIII-2010 (1), 18-VIII-2010 (1), A. Brunke; Waterloo Reg., Blair, Dickie Settlement Rd. nr. WhistleBear golf course, 43.373, -80.400, soybean field, pitfall, 23-VI-2009 (1), 7-VII-2009 (1), 21-VII-2009 (6), 4-VIII-2009 (1), A. Brunke; Blair, Dickie Settlement Rd. nr. WhistleBear golf course, 43.373, -80.400, hedgerow, canopy trap in buckthorn, 27-X-2009, A. Brunke (1); Blair, Fountain St. S. nr Speed River, 43.391 -80.373, soybean field, canopy trap, 15-IX-2009, A. Brunke (1);Blair, Whistlebare Rd. and Township Rd.1, 43.372, -80.362, hedgerow, pitfall, 4-V-2010, A. Brunke (1); Blair, Whistlebare Rd. and Township Rd.1, 43.372, -80.362, soybean field, pitfall, 29-VI-2010, A. Brunke (1); Blair, Whistlebare Rd. and Township Rd. 1, 43.367, -80.358, soybean field, pitfall trap, 13-VII-2010 (1), 25-VIII-2010 (1), A. Brunke; Wellington Co., Eramosa, Wellington County Rds. 124 and 29, 43.615, -80.215, hedgerow, pitfall, 4-V-2010, A. Brunke (2); Eramosa, Wellington County Rds. 124 and 29, 43.615, -80.215, soybean, pitfall, 15-VI-2010 (3), 29-VI-2010 (3), A. Brunke; Guelph, Victoria Rd. and Conservation Line, 43.580, -80.275, soybean field, pitfall, 21-VII-2009 (1), 4-VIII-2009 (6), 1-IX-2009 (4), A. Brunke; Guelph, Victoria Rd. and Conservation Line, 43.580, -80.275, soybean field, canopy trap, 4-VIII-2009 (1), 18-VIII-2009 (1), A. BrunkeGabrius appendiculatus can be distinguished from congenersin the northeast by the following combination of characters: area between basal lines on tergites two and three impunctate; basal antennomeres not distinctly paler than rest of antenna; males with sternite eight broadly notched; females with tergite 10 pointed (as opposed to truncate) apically.Gabrius subnigritulus (Reitter)) based on specimens collected as early as 1978 in Ormstown, Qu\u00e9bec and from other localities in British Columbia and Newfoundland; the earliest records from the west coast of North America were from 1979. Gabrius appendiculatus into the southern portion of Ontario from specimens collected in 2009\u20132010 ; Simcoe Co., Noisy River Prov. Pk., Res., beaver lodge, 28-IX-2008, S.A. Marshall (1).Gabrius vindex is easily distinguished from all other species of the genus in northeastern North America except Gabrius astutoides by the combinationPageBreak of: punctures of the elytra dense, separated by their widths or less; size large ; the area between the basal lines of tergites two and three punctate. From Gabrius astutoides it is most easily separated by the shape of the pronotum which is narrowed anteriorly in Gabrius vindex and parallel in Gabrius astutoides.Gabrius vindex from Ontario ; Leamington, pitfall trap, 17-VIII-1993 (1); Huron Co., Centralia, Dev 1A, pitfall, 16-VIII-1992 (1); Middlesex Co., London, southern crop protection research centre, corn pitfalls 3, 19-VII-1993 (1); London, southern crop protection research centre, pitfall/Masner trap, 2-VIII-1995, T. Sawinski (1).Neobisnius in northeastern North America by the combination of head completely lacking microsculpture, elytra with apically paler area limited to a narrow strip, and the maxillary palpi with at least one segment darkened.This species can be distinguished from other orange and black Neobisnius occidentoides is a widespread species and was previously known from Alberta, Alabama, Arkansas, Arizona, California, Colorado, Idaho, Illinois, Kansas, Kentucky, Louisiana, Manitoba, Minnesota, Mississippi, Missouri, Montana, Nebraska, Nevada, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, and Wyoming CANADA: ON: Essex Co.,Middle Is., shore, yellow pans, 11-VI-2003, S.A. Marshall (1); Niagara Reg., Grimsby, J. Pettit (1).PageBreakNeobisnius terminalis is easily recognized among other orange and black species of the genus in northeastern North America by the elytra with a broad, pale apical area was taken in pan traps on a gravel lake shore.This species was previously known from Arizona, California, Colorado, Iowa, Maine, Maryland, Michigan, New Hampshire, New Mexico, New York, Nova Scotia, Pennsylvania, Qu\u00e9bec, Texas, and Virginia . Herein Hatch, 1957CANADA: PEI: Brackley Beach, National Park, milieu mar\u00e9cageux (=marshy environment), 2-VIII-1979, R. Sexton (1); Long Pond, National Park, milieu mar\u00e9cageux (=marshy environment), 30-VII-1979, R. Sexton (2).This species is, at present, best identified by the shape of the median lobe of the aedeagus and branches of the paramere .Philonthus gavius is recognized among other northeastern Philonthus by the combination of: tergite eight distinctly emarginate in both sexes; elytra with most punctures separated by their widths; eyes longer than the temples.Philonthus gavius remain unknown but it is probably a species associated with wet areas similar to most other members of the Philonthus \u2018Quadricollis Group\u2019 sensu PageBreakThis species was previously known from Arkansas, Illinois, Louisiana, Oklahoma, Tennessee, and Texas . It was Hatch, 1957CANADA: PEI: Brackley Beach, National Park, milieu mar\u00e9cageux (=marshy environment), 2-VIII-1979, R. Sexton, (3).Philonthus leechensis may be recognized among other northeastern Philonthus except for Philonthus umbrinoides Philonthus umbrinoides it can be differentiated by the distinct, obtuse hind angles of the head.PageBreakThis species was previously known from Alaska, Alberta, Arizona, British Columbia, California, Colorado, Idaho, Manitoba, Minnesota, Montana, Newfoundland, Northwest Territories, Oregon, Qu\u00e9bec, Saskatchewan, Washington, Wisconsin, and Yukon Territory , 2-VIII-1979, R. Sexton (6).Philonthus lindrothi can be distinguished fromnortheastern congeners other than Philonthus pseudolodes Smetana 1996 by the combination of: pronotum with five punctures in the dorsal row on at least one side; head with hind angles present but rounded; tergite eight not emarginate in either sex; elytra without distinct markings on the disc; hind tarsus with first segment shorter than last segment; antennae with basal segments not distinctly paler than others and with segments seven and eight elongate. Males can be readily separated from Philonthus pseudolodes by the notch in sternite eight not continuing as a grove towards its base .Philonthus neonatus is separated from other northeastern Philonthus by the combination of: pronotum with six punctures in both dorsal rows; pronotum no more than vaguely narrowed anteriorly; elytra distinctly red and without dark markings; elytra with micropunctures between the regular punctures; abdominal segments paler apically.PageBreak Missouri, New Hampshire, New Jersey, New York, Ontario, Pennsylvania, and Qu\u00e9bec , 2-VIII-1979, R. Sexton (13).PageBreakPhilonthus by the combination of: pronotum with punctures widely distributed and not in rows; legs and antennae completely dark; head with hind angles indistinct CANADA: ON: Wellington Co., Guelph, University Arboretum, rotting Polyporus squamosus, 29-VI-2008, A. Brunke (2); Guelph, University campus nr. horse pen, grass sweep, 13-VII-2008, C. Ho (1).Quedius by the combination of: elytra with three rows of coarse punctures on the disc; head without a pair of punctures between the ocular punctures; pronotum with three punctures in each dorsal row CANADA: ON: Essex Co., Windsor, ~1.5km S Ojibway Prairie, forest-prairie edge, malaise trap, 15-V to 1-VI-2001, S. Paiero (1); Windsor, ~1.5 km S Ojibway Prairie, private prairie, malaise, 5 to 12-VI-2001, S. Paiero (3); Windsor, ~1.5km S Ojibway Prairie, private prairie, malaise, 19 to 30-VI-2001, P. Pratt (2); Hald. \u2013Norfolk Reg., Charlotte 2 Rd., ~480m E of Charlotteville, West Quarterline Rd., \u2018C.C.S.N. -5\u2019, purple prism trap, 13 to 19-VI-2009, S.M. Paiero (1); PageBreak Reg.Halton, Milton, Derry Rd. and 4th Line, under composter, 16-X-2008, S. M. Paiero (1); Oxford Co., Woodstock, trails nr. river, 14-VI-2008, S.A. Marshall (1). Simcoe Co., Midhurst, forest nr. Neretva St., 28-IX-2008, A. Brunke and K. Brunke (1); Wellington Co., Guelph, University Campus, dairy bush, dry Polyporus squamosus, 22-IX-2008, A. Brunke (1).Quedius cruentus may be distinguished from other northeastern Quedius by the combination of: elytra evenly punctate; labrum distinctly bilobed; eyes distinctly shorter than temples; antennomeres one to three distinctly paler than others; distal antennomeres strongly transverse; pronotum with sublateral row of punctures longer than dorsal row.Quedius cruentus from Maine, Massachusetts, New Jersey, Ohio, Pennsylvania, and Qu\u00e9bec, and established its presence in North America as early as 1983 in New York. Herein we newly report this species from Ontario .CANADA: ON: \u2018Ont.\u2019, 30-IX-1982, G. Abayo (1); Halton Reg., Oakville, nr hwy 25 and Burhamthorpe Rd., meadow, yellow pans, 12 to 14-IX-2003, S.M. Paiero (1); Hamilton Reg., Hamilton, 3-VIII-1984, M.T. Kasserra (1); Waterloo Reg., Blair, Fountain St. S. nr Speed River, 43.391, -80.373, hedgerow, pitfall, 28-IX-2009, A. Brunke (1); Wellington Co., Eramosa, Wellington County Rds. 124 and 29, 43.615, -80.215, hedgerow, pitfall, 4-V-2010 (1), 18-V-2010 (1), 2-XI-2010 (1), A. Brunke; Guelph, 17-VIII-1976, David Levin (1); Guelph, 7-VI-1983, C.F. Langlois (1); Guelph, University Arboretum, hand collected, 16-III-1983, L.B. Carlson (1); Guelph, 30-IX-1983, A. Harris (1); Guelph, 5-VII-1984, \u2018maple\u2019, T. Young (1); Guelph, 3-IV-1991, M. Kovacevick (1); Guelph, 14-X-1998, T. Phillips (1); Guelph, Victoria Rd. and Conservation Line, 43.580, -80.275, hedgerow, pitfall, 19-V-2009 (1), 17-XI-2009 (1), A. Brunke.Diagnosis. Quedius curtipennis can be distinguished from other northeastern Quedius by the combination of: elytra with even punctation; labrum not bilobed; scutellum impunctate; basal antennomeres not distinctly darker than the other segments CANADA: ON: Huron Co., Seaforth, 7-VII-1955, D. Keys (1).Quedius fulgidus may be distinguished from other northeastern Quedius by the combination of: elytra evenly punctate; labrum distinctly bilobed; eyes distinctly shorter than temples; antennomeres one to three not distinctly paler than others; distal antennomeres only slightly transverse; pronotum with sublateral row of punctures longer than dorsal row.Quedius iracundus but as Quedius iracundus (=Q. fulgidus)was described in 1834 from Indiana, Quedius fulgidus has surely been present long before 1874. Currently, Quedius fulgidus is known from Arizona, British Columbia, California, Colorado, District of Columbia, Georgia, Idaho, Illinois, Indiana, Kansas, Kentucky, Manitoba, Maryland, Massachusetts, Michigan, Minnesota, Mississippi, Missouri, New Jersey, New Mexico, New York, Oregon, Pennsylvania, Texas, Virginia, Washington, West Virginia, Wisconsin and has since become extremely common.This Palaearctic species was first correctly recognized in North America by racundus , a speciisconsin , and Tenisconsin . Herein isconsin . This spisconsin but occuisconsin . In its c region . QuediusPorrhodites fenestralis and Bisnius cephalicus were newly recorded in Ontario, joining previous records from adjacent provinces to suggest a transcontinental distribution. Six staphylinid species were newly discovered in Canada at the northern extreme of their range, two of which are apparently entirely restricted in Canada to the Carolinian ecoregion (Sepedophilus versicolor and Erichsonius parcus). This relatively small area of southernmost Ontario is the most biodiverse region in Canada in northeastern North America were previously fragmentary and were augmented by new data presented herein. Ten exotic species for which we give new state, or provincial, or national records are apparenly appear to be expanding their range in northeastern North America, and have the potential to become widespread across the continent. One of these species, Tachinus corticinus, was first collected in North America in 1967 but now dominates autumn leaf litter staphylinid assemblages in Ontario woodland fragments where it can comprise up to 47% of all individuals . Quedius curtipennis establishes its presence in eastern North America as early as 1976, seven years earlier than previously known.Curation of over 32,000 staphylinids deposited in the University of Guelph Insect Collection resulted in the discovery of thirty-five new provincial or state records, six new Canadian records, one new record for the United States and two new records for eastern Canada. Many of these specimens were aleocharines and a future publication is planned to report on the discoveries made while curating this subfamily. The majority of the records presented herein involved species of which were included in recent revisions (after 1970), suggesting that even of \u2018well-known\u2019 groups, our knowledge of staphylinid distributions remains incomplete. Two boreal beetles, n Canada and has PageBreak rare or or potentially rare insect species, and the effective detection of exotic species, depends on the routine identification of specimens in collections and the regular implentation of regional insect surveys. We recommend increased support for these activities to develop and maintain a clear picture of biodiversity, and biodiversity change, in northeastern North America.The results of this paper demonstrate the key role of curated insect collections in understanding biodiversity in the boreal region, the imperilled \u2018Carolinian\u2019 region in Canada, and northeastern North America in general. An improved understanding of"} +{"text": "AbstractAteleute F\u00f6rster 1869 belonging to the tribe Cryptini of the subfamily Cryptinae , collected from Jiangxi Province, China, are reported, of which two are new for science: Ateleute ferruginea Sheng, Broad & Sun, sp. n. and AAteleute zixiensis Sheng, Broad & Sun, sp. n. One, AAteleute densistriata , was previously known from China and Japan. A key to the species of genus Ateleute known in the Oriental Region is provided.Three species of Ateleute F\u00f6rster 1869, belonging to the subfamily Cryptinae of Ichneumonidae (Hymenoptera), comprises 33 described species , is known in Taiwan, China.The species distributed in Ethiopian Region were reported by Ateleute, collected in Jiangxi Province, P.R. China, are reported.In the last four years the authors have been exploring Jiangxi Province, situated near the northern border of the Oriental part of China, and have collected large numbers of ichneumonids. In this article, the species belonging to Specimens were collected using entomological sweep nets in the forests of Anfu, Ji\u2019an, Longnan, Qianshan, Quannan and Zixi Counties, Jiangxi Province (CHINA).Images of whole bodies were taken using a CANON Power Shot A650 IS. Other images were taken using a Cool SNAP 3CCD attached to a Zeiss Discovery V8 Stereomicroscope and captured with QCapture Pro version 5.1.The morphological terminology is mostly that of The new species were checked against the species described by Type specimens are deposited in the Insect Museum, General Station of Forest Pest Management (GSFPM), State Forestry Administration, People\u2019s Republic of China.F\u00f6rster, 1869http://species-id.net/wiki/AteleuteAteleuteAteleute linearis F\u00f6rster. F\u00f6rster, 1869. Verhandlungen des Naturhistorischen Vereins der Preussischen Rheinlande und Westfalens, 25(1868): 171. Type-species: PsychostenusPsychostenus minusculae Uchida. Uchida, 1955: 32. Type-species: TalorgaTalorga spinipes Cameron; monobasic. Cameron, 1911: 63. Type-species: TsirirellaTsirirella tsiriria Seyrig; designated by Townes, Townes and Gupta 1961. Seyrig, 1952: 44. Type-species: Ateleute can be distinguished from all other genera of Cryptini by combination of the following characters: Apical margin of clypeus sharp, truncate or coPageBreakncave. Lower tooth of mandible as long as or slightly longer than upper tooth. Epomia absent. Genal carina joining base of mandible or joining hypostomal carina near base of mandible. Sternaulus weak and shallow. Posterior transverse carina of mesosternum complete. Areolet large, receiving 2m-cu basal of its middle, 3rs-m absent or almost absent. Hind wing vein M+Cu strongly arched, 2-1A absent or very short. First tergum without median dorsal carina, often with longitudinal wrinkles, spiracle near its middle. Ovipositor sheath about 0.65 times as long as hind tibia. Tip of ovipositor distinctly elongate. Cryptothelea minuscula Butler and Astala confederata (Grote & Robinson) (Psychidae). According to previous records , hosts aSheng, Broad & Sun sp.n.urn:lsid:zoobank.org:act:34931ABC-632E-4AC7-B3CD-44D8BE899142http://species-id.net/wiki/Ateleute_ferruginea The specific name is derived from the terga being entirely brown.Holotype, Female, CHINA: Shuangjiang Forest Farm, Ji\u2019an County, 174 m, Jiangxi Province, 10 May 2009, leg. Lin-Da Li. Paratypes: 2 females, same data as holotype except 24 May 2009. Ateleute ferruginea can be distinguished from all other species of Ateleute by combination of the second tergum having circular, concentric striations http://species-id.net/Ateleute_densistriataPsychostenus densistriatus Uchida, 1955: 33. The propodeum of the female was described as reddish brown . The femPageBreakLin-Da Li. 2 males, CHINA: Matubei, 330 m, Quannan County, Jiangxi Province, 27 May 2009, leg. Shi-Chang Li. 3 males, CHINA: Wuyishan, 1170 to 1200 m, Qianshan County, Jiangxi Province, 22 June to 11 July 2009, leg. Zhi-Yu Zhong. 2 males, CHINA: Quannan County, Jiangxi Province, 4 to 11 October 2009, leg. Shi-Chang Li. 1 male, CHINA: Quannan County, Jiangxi Province, 31 May 2010, leg. Shi-Chang Li. 17 males, CHINA: Jiulianshan, 580 m to 680 m, Longnan County, Jiangxi Province, 20 April to 6 June 2011, leg. Mao-Ling Sheng and Shu-Ping Sun. 1 female, CHINA: Shizikou, 200 m to 210 m, Anfu County, Jiangxi Province, 21 June 2011, leg. Zhong-Ping Yu.PageBreak 1 female 1 male, CHINA: Ji\u2019an County, Jiangxi Province, 21 May 2008, leg. Yi Kuang. 1 male, CHINA: Quannan County, 530 m, Jiangxi Province, 28 May 2008, leg. Shi-Chang Li. 1 male, CHINA: Quannan County, 630 m, Jiangxi Province, 7 November 2008, leg. Shi-Chang Li. 18 males, CHINA: Shuangjiang Forest Farm, 174 m, Ji\u2019an County, Jiangxi Province, 25 April to 15 June 2009, leg."} +{"text": "There were errors in the Author Contributions. The correct contributions are: Conceived and designed the experiments: JC, EM, PH, DB.Performed the experiments: TS.Analyzed the data: AC, ATA, MO.Contributed reagents/materials/analysis tools: PH, WM, SA.Wrote the paper: PH, EM, JC, AC."} +{"text": "AbstractGlenea coomani Pic, 1926 distributed in Vietnam, Laos and China is redescribed, and its sibling species, Glenea neohumerosa sp. n. is described from China and North Vietnam. They are separated from each otherby differences in genitalia, and apical teeth and maculae of elytra. Another four related species and one subspecies are illustrated with short notes and new localities, and the lectotype and paralectotype of Glenea tonkinea Aurivillius, 1925 are designated. A key to the related species is presented. Glenea coomani Pic, 1926 was originally described from North Vietnam, and Glenea humerosa Gressitt, 1940, described from Hainan Island, China had been synonymized with it by PageBreakprisingly found another species, which had been identified as Glenea coomani or Glenea humerosa by predecessors. This new species is distinguishable from Glenea coomani by having different elytral maculae, longer elytral apical teeth, and differing structure of male genitalia. Therefore, we describe Glenea neohumerosa sp. n., and compare it with Glenea coomani which is redescribed. We show the habitus of similar species which are compared with short notes and new localities. The following species are mentioned and keyed: Glenea coomani Pic, 1926, Glenea neohumerosa sp. n., Glenea lacteomaculata Schwarzer, 1925, Glenea lacteomaculata quadriguttata Pic, 1926, Glenea laodice Thomson, 1879, Glenea subalcyone Breuning, 1964, Glenea tonkinea Aurivillius, 1925.Types and other material studied are deposited in the following institutions or private collections:\tBishop Museum, Honolulu, USABM\tCalifornia Academy of Sciences, San Francisco, USACAS\tChina Agricultural University, Beijing, ChinaCAU\tCollection of Wenxuan Bi, Shanghai, ChinaCBWX\tCollection of Chang-chin Chen, Tianjin, ChinaCCCC\tCollection of Ming Jin, Shanghai, ChinaCJM\tCollection of Dong Wen, Qingdao, Shandong, ChinaCWD\tInstitute of Zoology, Chinese Academy of Sciences, Beijing, ChinaIZAS\tMus\u00e9um National d'Histoire Naturelle, Paris, FranceMNHN\tMus\u00e9um d'Histoire Naturelle, Lyon, FranceMHNL\tSwedish Museum of Natural History, Stockholm, Sweden (= Naturhistoriska Riksmuseet Stockholm)NHRS\tNaturhistorisches Museum, Basel, Switzerland NMB\tShanghai Entomology Museum, Shanghai, ChinaSHEM\tSun-Yatsen University, Guangzhou, ChinaSYSUPichttp://species-id.net/wiki/Glenea_coomaniGlenea coomani Pic, 1926: 21(Tonkin). [MNHN]Glenea humerosa Gressitt, 1940: 206, pl. 6, fig. 4 (Hainan). .PageBreakHolotype of China: Yunnan: 1 male, Cheli to Damenglong, alt. 600 m, 1957.IV.22, leg. Dahua Liu (IZAS). Hainan: 1 male, Ledong, 1984.VIII.26, leg. Zhiqing Chen (IZAS). Vietnam: 1 male, Tonkin, Hoa-Binh (MNHN); 1 female, same data but ; 1 male, Tonkin, Hoa-Binh, leg. A. de Cooman (IZAS); 1 female, same data but . Laos: 2 males, Ban Van Heue, 20 km E. of Phou-kow kuei, 1965.V.1\u201315, leg. J. A. Rondon (BM); 18 males 18 females, Phontiou, 1965.V.15 .urn:lsid:zoobank.org:act:9C4BC446-D2E5-4E4E-9BDD-F66245CC93C5http://species-id.net/wiki/Glenea_neohumerosaMale : length:Head hardly broader than prothorax, deeply, and in part closely punctured, feebly concave at vertex. Eyes deeply emarginate, inferior eye lobes subequal to or 2 times as high as genae below it, width much less than half of frons. Antennae longer than body, male longer than female; scape thicknened apical without cicatrix not a ridge; antennomere ratio : 12 : 3 : 18 : 15 : 14 : 13 : 13 : 12 : 12 : 11 : 12; : 13 : 3 : 21 : 17 : 16 : 15 : 14 : 14 : 13 : 12 : 13. Prothorax almost as broad as long or broader than long , swollen laterally before middle, disc convex and somewhat deeply and closely punctured. Elytra rounded at humeri, slightly narrowed apically, each with 2 humeral longitudinal ridges beginning after humeri and reaching close to apex, truncated apically, with short and small teeth at the suture, long and sharp spine at the outer angle, surface with coarse and irregular punctures. Legs stout, middle tibiae grooved, hind femur reaching middle to apex of third abdominal segment, first hind tarsal segment longer than , or nearly as long as following two segments combined. Male claws: the anterior claws of the mid tarsi with a short tooth , fore anPageBreak bifurcated distally; median lobe plus median struts moderately curved, subequal to tegmen in length; the median struts about one half of the whole length of median lobe; dorsal plate shorter than ventral plate; apex of ventral plage .Named derived on similarity to and misidentification as The yellow color of the pubescence turns into white when the specimens are dried.China: Guangxi, Hainan, Fujian; Vietnam (Tonkin).China: Guangxi: 2 males, Jinxiu, Luoxiang, alt. 400 m, 1999.V.14, 15, leg. Decheng Yuan 1859449, 1859447); 1 male, Guangxi, Nanning, Wuming county, Mt. Damingshan , alt. 1200 m, 2011.VII.11, coll. Yanquan Lu (CWD). Hainan: 1 female, Hainan Exp. 1934.IV.18 1859445); 1 male, Hainan Exp. 1934.III.26 1859446); 1 male 1 female, Hainan, Lingshui county, Diaoluoshan, alt. 1000 m, 2010.IV.23, leg. Ziwei Yin (SHEM); 1 female, Hainan, Ledong, Jiangfengling, Mingfenggu, 2011.V.25, alt. 1000 m, leg. Wenxuan Bi (CBWX); 1 female, Hainan, Ledong, 1962.IX.17, leg. Yaoquan Li ; 1 male, Ledong, Jianfengling, Tianchi, 1948.VII.27, leg. Yi Liang . Fujian: 1 female, Wuyishan Nature Reserve, 2009.VII.10\u201317, leg. Ming Jin (CJM). Vietnam: 1 female, Tonkin, Backan, 1907, leg. Lemee 1859450).Holotype: male (10.2 mm long), Guangxi, Jinxiu, Shengtangshan, alt. 900 m, 1999.V.17, leg. Xingke Yang 1859448). Paratypes: Pichttp://species-id.net/wiki/Glenea_lacteomaculata_quadriguttataGlenea 4-guttata Pic, 1926: 22.Glenea (Glenea) lacteomaculataquadriguttata; Breuning, 1956: 743. sbsp. Glenea lacteomaculata Schwarzer, 1925 and Glenea lacteomaculata quadriguttata Pic, 1926 are doubtful for the authors. The specimens from Guangxi and Yunnan provinces are conspecific to Glenea lacteomaculata quadriguttata and herein the new localities are reported.Due to lack of material from Taiwan, the differences between new country record): Guangxi, Yunnan; Vietnam (Tonkin).China . Vietnam: 5 males 4 females, Tonkin occ. Env. de Hoa-Binh, 1919, leg. R.P.A. de Cooman ; 1 male 1 female, Tonkin Env. De Hoa-Binh ; 2 females, Tonkin, HoaBinh, 1939.VII, leg. A. de Cooman .: 1 male , LongzhoBreuninghttp://species-id.net/wiki/Glenea_subalcyoneGleneas. s) subalcyone Breuning, 1964: 20, fig. page 21. (Gleneas. str.) subalcyone; Rondon and Breuning 1971: 535. : Yunnan; Laos.China . [MNHN]Glenea (Glenea) tonkineabasirufofemorata Breuning, 1956: 743 (Tonkin). [MHNL] m. Glenea (Glenea) tonkineaapicetruncata Breuning, 1956: 743 (Tonkin). [NMB] m. Glenea pici Aurivillius in having pubescent maculae white; in having different male claws. Differs from Glenea lacteomaculata Schwarzer in having spot at middle of elytron transverse, anterior claw in mid tarsus of male with long tooth ; Vietnam (Tonkin), Myanmar (new country record).China Glenea (Glenea) tonkinea m. apicetruncata Breuning, male, Tonkin Mts. Mauson, alt. 2000\u20133000 feet, IV\u2013V, leg. H. Fruhstorfer . Type of Glenea (Glenea) tonkinea m. basirufofemorata Breuning, male, Tonkin, Hoa Binh ; paratype, female, same data.Lectotype, male, Tonkin, Hoo Binh (=Hoa Binh) . Paralectotype, female, Tonkin, Ho Bing (=Hoa Binh) (NHRS-JLKB000020243). Holotype of China: Guangxi: 1 male, Longzhou, Nonggang, alt. 330 m, 2000.VI.5, leg. Wenzhu Li (IZAS); 1 male, Longzhou, Shida, 1980.V.24 ; 1 female, Guangxi, Xiashi, 1963.V.7, leg. Jikun Yang (CAU). Vietnam: 1 female, Tonkin, Hoa-Binh (IRSNB); 3 males 3 females, same data but ; 1 male 1 female, Tonkin occ. Env. de Hoa-Binh, 1919, leg. A. de Cooman ; 1 female, Tonkin ; 1 male, Tonkin N. env. D'ha-Giang, 1914, leg. Lieut (MNHN); 1 female, Tonkin Reg. de Hao-Binh, 1927, leg. A. de Cooman (MNHN); 1 female, Tonkin, Baokan, 1907.VIII, leg. P. Lemee ; 1 female, Tonkin centr. Region de Chiem-Hoa et de Tuyen-Quam, 1901, leg. A. WeissPageBreak (MNHN). Myanmar: 1 female, Birmanie (Hte.) Mines des Rubis, alt. 1200\u20132300 m, 1890, leg. Doherty (MNHN).Glenea coomani group by the following characters : pronotum largely black, generally with a white or yellow median stripe; body covered with pubescence instead of metallic squama ; elytron black with an apical spot and 4 or 5 unequal sized spots. They differ from Glenea relicta group by elytral spots (not include the band just before apex) with unequal size and located in different position.The above species are grouped as"} +{"text": "AbstractThe herbarium of University of Extremadura (UNEX Herbarium) is formed by 36451 specimens of vascular plants whose main origin is the autonomous region of Extremadura (Spain) and Portugal, although it also contains a smaller number of specimens from different places, including the rest of peninsular Spain, the Baleares Islands, the Macaronesian region , northwest of Africa (Morocco) and Brazil. 98% of the total records are georeferenced.http://data.gbif.org/datasets/resource/255 and http://www.eweb.unex.es/eweb/botanica/herbario/. This paper describes the specimen associated data set of the UNEX Herbarium, with an objective to disseminate the data contained in a data set with potential users, and promote the multiple uses of the data.It is an active collection in continuous growth. Its data can be accessed through the GBIF data portal at Established in 1986, the specimens that the herbarium of vascular plants collection of University of Extremadura (UNEX Herbarium) incorporates is the result of the work of collections and identifications by different researchers, associated with the Botany Area of the University of Extremadura. Chief amongst these individuals include: Professor Juan Antonio Devesa, founder and director of the herbarium until 2004, and Dr. Trinidad Ruiz, curator and current director of the UNEX Herbarium. Significant contributions have also been made by Professor Ana Ortega-Olivencia, Dr. Rafael Tormo, Dr. Josefa L\u00f3pez, and Dr. Tom\u00e1s Rodr\u00edguez-Ria\u00f1o. Other researchers who contributed to the growth of the UNEX Herbarium includes, M\u00aa Carmen Viera, Jacinto Pedro Carrasco, Adolfo Mu\u00f1oz, Inmaculada Montero, and Francisco M\u00aa V\u00e1zquez. In addition, the disinterested work developed throughout time by a lot of students of the University of Extremadura, especially, M\u00aa Luisa Navarro P\u00e9rez and Dr. Francisco Javier Valtue\u00f1a.http://www.floraiberica.org/). Additionally, 4.5% of the material comes from the purchase of part of the herbarium of Dr. J.V.C. Malato-Beliz.The development of different research projects has made it possible to improve the quality of the herbarium. Among them, the numerous compilations carried out by differents members of the Botany Area in order to elaborate the first flora of the Extremadura region or the sLimited and unpredictable funding has always pose challenge for ensuring sustained growth of the collection facility since its establishment.Magnoliopsida (27143 specimens) and Liliopsida (8508 specimens). These classes are followed by Filicopsida (505 specimens), Lycopsida (138 specimens), Coniferopsida (104 specimens), Equisetopsida (24 specimens), Ophioglossopsida (14 specimens), Gnetopsida (6 specimens), Taxopsida (4 specimens) Cycadopsida and Gingkgopsida (both with 2 specimens), and Psilotopsida (1 specimen).As depicted in Poaceae and Fabaceae family respectively. This is followed by Asteraceae (15%), Scrophulariaceae (6%), Lamiaceae (6%), Caryophyllacae (5%), Brassicaceae (4%), Cyperaceae (4%), Rubiaceae (3%), Ranunculaceae (3%), Liliaceae (3%), Boraginaceae (3%), Apiaceae (3%), and Cistaceae (2%). The herbarium includes 1253 genera (Trifolium (1345 specimens), Ranunculus (623 specimens), Scrophularia (583 specimens), Vicia (537 specimens), Stipa (505 specimens), Galium (479 specimens), Juncus (439 specimens), Vulpia (381 specimens), Medicago (365 specimens) and Bromus (342 specimens).UNEX herbarium represents 210 families, of which 22% and 21% of the specimens belongs to 3 genera , signifiPageBreakKingdom:PlantaePhylum:Pteridophyta, SpermatophytaClass:Magnoliopsida, Liliopsida, Filicopsida, Lycopsida, Coniferopsida, Equisetopsida, Ophioglossopsida, Gnetopsida, Taxopsida, Cycadopsida, Gingkgopsida, Psilotopsida.Family:Acanthaceae, Aceraceae, Adiantaceae, Agavaceae, Aizoaceae, Alismataceae, Amaranthaceae, Amaryllidaceae, Anacardiaceae, Apiaceae, Apocynaceae, Aquifoliaceae, Araceae, Araliaceae, Araucariaceae, Arecaceae, Aristolochiaceae, Asclepiadaceae, Aspidiaceae, Aspleniaceae, Asteraceae, Athyriaceae, Azollaceae, Balanophoraceae, Balsaminaceae, Basellaceae, Begoniaceae, Berberidaceae, Betulaceae, Bignoniaceae, Blechnaceae, Boraginaceae, Brassicaceae, Buddlejaceae, Butomaceae, Buxaceae, Cactaceae, Callitrichaceae, Calycanthaceae, Calyceraceae, Campanulaceae, Cannabaceae, Cannaceae, Capparaceae, Caprifoliaceae, Caryophyllaceae, Casuarinaceae, Celastraceae, Ceratophyllaceae, Characeae, Chenopodiaceae, Cistaceae, Clethraceae, Clusiaceae, Cneoraceae, Commelinaceae, Convolvulaceae, Coriariaceae, Cornaceae, Crassulaceae, Cryptogrammaceae, Cucurbitaceae, Cunoniaceae, Cupressaceae, Cyathaceae, Cycadaceae, Cyperaceae, Davalliaceae, Dicksoniaceae, Dioscoreaceae, Dipsacaceae, Droseraceae, Ebenaceae, Elaeagnaceae, Elaphoglossaceae, Elatinaceae, Empetraceae, Ephedraceae, Equisetaceae, Ericaceae, Euphorbiaceae, Fabaceae, Fagaceae, Flacourtiaceae, Fontinalaceae, Frankeniaceae, Fumariaceae, Gentianaceae, Geraniaceae, Gesneriaceae, Ginkgoaceae, Globulariaceae, Grossulariaceae, Guttiferaceae, Haloragaceae, Hamamelidaceae, Hemionitidaceae, Hippocastanaceae, PageBreakPageBreakHydrangeaceae, Hydrophyllaceae, Hymenophyllaceae, Hypolepidaceae, Iridaceae, Isoetaceae, Juglandaceae, Juncaceae, Juncaginaceae, Lamiaceae, Lauraceae, Lemnaceae, Lentibulariaceae, Liliaceae, Linaceae, Loranthaceae, Lycopodiaceae, Lythraceae, Magnoliaceae, Malpighiaceae, Malvaceae, Maranthaceae, Marsileaceae, Melastomataceae, Meliaceae, Melianthaceae, Mimosaceae, Molluginaceae, Monimiaceae, Moraceae, Myoporaceae, Myricaceae, Myrsinaceae, Myrtaceae, Najadaceae, Nyctaginaceae, Nymphaeaceae, Oleaceae, Onagraceae, Ophioglossaceae, Orchidaceae, Orobanchaceae, Osmundaceae, Oxalidaceae, Paeoniaceae, Papaveraceae, Passifloraceae, Phytolaccaceae, Pinaceae, Piperaceae, Pittosporaceae, Plantaginaceae, Platanaceae, Plumbaginaceae, Poaceae, Podocarpaceae, Polemoniaceae, Polygalaceae, Polygonaceae, Polypodiaceae, Pontederiaceae, Portulacaceae, Potamogetonaceae, Primulaceae, Proteaceae, Psilotaceae, Pteridaceae, Punicaceae, Pyrolaceae, Rafflesiaceae, Ranunculaceae, Resedaceae, Rhamnaceae, Rosaceae, Rubiaceae, Ruppiaceae, Rutaceae, Salicaceae, Santalaceae, Sapindaceae, Saxifragaceae, Scrophulariaceae, Selaginellaceae, Simaroubaceae, Sinopteridaceae, Solanaceae, Sparganiaceae, Sterculiaceae, Styracaceae, Symplocaceae, Tamaricaceae, Taxaceae, Theaceae, Theligonaceae, Thelypteridaceae, Thymelaeaceae, Tiliaceae, Tropaeolaceae, Typhaceae, Ulmaceae, Umbelliferaceae, Urticaceae, Valerianaceae, Verbenaceae, Violaceae, Vitaceae, Zannichelliaceae, Zingiberaceae, ZygophyllaceaeSpecimens deposited in the UNEX Herbarium have been collected mainly from Iberian Peninsula northwest of Africa (Morocco) and Brazil. As indicated in The specimens better represented in the database correspond to elements of the Mediterranean forest and/or scrubland. These specimens are developed under a seasonal climate of mild winters and hot and dry summers, with abundant rainfall in autumn and spring. Frequent in this climate are forest fires, to which the vegetation is adapted. Specimens from Brazil (except one specimen collected in the state of Santa Catarina), are collected in the state of R\u00edo Grande do Sul. This state has a humid subtropical climate and a hydrography classified into three major regions: Uruguay River Basin, Guaiba River, and Litoral.Coordinates: 38\u00b00'0\"S and 52\u00b00'0\"N Latitude; 115\u00b00'0\"W and 65\u00b00'0\"E longitude.PageBreak1911 \u2013 2013. As shown in Collection name: UNEX Herbarium, University of Extremadura.Collection identifier:http://data.gbif.org/datasets/resource/255Formation period: 1986-2013Specimen preservation method: Dried and pressedCuratorial unit: 36451 with an uncertainty of 0 (Sheets)Curatorial unit: 1253 with an uncertainty of 0 (Genera)PageBreakthem to a flat surface and remove water from the tissue, thereby preventing their degeneration or attacks by bacteria, fungi or insects that would destroy them.Dried and pressed method has been adopted for preservation of the specimens deposited in the collection. After collection of specimens in the field (see \u201csampling description\u201d for the collection protocol) they are pressed and dried with the aim of adapting Assembly of specimens: The dried material is mounted on a holder constituted by an A3 cardboard (42 \u00d7 29.7 cm) and a resistant paper dimension A2 (42 \u00d7 59.4 cm) that perfectly covers the cardboard, thus protecting the specimen. The assembly is made on the cardboard with transparent tape, allowing both that the specimen be tighten to the holder and that the assembly be aesthetic.Registration of herbarium specimens: After assembly, specimens are registered and labeled. Registration is done in a database (Microsoft Office Access Database \u2192 DarwinCore 1.2) in which each specimen is assigned a reference number allocated consecutively. The information contained in the record of each specimen is: institution owner of the herbarium, reference number, scientific name of the family and species, date of collection, georeferencing data , habitat, Legitimavit, and Determinavit. All log data are printed and constitute the sheet label.Treatment of specimens: Before putting the specimens in the herbarium they are stored in hermetic plastic boxes and kept for 72 hours in cold storage (freezers) at -40\u00b0C. In this way the material is decontaminated from possible attacks of pathogens that can destroy them and the rest of material already in the herbarium.PageBreakStorage of specimens: Finally, the specimens are kept inside compact enclosures in shelves where they are arranged taking into account the four main groups: pteridophytes, gymnosperms, monocots, and dicots. Within each main group the specimens are alphabetical arranged by families and genera.Iberian Peninsula is the most significant geographic zone represented in UNEX Herbarium. As evident from the previous section, the specimens deposited in the UNEX Herbarium comes from diverse regions, which is outcome of several research projects depositing the specimens. As a result, specimens are not collected using a single, uniform protocol. Of the materials from donations or purchases the protocol followed for the collection of specimens is unknown. The methodology used in collecting plants by researchers from the Botany Area may change depending on the objectives pursued by the work they are carried out for.In general, collection takes place following previous available references drawn from scientific works, herbarium material or indications from reliable collectors. The collection campaigns are designed to be more or less exhaustive of different available areas depending on the purpose of the collection .PageBreakprising the taxonomic synthesis of families Adoxaceae, Caprifoliaceae, Dipsacaceae, Rubiaceae and Valerianaceae, and XVI in which these experts are responsible for the genera PageBreakArctium, Atractylis, Carlina, Crupina, Cynara, Echinops, Onopordum, Rhaponticum, Saussurea, Staehelina, and Xeranthemum. It is worth also to note the publications of new species of flora , whose typus are preserved in UNEX Herbarium.Each specimens and associated data record was subjected to two quality procedures; (a) taxonomic determination or identification and (b) geo-referencing. For taxonomic identification, trusted experts were contacted, the 85% of the material has been identified by investigators of the Botany Area of the University of Extremadura. These experts have authored number of monographs, which include Vegetaci\u00f3n y Flora de Extremadura in whichFabaceae , while at the same time maintaining the MGRS coordinates in the database. The accuracy of these coordinates grids varies from 1 km2 to 10 km2. The geographical coordinates have been taken through the description of localities and search of these localities in http://www.google.com/earth/index.html). The accuracy of geographic coordinate values \u200b\u200balso varies between 2 and 12 km depending on the number of decimal places contained.The 98% of the records in the collection are georeferenced. A total of 58.38% have MGRS coordinates and the rest geographical coordinates. The MGRS coordinate system has been transformed into geographical coordinates through a geographic calculator (Object name: Herbarium of Vascular Plants Collection of the University of Extremadura (Spain)Character encoding: UTF-8Format name: Darwin Core Archive formatFormat version: 1.0Distributionhttp://www.gbif.es:8080/ipt/resource.do?r=collectionherbariumextremaduraPublication date of data: 2013-05-18Language: EnglishLicenses of use: This database \u201cHerbarium of Vascular Plants Collection of the University of Extremadura (Spain)\u201dis made available under license Open Data Commons Attribution: http://www.opendatacommons.org/licenses/by/1.0/DarwinCore elements: Twenty two (22) DarwinCore (http://purl.org/dc/terms/) elements included in the dataset published through the GBIF network. These are (a) modified, (b) infraspecificEpithet, (c) eventDate, (d) family, (e) basisOfRecord, (f) kingdom, (g) typeStatus, (h) collectionCode, (i) catalogNumber, (j) scientificName, PageBreak(k) locality, (l) individualCount, (m) scientificNameAuthorship, (n) institutionCode (o) decimalLongitude, (p) country, (q) preparations, (r) identifiedBy, (s) stateProvince, (t) recordedBy, (u) recordNumber, (v) decimalLatitude, (w) genus, (x) specificEpithet and (y) occurrenceRemarks.Character encoding: iso-8859-1Format name: AccessFormat version: 1.0Distribution:http://data.gbif.org/datasets/resource/255Metadata language: EnglishDate of metadata creation: 2013-03-20Hierarchy level: Dataset"} +{"text": "Published 4 March 2014Ishikawa H, Ide T, Yagi T, Jiang X, Hirono M, Sasaki H, Yanagisawa H, Wemmer KA, Stainier DYR, Qin H, Kamiya R, Marshall WF. 2014. TTC26/DYF13 is an intraflagellar transport protein required for transport of motility-related proteins into flagella. In the published article, the legends for Videos 5 and 6 were switched.This has been corrected."} +{"text": "AbstractGastropoda were most species rich 50 species followed by Bivalvia (37), Aplacophora (5), Scaphopoda (3) and one from each of Polyplacophora and Monoplacophora.Information regarding the molluscs in this dataset is based on the epibenthic sledge (EBS) samples collected during the cruise BIOPEARL II / JR179 RRS James Clark Ross in the austral summer 2008. A total of 35 epibenthic sledge deployments have been performed at five locations in the Amundsen Sea at Pine Island Bay (PIB) and the Amundsen Sea Embayment (ASE) at depths ranging from 476 to 3501m. This presents a unique and important collection for the Antarctic benthic biodiversity assessment as the Amundsen Sea remains one of the least known regions in Antarctica. Indeed the work presented in this dataset is based on the first benthic samples collected with an EBS in the Amundsen Sea. However we assume that the data represented are an underestimation of the real fauna present in the Amundsen Sea. In total 9261 specimens belonging to 6 classes 55 families and 97 morphospecies were collected. The species richness per station varied between 6 and 43. Project title: BIOPEARL II-JR 179 RRS James Clark Ross 2008Personnel: Camille Moreau, Katrin Linse, Huw Griffiths, Peter Enderlein and David BarnesFunding: This study is part of the British Antarctic Survey Polar Science for Planet Earth Programme funded by the Natural Environment Research Council.Study extent description: The study area of this dataset was set in the eastern Amundsen Sea and focused on the continental shelf, upper slope and over-deepened shelf basins of the Amundsen Sea Embayment (ASE) and Pine Island Bay (PIB). This dataset presents species occurrences and species richness of the individual epibenthic sledge (EBS) deployments. PIB appears to be the third largest drainage outlet of the West Antarctic Ice Sheet . BIOPEARL , a core project at the British Antarctic Survey, studied the southern Bellingshausen and eastern Amundsen seas to assess the biodiversity at local and regional scales (comparable to the BIOPEARL 2006 cruise to the Scotia Sea) and investigate the phylogenetic relationships of selected marine invertebrate taxa and their biogeography in reference to the climatological, oceanographical and geological history of the Bellingshausen/Amundsen Seas. The results are used to determine of the role of Antarctica and extreme environments in general in evolutionary innovation and generation of global biodiversity. The species presence data are added to SOMBASE (Southern Ocean Mollusc Database www.antarctica.ac.uk/sombase). SOMBASE generated initial core data system upon which SCAR\u2019s Marine Biodiversity Information Network (SCAR-MarBIN) was built. As SCAR-MarBIN is the Antarctic Node of the international OBIS network, the SOMBASE data system was designed to comply with the Darwin Core standards. Regarding the dataset, the existing Data Toolkit from SCAR-MarBIN was used (http://www.scarmarbin.be/documents/SM-FATv1.zip), following PageBreakthe OBIS schema (http://iobis.org/data/schema-and-metadata). The dataset was uploaded in the ANTOBIS database , and the taxonomy was matched against the Register of Antarctic Marine Species, using the Taxon Match tool (http://www.scarmarbin.be/rams.php?p=match). The dataset meets the Darwin Core requirements and was designed around this data schema.Sampling description: Five locations in the Pine Island Bay (PIB) and Amundsen Sea Embayment (ASE) at different depths ranging from 476 to 3501m have been sampled using an epibenthic sledge (EBS). Most deployments were made along depth transects from shallow to overdeepened continental shelf and to deeper slope (https://www.bodc.ac.uk/data/information_and_inventories/cruise_inventory/report/8277/).er slope and 2. AThis dataset presents 34 EBS deployments: 21 of which were performed at a depth of 500m at four different sites , six at a 1000m depth in three areas , five at a depth of 1500m at three different sites , and two replicates at site BIO8-3500 in 3500m depth. For three of the five locations, sites were positioned along vertical transects sampling at 500m, 1000m and 1500m with repeat deployments of the EBS. The sites BIO4-1, BIO4-2 and BIO4-3 and BIO6-1, BIO6-2 and BIO6-3 were situated in the same local area; while the sites BIO5-1, BIO5-2 and BIO5-3 were dispersed over a wider area because of ice cover. The EBS consist of on an epi-(below) and a supra-(above) net. Each of these nets has a mesh size of 500\u03bcm and an opening of 100x33cm. The cod end of both nets is equipped with net-buckets containing a 300\u03bcm mesh window . The EBSQuality control description: A species name was given to each specimen when it was possible. Individuals not corresponding to described species have been included in the analyses with the family or genus name and a letter or numerical code (e.g. Turbinidae gen. sp.), however they represent a single morphospecies.For these specimens, further morphological and genetic analyses are necessary to give them a species name but they can be included in this dataset as different species. Finally, specimens too badly damaged for species identification have not been taken in account here.This dataset presents species occurrences and species richness of the individual EBS deployments.PageBreakPageBreakGeneral taxonomic coverage description: The present dataset focus on six molluscs classes . It includes respectively for each class:Class:AplacophoraSpecies:Aplacophora sp. 1, Aplacophora sp. 2, Aplacophora sp. 3, Aplacophora sp. 4, Aplacophora sp. 5Class:PolyplacophoraFamily:LeptochitonidaeGenus:LeptochitonSpecies:Leptochiton sp.Class:MonoplacophoraFamily:MicropilinidaeGenus:MicropilinaSpecies:Micropilina sp.Class:GastropodaFamily:Scissurellidae, Ataphridae, Mangeliidae, Capulidae, Calliotropidae, Seguenzioidea, Turbinidae, Turridae, Eulimidae, Limacinidae, Eatoniellidae, Cancellarioidea, Naticidae, Rissoidae, Diaphinidae, Fissurellidae, Raphitomidae, Cylichnidae, Lepetidae, Orbitestellidae, Buccinidae, Mathildidae, Newtoniellidae, Marginellidae, CavoloniidaeGenus:Anatoma, Trochaclis, Lorabela, Belalora, Torellia, Capulus, Calliotropis, Brookula, Brookula, Lissotesta, Liotella, Cirsonella, Balcis, Onoba, Hemiaclis, Limacina, Eatoniella, Cancellaridae gen., Falsilunatia, Pseudomauropsis, Sinuber, Powellisetia, Rissoid, Toledonia, Fissurellidae gen., Cornisepta, Zeidora, Pleurotomella, Cylichna, Iothia, Microdiscula, Pareuthria, Turritellopsis, Cerithiella, Eumetula, Marginella, ClioSpecies:Anatoma euglypta, Trochaclis antarctica, Lorabela pelseneeri, Belalora cf striatula, Torellia insignis, Capulus sp., Calliotropis pelseneeri, Brookula cf charleenae, Brookula sp. b, Lissotesta sp., Liotella sp., Liotella cf endeavourensis, Cirsonellaextrema, Turbinid sp. Turrid sp. 1, Turrid sp. 2, Balcis sp. Onoba cf gelida, Hemiaclis incolorata, Limacina helicina, Eatoniella cf kerguelenensis regularis, Cancellarid sp. Falsilunatia sp. Pseudomauropsis anderssoni, Sinuber microstriatum, Powellisetia cf deserta, Rissoid sp. Toledonia sp. 1, Toledonia sp. 2, Toledonia cf elata, Fissurellidae gen. sp. 1, Fisserulidae gen. sp. 2, Cornisepta antarctica, Zeidora antarctica, Pleurotomella cf simillima, Cylichna sp. Iothia sp. Microdiscula sp. Pareuthria cf innocens, Turritellopsis gratissima, Cerithiella cf lineata, Cerithiella cf erecta, Eumetula cf strebeli, Marginella ealesae, Clio antarcticaPageBreakClass:BivalviaFamily:Nuculanidae, Nuculidae, Yoldiidae, Limopsidae, Philobryidae, Mytilidae, Limidae, Pectinidae, Propeamussiidae, Thyasiridae, Motacutidae, Lasaeidae, Cyamiidae, Carditidae, Thraciidae, Cuspidariidae, Lyonsiidae, Poromyidae, Neoleptonidae, Siliculidae, Arcidae, Vesicomyidae, Tindariidae, BathyspinulidaeGenus:Propeleda, Ennucula, Yoldiella, Limopsis, Philobrya, Adacnarca, Dacrydium, Limatula, Adamussium, Hyalopecten, Cyclochlamys, Thyasira, Mysella, Waldo, Cyamiocardium, Cyclocardia, Thracia, Cuspidaria, Myonera, Lyonsia, Poromya, Neolepton, Silicula, Bathyarca, Vesicomya, Tindaria, BathyspinulaSpecies:Propeleda longicaudata, Ennucula sp. Yoldiella ecaudata, Yoldiella sabrina, Yoldiella valettei, Yoldiella cf profundorum, Yoldiella oblonga, Yoldiella sp. Limopsis longipilosa, Limopsis knudseni, Philobrya sublaevis, Philobrya quadrata, Adacnarca nitens, Dacrydium albidum, Limatula Limatula sp. Limatula Antarctolima sp. Adamussium colbecki, Hyalopecten pudicus, Cyclochlamys pteriola, Cyclochlamys gaussiana, Thyasira sp. Mysella antarctica, Waldo sp. Cyamiocardium denticulatum, Cyclocardia astartoides, Thracia meridionalis, Cuspidaria infelix, Cuspidaria minima, Myonera fragilissima, Lyonsia arcaeformis, Poromya antarctica, Neolepton sp. Silicula rouchi, Bathyarca sinuata, Vesicomya sirenkoi, Tindaria sp. Bathyspinula sp.Class:ScaphopodaFamily:Dentaliidae, Pulsellidae, GadilidaeGenus:Dentalium, Striopulsellum, CadulusSpecies:Dentalium majorinum, Striopulsellum minimum, Cadulus thieleiGeneral spatial coverage: Amundsen Sea, AntarcticaCoordinates: 74\u00b029'24\"S and 70\u00b01'12\"S; 110\u00b05'24\"W and 104\u00b020'24\"WTemporal coverage: February 18, 2008\u2013April 11, 2008Natural collections descriptionParent collection identifier: British Antarctic SurveyCollection name: BIOPEARL II EBS MolluscsCollection identifier: Moreau/LinseSpecimen preservation method: Ethanol/Formaldehyde- Epibenthic sledge sampling in the Amundsen SeaPageBreak- Once on the deck, the content of the samplers from the first deployment was immediately fixed in 96% undenaturated and pre-cooled (at -20\u00b0C) ethanol ( ethanol and kept- The taxonomic identification was performed in the British Antarctic Survey laboratory using a stereomicroscope.Object name: Darwin Core Archive amundsen_sea_molluscsCharacter encoding: UTF-8Format name: Darwin Core Archive formatFormat version: 1.0Distribution: http://ipt.biodiversity.aq/archive.do?r=amundsenseamolluscs_biopearl_iiPublication date of data: 2013-01-09Language: EnglishMetadata language: EnglishDate of metadata creation: 2013-01-09Hierarchy level: Dataset"} +{"text": "Affiliation number 5 for the seventh author, Anna-Maria Tokes, is incorrect. The correct affiliation is: 2nd Department of Pathology, Semmelweis University, MTA-SE Tumour Progression Research Group, Budapest, Hungary."} +{"text": "In \u201cInvestigation of Bioterrorism-Related Anthrax, United States, 2001: Epidemiologic Findings\u201d by Daniel B. Jernigan et al., errors occurred in the listing of the members of the Anthrax Epidemiologic Investigation Team on page 1019. Additional members of the National Anthrax Epidemiologic Investigation Team are:Francisco Alvarado-Ramy, MacKenzie Andre, MaryKate Appicelli, Mick Ballesteros, Mark Beatty, Omotayo Bolu, Louise Causer, Soju Chang, Ilin Chuang, John Crump, Marvin DeBerry, Rachel Gorwitz, Michelle Goveia, Thomas Handzel, Josh Harney, Dan Hewett, Vincent Hsu, Young Hur, Marialena Jefferds, Joshua Jones, Kathleen Julian, Richard Kanwal, Jane Kelly, Dennis Kim, Judy Kruger, Richard Leman, Steve Lenhart, Jill Levine, Naile Malakmadze, Els Mathieu, Rob McCleery, Shawn McMahon, Manoj Menon, Kelly Moore, Jill Morris, James Andy Mullins, Melanie Myers, Timothy Naimi, Lori Newman, Chima John Ohuabunwao, Michael O'Reilly, Lisa Pealer, Chris Piacitelli, Joe Posid, John Redd, Mary Reynolds, Julia Rhodes, Louie Rosencrans, Lisa Roth, Denise Roth-Allen, Sharon Roy, Taraz Samandari, Dejana Selenic-Stanacev, Jina Shah, Tanya Sharp, Allison Stock, Lauralynn Taylor, Pauline Terebuh, Christopher Thomas, Beth Tohill, Barna Tugwell, Angela Weber, Dana White, Sara Whitehead, Wally Wilhoite, Leigh Winston, Brad Winterton, Katharine Witgert, William Wong, Susie Wootton, and Weigong Zhou.http://wwwnc.cdc.gov/eid/article/8/10/02-0353_article.htm.The corrected article appears online at We regret any confusion these errors may have caused."} +{"text": "The byline published in the correction is incorrect. The correct byline is: Ho Dang Trung Nghia, Le Thi Phuong Tu, Marcel Wolbers, Cao Quang Thai, Nguyen Van Minh Hoang, Tran Vu Thieu Nga, Le Thi Phuong Thao, Nguyen Hoan Phu, Tran Thi Hong Chau, Dinh Xuan Sinh, To Song Diep, Hoang Thi Thanh Hang, Hoang Truong, James Campbell, Nguyen Van Vinh Chau, Nguyen Tran Chinh, Nguyen Van Dung, Ngo Thi Hoa, Brian G. Spratt, Tran Tinh Hien, Jeremy Farrar, Constance Schultsz."} +{"text": "New evidence and consensus has led to further revision of the McDonald Criteria for diagnosis of multiple sclerosis. The use of imaging for demonstration of dissemination of central nervous system lesions in space and time has been simplified, and in some circumstances dissemination in space and time can be established by a single scan. These revisions simplify the Criteria, preserve their diagnostic sensitivity and specificity, address their applicability across populations, and may allow earlier diagnosis and more uniform and widespread use. Ann Neurol 2011 Diagnostic criteria for multiple sclerosis (MS) include clinical and paraclinical laboratory assessmentsSince the revision of the McDonald Criteria in 2005, new data and consensus have pointed to the need for their simplification to improve their comprehension and utility and for evaluating their appropriateness in populations that differ from the largely Western Caucasian adult populations from which the Criteria were derived. In May 2010 in Dublin, Ireland, the International Panel on Diagnosis of MS (the Panel) met for a third time to examine requirements for demonstrating DIS and DIT and to focus on application of the McDonald Criteria in pediatric, Asian, and Latin American populations.multiple sclerosis and diagnosis, and from specific recommendations of relevant papers by Panel members. The Panel concluded that most recent research supports the utility of the McDonald Criteria in a typical adult Caucasian population seen in MS centers, despite only limited research and practical experience in general neurology practice populations.The Panel reviewed published research related to the diagnosis of MS and to the original and revised McDonald Criteria, gathered from literature searches of English language publications containing the terms In its discussions, the Panel stressed that the McDonald Criteria should only be applied in those patients who present with a typical clinically isolated syndrome (CIS) suggestive of MS or symptoms consistent with a CNS inflammatory demyelinating disease, because the development and validation of the Criteria have been limited to patients with such presentations. CIS presentations can be monofocal or multifocal, and typically involve the optic nerve, brainstem/cerebellum, spinal cord, or cerebral hemispheres.In applying the McDonald Criteria, it remains imperative that alternative diagnoses are considered and excluded. Differential diagnosis in MS has been the subject of previous data- and consensus-driven recommendations that point to common and less common alternative diagnoses for MS and identify clinical and paraclinical red flags that should signal particular diagnostic caution.Correct interpretation of symptoms and signs is a fundamental prerequisite for diagnosis.The Panel concluded that the underlying concepts of the original (2001) and revised (2005) McDonald CriteriaIn past versions of the McDonald Criteria, DIS demonstrated by MRI was based on the Barkhof/Tintor\u00e9 criteria.The 2005 revision of the McDonald Criteria simplified the MRI evidence required for DIT, basing it on the appearance of a new T2 lesion on a scan compared to a reference or baseline scan performed at least 30 days after the onset of the initial clinical event.More recently, the MAGNIMS group confirmed earlier studiesBy using the recommended simplified MAGNIMS criteria to demonstrate DISThe Panel reaffirmed that positive cerebrospinal fluid (CSF) findings can be important to support the inflammatory demyelinating nature of the underlying condition, to evaluate alternative diagnoses, and to predict CDMS.33In 2005, the Panel recommended revising the McDonald Criteria for diagnosis of primary progressive multiple sclerosis (PPMS) to require, in addition to 1 year of disease progression, 2 of the following 3 findings: positive brain MRI (9 T2 lesions or 4 or more T2 lesions with positive VEP); positive spinal cord MRI ; or positive CSF. These criteria reflected the special role of both CSF examination and spinal cord MRI in PPMS, have been found to be practical and are generally well accepted by the neurological community,The McDonald Criteria were developed with data gathered largely from adult Caucasian European and North American populations, and their applicability has been questioned for other populations, particularly pediatric cases,41Over 95% of pediatric MS patients have an initial relapsing\u2013remitting disease course, whereas PPMS is exceptional in children and should prompt detailed consideration of alternative diagnoses.51The Panel's consensus was that the proposed MAGNIMS-based MRI revisions for DIS will also serve well for most pediatric MS patients, especially those with acute demyelination presenting as CIS, because most pediatric patients will have >2 lesions and are very likely to have lesions in 2 of the 4 specified CNS locations . The frequency of spinal cord lesions in pediatric MS patients is currently unreported, but the appearance of cord lesions in pediatric MS patients with spinal cord symptoms appears generally similar to that of adults.52However, approximately 15 to 20% of pediatric MS patients, most aged <11 years, present with encephalopathy and multifocal neurological deficits difficult to distinguish from acute disseminated encephalomyelitis (ADEM).Among Asian patients with CNS inflammatory demyelinating disease, a phenotype characterized by NMO, longitudinally extensive spinal cord lesions, and positive AQP4 autoantibody seropositivity20The Panel recommends testing for AQP4 autoantibodies with validated assays in patients who are suspected of having NMO or NMO spectrum disorders, especially in patients with Asian or Latin American genetic background because of the higher prevalence of the disease in these populations. Such testing may be less important in those subjects presenting with conventional Western type MS. Although not all patients with an NMO-like presentation will be AQP4 antibody positive, the majority are, whereas those with MS are more likely to be AQP4 antibody negative.The Panel recommends revisions to the McDonald Criteria for diagnosis of MS Table focusingAlthough increased IgG index or the presence of oligoclonal bands in the CSF support an MS diagnosis, and AQP4 antibody assays can help in the differential diagnosis process, there are still no specific biomarkers to confirm the diagnosis. Several blood and CSF biomarkers may be promising,The McDonald Criteria were based on detection of lesions generally using 1.5T magnet strength in noncortical regions of the brain and spinal cord. However, a large proportion of MS lesions are in the cortexMany individuals with high lesion loads may have had a protracted subclinical disease course prior to their first clinical event. As a consequence, occasional individuals investigated by MRI for indications unrelated to MS have incidental findings of brain lesions with appearance and topography consistent with MS. Detection of this presymptomatic phase, or radiologically isolated syndrome, is increasingly common. Some of these individuals followed clinically and by serial imaging will develop DIT by MRI, and some have clinical disease-defining events after several years.The 2010 revisions to the McDonald Criteria will in some instances allow a more rapid diagnosis of MS, with equivalent or improved specificity and/or sensitivity compared with past Criteria and will in many instances clarify and simplify the diagnostic process with fewer required MRI examinations. A proportion of patients with nonspecific symptoms and nonspecific MRI findings are referred to secondary and tertiary MS centers in the developed world for a second opinion and do not in fact have MS.The Panel acknowledges that using these refined diagnostic criteria may change some of the outcomes of patients in natural history studies and clinical trials, when original expectations for outcomes may be based on subjects whose diagnosis was made using past, somewhat different criteria.C.H.P.: consultancy, Actelion, Biogen Idec, Bayer Schering, Teva, Merck-Serono, Novartis, Glaxo SK, UCB, Roche, Antisense Ther; expert testimony, Biogen Idec; grants/grants pending, Biogen Idec, Bayer Schering, Teva, Merck-Serono, Novartis, Glaxo SK, UCB. S.C.R.: travel support, US NMSS, ECTRIMS, Multiple Sclerosis International Federation, MS Ireland; payment for writing or reviewing manuscript, US NMSS, ECTRIMS; consultancy, US NMSS, ECTRIMS, Sanofi-Aventis, Bayer Schering Pharma, BioMarin, EMD Merck Serono, Mt Sinai College of Medicine , European Committee for Treatment and Research in MS, Eisai, INC Research, Eli Lilly Inc, Isis Pharmaceuticals Inc, MediciNova, Cleveland Clinic Foundation, Free University Amsterdam, Genentech/F. Hoffmann-LaRoche, Synthon BV, Antisense Therapeutics Ltd, BaroFold, Protein Design Laboratories; royalties, Demos Medical Publishers . B.B.: travel support, US NMSS, ECTRIMS, MSIF, MS Ireland; consultancy, Biogen Idec, Genzyme; grants/grants pending, Multiple Sclerosis Society of Canada, Canadian Institutes of Health Research; paid educational presentations, honoraria for symposia at the American Academy of Neurology. M.C.: board membership, GENMAB; consultancy, Biogen, Genzyme; grants/grants pending, Bayer Schering, Biogen Elan, Novartis, Merck Serono, Sanofi-Aventis, Teva. J.A.C.: travel expenses, US NMSS; consultancy, Biogen Idec, Lilly, Novartis, Serono, Teva; grants/grants pending, Department of Defense, NIH, US NMSS; speaking fees, Biogen Idec, Novartis, Sanofi-Aventis, Waterfront Media. M.F.: travel expenses, US NMSS, ECTRIMS, MSIF, MS Ireland; board membership, Teva Pharmaceutical Industries Ltd, Genmab A/S; consultancy, Bayer Schering Pharma, Biogen-Domp\u00e9 AG, Genmab A/S, Merck Serono, Pepgen Corporation, Teva Pharmaceutical Industries Ltd; grants/grants pending, Bayer-Schering, Biogen-Domp\u00e9 AG, Genmab A/S, Merck Serono, Teva Pharmaceutical Industries Ltd, Fondazione Italiana Sclerosi Multipla, Fondazione Mariani; speaking fees, Bayer Schering Pharma, Biogen-Domp\u00e9 AG, Genmab A/S, Merck Serono, Teva Pharmaceutical Industries Ltd; travel expenses, Teva, Biogen-Domp\u00e9 AG, Merck-Serono, Sanofi-Aventis, Genmab, Bayer Schering. K.F.: travel expenses, US NMSS, ECTRIMS, MSIF, MS Ireland; consultancy, Bayer Schering Pharma, Biogen Idec, Merck Serono; grants/grants pending, Bayer Schering Pharma, Biogen Idec, Asahi Kasei Kuraray Medical Co Ltd, Chemo-Sero-Therapeutic Research Institute, Mitsubishi Tanabe Pharma, Teijin Pharma, Theva Pharmaceutical, Eisai Inc, Kowa Pharmaceutical, Ministry of Education, Science, and Technology of Japan, Ministry of Health, Labor, and Welfare of Japan; speaking fees, Bayer Schering Pharma, Biogen Idec, Eisai Inc, Mitsubishi Tanabe Pharma, Astellas Pharma, Takeda Pharmaceutical Company Ltd, Asahi Kasei Kuraray Medical Co; paid manuscript preparation, Cosmic Corporation; royalties, Bunkodo. E.H.: travel expenses, US NMSS, ECTRIMS, MSIF, MS Ireland; consultancy, Biogen Idec, Genzyme, Merck Serono, Novartis, Grifols; grants/grants pending, Biogen Idec; speaking fees, Biogen Idec, Genzyme, Merck Serono, Novartis, Bayer Healthcare, Sanofi-Aventis; paid educational presentations, Novartis. M.H.: consultancy, Biogen Idec; grant/grants pending, Health Research Board Ireland; speaking fees, Biogen Idec. L.K.: travel expenses, US NMSS; board membership, Editorial Board of Multiple Sclerosis; grants/grants pending, National Research Foundation Switzerland, Rubatto Foundation, Swiss MS society, European Union, Roche Foundation, Novartis Foundation; speaking fees, various companies involved in development of MS therapeutics; paid educational presentations, Neurostatus System for Standardized Neurological Assessment. F.D.L.: travel support, US NMSS; consultancy, Novartis, Bayer, Biogen Idec, EMD Serono, Genentech, Teva Neuroscience, Genmab, Medicinova, Actelion, Allozyne, Sanofi-Aventis, Acorda, Questcor, Avanir, Roche, Celgene, Abbott, Pfizer, Morphosys; grants/grants pending, NIH, NMSS, Acorda, Biogen Idec, Teva, Novartis, Sanofi-Aventis; speaking fees, Genzyme, Teva, EMD Serono; paid educational presentations, various continuing medical education services; stock/stock options, cognition pharmaceuticals. X.M.: travel expenses, US NMSS; consultancy, Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Almirall; grants/grants pending, Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Almirall; speaking fees, Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis, Teva Pharmaceuticals, Almirall. M.S.-W.: travel support, US NMSS, ECTRIMS, MSIF, MS Ireland; fees for review activities, Genentech, Merck Serono, Roche; board membership, Board of Directors of Active Biotech, Sweden; consultancy, Elan, Merck Serono; speaking fees, Bayer Health Care, Merck Serono, Serono Symposia International Foundation, Sanofi-Aventis, Swedish Bank SEB. A.J.T.: travel support, US NMSS, ECTRIMS, MSIF, MS Ireland; board membership, National Hospital Development Foundation, Patrick Berthoud Charitable Trust; consultancy, Weleda AG/Society for Clinical Research, Medical Research Council, MS Society of Great Britain, Merck Serono, Biogen Idec, DIGNA Biotech, Novartis, Eisai London Research Laboratories, Teva Pharmaceuticals; grants/grants pending, National Institute for Health Research, MS Society of Great Britain; speaking fees, Serono Symposia, Sanofi-Aventis; travel expenses, MS International Federation, US NMSS, Biogen Idec; honoraria, Editor-in-Chief of Multiple Sclerosis. E.W.: consultancy, Roche, Actelion; grants/grants pending, US NMSS, NIH; speaking fees, Teva; received free drug for a trial given by Sanofi-Aventis and Biogen Idec. B.W.: travel support, US NMSS; European Committee for Treatment of MS; MS International Foundation; MS Ireland; consultancy, Novartis, Biogen Idec; employment, Mayo Clinic; royalties, RSR Ltd. J.S.W.: travel support, US NMSS, ECTRIMS, MSIF, MS Ireland; board membership, Antisense Therapeutics Ltd, BCDecker, Novartis Pharmaceuticals, Sanofi-Aventis, Teva Pharmaceuticals, Eli Lilly, UCB; consultancy, Genentech, Novartis Pharmaceuticals, Sanofi-Aventis, Teva Neuroscience, Teva Pharmaceuticals, Acorda, Acetilon, Bayer HealthCare, Facet Biotech, Peptimmune; grants/grants pending, NIH, Sanofi-Aventis, Clayton Foundation for Research, US NMSS; honoraria for lectures, Consortium MS Centers, Sanofi-Aventis New Zealand, Sterling Meeting Services, USF Health Professionals, Texas Neurological Society, Teva Pharmaceuticals, Lone Star Chapter NMSS, ICHE, Pfizer EMD Serono, SUNY, Stony Brook Foundation, UTMB, Medscape CME, University of Buffalo, Serono Symposia International Foundation, University of Utah; royalties, Millipore Corporation."} +{"text": "AbstractEustrophinae is reviewed, and consists of the following five genera and 12 species: Pseudoholostrophus (Pseudoholostrophus) impressicollis (LeConte), Pseudoholostrophus (Holostrophinus) discolor (Horn), Holostrophus bifasciatus (Say), Eustrophus tomentosus Say, Eustrophopsis confinis (LeConte), Eustrophopsis bicolor (Fabricius), Eustrophopsis brunneimarginatus (Dury), Eustrophopsis indistinctus (LeConte), Eustrophopsis arizonensis (Horn), Eustrophopsis ornatus (Van Dyke), Eustrophopsis crowdyisp. n., and Synstrophus repandus (Horn). A lectotype is designated for Eustrophus brunneimarginatus Dury. A key is given to separate genera and species, supplemented with illustrations of relevant features, including aedeagi of all Nearctic species of Eustrophopsis. Detailed distribution (including Mexican records) and natural history data are provided.The Nearctic fauna (north of Mexico) of Eustrophinae, like many groups within Tenebrionoidea, have not had a stable family-level placement until fairly recently. Various authors have commented on the taxonomic history of the group . Monophyly of Tetratomidae was not supported in this analysis; in fact, Eustrophopsis was shown to be the sister taxon to Orchesia (Melandryidae). Tetratoma (Tetratomidae: Tetratominae) and Penthe (Tetratomidae: Penthinae) were part of a monophyletic group that also contained Dipsaconia (Ulodidae) and Chalcodrya . An earlier study by Tetratomidae (data taken from the literature) as part of a very large, unresolved branch of basal Tenebrionoidea.The oup e.g. ; howeverEustrophinae specifically, although Tetratomidae. Also, Holostrophus, representing the only published work on a single genus of Eustrophinae. Coleoptera. The present study treats all taxa found in North America, north of Mexico, including the description of a new species from southern Arizona. Much of the descriptive, ecological and distributional data for species occurring in Canada, treated herein, were given previously by Eustrophinae. Therefore, descriptions are rather diagnostic in nature, except for the description of Eustrophopsis crowdyi, new species, which is more detailed and complete.There have been no large-scale studies of the Tetratomidae. The Eustrophinae have the following characteristics: body elongate oval, often more distinctly narrowed posteriorly; all legs with simple, narrow tarsi; antennomeres 3-7 more or less broadened, at least some antennomeres transverse; pronotum with two sublinear impressions basally, metepisterna distinctly subdivided into two sections; metendosternite without laminae.Eustrophinae comprises 5 genera and 86 species (compiled from various sources), distributed worldwide except for Australia and New Zealand. The greatest diversity occurs in tropical areas, especially in the Neotropical region. Members of the subfamily are relatively homogeneous structurally, and both larvae and adults are associated with various groups of fungi on dead trees (Eustrophinae. Most information available is taken from collection records. Lawrence (1991: 506) gave the following fungal associates with some genera and species of Eustrophinae: Eustrophopsis spp. ; Synstrophus repandus (Horn) ; Eustrophus tomentosus Say (Polyporus squamosus). Individual fungal/collection records are given below for each species (from label data).PageBreakThe world fauna of ad trees . No studEustrophinae are active at night, when they emerge from daytime hiding places and occupy exposed surfaces, on dead wood or on associated fungal bodies. Very long series of specimens are somewhat rare; collecting during the day will yield few specimens, whereas night collecting or mass-trapping can be very productive and effective methods for obtaining long series. During the day, potentially good, fungus-infested dead trees can be marked and returned to at night, to collect the active adults.Adults of Eustrophopsis are seemingly attracted to Lindgren funnel traps, and/or the scolytine baits often deployed along with these devices. For example, a single locality yielded the following specimens over a two-week period: 7.vii.2002 ; 14.vii.2002 .Adults of Tenebrionoidea, immature stages of Eustrophinae are rather imperfectly known. Larvae are found in the same habitats as adults; however, whereas adults are often found on surfaces at night, larvae remain within the rotting wood/fungal substrate (Pollock pers. observ.). Eustrophopsis and Holostrophus were included. A key to larvae of Holostrophus was also given by Eustrophopsis is that of Eustrophopsis quindecimmaculata (Laporte), a Neotropical species.As in the majority of Eustrophopsis bicolor (Fabricius); this is the most common species, so perhaps this is not surprising. Eustrophopsis bicolor also, but only illustrated the posterior end of the abdomen . Tetratomidae, with various details given for Eustrophinae (based on Eustrophopsis and Holostrophus).Among Nearctic eustrophines, the only species reasonably well known in the larval stage is This study is based on 6,600 adult specimens examined and/or borrowed from the following private and public collections and museums:AMNH American Museum of Natural History, New York, NYBBC Brian Baldwin Collection (private)BYUC Monte L. Bean Life Science Museum, Brigham Young University, Provo, UTCARR J.B. and A. Carr Collection (now part of CNC)PageBreakCAS California Academy of Sciences, San Francisco, CACBC Cheryl Barr Collection (private)CGMC Chris Majka Collection (private)CMNC Canadian Museum of Nature, Gatineau, QCCMNH Carnegie Museum of Natural History, Pittsburgh, PACNC Canadian National Collection of Insects, Ottawa, ONCNHM Cincinnati Natural History Museum, Cincinnati, OHCUIC Cornell University, Ithaca, NYDAPC Darren A. Pollock Collection (private)DSSC Derek Sikes Collection (private)EGRC Edward G. Riley Collection (private)EIUC Eastern Illinois University Collection, Charleston, ILFMNH Field Museum of Natural History, Chicago, ILFSCA Florida State Collection of Arthropods, Gainesville, FLINHS Illinois Natural History Survey, Champaign, ILJBWM J.B. Wallis Museum of Entomology, University of Manitoba, Winnipeg, MBLACM Los Angeles County Museum, Los Angeles, CALSU Louisiana State Arthropod Museum, Louisiana State University, Baton Rouge, LAMCZ Museum of Comparative Zoology, Harvard University, Cambridge, MAMKOC M.K. Oliver Collection (private)MSUC Michigan State University, East Lansing, MIMTEC Montana State University, Bozeman, MTMUNC Memorial University of Newfoundland, St. John\u2019s, NFNDSU North Dakota State University, Fargo, NDNSMC Nova Scotia Museum Collection, Halifax, NSODAC Oregon Department of Agriculture, Salem, OROSUC Ohio State University, Columbus, OHPFC Pacific Forestry Centre, Victoria, BCPKLC Paul K. Lago Collection (private)PPCD West Virginia Department of Agriculture, Charlestown, WVRBCM Royal British Columbia Museum, Vancouver, BCRLC Richard Leschen Collection (private)ROME Royal Ontario Museum, Toronto, ONRTC Robert Turnbow Collection (private)SLC Serge LaPlante Collection (private)SMC Scott McCleve Collection (private) [now in UAIC]TAMU Texas A&M University, College Station, TXUAIC University of Arizona, Tucson, AZUBC University of British Columbia, Vancouver, BCUCBC Essig Museum of Entomology, Berkeley, CAUCFC University of Central Florida, Orlando, FLUCMS University of Connecticut, Storrs, CTPageBreakUCRC University of California, Riverside, CAUGAC University of Georgia, Athens, GAUMIC University of Mississippi, Oxford, MSUMMZ University of Michigan, Ann Arbor, MIUMRM W.R. Enns Entomology Museum, Columbia, MOUSMN University of Nebraska State Museum, Lincoln, NEUSNM National Museum of Natural History, Smithsonian Institution, Wa- shington, DCWFBM W.F. Barr Entomological Collection, Moscow, IDWIRC University of Wisconsin Insect Research Center, Madison, WIZHFC Zack H. Falin Collection (private)Eustrophopsis only, because 1) this genus is larger than the other genera of Eustrophinae and species are more difficult to distinguish; and 2) genital structures have already been described and/or illustrated for other taxa within Eustrophinae and county names (where available); complete data for non-type specimens are given in Appendix 1. In the descriptions, TL = length from anterior pronotal margin to apex of elytra ; GEW = maximum width, across elytra. Type specimen label data are given verbatim, enclosed within quotation marks; individual labels are separated by a slash (/).\u00ae digital camera fitted to a Leica MZ95 stereoscope. The 10\u201330 separate images taken for each specimen/structure were imported into Combine ZP PageBreakPseudoholostrophus. According to Pseudoholostrophus differs from Holostrophus in its smaller and more weakly emarginate eyes, and in the prosternal process not extending behind the posterior edge of the procoxae. There are four species in Pseudoholostrophus (Pseudoholostrophus klapperichi (Pic) and Pseudoholostrophus chinensis Nikitsky, are known from China. Pseudoholostrophus discolor (Horn) are placed in the nominate subgenus. Holostrophus discolor (Horn) was transferred into the subgenus Holostrophinus of Pseudoholostrophus by This genus was described by strophus , two of http://species-id.net/wiki/Pseudoholostrophus_impressicollisEustrophus impressicollisHolostrophus impressicollis (LeConte).\u2014 Pseudoholostrophus (Pseudoholostrophus) impressicollis (LeConte).\u2014Eustrophinae by the following combination of characters: color uniformly red-brown; dorsal setae very short, inconspicuous; eyes widely separated; meso- and metatibiae smooth, without oblique ridges; distribution in westernmost North America.This distinctive species may be separated by all other Nearctic Pseudoholostrophus impressicollis.The following abbreviated description was taken from Pollock (2008: 268). TL 6.0-6.2 mm; GEW 2.0\u20132.7 mm. Body elongate oval, moderately parallel sided provided a fairly detailed description of el sided , moderatel sided ; dorsal el sided , medial el sided ; antennoel sided elongateel sided .CANADA: BRITISH COLUMBIA. UNITED STATES: CALIFORNIA: Alpine, Humboldt, Siskiyou, Trinity. OREGON: Curry, Josephine, Lane, Lincoln, Polk. (Complete label data given in Appendix 1).. The ranEustrophus impressicollis LeConte. LECTOTYPE, sex unknown, labeled \u201cVanc. / Type 4781 / Eu. impressicollis Lec.\u201d, in MCZ.Label data: under bark of pine; in rotten log; fungus.SubgenusNikitsky 1998http://species-id.net/wiki/HolostrophinusHolostrophinusHolostrophus discolor Horn (orig. des.)Pseudoholostrophus in its double pronotal punctation and the indistinct pair of pronotal impressions. There is only a single world species in subgenus Holostrophinus.According to http://species-id.net/wiki/Pseudoholostrophus_discolorHolostrophus discolorPseudoholostrophus (Holostrophinus) discolor (Horn).\u2014This species may be diagnosed on the following combination of characters: eyes widely separated; dorsal setae conspicuous; pronotum with anterior margin elevated above level of head; meso- and metatibiae smooth, without oblique ridges; distribution in eastern North America.Pseudoholostrophus (Holostrophinus) discolor, based on examination of a single specimen only. Pollock (2008: 269) provided the following shorter description: TL 3.6\u20135.7 mm; GEW 1.6\u20132.4 mm; body , inner eye margin slightly emarginate; antennae provided a description of the adult of mm; body elongatemm; body ; dorsal antennae relativeantennae elongateCANADA: NEW BRUNSWICK, QUEBEC. UNITED STATES: INDIANA: Parke. MARYLAND: Calvert, Prince Georges. MASSACHUSETTS: Middlesex. NEW HAMPSHIRE: Carroll, Grafton, Strafford. PENNSYLVANIA: Warren. RHODE ISLAND: Kent. TENNESSEE: Sevier. VIRGINIA. (complete label data in Appendix 1).. RelativHolostrophus discolor Horn. LECTOTYPE, sex unknown, labeled \u201cVa. / Henry Ulke Beetle Coll. CMNH Acc. No. 1645 / Holostrophus discolor Horn\u201d, in CMNH. Paralectotype in MCZ.Prunus pensylvanica and maples (Acer spp.).Label data: in polypore fungus; malaise trap ; intercept trap ; on or near fleshy polypore fungi on beech log. According to Horn 1888http://species-id.net/wiki/HolostrophusHolostrophusEustrophus bifasciatus Say . In further justifying his separation of the genera Pseudoholostrophus and Holostrophus, Nikitsky (1998: 40) stated that \u201cit seems noteworthy that species of Pseudoholostrophus display the elytra either one-color but not black or with a light humeral spot only, or with a clarified diffused transverse fascia in basal part. A more clearly evident reddish-yellow or red spotty pattern of the elytra is characteristic of Holostrophus,PageBreak not Pseudoholostrophus\u201d. Paraholostrophus), based on three Oriental species. The sole Nearctic species is a representative of the nominative subgenus.According to http://species-id.net/wiki/Holostrophus_bifasciatusMycetophagus 4 maculatusEustrophus bifasciatusEustrophus 4-maculatusHolostrophus bifasciatus (Say).\u2014Holostrophus bifasciatus is the only Nearctic species of Eustrophinae with a distinct, quadrimaculate elytral color pattern; other diagnostic features include the widely separated eyes and smooth meso- and metatibiae (without oblique ridges).from : 271 TL CANADA: NOVA SCOPageBreakTIA, ONTARIO, PRINCE EDWARD ISLAND, QUEBEC. UNITED STATES: ALABAMA: Dale, Lee, Shelby. ARKANSAS: Drew, Logan, Newton, Polk, Pulaski, Washington. CONNECTICUT: Fairfield, Hartford, Litchfield, New Haven. DELAWARE: Sussex. DISTRICT OF COLUMBIA. FLORIDA: Hamilton, Liberty, Monroe. GEORGIA: Bartow, Clarke, Fulton, Jackson, Taliaferro. ILLINOIS: Bond, Carroll, Champaign, Clark, Coles, Cook, DuPage, Edgar, Kendall, Knox, LaSalle, Peoria, Putnam, St. Clair, Sangamon, Union, Wabash, Will. INDIANA: Marion, Parke, Porter, Posey, Wayne. IOWA: Johnson. KANSAS: Shawnee. KENTUCKY: Butler, Jefferson. LOUISIANA: Natchitoches. MAINE: Kennebec. MARYLAND: Baltimore, Calvert, Cecil, Dorchester, Harford, Montgomery, Prince George\u2019s, Talbot, Wicomico, Worcester. MASSACHUSETTS: Hampden, Hampshire, Middlesex, Norfolk, Suffolk. MICHIGAN: Livingston, Oakland, Wayne. MINNESOTA: Cook. MISSISSIPPI: George. MISSOURI: Hickory, Randolph, St. Louis. NEBRASKA: Sarpy. NEW HAMPSHIRE: Hillsborough, Rockingham, Strafford. NEW JERSEY: Bergen, Burlington, Cumberland, Essex, Middlesex, Ocean. NEW YORK: Bronx, Erie, Monroe, Onondaga, Orange, Richmond, Suffolk, Queens, Tompkins, Westchester. NORTH CAROLINA: Buncombe, Gaston, Moore, Wake. OHIO: Clark, Hamilton, Franklin, Ross, Wyandot. PENNSYLVANIA: Adams, Allegheny, Armstrong, Berks, Dauphin, Philadelphia, Pike, Westmoreland. SOUTH CAROLINA: Florence, Oconee, Pickens. TENNESSEE: Chester, Cumberland, Morgan. TEXAS: Sabine. VIRGINIA: Bath, Clarke, Fairfax, Lee. WEST VIRGINIA: Berkeley, Kanawha, Lewis, Morgan, Roane. WISCONSIN: Dane, Grant, Waukesha. (Complete label data given in Appendix 1).. The ranEustrophus bifasciatus Say. NEOTYPE (designated by Laetiporus sulphureus (AR); ex polypore in pine logs (AR); Trametes versicolor (AR); Schizopora paradoxa (AR); BLT ; ex polypore on cherry tree (AR); under loose pine bark (DE); under pine bark (GA); Malaise trap ; oak log (IL); sugar trap ; UV light ; flight trap . Pinus strobus, on which polypores were growing; also, specimens are known from Polyporus betulinus.Specimens have been collected in association with dead logs and/or associated fungi. Label data: Illiger 1802http://species-id.net/wiki/EustrophusEustrophusMycetophagus dermestoidesPageBreak 246; Eustrophinae were originally placed in Eustrophus, before the description of Holostrophus and Eustrophinus. Now, only a single Nearctic species is placed in Eustrophus.This genus comprises four species, distributed in Europe, Russian Far East, Japan, southern China, and North America . All of Say 1826http://species-id.net/wiki/Eustrophus_tomentosusMycetophagus nigerMycetophagus tomentosusEustrophus nigerEustrophus tomentosusThe following combination of characters is diagnostic for this species: widely separated eyes; antennal sensilla interrupted, not completely annular; dorsal setae distinctly golden to brown; meso- and metatibiae with oblique ridges.from : 273. TLPageBreakewan and Alberta. Most records from the United States are eastern, but specimens are also known from the Pacific Northwest, California, and Arizona. The 983 specimens examined in this study are from the following: CANADA: BRITISH COLUMBIA, MANITOBA, NOVA SCOTIA, ONTARIO, QUEBEC. UNITED STATES: ALABAMA: Lee, Madison, Marion, Mobile. ARIZONA: Coconino, Pima. ARKANSAS: Crawford, Faulkner, Fulton, Logan, Polk, Pulaski. CALIFORNIA: Butte, Calaveras, El Dorado, Placer, Yuba. COLORADO. CONNECTICUT: Litchfield. DELAWARE: Sussex. DISTRICT OF COLUMBIA. FLORIDA: Dixie, Monroe. GEORGIA: Bartow, Clarke, Echols. IDAHO: Boundary, Clearwater, Latah. IOWA: Johnson, Keokuk, Story. ILLINOIS: Bond, Champaign, Clark, Coles, Cook, LaSalle, McHenry, St. Clair, Union, Wabash. INDIANA: Montgomery, Parke, Porter, Tippecanoe, Vigo. KANSAS: Douglas. KENTUCKY: Butler, Henderson. LOUISIANA: Natchitoches. MARYLAND: Anne Arundel, Charles, Dorchester, Montgomery, Prince George\u2019s, Talbot. MASSACHUSETTS. MICHIGAN: Berrien, Charlevoix, Fillmore, Gogebic, Ingham, Kalamazoo, Kent, Lapeer, Leelanau, Livingston, Macomb, Midland, Monroe, Oakland, St. Joseph, Shiawassee, Washtenaw, Wayne. MINNESOTA: Crow Wing, Hennepin, Sherburne, Washington. MISSISSIPPI: George, Pearl River. MISSOURI: Boone, Dent, Franklin, Randolph, St. Charles. MONTANA: Dawson, Lake, Lincoln, Missoula, Ravalli, Rosebud, Sanders. NEBRASKA: Douglas, Sarpy. NEW HAMPSHIRE: Carroll. NEW JERSEY: Burlington, Gloucester. NEW MEXICO: San Miguel. NEW YORK: Erie, Essex, Genesee, Niagara, Onondaga, Orleans, St. Lawrence, Tompkins. NORTH CAROLINA: Durham, Moore, Stokes, Wake. NORTH DAKOTA: Pembina, Richland. OHIO: Athens, Butler, Clinton, Delaware, Hocking, Ottawa, Portage, Scioto, Vinton, Wayne, Wyandot. OKLAHOMA: Latimer, Oklahoma. OREGON: Benton, Crook, Douglas, Harney, Jackson, Lane, Linn, Multnomah, Wallowa, Yamhill. PENNSYLVANIA: Allegheny, Tioga, Westmoreland. SOUTH CAROLINA: Anderson, Florence, Pickens. TENNESSEE: Shelby. TEXAS: Angelina, Brewster, Montgomery, Sabine, Walker. UTAH: Washington. VERMONT: Franklin. VIRGINIA: Alexandria, Hampton, Nelson, Shenandoah. WASHINGTON: Walla Walla. WEST VIRGINIA: Braxton, Doddridge, Greenbrier, Hampshire, Jackson, Kanawha, Lincoln, Mason, Mineral, Nicholas, Pendleton, Randolph, Ritchie, Roane, Taylor, Webster, Wirt, Wood. WISCONSIN: Dane, Racine, Sauk, Washington. (Complete label data given in Appendix 1).. The disEustrophus tomentosus Say. NEOTYPE (designated by Pseudotsuga taxifolia (BC), from fungus (BC), evening flight, 4.ix (BC), ex Populus trichocarpa (BC), in bark Larix occidentalis (BC), fleshy fungus on tree (ON), under bark of pine (ON), under wet moldy bark on dead tree (ON), elm (QC), uv light trap (QC), cut surface of stump (QC), Ulmus americana (QC), under bark of pine (AL), Spongipellis unicolor (AR), Climacodes septentrionale (AR), Trametes versicolor (AR), under pine bark (CA), Lindgren trap with turpentine bait (CA), on Pinus ponderosa (CA), ex. Polyporus fungus (FL), uv light in oak-maple forest (IA), fungus on dead pine (ID), under bark of old pine stump (MD), in PageBreakPeromyscus nest debris under bark of dead standing Liriodendron (MD), fungus on oak (MN), funnel traps (MT), at black light, vi.1970 (NC), malaise trap, viii-ix (NE), window trap, 8\u201314.vi (NH), light trap, vi (NY), Lindgren funnel trap, alpha-pinene and ethanol lure (OR), stale molasses trap (SC), at wound on oak trunk (SC), malaise in mature hardwood forest, vi (SC), under bark of old dead decid. tree (VT), ex dead oak stump (WI), under bark of chestnut oak (WV). According to Eustrophus tomentosus are found under bark of dead trees, especially Ulmus americanus, as well as at sap exudations.Label data: Champion, 1889http://species-id.net/wiki/EustrophopsisEustrophopsisOrchesia quindecimmaculatusEustrophinusMycetophagus bicolor Fabricius 1798 (orig. des.); Eustrophusnec. Eustrophopsis is the most diverse world genus of Eustrophinae, with approximately 55 species, known from Afrotropical, Neotropical and Nearctic regions. Descriptions of the species are scattered through the literature, and there does not exist a comprehensive work on the entire genus, which is in need of revision. Nikitsky (1998: 58) stated that it is \u201cremarkable that Eustrophopsis seems to be absent both from the Oriental Region and Palaearctic. It may be so that it is replaced there by species of the genera Holostrophus and Synstrophus unknown from the Neotropical and Afrotropical regions\u201d.Eustrophopsis was described by Eustrophinus Seidlitz and placed in Eustrophopsis. Eustrophopsis became a senior synonym of Eustrophinus.Eustrophopsis seem referable into a number of informal groupings: Eustrophopsis confinis (very widely separated eyes); Eustrophopsis bicolor, Eustrophopsis brunneimarginatus, and Eustrophopsis indistinctus ; Eustrophopsis arizonensis (very rugose macrosculpture of proepisterna), and Eustrophopsis ornatus and Eustrophopsis crowdyi, sp. n. .Although admittedly preliminary, the Nearctic species of http://species-id.net/wiki/Eustrophopsis_confinisEustrophus confinisEustrophinus confinis (LeConte).\u2014Eustrophopsis confinis (LeConte).\u2014Eustrophopsis confinis is the only Nearctic member of this genus with very widely separated eyes dorsally. Other diagnostic features include: uniformly dark body; meso- and metatibiae with oblique ridges.from : 280. TLEustrophopsis confinis are seemingly rarely collected, and localities are scattered across the northern United States and southern Canada. The record from northern Saskatchewan represents the northernmost extent of the entire subfamily in North America. The 32 specimens are from the following jurisdictions: CANADA: BRITISH COLUMBIA, MANITOBA, NOVA SCOTIA, ONTARIO, SASKATCHEWAN. UNITED STATES: IDAHO: Kootenai, Latah. MAINE: Androscoggin. MICHIGAN: Mackinac. MONTANA: Carter, Rosebud. NEBRASKA. NEW HAMPSHIRE: Coos, Hillsborough. SOUTH DAKOTA: Pennington. WASHINGTON: Stevens. WISCONSIN. (Complete label data given in Appendix 1).. SpecimeEustrophus confinis LeConte. LECTOTYPE (designated by Polyporus anceps (ME). PageBreakPageBreakLabel data: Eustrophopsis confinis seem to be unique within the genus, and are reminiscent of the condition seen in members of Holostrophini and Eustrophus.As mentioned elsewhere, the very widely separated eyes of individuals of http://species-id.net/wiki/Eustrophopsis_bicolorMycetophagus bicolorEustrophus bicolor (Fabricius).\u2014Eustrophinus bicolor (Fabricius).\u2014Eustrophopsis bicolor (Fabricius).\u2014Eustrophinae based on the following combination of characters: antennomeres distinctly contrasting: 1\u20134 rufous, 5\u201310 dark piceous to black, 11 yellow-orange; pronotal punctation very fine, punctures not larger than diameter of setae; males with oval, setiferous pit on ventral edge of profemur; meso- and metatibiae with numerous, oblique ridges.This common species may be separated from the other Nearctic from : 277. TLEustrophopsis bicolor is the most commonly collected and/or geographically widespread species in the subfamily. It exhibits an eastern distribuPageBreaktion in Canada, with no records west of Winnipeg, Manitoba. In the United States, most records are eastern; however, scattered localities are known from several western states. This species is the only otherwise Nearctic eustrophine recorded from the West Indies. The 2,799 examined specimens are from the following jurisdictions: BAHAMAS. CANADA: MANITOBA, ONTARIO, QUEBEC. UNITED STATES: ALABAMA: Colbert, Greene, Jefferson, Lee, Madison, Mobile, Tuscaloosa. ARIZONA. Santa Cruz. ARKANSAS: Faulkner, Fulton, Garland, Hempstead, Johnson, Polk, Pulaski, Washington. CALIFORNIA: Trinity. COLORADO: Larimer. CONNECTICUT: Fairfield, Litchfield, New Haven, Tolland. DELAWARE: New Castle, Sussex. DISTRICT OF COLUMBIA. FLORIDA: Alachua, Baker, Brevard, Calhoun, Dade, Duval, Hernando, Highlands, Hillsborough, Jackson, Liberty, Monroe, Okeechobee, Orange, Osceola, Pinellas, Polk, Seminole, St. Lucie, Volusia, Wakulla. GEORGIA: Baker, Bartow, Calhoun, Camden, Clarke, Dekalb, Dougherty, Floyd, Fulton, Greene, Gwinnett, Lowndes, McIntosh, Meriwether, Muscogee, Paulding, Rabun, Thomas. IDAHO: Jerome, Twin Falls. ILLINOIS: Adams, Alexander, Calhoun, Champaign, Clark, Clay, Clinton, Coles, Cook, DuPage, Edgar, Effingham, Jackson, Jasper, Jefferson, Jersey, Johnson, Kendall, lake, LaSalle, Lawrence, Macon, Marion, Mason, McHenry, McLean, Peoria, Pike, Platt, Pope, Putnam, Richland, Sangamon, Stephenson, Vermilion, Wabash, Washington, White, Whiteside, Will, Winnebago. INDIANA: Bartholomew, Crawford, Howard, Lake, Laporte, Monroe, Parke, Perry, Porter, Posey, Tippecanoe, Vigo, Wayne. IOWA: Benton, Henry, Keokuk, Johnson, Linn, Osceola, Story. KANSAS: Atchison, Douglas, Labette, Lyon, Miami, Riley, Sedgwick, Shawnee, Trego, Wilson, Wyandotte. KENTUCKY: Butler, Christian, Green, Henderson, Taylor. LOUISIANA: Bossier, Caddo, Claiborne, Concordia, East Baton Rouge, East Feliciana, Jefferson, Livingstone, Madison, Natchitoches, Orleans, Webster, West Feliciana. MARYLAND: Allegany, Anne Arundel, Baltimore, Calvert, Caroline, Cecil, Charles, Dorchester, Frederick, Montgomery, Prince George\u2019s, Queen Anne\u2019s, St. Mary\u2019s, Talbot, Wicomico, Worcester. MASSACHUSETTS: Bristol, Dukes, Essex, Hampden, Hampshire, Middlesex, Norfolk, Suffolk, Worcester. MICHIGAN: Allegan, Berrien, Branch, Charlevoix, Clare, Clinton, Eaton, Ingham, Isabella, Kalamazoo, Kent, Lake, Lenawee, Livingston, Marquette, Midland, Monroe, Oakland, Ottawa, Saginaw, Schoolcraft, Shiawassee, Washtenaw, Wayne. MINNESOTA: Crow Wing, Hennepin, Washington. MISSISSIPPI: Bolivar, George, Issaquena, Jackson, Lafayette, Montgomery, Perry, Prentiss, Tallahatchie, Tishomingo. MISSOURI: Boone, Butler, Clay, Franklin, Greene, Jackson, Morgan, Randolph, Reynolds, St. Charles, St. Louis, Vernon. MONTANA: Richland, Rosebud, Valley. NEBRASKA: Cass, Colfax, Cuming, Douglas, Fillmore, Hall, Keith, Lancaster, Merrick, Nemaha, Sarpy, Saunders, Sheridan, Sioux, Thomas. NEW HAMPSHIRE: Rockingham, Strafford. NEW JERSEY: Bergen, Burlington, Cape May, Essex, Gloucester, Mercer, Middlesex, Monmouth, Morris, Ocean, Passaic, Salem, Union. NEW MEXICO: Roosevelt. NEW YORK: Bronx, Columbia, Erie, Nassau, Niagara, Onondaga, Queens, Richmond, Rockland, St. Lawrence, Schuyler, Suffolk, Tompkins, Westchester, Wyoming. NORTH CAROLINA: Bladen, Buncombe, Carteret, Columbus, Durham, Haywood, Henderson,PageBreak Johnston, Macon, Moore, Robeson, Wake. NORTH DAKOTA: Burleigh, Cass, Ransom, Richland. OHIO: Ashland, Clark, Clermont, Clinton, Cuyahoga, Erie, Franklin, Greene, Hamilton, Hancock, Licking, Montgomery, Ottawa, Scioto, Union, Warren. OKLAHOMA: Adair, Atoka, Beckham, Bryan, Caddo, Cherokee, Cleveland, Garfield, Grady, Latimer, Lincoln, Love, Marshall, Mayes, Muskogee, Okfuskee, Oklahoma, Osage, Payne, Pontotoc, Roger Mills, Tillman, Tulsa, Wagoner. PENNSYLVANIA: Allegheny, Berks, Bucks, Butler, Centre, Chester, Cumberland, Dauphin, Delaware, Erie, Greene, Lancaster, Philadelphia, Westmoreland. RHODE ISLAND: Newport, Providence. SOUTH CAROLINA: Abbevilee, Beaufort, Chester, Clarendon, Dorchester, Florence, Greenville, Kershaw, Oconee, Pickens, Sumter. SOUTH DAKOTA: Brookings, Yankton. TENNESSEE: Cumberland, Davidson, Hardeman, Knox, Lake, Lauderdale, Madison, McMinn, Shelby. TEXAS: Anderson, Angelina, Aransas, Bastrop, Bexar, Blanco, Brazoria, Brazos, Brewster, Brown, Caldwell, Cameron, Cass, Cherokee, Comal, Dallas, Denton, Galveston, Gonzales, Hardin, Harris, Hidalgo, Houston, Jeff Davis, Kenedy, Kerr, Live Oak, Mason, McLennan, Montague, Montgomery, Palo Pinto, Polk, Robertson, Sabine, San Augustine, San Patricio, Smith, Tarrant, Throckmorton, Travis, Tyler, Walker, Williamson, Wood. UTAH: Utah, Washington. VIRGINIA: Bath, Chesapeake, Chesterfield, Clarke, Covington, Essex, Fairfax, Hampton, Loudoun, Newport News, Suffolk, Westmoreland, York. VERMONT: Bennington. WASHINGTON: Asotin. WISCONSIN: Columbia, Dane, Dodge, Green, Jackson,. EustropMilwaukee, Racine, Sauk, Wood. WEST VIRGINIA. Barbour, Braxton, Greenbrier, Hancock, Jackson, Marshall, Mineral, Preston, Putnam, Ritchie, Roane, Tyler, Webster. WYOMING: Goshen. (Complete label data given in Appendix 1).not examined. This species has been well characterized in the literature by authors such as Horn and LeConte.Acer negundo (MB), bracket fungus (ON), in rotting Pleurotus (QC), on trunk of dead Ulmus americana (QC), under bark of dead maple (QC), under bark of rotting trunk of Pinus eliottii with polypore fungi (Bahamas), ex Fomes on Salix (Bahamas), under bark of Fagus (AR), Trametes versicolor (AR), Meripilus giganteus (AR), polypore tree fungus (AR), under rotting oak bark (CT), in litter at base of dying Ailanthus (CT), large orange polypore shelf fungus [? Polyporus sulphureus] on standing tree trunk (CT), Omphalotus olearius (CT), under bark (DE), shelf fungi (FL), Griffolia fungus (FL), Polyporus hypnoides (FL), Polyporus sulphureus , under bark of dead pine (FL), hibernating under bark, (GA), under bands of tar paper on apple trees (IL), Armillariella mellea (GA), Pleurotus ostreatus (IL), on shelf fungi (KS), in sweetgum stump (LA), Polyporus adustus (LA), Panus rudis , under bark of dead Pinus virginiana (MA), under bark dead standing Quercus (MA), in Peromyscus nest debris under bark dead standing Liriodendron (MA), under bark of stump of Prunus serotina (MA), fungus on bark (MS), injured cypress (NC), oak (NC), under bark dead standing pine (NC), under oak bark (NC), Pleurotus sp. , in mushroom (NC), Trametes hispida (ND), under hardwood bark (NJ), ex fungus on Mimosa stump (NJ), on polypore on dead Quercus (TX), polypore PageBreakfungus (UT), Polyporus squamosus (VT), under poplar bark (WI). Eustrophopsis bicolor from Pleurotus, Polyporus, Poria, Lentinus and Daedalia. Pleurotus sapidus, Polyporus squamosus, Polyporus betulinus, Polyporus versicolor, Polyporus confragosa. Synstrophus repandus in the same microhabitats.Label data: underside of fungusy, dead log at night (MB), on piece of cut wood at night (MB), fungusy stump of Mycetophagus bicolor Fabr. is probably a Platydema.\u201d According to LeConte (1873: 335), \u201cthe proper authority for this species is Say, its first describer; Eustrophopsis bicolor from those of Eustrophopsis indistinctus proved to be the most difficult problem in this study. Specimens of Eustrophopsis bicolor from northern and eastern North America are very distinctive from the southern specimens of Eustrophopsis indistinctus . However, as the ranges approach one another, distinguishing features between individuals of the two species become somewhat less conclusive.Taxonomically, the separation of southern specimens of Eustrophopsis bicolor basal struts of median lobe long and narrow in Eustrophopsis bicolor, while shorter and wider in Eustrophopsis indistinctus; and 3) ring-like portion of sternite 9 U-shaped in Eustrophopsis bicolor, while Y-shaped in Eustrophopsis indistinctus .Analysis of the male genitalia has revealed several consistent differences between bicolor , 63 and stinctus , 64, as Eustrophopsis bicolor and Eustrophopsis indistinctus.There appears to be a rather narrow zone of sympatry between the two species, e.g. Roosevelt County, New Mexico and Randall County, Texas. Hybridization may be occurring in the southwestern United States; for example, multiple specimens from Hidalgo County, Texas seem to exhibit a combination of features of both species. Future studies using molecular methods may be fruitful in \u201cfine-tuning\u201d relationships between http://species-id.net/wiki/Eustrophopsis_brunneimarginatusEustrophus brunneimarginatusEustrophinus brunneimarginatus (Dury).\u2014 Eustrophopsis brunneimarginatus (Dury).\u2014Eustrophinae by the presence of the marginal bands of lighter color along the otherwise dark pronotum and elytra. It is possible that Eustrophopsis marginatus (Champion) also occursPageBreak in the Nearctic region ; however, the marginal light markings are even more extensive than in Eustrophopsis brunneimarginatus.Specimens of this species may be distinguished from other members of TL 4.2\u20135.4 mm; GEW 2.0\u20132.8 mm. Body broadly ovate, moderately tapered posteriorly , distincEustrophopsis brunneimarginatus are known from scattered localities in eastern United States, west to east-central Texas. The 45 examined specimens are from the following jurisdictions: UNITED STATES: ALABAMA: Dale, Madison. ARKANSAS: Pulaski. FLORIDA: Liberty. GEORGIA: Monroe. ILLINOIS: Edgar, Wabash. INDIANA: Tippecanoe. LOUISIANA: Grant, Natchitoches. MISSISSIPPI: Tishomingo. MISSOURI: Randolph. NEW HAMPSHIRE: Coos. NORTH CAROLINA: Rockingham. OKLAHOMA: Latimer. SOUTH CAROLINA: Anderson. TEXAS: Anderson, Milam, Sabine, San Augustine, Tyler, Wood. VIRGINIA: Norfolk. WEST VIRGINIA: Hardy. (Complete label data given in Appendix 1).. SpecimeEustrophus brunneimarginatus Dury. LECTOTYPE (here designated), sex unknown, labeled \u201cKy near Cin. O. / Type / [handwritten] Eustrophus brunneimarginatus Dury Type / CMNH E2065\", in CNHM. Paralectotype, with same label data as lectotype, except with \u201cJune\u201d written on top label.Label data: flight intercept trap (AL); blacklight trap (AR); malaise trap, mixed hardwood/closed canopy seepage slope (FL); beach wash-up (NH); malaise, mature hardwood forest (SC); malaise trap in beech-magnolia forest (TX).Eustrophopsis bicolor based on being smaller, broader, less shining, much less narrowed posteriorly, less distinctly striate, and the light colored border of the pronotum and elytra. However, in the next article in the same journal issue, PageBreakseemingly synonymized his new species with Eustrophopsis confinis LeConte. These two species are quite different, however, and it is likely that Dury never examined actual specimen(s) of Eustrophopsis confinis.Eustrophopsis brunneimarginatus, except that the marginal light markings are much more extensive on the pronotum and elytra. It is possible that these specimens represent Eustrophopsis marginatus Champion. In the description, Eustrophopsis marginatus to Eustrophopsis bicolor, as Eustrophopsis brunneimarginatus was not yet described. Another species described by Eustrophopsis ovatus \u2013 possesses similar elytral and pronotal markings except that they are even more extensive than Eustrophopsis marginatus. I defer judgment on placement of the above mentioned specimens from southern Texas, as well as a possible synonymy of Eustrophopsis brunneimarginatus and Eustrophopsis marginatus, pending further study of the Neotropical eustrophines and detailed examination of Champion\u2019s types.A series of specimens from Hidalgo Co., Texas (TAMU) resemble http://species-id.net/wiki/Eustrophopsis_indistinctusEustrophus indistinctusEustrophinus indistinctus (LeConte).\u2014 Eustrophopsis indistinctus (LeConte).\u2014Eustrophopsis with a distinctly brown dorsal color; other diagnostic features include: antennomeres 1\u20134 and 11 not very distinctly contrasting in color with 5\u201310; eyes distinctly separated dorsally; pronotal punctation relatively coarse.This is the only species of PageBreak ridges; male with small, ovate, setiferous pit on ventral edge of profemur; aedeagus ., 76. TheEustrophus indistinctus LeConte. SYNTYPE, sex unknown, labeled \u201cgold disk / Type 4779 / Eustrophus indistinctus Lec.\u201d Specimen with gold disk ; the \u201cColorado\u201d referred to in the description is actually the Colorado River, and not the state.Populus snags (NM); fungi on Salix (AZ).Fungi (AZ); on bracket fungus (AZ); ex fungus on dying willow (NM); on dead log at night (NM); at night on fungusy logs (NM); at fungi on burned Eustrophopsis bicolor by Horn (1888: 34) who stated that \u201cspecimens collected by me in very early spring, in Arizona, have a decidedly brownish color above...These are probably merely less mature specimens as no other structural differences have been observed\u201d. This synonymy was followed by subsequent authors, e.g. Eustrophopsis indistinctus. Therefore, Eustrophopsis indistinctus has been removed from synonymy with Eustrophopsis bicolor and re-established as a distinct species. There remains some difficulty in distinguishing southern specimens of Eustrophopsis bicolor from Eustrophopsis indistinctus .This species was one of the earliest described Nearctic eustrophines; however, it was synonymized early on with http://species-id.net/wiki/Eustrophopsis_arizonensisEustrophus arizonensisEustrophinus arizonensis (Horn).\u2014 Eustrophopsis arizonensis (Horn).\u2014PageBreakgose macrosculpture; meso- and metatibiae with oblique ridges; distribution: western United States.This distinctive species may be diagnosed on the following combination of features: eyes moderately widely separated; prothoracic episterna with distinctly ruPageBreak to near black; ventral color lighter than dorsal: venter rufous; legs, mouthparts and antennomeres 1\u20134 and 11 light to dark rufous; dorsal vestiture uniform, setae relatively short; eyes moderately widely separated dorsally south to Oaxaca, Mexico. The 516 individuals examined are from the following: MEXICO: DURANGO, MORELOS, OAXACA, SONORA. UNITED STATES: ARIZONA: Apache, Cochise, Coconino, Gila, Graham, Navajo, Pima, Pinal, Santa Cruz, Yavapai. CALIFORNIA: Riverside, San Bernardino. COLORADO: Douglas, La Plata. MONTANA: Powder River. NEW MEXICO: Catron, Cibola, Grant, Hidalgo, Lincoln, Los Alamos, San Miguel, Torrance. SOUTH DAKOTA: Fall River. TEXAS: Brewster, Jeff Davis. UTAH: Washington. (Complete label data given in Appendix 1)., 76. EusEustrophus arizonensis Horn. LECTOTYPE, sex unknown, labeled \u201cAriz / LectoTYPE 8038 / E. arizonensis Horn / MCZ Type 34038\", in MCZ. Paralectotypes (3) in MCZ.Quercus (MX), under bark , under pine bark (AZ), ex. fungi (AZ), dead oak at night (AZ), under log (AZ), pine stump (CA).Label data: under bark, Eustrophopsis arizonensis, based on possession of this feature.The rugose nature of the prothoracic episterna of this species seems to be unique in the genus, perhaps in the entire subfamily. The Mexican specimens have been included in http://species-id.net/wiki/Eustrophopsis_ornatusEustrophinus ornatusEustrophopsis ornatus (Van Dyke).\u2014Eustrophopsis ornatus share the following diagnostic features: antennomeres 5\u201310 distinctly widened, in males flattened on one side and with elongate, accessory setae; most specimens with at least faint indication of light elytral markings on ventral surface; last maxillary palpomere not widened distally, apex slightly oblique; prosternal process acute, narrowly rounded distally, not attaining posterior margin of procoxae; coarse elytral punctures forming striae; prothoracic episternal suture present, surface of proepisternum smooth, punctation not obscured by rugose macrosculpture; meso- and metatibiae with numerous, oblique ridges; male with small, ovate, setiferous pit on ventral edge of profemur; aedeagus ., 76.The Eustrophinus ornatus Van Dyke. HOLOTYPE, sex unknown, labeled \u201cChiricahua Mts. Ariz 7000ft. June 21, 1927 / Cave Creek Cochise Co. / J.A. Kusche Collector / Van Dyke Collection / Holotype Eustrophinus ornatus Van Dyke / California Academy of Sciences Type No. 2581\", in CASC.Label data: under dead pine bark (AZ); WPB-baited Lindgren funnel trap (AZ); at UV light (AZ).ornatus\u201d due to the presence of distinctive, lighter colored markings on the dark elytra. In fact, of all specimens of Eustrophopsis ornatus examined for this study (other than the types), only very few specimens exhibited this \u201ctypical\u201d coloration. Many specimens had only a very faint indication of the lighter coloration, while others were entirely dark. The remarkably modified male antennomeres of this species and Eustrophopsis crowdyi is an indication of their possible close relationship.Van Dyke described this species as \u201curn:lsid:zoobank.org:act:309E2731-414C-4F7D-8B73-7D2F86D30F4Dhttp://species-id.net/wiki/Eustrophopsis_crowdyi31\u00b051.280'N, 109\u00b019.883'W, 14.vii.02 ex. WPB-baited Lindgren funnel trap, ca. 2000 m. / HOLOTYPE \u2642 Eustrophopsis crowdyi Pollock\" (in USNM). ALLOTYPE, female, with same label data as holotype, except \u201cALLOTYPE \u2640 Eustrophopsis crowdyi Pollock\" (in USNM). Four male and 2 female paratypes, same label data as holotype; 5 male and 4 female paratypes, labeled: \u201cAZ, Cochise Co., Turkey Crk, 31\u00b051.280'N, 109\u00b019.883'W, 7.vii.02 ex. WPB-baited Lindgren funnel trap, ca. 2000m. / near XPB-infested Chihuahua pine B. Fitzgibbon, coll.\"; 1 male and 1 female paratypes, labeled: \u201cUSA, AZ, Apache Co., Apache N.F., Luna Lk cmpgrd, ca. 5 mi. E. Alpine, 33\u00b050'04\"N, 109\u00b005'03\"W; 22.vi.2002 / collected at night under ponderosa pine bark, 7960ft. D.A. Pollock\". HOLOTYPE, male, labeled: \"AZ, Cochise Co., Turkey Crk, Eustrophopsis crowdyi may be diagnosed from other species of Eustrophopsis on the following characters: overall dark body color; eyes not approximate dorsally; males with short antennal sensilla; prosternal process rather blunt, rounded distally. As mentioned above for Eustrophopsis ornatus, that species and Eustrophopsis crowdyi are thought to be close relatives, based on the modified antennomeres of the males.Individuals of TL 5.6\u20137.9 mm; GEW 2.5\u20133.5 mm. Body elongate oval, relatively narrow, moderately tapered posteriorly , moderatHead with uniformly spaced, relatively coarse punctation; eyes deeply ePageBreake and lateral margins; posterior margin of pronotum bisinuate, inner sinuation deeper than outer; bead distinct along lateral, anterior, and posterior margins, somewhat obscured on middle lobe of posterior margin; prothoracic episternal suture present; surface of proepisterna smooth, regularly punctuate, without coarse or rugose macrosculpture; prosternal process attractant; some specimens were labeled as having been collected near a scolytine-infested Chihuahua pine (Pinus leiophylla). Two specimens were collected at night under ponderosa pine bark.PageBreakAll known specimens, except two, were collected using Lindgren funnel traps baited with western pine beetle (Eustrophopsis indistinctus in a neighbor\u2019s fungus-colonized birch (Betula) stump, which were the first specimens of that species I had seen from New Mexico.I am very pleased to be able to name this new species after my oldest son, George \u201cCrowdy\u201d Pollock, who has accompanied me on many collecting expeditions and who has made many interesting discoveries along the way. In fact, he found larvae and adults of Eustrophopsis crowdyi shares with Eustrophopsis ornatus conspicuously sexually dimorphic antennae, in males with a widening of antennomeres, one side of which is flattened and with setiform sensilla. While certainly not all world species of Eustrophinae have been studied in detail, this antennal modification is unique (so far) to these two species. As mentioned above, specimens of Eustrophopsis crowdyi were collected with many specimens of Eustrophopsis arizonensis and Eustrophopsis ornatus at the same locality in Cochise County, Arizona.PageBreakSeidlitz 1898http://species-id.net/wiki/SynstrophusSynstrophusEustrophus macrophthalmusSynstrophus (Synstrophus repandus (Horn) might eventually merit placement in a different genus-group taxon. A single species of Synstrophus is represented among Nearctic Eustrophinae.PageBreakThere are five species of strophus , distribhttp://species-id.net/wiki/Synstrophus_repandusEustrophus repandusSynstrophus repandus (Horn).\u2014This species is easily diagnosed based on the following features: body color uniformly dark; eyes narrowly separated; meso- and metatibiae smooth, without oblique ridges.PageBreakgin moderately emarginate; antennomeres 2\u20134 short, submoniliform; antennomeres 5\u201310 widened, becoming more triangular toward antennomeres 9\u201310; antennal sensilla completely annular; last maxillary palpomere unmodified, fusiform; prosternal process .PageBreak. AnotherEustrophus repandus Horn. LECTOTYPE, sex unknown, labeled \u201cPen / LectoTYPE / Eustrophus repandus Horn / MCZ Type 34039\", in MCZ. Paralectotypes (3), in MCZ.Pinus ponderosa bark (BC), shelf fungus on birch (BC), fungus on cottonwood (BC), Populus trichocarpa (BC), ex fungus on BetulaPageBreak(BC), underside of Populus trichocarpa log (BC), fleshy bracket fungus (ON), under wet moldy bark on dead tree (ON), Pleurotus ostreatus , polypore on branch of old Quercus rubrus (QC), under dead pine bark (AL), Meripilus giganteus (AR), ex fungi and under bark (FL), large mushroom on log (IL), Polyporus adustus (IL), Laetiporus sulphureus (IL), under Pinus bark (LA), ex bracket fungi (NC), in slimy fungus under pine bark (NY), under dead bark (SC), ex. Polyporus schweinitzii (VT), under bark of pine (WY).Label data: Synstrophus repandus is labeled \u201cEustrophus concolor Linn.\u201d This is the only known instance of this name to me, and it seems doubtful that it represents a described species.Among specimens in the LeConte collection (MCZ) a specimen of Eustrophinae is a good example of a group that is simultaneously rather obscure and poorly known to most coleopterists, and yet rather abundant, widespread and aPageBreak conspicuous component of the saproxylic fauna associated with dead coarse, woody material. Saproxylic beetles are important members of the insect community associated with the dead tree habitat in most forest types; they can be associated with the dead wood itself, fruiting bodies of wood-decaying fungi, or with other saproxylic species was post-depositional, or was initiated before the log rafted north. In any event, the relative shade and moisture of the riverbank allowed for the maintenance of the moisture critical to fungal growth and development of multiple generations of eustrophine beetles (both Synstrophus repandus and Eustrophopsis bicolor).Specimens of Eustrophopsis exhibit a definite split between western and eastern faunas, except for Eustrophopsis confinis, which is the only species with a more or less continuous distribution across North America ; also, this species is restricted to northern latitudes, with specimens examined from more localities in Canada than the United States. The most common species of eustrophine, Eustrophopsis bicolor, is very widespread east of the central plains states, with only scattered rePageBreakcords from the western United States. In Canada, no records are known from west of Manitoba. Another eastern species is Eustrophopsis brunneimarginatus, which seems restricted to the southeastern United States, west to south-central Texas.Species of Eustrophopsis is the southwestern United States, especially Arizona. The forested mountains and canyons in southern Arizona represent a zone of sympatry for five of the seven species of Nearctic Eustrophopsis. Among these five, relatively few specimens of Eustrophopsis bicolor are known from the southwest. The vast majority of specimens of another western species, Eustrophopsis arizonensis, are known from Arizona and New Mexico, but specimens are also known from as far north as southeastern Montana. This species also has a Mexican range as far south as Oaxaca. Specimens of Eustrophopsis indistinctus are known mainly from New Mexico and Arizona, with a northern range limit in southeastern Colorado, and southern limit in Mexico. The two remaining species of Eustrophopsis: Eustrophopsis ornatus and Eustrophopsis crowdyi, are known only from southernmost Arizona and New Mexico, with Eustrophopsis ornatus extending south into Mexico as well. This preliminary analysis of Eustrophinae biogeography suggests that the Nearctic fauna is a mixture of elements with close relatives in Europe and/or Asia or in the Neotropics (e.g. some southwestern U.S. Eustrophopsis).The most \u201ccomplex\u201d region for Eustrophinae are relatively well known taxonomically , the one group in need of detailed revisionary work is Eustrophopsis. Many species have been described from Neotropical and Afrotropical regions (including Madagascar), with more undoubtedly remaining to be discovered and/or described. This represents a complex biogeographic scenario, and at this point it is unknown (but perhaps doubtful) whether Eustrophopsis is a monophyletic taxon.While most genera of the Eustrophinae a group deserving of further research. Future work on the group should concentrate not only on the nomenclature and taxonomy of adults, but also on the collection and description of immature stages, and possible host preferences / associations between the eustrophines and the wood-decaying fungi in which they occur. This will contribute not only to a better, more robust classification of the Tetratomidae, but also to the overall phylogeny and evolution of the \u201clower Tenebrionoidea\u201d.The seeming ecological importance of this group of tenebrionoid beetles, combined with the relatively high species diversity make the"} +{"text": "In the list of references, 29 is incorrect. Reference 29 should read, \"Coco C, Zannoni GF, Caredda E, Sioletic S, Boninsegna A, et al. (2012) Increased expression of CD133 and reduced dystroglycan expression are strong predictors of poor outcome in colon cancer patients. J Exp Clin Cancer Res. 31: 71.\" Additionally, the affiliation for Dr. Xian-Ming Mo should be Laboratory of Stem Cell Biology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China."} +{"text": "AbstractSchrankia H\u00fcbner, 1825, S. pelicanosp. n. is described from Sichuan, China. A diagnostic comparison is made with Schrankia taenialis and Schrankia separatalis ; illustrations of the male holotype and its genitalia are provided. A checklist of the genus with synonyms is given.A new species of the genus Schrankia H\u00fcbner, 1825 is a widespread genus of Erebidae, being distributed in the Northern hemisphere, the Oriental and Australasiatic regions. It is represented by three species in Europe , also inhabits North America have a smaller and thinner body, narrow wings, grey or brownish forewing ground color, upcurved labial palps; ocelli also are absent. The configuration of the male genitalia is very uniform throughout the genus, having a very simple, long, narrow valva with small and thin processes at the base, and a short, wide aedeagus with a tapered caecum.The genus the eye and the the eye , uncus lurn:lsid:zoobank.org:act:033BC935-14EC-4A82-B753-15C530773B3Dhttp://species-id.net/wiki/Schrankia_pelicanoHolotype male. China, Sichuan, 29\u00b052.808'N, 102\u00b050.240'E, near Ying Jing, bamboo forest, 700 m, 4.IV.2011, leg. Floriani; slide No.: OP1429m . Paratypes. China, Sichuan: 4 \u2642\u2642, with same data as the holotype ; 1 \u2642 (coll. O. Pekarsky); 1 \u2642 .PageBreakThe species name refers to the resemblance of the opened male genitalia to a pelican.Schrankia . The autapomorphic features of Schrankia pelicano are the very long palpi, being much longer than in other species of Schrankia, the biarticulate uncus, the extremely large sacculus, which is almost equal in size and similar in shape to the distal half of the valva. Considering the diagnostic characters mentioned previously, the new species is placed into Schrankia, but its generic position could change through a much needed revision of the entire genus. Among Schrankia, the new species is closest to the Oriental group of species known from Korea and Japan, Schrankia separatalis, Schrankia dimorpha, Schrankia kogii, Schrankia masuii and Schrankia seinoi. This species-group is characterized by the flat, thin, weakly sclerotized distal half of valva, which has a rounded apex, wider and more strongly sclerotized haunch-like valval base, the well-developed apical saccular projection, and the less broadened caecum. The numerous autapomorphic features of the male genitalia of the new species about 2.8 times longer than 3rd segment, which is porrect; antenna with fine ciliation ventrally along full length, basal joint without pectination. Forewing elongate, narrow with acute apex, outer margin with rounded termen; ground color grey brown; costa straight with five milk-white patches; basal line barely visible, semicircular; antemedial line black, straight, oblique, curved upward near costa; postmedial line black, straight, oblique, extending from 2/3 from base on hind margin of wing to 9/10 from base on costal margin, edged on outer side by narrow yellow postmedial fascia; subterminal line faint, pale, irregular, parallel to outer margin of wing; terminal line black, most prominent between wing veins; cilia yellow at base with dark medial line, grey distally. Hindwing ochreous grey, discal spot grey, terminal line black; cilia pale yellow at base, grey distally. Abdomen slender, long. Female unknown.Male . WingspaMale genitalia TL: Europealbistrigatis Haworth, 1809 [TL: Britain]syn. Schrankia costaestrigalis TL: Wittlesea Mere, Swaffham, Norfolkexsularis Meyrick, 1888 TL: New Zealand, Taranakisyn. triangulalis Hudson, 1923syn. PageBreaksyn. costistrigalis Dannehl, 1925 [TL: Italy]lugubralis Dannehl, 1925 TL: South Tirol, Italysyn. monotona Lempke, 1949 [TL: Holland]syn. unicolor Lempke, 1949 [TL: Holland]syn. virgata Lempke, 1966 [TL: Holland]syn. hartigi Berio, 1991 TL: Sardiniasyn. Schrankia balneorum TL: N. Caucasusbosporella Budashkin & Klyuchko, 1990 TL: Crimeasyn. AfricaSchrankia solitaria Fletcher, 1961 TL: Ruwenzori, Mahoma River [Uganda]Schrankia microscopica TL: Aldabra Islands [Seychelles]Schrankia namibiensis Hacker, 2004 TL: Namibia, Brandberg, Am K\u00f6nigsteinSchrankia scoparioides Hacker, 2004 TL: Namibia, Brandberg, Hungarob-valleyAsiatic regionSchrankia obstructalis TL: Sarawak [Malaysia]Schrankia croceipicta TL: Ceylon, Pundaloyacroceipicta aegrota Berio, 1962; 179, TL: Seychelles, Mahe B., Vallonsyn. Schrankia aurantilineata TL: CeylonSchrankia separatalis TL: Koreasqualida Wileman & South, 1917; 28, TL: Japansyn. Schrankia dimorpha Inoue, 1979 TL: Kagawa Pref., Shinoe, Fudodaki [Japan]Schrankia kogii Inoue, 1979 TL: Hokkaido, Shintoku, KuttariSchrankia masuii Inoue, 1979 TL: Kagawa Pref., Shinoe, Oyashiki [Japan]Schrankia seinoi Inoue, 1979 TL: Amami-Oshima Is., Sumiyoson [Japan]Schrankia bilineata Galsworthy, 1997 TL: Hong KongSchrankia pelicano sp. n. TL: China, SichuanSchrankia bruntoni Holloway, 2008 TL: Ulu Temburon, BruneiSchrankia dusunorum Holloway, 2008 TL: Sabah, Ulu Dusun, 30mls W of Sandakan [Malaysia]Schrankia spiralaedeagus Holloway, 2008 TL: Sarawak, Gunong Mulu Nat. Park [Malaysia]Australasiatic regionSchrankia calligrapha Snellen, 1880 TL: New Hebrides, Aneityum, Red Crest, 3 km NE of AnelgauhatSchrankia taona TL: Samoa, SavaiiSchrankia capnophanes TL: Tasmania, Mt. WellingtonSchrankia dochmographa Fletcher, 1957 TL: Solomon Is., Rennell I., HutunaSchrankia furoroa Robinson, 1975 TL: Fiji, Rotuma, FuroroaSchrankia vitiensis Robinson, 1975 TL: [Fiji]Schrankia boisea Holloway, 1977 TL: New Caledonia, Port BoiseSchrankia cheesmanae Holloway, 1977 TL: New Hebrides, Aneityum, Red Crest, 3 km NE of AnelgauhatPageBreakSchrankia daviesi Holloway, 1977 TL: Norfolk Is., N. Mission RoadSchrankia erromanga Holloway, 1977 TL: New Hebrides, Erromango I., Nouankao CampSchrankia karkara Holloway, 1977 TL: New Guinea, Karkar I., Dampier I.Schrankia nokowula Holloway, 1977 TL: New Hebrides, Sanot, Mt. Tabwemasana, NokowulaSchrankia nouankaoa Holloway, 1977 TL: New Hebrides, Erromango I., Nouankao CampSchrankia tabwemasana Holloway, 1977 TL: New Hebrides, Santo, Mt. Tabwemasana, NokowulaSchrankia tamsi Holloway, 1977 TL: Samoa, Upolu I., Mt. VaeaNeotropical regionSchrankia macula TL: Panama, ChiriquiSchrankia flualis TL: Panama, Trinidad RiverSchrankia musalis TL: Panama, Trinidad RiverOceanian regionSchrankia altivolans TL: Hawaii, Mauna Loasimplex TL: Hawaiisyn. oxygramma TL: Kaua, Kaholuamano [Hawaii]syn. sarothrura TL: Hawaii, Olasyn. arrhecta TL: Hawaii, Mt. Waimeasyn. Schrankia howarthi Davis & Medeiros, 2009 TL: Hawaii"} +{"text": "David A. Boas, Constantinos Pitris, and Nimmi Ramanujam, Eds.:Handbook of Biomedical OpticsCRC Press, Taylor and Francis Group, Boca Raton, London, New York, 2011ISBN: 978-1-4200-9036-9 (Hardback), 787 pages The authors declare that they have no competing interests."} +{"text": "AbstractProrophora Ragonot, 1887 is newly recorded for China. Of the three species treated here, Prorophora (Reisserempista) binacanthasp. n. is described as new; Prorophora (Prorophora) albidogilvella Roesler, 1970 and Prorophora (Reisserempista) mongolica Roesler, 1970 are diagnosed and newly recorded for China. Images of adults and illustrations of genital structures are provided, along with a key to the known species.The genus Prorophora was established by Ragonot in 1887, with Prorophora curvibasella Ragonot, 1887 as the type species from Namangan, Turkestan (now Uzbekistan). Following Ragonot, Prorophora dialeuca from Sri Lanka and Prorophora grisealella from Senegal. Reisserempista, with Prorophora (Reisserempista) mongolica Roesler, 1970 as the type species. The same author PageBreak(1973) revised part of the Phycitinae species of the Palaearctic Region, in which he treated Aproceratia Amsel, 1950 as a synonym of Epischidia Ragonot, 1901, and transferred the latter genus to Prorophora as a subgenus.Prorophora Ragonot, 1887, Epischidia Ragonot, 1901 and Reisserempista Roesler, 1970, based on the characters of the maxillary palp, the male antenna and the female antrum. As Epischidia Ragonot, 1901 is both a homonym and a synonym of Epischidia Rebel, 1901 (Prorophora (Aproceratia) Amsel, 1950 for Prorophora (Epischidia) Ragonot. Later on, Prorophora halothamni from Uzbekistan and Prorophora (Prorophora) kazachstaniella from Kazakhstan. To date, the genus Prorophora comprisesthree subgenera with twelve valid species, which occur in North Africa, Southeast Europe and Asia.el, 1901 , RoeslerProrophora Ragonot, 1887 and subgenera Reisserempista Roesler, 1970 and Prorophora Ragonot, 1887 are provided. The new species Prorophora binacantha sp. n. is described in the subgenus Reisserempista. The type specimens are deposited in the Insect Collection, College of Life Sciences, Nankai University, Tianjin, China.In the present paper, we report three species from China based on the specimens collected in Inner Mongolia Autonomous Region, Gansu Province and Ningxia Hui Autonomous Region. A key to all the known species, diagnoses for Ragonot, 1887http://species-id.net/wiki/ProrophoraProrophoraProrophora curvibasella Ragonot, 1887, by monotypy. Ragonot, 1887: 252. Type species: AproceratiaProceratia rhectogramma Meyrick, 1937 , by monotypy. Synonymised by Amsel, 1950: 224. Type species: ReisserempistaProrophora Type species: Prorophora (Reisserempista) mongolica Roesler, 1970, by monotypy. Roesler, 1970: 55. subgenus of Prorophora is characterized by the frons with a distinct laterally compressed projection , Uzbekistan, Kazakhstan, Turkey, Iraq, Iran, Afghanistan, Pakistan, Lebanon, Palestine, Egypt, Sudan, Senegal and Sri Lanka. Newly recorded for China .PageBreakSubgenusRoesler, 1970Maxillary palp present. Male antenna with basal 3\u22129 flagellomeres curved, flagellomeres 5\u22129 each with one thorn on dorsal surface; culcita absent. Female antrum with a pair of scent scale tufts posterolaterally(shed easily), accessory sac present.urn:lsid:zoobank.org:act:1DC86CF1-34DC-444A-B50F-AB36D78A6101http://species-id.net/wiki/Prorophora_binacanthaChina, Inner Mongolia Autonomous Region: Mt. Helan , Alxa Zuoqi, 1683 m, 29.VII.2010, coll. Hongxia Liu and Zhiwei Zhang. Paratypes: 1 \u2642, 1 \u2640, Erenhot , 960 m, 02.VIII.2002, coll. Zhiqiang Li and Dandan Zhang, genitalia slide nos. LJY10019 \u2642, LJY10289 \u2640; 1 \u2642, 1 \u2640, Buyant , Urad Houqi, 1075 m, 17.VIII.2006, coll. Zhiwei Zhang, genitalia slide nos. LJY10292 \u2642, LJY11034 \u2640; 30 \u2642\u2642, 15 \u2640\u2640, Mt. Helan , Alxa Zuoqi, 1683\u22121836 m, 29.VII.\u221203.VIII.2010, coll. Hongxia Liu and Zhiwei Zhang, genitalia slide nos. LJY10658 \u2642, LJY11031 \u2642, LJY11028 \u2640; Ningxia Hui Autonomous Region: 1 \u2642, Yinchuan , VI.1986, genitalia slide no. LJY10028 \u2642; 5 \u2642\u2642, Suyukou , Mt. Helan, 2000 m, 10.VIII.2005\u221209.VIII.2006, coll. Xinpu Wang, Feng Yang and Qi He, genitalia slide nos. LJY09037 \u2642, LJY09065 \u2642, LJY10195, \u2642.Holotype \u2642 \u2013 Prorophora (Reisserempista) mongolica Roesler, 1970, but can be distinguished by the following characters: the forewing dark brown along veins between antemedian and postmedian lines; in the male genitalia, the valva with one spine at ventral 2/3, and the phallus with 3\u22125 cornuti; in the female genitalia, the elongate signum extending from the entrance to posterior 1/3 of the corpus bursae. In Prorophora (Reisserempista) mongolica, the forewing is yellowish brown along veins between antemedian and postmedian lines; the valva lacks the ventral spine, and the phallus hasPageBreak two cornuti; the signum is a small sclerotized subrounded plate, located in posterior 1/4 of the corpus bursae.This species is similar to PageBreakclearly separated; postmedian line greyish white, curved slightly inward at middle, edged with a broad dark brown band along inner side, with a thin yellowish brown band along outer side; termen pale dark brown; cilia greyish white. Hindwing greyish brown, outer margin dark brown; cilia greyish white. Legs with femura and tibiae greyish white, mixed with black; tarsi dark brown, mixed greyish white, ringed with greyish white at apex of each tarsomere. Abdomen pale yellow to yellowish brown dorsally, grayish white ventrally, mixed with dark brown.Adult , 2, 3 wiMale genitalia .bin-, and acanthus (= spinous), referring to the valva having an apical spine on the costa and a strong free apical spine on the ventral margin. The specific name is derived from the Latin prefix Roesler, 1970http://species-id.net/wiki/Prorophora_mongolicaProrophora (Reisserempista) mongolicaPageBreak Roesler, 1970: 55; Roesler, 1973: 76; Roesler, 1987: 394. .China, Inner Mongolia Autonomous Region: 1 \u2642, Chengguanzhen, Dengkou County , 1000 m, 19.VIII.2002, coll. Zhiqiang Li and Dandan Zhang; 31 \u2642\u2642, 15 \u2640\u2640, Buyant , Urad Houqi, 1075 m, 17.VIII.2006, coll. Zhiwei Zhang; 2 \u2642\u2642, 4 \u2640\u2640, Mt. Helan , Alxa Zuoqi, 1836 m, 03.VIII.2010, coll. Hongxia Liu and Zhiwei Zhang; Gansu Province: 1 \u2640, Minqin County , 1343 m, 26.VII.2006, coll. Xinpu Wang and Xiangfeng Shi. .Adult with win China ; Mongolia.SubenusRagonot, 1887 Maxillary palp absent. Male culcita absent or one pair. Female antrum elongate; two signa prominent on surface of corpus bursae, covered with conical spines on inner surface; ductus seminalis from posterior part of corpus bursae.Roesler, 1970http://species-id.net/wiki/Prorophora_albidogilvellaProrophora albidogilvella Roesler, 1970: 50. .Prorophora (Prorophora) albidogilvella Roesler, 1970: Roesler, 1973: 65; Roesler, 1987: 394.China, Inner Mongolia Autonomous Region: 1 \u2642, 4 \u2640\u2640, Ejin Qi , 927 m, 17\u221218.VII.2006, coll. Xinpu Wang and Xiangfeng Shi; Gansu Province: 1 \u2642, Minqin County , 1343 m, 26.VII.2006, coll. Xinpu Wang and Xiangfeng Shi. .PageBreak; Mongolia."} +{"text": "Journal of Neuroinflammation 8:101.Correction to Rao J S, Kim H W, Kellom M, Greenstein D, Chen M, Kraft A D, Harry G J, Rapoport S I, Basselin M. Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in brain of HIV-1 transgenic rats. The authors observe that the original study contains"} +{"text": "AbstractPaectes H\u00fcbner [1818] related to Paectes arcigera (Guen\u00e9e) and Paectes longiformis Pogue (Brazil) are described: Paectes aspersp. n. , Paectes medialbasp. n. (Argentina), Paectes similissp. n. (Brazil), Paectes sinuosasp. n. , and Paectes tumidasp. n. . Adults and genitalia are illustrated for all species. Taxonomic changes include the rev. stat. of Paectes nana as a valid species and revised synonymsPaectes indefatigabilis Schaus and Paectes isabel Schaus as junior synonyms of Paectes nana instead of Paectes arcigera. New host records for Paectes sinuosa and Paectes nana reared on Brazilian peppertree are presented. The holotype and female genitalia of Paectes obrotunda (Guen\u00e9e) are illustrated.Five new species of Paectes longiformis Pogue were sent to me for identification from scientists at the Biological Control Research and Containment Laboratory, University of Florida, Ft. Pierce, FL. This species is being tested for possible release as a biological control agent of the Brazilian peppertree , an invasive species with severe economic impact. Specimens originated near the airport in Salvador, Bahia, Brazil. Originally thought to be Paectes obrotunda (Guen\u00e9e), it proved to be a new species and Paectes nana and five additional new species that are described here. Taxonomic changes included the revised status of Paectes nana as a valid species and not a synonym of Paectes arcigera. Paectes burserae (Dyar) is a syn. n. of Paectes nana. Paectes indefatigabilis Schaus and Paectes isabel Schaus, both from the Galapagos Islands, Ecuador, are synonyms of Paectes nana and not Paectes arcigera as previously thought (Paectes obrotunda (Guen\u00e9e) is also referred to the Paectes arcigera group.In the collection of the USNM there were over 250 specimens identified as thought . PaectesPaectes arcigera group includes only the species referred to in this paper. Species in this group can be recognized by the elongate free saccular extension in the male genitalia. Including the species in this revision there are 12 species of Paectes in North America and 40 species in the Neotropics. Two of these species, Paectes nana and Paectes asper Pogue, occur both in North America and the Neotropics.The Specimens and images were examined from the following collections: The Natural History Museum, London, UKBMNH Peter J. Landolt collection, Yakima, WA, USALAN McGuire Center for Lepidoptera and Biodiversity, University of Florida, Gainesville, FL, USAMGCL Terhune S. Dickel Collection, Ocala, FL, USATDC Cole\u00e7\u00e3o Entomol\u00f3gica Padre Jesus Santiago Moure, Universidade Federal do Paran\u00e1, Curitiba, BRAZILUFPC National Museum of Natural History, Washington, DC, USAUSNM Washington State University, Pullman, WA, USAWSUPageBreakogy follows Dissection of genitalia follows the method of \u00ae ArcMap\u2122 10.0 . Latitude and longitude coordinates were obtained from the label data or from a localities database that I maintain. The data points were entered into a FileMaker Pro 11.0 v 3 database and then directly assembled as a data layer onto a world map projection using a GCS-WGS-1984 Geographic Coordinate System.Distribution maps were genhttp://species-id.net/wiki/Paectes_arcigeraIngura arcigerain Guen\u00e9e Neotype: Dominica. USNM, here designated. This is a confusing group of species that can only be identified reliably by genitalic characters, so to ensure the stability of the name, a male labeled \u201cDOMINICA: Grande Savane, 1 July 1964, O. S. Flint, Jr., genitalia slide male, USNM 135918 [green label]\u201d is designated as neotype for Ingura arcigeraGuen\u00e9e, 1852.St. Thomas: lost. BRITISH VIRGIN ISLANDS: Guana Island, 1\u201314 July 1984 , Genitalia slides m, USNM 135957, 1359980, 135991, 135993, 136010, S.E. & P.M. Miller; Virgin Gorda Island, Virgin Gorda Peak, ca. 400 m, 17\u201319 July 1986 , Genitalia slide m, USNM 135958, S.E. Miller & M.G. Pogue. DOMINICA: same data as neotype , genitalia slide male, USNM 136004, 13 May 1964 , 14 June 1964 , 28 Oct. 1966 , E.L. Todd, 31 Oct. 1966 , genitalia USNM 136003, E.L. Todd, 1 Nov. 1966 , E.L. Todd; Clarke Hall, 11 Jan. 1965 , J. F. PageBreakPageBreakG. Clarke & Thelma M. Clarke, 16 Jan. 1965 , J. F. G. Clarke & Thelma M. Clarke; 2.2 mi E of Pont Casse, 7 May 1964, O. S. Flint, Jr. ; Roseau, Nov. 1967 , N.L.H. Krauss; S. Chiltern , 8\u201310 Dec. 1964 , P.J. Spangler; no specific locality, May-June 1905 , Genitalia slide m MGP 1325, E. A. Agar [BMNH], Oct. 1904 , Nov. 1904 , Apr. 1905 , E. A. Agar [BMNH], , Genitalia slide m MGP 1324, E. A. Agar [BMNH], [BMNH]; Portsmouth, 8 Oct. 1956 , E. Hamblett [BMNH]. GRENADA: St. George\u2019s Cave, July 18 , genitalia slide male MGP 1321 [BMNH]. GRENADINES: Union I., June 1905 , genitalia slide MGP 1322 [BMNH]. GUADELOUPE: Port de Jaray, 14 Sep. 1982 , B. Lalanne-Cassou. PUERTO RICO: Bayam\u00f3n, 15 Jan. 1933 , Anderson & Lesesny; Guanica, Fajardo, 29 July 1913 , E. G. S. Collector; Maricao, Centro Vacacional, Monte del Estado, nr. Maricao, 1\u20139 Mar. 1971 , C.P. Kimball; Puerto Rico, Mayaguez, 3\u20134 Aug. 1955 , J.A. Ramos; San Juan, June\u2013July 1932 , Genitalia slide USNM 135929, C.G. Anderson. ST. LUCIA: no specific locality, , Branch; , Maj. Cowrie, [BMNH]; 1 mi NW Soufriere, 18\u201323 Nov. 1975 , Genitalia slide USNM 135933, E.L. Todd. ST. VINCENT: Bequia I., Sep. 1903 ; windward side, , H. H. Smith [BMNH]. TRINIDAD: No specific locality , A. Busck. U. S. VIRGIN ISLANDS: ST. CROIX: 1 mi W airport, 6\u201316 July 1967 , Genitalia slide USNM 42808; Christiansted, 19 Nov. 1941 , H.A. Beatty; Gallows Point, 9 July 1956 , genitalia slide USNM 136045, J.G. Coutsis; Orangegrove, W. End, 6\u201316 July 1967 , E.L. Todd.All specimens in USNM unless noted . Paectes arcigera from Paectes asper Pogue is by characters in the male and female genitalia. Male genitalia of Paectes arcigera consist of a reduced, fingerlike valve and costa, and a greatly expanded free saccular extension on Isla Santa Fe, Galapagos Islands, but this record can be referred to Paectes nana.Trinidad . ProbablPaectes arcigera has been confused in collections and in the literature as Paectes obrotunda. Paectes arcigera as occurring in Florida, but these are based on a broad concept of Paectes arcigera that made this revision of the species complex necessary. These Florida records are now known to be referable to Paectes asper and Paectes nana. Paectes arcigera as occurring in North America, unaware that the name represented a species complex. Paectes arcigera as occurring on Little Cayman Island, but this is probably referable to Paectes asper. Paectes arcigera and Paectes asper occur sympatrically in the U.S. Virgin Islands, British Virgin Islands, and Dominica.Pogue, 2012http://species-id.net/wiki/Paectes_longiformisPaectes longiformisin Pogue Holotype male \u2013 BRAZIL: Bahia, nr. Salvador airport , March 2010, R. Diaz, V. Manrique, M. Vitorino; USNM ENT 00148675; HOLOTYPE / Paecteslongiformis Pogue\u201d [red label]. UFPC. Paratypes \u2013 Same data as holotype; genitalia slide male USNM 134921; genitalia slides female USNM 135919, 135976, 135920, 135015, 135016. UFPC, USNM, CNC, BMNH.Paectes longiformis is most likely to be confused with Paectes similis Pogue, but can be differentiated by the color of the medial area of the forewing. In Paectes longiformis stat. rev.http://species-id.net/wiki/Paectes_nanaEdema nana Walker, 1865: 425.Ingura burseraesyn. n. Dyar, 1901: 455. Paectes indefatigabilissyn. rev. (previously synonymized by Poole 1993 under Paectes arcigera) Schaus, 1923: 38. Paectes isabelsyn. rev. (previously synonymized by Poole 1993 under Paectes arcigera) Schaus, 1923: 39. Edema nana \u2013 Type locality: \u201cDominican Republic, Santo Domingo\u201d Holotype male. UMO; photograph examined.Ingura burserae \u2013 Type locality: USA: Florida, Palm Beach. Syntypes male, female. USNM; types examined. Dyar listed two types, a male and female, in his original description. I hereby designate the male as lectotypeto avoid confusion in this complicated group.Paectes indefatigabilis \u2013 Type locality: [Ecuador]: [Galapagos Islands]: Indefatigable, Conway Bay. Lectotype male. USNM; examined. Paectes isabel \u2013 Type locality: [Ecuador]: [Galapagos Islands]: Indefatigable, Conway Bay. Holotype male. USNM; examined.PageBreakCOLOMBIA: BOYACA: Muzo, 400\u2013800 m, , Fassl [BMNH]. CAUCA: Popayan, May 1972 , R. Perry [BMNB]. MAGDALENA: Don Amo, 2000 PageBreakft., June 1911 , genitalia slide male MGP 1302, female MGP 1304, 4000 ft., , H. H. Smith [BMNH]; Minca, 2000 ft., , June , H. H. Smith [BMNH]; Valparaiso, 4000 ft., , genitalia slide male MGP 1300, H. H. Smith [BMNH]. SANTA MARTA: Onaca, June\u2013Aug. , genitalia slide male MGP 1301, female MGP 1303, C. Engelke [BMNH]. COSTA RICA: no specific locality, genitalia slide MGP 1329, Underwood, BMNH; GUANACASTE: Area de Conservacion Guanacaste, Mundo Nuevo, Quebrada Tibio Perla, 300 m, 26 Nov. 2009 , J. Cortez, host: Bursera simaruba; Area de Conservacion Guanacaste, Potrerillos, Rio Azufrado, 95 m, 29 Sep. 2002 , G. Pereira, host: Bursera simaruba; Area de Conservacion Guanacaste, Santa Rosa, Quebrada Guapote, 240 m, 12 July 1994 , 280 m, 7 July 1993 , gusaneros, host: Bursera tomentosa; Area de Conservacion Guanacaste, Santa Rosa, Area Administrativa, 295 m, 4 May 1995 , genitalia slide male USNM 136087, gusaneros, 22 Aug. 1984 , D.H. Janzen, host: Bursera simaruba; Area de Conservacion Guanacaste, Santa Rosa, Bosque San Emillio, 300 m, 30 June 1983 , 7 July 1983 , D.H. Janzen, host: Bursera tomentosa; Area de Conservacion Guanacaste, Santa Rosa, Laguna Escondida 285 m, 23 June 2005 , R. Franco, host: Bursera tomentosa; Area de Conservacion Guanacaste, Santa Rosa, Bosque Humedo, 290 m, 21 Aug. 1991 , gusaneros, host: Bursera tomentosa; Area de Conservacion Guanacaste, Santa Rosa, Luces, 6 July 1992 , gusaneros, host: Bursera tomentosa; Area de Conservacion Guanacaste, Pocosol, Casa Garzal, 245 m, 1 July 2004 , R. Franco, host: Bursera simaruba; Area de Conservacion Guanacaste, Cacao, Sendero Guayabal, 500 m, 7 Oct. 2004 , D. Garcia, host: Bursera simaruba. CUBA: LA HABANA: Santiago de Las Vegas, 12 July 1931 , genitalia slide USNM 136068, A. Otero. ORIENTE: Santiago, , genitalia slide USNM 33943. DOMINICAN REPUBLIC: BARAHONA: nr. Filipinas, Larimar Mine, 20\u201326 June 1997 , genitalia slide male MGP 1334, P. Landolt, R. Woodruff, P. Skelley [LAN]. DAJABON:13 km S Loma de Cabrera, 400 m, 20\u201322 May 1973 , D. & M. Davis. LA VEGA: Hotel Montana, 520 m, 28 May 1973 , genitalia slide male USNM 135936, D. & M. Davis; Constanza, Hotel Nueva Suiza, 1164 m, 29 May 1973 , D. & M. Davis; vic. Jarabocoa, 22 June 1981 , 27 June 1981 , genitalia slide USNM 136266, C.V. Covell, Jr. NATIONAL DISTRICT: Santo Domingo, , A. Busck. ECUADOR: GALAPAGOS: Indefatigable, Conway Bay, 1 Apr. 1923 , genitalia slide male USNM 135966; South Seymour, 23 Apr. 1923 . IMBABURA: Paramba, Jan. \u2013May , genitalia slide MGP 1309 [BMNH]. GUATEMALA: BAJA VERAPAZ: Chejel, Schaus and Barnes Coll. , genitalia slide, USNM 135915. SUCHITEPEQUEZ: Univ. del Valle de Guatemala Research Station, nr. Aldea Adelaida/Finca Panama, nr. Santa Barbara, 1550 m, 12 Aug. 2010 , P.J. Landolt [LAN]. ZACAPA: Santa Cruz, Marble Quarry rd., NE of Teculutan, 560 m, 18 July 2007 , genitalia slide MGP 1339, 290 m, 19 July 2007 , genitalia slide MGP 1342, P.J. Landolt PageBreak[LAN], , R.S. Zack [WSU]. MEXICO: DISTRICTO FEDERAL: Mexico City, , C. Mayer [BMNH]. HIDALGO: 5 mi E Tulancingo, 7400 ft., 24 July 1963 , genitalia slide USNM 136055, Duckworth & Davis; nr. San Vicente, 2 July 1965 , genitalia slide USNM 135954, Flint & Ortiz; Zacualpan, 15 Aug. , genitalia slide male USNM 33942, R. Muller. JALISCO: Guadalajara, Coll. Wm. Schaus ; Guadalajara, Oct. \u2013Nov. 1898 , P. H. Goldsmith, Oct. 1896 , Schaus [BMNH]. OAXACA: Oaxaca, , genitalia slide male USNM 42805, Coll. Wm. Schaus, June 1896 , Schaus [BMNH]. PUEBLA: Tehuacan, 11 June , R. Muller. TAMAULIPAS: Rancho del Cielo, 6 km NNW Gomez Farias, 3500 ft., July 1982 , genitalia slide USNM 135056, M.A. Solis. VERACRUZ: Orizaba, 11 June , R. Muller; Jalapa, , genitalia slide MGP 1326, M. Trujillo [BMNH]. YUCUTAN: Chichen Itza, 7 July 1955 , E. C. Welling [BMNH]. U.S.A.: FLORIDA: Collier Co., Chokoloskee, , genitalia slides m USNM 136256, f USNM 136262. Hernando Co.: Bay Port, 24 Jan. 1989 , genitalia slides male MGP 1274, 1277, 1281, J. Gillmore MGCL. Lee Co.: no specific locality, 18 Sep. 1987 , genitalia slide USNM 136052, D. Maloney USNM. Levy Co.: Cedar Key, 20 Sep. 1995 , genitalia slide m MGP 1280, J. Gillmore & J. Medal MGCL. Manatee Co., Oneco, May 1954 , genitalia slide USNM 136258, P. Dillman. Miami-Dade Co.: Royal Palm State Park, , Mar. , genitalia slides female USNM 136041, 136261, F.M. Jones; Oweissa-Bauer Hammock, 27 Dec. 1979 , genitalia slide MGP 1287, H.D. Baggett MGCL. Monroe Co.: Big Pine Key, Cactus Hammock, 20 Sep. 1989 , genitalia slides male MGP 1282, 1283, D. Habeck, J. Gillmore, M. Hennessey MGCL; Crawl Key, 22 Mar. 1988 , genitalia Vial #83, D.H. Habeck MGCL; Fleming Key, 20 June 1979 , J.A. Acree & H.V. Weems, Jr. MGCL; Key Largo, 16 Sep. 1964 , Mrs. Spencer Kemp MGCL; Key Largo Key [sic], 20 Sep. 1964 , genitalia slide male MGP 1278, Mrs. Spencer Kemp MGCL; Long Key State Park, 21 Dec. 1983 , T.S. Dickel TDC; No Name Key, 29 July 1992 , W.L. Adair, Jr. MGCL. Pinellas Co.: Dunedin, Hammock Park, 19 Jan. 1986 , 2 Feb. 1986 , 8 Feb. 1986 , J.D. Worsley MGCL. Sarasota Co.: Siesta Key, 3 Jan. 1960 , 21 Nov. 1953 , genitalia slide USNM 136259, C.P. Kimball USNM, 2 Apr. 1954 , genitalia slide MGP 1286, 18 May 1957 , 18 May 1960 , 5 Nov. 1953 , C.P. Kimball MGCL; St. Lucie Co.: 8 mi N Ft. Pierce n Turnpike, 22 Sep. 1995 , D.H. Habeck, R. Goodson, G. McDermott MGCL. VENEZUELA: ARAGUA: Rancho Grande, 1100 m, 30\u201331 Mar. 1978 , 1\u20133 Apr. 1978 , genitalia slide male USNM 135964, J.B. Heppner, 22\u201331 July 1967 , genitalia slide male USNM 135963, genitalia slide female USNM 135960, 1\u20137 Aug. 1967 , 8\u201314 Aug. 1967 , 15\u201321 Aug. 1967 , genitalia slide male USNM 42804, R.W. Poole. LARA: Yacambu Nat. Park, 13 km SE Sanare, 1560 m, 28\u201331 July 1981 , 1\u20135 Aug. 1981 , Genitalia slide USNM 135968, J. PageBreakHeppner. MERIDA: Mucy Fish Hatchery, 7 km E Tabay, 6600 ft., 10\u201313 Feb. 1978 , J.B. Heppner. NORTE DE SANTANDER: Cucuta, , genitalia slide MGP 1305 [BMNH]. T.F. AMAZONIA: Cerro de la Neblina, Basecamp, 140 m, 1\u201310 Mar. 1984 , D. Davis & T. McCabe. YARACUY: Aroa, , Coll. Wm. Schaus.All from USNM unless noted. . Paectes nana has two distinct forms. The most easily recognized bears exaggerated dark markings on the apical portion of the postmedial line that is contiguous with the subapical dash, the posterior portion of the postmedial line from CuA1 to posterior margin, and the antemedial line from just dorsal to anal vein to posterior margin are common on gumbo-limbo (Bursera simaruba (L.) Sarg., Burseraceae). In Costa Rica Paectes nana collecting dates range from May through November and has been reared from Bursera simaruba and Bursera tomentosa (Jacq.) Triana & Planch.Paectes nana has two forms. A form that is easily confused with Paectes asper and a more boldly marked form where the antemedial and postmedial lines and marginal dash are heavily marked with black and there are scattered black scales along the forewing posterior margin adjacent to the antemedial line. The holotype of Paectes nana is a heavily marked form.Poguesp. n.urn:lsid:zoobank.org:act:16EDE70C-D0AF-4CF7-A020-27E4EB09AF8Fhttp://species-id.net/wiki/Paectes_asperHolotype male \u2013 CUBA: Santiago, Collection Wm. Schaus; HOLOTYPE / Paectes asper Pogue\u201d [red label]. USNM. Paratypes \u2013 . All from USNM unless noted. Same data as holotype genitalia slide male USNM 135978, genitalia slides female USNM 135977, 135981\u2013 135983; , genitalia slide male MGP 1314 [BMNH]. BAHAMAS: no specific locality [BMNH]. ABACO ISLANDS: no specific locality, , Mar. 1902 , genitalia slide male MGP 1313, J.J. Bonhote [BMNH]. ANDROS: Andros Town, 27\u201329 Jan. 1965 , genitalia slide USNM 135927, leg. W. U. R. Piath; Mangrove Cay, 11 Jan. 1902 , J.J. Bonhote [BMNH]. NEW PROVIDENCE: Nassau, , Col. Jacob Doll.; Nassau I., 8 July 1898 , 14 July 1898 , J.J. Bonhote [BMNH]. BRITISH VIRGIN ISLANDS: Great Camanoe Is., 1/3 mi ESE Cam Bay, 18 Mar. 1974 , C.L. Remington; Guana Island, North Bay, 0 m, 15\u201325 July 1986 , S.E. Miller & M.G. Pogue; Guana Island, 0-80 m, 13\u201326 July 1986 , genitalia slide USNM 135931, S.E. Miller & M.G. Pogue; Guana Island, 1\u201314 July 1984 , Genitalia slides male USNM 135979, 135990, 135992, 136009, genitalia slides female 135998, 136005, 136006, 136007, 9\u201315 July 1985 , S.E. and P.M. Miller; Tortola, 14 May 1980 , 29 May 1980 , 28 July 1973 , 23 Oct. 1972 , Oct. 1972 , genitalia slides MGP 1319, 1320, 12 Nov. 1973 , 14 Nov. 1972, , 18 Nov. 1972 , J. Lorimer, 5 June 1974 [BMNH]. CAYMAN ISLANDS: CAYMAN BRAC: behind Stakes Bay, 20 May 1938 , 21 May 1938 , 22 May 1938 , C.B. Lewis, G.H Thompson; N. coast of Stakes Bay, 20 May 1938 , 22 May 1938 , genitalia slide MGP 1318, C.B. Lewis, G.H Thompson; west end of Cotton-tree Land., 19 May 1938 , 22 May 1938 , C.B. Lewis, G.H Thompson [BMNH]. GRAND CAYMAN: east end of East End, 13 PageBreakMay 1938 , 16 May 1938 , C.B. Lewis, G.H Thompson; Georgetown, , genitalia slide male MGP 1317, A.W. Cardinall; N. coast of North Side, 11 July 1938 , 14 July 1938 , 16 July 1938 , PageBreakC.B. Lewis, G.H Thompson; west end of Georgetown, 14 May 1938 , C.B. Lewis, G.H Thompson [BMNH]. LITTLE CAYMAN: south coast of South Town, 31 May 1938 , 2 June 1938 , 4 June 1938 , C.B. Lewis, G.H Thompson [BMNH]. COLOMBIA: SAN ADRES, PROVIDENCIA, AND SANTA CATALINA: San Andr\u00e9s, 300 ft., Apr. 1926 , genitalia slides MGP 1328, 1351, F.W. Jackson [BMNH]. CUBA: no specific locality, , genitalia slide male USNM 42806, genitalia slides female USNM 135962, 135985, Coll. Wm. Schaus, , Dognin Coll.; no specific locality, , genitalia slide male MGP 1315 [BMNH]. GUANTANAMO: Baracoa, , Aug. Busck Collector, 12 Feb. 1958 , Genitalia slide USNM 135955, B. Wright. HOLGUIN: Holguin, , H.S. Parrish [BMNH]. LA HABANA: Cayamas, , E.A. Schwarz. ORIENTE: Santiago, , genitalia slide male MGP 1314, W. Schaus [BMNH], June 1902 , Nov. 1902 , W. Schaus [BMNH]. DOMINICA: 1 mi N Mahaut, 12 June 1964 , genitalia slide USNM 136002, O.S. Flint, Jr.; Clarke Hall, 3 June 1964 , genitalia slide USNM 135984, O.S. Flint, Jr.; Grande Savane, 13 May 1964 , genitalia slide USNM 135961, 20 May 1964 , genitalia slide male USNM 135975, genitalia slide female USNM 136057, 14 June 1964 , genitalia slide USNM 135995, 31 Oct. 1966 , genitalia slide male USNM 135994, genitalia slide female USNM 136008, O.S. Flint, Jr.; Macoucheri, 1 Feb. 1965 , genitalia slide USNM 136058, 12 Feb. 1965 , genitalia slide female USNM 42810, 5 Mar. 1965 , J.F.G. & Thelma Clarke. DOMINICAN REPUBLIC: San Cristobal, 8\u20139 June 1969 , genitalia slide USNM 135986, Flint & Gomez. HAITI: No specific locality, , genitalia slide male USNM 135928; no specific locality, , genitalia slide male MGP 1322 [BMNH]. JAMAICA: no specific locality, , genitalia slide male USNM 135930; no specific locality, [BMNH]. ST. ANDREW: Newcastle, , genitalia slide MGP 1316 [BMNH]. ST. JAMES: Montego Bay, 24 Jan. 1924 , Gillett; Up Camp [BMNH]; Kingston, July 17, at electric light, several were taken, Cockerell . TRELAWNY: Runaway Bay, 28 Mar. 1905 [BMNH]. PUERTO RICO: no specific locality, , genitalia slide MGP 1331 [BMNH]. U.S.A.: FLORIDA: Miami-Dade Co., Biscayne Bay, , Collection H.G. Dyar; Coconut Grove, Nov. 1897 , Roland Thaxter Coll. Florida City, 9 June 1937 ; Miami, , genitalia slide male USNM 136000, genitalia slide female USNM 136001. Monroe Co., Key Largo Key [sic], 13 Dec. 1968 , genitalia slide MGP 1285, Mrs. Spencer Kemp MGCL, 6 Jan. 1969 , genitalia slide USNM 136260, Mrs. Spencer Kemp USNM; Bahia Honda State Park, 6 Jan. 1989 , 17 Jan. 1990 , 21 Jan. 1996 , 12 Mar. 1989 , 23 Mar. 1990 , 29 Mar. 1990 , 28 Oct. 1988 , 8 Nov. 1988 , 29 Dec. 1989 , T.S. Dickel TDC; Long Key State Park, 5 Feb. 1986 , 16 Feb. 1985 , 4 Mar. 1994 , 26 Dec. 1994 , T.S. Dickel TDC; Key Largo Hammock Botanical State Park, 17 Jan. 1987 , PageBreak30 Jan. 1992 , 2 Feb. 1995 , 12 Feb. 1990 , 21 Feb. 1995 , T.S. Dickel TDC; No Name Key, 19 Oct. 1987 , T.S. Dickel TDC; Windley Key, 3 June 1983 , T.S. Dickel TDC. Palm Beach Co., Dec. 1897 , genitalia slide USNM 135932, Dec. 1898 , genitalia slide USNM 135999, R. Thaxter. Palm Beach Co., Palm Beach, Dec. 1897 , R. Thaxter. U.S. VIRGIN ISLANDS: ST. CROIX: Blue Mtn., 6\u201316 July , E.L. Todd; Christiansted, 19 Nov. 1941 , H.A. Beatty; Gallows Point, 11 July 1956 , genitalia slide USNM 136044, J.G. Coutsis; Kingshill, 6\u201316 July 1967 , E.L. Todd; Mt. Eagle, 6\u201316 July 1967 , E.L. Todd; Orangegrove, W End, 6\u201316 July 1967 , Genitalia slide m USNM 42807, E.L. Todd. USNM, CNC, BMNHThe species name is the Latin term for rough, which refers to the roughened texture of the apex of the free saccular extension in the male genitalia.Paectes asper and mostly gray with some ferruginous in Paectes arcigera. The medial area of the forewing is mostly white with a white apical spot in Paectes asper; in Paectes arcigera these areas are cream-colored.The forewing costa is ferruginous with some gray in Paectes asper and Paectes arcigera. The valve in Paectes asper has thick, curved dorsal setae; in Paectes arcigera the setae are hairlike. The costa is truncate in Paectes asper but triangulate in Paectes arcigera. The free saccular extension is narrow in Paectes asper and wide with an expanded apex in Paectes arcigera.The male genitalia are easily differentiated between Paectes asper; these projections are absent in Paectes arcigera. The ostium bursae is crescent shaped bearing minute spicules in Paectes asper whereas in Paectes arcigera the ostium bursae is semicircular in shape and bears large conical spines.The female genitalia have small, curved lateral projections at the base of the eighth sternite in Male.Head \u2013 antenna broadly bipectinate to 3/5 length then filiform; eyes large, globular; vertex with broad scales, light-brown mixed with pale- and dark-ferruginous scales; frons with broad scales, projecting slightly beyond anterior eye margin, concolorous with vertex, two small black dots on eye margin; labial palp porrect, mixture of light-brown and ferruginous scales, internal surface white. Thorax \u2013 prothorax pale ferruginous, with a thin, black anterior margin, posterior margin pale gray, can be mixed with black or dark-ferruginous scales; patagium pale gray variably mixed with ferruginous and a few black scales, mixed with hairlike scales; pro and mid tibia gray and ferruginous mixed with white scales, apical band present, tarsi ferruginous with white apical bands; hind tibia ferruginous mixed with white scales, lighter than pro or mid tibia, tarsi white mixed with ferruginous scales, apical bands not distinct; underside with white hairlike scales; forewing length 9.4\u201312.9 mm; costal area dark gray and ferruginous; ovate basal spot distinct; antemedial line black, sharply angulate basally, continues around ventral margin of ovate spot, arrowhead shaped; reniform a pair of small ferruginous spots, vertically oriented; interior of wing a variable mix of white, pale- ferruginous, and ferruginous scales, always lighter than costa and subterminal area; postmedial line black, black and ferruginous, or ferruginous, a double line from posterior margin to below M vein, then a single line to M1 vein; black horizontal dash between R5 and M1 vein continuing to outer marPageBreakgin; apical spot white; subterminal area gray, distal border ferruginous and dentate; terminal area with irregularly shaped tan patch near tornus; terminal line a series of dark-ferruginous spots between wing veins; fringe pale gray becoming white at apex; hind wing white, marginal shading dark gray, veins highlighted dark gray, anal fold with a white and dark-gray striped pattern; fringe white. Abdomen \u2013 dorsum variable from pale gray to dark gray mixed with ferruginous scale patches, distal margin of segments usually with a darker line that can be ferruginous or black, obscure cream-colored dorsal band from middle to antemedial segment; venter variable from white to tan to ferruginous, medial line black to ferruginous flanked by paler, wider, lateral lines variable in color and intensity from black to gray, or can be represented by a thin medial line; male eighth segment membranous with a pair of short, sternal, sclerotized bars and a pair of longer, slightly wider, dorsal sclerotized bars; a pair of lateral coremata bearing numerous, fine, elongate setae. Genitalia , and the British Virgin Islands, U.S. Virgin Islands, and Dominica in the Lesser Antilles and albus (white) to refer to the white medial area of the male forewing.The species name is derived from the combination of the Latin terms Paectes medialba has been confused with Paectes longiformis in the USNM collection. It differs from Paectes longiformis by the more pronounced white medial area of the male forewing and its distribution in northwestern Argentina versus the northeastern Brazil distribution of Paectes longiformis. There are many differences in the male genitalia of Paectes medialba and Paectes longiformis. The free extension of the sacculus in Paectes longiformis is much longer than in Paectes medialba and is spiculate in Paectes medialba and non-spiculate in Paectes longiformis. The setae on the dorsal surface of the valve are wide, elongate, curved apically, and numerous in Paectes medialba whereas in Paectes longiformis they are hairlike, shorter, straight, and more sparse. In the female genitalia the lateral projections of the eighth sternite are more produced and sharply pointed in Paectes medialba ARGENTINA: COLON: Sierras de Cordoba, La Granja, , A. Garcia [BMNH]. LA RIOJA: La Rioja, , genitalia slide MGP 1353, Jan.\u2013Feb. , [no date] F. Giacomelli [BMNH]. SALTA: Salta, Feb. 1905 , genitalia slide MGP 1312, J. Steinbach [BMNH]. SANTIAGO DEL ESTERO: Santiago del Estero, , J. Steinbach [BMNH]. TUCUMAN: Tucuman, , genitalia slides male, MGP 1311, MGP 1350, Schreiter, 450 m, Mar. 1902 , genitalia slide MGP 1353 [BMNH]. BOLIVIA: SANTA CRUZ: Ichilo, Buenavista, 750 m, Aug.-Apr. 1906-1907 , Steinbach [BMNH]; Sara, 450 m, Jan. , genitalia slide MGP 1349, Nov. , J. Steinbach [BMNH]. BRAZIL: AMAZONAS: Humait\u00e1, July-Sep. 1906 , W. Hoffmanns [BMNH]. BAHIA: S. Antonio de Barra, , [BMNH]. GOIAS: Chapada dos Veadeiros, 18\u201324 km N of Alto Paraiso, 1400\u20131500 m, 2\u20135 Oct. 1985 , S.E. Miller, genitalia slide USNM 135970, USNM. MINAS GERAIS: Tijuco, Dec. [BMNH]. PARAN\u00c1: Curitiba, 23 Apr. 1988 , L. Crestana, Genitalia slide Vial #79, MGCL; Entre Rios, [BMNH]. PERNAMBUCCO: Serra de Communaty, Dec. 1893 , E. Gounene [BMNH]. RIO DE JANIERO: Petropolis, 1888 , Germain [BMNH]. S\u00c3O PAULO: Alambari, 3 Sep. 1988 , 8 Dec. 1988 , 16 Dec. 1988 , L. Crestana, Genitalia slide f Vial #86, genitalia slides male MGP 1279, MGP 1288, MGCL; Porto Feliz, 1 June 1988 , L. Crestana, genitalia slide MGP 1289, MGCL. PARAGUAY: BOQUERON [NUEVA ASUNCION]: Nueva Asuncion, 313 m, 23\u201325 Mar. 1986 , M. Pogue and M. Solis, genitalia slide USNM 136014. GUAIRA: Villarrica, Dec. 1922 , J. Schade [BMNH]. PARAGUARI: Sapuca\u00ed, 24 June 1902 , genitalia slide male MGP 1310, W. Foster [BMNH]. PRESIDENTE HAYES: Primavera, 14 Apr. 1960 , E.J. Phillips [BMNH].sinuo (bend), referring to the sinuate free saccular extension of the male genitalia.The species name is derived from the Latin Paectes sinuosa than in Paectes medialba. The postmedial line is double in Paectes sinuosa . A specimen from Porto Feliz, S\u00e3o Paulo, Brazil, was reared from Lithraea molleoides (Vell.) Engl., Anacardiaceae.Specimens from the S\u00e3o Paulo, Alambari, Brazil, were reared from Brazilian Peppertree COLOMBIA: META: Villavicencio, 400 m, , genitalia slides MGP 1299, MGP 1344, Fassl [BMNH]. FRENCH GUIANA: Nouveau Chantier, May , genitalia slide MGP 1308, Le Moult [BMNH]; St. Jean du Maroni, , genitalia MGP 1346, Le Moult [BMNH]. GUYANA: CUYUNI-MAZARUNI: Bartica, June 1901 , genitalia slide MGP 1307 [BMNH]; POTARO-SIPARUNI: Potaro River, 9-13 July 1912 , genitalia slide MGP 1306, P. Rendall [BMNH]; Tumatumari, Dec. 1907 [BMNH]. SURINAME: PARAMARIBO: Paramaribo, , Genitalia MGP 1347 [BMNH].tumeo (swell), referring to the swollen base of the free saccular extension in the male genitalia.The species name is derived from the Latin Paectes tumida; in Paectes similis it consists of white-tipped gray scales, so the area is less contrasting than in Paectes tumida; in Paectes obrotunda medial area is mixed with gray, ferruginous, and a few cream-colored scales and also is less contrasting than in Paectes tumida. The postmedial line is faint and black in Paectes tumida; in Paectes similis it is black and well developed with a faint double line at the posterior margin; in Paectes obrotunda the postmedial line is ferruginous and double at the posterior margin and black and ferruginous where it curves toward the subapical black dash.Forewing with a white medial area in Paectes tumida have elongate, curved setae on the dorsal surface of the valve, whereas in Paectes obrotunda and Paectes similis the valve has shorter, hairlike setae. The costal margin is convex in Paectes tumida, but straight in Paectes similis, and slightly concave in Paectes obrotunda. The free saccular extension is elongate and extends above the costa in Paectes obrotunda, but is shorter and does not extend above the costa in Paectes tumida and Paectes similis. In Paectes tumida, the base of free saccular extension is swollen and densely covered with spicules, but in Paectes obrotunda and Paectes similis the base is not swollen and without spicules.The male genitalia of Male.Head \u2013 antenna broadly bipectinate to 1/2 length then filiform; eyes large, globular; vertex with broad scales, mixture of white, brown, and black scales; frons with broad scales, projecting slightly beyond anterior eye margin, white and brown scales; labial palp porrect, mixture of brown, white, and pale ferruginous scales, internal surface white. Thorax \u2013 prothorax mixture of pale-gray, gray, and brown scales, medial band dark brown; patagium of brown, pale-ferruginous, and white broad scales, mixed with hairlike scales; protibia white mixed with black, apical band white, obscure, tarsi black with distinct white apical bands; middle and hind legs missing in holotype; forewing length 10.9 mm; costal area brown; basal area mixture of white, pale-ferruginous, and brown scales, not a well-defined ovate spot; antemedial line consists of a few black scales between posterior margin and anal vein then extending along PageBreakanal vein a short distance before slightly curving upward; central area of wing from basal area to postmedial line mostly white mixed with brown scales and contrasted with subterminal and terminal areas, thin curved brown line from posterior margin to anal vein and contiguous with thin line from anal vein to CuA2 vein; reniform spot obscure, a pair of small, round brown spots; postmedial line brown and pale ferruginous, PageBreakdouble line from posterior margin to vein CuA2, single curved line between M2 and M1; black dash between veins R5 and M1 that extends to outer margin; apical spot white; subterminal area brown mixed with pale ferruginous and white scales; terminal line a series of black, shallow scalloped lines between veins; fringe brown; hind wing marginal shading dark gray, veins heavily highlighted dark gray, areas between veins PageBreakwhite; anal fold white with dark-gray striped pattern; fringe white. Abdomen \u2013male eighth segment membranous with a pair of short, sternal, sclerotized bars and a pair of longer, wider, dorsal sclerotized bars; a pair of lateral, coremata bearing numerous, fine, elongate setae. Genitalia http://species-id.net/wiki/Paectes_obrotundaIngura obrotundain Guen\u00e9e Paectes obrotunda ; Type locality: \u201cBrazil\u201d Holotype female. BMNH; photographs of adult and genitalia examined .Paectes obrotunda is only known from the female holotype it can be compared to females of Paectes longiformis, Paectes sinuosa, and Paectes medialba, which are found in Brazil, Argentina, and Paraguay. Paectes obrotunda has a distinct antemedial line that extends from the posterior margin to the anal vein then curves around faint basal area toward Cu vein. In Paectes longiformis the antemedial vein is faint and not well developed. The forewing subapical, marginal dash is black and distinct in Paectes obrotunda, but ferruginous and faint in Paectes longiformis. There is a faint area of white scales proximal to the postmedial line in Paectes obrotunda, which is absent in Paectes longiformis. Paectes sinuosa is distinct from Paectes obrotunda in having the antemedial line heavily developed with black scales along the anal vein and suffused with black scales along the posterior margin. The forewing subapical, marginal dash is longer in Paectes sinuosa than in Paectes obrotunda. In Paectes medialba the postmedial line is double from posterior margin to approximately middle of forewing whereas in Paectes obrotunda it is single and faint. The forewing subapical, marginal dash is slightly longer and more robust in Paectes medialba than in Paectes obrotunda. In the female genitalia the eighth sternite is longer than wide with lateral margins produced in Paectes medialba but sternite in Paectes obrotunda is wider than long and the lateral margins are not produced.Since Adult.Female.Head \u2013 antenna filiform; eyes large, globular; labial palp porrect. Thorax \u2013 prothorax light brown, anterior margin thin black line; forewing length 9.2 mm; a few white scales forming short dashes along costa, especially from postmedial band to just below apex; thin black antemedial line from posterior margin forming ventral border to faint basal spot; medial area of wing with some scattered white scales forming an indistinct area proximal to postmedial line; postmedial line black, faint at posterior margin becoming more distinct prior to subapical, marginal dash; black dash between veins R5 and M1 that extends to outer margin; apical spot white; terminal line a series of black, recurved lines between veins; fringe with white patches giving a checked appearance; hind wing with dark gray marginal band that extends to middle of wing with veins highlighted dark gray. Genitalia (PageBreaklike with lateral apices narrowed; base of ductus bursae narrower than ostium bursae; remainder of genitalia unknown.enitalia \u2013 PapillKnown only from Brazil, with no specific locality.Paectes obrotunda belongs in this species group because it shares with them the shape of the antemedial line, white medial area, white apical spot, and black marginal dash in the forewing. The female genitalia are different from those of the other species in this group and no other specimens from other groups examined during this study matched them, so Paectes obrotunda is only known from the holotype.PageBreakPaectes obrotunda has never been correctly identified in the literature. Paectes obrotunda extending from throughout the Caribbean to Paraguay. The Caribbean distribution could refer to either Paectes asper, Paectes nana or Paectes arcigera, and the Paraguay record is probably Paectes sinuosa. Paectes obrotunda from Florida and these specimens can be referred to either Paectes nana or Paectes asper. Paectes obrotunda from North America, undoubtedly following Paectes are currently being revised. A number of specimens from Costa Rica that have been analyzed using DNA barcoding of CO1 and their respective host plants will be included. A phylogenetic analysis using morphological characters of the Neotropical species included in this and the next study will be discussed.Due to the cryptic nature of this species complex, the remaining species of Neotropical"} +{"text": "AbstractTermitidae. We describe Bulbitermes 4 spp. and Nasutitermes 4 spp. from new field collections. Where possible we examine original holotype specimens, and describe the essential morphological characters for soldier and worker castes. We devise two new bifurcating keys to guide the field identification of each species. In addition, we develop a nucleotide sequence profile for the COI gene. From this molecular character matrix, we use Neighbour-Joining analysis to test the monophyly of each morphospecies and genus. We find that the morphological and molecular characters are highly concordant, whereby all taxa appear to represent distinct molecular clades. For termites, there is therefore agreement between the morphological taxonomic characters used to sort species from a bifurcating key and the molecular taxonomic characters used to sort species on a bifurcating tree. This joint analysis suggests that DNA barcoding holds considerable promise for termite taxonomy, especially for diverse clades like Bulbitermes and Nasutitermes for which a global morphological key would be intractable.The Sunda region of Southeastern Asia is rich in termite fauna, but termites from this region have been poorly described. In this study, we described eight species from two diverse genera from this region, and from the family Termitidae), the Nasutitermitinae include more than 650 species from over 80 genera and Bulbitermes (4 spp.), as represented from newly collected material from the Sunda region of Southeast Asia.As the largest subfamily among the higher termites within Southeast Asia. Specifically, we use morphological characters to describe eight species, and devise a key for their field identification. Further, we use molecular sequence information from the mitochondrial gene \u2018barcode\u2019 region to test the idea that Bulbitermes and Nasutitermes each form monophyletic and evolutionarily distinct genera.In this report we present the taxonomic notes for representative PageBreak by one person for one hour. For each section, 12 samples of surface soil with associated leaf litter and woody debris were scraped up and carefully examined for termites . Finally, tree trunks and buttress roots were also examined for the presence of termites. Particular attention was paid to the deep accumulations of litter and organic-rich soil between buttresses. Also, any carton sheeting or runways suggesting the presence of live termites were examined, up to a height of two meters. For random sampling, we simply used our best judgment to search for termites within the above types of habitat, but without the use of transects. Wherever possible, all castes and both sexes were sampled. In total, termites included in this study were sampled from multiple regions in Sunda region from 1999\u20132010.All specimens were collected from the field using a mix of random and systematic transect searches. For transect sampling we adopted a standardized protocol . We laidMorphological character terminology used for describing soldiers and workers follows the convention of To aid with taxonomic analysis, we developed a cytochrome c oxidase I gene (COI) profile. The profile consists of nucleotide sequence from the \u2018barcode\u2019 region of the mitochondrial genome . First, we removed single legs from representative specimens and used in-house protocols at the Canadian Center for DNA Barcoding to extract DNA and PCR-Using the BOLD on-line workbench, we aligned nucleotide sequences and calculated a pairwise Kimura-2-parameter (K2P) distance matrix. For each species in the matrix, we calculated the minimum, mean and maximum genetic distance. We also calculated the mean nearest neighbour distance (average distance to the most closely related species). From these data, we tested for the presence of a \u2018barcode gap\u2019 - a disjunction between levels of intraspecific and interspecific variability\u2013by plotting maximum intraspecific distance against mean distance to nearest neighbour (NN). A gap is evident from this plot when the NN distance consistently exceeds the intraspecific distance. Finally, we used the K2P distance matrix to build a Neighbour-Joining (NJ) Taxon ID tree.Bulbitermes, soldiers are profiled in Nasutitermes, soldiers are profiled in For all species described below, we provide comparative images of key morphological traits. For (Holmgren)http://species-id.net/wiki/Bulbitermes_flavicansEuternes (Euternes) flavicansEuternes (Euternes) flavicans : Bulbitermes flavicans : Bulbitermes flavicans : Bulbitermes flavicans : Bulbitermes flavicans : Syntype: soldier, West Sumatra, Harau, Pajacombo, 17.iii.1913, Oscar John Coll. B.M. 1926\u2013242 BMNH103898. Other material: SYK1999&2001-L-0146, 1453\u201356, 1463, 1465, 1467. Soldiers and workers from undisturbed forests, 1,000\u20131,400 m altitude, Kemiri Mountain, Southeast Aceh; SYK1999&2001-L-1457\u201360, 1462. Soldiers and workers from undisturbed forests, 150\u2013350 m altitude, Bukit Lawang, Langkat, North Sumatra; SYK2000-L-1466. Soldiers and workers from undisturbed forest, 500 m altitude, Ketambe, Southeast Aceh; SYK2006-AL-0001, 0777, 1613. Soldiers and workers from disturbed. SYK2010-KTB-011, 027, 051, 098. Soldiers and workers from undisturbed forest, 300\u2013500 m altitude, Ketambe Research Station, Ecosystem Leuser, Sumatra.Imago: Unknown.PageBreakSoldiers.Head: in dorsal view the anterior part darker than posterior part in coloration; rostrum dark brown with the apex paler; antenna much paler than anterior part of head capsule, uniformly coloured. Head with five or six scattered bristles, tip of nasus with four bristles, pronotum and abdominal tergites with microscopic hairs.Head capsule somewhat round, weakly constricted behind antennal sockets; posterior margin roundly convex; dorsal outline (including rostrum) in profile nearly straight with two shallow indentations near base of rostrum, and up-curved apically. Mandible with weak apical processes. Antenna with 12 articles; second clearly shorter than third and fourth; third clearly longer than fourth; fourth and fifth almost equal in length. Thorax: pronotum seen from above paler than anterior part of head capsule; its periphery paler than central area. Coxae pale brown; femora yellowish; tibiae whitish yellow. Anterior margin of pronotum nearly straight; posterior margin roundly convex. Abdomen: tergites pale brown.Soldiers in mm): head length including nasus (HLN) (1.22\u20131.40); head length measured to base of mandible (HL) (0.97\u20131.00); nasus length (NL) (0.30\u20130.42); nasus index = NL/HL (0.30\u20130.42); maximum head width at posterior part (HWP) (0.75\u20130.84); maximum height of head excluding postmentum (HH) (0.57\u20130.65); pronotum length (PL) (0.15\u20130.17); pronotum width (PW) (0.37\u20130.45).Workers. Antenna: whitish yellow to yellow; 13 articles; second shorter than third; third clearly longer than fourth; fourth wider than fifth. Left mandible: apical tooth and first marginal tooth almost equal in length; third marginal moderately protruding from cutting edge; fourth almost completely hidden behind molar prominence. Right mandible: posterior edge of second marginal tooth nearly straight; inner layer of molar plate undeveloped and notch at proximal end of molar plate obsolete. Sumatra, Peninsular Malaysia and Borneo.Snyder & Emersonhttp://species-id.net/wiki/Bulbitermes_neopusillusBulbitermes neopusillus Snyder & Emerson, 1949, p. 309.Bulbitermes neopusillus : PageBreak1612. Soldiers and workers from disturbed forest, 50 m altitude, Sekundur, Langkat, North Sumatra; SYK2000-L-1398, 1849. Soldiers and workers from disturbed forest, 80 m altitude, Soraya, Singkil, Aceh; SYK2000&2001-L-1394, 1395, 1415. Soldiers and workers from undisturbed forest, 300\u2013500 m altitude, Ketambe, Southeast Aceh; SYK2006-AL-0778, 0779, 0780. Soldiers and workers from disturbed forest, 30 m altitude, Maestong, Sungai Batang Hari, Jambi; SYK2007-SPR-0038. Soldiers and workers from disturbed forest, <100 m altitude, Tua Pejat, Sipora Island, Mentawai, WestPageBreak Sumatra. SYK2010-KTB-003, 004, 005, 018, 035, 044, 045, 047, 048, 054, 055, 056, 057, 059, 060, 065, 066, 067, 068, 071, 075. Soldiers and workers from undisturbed forest, 300\u2013500 m altitude, Ketambe Research Station, Ecosystem Leuser, Sumatra.Soldiers,Sumatra, Siak, 9.ii.1913, Oscar John Coll. B.M. 1926-242 BMNH103902. SYK2006-KSNP-0032, 0034, 0047. Soldiers and workers from disturbed forest, 500 m altitude, Air Hangat, Kerinci, Jambi; SYK1999-L-1409. Soldiers and workers from undisturbed forest, 1,250 m altitude, Kemiri Mountain, Southeast Aceh; SYK1999-L-1418, 1632, 1646, 1651, 1682. Soldiers and workers from undisturbed forest, 200-400 m altitude, Bengkung, Southeast Aceh; SYK1999&2000-L-1412, 1420, 1426, 1434, 1437, 1441, 1444, 1604, 1608, 1636, 1639, 1645, 1654, 1657, 1659, 1668, 1669. Soldiers and workers from undisturbed forest, 150-350 m altitude, Bukit Lawang, Langkat, North Sumatra; SYK1999-L-1405, 1442, 1448, Imago: Unknown.Soldiers. Head: in dorsal view anterior and posterior parts almost similar in coloration; rostrum paler than anterior part of head capsule. Antenna paler than anterior part of head capsule in coloration, with the first segment darkest.Head with two scattered bristles, tip of nasus with four bristles, pronotum and abdominal tergites with microscopic hairs. In dorsal view head capsule somewhat pear-shaped, strongly constricted behind antennal sockets; its posterior margin weakly indented in middle; dorsal outline (including rostrum) in profile nearly straight. Mandible with short apical processes. Antenna with 13 articles; second shorter than third; third twice as long as fourth; fourth shorter than fifth. Thorax: pronotum seen from above similar to the posterior part of head capsule in coloration; its periphery darker than central area. Coxae and femora pale brown; tibiae pale yellow. Anterior and posterior margins of pronotum nearly straight. Abdomen: tergites pale brown to brown.Soldiers in mm): head length including nasus (HLN) (1.45\u20131.60); head length measured to base of mandible (HL) (0.90\u20130.93); nasus length (NL) (0.55\u20130.62); nasus index = NL/HL (0.62\u20130.67); maximum head width at posterior part (HWP) (0.85\u20130.87); maximum height of head excluding postmentum (HH) (0.60\u20130.63); pronotum length (PL) (0.15\u20130.18); pronotum width (PW) (0.50\u20130.55).Workers. Antenna: whitish yellow; 14 articles; second longer than third and fourth; third clearly longer than fourth; fourth the shortest; fifth shorter than sixth. Left mandible: apical tooth shorter than first marginal tooth; third marginal tooth moderately protruding from cutting edge; fourth marginal tooth hidden behind molar prominence. Right mandible: posterior edge of second marginal tooth nearly straight; inner layer of molar undeveloped and notch at proximal end of molar plate weakly developed. Sumatra, Mentawai Islands, Peninsular Malaysia, Java and Borneo.(Haviland)http://species-id.net/wiki/Bulbitermes_constrictusTermes constrictus Haviland, 1898, pp. 420\u2013421.Eutermes (Eutermes) constrictus : Bulbitermes constrictus : Bulbitermes constrictus : Bulbitermes constrictus : PageBreak0083. Soldiers and workers from undisturbed forest, 300 m altitude, Sungai Manau, Merangin, Jambi; SYK2006-KSNP-0081, 0090. Soldiers and workers from disturbed forest, 500 m altitude, Air Hangat, Kerinci, Jambi; SYK2000-L-1507, 1522. Soldiers and workers from undisturbed forest, 250\u2013350 m altitude, Bukit Lawang, Langkat, North Sumatra; SYK2000&2001-L-1496, 1497, 1498. Soldiers and workers from disturbed forest, 50 m altitude, Sekundur, Langkat, North Sumatra. SYK2010-KTB-013,PageBreak 014, 015, 137, 038, 046, 049, 050, 100. Soldiers and workers from undisturbed forest, 300\u2013500 m altitude, Ketambe Research Station, Ecosystem Leuser, Sumatra. Syntype:Soldiers, Sarawak, Coll.& Det. G.D. Haviland, No. 292, (Ex. Dundee) (Bulbitermes) MNH103897. Other material: SYK2006-KSNP-0006, Imago: Unknown.Soldiers. Head: in dorsal view anterior and posterior parts almost similar in coloration; except around posterior margin, much paler in coloration; rostrum darker than anterior part of head capsule; antenna paler than anterior part of head capsule in coloration. Head with two bristles, tip of nasus with four bristles, pronotum with brittles, abdominal tergites with hairs and bristles.In dorsal view head capsule somewhat pear-shaped, strongly constricted behind antennal sockets; its posterior margin weakly indented; dorsal outline (including rostrum) in profile nearly straight. Mandible with moderately developed apical processes. Antenna with 14 articles; second longer than third; third the shortest; fourth and fifth almost equal in length. Thorax: pronotum seen from above paler than anterior part of head capsule; its periphery darker than central area. Coxae and femora yellow; tibiae pale yellow. Anterior margin of pronotum weakly indented in the middle, while posterior margin roundly convex. Abdomen: tergites yellowish to pale brown.Soldiers in mm): head length including nasus (HLN) (1.55\u20131.65); head length measured to base of mandible (HL) (1.05\u20131.13); nasus length (NL) (0.50\u20130.60); nasus index = NL/HL (0.47\u20130.53); maximum head width at posterior part (HWP) (0.95\u20130.10); maximum height of head excluding postmentum (HH) (0.60\u20130.65); pronotum length (PL) (0.22-0.25); pronotum width (PW) (0.52\u20130.55).Workers. Antenna: whitish yellow to yellow; 15 articles; second clearly longer than third; third the shortest; fourth and fifth almost equal in length. Left mandible: apical and first marginal teeth almost equal in length; third marginal moderately protruding from cutting edge; fourth almost completely hidden behind molar prominence. Right mandible: posterior edge of second marginal tooth nearly straight; inner layer of molar not developed; notch at proximal end of molar plate weakly developed. Sumatra and Borneo.(Haviland)http://species-id.net/wiki/Bulbitermes_singaporiensisTermes singaporiensis Haviland, 1898, pp. 429.Eutermes (Eutermes) singaporiensis : Bulbitermes singaporiensis : Bulbitermes singaporiensis : Termes singaporiensis, Singapore, 1893, Coll. & Det. G. D. Haviland, No. 16 (Ex. Dundee) (Bulbitermes) BMNH103923. Other material: SYK(1998\u20132001)-L-0205, 0212, 0219, 1802, 1812, 1817, 1821\u201323, 1825\u201329, 1831, 1832, 1834, 1835, 1839, 1840, 1843, 1846\u201348, 1851, 1853\u201355, PageBreakPageBreak1859, 1860, 1865, 1867, 1868, 1870, 1877, 1883, 1884, 1850, 1877, 1879, 1880, 1975, 1978. Soldiers and workers from undisturbed forest, 150\u2013350 m altitude, Bukit Lawang, Langkat, North Sumatra.; SYK2006-AL-0004, 0801, 0802, 1886. Soldiers and workers from disturbed forest, 30 m altitude, Maestong, Sungai Batang Hari, Jambi; SYK2006-L1852. Soldiers and workers from undisturbed forest, 50 m altitude, Sekundur, Langkat, North Sumatra; SYK1999-L-1882. Soldiers and workers from undisturbed forest, 400 m altitude, Bengkung, Southeast Aceh. SYK&FAZLY2009-ER-020, 022, 024, 039, 043, 044, 047, 051, 057, 058, 062, 063, 087. Soldiers and workers from undisturbed forest, >100 m altitude, Endau Rompin National Park, Johor, Peninsular Malaysia. Syntype: soldiers,Imago: Unknown.Soldiers. Head: in dorsal view anterior part of head capsule darker than the posterior part in coloration; rostrum slightly darker than anterior part of head capsule; antenna paler than anterior part of head capsule. Head with two bristles, tip of nasus with four bristles, pronotum with microscopic hairs, abdominal tergites with hairs and bristles.In dorsal view head capsule somewhat pear-shaped and weakly constricted behind antennal sockets; its posterior margin nearly straight in the middle; dorsal outline (including rostrum) in profile nearly straight; mandible with moderately developed apical processes. Antenna with 12 articles; second and third almost equal in length, the former wider than the latter in width; third the shortest; fourth and fifth almost equal in length. Thorax: pronotum seen from above paler than anterior part of head capsule; its anterior part slightly darker than posterior part. Coxae pale brown; femora yellowish; tibiae pale yellow. Anterior margin of pronotum moderately indented in the middle, while posterior margin nearly straight in the middle. Abdomen: tergites dark brown to very dark sepia brown.Soldiers in mm): head length including nasus (HLN) (1.24\u20131.35); head length measured to base of mandible (HL) (0.98\u20131.12); nasus length (NL) (0.32\u20130.37); nasus index = NL/HL (0.31\u20130.35); maximum head width at posterior part (HWP) (0.80\u20130.84); maximum height of head excluding postmentum (HH) (0.57\u20130.61); pronotum length (PL) (0.16\u20130.18); pronotum width (PW) (0.37\u20130.44).Workers. Antenna: whitish yellow to yellow with first article darker than the subsequent; 14 articles; second much longer than third and fourth; third longer than fourth; fourth the shortest. Left mandible: apical tooth shorter than first marginal tooth; third marginal moderately protruding from cutting edge; fourth almost completely hidden behind molar prominence. Right mandible: posterior edge of second marginal tooth weakly concave; inner layer of molar plate and notch at proximal end of molar plate obtuse. Sumatra, Peninsular Malaysia, Java and Borneo.(Haviland)http://species-id.net/wiki/Nasutitermes_matangensisTermes matangensis Haviland, 1898, pp. 427\u2013428.Eutermes (Eutermes) matangensiformis : PageBreakPageBreakEutermes (Eutermes) matangensis : Eutermes (Eutermes) matangensis : Nasutitermes matangensis : Nasutitermes matangensis : Nasutitermes matangensis : Nasutitermes matangensis : Termes matangensis, Sarawak, Coll. G. D. Haviland. BMNM No. 358. (Ex. Dundee) (Nasutitermes). Other material: SYK2006-KSNP-0017, 0023, 0025, 0041. Soldiers and workers from undisturbed forest, 300 m altitude, Sungai Manau, Merangin, Jambi; SYK1999&2001-L-1039, 1040, 1042, 1043, 1045, 3080. Soldiers and workers from undisturbed forest, 1,000\u20131,400 m altitude, Kemiri Mountain, Southeast Aceh; SYK2007-UGDT-0010, 0063\u201370. Soldiers and workers from disturbed forest, 900 m altitude, Ulu Gadut, Padang, West Sumatra; SYK2007-SRSR-0005, 0040, 0063, 0066, 0632. Soldiers and workers from disturbed forest, <100 m altitude, Siberut Tengah, Mentawai, West Sumatra; SYK2007-SBRT-0016, 0034, 0039, 0046, 0047, 0060, 0070, 0080. Soldiers and workers from undisturbed forest, <100 m altitude, Simabuggei, Siberut Island, Mentawai, West Sumatra; SYK2001-S-0128, 0030. Soldiers and workers from disturbed forest, 200 m altitude, Aceh Besar; SYK2006-SB-0001\u201304, 0044, 0045, 0050, 0051. Soldiers and workers from disturbed forest, <100 m altitude, Sabang, Weh Island, Aceh; SYK1999-L-1062. Soldiers and workers from undisturbed forest, 300 m altitude, Ketambe, Southeast Aceh; SYK2006-AL-0901. Soldiers and workers from disturbed forest, 30 m altitude, Maestong, Sungai Batang Hari, Jambi; SYK2002-NIAS-0111. Soldiers and workers from disturbed forest, <100 m altitude, Gunung Sitoli, Nias Island, North Sumatra; SYK2002-PRP-0100. Soldiers and workers from disturbed forest, 900 m altitude, Toba Lake, Parapat, North Sumatra; SYK2007-LP-0093. Soldiers and workers from disturbed forest, 1100 m altitude, Sumber Jaya, Kota Bumi, Lampung; SYK2007-LBAN-0004, 0012. Soldiers and workers from disturbed forest, 600 m altitude, Lembah Anai, Tanah Datar, West Sumatra; SYK2005&2006-RKT-0002, 0004, 0006, 0007, 0009\u20130021, 0033\u201340, 0042\u201348, 0050, 0055, 0056, 0058, 0059, 0061\u20130063, 0065, 0066, 0072. Soldiers and workers, <10\u2013300 m altitude, Rakata island, the Krakataus, Lampung; SYK2005&2006-ANK-0040, 0041, 0043, 0139, 0144\u201346, 0148, 0149, 0151, 0154, 0155, 0277\u201379, 0301, 0302. Soldiers and workers, <100 m altitude, Anak Krakatau, the Krakataus, Lampung; SYK2005&2006-PJG-0073\u20130083, 0092\u20130095, 0137, 0138, 0141, 0142, 0147, 0150\u20130153, 0156, 0157. Soldiers and workers, <100 m altitude, Panjang island, the Krakataus, Lampung; SYK2005&2006-SRTG-0006, 0120, 0126\u201330, 0041\u201344, 0173\u201390, 0192\u201395, 0197\u2013200, 0216, 0227\u201330, 0238. Soldiers and workers, <100 m altitude, Sertung island, the Krakataus, Lampung; SYK2005-SBK-0235, 0237\u201342, 0246, 0263. Soldiers and workers, <100 m altitude, Sebuku island, the Krakataus, Lampung; SYK2005-SBS- 0064, 0067, 0069\u201371, 0073\u201375, 0077\u201388, 0090. Soldiers and workers, <100 m altitude, Sebesi island, the Krakataus, Lampung; SYK2007-LGD-0031, 0050\u201352, PageBreak0058, 0059. Soldiers and workers, <100 m altitude, Legundi island, the Krakataus, Lampung; SYK2007-LP-0002, 0006. Soldiers and workers, from disturbed forest, <100 m altitude, Pantai Mutun, Lampung. SYK2010-KTB-002, 006, 019, 041, 095. Soldiers and workers from undisturbed forest, 300\u2013500 m altitude, Ketambe Research Station, Ecosystem Leuser, Sumatra; SYK2010-PK-005, 006. Soldiers and workers from disturbed forest, 150 m altitude, Peukan Biluy, Darul Kamal, Aceh Besar, Sumatra; SYK&FAZLY2009-ER-038, 050, 073. Soldiers and workers from undisturbed forest, >100 m altitude, Endau Rompin National Park, Johor, Peninsular Malaysia.Syntype:Soldiers, Imago: Unknown.Soldiers. Head: in dorsal view head capsule excluding rostrum brown to dark sepia brown; rostrum darker than head capsule; entire rostrum almost uniformly coloured; antenna paler than head capsule in coloration. Head with a few number of scattered bristles, tip of nasus with four bristles, pronotum hairs, abdominal tergites with hairs and brittles. In dorsal view head capsule round; its posterior margin nearly straight in the middle; dorsal outline (including rostrum) in profile nearly straight, down-curved apically. Antenna with 13 articles; second slightly longer than fourth; third the longest; fourth shorter than fifth. Thorax: pronotum seen from above paler than head capsule in coloration; its anterior part darker than posterior part. Coxae and femora sepia brown; tibiae yellowish. Anterior margin of pronotum moderately indented in the middle; posterior margin nearly straight in the middle. Abdomen: tergites yellowish to pale brown.Soldiers in mm): head length including nasus (HLN) (2.05\u20132.18); head length measured to base of mandible (HL) (1.20\u20131.25); nasus length (NL) (0.82\u20130.95); nasus index = NL/HL (0.68\u20130.76); maximum head width (HW) (1.37\u20131.50); maximum height of head excluding postmentum (HH) (0.90\u20130.95); pronotum length (PL) (0.25\u20130.30); pronotum width (PW) (0.60\u20130.70).Workers. Antenna: pale yellow to yellow; 14 articles; second clearly longer than third and fourth; third longer than fourth. Left mandible: apical tooth longer than first marginal tooth; third marginal moderately protruding from cutting edge; fourth almost completely hidden behind molar prominence. Right mandible: posterior edge of second marginal tooth nearly straight; inner layer of molar plate undeveloped; notch at proximal end of molar plate absent. Sumatra, Mentawai islands, Malay Peninsula, Java and Borneo.Thapahttp://species-id.net/wiki/Nasutitermes_neoparvusNasutitermes neoparvusPageBreak-KSNP-0054, 0076, 0085. Soldiers and workers from disturbed forest, 500m altitude, Air Hangat, Kerinci, Jambi; SYK2007-SRSR-0006, 0011. Soldiers and workers from disturbed forest, <100 m altitude, Surisura, Siberut Tengah, Mentawai, West Sumatra; SYK2006-SBRT-0006, 0028, 0077, 0084, 0103. Soldiers and workers from undisturbed forest, <100 m altitude, Simabuggei, Siberut island, Mentawai, West Sumatra; SYK1999&2000-L-0916, 0923, 0931, 0932, 0935, 0937, 0940, 0943. Soldiers and workers from undisturbed forest, 150\u2013350 m altitude, Bukit Lawang, Langkat, North Sumatra; SYK2000&2001-L- 0214, 0913, 0918, 0922, 0926, 0928, 0933, 0934, 0941, 0942. Soldiers and workers from disturbed forest, 50 m altitude, Sekundur, Langkat, North Sumatra; SYK1999-L-0208, 0235, 0241, 0930, 0917, 0921, 0924, 0936, 0939. Soldiers and workers from undisturbed forest, 200\u2013400 m altitude, Bengkung, Southeast Aceh; SYK1999-L-0211, 0225, 0911, 0914, 0915, 0919, 0920, 0925, 0927, 0929, 0938, 1171. Soldiers and workers from disturbed forest, 80 m altitude, Soraya, Singkil, Aceh; SYK1999-L- 0912, 0215, 0237, 0244, 0245. Soldiers and workers from undisturbed forest, 300\u2013500 m altitude, Ketambe, Southeast Aceh; SYK2007-LP-0081. Soldiers and workers from disturbed forest, <100 m altitude, Pantai Mutun, Lampung. SYK2010-KTB-029, 053, 058, 061. Soldiers and workers from undisturbed forest, 300\u2013500 m altitude, Ketambe Research Station, Ecosystem Leuser, Sumatra; SYK&FAZLY2009-ER-034. Soldiers and workers from undisturbed forest, >100 m altitude, Endau Rompin National Park, Johor, Peninsular Malaysia. SYK2006-KSNP-0007, 0053. Soldiers and workers from undisturbed forest, 300 m altitude, Sungai Manau, Merangin, Jambi; SYK2006Imago: Unknown.Soldiers. Head: in dorsal view head capsule excluding rostrum dark brown to sepia brown; rostrum darker than head capsule; antenna much paler than head capsule. Head with combination long and short bristles, tip of nasus with short hairs and four long bristles, pronotum with short and long bristles, abdominal tergites densely with short hairs and long bristles.In dorsal view head capsule somewhat round; its posterior margin roundly convex in the middle; dorsal outline of head capsule (excluding rostrum) in profile nearly straight. Antenna with 11 articles; second shorter than fourth; third longer than fourth; fourth and fifth almost equal in length. Thorax: pronotum seen from above paler than head capsule in coloration; its periphery darker than central area. Coxae and femora yellow; tibiae whitish yellow. Anterior margin of pronotum nearly straight in the middle; posterior margin strongly indented in the middle. Abdomen: tergites dark yellow to brown.Soldiers in mm): head length including nasus (HLN) (1.25\u20131.37); head length measured to base of mandible (HL) (0.62\u20130.77); nasus length (NL) (0.57\u20130.62); nasus index = NL/HL (0.79\u20130.80); maximum head width (HW) (0.77\u20130.80); maximum height of head excluding postmentum (HH) (0.50\u20130.60); pronotum length (PL) (0.12\u20130.15); pronotum width (PW) (0.37\u20130.42).PageBreak prominence. Right mandible: posterior edge of second marginal tooth nearly straight; inner layer of molar plate undeveloped, and notch at proximal end of molar plate obtuse.Workers. Antenna: pale yellow to yellow; 12 articles; second clearly longer than fourth; third longer than fourth; fourth shorter than fifth. Left mandible: apical tooth clearly shorter than first marginal tooth; third marginal moderately protruding from cutting edge; fourth visible in the gap between third marginal and molar Sumatra and Borneo.(Holmgren)http://species-id.net/wiki/Nasutitermes_longinasusEutermes (Eutermes) longinasusEutermes longinasus : Nasutitermes longinasus : Nasutitermes longinasus : Nasutitermes longinasus : Nasutitermes longinasus : SYK2006-KSNP-0040, 0049, 0052. Soldiers and workers from undisturbed forest, 300 m altitude, Sungai Manau, Merangin, Jambi; SYK(1998\u20132001)-L-0012, 0025, 0027, 0234, 0036, 0167, 0218, 0231, 0851, 0856, 1034, 1070, 1071, 1080, 1085, 1095. Soldiers and workers from disturbed forest, 80 m altitude, Soraya, Singkil, Aceh; SYK1999-L-0010, 0020, 0029, 0030, 0035, 0039, 0044, 0047\u201349, 0055, 0056, 0061, 0065, 0066, 0071, 0110, 0222, 0226, 0235, 0240, 0246, 0249, 0277, 0825, 0826, 0848\u201350, 0853\u201355, 0857, 0859\u201361, 1044, 1048, 1068, 1069, 1073, 1074, 1076, 1078, 1079, 1081\u201383, 1086, 1089\u201392, 1096, 1097. Soldiers and workers from undisturbed forest, 200\u2013400 m altitude, Bengkung, Southeast Aceh; SYK1999&2000-L-0069, 0210, 0233, 0858, 1072, 1075, 1077, 1087. Soldiers and workers from undisturbed forest, 300\u2013500 m altitude, Ketambe, Southeast Aceh; SYK(1999\u20132001)-L-0018, 0406, 1087, 1088, 1093. Soldiers and workers from undisturbed forest, 150\u2013350 m altitude, Bukit Lawang, Langkat, North Sumatra. SYK2010-KTB-026, 028, 031, 032, 033, 034, 076, 077, 079, 082, 083, 084, 085, 086, 088, 091, 092, 093, 094, 096, 097. Soldiers and workers from undisturbed forest, 300\u2013500 m altitude, Ketambe Research Station, Ecosystem Leuser, Sumatra.Imago: Unknown.PageBreak and femora yellow; tibiae whitish yellow. Anterior margin of pronotum moderately indented in the middle, while posterior margin roundly convex in the middle. Abdomen: tergites yellow to brown.Major soldiers. Head: in dorsal view head capsule excluding rostrum pale brown to brown; rostrum darker than head capsule; antenna much paler than head capsule in coloration. Head with hairs and two long bristles, tip of nasus with hairs and four brittles, pronotum with short and long bristles, pronotum and abdominal tergites with hairs and brittles. In dorsal view head capsule round; its posterior margin nearly straight in the middle; dorsal outline of head capsule (including rostrum) in profile nearly straight. Antenna with 13 articles; second longer than fourth; third clearly longer than fourth; fourth the shortest. Thorax: pronotum seen from above paler than head capsule in coloration; its periphery darker than central area. CoxaeMajor soldiers in mm): head length including nasus (HLN) (2.00\u20132.20); head length measured to base of mandible (HL) (1.07\u20131.15); nasus length (NL) (0.95\u20131.12); nasus index = NL/HL (0.88\u20130.97); maximum head width (HW) (1.15\u20131.30); maximum height of head excluding postmentum (HH) (0.80\u20130.85); pronotum length (PL) (0.25\u20130.30); pronotum width (PW) (0.52\u20130.58).Minor soldiers: in dorsal view head capsule excluding rostrum deep reddish brown; rostrum same color as head capsule; antenna paler than head capsule in coloration. Head with hairs and two long bristles, tip of nasus with hairs and four bristles, pronotum with short and long bristles, pronotum and abdominal tergites with hairs and bristles. In dorsal view head capsule round; its posterior margin weakly constricted in the middle; dorsal outline of head capsule (including rostrum) in profile nearly straight. Antenna with 13 articles; second longer than fourth; third clearly longer than fourth; fourth the shortest. Thorax: pronotum seen from above slightly paler than head capsule in coloration; its periphery darker than central area. Coxae and femora brownish yellow; tibiae yellow. Anterior margin of pronotum weakly to moderately indented in the middle, while posterior margin roundly convex in the middle. Abdomen: tergites brown.Minor soldiers in mm): head length including nasus (HLN) (172\u20131.82); head length measured to base of mandible (HL) (0.82\u20130.86); nasus length (NL) (0.71\u20130.77); nasus index = NL/HL (0.86\u20130.89); maximum head width (HW) (0.86\u20130.94); maximum height of head excluding postmentum (HH) (0.59\u20130.67); pronotum length (PL) (0.20- 0.23); pronotum width (PW) (0.49\u20130.51).Workers. Antenna: pale yellow to yellow, with the first article darker than the subsequent; 14 articles; second and third clearly longer than fourth; fourth the shortest. Left mandible: apical tooth longer than first marginal tooth; third marginal weakly protruding from cutting edge; fourth hidden behind molar prominence. Right mandible: posterior edge of second marginal tooth nearly straight; inner layer of molar plate weakly developed; notch at proximal end of molar plate obtuse. Sumatra, Peninsular Malaysia and Borneo.Thapahttp://species-id.net/wiki/Nasutitermes_longinasoidesNasutitermes longinasoidesPageBreak. Soldiers and workers from undisturbed forest, 300\u2013500 m altitude, Ketambe, Southeast Aceh; SYK2002-PRP-0101, 0102. Soldiers and workers from disturbed forest, 900 m altitude, Parapat, North Sumatra. SYK2010-KTB-012, 022, 030, 042, 043, 063, 069, 090. Soldiers and workers from undisturbed forest, 300\u2013500 m altitude, Ketambe Research Station, Ecosystem Leuser, Sumatra. SYK2006-KSNP-0028, 0031, 0037, 0039, 0050, 0058. Soldiers and workers from undisturbed forest, 300 m altitude, Sungai Manau, Merangin, Jambi; SYK2006-AL-0016, 0021, 0106, 0950-0952. Soldiers and workers from disturbed forest, 30 m altitude, Maestong, Sungai batang hari, Jambi; SYK1999&2000-L-1063\u20131066Imago: Unknown.Soldiers. Head: in dorsal view head capsule excluding rostrum pale yellow to yellow; rostrum darker than head capsule; antenna slightly paler than head capsule in coloration. Head with three or four scattered bristles, tip of nasus a hairs and four bristles, pronotum and abdominal tergites with hairs and brittles. In dorsal view head capsule round; its posterior margin roundly convex in the middle; dorsal outline of head capsule (including rostrum) in profile nearly straight. Antenna with 13 articles; second and fourth almost equal in length; third clearly longer than fourth; fourth shorter than fifth. Thorax: pronotum seen from above paler than head capsule in coloration; its periphery darker than central area. Coxae and femora pale yellow; tibiae whitish. Anterior and posterior margins of pronotum nearly straight in the middle. Abdomen: tergites yellow to pale brown.Soldiers in mm): head length including nasus (HLN) (2.10\u20132.20); head length measured to base of mandible (HL) (1.07\u20131.25); nasus length (NL) (0.92\u20131.07); nasus index = NL/HL (0.85\u20130.86); maximum head width (HW) (1.23\u20131.32); maximum height of head excluding postmentum (HH) (0.80\u20130.83); pronotum length (PL) (0.20\u20130.23); pronotum width (PW) (0.56\u20130.60).Workers. Antenna: pale yellow to yellow; 14 articles; second much longer than fourth; third longer than fourth; fourth the shortest. Left mandible: apical tooth shorter than first marginal tooth; third marginal moderately protruding from cutting edge; fourth completely hidden behind molar prominence. Right mandible: posterior edge of second marginal tooth nearly straight; inner layer of molar plate undeveloped, and notch at proximal end of molar plate obtuse. Sumatra and Borneo.Nasutitermes and an additional four assigned to Bulbitermes. The number of specimens sequenced from each morphospecies ranged from 1 to 21, depending on specimen availability and sequencing success.The study profile includes 48 COI sequences, representing eight putative species, as identified from the field using morphological characters. Of these taxa, there are four morphologically assigned to Nasutitermes and Bulbitermes form monophyletic groups within the NJ analysis. Moreover, each morphospecies within each of these genera form monophyletic groups. No genera or morphospecies were paraphyletic with respect to each other. There is therefore a high degree of concordance between the morphological taxonomic characters used to sort species from a bifurcating key and the molecular taxonomic characters used to sort species on a bifurcating tree revealed several other criteria for distinguishing species pairs. Eleven antennal articles distinguish PageBreakNasutitermes matangensis from other congeners from the region. Nasutitermes matangensis from its congeners. Other observations from our morphological analysis include: Nasutitermes neoparvus separates from the other three species by having exactly eleven antennal articles. In addition, the somewhat rounded head capsule in dorsal view and scattered setae are important characters in recognizing the species. Dimorphic soldiers can be used to differentiate Nasutitermes longinasus and Nasutitermes longinasoides. Finally, Nasutitermes longinasus.We find that the width of the head capsule is an easy character that can be used to separate Nasutitermes is monomorphic; it is rarely dimorphic. The soldier head capsule is, however, highly variable in size and shape, and without constriction behind antennal sockets. The rostrum of the Nasutitermes soldier caste is conical to cylindrical, and the antenna is with 11-14 articles. The pronotum is saddle-shaped, and legs relatively short with abdomen elongate. Bulbitermes was separated from Nasutitermes as a distinct new genus based on constrictions behind antennal sockets by Emerson . This finding is significant given the rapidly changing higher taxonomy that is currently affecting termite systematic classifications and phylogeny (Nasutitermes with more than 250) for which global morphology-based taxonomic keys would be intractable.Our study shows that DNA barcoding holds promise for helping to solve termite taxonomic problems, with nearest neighbout distances far exceeding maximum intraspecific divergence , at leashylogeny . Barcode"} +{"text": "Vadsala Baskaran, Amanda Goodwin, Lavanya Athithan, Ciro Roberto Rinaldi, and Alfredo Addeo.Author names are incorrectly listed as follows:\u2009Vadsala Baskaran, Amanda Goodwin, Lavanya Athithan, Alfredo Addeo, and Ciro Rinaldi.They are now listed as follows:"} +{"text": "The second and third authors are listed out of order. The correct author order is: Songtao Li, Xilu Liao, Fanyu Meng, Yemei Wang, Zonxiang Sun, Fuchuan Guo, Xiaoxia Li, Man Meng, Ying Li, Changhao Sun."} +{"text": "AbstractSeasogonia Young, 1986 is a sharpshooter genus with 13 species, four of them recorded from China. In this paper, Seasogonia sandaracata is recorded as new for China and Seasogonia rufipenna Li & Wang, 1992 is regarded as a junior synonym of Seasogonia nigromaculata Kuoh, 1991. The morphological diversity of the female genitalia of Seasogonia is still poorly known. We provide herein detailed descriptions and illustrations of three Chinese Seasogonia species. Notes on the female genitalia of Seasogonia, including intraspecific and interspecific variation, and comparisons between the female genitalia of Seasogonia and of other related genera from China are provided. The preliminary results indicate that the female genitalia may provide useful features for the taxonomy of Seasogonia and other members of the Old World Cicadellini. Seasogonia was established by Tettigoniella dunsiriensis Distant, 1908 as the type species. There was no species recorded from China at that time. Seasogonia from China, and later Seasogonia sanguinea, which was treated as a junior synonym of Seasogonia indosinica (Jacobi) (Seasogonia sikhimensis (Distant), which was treated as speciesPageBreak of uncertain position by Seasogonia sandaracata (Distant) is recorded as new for China and Seasogonia rufipenna Li & Wang is proposed as a junior synonym of Seasogonia nigromaculata Kuoh.The sharpshooter genus (Jacobi) . Wilson Seasogonia species were only briefly described. The present study provides a detailed description of the previously unknown female genitalia of three Chinese Seasogonia species. Notes on the female genitalia of Seasogonia, including intraspecific and interspecific variation, and comparisons between the female genitalia of Seasogonia and of other related genera from China are provided. We hope that this description will point out useful characters for the taxonomic studies on the Old World Cicadellini.The female genitalia have yielded useful characters for the taxonomy of sharpshooters , but theThe male and female genital structures were prepared according to the techniques described by (Jacobi)http://species-id.net/wiki/Seasogonia_indosinicaTettigoniella indosinica Jacobi, 1905: 445Seasogonia sanguinea Kuoh & Zhuo, 1996: 1PageBreak1 male, China, Guangxi Province, Huaping, 5 June 1997, coll. Yang Mao-fa; 3 males, 2 females, China, Guangxi Province, Jinxiu County, Dayaoshan, Alt. 500m, 28 April 2008, coll. Meng Ze-hong; 2 males, China, Hainan Province, Jianfengling, 14\u201315 May 1997, coll. Yang Mao-fa; 1 male, China, Hainan Province, Jianfengling, 17 April 2009, coll. Yang Zai-hua; 14 males, China, Hainan Province, Diaoluoshan, 10\u201312 April 2009, coll. Yang Zai-hua; 1 male, China, Hainan Province, Bawangling, 24 April 2009, coll. Yang Zai-hua; 1 male, China, Sichuan Province, Emeishan, 14 July 1995, coll. Yang Mao-fa; 3 males, China, Guizhou Province, Guiyang City, 5 June 1981, coll. Li Zi-zhong and Ma Gui-yan; 1 male, China, Guizhou Province, Guiyang City, 2 July 1986, coll. Li Zi-zhong; 4 males, 1 female, China, Guizhou Province, Guiyang City, 15 June 1992, coll. Zhang Yu-qiong; 10 males, China, Guizhou Province, Taijiang County, 9\u201317 May 1985, coll. Li Zi-zhong; 17 males, China, Guizhou Province, Libo County, 19\u201324 May 1995, coll. Chen Xiang-sheng; 8 males, China, Guizhou Province, Libo County, 24\u201330 May 1998, coll. Li Zi-zhong and Song Qiong-zhang; 2 males, China, Guizhou Province, Libo County, 14\u201317 June 2006, coll. Zhou Zhong-hui and Zhang Bin; 5 males, 3 females, China, Guizhou Province, Chishui County, 28 May 2000, Li Zi-zhong and Chen Xiang-sheng; 2 males, 3 females, China, Guizhou Province, Xishui City, 3 June, coll. Li Zi-zhong and Chen Xiang-sheng; 2 males, China, Guizhou Province, Chishui City, 28\u201330 May 2006, coll. Tang Yi and Yang Zai-hua; 1 male, China, Guizhou Province, Fanjingshan, 27 July 2001, coll. Li Zi-zhong; 2 males, 2 females, China, Guizhou Province, Fanjingshan, 2\u20133 June 2002, coll. Li Zi-zhong and Yang Mao-fa; 12 males, 7 females, China, Guizhou Province, Daozhen County, Dashahe, 22\u201327 May 2004, coll. Zhang Bin, Song Qiong-zhang, Xu Fang-ling and Chen Xiang-sheng; 39 males, 4 females, China, Guizhou Province, Leigongshan, 31 May to 5 June 2005, coll. Tang Yi, Li Zi-zhong, Zhang Bin, Song Qiong-zhang, Zhang Zheng-guang, Ge De-yan, Yang Zai-hua and Xu Fang-ling; 1 male, China, Guizhou Province, Anshun City, 20 July 2005, coll. Zhou Zhong-hui; 3 males, China, Guizhou Province, Duyun City, 5 May 2006, coll. Yang Zai-hua and Zhou Zhong-hui; 4 males, China, Guizhou Province, ShiBing County, Yuntaishan, 20\u201321 May 2009, coll. Yang Zai-hua; 43 males, 10 females, China, Guizhou Province, Suiyang County, Kuankuoshui, 2\u20139 June 2010, coll. Dai Ren-huai, Song Qiong-zhang, Li Hu, Li Yu-jian, Zhang Bin, Zheng Yan-li and Xing Ji-chun.Myanmar, Vietnam, India, China .PageBreakPageBreakrectangular, slightly expanded posteriorly, posteroventral margin angulate; in ventral view .PageBreakPageBreak macrosetae and some short microsetae on narrowed apical one-third portion. Aedeagus .Pygofer in laterSeasogonia indosinica. Other characteristics as in Seasogonia indosinica.Abdominal sternite VII , in vent(Distant)http://species-id.net/wiki/Seasogonia_sandaracataTettigoniella sandaracata Distant, 1908: 2175 males, 1 female, China, Yunnan Province, Yingjiang County, Tongbiguan, Alt. 1200m, 15 June 2001, coll. Tian Ming-yi; 10 females, China, Yunnan Province, Yingjiang County, Tongbiguan, Alt. 1400\u20131500m, 20 July 2002, coll. Yang Mao-fa, Li Zi-zhong, Song Hong-yan and Dai Ren-huai; 32males, 7 females, China, Yunnan Province, Yingjiang County, 29 May to 3 June 2011, coll. Yang Zai-hua and Li Yu-jian; 13 males, 2 females, China, Yunnan Province, Yingjiang County, Xima Town, Alt. 1700m, 8\u201310 June 2009, coll. Yang Zai-hua and Li Bin; 2 males, 1 female, China, Yunnan Province, Yingjiang County, Tongbiguan, Alt. 270m, 13 June 2009, coll. Yang Zai-hua and Li Bin; 1 male, 11 females, China, Yunnan Province, Tengchong County, Shangyun Village, Alt. 1400m, 14 July 2002, coll. Li Zi-zhong and Yang Mao-fa; 1 male, 3 females, China, Yunnan Province, Tengchong County, Gaoligongshan, Alt. 1900\u20132000m, 17 July 2002, coll. Yang Mao-fa, Li Zi-zhong, and Song Hong-yan; 5 females, China, Yunnan Province, Longling County, Longxin, Alt. 1800m, 24 July 2002, coll. Yang Mao-fa, Li Zi-zhong, and Song Hong-yan; 1 male, 1 female, China, Yunnan Province, Tengchong County, Gaoligongshan, Alt. 1800\u20132400m, 28 May to 5 June 2009, coll. Yang Zai-hua and Li Bin; 3 males, China, Yunnan Province, Ruili County, Moli, Alt. 770m, 15 June 2009, coll. Yang Zai-hua and Li Bin; 7 males, 5 females, China, Yunnan Province, Ruili County, 5\u20137 June 2011, coll. Li Yu-jian and Yang Zai-hua; 1 male, China, Yunnan Province, Pianma, 10 May 2010, coll. Zhang Bin; 18 males, 4 females, China, Yunnan Province, Pianma, 17\u201319 June 2011, coll. Li Yu-jian and Yang Zai-hua; 47 males, 30 females, China, Xizang Province, Muotuo County, 6 May to 4 June 1980, coll. Jin Gen-tao and Wu Jian-yi ).India, Myanmar, China . New Record for China.Seasogonia indosinica. Other characteristics as in Seasogonia indosinica.Abdominal sternite VII , in ventIntraspecific variation. The number of teeth on valvulae II often varied from 4\u20137 teeth. In addition, the location of each tooth varied among different specimens, or between each valvula of a single specimen.PageBreakInterspecific variation. Females of Chinese Seasogonia species can be distinguished from each other mainly by the following characters: (1) the posterior margin of sternite VII is well produced medially and forms a median lobe in Seasogonia indosinica in Seasogonia sandaracata, the macrosetae on the pygofer surface extend anteriorly distinctly farther than in the other two species theia rosea , and thehe lobes ; (4) in ia rosea , the basdaracata . Other cSeasogonia species, and the characters such as lateral and median lobes of posterior margin can efficiently distinguish Chinese Seasogonia species. The female abdominal sternite VII is widely used for separating species of a genus or genera in sharpshooters or several groups of other leafhoppers the posterior margin of the sternite VII is distinctly convex ; (2) the valvulae I and II are distinctly curved dorsally near apex (Seasogonia seems very unusual for Cicadellini in general. We compared the shape and teeth with other cicadellines, but found little similarities on our studied genera of Old world Cicadellini. Seasogonia are somewhat similar to the New World genus Versigonalia (Seasogonia species, the valvulae II are not very expanded beyond basal curvature, shaft just have poorly developed teeth in apical one-third or one-half and apex is narrowly rounded in Versigonalia, but the shaft of valvulae does not curve so distinctly as in Seasogonia and not have clear dentate apicoventral margin.Unfortunately, we did not have at hand specimens of om China \u201364. Basedorsally and 53; ear apex and 41; ear apex and 53; ear apex . It is iear apex . The strigonalia . Just asCicadellini are the reduced internal sternite VIII. The sclerotized parts of this sternite can provide shape-related characteristics useful for species distinctions in the subfamily (Cicadellini studied, which is consistent with Seasogonia and other members of the Old World Cicadellini.The sclerites of the genital chamber described by ubfamily . We did"} +{"text": "Torsten Schwede, Biozentrum Universit\u00e4t Basel & SIB Swiss Institute of Bioinformatics, Basel, SwitzerlandDagmar Iber, ETHZ & SIB Swiss Institute of Bioinformatics, Basel, SwitzerlandTorsten Schwede, Biozentrum Universit\u00e4t Basel & SIB Swiss Institute of Bioinformatics, Basel, SwitzerlandKatja Jenni, Biozentrum Universit\u00e4t Basel, SwitzerlandRita Manohar, Biozentrum Universit\u00e4t Basel, SwitzerlandSarah G\u00fcthe, Biozentrum Universit\u00e4t Basel & SIB Swiss Institute of Bioinformatics, Basel, SwitzerlandYvonne Steger, Biozentrum Universit\u00e4t Basel, SwitzerlandLorenza Bordoli, Biozentrum Universit\u00e4t Basel & SIB Swiss Institute of Bioinformatics, Basel, SwitzerlandIrene Perovsek, SIB Swiss Institute of Bioinformatics, Lausanne, SwitzerlandJocelyne Bocquet, SIB Swiss Institute of Bioinformatics, Lausanne, SwitzerlandMelissa Davis, SIB Swiss Institute of Bioinformatics, Lausanne, SwitzerlandRon Appel, SIB Swiss Institute of Bioinformatics, Lausanne, SwitzerlandAnna Tramontano (chair), University of Rome \u2018La Sapienza\u2019, ItalyJanet Thornton, EBI European Bioinformatics Institute, UKMichal Linial, Hebrew University, Jerusalem, IsraelRon Appel, SIB Swiss Institute of Bioinformatics, SwitzerlandAlfonso Valencia, Centro Nacional de InvestigacionesOncologicas, Madrid, SpainYves Moreau, University of Leuven, BelgiumMartin Vingron, Max Planck Institute for Molecular Genetics, Berlin, GermanyJulio Saez-Rodriguez, European Bioinformatics Institute (EMBL-EBI)Ioannis Xenarios, University of Lausanne & SIB, SwitzerlandSean O'Donoghue, CSIRO & Garvan Inst., AustraliaDagmar Iber, ETHZ & SIB, Basel, SwitzerlandYves Moreau, University of Leuven, BelgiumNiko Beerenwinkel, SIB and ETHZ, Basel, SwitzerlandAlfonso Valencia, Centro Nacional de Investigaciones Oncologicas, Madrid, SpainDietrich Rebholz-Schuhmann, European Bioinformatics Institute (EMBL-EBI)Nicolas Galtier, CNRS, Universit\u00e9 Montpellier 2, FranceMarc Robinson-Rechavi, University of Lausanne & SIB, SwitzerlandAnna Tramontano, University of Rome \u2018La Sapienza\u2019, ItalyTorsten Schwede, SIB & Biozentrum, University of Basel, SwitzerlandSven Bergmann, University of Lausanne & SIB, SwitzerlandRichard Durbin, Wellcome Trust Sanger Institute, Hinxton, UKRob Russel, University of Heidelberg, GermanyChristian von Mering, University of Zurich & SIB, SwitzerlandThomas H\u00f6fer, German Cancer Research Center (DKFZ) Heidelberg, GermanyFabian Theis, Helmholtz Zentrum M\u00fcnchen, GermanyMartin Vingron, Max Planck Institute for Molecular Genetics, Berlin, GermanyGaston Gonnet, ETH Z\u00fcrich & SIB, SwitzerlandJacques Rougemont, EPFL, Lausanne, SwitzerlandGert Vriend, Centre for Molecular and Biomolecular Informatics, Nijmegen, The NetherlandsFrederique Lisacek, SIB and University of Geneva, SwitzerlandMichael Stadler, Poster chair, SIB & FMI Friedrich Miescher Institut, Basel, SwitzerlandMohamed AbouelhodaJan AertsPankaj AgarwalChristian AhrensMario AlbrechtPatrick AloyGregoire Altan-BonnetAndre AltmannInka AppelKazuharu ArakawaSaul AresSusanna Assunto-SansonePhilip AwadallaFrancisco AzuajeRolf BackofenRuth BakerPedro BallesterMatteo BarberisGeoff BartonThomas BataillonAlex BatemanMichael BeckstetteNiko BeerenwinkelTim Bei\u00dfbarthAsa Ben-HurNir Ben-TalAndreas BenderSven BergmannAndreas BergnerSimon BernecheConrad BessantJoanna BettsInanc BirolJudith BlakeNils Bl\u00fcthgenBrigitte BoeckmannDanail BonchevPaola BonizzoniLorenza BordoliErich Bornberg-BauerAnne-Laure BoulesteixPhil BourneYana BrombergDavid BryantJavier Buceta Fern\u00e1ndezJanusz BujnickiAnita Burgun-ParenthoineHauke BuschRainer B\u00f6ckmannCarlos CamachoAlessandra CarboneRobert CasteloRui ChenJeong-Hyeon ChoiAndrea CilibiertoKevin CohenLachlan CoinNigel CollierAttila Csikasz-NagyAntoine DanchinThomas DandekarVincent DaubinHidde de JongXavier De La CruzRenee de MenezesRenee de MenezesDick de RidderJeroen de RidderCharlotte DeaneMauro DelorenziEmmanouil DermitzakisChristophe DessimozDiego Di BernardoAndreas DoncicJean-Philippe DoyonIvana DrobnjakOmer DushekMartin EbelingOliver Ebenh\u00f6hRichard EdwardsGeorg EhretLaurent ExcoffierAdam Eyre-WalkerLaurent FalquetLaurent FalquetGeorgios FengosJuan Fernandez RecioThilo FiggeSamuel FloresPaul Fran\u00e7oisFranca FraternaliErwin FreyCaroline FriedelDmitrij FrishmanHolger FroehlichToni GabaldonJulien GagneurNicolas GaltierTomas GedeonFlorian GeierOlivier GevaertRobert GiegerichAlejandro GiorgettiGeorgios GkoutosGiorgio GonnellaGaston GonnetBerthold GottgensJerome GoudetStephan GrillAndre GruningNicolas GuexJ\u00fcrgen HaasStefan HaasDieter HeermannManuela Helmer-CitterichJean-Karim HericheJaap HeringaHenning HermjakobRyan HernandezCarl HerrmannRalf HerwigDes HigginsMichael HillerRobert HoehndorfIvo HofackerDaniel HoffmannSteve HoffmannLiisa HolmFrank HolstegeHermann-Georg Holzh\u00fctterRob HooftSimon HubbardWolfgang HuberMartin HuynenThomas H\u00f6ferMark IbbersonDagmar IberFrancesco IorioChristian IseliKevin JanesAlfonso JaramilloKlaus JungIgor JurisicaOlga KalininaOlga KalininaWarren KaplanGuy KarlebachKazutaka KatohLaurence KelleyJanet KelsoPatrick KemmerenPhilipp KhaitovichJin-Dong KimJung-Jae KimPhilip KimWing Kin SungMartin KircherHisanori KiryuThomas KlabundeGunnar KlauJudith Klein-SeetharamanCarole KnibbeHeinz KoepplOliver KohlbacherRachel KolodnyJan KorbelSergei Kosakovsky PondRoland KrauseMichael KrauthammerAndriy KryshtafovychGregory LefebvreMatthieu LegendreHans-Peter LehnhofThomas LengauerUlf LeserChristina LeslieMingyao LiHao LinYao-Cheng LinMichal LinialFrederique LisacekHongfang LiuNuria Lopez-BigasPhilip LordDaniel MacArthurMatthias MachacekUlrich MansmannPaolo MarcatiliJohn MarioniFlorian MarkowetzBrian MarsdenLennart MartensMarc Marti-RenomMark McCarthyLiam McGuffinAlice McHardyDzianis MenshykauMichael Meyer HermannAnke Meyer-BaeseGeorge MichailidisAndrey MironovShabaz MohammedCarmen Molina-ParisStephen MontgomerySean MooneyYves MoreauBurkhard MorgensternSimon MoxonMatthieu MuffatoChris MungallFelix NaefMarkus NebelGoran NenadicZoran NikoloskiMichael NilgesZemin NingMagnus NordborgCedric NotredameJohn NovembreSe\u00e1n O'DonoghueJean-Christophe Olivo-MarinChristine OrengoMarko PagniJong ParkKiran PatilSabine PeresHerve PhilippeDavid PosadaJaime PriluskyNata\u0161a Pr\u017euljMiguel Angel PujanaTal PupkoZhaohui QinJ\u00f6rg Rahnenf\u00fchrerDomenico RaimondoSanguthevar RajasekaranDavid RandBen RaphaelDietrich Rebholz-SchuhmanKnut ReinertBernhard RenardSamuli RipattiDavid RitchieEric RivalsMark RobinsonPeter RobinsonMarc Robinson-RechaviStephane RombautsMichal Rosen-ZviVolker RothJacques RougemontRob RussellAndrey RzhetskyGunnar R\u00e4tschSten R\u00fcdigerJulio Saez-RodriguezNicolas SalaminMichael SammethIvo SbalzariniJ\u00f6rg SchaberWolfgang SchamelAvner SchlesingerAlexander SchliepAdrian SchneiderBirgit SchoeberlMichael SchroederJ\u00f6rg SchultzMarcel SchulzStefan SchulzStefan SchusterRussel SchwartzTorsten SchwedeBenno SchwikowskiJoachim SelbigNigam ShahRoded SharanNoam ShomronBarry SmithBerend SnelJohannes SoedingIngolf SommerRainer SpangAlexandros StamatakisOliver StegleJ\u00f6rg StellingRobert StevensJens StoyeKorbinian StrimmerJosh StuartJoakim SundnesEric TannierFabian TheisDenis ThieffryPaul ThomasPeter TielemanJerzy TiurynAnna TramontanoAchim TreschAla TrusinaJerry TsaiDavid UmulisSandor VajdaIlya VakserAlfonso ValenciaPascal VallottonRoeland van HamJacques van HeldenAntoine van KampenErik van NimwegenVera van NoortCeslovas VenclovasJean-Philippe VertMartin VingronArndt von HaeselerChristian von MeringGert VriendThomas WalterJohn WelchLodewyk WesselsSimon WhelanEdgar WingenderErnst WitShoshana WodakJerome WojcikJana WolfVerena WolfHaim WolfsonStephen WongCarolina W\u00e4hlbyIoannis XenariosJulien Yann DutheilMihaela ZavolanDaniel ZerbinoLouxin ZhangXiuwei ZhangRalf ZimmerAndrei ZinovyevAnder, ChristinaArnold, RolandAtias, NirAyshwarya, SubramanianBao, JieBayerlova, MichaelaBerman, BenBohl, KatrinBot, JanBoulesteix, Anne-LaureBusse, DorotheaBussotti, GiovanniCarbonell, PabloCastro, MauroChen, LiChen, XinChinappi, MauroChua, WatsonCifuentes, DanielColak, RecepCorcoran, DavidCorpas, ManuelCorre, TanguyCsaba, GergelyCzeizler, ElenaDaminelli, SimoneDe Brevern, Alexandre G.de Oliveira Martins, LeonardoDegroeve, SvenDi Camillo, BarbaraDinh, HieuDrewe, PhilippDutilh, Bas E.Erb, IonasErhard, FlorianFelizzi, FedericoFengos, GeorgiosFischer, BerndFortney, KristenFraternali, FrancaFriedel, CarolineFuchs, ChristianeFuchs, MathiasGambardella, GennaroGarijo, DanielGerstung, MoritzGevaert, OlivierGherardini, Pier FedericoGomes, MireilleGonnella, GiorgioGonnet, GastonGonzalez,Gori, KevinGriebel, ThassoGr\u00fcn, BettinaGuillemot, VincentHan, XuHeath, SimonHelsens, KennyHersch, MichaHill, JamieHoehndorf, RobertHoener Zu Siederdissen, ChristianHohm, TimHu, JialuH\u00f6fer, ThomasIsik, ZerrinJaenicke, SebastianJanjic, VukJeon, ClareJohn, MathiasJonnalagadda, SiddharthaJurman, GiuseppeKahles, AndreKeasar, ChenKelemen, JanosKemena, CarstenKemmeren, PatrickKnijnenburg, TheoKnudsen, MichaelKoes, DavidKolbe, DianaKorcsmaros, TamasKosloff, MickeyKowald, AxelKramer, FrankKrumsiek, JanKutalik, ZoltanK\u00fcffner, RobertLaenen, GrietLamparter, DavidLauria, MarioLe Crom, StephaneLee, MilerLeha, AndreasLensink, MarcLi, JieLi, YongLim, Jing QuanLord, PhillipLorenz, RonnyLoza, ElisaLu, XiaowenLuu, Anh TuanMace, AurelienMahfouz, AhmedMahlab, ShellyMahony, ShaunMancheron, AlbanMann, MartinMansmann, UlrichMarek, DianaMargelevi\u00e8ius, MindaugasMarschall, TobiasMazza, ArnonMeyer, FernandoMichaut, MagaliMituyama, ToutaiM\u00fcller, NikolaM\u00fcller, TobiasNicolae, MariusOesper, LaylaOlechnovic, KlimentOlechnovi\u00e8, KlimentOtto, ChristianPagliarini, RobertoPalmeri, AntonioParca, LucaParks, SarahPatil, Kaustubh RaosahebPelossof, RaphaelPemberton-Ross, PeterPenn, OsnatPfeifer, NicoPhilippe, NicolasPiasecka, BarbaraPorzelius, ChristinePrunotto, AndreaRajan, VaibhavRappoport, NadavRausch, TobiasReimann, MatthiasRichard, HuguesRisso, DavideRose, DominicRueedi, RicoSakoparnig, ThomasSchlesner, MatthiasSchoenhuth, AlexanderSetty, ManuShao, ChunxuanSilberberg, YaelSkunca, NivesSolari, AldoSoneson, CharlotteStaiger, ChristineStevenson, BrianSundermann, LindaTaly, Jean Fran\u00e7oisTer Horst, RobThomas, PhilippeTorii, ManabuTourinsky, AndreiTranchevent, Leon-CharlesTravers, TimothyTsai, Ming-ChiUlrich, MansmannValentini, GiorgioValouev, AntonValsesia, Armandvan der Lee, RobinVandenbon, AlexisVandin, Fabiovon der Heyde, SilviaVriend, GertWaldispuhl, JeromeWeber, SebastianWeigt, MartinWeinberg, ZashaWill, SebastianWillrodt, DirkWoollard, PeterYang, LunYang, RendongYaveroglu, Omer NebilYuan, ShuaiZakrzewski, MarthaZhang, ZhaoleiZhao, MengZhong, Yi"} +{"text": "Day-to-day functioning is a component of health-related quality of life and is an important end point for therapies to treat Huntington Disease (HD). Specific areas of day-to-day function changes have not been reported for prodromal or very early stages of HD. An exploratory self-report telephone interview was conducted with sixteen people with prodromal HD or early HD who met criteria designed to capture research participants most near to motor diagnosis. All completed semi-structured interviews on function in nine aspects of day-to-day life. Out of 16, 14 reported changes in at least one area. All day-to-day function areas were endorsed by at least one participant with driving being the most common area endorsed by 11/16. Changes in ability to perform some day-to-day tasks are experienced by people who are close to the time of clinical diagnosis for HD. Functional ability is likely to be an important component of outcome assessments of clinical trials and in ongoing clinical management. Huntington disease (HD) is an autosomal dominant, progressive neurodegenerative disorder in which losses of neurologic function continue until the end of the person\u2019s life. The diagnosis of HD traditionally is made with onset of motor symptoms. This typically occurs in the fourth decade of life In plain language, function refers to a person\u2019s abilities to do their daily tasks and routines in their daily life. However, the concept of ability to perform daily tasks is used in a variety of ways. The FDA description of patient-reported outcomes in clinical trials includes measures of any aspect of a patient\u2019s health status that document the effect of a disease on a person\u2019s quality of life, which in turn may include the person\u2019s ability to perform daily activities . In the public health arena, health related quality of life refers to the effect of chronic illness on a person\u2019s day-to-day life The earliest phase described in HD is referred to as the prodrome, and research findings have documented features of the disease up to 15 years prior to the diagnosis These global measures of functioning may not be sensitive to subtle changes in functional abilities that occur in prodromal HD. For example, when administered to 786 participants in PREDICT-HD, over 88% of participants scored at ceiling on the TFC or FAS. Among those participants, 5\u20137% reported some loss on questions about work and managing finances Research on the potential effect of interventions to delay or modify symptoms is limited by the absence of measures of day-to-day function activities across the prodromal and early diagnostic phases of HD. This includes those activities that may be diminishing at the time surrounding the time of diagnosis. Instruments are needed that document patient reported outcomes As reviewed above, the available quantitative data has been queried with regards to day-to-day functions in prodromal and very early HD. Findings have suggested that the currently available measures lack sensitivity to prodromal and very early diseases. This limitation is expected since most functional scales were initially developed for neurodegenerative diseases to track stages of dementia. Only more recently have we had the ability to identify and track persons at high risk for neurodegenerative diseases through efforts such as Mild Cognitive Impairment and PREDICT-HD. Findings suggest that new information is needed to better develop the earliest functional changes that occur prior to formal diagnosis of neurodegenerative disease. The current study was designed to solicit qualitative data to assist with the development of more sensitive measures. In an effort to maximize the data obtained through the qualitative interviews, we created an algorithm to recruit prodromal research volunteers who are considered most close to receiving a formal motor diagnosis and who were most likely to experience early functional decline. This is an exploratory study using descriptive qualitative methods and a single telephone semi-structured interview. Sixteen people who were enrolled at one of two PREDICT-HD research sites participated in the IRB-approved telephone interviews. Participants were selected from the PREDICT-HD study based on one of the following criteria:th percentile of longitudinal change in UHDRS total motor score. (1) were considered to be \u201cnear\u201d diagnosis based upon formula derived from CAG repeat length and current age The project received approval from The University of Iowa Institutional Review Board and the Centre for Addiction and Mental Health Research Ethics Board in Toronto, Canada. The majority of participants (11/16) were female. Six were from Canada and 10 from the US. The mean CAG length was 41.38 (SD 1.45) and range 38\u201344. Mean age was 65.6 (SD 10.0) and range 36.5\u201378.8. Twelve had been diagnosed at the time of the interview.A semi-structured interview guide was developed by the authors for this project. Topics were selected based on a review of the literature, clinical experience of the research team, and prior interviews conducted during the development of an instrument focused specifically on ability to perform tasks at work. After completion of informed consent procedures, each person participated in a telephone interview conducted by a team member who is an experienced interviewer. Interviews ranged from 4\u201335 minutes, with the average being 13.5 minutes. The shorter interview times were for those participants who had no functional changes to report. All interviews were audiotaped and transcribed verbatim. Data saturation was reached after six interviews; after that we did not learn of other day-to-day function changes not previously mentioned by other participants.Figure 1. Day-to-Day Function Semi-Structured Interview GuideTwo authors followed qualitative descriptive analysis techniques Fourteen of the 16 participants described one or more changes in performance of day-to-day tasks. Each participant reporting changes endorsed from 1\u20137 areas of function (Table 1). One person who did not endorse any of the 9 topics in the interview guide reported the presence of involuntary movements. Specific functional tasks and examples of statements are provided below. Participants are identified by a number only for the purpose of reporting the data. Table 1. Functional Changes (N=16)Driving: The most commonly endorsed day-to-day change was driving (11/16). Participants referred to concerns about doing more than one thing at a time, being slower, and concerns about safety. For example, I can only, kind of, do one thing at a time now, I need to be alert to the driving solely; my reaction time is slower (1), and one of the kids was nervous of me driving. Because of that I have said that I won\u2019t drive any of the grandkids (2).Interactions: When describing changes in interactions with others, participants described a variety of changes including lack of interest, anxiety, and irritability with others. I\u2019m, um, a little less patient, sometimes I have to watch myself, you know; I have to watch the way I speak (3), and it\u2019s not that I don\u2019t feel social, it\u2019s just . . . I get lazy and I don\u2019t want to go out (4).Household chores: Respondents were aware they were not keeping up with their usual responsibilities, but described a lack of interest or initiative. I used to change the beds and now it\u2019s not as often as I used to (5), You know, I could look at something, and you know, realize it was dusty, but . . . for that to register in my head that I, you know, had to clean a whole house . . . I just never thought about it (6), and it\u2019s not important any more (7).Telephone: Respondents were reluctant to respond on the telephone when they weren\u2019t prepared, and were selective when they did answer the telephone. Only if I know about it in advance. Spur of the moment . . . forget it . . . it\u2019s like because it was unexpected . . . my brain\u2019s not working that way (7), and I have it print out on my TV so I it tells me who it is . . . I don\u2019t want to get into the conversation . . . you just don\u2019t want to . . . initiate it (8).Shopping: Skills needed for shopping included being able to remember where to go for needed items, as well as what the items are. I make my list, and write it down . . . to make sure I remember to stop (8), and I forget things so I usually need to have a list for everything I\u2019m going to need (1).Finances: Not being able to remember to take care of finances was mentioned by several; others also noted that they could not keep up with the processes of calculating and managing them. Anything concerning the bills, or anything like that, I can\u2019t remember (3), uh, I just kind of don\u2019t do it, I mean, I don\u2019t know what happened (6), I\u2019m not very good at it, you know, adding in my head anymore (5). Paid work: All respondents who left paid employment had done so voluntarily. Some stated they were able to retire due to having reached the requirements for full retirement, or for family reasons. Others specifically addressed an inability to do their jobs. I had to leave my job because . . . I just couldn\u2019t work, like I just couldn\u2019t . . . mentally . . . I couldn\u2019t do it (3). I was falling behind (6). Cooking: Multiple demands in planning and executing preparing a meal were difficult for some participants. I think I make more of a mess . . . But for the most part it\u2019s ok; it takes me longer to clean up . . . I just forget to do things (4). Hobbies and other topics: When asked about changes in hobbies or leisure activities, none of the respondents reported changes that were related to having prodromal HD. When asked if there were other things they had noticed, comments were offered about motor skills. Oh God, that\u2019s bad too; I walk into walls (7), I guess what you call the involuntary movements . . . I definitely feel that it doesn\u2019t mean it makes any changes in your ability to do things . . . it\u2019s just something you have noticed over time, that\u2019s all (9). In responding to queries regarding potential changes in ability to carry out day-to-day tasks in specific areas, all respondents provided information on factors that, they believed, made it difficult to do these tasks. These factors ranged from emotional to cognitive to physical stamina topics. Apathy/Fatigue:I get really tired . . . It\u2019s not so much a physical thing; it\u2019s a, like in your mind (10). I don\u2019t have the excitement part of doing some things; it\u2019s just not there (11).Cognition:Part of my trade was . . . always learning stuff; I couldn\u2019t learn . . . I couldn\u2019t remember anything anymore (4); Memory\u2014it\u2019s just gone. Like my short-term memory (3).Irritability:I always seem to have that real quick to anger (6). I\u2019m a little short, a little cranky (12).This study examined self-reports of losses of abilities to perform day-to-day tasks in a small cohort of people in the prodromal HD or very early phase of HD and for whom scores on the UHRDS motor scale indicated a significant increase of motor decline. Findings indicate that changes in day-to-day task function vary in prodromal HD and those recently diagnosed with HD, but that when changes are experienced, they are more likely to be in the domains of tasks that require multiple cognitive, motor, and behavioral abilities. Driving is a good illustration of this because it is an activity that requires multiple domain skills and was the most frequently mentioned area of functional difficulty in this sample. Although few reports focus on components of day-to-day function in prodromal HD or early HD, the range of topics is consistent with those reported with less sensitive measures, specifically that of employment and managing finances \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0A potential limitation of this study includes the possibility of early lack of insight that is a component of HD http://knol.google.com/k/anthony-l-vaccarino/assessment-of-day-to-day-functioning-in/19jerwgzmryar/28#).\u00a0Further investigations may provide insight into factors associated with the domains in which people with prodromal HD perceive changes, as well as provide data to monitor progression of day-to-day function over time. \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0These findings suggest that day-to-day function may be impaired in some domains during the prodromal HD and recently diagnosed period, and that measures to document function must encompass the range of domains likely to be affected in prodromal HD.\u00a0Data from these interviews were used in the development of items to assess day-to-day functioning by FuRST-pHD; and initiative to develop a rating scale for assessing symptoms and functional ability in prodromal and early HD and CHDI Foundation, Inc.\u00a0We thank the PREDICT-HD sites, the study participants, and the National Research Roster for Huntington Disease Patients and Families. The full list of those involved with the PREDICT-HD study is shown below.The authors declare no competing interests.PREDICT-HD Investigators, Coordinators, Motor Raters, Cognitive RatersActive: September 2009\u2013August 2010\u00a0Thomasin Andrews, MD, BSC, MRCP, Elisabeth Rosser, MBBS, FRCP, and Sarah Tabrizi, MD, PhD ;\u00a0Anne Rosser, MD, PhD, MRCP, Kathy Price, RN, and Sarah Hunt, BSc ;\u00a0Frederick Marshall, MD, Amy Chesire, LCSW-R, MSG, Mary Wodarski, BA, and Charlyne Hickey, RN, MS ;\u00a0Oksana Suchowersky, MD, FRCPC, Sarah Furtado, MD, PhD, FRCPC, and Mary Lou Klimek, RN, BN, MA ;\u00a0Peter Panegyres, MB, BS, PhD, Elizabeth Vuletich, BSC, Steve Andrew, and Rachel Zombor, MPSYC ;\u00a0Joel Perlmutter, MD, Stacey Barton, MSW, LCSW, and Amy Schmidt ;\u00a0Zosia Miedzybrodzka, MD, PhD, Sheila A. Simpson, MD, Daniela Rae, RN, and Mariella D\u2019Alessandro, PhD ;\u00a0David Craufurd, MD, Ruth Fullam, BSC, and Elizabeth Howard, MD ;\u00a0Pietro Mazzoni, MD, PhD, Karen Marder, MD, MPH, and Paula Wasserman, MA ;\u00a0Rajeev Kumar, MD and Diane Erickson, RN ;\u00a0Vicki Wheelock, MD, Terry Tempkin, RNC, MSN, Nicole Mans, BA, MS, and Kathleen Baynes, PhD ;\u00a0Joseph Jankovic, MD, Christine Hunter, RN, CCRC, and William Ondo, MD ;\u00a0Justo Garcia de Yebenes, MD, Monica Bascunana Garde, Marta Fatas, BA,\u00a0 and Asuncion Martinez-Descales ;\u00a0Wayne Martin, MD, Pamela King, BScN, RN, and Satwinder Sran, BSC ;\u00a0Anwar Ahmed, PhD, Stephen Rao, PhD, Christine Reece, BS, Janice Zimbelman, PhD, PT, Alexandra Bea, BA, Emily Newman, BA, and Alex Bura, BA .Thomas Wassink, MD, Stephen Cross, BA, Nicholas Doucette, BA, Mycah Kimble, BA, Patricia Ryan, MSW, LISW, MA, Jessica Wood, MD, PhD, Eric A. Epping, MD, PhD, and Leigh J. Beglinger, PhD ;\u00a0Edmond Chiu, MD, Olga Yastrubetskaya, PhD, Joy Preston, Anita Goh, D.Psych, Chathushka Fonseka, and Liz Ronsisvalle ;\u00a0Phyllis Chua, MD, and Angela Komiti, BS, MA ;\u00a0Lynn Raymond, MD, PhD, Rachelle Dar Santos, BSc, and Joji Decolongon, MSC, CCRP ;\u00a0Adam Rosenblatt, MD, Christopher A. Ross, MD, PhD, Barnett Shpritz, BS, MA, OD, and Claire Welsh ;\u00a0William M. Mallonee, MD, Greg Suter, BA, and Judy Addison ;\u00a0Ali Samii, MD, and Alma Macaraeg, BS ;\u00a0Randi Jones, PhD, Cathy Wood-Siverio, MS, Stewart A. Factor, DO, and Claudia Testa, MD, PhD ;\u00a0Roger A. Barker, BA, MBBS, MRCP, Sarah Mason, BSC, Anna Goodman, PhD, Rachel Swain, BA, and Anna DiPietro ;\u00a0Elizabeth McCusker, MD, Jane Griffith, RN, Clement Loy, MD, David Gunn, BS, and Linda Stewart, RN ;\u00a0Bernhard G. Landwehrmeyer, MD, Michael Orth MD, PhD, Sigurd S\u00fc\u03b2muth, MD, RN, Katrin Barth, RN, and Sonja Trautmann, RN ;\u00a0Kimberly Quaid, PhD, Melissa Wesson, MS, and Joanne Wojcieszek, MD ;\u00a0Mark Guttman, MD, Alanna Sheinberg, BA, and Irita Karmalkar, BSc ;\u00a0Susan Perlman, MD and Arik Johnson, PsyD ;\u00a0Michael D. Geschwind, MD, PhD, Jon Gooblar, BA, and Gail Kang, MD ;\u00a0Tom Warner, MD, PhD, Maggie Burrows, RN, BA, Marianne Novak, MD,Steering CommitteeJane Paulsen, PhD, Principal Investigator, Eric A. Epping, MD, PhD, Hans Johnson, PhD, Megan Smith, PhD, Janet Williams, PhD, RN, FAAN, Leigh Beglinger, PhD, James Mills, MS ; Elizabeth Aylward, PhD ; Kevin Biglan, MD ; Blair Leavitt, MD ; Marcy MacDonald, PhD ; Martha Nance, MD ; and Cheryl Erwin, JD, PhD .Scientific SectionsBio Markers:\u00a0Blair Leavitt, MDCM, FRCPC (Chair) and Michael Hayden, PhD (University of British Columbia); Stefano DiDonato, MD ; Ken Evans, PhD (Ontario Cancer Biomarker Network); Wayne Matson, PhD ; Asa Peterson, MD, PhD , Sarah Tabrizi, MD, PhD ; Beth Borowsky, PhD (CHDI); Andrew Juhl, BS, James Mills, MS, Kai Wang, PhD (University of Iowa); and David Weir, BSc (University of British Columbia).Brain:\u00a0Jean Paul Vonsattell, PhD (Chair), and Carol Moskowitz, ANP, MS ; Anne Leserman, MSW, LISW, Lynn Schaul, BA, and Stacie Vik, BA (University of Iowa).Cognitive:\u00a0Deborah Harrington, PhD (Chair), Gabriel Castillo, BS, Jessica Morison, BS, and Jason Reed, BS , Michael Diaz, PhD, Ian Dobbins, PhD, Tamara Hershey, PhD, Erin Foster, OTD, and Deborah Moore, BA (Washington University Cognitive Science Battery Development); Holly Westervelt, PhD , Jennifer Davis, PhD, and Geoff Tremont, PhD, MS ; Megan Smith, PhD , David J. Moser, PhD, Leigh J. Beglinger, PhD, Kelly Rowe, and Danielle Theriault, BS (University of Iowa); Carissa Gehl, PhD ; Kirsty Matheson (University of Aberdeen); Karen Siedlecki, PhD (Fordham University); Marleen Van Walsem (EHDN); Susan Bonner, BA, Greg Elias, BA, and Melanie Faust, BS ; Beth Borowski, PhD (CHDI); Noelle Carlozzi (University of Michigan); Kevin Duff, PhD (University of Utah); Nellie Georgiou-Karistianis ; Julie Stout, PhD ; Herwig Lange (Air-Rahazentrum); and Kate Papp (University of Connecticut).Functional: Janet Williams, PhD (Chair), Leigh J. Beglinger, PhD, Anne Leserman, MSW, LISW, Eunyoe Ro, MA, Lee Anna Clark, Nancy Downing, RN, PhD, Joan Laing, PhD, Kristine Rees, BA, and Stacie Vik, BA (University of Iowa); Rebecca Ready, PhD (University of Massachusetts); Anthony Vaccarino, PhD (Ontario Cancer Biomarker Network); Sarah Farias, PhD\u00a0; Noelle Carlozzi, PhD (University of Michigan); and Carissa Gehl, PhD .Genetics:\u00a0Marcy MacDonald, PhD (Co-Chair), Jim Gusella, PhD, and Rick Myers, PhD ; Michael Hayden, PhD (University of British Columbia); Tom Wassink, MD (Co-Chair) Eric A. Epping, MD, PhD, Andrew Juhl, BA, James Mills, MS, and Kai Wang, PhD (University of Iowa); Zosia Miedzybrodzka, MD, PhD (University of Aberdeen); and Christopher Ross, MD, PhD (Johns Hopkins University).Imaging:\u00a0Administrative:\u00a0Ron Pierson, PhD (Chair), Kathy Jones, BS, Jacquie Marietta, BS, William McDowell, AA, Greg Harris, BS, Eun Young Kim, MS, Hans Johnson, PhD, and Thomas Wassink, MD (University of Iowa); John Ashburner, PhD ; Steve Potkin, MD ; and Arthur Toga, PhD .\u00a0Striatal:\u00a0Elizabeth Aylward, PhD .\u00a0Surface Analysis:\u00a0Eric Axelson, BSE (University of Iowa).\u00a0Shape Analysis:\u00a0Christopher A. Ross (Chair), MD, PhD, Michael Miller, PhD, and Sarah Reading, MD (Johns Hopkins University); Mirza Faisal Beg, PhD (Simon Fraser University).\u00a0DTI:\u00a0Vincent A. Magnotta, PhD ; Karl Helmer, PhD ; Kelvin Lim, MD ; Mark Lowe, PhD (Cleveland Clinic); Sasumu Mori, PhD (Johns Hopkins University); Allen Song, PhD (Duke University); and Jessica Turner, PhD .\u00a0fMRI:\u00a0Steve Rao, PhD (Chair), Erik Beall, PhD, Katherine Koenig, PhD, Michael Phillips, MD, Christine Reece, BS, and Jan Zimbelman, PhD, PT (Cleveland Clinic); and April Bryant (University of Iowa).Motor:\u00a0Kevin Biglan, MD (University of Rochester), Karen Marder, MD (Columbia University), and Jody Corey-Bloom, MD, PhD all Co-Chairs; Michael Geschwind, MD, PhD ; Ralf Reilmann, MD and Zerka Unds ; and Andrew Juhl, BS (University of Iowa).Psychiatric:\u00a0Eric A. Epping, MD, PhD (Chair), Nancy Downing, RN, PhD, Jess Fiedorowicz, MD, Robert Robinson, MD, Megan Smith, PhD, Leigh Beglinger, PhD, James Mills, MS, Kristine Rees, BA, Adam Ruggle, Stacie Vik, BA, Janet Williams, PhD, Dawei Liu, PhD, David Moser, PhD, and Kelly Rowe (University of Iowa); Karen Anderson, MD (University of Maryland); David Craufurd, MD (University of Manchester); Mark Groves, MD (Columbia University); Anthony Vaccarino, PhD and Ken Evans, PhD (Ontario Cancer Biomarker Network);\u00a0Hugh Rickards, MD ; Eric van Duijn, MD ; Irina Antonijevic, MD, PhD, and Joseph Giuliano (CHDI); Phyllis Chua ; and Kimberly Quaid, PhD (Indiana University School of Medicine).Core SectionsStatistics:\u00a0James Mills, MEd, MS, Dawei Liu, PhD, Jeffrey Long, PhD, Wenjing Lu, Kai Wang, PhD, and Ying Zhang, PhD (University of Iowa).Recruitment/Retention:\u00a0Martha Nance, MD ; Anne Leserman, MSW, LISW, Nicholas Doucette, BA, Mycah Kimble, BA, Patricia Ryan, MSW, LISW, MA, Kelli Thumma, BA, Elijah Waterman, BA, and Jeremy Hinkel, BA (University of Iowa).Ethics:\u00a0Cheryl Erwin, JD, PhD, ; Eric A. Epping, MD, PhD Janet Williams, PhD, Nicholas Doucette, BA, Anne Leserman, MSW, LISW, James Mills, MS, Lynn Schaul, BA, and Stacie Vik, BA (University of Iowa); Martha Nance, MD (University of Minnesota); and Lisa Hughes, MEd .IT/Management:\u00a0Hans Johnson, PhD (Chair), R.J. Connell, BS, Karen Pease, BS, Ben Rogers, BA, BSCS, Jim Smith, AS, Shuhua Wu, MCS, Roland Zschiegner, Erin Carney, Bill McKirgan, Mark Scully, and Ryan Wyse (University of Iowa); Jeremy Bockholt (AMBIGroup).Program ManagementAdministrative:\u00a0Chris Werling-Witkoske (Chair), Karla Anderson, BS, Kristine Bjork, BA, Ann Dudler, Jamy Schumacher, Sean Thompson, BA, Leann Davis, Machelle Henneberry, Greg Ennis, MA, and Stacie Vik, BA (University of Iowa).Financial:\u00a0Steve Blanchard, MSHA, Kelsey Montross, BA, and Phil Danzer (University of Iowa)."} +{"text": "The authors wish to add Dr. Han-Shui Hsu as an author to this paper. The correctedbyline is: Yi-Hung Carol Tan, Soundararajan Krishnaswamy, Suvobroto Nandi, RajaniKanteti, Sapana Vora, Kenan Onel, Rifat Hasina, Fang-Yi Lo, Essam El-Hashani,Gustavo Cervantes, Matthew Robinson, Han-Shui Hsu, Stephen C Kales, StanleyLipkowitz, Theodore Karrison, Martin Sattler, Everett E Vokes, Yi-Ching Wang, RaviSalgia. Dr. Hsu's affiliation is: Institute of Emergency and Critical Care Medicine,National Yang-Ming University School of Medicine, Taipei, Taiwan."} +{"text": "Lauren Comisar was erroneously omitted from the author list. Her affiliation is: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University.The updated author list is:Souriya Vang, Hsin-Ta Wu, Andrew Fischer, Daniel H. Miller, Shannon MacLaughlan, Elijah Douglass, Lauren Comisar, Margaret Steinhoff, Colin Collins,Peter J. S. Smith, Laurent Brard, Alexander S. BrodskyThe updated author contributions are:Pathology and tissue analysis: MS. Funding and intellectual support: CC PJS. Conceived and designed the experiments: ASB LB. Performed the experiments: SV AF DHM ED LC. Analyzed the data: HTW ASB. Contributed reagents/materials/analysis tools: SM. Wrote the paper: ASB."} +{"text": "AbstractAnthonomini are limited to those of the United States of America and Canada. A dichotomous key is presented to identify all genera of Mexican and Central American Anthonomini. Previous keys do not include the genera Achia, Botanebius, Loncophorus, Loncophorellus and Melexerus. A brief synopsis is given for each genus and photographs of representative species are included.Presently the only keys available for identification of genera of Curculionidae of Mexico and Central America is rich in species , Phyllotrox (Derelomini) or Tychius (Tychiini). These taxa can be distinguished from Anthonomini by the following combination of characters: Smicronyx have claws connate at base and pronotum with postocular lobes. Phyllotrox, femur with ventral margin simple, lacking tooth; procoxae closer to posterior margin than to anterior margin of prosternum. Tychius, suture between ventrites 2 and 3 markedly extended posterolaterally, reaching or passing suture between ventrites 3 and 4 , Anthonomus nigrinus (potato weevil), Anthonomus musculus (cranberry weevil), Anthonomus pomorum (apple blossom weevil) Anthonomus pyri (pear weevil), Anthonomus fulvipes (cherry weevil), Anthonomus quadrigibbus (apple curculio), and Pseudanthonomus validus (currant fruit weevil), (The host plants or plant associates of cum spp. . Other pweevil), .The objective of the key presented here is to allow identification of genera of this tribe in Mexico and Central America.PageBreakAnthonomini reported in Mexico and Central America was compiled from the following works: A list of genera of Anthonomini were examined from collections of the following institutions: Instituto de Ecolog\u00eda, A.C, Xalapa, Veracruz, Mexico. (IEXA), Facultad de Ciencias Naturales, Universidad Aut\u00f3noma de Quer\u00e9taro, Mexico (UAQE), Universidad Autonoma Agraria Antonio Narro, Saltillo, Coahuila, M\u00e9xico (UAAAN), Texas A&M University Insects Collection, College Station, Texas, U.S.A. (TAMUIC).Specimens of 1,529 adults of the tribe Images of specimens of each genus were captured with the aid of a stereoscopic microscope and digital camera and processed using COMBINEZP software . PHOTOSHAnthonomini , Belize, Costa Rica, Cuba, Dominica, Honduras, Jamaica, Mexico, Panam\u00e1, Puerto Rico, Saint Christopher, Virgin Islands, Brazil, Trinidad, Uruguay, Venezuela; states of Mexico: Chiapas, Oaxaca, Quintana Roo and Tamaulipas. Families of associated plants include: Malpighiaceae, Myrtaceae, Phytolaccaceae, Rhizophoraceae, Rubiaceae and Rutaceae. See Loncophorus Chevrolat, 1832. New World species 14, with 8 species from Mexico and Central America. Distribution: Argentina, Brazil, Colombia, Ecuador, French Guyana, Paraguay, Peru Surinam, Cuba, Costa Rica, Nicaragua, Mexico, Panama; states of Mexico: Oaxaca and Veracruz. Species have been associated with Bombacaceae. See Lonchophorellus Clark, 1989. New World species 4, with 2 species from Mexico and Central America. Distribution: Bolivia, Brazil, Colombia, Ecuador, Peru, VenePageBreakzuela, Costa Rica, El Salvador, Guatemala, Honduras, Mexico and Panama; states of Mexico: Chiapas, Guerrero, Morelos, Puebla and Veracruz. Individuals have been associated with: Flacourtiaceae, Malpighiaceae, Myrtaceae and Sterculiaceae. See Magdalinops Dietz, 1891. New World species 4, with 1 species from Mexico. Distribution: United States of America and Mexico; states of Mexico: Baja California. Individuals have been associated with Asteraceae. See Melexerus Burke, 1982. New World species 1, monotypic genus, Melexerus hispidusFagaceae (Fagaceae .Narberdia Burke, 1976. New World species 1, monotypic genus, Narberdia aridulusEuphorbiaceae (rbiaceae .Neomastix Dietz, 1891. New World species 10, with 4 species from Mexico and Central America. Distribution: Colombia, Brazil, Costa Rica, Cuba, El Salvador, United States of America, Guatemala, Honduras, Haiti, Island Virgin, M\u00e9xico, Nicaragua, Puerto Rico; states of Mexico: Guerrero, Morelos, Oaxaca, Puebla, Quintana Roo, Sonora, Tamaulipas. Families of associated plants include: Asteraceae, Ericaceae, Fabaceae, Palmaceae, Sapindaceae and Sterculiaceae. See Pseudanthonomus Dietz, 1891. New World species 35, with 14 species from Mexico and Central America. Distribution: Canada, Costa Rica, El Salvador, United States of America, Guadeloupe, Guatemala, Mexico, Panama and Venezuela; states of Mexico: Baja California and Baja California Sur, Chiapas, Durango Guanajuato Jalisco, Nayarit, Nuevo Le\u00f3n, Puebla, Quintana Roo, San Luis Potos\u00ed, Tabasco Tamaulipas and Veracruz. Families of associated plants include: Betulaceae, Boraginaceae, Caprifoliaceae, Ericaceae, Hamamelidaceae, Krameriaceae, Malpighiaceae, Malvaceae, RosaceaeSaxifragaceae and Verbenaceae. See Smicraulax Pierce, 1908. New World species 6, 6 in Mexico and Central America. Distribution: United States of America, Guatemala, Honduras, Mexico and Panama: states of Mexico: Chiapas, Durango, Guerrero, Oaxaca and Nuevo Le\u00f3n. Species have been associated with Santalaceae. See PageBreak"} +{"text": "AbstractMycetophagidae (hairy fungus beetles) of the Maritime Provinces of Canada are surveyed. Seven species in the genera Mycetophagus, Litargus, and Typhaea are found in the region. Six new provincial records are reported including Mycetophagus punctatus and Mycetophagus flexuosus, whichare newly recorded in the Maritime Provinces. The distribution of all species is mapped, colour habitus photographs of all species are figured, and an identification key to species is provided. The discussion notes that four of the species found in the region are apparently rare, possibly due to the history of forest management practices in the region; a situation similar to that of a significant proportion of other saproxylic beetles found in the Maritime Provinces.The Mycetophagidae (hairy fungus beetles) are a family of relatively small, fungus-eating beetles. Only five genera and 26 species are known in North America, 15 of which have been recorded in Canada (Mycetophagus quadriguttatus M\u00fcller and Typhaea stercorea (Linnaeus), have previously PageBreakbeen recorded from the Maritime Provinces of Canada , an adventive Palaearctic species, is associated with a large variety of moldy substances and is found both outdoors in natural environments, and indoors in association with a variety of stored products . Speciesehydrate . Typhaeaproducts . The bioing logs . The preAcronyms JCCJeffrey Ogden Collection, Truro, Nova Scotia, CanadaJOCKent Island Collection, Bowdoin College, Brunswick, Maine, USAKICNova Scotia Agricultural College, Bible Hill, Nova Scotia, CanadaNSAC\tNova Scotia Museum, Halifax, Nova Scotia, CanadaNSMCNova Scotia Department of Natural Resources Insectary, Shubenacadie, Nova Scotia, CanadaNSNRRichard Migneault Collection, Edmundson, New Brunswick, CanadaRMC, flight intercept trap.FITAbbreviations: PageBreakAn identification key to species [adapted from Mycetophagus species are variable.* Note: elytral markings on Mycetophagidae were examined \u2013 8 from New Brunswick, 149 from Nova Scotia, and 18 from Prince Edward Island. Included were specimens of seven species in three genera. Mycetophagus flexuosus Say is newly recorded in the Maritime Provinces from New Brunswick; Mycetophagus punctatus Say is newly recorded in the Maritime Provinces from Nova Scotia; Mycetophagus serrulatus Casey is newly recorded in New Brunswick; Mycetophagus pluripunctatus LeConte is newly recorded in New Brunswick; Mycetophagus quadriguttatus M\u00fcller is newly recorded in Nova Scotia; and Litargus tetraspilotus LeConte is newly recorded in Prince Edward Island \u2013 a total of five new provincial records, two of which are newly recorded PageBreakin the region. Four species are known from New Brunswick, six from Nova Scotia, and two from Prince Edward Island ; Edmundston, 47\u00b022.285'N; 68\u00b014.663'W, 22 August 2010, R. Migneault, in polypore on dead aspen log .Mycetophagus flexuosus is newly recorded in the Maritime Provinces from New Brunswick (Pleurotus ostreatus) Fries; Tramates versicolor (Fr.) Pil.); and Piptoporus betulinus) (Fr.) Kar.runswick . Cline aSay, 1826NOVA SCOTIA: Halifax Co.: Soldier Lake, 7 June 2005, J. Ogden, spruce beetle trap ; Hants Co.: Smileys Park, 6 July 2005, J. Ogden, spruce beetle trap .Mycetophagus punctatus Say is newly recorded in the Maritime Provinces from Nova Scotia. Both specimens were collected in the central mainland of Nova Scotia (Quercus velutina Lamb.) in Virginia (Polyporus radicatus Schw.) in Iowa (Pleurotus ostreatus) (Piptoporus betulinus) growing on gray birch in New York ; and on New York .Casey, 1900NEW BRUNSWICK: Charlotte Co.: Grand Manan archipelago, Kent Island, 23 July 2012, M. Steck, balsam fir forest, sweeping . NOVA SCOTIA: Annapolis Co.: Durland Lake, 21 June 2003, P. Dollin, hemlock/balsam fir/black spruce forest (120+ years), bracket fungi on white birch .Mycetophagus serrulatus Casey is newly recorded in New Brunswick. The species was reported from Nova Scotia by Betula papyrifera Marshall). Pleurotus ostreatus).PageBreakLeConte, 1856NEW BRUNSWICK: Madawaska County: Edmundston, 47\u00b022.285'N; 68\u00b014.663'W, 22 August 2010, R. Migneault, in polypore on dead aspen log . NOVA SCOTIA: Antigonish Co.: Cape George Point, 23 June1993, M. LeBlanc, funnel trap ; Colchester Co.: Kemptown, 1 June 1995, 28 June 1995, C. Corkum, young deciduous forest, FIT ; Upper Bass River, 18 May 1995, C. Corkum, old deciduous forest, FIT ; Upper Bass River, 3 June 1995, C. Corkum, old deciduous forest, FIT ; Cumberland Co.: East Leicester, 2 June 1995, C. Corkum, old deciduous forest, FIT ; East Leicester, 14 June 1995, C. Corkum, old deciduous forest, FIT ; East Leicester, 15 June 1995, C. Corkum, old deciduous forest, FIT ; Fox River, PageBreak17 May 1995, C. Corkum, young deciduous forest, FIT ; Fox River, 3 June 1995, C. Corkum, young deciduous forest, FIT ; Harrington River, 13 July 1995, C. Corkum, young deciduous forest, FIT ; Wentworth, 21 May-5 July 1965, B. Wright, sugar maple forest, window trap ; Halifax Co.: Halifax, 1 December 1986, B. Wright ; Soldier Lake, 30 July 2004, D. MacDonald, spruce beetle trap ; Lunenburg Co.: Card Lake, 2-15 June, 1997, D.J. Bishop, red spruce/hemlock forest (old growth), FIT ; Yarmouth Co.: Wellington, 23-29 August 1992, J. & F. Cook, mixed forest .Mycetophagus pluripunctatus LeConte is newly recorded in New Brunswick. The species was reported from Nova Scotia by Piptoporus betulinus), Pleurotus ostreatus), and Spongipellis unicolor (Schw.) growing on a fallen white oak in Arkansas. Schwartz (1876) said it was \u201cabundant in fungus\u201d in Michigan.PageBreakM\u00fcller, 1821NOVA SCOTIA: Annapolis Co.: Paradise, 11 June 2005, K. Webster, spruce beetle trap ; Colchester Co.: Balmoral Mills, 19 June 1974, B. Wright, grist mill ; Kings Co.: Kentville, 10 August 2005, D.H. Webster, compost heap, moldy corncobs .Mycetophagus quadriguttatus M\u00fcller is newly recorded in Nova Scotia NEW BRUNSWICK: Northumberland Co.: Tabusintac, 13 June 1939, 26 July 1939, W.J. Brown . NOVA SCOTIA: Colchester Co.: Truro, 4 March 1919, collector not recorded . PRINCE EDWARD ISLAND: Prince Co.: Central Bedeque, 29 July 1954, F.M. Cannon .Eighty-two specimens were examined. The earliest records from each province are: Typhaea stercorea (Linnaeus) was reported from New Brunswick, Nova Scotia, and Prince Edward Island by Typhaea stercorea has been found in corn fields (on decaying kernels of exposed ears), warehouses, stores, flour mills, mangers, railway boxcars, dwellings, and granaries in stored grain and seeds, tobacco, peanuts, cacao, corn, millet, wheat, apricots, and moldy grape skins, as well as in nests of swans and moorhens South and Central America (The dates of earliest detection are given above: New Brunswick (1939), Nova Scotia (1919), and Prince Edward Island (1954). ontinent , and is America .LeConte, 1856NOVA SCOTIA: Cape Breton Co.: East Bay, 9 September 2003, C.W. D\u2019Orsay ; Colchester Co.: Bible Hill, 8 July 2004, K.R. Aikens, pasture, sweep ; Bible Hill, 14 June 2005, S.M. Townsend, sweep ; Debert, 9 June 1994, J. Ogden ; Masstown, 7 September 2002, C.G. Majka, marshy swamp ; Shubenacadie, 26 August 1997, J. Ogden ; Digby Co.: Brier Island, Pond Cove, 9 August 2004, J. Ogden & K. Goodwin, knapweed, sweep ; Brier Island, Pond Cove, 10 August 2004, J. Ogden & K. Goodwin, sweep ; Brier Island, Westport, 9 August 2004, J. Ogden & K. Goodwin, grassland, sweep ; Halifax Co.: Big Indian Lake, 16 July 2003, P. Dollin, Picea rubens forest (80-120 years), in rotting mushroom ; Point Pleasant Park, 15 August 2000, 7 September 2000, C.G. Majka, mixed forest ; Point Pleasant Park, 9 September 2000, 2 June 2002, 23 July 2002, C.G. Majka, coniferous forest ; Point Pleasant Park, 12 May 2001, 10 June 2001, 25 May 2002, C.G. Majka, coniferous forest, on Picea rubens ; Point Pleasant Park, 19 May 2001, 29 May 2001, C.G. Majka, coniferous forest, on Pinus strobus ; 29 July 2001, 18 August 2001, Point Pleasant Park, C.G. Majka, mixed forest ; PageBreakPoint Pleasant Park, 9 May 2002, C.G. Majka, coniferous forest, on Abies balsamea ; Point Pleasant Park, 9 June 2002, C.G. Majka, mixed forest, on Aralia hispida ; Point Pleasant Park, 7 July 2002, C.G. Majka, seashore ; Point Pleasant Park, 14 September 2002, C.G. Majka, marsh, on herbaceous vegetation ; Point Pleasant Park, 30 June 2004, C.G. Majka, coniferous forest, on Pinus sylvestris ; West Dover, 7 September 2003, C.G. Majka, coastal barrens, heaths ; Kings Co.: Aldershot, 5 August 1949, 2 August 1949, 10 August 1949, 20 August 1949, 16 May 1950, H.T. Stultz ; Greenwich, 29 May 1958, H.T. Stultz ; Kingston, 30 June 2002, C.G. Majka, sandy pine barren ; Queens Co.: Eight Mile Lake, 11 August 2003, P. Dollin, PageBreakPicea rubens forest (40-80 years), in vegetation, sweep ; Little Ponhook Lake, 1 August 1993, B. Wright, in oak apple galls ; Ponhook Lake nr. Greenfield, 13 July 1993, J. Cook, ultraviolet light trap ; Shelburne Co.: Clyde River Road, 16 July 1992, S. & J. Peck, forest, car net ; Forbes Point, 9 July 2007, R. Gorham, grass/alders ; Victoria Co.: Cape Breton Highlands: Kelly Rd, 24 June 2005, J. Ogden, malaise trap ; Yarmouth Co.: Moses Lake, 8 km N of Argyle, 17-22 July 1993, J. & T. Cook, mixed forest, FIT . PRINCE EDWARD ISLAND: Queens Co.: Cavendish, 19 July 2001, C.G. Majka, coastal vegetation ; Princeton-Wharburton Road, 19 August 2002, C.G. Majka, old field ; St. Patricks, 18 August 2002, C.G. Majka, old field ; St. Patricks, 29 June 2003, C.G. Majka, mixed forest .Litargus tetraspilotus LeConte is newly recorded from Prince Edward Island. PageBreakmany records from the southern mainland of Nova Scotia, Cape Breton Island, and Prince Edward Island , jack pine (Pinus sylvestris L.), red spruce (Picea rubens Sarg.), balsam fir Mill.), on deciduous, and herbaceous vegetation, on bristly sarsaparilla , and in a rotting mushroom. Litargus tetraspilotus as an inquline inhabitant of oak apple galls on red oak (Quercus rubra L.) induced by Andricus sp. (Cynipidae) wasps. Phoradendron flavescens (Pursh) Nutt., and Ulyschen and Hanula (2010) reared it from decomposing loblolly pine (Pinus taeda L.) logs in South Carolina.In the Maritime Provinces Typhaea stercorea and Litargus tetraspilotus are abundant and widely distributed in the Maritime Provinces. Mycetophagus pluripunctatus appears to be uncommon but widely distributed on the mainland of Nova Scotia. The other four species of mycetophagids \u2013 Mycetophagus punctatus, Mycetophagus flexuosus, Mycetophagus serrulatus, and Mycetophagus quadriguttatus \u2013 are all represented by a handful of specimens or less. They would all appear to qualify asPageBreak \u201capparently rare\u201d saproxylic beetles as defined by Endomychidae and Erotylidae of the Maritime Provinces, two other families of beetles closely associated with fungi, Mycetophagus, three of which are closely associated with saproxylic fungi, may belong to this same suite of insects for similar reasons.In general, mycetophagids have received rather little attention by researchers in North America, and the bionomics of many species have not been carefully investigated. Certainly this is true in the Maritime Provinces and additional fieldwork in the region is required to ascertain more about their distribution, abundance, bionomics, and ecological role in the habitats that they inhabit."} +{"text": "In Collino, MassimoPini, AlessandroMastroianni, RosannaBenetti, ElisaLanzi, CeciliaBani, DanieleManoni, MarcoFantozzi, RobertoMasini, EmanuelaWe wish to apologise for any misunderstanding or inconvenience caused."} +{"text": "Navin Pokala and Cornelia I. Bargmann were erroneously omitted from the author list. The correct byline is:1,2, Christian Schultheis1,2, Navin Pokala3, Steven J. Husson1,2,4, Jana F. Liewald1,2, Cornelia I. Bargmann3, Alexander Gottschalk1,2*Cornelia Schmitt1 Buchmann Institute for Molecular Life Sciences, Goethe-University, Frankfurt, Germany, 2 Institute of Biochemistry, Goethe-University, Frankfurt, Germany, 3 Howard Hughes Medical Institute, Laboratory of Neural Circuits and Behavior, The Rockefeller University, New York, USA, 4 Functional Genomics and Proteomics, Katholieke Universiteit, Leuven, BelgiumThe correct citation is:Schmitt C, Schultheis C, Pokala N, Husson SJ, Liewald JF (2012) Specific Expression of Channelrhodopsin-2 in Single Neurons of Caenorhabditis elegans. PLoS ONE 7(8): e43164. doi:10.1371/journal.pone.0043164NP and CIBdesigned research, provided reagents and analyzed the data.The acknowledgments section should read as: We thank A. Hart, G. Jansen, E. Jorgensen, M. de Bono, M. Chalfie, and W. Schafer for plasmids and strains, and J. Stirman and H. Lu for help with the tracking and illumination system. We are indebted to P. Wood, L. Forrest, and E. Bamberg for help on evaluating structural and topological featuresof ChR2 and NpHR and derived fragments.glr-1::flox::ChR2::mCherry, pNP259: Pgpa-14::Cre, pNP260: Pnmr-1::flox::ChR2::mCherry.In the Plasmids section of Materials and Methods, the first sentence should read: The following plasmids used: pNP165: P"} +{"text": "The publisher would like to apologise on behalf of the authors of the following 4articles published in Inhalation Toxicology.1. Brorby, Sheehan, Berman, Green, Holm, Re-Creation of HistoricalChrysotile-Containing Joint Compounds, Inhalation Toxicology, 20: 1043-1053(2008).2. Bernstein, Donaldson, Decker, Gaering, Kunzendorf, Chevalier, Holm, ABiopersistence Study following Exposure To Chrysotile Asbestos Alone or inCombination with Fine Particles, Inhalation Toxicology, 20: 1009-1028 (2008).3. Bernstein, Rogers, Sepulveda, Donaldson, Schuler, Gaering, Kunzendorf, Chevalier,Holm, The pathological response and fate in the lung and pleura of chrysotile incombination with fine particles compared to amosite asbestosfollowing short-terminhalation exposure: interim results, Inhalation Toxicology, 2010, 22(11) 937-962(2010).4. Bernstein, Rogers, Sepulveda, Donaldson, Schuler, Gaering, Kunzendorf, Chevalier,Holm, Quantification of the pathological response and fate in the lung and pleura ofchrysotile in combination with fine particles compared to amosite-asbestos followingshort-term inhalation exposure, Inhalation Toxicology, 2011; 23(7):372-391(2011).Since publication of these 4 articles we have had a request to add the followinginformation to the Declaration of Interest section of each paper.The additional statement reads:\u201cGeorgia-Pacific has not sold chrysotile-containing joint compounds for morethan 30 years, but litigation is pending in which individuals claim exposure to theCompany's historic products. The articles listed above report on work thatGeorgia-Pacific commissioned to address issues that have arisen in that litigation.I, Stewart E. Holm, representing Georgia-Pacific, am an author on all four papers.The other authors are consulting experts retained by or on behalf of Georgia-Pacificto conduct the research and prepare the articles. Dr. Donaldson has been listed aspotential testifying expert witness by Georgia-Pacific, and Dr. Bernstein hastestified as an expert witness for Georgia-Pacific.\u201d"} +{"text": "AbstractItalica\u201d in the Ross Sea (Antarctica) in the austral summer 2004. A total of 18 epibenthic dredge deployments/samplings have been performed at four different locations at depths ranging from 84 to 515m by using a Rauschert dredge with a mesh size of 500\u03bcm. In total 8,359 specimens have been collected belonging to a total of 161 species. Considering this dataset in terms of occurrences, it corresponds to 505 discrete distributional records (incidence data). Of these, in order of abundance, 5,965 specimens were Gastropoda (accounting for 113 species), 1,323 were Bivalvia (accounting for 36 species), 949 were Aplacophora (accounting for 7 species), 74 specimens were Scaphopoda (3 species), 38 were Monoplacophora (1 species) and, finally, 10 specimens were Polyplacophora (1 species). This data set represents the first large-scale survey of benthic micro-molluscs for the area and provides important information about the distribution of several species, which have been seldom or never recorded before in the Ross Sea. All vouchers are permanently stored at the Italian National Antarctic Museum (MNA), Section of Genoa, enabling future comparison and crosschecking. This material is also currently under study, from a molecular point of view, by the barcoding project \u201cBAMBi\u201d (PNRA 2010/A1.10).Information regarding the molluscs in this dataset is based on the Rauschert dredge samples collected during the Latitudinal Gradient Program (LGP) on board the R/V \u201cPageBreak Italica\u201d, under the Latitudinal Gradient Program (LGP), by deploying a fine-mesh dredge (Rauschert dredge). This collection is now part of the Italian National Antarctic Museum and is published with the aim of increasing the knowledge of the distribution of mollusc species in the Ross Sea. The dataset is also the first Italian contribution to ANTABIF based on materials stored at the MNA.This dataset is about the mollusc samples obtained in the framework of the 2004 voyage of the RV \u201cProject title: Latitudinal Gradient Program (LGP) R/V \u201cItalica\u201d voyage 2004 - Mollusca.Curator and Promoter: Stefano Schiaparelli.Personnel: Claudio Ghiglione, Maria Chiara Alvaro, Huw J. Griffiths, Katrin Linse.Funding: This study is part of the Project 2002/8.6 and of the Project 2010/A1.10 funded by the Italian National Antarctic Research Program (PNRA). Vouchers are maintained at the Italian National Antarctic Museum (MNA), Section of Genoa.Study area description: This dataset lists the species that have been collected by deploying for the first time a Rauschert dredge in the Ross Sea and Terra Nova Bay (~75\u00b0S) (Ross Sea . Samples (~75\u00b0S) . The Rau (~75\u00b0S) . The dreDesign description: In the past decade, the Ross Sea has been the area studied by the Latitudinal Gradient Program which aimed at: i) understanding the complex ecosystems that exist along the Victoria Land coast; and ii) determining the effects of environmental change on these ecosystems; iii) maximising the transfer of information and ideas, by utilising joint logistic facilities. To achieve these targets, two temporally parallel research voyages took place during the Austral summer 2004: one PageBreakon board the Italian R/V \u201cItalica\u201d and one on board the R/V \u201cTangaroa\u201d organized, respectively, by NIWA and PNRA .http://afg.biodiversity.aq/about). The LGP contributed to the SCAR biology programme Evolution and Biodiversity in the Antarctic (EBA) and now to the SCAR programme State of the Antarctic Ecosystem (AntEco). The dataflow is illustrated in In the field, samples were collected by using a Rauschert dredge with a mesh size of 500\u03bcm . SamplesItalica\u201d 2004 LGP Expedition by Dr. Peter Rehm according the SCAR-MarBIN Data Toolkit (available at http://www.scarmarbin.be/documents/SM-FATv1.zip). The dataset was uploaded in the ANTOBIS database and added to SOMBASE . SOMBASE generated initial core data system upon which SCAR\u2019s Marine Biodiversity Information Network (SCAR-MarBIN) was built. Taxonomy was matched against the Register of Antarctic Marine Species, using the Taxon Match tool (http://www.scarmarbin.be/rams.php?p=match). Data from both the R/V \u201cItalica\u201d and the R/V \u201cTangaroa\u201d voyages were published in The present molluscs dataset has been formatted in order to fulfil the standards (Darwin Core) required by the OBIS scheme and Terra Nova Bay (~75\u00b0S). On the whole,eighteen stations, comprised between 84 and 515m of depth, were sampled.Ross Sea . SamplesSampling description: Sampling activities were done in four main areas of the Ross Sea: Cape Adare, Cape Hallett, Coulman Island, Cape Russell these have been included in this dataset as they could be clearly distinguished during sorting activities and were therefore considered as morphospecies. During all the phases of sorting, classification and storage of samples at the Italian National Antarctic Museum, quality controls and data cleaning have been undertaken at various steps in order to produce quality data and make consistent cross-references between the database and samples\u2019 labels. The MNA uses an SQL-based database (Specify 6) to manage its collections and link all the data to the physical samples. Georeferencing on board the R/V \u201cItalica\u201d is based on the interpolation of GPS satellite receivers (models 3S Navigation and Glonass ASHTECH GG24) and a gyrocompass. Station coordinates and sampling events were recorded during sampling activities through the \u201cItalica\u201d NetNav WEB system, which is based on the above GPS systems.General taxonomic coverage description: The present dataset focuses on the Kingdom Animalia, Phylum Mollusca and includes six molluscs classes: Gastropoda, Bivalvia, Monoplacophora, Solenogastres, Polyplacophora and Scaphopoda. In total 8,359 specimens have been collected belonging to 161 species and corresponding to 505 species distributional records. Of these, in order of abundance, 5,965 specimens were Gastropoda (accounting for 113 species), 1,323 were Bivalvia (accounting for 36 species), 949 were Aplacophora (accounting for 7 species), 74 specimens were Scaphopoda (3 species), 38 were Monoplacophora (1 species) and, finally, 10 specimens were Polyplacophora (1 species). This data set represent the first large-scale survey of benthic micromolluscs for the area and provides important information about the distribution of several species which have been seldom or never recorded before in the Ross Sea. A detailed analysis of the distribution of mollusc species sampled by PageBreakthe Rauschert dredge as well as the illustration of all new records for the Ross Sea is in PageBreakThe dataset includes respectively for each class:Kingdom:AnimaliaPhylum:MolluscaClass: SolenogastresFamily:NeomeniidaeSpecies:Solenogastres sp. 1, Solenogastres sp. 2, Solenogastres sp. 3, Solenogastres sp. 4, Solenogastres sp. 5, Solenogastres sp. 6, Neomenia sp. 1Kingdom:AnimaliaPhylum:MolluscaClass:PolyplacophoraFamily:CallochitonidaeGenus:CallochitonSpecies:Callochiton sp. 1Kingdom:AnimaliaPhylum:MolluscaClass:MonoplacophoraFamily:MicropilinidaeGenus:MicropilinaSpecies:Micropilina arntzi War\u00e9n & Hain, 1992PageBreakKingdom:AnimaliaPhylum:MolluscaClass:GastropodaFamily:Acteonidae, Cancellaridae, Anatomidae, Margaritidae, Doridae, Eulimidae, Mangeliidae, Seguenzioidea, Calliotropidae, Capulidae, Newtoniellidae, Buccinidae, Skeneidae, Cylichnidae, Diaphanidae, Dotidae, Eatoniellidae, Zerotulidae, Lepetidae, Naticidae, Cerithiopsidae, Collonidae, Skeneidae, Mangellidae, Margaritidae, Orbitestellidae, Triviidae, Omalogyridae, Volutomitridae, Buccinidae, Philinidae, Raphitomidae, Rissoidae, Akiodorididae, Cingulopsidae, Pyramidellidae, Tjaernoeiidae, Muricidae, Mathildidae, BorsoniidaeGenus:Acteon, Admete, Aegires, Anatoma, Antimargarita, Antistreptus, Austrodoris, Bathycrinicola, Belalora, Brookula, Calliotropis, Capulus, Cerithiella, Chlanidota, Cirsonella, Cylichna, Diaphana, Doto, Eatoniella, Eumetula, Frovina, Fusceulima, Haliella, Hemiaclis, Iothia, Kerguelenatica, Krachia, Leptocollonia, Liotella, Lissotesta, Lorabela, Margarites, Melanella, Microdiscula, Newnesia, Nothoadmete, Notoficula, Omalogyra, Paradmete, Pareuthria, Philine, Pleurotomella, Powellisetia, Probuccinum, Prodoridunculus, Prosipho, Sinuber, Skenella, Streptocionella, Thjaernoeia, Toledonia, Torellia, Trilirata, Trophon, Turritellopsis, TyphlodaphneSpecies:PageBreakActeon antarcticus Thiele, 1912, Admete haini Numanami, 1996, Aegires albus Thiele, 1912, Anatoma euglypta , Antimargarita dulcis , Doris kerguelensis , Bathycrinicola tumidula , Oneopota striatula , Bertellidae sp.1, Bertellidae sp.2, Brookula pfefferi Powell, 1951, Brookula cf. argentina Zelaya, Absalao & Pimienta, 2006, Brookula strebeli A.W.B. Powell, 1951, Calliotropis antarctica Dell, 1990, Cancellaridae sp.1, Cancellaridae sp.2, Capulus subcompressus Pelseneer, 1903, Cerithiella seymouriana , Chlanidota signeyana A.W.B. Powell, 1951, Cirsonella extrema Thiele, 1912, Cylichna gelida , Diaphana paessleri , Doto antarctica Eliot, 1907, Doto sp., Eatoniella aff. cana Ponder, 1983, Eatoniella cf. demissa , Eatoniella kerguelensis , Eulimidae sp.1, Eulimidae sp.2, Eulimidae sp.3, Eulimidae sp.4, Eulimidae sp.5, Eumetula dilecta , Eumetula cf. dilecta , Eumetula strebeli , Frovina sp.1, Frovina sp.2, Fusceulima sp.1, Fusceulima sp.2, Gastropoda sp.1, Haliella sp.1, Hemiaclis incolorata , Hemiaclis sp.1, Hemiaclis sp.2, Iothia emarginuloides , Kerguelenatica delicatula , Krachia antartica , Leptocollonia innocens , Liotella sp.1, Lissotesta macknighti , Lissotesta mammillata , Lissotesta minutissima , Lissotesta notalis , Lissotesta similis , Lissotesta sp.1, Lissotesta strebeli , Lissotesta unifilosa , Lorabela davisi , Margarites crebrilirulata , Margarites refulgens , Marseniopsis sp., Melanella antarctica , Melanella convexa , Microdiscula vanhoeffeni Thiele, 1912, Naticidae sp.1, Newnesia antartica E. A. Smith, 1902, Nothoadmete cf. delicatula , Notoficula bouveti , Omalogyra burdwoodiana Strebel, 1908, Omalogyra sp.1, Onoba egorovae Numanami, 1996, Onoba gelida , Onoba kergueleni , Onoba paucilirata , Onoba sp.1, Onoba subantarctica wilkesiana , Onoba turqueti , Paradmete fragillima , Pareuthria plicatula Thiele, 1912, Philine alata Thiele, 1912, Pleurotomella deliciosa Thiele, 1912, Powellisetia deserta , Probuccinum tenerum , Prodoridunculus gaussianus Thiele, 1912, Prosipho nodosus Thiele, 1912, Antistreptus contrarius , Prosipho glacialis Thiele, 1912,, Prosipho mundus E. A. Smith, 1915, Sinuber microstriatum Dell, 1990, Skenella paludinoides , Streptocionella pluralis Dell, 1990, Tjaernoeia michaeli Engl, 2002, Toledonia cf. perplexa Dall, 1902, Toledonia elata Thiele, 1912, Toledonia globosa Hedley, 1916, Toledonia limnaeaeformis , Toledonia major , Toledonia palmeri Dell, 1990, Toledonia punctata Thiele, 1912, Toledonia sp.1, Toledonia sp.2, Toledonia sp.3, Toledonia striata Thiele, 1912, Torellia antarctica , Torellia exilis , Trilirata macmurdensis , Trilirata sexcarinata War\u00e9n & Hain, 1996, Trophon coulmanensis E. A. Smith, 1907, Trophon minutus Melvill & Standen, 1907, Turritellopsis latior Thiele, 1912, Typhlodaphne innocentia Dell, 1990, Typhlodaphne sp.1Kingdom:AnimaliaPhylum:MolluscaClass:BivalviaFamily:Philobryidae, Astartidae, Cuspidariidae, Cyamiidae, Carditidae, Cyclochlamydidae, Propeamussiidae, Mytilidae, Kelliidae, Limidae, Limopsidae, Philibryidae, Lyonsiidae, Montacutidae, Poromyidae, Nuculanidae, Siliculidae, Cuspidariidae, Thraciidae, Thyasiridae, Galeommatoidea, YoldiidaeGenus:Adacnarca, Astarte, Cuspidaria, Cyamiomactra, Cyclocardia, Cyclochlamys, Cyclopecten, Dacrydium, Kellia, Limatula, Limopsis, Lissarca, Lyonsia, Montacuta, Mysella, Parathyasira, Philobrya, Poromya, Propeleda, Pseudokellya, Silicula, Subcuspidaria, Thracia, Waldo, YoldiellaSpecies:PageBreakAdacnarca nitens Pelseneer, 1903, Astarte longirostris d\u2019Orbigny, 1842, Cuspidaria tenella E. A. Smith, 1907, Cuspidaria kerguelensis , Cyamiomactra laminifera , Cyamiomactra robusta Nicol, 1964, Cyclocardia astartoides , Cyclochlamys gaussiana , Cyclochlamys pteriola , Dacrydium albidum Pelseneer, 1903, Kellia simulans E. A. Smith, 1907, Limatula hodgsoni , Limatula ovalis , Limatula simillima , Limopsis lilliei E. A. Smith, 1915, Limopsis marionensis E. A. Smith, 1885, Lissarca notorcadensis Melvill & Standen, 1907, Lyonsia arcaeformis Martens, 1885, Montacuta nimrodiana Hedley, 1911, Mysella cf. antarctica , Mysella charcoti Lamy, 1906, Mysella gibbosa , Mysella sp.1, Philobrya sublaevis Pelseneer, 1903, Philobrya wandelensis Lamy, 1906, Philobrydae sp.1, Poromya spinosula Thiele, 1912, Propeleda longicaudata , Pseudokellya gradate Thiele, 1912, Pseudokellya sp. juv., Silicula rouchi Lamy, 1911, Thracia meridionalis E. A. Smith, 1885, Parathyasira dearborni , Thyasira debilis , Waldo parasiticus , Yoldiella antarctica Kingdom:AnimaliaPhylum:MolluscaClass:ScaphopodaFamily:Pulsellidae, GadilidaeGenus:Pulsellum, SiphonodentaliumSpecies:Pulsellum sp. 1, Siphonodentalium dalli , Siphonodentalium sp. 1Ross Sea, Antarctica .71\u00b015'5\"S and 74\u00b049'3\"S Latitude; 164\u00b011'5\"E and 170\u00b041'9\"E Longitude.February 9, 2004\u2013February 21, 2004.Parent collection identifier: Italian Antarctic National Museum Collection name: Italica 2004 Rauschert MolluscsCollection identifier:http://www.mna.itSpecimen preservation method: Specimens were fixed in pre-cooled Ethanol immediately after the extraction from the dredge net. In this way any thermal shock which could potentially alter the integrity of DNA was avoided. After fixation, specimens were sorted under a stereomicroscope, divided into morphospecies and stored in \u201eScrew Thread Vials\u201c . For study, some specimens PageBreakper species have been dissected under the stereomicroscope and soft parts used for DNA extractions. Shells corresponding to these specimens have been dried in increasing ethanol concentrations, mounted on stubs and gold sputtered for scanning electron microscope observation. These specimens are maintained in a laboratory kiln with silica gel to prevent deterioration. All the other specimens are kept in ethanol in the collections of the Italian National Antarctic Museum.This dataset contains data about the Phylum Mollusca in the Ross Sea. In particular, it includes 161 species for a total of 8,359 specimens. By cconsidering this dataset in terms of incidence, it encompasses 505 discrete distributional records.The Darwin Core elements included in the dataset are: scientific name, collection code (i.e. MNA acronym), catalogue number , year of collection, date of collection, latitude and longitude , individual counts, and basis of records (type of preservation).Object name: Italica 2004_Rauschert dredge_Ross_sea_Mollusca_lgpCharacter encoding: UTF-8Format name: Darwin Core Archive formatFormat version: 1.0Distribution:http://ipt.biodiversity.aq/resource.do?r=ross_sea_mollusca_lgpLanguage: EnglishMetadata language: EnglishLicense of use: This dataset [Italica 2004_Rauschert dredge_Ross_sea_Mollusca_lgp] is made available under the Open Data Commons Attribution License: http://www.opendatacommons.org/licenses/by/1.0/Date of metadata creation: 2013-01-08Hierarchy level: Dataset"} +{"text": "The affiliations of the second author,Victor Chi-Hsiang Lin were not listed correctly. The correct author affiliations are as follows:Yuan-Hong Jiang 1, Victor Chia-Hsiang Lin 2,3, Chun-Hou Liao 4, Hann-Chorng Kuo 11. Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan2. Department of Urology, E-Da Hospital, Kaohsiung, Taiwan3. Department of Nursing, I-Shou University, Kaohsiung, Taiwan4. Depatment of Urology, Cardinal Tien Hospital and Fu-Jen Catholic University, New Taipei, Taiwan"} +{"text": "The affiliation currently reads:Irene Pichler, Fabiola Del Greco M., Martin G\u00f6gele, Peter P. Pramstaller, Andrew A. Hicks, Cosetta Minelli: Respiratory Epidemiology and Public Health, National Heart and Lung Institute, Imperial College, London, United KingdomThe affiliation should read:Irene Pichler, Fabiola Del Greco M., Martin G\u00f6gele, Peter P. Pramstaller, Andrew A. Hicks, Cosetta Minelli:Center for Biomedicine, European Academy Bozen/Bolzano (EURAC), Bolzano, Italy .Cosetta Minelli:Respiratory Epidemiology and Public Health, National Heart and Lung Institute, Imperial College, London, United Kingdom."} +{"text": "The order of authors is incorrect. Please see the correct author order here: Anna Urbanowicz, Dominik Lewandowski, Jadwiga Jodynis-Liebert, Czeslaw Sadowski, Marek Figlerowicz."} +{"text": "There is an error in sentence four of the \"Immunofluorescence\" section of Materials and Methods. The sentence should read: \"Primary antibodies were as follows: E-cadherin, BD, 610181, Mouse, 1:1500; N-cadherin, BD, 610921, Mouse, 1:300; Slug, LifeSpan Bio, LS-C30318, Rabbit, 1:1000; Snail, Abcam, ab17732, Rabbit, 1:700.\""} +{"text": "There was an error in affiliation 1 for authors Aleksandra W. Debowski, Phebe Verbrugghe,Hans-Olof Nilsson, Jonathan C. Gauntlett, Alma Fulurija, Tania Camilleri, Barry J. Marshall,and Mohammed Benghezal. Affiliation 1 should be: Ondek Pty Ltd and Helicobacter pyloriResearch Laboratory, School of Pathology & Laboratory Medicine, M504, Marshall Centre forInfectious Disease Research and Training, University of Western Australia, Nedlands, WesternAustralia"} +{"text": "Affiliation number 7 for the eighth author, Antonio Miranda-Vizuete, is incorrect. The correct affiliation is: Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Roc\u00edo/CSIC/Universidad de Sevilla, Sevilla, Spain."} +{"text": "Dr. Schnider should have been removed from the authors list. The correct authors list should be as follows: Lucas N, Saj A, Schwartz S, Ptak R, Thomas C, Conne P, Leroy R, Pavin S, Diserens K and Vuilleumier P."} +{"text": "The authors' names were incorrectly listed as Papastergiou G. Stergios, Konstantinidis A. Georgios, Natsis Konstantinos, Papathanasiou Efthymia, Koukoulias Nikolaos, and Papadopoulos G. Alexandros; this error is corrected here."} +{"text": "The authors would like to update the first affiliation. \"Geneart AG, BioPark, Regensburg, Germany\" should now be: \"Geneart/Life Technologies, BioPark, Regensburg, Germany.\""} +{"text": "Affiliation number 2 for the first, second, fourth, fifth, sixth and seventh authors is incorrect. The correct affiliation is: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi\u2019an, P. R. China."} +{"text": "There was an error in affiliations 1, 3, and 4 for authors Jonathan Maelfait, Kenny Roose, Pieter Bogaert, Mozes Sze, Xavier Saelens, Isabelle Carpentier, Geert van Loo, and Rudi Beyaert. Affiliation 1 should be: Unit of Molecular Signal Transduction in Inflammation, Department for Molecular Biomedical Research, VIB, Ghent, Belgium. Affiliation 3 should be: Unit of Molecular Virology, Department for Molecular Biomedical Research, VIB, Ghent, Belgium. Affiliation 4 should be: Cell Culture and Sorting Core Facility, Department for Molecular Biomedical Research, VIB, Ghent, Belgium."} +{"text": "AbstractAleurodaphis van der Goot is reviewed. One new species Aleurodaphis sinojackiae Qiao & Jiang, sp. n. on Sinojackia xylocarpa from Jiangsu and Zhejiang, China is described. Aleurodaphis sinisalicis Zhang, 1982 is synonymised with Aleurodaphis blumeae van der Goot, 1917. Keys to species, morphological description and features of the new species, host plants, and distribution are provided. The specimens including types are deposited in British Natural History Museum, London (BMNH), K\u00f4gakkan University, Japan and the National Zoological Museum of China, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (NZMC).The genus Aleurodaphis is erected in 1917 by van der Goot. He described the species Aleurodaphis blumeae as the type of the genus, from Blumea. Its remarkable characters are the followings, body of apterae is aleyrodiform, frontal horn is absent and wax glands are arranged along crenulated margin of body. Takahashi studied the specimens from East PageBreakAsia, and described two species Aleurodaphis mikaniae Takahashi, 1925 and Aleurodaphis asteris Takahashi & Sorin, 1958. More than 30 years later, one new species was found from India, Aleurodaphis antennata Chakrabarti & Maity, (1980) 1982 and one new species was reported in China, Aleurodaphis sinisalicis Zhang, 1982. Aleurodaphis impatientis, Aleurodaphis ligulariae and Aleurodaphis stewartiae. After identifying the specimens from China and checking the specimens of the genus in British Natural History Museum, one new species, Aleurodaphis sinojackiae Qiao & Jiang, sp. n. is found, and Aleurodaphis sinisalicis Zhang, 1982 is synonymised with Aleurodaphis blumeae van der Goot, 1917 here. Therefore, the genus has eight known species in the world , while the other paratypes in the National Zoological Museum of China, Institute of Zoology, Chinese Academy of Sciences, Beijing, China (NZMC) and K\u00f4gakkan University, Japan. All the other specimens studied are deposited in BMNH and NZMC.van der Goot, 1917http://species-id.net/wiki/AleurodaphisAleurodaphis van der Goot, 1917: 239.Aleurodaphis van der Goot: Aleurodaphis blumae van der Goot, 1917. PageBreak small and ciliated; eyes with 3 facets. Dorsal setae fine and sparse. Rostrum reaching mid-coxae, at most hind coxae. Ultimate rostral segment obviously longer than second hind tarsal segment. Legs short; first tarsal chaetotaxy: 2\u20134, 2\u20134, 2\u20134; dorsal-apical setae on second hind tarsal segments with funnel-shaped apex. Siphunculi ring-shaped. Cauda knobbed and anal plate bilobed. In alate viviparous females: antennae 5-segmented, with secondary rhinaria near ring-shaped, without cilia; eyes normal; first tarsal chaetotaxy: 4, 4, 4, sometimes 3 or 2; fore wings with media once branched, pterostigma extended and two cubitus fused or separated at base; hind wings with two obliques.Body oval and flat. In apterous females: body aleyrodiform, absence of frontal horns, and wax glands arranged along the crenulated margin of body. Head and prothorax, meso- and metathorax, abdominal tergites I\u2013VII fused, respectively; only abdominal tergite VIII free; antennae 4 or 5-segmented, primary rhinariaAleurodaphis is quite wide, including Compositae , Balsaminaceae (Impatiens), Gramineae (Bambusa), Moraceae (Ficus), Plantaginaceae (Plantago), Scrophulariaceae (Mazus), Styracaceae (Sinojackia), Theaceae (Stewartia),\u00a0Verbenaceae and Violaceae.The range of\u00a0host plantsin Aleurodaphis asteris, Aleurodaphis blumeae, Aleurodaphis impatientis, Aleurodaphis ligulariae and Aleurodaphis mikaniae, mainly feeding on Compositae species, have monoecious and anholocyclic life cycle. Aleurodaphis sinojackiae Qiao & Jiang, sp. n. and Aleurodaphis stewartiae can form galls on the leaves of the primary host plants, but their secondary hosts are unknown. The details of Aleurodaphis antennata wereunreported 1982http://species-id.net/wiki/Aleurodaphis_antennataAleurodaphis antennata Chakrabarti & Maity, (1980) 1982: 56.Aleurodaphis antennata Chakrabarti & Maity: Bambusa sp.PageBreakIndia .Takahashi & Sorin, 1958http://species-id.net/wiki/Aleurodaphis_asterisAleurodaphis asteris Takahashi & Sorin, 1958: 31.Aleurodaphis asteris Takahashi & Sorin: CHINA (NZMC): 2 apterous viviparous females, 15 April 1991, Jiangle, Fujiang, No. 10054, on Violaceae, coll. W. Y. Zhang; 8 apterous viviparous females, 13 August 2003, Motuo, Tibet, No. 15371, host plants unknown, coll. G. X. Qiao and X. L. Huang; JAPAN (BMNH):24 apterous viviparous females, 5 August 1966, Osaka, Chihaya, on Aster sp., coll. M. Sorin.; 9 apterous viviparous females, 29 May 1964, Osaka, Kongo Mt., on Aster sp., coll. v. d. Bosch; 4 apterous viviparous females, 7 June 1966, Kyushu, Hikosan, on Kalimeris sp., coll. H. Takada; 8 apterous viviparous females, 6 August 1980, Kyoto, Kibune Mt., on Aster yomena, coll. R. L. Blackman; KOREA (BMNH):2 apterous viviparous females, 15 September 1963, Ulnungdo, on Aster incisus, coll. W. H. Paik; 1 apterous viviparous female, 14 September 1963, Pusan, on Chrysanthemum zawidskii, coll. W. H. Paik. Carpesium abrotanoides, Aster yomena, Aster incisus, Chrysanthemum zawaidskii, Kalimeris sp. and Violaceae.The species feed on the stems, leafstalks, flower stalks and leaves of the host plants.China, Japan and Korea.van der Goot, 1917http://species-id.net/wiki/Aleurodaphis_blumeaeAleurodaphis blumeae van der Goot, 1917: 240.Aleurodaphis nobukii Shinji, 1923: 301.Astegopteryx japonica Takahashi, 1923: 150.Aleurodaphis sinisalicis Zhang, 1982: 20. syn. n.Aleurodaphis blumeae van der Goot: Aleurodaphis sinisalicis Zhang, 1982 were checked, including 48 apterous viviparous females, 25 July 1963, Sichuan (Guanxian County), No. Y0399, on Salix sp., coll. G. X. Zhang and T. S. Zhong. The result confirmed the queries of Aleurodaphis sinisalicis described it as a new species. In the original descriptions of Aleurodaphis sinisalicis Zhang, 1982, the diagnosis was: the ratio of body length to antennae length was 4.70 (Aleurodaphis blumeae: 2.70), the base of cauda restricted (Aleurodaphis blumeae: not restricted), and the anal plate bilobed (Aleurodaphis blumeae: not bilobed). Actually, the morphological characters of Aleurodaphis blumeae in this diagnosis were inaccurate. In A. blumeae, the ratio of body length to antennae length was 4.80 instead of 2.70, the base of cauda restricted instead of not restricted, and the anal plate bilobed instead of not bilobed.The original descriptions of Aleurodaphis sinisalicis, Salix sp., is perhaps mis-recorded.The host plant of CHINA (NZMC): 6 apterous viviparous females, 17 August 2004, Guizhou (Daozhen County), No. 15597, host plants unknown, coll. J. Y. Yang; 6 apterous viviparous females, 17 July 2001, Shaanxi (Nanzheng County), No. Y8606, host plants unknown, coll. S. H. Wang; 7 apterous viviparous females, 8 September 1995, Jiangxi (Jinggangshan City), No. 10852, on Compositae, coll. G. X. Zhang; 9 apterous viviparous females and 7 alate viviparous females, 25 April 1984, Shaanxi (Yangling County), No. 64, on Carpesium cernuum, coll. X. F. Dai; 5 alate viviparous females, May 1984, Shaanxi (Yangling County), No. Y6227, host plants unknown, coll. X. F. Dai; 3 apterous viviparous females, 26 June 1983, Zhejiang (Lin\u2019an City),PageBreak No. Y2692, on Carpesium abrotanoides, collector unknown; 5 apterous viviparous females, 8 April 1998, Guangxi (Napo County), No. 11772, on Callicarpa bodinieri, coll. G. X. Qiao; 14 apterous viviparous females, 21 April 1998, Guangxi (Fangchenggang City), No. 11840, on Senecio scandens, coll. G. X. Qiao; 16 apterous viviparous females, 22 March 1998, Guangxi (Pingxiang City), No. 11580, on Plantago asiatica, coll. G. X. Qiao; 7 apterous viviparous females, Hunan, No. 8887, on Compositae, the collector unknown; 3 apterous viviparous females and 2 nymphs, Feburary 1925, Taiwan (Taihoku), on Ficus sp., coll. R. Takahashi (BMNH); 107 apterous viviparous females, 1 alate viviparous female and 24 nymphs, 21 May 1985, Zhejiang (Hangzhou City), on Carpesium abrotanoides, coll. V. F. Eastop (BMNH); JAPAN (BMNH):2 apterous viviparous females and 4 nymphs, 29 August 1913, Kumamoto, on Blumea sp., coll. Theobald; 10 alate viviparous females, 22 September 1957, Osaka, on Carpesium abrotanoides var. tumbergianum, coll. M. Sorin; 2 apterous viviparous females, 2 alate viviparous females and 4 nymphs, 30 July 1957, Tokyo, Takao Mt., on Blumea sp., coll. R. Takahashi; 7 apterous viviparous females and 12 nymphs, 16 August 1991, Chiba, Sayama, on Carpesium sp., coll. D. L. Stern; KOREA (BMNH): 2 apterous viviparous females, 15 September 1963, Ulnungdo, on Mazus miguelii, coll. W. H. Paik; 1 apterous viviparous female, July 1969, Lri, host plants unknown, coll. W. H. Paik; INDONESIA (BMNH): 6 apterous viviparous females and 2 alate viviparous females, 13 July 1916, Garoet, on Compositae, coll. D. van der Goot; MALAYSIA (BMNH): 3 apterous viviparous females and 2 nymphs, 23 September 1944,Cameron Highlands, on Blumea sp., coll. R. Takahashi; PHILIPPINES (BMNH):1 alate viviparous female, September 1962, Davao Exp. Station, trap in Abacca grove, coll. M. R. Gavarra; 1 alate viviparous female, July 1963, Davao Exp. Station, host plants unknown, coll. M. R. Gavarra; 1 alate viviparous female, January 1964, Davao Exp. Station, host plants unknown, coll. M. R. Gavarra; 1 alate viviparous female, March 1964, Davao Exp. Station, host plants unknown, coll. M. R. Gavarra; 3 apterous viviparous females and 2 nymphs, 13 September 1964, Makiling, on Blumea sp., coll. V. S. Calilung. Carpesium cernuum, Carpesium abrotanoides, Carpesium abrotanoides var. tumbergianum, Senecio scandens, Blumea chinensis, Callicarpa bodinieri, Mazus miguelii, Ficus sp. and Plantago asiatica. The common hosts are various Compositae.Blumea on stems and undersides of young leaves, causing slight leaf-curl : 6 apterous viviparous females and 3 alate viviparous females, 24 August 2004, Guizhou (Daozhen County), No. 15638, host plants unknown, coll. J. Y. Yang; 4 apterous viviparous females, 15 August 2003, Sichuan (Baoxing County), No. 15017, on Parasenecio sp., coll. K. Guo; 7 apterous viviparous females, 27 June 1999, Shaanxi (Foping County), No. 12336, on Compositae, coll. T. L. He; 20 apterous viviparous females, 12 October 1988, Hunan (Zhangjiajie City), No. 8962, on Impatiens sp., coll. T. S. Zhong and G. X. Zhang; 4 apterous viviparous females, 26 September 1974, Guizhou (Guiyang City), No. Y2123, on Senecio scandens, coll. Y. Y. Rao; 10 apterous viviparous females, 31 March 1982, Yunnan (Kunming City), No. 7373, on Senecio scandens, coll. G. X. Zhang; 6 apterous viviparous females, 12 October 1996, Shaanxi (Zhouzhi County), No. 11096, host plants unknown, coll. G. X. Qiao; 4 apterous viviparous females, 18 August 2003, Sichuan (Baoxing County), host plants unknown, coll. K. Guo; 10 apterous viviparous females, 12 July 2002, Shaanxi (Meixian County), No. 13559, host plants unknown, coll. E. B. Ma; 14 apterous viviparous females, July 1936, Taiwan (Shinkwan),PageBreak host plants unknown, coll. R. Takahashi; JAPAN (BMNH): 41 apterous viviparous females, 6 August 1980, Kyoto, Kibune Mt., on Impatiens sp., coll. R. L. Blackman. Parasenecio sp., Impatiens sp., and Senecio scandens.China and Japan.Qiao & Jiang sp. n.urn:lsid:zoobank.org:act:4FE949A7-BF92-425C-BEDC-176EB4CA495Ahttp://species-id.net/wiki/Aleurodaphis_sinojackiaeChina (Jiangsu and Zhejiang).Sinojackia xylocarpa.The new species is named after its host plant, Apterous viviparous females , 21 May 1985, on Sinojackia xylocarpa, coll. V. F. Eastop (BMNH). Paratypes, 28 apterous viviparous females, 2 alate viviparous females and 8 nymphs, with the same collection data as holotype (BMNH); 9 apterous viviparous females and 11 alate viviparous females, CHINA: Jiangsu , No. Y7116, 10 June 1987, on Sinojackia xylocarpa, coll. T. S. Zhong (NZMC); 1 apterous viviparous female and 1 alate viviparous female, CHINA: Jiangsu , No. Y7116, 10 June 1987, on Sinojackia xylocarpa, coll. T. S. Zhong .Holotype, 1 apterous viviparous female, Sinojackia xylocarpa.The species induced the leaves of host plants to curl and form boat-shaped leaf galls.Aleurodaphis mikaniae: antennal segment III with 10\u201314 secondary rhinaria (Aleurodaphis mikaniae: 24\u201327); first tarsal chaetotaxy: 4, 4, 4, sometimes 3, 3, 3 .The new species differs from the other known speciesas follows: in apterous viviparous female: wax glands arranged in each segment, not connecting with each other ; in alate viviparous female compared to the most similar species As the detailed biological information is very important to research the taxonomic position of the genus and species identification, the life cycle of the new species will receive further study in future.Sorin & Miyazaki, 2004http://species-id.net/wiki/Aleurodaphis_stewartiaeAleurodaphis stewartiae Sorin & Miyazaki, 2004: 174.Stewartia monadelpha. Secondary hosts unknown.Primary host: PageBreakfrom the host tree, probably emigrating to some unknown secondary host (The aphid induces a leaf gall, which is formed by rolling the marginal part of the leaf upwards. The gall is about 47.5 long and 7.2 wide, with a surface rough to the touch. The alate viviparous females emerge in early August, and then disappear ary host .Japan ."} +{"text": "There is an error in the author by-line. Two authors, Leentje Van Lommel and Frans Schuit, were inadvertently omitted. The correct author by-line is: Geert A. Martens, Lei Jiang, Karine H. Hellemans, Geert Stang\u00e9, Harry Heimberg, Finn C. Nielsen, Olivier Sand, Jacques Van Helden, Leentje Van Lommel, Frans Schuit, Frans K. Gorus, and Daniel G. PipeleersBoth Leentje Van Lommel and Frans Schuit are affiliated with Gene Expression Unit, Katholieke Universiteit Leuven (KUL).Frans Schuit's contributions were: Conceived and designed the experiments, Performed the experiments, Analyzed the data, Contributed reagents/materials/analysis tools.Leentje Van Lommel's contributions were: Performed the experiments."} +{"text": "AbstractLiolophura japonica, Lottia luchuana, Nerita costata, Nerita rumphii, Diplommatina suganikeiensis, Littoraria undulata, Solenomphala taiwanensis, Assiminea sp., Siphonaria laciniosa, Laevapex nipponica, Carychium hachijoensis, Succinea erythrophana, Zaptyx crassilamellata, and Allopeas pyrgula. In Total, there are 126 species from 71 genera and 45 families of Mollusca on Gueishan Island. These data have been published through GBIF [http://taibif.org.tw/ipt/resource.do?r=gueishan_island] and integrated into the Taiwan Malacofauna Database (http://shell.sinica.edu.tw/).This dataset records the occurrence and inventory of molluscan fauna on Gueishan Island, the only active volcanic island in Taiwan, based on the literature survey and field investigation conducted between 2011 and 2012. The literature review involved seven studies published from 1934 to 2003, which collectively reported 112 species from 61 genera and 37 families of Mollusca on Gueishan Island. Through our field investigation, we identified 34 species from 28 genera and 23 families. Fourteen of these species were new records on Gueishan Island: Project title: Investigation of molluscan fauna of Gueishan Island, Taiwan.Personnel: Chih-Wei Huang , Ta-Wei Hsiung , Yen-Chen Lee (collection identifier), Si-Min Lin (Project Director), Wen-Lung Wu .PageBreakFunding: Academia Sinica; National Science Council, Executive Yuan, R.O.C.(Taiwan); Forest Bureau, Council of Agriculture, Executive Yuan, R.O.C.(Taiwan).Study area descriptions/descriptor: Gueishan Island is located about 10 km from Taiwan. The island was formed via volcanic activity about 1.65 Ma ago and experienced multiple volcanic eruption events until 20 ka ago and the other of freshwater (Tail Lake) (0 ka ago . It is cil Lake) . Humans Design description: Island species are vulnerable to extinction due to their relatively small population size and limited access to resources. The number of species on an island represents a dynamic equilibrium between immigration and extinction. Volcanic islands provide particularly interesting cases of island biogeography, in that their biota is erased by volcanic activity and recolonized from neighboring regions. Species on Gueishan Island may have under gone several cycles of extinction after volcanic eruption, followed by recolonization from Taiwan when the sea-level dropped during glacial periods. HuPageBreakman activity may also have provided opportunities for colonization of mollusks, either intentionally or accidentally. Investigations of molluscan fauna have been previously conducted on Gueishan Island, but these did not involve a comprehensive examination of land snails. We performed a literature survey using diverse databases, in order to collect previously identified reports on molluscan fauna of Gueishan Island. In addition, we performed field sampling of mollusks in marine, freshwater and terrestrial environments during 2011 and 2012 to establish the inventory of molluscan fauna of Gueishan Island. We considered both the topography of the island and the habitats of mollusks during our field investigation. We focused on the terrestrial environment, as the majority of the earlier investigations examined non-terrestrial habitats. In total, our literature survey and field investigation identified 126 species from 71 genera and 45 families of Mollusca on Gueishan Island. This dataset provides basic information on the island\u2019s biodiversity.General taxonomic coverage description: The coverage of this dataset includes 126 species from 71 genera and 45 families of Mollusks of marine, freshwater and terrestrial environments on Gueishan Island (Gastropoda (88.10%), Class Bivalvia (8.73%), Class Cephalopoda (1.59%), and Class Polyplacophora (1.59%). The top five representative families are Cypraeidae , Trochidae , Muricidae , Neritidae , and Littorinidae .PageBreakPageBreakPageBreakPageBreakPageBreakPhylum: MolluscaClass:Bivalvia, Cephalopoda, Gastropoda, PolyplacophoraOrder:Arcoida, Caenogastropoda, Heterobranchia, Neoloricata, Neritimorpha, Octopoda, Ostreoida, Patellogastropoda, Pterioida, Unionoida, Veneroida, VetigastropodaPageBreakFamily:Achatinidae, Aplysiidae, Arcidae,\u00a0Argonautidae,\u00a0Assimineidae, Bradybaenidae, Bursidae, Camaenidae,\u00a0Cardiidae, Chitonidae, Clausiliidae, Columbellidae, Conidae, Corbiculidae, Cypraeidae, Diplommatinidae, Ellobiidae, Fasciolariidae,\u00a0Haliotidae, Littorinidae, Lottiidae, Muricidae, Nassariidae, Neritidae, Octopodidae, Ostreidae, Ovulidae, Patellidae, Pectinidae, Philomycidae, Phyllidiidae, Planaxidae, Planorbidae, Potamididae,\u00a0Pteriidae, Ranellidae, Siphonariidae, Subulinidae, Succineidae, Thiaridae, Trochidae, Turbinellidae, Turbinidae, Unionidae, VeronicellidaeGenus:Achatina, Acusta, Aegista, Allopeas, Aplysia, Argonauta, Assiminea, Astralium, Barbatia, Batillaria, Bradybaena, Bursa, Calliostoma, Calpurnus, Carychium, Cellana, Chicoreus, Chlamys, Chlorostoma, Collisella, Coniglobus, Conus, Corbicula, Crassostrea, Cristaria, Cymatium, Cypraea, Diplommatina, Dolabrifera, Drupa, Ergalatax, Haliotis, Laevapex, Liolophura, Littoraria, Lottia, Lunella, Mancinella, Meghimatium, Monodonta, Morula, Nassarius, Nerita, Nodilittorina, Notoacmea, Octopus, Ovula, Patella, Peristernia, Phyllidia, Pinctada, Planaxis, Pteria, Purpura, Pyrene, Saccostrea, Siphonaria, Solenomphala, Stomatella, Succinea, Tarebia, Tectus, Telasco, Tenguella, Thais, Thiara, Tridacna, Trochus, Vaginulus, Vasum, Zaptyx.General spatial coverage: The spatial coverage of the literature and our field investigation ranged from a latitude of 24\u00b049'48\"N to 24\u00b051'0\"N and a longitude of 121\u00b055'48\"E to 121\u00b057'36\"E. It includes the marine, intertidal, freshwater and terrestrial environment of Gueishan Island, Taiwan associated with the molluscan fauna of Gueishan Island from the following databases: (1) the National Digital Library of Theses and Dissertations in Taiwan (http://ndltd.ncl.edu.tw) ; (2) the National Bibliographic Information Network (http://nbinet3.ncl.edu.tw) ; (4) Google Scholar (http://scholar.google.com.tw/) ; (5) Thications ). In addications were ideications were excField Sampling: The topology of Gueishan Island and the types of mollusk habitat were considered for field investigation. Visual search was conducted for mollusks in intertidal, freshwater and terrestrial environments . All the specimens collected during the field investigation were identified independently by Huang and Hsiung. Seven earlier studies described the mollucan fauna of Gueishan Island, but these publications lack PageBreakclear photos or other information for identifying specimens. Species identification was performed using the following guide books and publications about Taiwan malacofauna: http://www.marinespecies.org/).http://taibif.org.tw/ipt/resource.do?r=gueishan_islandThe data underpinning the analysis reported in this paper are deposited at GBIF, the Global Biodiversity Information Facility, Dataset description: This dataset incorporates seven publications , Lottia luchuana , Siphonaria laciniosa , Nerita costata Gmelin, 1791, Nerita rumphii Recluz,1841, and Littoraria undulata , which were sampled from the marine environment; Assiminea sp. and Laevapex nipponica , which were discovered in a freshwater environment, Tail Lake; and Solenomphala taiwanensis , Diplommatina suganikeiensis , Carychium hachijoensis Pilsbry, 1902, Zaptyx crassilamellata Kuroda, 1941, Allopeas pyrgula , and Succinea erythrophana Ancey, 1883 discovered in the terrestrial environment. This dataset provide basic information for the island\u2019s biodiversity and biogeography. This dataset will be maintained by the Malacology Lab, Biodiversity Research Center, Academia Sinica.ications associatObject name: Darwin Core Archive Molluscan fauna of Gueishan Island, TaiwanPageBreakCharacter encoding: UTF-8Format name: Darwin Core Archive formatFormat version: 1.0Distribution:http://taibif.org.tw/ipt/archive.do?r=gueishan_islandPublication date of data: 2012-12-21Language: EnglishLicenses of use: This work is licensed under a Creative Commons CCZero 1.0 License http://creativecommons.org/publicdomain/zero/1.0/legalcodeMetadata language: EnglishDate of metadata creation: 2012-09-21Hierarchy level: Dataset"} +{"text": "We, scientists from a variety of disciplines, declare the following:Parties to the Stockholm Convention have taken action on three brominated flame retardants that have been listed in the treaty for global elimination. These substances include components of commercial penta-bromodiphenyl ether and commercial octa-bromodiphenyl ether, along with hexabromobiphenyl. Another brominated flame retardant, hexabromocyclododecane, is under evaluation.Many commonly used brominated and chlorinated flame retardants can undergo long-range environmental transport.Many brominated and chlorinated flame retardants appear to be persistent and bioaccumulative, resulting in food chain contamination, including human milk.Many brominated and chlorinated flame retardants lack adequate toxicity information, but the available data raises concerns.Many different types of brominated and chlorinated flame retardants have been incorporated into products even though comprehensive toxicological information is lacking.Brominated and chlorinated flame retardants present in a variety of products are released to the indoor and outdoor environments.Near-end-of-life and end-of-life electrical and electronic products are a growing concern as a result of dumping in developing countries, which results in the illegal transboundary movement of their hazardous constituents. These include brominated and chlorinated flame retardants.There is a lack of capacity to handle electronic waste in an environ-mentally sound manner in almost all developing countries and countries with economies in transition, leading to the release of hazardous substances that cause harm to human health and the environment. These substances include brominated and chlorinated flame retardants.Brominated and chlorinated flame retardants can increase fire toxicity, but their overall benefit in improving fire safety has not been proven.When brominated and chlorinated flame retardants burn, highly toxic dioxins and furans are formed.Therefore, these data support the following:Brominated and chlorinated flame retardants as classes of substances are a concern for persistence, bioaccumulation, long-range transport, and toxicity.There is a need to improve the availability of and access to information on brominated and chlorinated flame retardants and other chemicals in products in the supply chain and throughout each product\u2019s life cycle.Consumers can play a role in the adoption of alternatives to harmful flame retardants if they are made aware of the presence of the substances, for example, through product labeling.The process of identifying alternatives to flame retardants should include not only alternative chemicals but also innovative changes in the design of products, industrial processes, and other practices that do not require the use of any flame retardant.Efforts should be made to ensure that current and alternative chemical flame retardants do not have hazardous properties, such as mutagenicity and carcinogenicity, or adverse effects on the reproductive, developmental, endocrine, immune, or nervous systems.When seeking exemptions for certain applications of flame retardants, the party requesting the exemption should supply some information indicating why the exemption is technically or scien-tifically necessary and why potential alternatives are not technically or scientifically viable; a description of potential alternative processes, products, materials, or systems that eliminate the need for the chemical; and a list of sources researched.Wastes containing flame retardants with persistent organic pollutant (POP) characteristics, including products and articles, should be disposed of in such a way that the POP content is destroyed or irreversibly transformed so that they do not exhibit the charac-teristics of POPs.Flame retardants with POP characteristics should not be permitted to be subjected to disposal operations that may lead to recovery, recycling, reclamation, direct reuse, or alternative uses of the substances.Wastes containing flame retardants with POP properties should not be transported across international boundaries unless it is for disposal in such a way that the POP content is destroyed or irreversibly transformed.It is important to consider product stewardship and extended producer responsibility aspects in the life-cycle management of products containing flame retardants with POP properties, including electronic and electrical products.San Antonio Statement on Brominated and Chlorinated Flame RetardantsSignatories as of publication date. Institutions are for identification purposes only.Sam Adu-Kumi, M.S., Deputy Director, Environmental Protection Agency, Accra, GhanaBj\u00f6rn Albinson, Fire Protection Engineer (retired), Karlstad, SwedenHenrik Alm, M.S., Doctoral Student, Pharmaceutical Biosciences, Division of Toxicology, Uppsala University, Uppsala, SwedenMisha Askren, M.D., F.A.A.F.P., Physician, Southern California Permanente Medical Group, Pasadena, CA, USARalph Baker, M.S., Ph.D., Chief Scientist, TerraTherm Inc., Fitchburg, MA, USAJohn Balmes, M.D., Professor of Medicine, University of California, San Francisco, San Francisco, CA, USA, and Professor of Environmental Health Sciences, University of California, Berkeley, Berkeley, CA, USAScott Bartell, Ph.D., Assistant Professor, University of California, Irvine, Irvine, CA, USAGeorg Becher, Ph.D., Department Director and Professor, Analytical Chemistry, Norwegian Institute of Public Health, Oslo, NorwayDavid C. Bellinger, Ph.D., Professor, Harvard Medical School and Harvard School of Public Health, Boston, MA, USAStephen Bent, M.D., Associate Professor of Medicine, Psychiatry, Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA, USA\u00c5ke Bergman, Ph.D., Professor, Environmental Chemistry, Stockholm University, Stockholm, Sweden, and Board Member, International Panel on Chemical Pollution, Z\u00fcrich, SwitzerlandAnders Bignert, Ph.D., Professor, Contaminant Research, Swedish Museum of Natural History, Stockholm, SwedenJustina Bj\u00f6rklund, M.S., Graduate Student, Applied Environmental Science, Stockholm University, Stockholm, SwedenArlene Blum, Ph.D., Visiting Scholar, Chemistry, University of California, Berkeley, Berkeley, CA, USAChristian Bogdal, Ph.D., Researcher, Swiss Federal Institute of Technology, Z\u00fcrich, SwitzerlandPhil Brown, Ph.D., Professor, Sociology and Environmental Studies, Brown University, Providence, RI, USADavid Camann, M.S., Staff Scientist, Southwest Research Institute, San Antonio, TX, USACarmela Centeno, M.S., Ph.D., Industrial Development Officer, United Nations Industrial Development Organization, Vienna, AustriaIbrahim Chahoud, Ph.D., Professor of Reproductive Toxicology, Institute of Clinical Pharmacology and Toxicology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, Berlin, GermanyEliza Chin, M.D., M.P.H., President, American Medical Women\u2019s Association, Philadelphia, PA, USABrock Chittim, M.S., General Manager, Wellington Laboratories, Guelph, Ontario, CanadaCarsten Christophersen, Ph.D., Associate Professor, Chemistry, University of Copenhagen, Copenhagen, DenmarkBradley Clarke, Ph.D., Research Fellow, Imperial College, London, United KingdomTheo Colborn, Ph.D., Professor Emeritus, University of Florida, Gainesville, Florida, USAKathleen Collins, Ph.D., Professor, Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USATerrence Collins, Ph.D., Teresa Heinz Professor of Green Chemistry and Director of the Institute for Green Science, Carnegie Mellon University, Pittsburgh, PA, USAAdrian Covaci, Ph.D., Professor, University of Antwerp, Antwerp, BelgiumCraig Criddle, Ph.D., Professor, Civil and Environmental Engineering, Stanford University, Palo Alto, CA, USAMargarita Curras-Collazo, Ph.D., Associate Professor, Cell Biology and Neuroscience, University of California, Riverside, Riverside, CA, USAKyle D\u2019Silva, Ph.D., Product Manager, Thermo Fisher Scientific, Dreieich, GermanyDevra Davis, M.A., Ph.D., M.P.H, Visiting Professor, Georgetown University, Washington, DC, USA, and Founder, Environmental Health Trust, Teton Village, WY, USAJoao De Assuncao, M.S., Ph.D., Professor and Department Head, Environmental Health, University of Sao Paulo School of Public Health, Sao Paulo, BrazilCynthia A. de Wit, Ph.D., Professor, Applied Environmental Science, Stockholm University, Stockholm, SwedenMike Denison, Ph.D., Professor of Environmental Toxicology, University of California, Davis, Davis, CA, USAMiriam Diamond, Ph.D., Professor, Geography, University of Toronto, Toronto, Ontario, CanadaJoseph DiGangi, Ph.D., Senior Scientist and Technical Advisor, International POPs Elimination Network, Berkeley, CA, USAAlin Dirtu, Ph.D., Researcher, University of Antwerp, Antwerp, BelgiumMichelle Douskey, Ph.D., Lecturer, Chemistry, University of California, Berkeley, Berkley, CA, USAAnne Ehrlich, Ph.D., Senior Research Scientist, Biology, Stanford University, Palo Alto, CA, USADavid Epel, Ph.D., Jane & Marshall Steel Jr. Professor Emeritus in Marine Sciences, Cell and Developmental Biology, Stanford University, Palo Alto, CA, USABrenda Eskenazi, M.A., Ph.D., Jennifer and Brian Maxwell Professor of Maternal Health and Epidemiology, University of California, Berkeley, Berkeley, CA, USATim Evans, Ph.D., Cancer Registration Information Manager, West Midlands Cancer Intelligence Unit, Birmingham, United KingdomPeter Fantke, Ph.D., Research Associate, Institute of Energy Economics and the Rational Use of Energy, University of Stuttgart, Stuttgart, GermanyJoseph Gardella Jr., Ph.D., Professor and Larkin Chair of Chemistry, University at Buffalo, State University of New York, Buffalo, NY, USAPhilip Germansderfer, D.Sc., International Marketing Sales, Fluid Managment Systems, Watertown, MA, USAGillian Gibson, M.Sc., Environmental Scientist, Gibson Consulting and Training, Cheshire, United KingdomAndreas Gies, Ph.D., Director and Professor, Department for Environmental Hygiene, Federal Environment Agency, Berlin, GermanyRobert Gould, M.D., President, San Francisco Bay Area Chapter of Physicians for Social Responsibility, Berkeley, CA, USAKonstanze Grote, Ph.D., Institute of Clinical Pharmacology and Toxicology, Charit\u00e9 University Medical School Berlin, Berlin, GermanyRui Guo, Ministry of Environment, Toronto, Ontario, CanadaJana Hajslova, Ph.D., Head of Department of Food Analysis, Institute of Chemical Technology, Prague, Czech RepublicRalph Hall, Ph.D., Assistant Professor, Virginia Polytechnic Institute, Blacksburg, VA, USABruce Hammock, Ph.D., Professor, Entomology, University of California, Davis, Davis, CA, USATran Thi Tuyet Hanh, M.P.H., Lecturer in Environmental Health, Hanoi School of Public Health, Hanoi, VietnamKim Harley, Ph.D., Associate Director, Center for Children\u2019s Environmental Health Research, University of California, Berkeley, Berkeley, CA, USAStuart Harrad, Ph.D., Professor, Environmental Chemistry, University of Birmingham, Birmingham, United KingdomRobert Harrison, M.D., M.P.H., Clinical Professor, Occupational and Environmental Medicine, University of California, San Francisco, San Francisco, CA, USALine Smastuen Haug, Doctoral Student, Norwegian Institute of Public Health, Oslo, NorwayYasuhiro Hirai, Ph.D., Associate Professor, Environment Preservation Engineering, Kyoto University, Kyoto, JapanIvan Holoubek, Ph.D., Director and Professor, Masaryk University, Research Centre for Toxic Compounds in the Environment, Brno, Czech RepublicRon Hoogenboom, Ph.D., Toxicologist, RIKILT Institute of Food Safety, Wageningen University and Research Center, Wageningen, the Netherlands, and Board Member, International Panel on Chemical Pollution, Z\u00fcrich, SwitzerlandDavid Hope, CEO, Pacific Rim Laboratories, Surrey, British Columbia, CanadaWilliam J. Hirzy, Ph.D., Chemist in Residence, American University, Washington, DC, USAHeinrich Huehnerfuss, Ph.D., Professor, University of Hamburg, Hamburg, GermanyAlastair Iles, Ph.D., Assistant Professor, Environmental Science, Policy, and Management, University of California, Berkeley, Berkeley, CA, USATomohiko Isobe, Ph.D., Senior Research Fellow, Ehime University, Matsuyama City, JapanKristina Jakobsson, Ph.D., Associate Professor, Occupational and Environmental Medicine, Lund University, Lund, SwedenSarah Janssen, M.D., Ph.D., M.P.H., Senior Scientist, Natural Resources Defense Council, New York City, NY, USANiklas Johansson, Scientist, Karolinska Institute, Stockholm, SwedenCatherine Karr, M.D., Ph.D., M.S., Assistant Professor and Director, Pediatric Environmental Health Specialty Unit, Pediatrics, University of Washington, Seattle, WA, USADonald Kennedy, Ph.D., Bing Professor of Environmental Science, Emeritus, Stanford University, Palo Alto, CA, USA, and Editor Emeritus, ScienceSergio Kuriyama, Ph.D., Guest Scientist, Laboratory of Environmental Toxicology, National School of Public Health, Fiocruz, BrazilJames Leckie, M.S., Ph.D., C.L. Peck, Class of 1906 Professor of Engineering and Director, Center for Sustainable Development and Global Competitiveness, Stanford University, Palo Alto, CA, USAPamela Lein, Ph.D., Professor, Molecular Biosciences, University of California, Davis, Davis, CA, USAJuliana Leonel, Ph.D., Postdoctoral Researcher, Universidade Federal do Rio Grande, Rio Grande, BrazilMark Levine, Ph.D., Leader, China Energy Group, and Former Director, Environmental Energy Technologies Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USADonald Lucas, Ph.D., Deputy Director, Environment, Health, and Safety Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USARichard Luthy, Ph.D., Silas H. Palmer Professor, Civil and Environmental Engineering, Stanford University, Palo Alto, CA, USAKarl Mair, D.Sc., Senior Scientist, Eco Research SRL, Bolzano, ItalyGovindan Malarvannan, Ph.D., Research Fellow, Center for Marine Environmental Studies, Ehime University, Matsuyama City, JapanJohn Meeker, M.S., Sc.D., Assistant Professor, Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USARichard Meigs, P.E., Senior Principal Engineer, RJR Engineering, Ventura, CA, USAMark Miller, M.D., M.P.H., Director, Pediatric Environmental Health Specialty Unit, and Assistant Clinical Professor, Pediatrics, University of California, San Francisco, San Francisco, CA, USAPaolo Mocarelli, M.D., Professor and Director, Department of Clinical Pathology, University of Milano Bicocca, Milano, ItalyRachel Morello-Frosch, M.P.H., Ph.D., Associate Professor, Department of Environmental Science Policy and Management, University of California, Berkeley, Berkeley, CA, USAJochen Mueller, Ph.D., Professor, University of Queensland, Brisbane, AustraliaTom Muir, M.S., Retired, Environment Canada, Qu\u00e9bec City, Quebec, CanadaMartin Mulvihill, Ph.D., Associate Director for Education and Outreach, Center for Green Chemistry, University of California, Berkeley, Berkeley, CA, USAAnbu Munasamy, M.S., Ph.D., National Institute for Interdisciplinary Science and Technology\u2013Council of Scientific and Industrial Research, Thiruvananthapuran, Kerala, IndiaRichard Murphy, Ph.D., Director of Science and Education, Jean-Michel Cousteau Ocean Futures Society, Santa Barbara, CA, USATakeshi Nakano, Ph.D., Research Professor, Center for Advanced Science and Innovation, Osaka University, Osaka, JapanShoji Nakayama, M.D., Ph.D., National Research Council Associate, U.S. Environmental Protection Agency, Washington, DC, USAAmgalan Natsagdorj, Ph.D., Department Head, Environmental Chemistry, National University of Mongolia, Ulaanbaatar, MongoliaWilliam Nazaroff, Ph.D., Daniel Tellep Distinguished Professor and Vice Chair for Academic Affairs, Civil and Environmental Engineering, University of California, Berkeley, Berkeley, CA, USAJohn Neuberger, Dr.Ph., M.P.H., M.B.A., Professor, Preventative Medicine and Public Health, University of Kansas School of Medicine, Kansas City, KS, USAJessica Norrgran, Doctoral Student, Stockholm University, Stockholm, SwedenFardin Oliaei, Ph.D., M.P.A., Consultant, Cambridge EnviroScience Consulting, LLC, Cambridge, MA, USAKees Olie, Ph.D., Associate Professor, University of Amsterdam, Amsterdam, the NetherlandsOlaf Paepke, Ph.D., Eurofins, Hamburg, GermanyVictoria Persky, M.D., Professor, University of Illinois at Chicago School of Public Health, Chicago, IL, USAAgneta Rannug, Ph.D., Professor, Institute of Environmental Medicine, Karolinska Institute, Stockholm, SwedenUlf Rannug, Ph.D., Professor, Genetics, Microbiology and Toxicology, Stockholm University, Stockholm, SwedenEric Reiner, Ph.D., Senior Research Scientist, Ontario Ministry of Environment, Toronto, Ontario, CanadaMartin Reinhard, Ph.D., Professor, Civil and Environmental Engineering, Stanford University, Palo Alto, CA, USAKaren Rice, M.D., Physician, Obstetrics and Gynecology, Walnut Creek Kaiser, Walnut Creek, CA, USARobert H. Rice, Ph.D., Professor of Environmental Toxicology, University of California, Davis, Davis, CA, USAAnthony Roach, Ph.D., Senior Research Scientist, Government of New South Wales, Sydney, AustraliaDavid Roberts, Ph.D., William R. Kenan, Jr. Professor of Astrophysics, Brandeis University, Waltham, MA, USAMary Roberts, Ph.D., Professor, Chemistry, Boston College, Boston, MA, USAChristina Ruden, Ph.D., Professor, Philosophy and the History of Technology, Royal Institute of Technology, Stockholm, SwedenCindy Lee Russell, M.D., Vice President of Community Health, Santa Clara County Medical Association, San Jose, CA, USAKenneth Sauer, Ph.D., Professor Emeritus of Chemistry, University of California, Berkeley, Berkeley, CA, USAArnold Schecter, M.D., M.P.H., Professor, Environmental and Occupational Health Sciences, University of Texas School of Public Health, Dallas, TX, USAMartin Scheringer, D.Sc., Senior Scientist, ETH Z\u00fcrich, Z\u00fcrich, Switzerland, and Board Member, International Panel on Chemical Pollution, Z\u00fcrich, SwitzerlandTed Schettler, M.D., M.P.H., Science Director, Science and Environmental Health Network, Ames, IA, USAKarl-Werner Schramm, Ph.D., Professor and Chair, German Research Center for Environmental Health, Neuherberg, GermanyMegan Schwarzman, M.D., M.P.H., Research Scientist, University of California, Berkeley, Berkeley, CA, USA, and Associate Physician, University of California, San Francisco, San Francisco, CA, USASusan D. Shaw, Dr.PH., Director, Marine Environmental Research Institute, Blue Hill, ME, USAHeather Stapleton, Ph.D., Assistant Professor, Nicholas School of the Environment, Duke University, Durham, NC, USAKristina Sundqvist, Ph.D., Project Assistant, Chemistry, Ume\u00e5 University, Ume\u00e5, SwedenPatrice Sutton, M.P.H., Research Scientist, Program on Reproductive Health and the Environment, University of California, San Francisco, San Francisco, CA, USAShanna Swan, Ph.D., Professor and Associate Chair for Research, Obstetrics and Gynecology, and Director, Center for Reproductive Epidemiology, University of Rochester School of Medicine, Rochester, NY, USATakumi Takasuga, Ph.D., Director, Shimadzu Techno-Research Inc., Kyoto, JapanChris Talsness, D.V.M., Working Group Leader in Reproductive Toxicology, Charite Universitatsmedizin Berlin, Berlin, GermanyCathrine Thomsen, Ph.D., Senior Scientist, Norwegian Institute of Public Health, Oslo, NorwayGregg Tomy, Ph.D., Adjunct Assistant Professor, Fisheries and Oceans, University of Manitoba, Winnipeg, Manitoba, CanadaJoao Paulo Machado Torres, Sc.D., Associate Professor, Universidade Federal do Rio de Janeiro, Rio de Janeiro, BrazilJames Trosko, Ph.D., Professor, Pediatrics and Human Development, Center for Integrative Toxicology, Michigan State University, East Lansing, MI, USAMary Turyk, Ph.D., M.P.H., Research Assistant Professor, University of Illinois at Chicago, Chicago, IL, USAGunther Umlauf, Ph.D., European Commission Joint Research Center, Ispra, ItalyBryan Vining, Ph.D., Analytical Perspectives, Wilmington, NC, USAQiuquan Wang, Ph.D., Professor of Chemistry, Xiamen University, Xiamen, ChinaYawei Wang, Ph.D., Research Center for Eco Environmental Science, Beijing, ChinaJulie Shu-Li Wang, Ph.D., Investigator, National Health Research Institute, Taipei, TaiwanRosemary Waring, Ph.D., Honorary Reader, Human Toxicology, University of Birmingham, Birmingham, United KingdomThomas F. Webster, D.Sc., Associate Professor and Associate Chair, Department of Environmental Health, Boston University School of Public Health, Boston, MA, USACharles Weschler, Ph.D., Adjunct Professor, UMDNJ\u2013Robert Wood Johnson Medical School and Rutgers University, New Brunswick, NJ, USA, and Continuing Visiting Professor, International Centre for Indoor Environment and Energy, Technical University of Denmark, Lyngby, DenmarkStevie Wilding, Chemist, U.S. Environmental Protection Agency, Region 3, Philadelphia, PA, USADuane Wilding, M.E., Senior Engineer, Maryland Environmental Service, Millersville, MD, USAGayle Windham, Ph.D., Researcher, Breast Cancer and the Environment Research Centers, Research Triangle Park, NC, USATracey Woodruff, Ph.D., M.P.H., Associate Professor and Director, Program on Reproductive Health and the Environment, University of California, San Francisco, San Francisco, CA, USAJae-Ho Yang, M.D., M.P.H., Professor, Catholic University of Daegu, Gyeongsan, KoreaTom Young, M.P.P., Ph.D., Professor, Civil & Environmental Engineering, University of California, Davis, Davis, CA, USABin Zhao, Doctoral Student, Environmental Toxicology, University of California, Davis, Davis, CA, USAR. Thomas Zoeller, M.A., Ph.D., Professor, Biology Department, University of Massachusetts, Amherst, Amherst, MA, USAAmi Zota, Sc.D., Postdoctoral Scholar, Program on Reproductive Health and the Environment, University of California, San Francisco, Oakland, CA, USA(212 KB) PDFAbbreviations and an Annotated StatementClick here for additional data file."} +{"text": "Following the publication of this article , we obseThe authors declare that they have no competing interests.MF, VEV, JRC, CF, AM, CFF, JRB, JAC, CBMM., HMJ, NM, WS and LCA designed research, analyzed data, and wrote the paper. All authors read and approved the final manuscript."} +{"text": "Background: Longer CAG repeat length is associated with faster clinical progression in Huntington disease, although the effect of higher repeat length on brain atrophy is not well documented. Method: Striatal volumes were obtained from MRI scans of 720 individuals with prodromal Huntington disease. Striatal volume was plotted against age separately for groups with CAG repeat lengths of 38\u201339, 40, 41, 42, 43, 44, 45, 46, and 47\u201354. Results: Slopes representing the association between age and striatal volume were significantly steeper as CAG repeat length increased. Discussion: Although cross-sectional, these data suggest that striatal atrophy, like clinical progression, may occur faster with higher CAG repeat lengths. It has long been known that greater CAG repeat lengths are associated with earlier onset of illness, especially for individuals with particularly high repeat number. More recent evidence demonstrates that higher CAG repeat lengths are also associated with faster clinical progression. Rosenblatt et al. The analyses presented here are based on baseline MRI data from participants of PREDICT-HD, a multi-site, longitudinal study of prodromal HD. The sample included 720 participants who tested positive for the HD gene mutation (CAG repeat lengths ranging from 38 to 54), but had not been diagnosed with the motor signs of HD at the time of study enrollment . An additional 206 participants were offspring of a parent with HD but who themselves had tested negative for the HD gene mutation (\u201ccontrols\u201d). All aspects of the study were approved by the Institutional Review Board at each participating institution, they were in compliance with the code of Ethics of the World Medical Association Declaration of Helsinki, and all participants gave written informed consent.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 All MRI scans were obtained using a standard multi-modal protocol that included a 3D volumetric spoiled gradient echo series and a dual echo proton density/T2 series. Scans were processed at The University of Iowa using an automated procedure implemented in BRAINS \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Analyses were performed to examine the association between age and striatal volume in each of nine groups defined by CAG repeat length . Each CAG group had at least 34 participants. Table\u00a01 presents demographics and clinical scores for participants in each CAG group. Within each group, a linear regression was performed to examine the association between age and striatal volume . The slopes resulting from each of these nine regressions were then correlated with CAG group (using Spearman correlation). This analysis was designed to determine whether the slope of the regressions for age and striatal volume became steeper with increasing CAG repeat length. For each CAG repeat group, a separate linear regression was also performed that included age and the quadratic term of age as predictors to explore the possibility of a curvilinear relationship between age and striatal volume.Table 1. Sample description and R2 of regression between age and striatal volume for each CAG group.2s ranging from 0.14 to 0.51, all p values < 0.005) but variable, with lower R2s generally observed for the lowest CAG repeat lengths. The slope for each group was highly associated with CAG group , with higher CAG repeat numbers associated with steeper slope, at least up through CAG = 44. \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Figure 1 shows the regression for each group depicting the association between age and striatal volume . These regressions were all highly significant , although this was due to a single outlier. When this outlier was removed, the addition of the age2 factor did not result in an increased significance in the model that was based on age alone . Although not quite reaching significance , the curve for the CAG = 38\u201339 group suggested a slightly steeper decline for older subjects than younger subjects. A significant effect of age2 was not observed in any other groups . \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 The quadratic effect of age in the linear regression model was statistically significant for CAG = 46 group (n = 13) including both affected and prodromal individuals, Henley et al. n = 62), the same group found that an increase of CAG repeat length by one was associated with an increase in whole-brain atrophy rate of 0.12% per year\u00a0Although based on cross-sectional data, our analyses suggest that increased CAG repeat length is associated with faster progression of striatal atrophy in prodromal HD, at least up through CAG = 44. Although it is clearly established that CAG repeat length has an effect on age at onset of HD n = 211 t = \u22122.64, p = 0.009) and total striatum , with a trend toward a significant association for putamen . No significant associations were observed for any other regions . Taken together with results from the current study, these findings yield evidence suggesting that rate of striatal atrophy is faster in individuals with higher CAG repeat lengths. Our results are not surprising, given previous research in affected patients with HD demonstrating that (a) faster rate of clinical progression is associated with higher CAG repeat number Our results are consistent with analyses of longitudinal data from a subsample of the current cross-sectional sample n = 211 that revy-intercept is below that of the other CAG groups . There is also a lack of cases with very high CAG repeat lengths, as these individuals usually have childhood onset and would not, therefore, qualify for a study of adult prodromal HD. If it were possible to include prodromal individuals younger than 18 years, striatal volumes for those with large CAG repeat lengths might be higher than those in the current study, resulting in even steeper slopes for these groups. Thus, our finding of similar association between age and striatal volume in the groups with CAG > 44 may not be valid across the entire age range. \u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 A major strength of the current study is its large sample size. Although the findings presented here are based on cross-sectional baseline data, it is expected that longitudinal results would be similar, as the regression between age and striatal volume for a given CAG repeat length can be assumed to be a good estimate of the trajectory of atrophy for the average participant within that CAG group. Lack of very young participants (< 18 years) may skew the data somewhat, especially for the longer CAG groups, where the p = 0.07) suggests that striatal atrophy remains fairly normal for prodromal individuals with relatively low CAG repeat lengths until they are older adults, at which time atrophy increases. This would be consistent with the fact that these individuals are usually not diagnosed until fairly late in life.\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 It is also noteworthy that the slope for the group with CAG = 38\u201339 is basically the same as for the control group, although absolute values for striatal volumes are lower. The age range for the two groups is similar and the results were not biased by any obvious outliers. The trend for a curvilinear relationship between age and striatal volume and CHDI Foundation, Inc.The authors have declared that no competing interests exist.PREDICT-HD Investigators, Coordinators, Motor Raters, Cognitive RatersSteering CommitteeJane Paulsen, PhD, Principal Investigator, Eric A. Epping, MD, PhD, Douglas Langbehn, MD, PhD, Hans Johnson, PhD, Megan Smith, PhD, Janet Williams, PhD, RN, FAAN ; Elizabeth Aylward, PhD ; Kevin Biglan, MD ; Blair Leavitt, MD ; Marcy MacDonald, PhD ; Martha Nance, MD ; Jean Paul Vonsattel, PhD . Scientific SectionsBio Markers: Blair Leavitt, MDCM, FRCPC (Chair) and Michael Hayden, PhD (University of British Columbia); Stefano DiDonato, MD ; Ken Evans, PhD (Ontario Cancer Biomarker Network); Wayne Matson, PhD ; Asa Peterson, MD, PhD , Sarah Tabrizi, PhD . Cognitive: Deborah Harrington, PhD , Tamara Hershey, PhD (Washington University Cognitive Science Battery Development); Holly Westervelt, PhD , Jennifer Davis, PhD, Pete Snyder, PhD, and Geoff Tremont, PhD, MS ; Megan Smith, PhD , David J. Moser, PhD, Leigh J. Beglinger, PhD (University of Iowa); Lucette Cysique, PhD ; Carissa Gehl, PhD ; Robert K. Heaton, PhD, David Moore, PhD, Joanne Hamilton, PhD, and David Salmon, PhD ; Kirsty Matheson (University of Aberdeen); Paula Shear, PhD (University of Cincinnati); Karen Siedlecki, PhD (Fordham University); Glenn Smith, PhD (Mayo Clinic); and Marleen Van Walsem (EHDN).Functional Assessment: Janet Williams, PhD (Co-Chair), Leigh J. Beglinger, PhD, Anne Leserman, MSW, LISW, Justin O\u2019Rourke, MA, Bradley Brossman, MA, Eunyoe Ro, MA (University of Iowa); Rebecca Ready, PhD (University of Massachusetts); Anthony Vaccarino, PhD (Ontario Cancer Biomarker Network); Sarah Farias, PhD ; Noelle Carlozzi, PhD ; and Carissa Gehl, PhD .Genetics: Marcy MacDonald, PhD (Co-Chair), Jim Gusella, PhD, and Rick Myers, PhD ; Michael Hayden, PhD (University of British Columbia); Tom Wassink, MD (Co-Chair) and Eric A. Epping, MD, PhD (University of Iowa).Imaging:Administrative: Ron Pierson, PhD (Chair), Kathy Jones, BS, Jacquie Marietta, BS, William McDowell, AA, Steve Dunn, BA, Greg Harris, BS, Eun Young Kim, MS, and Yong Qiang Zhao, PhD (University of Iowa); John Ashburner, PhD ; Vince Calhoun, PhD (University of New Mexico); Steve Potkin, MD ; Klaas Stephan, MD, PhD (University College of London); and Arthur Toga, PhD .Striatal: Elizabeth Aylward, PhD and Kurt Weaver, PhD .Surface Analysis: Peg Nopoulos, MD (Chair), Eric Axelson, BSE, and Jeremy Bockholt, BS (University of Iowa).Shape Analysis: Christopher A. Ross (Chair), MD, PhD, Michael Miller, PhD, and Sarah Reading, MD (Johns Hopkins University); Mirza Faisal Beg, PhD (Simon Fraser University).DTI: Vincent A. Magnotta, PhD ; Karl Helmer, PhD ; Kelvin Lim, MD ; Mark Lowe, PhD (Cleveland Clinic); Sasumu Mori, PhD (Johns Hopkins University); Allen Song, PhD (Duke University); and Jessica Turner, PhD . fMRI: Steve Rao, PhD (Chair), Erik Beall, PhD, Katherine Koenig, PhD, Mark Lowe, PhD, Michael Phillips, MD, Christine Reece, BS, and Jan Zimbelman, PhD, PT (Cleveland Clinic).Motor: Kevin Biglan, MD (University of Rochester), Karen Marder, MD (Columbia University), and Jody Corey-Bloom, MD, PhD all Co-Chairs; Michael Geschwind, MD, PhD ; and Ralf Reilmann, MD .Psychiatric: Eric A. Epping, MD, PhD (Chair), Nancy Downing, RN, MSN, Jess Fiedorowicz, MD, Robert Robinson, MD, and Megan Smith, PhD (University of Iowa); Karen Anderson, MD (University of Maryland); David Craufurd, MD (University of Manchester); Mark Groves, MD (Columbia University); Anthony Vaccarino, PhD and Ken Evans, PhD (Ontario Cancer Biomarker Network); Hugh Rickards, MD ; and Eric van Duijn, MD .Core SectionsStatistics: Douglas Langbehn, MD, PhD (Chair) and James Mills, MEd, MS (University of Iowa); and David Oakes, PhD (University of Rochester).Recruitment/Retention: Martha Nance, MD ; Anne Leserman, MSW, LISW, Stacie Vik, BA, Christine Anderson, BA, Nick Doucette, BA, Kelly Herwig, BA, MS, Mycah Kimble, BA, Pat Ryan, MSW, LISW, MA, Jessica Schumacher, BA, Kelli Thumma, BA, and Elijah Waterman, BA (University of Iowa); and Norm Reynolds, MD .Ethics: Cheryl Erwin, JD, PhD, ; Eric A. Epping, MD, PhD and Janet Williams, PhD (University of Iowa); and Martha Nance, MD (University of Minnesota).IT/Management: Hans Johnson, PhD (Chair), R.J. Connell, BS, Paul Allen, AASC, Sudharshan Reddy Bommu, MS, Karen Pease, BS, Ben Rogers, BA, BSCS, Jim Smith, AS, Kent Williams, BSA, MCS, MS, Shuhua Wu, MCS, and Roland Zschiegner (University of Iowa).Program ManagementAdministrative: Chris Werling-Witkoske (Chair), Karla Anderson, BS, Kristine Bjork, BA, Ann Dudler, Jamy Schumacher, Sean Thompson, BA (University of Iowa).Financial: Steve Blanchard, MSHA (Co-Chair), Machelle Henneberry, and Kelsey Montross, BA (University of Iowa).Peg Nopoulos, MD, Robert Rodnitzky, MD, Ergun Uc, MD, BA, Leigh J. Beglinger, PhD, Vincent A. Magnotta, PhD, Stephen Cross, BA, Nicholas Doucette, BA, Andrew Juhl, BS, Jessica Schumacher, BA, Mycah Kimble, BA, Pat Ryan, MS, MA, Jessica Wood, MD, PhD, Eric A. Epping, MD, PhD, Thomas Wassink, MD, and Teri Thomsen, MD ;David Ames, MD, Edmond Chiu, MD, Phyllis Chua, MD, Olga Yastrubetskaya, PhD, Joy Preston, Anita Goh, D.Psych, and Angela Komiti, BS, MA ; Lynn Raymond, MD, PhD, Rachelle Dar Santos, BSc, Joji Decolongon, MSC, and David Weir, BSc ; Adam Rosenblatt, MD, Christopher A. Ross, MD, PhD, Barnett Shpritz, BS, MA, OD, and Claire Welsh ; William M. Mallonee, MD and Greg Suter, BA ; Ali Samii, MD, Hillary Lipe, ARNP, and Kurt Weaver, PhD ; Randi Jones, PhD, Cathy Wood-Siverio, MS, Stewart A. Factor, DO, and Claudia Testa, MD, PhD ; Roger A. Barker, BA, MBBS, MRCP, Sarah Mason, BSC, Anna Goodman, PhD, and Anna DiPietro ;Elizabeth McCusker, MD, Jane Griffith, RN, and Kylie Richardson, PhD ; Bernhard G. Landwehrmeyer, MD, Daniel Ecker, MD, Patrick Weydt, MD, Michael Orth MD, PhD, Sigurd S\u00fc\u03b2muth, MD, RN, Katrin Barth, RN, and Sonja Trautmann, RN ;Kimberly Quaid, PhD, Melissa Wesson, MS, and Joanne Wojcieszek, MD ;Mark Guttman, MD, Alanna Sheinberg, BA, Adam Singer, and Janice Stober, BA, BSW ; Susan Perlman, MD and Arik Johnson, PsyD ; Michael D. Geschwind, MD, PhD and Jon Gooblar, BA ;Tom Warner, MD, PhD, Stefan Kl\u00f6ppel, MD, Maggie Burrows, RN, BA, Marianne Novak, MD, Thomasin Andrews, MD, BSC, MRCP, Elisabeth Rosser, MBBS, FRCP, and Sarah Tabrizi, BSC, PhD ; Anne Rosser, MD, PhD, MRCP and Kathy Price, RN ; Amy Chesire, LCSW-R, MSG, Frederick Marshall, MD, and Mary Wodarski, BA ; Oksana Suchowersky, MD, FRCPC, Sarah Furtado, MD, PhD, FRCPC, and Mary Lou Klimek, RN, BN, MA ; Peter Panegyres, MB, BS, PhD, Carmela Connor, BP, MP, DP, and Elizabeth Vuletich, BSC ; Joel Perlmutter, MD and Stacey Barton, MSW, LCSW ; Sheila A. Simpson, MD, Daniela Rae, RN, and Zosia Miedzybrodzka, PhD ; David Craufurd, MD, Ruth Fullam, BSC, and Elizabeth Howard, MD Pietro Mazzoni, MD, PhD, Karen Marder, MD, MPH, Carol Moskowitz, MS, and Paula Wasserman, MA ; Diane Erickson, RN, Dawn Miracle, BS, MS, and Rajeev Kumar, MD ; Vicki Wheelock, MD, Terry Tempkin, RNC, MSN, Nicole Mans, BA, MS, and Kathleen Baynes, PhD ; Joseph Jankovic, MD, Christine Hunter, RN, CCRC, and William Ondo, MD ; Justo Garcia de Yebenes, MD, Monica Bascunana Garde, Marta Fatas, BA, and Jose Luis L\u00f3penz Sendon, MD ; Martha Nance, MD, Dawn Radtke, RN, and David Tupper, PhD ; Wayne Martin, MD, Pamela King, BScN, RN, and Satwinder Sran, BSC ; Anwar Ahmed, PhD, Stephen Rao, PhD, Christine Reece, BS, Janice Zimbelman, PhD, PT, Alexandra Bea, BA, and Emily Newman, BA ;"} +{"text": "Three authors were indicated as having the incorrect affiliations. These authors and their correct affiliations are as follows:Marta Rusmini: Laboratory of Molecular Genetics, IRCCS, Giannina Gaslini Istitute, Genoa, Italy, Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, ItalyIvana Matera: Laboratory of Molecular Genetics, IRCCS, Giannina Gaslini Istitute, Genoa, Italy, Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center, Rozzano, Milan, ItalyRoberto Ravazzolo: Laboratory of Molecular Genetics, IRCCS, Giannina Gaslini Istitute, Genoa, Italy, DINOGMI Department, University of Genova, Genova, Italy"} +{"text": "J. Appl. Cryst. (2013), 46, 1031\u20131037] are corrected.Errors in the paper by Kanaki, Jackson, Hall-Wilton, Piscitelli, Kirstein & Andersen are corrected.Errors in the paper by Kanaki, Jackson, Hall-Wilton, Piscitelli, Kirstein & Andersen [ The correct equation isIn equation (5) of Kanaki al. 2013, a factoet al. of Kanaki al. 2013, the bra"} +{"text": "There was an error in the published author order. The correct by line is:Ruth B. Lathi, Jamie A. M. Massie, Megan Loring, Zachary P. Demko, David Johnson, Styrmir Sigurjonsson, George Gemelos, Matthew Rabinowitz.The correct citation is:Lathi RB, Massie JAM, Loring M, Demko ZP, Johnson D, et al. (2012) Informatics Enhanced SNP Microarray Analysis of 30 Miscarriage Samples Compared to Routine Cytogenetics. PLoS ONE 7(3): e31282."} +{"text": "Kenneth N. Timmis (Editor-in-Chief), Environmental Microbiology Laboratory, Helmholtz Center for Infection Research, Inhoffenstrasse 7, D-38124Braunschweig, Germany. Tel.: +49 531 6181 4000; Fax: +49 531 6181 4199;kti@helmholtz-hzi.dee-mail: Juan L. Ramos, Estaci\u00f3n Experimental del Zaid\u00edn \u2013 CSIC, C/ Prof. Albareda, 1, E-18008 Granada, Spain.Tel.: +34 958 181 608; Fax: +34 958 135 740;jlramos@eez.csic.ese-mail: Willem M. de Vos, Laboratory of Microbiology, Wageningen University, Dreijenplein 10Building 316, 6703 HB Wageningen, The Netherlands.Tel.: +31 317 483 100; Fax: +31 317 483 829;willem.deVos@wur.nle-mail: Willy Verstraete, Laboratory of Microbial Ecology and Technology (LabMET), Ghent University, Coupure Links 653, B-9000 Ghent, Belgium. Tel.: +32 9264 5976;Fax: +32 9264 6248;willy.verstraete@ugent.bee-mail: Martin Rosenberg, Research & Development, Promega Corporation, 2800 Woods Hollow Road, Madison, WI 53711-5399, USA.martin.rosenberg@promega.come-mail: REVIEWS AND SPECIAL ISSUE EDITORJuan L. Ramos, Estaci\u00f3n Experimentaldel Zaid\u00edn, Granada, SpainWEB ALERTSLarry Wackett, University of Minnesota, St Paul, USALars Angenent, USASteven A. Banwart, UKShimshon Belkin, IsraelGiovanni Bertoni, ItalyIan Booth, UKUwe Bornscheuer, GermanyMichael Bott, GermanyHarald Brussow, SwitzerlandRita Colwell, USAMilton Costa, PortugalJiri Damborsky, Czech ReplublicCraig Daniels, CanadaEduardo Diaz, SpainGerrit Eggink, GermanyThomas Egli, SwitzerlandRomilio Espejo, ChileManuel Ferrer, SpainJulia Foght, CanadaJim K Fredrickson, USAMichael Galperin, USAJose Luis Garcia, SpainHarry Gilbert, UKBernardo Gonzalez, ChileGuido Grandi, ItalyMiguel G. Guerrero, SpainCarlos A. Guzman, GermanyKen Hammel, USABernhard Hauer, GermanyTerry C. Hazen, USAMichael Hecker, GermanyHermann J. Heipieper, GermanyMonica H\u00f6fte, BelgiumKarl-Erich Jaeger, GermanyDieter Jahn, GermanyJunichi Kato, JapanStaffan Kjelleberg, AustraliaTodd R. Klaenhammer, USAAlexander M. 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Siezen, The NetherlandsDouwe van Sinderen, IrelandHauke Smidt, The NetherlandsGloria Sober\u00f3n Ch\u00e1vez, M\u00e9xicoAlexander Steinb\u00fcchel, GermanyBas Teusink, The NetherlandsSvein Valla, NorwayErick Vandamme, BelgiumJos Vanderleyden, BelgiumL. A. M. van der Wielen, The NetherlandsRene H. Wijffels, The NetherlandsRoland Wohlgemuth, SwitzerlandThomas K. Wood, USAGary Woodnutt, USAMichail Yakimov, ItalyLiping Zhao, ChinaMicrobial Biotechnology publishes papers of original research reporting significant advances in any aspect of microbial applications, including, but not limited to biotechnologies related to:microbial communities: structure:function relationships and communal behaviorGreen chemistryPrimary metabolitesFood, beverages and supplementsSecondary metabolites and natural productsPharmaceuticalsDiagnosticsAgricultureBioenergyBiomining, including oil recovery and processingBioremediationBiopolymers, biomaterialsBionanotechnologyBiosurfactants and bioemulsifiersCompatible solutes and bioprotectantsBiosensors, monitoring systems, quantitative microbial risk assessmentTechnology developmentProtein engineeringFunctional genomicsMetabolic engineeringMetabolic designSystems analysis, modellingProcess engineeringBiologically-based analytical methodsMicrobially based strategies in public healthMicrobially based strategies to influence global processesOpen Access and Copyright. 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To the fullest extent permitted by law Wiley disclaims all liability for any loss or damage arising out of, or in connection with, the use of or inability to use the content."} +{"text": "Biol. 377 (2013) 305\u2013317]\u201cLack of a, Anton Crombacha, Karl Richard Wottona, Damjan Cicin-Saina, Svetlana Surkovab, Chea Lu Limc, Maria Samsonovab, Michael Akamc, Johannes Jaegera,c,*Hilde JanssensaEMBL/CRG Research Unit in Systems Biology, CRG\u2014Centre de Regulaci\u00f2 Gen\u00f2mica, and Universitat Pompeu Fabra (UPF), Dr. Aiguader 88, 08003 Barcelona, SpainbDepartment of Computational Biology, Center for Advanced Studies, St. Petersburg State Polytechnical University, 29 Polytehnicheskaya Street, St. Petersburg 195251, RussiacDepartment of Zoology, Downing Street, Cambridge CB23EJ, UKThe articles mentioned above were meant to be published back to back as companion papers in the same issue.*Corresponding authors.E-mail addresses: samson@spbcas.ru (M. Samsonova), yogi.jaeger@crg.eu, yoginho@gmail.com (J. Jaeger)."} +{"text": "AbstractMonema Walker, 1855 are recognized from China, in which Monema tanaognatha Wu & Pan sp. n. is described as new, Monema coralina Dudgeon, 1895 and Monema meyi Solovyev & Witt, 2009 are newly recorded for China. The female of Monema meyi is reported for the first time. Monema nigrans de Joannis, 1901 and Monema melli Hering, 1931 are synonymized with Monema flavescens Walker, 1855. Cnidocampa rubriceps Matsumura, 1931 is regarded here as a subspecies of Monema flavescens Walker, 1855. The photographs of moths and their genitalia are given. A key to the species of the genus is provided.Four species and one subspecies of the genus Monema was erected by Walker in 1855, based on the type species, Monema flavescens Walker, 1855.The genus PageBreakMonema flavescens Walker, 1855, Monema nigrans de Joannis, 1901, Monema coralina Dudgeon, 1895, Monema rubriceps , Monema melli Hering, 1931 and Monema meyi Solovyev & Witt, 2009 and it is distributed in Nepal, Bhutan, China, Far East of Russia, Korea, Japan, and northern Vietnam , Beijing, P. R. China. All types of new species are deposited in IZCASPhotographs of moths and their genitalia were captured using Canon-EOS-7D with the help of micro-lens. Standard methods of dissection and mounting in Euparal follow Walker, 1855http://species-id.net/wiki/MonemaMonemaMonema flavescens Walker, 1855: 1112, by monotypy. Walker, 1855: 1102,1112. Type species: CnidocampaMonema Walker, 1855, . Dyar, 1905: 952. An unnecessary replacement name for 3 + R4 stalked from R5 and R2 stalked with their stem. Hindwings with M1 and Rs stalked. Forewings with two narrow brown fasciae running from apex to 3/4 and 1/3 of inner margin respectively; basal part of forewing bordered by proximal fascia yellow, rest brown. Hind tibiae with two pairs of spurs.Moths medium-sized, body yellowish. Male antennae filiform and thicker than in female. Labial palpi extremely long, more than three times eye diameter. Forewings with RMale genitalia: tegumen narrow; uncus narrow and long, usually with short ventral process at apex; gnathos narrow and long, nearly as long as uncus; juxta with lateral elongate process or spines; valva elongate, with apically saccular process; saccus usually long and large, more than half of valva\u2019s width.PageBreakthe abdomen, base narrow and straight, apical part wider and spiraled; corpus bursae ovate, large; a pair of signa trigonal, bearing spines.Female genitalia: posterior apophysis long, anterior apophysis very short and less than the half length of posterior one; sclerotized exterior flap at posterior margin of ostium bearing minute hair; ductus bursae very long, more than the half length of Monema flavescens. Its final instar larvae are 19\u201325mm in length. Head yellowish brown. Thorax yellowish green. Dorsum with a large purple-brown spot shaped as a dumbbell. Subdorsal scoli on T2-A9 and lateral scoli on T2, T3 and A2-8 .The genus is related to Walker, 1855http://species-id.net/wiki/Monema_flavescensMonema flavescens Walker, 1855: 1112, fig. 1c. Type locality: North China. Miresa flavescens : Seitz, 1913: 344, fig. 50c. Cnidocampa flavescens : Cai, 1981: 99. Cnidocampa johanibergmani Bryk, 1948: 219. Monema melli Hering, 1931: 691, fig. 87i. Type locality: Guangdong, China. syn. n. Monema flavescensnigrans de Joannis, 1901: 251. var. Monema nigransWing expanse 30\u201332 mm in male, 35\u201339 mm in female. In male genitalia, the juxta is short and ends in 1-3 long spines each side. In female genitalia, the sclerotized base of ductus bursae is diagnostic.PageBreakHeilongjiang, Jilin, Liaoning, Inner Mongolia, Beijing, Hebei, Shandong, Henan, Shaanxi, Qinghai, Jiangsu, Shanghai, Zhejiang, Hubei, Jiangxi, Fujian, Taiwan, Guangdong, Guangxi; Russia (Far East), Korea, Japan.PageBreakMonema melli was described based on a single male from Guangdong, China. It differs from Monema flavescens by the smaller size and the shorter labial palpus. According to the male genitalia of the holotype examined and provided by Mr. Solovyev, it matches well with that of Monema flavescens. Thus we synonymize Monema melli with Monema flavescens. Monema flavescens var. nigrans as a full species. However, the black form (var. nigrans) and the normal form (flavescens) are from the same population and the var. nigrans do not show any differences in the male or female genitalia with flavescens. Therefore we treat Monema flavescens var. nigrans merely as a dark form. In Guiyang 2.75% of the population of flavescens belonged to the black form; the black individuals can interbreed with the non black individuals and produce fertile offspring (ffspring .(a)Walker, 1855http://species-id.net/wiki/Monema_flavescens_flavescensMonema flavescens Walker, 1855: 1112, fig. 1c rubriceps. Frons yellow to yellowish red.Wing expanse 25\u201339 mm. The aedeagus is 1.6 times as long as valva, shorter than that in ssp. PageBreakPageBreakzhou, 4\u201321 June 1976, Chen Ruijin (1\u26403\u2642); Zhejiang, Wenzhou, 1953, Liao Dingxi (1\u2642); Zhejiang, Zhoushan, 18 June 1936, O. Piel (1\u2642); Zhejiang, Tianmu shan, May-July 1936 (1\u26403\u2642), 29 July 1972, Wang Ziqing (4\u2642), 21 July 1973, Zhang Baolin ; Shaanxi, Zhouzhi, 1350m, 24 June 1999, Yao Jian Jiangxi, Lushan, 17\u201319 June 1974, Zhang Baolin (2\u2642) (gen. slide WU0146); Jiangxi, Guling, July 1935 ; Jiangxi, 27\u201328 May 1957, Yu Peiyu ; Shanghai, 11\u201326Aug.1932, O. Piel , 14 June- 20 July 1933, A. Savio (4\u2642); Shanghai, Botanical Park, June 1974 (1\u2640); Jiangsu, Yangzhou, 15 May 1926 (1\u2642), 20 June 1974 ; Jiangsu, Nanjing, 1\u201310 June 1957, Yu Peiyu (3\u2640) (gen. slide WU0183); Guangdong, Guangzhou, July 1931 (5\u2642); Guangdong, Guangzhou, Shipai, 17 Sept. 1958, Wang Linyao (1\u2642); Guangdong, Nanling, 21 July 2008, Chen Fuqiang Beijing, 3\u201331 May 1957, Yu Peiyu ; Beijing, Xishan, 1\u2642, Aug.1955; Beijing, Qinghe, 1\u2642, 13 Mar.1957 (1\u2642); Beijing, Tanzhesi, 15 Aug. 1951 (1\u2642); Beijing, Bada ling, 24 June 1957 (1\u2642); Beijing, Baihua shan, 4\u201316 July 1973, Liu Youqiao, Zhang Baolin ; Beijing, Sanbu, 25 July 1964, (5\u2642), 21 July 1972, Zhang Baolin (1\u2640); Hebei, Changli, 15 June-8 July 1972 (1\u26426\u2640), 21 June 1973 ; Henan, Songxian, Baiyun shan, 1400m, 18\u201320 July 2003, Qiu Reng (2\u2642); Henan, Huixian Baligou, 700m, 12\u201315 July 2002 (1\u2640); Henan, Neixiang Baotianman, 12 July 1998, Shen Xiaocheng (1\u2642). Black form: Shanghai Datong Route, 28 July 1980 ; Shanghai Botanical Park, June 1974, Tian Lixin (1\u2640) (gen. slide L06053); Shanghai, July 1935 (2\u2642); Jilin, Manjiang, 9\u201331 July 1955 .Heilongjiang, Dailing, 390m, 30 June-16 July 1962, Bai Jiuju (25\u2642), 4\u20139 July 1957 ; Heilongjiang, Yichun, 9 July 1956 (2\u2642), 6 Sept. 1956 (1\u2642); Heilongjiang, Wuchang, Shengli Linchang, 10 July 1970 (3\u2642); Heilongjiang, Harbin, 17 July\u201317 Aug. 1936 (2\u2640), 81 Aug. 1940; Heilongjiang, Hulin 852 Farm, 10 July 1962, Chen Tailu (1\u2642); Liaoning, Qingyuan, 29\u201330 July 1954 ; Liaoning, XInjin, 1954 (2\u2642); Jilin, Manjiang, 19 June\u201327 July 1955 (4\u264010\u2642); Jilin, Changbai Shan, 800m, 2\u201313 July 1982, Zhang Baolin ; Inner Mongolia, Ulanhot 15 July 1987 (1\u2642), 5 June 1957 ; Hunan,Yongshun Shanmuhe, 600m, 3 Aug. 1988, Chen Yixin ; Hunan, Andong, 20 May 1954 ; Hunan, Guzhang Gaowangjie, 850m, 29 July 1988, Chen Yixin ; Hunan, Hengshan, 22Aug. 1979 ; Fujian, Wuyishan, Sangang, 3 Aug. 1979, Song Shimei ; Fujian, Wuyishan, Tongmu, 26 July 1979, Song Shimei ; Fujian, Xiamen, 1\u2642, 25 June 1973, Zhang Baolin ; Hubei, Shennongjia, 950\u20131640m, 18\u201324 July 1980, Yu Peiyu ; Hubei, Jingzhou, July 1980 ; Hubei, Xingshan Longmen River, 1350m, 16 June\u201317 July 1993, Yao Jian ; Hubei, Zigui, Jiutouling, 100m, 12\u201313 June 1993, Yao Jian ; Hubei, Xuanen, Fengshuiling 1200\u20131240m, 29 July 1989, Yang Longlong, Li Wei ; Guangxi, Longsheng, 10\u201315 June 1980, Wang Linyao (4\u2642), 26 May 1963, Wang Chunguang ; Guangxi, Gualin Forestry Institute, 5 July 1981, Liang Xinqiang ; Guangxi, Qinzhou, 15 Apr. 1980, Cai Rongquan ; Guangxi, Jinxiu, 1100m, 10 May 1999, LI Wenzhu (1\u2642) (gen. slide WU0141); Zhejiang, Hangzhou, 1 Aug. 1973, Zhang Baolin (2\u2642); Zhejiang, HangMainland China; Russia (Far East), Korea, Japan.(b)stat. n.http://species-id.net/wiki/Monema_flavescens_rubricepsCnidocampa rubriceps Matsumura, 1931: 105. Type locality: Taiwan, China. Monema rubriceps (Matsumura): Hering, 1931: 691. Monema flavescens flavescens Walker by the red frons. The aedeagus about twice as long as valva, longer than that of ssp. flavescens.Wing expanse 30\u201332mm. It differs from Monema rubriceps (Matsumura) was provided by Dr. Solovyev.None. The image of the male genitalia of Taiwan.Cnidocampa rubriceps is treated here as a subspecies of Monema flavescens because the male genitalia have the same structure, except for the aedeagus that is longer in ssp. rubriceps than in ssp. flavescens.PageBreakWu & Pan,sp. n.urn:lsid:zoobank.org:act:AAF50A42-14EA-45E5-AAD3-0F2E027119A8http://species-id.net/wiki/Monema_tanaognathaWing expanse 28\u201333mm. Labial palpus yellowish brown, tip black. Face yellow to pale red. Head and thorax yellow. Abdomen yellowish brown. Ground colour of forewing yellow, with two dark concave fasciae from apex to 1/3 and 2/3 of inner margin, distal part of forewing, bordered by proximal fascia, brown. Hindwing yellow to yellowish brown.flavescens; aedeagus slightly longer than valva, narrow and straight.Male genitalia: tegumen narrow; uncus narrow and long, ventrally with short process on apex; gnathos narrow and very long; juxta U-shaped, each lateral bar with distal tuft of long spines; valva elongate, with a strong short apically saccular process; saccus long and relatively narrower than that of Female genitalia: posterior apophysis long, anterior apophysis very short; sclerotized exterior flap at posterior margin of ostium smaller, bearing minute hair; ductus bursae very long, basal half narrow and straight, apical half wider and spiraled; corpus bursae ovate, large; a pair of signa trigonal, bearing spines.Holotype: male, Kunming, Yunnan, 16 May 1980, Song Shimei (gen. slide WU0156). Paratypes: 1\u2640\u2642, same data as holotype (gen. slide WU0157); Xuanwei, Yunna, 1890m, 1\u2642, 25 June 1979 (gen. slide WU0152). Shaanxi, Fuping, 900\u2013950m, 23\u201324 July 1998, Yuan Decheng, Yao jian, Zhang Youwei ; Shaanxi, Liuba Miaotaizi, 1350m, 21 July 1998, Yao jian (1\u2642); Shaanxi, Taibai Huangbaiyuan, 1350m, 14 July 1980, Zhang Baolin ; Shaanxi, Ningshan Huoditang, 1580\u20131650m, 27 July 1998, Yao Jian ; Gansu, Wenxian Tielou, 1450m, 1999 July 24, Yao jian, Wang Hongjian, Zhu Chaodong ; Gansu, Kangxian, Qinghe linchang, 1400\u20132250m, 15 July 1998, Yao Jian (3\u2642), 7\u20139 July 1999, Yao jian ; Gansu, Kangxian, Baiyun shan, 1250\u20131750m, 12 July 1998, Yao Jian(3\u2642) (gen. slide WU0165); Gansu, Diechang, 1800m, 7 July 1998, Yao Jian ; Gansu, Zhouqu, Shantan Linchang, 2400m, 15 July 1999, Wang Hongjian ; Sichua, Emei shan, 800\u20131000m, 21 June-25 July 1957, Huang Keren, Zhu fuxing, Lu Youcai ; Sichua, Dujiang Yan, Qingcheng Shan, 700\u20131000m, 3\u20134 June 1979, Gao Ping, Shang Jinwen (2\u2642) ; Hubei, Lichuan, Xingdou Shan, 800m, 21\u201323 July 1989, Li Wei ; Guangxi, Miaoer shan, Jiuniuchang, 1150m, 7 July 1985, Fang Chenglai .Shaanxi, Gansu, Hubei, Guangxi, Sichuan, Yunnan.Monema flavescens, but is well distinguished by male genitalia: gnathos is narrowing and very long; juxta is long and ending in a tuft of long spines at each side. In female genitalia, base of ductus bursae of the new species is narrow and membranous, while that of Monema flavescens is sclerotized.The species is similar externally to PageBreakThe name is derived from Greek \u201cTanaos\u201d (=Long) and \u201cgnathos\u201d (Greek for jaw), corresponding to the long gnathos in the male genitalia.PageBreakSolovyev & Witt, 2009,new record to Chinahttp://species-id.net/wiki/Monema_meyiMonema meyi Solovyev & Witt, 2009: 108\u2013109. Type locality: Vietnam (ZMHB). Monema flavescens, but well discriminated by male genitalia: saccular process divided apically, juxta with lateral row of elongate spines, very broad saccus, S-shaped aedeagus with long and strong apical spur.Wing expanse 35-38 mm in male, 36-42 mm in female. The species is similar externally to Female genitalia: posterior apophysis long, anterior apophysis very short; sclerotized exterior flap at posterior margin of ostium large and elongate, bearing minute hair; ductus bursae very long, basal 1/3 narrow and straight, apical 2/3 wider and spiralled; corpus bursae ovate, large; a pair of signa trigonal, bearing spines.Hunan, Sangzhi, Baxixiang, 370m, 13 July 2009, Chen Fuqiang (1\u2640) (gen. slide WU0052); Guangdong, Chebaling ; Sichuan, Emei Shan, 800-1000m, 21 June-25 July 1957, Huang Keren, Zhu Fuxing, Lu Youcai ; Sichuan, 21-24 July 1974 ; Guizhou, Jiangkou, Fanjing Shan, 500m, 11 July 1988, Li Wei ; Fujian, Wuyishan, 14 June 1982, Zhang Baolin ; Jiangle, Longqi Shan, 18Aug. 1991, Song Shimei ; Hubei, Xuanen, Fengshuiling, 1200-1240m, 25 July 1989, Yang Longlong, Li Wei ; Hubei, Lichuan, Xingdou Shan, 800m, 21-31 July 1989, Li Wei ; Hubei, Hefeng, Fengshuiling, 1240m, 29 July 1989, Li Wei; Guangxi, Jinxiu, Shengtang Shan, 900m, 17 May 1999, Li Wenzhu ; Guangxi, Jinxiu Luoxiang, 200-400m, 15-16 May 1999, Han Hongxiang ; Guangxi, Shangsi Hongqi Linchang, 250m, 28 May 1999, Yuan Decheng (1\u2642); Dayu, 16 Aug. 1985, Wang Ziqing (1\u2640); Jiangxi, Deyu Neiliang, 23 Aug. 1985 ; Jiangxi, Yifengyuan, 2 June 1959 ; Hainan, Wuzhi Shan, 25 Apr. 1984, Gu Maobin ; Yunnan, Menghai, 1200m, 18 July 1958, Wang Shuyong ; Yunnan, Binchuan, Aug. 1959 ; Yunnan, Weixi, 2320m, 6 July 1979 .Hubei, Hunan, Fujian, Jiangxi, Guangdong, Hainan, Guangxi, Sichuan, Guizhou, Yunnan; Vietnam.Monema flavescens and Monema tanaognatha.This species, newly recorded in China, was described based on two males from Vietnam . This isPageBreakPageBreakDudgeon, 1895,new record to Chinahttp://species-id.net/wiki/Monema_coralinaMonema coralina Dudgeon, 1895: 290. Type locality: Bhutan. Wing expanse 30-35mm. The mostly reddish wings are diagnostic. In the male genitalia, the uncus lacks the ventrally apical process.PageBreakYunnan, Xinshuangbanna, 700m, 4-15 Apr. 1993, Yang Longlong ; Xizang, Motuo, 1080m, 22 July 2006, Chen Fuqiang (1\u2640).Yunnan (Xinshuangbanna), Xizang (Motuo); Nepal, Bhutan.The abdomen of the female from Xizang is missing. The species is reported for the first time in China."} +{"text": "The author list for the article Epidemiology of Cryptoccocus gattii, British Colombia, Canada, 1999\u20132007 was incomplete. Authors were Eleni Galanis, Laura MacDougall, Sarah Kidd, Mohammad Morshed, and the British Columbia Cryptococcus gattii Working Group. Working Group members\u00a0involved in this study were Patrick Doyle, John Galbraith, Linda Hoang, Pamela Kibsey, Min-Kuang Lee, Sultana Mithani, Marc Romney, and Diane Roscoe. The article has been corrected online"} +{"text": "APOBEC3G is a host defense factor that potently inhibits HIV replication. We hypothesize that HIV-infected children with a genetic variant of APOBEC3G will have a more rapid disease progression.Human Antiretroviral therapy (ART)-na\u00efve children, aged 1\u201312 years old with CD4 15-24% and without severe HIV-related symptoms were enrolled. The children had CD4% and absolute CD4 counts every 12 weeks and HIV-RNA every 24 weeks until 144 weeks. ART was started when CD4% declined to < 15% or AIDS-related events developed.APOBEC3G genetic variants were performed by PCR-based restriction fragment length polymorphism techniques from peripheral blood mononuclear cells. Random-effect linear regression analysis was performed to correlate APOBEC3G genotypes and disease progression.3 for CD4 count and 4.7 log10copies/mL for HIV-RNA.147 children, 35% male, with a median (IQR) age of 6.5 (4.3-8.8) years were enrolled. CDC N:A:B were 1:63:36%. Median baseline values were 20% for CD4% 605 cells/mmAPOBEC3G genotypes AA (186H/H), AG (186H/R), GG (186R/R) were 86%, 12%, and 2% respectively. The APOBEC3G genotype GG was associated with a significant decline in CD4% -5.1% (\u22128.9 to \u22121.2%), p<0.001, and CD4 counts \u2212226 (\u2212415 to \u221234) cells/mm3, p<0.001 by random-effect liner regression analysis. No significant associations of APOBEC3G genotypes with HIV-RNA changes overtime (p=0.16) or progression to CDC B and C (p=0.49) were observed.The frequencies of APOBEC3G genotype GG was significantly associated with a more rapid decline in CD4. APOBEC3G\u2019s antiviral effects on HIV disease progression in children should be further explored. APOBEC3G)[Association between the nfection. Howevernfection. There ipies/ml].APOBEC3G genotypes and the AIDS disease progression. A previous report in Argentinian HIV-infected children has also shown that there was no affect of APOBEC3G genotypes and AIDS onset[APOBEC3G genotype GG, thus, the association of APOBEC3G genotypes and sharp decline of CD4% may have occurred by chance. The interpretation of our findings should be cautious as failure to demonstrate a statistically significant difference between study groups at baseline. For example, different of baseline CDC classification ratio, and higher baseline CD4 cell counts of subtype GG group than the other two groups, although the baseline CD4% was similar, does not ensure that the groups are equivalent, particularly with the small sample size of the subtype GG that limits statistical power. Second, we could not see a correlation of APOBEC3G genotypes with the clinical patterns of long term non-progressors, becaThe strengths of our study are the large number of ART-na\u00efve vertically transmitted HIV-infected children with moderate immune deficiency in Asia enrolled with the long-term clinical data with 144-weeks of follow-up. Further studies should be evaluated for better understanding of APOBEC3G\u2019s antiviral effects on the disease progression in the HIV-infected children.APOBEC3G genotypes, H186 in GG, was significantly associated with decline in CD4% and the CD4 count over time in Thai and Cambodian ART-na\u00efve HIV-infected children with moderate immune deficiency.In conclusion, our data showed that a genetic variant of th International Workshop on HIV Pediatrics, 20 \u2013 21 July 2012, Washington DC, USA.This study was presented as poster presentation (poster number P_11) in 4This is a sub-study of the Pediatric Randomized Early versus Deferred Initiation in Cambodia and Thailand study .All authors declare no conflict of interest and that member of their immediate families do not have a financial interest in or arrangement with any commercial organization that may have a direct interest in the subject matter of this article.TB, MI, YI, and WS were involved in the study design, collection of data, and writing of the manuscript. KM, TP, JA, AM, and SV were involved in the study design and collection of data. TN was involved in the study design. PP was involved in the study design and writing of the manuscript. JS and TB\u2009analyzed the data and wrote\u2009the manuscript.\u2009TI collected the data and assisted in the writing of the manuscript. All authors reviewed the draft of the manuscript before submission. All authors have read and approved the final manuscript.CIP TH001:HIV Netherlands Australia Thailand (HIV-NAT) Research Collaboration, Thai Red Cross AIDS Research Center, Bangkok, Thailand; Dr.Kiat Ruxrungtham, Dr.Jintanat Ananworanich, Dr.Thanyawee Puthanakit, Dr.Chitsanu Pancharoen, Dr.Torsak Bunupuradah, Stephen Kerr, Theshinee Chuenyam,Sasiwimol Ubolyam, Apicha Mahanontharit,Tulathip Suwanlerk,Jintana Intasan,Thidarat Jupimai,Primwichaya Intakan, Tawan Hirunyanulux, Praneet Pinklow, Kanchana Pruksakaew,Oratai Butterworth, Nitiya Chomchey,Chulalak Sriheara,Anuntaya Uanithirat,Sunate Posyauattanakul,Thipsiri Prungsin,Pitch Boonrak,Waraporn Sakornjun, Tanakorn Apornpong,Jiratchaya Sophonphan,OrmrudeeRit-im,Nuchapong Noumtong,Noppong Hirunwadee,Dr.Chaiwat Ungsedhapand,Chowalit Phadungphon,Wanchai Thongsee,Orathai Chaiya,Augchara Suwannawat,Threepol Sattong,Niti Wongthai,Kesdao Nantapisan,Umpaporn Methanggool,Narumon Suebsri,Dr.Chris Duncombe,Taksin Panpuy,Chayapa Phasomsap,Boonjit Deeaium,Pattiya JootakarnCIP TH003:Bamrasnaradura Infectious Diseases Institute, Nonthaburi,Thailand; Dr.Jurai Wongsawat,Dr.Rujanee Sunthornkachit, Dr.Visal Moolasart,Dr.Natawan Siripongpreeda,Supeda Thongyen,Piyawadee Chathaisong,Vilaiwan Prommool, Duangmanee Suwannamass,Simakan Waradejwinyoo,Nareopak Boonyarittipat,Thaniya Chiewcharn,Sirirat Likanonsakul,Chatiya Athichathana, Boonchuay Eampokalap,Wattana Sanchiem.CIP TH004:Srinagarind Hospital,Khon Kaen University,Khon Kaen,Thailand; Dr.Pope Kosalaraksa,Dr.Pagakrong Lumbiganon, Dr.Chulapan Engchanil,Piangjit Tharnprisan,Chanasda Sopharak,Viraphong Lulitanond,Samrit Khahmahpahte,Ratthanant Kaewmart, Prajuab Chaimanee, Mathurot Sala, Thaniita Udompanit,Ratchadaporn Wisai,Somjai Rattanamanee, Yingrit Chantarasuk,Sompong Sarvok,Yotsombat Changtrakun,Soontorn Kunhasura, Sudthanom KamollertCIP TH005:Queen Savang Vadhana Memorial Hospital, Chonburi,Thailand; Dr. Wicharn Luesomboon, Dr.Pairuch Eiamapichart,Dr.Tanate Jadwattanakul,Isara Limpet-ngam,Daovadee Naraporn,Pornpen Mathajittiphun,Chatchadha Sirimaskul,Woranun Klaihong,Pipat Sittisak,Tippawan Wongwian, Kansiri Charoenthammachoke,Pornchai Yodpo.CIP TH007:Nakornping Hospital,ChiangMai,Thailand;Dr.Suparat Kanjanavanit, Dr.Maneerat Ananthanavanich, Dr.Penpak Sornchai,Thida Namwong,Duangrat Chutima,Suchitra Tangmankhongworakun,Pacharaporn Yingyong,Juree Kasinrerk, Montanee Raksasang,Pimporn Kongdong,Siripim Khampangkome, Suphanphilat Thong-Ngao,Sangwan Paengta,Kasinee Junsom, Ruttana KhuankaewM,Parichat Moolsombat,Duanpen Khuttiwung,Chanannat Chanrin.CIP TH009:Chiangrai Regional Hopsital, ChiangRai, Thailand; Dr.Rawiwan Hansudewechakul,Dr.Yaowalak Jariyapongpaiboon, Dr.Chulapong Chanta,Areerat Khonponoi, Chaniporn Yodsuwan, WaruneeSrisuk,Pojjavitt Ussawawuthipong,Yupawan Thaweesombat,Polawat Tongsuk,Chaiporn Kumluang,Ruengrit Jinasen,Noodchanee Maneerat,Kajorndej Surapanichadul, Pornpinit Donkaew.CIP TH010:National Pediatric Hospital,PhnomPenh,Cambodia;Dr.Saphonn Vonthanak, Dr. Ung Vibol,Dr.Sam Sophan,Dr.Pich Boren,Dr.Kea Chettra,Lim Phary,Toun Roeun, Tieng Sunly,Mom Chandara,Chuop Sokheng,Khin Sokoeun,Tuey Sotharin.CIP TH011:Social Health Clinic,Phnom Penh,Cambodia;Dr.Saphonn Vonthanak,Dr.Ung Vibol,Dr.Vannary Bun,Dr.Somanythd Chhay Meng,Dr.Kea Chettra,Sam Phan,Wuddhika In vong,Khuon Dyna.CIP TH012:PrapokklaoHospital,Chantaburi,Thailand;Dr.Chaiwat Ngampiyaskul,Dr.Naowarat Srisawat, Wanna Chamjamrat,Sayamol Wattanayothin,Pornphan Prasertphan,Tanyamon Wongcheeree, Pisut Greetanukroh,Chataporn Imubumroong, Pathanee Teirsonsern."} +{"text": "But what might these morphological differences represent, in terms of physiology, along distinct regions across rodent's S1? Septal and barrel regions are physiologically/functionally distinct (Alloway, In this context, a comprehensive work published by Nogueira-Campos et al. in FrontAlloway, since seAlloway, . In addiAlloway, . AccordiAlloway, , both reAlloway, . So, morIn conclusion, data provided by Nogueira-Campos et al. offer ne"} +{"text": "The Vietnamese authors' names are out of order. The correct byline is: Ho Dang Trung Nghia, Le Thi Phuong Tu, Marcel Wolbers, Cao Quang Thai, Nguyen Van Minh Hoang, Tran Vu Thieu Nga, Le Thi Phuong Thao, Nguyen Hoan Phu, Tran Thi Hong Chau, Dinh Xuan Sinh, To Song Diep, Hoang Thi Thanh Hang, Nguyen Van Vinh Chau, Nguyen Tran Chinh, Nguyen Van Dung, Ngo Thi Hoa, Brian G. Spratt, Tran Tinh Hien, Jeremy Farrar, Constance Schultsz."} +{"text": "The Editorial Board greatly acknowledges the advice of the reviewers. They made an important contribution to the quality of the journal.Anthony Artino, Sanneke Bolhuis, Joseph Donald Boudreau, Johan Bred\u00e9\u00e9, Jamiu Busari, Patrick Cras, Menno de Bree, Esther de Groot, Peter de Jong, Benedicte De Winter, Joke Denekens, Diana Dolmans, Jos Draaisma, Michiel Eijkman, Petri Embregts, Frans Grosfeld, Harianne Hegge, Frank Krings, Jan Kuks, Rashmi Kusurkar, Mario Maas, Willemina Molenaar, Arko Oderwald, Karlijn Overeem, Martien Quaak, Roy Remmen, Jan-Joost Rethans, George Richard, Clemens Rommers, Judith Rosmalen, Johanna Sch\u00f6nrock-Adema, Robert Schoevers, Philippe Schucht, Lambert Schuwirth, Veronica Selleger, Arjun Singh, Ren\u00e9e Stalmeijer, Paul Stuyt, Edith ter Braak, Rene Tio, Nynke van Dijk, Paul Van Royen, Tineke Westerveld, David Whitford, Indah Widyahening, Margreet Wieringa-de Waard and Raniai Zaini."} +{"text": "The authors regret that Ryan M. McCormack and Eckhard R. Podack shown above were inadvertently omitted from the author list.The correct author list is shown below including the authorship statement.Eden Kleiman, Daria Salyakina, Magali De Heusch, Kristen L. Hoek, Joan M. Llanes, Iris Castro, Jacqueline A. Wright, Emily S. Clark, Derek M. Dykxhoorn, Enrico Capobianco, Akiko Takeda, Ryan M.\u2009McCormack, Eckhard R. Podack, Jean-Christophe Renauld, and Wasif N. KhanThe original article has been updated.Eden Kleiman, Daria Salyakina, Kristen L. Hoek, and Wasif N. Khan designed research, performed experiments, analyzed data, and wrote the manuscript; Magali De Heusch, Joan M. Llanes, Iris Castro, Jacqueline A. Wright, Emily S. Clark, Derek M. Dykxhoorn, and Ryan M. McCormack performed and analyzed the experiments; Akiko Takeda, Jean-Christophe Renauld, and Enrico Capobianco provided the materials and discussed results, and Eckhard R. Podack discovered and named Perforin-2, and interpreted and discussed the results.The authors apologize for this mistake. The correction does not affect the scientific validity of the results.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Canakinumab (CAN), a selective, human, anti- interleukin-1\u03b2 monoclonal antibody, has been shown to be efficacious in the treatment of SJIA .To explore baseline demographics and clinical characteristics that are most predictive of response to CAN in CAN-na\u00efve SJIA patients during the initial 12 weeks of therapy.Data from 3 trials were pooled for this analysis. CAN-na\u00efve patients aged 2\u201319 years with active SJIA were enrolled and received sc CAN 4 mg/kg/month; Predictors of response at Days (D) 15, 29, 57 and 85 were explored using univariate and multivariate logistic regression analyses. The candidate predictors of CAN-response considered were: Age group, Gender, Prior NSAIDS (no/yes), Prior MTX(no/yes), Steroids , Number of Active Joints and Joints with Limitation of Motion , CRP at baseline and at D15. All candidate predictors with p<0.1 in univariate analyses were included in the multivariate analysis. *ACR response plus absence of fever.By week 2 there was substantial clinical benefit with 102 pts (57%) and 36 pts (20%) achieving aACR70 and ID, respectively; by week 12, 108 pts (61%) had aACR70 and 50 pts (28%) ID. The multivariate analysis indicated that normal CRP at D15 is the only predictor significant for ID at all time-points at Day 15, lower baseline steroid doses, low number of active joints, no prior anti-TNF or prior NSAID use are those most likely to achieve inactive disease up to 12 weeks.N. Ruperto Grant / Research Support from: To Gaslini Hospital: Abbott, Astrazeneca, BMS, Centocor Research & Development, Eli Lilly and Company, \"Francesco Angelini\", Glaxo Smith & Kline, Italfarmaco, Novartis, Pfizer Inc., Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals Inc., Speaker Bureau of: Astrazeneca, Bristol Myers and Squibb, Janssen Biologics B.V., Roche, Wyeth, Pfizer, H. Brunner Consultant for: Novartis, Genentech, Pfizer, UCB, AstraZeneca, Biogen, Boehringer-Ingelheim, Regeneron, Paid Instructor for: Novartis, Speaker Bureau of: Novartis, Genentech, I. Kone-Paut Grant / Research Support from: SOBI, Chugai, Consultant for: Pfizer, SOBI, Novartis, AbbVie, Cellgene, Chugai, B. Magnusson: None declared., S. Ozen Consultant for: Novartis (Turkey), Speaker Bureau of: Speaker\u2019s fee from SOBI, F. Sztajnbok Grant / Research Support from: Institutional grant (UERJ) for participating in the canakinumab trial., Speaker Bureau of: Novartis-Brasil, J. Anton Consultant for: Novartis, Speaker Bureau of: Novartis, J. Barash Grant / Research Support from: Investigator in the Canakinumab study sponsored by Novartis, F. Corona: None declared., K. Lheritier Shareholder of: Novartis, Employee of: Novartis Pharma AG, C. Gaillez Employee of: Novartis Pharma AG, A. Martini Grant / Research Support from: Bristol Myers and Squibb, Centocor Research & Development,Glaxo Smith & Kline, Novartis, Pfizer Inc, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, I declare that the Gaslini Hospital which is the public Hospital where I work as full time employee has received contributions to support the PRINTO research activities from the industries above mentioned. OLD: Francesco Angelini S.P.A., Janssen Biotech Inc, Abbott. , Consultant for: Bristol Myers and Squibb, Centocor Research & Development, Glaxo Smith & Kline, Novartis, Pfizer Inc, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, I declare that the Gaslini Hospital which is the public Hospital where I work as full time employee has received contributions to support the PRINTO research activities from the industries above mentioned. , Speaker Bureau of: Abbott, Bristol Myers Squibb, Astellas, Boehringer, Italfarmaco, MedImmune, Novartis, NovoNordisk, Pfizer, Sanofi, Roche, Servier, D. Lovell Grant / Research Support from: National Institutes of Health- NIAMS , Consultant for: Astra-Zeneca, Centocor, Amgen, Bristol Meyers Squibb, Abbott, Pfizer, Regeneron, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson & Johnson, Speaker Bureau of: Novartis, Roche."} +{"text": "AbstractPageBreakfrom late 1992 to the end of 2012. This data paper discusses both datasets together, as both have a similar methodology and structure. The inland waters dataset contains over 350,000 fish observations, sampled between 1992 and 2012 from over 2,000 locations in inland rivers, streams, canals, and enclosed waters in Flanders. The dataset includes 64 fish species, as well as a number of non-target species (mainly crustaceans). The estuarine waters dataset contains over 44,000 fish observations, sampled between 1995 and 2012 from almost 50 locations in the estuaries of the rivers Yser and Scheldt (\u201cZeeschelde\u201d), including two sampling sites in the Netherlands. The dataset includes 69 fish species and a number of non-target crustacean species. To foster broad and collaborative use, the data are dedicated to the public domain under a Creative Commons Zero waiver and reference the INBO norms for data use.The Research Institute for Nature and Forest (INBO) has been performing standardized fish stock assessments in Flanders, Belgium. This Flemish Fish Monitoring Network aims to assess fish populations in public waters at regular time intervals in both inland waters and estuaries. This monitoring was set up in support of the Water Framework Directive, the Habitat Directive, the Eel Regulation, the Red List of fishes, fish stock management, biodiversity research, and to assess the colonization and spreading of non-native fish species. The collected data are consolidated in the Fish Information System or VIS. From VIS, the occurrence data are now published at the INBO IPT as two datasets: \u2018VIS - Fishes in inland waters in Flanders, Belgium\u2019 and \u2018VIS - Fishes in estuarine waters in Flanders, Belgium\u2019. Together these datasets represent a complete overview of the distribution and abundance of fish species pertaining in Flanders The occurrence datasets are available at:VIS - Fishes in inland waters in Flanders, Belgiumhttp://dataset.inbo.be/vis-inland-occurrencesSource: http://www.gbif.org/dataset/823dc56e-f987-495c-98bf-43318719e30fGBIF: VIS - Fishes in estuarine waters in Flanders, Belgiumhttp://dataset.inbo.be/vis-estuarine-occurrencesSource: http://www.gbif.org/dataset/274a36be-0626-41c1-a757-3064e05811a4GBIF: http://vis.milieuinfo.be/publicaties/rapporten-afvissingenReports (only in Dutch) can be generated or downloaded from: PageBreaktion for Flemish Red Lists of fishes and lampreys , along with one Petromyzontida (Lampetraplaneri) and 7 crustaceans from the order Decapoda.The inland waters dataset contains 64 fish species reported from Flemish enclosed waters and watercourses, as well as a number of non-target species (mainly crustaceans). This dataset also includes a number of typical brackish water fish species which sometimes can be found in inland water sites in proximity to the sea and/or behind the sluice gates. The class of Actinopterygii is most represented (67 species), along with two Petromyzontida. All the crustaceans in this dataset are from the order of the Decapoda.The estuarine waters dataset contains 69 fish species found in the estuaries of the River Yser and the River Scheldt, as well as 9 non-target crustacean species. The class of In Figures Kingdom:AnimaliaClass:Actinopterygii, Orders:Mugiliformes, Osmeriformes, Atheriniformes, Clupeiformes, Gadiformes, Pleuronectiformes, Siluriformes, Salmoniformes, Scorpaeniformes, Esociformes, Anguilliformes, Gasterosteiformes, Perciformes, Cypriniformes, Families:Anguillidae, Atherinidae, Centrarchidae, Clariidae, Clupeidae, Cobitidae, PageBreakCottidae, Cyprinidae, Esocidae, Gadidae, Gasterosteidae, Gobiidae, Ictaluridae, Lotidae, Moronidae, Mugilidae, Nemacheilidae, Osmeridae, Percidae, Petromyzontidae, Pleuronectidae, Salmonidae, Scophthalmidae, Siluridae, Soleidae, UmbridaeClass:Petromyzontida, Order:Petromyzontiformes, Family:PetromyzontidaeClass:Malacostraca, Order:Decapoda, Families:Atyidae, Cambaridae, Palaemonidae, VarunidaePageBreakKingdom:AnimaliaClass:Actinopterygii, Orders:Acipenseriformes, Anguilliformes, Atheriniformes, Clupeiformes, Cypriniformes, Esociformes, Gadiformes, Gasterosteiformes, Mugiliformes, Osmeriformes, Perciformes, Pleuronectiformes, Salmoniformes, Scorpaeniformes, Siluriformes, Syngnathiformes, Families:Acipenseridae, Agonidae, Ammodytidae, Anguillidae, Atherinidae, Blenniidae, Callionymidae, Carangidae, Centrachidae, Clupeidae, Cottidae, Cyprinidae, Esocidae, Gadidae, Gasterosteidae, Gobiidae, Liparidae, Lotidae, Moronidae, Mugilidae, Mullidae, Osmeridae, Percidae, Pholidae, Pleuronectidae, Salmonidae, Scophthalmidae, Siluridae, Soleidae, Syngnathidae, Trachinidae, Triglidae, ZoarcidaeClass:Petromyzontida, Order:Petromyzontiformes, Family:PetromyzontidaeClass:Malacostraca, Order:Decapoda, Families:Cambaridae, Cancridae, Crangonidae, Paguridae, Palaemonidae, Polybiidae, Portunidae, VarunidaeFlanders is one of the three administrative regions in the country of Belgium, located in the centre of Western Europe Figure . The FleThe inland waters dataset comprises enclosed waters, including cut off river arms, gravel pits, ponds, natural lakes, and artificial lakes; and riverine habitats, including head streams, tributaries, and canals part of the drainage basins of the rivers Yser, Scheldt and Meuse Figure . These tPageBreakPageBreakThe estuarine waters dataset comprises the estuaries of the River Scheldt, including tidal parts of the rivers Rupel, Durme, Zenne, Dijle and Grote Nete, and the River Yser.River Scheldt. The River Scheldt is a 435 km long lowland river originating on the plateau of Saint-Quentin . The Darwin Core terms (http://rs.tdwg.org/dwc/terms/) in the dataset at the time of publication are:The data are standardized to Darwin Core with a coccurrenceID, type, language, rights, rightsholder, accessRights, datasetID, institutionCode, datasetName, ownerInstitutionCode, basisOfRecord, informationWithheld, recordedBy, individualCount, samplingProtocol, samplingEffort, eventDate, habitat, locationID, continent, waterBody, countryCode, verbatimLocality, verbatimLatitude, verbatimLongitude, verbatimCoordinateSystem, verbatimSRS, decimalLatitude, decimalLongitude, geodeticDatum, coordinateUncertaintyInMeters, identifiedBy, scientificName, kingdom, taxonRank, scientificNameAuthorship, vernacularName, and nomenclaturalCode.The data are dedicated to the public domain under Creative Commons Zero waiver. It would be much appreciated if you follow our norms for data use and notify the corresponding authors of the respective dataset if you use the data, especially for research purposes.PageBreakObject name: VIS - Fishes in inland waters in Flanders, BelgiumCharacter encoding: UTF-8Format name: Darwin Core Archive formatFormat version: 1.0Distribution:http://dataset.inbo.be/vis-inland-occurrencesPublication date of data: 2013-12-20Language: EnglishLicenses of use:http://creativecommons.org/publicdomain/zero/1.0/ & https://github.com/LifeWatchINBO/norms-for-data-useMetadata language: EnglishDate of metadata creation: 2013-12-20Hierarchy level: DatasetObject name: VIS - Fishes in estuarine waters in Flanders, BelgiumCharacter encoding: UTF-8Format name: Darwin Core Archive formatFormat version: 1.0Distribution:http://dataset.inbo.be/vis-estuarine-occurrencesPublication date of data: 2014-04-02Language: EnglishLicenses of use:http://creativecommons.org/publicdomain/zero/1.0/ & https://github.com/LifeWatchINBO/norms-for-data-useMetadata language: EnglishDate of metadata creation: 2014-04-02Hierarchy level: DatasetLength and weight measurement data of the individual fishes, absence information, occurrence data since 2013, as well as abiotic data of the sampling points are not included in the Darwin Core Archives and are available upon request.PageBreakOver 2,000 locations in estuaries, inland rivers, streams, canals, and enclosed waters in Flanders, Belgium have been sampled, from March to November, since 1992 Figure . In 2001The geographic coordinates in both datasets are those of the defined sampling locations (dwc:locationID). However, as these coordinates are not always exact the actual coordinates of the catch, which may be located further up- or downriver, the coordinate uncertainty (dwc:coordinateUncertaintyInMeters) has been set to 250 meter.In inland waters, standardized sampling methods were used as described in The default method used in estuarine waters is paired fyke netting, which has been intercalibrated by the North East Atlantic Calibration Group, but additional techniques such as anchor netting, seine netting, pound netting, electric fishing, and eel fyke netting were used as well . All fisPageBreakperiod between 1995 and 1998. During this period we collected the same species with both survey methods but the species richness per day per fyke net was generally higher than that obtained on the filter screens served ahttps://github.com/LifeWatchINBO/vis-inland-occurrences and https://github.com/LifeWatchINBO/vis-estuarine-occurrences respectively.Users of the data can comment on the inland waters and estuarine waters dataset at PageBreakVIS \u2013 Fish Information SystemPrincipal investigator: Hugo Verreycken, Jan Breine, Gerlinde Van ThuyneResource contact, resource creator, metadata provider, point of contact: Gerlinde Van Thuyne (Inland Waters), Jan Breine (Estuarine Waters)Content providers: Daniel Bombaerts, Jan Breine, Jean-Pierre Croonen, Adinda De Bruyn, Franky Dens, Marc De Wit, Linde Galle, Isabel Lambeens, Yves Maes, Gerlinde Van ThuyneDeveloper: Tom De BoeckProcessors: Dimitri Brosens, Peter DesmetFlemish governmentPageBreak"} +{"text": "There is an error in affiliation 2 for authors Xin Zhao, Chao Nie, and Jian Wang. Affiliation 2 should be: BGI-Shenzhen, Shenzhen, 518083, China."} +{"text": "Dear Reader,Sports Medicine - Open, the editors and production staff at SpringerOpen wish to reflect on a successful year\u2019s achievements and pay thanks to all those who have contributed their time and effort to establish this new journal.As we approach the end of 2015 and the completion of the first ever volume of Sports Medicine - Open will close with more than 20 original research articles, a dozen review articles (including systematic reviews), one particularly well-downloaded current opinion piece, and two editorials. And while we must offer our sincere thanks to all the authors who have contributed thus far, the quality of published articles is, similarly, testament to the significant efforts of the peer reviewers, whose commitment ensures that our content is held to the highest possible standard.We have been delighted by the way the sports science community has embraced the new journal and grateful for the number of high-quality submissions that the journal has received. The inaugural volume of Sports Medicine - Open, since the journal began receiving submissions in mid-2014:In addition to the members of our Honorary Editorial Board, we would like to thank the following individuals who have acted as reviewers for Roger Adams, AustraliaMaicon R. Albuquerque, BrazilRoy D. Altman, USAIsabel Andia, SpainSophie Attwood, UKFilippo Aucella, ItalyAstrid Balemans, the NetherlandsKristoffer Barfod, DenmarkMichelle Barrack, USAParveen Bawa, CanadaDaniel A. Boullosa, BrazilChristian Brinkmann, GermanyDiego Brunelli, BrazilRobert Buresh, USARobin Callister, AustraliaHelmi Chaab\u00e8ne, TunisiaKarim Chamari, QatarJean-Claude Chatard, FranceKong Y. Chen, USAHsiu-Ching Chiu, TaiwanDemetra D. Christou, USAHamdi Chtourou, TunisiaImogen Nicola Clark, AustraliaMike Climstein, AustraliaBrian J. Cole, USAMark Connick, AustraliaRicardo Costa, AustraliaAntonio Crisafulli, ItalyNicole C. Dabbs, USAAbdolhamid Daneshjoo, IranJ. Derek Kingsley, USABeat Knechtle, SwitzerlandKarsten Koehler, USAJan Konarski, PolandNikolaos E. Koyndoyrakis, GreeceMichael Lamont, New ZealandEmilio Landolfi, CanadaRobert Lansing, USASteen Larsen, DenmarkDavid Lavallee, UKHeather Leach, CanadaJill Leckey, AustraliaRoss K. Leighton, CanadaShannon Lennon-Edwards, USAXinning Li, USAHarry Lim, SingaporeAdriano E. Lima da Silva, BrazilAlexis Lion, LuxembourgGrant S. Lipman, USAFabio Lira, BrazilJeremy P. Loenneke, USAAlfredo M. Lurati, ItalyTheresa Mann, South AfricaFrank Marino, AustraliaMyosotis Massidda, ItalyJames P. McClung, USAJane McDevitt, USAMike McGuigan, New ZealandAntti Mero, FinlandKevin Miller, USAChris Mills, UKBartosz Molik, PolandNicholas Murray, USAKathy Myburgh, South AfricaAra Nazarian, USAMathieu N\u00e9d\u00e9lec, FranceJeanne F. Nichols, USASean Davies, USAPhilip Davis, UKBenedito S. Denadai, BrazilStefano D'Ottavio, ItalyWong Jyh Eiin, MalaysiaJennifer Etnier, USANir Eynon, AustraliaIrene Faber, the Netherlands\u00c9anna Falvey, IrelandR\u00f4mulo Fernandes, BrazilJared Fletcher, CanadaMaria Francesca, QatarTim Gabbett, AustraliaJarred Gillett, AustraliaPaul Glazier, UKUrs Granacher, GermanyTyson Grier, USAJordan Guenette, CanadaEsther Hartman, the NetherlandsKeith G. Hauret, USAJaime Hinzpeter, ChileMartin D. Hoffman, USAChun-Jung Huang, USAJasmin Hutchinson, USAXanne Janssen, UKYong-Seok Jee, Republic of KoreaUffe J\u00f8rgensen, DenmarkJeremy D. Joslin, USALiz Joy, USAJyrki Kettunen, FinlandDavid Nieman, USAOnni Niemel\u00e4, FinlandVincent Nougier, FranceMicha\u0142 Nowicki, PolandAri Nummela, FinlandMichael P. Nyberg, DenmarkRob M. Orr, AustraliaDebbie Palmer-Green, UKAndy Pasternak, USACharles Pedlar, UKJesper Petersen, DenmarkMaria Francesca Piacentini, ItalyPaul Pillitteri, USAFl\u00e1vio Pires, BrazilClaudia L. Reardon, USAE. Justy Reed, USAChris Rhea, USAWilliam O. Roberts, USAAlejandro Santos-Lozano, SpainDean K. Simonton, USASabrina Skorski, GermanyAndrew Springer, USACathy Starr, USALaura Stewart, USAThomas Swensen, USAJohn Temesi, CanadaMasaru Teramoto, USARobert Thiebaud, USAKevin Till, UKArgyris Toubekis, GreeceTinna Traustad\u00f3ttir, USAEdith Van Dyck, BelgiumGeert Verheyden, BelgiumMegan Wenner, USANancy Williams, USAJinliang Xing, ChinaJames Zois, AustraliaWe hope that you have found the articles published this year to be both interesting and informative, and we look forward to keeping you up to date with more sport and exercise science research in 2016.Sports Medicine - Open and everyone at SpringerOpen.With best wishes from the staff of"} +{"text": "Dr. Mary F. Lopez is incorrectly listed as an author on this article. The authors apologize for this error. The correct author list is as follows:Paul E. Oran, Olgica Trenchevska, Dobrin Nedelkov, Chad R. Borges, Matthew R. Schaab, Douglas S. Rehder, Jason W. Jarvis, Nisha D. Sherma, Luhui Shen, Bryan Krastins, Dawn C. Schwenke, Peter D. Reaven, Randall W. NelsonThe legends for Additionally, the following sentence should be added to the Acknowledgements section:\u201cThis work was supported in part with resources and of facilities at the Phoenix VA Health Care System. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.\u201dThe complete Acknowledgements read:\u201cWe would also like to express gratitude and acknowledge the following ACT NOW study investigators for their assistance with sample collection: Ralph A. DeFronzo, MD. MaryAnn Banerji, MD, FACP, George A. Bray, MD, Thomas A. Buchanan, MD, Stephen C. Clement, MD, Robert R. Henry, MD, Abbas E. Kitabchi, Ph.D., MD, FACP, FACE, Sunder Mudaliar, MD, Robert E. Ratner, MD, FACP, Frankie B. Stentz, MS, PhD, Nicolas Musi, MD. This work was supported in part with resources and of facilities at the Phoenix VA Health Care System. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.\u201d"} +{"text": "In the phase 3 TENDER trial of TCZ in patients with sJIA, decreases in neutrophil count were commonly observed.To determine if neutropenia was associated with increased risk of infection and to investigate variables associated with development of neutropenia in patients treated with TCZ for up to 2 years in TENDER.9/L; grade 2, \u22651.0 and <1.5 \u00d7 109/L; grade 3, \u22650.5 and <1.0 \u00d7 109/L; grade 4, <0.5 \u00d7 109/L) and lowest observed neutrophil count (109/L) were identified for each patient. Univariate linear regression analysis was performed to investigate association of patient characteristics with lowest observed neutrophil count. Rates of infections and serious infections (per 100 patient years [PY]) in periods \u00b1 15 days around grade1-2 neutropenia (22.9 PY) and around grade 3-4 neutropenia (5.5 PY) were compared to corresponding rates in periods with normal neutrophil count (173.6 PY).112 children with active, persistent sJIA were randomised 2:1 to receive TCZ by body weight (12 mg/kg <30kg or 8 mg/kg \u226530kg) or placebo IV every 2 weeks for 12 weeks and continued in an ongoing, TCZ open-label extension., No trend for association between neutropenia and increased risk of infections was observed in the TENDER trial. Background MTX, and somewhat younger age, was associated with increased risk for neutropenia, while TCZ exposure and concurrent GC use were not.F. De Benedetti Grant / Research Support from: Abbott, Pfizer, BMS, Roche, Novimmune, Novartis, SOBI, H. I. Brunner Consultant for: Novartis, Genentech, MedImmune, EMD Serono, AMS, Pfizer, UCB, Janssen, Speakers Bureau: Genentech, E. Baildam: None Declared, R. Burgos-Vargas Grant / Research Support from: Abbott, Consultant for: Abbott, BMS, Janssen, Pfizer, Roche, Speakers Bureau: Abbott, BMS, Janssen, Pfizer, Roche, G. Horneff Grant / Research Support from: Abbott, Pfizer, H. I. Huppertz Consultant for: Abbott, Chugai, Pfizer, Roche, Swedish Orphan, K. Minden Grant / Research Support from: Pfizer, Abbvie, Consultant for: Pfizer, Abbvie, Roche, Chugai, Medac, B. L. Myones: None Declared, K. Onel: None Declared, J. Wang Employee of: Roche, K. Bharucha Employee of: Genentech, D. Lovell Grant / Research Support from: NIH, Consultant for: AstraZeneca, Centocor, Janssen, Wyeth, Amgen, Bristol-Meyers Squibb, Abbott, Pfizer, Regeneron, Hoffmann-La Roche, Novartis, Genentech, Speakers Bureau: Roche, Genentech, A. Martini Grant / Research Support from: Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, MerckSerono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Consultant for: Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, MerckSerono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Speakers Bureau: Abbott, Boehringer, BMS, Novartis, Astellas, Italfarmaco, MedImmune, Pfizer, Roche, N. Ruperto Grant / Research Support from: Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, MerckSerono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Consultant for: Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, MerckSerono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Speakers Bureau: Abbott, Boehringer, BMS, Novartis, Astellas, Italfarmaco, MedImmune, Pfizer, Roche."} +{"text": "Unfortunately, the original version of this article containea, Weiwei Xub, Shravanthi R Gandrac, Galin V MichailovaTamara Schmida Amgen GmbH, Munich, Germanyb Pharmerit International, Rotterdam, The Netherlandsc Amgen Inc., Thousand Oaks, CA, USA"} +{"text": "AbstractAgromyzidae (Diptera) recorded from Finland is presented. 279 (or 280) species are currently known from the country. Phytomyzalinguae Lundqvist, 1947 is recorded as new to Finland.A checklist of the Agromyzidae are called the leaf-miner or leaf-mining flies and not without reason, although a substantial fraction of the species feed as larvae on other parts of living plants. While Agromyzidae is traditionally placed in the superfamily Opomyzoidea, its exact relationships with other acalyptrate Diptera are poorly understood Europe: 914 species Finland: 279\u2013280 speciesFaunistic knowledge level in Finland: averageBrachycera Macquart, 1834suborder Eremoneura Lameere, 1906clade Cyclorrhapha Brauer, 1863clade Schizophora Becher, 1882infraorder Muscaria Enderlein, 1936clade Acalyptratae Macquart, 1835parvorder Opomyzoidea Newman, 1834superfamily AGROMYZIDAE Fall\u00e9n, 1823AGROMYZINAE Fall\u00e9n, 1823AGROMYZA Fall\u00e9n, 1810Agromyzaabiens Zetterstedt, 1848Agromyzaalbipennis Meigen, 1830Agromyzaalbitarsis Meigen, 1830Agromyzaalnibetulae Hendel, 1931Agromyzaalnivora Spencer, 1969Agromyzaalunulata Agromyzaambigua Fall\u00e9n, 1823niveipennis Zetterstedt, 1848= Agromyzaanthracina Meigen, 1830freyi Hendel, 1931= Agromyzabicaudata Agromyzacinerascens Macquart, 1835PageBreakAgromyzademeijerei Hendel, 1920Agromyzaerythrocephala Hendel, 1920Agromyzaflaviceps Fall\u00e9n, 1823Agromyzagraminicola Hendel, 1931Agromyzaidaeiana Hardy, 1853potentillae = spiraeae Kaltenbach, 1867= stackelbergi = Agromyzaigniceps Hendel, 1920lathyri misid.= Agromyzalapponica Hendel, 1931Agromyzalucida Hendel, 1920Agromyzaluteitarsis intermittens misid.= Agromyzamarionae Griffiths, 1963alandensis Spencer, 1976= Agromyzamobilis Meigen, 1830Agromyzanana Meigen, 1830Agromyzanigrella Agromyzanigrescens Hendel, 1920Agromyzanigripes Meigen, 1830Agromyzanigrociliata Hendel, 1931Agromyzaorobi Hendel, 1920Agromyzaphragmitidis Hendel, 1922Agromyzapseudoreptans Nowakowski, 1967urticae Nowakowski, 1964 preocc.= Agromyzaquadriseta Zlobin, 2001Agromyzareptans Fall\u00e9n, 1823Agromyzarufipes Agromyzasalicina Hendel, 1922Agromyzasulfuriceps Strobl, 1898Agromyzavicifoliae Hering, 1932HEXOMYZA Enderlein, 1936Hexomyzaschineri Hexomyzasimplicoides MELANAGROMYZA Hendel, 1920Melanagromyzaaenea Melanagromyzaaeneoventris Melanagromyzaangeliciphaga Spencer, 1969Melanagromyzachaerophylli Spencer, 1969Melanagromyzalappae Melanagromyzanigrissima Spencer, 1976Melanagromyzaoligophaga Spender, 1990PageBreakMelanagromyzapubescens Hendel, 1923Melanagromyzasubmetallescens Spencer, 1966OPHIOMYIA Braschnikov, 1897Ophiomyiabeckeri goniaea = Ophiomyiacunctata Ophiomyiacurvipalpis Ophiomyiafennoniensis Spencer, 1976eucodonus Hering, 1960?= melandryi misid.= Ophiomyiaheringi Star\u00fd, 1930penicillata misid.= Ophiomyialabiatarum Hering, 1937persimilis misid.= Ophiomyialongilingua rostrata misid.= Ophiomyiamaura Ophiomyianasuta Ophiomyiaorbiculata hexachaeta = nostradamus = paracelsus = Ophiomyiapinguis Ophiomyiapulicaria Ophiomyiaranunculicaulis Hering, 1949Ophiomyiavitiosa Spencer, 1964alliariae Hering, 1954?= PHYTOMYZINAE Fall\u00e9n, 1823AMAUROMYZA Hendel, 1931Amauromyzasg. Hendel, 1931Amauromyzamorionella Cephalomyzasg. Hendel, 1931Trilobomyza Hendel, 1931= Amauromyzachenopodivora Spencer, 1971abnormalis misid.= Amauromyzaflavifrons Amauromyzagyrans Amauromyzakarli Dizygomyzafacialis Frey, 1941 nom. nudum= Amauromyzalabiatarum Amauromyzaluteiceps Amauromyzamonfalconensis AULAGROMYZA Enderlein, 1936PageBreakParaphytomyza Enderlein, 1936= Aulagromyzabuhri Aulagromyzafulvicornis Aulagromyzahendeliana Aulagromyzaheringii Aulagromyzalucens Aulagromyzaluteoscutellata xylostei misid.= Aulagromyzasimilis Aulagromyzatremulae (Hering 1957)Aulagromyzatridentata Aulagromyzatrivittata CALYCOMYZA Hendel, 1931Calycomyzaartemisiae Calycomyzasubapproximata CERODONTHA Rondani, 1861Butomomyzasg. Nowakowski, 1967Cerodonthacaricivora Cerodonthaeucaricis Nowakowski, 1967Cerodontharohdendorfi Nowakowski, 1967Cerodonthascirpi scutellaris misid.= semiposticata misid.= Cerodonthastaryi Cerodonthasg. Rondani, 1861Cerodonthaaffinis Cerodonthadenticornis Cerodonthafulvipes femoralis = Cerodonthahennigi Nowakowski, 1967lateralis preocc.= Cerodonthastackelbergi Nowakowski, 1972Dizygomyzasg. Hendel, 1920Cerodonthabimaculata Cerodonthafasciata Cerodonthaireos Cerodonthaluctuosa Cerodonthamorosa Icteromyzasg. Hendel, 1931Cerodonthabohemani Cerodonthacapitata Cerodonthachurchillensis Spencer, 1969Cerodonthageniculata PageBreakCerodonthalineella Phytagromyzasg. Hendel, 1920Cerodonthaflavocingulata storai = Poemyzasg. Hendel, 1931Cerodonthaatra Cerodonthacalamagrostidis Nowakowski, 1967spenceri Nowakowski, 1967= tschirnhausi Nowakowski, 1973= Cerodonthacalosoma Cerodonthaimbuta deschampsiae = Cerodonthaincisa Cerodonthalateralis Cerodonthamuscina Cerodonthaphragmitidis Nowakowski, 1967Cerodonthapygmaea Cerodonthapygmella lapplandica = Cerodonthaspencerae Zlobin, 1993inconspicua auct. nec = Cerodonthathunebergi Nowakowski, 1967Xenophytomyzasg. Frey, 1946Cerodonthaatronitens Cerodonthabiseta crassinervis = Cerodonthaventurii Nowakowski, 1967CHROMATOMYIA Hardy, 1849Chromatomyiaasteris Chromatomyiaciliata Chromatomyiafarfarella Chromatomyiafuscula Chromatomyiaglacialis Chromatomyiahorticola Chromatomyiaisicae Chromatomyialinnaeae Griffiths, 1974Chromatomyialonicerae xylostei preocc.= Chromatomyialuzulae Chromatomyiamilii Chromatomyianigra Chromatomyianorwegica Chromatomyiaochracea PageBreakChromatomyiaopacella Chromatomyiapericlymeni Chromatomyiaprimulae Chromatomyiaramosa nigriventris = Chromatomyiastyriaca Griffiths, 1980Chromatomyiasyngenesiae Hardy, 1849GALIOMYZA Spencer, 1981Galiomyzamorio LIRIOMYZA Mik, 1894Liriomyzaamoena Liriomyzaangulicornis triglochinae Hendel, 1931= Liriomyzaapproximata Liriomyzaartemisicola de Meijere, 1924Liriomyzabryoniae Liriomyzabuhri Hering, 1937adolescens Frey, 1946= Liriomyzabulbata Hendel, 1931Liriomyzacanescens Spencer, 1976graminicola misid.= Liriomyzacannabis Hendel, 1931Liriomyzacongesta minima Hendel, 1931= parva Hendel, 1931= Liriomyzademeijerei Hering, 1930Liriomyzaequiseti de Meijere, 1924Liriomyzaeupatorii orbitella Hendel, 1931= Liriomyzaflaveola Liriomyzaflavopicta Hendel, 1931Liriomyzafreyella Spencer, 1976Liriomyzahieracii Liriomyzainfuscata Hering, 1926Liriomyzalutea Liriomyzaoccipitalis Hendel, 1931Liriomyzaorbona Liriomyzapedestris Hendel, 1931Liriomyzapseudopygmina Liriomyzaptarmicae de Meijere, 1925Liriomyzapusilla fasciola = Liriomyzapusio PageBreakgraminicola de Meijere, 1924= breviseta Frey, 1946= Liriomyzarichteri Hering, 1927Liriomyzasonchi Hendel, 1931Liriomyzastrigata pumila = Liriomyzatanaceti de Meijere, 1924Liriomyzataraxaci Hering, 1927Liriomyzavalerianae Hendel, 1932Liriomyzavirgo Liriomyzavirgula Frey, 1946Liriomyzawachtlii Hendel, 1920METOPOMYZA Enderlein, 1936Metopomyzaflavonotata Metopomyzainterfrontalis xanthaspida = Metopomyzascutellata flavoscutellaris misid.= Metopomyzaxanthaspioides Metopomyzaxanthaspis NAPOMYZA Westwood, 1840Napomyzaachilleanella von Tschirnhaus, 1992Napomyzabellidis Griffiths, 1967Napomyzacarotae Spencer, 1966Napomyzacichorii Spencer, 1966Napomyzaelegans Napomyzahirticornis Napomyzalateralis Napomyzamaritima von Tschirnhaus, 1981Napomyzamerita Zlobin, 1993Napomyzaplumea Spencer, 1969NEMORIMYZA Frey, 1946Nemorimyzaposticata PHYTOBIA Lioy, 1864Dendromyza Hendel, 1931= Phytobiaaucupariae Phytobiacambii betulae = tremulae = Phytobiamallochi PHYTOLIRIOMYZA Hendel, 1931Phytoliriomyzaarctica Phytoliriomyzadorsata Liriomyzafasciata misid.= PageBreakpectoralis misid.= Phytoliriomyzahilarella Phytoliriomyzamelampyga Phytoliriomyzamikii Phytoliriomyzaornata elegantula = Phytoliriomyzaperpusilla PHYTOMYZA Fall\u00e9n, 1810Phytomyzaabdominalis Zetterstedt, 1848gentianae misid.= Phytomyzaaconitophila Hendel, 1927Phytomyzaactaeae Hendel, 1922Phytomyzaadjuncta Hering, 1928Phytomyzaalbiceps Meigen, 1830rydeniana Hering, 1949= Phytomyzaalbipennis Fall\u00e9n, 1823Phytomyzaanemones Hering, 1925Phytomyzaangelicae Kaltenbach, 1872Phytomyzaangelicastri Hering, 1932Phytomyzaaquilegiae Hardy, 1849Phytomyzaaquilonia Frey, 1946Phytomyzaartemisivora Spencer, 1971Phytomyzabuhriella Spencer, 1969Phytomyzacalthophila Hering, 1931Phytomyzacampanulae Hendel, 1920Phytomyzachaerophylli Kaltenbach, 1856anthrisci Hendel, 1924= carvi Hering, 1931= Phytomyzacirsii Hendel, 1923cirsicola Hendel, 1927= Phytomyzacontinua Hendel, 1920polyarthrocera Frey, 1946= Phytomyzacrassiseta Zetterstedt, 1860Phytomyzadasyops Hendel, 1920Phytomyzadiversicornis Hendel, 1927Phytomyzaenigmoides Hering, 1937enigma Hering, 1936 preocc.= Phytomyzaerigerophila Hering, 1927Phytomyzaeumorpha Frey, 1946Phytomyzaevanescens Hendel, 1920calthivora misid.= opaca misid.= Phytomyzafallaciosa Brischke, 1880pseudohellebori Hendel, 1920= PageBreakbonsdorfi Hendel, 1935= Phytomyzaflavicornis Fall\u00e9n, 1823Phytomyzaflavofemorata Strobl, 1893distantipila Frey, 1950= aristata misid.= pratensis de Meijere, 1926= Phytomyzaglabra Hendel, 1935Phytomyzaglechomae Kaltenbach, 1862Phytomyzagymnostoma Loew, 1858? Phytomyzahellebori Kaltenbach, 1872Phytomyzahendeli Hering, 1923Phytomyzaheracleana Hering, 1937Phytomyzahirsuta Spencer, 1976Phytomyzaisais Hering, 1936Phytomyzakrygeri Hering, 1949Phytomyzalappae Goureau, 1851Phytomyzalinguae Lundqvist, 1947Phytomyzamarginella Fall\u00e9n, 1823Phytomyzaminuscula Goureau, 1851Phytomyzamurina Hendel, 1935Phytomyzamylini Hering, 1954Phytomyzanigrifemur Hering, 1934semitenella Hendel, 1935= Phytomyzanigripennis Fall\u00e9n, 1823Phytomyzanigritula Zetterstedt, 1838Phytomyzanotata Meigen, 1830Phytomyzaobscurella Fall\u00e9n, 1823Phytomyzapauliloewii Hendel, 1920Phytomyzapimpinellae Hendel, 1924Phytomyzaplantaginis Robineau-Desvoidy, 1851Phytomyzaptarmicae Hering, 1937Phytomyzapubicornis Hendel, 1920Phytomyzapullula Zetterstedt, 1848Phytomyzaranunculi Phytomyzaranunculivora Hering, 1932Phytomyzarapunculi Hendel, 1927campanulivora Spencer, 1971= Phytomyzarhabdophora Griffiths, 1964Phytomyzarostrata Hering, 1934Phytomyzarufescens von Roser, 1840Phytomyzarufipes Meigen, 1830Phytomyzarydeni Hering, 1934Phytomyzasedicola Hering, 1924PageBreakPhytomyzaselini Hering, 1922Phytomyzasocia Brischke, 1880Phytomyzasoenderupi Hering, 1941Phytomyzasolidaginis Hendel, 1920Phytomyzaspinaciae Hendel, 1935affinis misid.= Phytomyzaspoliata Strobl, 1906Phytomyzaspondylii Robineau-Desvoidy, 1851pastinacae misid.= Phytomyzasubrostrata Frey, 1946Phytomyzatanaceti Hendel, 1923Phytomyzatenella Meigen, 1830Phytomyzathysselini Hendel, 1923Phytomyzatrollii Hering, 1930Phytomyzatussilaginis Hendel, 1925Phytomyzavaripes Macquart, 1835Phytomyzavirgaureae Hering, 1926Phytomyzavirosae Pakalni\u0161kis, 2000Phytomyzawahlgreni Ryd\u00e9n, 1944robustella misid.= PSEUDONAPOMYZA Hendel, 1920Pseudonapomyzaatra Pseudonapomyzaeuropaea Spencer, 1973SELACHOPS Wahlberg, 1844Selachopsflavocinctus Wahlberg, 1844Cerodonthasilvatica misidentificationDizygomyzafacialis Frey, 1941 nomen nudumLiriomyzahuidobrensis importedLiriomyzasativae Blanchard, 1938 importedLiriomyzatrifolii importedPhytomyzaatricornis Meigen, 1838 nomen dubiumPhytomyzabrischkei Hendel, 1922 misidentificationAgromyzanigrociliata. First recorded from Finland by Thuneberg in PageBreakCerodonthapygmella. First described from the Russian Far East, then redescribed from northern Sweden as Cerodonthalapplandica (Ryd\u00e9n) Phytomyzaangelicae and Phytomyzaaegopodii. Phytomyzaaegopodii Hendel, 1923 with Phytomyzaangelicae Kaltenbach. Phytomyzaaegopodii as a valid species but opinions on its status are not unanimous. The Finnish material examined so far represents typical PhytomyzaangelicaesensuPhytomyzabrischkei. Recorded by Phytomyzagymnostoma. Recorded from Finland in Fauna Europaea (Allium), its host plants. Phytomyzagymnostoma is an expanding species with Central Europe and has lately damaged crops of Allium species (Europaea , but I h species .Phytomyzalinguae. Phytomyzaranunculivora Hering. Phytomyzaranunculivora from Ranunculusacer and Phytomyzalinguae from Ranunculuslingua from mines collected from Vehkalahti in 1972\u20133."} +{"text": "Authors Michael Milyavsky and Lisa Wiesm\u00fcller shared corresponding authorship of this paper. It is corrected as follows:Corrected correspondence information:Michael Milyavsky: Department of Pathology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, IsraelCorrespondence: Michael Milyavsky, mmilyavsky@post.tau.ac.ilLisa Wiesm\u00fcller: Division of Gynecological Oncology, Department of Obstetrics and Gynecology, Ulm University, Ulm, GermanyCorrespondence: Lisa Wiesm\u00fcller, lisa.wiesmueller@uni-ulm.de"} +{"text": "AbstractCnidaria: Hexacorallia: Zoantharia). In order to provide a basis for future research on the Indo-Pacific zoantharian fauna and facilitate comparisons between more well-studied regions such as Japan and the Great Barrier Reef, this report deals with CIP zoantharian specimens in the Naturalis collection in Leiden, the Netherlands; 106 specimens were placed into 24 morpho-species and were supplemented with 88 in situ photographic records from Indonesia, the Philippines, and Papua New Guinea. At least nine morpho-species are likely to be undescribed species, indicating that the region needs more research in order to properly understand zoantharian diversity within the CIP. The Naturalis\u2019 zoantharian specimens are listed by species, as well as all relevant collection information, and in situ images are provided to aid in future studies on zoantharians in the CIP.Despite the Central Indo-Pacific (CIP) and the Indonesian Archipelago being a well-known region of coral reef biodiversity, particularly in the \u2018Coral Triangle\u2019, little published information is available on its zoantharians ( Cnidaria: Anthozoa: Hexacorallia: Zoantharia) are a common component of benthos in subtropical and tropical coral reef systems, with many zooxanthellate species found in shallow waters of both the Atlantic and Indo-Pacific Oceans. Nevertheless, common understanding of zoantharian species diversity is relatively poor when compared to the hard corals (Scleractinia). This lack of knowledge is due to a variety of reasons, including (1) high levels of intraspecific morphological variation hindering reliable identification profication , and (3)fication .Despite these problems, an understanding of zoantharian diversity and their corresponding taxonomy have slowly become clearer as molecular techniques have been implemented into zoantharian research. The first molecular works of Burnett and co-workers , 1997 coScleractinia . Finally, we discuss the shallow water zoantharian diversity of CIP in relation to information from surrounding regions, and make recommendations for future zoantharian research in the region.The present study addresses this lack of Central Indo-Pacific (CIP) zoantharian data via examinations of specimen collections housed in Naturalis Biodiversity Center, Leiden, the Netherlands: RMNH (the former Rijksmuseum van Natuurlijke Historie) and ZMA (the former Zoologisch Museum van Amsterdam). These zoantharian collections are partly based on specimens from numerous surveys in Indonesia dating from the Snellius Expedition (1929\u20131930) to a recent Marine Biodiversity Workshop in Lembeh Strait (2012), with the large majority of these specimens collected from coral reef environments. Despite the presence of these large and scientifically valuable collections, no previous effort has been made to comprehensively catalogue or examine these historical collections for over 80 years, which could also serve as base-line material for studies on biotic change . Here, fZoantharian specimens from the Naturalis collections in Leiden (RMNH + ZMA) were collected primarily from expeditions to the Indonesia region, starting with the Snellius Expedition 1929\u20131930). Our examinations showed 22 regions in which either specimens or photographic records were present. All specimen/record localities are shown in Figure 929\u20131930.Regions :West Sumatra, Indonesia. Fieldwork by B.W. Hoeksema in collaboration with Dr. A. Kunzmann, Bung Hatta University, Padang, West Sumatra, in 1996\u20131997.Southwest Java, Indonesia. Collections from Teluk Pelabuhan Ratu by Dr. P.H. van Doesburg, RMNH, in 1977.northwest Java, Indonesia. Expedition organized by the Research Center for Oceanography (RCO\u2013LIPI) and Naturalis in 2005 , Indonesia. Fieldwork by B.W. Hoeksema in collaboration with K.S. Putra of WWF in 1997 and 1998 , Flores Sea, Indonesia. Indonesian \u2013 Dutch Snellius\u2013II Expedition in 1984 ( in 1984 .Tukang Besi Islands (Wakatobi), Southeast Sulawesi, Indonesia. Indonesian \u2013 Dutch Snellius\u2013II Expedition in 1984 : Ternate Expedition in 2009, involving reefs on volcanic slopes and reefs around sand-cays and Naturalis in 1994. Marine Biodiversity Workshop North Sulawesi organized by Research Center for Oceanography (RCO\u2013LIPI), Universitas Sam Ratulang and Naturalis in 2012.PageBreakBunaken, North Sulawesi, Indonesia. Fieldwork by B.W. Hoeksema in collaboration with Universitas Sam Ratulang, Manado, in 1994 and 1998.Berau Islands, East Kalimantan, Indonesia. East Kalimantan Program in 2003 and unregistered zoantharian specimens (n=570) of the Naturalis collection showed that of a total 622 specimens, 105 were from Indonesia, with an additional four from the Philippines. Of these 109 specimens, 106 form the basis of this research, as we excluded three specimens that could not be conclusively identified as zoantharians. 88 photographic records of zoantharians specimens were also examined.Epizoanthusilloricatus Tischbierek, 1930 specimens, as although some specimens were from >40 m (and down to 190 m), the range of this species does extend into shallower (<40 m) depths. Additionally, three specimens of Parazoanthus collected by rectangular dredge from depths of 50\u2013100 m were included in analyses. In this study, these 106 zoantharian specimens are collectively referred to as \u201cshallow-water zoantharians\u201d.Although most species are from depths in the range of SCUBA (<40 m), we also included all All unregistered specimens were newly registered into the Naturalis collection in the course of our research. All specimens, newly registered or not, were re-identified by the first author. A list of specimens, their collection information, and Naturalis (RMNH Coel) registration numbers are given within each species\u2019 section. Descriptions of each species are given to aid in field and specimen identification, and are not formal taxonomic redescriptions.Palythoaheliodiscus), very few records of zoantharians had previously been formally reported from the CIP/Coral Triangle region. Given these reasons, we followed recent research . However, many specimens were only identified to \u201cconfers with\u201d (cf.) or \u201caffinity\u201d (aff.) levels. Asides from a few species .PageBreakwere taken by B.W. Hoeksema unless otherwise noted. Duplicate photographic images of the same species from the same site are counted as one record. Latitude and longitude are given when available.From specimen examination, the 106 Indonesian zoantharian specimens in the Naturalis collection supplemented with images were placed into 24 morphospecies, detailed below. Locations are in Indonesia unless otherwise noted, and all photographic images Abbreviations: NA=not available.Taxon classificationAnimaliaZoanthariaZoanthidae1.Saville\u2013Kent, 189305\u00b007'S, 119\u00b020'E), depth = NA, collected May 31, 1994 by J.C. den Hartog; RMNH Coel 23411, west of Gusung (=Lae\u2013Lae Keke) (=1 km northwest of Makassar), Spermonde Archipelago, South Sulawesi , depth = NA, collected May 31, 1994 by J.C. den Hartog; RMNH Coel 24100, station MAL04, south coast northeast of Cape Hahurong, Ambon, Moluccas , depth = 2 to 28 m, collected June 6, 1996 by J.C. den Hartog; RMNH Coel 40361, NNM\u2013LIPI\u2013WWF Expedition station BAL.16, southeast side of Pulau Serangan, Bali , depth = to 10 m, collected April 6, 2001 by J. Goud; RMNH Coel 40549, Snellius\u2013II Expedition station 4.011, reef edge west of Mai, Maisel Islands, Banda Sea , depth = 1 to 30 m, collected September 7, 1984; RMNH Coel 40550, Snellius\u2013II Expedition station 4.001, near Tawiri, Ambon Bay, Moluccas , depth = approx. 1.5 to 8 m, collected September 4, 1984; RMNH Coel 40554, Snellius\u2013II Expedition station 4.006, near Eri, Ambon Bay, Moluccas , depth = approx. 1.5 to 5 m, collected September 4, 1984; RMNH Coel 40556, Snellius\u2013II Expedition station 4.006, near Eri, Ambon Bay, Moluccas , depth = approx. 1.5 to 5 m, collected August 29, 1984; RMNH Coel 40558, Snellius\u2013II Expedition station 4.030, west coast of Binongko, Tukang Besi Islands, Banda Sea , depth = approx. 3 to 4 m, collected September 10, 1984 by M. Slierings; RMNH Coel 40566, west side of Pulau Samalona, 7.5 km west of Makassar, Spermonde Archipelago, South Sulawesi , depth = NA, collected February 18, 1994 by B.W. Hoeksema; RMNH Coel 40569, Fauna Malesiana Marine Sulawesi Expedition station SUL.06, Pantai Parigi, Pulau Lembeh, Selat Lembeh, North Sulawesi , depth = 0 to 6 m, collected October 15, 1994 by M. Slierings.(n=16). RMNH Coel 23405, Tg. Bengteng , Ambon, Moluccas, depth = 3 to 4 m, collected November 10, 1990 by J.C. den Hartog; RMNH Coel 23406, outer bay, Ruhmatiga, Hitu, Ambon, Moluccas, depth = approx. 3 m, collected December 3, 1990 by J.C. den Hartog; RMNH Coel 23407, station 17, southeast side of Pombo Island, Ambon, Moluccas, depth = 6 m, collected November 17, 1994 by J.C. den Hartog; RMNH Coel 23408, west-northwest of Barrang Lompo, Spermonde Archipelago, South Sulawesi, depth = 1.5 to 4 m, collected December 23, 1994 by J.C. den Hartog; RMNH Coel 23409, entrance of harbor near light beacon, northwest of Gusung, Spermonde Archipelago, South Sulawesi, depth = 5 to 7 m, collected October 7, 1990 by J.C. den Hartog; RMNH Coel 23410, 7.5 km west of Makassar, Spermonde Archipelago, South Sulawesi , South Sulawesi, May 24, 1997; station MAL.19 , Tanjune Batu Dua, east of Hatu, north coast of Ambon Bay, Moluccas, November 19, 1996; station MAL.22 , southwest coast, east of Tunjung Nusanive, Ambon Bay, Moluccas, November 21, 1996; Nusa Penida, Lombok Strait, east Bali, May 26, 1998 ; northwest Pulau Samalona, Spermonde Archipelago, South Sulawesi , January 12, 1997; western slope of Bone Lola shoal, Spermonde Archipelago, South Sulawesi , April 22, 1998.(n=6). West side of Pulau Lae\u2013Lae . RMNH Coel 40476, Rumphius Biohistorical Expedition station 27, Leitimur, south coast, Hutumuri, Ambon, Moluccas, depth = intertidal, collected November 26, 1990 by M.S.S. Lavaleye.01\u00b044'S, 99\u00b015'E), December 15, 1996; east Menjangan Island, West Bali , May 21, 1998; west Pulau Lumu Lumu, Spermonde Archipelago, South Sulawesi , October 8, 1997; west Pulau Kudingareng Keke, Spermonde Archipelago, South Sulawesi , May 29, 1997; northwest Pulau Barang Lompo, Spermonde Archipelago, South Sulawesi , July 21, 1998; south Pulau Samalona, Spermonde Archipelago, South Sulawesi , October 27, 1997; west Pulau Lae Lae Besar, Spermonde Archipelago, South Sulawesi , November 12, 1997; northwest Pulau Lae Lae Keke, Spermonde Archipelago, South Sulawesi , October 11, 1997; Station BER.26, northeast Buliulin (south of Samama Island), Berau Islands, East Kalimantan, , October 15, 2003.(n=9). Southeast Siberut, West Sumatra . with polyps well clear and free of the coenenchyme (\u201cliberae\u201d) (Can form colonies of up to 1 miberae\u201d) . Adult piberae\u201d) (Reimer iberae\u201d) , 2006a (iberae\u201d) .Regions recorded in this study , Singapore , which has been reported to be a senior synonym of Zoanthusjukesii Haddon & Shackleton, 1891b, Zoanthusmacgillivrayi Haddon & Shackleton, 1891b, Zoanthusannae Carlgren, 1937, Zoanthusmantoni Carlgren, 1937, Zoanthusfraseri Carlgren, 1937, all described from the Great Barrier Reef based on nematocyst data , depth to 5 m, collected by L. P. van Ofwegen and M. Slierings on March 31, 2001; RMNH Coel 40457, piers of harbor, Cebu City, Cebu, Philippines by M. L. Esmeno in 1976 ; RMNH Coel 40516, Snellius\u2013II Expedition station 27, west side of Bone Tambung, South Sulawesi , depth = 1 m, collected October 23, 1980 by H. Moll; RMNH Coel 40537, Snellius\u2013II Expedition station 4.139, reef flat edge south of Tarupa Kecil, northeast Taka Bone Rate , depth = 30 m, collected September 25, 1984; RMNH Coel 40539, Snellius\u2013II Expedition station 4.011, reef edge west of Mai, Maisel Islands, Banda Sea , depth 1 to 30 m, collected September 7, 1984; RMNH Coel 40542, Snellius\u2013II Expedition station 4.084, Selat Linta, east of Komodo I. , depth = approx. 3 m, collected September 18, 1984; RMNH Coel 40551, Snellius\u2013II Expedition station 4.079, Selat Linta, east of Komodo I. , collected September 10, 1984; RMNH Coel 40560, Snellius\u2013II Expedition station 4.096, northeast cape of Komodo I. , from \u201cshallow water\u201d, collected September 20, 1984; RMNH Coel 40564, Fauna Malesiana Marine Sulawesi Expedition station SUL.08, channels between lava outflows, south of Tanjung Batuangus, Selat Lembeh, North Sulawesi , depth 5 to 10 m, collected by M. Slierings on October 16 or 25, 1994; RMNH Coel 40565, Fauna Malesiana Marine Sulawesi Expedition station SUL.08, channels between lava outflows, south of Tanjung Batuangus, Selat Lembeh, North Sulawesi , depth to 10 m, collected on October 16 or 25, 1994.(n=10). RMNH Coel 40360, NNM\u2013LIPI\u2013WWF Expedition station BAL.03, south of tidal channel, Palung Semawang, off Kesumasari Beach, Sanur, Bali , September 16, 1997; west side of Pulau Samalona, Spermonde Archipelago, South Sulawesi , September 16, 1997; west of Gusung (=Pulau Lae\u2013Lae Keke), Spermonde Archipelago, South Sulawesi , October 11, 1997.(n=3). West side of Pulau Lae\u2013Lae, Spermonde Archipelago, South Sulawesi (Zoanthus spp. specimens that could not be identified to species level (n=10). Almost all of these specimens are \u2018liberae\u2019 or \u2018intermediae\u2019, with polyps rising out from the coenenchyme and many described Zoanthus spp. present no readily diagnostic external characters, identification to species level is not potentially possible without detailed molecular examination. Attempts at molecular identification also failed for these (and most other specimens), perhaps due to initial preservation in 10% seawater formalin for older specimens, or in ethanol with additives for newer specimens.This designation simply consists of all PageBreakTaxon classificationAnimaliaZoanthariaZoanthidae4.Gray, 182803\u00b041'50\"S, 128\u00b017'00\"E), intertidal under stones, collected on November 27, 1990 by J.C. den Hartog; RMNH Coel 40473, Rumphius Biohistorical Expedition station 27, Leitimur, south coast, Hutumuri, Ambon Bay, Moluccas , intertidal under stones, collected on November 27, 1990 by J.C. den Hartog; RMNH Coel 40567, Fauna Malesiana Marine Sulawesi Expedition station SUL.04, bay south of Pulau Putus, Lembeh Strait, North Sulawesi , depth approx. 1 to 2 m, on October 27, 1994 by J.C. den Hartog.(n=3). RMNH Coel 40472, Rumphius Biohistorical Expedition station 27, Leitimur, south coast, Hutumuri, Ambon Bay, Moluccas to relatively small RMNH Coel 40473 . However, colonies . FurtherRegions recorded in this study , resulting in few reports of this species.As seen in previous studies , it appeTaxon classificationAnimaliaZoanthariaNeozoanthidae5.NA.NA.08\u00b023'55\"S, 115\u00b042'30\"E), on June 3, 1998; Lembongan Bay, Nusa Lembongan, Lombok Strait , on May 19, 26, 27, 29, 1998 (4 records); Tanjung Taal, Nusa Lembongan, Lombok Strait , on May 25, 1998; station WAK.22, north channel pass of Karang Koromaha, REA Wakatobi National Park, Wakatobi, Southeast Sulawesi , on May 12, 2003; station WAK.13, southwest tip of Tolandono Island, REA Wakatobi National Park, Wakatobi, Southeast Sulawesi , on May 9, 2003.(n=8). Gili Selang, eastern Bali (Isaurus (within family Zoanthidae). Zooxanthellate. Adapted from Unique among zoantharians, species in this genus have an endodermal sphincter with brachycnemic mesentery arrangement. Polyps are only partially incrusted, with the oral end of polyps lacking incrustation Figures . PhylogeRegions recorded in this study 03\u00b038'05\"S, 128\u00b012'36\"E), depth = intertidal, collected on November 28, 1990 by M.S.S. Lavaleye; RMNH Coel. 40470, Rumphius Biohistorical Expedition station 4, Leitimur, outer Ambon Bay, Wainitu, Moluccas , depth = littoral on old shipwreck, collected on November 7\u20138, 1990 by H. Strack; RMNH Coel. 40475, Rumphius Biohistorical Expedition station 27, Leitimur, south coast, Hutumuri, Moluccas , depth = intertidal, on November 26, 1990 by M.S.S. Lavaleye; RMNH Coel. 40514, Fauna Malesiana Maluku Expedition station MAL.15, Ambon Bay, south coast, cape west of Amahusu, Moluccas , collected on November 16, 1996; RMNH Coel. 40528, Snellius\u2013II Expedition station 4.096, northeast Komodo, Komodo , depth = to 30 m, collected on October 26, 1984; RMNH Coel 40532, NNM\u2013LIPI\u2013WWF Bali\u2013Lombok Strait 2001 Expedition station BAL.09, Loloan Batu Agung, Sanur, eastern Bali , depth = 10 to 15 m, collected on April 3, 2001 by B.W. Hoeksema; RMNH Coel. 40540, Snellius\u2013II Expedition station 4.010, near Tawiri, Ambon Bay, Moluccas , depth = 1 to 5 m, collected on September 5, 1984; RMNH Coel. 40559, Snellius\u2013II Expedition sta 4.012, north Pulau Mai, Maisel Islands, Banda Sea , depth = 0 to 1.5 m, collected on 07.09.1984; RMNH Coel. 40561, Snellius\u2013II Expedition station 4.133, east Pulau Tarupa Kecil, Taka Bone Rate , depth = 11 m, collected on September 26, 1984; RMNH Coel. 40562, Snellius\u2013II Expedition station 4.096, northeast Komodo, Komodo , depth = to 30 m, collected on September 20, 1984; RMNH Coel. 40741, Rumphius Biohistorical Expedition station 11, Leitimur, Tanjung Nasaniwe, Moluccas , depth = littoral, collected on November 12, 1990;(n=13): RMNH Coel 40458, harbor pier, Cebu City, Cebu, Philippines, collected in 1976 by M.L. Esmeno; RMNH Coel 40459, harbor pier, Cebu City, Cebu, Philippines, collected in 1976 by M.L. Esmeno; RMNH Coel. 40468, Rumphius Biohistorical Expedition station 29, Hitu, Ambon Bay, Ambon, Moluccas , May 22, 1998; west Pulau Bone Batang, South Sulawesi, Spermonde Archipelago , October 22, 1997.(n=2). Main coast, West Bali and overall morphology , eastern Australia and Singapore with this species. However, asides from the specimens directly examined by Ryland and Lancaster, there is much confusion over the true identity of these species. For example, Gemmariawilleyi is likely a Zoanthus species based on the figures in the original description. Ryland and Lancaster state \u201cProbably only the use of genetic methods, so successfully applied by Burnett et al. (1997), will settle identities over wide geographic areas\u201d.However, in the Pacific, records of this species with phylogenetic confirmation have previously been reported from the Great Barrier Reef in Australia , SingapoPalythoa is confused due to the close phylogenetic relationships between Palythoamutuki, Palythoatuberculosa, and some other undescribed species, and a potential reticulate evolutionary history , depth = 3 m, collected on November 15, 1996; RMNH Coel 40512, Pelabuhan Ratu, southwest Java , collected on October 13, 1977, by P.H. van Doesburg.(n=2): RMNH Coel 40508, Fauna Malesiana Maluku Expedition station MAL.13, west coast near Larike, Ambon, Moluccas , but the specimen is clearly a zoantharian due to sand encrustation in body wall.Taxon classificationAnimaliaZoanthariaSphenopidae8.03\u00b033'S, 128\u00b012'E), depth = 35 m, collected on November 13, 1996; RMNH Coel. 40513, Rumphius Biohistorical Expedition station 24, south Seri Bay, Ambon, Moluccas , depth = 12 m, November 22, 1990.(n=2). RMNH Coel 40504, Fauna Malesiana Maluku Expedition station MAL.12, north coast near Morela, Ambon, Moluccas , December 16, 1996; Pemuteran, West Bali , May 23, 1998; Tulamben, eastern Bali , July 12, 1997; Nusa Lembongan, Lombok Strait , May 29, 1998; west side Pulau Samalona, Spermonde Archipelago, South Sulawesi , November, 1984; northwest side Pulau Samalona, Spermonde Archipelago, South Sulawesi , November 23, 1997; northwest Kudingareng Keke, Spermonde Archipelago, South Sulawesi , August 6, 1997; west side Pulau Badi, Spermonde Archipelago, South Sulawesi , November 1, 1994; REA Wakatobi National Park station WAK.18, southwest Pulau Binongko, Southeast Sulawesi, Wakatobi, Tukang Besi Islands , May 10, 2003; REA Wakatobi National Park station WAK.22, north channel pass of Karang Koromaha, Southeast Sulawesi, Wakatobi, Tukang Besi Is. , May 12, 2003; Fauna Malesiana Maluku Expedition station MAL.12, north coast near Morela, Ambon , November 13\u201314, 1996; East Kalimantan\u2013Berau Expedition station BER.03, south side of Pulau Derawan, East Kalimantan , October 16, 2003; Christensen Research Institute, Madang, Papua New Guinea , June 1992.(n=13). Pulau Ular, off Padang, West Sumatra and subtidal distribution, compared to primarily intertidal Palythoamutuki, which also has longer tentacles .Sizes of specimens agree well with specimens seen in other localities . Depth of collected specimens (12 and 35 m) also fits well with the description of this species as primarily subtidal in the original description, and from data in Okinawa, Japan e.g. .Regions recorded in this study (n=1). RMNH Coel 40521, Snellius Expedition, Pulau Haroekoe, east of Ambon, Ambon, Moluccas, collected on May 03\u201307, 1930.NA.Palythoa sp. yoron sensu Palythoa sp. yoron from Okinawa. The current specimen consists of two large portions of colonies consisting of >50 polyps, while Palythoa sp. yoron usually is found in very small colonies of <10 polyps. As well, Palythoa sp. yoron consists of a very well developed coenenchyme from which all individual polyps partially emerge, while the current specimen appears to consist more of large robust polyps that have merged together at many locations, but not at others, giving the specimen the appearance of Palythoatuberculosa from the top, and often of Palythoamutuki from side angles. On the other hand, Palythoa sp. yoron has an appearance, although intermediate between Palythoatuberculosa and Palythoamutuki, unique to and of itself. Polyps\u2019 height (when not merged) is approximately 7.0 mm, and average width is 7.3 mm (n=10 polyps). Thus, for now, this specimen is identified as Palythoaaff.tuberculosa. For details on Palythoatuberculosa, refer to the relevant species section below.This specimen superficially resembles zooxanthellate Regions recorded in this study , depth = 2\u20135 m, collected on November 12, 1990; RMNH Coel 40466, Rumphius Biohistorical Expedition station 30, Hitu, Baguala Bay, Suli, Ambon, Moluccas , collected on November 29, 1990; RMNH Coel 40467, Rumphius Biohistorical Expedition station 15, Hitu, Baguala Bay, 0.5 km west of Tial, Ambon, Moluccas , depth = 2 m, collected on November 13\u201314, 1990; RMNH Coel 40471, Rumphius Biohistorical Expedition station 4, Leitimur, Ambon Bay, outer bay, Wainitu (near Ambon City), Ambon, Moluccas , littoral on old shipwreck, collected on November 7\u20138, 1990 by H. Strack; RMNH Coel 40474, Rumphius Biohistorical Expedition station 27, Leitimur, south coast, Hutumuri, Ambon, Moluccas , depth = 1 to 3 m, collected on November 27, 1990 by J.C. den Hartog; RMNH Coel 40505, south side of Barang Lompo, Spermonde Archipelago, South Sulawesi , depth = 18 m, collected on October 18, 1980, by H. Moll; RMNH Coel 40511, west side of Pulau Samalona, Spermonde Archipelago, South Sulawesi , depth = 2.5 m, collected on September 4, 1980 by H. Moll; RMNH Coel. 40517, west side of Pulau Samalona, Spermonde Archipelago, South Sulawesi , depth = 2.5 m, collected on September 4, 1980 by H. Moll; RMNH Coel 40519, Snellius Expedition, Rumah Fija, Bo Islands, Halmahera Sea, collected on October 7, 1930; RMNH Coel 40522, Snellius Expedition, Sulu Islands, Philippines, collected on September 11\u201317, 1930; RMNH Coel 40523, Snellius Expedition, probably Indonesia, no locality data; RMNH Coel 40524, Snellius\u2013II Expedition station 4.011, reef edge west of Mai, Maisel Islands, Banda Sea , depth = 1\u201330 m, collected on September 7, 1984; RMNH Coel 40526, Snellius\u2013II Expedition station 4.030, west coast of Pulau Binongko, Southeast Sulawesi, Tukang Besi Islands, Wakatobi , depth approx. 2 m, September 10, 1984; RMNH Coel 40527, Snellius\u2013II Expedition station 4.030, west coast of Pulau Binongko, Southeast Sulawesi, Tukang Besi Islands, Wakatobi , depth approx. 0.5 m, September 10, 1984; RMNH Coel 40529, Snellius\u2013II Expedition station 4.030, west coast of Pulau Binongko, Southeast Sulawesi, Tukang Besi Islands, Wakatobi , depth approx. 8 m, September 10, 1984; RMNH Coel 40530, Snellius\u2013II Expedition station 4.071, Slawi Bay, east Komodo, Komodo , depth sublittoral, collected on September 17, 1984; RMNH Coel 40531, Snellius\u2013II Expedition station 4.030, west coast of Pulau Binongko, Southeast Sulawesi, Tukang Besi Islands, Wakatobi , depth approx. 3 to 4 m, September 10, 1984; RMNH Coel 40534, Snellius\u2013II Expedition station 4.169, reef north of Pulau Bahuluang, Southwest Salayer, Salayer Island, South Sulawesi , collected on September 30, 1984; RMNH Coel 40535, Snellius\u2013II Expedition station 4.059, off Melolo, northeast Sumba , collected on September 14, 1984; RMNH Coel 40541, Snellius\u2013II Expedition station 4.006, Ambon Bay near Eri, Ambon, Moluccas , depth approx. 3 m, collected on August 29, 1984; RMNH Coel 40543, Snellius\u2013II Expedition station 4.006, Ambon Bay near Eri, Ambon, Moluccas , depth = 0 to 10 m, collected on August 29, 1984; RMNH Coel 40548, Snellius\u2013II Expedition station 4.052, east of Melolo, northeast Sumba , depth approx. 3 m, collected on September 13, 1984; RMNH Coel 40552, Snellius\u2013II Expedition station 4.048, east of Melolo, northeast Sumba , depth = 12 m, collected on September 14, 1984; RMNH Coel 40553, Snellius\u2013II Expedition station 4.096, northeast cape, Komodo , depth to 30 m, collected on September 20, 1984; RMNH Coel 40555, Snellius\u2013II Expedition station 4.096, northeast cape, Komodo , depth to 30 m, collected on September 20, 1984; RMNH Coel 40557, Snellius\u2013II Expedition station 4.096, northeast cape, Komodo , depth = \u201cshallow water\u201d, collected on September 20, 1984; RMNH Coel 40568, northwest of Pulau Kapoposang, Spermonde Archipelago, South Sulawesi , collected on May 2, 1998 by B.W. Hoeksema; RMNH Coel 40769, Snellius Expedition, Eude, South Flores, collected on March 6\u20138, 1930; RMNH Coel 40770, Snellius Expedition, Maratua, Berau Islands, East Kalimantan, collected on October 14\u201317, 1930; RMNH Coel 40771, Snellius Expedition, Maratua, Berau Islands, East Kalimantan, collected on October 14\u201317, 1930; RMNH Coel 40772, Snellius\u2013II Expedition station 4.006, Ambon Bay near Eri, Ambon, Moluccas , depth = 0 to 10 m, collected on August 29, 1984.(n=31). RMNH Coel 40465, Rumphius Biohistorical Expedition station 11, Leitimur, Tanjung Nasaniwe, Ambon, Moluccas , May 20, 1998; Pemuteran, West Bali , May 23, 1998; Napoleon Reef, West Bali , May 20, 1998; Nusa Lembongan, Lombok Strait, East Bali, July 13, 1997; Nusa Lembongan, Lombok Strait, east Bali, July 19, 1997; Nusa Lembongan, Lombok Strait, east Bali, May 26, 1998; south of Pulau Samalona, Spermonde Archipelago, South Sulawesi , October 27, 1997; northwest Pulau Samalona, Spermonde Archipelago, South Sulawesi , November 25, 1997; Fauna Malesiana Maluku Expedition station MAL.12, north coast near Morela, Ambon, Moluccas November 13, 1996; North Sulawesi, Bunaken, , April 9, 1996; Cebu, Philippines, November 21, 1998; Madang, Papua New Guinea, June 1992.(n=12). Pemuteran, West Bali , ranging from 2 to 8 mm. One specimen, RMNH Coel 40553, was notable for its very small polyps . Other colonies ranged from 3.1 to 6.5 mm in average diameter, similar to previous reported sizes. All specimens were \u2018immersae\u2019. Generally, morphology fit well within the accepted range of Regions recorded in this study 02\u00b023'14\"N, 118\u00b012'34\"E), depth = 12 m, collected on October 09, 2003 by B.W. Hoeksema; RMNH Coel 40509, East Kalimantan\u2013Berau Expedition station BER.01, east side of Pulau Derawan, Berau Islands, East Kalimantan , depth = 14 m, collected on October 11, 2003 by B.W. Hoeksema.(n=2). RMNH Coel 40506, East Kalimantan\u2013Berau Expedition station BER.14, lighthouse northeast side of Pulau Panjang, Berau Islands, East Kalimantan , October 06, 1997; east Bone Lola shoal, Spermonde Archipelago, South Sulawesi , October 27, 1997; east Pulau Kudingareng Keke, Spermonde Archipelago, South Sulawesi , September 17, 1997; north Pulau Kudingareng Keke, Spermonde Archipelago, South Sulawesi , October 1, 1997; station BER.01, east Pulau Derawan, East Kalimantan, Berau Islands , October 11, 2003; station BER.14, lighthouse northeast Pulau Panjang Island, East Kalimantan, Berau Islands , October 9, 2003; station BER.24, southeast Pulau Samama, East Kalimantan, Berau Islands , October 15, 2003.(n=7). west Pulau Barang Caddi, Spermonde Archipelago, South Sulawesi , and an average width of 8.4 mm (range 6 to 11 mm). The non-peduncle portions of the polyps are 15\u201320 mm in height, with the remainder made up of peduncle.Sphenopusmarsupialis specimens from the Indian Ocean. These polyps have regularly spaced small round \u201ctubercles\u201d (approx. 1 mm in diameter) on the upper half of their scapus arranged in vertical lines , making this portion of the polyp appear furrowed. As well, polyps have a small, stubby \u201cpeduncle\u201d (2 to 5 mm in width) that is not attached to any hard substrate, intermediate between Sphenopusmarsupialis with its completely rounded bottom end and Sphenopuspedunculatus with its long, attached peduncle. For now, we identify these specimens as Sphenopusmarsupialis as their peduncles were not attached to the substrate, but it is clear more examination of these specimens is needed.Specimen RMNH Coel 40506 has some polyps (five of seven) somewhat different in morphology from RMNH Coel 40509 and other Naturalis Specimen RMNH Coel 40509 consists of two polyps of different sizes, with the smaller one being 16 by 5 mm, and the larger one 24 by 15 mm. Both polyps have no peduncle and are tapered. Both polyps are somewhat rugged on their outer surface, with no discernable tubercles, and have intermittent (=not one clear stripe) small darker vertical patterns in between the capitulary ridges only on the top 3\u20135 mm of the oral end of polyps.Regions recorded in this study , depth = 30 m, collected on September 18, 2005 by B.W. Hoeksema; RMNH Coel 40510, East Kalimantan\u2013Berau Expedition station BER.03, south side of Pulau Derawan, East Kalimantan , depth = 15 m, collected on October 21, 2003 by B.W. Hoeksema.(n=2). RMNH Coel 40507, Kepulauan Seribu Expedition station SER.29, north side of Pulau Tikus, Thousand Islands off Jakarta, northwest Java ((n=2). Images of RMNH Coel. 40507 and RMNH Coel 40510 as above.Sphenopus species by the presence of a \u2018foot\u2019 (=peduncle) that is attached to substrate .This azooxanthellate species was originally described from the Philippines, and has not been reported in the literature for over 80 years, excepting two brief mentions in Sphenopus species) that currently nothing is known about intraspecific variation, and for now, we group these two specimens within this species.The two specimens here varied in length from 33 to 62 mm in polyp length, and had a width between 9 to 11 mm (polyp head). The \u201cswollen\u201d, non-peduncle part of the polyp was between 15 to 20 mm in height, with the remainder of the length made up of the peduncle, which was between 0.5 to 3 mm in width. RMNH Coel 40507 polyps were generally smooth in appearance, while the upper portions of polyps of RMNH Coel 40510 were somewhat rugged, with small round tubercules 0.5 mm in diameter roughly arranged in vertical lines. The spaces between these small tubercules were colored a much darker color than the remainder of the polyps\u2019 outer surfaces. The peduncle of specimens and images Figure are muchRegions recorded in this study sensu Di Camillo et al. (2010)08\u00b029'54\"S, 119\u00b038'06\"E), depth = 75 m, collected on September 19, 1984 by rectangular dredge; RMNH Coel. 40518, Snellius\u2013II Expedition station 4.022, north Pulau Mai, Maisel Islands, Banda Sea , depth = 0 to 1.5 m, collected on September 7, 1984; RMNH Coel 3816, Snellius Expedition, Sipankat Island, near Siburu Island, Sulu Islands, Philippines, collected on September 10\u201314, 1929.(n=3). RMNH Coel 40692, Snellius\u2013II Expedition station 4.098, East Komodo, Komodo , May 25, 1998; Desa Ped, Nusa Penida, Lombok Strait, east Bali , May 25, 1998; east Tanjung Taal, Nusa Lembongan, Lombok Strait, east Bali , May 24, 1998; Fauna Malesiana Maluku Expedition station MAL.21, west of Lilibooi, north coast Ambon Bay, Ambon, Moluccas , November 20, 1996; East Kalimantan Program station BER.16, northeast Pulau Maratua, East Kalimantan, Berau Islands , October 10, 2003.(n=5). Southwest Nusa Penida, eastern Bali , November 21, 1999.(n=1). Balicasag Island, Cebu Strait, Philippines , this species has much smaller polyps than Hydrozoanthusgracilis, forming colonies only on the main branch(es) of Plumulariahabereri colonies. Polyps are much less incrusted than Hydrozoanthusgracilis. The Plumulariahabereri colonies hosting this species are much bigger than those with Hydrozoanthusgracilis, as shown by , October 22, 2003.(n=1). East Kalimantan Program station BER.20, Tanjung Pandan shoal, southwest of Pulau Panjang, East Kalimantan, Berau Islands of Plumulariahabereri colonies informally described by Parazoanthus sp.\u201d. Specimens and DNA sequences are needed to properly describe this species.This undescribed species may be a different colored morphotype of Taxon classificationAnimaliaZoanthariaHydrozoanthidae16.03\u00b035'S, 128\u00b005'E), depth = NA, collected on November 7, 1996 by J.C. den Hartog.(n=1). RMNH Coel 40469, Fauna Malesiana Maluku Expedition station MAL.05, Leitimur, outer Ambon Bay, Tanjung Bentang, Ambon, Moluccas , September 29, 1997.(n=1). West Pulau Badi, Spermonde Archipelago, South Sulawesi , and collected from Okinawa, Japan , indicating a potential West Pacific distribution.Terrazoanthusonoi from the Galapagos and west coast of Central and South America.This species is similar in appearance but different in coloration to Taxon classificationAnimaliaZoanthariaHydrozoanthidae17.NA.05\u00b003'15\"S, 119\u00b021'15\"E), April 22, 1998.(n=1). West Bone Lola shoal, Spermonde Archipelago, South Sulawesi .Zoanthus spp. colonies in shallow water . Although undescribed, this putative species has been placed with the genus Terrazoanthus based on DNA sequences acquired from aquarium trade polyps , depth = to 24 m, collected on November 11, 1996; RMNH Coel 40768, Snellius Expedition, Pulau Bo Islands, Halmahera Sea, collected on October 5, 1930.(n=2). RMNH Coel 40766, Fauna Malesiana Maluku Expedition station MAL.09, southwest coast, Ambon, Latuhalat, Moluccas , October 22, 2003.(n=1). Station BER.30, north of Lighthouse 1 Reef, south of Pulau Derawan, East Kalimantan, Berau Islands , connected by coenenchyme visible on the outer surface of the octocoral colony. Polyps numerous, placed between smaller octocoral polyps, pale yellow in coloration, with outer surface of polyps slightly reddish in color similar to host octocoral. Tentacles relatively short, approximately half of the oral disk diameter, also pale yellow, and approximately 20 in number . However, the latter specimen is quite old and this difference may be due to fixation methods.Regions recorded in this study , depth = 60 m, collected on October 15, 1984 by rectangular dredge.(n=1). RMNH Coel 40762, Snellius\u2013II Expedition, Station 4.227, west Pulau Tinanja, Taka Bone Rate (NA.Cirripathes sp. (specimen RMNH Coel 24832). Polyps of this azooxanthellate zoantharian specimen are relatively small and do not protrude much from the coenenchyme, with polyp height approximately same as width. Polyps and coenenchyme are heavily encrusted, and golden yellow-brown in color. Coenenchyme forms a thin sheath over the antipatharian surface. Capitulary ridges not clearly discernable. Polyps form semi-regular vertical rows over short distances of the antipatharian (e.g. approx. 5 cm), but with no observable pattern for the entire colony , June 4, 1997; Cabilao Island, Cebu Strait, Philippines , November 16, 1999; station WAK.24, Ndaa Atoll northwest outer slope, REA Wakatobi National Park, Tukang Besi Islands, Wakatobi, Southeast Sulawesi, , May 12, 2003.(n=3). West side of Pulau Kudengareng Keke, Spermonde Archipelago, South Salawesi azooxanthellate polyps regularly spaced and embedded within encrusting sponge tissue Figure . Polyps Regions recorded in this study it appears that this group includes several undescribed species. The species has been found on cave ceilings Figure , which mTaxon classificationAnimaliaZoanthariaParazoanthidae21.09\u00b054'12\"S, 120\u00b043'30\"E), depth = 50 m, collected on September 15, 1984 by rectangular dredge; RMNH Coel. 40570, station 9, reef slope of southwest Pulau Nain, Bunaken, North Sulawesi , collected on May 8, 1998 by B.W. Hoeksema; RMNH Coel 40572, Ternate Expedition Station TER.27, Tanjung Ratemu (south of river), west Halmahera Sea, North Moluccas , depth = 20 m, collected on November 8, 2009 by B.W. Hoeksema; RMNH Coel 40757, Indonesia 2012 Expedition, Station LEM.34, west Pulau Sarena Kecil Lembeh, North Sulawesi , depth = 22 m, collected on February 17, 2012 by B.W. Hoeksema.(n=4). RMNH Coel 40544, Snellius\u2013II Expedition Station 4.061, east of Melolo, northeast Sumba , June 4, 1997; southeast Likuan, Bunaken, North Sulawesi , May 10, 1998; Main coast, West Bali , May 22, 1998.(n=3). West Pulau Kudingareng Keke, Spermonde Archipelago, South Sulawesi , depth 91 m, collected on September 19, 1984 by rectangular dredge; RMNH Coel 40545, Snellius\u2013II Expedition station 4.051, east of Melolo, northeast Sumba , depth 75-90 m, collected on September 13, 1984 by rectangular dredge.(n=2). RMNH Coel 40525, Snellius\u2013II Expedition station 4.100, east of Komodo Island and average width of 3.2 mm (range 2 to 4 mm). Some small dark incrustations visible on lower half of polyps\u2019 scapus. Approximately 20 capitulary ridges, indicating tentacle counts of approximately 40. Polyps range from cream (RMNH Coel 40525) to tan (RMNH Coel 50545) in color when preserved. Polyps arise from a well-developed stoloniferous coenenchyme in rows, with most found along the upper and outer edges of flat, paddle-shaped sponges than Parazoanthus sp. 2.Similar in size to Taxon classificationAnimaliaZoanthariaEpizoanthidae23.Tischbierek, 193006\u00b031'30\"S, 121\u00b008'00\"E), depth 58 m, collected on October 15, 1984 by rectangular dredge; RMNH Coel 40546, Snellius\u2013II Expedition Station 4.051, east of Melolo, northeast Sumba , depth = 75 to 90 m, collected on September 13, 1984 by rectangular dredge; RMNH Coel 40571, Ternate Expedition Station TER.27, Tanjung Ratemu, south of river, west Halmahera Sea , depth = 20 m, collected on November 08, 2007 by B.W. Hoeksema; RMNH Coel 40758, station LEM.32, north Sarena Kecil, Lembeh Strait, North Sulawesi , depth = 30 m, collected on February 16, 2012 by B.W. Hoeksema.(n=4). RMNH Coel 40533, Snellius\u2013II Expedition Station 4.222, south of Pulau Tarupa Kecil, Taka Bone Rate May 22, 1998 (3 different specimens); Maluku Expedition station MAL.21, north coast Ambon Bay, Tanjung Hatupero, east of Lilibooi, Ambon , November 20, 1996; southeast Likuan, Bunaken, North Sulawesi , May 10, 1998; station BER.04, south Pulau Derawan, East Kalimantan , October 18, 2003.(n=6). West Menjangan, West Bali have highly developed thin coenenchymes covering the entire worm tubes\u2019 surface, and are both dark black in color. On the other hand, the shallower specimens had some unitary polyps, and colonial polyps were often in clusters of two or three with poorly developed coenenchyme.Polyps of specimens in the RMNH collection are generally less than 1 mm in diameter, and never more than 2 mm, and of approximately equal height. Coenenchyme generally light gray in color, oral disk and tentacles semi-translucent brown. Tentacles in images 20\u201322 in number, much thinner than as seen in The morphological characters and dimensions observed in the specimens in this study agree well with the original description by Regions recorded in this study , depth = 180 m, collected on September 14, 1984 by rectangular dredge; RMNH Coel 40547, Snellius\u2013II Station 4.051, east of Melolo, northeast Sumba , depth = 75 to 90 m, collected on September 13, 1984 by rectangular dredge.(n=2). RMNH Coel 40536, Snellius\u2013II Station 4.058, east of Melolo, northeast Sumba , May 28, 1998; 4 specimens from Tulamben, east Bali , July 9\u201310, 1997; Nusa Penida, east Bali, , May 27, 1998; Kapoposang, Spermonde Archipelago, South Sulawesi , June 24, 1997, August 8, 1997; west Pulau Samalona, Spermonde Archipelago, South Sulawesi , September 16, PageBreak1997; Fauna Malesiana Maluku Expedition station MAL.10, south coast of Ambon Bay, east of Eri, Ambon , November 12, 1996; Maluku Expedition station MAL.12, north coast near Morela, Ambon , November 13\u201314, 1996; Maluku Expedition station MAL.19, Tanjung Batu Dua, east of Hatu, north coast Ambon Bay, Ambon , November 19, 1996; Fauna Malesiana Marine Sulawesi Expedition station SUL.16, bay east of Tanjung Labuhankompeni, Pulau Lembeh, Lembeh Strait, North Sulawesi PageBreak, October 23, 1994; west Pulau Siladen, Bunaken, North Sulawesi , May 2, 1998.(n=12). Desa Ped, north Nusa Penida, east Bali , and many times bigger in terms of volume. Additionally, both specimens have brown coenenchyme and scapus, different from the light gray coenenchyme and brownish oral disk reported for Epizoanthusilloricatus . It is likely records and museum specimens identified as Epizoanthusilloricatus from the central Indo-Pacific include both types mentioned in this study.Although the two specimens here were found at deeper depths (75 to 190 m), numerous photographic records show that this species and Brachycnemina and 12 from Macrocnemina. While by no means an extensive collection, with most specimens from Indonesia, these results indicate that the Central Indo-Pacific waters are at least as diverse in numbers of species, genera, and families as surrounding regions of Australia, Singapore, and Japan. In Australia, an examination of the brachycnemic shallow water zoantharians of the Great Barrier Reef indicated the presence of eight species are likely undescribed species. Some, such as Terrazoanthus sp. 2, have been known for years in the global aquarium trade, yet still no museum specimens exist, and thus we cannot formally describe them within this manuscript. Without formal descriptions and a clear understanding of species, future conservation work cannot proceed effectively, and immediate taxonomic efforts should focus on the obtaining of specimens and a formal description of this species. Similarly, many photographic records exist for Neozoanthus sp., yet no specimens are in the Naturalis collection.Of the 24 total species listed in this study, at least nine include a large number of undescribed species, and total numbers are as high or higher than previously reported for any other region.Furthermore, this study demonstrates that the central Indo-Pacific likely harbors very high levels of zoantharian diversity, as the numbers of putative species from this Finally, it is hoped that this study can serve as a temfig for the study of other understudied coral reef benthos in the Coral Triangle. In this study, past photographic records proved to be invaluable in aiding species identification, and understanding species distributions. Thus, while museum collections should remain the key tool in taxonomic and biogeographic research , archive"} +{"text": "Scientific Reports6: Article number: 27380; 10.1038/srep27380published online: 06072016; updated: 08252016In this Article, Hwa Jen Yap, Siti Zawiah Md Dawal, S. Ramesh and Sin Ye Phoon are incorrectly affiliated to \u2018Graduate School of Media Design, Keio University, 4-1-1, Hiyoshi, Kohoku, Yokohama, 223-8526, Japan\u2019. The correct affiliation is listed below:Department of Mechanical Engineering, Faculty of Engineering, University of Malaya, 50603, Kuala Lumpur, Malaysia."} +{"text": "Dr. Anne-Sophie Hamy should be included in the byline as the sixth author. Her affiliations are 6: Residual Tumor and Response to Treatment Lab, Translational Research Department, Institut Curie, Paris, France, and 7: UMR932 Immunity and Cancer, INSERM, Paris, France. The contributions of this author are as follows: Wrote the manuscript.10.1371/journal.pone.0144359The correct citation is: Bonsang-Kitzis H, Chaltier L, Belin L, Savignoni A, Rouzier R, Hamy AS, et al. (2015) Beyond Axillary Lymph Node Metastasis, BMI and Menopausal Status Are Prognostic Determinants for Triple-Negative Breast Cancer Treated by Neoadjuvant Chemotherapy. PLoS ONE 10(12): e0144359. doi:"} +{"text": "Systemic juvenile idiopathic arthritis (JIA) is the most severe category within the group of arthritis which are classified under the umbrella term of JIA. Systemic JIA has been considered a therapeutic orphan until few years ago when the disease was treated primarily with corticosteroids with the known side effect especially on child growth. More recently the availability of new treatment modalities with biologic agents such as anti L6 and anti IL1 therapies have greatly advanced the possibilities for these children to be adequately treated.This lecture will describe the current status of the treatment for systemic JIA and the future perspectives.N. Ruperto Grant / Research Support from: The Gaslini Hospital, which is the public Hospital where I work as full time public employee, has received contributions from the following industries: Abbott, BMS, \"Francesco Angelini\", GlaxoSmithKline (GSK), Hoffman-La Roche, Italfarmaco, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, Wyeth, Speakers Bureau of: Abbott/AbbVie, Astellas, Alter, AstraZeneca, Boehringer, BMS, CD-Pharma, Celgene, Crescendo Bio, EMD Serono, Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Sanofi Aventis, Vertex Pharmaceuticals, Servier"} +{"text": "AbstractNematoda.We present an updated list of terrestrial and freshwater nematodes from all regions of the Arctic, for which records of properly identified nematode species are available: Svalbard, Jan Mayen, Iceland, Greenland, Nunavut, Northwest territories, Alaska, Lena River estuary, Taymyr and Severnaya Zemlya and Novaya Zemlya. The list includes 391 species belonging to 146 genera, 54 families and 10 orders of the phylum Nematodes are one of the most numerous and abundant multicellular organisms on the planet in general and in the Arctic in particular. There are over 70 research papers published which include data on the fauna and distribution of nematodes in the region. Few faunistic overviews of the Arctic nematodes exist in the literature. The \"Catalogue of free-living soil and fresh-water nematodes of Arctic and Subarctic\" includesThe species list has been compiled based on literature data and refers to the area of the Arctic Fig. as definDorylaimus sp. from Spitzbergen . The context of the genus Dorylaimus had changed considerably since 1920 and now includes members of at least families Dorylaimidae, Qudsianematidae, Aporcelaimidae and Nordiidae, making it practically impossible to use Menzel's record in modern faunistic studies. Even genus-level identifications done more recently face similar problems. Species that are now considered to belong to the same genus may in future, when more data becomes available, be split into different, sometimes distantly related genera. It would thus be impossible to know in the future what author of the paper meant when he identified his material.Taxa identified in the literature to the genus level only were not considered in the review for the following reasons: 1) It is impossible to make sure how many actual species were considered by the author \u2013 just one, or if s/he had treated multiple species together in the same unit. 2) Taxa identified only to the genus level have limited usefulness when analyzing distribution, endemism and other aspects of biogeography. Nematode systematics is continuously improving. Desmodorida and Araeolaimida follows Enoplida follows that of Triplonchida \u2013 Dorylaimida \u2013 Mononchida \u2013 Monhysterida \u2013 Plectida \u2013 Rhabditida \u2013 General classification and classification of the orders Chromadorida, de Man, 1876Taymyr and Severnaya Zemlya, Russia .Thorne, 1939Svalbard ; Taymyr Loof, 1971*Svalbard .Thorne, 1939Svalbard .de Man, 1880Jan Mayen ; Taymyr Thorne, 1939Taymyr and Severnaya Zemlya, Russia .Thorne, 1939Taymyr and Severnaya Zemlya, Russia .Alaimusstriatus Loof, 1964Taymyr and Severnaya Zemlya, Russia .Alaimuselegans de Man, 1921Jan Mayen ; Taymyr Amphidelusdolichurus Svalbard ; Taymyr Gagarin, 1991*Taymyr and Severnaya Zemlya, Russia .Novaya Zemlya and Vaigach island, Russia .Amphideluspusillus Thorne, 1939Taymyr and Severnaya Zemlya, Russia .de Man, 1880Svalbard ; NunavutTrischistomaarenicola Nunavut, Canada .Taymyr and Severnaya Zemlya, Russia .Northwest territories, Canada .Gagarin, 1996*Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia ; Novaya Nunavut, Canada ; Lena RiTrilobuspseudallophysis Micoletzky 1925Greenland ; Taymyr Gagarin, 1996*Taymyr and Severnaya Zemlya, Russia .Gagarin, 1991*Taymyr and Severnaya Zemlya, Russia .Gagarin, 1991*Taymyr and Severnaya Zemlya, Russia .Lena River estuary, Russia ; Taymyr Taymyr and Severnaya Zemlya, Russia ; Novaya Shoshin, 1988EutobrilusantarcticusRaritobrilusantarcticus sensu Gagarin 1990, 1991 sensu Gagarin, 1993, 2001; Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Lena River estuary, Russia ; Taymyr Taymyr and Severnaya Zemlya, Russia .Lena River estuary, Russia ; Taymyr Micoletzky, 1922Taymyr and Severnaya Zemlya, Russia .Gagarin, 1991*Taymyr and Severnaya Zemlya, Russia .Eutobrilusarcticus Gagarin, 1991*Taymyr and Severnaya Zemlya, Russia .Gagarin, 1999*Lena River estuary, Russia .Eutobrilusstrenuus Gagarin, 1991*Taymyr and Severnaya Zemlya, Russia .EutobrilussteineriTobrilussteineri Micoletzky, 1925 ; Lena River estuary, Russia ; Taymyr Tsalolikhin, 2000*Tobriluslongicaudatus sensu Ebsary, 1982Northwest territories, Canada .Tobriluslongicaudatus Taymyr and Severnaya Zemlya, Russia .Tobrilusparapellucidus Ebsary, 1982*Northwest territories, Canada ; Taymyr Lena River estuary, Russia .de Man, 1880Nunavut, Canada ; Taymyr Gagarin, 1997*Novaya Zemlya and Vaigach island, Russia .de Man, 1880Taymyr and Severnaya Zemlya, Russia .Bastian, 1865Tripylapapillata B\u00fctschli, 1873Svalbard ; GreenlaBrzeski & Winiszewska-Slipinska, 1993Tripylafilipjevi Altherr in Altherr & Delamare Deboutteville, 1972Svalbard ; Taymyr Altherr in Altherr & Delamare Deboutteville, 1972Lena River estuary, Russia ; Taymyr B\u00fctschli, 1873Lena River estuary, Russia ; Taymyr de Man, 1880Svalbard ; Jan MaySvalbard ; Jan MayLoof, 1971*Svalbard .Loof, 1971*Svalbard .Gagarin & Kuzmin, 1972*Taymyr and Severnaya Zemlya, Russia .Hirschmann, 1952Novaya Zemlya and Vaigach island, Russia .de Man, 1876Svalbard ; NunavutDe Coninck, 1935Taymyr and Severnaya Zemlya, Russia .de Man, 1880Svalbard ; Taymyr de Man, 1880Taymyr and Severnaya Zemlya, Russia .Ivanova, 1958Taymyr and Severnaya Zemlya, Russia .Thorne, 1939Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Allen, 1957Alaska .Bernard, 1992*Alaska .Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Gagarin, 1997*Novaya Zemlya and Vaigach island, Russia .Andr\u00e1ssy, 1986Alaska .Dorylaimusfiliformis Bastian, 1865Greenland .Gagarin, 1996*Taymyr and Severnaya Zemlya, Russia .Mesodorylaimusflavomaculatus Taymyr and Severnaya Zemlya, Russia .Laimydorusdadayi Taymyr and Severnaya Zemlya, Russia .Altherr in Altherr & Delamare-Deboutteville, 1972Northwest territories, Canada .Dujardin, 1845Greenland ; NorthweTaymyr and Severnaya Zemlya, Russia .Thorne, 1975Novaya Zemlya and Vaigach island, Russia .Taymyr and Severnaya Zemlya, Russia ; Novaya DorylaimusbastianiDorylaimuslangii Cobb, 1888 B\u00fctschli, 1873; Svalbard ; Taymyr Taymyr and Severnaya Zemlya, Russia .Loof, 1969Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Actinolaimusmacrolaimus Greenland ; Alaska Eveleigh, 1982*Northwest territories, Canada .Taymyr and Severnaya Zemlya, Russia .Mulvey & Anderson, 1979*Northwest territories, Canada .Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .EudorylaimuslindbergiAllodorylaimusrarus Gagarin, 1999*; Eudorylaimuscurvicaudatus Eliava, 1968 Andr\u00e1ssy, 1960; Lena River estuary, Russia ; Taymyr Taymyr and Severnaya Zemlya, Russia ; Novaya DorylaimusacuticaudaDorylaimuscarteriacuticauda Micoletzky, 1922; DorylaimuscarteriBastian, 1865sf.acuticaudata de Man, 1880 (lapsus); DorylaimuscarteriBastian, 1865var.brevicaudatusf.typicasf.acuticauda de Man, 1880 de Man, 1880; Jan Mayen ; GreenlaTaymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Dorylaimuscarteri Bastian, 1865Svalbard ; Jan MayDorylaimuscentrocercusAporcelaimelluscentrocercus de Man, 1880; Jan Mayen ; Taymyr Dorylaimusgracilis de Man, 1876Jan Mayen .DorylaimuscarteriBastian, 1865var.brevicaudatusMicoletzly, 1922f.typica Micoletzky, 1922Greenland .Loof, 1971*Svalbard .Loof, 1971*Svalbard .Loof, 1971*Svalbard .DorylaimusagilisDorylaimuscarteriBastian, 1865var.agilis de Man, 1880; Eudorylaimusagilis ; Laimydorusagilis de Man, 1880; Svalbard ; Jan MayEudorylaimusanquilosus Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Eudorylaimushumilis Taymyr and Severnaya Zemlya, Russia .DorylaimuscarteriBastian, 1865sf.lugdunensisDorylaimuscarterilugdunensis Micoletzky, 1922; Eudorylaimuslugdunensis ; Dorylaimusreisingeri Ditlevsen, 1927* de Man, 1880; Svalbard ; Jan MayTaymyr and Severnaya Zemlya, Russia .Gagarin, 1991*Taymyr and Severnaya Zemlya, Russia .Eudorylaimusparvus Svalbard ; Taymyr Eudorylaimuscirculifer Loof, 1961Svalbard .EudorylaimusettersbergensisThonusettersbergensis ; Taymyr and Severnaya Zemlya, Russia .Thonuslaticollis Taymyr and Severnaya Zemlya, Russia .DorylaimuscarteriBastian, 1865sf.briophilus de Man, 1880Jan Mayen .DorylaimuscarteriBastian, 1865sf.pratensis de Man, 1880Jan Mayen .Taymyr and Severnaya Zemlya, Russia .Thorne, 1939Taymyr and Severnaya Zemlya, Russia .Altherr in Altherr & Delamare-Deboutteville, 1972Taymyr and Severnaya Zemlya, Russia .Andr\u00e1ssy, 1978Lena River estuary, Russia ; Novaya Altherr, 1968Alaska .Taymyr and Severnaya Zemlya, Russia .Eudorylaimuskrygeri Taymyr and Severnaya Zemlya, Russia ; Novaya Eudorylaimusobscurus Taymyr and Severnaya Zemlya, Russia .DorylaimusobtusicaudatusDorylaimusobtusicaudatusBastian, 1865f.butschlii Micoletzky, 1922; Aporcelaimusobtusicaudatus Bastian, 1865; Jan Mayen ; GreenlaAporcelaimuspapillatus Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Dorylaimustritici Bastian, 1865Jan Mayen ; GreenlaTaymyr and Severnaya Zemlya, Russia .Andr\u00e1ssy, 2003*Alaska .Taymyr and Severnaya Zemlya, Russia .Dorylaimuslabiatus de Man, 1880Jan Mayen .Eudorylaimusmaksymovi Svalbard .Dorylaimus (Doryllium) analatus Ditlevsen, 1927*Svalbard ; GreenlaDorylaimus (Doryllium) groenlandicus Ditlevsen 1927*Greenland ; Taymyr Svalbard .Dorylaimusmacrodorus de Man, 1880Svalbard ; Jan MayElshishka et al., 2012*Taymyr and Severnaya Zemlya, Russia .Baqri & Jairajpuri, 1974Taymyr and Severnaya Zemlya, Russia .Loof, 1971*Svalbard ; Taymyr Thorne, 1939Taymyr and Severnaya Zemlya, .Enchodelusarquatus Thorne, 1939Nunavut, Canada ; Taymyr DorylaimusconicaudatusEnchodelusconicaudatus Ditlevsen, 1927*; Svalbard ; GreenlaAltherr, 1952Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Eudorylaimusalleni Brzeski, 1962*Svalbard .Andr\u00e1ssy, 2003*Alaska .Ebsary, 1984*Nunavut, Canada .Loof, 1971*Svalbard ; Alaska Thorne, 1939Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Heyns, 1969Taymyr and Severnaya Zemlya, Russia .Loof & Jairajpuri, 1968Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Thorne, 1939Svalbard ; Taymyr Steiner, 1914Taymyr and Severnaya Zemlya, Russia .Thorne, 1939Svalbard ; Taymyr Baqri & Jairajpuri, 1969Taymyr and Severnaya Zemlya, Russia .Thorne, 1939Taymyr and Severnaya Zemlya, Russia .Lena River estuary, Russia ; Taymyr Gagarin, 1984Taymyr and Severnaya Zemlya, Russia .Coetzee, 1968Taymyr and Severnaya Zemlya, Russia .Schneider, 1925Northwest territories, Canada .Skwarra, 1921Nunavut, Canada .Mulvey, 1978*Northwest territories, Canada .Gagarin, 1991*Taymyr and Severnaya Zemlya, Russia .Bastian, 1865Northwest territories, Canada ; Taymyr Mulvey, 1978*Northwest territories, Canada .Nunavut, Canada ; Taymyr Gagarin, 2001*Novaya Zemlya and Vaigach island, Russia .Svalbard ; NunavutCobb, 1917Nunavut, Canada .Gagarin, 2000*Lena River estuary, Russia .Mononchusspectabilis Ditlevsen, 1911Greenland .Taymyr and Severnaya Zemlya, Russia .Mononchuspapillatus Bastian, 1865Jan Mayen ; GreenlaMulvey, 1978*Nunavut, Canada .Northwest territories, Canada .Alaska .Iotonchuszschokkei Taymyr and Severnaya Zemlya, Russia .Mononchusbrachyuris B\u00fctschli, 1873Greenland ; Alaska Gagarin, 1993Novaya Zemlya and Vaigach island, Russia .Cobb, 1917Taymyr and Severnaya Zemlya, Russia .Northwest territories, Canada .Taymyr and Severnaya Zemlya, Russia .Andr\u00e1ssy, 2003*Alaska .Gagarin, 1999*Chromadoridaarctica Gagarin, 1999 (lapsus)Novaya Zemlya and Vaigach island, Russia .Lena River estuary, Russia ; Taymyr Novaya Zemlya and Vaigach island, Russia .CyatholaimusmicoletzkyiAchromadorasteineri Mulvey, 1969 Steiner, 1916*; Taymyr and Severnaya Zemlya, Russia ; Novaya Nunavut, Canada ; Taymyr Altherr, 1952Svalbard .Svalbard .Cyatholaimusornatus Steiner, 1916*Greenland ; Nunavutde Man, 1880Ethmolaimusarcticus Steiner, 1916*Nunavut, Canada ; Lena Ride Man, 1880Taymyr and Severnaya Zemlya, Russia .Microlaimusarcticus Mulvey 1969*Nunavut, Canada ; Novaya Lena River estuary, Russia ; Taymyr Mulvey, 1969*Nunavut, Canada .Taymyr and Severnaya Zemlya, Russia .Gagarin, 1993*Taymyr and Severnaya Zemlya, Russia .Gagarin, 2000*Lena River estuary, Russia .Novaya Zemlya and Vaigach island, Russia .Monhysteraagilis de Man, 1880Jan Mayen ; Taymyr Schuurmans Stekhoven, 1935Novaya Zemlya and Vaigach island, Russia .Andr\u00e1ssy, 1981Novaya Zemlya and Vaigach island, Russia .Monhysteradispar Bastian, 1865Svalbard ; NunavutMonohysterafiliformisMonhysterafiliformis Butschlii, 1873 (lapsus) Bastian, 1865 (lapsus); Svalbard ; Lena RiGagarin, 1997*Novaya Zemlya and Vaigach island, Russia .Gagarin, 1996Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Monohysterapseudobulbosa Daday, 1896 (lapsus)Greenland .Taymyr and Severnaya Zemlya, Russia .Monhysterasimplex de Man, 1880Taymyr and Severnaya Zemlya, Russia .Gagarin, 1991Novaya Zemlya and Vaigach island, Russia .MonhysteravulgarisMonohysteravulgaris de Man, 1880 (lapsus) de Man, 1880; Svalbard ; Jan MayNovaya Zemlya and Vaigach island, Russia .Monhysteraparavillosa Meyl, 1954Nunavut, Canada .Monohysteravillosa Butschli, 1873 (lapsus)Svalbard ; Taymyr Monhysteradisjuncta Bastian, 1865Jan Mayen ; Novaya Gagarin, 1997*Novaya Zemlya and Vaigach island, Russia .Bastian, 1865Svalbard ; Taymyr Monhysteramacrura de Man, 1880Jan Mayen .EumonhysterabidenticulataTridentulusdiplodenticulata Gagarin, 1997 (lapsus); Eumonhysteradiplodenticulata Gagarin, 1997 (lapsus) Gagarin, 1997*; Novaya Zemlya and Vaigach island, Russia .Tridentulusobscurus Gagarin, 2000Novaya Zemlya and Vaigach island, Russia .Andr\u00e1ssy, 1959Taymyr and Severnaya Zemlya, Russia .de Man, 1880Taymyr and Severnaya Zemlya, Russia .de Man, 1880Svalbard ; Nunavutde Man, 1880Greenland .Taymyr and Severnaya Zemlya, Russia .Anaplectussubmersus Svalbard ; Alaska Plectusgranulosus Bastian, 1865Svalbard ; Jan MayAllen and Noffsinger, 1968Svalbard .Andr\u00e1ssy, 2003*Alaska .Periplectuslabiosus Sanwal, 1968*Nunavut, Canada .Andr\u00e1ssy, 2003*Alaska .Bastian, 1865Svalbard ; Alaska Ebsary, 1985Svalbard .Andr\u00e1ssy, 1984Svalbard .Butschli, 1873Svalbard .B\u00fctschli, 1873Ceratoplectusassimilis Svalbard ; GreenlaZullini, 1978Plectusthornei sensu Zell, 1993Nunavut, Canada .Bastian, 1865Svalbard ; Jan MayB\u00fctschli, 1873Svalbard ; IcelandMaggenti, 1961Ceratoplectuscornus Svalbard ; Taymyr Maggenti, 1961Taymyr and Severnaya Zemlya, Russia .de Man, 1880Plectusminor Novikova & Gagarin, 1971Svalbard ; Jan MayAndr\u00e1ssy, 1958Svalbard ; Alaska Cobb, 1893Nunavut, Canada .Butschli, 1873Svalbard ; Jan MayKuzmin, 1979Svalbard .Yeates, 1970Svalbard .Andr\u00e1ssy, 1952Svalbard .de Man, 1880Lena River estuary, Russia ; Taymyr Bastian, 1865PlectuscirratusBastian, 1865f.parietinus Bastian, 1865Svalbard ; Jan MayBastian, 1865Svalbard ; Icelandde Man, 1880PlectuscirratusBastian, 1865var.rhizophilus de Man, 1880Svalbard ; Jan MayZell, 1993Iceland .Bastian, 1865Lena River estuary, Russia ; Taymyr Maggenti, 1961Iceland ; Taymyr Bastian, 1865Svalbard .Plectusauriculatus B\u00fctschli, 1873Jan Mayen ; NunavutLoof, 1971*Svalbard .Anderson, 1966*Nunavut, Canada .Taymyr and Severnaya Zemlya, Russia ; Novaya TeratocephaluscrassidensEuteratocephaluscrassidens de Man, 1880; Svalbard ; Jan MayTaymyr and Severnaya Zemlya, Russia .de Man, 1880Taymyr and Severnaya Zemlya, Russia .Andr\u00e1ssy, 1958Teratocephalusdecarinus Anderson, 1969*Svalbard ; NunavutAndr\u00e1ssy, 1968Teratocephalussubvexus Anderson, 1969*Nunavut, Canada .Anderson, 1969*Svalbard ; NunavutAndr\u00e1ssy, 1958Taymyr and Severnaya Zemlya, Russia .Svalbard ; Jan MayCheilobusquadrilabiatus Cobb, 1924Taymyr and Severnaya Zemlya, Russia .Loof, 1971*Svalbard .Svalbard ; Taymyr de Man, 1876Cephalobusfiliformis species inquirendaJan Mayen .Bastian, 1865Svalbard ; Jan MayCephalobusbuetschlii de Man, 1884Svalbard ; Jan MayLoof, 1971*Svalbard .Cephalobusnanus de Man, 1880Svalbard .Svalbard .Loof, 1971*Svalbard .Taymyr and Severnaya Zemlya, Russia .Cephalobusoxyuroides de Man, 1876Svalbard ; Jan MayDe Coninck, 1943Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .CephalobuselongatusHeterocephalobuselongatus de Man, 1880; Svalbard ; Jan MayTaymyr and Severnaya Zemlya, Russia .Sumenkova in Sumenkova & Razjivin, 1968Chiloplacussaccatus Loof, 1971*Svalbard .Taymyr and Severnaya Zemlya, Russia .Steiner, 1940Taymyr and Severnaya Zemlya, Russia .CervidellusinsubricusYpsylonellusinsubricus ; Taymyr and Severnaya Zemlya, Russia .Stegelletamucronata Loof, 1971*Svalbard .CervidellusserratusYpsylonellusvexilliger ; Svalbard ; Taymyr Bostr\u00f6m, 1987*Svalbard .von Linstow, 1877Svalbard ; Taymyr Sanwal, 1965*Svalbard ; NunavutFranklin, 1952Lena River estuary, Russia .Haque, 1968Taymyr and Severnaya Zemlya, Russia .Aphelenchusgoeldii Steiner, 1914Jan Mayen .Sanwal, 1965*Nunavut, Canada ; Taymyr Aphelenchusmodestus de Man, 1876Jan Mayen ; Taymyr Gagarin, 1997*Novaya Zemlya and Vaigach island, Russia .Franklin, 1957Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Greenland ; Taymyr Tylenchuscostatus de Man, 1921Svalbard ; GreenlaLoof, 1971*Svalbard .TylenchusleptosomaAnguillulinaleptosoma ; Filenchusleptosoma de Man, 1880; Svalbard ; Jan MayTylenchuscylindricaudus Wu, 1969*Nunavut, Canada .Lena River estuary, Russia .LelenchusdiscrepansOttolenchusdiscrepans Andr\u00e1ssy, 1954; Taymyr and Severnaya Zemlya, Russia .Tylenchusditissimus Brzeski, 1963Taymyr and Severnaya Zemlya, Russia .Greenland .FilenchusfiliformisTylenchusfiliformis B\u00fctschli, 1873; Tylenchus (Filenchus) filiformis B\u00fctschli, 1873 species inquirenda; Taymyr and Severnaya Zemlya, Russia ; Novaya Greenland .TylenchushazenensisDactylotylenchusfiliformis Wu, 1969* Wu, 1969*; Nunavut, Canada .Filenchusminutus species inquirendaTaymyr and Severnaya Zemlya, Russia .Greenland .Andr\u00e1ssy, 1954Tylenchusaquilonius Wu, 1969*Greenland ; NunavutGreenland .Tylenchusthornei Andr\u00e1ssy, 1954Svalbard ; Taymyr Andr\u00e1ssy, 1968Lena River estuary, Russia ; Taymyr Tylenchusbryophilus Steiner, 1914Svalbard ; Novaya Ottolenchussulcis Wu, 1970*Nunavut, Canada .Bastian, 1865AnguillulinadavaineiFilenchusdavainei ; Svalbard ; Jan MayWu, 1969*Nunavut, Canada .Wu, 1969*Nunavut, Canada .Mulveyotushyalacus Anderson & Ebsary, 1982*Nunavut, Canada .Tylenchorhynchusarcticus Mulvey, 1969*Svalbard ; NunavutMerliniusbrevidens Taymyr and Severnaya Zemlya, Russia .Merliniuscircellus Anderson & Ebsary, 1982*Nunavut, Canada .Tetylenchusjoctus Thorne, 1949Taymyr and Severnaya Zemlya, Russia .TetylenchusjoctusMerliniusloofi Siddiqi, 1979 sensu Loof, 1971; Svalbard .Tylenchorhynchusmicrodorus Geraert, 1966Svalbard .Merliniustetylus Anderson & Ebsary, 1982*Nunavut, Canada .Powers, Baldwin & Bell, 1983*Alaska .Tylenchorhynchusgrandis Allen, 1955Taymyr and Severnaya Zemlya, Russia .Tylenchorhynchusleptus Allen, 1955Svalbard ; GreenlaTaymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Tylenchorhynchusparobscurus Mulvey, 1969*Nunavut, Canada .Bitylenchusdubius Taymyr and Severnaya Zemlya, Russia .Allen, 1955GeocenamusnanusMerliniusnanus ; Greenland ; Taymyr Allen, 1955Svalbard .Allen, 1955Bitylenchusparvus Taymyr and Severnaya Zemlya, Russia .Pararotylenchusbrevicaudatus Taymyr and Severnaya Zemlya, Russia .Perry in Perry, Darling & Thorne, 1959Greenland .Loof, 1971*Svalbard ; GreenlaYuen, 1964Taymyr and Severnaya Zemlya, Russia .Winslow, 1958Svalbard .Tylenchorhynchusmagnicauda Svalbard .Anguillulinapratense Jan Mayen .Tylenchusgracilis Cobb (lapsus)Svalbard .Gagarin, 2000*Novaya Zemlya and Vaigach island, Russia .Cobb in Taylor, 1936Criconemoideshemispaericaudatus Wu, 1965*Svalbard ; NunavutParatylenchusmacrophallusAnguillulinamacrophallum species inquirenda; Jan Mayen .Jenkins, 1956Greenland .Nunavut, Canada .Ditylenchusaskenasyi Taymyr and Severnaya Zemlya, Russia .Brzeski, 1991Greenland .Anderson & Mulvey, 1980*Nunavut, Canada .Heyns, 1964Greenland .Taymyr and Severnaya Zemlya, Russia .Thorne, 1941Nunavut, Canada ; Taymyr Khan, 1965Nunavut, Canada .Mulvey, 1969*Nunavut, Canada .Andr\u00e1ssy, 1960Nunavut, Canada .Nunavut, Canada .Mulvey, 1969*Nunavut, Canada .Das, 1964*Nunavut, Canada .Stictylusmucronatus Thorne & Malek, 1968Greenland ; NunavutSteiner, 1914Novaya Zemlya and Vaigach island, Russia .Richters, 1905Svalbard .Lena River estuary, Russia .Taymyr and Severnaya Zemlya, Russia .Taymyr and Severnaya Zemlya, Russia .Gagarin, 1995*Lena River estuary, Russia ; Novaya Fictorangarensis Lena River estuary, Russia ; Taymyr Fictorruricola Taymyr and Severnaya Zemlya, Russia .Gagarin, 1993Taymyr and Severnaya Zemlya, Russia .Rhabditisgracilicauda de Man, 1876Jan Mayen .Anguillulinaintermedia Jan Mayen .Dujardin, 1844Rhabditisaspera B\u00fctschli, 1873Jan Mayen .Aurivillius, 1883*Inquirenda et incertae sedis.\u00a0Svalbard .Allg\u00e9n, 1953*Inquirenda et incertae sedis.\u00a0Jan Mayen .Allg\u00e9n, 1953*Inquirenda et incertae sedis.\u00a0Jan Mayen .Allg\u00e9n, 1953*Inquirenda et incertae sedis.\u00a0Jan Mayen .Gagarin, 1993*Inquirenda et incertae sedis.\u00a0Taymyr and Severnaya Zemlya, Russia .Rahm, 1924Inquirenda et incertae sedis.\u00a0Taymyr and Severnaya Zemlya, Russia .Gagarin, 1997Nomen nudum. Novaya Zemlia and Vaigach island, Russia .Aphelenchusnivalis Aurivillius, 1883 remains uncertain and its type material can not be located for re-study. After Aurivillius, the nematode fauna of Svalbard archipelago was studied by Despite of more than 130 years of research, our knowledge on the diversity and distribution of Arctic nematodes is still very incomplete and limited to only few relatively small areas of the region. The first studies of Arctic nematodes date back to 1883, when the first nematode was described from Spitzbergen . The taxPlectus are listed from the areas near H\u00fasav\u00edk and Tj\u00f6rnes by Most of the nematological research in the Iceland was focused in southern and western part of the island , which iNematode fauna of the Arctic regions of Canada is studied comparatively better. The research was focused in several localities in the Nunavut province including Bathhurst, Ellef Ringnes, Ellesmere and Somerset islands , and in Fauna of the Russian part of the Arctic lists the largest number of nematode species, including many typical freshwater nematodes, but known from only three distinct geographic regions: Novaya Zemlya archipelago together with Vaygach island, Taymyr peninsula together with Severnaya Zemlya, and the Lena River estuary. So far, only 37 species of freshwater nematodes are know from the Lena River estuary . The lisNematoda are known from the entire Arctic . Even taking into consideration relatively low variety of habitats in this region, comparing to other areas of the world, as well as the rather harsh environmental conditions, this list is considered to be very incomplete and preliminary.In summary, 391 species, belonging to 146 genera, 54 families, and 10 orders of the phylum"} +{"text": "AbstractTephritoidea and Sciomyzoidea of Finland is provided. The following families are covered: Eurygnathomyiidae, Lonchaeidae, Neottiophilidae, Pallopteridae, Piophilidae, Platystomatidae, Tephritidae, Ulidiidae (Tephritoidea); Coelopidae, Dryomyzidae, Heterocheilidae, Phaeomyiidae, Sciomyzidae, Sepsidae (Sciomyzoidea).A revised checklist of the flies of superfamilies Tephritoidea is one of the larger Diptera superfamilies. The nominotypical family of Tephritoidea, the fruit flies (Tephritidae), includes over half of the currently known species in the superfamily. The highest diversity of tephritoids occurs in the tropics. Six of the nine extant tephritoid families have been found in Finland: no richardiid, ctenostylid or pyrgotid have been found in the country. The Tephritidae, Ulidiidae and Platystomatidae (plus Pyrgotidae) form a well-defined, probably monophyletic group. The other tephritoid families are more basal in their phylogenetic position and Ulidiidae we follow Lonchaeidae of Eastern Fennoscandia. This paper is now somewhat outdated, but still valuable.With over 7800 known extant species , Tephritposition . The exaerfamily . SeveralSciomyzoidea is a smaller superfamily with some 1150 described species (Sciomyzidae and Sepsidae) and nine smaller families comprising at most 30 species. The millipede parasitoids of family Phaeomyiidae are sometimes classified as a subfamily of Sciomyzidae. The coelopids and heterocheilids, with just one species each in Finland, are closely associated with stranded marine seaweed. The family placement of Heterocheila has been rather unstable: during the last 40 years it has been placed in Helcomyzidae, Dryomyzidae and Coelopidae or regarded as having a separate family status. Here we follow the recent world catalogue LONCHAEIDAE Rondani, 1856DASIOPINAE Morge, 1963Dasiopini Morge, 1963DASIOPS Rondani, 1856Dasiopsappendiculus Morge, 1959Dasiopsfacialis Collin, 1953Dasiopsmucronatus Morge, 1959hennigi misid.= latiterebra misid.= Dasiopsoccultus Collin, 1953albiceps preocc.= Dasiopsperpropinquus Morge, 1959Dasiopsspatiosus Dasiopstrichosternalis Morge, 1959EAROMYIINAE Morge, 1963CHAETOLONCHAEA Czerny, 1934Chaetolonchaeapallipennis dasyops misid.= EAROMYIA Zetterstedt, 1842Earomyialonchaeoides Zetterstedt, 1848Earomyiaschistopyga Collin, 1953Earomyiaviridana PROTEAROMYIA McAlpine, 1962Protearomyianigra LONCHAEINAE Rondani, 1856Lonchaeini Rondani, 1856LONCHAEA Fall\u00e9n, 1820Lonchaeaaffinis Malloch, 1920laxa auct. nec Collin, 1953= PageBreakLonchaeaalbigena Collin, 1953Lonchaeaalbitarsis Zetterstedt, 1838Lonchaeabruggeri Morge, 1967? Lonchaeabukowskii Czerny, 1934Lonchaeacaledonica MacGowan & Rotheray, 2000laticornis auct. nec Meigen, 1826= Lonchaeacarpathica Kovalev, 1974Lonchaeachorea Lonchaeacollini Hackman, 1956Lonchaeacontigua Collin, 1953? Lonchaeacorusca Czerny, 1934alni Ringdahl, 1947= lauta Collin, 1953= britteni Collin, 1953= Lonchaeadefecta McAlpine, 1964Lonchaeadeutschi Zetterstedt, 1838sarekensis Frey, 1916= Lonchaeadifficilis Hackman, 1956? Lonchaeafraxina MacGowan & Rotheray, 2000Lonchaeafreyi Czerny, 1934Lonchaeafugax Becker, 1895cariecola Czerny, 1934= Lonchaeahackmani Kovalev, 1981peregrina auct. nec Becker, 1895= Lonchaeaipsiphaga McAlpine, 1964maniola misid.= Lonchaealimatula Collin, 1953flavidipennis auct. nec Zetterstedt, 1847= Lonchaeanitens krogerusi Czerny, 1934= Lonchaeapalposa Zetterstedt, 1847Lonchaeapatens Collin, 1953Lonchaearagnari Hackman, 1956Lonchaeascutellaris Rondani, 1874Lonchaeasororcula Hackman, 1956Lonchaeastackelbergi Czerny, 1934Lonchaeasubneatosa Kovalenko, 1974Lonchaeasylvatica Beling, 1873lucidiventris Becker, 1895= Lonchaeatarsata Fallen, 1820Lonchaeaultima Collin, 1953Lonchaeazetterstedti Becker, 1902PageBreakNEOTTIOPHILIDAE Hendel, 1916ACTENOPTERA Czerny, 1904Actenopterahilarella NEOTTIOPHILUM Frauenfeld, 1868Neottiophilumpraeustum PALLOPTERIDAE Loew, 1862PALLOPTERA Fall\u00e9n, 1820Pallopteraanderssoni Rotheray & MacGowan, 1999Pallopteraformosa Frey, 1930Pallopteramarginata costalis Loew, 1873= Pallopteraumbellatarum arcuata auct. nec = Pallopteraustulata Fall\u00e9n, 1820TEMNOSIRA Enderlein, 1936Temnosiraambusta Temnosirasaltuum TOXONEURA Macquart, 1835Toxoneuraephippium Toxoneuralaetabilis Toxoneuramodesta umbellatarum auct. nec = Toxoneuratrimacula Toxoneurausta Toxoneuravenusta atriventris = PIOPHILIDAE Macquart, 1835PIOPHILINAE Macquart, 1835ALLOPIOPHILA Hendel, 1917Arctopiophila Duda, 1924= Boreopiophila Frey, 1930= Parapiophila McAlpine, 1977= Allopiophilacalceata Allopiophilaflavipes Allopiophilalonchaeoides Allopiophilaluteata Allopiophilapectiniventris Allopiophilatomentosa Frey, 1930Allopiophilavulgaris Allopiophila sp. APageBreakAMPHIPOGON Wahlberg, 1845Amphipogonflavus spectrum Wahlberg, 1845= MYCETAULUS Loew, 1845Mycetaulusbipunctatus PIOPHILA Fall\u00e9n, 1810Piophilacasei PROCHYLIZA Walker, 1849Liopiophila Duda, 1924= Prochylizanigrimana Prochylizavaripes lundbecki misid.= PSEUDOSEPS Becker, 1902Pseudosepssignata STEARIBIA Lioy, 1864Stearibianigriceps foveolata = coerulescens = PLATYSTOMATIDAE Schiner, 1862PLATYSTOMA Meigen, 1803Platystomaseminationis RIVELLIA Robineau-Desvoidy, 1830Rivelliasyngenesiae TEPHRITIDAE Newman, 1834TRYPETINAE Loew, 1861 sensu latoAdramini Hendel, 1914EUPHRANTA Loew, 1862Euphrantasg. Loew, 1862Euphrantaconnexa Rhacochlaenasg. Loew, 1862Euphrantatoxoneura Trypetini Loew, 1861ACIDIA Robineau-Desvoidy, 1830Acidiacognata ANOMOIA Walker, 1835Phagocarpus Rondani, 1870= Anomoiapurmunda CHETOSTOMA Rondani, 1856Chetostomastackelbergi CORNUTRYPETA Han, Wang & Kim, 1993Cornutrypetaspinifrons PageBreakCornutrypetasuperciliata EULEIA Walker, 1835Cryptaciura Hendel, 1927= Euleiaheraclei Euleiarotundiventris MYOLEJA Rondani, 1856Myolejalucida PHILOPHYLLA Rondani, 1870Philophyllacaesio RHAGOLETIS Loew, 1862Rhagoletisalternata Rhagoletiscerasi Rhagoletismeigenii TRYPETA Meigen, 1803Trypetaartemisiae Trypetaimmaculata hamifera Loew, 1846= Trypetazoe Meigen, 1826TEPHRITINAE Newman, 1834Terellini Hendel, 1927CHAETORELLIA Hendel, 1927Chaetorelliajaceae CHAETOSTOMELLA Hendel, 1927Chaetostomellacylindrica onotrophes = ORELLIA Robineau-Desvoidy, 1830Orelliafalcata TERELLIA Robineau-Desvoidy, 1830Cerajocerasg. Rondani, 1856Terelliaceratocera Terelliaplagiata Terelliatussilaginis Terelliasg. Robineau-Desvoidy, 1830Terelliacolon Terelliaruficauda Terelliaserratulae Terelliawinthemi Xyphosiini Hendel, 1927XYPHOSIA Robineau-Desvoidy, 1830Xyphosiamiliaria Noeetini Norrbom & Korneyev, 1999ENSINA Robineau-Desvoidy, 1830Ensinasonchi PageBreakNOEETA Robineau-Desvoidy, 1830Oplocheta Rondani, 1856= Noeetapupillata Myopitini Bezzi, 1910EURASIMONA Korneyev & White, 1991Eurasimonastigma UROPHORA Robineau-Desvoidy, 1830Urophoraaprica Urophoracardui Urophoracuspidata Urophorajaceana Urophorasolstitialis sonderupi = Urophorastylata Dithrycini Hendel, 1927DITHRYCA Rondani, 1856Dithrycaguttularis Eutretini Munro, 1952XANTHOMYIA Phillips, 1923Paracarphotricha Hendel, 1927= Xanthomyiaalpestris pseudoradiata = Tephritini Newman, 1834CAMPIGLOSSA Rondani, 1870Campiglossaabsinthii parvula = Campiglossaargyrocephala Campiglossadifficilis tessellata misid.= Campiglossagrandinata borealis Portschinsky, 1875= Campiglossaguttella achyrophori misid.= producta misid.= Campiglossaloewiana Campiglossaplantaginis Campiglossapunctella Campiglossasolidaginis Campiglossa sp. ADIOXYNA Frey, 1945Dioxynabidentis sororcula auct. nec = HERINGINA Acz\u00e9l, 1940PageBreakHeringinaguttata OXYNA Robineau-Desvoidy, 1830Oxynaflavipennis Oxynanebulosa Oxynaparietina SPHENELLA Robineau-Desvoidy, 1830Sphenellamarginata TEPHRITIS Latreille, 1804Tephritisangustipennis Tephritisbardanae Tephritiscometa Tephritisconura Tephritisdilacerata Tephritisfallax Tephritishyoscyami Tephritisleontodontis Tephritismutabilis Merz, 1992Tephritisneesii nesii misspelling= Tephritisruralis Tephritissp. cf.rydeni Hering, 1956dioscurea misid.= TRUPANEA Schrank, 1795Trupaneastellata Tephritinae (incertae sedis)Unplaced in ACINIA Robineau-Desvoidy, 1830Aciniacorniculata ULIDIIDAE Macquart, 1835OTITINAE Aldrich, 1932Myennidini Kameneva & Korneyev, 2006PSEUDOTEPHRITIS Johnson, 1802Pseudotephritistrypetoptera corticalis auct. nec = Otitini Aldrich, 1932CEROXYS Macquart, 1835Ceroxysurticae HERINA Robineau-Desvoidy, 1830Herinafrondescentiae Herinapaludum Herinapalustris MELIERIA Robineau-Desvoidy, 1830Melieriasg. Robineau-Desvoidy, 1830PageBreakMelieriacrassipennis Melieriaomissa obscuripes auct. nec = TETANOPS Fall\u00e9n, 1820Eurycephalomyiasg. Hendel, 1907Tetanopssintenisi Becker, 1909Tetanopssg. Fall\u00e9n, 1820Tetanopsmyopinus Fall\u00e9n, 1820ULIDIINAE Macquart, 1835Seiopterini Kameneva & Korneyev, 1994HOMALOCEPHALA Zetterstedt, 1838Homalocephalaalbitarsis Zetterstedt, 1838bipunctata = Homalocephalaangustata Homalocephalaapicalis biseta Frey, 1908= Homalocephalabimaculata Homalocephalabiumbrata albitarsis auct. nec Zetterstedt, 1838= SEIOPTERA Kirby, 1817Seiopteravibrans Ulidiini Macquart, 1835PHYSIPHORA Fall\u00e9n, 1810Physiphoraalceae demandata = Brachycera Macquart, 1834suborder Eremoneura Lameere, 1906clade Cyclorrhapha Brauer, 1863clade Schizophora Becher, 1882infraorder Muscaria Enderlein, 1936clade Acalyptratae Macquart, 1835parvorder Sciomyzoidea Fall\u00e9n, 1820superfamily COELOPIDAE Hendel, 1910COELOPA Meigen, 1830Fucomyiasg. Haliday, 1838Coelopafrigida DRYOMYZIDAE Schiner, 1862PageBreakDRYOMYZA Fall\u00e9n, 1820Neuroctena Rondani, 1868= Dryomyzaanilis Fall\u00e9n, 1820DRYOPE Robineau-Desvoidy, 1830Dryopedecrepita Dryopeflaveola PARADRYOMYZA Ozerov, 1987Paradryomyzaspinigera Ozerov, 1987PSEUDONEUROCTENA Ozerov, 1987Pseudoneuroctenasenilis HETEROCHEILIDAE McAlpine, 1991HETEROCHEILA Rondani, 1857Heterocheilabuccata PHAEOMYIIDAE Verbeke, 1950PELIDNOPTERA Rondani, 1856Pelidnopterafuscipennis fumipennis = Pelidnopteranigripennis SCIOMYZIDAE Fall\u00e9n, 1820SCIOMYZINAE Fall\u00e9n, 1820Sciomyzini Fall\u00e9n, 1820COLOBAEA Zetterstedt, 1837Colobaeabifasciella Colobaeadistincta Colobaeanigroaristata Rozko\u0161n\u00fd, 1984Colobaeapectoralis Colobaeapunctata DITAENIELLA Sack, 1939Ditaeniellagrisescens PHERBELLIA Robineau-Desvoidy, 1830Pherbelliaalbocostata Pherbelliaalpina Pherbelliaargyra Verbeke, 1967Pherbelliabrunnipes Pherbelliacinerella Pherbelliadubia Pherbelliagoberti stylifera Rozko\u0161n\u00fd, 1982= Pherbelliagriseicollis lapponica = PageBreakPherbelliagriseola Pherbelliahackmani Rozko\u0161n\u00fd, 1982Pherbellianana Pherbelliaobscura Pherbelliaobtusa Pherbelliapallidiventris Pherbelliarozkosnyi Verbeke, 1967scutellaris misid.= Pherbelliaschoenherri Pherbelliasordida Pherbelliastackelbergi Elberg, 1965Pherbelliaventralis PTEROMICRA Lioy, 1864Pteromicraangustipennis Pteromicraglabricula Pteromicraleucopeza Pteromicraoldenbergi Pteromicrapectorosa SCIOMYZA Fall\u00e9n, 1820Sciomyzadryomyzina Zetterstedt, 1846Sciomyzasebezhica Przhiboro, 2001Sciomyzasimplex Fall\u00e9n, 1820TETANURA Fall\u00e9n, 1820Tetanurapallidiventris Fall\u00e9n, 1820Tetanocerini Newman, 1834ANTICHETA Haliday, 1839Antichetaanalis Antichetaatriseta Antichetabrevipennis Antichetanigra Karl, 1921nigroaenea Frey, 1935= COREMACERA Rondani, 1856Coremaceramarginata tristis preocc.= DICHETOPHORA Rondani, 1868Dichetophorafinlandica Verbeke, 1964DICTYA Meigen, 1803Dictyaumbrarum ECTINOCERA Zetterstedt, 1838Ectinoceraborealis Zetterstedt, 1838ELGIVA Meigen, 1838Elgivacucularia Elgivadivisa PageBreakElgivasolicita sundewalli Kloet & Hincks, 1945= EUTHYCERA Latreille, 1829Euthycerachaerophylli Euthycerafumigata HYDROMYA Robineau-Desvoidy, 1830Hydromyadorsalis ILIONE Haliday in Curtis, 1837Tumidicerus Knutson & Berg, 1967= Ilionesg. Haliday in Curtis, 1837Ilionelineata Knutsoniasg. Verbeke, 1964Ilionealbiseta LIMNIA Robineau-Desvoidy, 1830Limniapaludicola Elberg, 1965Limniaunguicornis PHERBINA Robineau-Desvoidy, 1830Pherbinacoryleti PSACADINA Enderlein, 1939Psacadinazernyi punctata misid.= RENOCERA Hendel, 1900Renocerapallida Renocerastriata Renocerastroblii Hendel, 1900fuscinervis auct. nec = SEPEDON Latreille, 1804Sepedonsg. Latreille, 1804Sepedonsphegea Sepedonspinipes TETANOCERA Dum\u00e9ril, 1800Chaetotetanocerasg. Mayer, 1953Tetanocerarobusta Loew, 1847Tetanocerasg. Dum\u00e9ril, 1800Tetanoceraamurensis Hendel, 1909? Tetanoceraarrogans Meigen, 1830Tetanoceraelata Tetanoceraferruginea Fall\u00e9n, 1820brunnipennis Frey, 1924= Tetanocerafreyi Stackelberg, 1963Tetanocerafuscinervis unicolor Loew, 1847= Tetanocerahyalipennis von Roser, 1840PageBreakTetanocerakerteszi Hendel, 1901griseicollis Frey, 1924= ornatifrons Frey, 1924= Tetanoceralapponica Frey, 1924Tetanoceralatifibula Frey, 1924Tetanoceramontana Day, 1881borealis Frey, 1924= Tetanoceraphyllophora Melander, 1920nigricosta misid.= Tetanocerasilvatica Meigen, 1830TRYPETOPTERA Hendel, 1900Trypetopterapunctulata SEPSIDAE Walker, 1833ORYGMATINAE Frey, 1921ORTALISCHEMA Frey, 1925Ortalischemaalbitarse SEPSINAE Walker, 1833THEMIRA Robineau-Desvoidy, 1830Themiraannulipes Themiraarctica Themirabiloba Andersson, 1975Themiragermanica Duda, 1926Themiragracilis Themiraleachi Themiralucida Themiramalformans Melander & Spuler, 1917Themiraminor Themiranigricornis Themirapaludosa Elberg, 1963Themirapusilla Themiraputris Themirasuperba SALTELLA Robineau-Desvoidy, 1830Saltellasphondylii NEMOPODA Robineau-Desvoidy, 1830Nemopodanitidula cylindrica preocc.= Nemopodapectinulata Loew, 1873Nemopodaspeiseri MEROPLIUS Rondani, 1874Meropliusfukuharai Meropliusminutus PageBreakstercorarius = SEPSIS Fall\u00e9n, 1810Sepsisbiflexuosa Strobl, 1893Sepsiscynipsea Sepsisduplicata Haliday, 1838pilipes van der Wulp, 1871= Sepsisflavimana Meigen, 1826borealis Frey, 1825= Sepsisfulgens Meigen, 1826communis Frey, 1925= Sepsisluteipes Melander & Spuler, 1917lamellifera Frey, 1925= Sepsisnigripes Meigen, 1826Sepsisorthocnemis Frey, 1908Sepsispunctum luteipes misid.= Sepsisthoracica Sepsisviolacea Meigen, 1826Allopiophiladudai not found within present bordersBactrocera sp. imported with fruitCampiglossairrorata not found within present bordersCeratitiscapitata imported with fruitEaromyiacrystallophila not found within present bordersnigroviolacea = Lonchaeahirticeps Zetterstedt, 1838 misidentifiedOrygmaluctuosum Meigen, 1830 not found within present bordersPherbelliadorsata misidentifiedTephritisnigricauda misidentifiedAllopiophiladudai . This species was described by Allopiophila sp. A. An apparently undescribed arctic species near Allopiophilavulgaris.Campiglossa sp. A is a distinct, possibly undescribed species of Campiglossa. It is common on Saussureaalpina in Northern Finland .PageBreakLonchaeabruggeri Morge, 1967, Lonchaeacontigua Collin, 1953 and Lonchaeadifficilis Hackman, 1956. No males have been confirmed from the country. See Lonchaeabukowskii Czerny, 1934. No males have been confirmed from the country.Tephritissp. cf.rydeni Hering, 1956. Finnish material formerly assigned to Tephritisdioscurea belongs to a currently unrecognised species that may be Tephritisrydeni Hering (i Hering .Tetanoceraamurensis Hendel, 1909. Recorded from Finland in Fauna Europaea (Europaea and knowEuropaea . We have"} +{"text": "AbstractBackgroundChalcidoidea and Mymarommatoidea substantially updates the previous comprehensive checklist, dating from 1978. Country level data is reported where known.A revised checklist of the British and Irish New informationChalcidoidea species represents a 22% increase on the number of British species known in 1978.A total of 1754 British and Irish Hymenoptera of Britain and Ireland, starting with Hymenoptera species recorded reliably from Britain and Ireland.This paper continues the series of checklists of the Chalcidoidea is one of the largest and most diverse Hymenoptera superfamilies. Most species are under 3mm, and the group includes the smallest known winged insect, Kikikihuna Huber & Beardsley (a mymarid not found in the British Isles) measuring only 0.16 mm in body length , which contains original citations as well as references for all subsequent generic combinations and synonymies, and extensive lists of published host and distribution records. While the latter can be used to generate regional lists of Chalcidoidea, a British and Irish species list extracted from the UCD will not match the present checklist, from which published erroneous records have been removed and to which a large number of unpublished records based on reliably identified specimens in collections have been added.With more than 22,000 described species worldwide, y length . ChalcidChalcidoidea families are recognized, 16 of which are represented in the British and Irish fauna. There have been some changes to the family-level classification recently tribe Miscogasterini recently and morehecklist include erfamily , the resasterini , the inclophinae , and theomalinae .Chalcidoidea list, with 1754 species, is now 22% larger than in 1978 , Tetrastichustompanus (Erd\u00f6s) and Entedonulmi Erd\u00f6s. A detailed comparison of the 1978 checklist with the 2016 checklist can be found in Suppl. material The British and Irish Hymenoptera section, NHM Wasps.Some of the diversity of British chalcids is illustrated in Figs UCD, with further editing and research by the authors. Nomenclature follows the UCD, and distribution data are taken from the collections of the BMNH, the UCD and from various published sources, which are cited. Nomenclatural acts can be traced through the UCD; deviations from that source are cited. A more complete methodology can be found in UCD.The bulk of the data behind this checklist is from the The following conventions and abbreviations are used here:species] taxon deleted from the British and Irish list. nomen dubium, a name of doubtful status - England - Wales - England - England - England (included as a tentative synonym of Choreiainepta by Bou\u010dek & Graham (1978)) - England - England][suada nom. dub.] - listed as British by . - Recorded as new to Britain by [Bou\u010dek, 1994EnglandAdded by Bou\u010dek (1994)(Fonscolombe 1832)Cynipsaffinis Fonscolombe, 1832apicalisCallimome) Callimomeamurensis Walker, 1874England, IrelandCallimomeangelicae Walker, 1836abdominalis Boheman, 1834 preocc.IrelandT.cingulatus by Bou\u010dek and Graham (1978)Listed as a synonym of Boheman, 1834nobilis England, IrelandCallimomearundinis Walker, 1833compactusCallimome) Cynipsaurata M\u00fcller, 1764nigricornutusCynipsichneumon) Callimomebasalis Walker, 1833viridiaeneusCallimome) Ichneumonbedeguaris Linnaeus, 1758viridisCynips) ?elegans Boheman, 1834foersteri Ratzeburg, 1844divisusCallimome) Boheman, 1834Added by Graham and Gijswijt (1998)Graham & Gijswijt, 1998EnglandAdded by Graham and Gijswijt (1998)Graham & Gijswijt, 1998ScotlandAdded by Graham and Gijswijt (1998)Graham & Gijswijt, 1998EnglandAdded by Graham and Gijswijt (1998)Boheman, 1834distinctus F\u00f6rster, 1841Graham & Gijswijt, 1998EnglandAdded by Graham and Gijswijt (1998)Boheman, 1834Callimomechloromerus Walker, 1833abdominalisCallimome) Callimomeconfinis Walker, 1833curtusCallimome) Ratzeburg, 1844Added by Graham and Gijswijt (1998)Boheman, 1834Added by Graham and Gijswijt (1998)Graham & Gijswijt, 1998England, WalesAdded by Graham and Gijswijt (1998)Graham & Gijswijt, 1998EnglandAdded by Graham and Gijswijt (1998)Walker, 1847dubius Ratzeburg, 1848eurynotusCallimome) Ichneumonerucarum Schrank, 1781fulgensIchneumon) Fabricius, 1798 (purpurascensCynips) Boheman, 1834robustus Ratzeburg, 1852EnglandGraham & Gijswijt, 1998EnglandAdded by Graham and Gijswijt (1998)Callimomeflavipes Walker, 1833auratusCynips) preocc. Callimomeformosus Walker, 1833amoenus Boheman, 1834compressus F\u00f6rster, 1841EnglandCallimomefuscicornis Walker, 1833posticusCallimome) Boheman, 1834EnglandCallimomegeranii Walker, 1833cyniphidum Ratzeburg, 1844lusitanicus Tavares, 1901EnglandGraham & Gijswijt, 1998EnglandAdded by Graham and Gijswijt (1998)Bou\u010dek, 1994England, WalesAdded by Bou\u010dek (1994)Callimomehederae Walker, 1833Graham & Gijswijt, 1998EnglandAdded by Graham and Gijswijt (1998)Wachtl, 1883EnglandGraham, 1994EnglandAdded by Graham (1994)Mayr, 1874EnglandRondani, 1877bakkendorfiCallimome) Ichneumonjuniperi Linnaeus, 1758maestusCallimome) Callimomelaetus Walker, 1833congruens F\u00f6rster, 1841rufipes F\u00f6rster, 1841hormomyiae Kieffer, 1899England, IrelandGraham, 1994EnglandAdded by Graham (1994)Graham & Gijswijt, 1998EnglandAdded by Graham and Gijswijt (1998)Callimomemicrocerus Walker, 1833aeropeCallimome) Callimomemicrostigma Walker, 1833brevicaudaCallimome) ?pruni Cameron, 1883EnglandCallimomenigritarsus Walker, 1833alpinus Thomson, 1876taxi Ruschka, 1921EnglandCallimomenitidulus Walker, 1833pallidicornis Boheman, 1834nanulusCallimome) Callimomenotatus Walker, 1833incrassataSyntomaspis) Mayr, 1874Added by Bou\u010dek (1994)Ruschka, 1921schiodteiCallimome) Graham & Gijswijt, 1998EnglandAdded by Graham and Gijswijt (1998)Thomson, 1876IrelandGraham & Gijswijt, 1998WalesAdded by Graham and Gijswijt (1998)Boheman, 1834macrocentrus Ratzeburg, 1852Callimomeregalis Walker, 1833Callimomeroboris Walker, 1833nitidulus Nees, 1834 preoccEngland(Schrank 1781)Cynipsrubi Schrank, 1781macropterusCallimome) Callimomescutellaris Walker, 1833auronitens F\u00f6rster, 1841pleuralis Thomson, 1876EnglandBoheman, 1834Added by Graham and Gijswijt (1998)Graham, 1994EnglandAdded by Graham (1994)Ruschka, 1921Added by Jennings (2009d)Zetterstedt, 1838pumilus Ratzeburg, 1844EnglandRuschka, 1921EnglandCallimomevarians Walker, 1833annellusSyntomaspsis) Cinipsventralis Fonscolombe, 1832antennatusCallimome) Grissell, 1995Masi, 1921HOLASPIS 1874 preocc.SENEGALELLA Risbec, 1951THIESIA Risbec, 1951Callimomearvernicus Walker, 1833dubiusTorymus) Callimomefrontinus Walker, 1851carinataHolaspis) (Boheman 1834)Torymusmilitaris Boheman, 1834parellinusTorymus) Callimomenephthys Walker, 1848EnglandRuschka, 1923medicaginis misident.P.medicaginis was listed as doubtfully British by P.salicis.Walker, 1871DIMEROMICRUS Crawford, 1910MACRODONTOMERUS Girault, 1913DIDACTYLIOCERUS Masi, 1916AMEROMICRUS Nikol'skaya, 1954PONDOTORYMUS Bou?ek, 1978(Mayr 1874)Holaspiskiesenwetteri Mayr, 1874longicaudaDimeromicrus) F\u00f6rster, 1856WEBSTERELLUS Ashmead, 1893Torymuscaliginosus Walker, 1833fulvocinctus F\u00f6rster, 1859intermedius F\u00f6rster, 1859macromerus F\u00f6rster, 1859F\u00f6rster, 1856OLIGOSTHENUS F\u00f6rster, 1856(Fabricius 1793)Ichneumonstigma Fabricius, 1793aterTorymus) Lochitespapaveris F\u00f6rster, 1856EnglandAdded by Jennings (2007c)Ashmead, 1904Girault, 1912Girault, 1911LATHROMEROIDES Girault, 1913DIACLAVA Blood & Kryger, 1928KRYGERIOLA Novicki, 1934THALESANNA Girault, 1938LENGERKENIOLA Novicky, 1946ENCYRTOGRAMMA De Santis, 1957TANYGRAMMA De Santis, 1957Diaclavawaterhousei Blood & Kryger, 1928EnglandWalker, 1851CENTROBIA F\u00f6rster, 1856CENTROBIELLA Girault, 1912RATZEBURGALLA Girault, 1938Walker, 1851IrelandPteroptrixdoricha Walker, 1839errataCentrobia) Centrobiasilvestrii Kryger, 1920Trichogrammawalkeri F\u00f6rster, 1851F\u00f6rster, 1856LATHROMERELLA Girault, 1912GAROUELLA Risbec, 1956F\u00f6rster, 1856italicaLathromerella) Orthoneurabimaculata Blood, 1923EnglandGirault, 1913NEOCENTROBIA Blood, 1923STEPHANOTHEISA Soyka, 1931GRANTANNA Girault, 1939Centrobiafoersteri Kryger, 1919hirticornisNeocentrobia) Centrobiafumipennis Blood, 1923princeps Steffan, 1954EnglandNowicki, 1940Nowicki, 1940Ashmead, 1904Girault, 1914Brachystirapungens Mayr, 1904platoni Girault, 1914nigraBrachista) Brachistarufina Nowicki, 1936Girault, 1916PAROLIGOSITA Girault & Dodd, 1915 preocc.Oligositanudipennis Kryger, 1919Timberlake, 1924EnglandMegaphragma have been found in England ; listed here as a record of this genus from Britain and Ireland.BMNH, det. Noyes & Polaszek, added here. Two unidentified species of Walker, 1851WESTWOODELLA Ashmead, 1904PAROLIGOSITA Kurdjumov, 1911Pteroptrixacestes Walker, 1839werneriChaetostricha) Oligositakrygeri Girault, 1929pulchraChaetostricha) Monorthochaetapulchella Claridge, 1959EnglandHaliday, 1851Haliday, 1851Girault, 1915TRACHOCERA Blood & Kryger, 1928Asynactalongicauda Blood, 1923longicaudaTrachocera) preocc. Westwood, 1833CALLEPTILES Haliday, 1833PENTARTHRON Riley, 1872APROBOSCA Westwood, 1879OOPHTHORA Aurivillius, 1898XANTHOATOMUS Ashmead, 1904NEOTRICHOGRAMMA Girault, 1911NUNIELLA Kostadinov, 1988Marchal, 1927cacoeciae misspelling,flavum Marchal, 1936EnglandAdded by Fursov and Pintureau (1999)Birova & Kazimirova, 1997EnglandAdded by Fursov (2000)Dugast & Voegel\u201a 1984EnglandAdded by Fursov (2000)Matsumura, 1926pallida Meyer, 1940EnglandBMNH, det. Stouthamer, added hereWestwood, 1833latipennisCalleptiles) Riley, 1871minutissimum Packard, 1881odontotae Howard, 1885intermedium Howard, 1889albipesXanthoatomus) Anagrusniveiscapus Morley, 1950EnglandOophthorasemblidis Aurivillius, 1898schuberti Voegel\u201a & Russo, 1982EnglandDyurich, 1987EnglandAdded by Fursov (2000)Girault, 1911Trichogrammastammeri Novicky, 1946EnglandBMNH, det. Fursov, added hereDebauche, 1948Serphitoidea, with the extinct family Serphitidae, but there is very little justification for this other than the two-segmented petiole, the families being otherwise dissimilar Petiolariaanomala Blood & Kryger, 1922EnglandSupplementary material 1Chalcidoidea checklist 2016 dataBritish and Irish Data type: namesBrief description: Names of species included in the 2016 checklist, with notes and synonymyFile: oo_86736.xlsxNatalie Dale-SkeySupplementary material 2Comparison of 1978 checklist species with 2016 checklistData type: namesBrief description: This document lists the valid species included in the 1978 checklist with their corresponding entry in the 2016 checklist, indicating name changes and exclusions. It includes lists of the species lost and gained through taxonomic changes.File: oo_86644.xlsxNatalie Dale-SkeySupplementary material 3Taxa added from collections surveysData type: namesChalcidoidea checklist based on reliably identified specimens in collectionsBrief description: A list of new (unpublished) records in the British and Irish File: oo_86606.xlsxNatalie Dale-Skey"} +{"text": "AbstractSimuliidae (Diptera) is provided for Finland and recognizes 56 species. One new record has been added (Simuliumlatipes) and one name sunken in synonymy (Simuliumcarpathicum). Furthermore, Simuliumtsheburovae is treated as a doubtful record.A checklist of the family Simuliidae is a relatively small family of nematoceran flies, comprised of 2,163 species world-wide PROSIMULIUM Roubaud, 1906Prosimuliumhirtipes Prosimuliumluganicum Rubtsov, 1956Prosimuliummacropyga Prosimuliumursinum Simuliini Newman, 1834tribe CNEPHIA Enderlein, 1921Cnephiaeremites Shewell, 1952Cnephiapallipes lapponica = GRENIERA Doby & David, 1959Grenieraivanovae Ivashchenko, 1970METACNEPHIA Crosskey, 1969Metacnephiabilineata saileri = Metacnephialyra tabescentifrons = trigoniformis Yankovsky, 2003= Metacnephiatredecimata SIMULIUM Latreille, 1802Boophthorasg. Enderlein, 1921Simuliumerythrocephalum Eusimuliumsg. Roubaud, 1906Simuliumangustipes Edwards, 1915securiforme = PageBreakSimuliumaureum Fries, 1824Simuliumvelutinum Boreosimuliumsg. Rubzov & Yankovsky, 1982Simuliumannulus Simuliumbaffinense Twinn, 1936Simuliumcrassum Hellichiellasg. Rivosecchi & Cardinali, 1975Simuliumdogieli Simuliumlatipes Simuliumusovae Nevermanniasg. Enderlein, 1921Cnetha Enderlein, 1921= Simuliumangustitarse Simuliumbeltukovae carpathicum = Simuliumbicorne Dorogostaisky, Rubtsov & Vlasenko, 1935Simuliumcryophilum carthusiensef.brevicaulis Dorier & Grenier, 1961= Simuliumcurvans Simuliumdendrofilum Simuliumfontinale Radzivilovskaya, 1948Simuliumjuxtacrenobium Bass & Brockhouse, 1990Simuliumlundstromi Simuliumsilvestre Simuliumvernum Macquart, 1826pritzkowi = Schoenbaueriasg. Enderlein, 1921Simuliumpusillum Fries, 1824Simuliumsubpusillum Rubtsov, 1940Simuliumsg. Latreille, 1802Simuliumannulitarse Zetterstedt, 1838Simuliumargyreatum Meigen, 1838Simuliumfrigidum Rubtsov, 1940Simuliumintermedium Roubaud, 1906Simuliumlongipalpe Beltyukova, 1955curvistylus Rubtsov, 1957= Simuliummonticola Friederichs, 1920Simuliummorsitans Edwards, 1915Simuliummurmanum Enderlein, 1935forsi = Simuliumnoelleri Friederichs, 1920Simuliumornatum Meigen, 1818Simuliumparamorsitans Rubtsov, 1956PageBreakSimuliumposticatum Meigen, 1838austeni Edwards, 1915= verecundum misid.= Simuliumreptans Simuliumrostratum sublacustre Davies, 1966= Simuliumrubtzovi Smart, 1945Simuliumtransiens Rubtsov, 1940Simuliumtruncatum Simuliumtuberosum Simuliumtumulosum Rubtsov, 1956Simuliumvulgare Dorogostaisky, Rubtsov & Vlasenko, 1935Wilhelmiasg. Enderlein, 1921Simuliumequinum zetlandense = STEGOPTERNA Enderlein, 1930Stegopternatrigonium richteri = Simuliumfuscipes see NotesSimuliumlineatum misidentified, most likely SimuliumequinumSimuliummeigeni Rubzov & Carlsson, 1965 see Notespygmaeum of some authors= Simuliumtsheburovae see NotesSimuliumfuscipes . Simuliumruficorne species group in the subgenus Nevermannia, but no known records exist from Finland.Simuliummeigeni Rubzov & Carlsson, 1965. Simuliummeigeni within the subgenus Hellichiella, but there are no known records of this species in Finland. The name pygmaeum in pygmaeum that is a synonym for pusillum, not meigeni . No confirmed records of this species exist from Finland (Hellichiella ( Finland , and theichiella .PageBreak"} +{"text": "Outcomes were assessed by 27-joint JADAS (JADAS27), based on C-reactive protein, and Childhood Health Assessment Questionnaire Disability Index (CHAQ-DI). MDA was defined as JADAS27<3.8 and normal function as CHAQ-DI<0.5. Pts who entered the DB phase were included; data were stratified by MTX treatment (tx) at entry.This At baseline, 75 pts on MTX had a mean JADAS27 of 21.2 and CHAQ-DI of 0.9, and 58 pts who were MTX na\u00efve or had withdrawn from MTX had a mean JADAS27 of 23.8 and CHAQ-DI of 1.2. After 16wks of OL ADA, the mean JADAS27 was 6.1 and 6.7 and CHAQ-DI was 0.4 and 0.5 for ADA+MTX and ADA-MTX, respectively. Clinical improvements were seen at wk48 and wk88, and the mean JADAS27 at wk88 was 2.6, 3.0, 4.3, and 5.0 for ADA+MTX, ADA-MTX, PBO+MTX, and PBO-MTX, respectively. No pts had MDA or normal function at baseline; however, a good proportion achieved MDA and normal function during OL ADA. Fewer pts achieved MDA and normal function in the PBO tx compared with ADA continuation at both wk48 and wk88. Table P-value based on Cochran-Mantel-Haenszel statistics to test if there was a difference between ADA continuation vs. PBO.ADA\u00b1MTX resulted in a high percentage of pts achieving/sustaining MDA and normal function. Some improvement was seen with PBO during the DB period, but continued ADA tx shows better overall outcomes. A target of comprehensive disease control with MDA and normal function is achievable and aligned with current goals of JIA tx.NCT00048542N. Ruperto Grant / Research Support from: AbbVie, AstraZeneca, BMS, Janssen Biologics BV, Eli Lilly & Co, \"Francesco Angelini\", GlaxoSmithKline, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals, Employee of: GASLINI Hospital, Speaker Bureau of: Astellas, AstraZeneca, BMS, Italfarmaco, Janssen Biologics B.V., MedImmune, Roche, Wyeth/Pfizer, D. Lovell Consultant for: AbbVie, AstraZeneca, Centocor, BMS, Pfizer, Regeneron, Hoffman La-Roche, Novartis, UBC, Genentech, Xoma, Amgen, Forest Research, Speaker Bureau of: Wyeth Pharmaceuticals, P. Quartier Grant / Research Support from: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum, Consultant for: AbbVie, Novartis, Pfizer, BMS, Chugai-Roche, Medimmune, Servier, Swedish Orphan Biovitrum, A. Ravelli Grant / Research Support from: Pfizer, Consultant for: Hoffman La-Roche, Speaker Bureau of: Hoffman La-Roche, Centocore, BMS, Pfizer, Novartis, AbbVie, M. Karunaratne Shareholder of: AbbVie, Employee of: AbbVie, J. Kalabic Shareholder of: AbbVie, Employee of: AbbVie, A. Cardoso Shareholder of: AbbVie, Employee of: AbbVie, A. Martini Grant / Research Support from: AbbVie, AstraZeneca, BMS, Janssen Biologics BV, Eli Lilly & Co, \"Francesco Angelini\", GlaxoSmithKline, Italfarmaco, Naovartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals, Employee of: GASLINI Hospital, Speaker Bureau of: Astellas, AstraZeneca, BMS, Italfarmaco, MedImmune, G. Horneff Grant / Research Support from: AbbVie, Pfizer, Roche, Speaker Bureau of: AbbVie, Novartis, Pfizer, Roche."} +{"text": "Scientific Reports5: Article number: 1475610.1038/srep14756; published online: 10062015; updated: 01112016The original version of this Article contained errors in the spelling of the authors Idan Cohen, Peleg Rider, Elena Vornov, Martin Tomas, Cicerone Tudor, Mareike Wegner, Lydia Brondani, Marina Freudenberg, Gerhard Mittler, Elisa Ferrando-May, Ron N. Apte and Robert Schneider which were incorrectly given as Cohen Idan, Rider Peleg, Voronov Elena, Tomas Martin, Tudor Cicerone, Wegner Mareike, Brondani Lydia, Freudenberg Marina, Mittler Gerhard, Ferrando-May Elisa, Apte N. Ron and Schneider Robert respectively. These errors have now been corrected in the PDF and HTML versions of the Article."} +{"text": "Canakinumab (CAN), a selective, human anti-IL-1\u03b2 monoclonal antibody is approved for SJIA in over 30 countries. Efficacy and safety of CAN over 12 weeks have been demonstrated in 2 phase III trials . Higher aACR-JIA 70 and 90 responses were observed for ETN na\u00efve pts vs. those exposed to ETN ; while ADA- na\u00efve pts had similar responses to CAN as ADA-exposed pt (aACR-JIA 70: 61% vs 56%) and they had higher aACR-JIA 90 response (aACR-JIA90: 50% vs. 22%).In general, pts previously exposed to biologics achieved aACR-JIA 50,70 and 90 responses to CAN quickly in the first 2 weeks, and maintained their response up to Week 12; albeit at a numerically lower level than biologic-na\u00efve pts. These data support the consistent efficacy of CAN across different subgroups of pts.P. Quartier Grant / Research Support from: Abbvie, BMS, Chugai-Roche, Novartis, Pfizer and SOBI, Consultant for: Abbvie, Chugai-Roche, Novartis, Pfizer, Servier and SOBI, Speaker Bureau of: Chugai-Roche, MEDIMMUNE, Novartis, Pfizer, A. Grom Consultant for: Novartis, Roche, NovImmune, N. Ruperto Grant / Research Support from: To Gaslini Hospital: Abbott, Astrazeneca, BMS, Centocor Research & Development, Eli Lilly and Company, \"Francesco Angelini\", Glaxo Smith & Kline, Italfarmaco, Novartis, Pfizer Inc., Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals Inc., Speaker Bureau of: Astrazeneca, Bristol Myers and Squibb, Janssen Biologics B.V.,Roche, Wyeth/Pfizer, H. Brunner Consultant for: Novartis, Genentech, Pfizer, UCB, AstraZeneca, Biogen, Boehringer-Ingelheim, Regeneron, Paid Instructor for: Novartis, Speaker Bureau of: Novartis, Genentech, K. Schikler Grant / Research Support from: Pfizer, Novartis, Abbvie, Roche, Genentech, Forest, Speaker Bureau of: Abbvie, Novartis, M. Erguven: None declared., L. Goffin Consultant for: Novartis, Pfizer , M. Hofer Grant / Research Support from: Novartis, Pfizer, Abbvie, T. Kallinich Grant / Research Support from: Novartis, Speaker Bureau of: Roche, Novartis, ALK, K. Marzan Grant / Research Support from: Novartis, C. Gaillez Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, K. Abrams Shareholder of: Novartis, Employee of: Novartis, A. Martini Grant / Research Support from: The Gaslini Hospital, which is the public Hospital where I work as full time employee, has received contributions to support the PRINTO research activities from the following companies: Bristol Myers and Squibb, Centocor Research & Development, Glaxo Smith & Kline,Novartis,Pfizer Inc, Roche, Sanofi Aventis, Schwarz Biosciences GmbH , Speaker Bureau of: Abbott, Bristol MyersSquibb, Astellas, Behringer, Italfarmaco, MedImmune, Novartis, NovoNordisk, Pfizer,Sanofi,Roche, Servier, D. Lovell Grant / Research Support from: National Institutes of Health- NIAMS , Consultant for: Astra-Zeneca, Centocor, Amgen, Bristol Meyers Squibb, Abbott, Pfizer, Regeneron, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson & Johnson, Speaker Bureau of: Novartis, Roche"} +{"text": "Nippostrongylus brasiliensis\u201d [In our original published manuscript entitled \u201cType 2 immunity-dependent reduction of segmented filamentous bacteria in mice infected with the helminthic parasite liensis\u201d , a co-auThe correct author list should include Emmanuel Mongodin from the Department of Microbiology and Immunology, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA, and read \u201cW. Florian Fricke, Yang Song, An-Jiang Wang, Allen Smith, Viktoriya Grinchuk, Emmanuel Mongodin, Chenlin Pei, Bing Ma, Nonghua Lu, Joseph F. Urban, Terez Shea-Donohue and Aiping Zhao\u201d. Correspondingly, the authors contribution should read \u201cWFF and AZ conceived the study concept and design. YS, AJW, VG, EM, CP, and NL did the acquisition of data. WFF, YS, BM, and AZ interpreted and analyzed the data. WFF, YS, and AZ drafted the manuscript. WFF, JFU, TSD, and AZ made the critical revision of the manuscript. YS and AZ did the statistical analysis. WFF and AZ obtained funding. All authors read and approved the final manuscript\u201d."} +{"text": "After publication of this work , we noteThe authors declare that they have no competing interests.TM, HW, HN, ST and NS designed the experiment, interpreted the data and prepared the manuscript. TM, LW, HK, MM, MK, MKH, PD, TK, MT conducted the experiment, collected the data and helped to prepare the manuscript. All authors read and approved the final manuscript."} +{"text": "Renal Cell Carcinoma Metastasis to the Gallbladder Detected by FDG-PET/CT\u201d, by Aung Zaw Win, published in Vol. 6, No. 6, 2014, p482-486, doi: http://dx.doi.org/10.14740/jocmr1886w. The author would like to add a contributing author in the second position of author list, the new author list should read as follows.Corrections to article \u201ca, c, Carina Mari AparicibAung Zaw WinaDepartment of Radiology, San Francisco VA Medical Center, 4150 Clement Street, San Francisco, CA 94121, USAbDepartment of Radiology, University California San Francisco (UCSF), 500 Parnassus Ave, San Francisco, CA 94143, USAcCorresponding Author: Aung Zaw Win, Department of Radiology, San Francisco VA Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA. Email: aungzwin@gmail.comThis work was performed at the San Francisco VA Medical Center, 4150 Clement Street, San Francisco, CA 94121, USA"} +{"text": "AbstractBombyliidae, Diptera) have been listed in this paper as new to the Kingdom of Saudi Arabia. Four of the recorded species have been identified to the level of species, namely: Bombomyiadiscoidea , Spogostylumcandidum , Exoprosopalinearis Bezzi, 1924, and Exoprosopaminos , while the fifth one only to genus, Desmatoneura sp. The species have been collected from Al-Baha and Asir Provinces in the south-western part of the Kingdom. One of the four identified species, Exoprosopalinearis, has an Afrotropical affinity, and another two, Spogostylumcandidum and Bombomyiadiscoidea, have considerable Afrotropical distributions, and this result agrees to some extent with studies considering these parts of the Arabian Peninsula, including Al-Baha and Asir Provinces, having Afrotropical influences and may be included in the Afrotropical Region rather than in the Palaearctic Region or the Eremic zone.Five bee-fly species ( The two provinces are similarly divided into two main sectors, a lowland at the west which forms part of the coastal plain extending from north to south, known as \u201cTihama\u201d, and a mountainous area with an elevation of 1500 to about 3000 m above sea level at the east, known as \u201cAl-Sarat\u201d or \u201cAl-Sarah\u201d which forms part of the Al-Sarawat Mountains range .The climate in Al Baha Province is generally moderate in summer and cold in winter with average monthly temperatures ranging between 12\u201323 \u00b0C. While in Asir Province, the climate is moderate with average monthly temperatures ranging between 7\u201330 \u00b0C. In the lowland coastal plain, Tihama, the climate is hot in summer, warm in spring and mild in winter, with relative humidity (RH) ranging between 52\u201367% in Al-Baha Province and up to 90% in Asir Province, and a rainfall less than 100 mm annually in both. While in the mountainous area, Al-Sarah, the weather is generally cooler due to its high altitude, in addition to the formation of clouds and fog accompanied by thunderstorms in winter. The rainfall is throughout the year in the mountainous area (Al-Sarah) with an annual average of 405 mm in Al-Baha Province and 342 mm in Asir Province and Asir Province (Garf Raydah Protected Area) in 2013 and 2014 by the authors using aerial nets. All sites of collection were generally rich in acacia, cactus, olive, juniper and alder buckthorn trees, and support an exceptionally rich flora, with approximately 500 plant species recorded, including 63 key plant taxa including endemics and Afrotropical relicts.The global distributions of species were matched to that provided by Efflatoun collection, Entomology Department, Faculty of Science, Cairo University, Egypt.EFC King Saud University Museum of Arthropod Collection, Riyadh, Saudi Arabia.KSMAPageBreakExoprosopalinearis Bezzi, 1924, has an Afrotropical affinity, and another two, Spogostylumcandidum and Bombomyiadiscoidea , have considerable Afrotropical distributions. This result agrees to some extent with studies considering that parts of the Arabian Peninsula, including Al-Baha and Asir Provinces have Afrotropical influences and may be included in the Afrotropical Region rather than in the Palaearctic Region or the Eremic zone, and the northern limit of the Afrotropical Region should be placed along the Tropic of Cancer, about 200 km north to Al-Baha This is a robust species over 10 mm in length; with body, legs, and all spines and spicules black; with uniformly long hair on abdomen black at base, white at apex; thorax of female with gray to orange-brown hairs.Afrotropical: Botswana, Burundi, Chad, Congo, Eritrea, Ethiopia, Gambia, Ghana, Kenya, Malawi, Mali, Mozambique, Namibia, Niger, Nigeria, Oman, Saudi Arabia (South-western part), Senegal, South Africa, Swaziland, Tanzania, Togo, Uganda, Yemen, Zambia, Zimbabwe. Palaearctic: Algeria, Armenia, Austria, Azerbaijan, China, France, Greece, Hungary, Iran, Israel, Italy, Mongolia, Russia, Spain, Turkey, Turkmenistan, Ukraine, Uzbekistan.20.02.723N,41.28.565E, 2324m], 20.V.2013, (El-Hawagry); 1 female, same data, 2.VI.2013; 1 female, Asir Province, Garf Raydah Protected Area , 6.VI.2014, (El-Hawagry). All deposited in EFC.1 female, Al-Baha Province, Ghabet Shahba , Saudi Arabia (South-western part), United Arab Emirates. Oriental: Pakistan. Palaearctic: Iran, Turkey.19\u00b050.710'N, 41\u00b018.267'E, 1474 m], 4.VI.2014, (El-Hawagry). Deposited in KSMA.2 males, Al-Baha Province, Jabal Shada Al A\u2019Ala Protected Area , 27.III.2013, (El-Hawagry). Deposited in EFC.1 female, Al-Baha Province, Al-Mekhwa , VI-V.2013, (El-Hawagry). Deposited in EFC.1 male and 2 females, Al-Baha Province, Aqabet Al Baha-Tihama , 4.VI.2014, (El-Hawagry). Deposited in KSMA.1 male, Al-Baha Province, Jabal Shada Al A\u2019Ala Protected Area [PageBreak"} +{"text": "AbstractHymenoptera is revised. Species distribution is summarised for all species at the level of country .The checklist of British and Irish aculeate The 601 native species represent an increase of 25 on the 1978 checklist, comprising mostly new discoveries. This increase is nearly balanced by the 23 species now presumed to be extinct in Britain and Ireland. Hymenoptera checklist . With multiple evolutions of eusociality, importance as pollinators, predators and parasitoids and general conspicuousness, the aculeates have always attracted attention and very good summaries of their biology can be found in a diverse array of texts for a variety of different audiences, from The aculeate Hymenoptera checklist are laid out in The rationale and background to the updated Apidae and, as discussed in the introduction to this checklist series and because this is the system employed in the most authoritative treatise on bee classification handbook to the British fauna, except that we employ six families rather than including all bees in t series , we do nfication , as wellwebsite), the catalogue of Irish Hymenoptera or identification in the British Isles uncertainmisident. has been misidentified as this namenomen dubium, a name of unknown or doubtful applicationnom. dub. nomen oblitum, \u2018forgotten name\u2019, does not have priority over a younger namenom. ob. nomen novum, a replacement namenom. nov. nomen nudum, an unavailable name, with no type specimennom. nud. preocc. name preoccupied (junior homonym)status revocatus, revived status stat. rev. unavailable not meeting the requirements of the International Code of Zoological Nomenclaturevar. variety, only available as a valid name under the provisions of article 45.6 of the ICZNText and spreadsheet versions of the checklists are available as supplementary files: Suppl. materials Latreille, 1802Apoidea follows online checklist of Western Palaearctic bees. The \u2018traditional\u2019 family Sphecidae is paraphyletic with respect to the bee families Sphexboops Schrank, 1781abdominalisTiphia) Larrapinguis Dahlbom, 1832stigma misident.pinguisLarra) preocc. Pompiluslunicornis Fabricius, 1798kenediiAlyson) Gorytesfargeii Shuckard, 1837campestris misident.mongolensis Tsuneki, 1971przewalskyi Kazenas, 1971England, WalesSphexmystaceus Linnaeus, 1761campestrisVespa) Eusponguslaticinctus Lepeletier, 1832England, WalesMellinusquadrifasciatus Fabricius, 1804vicinusEuspongus) Pompilustumidus Panzer, 1801japonensisDienoplus) Crabrobicinctus Rossi, 1794EnglandLatreille, 1804Latreille, 1796SYNNEVRUS Costa, 1859Jurine, 1807wesmaeli Lepeletier, 1845distinguendus Chevrier, 1867England, WalesMellinusinterruptus Fabricius, 1798spinosusCeropales) Sphexspinosus Forster, 1771bidensVespa) preocc. Crabrotrimaculatus Rossi, 1790England, WalesLatreille, 1802Latreille, 1802Fabricius, 1775THYREOPUS Lepeletier & Brull\u00e9, 1835ANOTHYREUS Dahlbom, 1845THYREOCNEMUS Costa, 1871PARANOTHYREUS Ashmead, 1899SYNOTHYREOPUS Ashmead, 1899AGNOSICRABRO Pate, 1944DYSCOLOCRABRO Pate, 1944HEMITHYREOPUS Pate, 1944NORUMBEGA Pate, 1947PARANOTHYREUS Pate, 1944PARATHYREOPUS Pate, 1944PEMPHILIS Pate, 1944OTHYREUS Marshakov, 1977Vespacribraria Linnaeus, 1758patellariusSphex) Sphexpeltarius Schreber, 1784patellatus Panzer, 1797dentipes Panzer, 1797mediatus Fabricius, 1798England, Scotland, Wales, Ireland, Isle of ManSphexscutellatus von Scheven, 1781scutulariusSphex) Crabrocongener Dahlbom, 1844Englandadded by Crabropodagricus Vander Linden, 1829vicinus Dahlbom, 1842punctata \u0160noflak, 1948snoflaki Zavadil, 1948England, WalesPerkins, 1913CORENOCRABRO Tsuneki, 1974Crabrovagabundus Panzer, 1798varusCrabro) preocc. Blepharipusannulipes Lepeletier & Brull\u00e9, 1835gonagerBlepharipus) Crabrocapitosus Shuckard, 1837annulusCrabro) Crabrocetratus Shuckard, 1837vanderlindeniCrabro) Sphexleucostoma Linnaeus, 1758carbonariusCrabro) Crabromegacephalus Rossi, 1790leucostoma misident.bidensCrabro) Blepharipusnigritus Lepeletier & Brull\u00e9, 1835pubescensCrabro) Crabrostyrius Kohl, 1892pauxillusCrabro) Crabrowalkeri Shuckard, 1837aphidium misident.geniculatusCrabro) Crabrodistinguendus Morawitz, 1866mucronatusCrabro) CrabroelongatulusCrabro Vander Linden, annulatus Lepeletier & Brull\u00e9, 1835varipes Lepeletier & Brull\u00e9, 1835affinis Lepeletier & Brull\u00e9, 1835luteipalpis Lepeletier & Brull\u00e9, 1835morio Lepeletier & Brull\u00e9, 1835pallidipalpis Lepeletier & Brull\u00e9, 1835proximusCrabro) .The British population is considered to belong to the subspecies CrabroexiguusCrabro Vander Linden, aphidum Lepeletier & Brull\u00e9, 1835EnglandLepeletier & Brull\u00e9, 1835punctumCrabro) Sphexpalmipes Linnaeus, 1767palmariusSphex) Crabrotarsatus Shuckard, 1837palmipes misident.palmatus De Stefani Perez, 1884 preocc,England, Scotland, Wales, Ireland, Isle of ManLepeletier & Brull\u00e9, 1835 nomen protectumvarius misspellingpusillus Lepeletier & Brull\u00e9, 1835striatulus Lepeletier & Brull\u00e9, 1835spinipectusCrabro) CrabrowesmaeliCrabro Vander Linden, maurusCeratocolus) preocc. Crabrodimidiatus Fabricius, 1781subpunctatusCrabro) Crabroquadrimaculatus Fabricius, 1793quadripunctatusCrabro) Vander Linden, 1829, bimaculatus Lepeletier & Brull\u00e9, 1835quniquemaculatusCrabro) Crabrocavifrons Thomson, 1870cephalotes misident.England, Scotland, Wales, Ireland, Isle of ManCrabrolapidarius Panzer, 1804cinctusCrabro) Crabroruficornis Zetterstedt, 1838aurilabrisCrabro) Crabrosexcinctus Fabricius, 1775planifrons misident.quadricinctusCrabro) Crabroborealis Zetterstedt, 1838bipunctatusCrabro) Soleniusdives Lepeletier & Brull\u00e9, 1835octonotatusSolenius) preocc. Crabrocontinuus Fabricius, 1804vagus misident.sexmaculatusCrabro) preocc. Soleniusrubicola Dufour & Perris, 1840microstictusCrabro) Crabrocephalotes Olivier, 1792quadricinctus misident.floralisCrabro) preocc. Crabrolituratus Panzer, 1805petiolatusSolenius) Crabrobrevis Vander Linden, 1829apicalisLindenius) Apisclypeata Schreber, 1759ovataSphex) preocc. Crabroalbilabris Fabricius, 1793aenescensCrabro) Crabropanzeri Vander Linden, 1829venustus Lepeletier & Brull\u00e9, 1835latebrosusCrabro) Crabropygmaeus Rossi, 1794curtus Lepeletier & Brull\u00e9, 1835kratochviliCrabro) .Represented by the subspecies Stephens, 1829Stephens, 1829EUPLILIS Risso, 1826 nom. ob.PHYSOSCELUS Lepeletier & Brull\u00e9, 1835Sphexclavipes Linnaeus, 1758rufiventrisCrabro) Sphexcoarctata Scopoli, 1763crassipesCrabro) preocc. Astatanitida Spinola, 1805unicolor misident.ibericusTachytes) Tachytesobscuripennis Schenck, 1857lativalvisTachytes) Larrapompiliformis Panzer, 1805pectinipes misident.nigripennisTachytes) Larraunicolor Panzer, 1809nitidus misident.juriniiLarra) Dahlbom, 1844bicolor misident.moravicus Balthazar, 1957EnglandLatreille, 1809TENILA Br\u00e8thes, 1913RHINONITELA Williams, 1928Valkeila, 1974Englandadded by Felton (1987)Gayubo & Felton, 2000spinolae misident.EnglandNitelaspinolae Latreille, 1809 but described later as a new species Vespauniglumis Linnaeus, 1758punctataNomada) Sphexfigulus Linnaeus, 1758fuliginosaSphex) de Beaumont, 1945koma Tsuneki, 1956Englandadded by Felton (1988)Fox, 1895Panzer, 1806DINETUS Jurine, 1807 preocc.Crabropictus Fabricius, 1793guttatusSphex) preocc. Vespaarvensis Linnaeus, 1758vagusSphex) preocc. Sphexcrabronea Thunberg, 1791sabulosusCrabro) preocc. preocc. preocc. Crabrominutus Fabricius, 1793franclemonti Krombein, 1939England, Wales, Isle of ManPemphredontristis Vander Linden, 1829England, Scotland, WalesShuckard, 1837XYLOECUS Shuckard, 1837COELOECUS Verh\u00f6ff, 1890HEROECUS Verh\u00f6ff, 1890Faester, 1947angustus Gussakovskij, 1952EnglandShuckard, 1837England, WalesKohl, 1893Englandadded by Richards (1980)Diodontusgracilis Curtis, 1834insignis misident.turionum misident.brevicornis Morawitz, 1864EnglandPemphredoninsignis Vander Linden, 1829roettgeni Verh\u00f6ff, 1890shuckardi Yasumatsu, 1934England, WalesDahlbom, 1842England, Scotland, Wales, IrelandDahlbom, 1844gracilis misident.tenuis Morawitz, 1864gertrudis Krombein, 1938England, WalesDahlbom, 1844Englandadded by Guichard (2002)Latreille, 1796CEMONUS Panzer, 1806DINEURUS Westwood, 1837CERATOPHORUS Shuckard, 1837DIPHLEBUS Westwood, 1840CHEVRIERIA Kohl, 1883SUSANOWO Tsuneki, 1972Taxonomy follows Diphlebusaustriacus Kohl, 1888enslini misident.coracina Valkeila, 1972tener Valkeila, 1972nescia Merisuo, 1972EnglandPemphredonenslini . There has been much confusion over the identities of these taxa Cemonuslethifer Shuckard, 1837lethifera misspellingaustriaca misident.strigatusCemonus) Crabrolugubris Fabricius, 1793concolor Say, 1824ocellaris Gimmerthal, 1836luctuosa Shuckard, 1837morio Cresson, 1865 preocc.cressoni Dalla Torre, 1897provancheri Dalla Torre, 1897tinctipennis Cameron, 1908shawii Rohwer, 1917pacifica Gussakovkij, 1932England, Scotland, Wales, Ireland, Isle of ManVander Linden, 1829anthracinusCeratophorus) Cemonusrugifer Dahlbom, 1844rugifera misspellingunicolorSphex) preocc. in several publications, following the synonymy by Has been called Celiacurruca Dahlbom, 1844pulawskii Dolfuss, 1983nikkoensis Tsuneki, 1971EnglandBl\u00fcthgen, 1953England, IrelandStigmustroglodytes Vander Linden, 1829minutissimusStigmus) Morawitz, 1864europaeus Tsuneki, 1954verhoeffi Tsuneki, 1954England, WalesCosta, 1858Shuckard, 1837APORIA Wesmael, 1852 preocc.APORINA Gussakovskij, 1937 preocc.Psenbicolor Jurine, 1807equestris misident.rufaPsen) Trypoxylonequestre Fabricius, 1804bicolor misident.England, Scotland, WalesSphexlutarius Fabricius, 1787shuckardi Wesmael, 1852basirufa Packard, 1867nebrascensis Smith, 1908disparPsen) Mimesaatratina Morawitz, 1891carbonariaMimesa) Mimesadahlbomi Wesmael, 1852England, Scotland, WalesMimesalittoralis Bondroit, 1934unicolor misident.fulvitarsisPsen) preocc. Mimesaspooneri Richards, 1948EnglandPsenunicolor Vander Linden, 1829borealisMimesa) Latreille, 1796PSENUS Rafinesque, 1815PSENIA Stephens, 1829DAHLBOMIA Wissmann, 1849MESOPORA Wesmael, 1852CAENOPSEN Cameron, 1899Crabroater Olivier, 1792aterSphex) preocc. Psenconcolor Dahlbom, 1843intermediusPsen) Sphexpallipes Panzer, 1798atratusTrypoxylon) Psenschencki Tournier, 1889simplexPsen) Sphexarenarius Linnaeus, 1758xanthocephalaSphex) Philanthusquadricinctus Panzer, 1799fasciata Spinola, 1806EnglandCrabroquinquefasciatus Rossi, 1792interrupta misident.nasuta Dahlbom, 1844 preocc.subdepressa Lepeletier, 1845EnglandPhilanthusruficornis Fabricius, 1793labiata misident.bidensCrabro) Sphexrybyensis Linnaeus, 1771ornataPhilanthus) Philanthussabulosus Panzer, 1799emarginataPhilanthus) Vespatriangulum Fabricius, 1775ruspatrixVespa) nom. ob. Sphexsabulosus Linnaeus, 1758hortensisSphex) preocc. Ammophilaaffinis Kirby, 1798lutaria misident.ariasiAmmophila) Sphexhirsutus Scopoli, 1763viatica misident.arenariaSphex) preocc. . Note that 'apiformes' and the corresponding 'spheciformes') is an equivalent term proposed by Brothers (1975)Latreille, 1802Latreille, 1802Fabricius, 1775Taxonomy mostly follows Fabricius, 1775ANTHRENA Illiger, 1801ANTHOCHARESSA Gistel, 1850Smith, 1847England, Wales, IrelandMelittaclarkella Kirby, 1802England, Scotland, Wales, Ireland, Isle of ManSmith, 1847England, Scotland, Wales, Ireland, Isle of ManApisfulva M\u00fcller, 1766armataApis) Apishelvola Linnaeus, 1758subdentataMelitta) Apispraecox Scopoli, 1763smithellaMelitta) Melittavarians Kirby, 1802variansApis): misident. Nomadahattorfiana Fabricius, 1775lathamanaMelitta) Apisfulvago Christ, 1791constricta Smith, 1849England, WalesHedicke, 1933Melittadenticulata Kirby, 1802listerellaMelitta) Melittafuscipes Kirby, 1802England, Scotland, Wales, Ireland, Isle of ManMelittanigriceps Kirby, 1802lanifronsMelitta) Melittatridentata Kirby, 1802rufitarsisMelitta) Melittalabialis Kirby, 1802separata Smith, 1847England, Wales, Isle of ManP\u00e9rez, 1890Stephens, 1846eximia Smith, 1847longipes Smith, 1847England, WalesSmith, 1847distincta Smith, 1847EnglandPanzer, 1801eximia misident.zonalisMelitta) , following P. Westrich\u2019s (in lit.) interpretation of the type of carantonica, regards this is a separate species, with carantonica a junior synonym of trimmerana.Although usually referred to as ain e.g. , SchwarzMelittatrimmerana Kirby, 1802spinigeraMelitta) Melittabarbilabris Kirby, 1802sericeaApis) preocc. Apiscineraria Linnaeus, 1758England, Scotland, Wales, Ireland, Isle of ManMelittanigroaenea Kirby, 1802aprilina Smith, 1848England, Scotland, Wales, Ireland, Isle of Mansarnia Richards, 1979.The population on the Isles of Scilly and Channel Islands has been described as the subspecies Apisnitida M\u00fcller, 1776pubescens Olivier, 1789consimilis Smith, 1847England, Wales, IrelandApisthoracica Fabricius, 1775melanocephalaMelitta) Melittaminutula Kirby, 1802parvulaMelitta) Melittanana Kirby, 1802EnglandProbably extinct in Britain.Nylander, 1848Probably extinct in Britain.Friese, 1887spreta misident.England, WalesP\u00e9rez, 1903nana misident.saundersella Perkins, 1914England, Scotland, Wales, Ireland, Isle of ManNylander, 1848England, Scotland, Wales, IrelandP\u00e9rez, 1890Melittachrysosceles Kirby, 1802connectensMelitta) Melittacoitana Kirby, 1802shawellaMelitta) Melittabimaculata Kirby, 1802articulata Smith, 1847conjuncta Smith, 1847decorata Smith, 1847vitrea Smith, 1847England, WalesThomson, 1872Englandpilipes by nigrospina is treated as a valid species, following Although treated as a synonym of Fabricius, 1781carbonaria misident.spectabilis Smith, 1853praetexta Smith, 1872EnglandMelittatibialis Kirby, 1802mouffetellaMelitta) Melittaproxima Kirby, 1802digitalisMelitta) Melittaangustior Kirby, 1802lacinia Smith, 1847England, Scotland, Wales, Ireland, Isle of ManP\u00e9rez, 1890PLATANDRENA Viereck, 1924STENANDRENA Timberlake, 1949Schmiedeknecht, 1884confinis St\u00f6ckhert, 1930England, WalesMelittadorsata Kirby, 1802collinsonanaMelitta) Melittaovatula Kirby, 1802afzeliellaMelitta) Melittawilkella Kirby, 1802barbatulaMelitta) Apishaemorrhoa Fabricius, 1781albicans misident.England, Scotland, Wales, Ireland, Isle of ManHedicke, 1933Panzer, 1799contiguaMelitta) Apisbanksiana Kirby, 1802ursinus misident.England, WalesApiscalcarata Scopoli, 1763linnaeellaApis) Apisplumipes Pallas, 1772acervorum misident.pilipesApis) Apisfurcata Panzer, 1798England, Scotland, WalesBrooks, 1988Apisquadrimaculata Panzer, 1798subglobosaApis) Apisbimaculata Panzer, 1798England, IrelandBrooks, 1988Apisretusa Linnaeus, 1758haworthanaApis) Apiscryptarum Fabricius, 1775Scotland, Irelandadded by Bertsch et al. (2005)Apislucorum Linnaeus, 1761England, Scotland, Wales, Ireland, Isle of ManVogt, 1911Scotland, IrelandApisterrestris Linnaeus, 1758audaxApis) Apiscullumana Kirby, 1802EnglandExtinct in Britain since the 1940s.Dalla Torre, 1880Apissoroeensis Fabricius, 1777England, Scotland, WalesDalla Torre, 1880HORTOBOMBUS Vogt, 1911Apishortorum Linnaeus, 1761flavonigrescens Smith, 1846ivernicus Sladen, 1912splendida Stelfox, 1938England, Scotland, Wales, Ireland, Isle of ManB.hortorumivernicus.Populations in Ireland have been referred to the subspecies Apisruderata Fabricius, 1775pernigerApis) Apislapidaria Linnaeus, 1758England, Scotland, Wales, Ireland, Isle of ManLepeletier, 1832ALLOPSITHYRUS Popov, 1931ASHTONIPSITHYRUS Frison, 1927FERNALDAEPSITHYRUS Frison, 1927METAPSITHYRUS Popov, 1931Apisbarbutella Kirby, 1802England, Scotland, Wales, IrelandApisbohemicus Seidl, 1837distinctusPsithyrus) Apiscampestris Panzer, 1801rossiellusApis) Apisrupestris Fabricius, 1793albinellusApis) Psithyrussylvestris Lepeletier, 1832quadricolor misident.England, Scotland, Wales, IrelandApisvestalis Geoffroy, 1785England, Scotland, Wales, IrelandDalla Torre, 1880PRATOBOMBUS Vogt, 1911Apishypnorum Linnaeus, 1758England, Scotland, Walesadded by Goulson and Williams (2001)Apisjonella Kirby, 1802nivalis misident.scrimshiranusApis) .The following populations have been given subspecies names: Smith, 1849lapponicus misident.scoticus Pittioni, 1942England, Scotland, Wales, Ireland, Isle of ManApispratorum Linnaeus, 1761subinterruptusApis) Apissubterranea Linnaeus, 1758collinus Smith, 1844latreillellusApis) Apismuscorum Linnaeus, 1758arcticus misident.smithianus misident.pallidus Evans, 1901 preocc.laevis Vogt, 1909sladeni Vogt, 1911allenellus Stelfox, 1933orcadensis Richards, 1935scyllonius Richards, 1935celticus Yarrow, 1978agricolae Baker, 1996England, Scotland, Wales, Ireland, Isle of ManB.muscorumsladeni on the Irish mainland and southern England; B.muscorumallenellus on the Aran islands; B.muscorumorcadensis on Orkney; B.muscorumscyllonius on the Isles of Scilly; B.muscorumcelticus in mainland Scotland and Northern England; B.muscorumagricolae on the Shetland islands.The following populations have been given subspecies names: Apispascuorum Scopoli, 1763vulgoApis) preocc. Bremuspomorum Panzer, 1805Englandpomorum, collected near Deal in Kent Apisruderaria M\u00fcller, 1776derhamellusApis) Apissylvarum Linnaeus, 1761nigrescens P\u00e9rez, 1879distinctus Vogt, 1909England, Scotland, Wales, IrelandLatreille, 1802Scopoli, 1770Scopoli, 1770Apislongicornis Linnaeus, 1758linguariaApis) Apisalbifrons Forster, 1771punctataApis) preocc. Apisluctuosa Scopoli, 1770EnglandProbably extinct in Britain.Latreille, 1802Roberston, 1903Latreille, 1802Nomadacrucigera Panzer, 1799rufipes Thomson, 1870England, WalesApisvariegata Linnaeus, 1758notatus misident.productus Thomson, 1870England, Wales, Scotland, Isle of ManLatreille, 1802Scopoli, 1763Herrich-Sch\u00e4ffer, 1839atrata Smith, 1846England, IrelandHerrich-Sch\u00e4ffer, 1839kirbyella Stephens, 1846England, WalesSmith, 1844alboguttata misident.EnglandHerrich-Sch\u00e4ffer, 1839EnglandLepeletier, 1841EnglandApisfabriciana Linnaeus, 1767fabriciellaApis) Apisferruginata Linnaeus, 1767lateralis misident.xanthostictaApis) Apisflavoguttata Kirby, 1802rufocinctaApis) Apisflavopicta Kirby, 1802jacobaeae misident. [?]England, WalesPanzer, 1798England, WalesFabricius, 1793lineola Panzer, 1798sexcinctaApis) Apisgoodeniana Kirby, 1802succincta misident.alternataApis) Apislathburiana Kirby, 1802rufiventrisApis) Apisleucophthalma Kirby, 1802borealis Zetterstedt, 1838inquilina Smith, 1844England, Scotland, Wales, Ireland, Isle of ManApismarshamella Kirby, 1802alternata misident.England, Scotland, Wales, Ireland, Isle of ManNylander, 1848mistura Smith, 1851England, Scotland, Wales, Ireland, Isle of ManLepeletier, 1841ruficornis misident.England, Scotland, Wales, IrelandPanzer, 1799tormentillae Alfken, 1901England, Scotland, Wales, Isle of ManApisruficornis Linnaeus, 1758bifida Thomson, 1872England, Scotland, Wales, Ireland, Isle of ManFabricius, 1793solidaginis misident.pictaApis) Apissheppardana Kirby, 1802furva misident.dalii Curtis, 1832England, WalesJurine, 1807England, WalesFabricius, 1793hillanaApis) Apiscyanea Kirby, 1802EnglandLatreille, 1802Latreille, 1809Latreille, 1809Apisviolacea Linnaeus, 1758EnglandLepeletier, 1841Lepeletier, 1841Latreille, 1802Apiscunicularia Linnaeus, 1761England, WalesC.cuniculariuscelticus O\u2019Toole, 1974, and Else, Field & O\u2019Toole Apisfodiens Geoffroy, 1785England, Scotland, WalesVerhoeff, 1944EnglandSchmidt & Westrich, 1993Englandadded by Cross (2002)Smith, 1846England, WalesSchenck, 1853picistigma Thomson, 1872England, Wales, Ireland, Isle of ManApissuccincta Linnaeus, 1758England, Scotland, Wales, Ireland, Isle of ManViereck, 1916Fabricius, 1793Popov, 1939Curtis, 1831plantarius Smith, 1842EnglandFabricius, 1793Nylander, 1852rupestrisProsopis) Mellitaannularis Kirby, 1802euryscapus misident.spilotus Forster, 1871masoniProsopis) Mellitadilatata Kirby, 1802annularis misident.England, WalesPopov, 1939Nylander, 1852varipesProsopis) preocc. Sphexsignata Panzer, 1798England, WalesPopov, 1939Smith, 1842England, Scotland, Wales, Ireland, Isle of ManThomson, 1869Thomson, 1869Latreille, 1804Latreille, 1804Bl\u00fcthgen, 1931quadricinctus misident.tetrazonius misident.EnglandSmith, 1848EnglandProbably extinct in Britain.Apisrubicunda Christ, 1791quadrifasciatus Smith, 1870nesiotis Perkins, 1922England, Scotland, Wales, Ireland, Isle of ManRobertson, 1918Smith, 1853alpinus Alfken, 1907confususperkinsi Bl\u00fcthgen, 1926flavipes misident.EnglandApissubaurata Rossi, 1792gramineus Smith, 1849Probably extinct in Britain.Apistumulorum Linnaeus, 1758England, Scotland, Wales, IrelandCurtis, 1833Evylaeus' s. l.) updated from Evylaeus to a valid genus, nor have we adopted his numerous subgenera.Nomenclature for some species Halictuscupromicans P\u00e9rez, 1903England, Scotland, Wales, Ireland, Isle of Manhibernicum Ebmer, 1970, with other populations referred to the subspecies scoticum Ebmer, 1970.The Irish population has been described as the subspecies Melittaleucopus Kirby, 1802aeratumMelitta) Hylaeusmorio Fabricius, 1793England, Scotland, Wales, Isle of ManMelittasmeathmanella Kirby, 1802England, Scotland, Wales, Isle of ManCockerell, 1897Halictusangusticeps Perkins, 1895EnglandHalictusbrevicornis Schenck, 1869EnglandMelittaminutissima Kirby, 1802arnoldiHalictus) Melittanitidiuscula Kirby, 1802England, Scotland, Wales, Ireland, Isle of ManHylaeusparvulus Schenck, 1853minutum misident.England, WalesHalictuspauperatus Brull\u00e9, 1832brevicepsHalictus) Hylaeuspunctatissimus Schenck, 1853longicepsHalictus) Halictuspuncticollis Morawitz, 1872EnglandHalictusrufitarsis Zetterstedt, 1838atricorneHalictus) Halictussemilucens Alfken, 1914EnglandHalictussexstrigatus Schenck, 1870sabulosumHalictus) Melittavillosula Kirby, 1802punctulatumMelitta) Melittalaevigata Kirby, 1802lugubrisMelitta) Hylaeuslativentris Schenck, 1853decipiensHalictus) Halictusprasinus Smith, 1848England, WalesMelittaquadrinotata Kirby, 1802EnglandMelittasexnotata Kirby, 1802nitidum misident.EnglandMelittaxanthopus Kirby, 1802tricingulum Curtis, 1833England, WalesWarncke, 1975Apisleucozonia Schrank, 1781similisHalictus) Halictuszonulus Smith, 1848England, WalesAshmead, 1899Apisalbipes Fabricius, 1781England, Scotland, Wales, Ireland, Isle of ManApiscalceata Scopoli, 1763cylindricumHylaeus) Halictusfratellus P\u00e9rez, 1903nigrum misident.subfasciatumHalictus) Melittafulvicornis Kirby, 1802subfasciatum misident.England, Scotland, WalesMelittalaevis Kirby, 1802EnglandProbably extinct in Britain.Halictuslaticeps Schenck, 1869semipunctulatum misident.EnglandMelittamalachura Kirby, 1802longulumHalictus) Hylaeuspauxillus Schenck, 1853immarginatumHylaeus) Sphexephippia Linnaeus, 1767divisusMelitta) Melittageofrella Kirby, 1802affinis von Hagens, 1882fasciatus von Hagens, 1882England, Scotland, Wales, Ireland, Isle of ManSphexgibba Linnaeus, 1758piceaMelitta) Melittamonilicornis Kirby, 1802subquadratus Smith, 1845England, Scotland, Wales, Ireland, Isle of Manvon Hagens, 1874EnglandSmith, 1845pilifrons Thomson, 1870England, Scotland, Wales, IrelandThomson, 1870England, WalesThomson, 1870England, Walesvon Hagens, 1875ruficrus misident.rufiventris misident.England, WalesWesmael, 1835England, Walesvon Hagens, 1875England, WalesSchenck, 1866Lepeletier, 1841Rhophiteshalictulus Nylander, 1852EnglandProbably extinct in Britain.Lepeletier, 1841vulgaris Schenck, 1861EnglandProbably extinct in Britain.Spinola, 1808Spinola, 1808EnglandProbably extinct in Britain.Latreille, 1802Latreille, 1802Ashmead, 1899Fabricius, 1804Apismanicata Linnaeus, 1758England, Scotland, Walesnigrithorax Dalla Torre, 1877Represented by the subspecies Panzer, 1806Nylander, 1848Englandadded by Else and Spooner (1987)Gyrodromaornatula Klug, 1807octomaculata Smith, 1843England, WalesApisphaeoptera Kirby, 1802England, WalesApispunctulatissima Kirby, 1802aterrimaApis) preocc. Apisinermis Kirby, 1802Coelioxys (Boreocoelioxys) inermisacuminata Nylander, 1852 preocc.England, Wales, IrelandNylander, 1848England, WalesLatreille, 1809Anthophoraconoidea Illiger, 1806vectis Curtis, 1831England, Wales, IrelandLepeletier, 1841sponsa Smith, 1855England, Scotland, Wales, IrelandApisquadridentata Linnaeus, 1758England, WalesLepeletier & Serville, 1825umbrina Smith, 1843England, WalesLatreille, 1802Thomson, 1872Curtis, 1828dorsalis P\u00e9rez, 1879 synonymy by Gusenleitner and Schwarz (2012)argentata misident.England, WalesLatreille, 1802Apiscentuncularis Linnaeus, 1758England, Scotland, Wales, Ireland, Isle of ManThomson, 1872EnglandProbably extinct in Britain.Apisligniseca Kirby, 1802England, Wales, IrelandSmith, 1844England, Scotland, Wales, Ireland, Isle of Manhiberniae Perkins, 1925.Includes the subspecies Friese, 1899Megachileericetorum Lepeletier, 1841fasciataMegachile) Apiscircumcincta Kirby, 1802England, Scotland, WalesApismaritima Kirby, 1802England, Wales, Ireland, Isle of ManApiswillughbiella Kirby, 1802England, Scotland, Wales, Ireland, Isle of Manhibernica Perkins, 1925Includes the nominate subspecies and Newman, 1834Latreille, 1809Apiscampanularum Kirby, 1802EnglandApisflorisomnis Linnaeus, 1758maxillosumApis) Apistruncorum Linnaeus, 1758EnglandKlug, 1807Cresson, 1864Osmiaclaviventris Thomson, 1872leucomelana misident.England, WalesApisleucomelana Kirby, 1802parvulaOsmia) Apisspinulosa Kirby, 1802England, WalesPanzer, 1806Thomson, 1872Panzer, 1799England, Scotland, Wales, IrelandApiscaerulescens Linnaeus, 1758aeneaApis) Apisniveata Fabricius, 1804fulviventrisApis) Apisleaiana Kirby, 1802fulviventris misident.England, WalesSchmiedeknecht, 1884Anthophorainermis Zetterstedt, 1838parietina misident.ScotlandCurtis, 1828England, Scotland, WalesSmith, 1846England, WalesGerst\u00e4cker, 1869Scotlandadded by Else in Else and Spooner (1987)Apisxanthomelana Kirby, 1802atricapilla Curtis, 1828England, WalesTkalc, 1974Apisbicolor Schrank, 1781England, WalesPanzer, 1806Apisbicornis Linnaeus, 1758rufaApis) Andrenahirtipes Fabricius, 1793altercatorApis) nom. dub. Andrenahaemorrhoidalis Fabricius, 1775chrysura Kirby, 1802England, Scotland, Wales, Isle of ManKirby, 1802Apisleporina Panzer, 1799England, WalesKirby, 1802melanuraKirbya) EPISEMUS Thomson, 1862DIGONIOZUS Kieffer, 1905Anoxusboops Thomson, 1862Englandadded by Burn (1997)Perisemuscephalotes F\u00f6rster, 1860fuscicornisvar.tibialis Kieffer, 1905England, Scotland, Wales, Isle of ManRichards, 1939EnglandOmalusfuscicornis Jurine, 1807sygenesiae Haliday, 1834fulvicornis Curtis, 1838triareolatus F\u00f6rster, 1851variabilisEpisemus) synonymy by Rond (1994) Bethylusclaripennis F\u00f6rster, 1851fuscipennisBethylus) by formiciformis.Sclerochroagallicola Ashmead, 1887nubilipennisHolopedina) Ateleopterustarsalis Ashmead, 1893carinata Kieffer, 1907meridionalis Brethes, 1913kiefferi Fouts, 1920Gahan, 1931Westwood, 1832DOLUS Motshultsky, 1863MUELLERELLA Saussure, 1892HOMOGLENUS Kieffer, 1904 synonymy by Terayama (2003)PAREPYRIS Kieffer, 1913PSILEPYRIS Kieffer, 1913ARTIEPYRIS Kieffer, 1913Thomson, 1862fraternus Westwood, 1874saeva Westwood, 1874multidentatus Keiffer, 1906multidentatusvar.angustipennis Kieffer, 1906EnglandWestwood, 1832EnglandCameron, 1888]Supposedly described from the New Forest, the type is lost and the species has not been satisfactorily interpreted since.Kieffer, 1905MISEPYRIS Kieffer, 1913PAREPYRIS Brethes, 1913Tiphiaglabrata Fabricius, 1798hawaiiensisHolepyris) Parepyrissylvanidis Brethes, 1913zeaeRhabdepyris) Bethylusfemoralis F\u00f6rster, 1860microneurusAllepyris) Bethyluspedatus Say, 1836EnglandAdded by Kieffer, 1905SNAPPANIA Hedqvist, 1975Anoxuschittendenii Ashmead, 1893EnglandRichards, 1939Cephalonomiawestwoodi Kieffer, 1914kiefferi Gahan, 1931Kieffer, 1914Klug, 1808ACREPYRIS Kieffer, 1905MANGESIA Kieffer, 1911TRICHELOBRACHIUM Kieffer, 1914Bethylusdepressus Fabricius, 1805roubaliPseudisobrachium) Epyrissubcyaneus Haliday, 1838halidaiiEpyris) Sphexsemiaurata Linnaeus, 1761auratusIchneumon) Ichneumonnitidulus Fabricius, 1793EnglandLatreille, 1802Some distribution data from Latreille, 1802Linnaeus, 1761Chrysisignita group has varied from author to author. The number of species recognised in the Schenck, 1856brevidens Tournier, 1879England, Scotland, WalesValkeila, 1971Englandadded by Soon et al. (2014)Linnaeus, 1761EnglandF\u00f6rster, 1853saussurei Chevrier, 1862Englandadded by Morgan (1984)Sphexignita Linnaeus, 1758England, Scotland, Wales, Ireland, Isle of ManWesmael, 1839chrysoprasina Hell\u00e9n, 1919 preocc.helleni Linsenmaier, 1959succincta misident.EnglandSchenck, 1856England, Scotland, Wales, Ireland, Isle of ManAbeille de Perrin, 1879England, ScotlandLinsenmaier, 1951England, Wales, IrelandLinsenmaier, 1951EnglandShuckard, 1836auripes Wesmael, 1839England, Scotland, Wales, Isle of ManLinsenmaier, 1968schenckiana Linsenmaier, 1959 preocc.EnglandDahlbom, 1854Englandadded by Soon et al. (2014)Linsenmaier, 1959rutiliventris misident.England, Scotland, Wales, Ireland, Isle of ManLinnaeus, 1761bidentata Linnaeus, 1767England, WalesDahlbom, 1845Chrysishirsuta Gerst\u00e4cker, 1869osmiaeChrysis) Chrysisradians Harris, 1776pustulosaChrysis) Chrysisneglecta Shuckard, 1836England, WalesLichtenstein, 1876Sphexcyanea Linnaeus, 1758England, Scotland, WalesDahlbom, 1854Spinola, 1806NOTOZUS F\u00f6rster, 1853Chrysispanzeri Fabricius, 1804scutellarisChrysis) preocc. Chrysisardens Latreille, 1801England, Scotland, Wales, Ireland, Isle of ManHedychrumcoriaceum Dahlbom, 1854EnglandHedychrumcupreum Dahlbom, 1845integrumHedychrum) synonymy by Morgan (1984) Chrysisrosea Rossi, 1790EnglandLatreille, 1802Linsenmaier, 1959nobile misident.EnglandSphexnobilis Scopoli, 1763lucidulaChrysis) Chrysisaenea Fabricius, 1787England, WalesEllampuspuncticollis Mocs\u00e1ry, 1887England, Scotland, Walesaeneus in Fauna Europaea.Treated as a subspecies of Abeille de Perrin, 1879Chrysistruncata Dahlbom, 1831EnglandAshmead, 1902Sphexaurata Linnaeus, 1758England, Scotland, Wales, IrelandSphexviolacea Scopoli, 1763England, WalesHaliday, 1833Some distributional data and synonymy from Perkins, 1912Jurine, 1807CHELOGYNUS Haliday, 1838NEOCHELOGYNUS Perkins, 1905Kieffer, 1905imberbis Kieffer, 1905bensoni Richards, 1939jurineanum in part, Perkins, 1976England, Scotland, Wales, IrelandDryinusbrachycerus Dalman, 1823lydeDryinus) Gonatopusephippiger Dalman, 1818collarisGonatopus) Chelogynusexiguus Haupt, 1941subarcticus Hell\u00e9n, 1935 nom. nud.flaviscapus Jansson, 1950subarcticus Hell\u00e9n, 1953England, Walesadded by Burn (1995)Dryinusfacialis Thomson, 1860pseudohilare Burn, 1990EnglandGonatopusflavicornis Dalman, 1818sericeus Kieffer, 1905subflavicornis Haupt, 1941England, Scotland, Wales, IrelandDryinusfulviventris Haliday, 1828fuscipesDryinus) Dryinusinfectus Haliday, 1837luteicornissensuPerkins (1976) misident. inclytusDryinus) Gonatopuspubicornis Dalman, 1818tenuicornisDryinus) Dryinusscapularis Haliday, 1837longiforceps Kieffer, 1905carinatus Kieffer, 1905lanionisChelogynus) Gonatopusruficornis Dalman, 1818basalisGonatopus) Dryinusatratus Dalman, 1823holomelas Richards, 1939England, Scotland, Wales, IrelandRichards, 1939heidelbergensis Richards, 1939England, WalesGonatopusmelaleucus Dalman, 1818albipesCeraphron) Richards, 1939England, Scotland, Wales, IrelandRichards, 1939F\u00f6rster, 1856Ruthe, 1859EnglandKieffer, 1906Latreille, 1804CAMPYLONYX Westwood, 1835PARADRYINUS Perkins, 1905CHLORODRYINUS Perkins, 1905PLASTODRYINUS Kieffer, 1906MESODRYINUS Kieffer, 1906HESPERODRYINUS Perkins, 1907Sphexcollaris Linnaeus, 1767formicarius Latreille, 1805ampuliciformisCampylonyx) synonymy by Burn and Olmi (2011) Dryinusbicolor Haliday, 1828vitripennisLabeo) Gelisclavipes Thunberg, 1827sepsoides Westwood, 1833pilosus Thomson, 1860nigerrimusLabeo) Sz\u00e9pligeti, 1901, hispanicus Kieffer, 1905sociabilis Kieffer, 1907borealis Sahlberg, 1910wagneri Strand, 1919barbatellus Richards, 1939campestris Ponomarenko, 1965rhaensis Ponomarenko, 1970England, Scotland, Wales, IrelandKieffer, 1905septemdentatus Sahlberg, 1910robustusDicondylus) Donisthorpinaformicicola Richards, 1939England, WalesRaatikainen, 1961dichromus Kieffer, 1906rufescens Hell\u00e9n, 1935Englandadded by Burn (1997)Klug, 1810bifasciatus Kieffer, 1904gracilicornis Kieffer, 1904filicornis Kieffer, 1905gracilis Kieffer, 1905marshalli Kieffer, 1905myrmecophilus Kieffer, 1905gracilipes Kieffer, 1906raptoripes Strand, 1919England, WalesDalman, 1818ljunghii Westwood, 1833leucostomus Sahlberg, 1910arnoldiiPachygonatopus) Gonatopusoratorius Westwood, 1833EnglandF\u00f6rster, 1856Westwood, 1833MYRMECOMORPHUS Westwood, 1833POLYPLANUS Nees, 1834EMBOLIMUS Agassiz, 1846FORMILA De Romand, 1846PEDINOMMA F\u00f6rster, 1856AMPULICOMORPHA Ashmead, 1893AMPULICIMORPHA Brues, 1933Myrmecomorphusruddii Westwood, 1833rufescensMyrmecomorphus) synonymy by Hilpert (1989) ] Although this highly invasive species has the potential to establish itself in hothouses, given the correct climate, we are unaware of any established colonies being found in Britain. Any introductions have been of isolated workers.[LINEPITHEMA Mayr, 1866 # F\u00f6rster, 1850MICROMYRMA Dufour, 1857SEMONIUS Forel, 1910TAPINOPTERA Santschi, 1925ZATAPINOMA Wheeler, 1928NEOCLYSTOPSENELLA Kurian, 1955Formicaerratica Latreille, 1798caerulescensFormica) Formicamelanocephala Fabricius, 1793nanaFormica) preocc. preocc. Formicaaliena Foerster, 1850americanus Emery, 1893pannonica R\u00f6szler, 1942England, Scotland, Wales, IrelandFormicabrunnea Latreille, 1798pallidaFormica) Formicaemarginata Olivier, 1792brunneoemarginatus Forel, 1874brunneoides Forel, 1874nigroemarginatus Forel, 1874illyricus Zimmermann, 1935pontica St\u00e4rcke, 1944Englandadded by Smith and Williams (2008)Formicaflava Fabricius, 1781ruficornisFormica) Formicafuliginosa Latreille, 1798England, Scotland, Wales, Ireland, Isle of ManFormicinameridionalis Bondroit, 1920England, WalesFormicamixta Nylander, 1846England, Scotland, Wales, IrelandVan Loon, Boomsma & Andrasfalvy, 1990Englandadded by Fox (2009)Formicanigra Linnaeus, 1758nigerrimaFormica) Seifert, 1992England, Walesadded by Seifert (1992)Formicinasabularum Bondroit, 1918England, Wales, Isle of ManFormicaumbrata Nylander, 1846aphidicolaFormica) Formicalongicornis Latreille, 1802vagansFormica) but appear to have died out since. A native of the Azores and Madeira.Lepeletier, 1835The tribal classification follows Smith, 1858Westwood, 1841Formicamegacephala Fabricius, 1793edaxFormica) is an occasional accidental import with cork from southern Europe. It has never established in Britain and, with the decrease in the cork trade, imports of this species will probably become even rarer.Mayr, 1855SYMMYRMICA Wheeler, 1904Myrmicanitidula Nylander, 1846laeviusculaMyrmica) Formicaacervorum Fabricius, 1793lacteipennisMyrmica) Formicagraminicola Latreille, 1802latreillei Curtis, 1829striatulaMyrmica) Ecitontestaceum Schenck, 1852emarginatusMyrmus) Stenammaalbipennis Curtis, 1854tuberum misident.; Orledge (1998)tuberointerruptusLeptothorax) Myrmicainterrupta Schenck, 1852simpliciusculaMyrmica) Myrmicanylanderi Foerster, 1850cingulataMyrmica) Formicaunifasciata Latreille, 1798anoplogynusLeptothorax) Myrmicaatratula Schenck, 1852friedlandiAnergates) Myrmicabicarinata Nylander, 1846guineense misident.carinicepsMyrmica) Formicacaespitum Linnaeus, 1758fuscaFormica) Myrmicasimillima Smith, 1851parallelaMyrmica) Symbiomyrmakaravajevi Arnol\u2019di, 1930laurae misident.pecheiSifolinia) Formicarubra Linnaeus, 1758laevinodis Nylander, 1846longiscapus Curtis, 1854champlaini Forel, 1901europaea Finzi, 1926bruesi Weber, 1947microrubra Seifert, 1993EnglandNylander, 1846dimidiata Say, 1836diluta Nylander, 1849ruginodolaevinodis Forel, 1874silvestrii Wheeler, 1928sontica Santschi, 1937yoshiokai Weber, 1947macrogyna Brian & Brian, 1949microgyna Brian & Brian, 1949mutata Sadil, 1952England, Scotland, Wales, Ireland, Isle of ManMeinert, 1861scabrinodolobicornis Forel, 1874England, Scotland, Wales, Ireland, Isle of ManNylander, 1846rugulosoides Forel, 1915pilosiscapus Bondroit, 1920ahngeri Karavaiev, 1926scabrinodosabuleti Sadil, 1952England, Scotland, Wales, Ireland, Isle of ManViereck, 1903kutteri Finzi, 1926subopaca Arnol'di, 1934betuliana Ruzsky, 1946schenckioides Boer & Noordijk, 2005England, Wales, IrelandBondroit, 1918silvestrianum Emery, 1924striata Finzi, 1926sancta Karavaiev, 1926nevodovskiiLeptothorax) Forel, 1893Mayr, 1855Attafloricola Jerdon, 1851# Monomoriumfloricolacinnabari Roger, 1863# Monomoriumfloricolapoecilum Roger, 1863# Monomoriumfloricolaspecularis Mayr, 1866# Monomoriumfloricolaimpressum Smith, 1876# Monomoriumfloricolaphilippinensis Forel, 1910# Monomoriumfloricolafurina Forel, 1911# Monomoriumfloricolafloreanum Stitz, 1932# Monomoriumfloricolaangusticlava Donisthorpe, 1947Formicapharaonis Linnaeus, 1758antiguensisFormica) Formicafugax Latreille, 1798flavidulaMyrmica) Myrmicadebilis F\u00f6rster, 1850minkiiMyrmica) Westwood, 1839Englanddebile was described from a worker casually introduced to Britain.Ponerapunctatissima Roger, 1859androgynaPonera) Poneraergatandria Forel, 1893schauinslandiPonera) synonymy by Seifert (2013) Formicacoarctata Latreille, 1802contractaFormica) Latreille, 1802Nomenclature follows Latreille, 1802Linnaeus, 1758Linnaeus, 1758England, ScotlandThomson, 1870Mutillarufipes Fabricius, 1787EnglandFox, 1894Latreille, 1796Panzer, 1801melanocephalaMutilla) preocc. Sphexcarbonaria Scopoli, 1763punctumCeropales) Pompilusfasciatellus Spinola, 1808calcaratusPompilus) Sphexnotata Rossi, 1792guttusPompilus) Vander Linden, 1827, iracundusPompilus) preocc. Ichneumonbifasciatus Geoffroy, 1785hircanusPompilus) Pogoniussubintermedius Magretti, 1886nitidusDeuteragenia) Sphexvariegata Linnaeus, 1758erythropusAgenia) Pompilusagilis Shuckard, 1837obtusiventris Schi\u00f8dte, 1837fraterculus Junco, 1946England, Scotland, WalesWahis, 2006gracilis Haupt, 1927 preocc.gussakowskiji Wolf, 2004 preocc.England, IrelandHaupt, 1927EnglandSphexexaltata Fabricius, 1775gibbaSphex) Sphexhyalinata Fabricius, 1793femoralisPompilus) Calicurguspropinquus Lepeletier, 1845agenoides Dubois, 1920EnglandPompiluspusillus Schi\u00f8dte, 1837England, WalesHaupt, 1927England, Scotland, WalesJunco, 1946PRIOCNEMISSUS Haupt, 1949Dahlbom, 1843capciosus Junco, 1946EnglandSphexperturbator Harris, 1780fusca misident.ambustorIchneumon) Pompiluscinctellus Spinola, 1808clypeatusPompilus) Pompilussericeus Vander Linden, 1827vicinusPompilus) Dufour, 1834Dufour, 1834Pompiluscaviventris Aurivillius, 1907carduiPompilus) Pompilusconcinnus Dahlbom, 1845vacillansPompilus) Sphexnigerrima Scopoli, 1763nigrusSphex) preocc. Pompilusinfuscatus Vander Linden, 1827minorPompilus) infuscatuschalybeatus Anoplius (Arachnophroctonus) infuscatusdifformis disparPompilus) infuscatussabulicola Anoplius (Arachnophroctonus) infuscatusmeticulosa Anoplius (Arachnophroctonus) infuscatusaeruginosus Anoplius (Arachnophroctonus) infuscatusaerarius Anoplius (Arachnophroctonus) infuscatusargentatus Anoplius (Arachnophroctonus) infuscatuscalcatus Anoplius (Arachnophroctonus) infuscatusonus Anoplius (Arachnophroctonus) infuscatusstellatus Anoplius (Arachnophroctonus) infuscatusutendus Anoplius (Arachnophroctonus) infuscatusvivus Anoplius (Arachnophroctonus) infuscatusxysticus petulans Haupt, 1962cinctellusParacyphonyx) infuscatusfortunatus Wolf, 1975Anoplius (Arachnophroctonus) infuscatussimii Wolf, 1978England, WalesSphexviatica Linnaeus, 1758fuscusSphex) preocc. preocc. Pompilusanceps Wesmael, 1851vagaSphex) preocc. Pompilusconsobrinus Dahlbom, 1843aterPompilus) preocc. preocc. Pompilustrivialis Dahlbom, 1843gibba misident.aerumnataPompilus) Pompiluswesmaeli Thomson, 1870England, WalesBanks, 1939Pompilusminutulus Dahlbom, 1842cellularisPompilus) Pompilusspissus Schi\u00f8dte, 1837apennina Wolf, 1970England, Scotland, WalesKincaid, 1900PYCNOPOMPILUS Ashmead, 1902Psammocharesrufus Haupt, 1927adulterinaPsammochares) Pompilusgallicus Tournier, 1889intermedius Haupt, 1930tertius Bl\u00fcthgen, 1944Englandadded by Baldock (2006)Sphexrufipes Linnaeus, 1758laevigataSphex) preocc. preocc. Pompiluscrassicornis Shuckard, 1835dahlbomiPompilus) Aporusdubius Vander Linden, 1827bicolor Lepeletier, 1845servillei Costa, 1882rattusPompilus) Sphexpectinipes Linnaeus, 1758quadrispinosusPompilus) Sphexsanguinolenta Fabricius, 1793disparPompilus) preocc. Sphexcinerea Fabricius, 1775plumbeusSphex) Evaniamaculata Fabricius, 1775rusticaSphex) Evaniavariegata Fabricius, 1798destefanii Costa, 1887EnglandLatreille, 1810Pic, 1920Apisclavicornis Linnaeus, 1758England, WalesLatreille, 1796Scoliaquinquepunctata Fabricius, 1781England, WalesLeach, 1915Latreille, 1804METHOCA misspellingTaxonomy follows Latreille, 1792formicariaMutilla) nom. dub. Vespaantilope Panzer, 1798pictusOdynerus) nom. dub. Vespagazella Panzer, 1798emarginataVespa) preocc. Odynerusnigricornis Curtis, 1826callosusOdynerus) Odynerusoviventris Wesmael, 1836constansOdynerus) Vespaparietina Linnaeus, 1758domesticusSphex) Vespaparietum Linnaeus, 1758England, Scotland, Wales, Ireland, Isle of ManOdynerusscoticus Curtis, 1826trimarginatus misident.albotricinctusOdynerus) Vespatrifasciata M\u00fcller, 1776trimarginatusOdynerus) Vespacoarctata Linnaeus, 1758papillariusSphex) Vespaquadrifasciata Fabricius, 1793tomentosusOdynerus) Odyneruslaevipes Shuckard, 1837England, WalesThomson, 1874Odynerusexilis Herrich-Sch\u00e4ffer, 1839bivittatusOdynerus) Vespamelanocephala Gmelin, 1790England, WalesVespaspinipes Linnaeus, 1758quinquefasciataVespa) preocc. Vespareniformis Gmelin, 1790EnglandMorawitz, 1867EnglandSaussure, 1856Odynerusherrichii Saussure, 1855variegata misident.basalisOdynerus) Vespabifasciata Linnaeus, 1761sinuatusVespa) preocc. Odynerusconnexus Curtis, 1826bifasciatus misident.EnglandVespacrassicornis Panzer, 1798England, WalesOdynerusgracilis Brull\u00e9, 1832England, WalesTaxonomy follows Latreille, 1802Vespadominula Christ, 1791gallicus misident.italica Herrich-Sch\u00e4ffer, 1840 nom. nud.pectoralis Herrich-Sch\u00e4ffer, 1841lefebvrei Gu\u00e9rin, 1844bucharensis Erichson, 1849maculatus Rudow, 1889merceti Dusmet, 1903rufescens Buysson, 1912ornata Weyrauch, 1938pacfica Weyrauch, 1939 preocc.pseudopacificus Giordani Soika, 1970muchei Gusenleitner, 1976EnglandVespagallica Linnaeus, 1767pictior Radoszkowski, 1872foederata Kohl, 1898omissaPolistula) , who collected a single male in Co. Down; it is unknown whether a nest had been established but this southern European species is an unlikely colonist.Added by Nomenclature follows Rohwer, 1916PSEUDOVESPULA Bischoff, 1931BOREOVESPULA Bl\u00fcthgen, 1943METAVESPULA Bl\u00fcthgen, 1943Vespamedius Retzius, 1783geeriiVespa) Vespanorwegica Fabricius, 1781britannicaVespa) preocc. preocc. preocc. Vespasaxonica Fabricius, 1793bavaricaVespa) Vespasylvestris Scopoli, 1763parietumVespa) Vespaaustriaca Panzer, 1799borealisVespa) preocc. Vespagermanica Fabricius, 1793maculataVespa) preocc. Vesparufa Linnaeus, 1758schrenckiiVespa) Vespavulgaris Linnaeus, 1758sexcinctaVespa) (Panzer, 1799, England, Scotland, Wales, Ireland, Isle of ManSupplementary material 1Checklist of the British and Irish aculeatesData type: formatted textBrief description: Word document version of the checklistFile: oo_83170.docxElse, G., Bolton, B. & Broad, G.R.Supplementary material 2Checklist of the British and Irish aculeatesData type: spreadsheetBrief description: Excel spreadsheet version of the checklistFile: oo_83127.xlsxElse, G., Bolton, B. & Broad, G.R."} +{"text": "AbstractAcari, Oribatida) in the fauna of Vietnam is provided. During 1967\u20132015, a total of 535 species/subspecies from 222 genera and 81 families was registered. Of these, 194 species/subspecies were described as new for science from Vietnam.A species list of identified oribatid mite taxa ( Acari, Oribatida) of Vietnam were presented by The first data on oribatid mite fauna , to present primary references (in square brackets) on descriptions of new species or new findings for each species, and to provide the subsequent faunistic and taxonomic studies.Oribatida used in this paper mostly follows that of General taxonomic system of AcaronychidaeLoftacarussiefi Lee, 1981 Zetorchestessaltator Oudemans, 1915 Dolicheremaeusbartkei Rajski & Szudrowicz, 1974 Dolicheremaeusbugiamapensis Ermilov, Anichkin & Wu, 2012 [Wu, 2012 Dolicheremaeuscapillatus [h, 1959) Dolicheremaeuscontactus Ermilov & Anichkin, 2013 [in, 2013 Dolicheremaeusdamaeoides [e, 1913) Dolicheremaeusdonacunarensis Ermilov & Anichkin, 2014 [in, 2014 Dolicheremaeusdwalteri Ermilov & Anichkin, 2014 [in, 2014 Dolicheremaeusinsolitus Ermilov & Anichkin, 2014 [in, 2014 Dolicheremaeusjunichiaokii Sub\u00edas, 2010 [i, 2006) Dolicheremaeusinaequalis Balogh & Mahunka, 1967 [ka, 1967 Dolicheremaeuslineolatus Balogh & Mahunka, 1967 [ka, 1967 Dolicheremaeusorientalis [i, 1965) Dolicheremaeusornatus Balogh & Mahunka, 1967 [ka, 1967 Dolicheremaeusphilippinensis Aoki, 1967 [ki, 1967 PageBreakDolicheremaeussabahnus Mahunka, 1988 [ka, 1988 Fissicepheus (Fissicepheus) elegans Balogh & Mahunka, 1967 [ka, 1967 Fissicepheus (Fissicepheus) striganovae Ermilov & Anichkin, 2014 [in, 2014 Leptotocepheusmurphyi [a, 1989) Megalotocepheus (Archegotocepheus) crinitus Berlese, 1905 [se, 1905 Megalotocepheus (Archegotocepheus) singularis [a, 1988) Otocepheus (Otocepheus) spatulatus Mahunka, 2000 [ka, 2000 Otocepheus (Acrotocepheus) duplicornutusduplicornutus Aoki, 1965 [ki, 1965 Otocepheus (Acrotocepheus) duplicornutusdiscrepans Balogh & Mahunka, 1967 [ka, 1967 Otocepheus (Acrotocepheus) excelsus Aoki, 1965 [ki, 1965 Otocepheus (Acrotocepheus) triplicicornutus Balogh & Mahunka, 1967 [ka, 1967 Otocepheus (Acrotocepheus) vietnamicus Ermilov & Anichkin, 2011 [in, 2011 Papillocepheusprimus Ermilov, Anichkin & Tolstikov, 2014 [ov, 2014 Pseudotocepheussetiger [r, 1972) Umashtanchaeviellaplethotricha Ermilov, Anichkin & Tolstikov, 2014 [ov, 2014 CarabodidaeAokiellaflorens Balogh & Mahunka, 1967 [ka, 1967 Aokiellarotunda Hammer, 1979 [er, 1979 Aokiellaxuansoni Vu, Ermilov & Dao, 2010 [ao, 2010 Austrocarabodes (Austrocarabodes) alveolatus Hammer, 1973 [er, 1973 Austrocarabodes (Austrocarabodes) falcatus Hammer, 1973 [er, 1973 Austrocarabodes (Austrocarabodes) szentivanyi [a, 1967) Austrocarabodes (Austrocarabodes) vaucheri Mahunka, 1984 [ka, 1984 Austrocarabodes (Uluguroides) polytrichus Balogh & Mahunka, 1978 [ka, 1978 Carabodes (Klapperiches) mikhaetandreorum Ermilov & Anichkin, 2013 [in, 2013 Carabodes (Klapperiches) samoensis Balogh & Balogh, 1986 [gh, 1986 Carabodes (Klapperiches) strinovichi Balogh & Mahunka, 1978 [ka, 1978 Carabodes (Phyllocarabodes) inopinatus [a, 1985) Carabodes (Phyllocarabodes) schatzi Sub\u00edas, 2010 [as Phyllocarabodesornatus Balogh, 1986 \u2013 Chistyakovellainsolita Ermilov, Aoki & Anichkin, 2013 [in, 2013 Gibbicepheus (Gibbicepheus) baccanensis Jeleva & Vu, 1987 [Vu, 1987 Gibbicepheus (Gibbicepheus) fenestralis Hammer, 1979 [er, 1979 Gibbicepheus (Gibbicepheus) latohumeralis Hammer, 1982 [er, 1982 PageBreakYoshiobodes (Yoshiobodes) irmayi [as Yoshiobodesaokii Mahunka, 1987 \u2013 Yoshiobodes (Yoshiobodes) neotrichorostralis Ermilov, Shtanchaeva, Sub\u00edas & Anichkin, 2014 [in, 2014 Yoshiobodes (Dongnaibodes) biconcavus Ermilov, Shtanchaeva, Sub\u00edas & Anichkin, 2014 [in, 2014 Yoshiobodes (Dongnaibodes) hexasetosus Ermilov, Shtanchaeva, Sub\u00edas & Anichkin, 2014 [in, 2014 NippobodidaeNippobodesmonstruosus [u, 1987) TectocepheidaeTectocepheuselegans Ohkubo, 1981 [bo, 1981 Tectocepheusminor Berlese, 1903 [as Tectocepheuscuspidentatus Kn\u00fclle, 1954 \u2013 Tectocepheusvelatus [l, 1880) Tegeozetestunicatustunicatus Berlese, 1913 [se, 1913 Tegeozetestunicatusbreviclava Aoki, 1970 [ki, 1970 TegeocranellidaeTegeocranellusmartinezi Ermilov & Anichkin, 2014 [in, 2014 MicrotegeidaeMicrotegeusborhidii Balogh & Mahunka, 1974 [ka, 1974 Microtegeuscardosensis P\u00e9rez-\u00cd\u00f1igo, 1985 [go, 1985 Microtegeuscornutus Balogh, 1970 [gh, 1970 Microtegeusquadristriatus Mahunka, 1984 [ka, 1984 Microtegeusreticulatus Aoki, 1965 [ki, 1965 CymbaeremaeidaeScapheremaeusascissuratus Ermilov & Anichkin, 2015 [in, 2015 Scapheremaeuscellulatifer Mahunka, 1987 [ka, 1987 Scapheremaeuscrassus Mahunka, 1988 [ka, 1988 Scapheremaeusfisheri Aoki, 1966 [ki, 1966 Scapheremaeusfoveolatus Mahunka, 1987 [ka, 1987 LicneremaeidaeLicneremaeuslicnophorus [l, 1882) Licneremaeuspolygonalis Hammer, 1971 [er, 1971 PhenopelopidaeEupelopsforsslundi [h, 1959) Nesopelopsintermedius Hammer, 1979 [er, 1979 EremaeozetidaeMahunkaiabituberculata [a, 1983) IdiozetidaeIdiozetesjavensis Hammer, 1979 [er, 1979 LimnozetidaeLimnozetespustulatus [a, 1987) PageBreakMicrozetidaeBerlesezetesornatissimus [as Berlesezetesauxiliaris Grandjean, 1936 \u2013 Caucasiozetesfrankeae Ermilov & Anichkin, 2011 [in, 2011 Kaszabodesvelatus Mahunka, 1988 [ka, 1988 Schalleriellavietnamica Ermilov & Anichkin, 2011 [in, 2011 AchipteriidaeAchipteria (Achipteria) curta Aoki, 1970 [ki, 1970 Anachipteria (Anachipteria) svetlanae Ermilov & Anichkin, 2014 [in, 2014 Austrachipteriaphongnhae Ermilov & Vu, 2012 [Vu, 2012 Campachipteriadistincta [i, 1959) Campachipteriauenoi Aoki, 1995 [ki, 1995 Plakoribatesasiaticus Ermilov & Anichkin, 2013 [in, 2013 TegoribatidaeCeratobatescangioensis Ermilov & Anichkin, 2015 [in, 2015 Tegoribatesamericanus Hammer, 1958 [er, 1958 OribatellidaeNovoribatellaminutisetarum Engelbrecht, 1986 [ht, 1986 Ophidiotrichusussuricus Krivolutsky, 1971 [ky, 1971 Oribatella (Oribatella) gerdweigmanni Ermilov & Anichkin, 2012 [in, 2012 Oribatella (Oribatella) illuminata Hammer, 1961 [er, 1961 Oribatella (Oribatella) prolongata Hammer, 1961 [er, 1961 Oribatella (Oribatella) sculpturata Mahunka, 1987 [ka, 1987 Oribatella (Oribatella) umaetluisorum Ermilov & Anichkin, 2012 [in, 2012 HeterozetidaeFarchacarusphilippinensis [s, 1979) CeratozetidaeCeratozetes (Ceratozetes) bicornis Hammer, 1967 [er, 1967 Ceratozetes (Ceratozetes) gracilis [l, 1884) Ceratozetes (Ceratozetes) mediocris Berlese, 1908 [se, 1908 Fuscozetesfuscipes [h, 1844) Lepidozetestrifolius [a, 1972) Sphaerozetesbugiamapensis Ermilov, Anichkin & Wu, 2013 [Wu, 2013 PunctoribatidaeAllozetesafricanus Balogh, 1958 [gh, 1958 Allozetespusillus [e, 1913) Lamellobatesmolecula [Lamellobatespalustris Hammer, 1958 \u2013 Lamellobateshauseri Mahunka, 1977 \u2013 Lamellobatesocularis Jeleva & Vu, 1987 [Vu, 1987 PageBreakParalamellobatesmisella [as Paralamellobatesschoutedani \u2013 Paralamellobatesceylanicus \u2013 Punctoribateshexagonus Berlese, 1908 [se, 1908 Punctoribatespunctum [h, 1839) ChamobatidaeChamobates (Chamobates) javensis [r, 1979) MochlozetidaeMochlozetesryukyuensis Aoki, 2006 [ki, 2006 Unguizetesasiaticus Ermilov & Anichkin, 2012 [in, 2012 Unguizetescattienensis Ermilov & Anichkin, 2011 [in, 2011 Unguizetesclavatus Aoki, 1967 [ki, 1967 Unguizeteslatus Ermilov & Anichkin, 2013 [in, 2013 Unguizetessphaerula [e, 1905) Uracrobates (Uracrobates) magniporosus Balogh & Mahunka, 1967 [ka, 1967 OribatulidaeParaphauloppiagracilis [r, 1958) Zygoribatulapennata Grobler, 1993 [er, 1993 Zygoribatulaprima Ermilov & Anichkin, 2011 [in, 2011 Zygoribatulaundulata Berlese, 1916 [as Zygoribatulalongiporosa Hammer, 1953 \u2013 SellnickiidaeSellnickiacaudata [l, 1908) CaloppiidaeZetorchellalatior [e, 1913) Zetorchellareticulata [n, 1933) ScheloribatidaeAreozetesincertus Balogh, 1970 [gh, 1970 Cordiozetesolahi [a, 1987) Euscheloribates (Euscheloribates) samsinaki Kunst, 1958 [st, 1958 Euscheloribates (Trischeloribates) clavatus [a, 1988) Exoribatula (Multoribates) longior [r, 1958) Fijibatesaelleni [a, 1988) Fijibatesrostratus Hammer, 1971 [er, 1971 Liebstadia (Liebstadia) humerata Sellnick, 1928 [ck, 1928 Perscheloribates (Perscheloribates) lanceolatus [i, 1984) Perscheloribates (Perscheloribates) luminosus [r, 1961) Perscheloribates (Perscheloribates) luteus [r, 1962) Perscheloribates (Perscheloribates) minutus [n, 1965) Rhabdoribatessiamensis Aoki, 1967 [ki, 1967 Scheloribates (Scheloribates) crucisetus Jeleva & Vu, 1987 [Vu, 1987 Scheloribates (Scheloribates) fimbriatus Thor, 1930 [or, 1930 PageBreakScheloribates (Scheloribates) flagellisetosus Ermilov & Anichkin, 2014 [in, 2014 Scheloribates (Scheloribates) kraepelini [e, 1908) Scheloribates (Scheloribates) laevigatus [h, 1835) Scheloribates (Scheloribates) latipes [h, 1844) Scheloribates (Scheloribates) pallidulus [h, 1844) Scheloribates (Scheloribates) parvus Pletzen, 1963 [en, 1963 Scheloribates (Scheloribates) praeincisuspraeincisus [e, 1910) Scheloribates (Scheloribates) praeincisusinterruptus [e, 1916) Scheloribates (Scheloribates) vulgaris Hammer, 1961 [er, 1961 Scheloribates (Bischeloribates) mahunkai Sub\u00edas, 2010 [as Philoribatesheterodactylus \u2013 Tuberemaeuslineatus Balogh, 1970 [gh, 1970 Tuberemaeusperforatoides Hammer, 1979 [er, 1979 Tuberemaeussculpturatus Mahunka, 1987 [ka, 1987 Tuberemaeussingularis Sellnick, 1930 [ck, 1930 Vesiculobatessilvaticus Hammer, 1979 [er, 1979 OripodidaeBrachyoripodafoveolata Balogh, 1970 [gh, 1970 Cosmopirnodustridactylus Mahunka, 1988 [ka, 1988 Oripodaexcavata Mahunka, 1988 [ka, 1988 Oripodapinicola Aoki & Ohkubo, 1974 [bo, 1974 Subpirnodusmirabilis Mahunka, 1988 [ka, 1988 Truncopesmoderatusvariabilis Aoki & Yamamoto, 2007 [to, 2007 Truncopesorientalis Mahunka, 1987 [ka, 1987 HaplozetidaeAcutozetesrostratus Balogh, 1970 [gh, 1970 Indoribates (Indoribates) bicarinatus Ermilov & Anichkin, 2014 [in, 2014 Indoribates (Indoribates) microsetosus Ermilov & Anichkin, 2011 [in, 2011 Indoribates (Indoribates) nobilis [a, 1984) Indoribates (Indoribates) punctulatus [as Indoribatespanabokkei \u2013 Haplozetesvindobonensis [n, 1935) Lauritzenia (Incabates) major [i, 1967) Lauritzenia (Magnobates) glagellifer [r, 1967) Peloribates (Peloribates) gressitti Balogh & Mahunka, 1967 [ka, 1967 Peloribates (Peloribates) guttatoides Hammer, 1979 [er, 1979 Peloribates (Peloribates) guttatus Hammer, 1979 [er, 1979 PageBreakPeloribates (Peloribates) kaszabi Mahunka, 1988 [ka, 1988 Peloribates (Peloribates) paraguayensis Balogh & Mahunka, 1981 [ka, 1981 Peloribates (Peloribates) pseudoporosus Balogh & Mahunka, 1967 [ka, 1967 Peloribates (Peloribates) rangiroaensis Hammer, 1972 [er, 1972 Peloribates (Peloribates) ratubakensis Hammer, 1979 [er, 1979 Peloribates (Peloribates) spiniformis Ermilov & Anichkin, 2011 [in, 2011 Peloribates (Peloribates) stellatus Balogh & Mahunka, 1967 [ka, 1967 Peloribates (Peloribates) tatyanae Ermilov & Anichkin, 2014 [in, 2014 Perxylobatesbrevisetosus Mahunka, 1988 [ka, 1988 Perxylobatescrassisetosus Ermilov & Anichkin, 2011 [in, 2011 Perxylobatesguehoi Mahunka, 1978 [ka, 1978 Perxylobatesthanhoaensis Ermilov, Vu, Trinh & Dao, 2011 [ao, 2011 Perxylobatesvermisetus [a, 1968) Perxylobatesvietnamensis [u, 1987) Protoribates (Protoribates) capucinus Berlese, 1908 [se, 1908 Protoribates (Protoribates) cattienensis Ermilov & Anichkin, 2011 [in, 2011 Protoribates (Protoribates) dentatus [as Protoribatesmonodactylus \u2013 Protoribates (Protoribates) gracilis [i, 1982) Protoribates (Protoribates) lophotrichus [e, 1904) Protoribates (Protoribates) paracapucinus [a, 1988) Protoribates (Triaunguis) acutus [r, 1979) Protoribates (Triaunguis) bisculpturatus [a, 1988) Protoribates (Triaunguis) duoseta [r, 1979) Protoribates (Triaunguis) heterodactylus Ermilov & Anichkin, 2011 [in, 2011 Protoribates (Triaunguis) maximus [a, 1988) Setoxylobates (Setoxylobates) foveolatus Balogh & Mahunka, 1967 [ka, 1967 Setoxylobates (Polyxylobates) diversiporosus [r, 1973) Trachyoribatesirregularis [a, 1969) Trachyoribatesovulum Berlese, 1908 [as Rostrozetesfoveolatus Sellnick, 1925 \u2013 Rostrozetesareolatus \u2013 Rostrozetespunctulifer Balogh & Mahunka, 1979 \u2013 Rostrozetestrimorphus Balogh & Mahunka, 1979 \u2013 Transoribatesagricola [i, 1989) Vilhenabatessinatus [i, 1965) ParakalummidaeNeoribates (Neoribates) aurantiacus [s, 1914) Neoribates (Neoribates) jacoti [a, 1967) PageBreakNeoribates (Neoribates) monodactylus Ermilov & Anichkin, 2014 [in, 2014 Neoribates (Neoribates) paratuberculatus Ermilov, Shtanchaeva & Sub\u00edas, 2014 [as, 2014 Neoribates (Neoribates) spindleformis Ermilov & Anichkin, 2012 [in, 2012 GalumnidaeAllogalumna bipartita [u, 1993) Allogalumna costata Mahunka, 1996 [ka, 1996 Allogalumna monodactyla Ermilov & Anichkin, 2014 [in, 2014 Allogalumna multesima Grandjean, 1957 [an, 1957 Allogalumna paramachadoi Ermilov & Anichkin, 2014 [in, 2014 Allogalumna rotundiceps Aoki, 1996 [ki, 1996 Allogalumna upoluensis Hammer, 1973 [er, 1973 Allogalumna biporosa Ermilov & Anichkin, 2012 [in, 2012 Dimidiogalumnaazumai Aoki, 1996 [ki, 1996 Dimidiogalumnagrandjeani Ermilov & Anichkin, 2014 [in, 2014 Galumna aba Mahunka, 1989 [ka, 1989 Galumna acutirostrum Ermilov & Anichkin, 2010 [in, 2010 Galumna coronata Mahunka, 1992 [ka, 1992 Galumna discifera Balogh, 1960 [gh, 1960 Galumna flabellifera Hammer, 1958 [as Galumnaflabelliferaorientalis Aoki, 1965 \u2013 Galumna kebangica Ermilov & Vu, 2012 [Vu, 2012 Galumna khoii Mahunka, 1989 [ka, 1989 Galumna lanceata [s, 1900) Galumna levisensilla Ermilov & Anichkin, 2010 [in, 2010 Galumna microfissum Hammer, 1968 [er, 1968 Galumna obvia [e, 1914) Galumna paracalcicola Ermilov & Anichkin, 2014 [in, 2014 Galumna parakazakhstani Ermilov & Anichkin, 2014 [in, 2014 Galumna paramastigophora Ermilov, 2015 [ov, 2015 Galumna pseudokhoii Ermilov & Anichkin, 2011 [in, 2011 Galumna pseudotriquetra Ermilov, 2015 [ov, 2015 Galumna triquetra Aoki, 1965 [ki, 1965 PageBreakGalumna triops Balogh, 1960 [gh, 1960 Galumna dongnaiensis Ermilov & Anichkin, 2013 [in, 2013 Galumna praeoccupata Sub\u00edas, 2004 [as, 2004 Galumna tenensis Ermilov, Vu & Nguyen, 2011 [en, 2011 Galumna longilineata Ermilov & Anichkin, 2014 [in, 2014 Galumna seniczaki Ermilov & Anichkin, 2010 [in, 2010 Galumna tolstikovi Ermilov & Anichkin, 2014 [in, 2014 Leptogalumna ciliata Balogh, 1960 [gh, 1960 Notogalumnafoveolata Balakrishnan, 1989 [an, 1989 Notogalumnalagunaensis Ermilov & Corpuz-Raros, 2015 [os, 2015 Pergalumna altera [s, 1915) Pergalumna cattienica Ermilov & Anichkin, 2011 [in, 2011 Pergalumna granulata Balogh & Mahunka, 1967 [ka, 1967 Pergalumna hauseri Mahunka, 1995 [ka, 1995 Pergalumna indistincta Ermilov & Anichkin, 2011 [in, 2011 Pergalumna kotschyi Mahunka, 1989 [ka, 1989 Pergalumna longisetosa Balogh, 1960 [gh, 1960 Pergalumna magniporacapillaris Aoki, 1961 [ki, 1961 Pergalumna margaritata Mahunka, 1989 [ka, 1989 Pergalumna mauritii Mahunka, 1978 [ka, 1978 Pergalumna montana Hammer, 1961 [er, 1961 Pergalumna nuda Balogh, 1960 [gh, 1960 Pergalumna paraelongata Ermilov & Anichkin, 2012 [in, 2012 Pergalumna pseudosejugalis Ermilov & Anichkin, 2012 [in, 2012 Pergalumna punctulata Balogh & Mahunka, 1967 [ka, 1967 Pergalumna taprobanica Balogh, 1988 [gh, 1988 Pergalumna yurtaevi Ermilov & Anichkin, 2011 [in, 2011 Trichogalumnanipponica [i, 1966) Trichogalumnasubnuda Balogh & Mahunka, 1967 [ka, 1967 Trichogalumnavietnamica Mahunka, 1987 [ka, 1987 GalumnellidaeGalumnella cellularis [a, 1967) Galumnella geographica Mahunka, 1995 [ka, 1995 PageBreakGalumnella microporosa Ermilov & Anichkin, 2011 [in, 2011 Galumnella tiunovi Ermilov & Anichkin, 2013 [in, 2013 Galumnella paulinai Balogh, 1961 [gh, 1961 Galumnella scavasorum [a, 1994) Porogalumnellapulchella Aoki & Hu, 1993 [Hu, 1993 The list of oribatid mites of Vietnam includes now 535 species/subspecies, 222 genera and 81 families. Of these, 194 species/subspecies were described as new for science from Vietnam; 94 species have been described by Ermilov and co-authors, 30 species by Balogh and Mahunka, 28 species by Mahunka, 21 species by Niedba\u0142a, 6 species by Jeleva and Vu, 4 species by Fernandez and co-authors, 3 species by Krivolutsky, 2 species by Golosova, 2 species by Star\u00fd, 2 species by Vu and co-authors, 1 species by Balogh, 1 species by Rajski and Szudrowicz."} +{"text": "This article has beenThe following should be considered the version of record and used for citation purposes: \u201cIshida K, Aota Y, Mitsugi N, Kono M, Higashi T, Kawai T, Yamada K, Niimura T, Kaneko K, Tanabe H, Ito Y, Katsuhata T, Saito T, Relationship between bone density and bone metabolism in adolescent idiopathic scoliosis, Scoliosis 2015, 10:9, DOI:10.1186/s13013-015-0033-z\u201d.The duplicate \u201cIshida K, Aota Y, Mitsugi N, Kono M, Higashi T, Kawai T, Yamada K, Niimura T, Kaneko K, Tanabe H, Ito Y, Katsuhata T, Saito T, Relationship between bone density and bone metabolism in adolescent idiopathic scoliosis, Scoliosis 2015, 10:19, DOI:10.1186/s13013-015-0043-x\u201d is to be ignored."} +{"text": "In this article which was published in Cell J, Vol 17, No 4, Jan-Mar (Winter) 2016, onpages 711-719, the name of the all authors were published incorrectly as: \"Ristic Na-tasa, Stevanovic Darko, Nesic Dejan, Ajdzanovic Vladimir, Rakocevic Rastko, JaricIvana, Milosevic Verica\". The correct one is \"Natasa Ristic, Darko Stevanovic, DejanNesic, Vladimir Ajdzanovic, Rastko Rakocevic, Ivana Jaric, Verica Milosevic\".This correction was requested by the corresponding author."} +{"text": "AbstractDiptera: Culicidae) known to occur in Colombia is presented. A total of 324 species from 28 genera of Culicidae are included. The species names are organized in alphabetical order according to the current generic and subgeneric classification, along with their authorship. The list is compiled in order to support mosquito research in Colombia.A revised list of the mosquitoes , Johnbelkinialeucopus , Mansoniaindubitans Dyar & Shannon, 1925, Psorophorasaeva Dyar & Knab, 1906, Sabethesglaucodaemon , and Wyeomyiaintonca Dyar & Knab, 1909. Moreover, Wyeomyia (Dendromyia) luteoventralis Theobald, 1901 is recorded for Colombia for the first time. This work provides important insights into mosquito diversity in Colombia, using the current nomenclature and phylogenetic rankings.Our systematic review and literature survey found, by 16 February 2015, 13 records of culicid species previously overlooked by mosquito catalogs for Colombia: Culicidae are formally recognized and distributed over a diverse range of habitats around the world luteoventralis Theobald, 1901 is based on a female collected with CDC traps in September 2013 in a tropical dry forest in La Pintada (Antioquia) . The specimen was identified using The species list was compiled from information available in previously published mosquito catalogs for Colombia and othesensu auctorum' placement of 'Ochlerotatus (Protomacleaya)', product of the polyphyletic assemblage of species reflected in the Aedini phylogeny reconstructed by Anophelesallopha Peryass\u00fa, 1921, Culexaikenii Aiken & Rowland, 1906, Culexvirgultus Theobald, 1901, Trichoprosoponhyperleucum ) are not included.The species presented in this list are arranged alphabetically by genus and subgenus. Species names are followed by their authorship and year of description, and the catalog or other source that first reported the species in Colombia. Our list follows the most recent mosquito classification compiled by Dyar & Knab, 1906Wilkerson, 1991da Fonseca & da Silva Ramos, 1939Coquillett, 1902Root, 1927Wilkerson & Sallum, 1999Dyar & Knab, 1907Lutz & Neiva, 1911Curry, 1931Dyar & Knab, 1908Theobald, 1901Dyar & Knab, 1906Davis, 1931Dyar & Knab, 1906Komp, 1937Dyar & Knab, 1906Dyar & Knab, 1908Komp, 1937Zavortink, 1973Howard, Dyar & Knab, 1913Zavortink, 1973Osorno-Mesa, 1947Barreto-Reyes 1955Antunes, 1937Gabald\u00f3n, Cova Garc\u00eda & Lopez, 1941Wiedemann, 1820Lynch Arrib\u00e1lzaga, 1878Curry, 1932Robineau-Desvoidy, 1827Gabald\u00f3n, Cova Garc\u00eda & Lopez, 1941Chagas, 1907Root, 1926Causey, 1945Br\u00e8thes, 1926Galv\u00e3o & Damasceno, 1942Gabald\u00f3n, 1940Peryass\u00fa, 1922Chagas, 1907Gabald\u00f3n, Cova Garc\u00eda & Lopez, 1940Root, 1926Neiva & Pinto, 1922Faran, 1979Edwards, 1930Shannon, 1933Harbach, 2009Dyar, 1928Root, 1927Duret, 1969Theobald, 1903Root, 1927Rozeboom & Komp, 1948Komp, 1936Dyar & Knab, 1906Dyar & Knab, 1907Dyar & Knab, 1906Adames & Galindo, 1973Lane & Whitman, 1943Dyar & N\u00fa\u00f1ez Tovar, 1928Dyar, 1921Bonne-Wepster & Bonne, 1920Valencia, 1973Dyar, 1921Bonne-Wepster & Bonne, 1920Lane & Whitman, 1943Lane, 1936Root, 1927Forattini, 1965Dyar, 1929Forattini, 1965Dyar & Knab, 1906Bonne-Wepster & Bonne, 1920Dyar, 1925Dyar, 1921Duret, 1967Dyar & Knab, 1906Dyar & Knab, 1906Dyar, 1907Theobald, 1901Lane, 1945Evans, 1923Dyar & Knab, 1906Theobald, 1901Dyar, 1918Say, 1823Dyar, 1928Lutz, 1905Dyar, 1907Dyar, 1921Dyar, 1922Dyar, 1918Sirivanakarn & Galindo, 1980Bonne-Wepster & Bonne, 1920Dyar, 1918Dyar & Knab, 1906Rozeboom & Komp, 1948Senevet & Abonnenc, 1939Bonne-Wepster & Bonne, 1920Dyar, 1920Dyar & Knab, 1906Bonne-Wepster & Bonne, 1920Anduze, 1949Dyar, 1924Dyar, 1928Dyar, 1918Dyar, 1920Dyar & Knab, 1906Dyar, 1923Dyar & Knab, 1906Dyar, 1922Duret, 1968Duret, 1968Dyar, 1928Dyar & Knab, 1906Dyar, 1918Galindo & Mendez, 1961Komp & Rozeboom, 1951Komp, 1936Galindo & Mendez, 1961Dyar & Knab, 1919Dyar, 1923Sirivanakarn & Belkin, 1980Dyar, 1920Galindo & Blanton, 1954Rozeboom, 1935Root, 1927Dyar, 1924Dyar & Knab, 1907Dyar, 1918Komp, 1932Dyar, 1918Lane & Whitman, 1951Dyar & Knab, 1919Dyar & Knab, 1908Rozeboom & Komp, 1950Dyar and Knab, 1907Theobald, 1903Dyar & Knab, 1906Dyar & Knab, 1907Anduze, 1942Theobald, 1903Lane & Whitman, 1943Lane, 1945Theobald, 1903Dyar & Knab, 1906Adames, 1971Adames, 1971Theobald, 1901Adames, 1971Adames, 1971Belkin & Hogue, 1959Dyar & Knab, 1907Dyar & Knab, 1909Stone & Barreto, 1969Dyar, 1921Osorno-Mesa, 1944Osorno-Mesa, 1944Lutz, 1904Dyar & Nu\u00f1ez Tovar, 1927Dyar, 1921Theobald, 1903Dyar, 1921Br\u00e8thes, 1912Williston, 1896Theobald, 1901Howard, Dyar & Knab, 1915Bellardi, 1862Dyar & Knab, 1916Dyar & Shannon, 1925Protomacleaya' sensu auctorum.''Protomacleaya'sensu auctorum.Protomacleaya' sensu auctorum.''Protomacleaya' sensu auctorum.''Protomacleaya' sensu auctorum.Protomacleaya' sensu auctorum.''Protomacleaya' sensu auctorum.Duret, 1971Duret, 1971Dyar & Knab, 1906Dyar & Knab, 1907Harbach, 1995Harbach, 1995Theobald, 1903Neiva, 1908Peryass\u00fa, 1922Dyar & Knab, 1908Levi-Castillo, 1953Lutz, 1905Antunes, 1942Theobald, 1903Dyar & Knab, 1907Dyar & Knab, 1906Theobald, 1901Dyar & Knab, 1913Theobald, 1901Lynch Arrib\u00e1lzaga, 1891Duret, 1970Dyar & Knab, 1906Dyar & Knab, 1908Dyar & Knab, 1906Lane, 1945Edwards, 1922Lane & Cerqueira, 1942Lane, 1953Dyar & Knab, 1906Theobald, 1901Species newly recorded for Colombia .Dyar, 1922Dyar, 1918Lane & Cerqueira, 1942Porter & Wolff, 2004Dyar & Knab, 1910Dyar & Knab, 1906Dyar & Knab, 1907Dyar & Knab, 1906Dyar & Knab, 1906Dyar, 1919Anophelescostai, An.fluminensis and An.shannoni luteoventralis for the first time from Colombia. This species was originally described by Theobald (1901) from three females caught on human bait in Paran\u00e1 state (Brazil). Wyeomyialuteoventralis is the type species of the subgenus Dendromyia Theobald, 1903 (In addition, we record ld, 1903 . This spld, 1903 ; howeverld, 1903 .Wyeomyialuteoventralis indicates that future sampling may reveal further species records which could help improve the taxonomy and provide a more accurate estimate of Colombia's mosquito diversity. This work provides important insights into the mosquito diversity of Colombia. We expect it to serve as a useful platform for future work on the mosquitoes of Colombia as well as provide a context for non-vector species.Although this report represents the most comprehensive list of mosquito species for Colombia, the 324 species included in this updated listing are unlikely to be a complete inventory of the Colombian mosquito fauna. Biodiversity data suggest that around 1,000 mosquito species will eventually be described from southern U.S.A. to Colombia, Ecuador, and Peru . Colombi"} +{"text": "Following publication of our article , it has Pablo Alonso-Coello, Alonso Carrasco-Labra, Romina Brignardello-Petersen, Ignacio Neumann, Elie A Akl, Xin Sun, Bradley C Johnston, Matthias Briel, Jason W Busse, Demi\u00e1n Glujovsky, Carlos E Granados, Alfonso Iorio, Affan Irfan, Laura Mart\u00ednez Garc\u00eda, Reem A Mustafa, Anggie Ramirez-Morera, Iv\u00e1n Sol\u00e0, Kari A O Tikkinen, Shanil Ebrahim, Per O Vandvik, Yuqing Zhang, Anna Selva, Andrea J Sanabria, Oscar E Zazueta, Robin W M Vernooij, Holger J Sch\u00fcnemann and Gordon H Guyatt."} +{"text": "After publication of this work , we noteYK, BC and PG are the principal investigators of the CURHA study. Together with LG, SL, HP, MP, LR, OK, CS, BT, AN, JV, RW they conceived and designed the study. BK, MS and PR have/are coordinating the data collection campaigns in Canada and Luxembourg. All authors revised and approved the submitted manuscript."} +{"text": "After publication of this work , we noteRoger Olofsson, Lars Ny, Charlotta All-Ericsson, Malin Sternby Eilard, Magnus Rizell, Christian Cahlin, Ulrika Stierner, Ulf L\u00f6nn, Johan Hansson, Ingrid Ljuslinder, Lotta Lundgren, Gustav Ullenhag, Jens Folke Kiilgaard, Jonas Nilsson and Per Lindn\u00e9r."} +{"text": "After the publication of this work , it was It read as Samir Sulemane, Vasileios F. Panoulas, Klio Konstantinou, Athanasios Bratsas, Frederick W. Tam, Edwina A. Brown and Petros Nihoyannopoulos.The correct author list should have included Dr Graspa and is now included here.Samir Sulemane, Vasileios F. Panoulas, Klio Konstantinou, Athanasios Bratsas, Julia Graspa, Frederick W. Tam, Edwina A. Brown and Petros Nihoyannopoulos."} +{"text": "After publication of this work , we noteThe authors declare that they have no competing interests.Conception and design: LNS, MJB, MDW. Acquisition of data: LNS, RK, KIB, RMG, ZG. Analysis and interpretation of data: LNS, AVA, JCC, BW, HC, ZG, MJB, MDW. Drafting or revising of article: LNS, AVA, JCC, KIB, RMG, WNR, MJB, MDW. Final approval of the manuscript: LNS, AVA, JCC, MJB, MDW. All authors read and approved the final manuscript."} +{"text": "AbstractPlatygastroidea (Platygastridae) substantially updates the previous comprehensive checklist, dating from 1978. Distribution data is reported where known.A revised checklist of the British and Irish Platygastroidea represents a 47% increase on the number of British and Irish species reported in 1978.A total of 381 British and Irish Hymenoptera of Britain and Ireland, starting with This paper continues the series of checklists of the Scelionidae and Sparasionidae comprise egg parasitoids, utilising a range of insects and spiders as hosts and acting as idiobiont endoparasitoids. In contrast, the vast majority of the Platygastridae (Platygastrinae and Sceliotrachelinae) are koinobiont egg-larval endoparasitoids of Cecidomyiidae gall midges (Diptera). A conspicuous exception is the genus Amitus, which are parasitoids of whiteflies (Hemiptera: Aleyrodidae) (Platygastroidea). As a consquence of their host ranges, platygastroids are generally small and rather neglected. Figs Scelionidae are paraphyletic with respect to the Platygastridaes.s. or identification in the British Isles uncertainmisident. has been misidentified as this namenomen dubium, a name of unknown or doubtful applicationnom. dub. nomen oblitum, \u2018forgotten name\u2019, does not have priority over a younger namenom. ob. nomen novum, a new replacement namenom. nov. nomen nudum, an unavailable namenom. nud. preocc. name preoccupied (junior homonym)status revocatus, revived status stat. rev. unavailable not meeting the requirements of the International Code of Zoological Nomenclaturevar. variety, only available as a valid name under the provisions of article 45.6 of the ICZNAlternative versions of the checklist, as a formatted Word document and Excel spreadsheet, are provided here in the supplementary materials: Suppl. materials Photographs were taken using a Canon EOS 450D digital camera attached to a Leica MZ12 stereomicroscope and partially focused images were combined using Helicon Focus v.4.80 software.Haliday, 1833Haliday, 1833Haliday, 1833Masner, 1964Inostemmaboter Walker, 1838Ireland, Isle of ManAcerotahumilis Kieffer, 1913Irelandadded by Buhl and O'Connor (2012c)F\u00f6rster, 1856Platygasterabas Walker, 1835England, ScotlandPlatygasterbelus Walker, 1835IrelandPlatygastercrates Walker, 1835England, Ireland, Isle of ManPlatygasternereus Walker, 1835England, IrelandPlatygasterotreus Walker, 1835England, Scotland Ireland, Isle of ManPlatygasterprorsa Walker, 1835England, Scotland Ireland, Isle of ManPlatygasterroboris Haliday, 1835lasiophila Kieffer, 1913England, Ireland, Isle of ManKieffer, 1913ScotlandKieffer, 1913EnglandKieffer, 1913ScotlandKieffer, 1913Englandrufopetiolata as a valid species, not a subspecies of lasiophila, although he has not seen the type.PB regards Platygasterscelionoides Haliday, 1835furiusPlatygaster) Platygastertritici Walker, 1835England, Scotland, IrelandPlatygastervestinus Walker, 1835EnglandKieffer, 1913ScotlandF\u00f6rster, 1856Kieffer, 1926England, Scotland, Wales, Ireland, Isle of Manadded by O'Connor et al. (2004)Huggert, 1974Englandadded by Buhl and Notton (2009)Thomson, 1859Englandadded by Thomson, 1859Platygastercochleatus Walker, 1835filicornisPlatygaster) Platygasterlaricis Haliday, 1835England, Scotland, Wales, IrelandFouts, 1925XESTONOTUS F\u00f6rster, 1856 preocc.AXESTONOTUS Kieffer, 1926EOXESTONOTUS Debauche, 1947Buhl, 1995England, Scotlandadded by Platygastererror Fitch, 1861England, Scotland, Ireland, Isle of ManAdded by Buhl, 1995England, Wales, Ireland, Isle of Manadded by Buhl (1995b)Kieffer, 1913ScotlandBrues, 1922Brues, 1922Englandadded by Haliday, 1833PSILUS Jurine, 1807 preocc.ACEROTA F\u00f6rster, 1856CERATOPSILUS Kieffer, 1913BRACHINOSTEMMA Kieffer, 1916BRACHYNOSTEMMA Risbec, 1953; incorrect subsequent spelling INOCEROTA Szel\u00e9nyi, 1938Psilusboscii Jurine, 1807Ireland, Isle of ManSzel\u00e9nyi, 1938England, Irelandadded by O'Connor et al. (2004)Walker, 1838IrelandSzel\u00e9nyi, 1938Irelandadded by Buhl and O'Connor (2011b)Walker, 1838England, IrelandDebauche, 1947Irelandhyperici from England and Scotland.Added by Walker, 1835EnglandWalker, 1835England, IrelandWalker, 1835EnglandVlug, 1991EnglandAdded by Kieffer, 1906EnglandAdded by Szel\u00e9nyi, 1938Englandadded by Kieffer, 1916England, IrelandKieffer, 1914England, Scotland, IrelandHaliday, 1835Masner, 1957EnglandHaliday, 1835England, Scotland, Ireland, Isle of ManF\u00f6rster, 1856Kieffer, 1913ScotlandKieffer, 1913ScotlandKieffer, 1913ScotlandPlatygastercotta Walker, 1835England, ScotlandPlatygastererato Walker, 1835England, IrelandPlatygastergrandis Nees, 1834EnglandKieffer, 1913ScotlandPlatygastermatuta Walker, 1835EnglandKieffer, 1913ScotlandThomson, 1859Kieffer, 1926England, Scotland, IrelandF\u00f6rster, 1856MONOCRITA F\u00f6rster, 1856TRISINOSTEMMA Kieffer, 1914Ichneumoninserens Kirby, 1800EnglandPlatygasterpunctiger Nees, 1834atinusInostemma) .Recorded by F\u00f6rster, 1856MIRAMBLYASPIS Dodd, 1914PROSAMBLYASPIS Kieffer, 1926Buhl, 1999Englandadded by Buhl, 1998Irelandaadded by Platygasterhalia Walker, 1835England, IrelandPlatygasterlaodice Walker, 1835buchi Buhl, 1997England, Ireland, Isle of ManKieffer, 1916Englandadded by Platygasternice Walker, 1835EnglandPlatygasternydia Walker, 1835torispinula Huggert, 1980EnglandAnacorypheorchymonti Debauche, 1947LeptacisEngland, Wales, Ireland, Isle of ManPlatygasterozines Walker, 1835England, Wales, Ireland, Isle of ManIchneumontipulae Kirby, 1798scutellarisPlatygaster) Amblyaspistripartitus Kieffer, 1913ScotlandBuhl, 1997England, Ireland, Isle of Manadded by F\u00f6rster, 1856PARINOSTEMMA Kieffer, 1914Inostemmaareolata Haliday, 1835IrelandManeval, 1936England, Scotland, Irelandadded by Inostemmaocalea Walker, 1838EnglandDebauche, 1947England, Scotland, Walesadded by Brues, 1910DISYNOPEAS Kieffer, 1916Disynopeaslasiopterae Kieffer, 1916britannicus Jackson, 1966EnglandF\u00f6rster, 1856Platygastercatillus Walker, 1835England, IrelandKieffer, 1926EnglandPlatygastermamertes Walker, 1835England, IrelandPlatygasterseron Walker, 1835England, IrelandLatreille, 1809RHACODIA Panzer, 1838HYPOCAMPSIS F\u00f6rster, 1856POLYGNOTUS F\u00f6rster, 1856ANEURHYNCHUS Provancher, 1887COELOPELTA Ashmead, 1893ANEURON Brues, 1910PROSACTOGASTER Kieffer, 1914TRIPLATYGASTER Kieffer, 1914XESTONOTIDEA Gahan, 1919PAREPIMECES Kieffer, 1926Notton, 2006CYLINDROGASTER Huggert, 1980Brues, 1922England, Isle of Manadded by Notton (2006)Huggert, 1973Huggert, 1973England, Scotland, Walesadded by Notton (2006)Latreille, 1809Walker, 1835England, ScotlandWalker, 1835cleodaeus Walker, 1835England, IrelandBuhl, 1994Englandadded by Buhl (1995b)Walker, 1835England, IrelandBuhl, 2001England, Wales, Ireland, Isle of Manadded by Buhl and Bennett (2009)Walker, 1835England, Ireland, Isle of ManBuhl, 2009Englandadded by Buhl (2009b)Buhl, 2005Englandadded by Buhl & O\u2019Connor, 2012Irelandadded by Buhl and O'Connor (2012a)Walker, 1835England, Scotland, IrelandMisocyclopsbetulae Kieffer, 1916England, Wales, Irelandadded by Buhl and O'Connor (2009)Kieffer, 1916England, Scotland, Irelandadded by Buhl, 2009Englandadded by Walker, 1835EnglandWalker, 1835cratinus Walker, 1835olorus Walker, 1835England, Scotland, Wales, Isle of ManRatzeburg, 1852EnglandThomson, 1859England, Irelandadded by Walker, 1835EnglandBuhl, 1994Scotland, Walesadded by Thomson, 1859piniMisocyclops) Thomson, 1859Irelandadded by Buhl and O'Connor (2009)Kieffer, 1913ScotlandRatzeburg, 1844England, IrelandKieffer, 1913ScotlandKieffer, 1913Irelandadded by O'Connor et al. (2004)Walker, 1835England, Wales, IrelandBuhl, 1998Englandadded by Buhl, 1999Irelandadded by Buhl and O'Connor (2008)Walker, 1835EnglandWalker, 1835England, Ireland, Isle of ManWalker, 1835EnglandWalker, 1835Ireland, Isle of ManHaliday, 1833attenuata Walker, 1835evadne Walker, 1835England, Wales, IrelandEpimecesenneatomus Kieffer, 1913ScotlandWalker, 1835England, Scotland, IrelandEpimecesensifer Westwood, 1833England, IrelandBuhl, 1997England, Scotlandadded by Buhl (1997)Spittler, 1969Englandadded by Walker, 1835England, IrelandWalker, 1835England, Ireland, Isle of ManProsactogasterfloricola Kieffer, 1916England, Irelandadded by Buhl, 2006England, Irelandadded by Walker, 1835England, IrelandBuhl, 1998Englandadded by Zetterstedt, 1838nitida Thomson, 1859Englandadded by Walker, 1835EnglandHuggert, 1975England, Scotland, Ireland, Isle of Manadded by Buhl (1995b)Walker, 1835longiventris Thomson, 1859England, Scotland, IrelandBuhl, 1996England, Scotland, Irelandadded by Buhl and O'Connor (2008)Packard, 1841EnglandBuhl & O'Connor, 2009Irelandadded by Buhl and O'Connor (2009)Forbes, 1888EnglandAdded by Buhl, 1994England, Scotlandadded by Curtis, 1830Walker, 1835Irelandadded by Buhl and O'Connor (2008)Buhl, 2009intermedia Buhl, 2006 preocc.England, Irelandadded by Buhl and O'Connor (2008)Walker, 1835EnglandBuhl, 2006Englandadded by Buhl, 1995Englandadded by Walker, 1835England, Ireland, Isle of ManMisocyclopsleucanthemi Kieffer, 1916Walesrecorded by Buhl and Notton (2009)Kieffer, 1906Englandrecorded by Barnes (1948)Buhl, 1994Scotland, Irelandadded by Thomson, 1859England, Ireland, Isle of Manadded by Buhl and O'Connor (2008)Kieffer, 1906EnglandAdded by Walker, 1835lativentris Thomson, 1859England, Scotland, Ireland, Isle of ManKieffer, 1916hanseni Buhl, 2006England, Irelandadded by Buhl and O'Connor (2008)Buhl & Bennett, 2009Isle of Manadded by Buhl and Bennett (2009)Walker, 1835England, Scotland, Ireland, Isle of ManKieffer, 1906EnglandAdded by Thomson, 1859occipitalis Buhl, 1994England, Irelandadded by Buhl (1995b)Prosactogastermarshalli Kieffer, 1916EnglandBuhl, 2003England, Scotlandadded by Huggert, 1975England, Irelandadded by Buhl and O'Connor (2008)Kieffer, 1916EnglandBuhl, 1999Englandaadded by Walker, 1835laeviventris Thomson, 1859EnglandDalla Torre, 1898EnglandAdded by Buhl, 2006England, ScotlandAdded by Buhl, 1995England, Scotland, Walesadded by Walker, 1835England, Wales, IrelandBuhl & O\u2019Connor, 2011Irelandadded Buhl and O'Connor (2011b)Nees, 1834nigerrimusMisocyclops) Walker, 1835England, Ireland, Isle of ManWalker, 1835England, Scotland, IrelandWalker, 1835England, IrelandWalker, 1835England, IrelandWalker, 1835England, Scotland, Ireland, Isle of ManWalker, 1835fuscipes Thomson, 1859England, Ireland, Isle of ManWalker, 1835England, Scotland, IrelandWalker, 1835apicalis Thomson, 1859ruborum crevecoeuriMisocyclops) Cynipsphragmitis Schrank, 1781F\u00f6rster, 1861Englandadded by Buhl and Notton (2009)Walker, 1835EnglandWalker, 1835EnglandThomson, 1859Walesadded by Vlug, 1995nigripes Thomson, 1859 preocc.thomsoni Buhl, 1995England, Wales, Irelandadded by Buhl and O'Connor (2008)Buhl, 2006Irelandadded by Buhl and O'Connor (2010a)Polygnotusquadrifaria Kieffer, 1916EnglandBuhl, 1997Englandadded by Walker, 1835luteocoxalisProsactogaster) Polygnotussignatus F\u00f6rster, 1861Scotland, Irelandadded by Buhl and O'Connor (2009)Buhl, 2006Irelandadded by Buhl and O'Connor (2009)Buhl, 1998Englandadded by Walker, 1835EnglandRuthe, 1859leptocera Thomson, 1859hirticornis F\u00f6rster, 1861lissonota F\u00f6rster, 1861England, Ireland, Isle of Manadded by Buhl and O'Connor (2008)Walker, 1835England, Isle of ManWalker, 1835ScotlandBuhl, 1994England, Walesadded by Buhl, 2006Ireland, Isle of Manadded by Buhl and O'Connor (2009)Buhl, 2009Scotlandadded by Buhl (2009b)Prosactogastersubuliformis Kieffer, 1926Platygastersubulatus misident.England, Irelandadded by Murchie et al. (1999)Polygnotussuecicus Kieffer, 1926Irelandadded by Buhl and O'Connor (2008)Huggert, 1975crassus Sz\u00e9lenyi, 1958 preocc.England, Walesadded by Walker, 1835England, WalesWalker, 1835siphon F\u00f6rster, 1840England, Scotland, Wales, Ireland, Isle of ManKieffer, 1926tuberosa Kieffer, 1913 preocc.ScotlandKieffer, 1926Englandadded by Buhl, 2006England, Irelandadded by Walker, 1835ilione Walker, 1835EnglandDay, 1971England, Wales, IrelandBuhl, 1998Englandadded by Walker, 1838IrelandWalker, 1835EnglandManeval, 1936Thomson, 1859bettyaeParacyclops) Buhl, 1998Englandadded by Buhl, 1998Ireland, Isle of ManBMNH, det. PB.; added by O'Connor et al. (2004)Buhl, 2004England, Irelandadded by Thomson, 1859England, Ireland, Isle of ManThomson, 1859IrelandSynopeascf.convexum, occurring in England and Ireland, by Added by Platygastercraterus Walker, 1835gynomamertesEctadius) invalid Sactogastercurvicauda F\u00f6rster, 1856SynopeaslongicaudaSactogaster) Platygastereuryale Walker, 1835England, IrelandBuhl, 2000Englandadded by Box, 1921England, WalesKieffer, 1916EnglandBuhl, 1997England, Irelandadded by Buhl and O'Connor (2008)Buhl & O'Connor, 2009Irelandadded by Buhl and O'Connor (2009)Platygasterhyllus Walker, 1835figitiforme Thomson, 1859England, Scotland, Wales, IrelandThomson, 1859England, IrelandPlatygasterjasius Walker, 1835England, IrelandPlatygasterlarides Walker, 1835England, IrelandBuhl, 2009England, Isle of Manadded by Buhl and Bennett (2009)Buhl, 2009Englandadded by Buhl (2009b)Thomson, 1859England, Irelandadded by Notton (2008)Buhl & Bennett, 2009Isle of Manadded by Buhl and Bennett (2009)Platygastermyles Walker, 1835England, Scotland, Ireland, Isle of ManBuhl, 2009Englandadded by Buhl (2009b)Buhl, 2009England, Irelandadded by Buhl (2009b)Thomson, 1859England, Irelandadded by Buhl and O'Connor (2009)Platygasterosaces Walker, 1835England, IrelandPlatygasterrhanis Walker, 1835accoPlatygaster) Platygastersosis Walker, 1835muticus misident.England, Scotland, Ireland, Isle of ManSynopeasmuticus as recorded by sosis Platygastertarsa Walker, 1835England, IrelandPlatygastertrebius Walker, 1835England, Ireland, Isle of ManPlatygastervelutinus Walker, 1835England, IrelandDescribed from English specimens, omitted by Epimecesventralis Westwood, 1833abarisPlatygaster) Platygasterdidas Walker, 1835England, Ireland, Isle of ManPlatygasterpisis Walker, 1835opaca Thomson, 1859England, Ireland, Isle of ManPlatygasterremulus Walker, 1835EnglandBrues, 1908F\u00f6rster, 1856EUROSTEMMA Szel\u00e9nyi, 1938NASDIA Nixon, 1942PLATYTROPA Kozlov, 1976Inostemmaeuropus Walker, 1838IrelandInostemmamecrida Walker, 1836England, Ireland, Isle of ManHaldeman, 1850ZACRITA F\u00f6rster, 1878ELAPTUS Forbes, 1884Zacritalongicornis F\u00f6rster, 1878Englandadded by Buhl and Notton (2009)indet.EnglandAmitusminervae auctt., not A.minervae Silvestri; added by Polaszek (1997)Ashmead, 1894ROSNETA Brues, 1908TRICLAVUS Br\u00e8thes, 1916FAHRINGERIA Kieffer, 1921PLATYLLOTROPA Szel\u00e9nyi, 1938Popovici & Buhl, 2010synergorum misident.IrelandFidiobiasynergorum by Added by Nixon, 1937ANOPEDIELLA Sundholm, 1956Anopediastransversus Thomson, 1859strangaliophagus Nixon, 1937England, Scotland, IrelandHaliday, 1839Some Irish distribution data from Haliday, 1839F\u00f6rster, 1856PARATRIMORUS Kieffer, 1908TRICHACOLUS Kieffer, 1912Telenomusaethra Walker, 1836England, WalesOpisthacantha by Transferred from Trimorusasramanes Walker, 1836erdosiParatrimorus) Haliday, 1833ACOLUS F\u00f6rster, 1856HADRONOTUS F\u00f6rster, 1856MUSCIDEA Motschoulsky, 1863PLESIOBAEUS Kieffer, 1913Plesiobaeushospes Kieffer, 1913Haliday, 1833pumilioTeleas) Masner, 1976punctataApegus) Anterisbicolor Kieffer, 1908England, Walesadded by Latreille, 1805ALERIA Marshall, 1874CALOPTENOBIA Riley, 1878ENNEASCELIO Kieffer, 1910Latreille, 1805Kieffer, 1908Irelandadded by O'Connor et al. (2004)Kieffer, 1913Haliday, 1833NEOTHORON Masner, 1972Distribution and synonymy from Haliday, 1833fornicatusTeleas) Limnodytesgerriphagus Marchal, 1901kaszabiHungaroscelio) Scelioclavicornis Latreille, 1805longicornisScelio) Teleasaegle Walker, 1836England, Scotland, IrelandParagryonalgicola Kieffer, 1911Hoplogryonangustipennis Kieffer, 1908Hoplogryonantennalis Kieffer, 1908ScotlandTeleasapricans Walker, 1836IrelandTeleasaratus Walker, 1836England, Wales, IrelandHoplogryonbacilliger Kieffer, 1908Scotland, IrelandTrimoruspedestris (Nees) (now placed in Gryon) by Although described from Scotland by Teleasbassus Walker, 1836Prosacanthabrevicollis Thomson, 1859Hoplogryoncameroni Kieffer, 1908ScotlandHoplogryoncarinatus Kieffer, 1908Hoplogryoncarinifrons Kieffer, 1908ScotlandTeleascephisus Walker, 1836Teleaschesias Walker, 1836Teleaschyllene Walker, 1836Teleaselatior Walker, 1836England, Scotland, IrelandHoplogryonelongatus Kieffer, 1908England, Irelandpuncticollis by Although described from probable English material by Teleasephippium Walker, 1836England, IrelandTeleasflavipes Walker, 1836angustulaProsacantha) Teleasgalba Walker, 1836Teleasglaucus Walker, 1836Hoplogryonhalterata Kieffer, 1912Teleaslamus Walker, 1836IrelandHoplogryonlevigena Kieffer, 1908ScotlandTeleaslycaon Walker, 1836Hoplogryonmarshalli Kieffer, 1913Hoplogryonmicropterus Kieffer, 1908ScotlandHoplogryonmyrmecobius Kieffer, 1911Paragryonmyrmecophilus Kieffer, 1911Gryonnanno Walker, 1836Prosacanthanitidula Thomson, 1859pleuralisHoplogryon) preocc. Teleasocyroe Walker, 1836Prosacanthaopaca Thomson, 1859pedestris misident.IrelandProsacanthaovata Thomson, 1859orbiculatusProsacantha) Teleaspaula Walker, 1836England, Wales, IrelandTeleasprocris Walker, 1836England, IrelandHoplogryonpunctatifrons Kieffer, 1908ScotlandProsacanthapuncticollis Thomson, 1859hylanipennisProsacantha) Hoplogryonrufonotatus Kieffer, 1908England, Scotland, IrelandHoplogryonsectigena Kieffer, 1908Irelandadded by O'Connor and Mineo (2008)Hoplogryonstriatigena Kieffer, 1908ScotlandTeleastherycides Walker, 1836dotoTeleas) Teleastimareta Walker, 1836England, Scotland, IrelandHoplogryontuberculatus Kieffer, 1908Irelandadded by O'Connor and Mineo (2008)Teleasvaricornis Walker, 1836metabusTeleas) Teleasxenetus Walker, 1836Walker, 1836NITEOGRYON Szab\u00f3, 1966Distribution data and synonymy from Huggert, 1974hibernicus Mineo & O\u2019Connor, 2009mutatorTrimorus) Walker, 1836medonTeleas) Teleasdalmanni Ratzeburg, 1844orgyiae Fitch, 1865fiskei Brues, 1910IrelandPlatytelenomusdanubialis Szel\u00e9nyi, 1939unilineatusPlatytelenomus) Verrucosicephaliadepressa Szab\u00f3, 1975IrelandVerrucosicephalia.Added by Walker, 1836Walker, 1836IrelandBuhl & O\u2019Connor, 2012Irelandadded by Buhl and O'Connor (2012a)Mineo, 2006Irelandadded by O'Connor and Notton (2013)Haliday, 1833nonnitens Szab\u00f3, 1978pappi Szab\u00f3, 1978IrelandMayr, 1879Irelandadded by O'Connor and Mineo (2006)Walker, 1836Mayr, 1879Irelandadded by Buhl and O'Connor (2011a)Teleaslaeviusculus Ratzeburg, 1844Irelandadded by O'Connor and Mineo (2013)Walker, 1836IrelandVerrucosicephalia.Listed by Kozlov, 1967Irelandadded by O'Connor and Mineo (2009)Silvestri, 1932Irelandadded by O'Connor and Mineo (2013)Walker, 1838Hemisiusminutus Westwood, 1833Walker, 1836Phanurusnitidulus Thomson, 1861punctulatusTeleas) Teleasphalaenarum Nees, 1834Walker, 1836IrelandWalker, 1836Teleaspunctatissimus Ratzeburg, 1844Walker, 1836Walker, 1836IrelandPhanurustetratomus Thomson, 1861bombycis Mayr, 1879gracilis Mayr, 1879verticillatus Kieffer, 1917Walker, 1836Walker, 1836Teleastruncatus Nees, 1834linneiTeleas) ; synonymy by Mineo et al. (2011) Walker, 1836Ashmead, 1893ASOLCUS Nakagawa, 1900APHANURUS Kieffer, 1912IMMSIA Cameron, 1912MICROPHANURUS Kieffer, 1926Telenomusarminon Walker, 1838Englanddistribution data from Fergusson (1983b)Telenomusbelenus Walker, 1836Telenomuscultratus Mayr, 1879flavipes misident.England, ?IrelandTrissolcusflavipes by cultratus.Added by Asolcusdavatchii Javahery, 1968Telenomusgrandis Thomson, 1861nigripesTelenomus) Telenomustheste Walker, 1838Asolcuswaloffae Javahery, 1968Dahlbom, 1858Nomenclature follows Johnson et al. (2008)Latreille, 1802OXYURUS Lamarck, 1817BEBELUS Gistel, 1848PROSPARASION Kieffer, 1913Latreille, 1802frontalis Latreille, 1805Supplementary material 1PlatygastroideaChecklist of British and Irish Data type: spreadsheetPlatygastroidea checklistBrief description: Excel version of the File: oo_85283.xlsxBuhl, P., Broad, G.R, and Notton, D.G.Supplementary material 2PlatygastroideaChecklist of British and Irish Data type: text filePlatygastroidea checklist, presented as a Word document.Brief description: alternative version of the File: oo_85301.docxBuhl, P., Broad, G.R. and Notton, D.G."} +{"text": "In adults with inflammatory arthritis, insulin resistance (IR) is associated with diabetes and cardiovascular disease. Interleukin-6 (IL-6) is postulated to play a mechanistic role in IR.To evaluate the degree of IR among children with systemic juvenile idiopathic arthritis (sJIA) and whether treatment with tocilizumab (TCZ) results in attenuation of IR in sJIA.1 were included if baseline and wk 6 fasting insulin were measured. Glucocorticoid tapering was not permitted until wk 6. Insulin sensitivity was quantified using the homeostatic model of insulin resistance (HOMA-IR). Pts were classified as having IR if their HOMA-IR was \u22652.2 U. Change in HOMA-IR after 6 wks was assessed using paired t-test. Baseline associations with HOMA-IR and factors predicting change of HOMA-IR from baseline were assessed using regression analyses. Factors changing in association with HOMA-IR change were assessed.Patients (pts) from TENDER92 pts with sJIA were analysed. 62 were randomised to TCZ and 30 to placebo, 12 of whom required escape therapy with TCZ by wk 6. At baseline, 40 pts (43%) had IR. Baseline HOMA-IR was associated with higher standardised body mass index and higher IL-6 levels but not with JADAS, CRP, active joint count or presence of fever. Of the 74 pts who received TCZ, 34 (46%) had IR at baseline, including 4 pts who escaped from the placebo arm, compared with 6/18 (33%) who received only placebo. IR pts treated with TCZ but not placebo had significant reductions in HOMA-IR at wk 6 (Table). Across all IR pts, improvement in JADAS and active joint count was not associated with improvement in HOMA-IR .After only 6 wks of TCZ treatment, HOMA-IR was improved in IR pts with sJIA in the presence of unchanged glucocorticoid dose. These data support a mechanistic contribution of IL-6 to IR in vivo in humans.H. Mirjafari Employee of: Roche, N. Ruperto Grant/Research Support from: Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth, H. Brunner Consultant for: Novartis, Genentech, MedImmune, EMD Serono, AMS, Pfizer, UCB, Jannsen, Speakers Bureau: Genentech, Z. Zuber: None Declared, F. Zulian: None Declared, M. R. Maldonado-Vel\u00e1zquez: None Declared, E. Mantzourani: None Declared, K. Murray: None Declared, J. Roth: None Declared, J. Rovensky: None Declared, O. Vougiouka: None Declared, J. Wang Employee of: Roche, O. Harari Shareholder of: Roche, Employee of: Roche, D. Lovell Grant/Research Support from: NIH, Consultant for: AstraZeneca, Centocor, Janssen, Wyeth, Amgen, BMS, Abbott, Pfizer, Regeneron, Hoffmann-La Roche, Novartis, Genentech, Speakers Bureau: Genentech, Roche, A. Martini Grant/Research Support from: Abbott, AstraZeneca, BMS, Janssen, Lilly, Francesco Angelini, GSK, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth, The Gaslini Hospital, Consultant for: Abbott, AstraZeneca, BMS, Janssen, Lilly, Francesco Angelini, GSK, Italfarmaco, Novartis, Pfizer, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth, The Gaslini Hospital, Speakers Bureau: Astellas, AstraZeneca, BMS, GSK, Italfarmaco, MedImmune, Novartis, F. De Benedetti Grant/Research Support from: Abbott, Pfizer, BMS, Roche, Novimmune, Novartis, SOBI."} +{"text": "AbstractSciaridae (Diptera) recorded from Finland is provided. The genus Sciarosoma Chandler with a disputed family placement is also included in the list.A checklist of the family Sciaridae, the black fungus gnats, is one of the large families in Sciaroidea, little studied and notoriously difficult in its taxonomy. Up-to-date keys are not available for all European species, but various publications must be consulted for identification. Our knowledge of Finnish fauna stems from two classic publications: Sciaridae in Finland were published between the publication of PageBreakof Finnish nematoceran Diptera, the species lists in both works are essentially unchanged, despite some obvious lapses in the latter. Our knowledge of Finnish fauna has since grown mainly in the taxonomic treatment of various genera and species groups pusillima = Baeosciarasinuata Baeosciarascotica BRADYSIA Winnertz, 1867Bradysiaaffinis pratincola Tuomikoski, 1960= PageBreakBradysiaalbanensis Bradysiaalpicola mutabilis = morio auct. nec = Bradysiaangustata Tuomikoski, 1960Bradysiaangustostylata Menzel, 2005Bradysiaaprica Bradysiaarcana Menzel & Mohrig, 1998fenestralis auct. nec = Bradysiaarcula Vilkamaa, Salmela & Hippa, 2007Bradysiaascenda Rudzinski, 1994Bradysiabicolor Bradysiabispinifera Mohrig & Krivosheina, 1983Bradysiabrevispina Tuomikoski, 1960Bradysiabrowni diversiabdominalis = laurencei Menzel & Mohrig, 2000= Bradysiacinerascens lanicauda Tuomikoski, 1960= Bradysiaconfinis Bradysiaexcelsa Menzel & Mohrig, 1998Bradysiaflavipila Tuomikoski, 1960Bradysiaforcipulata Bradysiaforficulata nocturna Tuomikoski, 1960= Bradysiafungicola Bradysiagiraudii Bradysiaglobulifera Bradysiahilariformis Tuomikoski, 1960Bradysiahilaris Bradysiaholsatica Heller, 2004Bradysiahortensis Heller, 2000Bradysiaimpatiens difformis = paupera Tuomikoski, 1960= Bradysiainusitata Tuomikoski, 1960Bradysiairidipennis Bradysialapponica Bradysialatiterga Tuomikoski, 1960Bradysialeptoptera Tuomikoski, 1960Bradysialilienthalae Mohrig & Menzel, 1990Bradysialobulifera Frey, 1948Bradysialongicauda Mohrig & Menzel, 1990PageBreakBradysialongicubitalis cinereovittata Frey, 1948= Bradysiaminima Mohrig & Mamaev, 1989Bradysiamoesta Frey, 1948albosetosa Frey, 1948= Bradysiamoestula Tuomikoski, 1960Bradysianervosa Bradysianitidicollis atroparva Frey, 1948= Bradysianormalis Frey, 1948Bradysiaocellaris Bradysiapallipes brunnipes = picipes = Bradysiapauperata Bradysiaperaffinis Tuomikoski, 1960Bradysiapilistriata Frey, 1948Bradysiaplacida fimbricauda Tuomikoski, 1960= Bradysiapolonica Bradysiapraecox Bradysiarectinervis Frey, 1948Bradysiareflexa Tuomikoski, 1960Bradysiaregularis subnervosa Frey, 1948= Bradysiarufescens Bradysiascabricornis Tuomikoski, 1960subscabricornis Mohrig & Menzel, 1990= Bradysiasiberica Komarova, 2001Bradysiaspinostyla Mohrig & Menzel, 1990Bradysiastrigata Bradysiasubalpina Frey, 1948Bradysiasubamoena Mohrig & Krivosheina, 1989Bradysiasubmoesta Mohrig & Krivosheina, 1989Bradysiatilicola amoena = cellarum Frey, 1948= Bradysiatrivittata Bradysiavagans callicera Frey, 1948= Bradysiavernalis Bradysiazonata Rudzinski, 1993BRADYSIOPSIS Tuomikoski, 1960PageBreakBradysiopsisvittata leucotricha = Bradysiopsisvittigera CAMPTOCHAETA Hippa & Vilkamaa, 1994Camptochaetaaustriaca Heller, 2012Camptochaetabournei Camptochaetacamptochaeta Camptochaetaconsimilis Camptochaetadelicata Camptochaetaduplicata Hippa & Vilkamaa, 1994Camptochaetafallax Hippa & Vilkamaa, 1994Camptochaetahirtula fulvicollis = Camptochaetapropria Hippa & Vilkamaa, 1994Camptochaetascanica Hippa & Vilkamaa, 1994Camptochaetasicilicula Hippa & Vilkamaa, 1994Camptochaetasimulator Hippa & Vilkamaa, 1994Camptochaetastammeri Camptochaetatenuipalpalis Camptochaetauniformis Camptochaetavivax Camptochaetaxystica Hippa & Vilkamaa, 1994CHAETOSCIARA Frey, 1942Chaetosciaraestlandica CLAUSTROPYGA Hippa, Vilkamaa & Mohrig, 2003Claustropygaacanthostyla Claustropygabrevichaeta Claustropygaclausa Claustropygacorticis Claustropygactenophora Hippa, Vilkamaa & Mohrig, 2003Claustropygaheteroclausa Claustropygarefrigerata Claustropygasubcorticis CORYNOPTERA Winnertz, 1867Corynopterabarbata Tuomikoski, 1960Corynopterabicuspidata gymnops Tuomikoski, 1960= Corynopterabipartita Mohrig & Krivosheina, 1985Corynopterablanda Corynopteraboletiphaga geogenia Tuomikoski, 1960= Corynopterabreviformis Mohrig & Krivosheina, 1983Corynopteracracentis Vilkamaa, Hippa & Heller, 2013PageBreakCorynopteracuniculata caldariorum Tuomikoski, 1960= Corynopteradefecta Corynopteradentata Corynopteradeserta Heller & Menzel, 2006minutula = Corynopteradubitata Tuomikoski, 1960Corynopterafera Mohrig & Heller, 1992Corynopteraflavicauda Corynopteraforcipata Corynopterafurcifera Mohrig & Mamaev, 1987Corynopteraglobiformis Corynopterahypopygialis piniphila = Corynopterainari Vilkamaa, Hippa & Heller, 2013Corynopterainexspectata Tuomikoski, 1960Corynopterairmgardis Corynopteralevis Tuomikoski, 1960Corynopteraluteofusca Corynopteramarinae Mohrig & Krivosheina, 1986Corynopteramelanochaeta Mohrig & Menzel, 1992Corynopteramembranigera trispina Tuomikoski, 1960= Corynopteramontana Corynopteraninae Hippa, Vilkamaa & Heller, 2010Corynopteraobscuripila Tuomikoski, 1960Corynopteraparvula uncinata = Corynopteraparvulaformis Mohrig, 1985Corynopterapenna alneti Hippa, Vilkamaa & Heller, 2010= Corynopteraperochaeta Corynopteraplusiochaeta Hippa, Vilkamaa & Heller, 2010Corynopterapolana Rudzinski, 2009Corynopterapostforcipata Rudzinski, 1993Corynopterapostglobiformis Mohrig, 1993Corynopterapraeforcipata Mohrig & Mamaev, 1987Corynopteraquantula Corynopterasaccata Tuomikoski, 1960Corynopterasaetistyla Mohrig & Krivosheina, 1985Corynopterasalmelai Vilkamaa, Hippa & Heller, 2013Corynopterasphenoptera Tuomikoski, 1960Corynopteraspiciforceps Vilkamaa, Hippa & Heller, 2013PageBreakCorynopteraspinifera Tuomikoski, 1960Corynopterasubblanda Tuomikoski, 1960Corynopterasubdentata Mohrig, 1985Corynopterasubparvula Tuomikoski, 1960Corynopterasubsedula Mohrig & Mamaev, 1987Corynopterasubtetrachaeta Komarova, 1995Corynopterasubtilis longicornis = Corynopterasubvariegata Rudzinski, 1992Corynopteratetrachaeta Tuomikoski, 1960Corynopteratrepida clinochaeta Tuomikoski, 1960= Corynopteratriacantha Tuomikoski, 1960Corynopteratumidula Hippa, Vilkamaa & Heller, 2010Corynopteratuomikoskii Hippa, Vilkamaa & Heller, 2013Corynopteraunidentata Corynopteravagula Tuomikoski, 1960Corynopteraverrucifera Corynopteravoluptuosa Mohrig & Mamaev, 1987Corynopterawaltraudis Mohrig & Mamaev, 1987Corynopterawinnertzi Mohrig, 1993COSMOSCIARA Frey, 1942Cosmosciaraperniciosa CRATYNA Winnertz, 1867Plastosciara Berg, 1899= Decembrina Frey, 1948= Dendrosciara Frey, 1948= Cratynasg. Winnertz, 1867Cratynaambigua latiforceps = Cratynaatra Winnertz, 1867pictiventris = Cratynabetulae Cratynabreviflagellata Cratynamonumenta Rudzinski, 2009Cratynapernitida Cratynaschineri Cratynasicata Vilkamaa, Hippa & Heller, 2013Cratynasymplecta Cratynauliginosa Cratynavaporariorum Diversicratynasg. Menzel & Mohrig, 1998Cratynaspiculosa PageBreakSpathobdellasg. Frey, 1948Cratynacolei brachialis auct. nec = Cratynafalcata Cratynafalcifera Cratynalongispina tuberculata = Cratynanobilis brachialis = Cratynaperplexa socialis = brevicornis = CTENOSCIARA Tuomikoski, 1960Ctenosciaraexigua Salmela & Vilkamaa, 2005Ctenosciarahyalipennis DICHOPYGINA Vilkamaa, Hippa & Komarova, 2004Dichopyginaaculeata Vilkamaa, Hippa & Komarova, 2004Dichopyginaintermedia Dichopyginanigrohalteralis Dichopyginaramosa Vilkamaa, Hippa & Komarova, 2004DOLICHOSCIARA Tuomikoski, 1960Dolichosciaraflavipes 185Dolichosciarahippai Komarova & Vilkamaa, 2006Dolichosciaranigrovittata Dolichosciaraorcina Dolichosciaraornata Dolichosciarasaetosa Dolichosciaraspissispina Vilkamaa, Hippa & Heller, 2013EPIDAPUS Haliday, 1851Epidapussg. Haliday, 1851Epidapusalnicola Epidapusatomarius Epidapusgracilis Epidapusignotus gracilior = Epidapusmicrothorax gracilicornis = Epidapusschillei titan Frey, 1948= intermittens Tuomikoski, 1959= Pseudoaptanogynasg. Vimmer, 1926Epidapusabieticola Frey, 1948Epidapusbispinulosus Mohrig & Kauschke, 1994PageBreakEpidapusechinatum Mohrig & Koz\u00e1nek, 1992Epidapusignavus KEILBACHIA Mohrig, 1987Keilbachiaferrata LEPTOSCIARELLA Tuomikoski, 1960Hirtipenniasg. Mohrig & Menzel, 1997Leptosciarellahirtipennis Leptosciarellaholotricha Mohrig & Menzel, 1997Leptosciarellasg. Tuomikoski, 1960Leptosciarellabrevior Leptosciarellabrevipalpa Leptosciarellaclaviforceps Leptosciarelladimera Leptosciarellafuscipalpa Leptosciarellahelvetica Leptosciarellahispida Leptosciarellaignis Heller, 2012Leptosciarellakrille Heller, 2012Leptosciarellamelanoma Leptosciarellanudinervis Leptosciarellapilosa Leptosciarellareducta Heller & Menzel, 2013Leptosciarellarejecta Leptosciarellascutellata elegans = Leptosciarellasubcoarctata Mohrig & Menzel, 1997Leptosciarellasubpilosa Leptosciarellasubspinulosa Leptosciarellasubviatica Mohrig & Menzel, 1997Leptosciarellatrochanterata coarctata = Leptosciarellatruncata Leptosciarellaviatica Leptosciarellaviaticella Mohrig & Krivosheina, 1979Leptosciarellayerburyi Leptospinasg. Mohrig & Menzel, 1997Leptosciarellaatricha Trichosiopsissg. Tuomikoski, 1960Leptosciarellatuberculigera LYCORIELLA Frey, 1942Coelostylinasg. Tuomikoski, 1960Lycoriellaeflagellata Tuomikoski, 1960Lycoriellafreyi Tuomikoski, 1960PageBreakHemineurinasg. Tuomikoski, 1960Lycoriellaalgida Lycoriellacochleata Lycoriellaconspicua Lycoriellainflata venosa auct. nec = Lycoriellamodesta Lycoriellapiristylata Vilkamaa, Hippa & Heller, 2013Lycoriellathuringiensis Menzel & Mohrig, 1991Lycoriellavitticollis permutata = Lycoriellasg. Frey, 1942Lycoriellaaberrans Tuomikoski, 1960Lycoriellaacutostylia Mohrig & Menzel, 1990Lycoriellaagraria cellaris = Lycoriellaapproximatonervis Lycoriellabrevipila Tuomikoski, 1960Lycoriellainconspicua Tuomikoski, 1960Lycoriellaingenua solani = Lycoriellalatilobata Menzel & Mohrig, 2000Lycoriellalundstromi Lycoriellamicria Mohrig & Menzel, 1990Lycoriellaminutula Mohrig & Krivosheina, 1987Lycoriellapallidior Tuomikoski, 1960Lycoriellaparva obscuratipes = curvispina Tuomikoski, 1960= Lycoriellasativae castanescens = fucorum = Lycoriellasubterranea vanderwieli = Lycoriellatenera Vilkamaa, Hippa & Heller, 2013Lycoriellaweberi Menzel & Heller, 2013MOUFFETINA Frey, 1942Mouffetinaexpolita Mouffetinapulchricornis Mouffetinasilvestris PEYERIMHOFFIA Kieffer, 1903Peyerimhoffiacrassistylata Peyerimhoffiainfera Vilkamaa & Hippa, 2005PageBreakPeyerimhoffiamenzeli Vilkamaa & Hippa, 2005Peyerimhoffiaquadrifera Vilkamaa, Hippa & Heller, 2013Peyerimhoffiasepei Hippa & Vilkamaa, 2005Peyerimhoffiathula Vilkamaa & Hippa, 2005Peyerimhoffiavagabunda brachyptera Kieffer, 1903= PHYTOSCIARA Frey, 1942Phytosciarahalterata Phytosciaramacrotricha PNYXIA Johannsen, 1912Pnyxiascabiei PNYXIOPSIS Tuomikoski, 1960Pnyxiopsisaliger Tuomikoski, 1960Pnyxiopsisdegener PROSCIARA Frey, 1942Prosciarafurtiva Vilkamaa & Hippa, 1996Prosciaraplusiochaeta Hippa & Vilkamaa, 1991Prosciaraporrecta Prosciaraproducta Prosciaraprosciaroides Prosciaraungulata PSEUDOLYCORIELLA Menzel & Mohrig, 1998Pseudolycoriellabrunnea Pseudolycoriellajaponensis Pseudolycoriellakoreensis Pseudolycoriellamonticula Pseudolycoriellanodulosa Pseudolycoriellapaludum Pseudolycoriellasubbruckii SCATOPSCIARA Edwards, 1927Scatopsciarasg. Edwards, 1927Scatopsciaraatomaria vivida = Scatopsciarabucera Rudzinski, 1994Scatopsciaracalamophila Frey, 1948Scatopsciaracurviforceps myrmecophila Frey, 1948= Scatopsciaraedwardsi Freeman, 1983Scatopsciarafluviatilis Scatopsciarageophila Scatopsciaramultispina Scatopsciaraneglecta Menzel & Mohrig, 1998Scatopsciarapusilla PageBreakScatopsciarasubcalamophila Menzel & Mohrig, 1991Scatopsciarasubciliata Tuomikoski, 1960Scatopsciaratricuspidata degenerans = Scatopsciaravitripennis Xenopyginasg. Frey, 1948Scatopsciaragabyae Scatopsciaraobliqua Vilkamaa, Hippa & Heller, 2013Scatopsciaraparadoxa Scatopsciarasimillima SCHWENCKFELDINA Frey, 1942Schwenckfeldinacarbonaria Schwenckfeldinapectinea Menzel & Mohrig, 1991SCIARA Meigen, 1803Sciaraflavimana Zetterstedt, 1851Sciarahebes mendax Tuomikoski., 1960= nursei Freeman, 1983= ulrichi Menzel & Mohrig, 1998= Sciarahelvola Winnertz, 1867Sciarahemerobioides thomae = Sciarahumeralis Zetterstedt, 1851Sciaralackschewitzi SCYTHROPOCHROA Enderlein, 1911Scythropochroaquercicola Scythropochroaradialis Lengersdorf, 1926TRICHOSIA Winnertz, 1867Leptosciara Frey, 1942= Lestremioides Frey, 1942= Trichosia Winnertz, 1867Trichosiaacrotricha Tuomikoski, 1960Trichosiaborealis Trichosiaconfusa Menzel & Mohrig, 1997Trichosiaflavicoxa Tuomikoski, 1960Trichosiadiota Trichosiaglabra Trichosiahabilis edwardsi = Trichosiamorio caudata = Trichosiasplendens Winnertz, 1867Trichosiaussurica Mohrig & Antonova, 1978PageBreakXYLOSCIARA Tuomikoski, 1957Protoxylosciarasg. Tuomikoski, 1960Xylosciaralongiforceps Xylosciarasg. Tuomikoski, 1957Xylosciaraheptacantha Tuomikoski, 1957Xylosciaralignicola Xylosciaramicrodon Xylosciaramisella Xylosciaraphryganophila Xylosciarasenta Vilkamaa, Hippa & Heller, 2013Xylosciaraspinata betulae Tuomikoski, 1960= Xylosciarasteleocera Tuomikoski, 1960Xylosciaratrimera Tuomikoski, 1960Xylosciaravalidinervis Tuomikoski, 1960ZYGONEURA Meigen, 1830Allozygoneurasg. Menzel & Mohrig, 1998Zygoneuracalthae Tuomikoski, 1960Zygoneurasg. Meigen, 1830Zygoneurasciarina Meigen, 1830SCIAROIDEAUNPLACED IN SCIAROSOMA Chandler, 2002Sciarosomanigriclava borealis Chandler, 2002= Lycoriellaauripila , misidentified in Bradysiabetuleti , misidentified in Bradysiasubbetuleti Mohrig & Krivosheina, 1989, misidentified in Corynopteraconcinna , misidentified in Corynopterabistrispina , misidentified in Trichosiatrochanterata , misidentified in"} +{"text": "AbstractDiptera superfamilies Conopoidea (Conopidae), Nerioidea and Diopsoidea from Finland in presented. Myopavicaria Walker, 1849 is formally recorded for the first time from the country.A checklist of the Nerioidea. Two of them, Micropezidae and Pseudopomyzidae, occur in Finland. Neriids are mostly tropical and cypselomatids (sensu stricto) have only been found in the Australasian and Oriental regions. The pseudopomyzids were included in Cypselosomatidae Hendel, 1931 in the previous checklist , none particularly species-rich. Only four are found in Finland: Psilidae, Tanypezidae, Strongylophthalmyiidae and Megamerinidae. Tanypezidae and Strongylophthalmyiidae are here treated as separate families following Megamerinidae has been assigned to several superfamilies, most often Diopsoidea following Nerioidea, Sciomyzoidea, and recently Opomyzoidea ZODIONINAE Rondani, 1856ZODION Latreille, 1796Zodioncinereum notatum Meigen, 1804= SICINAE Zimina, 1960SICUS Scopoli, 1763Sicusferrugineus MYOPINAE Macquart, 1834MYOPA Fabricius, 1775Myopabuccata Myopafasciata Meigen, 1804Myopahirsuta Stuke & Clements, 2008strandi auct. nec Duda, 1940= Myopaocculta Wiedemann, 1824nigrifrons von Bonsdorff, 1866= Myopatessellatipennis Motschulsky, 1859polystigma auct. nec Rondani, 1857= Myopatestacea Myopavicaria Walker, 1849villosa Ringdahl, 1945= strandi Duda, 1940= MYOPOTTA Zimina, 1969Myopottapallipes THECOPHORA Rondani, 1845Occemyia Robineau-Desvoidy, 1853= Thecophoracinerascens pusilla = atra misid.= Thecophoradistincta melanopa misid.= Thecophorafulvipes sundewalli = PageBreakThecophorajakutica Zimina, 1974atra misid.= DALMANNIINAE Hendel, 1916DALMANNIA Robineau-Desvoidy, 1830Dalmanniadorsalis punctata misid.= Brachycera Macquart, 1834suborder Eremoneura Lameere, 1906clade Cyclorrhapha Brauer, 1863clade Schizophora Becher, 1882infraorder Muscaria Enderlein, 1936clade Acalyptratae Macquart, 1835parvorder Nerioidea Westwood, 1840superfamily MICROPEZIDAE Blanchard, 1840CALOBATINAE Bigot, 1853CALOBATA Meigen, 1803Calobatapetronella NERIA Robineau-Desvoidy, 1830Neriacibaria Neriacommutata nigricornis auct. nec Zetterstedt, 1838= Neriaephippium Nerianigricornis helleni = nitidicollis = MICROPEZINAE Blanchard, 1840MICROPEZA Meigen, 1803Micropezacorrigiolata PSEUDOPOMYZIDAE McAlpine, 1966PSEUDOPOMYZA Strobl, 1893Pseudopomyzaatrimana Diopsoidea Billberg, 1820superfamily MEGAMERINIDAE Hendel, 1913MEGAMERINA Rondani, 1861Lissa Meigen, 1826 preocc.= PageBreakMegamerinadolium loxocerina = PSILIDAE Macquart, 1835CHYLIZINAE Rondani, 1856CHYLIZA Fall\u00e9n, 1820Chylizasg. Fall\u00e9n, 1820Chylizaannulipes Macquart, 1835fuscipennis auct. nec Robineau-Desvoidy, 1830= Chylizaleptogaster scutellata = Chylizanova Collin, 1944Chylizavittata Meigen, 1826PSILINAE Macquart, 1835Loxocerini Macquart, 1835tribe IMANTIMYIA Frey, 1925Imantimyiaalbiseta ichneumonea nom. dubium (see Notes)= Imantimyiafulviventris Imantimyianigrifrons Imantimyiasylvatica LOXOCERA Meigen, 1803LOXOCERAsg. Meigen, 1803Loxoceraaristata ichneumonea nom. dubium (see Notes)= Psilini Macquart, 1835tribe CHAMAEPSILA Hendel, 1917Tetrapsila Frey, 1925= Chamaepsilaatra Chamaepsilabicolor nigromaculata = Chamaepsilabuccata gracilis = Chamaepsilahumeralis Chamaepsilalimbatella Chamaepsilamorio Chamaepsilanigra Chamaepsilanigricornis Chamaepsilanigrosetosa Frey, 1925Chamaepsilaobscuritarsis Chamaepsilapallida Chamaepsilapectoralis PageBreakChamaepsilarosae Chamaepsilarufa Chamaepsilaunilineata PSILA Meigen, 1803FREYOPSILAsg. Shatalkin, 1986Psilasibirica PSILAsg. Meigen, 1803Psilafimetaria Psilamerdaria Collin, 1944PSILOSOMA Zetterstedt, 1860Psilosomaaudouini Psilosomalefebvrei STRONGYLOPHTHALMYIIDAE Hendel, 1917STRONGYLOPHTHALMYIA Heller, 1902Strongylophthalmyiapictipes Frey, 1935Strongylophthalmyiaustulata TANYPEZIDAE Rondani, 1856TANYPEZA Fall\u00e9n, 1820Tanypezalongimana Fall\u00e9n, 1820Dalmanniapunctata not found within present borders.Chamaepsilaunilineata and Chamaepsilanigrosetosa Frey, 1925 were synonymized with Chamaepsilapallida but they have recently been reinstated as valid species . This name has been used for Loxoceraaristata (Panzer) and Loxoceraalbiseta (Schrank). Unfortunately no type material is known. Linn\u00e9\u2019s original description is insufficient and may in fact belong to a hoverfly (see rfly see .Myopavicaria Walker, 1849. One of the common Myopa species through Finland, but previously unreported due to difficulties in identification. Recorded from provinces Ab, N, Ka, St, Ta, Sa, Kl, Om, Ok, Lkoc and Li.PageBreak"} +{"text": "The TENDER clinical trial is a 3-part, 5-year, phase 3 study of tocilizumab (TCZ) in patients with active systemic juvenile idiopathic arthritis (sJIA). After 2 years of treatment, sJIA patients who have maintained clinically inactive disease (CID) for 3 months are given the option to participate in an alternative TCZ dosing regimen aimed at spacing the infusions and eventually withdrawing TCZ.To describe the patients registered to participate in the optional alternative dosing schedule in the TENDER study.To qualify for the optional alternative dosing schedule, patients had to be in the study for a minimum of 2 years and had to achieve American College of Rheumatology JIA CID status. Among the 112 patients enrolled, 39 (35%) entered the optional alternative dosing regimen. This entailed a staged prolongation of the time interval between TCZ infusions from 2 weeks to 3 weeks, then 4 weeks, with the option of terminating TCZ after the discontinuation of any treatment, including oral corticosteroids, NSAIDs, and MTX (if being treated with MTX).Twenty-three male and 16 female patients entered the optional alternative dosing schedule. The mean characteristics of these patients at the start of TCZ treatment were 14.2 active joints, 15.4 joints with limitation of motion, physician global VAS score of 58.5, CHAQ-DI score of 1.62, and erythrocyte sedimentation rate of 56.8. Fifteen had fever. Of these 39 patients, 20 patients lost CID status at different points along the alternative dosing schedule until the data review of May 2014. In these 20 patients, the time to loss of CID status ranged from 1.4 to 27.9 months from initiation of the optional alternative dosing schedule . Risk for losing inactive disease status on the optional alternative dosing schedule was 62.5% (10/16) in patients on concomitant methotrexate and 43.5% (10/23) in patients not on it. During the April 2013 data review, inactive disease status was maintained in 26 of 39 patients (67%), whereas during the May 2014 data review inactive disease status was maintained in 19 of the 39 patients (49%) entering the optional alternative dosing schedule. Dosing intervals were every 3 weeks in 3 patients and every 4 weeks in 9 patients; 7 patients were able to discontinue TCZ (range of time since discontinuation: 13.7-20.8 months). During the April 2013 data review, 9 patients were able to discontinue TCZ. During the May 2014 data review, 7 patients maintained CID status and remained off TCZ, and 2 patients returned to the 2-week dosing interval.A proportion of patients with sJIA who maintain clinically inactive disease status can progressively space TCZ infusions. Of the 35% who entered the optional alternative dosing regimen, approximately half were able to maintain inactive disease over an extended period of time.TENDER, NCT00642460F. De Benedetti Grant / Research Support from: Abbott, Pfizer, BMS, Roche, Novimmune, Novartis, S0BI, N. Ruperto Grant / Research Support from: Abbott, AstraZeneca, BMS, Centocor, Eli Lilly, Francesco Angelini s.p.a., GlaxoSmithKline, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Consultant for: Abbott, AstraZeneca, BMS, Centocor, Eli Lilly, Francesco Angelini s.p.a., GlaxoSmithKline, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, H. Brunner Consultant for: Novartis, Genentech, MedImmune, EMD Serono, AMS, Pfizer, UCB, Janssen, Speaker Bureau of: Genentech, A. Grom Grant / Research Support from: Roche, Consultant for: Novartis, N. Wulffraat Grant / Research Support from: Novartis, Roche, Pfizer, AbbVie, Consultant for: Novartis, Roche, Pfizer, M. Henrickson: None declared., R. Jerath: None declared., Y. Kimura: None declared., A. Kadva Employee of: Genentech, a member of the Roche group, J. Wang: None declared., A. Martini Grant / Research Support from: Abbott, AstraZeneca, BMS, Centocor, Eli Lilly, Francesco Angelini s.p.a., GlaxoSmithKline, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Consultant for: Abbott, AstraZeneca, BMS, Centocor, Eli Lilly, Francesco Angelini s.p.a., GlaxoSmithKline, Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, D. Lovell Consultant for: AstraZeneca, Centocor, Janssen, Wyeth, Amgen, BMS, Abbott, Pfizer, Regeneron, Hoffmann La-Roche, Novartis, Genentech, Speaker Bureau of: Genentech, Roche."} +{"text": "AbstractAtelestidae, Brachystomatidae, Dolichopodidae, Empididae and Hybotidae (Diptera) recorded from Finland is presented. The genera with uncertain placement within superfamily Empidoidea (= the Iteaphila group) are also included in this paper.An updated checklist of the Empidoidea (dance flies and long-legged flies) is one of the most diverse lineages of Diptera with some 13,000 species currently recognized worldwide . Two of the Finnish genera, Anthepiscopus Becker and Iteaphila Zetterstedt, remain unassigned on family level and by Dolichopodidae. Two updates to the dolichopodid checklist have since been published Uncertain family position within ITEAPHILA Zetterstedt, 1838Iteaphilamacquarti Zetterstedt, 1838Iteaphilanitidula Zetterstedt, 1838obscura Zetterstedt, 1849= ANTHEPISCOPUS Becker, 1891Anthepiscopusoedalinus EMPIDIDAE Latreille, 1809HEMERODROMIINAE Schiner, 1862Chelipodini Hendel, 1936CHELIPODA Macquart, 1823Chelipodaalbiseta PageBreakChelipodainexspectata Tuomikoski, 1966Chelipodavocatoria PHYLLODROMIA Zetterstedt, 1837Phyllodromiamelanocephala Hemerodromiini Schiner, 1862CHELIFERA Macquart, 1823Cheliferaconcinnicauda Collin, 1927lapponica Frey, 1950= stigmatica misid.= Cheliferaflavella Cheliferafrigelii Cheliferaprecabunda Collin, 1961Cheliferaprecatoria Cheliferasubangusta Collin, 1961Cheliferatrapezina HEMERODROMIA Meigen, 1822Hemerodromiaadulatoria Collin, 1927Hemerodromiaoratoria Hemerodromiaraptoria Meigen, 1830EMPIDINAE Latreille, 1809Empidini Latreille, 1809EMPIS Linnaeus, 1758Anacrostichussg. Bezzi, 1909Empislucida Zetterstedt, 1838Coptophlebiasg. Bezzi, 1909Empishyalipennis Fall\u00e9n, 1816Empissg. Linnaeus, 1758Empisacinerea Chvala, 1985cinerea Zetterstedt, 1855 preocc.= Empisbicuspidata Collin, 1927Empiscaudatula Loew, 1867Empischioptera Meigen, 1804Empislaminata Collin, 1927Empisnigripes Fabricius, 1794pennaria Fall\u00e9n, 1816= vernalis Meigen, 1822= Empispennipes Linnaeus, 1758Empisprodromus Loew, 1867Empisstaegeri Collin, 1963planetica misid.= Empissyrovatkai Chv\u00e1la, 1985plumipes Zetterstedt, 1842 preocc.= Euempissg. Frey, 1953PageBreakEmpispicipes Meigen, 1804maculipes Zetterstedt, 1842= Empistessellata Fabricius, 1794Kritempissg. Collin, 1926Empislivida Linnaeus, 1758Leptempissg. Collin, 1926Empisgrisea Fall\u00e9n, 1816Platypterasg. Meigen, 1803Empisborealis Linnaeus, 1758Xanthempissg. Bezzi, 1909Empisaemula Loew, 1873Empisdigramma Meigen in Gistl, 1835diagramma misspelling= Empislaetabilis Collin, 1926Empisstercorea Linnaeus, 1761Empisunivittata Loew, 1867RHAMPHOMYIA Meigen, 1822Aclonempissg. Collin, 1926Rhamphomyiagalactoptera Strobl, 1893Amydroneurasg. Collin, 1926Rhamphomyiagibba Holoclerasg. Schiner, 1860Rhamphomyiabohemica Bart\u00e1k & Kub\u00edk, 2012caliginosa misid.= trigemina misid.= Rhamphomyiaculicina Rhamphomyianigripennis Rhamphomyiasciarina Rhamphomyiaumbripennis Meigen, 1822Rhamphomyiavariabilis tenuirostris = Lundstroemiellasg. Frey, 1922Rhamphomyiadudai Oldenberg, 1927Rhamphomyiahybotina Zetterstedt, 1838Megacyttarussg. Bigot, 1880Rhamphomyiaanomalina Zetterstedt, 1838Rhamphomyiaanomalipennis Meigen, 1822anomala misid.= Rhamphomyiacrassirostris nigripes auct. nec = Rhamphomyiagufitar Frey, 1922Rhamphomyiamaculipennis Zetterstedt, 1842tephraea misid.= PageBreakpoissoni misid.= Rhamphomyianodipes spissirostris = Rhamphomyiaparadoxa Wahlberg, 1844Pararhamphomyiasg. Frey, 1922Rhamphomyiaalbidiventris Strobl, 1898woldstedti Frey, 1913= Rhamphomyiaalbipennis Rhamphomyiaalbitarsis Collin, 1926Rhamphomyiaalbissima Frey, 1913Rhamphomyiaalpina Zetterstedt, 1838Rhamphomyiaamoena Loew, 1840Rhamphomyiaangulifera Frey, 1913Rhamphomyiabreviventris Frey, 1913Rhamphomyiacaesia Meigen, 1822filata Zetterstedt, 1842= Rhamphomyiacaudata Zetterstedt, 1838aethiops Zetterstedt, 1838= Rhamphomyiachibinensis Frey, 1922Rhamphomyiacribrata Oldenberg, 1927Rhamphomyiacurvula Frey, 1913Rhamphomyiadentata Oldenberg, 1910Rhamphomyiafascipennis Zetterstedt, 1838Rhamphomyiafilicaudula Frey, 1949Rhamphomyiafuscipennis Zetterstedt, 1838Rhamphomyiafuscula Zetterstedt, 1838Rhamphomyiageniculata Meigen, 1830plumipes auct. nec = Rhamphomyiagriseola dispar Zetterstedt, 1838= aperta Zetterstedt, 1859= Rhamphomyiahelleni Frey, 1922Rhamphomyialividiventris Zetterstedt, 1838Rhamphomyialongestylata Frey, 1916caudata auct. nec Zetterstedt, 1838= Rhamphomyialucidula Zetterstedt, 1842Rhamphomyiamarginata Rhamphomyiamodesta Wahlberg, 1844Rhamphomyiamurina Collin, 1926Rhamphomyianiveipennis Zetterstedt, 1838Rhamphomyiaobscura Zetterstedt, 1838Rhamphomyiaobscuripennis Meigen, 1830nitidicollis Frey, 1913= PageBreakRhamphomyiaphysoprocta Frey, 1913Rhamphomyiapilifer Meigen, 1838dentipes Zetterstedt, 1842= glaucella Zetterstedt, 1842= intermedia Frey, 1922= Rhamphomyiaplumifera Zetterstedt, 1838Rhamphomyiapoplitea Wahlberg, 1844Rhamphomyiapraestans Frey, 1913Rhamphomyiapusilla Zetterstedt, 1838Rhamphomyiarufipes Zetterstedt, 1838lapponica Frey, 1955= Rhamphomyiasimplex Zetterstedt, 1849Rhamphomyiasubglaucella Frey, 1922Rhamphomyiatibiella Zetterstedt, 1842Rhamphomyiatipularia Rhamphomyiaunguiculata Frey, 1913Rhamphomyiasp. aff.albipennisRhamphomyiasg. Meigen, 1822Rhamphomyiaalbosegmentata Zetterstedt, 1838Rhamphomyiacinerascens Rhamphomyiacoracina Zetterstedt, 1849Rhamphomyiadorsata Becker, 1915phanerostigma Frey, 1918= Rhamphomyiahambergi Frey, 1916Rhamphomyiaignobilis Zetterstedt, 1859attenuata Frey, 1913= Rhamphomyialaevipes tephraea Meigen, 1822= Rhamphomyialatifrons Frey, 1913Rhamphomyiamorio Zetterstedt, 1838Rhamphomyianitidula Zetterstedt, 1842Rhamphomyiapalmeni Frey, 1913Rhamphomyiaplumipes vespertilio Zetterstedt, 1842= Rhamphomyiareflexa Zetterstedt, 1838Rhamphomyiaspinipes Rhamphomyiastigmosa Macquart, 1827conformis auct. nec Kowarz, 1867= Rhamphomyiasulcata tibialis auct. nec Meigen, 1822= Rhamphomyiatrilineata Zetterstedt, 1859sulcatina Collin, 1926= tibialis auct. nec Meigen, 1822= PageBreakpropinqua misid.= Rhamphomyiavesiculosa Hilarini Collin, 1961HILARA Meigen, 1822Hilaraabdominalis Zetterstedt, 1838obscuritarsis Zetterstedt, 1859= Hilaraalbitarsis von Roser, 1840Hilaraanglodanica Lundbeck, 1913Hilarabarbipes Frey, 1908Hilarabeckeri Strobl, 1892Hilarabiseta Collin, 1927Hilarabistriata Zetterstedt, 1842Hilarabrevistyla Collin, 1927Hilaracampinosensis Niesiolowski, 1986Hilaracanescens Zetterstedt, 1849Hilarachorica Hilaraclavipes spinimana Zetterstedt, 1838= Hilaraclypeata Meigen, 1822Hilaracoracina Oldenberg, 1916quadrifaria Strobl, 1892= Hilaracornicula Loew, 1873Hilaradiscoidalis Lundbeck, 1910Hilaradiversipes Strobl, 1892germanica Engel, 1941= Hilaraeviana Straka, 1976Hilarafemorella Zetterstedt, 1842Hilaragallica Hilaragriseola Zetterstedt, 1838Hilarahirta Strobl, 1892hirtella misid.= Hilarahybrida Collin, 1961Hilarahyposeta Straka, 1976Hilaraimplicata Collin, 1927Hilaraintermedia pubipes Loew, 1873= Hilarainterstincta Hilaramonedula Collin, 1927longifurca auct. nec Strobl, 1892= Hilaralapponica Chv\u00e1la, 2002Hilaralitorea Hilaralongivittata Zetterstedt, 1842Hilaralurida PageBreakHilaranigritarsis Zetterstedt, 1838infans Zetterstedt, 1842= Hilaranitidula Zetterstedt, 1838Hilarapilipes Zetterstedt, 1838Hilarapseudochorica Strobl, 1892Hilarapulchripes Frey, 1913Hilaraquadrifasciata Chv\u00e1la, 2002quadrivittata auct. nec Meigen, 1822= Hilarasturmii Meigen, 1822cingulata misid.= Hilarasubmaura Collin, 1927Hilaratanythrix Frey, 1913Hilaratenuinervis Zetterstedt, 1838Hilarawoodiella Chv\u00e1la, 1999CLINOCERINAE Collin, 1928CLINOCERA Meigen, 1803Clinoceraappendiculata simplicinervis Frey, 1913= Clinoceraaucta Clinoceranivalis Clinocerastagnalis Clinocerawesmaeli DOLICHOCEPHALA Macquart, 1823Dolichocephalaguttata Dolichocephalairrorata Dolichocephalathomasi Wagner, 1983ocellata misid.= WIEDEMANNIA Zetterstedt, 1838Eucelidiasg. Mik, 1881Wiedemanniazetterstedti Philolutrasg. Mik, 1881Wiedemanniabohemani Wiedemanniasimplex fallaciosa auct. nec Loew, 1873= Wiedemanniasg. Zetterstedt, 1838Wiedemanniabistigma Empididae (incertae sedis)Uncertain subfamily position within HORMOPEZA Zetterstedt, 1838Hormopezacopulifera Melander, 1927Hormopezaobliterata Zetterstedt, 1838RAGAS Walker, 1837Ragasunica Walker, 1837PageBreakATELESTIDAE Hennig, 1970ATELESTINAE Hennig, 1970ATELESTUS Walker, 1837Atelestuspulicarius MEGHYPERUS Loew, 1850Meghyperussudeticus Loew, 1850HYBOTIDAE Meigen, 1820TRICHININAE Chv\u00e1la, 1983TRICHINA Meigen, 1830Trichinabilobata Collin, 1926Trichinaclavipes Meigen, 1830Trichinaelongata Haliday, 1833Trichinaopaca Loew, 1864picipes Tuomikoski, 1935= Trichinapallipes TRICHINOMYIA Tuomikoski, 1959Trichinomyiaflavipes Trichinomyiafuscipes OCYDROMIINAE Schiner, 1862Ocydromiini Schiner, 1862CHVALAEA Papp & F\u00f6ldv\u00e1ri, 2001Chvalaeasopianae Papp & F\u00f6ldv\u00e1ri, 2001LEPTODROMIELLA Tuomikoski, 1936Leptodromiellacrassiseta Tuomikoski, 1936LEPTOPEZA Macquart, 1834Leptopezaborealis Zetterstedt, 1842Leptopezaflavipes OCYDROMIA Meigen, 1820Ocydromiaglabricula Ocydromiamelanopleura Loew, 1840OEDALEINAE Chv\u00e1la, 1983ALLANTHALIA Melander, 1927Allanthaliapallida ANTHALIA Zetterstedt, 1838Anthaliaschoenherri Zetterstedt, 1838EUTHYNEURA Macquart, 1836Euthyneuraalbipennis Euthyneuragyllenhali Euthyneuramyrtilli Macquart, 1836myricae Haliday, 1851 misid.= OEDALEA Meigen, 1820PageBreakOedaleafreyi Chv\u00e1la, 1983Oedaleaholmgreni Zetterstedt, 1852Oedaleahybotina Oedaleastigmatella Zetterstedt, 1842Oedaleatibialis Macquart, 1827Oedaleazetterstedti Collin, 1926TACHYDROMIINAE Meigen, 1822Symballophthalmini Sinclair & Cumming, 2006SYMBALLOPHTHALMUS Mecker, 1889Symballophthalmusdissimilis Symballophthalmusfuscitarsis scapularis Collin, 1961= Tachydromiini Meigen, 1822PLATYPALPUS Macquart, 1827Platypalpusagilis Platypalpusalbicornis Platypalpusalbiseta Platypalpusalbocapillatus Platypalpusalpinus Chv\u00e1la, 1971Platypalpusalter Platypalpusannulatus fulvipes = Platypalpusannulipes Platypalpusarticulatoides Platypalpusarticulatus Macquart, 1827? Platypalpusater atra misspelling= Platypalpusboreoalpinus Frey, 1943Platypalpusbrachystylus brunneitibia = Platypalpusbrevicornis Platypalpuscalceatus Platypalpuscandicans Platypalpusciliaris Platypalpusconfiformis Chv\u00e1la, 1971Platypalpusconfinis Platypalpuscothurnatus Macquart, 1827Platypalpuscryptospina tantulus = Platypalpuscursitans bicolor = Platypalpusecalceatus Platypalpusexcavatus Yang & Yao, 2007PageBreakexcisus preocc.= Platypalpusexilis Platypalpusfenestella Kovalev, 1971Platypalpusflavicornis Platypalpusfuscicornis Platypalpushackmani Chv\u00e1la, 1972Platypalpusinfectus Platypalpusinterstinctus Platypalpuslaestadianorum Platypalpuslapponicus Frey, 1943Platypalpuslongicornis Platypalpuslongiseta extricatus = Platypalpusluteicornis difficilis = interjectus = Platypalpusluteus Platypalpusmaculus Platypalpusmaculimanus articulatus auct. nec Macquart, 1827= Platypalpusmaculipes Platypalpusmajor Platypalpusmelancholicus Platypalpusminutus Platypalpusnigricoxa Platypalpusnigritarsis Platypalpusnigrosetosus Platypalpusnonstriatus Strobl, 1901Platypalpusnotatus Platypalpuspallidicornis Platypalpuspallidicoxa Platypalpuspallidiventris flavipes = Platypalpuspallipes Platypalpuspectoralis Platypalpuspseudofulvipes coarctatus = Platypalpuspseudorapidus Kovalev, 1971Platypalpuspulicarius Platypalpusrapidus Platypalpussahlbergi Platypalpusscandinavicus Chv\u00e1la, 1972Platypalpussordidus PageBreakPlatypalpusstabilis Platypalpusstackelbergi Kovalev, 1971Platypalpusstigmatellus Platypalpusstrigifrons Platypalpussubbrevis Platypalpussubtilis Platypalpussylvicola Platypalpustuomikoskii Chv\u00e1la, 1972Platypalpusunguiculatus Platypalpusverralli Platypalpusvividus albisetoides Chv\u00e1la, 1973= Platypalpuszetterstedti Chv\u00e1la, 1971TACHYDROMIA Meigen, 1803Tachydromiaaemula Tachydromiaarrogans Tachydromiaconnexa Meigen, 1822Tachydromiaincompleta Tachydromialundstroemi Tachydromiamorio Tachydromiapunctifera Tachydromiasabulosa Meigen, 1830Tachydromiaterricola Zetterstedt, 1819Tachydromiaumbrarum Haliday, 1833TACHYPEZA Meigen, 1830Tachypezafennica Tuomikoski, 1932Tachypezafuscipennis Tachypezaheeri Tachypezanubila Tachypezatruncorum Tachypezawinthemi Drapetini Collin, 1961CHERSODROMIA Haliday, 1851Chersodromiaarenaria Chersodromiacursitans CROSSOPALPUS Bigot, 1857Crossopalpuscurvinervis Crossopalpuscurvipes Crossopalpushumilis Crossopalpusnigritellus Crossopalpussetiger DRAPETIS Meigen, 1822Drapetisarcuata Loew, 1859PageBreakDrapetisassimilis Drapetisexilis Meigen, 1822Drapetisinfitialis Collin, 1961Drapetisingrica Kovalev, 1972Drapetisparilis Collin, 1926Drapetispusilla Loew, 1859Drapetissimulans Collin, 1961Elaphropeza Macquart, 1827Elaphropezaephippiata STILPON Loew, 1859Stilpongraminum HYBOTINAE Meigen, 1820Bicellariini Sinclair & Cumming, 2006BICELLARIA Macquart, 1823Cyrtoma Meigen, 1824= Bicellariaaustriaca Tuomikoski, 1955Bicellariaintermedia Lundbeck, 1910Bicellarianigra Bicellariapilosa Lundbeck, 1910Bicellariasimplicipes Bicellariaspuria Bicellariasubpilosa Collin, 1926Bicellariasulcata Bicellariauvens Melander, 1928bisetosa Tuomikoski, 1936= Hybotini Meigen, 1820HYBOS Meigen, 1803Hybosculiciformis Hybosfemoratus femoralis misspelling= Hybosgrossipes SYNDYAS Loew, 1857Syndyasnigripes BRACHYSTOMATIDAE Melander, 1908TRICHOPEZINAE Vaillant, 1981GLOMA Meigen, 1822Glomafuscipennis Meigen, 1822HELEODROMIA Haliday, 1833Heleodromiasg. Haliday, 1833Heleodromiaimmaculata Haliday, 1833TRICHOPEZA Rondani, 1856Trichopezaalbocincta PageBreakalbicincta Frey, 1913= Trichopezalongicornis DOLICHOPODIDAE Latreille, 1809MICROPHORINAE Collin, 1960MICROPHOR Macquart, 1827Microphorus misspelling= Microphoranomalus Microphorcrassipes Macquart, 1827Microphorholosericeus velutinus Macquart, 1827= PARATHALASSIINAE Chv\u00e1la, 1981MICROPHORELLA Becker, 1909Microphorellapraecox DOLICHOPODINAE Latreille, 1809DOLICHOPUS Latreille, 1796Hygroceleuthus Loew, 1857= Dolichopussg. Latreille, 1796Dolichopusacuticornis Wiedemann, 1817Dolichopusannulitarsis Ringdahl, 1920Dolichopusapicalis Zetterstedt, 1849Dolichopusargyrotarsis Wahlberg, 1850Dolichopusarmillatus Wahlberg, 1850stenhammari var. b Zetterstedt, 1843= Dolichopusatripes Meigen, 1824Dolichopusaustriacus Parent, 1927Dolichopusbonsdorffi Frey, 1915Dolichopusbrevipennis Meigen, 1824Dolichopuscaligatus Wahlberg, 1850flavipes misid.= albifrons misid.= Dolichopuscalinotus Loew, 1871Dolichopuscampestris Meigen, 1824Dolichopuscilifemoratus Macquart, 1827pseudocilifemoratus Stackelberg, 1930= Dolichopuscinctipes Wahlberg, 1850Dolichopusclaviger Stannius, 1831Dolichopusclavipes Haliday, 1832Dolichopuscostalis Frey, 1915Dolichopusdiscifer Stannius, 1831nigricornis Meigen, 1824?= Dolichopusdiscimanus Wahlberg, 1851Dolichopusfraterculus Zetterstedt, 1843PageBreakDolichopusgriseipennis Stannius, 1831Dolichopusgubernator Mik, 1878Dolichopushilaris Loew, 1862Dolichopuslancearius Hedstr\u00f6m, 1966Dolichopuslatilimbatus Macquart, 1827Dolichopuslatipennis Fall\u00e9n, 1823Dolichopuslepidus Staeger, 1842cruralis Wahlberg, 1850= lapponicus Becker, 1917= Dolichopuslinearis Meigen, 1824Dolichopuslineatocornis Zetterstedt, 1843Dolichopuslongicornis Stannius, 1831Dolichopuslongitarsis Stannius, 1831Dolichopusmaculipennis Zetterstedt, 1843Dolichopusmannerheimi Zetterstedt, 1838Dolichopusmigrans Zetterstedt, 1843Dolichopusnigripes Fall\u00e9n, 1823Dolichopusnitidus Fall\u00e9n, 1823Dolichopusnotatus Staeger, 1842notabilis Zetterstedt, 1843= Dolichopusnubilus Meigen, 1824Dolichopuspennatus Meigen, 1824Dolichopuspicipes Meigen, 1824consimilis Wahlberg, 1850= Dolichopusplanitarsis Fall\u00e9n, 1823Dolichopusplumipes parvicaudatus Zetterstedt, 1843= pectinitarsis Stenhammar, 1851= Dolichopuspopularis Wiedemann, 1817Dolichopuspseudomigrans Ringdahl, 1928Dolichopuspunctum Meigen, 1824Dolichopusremipes Wahlberg, 1839Dolichopusrupestris Haliday, 1833Dolichopusruthei Loew, 1847Dolichopussabinus Haliday, 1838Dolichopussetiger Negrobov, 1973Dolichopussignatus Meigen, 1824Dolichopussignifer Haliday, 1832Dolichopussimplex Meigen, 1824Dolichopusstenhammari Zetterstedt, 1843annulipes Zetterstedt, 1838 invalidated= Dolichopussubpennatus d\u2019Assis-Fonseca, 1976Dolichopustrivialis Haliday, 1832PageBreakcilifemoratus auct. nec Macquart, 1827= Dolichopusungulatus Dolichopusurbanus Meigen, 1824Dolichopusvitripennis Meigen, 1824Dolichopuswahlbergi Zetterstedt, 1843Dolichopuszetterstedti Stenhammar, 1852Macrodolichopussg. Stackelberg, 1933Dolichopusdiadema Haliday, 1832ETHIROMYIA Brooks, 2005Ethiromyiachalybeus GYMNOPTERNUS Loew, 1857Gymnopternusaerosus Gymnopternusangustifrons Gymnopternusbrevicornis Gymnopternusceler Gymnopternusmetallicus HERCOSTOMUS Loew, 1857Hercostomusgermanus Hercostomusnigrilamellatus Hercostomusnigriplantis Hercostomussahlbergi SYBISTROMA Meigen, 1824Sybistromadiscipes Sybistromaobscurellum TACHYTRECHUS Haliday, 1851Ammobates Stannius, 18312 preocc.= Tachytrechusammobates plumipes preocc.= Tachytrechushamatus Loew, 1871Tachytrechusnotatus SCIAPODINAE Becker, 1917SCIAPUS Zeller, 1842Sciopus misspelling= Sciapusalbifrons Sciapusbasilicus Meuffels & Grootaert, 1990Sciapuslobipes Sciapuslongulus Sciapusmaritimus Becker, 1918flavomaculatus Ringdahl, 1949= Sciapusplatypterus Sciapuswiedemanni Sciapuszonatulus contristans misid.= PageBreakSYMPYCNINAE Aldrich, 1905CAMPSICNEMUS Haliday, 1851Ectomus Mik, 1878= Campsicnemusalpinus Campsicnemusarmatus Campsicnemusarticulatellus pilosellus = dasycnemus Loew, 1857= Campsicnemuscompeditus Loew, 1857Campsicnemuscurvipes Campsicnemusfemoratus Ringdahl, 1949Campsicnemusloripes Campsicnemuslumbatus Loew, 1857Campsicnemusmarginatus Loew, 1857Campsicnemusparadoxus Campsicnemuspicticornis Campsicnemuspumilio pectinulatus Loew, 1864= Campsicnemuspusillus Campsicnemusscambus LAMPROCHROMUS Mik, 1878Lamprochromusstrobli Parent, 1925SYMPYCNUS Loew, 1857Sympycnusaeneicoxa Sympycnuspulicarius annulipes ?= desoutteri Parent, 1925?= SYNTORMON Loew, 1857Bathycranium Strobl, 1892= Syntormonbicolorellus Syntormonfiliger Verrall, 1912rufipes misid.= simplicipes Frey, 1915= Syntormonfreymuthae Loew, 1873Syntormondenticulatus misid.= Syntormonmetathesis Syntormonpallipes Syntormonpumilus Syntormontarsatus aulicus misid.= TELMATURGUS Mik, 1874Telmaturgustumidulus TEUCHOPHORUS Loew, 1857PageBreakTeucophorus misspelling= Teuchophorusmonacanthus Loew, 1859Teuchophorusnigricosta pectinifer Kowarz, 1868= signatus Zetterstedt, 1849= Teuchophorusspinigerellus DIAPHORINAE Schiner, 1864ARGYRA Macquart, 1834Leucostola Loew, 1857= Argyraargentina Argyraargyria Argyraauricollis Argyradiaphana Argyraelongata Argyrailonae Geoffries, 1989confinis preocc.= Argyraleucocephala Argyramagnicornis Argyrasetulipes Becker, 1918Argyrasetimana Loew, 1859subarctica misid.= Argyraspoliata Kowarz, 1879Argyravestita ASYNDETUS Loew, 1869Asyndetuslatifrons CHRYSOTUS Meigen, 1824Chrysotusangulicornis Kowarz, 1874Chrysotuscilipes Meigen, 1824Chrysotuscupreus Chrysotusfemoratus Zetterstedt, 1843Chrysotusgramineus microcerus Kowarz, 1874= varians Kowarz, 1874= Chrysotuslaesus amplicornis Zetterstedt, 1849= Chrysotusneglectus Chrysotusobscuripes Zetterstedt, 1838kowarzi Lundbeck, 1912= Chrysotuspulchellus Kowarz, 1874Chrysotussuavis Loew, 1857DIAPHORUS Meigen, 1824Diaphorushoffmannseggi Meigen, 1830Diaphorusnigricans Meigen, 1824PageBreakDiaphorusoculatus MELANOSTOLUS Kowarz, 1884Melanostolusmelancholicus MEDETERINAE Lioy, 1864DOLICHOPHORUS Lichtward, 1902Dolichophoruskerteszi Lichtward, 1902MEDETERA Fischer von Waldheim, 1819Medeteraabstrusa Thuneberg, 1955Medeteraacanthura Negrobov & Thuneberg, 1970Medeteraadjaniae Gosseries, 1989breviseta Parent, 1927 preocc.= Medeteraambigua Medeteraapicalis Medeterabelgica Parent, 1936 sensu Negrobov & Stackelberg, 1972Medeterabetulae Ringdahl, 1949Medeteraborealis Thuneberg, 1955Medeteracuspidata Collin, 1941Medeteradichrocera Kowarz, 1877Medeteraexcellens Frey, 1909Medeterafasciata Frey, 1915Medeterafreyi Thuneberg, 1955Medeterafumida Negrobov, 1967Medeteraimpigra Collin, 1941Medeteraincrassata Frey, 1909Medeterainfumata Loew, 1857Medeterainspissata Collin, 1952Medeterajacula Medeterajugalis Collin, 1941Medeteramelancholica Lundbeck, 1912Medeteramuralis Meigen, 1824Medeteranitida stackelbergi Parent, 1927= Medeteraobscura Medeterapallipes Medeteraparenti Stackelberg, 1925collini Thuneberg, 1955= Medeterapinicola Kowarz, 1877nuortevai Thuneberg, 1955= Medeteraplumbella Meigen, 1824Medeteraprjachinae Negrobov & Stackelberg, 1974Medeteraprotuberans Negrobov, 1967Medeterapseudoapicalis Thuneberg, 1955Medeteraseguyi Parent, 1926PageBreakMedeterasenicula Kowarz, 1877Medeterasetiventris Thuneberg, 1955Medeterasignaticornis Loew, 1857Medeterastriata Parent, 1927Medeteratristis Medeteravagans Becker, 1917fennica Thuneberg, 1955= Medeteraveles Loew, 1861bilineata Frey, 1915= Medeterazinovjevi Negrobov, 1967SYSTENUS Loew, 1857Systenusbipartitus Systenuspallipes adpropinquus = Systenusscholtzi THRYPTICUS Gerst\u00e4cker, 1864Thrypticusatomus Frey, 1915Thrypticusbellus Loew, 1869Thrypticuscuneatus Thrypticusdivisus Strobl, 1880fennicus Becker, 1917= Thrypticusintercedens Negrobov, 1967Thrypticuslaetus Verrall, 1912Thrypticusnigricauda Wood, 1913Thrypticuspollinosus Verrall, 1912Thrypticuspruinosus Parent, 1932Thrypticussmaragdinus Gerst\u00e4cker, 1864Thrypticustarsalis Parent, 1932Thrypticus sp. AHYDROPHORINAE Lioy, 1864HYDROPHORUS Fall\u00e9n, 1823Hydrophorusalbiceps Frey, 1915Hydrophorusalpinus Wahlberg, 1844Hydrophorusaltivagus Aldrich, 1911wahlgreni Frey, 1915= Hydrophorusbipunctatus Hydrophorusborealis Loew, 1857Hydrophorusbrunnicosus Loew, 1857Hydrophoruscallosoma Frey, 1915albosignatus Ringdahl, 1919= Hydrophorusfreyi Stor\u00e5, 1954Hydrophorusgeminus Frey, 1915Hydrophoruslitoreus Fall\u00e9n, 1823PageBreakHydrophorusnebulosus Fall\u00e9n, 1823Hydrophorusnorvegicus Ringdahl, 1928Hydrophoruspectinatus Gerst\u00e4cker, 1864forcipatus Frey, 1915= Hydrophoruspilipes Frey, 1915Hydrophoruspraecox Hydrophorusrufibarbis Gerst\u00e4cker, 1864micans Frey, 1915= Hydrophorussigniferus Coquillett, 1899magnicornis Frey, 1915= Hydrophorusviridis LIANCALUS Loew, 1857Liancalusvirens PEODES Loew, 1857Peodespetsamoensis Frey, 1930SCELLUS Loew, 1857Scellusspinimanus THINOPHILUS Wahlberg, 1844Thinophilussg. Wahlberg, 1844Thinophilusflavipalpis Thinophilusruficornis NEURIGONINAE Aldrich, 1905NEURIGONA Rondani, 1856Neurigonaabdominalis Neurigonapallida Neurigonaquadrifasciata Neurigonasuturalis Neurigona sp. ARHAPHIINAE Bigot, 1852RHAPHIUM Meigen, 1803Xiphandrium Loew, 1857= Porphyrops auctt.= Rhaphiumalbifrons Rhaphiumappendiculatum macrocerum auct. nec Meigen, 1824= Rhaphiumbasale Loew, 1850Rhaphiumcaliginosum Meigen, 1824zetterstedti = Rhaphiumcommune spinicoxa Loew, 1850= Rhaphiumconfine Zetterstedt, 1843Rhaphiumcrassipes Rhaphiumdiscolor Zetterstedt, 1838PageBreakconsobrinum Zetterstedt, 1843= riparium auct. nec = Rhaphiumelegantulum Rhaphiumfasciatum Meigen, 1824Rhaphiumfascipes Rhaphiumfissum Loew, 1850Rhaphiumglaciale Rhaphiumholmgreni luteipenne = Rhaphiumlanceolatum Loew, 1850caliginosum auct. nec Meigen, 1824= Rhaphiumlaticorne nemorum Meigen, 1830= Rhaphiumlatimanum Kahanp\u00e4\u00e4, 2007Rhaphiumlongicorne Rhaphiummicans Rhaphiummonotrichum Loew, 1850auctum misid.= Rhaphiumnasutum Rhaphiumnigribarbatum Rhaphiumpatulum antennatum misid.= Rhaphiumpenicillatum Loew, 1850Rhaphiumriparium praerosum Loew, 1850= Rhaphiumrivale Rhaphiumtridactylum Rhaphiumumbripenne ACHALCINAE Grootaert & Meuffels, 1997ACHALCUS Haliday, 1857Achalcuscinereus Achalcusflavicollis Achalcusnigropunctatus Poll\u00e9t & Brunhues, 1996Achalcusvaillanti Brunhues, 1987PELOROPEODINAE Robinson, 1970CHRYSOTIMUS Loew, 1857Chrysotimusmolliculus MICROMORPHUS Mik, 1878Micromorphusclaripennis XANTHOCHLORINAE Aldrich, 1905XANTHOCHLORUS Loew, 1857Xanthochlorusornatus Xanthochlorustenellus PageBreakCheliferaastigma Collin, 1927 misidentifiedChrysotusarcticus Frey, 1915 not found within present bordersChrysotuslongipalpus Aldrich, 1896 importedpallidipalpus van Duzee, 1933= Chrysotusringdahli Parent, 1929 not found within present bordersClinoceranigra Meigen, 1804 misidentifiedCrossopalpusabditus Kovalev, 1972 not found within present bordersDolichopusangustipennis Kertesz, 1901 not found within present bordersadustus Frey, 1915= Dolichopusgrandicornis Wahlberg, 1850 not found within present bordersDolichopusmediicornis Verrall, 1875 not found within present bordersDolichopusplumitarsis Fall\u00e9n, 1823 misidentifiedDolichopuspropinquus Zetterstedt, 1852 misidentifiedDrapetisincompleta Collin, 1926 misidentifiedEmpispunctata Meigen, 1804 not found within present bordersGymnopternusassimilis misidentifiedHilaraflavipes Meigen, 1822 misidentifiedHilaramaura not found within present bordersHilarascrobiculata Loew, 1873 misidentifiedHilaratetragramma Loew, 1873 misidentifiedHydrophorusbalticus not found within present bordersHydrophorusponojensis Frey, 1915 not found within present bordersIteaphilafurcata not found within present bordersMedeteraannulitarsus von Roser, 1840 misidentifiedMedeteraglauca Loew, 1869 misidentifiedMedeterafeminina Negrobov, 1967 misidentifiedMedeteratruncorum Meigen, 1824 importedOedaleaflavipes Zetterstedt, 1842 misidentifiedParathalassiuskrogerusi Frey, 1927 nomen nudumRhamphomyiatibialis Meigen, 1822 misidentifiedRhaphiumantennatum misidentifiedRhaphiumobscuripes Zetterstedt, 1849 misidentifiedRhaphiumsuave not found within present bordersTachytrechusinsignis misidentifiedTrichoclinoceralapponica not found within present bordersPageBreakDolichopuscaligatus Wahlberg, 1850 was synonymized with Dolichopusflavipes Stannius, 1831 by Dolichopuscaligatus as a valid species. True Dolichopusflavipes has not been found in Finland but some specimens have been recorded from Northwestern European Russia.Dolichopusstenhammari Zetterstedt, 1843. Dolichopusannulipes. Later he proposed Dolichopusstenhammari Zett., 1843 as an (unnecessary) replacement name for the taxon: Porphyropsannulipes Meigen, 1824 was recognized in Dolichopus at the time, but only as a junior synonym of what is now Sympycnuspulicarius . NonetheHilarapseudochorica Strobl, 1892. Erroneously deleted from the Finnish checklist by Iteaphilafurcata (Zetterstedt 1842). Neurigona sp. A is probably Neurigonauralensis Becker, 1918.Platypalpusarticulatus and Platypalpusmaculimanus. According to Platypalpusarticulatus Macquart by Platypalpusmaculimanus (Zett.). Upon re-examination, all Finnish material previously identified as Platypalpusarticulatus belonged to Platypalpusmaculimanus and Platypalpusarticulatoides Frey. It remains unclear whether the real Platypalpusarticulatus occurs in Finland.Rhamphomyiasp. nr.albipennis. An apparently undescribed species near Rhamphomyiaalbipennis .Sympycnuspulicarius . Sympycnusannulipes and Sympycnusdesoutteri Parent, 1925 as valid species and lists Sympycnuspulicarius as a synonym of the latter but notes that it might actually be a synonym of Sympycnusannulipes.Thrypticus sp. A is probably Thrypticusincanus Negrobov, 1967 described from the Leningrad Oblast, Russia . The type locality of this species, \u201dLappland n\u00e4ra Tjuonajaure\u201d, (ajaure\u201d, is in Sw"} +{"text": "AbstractTipulomorpha: families Trichoceridae, Pediciidae, Limoniidae, Cylindrotomidae and Tipulidae (Diptera) recorded from Finland.A checklist of the infraorder Trichoceridae is a small family of medium sized gnats, mostly of Holarctic distribution. Larvae live in different decaying matter like leaves, wood, fungi or dead mammals. Adults form numerous swarms that are encountered during colder fall and spring months or warmer winter days in warmer climates or during the short summer months in northern latitudes.No comprehensive and up to date key exists for north European adults or larvae, but a combination of PageBreakTipuloidea crane flies belong to the infraorder Tipulomorpha together with trichocerids aquatic habitats, but larvae may also be found on mosses, in dry soil, fungal fruiting bodies and dead wood. Cylindrotomids are herbivorous, feeding on vascular plants or mosses. Most larvae of (semi)aquatic species have open spiracles and are dependent on aerial oxygen supply, but truly aquatic species are able to withdraw dissolved oxygen through the cuticle of tracheal gills.hocerids . Followir tribes . Accordir tribes , two famAn annotated list of Finnish crane flies was provided by Nematocera Dumeril, 1805Tipulomorpha Rohdendorf, 1961infraorder TRICHOCERIDAE R\u00f3ndani, 1841CLADONEURA Scudder, 1894Diazosma Bergroth, 1913= Cladoneurahirtipenne ? TRICHOCERA Meigen, 1803Metatrichocerasg. Dahl, 1966PageBreakTrichoceragigantea Trichoceralutea Becher, 1886Trichoceramackenziei Saltrichocerasg. Krzeminska, 2002Trichoceraannulata Meigen, 1818Trichoceraarctica Lundstr\u00f6m, 1915? Trichoceraimplicata Dahl, 1976Trichoceramaculipennis Meigen, 1818Trichoceraparva Meigen, 1804Trichoceraregelationis Trichocerarufescens Edwards, 1921Trichocerasaltator fuscata Meigen, 1818= Trichocerasparsa Star\u00fd & Martinovsk\u00fd, 1996Trichocerasg. Meigen, 1803Trichocerahiemalis Trichocerainexplorata Trichoceramajor Edwards, 1921Trichocerasibirica Edwards, 1920PEDICIIDAE Osten Sacken, 1860PEDICIINAE Osten Sacken, 1860DICRANOTA Zetterstedt, 1838Dicranotasg. Zetterstedt, 1838Dicranotabimaculata Dicranotacrassicauda Tjeder, 1972Dicranotaguerini Zetterstedt, 1838Paradicranotasg. Alexander, 1934Dicranotagracilipes Wahlgren, 1905Dicranotapavida Dicranotarobusta Lundstr\u00f6m, 1912Dicranotasubtilis Loew, 1871Rhaphidolabissg. Osten Sacken, 1869Dicranotaexclusa PEDICIA Latreille, 1809Crunobiasg. Kolenati, 1859Pediciastraminea Pediciasg. Latreille, 1809Pediciarivosa TRICYPHONA Zetterstedt, 1837Tricyphonasg. Zetterstedt, 1837Tricyphonaimmaculata Tricyphonalivida Madarassy, 1881PageBreakTricyphonaschummeli Edwards, 1921Tricyphonaunicolor ULINAE Alexander, 1920ULA Haliday, 1833Ulasg. Haliday, 1833Ulabolitophila Loew, 1869Ulakiushiuensis Loew, 1869Ulamixta Star\u00fd, 1983Ulamollissima Haliday, 1833inconclusa = Ulasylvatica LIMONIIDAE Speiser, 1909CHIONEINAE R\u00f3ndani, 1841ARCTOCONOPA Alexander, 1955Arctoconopaforcipata Arctoconopaobscuripes Arctoconopazonata CHEILOTRICHIA Rossi, 1848Cheilotrichiasg. Rossi, 1848Cheilotrichiaimbuta Empedasg. Osten Sacken, 1869Cheilotrichiaareolata Cheilotrichiacinerascens nubila = Cheilotrichianeglecta CHIONEA Dalman, 1816Chioneasg. Dalman, 1816Chioneaaraneoides Dalman, 1816minuta Tahvonen, 1932= Chioneacrassipes Boheman, 1846Sphaeconophilussg. Becker, 1912Chionealutescens Lundstr\u00f6m, 1907brevirostris Tahvonen, 1932= CRYPTERIA Bergroth, 1913Crypterialimnophiloides Bergroth, 1913ERIOCONOPA Stary, 1976Erioconopadiuturna Erioconopatrivialis ERIOPTERA Meigen, 1803Eriopterasg. Meigen, 1803Eriopterabeckeri Kuntze, 1914fuscipennis misid.= PageBreakEriopteradivisa Eriopteraflavata gemina Tjeder, 1967= Eriopteragriseipennis Meigen, 1838Eriopteralutea Meigen, 1804Eriopteranielseni Meijere, 1921Eriopterapederi Tjeder, 1969Eriopterasordida Zetterstedt, 1838Eriopterasqualida Loew, 1871Eriopteratordi Tjeder, 1973GNOPHOMYIA Osten Sacken, 1860Gnophomyiaacheron Alexander, 1950Gnophomyialugubris Gnophomyiaviridipennis Gonempeda Alexander, 1924Gonempedaflava GONOMYIA Meigen, 1818Gonomyiasg. Meigen, 1818Gonomyiaabscondita Lackschewitz, 1935lucidula misid.= Gonomyiabifida Tonnoir, 1920Gonomyiadentata Meijere, 1920Gonomyiasimplex Tonnoir, 1920Gonomyiastackelbergi Lackschewitz, 1935Gonomyiatenella Teuchogonomyiasg. Alexander, 1968Gonomyiaedwardsi Lackschewitz, 1925HOPLOLABIS Osten Sacken, 1869Parilisiasg. Savchenko, 1976Hoplolabisareolata Hoplolabisvicina MOLOPHILUS Curtis, 1833Molophilussg. Curtis, 1833Molophilusappendiculatus Molophilusater Molophilusbifidus Goetghebuer, 1920Molophilusbihamatus Meijere, 1918Molophiluscinereifrons Meijere, 1920Molophiluscorniger Meijere, 1920Molophiluscrassipygus Meijere, 1918ochrescens Edwards, 1938= Molophilusflavus Goetghebuer, 1920Molophilusgriseus PageBreakMolophilusmedius Meijere, 1918Molophilusobscurus Molophilusoccultus Meijere, 1918Molophilusochraceus Molophiluspropinquus Molophiluspullus Lackschewitz, 1927NEOLIMNOPHILA Alexander, 1920Neolimnophilacarteri Neolimnophilaplacida ORMOSIA Rondani, 1856Oreophilasg. Lackschewitz, 1935Ormosiasootryeni Ormosiasg. Rondani, 1856Ormosiabrevinervis Ormosiaclavata Ormosiadepilata Edwards, 1938Ormosiafascipennis Ormosiahederae Ormosialineata Ormosialoxia Star\u00fd, 1983Ormosiapseudosimilis Ormosiaruficauda Ormosiastaegeriana Alexander, 1953PHYLLOLABIS Osten Sacken, 1877Phyllolabismacroura RHABDOMASTIX Skuse, 1890Rhabdomastixborealis Alexander, 1924Rhabdomastixlaeta Rhabdomastixparva RHYPHOLOPHUS Kolenati, 1860Rhypholophushaemorrhoidalis Rhypholophusvarius SCLEROPROCTA Edwards, 1938Scleroproctapentagonalis Scleroproctasororcula danica = SYMPLECTA Meigen, 1830Psiloconopasg. Zetterstedt, 1838Symplectalindrothi Symplectameigeni Symplectastictica Symplectasg. Meigen, 1830Symplectachosenensis PageBreakSymplectahybrida Symplectamabelana Symplectascotica Trimicrasg. Osten Sacken, 1861Symplectapilipes TASIOCERA Skuse, 1890Dasymolophilussg. Goetghebuer, 1920Tasioceraexigua Savchenko, 1973Tasiocerafuscescens Tasioceramurina LIMNOPHILINAE Bigot, 1854ADELPHOMYIA Bergroth, 1891Adelphomyiapunctum AUSTROLIMNOPHILA Alexander, 1920Archilimnophilasg. Alexander, 1934Austrolimnophilaharperi Austrolimnophilaunica DICRANOPHRAGMA Osten Sacken, 1860Brachylimnophilasg. Alexander, 1966Dicranophragmaadjunctum Dicranophragmaseparatum nemorale misid.= leucophaea misid.= ELOEOPHILA Rondani, 1856Eloeophilamaculata Eloeophilamundata Eloeophilasubmarmorata Eloeophilatrimaculata Eloeophilaverralli EPIPHRAGMA Osten Sacken, 1860Epiphragmasg. Osten Sacken, 1860Epiphragmaocellare EUPHYLIDOREA Alexander, 1972Euphylidoreadispar lineola misid.= Euphylidoreameigeni Euphylidoreaphaeostigma EUTONIA van der Wulp, 1874Eutoniabarbipes HEXATOMA Latreille, 1809Hexatomasg. Latreille, 1809Hexatomafuscipennis nubeculosa misid.= PageBreakIDIOPTERA Macquart, 1834Idiopteralinnei Oosterbroek, 1992fasciata preocc.= Idiopterapulchella pulchellavar. macropteryx = LIMNOPHILA Macquart, 1834Limnophilasg. Macquart, 1834Limnophilapictipennis Limnophilaschranki Oosterbroek, 1992punctata = NEOLIMNOMYIA Seguy, 1937Neolimnomyiasg. Seguy, 1937Neolimnomyiabatava PARADELPHOMYIA Alexander, 1936Oxyrhizasg. de Meijere, 1946Paradelphomyiafuscula Paradelphomyianigrina PHYLIDOREA Bigot, 1854Macrolabinasg. Savchenko, 1986Phylidoreanigronotata Paraphylidoreasg. Savchenko, 1986Phylidoreafulvonervosa Euphylidorealineola misid.= Phylidoreasg. Bigot, 1854Phylidoreaabdominalis Phylidoreabicolor Phylidoreaferruginea Phylidoreaheterogyna Phylidorealongicornis glabricula = Phylidoreanervosa nigricollis = Phylidoreasqualens Phylidoreaumbrarum PILARIA Sintenis, 1889Pilariadecolor Pilariadiscicollis Pilariameridiana Pilarianigropunctata fuscipennis misid.= Pilariascutellata PSEUDOLIMNOPHILA Alexander, 1919Pseudolimnophilasg. Alexander, 1919PageBreakPseudolimnophilalucorum LIMONIINAE Speiser, 1909ACHYROLIMONIA Alexander, 1965Achyrolimoniadecemmaculata ANTOCHA Osten Sacken, 1860Antochasg. Osten Sacken, 1860Antochavitripennis ATYPOPHTHALMUS Brunetti, 1911Atypophthalmussg. Brunetti, 1911Atypophthalmusinustus DICRANOMYIA Stephens, 1829Dicranomyiasg. Stephens, 1829Dicranomyiaaperta Wahlgren, 1904Dicranomyiaautumnalis Dicranomyiaconsimilis Dicranomyiadidyma Dicranomyiadistendens Lundstr\u00f6m, 1912Dicranomyiafrontalis Dicranomyiahalterata Osten Sacken, 1869Dicranomyiahandlirschi Lackschewitz, 1928Dicranomyiahyalinata Dicranomyialongipennis Dicranomyiamitis Dicranomyiamodesta Dicranomyiamoniliformis Doane, 1900Dicranomyiaomissinervis Meijere, 1918Dicranomyiapatens Lundstr\u00f6m, 1907Dicranomyiaradegasti Star\u00fd, 1993Dicranomyiasera Dicranomyiaterraenovae Alexander, 1920Dicranomyiaventralis Dicranomyiazernyi Lackschewitz, 1928Glochinasg. Meigen, 1830Dicranomyialiberta Osten Sacken, 1860Dicranomyiatristis subtristis Alexander, 1924= schineri misid.= schineriana misid.= Idiopygasg. Savchenko, 1987Dicranomyiadanica Kuntze, 1919Dicranomyiaesbeni Dicranomyiahalterella Edwards, 1921Dicranomyiaintricata Alexander, 1927PageBreakDicranomyiaklefbecki Dicranomyialulensis Dicranomyiamagnicauda Lundstr\u00f6m, 1912Dicranomyiamurina Dicranomyiaponojensis Lundstr\u00f6m, 1912Dicranomyiastigmatica Melanolimoniasg. Alexander, 1965Dicranomyiacaledonica Edwards, 1926Dicranomyiamorio Dicranomyiaoccidua Edwards, 1926Dicranomyiarufiventris Dicranomyiastylifera Lackschewitz, 1928Numantiasg. Bigot, 1854Dicranomyiafusca DICRANOPTYCHA Osten Sacken, 1860Dicranoptychacinerascens Dicranoptychafuscescens DISCOBOLA Osten Sacken, 1865Discobolaannulata Discobolacaesarea ELEPHANTOMYIA Osten Sacken, 1860Elephantomyiasg. Osten Sacken, 1860Elephantomyiaedwardsi Lackschewitz, 1932Elephantomyiakrivosheinae Savchenko, 1976HELIUS Lepeletier & Serville, 1828Heliussg. Lepeletier & Serville, 1828Heliusflavus Heliuslongirostris Heliuspallirostris Edwards, 1921LIBNOTES Westwood, 1876Afrolimoniasg. Alexander, 1965Libnotesladogensis LIMONIA Meigen, 1803Limnobiasg. Meigen, 18018Limoniabadia Limoniaflavipes Limoniamacrostigma Limoniamaculicosta Limoniamessaurea Mendl, 1971Limonianubeculosa Meigen, 1804Limoniaphragmitidis tripunctata Fabricius, 1781= Limoniastigma Limoniasylvicola PageBreakLimoniatrivittata LIPSOTHRIX Loew, 1873Lipsothrixecucullata Edwards, 1938Lipsothrixerrans METALIMNOBIA Matsumura, 1911Metalimnobiasg. Matsumura, 1911Metalimnobiabifasciata Metalimnobiacharlesi Salmela & Star\u00fd, 2008Metalimnobiaquadrimaculata Metalimnobiaquadrinotata Metalimnobiatenua Savchenko, 1976Metalimnobiazetterstedti elegans Zetterstedt, 1838 preocc.= NEOLIMONIA Alexander, 1964Neolimoniadumetorum ORIMARGA Osten Sacken, 1869Orimargasg. Osten Sacken, 1869Orimargaattenuata Orimargajuvenilis RHIPIDIA Meigen, 1818Rhipidiasg. Meigen, 1818Rhipidiamaculata Meigen, 1818duplicata = Rhipidiauniseriata Schiner, 1864CYLINDROTOMIDAE Schiner, 1863CYLINDROTOMA Macquart, 1834Cylindrotomaborealis Peus, 1952Cylindrotomadistinctissima Cylindrotomanigriventris Loew, 1849DIOGMA Edwards, 1938Diogmacaudata Takahashi, 1960Diogmaglabrata PHALACROCERA Schiner, 1863Phalacrocerareplicata TRIOGMA Schiner, 1863Triogmatrisulcata TIPULIDAE Latreille, 1802CTENOPHORINAE Osten Sacken, 1887Ctenophorini Osten Sacken, 1887tribe CTENOPHORA Meigen, 1803Ctenophorasg. Meigen, 1803Ctenophoraflaveolata PageBreakCtenophoraguttata Meigen, 1818Ctenophoranigriceps Ctenophorapectinicornis DICTENIDIA Brulle, 1833Dictenidiabimaculata PHOROCTENIA Coquillett, 1910Phorocteniavittata Tanypterini Savchenko, 1966tribe TANYPTERA Latreille, 1804Tanypterasg. Latreille, 1804Tanypteraatrata Tanypteranigricornis DOLICHOPEZINAE Osten Sacken, 1887DOLICHOPEZA Curtis, 1825Dolichopezasg. Curtis, 1825Dolichopezaalbipes Dolichopezabifida Osterbrook & Lantsov, 2011nitida of authors= TIPULINAE Latreille, 1802Prionocerini Savchenko, 1966tribe PRIONOCERA Loew, 1844Prionoceraabscondita Lackschewitz, 1933Prionocerachosenicola Alexander, 1945dimidiata misid.= absentiva misid.= Prionocerapubescens Loew, 1844Prionocerarecta Tjeder, 1948lapponica Tjeder, 1948= lackschewitzi Mannheims, 1951= Prionoceraringdahli Tjeder, 1948Prionoceraserricornis Prionocerasubserricornis proxima Lackschewitz, 1933= Prionoceraturcica Prionocerawoodoorum Brodo, 1987Tipulini Latreille, 1802tribe ANGAROTIPULA Savchenko, 1961Angarotipulatumidicornis NEPHROTOMA Meigen, 1803Nephrotomaaculeata Nephrotomaanalis Nephrotomaappendiculata Nephrotomacornicina PageBreakNephrotomacrocata Nephrotomadorsalis Nephrotomaflavescens Nephrotomalundbecki Nephrotomalunulicornis Nephrotomapratensis Nephrotomaquadristriata Nephrotomarelicta Nephrotomascurra Nephrotomasubmaculosa Edwards, 1928Nephrotomatenuipes NIGROTIPULA Hudson & Vane-Wright, 1969Nigrotipulanigra TIPULA Linnaeus, 1758Acutipulasg. Alexander, 1924Tipulafulvipennis De Geer, 1776Tipulamaxima Poda, 1761Arctotipulasg. Alexander, 1934Tipulasalicetorum Siebke, 1870nigricornis Zetterstedt, 1851= Beringotipulasg. Savchenko, 1961Tipulaunca Wiedemann, 1817hortensis Meigen, 1818= Dendrotipulasg. Savchenko, 1964Tipulaflavolineata Meigen, 1804Emodotipulasg. Alexander, 1966Tipulaobscuriventris Strobl, 1900Lindnerinasg. Mannheims, 1965Tipulabistilata Lundstr\u00f6m, 1907Tipulasubexcisa Lundstr\u00f6m, 1907Lunatipulasg. Edwards, 1931Tipulaaffinis Schummel, 1833Tipulacircumdata Siebke, 1863livida misid.= Tipulafascipennis Meigen, 1818Tipulahumilis Staeger, 1840Tipulalaetabilis Zetterstedt, 1838dilatata Schummel, 1833= Tipulalimitata Schummel, 1833Tipulalunata Linnaeus, 1758luna mistake= Tipulapeliostigma Schummel, 1833? Tipularecticornis Schummel, 1833PageBreakTipulaselene Meigen, 1830Tipulatrispinosa Lundstr\u00f6m, 1907Tipulavernalis Meigen, 1804Odonatiscasg. Savchenko, 1956Tipulanodicornis Meigen, 1818juncea Meigen, 1818= Platytipulasg. Matsumura, 1916Tipulaluteipennis Meigen, 1830Tipulamelanoceros Schummel, 1833Pterelachisussg. R\u00f3ndani, 1842Tipulacinereocincta Lundstr\u00f6m, 1907Tipulacrassicornis Zetterstedt, 1838Tipulairrorata Macquart, 1826Tipulajutlandica Nielsen, 1947Tipulakaisilai Mannheims, 1954Tipulalaetibasis Alexander, 1934Tipulaluridorostris Schummel, 1833Tipulamatsumurianassp.pseudohortensis Lackschewitz, 1932Tipulamutila Wahlgren, 1905Tipulaoctomaculata Savchenko, 1964Tipulapabulina Meigen, 1818Tipulapauli Mannheims, 1964Tipulapseudoirrorata Goetghebuer, 1921Tipularecondita Pilipenko & Salmela, 2012Tipulastenostyla Savchenko, 1964Tipulasubmarmorata Schummel, 1833meigeni Mannheims, 1966= Tipulatruncorum Meigen, 1830Tipulavaripennis Meigen, 1818pseudovariipennis misid.= Tipulawahlgreni Lackschewitz, 1925Tipulawinthemi Lackschewitz, 1932Savtshenkiasg. Alexander, 1965Tipulaalpium Bergroth, 1888Tipulabenesignata Mannheims, 1954Tipulaconfusa van der Wulp, 1883marmorata Meigen, 1818= Tipulagimmerthali Lackschewitz, 1925Tipulagrisescens Zetterstedt, 1851Tipulainterserta Riedel, 1913Tipulainvenusta Riedel, 1919Tipulalimbata Zetterstedt, 1838Tipulaobsoleta Meigen, 1818PageBreakTipulapagana Meigen, 1818Tipulasignata Staeger, 1840Tipulasubnodicornis Zetterstedt, 1838Schummeliasg. Edwards, 1931Tipulavariicornis Schummel, 1833Tipulasg. Linnaeus, 1758Tipulapaludosa Meigen, 1830oleracea misid.= Tipulasubcunctans Alexander, 1921czizeki de Jong, 1925= Vestiplexsg. Bezzi, 1924Tipulaexcisa Schummel, 1833Tipulahortorum Linnaeus, 1758Tipulalaccata Lundstr\u00f6m & Frey, 1916Tipulamontana Curtis, 1834Tipulanubeculosa Meigen, 1804Tipulapallidicosta Pierre, 1924Tipulascripta Meigen, 1830Tipulasintenisi Lackschewitz, 1933Tipulatchukchi Alexander, 1934bo Mannheims, 1967= Yamatotipulasg. Matsumura, 1916Tipulachonsaniana Alexander, 1945Tipulacoerulescens Lackschewitz, 1923Tipulacouckei Tonnoir, 1921Tipulafendleri Mannheims, 1963Tipulafreyana Lackschewitz, 1936Tipulalateralis Meigen, 1804Tipulamarginella Theowald, 1980marginata Meigen, 1818= Tipulamoesta Riedel, 1919Tipulamontium Egger, 1863Tipulapierrei Tonnoir, 1921solstitialis Westhoff, 1879= Tipulapruinosa Wiedemann, 1817Tipulaquadrivittata Staeger, 1840Trichocerajaponica Matsumura, 1915Twenty-two previously reported crane fly species were deleted from the Finnish list by PageBreak"} +{"text": "The efficacy of canakinumab (CAN), a selective, human, anti-IL-1\u03b2 monoclonal antibody, was previously demonstrated in SJIA in phase III trials using aACR-JIA response criteria3.The composite score JADASTo assess the level of disease activity in CAN-treated SJIA patients, using J10 and J27 in a 12-week pooled (phase III studies) data set.Patients, 2\u201319 years of age, with active SJIA were enrolled and received sc CAN 4 mg/kg. This post-hoc analysis focuses on a 12-week pooled dataset (from 3 phase III studies) in a total of 178 CAN-na\u00efve patients, assessing the J10 and J27 scores at Days (D) 15, 29, 57, 85, and applies the appropriate cut-off values for ID, LDA, MDA and HDA.At baseline, the median Q1,Q3] J10 for completer patients (i.e. patients who complete 12 weeks treatment) was 29.1 , and the median change from baseline at D15 and D85 was -19.4 and -21.2 , respectively. Results for J27 were very similar. The disease status at all time points for J10 and J27 are reported in Table ,Q3 J10 fIn the pooled 12-week dataset, there was a dramatic reduction in disease activity from baseline to D85, with much of the reduction taking place by D15 onwards in both completers and in the full analysis set. An increasing proportion of CAN patients achieved ID or LDA - according to J10 and J27 - in the first 12 weeks of treatment, despite corticosteroid tapering, a finding consistent with that using the previous ID definition from the phase III trials. These data confirm the early onset of effect as well as the short-term and sustained efficacy over 12 weeks of canakinumab, and suggest that JADAS may represent a useful tool to monitor treatment response.A. Ravelli Grant / Research Support from: Pfizer, Consultant for: Abbvie, Bristol Myers Squibb, Novartis, Pfizer, Roche and Johnson & Johnson, Speaker Bureau of: Abbvie, Bristol Myers Squibb, Novartis, Pfizer, Roche and Johnson & Johnson, H. Brunner Consultant for: Novartis, Genentech, Pfizer, UCB, AstraZeneca, Biogen, Boehringer-Ingelheim, Regeneron, Paid Instructor for: Novartis, Speaker Bureau of: Novartis, Genentech, N. Ruperto Grant / Research Support from: To Gaslini Hospital: Abbott, Astrazeneca, BMS, Centocor Research & Development, Eli Lilly and Company, \"Francesco Angelini\", Glaxo Smith & Kline, Italfarmaco, Novartis, Pfizer Inc., Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals Inc.,, Speaker Bureau of: Astrazeneca, Bristol Myers and Squibb, Janssen Biologics B.V.,Roche, Wyeth/Pfizer, P. Quartier Grant / Research Support from: Abbvie, BMS, Chugai-Roche, Novartis, Pfizer and SOBI, Consultant for: Abbvie, Chugai-Roche, Novartis, Pfizer, Servier and SOBI,, Speaker Bureau of: Chugai-Roche, MEDIMMUNE, Novartis, Pfizer, A. Consolaro Consultant for: Novartis, N. Wulffraat Grant / Research Support from: Abbvie, Roche, Consultant for: Novartis, Pfizer, Roche, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, C. Gaillez Shareholder of: Novartis, Employee of: Novartis, A. Martini Grant / Research Support from: The Gaslini Hospital, which is the public Hospital where I work as full time employee, has received contributions to support the PRINTO research activities from the following companies: Bristol Myers and Squibb, Centocor Research & Development, Glaxo Smith & Kline,Novartis,Pfizer Inc, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Speaker Bureau of: Abbott, Bristol MyersSquibb, Astellas, Behringer, Italfarmaco, MedImmune, Novartis, NovoNordisk, Pfizer,Sanofi,Roche, Servier, D. Lovell Grant / Research Support from: National Institutes of Health- NIAMS, Consultant for: Astra-Zeneca, Centocor, Amgen, Bristol Meyers Squibb, Abbott, Pfizer, Regeneron, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson & Johnson, Speaker Bureau of: Novartis, Roche."} +{"text": "The Journal of Experimental Orthopaedics is very fortunate to have excellent reviewers who kindly agree and spend their time reviewing manuscripts for the journal. Our reviewers work hard to ensure a rapid, rigorous and fair peer review process of each manuscript. Such peer review, focusing solely on the scientific integrity to determine the quality of the research submitted, is very critical to the success of our young journal.I wish to thank very much those reviewers who provided their time and expertise in evaluating manuscripts for the Journal of Experimental Orthopaedics in 2014/2015.Sincerely,Henning MadryEditor in ChiefReviewers 2014/2015Ashraf Abdelkafy, Ismailia, EgyptRoy Altman, Los Angeles, United States of AmericaOlufemi Ayeni, Hamilton, CanadaMagali Cucchiarini, Homburg, GermanyNikica Darabos, Zagreb, CroatiaLaura De Girolamo, Milan, ItalyPatricia D\u00edaz Rodr\u00edguez, Troy, United States of AmericaSabrina Ehnert, T\u00fcbingen, GermanyMuhammad Farooq Rai, St Louis, United States of AmericaLiang Gao, Homburg, GermanyAlan Getgood, Cambridge, United KingdomLars Goebel, Homburg, GermanyEnrique Gom\u00e9z-Barrena, Madrid, SpainTobias Gotterbarm, Heidelberg, GermanySibylle Grad, Davos, SwitzerlandFarshid Guilak, Durham, United States of AmericaAlan Hargens, San Diego, United States of AmericaEmily Hu, Palo Alto, United States of AmericaClark Hung, New York, United States of AmericaChristof Hurschler, Hannover, GermanyTao Ke, Homburg, GermanyTomonori Kenmoku, Kanagawa, JapanClemens Koesters, M\u00fcnster, GermanyElizaveta Kon, Bologna, ItalySebastian Kopf, Berlin, GermanyAlexis Lion, Luxembourg, LuxembourgChristopher Little, St Leonards, AustraliaPunyawan Lumpaopong, Phitsanulok, ThailandMarina Macias-Silva, M\u00e9xico D. F., M\u00e9xicoLaurent Malisoux, Luxembourg, LuxembourgHermann Mayr, M\u00fcnchen, GermanyBabak Moradi, Heidelberg, GermanyCaroline Mouton, Strassen, LuxembourgJason Mussell, New Orleans, United States of AmericaKoichi Nakagawa, Sakura-shi, Chiba, JapanNorimasa Nakamura, Osaka, JapanSven Nebelung, Aachen, GermanyGeoffroy Nourissat, Paris, FrancePatrick Orth, Homburg, GermanyDietrich Pape, Luxembourg, LuxembourgStephen Parada, Fort Gordon, United States of AmericaSilvia Pianigiani, Milan, ItalyBernd Rolauffs, T\u00fcbingen, GermanyClaudio Rosso, Basel, SwitzerlandRyan Rubin, New Orleans, United States of AmericaGian Salzmann, Zurich, SwitzerlandJose Sanhudo, Porto Alegre, BrazilJohn Segreti, Chicago, United States of AmericaRomain Seil, Luxembourg, LuxembourgLori Setton, Durham, United States of AmericaLazar Sijak, Belgrade, SerbiaDaniel Theisen, Luxembourg, LuxembourgJordan Trafimow, Chicago, United States of AmericaRonald van Heerwaarden, Woerden, The NetherlandsFrancesca Vannini, Bologna, ItalyPeter Verdonk, Antwerp, BelgiumWilliam Walsh, Randwick, Australia"} +{"text": "AbstractBraulidae (1 species), Camillidae (3 spp.), Diastatidae (10 spp.) and Drosophilidae (67 spp.) of Finland is presented. Campichoetinae is included as a subfamily of Diastatidae.A checklist of the Ephydroidea is now recognized as a well-supported, probably monophyletic clade of acalyptrate flies has its own treatment in this volume of ZooKeys. The families missing from Finland are the Curtonotidae, Cryptochetidae, and Nannodastiidae with uncertain affinities subfuscipes Collin, 1933= PageBreakDIASTATIDAE Hendel, 1917CAMPICHOETINAE Griffiths, 1972CAMPICHOETA Macquart, 1835Campichoetagriseola Campichoetaobscuripennis DIASTATINAE Hendel, 1917DIASTATA Meigen, 1830Diastataadusta Meigen, 1830unipunctata Zetterstedt, 1847= Diastataboreonigra Chandler, 1987Diastatacostata Meigen, 1830Diastataflavicosta Chandler, 1987Diastatafuscula Diastatanebulosa Diastataornata Meigen, 1830Diastatavagans Loew, 1864DROSOPHILIDAE Rondani, 1856STEGANINAE Hendel, 1917AMIOTA Loew, 1862Amiotasg. Loew, 1862Amiotaalbilabris Amiotaalboguttata Amiotarufescens Amiotasubtusradiata Duda, 1934CACOXENUS Loew, 1858Paracacoxenussg. Hardy & Wheeler, 1960Cacoxenusargyreator Frey, 1932LEUCOPHENGA Mik, 1886Neoleucophengasg. Oldenberg, 1915Leucophengaquinquemaculata Strobl, 1893PHORTICA Schiner, 1862Phorticasg. Schiner, 1862Phorticavariegata Fall\u00e9n, 1823STEGANA Meigen, 1830Steganasg. Meigen, 1830Steganafurta curvipennis = Steganinasg. Wheeler, 1960Steganabaechlii La\u0161tovka & M\u00e1ca, 1982Steganacoleoptrata Steganahypoleuca Meigen, 1830Steganalongifibula Takada, 1968PageBreakSteganamehadiae Duda, 1924Stegananigrithorax Strobl, 1898Steganasimilis La\u0161tovka & M\u00e1ca, 1982DROSOPHILINAE Rondani, 1856CHYMOMYZA Czerny, 1903Chymomyzaamoena Chymomyzacaudatula Oldenberg, 1914Chymomyzacostata Chymomyzadistincta Chymomyzafuscimana DROSOPHILA Fall\u00e9n, 1823Dorsilophasg. Sturtevant, 1942Drosophilabusckii Coquillett, 1901Drosophilasg. Fall\u00e9n, 1823Drosophilaezoana Takada & Okada, 1957Drosophilafunebris Drosophilahistrio Meigen, 1830Drosophilahydei Sturtevant, 1921repleta misid.= Drosophilaimmigrans Sturtevant, 1921tripunctata Becker, 1908 preocc.= Drosophilalimbata von Roser, 1840Drosophilalittoralis Meigen, 1830Drosophilalummei Hackman, 1972Drosophilamontana Stone, Griffen & Patterson, 1941ovivororum Lakovaara & Hackman, 1973= Drosophilaphalerata Meigen, 1830Drosophilapicta Zetterstedt, 1847Drosophilarepleta Wollaston, 1858Drosophilasubarctica Hackman, 1969Drosophilatestacea von Roser, 1840Drosophilatransversa Fall\u00e9n, 1823Drosophilavireni B\u00e4chli, Vilela & Haring, 2002Sophophorasg. Sturtevant, 1942Drosophilaalpina Burla, 1948Drosophilaambigua Pomini, 1940Drosophilabifasciata Pomini, 1940Drosophilaeskoi Lakovaara & Lankinen, 1974Drosophilaingrica Hackman, 1957Drosophilamelanogaster Meigen, 1830Drosophilaobscura Fall\u00e9n, 1823Drosophilasimulans Sturtevant, 1919Drosophilasubobscura Collin, 1936PageBreakDrosophilasubsilvestris Hardy & Kaneshiro, 1968silvestris Basden, 1954 preocc.= Drosophilatristis Fall\u00e9n, 1823HIRTODROSOPHILA Duda, 1924Hirtodrosophilacameraria Hirtodrosophilaconfusa Hirtodrosophilalundstroemi Hirtodrosophilaoldenbergi Hirtodrosophilatrivittata LORDIPHOSA Basden, 1961Lordiphosafenestrarum Lordiphosanigricolor MICRODROSOPHILA Malloch, 1921Microdrosophilasg. Malloch, 1921Microdrosophilacongesta Oxystylopterasg. Duda, 1924Microdrosophilazetterstedti Wheeler, 1959nigriventris preocc.= SCAPTODROSOPHILA Duda, 1923Scaptodrosophiladeflexa guyenoti = SCAPTOMYZA Hardy, 1849Hemiscaptomyzasg. Hackman, 1959Scaptomyzatrochanterata Collin, 1953Scaptomyzaunipunctum Parascaptomyzasg. Duda, 1924Scaptomyzapallida disticha = Scaptomyzasg. Hardy, 1849Scaptomyzaconsimilis Hackman, 1955Scaptomyzaflava flaveola = apicalis Hardy, 1849= Scaptomyzagraminum Scaptomyzagriseola Scaptomyzamontana Wheeler, 1949Scaptomyzateinoptera Hackman, 1955Steganastrobli Mik, 1898 misidentificationLordiphosahexasticha not found within present bordersPageBreak"} +{"text": "We regret any confusion or inconvenience this error may have caused.In the article \u201cStakeholder Perspectives on Changes in Hypertension Care Under the Patient-Centered Medical Home,\u201d the order of authors listed in the byline was incorrect. The correct order should have been, \u201cAlison J. O\u2019Donnell, DO, MPH; Hillary R. Bogner, MD, MSCE; Katherine Kellom, BA; Michelle Miller-Day, PhD; Heather F. de Vries McClintock, PhD; Elise M. Kaye, CNM; Robert Gabbay, MD, PhD; Peter F. Cronholm, MD, MSCE, FAAFP.\u201d The change was made to our website on May 3, 2016, and appears online at"} +{"text": "AbstractScathophagidae, Fanniidae and Muscidae recorded from Finland is presented. Phaoniaamicula Villeneuve, 1922 is noted from Finland for the first time.A revised checklist of the Muscoidea: Scathophagidae, Anthomyiidae, Fanniidae and Muscidae. The monophyly of the superfamily has been strongly questioned is covered in a separate paper in this issue of ZooKeys. All three are important components of the Finnish fly fauna as can be seen from the large number of species involved and the fact that the species recorded from the country represent up to one fifth of the world fauna in the case of Scathophagidae.Three of the four families of PageBreakDiptera families. Lauri Tiensuu concentrated on these families during the 1930s and Walter Scathophagidae. During the last ten years, both the fanniids LEPTOPA Zetterstedt, 1838Leptopafiliformis Zetterstedt, 1838MICROPSELAPHA Becker, 1894Micropselaphafiliformis PARALLELOMMA Strobl, 1894Chylizosoma Hendel, 1924= Parallelommamedium Becker, 1894Parallelommaparidis Hering, 1923 (see Notes)? Parallelommasellatum Parallelommavittatum PHROSIA Robineau-Desvoidy, 1830PageBreakPhrosiaalbilabris SCATHOPHAGINAE Robineau-Desvoidy, 1830ACANTHOCNEMA Becker, 1894Clinoceroidessg. Hendel, 1917Acanthocnemaglaucescens nigripes Ringdahl, 1936= ACEROCNEMA Becker, 1894Acerocnemamacrocera tiefi Becker, 1894= pokornyi Becker, 1894= ALLOMYELLA Malloch, 1923Allomyellaalbipennis Allomyellafrigida portenkoi misid.= BOSTRICHOPYGA Becker, 1894Bostrichopygacrassipes CHAETOSA Coquillett, 1898Chaetosapunctipes CLEIGASTRA Macquart, 1835Cnemopogon Rondani, 1856= Cleigastraapicalis CONISTERNUM Strobl, 1894Coniosternum Becker, 1894= Conisternumlapponicum Conisternumobscurum Conisternumtinctinerve CORDILURA Fall\u00e9n, 1810Cordylura Meigen, 1826 emend.= Cordilurasg. Fall\u00e9n, 1810Cordiluraaberrans Becker, 1894Cordiluraaemula Collin, 1958Cordiluraatrata Zetterstedt, 1846Cordiluraciliata Meigen, 1826Cordilurapicipes Meigen, 1826Cordilurapicticornis Loew, 1864Cordiluraproboscidea Zetterstedt, 1838Cordilurapubera Cordilurapudica Meigen, 1826Cordilurarufimana Meigen, 1826Cordilurasocialis freyi Hackman, 1956= Cordilurinasg. James, 1955Parallelomma Becker, 1894 preocc.= PageBreakCordiluraalbipes Fall\u00e9n, 1819Cordilurafuscipes Zetterstedt, 1838Scoliaphlepssg. Becker, 1894Cordiluraustulata Zetterstedt, 1838melanacra Loew, 1873= COSMETOPUS Becker, 1894Cosmetopusdentimana fulvipes = Cosmetopuslonga bergrothi Becker, 1900 in part= fulvipes auct. nec = Cosmetopusringdahli Andersson, 1974bergrothi Becker, 1900 in part= ERNONEURA Becker, 1894Ernoneuraargus GONARCTICUS Becker, 1894Gonarcticusabdominalis GONATHERUS Rondani, 1856Gonatherusplaniceps GIMNOMERA Rondani, 1866Cochliarium Becker, 1894= Gimnomeraalbipila Gimnomeracuneiventris Gimnomeradorsata Gimnomerahirta Hendel, 1930Gimnomeratarsea HEXAMITOCERA Becker, 1894Hexamitoceraloxoceratum HYDROMYZA Fall\u00e9n, 1823Hydromyzalivens MEGAPHTHALMA Becker, 1894Megaphthalmapallida MEGAPHTHALMOIDES Ringdahl, 1936Megaphthalmoidesunilineatus MICROPROSOPA Strobl, 1894Microprosopahaemorrhoidalis Microprosopalacteipennis Ringdahl, 1920Microprosopalineata Microprosopapallidicauda NANNA Strobl, 1894Amaurosoma Becker, 1894= Nannaarmillata Nannaarticulata PageBreakNannabispinosa Nannabrevifrons Nannafasciata Nannaflavipes minuta = multisetosa ?= Nannainermis Nannaleucostoma Nannatibiella nigripes = NORELLIA Robineau-Desvoidy, 1830Norelliatipularia (see Notes)NORELLISOMA Hendel, 1910Norellisomalituratum Norellisomaspinimanum OKENIELLA Hendel, 1907Okeniellacaudata Okenielladasyprocta ORTHACHETA Becker, 1894Orthachetapilosa PLEUROCHAETELLA Vockeroth, 1965Pleurochaetellasimplicipes POGONOTA Zetterstedt, 1860Pogonotasg. Zetterstedt, 1860Pogonotabarbata Lasioscelussg. Becker, 1894Pogonotaimmunda clavatus = Pogonotasahlbergi Becker, 1900SCATHOPHAGA Meigen, 1803Scatophaga Frabricius, 1805 emend.= Scopeuma Meigen, 1800 suppr.= Scatomyza Fall\u00e9n, 1810= Scathophagaapicalis Curtis in Ross, 1835Scathophagafurcata Scathophagaincola Becker, 1900Scathophagainquinata analis Meigen, 1826= Scathophagalitorea Scathophagalutaria Scathophagaobscurinervis Becker, 1900Scathophagapictipennis Oldenberg, 1923Scathophagascybalaria PageBreakScathophagastercoraria Scathophagasuilla SPAZIPHORA Rondani, 1856Spaziphorahydromyzina fascipes = STAEGERIA Rondani, 1856Staegeriakunzei TRICHOPALPUS Rondani, 1856Trichopalpusfraternus Trichopalpusnigribasis Curran, 1927pilirostris = Trichopalpusobscurellus subarcticus = FANNIIDAE Schnabl & Dziezicki, 1911FANNIA Robineau-Desvoidy, 1830Homalomyia Bouch\u00e9, 1834= Coelomyia Haliday, 1840= Fanniaaethiops Malloch, 1913Fanniaalpina Pont, 1970Fanniaarmata Fanniaatra Fanniacanicularis Fanniacarbonaria Fanniacarbonella Fanniacoracina Fanniacorvina halterata Ringdahl, 1918= Fanniacothurnata Fanniadifficilis Fanniafuscitibia Stein, 1920Fanniafuscula Fanniagenualis Fanniagotlandica Ringdahl, 1926Fanniahirticeps Fanniahirundinis Ringdahl, 1948Fanniaimmutica Collin, 1939Fanniaincisurata Fannialatifrontalis Hennig, 1955Fannialatipalpis Fannialepida mutica = Fannialeucosticta PageBreakFannialimbata berolinensis Hennig, 1955= Fannialucidula glaucescens auct. nec = Fannialugubrina Fannialustrator hamata = Fanniamanicata Fanniamelania ciliata = Fanniametallipennis kowarzi = Fanniaminutipalpis Fanniamollissima spathulata = Fanniamonilis Fanniapallitibia Fanniaparva Fanniapauli Pont, 1997nitida preocc.= Fanniapolychaeta Fanniapostica Fanniaposticata pretiosa = Fanniarabdionata Karl, 1940Fanniaringdahlana Collin, 1939umbrosa auct. nec = Fanniarondanii carbonaria preocc.= aerea misid.= Fanniascalaris subscalaris Zimin, 1946= Fanniaserena Fanniasimilis Fanniaslovaca Gregor & Rozko\u0161n\u00fd, 2005Fanniasociella Fanniaspathiophora Malloch 1918nodulosa Ringdahl, 1926= Fanniaspeciosa Fanniastigi Rognes, 1982Fanniasubatripes d\u2019Assis-Fonseca, 1967Fanniasubpellucens Fanniasubpubescens Collin, 1958PageBreakFanniatuberculata Fanniaumbratica Collin, 1939Fanniaumbrosa subumbrosa Ringdahl, 1934= Fanniaverrallii Fanniavesparia Fanniavespertilionis Ringdahl, 1934PIEZURA Rondani, 1844Platycoenosia Strobl, 1894= Piezuragraminicola boletorum = mikii = Piezurapardalina graminicola auct. nec = MUSCIDAE Latreille, 1802ACHANTHIPTERINAE Hennig, 1962ACHANTHIPTERA Rondani, 1856Achanthipterarohrelliformis inanis preocc.= COENOSIINAE Verrall, 1888Coenosiini Verrall, 1888tribe COENOSIA Meigen, 1826Caricea Robineau-Desvoidy, 1830= Oplogaster Rondani, 1856= Dexiopsis Pokorny, 1893= Coenosiaacuminata Strobl, 1898annulipes Ringdahl, 1932= Coenosiaagromyzina Coenosiaambulans Meigen, 1826Coenosiabilineella Coenosiacampestris sexnotata auct. nec Meigen, 1826= Coenosiacomita (see Notes)? ovulifera Tiensuu, 1938= Coenosiadealbata fulvicornis = Coenosiaflavimana albatella = Coenosiahumilis Meigen, 1826Coenosiaintermedia Coenosialacteipennis Coenosialineatipes PageBreakalbicornis misid.= Coenosiameans Meigen, 1826Coenosiamollicula Coenosiaoctopunctata Coenosiapaludis Tiensuu, 1939Coenosiapedella decipiens Meigen, 1826= Coenosiaperpusilla Meigen, 1826Coenosiapudorosa Collin, 1953Coenosiapulicaria Coenosiapumila Coenosiapygmaea Coenosiaruficornis Macquart, 1835litoralis = Coenosiarufipalpis Meigen, 1826flavicauda Ringdahl, 1937= Coenosiasallae Tiensuu, 1938Coenosiatestacea tricolor = alleni d\u2019Assis-Fonseca, 1966= Coenosiatigrina Coenosiatrilineella trilineata emend.= Coenosiaverralli Collin, 1953steini Verrall, 1912 preocc.= LIMNOSPILA Schnabl, 1902Limnospilaalbifrons LISPOCEPHALA Pokorny, 1893Lispocephalaalma Lispocephalaerythrocera Lispocephalafalculata Collin, 1963Lispocephalafuscitibia Ringdahl, 1944Lispocephalapallipalpis Lispocephalaspuria vitripennis Ringdahl, 1951= Lispocephalaverna MACRORCHIS Rondani, 1877Macrorchismeditata PSEUDOCOENOSIA Stein, 1916Pseudocoenosiaabnormis Stein, 1916Pseudocoenosiasolitaria longicauda = SCHOENOMYZA Haliday, 1833PageBreakSchoenomyzalitorella Limnophoriini Villeneuve, 1902tribe LIMNOPHORA Robineau-Desvoidy, 1830Limnophoranigripes Limnophorapandellei S\u00e9guy 1923 (see Notes)Limnophorariparia Limnophorarotundata Collin, 1930Limnophoratigrina notata preocc.= Limnophoratriangula Limnophorauniseta Stein, 1916LISPE Latreille, 1796Lispeconsanguinea Loew, 1858Lispehydromyzina Fall\u00e9n, 1825Lispelitorea Fall\u00e9n, 1825Lispemelaleuca Loew, 1847Lispepygmaea Fall\u00e9n, 1825Lispetentaculata Lispeuliginosa Fall\u00e9n, 1825SPILOGONA Schnabl, 1911Spilogonaaerea Spilogonaalbisquama Spilogonaalpica Spilogonaarenosa Spilogonaatrisquamula Hennig, 1959Spilogonabaltica Spilogonabrunneifrons Ringdahl, 1931Spilogonabrunneisquama Spilogonacarbonella Spilogonacontractifrons Spilogonadenigrata Spilogonadepressiuscula Spilogonadepressula Spilogonadispar funeralis Rondani, 1866= Spilogonafalleni Pont, 1984litorea auct. nec = Spilogonakrogerusi micans misid.= Spilogonaleucogaster Spilogonamalaisei Spilogonamarginifera Hennig, 1959marginalis preocc.= PageBreakSpilogonameadei Spilogonamegastoma Spilogonanigriventris Spilogonanitidicauda Spilogonanovemmaculata Spilogonaopaca Spilogonapacifica vana = Spilogonapalmeni Spilogonapseudodispar spinitibia = Spilogonapusilla Spilogonaquinquelineata Spilogonasemiglobosa Spilogonasororcula zetterstedti preocc.= Spilogonaspectabilis Spilogonasurda Spilogonatenuis Hennig, 1959Spilogonatornensis Spilogonatriangulifera Spilogonatrianguligera insularis = Spilogonatrigonata Spilogonatundrae macropyga = Spilogonatundrica Spilogonavarsaviensis glauca = Spilogonaveterrima VILLENEUVIA Schnabl & Dziedzicki, 1911Villeneuviaaestuum AZELIINAE Robineau-Desvoidy, 1830Azeliini Robineau-Desvoidy, 1830tribe AZELIA Robineau-Desvoidy, 1830Azeliaaterrima Azeliacilipes Azeliagibbera Azeliamonodactyla Loew, 1874Azelianebulosa Robineau-Desvoidy, 1830macquarti = Azeliatrigonica Hennig, 1956nuda Hennig, 1956= PageBreakAzeliatriquetra Azeliazetterstedtii Rondani, 1866DRYMEIA Meigen, 1826Pogonomyia Rondani, 1871= Trichopticoides Ringdahl, 1931= Drymeiahamata Drymeiatetra Drymeiavicana decolor = HYDROTAEA Robineau-Desvoidy, 1830Ophyra Robineau-Desvoidy, 1830= Lasiops Meigen, 1838= Hydrotaeaaenescens Hydrotaeaalbipuncta Hydrotaeaanxia bispinosa = Hydrotaeaarmipes occulta = Hydrotaeabasdeni Collin, 1939Hydrotaeaborussica Stein, 1899Hydrotaeacyrtoneurina Hydrotaeadentipes Hydrotaeadiabolus ciliata preocc.= bimaculata = Hydrotaeafloccosa Macquart, 1835armipes auct. nec = Hydrotaeaignava leucostoma = Hydrotaeairritans Hydrotaeameridionalis Portschinsky, 1882Hydrotaeameteorica Hydrotaeamilitaris Hydrotaeanidicola Malloch, 1925Hydrotaeapalaestrica Hydrotaeapandellei Stein, 1899Hydrotaeaparva Meade, 1889Hydrotaeapellucens Portschinsky, 1879Hydrotaeapilipes Stein, 1903Hydrotaeapilitibia Stein, 1916Hydrotaearingdahli Stein, 1916Hydrotaeascambus Hydrotaeasimilis Meade, 1887PageBreakHydrotaeatuberculata Rondani, 1866Hydrotaeavelutina Robineau-Desvoidy, 1830POTAMIA Robineau-Desvoidy, 1830Dendrophaonia Malloch, 1923= Potamialittoralis Robineau-Desvoidy, 1830querceti = THRICOPS Rondani, 1856Alleostylus Schnabl, 1888= Thricopsaculeipes Thricopsalbibasalis sudeticus auct. nec = Thricopscoquilletti Thricopscunctans hirsutulus auct. nec = Thricopsdiaphanus Thricopsfoveolatus Thricopsgenarum sundewalli = Thricopshirtulus subrostratus = Thricopsinnocuus Thricopslividiventris Thricopslongipes Thricopsnigrifrons Thricopsnigritellus Thricopsrostratus Thricopsrufisquamus penicillatus = Thricopssemicinereus Thricopssepar Thricopssimplex Reinwardtiini Brauer & Bergenstamm, 1889tribe MUSCINA Robineau-Desvoidy, 1830Muscinaangustifrons Muscinalevida assimilis = Muscinapascuorum Muscinaprolapsa pabulorum = Muscinastabulans MUSCINAE Latreille, 1802Muscini Latreille, 1802tribe EUDASYPHORA Townsend, 1911PageBreakEudasyphoracyanicolor Eudasyphorazimini MESEMBRINA Meigen, 1826Hypodermodes Townsend, 1912= Mesembrinaintermedia Zetterstedt, 1848?Mesembrinameridiana Mesembrinamystacea Mesembrinaresplendens Wahlberg, 1844MORELLIA Robineau-Desvoidy, 1830Morelliasg. Robineau-Desvoidy, 1830Morelliaaenescens Robineau-Desvoidy, 1830Morelliahortorum Morelliapodagrica Ziminiellasg. Nihei & Carvalho, 2007Morelliasimplex MUSCA Linnaeus, 1758Muscaautumnalis De Geer, 1776corvina Fabricius, 1781= Muscadomestica Linnaeus, 1758Muscatempestiva Fall\u00e9n, 1817NEOMYIA Walker, 1859Orthellia Robineau-Desvoidy, 1863= Neomyiacornicina caesarion = fennica = Neomyiaviridescens cornicina auct. nec = POLIETES Rondani, 1866Polietesdomitor albolineatus = Polieteslardarius Polietesnigrolimbatus Polietessteinii PYRELLIA Robineau-Desvoidy, 1830Pyrelliavivida Robineau-Desvoidy, 1830cadaverina auct. nec = Stomoxyini Meigen, 1824tribe HAEMATOBIA Le Peletier & Serville, 1828Lyperosia Rondani, 1856= Haematobiairritans HAEMATOBOSCA Bezzi, 1907Haematoboscaalcis Snow, 1891crassipalpis = PageBreakHaematoboscastimulans STOMOXYS Geoffroy, 1762Stomoxyscalcitrans MYDAEINAE Verrall, 1888GRAPHOMYA Robineau-Desvoidy, 1830Graphomyamaculata Graphomyaminor Robineau-Desvoidy, 1830GYMNODIA Robineau-Desvoidy, 1863Brontaea Kowarz, 1873= Gymnodiahumilis HEBECNEMA Schnabl, 1889Hebecnemafumosa Hebecnemanigra vespertina auct. nec = Hebecnemanigricolor Hebecnemaumbratica Hebecnemavespertina affinis Malloch, 1921= MYDAEA Robineau-Desvoidy, 1830Mydaeaaffinis Meade, 1891discimana Malloch, 1920= Mydaeaancilla Mydaeaanicula Mydaeacorni Scopoli, 1763pagana preocc.= scutellaris Robineau-Desvoidy, 1830= Mydaeadeserta Mydaeadetrita electa = Mydaeahumeralis Robineau-Desvoidy, 1830tincta = Mydaeanebulosa Mydaeaobscurella Malloch, 1921bengtssoni Ringdahl, 1924= Mydaeaorthonevra detrita auct. nec = Mydaeapalpalis Stein, 1916Mydaeasetifemur Ringdahl, 1924Mydaeasootryeni Ringdahl, 1928Mydaeaurbana MYOSPILA Rondani, 1856Myospilabimaculata Myospilameditabunda PageBreakOPSOLASIA Coquillett, 1910Opsolasiaorichalcea PHAONIINAE Malloch, 1917Phaoniini Malloch, 1917tribe HELINA Robineau-Desvoidy, 1830Helinaabdominalis Helinaallotalla Helinaannosa Helinaatricolor denudata = denutata emend.= Helinabohemani Helinacelsa quadrimaculata preocc.= quadrimaculella Hennig, 1957= Helinaciliata Karl, 1929 (see Notes)? Helinaciliatocosta ciliatocostata emend.= Helinacilipes Helinacinerella vanderwulpi = calceata misid.= Helinaconfinis anceps = Helinaconsimilis Helinacothurnata obscuripes auct. nec = Helinadaicles binotata = Helinadepuncta Helinaevecta lucorum preocc.= laetifica = Helinaflavisquama Helinafratercula Helinafulvisquama Helinaimpuncta Helinalatitarsis Ringdahl, 1924Helinalaxifrons Helinalongicornis Helinaluteisquama Helinamaculipennis obscuripes = PageBreakHelinaobscurata Helinapertusa Helinaprotuberans Helinapubiseta Helinaquadrinotata Helinaquadrum Helinareversio duplicata = duplaris auct. nec = communis = Helinasetiventris Ringdahl, 1924Helinasexmaculata uliginosa preocc.= punctata = Helinaspinicosta Helinasqualens borealis = Helinasubvittata rothi Ringdahl, 1939= marmorata auct. nec = Helinatetrastigma flagripes = Helinatrivittata atripes = Helinaveterana Helinavicina suecica Ringdahl, 1924= LOPHOSCELES Ringdahl, 1922Lophoscelescinereiventris cristata = Lophoscelesfrenatus Lophosceleshians Lophoscelesmutatus PHAONIA Robineau-Desvoidy, 1830Wahlgrenia Ringdahl, 1929= Dialytina Ringdahl, 1945= Phaoniaaeneiventris cinctinervis = Phaoniaalpicola Phaoniaamabilis Phaoniaamicula Villeneuve, 1922 (see Notes)Phaoniaangelicae basalis = PageBreakPhaoniaangulicornis erinacea = Phaoniaapicalis Stein, 1914Phaoniaatriceps Phaoniaatrocyanea Ringdahl, 1916Phaoniacanescens Stein, 1916Phaoniaconsobrina Phaoniaczernyi Hennig, 1963steinii Czerny, 1900 preocc.= Phaoniaerrans erratica preocc.= Phaoniaerronea Phaoniafalleni vagans preocc.= Phaoniafugax Tiensuu, 1946Phaoniafuscata Phaoniagobertii Phaoniagracilis Stein, 1916Phaoniagrandaeva Phaoniahalterata Phaoniahybrida Phaoniaincana Phaoniajaroschewskii crinipes Stein, 1913= Phaoniakowarzii fulvicornis Tiensuu, 1936= Phaonialaeta Phaonialatipalpis Schnabl, 1911umbraticola d\u2019Assis-Fonseca, 1957= Phaonialongicornis Stein, 1916Phaonialugubris morio = Phaoniamagnicornis Phaoniameigeni Pont, 1986lugubris auct. nec = Phaoniamystica vittifera = Phaonianymphaearum nitida = Phaoniapallida Phaoniapallidisquama Phaoniapalpata Phaoniaperdita Phaoniapratensis PageBreaklaeta auct. nec = Phaoniarufipalpis Phaoniarufiventris populi = Phaoniaserva Phaoniasteinii Phaoniasubfuscinervis Phaoniasubventa variegata = Phaoniataigensis Zinovjev, 1987Phaoniatiefii Schnabl, 1888Phaoniatrimaculata (Bouch\u00e9)servaeformis Ringdahl, 1916= Phaoniatuguriorum signata = Phaoniavalida viarum = erratica auct. nec = Phaoniavillana Robineau-Desvoidy, 1830mystica auct. nec = Phaoniavivida austriaca = Phaoniawahlbergi Ringdahl, 1930Phaoniazugmayeriae humeralis ?= humerella = Coenosiafemoralis misidentifiedFanniabarbata not found within present bordersFannialineata not found within present bordersFannianigra Malloch, 1910 not found within present bordersHydrotaeaglabricula Limnophorapollinifrons Stein, 1916 not found within present bordersPhaoniabitincta misidentifiedScathophagacalida Haliday in Curtis, 1832 not found within present bordersSpilogonaacrostichalis Spilogonanorvegica Spilogonaobscuripennis not found within present bordersSpilogonaseptemnotata misidentifiedSpilogonasetigera Spilogonaspininervis PageBreakCoenosiacomita . Collected only from Salla. The type locality of Coenosiaovulivera Tiensuu, Vuorij\u00e4rvi, is now Russian territory . This species was first recorded from Finland by Norelliatipularia a nomen dubium and probably synonymous with Norelliaspinipes Meigen, but Parallelommaparidis Hering, 1923. This name was synonymized with Parallelommavittatum (Meigen) by Parallelommaparidis and upheld the synonymy. Not everyone agrees with this synonymy (Paris (Liliaceae) and adults caught among Dactylorhiza (Orchidaceae) suggest that two species are involved.synonymy . FinnishPhaoniaamicula Villeneuve, 1922. New to Finland. Recorded as Phaoniasp. nr.halterata by Ab: Turku, Ruissalo (67093:32336), 3.vii.2008, leg K. Winqvist, 1 male."} +{"text": "Corrigenda for three articles. et al. , Vishnupriya, Suresh, Gunasekaran et al. , and Vishnupriya, Suresh, Sakthi et al. .The schemes and chemical names are corrected in three related papers: Vishnupriya, Suresh, Bharkavi"} +{"text": "Canakinumab (CAN), a selective, fully human, anti-interleukin-1\u03b2 monoclonal antibody, has been shown to be efficacious in SJIA patients (pts) in 2 phase 3 trials: Trial 1 and Trial 2 . In Trial 1, statistically significantly more CAN than PBO group pts achieved an adapted pediatric ACR 30 response and in Trial 2, CAN allowed successful reduction/discontinuation of steroids and significantly reduced risk of flare. Safety profile of CAN was in line with expectations for a biologic agent in active SJIA. The persistent disabling features of SJIA and chronic pain can have a negative impact on health-related quality of life (hrqol). These outcomes were evaluated in the CAN phase 3 program.To report pt-reported functional ability and hrqol outcomes from the CAN phase 3 program.\u00a9]), pain , and physical (phs) and psychosocial (pss) health status in 5-18 year old pts., according to the Child Health Questionnaire-Parent Form (CHQ-PF50).The phase 3 analysis included 84 pts in Trial 1 and 177 pts in Trial 2 in Part 1, and 100 rolled into Part 2 . Pt-reported assessments included functional ability , which was ~3.6 \u00d7 the minimal clinically important difference of -0.19. The LSM in overall pain intensity were significantly lower (both p < 0.0001) in the CAN group vs PBO both at Day 15 and Day 29 . CHQ-PF50 phs and pss scores also showed significant improvements over time . Improvements in CHAQ disability, CHQ-PF50 phs and pss, and VAS pain scores were also observed in Trial 2 , Consultant for: Abbott, Astrazeneca, Bristol Myers and Squibb, Janssen Biologics B.V., Ely Lilly and Company, Francesco A, Glaxo Smith & Klime, Italfarmaco, Novartis, Pfizer Inc., Roche, Sanofi Aventis, Schwarz Biosciences gmbh, Xoma, Wyeth Pharmaceuticals, Speakers Bureau: Astellas, Astrazeneca, Bristol Myers and Squibb, Glaxo Smith & Kline, Italfarmaco, medimmune, Novartis, D. Lovell Grant/Research Support from: NIH, Consultant for: Astra-Zeneca, Centocor, Jannsen, Wyeth, Amgen, Bristol-Meyers Squibb, Abbott, Pfizer, Regeneron, Hoffman La-Roche, Novartis, Genentech, Speakers Bureau: Genentech, Roche.P. Quartier Grant/Research Support from: Abbvie, Chugai-Roche, Novartis, Pfizer, Consultant for: Abbvie, BMS, Chugai-Roche, Novartis, Pfizer, Servier, Sweedish Orphan Biovitrum, Speakers Bureau: Chugai-Roche, Novartis, Pfizer, N. Ruperto Grant/Research Support from: To Gaslini Hospital: Abbott, Astrazeneca, BMS, Centocor Research & Development, Eli Lilly and Company, \"Francesco Angelini\", Glaxo Smith & Kline, Italfarmaco, Novartis, Pfizer Inc., Roche, Sanofi Aventis, Schwarz Biosciences gmbh, Xoma, Wyeth Pharmaceuticals Inc., Speakers Bureau: Astrazeneca, Bristol Myers and Squibb, Janssen Biologics B.V., Roche, Wyeth/Pfizer, N. Wulffraat Consultant for: Novartis, Pfizer, Roche, H. Brunner Consultant for: Novartis, Genentech, Medimmune, EMD Serono, AMS, Pfizer, UCB, Jannsen, Speakers Bureau: Genentech, R. Brik Grant/Research Support from: Novartis, Consultant for: Novartis, L. Mccann: None declared., H. Foster Grant/Research Support from: Pfizer, biomarin, Speakers Bureau: Pfizer, M. Frosch: None declared., V. Gerloni: None declared., L. Harel: None declared., C. Len: None declared., K. Houghton: None declared., R. Joos: None declared., K. Abrams Shareholder of: Novartis, Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, S. Kessabi Employee of: Novartis, A. Martini Grant/Research Support from: Abbott, Astrazeneca, Bristol Myers and Squibb, Janssen Biologics B.V., Ely Lilly and Company, \"Francesco Angelini\", Glaxo Smith & Kline, Italfarmaco, Novartis, Pfizer Inc., Roche, Sanofi Aventis, Schwarz Bisciences, gmbh, Xoma, Wyeth Pharmaceuticals Inc.(Consulting fee). The GASLINI hospital which is a public hospital where I work as full time employee has received contributions to support the research activities of the network of PRINTO ("} +{"text": "Although fever and hypothermia are common abnormal physical signs observed in patients admitted to intensive care units (ICU), little data exist on their optimal management. The objective of this study was to describe contemporary practices and determinants of management of temperature abnormalities among patients admitted to ICUs.Site leaders of the multi-national EUROBACT study were surveyed regarding diagnosis and management of temperature abnormalities among patients admitted to their ICUs.Of the 162 ICUs originally included in EUROBACT, responses were received from 139 (86%) centers in 23 countries in Europe (117), South America (8), Asia (5), North America (4), Australia (3) and Africa (2). A total of 117 (84%) respondents reported use of a specific temperature threshold in their ICU to define fever. A total of 14 different discrete levels were reported with a median of 38.2\u00b0C . The use of thermometers was protocolized in 91 (65%) ICUs and a wide range of methods were reportedly used, with axillary, tympanic and urinary bladder sites as the most common as primary modalities. Only 31 (22%) of respondents indicated that there was a formal written protocol for temperature control among febrile patients in their ICUs. In most or all cases practice was to control temperature, to use acetaminophen, and to perform a full septic workup in febrile patients and that this was usually directed by physician order. While reported practice was to treat nearly all patients with neurological impairment and most patients with acute coronary syndromes and infections, severe sepsis and septic shock, this was not the case for most patients with liver failure and fever.A wide range of definitions and management practices were reported regarding temperature abnormalities in the critically ill. Documenting temperature abnormality management practices, including variability in clinical care, is important to inform planning of future studies designed to optimize infection and temperature management strategies in the critically ill. Temperature abnormalities occur in approximately 50% of patients admitted to adult intensive care units (ICUs) and are associated with increased mortality in select groups of patients -8. AlthoA number of small clinical trials have investigated temperature control strategies in febrile critically ill patients -14,19. DA survey exploring fever management practices was developed specifically for this study . Analyses were primarily descriptive. Non-normally distributed (skewed) continuous data were reported as medians with interquartile ranges (IQR) and groups were compared using the Mann-Whitney test. Grouped categorical data were compared using the Fisher's exact test or chiP = 0.018) and were more likely to be from non-European centers .Of the 162 ICUs originally included in EUROBACT, responses were received from 139 (86%) centers in 23 countries in Europe (117), South America (8), Asia (5), North America (4), Australia (3) and Africa (2). There were no statistically significant differences among responders and non-responders with regard to reported average ICU case-fatality rate, ICU specialty type, university-affiliation or public/private ICU. However, non-respondents had significantly larger ICUs reported use of a specific temperature threshold in their ICU to define fever. A total of 14 different discrete levels were reported to define fever ranging from 37.0\u00b0C to 40.0\u00b0C with a median of 38.2\u00b0C . The use of thermometers was protocolized in 91 (65%) ICUs. A wide range of temperature measurement methods were used, with axilla, pulmonary artery catheter, and rectal thermometry the most commonly reported modalities reported these were only done by specific physician order, 25 (18%) stated these were routinely performed by nurses unless requested otherwise, 24 (17%) routinely performed these per protocol based on a predefined temperature threshold, and 7 (5%) indicated use of other approaches. When asked to report a usual threshold of hypothermia that would trigger the ordering of blood cultures, 129 (93%) responses were received. Fourteen different discrete levels were reported which ranged from 34\u00b0C to 38.3\u00b0C with a median of 36.0\u00b0C . In the event of hypothermia, 104 (75%) performed cultures only with specific physician order, 21 (15%) routinely cultured per protocol based on a specific temperature threshold, 10 (7%) routinely cultured blood as performed by nurses unless requested otherwise, and 4 (3%) indicated other approaches.When asked specifically about ordering blood cultures in response to new fever or hypothermia, 136 (98%) indicated systematic use of aerobic culture bottles, 113 (81%) systematic use of anaerobic bottles, 37 (27%) systematic use of bottles for fungi, and 42 (30%) indicated that the type of bottles were specifically defined by physician order.P = 0.034) and were more likely to use acetaminophen for fever control .In the management of patients, only 31 22%) respondents indicated that there was a formal written protocol in place for temperature control among febrile patients in their ICUs. In most or all cases the practice was to control temperature, to use acetaminophen and to perform a septic workup in febrile patients and that this was usually directed by physician order as shown in Table 2% responAn exploratory analysis was conducted by comparing survey results with clinical variables obtained in the original EUROBACT study. No significant relationships were found between reported temperature thresholds in the survey for defining fever and median time to adequate therapy, case-fatality rate or the proportion of patients with fever in the original study. In addition, participating ICUs were dichotomized into those that had case-fatality rates of 30% or less (low) and those that were greater than 30% (high) for hospital acquired bloodstream infection requiring ICU admission. No relationship between any of the survey variables and high or low case-fatality rate was observed.This study documents major variability in reported practices in the diagnosis and management of temperature abnormalities in critically ill patients worldwide. A total of 14 different discrete thresholds for fever were reported in this study confirming that there is not widespread accepted levels or consensus for the diagnosis of fever. Furthermore, the modalities used to measure temperature varied widely across study centers Hospital, Athens, Greece; Georgios Anthopoulos, Georgios Choutas, Intensive Care Unit, 251 Air Force General Hospital, Athens, Greece; Anastasia Koutsikou, Ilona Nikolaidou, Intensive Care Unit , General Hospital of Athens \"Asklepieion Voulas,\" Athens, Greece; Vasileios Bekos, Anna Spring, Intensive Care Unit, Naval Hospital of Athens, Athens, Greece; Haralambos Paskalis, Vassiliki Psallida, Intensive Care Unit, Hygeia General Hospital, Athens, Greece; Aikaterini Ioakeimidou, Alexandra Lahana, Intensive Care Unit, Athens Veterans Hospital (Nimits), Athens, Greece; Paraskevi Plantza, Aikaterini Nodarou, ICU Kaa Sotiria General Hospital, Sotiria General Hospital, Athens, Greece; Antonia Koutsoukou, Magdalini Kyriakopoulou, ICU 1st Resp. Medicine Depart. Athens University, Sotiria General Hospital, Athens, Greece; Martha Michalia, Phyllis Clouva-Molyvdas, Department of Critical Care Medicine, \"Thriassion\" General Hospital of Eleusis, Elefsina, Athens, Greece; Dimitrios Sfyras, Christos Georgiadis, Intensive Care Unit, General Hospital of Lamia, Lamia, Greece; Pavlos Polakis, Spiros Papanikolaou, Intensive Care Unit, \"Peiraiko\" Therapeftirio, Pireus, Greece; Christos Christopoulos, Efstratia Vrettou, Intensive Care Unit, General Hospital of Pyrgos, Pyrgos, Greece; Kostoula Arvaniti, Dimitrios Matamis, Critical Care Department, \"Papageorgiou\" General Hospital of Thessaloniki, Thessaloniki, Greece; Theoniki Paraforou, Kyriaki Spiropoulou, ICU, General Hospital of Trikala, Trikala, Greece; Dimitris Georgopoulos, Maria Klimathianaki, Critical Care Department, University General Hospital of Heraklion, Crete, Heraklion, Greece; Georgios Nakos, Vasilios Koulouras, Critical Care Department, University Hospital of Ioannina, Ioannina, Greece; Apostolos Komnos, Achilleas Chovas, Department of Critical Care Medicine, General Hospital of Larisa, Larisa, Greece; Athanasios Prekates, Eleni Magira, Critical Care Department, \"Tzaneion\" General Hospital of Pireus, Pireus, Greece; Maria Giannakoy, Eleni Gkeka, Intensive Care Unit, \"Ahepa\" General Hospital, Thessaloniki, Greece; Eleni Antoniadou, Elli Antypa, Critical Care Department, General Hospital of Thessaloniki \"G. Genimatas,\" Thessaloniki, Greece; Nikoletta Gritsi-Gerogianni, Christina Kydona, Critical Care Department, \"Hippokrateion\" General Hospital of Thessaloniki, Thessaloniki, Greece; Epaminondas Zakynthinos, Nikolas Tzovaras, Critical Care Department, University Hospital of Larissa, Larissa, Greece; Akos Csomos, Surgical Intensive Care, Semmelweis University, Budapest, Hungary; Cs\u00f3ka G\u00e1bor, S\u00fcrg\u0151ss\u00e9gi Beteg Ell\u00e1t\u00f3 Egys\u00e9g, F\u0151v\u00e1rosi \u00d6nkorm\u00e1nyzat Szent Imre K\u00f3rh\u00e1z, Budapest, Hungary; Borbala Mikos, Gy\u00f6rgy Velkey, Pediatric Anaesthesia and Intensive Care Unit, Bethesda Children's Hospital of The Hungarian Reformed Church, Budapest, Hungary; Eszter Vit\u00e1lis, Auguszta Seb\u00e9szet Intenz\u00edv, The Medical And Health Science Centre of the University of Debrecen, Debrecen, Hungary; N\u00f3ra, \u00c1gota Kov\u00e1cs, Aito Fl\u00f3r Ferenc, Kistarcsa, Hungary; Lajos Bogar, Tamas Kiss, Department of Anaesthesia and Intensive Therapy, University of P\u00e9cs, P\u00e9cs, Hungary; Zollei Eva, Medical ICU, University of Szeged, Szeged, Hungary; Valerio Mangani, Giorgio Tulli, Intensive Care Unit, S. Giovanni Di Dio, Firenze, Italy; Guido Stefania, Ronco Chiara, Centro Rianimazione, Maggiore Della Carit\u00e0, Novara, Italy; Massimo Antonelli, Luca Montini, Rianimazione E Terapia Intensiva, Policlinico Universitario A. Gemelli, Rome, Italy; Monica Rocco, Giorgia Citterio, Centro Di Rianimazione, Policlinico Umberto I, Rome, Italy; Shigeki Fujitani, Emergency & Critical Care Medicine, St. Marianna University School of Medicine Hospital, Kanagawa, Japan; Koji Hosokawa, Intensive Care Unit, Kyoto Prefectural University of Medicine, Kyoto, Japan; Motaouakkil Said, Charra Boubaker, Reanimation Medicale, CHU Ibn Rochd, Casablanca, Morocco; Marcus Schultz, Annelou Van Der Veen, ICU, Academic Medical Center, Amsterdam, The Netherlands; Heleen Aardema, Intensive and Respiratory Care Unit, University Medical Center Groningen, Groningen, The Netherlands; Dennis Bergmans, Rik Schoemakers, Department of Intensive Care, Maastricht University Medical Centre, Maastricht, The Netherlands; Ronald Wesselink, ICU, St. Antonius Ziekenhuis, Nieuwegein, The Netherlands; Evelien A.N. Oostdijk, Marc J.M. Bonten, Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, The Netherlands; Iwona Dragan, ICU, General Hospital, Gniezno, Poland; W\u0142odzimierz Kostyrka, Medical ICU, Szpital Powiatowy, Ostr\u00f3w Wielkopolski, Poland; Barbara Tamowicz, Adam Mikstacki, Department of Anaesthesiology and Intensive Therapy, Poznan University of Medical Sciences, Regional Hospital, Poznan, Poland; Piotr Smuszkiewicz, Department of Anaesthesiology and Intensive Therapy, University Hospital, Poznan, Poland; Jacek Nadolski, Oa I It, Wielkopolska Center of Pulmonology and Thoracic Surgery, Pozna\u0144, Poland; Robert Choma, Oddzia\u0142 Anestezjologii I Intensywnej Terapii, Szpital W \u015aremie, \u015arem, Poland; Wladyslaw Koscielniak, Pawel Pietraszek, Oddzial Anestezjologii I Intesywnej Terapii, Regional Hospital Zielona Gora, Zielona Gora, Poland; Edward Maul, Servi\u00e7o De Medicina Intensiva, Hospital Central Do Funchal, Funchal, Portugal; Anabela B\u00e1rtolo, Salom\u00e9 Martins, UCIP, Chaa, Guimar\u00e3es, Guimar\u00e3es, Portugal; Isabel Miranda, Mariana Oliveira, UCIP02, Hospital De St. Ant\u00f3nio Dos Capuchos, Centro Hospitalar De Lisboa Central, E.P.E., Lisboa, Portugal; Carlos Fran\u00e7a, Ana Tornada, Smi, Hospital De Santa Maria, Lisbon, Portugal; Lu\u00eds Telo, Leonardo Ferreira, UCIP, Pulido Valente, Lisboa, Portugal; Teresa Cardoso, Unidade De Cuidados Intensivos Polivalente, Hospital De Santo Ant\u00f3nio, Porto, Portugal; Lurdes Santos, Alcina Ferreira, UCI-DI, Hospital S. Jo\u00e3o, Porto, Portugal; Jos\u00e9 Manuel Pereira, UCIP Geral, Hospital S Jo\u00e3o, Porto, Portugal; Celeste Dias, UCI Neurocriticos, Hospital Sao Joao, Porto, Portugal; Maria Concei\u00e7\u00e3o Dias, UCIPU, UCIP Urgencia, Hospital De S. Jo\u00e3o, Porto, Portugal; Ana J. Marques, Paula Castel\u00f5es, Ucipolivalente Do Chvngaia, Hospital Santos Silva, Centro Hospitalar Vila Nova De Gaia, Vila Nova Gaia, Portugal; Uros Batranovic, Srdjan Gavrilovic, Intensive Care Unit, Institute For Pulmonary Diseases of Vojvodina, Sremska Kamenica, Republic of Serbia; Daniela Filipescu, Cardiac Anesthesia and Intensive Care, Emergency Institute of Cardiovascular Diseases, Bucharest, Romania; Francisco Alvarez-Lerma, Maria Pilar Gracia, Intensive Care Unit, Hospital Del Mar, Barcelona, Spain; Fernando Armestar-Rodriguez, Eduard, Mesalles-Sanju\u00e1n, Medicina Intensiva, Hospital Universitari Germans Trias I Pujol, Badalona, Spain; Nerea Lopez De Arbina, Josep Sirvent, Servicio De Medicina Intensiva, Hospital Universitari De Girona Dr Josep Trueta, Girona, Spain; Pau Garro, UCI General, Hospital General De Granollers, Granollers (Barcelona), Spain; Juan Ram\u00f3n Cort\u00e9s Ca\u00f1ones, Unidad Cuidados Intensivos, Complexo Hospitalario Ourense Cristal Pi\u00f1or, Orense, Spain; Armando Blanco, Lara Marqu\u00e9s, Unidad De Medicna Intensiva I, Hospital Universitario Central De Asturias (HUCA), Oviedo, Spain; Josu Insausti, I\u00f1igo Martija, UCI, Hospital De Navarra, Pamplona, Spain; Jordi Valles, Ricard Ferrer, Critical Care Center, Hospital Sabadell, Sabadell, Spain; Alejandro Ubeda, Francisco Lucena, Polyvalent ICU, H.U. Valme, Seville, Spain; Maricarmen Gilavert Cuevas, UCI, Hospital Universitario Joan Xxiii-Instituto Pere Virgili, Tarragona, Spain; Rafael Zaragoza, Susana Sancho, ICU, Hospital Univ. Dr. Peset, Hospital Universitario Dr. Peset, Valencia, Spain. Markus Laube, Madeleine Rothen, Intensivstation, Spitalzentrum, Biel, Switzerland; Philippe Eggimann, Jean-Luc Pagani, Service De M\u00e9decine Intensive Adulte, Chuv, Lausanne, Switzerland; Samia Ayed, Service De Reanimation Medicale, CHU Tahar Sfar, Mahdia, Tunisia; Islem Ouanes, Fekri Abroug, R\u00e9animation Polyvalente, Chu Fattouma Bourguiba, Monastir, Tunisia; Dilek \u00d6zcengiz, Reanimation, Cukurova Medical University, Adana, Turkey; Seyhan Ya\u011far, Cardiovascular Surgery, ICU, T\u00fcrkiye Y\u00fcksek Ihtisas Hospital, Ankara, Turkey; S\u00fcheyla \u00dcnver, Yeliz Irem Tun\u00e7el, Anestesia Intensive Care Unit, Ankara Dr Abdurrahman Yurtaslan Onkoloji E. A. Hastanesi, Ankara, Turkey; Unase Buyukkocak, Esra Aykac, Intensive Care Unit and Anaesthesia, Kirikkale University, The School of Medicine Hospital, Kirikkale, Turkey; Ahmet CO\u015eAR, H\u00fcseyin O\u011fuz Yilmaz, Anesteziyoloji Ve Reanimasyon Ad Yb\u00fc, G\u00fclhane Askeri T\u0131p Akademisi, Ankara, Turkey; Arash Pirat, Pinar Zeyneloglu, Surgical Intensive Care Unit, Baskent University Hospital, Ankara, Turkey; Nermin Kelebek Girgin, Halis Akal\u0131n, Anaesthesiology and ICU, Uludag University Medical Faculty, Bursa, Turkey; Hulya Sungurtekin, Simay Serin, Anaesthesiology and ICU, Pamukkale University, Denizli, Turkey; I. Ozkan Akinci, Neuro Icu, Istanbul Medical Faculty, Istanbul, Turkey; Tayfun Adanir, Atilla Sencan, Anaesthesiology and ICU, Ataturk Training And Research Hospital, Izmir, Turkey; Ahmet Dilek, Mikail Y\u00fcksel Intensive Care Unit, Ondokuz Mayis University, School of Medicine, Samsun, Turkey; Ismail KATI, Ugur Goktas, Anaesthesia and Intensive Care Unit, Yuzuncu Yil University Medical Faculty, Van, Turkey; Ashraf El Houfi, MICU-SICU, Dubai Hospital, Dubai, United Arab Emirates.The EUROBACT Study Investigators (listed by country) are Jeffrey Lipman, Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia; Anne Leditschke, Helen Rodgers, Canberra Hospital Intensive Care Unit, Canberra Hospital, Canberra, Australia; David Milliss, Thomas Gottlieb, Intensive Care Services, Concord Hospital, NSW, Australia; Stuart Baker, Brigit Roberts, ICU, Sir Charles Gairdner Hospital, Perth, Australia; Peter Krafft, Silvia Bernreiter, Intensiv 1b, Hospital Rudolfstiftung, Vienna, Austria; Pieter Depuydt, Intensieve Zorg, Universitair Ziekenhuis Gent, Ghent, Belgium; Philippe Jamaer, ICU A3 and C3, Jessa Hospital, Campus Virga Jesse, Hasselt, Belgium; Herv\u00e9 Lebbinck, Iz Az Sint Augustinus Veurne, Veurne, Belgium; Frederico Bruzzi De Carvalho, Juliana Pereira, Centro De Terapia Intensiva, Hospital Mater Dei, Belo Horizonte, Brazil; Aline Camille Yehia, Felipe Carrh\u00e1 Machado, Ana Luiza Horta de sa Carneiro, Cti Hospital, Julia Kubitschek, Belo Horizonte, Brazil; Antonio Fagundes Jr, Unidade De Terapia Intensiva, Hospital Do Cora\u00e7\u00e3o Do Brasil, Bras\u00edlia, Brazil; Fernando Rodriguez, Cti Geral, Hospital De Cl\u00ednicas Niter\u00f3i, Niter\u00f3i, Brazil; Marcio Soares, Jorge Salluh, Cti, Instituto Nacional De Cancer, Rio de Janeiro, Brazil; Renata Beranger, ICU, S\u00e3o Lucas Hospital, Rio de Janeiro, Brazil; Marcelo Lugarinho, Cti Do Hospital De Cl\u00ednicas Mario Lioni, Hospital De Cl\u00ednicas Mario Lioni, Rio de Janeiro, Brazil; Alexandre Carvalho, Livia Reis, Uti 1-2-3, Udi Hospital, S\u00e3o Luis, Ma, Brazil; Cyntia de Lima, Uti Cl\u00ednica, Hospital Santa Izabel, Salvador, Brazil; Claudio Piras, Cpc, Vitoria Apart Hospital, Vitoria, Brazil; Eliana Caser, Jansen Falc\u00e3o, Uti Geral Adulto, Centro Integrado De Aten\u00e7a\u00f5 A Sa\u00fade, Cias Unimed Vit\u00f3ria, Vit\u00f3ria, ES, Brazil; Kevin B. Laupland, ICU, Peter Lougheed Centre, Calgary, Canada; Kevin B. Laupland, ICU, Foothills Medical Centre, Calgary, AB, Canada; Kevin B. Laupland, CVICU, Foothills Medical Centre, Calgary, AB, Canada; Kevin B. Laupland, ICU, Rockyview General Hospital, Calgary, AB, Canada; Zhidan Zhang, Xiaochun Ma, Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China; Xian Yao Wan, Jiu Zhi Zhang, Department of Intensive Care Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China; Ke-Jian Qian, Liang Xia, Intensive Care Unit, The First Affiliated Hospital of Nan Chang University, Nan Chang, China; Congshan Yang, Department of Critical Care Medicine, Zhongda Hospital, Southeast University, Nanjing, China; Deng Lijing, Central ICU, West China Hospital of Sichuan University, Chengdu, China; Meili Duan, Department of Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, China; Tang Zhanhong, Pan Yiping, Intensive Care Unit, The First Hospital of Guangxi Medical University, Nanning, China; Wang Yongqiang, Luo Ning, ICU, Tianjin First Center Hospital, Tianjin, China; Zhou Li-Xin, LI Jin-Quan, Intensive Care Unit, The Affiliated Foshan Hospital of Sun Yat-Sen University, Foshan, China; Xian Yao Wan, ICU, Beijing Tongren Hospital, Beijing, China; Ivan Gornik, Medical Intensive Care Unit, University Hospiral Centre Zagreb, Zagreb, Croatia; Vesna Degoricija, Medical ICU, University Hospital Sisters of Mercy and University of Zagreb School of Medicine, Zagreb, Croatia; Achille Kouatchet, D\u00e9partement De R\u00e9animation M\u00e9dicale Et M\u00e9decine Hy, Chu Angers, Angers Cedex 9, France; Gaetan Plantefeve, Olivier Pajot, R\u00e9animation Polyvalente, Ch Victor Dupouy, Argenteuil, France; Hatem Kallel, Polyvalent ICU, Andr\u00e9e Rosemon, Cayenne, France; Lherm Thierry, Kalfon Pierre, R\u00e9animation Polyvalente, Louis Pasteur, Chartres, France; David Petitpas, R\u00e9animation polyvalente, Chg Ch\u00e2lons En Champagne, Ch\u00e2lons En Champagne, France; Henry Lessire, R\u00e9animation M\u00e9dicale, Ch Pasteur, Colmar, France; Christian Brun-Buisson, Tai Pham, R\u00e9animation M\u00e9dicale, Chu Henri Mondor, Cr\u00e9teil, France; Djillali Annane, Virginie Maxime, R\u00e9animation M\u00e9dicale, Chu, Garches, France; Herault Marie-Christine, Reanimation Polyvalente Chirurgicale, Chu Michallon, Grenoble, France; Sybille Merceron, Medico-Surgical ICU, Andr\u00e9 Mignot Versailles Hospital Centre, Le Chesnay, France; Eric Kipnis, Marielle Boyer-Besseyre, R\u00e9animation Chirurgicale, CHRU De Lille, Lille, France; Benoit Tavernier, Sebastien Faivre, R\u00e9animation Neurochirurgicale, CHRU de Lille, Lille, France; Voillet Francois, Renaud Lepaul Ercole, Medical Intensive Care Unit, Hopital North, Marseille, France; Vincent Willems, R\u00e9animation Polyvalente, Centre Hospitalier De Meaux, Meaux, France; Kada Klouche, Jean Philippe Delabre, Medical Intensive Care Unit, Lapeyronie University Hospital, Montpellier, France; Cartier Julien, Gleyse Brigitte, Service De R\u00e9animation Polyvalente, Ch De Mont\u00e9limar, Mont\u00e9limar, France; Sebastien Gibot, R\u00e9animation M\u00e9dicale, Hopital Central, Nancy, France; Bruno M\u00e9garbane, R\u00e9animation M\u00e9dicale Et Toxicologique, H\u00f4pital Lariboisi\u00e8re, Paris, France; Philippe Seguin, R\u00e9animation Chirurgicale, Chu De Rennes, Rennes, France; Anne Launoy, Service De R\u00e9animation Chirurgicale Hautepierre, H\u00f4pitaux Universitaires De Strasbourg, Strasbourg, France; Tixier Vincent, Medical, Gabriel Montpied, Clermont-Ferrand, France; Samir Jamali, Unit\u00e9 De Soins Intensifs, Centre Hospitalier De Dourdan, Dourdan, France; Silvia Calvino, Alexis Tabah, R\u00e9animation M\u00e9dicale, Grenoble Teaching Hospital, Grenoble, France; Michel Durand, Marine Rossi-Blancher, Reanimation Cardiovasculaire et Thoracique, Hopital Michallon, Grenoble, France; Alexandre Debrumetz, Elie Azoulay, Service De R\u00e9animation M\u00e9dicale, CHU Saint Louis, Paris, France; Julien Charpentier, Jean-Daniel Chiche, R\u00e9animation M\u00e9dicale Polyvalente, Cochin, Paris, France; Mait\u00e9 Garrouste-Orgeas, Benoit Misset, R\u00e9animation Polyvalente, Paris Saint-Joseph, Paris, France; Gernot Marx, Klinik F\u00fcr Operative Intensivmedizin Und Intermediate Care, University Hospital Aachen, Aachen, Germany; Wolfgang A. Krueger, Anaesthesiology and Intensive Care Medicine, Clinics of Constance, Constance, Germany; Thomas Felbinger, Department of Anaesthesiology, The Munich Municipal Hospitals Ltd., Munich, Germany; Alexandra Heininger, ICU 20-22, Universit\u00e4tsklinik F\u00fcr Anaesthesiologie Und Intensivmedizin, Tuebingen, Germany; Ingo Voigt, Kardiologische Intensivstation, Elisabeth Krankenhaus, Essen, Germany; Torsten Schroeder, Interdisziplin\u00e4re Intensivstation, Karl-Olga Krankenhaus, Stuttgart, Germany; Ioannis Pneumatikos, Vassiliki Theodorou, Critical Care Department, University Hospital of Alexandroupoli, Alexandroupoli, Greece; Despoina Koulenti, Apostolos Armaganidis, 2EUROBACT Investigators Survey. This survey was sent to study participants.Click here for file"} +{"text": "Recent advances in the management of SJIA considered the induction or maintenance of inactive disease according to the JADAS 10-CRP (J10) or 27-CRP (J27) scoring system [To evaluate the maintenance of efficacy at the level of the individual patient from Week 2 to 12, using the adapted ACR-JIA response criteria (aACR) as well as J10 and J27 on the 12-week pooled data set (3 phase III studies).For this post-hoc analysis of the CAN Phase III program in SJIA, the change in disease states between Day(D) 15 and D85 of a total of 178 CAN-na\u00efve patients was assessed. Subjects were 2\u201319 years of age and had active SJIA at enrollment. This shift analysis considered the aACR response and certain disease activity states as defined using J10 and J27: Inactive Disease (ID), Low Disease Activity (LDA), Moderate Disease Activity (MDA); High Disease Activity (HDA).J10 changes during the study period are provided in Table The D15-D85 aACR shift analyses, including only patients who had a D15 and a D85 value, likewise indicated that the majority of patients maintained or improved their response: NR (n=32): 12.5% of patients improved; aACR30 (n=14): 0.0% were maintained/78.6% improved; aACR50 (n=21): 33.3% were maintained/42.9% improved; aACR70 (n=36): 25.0% were maintained/58.3% improved; aACR90 (n=26): 30.8% were maintained/57.7% improved; aACR100 (n=34): 82.4% were maintained.The great majority of CAN patients either maintained or improved their JADAS status or aACR response level from week 2 to 12. These data confirm the consistent maintenance of efficacy of CAN at the individual level in the first 3 months, irrespective of the measure of response, i.e. aACR criteria or JADAS-derived criteria, and extend previous findings at the study group level.A. Ravelli Grant / Research Support from: Pfizer, Consultant for: Abbvie, Bristol Myers Squibb, Novartis, Pfizer, Roche and Johnson & Johnson, Speaker Bureau of: Abbvie, Bristol Myers Squibb, Novartis, Pfizer, Roche and Johnson & Johnson, H. Brunner Consultant for: Novartis, Genentech, Pfizer, UCB, AstraZeneca, Biogen, Boehringer-Ingelheim, Regeneron, Paid Instructor for: Novartis, Speaker Bureau of: Novartis, Genentech, N. Ruperto Grant / Research Support from: To Gaslini Hospital: Abbott, Astrazeneca, BMS, Centocor Research & Development, Eli Lilly and Company, \"Francesco Angelini\", Glaxo Smith & Kline, Italfarmaco, Novartis, Pfizer Inc., Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Xoma, Wyeth Pharmaceuticals Inc., , Speaker Bureau of: Astrazeneca, Bristol Myers and Squibb, Janssen Biologics B.V.,Roche, Wyeth/Pfizer, P. Quartier Grant / Research Support from: Abbvie, BMS, Chugai-Roche, Novartis, Pfizer, SOBI, Consultant for: Abbvie, Chugai-Roche, Novartis, Pfizer, Servier and SOBI, Speaker Bureau of: Chugai-Roche, MEDIMMUNE, Novartis, Pfizer, A. Consolaro Consultant for: Novartis, N. Wulffraat Grant / Research Support from: Abbvie, Roche, Consultant for: Novartis, Pfizer, Roche, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, C. Gaillez Shareholder of: Novartis, Employee of: Novartis, A. Martini Grant / Research Support from: The Gaslini Hospital, which is the public Hospital where I work as full time employee, has received contributions to support the PRINTO research activities from the following companies: Bristol Myers and Squibb, Centocor Research & Development, GlaxoSmith & Kline,Novartis,Pfizer Inc, Roche, Sanofi Aventis, Schwarz Biosciences GmbH, Speaker Bureau of: Abbott, Bristol MyersSquibb, Astellas, Behringer, Italfarmaco, MedImmune, Novartis, NovoNordisk, Pfizer,Sanofi,Roche, Servier, D. Lovell Grant / Research Support from: National Institutes of Health- NIAMS, Consultant for: Astra-Zeneca, Centocor, Amgen, Bristol Meyers Squibb, Abbott, Pfizer, Regeneron, Roche, Novartis, UBC, Forest Research Institute, Horizon, Johnson & Johnson , Speaker Bureau of: Novartis, Roche."} +{"text": "AbstractThe free-living marine nematodes of San Juli\u00e1n Bay dataset is based on sediment samples collected in January 2009 during the project PICT AGENCIA-FONCYT 2/33345-2005. A total of 36 samples have been taken at three locations in the San Juli\u00e1n Bay, Santa Cruz Province, Argentina on the coastal littoral at three tidal levels. This presents a unique and important collection for the nematode benthic biodiversity assessment as this area remains one of the least known regions in Patagonia. In total 10,030 specimens of free-living marine nematodes belonging to 2 classes, 9 orders, 35 families, 78 genera and 125 species were collected. The San Juli\u00e1n city site presented a very high species richness. The objectives of the study were to collect, identify and discover the structure and diversity of nematode community of San Juli\u00e1n Bay. The coverage Figure of this Enoplea 8%; nine Kingdom:AnimaliaPhylum:NematodaClass:Chromadorea, EnopleaOrder:Monhysterida, Enoplida, Chromadorida, Desmodorida, Araeolaimida, Plectida, Rhabditida, Dorylaimida, TriplonchidaFamily:Xyalidae, Linhomoeidae, Monhysteridae, Microlaimidae, Chromadoridae, Comesomatidae, Leptolaimidae, Oncholaimidae, Oxystominidae, Cyatholaimidae, Desmodoridae, Sphaerolaimidae, Diplopeltidae, Dorylaimidae, Ironidae, Neotonchidae, Thoracostomopsidae, Tripyloididae, Tylenchidae, Aegialoalaimidae, Anoplostomatidae, Aphelenchoididae, Axonolaimidae, Enchelidiidae, Ethmolaimidae.Genera:Odontophora, Hopperia, Laimella, Sabatieria, Campylaimus, Chromadora, Chromadorella, Prochromadora, Dichromadora, Neochromadora, Spilophorella, Marylynnia, Paracanthonchus, Paracyatholaimus, Pomponema, Paraethmolaimus, Gomphionema, Neotonchus, Halichoanolaimus, Molgolaimus, Polysigma, Spirinia, Bolbolaimus, Microlaimus, Desmolaimus, Metalinhomoeus, Terschellingia, Paralinhomoeus, Siphonolaimus, Diplolaimella, Diplolaimelloides, Halomonhystera, Monhystera, Sphaerolaimus, Subsphaerolaimus, Amphimonhystera, Daptonema, Linhystera, Metadesmolaimus, Paramonohystera, Pseudosteineria, Steineria, Theristus, Haliplectus, Cyartonema, Camacolaimus, Deontolaimus, Antomicron, Leptolaimoides, Leptolaimus, Paramicrolaimus, Mesorhabditis, Aphelenchoides, Panagrolaimus, Boleodorus, Tylenchorhynchus, Tylenchus, Dorylaimus, Eudorylaimus, Chaetonema, Thoracostomopsis, Dolicholaimus, Syringolaimus, Halalaimus, Thalassoalaimus, Wieseria, Calyptronema, Adoncholaimus, Oncholaimellus, Viscosia, Oncholaimus, Rhabdocoma, Bathylaimus, Tripyloides, Trichodorus, Pandolaimus.Species with higher occurrences:Paraethmolaimusdahli, Sabatieriamortenseni, Daptonemarectangulatum, Metalinhomoeusparafiliformis, Leptolaimuspuccinelliae, Diplolaimelloidesoschei, Leptolaimussebastiani, Metalinhomoeusgloriae, Thalassomonhysteraparva, Metalinhomoeustypicus, Haliplectussalicornius.PageBreakGeneral spatial coverage: San Juli\u00e1n Bay, Santa Cruz Province, Argentina were sampled with a PVC syringe and separated by a distance of 5-10 m each: four for marine nematodes counts, two for organic matter and two for sediment analyses. Each sample was fixed in situ, with a solution of 5% formaldehyde in filtered sea water with the addition of Rose Bengal tint.PageBreaktifying only organisms passing through a 500 \u00b5m mesh and then retained by a 63 \u00b5m mesh. Samples were evaporated to anhydrous glycerol and permanent slides made method at a specific gravity of 1.15, quandes made .The taxonomic classification followed proposed by Project title: \u201cEvaluaci\u00f3n del impacto urbano en costas areno-limosas de la provincia de Santa Cruz, usando m\u00e9todos r\u00e1pidos de an\u00e1lisis de cambios en estructura comunitaria del bentos.\u201d .Personnel: Catalina Pastor de Ward ; H\u00e9ctor Zaixso , Virginia Lo Russo , Gabriela Villares , Viviana Milano , Lidia Miyashiro (Darwin core data input), Renato Mazzanti .Funding: PICT AGENCIA-FONCYT 2/33345-2005Study extent description: The San Juli\u00e1n Bay marine nematodes is a dataset that gives new insights on the taxonomic and geographic distribution of south Atlantic marine nematodes, covering an under-explored region of the southern Atlantic coasts. This is the first study on marine nematodes in this locality. This dataset presents species occurrences and species richness of the individual free-living marine nematodes present at three coastal areas of the San Juli\u00e1n Bay at three different tidal levels .In total 10,030 specimens of free-living marine nematodes belonging to 2 classes, 9 orders, 35 families, 78 genera and 125 species were collected.PageBreakPageBreakPageBreakQuality control description: The geo-referencing of all specimens were recorded using a Garmin eTrex Legend GPS (WGS84 Datum) with an accuracy of less than 10 m and with at least 5 satellites.http://www.gbif.es/darwin_test/Darwin_Test_in.php).The taxonomic identification of specimens, scientific names, and their current accurate spelling were verified by C. Pastor de Ward, a free-living marine nematode specialist. Other post-validation procedures were checked using the Darwin Test software Character encoding: UTF-8Format name: Darwin Core Archive formatFormat version: 1.0Distribution:http://www.cenpat-conicet.gov.ar:8080/ipt-2.0.3/resource.do?r=sjnemPublication date of data: 2013-10-17Language: EnglishLicenses of use: This work is licensed under a Creative Commons CC0 1.0 License http://creativecommons.org/publicdomain/zero/1.0/legalcodeObject name: Centro Nacional Patag\u00f3nico (CENPAT-CONICET)Distribution:http://www.cenpat-conicet.gov.ar:8080/ipt-2.0.3/resource.do?r=sjnemObject name: Ministerio de Ciencia y Tecnolog\u00eda de Argentina Distribution: GBIF: http://www.gbif.org/dataset/06df03fc-8973-490c-af74-089fffae9e24Formatted: English (U.K.)Field Code ChangedMetadata language: EnglishDate of metadata creation: 2013-10-17Hierarchy level: DatasetPageBreak"} +{"text": "Emphysematous cystitis and emphysematous pyelitis: a clinically misleading association. Mustapha Ahsaini, Amadou Kassogue, Mohammed Fadl Tazi, Anas Zaougui, Jalal Edine Elammari, Abdelhak Khallouk, Mohammed Jamal El Fassi, My Hassan Farih. The Pan African Medical Journal. 2013;16:18. (doi:10.11604/pamj.2013.16.18.2505).This retracts article Emphysematous cystitis and emphysematous pyelitis: a clinically misleading association(doi:10.11604/pamj.2013.16.18.2505) by Mustapha Ahsaini, Amadou Kassogue, Mohammed Fadl Tazi, Anas Zaougui, Jalal Edine Elammari, Abdelhak Khallouk, Mohammed Jamal El Fassi and My Hassan Farih of the Department of Urology, University Hospital, Center Hassan II, Fes, Morocco [We hereby inform to our readership of the retraction of the article"} +{"text": "To date there are no head-to-head trials comparing the efficacy of biologic treatments for polyarticular-course JIA (pcJIA).To use statistical methods to estimate the relative efficacy of biologic treatments, alone and in combination with methotrexate (MTX), in the management of pcJIA by means of indirect comparison of randomised controlled trials (RCTs).Based on a literature review, we identified RCTs of abatacept, adalimumab (ADA), etanercept, infliximab and tocilizumab (TCZ) in pcJIA. Comparative effectiveness was estimated on the reported American College of Rheumatology response rates (JIA ACR30/50/70/90) measured at the end of the randomised, double-blind phase by means of a Bayesian indirect comparison using a fixed-effects ordered probit model. Probabilities of achieving different levels of JIA ACR response were calculated for biologic treatments and placebo using all observed comparisons.The 5 RCTs identified showed differences in reporting JIA ACR responses with regard to methods of non-responder imputation during the blinded, controlled phase, allowing only for the comparison of ADA and TCZ. In the base-case analysis, for a JIA ACR30 placebo response of 31%, TCZ monotherapy had a higher predicted probability of JIA ACR30 (62%), JIA ACR50 (59%), JIA ACR70 (54%) and JIA ACR90 (35%) response than ADA monotherapy . On MTX background therapy and a JIA ACR30 placebo response of 53%, ADA had a higher expected probability of response at JIA ACR30 (76%), JIA ACR50 (75%), JIA ACR70 (66%) and JIA ACR90 (49%) than TCZ . In neither monotherapy nor combination therapy did differences between TCZ and ADA reach statistical significance. Differences in the study populations, including previous use of biologics, were explored with sensitivity analysis.Based on JIA ACR response rates from this analysis, the expected efficacy of ADA vs TCZ appears comparable in pcJIA. These data should be interpreted in the context of differences in the duration of the withdrawal phase, which was shorter in the TCZ study (CHERISH) than in the ADA trial and might have resulted in a smaller difference in the number of flares observed between placebo and TCZ. Differences in previous exposure to biologics might also have affected the results.L. Sawyer Consultant for: F. Hoffmann-La Roche, A. Diamantopoulos Consultant for: F. Hoffmann-La Roche, H. I. Brunner Consultant for: Novartis, Genentech, MedImmune, EMD Serono, AMS, Pfizer, UCB, Janssen, Speakers Bureau: Genentech, F. De Benedetti Grant/Research Support from: Abbott, Pfizer, BMS, Roche, Novimmune, Novartis, SOBI, N. Ruperto Grant/Research Support from: Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, MerckSerono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Consultant for: Abbott, AstraZeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, MerckSerono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Speakers Bureau: Abbott, Boehringer, BMS, Novartis, Astellas, Italfarmaco, MedImmune, Pfizer, Roche, F. Dejonckheere Employee of: F. Hoffmann-La Roche, C. Keane Employee of: Roche."} +{"text": "AbstractBraconidae is revised, based in large part on the collections of the National Museums of Scotland, Edinburgh, and the Natural History Museum, London. Distribution records are provided at the country level together with extensive synonymy and bibliography.The checklist of British and Irish Dyscritussuffolciensis Morley, 1933 = Syntretussplendidus syn. nov.)Of the 1,338 species regarded as valid, presumed native and certainly identified, 83 are here recorded for the first time from the British Isles. One new synonym is established ( Braconidae is one of two families of the superfamily Ichneumonoidea, along with the Ichneumonidae. Given the size of each family in Britain we are publishing the two checklists separately. This is one part of a series of papers revising the British and Irish list of Hymenoptera, that started with Hymenoptera checklists see Fauna Europaea and Taxapad or identification in the British Isles uncertainmisident. has been misidentified as this namenomen dubium, a name of doubtful statusnom. dub. nomen oblitum, \u2018forgotten name\u2019, does not have priority over a younger namenom. ob. nomen novum, a replacement namenom. nov. nomen nudum, an unavailable name, with no type specimennom. nud. preocc. name preoccupied (junior homonym)status revocatus, revived status stat. rev. unavailable name unavailable under provisions of the ICZN codevar. variety, only available as a valid name under certain provisions of the ICZN codeHymenoptera of the British Isles.Word document and spreadsheet versions of the checklist are available in the supplementary materials. Future updates to the British and Irish list will be incorporated in an online version of the checklist at Haliday, 1833Agathis and \u2018Bassus\u2019 species (i.e. including Lytopylus and Therophilus), distribution and synonymic data from Except for Nees, 1814BASSINI Nees, 1812 invalidEUMICRODINI F\u00f6rster, 1863BASSINI F\u00f6rster, 1869 preocc.MICRODINI Ashmead, 1900MESOCOELINI Viereck, 1918ANEUROBRACONINI Fahringer, 1936EARININI Sharkey, 1992Latreille, 1804AENIGMOSTOMUS Ashmead, 1900METRIOSOMA Sz\u00e9pligeti, 1902BAEOGNATHA Kokujev, 1903 synonymy by Achterberg (2011)LISSAGATHIS Cameron, 1911RHAMPHAGATHIS Tobias, 1962Distribution and synonymic data from Agathis excluded from the British and Irish list:Species of malvacearum Latreille, 1805; syn. panzeri ; metzneriae Muesebeck, 1967] Listed by varipes. Listed as a \u2018species inquirendae\u2019 by Bassus by Therophilus by Listed by T. Munk (pers. comm.) regarded this as an unidentified species; the type has been destroyed. Listed as British by Included as a British species by There have been no references to this species other than catalogue listings suppressed Haliday, 1834Haliday, 1834infirmusBracon) Marshall, 1896berberidis Smith, 1944England, WalesHaliday, 1834arundinis Haliday, 1834cirsii Haliday, 1834 preocc.phorodontis Ashmead, 1889chrysanthemi Marshall, 1896lychnidis Marshall, 1896polygoni Marshall, 1896affinis Quilis, 1931baudysi Quilis, 1931discrytus Quilis, 1931merceti Quilis, 1931obscuriformis Quilis, 1931valentinus Quilis, 1931renominatus Hincks, 1943nigriteleus Smith, 1944England, Wales, IrelandPennacchio & Tremblay, 1987England, WalesAdded by de Stefani-Perez, 1902equiseticola Star\u00fd, 1963poacearum Star\u00fd, 1963EnglandHaliday, 1834ribaphidisLysiphlebus) nom. ob. nom. ob. Euaphidiussetiger Mackauer, 1961aceri Ivanov, 1925Walesadded by Baker and Broad (2009)Marshall, 1896England, WalesMackauer, 1962tanaceti Curtis, 1837 nom. nud.tanaceticola Star\u00fd, 1963tanacetarius as the valid name for tanaceti, which is a nomen nudum. This species has not been listed as British since its original description Aphidiusuzbekistanicusbeltrani Quilis, 1931 ?Aphidiusuzbekistanicusindivisus Quilis, 1931 ?Aphidiusuzbekistanicusmacropterus Quilis, 1931 ?Aphidiusuzbekistanicuspailloti Quilis, 1931 ?impressus Mackauer, 1965EnglandAphidiusbeltrani is a possible senior synonym of uzbekistanicus Trioxyscompressicornis Ruthe, 1859testaceusTrioxys) , Misaphidus Rondani, 1848 s.l. ) is a nomen oblitum according to Article 23.9 of ICZN.In Aphidiusacalephae Marshall, 1896rietscheliTrioxys) Aphidiusangelicae Haliday, 1833placidusTrioxys) nom. nud. Aphidiusbrevicornis Haliday, 1833minutusAphidius) Aphidiuscentaureae Haliday, 1833crudelisMisaphidus) Aphidiusheraclei Haliday, 1833obsoletusAphidius) Aphidiusletifer Haliday, 1833IrelandStar\u00fd, 1960Aphidiusephippium Haliday, 1834England, IrelandStar\u00fd, 1960Aphidiusrapae McIntosh, 1855vulgarisAphidius) preocc. nom. nud. nom. nud. Aphidiusleucopterus Haliday, 1834exspectatusAphidius) Bracondissolutus Nees, 1811macrocornis Mackauer, 1960EnglandStar\u00fd, 1975APHIDARIA Provancher, 1888 preocc.Tremblay & Eady, 1978England, Walesambiguus sensu Mackauer and Star\u00fd nec Haliday, later described by confusus, the true ambiguus belonging in Adialytus.Added here on the basis of specimens in BMNH, identified by R.D. Eady as Aphidiusfabarum Marshall, 1896aphidiperdaMisaphidus) preocc. Haliday, 1833Mackauer, 1961Aphidiuspseudoplatani Marshall, 1896England, WalesHaliday, 1833Aphidiuscaricis Haliday, 1833England, WalesAphidiuscerasi Marshall, 1896EnglandAphidiuscrepidis Haliday, 1834tuberculatusAphidius) Aphidiusnervosus Haliday, 1833paulensisAphidius) Aphidiusenervis Nees, 1834mandibularisMyrmecobosca) excluded from the British and Irish list:species of silvestris ] added by A Nearctic species, listed by Seems to have been recorded in error by Listed as a doubtfully British species in The only record was due to a misidentification of Pseudovipioguttiventris Braconbarypus Marshall, 1885hungaricus Sz\u00e9pligeti, 1901caucasicus Telenga, 1936apti Gy\u00f6rfi, 1953EnglandSee Fabricius, 1804Bracon are lacking for all but a few species groups. Published works differ substantially in their treatments of valid species, synonyms and subgeneric placements polonicus Fahringer, 1927; synonymy by Papp (2008a)pallidalatus Tobias, 1957England, ScotlandNMS, det. Papp, added hereNees, 1834EnglandNees, 1834carinatus Sz\u00e9pligeti, 1901marshalli Vayssi\u00e8re, 1902 preocc.glabratus Fahringer, 1927apionis Strand, 1928sylvanus Greese, 1928kiritshenkoi Telenga, 1936England, Scotland, Wales, Ireland, Isle of ManNees, 1834laetusBraco); synonymy by intercessor Bracolongicollis Wesmael, 1838fraudator Marshall, 1885brevicauda Thomson, 1892 preocc.crassicauda Thomson, 1892pseudowesmaeli Strand, 1928wesmaeli Fahringer, 1927 preocc.England, Scotland, Wales, Isle of Manspme distribution data from Papp (1999c)Spinola, 1808nigripedator Nees, 1834filicauda Costa, 1888hypopygialis Sz\u00e9pligeti, 1901intermedius Sz\u00e9pligeti, 1901pilosulus Sz\u00e9pligeti, 1901Englandadded by Braconigratus Wesmael, 1838England, IrelandBracopectoralis Wesmael, 1838ochrosus Sz\u00e9pligeti, 1896sulphurator Sz\u00e9pligeti, 1896unicolor Sz\u00e9pligeti, 1896fumigatus Sz\u00e9pligeti, 1901; synonymy by Papp (2008a)EnglandSz\u00e9pligeti, 1901depressiusculus Sz\u00e9pligeti, 1901neglectus Sz\u00e9pligeti, 1904spurnensis Hincks, 1951England, Scotland, Walesrugulosus Sz\u00e9pligeti is preoccupied by Braconrugulosus Nees, 1811 . Omitted by According to Taxapad , rugulosBracoscutellaris Wesmael, 1838England, Scotland, IrelandSchmiedeknecht, 1897Englandadded by Papp (1999a)Sz\u00e9pligeti, 1901sulcatulus Sz\u00e9pligeti, 1896subglaber Sz\u00e9pligeti, 1901quinquemaculatus Sz\u00e9pligeti, 1901trypetanus Fahringer, 1927; synonymy by Papp (2008a)tauricus Telenga, 1936Englandadded by Papp (2008a)Marshall, 1888minutator misident.bilineatus Thomson, 1892hilaris Marshall, 1897pannonicus Sz\u00e9pligeti, 1901marshalli Telenga, 1936 preocc.Englandminutator . Both species are present in the BMNH and NMS collections, det. Papp and van Achterberg.BMNH, NMS, added here; previously confused under Spinola, 1808melanosoma Sz\u00e9pligeti, 1901micros Sz\u00e9pligeti, 1901nanulus Sz\u00e9pligeti, 1901lineatellaeHabrobracon); synonymy by Papp (2008b) excluded from the British and Irish list:Species of coniferarum Fahringer, 1928] Should not have been listed by England and Ireland are listed under the distribution in Coeloides but Bracon (Lucobracon). Swiss specimens identified as strobilorum by Papp in NMS and BMNH belong in Bracon. Probably not a valid British or Irish species now that B. (Lucobracon) erythrostictus has been taken out of synonymy Bracodiscoideus Wesmael, 1838opionus Fahringer, 1928sculpturatus Fahringer, 1928sculpturifera Strand, 1928England, Scotland, IrelandMarshall, 1885pallidipes Sz\u00e9pligeti, 1896; synonymy by Papp (2008a)melanogaster Sz\u00e9pligeti, 1901England, Scotland, Wales, Irelandsome distribution data from Papp (1999c)Nees, 1834satanasBraco) Bracoroberti Wesmael, 1838England, IrelandFahringer, 1927England, Scotland, Wales, IrelandNMS, det. Papp, added hereBracosubcylindricus Wesmael, 1838nigerBaryproctus) Bracotitubans Wesmael, 1838tarsator Thomson, 1892terebrator Sz\u00e9pligeti, 1901EnglandNMS, BMNH, det. Papp, added hereMarshall, 1897lineifer van Achterberg, 1988; synonymy by Papp (1999c)England, Scotlandsome distribution data from Shaw and Bailey (1991)Papp, 2008Nees, 1811bisignatusBraco) Bracopiger Wesmael, 1838rotundatus Sz\u00e9pligeti, 1901; synonymy by Papp (2008a)rotundulus Sz\u00e9pligeti, 1904England, IrelandBraconsemiluteus Walker, 1874 is not a synonym of piger .Pigeriawolschrijni van Achterberg, 1985WalesNMS, det. van Achterberg, added hereTobias, 1957Bracon (Rostrobracon) excluded from the British and Irish list:species of urinator ; syn. cuspidator ; comptus Marshall, 1897] not British, recorded in error Promachusaartseni van Achterberg, 1994Englandadded by Shaw (1999)Braconanalis Nees, 1834flavifrons Haliday, 1840cephalotesOpius) preocc. Ichneumonsecalis Linnaeus, 1758agricolatorIchneumon) ?England, Scotland, Wales, Ireland, Isle of Manbrevicauda as a \u2018form\u2019 of cruentatus, the possibility of a separate species requires investigation.Although Ichneumonextensor Linnaeus, 1758gracilisEubadizon) Distribution and synonymic data taken from Ascogster excluded from the British and Irish list:Species of bicarinata ; syn. mlokossewitschi Kokujev, 1895; syn. rufiventris Telenga, 1941; preocc.] Included by [similis ] The type is lost and the species is unplaceable Prior to van Achterberg\u2019s Chelonusdentatus Panzer, 1805dentatorSigalphus) EnglandSigalphusrufescens Latreille, 1809 as a junior synonym of dentata but this is now considered to be a separate species, not occurring in Britain or Ireland flavitestacea Fischer, 1939; synonymy by Achterberg (1990)caboverdensis Hedqvist,1965EnglandPhanerotomarjabovi Vojnovskaja-Krieger, 1929 and media Shestakov, 1930, synonymised under leucobasis by fracta Kokujev, 1903 SZEPLIGETIA Schulz, 1911; synonymy by Achterberg (1990)TRITOMIOS Strand, 1921; synonymy by Achterberg (1990)UNICA \u0160nofl\u00e1k, 1951Lyle, 1924gregori \u0160nofl\u00e1k, 1951EnglandChelonustritomus Marshall, 1898antennalis \u0160nofl\u00e1k, 1951; synonymy by Achterberg (1990)England, Wales, IrelandF\u00f6rster, 1863Tribal classification follows F\u00f6rster, 1863Wesmael, 1838EURYBOLUS Ratzeburg, 1848CAENOPACHYS F\u00f6rster, 1863Caenopachys should be treated as a separate genus, Caenopachys\u2019 species (including hartigii in Britain) are nested within Dendrosoter.Although Braconhartigii Ratzeburg, 1848flaviventris F\u00f6rster, 1878caenopachoides Ruschka, 1925; synonymy by Gebiola et al. (2015)hartigi misspellingEnglandBraconmiddendorffi Ratzeburg, 1848schimitscheki Fahringer, 1941EnglandNMS, det. Shaw, added in Fauna EuropaeaBraconprotuberans Nees, 1834insignis F\u00f6rster, 1878EnglandHaliday, 1836ISCHIOGONUS Wesmael, 1838Neodoryctes Sz\u00e9pligeti, 1914UDAMOLCUS Enderlein, 1920PRISTODORYCTES Kieffer, 1921Paradoryctes Granger, 1949PLYCTES Fischer, 1970Reinhard, 1865EnglandBraconleucogaster Nees, 1834#Probably occurred only in imported timber. Its British status appears to depend solely on specimens reared in July 1908 from Austrian oak imported to a timber yard near Millwall docks .Braconobliteratus Nees, 1834mutillator misident.tabidusRogas) Braconstriatellus Nees, 1834maculipes Curtis, 1837 nom. nud.disparatorBracon) Braconundulatus Ratzeburg, 1852EnglandHedqvist, 1974Dendrosotinus Telenga, 1941 by Removed from synonymy with Dendrosotinussimilis Bou\u010dek, 1955Englandadded by Shaw (1998)Cameron, 1900DORYCTODES Hell\u00e9n, 1927Ontsira as monophyletic and consequently some authors Clinocentrusanticus Wollaston, 1858gallicaDoryctes) Braconigneus Ratzeburg, 1852EnglandNMS, det. Shaw and van Achterberg, added hereRogasimperator Haliday, 1836zonataIschiogonus) Sz\u00e9pligeti, 1900Wachsmannia under Ontsira but van Wachsmannia under Hypodoryctes Kokujev, 1900. Van Achterberg (pers. comm. and in Fauna Europaea) now regards Wachsmannia as a separate genus again.Braconspathiiformis Ratzeburg, 1848maculipennis Sz\u00e9pligeti, 1900; synonymy by Achterberg (1995)obliteratus misident.EnglandHell\u00e9n, 1957F\u00f6rster, 1863TERENUSA Marshall, 1885PARAECPHYLUS Ashmead, 1900SACTOPUS Ashmead, 1900silesiacus by Other species are treated as synonyms of Braconeccoptogastri Ratzeburg, 1848Braconhylesini Ratzeburg, 1852EnglandNMS, det. Shaw and van Achterberg, added in Fauna EuropaeaHedqvist, 1967England, ScotlandNMS, det. Shaw and van Achterberg, added in Fauna EuropaeaBraconsilesiacus Ratzeburg, 1848minutissimusBracon) preocc. . Listed in eccoptogastri.NMS, det. Shaw and van Achterberg, added in Fauna Europaea; F\u00f6rster, 1863Curtis, 1834ANISOPELMA Wesmael, 1838Curtis, 1834belgicusAnisopelma) ; minimus ; utilis ; doderoi ; lavagnei Picard, 1913; atis Nixon, 1943] Seems to have been included on the British list only on the basis of specimens emerging from Oak (Quercus) timber imported from the USA misident.] Excluded by Not included in Listed by Peristenus or Leiophron, by Leiophron and by van Achterberg ; syn. brevicornis preocc.] According to brevicornis (Ruthe) is lost and the species cannot be identified with certainty. Recorded as British by Peristenus (=Leiophron according to Belokobylskij).[mitis ] According to van Achterberg Leiophronaccinctus Haliday, 1835laeviventrisMicroctonus) preocc.Leiophronantennalis Hincks, 1943picipesLeiophron) preocc. . Preoccupied by Leiophronantennalis Watanabe, 1937 (now classified in Centistes (Ancylocentrus)).Added by Euphorusfacialis Thomson, 1892fascialis misspellingmicrocerusEuphorus) Euphorusgrandiceps Thomson, 1892England, Irelandorchesiae by Not listed by Loan, 1976Scotlanddistribution data from Loan (1976)Leiophronnitidus Curtis, 1833EnglandLeiophronorchesiae Curtis, 1833rufibarbisLeiophron) Leiophronorthotyli Richards, 1967EnglandLeiophronpallipes Curtis, 1833barbigerMicroctonus) preocc.Perilituspallipes Herrich-Sch\u00e4ffer, 1838mellipesEuphorus) Leiophronpicipes Curtis, 1833coactusEuphorus) Helorimorphahungaricus Kiss, 1927chrysopimaginis Goidanich, 1948elegans Tobias, 1961Englandadded by Shaw (1996a)F\u00f6rster, 1863Euphoruspetiolatus Wollaston, 1858pendula F\u00f6rster, 1863cremasta Marshall, 1872americana Myers, 1917asiatica Shestakov, 1932EnglandChen & van Achterberg, 1997LOXOCEPHALINI Shaw, 1985 invalidMarshall, 1897LOXOCEPHALUS F\u00f6rster, 1863 preocc.SPILOMMA Morley, 1909Microctonusboops Wesmael, 1835longipesLoxocephalus) Haliday, 1838ECCLITES F\u00f6rster, 1863SIXIA Vollenhoven, 1867; synonymy by Achterberg (1997)Elasmosomaaucta Thomson, 1895halidaii Marshall, 1897bistigmaticusEuphorus) but as Microctonus was raised to generic rank by Microctonus. Synonymy follows Perilitusaciculatus Haeselbarth, 2008Irelandadded by Haeselbarth (2008)Nees, 1834spurius Ruthe, 1856Microctonusaethiopsbrevispina ?aethiopoides Loan, 1975England, IrelandPerilitusalticae Haeselbarth, 2008Englandadded by Haeselbarth (2008)Perilitusaphthonae Haeselbarth, 2008England, Irelandadded by Haeselbarth (2008)Loan, 1974Perilitusareolatus Thomson, 1892EnglandPerilitusbelokobylskiji Haeselbarth, 2008Irelandadded by Haeselbarth (2008)Perilitusbrassicae Haeselbarth, 2008Englandadded by Haeselbarth (2008)Perilitusbrevicollis Haliday, 1835England, IrelandPerilituscerealium Haliday, 1835secalisPerilitus) unavailable Perilitusconsuetor Nees, 1834Scotlandadded by Haeselbarth (2008)Perilitusdebilis Wollaston, 1858Microctonusdebilisgracilipes ?Irelandadded by Haeselbarth (2008)Perilitusfagi Haeselbarth, 2008England, IrelandAdded by Perilitusfittkaui Haeselbarth, 2008Englandadded by Haeselbarth (2008)Perilitusflaviventris Thomson, 1892areolatusPerilitus) Perilitushaszprunari Haeselbarth, 2008Irelandadded by Haeselbarth (2008)\u010capek & Star\u00fd, 1995Englandadded by Haeselbarth (2008)Ruthe, 1856England, Scotland, Irelandadded by Haeselbarth (2008)Ruthe, 1856EnglandPerilitusperforatus Haeselbarth, 2008Englandadded by Haeselbarth (2008)Perilituspodargae Haeselbarth, 2008Englandadded by Haeselbarth (2008)Ruthe, 1856lancearius Ruthe, 1856caudatusPerilitus) Perilitussilvularis Haeselbarth, 2008Scotland, Irelandadded by Haeselbarth (2008)Perilitusstenocari Haeselbarth, 2008Scotlandadded by Haeselbarth (2008)Perilitusstrophosomi Haeselbarth, 2008Scotland, Irelandadded by Haeselbarth (2008)Perilitusthyellae Haeselbarth, 2008England, Scotlandadded by Haeselbarth (2008)Nees, 1818Perilitus excluded from the British and Irish list:species of falciger ] Not listed as British or Irish by Included in Huddleston\u2019s Meteoruscaligatus Haliday, 1835neesiiMeteorus) Braconchlorophthalmus Spinola, 1808chrysophthalmusBracon) ; synonymy by Stigenberg and Ronquist (2011) Perilitusdeceptor Wesmael, 1835pallitarsisPerilitus) , Cotesia, Deuterixys, Diolcogaster, Hygroplitis, Microgaster, Microplitis, Paroplitis and Protapanteles . Some distribution data taken from The generic classification of Nixon\u2019s assignmeerberg\u2019s recent gViereck, 1918F\u00f6rster, 1863UROGASTER Ashmead, 1898XESTAPANTELES Cameron, 1910ALLAPANTELES Br\u00e8thes, 1915AREOLATUS Rao & Chalikwar, 1976 unavailablemetacarpalis group, here largely apportioned between Apanteles and Dolichogenidea following The generic placement of several species treated by Apanteles excluded from the British and Irish list:species of anomalon ] This name appeared in [nigripes ] This name appeared in [picipes ] A.xanthostigma, but there is no mention there of picipes. It is presumed that the name picipes is a synonym or a nomen dubium; it is not listed as a valid species by Listed as a British species by Listed as a British species by [ensiformis ] Listed as a British species by Napamusvipio). Listed as a British species by [impura ] Notwithstanding Mistakenly listed as a British species by Lepidoptera-parasitoid asscociations, whereas their listings also included non-British rearings from hosts that occur in Britain. vipio, who does not mention Britain. Apantelesvipio was transferred from Illidops by Not a British or Irish species. Marshall\u2019s description was based on unprovenanced material reared from a host that, on inspection by MRS, is almost certainly not British. The current synonymy is also in doubt. Although listed as a British species by various authors we can find no evidence that it has occurred here.[saltator preocc.] Appeared in tenebrosa under saltator. No evidence that this is a British or Irish species. Listed as a British species by Both of these species were mistakenly listed by Listed as doubtfully British by Listed as a British species by British specimens, misidentified as fischeri by raschkiellae. Listed as doubtfully British by Recorded as British by Microgaster species in the modern sense. Papp\u2019s Thomson, 1895England, ScotlandShaw, 2012Scotlandadded by Shaw (2012)Nixon, 1968EnglandRuthe, 1860EnglandNixon, 1968Englandadded by Shaw (2012)Thomson, 1895striatoscutellaris Kiss, 1927England, Scotland, Ireland, Isle of ManIchneumonglobatus Linnaeus, 1758laeviscuta Thomson, 1895gossypinaIchneumon) England, Scotlandlaeviscuta has been included as a junior synonym of hospes in Fauna Europaea, with globata not referred to. globata as perceived by Some distribution data from Marshall, 1885comptanae Viereck, 1911England, Scotland, WalesHaliday, 1834curvicrus Thomson, 1895; synonymy by Achterberg (1997)England, Scotland, WalesHaliday, 1834spinolae Haliday, 1834 preocc.; synonymy by Achterberg (1997)alexis Haliday, 1834 nom. nud.grandis Thomson, 1895; synonymy by Achterberg (1997)contubernalis Marshall, 1898England, Scotland, Wales, Ireland, Isle of ManHaliday, 1834tibialis Nees, 1834 preocc.; synonymy by Achterberg (1997)vulgaris Ruthe, 1860pluto Morley, 1936England, Scotland, Wales, Irelandtibialis probably do not belong here Some Ruthe names traditionally regarded as synonyms of Nees, 1834nigricans as a British species and A species of doubtful status. Shaw, 2004England, Walesadded by Shaw (2004)Marshall, 1885swammerdamiae Muesebeck, 1922England, ScotlandNixon, 1968IrelandMuesebeck, 1922EnglandThomson, 1895England, ScotlandMarshall, 1885carinata Bengtsson, 1926 preocc.bengtssoni Fahringer, 1937England, Scotland, IrelandRuthe, 1860intermedia Ivanov, 1899IrelandShaw, 2012fischeri misident.England, Scotland, Walesadded by Shaw (2012)Ruthe, 1858confusa Papp, 1971England, Scotland, Wales, Isle of ManNees, 1834annulipes Curtis, 1830carinata Packard, 1881England, Scotland, Wales, Ireland, Isle of ManMason, 1981Microgasterwesmaeli Ruthe, 1860picipesMicrogaster) preocc. Microgasterfalcatus Nees, 1834equestrisMicrogaster) Microgasteraduncus Ruthe, 1860brachycerusMicrogaster) Ichneumondeprimator Fabricius, 1798ingratusMicrogaster); synonymy by Achterberg (1997) Microgasterflavipalpis Brull\u00e9, 1832ruricola Lyle, 1918EnglandNixon, 1970England, Scotlandsemicircularis (type destroyed) may be a senior synonym.Microgasterfulvicornis Wesmael, 1837calcarata misident.pallidicornis Marshall, 1898England, WalesMicrogasterimpressus Wesmael, 1837sispes Nixon, 1970Englandadded by Shaw (2012)Microgasterlugubris Ruthe, 1860borealis Marshall, 1885coracinusMicrogaster) Microgastermalimba Papp, 1984trochanterata misidentEnglandtrochanterata is actually referable to malimbus Microgastermediator Haliday, 1834medianusMicrogaster) Microgastermoestus Ratzeburg, 1852Nixon, 1970EnglandMicrogasterocellatae Bouch\u00e9, 1834canaliculatusMicrogaster) Nixon, 1970Microplitissofronstigmaticus ?England, Scotland, Irelandstigmaticus may be a senior synonym.Microgasterspectabilis Haliday, 1834fossulatusMicrogaster) ?seuratii Marshall, 1898testaceipesDapsilotoma) Microgasterspinolae Nees, 1834sapporoensis Ashmead, 1906radiorimatus Telenga, 1955Microplitisspinolaequadridentatus ?EnglandReinhard, 1880gracilisMicrogaster) preocc. Microgastertristis Nees, 1834dolens Marshall, 1885England, Scotland, WalesMicrogastertuberculatus Bouch\u00e9, 1834fumipennisMicrogaster) Microgastertuberculifer Wesmael, 1837calcaratusMicrogaster) Microgasterviduus Ruthe, 1860EnglandMicrogasterxanthopus Ruthe, 1860tenuipesMicrogaster) . This relationship was originally suggested by Ratzeburg, 1848SIMILEARINUS Glowacki & Karpi\u0144ski, 1967Nomenclature follows Ratzeburg, 1848dioryctriae Rohwer, 1920Englandadded by Shaw (1992a)Viereck, 1918Haliday, 1833CENTISTIDEA Rohwer, 1914There are also several unrecognised species in Britain.Haliday, 1833spartii Haliday, 1835dryochares Marshall, 1898nanivorae Fischer, 1957England, Scotlandsome distribution data from Blanchard, 1845Opiinae (in prep.), which are followed here. Some changes to the generic classification have been published by Opiinae, except perhaps Ademonini (for the genus Ademon), with all the other genera in Opiini; van Achterberg (in prep.) does not recognise Ademonini. Some distribution data from The generic and tribal classification of opiines has been largely chaotic . In FaunHaliday, 1833GIARDINAIA de Stefani-Perez, 1902ANALOSTANIA Viereck, 1916Bracondecrescens Nees, 1811mutuatorBracon) Opiusaemulus Haliday, 1836melbaOpius) Opiuscurvatus Fischer, 1957England, Scotlandadded by Godfray (1986)Opiusirregularis Wesmael, 1835bipustulataOpius) Opiusocellatus Wesmael, 1835areolarisOpius) Opiusposticatae Fischer, 1957seebensteinensisOpius) Opiusrufipes Wesmael, 1835taeniata F\u00f6rster, 1863taeniataOpius) preocc. Opiussaevus Haliday, 1837England, ScotlandOpiussaevulus Fischer, 1958EnglandOpiussimilis Sz\u00e9pligeti, 1898xylosteiOpius) ; synonymy by van Achterberg (in prep.) Opiusvictus Haliday, 1837tarniOpius) formally synonymised Compressaria and pugnatrix. Compressariapugnatrix as a species of Rogadinae.Although F\u00f6rster, 1863pugnatrixMesocrina) ; synonymy by van Achterberg (in prep.) Opiusbajulus Haliday, 1837beieriSternaulopius); synonymy by Wharton (2006) Opiusanalis Wesmael, 1835colorativentrisOpius) Opiusarenarius Stelfox, 1959IrelandWesmael, 1835vagatorStenospilus) Braconcarbonarius Nees, 1834impressusOpius) ; synonymy by Achterberg (2014) Opiushaemorrhoeus Haliday, 1837castaneiventrisOpius) Opiusmagnicornis Wesmael, 1835England, IrelandOpiusmicans Stelfox, 1957nitidusOpius) preocc. Opiusplacidus Haliday, 1837melanocerusOpius) Opiusrusticus Haliday, 1837England, Scotland, IrelandOpiusscabriculus Wesmael, 1835IrelandOpiusspinaciae Thomson, 1895pegomyiaeOpius) Opiussylvaticus Haliday, 1837clypealisOpius) Opiuswesmaelii Haliday, 1837carbonariusOpius) preocc. preocc. Opiusrugosus Wesmael, 1838rugiventrisOpius); synonymy by Achterberg (2014) Opiusblandus Haliday, 1837England, IrelandF\u00f6rster, 1863Opius.Regarded by Wharton as a junOpiusparvulus Wesmael, 1835nudiscutumOpius) Opiuscaffer Wesmael, 1835stygiumLytacra) Opiuscephalotes Wesmael, 1835EnglandOpiusfulgidus Haliday, 1837England, IrelandF\u00f6rster, 1863F\u00f6rster, 1863Opiusabnormis Wesmael, 1835England, IrelandOpiusparadoxus Ratzeburg, 1848, sometimes treated as a valid name (synonymous with abnormis) should be regarded as invalid as it was first proposed as a synonym of abnormis; According to Fischer, 2006EnglandEurytenes .Added by Fischer, 1986Stigmatopoea has been treated as a synonym of Xynobius by macrocerus, has been regarded as a species of Eurytenes, a genus which was ignored by Xynobius and Stigmatopoea are treated as subgenera of Eurytenes, following Stigmatopoea with Xynobius.The generic name Opiusmacrocerus Thomson, 1895hiansOpius) Opiusaciculatus Thomson, 1895tenuicornisOpius); synonymy by van Achterberg (in prep.) Opiusaemuloides Fischer, 1958EnglandOpiuscaelatus Haliday, 1837isomeraAclisis) Opiuscomatus Wesmael, 1835sulciferDapsilarthra) Opiusgeniculatus Thomson, 1895albicoxisOpius) Opiusholconotus Fischer, 1958EnglandWesmael, 1835addendus Fischer, 1959turcmenicus Fischer, 1959England, IrelandOpiuspolyzonius Wesmael, 1835England, ScotlandDiachasmasilenis Fischer, 1967WalesDescribed from Welsh material but omitOpiusthomsoni Fischer, 1971annulicornisOpius) preocc. Opiusrudis Wesmael, 1835carinaticeps Gahan, 1917England, IrelandFischer, 1972Phaedrotoma by Raised from synonymy with Opiuspactus Haliday, 1837England, IrelandFischer, 1972SNOFLAKOPIUS Fischer, 1972JUCUNDOPIUS Fischer, 1984OETZALOTENES Fischer, 1998OPIOTENES Fischer, 1998Opius by Raised from synonymy with Opiusaureliae Fischer, 1957England, Scotlandadded by Godfray and Achterberg (2015)Opiuscampanariae Fischer, 1959Scotlandadded by Godfray and Achterberg (2015)Opiusgriffithsi Fischer, 1962EnglandOpiusleptostigma Wesmael, 1835percontatorOpius) longipes Fischer, 1957phytomyzae Fischer, 1957England, Scotland, IrelandThomson, 1895mutus Fischer, 1964gyoerfii Fischer, 1958; synonymy by Achterberg (2014)EnglandFischer, 1958longicornis misident.Englandlongicornis but omitted by Listed as a synonym of longicornis Thomson, 1895, in Taxapad , regardeWesmael, 1835dentifer Thomson, 1895stramineipes Thomson, 1895Marshall, 1894pulchrithorax Fischer, 1958Wesmael, 1835EnglandFischer, 1959EnglandWesmael, 1835latipes misident.England, Irelandpygmaeator in Taxapad (latipes sensu Fischer) by van Achterberg (in prep.).Listed as a synonym of Taxapad , regardeWesmael, 1835Englandfuscipennis , a separate species now placed in the genus Pseudorhinoplus Fischer, 1972.Fischer, 1957csikii Fischer, 1957minor Fischer, 1957nigrithorax Fischer, 1958 preocc.EnglandWesmael, 1835Wesmael, 1835apiculatorBracon) Scotland, Walesadded by Godfray and Achterberg (2015)Wesmael, 1835nigriceps Sz\u00e9pligeti, 1898neopusillus Fischer, 1957England, Scotland, IrelandBraconorbiculator Nees, 1811breviscapus Thomson, 1895IrelandWesmael, 1835exilis Haliday, 1837; synonymy by Achterberg (1997)pallidipesHypolabis) nom. nud. nom. nud. nom. nud. Fischer, 1958EnglandBraconpygmaeator Nees, 1811ruminans Fischer, 1957dilatatus Fischer, 1960meracus Fischer, 1960England, IrelandFischer, 1962EnglandWesmael, 1835clarus Haliday, 1836; synonymy by Fischer (1997)spretus Haliday, 1836; synonymy by Fischer (1997)vindex Haliday, 1837; synonymy by van Achterberg (in prep.)arenosus Sz\u00e9pligeti, 1898England, Irelandclarus and spretus were also synonymised by Both Fischer, 1967Englandadded by Godfray and Achterberg (2015)Fischer, 1969Scotland, IrelandF\u00f6rster, 1863EUTRICHOPSIS F\u00f6rster, 1863NOSOPOEA F\u00f6rster, 1863TOLBIA Cameron, 1907BRACHYCENTRUS Sz\u00e9pligeti, 1907COELOREUTEUS Roman, 1910HEXAULAX Cameron, 1910BAEOCENTRUM Schulz, 1911NEODIOSPILUS Sz\u00e9pligeti, 1911NEOPIUS Fischer, 1965EUOPIUS Fischer, 1967GASTROSEMA Fischer, 1972GERIUS Fischer, 1972GRIMNIRUS Fischer, 1972HOENIRUS Fischer, 1972MEROTRACHYS Fischer, 1972MIMIRUS Fischer, 1972PHLEBOSEMA Fischer, 1972NEOEPHEDRUS Samanta, Tamili, Saha & Raychaudhuri, 1983ADONTOPIUS Fischer, 1984KAINOPAEOPIUS Fischer, 1987MILLENIOPIUS Fischer, 1996NEOTROPOPIUS Fischer, 1999Phaedrotoma was raised from synonymy with Opius by Opius. Generic synonymy follows Phaedrotoma excluded from the British and Irish list:species of viennensis ] Listed by Listed in Fauna Europaea as occurring in Britain, but presumably mistakenly as no literature or specimen records can be located. Known only from Georgia, Greece and Ukraine Opiuscaudatus Wesmael, 1835exsertusOpius) Opiuscoracinus Thomson, 1895EnglandFauna Europaea; there may be a literature citation for its occurrence in Britain but we have been unable to trace it.BMNH, det. Fischer, added in Opiusfulvicollis Thomson, 1895cupidusOpius) Opiusrotundiventris Thomson, 1895EnglandOpiusruficeps Wesmael, 1835EnglandOpiustestaceus Wesmael, 1838EnglandOpiustruncatus Wesmael, 1838EnglandOpiuszelotes Marshall, 1891insertusOpius) Tobias, 1986ukrainicus Tobias, 1986EnglandNMS, det. Taeger, added hereTaeger, 1989Englandadded by Taeger (1989)Marshall, 1898subtilirugosus Papp, 1971England, WalesHartig, 1838obscurator misident.rugulosus Fahringer, 1937hyperboreus Hell\u00e9n, 1958Irelandobscurator auctt. as leptocephalus, this species was recorded as obscurator by Although Taeger, 1989EnglandNMS, det. Taeger, added hereThomson, 1895micropterus Morley, 1907macropteraAptesis) Microduspunctulator Nees, 1811rufiventris Fahringer, 1937Englandadded by Taeger (1989)Microgasterrugosus Nees, 1834EnglandNMS, det. Taeger, added hereTaeger, 1989Wales, Irelandadded by Taeger (1989)Marshall, 1885Hell\u00e9n, 1957Haliday, 1833PENECERUS Wesmael, 1838PARAMESOCRINA Nagamori, 1925Haliday, 1833rubiginosusHormius) Phaenoduspallipes F\u00f6rster, 1863flavipesAraphis) Haliday, 1836ARAPHIS Ruthe, 1854ARRHAPHIS misspellingARHAPHIS misspellingFOLCHINIA Kieffer, 1906PARAMBOLUS Dahl, 1912Pambolus (Pambolus) excluded from the British and Irish list:species of biglumis ; syn. rosenhaueri ; dubius ; imminens ] Included as British in Fauna Europaea and Taxapad F\u00f6rster, 1863Most synonymy has been omitted; published taxonomy has been confused and there are several more species present than have been recorded in the literature, with the application of names not yet settled.Rogasdecorator Haliday, 1836ruficepsExothecus) Rogashariolator Haliday, 1836barbatusExothecus) Rogasmeditator Haliday, 1836England, ScotlandXenarchavariabilis Sz\u00e9pligeti, 1896Englandmeditator by NMS, det. Shaw & van Achterberg, added here; treated as a synonym of Exothecusvaricoxa Thomson, 1892Englandmeditator by NMS, det. Shaw & van Achterberg, added here; treated as a synonym of F\u00f6rster, 1863HISTEROMERINAE Fahringer, 1930Hell\u00e9n, 1957F\u00f6rster, 1863EUCHASMUS Marshall, 1888EPISIGALPHUS Ashmead, 1900Euchasmusexiguus Marshall, 1888EnglandTobias, 1983Acrisis in Fauna Europaea, as a separate genus by Treated as a synonym of Tobias, 1983EnglandNMS, det. Shaw & van Achterberg, added hereTobias, 1983EnglandFauna EuropaeaNMS, det. Shaw & van Achterberg, added on Fahringer, 1930Histeromerus belongs in Rhyssalinae; however, there is as yet no indication as to how Histeromerus can be accommodated within the existing tribal classification of Rhyssalinae, so we simply use Histeromerini for now.Wesmael, 1838MITHOTYNIA Hedqvist, 1976Wesmael, 1838apterusMithotynia) Rogasindagator Haliday, 1836tuberculataExothecus) F\u00f6rster, 1863EPIRHYSSALUS Ashmead, 1900Exothecusminutus Wesmael, 1838lanceolatorBracon) preocc. , laevigatus was synonymised by Traditionally treated as a species separate from Belokobylskij, 1986Rogasfunestus Haliday, 1836schmiedeknechtiBathystomus) Oncophanestobiasi Zaykov, 1980England, ScotlandFauna EuropaeaNMS, det. Shaw & van Achterberg, added on Belokobylskij, 1994England, ScotlandFauna EuropaeaNMS, det. Shaw & van Achterberg, added on Haliday, 1833EURHOPTROCENTRUS Tobias,1977Haliday, 1833England, Scotland, Ireland, Isle of ManEurhoptrocentruslongicaudis Tobias & Belokobylskij, 1991WalesFauna EuropaeaNMS, det. Shaw & van Achterberg, added on F\u00f6rster, 1863Distribution data mostly from NMS and BMNH.Muesebeck, 1928Resurrected by Wesmael, 1838ROGAS misident.RHOGAS misident.PETALODES Wesmael, 1838NEORHOGAS Sz\u00e9pligeti, 1906CHELONORHOGAS Enderlein, 1912Aleiodes species are further subdivided in Taxapad ; the latter is considered here to be a distinct genus (see note under Heterogamus). Taxapad into theAleiodes excluded from the British and Irish list:species of arcticus ] MRS has seen the specimens that this record is based upon (in Ipswich Museum) and they are not arcticus. A species of uncertain status , listed as a synonym of excubitor in Taxapad Exothecusbrevicalcar Thomson, 1891England, ScotlandRogascunctator Haliday, 1836analisExothecus) Rogasexcubitor Haliday, 1836marginellusExothecus) Braconexsertor Nees, 1811orbitatorBracon) Rogasvestigator Haliday, 1836stigmaticus Marshall, 1897jaroshevskyi Telenga, 1941obsoletusOncophanes) preocc. ; syn. solitarius ; synonymy by Lepidoptera that occur in Britain and there is no evidence that tricolor, a parasitoid of Apodalimacodes (Hufnagel) (Lepidoptera: Limacodidae), has ever been found in Britain or Ireland. [Supplementary material 1HymenopteraChecklist of British and Irish Data type: formatted text fileBrief description: Word document version of the checklistFile: oo_84392.docxBroad, G.R., Shaw, M.R. & Godfray, H.C.J.Supplementary material 2BraconidaeChecklist of British and Irish Data type: spreadsheetBrief description: Excel spreadsheet version of the checklistFile: oo_84393.xlsxBroad, G.R., Shaw, MR. & Godfray, H.C.J."} +{"text": "T. turgidum, 56,343 unigenes were matched with 103,327 unigenes of T. turgidum. Compared with the genomes of rice and barley, 14,404 and 7,007 unigenes were matched with 14,608 genes of barley and 7,708 genes of rice, respectively. On the other hand, 2,148, 1,611, and 2,707 unigenes were expressed specifically in roots, stems, and leaves, respectively. Finally, 5,531 SSR sequences were observed from 4,531 unigenes, and 518 primer pairs were designed.Construction as well as characterization of a polish wheat transcriptome is a crucial step to study useful traits of polish wheat. In this study, a transcriptome, including 76,014 unigenes, was assembled from dwarf polish wheat (DPW) roots, stems, and leaves using the software of Trinity. Among these unigenes, 61,748 (81.23%) unigenes were functionally annotated in public databases and classified into differentially functional types. Aligning this transcriptome against draft wheat genome released by the International Wheat Genome Sequencing Consortium (IWGSC), 57,331 (75.42%) unigenes, including 26,122 AB-specific and 2,622 D-specific unigenes, were mapped on A, B, and/or D genomes. Compared with the transcriptome of All annotated information was also deposited at GenBank under the accession GEDT00000000.Among these 76,014 unigenes, 61,748 (81.23%) unigenes were functionally annotated in at least one database of the NCBI Nr, Nt, Swiss-Prot, KEGG, KOG, and COG using blastx with an T. turgidum [ Dendrocalamus latiflorus [Previously well-studied transcriptomes reported that many unigenes were not functionally annotated, such as 30% inturgidum , 32.12% turgidum , and 45.tiflorus . In thistiflorus , these utiflorus .On the other hand, as the lengths of unigenes were longer, the annotated efficiencies were higher . In the http://dx.doi.org/10.1155/2016/5781412; T. turgidum [ T. turgidum (SFile 2). Approximately, 25% of unigenes of DPW transcriptome did not match on draft wheat genome or the transcriptome of T. turgidum, which suggested polish wheat has low genetic similarity with T. durum, T. turgidum, and T. aestivum [ T. ispahanicum and T. durum [Blasted against the draft wheat genome released by IWGSC, 57,331 (75.42%) unigenes were mapped on A, B, and/or D genomes, including 26,122 AB genome-specific and 2,622 D genome-specific unigenes, respectively and 7,007 unigenes were matched with 14,608 genes of barley and 7,708 genes of rice, respectively, which were lower than 70% of unigenes of bread wheat matched with rice and barley genes [Meanwhile, all unigenes were also blasted against the published genomes of barley and riceey genes .Since this transcriptome was constructed from roots, leaves, and stems, there should be some tissue-specific unigenes. Among 76,014 unigenes, 39,083 unigenes, which were involved in basic development and life cycles, such as translation, secondary metabolites biosynthesis, DNA replication, recombination and repair, transcription, signal transduction, carbohydrate transport and metabolism, cell cycle control, cell division, chromosome partitioning, chromatin structure and dynamics, coenzyme transport and metabolism, defense mechanisms, energy production and conversion, and RNA processing and modification, coexisted in all tissues , SFile 5 ABC transporter B and C members, high affinity nitrate transporters, peroxidases, and glutathione S-transferases which participated in metal tolerances [ cytochrome P450, ABC transporter B and G members, beta-galactosidases, glucoside dioxygenases, auxin efflux carriers, and glycosyltransferases that participated in phytohormones transport, cell wall metabolism [ G-type lectin S-receptor-like serine and leucine-rich repeat receptor-like protein kinase which were involved in abiotic-stresses tolerance [On the other hand, 2,148 unigenes, such aslerances \u201330, weretabolism \u201333, respolerance \u201336, wereDue to high level of polymorphism, locus specificity, codominance, convenience, and uniform distribution throughout the genome , SSR marT. turgidum. SFile 3 Comparative information against barley. SFile 4 Comparative information against rice. SFile 4 The information of unigenes expressions. SFile 6 The sequences of SSRs in unigenes. SFile 7 The primers of SSRs. SFile 1 The location of unigenes in wheat chromosomes. SFile 2 Comparative information against"} +{"text": "The ant fauna of Greece has been an object of investigations for almost two centuries, but most of the contributions were restricted to particular parts or regions of the country. The first comprehensive checklist, comprising the past studies on Greek ants, was done only recently by Greek Thrace (or Western Thrace) is one of the geographic and historical regions of Greece. It is the eastern-most mainland part of the country, bordered by Greek Macedonia to the west, Bulgaria to the north , Turkish (or Eastern) Thrace to the east and the Aegean Sea to the south. Most of the northern part of Greek Thrace is occupied by the Rhodope Mountains. Larger plains are situated especially in the south-western, central and north-eastern part of the region. A Mediterranean climate prevails in the southern part of Thrace and is modified by continental influences in the Rhodope Mountains .To improve the knowledge on Thracian ants, we conducted two field trips, in spring 2014 and in summer 2015, and included some previously collected unpublished material. Altogether, we compiled the samples from more than 70 localities throughout the region. As a result we present a check-list of all ant species recorded so far in Greek Thrace with comments on the taxonomy and distribution of poorly known or unnamed species.We sampled ants in spring 2014 and in summer 2015 from the sites in different parts of Greek Thrace. The main method, applied at all sites, was direct sampling (hand collecting). Ant nests and individual specimens were collected on the ground, in leaf litter, under stones, in dead wood, on tree trunks and twigs. This method was occasionally supplemented by litter sifting. Leaf litter from the ground was sieved into sifter with 1 x 1 cm wire mesh. Sieved material was placed on a white sheet and ants were collected.All specimens were preserved in 70-75% ethanol. Material sampled in 2014 is deposited in the personal collection of G. Bra\u010dko and in the collection of the Biological Department of Trakya University . Material sampled in 2015 is stored in the Department of Biodiversity and Evolutionary Taxonomy of the University of Wroc\u0142aw . In this study we also included unpublished material collected in 2013 during general sampling of invertebrate fauna, deposited in the Biological Department of Trakya University. Finally, we examined ants deposited in the Natural History Museum of Crete , sampled in 1999. All sampled localities are described in Table http://www.antweb.org). In the checklist all recently proposed nomenclatural changes made in the subfamily MyrmicinaeFormicinaeThe following taxonomic literature was used for the identification of the collected ants: www.antweb.org.Images of ant specimens shown in this paper were taken using a Nikon SMZ 1500 and Nikon SMZ 18 stereomicroscopes, Nikon D5200 photo camera and Helicon Focus software. All of them have assigned a CASENT number and are available on Below, we present a list of all known ant species from Greek Thrace with the localities of the sampled material Records in Greek Thrace: 9, 13, 25, 51, 70Distribution in Greece and neighbouring regions: East Aegean Is., Ionian Is., Macedonia, Peloponnese, Sterea Ellas; Bulgarian Thrace, Turkish ThraceAphaenogasterfestae Emery, 1915 Records in Greek Thrace: 5, 8, 18, 36, 41, 43, 44, 45, 46, 47, 51, 52, 53, 54, 56, 57, 59, 60, 61, 62, 63, 65, 66, 67, 70Distribution in Greece and neighbouring regions: Cyclades, East Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceAphaenogastercf.subterranea and A.lesbica Forel, 1913. Specimens sampled in the vicinity of Lefkimmi (62) look very similar to samples of A.lesbica, recorded hitherto only from Lesbos and to another unnamed morphospecies, spreaded in various localities of Pieria Mountains in southern part of Macedonia. This complex is now under revision and status of the sample from Thrace will be explained in the future.Notes: Our material from Greece showed that at least seven morphospecies belonging to Bothriomyrmexcommunistus Santschi, 1919Records in Greek Thrace: 51, 58Distribution in Greece and neighbouring regions: Dodecanese, Eastern Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceBothriomyrmexcorsicus Santschi, 1923Records in Greek Thrace: 69Distribution in Greece and neighbouring regions: East Aegean Is., Ionian Is., Macedonia, Peloponnese; Bulgarian Thrace, Turkish ThraceCamponotusaegaeus Emery, 1915Records in Greek Thrace: 66, 68Distribution in Greece and neighbouring regions: Crete, Dodecanese, East Aegean Is., Macedonia; Turkish ThraceCamponotusaethiops Camponotusmarginatus ]Records in Greek Thrace: 3, 5, 7, 9, 12, 13, 25, 30, 31, 32, 33, 38, 48, 51, 53, 58, 63, 66, 68, 69, 70; Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceCamponotusatricolor Records in Greek Thrace: 3, 7, 51, 69, 71Distribution in Greece and neighbouring regions: Dodecanese, East Aegean Is., Macedonia, Peloponnese; Turkish ThraceCamponotusdalmaticus Records in Greek Thrace: 30, 35, 36, 41, 44, 46, 61, 69Distribution in Greece and neighbouring regions: East Aegean Is., Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceCamponotusfallax Records in Greek Thrace: 20, 71Distribution in Greece and neighbouring regions: East Aegean Is., Ionian Is., Macedonia, Peloponnese; Bulgarian Thrace, Turkish ThraceCamponotusgestroi Emery, 1878Records in Greek Thrace: 13, 35, 38Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Ionian Is., Macedonia, Peloponnese; Bulgarian Thrace, Turkish ThraceCamponotusionius Emery, 1920Records in Greek Thrace: 6Distribution in Greece and neighbouring regions: Cyclades, Dodecanese, East Aegean Is., Ionian Is., Macedonia, Peloponnese, Sterea Ellas, ThessalyCamponotuskiesenwetteri Records in Greek Thrace: 38Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Ionian Is., Macedonia, Peloponnese, Sterea EllasCamponotuslateralis Records in Greek Thrace: 10, 12, 17, 18, 20, 30, 31, 33, 35, 36, 37, 41, 42, 43, 44, 45, 46, 47, 48, 50, 51, 61, 62, 63, 64, 65, 66, 67, 69, 71Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceCamponotusoertzeni Forel, 1889 .Notes: This poorly known species was recorded from five Greek regions . Our matCamponotuspiceus Records in Greek Thrace: 4, 17, 25, 46, 69, 70Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceCamponotussamius Forel, 1889Records in Greek Thrace: 12, 34, 46, 69, 70Distribution in Greece and neighbouring regions: Cyclades, Dodecanese, East Aegean Is., Macedonia, Peloponnese, Sterea Ellas; Bulgarian Thrace, Turkish ThraceCamponotusvagus Records in Greek Thrace: 20, 53, 56Distribution in Greece and neighbouring regions: East Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceCardiocondylabulgarica Forel, 1892Records in Greek Thrace: 42, 71Distribution in Greece and neighbouring regions: Dodecanese, East Aegean Is., Macedonia; Bulgarian Thrace, Turkish ThraceCataglyphisnodus Records in Greek Thrace: 3, 7, 9, 11, 16, 17, 18, 20, 30, 31, 32, 35, 41, 43, 46, 48, 52, 61, 66, 69, 71Distribution in Greece and neighbouring regions: Crete, Dodecanese, East Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceCataglyphisviaticoides Fig. \u200bRecords in Greek Thrace: 38Distribution in Greece and neighbouring regions: East Aegean Is.; Turkish ThraceMyrmecocystusalbicansvar.viaticoides were collected in Beyruth (Lebanon). As diagnostic features he noted red colouration of the head and mesosoma and mostly black gaster. In the same paper he described another taxon: Myrmecocystusalbicansvar.lividus. Specimens of this species were collected in Jaffa, Syria (now Israel) and were distinguished by whole body pale reddish and only apex of gaster infuscate . Surprisingly, in the material preserved in Paris Museum one bicoloured syntype with dark gaster with determination label \u201cviaticoides\u201d has locality label \u201cSyrie\u201d (available in AntWeb https://www.antweb.org/specimen/CASENT0912236) and another one, uniformly yellow syntype with determination label \u201cviaticoides\u201d, has locality label \u201cBeyrouth\u201d (available in AntWebhttps://www.antweb.org/specimen/CASENT0915503). In the same collection there is also one syntype of uniformly yellow body with determination label \u201clividus\u201d and locality label \u201cSyrie\u201d (available in AntWebhttps://www.antweb.org/specimen/CASENT0915499). We found two other syntypes with determination label \u201clividus\u201d and locality label \u201cJaffa\u201d in Forel\u2019s collection in Gen\u00e8ve (available in AntWeb https://www.antweb.org/specimen/CASENT0911099) and in Santschi\u2019s collection in Basel (available in AntWeb https://www.antweb.org/specimen/CASENT0912207). Cataglyphisviaticoides from Turkey, Caucasus and Iran concern Cataglyphisrubra . In his next paper with a key to Asian members of the genus Cataglyphis . Cataglyphisviaticoides is the only species of the mentioned above two taxa which occurs in Greece. Data on the distribution of C.bicolor in Transcaucasia, Asia Minor, Iran, the Middle East and Arabian Peninsula should refer to C.viaticoides. True C.bicolor is restricted only to North Africa Records in Greek Thrace: 7, 10, 71Distribution in Greece and neighbouring regions: Crete, Dodecanese, East Aegean Is., Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceCrematogasterionia Forel, 1911Records in Greek Thrace: 6Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Turkish ThraceCrematogasterlorteti Forel, 1910Records in Greek Thrace: 25, 51, 69Distribution in Greece and neighbouring regions: East Aegean Is., Macedonia, Sterea Ellas; Turkish ThraceCrematogasterschmidti Records in Greek Thrace: 3, 5, 9, 10, 12, 17, 18, 20, 30, 31, 33, 34, 35, 36, 37, 40, 41, 42, 43, 44, 45, 46, 47, 48, 50, 51, 54, 61, 62, 63, 65, 66, 68, 69, 70, 71Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceCrematogastersordidula Crematogastermayri ]Records in Greek Thrace: 6, 9, 12, 38, 46, 69, 70; Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceDolichoderusquadripunctatus Records in Greek Thrace: 18, 20, 35, 47, 65Distribution in Greece and neighbouring regions: East Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Thessaly; Bulgarian Thrace, Turkish ThraceFormicacinerea Mayr, 1853Records in Greek Thrace: 5Distribution in Greece and neighbouring regions: Epirus, Macedonia, Thessaly; Bulgarian Thrace, Turkish ThraceFormicaclara Forel, 1886Records in Greek Thrace: 7, 10, 15, 16, 22, 27, 28, 29, 42, 48, 49, 53, 62, 71, 72Distribution in Greece and neighbouring regions: East Aegean Is., Macedonia, Peloponnese; Bulgarian Thrace, Turkish ThraceFormicacunicularia Latreille, 1798Records in Greek Thrace: 1, 2, 5, 42, 46, 47, 49, 53, 58, 59, 60Distribution in Greece and neighbouring regions: Crete, East Aegean Is., Epirus, Macedonia, Sterea Ellas; Bulgarian Thrace, Turkish ThraceFormicafusca Linnaeus, 1758Records in Greek Thrace: 5, 56, 60Distribution in Greece and neighbouring regions: Epirus, Ionian Is., Macedonia, Peloponnese; Bulgarian Thrace, Turkish ThraceFormicagagates Latreille, 1798Records in Greek Thrace: 5, 26, 40, 53, 55, 65Distribution in Greece and neighbouring regions: Epirus, Ionian Is., Macedonia, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceFormicapratensis Retzius, 1783Records in Greek Thrace: 1, 2, 7Distribution in Greece and neighbouring regions: Macedonia; Bulgarian Thrace, Turkish ThraceFormicarufa Linnaeus, 1761Records in Greek Thrace: 56; Legakis 2011Distribution in Greece and neighbouring regions: Macedonia; Bulgarian ThraceFormicarufibarbis Fabricius, 1793Records in Greek Thrace: 1, 5Distribution in Greece and neighbouring regions: Cyclades, East Aegean Is., Epirus, Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceFormicasanguinea Latreille, 1798Records in Greek Thrace: 1, 5, 53Distribution in Greece and neighbouring regions: Macedonia, Peloponnese; Bulgarian Thrace, Turkish ThraceLasiusalienus Records in Greek Thrace: 1, 2, 8, 19, 26, 33, 34, 35, 36, 37, 42, 43, 46, 47, 58, 60, 66, 67, 70Distribution in Greece and neighbouring regions: Cyclades, East Aegean Is., Epirus, Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceLasiusbalcanicus Seifert, 1988 or L.distinguendus L.distinguendus]Records in Greek Thrace: 1, 69; Distribution in Greece and neighbouring regions: Macedonia; Bulgarian Thrace, Turkish ThraceNotes: Proper identification of both species requires nest samples with gynes . We haveLasiusbrunneus Records in Greek Thrace: 26, 47, 50, 53, 54, 59Distribution in Greece and neighbouring regions: East Aegean Is., Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceLasiusflavus Records in Greek Thrace: 42Distribution in Greece and neighbouring regions: East Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceLasiusfuliginosus Records in Greek Thrace: 1, 52, 69, 71Distribution in Greece and neighbouring regions: Macedonia; Bulgarian Thrace, Turkish ThraceLasiusillyricus Zimmermann, 1935Records in Greek Thrace: 4, 5, 8, 20, 26, 52, 53, 54, 55, 56, 58, 59, 60Distribution in Greece and neighbouring regions: Crete, Ionian Is., Macedonia, PeloponneseLasiusjensi Seifert, 1982Records in Greek Thrace: 4Distribution in Greece and neighbouring regions: Macedonia; Bulgarian ThraceLasiuslasioides Records in Greek Thrace: 48Distribution in Greece and neighbouring regions: Crete, Dodecanese, Ionian Is., Macedonia, Thessaly; Turkish ThraceLasiusmyops Forel, 1894Records in Greek Thrace: 44Distribution in Greece and neighbouring regions: Macedonia; Turkish ThraceLasiusneglectus/turcicus complexRecords in Greek Thrace: 6, 12, 13, 18, 20, 22, 30, 32, 38, 42, 45, 47, 48, 49, 50, 51, 56, 65, 68, 69Distribution in Greece and neighbouring regions: Crete, Dodecanese, East Aegean Is., Macedonia, Peloponnese, Sterea Ellas; Turkish ThraceL.neglectus Van Loon, Boomsma & Andrasfalvy, 1990 and L.turcicus Santschi, 1921, is still under discussion. Populations of both taxa show differences in biology and ecology and quite expressed morphometric differences in males , which could indicate that these are two distinct species Records in Greek Thrace: 71Distribution in Greece and neighbouring regions: Macedonia (see notes below); Bulgarian Thrace, Turkish ThraceLasiusniger was listed for six Greek regions Records in Greek Thrace: 6, 12, 13, 18, 20, 22, 24, 25, 29, 30, 32, 34, 35, 43, 44, 46, 47, 48, 49, 50, 67, 68Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceLeptothoraxacervorum Records in Greek Thrace: 1Distribution in Greece and neighbouring regions: Macedonia (see notes below); Bulgarian Thrace, Turkish ThraceLeptothoraxacervorum was only recorded generally from Greece by Notes: Liometopummicrocephalum Records in Greek Thrace: 6, 16, 17, 24, 25, 42, 47Distribution in Greece and neighbouring regions: East Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceMessorcf.ebeninus belong to the Messorsemirufus complex. This complex comprises numerous names of various rank, partly available to nomenclature. Most taxa were described from the eastern part of the Mediterranean Basin Records in Greek Thrace: 5, 9, 13, 17, 25, 30, 33, 35, 43, 48, 49, 58Distribution in Greece and neighbouring regions: Crete, Dodecanese, East Aegean Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Turkish ThraceMessorcf.semirufusRecords in Greek Thrace: 3Distribution in Greece and neighbouring regions: Turkish ThraceM.cf.ebeninus.Notes: See notes under Messorcf.structorRecords in Greek Thrace: 2, 23, 27, 29, 50, 53, 72Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Ionian Is., Macedonia, Peloponnese, Sterea Ellas; Bulgarian Thrace, Turkish ThraceMessorstructor comprises two cryptic species. Both can be found in different parts of the Balkan Peninsula, also in southern Bulgaria close to Greek border Records in Greek Thrace: 5, 6, 9, 60, 70, 71Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceMyrmicahellenica Finzi, 1926Records in Greek Thrace: 7, 10Distribution in Greece and neighbouring regions: Ionian Is., Macedonia, Peloponnese; Bulgarian Thrace, Turkish ThraceMyrmicalonae Finzi, 1926Records in Greek Thrace: 69Distribution in Greece and neighbouring regions: Macedonia; Bulgarian Thrace, Turkish ThraceMyrmicasabuleti Meinert, 1861Records in Greek Thrace: 1, 55, 59, 60Distribution in Greece and neighbouring regions: Dodecanese, Epirus, Macedonia, Sterea Ellas; Bulgarian Thrace, Turkish ThraceMyrmicascabrinodis Nylander, 1846Records in Greek Thrace: 1, 5Distribution in Greece and neighbouring regions: Ionian Is., Macedonia; Bulgarian Thrace, Turkish ThraceMyrmicaspecioides Bondroit, 1918Records in Greek Thrace: 71Distribution in Greece and neighbouring regions: Macedonia; Bulgarian Thrace, Turkish ThracePheidolecf.pallidulaRecords in Greek Thrace: 3, 5, 6, 8, 9, 12, 14, 17, 18, 20, 22, 26, 30, 32, 33, 35, 36, 37, 38, 41, 42, 43, 46, 47, 48, 50, 51, 54, 64, 67, 68, 69, 70Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThracePheidolepallidula are now under revision (B. Seifert pers. comm.). Preliminary results suggest occurrence of at least three taxa in the Mediterranean Basin. True P.pallidula is restricted mostly to the western part of the studied area, while in Greece probably occur two other species although introduction of true P.pallidula to tourist resorts is also possible.Notes: Mediterranean populations of taxon named Plagiolepispallescens sensu Radchenko which is yellowish and has first gaster tergite sparsely pubescent. We have many samples of yellow coloured and sparsely pubescent mature workers collected from Rhodes and observed nests with workers of exclusively yellow aberration and nests with mixed yellow and brown aberrations. Both light and dark colored specimens showed similar level of sclerotization of cuticle. Thus the light colour in this case is not indicative of callow workers. Our specimens of Plagiolepispallescens sensu Radchenko have darker colouration, from yellowish brown to brown. Only the callow workers are lighter yellowish. In morphometric characters samples of both yellow and dark aberrations from Rhodes appear to be conspecific with Plagiolepistaurica Santschi, 1920, a sparsely pubescent species which is also variable in colour . Plagiolepisschmitzi Forel, 1885 is the only other densely pubescent taxon from the Mediterranean area, distributed from Portugal to Sicily Records in Greek Thrace: 6, 8, 9, 12, 17, 20, 30, 32, 35, 36, 37, 41, 42, 43, 44, 45, 46, 47, 50, 51, 61, 64, 65, 66, 69, 70Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThracePlagiolepistaurica Santschi, 1920Records in Greek Thrace: 2, 4, 6, 22, 38, 58, 68Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Ionian Is., Macedonia, Peloponnese; Bulgarian Thrace, Turkish ThracePoneracoarctata Records in Greek Thrace: 30, 60, 71Distribution in Greece and neighbouring regions: Epirus, Ionian Is., Macedonia, Sterea Ellas, Peloponnese, Thessaly; Bulgarian Thrace, Turkish ThracePoneratestacea Emery, 1895Records in Greek Thrace: 46, 69, 70Distribution in Greece and neighbouring regions: Crete, Ionian Is., Macedonia, Peloponnese; Bulgarian ThracePrenolepisnitens Records in Greek Thrace: 5, 8, 51, 69, 70Distribution in Greece and neighbouring regions: East Aegean Is., Epirus, Ionian Is., Macedonia, Sterea Ellas, Peloponnese, Thessaly; Bulgarian Thrace, Turkish ThraceSolenopsisfugax Records in Greek Thrace: 1Distribution in Greece and neighbouring regions: Macedonia; Bulgarian Thrace, Turkish ThraceS.cf.lusitanica.Notes: See notes under Solenopsiscf.lusitanica Records in Greek Thrace: 1, 3, 4, 9, 10, 13, 25, 43, 51, 55, 56, 57, 58, 67, 68, 69, 70, 71Distribution in Greece and neighbouring regions: Crete, Dodecanese, East Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceTapinomasimrothi Krausse, 1911Records in Greek Thrace: 48Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Turkish ThraceTemnothoraxaeolius Records in Greek Thrace: 8, 43Distribution in Greece and neighbouring regions: Cyclades, East Aegean Is., Macedonia, Sterea Ellas; Bulgarian Thrace, Turkish ThraceTemnothoraxcf.affinis Records in Greek Thrace: 25, 43Distribution in Greece and neighbouring regions: Dodecanese, East Aegean Is., Ionian Is., Peloponnese; Bulgarian Thrace, Turkish ThraceTemnothoraxcf.bulgaricus.Notes: See notes under Temnothoraxcf.bulgaricus Records in Greek Thrace: 6, 30, 33, 38, 68Distribution in Greece and neighbouring regions: Crete, Dodecanese, East Aegean Is., Ionian Is., Macedonia, Peloponnese, Sterea Ellas; Turkish ThraceTemnothoraxcf.graecus does not occur in Greece. All Greek populations belong to one or more undescribed taxa of the T.interruptus complex .Notes: Recent studies suggest that true Temnothoraxlichtensteini Records in Greek Thrace: 18, 65Distribution in Greece and neighbouring regions: Epirus, Macedonia, Sterea Ellas, Thessaly; Turkish ThraceTemnothoraxmediterraneus Ward, Brady, Fisher & Schultz, 2015Records in Greek Thrace: 8Distribution in Greece and neighbouring regions: Crete, MacedoniaTemnothoraxnigriceps Records in Greek Thrace: 58Distribution in Greece and neighbouring regions: Ionian Is., Macedonia, Peloponnese; Turkish ThraceTemnothoraxparvulus Records in Greek Thrace: 26, 57, 59, 60Distribution in Greece and neighbouring regions: Ionian Is., Macedonia; Bulgarian Thrace, Turkish ThraceTemnothoraxrecedens Records in Greek Thrace: 6, 8, 17, 20, 31, 36, 39, 41, 43, 44, 46, 47, 50Distribution in Greece and neighbouring regions: Crete, Dodecanese, East Aegean Is., Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceTemnothoraxsemiruber Records in Greek Thrace: 10, 26, 31, 37, 69, 71Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceTemnothoraxsubtilis Cs\u0151sz, Heinze & Mik\u00f3, 2015 Records in Greek Thrace: 5, 53Distribution in Greece and neighbouring regions: Epirus, Macedonia, Thessaly; Bulgarian ThraceTemnothoraxcf.tuberum sp. 1 and sp. 2Records in Greek Thrace: 1, 43Distribution in Greece and neighbouring regions: Crete, East Aegean Is., Ionian Is., Macedonia, Thessaly; Turkish ThraceTemnothoraxtuberum group need revision based on detailed morphometric studies. Our material from various parts of Greece suggests that in this area occur more than one species related to T.tuberum . Specimens collected in Thrace appear to belong to two closely related species.Notes: Greek taxa belonging to Temnothoraxturcicus Records in Greek Thrace: 71Distribution in Greece and neighbouring regions: Macedonia, Thessaly; Bulgarian Thrace, Turkish ThraceTemnothoraxcf.unifasciatus sp. 1 and sp. 2Records in Greek Thrace: 8, 18, 25, 26, 50, 52, 56, 57, 60, 61, 63, 66Distribution in Greece and neighbouring regions: East Aegean Is., Epirus, Ionian Is., Macedonia, Thessaly; Turkish ThraceTemnothoraxunifasciatus group need revision based on detailed morphometric studies. Our material from various parts of Greece suggests that in this area occur at least two species related to T.unifasciatus . Also, in our material from Thrace we have identified two morphospecies of this group.Notes: Greek taxa belonging to Tetramoriumatratulus Records in Greek Thrace: 47Distribution in Greece and neighbouring regions: Macedonia; Turkish ThraceTetramoriumcf.caespitum sp. 1 and sp. 2Records in Greek Thrace: 2, 6, 7, 10, 22, 33, 35, 42, 45, 46, 47, 48, 49, 59, 71Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Epirus, Ionian Is., Macedonia, Peloponnese, Sterea Ellas, Thessaly; Bulgarian Thrace, Turkish ThraceTetramoriumcaespitum/impurum complex in Europe and the Mediterranean area, but so far only five were named formally (T.hungaricum and T.impurum) and two not formally described morphospecies we list here as T.cf.caespitum sp. 1 and sp. 2.Notes: Molecular and morphometric studies suggest occurrence of at least nine species of formally . Our samTetramoriumchefketi Forel, 1911Records in Greek Thrace: 5, 22, 27, 35, 49, 51, 65, 67, 68, 70, 71Distribution in Greece and neighbouring regions: Crete, East Aegean Is., Ionian Is., Macedonia, Thessaly; Bulgarian Thrace, Turkish ThraceTetramoriumcf.davidiRecords in Greek Thrace: 25Distribution in Greece and neighbouring regions: Dodecanese; Turkish ThraceNotes: This sample belongs to a species group with head costulae diverging on occipital part of head and needs a revision. Our material from the eastern part of the Mediterranean suggests the occurrence of at least two distinct morphospecies.Tetramoriumcf.depressum sp. 1Records in Greek Thrace: 12, 68Tetramoriumcf.semilaeve.Notes: See notes under Tetramoriumcf.depressum sp. 2Records in Greek Thrace: 71Tetramoriumcf.semilaeve.Notes: See notes under Tetramoriumferox Ruzsky, 1903Records in Greek Thrace: 27, 42, 46, 72Distribution in Greece and neighbouring regions: Crete, Cyclades, Dodecanese, East Aegean Is., Ionian Is., Macedonia; Bulgarian Thrace, Turkish ThraceTetramoriumcf.flavidulum . Our material from Greece suggests the occurrence of at least three distinct species in this country. Male genitalia, petiole and postpetiole sculpture of the members of this group are very similar to those of the species of T.chefketi group revised by T.chefketi group. Proper identification of the sample from Thrace is impossible prior to the revision of all taxa of T.flaviulum group.Notes: In the eastern part of Mediterranean Basin, Tetramoriumhippocratis Agosti & Collingwood, 1987 Records in Greek Thrace: 1Distribution in Greece and neighbouring regions: Macedonia; Turkish ThraceTetramoriummoravicum Kratochvil, 1941Records in Greek Thrace: 3, 4, 5, 7, 26, 55, 56, 57, 58, 59Distribution in Greece and neighbouring regions: Crete, Epirus, Macedonia, Peloponnese, Thessaly; Bulgarian Thrace, Turkish ThraceTetramoriumrhodium Emery, 1924 . We grouped samples with mostly reduced head sculpture under name T.depressum complex (T.hippocratis and at least three unnamed species) and taxa with more expressed head sculpture under T.semilaeve complex . For proper identification of all taxa nest samples with males and gynes are required. In our material from Thrace we have three species from T.depressum complex and at least one species from T.semilaeve complex (T.cf.semilaeve). We managed to collect only one nest sample of T.semilaeve complex and it belongs to an undescribed species which seems to be widespread in Greece. Probably most literature records of T.semilaeve from Greece concern this undescribed taxon. True T.semilaeve Andr\u00e9, 1883 is distributed only in western part of Mediterranean basin A.splendida group, occurs only in Italy. Four other members of the group were recorded from Greece: A.muelleriana Wolf, 1915 from Epirus and Ionian Is., A.splendida from Macedonia, Peloponnese and Sterea Ellas, A.rugosoferruginea Forel, 1889 endemic to Crete and A.festae Emery, 1915 from Dodecanese, East Aegean Is., Epirus, Macedonia and Thrace. Without voucher specimens it is impossible to determine which species was recorded by Notes: This species, a member of Lepisiotamelas L.melas is distingushed from L.frauenfeldi by the colouration of the mesosoma , being mainly or entirely reddish in L.melas and mainly or entirely dark in L.frauenfeldi. After examining photos of type specimens of both taxa it is evident that these species were misinterpreted and L.melas sensu Agosti & Collingwood = L.frauenfeldi while L.frauenfeldi sensu Agosti & Collingwood = L.melas. Lepisiotamelas is southern species, in Greece occurs in the area south of Macedonia and Thrace while L.frauenfeldi is common in northern part of the country. With great probability the record of L.melas from Thrace in L.frauenfeldi.Notes: In the key to Balkan ants L.melasMessorcaducus M.caducus, and described several infraspecific taxa. The closest to Greek border described taxon is M.caducuscaucasicola Arnoldi, 1977 with type locality in Transcaucasia. Specimens of this taxon were recently collected in southwestern Turkey (our unpublished data). In our collection we also have a new endemic species from Crete, belonging to M.caducus group. Since all known localities for taxa of M.caducus group are far from Greek Thrace, we assume the record in M.semirufus group.Notes: Messorbouvieri Bondroit, 1918M.bouvieri is a western Mediterranean species distributed from Portugal to Italy and its occurrence in Greece is unlikely. Record in M.semirufus group.Notes: Tetramoriumlucidulum Menozzii, 1933T.lucidulum is a distinct species of T.semilaeve group (T.depressum complex), well distinguished by extremely narrow frons. It was described from \u201cSyrien, Kleinasien, Turkestan\u201d by Tetramoriumcaespitumpunicumvar.lucidula, and is most probably absent from Greece. At least four other species of T.depressum complex occur in Greece and it is impossible to conclude what is the identity of the species mentioned in T.lucidulum. See also notes under T.cf.semilaeve.Notes: This species was misinterpreted in the key to Balkan ants . True T.Aphaenogasterfestae, Camponotuskiesenwetteri, Camponotussamius, Cataglyphisviaticoides, Temnothoraxhelenae) as well as species with more northern distribution that are rarely found in other parts of Greece . Among the collected material, we have some particulary interesting species, as they have not been found in the continental part of Greece yet, namely Cataglyphisviaticoides, Temnothoraxaeolius, Tetramoriumcf.davidi, Tetramoriumhippocratis and Tetramoriumrhodium. Temnothoraxaeolius and Tetramoriumrhodium are also absent from the neighbouring regions of Bulgarian and Turkish Thrace. In the checklist of species, we listed some taxa under names that have not been mentioned in the literature for Greece, i.e. Messorcf.ebeninus, Messorcf.semirufus, Temnothoraxcf.affinis, Temnothoraxcf.bulgaricus, Tetramoriumcf.depressum sp. 1, Tetramoriumcf.depressum sp. 2. Since they belong to taxonomically problematic groups it is very possible that they have already been recorded under different names from other parts of the country. Many ant genera and species groups are taxonomically unresolved so we cannot give the exact names for several species from the checklist. Some of them probably have available specific or infraspecific names now trated as synonyms of different taxa, and some are probably taxa new to science.Although Thracian ant fauna has been almost totally neglected thus far, we can consider this Greek region as relatively diverse. We collected 115 species, only 7 already mentioned in the checklist in Results of the present study and recent investigations from other parts of the country show great richness of Greek ant fauna. Based on the material we have collected from various parts of Greece and which includes many still unidentified taxa , it is estimated that at least 320 ant species occur in the fauna of Greece, several of them new to science."} +{"text": "AbstractCymatodera are described from Mexico: Cymatoderatortuosa Burke & Rifkind, sp. n. from Hidalgo and Tamaulipas; Cymatoderaortegae Burke, sp. n. from Colima, Jalisco and Michoacan; Cymatoderagerstmeieri Burke & Rifkind, sp. n. from Chiapas; and Cymatoderamixteca Burke & Rifkind, sp. n. from Puebla and Guerrero. Male genitalia and other characters of taxonomic value are illustrated.Four new species of Cleridae, the present work describes four new species of Cymatodera Gray from the central and southern states of Mexico. As previously discussed . Holotype, red labeled, male: Mexico, Hidalgo, La Florida, municipio de Cardonal, Sitio 1A, 4-V-2014, S. Qui\u00f1onez; holotype deposited in CNIN. Paratype: 1 female: Mexico, Tamaulipas Mpio. Tula, La Presita, Canon de Coyote, 1,900 m, 16-III-1987, P. Kovarik, R. Jones, R. Trevino; paratype deposited in TAMU.Cymatoderatortuosa superficially resembles a number of species that share a similar pattern of fuscous and testaceous elytral banding, such as Cymatoderabalteata LeConte, Cymatoderasirpata Horn, Cymatoderaundulata (Say), and Cymatoderawolcotti Barr. Cymatoderatortuosa, however, can be readily differentiated from those species based on clear differences in the male and female pygidium as well as discontinuity in geographic distribution. Specifically, the new species has the male pygidium distinctly modified , is a reference to the intricate and elaborate structure of the male pygidium of this species.The specific epithet Taxon classificationAnimaliaColeopteraCleridaeBurkesp. n.http://zoobank.org/27646149-9E6B-4397-ACD2-DB7E55F37A7C19\u00b042'N, 104\u00b024'W, 12 km SSD Autlan, mixed hardwood forest 15-VII-1993, R. L. Westcott; holotype deposited in CASC. Paratypes yellow labeled: 1 male: same data as holotype (WFBM); 1 female: Mexico: PageBreakJalisco, 81 km E of El Grullo, 6-X-1992, R. Turnbow (RHTC); 2 males, 1 female: Mex: Jalisco, N slope Nevado de Colima, 8000\u2019, 17-VII-1990, J. Wappes (JEWC); 1 male, Jalisco, Autl\u00e1n, Res. de la Biosfera Manantl\u00e1n, Est. Cientifica Las Joyas, 19\u00b035'443\"N, 104\u00b016'468\"W, 30-VIII-2001, Col. V. H. Toledo (CIUM); 1 male, 2 females: Mexico, Jalisco, 2 km S La Manzanilla, 12-X-2001, F. Hovore (JNRC); 1 female: Mexico, Jalisco, Nevado de Colima, 8200\u2019, Parque Nacional, 10.7 mi N Hwy 54, 17-IX-1986, [no collector data] (KSUC); 1 male: Mexico, Jalisco, 24.8 km SW Ciudad Guzman, 2286 m, 2-VII-1988, R. S. Anderson, pine-oak forest (JNRC); 1 male: Mexico: Sierra de Manantlan, Jalisco, Las Joyas, 1870 m, 18-VII-1985, J. Doyen, black and white light (EMEC); 1 male, 1 female: Mexico, Sierra de Manantlan, Jalisco, 1800-1900 m, 17-VII-1985, J. Doyen (EMEC); 4 females: Mexico, Jalisco, 5.4 km NE de Apango, 19 48 N, 103 41 W, 20-X-1996, beating dead leaf clumps of Quercus sp., R. L. Westcott (WFBM); 1 female: Mexico, Jalisco, Manantlan, Lab. Nat. Las Joyas, 8-VII-1988, F. A. Noguera and Y. A. Rodriguez (CNIC); 1 female: Mexico, Jalisco, 19 km E El Jazmin, (SW Ciudad Guzman), 2005 m, 19-VII-1993, pine-oak forest, R. L. Westcott, collected on Quercus sp. (WFBM); 2 males, 2 females: Mexico, Jalisco, km 3.5-4 Nevado de Colima, 24-VII-2011, R. Turnbow (RHTC); 1 female: Mex: Colima, nr El Terrero, 7800\u2019, 18-VII-199, J. E. Wappes (JEWC); 1 male: Mexico, on elderberry stems, lot 72-11927, 27-VII-1972, Racine and Turk (WFBM); 1 male: Mexico, Colima, NW slope Nevado de Colima, 17-VII-1990, E. Giesbert (JNRC); 1 female: Colima, W rd. to El Terrero, 5000\u2019, 3-5-X-1992, J. E. Wappes (JEWC); 1 male: Mexico, Michoacan, 2 km N Tancitaro, 2700-800 m, 26-I-1947, 53, T. H. Hubbell (JNRC).(n = 30). Holotype red labeled, male: Jalisco, road to microondas Los Mazos, Sierra Manantl\u00e1n, 1425-1610 m, Cymatodera. Cymatoderaortegae appears to be allied to several Mexican congeners that share similar body shape, integumental color, brachypterous condition, and a reduced anterior elytral margin. Of these, Cymatoderabarri Rifkind, Cymatoderamaculifera Barr, and Cymatoderamonticola Rifkind are most similar. Unlike Cymatoderaortegae, however, the males of Cymatoderabarri and Cymatoderamaculifera possess a distinct pair of feebly to moderately developed tubercles on the median posterior portion of the metasternum. Both sexes of these species lack the irregular, infuscate elytral pattern of the new species. Cymatoderamonticola possesses distinctly different terminalia from Cymatoderaortegae, as well as sinuate elytral apices.The undulate fascia pattern on the elytral ground, the testaceous to slightly greenish integumental color, general body shape, and geographic distribution of the new species will, in combination, serve to separate it from other species of PageBreaklocated at the elytral mid-length, moderately wide, extending from the elytral suture to before the epipleural fold. Punctation on elytral ground infuscate . Anterior margin arcuately emarginate; narrower than widest portion of pronotum; humeri very feebly indicated; sides widest on posterior fourth; disc convex; apex rounded, broadly dehiscent, not covering sixth ventrite; surface smooth, moderately clothed with short, fine, pale, recumbent setae intermixed with long, pale, fine, erect setae; sculpturing consisting of small, coarse punctures and larger punctation irregularly arranged from base to apex, punctures becoming less numerous behind anterior third, interstices about 3 \u00d7 the diameter of punctures at elytral base.Abdomen: Ventrites 1\u20135 rugulose; shallowly, moderately punctate; each segment with a pair of large, shallow impressions near sides; surface clothed with short, recumbent setae intermixed with less numerous, long, semi-erect setae. Fifth ventrite Fig. moderatePageBreakbly oblique; phallobase moderately broad; phallus with copulatory piece feebly tapered distally; phallic plate armed with a row of moderately long denticles along the dorsal margin, these denticles increasing in size toward distal end; phallobasic apodeme short, PageBreakrobust, dilated distally; phallobasic struts slender throughout their length, each as long as phallobasic apodeme : Holotype, red labeled, male: Mexico, Chiapas, El Aguacero, 680 m, 17-VI-1990, at light, R. A. Cunningham; holotype deposited in CSCA. Paratypes, yellow labeled: 4 males, 2 females: same data as holotype (JNRC), except 2 males and 1 female collected on 16-VI-1990, and 1 male collected on 01-IX-1990; 1 female: Mexico Chiapas, Aguacero, 16 km W Ocoz[ocuautla], 1-7-VII-1986, 2500\u2019, J. E. Wappes (JEWC).Cymatoderagerstmeieri is similar to a number of New World tilline species that share a testaceous to ferrugineous integument and a median, dark fascia on the elytral ground; those closest include Cymatoderamitae Burke, Bogciadisjuncta Barr, and Cymatoderainsignis Schenkling. The new species can be separated from the former as follows: male specimens of Cymatoderagerstmeieri have the eleventh antennomere medially depressed, acuminate posteriorly, and approximately 2\u00d7 longer than tenth antennomere , in recognition of his many contributions to the study of Taxon classificationAnimaliaColeopteraCleridaeBurke & Rifkindsp. n.http://zoobank.org/580DD2DD-2760-4140-9FCC-5D1E2B495D65PageBreak1973, Mastro and Schaffner (TAMU); 1 female: Mexico, Puebla, 8 mi SE Tehuitzingo, 29-VI-1961, 4100\u2019, University of Kansas, Mexico expedition (SEMC); 1 male: Mexico, Puebla, 6 mi SW Tehuacan, 7-VII-1973, taken at light, Mastro and Schaffner (TAMU); 3 females: Mexico, Guerrero, Mexcala, 29-VI-1959 P. D. Hurd (EMEC);(n = 16): Holotype, red labeled, male: Cacaloapan, Puebla, Mexico, 26-IV-1962, L. A. Stange. Holotype deposited in CASC. Paratypes, yellow labeled: 1 male, 1 female: same data as holotype (FMNH); 2 males: Mexico, Puebla, 2 mi SW Tehuacan, 5300\u2019, 4-X-1975, blacklight trap, 2300-0600, Powell (EMEC); 1 male: Tehuacan, Puebla, Mexico, 23-VI-1953, P. D. Hurd (JNRC); 1 female: 82 km NE Tehuacan, Puebla, Mexico, 5480 ft, rt. 2A, km 242, 7-VI-1948, desert, at light, F. Werner and W. Nutting (KSUC); 2 males, 1 female: Mexico, Puebla, 10 km N Tehuacan, 1650 m, 20-VII-1987, J. T. Doyen (EMEC); 1 female: Mexico, Puebla, 5 mi SW Zapotitlan, 8-VII-Cymatoderamixteca is most similar to the allopatric Cymatoderapallida Schaeffer, but the two species can be readily differentiated based on the structure of the antennae. Antennomeres 2\u20133 of Cymatoderamixteca are about the same length and width but shorter and narrower than the fourth antennomere (Fig. Cymatoderapallida (Fig. Cymatoderamixteca is uniformly pale-testaceous to testaceous (Fig. Cymatoderapallida has a faint, wide, transversal, dark-testaceous band on the last third of the elytral ground (Fig. Cymatoderamixteca is restricted to central Mexico while Cymatoderapallida is found in the southwest portion of the United States and the northern state of Chihuahua, Mexico. Male pygidia of Cymatoderamixteca and Cymatoderapallida (Figs Cymatoderacylindricollis Chevrolat is darker and moderately larger than Cymatoderamixteca.ere Fig. , while aida Fig. . The elyous Fig. while Cyund Fig. . In addiida Figs closely Holotype male. Small, moderately slender, metathoracic wings complete. TL = 9.3 mm. Color: head, pronotum, prosternum, mesosternum and mouthparts testaceous; remainder of body pale testaceous Fig. .Head. HL = 1.1 mm, HW = 1.6 mm. Measured across eyes wider than pronotum; surface feebly rugose, shiny; frons not bi-impressed; moderately, finely punctate; vested with pale, short, recumbent, fine setae interspersed with some erect, fine, long and less numerous setae; eyes moderately rounded, large, slightly longer than wide, feebly emarginate in front, conspicuously bulging laterally. Antennae long, extending to posterior half of elytral length; second and third antennomere small, slender, about the same length; fourth antennomere about 3\u00d7 longer than third antennomere, antennomeres 4\u201310 robust, moderately elongate, subequal in length; antennomeres 2\u20133 subcylindrical; antennomeres 4\u201310 moderately serrate; last antennomere acuminate posteriorly, flattened apically, about the same length of tenth antennomere Fig. .Thorax: PL = 1.7 mm, PW = 0.9 mm. Pronotum moderately rugose, feebly, finely punctate; anterior margin as wide as middle and posterior margin; sides feebly constricted subapically; more constricted behind middle; disc flat, feebly impressed in front of middle; anterior pronotal impression present, subbasal tumescence obvious; surface moderately clothed with pale, stiff, short and long, semirecumbent setae. Prosternum sparsely vested, feebly, finely punctate. Mesosternum convex; surface shiny, smooth, moderately, shallowly punctate. Metasternum with surface feebly rugose, moderately, shallowly puncticulate. Scutellum ovoid, wider than long, posteriorly emarginate.Legs: Moderately vested with pale, fine, recumbent setae intermixed with some scattered, very long, pale, stiff setae; femora transversally rugulose; tibia feebly punctate, longitudinally, finely rugulose.PageBreaktened above, slightly depressed medially, smooth; apices subtriangular, feebly dehiscent; elytral declivity steep; integument clothed with short, pale, fine, recumbent setae intermixed with long, erect, pale, stiff setae; sculpture consisting of moderately coarse punctation arranged in regular striae that gradually become smaller and shallower on toward apex, punctation disappear before elytral apex; interstices at elytral base smooth, about 2.0\u00d7 the width of punctation.Elytra: EL = 4.9 mm, EW = 2.1 mm. Broader than pronotum; humeri pronounced, rounded; sides slightly ovoid; widest portion at posterior fourth; disc moderately flatAbdomen: Ventrites 1\u20134 shiny, smooth; feebly, finely punctate; clothed with few short, pale, fine, recumbent setae; posterior margins truncate; lateral margins not depressed. Fifth ventrite Fig. conspicuAedeagus 0.9 mm long; feebly sclerotized; moderately wide; ratio of length of paramere to whole tegmen 0.3:1; tegmen partially covering phallus; parameres ovoid; lateral margins obtuse, oblique, pointed distally; phallobase wide; phallic plate devoid of denticles, distal portion of phallic plate spinous, spines reduced; phallus rounded at apex, conspicuously wide at middle; phallobasic apodeme robust, swollen distally, longer than phallobasic struts; phallobasic struts moderately robust, swollen distally, approximately 1.2 \u00d7 the length of phallobasic apodeme Fig. .Females of the type series can be differentiated from males by the shape of the sixth ventrite. This segment is broadly rounded posteriorly Fig. , rather Length of males ranges from 6.3\u20138.4 mm; length of females from 7.1\u20137.9 mm. Individuals in the type series vary somewhat in integument color, ranging from pale testaceous to brown. Such color variation is observable in male and female members in the type series. Remaining characters in the type series remain consistent.The type series was collected from various localities in the Sierra Mixteca of Mexico, specifically in the south and southwestern portion of the state of Puebla, and in central Guerrero state Fig. . This reThe specific epithet makes allusion to the regional home of the Mixteca people, and of this new species."} +{"text": "P. Anversa, Boston, USAJ.J.M. Bergeron, Montreal, CanadaM. Bhatia, Christchurch, New ZealandO. Binah, Haifa, IsraelH.E. Blum, Freiburg, GermanyT.B. Bolton, London, UKC. Bona, New York, USAM.D. Bootman, Cambridge, UKN. Bornstein, Tel Aviv, IsraelG. Bussolati, Turin, ItalyK. Camphausen, Bethesda, USAM. Caraglia, Naples, ItalyY.H. Chen, Shanghai, ChinaC.-M. Cheng, Hsinchu, TaiwanS.N. Constantinescu, Brussels, BelgiumP. Doevendans, Utrecht, The NetherlandsB. Eyden, Manchester, UKM.S. Faussone-Pellegrini, Florence, ItalyW. Franke, Heidelberg, GermanyL. Frati, Rome, ItalyT. Fujimoto, Nagoya, JapanP.M. Glazer, New Haven, USAJ. Gooch, Atlanta, USAH. zur Hausen, Heidelberg, GermanyA.M. Hofer, Boston, USAR.E. Horch, Erlangen, GermanyO. Hovatta, Huddinge, SwedenS.S. Hu, Beijing, ChinaJ.D. Huizinga, Hamilton, CanadaM. Ivan, Indianapolis, USAB. Jena, Detroit, USAY.T. Konttinen, Helsinki, FinlandT. Kornberg, San Francisco, USAS. Kostin, Bad Nauheim, GermanyR.C. Kukreja, Richmond, VA, USAR. Langer, Cambridge, USAJ.W. Lawler, Boston, USAF. Lupu, Oklahoma City, USAJ. Meldolesi, Milan, ItalyM. Mercola, San Diego, USAV.M. Miller, Rochester, USAK. Morgan, Boston, USAJ.F. Morris, Oxford, UKC. Mummery, Utrecht, The NetherlandsF. Murad, Houston, USAD.F. Mure\u015fanu, Cluj-Napoca, RomaniaH. O\u2019Neil, Canberra, AustraliaK.P. Nephew, Bloomington, USAM. Pesce, Milan, ItalyO.H. Petersen, Liverpool, UKN.C. Popescu, Bethesda, USAD. Pozo, Sevilla, SpainM.Z. Ratajczak, Louisville, USAU. Ripamonti, Johannesburg, South AfricaJ. Rubin, Bethesda, USAA. Samali, Galway, IrelandP.R. Sanberg, Tampa, USAR.C. dos Santos Goldenberg Rio de Janeiro, BrasilM. Simionescu, Bucharest, RomaniaG.W. Sledge, Indiana, USAR.V. Stan, Hanover, USAG. Steinhoff, Rostock, GermanyM. St\u00fcrzl, Erlangen, GermanyM. Taggart, Newcastle upon Tyne, UKA. Tosaki, Debrecen, HungaryN.A. Turner, Leeds, UKC.A. Vacanti, Boston, USAA. Vaheri, Helsinki, FinlandL. V\u00e9csei, Szeged, HungaryV. Velculescu, Baltimore, USAC. Wang, Beijing, ChinaR.A. Wang, Xi\u2019an, ChinaB. Winblad, Stockholm, SwedenC. Zhang, Newark, USAM. Leabu, Bucharest, RomaniaAsia OfficeX. Wang, Shanghai, ChinaH. Amin, Houston, USAK. Cheng, Los Angeles, CA, USAL. Chirieac, Boston, USASanda M. Ciontea, Bucharest, RomaniaV. Cismasiu, Oxford, UKCamelia Iancu-Rubin, New York, USAElisa-Anamaria Liehn, Aachen, GermanyN.I. Moldovan, Columbus, USAM. Oprica, Stockholm, SwedenA.G. Papavassiliou, Athens, GreeceR.A. Towner, Oklahoma City, USAD. Cretoiu, Bucharest, RomaniaC.G. Manole, Bucharest, RomaniaJournal of Cellular and Molecular Medicine, P.O. Box 35-29, Bucharest 35, Romania. Tel./Fax: +40 21 312 4885. E-mail: editors@jcmm.orgJournal of Cellular and Molecular Medicine, Blackwell Publishing Ltd, 9600 Garsington Road, Oxford, OX4 2DQ UK. Tel.: +44 1865 776868, Fax: +44 1865 714591.jcmm@wiley.com)Production Editor: Jeremy Chua , Short Communications, Editorials and Points of View, as well as Letters to the Editor. From time to time the journal publishes Retro-views of significant ideas and discoveries, and Commentaries.The http://www.wileyopenaccess.com/details/content/12f25db4c87/Copyright--License.html.From12th September 2012 all articles accepted by the Journal of Cellular and Molecular Medicine are fully open access: immediately freely available to read, download and share. All articles accepted from 12th September 2012 are published under the terms of the Creative Commons Attribution License. Articles accepted before this date were published under the agreement as stated in the final article. The Creative Commons Attribution License permits use, distribution and reproduction in any medium, provided the original work is properly cited and allows the commercial use of published articles. Copyright on any research article in a journal published by the Journal of Cellular and Molecular Medicine is retained by the author(s). Authors grant Wiley a license to publish the article and identify itself as the original publisher. Authors also grant any third party the right to use the article freely as long as its integrity is maintained and its original authors, citation details and publisher are identified. Further information about open access license and copyright can be found at corporatesales@wiley.com.Print reprints of Wiley Open Access articles can be purchased from The Publisher and Editors cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed do not necessarily reflect those of the Publisher and Editors, neither does the publication of advertisements constitute any endorsements by the Publisher and Editors of the products advertised.Wiley Open Access articles posted to repositories or websites are without warranty from Wiley of any kind, either express or implied, including, but not limited to, warranties of merchantability, fitness for a particular purpose, or non-infringement. To the fullest extent permitted by law Wiley disclaims all liability for any loss or damage arising out of, or in connection with, the use of or inability to use the content.Wiley's Corporate Citizenship initiative seeks to address the environmental, social, economic, and ethical challenges faced in our business and which are important to our diverse stakeholder groups. Since launching the initiative, we have focused on sharing our content with those in need, enhancing community philanthropy, reducing our carbon impact, creating global guidelines and best practices for paper use, establishing a vendor code of ethics, and engaging our colleagues and other stakeholders in our efforts.http://www.wiley.com/go/citizenshipFollow our progress at Journal of Cellular and Molecular Medicine is published in 12 issues per year in an online-only format available at Wiley Online Library. Visit wileyonlinelibrary.com to search the articles and register for table of contents e-mail alerts.http://www.healthinternetwork.orgAccess to this journal is available free online within institutions in the developing world through the HINARI initiatives with the WHO.For information, visit This journal is indexed by Science Citation Index Expanded, Current Contents/Life Sciences, Journal Citation Reports/Science Edition, Biological Abstracts, BIOSIS Previews.ISSN (1582-4934) (Online)http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1582-4934For submission instructions, subscription and all other information visit:"} +{"text": "Scientific Reports6: Article number: 23488; 10.1038/srep23488published online: 03222016; updated: 04222016In this Article, Affiliation 2 was omitted for Jing Zhang. The correct affiliation is listed below:College of Forestry, Beijing Forestry University, No. 35, Tsinghua East Road, Haidian District, Beijing, 100083, China."} +{"text": "A phase 3 trial (TENDER) demonstrated the efficacy of the interleukin-6 receptor inhibitor TCZ in pts with sjia ,2.To investigate progression of radiographic joint damage in pts with sjia treated with TCZ for up to 2 years in TENDER.112 pts 2-17 yrs old with active, refractory sjia of \u22656 months' duration and inadequate response to previous non-steroidal anti-inflammatory drugs and oral corticosteroids were enrolled in TENDER. Pts were randomised 2:1 to receive TCZ according to body weight (12 mg/kg <30 kg or 8 mg/kg \u226530 kg) or placebo IV every 2 wks for 12 wks. Pts then received open-label TCZ in the ongoing long-term extension. Radiographic progression was calculated as change in adapted Sharp/van der Heijde score (ash) score and/or Poznanski score, assessed on hand and wrist radiographs, from baseline to wks 52 and 104. Radiographic progression was indicated by a positive ash score change or negative Poznanski score change. Clinical efficacy endpoints included American College of Rheumatology (ACR) Paediatric (Pedi) 70/90 responses.Baseline and \u22651 postbaseline ash and Poznanski scores were available for 47 and 33 pts, respectively . Baseline characteristics for pts with radiographic data were similar to the whole TCZ population [Though changes in radiographic scores over time were seen in many pts, on average, pts with sjia did not experience noticeable progression of radiographic damage over 2 yrs of treatment with TCZ.C. Malattia: None declared., N. Ruperto Grant/Research Support from: Abbott, astrazeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, merckserono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Consultant for: Abbott, astrazeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, merckserono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Speakers Bureau: Abbott, Boehringer, BMS, Novartis, Astellas, Italfarmaco, medimmune, Pfizer, Roche, E. Palmisani: None declared., S. Pederzoli: None declared., A. Pistorio: None declared., H. I. Brunner Consultant for: Novartis, Genentech, medimmune, EMD Serono, AMS, Pfizer, UCB, Janssen, Speakers Bureau: Genentech, R. Cuttica Speakers Bureau: Roche, Abbott, Pfizer, Novartis, BMS, I. Calvo: None declared., S. M. Garay: None declared., D. Eleftheriou: None declared., C. Wouters: None declared., J. Wang Employee of: Roche Products Ltd, C. Devlin Employee of: Roche Products Ltd, D. Lovell Grant/Research Support from: NIH, Consultant for: astrazeneca, Centocor, Janssen, Wyeth, Amgen, Bristol-Meyers Squibb, Abbott, Pfizer, Regeneron, Hoffmann-La Roche, Novartis, Genentech, Speakers Bureau: Roche, Genentech, A. Martini Grant/Research Support from: Abbott, astrazeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, merckserono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Consultant for: Abbott, astrazeneca, BMS, Centocor, Lilly, Francesco Angelini, GSK, Italfarmaco, merckserono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, Speakers Bureau: Abbott, Boehringer, BMS, Novartis, Astellas, Italfarmaco, medimmune, Pfizer, Roche, F. De Benedetti Grant/Research Support from: Abbott, Pfizer, BMS, Roche, Novimmune, Novartis, SOBI, A. Ravelli: None declared."} +{"text": "P. Anversa, Boston, USAJ.J.M. Bergeron, Montreal, CanadaM. Bhatia, Christchurch, New ZealandO. Binah, Haifa, IsraelH.E. Blum, Freiburg, GermanyT.B. Bolton, London, UKC. Bona, New York, USAM.D. Bootman, Cambridge, UKN. Bornstein, Tel Aviv, IsraelG. Bussolati, Turin, ItalyK. Camphausen, Bethesda, USAM. Caraglia, Naples, ItalyY.H. Chen, Shanghai, ChinaC.-M. Cheng, Hsinchu, TaiwanS.N. Constantinescu, Brussels, BelgiumP. Doevendans, Utrecht, The NetherlandsB. Eyden, Manchester, UKM.S. Faussone-Pellegrini, Florence, ItalyW. Franke, Heidelberg, GermanyL. Frati, Rome, ItalyT. Fujimoto, Nagoya, JapanP.M. Glazer, New Haven, USAJ. Gooch, Atlanta, USAH. zur Hausen, Heidelberg, GermanyA.M. Hofer, Boston, USAR.E. Horch, Erlangen, GermanyO. Hovatta, Huddinge, SwedenS.S. Hu, Beijing, ChinaJ.D. Huizinga, Hamilton, CanadaM. Ivan, Indianapolis, USAB. Jena, Detroit, USAY.T. Konttinen, Helsinki, FinlandT. Kornberg, San Francisco, USAS. Kostin, Bad Nauheim, GermanyR.C. Kukreja, Richmond, VA, USAR. Langer, Cambridge, USAJ.W. Lawler, Boston, USAF. Lupu, Oklahoma City, USAJ. Meldolesi, Milan, ItalyM. Mercola, San Diego, USAV.M. Miller, Rochester, USAK. Morgan, Boston, USAJ.F. Morris, Oxford, UKC. Mummery, Utrecht, The NetherlandsF. Murad, Houston, USAD.F. Mure\u015fanu, Cluj-Napoca, RomaniaH. O\u2019Neil, Canberra, AustraliaK.P. Nephew, Bloomington, USAM. Pesce, Milan, ItalyO.H. Petersen, Liverpool, UKN.C. Popescu, Bethesda, USAD. Pozo, Sevilla, SpainM.Z. Ratajczak, Louisville, USAU. Ripamonti, Johannesburg, South AfricaJ. Rubin, Bethesda, USAA. Samali, Galway, IrelandP.R. Sanberg, Tampa, USAR.C. dos Santos Goldenberg Rio de Janeiro, BrasilM. Simionescu, Bucharest, RomaniaG.W. Sledge, Indiana, USAR.V. Stan, Hanover, USAG. Steinhoff, Rostock, GermanyM. St\u00fcrzl, Erlangen, GermanyM. Taggart, Newcastle upon Tyne, UKA. Tosaki, Debrecen, HungaryN.A. Turner, Leeds, UKC.A. Vacanti, Boston, USAA. Vaheri, Helsinki, FinlandL. V\u00e9csei, Szeged, HungaryV. Velculescu, Baltimore, USAC. Wang, Beijing, ChinaR.A. Wang, Xi\u2019an, ChinaB. Winblad, Stockholm, SwedenC. Zhang, Newark, USAM. Leabu, Bucharest, RomaniaAsia OfficeX. Wang, Shanghai, ChinaH. Amin, Houston, USAK. Cheng, Los Angeles, CA, USAL. Chirieac, Boston, USASanda M. Ciontea, Bucharest, RomaniaV. Cismasiu, Oxford, UKCamelia Iancu-Rubin, New York, USAElisa-Anamaria Liehn, Aachen, GermanyN.I. Moldovan, Columbus, USAM. Oprica, Stockholm, SwedenA.G. Papavassiliou, Athens, GreeceR.A. Towner, Oklahoma City, USAD. Cretoiu, Bucharest, RomaniaC.G. Manole, Bucharest, RomaniaM.E. Hinescu, Bucharest, RomaniaJournal of Cellular and Molecular Medicine, P.O. Box 35-29, Bucharest 35, Romania. Tel./Fax: +40 21 312 4885. E-mail: editors@jcmm.orgJournal of Cellular and Molecular Medicine, Blackwell Publishing Ltd, 9600 Garsington Road, Oxford, OX4 2DQ UK. Tel.: +44 1865 776868 Fax: +44 1865 714591.jcmm@wiley.com)Production Editor: Jeremy Chua , Short Communications, Editorials and Points of View, as well as Letters to the Editor. From time to time the journal publishes Retro-views of significant ideas and discoveries, and Commentaries.The http://www.wileyopenaccess.com/details/content/12f25db4c87/Copyright--License.html.From12th September 2012 all articles accepted by the Journal of Cellular and Molecular Medicine are fully open access: immediately freely available to read, download and share. All articles accepted from 12th September 2012 are published under the terms of the Creative Commons Attribution License. Articles accepted before this date were published under the agreement as stated in the final article. The Creative Commons Attribution License permits use, distribution and reproduction in any medium, provided the original work is properly cited and allows the commercial use of published articles. Copyright on any research article in a journal published by the Journal of Cellular and Molecular Medicine is retained by the author(s). Authors grant Wiley a license to publish the article and identify itself as the original publisher. Authors also grant any third party the right to use the article freely as long as its integrity is maintained and its original authors, citation details and publisher are identified. 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Visit wileyonlinelibrary.com to search the articles and register for table of contents e-mail alerts.http://www.healthinternetwork.orgAccess to this journal is available free online within institutions in the developing world through the HINARI initiatives with the WHO.For information, visit This journal is indexed by Science Citation Index Expanded, Current Contents/Life Sciences, Journal Citation Reports/Science Edition, Biological Abstracts, BIOSIS Previews.ISSN (1582-4934) (Online)http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1582-4934For submission instructions, subscription and all other information visit:"} +{"text": "Kathleen McCaffrey has been added as the third author. The updated author order is as follows: Niyas Kudukkil Pulloor, Sajith Nair, Kathleen McCaffrey, Aleksandar D. Kostic, Pradeep Bist, Jeremy D. Weaver, Andrew M. Riley, Richa Tyagi, Pradeep D. Uchil, John D. York, Solomon H. Snyder, Adolfo Garc\u00eda-Sastre, Barry V. L. Potter, Rongtuan Lin, Stephen B. Shears, Ramnik J. Xavier, Manoj N. Krishnan.The second, third, fourth, and fifth authors, Sajith Nair, Kathleen McCaffrey, Aleksandar D. Kostic, and Pradeep Bist, should be noted as contributing equally to this work.Kathleen McCaffrey is affiliated with 1: Program on Emerging Infectious Diseases, DUKE-NUS Graduate Medical School, Singapore. Her current address is: Cellular Protein Chemistry, Faculty of Science, Utrecht University, Utrecht, the Netherlands.The correct citation is: Pulloor NK, Nair S, McCaffrey K, Kostic AD, Bist P, et al. (2014) Human Genome-Wide RNAi Screen Identifies an Essential Role for Inositol Pyrophosphates in Type-I Interferon Response. PLoS Pathog 10(2): e1003981. doi:10.1371/journal.ppat.1003981.The originally published The corrected version of"} +{"text": "After publication of this work , we noteCaroline Murphy, Joanna Kelly, John Hodsoll, Evangelos Georgiou, Lloyd Morgan, Christopher Rowson, Victoria Cole, Fatima Jichi, and Andrew Pickles."} +{"text": "Scientific Reports6: Article number: 2626910.1038/srep26269; published online: 05192016; updated: 08012016In this Article, Wen Jiang is incorrectly affiliated with:Department of Hematology/Oncology, Mayo Clinic College of Medicine, 4500 San Pablo Road, Jacksonville FL, 32224, USA.The correct affiliation is listed below:Department of Radiation Oncology, UT-MD Anderson Cancer Center, 1515 Holcombe Blvd Houston TX, 77030, USA."} +{"text": "After publication of the original article it was fMTH, NS, and SJL drafted the manuscript. NS, NL, and JT devised and performed LCMS analyses. NJW, NPJD, and AMD conceived of the study. SD, MTH, RJM, MAF, MMUH, MAH, SMo, SMi, CJW, and AG contributed to the design. MTH, SJL, SD, RJM, HWFK, KP, PC, KS, and KC provided clinical and diagnostic data collection and critically revised the manuscript. All authors read and approved the final manuscript."} +{"text": "IL-1\u03b2, an inflammatory cytokine, plays an important role in SJIA, a rare autoinflammatory disease. Canakinumab (CAN), a selective fully human, anti-IL-1\u03b2 monoclonal antibody, is reported to be efficacious in treating SJIA.To characterize changes in peripheral blood gene expression and inflammatory proteins in SJIA patients (pts) treated with CAN and to identify baseline biomarkers that predict clinical response to CAN treatment.Levels of inflammatory biomarkers and gene expression profiles of active SJIA pts (aged 2-19 yrs) before and during CAN treatment enrolled in 2 phase III trials were analyzed.Transcriptional changes upon CAN treatment at Day 3 were assessed. When applying cut-offs of \u22652 fold and p \u2264 0.05, no transcript passed this filter for placebo pts and for CAN pts that were ACR30 (adapted pediatric ACR) non-responders at Day 15, while 171 probesets passed the filter for pts showing \u2265ACR30 response. Pts who showed strong transcriptional changes also showed a strong ACR response (\u2265ACR50) at Day 15, while pts with 30 kg/m2 .In total, 59 COVID-19 were recorded among cases (n\u00a0= 32) and controls (n\u00a0= 27), including 2 severe COVID-19 but no death. No difference was observed between healthcare workers and controls regarding the overall incidence rates of COVID-19 4.9 \u00b1 2.2 Healthcare workers with IBD do not have an increased risk of COVID-19 compared with other patients with IBD. Coronavirus disease 2019 (COVID-19) is a respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in healthcare workers and severe COVID-19 in 5% [3%\u20138%] % in heal.We thus conducted a multicenter case-control study in a real-life setting aiming to assess the incidence rate of COVID-19 in healthcare workers with IBD compared with other non-healthcare worker patients with IBD, and to identify the predictors of COVID-19.st 2020.The present study was a follow-up extension of a retrospective observational multicenter case-control study conducted in 17 French and Belgian academic centers affiliated with the Groupe d'Etude Th\u00e9rapeutique des Affections Inflammatoires du tube Digestif (GETAID). In this study, 482 patients with IBD who were healthcare workers and 482 controls patients were included from the MICISTA registry, a tertiary monocentric clinical database of all consecutive patients with IBD at Saint-Antoine Hospital . It is cIn the recent meta-analysis on the risk of COVID-19 in patients with IBD, 9 out of 23 studies reported specific outcomes according to ongoing treatments. Worse outcomes were noted in patients treated with steroids and aminosalicylates and better outcomes for those treated with biologics and immunosuppressants . This co2. Obesity has been repeatedly reported as a risk factor of COVID-19 and severe COVID-19 in various cohort and epidemiological studies , [ studies . The lin studies ,24. Thos studies . However studies .Whereas, we included a large number of healthcare workers with IBD, we acknowledge a number of limitations in this study. First, the size of the present study may be too small to assess statistical difference between both groups. Second, data collection was retrospective during year 2021. However, all the participating centres are tertiary care centre with standardized clinical, biological, endoscopic and morphological prospective follow-up that lower the impact of such bias. Third, we focused on COVID-19 defined as symptomatic SARS-CoV-2 infection with positive RT-PCR test for SARS-CoV-2 on nasopharyngeal swab and/or a positive serological test for SARS-CoV-2 without prior vaccination. Nonetheless, this bias should be balanced in both groups. Fourth, we lost one third of the original cohort in both the healthcare worker and control groups and had to subsequently proceed to a rematch process of cases and controls. However, both groups were ultimately well balanced with few significant differences.We concluded that healthcare workers with IBD did not exhibit an increased risk of COVID-19 compared with controls. Special attention should be given to nurses' aides with regard to closest contact with patients and underlying risk of transmission of SARS-CoV-2. Those data are reassuring as well as the low incidence of severe COVID-19 either in healthcare workers and control patients with IBD.Conception and design of the study: CG, SN, LPB, PS, AAGeneration, Collection, Assembly, Analysis and/or Interpretation of data: AA, AB, PS, JMG, OD, SN, RA, VA, DL, CR, AB, MN, SV, LV, CS, PM, GB, AADrafting or revision of the manuscript: AA, AB, PS, JMG, OD, SN, RA, VA, DL, CR, AB, MN, SV, LV, CS, PM, GB, AAApproval of the final version of the manuscript: AA, AB, PS, JMG, OD, SN, RA, VA, DL, CR, AB, MN, SV, LV, CS, PM, GB, AAWe wish to confirm that all the authors have approved the current submission.Aurelien Amiot received consulting fees from Abbvie, Hospira, Janssen, Tillotts, Pfizer, Takeda, Gilead and Biocodex as well as lecture fees and travel accommodations from Abbvie, Janssen, Biocodex, Hospira, Ferring, Pfizer, Biogen, Amgen, Fresenius Kabi, Ferring, Tillotts, Takeda and MSD. This author also received advisory board fees from Gilead, Tillotts, Takeda and AbbvieJean-Marc Gornet received fees from Sanofi, Merck Serono, Roche, Novartis, Amgen and travel accommodation from Abbvie and MSD.Olivier DeWit received consulting, lecture fees or travel accommodations from Abbvie, Biogen, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Galapagos, Janssen, MSD, Mylan, Pfizer, Sandoz.Stephane Nancey received consulting fees from Merck, Abbvie, Takeda, Ferring, Norgine, Vifor Pharma, Novartis, Janssen-Cilag, Hospira, Takeda and HAC-Pharma.Romain Altwegg received board or lectures fees from Abbvie, Janssen, Pfizer, Takeda, Amgen, Celltrion, Norgine, FerringVered Abitbol received lecture fees from Biogen Amgen Sandoz Mylan Pfizer Takeda Janssen Gilead TillotsDavid Laharie received counseling, boards or transports fees from Abbvie, Biogaran, Biogen, Ferring, HAC-pharma, Janssen, MSD, Novartis, Pfizer, Prometheus, Roche, Takeda, Theradiag, Tillots.Catherine Reenaers received lecture fees from Abbvie, Takeda, Ferring, Pfizer, Galapagos, Celltrion, Janssen, Fresenius-Kabi, Bristol Myers Squibb, Thermo-Fisher and consultancy fees from Galapagos, Celltrion, Janssen, Fresenius-Kabi, Bristol Myers SquibbCharlotte Gagniere received travel accommodations from Takeda.Anthony Buisson has received research funding from Pfizer, lecture fees from Abbvie, Ferring, Hospira, MSD, Janssen, Sanofi-Aventis, Takeda and Vifor Pharma and consulting fees from Abbvie, Biogen, Janssen, Pfizer and Takeda.Maria Nachury received board membership, consultancy, or lecture fees from Abbvie, Adacyte, Amgen, Arena, Biogen, CTMA, Celltrion, Ferring, Fresenius-Kabi, Janssen, Mayoli-Spindler, MSD, Pfizer, TakedaStephanie Viennot has received consulting fees from Abbvie, MSD, Takeda, Vifor Pharma and Ferring.Lucine Vuitton received lecture fees from Abbvie, MSD, Takeda, Ferring, Mayoli, Janssen and Pfizer, and research grants from MSD, Takeda and Pfizer.Guillaume Bouguen received lecture fees from Abbvie, Ferring, MSD, Takeda and Pfizer and consultant fees from Takeda, Janssen, Sandoz and Mylan.Seksik P reports consulting fees from Pfizer, Astellas, Janssen, Fresenius Kabi, Takeda, Pil\u00e8ge and Biocodex and grants from Biocodex and Janssen.These conflicts of interest are unrelated to the current work.None for the remaining authors.None"} +{"text": "Scientific Reports 10.1038/s41598-022-20709-3, published online 05 October 2022Correction to: The original version of this Article contained an error in the order of the author names, which was incorrectly given as Junyan Wang, Rui Li, Minai Zhang, Chensheng Gu, Haili Wang, Jianjian Feng, Linjie Bao, Yihe Wu, Xichun Zhang & Shuming Chen.The original Article has been corrected."} +{"text": "Oxford Medical Case Reports, Volume 2022, Issue 7, July 2022, omac072, https://doi.org/10.1093/omcr/omac072This is a correction to: Yuki Muta, Akio Odaka, Seiichiro Inoue, Yuta Takeuchi, Yoshifumi Beck, Minimally invasive fenestration for congenital hepatic cyst in infant, In the originally published version of this manuscript, Yuta Takeuchi's name was mis-spelled as Yuta Takechi.This error has been corrected."} +{"text": "International Journal of Integrated Care. 2022; 22: 19. DOI: http://doi.org/10.5334/ijic.5997.This article details a correction to: Blythe R, Carter H, Abell B, Brain D, Dyer C, White N, et al. Application of a Mixed Methods Multi-Criteria Decision Analysis Framework in Integrated Health Care. Blythe et al. (2022) was publThe original author list was:Robin Blythe, Hannah Carter, Bridget Abell, David Brain, Carly Dyer, Nicole White, Sanjeewa Kularatna, Steven McPhailThe author list should instead read:Robin Blythe, Hannah Carter, Bridget Abell, Megan Campbell, David Brain, Carly Dyer, Nicole White, Sanjeewa Kularatna, Steven McPhailAll authors fit the authorship definitions and have confirmed the new list is correct."} +{"text": "The rapid development and distribution of SARS-CoV-2 vaccines has raised concerns surrounding vaccine safety in immunocompromised populations, such as those with inflammatory bowel disease (IBD).We described adverse events (AEs) following SARS-CoV-2 vaccination in those with IBD and determined relationships between AEs to post-vaccination antibody titres.n=670) who received a 1st, 2nd, 3rd, and/or 4th dose of a SARS-CoV-2 vaccine were interviewed via telephone for AEs using the Adverse Events Following Immunization form. Subsequently, we assessed injection site reaction as a specific AE outcome. Multivariable logistic regression models were used to assess the association between anti-SARS-CoV-2 spike protein antibody (anti-S) levels within 1\u201312 weeks of vaccination and injection site reaction following 1st, 2nd, and 3rd dose vaccination. Models were adjusted for age, sex, IBD type, IBD medications, vaccine type, and prior COVID-19 infection. Additionally, we evaluated the risk of flare of IBD within 30 days of vaccination via chart review.Individuals with IBD from a prospective cohort in Calgary, Canada (st dose (n=331), 2nd dose (n=331), 3rd dose (n=195), and 4th dose (n=100) of a SARS-CoV-2 vaccine. AEs were reported in 83.3% of participants after 1st dose, 79.1% after 2nd dose, 77.4% after 3rd dose, and 67.0% after 4th dose. Injection site reaction was the most common AE (50.8% of AEs), with fatigue and malaise (18.1%), headache and migraine (8.6%), musculoskeletal discomfort (8.2%), and fever and chills (6.5%) also commonly reported. Multivariable logistic regression determined no associations between anti-S concentration and injection site reaction for all doses. Age above 65 years was associated with decreased injection site reaction following 1st and 3rd doses, while female sex and mRNA vaccine type were associated with increased injection site reaction following 1st and 2nd doses. Prior COVID-19 infection, IBD type, and medication class were not associated with injection site reaction with any dose. Only one participant was diagnosed with a severe AE requiring hospitalization: Immune thrombocytopenic purpura (ITP) following 2nd dose of a Pfizer vaccination. No cases of IBD flare occurred within 30 days of vaccination.Table 1 describes AEs in individuals with IBD following 1AEs following SARS-CoV-2 vaccination are generally mild and become less common with each consecutive dose. Antibody levels following each dose of the vaccine were not associated with injection site reactions. Females, those under 65 years of age, and those administered mRNA vaccines were more likely to experience an injection site reaction. Prior COVID-19 infection, IBD type, and IBD medication class did not predict injection site reactions. Vaccination was not associated with IBD flare within 30 days of vaccination.OtherHelmsleyA. Markovinovic: None Declared, M. Herauf: None Declared, J. Quan: None Declared, L. Hracs: None Declared, J. Windsor: None Declared, N. Sharifi: None Declared, S. Coward: None Declared, L. Caplan: None Declared, J. Gorospe: None Declared, C. Ma Grant / Research support from: Ferring, Pfizer, , Consultant of: AbbVie, Alimentiv, Amgen, Ferring, Pfizer, Takeda, , Speakers bureau of: AbbVie, Alimentiv, Amgen, Ferring, Pfizer, Takeda, R. Panaccione Grant / Research support from: AbbVie, Ferring, Janssen, Pfizer, Takeda, Consultant of: Abbott, AbbVie, Alimentiv, Amgen, Arena, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Therapeutics, Pandion Pharma, Pfizer, Progenity, Protagonist, Roche, Sandoz, Satisfai Health, Schering-Plough, Shire, Sublimity Therapeutics, Takeda, Theravance, UCB, Speakers bureau of: AbbVie, Arena, Celgene, Eli Lilly, Ferring, Gilead Sciences, Janssen, Merck, Pfizer, Roche, Sandoz, Shire, Takeda, R. Ingram: None Declared, J. Kanji: None Declared, G. Tipples: None Declared, J. Holodinsky: None Declared, C. Berstein Grant / Research support from: AbbVie, Amgen, Janssen, Pfizer, Takeda, Speakers bureau of: AbbVie, Janssen, Pfizer, Takeda, D. Mahoney: None Declared, S. Bernatsky: None Declared, E. Benchimol: None Declared, G. Kaplan Grant / Research support from: Ferring, Speakers bureau of: AbbVie, Janssen, Pfizer"} +{"text": "PLOS ONE Editors retract this article [The article because MButt, ASattar, TA, RH, MI, ASher, US, MBrestic, MZ, BSA, AMES, and ATKZ did not agree with the retraction. SU and KG either did not respond directly or could not be reached."} +{"text": "PLOS ONE Editors retract this article [The article , 2 becauSK, DI, SI, ZH, and ATKZ did not agree with the retraction. NR, AW, AB, JA, MSA, and MRAG either did not respond directly or could not be reached."} +{"text": "Scientific Reports 10.1038/s41598-019-50538-w, published online 01 November 2019Retraction of: The Authors have retracted this Article.Subsequent to the publication of a Correction , a numbeShady Kotb, Robert Pola, Michal Pechar, Rajiv Kumar, Bijay Singh, Reza Taleeli, Florian Trichard, Vincent Motto-Ros, Lucie Sancey, Alexandre Detappe, Sayeda Yasmin-Karim, Andrea Protti, Ilanchezhian Shanmugam, Thomas Ireland, Tomas Etrych, Srinivas Sridhar, Olivier Tillement, Mike Makrigiorgos, and Ross I. Berbeco agree with the retraction and its wording. Sijumon Kunjachan and Felix Gremse did not respond to the correspondence about this retraction."} +{"text": "Editor-in-ChiefTibor F\u00fcl\u00f6p, MD, PhD; Medical University of South Carolina, Charleston, South Carolina, USADeputy EditorMih\u00e1ly Tapolyai, MD, PhD; FMC Hungary, Hatvan, HungaryAssociate EditorsBasic SciencesIstv\u00e1n Arany, PhD,CSc; University of Mississippi Medical Center (ret.), Jackson, Mississippi, USAClinical SciencesSohail Abdul Salim, MD; University of Mississippi Medical Center, Jackson, Mississippi, USALajos Zsom, MD; FMC Hungary, Cegl\u00e9d, HungaryBiostatistics and Clinical EpidemiologyWisit Cheungpasitporn, MD; University of Mississippi Medical Center, Jackson, Mississippi, USAEditorial Board Members:Anand Achanti, MD; Medical University of South Carolina, Charleston, South Carolina, USAAysen Akalin, MD; Eskisehir Osmangazi University, Eskisehir, TurkeyAndrea Angioi, MD; Azienda Ospedaliera G. Brotzu, Cagliari, ItalySebastjan Bevc, MD; University of Maribor, Maribor, SloveniaAna de Lurdes Agostinho Cabrita, MD, Faro, PortugalJorge Castaneda, MD; University of Mississippi Medical Center, Jackson, Mississippi, USAOrsolya Cseprekal, MD, PhD; Semmelweis University, Budapest, HungaryErsin Fad\u0131ll\u0131o\u011flu, MD; Ankara, TurkeyAbduzhappar Gaipov, MD, PhD; Nazarbayev University School of Medicine, Nur-Sultan city, KazakhstanMehul P. Dixit, MD; University of Mississippi Medical Center, Jackson, Mississippi, USANeville R. Dossabhoy, MD; Louisiana State University, Shreveport, LA, USAChristian A. Koch, MD, PhD; Fox-Chase Cancer Institute, Temple University, Philadelphia, PA, USAS. Mehrdad Hamrahian, MD; Thomas Jefferson University, Philadelphia, Pennsylvania, USACsaba Kopitko, MD, PhD; Uzsoki Utcai K\u00f3rh\u00e1z, Budapest, HungaryNicolas Hanset, MD; University Hospital Saint-Luc, Brussels, BelgiumJolanta Malyszko, MD, PhD, Medical University of Warsaw, Warsaw, PolandMiklos Z. Molnar, MD, PhD; University of Tennessee Health Science Center, Memphis, TN, USADr. Lovelesh Nigam, MD; Dr. H.L. Trivedi Institute of Transplantation Sciences, Asarwa, Ahmedabad, IndiaKen Sakai, MD, PhD; Toho University Faculty Medicine, Tokyo, JapanKarim M. Soliman, MD, MSc; Cairo University, Cairo, EgyptBlaithin A. McMahon, MD, PhD; Medical University of South Carolina, Charleston, South Carolina, USADaniela Ponce, MD, University of Sao Paulo State, UNESP \u2013 Botucatu, BrazilVinaya Rao, MD; Medical University of South Carolina, Charleston, South Carolina, USAL\u00e1szl\u00f3 Rosiv\u00e1ll, MD, PhD, DSc Med, Med habil.; Semmelweis University, Budapest, HungaryMichael E. Ullian, MD; Medical University of South Carolina, Charleston, South Carolina, USAWisit Kaewput, MD; Phramongkutklao Hospital, Bangkok, ThailandStatistical Consultant Advisor:Zsolt Lengv\u00e1rszky, PhD; Louisiana State University Shreveport; Shreveport, LA, USAPrevious Editor:William F. Finn, MD - University of North Carolina, USA"} +{"text": "PLOS ONE Editors retract this article [The article because AS, XW, TA, AS, MIjaz, SUA, MB, MAW, MC, SF, AQ, MJA, FA, and ATKZ did not agree with the retraction. MIrfan, SAA, MW, and KX either did not respond directly or could not be reached."} +{"text": "Scientific Reports 10.1038/s41598-022-24608-5, published online 22 November 2022Correction to: In the original version of this Article the author R. Silva was incorrectly affiliated with \u2018Instituto de F\u00edsica Gleb Wataghin, Universidade Estadual de Campinas, Campinas, SP, 13083-859, Brasil\u2019 and \u2018International Institute of Physics, Universidade Federal do Rio Grande do Norte, Natal, RN, 59078-970, Brasil\u2019. The correct affiliation is listed below.Departamento de F\u00edsica, Universidade Federal do Rio Grande do Norte, Natal, RN, 59078-970, Brasil.The original Article has been corrected."} +{"text": "Correction to: Current Treatment Options in Oncology (2022) 23:1503-152110.1007/s11864-022-01006-7The original version of this article, unfortunately, contained mistakes.The author list was arranged incorrectly. The correct sequence of authors is presented below:Jingqin Zhong, MDWangjun Yan, PhDChunmeng Wang, PhDWanlin Liu, MDXinyi Lin, MDZijian Zou, MDWei Sun, PhD*Yong Chen, PhD**Email: Yong Chen, chenyong@fudan.edu.cn; Wei Sun, wsun14@fudan.edu.cn"} +{"text": "Journal of Occupational Health from October 1, 2021, to September 30, 2022.The Japan Society for Occupational Health expresses its sincere appreciation to the following volunteers for reviewing manuscripts for Ae, Ryusuke (Japan)Allison, Penelope J. (United States)Amadi Obasi, Cecilia Nwadiuto (Nigeria)Anami, Kunihiko (Japan)Arakawa, Ritsuko (Japan)Araki, Yoko (Japan)Berthelsen, Hanne (Sweden)Bocalini, Danilo (Brazil)Chang, Wushou (Taiwan)Cheng, Yawen (Taiwan)Craddock, Tina (United States)De Beer, Leon (South Africa)Du, Tanghuizi (Japan)Duarte, Joana (Sweden)Ebara, Takeshi (Japan)Eguchi, Hisashi (Japan)Eguchi, Yasumasa (Japan)Endo, Motoki (Japan)Endo, Shota (Japan)Ferri, Paola Fujii, Tomoko (Japan)Fujino, Yoshihisa (Japan)Fujisawa, Koichi (Japan)Fujita, Takako (Japan)Fujiwara, Takeshi (Japan)Fukushima, Noritoshi (Japan)Gatimu, Samwel (Kenya)Griep, Rosane (Brazil)Haga, Chiyori (Japan)Hama, Sarkawt (United Kingdom of Great Britain and Northern Ireland)Hamamura, Toshitaka (Japan)Hara, Megumi (Japan)Harris, Mark N. Hayashi, Toshio (Japan)Heinonen, Noora (Finland)Hidaka, Tomoo (Japan)Hikichi, Hiroyuki (United States)Hiraku, Yusuke (Japan)Hirokawa, Kumi (Japan)Hisanaga, Naomi (Japan)Hori, Hajime (Japan)Hori, Hikaru (Japan)Horie, Seichi (Japan)Ichiba, Masayoshi (Japan)Ichihara, Gaku (Japan)Ichihara, Sahoko (Japan)Ikeda, Atsuko (Japan)Ikegami, Kazunori (Japan)Inaba, Ryoichi (Japan)Irigoyen\u2010Oti\u00f1ano, Mar\u00eda (Spain)Irokawa, Toshiya (Japan)Ishimaru, Tomohiro (Japan)Ishitake, Tatsuya (Japan)Ito, Yuki (Japan)Iwakiri, Kazuyuki (Japan)Iwata, Hiroko (Japan)Iwata, Toyoto (Japan)Izumi, Hiroyuki (Japan)Jang, Tae\u2010Won Jiang, Ying (Japan)Kabe, Isamu (Japan)Kajiki, Shigeyuki (Japan)Kakamu, Takeyasu (Japan)Kaltofen, Marco Paul Johann (United States)Kamijima, Michihiro (Japan)Kanamori, Satoru (Japan)Kang, Mo\u2010Yeol Katayama, Akihiko (Japan)Kawakami, Tsuyoshi (Switzerland)Kawamura, Yoko (Japan)Kawanami, Shoko (Japan)Kawashima, Masatoshi (Japan)Khalili, Arash Kido, Takamasa (Japan)Kim, Inah Kingma, Idsart (Netherlands)Kitamura, Hiroko (Japan)Kiyono, Ken (Japan)Kobayashi, Sumitaka (Japan)Kobayashi, Tomoko (Japan)Kobayashi, Yuka (Japan)Kondo, Naoki (Japan)Kozaki, Tomoaki (Japan)Kubo, Tomohide (Japan)Kudo, Yasushi (Japan)Kumagai, Shinji (Japan)Kuroda, Reiko (Japan)Kurosawa, Hajime (Japan)Kusama, Taro (Japan)Kuwahara, Keisuke (Japan)Lars, Van Tuin (Netherlands)Lee, Wanhyung Li, Yongxin (China)Lin, Ro\u2010Ting (Taiwan)Lu, Ming\u2010Lun (United States)Machida, Shuichi (Japan)Mafune, Kosuke (Japan)Massimi, Azzurra Masuda, Masashi (Japan)Matsugaki, Ryutaro (Japan)Michishita, Ryoma (Japan)Miyagawa, Naoko (Japan)Miyake, Yoshihiro (Japan)Miyamoto, Toshiaki (Japan)Miyauchi, Hiroyuki (Japan)Momma, Haruki (Japan)Mori, Koji (Japan)Morimoto, Yasuo (Japan)Morioka, Ikuharu (Japan)Morita, Manabu (Japan)Morita, Yusaku (Japan)Mulkhan, Unang (Indonesia)Murakami, Takahisa (Japan)Muraki, Satoshi (Japan)Murayama, Hiroshi (Japan)Mustafaoglu, Rustem (Turkey)Muto, Go (Japan)Nagano, Chikage (Japan)Nagata, Tomohisa (Japan)Nakamura, Mieko (Japan)Nishimura, Yoshito (Japan)Nogawa, Kazuhiro (Japan)Oda, Eiko (Japan)Odagiri, Yuko (Japan)Oe, Misari (Japan)Ogami, Akira (Japan)Ogawa, Masanori (Japan)Ohta, Masanori (Japan)Ojima, Jun (Japan)Ojima, Toshiyuki (Japan)Okazaki, Ryuji (Japan)Omiya, Tomoko (Japan)Oshio, Takashi (Japan)Ota, Atsuhiko (Japan)Otsuka, Yasumasa (Japan)Owari, Yutaka (Japan)Rabal\u2010Pelay, Juan (Spain)Revilla, Josefa Angelie (Philippines)Ruseski, Jane (United States)Sado, Mitsuhiro (Japan)Saengboonmee, Charupong (Thailand)Saijo, Yasuaki (Japan)Saito, Isao (Japan)Saitoh, Hiroyuki (Japan)Sakakibara, Keiko (Japan)Sasaki, Natsu (Japan)Sato, Yukihiro (Japan)Sawada, Shinichi (Japan)Shibata, Eiji (Japan)Shibata, Nobuyuki (Japan)Shibuya, Tomoaki (Japan)Shimanoe, Chisato (Japan)Shimura, Akiyoshi (Japan)So, Rina (Japan)Sugama, Atsushi (Japan)Sugawara, Norio (Japan)Sugiyama, Daisuke (Japan)Sun, Rui (Netherlands)Suwazono, Yasushi (Japan)Tabuchi, Takahiro (Japan)Tachi, Norihide (Japan)Tahara, Hiroyuki (Japan)Takahara, Ryuji (Japan)Takahashi, Masaya (Japan)Takahashi, Toru (Japan)Takaya, Mitsutoshi (Japan)Tamakoshi, Koji (Japan)Tanaka, Rie (Japan)Tani, Naomichi (Japan)Tanihara, Shinichi (Japan)Tateishi, Seiichiro (Japan)Tatemichi, Masayuki (Japan)Tatsumi, Yukako (Japan)Theodoro, Helo\u00edsa (Brazil)Togo, Fumiharu (Japan)Tokizawa, Ken (Japan)Tominaga, Maki (Japan)Tomonaga, Taisuke (Japan)Tr\u00e9panier, Sarah\u2010Genevi\u00e8ve (Canada)Tsuchiya, Masao (Japan)Tsuno, Kanami (Japan)Uchida, Mitsuo (Japan)Ueno, Satoru (Japan)Ueyama, Jun (Japan)Uitti, Jukka (Finland)Ukawa, Shigekazu (Japan)Van Wijk, Charles (South Africa)Vicente Herrero, Maria Teofila (Spain)Videira\u2010Silva, Antonio Vinnikov, Denis (Russian Federation)Wada, Hiroo (Japan)Wongrathanandha, Chathaya (Thailand)Wang, Faming (China)Wang, Rui\u2010Sheng (Japan)Watai, Izumi (Japan)Watanabe, Kazuhiro (Japan)Watanabe, Sintaroo (Japan)Weller, R. B. (United Kingdom of Great Britain and Northern Ireland)Yamada, Keiko (Japan)Yamamoto, Naofumi (Japan)Yamauchi, Takashi (Japan)Yasaci, Zeynal (Turkey)Yoda, Takeshi (Japan)Yokoyama, Sumi (Japan)Yoshikawa, Etsuko (Japan)Yoshioka, Eiji (Japan)Zaitsu, Masayoshi (Japan)"} +{"text": "PLOS ONE Editors retract this article [The article because MAC, MAB, and MJA did not agree with the retraction. JSD, MIAR, SK, SR, ALV, SH, SMA, FMAZ, and KH either did not respond directly or could not be reached."} +{"text": "Bioinformatics, Volume 38, Issue 15, 1 August 2022, Pages 3850\u20133852, https://doi.org/10.1093/bioinformatics/btac375This is a correction to: Philipp Wegner, Sebastian Schaaf, Mischa Uebachs, Daniel Domingo-Fern\u00e1ndez, Yasamin Salimi, Stephan Gebel, Astghik Sargsyan, Colin Birkenbihl, Stephan Springstubbe, Thomas Klockgether, Juliane Fluck, Martin Hofmann-Apitius, Alpha Tom Kodamullil, Integrative data semantics through a model-enabled data stewardship, https://data-steward.bio.scai.fraunhofer.de/data-steward instead of https://data-steward.bio.sca.fraunhofer.de/data-steward. This error has been corrected online.In the originally published version of the manuscript, there was an error in the Abstract. In the \u201cAvailability and implementation\u201d section, the link to where the DST is hosted should read"} +{"text": "PLOS ONE Editors retract this article [The article because MT, BA, MAdnan, IAM, SK, SF, MHS, MAli, MM, MAhmad, MR, and SA did not agree with the retraction. MSC and MAES either did not respond directly or could not be reached."} +{"text": "The safety profile of the novel oral JAK2/IRAK1 inhibitor pacritinib in patients with cytopenic myelofibrosis was described in the Phase 2 PAC203 and Phase 3 PERSIST\u20102 studies. To account for longer treatment durations on the pacritinib arms compared to best available therapy (BAT), we present a risk\u2010adjusted safety analysis of event rates accounting for different time on treatment. While the rate of overall events was higher on pacritinib compared to BAT, the rate of fatal events was lower, and there was no excess in bleeding, cardiac events, secondary malignancy, or thrombosis on pacritinib, including in patients with severe thrombocytopenia. This approval marks pacritinib as the third\u2010in\u2010class approved JAK inhibitor for patients with intermediate/higher risk MF, after ruxolitinib and fedratinib, and the only JAK inhibitor recommended for patients with severe thrombocytopenia, it is important to consider how new therapies will impact these risks. Recently, JAK inhibitors have come under increased scrutiny due to specific, emerging toxicities seen with drugs in this class, with the United States Food and Drug Administration (FDA) now requiring product label warnings regarding the increased risk of serious cardiac events, thromboses, cancer, deaths, and infections for all JAK inhibitors, including the JAK1/3 inhibitor tofacitinib and the JAK1/2 inhibitor baricitinib, agents approved currently in rheumatoid arthritis.), heart failure events , major adverse cardiac events , thrombotic events , bleeding events (by SMQ), infection events , and secondary malignancies . Risk\u2010adjusted incidence rates were reported per 100 patient\u2010years and were calculated as 100 \u00d7 (number of patients with an event)/.n\u00a0=\u00a0106 from PERSIST\u20102 and 54 from PAC203), and 98 patients were treated with BAT (including n\u00a0=\u00a044 with ruxolitinib). Baseline characteristics are shown in Table\u00a0A total of 160 patients were treated with pacritinib 200\u00a0mg BID , Patient Power, PharmaEssentia, Protagonist Therapeutics, Sanofi\u2010aventis, Stemline Therapeutics Inc., and Total CME; has served on scientific/advisory committees for Cancer.Net, CareDx, CTI BioPharma, EUSA Pharma Inc., Novartis, Pacylex, and PharmaEssentia; and reports speaker/preceptorship for AbbVie, Aplastic Anemia & MDS International Foundation, Curio Science LLC, Dava Oncology, Imedex, Magdalen Medical Publishing, Medscape, Neopharm, PeerView Institute for Medical Education, Physician Education Resource (PER), Physicians Education Resource (PER), Postgraduate Institute for Medicine, and Stemline Therapeutics Inc. Claire Harrison received honoraria from AbbVie, CTI BioPharma, Geron, Janssen, and Novartis; has served in consulting/advisory capacity for AOP, Celgene/ BMS, Constellation Pharmaceuticals, CTI BioPharma, Galecto, Geron, Gilead, Janssen, Keros, Promedior, Roche, Shire, Sierra Oncology, and Novartis; has served on a speakers bureau for AbbVie, BMS, CTI BioPharma, Geron, Sierra Oncology, and Novartis; and has received research funding from BMS, Constellation Pharmaceuticals, and Novartis. Vikas Gupta has consulted for AbbVie, Celgene/BMS, Constellation Pharmaceuticals, Novartis, Pfizer, and Sierra Oncology; he has received honoraria from Celgene/BMS, Constellation Pharmaceuticals, and Novartis; and has served in consulting/advisory capacity for AbbVie, Celgene/BMS, Pfizer, and Roche. Srdan Verstovsek has consulted for BMS, Constellation Pharmaceuticals, Incyte, Novartis, and Sierra Oncology; and has received researching funding from AstraZeneca, Blueprint Medicines, Celgene, CTI BioPharma, Genentech, Gilead, Incyte, Italfarmaco, Novartis, NS Pharma Inc., PharmaEssentia, Promedior, Protagonist Therapeutic, Roche, and Sierra Oncology. Bart Scott has consulted for Acceleron Pharma, Celgene, and Novartis; has served on speakers\u2019 bureaus for Alexion Pharmaceuticals, Celgene, Jazz Pharmaceuticals, and Novartis; has received honoraria from BMS, Incyte, and Taiho Oncology, and reports his institution receiving research funding from Celgene. Stephen T. Oh has consulted for AbbVie, Blueprint Medicines, Celgene/BMS, Constellation Pharmaceuticals, CTI BioPharma, Disc Medicine, Geron, Incyte, and PharmaEssentia; and has received research funding from Actuate Therapeutics, Blueprint Medicines, Celgene/BMS, Constellation Pharmaceuticals, CTI BioPharma, Incyte, Kartos Therapeutics, Sierra Oncology, and Takeda. Francesca Palandri received honoraria and has served in consulting/advisory capacity for AOP, Celgene, CTI BioPharma, Novartis, and Sierra Oncology. Haifa Kathrin Al\u2010Ali has received grants from BMS, Deutsche Leuk\u00e4mie und Lymphom Stiftung, and East German Study Group for Hematology and Oncology; and has consulted for AbbVie, AOP, Blueprint Medicines, BMS, Novartis, Pfizer, and Takeda. Marta Sobas received honoraria and has served in consulting/advisory capacity for Celgene, CTI BioPharma, and Novartis. Mary Frances McMullin has served in consulting/advisory capacity for AbbVie, BMS, Incyte, Novartis, and Sierra Oncology; and has served on a speakers\u2019 bureau for AbbVie, AOP, Incyte, Pfizer, and Novartis. Ruben Mesa has consulted for Constellation Pharmaceuticals, LaJolla Pharmacuetical, Novartis, and Sierra Oncology; has received research support from AbbVie, Celgene, Constellation Pharmaceuticals, CTI BioPharma, Genotech, Incyte, Promedior, and Samus; and has received a P30 grant (Mays Cancer Center P30 Cancer Center Support Grant) from National Cancer Institute (CA054174). Sarah Buckley is employed by, owns stock in, and has received travel funding from CTI BioPharma. Karisse Roman\u2010Torres is employed by and owns stock in CTI BioPharma. Alessandro Vannucchi has served in consulting/advisory capacity and has served on speakers\u2019 bureaus for AbbVie, AOP, Blueprint Medicines, BMS, Incyte, and Novartis. Abdulraheem Yacoub has served in consulting/advisory capacity for AbbVie, Acceleron Pharma, Apellis, CTI BioPharma, Gilead, Incyte, Notable Labs., Novartis, Pfizer, PharmaEssentia, and Servier.PERSIST\u20102 and PAC203 were approved by the institutional review boards at each institution and conducted in accordance of the principles outlined in the Declaration of Helsinki."} +{"text": "PLOS ONE Editors retract this article [The article because AA responded but expressed neither agreement nor disagreement with the editorial decision. SM, MSB, RU, MBilal, SK, MIL, MA, IA, MBrestic, ATKZ, EAAS, and AAH either did not respond directly or could not be reached."} +{"text": "Error in Author ListIn the published article, there was an error in the author list; author Alberto Alonso was erroneously excluded. The corrected author list appears below.1*, Adriana Ayestaran1, Javier Serrano1, Mauricio Cambeiro1, Jacobo Palma1, Rosa Meiri\u00f1o1, Miguel A. Morcillo2, Fernando Lapuente3, Luis Chiva4, Borja Aguilar5, Diego Azcona5, Diego Pedrero5, Javier Pascau6, Jos\u00e9 Miguel Delgado1, Javier Aristu1, Alberto Alonso7 and Yolanda Prezado8,9Felipe A. Calvo1Department of Radiation Oncology, Clinica Universidad de Navarra, Madrid, Spain2Medical Applications Unit, Centro de Investigaciones Energ\u00e9ticas, Medioambientales y Tecnol\u00f3gicas (CIEMAT), Madrid, Spain3Department of Surgery, Clinica Universidad de Navarra, Madrid, Spain4Department of Gynecology and Obstetrics, Clinica Universidad de Navarra, Madrid, Spain5Department of Medical Physics, Clinica Universidad de Navarra, Madrid, Spain6Department of Bioengineering and Aerospace Engineering, Universidad Carlos III de Madrid, Madrid, Spain7Department of Radiology, Unit of Vascular Surgery and Interventional Radiology, Clinica Universidad de Navarra, Madrid, Spain8Translational Research Department. Institut Curie, Universit\u00e9 PSL, CNRS UMR, Inserm, Signalisation, Radiobiologie et Cancer, Orsay, France9Universit\u00e9 Paris-Saclay, CNRS UMR, Inserm, Signalisation, Radiobiologie et Cancer, Orsay, FranceAuthor Contributions StatementIn the Author Contributions statement in the published article, there was an error; author Alberto Alonso was erroneously excluded.This paragraph previously stated:Conceptualization: FC, JA, MC and YP. Data curation: FC, AA, JS, MC, JA, RM, JPas, FL, BA, LC, MM, JP, JD, and YP. Formal analysis: FC, JS, and JP. Investigation: FC, AA, MM, RM, BA, DP, DA, and YP. Methodology: JS, AA, DP, DA, and YP. Project administration: FC. Supervision: FC, JA, and AA. Writing-original draft: FC, AA, JS, and YP. Writing-review and editing: FC, YP, JA, JS, RM, JP, JPas, LC, DP, DA, and AA. All authors contributed to the article and approved the submitted version.The corrected paragraph appears below:Conceptualization: FC, JA, MC, and YP. Data curation: FC, AA, JS, MC, JA, RM, JPas, FL, BA, LC, MM, JP, JD, AAlon, and YP. Formal analysis: FC, JS, and JP. Investigation: FC, AA, MM, RM, BA, DP, DA, AAlon, and YP. Methodology: JS, AA, DP, DA, and YP. Project administration: FC. Supervision: FC, JA, and AA. Writing-original draft: FC, AA, JS, and YP. Writing review and editing: FC, YP, JA, JS, RM, JP, JPas, LC, DP, DA, AAlon, and AA. All authors contributed to the article and approved the submitted version.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated."} +{"text": "Brain Communications, Volume 4, Issue 1, 2022, fcac032, https://doi.org/10.1093/braincomms/fcac032Antonino Errante, Alice Rossi Sebastiano, Settimio Ziccarelli, Valentina Bruno, Stefano Rozzi, Lorenzo Pia, Leonardo Fogassi, Francesca Garbarini, Structural connectivity associated with the sense of body ownership: a diffusion tensor imaging and disconnection study in patients with bodily awareness disorder, In the originally published version of this manuscript, there was an error in the This error has been corrected."} +{"text": "PLOS ONE Editors retract this article [The article because MES, CO, MAsif, MAdnan, and ATKZ did not agree with the retraction. XW, MA, WW, KG, ON, and MJA either did not respond directly or could not be reached."} +{"text": "Precision Clinical Medicine, Volume 5, Issue 2, June 2022, pbac007, https://doi.org/10.1093/pcmedi/pbac007This is a correction to: Linghui Deng, Kun Jin, Xianghong Zhou, Zilong Zhang, Liming Ge, Xingyu Xiong, Xingyang Su, Di Jin, Qiming Yuan, Chichen Zhang, Yifan Li, Haochen Zhao, Qiang Wei, Lu Yang, Shi Qiu, Blockade of integrin signaling reduces chemotherapy-induced premature senescence in collagen cultured bladder cancer cells, In the originally published version of this manuscript, p53/p21 pathway was erroneously referred to as p21/p53 pathway in four places.This error has now been corrected."} +{"text": "Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTN's 32 member institutions utilize a shared regulatory governance architecture at the Children's Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4700 subjects, over 1500 parents,\u00a0and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1000 tumors and germline material are currently available with data generation for > 5000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and Brain and other central nervous system (CNS) tumors are the leading cause of cancer-related death in children and frequently result in substantial long-term morbidity and disability https://cbtn.org/), launched in 2011 as the Children's Brain Tumor Tissue Consortium (CBTTC), is to serve as a collaborative multi-institutional research consortium with a publicly-accessible biosample and data repository dedicated to the study and treatment of childhood brain tumors. CBTN seeks to address critical unmet needs for integrated, large-scale biospecimen, multi-omic, and longitudinally clinically-annotated resources. As of 2022, the CBTN comprises 32 member institutions within the United States, Italy, Switzerland, and Australia. To overcome the challenges of global, collaborative research and siloed resources, CBTN spearheaded the development of cloud-based informatics and data applications that allow researchers to access and collaboratively analyze datasets. As such, CBTN's foundation of \u201cInnovation through Collaboration\u201d is being realized through its creation of a state-of-the-art biorepository, innovative analytics platforms, and real-time sharing of data and specimens. By design, CBTN initiatives build upon the success of The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research To Generate Effective Treatments (TARGET) consortia by further developing standards for the collection of specimens and\u00a0comprehensive longitudinal clinical data while addressing gaps in pediatric brain tumor representation in such resources. Recently, CBTN resources have contributed to the development of cross-disease resources such as the Gabriella Miller Kids First (GMKF) Data Resource and the NCI's Childhood Cancer Data Initiative (CCDI).The mission of the Children's Brain Tumor Network , the Embryonal Tumor with Multilayered Rosettes One Registry (https://hmh-cdi.org/etmr/), the Chordoma Foundation (https://www.chordomafoundation.org/), and OligoNation (https://www.oligonation.org/). These collaborative efforts advance disease-specific research while harnessing CBTN's operational and research infrastructure.In addition, CBTN's cross-disease research platform supports the integration and management of partnered, disease-specific biospecimen and data resources including NF2 Biosolutions includes matched tumor-normal whole genome sequencing (WGS), tumor RNA-Seq, methylation, and proteomics, as well as longitudinal clinical data, images , and pathology reports http://kidsfirstdrc.org/) enabling cross-disease analysis with other GMKF datasets or those hosted by NCI's cloud resources, such as TCGA and TARGET. In 2019, Researchers at D3b and Alex's Lemonade Stand Foundation's Childhood Cancer Data Lab launched the Open Pediatric Brain Tumor Atlas (OpenPBTA). OpenPBTA is a first-in-kind, open-science, collaborative analysis and manuscript-writing effort to comprehensively analyze PBTA tumors https://moleculartargets.ccdi.cancer.gov/) developed with the CCDI in support of the Research to Accelerate Cures and Equity (RACE) for Children Act In partnership with CHOP's Center for Data Driven Discovery and Biomedicine (D3b) and the NIH GMKF Data Resource Center, the PBTA data has been integrated into cloud-based resources within the GMKF portal .Embedded in the mission and vision of CBTN is the notion that collaboration is key for accelerated discoveries required to improve clinical outcomes. CBTN has benefitted from many academic, commercial, government, and advocacy partnerships , empowerCBTN's successes to date are empowered by its commitment to partnering with families and advocates supporting the sharing of biospecimens and data on behalf of accelerating clinical translation. CBTN, together with its partners, has developed a combination of open-science governance and platform resources that support the largest, accessible genomic and proteomic pediatric brain tumor data repository annotated with longitudinal clinical data, pathology reports and histologic images, MRI reports and images, and available biospecimens and preclinical models.CBTN's support of > 300 research projects generated reagents, models, data, and publications that have, in turn, enriched the CBTN's offerings. Likewise, consortium-wide efforts towards foundational data generation like the OpenPBTA, in combination with cloud-based platforms, support a dynamic research ecosystem that continually increases the volume and rate of brain tumor research, accelerates the development of clinical trials, and provides decision support resources to improve the outcomes of children diagnosed with CNS tumors. Importantly, CBTN is also poised to help support enforcement of the RACE Act Past and present members of CBTN's Executive Council and CHOP's Brain Tumor Board of Visitors who inspired the creation and ensured the sustainability of CBTN are Alan Stalling, Jr., Al Gustafson, Al Musella, Amanda Haddock, Amy Summy, Amy Weinstein, Amy Wood, Andrea Gorsegner, Anita Nirenberg, Ann Friedholm, Bob Budlow, Caroline Court, Carrie Ann Stallings, Charles Genaurdi, Jr., Daniel Hare, Daniel Lipka, David Bovard, Dean Crowe, Deborah Eaise, Eliza Greenbaum, Gerald Kilhefner, Geralyn Ryerson, Ginny McLean, Graham Cox, Heather Ward, Hank Summy, James Blauvelt, James Minnick, James Ryerson, Jeannine Norris, Jessica Kilhefner, John Nilon, Kevin Eaise, Kim Hare, Kim MacNeill, Kim Wark, Kristen Gillette, Laura Cooke, Leigh Anna Lang, Lisa Ward, Liz Dawes, Mario Lichtenstein, Mark Mosier, Meghan Gleeson, Meghan Gould, Nancy Minnick, Nicole Giroux, Patti Gustafson, Patricia Genuardi, Paula Olson, Paul Touhey, Peter Norris, Richard Haddock, Robert Martin, Sarah Lilly, Scott Perricelli, Stacia Wagner, Stephanie Strotbeck, Stephanie Marvel, Stephan Ward, Sue Perricelli, Susan Funck, Timothy Court, Toni HeadTrisha Danze, W. Craig Marvel, and Wendy Payton.Past and present members of CBTN who contributed to the generation of biospecimens and clinical and/or genomic data are Adam A. Kraya, Adam C. Resnick, Alex Felmeister, Alexa Plisiewicz, Allison M. Morgan, Allison P. Heath, Amanda Toke, Ammar S. Naqvi, Avi Kelman, Alex Felmeister, Alex Gonzalez, Alyssa Paul, Amanda Saratsis, Amy Smith, Ana Aguilar, Ana Guerreiro St\u00fccklin, Anastasia Arynchyna, Andrea Franson, Angela J. Waanders, Angela N. Viaene, Anita Nirenberg, Anna Maria Buccoliero, Anna Yaffe, Anny Shai, Anthony Bet, Antoinette Price, Arlene Luther, Ashley Plant, Augustine Eze, Bailey K. Farrow, Baoli Hu, Beth Frenkel, Bo Zhang, Bonnie Cole, Brian M. Ennis, Brian R. Rood, Brittany Lebert, Caralyn Higginbottom, Carina A. Larouci, Carl Koschmann, Caroline Caudill, Caroline Drinkwater, Carrie Coleman-Campbell, Cassie N. Kline, Catherine Sullivan, Chanel Keoni, Chiara Caporalini, Christine Bobick-Butcher, Christopher Mason, Chunde Li, Claire L. Carter, Ciana Anthony, Claudia MaduroCoronado, Clayton Wiley, Colleen Raftery, Cynthia Wong, Dan Kolbman, David E. Kram, David Haussler, David Pisapia, David R. Beale, David Stokes, David S. Ziegler, Denise Morinigo, Derek Hanson, Donald W. Parsons, Elizabeth Appert, Emily Drake, Emily Golbeck, Emma Connell, Ena Agbodza, Eric H. Raabe, Eric M. Jackson, Erin Alexander, Esteban Uceda, Eugene Hwang, Fausto Rodriquez, Gabrielle S. Stone, Gary Kohanbash, Gavriella Silverman, George Rafidi, Gerald Grant, Gerri Trooskin, Gilad Evrony, Graham Keyes, Hagop Boyajian, Holly B. Lindsay, Holly C. Beale, Holly Sammartino, Ian Biluck, Ian F. Pollack, James Johnston, James Palmer, Jane Minturn, Jared Donahue, Jared Pisapia, Jason E. Cain, Jason R. Fangusaro, Javad Nazarian, Jeanette Haugh, Jeff Stevens, Jeffrey P. Greenfield, Jeffrey Rubens, Jena V. Lilly, Jennifer L. Mason, Jessica B. Foster, Jessica Cuba, Jessica Legaspi, Jim Olson, Jo Lynne Rokita, Joanna J. Phillips, Jonathan Waller, Josh Rubin, Judy E. Palma, Justin McCroskey, Justine Rizzo, Kaitlin Lehmann, Kamnaa Arya, Karlene Hall, Katherine Pehlivan, Ken Mosby, Kenneth Seidl, Kimberly Diamond, Komal S. Rathi, Kristen Harnett, Kristina A. Cole, Krutika S. Gaonkar, Kundan Kunapareddy, Lamiya Tauhid, Laura Prolo, Leah Holloway, Leslie Brosig, Lina Lopez, Lionel Chow, Madhuri Kambhampati, Mahdi Sarmady, Madison L. Hollawell, Margaret Nevins, Mari Groves, Mariarita Santi-Vicini, Marilyn M. Li, Marion Mateos, Mateusz Koptyra, Matija Snuderl, Matthew Miller, Matthew Sklar, Matthew D. Wood, Meghan Connors, Melissa Williams, Meredith Egan, Michael D. Kelly, Michael Fisher, Michael Koldobskiy, Michelle Monje, Migdalia Martinez, Miguel A. Brown, Mike Prados, Mike Wilder, Miriam Bornhorst, Mirko Scagnet, Mohamed AbdelBaki, Monique Carrero-Tagle, Nadia Dahmane, Nalin Gupta, Namrata Choudhari, Natasha Singh, Nathan Young, Nicholas A. Vitanza, Nicholas Tassone, Nicholas Van Kuren, Nicolas Gerber, Nithin D. Adappa, Nitin Wadhwani, Noel Coleman, Obi Obayashi, Olena M. Vaske, Olivier Elemento, Oren Becher, Parimala Killada, Phanindra Kuncharapu, Philbert Oliveros, Phillip B. Storm, Pichai Raman, Prajwal Rajappa, Remo Williams, Rintaro Hashizume, Rishi R. Lulla, Robert Keating, Robert M. Lober, Robert (Bobby) Moulder, Ron Firestein, Sabine Mueller, Sameer Agnihotri, Samuel G. Winebrake, Samuel Rivero-Hinojosa, Sarah Diane Black, Sarah Leary, Schuyler Stoller, Shannon Robins, Sharon Gardner, Shelly Wang, Sherri Mayans, Sherry Tutson, Shida Zhu, Sofie R. Salama, Sonia Partap, Sonika Dahiya, Sriram Venneti, Stacie Stapleton, Stephani Campion, Stephanie Stefankiewicz, Stewart Goldman, Susan Jones, Swetha Thambireddy, Tatiana S. Patton, Teresa Hidalgo, Theo Nicolaides, Thinh Q. Nguyen, Thomas W. McLean, Tiffany Walker, Toba Niazi, Tobey MacDonald, Valeria Lopez-Gil, Valerie Baubet, Whitney Rife, Xiao-Nan Li, Xiaoyan Huang, Ximena P. Cuellar, Xu Zhu, Yiran Guo, Yuankun Zhu, and Zeinab Helil.Jena V. Lilly: Writing \u2013 original draft, Conceptualization, Project administration, Supervision, Data curation, Resources. Jo Lynne Rokita: Writing \u2013 original draft, Formal analysis, Visualization, Writing \u2013 review & editing, Investigation, Data curation. Jennifer L. Mason: Writing \u2013 original draft, Project administration, Supervision, Data curation, Resources, Investigation. Tatiana Patton: Writing \u2013 review & editing, Project administration, Supervision, Data curation, Resources. Stephanie Stefankiewiz: Project administration, Methodology, Writing \u2013 original draft. David Higgins: Project administration, Methodology, Resources. Gerri Trooskin: Project administration, Methodology, Funding acquisition. Carina A. Larouci: Data curation, Resources. Kamnaa Arya: Project administration, Writing \u2013 original draft, Resources. Elizabeth Appert: Data curation, Resources, Writing \u2013 original draft. Allison P. Heath: Software, Validation, Visualization. Yuankun Zhu: Software, Validation, Visualization. Miguel A. Brown: Software, Validation, Visualization. Bo Zhang: Software, Validation, Visualization. Bailey K. Farrow: Project administration, Validation, Visualization. Shannon Robins: Data curation, Resources, Investigation. Allison M. Morgan: Data curation, Resources, Project administration. Thinh Q. Nguyen: Data curation, Resources, Investigation. Elizabeth Frenkel: Data curation, Resources, Investigation. Kaitlin Lehmann: Data curation, Resources, Project administration. Emily Drake: Data curation, Resources, Investigation. Catherine Sullivan: Data curation, Resources, Supervision. Alexa Plisiewicz: Data curation, Resources, Project administration. Noel Coleman: Data curation, Resources, Project administration. Luke Patterson: Data curation, Resources, Project administration. Mateusz Koptyra: Project administration, Supervision, Resources, Methodology. Zeinab Helili: Data curation, Resources, Supervision. Nicholas Van Kuren: Data curation, Validation, Visualization. Nathan Young: Data curation, Validation, Visualization. Meen Chul Kim: Data curation, Software, Validation. Christopher Friedman: Data curation, Validation, Software. Alex Lubneuski: Software, Validation, Visualization. Christopher Blackden: Software, Validation, Visualization. Marti Williams: Data curation, Resources, Project administration. Valerie Baubet: Resources, Methodology, Project administration. Lamiya Tauhid: Resources, Methodology. Jamie Galanaugh: Data curation, Resources. Katie Boucher: Resources, Methodology. Heba Ijaz: Resources, Methodology. Kristina A. Cole: Resources, Methodology. Namrata Choudhari: Resources, Methodology. Mariarita Santi: Supervision, Resources, Project administration. Robert W. Moulder: Project administration, Resources. Jonathan Waller: Project administration, Resources. Whitney Rife: Project administration, Resources. Sharon J. Diskin: Formal analysis. Marion Mateos: Project administration, Supervision, Data curation, Resources. Donald W. Parsons: Project administration, Supervision, Data curation, Resources. Ian F. Pollack: Project administration, Supervision, Data curation, Resources. Stewart Goldman: Project administration, Supervision, Data curation, Resources. Sarah Leary: Project administration, Supervision, Data curation, Resources. Chiara Caporalini: Data curation, Resources. Anna Maria Buccoliero: Project administration, Supervision, Data curation, Resources. Mirko Scagnet: Project administration, Supervision, Data curation, Resources. David Haussler: Project administration, Supervision, Formal analysis. Derek Hanson: Project administration, Supervision, Data curation, Resources. Ron Firestein: Project administration, Supervision, Data curation, Resources. Jason Cain: Project administration, Supervision, Data curation, Resources. Joanna J. Phillips: Project administration, Supervision, Data curation, Resources. Nalin Gupta: Project administration, Supervision, Data curation, Resources, Writing \u2013 review & editing. Sabine Mueller: Project administration, Supervision, Data curation, Resources. Gerald Grant: Project administration, Supervision, Data curation, Resources. Michelle Monje-Deisseroth: Project administration, Supervision, Data curation, Resources. Sonia Partap: Project administration, Supervision, Data curation, Resources. Jeffrey P. Greenfield: Project administration, Supervision, Data curation, Resources. Rintaro Hashizume: Project administration, Supervision, Data curation, Resources. Amy Smith: Project administration, Supervision, Data curation, Resources. Shida Zhu: Project administration, Supervision, Data curation, Resources. James M. Johnston: Project administration, Supervision, Data curation, Resources. Jason R. Fangusaro: Project administration, Supervision, Data curation, Resources. Matthew Miller: Project administration, Supervision, Data curation, Resources. Matthew D. Wood: Project administration, Supervision, Data curation, Resources, Writing \u2013 review & editing. Sharon Gardner: Project administration, Supervision, Data curation, Resources. Claire L. Carter: Project administration, Supervision, Data curation, Resources. Laura M. Prolo: Project administration, Supervision, Data curation, Resources. Jared Pisapia: Project administration, Supervision, Data curation, Resources. Katherine Pehlivan: Project administration, Supervision, Data curation, Resources. Andrea Franson: Project administration, Supervision, Data curation, Resources. Toba Niazi: Project administration, Supervision, Data curation, Resources. Josh Rubin: Project administration, Supervision, Data curation, Resources. Mohamed Abdelbaki: Project administration, Supervision, Data curation, Resources. David S. Ziegler: Project administration, Supervision, Data curation, Resources. Holly B. Lindsay: Project administration, Supervision, Data curation, Resources. Ana Guerreiro Stucklin: Project administration, Supervision, Data curation, Resources. Nicolas Gerber: Project administration, Supervision, Data curation, Resources. Olena M. Vaske: Project administration, Supervision, Data curation, Resources. Carolyn Quinsey: Project administration, Supervision, Data curation, Resources. Brian R. Rood: Project administration, Supervision, Data curation, Resources, Writing \u2013 review & editing. Javad Nazarian: Project administration, Supervision, Data curation, Resources. Eric Raabe: Project administration, Supervision, Data curation, Resources. Eric M. Jackson: Project administration, Supervision, Data curation, Resources. Stacie Stapleton: Project administration, Supervision, Data curation, Resources. Robert M. Lober: Project administration, Supervision, Data curation, Resources. David E. Kram: Project administration, Supervision, Data curation, Resources. Carl Koschmann: Project administration, Supervision, Data curation, Resources, Writing \u2013 review & editing. Phillip B. Storm: Project administration, Supervision, Data curation, Resources. Rishi R. Lulla: Writing \u2013 original draft, Project administration, Supervision, Data curation, Resources. Michael Prados: Project administration, Supervision, Data curation, Resources, Writing \u2013 review & editing. Adam C. Resnick: Conceptualization, Project administration, Supervision, Data curation, Resources. Angela J. Waanders: Writing \u2013 original draft, Project administration, Supervision, Data curation, Resources, Writing \u2013 review & editing.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.David S. Ziegler is a consultant, or on the advisory board, of Bayer, AstraZeneca, Accendatech, Novartis, Day One, FivePhusion, Amgen, Alexion, and Norgine. Angela J. Waanders is on the advisory board of Alexion and Day One."} +{"text": "Desmopachria Babington, 1841 are described from multiple species groups. Two new species groups are erected, the Desmopachriaapicodente species group and the Desmopachriabifurcita species group. Desmopachriadivergenssp. nov. (Venezuela), Desmopachrialineatasp. nov. (Venezuela), Desmopachriasurinamensissp. nov. (Suriname), and Desmopachriatenuasp. nov. (Guyana) are described in Desmopachria but are not assigned to a species group. Desmopachriaapicodentesp. nov. , Desmopachrialateralissp. nov. (Venezuela), and Desmopachriatumidasp. nov. (Venezuela) are described in the new Desmopachriaapicodente species group and are the only members of the group. Desmopachriabifurcitasp. nov. (Peru), and Desmopachrialatasp. nov. (Brazil) are described in the new Desmopachriabifurcita group. Other members of the Desmopachriabifurcita group are Desmopachriabifasciata Zimmermann, Desmopachriabolivari Miller, Desmopachriaovalis Sharp, and Desmopachriavarians (each previously \u201cungrouped\u201d). Desmopachriapseudocaviasp. nov. (Venezuela) is described in the Desmopachriaconvexa-signata species group. Desmopachriawolfeisp. nov. (Venezuela) is described in the Desmopachrianitida species group. Desmopachriaangulatasp. nov. , Desmopachriaemarginatasp. nov. , Desmopachriaimparissp. nov. (Guyana), Desmopachriaimpunctatasp. nov. , and Desmopachriatruncatasp. nov. are described in the Desmopachriaportmanni-aldessa species group. Desmopachriabisulcatasp. nov. (Suriname), and Desmopachriairregularasp. nov. (Venezuela) are described in the Desmopachriaportmanni-portmanni species group. Desmopachriarobustasp. nov. (Venezuela) is described in the Desmopachriastriola species group. A key to the species groups is included. Male genitalia are figured for all new species and dorsal habitus images are provided for most new species.Nineteen new species of Dytiscidae) genus Desmopachria Babington includes approximately 133 species prior to this paper have rather distinctive synapomorphies and are likely monophyletic, there are many species that are not currently well-placed into them, which is partly what led to the obliteration of the subgenera and the recognition of an \u201cungrouped\u201d collection of species .MIZAMuseo del Instituto de Zoolog\u00eda Agr\u00edcola Francisco Fern\u00e1ndez Y\u00e9pez, Universidad Central de Venezuela, Maracay, Venezuela (L. Joly).MSBAMuseum of Southwestern Biology Division of Arthropods, University of New Mexico, Albuquerque, NM, USA (K.B. Miller).NZCSNational Zoological Collection of Suriname, Paramaribo, Suriname (P. Ouboter).USNMUnited States National Collection of Insects, Smithsonian Institution, Washington, DC, USA (C. Micheli).Desmopachria species do not have the distinctive synapomorphies of the various species groups recognized by Desmopachria (Desmopachria) Babington, but that subgenus does not exhibit a clear synapomorphy, instead it is a collection of species that do not have features present in other subgroups of Desmopachria. The following new species also do not fit into any of the defined species groups and are placed among the ungrouped Desmopachria.Many Taxon classificationAnimaliaColeopteraDytiscidae\ufeffB315FC3A-8513-56A5-80EF-E3130F847C99http://zoobank.org/BEF901E2-265C-4401-8121-57E66ED970DF4\u00b058.838'N 67\u00b044.341'W.Venezuela, Amazonas State, Communidad Ca\u00f1o Gato on Rio Sipapo, Desmopachriaportmanni species group. This makes it somewhat similar to specimens in the Desmopachriaubangoides species group, but Desmopachriadivergens lacks the sexually dimorphic anterior clypeal margins of that group ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, lobed at anterodorsal angle, antennomere XI elongate, apically pointed. Pronotum moderately short, lateral margins short, distinctly curved with continuous narrow bead, similar width throughout; surface shiny, very finely, evenly punctate. Elytron moderately broad, laterally broadly curved; surface shiny, more coarsely and evenly punctate than pronotum, punctation distinctive and prominent, densely and evenly punctate. Prosternum extremely short, longitudinally compressed, medially slightly carinate; prosternal process slender anteriorly, with distinctive, small medial tubercle, apically short and broad, medially flattened, apically broadly rounded. Metaventrite broad and evenly smoothly convex medially, surface shiny, finely, sparsely, and evenly punctate; metaventrite wings extremely slender. Metacoxa with medial portion short, < 1/3 length of metaventrite medially, metacoxal lines slightly divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface shiny, finely, sparsely, and evenly punctate. Metatrochanter large, subequal to length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, very finely and sparsely punctate.Male genitalia. Male median lobe in ventral aspect very broad, lateral margins linear to very broad, truncate apex . This species is similar to members of the Desmopachriaportmanni group, especially Desmopachriagrammosticta Braga & Ferreira\u2011Jr., which also has linear series of elytral punctures. However, Desmopachrialineata does not have the characteristic sexually dimorphic prosternal process of the Desmopachriaportmanni species-group (including Desmopachriagrammosticta). The prosternal process in males of Desmopachrialineata is not bifurcate with a medial pit, instead it is similar to the process in females. This is an unusual species in that it appears phonetically similar to members of the Desmopachriaportmanni group, but it lacks the bifid male prosternal process. It is certainly possible that the character states and relationships among these taxa is more complicated than currently understood. It seems clear that investigation of the utility and diversity of these and other characters among this group of Desmopachria should be investigated in the future.This species is distinct in having coarse punctation on the pronotum and elytron with many punctures on the elytron arranged in distinctive longitudinal linear series, often confluent such that linear grooves are formed Fig. . The malMeasurements.TL = 2.6\u20132.8 mm, GW = 1.9\u20132.0 mm, PW = 1.4\u20131.5 mm, HW = 1.0 mm, EW = 0.5\u20130.6 mm, TL/GW = 1.4, HW/EW = 1.8. Body large for genus, very broad, rounded, laterally broadly curved, lateral margins slightly continuous between pronotum and elytron, body broadest across elytra anterior at ca. midlength of body ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, lobed at anterodorsal angle, antennomere XI elongate, apically pointed. Pronotum very short, lateral margins short, broadly curved, more so anteriorly, with continuous narrow bead; surface shiny, coarsely punctate medially and along most of anterior margin, less punctate lateromedially, punctures irregular, some confluent. Elytron moderately broad, laterally broadly curved; surface shiny, more coarsely punctate than pronotum, punctation distinctive and prominent, irregular, many punctures confluent forming distinctive longitudinal lines and grooves. Prosternum extremely short, longitudinally compressed, medially slightly carinate; prosternal process slender anteriorly, with distinctive, low medial tubercle, apical portion broad basally with broad basal U-shaped region and concave slender apical process emerging from between branches of U, apically narrowly rounded. Metaventrite broad and evenly convex medially, surface shiny, coarsely punctate, punctures forming longitudinal, linear series; metaventrite wings extremely slender. Metacoxa with medial portion short, < 1/3 length of metaventrite medially, metacoxal lines slightly divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface shiny, evenly and coarsely punctate. Metatrochanter large, subequal to length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, most of surface coarsely punctate.Male genitalia. Male median lobe in dorsal aspect short and broad, < 1/2 length of lateral lobe, apex slightly broadened, apically truncate with rounded lateral margins, medially very finely emarginate, and having a very distinctive, flattened bead along the anterior clypeal margin. However, Desmopachriasurinamensis lacks the apical tooth on the lateral lobe characteristic of the Desmopachriaapicodente group (see below). The male genitalia are distinctive. The median lobe in ventral aspect is elongate, broad, and comprised of long, slender, evenly curved lateral margins with a thin region in between ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, lobed at anterodorsal angle, antennomere XI elongate, apically pointed. Pronotum very short, lateral margins short, slightly curved with continuous narrow bead, of even width throughout length; surface shiny, nearly impunctate medially, punctate around margins, punctation somewhat variable, with few larger punctures. Elytron moderately broad, laterally broadly curved; surface shiny, somewhat more coarsely and evenly punctate than pronotum, punctation fine, some punctures anteromedially on elytron forming moderately distinct longitudinal linear series; laterally with distinctive longitudinal rounded ridge extending posteriorly from humeral angle ~ 1/3 length of elytron. Prosternum extremely short, longitudinally compressed, medially slightly carinate; prosternal process slender anteriorly, with distinctive, small medial tubercle, apically short and broad, medially flattened, apically acutely pointed. Metaventrite broad and evenly smoothly convex medially, surface shiny, impunctate; metaventrite wings extremely slender. Metacoxa with medial portion short, ~ 1/3 length of metaventrite medially, metacoxal lines slightly divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface shiny, impunctate. Metatrochanter large, subequal to length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, very finely and sparsely punctate.Male genitalia. Male median lobe comprised of slender lateral margins between which is a membranous region, in lateral aspect entire median lobe broad, shallowly curved to rounded apex ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, lobed at anterodorsal angle, antennomere XI elongate, apically pointed. Pronotum short, lateral margins short, slightly curved with continuous narrow bead, slightly wider medially; surface shiny, finely, indistinctly punctate. Elytron moderately broad, laterally broadly curved; surface shiny, finely punctate throughout. Prosternum extremely short, longitudinally compressed, medially slightly carinate; prosternal process slender anteriorly, with distinctive, small medial tubercle, apically short and moderately broad, medially concave, apically pointed. Metaventrite broad and evenly smoothly convex medially, surface shiny, very finely punctate; metaventrite wings extremely slender. Metacoxa with medial portion short, < 1/3 length of metaventrite medially, metacoxal lines slightly divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface shiny, extremely finely punctate. Metatrochanter large, subequal to length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, very finely and sparsely punctate.Male genitalia. Male median lobe in lateral aspect long, extremely slender, and slightly curved, slightly expanded subapically on dorsal surface, apex narrowly pointed Desmopachriabalfourbrownei Young, 1990 \u2013 Brazil (Braga and Ferreira-Jr. 2014)Desmopachriabarackobamai Makhan, 2015 \u2013 French Guiana. Although described as being near Desmopachriageijskesi, this species appears more likely to be in the Desmopachriaubangoides species-group given the shape of the genitalia and the seemingly prominent male anterior clypeal margin in the illustrations provided is characterized by the lateral lobe with a distinctive apical socketed spur or \u201ctooth\u201d that is directed apicomedially has a distinctive longitudinal lateral rounded tumidity, but this species lacks the apical tooth on the lateral lobe also has two similar spurs apically on the lateral lobe.obe Fig. . It is nTaxon classificationAnimaliaColeopteraDytiscidae\ufeff474981F0-5664-5E72-93DC-CC66BB5259DFhttp://zoobank.org/55AFEE8C-DD1B-4E19-9B34-FB6DABA69C926\u00b030.900'N, 67\u00b032.604'W.Venezuela, Apure State, between Orinoco and Cinaruco Rivers, Desmopachria species (TL = 1.7\u20131.8 mm). The dorsal color pattern is distinctive with a large dark brown region on the elytron medially near the suture and with a large, diffuse pale macula apicomedially and along the lateral margins to the apex ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, antennomere XI elongate, apically pointed. Pronotum short, lateral margins short, curved with continuous narrow bead; surface shiny, punctation very fine, of the same size and evenly distributed, posterior margin slightly sinuate. Elytron broad, laterally broadly curved; surface shiny, punctation small, some punctures arranged into indistinct series, especially anteromedially. Prosternum extremely short, longitudinally compressed, medially flattened; prosternal process short, broad, flattened, apically pointed. Metaventrite broad and evenly smoothly convex medially, surface shiny, impunctate; metaventrite wings extremely slender. Metacoxa with medial portion short, < 1/3 length of metaventrite medially, metacoxal lines slightly sinuate, divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface shiny, impunctate. Metatrochanter very large, longer than length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, surface impunctate.Male genitalia. Male median lobe in lateral aspect moderately broad, elongate, straight, and of even width to sharply pointed apex, apically slight curved ventrad . The dorsal color pattern is distinctive in many specimens with most of the elytron brown with a broad region longitudinally along the suture dark brown ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, antennomere XI elongate, apically pointed. Pronotum short, lateral margins short, curved with continuous narrow bead; surface shiny, punctation very fine over most of surface, larger and denser posteromedially. Elytron broad, laterally broadly curved; surface shiny, punctation variable, some punctures arranged into indistinct series, especially anteromedially Altamira (ca 60km S.) 11 Oct 2986 P.Spangler & R.Crombie/\u2026\u201d Each paratype with different barcode labels . Desmopachrialateralis also has a prominent lateral longitudinal elytral tumidity, but that species has differently shaped male genitalia ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, antennomere XI elongate, apically pointed. Pronotum short, lateral margins short, gently curved with continuous narrow marginal bead; surface shiny, punctation very fine, of the same size and evenly distributed except more coarsely punctate posteromedially. Elytron broad, laterally broadly curved, lateral margin distinctly sinuate at humeral angle, with distinct lateral tumidity extending posteriorly from humeral angle is characterized by the median lobe very short and stout and the lateral lobes long, broad, flattened, and medially bent dorsad . The group does not have many other similarities. Some are dorsally maculate, others are not. They are of somewhat variable shape. More investigation will be needed to determine the naturalness of this grouping. In addition, other species of Desmopachria also have similar genitalia. Desmopachriachei Miller has diagnostically similar genitalia (Desmopachriastriola species group (Desmopachriamendozana (Steinheil) also has similar genitalia .Peru, Jun\u00edn, Sani Beni. The type locality is ambiguous. According to Desmopachria have the median lobe short with long, medially bent lateral lobes like Desmopachriabifurcita, including Desmopachriabifasciata Zimmermann, Desmopachriabolivari Miller, Desmopachriachei Miller, Desmopachrialata sp. nov., Desmopachriavarians Wehncke, and Desmopachriaovalis Sharp. Among these, Desmopachriabifurcita is the only one with a bifid median lobe ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, lobed at anterodorsal angle, antennomere XI elongate, apically pointed. Pronotum very short, lateral margins short, slightly curved with continuous narrow bead, slightly wider medially; surface shiny, impunctate medially, punctate around margins, punctation variable, fine to course. Elytron moderately broad, laterally broadly curved; surface shiny, more coarsely and evenly punctate than pronotum, punctation distinctive and prominent. Prosternum extremely short, longitudinally compressed, medially slightly carinate; prosternal process slender anteriorly, with distinctive, small medial tubercle, apically short and broad, medially slightly carinate, concave, apically acutely pointed. Metaventrite broad and evenly smoothly convex medially, surface shiny, moderately and irregularly punctate; metaventrite wings extremely slender. Metacoxa with medial portion short, < 1/3 length of metaventrite medially, metacoxal lines slightly divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface shiny, evenly punctate, punctures evenly distributed. Metatrochanter large, subequal to length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, very finely and sparsely punctate.Male genitalia. Male median lobe in lateral aspect extremely short, apically distinctly bifid, each branch apicolaterally pointed, ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, lobed at anterodorsal angle, antennomere XI elongate, apically pointed. Pronotum very short, lateral margins short, slightly curved with continuous narrow bead, slightly wider medially; surface shiny, impunctate medially, finely punctate around margins. Elytron very broad, laterally broadly curved; surface shiny, more coarsely and evenly punctate than pronotum, punctation distinctive and prominent, moderately fine. Prosternum extremely short, longitudinally compressed, medially slightly carinate; prosternal process slender anteriorly, with distinctive, small medial tubercle, apically short and moderately broad, medially evenly convex, apically broadly pointed. Metaventrite broad and evenly smoothly convex medially, surface shiny, impunctate; metaventrite wings extremely slender. Metacoxa with medial portion short, < 1/3 length of metaventrite medially, metacoxal lines indistinct, slightly divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface shiny, evenly, finely punctate. Metatrochanter large, subequal to length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, very finely and sparsely punctate.Male genitalia. Male median lobe in lateral aspect short, slightly curved, apically simple; in ventral aspect short, slender, parallel-sided to narrowly rounded apex . Also, although both species are extremely small diving beetles, Desmopachriapseudocavia (TL = 1.1\u20131.2 mm) are even smaller than Desmopachriacavia .This species belongs to the obe Fig. . Specimeiad Fig. . In DesmMeasurements.TL = 1.1\u20131.2 mm, GW = 0.8 mm, PW = 0.6 mm, HW = 0.4\u20130.5 mm, EW = 0.2 mm, TL/GW = 1.4\u20131.5, HW/EW = 2.3\u20132.4. Body broad, ovoid, laterally broadly curved, lateral margins continuous between pronotum and elytron, body broadest across elytra at midlength of body ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, lobed at anterodorsal angle, antennomere XI elongate, apically pointed. Pronotum short, lateral margins short, curved with continuous narrow bead of even width throughout; surface shiny, impunctate to very finely and sparsely punctate. Elytron broad, laterally broadly curved; surface shiny, very finely and sparsely punctate. Prosternum extremely short, longitudinally compressed, medially slightly carinate; prosternal process slender anteriorly, with distinctive, small, sharp medial tubercle, apically short and broad, medially slightly carinate, concave, apically acutely pointed. Metaventrite broad and evenly smoothly convex medially, surface shiny, impunctate; metaventrite wings extremely slender. Metacoxa with medial portion short, < 1/3 length of metaventrite medially, metacoxal lines divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface shiny, impunctate. Metatrochanter large, subequal to length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, very finely and sparsely punctate; abdominal sternite VI with medial longitudinally oval depression with field of setae around margins ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, lobed at anterodorsal angle, antennomere XI elongate, apically pointed. Pronotum short, lateral margins short, sublinear with continuous narrow bead, slightly wider medially; surface shiny, impunctate medially, punctation denser along anterior and posterior margins, punctation fine. Elytron moderately broad, laterally broadly curved; surface shiny, more coarsely and evenly punctate than pronotum, punctation distinctive and prominent. Prosternum extremely short, longitudinally compressed, medially slightly carinate; prosternal process slender anteriorly, with distinctive, small medial tubercle, apical blade short and broad, basally transversely carinate, medially concave, apically broadly pointed. Metaventrite broad and evenly smoothly convex medially, surface shiny, very finely and sparsely; metaventrite wings extremely slender. Metacoxa with medial portion short, < 1/3 length of metaventrite medially, metacoxal lines divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface shiny, very finely and sparsely punctate. Metatrochanter large, subequal to length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, very finely and sparsely punctate.Male genitalia. Male genitalia complex; median lobe elongate in lateral aspect, broad basally, medially constricted, broadly sinuate, apex strongly curved dorsal, apically pointed .Desmopachriacurseenae Miller & Wolfe, 2018 \u2013 SurinameDesmopachriadarlingtoni Young, 1989 \u2013 Jamaica, Cuba, Haiti, ColombiaDesmopachriadelongi Miller & Wolfe, 2018 \u2013 SurinameDesmopachriadraco Miller, 1999 \u2013 Bolivia, Brazil (Braga and Ferreira-Jr. 2010)Desmopachriagingerae Miller & Wolfe, 2018 \u2013 VenezuelaDesmopachriagranoides Young, 1986 \u2013 Brazil (Braga and Ferreira-Jr. 2014), Bolivia, Suriname, Venezuela, TrinidadDesmopachriagyrationi Miller & Wolfe, 2018 \u2013 GuyanaDesmopachriahardyae Miller & Wolfe, 2018 \u2013 GuyanaDesmopachriakemptonae Miller & Wolfe, 2018 \u2013 VenezuelaDesmopachrialeptophallica Braga & Ferreira-Jr., 2014 \u2013 BrazilDesmopachrialiosomata Young, 1986 \u2013 BrazilDesmopachrialloydi Miller & Wolfe, 2018 \u2013 BoliviaDesmopachriamargarita Young, 1990 \u2013 Panama, Brazil? (Braga and Ferreira-Jr. 2014).Desmopachrianitida Babington, 1841 \u2013 BrazilDesmopachrianitidoides Young, 1990 \u2013 ParaguayDesmopachriaphacoides Guignot, 1950 \u2013 Paraguay, BoliviaDesmopachriapsarammo Miller, 1999 \u2013 BoliviaDesmopachriarhea Miller, 1999 \u2013 BoliviaDesmopachriasinghae Miller & Wolfe, 2018 \u2013 VenezuelaDesmopachriasubnotata Zimmermann, 1921 \u2013 Brazil (Braga and Ferreira-Jr. 2010).Desmopachriasubtilis Sharp, 1882 \u2013 BrazilDesmopachriavohrae Miller & Wolfe, 2018 \u2013 VenezuelaDesmopachriawolfei sp. nov. \u2013 VenezuelaDesmopachriazelota Young, 1990 \u2013 BrazilDiagnosis. The Desmopachriaportmanni group is well characterized morphologically by males with a bifid prosternal process with a deep medial pit , but others are not (the Desmopachriaportmanni-portmanni subgroup). Other species in Desmopachria are iridescent but lack the forked, pitted process and are not included in the Desmopachriaportmanni group (see Desmopachriadivergens sp. nov. (described above). There are also additional species that have similar genitalia Young) and those without dorsal iridescence (the subgenus Desmopachria (Portmannia) Young). Given the exceptional uniqueness of the forked prosternal feature, Desmopachriaportmanni species group. Another group, the Desmopachriaubangoides species group sensu Desmopachria (Hintonia) Young) exhibits dorsal iridescence, like some species in the Desmopachriaportmanni group. These species seem rather different in other ways since they lack the forked prosternal process and have male genitalia that are not consistent with the relatively simple structures present in the Desmopachriaportmanni group. Their genitalia are relatively more complex and differently shaped. Also, the anterior clypeal margin is sexually dimorphic. In males it is strongly modified, flattened, and upturned, whereas in females it is beaded, but not so conspicuously modified. For this reason, they are still regarded here as a separate species group (the Desmopachriaubangoides species group). Prior to this paper 23 species were assigned to the Desmopachriaportmanni group (Nilsson 2016).Desmopachriaportmanni group (Desmopachria (Portmannia) Young), Desmopachriaportmanni-aldessa subgroup and the Desmopachriaportmanni-portmanni subgroup (see below).Within the Desmopachriaportmanni group (as Desmopachria (Portmannia) Young to be found mainly in higher elevations rather than lowland tropics. This may be true in North and Central American species but does not appear to be entirely consistent with northern South American species.Desmopachria, these are still tiny diving beetles occurring in a variety of habitats, but especially in tropical forest pools and streams. It should be noted that no specific adaptive significance is known for either the uniquely forked and deeply pitted male prosternal process nor the dorsal iridescence of specimens of both sexes of many species. Although somewhat larger than many other Desmopachria in general ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, antennomere XI elongate, apically pointed. Pronotum short, lateral margins short, broadly curved with continuous narrow bead; surface shiny, punctation fine, slightly irregular in size, few larger punctures; posterior margin sinuate. Elytron broad, laterally broadly curved; surface shiny, conspicuously punctate, punctures dual with fine and large interspersed. Prosternum extremely short, longitudinally compressed, medially slightly carinate; prosternal process in male very slender anteriorly, with low, indistinct medial tubercle, bifid apically with deep medial pit, in female slender anteriorly, with distinctive, small medial tubercle, apically short and broad, medially slightly carinate, apically acutely pointed. Metaventrite broad and evenly smoothly convex medially, surface shiny, impunctate; metaventrite wings extremely slender. Metacoxa with medial portion short, < 1/3 length of metaventrite medially, metacoxal lines sinuate, strongly divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface shiny, impunctate. Metatrochanter very large, subequal to length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, very finely and sparsely punctate.Male genitalia. Male median lobe in lateral aspect with basal portion broad and rounded, apically long and slender, medially conspicuously bent, with distinctive subapical lobe on ventral surface , CSBD and SEMC (from Guyana), and MSBA (various), each with different barcode labels . The elytra are more distinctly punctate than most species with distinctive dual punctation. Also, the elytra are very noticeably iridescent in most specimens, but a series from Raleighfallen Nature Preserve, Sipaliwini District, Suriname (NZCS) are less conspicuously iridescent. These specimens are similar in size, punctation and male genitalia, however. The male genitalia are most similar to Desmopachriaimpunctata, but the apical emargination in the median lobe is relatively deeper and in lateral aspect the apex is not distinctly hooked ventrad than Desmopachriaimpunctata (TL = 1.8\u20131.9 mm).This species includes some of the largest specimens in the group ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, antennomere XI elongate, apically pointed. Pronotum short, lateral margins short, slightly curved with continuous marginal bead; surface shiny, impunctate medially, but laterally and posteriorly with fine punctation. Elytron broad, laterally broadly curved and rounded; surface shiny, prominently punctate, punctures dual, some larger, some smaller, interspersed. Prosternum extremely short, longitudinally compressed, medially carinate; prosternal process in male very slender anteriorly, with low, indistinct medial tubercle, bifid apically with deep medial pit, in female slender anteriorly, with distinctive, small medial tubercle, apically short and broad, medially slightly carinate, apically acutely pointed. Metaventrite broad and evenly smoothly convex medially, surface shiny, impunctate or with few extremely minute punctures laterally; metaventrite wings extremely slender. Metacoxa with medial portion short, ~ 1/3 length of metaventrite medially, metacoxal lines slightly sinuate, divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface shiny, impunctate or with few extremely fine punctures. Metatrochanter very large, subequal to length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, impunctate, some specimens with few very fine punctures.Male genitalia. Male median bilaterally symmetrical, in lateral aspect elongate, evenly broad, evenly and broadly curved on both dorsal and ventral margins, apex linear and apically broadly rounded ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, antennomere XI elongate, apically pointed. Pronotum short, lateral margins short, slightly curved with continuous narrow bead; surface shiny, extremely finely and sparsely punctate, posterior margin sinuate. Elytron broad, laterally broadly curved and rounded; surface shiny, punctate, punctures dual, mostly larger, interspersed with smaller ones. Prosternum extremely short, longitudinally compressed, medially carinate; prosternal process in male very slender anteriorly, with low, indistinct medial tubercle, bifid apically with deep medial pit, in female slender anteriorly, with distinctive, small medial tubercle, apically short and broad, medially slightly carinate, apically acutely pointed. Metaventrite broad and evenly smoothly convex medially, surface shiny, impunctate medially, shallowly and minutely punctate laterally and posteromedially; metaventrite wings extremely slender. Metacoxa with medial portion short, < 1/3 length of metaventrite medially, metacoxal lines slightly sinuate, divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface irrorate, somewhat opalescent. Metatrochanter very large, subequal to length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, somewhat opalescent, very finely and sparsely punctate.Male genitalia. Male median lobe slightly but distinctly asymmetrical; in lateral aspect long, evenly broad, evenly and broadly curved on both dorsal and ventral margins, apex narrowly rounded labeled same as holotype except with different specimen barcode labels and each with \u201c\u2026PARATYPE Desmopachriaimparis Miller, 2021 [blue label with black line border].\u201dHolotype in Taxon classificationAnimaliaColeopteraDytiscidae\ufeff504C87B0-41C5-5B09-B60F-F95FA9368BBAhttp://zoobank.org/8248D6E7-C6F1-43F0-B298-704E02A9F4D404\u00b040.910'N, 56\u00b011.138'W.Suriname, Sipaliwini District, Raleighfallen Nature Reserve, Voltzberg Trail, Desmopachria specimens in this group (TL = 1.8\u20131.9 mm). The elytra are more finely and indistinctly punctate than many species and punctures are of only a single, fine size. Also, the elytra are only slightly iridescent. The male genitalia are most similar to Desmopachriaemarginata than Desmopachriaemarginata (TL = 2.0\u20132.2 mm).This species includes medium-sized ata Figs , but therad Figs , 61. AlsMeasurements.TL = 1.8\u20131.9 mm, GW = 1.2\u20131.3 mm, PW = 1.0\u20131.1 mm, HW = 0.6\u20130.7 mm, EW = 0.4\u20130.5 mm, TL/GW = 1.5\u20131.6, HW/EW = 1.7\u20131.8. Body very broadly oval, laterally broadly curved, lateral margins slightly discontinuous between pronotum and elytron.Coloration. Head orange to orange yellow. Pronotum evenly yellow, in most specimens paler in color than head or elytron. Elytron evenly brownish orange, iridescent, especially laterally and apically. Ventral surface of head, prosternum, head appendages, and pro- and mesolegs yellow, other ventral surfaces and metalegs orange.Sculpture and structure. Head broad, short; anterior margin of clypeus broadly curved, flattened, finely margined with conspicuous, continuous narrow bead; surface of head shiny, extremely finely and sparsely punctate; eyes moderately large (HW/EW = 1.7\u20131.8); antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, antennomere XI elongate, apically pointed. Pronotum short, lateral margins short, slightly curved with continuous marginal bead; surface shiny, extremely finely and sparsely punctate, posterior margin sinuate. Elytron broad, laterally broadly curved and rounded; surface shiny, extremely minutely punctate, punctures of even size, somewhat denser along elytral suture. Prosternum extremely short, longitudinally compressed, medially carinate; prosternal process in male very slender anteriorly, with low, indistinct medial tubercle, bifid apically with deep medial pit, in female slender anteriorly, with distinctive, small medial tubercle, apically short and broad, medially slightly carinate, apically acutely pointed. Metaventrite broad and evenly smoothly convex medially, surface shiny, impunctate medially, shallowly and minutely punctate laterally and posteromedially; metaventrite wings extremely slender. Metacoxa with medial portion short, < 1/2 length of metaventrite medially, metacoxal lines slightly sinuate, divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface shiny, very finely punctate. Metatrochanter very large, subequal to length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, very finely and sparsely punctate.Male genitalia. Male median bilaterally symmetrical, in lateral aspect elongate, evenly broad, evenly and broadly curved on both dorsal and ventral margins, apex slightly curved ventrad, pointed ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, antennomere XI elongate, apically pointed. Pronotum short, lateral margins short, broadly curved with continuous narrow bead; surface shiny, punctation very fine, irregular, sparse; posterior margin sinuate. Elytron broad, laterally broadly curved; surface shiny, punctate, punctures dual, fine and large interspersed, without linear series. Prosternum extremely short, longitudinally compressed, medially slightly carinate; prosternal process in male very slender anteriorly, with low, indistinct medial tubercle, bifid apically with deep medial pit, in female slender anteriorly, with distinctive, small medial tubercle, apically short and broad, medially slightly carinate, apically acutely pointed. Metaventrite broad and evenly smoothly convex medially, surface shiny, impunctate; metaventrite wings extremely slender. Metacoxa with medial portion short, < 1/3 length of metaventrite medially, metacoxal lines sinuate, divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface shiny, impunctate. Metatrochanter very large, subequal to length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, very finely and sparsely punctate.Male genitalia. Male median lobe in lateral aspect elongate, evenly curved, apically narrowly rounded , TrinidadDesmopachriaanastomosa sp. nov. \u2013 GuyanaDesmopachriaangulata sp. nov. \u2013 Guyana, SurinameDesmopachriaaurea Young, 1980 \u2013 Brazil (Braga and Ferreira-Jr. 2014), SurinameDesmopachriaemarginata sp. nov. \u2013 SurinameDesmopachriaimparis sp. nov. \u2013 GuyanaDesmopachriaimpunctata sp. nov. \u2013 SurinameDesmopachriairidis Young, 1980 \u2013 BrazilDesmopachrianovacula Young, 1980 \u2013 SurinameDesmopachriatruncata sp. nov. \u2013 Guyana, Suriname.Diagnosis. Within the Desmopachriaportmanni species-group, these species have the dorsal surface not iridescent.Comments. These species tend to be either dorsally distinctly maculate or evenly darkly colored, but all without iridescence, but males have a distinctive bifid prosternal process with a medial pit as with all Desmopachriaportmanni-species.Taxon classificationAnimaliaColeopteraDytiscidae\ufeffF4A9B5E0-F1E4-525E-862E-E776AF77F196http://zoobank.org/2F6FFF06-FD08-423A-97E4-890185DAB3DA2\u00b022.259'N 56\u00b041.227'W, 229m.Suriname, Sipaliwini District, Camp 3, Werehpai, SE Kwamala, Desmopachriabisulcata display iridescence. In some specimens of both males and females the dorsum is matte, with a microreticulation that obscures the punctation. Other species with similar male median lobe shapes are Desmopachriairidis and Desmopachriaanastomosis, but specimens of each of these are dorsally iridescent, whereas those of Desmopachriabisulcata are not.This species has a relatively simple median lobe that is slender, elongate, and curved in lateral aspect, and broad basally and apically evenly narrowed to a narrowly rounded apex in ventral aspect Figs , 67. TheMeasurements.TL = 2.0\u20132.1 mm, GW = 1.4\u20131.5 mm, PW = 1.0\u20131.1 mm, HW = 0.7\u20130.8 mm, EW = 0.4\u20130.5 mm, TL/GW = 1.4, HW/EW = 1.9\u20132.0. Body very broad, laterally rounded, lateral margins continuous between pronotum and elytron; dorsoventrally compressed.Coloration. Head and pronotum evenly orange-red, same coloration. Elytron evenly brownish orange, not iridescent. Ventral surfaces evenly orange-red.Sculpture and structure. Head broad, short; anterior margin of clypeus finely margined with continuous flattened narrow bead; surface of head shiny, but matte; eyes large (HW/EW = 1.9\u20132.0); antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, antennomere XI elongate, apically pointed. Pronotum short, lateral margins short, broadly curved with continuous narrow bead; surface matte to shiny, but punctation very fine, of the same size and evenly distributed, posterior margin sinuate. Elytron broad, laterally broadly curved; surface matte or, less commonly, shiny; punctation very fine, of the same size and evenly distributed across most of elytron, when punctate, dual with a few minute, interspersed punctures laterally. Prosternum extremely short, longitudinally compressed, medially slightly carinate; prosternal process in male very slender anteriorly, with low, indistinct medial tubercle, bifid apically with deep medial pit, in female slender anteriorly, with distinctive, small medial tubercle, apically short and broad, medially slightly carinate, apically acutely pointed. Metaventrite broad and evenly smoothly convex medially, surface matte, finely and irregularly punctate laterally; metaventrite wings extremely slender. Metacoxa with medial portion short, < 1/3 length of metaventrite medially, metacoxal lines sinuate, divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface matte, finely, evenly punctate, not iridescent. Metatrochanter very large, subequal to length of ventral margin of metafemur; legs otherwise not noticeably modified. Abdomen with surfaces shiny and smooth, very finely and sparsely punctate.Male genitalia. Male median lobe in lateral aspect slender, evenly curved on both ventral and dorsal margins to narrowly pointed apex ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, antennomere XI elongate, apically pointed. Pronotum short, lateral margins short, shallowly curved with continuous narrow bead; surface shiny, punctation very fine and sparse over most of surface, punctation large and dense posteromedially, posterior margin sinuate. Elytron broad, laterally broadly curved; surface shiny, punctation dual, mostly large, relatively dense, with fewer fine punctures interspersed. Prosternum extremely short, longitudinally compressed, medially slightly carinate; prosternal process in male very slender anteriorly, with low, indistinct medial tubercle, bifid apically with deep medial pit, in female slender anteriorly, with distinctive, small medial tubercle, apically short and broad, medially slightly carinate, apically acutely pointed. Metaventrite broad and evenly smoothly convex medially, surface shiny, impunctate; metaventrite wings extremely slender. Metacoxa with medial portion short, < 1/3 length of metaventrite medially, metacoxal lines sinuate, divergent anteriorly; lateral portion of metacoxa extremely large, anteriorly strongly expanded; surface shiny, very finely punctate, not iridescent. Metatrochanter very large, subequal to length of ventral margin of metafemur; male metafemur curved ventrally with conspicuous series of short setae long entire margin. Abdomen with surfaces shiny and smooth, finely punctate.Male genitalia. Male median lobe in lateral aspect irregular, ventral margin abruptly expanded submedially, evenly convexly curved in apical 2/5, ventral margin with large, apically subtruncate lobe medially, apex slight broadened, apex subtruncate Desmopachriamutata Sharp, 1882 \u2013 Brazilnomen novum for Desmopachriabryanstoni Sharp, 1882Desmopachrianiger Zimmermann, 1923 \u2013 Brazil ; antennae short, scape and pedicel relatively large and rounded, flagellomere III long and slender, apically expanded, antennomeres IV-X short and broad, lobed at anterodorsal angle, antennomere XI elongate, apically pointed. Pronotum very short, lateral margins short, slightly curved with continuous narrow bead, slightly wider medially; surface shiny, impunctate medially, very finely and indistinctly punctate around margins. Elytron moderately broad, laterally broadly curved; surface shiny, extremely finely punctate across surface; with distinctive subsutural stria, or groove, extending most of length of elytron Desmopachriaatropos Miller & Wolfe, 2019 \u2013 VenezuelaDesmopachriachei Miller, 1999 \u2013 BoliviaDesmopachriachlotho Miller & Wolfe, 2019 \u2013 SurinameDesmopachriaferrugata R\u00e9gimbart, 1895 \u2013 BrazilDesmopachriafossulata Zimmermann, 1928 \u2013 Brazil (Braga and Ferreira-Jr. 2014)Desmopachriagrouvellei R\u00e9gimbart, 1895 \u2013 Mexico, Argentina, Paraguay?Desmopachrialachesis Miller & Wolfe, 2019 \u2013 Guyana, Suriname, VenezuelaDesmopachriarobusta sp. nov. \u2013 VenezuelaDesmopachriaruginosa Young, 1990 \u2013 BrazilDesmopachriastriola Sharp, 1887 \u2013 Argentina, Bolivia, Brazil (Braga and Ferreira-Jr. 2010), Colombia, Costa Rica, Ecuador, Guatemala, Panama, Peru, Suriname, Trinidad, USA (Florida), Venezuela.Diagnosis. This group is characterized by the anterior metatibial spine serrate (D. (Nectoserrula) Guignot, 1949 \u2013 Argentina.Desmopachriapunctatissima Zimmermann, 1923 \u2013 ArgentinaDesmopachriavicina Sharp, 1887 \u2013 MexicoDiagnosis. These are iridescent Desmopachria without a forked male prosternum and with the anterior clypeal margin dimorphic, more developed in male (= Desmopachria (Hintonia) Young, 1980 .Diagnosis. These are iridescent Desmopachria without a forked male prosternum and with the anterior clypeal margin dimorphic and more developed in males (= Desmopachria (Hintonia) Young, 1980 (ng, 1980 Comments. New species have been described recently in this group (Braga and Ferreira-Jr. 2014; Desmopachriaaphronoscelus Miller, 1999 \u2013 BoliviaDesmopachriaflavida Young, 1981 \u2013 Mexico.Desmopachriaglabricula Sharp, 1882 \u2013 Guatemala.Desmopachrialeechi Young, 1981 \u2013 USA, Florida.Desmopachriastethothrix Braga & Ferreira Jr., 2014 \u2013 Brazil.Desmopachriastrigata Young, 1981 \u2013 Brazil.Desmopachriavolatidisca Miller, 2001 \u2013 Bolivia.Desmopachriavolvata Young, 1981\u2013 Panama.Desmopachriazimmermani Young, 1981 \u2013 Mexico."} +{"text": "Bioinformatics, Volume 38, Issue 5, 1 March 2022, Pages 1420\u20131426, https://doi.org/10.1093/bioinformatics/btab822This is a correction to: Andrew Cox, Chanhee Park, Prasad Koduru, Kathleen Wilson, Olga Weinberg, Weina Chen, Rolando Garc\u00eda, Daehwan Kim, Automated classification of cytogenetic abnormalities in hematolymphoid neoplasms, In the originally published version of this manuscript, the funder was incorrectly identified as the Cancer Prevention Research Institute of Health. This should be the Cancer Prevention Research Institute of Texas.This error has been corrected online."} +{"text": "PLOS ONE Editors retract this article [The article because JD agreed with the retraction. MZA, HIA, AG, ZS, BA, SA, AJ, and JAN did not agree with the retraction. AAA-G, MSE, and HD either did not respond directly or could not be reached."} +{"text": "Upon the original publication of the below listed articles, the Data Availability statement was inadvertently omitted. This erratum has been published to address the omission and note that the statements have been instated for the following papers:Back to the vinyl age: a narrative report of a total computer blackout at a large university medical centreLorenz H. Lehmann and Benjamin MederEuropean Heart Journal - Digital Health, Volume 2, Issue 1, March 2021, Pages 167\u2013170, https://doi.org/10.1093/ehjdh/ztab006Voice-based screening for SARS-CoV-2 exposure in cardiovascular clinicsAbhinav Sharma, Emily Oulousian, Jiayi Ni, Renato Lopes, Matthew Pellan Cheng, Julie Label, Filipe Henriques, Claudia Lighter, Nadia Giannetti, and Robert AvramEuropean Heart Journal - Digital Health, Volume 2, Issue 3, September 2021, Pages 521\u2013527, https://doi.org/10.1093/ehjdh/ztab055"} +{"text": "PLOS ONE Editors retract this article [The article because MI, AN, SUA, MAW, and KH did not agree with the retraction. ASher, ASattar, MS, IH, AUR, and MJA either did not respond directly or could not be reached."} +{"text": "Scientific Reports 10.1038/s41598-022-12568-9, published online 20 May 2022Correction to: The original version of this Article omitted affiliations for Dariusz Plewczynski. The correct affiliations are listed below.The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT, 06030, USACentre of New Technologies, University of Warsaw, S. Banacha 2c, 02-097, Warsaw, PolandFaculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, PolandThe original Article has been corrected."} +{"text": "Anderson, Sahaya J. Pravinkumar, Robert Van Der Meer and Itamar Megiddo"} +{"text": "Brain Communications, Volume 5, Issue 1, 2023, fcad005, https://doi.org/10.1093/braincomms/fcad005This is a correction to: Jarred M Griffin, Sonia Hingorani Jai Prakash, Till Bockem\u00fchl, Jessica M Benner, Barbara Schaffran, Victoria Moreno-Manzano, Ansgar B\u00fcschges, Frank Bradke, Rehabilitation enhances epothilone-induced locomotor recovery after spinal cord injury, In the originally published version of this manuscript online, the link to Video 1 was lacking in the supplementary data file. This lacuna has been supplied in the article online."} +{"text": "PLOS ONE Editors retract this article [The article because AH, MA, MY, MWA, HMZUG, and PV did not agree with the retraction. ZA, NAR, AR, SS, NL, KF, KT, SJ, SHS, and MJA either did not respond directly or could not be reached."} +{"text": "PLOS ONE Editors retract this article [The article because IA, SI, TJ, AT, MK, QS, KM, and MHS did not agree with the retraction. HMA either did not respond directly or could not be reached."} +{"text": "Correction to: Acta Neuropathologica Communications (2022) 10:143 10.1186/s40478-022-01446-0Following publication of the original article , the autThe incorrect author names are: Misove Adela, Vicha Ales, Broz Petr, Vanova Katerina, Sumerauer David, Stolova Lucie, Sramkova Lucie, Koblizek Miroslav, Zamecnik Josef, Kyncl Martin, Holubova Zuzana, Liby Petr, Taborsky Jakub, Benes Vladimir III, Pernikova Ivana, Jones T. W. David, Sill Martin, Stancokova Terezia, Krskova Lenka and Zapotocky MichalThe correct author names are: Adela Misove, Ales Vicha, Petr Broz, Katerina Vanova, David Sumerauer, Lucie Stolova, Lucie Sramkova, Miroslav Koblizek, Josef Zamecnik, Martin Kyncl, Zuzana Holubova, Petr Liby, Jakub Taborsky, Vladimir Benes III, Ivana Pernikova, David T. W. Jones, Martin Sill, Terezia Stancokova, Lenka Krskova and Michal ZapotockyThe author group has been updated above and the original article has been"} +{"text": "PLOS ONE Editors retract this article [The article because AY, NK, MA, WS, MH, and AN did not agree with the retraction. ZFR, HASA, KAM, TSA, SA, and SHQ either did not respond directly or could not be reached."} +{"text": "Cerebral Cortex Communications, Volume 3, Issue 2, 2022, tgac019, https://doi.org/10.1093/texcom/tgac019Stephen Green, PhD, Keerthana Deepti Karunakaran, PhD, Ke Peng, PhD, Delany Berry, BS, Barry David Kussman, MBBCh, Lyle Micheli, MD, David Borsook, MD, PhD, Measuring \u201cpain load\u201d during general anesthesia, In the originally published version of this manuscript, the third author's name, Ke Peng, was mistakenly omitted.Also, the authors' affiliations have been updated.1. The Center for Pain and the Brain, Department of Anesthesiology, Critical Care and Pain Medicine, Harvard Medical School, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, United States.2. Departement en Neuroscience, Centre de Recherche du CHUM, l'Universit\u00e9 de Montr\u00e9al Montreal, 2900 Edouard Montpetit Blvd, Montreal, Quebec H3T 1J4, Canada3. Departments of Orthopedics, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA, 02115, United States.4. Departments of Psychiatry and Radiology, Massachusetts General Hospital, 55 Fruit St, Boston, MA, 02114, United States.These errors have been corrected."} +{"text": "In the manuscript \u201cStrategies to optimize MEDLINE and EMBASE search strategies for anesthesiology systematic reviews. An experimental study\u201d, published in the Sao Paulo Med J. 2018 Jan 15:0. doi: 10.1590/1516-3180.2017.0277100917. [Epub ahead of print]:Where it read:\u201cVolpato ESN, Betini M, Puga ME, Agarwal A, Cataneo AJM, Oliveira LD, Ferreira RP, Bazan R, Braz LG, Pereira JEG, Dib RE\u201dIt should read:\u201cVolpato ESN, Betini M, Puga ME, Agarwal A, Cataneo AJM, Oliveira LD, Bazan R, Braz LG, Pereira JEG, El Dib R\u201d"} +{"text": "PLOS ONE Editors retract this article [The article because AG, AA, RAslam, RAmir, FM, TSB, MI, MAN, SF, and MABZ did not agree with the retraction. MS and FSB either did not respond directly or could not be reached."} +{"text": "PLOS ONE Editors retract this article [The article because SA, YL, MM, MS, and ATKZ did not agree with the retraction. IUH, WA, MZS, MMK, YN, TF, OM, and MJA either did not respond directly or could not be reached."} +{"text": "PLOS ONE Editors retract this article [The article because KD, PS, SH, RD, SAhmad, AAH, and SD did not agree with the retraction. AK, IAM, BK, SAli, and MAA either did not respond directly or could not be reached."} +{"text": "Molecular Psychiatry 10.1038/s41380-022-01616-5, published online 14 June 2022Correction to: http://creativecommons.org/licenses/by/4.0/.The article \u201cObesity and brain structure in schizophrenia \u2013 ENIGMA study in 3021 individuals\u201d, written by Sean R. McWhinney, Katharina Brosch, Vince D. Calhoun, Benedicto Crespo-Facorro, Nicolas A. Crossley, Udo Dannlowski, Erin Dickie, Lorielle M. F. Dietze, Gary Donohoe, Stefan Plessis, Stefan Ehrlich, Robin Emsley, Petra Furstova, David C. Glahn, Alfonso Gonzalez- Valderrama, Dominik Grotegerd, Laurena Holleran, Tilo T. J. Kircher, Pavel Knytl, Marian Kolenic, Rebekka Lencer, Igor Nenadi\u0107, Nils Opel, Julia-Katharina Pfarr, Amanda L. Rodrigue, Kelly Rootes-Murdy, Alex J. Ross, Kang Sim, Anton\u00edn \u0160koch, Filip Spaniel, Frederike Stein, Patrik \u0160vancer, Diana Tordesillas-Guti\u00e9rrez, Juan Undurraga, Javier V\u00e1quez-Bourgon, Aristotle Voineskos, Esther Walton, Thomas W. Weickert, Cynthia Shannon Weickert, Paul M. Thompson, Theo G. M. Erp, Jessica A. Turner, Tomas Hajek, was originally published electronically on the publisher\u2019s internet portal on 14 June 2022 without open access. With the author(s)\u2019 decision to opt for Open Choice the copyright of the article changed on 20 May 2022 to \u00a9 The Author(s) 2022 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article\u2019s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article\u2019s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit"} +{"text": "Bioinformatics, Volume 38, Issue 11, 1 June 2022, Pages 3141\u20133142, https://doi.org/10.1093/bioinformatics/btac195This is a correction to: Isuru Liyanage, Tony Burdett, Bert Droesbeke, Karoly Erdos, Rolando Fernandez, Alasdair Gray, Muhammad Haseeb, Simon Jupp, Flavia Penim, Cyril Pommier, Philippe Rocca-Serra, M\u00e9lanie Courtot, Frederik Coppens, ELIXIR biovalidator for semantic validation of life science metadata, In the originally published version of this manuscript, the acknowledgement section was incomplete. The authors acknowledge Danielle Welter\u2019s contribution to the conception and development of the graph restriction framework.This error has been corrected online."} +{"text": "Aesthetic Surgery Journal Open Forum, Volume 4, 2022, ojac084, https://doi.org/10.1093/asjof/ojac084This is a correction to: Hani Y Nasr, MD, Carter J Boyd, MD, MBA, Zachary M Borab, MD, Neil M Vranis, MD, Michael F Cassidy, BA, Alexis K Gursky, BS, Rebecca Gober, BA, Barry M Zide, MD, DMD, Daniel J Ceradini, MD, Productivity and Efficiency of a Department Resident Aesthetic Plastic Surgery Clinic, In the originally published version of this manuscript the images used for figures two and four were inadvertently swapped. There is no change to the associated captions.This error, for which the publisher apologizes, has been corrected."} +{"text": "In the originally published version of this manuscript, there were errors in the order of the affiliations. These errors have been corrected.This is a correction to: Yi Wang, Jun Xie, Hongna Zhang, Weidong Li, Zhanjun Wang, Huayang Li, Qian Tong, Gaixia Qiao, Yujuan Liu, Ying Tian, Yongzan Wei, Ping Li, Rong Wang, Weiping Chen, Zhengchang Liang, Meilong Xu, The genome of Prunus humilis provides new insights to drought adaption and population diversity, DNA Research, Volume 29, Issue 4, August 2022, dsac021,"} +{"text": "PLOS ONE Editors retract this article [The article because DR, NAB, and MYK either did not respond directly or could not be reached. PR, MM, AAH, RMS, BH, HAEE, SZH, and RZS did not agree with the retraction."} +{"text": "The aim of this article is to compare the aims, measures, methods, limitations, andscope of studies that employ vendor-derived and investigator-derived measures ofelectronic health record (EHR) use, and to assess measure consistency acrossstudies.We searched PubMed for articles published between July 2019 and December 2021 thatemployed measures of EHR use derived from EHR event logs. We coded the aims, measures,methods, limitations, and scope of each article and compared articles employingvendor-derived and investigator-derived measures.P\u2009=\u2009.002) and only by physicians or advanced practice providers. Studies employing vendor-derivedmeasures were also more likely to measure durations of EHR use(P\u2009<\u2009.001 for 6 different activities), but definitions of measuressuch as time outside scheduled hours varied widely. Eight articles reported measurevalidation. The reported limitations of vendor-derived measures included measuretransparency and availability for certain clinical settings and roles.One hundred and two articles met inclusion criteria; 40 employed vendor-derivedmeasures, 61 employed investigator-derived measures, and 1 employed both. Studiesemploying vendor-derived measures were more likely than those employinginvestigator-derived measures to observe EHR use only in ambulatory settings (83% vs48%, Vendor-derived measures are increasingly used to study EHR use, but only by certainclinical roles. Although poorly validated and variously defined, both vendor- andinvestigator-derived measures of EHR time are widely reported.The number of studies using event logs to observe EHR use continues to grow, but withinconsistent measure definitions and significant differences between studies that employvendor-derived and investigator-derived measures. From measuring the impact ofpolicy and pandemic on EHR use,EHR event logs are a diverse set of computer-generated files that track EHR operation anduse. These logs track system events, which may be prompted by user actions or events internal to the EHR . All certified EHRs are required to maintain at least 1 event log to supportaudits of record access; an \u201caudit log\u201d tracking when users view, edit, or print any portionof a patient record. Many EHRs also maintain additional event logs tracking specific useractivities such as note writing or inbox messaging. For example, many EHRs maintain logstracking how text templates are used to write documents such as notes . Together, these diverse event logsenable investigators to constantly and passively collect data on EHR use without the costsor biases of surveys or direct observation.However, raw EHR event logs contain tremendous amounts of data. A year of raw event logsfor a single institution can reach 100s of Gigabytes, making them difficult to store,access, and analyze. These logs must also be heavily processed to derive meaningful measuressuch as the time clinicians spend using the EHR. More concretely, creating time-basedmeasures requires making nontrivial decisions about how to map individual actions toclinical activities and how to handle gaps between recorded actions .Several EHR vendors now automatically derive measures of EHR use from event logs\u2014typicallysummarized by week or month\u2014and present them to administrators in interactivedashboards.We previously reviewed the literature published before July 2019 in which investigatorsderived their own measures of EHR use from EHR audit logs.The objective of this scoping review is to compare the aims, measures, methods,limitations, and scope of studies that employ vendor-derived and investigator-derivedmeasures of EHR use, and to assess measure consistency across studies.https://osf.io/h6d7j). Weincluded peer-reviewed articles which (1) reported original research, (2) analyzed measuresderived from EHR event logs, and (3) were published between July 2019 and December 2021. Werestricted our search to this period to avoid overlapping with the prior review,We followed PRISMA guidelines for this scoping review and registered our protocol with theOpen Science Framework . While most vendor-measure studies (83%)observed EHR use exclusively in ambulatory settings,,,,P\u2009<\u2009.001). While vendor-measurestudies only ever included physicians or advanced practice providers (APPs), a third ofinvestigator-measure studies (34%) included all EHR users who performedthe observed activity,,,,,,P\u2009=\u2009.025) and to observeoverall EHR use, rather than only collect data on a specific activity such as note writingor inbox management . The mediannumber of participants and organizations observed were not significantly different between vendor-measureand investigator-measure studies. However, 6 vendor-measure studies included data frommore than 100 health systems, while just 1 investigator-measure study did.We observed several significant differences in the scope of studies employing vendor andinvestigator-derived measures .First, measured an amount of EHR use ,,,,,,,,,,,,,,,,,P\u2009<\u2009.001). Vendor-measure studies were more likely tocharacterize EHR or clinical workflows, such as when EHR activitieswere performed during the day , whileinvestigator-measure studies were more likely to characterize teamdynamics, for example, using record coaccess to determine which cliniciansroutinely worked together .We coded study aims using the 3 aims of EHR log research identified in the prior review.11 Aims ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,P\u2009<\u2009.001).Most studies were observational (91 articles) while a minority were experimental (11articles). Nine of the observational studies examined associations between EHR use and anoutcome in the cohort of observed users such as burnout,P\u2009<\u2009.001). Second, novendor-measure study created clinician networks while 9 investigator-measure studies did.The prior review of EHR audit log research identified 5 general measures that can bederived from EHR logs.,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,P\u2009<\u2009.001 in each case). While all vendor-measure studies reportedat least 1 duration of active EHR use , just 28% ofinvestigator-measure studies did so, with the remainder reporting specific measuresrelated to counts of EHR actions , the structure of clinical teams , or theduration of clinical events .Looking at specific measures of EHR use reported in each study reveals additionaldifferences, particularly regarding durations of EHR use . Reportepm\u20138:30am and 12:30 pm\u20131:30 pm, 5:30 pm\u20137 am, 6pm\u20136 am, 6 pm\u20137 am, 7 pm\u20137 am, 7pm\u20138 am, and 7:30 pm\u20137:30 am).,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Definitions of what constituted EHR use outside normal working hours varied . Twenty-,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,A variety of denominators were used to normalize measures of EHR time. The most frequentdenominator was days (31 articles) including days in a reporting period, days with ascheduled appointment/shift, weekdays, or weekend days/holidays.,,,,P\u2009=\u2009.008), but there were no significant differences in the reportingof undivided attention or message volume, though the number of studies reporting eithermeasure was low.Five articles measured teamwork for orders,Two decisions analysts make when creating time-based measures from EHR logs are (1) howto determine when a user is actively using the EHR and (2) how to map individual actions,such as clicking on an information panel, to activities such as inbox management or chartreview. We review how these methods were reported and validated.,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,P\u2009=\u20091.000), but there were differences in method. The vendor-measurestudies all used Epic\u2019s 5-s threshold to identify periods of inactivity or Cerner\u2019s methodof defining active use as either actions occurring less than 45 seconds apart orperforming more than 15 keystrokes, 3 mouse clicks, or 1700 pixels of mouse movement in aminute. Investigator-measure studies used a wider range of methods to determine active EHRuse including timeouts for inactivity and lookingfor any activity in 1- or 5-min blocks of time.While 70 articles measured a duration of time,These differences in how active EHR use was defined, combined with differences in howmeasures were normalized, limit comparison of EHR times across studies, especially studiesthat rely on investigator-derived measures . While 1,,,,,,,,,,,,,,,,,,,,,,,,,P\u2009=\u2009.370).Of the 37 articles that reported durations of EHR use for specific activities such asinbox management or chart review,P\u2009=\u2009.473).,,,,,,,,,,,,Eight articles reported the results of measure validation, with no difference inreporting between vendor-measure and investigator-measure studies . Seventeen articles argued thatcurrent measures may systematically underestimate EHR use,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,Reviewed articles also raised 8 new limitations not identified in the prior review. Fourof these limitations related to measure accuracy and granularity, each of which wasmentioned in both investigator-measure and vendor-measure studies with no difference inreporting rates (P\u2009<\u2009.05 in each case). Seven articles cited difficulties withinterpreting proprietary vendor-derived metrics,,,,,,,,,,,,,,,,,,,,,,,,,,,Four additional limitations referenced measure interpretability and scope. While theselimitations were mentioned in both vendor-measure and investigator-measure studies, thefirst 3 limitations were raised more often in vendor-measure studies. Studies employing vendor-derived measures were more likely to report durationsof EHR use while those employing investigator-derived measures were more likely to examinecommunication and collaboration in care teams. While most studies reported a duration ofactive EHR use , variation in how active use was defined and how measureswere normalized limit comparison across studies,especially studies employing investigator-derived measures. And while all studies based onevent logs share a common set of strengths and limitations, studies employingvendor-derived measures were more likely to raise concerns about measure opacity ,misalignment with typical clinic schedules, and measure availability for certain clinicalroles.This scoping review updates a prior review of audit log research and expands it toinclude all research based on EHR event logs,Vendor-provided measures remove many of the barriers to conducting log-based research butare limited in scope. The reviewed studies only reported vendor-derived measures forphysicians and advanced practiced providers, and most of these only measured EHR use inambulatory settings. However, the work of nurses, medical assistants, students,technicians, scribes, and other team members\u2014many of whom experience significantdocumentation burden\u2014should not be overlooked.Vendor-provided measures automate the process of turning strings of logged events intodurations of EHR use. However, vendor-provided measures are largely lacking for constructssuch as workflow and teamwork. Given the strong association between EHR time outsidescheduled hours and physician burnout,While widely reported, durations of active EHR use are variouslydefined, which limits synthesis of evidence on critical topics such as documentationburden and its link to burnout. This was particularly true of studies that employedinvestigator-derived measures, most of which had unique definitions of active EHR use.Vendor-derived measures enable greater consistency across studies, though differentvendors use different methods of defining and normalizing EHR time, making cross-vendorcomparison difficult.criterion validity of measures they employ , aswell as content validity and construct validity . The number of uniquedefinitions of EHR time outside scheduled hours . Dr ERM is supported by grants and contracts from the National Instituteon Drug Abuse, American Medical Association, and Agency for Healthcare Research and Qualityunrelated to this work. Funding for open access publishing was provided by the Sarah M.Pritchard Faculty Support Fund.AR and NCA contributed to the research design, data analysis, and manuscript preparation.ERM contributed to the research design and manuscript preparation.Journal of the American Medical Informatics Associationonline.ocac177_Supplementary_DataClick here for additional data file."} +{"text": "Xya riparia, Genome Biology and Evolution, Volume 14, Issue 1, January 2022, evac001, https://doi.org/10.1093/gbe/evac001.Xiaolei Feng, Nan Yang, Qilu Wang, Hao Yuan, Xuejuan Li, Muhammad Majid, Xue Zhang, Chengquan Cao, Yuan Huang, A Chromosome-Level Genome Assembly of the Pygmy Mole Cricket https://doi.org/10.6084/m9.figshare.19336391.v1.In the originally published version of this manuscript, the Data Availability section was incomplete. Another 3 files, including all data of genome assembly and annotations, are available on figshare, and can be accessed at This error has been corrected."} +{"text": "BJS Open, Volume 6, Issue 5, October 2022, zrac115, https://doi.org/10.1093/bjsopen/zrac115This is an erratum to: Ryusei Yamamoto, Teiichi Sugiura, Ryo Ashida, Katsuhisa Ohgi, Mihoko Yamada, Shimpei Otsuka, Takeshi Aramaki, Koiku Asakura, Katsuhiko Uesaka, Preoperative risk factors for early recurrence after resection of perihilar cholangiocarcinoma, Statistical analyses section was erroneously given as 0.005.In the originally published version of this manuscript, the P value in the The correct P value is 0.050.This error has been corrected."} +{"text": "Moderate to severe ulcerative colitis (UC) exerts a significant burden on patients\u2019 lives. Patients with UC report that bowel urgency has a substantial negative impact on their quality of life and psychosocial functioning, however, this symptom is missing from most disease activity indices.The Communicating Needs and Features of IBD Experiences (CONFIDE) study aims to increase understanding of the impact of symptoms, including bowel urgency, on the lives of patients (pts) with moderate to severe UC and Crohn\u2019s disease in the United States (US), Europe (EUR), and Japan. These data focus on pts in the US and EUR.Online, quantitative, cross-sectional surveys of pts with moderate to severe UC were conducted in the US and EUR . Data included pt perspectives on their UC symptoms and the impact on their daily lives. Moderate to severe UC was defined based on treatment, steroid use, and/or hospitalization history. Descriptive statistics summarise the data.200 US pts and 556 EUR pts completed the survey, with 77% and 54% currently receiving advanced therapies , respectively. The top 3 symptoms currently (past month) experienced by US and EUR pts were diarrhoea (63% and 50%), bowel urgency (47% and 30%) and increased stool frequency (39% and 30%). In past 3 months, pts who have ever experienced bowel urgency or urge incontinence reported bowel urgency and urge incontinence at least once a month (Table). 69% and 65% of all US and EUR pts, respectively, reported wearing a diaper/pad/protection at least once a month in the past 3 months due to fear/anticipation of urge incontinence. For pts receiving advanced therapies, similar patterns were observed. Among both US and EUR pts, the most common UC-related reasons for declining participation in social events were bowel urgency (43% and 30%) and fear of urge incontinence (40% and 32%). Similarly, the most common reasons for declining participation in work/school and sports/physical exercise were bowel urgency and fear of urge incontinence.Bowel urgency, which was the second-most frequently reported symptom, has an extensive impact on the lives of pts with moderate to severe UC. In this younger pt population, including pts receiving advanced therapies, almost two thirds of US and EUR pts reported wearing diapers/pads/protection at least once a month in the past 3 months due to fear/anticipation of urge incontinence. Both US and EUR pts reported bowel urgency and fear of urge incontinence as the top reasons for declining participation in social events, work/school, and sports/physical exercise.OtherEli Lilly and CompanyS. Schreiber Grant / Research support from: personal fees and/or travel support from: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Dr. Falk Pharma, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Gilead Sciences, I-MAB Biopharma, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Biopharma, and UCB Pharma, A. Bleakman Employee of: Eli Lilly and Company, M. Dubinsky Shareholder of: Trellus Health, Grant / Research support from: AbbVie, Janssen, Pfizer, and Prometheus Biosciences, Consultant of: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Pfizer, Prometheus Therapeutics and Diagnostics, Takeda, and UCB Pharma, D. Rubin Grant / Research support from: Takeda, Consultant of: AbbVie, Allergan, AltruBio, American College of Gastroenterology, Arena Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene/Syneos Health, Cornerstones Health (non-profit), Eli Lilly and Company, Galen/Atlantica, Genentech/Roche, Gilead Sciences, GoDuRn, InDex Pharmaceuticals, Ironwood Pharmaceuticals, Iterative Scopes, Janssen, Materia Prima, Pfizer, Prometheus Therapeutics and Diagnostics, Reistone Biopharma, Takeda, and TechLab, T. Hibi Grant / Research support from: AbbVie, Activaid, Alfresa Pharma, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical K.K., JMDC, Nippon Kayaku, Mochida Pharmaceutical, Pfizer Japan, and Takeda, Consultant of: AbbVie, Apo Plus Station, Bristol Myers Squibb, Celltrion, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen, Kyorin, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical, Pfizer, Takeda, and Zeria Pharmaceutical, Speakers bureau of: AbbVie, Aspen Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda, R. Panaccione Grant / Research support from: AbbVie, Ferring Pharmaceuticals, Janssen, Pfizer, and Takeda, Consultant of: Abbott, AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmo Pharmaceuticals, Eisai, Elan Pharma, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Therapeutics, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, and UCB Pharma, T. Gibble Employee of: Eli Lilly and Company, C. Kayhan Employee of: Eli Lilly and Company, E. Flynn Employee of: Eli Lilly and Company, C. Sapin Employee of: Eli Lilly and Company, C. Atkinson Consultant of: Eli Lilly and Company in connection with the development of this publication, Employee of: Adelphi Real World, S. Travis Grant / Research support from: AbbVie, BUHLMANN Diagnostics, ECCO, Eli Lilly and Company, Ferring Pharmaceuticals, International Organization for the Study of Inflammatory Bowel Disease, Janssen, Merck Sharp & Dohme, Normal Collision Foundation, Pfizer, Procter & Gamble, Schering-Plough, Takeda, UCB Pharma, Vifor Pharma, and Warner Chilcott, J. Jones: None Declared"} +{"text": "Haiming Zhang, Shipeng Li, Haixu Xu, Liying Sun, Zhijun Zhu, Zhi Yaohttps://doi.org/10.1002/mco2.25First published: 20 August 2020, In the process of checking the raw data"} +{"text": "PLOS ONE Editors retract this article [The article because TH, SD, OL, TB, SF, HA, ST, EK, RD, OM, and MB did not agree with the retraction. JH, AK, PS, and GSH either did not respond directly or could not be reached."} +{"text": "Epidemiologia was able to uphold its high standards for published papers due to the outstanding efforts of our reviewers. Thanks to the efforts of our reviewers in 2022, the median time to first decision was 37.5 days and the median time to publication was 60.5 days. Regardless of whether the articles they examined were ultimately published, the editors would like to express their appreciation and thank the following reviewers for the time and dedication that they have shown Epidemiologia:\u00c1gnes, CsivincsikMadadizadeh, FarzanAli, AshaqMancon, AlessandroAl-sayyed, HibaMa\u0144czuk, MartaArguni, EggiManne, KartikAtalan, AbdulkadirMansor, RozaihanBaccolini, ValentinaMcCartney, GerryBailey, EmilyMendy, Vincent LutherBanerjee, AnkonaMilenkovi\u0107, BranislavaBie\u0144kowski, CarloMonteiro, Lu\u00edsButt, Muhammad HammadM\u00fa\u00f1ez, ElenaBuzhilova, Alexandra P.Mu\u00f1oz-Garc\u00eda, Claudia I.Canora Lebrato, JesusNi\u0161avi\u0107, Jakov J.Cardoso, RodrigoNovozhilov, Artem S.Cerda, ArcadioOtrisal, PavelChodick, GabrielPanthee, BimalaDa Mota, Jurema Corr\u00eaaPertea, MihaelaDartnall, ElizabethPrasad, VibhuDelgado-Gallegos, Juan LuisPrestileo, TullioDianatinasab, MostafaRamalho, Alanderson AlvesDileepan, MythiliRizzo, EmanueleEl Hidan, Moulay AbdelmonaimRocha, Ian Christopher N.Elfaky, MahmoudRodic, AndjelaFal, AndrzejRodr\u00edguez-Hurtado, DianaFilho, Arnaldo Jorge MartinsS\u00e0, FilipaFranco, ChristianSanz Mu\u00f1oz, IvanGanusov, VitalySchultz, DavidGarcia Cabrera, EmilioSilva, C\u00e2ndidaGentile, St\u00e9phanie G.Silva, Gustavo Sousa E.Gupta, RituSilverii, Antonio GiovanniGutkowska, OlgaSong, KunGyawali, BishalSzczepaniak, KlaudiuszIoan\u0103\u0219, CorinaTakita, MorihitoIqhrammullah, MuhammadThevkar Nagesh, PrashanthIslam, Md. TaohidulTok, Peter Seah KengJagielska, AnnaTroup, LucyJain, Hemant KUllah, QudratJin, YingUpadhyay, Sushil K.Jur\u010dev Savi\u010devi\u0107, AnamarijaVilinov\u00e1, Katar\u00ednaKapczuk, PatrycjaVillani, Emanuele RoccoKarmaoui, AhmedWaap, HelgaKundnani, Nilima RajpalWang, BoL\u0103zureanu, Voichi\u021ba ElenaYakoob, Mohammad YawarLi, XinleiYin, XinL\u00f3pez-Garc\u00eda, Xos\u00e9Zhang, TianouLundin, RebeccaZincir, HandanHigh-quality academic publishing is built on rigorous peer review."} +{"text": "PLOS ONE Editors retract this article [The article because ZAD, SAD, SL, AI, SHW, MB, and MJA did not agree with the retraction. JAK, AAL, BAL, RHK, JR, SA, and SAA either did not respond directly or could not be reached."} +{"text": "Yang Han, Xin Huang, Xiaoyu Cao, Yuchen Li, Lei Gao, Jin Jia,Gang Li, Hejiang Guo, Xiaochang Liu, Hongling Zhao, Hua Guan, Pingkun Zhou,Shanshan GaoMedComm \u00a0https://doi.org/10.1002/mco2.123, published online 22 March 2022Correction to:\u00a0In the process of checking the raw data,"} +{"text": "The Communicating Needs and Features of IBD Experiences (CONFIDE) study aims to increase understanding of the impact of symptoms on patients with moderate to severe UC and Crohn\u2019s disease and to investigate gaps in communication with healthcare professionals (HCPs) in the United States (US), Europe (EUR), and Japan.This report focuses on patients with moderate to severe UC and HCPs from the US and EUR.Online, quantitative, cross-sectional surveys of patients with UC and HCPs were conducted in the US and EUR . HCP surveys included physicians and non-physician HCPs responsible for making prescribing decisions. Moderate to severe UC was defined based on treatment, steroid use, and/or hospitalization history. Data collected included perspectives on the experience of patients with UC.A total of 200 US and 556 EUR patients , and 200 US and 503 EUR HCPs completed the survey. According to US and EUR patients, the top 3 symptoms currently (past month) experienced were diarrhoea (63% and 50%), bowel urgency (47% and 30%) and increased stool frequency (39% and 30%). Blood in stool was reported as currently experienced by 27% and 24% of US and EUR patients, respectively. Among patients currently experiencing bowel urgency, 47% of US and 27% of EUR patients discuss this symptom at every appointment. Among those who do not discuss bowel urgency at every appointment, 74% and 75% of US and EUR patients would like to discuss this symptom more frequently with their HCP. A total of 30% and 43% of US and EUR patients that ever experienced bowel urgency were not comfortable reporting it to their HCP, with 62% and 58% of these US and EUR patients feeling embarrassed talking about this symptom (Table). HCPs in both the US and EUR ranked diarrhoea (74% and 65%), blood in stool (69% and 65%) and increased stool frequency (38% and 34%) as the top 3 symptoms most reported by patients. According to US and EUR HCPs, the top 4 symptoms proactively discussed in routine appointments were blood in stool (93% and 94%), diarrhoea (90% and 91%), increased stool frequency (82% and 82%) and bowel urgency (76% and 82%). Among HCPs who did not proactively discuss bowel urgency, 47% of US and 40% of EUR HCPs expect patients to bring this up if it is an issue.Communication gaps were similar between US and EUR patients and HCPs. Bowel urgency is the second-most reported symptom by patients with moderate to severe UC. However, this symptom is not among the HCP-perceived top 3 most reported symptoms. Although a substantial proportion of patients reported a desire to discuss bowel urgency more frequently with their HCP, some patients reported feeling embarrassed talking about it. Many HCPs who do not proactively discuss this symptom expect patients to bring this up. A communication gap was identified and highlights the under-appreciation of bowel urgency as an important symptom of UC.OtherEli Lilly and CompanyS. Travis Grant / Research support from: AbbVie, BUHLMANN Diagnostics, ECCO, Eli Lilly and Company, Ferring Pharmaceuticals, International Organization for the Study of Inflammatory Bowel Disease, Janssen, Merck Sharp & Dohme, Normal Collision Foundation, Pfizer, Procter & Gamble, Schering-Plough, Takeda, UCB Pharma, Vifor Pharma, and Warner Chilcott, A. Bleakman Employee of: Eli Lilly and Company, D. Rubin Grant / Research support from: Takeda, Consultant of: AbbVie, Allergan, AltruBio, American College of Gastroenterology, Arena Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene/Syneos Health, Cornerstones Health (non-profit), Eli Lilly and Company, Galen/Atlantica, Genentech/Roche, Gilead Sciences, GoDuRn, InDex Pharmaceuticals, Ironwood Pharmaceuticals, Iterative Scopes, Janssen, Materia Prima, Pfizer, Prometheus Therapeutics and Diagnostics, Reistone Biopharma, Takeda, and TechLab, M. Dubinsky Shareholder of: Trellus Health, Grant / Research support from: AbbVie, Janssen, Pfizer, and Prometheus Biosciences, Consultant of: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Pfizer, Prometheus Therapeutics and Diagnostics, Takeda, and UCB Pharma, R. Panaccione Grant / Research support from: AbbVie, Ferring Pharmaceuticals, Janssen, Pfizer, and Takeda, Consultant of: Abbott, AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmo Pharmaceuticals, Eisai, Elan Pharma, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Therapeutics, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, and UCB Pharma, T. Hibi Grant / Research support from: AbbVie, Activaid, Alfresa Pharma, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical K.K., JMDC, Nippon Kayaku, Mochida Pharmaceutical, Pfizer Japan, and Takeda, Consultant of: AbbVie, Apo Plus Station, Bristol Myers Squibb, Celltrion, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen, Kyorin, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical, Pfizer, Takeda, and Zeria Pharmaceutical, Speakers bureau of: AbbVie, Aspen Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda, T. Gibble Employee of: Eli Lilly and Company, C. Kayhan Employee of: Eli Lilly and Company, E. Flynn Employee of: Eli Lilly and Company, C. Sapin Employee of: Eli Lilly and Company, C. Atkinson Consultant of: Eli Lilly and Company in connection with the development of this publication, Employee of: Adelphi Real World, S. Schreiber Grant / Research support from: personal fees and/or travel support from: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Dr. Falk Pharma, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Gilead Sciences, I-MAB Biopharma, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Biopharma, and UCB Pharma, J. Jones: None Declared"} +{"text": "Neuro-Oncology Advances, Volume 4, Issue 1, January\u2013December 2022, vdac096, https://doi.org/10.1093/noajnl/vdac096This is a corrigendum to: Manjari Pandey, Joanne Xiu, Sandeep Mittal, Jia Zeng, Michelle Saul, Santosh Kesari, Amir Azadi, Herbert Newton, Karina Deniz, Katherine Ladner, Ashley Sumrall, W Michael Korn, Emil Lou, Molecular alterations associated with improved outcome in patients with glioblastoma treated with Tumor-Treating Fields, In the originally published version of this manuscript, PIK3CA MT vs WT, NF1 MT vs WT, and EGFR WT vs MT were incorrectly labeled in Figure 3.PFS values for PIK3CA MT and WT were incorrectly labeled in Supplementary Table 1.These errors have been corrected."} +{"text": "BRCA1-mutated prostate cancer has been shown to be less responsive to poly (ADP-ribose) polymerase (PARP) inhibitors as compared to BRCA2-mutated prostate cancer. The reason for this differential response is not clear. We hypothesized this differential sensitivity to PARP inhibitors may be explained by distinct genomic landscapes of BRCA1 versus BRCA2 co-segregating genes. In a large dataset of 7,707 men with advanced prostate cancer undergoing comprehensive genomic profiling (CGP) of cell-free DNA (cfDNA), 614 men harbored BRCA1 and/or BRCA2 alterations. Differences in the genomic landscape of co-segregating genes was investigated by Fisher\u2019s exact test and probabilistic graphical models (PGMs). Results demonstrated that BRCA1 was significantly associated with six other genes, while BRCA2 was not significantly associated with any gene. These findings suggest BRCA2 may be the main driver mutation, while BRCA1 mutations tend to co-segregate with mutations in other molecular pathways contributing to prostate cancer progression. These hypothesis-generating data may explain the differential response to PARP inhibition and guide towards the development of combinatorial drug regimens in those with BRCA1 mutation. BRCA1 and BRCA2 alterations , lower overall response rate (26.3% vs. 50%) and a lower median radiographic progression-free survival (4.1 months vs. 10.1 months) (BRCA1 versus BRCA2 mutation.Poly (ADP-ribose) polymerase (PARP) inhibitors such as olaparib and rucaparib are currently approved for patients with metastatic castration-resistant prostate cancer (mCRPC) with BRCA1/2 mutations. This included all cfDNA somatic alterations defined as reportable by clinical testing parameters. All variants of unknown significance were excluded from the analysis. Frameshift and nonsense mutations were included as pathogenic. All patients with advanced prostate cancer who underwent comprehensive genomic profiling (CGP) of cell-free DNA (cfDNA) by a Clinical Laboratory Improvement Amendments (CLIA)-certified, College of American Pathologists (CAP)-accredited laboratory between 11/2016 to 8/2020 were eligible. First available cfDNA CGP results from consecutive patients with advanced prostate cancer tested were evaluated for the presence of BRCA1 and BRCA2 mutations in our cohort of patients was compared to published reports by the chi-squared test. Pairwise associations of mutation-positive BRCA1 or BRCA2 genes with other mutated genes was independently assessed by Fisher\u2019s exact test, and p-values were adjusted for false discovery rate* (FDR) to control multiple testing. Statistical significance was defined as a p-value \u2264 0.05.The prevalence of BRCA1 or BRCA2 were assessed using a combination of two probabilistic graphical model (PGM) machine learning approaches. To account for the high computational cost of the PGM dependence structure discovery, we identified the nearest BRCA1 or BRCA2 neighboring genes by an approximate PGM structure finding algorithm . All significant relations were captured by the PGM.Once the candidate genes were identified, we used the \u201cexact\u201d DP-A* structurBRCA1 and/or BRCA2. The median age for the total cohort was 72 years (interquartile range 65-78 years). Pathogenic mutations in BRCA1/2 were found in 614 of 7,707 unique patients. The frequency of alterations in BRCA1 (4.6%) and BRCA2 (7.97%) detected in cfDNA was similar to what has been reported from CGP of primary tissue was identified by Fisher\u2019s exact test and selected for further analysis by the costly, \u201cexact\u201d DP-A* , as well as the inability to definitively determine the origin of mutations identified in cfDNA (e.g. tumor versus germline versus hematopoietic). Strengths of the study include the number of patients and centers included and the dataset\u2019s real-world nature. These hypothesis-generating data reveal differential genomic signatures associated with lkiedrowski@guardanthealth.com.The datasets generated and/or analyzed for the current study are not publicly available, as they are derived from commercial testing. This data may be made available under a fully executed data use agreement. Requests to access these datasets should be directed to Lesli Kiedrowski, The studies involving human participants were reviewed and approved by University of Utah IRB. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.Conception and design: US, RN, NA. Acquisition of data: LK, RN. Analysis and interpretation of data: US, RZ, RN, EJH, BH, MY, NA. Drafting of the manuscript: US, RZ, RN, NA. Critical revision of the manuscript for important intellectual content: US, RZ, RN, EJH, YJ, NS, SW, LK, PB, GL, MB, EIH, LN, HB, SP, ML, BM, BH, MY, OS, NA. Statistical analysis: US, RZ, RN, EJH, YJ, BH. All authors contributed to the article and approved the submitted version.NA reports consultancy to Astellas, Astra Zeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics; and additionally reports institutional research funding from Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Glaxo Smith Kline, Immunomedics, Janssen, Medivation, Merck, Nektar, New Link Genetics, Novartis, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. LK is an employee and stockholder of Guardant Health. PB declares grants or contracts from Merck, Seagen, Blue Earth Diagnostics, Pfizer, and EMD Serono; consulting fees from Dendreon, Pfizer, Caris Life Sciences, Astellas, Eisai, Janssen, EMD Serono, Seattle Genetics, Bristol-Myers Squibb, Bayer, and Guardant Health; payments or honoraria from Caris Life Sciences, Bayer, and Pfizer; and participation on boards for Bristol-Myers Squibb, Seagen, Astellas, Eisai, Janssen, EMD Serono, Dendreon, Pfizer, Seattle Genetics, Bayer, and Guardant Health. MB declares consulting fees from Exelixis, Bayer, Bristol-Myers Squibb, Eisai, Pfizer, AstraZeneca, Janssen, Calithera Biosciences, Genomic Health, Nektar, EMD Serono, Seagen, and Sanofi and institutional research support from Merck, Xencor, Bayer, Bristol-Myers Squibb, Genentech/Roche, Seagen, Incyte, Nektar, AstraZeneca, Tricon Pharmaceuticals, Genome & Company, AAA, Peloton Therapeutics, and Pfizer for work performed outside the current study. EIH has received honoraria from Bayer, Sanofi, and Seattle Genetics; acted as a consultant/advisor for Astellas Pharma; is an Advisory Board and/or Speakers\u2019 Bureau member for AstraZeneca, Bayer, Bristol-Myers Squibb, Sanofi; and has received paid travel from Astellas Pharma, Caris Life Sciences, Sanofi, and Seattle Genetics; in addition, her institution has received research funding from Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Caris Life Sciences, Celgene, Celldex, Corcept Therapeutics, Curementa, Dendreon, eFFECTOR Therapeutics, Esanik, Fortis Therapeutics, Genetech/Roche, GlaxoSmithKline, Ignyta, Inovio Pharmaceuticals, Medivation, Merck Sharp & Dohme, Merck, Millennium, Oncolys BioPharma, Plexxicon, Seattle Genetics, Synta, Tokai Pharmaceuticals, and Zenith Epigenetics. HB Consulting or Advisory Role: Endocyte, Celgene, Idera, Myovant Sciences Speakers' Bureau: Guardant Health. SP reports personal fees from F. Hoffman-La Roche outside the submitted work, as well as research funding to his institution from Eisai, Genentech, Roche, Exelixis, and Pfizer; and reports a consulting/advisory role for Novartis, Medivation, Astellas Pharma, Pfizer, Aveo, Myriad, Genentech, Exelixis, and Bristol-Myers Squibb. US reports consultancy to Astellas, Exelixis and Seattle Genetics and research funding to institute from Janssen, Exelixis and Astellas/Seattle Genetics. OS is a consultant for Advanced Accelerator Applications, Astellas, AstraZeneca, Bayer Blue Earth Diagnostics Inc., Bavarian, Nordic, Bristol, Myers, Squibb, Clarity, Pharmaceuticals, Clovis, Constellation, Dendreon, EMD, Serono, Fusion, Janssen, Myovant, Myriad, Noria, Therapeutics, Inc., Novartis, Noxopharm, Progenics, POINT, Biopharma, Pfizer, Sanofi, Tenebio, Telix, Theragnostics, Dendreon, Endocyte, Innocrin, Invitae, Merck, and SOTIO; research funding from Advanced Accelerator Applications, AstraZeneca, Bayer, Invitae, and Merck. BH reports receiving travel assistance from Flatiron Health, and served as a consultant for AstraZeneca, Value Analytics, National Kidney Foundation, and Prometic Life Sciences. MY is a stock holder or has received stock option awards from Fabric Genomics Inc. and has received consulting fees from Fabric Genomics Inc. BM has consulted for Janssen Oncology, Exelixis, Tempus, Peloton Therapeutics and Astellas. RN has consulted for Tempus.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "PLOS ONE Editors retract this article [The article because BH and SB either did not respond directly or could not be reached. AA, AHA, FB, HAEE, MM, RP, RZS, KR, and SH did not agree with the retraction."} +{"text": "This is Publisher's Note regarding:FEMS Yeast Research, Volume 22, Issue 1, 2022, foac036, https://doi.org/10.1093/femsyr/foac036Elena Vanacloig-Pedros, Kaitlin J Fisher, Lisa Liu, Derek J Debrauske, Megan K M Young, Michael Place, Chris Todd Hittinger, Trey K Sato, Audrey P Gasch, Comparative chemical genomic profiling across plant-based hydrolysate toxins reveals widespread antagonism in fitness contributions, in vivo assay system for analyzing efflux of sugars mediated by glucose and xylose transporters, FEMS Yeast Research, Volume 22, Issue 1, 2022, foac038, https://doi.org/10.1093/femsyr/foac038Sebastian A Tamayo Rojas, Eckhard Boles, Mislav Oreb, A yeast-based Candida glabrata, FEMS Yeast Research, Volume 22, Issue 1, 2022, foac045, https://doi.org/10.1093/femsyr/foac045Daniel Elias, Nora Toth Hervay, Juraj Jacko, Marcela Morvova, Jr, Martin Valachovic, Yvetta Gbelska, Erg6p is essential for antifungal drug resistance, plasma membrane properties and cell wall integrity in These three papers were inadvertently assigned to Volume 2021, Issue 1 (2021) instead of Volume 22, Issue 1 (2022). This error, for which the publisher apologizes, has now been corrected."} +{"text": "Ulcerative colitis (UC) can result in a high prevalence of bowel movement urgency (BU), significantly reducing patient quality of life.Early BU improvement association with later clinical endpoint improvements was examined in moderately-to-severely active UC patients (pts) treated with mirikizumab (miri).BU was evaluated in Phase 3 randomized placebo (PBO)-controlled 12-week induction and 40-week maintenance trials with miri. Pts received IV miri 300mg or PBO during induction. Week (W)12 miri responders were rerandomized at LUCENT-2 baseline (BL) to subcutaneous miri 200mg or PBO. BU was measured with 11-point Urgency Numeric Rating Scale (UNRS) from 0 (no urgency) to 10 (worst possible). Pts\u2019 UNRS scores were an average from 7 consecutive days prior to visit. Association of pts with BU Clinically Meaningful Improvement (CMI) or BU remission between BL and W4 with the proportion of pts achieving clinical response, and clinical, endoscopic, or symptomatic remission at end of W12 was assessed. For pts who achieved clinical response at W12, the analyses were repeated for the end of maintenance based on W12 BU status. Logistic regression models with treatment, urgency (BU CMI or BU Remission), treatment-by-urgency group interaction, and stratification factors were fitted to examine the association between early urgency improvement and later clinical endpoints.Treatment-by-urgency group interactions were not statistically significant across clinical outcomes for induction and maintenance. For induction, treatment and urgency status were statistically significant. Pts experiencing BU CMI or BU remission at W4 were consistently more likely to achieve clinical response, and clinical, endoscopic, or symptomatic remission at W12 for both treatment groups. For remission, only treatment main effect was statistically significant. Among miri induction clinical responders (an enriched population), BU CMI or BU Remission at end of induction (W12) was not associated with later maintenance efficacy outcomes (W52). Miri-treated pts achieved higher rates of clinical response, and clinical, endoscopic, or symptomatic remission at W52 than with PBO regardless of BU CMI or BU Remission at W12 (Table).Early BU Improvement, CMI or Remission, was associated with better clinical outcomes during induction for miri and PBO pts, showing BU is a sensitive predictor of early clinical outcomes. Among miri induction responders, miri consistently provided better maintenance of response and remission rates than PBO.OtherEli Lilly and CompanyD. Clemow Employee of: Eli Lilly and Company, C. Sapin Employee of: Eli Lilly and Company, T. Hibi Grant / Research support from: AbbVie, ActivAid, Alfresa Pharma, Bristol Myers Squibb, Eli Lilly Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen Pharmaceutical K.K., JMDC, Mochida Pharmaceutical, Nippon Kayaku, Pfizer Japan, and Takeda, Consultant of: AbbVie, Apo Plus Station, Bristol Myers Squibb, Celltrion, EA Pharma, Eli Lilly and Company, Gilead Sciences, Janssen, Kyorin, Mitsubishi Tanabe Pharma, Nichi-Iko Pharmaceutical, Pfizer, Takeda, and Zeria Pharmaceutical, Speakers bureau of: AbbVie, Aspen Japan K.K., Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer, and Takeda, M. Dubinsky Shareholder of: Trellus Health, Grant / Research support from: AbbVie, Janssen, Pfizer, and Prometheus Biosciences, Consultant of: AbbVie, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, F. Hoffmann-La Roche, Genentech, Gilead Sciences, Janssen, Pfizer, Prometheus Therapeutics and Diagnostics, Takeda, and UCB Pharma, S. Vermeire Consultant of: AbbVie, Arena Pharmaceuticals, Avaxia Biologics, Boehringer Ingelheim, Celgene, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Gilead Sciences, Hospira, Janssen, Mundipharma, Merck Sharp & Dohme, Pfizer, ProDigest, Progenity, Prometheus Therapeutics and Diagnostics, Robarts Clinical Trials, Second Genome, Shire, Takeda, Theravance Biopharma, and Tillots Pharma AG, Speakers bureau of: AbbVie, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos NV, Genentech/Roche, Gilead Sciences, Janssen, Pfizer, Robarts Clinical Trials, and Takeda, S. Schreiber Grant / Research support from: personal fees and/or travel support from: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Dr. Falk Pharma, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Gilead Sciences, I-MAB Biopharma, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Biopharma, and UCB Pharma, T. Gibble Employee of: Eli Lilly and Company, L. Peyrin-Biroulet Grant / Research support from: AbbVie, Fresenius Kabi, Merck Sharp & Dohme, and Takeda, Consultant of: AbbVie, Alimentiv, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Enthera, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, Gossamer Bio, InDex Pharmaceuticals, Inotrem, Janssen, Merck Sharp & Dohme, Mylan, Norgine, Ono Pharmaceutical, OSE Immunotherapeutics, Pandion Therapeutics, Pfizer, Roche, Samsung Bioepis, Sandoz, Takeda, Theravance Biopharma, Thermo Fisher Scientific, Tillots Pharma AG, Viatris, and Vifor Pharma, M. Watanabe Grant / Research support from: AbbVie, Alfresa Pharma, EA Pharma, Kissei, Kyorin, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Takeda, and Zeria Pharmaceutical, Consultant of: AbbVie, Boehringer Ingelheim, EA Pharma, Eli Lilly Japan K.K., Gilead Sciences, Nippon, and Takeda, Speakers bureau of: EA Pharma, Eli Lilly Japan K.K., Gilead Sciences, Janssen, JIMRO, Kissei, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Pfizer Japan, Takeda, and Zeria Pharmaceutical, R. Panaccione Grant / Research support from: AbbVie, Ferring Pharmaceuticals, Janssen, Pfizer, and Takeda, Consultant of: Abbott, AbbVie, Alimentiv, Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Cosmo Pharmaceuticals, Eisai, Elan Pharma, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Oppilan Pharma, Pandion Therapeutics, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, and UCB Pharma, J. Jones: None Declared"} +{"text": "GABRA1, GABRB2 and GABRG2 define the genetic landscape of defects of GABAA receptors, Brain Communications, Volume 3, Issue 2, 2021, fcab033, https://doi.org/10.1093/braincomms/fcab033This is a correction to: Ciria C. Hernandez, XiaoJuan Tian, Ningning Hu, Wangzhen Shen, Mackenzie A. Catron, Ying Yang, Jiaoyang Chen, Yuwu Jiang, Yuehua Zhang, Robert L. Macdonald, Dravet syndrome-associated mutations in GABRB2 mentioned in the article have been reported previously. A reference to the previous report has been added.In the originally published version of this manuscript, a reference was omitted. The authors have added a clarification that the three cases of"} +{"text": "PNAS Nexus, Volume 1, Issue 4, September 2022, pgac174, https://doi.org/10.1093/pnasnexus/pgac174This is a correction to: Romain Tisserand, Brandon G Rasman, Nina Omerovic, Ryan M Peters, Patrick A Forbes, Jean-S\u00e9bastien Blouin, Unperceived motor actions of the balance system interfere with the causal attribution of self-motion, In the originally published version of this manuscript, one of Patrick A Forbes's affiliations was inadvertently omitted. The omitted affiliation is Department of Biomechanical Engineering, Delft University of Technology, Delft, The Netherlands.This error has now been corrected."} +{"text": "Martin S, Tyrrell J, Thomas EL, Bown MJ, Wood AR, Beaumont RN, Tsoi LC, Stuart PE, Elder JT, Law P, Houlston R, Kabrhel C, Papadimitriou N, Gunter MJ, Bull CJ, Bell JA, Vincent EE, Sattar N, Dunlop MG, Tomlinson IPM, Lindstr\u00f6m S, INVENT consortium, Bell JD, Frayling TM, Yaghootkar H. 2022. Disease consequences of higher adiposity uncoupled from its adverse randomisation metabolic effects using Mendelian. Published 25 January 2022The main analysis in the final paper involved a genome-wide association study (GWAS) summary statistic dataset for venous thromboembolism. This GWAS was conducted by the International Network of Venous Thromboembolism Clinical Research Networks (INVENT) consortium. In addition, Dr Sara Lindstr\u00f6m was instrumental in this GWAS and sharing the data. We are therefore formally correcting the eLife paper to include both Dr Lindstr\u00f6m and the INVENT consortium on this paper. Both have reviewed the manuscript and support the conclusions, and agree to be responsible for all parts of the paper in its published form.The details of Dr Lindstr\u00f6m\u2019s and the INVENT consortium\u2019s contributions are given below:Dr Lindstr\u00f6m and the INVENT consortium were both instrumental in conducting the GWAS of venous thromboembolism and sharing the associated summary statistic dataset. Both Dr Lindstr\u00f6m and the INVENT consortium have reviewed the manuscript and its conclusions.New authors list:Susan Martin, Jessica Tyrrell, E Louise Thomas, Matthew J Bown, Andrew R Wood, Robin N. Beaumont, Lam C Tsoi, Philip E. Stuart, James T Elder, Philip Law, Richard Houlston, Christopher Kabrhel, Nikos Papadimitriou, Marc J Gunter, Caroline J Bull, Joshua A Bell, Emma E Vincent, Naveed Sattar, Malcolm G Dunlop, Ian PM Tomlinson, Sara Lindstr\u00f6m, INVENT consortium, Jimmy D Bell, Timothy M Frayling, Hanieh Yaghootkar.Original authors list:Susan Martin, Jessica Tyrrell, E Louise Thomas, Matthew J. Bown, Andrew R Wood, Robin N Beaumont, Lam C Tsoi, Philip E Stuart, James T Elder, Philip Law, Richard Houlston, Christopher Kabrhel, Nikos Papadimitriou, Marc J Gunter, Caroline J Bull, Joshua A Bell, Emma E Vincent, Naveed Sattar, Malcolm G Dunlop, Ian PM Tomlinson, Jimmy D Bell, Timothy M Frayling, Hanieh Yaghootkar.Details for the omitted authors:Sara Lindstr\u00f6mDepartment of Epidemiology, University of Washington, Seattle, WA, USA.Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.Contribution: Resources, Writing - review and editingCompeting Interests: SL declares no competing interests.INVENT consortiumContribution: Resources, Writing - review and editingCompeting Interests: INVENT declares no competing interests.The article has been corrected accordingly."} +{"text": "PLOS ONE Editors retract this article [The article , 2 becauHAR, HF, MAT, MH, MS, MYA, RAA, SAlamri, and SAtta either did not respond directly or could not be reached. MAB did not agree with the retraction."} +{"text": "This article was published in Psychological Medicine with the reference \u2018Ikeda, S., Azuma, M., Fujimoto, K., Shibahara, H., Inoue, S., Moline, M., & Ishii, M. . PMH8 EQThe authors apologise for this error."} +{"text": "Following publication of the original article (1), The author names were incorrectly published as Ambrosio Marco, Virgilio Agnese, Raffone Antonio, Arena Alessandro, Raimondo Diego, Alletto Andrea, Seracchioli Renato and Casadio Paolo. But this should have been Marco Ambrosio, Agnese Virgilio, Antonio Raffone, Alessandro Arena, Diego Raimondo, Andrea Alletto, Renato Seracchioli, and Paolo Casadio.The original article has been updated."} +{"text": "Scientific Reports 10.1038/s41598-022-19847-5, published online 14 September 2022Correction to: The original version of this Article contained errors. The names of the authors Polina Vishnyakova, Maria Kuznetsova, Anastasiya Poltavets, Mariia Fomina, Viktoriia Kiseleva, Kamilla Muminova, Alena Potapova, Zulfiya Khodzhaeva, Alexey Pyregov, Dmitry Trofimov, Andrey Elchaninov, Gennady Sukhikh and Timur Fatkhudinov were incorrectly given as Vishnyakova Polina, Kuznetsova Maria, Poltavets Anastasiya, Fomina Mariia, Kiseleva Viktoriia, Muminova Kamilla, Potapova Alena, Khodzhaeva Zulfiya, Pyregov Alexey, Trofimov Dmitry, Elchaninov Andrey, Sukhikh Gennady and Fatkhudinov Timur. Consequently, the initials of the author names were also reversed in the Author Contributions section.The original Article has been corrected."} +{"text": "In the original publication, the study group author names are listed under Appendix section and it should be listed in Acknowledgement section as follows.AcknowledgementsSimplified Histologic Mucosal Healing Scheme (SHMHS) study group participants, all based in Italy: Davide Giuseppe Ribaldone and Marta Vernero, Department of Medical Sciences, University of Torino, Turin; Federica Grillo and Luca Mastracci, Department of Pathology, University of Genoa, Genoa; Chiara Vigan\u00f2, UOC Gastroenterologia, ASST Monza Ospedale San Gerardo, Monza; Giulia Scardino, Department of Gastroenterology, Ospedale Valduce, Como; Stefania Gambini, Department of Pathology, ASST Melegnano-Martesana, Milan; Francesca Boni, Department of Gastroenterology, ASST Melegnano-Martesana, Milan; Federica Furfaro, Department of Gastroenterology, IRCCS Humanitas, Milan; Cristina Bezzio and Simone Saibeni, Department of Gastroenterology, Ospedale di Rho, Milan; Michela Campora, Department of Pathology, Ospedale Santa Chiara, Trento; Eliana Greco, Edoardo V. Savarino and Fabiana Zingone, Department of Surgery, Oncology and Gastroenterology \u2013 DiSCOG, University of Padua, Padua; Daniele Canova, UOC di Gastroenterologia, AULSS 8 Berica, Vicenza; Irene Coati, Department of Pathology, Ospedale dell'Angelo, Mestre (VE); Davide Checchin, Department of Gastroenterology, Ospedale dell'Angelo, Mestre (VE); Marta Gobbato, Department of Pathology, Ospedale di Feltre, Belluno; Antonio Ferronato, UOSVD Endoscopia Digestiva, PO Alto Vicentino, Santorso (VI); Alice Morini, Department of Pathology, PO Alto Vicentino, Santorso (VI); Michele Campigotto, Department of Medicine and Surgery, University of Trieste, Trieste; Maria Raffaella Ambrosio, UOC Anatomia Patologica, Azienda Toscana Nord Ovest, Massa; Andrea Sbrozzi-Vanni, UOC Endoscopia Digestiva, Azienda Toscana Nord Ovest, Massa; Francesca De Nigris, Nicola Libert\u00e0 Decarli, Martina Giannotta and Andrea Nucci, Department of Gastroenterology, USL Centro Toscana, Florence; Stefano Lazzi, Department of Medical Biotechnology, University of Siena, Siena; Marco Valvano, Department of Gastroenterology, P.O. S. Salvatore, L'Aquila; Ambra Magiotta, Department of Gastroenterology, AOU Sant\u2019Andrea, Rome; Chiara Taffon, Department of Pathology, Campus Biomedico, Rome; Paola Balestrieri, Department of Gastroenterology, Campus Biomedico, Rome; Fabrizio Bossa, Department of Gastroenterology, IRCCS Ospedale Casa Sollievo della Sofferenza, Foggia; Gerardo Cazzato, Anna Colagrande, Antonio d\u2019Amati, Giuseppe Ingravallo, Domenico Piscitelli and Luciana Scuccimarri, Department of Pathology, Policlinico di Bari, Bari; Rocco Spagnuolo, Department of Gastroenterology, University Magna Graecia, Catanzaro; Barbara Scrivo, UOC Gastroenterologia ed Endoscopia digestiva, Arnas Civico Di Cristina Benfratelli, Palermo; Walter Fries and Anna Viola, Department of Gastroenterology, AOU Policlinico di Messina, Messina."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-13522-5, published online 08 June 2022Correction to: In the original version of this Article, Mohamed S. Soliman was incorrectly affiliated with \u2018Department of Electrical Engineering, Faculty of Energy Engineering, Aswan University, Aswan, 81528, Egypt\u2019. The correct affiliation is listed below.4. Department of Electrical Engineering, College of Engineering, Taif University, PO Box 11099, Taif 21944, Saudi Arabia.The original Article has been corrected."} +{"text": "Scientific Reports 10.1038/s41598-022-19894-y, published online 26 September 2022Correction to: In the original version of this Article, Himisha Dixit was incorrectly affiliated with \u2018Centre for Computational Biology and Bioinformatics, School of Life Sciences, Central University of Himachal Pradesh, TAB Shahpur, Kangra, HP, 176206, India\u2019.The correct affiliation is listed below.Department of Plant Pathology, COA, CSKHPKV, Palampur, HP, 176061, IndiaThe original Article has been corrected."} +{"text": "PLOS ONE Editors retract this article [The article because NRA, TJ, MA, UK, RCC, HLB, PS, LNM, SKS, and RR did not agree with retraction. KL, MMH, and AAAS either did not reply or could not be reached."} +{"text": "Gymnogryllus Saussure, 1877 and Phonarellus Gorochov, 1983. We found that the characters , and coloration of the hind leg in Phonarellusminor ) exhibit considerable amounts of variation within species, and are thus not reliable characters for species differentiation. Therefore, we revised the taxonomy of these two genera. Five synonyms are proposed: G.yunnanensis syn. nov., G.striatus syn. nov., G.longus syn. nov., G.tumidulus syn. nov., and P.flavipes (= P.minor) syn. nov. All species mentioned above are described and illustrated. Keys and a distribution map are provided.After extensive sampling of specimens from species found in China, we examined the intraspecific morphological variation of several characters used for species delimitation in two closely related cricket genera, Gymnogryllus Saussure, 1877 and Phonarellus Gorochov, 1983 have species in China that are difficult to distinguish based on morphology, and we found that some of the \u201cdifferent\u201d species co-occur at the same collection site and at the same time. Many of these species were proposed based on a limited number of specimens , oblique veins (slightly curved), and the ovipositor . Species of this genus have a similar appearance, and the male genitalia features are the primary characteristics for species identification. Currently, 45 species are reported worldwide, from India to Australia, and most of them are found in tropical Southeast Asia . These six Chinese species are distributed in the same province and are similar in body size and forewing morphology, for example, inclined rectangular mirror and internal dividing vein with three branches. The only characteristic for identifying these species is the posterior angle of the epiphallus. Here, we examined whether this diagnostic feature is stable by using multiple specimens per species to assess the amount of intraspecific variation.alaysia) . In ChinPhonarellus for species originally belonging to Gymnogryllus and designated Gymnogryllusminor Chopard, 1959 as the type species . Compared to Gymnogryllus, species of Phonarellus are smaller, the cercus base is of light color, and the apical area of the genitalia is obviously different between both genera. We recognize the genus by its contrasting coloration of antennae , ocelli almost arranged in a line, shiny and smooth pronotum, and somewhat leathery elytra , Phonarellusminor , Phonarellusflavipes Xia, Liu & Yin, 1991, and Phonarelluszebripe He, 2022). Two species, P.minor and P.flavipes, occur in Yunnan and Guangdong and are of very similar appearance. The only difference between P.minor and P.flavipes is that the posterior femora of P.flavipes have no black area and the markedly separated first and second oblique veins at the base and examined their morphological characteristics. Based on our results, we consider that four species in Gymnogryllus are junior synonyms of G.odonopetalus, and P.flavipes is a junior synonym of P.minor. The diagnostic characteristics previously proposed for species identification are unreliable because of extensive variation. New checklists of Chinese Gymnogryllus and Phonarellus species, with keys to species and distribution maps in the field. The specimens were preserved in analytical-grade ethanol during fieldwork and then pinned and dry-preserved in laboratory. After softening, dissecting needles were used to pull out the male genitalia from the gonopore. The dissected genitalia complexes were prepared by placing them into a concentrated solution of alkaline protease with a water bath temperature of 40\u201350 \u00b0C for 48 hours. Identification of involved species is mainly based on male morphology. Whole bodies were photographed with a VHX-6000 digital microscope . Figures of genitalia and body details were produced using a ToupCam Digital camera and bundled software .BL body length (from head to tip of abdomen); HW head width; EW eye width; PL pronotum length; PW pronotum width (max. width of pronotum); FWL forewing length; HWL hind wing length (length of uncovered part); DVL length of dialogue vein; ML mirror length (from fore to hind margin); CL cercus length; FTL fore tibiae length; TTL length of tibial tympanum; MTL middle tibiae length; HLL hind femur length; HTL hind tibiae length.All specimens were measured using ToupCam Digital camera (E3ISPM05000KPA) and bundled software . All the measurements are in millimeters (mm). Nomenclature of male genitalia follows P.minor specimens with at least one intact hind leg. Photos of these posterior femora were taken with a VHX-6000 digital microscope and processed in ImageJ. We used the Threshold function in ImageJ ver.1.53k and bundled software to measure the distances between the first and second oblique veins at the base of 42 specimens. The distributions were graphed in Microsoft Excel (Microsoft Office 2016).Acronyms used for the institutions where those examined materials are deposited:SNNUMuseum of Flora and Fauna of Shaanxi Normal University, Xi\u2019an, China;NWAFU Entomological Museum of Northwest A&F University, Yangling, China;SEM (IEAS) Shanghai Entomological Museum, CAS, Shanghai, China.Gymnogryllus Saussure, 1877Genus Gymnogrylluscontractus Liu, Yin & Liu, 1995Chinese name. \u72ed\u819c\u88f8\u87cbDistribution. Yunnan.Gymnogryllusodonopetalus Xie & Zheng, 2003Gymnogryllusyunnanensis Ma & Zhang, 2011, syn. nov.Gymnogryllusstriatus Ma & Zhang, 2011, syn. nov.Gymnogrylluslongus Ma & Zhang, 2011, syn. nov.Gymnogryllustumidulus Ma & Zhang, 2011, syn. nov.Chinese name. \u9f7f\u74e3\u88f8\u87cbDistribution. Yunnan, Guangxi, Guangdong.Gymnogryllusdolichodens Ma & Zhang, 2011Chinese name. \u957f\u7a81\u88f8\u87cbDistribution. Yunnan.Gymnogryllusextrarius Ma & Zhang, 2011Chinese name. \u5916\u7a81\u88f8\u87cbDistribution. Yunnan.Phonarellus Gorochov, 1983Genus Phonarellusminor Phonarellusflavipes Xia, Liu & Yin, 1991, syn. nov.Chinese name. \u5c0f\u97f3\u87cbDistribution. Guangxi, Hainan, Guangdong, Yunnan.Phonarellusritsemae Chinese name. \u5229\u7279\u97f3\u87cbDistribution. Guangxi, Zhejiang, Yunnan, Guangdong, Hong Kong.Phonarelluszebripes He, 2022Chinese name. \u6591\u817f\u97f3\u87cbDistribution. Yunnan.Orthoptera: Grylloidea; Gryllidae; GryllinaeTaxon classificationAnimaliaOrthopteraGryllidae\ufeffGenusSaussure, 18771300E0C5-9285-53CC-8D7D-A8DB4711C8BEGymnogryllus Brunner von Wattenwyl 1893: 197; Brachytrypus (Gymnogryllus) Saussure, 1877: 291.Grylluselegans (= Gymnogryllusleucostictus). Brachytrypus (Gymnogryllus) Saussure, 1877: 291.India, Australia, western Himalayas, Burma, Vietnam, Malaysia, China.Body large. Head, pronotum and much of hind femur blackish brown; rest of body of light color. Light brown bands uniformly distributed over posterior peduncle. Forewings not reaching tip of abdomen; hind wings largely surpassing abdomen. Mirror inclined rectangular. The length of the apical field of forewings varies among individuals. Subgenital plate shaped as hook. Genitalia large, in caudal view, epiphallus arch-shaped and the apically armed with a pair of long teeth. The space between the teeth and the shape of them varied among individuals Fig. . OviposiGymnogryllus are reported from China, and six of them have been found in Yunnan. Among them, G.longus, G.tumidulus, G.yunnanensis, and G.striatus have been described for differences in the angle of the epiphallic apex and the length of the apical field of tegmen. However, they are similar to G.odonopetalus in appearance and can be collected from the same location at the same time. We compared specimens collected from the same site and concluded that these two features present intraspecific variation and are unreliable for species delimitation. We consider that all four taxa are synonyms of G.odonopetalus.Eight species of Taxon classificationAnimaliaOrthopteraGryllidae\ufeffXie & Zheng, 2003B188F7B0-6336-55AD-91F9-1F3BA1430361Gymnogryllusodonopetalus Xie & Zheng, 2003: 496, 498.Gymnogryllusyunnanensis Ma & Zhang, 2011: 31\u201340, syn. nov.Gymnogrylluslongus Ma & Zhang, 2011: 31\u201340, syn. nov.Gymnogryllustumidulus Ma & Zhang, 2011: 31\u201340, syn. nov.Gymnogryllusstriatus Ma & Zhang, 2011: 31\u201340, syn. nov.\u2019an, China (SNNU).Type locality: Menglun, Xishuangbanna, Yunnan, China. Deposited at Museum of Flora and Fauna of Shaanxi Normal University, XiChina: 1 male (holotype), Yunnan, Xishuangbanna, Menglun, Sept. 8, 1999, Xie, Lingde coll. (SNNU); 2 males and 1 female, Yunnan, Honghe, Wengdang, Jun. 11, 2009, Ma, Libin coll. (SNNU); 1 female, Yunnan, Mengla, Shangyong, Longmen, May 13, 2013, Ma, Libin coll. (SNNU); 1 male, Yunnan, Mengla (or Wangtianshu), Oct. 2, 2014, Zhang, Tao coll. (SNNU); 3 males, Yunnan, Jinghong, Jul. 11, 2018, Peng, Zhong coll. (SNNU); 2 males, Yunnan, Pu\u2019er, Jinggu, Aug. 17, 2021, He, Zhixin coll. (SNNU); 7 males, Yunnan, Pu\u2019er, Simaoqu, Aug. 18, 2021, He, Zhixin coll. (SNNU); 15 males, Yunnan, Mengla, Menglun, Aug. 25, 2021, He, Zhixin coll. (SNNU); 3 females, Yunnan, Mengla, Menglun, Aug. 25, 2021, He, Zhixin coll. (SNNU).Fig. . China (N = 30)Male , and the outer apical spurs three . Subgenital plate hook-like. Cercus straight and short; with long hair sparse and short hair dense.Genitalia . Therefore, we regard G.yunnanensis, G.striatus, G.longus, and G.tumidulus as junior synonyms of G.odonopetalus.ens Fig. . BesidesG.odonopetalus has some charecters showing intraspecific variation even within specimens collected from the same place and time. In lateral view, the angle between the apical teeth and the posterior edge of the medial lobe of epiphallus is variable among individuals . Phonarellusflavipes has been described for its yellow hind legs and the interval between the anterior of the first and second oblique veins. But these characters can also be found in P.minor living side by side with P.flavipes. Studying a large number of specimens of these three taxa from Yunnan and Guangdong, we tested whether the color of hind legs is a valid trait for species delimitation, and provided a description of P.ritsemae.Four species of this genus have been reported from China DDCBC5BC-25BA-5527-81C5-DC60A4AB005BGymnogryllusminor Chopard, 1959: 1; Gymnogrylluskashmirensis Bhowmik, 1977: 24, misidentification.Phonarellus (Phonarellus) minor : Phonarellusminor : Gymnogryllus (Phonarellus) minor : PhonarellusflavipesType locality: Asia-Tropical, Indian Subcontinent, India, Kerala, Malabar Coast, Mah\u00e9. Deposited at Mus\u00e9um National d\u2019Histoire Naturelle, Paris, France (not examined).China: 36 males and 28 females, Yunnan, Mengla, Shangyong, Longmen, 1030 m, May 13, 2013, Ma, Libin coll. (SNNU); 5 females, same location as before, 1030 m, May 18, 2013, Ma, Libin coll. (SNNU); 4 males and 4 females, same location as before, 943 m, May 13, 2013, Ma, Libin coll. (SNNU); 3 males, same location as before, 996 m, May 13, 2013, Ma, Libin coll. (SNNU); 1 male, Yunnan, Jinping, Mengla, Xinmeng, 450 m, May 3, 2013, Ma, Libin coll. (SNNU); 3 males, Yunnan, Mengla, Mengban, Hebianzhai, 855 m, May 23, 2013, Ma, Libin coll. (SNNU); 4 males, Yunnan, Mengla, Menglun, 690 m, May 28, 2013, Ma, Libin coll. (SNNU) ; 6 males, Yunnan, Cangyuan, Banlao, 1134 m, Jun. 5, 2013, Ma, Libin coll. (SNNU); 2 males, Yunnan, Hekou, 100 m, Jun. 7, 1982, Jin, Gentao coll. (SEM); 2 males and 1 female, Yunnan, Xishuangbanna, Menglun, 1000 m, Jun. 3, 2009, Liu, Xianwei coll. (SEM); 3 males and 2 females, Yunnan, Mengla, Yaoqu, Jun. 1, 2009, Ma, Libin coll. (NWAFU). Vietnam: 1 female, Tonkin, Jul. 1940, A. De Cooman coll. (SEM).Fig. . China 2ED2606A-C085-5184-BF8A-C6907CB44447Liogryllusritsemae Saussure, 1877: 304; Achetaritsemae : Gryllusritsemae : Hisumatsu 1952: 43.Tartarogryllusritsemae : Chopard 1961: 272; Randell 1964: 1582; Leroy 1966: 39; Chopard 1967: 73.Phonarellusritsemae : Yin and Liu, 1995: 138\u2013139; Type locality: Japan. Deposited at National Nature Historical Museum, Leiden, Netherlands (not examined).China: 1 female, Yunnan, Mengla, Shangyong, Longmen, May 13, 2013, Ma, Libin (SNNU); 1 male, same location as before, May 14, 2013, Ma, Libin (SNNU); 1 male and 2 females, same location as before, May 18, 2013, Ma, Libin (SNNU); 1 male, Yunnan, Lvchun, Banpo, May 9, 2013, Ma, Libin. (SNNU); 1 female, Yunnan, Mengla, Yaoqu, May 25, 2013, Ma, Libin (SNNU); 1 female, Yunnan, Mengla, Menglun, May 28, 2013, Ma, Libin (SNNU); 9 males and 1 female, Guangdong, Shaoguan, Luoshanzhen, May 13, 2015, Zhang, Tao (SNNU); 8 males, Guangdong, Shenzhen, May 17, 2015, Zhang, Tao (SNNU); 1 male, Guangxi, Jingxi, Longbang, May 2, 2019, Ma, Libin and Zhang, Tao (SNNU); 1 male, Hong Kong, Damaoshan, May 9, 2018, Ma, Libin (SNNU); 1 male, Hong Kong, Fei\u2019eshan, May 18, 2018, Ma, Libin and Peng, Zhong (SNNU).China , Japan..N = 22)Male Female the posterior teeth of the epiphallus are variable among individuals in lateral view , which reduces the number of Chinese species of the genera Gymnogryllus and Phonarellus to four and three, respectively. Our work highlights the importance of extensive specimen collection and considering intraspecific variation in species identification.Based on our discovery of intraspecific variation, we considered some diagnostic features previously used as characters for separating species in these two genera invalid. The new species checklist showed five synonymus ("} +{"text": "Page 1: The affiliation for Evan Dekker, which previously read:2Academic Services and Support Directorate, University Drive, Mt. Helen, Ballarat, VIC\u00a03350, Australiahas now been updated to read:2Academic Services and Support Directorate, Federation University, University Drive, Mt. Helen, Ballarat, VIC\u00a03350, AustraliaThe original article has been corrected."} +{"text": "PMID: 35892078; PMCID: PMC9281584, authors requested to change the order of the co-authors, making Dr Tianye Lin as the first author. As a result of that the correct order of the authors is as follows:In the published article Zhang Z, Lin T, Zhong Y, Song W, Yang P, Wang D, Yang F, Zhang Q, Wei Q, He W. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study. Open Med. (Wars) 2022 Jul 13;17(1):1282\u201391. doi: Tianye Lin, Zhaoming Zhang, Yuan Zhong, Wenting Song, Peng Yang, Ding Wang, Fan Yang, Qingwen Zhang, Qiushi Wei and Wei He."} +{"text": "PLOS ONE Editors retract this article [The article because YC, MHS, and HMA did not agree with the retraction. RN, QuZ, SN, NK, KA, AAAH, AA, FK, KS, and QK either did not respond directly or could not be reached."} +{"text": "Bioinformatics, Volume 38, Issue Supplement_2, September 2022, Pages ii5\u2013ii12, https://doi.org/10.1093/bioinformatics/btac455This is a correction to: Maura John, Markus J. Ankenbrand, Carolin Artmann, Jan A. Freudenthal, Arthur Korte, and Dominik G. Grimm, Efficient permutation-based genome-wide association studies for normal and skewed phenotypic distributions, In the originally published version of this manuscript, the incorrect btac690_Supplementary_DataClick here for additional data file."} +{"text": "Scientific Reports 10.1038/s41598-022-16755-6, published online 22 July 2022Correction to: In the original version of this Article, A. M. El Shamy and S. Zein El Abedin were incorrectly affiliated with \u2018Petrochemicals Department, Egyptian Petroleum Research Institute, P.B. 11,727, Nasr City, Cairo, Egypt.\u2019 Their correct affiliation is listed below.Electrochemistry and Corrosion Laboratory, Physical Chemistry Department, National Research Centre, Dokki, 12622, Cairo, Egypt.The original Article has been corrected."} +{"text": "PLOS ONE Editors retract this article [The article because AEA, AFG, AMUD, AQ, AUR, BHE, JA, JI, KAI, NA, MIT, MJ, SAjmal, SAsghar, SB, SF, and SG did not agree with the retraction. AA either did not respond directly or could not be reached."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-22038-x, published online 27 December 2022Correction to: The original version of the Article contained an error in the Author Information section.\u201cThese authors contributed equally: Satish Anandan, Hittanahallikoppal Gajendramurthy Gowtham, C. S. Shivakumara, Anjana Thampy, Sudarshana Brijesh Singh, Mahadevamurthy Murali, Chandan Shivamallu, Sushma Pradeep, Natarajamurthy Shilpa, Ali A. Shati, Mohammad Y. Alfaifi, Serag Eldin I. Elbehairi, Joaqu\u00edn Ortega\u2011Castro, Juan Frau, Norma Flores\u2011Holgu\u00edn, Shiva Prasad Kollur and Daniel Glossman\u2011Mitnik.\u201dnow reads:\u201cThese authors contributed equally: Satish Anandan and Hittanahallikoppal Gajendramurthy Gowtham.\u201dIn addition, Shiva Prasad Kollur was incorrectly affiliated with \u201cDepartment of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506\u20115606, USA\u201d and \u201cMidwest Veterinary Services, Inc., Oakland, NE 68045, USA\u201d.The correct affiliation is listed below.School of Physical Sciences, Amrita Vishwa Vidyapeetham, Mysuru Campus, Mysuru, Karnataka, 570 026, India.The author, Mohammad Y. Alfaifi, was incorrectly affiliated with \u201cCell Culture Lab, Egyptian Organization for Biological Products and Vaccines (VACSERA Holding Company), 51 Wezaret El-Zeera St., Agouza, Giza, Egypt\u201d.The correct affiliation is listed below:Biology Department, Faculty of Sciences, King Khalid University, Abha, Saudi Arabia.The original version of this Article also contained an error in Affiliation 10, which was incorrectly given as \u2018Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506\u20115606, USA.\u2019 The correct affiliation is listed below:School of Physical Sciences, Amrita Vishwa Vidyapeetham, Mysuru Campus, Mysuru, Karnataka, 570 026, India.In addition, Affiliation 11 \u2018Midwest Veterinary Services, Inc., Oakland, NE 68045, USA\u2019 was removed.The original Article has been corrected."} +{"text": "Journal of Tropical Pediatrics, Volume 68, Issue 2, April 2022, https://doi.org/10.1093/tropej/fmac012This is a correction to: Emma Kortekangas, MD, Yue-Mei Fan, PhD, David Chaima, PhD, Kirsi-Maarit Lehto, PhD, Chikondi Malamba-Banda, MPhil, Andrew Matchado, PhD, Chilungamo Chingwanda, PhD, Zhifei Liu, MPH, Ulla Ashorn, PhD, Yin Bun Cheung, PhD, Kathryn G Dewey, PhD, Kenneth Maleta, PhD, Per Ashorn, PhD, Associations between Gut Microbiota and Intestinal Inflammation, Permeability and Damage in Young Malawian Children, In the originally published version of this manuscript, the boxes in subfigure (b) of Figure 5 were in the wrong order.This error has been corrected."} +{"text": "Health Policy and Planning, Volume 37, Issue 3, March 2022, Pages 369\u2013375, https://doi.org/10.1093/heapol/czab155This is a correction to: Fiammetta M Bozzani, Karin Diaconu, Gabriela B Gomez, Aaron S Karat, Karina Kielmann, Alison D Grant, Anna Vassall, Using system dynamics modelling to estimate the costs of relaxing health system constraints: a case study of tuberculosis prevention and control interventions in South Africa, In the originally published version of this manuscript, the incorrect czac110_SuppClick here for additional data file."} +{"text": "PLOS ONE Editors retract this article [The article because JS, RB, BSD, MHS, HMA, and RK did not agree with the retraction. DSS, AAAH, AA, and FK either did not respond directly or could not be reached."} +{"text": "The inflammatory bowel disease questionnaire (IBDQ) is a measure of health-related quality of life (QoL), with higher scores indicating greater QoL. In a prior phase 2 study (NCT02589665), mirikizumab, an anti-IL23p19 antibody, demonstrated efficacy and improvement in IBDQ scores in participants with moderately to severely active ulcerative colitis (UC).This analysis evaluated effect of mirikizumab (miri) vs placebo (PBO) on IBDQ scores in patients (pts) with moderately to severely active ulcerative colitis (UC) who had failed prior conventional or biologic therapy in a Phase 3, double-blind, 12-week (W) induction study (LUCENT-1) followed by a 40W maintenance study (LUCENT-2) for a total of 52W continuous therapy.Pts (N=1162) in LUCENT-1 were randomized 3:1 to receive 300mg miri or PBO intravenously once every four weeks (Q4W). 544 pts who achieved Modified Mayo Score Clinical Response to miri by W12 of induction were rerandomized 2:1 in LUCENT-2 to subcutaneous miri 200mg or PBO Q4W in maintenance period. Randomization was stratified by previous biologic therapy failure, baseline corticosteroid use, and region. LUCENT-1 stratification included baseline (BL) disease activity, and LUCENT-2 included LUCENT-1 clinical remission status. The least squares mean change from BL in IBDQ scores at W12 of induction and W40 of maintenance was determined using analysis of covariance models. BL was W0 of therapy and stratification factors and BL scores were used as covariates. The Minimal Clinically Important Difference (MCID) was defined as an improvement of \u226516 points in total IBDQ score (IBDQ response) and IBDQ remission as a total score \u2265170 points. IBDQ response and remission were calculated using non-responder imputations. Treatments were compared using the common risk difference (risk diff).Miri treatment resulted in significantly greater improvement from BL in IBDQ total and domain scores vs PBO at both W12 of induction and W40 of maintenance (52W treatment) (Table). The proportions of pts who achieved an IBDQ response was significantly greater for miri treated pts vs PBO at W12 and W40 . Significantly greater proportions of pts receiving miri achieved IBDQ remission at W12 and W40 vs PBO .Pts reported significantly greater improvements in IBDQ scores at induction and maintenance with miri compared to PBO. Over 75% of pts achieved a clinically meaningful improvement in QoL, as measured by IBDQ response, at the end of the 52 weeks of miri treatment.OtherEli Lilly and CompanyB. Sands Consultant of: Abivax, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Calibr, Celltrion, ClostraBio, Eli Lilly and Company, Enthera, Evommune, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Kaleido Biosciences, Kallyope, MiroBio, Morphic Therapeutic, MRM Health, Pfizer, Progenity, Prometheus Therapeutics and Diagnostics, Protagonist Therapeutics, Q32 Bio, Surrozen, Takeda, Teva, TLL Pharmaceutical, USWM Enterprises, and Viela Bio, B. Feagan Shareholder of: Gossamer Bio, Consultant of: AbbVie, AdMIRx, AgomAb Therapeutics, Akebia Therapeutics, Alivio Therapeutics, Allakos, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Avir Pharma, Azora Therapeutics, Boehringer Ingelheim, Boston Scientific, Celgene/Bristol Myers Squibb, Connect BioPharma, Cytoki Pharma, Disc Medicine, Ecor1 Capital, Eli Lilly and Company, Equillium, Everest Clinical Research, F. Hoffmann-La Roche, Ferring Pharmaceuticals, Galapagos NV, Galen/Atlantica, Genentech/Roche, Gilead Sciences, GlaxoSmithKline, Glenmark Pharmaceuticals, Gossamer Bio, HotSpot Therapeutics, Imhotex, ImmuNext, InDex Pharmaceuticals, Intact Therapeutics, Janssen, Japan Tobacco, Kaleido Biosciences, Leadiant Biosciences, Millennium Pharmaceuticals, MiroBio, Morphic Therapeutics, Mylan, Novartis, OM Pharma, Origo Biopharma, Otsuka, Pandion Therapeutics, Pfizer, Progenity, Prometheus Therapeutics and Diagnostics, PTM Therapeutics, Q32 Bio, Rebiotix, RedHill, Biopharma, Redx Pharma, Sandoz, Sanofi, Seres Therapeutics, Surrozen, Takeda, Teva, Thelium Therapeutics, Theravance Biopharma, TiGenix, Tillotts Pharma AG, UCB Pharma, VHsquared, Viatris, Ysios Capital, and Zealand Pharma, T. Gibble Employee of: Eli Lilly and Company, K. Traxler Employee of: Eli Lilly and Company, N. Morris Employee of: Eli Lilly and Company, X. Li Employee of: Eli Lilly and Company, S. Schreiber Grant / Research support from: personal fees and/or travel support from: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Dr. Falk Pharma, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos NV, Gilead Sciences, I-MAB Biopharma, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Theravance Biopharma, and UCB Pharma, V. Jairath Consultant of: AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Celltrion, Eli Lilly and Company, Ferring Pharmaceuticals, Flagship Pioneering, Fresenius Kabi, Galapagos NV, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Merck, Mylan, Pandion Therapeutics, Pendopharm, Pfizer, Protagonist Therapeutics, Reistone Biopharma, Roche, Sandoz, Second Genome, Shire, Takeda, Teva, Topivert, Ventyx Biosciences, and Vividion Therapeutics, A. Armuzzi Consultant of: AbbVie, Allergan, Amgen, Arena Pharmaceuticals, Biogen, Bristol Myers Squibb, Celgene, Celltrion, Eli Lilly and Company, Ferring Pharmaceuticals, Galapagos NV, Gilead Sciences, Janssen, Merck Sharp & Dohme, Mylan, Novartis, Pfizer, Protagonist Therapeutics, Roche, Samsung Bioepis, Sandoz, Takeda, and TiGenix, J. Jones: None Declared"} +{"text": "PLOS ONE Editors retract this article [The article because KZ, ON, SAA and MW either did not respond directly or could not be reached. FH, MAbbas, MArshad, SA, MF, AI, MJS, ATKZ, YL, and MJA did not agree with the retraction."} +{"text": "Correction: BMC Emerg Med 22, 13 (2022)https://doi.org/10.1186/s12873-022-00566-zThe original article containe\"Department of Emergency Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, No. 138 Sheng-Li Road, Tainan City, 70403, Taiwan.\""} +{"text": "Scientific Reports 10.1038/s41598-022-26610-3, published online 05 January 2023Correction to: The original version of this Article contained errors in the Affiliations.Mojtaba Ijadi was incorrectly affiliated with \u2018Instituto de Investigaciones Cient\u00edficas Y Servicios de Alta Tecnolog\u00eda (INDICASAT AIP), City of Knowledge, Neuroscience Center, Panama City, Panama.\u2019The correct affiliation for Mojtaba Ijadi is listed below.Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.Behnam Keshtkarhesamabadi was incorrectly affiliated with \u2018Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.\u2019The correct affiliations for Behnam Keshtkarhesamabadi are listed below.Iranian Neuroscience Society\u2011Fars Chapter, DANA Brain Health Institute, Shiraz, Iran.High Performance Brain, Helena F\u00e9lix Street, No. 7 to 7 D, 1600\u2011121 Lisbon, Portugal.Reza Mahmoudi was incorrectly affiliated with \u2018High Performance Brain, Helena F\u00e9lix Street, No. 7 to 7 D, 1600\u2011121 Lisbon, Portugal.\u2019The correct affiliation for Reza Mahmoudi is listed below.Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.Amrollah Roozbehi was incorrectly affiliated with \u2018High Performance Brain, Helena F\u00e9lix Street, No. 7 to 7 D, 1600\u2011121 Lisbon, Portugal.\u2019The correct affiliation for Amrollah Roozbehi is listed below.Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran.Mohammad Nami was incorrectly affiliated with \u2018High Performance Brain, Helena F\u00e9lix Street, No. 7 to 7 D, 1600\u2011121 Lisbon, Portugal.\u2019The correct affiliations for Mohammad Nami are listed below.Neuroscience Laboratory, NSL , Department of Neuroscience, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.Iranian Neuroscience Society\u2011Fars Chapter, DANA Brain Health Institute, Shiraz, Iran.Instituto de Investigaciones Cient\u00edficas Y Servicios de Alta Tecnolog\u00eda (INDICASAT AIP), City of Knowledge, Neuroscience Center, Panama City, Panama.Harvard Alumni in Healthcare, Harvard University, Boston, MA, USA.Brain, Cognition, and Behavior Unit, BrainHub Academy, Dubai, United Arab Emirates.In addition, affiliation \u2018Department of Physiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.\u2019 was removed.As a result, the Affiliations have been renumbered.The original Article has been corrected."} +{"text": "The authors regret that Richard O. Adeyemi, who constructed and provided the redox CRISPR library, was mistakenly included in the acknowledgements section instead of the author list. The updated author list and affiliations are as follows:a, Nathan P. Warda, Nicolas Prieto-Fariguaa, Yun Pyo Kanga, Anish Thalakolaa, Richard O. Adeyemib, Mingxiang Tengc, Gina M. DeNicolaaChang JiangaDepartment of Cancer Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USAbBasic Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USAcDepartment of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USAThe authors would like to apologise for any inconvenience caused."} +{"text": "PLOS ONE Editors retract this article [The article because IEZ, SA, MHS, HSY, AM, ZA, and MR did not agree with the retraction. MHA, AA, and XW either did not respond directly or could not be reached."} +{"text": "Dear Sir,Comments from Drs. Birkett, Miller, and Soisson"} +{"text": "Scientific Reports 10.1038/s41598-022-22896-5, published online 11 November 2022Correction to: In the original version of this Article Lin Liu was incorrectly affiliated with \u2018School of Nursing, Shaoyang University, Shaoyang, 422000, Hunan Province, China\u2019. The correct affiliation is listed below.School of Nursing, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.In addition, Fenfang Lei was incorrectly affiliated with \u2018Graduate School, Guangxi Medical University, Nanning, 530022, Guangxi Zhuang Autonomous Region, China\u2019 and \u2018Department of Anesthesiology, Central Hospital of Shaoyang, Shaoyang City, 422000, Hunan Province, China\u2019. The correct affiliation is listed below.School of Nursing, Shaoyang University, Shaoyang, 422000, Hunan Province, China.The original Article has been corrected."} +{"text": "PLOS ONE Editors retract this article [The article because MSN did not agree with the retraction. SA, TH, HR, YN, IUH, FA, MSA, MSE, HMK, AT, MAAA, and MIM either did not respond directly or could not be reached."} +{"text": "Hospitalizations pose a significant burden on both the individual and the healthcare system. Those with inflammatory bowel disease (IBD) are at increased risk of hospitalization as compared to the general population due to flaring of disease activity and complications related to IBD. The advent of biologics over the past twenty years may have influenced the rates of hospitalization for IBD.To assess current and forecast the overall hospitalization rates of those with IBD stratified by types of hospitalizations .Population-based administrative data on hospitalization of IBD (2002-2014) were obtained from: AB, BC, MB, and SK. Data were age and sex standardized to the matching year and aggregated into a representative sample of the Canadian population. Hospitalization rates were assessed as follows: 1. All cause hospitalizations: all admissions regardless of indication; 2. IBD-specific: an admission directly resulting from IBD ; 3. IBD-related: an admission for IBD, or a symptom or comorbidity associated with IBD (e.g. rheumatoid arthritis). Using prevalence estimates from the provinces, hospitalization rates (per 100 persons with IBD) were calculated, with 95% confidence intervals (CI). Autoregressive Integrated Moving Average models were created to estimate number of hospitalizations and corresponding prevalence to forecast hospitalization rates to 2030 with 95% prediction intervals (PI). Poisson regression estimated the Average Annual Percentage Change (AAPC), with 95% CIs, of the forecasted data.In 2002 there were 35.3 per 100 all cause hospitalizations for IBD patients and this decreased to 24.9 per 100 in 2014. Similar trends were seen for IBD-specific hospitalizations [16.8 per 100 in 2002 to 8.7 per 100 in 2014] and IBD-related in 2002 to 13.4 per 100 in 2014). When forecasted out to 2030 all hospitalization types were significantly decreasing\u2014the AAPC for all cause hospitalizations was -2.12% , -3.77% for IBD-specific, and -3.09% for IBD-related. By 2030, the rates of hospitalization are forecasted to be 17.0 per 100 , 4.6 per 100 , and 7.9 per 100 for all cause, IBD-specific, and IBD-related, respectively.In Canada, rates of hospitalizations for those with IBD have decreased from 2002 to 2014. The use of anti-TNF therapy in conjunction with the evolution of clinical monitoring, management and guidelines, likely has contributed to dropping hospitalization rates. Forecast models estimate a continued drop in hospitalization rates out to 2030. Importantly, healthcare resource planning should account for the shift from hospital-based to clinic-centric models of IBD care.CIHRS. Coward: None Declared, E. Benchimol Consultant of: Hoffman La-Roche Limited and Peabody & Arnold LLP for matters unrelated to medications used to treat inflammatory bowel disease and McKesson Canada and the Dairy Farmers of Ontario for matters unrelated to medications used to treat inflammatory bowel disease., C. Bernstein Grant / Research support from: Unrestricted educational grants from Abbvie Canada, Janssen Canada, Pfizer Canada, Bristol Myers Squibb Canada, and Takeda Canada. Has received research grants from Abbvie Canada, Amgen Canada, Pfizer Canada, and Sandoz Canada and contract grants from Janssen, Abbvie and Pfizer, Consultant of: Abbvie Canada, Amgen Canada, Bristol Myers Squibb Canada, JAMP Pharmaceuticals, Janssen Canada, Pfizer Canada, Sandoz Canada, and Takeda., Speakers bureau of: Abbvie Canada, Janssen Canada, Pfizer Canada and Takeda Canada, J. A. Avina-Zubieta: None Declared, A. Bitton: None Declared, L. Hracs: None Declared, J. Jones Consultant of: Janssen, Abbvie, Pfizer, Takeda, Speakers bureau of: Janssen, Abbvie, Pfizer, Takeda, E. Kuenzig: None Declared, L. Lu: None Declared, S. Murthy: None Declared, Z. Nugent: None Declared, A. Otley Grant / Research support from: Unrestricted educational grants from AbbVie Canada and Janssen Canada, Consultant of: Advisory boards of AbbVie Canada, Janssen Canada and Nestle, R. Panaccione Consultant of: Abbott, AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, UCB. Advisory Boards for: AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Speakers bureau of: AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, Takeda Pharmaceuticals, J.-N. Pena-Sanchez: None Declared, H. Singh Consultant of: Pendopharm, Amgen Canada, Bristol Myers Squibb Canada, Roche Canada, Sandoz Canada, Takeda Canada, and Guardant Health, Inc.,, L. Targownik Grant / Research support from: Investigator initiated funding from Janssen Canada, Consultant of: [Advisory board] AbbVie Canada, Takeda Canada, Merck Canada, Pfizer Canada, Janssen Canada, Roche Canada, and Sandoz Canada, J. Windsor: None Declared, G. Kaplan Grant / Research support from: Ferring, Janssen, AbbVie, GlaxoSmith Kline, Merck, and Shire, Consultant of: Gilead, Speakers bureau of: AbbVie, Janssen, Pfizer, Amgen, and Takeda"} +{"text": "Correction: Cancer Cell International (2022) 22: 47https://doi.org/10.1186/s12935-021-02372-2In this article , the affThe correct affiliations are given below:Caiyan Shi: The Department of Medical Oncology, Hainan West Central Hospital, Danzhou, 571700, Hainan, China.Yilin Xu: Department of Nephrology, Affiliated Huaian Hospital of Xuzhou Medical University, Huaian, 223001, Jiangsu, China."} +{"text": "E-adjuvanted RSVPreF3 OA in adults \u2265 60 YOA.RSV-associated acute respiratory infections (ARI), particularly lower respiratory tract diseases (LRTD), present a significant disease burden in older adults. Currently, there are no approved vaccines against RSV. We present results from an ongoing study designed to demonstrate the vaccine efficacy (VE) of the AS01This ongoing, phase 3, observer-blind, placebo-controlled, multi-country study (NCT04886596) enrolled adults \u2265 60 YOA from the northern and southern hemispheres. Participants were randomized (1:1) to receive a single dose of RSVPreF3 OA or placebo before the RSV season. The primary objective was to demonstrate VE of a single dose of RSVPreF3 OA in preventing RSV-confirmed LRTD during one RSV season . VE is reported also against severe RSV-confirmed LRTD, RSV-confirmed ARI, RSV-confirmed LRTD and RSV-confirmed ARI by RSV subtype (RSV-A and RSV-B), and RSV-confirmed LRTD by age, baseline comorbidity and frailty status. RSV-A/B was confirmed by quantitative RT-PCR.Figure\u00a01). Cumulative incidence curves for RSV-confirmed LRTD and RSV-confirmed ARI showed persistent efficacy throughout the follow-up .A total of 26,664 participants were enrolled, of whom 24,966 were included in the exposed set and 24,960 in the efficacy analysis. The mean age was 69.5 (\u00b16.5) years and 51.7% were women. Over a median follow-up of 6.7 months (maximum 10.1 months), 47 RSV-confirmed LRTD episodes were reported , resulting in a VE of 82.6% (96.95% CI: 57.9\u201394.1), thus the primary objective was met. Consistently high VE across the clinical spectrum of RSV disease, from RSV-confirmed ARI (71.7% [95% CI: 56.2\u201382.3]) to severe RSV-confirmed LRTD (94.1% [95% CI: 62.4\u201399.9]) was observed. High VE was seen in different age groups and regardless of RSV subtype, baseline comorbidity or pre-frail status .Michael G. Ison, MD MS, GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support Alberto Papi, MD, CHIESI, ASTRAZENECA, GSK, BI, MENARINI, NOVARTIS, ZAMBON, MUNDIPHARMA, SANOFI, AVILLION: Honoraria|CHIESI, ASTRAZENECA, GSK, NOVARTIS, SANOFI, IQVIA, AVILLION, ELPEN PHARMACEUTICALS: Advisor/Consultant|CHIESI, ASTRAZENECA, GSK, NOVARTIS, SANOFI, IQVIA, AVILLION, ELPEN PHARMACEUTICALS: Board Member|CHIESI, ASTRAZENECA, GSK, SANOFI: Grant/Research Support Joanne M. Langley, MD, GSK, Merck, Medicago, Sanofi, VBI, VIDO, Entos, Pfizer: Grant/Research Support Isabel Leroux-Roels, PhD MD, Curevac: payment to my institution for the conduct of clinical trials|GSK: payment to my institution for the conduct of clinical trials|ICON Genetics: payment to my institution for the conduct of clinical trials|Janssen Vaccines (J&J): Board Member|Janssen Vaccines (J&J): payment to my institution for the conduct of clinical trials|Osivax: payment to my institution for the conduct of clinical trials Federico Martinon-Torres, MD, PhD, Assoc. Prof, GlaxoSmithKline, Pfizer, Sanofi, Merck, Moderna, Astra Zeneca, Biofabri, Janssen, Novavax: Advisor/Consultant|GlaxoSmithKline, Pfizer, Sanofi, Merck, Moderna, Astra Zeneca, Biofabri, Janssen, Novavax: Grant/Research Support|GlaxoSmithKline, Pfizer, Sanofi, Merck, Moderna, Astra Zeneca, Biofabri, Janssen, Novavax: Honoraria|GlaxoSmithKline, Pfizer, Sanofi, Merck, Moderna, Astra Zeneca, Biofabri, Janssen, Novavax: Cl\u00ednical trials fees paid to my institution Tino F. Schwarz, Prof. Dr. MD, GlaxoSmithKline: Advisor/Consultant Richard N. Van Zyl-Smit, PhD MD, MSD, Pfizer, GSK, Astra Zeneca, Roche, Novartis, Boehringer Ingelheim, Cipla, J&J, Glenmark: Advisor/Consultant|MSD, Pfizer, GSK, Astra Zeneca, Roche, Novartis, Boehringer Ingelheim, Cipla, J&J, Glenmark: Honoraria Nancy Dezutter, PhD, PharmD, GlaxoSmithKline: GSK employee|GlaxoSmithKline: Stocks/Bonds Nathalie De Schrevel, PhD, GlaxoSmithKline: GSK employee Laurence Fissette, Master in Statistics, GlaxoSmithKline: GSK employee|GlaxoSmithKline: Stocks/Bonds Marie-Pierre David, Master in Statistics, GlaxoSmithKline: GSK employee|GlaxoSmithKline: Stocks/Bonds Marie Van Der Wielen, MD, GlaxoSmithKline: GSK employee|GlaxoSmithKline: Stocks/Bonds Lusine Kostanyan, MD, GlaxoSmithKline: GSK employee|GlaxoSmithKline: Stocks/Bonds Veronica Hulstr\u00f8m, PhD MD, GlaxoSmithKline: GSK employee."} +{"text": "February 28, 2022, In the article \u201cDifferential Electrographic Signatures Generated by Mechanistically-Diverse Seizurogenic Compounds in the Larval Zebrafish Brain,\u201d by Joseph Pinion, Callum Walsh, Marc Goodfellow, Andrew D. Randall, Charles R. Tyler, and Matthew J. Winter, which was published online on"} +{"text": "Neuro-Oncology Advances, Volume 4, Issue 1, January-December 2022, vdac084, https://doi.org/10.1093/noajnl/vdac084This is a corrigendum to: Michelle A Wedemeyer, Ivo Muskens, Ben A Strickland, Oscar Aurelio, Vahan Martirosian, Joseph L Wiemels, Daniel J Weisenberger, Kai Wang, Debraj Mukerjee, Suhn K Rhie, Gabriel Zada, Epigenetic dysregulation in meningiomas, In the originally published version of this manuscript Gabriel Zada was listed as the corresponding author in error. Both Gabriel Zada and Suhn K. Rhie should have been listed as co-corresponding authors.This error has been corrected."} +{"text": "Mirikizumab (miri) improved symptom control in a Phase 3, multicenter, randomized, double-blind, parallel, placebo-controlled induction study at Week (W)12, in patients (pts) with moderately-to-severely active ulcerative colitis .This analysis assessed sustained symptom control during the maintenance phase through W40 (W52 of continuous therapy), among pts who were induced into clinical response with miri.During the 40W maintenance study (LUCENT-2), pts (N=544) who achieved clinical response to miri 300mg Q4W by W12 of induction, were re-randomized 2:1 to subcutaneous (SC) miri 200mg (n=365) or PBO Q4W (n=179). We evaluated sustained control of stool frequency (SF), rectal bleeding (RB), bowel movement urgency (BU) and abdominal pain (AP). The proportion of pts achieving SF Remission , RB Remission (RB=0), Symptomatic Remission (both SF and RB Remission), Stable Maintenance of Symptomatic Remission , and AP Improvement were assessed. BU NRS change from baseline, and the proportion of pts achieving BU Remission (NRS 0 or 1 in pts with BU NRS \u22653 at baseline) were evaluated.A greater proportion of miri-treated pts achieved SF Remission, RB Remission and Symptomatic Remission compared to PBO at W40 (Table), with significant differences observed from W8 of LUCENT-2 and maintained through W40. Miri-treated pts had a significantly higher percentage of Stable Maintenance of Symptomatic Remission (p<0.001). Pts in the miri-treatment group had a significantly greater mean reduction in BU NRS change from induction BL starting at W12 (p=0.034) onwards compared to PBO (Table). Pts assigned to miri accrued an additional 13.6 percentage-point benefit in BU Remission during the first 8W of maintenance therapy and achieved a significant greater improvement at W40 compared to PBO . Similarly, AP was significantly improved for the miri-treated group starting at W16 (p=0.034) onwards compared to PBO.Miri provides sustained control of UC symptoms including BU, RB, and SF compared to PBO in pts with moderately to severely active UC.OtherEli Lilly and CompanyA. Dignass Consultant of: AbbVie, Abivax, Amgen, Arena Pharmaceuticals, Bristol Myers Squibb (Celgene), Celltrion, Dr. Falk Pharma, Eli Lilly and Company, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, Pharmacosmos, Roche, Sandoz/Hexal, Takeda, Tillotts Pharma AG, and Vifor Pharma; has received lecture fees or honoraria from: AbbVie, Amgen, Bristol Myers Squibb, Dr. Falk Pharma, Ferring Pharmaceuticals, Galapagos, High5Md, Janssen, Materia, Merck Sharp & Dohme, Pfizer, Sandoz, Takeda, Tillotts Pharma AG, and Vifor Pharma, S. Danese Consultant of: AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr. Falk Pharma, Eli Lilly and Company, Enthera, Ferring Pharmaceuticals, Gilead Sciences, Hospira, Inotrem, Janssen, Johnson & Johnson, Merck Sharp & Dohme, Mundipharma, Mylan, Pfizer, Roche, Sandoz Sublimity, Takeda, TiGenix, UCB Pharma, and Vifor Pharma, Speakers bureau of: AbbVie, Amgen, Ferring Pharmaceuticals, Gilead Sciences, Janssen, Mylan, Pfizer, and Takeda, K. Matsuoka Grant / Research support from: AbbVie, EA Pharma, JIMRO, Kissei Pharmaceutical, Kyowa Kyorin, Mitsubishi Tanabe, Mochida Pharmaceutical, and Zeria Pharmaceutical Nippon; lecture fees from: AbbVie, EA Pharma, JIMRO, Kissei Pharmaceutical, Kyowa Kyorin, Mitsubishi Tanabe, Mochida Pharmaceutical, Takeda, and Zeria Pharmaceutical Nippon, M. Ferrante Grant / Research support from: AbbVie, Amgen, Biogen, Janssen Cilag, Pfizer, Takeda, and Viatris, Consultant of: AbbVie, Boehringer Ingelheim, Celltrion, Eli Lilly and Company, Janssen Cilag, Medtronic, Merck Sharp & Dohme, Pfizer, Regeneron, Sandoz, Takeda, and Thermo Fisher Scientific, Speakers bureau of: AbbVie, Amgen, Biogen, Boehringer Ingelheim, Celltrion, Dr. Falk Pharma, Eli Lilly and Company, Ferring Pharmaceuticals, Janssen, Lamepro, Medtronic, Merck Sharp & Dohme, Mylan, Pfizer, Samsung Bioepis, Sandoz, Takeda, and Thermo Fisher Scientific, M. Long Consultant of: AbbVie, Bristol Myers Squibb, Calibr, Eli Lilly and Company, Genentech, Janssen, Pfizer, Prometheus Biosciences, Roche, Takeda, TARGET PharmaSolutions, and Theravance Biopharma, I. Redondo Employee of: Eli Lilly and Company, T. Gibble Employee of: Eli Lilly and Company, R. Moses Employee of: Eli Lilly and Company, X. Li Employee of: Eli Lilly and Company, N. Morris Employee of: Eli Lilly and Company, C. Milch Employee of: Former employee, was employed at Eli Lilly and Company at the time of study, M. Abreu Grant / Research support from: Pfizer, Prometheus Biosciences, and Takeda, Consultant of: AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Eli Lilly and Company, Gilead Sciences, Janssen, Microba Life Sciences, Prometheus Biosciences, UCB Pharma, and WebMD, Speakers bureau of: Alimentiv, Intellisphere LLC , Janssen, Prime CME, and Takeda, J. Jones: None Declared"} +{"text": "Ventilation weaning and extubation readiness in children in pediatric intensive care unit: A review By Poletto E, Cavagnero F, Pettenazzo M, Visentin D, Zanatta L, Zoppelletto F, Pettenazzo A, Daverio M and Bonardi CM. (2022) Front. Pediatr. 10: 867739. doi: 10.3389/fped.2022.867739A corrigendum on In the published article, the first and last names were switched. The author list has been changed from Poletto Elisa, Cavagnero Francesca, Pettenazzo Marco, Visentin Davide, Zanatta Laura, Zoppelletto Fabrizio, Pettenazzo Andrea, Daverio Marco and Bonardi Claudia Maria to Elisa Poletto, Francesca Cavagnero, Marco Pettenazzo, Davide Visentin, Laura Zanatta, Fabrizio Zoppelletto, Andrea Pettenazzo, Marco Daverio and Claudia Maria Bonardi.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-15717-2, published online 06 July 2022Correction to: The original version of this Article omitted an affiliation for the corresponding author Amanda Lange Salvia.The correct affiliations are listed below:Graduate Program in Civil and Environmental Engineering, University of Passo Fundo, Campus I - BR 285, S\u00e3o Jos\u00e9, Passo Fundo, RS, 99052-900, BrazilEuropean School of Sustainability Science and Research, Hamburg University of Applied Sciences, Ulmenliet 20, D-21033, Hamburg, GermanyThe original Article has been corrected."} +{"text": "PLOS ONE Editors retract this article [The article because AMAS agreed with the retraction. MY, NAR, NAK, AAZ, GAK, MWA, and MA either did not respond directly or could not be reached. HZ, TL, SH, SS, HK, MJA, ATKZ, and YL did not agree with the retraction."} +{"text": "Salmonella enterica serovars recovered from poultry processing environments at wet markets in Dhaka, Bangladesh. PLoS ONE 17(2): e0254465.The second, third, fourth, and fifth authors\u2019 names are spelled incorrectly. The correct names are: Md Samun Sarker, Md. Shahidur Rahman Khan, Md. Tanvir Rahman, and Md. Abdul Kafi. The correct citation is: Siddiky NA, Sarker MS, Khan MSR, Rahman MT, Kafi MA, Samad MA (2022) Virulence and antimicrobial resistance profile of non-typhoidal The publisher apologizes for the errors."} +{"text": "Fifteen percent of patients with cancer experience symptomatic sequelae, which impair post\u2013COVID-19 outcomes. In this study, we investigated whether a proinflammatory status is associated with the development of COVID-19 sequelae.OnCovid recruited 2795 consecutive patients who were diagnosed with Severe Acute Respiratory Syndrome Coronavirus 2 infection between February 27, 2020, and February 14, 2021. This analysis focused on COVID-19 survivors who underwent a clinical reassessment after the exclusion of patients with hematological malignancies. We evaluated the association of inflammatory markers collected at COVID-19 diagnosis with sequelae, considering the impact of previous systemic anticancer therapy. All statistical tests were 2-sided.P\u2009<\u2009.001), lactate dehydrogenase , and the neutrophil to lymphocyte ratio were statistically significantly higher among patients who experienced sequelae, whereas no association was reported for the platelet to lymphocyte ratio and the OnCovid Inflammatory Score, which includes albumin and lymphocytes. The widest area under the ROC curve (AUC) was reported for baseline CRP , followed by the NLR and lactate dehydrogenase . Using a fixed categorical multivariable analysis, high CRP and NLR were confirmed to be statistically significantly associated with an increased risk of sequelae. Exposure to chemotherapy was associated with a decreased risk of sequelae , whereas no associations with immune checkpoint inhibitors, endocrine therapy, and other types of systemic anticancer therapy were found.Of 1339 eligible patients, 203 experienced at least 1 sequela (15.2%). Median baseline C-reactive protein (CRP; 77.5\u2009mg/L vs 22.2\u2009mg/L, Although the association between inflammatory status, recent chemotherapy and sequelae warrants further investigation, our findings suggest that a deranged proinflammatory reaction at COVID-19 diagnosis may predict for sequelae development. Increasing evidence highlights that an important proportion of COVID-19 survivors are at risk of protracted symptomatic consequences after the acute Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection . A wide In the general population, between 13% and 60% of COVID-19 survivors are at risk of developing post\u2013COVID-19 symptoms . ConsideThe OnCovid study, the largest European COVID-19 and cancer registry , has higAgainst this background, the lack of biomarkers that can predict for the future emergence of COVID-19 sequelae in patients who survive the acute phase is a point of the utmost interest. The discovery of reproducible clinical and biologic predictors is an area of high unmet need, because it would allow clinicians to identify patient subgroups who should be prioritized for enhanced follow-up, preventative strategies, and therapeutic interventions.Inflammation is a recognized driver of severe COVID-19 also in patients with cancer ; we prevThe purpose of this study is to verify whether noninvasive biomarkers of the systemic inflammatory response measured at SARS-CoV-2 infection diagnosis are associated with the emergence of sequelae in patients who survive COVID-19.OnCovid (NCT04393974) is an active European registry study enrolling consecutive patients fulfilling the following inclusion criteria: 1) aged 18\u2009years and older; 2) diagnosis of SARS-CoV-2 infection confirmed by reverse transcription-polymerase chain reaction (RT-PCR) of a nasopharyngeal swab ; and 3) For the purpose of this analysis, we focused on patients who survived COVID-19 and underwent a formal clinical post\u2013COVID-19 assessment at participating institutions .Methodology of data collection for the OnCovid registry was described elsewhere ,10,11, aThe study population was accrued from 35 institutions across 6 countries and diagnosed with COVID-19 between February 27, 2020, and February 14, 2021. The data lock for the present analysis was March 1, 2021.The primary objective of this study was to evaluate a panel of proinflammatory biomarkers of consolidated prognostic role in patients with cancer measured9/L] as a derivation of the prognostic nutritional index, already renamed in the context of COVID-19) , lactate dehydrogenase , the neutrophil to lymphocyte ratio (NLR), the platelet to lymphocyte ratio (PLR), and the OnCovid Inflammatory Score (OIS), which combines lymphopenia and hypoalbuminemia only .Before any clinicopathologic correlation, we first reported the distribution of each biomarker and then evaluated their individual predictive ability for the association with COVID-19 sequelae as continuous variables through receiver operating characteristic (ROC) analyses. Acknowledging that the effect of inflammatory indices in the post\u2013COVID-19 setting had not been investigated before, we also computed optimal cutoffs to test them as categorical variables in fixed multivariable models for COVID-19 sequelae overall, respiratory sequalae, and post\u2013COVID-19 fatigue. Considering missing data for laboratory values and their scattered distribution, each inflammatory biomarker was evaluated independently. An exploratory ROC curves comparison was also performed. We also evaluated the impact on post\u2013COVID-19 survival of inflammatory biomarkers assessed at the time of first oncologic reassessment, which included the laboratory testing with remote clinical consultations or face-to-face visits.Accounting for the unbalanced distribution of patient- and disease-related features across the subgroups, we used fixed multivariable regression models, adjusting all estimates for clinical characteristics already known to influence outcomes in patients with COVID-19 and cancer and as already performed in previously published analyses from the OnCovid study ,10\u201312. KIn addition, we evaluated the relationship between COVID-19 sequelae and exposure to different types of SACT at COVID-19 diagnosis. Patients who were not on SACT were elected as the reference group. Exposure to SACT was defined as the receipt of any SACT regimen within 4\u2009weeks before SARS-CoV-2 infection diagnosis and was categorized as follows: chemotherapy ; ICI-based regimens (without chemotherapy); endocrine therapy; tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (MABs); and poly adenosine diphosphate-ribose polymerase inhibitors (PARPi) and cyclin dependent kinase 4/6 inhibitors (CDK4/6i).In consideration of the complex interrelationships between SACT and the underlying tumor in influencing clinical outcomes in cancer patients diagnosed with COVID-19, the interaction terms between SACT regimens and primary tumor, tumor stage, and tumour status were also tested in independent models, and separate additional analyses among patients with advanced and nonadvanced disease were presented. Lastly, we tested the distribution of median baseline inflammatory markers or indices statistically significantly associated with COVID-19 sequelae according to different SACT regimens. Detailed study methodology is summarized in OnCovid was granted central approval by the United Kingdom Health Research Authority (20/HRA/1608) and by the corresponding research ethics committees at each participating institution. A full waiver of consent because of the retrospective nature of the study was granted by the UK Health Research Authority in accordance with UK law because of the anonymized nature of the patient data and retrospective design of the study.2 test. Inflammatory markers were reported as median with interquartile ranges (IQRs). The Kruskal\u2013Wallis test was used to compare the median values of continuous data. A ROC curve analysis with the computation of the area under the curve (AUC) was performed for each inflammatory marker with respect of COVID-19 sequelae, then the optimal cutoffs were determined using the Youden\u2019s J statistic. Fixed multivariable logistic regression models were used to assess the impact of analyzed factors on the risk of COVID-19 sequelae and presented as odds ratios (ORs) with 95% confidence intervals (CIs). Through the fixed models, each inflammatory index was evaluated separately but adjusting for all the same preselected covariates. Post\u2013COVID-19 survival was defined as the length of time from the date of the first post\u2013COVID-19 assessment to the date of a patient\u2019s death (for any cause) or last follow-up and was estimated with the Kaplan\u2013Meier method, with comparisons computed with the log-rank test. The median post\u2013COVID-19 follow-up was estimated with the reverse Kaplan-Meier method. Multivariable Cox proportional hazards models were used to assess the impact on the risk of death after COVID-19 recovery and were presented as hazard ratios (HRs) with 95% confidence intervals. To verify hazards distribution proportionality, the interaction with time of each inflammatory marker at the post\u2013COVID-19 reassessment was tested. P less than .05 was considered statistically significant, and all statistical tests were 2-sided. Analyses were performed using the MedCalc Statistical Software version 20 and the IBM SPSS Statistics software, Version: 28.0.1.0 (142). Figures were created in Prism V.8 .Baseline characteristics were summarized as categorical variables and reported using descriptive statistics. Associations between categorical variables were tested using the Pearson \u03c7As previously reported , 2795 coP\u2009=\u2009.78). Baseline patient, tumor, and COVID-19 characteristics of the included population overall and according to the experience of COVID-19 sequelae are reported in Overall, at least 1 sequela was reported for 203 patients (15.2%), including respiratory symptoms , residual fatigue , weight loss , neuro-cognitive symptoms , and others . The median times from COVID-19 to the post\u2013COVID-19 reassessment according to the experience of sequelae were 42\u2009days (IQR = 27-63.7 days) and 44\u2009days (IQR = 27-64 days) (P\u2009<\u2009.001), LDH , and NLR were statistically significantly higher among patients who experienced sequelae, whereas no association were reported regarding median baseline PLR and OIS. ROC curve analyses are summarized in Median baseline values of inflammatory markers (at COVID-19 diagnosis) among the overall population and according to COVID-19 sequelae are reported in A further post\u2013COVID-19 survival follow-up was available for 780 patients, with a median value of 123\u2009days (95% CI = 103 to 147 days) and a median post COVID-19 survival, which was not reached (126 events) in the overall population.Median values of post\u2013COVID-19 inflammatory markers or indices were assessed at the same time as the clinical reassessment (median of 44\u2009days from COVID-19), and their categorical distribution is summarized in P\u2009=\u2009.33). The proportions of patients receiving SACT within 4\u2009weeks of COVID-19 diagnosis are reported in P\u2009=\u2009.012; P\u2009=\u2009.04; The median baseline CRP was statistically significantly different across different SACT categories (P\u2009=\u2009.06), tumor stage (P\u2009=\u2009.41), and tumor status (P\u2009=\u2009.82). The receipt of chemotherapy was confirmed to be associated with a decreased risk of sequelae among patients with nonadvanced disease on the multivariable analysis .Role of the funder: Neither sponsor nor the funders of the study had any role in study design, data collection, data analysis, data interpretation, or writing of the report.Disclosures: DJP received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, EISAI, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra and Astra Zeneca; research funding (to institution) from MSD and BMS. AP has declared personal honoraria from Pfizer, Roche, MSD Oncology, Eli Lilly, and Daiichi Sankyo; travel, accommodations, and expenses paid by Daiichi Sankyo; research funding from Roche and Novartis; and consulting/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol-Myers Squibb.Matteo Lambertini acted as consultant for Roche, Novartis, Lilly, AstraZeneca, Exact Sciences, MSD, Pfizer, Seagen and received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, Ipsen and Sandoz outside the submitted work. EF declared research founding to institution be Pfizer and travel expenses from Lilly, Novartis, Pfizer and Esai. TND has declared consulting/advisory role for Amgen, Bayer, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Otsuka, Pfizer, Roche, and Takeda; speakers fees from AstraZeneca, MSD, Roche, Takeda and travel, accommodations and expenses paid by AstraZenca, BMS, Boehringer Ingelheim, Lilly, MSD, Otsuka, Roche, and Takeda. JB has declared consulting/advisory role for MSD and Astra Zeneca. MT declares travel grants from Roche, Bristol-Myers Squibb, AstraZeneca, Takeda and Honoraria as medical writer from Novartis, Amgen outside the submitted work. AG has declared consulting/advisory role for Roche, MSD, Eli Lilly, Pierre Fabre, EISAI, and Daichii Sankyo; speakers bureau for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, Astra Zeneca, Celgene, and Daichii Sankyo; research funds: EISAI, Eli Lilly, and Roche. CMV has received travel grants and other honoraria from BMS, MSD, Novartis and Roche. GG has declared consulting/advisory role for Janssen, Abbvie, Astra-Zeneca and BeiGene, and speaker fees from Janssen and Abbvie. LR received consulting fees from Servier, Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks.AC received consulting fees from MSD, BMS, AstraZeneca, Roche; speakers\u2019 fee from AstraZeneca, MSD, Novartis and Eisai. All remaining authors have declared no conflicts of interest.Author contributions: Conceptualization: AC, DJP. Methodology: AC, DJP. Software: AC. Validation: AC, DJP. Formal analysis: AC, LS, DF. Investigation: AC, AG, DJP. Resources: AG, DJP. Data Curation: AC, AG, FP, EC, GP TND, AB, MV, JAC, OM, EF, AJCL, ADP, RS, JB, AC, JC, UM, LS, SD, ASL, DF, MVH, CM, BR, ES, FB, MK, JMH, GG, AP, RB, ER, LF, AP, FG, RS, CMV, AS, AL, CM, AS, MI, PP, GR, AS, LR, SR, NH, ASdT, BV, ML, SP, DG, SG, RB, MT, FM, ML, MT, AP, FZ, PQ, RG, AG, AZ, CT, AM, MB, EC, ND, AS, MB, IRC, DJP. Writing\u2014Original Draft: AC, DJP. Writing\u2014Review and Editing: AC, AG, FP, EC, GP TND, AB, MV, JAC, OM, EF, AJCL, ADP, RS, JB, AC, JC, UM, LS, SD, ASL, DF, MVH, CM, BR, ES, FB, MK, JMH, GG, AP, RB, ER, LF, AP, FG, RS, CMV, AS, AL, CM, AS, MI, PP, GR, AS, LR, SR, NH, ASdT, BV, ML, SP, DG, SG, RB, MT, FM, ML, MT, AP, FZ, PQ, RG, AG, AZ, CT, AM, MB, EC, ND, AS, MB, IRC, DJP. Visualization: AC. Supervision: DJP. Project administration: AC. Funding acquisition: DJP.Acknowledgements: OnCovid received direct project funding and infrastructural support by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC). D.J. Pinato is supported by grant funding from the Wellcome Trust Strategic Fund (PS3416) and acknowledges grant support from the Cancer Treatment and Research Trust (CTRT) and the Associazione Italiana per la Ricerca sul Cancro (AIRC MFAG Grant ID 25697). A. Cortellini is supported by the NIHR Imperial BRC. G. Gaidano is supported by the AIRC 5\u2009\u00d7\u20091000 Grant, No. 21198, Associazione Italiana per la Ricerca sul Cancro Foundation, Milan, Italy. A. Gennari is supported by the AIRC IG Grant, No. 14230, Associazione Italiana per la Ricerca sul Cancro Foundation, Milan, Italy. A. Gennari and G. Gaidano from the University of Piemonte Orientale acknowledge support from the UPO Aging Project.Members of the OnCovid study group: Georgina Hanbury, Chris Chung, Meera Patel , Gino Dettorre , Christopher CT Sng, Tamara Yu, Marianne Shawe-Taylor, Hamish DC Bain, Lee Cooper, Lucy Rogers, Katherine Belessiotis, Cian Murphy, Samira Bawany, Saira Khalique, Ramis Andaleeb , Eleanor Apthorp , Roxana Reyes , David Garcia-Illescas, Nadia Saoudi , Ariadna Roqu\u00e9 Lloveras , Ricard Mesia, Andrea Plaja, Marc Cucurull , Federica Grosso, Vittorio Fusco, , Alice Baggi, , Maristella Saponara , Luca Cantini .Disclaimer: The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.The data that support the findings of this study are not publicly available. They can be made available upon reasonable to the corresponding author [AC].djac057_Supplementary_DataClick here for additional data file."} +{"text": "The pathogenesis of inflammatory bowel disease (IBD) which includes Crohn\u2019s disease (CD) and ulcerative colitis (UC), is believed to involve activation of the intestinal immune system in response to the gut microbiome among genetically susceptible hosts. IBD has been historically regarded as a disease of developed nations, though in the past two decades there has been a reported shift in the epidemiological pattern of disease. High-income nations with known high prevalence of disease are seeing a stabilization of incident cases, while a rapid rise of incident IBD is being observed in developing nations. This suggests that environmental exposures may play a role in mediating the risk of developing IBD. The potential environmental determinants of IBD across various regions is vast, though medications have been increasingly recognized as one broad category of risk factors.Several medications have been considered to contribute to the etiology of IBD. This study assessed the association between medication use and risk of developing IBD using the Prospective Urban Rural Epidemiology (PURE) cohort.This was a prospective cohort study of 133,137 individuals between the ages of 20-80 from 24 countries. Country-specific validated questionnaires documented baseline and follow-up medication use. Participants were followed prospectively at least every 3 years. The main outcome was development of IBD, including CD and UC. Short-term (baseline but not follow-up use) and long-term use (baseline and subsequent follow-up use) was evaluated. Results are presented as adjusted odds ratios (aOR) with 95% confidence intervals (CI).During the median follow-up of 11.0 years [interquartile range (IQR) 9.2-12.2], we recorded 571 incident cases of IBD (143 CD and 428 UC). Higher risk of incident IBD was associated with baseline antibiotic use and hormonal medication use . Among females, previous or current oral contraceptive use was also associated with IBD development . NSAID users were also observed to have increased risk of IBD , which was driven by long-term users . All significant results were consistent in direction for CD and UC with low heterogeneity.Antibiotics, hormonal medications, oral contraceptives, and long-term NSAID use were associated with increased odds of incident IBD after adjustment for covariates.OtherSalim Yusuf is supported by the Heart & Stroke Foundation/Marion W. Burke Chair in Cardiovascular Disease. The PURE Study is an investigator-initiated study funded by the Population Health Research Institute, the Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Ontario, support from CIHR\u2019s Strategy for Patient Oriented Research (SPOR) through the Ontario SPOR Support Unit, as well as the Ontario Ministry of Health and Long-Term Care and through unrestricted grants from several pharmaceutical companies, with major contributions from AstraZeneca (Canada), Sanofi-Aventis (France and Canada), Boehringer Ingelheim (Germany and Canada), Servier, and GlaxoSmithkline, and additional contributions from Novartis and King Pharma and from various national or local organisations in participating countries; these include: Argentina: Fundacion ECLA; Bangladesh: Independent University, Bangladesh and Mitra and Associates; Brazil: Unilever Health Institute, Brazil; Canada: Public Health Agency of Canada and Champlain Cardiovascular Disease Prevention Network; Chile: Universidad de la Frontera; China: National Center for Cardiovascular Diseases; Colombia: Colciencias, grant number 6566-04-18062; India: Indian Council of Medical Research; Malaysia: Ministry of Science, Technology and Innovation of Malaysia, grant numbers 100 -IRDC/BIOTEK 16/6/21 (13/2007) and 07-05-IFN-BPH 010, Ministry of Higher Education of Malaysia grant number 600 -RMI/LRGS/5/3 (2/2011), Universiti Teknologi MARA, Universiti Kebangsaan Malaysia (UKM-Hejim-Komuniti-15-2010); occupied Palestinian territory: the UN Relief and Works Agency for Palestine Refugees in the Near East, occupied Palestinian territory; International Development Research Centre, Canada; Philippines: Philippine Council for Health Research & Development; Poland: Polish Ministry of Science and Higher Education grant number 290/W-PURE/2008/0, Wroclaw Medical University; Saudi Arabia: the Deanship of Scientific Research at King Saud University, Riyadh, Saudi Arabia (research group number RG -1436-013); South Africa: the North-West University, SANPAD (SA and Netherlands Programme for Alternative Development), National Research Foundation, Medical Research Council of SA, The SA Sugar Association (SASA), Faculty of Community and Health Sciences (UWC); Sweden: grants from the Swedish state under the Agreement concerning research and education of doctors; the Swedish Heart and Lung Foundation; the Swedish Research Council; the Swedish Council for Health, Working Life and Welfare, King Gustaf V\u2019s and Queen Victoria Freemasons Foundation, AFA Insurance, Swedish Council for Working Life and Social Research, Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning, grant from the Swedish State under the L\u00e4kar Utbildnings Avtalet agreement, and grant from the V\u00e4stra G\u00f6taland Region; Turkey: Metabolic Syndrome Society, AstraZeneca, Turkey, Sanofi Aventis, Turkey; United Arab Emirates (UAE): Sheikh Hamdan Bin Rashid Al Maktoum Award For Medical Sciences and Dubai Health Authority, Dubai UAE.C. Pray: None Declared, N. Narula Grant / Research support from: Neeraj Narula holds a McMaster University Department of Medicine Internal Career Award. Neeraj Narula has received honoraria from Janssen, Abbvie, Takeda, Pfizer, Merck, and Ferring, E. C. Wong: None Declared, J. K. Marshall Grant / Research support from: John K. Marshall has received honoraria from Janssen, AbbVie, Allergan, Bristol-Meyer-Squibb, Ferring, Janssen, Lilly, Lupin, Merck, Pfizer, Pharmascience, Roche, Shire, Takeda and Teva., S. Rangarajan: None Declared, S. Islam: None Declared, A. Bahonar: None Declared, K. F. Alhabib: None Declared, A. Kontsevaya: None Declared, F. Ariffin: None Declared, H. U. Co: None Declared, W. Al Sharief: None Declared, A. Szuba: None Declared, A. Wielgosz: None Declared, M. L. Diaz: None Declared, R. Yusuf: None Declared, L. Kruger: None Declared, B. Soman: None Declared, Y. Li: None Declared, C. Wang: None Declared, L. Yin: None Declared, M. Erkin: None Declared, F. Lanas: None Declared, K. Davletov: None Declared, A. Rosengren: None Declared, P. Lopez-Jaramillo: None Declared, R. Khatib: None Declared, A. Oguz: None Declared, R. Iqbal: None Declared, K. Yeates: None Declared, \u00c1. Avezum: None Declared, W. Reinisch Consultant of: Speaker for Abbott Laboratories, Abbvie, Aesca, Aptalis, Astellas, Centocor, Celltrion, Danone Austria, Elan, Falk Pharma GmbH, Ferring, Immundiagnostik, Mitsubishi Tanabe Pharma Corporation, MSD, Otsuka, PDL, Pharmacosmos, PLS Education, Schering-Plough, Shire, Takeda, Therakos, Vifor, Yakult, Consultant for Abbott Laboratories, Abbvie, Aesca, Algernon, Amgen, AM Pharma, AMT, AOP Orphan, Arena Pharmaceuticals, Astellas, Astra Zeneca, Avaxia, Roland Berger GmBH, Bioclinica, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Covance, Danone Austria, DSM, Elan, Eli Lilly, Ernest & Young, Falk Pharma GmbH, Ferring, Galapagos, Genentech, Gilead, Gr\u00fcnenthal, ICON, Index Pharma, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, LivaNova, Mallinckrodt, Medahead, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nash Pharmaceuticals, Nestle, Nippon Kayaku, Novartis, Ocera, Omass, Otsuka, Parexel, PDL, Periconsulting, Pharmacosmos, Philip Morris Institute, Pfizer, Procter & Gamble, Prometheus, Protagonist, Provention, Robarts Clinical Trial, Sandoz, Schering-Plough, Second Genome, Seres Therapeutics, Setpointmedical, Sigmoid, Sublimity, Takeda, Therakos, Theravance, Tigenix, UCB, Vifor, Zealand, Zyngenia, and 4SC, Advisory board member for Abbott Laboratories, Abbvie, Aesca, Amgen, AM Pharma, Astellas, Astra Zeneca, Avaxia, Biogen IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Cellerix, Chemocentryx, Celgene, Centocor, Celltrion, Danone Austria, DSM, Elan, Ferring, Galapagos, Genentech, Gr\u00fcnenthal, Inova, Janssen, Johnson & Johnson, Kyowa Hakko Kirin Pharma, Lipid Therapeutics, MedImmune, Millenium, Mitsubishi Tanabe Pharma Corporation, MSD, Nestle, Novartis, Ocera, Otsuka, PDL, Pharmacosmos, Pfizer, Procter & Gamble, Prometheus, Sandoz, Schering-Plough, Second Genome, Setpointmedical, Takeda, Therakos, Tigenix, UCB, Zealand, Zyngenia, and 4SC, P. Moayyedi: None Declared, S. Yusuf: None Declared"} +{"text": "Journal of Surgical Case Reports, Volume 2021, Issue 8, August 2021, rjab351, https://doi.org/10.1093/jscr/rjab351This is a correction to: Rema J. Malik, Mark H. Falahee, Elyne N. Kahn, Michael J. Heidenreich, David Springstead, and Abdulhameed Aziz, Rapid, midline retroperitoneal exposure for four-level anterior lumbar interbody fusion\u2013technical case atlas, In the originally published version of this manuscript, the order of authors was incorrect: Mark H. Falahee, Elyne N. Kahn, Michael J. Heidenreich, Abdulhameed Aziz, David Springstead, Rema J MalikThe correct order of authors is Rema J. Malik, Mark H. Falahee, Elyne N. Kahn, Michael J. Heidenreich, David Springstead, Abdulhameed AzizThis error has been corrected online."} +{"text": "A scientific journal exists only because of the good will and assistance of its reviewers. We can only publish approximately 25% of the papers we receive. In order to publish really high-quality papers, we depend on the expertise of many people. In 2022, a total of 344 reviewers provided their expert opinions for us to decide about the papers that we should publish. Their names are listed below and we would like to take this opportunity to thank them.Muhammad Abbas, ChinaBal\u00e1zs \u00c1d\u00e1m, HungaryR\u00f3za \u00c1d\u00e1ny, HungaryMathilde Adsersen, DenmarkGunnar \u00c5gren, SwedenCharles Agyemang, NetherlandsJohan \u00c5hlen, SwedenAbdulbaghi Ahmad, SwedenAdebisi Akande, CanadaYannis Alamanos, GreeceFrancois Alla, FranceSara Allin, CanadaJavier Almela-Baeza, SpainRidwanul Amin, SwedenPeter Angelopoulos, GreeceJohanna Anneser, United StatesCigdem Apaydin Kaya, TurkeyRamiz Arabaci, TurkeyBenjamin Aretz, GermanyDavid Armstrong, United KingdomLUCIA ARTAZCOZ, SpainBarbara Artnik, SloveniaPeter Aspinall, United KingdomPilar Astier, SpainBontha Babu, IndiaSekene Badiaga, FranceBirna Baldursdottir, IcelandAngelo Barbato, ItalyMArtina Barchitta, United StatesPepita Barlow, United KingdomOrna Baron-Epel, IsraelBen Barr, United KingdomXavier Bartoll, SpainSarah Basharat, PakistanLinda Bell, United KingdomJohannes Beller, GermanyNetta Bentur, IsraelD\u00e1niel Bereczki, HungaryLisa Berkman, United StatesMarriot Bernadette, United StatesVesna Bjegovic Mikanovic, SerbiaJonas Bj\u00f6rk, SwedenAnders Bjorkman, SwedenJenni Blomgren, FinlandEdwin Boezeman, NetherlandsHenrik B\u00f8ggild, DenmarkMicha\u00ebl Boissonneault, NetherlandsAlexander Bor, DenmarkGuilherme Borges, MexicoAlberto Borgetti, United StatesJennifer Boyd, United KingdomErica Briones-Vozmediano, Spain\u00d3scar Brito Fernandes, NetherlandsCorinne Brooks, United StatesHeather Brown, United KingdomLaura Brunelli, ItalyAnna Bucsics, AustriaAlex Burdorf, NetherlandsAndrea Buron, SpainHermann Burr, GermanyBo Burstr\u00f6m, SwedenMarcel Buster, NetherlandsNoriko Cable, United KingdomChiara Cadeddu, ItalyGabriella Cadoni, ItalyTimothy Callaghan, United StatesCristina Canova, ItalySimon Capewell, United KingdomMartin Caraher, United KingdomMargarida Cardoso, PortugalS Carol, United StatesEwan Carr, United KingdomSusan Carr, United KingdomPilar Carrasco-Garrido, SpainR Catalano, United StatesAngela Chang, DenmarkBoris Chapoton, FranceFrank Chesser, United StatesJenny Cisneros, SwedenSheelah Connolly, IrelandElisabeth Corker, United StatesClaudia Costa, PortugalHannah Covert, United StatesMatty Crone, NetherlandsPaolo Crosignani, ItalyCarol B. Cunradi, United StatesSarah Cuschieri, MaltaShaonong Dang, ChinaZuzana Dankulincova, SlovakiaMike Daube, AustraliaSascha de Breij, NetherlandsPauline de Heer, NetherlandsEline de Heus, NetherlandsJudith de Jong, NetherlandsEvelyne De Leeuw, Australiaalessandro de matteis, United KingdomAugusto Cesar De Moraes, BrazilCorrado De Vito, ItalyDJH Deeg, NetherlandsPatricia M. Dekkers-S\u00e1nchez, NetherlandsStefaan Demarest, BelgiumEvangelia Demou, United Kingdomalexis descatha, FranceFinn Diderichsen, DenmarkHenri\u00ebtte Dijkshoorn, NetherlandsCharalabos-Markos Dintsios, GermanyKritika Dixit, NepalAnnette J Dobson, AustraliaFel\u0131citas Dom\u0131nguez-Berjon, SpainDunja Dreesens, NetherlandsRuth Dundas, United KingdomXavier Duran, SpainAnna Dzielska, PolandFrida Eek, SwedenMikael Ekblad, FinlandOla Ekholm, DenmarkAnna Mia Ekstr\u00f6m, SwedenGeorge Ellison, United KingdomLeonardo Emberti Gialloreti, ItalyEric Emerson, United KingdomErdem Erkoyun, TurkeyMiriam Evensen, NorwayMichelle Falkenbach, United StatesDaniel Falkstedt, SwedenSara Farina, ItalyMichael Farrell, AustraliaAlbert Faye, FranceAriadna Feliu, SpainCarmine Finelli, ItalyFlorian Fischer, GermanyP\u00e4r Flodin, SwedenCarla Fornari, ItalyStefan Fors, SwedenThomas Fr\u00f6hlich, GermanySari Fr\u00f6jd, Finlandkarine gallopel-morvan, FranceAna Gama, PortugalThomas Gamsj\u00e4ger, AustriaHeike Garritsen, NetherlandsVijay Gc, United KingdomLaurent Gerbaud, FranceMariette Gerber, FranceAli Ghaddar, SpainDelaram Ghodsi, IranMONICA GIANCOTTI, ItalyKatja Gillander Gadin, SwedenAlejandro Gil-Salmer\u00f3n, United KingdomLinn Gjersing, NorwayPere Godoy, SpainRosa Gofin, IsraelUnni Gopinathan, NorwayScott Greer, United StatesAikaterini Grimani, United StatesMaria Gualano, ItalyC Guijarro, United StatesLuc Hagenaars , United StatesFaisal Hakeem, United KingdomChristian Hakulinen, FinlandTorleif Halkjelsvik, NorwaySamah Hayek, IsraelK Hedna, SwedenN Heinonen, United StatesJolyn Hersch, AustraliaAnders Hjern, SwedenTheodore Holford, United StatesZakir Hossin, SwedenH Hoven, GermanyKuo-Cherh Huang, TaiwanD Ivankovic, United StatesAnant Jani, United KingdomStaffan Janson, SwedenLeticia Januario, SwedenBengt J\u00e4rvholm, SwedenDomantas Jasilionis, GermanyDmitri Jdanov, GermanyJunia Joffer, United StatesT J\u00f6rgensen, DenmarkKarsten J\u00f8rgensen, DenmarkLeena Kaila-Kangas, FinlandMichelle Kelly Irving, FranceCarolin Kilian, GermanyKennedy Kipkoech, United StatesMarte Kj\u00f8llesdal, NorwayCecile Knai, United KingdomAK Knudsen, NorwaySari Kovats, United KingdomSlawomir Koziel, PolandAlfgeir Kristjansson, IcelandAnton Kunst, NetherlandsSandra Kuntsche, AustraliaDaniel La Parra-Casado, SpainCarlo La Vecchia, ItalyMikko Laaksonen, FinlandUlrich Laaser, GermanyAngela Labberton, NorwayMaude Laberge, CanadaTea Lallukka, FinlandPaul Lambert, United StatesAnthony D. LaMontagne, AustraliaChris Lane, United StatesPeter Lansberg, NetherlandsSeo Yoon Lee, Korea (the Republic of)Dan Lewer, United KingdomAlastair Leyland, United KingdomGiovanna Liuzzo, United StatesFrancesco Longo, ItalyE Lothian, United KingdomMarty Lynch, United KingdomRonan Lyons, United KingdomGeorgina MacArthur, United KingdomAnne MacFarlane, IrelandAnna Macios, United StatesJo\u00e3o Paulo Magalh\u00e3es, PortugalManfred Maier, AustriaSteven Mann, United KingdomTanja Marschall, GermanyJoachim Marti, SwitzerlandLeslie Martin, United StatesJolanda Mathijssen, NetherlandsDonovan Maust, United StatesLaia Maynou, United KingdomJoanna Mazur, PolandMary McEniry, United StatesPhil McHale, United KingdomMartin McKee, United KingdomCourtney McNamara, NorwayEmmanouil Mentzakis, United KingdomJulien Mercille, United StatesRay Merrill, United StatesAnu Molarius, SwedenLinda Montanari, PortugalMaria Mour\u00e3o-Carvalhal, PortugalMassimo Mucciardi, ItalyCsilla Nagy, HungaryNeetu S. Neetu Abad Abad, United StatesDavide Negrini, ItalyBertalan N\u00e9meth, HungaryMelanie Nichols, AustraliaSuzanne Nielsen, United StatesPeter Nilsson, SwedenChristiana N\u00f6stlinger, BelgiumMario Cesare Nurchis, ItalyS Ofori, United StatesLeslie Ogilvie, GermanyOrkan Okan, GermanyHans Ossebaard, NetherlandsFred Paccaud, SwitzerlandAntoine Pariente, FranceSam Parsons, United StatesDomenico Pascucci, ItalyJulian Perelman, PortugalPamela Pereyra-Zamora, SpainVLADIMIR PETROVIC, SerbiaIsabelle Peytremann-Bridevaux, United StatesAngelo Maria Pezzullo, ItalyH Susan J Picavet, NetherlandsSylvain Pichetti, FrancePeter Piko, HungaryTom Platteau, BelgiumThomas Pl\u00fcmper, AustriaAndrea Poscia, ItalyValentina Prevolnik Rupel, SloveniaTina PURNAT, SwedenPekka Puska, FinlandXun Qi, United StatesJustina Ra\u010dait\u0117, LithuaniaCecilia Radkiewicz, United StatesOssi Rahkonen, FinlandSyed Rahman, SwedenFrancesco Ramponi, SpainSofia Ravara, PortugalSarah Reed, United KingdomSijmen Reijneveld, NetherlandsRainer Reile, EstoniaGr\u00e9goire Rey, FranceSofia Ribeiro, PortugalVladimir Rogalewicz, Czech RepublicHana Ross, South AfricaAnnalisa Rosso, ItalyAmeed Saabneh, IsraelHenrique Sachse-Bonhof, NetherlandsMuhammad Saeed, PakistanLaura Samuel, United StatesMiguel San Sebastian, SwedenFabian Sanchis-Gomar, SpainP Santia, United StatesCornelia Santoso, HungaryIngrid Seinen, NetherlandsMehmet Sukru Sever, TurkeyMohsen Shamsi, Iran (the Islamic Republic of)Wensong Shen, Hong KongKoichiro Shiba, United StatesIlana Shoham-Vardi, IsraelColin Shore, United KingdomKarri Silventoinen, FinlandFlorian Slimano, FranceMaja So\u010dan, SloveniaLotti Sofia, ItalyJeppe Karl S\u00f8rensen, DenmarkEmily South, United KingdomGordana Stankovska, United StatesKaspar Staub, SwitzerlandAgnes Stenius-Ayoade, FinlandTom Sterud, NorwayAbigail Stevely, United KingdomSusanne Stolpe, GermanyJack Stone, United StatesStefan Storcksdieck genannt Bonsmann, GermanyCosmo Strozza, DenmarkJukka Takala, FinlandDudley Tarlton, United StatesNicholas Taylor, AustraliaPerihan Torun, TurkeySwenne G van den Heuvel, NetherlandsJ. van der Velden, NetherlandsHans van der Wouden, NetherlandsChristel van Dijk, NetherlandsCarla van El, NetherlandsMarieke van Hoffen, NetherlandsGeert van Kemenade, NetherlandsJeroen van Meijgaard, United StatesHanna van Solinge, NetherlandsMaarten van Wijhe, DenmarkKo van Wouwe, NetherlandsSander van Zon, NetherlandsCarine Vande Voorde, BelgiumLeonardo Villani, ItalyMichal Vinker-Shuster, United StatesPekka Virtanen, FinlandSven Voigtl\u00e4nder, GermanyDavid Walsh, United KingdomHeather Wardle, United StatesRoger Webb, United KingdomDominic Weinberg, NetherlandsDr. H. Gilbert Welch, United StatesShicheng Yu, ChinaVirginia Zarulli, DenmarkMateusz Zatonski, United KingdomJennifer Zeitlin, FranceCaixia Zhang, ChinaPengxiang Zhao, SwedenCheryl Zlotnick, IsraelIrini Zografaki, GreeceCorina-Aurelia Zugravu, Romania"} +{"text": "Molecular Psychiatry 10.1038/s41380-022-01758-6, published online 21 September 2022Correction to: In the original version of this article, the given and family names of Riccardo Barchiesi, Kanat Chanthongdee, Michele Petrella, Li Xu, Simon S\u00f6derholm, Esi Domi, Gaelle Augier, Andrea Coppola, Joost Wiskerke, Ilona Szczot, Ana Domi, Louise Adermark, Eric Augier, Claudio Cant\u00f9, Markus Heilig, Estelle Barbier were incorrectly structured. The names were displayed correctly in all versions at the time of publication.The original article has been corrected."} +{"text": "PLOS ONE Editors retract this article [The article because UY, AAR, SD, MAA, RD, SF, JH, TH, MB, TZ, AES and BRG did not agree with the retraction. NA and AB either did not respond directly or could not be reached."} +{"text": "The stroke rate 30 days after TAVR was reported as 3.4% in low-risk patients.2 Prior studies including intermediate- and high-surgical risk cases suggested the use of the SENTINEL Cerebral Protection System (SENTINEL-CPS) during TAVR may reduce the incidence of ischemic stroke and in-hospital mortality.4 However, the effectiveness of the SENTINEL-CPS during TAVR in lower-risk patients has not been studied yet. The SENTINEL-LIR study aimed to quantify the frequency of embolic debris captured by the SENTINEL-CPS in lower-risk TAVR cases.Indications for transcatheter aortic valve replacement (TAVR) have expanded to aortic stenosis patients with low- and intermediate-risk of surgery.https://www.clinicaltrials.gov; Unique identifier: NCT04131127). All patients provided written informed consent. The study protocol was approved by the institutional ethics review committee at each site. Patients with severe, symptomatic aortic stenosis, undergoing transfemoral TAVR with planned use of the SENTINEL-CPS, and a Society of Thoracic Surgeons Predicted Risk of Mortality score of <4% were included. Exclusion criteria were (1) a history of stroke or transient ischemic attack within 6 months of TAVR, (2) carotid artery intervention within 6 weeks of TAVR, (3) prior aortic valve replacement, or (4) concomitant surgical procedure. The clinical team decided the types of transcatheter heart valves implanted .The incidence of debris, size, and tissue types captured by the SENTINEL-CPS were histologically analyzed. The details of sample processing and analysis methods have been described previously.5We will make the data available upon reasonable request. The SENTINEL-LIR registry was a multicenter, prospective clinical study between March and August 2020. One case was excluded due to valve-in-valve TAVR. Participants had a mean age of 76-years and 45% were women. The median Society of Thoracic Surgeons Predicted Risk of Mortality score was 1.7%, with 86% and 14% of participants classified by the heart team as low- and intermediate-risk, respectively.P=0.36; postdilatation: 15% versus 23%, P=0.48). Both proximal and distal filters of the SENTINEL-CPS were successfully placed in all patients. The SENTINEL-CPS was delivered and retrieved via radial access in 96%, brachial access in 2%, and ulnar artery approach in 2%. No vascular complications caused by upper extremity access were observed. The rates of death or stroke within 30 days post-TAVR were 2% and 4% (2/49), respectively. This study did not include routine brain imaging evaluation.Fifty-five percent of patients received the CoreValve, while 45% had theSapien 3. Predilatation and postdilatation were performed in 43% and 18% of cases, respectively. The frequency of predilatation and postdilatation were not different between the 2 transcatheter heart valves . Debris was composed of arterial wall (98% of cases), acute thrombus (96%), valve tissue (71%), calcification (55%), and foreign materials (43%). Myocardial tissue (20%), organizing thrombus (4%), and necrotic core (4%) were found less frequently .P=0.046). However, predilatation or postdilatation did not alter particle numbers or sizes .Most captured debris had a size of <500 \u03bcm (78% were 150\u2013500 \u03bcm). Nearly 5% of the captured particles were \u22651000 \u03bcm , and these were detected in 67% of cases. Transcatheter heart valve type did not impact the debris tissue types, particle numbers, or sizes. Calcified particles were more common in patients treated with predilatation . Second, the type of transcatheter heart valve was selected at the operators\u2019 discretion, not assigned randomly. Thus, the superiority of transcatheter heart valves might not be evaluated precisely. These limitations will be best addressed in the future large-scale randomized studies.In conclusion, the SENTINEL-LIR study demonstrates that embolic debris capture by the SENTINEL-CPS during TAVR in low- to intermediate-risk patients was similar to that in previous studies conducted among higher-risk patients. Larger size particles (\u22651000 \u03bcm), which can cause significant vessel obstruction, were present in 67% of cases. These findings suggest lower-risk patients undergoing TAVR have potentially a similar embolic risk as high-risk patients as evidenced by embolic debris capture.We thank the participants and staff of this registry.This clinical study was funded by the Boston Scientific.CVPath Institute have received institutional research support from NIH-HL141425, Leducq Foundation Grant, 4C Medical, 4Tech, Abbott Vascular, Ablative Solutions, Absorption Systems, Advanced NanoTherapies, Aerwave Medical, Alivas, Amgen, Asahi Medical, Aurios Medical, Avantec Vascular, BD, Biosensors, Biotronik, Biotyx Medical, Bolt Medical, Boston Scientific, Canon,Cardiac Implants, Cardiawave, CardioMech, Cardionomic, Celonova, Cerus, EndoVascular, Chansu Vascular Technologies, Childrens National, Concept Medical, Cook Medical, Cooper Health, Cormaze, CRL, Croivalve, CSI, Dexcom, Edwards Lifesciences, Elucid Bioimaging, eLum Technologies, Emboline, Endotronix, Envision, Filterlex, Imperative Care, Innovalve, Innovative, Cardiovascular Solutions, Intact Vascular,Interface Biolgics, Intershunt Technologies, Invatin, Lahav, Limflow, L&J Bio, Lutonix, Lyra Therapeutics, Mayo Clinic, Maywell, MDS, MedAlliance, Medanex, Medtronic, Mercator, Microport, Microvention, Neovasc, Nephronyx, Nova Vascular, Nyra Medical, Occultech, Olympus, Ohio Health, OrbusNeich, Ossio, Phenox, Pi-Cardia, Polares Medical, Polyvascular, Profusa, ProKidney, LLC, Protembis, Pulse Biosciences, Qool Therapeutics, Recombinetics, Recor Medical, Regencor, Renata Medical, Restore Medical, Ripple Therapeutics, Rush University, Sanofi, Shockwave, SMT, SoundPipe, Spartan Micro, Spectrawave, Surmodics, Terumo Corporation, The Jacobs Institute, Transmural Systems, Transverse Medical, TruLeaf, University of California, San Francisco (UCSF), University of Pittsburgh Medical Center (UPMC), Vascudyne, Vesper, Vetex Medical, Whiteswell, WL Gore, and Xeltis. Dr Kawakami has received research grants from Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad. Dr Gada has received honoraria from Medtronic, Abbott, Bard, Boston Scientific and is a consultant of Medtronic, Abbott, Bard, and Boston Scientific. Dr Rinaldi received research grant from Boston Scientific, honoraria from Abbott Vascular, Boston Scientific, Edwards and is a consultant of Abbott Vascular, Boston Scientific, and Edwards. Dr Nazif has received honoraria from Boston Scientific, Edwards LifeSciences, Medtronic, and Venus MedTech. Dr Leon has received the institutional grants for clinical research from Abbott, Boston Scientific, Edwards, and Medtronic. Dr Cornelissen receives research grants from University Hospital RWTH Aachen. Dr Virmani has received honoraria from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Cook Medical, Cordis, CSI, Lutonix Bard, Medtronic, OrbusNeich Medical, CeloNova, SINO Medical Technology, ReCor Medical, Terumo Corporation, W. L. Gore, Spectranetics and is a consultant Abbott Vascular; Boston Scientific, Celonova, Cook Medical, Cordis, CSI, Edwards Lifescience, Lutonix Bard, Medtronic, OrbusNeich Medical, ReCor Medical, Sinomededical Technology, Spectranetics. Dr Finn has received honoraria from Abbott Vascular, Biosensors, Boston Scientific, Celonova, Cook Medical, CSI, Lutonix Bard, Sinomed, Terumo Corporation and is a consultant to Amgen, Abbott Vascular, Boston Scientific, Celonova, Cook Medical, Lutonix Bard, Sinomed, Surmodics, Terumo Corporation, W. L. Gore, and Xeltis. The other authors report no conflicts."} +{"text": "Several models have been developed to predict the severity and prognosis of chronic obstructive pulmonary disease (COPD). This study aimed to identify potential predictors and construct a prediction model for COPD severity using biochemical and immunological parameters.A total of 6,274 patients with COPD were recruited between July 2010 and July 2018. COPD severity was classified into mild, moderate, severe, and very severe based on the Global Initiative for Chronic Obstructive Lung Disease guidelines. A multivariate logistic regression model was constructed to identify predictors of COPD severity. The predictive ability of the model was assessed by measuring sensitivity, specificity, accuracy, and concordance.P < 0.001), high-density lipoprotein (HDL) , plasma fibrinogen , fructosamine , standard bicarbonate concentration , partial pressure of carbon dioxide , age , eosinophil count , lymphocyte ratio , and apolipoprotein A1 . The factors that could distinguish between mild/moderate and very severe cases were vascular disorders , HDL , plasma fibrinogen , fructosamine , partial pressure of oxygen , plasma carbon dioxide concentration , standard bicarbonate concentration , partial pressure of carbon dioxide , age , sex , allergic diseases , eosinophil count , lymphocyte ratio , and apolipoprotein A1 . The prediction model correctly predicted disease severity in 60.17% of patients, and kappa coefficient was 0.35 (95% CI: 0.33\u20130.37).Of 6,274 COPD patients, 2,644, 2,600, and 1,030 had mild/moderate, severe, and very severe disease, respectively. The factors that could distinguish between mild/moderate and severe cases were vascular disorders (OR: 1.44; This study developed a prediction model for COPD severity based on biochemical and immunological parameters, which should be validated in additional cohorts. Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow obstruction to the lungs. This disease is not fully reversible and is a leading cause of adult morbidity worldwide \u20133. Appro1) and FEV1/forced vital capacity (FVC) guidelines, including forced expiratory volume in 1 s (FEVty (FVC) . The claty (FVC) \u201311. COPDty (FVC) . Howeverty (FVC) \u201315.A prediction model for COPD severity was developed and validated using a claims-based algorithm. The final model included age, sex, comorbidities, COPD-related resource utilization, and all-cause healthcare utilization . The mod1/FVC < 70% according to GOLD criteria , plasma carbon dioxide concentration, bicarbonate concentration, standard bicarbonate concentration, extracellular fluid volume depletion, partial pressure of carbon dioxide (pCO2), base excess, percentage and absolute number of granulocytes, high-sensitivity C-reactive protein (hsCRP), and D-dimer.Demographic and clinical data were extracted from electronic medical records, including age, sex, diabetes mellitus, vascular disorders, psychiatric disorders, infections, allergic diseases, hypertension, tumors, gastrointestinal diseases, and osteoarticular diseases. In addition, data on the following biochemical and immunological parameters were collected: platelet-large cell ratio (P-LCR), platelet count, eosinophil count, mean platelet volume (MPV), eosinophil ratio, basophilic granulocytes, platelet distribution width (PDW), lymphocyte count, lymphocyte ratio, basophil ratio, low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratio, HDL, albumin/globulin ratio, serum iron, indirect bilirubin, direct bilirubin/total bilirubin ratio, globulin, magnesium, LDL, erythrocyte sedimentation rate (ESR), apolipoprotein A1, lipoprotein (a), carcinoembryonic antigen (CEA), plasma fibrinogen, prothrombin time (PT), PT activity, plasma thrombin time, fructosamine, myoglobin, cystatin C, serum procalcitonin, partial pressure of oxygen to standardize the number of patients in each group.The severity of COPD was classified as mild, moderate, severe, and very severe, according to the GOLD guidelines . Mild, mP < 0.05 were included in the multivariate regression model. The final set of predictors was determined using stepwise selection at a threshold of P < 0.05. The multivariable model was used to predict the probability of each patient being assigned to each COPD severity. Model performance was assessed by calculating sensitivity, specificity, and accuracy. The agreement between predicted and actual values was assessed using Cohen\u2019s kappa test. All statistical tests were two-sided, and P-values of less than 0.05 were considered statistically significant. All statistical analyses were conducted using SPSS Statistics 19.0 for Windows .The data were presented as mean \u00b1 standard deviation for normally distributed continuous variables and as medians (interquartile range) for non-normally distributed continuous variables. Categorical variables were expressed as numbers and percentages. Differences between groups were assessed using analysis of variance, the Kruskal\u2013Wallis test, and the chi-square test. Potential predictors of COPD severity were identified by logistic regression, and COPD severity was considered the dependent variable. Covariates with a 2, plasma carbon dioxide concentration, bicarbonate concentration, standard bicarbonate concentration, extracellular fluid volume depletion, pCO2, base excess, and hsCRP. However, there were no significant differences in diabetes mellitus prevalence, LDL, apolipoprotein A1, lipoprotein (a), fructosamine, myoglobin, percentage of granulocytes, absolute number of granulocytes, and D-dimer concentration. The details characteristics of the cohorts among three groups are shown in A total of 2,644, 2,600, and 1,030 patients had mild/moderate, severe, and very severe COPD. There were significant differences among three groups for mostly variables, including age, sex, vascular disorders, psychiatric disorders, infections, allergic diseases, hypertension, tumors, gastrointestinal diseases, osteoarticular diseases, P-LCR, platelet count, eosinophil count, MPV, eosinophil ratio, basophilic granulocytes, PDW, lymphocyte count, lymphocyte ratio, basophil ratio, LDL/HDL ratio, HDL, albumin/globulin ratio, serum iron, indirect bilirubin, direct bilirubin/total bilirubin ratio, globulin, magnesium, ESR, CEA, plasma fibrinogen, PT, PT activity, plasma thrombin time, cystatin C, serum procalcitonin, pO2, base excess, and hsCRP were significantly associated with an increased risk of severe COPD. In contrast, age, allergic diseases, hypertension, tumors, P-LCR, eosinophil count, MPV, eosinophil ratio, PDW, lymphocyte count, lymphocyte ratio, basophil ratio, LDL/HDL ratio, globulin, and magnesium were significantly associated with a reduced risk of severe COPD.The results of the univariate analysis are shown in 2, and base excess were associated with an increased risk of very severe COPD. In turn, sex, allergic diseases, hypertension, tumors, gastrointestinal and osteoarticular diseases, P-LCR, platelet count, eosinophil count, MPV, eosinophil ratio, basophilic granulocytes, lymphocyte count, lymphocyte ratio, basophil ratio, LDL/HDL ratio, globulin, magnesium, ESR, PT activity, cystatin C, and the percentage of granulocytes were associated with a reduced risk of very severe COPD.Vascular and psychiatric disorders, infections, HDL, albumin/globulin ratio, direct bilirubin/total bilirubin ratio, PT, plasma thrombin time, fructosamine, plasma carbon dioxide concentration, bicarbonate concentration, standard bicarbonate concentration, extracellular fluid volume depletion, pCOP < 0.001), HDL , plasma fibrinogen , fructosamine , standard bicarbonate concentration , and pCO2 were significantly associated with an increased risk of severe COPD. In contrast, age , eosinophil count , lymphocyte ratio , and apolipoprotein A1 were significantly associated with a reduced risk of severe COPD. Vascular disorders , HDL , plasma fibrinogen , fructosamine , pO2 , plasma carbon dioxide concentration , standard bicarbonate concentration , and pCO2 were significantly associated with an increased risk of very severe COPD. In turn, age , sex , allergic diseases , eosinophil count , lymphocyte ratio , and apolipoprotein A1 were associated with a reduced risk of very severe COPD.The results of the multivariate analysis are shown in A prediction model was constructed based on the results of multivariate analysis . The mod2, age, eosinophil count, lymphocyte ratio, and apolipoprotein A1. The factors that could distinguish between mild/moderate and very severe cases were vascular disorders, HDL, plasma fibrinogen, fructosamine, pO2, plasma carbon dioxide concentration, standard bicarbonate concentration, pCO2, age, sex, allergic diseases, eosinophil count, lymphocyte ratio, and apolipoprotein A1. The prediction model correctly predicted disease severity in 60.17% of the cases, with a kappa coefficient of 0.35.None of the existing prediction models for COPD severity assessed patient prognosis using biochemical and immunological parameters \u201315. AfteSeveral studies have developed prediction models for COPD severity based on various parameters , 17. For2, age, eosinophil count, lymphocyte ratio, apolipoprotein A1, pO2, plasma carbon dioxide concentration, sex, and allergic diseases. This result may be due to several reasons: (1) systematic inflammatory responses could explain the increased risk of severity of COPD in patients with vascular disorders (2 is significantly related to higher scores for disease severity indicators (BODE or GOLD) and is a good predictor of severe COPD apoisorders \u201321; (3) isorders , 23; (4)isorders ; (5) bloisorders ; (6) pCOere COPD ; (7) theere COPD ; (9) lymere COPD .Our model had a moderate ability to differentiate COPD severity based on the selected variables and correctly predicted severity in 60.17% of the patients. The predictive performance of this model was better than that of the null model. Moreover, the sensitivity and specificity for detecting mild/moderate cases were 72.31 and 72.94%, and accuracy was 72.68%. The sensitivity and specificity for detecting severe cases were 56.28 and 66.07%, and accuracy was 61.96%. The sensitivity and specificity for detecting very severe disease were 40.71 and 94.99%, and accuracy was 85.69%. This result suggests that the model\u2019s ability to differentiate severe COPD was low, while the accuracy for detecting very severe COPD (85.69%) and mild/moderate COPD (72.68%) was high.This study firstly constructed a prediction model based on biochemical and immunological parameters in hospitalized patients with stable COPD. This prediction model could used to assess the severity of COPD for patients are unable to perform breath test, and the ratings COPD severity could generate automatically based on electronic medical record. Thus, high risk patients could identified using constructed model, and early treatment strategies could provide to improve the prognosis of COPD.Several strengths of this study should be highlighted: (1) the current retrospective cohort study contained large sample size, and the conclusion was robustness; (2) both univariate and multivariate analyses were applied to identify potential predictive factors; (3) the prediction model was constructed and a risk scoring system was established based on multivariate analyses; and (4) the predictive value of constructed model was assessed using sensitivity, specificity, accuracy, and Cohen\u2019s kappa test.This study has limitations. First, the retrospective design may lead to selection and recall bias. Second, non-treatment may have increased COPD severity. Third, serum iron, magnesium, ESR, CEA, myoglobin, serum procalcitonin, extracellular fluid volume depletion, base excess, the percentage and absolute number of granulocytes, hsCRP, and D-dimer were excluded from the multivariate analysis because of missing data. Fourth, the prediction model was not validated externally.2, age, eosinophil count, lymphocyte ratio, apolipoprotein A1, pO2, plasma carbon dioxide concentration, sex, and allergic diseases. The model\u2019s ability to predict very severe COPD was high. Nonetheless, larger studies are needed to validate these findings.This study identified predictors of COPD severity, and a prediction model was constructed using biochemical and immunological parameters from patients from a single center. The predictors of COPD severity included vascular disorders, HDL, plasma fibrinogen, fructosamine, standard bicarbonate concentration, pCOThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Suining Central Hospital. The ethics committee waived the requirement of written informed consent for participation.Y-FG: conceptualization, data curation, methodology, supervision, writing\u2014original draft, project administration, and writing\u2014review and editing. Y-FG and LC: data curation and writing\u2014review and editing. LC: methodology, formal analysis, software, writing\u2014review and editing, and investigation. Y-FG and RQ: methodology and writing\u2014review and editing. S-HW and PC: investigation, methodology, and writing\u2014review and editing. All authors contributed to the article and approved the submitted version."} +{"text": "A Rare Mutation in SPLUNC1 Affects Bacterial Adherence and Invasion in Meningococcal Disease. Clin Infect Dis 2020; 70(10): 2045-53. Currently the author list on the title page states \u201cBayarchimeg Mashbat, Evangelos Bellos, Stephanie Hodeib, Fadil Bidmos, Ryan S. Thwaites, Yaxuan Lu, Victoria Wright, Jethro Herberg, Daniela S. Klobassa, Werner Zenz, Trevor T. Hansel, Simon Nadel, Paul R. Langford, Luregn J. Schlapbach, Ming-Shi Li, Matthew Redinbo, Y. Peter Di, Michael Levin and Vanessa Sancho-Shimizu\u201dThe correct author list, adding William G. Walton, should be as follows: \u201cBayarchimeg Mashbat, Evangelos Bellos, Stephanie Hodeib, Fadil Bidmos, Ryan S. Thwaites, Yaxuan Lu, Victoria Wright, Jethro Herberg, Daniela S. Klobassa, William G. Walton, Werner Zenz, Trevor T. Hansel, Simon Nadel, Paul R. Langford, Luregn J. Schlapbach, Ming-Shi Li, Matthew Redinbo, Y. Peter Di, Michael Levin and Vanessa Sancho-Shimizu\u201dThe author regrets this error."} +{"text": "In the published article, there was an error in the author list, and author Marina Amores-Borge was erroneously excluded. The corrected author list appears below.\u201cDiego Pazos-Castro, Cl\u00e9mence Margain, Zulema Gonzalez-Klein, Marina Amores-Borge, Carmen Yuste-Calvo, Maria Garrido-Arandia, Lucia Zurita, Vanesa Esteban, Jaime Tome-Amat, Araceli Diaz-Perales, Fernando Ponz\u201dAuthor Contributions section.In the published article, there was an error. The missing author was not included in the Author contributions. This sentence previously stated:A correction has been made to \u201cDP-C: Conceptualization, investigation, writing original draft. CM: Investigation. ZG-K: Conceptualization, investigation, writing review. CY-C: Investigation. MG-A: Investigation, writing review. LZ: Investigation. VE: Writing review, resources, funding acquisition. JT-A: Conceptualization, investigation, writing original draft. AD-P: Conceptualization, writing original draft, resources, funding acquisition. FP: Conceptualization, writing review, resources, funding acquisition. All authors contributed to the article and approved the submitted version.\u201dThe corrected sentence appears below:\u201cDP-C: Conceptualization, investigation, writing original draft. CM: Investigation. ZG-K: Conceptualization, investigation, writing review. MA-B: Investigation. CY-C: Investigation. MG-A: Investigation, writing review. LZ: Investigation. VE: Writing review, resources, funding acquisition. JT-A: Conceptualization, investigation, writing original draft. AD-P: Conceptualization, writing original draft, resources, funding acquisition. FP: Conceptualization, writing review, resources, funding acquisition. All authors contributed to the article and approved the submitted version.\u201dThe authors apologize for these errors and state that they do not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "PLOS ONE Editors retract this article [The article because QA agreed with retraction. HN, KS, NZ, MBH, AR, MN, MAQ, MHS, and HMA did not agree with retraction. AAA-H did not reply or could not be reached."} +{"text": "Correction to: BMC Health Serv Res (2021) 21:1186https://doi.org/10.1186/s12913-021-07195-5Following publication of the original article , the autThe incorrect author names are: Huguet Nathalie, Valenzuela Steele, Marino Miguel, Moreno Laura, Hatch Brigit, Baron Andrea, J. Cohen Deborah and E. DeVoe JenniferThe correct author names are: Nathalie Huguet, Steele Valenzuela, Miguel Marino, Laura Moreno, Brigit Hatch, Andrea Baron, Deborah J. Cohen and Jennifer E. DeVoeThe author group has been updated above and the original article has been"} +{"text": "PLOS ONE Editors retract this article [The article because LA agreed with the retraction. MY, HZ, MWA, MNA, AMES, ATKZ, YL, and MA did not agree with the retraction. TL, WA, SH, TAH, AH, GAK, and MME either did not respond directly or could not be reached."} +{"text": "The original version of this article unfortunately contained a mistake. The given and family names of authors were Interchanged and Dr. Spiezia has two given names (Antonio Luca).The author names should beAntonio Riccardo Buonomo, Giulio Viceconte, Massimiliano Calabrese, Giovanna De Luca, Valentina Tomassini, Paola Cavalla, Giorgia Teresa Maniscalco, Diana Ferraro, Viviana Nociti, Marta Radaelli, Maria Chiara Buscarinu, Damiano Paolicelli, Alberto Gajofatto, Pietro Annovazzi, Federica Pinardi, Massimiliano Di Filippo, Cinzia Cordioli, Emanuela Zappulo, Riccardo Scotto, Ivan Gentile, Antonio Luca Spiezia, Martina Petruzzo, Marcello De Angelis, Vincenzo Brescia Morra, Claudio Solaro, Claudio Gasperini, Eleonora Cocco, Marcello Moccia, Roberta LanzilloThe original article has been corrected."} +{"text": "The original version of this article unfortunately contained a mistake. Affiliation details for Authors\u2019 Stefano Forte, Cesarina Giallongo, Giuseppe Broggi, Rosario Caltabiano, Giuseppe Maria Vincenzo Barbagallo, Roberto Altieri, Giuseppina Raciti and Arcangelo Liso were incorrectly given.The correct affiliations details for Authors\u2019 Stefano Forte, Cesarina Giallongo, Giuseppe Broggi, Rosario Caltabiano, Giuseppe Maria Vincenzo Barbagallo, Roberto Altieri, Giuseppina Raciti and Arcangelo Liso should be:2 IOM Ricerca, 95029 Viagrande, CT, Italy3 Department of Medical and Surgical Sciences and Advanced Technologies, F. Ingrassia, Anatomic Pathology, University of Catania, Catania, Italy4 Department of Drug Sciences, University of Catania, Catania, Italy5 Department of Medical and Surgical Sciences, University of Foggia, 71100 Foggia, Italy"} +{"text": "The materials were characterized using Fourier-transform infrared spectroscopy, 1H- and 13C- nuclear magnetic resonance spectroscopy, size exclusion chromatography as well as X-ray diffraction, and differential scanning calorimetry. PCL-based copolymers exhibited distinct melting point as well as a crystalline phase of up to 47%, while copolymers with PLA segments were highly amorphous, showing a broad amorphous reflex in the XRD spectra, and no melting or crystallization points were discernible using differential scanning calorimetry.The use of biodegradable materials such as cellulose and polyesters can be extended through the combination, as well as modification, of these biopolymers. By controlling the molecular structure and composition of copolymers of these components, it should also be possible to tailor their material properties. We hereby report on the synthesis and characterization of cellulose-based graft copolymers with a precise molecular composition and copolymer architecture. To prepare such materials, we initially modified cellulose through the regioselective protection of the 6-OH group using trityl chloride. The 6-O protected compound was then alkylated, and deprotection at the 6-OH group provided the desired 2,3-di-O-alkyl cellulose compounds that were used as macroinitiators for ring opening polymerization. Regioselective modification was hereby necessary to obtain compounds with an exact molecular composition. Ring opening polymerization, catalyzed by Sn(Oct) The preparation of tailored polymers and copolymers that exhibit certain properties is of high relevance for various applications, such as tissue and bone engineering, controlled drug release, as well as other fields that require biocompatible or biodegradable functional materials . Both cePoly(caprolactone) (PCL) and poly(lactic acid) (PLA) are aliphatic polymers that can be produced from sustainable resources and exhibit biodegradable properties, while cellulose represents the most abundant biopolymer ,6. Both With respect to global environmental sustainability, cellulose-based materials hold great promise due to the abundance of cellulose as a natural resource . AnotherOnly few advances towards the synthesis of regioselectively substituted copolymers of cellulose have been reported to date in the literature. One approach for the preparation of regiocontrolled cellulose\u2013PCL graft-copoylmers was reported by Wang et al. In their research, an aqueous zinc chloride solution was used as solvent for cellulose which favored grafting of PCL at OH-2 and OH-3 of the anhydroglucose units. PCL was thereby \u201cgrafted from\u201d secondary hydroxyl groups of the AGU . RecentlAdvances by other authors towards the preparation of polysaccharide-based graft copolymers without a special focus on regioselectivity include the works of Tian et al., and Wohlhauser et al., who grafted PCL onto cellulose nanocrystals using a \u201cgrafting from\u201d approach, and verified their successful reaction via infrared spectroscopy ,27. FurtFor this work, we hypothesize that cellulose\u2013backbone graft copolymers would exhibit thermal properties, such as melting points, that are traceable to the thermoplastic component, i.e., the PCL or PLA sidechains in the copolymers, while it is possible to impose a copolymer architecture through initial regioselective modification of the cellulose macroinitiators.Therefore, for our research, we prepared regioselectively modified cellulose derivatives bearing functional groups, such as benzyl-, allyl-, and propyl moieties at OH-2 and OH-3 of the AGU, to demonstrate the versatility of the cellulose biopolymer in regards to the functionalities that may be introduced into polysaccharide-based copolymers through targeted modification and regioselective reactions, as in our study. After introduction of functionality, the physical properties of these cellulose-based macroinitiators can be further enhanced through the homogeneous ring opening polymerization of L-lactide or \u03b5-caprolactone via the unprotected hydroxyl group at C6 in a \u201cgrafting from\u201d approach to prepare the respective copolymers that exhibit a precise and controllable structural composition.N,N-dimethylacetamide , tetrahydrofuran , toluene , sodium hydride tin(II) 2-ethylhexanoate (Sn(Oct)2, AB106427, ABCR, Karlsruhe, Germany) were used in the experiments as received unless otherwise stated. THF and toluene were distilled under inert gas using standard Schlenk techniques and stored over molecular sieves (4 \u00c5) before use. Sn(Oct)2 and \u03b5-caprolactone were distilled under reduced pressure in accordance with the procedure reported by Lee et al. 3463, 3058, 2883, 1597, 1490, 1029, 899, 763, 746, 699, 643, 632.IR 3060, 2876, 1646, 1597, 1490, 1448, 1419, 1345, 1315, 1220, 1073, 1045, 996, 919, 764, 746, 737, 700, 644, 631, 531.IR 3060, 3029, 2878, 1598, 1493, 1448, 1359, 1316, 1208, 1153, 1070, 1042, 1028, 1001, 899, 844, 733, 695, 631, 552, 460.IR 3059, 2960, 2876, 2933, 1598, 1490, 1448, 1361, 1316, 1218, 1152, 1084, 1040, 1001, 945, 898, 762, 746, 698, 644, 631, 563.IR 3406, 3080, 2874, 1733, 1646, 1458, 1420, 1348, 1058, 996, 922, 559.IR 3430, 3063, 2873, 1496, 1453, 1359, 1209, 1060, 1027, 910, 733, 695, 619, 555, 460.IR 3410, 2962, 2934, 2877, 1462, 1363, 1032, 950, 896, 578.IR 3443, 3031, 2942, 2865, 1722, 1497, 1455, 1418, 1397, 1365, 1294, 1241, 1188, 1162, 1087, 1064, 1045, 961, 933, 840, 733, 698 583, 453.IR 3441, 2944, 2865, 1721, 1470, 1419, 1397, 1366, 1294, 1187, 1106, 1065, 1045, 961, 932, 840, 772, 731, 710.IR 3442, 2943, 2866, 1721, 1470, 1419, 1397, 1366, 1294, 1240, 1187, 1163, 1105, 1089, 1065, 1045, 961, 934, 840, 732, 710, 583.IR 3509, 2993, 2942, 1749, 1552, 1497, 1453, 1381, 1359, 1309, 1265, 1183, 1124, 1084, 1044, 914, 863, 737, 697, 620, 546.IR 3492, 2993, 2941, 1749, 1453, 1382, 1358, 1264, 1182, 1127, 1084, 1044, 927, 867, 755, 699.IR 3492, 2943, 1750, 1452, 1381, 1361, 1265, 1182, 1127, 1084, 1043, 952, 867, 755, 702.IR g mol\u22121 denote the molar masses of glucose and of the ligands.For materials with PLA ligands, the glass transition points terature ,52,53. Tmol\u00a0K)\u22121 , and cp, toluene , propene toluene and prop toluene , respectThis finding confirms the near quantitative etherification of the cellulose C2 and C3 hydroxyl groups, and the linear mixing of the heat capacities of the constituents of all the materials. The equilibrium melting temperature of PLA was reported to be m0\u2248480\u00a0K ,52. Actum0\u2248480\u00a0K , being lHence, the lack of melting points determined using DSC in this work supports our findings with XRD, namely that the materials with PLA ligands consisted of exclusively amorphous atomic arrangements.Tg = 209 K were reported after several days incubation at room temperature\u201d [xc determined in the first DSC heating run are lower than those reported in the literature, where crystallinities larger than 0.6 were reported [12121 crystalline poly(3-hydroxybutyrate) [In the materials with PCL ligands, we consider the properties of the crystalline phase: The higher values of erature\u201d . The valreported . This isutyrate) . Our resutyrate) and via utyrate) that the2 and the heat of fusion Hf = 1.63 \u00b7 109 erg/cm3 [Additionally at odds are the melting temperatures reported in \u2248 342 K ,63 and as et al. To invess et al. , togetheTm,1 \u2212 15 K into (5), thereby obtaining values of L \u2248 11 nm. This supports our finding that the dimensions of the primary crystallites are indeed \u224810 nm, as directly determined using XRD.Since the melting points reported in Given the lack of isolated intense {010} reflexes, the corresponding value of the average directional crystallite size utyrate) ,65, the In this work, we were able to prepare graft copolymers of cellulose derivatives via regioselective modification of cellulose with consecutive ring opening polymerization of the \u03b5-caprolactone or L-lactide monomers. The high emphasis on regioselectivity in our research thereby allowed the synthesis of high precision copolymers with an exact copolymer architecture, and through etherification, the implementation of functional groups onto the cellulose scaffold was possible while improving upon the material properties of native cellulose via consecutive ring opening polymerization. Structural analysis of the copolymers was performed using IR and NMR spectroscopy, as well as XRD and DSC measurements.The prepared copolymers show great potential for further investigation concerning variation of the substituents at C2 and C3 of the cellulose backbone and post polymerization modification, either via functional groups at the cellulose hydroxyl groups, by endgroup modification of the polyester sidechains, or via the implementation of functionalized monomers for grafting polymerization. It is also possible to implement different polymers onto the cellulose backbone to obtain bottlebrush copolymers with two entirely different polymer segments through consecutive polymerizations, albeit adhering to a well-defined polymer architecture and simultaneously tailoring polymer properties in a targeted manner. The properties of such copolymers could then be exploited, e.g., for protein stabilization as well"} +{"text": "The Editors of Public Health Reviews would like to thank all Reviewers in 2021 for the time they have spent and the valuable contributions they have made to ensure the scientific quality of the journal.Christine A\u2019Court, United KingdomBabatunde Akinwunmi, United States Sinaa Al Aqeel, Saudi ArabiaChantal Arditi, SwitzerlandH\u00e9l\u00e8ne Aschmann, United StatesIn\u00eas Ba\u00eda, PortugalEduard Baladia, SpainRebecca Bennett, AustraliaTomasz Bochenek, PolandKatarina Braun, United States Katie Cederberg, United StatesHarrison Ng Chok, AustraliaAna Cruz, PortugalNicole Geovana Dias, BrazilDominik Dietler, SwitzerlandNicola Diviani, SwitzerlandAlicja Domaga\u0142a, PolandMarta Fadda, SwitzerlandGuihong Fan, United StatesMichele Dalla Fontana, BrazilSaswata Ghosh, IndiaGabriel Gulis, DenmarkLouise Hartley, United KingdomHerwansyah Herwansyah, NetherlandsMusa Abubakar Kana, NigeriaMelkamu Dugassa Kassa, South AfricaRobin Van Kessel, NetherlandsAnisur Khan, BangladeshAndrew Kim, United StatesEvdoxia Kyriazopoulou, GreeceRaquel Lucas, PortugalTim Lucas, United KingdomLaura Maga\u00f1a, United StatesPatricia McDaniel, United StatesSinenhlanhla Memela, South AfricaGage Moreno, United StatesAlexandra Moura, FranceJessica Neicun, NetherlandsTaco Niet, CanadaRachel Nugent, United StatesEkwaro Obuku, UgandaOsorio, Camilo Gutierrez Osorio, ColombiaMadhuri Pattamatta, IndiaPaul, Ayan Paul, GermanyPaul Pavli, AustraliaPablo Perel, United KingdomPriyanka Priyanka, United StatesAna Catarina Queiroga, PortugalAzizur Rahman, AustraliaNandini Ramanujam, CanadaAndres Roman-Urrestarazu, United KingdomJo\u00e3o Cavaleiro Rufo, PortugalMarco Scherz, AustriaDenise Sharon, United StatesB. Shayak, United StatesBritt Singletary, United StatesNanny Natalia Mulyani Soetedjo, IndonesiaAsha Soletti, NetherlandsMindaugas Stank\u016bnas, LithuaniaAmbra Stefani, AustriaLiz Tobin-Tyler, United StatesSusanne Unverzagt, GermanyCherian Varghese, SwitzerlandDuoquan Wang, ChinaBrian Li Han Wong, SwitzerlandClaudia Zanini, SwitzerlandJan Anton Van Zanten, Netherlands"} +{"text": "Retraction note to: Mol Cancer 19, 85 (2020)https://doi.org/10.1186/s12943-020-01206-5The Editor-in-Chief has retracted this article. After publication, the authors alerted the journal that there were errors in Figs. 3b, 4j, S2g and S2h, resulting in overlap between images representing different treatment groups. The Editor-in-Chief therefore no longer has confidence in the presented data.Yiran Liang, Xiaojin Song, Yaming Li, Bing Chen, Wenjing Zhao, Lijuan Wang, Hanwen Zhang, Ying Liu, Dianwen Han, Ning Zhang, Yajie Wang, Fangzhou Ye, Dan Luo, Xiaoyan Li and Qifeng Yang agree to this retraction. Tingting Ma has not responded to any correspondence from the editor or publisher about this retraction."} +{"text": "PLOS ONE Editors retract this article [The article because QA agreed with retraction. MH, SI, MBH, MSS, NZ, AR, MUI, TJ, HMA, and MHS did not agree with the retraction. JI and MK either did not respond directly or could not be reached."} +{"text": "MATRC offers technical assistance and other resources within the following mid-Atlantic states: Delaware, District of Columbia, Kentucky, Maryland, North Carolina, New Jersey, Pennsylvania, Virginia and West Virginia.The Mid-Atlantic Resource Center (MATRC; The 2020 MATRC Summit will be held April 5-7, 2020, at The Embassy Suites Charlotte\u2013Concord Golf Resort and Spa, Concord, NC. Attendees need not reside in a mid-Atlantic state. This year's Summit will explore how disruptive technologies and innovations are shaping the future of healthcare. The inter-disciplinary program will feature pre-Summit educational sessions, keynotes, panels, \u201cresearch flash\u201d presentations, state meetings, poster sessions, a hackathon, a telehealth technology showcase, and other exhibits.http://matrcsummit.org/registration.htmlFor further information and registration, visit: Discounted early bird registration will close January 31, 2020."} +{"text": "There remains a need to develop effective medical therapies for patients with microscopic colitis (MC) who do not respond, are intolerant, or relapse on budesonide. Conducting randomized trials in MC is logistically and ethically challenging: budesonide is highly effective, and therefore, some institutional review boards have not allowed trials that randomize MC patients to placebo. However, comparing an investigational drug to budesonide is statistically infeasible: powering a non-inferiority study against a budesonide comparator arm with 90% power for a 10% non-inferiority margin would require over 700 subjects, yet fewer than 400 patients have been randomized in all historical MC trials. Therefore, alternative trial designs should be explored in MC, including the use of a historical control arm.To conduct a systematic review and meta-analysis to determine the proportion of placebo responders in MC trials that will inform future trials using a historical placebo comparator, and evaluate factors associated with placebo response.EMBASE, MEDLINE, and CENTRAL were searched from inception to January 7, 2022, and supplemented with conference abstracts to identify randomized controlled trials (RCTs) using a placebo comparator in adult patients with confirmed MC . The proportion of clinical and histologic responders in the placebo arms were pooled using random-effect models, statistical heterogeneity was evaluated using the I2 method, and the Freeman-Tukey double arcsine transformation was used to compute 95% confidence intervals (CI) using the score statistic and exact binomial method. All analyses were conducted in Stata 17.0.Twelve placebo controlled RCTs were included, evaluating a total of 391 patients (163 randomized to placebo). The pooled placebo clinical response rate was 24.4% , with substantial heterogeneity . The pooled histologic response rate was 19.9% , with substantial heterogeneity . Subgroup analysis demonstrated higher placebo responses in lymphocytic colitis compared to collagenous colitis , but not by allowance of baseline anti-diarrheals. Leave-one-out meta-analysis showed a reduction in heterogeneity after removal of Miehlke et al. 2014 .Approximately 1 in 4 patients in MC trials will respond clinically to placebo and 1 in 5 will demonstrate a histologic response, although with substantial heterogeneity. T his highlights the need for standardized outcome definitions in MC trials and can serve to inform a Bayesian prior estimate for future trials that may consider using a historical placebo comparator.NoneP. Hamilton: None Declared, K. Buhler: None Declared, G. Kaplan Grant / Research support from: Ferring, Janssen, AbbVie, GlaxoSmith Kline, Merck, and Shire, Consultant of: AbbVie, Janssen, Pfizer, Amgen, Takeda, and Gilead, C. Lu Consultant of: Abbvie, Janssen, Ferring, and Takeda, Speakers bureau of: Janssen and Abbvie, C. Seow Consultant of: Advisory Boards: Janssen, Abbvie, Takeda, Ferring, Shire, Pfizer, Sandoz, Pharmascience, Fresenius Kabi, Amgen, Speakers bureau of: Janssen, Abbvie, Takeda, Ferring, Shire, Pfizer, Pharmascience, K. Novak Grant / Research support from: AbbVie and Janssen, Consultant of: Advisory board fees from AbbVie, Janssen, Pfizer, Ferring, and Takeda, speaker\u2019s fees from AbbVie, Janssen, and Pfizer, R. Panaccione Consultant of: Abbott, AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pendopharm, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, UCB. Advisory Boards for: AbbVie, Alimentiv (formerly Robarts), Amgen, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, Glaxo-Smith Kline, JAMP Bio, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, SandozShire, Sublimity Therapeutics, Takeda Pharmaceuticals, Speakers bureau of: AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Eli Lilly, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, Takeda Pharmaceuticals, C. Ma Grant / Research support from: Ferring, Pfizer, Consultant of: AbbVie, Alimentiv, American College of Gastroenterology, Amgen, AVIR Pharma Inc, BioJAMP, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Sanofi/Regeneron, Takeda, Pendopharm, Pfizer, Roche, Speakers bureau of: : AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Takeda, Pendopharm, and Pfizer"} +{"text": "Nature Communications 10.1038/s41467-022-30139-4, published online 04 May 2022.Correction to: In this article the affiliation details for authors Chase C. James, Lisa A. Zeigler, Robert H. Lampe, Ariel Rabines, Anne Schulberg, Hong Zheng, Andrew E. Allen were incorrectly given as \u2018Section of Ecology, Behavior and Evolution, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, United States\u2019 but should have been \u2018J. Craig Venter Institute, 4120 Capricorn Lane, La Jolla, CA 92037, United States\u2019 and the affiliation details for author Andrew D. Barton was incorrectly given as \u2018J. Craig Venter Institute, 4120 Capricorn Lane, La Jolla, CA 92037, United States\u2019 but should have been \u2018Section of Ecology, Behavior and Evolution, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093, United States\u2019. The original article has been corrected."} +{"text": "The original version of this paper did not contain a list of Bio4amb investigators. The purpose of this correction is to acknowledge the contribution of all investigators who participated in the study. The ESM file of the original article has been corrected.Contributors: Bio4amb investigators: Olivier Regnard, Marianne Brodmann, Koen Deloose, Jens Carsten Ritter, Ludovic Berger, Johannes Dahm, Shirley Jansen, Bibombe Patrice Mwipatayi, Joseph Touma, Eric Ducasse, Antoine Millon, S\u00e9bastien Veron, Raphael Coscas, Eric Steinmetz, Fabrice Schneider, Lieven Maene, Bahaa Nasr, Gilles Miltgen, Vikram Puttaswamy, J\u00fcrgen Torsten Verbist, Jonathan Sobocinski, Armand Bourriez, Mark Jackson, Laurent Casbas, Didier Paneau, Isabelle Bayens, Klaus Hausegger, David Lambrechts, Adrien Kaladji, Flemming Randsbaek, Pierre Jules Delannoy, Manfred Spanger, Jos C. van den Berg."} +{"text": "Staphylococcus epidermidis, 53 other coagulase-negative staphylococci (CoNS), 3 S. aureus, and 66 Gram-negative isolates consisting of Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii.PLG0206 is a novel engineered cationic antimicrobial peptide being evaluated for treatment of prosthetic joint infections. In this study, the activity of PLG0206 was evaluated by broth microdilution against 104 isolates of Imipenem, levofloxacin, tigecycline, linezolid, vancomycin, oxacillin, ceftazidime, colistin, and amikacin were tested as comparators. Testing was conducted in accordance with guidelines from the Clinical and Laboratory Standards Institute . Test organisms consisted of reference strains from the American Type Culture Collection, the Centers for Disease Control Antibiotic Reference Bank and clinical isolates from the Micromyx repository. The media employed for testing in the broth microdilution MIC assay for all organisms were cation-adjusted Mueller Hinton Broth and for PLG0206 only included RPMI-1640 medium supplemented with 0.002% P-80.S. aureus, and resistant Gram-negative* pathogens are shown in Table.Activity of PLG0206 in RPMI against CoNS, Activity of PLG0206 in RPMI against CoNS, S. aureus and resistant Gram-negative* pathogensActivity of PLG0206 in RPMI against CoNS, S. aureus and resistant Gram-negative* pathogensPLG0206 was found to have potent antimicrobial activity when evaluated in RPMI against S. epidermidis, CoNS non-epidermidis, S. aureus, Enterobacterales, P. aeruginosa, and A. baumannii, including isolates with multi-drug resistance.David Huang, MD, PhD, Peptilogics (Employee) Jonathan Steckbeck, PhD, Peptilogics (Employee) Chris Pillar, PhD, Micromyx (Employee) Bev Murray, BS, Micromyx (Employee) David Huganfel, BS, Micromyx (Employee) Dean Shinabanger, PhD, Micromyx (Employee)"} +{"text": "For many traits, males show greater variability than females, with possible implications for understanding sex differences in health and disease. Here, the ENIGMA Consortium presents the largest\u2010ever mega\u2010analysis of sex differences in variability of brain structure, based on international data spanning nine decades of life. Subcortical volumes, cortical surface area and cortical thickness were assessed in MRI data of 16,683 healthy individuals 1\u201090\u2009years old . We observed significant patterns of greater male than female between\u2010subject variance for all subcortical volumetric measures, all cortical surface area measures, and 60% of cortical thickness measures. This pattern was stable across the lifespan for 50% of the subcortical structures, 70% of the regional area measures, and nearly all regions for thickness. Our findings that these sex differences are present in childhood implicate early life genetic or gene\u2010environment interaction mechanisms. The findings highlight the importance of individual differences within the sexes, that may underpin sex\u2010specific vulnerability to disorders. This seMany prior studies report sex differences in brain structure, but the specificity, regional pattern and functional relevance of such effects are not clear of participants aged 1 to 90\u2009years was included. We investigated subcortical volumes and regional cortical surface area and thickness. Our first aim was to replicate previous findings of greater male variability in brain structure in a substantially larger sample. Based on prior studies Lifespan working group was estimated by dividing variance measures for males and females. VR was log transformed to account for VR bias is an indicator function that is 1 when Tb\u2009\u2265\u2009T, and 0 otherwise. Thus, the p\u2010value is the proportion of permuted test statistics (Tb) that were greater than the observed value T of the test statistic above. Here B was set to 10,000. FDR corrected values are reported as significant.where 2.6q be a probability between 0 and 1. The quantile function specifies the values at which the volume of a brain measure will be at or below any given q. The quantile function for males is given as Q and for females as Q. The quantile distance function is then defined as:To assess the nature of the variability difference between males and females, shift functions were estimated for each brain measure that showed significant variance differences between males and females using quantile regression forests age by sex interaction effect using a linear model 1 and quadratic model 2:The absolute value of 2.8Inter\u2010regional anatomical associations were assessed by defining the correlation between two brain structures, after accounting for age and other covariates as described above. Anatomical correlation matrices were estimated as previously applied in several structural MRI studies for males and females separately ranging from 0.41 (left accumbens) to 0.92 , and an average effect size of 0.7. In follow\u2010up analyses with total brain volume as an additional covariate we found a similar pattern, although effect sizes were smaller age. As a background analysis, we first assessed whether brain structural measures showed mean differences between males and females to align our findings to previous reports Figure\u00a0, Table\u00a02 smaller . Also fo smaller . Cortica smaller .We then tested for sex differences in variance of brain structure, adjusted for cohort, field strength, FreeSurfer version and (non\u2010linear) age Figure\u00a0. All subd\u2010values , but no significant relation for regional cortical surface area (r (66) =\u20090.18, p\u2010value = .14), or thickness (r (66) = \u20100.21, p\u2010value = .09).Next, we directly tested whether the regions showing larger variance effects were also those showing larger mean differences, by correlating the variance ratios with the vector of 3.2In order to characterise how the distributions of males and females differ, quantiles were compared using a shift function , the significance of correlation differences between males and females was assessed.X2 =\u200910.889, p < .001. For surface area, no significant difference between males and females were observed: significantly stronger male homogeneity was observed in 4% of the 2,278 unique anatomical correlations, and similarly females also showed significantly stronger correlations in 4% of the anatomical associations =\u2009460.300, p < .001.Of the 91 subcortical\u2010subcortical correlation coefficients, 2% showed significantly stronger correlations in males, while, unexpectedly, 19% showed stronger correlations in females (tested two\u2010sided) Figure\u00a0. A chi\u2010ss Figure\u00a0. For this Figure\u00a0. This di4In this study, we analyzed a large lifespan sample of neuroimaging data from 16,683 participants spanning nine decades of life starting at birth. Results confirmed the hypothesis of greater male variability in brain structure , episodic memory (hippocampus), and multimodal sensory integration , and the neural embedding of social influences during the life span and the investigation of variance effects. These points are important, as most observed mean sex differences in the brain are modest in size (Joel and Fausto\u2010Sterling\u00a0http://enigma.ini.usc.edu/protocols/imaging-protocols/), which involve a combination of statistical outlier detection and visual quality checks and a similar number of males and females had partially missing data , we cannot exclude the possibility that in\u2010scanner subject movement may have affected the results. Nevertheless, we do not think this can explain our finding of greater male variance in brain morphometry measures, as this was seen at both the upper and lower ends of the distributions.The current study has some limitations. First, the multi\u2010site sample was heterogeneous and specific samples were recruited in different ways, not always representative of the entire population. Furthermore, although structural measures may be quite stable across different scanners, the large number of sites may increase the variance in observed MRI measures, but this would be unlikely to be systematically biased with respect to age or sex. In addition, variance effects may change in non\u2010linear ways across the age\u2010range. This may be particularly apparent for surface area and subcortical volume measures, as these showed pronounced non\u2010linear developmental patterns through childhood and adolescence sex differences in brain structure. Furthermore, the results of decreasing sex differences in variance across age opens a new direction for research focusing on lifespan changes in variability within sexes. Our findings of sex differences in regional brain structure being present already in childhood may suggest early genetic or gene\u2010environment interaction mechanisms. Further insights into the ontogeny and causes of variability differences in the brain may provide clues for understanding male biased neurodevelopmental disorders.1, Flyckt L1, Engberg G2, Erhardt S2, Fatouros\u2010Bergman H1, Cervenka S1, Schwieler L2, Piehl F3, Agartz I1,4,5, Collste K1, Sellgren CM2, Victorsson P1, Malmqvist A2, Hedberg M2, Orhan F2. 1 Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, & Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden; 2 Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden; 3 Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; 4 NORMENT, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway; 5 Department of Psychiatry, Diakonhjemmet Hospital, Oslo, Norway.Members of the Karolinska Schizophrenia Project (KaSP) consortium: Farde LThe authors declare the following competing interests: OAA: Speaker's honorarium from Lundbeck, Consultant of HealthLyti; PA: Received payments for consultancy to Shire/Takeda, Medic, educational/research awards from Shire/Takeda, GW Pharma, Janssen\u2010Cila, speaker at sponsored events for Shire, Flynn Pharma, Medic; TB: advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm, conference support or speaker's fee by Lilly, Medice, and Shire, received royalities from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press \u2010 the present work is unrelated to the above grants and relationship; DB: serves as an unpaid scientific consultant for an EU\u2010funded neurofeedback trial that is unrelated to the present work; HB: Advisory Board, Nutricia Australi; CRKC: received partial research support from Biogen, Inc. for work unrelated to the topic of this manuscript; BF: received educational speaking fees from Medice; HJG: received travel grants and speakers honoraria from Fresenius Medical Care, Neuraxpharm, Servier and Janssen Cilag as well as research funding from Fresenius Medical Care; NJ and PMT: MPI of a research related grant from Biogen, Inc., for research unrelated to the contents of this manuscript; JK: given talks at educational events sponsored by Medic; all funds are received by King's College London and used for studies of ADHD; DM\u2010C: receives fees from UpToDate, Inc and Elsevier, all unrelated to the current work; AMM: received research support from Eli Lilly, Janssen, and the Sackler Foundation, and speaker fees from Illumina and Janssen; DJS: received research grants and/or honoraria from Lundbeck and Sun. The remaining authors declare no competing interests.Cohort PI/ENIGMA core: DD, IA, OAA, PA, TB, AB, DIB, SB, DB, HB, GFB, DMC, XC, TMCA, CRKC, VPC, PJC, AC, DvE, SEF, BF, ADG, DCG, IHG, HJG, OG, PG, REG, RCG, LdH, BJH, PJH, OAvdH, FMH, HEHP, CH, NJ, JAJ, AJK, JK, LL, ISL, CL, NGM, DM\u2010C, BM, BCM, CMcD, AMM, KLM, JMM, LN, JO, PP, EP\u2010C, MJP, JR, JLR, PGPR, MDS, PSS, TDS, AJS, KS, AS, JWS, IES, CS\u2010M, AJS, DJS, SIT, JNT, DJV, HW, YW, BW, LTW, HCW, SCRW, MJW, MVZ, GIdZ, YW, PMT, EAC, SF. Image data collection: IA, TNA, AA\u2010E, KIA, PA, SB, RB\u2010S, AB, AB, SB, JB, AdB, AB, VDC, XC, FXC, TMCA, VPC, AC, FC, CGD, DvE, PF\u2010C, EJCdG, ADG, DCG, IHG, HJG, PG, REG, LdH, BH, BJH, SNH, IBH, OAvdH, IBB, CAH, DJH, SH, AJH, MH, NH, FMH, CH, ACJ, EGJ, AJK, KKK, JL, LL, LdH, ISL, CL, MWJM, BM, BCM, YW, CMcD, AMM, GM, JN, YP, PP, GP, EP\u2010C, JR, SS, AR, GR, JLR, PSS, RS, SS, TDS, AJS, MHS, KS, AS, LTS, PRS, AST, JNT, AU, N, HV, LW, YW, BW, WW, JDW, LTW, SCRW, DHW, YNY, MVZ, GCZ, EAC. Image data processing/quality control: GED, MA, TNA, AA\u2010E, DA, KIA, AA, NB, SB, SE, AB, JB, AdB, RMB, VDC, EJC\u2010R, XC, FXC, CRKC, AC, CGD, EWD, SE, DvE, JPF, PF\u2010C, ADG, DCG, IHG, PG, TPG, BJH, SNH, OAvdH, AJH, MH, CH, ACJ, JJ, LK, BK, JL, ISL, PHL, MWJM, SM, IM\u2010Z, BM, BCM, YW, GM, DvdM, JN, RS, EJC\u2010R, YP, JR, GR, MDS, RS, TDS, KS, AS, LTS, PRS, SIT, AST, AU, IMV, LW, YW, WW, JDW, SCRW, KW, DHW, YNY, CKT. Manuscript revision: GED, IA, MA, AA\u2010E, PA, AB, HB, RMB, JKB, VDC, EJC\u2010R, XC, AC, CGD, DD, SE, PF\u2010C, EJCdG, ADG, DCG, IHG, HJG, REG, RCG, TPG, BH, BJH, CAH, OAvdH, AJH, NH, FMH, ACJ, EGJ, JAJ, MK, JL, PHL, CL, DM\u2010C, BM, BCM, AMM, DvdM, YP, GP, EP\u2010C, MJP, JR, GR, PSS, RS, AJS, KS, AS, DJS, HST, AST, JNT, AU, N, HV, BW, LTW, KW, DHW.LMW developed the theoretical framework and prepared the manuscript with support from GED, PMT, EAC, SF, and CKT. LMW designed the models and scripts, GED and SF analyzed the data. All sites processed the imaging data and conducted quality control. GD, DD, and SF brought together and organized the datasets. Appendix S1: Supplementary InformationClick here for additional data file.Supplemental Figure 1. Boxplot visualization of comparison of Right hippocampal volume, and parahippocampal surface area and thickness before and after adjustment. As age ranges differed for each cohort adjustments were performed in two steps: initially, a linear model was used to account for cohort and non\u2010linear age effects. Next, random forest regression modelling was used to additionally account for field strength and FreeSurfer version. In the Left panel, volumes were not adjusted, this displays the raw data for each cohort. In the Right panel, volumes were adjusted.Click here for additional data file.Supplemental Figure 2. Correlation between variance ratio and vector of d\u2010values for each region. Results show a significant association for subcortical volumes (Left), but no significant relation for regional cortical surface area (middle), or thickness (Right).Click here for additional data file.Supplemental Figure 3: (A) Sex differences in variability interacted with age in 50% of the subcortical volumes. Absolute residual values are modeled across the age range. Effects showed larger male than female variance in the younger age group, and a general trend of decreasing sex differences in variance with increasing age. (B) Sex differences in variability interacted with age in 30% of cortical surface area measures. Absolute residual values are modeled across the age range. Effects showed larger male than female variance in the younger age group, and a general trend of decreasing sex differences in variance with increasing age.Click here for additional data file.Supplementary Table 1. Screening Process and Eligibility Criteria, Scanner, Image Acquisition Parameters and Image Segmentation SoftwareClick here for additional data file.Supplementary Table 2. Supplementary Tables.Click here for additional data file."} +{"text": "Sarcopenia and muscle wasting are not just innocent bystanders in abdominal sepsis but play a significant role in determining patient outcome.Cachexia and sarcopenia have already been established as risk factors for unfavourable clinical outcomes in chronic disease; we are however still gaining a better understanding of the relevance of acute muscle loss in acute abdominal sepsis. Cox No funding involved.Catherine S. Reid, Vanessa M. Banz, Joerg C. Schefold, and Markus M. Luedi helped in writing the article.Catherine S. Reid reports no conflicts of interest, Vanessa M. Banz reports no conflicts of interest, and Joerg C. Schefold reports grants unrelated to the submitted work from Orion Pharma, Abbott Nutrition International, B. Braun Medical AG, CSEM AG, Edwards Lifesciences Services GmbH, Kenta Biotech Ltd., Maquet Critical Care AB, Omnicare Clinical Research AG, Nestle, Pierre Fabre Pharma AG, Pfizer, Bard Medica S.A., Abbott AG, Anandic Medical Systems, Pan Gas AG Healthcare, Bracco, Hamilton Medical AG, Fresenius Kabi, Getinge Group Maquet AG, Dr\u00e4ger AG, Teleflex Medical GmbH, Glaxo Smith Kline, Merck Sharp and Dohme AG, Eli Lilly and Company, Baxter, Astellas, Astra Zeneca, CSL Behring, Novartis, Covidien, Philips Medical, Phagenesis Ltd., Prolong Pharmaceuticals, and Nycomed. The money was added to departmental funds. No personal financial gain applied. Markus M. Luedi reports no conflicts of interest."} +{"text": "Bone Marrow Transplantation 10.1038/s41409-020-0854-0, published online 17 March 2020Correction to: http://creativecommons.org/licenses/by/4.0. Open access funding was enabled and organized by Projekt DEAL.The article \u201cMyeloablative conditioning for allo-HSCT in pediatric ALL: FTBI or chemotherapy?\u2014A multicenter EBMT-PDWP study,\u201d written by Andre Manfred Willasch, Christina Peters, Petr Sedl\u00e1\u010dek, Jean-Hugues Dalle, Vassiliki Kitra-Roussou, Akif Yesilipek, Jacek Wachowiak, Arjan Lankester, Arcangelo Prete, Amir Ali Hamidieh, Marianne Ifversen, Jochen Buechner, Gergely Kriv\u00e1n, Rose-Marie Hamladji, Cristina Diaz-de-Heredia, Elena Skorobogatova, G\u00e9rard Michel, Franco Locatelli, Alice Bertaina, Paul Veys, Sophie Dupont, Reuven Or, Tayfun G\u00fcng\u00f6r, Olga Aleinikova, Sabina Sufliarska, Mikael Sundin, Jelena Rascon, Ain Kaare, Damir Nemet, Franca Fagioli, Thomas Erich Klingebiel, Jan Styczynski, Marc Bierings, K\u00e1lm\u00e1n Nagy, Manuel Abecasis, Boris Afanasyev, Marc Ansari, Kim Vettenranta, Amal Alseraihy, Alicja Chybicka, Stephen Robinson, Yves Bertrand, Alphan Kupesiz, Ardeshir Ghavamzadeh, Antonio Campos, Herbert Pichler, Arnaud Dalissier, Myriam Labopin, Selim Corbacioglu, Adriana Balduzzi, Jacques-Emmanuel Galimard, Peter Bader, on behalf of the EBMT Paediatric Diseases Working Party, was originally published online first without Open Access. After publication in volume 55, issue 8, page 1540\u20131551, the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to \u00a9 The Author(s) 2020 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 InternationalS License, which permits use, sharing, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third-party material in this article are included in the article\u2019s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article\u2019s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit"} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-02678-1, published online 02 December 2021Correction to: The original version of this Article contained an error in Affiliation 2, which was incorrectly labelled as a present address.As a result, this affiliation was incorrectly captured for Gen Kobashi. The correct affiliations are listed below.Integrated Research Faculty for Advanced Medical Sciences, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, JapanDepartment of Public Health, Dokkyo Medical University School of Medicine, Tochigi, 321-0293, JapanThe original Article has been corrected."} +{"text": "See, forexample, ref (In addition, following the initial appearanceof this work, werealized that the hydride transfer converting ple, ref ."} +{"text": "Aparapotamon Dai & Chen, 1985 are described from Yunnan Province, southwest China. Morphological comparisons were made between the two new species and type materials of other 11 species of Aparapotamon. Aparapotamonbinchuanensesp. nov. and A.huizeensesp. nov. can be separated from their congeners by the shape of the epibranchial tooth, the frontal view of the cephalothorax, the male first gonopod, and the female vulvae. The molecular analyses based on partial mitochondrial 16S rRNA gene are also included. This study brings the number of Aparapotamon species to 13.Two new species of freshwater crab of the genus Potamid Potamidae Ortmann, 1896 spend their whole life history in freshwater or terrestrial environments , Lawu Town, Binchuan County, Dali Bai Autonomous Prefecture, Yunnan Province and Yue Huang from Zebu Village , Nagu Town, Huize County, Qujing City, Yunnan Province, respectively. All materials were preserved in 95% ethanol and deposited in the Department of Parasitology of the Medical College of Nanchang University, Jiangxi, China (NCU MCP). Carapace width and length were measured in millimeters. The abbreviation of G1 and G2 are for male first gonopod and the male second gonopod, respectively. The terminology used primarily follows that of Specimens were collected by Han Dai from Biji Village . Comparative materials are as follows:We compared two new species with type materials of other eleven species of Aparapotamon arcuatum Dai & Chen, 1985: Holotype, CAS CB 05091, 1\u2642, China, Yunnan Province, Lijiang City, Ninglang Yi Autonomous County, Daxing Town, 14 Aug 1981; NCU MCP 4032, 1\u2642, China, Yunnan Province, Lijiang City, Yongsheng County, Yangping Yi Autonomous Town, 6 Jul 2017.Aparapotamon emineoforaminum Dai & Chen, 1985: Holotype, CAS CB 05090, 1\u2642, China, Sichuan Province, Liangshan Yi Autonomous Prefecture, Mianning County, Jionglong Town, Aug 1982.Aparapotamon gracilipedum Chen & Chang, 1982: Holotype, CAS CB 05148, 1\u2642, China, Henan Province, Luoyang City, Luanchuan County, Chenguan Town, 20 Sep 1978.Aparapotamon grahami Rathbun, 1929: CAS CB 00142, 1\u2642, China, Hubei Province, Nanyang City, 1977; CAS CB 00150, 1\u2642, China, Shannxi Province, Ankang City, Zhenping County, 16 Jul 1978; NCU MCP 4057, 1\u2642, China, Chongqing City, Wulong County, Dadonghe Town, 24 Jun 2018; NCU MCP 4241, 1\u2642, China, Yunnan Province, Kunming City, 31 Aug 2019.Aparapotamon huiliense Dai & Chen, 1985: Holotype, CAS CB 05089, 1\u2642, China, Sichuan Province, Liangshan Yi Autonomous Prefecture, Huili County, 2 Jun 1982; NCU MCP 4027, 1\u2642, China, Yunnan Province, Lijiang City, Huaping County, Zhongxin Town, Zuofang Village, 5 Jul 2017.Aparapotamon inflomanum Dai & Chen, 1985: Holotype, CAS CB 05096, 1\u2642, China, Yunnan Province, Diqing Zang Autonomous Prefecture, Zhongdian County, Sanba Town, 8 Sep 1981.Aparapotamon molarum Dai & Chen, 1985: Holotype, CAS CB 05094, 1\u2642, China,Yunnan Province, Lijiang City, Yulong Naxi Autonomous County, Jade Dragon Snow Mountain, 28 Aug 1981.Aparapotamon muliense Dai & Chen, 1990: Holotype, CAS CB 05088, 1\u2642, China, Sichuan Province, Liangshan Yi Autonomous Prefecture, Muli Zang Autonomous County, Xiaojin River, 5 Dec 1984.Aparapotamon protinum Dai & Chen, 1985: Holotype, CAS CB 05093, 1\u2642, China, Yunnan Province, Lijiang City, Yongsheng County, Songping Town, 22 Aug 1981.Aparapotamon similium Dai & Chen, 1985: Holotype, CAS CB 05095, 1\u2642, China, Yunnan Province, Lijiang City, Yongsheng County, Renli Town, 22 Aug 1981; NCU MCP 4031, 1\u2642, China,Yunnan Province, Lijiang City, Ninglang Yi Autonomous County, Paomaping Town, 6 Jul 2017.Aparapotamon tholosum Dai & Chen, 1985: Holotype, CAS CB 05092, 1\u2642, China, Yunnan Province, Lijiang City, Yongsheng County, Chenguan Town, 22 Aug 1981; NCU MCP 4034, 1\u2642, China, Yunnan Province, Dali Bai Autonomous Prefecture, Binchuan County, Zhoucheng Town, 5 Jul 2017.Institutional abbreviations used in the paper are as follows:CAS CBChinese Academy of Sciences, Beijing, China;NCHUZOOLZoological Collections of the Department of Life Science, National Chung Hsing University, Taichung, Taiwan;NCU MCPDepartment of Parasitology of the Medical College of Nanchang University, Jiangxi, China;NNU College of Life Sciences, Nanjing Normal University, Nanjing, China;SYSBM Sun Yat-sen Museum of Biology, Sun Yat-Sen University, Guangzhou, China;ZRCZoological Reference Collection of the Raffles Museum of Biodiversity Research, National University of Singapore, Singapore.The pereiopod muscle tissue was extracted from specimens of the new species with a DP1902 Tissue Kit (BioTeKe Inc. Beijing). Partial mitochondrial 16S rRNA gene sequences were obtained by PCR amplification with the primers 1471 (5\u2019-CCTGTTTANCAAAAACAT-3\u2019) and 1472 (5\u2019-AGATAGAAACCAACCTGG-3\u2019) . The parBI and ML phylogenetic trees, including those of 27 species in 22 genera of potamids (Table BI) analysis was determined by MrModeltest ver. 2.3 (AIC). The obtained model was GTR+I+G. MrBayes 3.2.6 analysis was HKY+G, determined by MEGA X , China, Yunnan Province, Dali Bai Autonomous Prefecture, Binchuan County, Lawu Town, 25\u00b053'34\"N, 100\u00b055'30\"E, alt. 1658 m, 10 Aug 2010, Han Dai leg. Paratypes: NCU MCP 170702, NCU MCP 170704, NCU MCP 170705, 3\u2642\u2642 and NCU MCP 170703, NCU MCP 170706, NCU MCP 170707, 3\u2640\u2640 , same data as holotype.G1 slender, distal end tapering, distinctly bent. G2 basal segment ovate, tip of terminal segment laterally flattened.Carapace trapezoidal, regions defined. External orbital angle triangular, postorbital cristae convex, postfrontal lobe prominent. Cervical groove indistinct, H-shaped groove conspicuous. Epibranchial tooth blunt, anterolateral margin lined with numerous granules. Third maxilliped exopod without flagellum. Adult male and female chelipeds slightly unequal. Ambulatory legs relatively slender. Male sterno-pleonal cavity deep, median longitudinal groove between sternites 7/8 long. Male pleon narrow triangular, telson triangular. Vulva small, ovate, located close to each other at anterior part of sternites 6, posterior margin not convex. Carapace width 1.25 \u00d7 length (n = 7), regions defined; dorsal surface slightly convex Figs , 3A. ExtThird maxilliped exopod without flagellum, claviform, reaching proximal 1/3 of merus lateral margin Figs , 2B, E. Chelipeds slightly unequal in both adult male and female, right cheliped larger Fig. . Palm ofMale thoracic sternum punctate, formed by tidy depression; sternites 1\u20134 broad, sternites 1/2 completely continuous; suture 2/3 complete, transverse; suture 3/4 visible, mesially reaching distolateral part of sterno-pleonal cavity Fig. . Male stG1 slender; terminal segment claviform, distal end tapering, distinctly bent, inner margin arc-shaped, outer margin straight, dorsal lobe barely visible in ventral view , China, Yunnan Province, Qujing City, Huize County, Nagu Town, Zebu Village, 26\u00b030'41\"N, 103\u00b010'25\"E, alt. 1954 m, 25 Aug 2011, Yue Huang leg. Paratypes: NCU MCP 179802, 1\u2642 (26.9 \u00d7 21.9 mm) and NCU MCP 179803\u2013179808, 6\u2640\u2640 , same data as holotype.G1 very slender, dorsal lobe well developed, exceeding suture 4/5 in situ, G2 basal segment ovate, tip of terminal segment round.Carapace trapezoidal, dorsal surface slightly convex, regions defined. External orbital angle round, separated from anterolateral margin, postorbital cristae convex, postfrontal lobe prominent. Cervical groove shallow, H-shaped groove distinct, especially in female specimen. Epibranchial tooth distinct, especially in female specimen. Third maxilliped exopod without flagellum. Ambulatory legs slender. Male pleon broad triangular, telson triangular, apex rounded. Vulva ovate, covering anterior half of sternite 6, with the posterior margin distinctly convex. Carapace width 1.25 \u00d7 length (n = 8), regions distinctly defined; dorsal surface slightly convex, anterolateral and frontal region covered with conspicuous round granules Fig. . ExternaThird maxilliped exopod without flagellum, claviform, reaching proximal 1/3 of merus lateral margin Figs , 6B. IscMale thoracic sternum punctate, formed by tidy depression; sternites 1\u20134 broad, sternites 1/2 completely continuous; suture 2/3 complete, transverse; suture 3/4 visible, mesially reaching distolateral part of sterno-pleonal cavity Fig. . Male stG1 very slender; terminal segment claviform, slightly bent distally, inner margin arc-shaped, outer margin straightly, dorsal lobe well developed and gonopod pore located in it for further phylogenetic studies of this genus. If the results of other makers indicate that the genetic distance between Aparapotamon is also too small compared to other freshwater crab genera, revision of Aparapotamon is necessary.In this study, 30 sequences of 16S rRNA gene from 27 species of 22 genera were used to performed phylogenetic analyses. Since the two new species cluster with other ade Fig. , the phyent Fig. [vs. terent Fig. ]. In thiAparapotamon were clustered into one clade. And Aparapotamon cluster with other genera from Yunnan form \u2018Yunnan\u2019 clade. The genera in the branch of \u2018Yunnan\u2019 have many similarities in terms of morphological structure, such as the G1 slender, the terminal segment is longer than the half of subterminal segment, third maxilliped exopod without flagellum, and the ability to live at an altitude of 1500\u20132900 meters (A.molarum were collected at Baishui River, Yulong Naxi Autonomous County, Lijiang City, Yunnan Province at an altitude of 2910 meters, which is the highest altitude at which freshwater crab specimens have been discovered in China so far (The present molecular results show five species of 0 meters . Specimea so far ."} +{"text": "Proceratophrys Miranda-Ribeiro, 1920, which is widely distributed in South America. P. cristiceps distribution is limited to the Caatinga biome in Brazil. We examined its chromatic variation from a populational perspective, looking at different phenetic polymorphism levels and probable chromotypic association by applying statistical and GIS tools that could facilitate future taxonomic research regarding this and other species. We characterized P. cristiceps colour patterns and re-evaluated its geographic variation, highlighting potential consequences for the taxonomy of the genus. Our results revealed six principle chromotypes whose frequencies varied among sex and ontogenetic classes. Phenotypic expression appeared to respect defined proportions and evidenced selective value for the species. We conclude that individual variation, together with typological traditionalism may overestimate the polymorphic magnitude at the population level and cause taxonomic inflation. Our data support the usefulness of P. cristiceps as a model for microevolutionary studies.Quantifying variability is important for understanding how evolution operates in polymorphic species such as those of the genus Morphological variation plays a fundamental role in the evolution of species. Although not all characteristics are heritable, natural selection can potentially act on those that are transmissible to new generations . UnderstProceratophrys.Such studies seek, in principle, to understand the origin of biodiversity, and how it can be accessed from the recognizable and comparable differences and similarities among organisms. Assessing morphological variation in an operationally adequate approach making use of different techniques, methods, or philosophies has proven to be a huge challenge by taxonomic, or even conservationist, criteria , principProceratophrysCeratophrys Wied-Neuwied, 1824, and often placed within the same genus ; P. cristiceps and P. renalis along defined geographic gradients that could corroborate or bring into question certain taxonomic proposals. We also attempt to heuristically explain the origin of the variability found, and produce information that could facilitate identifying the species and their congeners, and thus favour future studies of the ecology, biogeography and systematics of the genus\u2014as well as of other species.In light of the importance of populational polymorphism in taxonomic and evolutionary research, we have sought to precisely examine the chromatic variation in our model organism, Proceratophrys cristiceps specimens from 37 localities were analyzed (Appendix). All the individuals were available in the Animal Ecophysiology Laboratory (UFPB) and the Herpetological Collection of the Universidade Federal da Para\u00edba (CHUFPB). The taxonomic identities of the samples were verified by consulting descriptions and diagnoses consistent with each suggested post-larval developmental phase , whose cProceratophrys cristiceps specimens was performed based on the standardisation suggested by the colour catalogue for field herpetologists were immersed in water to enhance the contrasts of their spots, stripes, and colouration under both natural and artificial light. That technique improved pattern identification as well as the descriptions and classifications of possible chromotypes.The chromatic characterization of both living and preserved ologists to decreP. cristiceps were recorded as digital images . All image captures were made at the same distance (25 cm) from the specimens with the camera lens in a horizontal position (using flash and a white background to highlight contrasts). We considered the numbers and sizes of the dark spots on the dorsal surface of the body of each specimen (2) even the smallest spots (by gradient), considering the total body area of each specimen tested in recognized populations. With that in mind, we attempted to identify different forms of variability in our samples and test them within and among the chromatic observed categories.Proceratophrys cristiceps were tested using multiway ANOVA with unequal replications and the Kruskal\u2013Wallis test, the latter being indicated for samples with unknown distributions. Comparisons among frequency proportions were achieved through cross-tabulation and were carried out using Pearson\u2019s Chi-square tests. That representation was found to be very informative, enabling us to re-examine the data in a simplified manner (line plots).The morphometric and chroThe collection localities were accepted here as true populations for strictly operational reasons. This was done with the intention of producing sub-samples, presumably considered as distinct populations separated by geographical gaps of relative lengths . The predemes\u201d , without necessarily supporting any possible taxonomic distinction at the species level, but conferring a particular identity .We therefore decided to identify presumed breeding cross sets to mitigate methodological eventualities, or the \u201cdemes\u201d . Accordin = 6) to access part of the variability of the presumed populations (the phenons) through certain attributes (see below). We established 15 individuals per location as the minimum sample size due to circumstantial and operational limitations. We considered here a statement of the central limit theorem . The choice of the number of dimensions was determined by the traditional scree test and the symmetry of the multivariate population distributions prior to the analyses and S3. demes, we collected information on several explanatory variables such as vegetation cover; climate, following the K\u00f6ppen\u2013Geiger classification by including them in a relatively larger prediction compared to Maxent in GCS WGS 1984 projections.Our predictions were generated through the information available in the WorldClim portal (Version 2.1), which were scenopoetic variables (temperatures and precipitation) with a range of annual means from 1970 to 2000 . All theProceratophrys. We tested the functionality of the information provided by the authors (see below) by comparing them to each other and with the phenotypic traits of our samples P. cristiceps individuals. We also checked the types of taxonomic features, and counted how many times they were applied by different authors (to different species). When one of those characteristics was recognized in our samples, or among the different authors, we could then verify the ambiguity of that phenetic trait. Our objective was to verify if identical diagnostic features could be found among distinct species (refutability principle). We constructed a matrix of meristic variables according to the frequency of the characteristics used. Next, we produced a set of common values from the available data based on six phenetic variables: colour; bone (considering the description of the head form); tissue ; measurements; sonogram and genetics (including karyotype).We analyzed the ambiguity and the frequencies of the diagnostic characteristics commonly used at the taxonomic level within the genus k groups, so that the sets were brought together in a greater order of similarity : brown bichromatic colouration in diverse hues (C22\u2013C25) on a tawny olive and drab brown background (C17 and C19), whose spots or stripes, sometimes distributed in a well-defined direction, impede the recognition of a characteristic dorsal geometric figure\u2014\u201carrowhead\u201d : similar to chromotype 1 in terms of having brown colouration and suborbital or interorbital bands , however, there is a well-defined dorsal geometric figure laterally limited by dark bands (maroon\u2014C38) in the orbit-cloaca direction. There are also lighter nuances on the flanks and on the limbs, stomach and snout (cyan white\u2014C155). Usually occuring in leaf litter (97.02%) or gravel (2.98%);Chromotype 2 : with very clear brown-grey colouration, and slightly variegated (C256 to C259). Evident dorsal geometric figure and yellow-brown colouration (C84), distributed in the orbit-cloaca direction; limited by two bands (in opposing toothed arches) and lines of semi-parallel glandular nodules. Single interocular stripe and two well-defined suborbital stripes. May have discrete rusty tones (C253) in the supraocular portions and sides of the body. Generally occurring in earthy soil with sparse leaf litter (92.83%);Chromotype 3 : with evident trichromatic colouration, whose rusty red hue (C35 and C253) cover a large part of the body. Clear dorsal geometric figure with a pale-yellow colouration (C2 and C3), laterally limited by regular dark bands (C30) in an orbit-cloaca direction. Suborbital stripes are not clearly evident; presence of only one interocular stripe. A pineal spot present. There are also white hues (C155 and C261) in the lateral portions of the body and limbs, similar to Chrom2. Generally inhabiting sandy soils (6.25%), grit or gravel (93.75%);Chromotype 4 : general colouration monochromatic as compared to the others chromotypes, generally with rusty red hues (C57 and C58) or yellow-brown characteristic (C17). Barely visible spots or streaks. Generally occurs in grit or gravel (93.30%);Chromotype 5 : general brown-grey colouration (C19) with diverse nuances, with evident yellow-brown spots (or lighter hues C12 and C111) distributed in characteristic areas: snout and suprascapula. The dorsal geometric figure is laterally outlined by spots in a toothed arch shape, although not well defined. Generally inhabiting earthy or sandy soils (81.26%) and even in leaf litter (18.74%).Chromotype 6 (P. cristiceps (\u224814:43:6:9:8:20), which was also maintained internally among the samples and localities . The Chrom5 individuals found studied here were less saturated than the others , with a 2) was greater in females; they were also more saturated than those of the males , but those variations were absent in juveniles and even in sub-adults \u2013S11. Maldemes, and they were not easily explained by the environmental predictors. Geographically supported and consistent groups were produced, however, when the multidimensional scaling diagram was associated with the phenetic trait diversity mapping. The results indicated Almas and S\u00e3o Mamede; Serra Talhada and Caic\u00f3; Junco and Jaguaribe; Cabaceiras and S\u00e3o Jo\u00e3o do Cariri as markers of zones with shared phenons found in tegories , phenotytegories and is rtegories .demes (understood herein as conglomerate populations) that were morphometrically smaller (on the average) in the north-western (hotter and drier) regions of the Caatinga. The most likely explanation for that observation would involve temperature-associated effects is difficult to approach experimentally, and taxonomic studies often view operational morphological units (OMUs) as different sub-species or even species. There are also underlying factual requirements necessary to explain the morphological divergence and the alleged taxonomic diversity , which inhabits open and dry environments in the Cerrado and Caatinga (Proceratophrys cristiceps (and other species of the genus) has been studied and debated for decades characteristics for all species in the as well) \u2014suggestiOur observations, for example, indicated that nodules (including warts and tubercles) are extremely variable in terms of numbers, shapes and distributions, either isolated or regionally, on the same individual or among specimens and S17.Another common characteristic used in descriptions of these species are the rows of opposite oculum-dorsal nodules and their associated spots and stripes. Those rows appear to be important in forming the arrowhead shape of the dorsal design . This shi.e., disregarding probable variation) is that species descriptions may not be sustainable in reality : UFPB12112, UFPB12114, UFPB12115, UFPB12116, UFPB12118, UFPB12124. Santa Terezinha : CHUFPB24169. CEAR\u00c1| Crato : CHUFPB19690, CHUFPB20690. Ipu : UFPB6127. Jaguaribe : CHUFPB19946, CHUFPB20656, CHUFPB20657, CHUFPB20675, CHUFPB20940, CHUFPB21058, CHUFPB22183, CHUFPB22188, CHUFPB22195, CHUFPB22233. Junco : UFPB10033, UFPB10034, UFPB10035, UFPB10036, UFPB10037. Quixad\u00e1 : CHUFPB19935, CHUFPB22177, CHUFPB22191. Santa Quit\u00e9ria : UFPB10752, UFPB10759, UFPB10760. Ubajara : CHUFPB19726, CHUFPB19729, CHUFPB19886, CHUFPB19925, CHUFPB19969, CHUFPB20654, CHUFPB20662, CHUFPB20671, CHUFPB20680, CHUFPB20681, CHUFPB20683, CHUFPB20792, CHUFPB20818, CHUFPB20820, CHUFPB20821, CHUFPB20822, CHUFPB20827, CHUFPB20830, CHUFPB20854, CHUFPB20876, CHUFPB20894, CHUFPB20896, CHUFPB20921, CHUFPB20930, CHUFPB20933, CHUFPB20938, CHUFPB20939, CHUFPB20943, CHUFPB20946, CHUFPB21056, CHUFPB21347, CHUFPB21349, CHUFPB21351, CHUFPB21355, CHUFPB22178, CHUFPB22179, CHUFPB22187, CHUFPB22190, CHUFPB22194, CHUFPB22201, CHUFPB22205, CHUFPB22217, CHUFPB22222, CHUFPB22225. PARA\u00cdBA| Boa Vista : UFPB1571, UFPB1572, UFPB1573, UFPB1574, UFPB1575, UFPB1576, UFPB1577, UFPB1579, UFPB1580, UFPB1581. Cabaceiras : UFPB11266, UFPB11267, UFPB11268, UFPB11269, UFPB11270, UFPB11271, UFPB11272, UFPB11273, UFPB11274, UFPB11275, UFPB11276, UFPB6691, UFPB6692, UFPB6693, UFPB6694. Desterro : UFPB1582, UFPB1583, UFPB1584, UFPB1585, UFPB1586. Fazenda Almas : FA01, FA44, FA45, FA46, FA149, FA154, FA158, FA159, UFPB4267, UFPB4270, WLSV1308, WLSV1346, WLSV1349, WLSV1463, WLSV1470, WLSV1472, WLSV1474, WLSV1475, WLSV1476, WLSV1477, WLSV1485, WLSV1487, WLSV1488, WLSV1497, WLSV1505, WLSV1566, WLSV1567, WLSV1572, WLSV2021, WLSV2026, WLSV2042, WLSV2131, WLSV2170, WLSV2252, WLSV2259, WLSV2260, WLSV2339, WLSV2340, WLSV2341, WLSV2388, WLSV2391, WLSV2935, WLSV3007, WLSV3016, WLSV3017A, WLSV3018, WLSV3019, WLSV3031, WLSV3032, WLSV3303, WLSV3304, WLSV3305, WLSV3318, WLSV3319, WLSV3320, WLSV3321, WLSV3990, WLSV4057, WLSV4063, WLSV4091, WLSV4093, WLSV4095, WLSV4207, WLSV4208, WLSV4209, WLSV4237, WLSV4335, WLSV4365, WLSV4375, WLSV4388, WLSV4397, WLSV4398, WLSV4399, WLSV4411, WLSV4492, WLSV4493, WLSV4494, WLSV4515, WLSV4529, WLSV4530, WLSV4533, WLSV4604, WLSV4646, WLSV4647, WLSV4765, WLSV4766, WLSV4767, WLSV4768, WLSV4769, WLSV4770, WLSV4771, WLSV4772, WLSV4773, WLSV4774, WLSV4775, WLSV4776, WLSV4777, WLSV4778, WLSV4779, WLSV4780, WLSV4789, WLSV4791, WLSV813, WLSV814, Y039. Patos : KSV041, KSV053, KSV055, KSV079, KSV113, KSV196, KSV232, KSV233, KSV237, KSV246, KSV247, KSV248, KSV251, KSV266, KSV278, KSV313, KSV319, KSV320, KSV321, KSV322, KSV325, KSV326, KSV327, KSV328, KSV330, KSV346. Pedra da Boca : KSV02, UFPB8423, UFPB8424, UFPB8425, UFPB8426, UFPB8427, UFPB8428, UFPB8429, UFPB8430, UFPB8431, UFPB8432, UFPB8433, UFPB8434, UFPB8435, UFPB8436, UFPB8437, UFPB8438, UFPB8439, UFPB8440, UFPB8441, UFPB8442, UFPB8443, UFPB8444, UFPB8445, UFPB8446, UFPB8447, UFPB8448, UFPB8449, UFPB8450, UFPB8451, UFPB8452, UFPB8453, UFPB8454, UFPB8455, UFPB8456, UFPB8457, UFPB8458, UFPB8459, UFPB8460, UFPB8461, UFPB8462, UFPB8463, UFPB8464, UFPB8465, UFPB8466, UFPB8467, UFPB8468, UFPB8470, UFPB8471, UFPB8472, UFPB8473, UFPB8474, UFPB8475, UFPB8476, UFPB8477, UFPB8478, UFPB8479, UFPB8480, UFPB8481, UFPB8482, UFPB8483, UFPB8484, UFPB8485, UFPB8486, UFPB8487, UFPB8488, UFPB8489, UFPB8490, UFPB8491, UFPB8492, YL005, YL013, YL101, YL117, YL135, YL144, YL173, YL238, YL280, YL283, YL293, YL325, YL348. S\u00e3o Jo\u00e3o do Cariri : WLSV001, WLSV002, WLSV173, WLSV209, WLSV244, WLSV245, WLSV258, WLSV596, WLSV884, WLSV885, WLSV886, WLSV899, WLSV900, WLSV901, WLSV902, WLSV903, WLSV904, WLSV904, WLSV905, WLSV906, WLSV965, WLSV966, WLSV967. S\u00e3o Jos\u00e9 dos Cordeiros : UFPB11253, UFPB11254, UFPB11255, UFPB11256, UFPB11257, UFPB11258, UFPB11259, UFPB11260, UFPB11261, UFPB11262, UFPB11263, UFPB11264, UFPB11265, UFPB5866. S\u00e3o Mamede : UFPB11686, UFPB11687. PERNAMBUCO| Arcoverde : UFPB9678, UFPB9679, UFPB9680, UFPB9681, UFPB9682, UFPB9683, UFPB9684, UFPB9685, UFPB9686, UFPB9687, UFPB9688, UFPB9689, UFPB9690, UFPB9691, UFPB9692, UFPB9693, UFPB9694, UFPB9695, UFPB9696, UFPB9697, UFPB9698, UFPB9699, UFPB9701. Bezerros: UFPB7098. Bu\u00edque : CHUFPB19895, CHUFPB19903, CHUFPB19908, CHUFPB19920, CHUFPB19921, CHUFPB19977, CHUFPB19978, CHUFPB20672, CHUFPB20830, CHUFPB20833, CHUFPB20855, CHUFPB20868, CHUFPB20884, CHUFPB20924, CHUFPB21057, CHUFPB22174, CHUFPB22175. Ex\u00fa : UFPB7208, UFPB7209, UFPB7210, UFPB7211, UFPB7212, UFPB7213, UFPB7214, UFPB7216, UFPB7217. Nascente : UFPB9670, UFPB9671. Serra Talhada : UFPB9655, UFPB9656, UFPB9657, UFPB9658, UFPB9659. Trindade : UFPB9672, UFPB9673, UFPB9674, UFPB9676, UFPB9677, UFPB974. V\u00e1rzea da Concei\u00e7\u00e3o : UFPB9661, UFPB9662, UFPB9666, UFPB9668, UFPB9664, UFPB9667, UFPB9665, UFPB9663. PIAU\u00cd| Cajueiro : UFPB7086. Caracol : GGS2-01, GGS2-02, GGS2-03, GGS2-04, GGS2-05, GGS2-06, GGS2-07. Paulistana : UFPB9669. Piripiri : UFPB10339. Serra das Confus\u00f5es : GGS560, GGS608, GGS656, GGS657, GGS658, GGS673, GGS674, CHUFPB19973, CHUFPB19986, CHUFPB20878, CHUFPB22176, CHUFPB22193, CHUFPB22215, CHUFPB22219, CHUFPB22221, CHUFPB22227. RIO GRANDE DO NORTE| Caic\u00f3 : UFPB14903, UFPB14904, UFPB14905, UFPB14906. Jo\u00e3o C\u00e2mara : GGS01, GGS02, GGS03, GGS04, GGS05, GGS06, GGS07, GGS08, GGS09, GGS10, GGS11, GGS12, GGS13, GGS14, GGS15, GGS16, GGS17, GGS18, GGS19, GGS20, GGS21, GGS22, GGS23, GGS24, GGS25, GGS26, GGS27, GGS28, GGS29, GGS30, GGS31, GGS100, GGS101, GGS102, GGS103, GGS104, GGS105, GGS106, GGS107, GGS108, GGS109, GGS110, GGS111, GGS112, GGS113, GGS114, GGS115, GGS116, GGS117, GGS118, GGS119, GGS120, GGS121, GGS122, CHUFPB19900, CHUFPB19984, CHUFPB20872, CHUFPB21300, CHUFPB21844, CHUFPB21860, CHUFPB21884, CHUFPB22224, CHUFPB23174. Maca\u00edba : CHUFPB19847, CHUFPB19948, CHUFPB19949, CHUFPB19953, CHUFPB19961, CHUFPB19966, CHUFPB19972, CHUFPB19974, CHUFPB19976, CHUFPB19980, CHUFPB19995, CHUFPB20679, CHUFPB20682, CHUFPB20684, CHUFPB20790, CHUFPB20802, CHUFPB20834, CHUFPB20842, CHUFPB20848, CHUFPB20858, CHUFPB20864, CHUFPB20866, CHUFPB20869, CHUFPB20874, CHUFPB20883, CHUFPB20900, CHUFPB20903, CHUFPB21063, CHUFPB21348. Santa Cruz : CHUFPB21054. Santana dos Matos : CHUFPB19938, CHUFPB20660, CHUFPB20840, CHUFPB20857, CHUFPB20890, CHUFPB20897, CHUFPB20928. Serra de S\u00e3o Bento : CHUFPB22200, CHUFPB22203. TOCANTINS| Alian\u00e7a : UFPB1588.10.7717/peerj.12879/supp-1Supplemental Information 1(B) Characteristic dorsal (8-bit) chromatic pattern. (C) Total area of spots (red colour) calculated along the dorsal surface of the specimen. Measurements sets: area; minimum and maximum grey value; mean grey value. Bar: 56 mm. Photo credit: Kleber Vieira.Click here for additional data file.10.7717/peerj.12879/supp-2Supplemental Information 2Click here for additional data file.10.7717/peerj.12879/supp-3Supplemental Information 3Click here for additional data file.10.7717/peerj.12879/supp-4Supplemental Information 4Chrom5 individuals are significantly different (\u03b1 = 0.05) from the other chromotypes, demonstrating smaller spots. Curiously, females generally demonstrated a greater average spot size compared to males.Click here for additional data file.10.7717/peerj.12879/supp-5Supplemental Information 5Chrom5 individuals are significantly different (\u03b1 = 0.05) from the other chromotypes, demonstrating smaller spots that are located farther apart from one another.Click here for additional data file.10.7717/peerj.12879/supp-6Supplemental Information 6Chrom 5 individuals are significantly different (\u03b1 = 0.05) from the other chromotypes, demonstrating smaller spots. Some values not observed. Click here for additional data file.10.7717/peerj.12879/supp-7Supplemental Information 7Chrom5 individuals are significantly different (\u03b1 = 0.05) from the other chromotypes, demonstrating smaller spots that are located farther apart from one another. Males exhibit a smaller average distribution area as compared to females. Some values not observed. Click here for additional data file.10.7717/peerj.12879/supp-8Supplemental Information 8indicating that males and females are equivalent when comparing them in terms of ontogenetic classes . Wilks\u2019 lambda = 0.81; F = 1.05; p = 0.34. Vertical bars denote 0.95 confidence intervals .Click here for additional data file.10.7717/peerj.12879/supp-9Supplemental Information 9p = 0.34. Vertical bars denote 0.95 confidence intervals .indicating that males and females were equivalent when comparing ontogenetic classes . Wilks\u2019 lambda = 0.81; F = 1.05; Click here for additional data file.10.7717/peerj.12879/supp-10Supplemental Information 10p = 0.063. Vertical bars denote 0.95 confidence intervals .indicating that the males and females were equivalent when comparing maturity classes (Immature and Mature). Wilks\u2019 lambda = 0.80; F = 1.33; Click here for additional data file.10.7717/peerj.12879/supp-11Supplemental Information 11p = 0.063. Vertical bars denote 0.95 confidence intervals .indicating that the males and females were equivalent when comparing maturity classes (Immature and Mature). Wilks\u2019 lambda = 0.80; F = 1.33; Click here for additional data file.10.7717/peerj.12879/supp-12Supplemental Information 12PC1 is correlated with size dimensions, whereas PC2 is correlated with saturation. It is possible to verify that Chrom5 and Dem5 are more concentrated and distributed along the superior portion of the second component, suggesting the presence of low saturated specimens. The environmental predictors did not explain the chromatic variance observed, indicating the existence of underlying operating factors. Click here for additional data file.10.7717/peerj.12879/supp-13Supplemental Information 13The data indicated that the species is typical of the Caatinga, being found with greater probability in the tropical savanna and semi-arid climate zones of this biome, according to the K\u00f6ppen\u2013Geiger classification.Click here for additional data file.10.7717/peerj.12879/supp-14Supplemental Information 14(A) Chrom1 and (B) Chrom2. The contrast of the animals\u2019 coloring in relation to the soil suggests adaptive reinforcement of the individual survival capacity (crypsis). Photo credit: Washington L. S. Vieira. Click here for additional data file.10.7717/peerj.12879/supp-15Supplemental Information 15Leptodactylus and Rhinella increased at similar rates over the decades, being later surpassed by Proceratophrys due to its faster rate of annual descriptions (A). When compared among congeneric groups (B), the highest description rates are observed in the cristiceps group. The bigibbosa group has been reasonably stable, but the boiei group rate has declined in relation to the total. Data obtained from Frost, D. R. (2021). Amphibian Species of the World: an Online Reference. Version 6.1.The lines represent least squares regressions, while the numbers over the dots represent the periodic rate (%) of the descriptions (A). We found that the species of the genera Click here for additional data file.10.7717/peerj.12879/supp-16Supplemental Information 16Gular region: slightly globular and smooth (A) or rough (B); dorsal glandular nodules varying in shape and size (C and D); ventral posterior portion: elongated and flattened (E). Photo credit: Kleber Vieira.Click here for additional data file.10.7717/peerj.12879/supp-17Supplemental Information 17P. cristiceps. A (WLSV 1474); B (WLSV 4095); C (WLSV 4791); D (UFPB 23174); E (UFPB 7214) e F (KSV 237). Photo credit: Kleber Vieira.on the outer portion of the right forearm and buccal (and/or subocular) commissure in specimens of Click here for additional data file.10.7717/peerj.12879/supp-18Supplemental Information 18The relative frequencies varied little among the sample categories analysed: ~14:43:6:9:8:20. Significant variations were not observed (\u03b1=0.05).Click here for additional data file.10.7717/peerj.12879/supp-19Supplemental Information 19Click here for additional data file."} +{"text": "Mol Psychiatry 10.1038/s41380-020-0774-9Correction to: http://creativecommons.org/licenses/by/4.0. Open Access funding enabled and organized by Projekt DEAL.The article \u201cBrain structural abnormalities in obesity: relation to age, genetic risk, and common psychiatric disorders\u201d, written by Nils Opel, Anbupalam Thalamuthu, Yuri Milaneschi, Dominik Grotegerd, Claas Flint, Ramona Leenings, Janik Goltermann, Maike Richter, Tim Hahn, Georg Woditsch, Klaus Berger, Marco Hermesdorf, Andrew McIntosh, Heather C. Whalley, Mathew A. Harris, Frank P. MacMaster, Henrik Walter, Ilya M. Veer, Thomas Frodl, Angela Carballedo, Axel Krug, Igor Nenadic, Tilo Kircher, Andre Aleman, Nynke A. Groenewold, Dan J. Stein, Jair C. Soares, Giovana B. Zunta-Soares, Benson Mwangi, Mon-Ju Wu, Martin Walter, Meng Li, Ben J. Harrison, Christopher G. Davey, Kathryn R. Cullen, Bonnie Klimes-Dougan, Bryon A. Mueller, Philipp G. S\u00e4mann, Brenda Penninx, Laura Nawijn, Dick J. Veltman, Lyubomir Aftanas, Ivan V. Brak, Elena A. Filimonova, Evgeniy A. Osipov, Liesbeth Reneman, Anouk Schrantee, Hans J. Grabe, Sandra Van der Auwera, Katharina Wittfeld, Norbert Hosten, Henry V\u00f6lzke, Kang Sim, Ian H. Gotlib, Matthew D. Sacchet, Jim Lagopoulos, Sean N. Hatton, Ian Hickie, Elena Pozzi, Paul M. Thompson, Neda Jahanshad, Lianne Schmaal, Bernhard T. Baune & Udo Dannlowski, was originally published electronically on the publisher\u2019s internet portal on 28 May 2020 without open access. With the author(s)\u2019 decision to opt for Open Choice the copyright of the article changed on 4 June 2021 to \u00a9 The Author(s) 2021 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article\u2019s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article\u2019s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit"} +{"text": "Clinical and Translational Medicine, \u201cCD248 as a novel therapeutic target in pulmonary arterial hypertension\u201d by Tao Xu, Lei Shao, Aimei Wang, Rui Liang, Yuhan Lin, GuanWang, Yan Zhao, Jing Hu, and Shuangyue Liu,The following article from"} +{"text": "Scientific Reports 10.1038/s41598-021-93650-6, published online 14 July 2021Correction to: The original version of this Article contained an error in Affiliation 1, which was incorrectly given as \u2018Environmental Research Laboratory, INRASTES, NCSR Demokritos, 15310 Ag. Paraskevi, Athens, Greece\u2019. The correct affiliation is listed below:Environmental Radioactivity Laboratory, INRASTES, NCSR Demokritos, 15310 Ag. Paraskevi, Athens, GreeceThe original Article has been corrected."} +{"text": "Scientific Reports 10.1038/s41598-019-46634-6, published online 15 July 2019Correction to: The original version of this Article omitted an affiliation for Hassan Alkharaan. The correct affiliations are listed below.Division of Clinical Diagnostics and Surgery, DENTMED, Karolinska Institutet, Huddinge, Sweden.College of Dentistry, Prince Sattam bin Abdulaziz University, Al-Kharj, Saudi ArabiaThe original Article has been corrected."} +{"text": "The initials of the third, sixth, eighth, ninth, tenth, eleventh, twelfth, thirteenth, and sixteenth authors are indexed incorrectly in PubMed. The correct initials are, respectively: Arthur CPS; Oliveira MAP; Segalote RC; Tiveron MG; de Barros e Silva PGM; Nakazone MA; Lisboa LAF; Dallan LAO; and Jatene FB.https://doi.org/10.1371/journal.pone.0255662The correct citation is: Goncharov M, Mejia OAV, Arthur CPS, Orlandi BMM, Sousa A, Oliveira MAP, et al. (2021) Mortality risk prediction in high-risk patients undergoing coronary artery bypass grafting: Are traditional risk scores accurate? PLoS ONE 16(8): e0255662."} +{"text": "This study had no funding source.Victor Hugo Fonseca de Jesus: conceptualisation, methodology, data curation, data analyses, writing and visualisation; Rachel Pimenta Riechelmann: methodology, writing and visualisation."} +{"text": "Oncogene 10.1038/s41388-021-02006-x, published online 10 September 2021Correction to: In this article the affiliation details for Author Jean-Christophe Marine were incorrectly given as Laboratory for RNA Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium. but should have been Laboratory for Molecular Cancer Biology, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory for Molecular Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium.The original article has been corrected."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-05602-3, published online 28 January 2022Correction to: The original version of this Article contained an error in the Affiliation, which was incorrectly given as \u2018Department of Physical Education, Shanghai Jiao Tong University, 204 Guangming Hall, NO. 800 Dongchuan Street, Minhang District, Shanghai, 200240, USA\u2019. The correct affiliation is listed below:Department of Physical Education, Shanghai Jiao Tong University, 204 Guangming Hall, NO. 800 Dongchuan Street, Minhang District, Shanghai, 200240, China.The original Article has been corrected."} +{"text": "Scientific Reports 10.1038/s41598-021-84540-y, published online 03 March 2021Correction to: The original version of this Article contained errors.Affiliation 2 was incorrectly given as \u2018Department of Chemistry, Science College, Qassim University, Buraidah, Saudi Arabia\u2019. Additionally, an affiliation was omitted for both Sayed M. Saleh and Reham Ali. The correct affiliations are listed below:Affiliation 1:Department of Chemistry, Faculty of Applied Science, Umm Al-Qura University, P.O. Box 16722, Makkah, 21955, Saudi ArabiaDina F. Katowah\u00a0&\u00a0Gharam I. MohammedAffiliation 2:Department of Chemistry, College of Science, Qassim University, Buraidah, 51452, Saudi Arabia.Sayed M. Saleh\u00a0&\u00a0Reham AliAffiliation 3:Chemistry Branch, Department of Science and Mathematics, Faculty of Petroleum and Mining Engineering, Suez University, 43721, Suez, Egypt.Sayed M. SalehAffiliation 4:Department of Chemistry, College of Science, University of Jeddah, Jeddah, Saudi ArabiaSara A. AlqarniAffiliation 5:Department of Chemistry, Faculty of Science, Suez University, 43518 Suez, EgyptReham AliAffiliation 6:Department of Chemistry, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi ArabiaMahmoud A. HusseinAffiliation 7:Polymer Chemistry Lab, Chemistry Department, Faculty of Science, Assiut University, Assiut, 71516, EgyptMahmoud A. HusseinThe original Article has been corrected."} +{"text": "Ovarian cancer (OCa) is characterized as one of the common reasons for cancer-associated death in women globally. This gynecological disorder is chiefly named the \u201csilent killer\u201d due to lacking an association between disease manifestations in the early stages and OCa. Because of the disease recurrence and resistance to common therapies, discovering an effective therapeutic way against the disease is a challenge. According to documents, some popular herbal formulations, such as curcumin, quercetin, and resveratrol, can serve as an anti-cancer agent through different mechanisms. However, these herbal products may be accompanied by some pharmacological limitations, such as poor bioavailability, instability, and weak water solubility. On the contrary, using nano-based material, e.g., nanoparticles (NPs), micelles, liposomes, can significantly solve these limitations. Therefore, in the present study, we will summarize the anti-cancer aspects of these herbal and-nano-based herbal formulations with a focus on their mechanisms against OCa. In. InQuerc protein . Regardil-2 axis . In thiser types ,85,86. Ts phenol . DR4 ands phenol ,88,89. Bpression . Howeverpression ,92,93. Ipression . Micellepression . The linpression . In the pression ,96. Anotpression . Liposompression . GeneralResveratrol (Res) is defined as a non-flavonoid polyphenol compound possessing stilbene structural components, which are extensively found in lilies, grapes, and other herbs [Res has been illustrated to have anti-tumor, anti-inflammatory, anti-oxidation, immunoregulatory, anti-virus, anti-microbial, neuroprotective, and anti-atherosclerosis influences [Res in different cancers, such as skin, ovarian, breast, colorectal, lung, and uterine cancer [Res, for example, inflammation suppression through NLRP3 inflammasome inhibition, cyclooxygenase (COX) curbing, nuclear factor erythroid 2-related factor 2 (Nrf2) induction, and mitogen-activated protein (MAP) kinase phosphatase-1 (MKP-1) stimulation, which inhibits NF-\u0138B pathway [Res curbs growth and stimulates cell death through apoptosome complex formation, caspase activation, and mitochondrial secretion of cytochrome c [Res suppressed glucose metabolism in OCa cells [Res against OCa through AMPK activation, downregulation of the protein cyclin D1, EMT inhibition [Res\u2014(Zinc oxide) ZnO nanohybrid against OCa cell lines and demonstrated that this nanoformulation exerts anti-cancer effects by the generation of ROS [er herbs . Res hasfluences ,98,99. Se cancer ,104,105. pathway ,107,108.chrome c . In the Ca cells . It seemCa cells . AnotherCa cells . Some othibition ,114,115.hibition ,117,118.hibition . In thisn of ROS . ZnO NPsn of ROS . An in vn of ROS . BSA (bon of ROS . In summRecently, herbal remedy using some popular herbal spices, including CUR, Que, and Res has acquired much attention in the treatment of OCa, as one of the common gynecologic cancers, through different mechanisms. For example, CUR through suppression of EMT, angiogenesis, and STAT3 and NF-\u0138B signaling, modulation of the expression of tumor-related-ncRNA, apoptosis stimulation, AMPK activation, inhibition of STAT3 and NF-\u0138B signaling, and induction of autophagy can affect OCa. Que decreases the expression of survivin protein, induces the expression DR5 and ATM phosphorylation, and increases p53 protein expression. Res through mitochondrial secretion of cytochrome c, inhibition of glucose metabolism and STAT3, Notch, and Wnt signaling, and downregulation of the protein cyclin D1 can fight against OCa. However, these herbal products can have some negative aspects in terms of pharmacology, such as instability, poor bioavailability, and poor water solubility. Based on the evidence, using nano-based formulations from these herbal therapeutic candidates, for instance, gemini, ZnO nanohybrids, PEGylated liposome, NPs, micelles, niosome, not only can overcome these obstacles but also can improve the therapeutic potential of herbal medicine against OCa. However, more and larger researches are needed to show their therapeutic effects and mechanisms."} +{"text": "Correction to: BMC Neurol 21, 308 (2021)https://doi.org/10.1186/s12883-021-02340-3Following publication of the original article , the autCheeloo College of Medicine, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China\u201d, it should be \u201cDepartment of Emergency, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China\u201d.Affiliation 1: Instead of \u201cDepartment of Emergency, Cheeloo College of Medicine, Shandong Provincial Chest Hospital, Shandong University, Jinan, Shandong, 250013, China\u201d, it should be \u201cDepartment of Critical Care Medicine, Shandong Provincial Chest Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250013, China\u201d.Affiliation 4: Instead of \u201cDepartment of Critical Care Medicine, Cheeloo College of Medicine, Shandong Provincial Hospital, Shandong University, Jinan, Shandong, 250021, China\u201d, it should be \u201cDepartment of Infectious Diseases, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China\u201d.Affiliation 5: Instead of \u201cDepartment of Infectious Diseases, The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way.The original article has been"} +{"text": "Aging Cell, 20, e13500. https://doi.org/10.1111/acel.13500Archana Unnikrishnan, Stephanie Matyi, Karla Garret, Michelle Ranjo\u2010Bishop, David B. Allison, Keisuke Ejima, Xiwei Chen, Stephanie Dickinson and Arlan Richardson, In the published version of Unnikrishnan et al. , the autThe authors apologize for this error."} +{"text": "Correction to: BMC Ophthalmol 21, 414 (2021)https://doi.org/10.1186/s12886-021-02175-zFollowing the publication of the original article , we wereOriginally published names: Zheng Ying, Casagrande Maria, Dimopoulos Spyridon, Bartz Schmidt Karl Ulrich, Spitzer Matin Stephan and Skevas Christos.Corrected names: Ying Zheng, Maria Casagrande, Spyridon Dimopoulos, Karl Ulrich Bartz Schmidt, Martin Stephan Spitzer and Christos Skevas.Also, Spitzer Martin Stephan was originally spelled as Spitzer Matin Stephan.The original article has been corrected."} +{"text": "Regdanvimab is a monoclonal antibody with activity against SARS-CoV-2. A Phase 2/3 study with two parts is currently ongoing and data up to Day 28 of Part 1 is available while the data from 1315 patients enrolled in Part 2 are expected in June 2021.This phase 2/3, randomized, parallel-group, placebo-controlled, double-blind study with 2 parts is aimed to assess the therapeutic efficacy of regdanvimab in outpatients with mild to moderate COVID-19, not requiring supplemental oxygen therapy. Patients aged >18 with the onset of symptoms within 7 days were eligible to be enrolled.In Part 1, 307 patients were confirmed to have COIVD-19 by RT-qPCR at Day 1 (or Day 2). Regdanvimab significantly reduced the proportion of patients who required hospitalization or supplemental oxygen therapy compared to placebo (8.7% in the placebo vs. 4.0% in the regdanvimab 40 mg/kg). The difference in events rate was even larger in patients who met the high-risk criteria and confirmed a 66.1% reduction in patients receiving regdanvimab 40 mg/kg (Table 1). The median time to clinical recovery was shortened by 2.9 days . Also, greater reductions from baseline viral load were shown in regdanvimab groups . The safety results confirmed that the regdanvimab was safe and well-tolerated. Occurrence of adverse events (Table 2) and results of other safety assessments were generally comparable among the 3 groups. The overall rate of infusion-related reaction was low and no serious adverse events or deaths were reported. The anti-drug antibody positive rate was low in the regdanvimab groups (1.4% in regdanvimab vs. 4.5% in placebo), and no antibody-dependent enhancement was reported.Results from the first part of the study indicate that regdanvimab may lower the rate of hospitalisation or requirement of oxygen supplementation, with the greatest benefit noted in patients at high-risk of progressing to severe COVID-19. The second part of the study remains ongoing and blinded. Therefore, results for the primary endpoint are forthcoming and will be presented at IDWeek.Michael G. Ison, MD, MS, Celltrion, Inc. (Consultant) Jin Yong Kim, MD, MPH, Celltrion, Inc. (Scientific Research Study Investigator) Oana Sandulescu, MD, PhD, Algernon Pharmaceuticals (Scientific Research Study Investigator)Atea Pharmaceuticals (Scientific Research Study Investigator)Celltrion, Inc. (Scientific Research Study Investigator)Diffusion Pharmaceuticals (Scientific Research Study Investigator)Regeneron Pharmaceuticals (Scientific Research Study Investigator) Liliana-Lucia Preotescu, MD, PhD, Celltrion, Inc. (Scientific Research Study Investigator) Norma Erendira Rivera Martinez, MD, Celltrion, Inc. (Scientific Research Study Investigator) Marta Dobryanska, MD, Celltrion, Inc. (Scientific Research Study Investigator) Victoria Birlutiu, Assoc. Prof. M.D. Ph.D., Celltrion, Inc. (Scientific Research Study Investigator)Lucian Blaga University of Sibiu, Romania & Hasso Plattner Foundation (Research Grant or Support) Egidia Gabriela Miftode, MD, PhD, Celltrion, Inc. (Scientific Research Study Investigator) Natalia Gaibu, MD, Celltrion, Inc. (Scientific Research Study Investigator) Olga Adriana Caliman-Sturdza, MD, PhD, Celltrion, Inc. (Scientific Research Study Investigator)Stefan cel Mare University of Suceava, Romania (Research Grant or Support) Simin-Aysel Florescu, MD, PhD, Celltrion, Inc. (Scientific Research Study Investigator) Anca Streinu-Cercel, MD, PhD, Assoc.Prof. Infectious diseases, Algernon Pharmaceuticals (Scientific Research Study Investigator)Atea Pharmaceuticals (Scientific Research Study Investigator)Celltrion, Inc. (Scientific Research Study Investigator)Diffusion Pharmaceuticals (Scientific Research Study Investigator)Regeneron Pharmaceuticals (Scientific Research Study Investigator) Sang Joon Lee, n/a, Celltrion, Inc. (Employee) Sung Hyun Kim, n/a, Celltrion, Inc. (Employee) Il Sung Chang, n/a, Celltrion, Inc. (Employee) Yun Ju Bae, n/a, Celltrion, Inc. (Employee) Jee Hye Suh, n/a, Celltrion, Inc. (Employee) Mi Rim Kim, n/a, Celltrion, Inc. (Employee) Da Re Chung, n/a, Celltrion, Inc. (Employee) Sun Jung Kim, n/a, Celltrion, Inc. (Employee) Seul Gi Lee, n/a, Celltrion, Inc. (Employee) Ga Hee Park, n/a, Celltrion, Inc. (Employee) Joong Sik Eom, MD, PhD, Celltrion, Inc. (Consultant)"} +{"text": "Brain. 2021;144(3);e30. doi:10.1093/brain/awaa442Rauan Kaiyrzhanov, Saskia Wortmann, Taryn Reid, Mohammadreza Dehghani, Mohammad Yahya Vahidi Mehrjardi, Bader Alhaddad, Matias Wagner, Marcus Deschauer, Isabell Cordts, J. Pedro Fernandez-Murray, Veronika Treffer, Zahra Metanat, Alan Pittman, Henry Houlden, Thomas Meitinger, Christopher Carroll, Christopher R. McMaster, Reza Maroofian. Defective phosphatidylethanolamine biosynthesis leads to a broad ataxia-spasticity spectrum. The authors apologize for misspelling the last name of the author Alan Pittman. This has been corrected."} +{"text": "Correction to: BMC Ophthalmol 21, 334 (2021)https://doi.org/10.1186/s12886-021-02095-yOriginally published names: Ivastinovic Domagoj, Haas Anton, Weger Martin, Seidel Gerald, Mayer-Xanthaki Christoph, Lindner Ewald, Guttmann Andreas and Wedrich AndreasCorrected names: Domagoj Ivastinovic, Anton Haas, Martin Weger, Gerald Seidel, Christoph Mayer-Xanthaki, Ewald Lindner, Andreas Guttmann and Andreas WedrichFollowing the publication of the original article , we wereThe original article has been corrected."} +{"text": "The given names and family names of the authors were interchanged. The correct author names are Ruben M\u00fchl-Benninghaus, Toshiki Tomori, Stefanie Krajewski, Philipp Dietrich, Andreas Simgen, Umut Yilmaz, Christoph Brochhausen, Mara Kie\u00dfling, Wolfgang Reith, Giorgio Cattaneo. The original article was corrected."} +{"text": "Scientific Reports 10.1038/s41598-021-86807-w, published online 31 March 2021Correction to: The original version of this Article contained errors in the spelling of the authors Satoru Takano, Kohei Yamaguchi, Kazuharu Nakagawa, Kanako Yoshimi, Ayako Nakane, Takuma Okumura & Haruka Tohara which were incorrectly given are S. Takano, Kohei Yamaguchi, K. Nakagawa, K. Yoshimi, A. Nakane, T. Okumura & H. Tohara respectively.These errors have now been corrected in the PDF and HTML versions of the Article."} +{"text": "Correction to: Arthritis Res Ther 23, 241 (2021)https://doi.org/10.1186/s13075-021-02621-9Following publication of the original article , the autIn the Authors information section, Holly Richendrfer who is not an author on the manuscript was removed. The corrected author information is listed below:Marwa Qadri, Pharm.D., Ph.D.: Assistant Professor of Pharmacology, Jazan University School of Pharmacy, Jazan, Kingdom of Saudi Arabia.Gregory D. Jay, MD, Ph.D.: Professor, Emergency Medicine and Engineering, Brown University, Providence, RI, USA.Ling Zhang, MD: Senior Research Assistant, Rhode Island Hospital, Providence, RI, USA.Tannin A. Schmidt, Ph.D.: Associate Professor of Biomedical Engineering, University of Connecticut Health Center, Farmington, CT, USA.Jennifer Totonchy, Ph.D.: Assistant Professor of Biomedical and Pharmaceutical Sciences, Chapman University, Irvine, CA, USA.Khaled A. Elsaid, Pharm. D, Ph.D.: Associate Professor of Biomedical and Pharmaceutical Sciences, Chapman University, Irvine, CA, USA."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-95454-0, published online 17 August 2021Correction to: The original version of this Article contained an error in Affiliation 8, which was incorrectly given as \u2018CNRS, Ifremer, IRD, MARBEC, Univ. Montpellier, Montpellier, France\u2019.The correct affiliation is listed below.MARBEC, Univ. Montpellier, CNRS, Ifremer, IRD, S\u00e8te, France.The original Article has been corrected."} +{"text": "The COVID-19 vaccine is considered to be the most promising approach to alleviate the pandemic. However, in recent surveys, acceptance of the COVID-19 vaccine has been low. To design more effective outreach interventions, there is an urgent need to understand public perceptions of COVID-19 vaccines.Our objective was to analyze the potential of leveraging transfer learning to detect tweets containing opinions, attitudes, and behavioral intentions toward COVID-19 vaccines, and to explore temporal trends as well as automatically extract topics across a large number of tweets.P values from the Augmented Dickey-Fuller test were used to assess whether users\u2019 perceptions changed over time. The main topics in tweets were extracted by latent Dirichlet allocation analysis.We developed machine learning and transfer learning models to classify tweets, followed by temporal analysis and topic modeling on a dataset of COVID-19 vaccine\u2013related tweets posted from November 1, 2020 to January 31, 2021. We used the F1 values as the primary outcome to compare the performance of machine learning and transfer learning models. The statistical values and We collected 2,678,372 tweets related to COVID-19 vaccines from 841,978 unique users and annotated 5000 tweets. The F1 values of transfer learning models were 0.792 (95% CI 0.789-0.795), 0.578 (95% CI 0.572-0.584), and 0.614 (95% CI 0.606-0.622) for these three tasks, which significantly outperformed the machine learning models . The prevalence of tweets containing attitudes and behavioral intentions varied significantly over time. Specifically, tweets containing positive behavioral intentions increased significantly in December 2020. In addition, we selected tweets in the following categories: positive attitudes, negative attitudes, positive behavioral intentions, and negative behavioral intentions. We then identified 10 main topics and relevant terms for each category.Overall, we provided a method to automatically analyze the public understanding of COVID-19 vaccines from real-time data in social media, which can be used to tailor educational programs and other interventions to effectively promote the public acceptance of COVID-19 vaccines. The outbreak of COVID-19 has affected 219 countries and territories with 102,083,344 confirmed cases causing 2,209,195 deaths as of January 31, 2021, as reported by the World Health Organization (WHO) . HoweverVaccine hesitancy, defined as \u201ca behavior with delay in acceptance or refusal of vaccines despite available services,\u201d was identified by the WHO as a global threat in 2019 . Unlike With the increased growth of internet-based applications, more people have begun sharing their opinions on social media platforms. In particular, during the current COVID-19 pandemic, people may increase their use of social media due to social distancing . Social Machine learning and deep learning techniques have been used as efficient methods to detect public perceptions on social media platforms. In health care, researchers have developed deep learning models to perform longitudinal and geographic analyses to understand human papillomavirus (HPV) vaccine discussions . These mAlthough previous studies have explored additional knowledge in the context of other vaccines using machine learning and deep learning methods, several questions related to COVID-19 vaccines remain unknown: What is the prevalence of user opinions on a social media platform? How many tweets express positive/negative attitudes and behavioral intentions to take vaccines? Which topics are mostly associated with these contents? To answer these questions, we developed machine learning models and transfer learning models to detect the content expressing user opinions, attitudes, and behavioral intentions toward COVID-19 vaccines. We then performed a temporal analysis to explore trends over time and developed probabilistic topic models to obtain the most important and valuable topics. We believe that this study will be of great benefit to the timely rollout of COVID-19 vaccines by extracting the latest public opinions, attitudes, and behavioral intentions that can help tailor promotion programs to fit different populations.We collected tweets related to COVID-19 vaccines posted from November 1, 2020 to January 31, 2021, and annotated 5000 tweets as the gold standard. We developed machine learning and transfer learning models to classify tweets for three tasks: (1) opinions ; (2) attitudes ; and (3) behavioral intentions . The above tasks all focused on COVID-19 vaccines. We then applied the models to predict unlabeled tweets and performed a temporal analysis to capture trends in the unlabeled tweets. In addition, we performed a topic analysis using word clouds and a latent Dirichlet allocation (LDA) model to further understand the content of tweets in the following categories: positive attitudes, negative attitudes, positive behavioral intentions, and negative behavioral intentions. The overall framework is shown in We used a combination of keywords and hashtags related to COVID-19 vaccines to collect tweets in English published from November 1, 2020 to January 31, 2021. We intentionally chose November, following the announcement of the first effective vaccine on November 9, 2020, to determine if the announcement of successful vaccine trial results might influence the perceptions of vaccines or vaccination. The search strategy employed the following search terms: \u201c(#covid OR covid OR #covid19 OR covid19) AND (#vaccine OR vaccine OR #vacine OR vacine OR vaccinate OR immunization OR immune OR vax) since:2020-11-01 until:2021-01-31 lang:en.\u201d We used snscrape and tweepy in Python 3 to collect data and to exclude retweets. To clean up the original tweets, we removed nonalphanumeric characters and converted the text to lowercase. We randomly selected 5000 tweets from November 1, 2020 to November 22, 2020, annotated by two independent reviewers (SL and JL) in batches of 200. Any annotation disagreements were discussed and adjudicated by the supervising investigators. For each tweet, we first labeled whether it included a user opinion toward the COVID-19 vaccines (yes or no). We considered a tweet to include an opinion about the COVID-19 vaccines if it met both of the following conditions: (1) targeted at the COVID-19 vaccines and (2) generated by a user. For the tweets that expressed user opinions toward the COVID-19 vaccines, we labeled the attitude and the behavioral intention toward COVID-19 vaccines. The attitude category used the traditional emotional polarity. The analysis of attitude was performed on the aspect level. If both positive and negative attitudes toward COVID-19 vaccines were present in the same tweet, we labeled it in the unknown category. The coding rules were iteratively developed by our group in which an independent review was performed, disagreements were discussed, and coding rules were revised. This process continued until the interrater agreement reached \u22650.80. The annotated corpus was used as a gold standard to train and evaluate the machine learning and transfer learning models.For data preprocessing, we used the tweet-preprocessor package in Python 3 to remove URLs, hashtags, mentions, reserved words , emojis, smileys, and numbers in each tweet. We split the annotated dataset into three parts: training (60%), validation (20%), and testing (20%). The training and validation datasets were used to train models and select optimal hyperparameters through 5-fold cross-validation. We applied transfer learning using text frequency-inverse document frequency to compare traditional machine learning algorithms to transfer learning models. The machine learning models were developed using the scikit-learn package in Python 3.For transfer learning, we used the BERT-base-cased as the pretrained language model and the \u201cBERT for sequence classification\u201d model as the pretrained classification model. Because the BERT model requires each sentence to be the same length, we padded each tweet with 64 tokens, as most tweets have lengths in this range. We then fine-tuned this model on the training and validation datasets using the Adam algorithm with weight decay (AdamW) as an optimizer. We performed three text classification tasks. We first developed a binary classifier to determine whether the tweets state an opinion related to the COVID-19 vaccines. We then developed two multiclass classifiers to categorize attitudes and behavioral intentions, respectively. The BERT models were generated using the huggingface package in Python 3. The models were developed with the Google Colab platform using a high-RAM GPU.We evaluated the models on the testing dataset and report outcomes with 1000 rounds of bootstrapping. The primary outcome was the macro-F1 value and the secondary outcomes were recall, precision, and accuracy. We performed the Nemenyi test to compare the F1 values of traditional machine learning models and transfer learning models . The modP<.05. The ADF test is a unit root test, which is commonly used to determine the stationarity of a time-series sample.We applied the optimal models to predict the unlabeled data for 3 months starting from November 1, 2020. For the task of extracting opinions, we calculated the proportion of tweets classified as containing opinions to the total number of tweets posted each day about the COVID-19 vaccines. For the tasks of classifying attitudes and behavioral intentions toward the COVID-19 vaccines, we calculated the percentage of tweets predicted to exhibit a particular attitude or behavioral intention to all tweets indicating attitudes or behavioral intentions, respectively. To assess the statistical significance of variability over time, we performed the Augmented Dickey-Fuller (ADF) test with a sTo understand the content of tweets in each category, we used word clouds to illustrate the frequency of words appearing in the content. The more frequently used words have larger sizes, indicating more importance in the category . FurtherWe annotated 5000 tweets from 4796 unique users with an average interrater reliability (\u03ba) of 0.76. The prediction performances of models on the testing dataset using four different algorithms for three tasks are presented in P<.001), indicating that the time-series data were stationary. This reflects that the prevalence of tweets expressing opinions did not change significantly over time. For tweets containing attitudes toward the COVID-19 vaccines, the rate of negative attitudes was 0.754 (95% CI 0.707-0.795), while the rate of positive attitudes was only 0.246 (95% CI 0.204-0.293). The daily prevalence of attitudes was nonstationary , which indicated a significant change in users\u2019 attitudes toward vaccines over time. Among tweets related to behavioral intentions, the rate of tweets indicating that users will not get vaccinated was 0.342 (95% CI 0.229-0.461), whereas the rate of tweets indicating that users will get vaccinated was 0.652 (95% CI 0.539-0.771). The behavioral intention prevalence was also nonstationary , indicating that it varied significantly over time. Notably, we observed a substantial increase in the prevalence of tweets expressing positive behavioral intention starting from mid-December 2020.We collected 2,678,372 tweets related to COVID-19 vaccines posted by 841,978 unique users from November 1, 2020 to January 31, 2021. The daily prevalence distributions of opinions, attitudes, and behavioral intentions are shown in After tuning hyperparameters of the LDA models, each model had 10 components (topics). Negative attitudes1. worry, prevent, covid, stop, need, spread, symptom, transmission, catch, people, reduce, infection, virus, eat, doesn2. death, covid, case, people, rate, die, number, cause, population, test, trial, fear, report, survival, day3. risk, covid, test, people, health, worker, trial, know, need, woman, work, child, pregnant, safe, age4. effect, long, term, know, covid, bad, unknown, risk, affect, people, study, concern, damage, potential, impact5. covid, year, make, anti, month, mask, rush, people, want, safe, need, just, know, sense, wear6. covid, dose, use, virus, immune, antibody, body, immunity, trial, second, make, protein, cell, test, response7. virus, new, covid, strain, effective, work, mutate, year, develop, mutation, research, cold, variant, different, make8. covid, people, just, say, think, make, know, trust, want, cure, government, believe, thing, come9. covid, die, people, life, chance, treatment, old, kill, effective, want, say, sick, save, safe, family10. flu, covid, reaction, shot, drug, adverse, expect, people, shoot, allergic, just, high, bad, year, polioPositive attitudes1. covid, thank, work, great, today, day, make, worker, scientist, happy, mom, care, just, hard, nurse2. covid, feel, effect, day, long, arm, just, little, work, fine, hour, term, good, excited, sore3. safe, stay, end, covid, news, pandemic, effective, trial, good, amp, light, continue, home, hope, step4. covid, hope, soon, look, forward, normal, life, hopefully, come, available, new, world, news, return, year5. covid, good, year, just, time, wait, thing, hope, think, come, pray, love, wish, news, day6. people, covid, want, need, know, die, risk, just, really, say, think, make, life, safe, fear7. covid, dose, receive, today, grateful, second, family, feel, patient, able, thankful, protect, friend, happy, excited8. flu, virus, covid, make, immune, fight, sure, body, new, immunity, just, strain, world, distribute, cause9. mask, wear, covid, stop, social, spread, distancing, hand, catch, need, distance, people, virus, stay, help10. covid, vaccinate, amp, case, symptom, prevent, ready, immunity, just, mean, virus, reduce, life, rate, infectionNegative behavioral intentions1. covid, virus, stop, prevent, symptom, test, dose, immune, spread, mask, antibody, sick, just, catch, body2. covid, flu, shot, shit, shoot, just, allow, work, win, scare, dead, year, virus, arm, sure3. risk, covid, say, immune, make, high, virus, people, disease, just, healthy, sense, dangerous, case, good4. want, covid, vaccinate, child, use, kill, kid, new, wait, way, cure, effective, doctor, just, people5. covid, body, rate, vaccination, survival, choice, eat, mandatory, know, worry, life, fear, want, hear, need6. covid, anti, just, tell, say, refuse, vaxxer, afraid, reason, people, stop, right, make, job, stupid7. covid, year, trust, chance, inject, month, government, test, old, develop, cold, make, research, come8. effect, know, long, term, covid, dna, affect, change, people, bad, rush, chance, unknown, study, test9. people, covid, die, need, think, just, kill, family, care, damn, believe, say, real, death, chance10. covid, force, try, reaction, people, bad, severe, look, allergic, medical, receive, say, fine, payPositive behavioral intentions1. covid, people, want, just, think, say, know, mask, wear, make, really, ask, scare, right2. covid, want, need, look, tomorrow, let, know, life, forward, ready, dose, morning, normal, receive, volunteer3. covid, wait, long, turn, effect, line, term, finally, eat, excited, worried, afraid, use, drink, polio4. just, dose, covid, second, got, day, effect, symptom, receive, fever, ache, hour, experience, headache, body5. flu, covid, shot, year, time, bad, shoot, sick, immune, just, need, month, make, think, doctor6. covid, arm, sore, sign, just, feel, today, hour, little, hurt, yesterday, injection, far, nervous, appointment7. work, covid, home, thank, stay, patient, hospital, help, safe, care, protect, family, trial, receive, vaccinate8. covid, risk, immune, die, people, virus, chance, high, know, need, vaccinate, healthy, live, just, catch9. covid, today, hope, mom, test, dose, happy, able, soon, dad, positive, receive, good, grateful10. feel, covid, day, week, fine, great, make, shit, ago, better, worker, body, job, good, healthcareTen topics were extracted among the tweets that contained negative attitudes. The interactive display interface of pyLDAvis is shown in For tweets containing positive attitudes, in a dominant topic (topic 3), relevant key terms included \u201csafe,\u201d \u201cstay,\u201d \u201cend,\u201d pandemic,\u201d \u201cnews,\u201d \u201ceffective,\u201d \u201ctrial,\u201d \u201ccontinue,\u201d and \u201chope.\u201d This indicates that some positive attitudes might be derived from news of effective trial results and some users hoped that COVID-19 vaccines could end the pandemic. Relevant terms for topic 4 were \u201chope,\u201d \u201cnormal,\u201d \u201clife,\u201d \u201creturn,\u201d \u201cstart,\u201d \u201cnew,\u201d \u201cworld,\u201d and \u201cgreat.\u201d Tweets in topic 4 showed that some users expressed positive attitudes toward vaccines because of the desire to return to a normal life.For tweets containing negative behavioral intentions, topics 8 and 10 clustered independently; however, other topics showed some degree of mutual inclusiveness, indicating that similarities existed in those topics. Key terms for topic 8 were \u201ceffect,\u201d \u201cknow,\u201d \u201clong,\u201d \u201cterm,\u201d \u201cDNA,\u201d \u201cunknown,\u201d and \u201crush.\u201d This topic reflected that some users\u2019 negative behavioral intentions came from the concerns of the long-term and unknown side effects of COVID-19 vaccines. As another unique topic, the most relevant terms for topic 10 were \u201cforce,\u201d \u201creaction,\u201d \u201cbad,\u201d \u201callergic,\u201d \u201cpay,\u201d \u201cadverse,\u201d and \u201cgovernment.\u201d This analysis highlighted that some users mentioned that they would not take the vaccine if it was forced on them by the government. Others worried about the adverse reactions to the COVID-19 vaccines. Some users compared COVID-19 to influenza and mentioned that because they had not previously been vaccinated against influenza, there was also no need to vaccinate against a disease they mistakenly thought had the same low lethality (topic 2). Other users reported that their immune system could naturally help them fight the virus.For tweets containing positive behavioral intentions, mutual inclusivity existed among topics 1-4 and between topics 9 and 10. Other topics clustered independently. In topic 8, the keywords were \u201crisk,\u201d \u201cimmune,\u201d \u201chealthy,\u201d \u201cantibody,\u201d and \u201cimmunity.\u201d In this topic, users would like to become immune to the virus causing COVID-19 and stay healthy by being vaccinated.In this study, we provided an annotated dataset with 5000 COVID-19 vaccine\u2013related tweets with labels supporting three classification tasks . We assessed that transfer learning could be used to analyze COVID-19 vaccine content tweets and proved that they outperformed common machine learning models. We analyzed the temporal trends and topics in the COVID-19 vaccine\u2013related tweets posted over a 3-month period . The prevalence of tweets containing positive behavioral intentions increased over time. The word clouds and the LDA analysis proved to be efficient tools to understand topics for tweets in each category.Transfer learning is now widely used to analyze social media content. Some researchers have applied transfer learning with datasets of tweets related to COVID-19 -38 ratheSeveral researchers have applied the Valence Aware Dictionary and Sentiment Reasoner (VADER) tool ,40, machTemporal analysis and topic modeling provide an efficient approach to monitor public perceptions of the COVID-19 vaccines on social media platforms. The following events could explain the significant increase in the prevalence of positive behavioral intentions in mid-December. For example, the FDA issued Pfizer-BioNTech COVID-19 vaccines on December 11, 2020, turning the vaccines from a hypothetical situation into a reality. The United States launched its rollout to high-risk health care facilities on December 14, 2020. A large number of health care workers and influential figures such as Joe Biden received COVID-19 vaccines to increase public confidence. This also suggests that more people might be willing to be vaccinated after successful vaccine development and a large-scale rollout. Indeed, social influence has been shown to positively affect the acceptance rate . At the This study has several limitations. First, users of the Twitter platform are not representative of the entire public. The Twitter platform is usually considered to gather more antivaccinators and spread misinformation. This group of users is the main subgroup of the population with sentiments of vaccine hesitancy and should therefore be one of the main targets to receive vaccine education. Compared to other populations, they tend to question vaccines from specific perspectives such as the presence of microchips in vaccines and the For future work, we will perform a theory-based content analysis to gain insight into the reasons that led to the changes in behavioral intentions we noted in the temporal analysis. Using the transfer learning model in this study, researchers can automatically collect tweets containing COVID-19 vaccine\u2013related behavioral intentions and systematically analyze the data through a theoretical model to pIn this study, we presented an annotated corpus of 5000 tweets and analyzed the potential to use transfer learning with a pretrained BERT model to automatically identify public opinions, behavioral intentions, and attitudes toward COVID-19 vaccines from social media. We demonstrated that transfer learning models outperformed traditional machine learning models in general. In addition, we explored the temporal trends of the public\u2019s change in attitudes and behavioral intentions on a larger dataset with 2,678,372 tweets from November 1, 2020 to January 31, 2021. We found that the LDA technique is useful to extract topics from identified tweets. Overall, we provided an automatic method to analyze the public\u2019s understanding of COVID-19 vaccines from real-time data, which could be used to tailor education programs and other interventions to promote COVID-19 vaccine acceptance urgently."} +{"text": "Simon Harvey, Stephen Malone, Hongdo Do, Wirginia Maixner, Amy Schneider, Bernadette Nolan, Martin Wood, Wei Shern Lee, Greta Gillies, Kate Pope, Michael Wilson, Paul J Lockhart, Alexander Dobrovic, Ingrid E Scheffer, Melanie Bahlo, Richard J Leventer, Ryan Lister, Samuel F Berkovic, Michael S Hildebrand. Cerebrospinal fluid liquid biopsy for detecting somatic mosaicism in brain. Brain Communications 2021. doi:In the originally published version of this manuscript, there was an error in the spelling of Co-author A. Simon Harvey\u2019s name. The full name should read: \u201cA. Simon Harvey\u201d instead of \u201cAnthony Simon Harvey\u201d. This has now been corrected online."} +{"text": "Correction to: Mol Biomed 1, 6 (2020)https://doi.org/10.1186/s43556-020-00007-yIn article , the autCompeting interestsYW, HY and DG have patent 10669252 . YW, HY, HL, SZ, YZ, PZ, XL, XS, LW, GF, YG, PW and DG are the employees of Shanghai Denovo Pharmatech Co., Ltd.. This work was supported by Shanghai Denovo Pharmatech Co., Ltd.."} +{"text": "For the authors Ladan Khodaparast, Laleh Khodaparast, Bert Houben, Frederic Rousseau, and Joost Schymkowitz, the affiliation \u201cVIB, Center for Brain & Disease Research, Leuven, Belgium\u201d should be included as shown above.Volume 12, no. 4, e01129-21, 2021,"} +{"text": "Details of new titles for systematic reviews or evidence and gap maps that have been accepted by the Editor of a Campbell Coordinating Group are published in each issue of the journal. If you would like to receive a copy of the approved title registration form, please send an email to the Managing Editor of the relevant Coordinating Group.Interventions that address domestic abuse for mothers in or exiting prison: A systematic reviewMichaela Rogers, Kelly Lockwood, Elizabeth SpeakeCJCG28 August 2021Policing interventions to engage with immigrant communities: A systematic reviewMichelle Sydes, Angela Higginson, Lorelei Hine, Lorraine Mazerolle14 October 2021Instruments for the evaluation of emotional intelligence in persons with hearing impairments: A scoping reviewPetra Potmesilova, Milon Potmesil, Jana Mareckova5 August 2021The role of school\u2010work experience programmes in promoting career orientation in high school students: A systematic reviewDonatella Poliandri, Mauro Palumbo, Antonio Fasanella, Alessandra Decataldo, Rita Marzoli, Sebastiano Benasso, Maria Dentale, Maria Paola Faggiano, Ughetta Favazzi, Brunella Fiore, Paola Giannoni, Grazia Graziosi, Monica Guerra, Veronica Lo Presti, Lorenzo Mancini, Beba Molinari, Enrico Nerli\u2010Ballati, Noemi Novello, Valentina Pacetti, Valeria Pandolfini, Fiorenzo Parziale, Stefania Sette, Claudio Torrigiani24 August 2021How does education affect health: A systematic reviewFatima Zahra, Nicole Haberland, Lauren Woyczynski, Stephanie Psaki19 March 2021Barriers and facilitators to enhancing access to business information through uptake of ICTs by women owning enterprises in low\u2010 and middle\u2010income countries: A qualitative synthesisRuth Nsibirano, Alison Annet Kinengyere, Agatha Kisa, Consolata Kabonesa, Howard White30 April 2021Value chain interventions for improving women's economic empowerment: A mixed\u2010method systematic reviewSabina Singh, Suchi Malhotra, Ashrita Saran, Howard White, Ranjitha Puskur, Hugh Sharma Waddington, Edoardo Masset23 August 2021The impact of agricultural mechanisation on women's economic empowerment: A mixed\u2010methods systematic reviewEdoardo Masset, Monisha Narayan, Ashwani Verma, Ashrita Saran, Howard White, Ranjitha Puskur, Niyati Singaraju, Hugh Sharma Waddington23 August 2021Global elder abuse: A mega\u2010map of systematic reviews on prevalence, consequences, risk and protective factors and interventionsChristopher Mikton, Yongjie Yon, Marie Beaulieu; Kevin St\u2010Martin, Julien Cadieux Genesse, Jennifer Storey, Fiona Campbell, Michaela Rogers, Amanda Phelan, Mark Byrne, Parveen Ali, David Burnes, Bridget Penhale, Tova Band\u2010Winterstein, Mark Lachs, Karl Pillemer, Lilly Estenson, Kelly Marnfelt30 June 2021Indigenous people's experiences and related processes that support healing and recovery from child sexual abuse: A systematic mapping literature review and evidence gap mapGraham Gee, Jordan Gibbs, Stephanie Brown, Helen Milroy6 August 2021Child and adolescent mental health and psychosocial support interventions: An evidence and gap map of low\u2010 and middle\u2010income countriesManasi Sharma, Camila Perera, Alessandra Ipince, Shivit Bakrania, Farhad Shokraneh, Priscilla Idele, David Anthony, Prerna Banati19 August 2021Group\u2010based interventions for posttraumatic stress disorder: A systematic review and meta\u2010analysis of the role of trauma typeSiobh\u00e1n M. Griffin, Elayne Ahern, Daragh Bradshaw, Orla T. Muldoon, Alastair Nightingale, Grace McMahon, Islam Bornica21 August 2021Informal social support interventions for improving outcomes for victim\u2010survivors of domestic violence and abuse: An evidence gap mapKaren Schucan Bird, Kate Hinds, Nicola Stokes, Carol Rivas, Martha Tomlinson9 September 2021"} +{"text": "Scientific Reports 10.1038/s41598-021-03695-w, published online 17 December 2021Correction to: The original version of this Article contained an error in Affiliation 1, which was incorrectly given as \u2018Department of Entomology, Purdue University, Tucson, AZ, 47907, USA\u2019. The correct affiliation is listed below:Department of Entomology, Purdue University, West Lafayette, IN 47907, USA.The original Article has been corrected."} +{"text": "Bacillus sp. strain GG161 and Rhodococcus sp. strain GG48 and the Gram-negative Achromobacter sp. strain GG226 and Shigella sp. strain GCP5 were all isolated from the gut of the optionally intestine-breathing freshwater fish Lepidocephalichthys guntea.We report the draft genome sequences of four bacterial strains belonging to four different genera. The Gram-positive Lepidocephalichthys guntea , which cn, 1822) due to in, 1822) . Live fin, 1822) , and disn, 1822) , and inc(CPCSEA) through Genomic DNA of the isolates was extracted using the PureLink genomic DNA isolation kit and quantified using a SPECTROstar Nano microplate reader . GenomicShigella sp. strain GCP5 included genes for resistance against fluoroquinolones, macrolides, cephalosporins, cephamycins, penems, tetracycline, aminoglycosides, carbapenems, glycylcyclines, peptide antibiotics, aminocoumarins, rifamycins, phenicols, triclosan, monobactams, benzalkonium chloride, and rhodamine. As revealed by RAST . All relevant accession numbers are given in"} +{"text": "Below is a list of all titles for systematic reviews or evidence and gap maps that have been accepted by the Editor of a Campbell Coordinating Group. When titles progress to protocol stage, the protocol is published in the Campbell Systematic Reviews journal.The details of new titles are published in each issue of the journal and added to this page at the same time.If you would like to receive a copy of the approved title registration form, please send an email to the Managing Editor of the relevant Coordinating Group.1Predictors of virtual team outcomes, Iulia Cioca, Oana Fodor, Shannon Marlow, 13 February 2019.Multisource feedback and work performance, Emilia Wietrak, Iulia Cioca and Jonny Gifford, 13 February 2019.2Police programs that seek to increase community connectedness for reducing violent extremism behaviour, attitudes, and beliefs, Lorraine Mazerolle, Adrian Cherney, Elizabeth Eggins, Angela Higginson, Lorelei Hine, Emma Belton, 05 March 2019.Multiagency programs with police as a partner for reducing radicalisation to violence, Lorraine Mazerolle, Adrian Cherney, Elizabeth Eggins, Angela Higginson, Lorelei Hine, Emma Belton, 10 April 2019.Effects of opioid\u2010specific medication assisted therapies on criminal justice and overdose outcomes, Catherine Strange, Sarah M. Manchak, Cory Haberman, Jordan M. Hyatt, Alisha Desai, 21 May 2019.3Effectiveness of interventions for improving livelihood outcomes for people with disabilities in low\u2010 and middle\u2010income countries, Hannah Kuper, Ashrita Saran, Lena Morgon Banks, Howard White, 12 March 2019.Social interventions to improve well\u2010being of people with mental disorders: global evidence and gap map, Sherize Merlin Dsouza, Jisha B. Krishnan, Ann Mary Sebastian, Ashrita Saran, 13 March 2019.Nutrition status and its relationship with health status in individuals with spinal cord injury, Jia Li, Devin Drummer, Thomas Hoover, Christian Sidebottom, Rachel Cowan, John\u2010Paul Tortorich, Cindy Cai, Elizabeth Scalia, Ceren Yarar\u2010Fisher, 29 March 2019.What is the relationship between back shape/posture, balance, falling, and fear of falling in older adults with hyperkyphosis?, Roongtip Duangkaew, Josette Bettany\u2010Saltikov, Paul van\u2010Schaik, Gok Kandasamy, Julie Hogg, 20 March 2019.Exercise interventions to improve back shape/posture, balance, falls and fear of falling in older adults with hyperkyphosis, Roongtip Duangkaew, Josette Bettany\u2010Saltikov, Paul van\u2010Schaik, Gok Kandasamy, Julie Hogg, 20 March 2019.4The effectiveness of homework in primary school, Jennifer Hanratty, Sarah Miller, Aoibheann Brennan\u2010Wilson, Maria Cockerill, Jenny Davison, Jennifer Roberts, Karen Winter, 13 February 2019.School\u2010based reading interventions for improving reading skills and educational outcomes on primary school students in low\u2010 and middle\u2010income countries, Qiufeng Gao, Huan Wang, Scott Rozelle, Yaojiang Shi, Jason Li, Lifang Zhang, Wei Nie, 11 March 2019.5Effectiveness of transport sector interventions in low\u2010 and middle\u2010income countries: an evidence and gap map, Denny John, Howard White, Nina Bl\u00f6ndal, 26 February 2019.6Systematic review of methods of reducing risk of bias in the evaluation of knowledge translation strategies for evidence\u2010informed health policymaking, Ayat Ahmadi, BaharehYazdizadeh, Leila Doshmangir, Reza Majdzadeh, ShabnamAsghari, 25 February 2019.7The methodological and reporting characteristics of economic methods and outcomes in Campbell reviews, Denny John, Pauline Sobiesuo, Devarshi Bhattacharyya, Luke Vale, 05 April 2019.8Effectiveness of adult day care centres for improving quality of life in older adults in low\u2010 and middle\u2010income countries, Saritha Susan Vargese, Nisha Kurian, Elsheba Mathew, Daies Idiculla, Geethu Mathew, Sunu Alice Cherian, Denny John, 22 January 2019.Book reading for promoting physical and mental health in older adults, Jorien Laermans, Hans Scheers, Philippe Vandekerckhove, Emmy De Buck, 22 January 2019.Friendly visiting by a volunteer for reducing loneliness and social isolation, and improving wellbeing in older adults, Jorien Laermans, Hans Scheers, Philippe Vandekerckhove, Emmy De Buck, 22 January 2019.Interventions for reducing violence against children in low\u2010 and middle\u2010income countries: an evidence and gap map, Prachi Pundir, Ashrita Saran, Howard White, Jill Adona, Ramya Subrahmanian, 04 February 2019.Institutional responses to child maltreatment: an evidence and gap map, Bianca Albers, Caroline Fiennes, Aron Shlonsky, Ludvig Bj\u00f8rndal, James Hennessy, Joachim Krapels, Robyn Mildon, 14 February 2019.Improving access to health and social services for individuals experiencing, or at risk of experiencing, homelessness, Sarah Miller, Ciara Keenan, Jennifer Hanratty, 21 February 2019.Discharge programmes for individuals experiencing, or at risk of experiencing, homelessness, Jennifer Hanratty, Sarah Miller, Ciara Keenan, 21 February 2019.Accommodation\u2010based interventions for individuals experiencing, or at risk of experiencing, homelessness: a network meta\u2010analysis, Ciara Keenan, Sarah Miller, Jennifer Hanratty, 21 February 2019.The effectiveness of supported employment for young adults with severe mental illness in improving work outcomes, Yue Bai, Zhaowen Cheng, Wei Bian, Zhenggang Bai, Jia Li, Iris Chi, 28 February 2019.Interventions for adults exposed to war and armed conflict: an evidence and gap map, Anne Farina, Brandy R. Maynard, 14 March 2019.The effectiveness of social protection interventions in low\u2010 and middle\u2010income countries: an evidence and gap map, Latha T, Zinnia Sharma, Linu A John, Ashrita Saran, 19 March 2019.Examining the best time of day for exercise, Meixuan Li, Xiaoqin Wang, Liang Yao, Huijuan Li, Liujiao Cao, Peijing Yan, Xiuxia Li, Kehu Yang, 03 May 2019.Effectiveness of road safety interventions: an evidence and gap map, Dinesh Mohan, Geetam Tiwari, Mathew Varghese, Kavi Bhalla, Denny John, Ashrita Saran, Howard White, 09 May 2019."} +{"text": "Correction to: Trials 22, 86 (2021)https://doi.org/10.1186/s13063-021-05035-9Following the publication of the original article , we wereTheir affiliation was initially mentioned as: \u201cPartnership for Research on Ebola Virus in Liberia (PREVAIL), Monrovia, Liberia\u201dHowever, their correct affiliation is: Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, UMR 1219, CHU Bordeaux, CIC 1401, EUCLID/F-CRIN Clinical Trials Platform, F-33000, Bordeaux, France.tp"} +{"text": "Leukemia 10.1038/s41375-020-0976-9Correction to: The article Bortezomib-based induction, high-dose melphalan and lenalidomide maintenance in myeloma up to 70 years of age, written by Elias K. Mai, Kaya Miah, Uta Bertsch, Jan D\u00fcrig, Christof Scheid, Katja C. Weisel, Christina Kunz, Markus Munder, Hans-Walter Lindemann, Maximilian Merz, Dirk Hose, Anna Jauch, Anja Seckinger, Steffen Luntz, Sandra Sauer, Stephan Fuhrmann, Peter Brossart, Ahmet Elmaagacli, Martin Goerner, Helga Bernhard, Martin Hoffmann, Marc S. Raab, Igor W. Blau, Mathias H\u00e4nel, Axel Benner, Hans J. Salwender, and Hartmut Goldschmidt for the German-speaking Myeloma Multicenter Group (GMMG), was originally published Online First without Open Access. After publication in volume 35, pages 809\u2013822, the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to \u00a9 The Author(s) 2020 and the article is forthwith distributed under the terms of the Creative Commons Attribution."} +{"text": "Forensic Sciences Research (FSR) wish to thank the following people, and any other reviewer whose name has been inadvertently omitted, for giving your time and expertise to review papers and facilitate the smooth running of FSR between November 2020 and October 2021.The Editors of the NigeriaAugustine Kolapo Ademola, SpainMiriam Baeta, USAEric J. Bartelink, DenmarkSusanne Bengtson, AustraliaJohn William Berketa, USACarol Berkowitz, ItalyCarla Bini, ItalyAlessandro Bonsignore, USANathan W. Bower, USAMichael P. Caligiuri, UKAlessandra Caso, ItalyValerio Causin, Czech RepublicMark\u00e9ta \u010cechov\u00e1, ChinaXiaohong Chen, CanadaDerek Congram, PortugalDiana Dias da Silva, AustraliaShanlin Fu, IndiaBinita Gandhi, ChinaYuzhen Gao, SwitzerlandDominic Gascho, USALorenzo Gitto, Tony Godet, SwitzerlandAustraliaMichael S. Gordon, ChinaFei Guo, MalaysiaRafizah Mohd Hanifa, USABryan T. Johnson, USAKaveh Jorabchi, USAKelly Kamnikar, PakistanShakeel Kazmi, AustraliaMichael Kennedy, MalawiLay See Khoo, SwedenArdavan Khoshnood, IndiaRaj Kumar, ChinaZhengdong Li, ChinaShiquan Liu, ChinaNingguo Liu, UKHelen M. Liversidge, SpainJoaquin Lucena, ChinaYehui Lvy, ChinaDong Ma, Portugal\u00c1urea Madureira-Carvalho, BrazilEdgard Michel-Crosato, SpainRuben Miranda, USAMolly Miranker, USALinton A. Mohammed, PortugalDavid Senhora Navega, AustraliaZuzana Obertov\u00e1, PortugalJos\u00e9 Restolho, BrazilRachel Lima Ribeiro Tinoco, AfricaServaas Rossouw South, RomaniaCalin Scripcaru, PakistanMuhammad Shahzad, ChinaYu Shao, SpainM. Paz Suarez-Mier, ChinaQiran Sun, USASusan Vanderplas, ColombiaMilena V\u00e1squez-Am\u00e9zquita, ChinaFang Wang, ChinaQi Wang, ChinaZheng Wang, AustraliaLinzi Wilson-Wilde, ChinaHui Yan, ChinaShaohua Yi, TunisiaRabaa Zaibi, USAMaoxiu Zhang, ChinaCuiling Zhang, ChinaQinting Zhang, ChinaSuhua Zhang, ChinaXinqing Zhang,"} +{"text": "Correction to: BMC Plant Biol 21, 206 (2021)https://doi.org/10.1186/s12870-021-02978-83Shanxi Key Laboratory of Minor Crop Germplasm Innovation and Molecular Breeding, Taiyuan, 030031, Shanxi, ChinaFollowing publication of the original article , the aut4Center for Agricultural Genetic Resources Research, Shanxi Agricultural University, Taiyuan, 030031, Shanxi, ChinaThe original article has been corrected.Mingchuan Ma and Longlong Liu are affiliated to:"} +{"text": "Scientific Data 10.1038/s41597-021-01045-z, published online 15 October 2021Correction to: In this article the affiliation details for Dongdong Xu, Ruiyi Chen, Hongbin Song, Lu Tian, Peng Tan, Ligai Wang, Qihui Zhu were incorrectly given as \u2018Zhejiang Academy of Agricultural Sciences, 310021, Hangzhou, China\u2019 but should have been \u2018Key Lab of Mariculture and Enhancement of Zhejiang Province, Zhejiang Marine Fisheries Research Institute, 316100, Zhoushan, China\u2019. The original article has been corrected."} +{"text": "A tool that analyzes the genome of parasites found in the blood of malaria patients can help inform policy decisions on how best to tackle the rise in drug-resistant infections. Related research article Jacob CG, Thuy-Nhien N, Mayxay M, Maude RJ, Quang HH, Hongvanthong B, Vanisaveth V, Ngo Duc T, Rekol H, van der Pluijm R, von Seidlein L, Fairhurst R, Nosten F, Hossain MA, Park N, Goodwin S, Ringwald P, Chindavongsa K, Newton P, Ashley E, Phalivong S, Maude R, Leang R, Huch C, Dong LT, Nguyen KT, Nhat TM, Hien TT, Nguyen H, Zdrojewski N, Canavati S, Sayeed AA, Uddin D, Buckee C, Fanello CI, Onyamboko M, Peto T, Tripura R, Amaratunga C, Myint Thu A, Delmas G, Landier J, Parker DM, Chau NH, Lek D, Suon S, Callery J, Jittamala P, Hanboonkunupakarn B, Pukrittayakamee S, Phyo AP, Smithuis F, Lin K, Thant M, Hlaing TM, Satpathi P, Satpathi S, Behera PK, Tripura A, Baidya S, Valecha N, Anvikar AR, Ul Islam A, Faiz A, Kunasol C, Drury E, Kekre M, Ali M, Love K, Rajatileka S, Jeffreys AE, Rowlands K, Hubbart CS, Dhorda M, Vongpromek R, Kotanan N, Wongnak P, Almagro Garcia J, Pearson RD, Ariani CV, Chookajorn T, Malangone C, Nguyen T, Stalker J, Jeffery B, Keatley J, Johnson KJ, Muddyman D, Chan XHS, Sillitoe J, Amato R, Simpson V, Gon\u00e7alves S, Rockett K, Day NP, Dondorp AM, Kwiatkowski DP, Miotto O. 2021. Genetic surveillance in the Greater Mekong subregion and South Asia to support malaria control and elimination. eLife10:e62997. doi: 10.7554/eLife.62997Plasmodium falciparum parasites (which cause the most severe form of the disease) no longer respond to the most widely used antimalarial drugs . A cutting-edge sequencing technology was then applied to extract and amplify specific genes from the parasitic genome. Jacob et al. analyzed this genetic data for variants which are known to reduce parasites\u2019 susceptibility to the most widely used treatments, including artemisinin provided concrete examples of how this information can be translated into policy decisions. For example, the database found that\u00a0parasites less susceptible to artemisinin and one of its partner drugs had spread to southern provinces in Vietnam and Laos which were previously unaffected by these resistant strains. This led National Malaria Control Programs in these regions to reassess which frontline therapies to use and where to allocate resources to help combat the rise in drug resistance.Beyond providing actionable information on the spread of resistance, the approach could also shed light on the complexity of infection, revealing whether a patient was carrying different species or strains of parasites at the same time. It could also be used to infer where the strains detected originated, which could help to reconstruct how parasites resistant to multiple drugs spread to different regions.P. falciparum at the same time, which makes it difficult to apply the method across many variant genes and classify the resistance profile. Nevertheless, the work by Jacob et al. demonstrates how genetic data can be a tremendously practical tool that can help policy makers rapidly adapt their treatment strategies in response to rising levels of drug resistance.Although this platform could rapidly become\u00a0an essential,\u00a0complementary strategy\u00a0for eliminating malaria, additional work is needed to overcome some drawbacks. First, the changes in drug susceptibility caused by the genetic variants is not directly tested, but assumed on the basis of earlier research . Second,"} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-86914-8, published online 01 April 2021Correction to: The original version of this Article contained an error in Affiliation 1, which was incorrectly given as \u201cEye School of Chengdu, University of T.C.M., 37 Shi Er Qiao Road, Jinniu District, Chengdu, 610036, China.\u201d The correct affiliation is listed below:, 37 Shi Er Qiao Road, Jinniu District, Chengdu, 610036, China.Eye School, Chengdu University of Traditional Chinese MedicineThe original Article has been corrected."} +{"text": "Rhaponticum carthamoides, Lepidium meyenii, Eleutherococcus senticosus, and Panax ginseng. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Results: This review includes data from 259 articles. The phytochemicals isolated from Rhaponticum carthamoides, Lepidium meyenii, Eleutherococcus senticosus, and Panax ginseng were described and classified in several categories. Conclusions: Plant species have always played an important role in drug discovery because their effectiveness is based on the hundreds of years of experience with folk medicine in different nations. In our view, there is great potential in the near future for some of the phytochemicals found in these plants species to become pharmaceutical agents.Background: In the 1960s, research into plant adaptogens began. Plants with adaptogenic properties have rich phytochemical compositions and have been used by humanity since ancient times. However, it is not still clear whether the adaptogenic properties are because of specific compounds or because of the whole plant extracts. The aim of this review is to compare the bioactive compounds in the different parts of these plants. Methods: The search strategy was based on studies related to the isolation of bioactive compounds from The term adaptogen was introduced for the first time in the 1940s by Dr. Nikolai Lazarev ,3. ThesePanax ginseng C. A. Mey., Eleutherococcus senticosus Max. and Rhaponticum carthamoides (Wild.) Iljin from Araliaceae family, Rhodiola rosea L. from Crassulaceae family and Schisandra chinensis from Schisandraceae family are plants with adaptogenic properties ether and tricin 4\u2032-O-(erythro-\u03b2-guaiacyl-glyceryl) ether [The main compounds isolated form this part of the plant are the macamides, imidazole alkaloids, pyrrole alkaloids, glucosinolates, flavolignans, polysaccharides, and others ,148,151.l) ether .Lepidium meyenii tuber contains sterols, glucosinolates, macamides, macaenes, alkamides, and others [Lepidium meyenii tuber [Lepidium meyenii are N-benzyl-9-oxo-12Z-octadecenamide, N-benzyl-9-oxo-12Z,15Z-octadecadienamide, N-benzyl-15Z-tetracosenamide, N-(m-methoxybenzyl) hexadecanamide and N-benzyl-13-oxo-9E,11E-octadecadienamide [The d others ,103,149.ii tuber . Benzylgii tuber ,143. TheN-benzylhexadecaanamide, N-benzyloctadecanamide, N-benzyl--octadecadienamide, N-benzyl--octadecatrienamide, and methoxy-N-benzyl--octadecatrienamide [The hypocotyls are rich in benzylamine, benzyl glucosinolates, and their derivates, alkaloids, macamides, sterols, and phenols ,147,150.ienamide ,115,147.ienamide Sterols ienamide .Lepidium meyenii contains some essential nutrients, such as amino acids, fibers, fatty acids, lipids, proteins, and minerals [Lepidium meyenii are described in minerals ,22. Becaminerals ,111,153.minerals ,155,156.minerals . Super fminerals . The intminerals . The mosLepidium meyenii\u2019s roots/tuber and its hypocotyls are: proteins, oil, amino acids, fatty acids, and minerals [The nutritional ingredients isolated from minerals ,30,114. minerals ,30, and minerals . The conminerals . The essminerals ,30,155. minerals ,30,155. minerals ,30,155.Eleutherococcus senticosus is a small, woody shrub, known also as \u201cSiberian ginseng\u201d, which naturally grows in East Russia, Korea, China, and Japan [nd Japan ,160. It nd Japan ,161.Eleutherococcus senticosus rhizome and radices are also considered especially valuable, and are included in the European and Russian pharmacopoeias [Nowadays, copoeias ,162.Eleutherococcus senticosus rhizome has a diameter of 4.0 cm with an irregular cylindrical shape. The bark thickness is 2 mm with a greyish brown to blackish-brown color. The roots can be up to 15 cm in length with a diameter of 0.3 to 1.5 cm [The knotty o 1.5 cm .Eleutherococcus senticosus extract is associated with antioxidant, anti-inflammatory, adaptogenic, antidiabetic, and choleretic effects [Eleutherococus senticosus are immunoregulation, hepatoprotection, antiviral, and antibacterial effects [The intake of effects ,164,165. effects ,164,165. effects ,167,168.Eleutherococcus senticosus roots are composed of phenylpropanoids, saponins, coumarins, lignans, polysaccharides, phenolic acids, and provitamins [The phytochemicals of vitamins ,165,169.vitamins . Eleuthevitamins ,172. Couvitamins ,125,173.vitamins .Eleutherococcus senticosus extract has the potential to improve oxygen consumption, mental health, lipid, and glycemic profile [Although all parts of this plant have rich phytochemical compositions, the roots are the most utilized. Roots are used in the form of liquid extracts, powders, etc. ,175. Acc profile ,176,177. profile ,178,179.Eleutherococcus senticosus with the greatest potential to become novel drug molecules are Eleutheroside B and Eleutheroside E.The molecules isolated from Studies investigating Eleutheroside B and Eleutheroside E activity in humans are limited. However, according to data obtained from animal studies, they have great potential to be used for the treatment of inflammation, cancer, osteoporosis, and diabetes ,183,184.Eleutherococcus senticosus.Eleutherococcus senticosus include eleutheroside A, eleutheroside B ,195,196.Panax ginseng naturally grows in Korea and China [nd China ,198. Thend China . The wornd China .Panax ginseng seeds are obtained from plants no less than four years old. Panax ginseng roots may be white or pale yellow, and grow upright. There is one stout primary root and two or five rootlets and root hairs. The size and shape of the rootlets depends on water content, soil quality, weather, and other factors. Ginseng roots are considered most valuable between 4 and 6 years of age. Roots younger than 4 years are considered immature, and should not be used for medical purposes [It is a perennial, self-pollinating plant. It has one stalk and palmate leaves at its end. The flowering starts in its third-year growth stage. purposes .Panax ginseng radix is included in the European pharmacopoeia [acopoeia . Accordiacopoeia .Panax ginseng extract is associated with antitumor, anti-fatigue, antioxidative, immunostimulating, anti-inflammation, anti-obesity, cardioprotective, antimicrobial and neuroprotective activities. The extract is also used because of its adaptogenic properties, as an antioxidant and as an aphrodisiac [Nowadays, rodisiac ,201,202.rodisiac ,205,206.Panax ginseng are saponins, also known as ginsenosides [Panax ginseng [Panax ginseng, but also from all of Panax species, such as Panax quinquefolius L., Panax notoginseng (Burkill) F. H. Chen, Panax japonicas (T. Nees) C. A. Mey. and Panax zingiberensis C. Y. Wu and K. M. Feng [The main active ingredients in enosides . They inenosides ,207,208.enosides . Over 30enosides . It is c ginseng . Other w ginseng ,212. The ginseng . Ginseno M. Feng ,215,216.According to studies involving humans, ginsenosides may improve calmness, mental health, and the overall quality of life. Moreover, their intake is associated with antihyperlipidemic, antidiabetic, and anti-fatigue effects ,219,220.Panax ginseng is a source of plenty of biological active compounds, the molecules with the greatest potential to become drug molecules are ginsenosides. According to data obtained from animal studies, ginsenosides have great potential to be used for the treatment of cardiovascular diseases, hepatic disorders and obesity [Although obesity ,232,233. obesity ,236,237.Panax ginseng.Panax ginseng include ginsenoside Ra1, ginsenoside Ra2, ginsenoside Rb1, ginsenoside Rb2, ginsenoside Rb3, ginsenoside Rc, ginsenoside Rd, ginsenoside Re, ginsenoside Rh, ginseoside Rg1, ginsenoside Rg2, ginsenoside Rg5, ginsenoside Rf, ginsenoside F2, ginsenoside Rk1, ginsenoside Rs4, and ginsenoside Rs6 [Panax ginseng roots [The main phytochemicals are ginsenosides and their isomers ,250,252.side Rs6 ,249,250.side Rs6 . Notoginng roots ,240,245.Panax ginseng may be used as melanogenic inhibitors [The main bioactive compounds are the ginsenosides ginsenoside Rd, ginsenoside Rh5, ginsenoside Rh6, ginsenoside Rh7, ginsenoside Rh8, ginsenoside Rh9, ginsenoside Rg1, ginsenoside Rg7 ginsenoside Re, ginsenoside F1, ginsenoside F2, and ginsenoside F3 ,246. Thehibitors . The phyhibitors . The ginhibitors ,255.Bioactive compounds and their concentration isolated from plants are not constant. For example, the content of the phytochemicals varies in different parts of the species and also depends on many factors like soil, soil management, climate, and pollutants ,257,258.For that reason, it is very important the feature research about these plants to be focused mostly on their active molecules that to the whole extracts. However, comparison between the biological activity of the extracts and the active molecules would provide valuable data.Rhaponticum carthamoides is the only plant among these which has the greatest potential to be used as a remedy for improvement physical performance, because of potential ergogenic activity. Ecdysterone, which is one of its active compounds is in process of monitoring by WADA as a doping compound [Although the four plants have quite different phytochemical composition , the futcompound . Moreovecompound ,260.Rhaponticum carthamoides, Lepidium meyenii, Eleutherococcus senticosus, Panax ginseng/their active compounds, cell cultures research would be especially useful to give the right direction for future investigations.In term to establish the biological activity of Rhaponticum carthamoides, Eleutherococcus senticosus, and Panax ginseng. Later, Lepidium meyenii was also included in the plant adaptogens family.Plants have always played an important role in drug discovery, and their effectiveness is based on hundreds of years\u2019 experience in the folk medicines of different nations. In the 1960s, the first plants with adaptogenic activities were described: The main phytochemicals isolated from these plants are phytosteroids, phytosterols, alkaloids, and saponins. These biologically active compounds determine the therapeutic effects of plants not only as adaptogens, but also as antioxidants, hepatoprotectors, immunomodulators, hormone regulators, and others. Plants have always been an important source of past and novel drug molecules. In our view, there is great potential for some of the phytochemicals found in these plant species, such as ginsenosides, ecdysterone, macamides, macaenes, and eleutherosides to become novel drug molecules. However, their biological activity should be studied in more detail in cell cultures, in mammals, and in randomized clinical trials."} +{"text": "European Journal of Public Health, 2021; https://doi.org/10.1093/eurpub/ckab194In the originally published version of this manuscript, an author was erroneously omitted from the list of authors. The list should read: \u201cLorenzo Monasta, Gianfranco Alicandro, Maja Pasovic, Matthew Cunningham, Benedetta Armocida, Christopher J L Murray, Luca Ronfani, Mohsen Naghavi, GBD 2019 Italy Causes of Death Collaborators\u201d instead of \u201cLorenzo Monasta, Gianfranco Alicandro, Maja Pasovic, Matthew Cunningham, Benedetta Armocida, Luca Ronfani, Mohsen Naghavi, GBD 2019 Italy Causes of Death Collaborators\u201d. This error has been corrected online."} +{"text": "Scientific Reports 10.1038/s41598-021-95735-8, published online 06 September 2021Correction to: The original version of this Article contained errors in the Affiliations.Maulin Raval was incorrectly affiliated with \u2018Department of Industrial Engineering, University of Houston, Victoria, USA\u2019.In addition, Pavithra Sivashanmugam, Vu Pham and Yun Wan were incorrectly affiliated with \u2018Department of Computer Science, University of Houston-Victoria, Victoria, USA\u2019.The correct affiliations are listed below:1. Applied Artificial Intelligence Laboratory, University of Houston-Victoria, Victoria, USA.Maulin Raval, Pavithra Sivashanmugam, Vu Pham, Hardik Gohel & Yun Wan.2. NanoBioTech Laboratory Florida Polytechnic University, Lakeland, USA.Ajeet Kaushik.The original Article has been corrected."} +{"text": "Unfortunately, some authors' first name and surname were incorrectly published in the original publication. The complete correct names of authors are given below.Riccardo Serra, Chiara Di Nicolantonio, Riccardo Di Febo, Franco De Crescenzo, Johan Vanderlinden, Elske Vrieze, Ronny Bruffaerts, Camillo Loriedo, Massimo Pasquini, Lorenzo Tarsitani.The original article has been corrected."} +{"text": "Unfortunately, in the articlePorphyridium sordidumCharacterization and potential antitumor effect of a heteropolysaccharide produced by the red alga By Biliana Nikolova, Severina Semkova, Iana Tsoneva, Georgi Antov, Juliana Ivanova, Ivanina Vasileva, Proletina Kardaleva, Ivanka Stoineva, Nelly Christova, Lilyana Nacheva and Lyudmila Kabaivanova,https://doi.org/10.1002/elsc.201900019,the second affiliation of the author Georgi Antov was erroneously omitted. The correct affiliations for Prof. Dr. Antov are:1 Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Sofia, Bulgaria2 Institute of Plant Physiology and Genetics, Bulgarian Academy of Sciences, Sofia, Bulgaria"} +{"text": "In \u201cQuantifying Online News Media Coverage of the COVID-19 Pandemic: Text Mining Study and Resource\u201d :e28253), one error was noted.Due to a system error, the name of one author, Benjamin Gibert, was replaced with the name of another author on the paper, Seth Flaxman. In the originally published paper, the order of authors was listed as follows:Konrad Krawczyk, Tadeusz Chelkowski, Daniel J Laydon, Swapnil Mishra, Denise Xifara, Seth Flaxman, Seth Flaxman, Thomas Mellan, Veit Schw\u00e4mmle, Richard R\u00f6ttger, Johannes T Hadsund, Samir BhattThis has been corrected to:Konrad Krawczyk, Tadeusz Chelkowski, Daniel J Laydon, Swapnil Mishra, Denise Xifara, Benjamin Gibert, Seth Flaxman, Thomas Mellan, Veit Schw\u00e4mmle, Richard R\u00f6ttger, Johannes T Hadsund, Samir BhattIn the originally published paper, the ORCID of author Benjamin Gibert was incorrectly published as follows:0000-0002-2477-4217This has been corrected to:0000-0001-8457-3137The correction will appear in the online version of the paper on the JMIR Publications website on July 14, 2021, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories."} +{"text": "Following publication of the original article , the autThe incorrect author names: Micheloni Gian Mario, Tarallo Luigi, Negri Alberto, Giorgini Andrea, Merolla Giovanni and Porcellini Giuseppe.The correct author names: Gian Mario Micheloni, Luigi Tarallo, Alberto Negri, Andrea Giorgini, Giovanni Merolla, Giuseppe Porcellini.The author group has been updated above and the original article has been"} +{"text": "Embioptera from Brazil are described, diagnosed, and illustrated. For Anisembiidae: Chelicercaachilata Szumik, Pereyra & Ju\u00e1rez, sp. nov.; Saussurembiaborba Szumik, Pereyra & Ju\u00e1rez, sp. nov. For Archembiidae: Archembiaoruma Szumik, sp. nov.; Embolynthaoriximina Szumik, Pereyra & Ju\u00e1rez, sp. nov.; Pararhagadochirbonita Szumik, Pereyra & Ju\u00e1rez, sp. nov., Pararhagadochirmarielleae Szumik, Pereyra & Ju\u00e1rez, sp. nov.; Pararhagadochirpara Szumik, Pereyra & Ju\u00e1rez, sp. nov. For Clothodidae: Chromatoclothodalanga Szumik, Pereyra & Ju\u00e1rez, sp. nov. To clarify the higher classification of the Order and to have an accurate taxonomy, a species catalog and introduction to the four families present in Brazil is also detailed, including phylogenetic relationships, taxonomic actions, composition, distributions, and records maps. Herein, several taxonomic acts are proposed: (1) the synonymy of Chelicerca Ross and Saussurembia Davis . (2) new status and delimitation for family Archembiidae Ross, stat. rev.; subfamily Archembiinae Ross, stat. rev.; subfamily Pachylembiinaestat. rev.; subfamily Scelembiinaestat. rev., and their genera included. (3) Diradiusunicolor (Ross) (Teratembiidae) comb. nov., and (4) new locality records for previously cited species in the region.Eight new species of Embioptera whose representativeness of species is very low if we consider the surface and the diversity of biomes present in the country are the result of the collection studies from several museums as well as the Ross collection . Museum collections acronyms:Many of the species known for Brazil were described by E.S. Ross in his last monographs e.g., , 2003, wAMNHAmerican Museum of Natural History, New York, USA;CASCalifornia Academy of Science, Department of Entomology, Golden Gate Park, San Francisco, California, USA;FMLFundaci\u00f3n Miguel Lillo, Tucum\u00e1n, Argentina;INPAInstituto Nacional de Pesquisas da Amaz\u00f4nia, Manaus, Brazil;LABEILaborat\u00f3rio de Ecologia de Insetos, da Universidade Federal de Pelotas, Rio Grande do Sul, Brazil;MCZMuseum of Comparative Zoology, Harvard University, Cambridge, Massachusetts, USA;MNHNPMuseum National d\u2019Histoire Naturelle, Paris, France;MNHNPAMuseo Nacional de Historia Natural del Paraguay;MNRJMuseo Nacional do Rio de Janeiro, Rio de Janeiro, Brazil;MZUSPMuseu de Zoologia, Universidade de S\u00e3o Paulo, S\u00e3o Paulo, Brazil;MZVMuseum and Institute of Zoology of the Polish Academy of Sciences, Warsaw, Poland;NHMUKNatural History Museum, London, United Kingdom;USNMNational Museum of Natural History, Washington, USA;ZMBZoologisches Museum, Berlin, Germany.http://www.qgis.org). All measurements are given in millimeters. Ocular ratio (OR) is defined as in Maps created using the free and open source QGIS ver 2.18 ; Chorisembia Ross, 2003; Ectyphocerca Ross, 2003; Exochosembia Ross, 2003; Glyphembia Ross, 2003; Isosembia Ross, 2003; Mesembia Ross, 1940; Microembia Ross, 1944; Oncosembia Ross, 2003; Phallosembia Ross, 2003; Platyembia Ross, 2003; Pogonembia Ross, 2003; \u2020Poinarembia Ross, 2003; Saussurembia Davis, 1940 ; Scolembia Ross, 2003. species . However species , since s species , 2019. A species , the incAnisembiidae are described, the synonymy of various genera is confirmed and, a complete list of known Brazilian species and new locality records are added. Consequently, in Brazil, Anisembiidae is represented by 13 species belonging to six genera .In this work, two new species of Taxon classificationAnimaliaEmbiopteraAnisembiidae\ufeffGenusRoss, 1940184F2859-257C-568A-8956-C9DE852F455CAnisembia (Chelicerca)Anisembia Krauss, type species Anisembia (Chelicerca) davisi Ross by original designation. Ross, 1940: 656, as subgenus of Chelicerca Ross, 1944: 448; Chelicerca (Protrochelicerca)ChelicercadampfiChelicerca Ross. Ross, 1944: 449, type species Anisembia (Dactylocerca)Anisembia Krauss, type species Anisembia (Dactylocerca) rubra Ross by original designation; 1944: 454, as subgenus of Chelicerca. Ross, 1940: 659, as subgenus of DactylocercaChelicerca Ross; Chelicerca Ross; confirmed junior synonym of Chelicerca Ross. 1984a: 85, genus status; 1984b: 37, diagnosis; SchizembiaSchizembiagrandisChelicercaChelicerca Ross; Chelicerca Rossnew junior synonym of . Ross, 1944: 440, type species PelorembiaPelorembiatumidiceps Ross; Chelicerca Ross; Chelicerca Ross; confirmed junior synonym of Chelicerca Ross. Ross, 1984a: 41, type species CryptembiaCryptembiaamazonica Ross; Chelicerca Ross; Chelicerca Rossnew junior synonym of . Ross, 2003: 49, type species 10T with completely separate hemitergites, 10Lp1 and 10Rp1 usually with discoidal form ending with a spine. H globose, Hp elongate, ending with a complex apical margin, in some cases ending in a spine-shaped lobe, in other cases ending truncated or in two small lobes; Rpp totally fused to Hp and almost inconspicuous.Pelorembia, Dactylocerca, Schizembia, and Cryptembia were previously treated as probable junior synonym of Chelicerca and here these synonymies are confirmed (see below for relationships). Thus, the genus Chelicerca contains 76 species distributed from the southern United States to Argentina comb. nov.; Chelicercamanauara comb. nov.; Chelicercaparaense comb. nov.; Chelicercarioensis Ross, 2003; Chelicercarondonia ; Chelicercarossi nom. nov. because Chelicercarondonia Ross, 2003 is a junior primary homonym of Cryptembiarondonia Ross, 2003 and is transferred to Chelicerca . New locality records for C.manaurara are added for two states of Brazil .Herein we only list the seven species of America.Chelicerca appeared as a paraphyletic group in all the phylogenetic analyses performed for the Order Embioptera .Male ; Saussurembiadavisi Ross as new name for Saussurembiaruficollis Davis, specimen type misidentified by Davis; Davis, 1940a: 191, for StenembiaStenembiaparenensis Ross, 1896 by original designation; Saussurembia Davis; Saussurembia Davis; Saussurembia Davisnew junior synonym of . Ross, 1972: 139, type species LC1 symmetrical (processes and setae absent), Hp elongate, Ep narrow (stick-like), wing venation (only veins Rs + Ma and Rs sclerotized and cross veins absent except between R1 and Rs), 10Lp1 and 10Rp1 simple, laminate narrow lobe.Md acute and small, Stenembia Ross, 1972 is proposed here as junior synonym of Saussurembia Davis, 1940 (see arguments below under phylogenetic relationships), currently the genus includes seven species: Saussurembiadavisi Ross, 1992 from Costa Rica, Saussurembiaalbicauda Ross, 1992 from Panama, SaussurembiacalypsoSaussurembiasymmetrica Ross, 1944 from Colombia; Saussurembiaperenensis from Peru; Saussurembiaexigua from Brazil and the new species described below, also from Brazil.Given that Central and South America.Saussurembia was considered closely related to Stenembia based on the combination of characters discussed and described by Saussurembiacalypso which share with Saussurembia the presence of a sclerotized line starting from the inner margin of 10Lp1, the ventrally curved 10Rp1 and the basally broad 10Lp1 with acute apex and, with Stenembia the well-defined Lpp and Rpp, the dorsally curved Lpp and the directed leftward Hp , Hp elongate, Ep narrow (stick-like), wing venation (Rs + Ma and Rs are the only veins sclerotized) and the general shape of 10Lp1 and 10Rp1 (Saussurembia the autapomorphic form (The genus tward Hp . Saussurization) . Thus, ohic form .Embioptera .Male ( Uniformly yellowish brown with some color details: abdomen (except nine and ten segment) and cerci whitish. Total length 7.25. Head oval and elongate and elevating Scelembiinae to family level and including there the remainder of archembiids. In the last cladistic analysis of the Order and 18 modern genera (from America and Africa), accounting for a total of 86 species (including the new species described below) : Archembia Ross, 1971; Calamoclostes Enderlein, 1909; Ecuadembia Szumik, 2004; subfamily Pachylembiinae (four genera): Conicercembia Ross, 1984; Neorhagadochir Ross, 1944 ; Pachylembia Ross, 1984; \u2020Sorellembia Engel & Grimaldi, 2006; subfamily Scelembiinae (14 genera): Ambonembia Ross, 2001 ; Biguembia Szumik, 1997; Chirembia Davis, 1940 ; Dolonembia Ross, 2001; Embolyntha Davis, 1940 ; Gibocercus Szumik, 1997; \u2020Kumarembia Engel & Grimaldi, 2011; \u2020Lithembia Ross, 1984; Litosembia Ross, 2001; Malacosembia Ross, 2001; Ochrembia Ross, 2001; Pararhagadochir Davis, 1940; Rhagadochir Enderlein, 1912 ; Xiphosembia Ross, 2001.The classification proposed by he Order , with a d below) . We alsoArchembiidae from Brazil (one Archembiinae and four Scelembiinae) are described and a complete list of archembiids species and new locality records are added . Thus, in Brazil, the family is represented by 30 species belonging to nine genera.Here, five new species of Taxon classificationAnimaliaEmbiopteraArchembiidae\ufeffGenusRoss, 1971203627CC-7A7C-5EEB-8B38-67B07761B320ArchembiaArchembialacombea Ross by original designation; Archembiakotzbaueri , senior synonym of A.lacombea; Ross, 1971: 30, type species Archembia differs from the close related genera Calamoclostes and Ecuadembia by having mandibles with incisive teeth concentrated in the apex, anterior edge of Sm diffuse; apical cerci longer than basal cerci, and medial position of LC1dp , Archembiabahia Ross, 2001, Archembiabatesi McLachlan, 1877 also present in Peru, Archembiadilata Ross, 2001 also present in Argentina, and Archembiaparanae Ross, 2001, exclusively from Brazil . Here, one new species is described from Brazil. Almost all the species of the genus were described by A.peruviana Ross, 2001 and A.lacombea Ross, 1971; see Catalog) or transferred to another genus ; see According to Szumik (2004)CAS as well as material deposited at INPA, MZUSP, MCZ, and USNM we have a better understanding of the distribution of this genus, with one species being present in the Amazon basin (A.batesi), four species present in the Atlantic Forest , and a new species described from the Cerrado and Pantanal ecoregion.Thanks to the observations on Ross\u2019s collection at South America.Archembia is a well-supported genus . Uniformly orangish brown with some color details: prothorax yellowish brown and wings brown. Total length 14.00. Head quite hirsute, almost circular, postocular suture scarcely marked, width/length = 0.79; eyes not large OR = 0.60; Md: 3\u20132 incisor teeth and 2\u20131 molar teeth. Mm conspicuous, Sm hirsute, anterior margin membranous and basally broad \u2019 \u2018Barro Alto, Est. Minas, Brazil Nov.\u2019 \u201831 (Jos\u00e9 Blaser) det. Davis Proc. L.S. N.S.W., 1940 65:348\u2019, MCZ.Brazil \u2022 Taxon classificationAnimaliaEmbiopteraArchembiidae\ufeffGenusDavis, 19400C06867E-E886-5764-9F89-BB53222A868FEmbiusEmbiusbrasilinesis Gray. ? Griffith & Pidgeon, 1832: 786, name and illustration, type species OlynthaEmbia Latreille, type species Olynthabrasiliensis Griffith and Pidgeon; Embia; Coleoptera. Griffith & Pidgeon, 1832: 347, as subgenus of EmbolynthaOlynthabrasiliensis, Embius and Olyntha preoccupied names; Davis, 1940c: 344, description and diagnosis, key to the species, type species ArgocercembiaArgocercembiaguyana Ross; Embolyntha Davis. Ross, 2001: 63, type species Embolyntha can be distinguished from other Archembiidae by Sm with anterior margin membranous, 10Lp1 simple and starting at inner caudal angle of 10L, 10Lp1 leaf-like with many longitudinal carinae from Brazil (without any specific location) and Embolynthaguyana from Guyana and Brazil . In addition, one new species from Brazil is described below. species : EmbolynSouth America.Argocercembia was synonymized with Embolyntha by 10Lp1 shape, a small medial bladder in males, and LC1dp in a medial position, both forming a well-supported group. In the higher classification of the Order or domed (E.guyana), absence of medial bladder on hind basitarsus, present in the other species.Male (holotype). General coloration brownish white with head, first antennomer, and fore tarsi brown, prothorax light brown and cerci whitish. Total length 4.00. Head and the external tip (flat lobe) separated, with both tips always shorter than the width of 10L. It can be differentiated by the presence of a sclerotized node between 10L and the base of LC1 and 10Rp2 with more than one longitudinal laminate keel from Trinidad and Venezuela, P.surinamensis from Surinam, P.balteata Ross, 1972, P.bicingillata , P.castaneus Salvatierra, 2020, P.christae Ross, 1972, P.minuta Ross, 2001, P.noronhensisP.flavicollis , P.tenuis from Bolivia; P.confusa Ross, 1944, P.schadei Ross, 1944, from Paraguay and Argentina; P.birabeni , P.pallida Ross, 2001, P.trachelia from Argentina and P.picchua Ross, 2001 from Peru. Recently, P.confusa was also found in Brazil . Head, prothorax, and legs light brown, pterothorax and abdomen orangish brown, terminalia and basal cerci whitish brown, antennal tips and apical cerci white. Total length 13.21. Head . Uniformly light brown with some color details: antenna, prothorax, and legs brownish; abdomen (except segments 9 and 10) and cerci whitish with edges of LC1dp brownish. Total length 10.18. Head width/length = 0.84, anterior margin of the clypeus slightly convex, postocular suture well developed . Head dark brown, thorax and abdomen orangish brown, except cerci brownish white. Total length 5.89. Head .Here, one new species is described for the family Taxon classificationAnimaliaEmbiopteraClothodidae\ufeffGenusRoss, 1987E0C51E01-4266-52F7-A825-5DE385B7CCBDChromatoclothodaChromatoclothodaelegantula Ross by original designation; Ross, 1987: 26, type species Chromatoclothoda can be distinguished from the other three genera of Clothodidae by having the male left paraproct well developed as a plate : one Peruvian species, Chromatoclothodaaurata Ross, 1987; C.albicauda Ross, 1987 from Colombia and Ecuador; C.neblina Szumik, 2001 from Venezuela and two Brazilian species, C.elegantula Ross, 1987 and the new species. For C.elegantula new records are added . The Peruvian species, C.nana Ross, 1987 and C.nigricauda Ross, 1987, were recently transferred to the genus Nonaia . Head dark brown, thorax brownish yellow, antenna, legs, and abdomen brown, except for the apical antennomeres and LC2 which are white. Total length 12.22. Head width/length = 0.82, postocular suture well developed; OR = 0.62; Md with 3\u20132 incisor teeth and 3\u20132 molar teeth; Mm inconspicuous, Sm strongly depressed, base broad, wider than anterior margin, anterior margin concave .Teratembiidae family is composed of five genera and considered a monophyletic group and sister group to Oligotomidae family ; D.unicolor comb. nov.; O.bicolor Ross, 1944; O.versicolor Ross, 1972; Teratembiaproducta Ross, 1944, and a new record reported here, T.bancksi Davis, 1939. New locality records are added as well as a complete list of the species known for Brazil .e family . IncludeOligotomasaundersii Westewood; for details see The list of species occurring in Brazil , 2100 m; SC, 20 km N Itajai; near Barra Velha, 50 m; 15 km W Blumenau; PR, Rondon, CAS.Chelicercaachilata Szumik, Pereyra & Ju\u00e1rez, sp. nov.Chelicercaachilata Szumik, Pereyra & Ju\u00e1rez, sp. nov., Male Holotype INPA, type locality: Brazil: RJ, Nova Friburgo, Maca\u00e9 de Cima.Chelicercaamazonica comb. nov.Cryptembiaamazonica Ross, 2003: 50, Male Holotype, Female Allotype CAS, type locality: Brazil: AP, Vila Amazonas, near Macap\u00e1.Additional record: Brazil: AP, Vila Amazonas, near Macap\u00e1, Paratypes CAS.Chelicercamanauara comb. nov.Cryptembiamanauara Ross, 2003: 52, Male Holotype CAS, Female unknown, type locality: Brazil: AM, 10 km N Manaus.New records: Brazil: AM, Manaus, Rod. AM-010, km 26, Reserva Ducke; Ig. Ubere; Ig. Acara, INPA.Chelicercaparaense comb. nov.Cryptembiaparaense Ross, 2003: 51, Male Holotype CAS, Female unknown, type locality: Brazil: PA, Mata da Pirelli, Marituba.Chelicercarioensis Ross, 2003Chelicercarioensis Ross, 2003: 108, Male Holotype, Female Allotype MZUSP, type locality: Brazil: RJ, Rio de Janeiro. Material observed: Male and Female, Paratypes same locality as holotype CAS.Chelicercarondonia comb. nov.Chriptembiarondonia Ross, 2003: 55, Male Holotype, Female Allotype CAS, type locality: Brazil: RO, Schmidt Farm, 67 km SW Ariquemes.Chelicercarossi Szumik, Pereyra & Ju\u00e1rez, nom. nov.Chelicercarondonia Ross, 2003: 113, Male Holotype, Female Allotype CAS, type locality: Brazil: RO, 62 km S Ariquemes, Fazenda Rancho Grande [primary junior homonym of Chelicercarondonia comb. nov.]Isosembiaaequalis Mesembiaaequalis Ross, 1944: 438, Holotype male USNM, type data: Brazil: SC, Nova Teutonia; Mari\u00f1o 1984: 91, distinguished from Mesembiajuarenzis Mari\u00f1o; Isosembiaaequalis: Additional records: Brazil: SC, Nova Teut\u00f4nia, Paratypes, MZUSP; Ridge immediately north of Seara, CAS.Oncosembiabiarmata Ross, 2003Oncosembiabiarmata Ross, 2003: 120, Holotype Male CAS, type data: Brazil: BA, 20 km SW Jequie.Additional record: Brazil: BA, 10 km SE of lpiau, CAS.Platyembiatessellata Ross, 2003Platyembiatessellata Ross, 2003: 47, Male Holotype, Female Allotype CAS, type locality: Peru: Madre de Dios, Explorer\u2019s Inn Rio Tambopata; Teixeira et al. 2018: 120, new record, Brazil: RO, close to rio Jaci Paran\u00e1, LABEI.Saussurembiaborba Szumik, Pereyra & Ju\u00e1rez, sp. nov.Saussurembiaborba Szumik, Pereyra & Ju\u00e1rez, sp. nov., Male Holotype INPA, type locality: Brazil: AM, Borba, Rio Abacaxis.Saussurembiaexigua comb. nov.Stenembiaexigua Ross, 1972: 142, Male Holotype, Female Allotype CAS, type locality: Brazil: PA, Bel\u00e9m; Additional record: Brazil: PA, Bel\u00e9m, Paratype, USNM.ARCHEMBIINAEFig. 49Archembiabahia Ross, 2001Archembiabahia Ross, 2001: 11, Male Holotype, Female Allotype CAS, type data: Brazil: BA, on hill 20 km SW Jequi\u00e9; Additional record: Brazil: ES, 20 km N of Linhares, CAS.Archembiabatesi Embiabatesi MacLachlan, 1877: 380, Male Holotype NHMUK, type data: Brazil: collected by Mr. Bates in the Amazons; Nav\u00e1s 1918: 96, 99, species key, male redescription.Embia (Olyntha) batesi: Hagen, 1885: 195, discussion; Kraus 1899: 148, list of Brazilian species.Olynthabatesi: Ragadochirbatesi: Embolynthabatesi: Davis 1940: 347, comb. nov., redescription; Barth 1954: 172, spinning apparatus; Barth and Lacombe 1955: 69, digestive system; Lacombe 1958: 177, respiratory system; 1958: 655, sexual dimorphism; 1960: 1, digestive system; 1963: 393, nervous system; 1964: 1, cephalic muscles; 1965: 503-513, Malpighian tubule system.Archembiabatesi: Archembiaperuviana Ross, 2001: 7 ; Archembiabatesi.CAS): BrazilAdditional records , Rio Negro; Manaus; M\u00e9dio Javari; RO: Rancho Grande, 62 km S Ariquemes; Colombia: Nari\u00f1o: Macoa; Ecuador: Napo: Ali\u00f1ahui, 25 km E Puerto Napo; Santa Rosa de Sucumb\u00edos; Napo-Pastaza: 5 km N Puyo; Marona-Santiago: 15 km N Limon. Peru: Ucayali: E end Boquer\u00f3n de Padre Abad; Pucallpa; Loreto: Iquitos; Amazon Camo, Rio Mom\u00f3n, 97.5 m (near Iquitos); Huanuco: Tingo Mar\u00eda; 4 mi SW Las Palmas.New records: Brazil: AM, Manaus, Campus do INPA; Reserva Ducke, INPA; PA, Rio Xingu Camp, 60 km S Altamira, USNM; Ecuador: Pastaza, Mera, CAS; Peru: Junin, Huacapistano, AMNH; Ucayali, Cordillera Azul, west end Boqueron de Padre Abad, CAS; 34 mi E of Tingo Maria, CAS.Archembiadilata Ross, 2001Archembiadilata Ross, 2001: 12, Male Holotype CAS, type data: Brazil: PR, Foz do Iguazu; Additional record: Brazil: PR, Rondon, CAS.New records (FML): Argentina: Misiones, Parque Nacional Iguaz\u00fa; PNI and RP101; Parque Provincial Urugua-\u00ed; Arroyo Pinalito, RP101.Archembiakotzbaurei Embiakotzbaurei Nav\u00e1s, 1925: 67, Male Holotype, type data: Brazil: RJ: Niter\u00f3i; Davis 1939: 379, probably referable to Clothoda or may be listed as a species inquirenda.Archembiakotzbaurei: MNRJ, Type Data: Brazil: RJ, Parque Nacional Tijuca (at Paineiras) above Rio de Janeiro, Paraneotypes CAS; Archembialacombea Ross, 1971: 33, Male Holotype, Female Allotype CAS, Type Data: Brazil: RJ, Ponte Maromba, Parque Nacional do Itatiaia; 2001: 8, redescription, new records; Szumik, 2004: 222, 224, junior syn. of Embiakotzbaurei Nav\u00e1s, phylogenetic analysis.CAS): BrazilAdditional records .New records: Brazil: RJ, Cabo Frio, CAS; Paineiras, CAS; Parque Lague, MNRJ; Tijuca, CAS; MNHNP; MG, 24 km E Soledade de Minas, CAS; SP, Jard\u00edn Bot\u00e1nico de S\u00e3o Paulo, MZUSP.Archembiaoruma Szumik, sp. nov.Archembiaoruma sp. nov., Male Holotype MZUSP, type data: Brazil: MS, Serra do Urucum-Corumb\u00e1.Additional record: Brazil: GO, Barro Alto, Est. Minas, MCZ.Archembiaparanae Ross, 2001Archembiaparanae Ross, 2001: 14, Male Holotype, Female Allotype MZUSP, type data: Brazil: PR, Pousada Recanto Bela Vista, picnic ground above S\u00e3o Jo\u00e3o da Graciosa, between Moretes and PR410, 800 m; CAS): BrazilAdditional records Ischnosembiaamazonica Ross, 2001: 33, Male Holotype, Female Allotype MNRJ, type locality: Brazil: AP, Vila Amazonas near Macap\u00e1.Ambonembiaamazonica: CAS): BrazilAdditional record Additional records Additional record : BrazilAdditional records Aphanembiaobscura Ross, 2001: 65, Male Holotype, Female Allotype CAS, type data: Peru: Ucayali, Yurac Plantation, 67 mi E of Tingo Mar\u00eda.Biguembiaobscura: Biguembiatroncol Szumik.CAS): PeruAdditional records EmbiusbrasiliensisOlynthabrasiliensisNHMUK, type data: Brazil; Embia (Olyntha) brasiliensis: Krauss 1899: 148, Brazilian species and relationship with Condylopalamaagilis Sund. as probable junior synonym.Embiabrasiliensis: Embia.Embolynthabrasiliensis: Davis 1940: 345, redescription, species type of Embolyntha Davis, specimen described by Embiabrasiliensis seems to be conspecific; Archembia; Brazil: RJ, Paineiras, 450 m, Parque Nac. da Tijuca; Additional records: Brazil: RJ, Rio de Janeiro, USNM; Itatiaia, CAS.New record: Brazil: PR, Virmond S., ZMB.Embolynthaguyana new recordArgocercembiaguyanaCAS, type data: Guyana: Demerara-Mahaica, Atkinson Airport .Embolynthaguyana: Argocercembia j. syn. of Embolyntha; New records: Brazil: AP, Vila Amazona; PA, Mata da Pirelli, near Bel\u00e9m; RR, 20 km N Caracarai; Boa Vista, CAS. These materials appeared in E.guyana.Embolynthaoriximina Szumik, Pereyra & Ju\u00e1rez, sp. nov.Embolynthaoriximina Szumik, Pereyra & Ju\u00e1rez, sp. nov., Male Holotype INPA, type data: Brazil: PA, Oriximin\u00e1, Rio Trombetas.INPA): Brazil: PAAdditional records Additional record ; P.noronhensisAdditional material: Brazil: SP, S\u00e3o Paulo (Park next Museu de Zoologia) Paratypes USNM, MZUSP; Usina Ester, near Cosm\u00f3polis, CAS.New records: Brazil: AM, Manaus, Petropolis; Conj. Tiradentes; RO, UHE Samuel, CDC 20 mts; RR, Ilha de Marac\u00e1 (EE Marac\u00e1), Rio Uraricoera, INPA; Alto Alegre, Reserva Biol\u00f3gica Ilha de Marac\u00e1; Surumu, MZUSP; SP, S\u00e3o Paulo, Ipiranga; Buritizal, Faz. Buritiz, MZUSP; TO, S\u00e3o Salvador, INPA.Pararhagadochirbicingillata Oligotomabicingillata Enderlein 1909: 111, Female Holotype MZV, type data: Brazil: Para; Oligotomasaundersii; Pararhagadochirbicingillata: CAS, type data: Brazil: PA, Bel\u00e9m; 2001: 50; PararhagadochirdavisiMCZ, type data: Brazil: AM, Parintins; 1972: 138, junior synonym of P.bicingillata; P.bicingillata.Additional records: Brazil: SP, R. Preto zw Boquerao Usina Sta. Rita, NHMV; TO, Santa Isabel, Rio Araguaia, CAS; AM, Uaup\u00e9s, R. Negro, CAS; Manaus, CAS; AP, Coracao near Macap\u00e1; RR, Mun. Boa Vista, Fazenda do Cabloco, CAS; Guyana: Mahaica-Berbice, Blairmont, CAS; Tobago: Canaan, Pigeon Point, CAS.New records: Brazil: RR, Boa Vista, leaf litter. CAS; MA, 15 km S Imperatriz, CAS; RO, 62 km SW Ariquemes Fazenda Rancho Grande, CAS; AM, 10 km N Manaus, CAS; Manaus, AM-010 km 35, Sitio Vida Tropical, INPA; Manaus, INPA-II Aleixo, INPA; Manaus, INPA, Campus II, INPA; Manaus, BR 174 km 43, Est. Exp. Sil. Trop., INPA; PA, Taperinha, Santarem, MZUSP.Pararhagadochirbonita Szumik, Pereyra & Ju\u00e1rez, sp. nov.Pararhagadochirbonita Szumik, Pereyra & Ju\u00e1rez, sp. nov., Male Holotype INPA, type locality: Brazil: BA, Camacan, Res. Serra Bonita.Pararhagadochircastaneus Salvatierra, 2020PararhagadochircastaneusINPA, type locality: Brazil: TO, Aragua\u00edna.Pararhagadochirchristae Ross, 1972PararhagadochirchristaeCAS, type data: Brazil: PA, Bel\u00e9m; 2001: 51; Additional records: Brazil: PA, Bel\u00e9m, Paratypes USNM; CE, near Minas do Uranio, CAS.New record: Brazil: MA, 15 km S Imperatriz, CAS.Pararhagadochirconfusa Ross, 1944Pararhagadochirargentina (Nav\u00e1s) MCZ; Ross, 1944: 428, erroneously identified by Davis.PararhagadochirconfusaMCZ, type data: Paraguay: Guair\u00e1, Villa Rica; Szumik 1998: 35, on the presence of the species in Argentina; Additional records: Brazil: RS, Rio Grande do Sul; Argentina: Buenos Aires, City Zoo; Corrientes, CAS.New records: Brazil: RO, Ariquemes, Rio Ji-Paran\u00e1, INPA; RS, Porto Alegre, FML; Santa Maria, MCZ; Pelotas; Cap\u00e3o do Le\u00e3o, LABEI; Paraguay: Central, Asunci\u00f3n, FML, MNHNPA; San Lorenzo; Villeta, MNHNPA; Concepci\u00f3n, Concepci\u00f3n, USNM; Guair\u00e1, Villa Rica, MCZ; Argentina: Buenos Aires, Capital Federal; Coghlan; Costanera Sur, INIDEP; Ciudad Universitaria; Facultad de Veterinaria; Lago Golf, Palermo; Parque Saavedra; Adrogu\u00e9; Campo de Mayo; km 26 F.C.G.B. Campo de Mayo; Ca\u00f1uelas; Coghlan; Castelar; Grand Bourg; Hurlingham; Isla Mart\u00edn Garc\u00eda; La Plata; Mart\u00ednez; Otamendi, INTA Delta; San Pedro; Temperley; Tigre; Rio Lujan, FML; Chaco, Colonia Ben\u00edtez, CAS, FML; Corrientes, PN Mburucuy\u00e1, parcela 6; Entre R\u00edos, Arroyo Tigrecito y RN18; Arroyo Villaguay (Villaguay); Balneario La Lana; Ceibas; Crespo; 5 km R\u00edo Gualeguay; RN12 (ex R126), Arroyo Orillas del Monte; Rosario del Tala, RP39 y Arroyo Gualeguay; Villa Urquiza; Formosa, Clorinda; PN Pilcomayo; Santa Fe, Santa Fe, FML.Pararhagadochirmarielleae Szumik, Pereyra & Ju\u00e1rez, sp. nov.Pararhagadochirmarielleae Szumik, Pereyra & Ju\u00e1rez, sp. nov., Male Holotype MZUSP, type locality: Brazil: MG, Serra do Cara\u00e7a, Exp. Mus. Zool.Pararhagadochirminuta Ross, 2001PararhagadochirminutaMZUSP , Paratypes CAS, type data: Brazil: CE, 37 km NE Tau\u00e1, 425 m; CAS): Brazil: CEAdditional records ; PB, 15 km SE Patos; S\u00e3o Bentinho; PI, 15 km N Sao Raimundo Nonato, 500 m; 24 km SW Picos.Pararhagadochirnoronhensis Costa-Pinto, Olivier & Rafael, 2021PararhagadochirnoronhensisINPA, type data: Brasil: PE, Fernando de Noronha, Trilha Sancho.Pararhagadochirpara Szumik, Pereyra & Ju\u00e1rez, sp. nov.Pararhagadochirpara Szumik, Pereyra & Ju\u00e1rez, sp. nov., Male Holotype INPA, type locality: Brazil: PA, Concei\u00e7\u00e3o do Araguaia.Xiphosembiaamapae Ross, 2001XiphosembiaamapaeMNRJ, Paratypes CAS, type data: Brazil: AP, Vila Amazonas, port of Icomi Mine, near Macap\u00e1; CAS)Additional record Embianobilis Gerstaecker 1888: 1, male and female, type data: Brazil: AM, Itaituba; Embia (Olyntha) nobilis Kraus 1899: 148, list of species from Brazil.Clothodanobilis: Enderlein 1909: 175, species type of Clothoda Enderlein; Brazil: AM, Fonteboa, 374, redescription based on a specimen from Itaituba, Brazil from McLachlan Collection NHMUK, according Davis probably belongs to series from which Gerstaerker\u2019s description was made; Ross, 1944: 406; 1987: 13 specimen of NHMUK assigned as neotype, redescription and new records; Ross 2000: 4, plesiomorphic conditions regarding fossil records, 41, female terminalia, 44, male terminalia; Szumik, 1996: 62, phylogeny; 2004: 234, outgroup on Archembiidae phylogeny; Blattodea phylogeny; Kluge 2012: 381, comparison with the new species Clothodaamazonica Kluge from Per\u00fa; Clothodatocantinensis Krolow and Valadares, species key; Gibocercus and Biguembia.Olynthanobilis: Additional records: Brazil: AM, Fonte Boa, MZV; Amazon basin, Reserva Ducke, 25 km N Manaus, CAS; 20 km N Manaus, CAS, USNM; Ponte da Bolivia; AP, Porto Platon; Serro do Navio; Casa do Sette, Amapari R, CAS.New Records: Brazil: AM, Manaus, AM-010 km 35, Sitio Vida Tropical; Ramal Agua Branca, Sitio Vida Tropical; Coari, Lago Coari; PA, Medicil\u00e1ndia Rod. Transamaz\u00f3nica, Bain. Ponte de Pedra, INPA; AP, Amap\u00e1, MNHNP.Clothodatocantinensis Krolow & Valadares, 2016ClothodatocantinensisINPA, Brazil: TO, Palmas, Distrito de Taquaru\u00e7u, Fazenda Encantada, 10\u00b015'02.3\"S, 48\u00b007'33.6\"W, 07\u201314.XII.2012, Malaise trap, TK Krolow and HIL Lima, coll.; 2 male paratypes, same locality and collectors, 14\u201321.XII.2012, CEUFT and INPA.Cryptoclothodaspinula Ross, 1987CryptoclothodaspinulaCAS, type data: Brazil: PA, 50 km N Paragominas; Fig. 53Diradiusplaumanni Oligembia (Dilobocerca) plaumanniUSNM, type data: Brazil: SC, Nova Teutonia.Diradiusplaumanni: Ross 1984: 45, comb. nov.; 2000: 48, anomalous male terminalia; Diradiusnougues Szumik; Additional records: Brazil: SC, Nova Teutonia, Paratypes CAS, USNM, MNHNP, MZUSP.New records: Brazil: SP, Providencias, MZUSP; Paraguay, MCZ; Argentina: Misiones, Parque Nac. Iguaz\u00fa, laboratorio; Parque Nac. Iguaz\u00fa, escuela; Parque Nac. Iguaz\u00fa, RP101: Corrientes, Parque Nac. Mburucuya, FML.Diradiuspusillus Friederichs, 1934DiradiuspusillusBrazil: SC, Isabelle, Humboldt Region; Davis 1940: 528, redescription; Diradiusnougues Szumik; New Record: Brazil: SC, 5 mi N. Itaja\u00ed, MNHNP.Diradiusunicolor comb. nov.OligembiaunicolorCAS, type data: Brazil: SC, Nova Teutonia; Diradiuserba Szumik; Additional record: Brazil: SC, Nova Teutonia, Paratypes, FML, MZUSP, MNHNP.New records: Brazil: DF, Planaltina, USNM; SP, Est. Exp. Pirassununga, MZUSP; Argentina: Misiones, 44 km E de El Dorado, RP17; A\u00b0 Pi\u00f1alito, 2 km r\u00edo abajo de RP101; Parque Nac. Iguaz\u00fa, laboratorio; Parque Nac. Iguaz\u00fa, RP101; Parque Nac. Iguaz\u00fa, RP101, 10 km del cruce; Parque Nac. Iguaz\u00fa, RP101, ca. de El Palmital; Parque Prov. Urugua-i, FML.Oligembiabicolor Ross, 1944OligembiabicolorUSNM, type data: Brazil: SC, Nova Teutonia; Oligembiamini Szumik; Additional records: Brazil: SC, Nova Teutonia, paratypes CAS, USNM, MCZ, MZUSP, MNHNP.New records: Brazil: TO, Ig. Sao Salvador, INPA.Oligembiaversicolor Ross, 1972OligembiaversicolorCAS, type data: Brazil: PA, Ilha Marajozinho; Additional record: Brazil: PA, Ilha Marajozinho Paratypes USNM.Teratembiabancksi new recordOligembiabanksi Davis 1939: 221, Male holotype MCZ, type data: Paraguay: Guair\u00e1, Villa Rica.Idioembiabanksi: Teratembiabanksi: Additional records: Paraguay: Guair\u00e1, Villa Rica, paratype MCZ.New records: Brazil: DF, Planaltina, USNM; Argentina: Misiones, PN Iguaz\u00fa, RP101; Salta, La Quena, RP34, FML.Teratembiaproducta IdioembiaproductaUSNM, type data: Brazil: SC, Nova Teutonia.Teratembiaproducta: Ross, 1952: 227, comb. nov., comparison with T.geniculata Krauss; Additional records: Brazil: SC, Nova Teutonia, Paratypes CAS, MCZ, USNM, MZUSP.New records: Brazil: SP, Campinas USNM; Rio Grande do Sul, Porto Alegre FML; Argentina: Misiones, Parque Nac. Iguaz\u00fa, escuela; Parque Nac. Iguaz\u00fa, laboratorio; Puerto Libertad; Formosa, Parque Nac. Pilcomayo, Estero Poi, FML."} +{"text": "Ongoing monitoring of COVID-19 disease burden in children will help inform mitigation strategies and guide pediatric vaccination programs. Leveraging a national, comprehensive dataset, we sought to quantify and compare disease burden and trends in hospitalizations for children and adults in the US. Data on coronavirus disease 2019 (COVID-19) in children and adolescents remain limited, even though 3.6 million pediatric cases have been reported in the US to date and several disease manifestations unique to children have been identified . P-values were estimated with parametric bootstrapping and deemed significant when adjusted for Bonferroni correction (P < 0.005). Significant p-values reflect the likelihood of a change point existing within the time interval.We used US Census population estimates to calculate weekly hospitalizations per 100,000 children 0\u201317 years) and adults, nationally and by region . Regions years anP = 0.0001 and P = 0.0004, respectively). Adult hospitalizations peaked during the week of January 1, at a rate of 44.3 per 100,000 adults, while pediatric hospitalizations peaked the following week, at a rate of 2.1 per 100,000 children.Over the 37-week study period, there were 35,919 pediatric and 2,052,932 adult COVID-19 hospitalizations, corresponding to a weekly median of 906 pediatric and 38,675 adult hospitalizations. National weekly hospitalization rates were 1.2 (IQR 1\u20131.7) per 100,000 children and 15.1 (IQR 12.6\u201332.9) per 100,000 adults . Change P = 0.0002) and October 2 (P = 0.0041), respectively. Across the other regions, significant change points were detected during the weeks of October 23 and October 30 for both pediatric and adult hospitalizations. Among children, the earliest peak occurred in the Midwest the week of November 6, while hospitalizations continued to rise in the Northeast until early February.Hospitalization rates and timing of change points varied by region . Median These national data indicate that peaks in COVID-19 hospitalization rates were 20-fold less for children than adults, though temporal trends were generally similar for pediatric and adult hospitalizations. There was substantial variation across regions, both in rates of hospitalizations observed and timing of changes in disease activity. Our findings highlight the importance of dedicated analyses of pediatric COVID-19 data to measure the impact of the pandemic on children, assess public health measures, and anticipate pediatric healthcare resource needs. Our study builds on prior work by Levin et al. by evaluating a comprehensive data source covering all 50 states and providing a direct comparison of pediatric and adult hospitalization rates through the launch of vaccination programs .Limitations of our study include use of an observational dataset subject to potential misclassification and under-reporting. We also were not able to perform additional patient-level or age group specific analyses as the dataset only identifies patients as pediatric and does not provide detailed demographic or other clinical information.COVID-19-related hospitalizations are a more robust measure of disease activity than COVID-19 case counts, as they are not subject to biases in testing strategies and represent a relevant health outcome. Evaluation of pediatric and adult hospitalization rates may inform policies for return to work and school activities as adults and children are vaccinated, as well as guide targeted protection of specific population groups. For any policy, the large variations in regional hospitalization rates underscore the need to consider local disease activity in implementation and assessment of mitigation strategies.https://healthdata.gov/Hospital/COVID-19-Reported-Patient-Impact-and-Hospital-Capa/g62h-syeh.Publicly available datasets were analyzed in this study. These data can be found at: MH conceptualized and designed the study, collected data, performed the analyses, drafted the initial manuscript, and revised the manuscript. ML performed data analysis and revised the manuscript. PA critically reviewed the manuscript for important intellectual content and revised the manuscript. YL coordinated and supervised data collection, critically reviewed the manuscript for important intellectual content, and revised the manuscript. FB conceptualized and designed the study, coordinated and supervised data collection, critically reviewed the manuscript for important intellectual content, and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.James R Aaron, Giuseppe Agapito, Adem Albayrak, Mario Alessiani, Danilo F Amendola, Li L. L. J Anthony, Bruce J Aronow, Fatima Ashraf, Andrew Atz, Paul Avillach, James Balshi, Brett K Beaulieu-Jones, Douglas S Bell, Antonio Bellasi, Riccardo Bellazzi, Vincent Benoit, Michele Beraghi, Jos\u00e9 Luis Bernal Sobrino, M\u00e9lodie Bernaux, Romain Bey, Alvar Blanco Mart\u00ednez, Martin Boeker, Clara-Lea Bonzel, John Booth, Silvano Bosari, Florence T Bourgeois, Robert L Bradford, Gabriel A Brat, St\u00e9phane Br\u00e9ant, Nicholas W Brown, William A Bryant, Mauro Bucalo, Anita Burgun, Tianxi Cai, Mario Cannataro, Aldo Carmona, Charlotte Caucheteux, Julien Champ, Jin Chen, Krista Chen, Luca Chiovato, Lorenzo Chiudinelli, Kelly Cho, James J Cimino, Tiago K Colicchio, Sylvie Cormont, S\u00e9bastien Cossin, Jean B Craig, Juan Luis Cruz Berm\u00fadez, Jaime Cruz Rojo, Arianna Dagliati, Mohamad Daniar, Christel Daniel, Priyam Das, Anahita Davoudi, Batsal Devkota, Julien Dubiel, Loic Esteve, Hossein Estiri, Shirley Fan, Robert W Follett, Paula S. A Gaiolla, Thomas Ganslandt, Noelia Garc\u00eda Barrio, Lana X Garmire, Nils Gehlenborg, Alon Geva, Tobias Gradinger, Alexandre Gramfort, Romain Griffier, Nicolas Griffon, Olivier Grisel, Alba Guti\u00e9rrez-Sacrist\u00e1n, David A Hanauer, Christian Haverkamp, Bing He, Darren W Henderson, Martin Hilka, Yuk-Lam Ho, John H Holmes, Chuan Hong, Petar Horki, Kenneth M Huling, Meghan R Hutch, Richard W Issitt, Anne Sophie Jannot, Vianney Jouhet, Mark S Keller, Katie Kirchoff, Jeffrey G Klann, Isaac S Kohane, Ian D Krantz, Detlef Kraska, Ashok K Krishnamurthy, Sehi L'Yi, Trang T Le, Judith Leblanc, Andressa RR Leite, Guillaume Lemaitre, Leslie Lenert, Damien Leprovost, Molei Liu, Ne Hooi Will Loh, Sara Lozano-Zahonero, Yuan Luo, Kristine E Lynch, Sadiqa Mahmood, Sarah Maidlow, Adeline Makoudjou, Alberto Malovini, Kenneth D Mandl, Chengsheng Mao, Anupama Maram, Patricia Martel, Aaron J Masino, Maria Mazzitelli, Arthur Mensch, Marianna Milano, Marcos F Minicucci, Bertrand Moal, Jason H Moore, Cinta Moraleda, Jeffrey S Morris, Michele Morris, Karyn L Moshal, Sajad Mousavi, Danielle L Mowery, Douglas A Murad, Shawn N Murphy, Thomas P Naughton, Antoine Neuraz, Kee Yuan Ngiam, Wanjiku FM Njoroge, James B Norman, Jihad Obeid, Marina P Okoshi, Karen L Olson, Gilbert S Omenn, Nina Orlova, Brian D Ostasiewski, Nathan P Palmer, Nicolas Paris, Lav P Patel, Miguel Pedrera Jimenez, Emily R Pfaff, Danielle Pillion, Hans U Prokosch, Robson A Prudente, V\u00edctor Quir\u00f3s Gonz\u00e1lez, Rachel B Ramoni, Maryna Raskin, Siegbert Rieg, Gustavo Roig Dom\u00ednguez, Pablo Rojo, Carlos S\u00e1ez, Elisa Salamanca, Malarkodi J Samayamuthu, L. Nelson Sanchez-Pinto, Arnaud Sandrin, Janaina CC Santos, Maria Savino, Emily R Schriver, Petra Schubert, Juergen Schuettler, Luigia Scudeller, Neil J Sebire, Pablo Serrano Balazote, Patricia Serre, Arnaud Serret-Larmande, Zahra Shakeri, Domenick Silvio, Piotr Sliz, Jiyeon Son, Charles Sonday, Andrew M South, Anastasia Spiridou, Amelia LM Tan, Bryce WQ Tan, Byorn WL Tan, Suzana E Tanni, Deanne M Taylor, Ana I Terriza Torres, Valentina Tibollo, Patric Tippmann, Carlo Torti, Enrico M Trecarichi, Yi-Ju Tseng, Andrew K Vallejos, Gael Varoquaux, Margaret E Vella, Guillaume Verdy, Jill-J\u00eann Vie, Shyam Visweswaran, Michele Vitacca, Kavishwar B Wagholikar, Lemuel R Waitman, Xuan Wang, Demian Wassermann, Griffin M Weber, Zongqi Xia, Nadir Yehya, William Yuan, Alberto Zambelli, Harrison G Zhang, Daniel Zoeller, Chiara Zucco.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The inaugural issue of each SoSyM volume-year is usually written during a time of personal and professional reflection. Over the past 12\u00a0months, researchers from all disciplines continued to experience the need for flexibility as the COVID-19 pandemic extended its impact across the globe through many variants. This has forced us all to adapt in many ways such that the idea of \u201cvirtual everything\u201d permeates our daily discussions. The software and systems modeling community continued to thrive and exhibited a great degree of flexibility and increased production in the overall research output, despite the limitations for in-person collaborations. In fact, for many years, the first issue of each SoSyM volume-year has reported growth in submissions and other important metrics. The same is true for the 2021 publication year of SoSyM. The journal continues a positive and healthy trajectory in the increased number of submissions and an impact factor that ranks SoSyM among the top publication venues for software engineering.The following sections report on various statistics and general updates about SoSyM that occurred over 2021. We invite all authors to continue submitting their contributions to SoSyM, and we are always available to correspond regarding questions about the suitability of an idea or potential submission. We wish you all of the best for a productive and satisfying year of research and personal growth in 2022!The six SoSyM issues published in 2021 contained 40 Regular papers, 32 Special Section papers, 5 Theme Section papers, 4 Expert Voices, 6 Guest Editorials, and 1 Erratum. In total, 2197 pages were published in volume 20. This is a 38% increase compared to the previous year and continues to represent the commitment by our publisher (Springer) in reducing the time to publication by processing papers expeditiously after acceptance. We are grateful to Elizabeth Dziubela, our Springer liaison, for her helpful efforts in assisting us with the expansion.https://www.sosym.org/.We are excited to report that the 2-year impact factor (IF) for SoSyM remains very respectable at 1.910 (previously at 1.876 in 2020 and 2.66 in the record year of 2019). The 5-year IF increased to 2.074 (from 1.915 last year). Furthermore, the h-5 Google Scholar ranking places SoSyM at #14 among all conferences and journals related to software engineering and programming languages. Further rankings can be found at We have observed that modeling continues to develop in overall maturity across the core domains of Software Engineering and Information Systems. Additionally, there is a growing interest in SoSyM among researchers who focus on model-based/model-driven activities in a wider area of software and systems engineering. This includes man-made systems, such as cars, airplanes, cell phones, and health care devices, but also existing systems from nature, which include biological systems, chemical structures and interactions, and of course complex physical or medical activities in various areas. Thus, it was natural that the number of submissions increased in 2021 over previous years. Over the past year, SoSyM received 420 submissions\u2014more than 50 additional submissions compared to 2020 and the largest number for any year in our history. Also, the number of downloads increased again. At the end of 2020, there were 179,555 downloaded SoSyM articles during the calendar year. Comparatively, the final 2021 yearly download total was 197,730.The acceptance rate increased in 2021 to 34.9% which seems to be coming from the fact that SoSyM has a strong reputation and the number of low-quality papers submitted has considerably decreased. Unfortunately, the average time from submission to the final decision (accept or reject) has also increased to 170\u00a0days (146\u00a0days in 2020). It remains a challenge for our Editors to identify reviewers amid a community that has the specific expertise in areas covered by SoSyM and the increased submissions are starting to exhibit new challenges in the decision time.When a research community matures, it is often interesting to take a look back through history to observe what contributions had the most impact and what topics emerged as most prominent over specific periods of time. Our collaboration with the MODELS conference has provided an opportunity for us to honor the authors of the most influential papers in our community. Each year, SoSyM identifies the two papers (from the Regular and Theme Section areas) that had the most impact over the past decade since their publication. The selection is based on the ISI citation index among papers published in SoSyM since 2010. The following two papers were presented virtually at MODELS 2021, and each author received an award certificate. We congratulate the authors for these \u201cMost Influential\u201d papers of SoSyM over the past decade.SoSyM 2021 \"10-year most influential Regular paper award\" was given to:Journal on Software and Systems Modeling (SoSyM), Volume 10, Issue 4, pp. 489\u2013514, Springer, October 2011.Zolt\u00e1n Micskei and H\u00e9l\u00e8ne Waeselynck, \"The many meanings of UML 2 Sequence Diagrams: A survey\", In: https://doi.org/10.1007/s10270-010-0157-9The SoSyM 2021 \"10-year most influential Theme Section paper award\" was given to:Journal on Software and Systems Modeling (SoSyM), Volume 10, Issue 3, pp. 313\u2013336, Springer, July 2011.Simona Bernardi, Jos\u00e9 Merseguer, and Dorina C. Petriu, \"A dependability profile within MARTE\", In: https://doi.org/10.1007/s10270-009-0128-1More information about the awards can be found at: http://www.sosym.org/awards/.The Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 3, pp. 611\u2013639, Springer, June 2021. https://doi.org/10.1007/s10270-021-00876-zMoussa Amrani, Dominique Blouin, Robert Heinrich, Arend Rensink, Hans Vangheluwe, and Andreas Wortmann, \"Multi-paradigm modelling for cyber\u2013physical systems: A descriptive framework\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 3, pp. 685\u2013709, Springer, June 2021. https://doi.org/10.1007/s10270-020-00856-9Sebastian Pilarski, Martin Staniszewski, Matthew Bryan, Frederic Villeneuve, and D\u00e1niel Varr\u00f3, \"Predictions-on-chip: model-based training and automated deployment of machine learning models at runtime\", In: Journal on Software and Systems Modeling (SoSyM), Springer, in press, 2021. https://doi.org/10.1007/s10270-021-00900-2Ferenc A. Somogyi, Gergely Mezei, Zolt\u00e1n Theisz, S\u00e1ndor B\u00e1csi, and D\u00e1niel Palatinszky, \"Playground for multi-level modeling constructs\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 3, pp. 711\u2013724, Springer, June 2021. https://doi.org/10.1007/s10270-020-00858-7Adrien Le Co\u00ebnt, Julien Alexandre dit Sandretto, and Alexandre Chapoutot, \"Guaranteed master for interval-based cosimulation\", In: Journal on Software and Systems Modeling (SoSyM), Springer, in this issue, 2021. https://doi.org/10.1007/s10270-021-00897-8L\u00e9a Brunschwig, Esther Guerra, and Juan de Lara, \"Modelling on mobile devices\u2014A systematic mapping study\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 6, pp. 2155\u20132197, Springer, December 2021. https://doi.org/10.1007/s10270-021-00888-9Sa\u0161a Kuhar and Gregor Polancic, \"Conceptualization, measurement, and application of semantic transparency in visual notations\u2014A systematic literature review\", In: Journal on Software and Systems Modeling (SoSyM), Springer, in this issue, 2021. https://doi.org/10.1007/s10270-021-00899-6Walter Cazzola, Sudipto Ghosh, Mohammed Al-Refai, and Gabriele Maurina, \"Bridging the model-to-code abstraction gap with fuzzy logic in model-based regression test selection\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 5, pp. 1735\u20131774, Springer, October 2021. https://doi.org/10.1007/s10270-021-00879-wG\u00e1bor Bergmann, \"Controllable and decomposable multidirectional synchronizations\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 4, pp. 1183\u20131213, Springer, August 2021. https://doi.org/10.1007/s10270-020-00842-1Javier Troya, Nathalie Moreno, Manuel F. Bertoa, and Antonio Vallecillo, \"Uncertainty representation in software models: A survey\", In: Journal on Software and Systems Modeling (SoSyM), Springer, in this issue, 2021. https://doi.org/10.1007/s10270-021-00905-xLissette Almonte, Esther Guerra, Iv\u00e1n Cantador, and Juan de Lara, \"Recommender systems in model-driven engineering\u2014A systematic mapping review\", In: Journal on Software and Systems Modeling (SoSyM), Springer, in this issue, 2021. https://doi.org/10.1007/s10270-021-00907-9Martina De Sanctis, Ludovico Iovino, Maria Teresa Rossi, and Manuel Wimmer, \"MIKADO: A smart city KPIs assessment modeling framework\", In: Journal on Software and Systems Modeling (SoSyM), Springer, in this issue, 2021. https://doi.org/10.1007/s10270-021-00898-7Wenjun Xiong, Emeline Legrand, Oscar \u00c5berg, and Robert Lagerstr\u00f6m, \"Cyber security threat modeling based on the MITRE Enterprise ATT&CK Matrix\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 6, pp. 2111\u20132130, Springer, December 2021. https://doi.org/10.1007/s10270-021-00883-0Alexander Boll, Florian Brokhausen, Tiago Amorim, Timo Kehrer, and Andreas Vogelsang, \"Characteristics, potentials, and limitations of open-source Simulink projects for empirical research\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 5, pp. 1713\u20131734, Springer, October 2021. https://doi.org/10.1007/s10270-021-00884-zOszk\u00e1r Semer\u00e1th, Aren A. Babikian, Boqi Chen, Chuning Li, Krist\u00f3f Marussy, G\u00e1bor Sz\u00e1rnyas, and D\u00e1niel Varr\u00f3, \"Automated generation of consistent, diverse and structurally realistic graph models\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 5, pp. 1609\u20131631, Springer, October 2021. https://doi.org/10.1007/s10270-021-00869-ySt\u00e9phanie Challita, Fabian Korte, Johannes Erbel, Faiez Zalila, Jens Grabowski, and Philippe Merle, \"Model-based cloud resource management with TOSCA and OCCI\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 5, pp. 1553\u20131586, Springer, October 2021. https://doi.org/10.1007/s10270-021-00868-zShahar Maoz and Jan Oliver Ringert, \"Spectra: A specification language for reactive systems\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 4, pp. 1123\u20131158, Springer, August 2021. https://doi.org/10.1007/s10270-020-00854-xSwaib Dragule, Thorsten Berger, Claudio Menghi, and Patrizio Pelliccione, \"A survey on the design space of end-user-oriented languages for specifying robotic missions\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 3, pp. 897\u2013916, Springer, June 2021. https://doi.org/10.1007/s10270-020-00834-1Weslley Torres, Mark G. J. van den Brand, and Alexander Serebrenik, \"A systematic literature review of cross-domain model consistency checking by model management tools\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 3, pp. 767\u2013793, Springer, June 2021. https://doi.org/10.1007/s10270-020-00827-0Pablo G\u00f3mez-Abajo, Esther Guerra, Juan de Lara, and Mercedes G. Merayo, \"Wodel-Test: A model-based framework for language-independent mutation testing\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 5, pp. 1653\u20131688, Springer, October 2021. https://doi.org/10.1007/s10270-021-00870-5Jaime Font, Lorena Arcega, \u00d8ystein Haugen, and Carlos Cetina, \"Handling nonconforming individuals in search-based model-driven engineering: nine generic strategies for feature location in the modeling space of the meta-object facility\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 5, pp. 1689\u20131712, Springer, October 2021. https://doi.org/10.1007/s10270-021-00878-xSina Madani, Dimitris Kolovos, and Richard F. Paige, \"Distributed model validation with Epsilon\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 5, pp. 1587\u20131608, Springer, October 2021. https://doi.org/10.1007/s10270-021-00864-3Maher Fakih, Oliver Klemp, Stefan Puch, and Kim Gr\u00fcttner, \"A modeling methodology for collaborative evaluation of future automotive innovations\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 5, pp. 1491\u20131523, Springer, October 2021. https://doi.org/10.1007/s10270-020-00853-yMahsa Panahandeh, Mohammad Hamdaqa, Bahman Zamani, and Abdelwahab Hamou-Lhadj, \"MUPPIT: A method for using proper patterns in model transformations\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 5, pp. 1525\u20131551, Springer, October 2021. https://doi.org/10.1007/s10270-020-00855-wSiamak Farshidi, Slinger Jansen, and Sven Fortuin, \"Model-driven development platform selection: Four industry case studies\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 4, pp. 1159\u20131181, Springer, August 2021. https://doi.org/10.1007/s10270-020-00841-2Arvind Nair, Xia Ning, and James H. Hill, \"Using recommender systems to improve proactive modeling\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 3, pp. 867\u2013895, Springer, June 2021. https://doi.org/10.1007/s10270-020-00833-2David Granada, Juan M. Vara, Mercedes Merayo, and Esperanza Marcos, \"CEViNEdit: Improving the process of creating cognitively effective graphical editors with GMF\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 4, pp. 1043\u20131077, Springer, August 2021. https://doi.org/10.1007/s10270-020-00839-wMatias Pol'la, Agustina Buccella, and Alejandra Cechich, \"Analysis of variability models: A systematic literature review\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 3, pp. 821\u2013835, Springer, June 2021. https://doi.org/10.1007/s10270-020-00830-5Feng Zhu and Jun Tang, \"Graphical composite modeling and simulation for multi-aircraft collision avoidance\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 3, pp. 837\u2013866, Springer, June 2021. https://doi.org/10.1007/s10270-020-00831-4Stefan Klikovits and Didier Buchs, \"Pragmatic reuse for DSML development\", In: Journal on Software and Systems Modeling (SoSyM), Volume 20, Issue 3, pp. 795\u2013819, Springer, June 2021. https://doi.org/10.1007/s10270-020-00829-yMojtaba Bagherzadeh, Karim Jahed, Benoit Combemale, and Juergen Dingel, \"Live modeling in the context of state machine models and code generation\", In: The collaboration between SoSyM and the MODELS conference continued with the organization of the SoSyM \u201cJournal-First\u201d option. This collaboration enables authors of recent SoSyM papers to present their work across the core conference sessions at MODELS. Through this collaboration, SoSyM authors have the opportunity to reach a broader audience to present their work. This includes research talks that explore more depth through analytical and empirical evidence than found in a typical MODELS conference paper. At MODELS 2021, a record number of \u201cSoSyM First\u201d papers were presented (30 papers). We are very thankful to the MODELS 2021 PC Chairs, Shiva Nejati and Daniel Varro, for their help in the integration of the SoSyM First papers into the general MODELS 2021 schedule. The SoSyM First papers presented at MODELS 2021 were the following :Jon Whittle is pursuing interesting new opportunities in his position as director of Australia\u2019s national science agency, CSIRO Data61. His new focus spans many different disciplines of scientific inquiry. Jon stepped down from the SoSyM Editorial Board this year after nearly 20\u00a0years of service to the software and systems modeling community. We are grateful for his assistance and wish him all of the best in his new professional endeavors.Colin Atkinson, Dominik Bork, Erwan Bousse, Travis Breaux, Carlos Cuesta, Martina De Sanctis, Juergen Dingel, Dirk Fahland, Loic Helouet, Nicolas Hili, J\u00f6rg Holtmann, Jennifer Horkoff, Thomas K\u00fchne, Akhil Kumar, Xavier Le Pallec, Assaf Marron, Bentley Oakes, Anthony Simons, Thomas Vogel, and Marco Wehrmeister.Below is a list of those who reviewed one or more papers for the journal in the last year. The complete list of reviewers can also be found on our website http://www.sosym.org/people/.Mohamed Abdelrazek, Suraj Ajit, Omar Alam, Ian Alexander, Hessa Alfraihi, Shaukat Ali, Joao Paulo Almeida, Ahmad Salim Al-Sibahi, Sanaa Alwidian, Vasco Amaral, Daniel Amyot, Paolo Arcaini, Wesley K. G. Assuncao, Colin Atkinson, Joanne Atlee, Claudia Ayala, Onder Babur, Omar Badreddin, Mira Balaban, Arosha Bandara, Torsten Bandyszak, Olivier Barais, Mikhail Barash, Luciano Baresi, Ankica Barisic, Konstantinos Barmpis, Jorge Barreiros, Angela Barriga, Thais Batista, Edouard Batot, Dinesh Batra, Steffen Becker, Nelly Bencomo, Luca Berardinelli, Robin Bergenthum, Thorsten Berger, Gabor Bergmann, Ilia Bider, Gordon Blair, Dominique Blouin, Alvine Boaye-Belle, Francis Bordeleau, Dominik Bork, Artur Boronat, Paolo Bottoni, Juan Boubeta-Puig, Johann Bourcier, Erwan Bousse, Jonathan Bowen, Drazen Brdjanin, Travis Breaux, Isabel Brito, Jan Broenink, Jean-Michel Bruel, Davide Brugali, Hugo Bruneliere, Alessio Bucaioni, Antonio Bucchiarone, Robert Buchmann, Thomas Buchmann, Andrea Burattin, Erik Burger, Loli Burgue\u00f1o, Rimantas Butleris, Cristina Cabanillas, Jordi Cabot, Javier Luis Canovas Izquierdo, Rafael Capilla, Emerson Carneiro de Andrade, Victorio Carvalho, K\u0101rlis \u010cer\u0101ns, Carlos Cetina, Moharram Challenger, Michel Chaudron, Xin Chen, Antonio Cicchetti, Federico Ciccozzi, Robert Claris\u00f3, Tony Clark, Manuel Clavel, Jane Cleland-Huang, Loek Cleophas, Benoit Combemale, Carlo Combi, Jos\u00e9 Conejero, Carl Corea, Dolors Costal, Jes\u00fas S\u00e1nchez Cuadrado, Carlos Cuesta, Alcino Cunha, Alberto da Silva, Fabiano Dalpiaz, Andrea D'Ambrogio, Nancy Day, Jose Luis de la Vara, Juan de Lara, Martina De Sanctis, Pierre De Saqui-Sannes, Marne de Vries, Julien DeAntoni, Renzo Degiovanni, Thomas Degueule, Joerg Desel, Byron DeVries, Xavier Devroey, Claudio Di Ciccio, Juri Di Rocco, Davide Di Ruscio, Vasiliki Diamantopoulou, Marcos Didonet Del Fabro, Juergen Dingel, Julio do Prado Leite, Marlon Dumas, Francisco Duran, Johann Eder, Alexander Egyed, Neil Ernst, Bedilia Estrada, Dirk Fahland, Kleinner Farias, Michael Fellmann, Jo\u00e3o Miguel Fernandes, Eduardo Fernandez, Nicolas Ferry, Robson Fidalgo, Hans-Georg Fill, Xavier Franch, Ulrich Frank, Marc Frappier, Piero Fraternali, Walid Gaaloul, Kelly Garces, Felix Garcia, Luciano Garcia Banuelos, Antonio Garc\u00eda-Dom\u00ednguez, Ning Ge, Sebastien Gerard, Sepideh Ghanavati, Mohamad Gharib, Aditya Ghose, Holger Giese, Christophe Gnaho, Sebastian Goetz, Arda Goknil, Thomas Goldschmidt, Cl\u00e1udio Gomes, Abel G\u00f3mez, Elena G\u00f3mez-Mart\u00ednez, Miguel Goul\u00e3o, Catarina Gralha, David Granada, Joel Greenyer, Paul Grefen, Georg Grossmann, Eoin Grua, John Grundy, Giancarlo Guizzardi, Renata Guizzardi, Sarra Habchi, Simon Hacks, Irit Hadar, Nabil Hameurlain, Regina Hebig, Monika Heiner, Robert Heinrich, Maritta Heisel, Nicolas Hili, Georg Hinkel, Knut Hinkelmann, Frank Hogrebe, J\u00f6rg Holtmann, Stijn Hoppenbrouwers, Jennifer Horkoff, Marianne Huchard, John Hutchinson, Emilio Insfran, Ludovico Iovino, Muhammad Zohaib Iqbal, Fuyuki Ishikawa, Ana Ivanchikj Moroni, Amin Jalali, Dietmar Jannach, Axel Jantsch, Steve Jenkins, Manfred A. Jeusfeld, Mohamed Jmaiel, Paul Johannesson, Reyes Juarez-Ramirez, Nafiseh Kahani, J\u0101nis Kampars, Geylani Kardas, Gabor Karsai, Timo Kehrer, Steven Kelly, Wael Kessentini, Djamel Eddine Khelladi, Marite Kirikova, Alexander Knapp, Shekoufeh Kolahdouz-Rahimi, Dimitrios Kolovos, Dimitris Kolovos, Anil Koyuncu, Lars Michael Kristensen, Thomas Kuehn, Thomas K\u00fchne, G\u00e9za Kulcs\u00e1r, Vinay Kulkarni, Akhil Kumar, Yvan Labiche, Katsiaryna Labunets, Robert Lagerstr\u00f6m, Leen Lambers, Elyes Lamine, Yngve Lamo, Kevin Lano, Xavier Le Pallec, Edward Lee, Martti Lehto, Henrik Leopold, Timothy Lethbridge, Nianyu Li, Shuai Li, Tong Li, Grischa Liebel, Crescencio Lima, Igor Linkov, Patricia Lopez, V\u00edctor L\u00f3pez-Jaquero, Oscar Luis, Roman Lukyanenko, Mass Soldal Lund, Xiaoxing Ma, Nuno Macedo, Fernando Mac\u00edas, Paulo Maia, Mahdi Manesh, Beatriz Mar\u00edn, Assaf Marron, Salvador Martinez, Nicholas Matragkas, Raimundas Matulevicius, Davide Andrea Mauro, Julio Medina, Anna Medve, Claudio Menghi, Giovanni Meroni, Jose Merseguer, Judith Michael, Fredrik Milani, Mark Minas, Miguel Mira da Silva, Pieter Mosterman, Hassan Mountassir, Haralambos Mouratidis, Saad Mubeen, Paula Mu\u00f1oz, John Mylopoulos, Elisa Yumi Nakagawa, Elena Navarro, Lukas Netz, Bernd Neumayr, Phu Nguyen, Phuong Nguyen, Nan Niu, Arne Nordmann, Bentley Oakes, Ileana Ober, Johnny \u00d6berg, Edson OliveiraJr, Alessandro Oltramari, Xavier Oriol, Michiel Overeem, Richard Freeman Paige, Elda Paja, Liliana Pasquale, Oscar Pastor, Cecile P\u00e9raire, Francisca P\u00e9rez, Robert Pettit, Alfonso Pierantonio, Joao Pimentel, Monica Pinto, Stephan Poelmans, Geert Poels, Pascal Poizat, Andrea Polini, Saheed Popoola, Pasqualina Potena, Henderik Proper, Truong Ho Quang, Elisa Quintarelli, Ansgar Radermacher, Akshay Rajhans, Jolyta Ralyt\u00e9, Qusai Ramadan, Nacim Ramdani, Aurora Ram\u00edrez, Eric J. Rapos, Alexander Raschke, Gil Regev, Manfred Reichert, Hajo Reijers, Elvinia Riccobene, Jan Oliver Ringert, Erkuden Rios Velasco, Roberto Rodr\u00edguez-Echeverr\u00eda, Michael Rosemann, Pedro Rossel, Ivan Ruchkin, Marcela Ruiz, Adrian Rutle, Mehrdad Saadatmand, Mahsa Sadi, Andrey Sadovykh, Neda Saeedloei, Houari Sahraoui, Rijul Saini, Mattia Salnitri, Leila Samimi, Jes\u00fas S\u00e1nchez Cuadrado, Kurt Sandkuhl, Stefan Sauer, Clemens Sauerwein, Christian Schilling, David Schmalzing, David Schmelter, Rainer Schmidt, Stefan Sch\u00f6nig, Stefan Schulte, Ulrik Schultz, Christoph Sch\u00fctz, Ed Seidewitz, Ronny Seiger, Bran Selic, Laura Semini, Sagar Sen, Arik Senderovich, Estefan\u00eda Serral Asensio, Mojtaba Shahin, Ramy Shahin, Mohammadreza Sharbaf, Carla Silva, Anthony Simons, Monique Snoeck, Pnina Soffer, Oleg Sokolsky, Hui Song, Wei Song, Jean-Sebastien Sottet, Thomas Springer, Emmanouela Stachtiari, Matthew Stephan, Perdita Stevens, Janis Stirna, Ketil St\u00f8len, Volker Stolz, Daniel Str\u00fcber, Arnon Sturm, Allison Sullivan, Yu Sun, Daniel Sundmark, Gerson Sunye, Angelo Susi, Andreas Symeonidis, Eugene Syriani, Gabriele Taentzer, J\u00e9r\u00e9mie Tatibouet, Paul Temple, Ernest Teniente, Thomas Th\u00fcm, Matthias Tichy, Ulyana Tikhonova, Massimo Tisi, Juha-Pekka Tolvanen, Victoria Torres, Konstantinos Traganos, Hanh Nhi Tran, Marina Tropmann-Frick, Javier Troya, Christos Tsigkanos, Katja Tuma, Samuel Tweneboah-Koduah, Mark Utting, Antonio Vallecillo, Nick R. T. P. van Beest, Mark van den Brand, Han van der Aa, Wil M.P. van der Aalst, Tijs van der Storm, Jean Vanderdonckt, Irene Vanderfeesten, Hans Vangheluwe, Juan Manuel Vara, Daniel Varro, Eric Verbeek, Eugenio Villar, Thomas Vogel, Johannes von Oswald, Yves Wautelet, Barbara Weber, Thomas Weber, Marco Wehrmeister, Ran Wei, Nils Weidmann, Hans Weigand, Mathias Weske, Bernhard Westfechtel, Martin Weyssow, Manuel Wimmer, Genta Indra Winata, Carson Woo, Andreas Wortmann, Franz Wotawa, Sebastian Wrede, Jianqing Wu, Wenhua Yang, Bahman Zamani, Anna Zamansky, Jelena Zdravkovic, Philipp Zech, Bernard P. Zeigler, Lingfang Zeng, Peng Zeng, Li Zhang, Man Zhang, Nan Zhang, Haiyan Zhao, Athanasios Zolotas, Steffen Zschaler, and Albert Zuendorf.A strong research community depends on the efforts of volunteers who help serve as reviewers. The software and systems modeling community has always risen to the request for help from SoSyM. We appreciate all of the help that the reviewers provided in service to the modeling community! We would also like to offer special recognition to the following reviewers, who were recommended as the SoSyM Best Reviewers of 2021, based on the technical depth and feedback provided to authors over the past year\u2014congratulations! Each of the following reviewers received a certificate of recognition:\u201cModels: The fourth dimension of computer science\u2014Towards studies of models and modelling,\u201d contributed by Bernhard Thalheim. Bernhard is a long-time member of our community, and his paper contains many insights and action points for your consideration. We strongly recommend his paper for your consideration and reflection on the role of modeling in computer science.This issue also includes a special Expert Voice article, with the thought provoking title, Expert voice\u201cModels: The fourth dimension of computer science\u2014Towards studies of models and modelling\u201d by Bernhard ThalheimOverview paper\"Model-driven engineering for mobile robotic systems: A systematic mapping study\" by Giuseppina Casalaro, Giulio Cattivera, Federico Ciccozzi, Ivano Malavolta, Andreas Wortmann, and Patrizio PelliccioneRegular papers\"On the automation-supported derivation of domain-specific UML profiles considering static semantics\" by Alexander Kraas\"Suggesting model transformation repairs for rule-based languages using a contract-based testing approach\" by Roberto Rodr\u00edguez-Echeverr\u00eda, Fernando Mac\u00edas, Adrian Rutle, and Jos\u00e9 Conejero\"An ontological metamodel for cyber-physical system safety, security, and resilience coengineering\" by Georgios Bakirtzis, Tim Sherburne, Stephen Adams, Barry Horowitz, Peter Beling, and Cody Fleming\"A generic LSTM neural network architecture to infer heterogeneous model transformations\" by Loli Burgue\u00f1o, Jordi Cabot, Shuai Li, and Sebastien Gerard\"Cyber security threat modeling based on the MITRE Enterprise ATT&CK Matrix\" by Wenjun Xiong, Emeline Legrand, Oscar \u00c5berg, and Robert Lagerstr\u00f6m\"Modelling on mobile devices\u2014A systematic mapping study\" by L\u00e9a Brunschwig, Esther Guerra, and Juan de Lara\"Bridging the model-to-code abstraction gap with fuzzy logic in model-based regression test selection\" by Walter Cazzola, Sudipto Ghosh, Mohammed Al-Refai, and Gabriele Maurina\"Guiding the evolution of product-line configurations\" by Michael Nieke, Gabriela Sampaio, Thomas Th\u00fcm, Christoph Seidl, Leopoldo Teixeira, and Ina Schaefer\"Recommender systems in model-driven engineering\u2014A systematic mapping review\" by Lissette Almonte, Esther Guerra, Iv\u00e1n Cantador, and Juan de Lara\"MIKADO: A smart city KPIs assessment modeling framework\" by Martina De Sanctis, Ludovico Iovino, Maria Rossi, and Manuel Wimmer\"A method for transforming knowledge discovery metamodel to ArchiMate models\" by Ricardo P\u00e9rez-Castillo, Andrea Delgado, Francisco Ruiz, Virginia Bacigalupe, and Mario Piattini\"Efficient model similarity estimation with robust hashing\" by Salvador Martinez, Sebastien Gerard, and Jordi Cabot\"Graphic modeling in Distributed Autonomous and Asynchronous Automata (DA3)\" by Wiktor Daszczuk\"Enhancing software model encoding for feature location approaches based on machine learning techniques\" by Ana Cristina Marc\u00e9n, Francisca P\u00e9rez, Oscar Pastor, and Carlos CetinaThe contents of this issue are as follows:We wish you a Happy New Year with the hope that you enjoy reading the papers in this issue!Huseyin Ergin, Jeff Gray, Bernhard Rumpe, and Martin Schindler."} +{"text": "In Dong et\u00a0al.,Ming Dong, Xin Wang, Tong L1, Jing Wang, Yunwei Yang, Yi Liu, Yaqing Jing, Honglin Zhao, Jun ChenThe author name, \u2018Tong L1\u2019, was incorrect and should have read, \u2018Tong Li\u2019. The corrected article byline is below:Ming Dong, Xin Wang, Tong Li, Jing Wang, Yunwei Yang, Yi Liu, Yaqing Jing, Honglin Zhao, Jun ChenThe online version of this article was corrected.We apologise for this error."} +{"text": "The original version of this paper did not contain a list of BIOLUX P-III investigators. The purpose of this addendum is to acknowledge the contribution of all investigators who participated in the study.Collaborators: BIOLUX P-III Global Registry Investigators: Marianne Brodmann, Thomas Zeller, Jean-Marc Corpataux, Matej Moscovic, Gunnar Tepe, Koen Keirse, Giovanni Nano, Johannes B. Dahm, Johnny Kent Christensen, Reza Ghotbi, Christoph Binkert, Henrik Schr\u00f6der, Denis Henroteaux, John Wang Chaw Chian, Eric Rosset, Enrique Alejandre Lafont, Sabrina Houthoofd, Miguel Araujo; Shaiful Azmi Yahaya, Don Robertson, Martin Freund, Lonneke Yo, Uei Pua, Roxanne Wu, Frank Hammer, Michael Lichtenberg, Janne Korhonen, Della Schiava, Ralf Langhoff, Stefano Michelagnoli, Secundino Llagostera, Jose-Maria Romero, Max Amor, Daniel Kretzschmar, Steven Kum, Patrice Mwipatayi, Albert J Smeets, Francisco Javier Serrano Hernando, Jost Philipp Sch\u00e4fer, Gil Marques, Jos C. van den Berg, Ramesh Velu, Karlis Kupcs"} +{"text": "LSU, rpb2, tub2 and ITS sequence data of representative Xylariales taxa indicated that Diabolocovidia, Didymobotryum and Vamsapriya cluster together and form a distinct clade in Xylariales. Morphological comparison also shows their distinctiveness from other families of Xylariales. Therefore, we introduce it as a novel family, Vamsapriyaceae. Based on morphological characteristics, Podosporium and Tretophragmia, which were previously classified in Ascomycota genera incertae sedis, are now included in the Vamsapriyaceae. In addition, three Vamsapriya species, V. chiangmaiensis sp. nov, V. uniseptata sp. nov, and V. indica are described and illustrated in this paper.Phylogenetic analyses of combined Xylariales is a large order with both conspicuous and inconspicuous fruiting bodies, and unitunicate, perithecial ascomycetes Index Fungorum number: IF29041; Facesoffungi number: FoF00372Vamsapriya indica Gawas & Bhat, Mycotaxon 94: 150 (2006) [2005]Type species: Saprobic on dead wood. Sexual morph: Ascomata solitary, scattered, immersed, subglobose, black, ostiolate. Peridium thin-walled, brown. Paraphyses hyaline, septate. Asci 8-spored, unitunicate, cylindrical, straight, short pedicellate, with a J+ apical ring. Ascospores uniseriate or overlapping uniseriate, fusiform to broad fusiform, apiosporous, hyaline, pointed at both ends, surrounded by a mucilaginous sheath. Asexual morph: Hyphomycetous. Colonies on natural substrate effuse, black, velvety. Mycelium immersed, septate, branched. Conidiophores macronematous, synnematous, erect, straight or curved, dark brown, cylindrical, septate. Synnemata erect, rigid, dark brown, composed of compact parallel conidiophores. Conidiogenous cells monotretic, integrated, terminal, clavate to cylindrical. Conidia catenate or solitary, acrogenous, cylindrical, oblong, fusiform or obclavate, brown to dark brown, septate, verruculose.Vamsapriya species are reported from tropical and subtropical regions, and most species are found in terrestrial as saprobes Index Fungorum number: IF550801; Facesoffungi number: FoF00374, Figure 3Saprobic on dead bamboo culms. Sexual morph: Undetermined. Asexual morph: Hyphomycetous. Colonies effuse, dark brown, hairy. Conidiophores macronematous, synnematous, single, erect, cylindrical, straight or slightly flexuous, dark brown, smooth-walled. Synnemata erect, straight or slightly flexuous, dark brown, rigid, with cylindrical to clavate apical fertile part, composed of compactly arranged conidiophores, 1300\u20131900 um long, 80\u2013150 \u03bcm wide at the base, 30\u201340 \u03bcm wide in the middle, 60\u2013140 \u03bcm wide at the apical fertile region, with basal portion immersed. Conidiogenous cells monotretic, integrated, terminal, brown, cylindrical to clavate, apically rounded, smooth-walled, 4.5\u20138.5 \u00d7 3\u20134.5 \u03bcm (n = 30). Conidia catenate, acrogenous, cylindrical, rounded at the apex, taper and subtruncate at the base, olivaceous brown to brown, 2\u20138-septate, slightly constricted at the septa, smooth, 20\u201348 \u00d7 4.5\u20136.5 \u03bcm (n = 20).Cultural characters: Conidia germinated on PDA within 12 h, germ tubes produced from both ends. Colonies reached 20 mm diam. within four weeks at 26 \u00b0C, cottony, flat, circular, edge entire, white from above, white to yellow from the below.Material examined: Thailand, Chiang Mai Province, Mae Taeng District, Pa Pae, Mushroom Research Center, on bamboo culms, 10 September 2020, H.W. Shen, M38 .Vamsapriya indica is the type species of Vamsapriya Index Fungorum number: IF9487; Facesoffungi number: FoF09931.Saprobic on decaying plants materials in terrestrial habitats. Colonies on natural substrate effuse, brown, velvety. Mycelium mostly immersed, composed of septate, flexuous branched hyphae. Asexual morph: Hyphomycetous. Conidiophores arranged in synnemata, brown, septate, sometimes branched at the apex. Synnemata erect, rigid, brown to dark. Conidiogenous cells mono- or polytretic, integrated or discrete, subulate or cylindrical, darkly pigmented. Conidia solitary, obclavate or bacilliform, multi-septate, brown to dark brown. Sexual morph: Unknown.Podosporium rigidum Schwein.Type species: Podosporium was introduced by Schweinitz Index Fungorum number: IF10265; Facesoffungi number: FoF09932.Saprobic on plants materials in terrestrial habitats. Colonies on natural substrate effuse, dark, velvety. Asexual morph: Hyphomycetous. Conidiophores macronematous, synnematous, brown, septate, erect, straight or broadly curved. Synnemata rigid, brown to dark, simple, erect, straight, consisting of a stalk and a capitate, broadened, fertile head. Conidiogenous cells monotretic, subulate or cylindrical, darkly pigmented. Conidia solitary, obclavate to fusiform or irregular in shape, straight, curved or bent, multi-septate, dark brown. Sexual morph: Unknown.Tretophragmia nilgirensis (Subram.) Subram. & NatarajanType species: Tretophragmia was introduced in 1974. The asexual morph of Tretophragmia is similar to Didymobotryum, Podosporium and Vamsapriya, while no sexual morph is reported. Seifert et al. [Tretophragmia as a synonym of Podosporium. However, Tretophragmia is accepted in the Index Fungorum [Tretophragmia have been described [Notes: t et al. treated Fungorum and the Fungorum as a sepescribed and no sVamsapriya species, V. chiangmaiensis, V. indica and V. uniseptata were collected from bamboo in terrestrial habitats. In our phylogenetic analyses of combined LSU, rpb2, tub2 and ITS sequence data, Diabolocovidia, Didymobotryum and Vamsapriya formed a distinct clade in Xylariales. Morphological comparison also shows their distinctiveness from other families in Xylariales. Therefore, we propose Vamsapriyaceae as a new family in Xylariales. The sexual morph of Vamsapriya differs from those of Xylariaceae in having hyaline apiospores [Vamsapriya is similar to Induratiaceae in having 8-spored asci with J+ apical ring and hyaline, apiospores, but Induratia (Induratiaceae) differs in having geniculosporium asexual morphs [Apioclypea is morphologically similar to the sexual morph of Vamsapriya in having 8-spored, pedunculate, cylindrical asci and biseriate, fusiform, hyaline ascospores with a mucilaginous sheath, but its asexual morph is unknown [In this study, three iospores ,30. It il morphs . Apiocly unknown ,21.Clypeosphaeriaceae and Induratiaceae are two other families that are phylogenetically related to Vamsapriyaceae, but they are distinct in morphology. Apioclypea, Aquasphaeria, Brunneiapiospora, Clypeosphaeria, Crassoascus, and Palmaria (Clypeosphaeriaceae) lack asexual morph descriptions and Diabolocovidia, Didymobotryum, Podosporium and Tretophragmia (Vamsapriyaceae) do not have sexual morph descriptions for the comparisons in Diabolocovidia claustri was isolated on leaves of Serenoa repens by Crous et al. [Vamsapriya, they are quite different in morphology. Diabolocovidia has micronematous rather than synnematous conidiophores, blastic rather than tretic conidiogenous cells, and ellipsoid to obovoid, aseptate conidia [Diabolocovidia mixes with synnematous and tretic genera like Didymobotryum and Vamsapriya reminds us of an example that Vanakripa with blastic conidiogenous resides in the phialidic genus Conioscypha [D. claustri is the only species represented by one isolate in Diabolocovidia, we suggest using more collections to confirm its phylogenetic placement in the future.s et al. . Althoug conidia . The pheioscypha . These pVamsapriya, Gawas and Bhat [Vamsapriya exhibits a combination of morphological characters of Didymobotryum [Podosporium [V. uniseptata resembles species of Didymobotryum in having catenate, oblong, and 1-septate conidia, but it clusters with the type species of Vamsapriya, V. indica. Vamsapriya breviconidiophora and V. yunnana resemble Podosporium species in having obclavate, solitary, and multi-septate conidia, but they are grouped with V. aquatica, which has catenate, cylindrical to obclavate, multi-septate conidia in the phylogenetic tree. Either the authors did not follow the generic concepts strictly when introducing species, or these three genera are probably congeneric. We tend to infer the latter; however, the conclusion requires a detailed re-examination of herbarium specimens and molecular data.When introducing and Bhat pointed sporous) ,53,54 ansporous) ,61,63. H"} +{"text": "Correction to: Arthritis Res Ther 23, 210 (2021)https://doi.org/10.1186/s13075-021-02593-wFollowing publication of the original article , the autWe would like to thank the PREVeNT-RA participants and principal investigators as follows: Dr Michael Batley - Maidstone and Tunbridge Wells NHS Trust, Dr Marwan Bukhari - Royal Lancaster Infirmary, Lancaster, Dr James Burns - Antrim Area Hospital, Northern Ireland, Dr Lucy Coates - Tameside General Hospital, Manchester, Dr Andrew Cope - Guy\u2019s Hospital, London, Dr Emily Deeney - Queen Elizabeth Hospital, Gateshead, Dr Karen Douglas - Russells Hall Hospital, Dudley, Dr Paul Emery - Leeds Teaching Hospital, Dr Andrew Filer - Birmingham Queen Elizabeth hospital, Dr Charlotte Filer - Stepping Hill Hospital, Stockport, Dr James Galloway - Kings College hospital, London, Dr Phillip Gardiner - Altnagelvin Hospital , Northern Ireland, Dr John Isaacs - Freeman Hospital, Newcastle, Dr Rachel Jeffrey - Northampton General Hospital, Dr Sophia Khan - Heart of England NHS foundation Trust, Solihull, Dr Suzanne Lane - Ipswich Hospital, Suffolk, Dr Sara Littlejohns - North Devon District Hospital, Barnstable, Dr Kirsten Mackay - Torbay Hospital, Torquay, Dr Nicola Maiden - Craigavon Area Hospital, Portadown, Dr Tarnya Marshall - Norfolk and Norwich University Hospital, Norfolk, Dr Sophia Naz - Fairfield General Hospital, Bury, Dr Sophia Naz - North Manchester General Hospital, Manchester, Dr Terence O'Neill - Salford Royal Hospital, Salford, Dr Ira Pande - Queens Medical Centre, Nottingham, Dr Yusef Patel - Hull Royal Infirmary, Hull, Dr Anandita Paul - Bolton NHS Foundation Trust, Dr John Pauling - Royal National Mineral Hospital for Rheumatic Diseases, Bath, Dr Adrian Peall - The County Hospital, Hereford, Dr Suzannah Pegler - Great Western Hospital, Swindon, Dr Helen Prady - Warrington and Halton Teaching Hospitals NHS Foundation Trust, Warrington, Dr Karim Raza - Birmingham City Hospital, Birmingham, Dr Lindsay Robertson - Derriford Hospital, Plymouth, Dr Richard Smith - Salisbury District Hospital, Wiltshire, Dr Peter Taylor - Oxford University Hospitals NHS Foundation Trust, Oxford, Dr Julia Taylor - Poole Hospital, Dorset, Jessica Thrush - Worcestershire Acute Hospitals NHS Trust, Redditch Dr Lisa Trembath - Royal Cornwall Hospital, Truro, Professor David Walsh - Sherwood Forest Hospitals NHS Foundation Trust, Nottinghamshire, Dr Pippa Watson - Manchester University NHS Foundation Trust, Manchester, Professor Simon Bowman - Milton Keynes University Hospital NHS Foundation Trust, Milton Keynes, Helena Cox - Burton Hospitals & Royal Derby Hospital, Dr Emily Deeney - Gateshead Health NHS Foundation Trust, Gateshead, Dr Sam Hider - Haywood Hospital, Stoke, Dr Cath Lawson - Harrogate District Hospital, Harrogate, Dr Paul McCabe - Trafford General Hospital, Manchester, Dr Constantino Pitzalis - Mile End Hospital, London, Dr Lee Suan - The Royal Blackburn Hospital, Blackburn, Dr Louise Warburton - Shropshire Community Health NHS Trust, Shrewsbury.The original article has been"} +{"text": "BRCA1 and BRCA2 pathogenic variant carriers.Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)\u2013negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.483 ER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 and BRCA2 carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85\u2009years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.PRSBRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variants are associated with increased male breast cancer and prostate cancer risks that combine the effects of multiple disease-associated single nucleotide polymorphisms (SNPs) provide marked cancer risk stratification in the general population ,15 and Bcarriers . Our prek levels . Recent k levels ,20 and hk levels .The Breast Cancer Association Consortium recently developed and validated a 313-SNP PRS in European ancestry women, which was further optimized to predict estrogen receptor (ER)\u2013specific disease . The estBRCA1 and BRCA2 carriers are likely to benefit from more personalized breast and prostate cancer risk estimates . We used the results to estimate age-specific absolute risks of developing breast and prostate cancers for male carriers by PRS distribution percentiles.Here, we assessed the associations of the newly developed 313-SNP breast cancer PRS and 147-SNP prostate cancer PRS derived using population-based data, with breast and prostate cancer risks, respectively, for male Statistical analyses were performed using R-3.6.3 (commands can be found in the BRCA1 and BRCA2 pathogenic variant carriers were recruited through 40 studies from 19 countries participating in the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) . The maj (CIMBA) . When a eviously and in SBRCA1 and BRCA2 pathogenic variants (detailed pathogenicity description: http://cimba.ccge.medschl.cam.ac.uk/files/CIMBA_Mutation_Classification_guidelines_May16.pdf) were categorized according to their known or predicted effect on protein function: class I included loss-of-function variants expected to yield unstable or no protein; class II included variants likely to produce stable mutant proteins , ER-negative (PRSER-), and ER-positive (PRSER+) breast cancer (PC) was scaled to the standard deviation calculated from population-based controls and Gleason scores of 7 or greater (cases).To assess the PRSDiscriminatory ability of each PRS was assessed by calculating the area under the receiver operator characteristic curve (AUC). Under the sampling design, the majority of male carriers were identified through clinical genetics. Therefore, the majority of both affected and unaffected carriers are expected to have family history of cancer. To determine whether this introduces any biases in the PRS associations, we fitted models that were adjusted for family history in first- and second-degree relatives.To determine whether PRS associations varied by age (continuous), pathogenic variant location, or pathogenic variant effects on protein function (class I or class II variants), we estimated interaction terms between these factors with the PRS, and statistical significance was assessed using likelihood ratio tests (LRT). Pathogenic variants were categorized based on previously reported nucleotide position differences in breast and ovarian, or prostate cancer risks .We undertook a sensitivity analysis to test for PRS heterogeneity across study countries and 1318 BRCA2 (244 breast and 141 prostate cancer cases) carriers of European ancestry and BRCA2 carriers. The PRSBC resulted in nearly identical associations as the PRSER+. There was no statistically significant evidence that the PRSER+ associations differed by country compared with men in the lowest quartile . The odds ratio for the association between the PRSER+ to discriminate between controls and breast cancer cases was estimated as an AUC of 0.60 (95% CI = 0.51 to 0.69) for BRCA1 and 0.59 (95% CI = 0.55 to 0.63) for BRCA2 carriers.The ability of PRSPC and prostate cancer risk for male carriers are reported in PC standard deviation were estimated to be 1.73 (95% CI = 1.28 to 2.33) for BRCA1 and 1.60 (95% CI = 1.34 to 1.91) for BRCA2 carriers. There was no statistically significant evidence that the PRSPC associations differed by country compared with men in the lowest quartile , also supported by the case-only analysis for BRCA1 and 0.62 (95% CI = 0.57 to 0.67) for BRCA2 carriers.The PRSER+ associations with breast cancer risk carriers compared with class I BRCA1 and BRCA2 variant carriers (LRT \u2265 .26).The PRScarriers . HoweverER+ (PLRT \u2265 .61) or PRSPC (PLRT = .52) associations differed by the pathogenic variant location in the gene for BRCA1 carriers. This pattern was not observed for BRCA2 carriers, who tend to develop more aggressive disease under IG 2018 - ID. 21389 and the Italian League for the Fight Against Cancer (LILT) under IG 2019 projects, P.I. Ottini Laura and Italian Ministry of Education, Universities and Research-Dipartimenti di Eccellenza-L. 232/2016. CIMBA: GCT is a National Health and Medical Research Council (NHMRC) Research Fellow. iCOGS and OncoArray data: the European Community\u2019s Seventh Framework Programme under grant agreement No. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK , the National Institutes of Health (NIH) (CA128978) and Post-Cancer GWAS initiative , the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Personalized Risk Stratification for Prevention and Early Detection of Breast Cancer (PERSPECTIVE) and PERSPECTIVE I&I projects were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy and Innovation through Genome Qu\u00e9bec, and The Quebec Breast Cancer Foundation and the Ontario Research Fund. Breast Cancer Family Registry (BCFR): UM1 CA164920 from the National Cancer Institute (NCI). Baltic Familial Breast Ovarian Cancer Consortium (BFBOCC): Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015. Beth Israel Deaconess Medical Center (BIDMC): Breast Cancer Research Foundation. BRCA-gene mutations and breast cancer in South African women (BMBSA): Cancer Association of South Africa (PI Elizabeth J. van Rensburg). Spanish National Cancer Centre (CNIO): Spanish Ministry of Health PI16/00440 supported by Fondo Europeo de Desarrollo Regional (FEDER) funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). City of Hope - Clinical Cancer Genomics Community Research Network (COH-CCGCRN): Research reported in this publication was supported by the NCI of the NIH under grant No. R25CA112486, and RC4CA153828 (PI: J. Weitzel) from the NCI and the Office of the Director, NIH. CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella (CONSIT TEAM): Associazione Italiana Ricerca sul Cancro to P. Radice. Funds from Italian citizens who allocated the 5x1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws to S. Manoukian. Associazione CAOS Varese to M.G. Tibiletti. AIRC (IG2015 No.16732) to P. Peterlongo. National Centre for Scientific Research Demokritos (DEMOKRITOS): European Union and Greek national funds through the Operational Program \u201cEducation and Lifelong Learning\u201d of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. German Cancer Research Center (DFKZ): German Cancer Research Center. Epidemiological Study of Familial Breast Cancer (EMBRACE): Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an National Institute for Health Research (NIHR) grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden National Health Service (NHS) Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Fox Chase Cancer Center (FCCC): The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. AKG was in part funded by the NCI (R01 CA214545 and R01 CA140323), The Kansas Institute for Precision Medicine (P20 GM130423), and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. is the Chancellors Distinguished Chair in Biomedical Sciences Professor. Fundaci\u00f3n P\u00fablica Galega de Medicina Xen\u00f3mica (FPGMX): FISPI05/2275 and Mutua Madrile\u00f1a Foundation (FMMA). German Familial Breast Group (GC-HBOC): German Cancer Aid and the European Regional Development Fund and Free State of Saxony, Germany . Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO): Ligue Nationale Contre le Cancer; the Association \u201cLe cancer du sein, parlons-en!\u201d Award, the Canadian Institutes of Health Research for the \u201cCIHR Team in Familial Risks of Breast Cancer\u201d program and the French National Institute of Cancer (INCa grants 2013-1-BCB-01-ICH-1 and SHS-E-SP 18-015). Georgetown University (GEORGETOWN): the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing Fore the Cure. Ghent University Hospital (G-FAST): Bruce Poppe is a senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. Hospital Clinico San Carlos (HCSC): Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. Helsinki Breast Cancer Study (HEBCS): Helsinki University Hospital Research Fund, the Finnish Cancer Society and the Sigrid Juselius Foundation. Hereditary Breast and Ovarian cancer study the Netherlands (HEBON): the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of Dutch Cancer Registry and the Dutch Pathology database for part of the data collection. Study of Genetic Mutations in Breast and Ovarian Cancer patients in Hong Kong and Asia (HRBCP): Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health1R 03CA130065, and North California Cancer Center. Molecular Genetic Studies of Breast- and Ovarian Cancer in Hungary (HUNBOCS): Hungarian Research Grants KTIA-OTKA CK-80745 and NKFI_OTKA K-112228. Institut Catal\u00e0 d\u2019Oncologia (ICO): The authors would like to particularly acknowledge the support of the Asociaci\u00f3n Espa\u00f1ola Contra el C\u00e1ncer (AECC), the Instituto de Salud Carlos III and \u201cFEDER, una manera de hacer Europa\u201d and the Institut Catal\u00e0 de la Salut and Autonomous Government of Catalonia . International Hereditary Cancer Centre (IHCC): PBZ_KBN_122/P05/2004. Iceland Landspitali \u2013 University Hospital (ILUH): Icelandic Association \u201cWalking for Breast Cancer Research\u201d and by the Landspitali University Hospital Research Fund. INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility (INHERIT): Canadian Institutes of Health Research for the \u201cCIHR Team in Familial Risks of Breast Cancer\u201d program\u2014grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade\u2014grant No. PSR-SIIRI-701. Istituto Oncologico Veneto (IOVHBOCS): Ministero della Salute and \u201c5x1000\u201d Istituto Oncologico Veneto grant. Portuguese Oncology Institute-Porto Breast Cancer Study (IPOBCS): Liga Portuguesa Contra o Cancro. Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab): The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Korean Hereditary Breast Cancer Study (KOHBRA): the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea . Mayo Clinic (MAYO): NIH grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer Research Foundation. McGill University (MCGILL): Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. Marc Tischkowitz is supported by the funded by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). Modifier Study of Quantitative Effects on Disease (MODSQUAD): MH CZ\u2014DRO , MEYS\u2014NPS I\u2014LO1413 to LF, and by Charles University in Prague project UNCE204024 (MZ). Memorial Sloane Kettering Cancer Center (MSKCC): the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). Women\u2019s College Research Institute Hereditary Breast and Ovarian Cancer Study (NAROD): 1R01 CA149429-01. National Cancer Institute (NCI): the Intramural Research Program of the US NCI, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD. National Israeli Cancer Control Center (NICCC): Clalit Health Services in Israel, the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. N.N. Petrov Institute of Oncology (NNPIO): the Russian Foundation for Basic Research . NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. The Ohio State University Comprehensive Cancer Center (OSUCCG): Ohio State University Comprehensive Cancer Center. Universit\u00e0 di Pisa (PBCS): AIRC [IG 2013\u2009N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. South East Asian Breast Cancer Association Study (SEABASS): Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. Sheba Medical Centre (SMC): the Israeli Cancer Association. Swedish Breast Cancer Study (SWE-BRCA): the Swedish Cancer Society. University of Chicago (UCHICAGO): NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women\u2019s Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an American Cancer Society (ACS) Clinical Research Professor. University of California Los Angeles (UCLA): Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. University of California San Francisco (UCSF): UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UK Familial Ovarian Cancer Registry (UKFOCR): Cancer Research UK. University of Pennsylvania (UPENN): NIH (R01-CA102776 and R01-CA083855); Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. Cancer Family Registry University of Pittsburg (UPITT/MWH): Hackers for Hope Pittsburgh. Victorian Familial Cancer Trials Group (VFCTG): Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. Women\u2019s Cancer Program at Cedars-Sinai Medical Center (WCP): Dr Karlan is funded by the ACS Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. TN-D is a recipient of a Career Development Fellow from the National Breast Cancer Foundation .Role of the funders: The study sponsors had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication.Disclosures: ILA has received funding from the NIH. NA has received lecture fees from AstraZeneca and Clovis Oncology. \u00c5B has received personal honoraria for lectures at courses in tumor biology and genetics for medical students and physicians, courses organized by AstraZeneca and Roche. LC has received honoraria from AstraZeneca, MSD, Pfizer and Novartis. SMD has received honoraria from AstraZeneca. CE received funding from German Cancer Aid. DGE has received honoraria from AstraZeneca, Springworks and Cerexis. AKG has received funding from the NIH, NCI, and NIGMS and honoraria from VITRAC Therapeutics and NanoString Technologies, and is co-founder of Sinochips Diagnostics. TVOH has received lecture honoraria from Pfizer. GK received advisory board honoraria from AstraZeneca, Sanofi-Aventis, Janssen, Bayer, AMGEN, Ferring and Astellas. H.N has funding from the Helsinki University Hospital Research Fund, The Sigrid Juselius Foundation, The Finnish Cancer Society and honoraria from AstraZeneca. OIO is co-Founder of Cancer IQ and serves on the boards of 54gene and Tempus. ZS\u2019s immediate family member received consulting fees from Genentech/Roche, Novartis, RegenexBio, Neurogene, Optos Plc, Regeneron, Allergan, Gyroscope Tx and Adverum. L.S has received funding from the NCI paid to institution. AET has received funding from the NCI paid to institution. ATo has received honoraria from Lilly, Roche, Novartis and MSD. JV has received funding from the Breast Cancer Research Foundation. FJC has received funding from the NIH and the Breast Cancer Research Foundation paid to institution. RKS has received funding from German Cancer Aid. JS has received funding from the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Minist\u00e8re de l\u2019\u00c9conomie et de l\u2019Innovation du Qu\u00e9bec through Genome Qu\u00e9bec, the Quebec Breast Cancer Foundation, the CHU de Quebec Foundation, and the Ontario Research Fund. DFE has received funding from Cancer Research UK paid to institution. ACA is listed as creator of the BOADICEA algorithm, which has been licensed to Cambridge Enterprise. LO has received funding from the Italian Association for Cancer Research. All other authors have no disclosures.Author contributions: Conceptualization: GC-T, ACA and LO. Data curation: DRB, GL, LMc, JD and XY. Formal analysis: DRB and VS. Funding acquisition: KO, MTh, FJC, RKS, JS, DFE, GC-T, ACA and LO. Investigation: DRB, VS, JAd, BAA, MA, KA, ILA, AA, NA, BA, JAz, JBal, RBB, DB, JBar, MB, JBe, PBe, SEB, \u00c5B, ABo, ABr, PBr, CB, JBr, ABu, SSB, TC, MAC, IC, HC, LLC, GC, KBMC, JC, AC, LC, GD, ED, RD, MDLH, KDL, RDP, JDV, OD, YCD, SMD, AD, JE, RE, CE, DGE, LF, FF, MF, DF, DG, AG, SG, GG, AKG, DEG, MHG, HG, EG, EH, UH, TVOH, HH, JHe, JHo, LI, AI, PAJ, RJ, UBJ, OTJ, EMJ, GK, LK, TAK, CLau, CLaz, FL, AL-F, PLM, SM, ZM, LMa, KNM, NM, AMe, MM, ANM, PJM, TAM, AMu, KLN, SLN, HN, TN-D, DN, EO, OIO, DP, MTP, ISP, BP, PP-S, PPe, AHP, PPi, MEP, CP, MAP, PR, JRam, JRan, MR, MTR, KR, AR, AMSDA, PDS, SS, LES, CFS, ZS, LS, DS-L, CS, YYT, MRT, ATe, DLT, MTi, AET, ST, ATo, AHT, VT, VV, CJVA, MV, AV, JV, LW, SW-G, BW, AW, IZ, KO, MTh, FJC, RKS, JS, DFE, GC-T, ACA and LO. Methodology: DRB, VS, ACA and LO. Project administration: GL, LMc, ACA and LO. Resources: JAd, BAA, MA, KA, ILA, AA, NA, BA, JAz, JBal, RBB, DB, JBar, MB, JBe, PBe, SEB, \u00c5B, ABo, ABr, PBr, CB, JBr, ABu, SSB, TC, MAC, IC, HC, LLC, GC, KBMC, JC, AC, LC, GD, ED, RD, MDLH, KDL, RDP, JDV, OD, YCD, SMD, AD, JE, RE, CE, DGE, LF, FF, MF, DF, DG, AG, SG, GG, AKG, DEG, MHG, HG, EG, EH, UH, TVOH, HH, JHe, JHo, LI, AI, PAJ, RJ, UBJ, OTJ, EMJ, GK, LK, TAK, CLau, CLaz, FL, AL-F, PLM, SM, ZM, LMa, KNM, NM, AMe, MM, ANM, PJM, TAM, AMu, KLN, SLN, HN, TN-D, DN, EO, OIO, DP, MTP, ISP, BP, PP-S, PPe, AHP, PPi, MEP, CP, MAP, PR, JRam, JRan, MR, MTR, KR, AR, AMSDA, PDS, SS, LES, CFS, ZS, LS, DS-L, CS, YYT, MRT, ATe, DLT, MTi, AET, ST, ATo, AHT, VT, VV, CJVA, MV, AV, JV, LW, SW-G, BW, AW, IZ, KO, MTh, FJC, RKS, JS, DFE, GC-T, ACA and LO. Software: DRB. Supervision: ACA and LO. Visualization: DRB. Writing\u2014original draft: DRB, VS, ACA and LO. Writing\u2014review & editing: DRB, VS, GL, LMc, JD, XY, JAd, BAA, MA, KA, ILA, AA, NA, BA, JAz, JBal, RBB, DB, JBar, MB, JBe, PBe, SEB, \u00c5B, ABo, ABr, PBr, CB, JBr, ABu, SSB, TC, MAC, IC, HC, LLC, GC, KBMC, JC, AC, LC, GD, ED, RD, MDLH, KDL, RDP, JDV, OD, YCD, SMD, AD, JE, RE, CE, DGE, LF, FF, MF, DF, DG, AG, SG, GG, AKG, DEG, MHG, HG, EG, EH, UH, TVOH, HH, JHe, JHo, LI, AI, PAJ, RJ, UBJ, OTJ, EMJ, GK, LK, TAK, CLau, CLaz, FL, AL-F, PLM, SM, ZM, LMa, KNM, NM, AMe, MM, ANM, PJM, TAM, AMu, KLN, SLN, HN, TN-D, DN, EO, OIO, DP, MTP, ISP, BP, PP-S, PPe, AHP, PPi, MEP, CP, MAP, PR, JRam, JRan, MR, MTR, KR, AR, AMSDA, PDS, SS, LES, CFS, ZS, LS, DS-L, CS, YYT, MRT, ATe, DLT, MTi, AET, ST, ATo, AHT, VT, VV, CJVA, MV, AV, JV, LW, SW-G, BW, AW, IZ, KO, MTh, FJC, RKS, JS, DFE, GC-T, ACA and LO.djab147_Supplementary_DataClick here for additional data file."} +{"text": "The article, Japan Society of Clinical Oncology Clinical Practice Guidelines 2017 for fertility preservation in childhood, adolescent, and young adult cancer patients: part 2 written by Akiko Tozawa, Fuminori Kimura, Yasushi Takai, Takeshi Nakajima, Kimio Ushijima, Hiroaki Kobayashi, Toyomi Satoh, Miyuki Harada, Kohei Sugimoto, Shigehira Saji, Chikako Shimizu, Kyoko Akiyama, Hiroko Bando, Akira Kuwahara, Tatsuro Furui, Hiroshi Okada, Koji Kawai, Nobuo Shinohara, Koichi Nagao, Michio Kitajima, Souichi Suenobu,Toshinori Soejima, Mitsuru Miyachi, Yoko Miyoshi, Akihiro Yoneda, Akihito Horie,Yasushi Ishida, Noriko Usui, Yoshinobu Kanda, Nobuharu Fujii, Makoto Endo, Robert Nakayama, Manabu Hoshi, Tsukasa Yonemoto, Chikako Kiyotani, Natsuko Okita, Eishi Baba, Manabu Muto, Iwaho Kikuchi, Ken\u2011ichirou Morishige, Koichiro Tsugawa, Hiroyuki Nishiyama, Hajime Hosoi, Mitsune Tanimoto, Akira Kawai, Kazuhiko Sugiyama, Narikazu Boku, Masato Yonemura, Naoko Hayashi, Daisuke Aoki, Nao Suzuki, Yutaka Osuga was originally published Online First without Open Access.http://creativecommons.org/licenses/by/4.0.With the author(s)\u2019 decision to opt for Open Choice the copyright of the article changed on February 14, 2022 to \u00a9 Author(s) 2021 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article\u2019s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article\u2019s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The original article has been corrected."} +{"text": "Psoriasis vulgaris is a chronic inflammatory skin disease characterized by well-demarcated scaly plaques. Oxidative stress plays a crucial role in the psoriasis pathogenesis and is associated with the disease severity. Dimethyl fumarate modulates the activity of the pro-inflammatory transcription factors. This is responsible for the downregulation of inflammatory cytokines and an overall shift from a pro-inflammatory to an anti-inflammatory/regulatory response. Both steps are necessary for the amelioration of psoriatic inflammation, although additional mechanisms have been proposed. Several studies reported a long-term effectiveness and safety of dimethyl fumarate monotherapy in patients with moderate-to-severe psoriasis. Furthermore, psoriasis is a chronic disease often associated to metabolic comorbidities, as obesity, diabetes, and cardiovascular diseases, in which glutathione-S transferase deregulation is present. Glutathione-S transferase is involved in the antioxidant system. An increase of its activity in psoriatic epidermis in comparison with the uninvolved and normal epidermal biopsies has been reported. Dimethyl fumarate depletes glutathione-S transferase by formation of covalently linked conjugates. This review investigates the anti-inflammatory role of dimethyl fumarate in oxidative stress and its effect by reducing oxidative stress. The glutathione-S transferase regulation is helpful in treating psoriasis, with an anti-inflammatory effect on the keratinocytes hyperproliferation, and in modulation of metabolic comorbidities. The MMFceptor 2 . Such ims of DMF . Recent s of DMF . Some ofs of DMF . Importauccinate , 43. Prouccinate . This evpulation . A metabpulation . The DMFresponse . Immune obtained . Fumaratobtained . Upon DMobtained . Besidesobtained \u201354, like adducts , and thi adducts , 56, mak adducts .Several studies have demonstrated that glutathione binding to DNA is able to regulate Nf-\u03baB proinflammatory activity. In particular, the Nf-\u03baB complex and the upstream proteins, as TRAF6, are negatively regulated by glutathione . GeneticGlutathione plasmic levels and GP activity in patients with psoriasis were significantly lower than in general population . ConsequGlutathione intracellular depletion in human antigen-presenting cells causes IL-10 production, with immuno-modulatory action, instead of the pro-inflammatory cytokines IL-12 and IL-23, responsible for Th1/Th17 immune system response switch in psoriasis. In this context, DMF promotes Th2 cell differentiation, with immunoregulatory functions .In summary, the rationale of employing DMF in psoriasis consists in reducing cellular inflammation both by decreasing glutathione intracellular levels and by inducing a switch in immune response toward an anti-inflammatory/immunoregulatory setting , 69. EurPatients with psoriasis are characterized by a higher prevalence of cardiovascular disease and metabolic syndrome . In partConceptualization was contributed by EC, SM, MD, AD, TC, DL, GC, CL, VM, RG, FP, FCo, KA, and LB. Methodology was contributed by EC, MD, AD, TC, DL, GC, CL, VM, RG, FP, FCo, FCi, KA, and LB. Validation was contributed by EC, SM, MD, TC, DL, GC, CL, VM, RG, FP, FCo, FCi, KA, and LB. Formal analysis was contributed by EC, SM, MD, AD, DL, GC, CL, VM, RG, FP, FCo, KA, and LB. Investigation was contributed by EC, SM, MD, AD, TC, GC, CL, VM, RG, FP, FCo, KA, and LB. Resources was contributed by EC, SM, MD, AD, TC, DL, CL, VM, RG, FP, FCo, KA, and LB. Data curation was contributed by EC, SM, MD, AD, TC, DL, GC, VM, RG, FP, FCo, KA, and LB. Writing\u2014original draft preparation was contributed by EC, SM, MD, AD, TC, DL, GC, CL, RG, FP, FCo, KA, and LB. Writing\u2014review and editing were contributed by EC, SM, MD, AD, TC, DL, GC, CL, VM, FP, FCo, FCi, KA, and LB. Visualization was contributed by EC, SM, MD, AD, TC, DL, GC, CL, VM, RG, FCo, KA, and LB. Supervision was contributed by EC, SM, MD, AD, TC, DL, GC, CL, VM, RG, FP, FCi, KA, and LB. Project administration was contributed by EC, SM, MD, AD, TC, DL, GC, CL, VM, RG, FP, FCo, and LB. All authors approved the submitted version and agreed to be personally accountable for the author's own contributions and for ensuring that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and documented in the literature.This study received funding from Almirall S.p.A. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Objective: To assess current management of diverticulitis in Switzerland.Methods: Prospective observational study of diverticulitis management and outcomes in surgical departments over a 3-month time period. Hospital category was graded according to the Swiss Medical Association (FMH) as: U: University; A: Cantonal; B: Regional; P: Private.Results: 75 participating hospitals treated 1,015 patients, among whom 214 patients (21%) had elective sigmoid resections in 49 hospitals. Indication for elective resection were recurrent diverticulitis, previous complicated diverticulitis, fistulas, and stenosis. Surgeries were performed completely laparoscopically in 185 cases (86%) and required conversion to open in 19 cases (9%). Overall postoperative complication rate was 18% (n = 39) and no mortality was observed. Operation time, surgeons experience and hospital stay differed considerably between hospital categories.Conclusions: Elective sigmoid resection for diverticulitis in Switzerland was mainly performed laparoscopically with low postoperative morbidity. Different practices and outcomes between institutions were observed. Traditionally, surgical resection was offered after the 2nd or 3rd episode of simple acute diverticulitis, in order to prevent recurrence and more serious forms , 2. CohoThe Swiss healthcare system is a public-private mix. Health care providers such as doctors and hospitals are partly private and public. In addition, care is the responsibility of the cantons, but certain aspects are regulated at the federal level. Every citizen is obligatorily covered by a basic insurance and pays monthly premiums to the health insurance of his choice. Basic insurance covers efficient and economical services which are defined by legal regulations. In order to supplement the basic insurance benefits, a citizen can take out an additional private insurance, which covers additional services in hospitals or private clinics, with free choice of location and caregiver. In principle, surgical residencies take place in University hospitals, and surgeons who work in public hospitals do not work in private hospitals.Considering these variations in the health system and the latest published management recommendations, the aim of the present study was to assess practice and outcomes of elective surgery for diverticulitis among different institutions in Switzerland over a specific previous period.This study assessed secondary outcomes of a prospective observational Swiss Snapshot Diverticulitis study which assessed the in-hospital management of colonic diverticulitis in surgical departments in Switzerland over a 3-month time period in 2014 . Particip \u2264 0.05 was considered statistically significant. Analyses performed using SPSS 26.0 software .Descriptive statistics for categorical variables were reported as number and percentage, while continuous variables were reported mean and standard deviation. Continuous variables were compared with the Kruskal\u2013Wallis test, while categorial variables were compared with the Pearson's chi square test. A n = 209, 98%). Surgeries were performed completely laparoscopically in 185 cases (86%) and required conversion to open in 19 cases (9%). The reasons for conversion were adhesions (n = 10), local inflammation (n = 5), inflammatory fistulas (n = 2), patient obesity (n = 1), and a ruptured suture line (n = 1). Nine complications occurred intraoperatively (4%), in particular spleen decapsulation (n = 3), anastomotic leakage at air test (n = 3), rectal perforation (n = 2), and small bowel perforation (n = 1).During study period, 75 participating hospitals treated 1,015 patients, among whom 214 patients (21%) had elective sigmoid resections in 49 hospitals. Indication for elective resection were recurrent diverticulitis, previous complicated diverticulitis, fistulas, and stenosis, which varied between categories of hospitals . Most pen = 39). Major complications occurred in eight patients (4%) and no mortality was observed. Surgical site infections occurred in 13 patients (6%), anastomotic leak in five patients (2%), bleeding in eight patients (4%), and postoperative ileus in five patients (2%).Overall postoperative complication rate was 18% , regardless of the type of hospital. This is a validated approach with increasing popularity in recent years, and it seems indicated on patients with recurrent disease or persistent symptoms after uncomplicated and complicated diverticulitis in order to improve their quality of life %, regard.The aim of elective surgical treatment of diverticular disease is the removal of the disease with prevention of its recurrence and restoration of bowel continuity whenever possible . There aRegarding the surgical approach, a systematic review of randomized controlled trials showed that there was insufficient evidence to support the efficacy and safety of laparoscopy compared to open surgery . HoweverSeveral limitations of the present study need to be addressed. First, there may be a selection bias, which limits generalization. Indeed, more health-conscious surgeons may choose to participate in studies assessing practices and outcomes. The inclusion of qualitative aspects focusing on patient and care provider perspectives on the elective management of diverticulitis would have been interesting and should be planned in future research. Lastly, the study provides a glimpse of what was happening in 2014, but probably the practices are the same nowadays. Two international guidelines were updated in 2020 , 8, howeIn conclusion, elective sigmoid resection for diverticulitis in Switzerland was mainly performed laparoscopically with low conversion and complication rates, and different practices and outcomes between institutions were observed.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Commission cantonale d'\u00e9thique de la recherche sur l'\u00eatre humain CER-VD, protocol 68/14. The patients/participants provided their written informed consent to participate in this study.SF, MH, ND, DH, and DM: study design, manuscript writing, and critical revision of the manuscript. SF, MH, and DH: data collection. DM: statistical analysis. ND: supervision. All authors contributed to the article and approved the submitted version.Swiss Snapshot Diverticulitis Group: Paolo Abitabile, Dritan Abrazhda, Michele Arigoni, Vahid Bakhshi-Tahami, Jean-Pierre Barras, Thomas Beck, Vincent Bettschart, Paul Biegger, Karin Bl\u00e4uer, Stefan Breitenstein, Franziska Brinkmann, Lukas Br\u00fcgger, Hans Brunner, Walter Brunner, Claude Bussard, Jean-Marie Calmes, Jean-Pierre Chevalley, Michael Chilcott, Denis Christinaz, Dimitri Christoforidis, Carlo Coduri, Nadine Crivelli, Aris D'Ambrogio, Branimir Damjanovic, Wiebke Decking, Diego De Lorenzi, Charles de Montmollin, Sona Deretti, Alexandre Descloux, Urs Diener, Marco Di Lazzaro, Luca Di Mare, Rok Dolanc, Andrea Donadini, Georg Donner, Bernhard Egger, Michel Erne, Fabrizio Fasolini, Charlotte-Ulrike Finkenzeller, Ivo Ralf Fischer, Daniel Frey, Raffaele Galli, Walter Gantert, Alain Garcia, J\u00f6rg Genstorfer, Pascal Gervaz, Bijan Ghavami, Nicola Ghisletta, Duri Gianom-Campell, Mauro Giuliani, Christine Glaser, Emanuel Gm\u00fcr, Federico Goti, J\u00fcrg Gresser, Felix Grieder, Gerald Gubler, Adriano Guerra, Silvio Gujer, J\u00fcrg Gurzeler, Susanne Habelt, Peter H\u00e4fliger, Andres Heigl, Dominik Heim, Juliette Henri, Mark Henschel, Rudolf Herzig, Franc Hetzer, Henry Hoffmann, Markus Huber, Regula Humm, Adrienne Imhof, Daniel Inderbitzin, Manuel Jakob, Renata Jori, Philomena Kastner, Andreas Keerl, Ulf Kessler, Philipp Kirchhoff, Jennifer Klasen, Katrin Kleinschmidt, J\u00fcrg Knaus, Markus Koch, Michael Kodsi, Erwin Kohlberger, Stefan Kull, Beat K\u00fcnzli, Sebastian Lamm, St\u00e9phanie Laperrousaz, Andr\u00e9 Leuenberger, Patrick M\u00e4der, Styliani Mantziari, Florian Martens, Lukas Marti, Olivier Martinet, Jean M\u00e9gevand, Gian Melcher, Antoine Meyer, Pierre Meyer, Philippe Morel, Murielle Mormont, Beat Muggli, Markus M\u00fcller, Stephan M\u00fcller, Andrew Munday, Surennaidoo Naiken, Antonio Nocito, Peter Nussbaumer, Daniel Oertli, Alexandre Paroz, Angelo Pelloni, J\u00f6rg Peltzer, Matthias Peter, Sebastian Pohle, Philippe Posso, Herv\u00e9 Probst, Alexander Radke, Martin Reber, Luca Regusci, Verena Reichl, Andreas Remiger, Jean-Claude Renggli, Monika Richter, Paavo Rillmann, Fr\u00e9d\u00e9ric Ris, Nadja Ristagno, Luca Rondi, Robert Rosenberg, Raffaele Rosso, Alend Saadi, Bernd Schenkluhn, Martin Schilling, Rolf Schlumpf, Bruno Schmied, Michael Schmitz, R\u00e9mi Schneider, Othmar Sch\u00f6b, Claudio Soravia, Ren\u00e9 Spalinger, Rudolf Steffen, Daniel Steinemann, Reto Stocker, Ulrich Stricker, Alexander Stupnicki, Michel Suter, Daniel Tassile, Adrien Tempia, Derya Topal, Rebekka Troller, Daniel Tr\u00f6tschler, C\u00e9dric Vallet, Denise Vettorel, Carsten Viehl, Peter Villiger, Peter Vogelbach, Marco von Strauss und Torney, Stephan Vorburger, Matthias Walting, Markus Weber, Heinz Wehrli, Bernhard Widmann, Stefan Wildi, Alessandro Wildisen, Bernd Wilhelm, Mariano Winckler, Marc Worreth, J\u00f6rg Wydler, Sidika Yakarisik, Urs Zingg, Christof Z\u00f6llner, Markus Zuber, Michael Z\u00fcnd.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Epigenomes was able to maintain its standards for the high quality of its published papers. Thanks to the contribution of our reviewers, in 2021, the median time to first decision was 19 days and the median time to publication was 50 days. The editors would like to extend their gratitude and recognition to the following reviewers for their precious time and dedication, regardless of whether the papers they reviewed were finally published:Argentiero, AntonellaLiss, AndrewArgo, AntoninaLyons, David B.Binda, OlivierMargalit, NevoBlanco, EnriqueMaugeri, Andrea GiuseppeChen, MuyanMcKeon, PeterEhrlich, Kenneth C.Michelhaugh, Sharon K.Flinn, JaneMomparler, Richard L.Fuso, AndreaMoreaux, JeromeGallego-Bartolom\u00e9, JavierMorris, MarkGauchotte, GuillaumeOlova, NellyGentile, Maria TeresaRathert, PhilippGrafi, GideonRavichandran, MirunaliniGulya, K.Robin, J\u00e9r\u00f4me D.Hathaway, Nate A.R\u00f6der, StefanHepworth, JoRoy, BidishaHersey, PeterSeeboeck, RitaJeong, Dong-HoonSen, RwikJohnson, BenStevens, AaronKaur, GagandeepTiffen, Jessamy C.Kisiel, John B.Turner, JonathanKukreja, ShwetaTzelepi, VasilikiKumar, DhirendraVeluchamy, AlagurajKwon, So HeeVlachonasios, KonstantinosLazare, SekaWidemann, EmilieLegartov\u00e1, So\u0148aWong, Kwan YeungLeit\u00e3o, Jos\u00e9 M.Zhang, HongmeiLeone, MarinaRigorous peer-reviews are the basis of high-quality academic publishing. Thanks to the great efforts of our reviewers,"} +{"text": "International Journal of Telerehabilitation, 13(1). https://doi.org/10.5195/ijt.2021.6371Correction to the Metadata for: Bican, R., Christensen, C., Fallieras, K., Sagester, G., O\u2019Rourke, S., Byars, M., & Tanner, K. (2021). Rapid Implementation of Telerehabilitation for Pediatric Patients During COVID-19. The affiliation for each author was incorrectly stated as: Physical Medicine & Rehabilitation, Children's Minnesota, Minneapolis, Minnesota, USAThe correct affiliation for each author is: Clinical Therapies, Nationwide Children's Hospital, Columbus, Ohio, USAThe metadata for the original article has been corrected."} +{"text": "The authors names were incorrectly spelled as Rony Maelle, Ratone Jean-Philippe, Walz Jochen, Pignot Geraldine, Caillol Fabrice, Pesenti Christian, Guerin Mathilde, Dermeche Slimane, Brunelle Serge, Salem Naji, Vicier Cecile, Rybikowski Stanislas, Maubon Thomas, Fakhfakh Sami, Tejeda Manuel, Giovannini Marc and Gravis Gwenaelle. The correct spelling is Maelle Rony, Jean-Philippe Ratone,Jochen Walz, Geraldine Pignot, Fabrice Caillol, Christian Pesenti, Mathilde Guerin, Slimane Dermeche, Serge Brunelle, Naji Salem, Cecile Vicier, Stanislas Rybikowski, Thomas Maubon, Sami Fakhfakh, Manuel Tejeda, Marc Giovannini and Gwenaelle GravisThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "EditorialEmma Pitchforth, Julia Hussein Moving ahead together, on a foundation of rights-based evidence1\u2003CommentariesAnthony Idowu Ajayi, Ramatou Ouedraogo, Kenneth Juma, Grace Kibunja, Collins Cheruiyot, Meggie Mwoka, Emmy Kageha Igonya, Winnie Opondo, Emmanuel Otukpa, Caroline W. Kabiru, Boniface Ayanbekongshie Ushie Research priorities to support evidence-informed policies and advocacy for access to safe abortion care in sub-Saharan Africa5\u2003Alexandria K. Mickler, Maria A. 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Charlton Mapping the scientific literature on reproductive health among transgender and gender diverse people: a scoping review57\u2003Roopan K. Gill, Amanda Cleeve, Antonella F. Lavelanet Abortion hotlines around the world: a mixed-methods systematic and descriptive review75\u2003Andrea Hannah Kaiser, Bj\u00f6rn Ekman, Madeleine Dimarco, Jesper Sundewall The cost-effectiveness of sexual and reproductive health and rights interventions in low- and middle-income countries: a scoping review90\u2003Anna K\u00e5gesten, Miranda van Reeuwijk Healthy sexuality development in adolescence: proposing a competency-based framework to inform programmes and research104\u2003AbortionResearch articles Samantha Chareka, Tamaryn L. 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Moore, Juliette Ortiz, Nakeisha Blades, Hannah Whitehead, Cristina Villarreal Women\u2019s experiences using drugs to induce abortion acquired in the informal sector in Colombia: qualitative interviews with users in Bogot\u00e1 and the Coffee Axis146\u2003Lianne Holten, Eva de Goeij, Gunilla Kleiverda Permeability of abortion care in the Netherlands: a qualitative analysis of women\u2019s experiences, health professional perspectives, and the internet resource of Women on Web162\u2003Leen De Kort, Edwin Wouters, Sarah Van de Velde Obstacles and opportunities: a qualitative study of the experiences of abortion centre staff with abortion care during the first COVID-19 lockdown in Flanders, Belgium180\u2003Jill Durocher, Catherine Kilfedder, Laura J. 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Danielle Wagner, Ariane van der Straten, on behalf of the TRIO Study Team Giving voice to the end-user: input on multipurpose prevention technologies from the perspectives of young women in Kenya and South Africa246\u2003Katherine Watson, Elsie Akwara, Patricia Machawira, Maria Bakaroudis, Renata Tallarico, Venkatraman Chandra-Mouli The East and Southern Africa Ministerial Commitment: a review of progress toward fulfilling young people's sexual and reproductive health and rights (2013\u20132018)261\u2003Ruba Al Akash, Morgen A. Chalmiers Early marriage among Syrian refugees in Jordan: exploring contested meanings through ethnography287\u2003Family planning and contraceptionBatula Abdi, Jerry Okal, Gamal Serour, Marleen Temmerman Muslim men\u2019s perceptions and attitudes on family planning: a qualitative study in Wajir and Lamu counties in Kenya303\u2003Euphemia Sibanda, Ania Shapiro, Bradley Mathers, Annette Verster, Rachel Baggaley, Mary E. 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Schwab School and work absenteeism due to menstruation in three West African countries: findings from PMA2020 surveys409\u2003Lashanda Skerritt, Alexandra de Pokomandy, Nadia O\u2019Brien, Nadia Sourial, Ann N Burchell, Gillian Bartlett, Tibor Schuster, Danielle Rouleau, Kar\u00e8ne Proulx-Boucher, Neora Pick, Deborah Money, Rebecca Gormley, Allison Carter, Mark H Yudin, Mona Loutfy, Angela Kaida, CHIWOS Research Team Discussing reproductive goals with healthcare providers among women living with HIV in Canada: the role of provider gender and patient comfort425\u2003Jasmine Sprague Hepburn, Idil Shekh Mohamed, Bj\u00f6rn Ekman, Jesper Sundewall Review of the inclusion of SRHR interventions in essential packages of health services in low- and lower-middle income countries441\u2003Lucila Szwarc, Victoria S\u00e1nchez Antelo, Melisa Paolino, Silvina Arrossi \u201cI\u2019m neither here, which would be bad, nor there, which would be good\u201d: the information needs of HPV+ women. 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Chao, Maurice-Andre Recanati Unequal medicine harms: reflections on the experiences of an intersex physician467\u2003Editor-in-Chief: Julia Hussein (to March)Executive Editor: Emma Pitchforth (from April)Chief Executive: Eszter Kism\u00f6diSenior Editors: Sarah Keogh, TJ Sundari RavindranManaging Editor: Pete ChapmanMonitoring Editor: Pathika MartinSouth Asia Hub Manager: Sanjeeta GawriCommunications Manager: Alexane BremsheyOperations Manager: Amy GriffithsAssociate Editors: Laura Ferguson, Atsumi Hirose, Nambusi Kyegombe, Helen Potts, Mindy Jane Roseman, Nina Sun, Joyce WamoyiFunding: SRHM's work in 2021 has been supported by the Bill and Melinda Gates Foundation and the Open Society Foundations.Cover image: \u201cA Certain Blindness\u201d by Grace Cross.Translation: Fran\u00e7oise de Luca-Lacoste translated abstracts from English to French and Lisette Silva translated abstracts from English to Spanish.Copyright \u00a9 2022 Sexual and Reproductive Health Matters. This is an Open Access journal distributed under the terms of the Creative Commons Attribution License (http:// creativecommons.org/licenses/ by/4.0/), which allows for sharing and adapting the work for any purpose, even commercially, provided appropriate credit is given with a link to the originally published item, a reference to the author(s) and links to their homepages, reference to the license under which the article is published and a link to this, as well as an indication of any changes that have been made to the original. ISSN (Online) 2641-0397Peer reviewers:Claudia Abreu Lopes, Timothy Osebe Abuya, Pranita Achyut, Tahera Ahmed, Carolyne Ajema, James Akazili, Elsie Akwara, Cristina Alonso, Ilana Ambrogi, Joe Amon, Lise Ulrik Andreasen, Samuel Kojo Antobam, Subha Sri B, Finley Baba, Rob Bain, Barbara Baird, Aduragbemi Banke-Thomas, Suchi Bansai, Heidi Bart Johnson, Alka Barua, Suzanne Bell, Gervais Beninguiss\u00e9, Tshegofatso Phalane Bessenaar, Nandiat Bhan, Lekha D Bhat, Ann Biddlecom, Antonia Biggs, Kelly Blanchard, Nina Brooks, Shyam Sundar Budhathoki, Abigail Burgess, Lisa Caruana-Finkel, Lidia Cecilia Casas, Ishita Chatterjee, Sreeparna Chattopadhyay, Sylvester C Chima, Megan Christofield, Carly A Comins, Bergen Cooper, Jane Cover, Suchitra Dalvie, Shrinivas Satyanarayan Darak, Jashodhara Dasgupta, Jocelyn DeJong, Preeti Dhillon, Farah Diaz-Tello, Catherine Dodds, Soo Downe, Ilana Dzuba, Myles Elledge, Joanna Erdman, Fatima Estrada, Sandra Fern\u00e1ndez, Katherine Footman, Barbara Friedland, Katherine Gambir, Samantha Garbers, Rakhi Ghoshal, Roopan Gill, Srinivas Goli, Meena Gopal, Arne Gouwy, Yufu Iguchi, Katja Isaksen, Olena Ivanova, Sharad D Iyengar, Heather Jacobson, Vathsala Jaysuriya-Illesinghe, Dyah Juliastuti, Shveta Kalyanwala, Shanna Katz Kattari, Talat Khadivzadeh, Renu Khanna, Andrea Gael Kinnear Wilson, Abhay Kudale, Ekaterina Kulchavenya, Bhavita Kumari, Sara Larrea, David Lawson, Ana Flavia Lucas d'Oliveira, Anna K-J Macintyre, Kerry MacQuarrie, Muriel Mac-Seing, Emily Ann Maistrellis, Shelly Makleff, Cicely Alice Marston, Crinda Marwah, Julia McReynolds-Perez, G J Melendez-Torres, Erica Millar, Kirstin Mitchell, Ismalia Z Mohammed, Sanjay K Mohanty, Abdu Mohiddin, Florence Muheirwe, Poonam Muttreja, Jefferson Mwaisaka, Denise Nacif Pimenta, Priya Nanda, Sharmishtha Nanda, Rishita Nandagiri, Nakkeeran Nanjappan, Francis Obare, Funmilola Morinoye OlaOlorun, Jeffrey O'Malley, Tricia Maria Ong, Bayla Ostrach, Sabu S Padmadas, Jitendra Pariyar, Lucia Berro Pizzarossa, Chelsea Polis, Tosin Popoola, Helen Potts, Davoud Pourmazi, Mizanur Rahman, Preety Rajbangshi, Mala Ramanathan, Anubha Rastogi, Juliet Richters, Anissa Rizkianti, Kathryn W Roberts, Sam Rowa, Ana Paola Ruiz, Malabika Sarker, Marta Schaaf, Erica Sedlander, Sumitra Sharma, Kristen Shellenberg, Aamod Dhoj Shrestha, Suzanne Sicchia, Holly Donahue Singh, Arushi Singh, Nelloy Sircar, Ilene S Speizer, Rachel Spitzer, Lara Stemple, Bianca Maria Stifani, Lucila Szwarc, Mildred Tambudzai Mushunje, Amanda Tanner, Siri Tellier, Jennifer Thomson, Jissa Vinoda Thulaseedharan, Mahhub Ul Alam, Ver\u00f3nica Undurraga, Boniface Ushie, Heini V\u00e4is\u00e4nen, Cecilia Van Hollen, Ravi Verma, Leela Visaria, Krani Vora, Yohannes Wado, Megan Wainwright, Helen A Weiss, T Charles Witzel, Susan Yanow, Erick Kiprotich Yegon, Katherine Young, Bethany Young Holt, Phyu Phyu Thin Zawwww.srhm.org / www.srhmjournal.orgTwitter @SRHMJournalFacebook @SRHMJournal"} +{"text": "Dear Editor,The COVID-19 pandemic has had profound impacts on safe healthcare delivery, particularly within surgical specialtiesVaccines against the SARS-CoV-2 virus have demonstrated efficacy, however timely accessibility for healthcare workers, let alone the global population, remains inequitableUtilizing an international survey of practice, distributed through an existing COVIDSurg head and neck (HN) collaborative, social media and international HN clinical networks, the authors sought to assess the extent to which COVID-safe HN cancer surgery and individual surgeon-specific protection were implemented between the initial stages of the pandemic (March\u2013June 2020) and a subsequent period in February 2021 after well documented increases in COVID-19 incidence globally and an evolving, evidence-based understanding of the disease or PPE use (49 per cent) compared with global averages (89 and 62 per cent respectively).Further evidence of significant global inequality was apparent in disparate vaccination access: less than one third of surgical staff in low- and low\u2013middle-income countries received a first vaccine dose by spring 2021 per cent).HN centres in countries experiencing highest levels of population COVID incidence (25 or more per 100 000 population) in spring 2021 correlated to highest levels of testing, PPE use and vaccination (Reported COVID-19 infections amongst surgeons (16 per cent) within this survey are at least double those of conservative contemporaneous population-level estimates. In countries yet to receive nationwide vaccination, HN surgeons had even higher levels of prior COVID infection (26 per cent), highlighting further global wealth inequalities and populations with potentially greater latent need.Whilst the authors recognize inherent limitations to these data, including the intrinsic bias associated with surveys, it is evident that global wealth inequality appears to drive disparities in access to critical elements of appropriate healthcare, risking both patient and staff safety.HN surgery exemplifies many of the highest risks of surgery in general and remains critically reliant on COVID-secure pathways supported by robust testing, adequate PPE provision and vaccination. These data share yet another indicator of inequitable distribution of healthcare resource at a time when we are all reliant upon worldwide solutions.Writing groupAndrew G Schache, Richard Shaw, Michael Wing Sung Ho, Stuart C Winter, James Glasbey, Ian Ganly, Martin Batstone, Juan Rey Biel, Paul C Nankivell, Christian Simon, Omar Omar, Joana FF Simoes, Dmitri Nepogodiev, Aneel Bhangu, Tom Pinkney, Laura McGill, Rita Perry, Terry Hughes, Richard Jackson.CovidSurg Operations CommitteeKwabena Siaw-Acheampong, Ruth A Benson, Edward Bywater, Daoud Chaudhry, Brett E Dawson, Jonathan P Evans, James C Glasbey, Rohan R Gujjuri, Emily Heritage, Conor S Jones, Sivesh K Kamarajah, Chetan Khatri, Rachel A Khaw, James M Keatley, Andrew Knight, Samuel Lawday, Elizabeth Li, Harvinder S Mann, Ella J Marson, Kenneth A McLean, Siobhan C Mckay, Emily C Mills, Dmitri Nepogodiev, Gianluca Pellino, Maria Picciochi, Elliott H Taylor, Abhinav Tiwari, Joana FF Simoes, Isobel M Trout, Mary L Venn, Richard JW Wilkin, Aneel Bhangu.International Cancer Leads Chair); Head and neck: Richard Shaw*, Andrew G Schache, Stuart C Winter, Michael W S Ho, Paul Nankivell, Juan Rey Biel, Martin Batstone, Ian Ganly, Christian Simon.James C Glasbey (Dissemination CommitteeChair); Tom EF Abbott, Michel Adamina, Adesoji O Ademuyiwa, Arnav Agarwal, Ehab Alameer, Derek Alderson, Felix Alakaloko, Markus Albertsmeiers, Osaid Alser, Muhammad Alshaar, Sattar Alshryda, Alexis P Arnaud, Knut Magne Augestad, Faris Ayasra, Jos\u00e9 Azevedo, Brittany K Bankhead-Kendall, Emma Barlow, Ruth A Benson, Ruth Blanco-Colino, Amanpreet Brar, Ana Minaya-Bravo, Kerry A Breen, Chris Bretherton, Igor Lima Buarque, Joshua Burke, Edward J Caruana, Mohammad Chaar, Sohini Chakrabortee, Peter Christensen, Daniel Cox, Moises Cukier, Miguel F Cunha, Giana H Davidson, Anant Desai, Salomone Di Saverio, Thomas M Drake, John G Edwards, Muhammed Elhadi, Sameh Emile, Shebani Farik, Marco Fiore, J Edward Fitzgerald, Samuel Ford, Tatiana Garmanova, Gaetano Gallo, Dhruv Ghosh, Gustavo Mendon\u00e7a Ata\u00edde Gomes, Gustavo Grecinos, Ewen A Griffiths, Madalegna Gr\u00fcndl, Constantine Halkias, Ewen M Harrison, Intisar Hisham, Peter J Hutchinson, Shelley Hwang, Arda Isik, Michael D Jenkinson, Pascal Jonker, Haytham MA Kaafarani, Angelos Kolias, Schelto Kruijff, Ismail Lawani, Hans Lederhuber, Sezai Leventoglu, Andrey Litvin, Andrew Loehrer, Markus W L\u00f6ffler, Maria Aguilera Lorena, Maria Marta Madolo, Piotr Major, Janet Martin, Hassan N Mashbari, Dennis Mazingi, Symeon Metallidis, Ana Minaya-Bravo, Helen M Mohan, Rachel Moore, David Moszkowicz, Susan Moug, Joshua S Ng-Kamstra, Mayaba Maimbo, Milagros Niquen, Faustin Ntirenganya, Maricarmen Olivos, Kacimi Oussama, Oumaima Outani, Marie Dione Parreno-Sacdalanm, Francesco Pata, Carlos Jose Perez Rivera, Thomas D Pinkney, Willemijn van der Plas, Peter Pockney, Ahmad Qureshi, Dejan Radenkovic, Antonio Ramos-De la Medina, Keith Roberts, April C Roslani, Martin Ruteg\u00e5rd, Ir\u00e8ne Santos, Sohei Satoi, Raza Sayyed, Andrew Schache, Andreas A Schnitzbauer, Justina O. Seyi-Olajide, Neil Sharma, Richard Shaw, Sebastian Shu, Kjetil Soreide, Antonino Spinelli, Grant D Stewart, Malin Sund, Sudha Sundar, Stephen Tabiri, Philip Townend, Georgios Tsoulfas, Gabrielle H van Ramshorst, Raghavan Vidya, Dale Vimalachandran, Oliver J Warren, Duane Wedderburn, Naomi Wright, EuroSurg, European Society of Coloproctology (ESCP), Global Initiative for Children\u2019s Surgery (GICS), GlobalSurg, GlobalPaedSurg, ItSURG, PTSurg, SpainSurg, Italian Society of Colorectal Surgery (SICCR), Association of Surgeons in Training (ASiT), Irish Surgical Research Collaborative (ISRC), Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG), Italian Society of Surgical Oncology (SICO).Joana FF Simoes .Australia: Batstone M, Hodge R .Belgium: Abeloos J, De Backer T, De Ceulaer J, Dick C, Diez-Fraile A, Lamoral P, Spaas C (AZ Sint-Jan Brugge-Oostende AV); Schrijvers DLAL ; Willemse EBM (Jules Bordet Institute); Faris C, Maari\u00ebn S, Van Haesendonck G, Van Laer C ; Deron P .Brazil: Abdallah EA, Carvalho GB, Kowalski L, Vartanian J (A.C. Camargo Cancer Center); Gatti AP, Nardi CN, Oliva RNL ; Salem MC (Irmandade da Santa Casa de Miseric\u00f3rdia de Porto Alegre).Canada: Cheng D, MacNeil D, Martin J, Mayer R, ; Groot G .Colombia: Acosta L, Mejia M, Perez CJ (Fundacion Cardioinfantil-IC).Croatia: Lorencin M, Luksic I, Mamic M .Egypt: Ashoush FM ; Osman NA ; Safwat Shahine M ; Eldaly A ; Elfiky MMA ; Amin A ; Elmorsi R, Refky B (Oncology Center Mansoura University); Essa MM .Ethiopia: Mengistu G Mengesha .France: Dakp\u00e9 s (CHU Amiens); Boucher S (CHU Angers); Ballouhey Q, Laloze J, Usseglio J (CHU Limoges); Hoffmann C (Curie Institute); Gregoire V (L\u00e9on B\u00e9rard Cancer Center); Lallemant B .Germany: Blaurock M ; Reim D (Klinikum Rechts der Isar TUM School of Medicine); Boehm A ; Guntinas-Lichius O (Universit\u00e4tsklinikum Jena); H\u00f6lzle F, Modabber A, Winnand P ; Kleeff J, Lorenz K, Ronellenfitsch U, Schneider R ; Betz CS, B\u00f6ttcher A, Busch C, M\u00f6ckelmann N ; Inhestern JM (Oberhavelkliniken Hennigsdorf) Greve J, Hoffmann TK, Laban S, Vahl JM .Ghana: Agyeman-Prempeh A, Aning D, Barnor I, Darko-Asante R, Dzogbefia M, Gaveh V, Gyimah D, Issahalq MD, Konney A, Poku M ; Adjeso T, Akornor ET, Amankwaa WO, Antwi DA, Apppiah-Thompson P, Damah M, Kumi EO, Manan L, Murphy JP, Osei L, Setuagbe J .Greece: Arkadopoulos N, Danias N, Economopoulou P, Frountzas M, Kokoropoulos P, Larentzakis A, Michalopoulos NV, Nastos K, Parasyris S, Pikoulis E, Selmani J, Sidiropoulos TA, Vassiliu P ; Kalfountzos CE ; Chatziioannou I, Corais C, Gkrinia E, Ntziovara A, Saratziotis A ; Antoniadis K, Orestis O, Tatsis D ; Baili E, Charalabopoulos A, Liakakos T, Schizas D, Spartalis E, Syllaios A, Zografos C .Guatemala: Aguilera-Ar\u00e9valo M .India: Misra S, Pareek P, Vishnoi J ; Chappity P, Kar M, Muduly DK, Sultania M ; Agarwal S, Garg PK, Maharaj DD, Majumdar KS, Mishra N, Poonia D, Seenivasagam RK, Singh MP, Tiwari AR ; Penumadu P ; Rajan S ; Kumar S ; Raychowdhury R (Ramakrishna Mission Seva Pratishthan); Ghodke R ; Raychowdhury R .Ireland: Barry C, Callanan D, Dias A, Haung L, Ionescu A, Sheahan P ; Lennon P, Fitzgerald C .Israel: Mizrachi A .Italy: Deganello A ; Pellini R, Pichi B ; Lemma F ; Marino MV ; Bergonzani M, Varazzani A ; Bussu F, Perra T, Piras A, Porcu A, Rizzo D ; Campisi G, Cordova A, Franza M, Rinaldi G, Toia F ; Gianni A ; Giannini L ; Gordini L (Fondazione Policlinico Universitario Agostino Gemelli); Baldini E, Conti L ; De Virgilio A, Ferreli F, Gaino F, Mercante G, Spriano G ; Ansarin M, Chu F, De Berardinis R, Ietrobon G, Tagliabue M (Istituto Europeo di Oncologia - IRCCS -Milano); Ionna F ; Baietti A, Maremonti P, Neri F, Prucher G, Ricci S ; Casaril A, Nama M ; Cotoia A, Lizzi V, Vovola F ; Bruzzaniti P, Familiari P, Lapolla P, Marruzzo G, Mingoli A, Ribuffo D (Policlinico Umberto I); Cipriani R, Contedini F, Lauretta M, Marchetti C, Melotti M, Pignatti M, Pinto V, Pizzigallo A, Ricotta F, Tarsitano A ; Catarzi L, Consorti G .Libya: Abdulwahed EA, Alshareea EA, Biala MI, Ghmagh RJ .Malaysia: Ibrahim AF ; Liew YT .Mexico: Alvarez MR, Arrangoiz R, Cordera F, G\u00f3mez-Pedraza A ; Soul\u00e9-Mart\u00ednez CE ; Becerril OS ; Becerra GFC .Morocco: Arkha Y, Bechri H, El Ouahabi A, Oudrhiri M ; Benkabbou A, Majbar M, Mohsine R, Souadka A .Nepal: Lageju N .Netherlands: Schreuder WH (Antoni van Leeuwenhoek Ziekenhuis); Hardillo J (Erasmus Medisch Centrum); de Bree R ; Schweitzer D .Nigeria: Adeyeye AA, Enoch EE ; Sholadoye TSTT ; Wuraola F ; Oyelakin O .Pakistan: Khokhar MI ; Ayub B .Poland: Wal\u0119dziak M (Military Institute Of Medicine); Szewczyk M (The Gerater Poland Cancer Center).Portugal: Faria C ; Cardoso P ; Castro Silva J (IPO Porto).Saudi Arabia: AlKharashi E .Serbia: Jelovac D, Petrovic M, Sumrak S ; Asceric RR, Bojicic JM, Kovacevic BM, Krdzic ID, Milentijevic MA, Milutinovic VZ, Stefanovic ZB .Spain: Villacampa JM ; Jim\u00e9nez Carneros V, Salazar Carrasco A, Carabias Hernandez A, Alonso Lamberti L, Le\u00f3n Ledesma R, Jim\u00e9nez Miram\u00f3n FJ, Jover Naval\u00f3n JM, Garcia Quijada J, Ramos Rodriguez J, Valle Rubio A ; Vilaseca I ; Escartin J ; Estaire-Gomez M, Padilla Valverde D ; Tousidonis M ; Lopez F ; Deandr\u00e9s-Olabarria U, Dur\u00e1n-Ballesteros M, Fern\u00e1ndez-Pablos F, Ib\u00e1\u00f1ez-Aguirre F, Sanz-Larrainzar A, Ugarte-Sierra B ; Di Martino M, Prada J ; Jariod-Ferrer UM ; Landaluce Olavarria A ; Rey-Biel J ; D\u00edaz de Cerio P ; S\u00e1nchez Barrueco A .Sweden: Lindqvist EK ; Sund M .Switzerland: Piantanida R ; Giger R, Hool S, M\u00fcller SA ; Stoeckli SJ ; Simon C .Syrian Arab Republic: Toutounji T ;Al assaf A ; Hammed AM, Hammed SM, Mahfoud M .Turkey: Arikan A ; Yalkin \u00d6 ; \u0130flazo\u011flu N ; Isik A, Leventoglu S ; Aydemir L, Basaran B, Sen C, Comert -Ulusan M (Istanbul University Faculty of Medicine); Basaran B ; Saracoglu KT ; Saracoglu A ; Mantoglu B (Sakarya Faculty Of Medicine); Kucuk G ; Aygun N, Baran E, Tanal M, Eray Tufan A, Uludag M, G\u00fcrkan Yetkin S, Yigit B ; Calik B, Demirli Atici S, Kaya T .Uganda: Sikakulya FK .United Arab Emirates: Abdel-Galil KMAH .UK: Lowe T ; Durrani AJ, Habeeb A, Irune E, Luke L, Masterson L, Murphy SH, Segaren N, Walker C, Waseem S ; Jones TM, Loh C, Pringle S, Schache AG, Shaw RJ ; Stenhouse J ; Armstrong M ; Sood S, Sutton D ; Thomas S ; Clarke P ; Winter SC ; Hislop S ; Counter PR (Cumberland Infirmary); Ghazali N ; Lloyd C ; Prabhu V ; Godden D, Whitley S ; Butler C, Nash R ; El-Boghdadly K, Fry A, Niziol R ; De M, Gill CK ; Crank S ; Mace AD ; Ho M ; Mair M ; Kothari P ; Homer J, Sainuddin S ; Egan RJ, Kittur M ; Burgess C ; O\u2019Hara J ; Manickavasagam J, McDonald C ; Burrows S ; Java KR, Katre C ; Ahmed A, Siddique H ; King E, Ramchandani P ; Naredla PR Brennan P, Ringrose T, Schmidt F ; Mak JKC, Nankivell P, Parmar S, Sharma N ; Douglas C, McCaul J, McCaul J ; Dhanda J ; Ghazali N, Kyzas P, Vassiliou L ; Kumar A ; Husband A ; Hulbert J ; Ingrams D, Parkin R ; Varley I ; Gahir D, George A, Zakai D ; Bater M ; Surwald C ; Devlin B, Leonard CG ; Pigadas N, Snee D ; Singh RP ; Hyde NC ; Paley M ; Cocks H, Wilson A ; Choi D ; Kerawala CJ, Riva F ; Dickason A (Torbay and South Devon NHS Trust); Semple CJ ; Schilling C ; Naredla PR, Walton G ; Rees-Stoner O ; Scott N ; Nixon IJ ; Tighe D ; Mattine S ; Chu MMH, Pothula V .USA: Lee W ; Brown L, Ganly I ; Alpert N, Illezeau CN, Miles B, Rapp J, Taioli E ; Azam MT, Choudhry AJ, Marx W ; Stein J ; Ying Y (University of Alabama Birmingham); Gross ND (University of Texas MD Anderson Cancer Center); Almasri M, Joshi R, Kulkarni G, Marwan H, Mehdi M ; Sumer B .The research detailed in this manuscript was funded by the British Association of Head & Neck Oncologists (BAHNO).zrab112_Supplementary_DataClick here for additional data file."} +{"text": "Viruses are obligate intracellular parasites that depend on the host\u2019s protein synthesis machinery for translating their mRNAs. The viral mRNA (vRNA) competes with the host mRNA to recruit the translational machinery, including ribosomes, tRNAs, and the limited eukaryotic translation initiation factor (eIFs) pool. Many viruses utilize non-canonical strategies such as targeting host eIFs and RNA elements known as internal ribosome entry sites (IRESs) to reprogram cellular gene expression, ensuring preferential translation of vRNAs. In this review, we discuss vRNA IRES-mediated translation initiation, highlighting the role of RNA-binding proteins (RBPs), other than the canonical translation initiation factors, in regulating their activity. Viruses depend on the host cell for their replication. This dependency is evident during protein synthesis as viruses, except for giant viruses , lack anThe eukaryotic mRNA features a 5\u2032 end modification known as the \u201ccap\u201d, a 7-methylguanosine linked, via a 5\u2032 to 5\u2032 triphosphate bridge, to the first transcribed nucleotide (m7GpppN) and, excEnterovirus) and the encephalomyocarditis virus , both members of the Picornaviridae family of viruses, pioneered the discovery of IRES-mediated translation initiation [Picornaviridae [The study of the monocistronic uncapped/polyadenylated vRNAs of poliovirus paveiviridae ,66, Retroviridae ,68, and sviridae ,70,71. Isviridae , insect sviridae ,74, and sviridae ,76,77 visviridae ,83,84,85sviridae . Since, sviridae ,79,82,87sviridae , IRESitesviridae ,90, IRESsviridae , and thesviridae , list viFlaviviridae, genus Hepacivirus) IRES is ~332 nts in length [Flaviviridae, genus Flavivirus) IRES is ~107 nts in length [Flaviviridae, genus Flavivirus) vRNA harbors the shortest viral IRES documented to date, being only ~96 nts in length [Picornaviridae vRNAs harbor a single IRES positioned in the 5\u2032 UTR of the vRNAs [Picornaviridae, genus Dicipivirus) is the only known exception [Dicistroviridae family of viruses encompasses small non-enveloped viruses with vRNAs that harbor two non-overlapping large ORFs (ORF 1 and ORF2) is ~352 nts long [Aedes albopictus mosquito cell lines [Cyprinus carpio) [Herpesviridae, genus Rhadinovirus), also known as the Kaposi\u2019s sarcoma-associated herpesvirus (KSHV), has been reported [Retroviridae, genus Lentivirus) [Retroviridae, genus Lentivirus) [Retroviridae, genus Lentivirus) [Retroviridae [Viral IRESs are, in general, highly structured RNA segments that, when compared, are highly diverse in nucleotide (nt) length, primary sequence, and secondary/tertiary structure ,94,95,96n length , while tn length . The Denn length . IRESs mn length ,99. The n length ,100,101,n length ,102. IREhe vRNAs ,100,101.xception . The CDVxception . The Dicnd ORF2) C. Indiviae vRNAs . The 5\u2032 ae vRNAs . As an ents long . The 5\u2032 nts long . Little nts long . In contnts long . The actll lines ,111. Thell lines ,113,114.ll lines ,108,112.ll lines . Therefoll lines ,116. It ll lines , isolate carpio) . An IGR reported . It is nreported ,120,121.reported . Similarreported . The intreported ,68. As ativirus) ,125, thetivirus) , and thetivirus) , also hativirus) ,130,131.oviridae ,68. The oviridae ,126, whioviridae ,130. Theoviridae ,133,134.oviridae ,133. Theoviridae . A similoviridae . The molPicornaviridae, genus Aphthovirus), and PV IRESs, is ATP-dependent and requires the same initiation factors as the canonical cap-dependent initiation mechanism, except for eIF4E [Picornaviridae, genus Hepatovirus) IRES requires intact eIF4G to function [Flaviviridae, genus Pestivirus) is independent of any eIF [Viral IRESs also differ in the subset of host factors required to initiate translation B 82,93,,95,96. Ior eIF4E ,137,138.or eIF4E . The scafunction ,141. Howfunction . Interesfunction . The for any eIF ,99. In H any eIF ,143,144. any eIF ,144,145. any eIF .Virgaviridae, genus Tobamovirus) is not structured, and its function is attributed to two polypurine (A-rich) sequences [Dicistroviridae, genus Cripavirus) IRES relies on a non-structured RNA region, and 5\u2032 and 3\u2032 terminal deletions showed only minor effects on its activity [For most vRNAs, IRES-mediated translation initiation is highly dependent on the structural integrity of the IRES ,147,148.equences . Likewisactivity ,166.Thus, viral IRESs behave as a complex RNA scaffold interacting with specific RBPs, the 40S ribosomal subunit, or with components of the canonical translational apparatus enabling translation initiation ,168. ForCardiovirus and the Aphthovirus; and type III, the Enterovirus and Rhinovirus [Aphthovirus, Cardiovirus, and Parechovirus genus vRNAs, with EMCV and FMDV IRESs as prototypes [Aquamavirus, Avihepatovirus, Megrivirus, Sapelovirus, Senecavirus, Teschovirus, Tremovirus, and the porcine kobuvirus (PKV), a member of the Kobuvirus genus. The minimal requirements for 48S assembly on the porcine teschovirus type 1 IRES, a member of the type IV IRESs, are the 40S ribosomal subunit and the TC [Kobuvirus, Salivirus, and Paraturdivirus genera [Despite the divergences in sequence, RNA structure, eIFs and ITAF requirements, and the molecular mechanisms involved in 40S recruitment, when they are from viruses from the same family and genus, IRESs tend to share features ,174,175.inovirus . This clinovirus . Type IIototypes , and typototypes . This clototypes ,177. Typd the TC . Howeverd the TC . The less genera ,99,175. s genera ,96,175 cs genera , but is s genera ,96. IndePicornaviridae deploy different strategies to suppress cap-dependent translation initiation. PV, coxsackievirus , and human rhinovirus encode the 2A proteases, while FMDV, the leader (L) protease (reviewed in [Enterovirus) induces microRNA (miRNA) 141 that targets eIF4E encoding mRNA [Enterovirus) IRESs in a neuronal cell line treated, or not treated, with the 2A protease [During viral infections, the host triggers an antiviral response that includes, among other targets, blocking global translation to counteract viral protein synthesis ,3,8. Howiewed in ,179). Thiewed in ,181,182.iewed in . Interesiewed in ,185. In iewed in . During ing mRNA . Therefoprotease . PV, HRVprotease . Howeverprotease . A similprotease . DENV IRprotease . Thus, iprotease ,189. Thuprotease ,191. ZIKprotease . Retroviprotease ,197,198.In contrast to PV and FMDV, EMCV does not cleave eIF4G; however, the virus reduces cellular cap-dependent translation initiation by inducing 4E-binding protein (4E-BP) dephosphorylation . 4E-BPs As mentioned above, DENV and ZIKV vRNAs possess a translationally functional 5\u2032 cap-structure yet harbor an IRES ,122. ThePicornaviridae, genus Cardiovirus), but not the IRESs of PV and HRV, were efficiently translated in rabbit reticulocyte lysate (RRL) [Early studies reported that the IRESs of EMCV, FMDV, and Theiler\u2019s murine encephalomyelitis virus ,216,217.te (RRL) ,216,217.te (RRL) . The HIVte (RRL) . Togethete (RRL) ,222,223.te (RRL) ,222,223.te (RRL) ,147,168.te (RRL) ,95,168. te (RRL) .45) [The pyrimidine tract-binding protein ) ,226,227,45) ,235; the45) ,237,238;45) ; PTB Ass45) ; Elav-li45) ; Argonau45) ; SRC ass45) ; heat-sh45) ,244,245,45) ,246,247,45) ,248,249.45) ; PTB, Un45) ; PTB plu45) ; the spl45) . It is n45) . Therefo45) ,254,255.45) ,257, whi45) .As indicated above, the HCV IRES does not require ITAFs for 40S ribosomal subunit recruitment or 80S assembly . HoweverRetroviridae, genus Betaretrovirus) IRES activity [The impact of a particular RBP on the function of an IRES cannot be predicted and has to be determined experimentally, because an ITAF that stimulates one viral IRES might act as a repressor for another. For example, HuR stimulates the EV71 and HCV IRESs ,241,293,activity . PCBP , such as cold-shock domains (CSD), RNA-recognition motif (RRM), zinc fingers (ZF), double-stranded RBD (dsRBD), K-homology domain (KH), glycine-arginine-rich (GAR) domains , as well as other less classical RBDs , Table 1Under normal conditions, most RBP/ITAFs reside in the cell nucleus. However, several viruses, including picornaviruses, subvert the host nucleocytoplasmic trafficking machinery to their benefit during infection 334,351,353. DifRetroviruses might use a different strategy to load some RBP onto their vRNA . SimilarIt is noteworthy that, in the case of RBPs, their availability alone is not necessarily responsible for IRES function, as accessibility is also important ,371. FurRetroviridae, genus Deltaretrovirus) IRES, HTLV-1 basic leucine zipper protein (HBZ) IRES, and the MMTV IRES [The mRNP code of any particular mRNA, including vRNAs, is not fixed and can be fine-tuned through PTMs of its associated proteins 375,376,382,383.MTV IRES ,386. TheMTV IRES ,386, sugMTV IRES ,382,383.MTV IRES ,225,387.MTV IRES . The treMTV IRES IGR IRES, which are functional in mammalian, insect, and plant cell-free in-vitro translation systems [Dicistroviridae IRESs share the ability to be active in all cellular backgrounds. For example, the CrPV 5\u2032 IRES does not function efficiently in plant-cell-free in-vitro translation systems [The need for specific ITAFs and their uneven distribution among different cell types might partially explain why the function of some viral IRESs is cell-type-dependent ,416,418.ts cells . A few vts cells ,421,422.ts cells . The RhPts cells ,166. Oth systems ,421,424. systems ,421,422, systems ,419. Fur systems , and the systems .As mentioned above, about 10\u201315% of all cellular mRNAs harbor IRESs ,79,82,87The diversity of RNA structures, or RNP-complexes, that different viral RNAs have evolved to enable internal initiation to outcompete the host\u2019s mRNAs during infection is remarkable. For many viral IRESs, there are still many unknowns regarding the molecular mechanisms driving their function. Fine-tuning of IRES activity during viral replication also emerges as a novel and exciting question. As IRESs might not be isolated players that turn on to enable viral protein synthesis, but are part of a more complex network of signals that sense the cellular environment regulating viral gene expression accordingly during infection. This would imply that ITAFs play an essential role in fine-tuning viral IRES function through their localization (nucleus/cytoplasm), binding affinity, and capacity to interact with other regulatory proteins. The understanding of how the PTMs of ITAFs impact viral IRES activity also emerges as a fascinating research area. Furthermore, little is known on how viral and cellular-induced PTMs of ITAFs are important for timing viral gene expression during replication, or their relevance in virus-induced pathogenesis."} +{"text": "Clin Pract Cases Emerg Med. 2021:5(4)432\u2013435.A Chemist with a Strange Etiology of Rhabdomyolysis: A Case Report of a RareToxicological EmergencyR Meenakshisundaram, JVJoseph, P Perumal, A Areeb, P Pancheti, DK Sampath, EM Jared, AKRyan This article includes anadditional author, Allison K Ryan, MD."} +{"text": "Scientific Reports 10.1038/s41598-021-93518-9, published online 14 July 2021Correction to: In the original version of this Article Ahmed F. Thabet and Hessien A. Boraei were incorrectly affiliated with \u2018The Kyushu University Museum, Fukuoka, Japan\u2019. The correct affiliations are listed below.Affiliation 1:Economic Entomology Department, Faculty of Agriculture, Kafrelsheikh University, Kafr El-sheikh, EgyptAhmed F. Thabet and\u00a0Hessien A. BoraeiAffiliation 2:Genetics Department, Faculty of Agriculture, Kafrelsheikh University, Kafr El-sheikh, EgyptAhmed F. ThabetAffiliation 3:Field Crop Pests Research Department, Plant Protection Research Institute, Agricultural Research Center, Sakha, Kafr El-sheikh, EgyptAhmed F. ThabetAffiliation 4:Laboratory of Insect Natural Enemies, Institute of Biological Control, Department of Bioresource Sciences, Faculty of Agriculture, Kyushu University, Fukuoka, 819-0395, JapanAhmed F. ThabetIn addition, Ahmed F. Thabet and Hessien A. Boraei were incorrectly listed as equally contributing authors.Finally, Hessien A. Boraei is deceased.The original Article has been corrected."} +{"text": "Scientific Reports 10.1038/s41598-021-02179-1, published online 23 November 2021Correction to: The original version of this Article omitted an affiliation for Guillermo J. Ortega. The correct affiliations are listed below.Instituto de Investigacion Sanitaria del Hospital Universitario de La Princesa, Madrid, SpainScience and Technology Department, National University of Quilmes, Bernal, ArgentinaConsejo Nacional de Investigaciones Cientificas y Tecnicas, CONICET, Buenos Aires, ArgentinaThe original Article has been corrected."} +{"text": "Scientific Reports 10.1038/s41598-021-94877-z, published online 28 July 2021Correction to: The original version of this Article contained errors in the spelling of the authors Valeria Stella Vanni, Roberta Villanacci, Noemi Salmeri, Enrico Papaleo, Diana Delprato, Jessica Ottolina, Patrizia Rovere-Querini, Stefano Ferrari, Paola Vigan\u00f2 & Massimo Candiani which were incorrectly given as Vanni Valeria Stella, Villanacci Roberta, Salmeri Noemi, Papaleo Enrico, Delprato Diana, Ottolina Jessica, Rovere-Querini Patrizia, Ferrari Stefano, Vigan\u00f2 Paola & Candiani Massimo.The original Article has been corrected."} +{"text": "This study sought to establish the long-term effects of Covid-19 following hospitalisation.327 hospitalised participants, with SARS-CoV-2 infection were recruited into a prospective multicentre cohort study at least 3 months post-discharge. The primary outcome was self-reported recovery at least ninety days after initial Covid-19 symptom onset. Secondary outcomes included new symptoms, disability , breathlessness and quality of life (EQ5D-5L).55% of participants reported not feeling fully recovered. 93% reported persistent symptoms, with fatigue the most common (83%), followed by breathlessness (54%). 47% reported an increase in MRC dyspnoea scale of at least one grade. New or worse disability was reported by 24% of participants. The EQ5D-5L summary index was significantly worse following acute illness . Females under the age of 50 years were five times less likely to report feeling recovered , were more likely to have greater disability , twice as likely to report worse fatigue and seven times more likely to become more breathless than men of the same age.Survivors of Covid-19 experienced long-term symptoms, new disability, increased breathlessness, and reduced quality of life. These findings were present in young, previously healthy working age adults, and were most common in younger females.National Institute for Health Research, UK Medical Research Council,\u00a0Wellcome\u00a0Trust, Department for International Development and the Bill and Melinda Gates Foundation. Funding for research to understand mechanisms underlying long-Covid and identify potential interventions for testing in randomised trials is urgently required.\u00a0Alt-text: Unlabelled box1Our understanding of long-term outcomes after acute Covid-19 remains limited. It is becoming increasingly evident that some patients who have had acute Covid-19 go on to experience persistent symptoms, known as long-Covid or post-Covid syndrome Many clinical trials or studies that aim to characterise the immediate course of Covid-19 have used mortality as a primary outcome ,13. ThisThe objective of this study was to characterise long-term patient reported outcomes in individuals who survived hospitalisation for Covid-19, in those who engaged with post hospital follow-up, using the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol (CCP-UK) and follow-up protocol 22.1ISARIC4C.net website. Hospitals providing acute care throughout the United Kingdom were eligible to enrol participants into the study. This analysis is reported in line with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines The ISARIC WHO Clinical Characterisation Protocol (CCP) was first developed by international consensus in 2012 to respond to any emerging or re-emerging pathogen of public health interest 2.2th January to 5th October 2020 with confirmed or highly suspected SARS-CoV-2 infection at 31 centres, who consented to be contacted for post hospital follow-up and were discharged at least 90 days ago were eligible for inclusion. Participants experienced post-Covid sequelae without formal treatment as management pathways for long Covid were not available at this time. Confirmation of SARS-CoV-2 was by reverse-transcriptase polymerase chain reaction (RT-PCR). Individuals with clinically diagnosed highly suspected, Covid-19 were also eligible for inclusion, given that SARS-CoV-2 was an emergent pathogen in the earlier stages of the pandemic and laboratory confirmation was dependent on local availability of PCR testing.Patients aged 18 years and over, admitted to hospital between 172.3Patient questionnaires for adults were developed by a multidisciplinary team of researchers, clinicians and psychologists through a series of meetings and e-mail iterations Explanatory variables at the time of hospital admission, including age, sex, pre-existing comorbidities, and treatment received during the hospital admission were recorded. Maximum severity of Covid-19 during the acute hospital admission with Covid-19 was classified using the WHO COVID-19 ordinal severity scale 2.4The primary outcome was self-reported recovery at 3 to 12 months following initial Covid-19 symptoms. Secondary outcomes included persistent or new symptoms, new or worsened disability assessed using the Washington Disability Group (WG) Short Form 2.5th and 75th centile values. To test for differences across comparison groups in categorical data, we used Fisher's exact test and for continuous data, used the Wilcoxon rank-sum test for two-sample testing and Kruskal-Wallis where there were more than 2 groups. Analysis of symptom co-occurrence was done using the Jaccard similarity index and represented visually as heatmaps with dendrograms constructed from complete hierarchical clustering results (where 0 is no co-occurrence and 1 is perfect co-occurrence). We then identified clusters of symptoms based upon the hierarchical dendrograms and clusters that were seen on the heatmap.Categorical data were summarised as frequencies and percentages, and continuous data as median, alongside the corresponding interquartile range (IQR) presented as the 25For disability, breathlessness, and EQ5D-5L index , we calculated the change in value reported by participants before onset of their Covid-19 illness compared to the follow up assessment. For health state at the follow up assessment, we used the EQ5D-5L with the English standardised valuation study protocol (EQ-VT) value set, developed by the EuroQol group on the composite time trade-off (cTTO) valuation We created models to adjust for age, sex, presence of comorbidities and in-hospital severity of Covid-19, according to the maximum level of respiratory support that was required. Multilevel logistic regression was used for binary outcomes, and linear regression models were used for continuous outcomes. In both model types, we adjusted for the effects of explanatory variables using fixed-effects and centre by including a random-effects term. For all models, variable selection was performed based on clinical plausibility, and final models were selected based on clinical relevance guided by minimisation of the Akaike information criterion (AIC). Variables were only included in the model if they were present during the first hospital admission for Covid-19. All models were checked for first order interactions and any meaningful interactions were retained and incorporated as dummy variables. Effect estimates are presented as odds ratios for binary outcomes or mean differences for continuous outcomes, alongside the corresponding 95% confidence interval (95% CI). Statistical analyses were performed using R version 3.6.3 with the tidyverse, finalfit, eq5d and Hmisc packages. Statistical significance was taken at the level of P \u2264 0.05.2.6This was an urgent public health research study in response to a public health emergency of international concern. Patients and the public were therefore not involved in the design, of the acute phase rapid response research. However, patients and people living with long Covid were involved in the design, conduct and interpretation of the follow up study. The follow up data collection survey and associated patient information was informed by the founding members of the Long Covid support group, who themselves are living with long Covid. The survey was also piloted in several settings in the UK with patients affected by Covid-19 from different demographics, and feedback incorporated into the final version. This included suggestions on the data on symptoms collected and the way questions were asked as well as on the patient information. The results and interpretation of the findings and final manuscript were informed by members of the Long Covid support group.2.7The study sponsors and funders had no role in the study design, collection, analysis, interpretation of data, writing of the report, or the decision to submit the article for publication. Investigators were independent from funders and the authors have full access to\u00a0all of\u00a0the data, including any statistical analysis and tables.3Of the 2150 eligible people in the CCP-UK study who were discharged from their acute admission alive, 40\u20221% (862/2150) provided consent to be contacted for follow-up. Of these, 97\u20228% (843/862) were contacted. From these 843 people, 97\u20227% (824/843) were 18 or over and 53\u20227% (443/824) completed the follow-up questionnaire. Finally, of respondents 73\u20228% (327/443) responded 90 days or more after symptom onset. Included participants completed the follow-up questionnaire through self-assessment (71\u00b76% 234/327), telephone (24\u00b75% 80/327) or in outpatient clinic years and of white ethnicity did not feel they had fully recovered at the time of follow-up. At the univariable level, there were no associations between not feeling recovered and the risk factors of age, sex, ethnicity, and comorbidities but we fA heatmap and dendrogram of symptom co-occurrence identified two major clusters of symptoms B; a fatiIn addition to symptomatic breathlessness, 46\u00b78% (153/327) of participants reported increased breathlessness compared to their pre-Covid-19 baseline. Overall, change in breathlessness was not affected by age or number of comorbidities , but wasOverall, intensity of fatigue was unrelated to age or disease severity in hospital , Table 2New or worsened disability in at least one Washington Group domain was experienced by 24\u00b72% (79/327). This did not change by in-hospital Covid-19 severity or comorth centile to 0\u00b70 75th centile, Overall summary EQ5D-5L index was 10% lower overall following Covid-19 , the presence of comorbidity and initial in-hospital severity of Covid-19. This generated 6 groups; Males under 50 (34/327), males between 50 and 69 (114/327), males 70 and over (44/327), females under 50 (36/327), females between 50 and 69 (81/327), and females 70 and over (18/327). For the primary outcome of self-reported overall recovery, females under 50 were 5 times less likely to feel fully recovered . SimilarTo explore these findings further, we then looked to see if there were any differences in comorbidity or in-hospital disease severity by sex. We found males were significantly more likely to have greater comorbidity and more4We found high rates of long-term symptoms and poor long-term outcomes, which were present several months after hospitalisation for Covid-19. This has implications for planning of care and rehabilitation pathways. These patients may present to multiple specialities within the health care system unless coordinated by a dedicated long Covid service. The range of syndromes identified highlights a need for long Covid clinics to triage patients for further comprehensive diagnostics, based on symptom cluster, including specialist imaging, for assessing underlying aetiology to inform treatment and improve outcomes. Females under 50, and those with severe acute disease requiring critical care had the worst long-term outcomes even after adjusting for severity of the initial illness. Interestingly, our findings were largely unaffected by existing patient comorbidities or disability.Our findings add considerably to the current literature, as we identify the main risk factor for worse long-term outcomes are being female and under the age of 50. We also have been able to quantify the significant deterioration in disability and breathlessness-related disability in detail. The range of symptoms reported include those which may be related to direct lung damage, such as breathlessness, and also those for which an underlying pathophysiological mechanism may be less clear such as fatigue, muscle pain and cognitive complaints. The latter group are also features of other post infectious syndromes and post intensive care syndrome, and may have a similar aetiology, such as infection triggered autoimmunity, dysautonomia or other mechanism Many of our findings are largely in agreement with other recent studies in other populations globally, which also found high rates of breathlessness and fatigue ,5. In thIn our study, being young, female and having a high severity of acute disease were the strongest independent predictors of poor long-term outcomes. It is unclear why females had the worst outcomes. This could be to do with the effects of initial exposure, where females are more likely to be in industries where exposure to SARS-CoV-2 may be higher There are several limitations to our study. First, we were not able to follow all the cases that were discharged from hospital, either because they did not give permission or because they did not respond to repeated requests for information. We attempted to reach non-responders to the survey via telephone follow-up to limit potential for selection bias, but not all could be reached. However the 73% response rate is substantially above the expected response rate for multi-modal questionaires (60%) Secondly, we did not include patients hospitalised with other non-Covid-19 illness or a contemporaneous control group, therefore it is unknown if the changes in our outcomes e.g. quality of life, are specific to recovery from Covid-19 or may be linked to other aspects of life during the pandemic. The study used to generate this data is a prospective pandemic preparedness protocol which is agnostic to disease and has a pragmatic design to allow recruitment during pandemic conditions. Thirdly, patients only completed the survey at one timepoint, limiting comparison across repeat measures. This also meant retrospective measures asking patients to rate outcomes before their Covid-19 illness were included, which are open to recall bias. Fourth, the differences in collecting data may add to heterogeneity in the data. Finally, as our study focussed on hospitalised patients primarily from the first wave of infection in the UK, our data cannot be generalised to those with disease managed in the community who comprise the majority of individuals affected by Covid-19.Future research should focus on establishing the optimal care of this cohort, identifying interventions to test in randomised trials and to identify the mechanisms underlying adverse long-term outcomes. The PHOSP-Covid study is ongoing and will inform patient care by adding to our data on the long-term sequelae of Covid-19, looking at the impact on these of acute and post-discharge interventions, and exploring possible mechanisms including measurement of laboratory parameters and functional diagnostics 5In our study of 327 patients who were discharged alive from hospital, we found most participants reported symptoms months after acute Covid-19 infection. The most common symptoms were fatigue and breathlessness. Participants reported significant difficulties, including increased breathlessness, new or worsened disability and worse quality of life following Covid-19. These symptoms were largely independent of age and prior comorbidity, suggesting that the long-term effects of Covid-19 are determined by factors that differ from those that predict increased mortality. Moreover, the high frequency and severity of long-term symptoms emphasise the importance of long-Covid symptoms and the potential long-term impact on population health and wellbeing. The data highlights an urgent need for access to comprehensive assessments for people living with long Covid, including complex diagnostics to identify aetiology and inform appropriate treatment to improve long term Covid-19 outcomes.^ISARIC Global Covid-19 follow up working group:Adam Ali, John H Amuasi, Andrea Angheben, John Kenneth Baille, Valeria Balan, Ibrahim Richard Bangura, Anna Beltrame, Frank Bloos, Lucille Blumberg, Fernando Bozza, Danilo Buonsenso, Caterina Caminiti, Gail Carson, Daniel Cassaglia, Muge Cevik, Allegra Chatterjee, Andrew Dagens, Yash Doshi, Thomas M. Drake, Murray Dryden, Anne Margarita Dyrhol Riise, Michael Edelstein, Rob Fowler, Kyle Gomez, Katrina Hann, Ewen M Harrison, Madiha Hashmi, Lars Hegelund, Aquiles Henriquez Trujillo, Antonia Ho, Jan Cato Holter, Jane Ireson, Nina Jamieson, Waasila Jassat, Edwin Jesudason, Anders Benjamin Kildal, Sulaiman Lakoh, Nicola Latronico, James Lee, Wei Shen Lim, Sam Lissaeur, Nazir Lone, David J Lowe, Sinnadurai Manohan, Romans Matulevics, Joanne McPeake, Laura Merson, Roberta Meta, Melina Michelen, Sarah Moore, Ben Morton, Caroline Mudara, Daniel Munblit, Srinivas Murthy, Behzad Nadjm, Ebrahim Ndure, Nikita Nekliudov, Piero Olliaro, Carlo Palmieri, Prasan K Panda, Simone Piva, Daniel R Plotkin, Matteo Puntini, Jordi Rello, Liliana Resende, Luis Felipe Reyes, Ishmeala Rigby, Sergio Ruiz Saltana, Clark D Russell, Steffi Ryckaert, Janet T Scott, Malcolm G. Semple, Louise Sigfrid, Girish Sindhwani Pulm, Arne S\u00f8raas, Renaud Tamisier, Lance Turtle, Caroline Vika, Natalie Wright^^ISARIC4C investigators Consortium lead investigator:J Kenneth Baillie, Malcolm G Semple, Peter JM Openshaw; Gail Carson, Benjamin Bach, Wendy S Barclay, Debby Bogaert, Meera Chand, Graham S Cooke, Annemarie B Docherty, Jake Dunning, Ana da Silva Filipe, Tom Fletcher, Christoper A Green, Ewen M Harrison, Julian A Hiscox, Antonia Ying Wai Ho, Peter W Horby, Samreen Ijaz, Saye Khoo, Paul Klenerman, Andrew Law, Wei Shen Lim, Alexander J Mentzer, Laura Merson, Alison M Meynert, Mahdad Noursadeghi, Shona C Moore, Massimo Palmarini, William A Paxton, Georgios Pollakis, Nicholas Price, Andrew Rambaut, David L Robertson, Clark D Russell, Vanessa Sancho-Shimizu, Janet T Scott, Thushan de Silva, Louise Sigfrid, Tom Solomon, Shiranee Sriskandan, David Stuart, Charlotte Summers, Richard S Tedder, Emma C Thomson, AA Roger Thompson, Ryan S Thwaites, Lance CW Turtle, Rishi K Gupta, Carlo Palmieri, Maria Zambon, Chloe Donohue, Ruth Lyons, Fiona Griffiths, Wilna Oosthuyzen, Riinu Pius, Thomas M Drake, Cameron J Fairfield, Stephen R Knight, Kenneth A Mclean, Derek Murphy, Catherine A Shaw, Michelle Girvan, Egle Saviciute, Stephanie Roberts, Janet Harrison, Laura Marsh, Marie Connor, Sophie Halpin, Clare Jackson, Carrol Gamble, Andrew Law, Murray Wham, Sara Clohisey, Ross Hendry, James Scott-Brown, Victoria Shaw, Sarah E McDonald, Jane A Armstrong, Milton Ashworth, Innocent G Asiimwe, Siddharth Bakshi, Samantha L Barlow, Laura Booth, Benjamin Brennan, Katie Bullock, Benjamin WA Catterall, Jordan J Clark, Emily A Clarke, Sarah Cole, Louise Cooper, Helen Cox, Christopher Davis, Oslem Dincarslan, Chris Dunn, Philip Dyer, Angela Elliott, Anthony Evans, Lorna Finch, Lewis WS Fisher, Terry Foster, Isabel Garcia-Dorival, William Greenhalf, Philip Gunning, Catherine Hartley, Rebecca L Jensen, Christopher B Jones, Trevor R Jones, Shadia Khandaker, Katharine King, Robyn T. Kiy, Chrysa Koukorava, Annette Lake, Suzannah Lant, Diane Latawiec, Lara Lavelle-Langham, Daniella Lefteri, Lauren Lett, Lucia A Livoti, Maria Mancini, Sarah McDonald, Laurence McEvoy, John McLauchlan, Soeren Metelmann, Nahida S Miah, Joanna Middleton, Joyce Mitchell, Shona C Moore, Ellen G Murphy, Rebekah Penrice-Randal, Jack Pilgrim, Tessa Prince, Will Reynolds, P. Matthew Ridley, Debby Sales, Victoria E Shaw, Rebecca K Shears, Benjamin Small, Krishanthi S Subramaniam, Agnieska Szemiel, Aislynn Taggart, Jolanta Tanianis-Hughes, Jordan Thomas, Erwan Trochu, Libby van Tonder, Eve Wilcock, J. Eunice Zhang, Lisa Flaherty, Nicole Maziere, Emily Cass, Alejandra Doce Carracedo, Nicola Carlucci, Anthony Holmes, Hannah Massey, Nicola Wrobel, Sarah McCafferty, Kirstie Morrice, Alan MacLean, Daniel Agranoff, Ken Agwuh, Dhiraj Ail, Erin L. Aldera, Ana Alegria, Brian Angus, Abdul Ashish, Dougal Atkinson, Shahedal Bari, Gavin Barlow, Stella Barnass, Nicholas Barrett, Christopher Bassford, Sneha Basude, David Baxter, Michael Beadsworth, Jolanta Bernatoniene, John Berridge, Nicola Best, Pieter Bothma, David Chadwick, Robin Brittain-Long, Naomi Bulteel, Tom Burden, Andrew Burtenshaw, Vikki Caruth, David Chadwick, Duncan Chambler, Nigel Chee, Jenny Child, Srikanth Chukkambotla, Tom Clark, Paul Collini, Catherine Cosgrove, Jason Cupitt, Maria-Teresa Cutino-Moguel, Paul Dark, Chris Dawson, Samir Dervisevic, Phil Donnison, Sam Douthwaite, Ingrid DuRand, Ahilanadan Dushianthan, Tristan Dyer, Cariad Evans, Chi Eziefula, Chrisopher Fegan, Adam Finn, Duncan Fullerton, Sanjeev Garg, Sanjeev Garg, Atul Garg, Effrossyni Gkrania-Klotsas, Jo Godden, Arthur Goldsmith, Clive Graham, Elaine Hardy, Stuart Hartshorn, Daniel Harvey, Peter Havalda, Daniel B Hawcutt, Maria Hobrok, Luke Hodgson, Anil Hormis, Michael Jacobs, Susan Jain, Paul Jennings, Agilan Kaliappan, Vidya Kasipandian, Stephen Kegg, Michael Kelsey, Jason Kendall, Caroline Kerrison, Ian Kerslake, Oliver Koch, Gouri Koduri, George Koshy, Shondipon Laha, Steven Laird, Susan Larkin, Tamas Leiner, Patrick Lillie, James Limb, Vanessa Linnett, Jeff Little, Mark Lyttle, Michael MacMahon, Emily MacNaughton, Ravish Mankregod, Huw Masson, Elijah Matovu, Katherine McCullough, Ruth McEwen, Manjula Meda, Gary Mills, Jane Minton, Mariyam Mirfenderesky, Kavya Mohandas, Quen Mok, James Moon, Elinoor Moore, Patrick Morgan, Craig Morris, Katherine Mortimore, Samuel Moses, Mbiye Mpenge, Rohinton Mulla, Michael Murphy, Megan Nagel, Thapas Nagarajan, Mark Nelson, Matthew K. O'Shea, Igor Otahal, Marlies Ostermann, Mark Pais, Selva Panchatsharam, Danai Papakonstantinou, Hassan Paraiso, Brij Patel, Natalie Pattison, Justin Pepperell, Mark Peters, Mandeep Phull, Stefania Pintus, Jagtur Singh Pooni, Frank Post, David Price, Rachel Prout, Nikolas Rae, Henrik Reschreiter, Tim Reynolds, Neil Richardson, Mark Roberts, Devender Roberts, Alistair Rose, Guy Rousseau, Brendan Ryan, Taranprit Saluja, Aarti Shah, Prad Shanmuga, Anil Sharma, Anna Shawcross, Jeremy Sizer, Manu Shankar-Hari, Richard Smith, Catherine Snelson, Nick Spittle, Nikki Staines, Tom Stambach, Richard Stewart, Pradeep Subudhi, Tamas Szakmany, Kate Tatham, Jo Thomas, Chris Thompson, Robert Thompson, Ascanio Tridente, Darell Tupper-Carey, Mary Twagira, Andrew Ustianowski, Nick Vallotton, Lisa Vincent-Smith, Shico Visuvanathan, Alan Vuylsteke, Sam Waddy, Rachel Wake, Andrew Walden, Ingeborg Welters, Tony Whitehouse, Paul Whittaker, Ashley Whittington, Padmasayee Papineni, Meme Wijesinghe, Martin Williams, Lawrence Wilson, Sarah Cole, Stephen Winchester, Martin Wiselka, Adam Wolverson, Daniel G Wooton, Andrew Workman, Bryan Yates, Peter Young.JTS, LS, MGS developed the concept of the follow up study. JTS, LS, LWS, TMD, EJ, WLS, CB, DJL, MC, JMcP, NL, EMH, DM, CR, AH, LT, PB, and the ISARIC Global Covid-19 follow up working group developed the follow up protocol and methodology. ISARIC4C investigators identified participants during the acute admission and entered acute phase data. PB, CD, HH, RS, JH, AG coordinated follow up survey distribution, data entry, AG, AC, LG conducted telephone follow up. LS, JTS, GC, HH coordinated resources. LS, JTS, TMD, EP, AD, PO, EH, ABD were involved in data visualisation. TMD, EP, LS, JTS, MEO'H, PJMO, CH, CEH, JKB, ABD, MGS analysed and interpreted the data. LS, TMD, EP, JTS wrote the original draft of the manuscript. All authors reviewed, and revised the manuscript prior to submission. JTS is the guarantor.CRD declares funding from the Medical Research Council, UK. JM reports a University of Cambridge Research Fellowship.\u00a0WSL reports unrestricted investigator-initiated research funding from Pfizer for an unrelated multi-centre study in pneumonia, in which WSL is the CI and UK NIHR research funding for unrelated clinical trials in the fields of COVID-19, tuberculosis and community-acquired pneumonia. WSL's role on the Joint Committee on Vaccination and Immunisation (JCVI), UK and chair of COVID-19 Immunisation and as National Lead on British Thoracic Society community acquired pneumonia audit programme is unpaid and unrelated to this work. CB declares a British Heart Foundation Centre award, and a project grants from the Chief Scientist Office, Scottish Government CSO Long Term Effects and from Heart Research UK unrelated to this work. LG declares support from Pfizer & Gilead for attendance at an educational meeting in Nov 2018 and April 2019, for cost of conference registration fee, accommodation and flights unrelated to this work. PJMO reports personal fees from consultancy, grants from MRC, EU, NIHR Biomedical Research Centres, MRC/GSK, Wellcome Trust, NIHR (HPRU) and NIHR Senior Investigator Award. Personal fees from European Respiratory Society, grants from MRC Global Challenge Research fund, other from Nestle Discussion Forum (unpaid), Pfizer antivirals advisory board (unpaid) outside of the submitted work and the role of President of the British Society for Immunology was an unpaid appointment but PJMO's travel and accommodation at some meetings is provided by the Society. MGS reports grants from the National Institute for Health Research (NIHR), Medical Research Council. NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. All other authors have no interests to declare."} +{"text": "Human Reproduction Open, 2021, hoab002, https://doi.org/10.1093/hropen/hoab002In the originally published version of this manuscript, the first name/family name order of each of the authors\u2019 names were incorrect. The author list should read: \u201cMarjan Van Reckem, Christophe Blockeel, Maryse Bonduelle, Andrea Buysse, Mathieu Roelants, Greta Verheyen, Herman Tournaye, Frederik Hes, and Florence Belva\u201d instead of \u201cVan Reckem Marjan, Blockeel Christophe, Bonduelle Maryse, Buysse Andrea, Roelants Mathieu, Verheyen Greta, Tournaye Herman, Hes Frederik, and Belva Florence\u201d. This error has now been corrected online."} +{"text": "Muhammad Ammar Malik is not included in the author byline. Muhammad Ammar Malik should be listed as the third author, and their affiliations are the Department of Information and Communications Engineering, Chosun University, Gwangju, Republic of Korea and the Department of Informatics, University of Bergen, Bergen, Norway.https://doi.org/10.1371/journal.pone.0236493The correct citation is: Lee B, Yamanakkanavar N, Malik MA, Choi JY (2020) Automatic segmentation of brain MRI using a novel patch-wise U-net deep architecture. PLoS ONE 15(8): e0236493. The contributions of this author are as follows: Formal analysis, Investigation, Methodology, Software, Writing\u2013original draftThe complete author contributions are therefore as follows:Conceptualization: BL, JYCFormal analysis: BL, MAM, JYCFunding acquisition: BLInvestigation: NY, MAM, JYCMethodology: BL, NY, MAMProject administration: BLSoftware: BL, NY, MAMSupervision: JYCValidation: NY, JYC,Visualization: NY, JYCWriting\u2013original draft: BL, MAM, JYCWriting\u2013review & editing: BL, NY, JYC"} +{"text": "In\u00a0vitro, we show that, although \u0394H69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. \u0394H69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on \u0394H69/V70. Therefore, as \u0394H69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted.We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike \u0394H69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. \u2022Spike \u0394H69/V70 does not confer escape from antibodies\u2022Spike \u0394H69/V70 increases cleaved S2 and spike infectivity\u2022B.1.1.7 requires \u0394H69/V70 for efficient cleaved spike incorporation and infectivity\u2022B.1.1.7 spike requires \u0394H69/V70 for rapid syncytium formation Meng et\u00a0al. report that the SARS-CoV-2 spike \u0394H69/V70 has arisen multiple times. The deletion increases entry efficiency associated with increased cleaved spike in virions and can compensate for loss of infectivity. The B.1.1.7 spike requires \u0394H69/V70 for efficient cell entry and cell-cell fusion activity. In addisma (CP) . Deletiosma (CP) and redusma (CP) .Here we analyze global SARS-CoV-2 data and find that \u0394H69/V70 occurs independently, often emerging after a significant RBD amino acid replacement, such as Y453F and N439K, which are known to facilitate neutralizing antibody escape or alter ACE2 binding while incurring an infectivity defect, according to some reports . AlthougThe deletion H69/V70 is present in over 600,000 SARS-CoV-2 genome sequences worldwide and has seen global expansion, particularly across much of Europe, Africa, and Asia . \u0394H69/V7in silico. The \u0394H69/V70 was predicted to alter the conformation of a protruding loop comprising residues 69\u201376, pulling it in toward the NTD was co-transfected in HEK293T producer cells along with plasmids encoding a lentiviral capsid and genome for luciferase. Infectivity was adjusted for input reverse-transcriptase activity; we observed a 2-fold increase in PV infectivity of \u0394H69/V70 compared with the WT in HeLa cervical epithelial cells stably expressing human ACE2 A and 3B.Western blotting for S2 spike indicated a higher amount of cleaved spike in \u0394H69/V70 bearing virions and in the HEK293T producer cell lysates. We also noted a corresponding reduction in uncleaved full-length (FL) spike C. DensitSARS-CoV-2 entry into target cells is thought to take place by two distinct routes following binding to ACE2 A. The fiThe altered level of S1/S2 cleavage in SARS-CoV-2 has been linked to its dependence on viral entry through membrane fusion or endocytosis in HEK293T and A549 cells . We therin\u00a0vitro PVs in VeroE6 target cells expressing TMPRSS2. We found that 7 of 12 NTD-specific mAbs (58%) showed a marked decrease or complete loss of neutralizing activity to B.1.1.7 and B.1.1.7 H69/V70 (>30-fold-change reduction), suggesting that, in a sizeable fraction of NTD antibodies, the H69/V70 deletion is not responsible for their loss of neutralizing activity or cells . The rolor cells . We expror cells A. All spor cells B\u20137D. We Finally, to investigate the importance of this part of spike beyond SARS-CoV-2 for other coronaviruses with zoonotic potential, we examined the 69/70 region of spike in a set of other known sarbecoviruses A\u2013S4C. WeFurthermore, the two almost identical bat viruses sequenced recently from Cambodian samples, RShSTT182 and RShSTT200 , possessWe have presented data demonstrating multiple independent and circulating lineages of SARS-CoV-2 variants bearing spike \u0394H69/V70. This recurring deletion, spanning 6 nt, is due to an out-of-frame deletion of 6 nt and occurs in the terminal loop of a helix loop motif within the predicted RNA structure, as do other NTD deletions observed in new variants, such as B.1.1.7 (Alpha), B.1.617 (Delta), B.1.351 (Beta), and P.1 (Gamma) . Stable We find that \u0394H69/V70 does not significantly reduce the sensitivity of spike to neutralizing antibodies in serum from a group of recovered individuals or binding of multiple mAbs directed against the NTD. In addition, we have shown that repair of \u0394H69/V70 does not appreciably alter the potency of NTD antibodies against the B.1.1.7 spike. Thus, the deletion is unlikely to be an immune escape mechanism. Instead, our experimental results demonstrate that \u0394H69/V70 is able increase infectivity of the Wuhan-1 D614G spike PV as well as the PV bearing the additional RBD mutations N439K or Y453F, explaining why the deletion is often observed after these immune escape mutations that carry infectivity cost . We showin\u00a0vivo.We have found consistent differences in spike as well as cleaved spike in the producer cell and its incorporation into PV particles when comparing \u0394H69/V70 with a Wuhan-1 spike (both with D614G). This could be explained by stability during intracellular trafficking or the route taken to the surface, differences in post-translational modification of the spike protein, or membrane characteristics at the budding site of virus or virus-like particles. Because the amount of spike incorporation into virions reflects the spike in the cells, virion formation is likely unaffected by \u0394H69/V70. Interestingly, although pharmacological inhibition of furin by CMK in producer cells did prevent S1/S2 cleavage and altered the balance of S2:FL spike in cells and virions, PV infectivity was not reduced by drug treatment. These data suggest that the increase in entry efficiency conferred by spike \u0394H69/V70 is independent of spike S1/S2 cleavage. Similar findings regarding the lack of relationship between the balance of S2:FL and infectivity have been reported in the context of furin knockout cells rather than furin inhibition with CMK . In addiWe explored the entry route of \u0394H69/V70 spike using cathepsin inhibition to block endosomal entry and camostat to block entry via plasma membrane fusion. \u0394H69/V70 spike was as sensitive to camostat and the cathepsin inhibitor ED64 as the WT, arguing that the efficiency of entry route is similar despite differences in cleaved spike. Although S1/S2 cleavage allows\u00a0avoidance of endosome-associated IFITM restriction and appears to be critical for transmission in animal models , cleavedThe Alpha variant Al (B.1.1.7), bearing seven spike mutations, is responsible for a new pandemic phase that is demonstrably more pathogenic and moreWe show that Alpha variant B.1.1.7 spike has similar infectivity as WT D614G spike, consistent with data on live B.1.1.7 virus in human airway epithelial cells but in cOf greatest potential importance is our observation that Alpha variant B.1.1.7 spike mediates faster syncytium formation and that this enhanced cell-cell fusion activity is dependent on \u0394H69/V70. Syncytium formation is a key feature of severe and fatal COVID-19 and implAlthough we combined epidemiological, evolutionary, protein and RNA structure, and experimental data in our study, a limitation is that the experiments were conducted with PVs and coronavirus-like particles rather than replication-competent viruses. We also carried out experiments in cells overexpressing receptors, although the results were recapitulated in lung\u00a0cell lines expressing endogenous levels of ACE2 and TMPRSS2.Detection and surveillance of B.1.1.7 has been facilitated in the United Kingdom by the phenomenon of SGTF (S[pike] gene target failure) because of primers in the Thermo Fisher Scientific SARS-CoV-2 diagnostic qPCR assay used by a significant number of testing facilities. The S gene target (binding in the region of H69/V70) is one of three; therefore, a marker for the spread of B.1.1.7 has been tracked by loss of signal in the S gene target . HoweverGiven the emergence of multiple clusters of variants carrying RBD mutations and \u0394H69/V70 , limitation of transmission takes on renewed urgency. As another example, a new VOC bearing \u0394H69/V70 with E484K was recently identified (B.1.525). Comprehensive vaccination efforts should be accelerated to limit transmission and acquisition of further mutations, and future vaccines could include \u0394H69/V70 to close this route for virus evolution, assuming that effective neutralizing antibodies to this region are generated. Fortunately, our experiments with RaTG13 demonstrate that \u0394H69/V70 may not enhance the infectivity of other bat sarbecoviruses with zoonotic potential.We found that a two-amino-acid deletion, \u0394H69/V70, promotes SARS-CoV-2 spike incorporation into viral particles and increases infectivity by a mechanism that remains to be fully explained. This deletion has arisen multiple times and often after spike antibody escape mutations that reduce spike-mediated entry efficiency. Critically, B.1.1.7 spike mediates faster syncitium formation, and this enhanced cell-cell fusion activity is dependent on \u0394H69/V70. In addition, B.1.1.7 spike requires \u0394H69/V70 for optimal infectivity, and we conclude that \u0394H69/V70 enables SARS-CoV-2 to tolerate multiple immune escape mutations while maintaining infectivity and fusogenicity.The members of the COVID-19 Genomics UK (COG-UK) Consortium are Samuel C. Robson, Nicholas J. Loman, Thomas R. Connor, Tanya Golubchik, Rocio T. Martinez Nunez, Catherine Ludden, Sally Corden, Ian Johnston, David Bonsall, Colin P. Smith, Ali R. Awan, Giselda Bucca, M. Estee Torok, Kordo Saeed, Jacqui A. Prieto, David K. Jackson, William L. Hamilton, Luke B. Snell, Catherine Moore, Ewan M. Harrison, Sonia Goncalves, Derek J. Fairley, Matthew W. Loose, Joanne Watkins, Rich Livett, Samuel Moses, Roberto Amato, Sam Nicholls, Matthew Bull, Darren L. Smith, Jeff Barrett, David M. Aanensen, Martin D. Curran, Surendra Parmar, Dinesh Aggarwal, James G. Shepherd, Matthew D. Parker, Sharon Glaysher, Matthew Bashton, Anthony P. Underwood, Nicole Pacchiarini, Katie F. Loveson, Kate E. Templeton, Cordelia F. Langford, John Sillitoe, Thushan I. de Silva, Dennis Wang, Dominic Kwiatkowski, Andrew Rambaut, Justin O\u2019Grady, Simon Cottrell, Matthew T. G. Holden, Emma C. Thomson, Husam Osman, Monique Andersson, Anoop J. Chauhan, Mohammed O. Hassan-Ibrahim, Mara Lawniczak, Alex Alderton, Meera Chand, Chrystala Constantinidou, Meera Unnikrishnan, Alistair C. Darby, Julian A. Hiscox, Steve Paterson, Inigo Martincorena, Erik M. Volz, Andrew J. Page, Oliver G. Pybus, Andrew R. Bassett, Cristina V. Ariani, Michael H. Spencer Chapman, Kathy K. Li, Rajiv N. Shah, Natasha G. Jesudason, Yusri Taha, Martin P. McHugh, Rebecca Dewar, Aminu S. Jahun, Claire McMurray, Sarojini Pandey, James P. McKenna, Andrew Nelson, Gregory R. Young, Clare M. McCann, Scott Elliott, Hannah Lowe, Ben Temperton, Sunando Roy, Anna Price, Sara Rey, Matthew Wyles, Stefan Rooke, Sharif Shaaban, Mariateresa de Cesare, Laura Letchford, Siona Silveira, Emanuela Pelosi, Eleri Wilson-Davies, Myra Hosmillo, \u00c1ine O\u2019Toole, Andrew R. Hesketh, Richard Stark, Louis du Plessis, Chris Ruis, Helen Adams, Yann Bourgeois, Stephen L. Michell, Dimitris Gramatopoulos, Jonathan Edgeworth, Judith Breuer, John A. Todd, Christophe Fraser, David Buck, Michaela John, Gemma L. Kay, Steve Palmer, Sharon J. Peacock, David Heyburn, Danni Weldon, Esther Robinson, Alan McNally, Peter Muir, Ian B. Vipond, John Boyes, Venkat Sivaprakasam, Tranprit Salluja, Samir Dervisevic, Emma J. Meader, Naomi R. Park, Karen Oliver, Aaron R. Jeffries, Sascha Ott, Ana da Silva Filipe, David A. Simpson, Chris Williams, Jane A. H. Masoli, Bridget A. Knight, Christopher R. Jones, Cherian Koshy, Amy Ash, Anna Casey, Andrew Bosworth, Liz Ratcliffe, Li Xu-McCrae, Hannah M. Pymont, Stephanie Hutchings, Lisa Berry, Katie Jones, Fenella Halstead, Thomas Davis, Christopher Holmes, Miren Iturriza-Gomara, Anita O. Lucaci, Paul Anthony Randell, Alison Cox, Pinglawathee Madona, Kathryn Ann Harris, Julianne Rose Brown, Tabitha W. Mahungu, Dianne Irish-Tavares, Tanzina Haque, Jennifer Hart, Eric Witele, Melisa Louise Fenton, Steven Liggett, Clive Graham, Emma Swindells, Jennifer Collins, Gary Eltringham, Sharon Campbell, Patrick C. McClure, Gemma Clark, Tim J. Sloan, Carl Jones, Jessica Lynch, Ben Warne, Steven Leonard, Jillian Durham, Thomas Williams, Sam T. Haldenby, Nathaniel Storey, Nabil-Fareed Alikhan, Nadine Holmes, Christopher Moore, Matthew Carlile, Malorie Perry, Noel Craine, Ronan A. Lyons, Angela H. Beckett, Salman Goudarzi, Christopher Fearn, Kate Cook, Hannah Dent, Hannah Paul, Robert Davies, Beth Blane, Sophia T. Girgis, Mathew A. Beale, Katherine L. Bellis, Matthew J. Dorman, Eleanor Drury, Leanne Kane, Sally Kay, Samantha McGuigan, Rachel Nelson, Liam Prestwood, Shavanthi Rajatileka, Rahul Batra, Rachel J. Williams, Mark Kristiansen, Angie Green, Anita Justice, Adhyana I. K. Mahanama, Buddhini Samaraweera, Nazreen F. Hadjirin, Joshua Quick, Radoslaw Poplawski, Leanne M. Kermack, Nicola Reynolds, Grant Hall, Yasmin Chaudhry, Malte L. Pinckert, Iliana Georgana, Robin J. Moll, Alicia Thornton, Richard Myers, Joanne Stockton, Charlotte A. Williams, Wen C. Yew, Alexander J. Trotter, Amy Trebes, George MacIntyre-Cockett, Alec Birchley, Alexander Adams, Amy Plimmer, Bree Gatica-Wilcox, Caoimhe McKerr, Ember Hilvers, Hannah Jones, Hibo Asad, Jason Coombes, Johnathan M. Evans, Laia Fina, Lauren Gilbert, Lee Graham, Michelle Cronin, Sara Kumziene-Summerhayes, Sarah Taylor, Sophie Jones, Danielle C. Groves, Peijun Zhang, Marta Gallis, Stavroula F. Louka, Igor Starinskij, Chris Jackson, Marina Gourtovaia, Gerry Tonkin-Hill, Kevin Lewis, Jaime M. Tovar-Corona, Keith James, Laura Baxter, Mohammad T. Alam, Richard J. Orton, Joseph Hughes, Sreenu Vattipally, Manon Ragonnet-Cronin, Fabricia F. Nascimento, David Jorgensen, Olivia Boyd, Lily Geidelberg, Alex E. Zarebski, Jayna Raghwani, Moritz U. G. Kraemer, Joel Southgate, Benjamin B. Lindsey, Timothy M. Freeman, Jon-Paul Keatley, Joshua B. Singer, Leonardo de Oliveira Martins, Corin A. Yeats, Khalil Abudahab, Ben E. W. Taylor, Mirko Menegazzo, John Danesh, Wendy Hogsden, Sahar Eldirdiri, Anita Kenyon, Jenifer Mason, Trevor I. Robinson, Alison Holmes, James Price, John A. Hartley, Tanya Curran, Alison E. Mather, Giri Shankar, Rachel Jones, Robin Howe, Sian Morgan, Elizabeth Wastenge, Michael R. Chapman, Siddharth Mookerjee, Rachael Stanley, Wendy Smith, Timothy Peto, David Eyre, Derrick Crook, Gabrielle Vernet, Christine Kitchen, Huw Gulliver, Ian Merrick, Martyn Guest, Robert Munn, Declan T. Bradley, Tim Wyatt, Charlotte Beaver, Luke Foulser, Sophie Palmer, Carol M. Churcher, Ellena Brooks, Kim S. Smith, Katerina Galai, Georgina M. McManus, Frances Bolt, Francesc Coll, Lizzie Meadows, Stephen W. Attwood, Alisha Davies, Elen De Lacy, Fatima Downing, Sue Edwards, Garry P. Scarlett, Sarah Jeremiah, Nikki Smith, Danielle Leek, Sushmita Sridhar, Sally Forrest, Claire Cormie, Harmeet K. Gill, Joana Dias, Ellen E. Higginson, Mailis Maes, Jamie Young, Michelle Wantoch, Dorota Jamrozy, Stephanie Lo, Minal Patel, Verity Hill, Claire M. Bewshea, Sian Ellard, Cressida Auckland, Ian Harrison, Chloe Bishop, Vicki Chalker, Alex Richter, Andrew Beggs, Angus Best, Benita Percival, Jeremy Mirza, Oliver Megram, Megan Mayhew, Liam Crawford, Fiona Ashcroft, Emma Moles-Garcia, Nicola Cumley, Richard Hopes, Patawee Asamaphan, Marc O. Niebel, Rory N. Gunson, Amanda Bradley, Alasdair Maclean, Guy Mollett, Rachel Blacow, Paul Bird, Thomas Helmer, Karlie Fallon, Julian Tang, Antony D. Hale, Louissa R. Macfarlane-Smith, Katherine L. Harper, Holli Carden, Nicholas W. Machin, Kathryn A. Jackson, Shazaad S. Y. Ahmad, Ryan P. George, Lance Turtle, Elaine O\u2019Toole, Joanne Watts, Cassie Breen, Angela Cowell, Adela Alcolea-Medina, Themoula Charalampous, Amita Patel, Lisa J. Levett, Judith Heaney, Aileen Rowan, Graham P. Taylor, Divya Shah, Laura Atkinson, Jack C. D. Lee, Adam P. Westhorpe, Riaz Jannoo, Helen L. Lowe, Angeliki Karamani, Leah Ensell, Wendy Chatterton, Monika Pusok, Ashok Dadrah, Amanda Symmonds, Graciela Sluga, Zoltan Molnar, Paul Baker, Stephen Bonner, Sarah Essex, Edward Barton, Debra Padgett, Garren Scott, Jane Greenaway, Brendan A. I. Payne, Shirelle Burton-Fanning, Sheila Waugh, Veena Raviprakash, Nicola Sheriff, Victoria Blakey, Lesley-Anne Williams, Jonathan Moore, Susanne Stonehouse, Louise Smith, Rose K. Davidson, Luke Bedford, Lindsay Coupland, Victoria Wright, Joseph G. Chappell, Theocharis Tsoleridis, Jonathan Ball, Manjinder Khakh, Vicki M. Fleming, Michelle M. Lister, Hannah C. Howson-Wells, Louise Berry, Tim Boswell, Amelia Joseph, Iona Willingham, Nichola Duckworth, Sarah Walsh, Emma Wise, Nathan Moore, Matilde Mori, Nick Cortes, Stephen Kidd, Rebecca Williams, Laura Gifford, Kelly Bicknell, Sarah Wyllie, Allyson Lloyd, Robert Impey, Cassandra S. Malone, Benjamin J. Cogger, Nick Levene, Lynn Monaghan, Alexander J. Keeley, David G. Partridge, Mohammad Raza, Cariad Evans, Kate Johnson, Emma Betteridge, Ben W. Farr, Scott Goodwin, Michael A. Quail, Carol Scott, Lesley Shirley, Scott A. J. Thurston, Diana Rajan, Iraad F. Bronner, Louise Aigrain, Nicholas M. Redshaw, Stefanie V. Lensing, Shane McCarthy, Alex Makunin, Carlos E. Balcazar, Michael D. Gallagher, Kathleen A. Williamson, Thomas D. Stanton, Michelle L. Michelsen, Joanna Warwick-Dugdale, Robin Manley, Audrey Farbos, James W. Harrison, Christine M. Sambles, David J. Studholme, Angie Lackenby, Tamyo Mbisa, Steven Platt, Shahjahan Miah, David Bibby, Carmen Manso, Jonathan Hubb, Gavin Dabrera, Mary Ramsay, Daniel Bradshaw, Ulf Schaefer, Natalie Groves, Eileen Gallagher, David Lee, David Williams, Nicholas Ellaby, Hassan Hartman, Nikos Manesis, Vineet Patel, Juan Ledesma, Katherine A. Twohig, Elias Allara, Clare Pearson, Jeffrey K. J. Cheng, Hannah E. Bridgewater, Lucy R. Frost, Grace Taylor-Joyce, Paul E. Brown, Lily Tong, Alice Broos, Daniel Mair, Jenna Nichols, Stephen N. Carmichael, Katherine L. Smollett, Kyriaki Nomikou, Elihu Aranday-Cortes, Natasha Johnson, Seema Nickbakhsh, Edith E. Vamos, Margaret Hughes, Lucille Rainbow, Richard Eccles, Charlotte Nelson, Mark Whitehead, Richard Gregory, Matthew Gemmell, Claudia Wierzbicki, Hermione J. Webster, Chloe L. Fisher, Adrian W. Signell, Gilberto Betancor, Harry D. Wilson, Gaia Nebbia, Flavia Flaviani, Alberto C. Cerda, Tammy V. Merrill, Rebekah E. Wilson, Marius Cotic, Nadua Bayzid, Thomas Thompson, Erwan Acheson, Steven Rushton, Sarah O\u2019Brien, David J. Baker, Steven Rudder, Alp Aydin, Fei Sang, Johnny Debebe, Sarah Francois, Tetyana I. Vasylyeva, Marina Escalera Zamudio, Bernardo Gutierrez, Angela Marchbank, Joshua Maksimovic, Karla Spellman, Kathryn McCluggage, Mari Morgan, Robert Beer, Safiah Afifi, Trudy Workman, William Fuller, Catherine Bresner, Adrienn Angyal, Luke R. Green, Paul J. Parsons, Rachel M. Tucker, Rebecca Brown, Max Whiteley, James Bonfield, Christoph Puethe, Andrew Whitwham, Jennifier Liddle, Will Rowe, Igor Siveroni, Thanh Le-Viet, Amy Gaskin, Rob Johnson, Irina Abnizova, Mozam Ali, Laura Allen, Ralph Anderson, Cristina Ariani, Siobhan Austin-Guest, Sendu Bala, Jeffrey Barrett, Andrew Bassett, Kristina Battleday, James Beal, Mathew Beale, Sam Bellany, Tristram Bellerby, Katie Bellis, Duncan Berger, Matt Berriman, Paul Bevan, Simon Binley, Jason Bishop, Kirsty Blackburn, Nick Boughton, Sam Bowker, Timothy Brendler-Spaeth, Iraad Bronner, Tanya Brooklyn, Sarah Kay Buddenborg, Robert Bush, Catarina Caetano, Alex Cagan, Nicola Carter, Joanna Cartwright, Tiago Carvalho Monteiro, Liz Chapman, Tracey-Jane Chillingworth, Peter Clapham, Richard Clark, Adrian Clarke, Catriona Clarke, Daryl Cole, Elizabeth Cook, Maria Coppola, Linda Cornell, Clare Cornwell, Craig Corton, Abby Crackett, Alison Cranage, Harriet Craven, Sarah Craw, Mark Crawford, Tim Cutts, Monika Dabrowska, Matt Davies, Joseph Dawson, Callum Day, Aiden Densem, Thomas Dibling, Cat Dockree, David Dodd, Sunil Dogga, Matthew Dorman, Gordon Dougan, Martin Dougherty, Alexander Dove, Lucy Drummond, Monika Dudek, Laura Durrant, Elizabeth Easthope, Sabine Eckert, Pete Ellis, Ben Farr, Michael Fenton, Marcella Ferrero, Neil Flack, Howerd Fordham, Grace Forsythe, Matt Francis, Audrey Fraser, Adam Freeman, Anastasia Galvin, Maria Garcia-Casado, Alex Gedny, Sophia Girgis, James Glover, Oliver Gould, Andy Gray, Emma Gray, Coline Griffiths, Yong Gu, Florence Guerin, Will Hamilton, Hannah Hanks, Ewan Harrison, Alexandria Harrott, Edward Harry, Julia Harvison, Paul Heath, Anastasia Hernandez-Koutoucheva, Rhiannon Hobbs, Dave Holland, Sarah Holmes, Gary Hornett, Nicholas Hough, Liz Huckle, Lena Hughes-Hallet, Adam Hunter, Stephen Inglis, Sameena Iqbal, Adam Jackson, David Jackson, Carlos Jimenez Verdejo, Matthew Jones, Kalyan Kallepally, Keely Kay, Jon Keatley, Alan Keith, Alison King, Lucy Kitchin, Matt Kleanthous, Martina Klimekova, Petra Korlevic, Ksenia Krasheninnkova, Greg Lane, Cordelia Langford, Adam Laverack, Katharine Law, Stefanie Lensing, Amanah Lewis-Wade, Jennifer Liddle, Quan Lin, Sarah Lindsay, Sally Linsdell, Rhona Long, Jamie Lovell, Jon Lovell, James Mack, Mark Maddison, Aleksei Makunin, Irfan Mamun, Jenny Mansfield, Neil Marriott, Matt Martin, Matthew Mayho, Jo McClintock, Sandra McHugh, Liz McMinn, Carl Meadows, Emily Mobley, Robin Moll, Maria Morra, Leanne Morrow, Kathryn Murie, Sian Nash, Claire Nathwani, Plamena Naydenova, Alexandra Neaverson, Ed Nerou, Jon Nicholson, Tabea Nimz, Guillaume G. Noell, Sarah O\u2019Meara, Valeriu Ohan, Charles Olney, Doug Ormond, Agnes Oszlanczi, Yoke Fei Pang, Barbora Pardubska, Naomi Park, Aaron Parmar, Gaurang Patel, Maggie Payne, Sharon Peacock, Arabella Petersen, Deborah Plowman, Tom Preston, Michael Quail, Richard Rance, Suzannah Rawlings, Nicholas Redshaw, Joe Reynolds, Mark Reynolds, Simon Rice, Matt Richardson, Connor Roberts, Katrina Robinson, Melanie Robinson, David Robinson, Hazel Rogers, Eduardo Martin Rojo, Daljit Roopra, Mark Rose, Luke Rudd, Ramin Sadri, Nicholas Salmon, David Saul, Frank Schwach, Phil Seekings, Alison Simms, Matt Sinnott, Shanthi Sivadasan, Bart Siwek, Dale Sizer, Kenneth Skeldon, Jason Skelton, Joanna Slater-Tunstill, Lisa Sloper, Nathalie Smerdon, Chris Smith, Christen Smith, James Smith, Katie Smith, Michelle Smith, Sean Smith, Tina Smith, Leighton Sneade, Carmen Diaz Soria, Catarina Sousa, Emily Souster, Andrew Sparkes, Michael Spencer-Chapman, Janet Squares, Robert Stanley, Claire Steed, Tim Stickland, Ian Still, Mike Stratton, Michelle Strickland, Allen Swann, Agnieszka Swiatkowska, Neil Sycamore, Emma Swift, Edward Symons, Suzanne Szluha, Emma Taluy, Nunu Tao, Katy Taylor, Sam Taylor, Stacey Thompson, Mark Thompson, Mark Thomson, Nicholas Thomson, Scott Thurston, Dee Toombs, Benjamin Topping, Jaime Tovar-Corona, Daniel Ungureanu, James Uphill, Jana Urbanova, Philip Jansen Van, Valerie Vancollie, Paul Voak, Danielle Walker, Matthew Walker, Matt Waller, Gary Ward, Charlie Weatherhogg, Niki Webb, Alan Wells, Eloise Wells, Luke Westwood, Theo Whipp, Thomas Whiteley, Georgia Whitton, Sara Widaa, Mia Williams, Mark Wilson, and Sean Wright.rkg20@cam.ac.uk.Further information should be directed to and will be fulfilled by the Lead Contact, Ravindra K. Gupta This study did not generate new unique reagents.Raw anonymized data are available from the lead contact without restriction.The study was primarily a laboratory based study using pseudotyped virus (PV) with mutations generates by site directed mutagenesis. We tested infectivity in cell lines with a range of drug inhibitors and monoclonal antibodies. Sensitivity to antibodies in serum was tested using convalescent sera from recovered individuals collected as part of the Cambridge NIHR Bioresource. We also performed phylogenetic analyses of data available publicly in GISAID.Ethical approval for use of serum samples. Controls with COVID-19 were enrolled to the NIHR BioResource Centre Cambridge under ethics review board (17/EE/0025).https://gisaid.org/; th February 2021. Low-quality sequences (> 5% N regions) were removed, leaving a dataset of 491,395 sequences with a length of > 29,000bp. Sequences were deduplicated and then filtered to find the mutations of interest. All sequences were realigned to the SARS-CoV-2 reference strain MN908947.3, using MAFFT v7.475 with automatic strategy selection and the\u2013keeplength\u2013addfragments options (https://clades.nextstrain.org/), Pangolin v2.4.2 (https://github.com/cov-lineages/pangolin) and a local instance of the PangoLEARN model, dated 18th April 21:49 (https://github.com/cov-lineages/pangoLEARN).All available full-genome SARS-CoV-2 sequences were downloaded from the GISAID database and ggtree v2.2.4 rooted on the SARS-CoV-2 reference sequence and nodes arranged in descending order. Nodes with bootstraps values of\u00a0< 50 were collapsed using an in-house script.Maximum likelihood phylogenetic trees were produced using the above curated dataset using IQ-TREE v2.1.2 . EvolutiSarbecoviruses examined in To reconstruct a phylogeny for the 69/70 spike region of the 20 7C2L was modeled using I-TASSER , a metho7C2L ) using P2L, 6M0J , 6ZGE28 2L, 6M0J .12 were aligned in CLUSATL-Omega (nucleotides 20277-23265 of the Wuhan isolate MN908947.3) and a consensus structure was generated using RNAalifold .HEK293T CRL-3216, Vero CCL-81 were purchased from ATCC and maintained in Dulbecco\u2019s Modified Eagle Medium (DMEM) supplemented with 10% fetal calf serum (FCS), 100\u00a0U/ml penicillin, and 100mg/ml streptomycin. All cells are regularly tested and are mycoplasma free. H1299 cells were a kind gift from Simon Cook. Calu-3 cells were a kind gift from Paul Lehner, A549 A2T2 cells wePlasmids encoding the spike protein of SARS-CoV-2 D614 with a C-terminal 19 amino acid deletion with D614G, were used as a template to produce variants lacking amino acids at position H69 and V70, as well as mutations N439K and Y453F. Mutations were introduced using Quickchange Lightning Site-Directed Mutagenesis kit (Agilent) following the manufacturer\u2019s instructions. B.1.1.7\u00a0S expressing plasmid preparation was described previously by step wise mutagenesis . Viral vPlasmids encoding the full-length spike protein of SARS-CoV-2 D614 (Wuhan) and RaTG13, in frame with a C \u2013 terminal Flag tag , were usThe reverse transcriptase activity of virus preparations was determined by qPCR using a SYBR Green-based product-enhanced PCR assay (SG-PERT) as previously described . Briefly12\u03bcl of each sample lysate was added to 13\u03bcl of a SYBR Green master mix embrane, (E)nvelope and (N)ucleocapsid proteins of SARS-CoV-2 were a kind gift from Nevan Krogan . For exp6 293T cells in 10\u00a0cm dishes were transfected using TransIT-LT1 (Mirus) with a total of 4\u00a0\u03bcg DNA comprising 1\u00a0\u03bcg each of plasmids encoding S (WT or \u0394H69/V70), M, E and N. Media was replaced after 16 h.Coronavirus-like particles were prepared essentially as previously described . In brieSupernatants containing coronavirus-like particles were harvested after 2 d, spun for 10\u00a0min at 2,000 g, then passed through a 0.45\u00a0\u03bcm filter. For each condition, 9\u00a0mL supernatant was layered on a 2\u00a0mL cushion of 20% sucrose in PBS and spun for 2\u00a0h at 100,000\u00a0g in a Type 70 Ti Beckman Coulter Ultracentrifuge Rotor. The pellet was washed once with PBS, then resuspended in 100\u00a0\u03bcl 2% SDS in PBS. After aspiration of supernatant, cells were washed twice in PBS, then lysed in 800\u00a0\u03bcl of 2% SDS in TBS with 500 units of Benzonase (Sigma-Aldrich). Lysates were incubated for 30\u00a0m at room temperature, then spun for 10\u00a0min at 13,000 g.Resuspended pellets containing concentrated coronavirus-like particles were heated in Laemmli buffer with DTT at 95\u00b0C for 5\u00a0min. For each condition, 30\u00a0\u03bcL was loaded on a 4%\u201320% Mini-PROTEAN TGX Precast Protein Gel (Bio-Rad). Cell lysates were quantified using the Pierce BCA Protein Assay Kit (Thermo Scientific), then heated in Laemmli buffer with DTT at 95\u00b0C for 5\u00a0min. For each condition, 20\u00a0\u03bcg protein was loaded on an identical gel. Proteins were transferred to 45\u00a0nm PDVF membranes and blocked with 5% milk in PBS-Tween 0.2%. The following antibodies were used for immunoblotting: anti-S ; anti-N and anti-\u03b2-actin .CMK furin inhibitor experiments: 293T cells were transfected with plasmids expressing Gag/pol, luciferase, and spike. Furin inhibitor CMK was added at either 5\u00a0M or 25 \u03bcM concentration three hours post transfection. The supernatants and cell lysates were collected after 48 hours for infectivity on target cells or for western blotting.E64D and camostat experiments: ACE2 or ACE2 and TMPRSS2 transfected 293T cells were either E64D (Tocris) or camostat (Sigma-Aldrich) treated for 3 hours at each drug concentration before the addition of a comparable amount of input viruses pseudotyped with WT, H69/V70 deletion or VSV-G (approx. 1 million RLU). The cells were then left for 48 hours before addition of substrate for luciferase (Promega) and read on a Glomax plate reader (Promega). The RLU was normalized against the no-drug control which was set as 100%.Cell fusion assay was carried out as previously described . BrieflyCells were lysed and supernatants collected 18 hours post transfection. Purified virions were prepared by harvesting supernatants and passing through a 0.45\u00a0\u03bcm filter. Clarified supernatants were then loaded onto a thin layer of 8.4% optiprep density gradient medium (Sigma-Aldrich) and placed in a TLA55 rotor (Beckman Coulter) for ultracentrifugation for 2 hours at 20,000\u00a0rpm. The pellet was then resuspended for western blotting. Cells were lysed with cell lysis buffer or were treated with Benzonase Nuclease (Millipore) and boiled for 5\u00a0min. Samples were then run on 4%\u201312% Bis Tris gels and transferred onto nitrocellulose or PVDF membranes using an iBlot or semidry .Membranes were blocked for 1 hour in 5% non-fat milk in PBS\u00a0+ 0.1% Tween-20 (PBST) at room temperature with agitation, incubated in primary antibody , anti-GAPDH (proteintech) or anti-p24 (NIBSC)) diluted in 5% non-fat milk in PBST for 2 hours at 4\u00b0C with agitation, washed four times in PBST for 5\u00a0minutes at room temperature with agitation and incubated in secondary antibody (anti-rabbit or anti-mouse HRP conjugate), anti-bactin HRP (Santa Cruz) diluted in 5% non-fat milk in PBST for 1 hour with agitation at room temperature. Membranes were washed four times in PBST for 5\u00a0minutes at room temperature and imaged directly using a ChemiDoc MP imaging system (Bio-Rad).2 environment at 37\u00b0C, the luminescence was measured using Steady-Glo Luciferase assay system (Promega).Spike pseudotype assays have been shown to have similar characteristics as neutralization testing using fully infectious wild-type SARS-CoV-2 .Virus nePreparation of B.1.1.7 or B.1.1.7 H69/V70 SARS-CoV-2\u00a0S glycoprotein-encoding-plasmid used to produce SARS-CoV-2-MLV based on overlap extension PCR. Briefly, a modification of the overlap extension PCR protocol was usedHuman mAbs were isolated from plasma cells or memory B cells of SARS-CoV or SARS-CoV-2 immune donors. Recombinant antibodies were expressed in ExpiCHO cells at 37\u00b0C and 8% CO2. Cells were transfected using ExpiFectamine. Transfected cells were supplemented 1\u00a0day after transfection with ExpiCHO Feed and ExpiFectamine CHO Enhancer. Cell culture supernatant was collected eight days after transfection and filtered through a 0.2\u00a0\u03bcm filter. Recombinant antibodies were affinity purified on an \u00c4KTA xpress FPLC device using 5\u00a0mL HiTrap MabSelect PrismA columns followed by buffer exchange to Histidine buffer using HiPrep 26/10 desalting columns.2 before harvesting the supernatant. VeroE6 stably expressing human TMPRSS2 were cultured in Dulbecco\u2019s Modified Eagle\u2019s Medium (DMEM) containing 10% fetal bovine serum (FBS), 1% penicillin\u2013streptomycin , 8\u00a0\u03bcg/mL puromycin and plated into 96-well plates for 16\u201324 h. Pseudovirus with serial dilution of mAbs was incubated for 1\u00a0h at 37\u00b0C and then added to the wells after washing 2 times with DMEM. After 2\u20133\u00a0h DMEM containing 20% FBS and 2% penicillin\u2013streptomycin was added to the cells. Following 48-72\u00a0h of infection, Bio-Glo (Promega) was added to the cells and incubated in the dark for 15\u00a0min before reading luminescence with Synergy H1 microplate reader (BioTek). Measurements were done in duplicate and relative luciferase units were converted to percent neutralization and plotted with a non-linear regression model to determine IC50 values using GraphPad PRISM software (version 9.0.0).MLV-based SARS-CoV-2 S-glycoprotein-pseudotyped viruses were prepared as previously described . HEK293T50 values using GraphPad PRISM software (version 9.0.0). The 50% inhibitory dilution (EC50) was defined as the serum dilution at which the relative light units (RLUs) were reduced by 50% compared with the virus control wells (virus\u00a0+ cells) after subtraction of the background RLUs in the control groups with cells only. The EC50 values were calculated with non-linear regression, log (inhibitor) versus normalized response using GraphPad Prism 8 . The neutralization assay was positive if the serum achieved at least 50% inhibition at 1 in 3 dilution of the SARS-CoV-2 spike protein pseudotyped virus in the neutralization assay. The neutralization result was negative if it failed to achieve 50% inhibition at 1 in 3 dilution. Statistical tests are described in the figure legends along with the value of n, mean, and standard deviation/error. Data were normally distributed consistent with statistical methods used.Measurements were done in duplicate and relative luciferase units were converted to percent neutralization against no-drug control which was set as 100%. Data were plotted with a non-linear regression model to determine ICMeasurements were done in duplicate and relative luciferase units measured with a Glomax luminometer. Data were analyzed using GraphPad PRISM software (version 9.0.0). Statistical tests are described in the figure legends along n, mean, and standard deviation/error. Data were normally distributed consistent with statistical methods used."} +{"text": "Cell Death and DiseaseCorrection to: 10.1038/s41419-021-03713-9 published online 01 May 2021The original version of this article unfortunately contained a mistake. The author names were given in the wrong order (family name) (given name) and were therefore tagged incorrectly. The authors apologize for the mistake. The original article has been corrected. The correct names are given below (given name) (family name):Germana Zaccagnini, Simona Greco, Marialucia Longo, Biagina Maimone, Christine Voellenkle, Paola Fuschi, Matteo Carrara, Pasquale Creo, Davide Maselli, Mario Tirone, Massimiliano Mazzone, Carlo Gaetano, Gaia Spinetti, Fabio Martelli"} +{"text": "Scientific Reports 10.1038/s41598-021-02974-w, published online 08 December 2021Correction to: The original version of this Article contained errors in the Affiliations.Peter H. Dziedzic and Pawel Kudela were incorrectly affiliated with \u2018Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA\u2019.Eusebia Calvillo and Han B. Kim were incorrectly affiliated with \u2018Department of Neurosurgery, Johns Hopkins University, Baltimore, MD, USA\u2019.Pawel Kudela was incorrectly affiliated with \u2018Department of Neurology, Johns Hopkins University, Baltimore, MD, USA\u2019.The correct affiliations for Peter H. Dziedzic are listed below.Laboratory of Computational Intensive Care Medicine, Johns Hopkins University, Baltimore, MD, USA.Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.The correct affiliation for Pawel Kudela is listed below.Department of Neurosurgery, Johns Hopkins University, Baltimore, MD, USA.The correct affiliation for Eusebia Calvillo is listed below.Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.The correct affiliations for Han B. Kim are listed below.Laboratory of Computational Intensive Care Medicine, Johns Hopkins University, Baltimore, MD, USA.Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.As a result, the Affiliations have been renumbered.The original Article has been corrected."} +{"text": "In \u201cEffect of Physician-Pharmacist Participation in the Management of Ambulatory Cancer Pain Through a Digital Health Platform: Randomized Controlled Trial\u201d :e24555), one error was noted.In the originally published article, the name of Corresponding Author \u201cJian Xiao\u201d was formatted incorrectly as \u201cXiao Jian.\u201d The original order of authors was listed as follows:Lu Zhang, Howard L McLeod, Ke-Ke Liu, Wen-Hui Liu, Hang-Xing Huang, Ya-Min Huang, Shu-Sen Sun, Xiao-Ping Chen, Yao Chen, Fang-Zhou Liu, Xiao JianThis has been corrected to:Lu Zhang, Howard L McLeod, Ke-Ke Liu, Wen-Hui Liu, Hang-Xing Huang, Ya-Min Huang, Shu-Sen Sun, Xiao-Ping Chen, Yao Chen, Fang-Zhou Liu, Jian XiaoThe correction will appear in the online version of the paper on the JMIR Publications website on September 13, 2021, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article has also been resubmitted to those repositories."} +{"text": "SARS-CoV-2 infects cells by the endocytosis process roteases \u20136. Endolroteases ,7\u20139. Theroteases ,10,11. Mroteases ,13, TRPMroteases , two-porroteases , SLC38A9roteases \u201318, and roteases , regulatin vitro and in vivo conditions [mTOR downstream signaling pathways regulate fundamental cellular processes such as metabolism, transcription, protein synthesis, apoptosis, cell cycle, endolysosomes, autophagy, and immune regulation and tolerance \u201326. Howenditions . Table 1Here briefly concludes that the mTOR sensor might be a potential therapeutic target to suppress SARS-CoV-2 infection and its pathogenesis, COVID-19. Hence, mTOR inhibitors, synthetic and mainly naturally available compounds, should be screened to determine their potency to suppress SARS-CoV-2 infection and COVID-19."} +{"text": "Correction to: Trials 22, 566 (2021)https://doi.org/10.1186/s13063-021-05529-6Originally published affiliation: School of Nursin, Shandong First Medical University , Jinan 250000, Shandong, ChinaCorrected affiliation: School of Public Health, Xinxiang Medical University, Xinxiang 453003, Henan, ChinaFollowing the publication of the original article , we wereThe original article has been corrected."} +{"text": "Scientific Reports 10.1038/s41598-021-97258-8, published online 10 September 2021Correction to: In the original version of this Article, Affiliation 5 and 6 were incorrectly given as \u2018Present address: High Definition Disease Modelling Lab, Stem Cell and Organoid Epigenetics, Department of Oncology and Hemato-Oncology, IEO, European Institute of Oncology, IRCCS, University of Milan, Milan, Italy\u2019. The correct affiliations are listed below:Present address: High Definition Disease Modelling Lab, Stem Cell and Organoid Epigenetics, IEO, European Institute of Oncology, IRCCS, Milan, Italy.Present address: Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.In addition, Raoul J. P. Bonnal was incorrectly affiliated with \u2018Present address: High Definition Disease Modelling Lab, Stem Cell and Organoid Epigenetics, Department of Oncology and Hemato-Oncology, IEO, European Institute of Oncology, IRCCS, University of Milan, Milan, Italy\u2019. The correct affiliations are listed below.Integrative Biology, Istituto Nazionale Genetica Molecolare \u201cRomeo ed Enrica Invernizzi\u201d, 20122, Milan, Italy.Present address: FIRC Institute of Molecular Oncology (IFOM), 20139, Milan, Italy.The original Article has been corrected."} +{"text": "Scientific Reports 10.1038/s41598-020-77586-x, published online 24 November 2020Correction to: The original version of this Article contained an error in Affiliation 3, which was incorrectly given as \u2018GENOTOUL Platform, INRA, 31,326, Castanet-Tolosan, France\u2019. The correct affiliation is listed below:Genotoul, INRA, US 1426 GeT PlaGe, Castanet Tolosan, France.The original Article and accompanying Supplementary Information files have been corrected."} +{"text": "Scientific Reports 10.1038/s41598-020-79872-0, published online 13 January 2021Correction to: In the original version of this Article, Francis Opoku, Ephraim Muriithi Kiarii and Poomani Penny Govender were incorrectly affiliated with \u2018Department of Chemical Engineering, Quchan University of Technology, Quchan, Iran\u2019. The correct affiliation for these authors is listed below.Department of Chemistry, University of Johannesburg, P.O. Box 17011, Doornfontein Campus, Johannesburg, 2028, South AfricaThe original Article has been corrected."} +{"text": "Correction to: BMC Psychiatry 20, 347 (2020)https://doi.org/10.1186/s12888-020-02759-xFollowing the publication of the original article , the autPhysiology Section, Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain.The original article has been"} +{"text": "Nature Communications 10.1038/s41467-021-26847-y, published online 09 November 2021.Correction to: Vibrio cholerae strains was incorrectly reported as Bangladesh: A46, A51, A111, A57, A61, A49, A103 and A279. The correct origins of the strains are, respectively: unknown, Egypt, unknown, India, India, unknown, unknown and Sweden. This has been corrected in both the PDF and HTML versions of the Article.The original version of this Article contained errors in Fig. 4A, in which the country of isolation for the following"} +{"text": "Bandali, Sameer KamaluddinMemberBeckett, Henry DaleMemberBethell, Maxwell SlingsbyFellow ~ Over 40 Years memberBhaumik, SabyasachiHonorary FellowCarroll, Bernard JamesFellow ~ Over 40 Years memberFleminger, John JackFellow ~ Over 40 Years memberGosselin, Jean-YvesFellow ~ Over 40 Years memberHeine, Bernard EdmundFellow ~ Over 40 Years memberHolden, Hyla MontgomeryMember ~ Over 40 Years memberKanakaratnam, GunaseelanFellow ~ Over 40 Years memberKanjilal, Gopal ChandraFellow ~ Over 40 Years memberKolakowska, TamaraRetiredMember ~ Over 40 Years memberMay, Kathleen MackenzieMember ~ Over 40 Years memberMirza, Yousuf KamalConsultantMemberScott, John ClellandFellow ~ Over 40 Years memberSirag, Ahmed OsmanRetiredFellowWat, Hong-Yun Karen MemberAlexander, David AHonorary FellowAlexander, Eric RichardsonMember ~ Over 40 Years memberAllan, FrancesMember ~ Over 40 Years memberBeauchemin, Barbara Susannah SeymourAffiliateBurkitt, Eric AylmerFellow ~ Over 40 Years memberDadds, Violet ElsieMemberDavies, Roy JamesFellow ~ Over 40 Years memberde Mowbray, Michael StuartMemberDenham, Maureen MilburnMember ~ Over 40 Years memberEngelhardt, Wolfram Detlev AchimMemberFenton, Thomas WilliamFellow ~ Over 40 Years memberForrest, Alastair JohnFellow ~ Over 40 Years memberGallagher, Elizabeth GibbMember ~ Over 40 Years memberGarry, John WilliamFellow ~ Over 40 Years memberGillham, Adrian BayleyFellowGray, Anne MargaretFellow ~ Over 40 Years memberGrimshaw, John StuartFellow ~ Over 40 Years memberHamour, Mohamed AbdelaalMemberHersov, Lionel AbrahamFellow ~ Over 40 Years memberIskander, Trevor NagibMember ~ Over 40 Years memberKelleher, F JosephMember ~ Over 40 Years memberKnox, Stafford JosephFellow ~ Over 40 Years memberLeslie, Nasnaranpattiyage Don GeorgeMember ~ Over 40 Years memberMacleod, Iain Roderic WilliamMemberMasih, HarnekMemberMatthews, Peter CharlesMember ~ Over 40 Years memberMcNeill, Desmond Lorne MarcusFellow ~ Over 40 Years memberNasser, Zeinab Abdel-Aziz IbrahimMemberRogers, Paul HaydonFellowRyle, AnthonyFellow ~ Over 40 Years memberTodes, Cecil JacobFellow ~ Over 40 Years memberYoussef, Hanafy Ahmed MahmoudFellow ~ Over 40 Years memberArie, Thomas Harry DavidHonorary FellowPant, AnshumanMemberSmith, Eileen DorothyFellow ~ Over 40 Years memberWhite, Daniel PaulMemberChan, Chee HungMemberCoia, Denise AssundaHonorary FellowDuddle, Constance MayFellow ~ Over 40 Years memberDunlop, Joyce LilianFellow ~ Over 40 Years memberHickling, Frederick WFellow ~ Over 40 Years memberHilary-Jones, Evan PeterFellowJones, David AlunFellowMcGovern, Gerald PatrickFellow ~ Over 40 Years memberPant, AnshumanMemberPathak, Rudresh Kumar DinanathMemberSmith, Eileen DorothyFellow ~ Over 40 Years memberWhite, Daniel PaulMemberD'Orban, Paul TRetiredFellow ~ Over 40 Years memberHewland, Helen RobynRetiredFellow ~ Over 40 Years memberHughes, John SamuelRetiredFellow ~ Over 40 Years memberImrie, Alison WendyConsultantMemberLader, Malcolm HaroldEmeritus ProfessorFellow ~ Over 40 Years memberMcLaughlin, Jo-AnnRetiredMemberMubbashar, Malik HussainConsultantFellow ~ Over 40 Years memberRobinson, John RichardRetiredFellow ~ Over 40 Years memberWashbrook, Reginald Alfred HryhorukFellow ~ Over 40 Years memberGillis, LynnRetiredFellowKenyon, Frank EdwinRetiredFellowPalmer, BobFellowRana, MamoonaWest, DonaldFellowBrown, Philip MorrisonFellow \u2013 North Division"} +{"text": "Yong Liao and Dr. Yu Zhao. The author list, affiliations and contributions have been updated accordingly and now appear as:In the article, \u201cYu ping feng san for pediatric allergic rhinitis: A systematic review and meta-analysis of randomized controlled trials\u201d,ab, Juan Zhong, PhDb,c, Shuqin Liu, MDc, Menglin Dai, PhDc, Yang Liu, PhDc, Xinrong Li, PhDc, Yepeng Yang, PhDc, Dazheng Zhang, PhDe,f,g, Dan Lai, PhDh, Tao Lu, PhDi, Qinxiu Zhang, PhDc,d, Yu Zhao, MD, PHDa\u2217Yong Liao, PHDa Department of Otorhinolaryngology Head and Neck Surgery, West China Hospital of Sichuan University, Chengdu,b Department of Otorhinolaryngology Head and Neck Surgery, Minda Hospital of Hubei Minzu University, Enshic Hospital of Chengdu University of Traditional Chinese Medicine, d School of Medical and Life Sciences/Reproductive and Women-Children Hospital, ChengduUniversity of Traditional Chinese Medicine, e Chengdu University of Traditional Chinese Medicine, f Dujiangyan medical centre, g China qingcheng medical researchlaboratory of Traditional Chinese Medicine, h Department of Otolaryngology Head and Neck Surgery, The Affiliated Hospital of Southwest Medical University, No. 25TaiPing Street, Luzhou, Sichuan, China, i Otolaryngology and Head & Neck Surgery Department One, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan.Conceived and designed the experiments: YL, JZ, YZ, SQL. Performedthe experiments: YL, ZJ, MLD, YPY, HYH. Analyzed the data: DL, TL, DZZ. Contributedreagents/materials/analysis tools: SQL,YPY,HMZ. Wrote the paper: YL, JZ, YZ.Conceptualization: Yang Liu.Data curation: Yu Zhao, Menglin Dai, Dazheng Zhang, Dan Lai, Tao Lu.Formal analysis: Yu Zhao, Yang Liu.Funding acquisition: Yu Zhao.Methodology: Yu Zhao, Yepeng Yang, Dazheng Zhang, Dan Lai, Tao Lu.Software: Xin rong Li, Dan Lai, Tao Lu.Writing \u2013 original draft: Yong Liao, Juan ZhongDr. Yu Zhao has been updated to the corresponding author."} +{"text": "Scientific Reports 10.1038/s41598-021-00884-5, published online 01 November 2021Correction to: The original version of this Article contained an error in Affiliation 2, which was incorrectly given as \u2018Mucosal Immunology and Microbiota Unit, Humanitas Research Hospital, 20090, Pieve Emanuele, Milan, Italy\u2019. The correct affiliation is listed below:IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, ItalyIn addition, an affiliation for Maria Rescigno was omitted. The correct affiliations are listed below.IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089, Rozzano, Milan, ItalyDepartment of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, ItalyThe original Article and accompanying Supplementary Information file have been corrected."} +{"text": "Scientific Reports 10.1038/s41598-021-92338-1, published online 24 June 2021Correction to: The Supplementary Information published with this Article contained errors.The order of authors was incorrectly given as Anushikha Thakur, Rekha Nagpal, Deepak Gadamshetty, Sirisha N., Malini Subbarao, Shreshtha Rakshit, Sneha Padiyar, Suma Sreenivas, Nagaraja G., Harish V Pai, Ramakrishnan M. S, Avik Kumar Ghosh.In addition, Affiliation 1 was incorrectly given as \u201cScience and Technology Innovation Center (SnTIC), Biocon Biologics, Biocon Park, SEZ, Bommasandra Industrial Area, Jigani Link Road, Bangalore, India 560100.\u201dThese errors have now been corrected in the Supplementary Information file that accompanies the original Article."} +{"text": "Laboratory Investigation 10.1038/s41374-021-00612-7, published online 21 May 2021Correction to: The original version of this article unfortunately contained a mistake. Due to the submission of Table 1 in a separate file, the following citations were missing in the references, leading to an incorrect linking in the table caption. The missing reference are:(A) Sheldon CA, Clayman RV, Gonzalez R, Williams RD, Fraley EE. Malignant urachal lesions. J Urol. 131, 1\u20138 (1984).(B) Ashley RA, Inman BA, Sebo TJ, Leibovich BC, Blute ML, Kwon ED, et al. Urachal carcinoma: clinicopathologic features and long-term outcomes of an aggressive malignancy. Cancer. 107, 712\u2013720 (2006).(C) Brierley J, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumors. In: Brierley J, Gospodarowicz MK, Wittekind C, editors. Chichester, West Sussex, UK, Hoboken, NJ: John Wiley & Sons Inc; 2017.The authors apologize for the mistake. The original article has been corrected."} +{"text": "We present evidence for multiple independent origins of recombinant SARS-CoV-2 viruses sampled from late 2020 and early 2021 in the United Kingdom. Their genomes carry single-nucleotide polymorphisms and deletions that are characteristic of the B.1.1.7 variant of concern but lack the full complement of lineage-defining mutations. Instead, the remainder of their genomes share contiguous genetic variation with non-B.1.1.7 viruses circulating in the same geographic area at the same time as the recombinants. In four instances, there was evidence for onward transmission of a recombinant-origin virus, including one transmission cluster of 45 sequenced cases over the course of 2\u00a0months. The inferred genomic locations of recombination breakpoints suggest that every community-transmitted recombinant virus inherited its spike region from a B.1.1.7 parental virus, consistent with a transmission advantage for B.1.1.7\u2019s set of mutations. \u2022We find evidence for recombination in SARS-CoV-2\u2022We identify eight clear recombination events, four of which lead to onward transmission\u2022Estimated breakpoints are consistent with coronavirus cellular replication dynamics\u2022Transmitted recombinants inherited the more-transmissible B.1.1.7 spike gene Sampling from late 2020 to early 2021 provides evidence for SARS-CoV-2 recombination and onward community transmission of recombinant viruses that inherited the spike region from the B.1.1.7 variant. Recombination, the transfer of genetic information between molecules derived from different organisms, is a fundamental process in evolution, because it can generate novel genetic variation upon which selection can act . GeneticThe molecular mechanism of homologous recombination in unsegmented positive-sense RNA viruses such as SARS-CoV-2 is generally by copy-choice replication, a model first suggested in poliovirus . In thisConditions conducive to SARS-CoV-2 recombination existed in the United Kingdom (UK) during the latter part of 2020 and early in 2021. From mid-October 2020 to January 2021, SARS-CoV-2 prevalence was estimated to be between 1% and 2% in England . During To identify putative SARS-CoV-2 recombinant viruses, we carried out an analysis of all complete UK SARS-CoV-2 genomes that had been assigned to lineage B.1.1.7 and that showed evidence of being the product of combining different genetic lineages, indicative of recombination. Specifically, we scanned the UK dataset for genomes that were alternately composed of long contiguous tracts of B.1.1.7 and non-B.1.1.7 genetic variation. The genetic composition and epidemiological context of each candidate mosaic genome was carefully explored to determine whether it was recombinant in origin. We subsequently determined whether the recombinants showed evidence of onward transmission within the UK population. One recombinant lineage continued to circulate for at least 9\u00a0weeks and, as of May 5, 2021, was associated with 45 linked infections.We identified a total of 16 recombinant sequences from the whole UK dataset of 279,000 sequences up to March 7, 2021 using our bioinformatic and evolutionary analysis pipeline see . Twelve To rule out the possibility that any of the 16 recombinants could have resulted from artifacts as a result of assembling sequence reads from a co-infected sample , we examined the read coverage and minor allele frequencies and assessed the likelihood of a mixed sample. Several lines of evidence suggested the recombinant sequences were not the products of sequencing a mixture of genomes. First, the sequencing protocol used in the UK generateThe nucleotide variation for the putative recombinants and their closest neighbors by genetic similarity (for each of the regions of their genomes either side of the recombination breakpoint) is shown in m,n,2 statistic for these two candidate recombinants showed the greatest support for mosaicism possible among the ancestry-informative polymorphic sites with their closest neighbors by genetic similarity as parentals . The associated uncorrected p value of 5.7e-7 does not survive a multiple comparisons correction due to the number of putative parental lineages and descendants that were tested .A follow-up investigation of the eight sets of putative recombinants (groups A\u2013D and the four singletons) on May 5, 2021 found 41 sequences that were descended from group A . No descHere, we report the first unambiguous detection and characterization of the arisal and subsequent community transmission of\u00a0recombinant SARS-CoV-2 viruses. Comparison of intra-genomic variation, supported by geographic and epidemiological data, demonstrates the occurrence of multiple independent recombination events involving UK virus lineages in late 2020. Recombinant genomes that share genetic identity were sampled from the same geographic location and time period, indicating they represent successful onward transmission after the occurrence of a single ancestral recombination event. In one instance, this resulted in a significant transmission cluster comprising 45 observed cases, which has been given the Pango lineage name XA. While no obvious biological advantage can be attributed to this cluster (or any of the observed recombinants) beyond the acquisition of B.1.1.7\u2019s set of spike mutations, these recombinants are sentinel events for continued monitoring for new variants. With the increasing co-circulation of VOCs in the same geographic areas, careful monitoring is warranted.Large-scale bioinformatic approaches have identified statistical signals of recombination among SARS-CoV-2 sequences using clade assignment and its changes along the genome as the primary characteristic under investigation . Due to in situ , the consensus genome sequences of the complete set of UK samples were aligned to the SARS-CoV-2 reference sequence (GenBank: MN908947.3) using Minimap2 (https://github.com/cov-ert/type_variants), then discarded sequences with missing data at any of the 22 sites. We visualized the resulting table of genotype calls in order to identify sequences that showed evidence of a potential mosaic genome structure .A national SARS-CoV-2 sequencing effort in the UK, the COG-UK consortium . Subsequently, an alignment was compiled for each putative recombinant, which contained the putative recombinant as well as the most-genetically similar background sequences (as identified above) for each component region of that mosaic genome. The single nucleotide differences between the putative recombinant and the closely related reference sequences were visualized using snipit (https://github.com/aineniamh/snipit). The genomic coordinates of the boundaries between each mosaic genome region were then refined by taking into account observed lineage-defining nucleotide and deletion variation. Specifically, we set the boundary coordinates to the ends of sequential tracts of mutations specific to the putative parental sequences. This is a conservative approach to assigning parental lineages and consequently no parental lineage is assigned to those genome regions that do not contain unambiguous lineage-defining mutations or deletions. Lastly, using these refined region boundaries, we reiterated the genetic distance calculation above to identify a final set of most-genetically similar sequences for each putative recombinant.To identify candidate parental genome sequences in a computationally-tractable manner we created a set of all UK SARS-CoV-2 sequences that (i) contained no N nucleotide ambiguity codes after masking the 3\u2032 and 5\u2032 UTRs, (ii) spanned the dates 2020/12/01 to 2021/02/28, which represents two weeks before the date of the earliest putative recombinant, to one week after the date of the latest, and (iii) excluded the putative recombinant genomes identified above. This set consisted of 98859 sequences in total. For each putative recombinant, we split its genome sequence into B.1.1.7-like regions and non-B.1.1.7 regions at the junction of genetic regions according to the mosaic structure detected by the custom Python script described above (https://ec.europa.eu/eurostat/web/nuts/history).When reporting geographic locations for UK virus genome sequences we use level 1 of the Nomenclature of Territorial Units for Statistics (NUTS) geocode standard (https://github.com/robj411/sequencing_coverage). We use this dataset to investigate the phylogenetic placement of the alternate regions of recombinant genomes, and as a dataset of putative parental sequences to statistically test for recombination using 3SEQ.To generate a limited set of genomes that are suitable for computationally-expensive analysis yet are also representative of the genetic diversity of the SARS-CoV-2 epidemic in the UK, we randomly sampled 2000 sequences from 21st March 2020, when sequence data first became available, to 1st March 2021, weighting the probability of choosing a sequence accounting for the sequencing coverage and covid19 prevalence in individual geographic regions of the UK over time, using the same method as in Almost all sequencing sites in the COG-UK consortium use the ARTIC PCR protocol to produce tiled PCR amplicons, which are then sequenced . The genMN908947.3) by a nucleotide change in B.1.1.7 (the 27 positions include those with nucleotide changes that were inherited from the ancestor of B.1.1.7). We define the MAF at a single site as the number of sequencing reads not containing the most frequently observed single nucleotide allele that mapped to that site, divided by the total number of sequencing reads that include any nucleotide allele that mapped to that site. For each virus genome, we defined a set of genomic positions from which to calculate MAF as follows. For each recombinant, we considered every site that differed from MN908947.3 by a nucleotide in its own consensus genome, or in the consensus genome of either of its parentals by genetic similarity. For the sequences that we suspected of being mixtures we considered the 27 genomic positions where sequences belonging to B.1.1.7 differ from MN908947.3 by a nucleotide change. We used samtools , rather than representing a true recombinant genome. To do this we calculated minor allele frequencies (MAFs) from the read data and compared their distribution between the 16 recombinant genomes and 20 samples that we suspected of being the product of sequencing a mixture of genomes, potentially because of coinfection or laboratory contamination. To define sequences that we suspected of being mixtures, we scanned the dataset for consensus sequences that possessed an IUPAC ambiguity code at the 27 genomic positions that differ from the SARS-CoV-2 reference genome against each putative recombinant in the child dataset (n\u00a0= 16), and report p values that are uncorrected and that are Dunn-Sidak corrected for multiple comparisons (n\u00a0= 64.0 million). We performed a single additional run of 3SEQ with two putative recombinant sequences that were not found to be significantly the mosaic product of any of the sequences in the representative background as children, and their closest neighbors by genetic similarity as parentals. P values for this test were reported without correction and after correction for multiple testing assuming that this test was in addition to the 64 million comparisons that we had already performed. The input and output files for the 3SEQ analysis are available at https://github.com/COG-UK/UK-recombination-analysis.We used 3SEQ as a stahttps://github.com/COG-UK/UK-recombination-analysis.For each of the eight sets of recombinants (Groups A-D and the four singletons) we carried out the following procedure to test for incongruence between the phylogenetic placements of the two regions of their genomes. We independently added each set\u2019s genome(s) to the representative background of 2000 sequences, along with the reference sequence, to create eight alignments in total. We masked the resulting alignments according to the breakpoints defined by the closest neighbors by genetic similarity, so that for each set, we produced two sub-alignments: one consisting of the region that was inherited from the B.1.1.7 parental in the recombinant(s), and one consisting of the region that was inherited from the other parental. This resulted in 16 alignments in total. We reconstructed the phylogenetic relationships for each with IQTREE v2.1 , using tTo determine the placement of the different regions of each recombinant genome in a single context, we also built a phylogenetic tree of the representative background\u2019s complete genomes, to which we added the masked recombinant genomes, so that each recombinant was present in the alignment twice, once with the B.1.1.7 region of its genome unmasked, and once with the opposing region unmasked. We ran IQTREE as above.th July 2021 using the same procedure as above.To test for onward community transmission of the putative recombinants, we searched the whole UK dataset as of the 5th May 2021 for additional sequences whose genetic variation matched the variation of the recombinants. For each of the eight set of recombinants, we defined a set of SNPs and deletions by which all the recombinants within that set differed from the reference sequence (MN908947.3). Then we used type_variants to scan the UK dataset for genomes whose SNP and deletion variation was compatible with being a descendant or sibling of the putative recombinants. Group A represented the only recombination event with evidence for further transmission according to the results of this procedure. We carried out the following additional analyses to further investigate transmission of Group A genomes. First, we visualized the nucleotide variation of the additional matching genomes using snipit and extracted their sampling locations and dates. Second, to explore the phylogenetic context of Group A and its derivatives, we reconstructed their (whole-genome) phylogenetic relationships using IQTREE. We also extracted the 100 closest sequences by genetic similarity for each alternate region of the genome (B.1.1.7-like and non-B.1.1.7-like) for each of the four original members of Group A to provide phylogenetic context to the parental sequences. This resulted in a dataset of 216 sequences in total when the two groups of neighbors were combined, and duplicates removed. We reconstructed their (whole-genome) phylogenetic relationships with the IQTREE, as above. We generated a time-scaled phylogenetic tree from the divergence tree of parental sequences using TreeTime , settinghttps://www.sanger.ac.uk/covid-team), Dorota Jamrozy, Stephanie Lo, Minal Patel, Claire M. Bewshea, Sian Ellard, Cressida Auckland, Ian Harrison, Chloe Bishop, Vicki Chalker, Alex Richter, Andrew Beggs, Angus Best, Benita Percival, Jeremy Mirza, Oliver Megram, Megan Mayhew, Liam Crawford, Fiona Ashcroft, Emma Moles-Garcia, Nicola Cumley, Richard Hopes, Patawee Asamaphan, Marc O. Niebel, Rory N. Gunson, Amanda Bradley, Alasdair Maclean, Guy Mollett, Rachel Blacow, Paul Bird, Thomas Helmer, Karlie Fallon, Julian Tang, Antony D. Hale, Louissa R. Macfarlane-Smith, Katherine L. Harper, Holli Carden, Nicholas W. Machin, Kathryn A. Jackson, Shazaad S.Y. Ahmad, Ryan P. George, Lance Turtle, Elaine O\u2019Toole, Joanne Watts, Cassie Breen, Angela Cowell, Adela Alcolea-Medina, Themoula Charalampous, Amita Patel, Lisa J. Levett, Judith Heaney, Aileen Rowan, Graham P. Taylor, Divya Shah, Laura Atkinson, Jack C.D. Lee, Adam P. Westhorpe, Riaz Jannoo, Helen L. Lowe, Angeliki Karamani, Leah Ensell, Wendy Chatterton, Monika Pusok, Ashok Dadrah, Amanda Symmonds, Graciela Sluga, Zoltan Molnar, Paul Baker, Stephen Bonner, Sarah Essex, Edward Barton, Debra Padgett, Garren Scott, Jane Greenaway, Brendan A.I. Payne, Shirelle Burton-Fanning, Sheila Waugh, Veena Raviprakash, Nicola Sheriff, Victoria Blakey, Lesley-Anne Williams, Jonathan Moore, Susanne Stonehouse, Louise Smith, Rose K. Davidson, Luke Bedford, Lindsay Coupland, Victoria Wright, Joseph G. Chappell, Theocharis Tsoleridis, Jonathan Ball, Manjinder Khakh, Vicki M. Fleming, Michelle M. Lister, Hannah C. Howson-Wells, Louise Berry, Tim Boswell, Amelia Joseph, Iona Willingham, Nichola Duckworth, Sarah Walsh, Emma Wise, Nathan Moore, Matilde Mori, Nick Cortes, Stephen Kidd, Rebecca Williams, Laura Gifford, Kelly Bicknell, Sarah Wyllie, Allyson Lloyd, Robert Impey, Cassandra S. Malone, Benjamin J. Cogger, Nick Levene, Lynn Monaghan, Alexander J. Keeley, David G. Partridge, Mohammad Raza, Cariad Evans, Kate Johnson, Emma Betteridge, Ben W. Farr, Scott Goodwin, Michael A. Quail, Carol Scott, Lesley Shirley, Scott A.J. Thurston, Diana Rajan, Iraad F. Bronner, Louise Aigrain, Nicholas M. Redshaw, Stefanie V Lensing, Shane McCarthy, Alex Makunin, Carlos E. Balcazar, Michael D. Gallagher, Kathleen A. Williamson, Thomas D. Stanton, Michelle L. Michelsen, Joanna Warwick-Dugdale, Robin Manley, Audrey Farbos, James W. Harrison, Christine M. Sambles, David J. Studholme, Angie Lackenby, Tamyo Mbisa, Steven Platt, Shahjahan Miah, David Bibby, Carmen Manso, Jonathan Hubb, Gavin Dabrera, Mary Ramsay, Daniel Bradshaw, Ulf Schaefer, Natalie Groves, Eileen Gallagher, David Lee, David William, Nicholas Ellaby, Hassan Hartman, Nikos Manesis, Vineet Patel, Juan Ledesma, Katherine A. Twohig, Elias Allara, Clare Pearson, Jeffrey K.J. Cheng, Hannah E. Bridgewater, Lucy R. Frost, Grace Taylor-Joyce, Paul E. Brown, Lily Tong, Alice Broos, Daniel Mair, Jenna Nichols, Stephen N. Carmichael, Katherine L. Smollett, Kyriaki Nomikou, Elihu Aranday-Cortes, Natasha Johnson, Seema Nickbakhsh, Edith E. Vamos, Margaret Hughes, Lucille Rainbow, Richard Eccles, Charlotte Nelson, Richard Gregory, Matthew Gemmell, Chloe L. Fisher, Adrian W. Signell, Gilberto Betancor, Harry D. Wilson, Gaia Nebbia, Flavia Flaviani, Alberto C. Cerda, Tammy V. Merrill, Rebekah E. Wilson, Marius Cotic, Nadua Bayzid, Thomas Thompson, Erwan Acheson, Steven Rushton, Sarah O\u2019Brien, David J. Baker, Steven Rudder, Alp Aydin, Fei Sang, Johnny Debebe, Sarah Francois, Tetyana I. Vasylyeva, Marina Escalera Zamudio, Bernardo Gutierrez, Angela Marchbank, Joshua Maksimovic, Karla Spellman, Kathryn McCluggage, Mari Morgan, Robert Beer, Safiah Afifi, Trudy Workman, William Fuller, Catherine Bresner, Adrienn Angyal, Luke R. Green, Paul J. Parsons, Rachel M. Tucker, Rebecca Brown, Max Whiteley, James Bonfield, Christoph Puethe, Andrew Whitwham, Jennifier Liddle, Will Rowe, Igor Siveroni, Thanh Le-Viet, Amy Gaskin, and Rob Johnson.The members of the COG-UK Consortium are Samuel C. Robson, Tanya Golubchi, Rocio T. Martinez Nunez, Catherine Ludden, Sally Corden, Ian Johnston, David Bonsall, Colin P. Smith, Ali R. Awan, Giselda Bucca, M. Estee Torok, Kordo Saeed, Jacqui A. Prieto, David K. Jackson, William L. Hamilton, Luke B. Snell, Catherine Moore, Ewan M. Harrison, Sonia Goncalves, Leigh M. Jackson, Ian G. Goodfellow, Derek J. Fairley, Matthew W. Loose, Joanne Watkins, Rich Livett, Samuel Moses, Roberto Amato, Darren L. Smith, Jeff Barrett, David M. Aanensen, Martin D. Curran, Surendra Parmar, Dinesh Aggarwal, James G. Shepherd, Matthew D. Parker, Sharon Glaysher, Matthew Bashton, Anthony P. Underwood, Katie F. Loveson, Alessandro M. Carabelli, Kate E. Templeton, Cordelia F. Langford, John Sillitoe, Thushan I. de Silva, Dennis Wang, Dominic Kwiatkowski, Justin O\u2019Grady, Simon Cottrell, Matthew T.G. Holden, Emma C. Thomson, Husam Osman, Monique Andersson, Anoop J. Chauhan, Mohammed O. Hassan-Ibrahim, Mara Lawniczak, Ravi Kumar Gupta, Alex Alderton, Meera Chand, Chrystala Constantinidou, Meera Unnikrishnan, Julian A. Hiscox, Steve Paterson, Inigo Martincorena, Erik M. Volz, Andrew J. Page, Andrew R. Bassett, Cristina V. Ariani, Michael H. Spencer Chapman, Kathy K. Li, Rajiv N. Shah, Natasha G. Jesudason, Yusri Taha, Martin P. McHugh, Rebecca Dewar, Aminu S. Jahun, Claire McMurray, Sarojini Pandey, James P. McKenna, Andrew Nelson, Gregory R. Young, Clare M. McCann, Scott Elliott, Hannah Lowe, Ben Temperton, Sunando Roy, Anna Price, Sara Rey, Matthew Wyles, Stefan Rooke, Sharif Shaaban, Mariateresa de Cesare, Laura Letchford, Siona Silveira, Emanuela Pelosi, Eleri Wilson-Davies, Myra Hosmillo, Andrew R. Hesketh, Richard Stark, Louis du Plessis, Chris Ruis, Helen Adams, Yann Bourgeois, Stephen L. Michell, Dimitris Grammatopoulos, Jonathan Edgewort, Judith Breuer, John A. Todd, Christophe Fraser, David Buck, Michaela John, Gemma L. Kay, Steve Palmer, Sharon J. Peacock, David Heyburn, Danni Weldon, Esther Robinson, Alan McNally, Peter Muir, Ian B. Vipond, John Boyes, Venkat Sivaprakasam, Tranprit Salluja, Samir Dervisevic, Emma J. Meader, Naomi R. Park, Karen Oliver, Aaron R. Jeffries, Sascha Ott, Ana da Silva Filipe, David A. Simpson, Chris Williams, Jane A.H. Masoli, Bridget A. Knight, Christopher R. Jones, Cherian Koshy, Amy Ash, Anna Casey, Andrew Bosworth, Liz Ratcliffe, Li Xu-McCrae, Hannah M. Pymont, Stephanie Hutchings, Lisa Berry, Katie Jones, Fenella Halstead, Thomas Davis, Christopher Holmes, Miren Iturriza-Gomara, Paul Anthony Randell, Alison Cox, Pinglawathee Madona, Kathryn Ann Harris, Julianne Rose Brown, Tabitha W Mahungu, Dianne Irish-Tavares, Tanzina Haque, Jennifer Hart, Eric Witele, Melisa Louise Fenton, Steven Liggett, Clive Graham, Emma Swindells, Jennifer Collins, Gary Eltringham, Sharon Campbell, Patrick C. McClure, Gemma Clark, Tim J. Sloan, Carl Jones, Jessica Lynch, Ben Warne, Steven Leonard, Jillian Durham, Thomas Williams, Nathaniel Storey, Nabil-Fareed Alikhan, Nadine Holmes, Christopher Moore, Matthew Carlile, Malorie Perry, Noel Craine, Ronan A. Lyons, Angela H. Beckett, Salman Goudarzi, Christopher Fearn, Kate Cook, Hannah Dent, Hannah Paul, Robert Davies, Beth Blane, Sophia T. Girgis, Mathew A. Beale, Katherine L. Bellis, Matthew J. Dorman, Eleanor Drury, Leanne Kane, Sally Kay, Samantha McGuigan, Rachel Nelson, Liam Prestwood, Shavanthi Rajatileka, Rahul Batra, Rachel J. Williams, Mark Kristiansen, Angie Green, Anita Justice, Adhyana I.K. Mahanama, Buddhini Samaraweera, Nazreen F. Hadjirin, Joshua Quick, Leanne M. Kermack, Nicola Reynolds, Grant Hall, Yasmin Chaudhry, Malte L. Pinckert, Iliana Georgana, Robin J. Moll, Alicia Thornton, Richard Myers, Joanne Stockton, Charlotte A. Williams, Wen C. Yew, Alexander J. Trotter, Amy Trebes, George MacIntyre-Cockett, Alec Birchley, Alexander Adams, Amy Plimmer, Bree Gatica-Wilcox, Caoimhe McKerr, Ember Hilvers, Hannah Jones, Hibo Asad, Jason Coombes, Johnathan M. Evans, Laia Fina, Lauren Gilbert, Lee Graham, Michelle Cronin, Sara Kumziene-SummerhaYes, Sarah Taylo, Sophie Jones, Danielle C. Groves, Peijun Zhang, Marta Gallis, Stavroula F. Louka, Igor Starinskij, Chris J. Illingworth, Chris Jackson, Marina Gourtovaia, Gerry Tonkin-Hill, Kevin Lewis, Jaime M. Tovar-Corona, Keith James, Laura Baxter, Mohammad T. Alam, Richard J. Orton, Joseph Hughes, Sreenu Vattipally, Manon Ragonnet-Cronin, Fabricia F. Nascimento, David Jorgensen, Olivia Boyd, Lily Geidelberg, Alex E. Zarebski, Jayna Raghwani, Moritz U.G. Kraemer, Joel Southgate, Benjamin B. Lindsey, Timothy M. Freeman, Jon-Paul Keatley, Joshua B. Singer, Leonardo de Oliveira Martins, Corin A. Yeats, Khalil Abudahab, Ben E.W. Taylor, Mirko Menegazzo, John Danesh, Wendy Hogsden, Sahar Eldirdiri, Anita Kenyon, Jenifer Mason, Trevor I. Robinson, Alison Holmes, James Price, John A. Hartley, Tanya Curran, Alison E. Mather, Giri Shankar, Rachel Jones, Robin Howe, Sian Morgan, Elizabeth Wastenge, Michael R. Chapman, Siddharth Mookerjee, Rachael Stanley, Wendy Smith, Timothy Peto, David Eyre, Derrick Crook, Gabrielle Vernet, Christine Kitchen, Huw Gulliver, Ian Merrick, Martyn Guest, Robert Munn, Declan T. Bradley, Tim Wyatt, Charlotte Beaver, Luke Foulser, Sophie Palmer, Carol M. Churcher, Ellena Brooks, Kim S. Smith, Katerina Galai, Georgina M. McManus, Frances Bolt, Francesc Coll, Lizzie Meadows, Stephen W. Attwood, Alisha Davies, Elen De Lacy, Fatima Downing, Sue Edwards, Garry P. Scarlett, Sarah Jeremiah, Nikki Smith, Danielle Leek, Sushmita Sridhar, Sally Forrest, Claire Cormie, Harmeet K. Gill, Joana Dias, Ellen E. Higginson, Mailis Maes, Jamie Young, Michelle Wantoch, Sanger Covid Team ("} +{"text": "Casirivimab and imdevimab (CAS/IMDEV) is authorized for emergency use in the US for outpatients with COVID-19. We present results from patient cohorts receiving low flow or no supplemental oxygen at baseline from a phase 1/2/3, randomized, double-blinded, placebo (PBO)-controlled trial of CAS/IMDEV in hospitalized patients (pts) with COVID-19.Hospitalized COVID-19 pts were randomized 1:1:1 to 2.4 g or 8.0 g of IV CAS/IMDEV (co-administered) or PBO. Primary endpoints were time-weighted average (TWA) change in viral load from baseline (Day 1) to Day 7; proportion of pts who died or went on mechanical ventilation (MV) through Day 29. Safety was evaluated through Day 57. The study was terminated early due to low enrollment (no safety concerns).Fig. 1). The primary clinical analysis had a strong positive trend, though it did not reach statistical significance (P=0.2048), and 4/6 clinical endpoints prespecified for hypothesis testing were nominally significant (Table 1). In seroneg pts, there was a 47.0% relative risk reduction (RRR) in the proportion of pts who died or went on MV from Day 1\u201329 . There was a 55.6% and 35.9% RRR in the prespecified secondary endpoint of mortality by Day 29 in seroneg pts and the overall population, respectively . No harm was seen in seropositive patients, and no safety events of concern were identified.Analysis was performed in pooled cohorts as well as combined treatment doses (2.4 g and 8.0 g). The prespecified primary virologic analysis was in seronegative (seroneg) pts , where treatment with CAS/IMDEV led to a significant reduction in viral load from Day 1\u20137 (TWA change: LS mean (SE): -0.28 (0.12); 95% CI: -0.51, -0.05; P=0.0172; Figure 1: TWA daily viral load decreased from baseline (Day 1) in seronegative patients receiving low flow or no supplemental oxygenTable 1. Primary virologic and clinical endpointsFigure 2: Clinical outcomes in hospitalized patients receiving low flow or no supplemental oxygen*Co-administration of CAS/IMDEV led to a significant reduction in viral load in hospitalized, seroneg pts requiring low flow or no supplemental oxygen. In seroneg pts and the overall population, treatment also demonstrated clinically meaningful, nominally significant reductions in 28-day mortality and proportion of pts dying or requiring MV.Eleftherios Mylonakis, MD, PhD, BARDA Chemic labs/KODA therapeutics (Grant/Research Support)Cidara (Grant/Research Support)Leidos Biomedical Research Inc/NCI (Grant/Research Support)NIH/NIAID (Grant/Research Support)NIH/NIGMS (Grant/Research Support)Pfizer (Grant/Research Support)Regeneron (Grant/Research Support)SciClone Pharmaceuticals (Grant/Research Support) Selin Somersan-Karakaya, MD, BARDA Regeneron Pharmaceuticals, Inc. Sumathi Sivapalasingam, MD, BARDA Excision BioTherapeutics (Employee)Regeneron Pharmaceuticals, Inc. Shazia Ali, PharmD, BARDA Regeneron Pharmaceuticals, Inc. Yiping Sun, PhD, BARDA Regeneron Pharmaceuticals, Inc. Rafia Bhore, PhD, BARDA Regeneron Pharmaceuticals, Inc. Jingning Mei, PhD, BARDA Regeneron Pharmaceuticals, Inc. Jutta Miller, BS, RN, BARDA Regeneron Pharmaceuticals, Inc. Lisa Cupelli, PhD, BARDA Regeneron Pharmaceuticals, Inc. (Employee) Andrea T. Hooper, PhD, BARDA Pfizer, Inc. Regeneron Pharmaceuticals, Inc. Jennifer D. Hamilton, PhD, BARDA Regeneron Pharmaceuticals, Inc. Cynthia Pan, BPharm, BARDA Regeneron Pharmaceuticals, Inc. Viet Pham, BS, BARDA Regeneron Pharmaceuticals, Inc. Yuming Zhao, MS, BARDA Regeneron Pharmaceuticals, Inc. Romana Hosain, MD, MPH, BARDA Regeneron Pharmaceuticals, Inc. Adnan Mahmood, MD, BARDA Regeneron Pharmaceuticals, Inc. John D. Davis, PhD, BARDA Regeneron Pharmaceuticals, Inc. Kenneth C. Turner, PhD, BARDA Regeneron Pharmaceuticals, Inc. Yunji Kim, PharmD, BARDA Regeneron Pharmaceuticals, Inc. Amanda Cook, BS, Dip Reg Aff, BARDA Regeneron Pharmaceuticals, Inc. Jason C. Wells, MD, BARDA Bari Kowal, MS, BARDA Regeneron Pharmaceuticals, Inc. Yuhwen Soo, PhD, BARDA Regeneron Pharmaceuticals, Inc. A. Thomas DiCioccio, PhD, BARDA Regeneron Pharmaceuticals, Inc. Gregory P. Geba, MD, DrPH, BARDA Regeneron Pharmaceuticals, Inc. (Shareholder) Neil Stahl, PhD, BARDA Regeneron Pharmaceuticals, Inc. Leah Lipsich, PhD, BARDA Regeneron Pharmaceuticals, Inc. Ned Braunstein, MD, BARDA Regeneron Pharmaceuticals, Inc. Gary Herman, MD, BARDA Regeneron Pharmaceuticals, Inc. George D. Yancopoulos, MD, PhD, BARDA Regeneron Pharmaceuticals, Inc. David M. Weinreich, MD, BARDA Regeneron Pharmaceuticals, Inc."} +{"text": "Correction to: BMC Musculoskelet Disord 22, 1007 (2021)https://doi.org/10.1186/s12891-021-04893-3Following the publication of the original article the authThe affiliations of these authors should be:Zhong-Yan Li:Department of Medicine, Chang Gung University, No.259, Wenhua 1st Rd., Guishan Dist., Taoyuan 33302, Taiwan, Republic of ChinaTung-Wu Lu:Department of Biomedical Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei 10617, Taiwan, Republic of ChinaSheng-Hsun Lee:Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Linkou, No.5, Fuxing St., Guishan Dist., Taoyuan 33,305, Taiwan, Republic of ChinaBone and Joint Research Center, Chang Gung Memorial Hospital, Linkou, No.5, Fuxing St., Guishan Dist., Taoyuan 33305, Taiwan, Republic of ChinaDepartment of Biomedical Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei 10617, Taiwan, Republic of ChinaThe original article has been"} +{"text": "Correction to: BMC Psychiatry 22, 176 (2022)https://doi.org/10.1186/s12888-022-03819-0Following publication of the original article , the autInstitute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, Tianjin, China, 300222.The original article has been"} +{"text": "Scientific Reports 10.1038/s41598-022-05886-5, published online 02 February 2022Correction to: In the original version of this Article Naoki Watanabe was incorrectly affiliated with \u2018Department of Ophthalmology, Faculty of Medical Sciences, University of Fukui, 23-3 Shimoaizuki, Matsuoka, Eiheiji, Yoshida, Fukui, 910-1193, Japan\u2019. The correct affiliation is listed below.Prometech Software Inc, Round Terrace Fushimi, 3F, 17-26, Nishiki 1-chome, Naka-ku, Nagoya 460-0003, JapanThe original Article has been corrected."} +{"text": "Severe coronavirus disease 2019 (COVID-19) often results from the immune-mediated cytokine storm, triggered by granulocyte macrophage-colony stimulating factor (GM-CSF), potentially leading to respiratory failure and death. Lenzilumab, a novel anti-human GM-CSF monoclonal antibody, neutralizes GM-CSF and demonstrated potential to improve clinical outcomes in a matched case-cohort study of patients with severe COVID-19 pneumonia. This Phase 3 randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of lenzilumab to improve the likelihood of survival without invasive mechanical ventilation (SWOV), beyond available treatments. Hypoxic patients, hospitalized with COVID-19 (n=520), requiring supplemental oxygen, but not invasive mechanical ventilation, were randomized on Day 0 to receive lenzilumab or placebo (n=259), and available treatments, including remdesivir and/or corticosteroids; and were followed through Day 28. Baseline demographics were comparable between groups: male, 64.7%; mean age, 60.5 years; median CRP, 79.0 mg/L. Patients across both groups received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab improved the primary endpoint, likelihood of SWOV in the mITT population, by 1.54-fold . Lenzilumab improved SWOV by 1.91-fold and 1.92-fold in patients receiving remdesivir or remdesivir and corticosteroids, respectively. A key secondary endpoint of incidence of IMV, ECMO or death was also improved in patients receiving remdesivir (p=0.020) or remdesivir and corticosteroids (p=0.0180). Treatment-emergent serious adverse events were similar across both groups.Lenzilumab significantly improved SWOV in hypoxic COVID-19 patients upon hospitalization, with the greatest benefit observed in patients receiving treatment with remdesivir and corticosteroids. NCT04351152Zelalem Temesgem, MD, Humanigen, Inc (Grant/Research Support) Jason Baker, MD, Humanigen, Inc (Grant/Research Support) Christopher Polk, MD, Atea (Research Grant or Support)Gilead Humanigen (Research Grant or Support)Regeneron (Research Grant or Support) Claudia R. Libertin, MD, Gilead (Grant/Research Support) Colleen F. Kelley, MD, MPH, Gilead Sciences Involved: Self): Grant/Research Support; Moderna Involved: Self): Grant/Research Support; Novavax Involved: Self): Grant/Research Support; Viiv Involved: Self): Grant/Research Support Vincent Marconi, MD, Bayer Eli Lilly Gilead Sciences ViiV Victoria Catterson, PhD, Humanigen, Inc (Consultant) William Aronstein, MD, PhD, Humanigen, Inc (Consultant) Cameron Durrant, MD, Humanigen, Inc (Employee) Dale Chappell, MD, Humanigen, Inc (Employee) Omar Ahmed, PharmD, Humanigen, Inc (Employee) Gabrielle Chappell, MSc, Humanigen, Inc (Consultant) Andrew Badley, M.D., AbbVie (Consultant) for the LIVE-AIR Study Group, n/a, Humanigen, Inc (Grant/Research Support)"} +{"text": "Scientific Reports 10.1038/s41598-020-57627-1, published online 20 January 2020Correction to: The original version of this Article contained an error in Affiliation 4, which incorrectly given as \u2018Department of Experimental Oncology, European Institute of Oncology, via Adamello 16, 20139, Milan, Italy.\u2019 The correct affiliation is listed below:Department of Experimental Oncology, European Institute of Oncology, IRCCS, via Adamello 16, 20139, Milan, Italy.The original Article has been corrected."} +{"text": "A., Jowitt, T. A., Knauer, S. H., Uebel, S., Williams, M. A., Sedivy, A., Abian, O., Abreu, C., Adamczyk, M., Bal, W., Berger, S., Buell, A. K., Carolis, C., Daviter, T., Fish, A., Garcia-Alai, M., Guenther, C., Hamacek, J., Holkov\u00e1, J., Houser, J., Johnson, C., Kelly, S., Leech, A., Mas, C., Matulis, D., McLaughlin, S. H., Montserret, R., Nasreddine, R., Nehm\u00e9, R., Nguyen, Q., Ortega-Alarc\u00f3n, D., Perez, K., Pirc, K., Piszczek, G., Podobnik, M., Rodrigo, N., Rokov-Plavec, J., Schaefer, S., Sharpe, T., Southall, J., Staunton, D., Tavares, P., Vanek, O., Weyand, M., Wu, D. was originally published Online First without Open Access. After publication in volume 50, issue 3\u20134, pages 411\u2013427 the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to \u00a9 The Author(s) 2021 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article\u2019s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article\u2019s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The original article has been corrected."} +{"text": "Scientific Reports 10.1038/s41598-021-00767-9, published online 28 October 2021Correction to: The original version of this Article contained errors in the spelling of the authors Chiara Montanari, Giulia Tabanelli, Federica Barbieri, Diego Mora, Robin Duncan, Fausto Gardini & Stefania Arioli, which were incorrectly given as Montanari Chiara, Tabanelli Giulia, Barbieri Federica, Mora Diego, Duncan Robin, Gardini Fausto & Arioli Stefania.The original Article has been corrected."} +{"text": "Correction to: BMC Med Res Methodol 21, 103 (2021)https://doi.org/10.1186/s12874-021-01288-9Two names are missing from the acknowledgements section under \u201cObstetric Emergency Consensus Authorship Group\u201d (\u201cRachel Corry\u201d and \u201cCeline McKeown\u201d). The list in that section should read:Amanda Andrews, Rita Arya, Sarah F. Bell, Denise Chaffer, Andrew Cooney, Rachel Corry, Mair G.P. Davies, Lisa Duffy, Caroline Everden, Theresa Fitzpatrick, Courtney Grant, Mark Hellaby, Tracey A. Herlihey, Sue Hignett, Sarah Hookes, Fran R. Ives, Gyuchan T. Jun, Owen J. Marsh, Tanya R. Matthews, Celine McKeown, Alexandra Merriman, Giulia Miles, Susan Millward, Neil Muchatata, David Newton, Valerie G. Noble, Pamela Page, Vincent Pargade, Sharon P. Pickering, Laura Pickup, Dale Richards, Cerys Scarr, Jyoti Sidhu, James Stevenson, Ben Tipney, Stephen Tipper, Jo Wailling, Susan P. Whalley-Lloyd, Christian Wilhelm, Juliet J. Wood.These two names are also missing from the Authorship Group name and the tagging of them in databases such as Pubmed. The two names need to be added accordingly as well.Following publication of the original article , the autThe original article has been corrected."} +{"text": "Acknowledgements Members of the Echinococcosis Working Group Ulm: Thomas FE Barth, Sven Baumann, Johannes Bloehdorn, Iris Fischer, Tilmann Graeter, Natalja Graf, Beate Gruener, Doris Henne-Bruns, Andreas Hillenbrand, Tanja Kaltenbach, Peter Kern, Petra Kern, Katharina Klein, Wolfgang Kratzer, Niloofar Ehteshami, Patrycja Schlingelof, Julian Schmidberger, Rong Shi, Yael Staehelin, Frauke Theis, Daniil Verbitskiy, Ghaith Zarour.The original version of this article unfortunately contained a mistake. Figure\u00a03 in the original version of this article has been replaced. The corrected Fig.\u00a0The original article has been corrected."} +{"text": "The eCRM carrier protein contains multiple insertions of the non-native amino acid para-azidomethyl-L-phenylalanine (pAMF) that facilitates site-specific conjugation of the pneumococcal polysaccharides (PS) to eCRM. Unlike conventional methodologies, site-selective conjugation enhances process consistency and increases capacity for inclusion of additional serotypes in a PCV without promoting carrier suppression. Using this platform, the aim of the current study was to employ CFPS technology to construct a 31-valent PCV and evaluate its immunogenicity in New Zealand White (NZW) rabbits. Due to the diversity of serotypes, exacerbated by the phenomenon of serotype replacement, there remains an unmet medical need for a pneumococcal conjugate vaccine (PCV) containing additional serotypes. Using a cell-free protein synthesis (CFPS) platform to produce an enhanced carrier protein , which were then mixed with aluminum phosphate to produce the VAX-XP Drug Product. 24 of the DS conjugates in VAX-XP were generated at manufacturing scale. Two doses of VAX-XP were administered to NZW rabbits at 0 and 21 days to assess its ability to elicit anti-capsular IgG antibodies. Additionally, rabbits were also administered either Prevnar13 or a mixture of Pneumovax 23 and 8 incremental PS in isotonic saline, as comparators.VAX-XP showed conjugate-like immune responses for all 31 serotypes, as demonstrated by superior responses to PS-based vaccines and comparable responses to Prevnar13. IgG responses for VAX-XP compared with Prevnar13 and Pneumovax 23 at 14 days post dose 2These results demonstrate that increasing the number of pneumococcal serotypes does not result in immunological attenuation in any of the serotypes contained in VAX-XP relative to the current standard of care. Furthermore, the data confirm the scalability and reproducibility of the CFPS platform in the production of VAX-XP conjugates, creating the foundation for a next generation broad-valency PCV.Chris Behrens, PhD, Vaxcyte, Inc. (Employee) Jeff Fairman, PhD, Vaxcyte, Inc. (Employee) Paresh Agarwal, PhD, Vaxcyte, Inc. (Employee) Shylaja Arulkumar, MS, Vaxcyte, Inc. (Employee) Sandrine Barbanel, MS, Vaxcyte, Inc. (Employee) Leslie Bautista, n/a, Vaxcyte, Inc. (Employee) Aym Berges, PhD, Vaxcyte, Inc. (Employee) John Burky, BS, Vaxcyte, Inc. (Employee) Peter Davey, MS, Vaxcyte, Inc. (Employee) Chris Grainger, PhD, Vaxcyte, Inc. (Employee) Sherry Guo, PhD, Vaxcyte, Inc. (Employee) Sam Iki, MS, Vaxcyte, Inc. (Employee) Mark Iverson, BS, Vaxcyte, Inc. (Employee) Neeraj Kapoor, PhD, Vaxcyte, Inc. (Employee) Olivier Marcq, PhD, Vaxcyte, Inc. (Employee) Thi-Sau Migone, PhD, Vaxcyte, Inc. (Employee) Lucy Pill, MS, Vaxcyte, Inc. (Employee) Mohammed Sardar, n/a, Vaxcyte, Inc. (Employee) Paul Sauer, MBA, Vaxcyte, Inc. (Employee) James Wassil, MS MBA, Vaxcyte, Inc. (Employee)"} +{"text": "Communications Biology 10.1038/s42003-021-02595-z, published online 22 September 2021.Correction to: In this article, the institute \u201cIRCCS Humanitas Research Hospital\u201d was incorrectly given as \u201cIRCSS Humanitas Research Hospital\u201d in the following affiliations. The original article has been corrected.Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.Breast Surgery Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.Department of Pathology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.Humanitas Flow Cytometry Core, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.Genomic Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy."} +{"text": "Future Science OA 7(2), FSO662; doi: 10.2144/fsoa-2020-0159, it has been brought to our attention that an author was erroneously absent from the author list.Following publication of the Research Article by KL Reckamp, JA McQuerry, I\u00a0Mambetsariev, R\u00a0Pharaon, SE Yost, J\u00a0Fricke, T\u00a0Mirzapoiazova, RK Pillai, L\u00a0Arvanitis, Z\u00a0Khan, M\u00a0Fakih, Y\u00a0Yuan, M\u00a0Koczywas, E\u00a0Massarelli, P\u00a0Kulkarni, SK Pal, M\u00a0Sattler, A\u00a0Bild & R\u00a0Salgia\u00a0titled \u201cCo-stimulatory and co-inhibitory immune markers in solid tumors with MET alterations\u201d, which appeared in the February 2021 issue of The author list has now been corrected to include Leonidas Arvanitis, and reads:Karen L Reckamp, Jasmine A McQuerry, Isa Mambetsariev, Rebecca Pharaon, Susan E Yost, Jeremy Fricke, Tamara Mirzapoiazova, Raju K Pillai, Leonidas Arvanitis, Ziad Khan, Marwan Fakih, Yuan Yuan, Marianna Koczywas, Erminia Massarelli, Prakash Kulkarni, Sumanta K Pal, Martin Sattler, Andrea Bild & Ravi Salgia.The author contributions list has also been updated as follows:K L Reckamp: conceptualization, design, methodology, validation, formal analysis, original draft preparation, data accrual, tissue acquisition and writing review and editing. J McQuerry: conceptualization, design, methodology, validation, formal analysis, original draft preparation and writing review and editing. I Mambetsariev: conceptualization, design, methodology, data curation, original draft preparation and writing review and editing. R Pharaon: methodology, validation, data curation and writing review and editing. J Fricke: methodology, validation, data curation and writing review and editing. T Mirzapoiazova: methodology, validation, data curation and writing review and editing. R K Pillai: methodology, validation and tissue acquisition. L Arvanitis: methodology, validation and tissue acquisition. Z Khan: validation, data accrual and tissue acquisition. M Fakih: validation, data accrual and tissue acquisition. Y Yuan: validation, data accrual and tissue acquisition. M Koczywas: validation, data accrual and tissue acquisition. E Massarelli: validation, data accrual and tissue acquisition. P Kulkarni: supervision, methodology and writing review and editing. S K Pal: supervision, methodology, data accrual, tissue acquisition and writing review and editing. M Sattler: methodology and writing review and editing. A Bild: supervision, conceptualization, design, methodology, validation, original draft preparation and writing review and editing. R Salgia: supervision, funding acquisition, conceptualization, design, methodology, validation, original draft preparation and writing review and editing. All authors contributed to the review, editing and approval of the final manuscript.Future Science OA would like to sincerely apologize for any confusion or inconvenience this may have caused our readers.The authors and editors of"} +{"text": "The original version of this article unfortunately contained a mistake.The Acknowledgement with the members of the Appendicitis-COVID study group is missing. The correct version of is given below.AcknowledgementsMembers of the Appendicitis-COVID study group:Monza: Marco Nizzardo, Luca Nespoli, Luca Fattori, Luca Degrate, Stefano Perrone, Marco CeredaBergamo: Michele Pisano, Elia Poiasina, Paolo BertoliLodi: Michele Ballabio, Stefano BragaPavia: Giorgio GrazianoPisa: DarioTartaglia, Francesco ArcesLecco: Marco Mariani, Fulvio TagliabueParma: Gennaro Perrone, Alfredo Annicchiarico, Mario GiuffridaLegnano: Giovanni Ferrari, Antonio Benedetti, Niccol\u00f2 AllieviPonte San Pietro: Michele Ciocca, Enrico Pinotti, Mauro MontuoriSan Raffaele: Michele Carlucci, Valentina TomajerCesena: Paola FugazzolaThe original article has been corrected."} +{"text": "The following statement should be added to the Acknowledgments section of this paper: \u201cCRediT roles for this study are as follows: Mohammed Mufrrih: Investigation; Biyao Chen: Formal analysis, Investigation; Shiu-Wan Chan: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing.\u201dVolume 6, no. 3, e00361-21, 2021,"} +{"text": "Scientific Reports 10.1038/s41598-021-96310-x, published online 19 August 2021Correction to: The original version of this Article contained errors in the spelling of the authors Lennart Well, Anna Careddu, Maria Stark, Said Farschtschi, Peter Bannas, Gerhard Adam, Victor-Felix Mautner & Johannes Salamon which were incorrectly given as Well Lennart, Careddu Anna, Stark Maria, Farschtschi Said, Bannas Peter, Adam Gerhard, Mautner Victor-Felix & Salamon Johannes.The original Article has been corrected."} +{"text": "Correction to: Mol Neurobiol10.1007/s12035-021-02287-zThe original version of this article unfortunately contained some mistakes.The surnames and given names of authors were interchanged. It should be:Elisabetta Signoriello, Marta Mallardo, Ersilia Nigro, Rita Polito, Sara Casertano, Andrea Di Pietro, Marcella Coletta, Maria Ludovica Monaco, Fabiana Rossi, Giacomo Lus, and Aurora DanieleThe original article has been corrected."} +{"text": "Correction to: J Exp Clin Cancer Res 40, 140 (2021)https://doi.org/10.1186/s13046-021-01940-81Department of Gastroenterology, Putuo People\u2019s Hospital, Tongji University School of Medicine, number 1291, Jiangning road, Putuo, Shanghai, 200060, China2Department of Gastroenterology, Shanghai Tenth People\u2019s Hospital, Tongji University School of Medicine, Number 301, Middle Yanchang road, Jing\u2019an, Shanghai 200072, ChinaFollowing publication of the original article , the autThe original article has been corrected."} +{"text": "Leukemia 10.1038/s41375-020-0779-z, published online 03 March 2020Correction to: The article Comprehensive genomic characterization of gene therapy-induced T-cell acute lymphoblastic leukemia, written by Peter Horak, Sebastian Uhrig, Maximilian Witzel, Irene Gil-Farina, Barbara Hutter, Tim Rath, Laura Gieldon, Gnana Prakash Balasubramanian, Xavier Pastor, Christoph E. Heilig, Daniela Richter, Evelin Schr\u00f6ck, Claudia R. Ball, Benedikt Brors, Christian J. Braun, Michael H. Albert, Claudia Scholl, Christof von Kalle, Manfred Schmidt, Stefan Fr\u00f6hling, Christoph Klein & Hanno Glimm, was originally published Online First without Open Access. After publication in volume 34, pages 2785\u20132789, the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to \u00a9 The Author(s) [year of online publication] and the article is forthwith distributed under the terms of the Creative Commons Attribution."} +{"text": "Scientific Reports 10.1038/s41598-021-93143-6, published online 02 July 2021Correction to: The original version of this Article omitted an affiliation for Kurenai Kinno. The correct affiliations for Kurenai Kinno are listed below:Department of Urology, Toho University Graduate School of Medicine, 5-21-16 Omorinishi, Ota City, Tokyo, 143-8540, JapanDepartment of Urology, Toho University Ohashi Medical Center, 2-22-36 Ohashi, Meguro City, Tokyo, 153-8515, JapanDepartment of Urology, Yotsuya Medical Cube, 7-7 Nibancho, Chiyoda City, Tokyo, 102-0084, JapanThe original Article and accompanying Supplementary Information file have been corrected."} +{"text": "RPB1, RPB2, and TEF1). In this study, one new order, one new family, four new genera, twenty new species, and two new combinations were proposed. They are Franziozymales ord. nov., Franziozymaceae fam. nov., Baueromyces gen. nov., Franziozyma gen. nov., Guomyces gen. nov., Yunzhangomyces gen. nov., Baueromyces planticola sp. nov., Franziozyma bambusicola sp. nov., Gjaerumia cyclobalanopsidis sp. nov., Gjaerumia pseudominor sp. nov., Jamesdicksonia aceris sp. nov., Jaminaea lantanae sp. nov., Kalmanozyma hebeiensis sp. nov., Langdonia ligulariae sp. nov., Meira hainanensis sp. nov., Meira pileae sp. nov., Meira plantarum sp. nov., Phragmotaenium parafulvescens sp. nov., Sporisorium cylindricum sp. nov., Sympodiomycopsis europaea sp. nov., Tilletiopsis lunata sp. nov., Tilletiopsis pinicola sp. nov., Yunzhangomyces clavatus sp. nov., Yunzhangomyces cylindricus sp. nov., Yunzhangomyces qinlingensis sp. nov., Yunzhangomyces orchidis sp. nov., Guomyces nicotianae comb. nov., and Yunzhangomces scirpi comb. nov.Two hundred and forty-four ustilaginomycetous yeast or yeast-like strains were isolated from the soil, skin of animals or humans and plant materials during the past 20 years. Among them, 203 strains represent 39 known species, whereas 41 strains represent several novel species based on the sequence analyses of the rDNA genes and three protein genes ( Ustilaginomycotina comprises a variety of lifestyles. The majority of species are biotrophic pathogens known as smuts, whereas some anamorphic yeast lineages are saprotrophs or, possibly, mycoparasites and the ITS sequences in the State Key Laboratory of Mycology, China. Most of them belonging to The yeast or yeast-like strains studied are listed in RPB1 and RPB2) and the translation elongation factor 1-\u03b1 (TEF1), were performed as described in Deoxyribonucleic acid (DNA) was extracted following the method proposed by Sequence alignments were performed with the MAFFT algorithm using thEntyloma, Exobasidium, Gjaerumia, Golubevia, Langdonia, Meira, Moesziomyces, Mycosarcoma, Phragmotaenium, Pseudozyma pro. tem, Quambalaria, Robbauera, Sporisorium, Tilletiopsis, and Ustilago, and 20 undescribed species , the skin of animals or humans , and plant materials , including leaves, tree bark, and rotten wood, were identified as 39 known species distributed in 15 genera, i.e., species based onTilletiopsis washingtonensis were obtained from eight provinces in China, which occupy 32.8% isolate frequency . The other frequently isolated species are Mycosarcoma maydis (Ustilago maydis) (9.4%), Pseudozyma hubeiensis pro. tem (6.6%), Moesziomyces aphidis (6.1%), Golubevia pallescens (5.7%), Phragmotaenium oryzicola (5.3%), Moesziomyces antarcticus (4.1%), Gjaerumia minor (3.7%), and Meira geulakonigii (2.9%) , and shepherds (My. maydis infection have been reported (Mo. aphidis was isolated both from plants (leaves), animals (cows), and in the soil. Ex. reticulatum, Go. pallescens, Ph. oryzicola, Ps. fusiformata, Ps. tsukubaensis, and T. lilacina were also isolated from the soil and from plant materials . T. washhepherds . The casreported . The resreported . Mo. aphaterials .Ustilaginomycotina, most of which represent rare taxa. A few not included potentially conspecific strains were not available for the study, inactive, or lost. These descriptions were made on a limited number of isolates because more strains could not be obtained despite of extensive sampling and analysis of more than 200 isolates.The below analyses illustrate the undescribed diversity of yeasts in Ustilaginomycotina. While nucleotide sequences of D1/D2 domains are often too conservative to distinguish closely related species, this region is useful for phylogenetic analyses. In contrast, the variability of ITS is often sufficient to identify new species from pair-wise similarity comparisons (see below).The two most frequently used for identification of yeast genetic markers, ribosomal ITS, and D1/D2 domains of LSU proved their utility for identification and delimitation of species in Ustilaginomycotina includes mainly parasitic fungi and few of saprobic yeast or yeast-like members (Ustilaginomycotina have been reported (Pseudozyma prolifica (teleomorph My. maydis), Pseudozyma tsukubaensis , Mo. aphidis, Mo. antarcticus, and Mo. rugulosus .Forty-one strains were groic trees \u20133 and caNote that the ex-type strains (or reference strains) of known species were used for sequence similarity analyses for novel species comparisons, and that the GenBank and strain numbers can be found in Ustilaginaceae in the southeastern United States in 2018 . This is the first case in the genus Langdonia for the connection between the sexual and asexual states. CGMCC 2.6313 has affinity with L. aristidae and L. confusa, and differs from them by more than 9 nt and 72\u201375 nt (10%) in the D1/D2 and ITS regions, respectively.The genus walkerae , among wequences and diff species , 3. The in 2018 . CGMCC 2Kalmanozyma clade in the ITS region.Strain CGMCC 2.3457 locates in the anamorphic genus ma clade , 2. It dBrachybasidiaceae contains Brachybasidium, Dicellomyces, Exobasidiellum, Kordyana, Meira, and Proliferobasidium in the ITS region, indicating that they are different species. Strain CGMCC 2.3537 was located in a basal branch in the Meira clade, and differs from Meira sp. 07F1061 (JX575187) and Meira sp. 08F0291 (JX575186) by 6\u20137 nt and from other know Meira species by more than 51 nt (8%) in the D1/D2 domain.The family basidium . Eleven idiaceae , 3. The iamensis . Strainsra clade , 3. The ashicola , 3. The Meira nicotianae was described by Meira clade in the LSU and ITS+LSU trees. However, Meira was polyphyletic and that Me. nicotianae was separated from the Meira clade and was more closely related to Dicellomyces scirpi in the ITS + LSU tree. Our analyses as C. bombacis .Strains CGMCC 2.3451, CGMCC 2.4433, CGMCC 2.4533, CGMCC 2.6304, and XZ128D1 represent four undescribed species , 3 whicheosporus , 3. TherGeorgefischeriales in the D1/D2 domain. More than 6% diversity between those taxa was found in the ITS region.Strains CGMCC 2.3573, CGMCC 2.5616, CGMCC 2.6419, CGMCC 2.5679, CGMCC 2.2370, CGMCC 2.5602, and XZ156C4 are placed in heriales , 2. The ng taxon . Strain Gjaerumia comprises three parasitic smut fungi infecting the Asparagaceae, Melanthiaceae, and Xanthorrhoeaceae plant and two yeast species , was recently described and known as an asexual culturable yeast based on phylogenetic analysis belong to the Gjaerumia clade and differ from the closely related species G. minor by 15 (2.5%) and 74 nt (11%) in the D1/D2 and ITS regions, respectively. These two novel strains differ from each other by 8 nt in the D1/D2 domain and 72 nt in the ITS region, which indicates that they belong to different species.The genus species . Gjaerumanalysis . StrainsJamesdicksonia, i.e., J. dactylidis, J. ischaemiana, J. irregularis, and J. mali, have available D1/D2 sequence (Acer pectinatum (Sapindaceae), cluster with the Jamesdicksonia species and are closely related to the asexual species J. mali isolated from apple recently described by J. mali CBS 111628 and CBS 111625 by 0\u20131 nt in the D1/D2 domain. However, there are 27\u201333 nt (6\u20137%) differences in the ITS region. They also have more divergence in the assimilation of carbon and nitrogen in the ITS region.Five species of sequence . They diNote: Strain CGMCC 2.6419 differs from the two Japanese strains, NIP003 (AB726595) and NIP007 (AB726598), by 2\u20133 nt in the D1/D2 domain, which indicate that they may be conspecific.Tilletiopsis cremea, T. lilacina, and T. washingtonensis, were included in the revised genus Tilletiopsis (Tilletiopsis clade (T. washingtonensis and differ from it by 3 and 10\u201312 nt (\u223c2%) in the D1/D2 domain and ITS region, respectively. Strain CGMCC 2.5613 has identical D1/D2 sequences with Tilletiopsis lilacina. However, they differ from each other by 11 nt (\u223c2%) in the ITS region. Physiological profiles of HE6AB1, HE2A5, and CGMCC 2.5613 differed from their closely related species T. washingtonensis and T. lilacina from lichen biocrust soil in Utah, USA and Tilletiopsis sp. isolate YP-240 (KU702544/KU702557) from Duke pine Forest soil in North Carolina, United States have identical D1/D2 sequences, but they differ from each other by 9\u201310 nt in the ITS region. A multigene approach is needed to determine whether or not they may represent different species.Microstromales comprises Jaminaea, Parajaminaea, Pseudomicrostroma, Microstroma, Quambalaria, Sympodiomycopsis, and Volvocisporium. Parajaminaea, Pseudomicrostroma, and Microstroma are teleomorphic genera and contain both sexual and asexual species. The other genera in Microstromales belong to strictly anamorphic fungi. Our 14 isolates in the D1/D2 domain and by 60 nt (9%) in the ITS region.Three species, namely, mycopsis . StrainsParajaminaea and Jaminaea in the Microstromatales and 90 nt (13%), respectively. The above data indicate that strains CGMCC 2.4532, CGMCC 2.4534, CGMCC 2.4535, and CGMCC 2.4536 represent a new genus in the Microstromatales because they cannot be placed in the existing genera in Microstromatales.Strains CGMCC 2.4532, CGMCC 2.4534, CGMCC 2.4535, and CGMCC 2.4536 form a separate branch with 100% BP support and are closely related to the genera omatales , 6. ThesNote: The CGMCC 2.4532 group has identical ITS sequences with two strains 5CL1 (KJ460375) and 4FL2 (KJ460376) from Brazil, and identical D1/D2 sequences with strain BMA 85 (MH908976) from Brazil, which indicates they are conspecific.Microstromales, such as Ps. phylloplanum and Quambalaria cyanescens, with 94% similarity. However, the best match is with Golubevia pallescens and \u2018Entyloma dahliae\u2019 with 57\u201379% coverage and 79\u201383% similarity using ITS sequences as the query. To confirm the phylogenetic position of these two strains, a multiple gene phylogenetic tree was constructed and 71% (449/632), respectively, which are too distant to place XZ4C4 in the genus Golubevia and order Golubeviales. The above analyses indicated that strain XZ4C4 could represent a new order, distinct from Golubeviales. Therefore, Franziozyma bambusoicola gen. et sp. nov., Franziozymaceae fam. nov., and Franziozymales ord. nov. are proposed for strains XZ4C4 and XZ4A1.Two strains, XZ4C4 and XZ4A1, have the same sequences in both the ITS and D1/D2 regions. A BLASTn search using the D1/D2 sequence of XZ4C4 showed that the top matched sequences were that of species in structed . Strain Etymology: the specific epithet cylindricum refers to the cell morphology of the type strain.After 7 days at 17\u00b0C in YM broth, cells are cylindrical, 1.5\u20133.5 \u00d7 6.5\u201314.0 \u03bcm and single, a sediment is produced, budding is polar . After 1D-ribose, D-xylose, L-rhamnose, \u03b1-Methyl-D-glucoside, salicin, succinic acid, and inositol are assimilated. L-sorbose, lactose, inulin, D-arabinose, L-arabinose, D-glucosamine, N-Acetyl-D-glucosmine, ethanol, glycerol, D-mannitol, D-glucitol, methanol, erythritol, ribitol, galactitol, D-glueonale, DL-lactic acid, citric acid, and hexadecane are not assimilated. Ammonium sulfate and L-lysine are assimilated. Potassium nitrate, sodium nitrite, ethylamine, and cadaverine are not assimilated. Maximum growth temperature is 30\u00b0C. Growth does occur in a vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar. Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose, sucrose, maltose, cellobiose, trehalose, melibiose, raffinose, melezitose, soluble starch, Typus: China, Tibet, obtained from a leaf of an unidentified plant, Oct. 2007, Qi-Ming Wang, holotype CGMCC 2. 3756T preserved in a metabolically inactive state in the China General Microbiological Culture Collection Center (CGMCC), Beijing, China. Ex-type CBS 15755 is deposited at the CBS collection of the Westerdijk Fungal Biodiversity Institute, Utrecht, Netherlands. Kunming county, Yunnan province, obtained from a leaf of an unidentified plant, May. 2007, Qi-Ming Wang, paratype CGMCC 2.3576.Note: S. arthraxonis, S. ophiuri, S. fastigiatum, S. reilianum, S. lacrymae-jobi, and S. pseudechinolaenae are all parasitized on Poaceae. The two yeasts, CGMCC 2.3576 and CGMCC 2.3756, also isolated from leaves of the plant. Unfortunately, those plants were not identified. Except the worldwide distributed S. reilianum, the above five parasitic species mostly occur in the tropic region including southern China and Southeast Asia and Hanan province (southern China), respectively, which indicated that they have similar ecological and biogeographical characters to those parasitic species.ast Asia . The twoEtymology: the specific epithet hebeiensis refers to the geography from which the type strain was isolated.After 7 days at 17\u00b0C in YM broth, cells are cylindrical, 1.7\u20133.0 \u00d7 5.8\u201310.0 \u03bcm, and single or in pairs, a sediment is produced, budding is polar . After 1D-xylose, L-arabinose, D-arabinose (weak), D-ribose (weak), D-glucosamine, ethanol, glycerol, ribitol, D-mannitol, D-glucitol, \u03b1-Methyl-D-glucoside, salicin (weak), succinic acid and citric acid are assimilated. L-sorbose, melibiose, inulin, soluble starch, L-rhamnose, methanol, erythritol, galactitol, DL-lactic acid, inositol, and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate, sodium nitrite, L-lysine (weak), and ethylamine (latent and weak) are assimilated. Cadaverine is not assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does occur in a vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar. Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose, sucrose, maltose, cellobiose, trehalose, lactose (latent and weak), raffinose (weak), melezitose, K. hebeiensis differs from its closely related species, K. brasiliensis and K. vetiver, in its inability to assimilate L-sorbose and inositol , and succinic acid (weak) are assimilated. Galactose, L-sorbose, maltose, melibiose, D-arabinose, D-ribose, L-rhamnose, D-glucosamine, N-Acetyl-D-glucosmine, methanol, ethanol, glycerol, erythritol, ribitol, galactitol, D-glucitol, \u03b1-Methyl-D-glucoside, salicin, DL-lactic acid, citric acid, myo-inositol, and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate, sodium nitrite, L-lysine, ethylamine, and cadaverine are assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does not occur in vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, sucrose, cellobiose (weak), trehalose (weak), lactose (weak), raffinose (weak), melezitose (weak), inulin (weak), soluble starch (weak), L. walkerae differs from its closely related species, L. jejuensis, and L. ligulariae, in its inability to assimilate maltose and its ability to assimilate succinic acid are assimilated. Galactose, L-sorbose, lactose, melibiose, D-arabinose, D-ribose, L-rhamnose, D-glucosamine, N-Acetyl-D-glucosmine, methanol, erythritol, galactitol, D-glucitol, salicin, DL-lactic acid, succinic acid, citric acid, and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate, sodium nitrite (weak), L-lysine, ethylamine, and cadaverine are assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does occur in the vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, sucrose, maltose, cellobiose, trehalose, raffinose, melezitose, inulin (weak), soluble starch (weak), L. ligulariae differs from its closely related species, L. walkerae and L. jejuensis, in its inability to assimilate lactose and its ability to use ethanol, glycerol, ribitol, and \u03b1-Methyl-D-glucoside . The asexual yeast species L. jejuensis was isolated from a leaf of Citrus unshiu (Rutaceae) in South Korea. CGMCC 2.6313 was isolated from a leaf of Ligularia tsangchanensis (Asteraceae) in Tibet, China. Although CGMCC 2.6313 and L. jejuensis were all isolated from the leaf of plant (Asteraceae and Rutaceae), they differ from the parasitic species of Langdonia whose host is the Poaceae grass, which indicated that the asexual yeast stage and the sexual stage of Langdonia may have different ecological inches in nature.Etymology: the specific epithet plantarum refers to the substrates from which the type strain was isolated.After 7 days at 17\u00b0C in YM broth, cells are fusiform and cylindrical to elongate, 1.7\u20132.1 \u00d7 4.2\u201328.3 \u03bcm and single, a sediment is produced, and budding is polar . After 1D-xylose, L-arabinose, D-ribose, erythritol, galactitol (variable), D-mannitol, D-glucitol, salicin (latent and weak), and succinic acid (latent and weak) are assimilated. L-sorbose, lactose, inulin, soluble starch, D-arabinose, L-rhamnose, D-glucosamine, methanol, ethanol, glycerol, ribitol, \u03b1-Methyl-D-glucoside, DL-lactic acid, citric acid, inositol, and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate, sodium nitrite, ethylamine, and cadaverine (latent) are assimilated. L-lysine (or latent and weak) is not assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does occur in the vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose, sucrose, maltose, cellobiose, trehalose, melibiose, raffinose, melezitose, M. plantarum differs from its closely related species, M. nashicola and M. pileae, in its inability to assimilate D-arabinose , ethanol (weak), glycerol (weak), ribose (weak), erythritol (weak), D-mannitol (weak), D-glucitol (weak), salicin, and succinic acid (latent and weak) are assimilated. L-sorbose, lactose, galactitol, soluble starch, L-rhamnose, D-glucosamine, methanol, \u03b1-Methyl-D-glucoside, D-glueonale, DL-lactic acid, citric acid, inositol, and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate, sodium nitrite, L-lysine, ethylamine, and cadaverine are assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does occur in the vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose, sucrose, maltose, cellobiose, trehalose, melibiose, inulin, raffinose, melezitose, Me. pileae differs from its closely related species, Me. nashicola and Me. Plantarum, in its ability to assimilate inulin , erythritol, ribitol (latent and weak), galactitol, D-mannitol, D-glucitol, and succinic acid (weak) are assimilated. L-sorbose, lactose, L-rhamnose, D-glucosamine, methanol, \u03b1-Methyl-D-glucoside, salicin, DL-lactic acid, citric acid, inositol, and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate (weak), sodium nitrite, and cadaverine are assimilated. L-lysine and ethylamine are not assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does occur in the vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose, sucrose, maltose, cellobiose, trehalose, melibiose, raffinose, melezitose, inulin, soluble starch, Me. hainanensis differs from its closely related species Me. argovae in its inability to assimilate salicin and citric acid from citrus leaves (Ricinus communis and Citrus paradisi) in Israel . The genus is mainly circumscribed by the description of Dicellomyces scirpi and the phylogenetic analysis of the six-genes sequences (This genus is proposed for the branch represented by equences .Scirpus sylvaticus (Cyperaceae); basidia developing in gelatinous basidiocarps breaking through epidermis, swollen, not persistent probasidia, with paraphyses, sterigmata 2; producing allantoid or coiled conidia Q.M. Wang, E. Tanaka, M. Groenew. and D. Begerow.Basionym: Dicellomyces scirpi Raitv., in Parmasto, Eesti NSV Tead. Akad. Toim. 17(2): 223 (1968).Etymology: the specific epithet orchidis refers to plant host, Orchidaceae sp., from which the type strain was isolated.After 7 days at 17\u00b0C in YM broth, cells are cylindrical to elongate, .08\u20131.7 \u00d7 2.8\u201316.7 \u03bcm and single, a sediment is produced, budding is polar, and hyphae are narrow , raffinose, melezitose, inulin, D-xylose, L-arabinose, D-arabinose, D-ribose, ethanol, glycerol, erythritol, ribitol, D-mannitol, D-glucitol, salicin, succinic acid (latent and weak), and citric acid (latent and weak) are assimilated. Lactose, soluble starch, L-rhamnose, D-glucosamine, methanol, galactitol, \u03b1-Methyl-D-glucoside, DL-lactic acid, inositol, and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate, sodium nitrite, L-lysine, ethylamine, and cadaverine are assimilated Optimal growth is at 17\u201325\u00b0C. Growth does occur in the vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose, Y. orchidis differs from its closely related culturable species Y. clavatus in its ability to assimilate inulin, D-arabinose, and glycerol , sucrose, maltose, cellobiose (variable), trehalose, melibiose, raffinose, melezitose, D-xylose, L-arabinose, D-ribose (variable), ethanol (or latent and weak), erythritol (variable), ribitol (variable), D-mannitol, and D-glucitol are assimilated. Lactose, inulin, soluble starch, D-arabinose, L-rhamnose, D-glucosamine, methanol, glycerol, galactitol, \u03b1-Methyl-D-glucoside, salicin (or latent and weak), succinic acid (or weak), DL-lactic acid, citric acid, inositol, and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate, sodium nitrite, L-lysine (variable), ethylamine, and cadaverine are assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does occur in the vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose (variable), Y. clavatus differs from its closely related species, Y. orchis, in its inability to assimilate inulin, D-arabinose, and glycerol , D-ribose, ethanol, erythritol, ribitol (latent and weak), D-mannitol, D-glucitol, \u03b1-Methyl-D-glucoside (latent and weak), salicin (latent), succinic acid and citric acid are assimilated. Cellobiose, lactose, melibiose, inulin, soluble starch, L-rhamnose, D-glucosamine, N-Acetyl-D-glucosmine, methanol, glycerol, galactitol, DL-lactic acid, inositol, and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate, L-lysine (latent and weak), ethylamine (latent and weak), and cadaverine (latent and weak) are assimilated. Sodium nitrite is not assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does occur in the vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose, Y. qinlingensis differs from its closely related species Y. cylindricus in its inability to assimilate cellobiose and inulin and its ability to use melezitose, succinic acid, and citric acid , Beijing, China. Ex-type CBS 144910 is deposited at the CBS collection of the Westerdijk Fungal Biodiversity Institute, Utrecht, Netherlands.Etymology: the specific epithet cylindricus refers to the vegetative cell morphology of the type strain.After 7 days at 17\u00b0C in YM broth, cells are cylindrical, club-shaped, 1.2\u20131.8 \u00d7 6.0\u201320.8 \u03bcm and single, a sediment is produced, budding is polar, and hyphae are narrow glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose, Y. cylindricus differs from its closely related species Y. qinlingensis in its inability to assimilate melezitose, succinic acid, and citric acid and its ability to use cellobiose and inulin . The genus is mainly circumscribed by the phylogenetic analysis of the ITS+LSU sequences Q.M. Wang, E. Tanaka, M. Groenew., and D. Begerow.Basionym: Meira nicotianae H.K. Wang and F.C. Lin, in Cao et al. Phytotaxa 365 (2): 176 (2018).Etymology: the specific epithet, parafulvescens, refers to a similar colony morphology to that of Phragmotaenium fulvescens.After 7 days at 17\u00b0C in YM broth, cells are cylindrical, 1.0\u20131.7 \u00d7 10.8\u201325.0 \u03bcm and single, a sediment is produced, budding is polar, and hyphae are narrow , sucrose, maltose, trehalose, Lactose (latent and weak), melibiose (latent and weak), raffinose, melezitose, inulin, soluble starch, D-xylose, L-arabinose, D-arabinose, glycerol, ribitol (latent and weak), D-mannitol, D-glucitol, D-gluenoale, and succinic acid are assimilated. Cellobiose, D-ribose, L-rhamnose, D-glucosamine, N-Acetyl-D-glucosmine, methanol, ethanol, erythritol, galactitol, \u03b1-Methyl-D-glucoside, salicin, DL-lactic acid, citric acid, inositol, and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate, and L-lysine (latent and weak) are assimilated. Sodium nitrite, ethylamine, and cadaverine are not assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does occur in the vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose (latent and weak), P. parafulvescens differs from its closely related species, P. fulvescens, in its inability to assimilate cellobiose, D-ribose, erythritol, citric acid, and sodium nitrite and its positive growth in vitamin-free medium . No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, sucrose, maltose, cellobiose, trehalose, melezitose, solube starch, G. pseudominor differs from its closely related species G. minor and G. cyclobalanopsidis in its inability to assimilate galactose, lactose, melibiose, raffinose, inulin, D-arabinose, and D-ribose , sucrose, maltose, cellobiose, trehalose, lactose, melibiose, raffinose, melezitose, inulin, D-xylose, L-arabinose, D-arabinose, glycerol, ribitol (weak), D-mannitol (weak), and D-glucitol (weak) are assimilated. Solube starch, D-ribose, L-rhamnose, D-glucosamine, N-Acetyl-D-glucosmine, methanol, ethanol, erythritol, galactitol, \u03b1-Methyl-D-glucoside, salicin, DL-lactic acid, succinic acid, citric acid, inositol, and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate (weak), sodium nitrite, L-lysine (weak), and cadaverine (latent and weak) are assimilated. Ethylamine is not assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does not occur in vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose, G. cyclobalanopsidis differs from its closely related species G. pseudominor and G. minor in its inability to assimilate soluble starch, DL-lactic acid, and succinic acid , L-arabinose, D-arabinose, D-ribose, L-rhamnose, glycerol, erythritol, ribitol, D-mannitol, D-glucitol, and succinic acid (variable) are assimilated. L-sorbose, melibiose, D-glucosamine, methanol, ethanol, galactitol, \u03b1-Methyl-D-glucoside, salicin, DL-lactic acid, citric acid, inositol, and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate, L-lysine, ethylamine, and cadaverine are assimilated. Sodium nitrite is not assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does occur in the vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose (variable), sucrose, maltose, cellobiose, trehalose, lactose (variable), raffinose (or weak), melezitose (or weak), inulin (variable), soluble starch (variable), J. aceris differs from its closely related species J. mali in its inability to assimilate melibiose, D-glucosamine, and sodium nitrite and its ability to use D-arabinose, ribitol, and cadaverine , succinic acid (weak), and citric acid (weak) are assimilated. L-sorbose, cellobiose, lactose, inulin, soluble starch, L-rhamnose, D-glucosamine, N-Acetyl-D-glucosmine, methanol, ribitol, galactitol, D-mannitol, \u03b1-Methyl-D-glucoside, salicin, DL-lactic acid, inositol, and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate, L-lysine, ethylamine, and cadaverine are assimilated. Sodium nitrite is not assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does occur in the vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose, sucrose, maltose, trehalose, melibiose (weak), raffinose, melezitose, T. pinicola differs from its closely related species, T. lilacina, in its inability to assimilate cellobiose, soluble starch, ribitol, D-mannitol, \u03b1-Methyl-D-glucoside, DL-lactic acid, and sodium nitrite and its ability to assimilate ethanol and grow in the vitamin-free medium , D-mannitol, D-glucitol, succinic acid, and citric acid are assimilated. L-sorbose, cellobiose, lactose, D-arabinose, L-rhamnose, D-glucosamine, N-Acetyl-D-glucosmine, methanol, galactitol, \u03b1-Methyl-D-glucoside, salicin, D-glueonale, DL-lactic acid, inositol, and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate, sodium nitrite (variable), L-lysine, and cadaverine are assimilated. Ethylamine is not assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does occur in the vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose, sucrose, maltose, trehalose, raffinose, melezitose, inulin, soluble starch, T. lunata differs from its closely related species, T. washingtonensis, in its inability to assimilate D-arabinose, D-glueonale, and DL-lactic acid and its ability to use inulin, and its positive growth in the vitamin-free medium , maltose (latent and weak), cellobiose (latent and weak), melezitose (latent and weak), D-xylose (latent), L-arabinose, D-glucosamine (latent), N-Acetyl-D-glucosmine, ethanol, glycerol, erythritol, D-mannitol (latent), D-glucitol (latent and weak), \u03b1-Methyl-D-glucoside (latent and weak), and salicin (latent and weak) are assimilated. Galactose, trehalose, melibiose, raffinose, lactose, inulin, soluble starch, D-arabinose, D-Ribose, L-rhamnose, methanol, ribitol, galactitol, D-glueonale, DL-lactic acid, succinic acid, citric acid, inositol, and hexadecane are not assimilated. Ammonium sulfate, L-lysine, ethylamine, and cadaverine are assimilated. Potassium nitrate and sodium nitrite are not assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does occur in the vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, Typus: China, Haikou county, Hainan province, obtained from a leaf of Lantana camara, Aug. 2007, Qi-Ming Wang, holotype CGMCC 2.3529T preserved in a metabolically inactive state in the CGMCC, Beijing, China. Ex-type CBS 15493 is deposited at the CBS collection of the Westerdijk Fungal Biodiversity Institute, Utrecht, Netherlands. Haikou county, Hainan province, obtained from a leaf of Lantana camara, Aug. 2007, Qi-Ming Wang, paratype CGMCC 2.3622.Note: J. angkorensis was isolated from fallen decaying leaves in Cambodia, J. lanaiensis from marine driftwood in Hawaiian, J. pallidilutea from plant material from mangrove in Iran, J. rosea from phylloplane of Plumeria in Florida , lactose, melibiose, raffinose, melezitose, soluble starch (weak), D-xylose, L-arabinose (or latent and weak), D-ribose, ethanol, glycerol, erythritol, D-mannitol, D-glucitol (or latent and weak), and \u03b1-Methyl-D-glucoside (or latent and weak) are assimilated. Cellobiose, inulin, D-arabinose, L-rhamnose, D-glucosamine, methanol, ribitol, galactitol, salicin, DL-lactic acid, succinic acid (or weak), citric acid (or latent and weak), inositol (or weak), and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate (variable), L-lysine (weak), and cadaverine are assimilated. Sodium nitrite and ethylamine are not assimilated. Optimal growth is at 17\u201325\u00b0C. Growth does occur in the vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose, S. europaea differs from its closely related species, S. kandeliae and S. paphiopedili, in its inability to assimilate cellobiose, D-arabinose, and grow in the 50% glucose medium . The genus is mainly circumscribed by the phylogenetic analysis of the six-gene sequences , L-arabinose, D-ribose (variable), L-rhamnose (variable), N-Acetyl-D-glucosmine (variable), glycerol, erythritol (latent and weak), D-mannitol, and D-glucitol are assimilated. L-sorbose, soluble starch, D-arabinose, D-glucosamine, methanol, ethanol (or weak), ribitol, galactitol, \u03b1-Methyl-D-glucoside (weak), salicin (or latent and weak), DL-lactic acid, succinic acid (or weak), citric acid, inositol (or latent and weak), and hexadecane are not assimilated. Ammonium sulfate, potassium nitrate (or weak), L-lysine (or weak), ethylamine (or weak), and cadaverine (or weak) are assimilated. Sodium nitrite (or latent and weak) is not assimilated. The maximum growth temperature is 30\u201332\u00b0C. Growth does occur in the vitamin-free medium. No starch-like substrate is produced. Growth does not occur on 50% (w/w) glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, galactose, sucrose, maltose (week), cellobiose, trehalose (latent and weak), lactose (weak), melibiose (variable), raffinose, melezitose (variable), inulin, Typus: China, Xingshan County, Hubei province, obtained from a leaf of the unidentified plant, March 2012, Qi-Ming Wang, holotype CGMCC 2.4532T preserved in a metabolically inactive state in the CGMCC, Beijing, China. Ex-type CBS 144909 is deposited at the CBS collection of the Westerdijk Fungal Biodiversity Institute, Utrecht, Netherlands. Maotai county, Guizhou province, obtained from a leaf of the unidentified plant, March 2012, Qi-Ming Wang, CGMCC 2.4534. Fanjingshan, Guizhou province, obtained from a leaf of the unidentified plant, March 2012, Qi-Ming Wang, paratypes CGMCC 2.4535 and CGMCC 2.4536.Exobasidiomycetes. The diagnosis of the order Franziozymales is based on the description of the genus Franziozyma. The nomenclature of the order is based on the genus Franziozyma.Member of Type family: Franziozymaceae Q.M. Wang, D. Begerow, M. Groenew.Franziozymales (Exobasidiomycetes). The diagnosis of the family Franziozymaceae is based on the description of the genus, Franziozyma. The nomenclature of the family is based on the genus.Member of Type genus: Franziozyma Q.M. Wang, D. Begerow and M. Groenew.Genus accepted: Franziozyma Q.M. Wang, D. Begerow and M. Groenew.Etymology: the genus is named in honor of Franz Oberwinkler for his pioneering work on the taxonomy of smuts.T, which formed a separate branch from Golubeviales and other orders in Exobasidiomycetes. The genus is mainly circumscribed by the phylogenetic analysis of the six loci dataset glucose-yeast extract agar Urease and Diazonium blue B reactions are positive.Glucose is not fermented. Glucose, sucrose, maltose, cellobiose, trehalose, raffinose, inulin, soluble starch, glycerol, erythritol, Typus: China, Bomi County, Tibet, obtained from a leaf of bamboo, Sep. 2004, Qi-Ming Wang, holotype CGMCC 2.2620T preserved in a metabolically inactive state in the CGMCC, Beijing, China. Ex-type CBS 15774 is deposited at the CBS collection of the Westerdijk Fungal Biodiversity Institute, Utrecht, Netherlands. Bomi county, Tibet, obtained from a leaf of bamboo, September 2004, Qi-Ming Wang, paratype XZ4A1.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Q-MW conceived and designed the project. Q-MW, Y-YL, Y-TG, and FW performed sampling and yeast isolation. Y-YL, A-HL, M-MW, and Q-MW performed phenotypic characterization and analyzed the molecular data. B-QZ registered the taxa in MycoBank submitted the sequence data in TreeBASE. Q-MW, M-MW, MG, and DB wrote the manuscript. ET and F-YB revised the manuscript. ET supported the sequences generated in his laboratory. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Correction to: Arch Public Health 78, 121 (2020)https://doi.org/10.1186/s13690-020-00505-zFollowing publication of the original article , the autThe original first affiliation was1. Public health and genome, Scientific Directorate of Epidemiology and public health, Sciensano, J. Wytsmanstraat 14, 1050 Brussels, BelgiumThe correct affiliation has been provided in this Correction.1. Scientific Directorate of Epidemiology and public health, Sciensano, J. Wytsmanstraat 14, 1050 Brussels, BelgiumThe original article has been"} +{"text": "Amongst the countless marine organisms, seaweeds are considered as one of the richest sources of biologically active ingredients having powerful biological activities. Seaweeds or marine macroalgae are macroscopic multicellular eukaryotic photosynthetic organisms and have the potential to produce a large number of valuable compounds, such as proteins, carbohydrates, fatty acids, amino acids, phenolic compounds, pigments, etc. Since it is a prominent source of bioactive constituents, it finds diversified industrial applications viz food and dairy, pharmaceuticals, medicinal, cosmeceutical, nutraceutical, etc. Moreover, seaweed-based cosmetic products are risen up in their demands by the consumers, as they see them as a promising alternative to synthetic cosmetics. Normally it contains purified biologically active compounds or extracts with several compounds. Several seaweed ingredients that are useful in cosmeceuticals are known to be effective alternatives with significant benefits. Many seaweeds\u2019 species demonstrated skin beneficial activities, such as antioxidant, anti-melanogenesis, antiaging, photoprotection, anti-wrinkle, moisturizer, antioxidant, anti-inflammatory, anticancer and antioxidant properties, as well as certain antimicrobial activities, such as antibacterial, antifungal and antiviral activities. This review presents applications of bioactive molecules derived from marine algae as a potential substitute for its current applications in the cosmetic industry. The biological activities of carbohydrates, proteins, phenolic compounds and pigments are discussed as safe sources of ingredients for the consumer and cosmetic industry. Himanthalia elongata), OSEA Ocean Cleansing Mudd (Fucus vesiculosus), Biossance Squalane + Probiotic Gel Moisturizer (Chrondrus crispus), Rep\u00eachage Vita Cura B3 Serum Complex (Laminaria digitata), and Ayla Sea Soak (Macrocystis pyrifera). Some other products, such as True Botanicals Clear Pure Radiance Oil, Skinceuticals Daily Moisture, Mario Badescu Seaweed Night Cream, and Dr. Dennis Gross Skincare Hyaluronic Marine Oil-Free Moisture Cushion, etc., also occupy the cosmetic market. In addition, Heo et al. [Cosmeceuticals are defined by cosmetic producers as products to improve or alter the skin functions and appearance, causing skin benefits . The tero et al. reportedThe chemically diversified nature and unique potential of seaweeds are the reason why they have been the focus of interest for the past few years in various cosmetic applications. Seaweed-based protein, polysaccharides, phenolic compounds, and pigment profiles present cosmetic and cosmeceutical potential. This review study gives an overall view of an exploitation of seaweed for cosmetic beneficial activities. Mainly, the role of polysaccharide, protein, phenolic compounds, and pigments in different skin cosmetic beneficial activities are discussed.Fucus vesiculosis extract to reduce the appearance of dark circles on the skin area by enhancing the expression of hemeoxygenase-1. By removing heme catabolites, it eliminates the heme production on skin. Hagino and Saito [Macrocystis pyrifera. They also reported good antidiabetic and antioxidant activity of phlorotannins, which can prevent skin aging.Marine macroalgae produce both primary metabolites, including proteins, amino acids, polysaccharides, fatty acids, etc., and secondary metabolites, such as phenolic compounds, pigments, sterols, vitamins, and other bioactive components ,52,53,54nd Saito reportednd Saito identifiPyropia yezoensis had skin beneficial functions, such as antioxidant, anti-inflammation, photoaging protection, etc. [Laminaria japonica; it is reported to inhibit tyrosinase activity and melanogenesis in UVB-irradiated mice.Additionally, Yu and Gu reportedon, etc. . In the on, etc. . Moreoveon, etc. isolatedKappaphycus alvarezii (formerly Eucheuma cottonii) (Rhodophyta), Sargassum polycystum (Phaeophyceae), Padina boryana (formerly Padina tenuis) (Phaeophyceae), Fucus vesiculosus (Phaeophyceae), Porphyra umbilicalis (Rhodophyta), etc. Moreover, polysaccharides have a wide variety of applications, such as photoprotection, moisturizer, wound-healing agents, thickening agents, emulsifiers, and preservatives [Fucus vesiculosus into creams and lotion, providing antiaging and anti-wrinkle benefits. They also reported collagenase expression, anti-inflammatory activity, and inhibition of matrix enzymes against hyaluronidase, heparinase, tyrosine kinase, and phospholipase A2. Holtkamp et al. [Gelidium amansii to induced apoptosis of cancer cells in vitro [Laminaria species and also Macrocystis pyrifera, Ascophyllum nododsum, Ecklonia maxima, Lessonia nigrescens, Ascophyllum nodosum, Durvillea antarctica, and Sargassum sp. [+2 and absence of non-gelling ions Na+.The polysaccharides are the most significant and beneficial compounds present in macroalgae and characterized for their biological skin beneficial activity. Seaweeds are well-known for many different types of a polysaccharides, such as chitin, fucoidans, agar, carrageenan, alginates, ulvans, terpenoids, and tocopherol ,75,76,77rvatives ,88,89,90rvatives ,94,95,96rvatives explainep et al. also repp et al. illustrap et al. revealedin vitro . Like fuin vitro . It has in vitro . Anotherssum sp. ,103. Podssum sp. also empssum sp. . Skjak-Bssum sp. suggesteGelidium sp., Gracilaria sp., Gelidiela sp., Pterocladiella sp., etc., are well-known producers of agar-agar [Ascophyllum sp., Durvillaea sp., Ecklonia sp., Laminaria sp., Macrocystis sp., Saccharina sp., Sargassum sp., and Turbinaria sp.) [Betaphycus gelatinum, Chondrus crispus, Eucheuma denticulatum, Gigartina sp., Kappaphycus alvarezii, Hypnea musciformis, Mastocarpus sp., and Mazzaella sp., from the Rhodophyta. It is used in cosmetology for various applications, such as lotion, sun-ray protectors, medicines, deodorant sticks, sprays, and foams [There are a wide variety of polysaccharides that are useful in skin cosmetics, such as agar, alginic acid, carrageenan, porphyrin, laminarin, fucoidan, and ulvan. Many genera of agrophytes algae, such as gar-agar ,134. Balgar-agar suggesteria sp.) ,137,138.ria sp.) and Fabrria sp.) reportednd foams ,143,144.Porphyra sp. and Bangia sp. [Laminaria sp., Saccharina sp., Ascophyllum sp., Fucus sp., Sargassum sp., and Undaria sp., are well-known for laminaran properties, such as antitumor, anti-inflammatory, antiviral, antioxidant, anticoagulant, and anti-cellulite properties [Moreover, porphyrin is a well-studied class of sulfated polysaccharides obtained from the aqueous extract of red algae ngia sp. ,146. It operties ,148,149.operties ,152,153.operties found thoperties suggesteoperties ,157. Peroperties , Carvalhoperties , and Gesoperties suggesteoperties ,162. Yaioperties describeoperties .Palmaria palmata, Chondrus crispus, Porphyra sp. (Rhodophyta), Undaria pinnatifida (Phaeophyceae), Ulva sp. (Chlorophyta), and Euchema sp. (Rhodophyta) are reported for the quantity of amino acids they contain [Biological macromolecule protein is a polymer of amino acids that is present in all living organisms. It is a basic building block of almost all cellular processes. It may present itself in the form of enzymes, hormones, vitamins, and pigments ,165. Mor contain ,167,168. contain ,170. Acc contain , protein contain ,174,175. contain reported contain . Further contain .Ulva australis to be a good source of essential amino acids, such as histidine and taurine. whereas Galland-Irmouli et al. [Palmaria palmata and Himanthalia elongata are a high source of serine, alanine, and glutamic acid. Reef et al. [Chondrus crispus, Palmaria palmata, Gelidium sp., Porphyra sp., Gracillaria cornea, Asparagopsis armata, Grateloupia lanceola, and Curdiea sp. Pereira, [Galland-Irmouli et al. and Samai et al. , Pereirai et al. , and Mari et al. have shof et al. and Peref et al. detectedPereira, showed rPorphyra rosengurtii\u2013derived mycosporine-like amino acids Porphyra-334 and Shinorine are isolated and found to be very photostable and photoprotective when exposed to radiation [The red alga adiation . These Madiation . This coCorallina pilulifera (Rhodophyta) can inhibit the expression of MMP-2 and MMP-9. Another phenolic compound, sargachromanol E, from Sargassum horneri (Phaeophyceae), expressed its effect on antiaging activity [Phycocalidia vietnamensis (formerly Porphyra vietnamensis) (Rhodophyta), showed UV-absorbing properties [Ecklonia cava-derived compounds, such as phlorotannins, exhibit skin whitening/antityrosinase effect, whereas zeaxanthin from the microalga Nannochloropsis oculata (Ochrophyta and Eustigmatophyceae) extracts showed skin-whitening activity [Sargassum fusiforme (Hijikia fusiformis). Phlorotannins, eckol, Fucols, Fucophorethols, Fuhalols, Phlorethols from Corallina pilulifera have beneficial cosmetic properties: antiaging, antiphotoaging, antioxidant, anti-allergic, anti-inflammatory, tyrosinase inhibition, and hyaluronidase inhibition [Ecklonia cava\u2013derived phlorotannins on melanin synthesis and protective effects on UV damage.Marine macroalgae are richer in various phenolic compounds, such as catechins, flavonols, flavonolglycosides, phloroglucinol, gallic acid, epicatechin, pyrocatechol, gallate, flavonoids, anthocyanins, stilbenes, lignans, and phenolic polymers ,207. Theactivity . Porphyroperties . Catechioperties ,213. Moractivity . The benactivity and Bravactivity identifiactivity ,218. Feractivity and Sanjactivity reportedactivity studied hibition ,224,225.hibition . Likewishibition and Wanghibition revealedArthrospira species (Cyanobacteria) and Chlorella valgaris (Chlorophyta) [Macroalgae is cultivated in a controlled condition to regulate the production of bioactive compounds such as phenolic compounds, pigments, carbohydrates, proteins, amino acids, vitamins, and minerals . These arophyta) ,262. Marrophyta) ,264. As rophyta) ,270,271.rophyta) ,275,276.rophyta) , Quilodrrophyta) , and Amorophyta) , algae srophyta) evaluaterophyta) and La-Mrophyta) suggesterophyta) ,284.Carotenoids are widely applicable as natural dyes and antioxidants with antitumor, anti-inflammatory, and radical sequestering benefits ,286,287.Cosmetic researchers have focused their attention on marine organisms as an additional source of novel and useful natural ingredients. Diversified marine-algae-derived secondary metabolites are structurally more complex, with unique functionalities and properties. This review surveyed the potential applications of marine-algae-derived compounds for various skin benefits in the cosmetic industry. Though many seaweeds are exploited for their cosmetic properties, the research work on them is still incomplete, and so many species, either in full or in part, have not been explored. Hence, the cost-effective and efficient alternative standardized method to extract the bioactive phyco-constituents with significant productivity and activity is in growing demand. In future perspectives, the responsible molecular mechanism and safety concerns of these compounds are very important for future challenges in cosmeceuticals. Therefore, further investigations to study the precise molecular basis for the beneficial activity of marine algal components should be undertaken. Recently, in silico tools and techniques have been used to select functional materials derived from natural resources quickly and to predict the mechanisms of actions. Thus, this approach will be a helpful strategy for finding and understanding more effective compounds with the novel property.The overexposure of human skin to different environmental stresses, such as pollutants and sun radiation, as well as chemical cosmeceutical ingredients\u2014it increases the production of reactive oxygen species (ROS)\u2014leads to many skin-damaging problems, such as aging, dullness, carcinogenesis, wrinkles, age spots, dark circles, etc. Marine-algae-based bioactive purified compounds demonstrated highly significant beneficiary applications in cosmetic formulas, as multiple functions, where they can be natural active constituents to the synthetic ingredients. Under different environmental factors, marine algae have the biosynthesis of primary and secondary metabolites for their survival. These biologically active constituents can be used as an active ingredient in the cosmetic industries due to their various skin benefits. It could be used as an antioxidant, antimicrobials, antibacterial, whitening agent, antiaging, anti-wrinkle, anti-acne, moisturizing, UV protection, deodorizing, anti-allergic, anti-inflammatory, sensory enhancer, viscosifying, stabilizer, and also for thickening in cosmetic industries. Sustainable use of marine algae and marine-algae-based molecules is crucial for humankind. Moreover, there are many cosmeceutical industries that already use extracts of marine algae and compounds in the formulation of many products. However, the monitoring of its biochemical profile presents a problem that needs to overcome. This can be solved by the development of seaweed cultivation and green extraction methods that are being analyzed with promising research results. However, many cosmetic companies\u2019 collaboration at the national and international level can improve the analytical methods of its screening for safety, thus enhancing consumer\u2019s safety towards marine-algae-based bioactive compounds in the cosmetic products. All mentioned marine algae in this review, possessing various bioactivities, are considered and utilized as a natural inexhaustible source for different cosmeceutical benefits."} +{"text": "Ji JL, Helmer M, Fonteneau C, Burt JB, Tamayo Z, Dem\u0161ar J, Adkinson BD, Savi\u0107 A, Preller KH, Moujaes F, Vollenweider FX, Martin WJ, Repov\u0161 G, Murray JD, Anticevic A. 2021. Mapping brain-behavior space relationships along the psychosis spectrum. A supplemental analysis in the final paper involved an independent replication dataset. This replication dataset describes a sub-sample of patients diagnosed with Obsessive Compulsive Disorder (OCD) and schizophrenia which was collected as part of a larger project in collaboration with Dr. Chris Pittenger. In addition, Dr. Youngsun T. Cho played a key role in coordinating the data collection and management of this project. We are therefore formally correcting the eLife paper to include both Dr. Pittenger and Dr. Cho as co-authors on this paper. Both have reviewed the manuscript and support the conclusions, and agree to be responsible for all parts of the paper in its published form.The details of Dr. Pittenger and Dr. Cho\u2019s contributions are explained below:Dr. Pittenger and Dr. Cho provided key support in the data acquisition and coordination of the project from which the independent replication dataset was obtained. This replication dataset involved a subsample of data with OCD and schizophrenia that were collected as part of a larger study in collaboration with Dr. Pittenger. Dr. Cho was also integral for the project management of this study. Both Dr. Pittenger and Dr. Cho have reviewed the manuscript and its conclusions.New authors list:Jie Lisa Ji, Markus Helmer, Clara Fonteneau, Joshua B Burt, Zailyn Tamayo, Jure Dem\u0161ar, Brendan D Adkinson, Aleksandar Savi\u0107, Katrin H Preller, Flora Moujaes, Franz X Vollenweider, William J Martin, Grega Repov\u0161, Youngsun T. Cho, Christopher Pittenger, John D Murray, Alan AnticevicOriginal authors list:Jie Lisa Ji, Markus Helmer, Clara Fonteneau, Joshua B Burt, Zailyn Tamayo, Jure Dem\u0161ar, Brendan D Adkinson, Aleksandar Savi\u0107, Katrin H Preller, Flora Moujaes, Franz X Vollenweider, William J Martin, Grega Repov\u0161, John D Murray, Alan AnticevicDetails for the omitted authors:Youngsun T. ChoDepartment of Psychiatry, Yale University School of Medicine, New Haven, United States; Child Study Center, Yale University School of Medicine, New Haven, United States.Contribution: Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Investigation, MethodologyCompeting Interests: YC declares no competing interests.Christopher PittengerDepartment of Psychiatry, Yale University School of Medicine, New Haven, United States; Child Study Center, Yale University School of Medicine, New Haven, United States.Contribution: Conceptualization, Resources, Data curation, Supervision, Funding acquisition, Investigation, Methodology CP has consulted in the past 3 years to Biohaven Pharmaceuticals, Lundbeck Parmaceuticals, Ceruvia Therapeutics, Transcend Therapetics, Freedom Biosciences, Teva Pharmaceuticals and Brainsway Therapeutics and receives research funding from Biohaven Pharmaceuticals, the Usona Institute, and Transcend Pharmaceuticals. [1] None of these sources of support are related to the present work. CP is an inventor on two pending patent applications, 16/304,925 and 63/074,275, neither of which is relevant to the current work.The article has been corrected accordingly."} +{"text": "Heaney\u201d as per the corrected author list below:Yoshiyuki Yazaki, Kenichi Aizawa, Muhammad Zubair Israr, Keita Negishi, Andrea Salzano, Yuka Saitoh, Natsuka Kimura, Ken Kono, Liam M. Heaney, Shabana Cassambai, Dennis Bernieh, Florence Lai, Yasushi Imai, Kazuomi Kario, Ryozo Nagai, Leong L. Ng, Toru Suzuki."} +{"text": "ICU universal decolonization with daily chlorhexidine (CHG) baths plus mupirocin nasal decolonization reduces all-cause bloodstream infections (BSI) and MRSA clinical cultures. We assessed nasal iodophor, an antiseptic less susceptible to resistance, in place of mupirocin. Mupirocin-CHG: daily CHG baths and 5 days of twice daily nasal mupirocin, to 2) Iodophor-CHG: same regimen, substituting twice daily 10% povidone-iodine for mupirocin. All adult ICUs in a hospital were assigned to the same strategy. We compared each hospital\u2019s outcomes during the 18-month intervention (Nov 2017-Apr 2019) to its own baseline (May 2015-Apr 2017), during which all hospitals used mupirocin-CHG. The primary outcome was ICU-attributable S. aureus clinical isolates. Secondary outcomes included ICU-attributable MRSA clinical isolates and all-cause BSI. As randomized and as treated analyses used unadjusted proportional hazards models assessing differences in outcomes between baseline and intervention periods across the two groups, accounting for clustering by hospital and patient. We conducted a cluster randomized non-inferiority trial in ICUs, comparing universal decolonization with: 1) S. aureus clinical cultures and for MRSA clinical cultures . The regimens had similar BSI hazards. Analyses of fully adherent patients are in progress.We randomized 137 hospitals with 233 ICUs in 18 states. There were 442,544 admissions in the baseline period and 349,262 in the intervention period. Median ICU length of stay was 4 days. ICU types included mixed medical surgical (56%), medical (9%), surgical (11%), cardiac (15%), and neurologic (9%). CHG adherence was similar in both arms (85%), but adherence was greater for mupirocin (90%) than iodophor (82%). Primary as-randomized results exceeded the non-inferiority margin in favor of mupirocin, for Figure - Primary and Secondary Outcomes of Mupirocin Iodophor Swap Out TrialS. aureus and MRSA clinical isolates, potentially due to greater adherence to mupirocin. Universal iodophor-CHG was equivalent to mupirocin-CHG for ICU BSI prevention. Mupirocin-CHG was superior to iodophor-CHG for Susan S. Huang, MD, MPH, Medline Molnlycke Stryker (Sage) Xttrium Edward Septimus, MD, Medline Molnlycke Ken Kleinman, PhD, Medline Molnlycke Lauren Heim, MPH, Medline Molnlycke Stryker (Sage) Xttrium Julia Moody, MS, Medline Molnlycke Taliser R. Avery, MS, Medline Molnlycke Syma Rashid, MD, Medline Stryker (Sage) Xttrium Katherine Haffenreffer, BS, Medline Molnlycke Lauren Shimelman, BA, Medline Molnlycke Caren Spencer-Smith, MS, Medline Molnlycke Selsebil Sljivo, MPH, Medline Ed Rosen, BS, Medline Russell Poland, PhD, Medline Micaela H. Coady, MS, Medline Molnlycke Eunice J. Blanchard, MSN RN, Medline Kimberly Reddish, DNP, Medline Brandon Carver, BA, Medline Kimberly N. Smith, MBA, Medline Jason Hickok, MBA, Medline Molnlycke Karen Lolans, BS, Medline (Research Grant or Support) Nadia Khan, BS, Medline (Research Grant or Support) John A. Jernigan, MD, MS, Nothing to disclose Kenneth Sands, MD, MPH, Medline Jonathan B. Perlin, MD, PhD, Medline Molnlycke Richard Platt, MD, MSc, Medline Molnlycke"} +{"text": "Scientific Reports 10.1038/s41598-022-06498-9, published online 16 February 2022Correction to: The original version of this Article contained errors in the spelling of the authors Jiri Jungwirth, Marketa Urbanova, Arnoud Boot, Petr Hosek, Petra Bendova, Anna Siskova, Jiri Svec, Milan Kment, Daniela Tumova, Sandra Summerova, Zdenek Benes, Tomas Buchler, Pavel Kohout, Tomas Hucl, Radoslav Matej, Ludmila Vodickova, Tom van Wezel, Pavel Vodicka & Veronika Vymetalkova which were incorrectly given as Jungwirth Jiri, Urbanova Marketa, Boot Arnoud, Hosek Petr, Bendova Petra, Siskova Anna, Svec Jiri, Kment Milan, Tumova Daniela, Summerova Sandra, Benes Zdenek, Buchler Tomas, Kohout Pavel, Hucl Tomas, Matej Radoslav, Vodickova Ludmila, van Wezel Tom, Vodicka Pavel & Vymetalkova Veronika respectively.The original Article has been corrected."} +{"text": "Leukemia; 10.1038/s41375-021-01295-1Correction to: The article Genomic analysis of cellular hierarchy in acute myeloid leukemia using ultrasensitive LC-FACSeq, written by Caner Saygin, Eileen Hu, Pu Zhang, Steven Sher, Arletta Lozanski, Tzyy-Jye Doong, Deedra Nicolet, Shelley Orwick, Jadwiga Labanowska, Jordan N. Skinner, Casey Cempre, Tierney Kauffman, Virginia M. Goettl, Nyla A. Heerema, Lynne Abruzzo, Cecelia Miller, Rosa Lapalombella, Gregory Behbehani, Alice S. Mims, Karilyn Larkin, Nicole Grieselhuber, Alison Walker, Bhavana Bhatnagar, Clara D. Bloomfield, John C. Byrd, Gerard Lozanski & James S. Blachly, was originally published electronically on the publisher\u2019s internet portal on 21 May 2021 without open access. With the author(s)\u2019 decision to opt for Open Choice the copyright of the article changed on 16 August 2021 to \u00a9 The Author(s) 2021 and the article is forthwith distributed under a Creative Commons Attribution."} +{"text": "The authors noticed that content of \u201cConflicts of Interest\u201d in the original version was missIt should be changed from \u201cConflicts of Interest: The authors declare no conflict of interest.\u201d to \u201cConflicts of Interest: Nadia Hindi reports grants, personal fees and non-financial support from PharmaMar, personal fees from Eli Lilly, grants from Eisai, and Novartis, outside the submitted work and research funding for clinical studies from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GlaxoSmithKline, Novartis, Blueprint, Nektar, Forma, Amgen, Bristol Myers Squibb, Pfizer and Daichii-Sankyo. Irene Carrasco Garc\u00eda, Alberto S\u00e1nchez-Camacho, Johanna Benedetti, Pilar Sancho, and Paloma Santos declare research funding for clinical studies from PharmaMar, Eli Lilly and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GlaxoSmithKline, Novartis, Blueprint, Nektar, Forma, Amgen, and Daichii\u2013Sankyo. Paloma Sanchez-Bustos and David S. Moura report institutional research grants from PharmaMar, Eisai, Immix BioPharma, and Novartis outside the submitted work; travel support from PharmaMar, Eisai, Celgene, Bayer, and Pfizer. Javier Martin-Broto reports research grants from PharmaMar, Eisai, Immix BioPharma, and Novartis outside the submitted work; honoraria for advisory board participation and expert testimony from PharmaMar, Eli Lilly, and Company, Bayer, and Eisai; and research funding for clinical studies from PharmaMar, Eli Lilly, and Company, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, GlaxoSmithKline, Novartis, Blueprint, Nektar, Forma, Amgen, Bristol Myers Squibb, Pfizer, and Daichii-Sankyo. All the other authors report no conflicts of interest.\u201dWe apologize for this error and state that the scientific conclusions are unaffected. The original article has been updated."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-88018-9, published online 30 April 2021Correction to: The original version of this Article contained errors in the Affiliations.Affiliation 8 was a duplicate of affiliation 5. The correct affiliation 8 is listed below.Laboratory for Advanced Genomics Circuit, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.Consequently, affiliation 8 was removed from authors Yosuke Ito and Hideya Kawaji.In addition, Masayoshi Itoh was incorrectly affiliated with \u2018Laboratory for Comprehensive Genomic Analysis, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.\u2019The correct affiliations are listed below:RIKEN Preventive Medicine and Diagnosis Innovation Program, 2-1 Hirosawa, Wako, Yokohama, Saitama 351-0198, Japan.Laboratory for Advanced Genomics Circuit, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.The original Article and accompanying Supplementary Information files have been corrected."} +{"text": "PLoS Computational Biology, vol 2, issue 3: 10.1371/journal.pcbi.0020021In Contributing author Blake Meyers' name and institution should appear:Blake C. Meyers, Department of Plant and Soil Sciences, Delaware Biotechnology Institute, Newark, Delaware, United States of America"} +{"text": "PLoS Medicine, volume 3, issue 9: doi:10.1371/journal.pmed.0030346In The competing interests statement was incomplete and should have read: \u201cJean-Louis Vincent is the current chairman of the International Sepsis Forum, and a member of the steering committee of the Surviving Sepsis Campaign. His personal views do not necessarily reflect those of the other members of these committees. The Surviving Sepsis Campaign has received funding from Eli Lilly, Baxter, and Edwards. The International Sepsis Forum is currently sponsored by bioM\u00e9rieux, Biosite, Brahms Diagnostics, EBI, Eli Lilly Corporation, Eisai Global Clinical Development, GlaxoSmithKline, Novo Nordisk, Roche Diagnostics, Spectral Diagnostics, Takeda, and Toray. The author declares that he has received grants and/or honorariums from AstraZeneca, Baxter, bioM\u00e9rieux, Biosite, Brahms Diagnostics, Edwards LifeSciences, Eli Lilly Corporation, Eisai Global Clinical Development, GlaxoSmithKline, Novo Nordisk, Spectral Diagnostics, Takeda, Toray, and Wyeth.\u201d"} +{"text": "The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study is examining the effects of long-term fibrate therapy on coronary heart disease (CHD) event rates in patients with diabetes mellitus. This article describes the trial's run-in phase and patients' baseline characteristics.FIELD is a double-blind, placebo-controlled trial in 63 centres in 3 countries evaluating the effects of fenofibrate versus placebo on CHD morbidity and mortality in 9795 patients with type 2 diabetes mellitus. Patients were to have no indication for lipid-lowering therapy on randomization, but could start these or other drugs at any time after randomization. Follow-up in the study was to be for a median duration of not less than 5 years and until 500 major coronary events had occurred.About 2100 patients (22%) had some manifestation of cardiovascular disease (CVD) at baseline and thus high risk status. Less than 25% of patients without CVD had a (UKPDS determined) calculated 5-year CHD risk of <5%, but nearly all had a 5-year stroke risk of <10%. Despite this, half of the cohort were obese (BMI > 30), most were men, two-thirds were aged over 60 years, and substantial proportions had NCEP ATP III features of the metabolic syndrome independent of their diabetes, including low HDL (60%), high blood pressure measurement or treatment for hypertension (84%), high waist measurement (68%), and raised triglycerides (52%).After a 6-week run-in period before randomisation with all participants receiving 200 mg comicronized fenofibrate, there were declines in total and LDL cholesterol (10%) and triglycerides (26%) and an increase in HDL cholesterol (6.5%).The study will show the effect of PPAR-alpha agonist action on CHD and other vascular outcomes in patients with type 2 diabetes including substantial numbers with low to moderate CVD risk but with the various components of the metabolic syndrome. The main results of the study will be reported in late 2005. The cardiovascular benefits of long-term treatment using HMG-CoA reductase inhibitors (statins) have been conclusively shown in several studies (summarized in ) of peopIf PPAR alpha agonists (and other modulators of the PPAR axis) are to assume a role as mainstream agents for reducing the risk of fatal and nonfatal cardiovascular events, adequately powered placebo-controlled trials, similar to the statin trials, are needed. They should include patients with diabetes of both sexes across a wide range of age and absolute cardiovascular risk.The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study is a 3-country , 63-centre, double-blinded placebo-controlled trial evaluating the effects of fenofibrate compared with placebo on coronary heart disease morbidity and mortality in 9795 patients with type 2 diabetes . The stuThe design of the FIELD study has been described in detail elsewhere . The stuPatients were recruited from 63 centres in Australia, New Zealand and Finland. Those with and without known vascular disease were eligible for participation provided that, at randomization, the usual physician considered that there was no current indication for lipid-modifying treatment. This meant that some patients meeting the FIELD eligibility criteria for lipid levels were instead treated by their usual doctors once they became aware of the patients' lipid profile at screening; therefore, such patients were not randomized and were not included in the study. Patients with or without lipid abnormalities, such as low HDL cholesterol or elevated triglycerides, were eligible if the total blood cholesterol level at screening fell between 3.0 and 6.5 mmol/L (about 115\u2013250 mg/dL) and either the total-to-HDL cholesterol ratio was 4.0 or higher, or the triglyceride level was over 1.0 mmol/L. Patients were excluded if they had triglyceride levels over 5.0 mmol/L. Lipid entry criteria were consistent with recruiting people who would not qualify for fully subsidised lipid-modifying treatment under the government guidelines in all 3 countries. Participants could not be taking any lipid-modifying therapy at the start of the dietary run-in period. However, the protocol allows for statin or other lipid-lowering therapy to be added at any time after randomization and recommends continuing study medication. The study is thus evaluating the role of fenofibrate on a background of usual care and will provide safety data on fibrate therapy in combination with other lipid-lowering treatments. A prespecified analysis will explore the effects of fenofibrate separately among those patients taking other lipid-lowering agents during follow-up and those taking study treatment alone. Intention-to-treat methods of analysis will result in conservative estimates of any effects of fenofibrate in the event that drop-ins to statin treatment are more frequent in the placebo-treated group. Confounding with respect to other drug use should be prevented by the randomization process, which will result in good balance across the treatment groups.Patients known to have type 2 diabetes were invited to attend a special clinic. After clinical screening of patients for eligibility and obtaining informed consent, blood was taken for biochemical measurements of fasting glucose, lipids, apolipoproteins, fibrinogen, HbA1c, insulin, renal and liver biochemistry, and homocysteine, and urine was collected for albumin-to-creatinine ratio. The LDL cholesterol level was calculated from the Friedewald formula . BiochemAfter the 16-week run-in procedures had been completed, a further blood sample was taken at the time of randomization (week 0) to determine the short-term effects of the comicronized fenofibrate on total cholesterol, HDL cholesterol, triglycerides, LDL cholesterol and fibrinogen. At this visit, patients were randomized, by a stratified adaptive randomization scheme, to receive either fenofibrate (200 mg comicronized formulation) or matching long-term placebo as one capsule daily with breakfast [All patients were then followed up through regular visits to a special clinic set in place for the purposes of the study in addition to routine care provided through the family doctor and usual diabetes clinics.7 For a primary outcome of CHD events , it is projected that approximately 500 CHD events will have occurred when a median of 5 years of follow-up has elapsed (during the first quarter of 2005); this represents an event rate of approximately 1% per annum. By this time the trial will have 80% power to detect an observed 22% reduction in CHD events . This will also provide 90% power to detect a 25% relative reduction in CHD events . These calculations assumed an average drop-out rate from active treatment of 10% over the course of the study but allowed for a larger drop-in rate from placebo to open-cholesterol treatment of 17%* by the mid-point of the trial and 32% by study close, in view of the possible increased uptake of statin therapy after the Heart Protection Study.Therefore, follow-up in the study, as stipulated in the protocol, was to be for a median duration of not less than 5 years and until 500 major coronary events had occurred, unless the study was terminated prematurely on the recommendation of the independent Safety and Data Monitoring Committee.Of the 13 900 patients screened in study clinics, 75.9% (10 553) proceeded to enter the placebo run-in phase and 73.4% (10 203) the active run-in phase, and ultimately 9795 (70.5%) patients were randomized . The median periods from diabetes diagnosis to randomization were 5, 7 and 5 years, respectively. The patients recruited were a mix from hospital and the community, and therefore were diverse in absolute risk. The 7664 participants who had no history of cardiovascular disease were at lower risk on the basis of interim determination using the modified Framingham equation of the UKPDS Risk Engine and the Bezafibrate Infarct Prevention (BIP) trial enrolled subjects with and without diabetes mellitus. Both studies were limited to people with prior myocardial infarction and reported reductions in major cardiovascular events among participants with low HDL and high triglycerides at baseline, which were greater than with use of the same fibrate among those without dyslipidemia ,25. The The identification of the PPAR transcription factor as the primary pathway through which fibrate and glitazone-agonist actions are triggered has stimThese baseline data of the FIELD study cohort without known prior cardiovascular disease show that over half such patients had a (UKPDS-determined) calculated 5-year coronary heart disease risk of less than 10% and nearly all patients had a stroke risk of less than 10% over 5 years. Part of the reason for this low-risk status may be that the duration of diabetes was only 5 years, on average, and reflecting this short duration, the median HbA1c was 6.9% for the entire cohort and the proportion of patients using no diabetes glucoregulatory therapy was just over a quarter. This probably reflects the recruitment process, in that many community-based subjects chose to enter the study in response to information provided by newsletters sent through Diabetes Australia, the Finnish Diabetes Society, the New Zealand Society for the Study of Diabetes and a New Zealand national diabetes consumer database.Nonetheless, the cohort still had a profile with many characteristics of high cardiovascular risk. Half of the patients were obese (BMI > 30), most were male, two-thirds were over the age of 60 years, and substantial proportions had NCEP ATP III features of the metabolic syndrome additional to their diabetes mellitus, including low HDL cholesterol, either high blood pressure measurement and/or treatment for hypertension, high waist measurement and raised triglyceride. Over 2100 (22%) had established cardiovascular disease, and 39% of those without known cardiovascular disease had a projected 5-year absolute risk of a coronary event higher than 10%.Evaluation of the effect of comicronized fenofibrate over 6 weeks immediately before randomization was included in the protocol. The purpose of this was to measure the effect of the agent in the entire cohort. After 6 weeks there were major reductions in triglycerides, lesser decreases in LDL cholesterol, and rises in HDL cholesterol. Creatinine levels rose while fibrinogen fell, several of the effects that have been observed elsewhere and with other fibrate agents ,29.Approximately 140 million adults were estimated to have diabetes mellitus in 1997; it is the most common endocrine disorder worldwide. Projections put diabetes prevalence by 2010 at 221 million, about 60 percent higher. Just as many people again have an elevated fasting glucose level, or impaired fasting glucose, which can progress rapidly to diabetes . WithoutOf the Management Committee of the FIELD Study:PB, YAK and RS have received reimbursements, fees, funding, or salary in the past five years from an organization that may in any way gain or lose financially from the publication of this paper;No authors hold or have held stocks or shares in such an organization;No authors have other financial competing interests;AK has the following nonfinancial competing interest: Advisory board membership.The Writing Committee are the authors responsible for this article.R Scott, J Best, P Forder, M-R Taskinen, J Simes, P Barter, A KeechP Barter*, J Best*, P Colman, M d'Emden, T Davis, P Drury, C Ehnholm, P Glasziou, D Hunt, A Keech* , YA Kesaniemi, M Laakso, R Scott*, RJ Simes*, D Sullivan, M-R Taskinen*, M Whiting; J-C Ansquer, B Fraitag (non-voting sponsor representatives). * Executive Committee membersN Anderson, G Hankey, D Hunt (chairman), S Lehto, S Mann, M Romo; LP Li ,C Hennekens, S MacMahon (chairman), S Pocock, A Tonkin, L Wilhelmsen; P Forder .Australia: H Akauola, F Alford, P Barter, I Beinart, J Best, S Bohra, S Boyages, P Colman, H Connor, D Darnell, T Davis, P Davoren, F Lepre, F De Looze, M d'Emden, A Duffield, R Fassett, J Flack, G Fulcher, S Grant, S Hamwood, D Harmelin, R Jackson, W Jeffries, M Kamp, L Kritharides, L Mahar, V McCann, D McIntyre, R Moses, H Newnham, G Nicholson, R O'Brien, K Park, N Petrovsky, P Phillips, G Pinn, D Simmons, K Stanton, B Stuckey, D R Sullivan, M Suranyi, M Suthers, Y Tan, M Templer, D Topliss, J H Waites, G Watts, T Welborn, R Wyndham; Finland: H Haapamaki, A Kesaniemi, M Laakso, J Lahtela, H Levanen, J Saltevo, H Sodervik, M Taskinen, M Vanhala; New Zealand: J Baker, A Burton, P Dixon, J Doran, P Drury, P Dunn, N Graham, A Hamer, J Hedley, J Lloyd, P Manning, I McPherson, S Morris, C Renner, R Scott, R Smith, M Wackrow, S Young.Australia: F Alard, J Alcoe, F Alford, C Allan, J Amerena, R Anderson, N Arnold, T Arsov, D Ashby, C Atkinson, L Badhni, M Balme, D Barton, B Batrouney, C Beare, T Beattie, J Beggs, C Bendall, C Bendall, A Benz, A Bond, R Bradfield, J Bradshaw, S Brearley, D Bruce, J Burgess, J Butler, M Callary, J Campbell, K Chambers, J Chow, S Chow, K Ciszek, P Clifton, P Clifton-Bligh, V Clowes, P Coates, C Cocks, S Cole, D Colquhoun, M Correcha, B Costa, S Coverdale, M Croft, J Crowe, S Dal Sasso, W Davis, J Dunn, S Edwards, R Elder, S El-Kaissi, L Emery, M England, O Farouque, M Fernandez, B Fitzpatrick, N Francis, P Freeman, A Fuller, D Gale, V Gaylard, C Gillzan, C Glatthaar, J Goddard, V Grange, T Greenaway, J Griffin, A Grogan, S Guha, J Gustafson, P S Hamblin, T Hannay, C Hardie, A Harper, G Hartl, A Harvey, S Havlin, K Haworth, P Hay, L Hay, B Heenan, R Hesketh, A Heyworth, M Hines, G Hockings, A Hodge, L Hoffman, L Hoskin, M Howells, D Hunt, A Hunt, W Inder, W Inder, D Jackson, A Jovanovska, K Kearins, P Kee, J Keen, D Kilpatrick, J Kindellan, M Kingston-Ray, M Kotowicz, A Lassig, M Layton, S Lean, E Lim, F Long, L Lucas, D Ludeman, D Ludeman, C Ludeman-Robertson, M Lyall, L Lynch, C Maddison, B Malkus, A Marangou, F Margrie, K Matthiesson, J Matthiesson, S Maxwell, K McCarthy, A McElduff, H McKee, J McKenzie, K McLachan, P McNair, M Meischke, A Merkel, C Miller, B Morrison, A Morton, W Mossman, A Mowat, J Muecke, P Murie, S Murray, P Nadorp, S Nair, J Nairn, A Nankervis, K Narayan, N Nattrass, J Ngui, S Nicholls, V Nicholls, JA Nye, E Nye, D O'Neal, M O'Neill, S O'Rourke, J Pearse, C Pearson, J Phillips, L Pittis, D Playford, L Porter, L Porter, R Portley, M Powell, C Preston, S Pringle, W A Quinn, J Raffaele, G Ramnath, J Ramsden, D Richtsteiger, S Roffe, S Rosen, G Ross, Z Ross, J Rowe, D Rumble, S Ryan, J Sansom, C Seymour, E Shanahan, S Shelly, J Shepherd, G Sherman, R Siddall, D Silva, S Simmons, R Simpson, A Sinha, R Slobodniuk, M Smith, P Smith, S Smith, V Smith-Orr, J Snow, L Socha, T Stack, K Steed, K Steele, J Stephensen, P Stevens, G Stewart, R Stewart, C Strakosch, M Sullivan, S Sunder, J Sunderland, E Tapp, J Taylor, D Thorn, D Thorn, A Tolley, D Torpy, G Truran, F Turner, J Turner, J van de Velde, S Varley, J Wallace, J Walsh, J Walsh, J Walshe, G Ward, B Watson, J Watson, A Webb, F Werner, E White, A Whitehouse, N Whitehouse, S Wigg, J Wilkinson, E Wilmshurst, D Wilson, G Wittert, B Wong, M Wong, S Worboys, S Wright, S Wu, J Yarker, M Yeo, K Young, J Youssef, R Yuen, H Zeimer, R W Ziffer; Finland: A Aura, A Friman, J Hanninen, J Henell, N Hyvarinen, M Ikonen, A Itkonen, J Jappinen, A Jarva, T Jerkkola, V Jokinen, J Juutilainen, H Kahkonen, T Kangas, M Karttunen, P Kauranen, S Kortelainen, H Koukkunen, L Kumpulainen, T Laitinen, M Laitinen, S Lehto, R Lehto, E Leinonen, M Lindstron-Karjalainen, A Lumiaho, J Makela, K Makinen, L Mannermaa, T Mard, J Miettinen, V Naatti, S Paavola, N Parssinen, J Ripatti, S Ruotsalainen, A Salo, M Siiskonen, A Soppela, J Starck, I Suonranta, L Ukkola, K Valli, J Virolainen; New Zealand: P Allan, W Arnold, W Bagg, K Balfour, T Ball, B Ballantine, C Ballantyne, C Barker, C Barker, F Bartley, E Berry, G Braatvedt, A Campbell, T Clarke, R Clarke, A Claydon, S Clayton, P Cresswell, R Cutfield, J Daffurn, J Delahunt, A Dissnayake, C Eagleton, C Ferguson, C Florkowski, D Fry, P Giles, M Gluyas, C Grant, P Guile, M Guolo, P Hale, M Hammond, M Hammond, P Healy, M Hills, J Hinge, J Holland, B Hyne, A Ireland, A Johnstone, S Jones, G Kerr, K Kerr, M Khant, J Krebs, L Law, B Lydon, K MacAuley, R McEwan, P McGregor, B McLaren, L McLeod, J Medforth, R Miskimmin, J Moffat, M Pickup, C Prentice, M Rahman, E Reda, C Ross, A Ryalls, D Schmid, N Shergill, A Snaddon, H Snell, L Stevens, A Waterman, V Watts.NHMRC Clinical Trials Centre, Sydney: K Jayne, E Keirnan, P Newman, G Ritchie, A Rosenfeld (project directors), E Beller, P Forder, V Gebski, A Pillai (study statisticians), C Anderson, S Blakesmith, S-Y Chan, S Czyniewski, A Dobbie, S Doshi, A Dupuy, S Eckermann, M Edwards, N Fields, K Flood, S Ford, C French, S Gillies, C Greig, M Groshens, J Gu, Y Guo, W Hague, S Healy, L Hones, Z Hossain, M Howlett, J Lee, L-P Li, T Matthews, J Micallef, A Martin, I Minns, A Nguyen, F Papuni, A Patel, J Pearse, R Pike, M Pena, K Pinto, D Schipp, J Schroeder, B Sim, C Sodhi, T Sourjina, C Sutton, R Taylor, P Vlagsma, S Walder, R Walker, W Wong, J Zhang, B Zhong, A Keech (deputy director), RJ Simes (director); Helsinki Project Office: A Kokkonen, P Narva, E-L Niemi, A Salo, A-M Syrjanen, M-R Taskinen (director); Christchurch Project Office: C Lintott, R Scott (director).Adelaide: R Tirimacco, M Whiting; Helsinki: C Ehnholm, M Ikonen, M Kajosaari, L Raman, J Sundvall, M Tukianen.Laboratoires Fournier SA liaison: Dijon: J-C Ansquer, B Fraitag, D Crimet, I Sirugue, Sydney: P Aubonnet."} +{"text": "Warning - this is an unedited draft, which will be replaced by a final version mid of October [will be posted at this URL].Following a meeting convened to discuss the EU-funded MedCERTAIN project on improving information quality on the Internet, a broad group of individuals from 4 continents and 21 countries, drawn from a wide range of sectors including industry, leading Web sites, governmental and intergovernmental bodies, academia, consumer organisations, standards and ethical code bodies and publishers agree that:1. Despite the enormous value for the public, patients and professionals of the health and medical Internet, the participants are concerned about its potential for harm. However, it is also important not to limit freedom of expression and use of the internet for health related purposes.2. The participants wish to explore in an ongoing collaborative effort opportunities for helping people, patients and professionals to identify health information useful to them, addressing certain key issues, including:What is an appropriate way to describe the characteristics of the full range of Internet health and medical sites ?How can the descriptions be summarised as metadata for different purposes and users of health information ?How do the identity, training and other factors influence the description and summary ?Can criteria be developed to indicate quality for different users and purposes ?How can the potential of information and communications technology, such as the MedCERTAIN project, be harnessed in a consistent and cost-effective way ?What are the legal and other implications of trustmarks and other devices or mechanisms to denote quality ?How to establish and motivate a worldwide, representative network of evaluators?What are the areas of potential overlap with other initiatives and organisations?3. The participants resolve to work together, building on experience and expertise of this group, key quality improvement initiatives such as Discern, eHealth ethics code, HONcode, Hi-Ethics code, OMNI and others, and working towards a methodological clarification and resolution of the above and other related issues in the near future, providing constructive support to the MedCERTAIN and other projects and continuing to build together trust on the health Internet.Participants:Lucas M. Bachmann , Carl R. Blesius , Markus Blume , Carl J. Brandt , Dan Brickley , Alejandro Cacherosky , Ken Campell , Richard Cleland , Phil Cross , Elenice de Castro , Guy de Roy , Tony Delamothe , Martin D. Denz , Persephone Doupi , Joan Dzenowagis , Christer Edling , Gunther Eysenbach , Gerard Freriks , Franz Fr\u00fchwald , Lisa Gray , Pelle Gustafsson , Gerhard Heine , Katrin H\u00f6rner , Robert Hsiung , Jostein Ingulfsen , Thomas Isenberg , Edward Jacob , Alex R. Jadad , Jacobo Kelber , Hugo Kitzinger , Inge Kokot , Hans-Joachim Koubenec , Michel Labrecque , Kristian Lampe , Stephane Lejeune , Leonard B. Lerer , Odile Leroy , Nicolas Lienert , P\u00e5l Lindstr\u00f6m , S\u00e1ndor Lipp , Leena Lodenius , Antti Malmivaara , Miquel Angela Mayer Pujadas , Peter Mills , Cesar Molinero , Marc Muret , Wolfgang Nagel , Tim Nater , Joerg Nitzsche , Debra O\u00b4Connor , Gert Purkert , Ramon Sarrias Ramis , Christine Reuter , Ahmad Risk , Carl B\u00e9n\u00e9dict Roth , Sebastian Schmid , Christiane Schmitz , Luk Schoonbaert , Frank Schuler , Ulrich Schwanke , Sasha Shepperd , Myra Sidrassi , Chris Sigouin , Chris Silagy , Denise Silber , Martin Sonderegger , Anke Steckelberg , Frederik Tautz , Nicolas P. Terry , Christian Thomeczek , Wouter Tukker, , Gerard H. van der Zanden , Georg von Below , Frank von Danwitz , C.-Peter Waegemann , Thomas Wetter , Petra Wilson, , Margaret A. Winker , Jeremy Wyatt , Gabriel Yihune"} +{"text": "PLoS Biology, volume 4, issue 11: DOI: 10.1371/journal.pbio.0040348In The author contributions were listed incorrectly. The correct author contributions are as follows: BAH conceived and designed the experiments. MS, ML, JNN, LGF, CMC, and BAH performed the experiments and analyzed the data. MS, LGF, JNN, and BAH wrote the paper."} +{"text": "Fibrates correct the typical lipid abnormalities of type 2 diabetes mellitus, yet no study, to date, has specifically set out to evaluate the role of fibrate therapy in preventing cardiovascular events in this setting.Subjects with type 2 diabetes, aged 50\u201375 years, were screened for eligibility to participate in a long-term trial of comicronized fenofibrate 200 mg daily compared with matching placebo to assess benefits of treatment on the occurrence of coronary and other vascular events. People with total cholesterol levels 3.0\u20136.5 mmol/L plus either a total-to-HDLc ratio >4.0 or triglyceride level >1.0 mmol/L with no clear indication for lipid-modifying therapy were eligible.P = 0.05 a 22% reduction in such events, using intention-to-treat methods.A total of 9795 people were randomized into the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. All received dietary advice, followed by a 6-week single-blind placebo run-in, then a 6-week active run-in period before randomization. Participants are being followed up every 6 months for outcome events and safety assessments. The study is designed to yield at least 500 coronary events over 5 years, to have 80% power to identify as statistically significant at 2Type 2 diabetes is the most common endocrine disorder worldwide, and its prevalence is increasing. The current evidence about use of fibrates in type 2 diabetes, from around 2000 people treated, will increase with FIELD to evidence from around 12000. FIELD will establish the role of fenofibrate treatment in reducing cardiovascular risk in people with type 2 diabetes. The main results are expected to be available in late 2005. Type 2 diabetes mellitus is an increasingly common condition associated with a high cardiovascular risk. To date, very few trials of lipid-lowering therapy have focused on this condition, and in particular, no large trials of fibrate therapy in diabetes have been conducted. As fibrates are known to correct the typical dyslipidaemia of diabetes, their role in cardiovascular risk reduction in diabetes may be especially important. The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study is a multicentre, double-blind, placebo-controlled trial evaluating the effects on coronary morbidity and mortality of long-term treatment with fenofibrate to elevate high-density lipoprotein (HDL) cholesterol levels and lower triglyceride (TG) levels in patients with type 2 diabetes and total blood cholesterol between 3 and 6.5 mmol/L (115 and 250 mg/dL) at study entry. In type 2 diabetes, rates of coronary heart disease (CHD) are 3 to 4 times higher than those of persons without diabetes at any given level of blood cholesterol, and at any given age [Blood total cholesterol levels are not substantially different between patients with type 2 diabetes and those of nondiabetic populations of similar age and sex . HoweverThe strength of the cholesterol-CHD relationship is very similar for those with type 2 diabetes as for nondiabetics, although at a higher background rate of CHD , which tFor patients with type 2 diabetes and its typical dyslipidaemia, many physicians believe that fibrates are the logical first choice of drug treatment. The fibrates have been in clinical use for a long time, being well tolerated and with few short-term side-effects. Fenofibrate has been widely used and marketed for more than 20 years and is an effective agent for reducing plasma triglyceride and raising HDL cholesterol . AlthougFIELD is designed to provide the first properly randomized evidence as to whether the substantial effects of fenofibrate confer a benefit on clinical cardiovascular events in persons with type 2 diabetes. A clearly favourable result might be expected to help physicians determine which type of lipid-modifying drug therapy is likely to be most cost-effective for such people.FIELD is a randomized, double-blind, placebo-controlled parallel-group trial among middle-aged to elderly people with type 2 diabetes mellitus considered to be at increased risk of CHD. Those with and without pre-existing vascular disease or other lipid abnormalities, such as low HDL cholesterol and elevated TG, were eligible, provided the total blood cholesterol level at screening fell between 3.0 and 6.5 mmol/L (about 115\u2013250 mg/dL) plus either a total-to-HDL cholesterol ratio of >4.0 or a blood TG level >1.0 mmol/L (88.6 mg/dL) or matching placebo as one capsule daily with breakfast. There was no formal restriction on randomization related to compliance during the run-in period. Randomization was carried out using a dynamic allocation method with strThe run-in phase for the study consists of a 4-week diet-only period, followed by a 6-week single-blind placebo period, then a 6-week single-blind active run-in period on comicronized fenofibrate 200 mg once daily for all patients, before randomization Figure . This waFollow-up in the study will be for not less than 5 years of median duration and until a total of at least 500 first coronary events have accumulated in the trial, unless the study is terminated earlier by advice from the Safety and Data Monitoring Committee.The principal study outcome is the combined incidence of first nonfatal MI or CHD death among all randomized patients during the scheduled treatment period Table . SecondaTertiary outcomes include the effects of treatment on development of vascular and neuropathic amputations, nonfatal cancers, the progression of renal disease, laser treatment for diabetic retinopathy, hospitalization for angina pectoris, and numbers and duration of all hospital admissions. The effects of treatment on the outcome of total cardiovascular events will be examined inThe rates of events various subgroups of particular interest, such as men and women, those <65 years and \u2265 65 years of age, by subgroup of each of baseline total cholesterol, HDL cholesterol, triglyceride and fibrinogen, baseline insulin use, or not, and the presence, or absence, at baseline of microalbuminuria.The primary analysis will be of time to first study outcome, using standard log-rank methods ,19, and The rates of events used for the original study power calculations were based on information from a variety of sources. During recruitment, when the numbers of participants with prior MI was falling well short of the number originally planned (in about 2000), the sample size was extended from the original total of 8000 to a final number of 9795 reached in November 2000. In late 2002, the statistical power of the trial was reviewed again. These reviews were planned in the original protocol design and were undertaken by reviewers completely blinded to all treatment allocation. The reassessment included information on final sample size, overall rate of discontinuation of study medication and commencement of open-label cholesterol treatment, and overall event rates in relation to CHD death, MI, and stroke.After the review it was clear that the trial would yield too few deaths from CHD to retain sufficient power, over its planned duration of around 5 years, to show a significant reduction in this endpoint. The FIELD Management Committee determined that the primary outcome of the trial should be amended from CHD death to CHD events . It was also decided to change the principal outcome for subgroup analyses to look at the effects of fenofibrate in subjects with and without prior cardiovascular disease (CVD) .For a primary outcome of CHD events , it is projected that approximately 500 CHD events will have occurred when 5 years median follow-up has elapsed (during the first quarter of 2005); by this time the trial will have 80% power to detect an observed 22% reduction in CHD events . This will also provide 90% power to detect a 25% relative reduction in CHD events . Both calculations allow for the effects of an average drop-out rate from active treatment over the course of the study of 10% and a similar drop-in rate of 10% from placebo to open cholesterol-lowering therapy Table . These aIf the uptake of cholesterol-lowering therapy proves to be greater in the placebo group than in the fenofibrate-allocated group, the observed treatment effect of fenofibrate will underestimate its true efficacy.P = 0.003) to preserve an overall type 1 error probability of no more than 0.05. The events to be used for these analyses are counts of death from CHD. The Management Committee, the collaborators, the study sponsor and all the central administrative staff, with the exception of the unblinded statistician, will remain ignorant of the interim results for mortality and major morbidity. During the study, the group effects of treatment on biochemical parameters, such as lipid fractions, and other surrogate endpoints may be published, subject to prior approval of the Management Committee, provided that individual patient treatment assignments are not revealed. Patients are being monitored regularly by lipid profiles, liver function tests, creatine phosphokinase, fasting glucose, HbA1c, and urinary microalbumin. The study has been approved by local ethics committees at each participating institution, which also approved the information discussed and informed-consent procedures. The first patient in FIELD was registered in November 1997 and randomized in February 1998. The study has recruited 9795 patients; the final patient was randomized on 3 November 2000.The trial has an independent Safety and Data Monitoring Committee to safeguard the patients' interests and to formally evaluate from time to time on a regular basis whether, for any reason, they would recommend that the study should be modified or stopped. Up to 5 formal interim analyses are planned, at time points to be determined by the Safety and Data Monitoring Committee, with a stringent nominal significance level to have the power to show reliably whether these benefits would translate into reductions in CHD mortality in the setting of diabetes, nor the effects in them of treatment on noncoronary events and mortality. Further, the West of Scotland (WOSCOPS) study of pravastatin in hypercholesterolaemic men with no prior CHD, which reported a marginally significant reduction in overall mortality, had fewer than 100 subjects with diabetes [In 1997, before the FIELD study commenced, the role of lipid modification in diabetes remained uncertain, except possibly for hypercholesterolaemic people with a prior MI. Two large-scale trials, the Scandinavian Simvastatin Survival Study (4S) and the diabetes .Since that time, numerous other trials of statin treatment have been reported, with randomized data now reported on over 18000 persons with diabetes. Those involving more than 1000 people with diabetes include the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study ,23, the Two large-scale trials of fibrate therapy have also been completed: the Veterans Low-HDL Cholesterol Intervention Trial (VA-HIT) ,30 and tAt the same time, our understanding of the mechanism of action of fibrates has grown, with identification of the peroxisome proliferator-activated receptor alpha transcription factor as the primary pathway through which fibrate-mediated effects are triggered ,35. The Approximately 140 million adults were estimated to be suffering from diabetes mellitus, the most common endocrine disorder worldwide, in 1997. By 2010, projections put diabetes prevalence about 60 percent higher, at 221 million. Just as many persons again have an elevated fasting glucose level, or impaired fasting glucose, which can progress rapidly to diabetes. Without the FIELD study, doctors would remain uncertain about the merits of using a fibrate when confronted with a patient with diabetes at risk of clinical CHD. It is expected that the main results of FIELD will be reported in late 2005.Of the Management Committee of the FIELD Study:PB, YAK and RS have received reimbursements, fees, funding, or salary in the past five years from an organization that may in any way gain or lose financially from the publication of this paper;No authors hold or have held stocks or shares in such an organization;No authors have other financial competing interests;AK has the following nonfinancial competing interests: Advisory board membership.The FIELD Management Committee conceived and developed the study protocol and are the responsible authors of this manuscript.P Barter*, J Best*, P Colman, M d\u2019Emden, T Davis, P Drury, C Ehnholm, P Glasziou, D Hunt, A Keech* , YA Kesaniemi, M Laakso, R Scott*, RJ Simes*, D Sullivan, M-R Taskinen*, M Whiting; J-C Ansquer, B Fraitag (non-voting sponsor representatives). * Executive Committee members.N Anderson, G Hankey, D Hunt (chairman), S Lehto, S Mann, M Romo; LP Li .C Hennekens, S MacMahon (chairman), S Pocock, A Tonkin, L Wilhelmsen; P Forder . Australia: H Akauola, F Alford, P Barter, I Beinart, J Best, S Bohra, S Boyages, P Colman, H Connor, D Darnell, T Davis, P Davoren, F Lepre, F De Looze, M d'Emden, A Duffield, R Fassett, J Flack, G Fulcher, S Grant, S Hamwood, D Harmelin, R Jackson, W Jeffries, M Kamp, L Kritharides, L Mahar, V McCann, D McIntyre, R Moses, H Newnham, G Nicholson, R O'Brien, K Park, N Petrovsky, P Phillips, G Pinn, D Simmons, K Stanton, B Stuckey, D R Sullivan, M Suranyi, M Suthers, Y Tan, M Templer, D Topliss, J H Waites, G Watts, T Welborn, R Wyndham; Finland: H Haapamaki, A Kesaniemi, M Laakso, J Lahtela, H Levanen, J Saltevo, H Sodervik, M Taskinen, M Vanhala; New Zealand: J Baker, A Burton, P Dixon, J Doran, P Drury, P Dunn, N Graham, A Hamer, J Hedley, J Lloyd, P Manning, I McPherson, S Morris, C Renner, R Scott, R Smith, M Wackrow, S Young.Australia: F Alard, J Alcoe, F Alford, C Allan, J Amerena, R Anderson, N Arnold, T Arsov, D Ashby, C Atkinson, L Badhni, M Balme, D Barton, B Batrouney, C Beare, T Beattie, J Beggs, C Bendall, C Bendall, A Benz, A Bond, R Bradfield, J Bradshaw, S Brearley, D Bruce, J Burgess, J Butler, M Callary, J Campbell, K Chambers, J Chow, S Chow, K Ciszek, P Clifton, P Clifton-Bligh, V Clowes, P Coates, C Cocks, S Cole, D Colquhoun, M Correcha, B Costa, S Coverdale, M Croft, J Crowe, S Dal Sasso, W Davis, J Dunn, S Edwards, R Elder, S El-Kaissi, L Emery, M England, O Farouque, M Fernandez, B Fitzpatrick, N Francis, P Freeman, A Fuller, D Gale, V Gaylard, C Gillzan, C Glatthaar, J Goddard, V Grange, T Greenaway, J Griffin, A Grogan, S Guha, J Gustafson, P S Hamblin, T Hannay, C Hardie, A Harper, G Hartl, A Harvey, S Havlin, K Haworth, P Hay, L Hay, B Heenan, R Hesketh, A Heyworth, M Hines, G Hockings, A Hodge, L Hoffman, L Hoskin, M Howells, D Hunt, A Hunt, W Inder, W Inder, D Jackson, A Jovanovska, K Kearins, P Kee, J Keen, D Kilpatrick, J Kindellan, M Kingston-Ray, M Kotowicz, A Lassig, M Layton, S Lean, E Lim, F Long, L Lucas, D Ludeman, D Ludeman, C Ludeman-Robertson, M Lyall, L Lynch, C Maddison, B Malkus, A Marangou, F Margrie, K Matthiesson, J Matthiesson, S Maxwell, K McCarthy, A McElduff, H McKee, J McKenzie, K McLachan, P McNair, M Meischke, A Merkel, C Miller, B Morrison, A Morton, W Mossman, A Mowat, J Muecke, P Murie, S Murray, P Nadorp, S Nair, J Nairn, A Nankervis, K Narayan, N Nattrass, J Ngui, S Nicholls, V Nicholls, JA Nye, E Nye, D O'Neal, M O'Neill, S O'Rourke, J Pearse, C Pearson, J Phillips, L Pittis, D Playford, L Porter, L Porter, R Portley, M Powell, C Preston, S Pringle, W A Quinn, J Raffaele, G Ramnath, J Ramsden, D Richtsteiger, S Roffe, S Rosen, G Ross, Z Ross, J Rowe, D Rumble, S Ryan, J Sansom, C Seymour, E Shanahan, S Shelly, J Shepherd, G Sherman, R Siddall, D Silva, S Simmons, R Simpson, A Sinha, R Slobodniuk, M Smith, P Smith, S Smith, V Smith-Orr, J Snow, L Socha, T Stack, K Steed, K Steele, J Stephensen, P Stevens, G Stewart, R Stewart, C Strakosch, M Sullivan, S Sunder, J Sunderland, E Tapp, J Taylor, D Thorn, D Thorn, A Tolley, D Torpy, G Truran, F Turner, J Turner, J van de Velde, S Varley, J Wallace, J Walsh, J Walsh, J Walshe, G Ward, B Watson, J Watson, A Webb, F Werner, E White, A Whitehouse, N Whitehouse, S Wigg, J Wilkinson, E Wilmshurst, D Wilson, G Wittert, B Wong, M Wong, S Worboys, S Wright, S Wu, J Yarker, M Yeo, K Young, J Youssef, R Yuen, H Zeimer, R W Ziffer; Finland: A Aura, A Friman, J Hanninen, J Henell, N Hyvarinen, M Ikonen, A Itkonen, J Jappinen, A Jarva, T Jerkkola, V Jokinen, J Juutilainen, H Kahkonen, T Kangas, M Karttunen, P Kauranen, S Kortelainen, H Koukkunen, L Kumpulainen, T Laitinen, M Laitinen, S Lehto, R Lehto, E Leinonen, M Lindstron-Karjalainen, A Lumiaho, J Makela, K Makinen, L Mannermaa, T Mard, J Miettinen, V Naatti, S Paavola, N Parssinen, J Ripatti, S Ruotsalainen, A Salo, M Siiskonen, A Soppela, J Starck, I Suonranta, L Ukkola, K Valli, J Virolainen; New Zealand: P Allan, W Arnold, W Bagg, K Balfour, T Ball, B Ballantine, C Ballantyne, C Barker, C Barker, F Bartley, E Berry, G Braatvedt, A Campbell, T Clarke, R Clarke, A Claydon, S Clayton, P Cresswell, R Cutfield, J Daffurn, J Delahunt, A Dissnayake, C Eagleton, C Ferguson, C Florkowski, D Fry, P Giles, M Gluyas, C Grant, P Guile, M Guolo, P Hale, M Hammond, M Hammond, P Healy, M Hills, J Hinge, J Holland, B Hyne, A Ireland, A Johnstone, S Jones, G Kerr, K Kerr, M Khant, J Krebs, L Law, B Lydon, K MacAuley, R McEwan, P McGregor, B McLaren, L McLeod, J Medforth, R Miskimmin, J Moffat, M Pickup, C Prentice, M Rahman, E Reda, C Ross, A Ryalls, D Schmid, N Shergill, A Snaddon, H Snell, L Stevens, A Waterman, V Watts.NHMRC Clinical Trials Centre, Sydney: K Jayne, E Keirnan, P Newman, G Ritchie, A Rosenfeld (project directors), E Beller, P Forder, V Gebski, A Pillai (study statisticians), C Anderson, S Blakesmith, S-Y Chan, S Czyniewski, A Dobbie, S Doshi, A Dupuy, S Eckermann, M Edwards, N Fields, K Flood, S Ford, C French, S Gillies, C Greig, M Groshens, J Gu, Y Guo, W Hague, S Healy, L Hones, Z Hossain, M Howlett, J Lee, L-P Li, T Matthews, J Micallef, A Martin, I Minns, A Nguyen, F Papuni, A Patel, J Pearse, R Pike, M Pena, K Pinto, D Schipp, J Schroeder, B Sim, C Sodhi, T Sourjina, C Sutton, R Taylor, P Vlagsma, S Walder, R Walker, W Wong, J Zhang, B Zhong, A Keech (deputy director), RJ Simes (director); Helsinki Project Office: A Kokkonen, P Narva, E-L Niemi, A Salo, A-M Syrjanen, M-R Taskinen (director); Christchurch Project Office: C Lintott, R Scott (director).Adelaide: R Tirimacco, M Whiting; Helsinki: C Ehnholm, M Ikonen, M Kajosaari, L Raman, J Sundvall, M Tukianen. .Laboratoires Fournier SA liaison: Dijon: J-C Ansquer, B Fraitag, D Crimet, I SirugueSydney: P Aubonnet."} +{"text": "More than 80 eHealth experts from 20 different countries and four continents attended an international workshop in Heidelberg/Germany to agree on an international scientific collaboration in the field of ehealth, to work on a metadata structure for ehealth providers and to discuss trustmark concept and other ways to enhance trust, implement eHealth ethics and improve the quality of health information on the Internet.List of attendees, in alphabetical order:Lucas M. Bachmann Carl R. Blesius , Markus Blume , Carl J. Brandt , Dan Brickley , Alejandro Cacherosky , Ken Campell , Richard Cleland , Phil Cross , Elenice de Castro , Guy de Roy , Tony Delamothe , Martin D. Denz , Persephone Doupi , Joan Dzenowagis , Christer Edling , Gunther Eysenbach , Gerard Freriks , Franz Fr\u00fchwald , Lisa Gray , Pelle Gustafsson , Gerhard Heine , Katrin H\u00f6rner , Robert Hsiung , Jostein Ingulfsen , Thomas Isenberg , Edward Jacob , Alex R. Jadad , Jacobo Kelber , Hugo Kitzinger , Inge Kokot , Hans-Joachim Koubenec , Michel Labrecque , Kristian Lampe , Stephane Lejeune , Leonard B. Lerer , Odile Leroy , Nicolas Lienert , P\u00e5l Lindstr\u00f6m , S\u00e1ndor Lipp , Leena Lodenius , Antti Malmivaara , Miquel Angela Mayer Pujadas , Peter Mills , Cesar Molinero , Marc Muret , Wolfgang Nagel , Tim Nater , Joerg Nitzsche , Debra O\u00b4Connor , Gert Purkert , Ramon Sarrias Ramis , Christine Reuter , Ahmad Risk , Carl B\u00e9n\u00e9dict Roth , Sebastian Schmid , Christiane Schmitz , Luk Schoonbaert , Frank Schuler , Ulrich Schwanke , Sasha Shepperd , Myra Sidrassi , Chris Sigouin , Chris Silagy , Denise Silber , Martin Sonderegger , Anke Steckelberg , Frederik Tautz , Nicolas P. Terry , Christian Thomeczek , Wouter Tukker, , Gerard H. van der Zanden , Georg von Below , Frank von Danwitz , C.-Peter Waegemann , Thomas Wetter , Petra Wilson, , Margaret A. Winker , Jeremy Wyatt , Gabriel Yihune"} +{"text": "European Journal of General Practice should like to express their gratitude to all reviewers who have advised us during the year 2016. To acknowledge their indispensable contribution to the European Journal of General Practice, we have listed the names of all referees who completed at least one review report between 16 December 2015 and 16 December 2016.The Editors of the Heinz-Harald Abholz, Erik Abilsnes, Jeffery Adams, Gisele Apter, Enric Aragon\u00e9s, Chris Arden, Davut Baltaci, Tadej Battelino, Carol Bayona, Jaume Benavent, Ria Benko, Anette Berendsen, Christophe Berkhout, Sonja Bidmon, Peter Birner, Bj\u00f8rn Bjorvatn, Marco Blanker, Jan Bosmans, Colin Bradley, Carlos Brotonos, Mateja Bulc, L.H. Burridge, Manuel Campi\u00f1ez, Meltem Ciceklioglu, Peter Clarys, David Cohen, Gloria Cordoba, Lizzie Cottrell, Anne-Marie Cox, An de Sutter, Jan Degryse, Dorner, Thomas, Chris Dowrick, Sandra Fahrenkrog, Gabriele Fischer, Thomas Frese, Zbigniew Gaciong, Luis Galvez, Jochen Gensichen, Sherly George, Juan Gervas, Christoph Gisinger, Liam Glynn, Maciek Godycki-Cwirko, Alexandre Gouveia, Tomasz Grodzicki, Dilek G\u00fcldal, Ronny Gunnarsson, Peter Hjertholm, Kathryn Hoffmann, Eva Hummers-Pradier, Thomas Kahan, Laszlo Kalabay, Ruth Kalda, Gustav Kamenski, Bridget Kane, Brian Kelly, Martina Kelly, Marko Kol\u0161ek, Evan Kontopantelis, Dionne S. Kringos, Ron Kusters, Ilias-Ioannis Kyriopoulos, Toine Lagro, Amnon Lahad, A. J. Larner, Asam Latif, Klaus Linde, Christos Lionis, Carl Llor, Jos\u00e9 Ramon Loayssa, Nicole Lowres, Heidi Lyshol, Roar Maagaard, Aldo Pietro Maggioni, Christian Mallen, Niina Markkula, Inaki Martin-Lesende, Merc\u00e8 Marzo-Castillejo, Marion McAllister, Saskia Mol, Jose M. Molero, Ana Moragas-Moreno, Maria Luisa Morato, Tania Morris, Luke Mounce, Anders Munck, Miguel Mu\u00f1oz, Peter Murchie, Markus Nielen, Caitlin Notley, Peter Nygaard, Abimbola Obimakinde, Zeliha Ocek, Eric Olsman, Graziano Onder, Ennio Ongini, John Paget, Davorina Petek, Soeren Prins, Enriqueta Pujol-Ribera, Jesus Pujol, Maja Racic, S. Ramlall, Sofia B. Ravara, Shmuel Reis, Claire Rondet, Jim Ross, Danica Rotar Pavli\u010d, Marie-Eve Roug\u00e9 Bugat, Guy Rutten, Antonio Sarr\u00eda Santamera, Willemijn Sch\u00e4fer, Nynke Scherpbier, Henrik Schroll, Michaela Schunk, Polona Selic, Monika Seltenhammer, Helmut Sinzinger, Jef Sisler, Antoni Sis\u00f3 Almirall, Marleen Smits, Hilde Solberg, Sal Stapley, Igor \u015cvab, Dorota Szczesniak, Angela Taft, Clare Taylor, Gabriela Heiden Telo, Berend Terluin, Bratt Thombs, Tomasz Tomasik, Salvador Tranche, Michael J. Twigg, Anne-Marie Uijen, Steven Uittenbogaart, Sabina Ulbricht, Aysegul Uludag, Juan Valdes-Stauber, Joan Antoni Valles, Wil van den Bosch, Marc van der Wel, Tineke van Geel, Evelien van Riet, Piet Vanden Bussche, Juha Varis, Jos\u00e9 V\u00e1zquez Villegas, Theo Verheij, Ernest Vinyoles, Johannes Wancata, Jane Wilcock, Oriol Yuguero Torres.European Journal of General Practice accepts around 30% of all submitted manuscripts.We want to thank you all for your appreciated assistance! Your review reports were very valuable feedback to the authors and helped us to make our editorial decisions. Currently, the http://mc.manuscript-central.com/ejgp and log in to modify your profile. In addition, we invite all readers of the European Journal of General Practice who would like to review manuscripts for this journal, to visit http://mc.manuscriptcentral.com/ejgp and to register as \u2018new user\u2019, i.e. to complete the details of their expertise. We provide a format to facilitate the review.Although our database of authors and reviewers steadily increases, the Editors do not always find it easy to find referees within the journal\u2019s deadlines. Therefore, we sincerely hope that all reviewers want to continue their review work in the future. If you would like to update your reviewer account, e.g. to specify your expertise, please visit ejgp-agermeraad@maastrichtuniversity.nl).If you have comments regarding the journal or its peer review process, we invite you to contact the editorial office (Ms. Anneke Germeraad-Uriot, Editorial Assistant:"} +{"text": "Life would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.The editors of https://publons.com) to receive recognition. Of course, in these intiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make.We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (Life, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Life in 2016:Amachi, SeigoGerday, CharlesOsterman, AndreiAnton, JosefaGerland, UlrichPaleos, C.M.Armengod, M.-EugeniaGogarten, Johann PeterParadisi, FrancescaBaxter, BonnieHellingwerf, Klaas J.Pfeifer, FelicitasBernhardt, Harold S.Higgs, PaulPhizicky, EricBininda-Emonds, Olaf R.P.Holliger, PhilippRajamani, SudhaBlack, Roy A.Hu, GuofuRettberg, PetraBlackstone, NeilHud, NicholasRibo, Josep M.Borghese, RobertoIkehara, KenjiRodriguez Valera, FranciscoBoto, LuisIvanov, PavelRoot-Bernstein, RobertBrack, AndreJordi, G\u00f3mezRoss, IanBrazelton, WilliamKarev, GeorgyRuiz-Mirazo, KepaBrooks, NickKawamura, KunioSakamoto, KensakuBudisa, NediljkoKim, SeonghoSantander, JavierBurton, Aaron S.Kimchi-Sarfaty, ChavaSaraiva, Jorge A.Carrapi\u00e7o, FranciscoLamba, DorianoSass, HenrikCarter, Charles W.LaPres, John J.Schierwater, BerndCayol, Jean-LucLeidel, SebastianSchoepp-Cothenet, BarbaraCohen, PinchasLeuko, StefanShcherbakova, ViktoriaCrowley, DavidLindberg, PiaStadler, PeterCs\u0171r\u00f6s, Mikl\u00f3sLindsey, Jonathan S.Strasdeit, HenryDamer, BruceLuisi, PierSugawara, Tadashide Crecy Lagard, ValerieMandt, Kathleen E.Syvanen, Michaelde La Escosura, Andr\u00e9sMartin, William F.Takai, Kende Vladar, Harold P.Maurel, Marie-christineTatarinova, Tatiana V.Deamer, DavidMayer, ChristianTessera, MarcDedon, PeterMeierhenrich, Uwe J.Tyystj\u00e4rvi, TainaDi Giulio, MassimoMichel, ChristianVan Doninck, KarineDoolittle, Russell F.Miller, Laurence G.Varfolomeev, Sergei D.Eichler, JerryMillet, OscarVolkovich, ZeewEkstig, B\u00f6rjeMoras, DinoWalde, PeterEngelhart, AaronMormile, MelanieWang, JunFederighi, MichelMulkidjanian, ArmenWideman, Jeremy G.Fournier, GregoryO\u2019Brien, EdwardWills, Peter R.Fox, GeorgeO'Donoghue, PatrickWolf, YuriGeisler, SarahOrengo, ChristineThe following reviewed for"} +{"text": "Insects would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.The editors of https://publons.com) to receive recognition. Of course, in these intiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make.We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons Way, M. O.Erlandson, MartinMurchie, ArchieWebb, Cameron E.Etges, WilliamNatsopoulou, Myrsini E.Weeks, EmmaEvenden, Maja L.Nayak, ManojWeetman, DavidFar\u00edas Franco, FernandoNeafsey, D. E.Whyard, SteveFeldhaar, HeikeNeoh, Kok-BoonWiggins, GregFerguson, ScottNewton, Irene L. G.Williams, ErnestFernandez-Grandon, G. MandelaOchoa, RonaldoWilusz, JeffreyFerrandon, DominiqueOg\u00f3rek, Rafa\u0142Witzgall, PeterFettig, ChrisOi, FaithWolf, StephanFields, PaulOliver, JasonXu, BaohuaFitzpatrick, SheilaOsbrink, WesteYang, Chiou-HerrFoster, StephenPalmeri, VincenzoYang, ShengFujimoto, IzumiPaluzzi, Jean-Paul V.Yano, EiziFunderburk, JoePappas, Maria L.Zalucki, MyronGangloff-Kaufman, JodyPark, YoonseongZettler, ErikGarc\u00eda, Josefa VelascoPeletto, SimoneZhang, GuanyangGasch, TinaPereira-Peixoto, Maria-HelenaZhang, Qing-heGeorge, DavidPeterson, RobertZhou, XuguoThe following reviewed for"} +{"text": "Previous name:3 Department of Cardiology, Guangdong General Hospital Zhuhai Hospital, Zhuhai, Guangdong, ChinaCurrent name:3 Department of Cardiology, Guangdong General Hospital Zhuhai Hospital , Zhuhai, Guangdong, China109762-109771. https://doi.org/10.18632/oncotarget.19034Original article: Oncotarget. 2017; 8:"} +{"text": "PAI\u20101) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI\u20101 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI\u20101 on CHD risk.Plasminogen activator inhibitor type 1 in an age\u2010 and sex\u2010adjusted model. The effect size was reduced in studies using a multivariable\u2010adjusted model . The Mendelian randomization analyses suggested a causal effect of increased PAI\u20101 level on CHD risk . In addition, we also detected a causal effect of PAI\u20101 on elevating blood glucose and high\u2010density lipoprotein cholesterol.To evaluate the association between PAI\u20101 level on CHD risk, which may be mediated by glucose dysfunction.Our study indicates a causal effect of elevated Plasminogen activator inhibitor type 1 (PAI\u20101) is the major inhibitor of the fibrinolytic system. It inhibits the effect of plasminogen activators, thereby inhibiting plasmin formation and downregulating breakdown of fibrin clots. PAI\u20101 deficiency caused by mutations has been reported to lead to a moderate bleeding disorder.However, the relationship between PAI\u20101 and early atherosclerosis and incident CHD remains unclear. Previous studies reported the correlation of PAI\u20101 with multiple conventional risk factors of CHD, eg, obesity, glycemic traits, and type 2 diabetes mellitus,SERPINE1, with PAI\u20101 and CHD risk was based on a meta\u2010analysis using published candidate gene studies between 1993 and 2010.To overcome these obstacles, epidemiological studies have adapted instrumental variable (IV) analysis to assess causality and to limit confounding through the use of single nucleotide polymorphisms (SNPs) as IV. This method is referred to as the Mendelian randomization (MR) approach.SERPINE1 gene locus, the coding gene region of PAI\u20101, on chr7q22.1. The lead SNP rs2227631 is in the promoter region of SERPINE1 and highly correlated with the well\u2010characterized functional variant 4G/5G SERPINE1 polymorphism (r2=0.78). Following conditional analysis for the lead SNP, a second independent signal (rs6976053) in the same chr7q22.1 locus was observed 200\u00a0kb upstream of rs2227631.In the largest genome\u2010wide association study (GWAS) for PAI\u20101 , the CHARGE Hemostatic Working Group reported 4 independent genetic variants from 3 loci .In this investigation, we aimed to understand whether plasma PAI\u20101 levels played a causal role in CHD risk. To achieve the goal, we first investigated the observational association between PAI\u20101 and CHD using a systematic meta\u2010analysis. We then explored the causal effect of PAI\u20101 on CHD using a MR approach. Finally, we further investigated the causal effect of PAI\u20101 on known cardiovascular risk factors, including metabolic risk factors and subclinical atherosclerosis measures .We applied a systematic review to understand the observational association of PAI\u20101 with CHD. An electronic literature search was conducted in PubMed by 2 researchers independently using the following criteria: (1) including \u201cCoronary heart disease\u201d or \u201cCoronary artery disease\u201d or \u201cMyocardial infarction\u201d; (2) including \u201cplasminogen activator inhibitor type 1\u201d; (3) published in English from January 1992 to April 2016; and (4) study in human subjects. Two reviewers independently performed the literature screen and found consistent results. In total, we found 1228 articles available in PubMed. There were 33 publications that reported an effect size of PAI\u20101 on CHD. To focus on association between PAI\u20101 and incident CHD, we excluded those studies that reported prevalent CHD (13 publications), recurrent CHD (5 publications), or stroke (1\u00a0publication). In addition, considering that the majority of publications reported the relative risk of CHD comparing the highest with the lowest quantile, we included only publications using categorical analyses of PAI\u20101. Ten studies that adjusted only for age and sex reported association between PAI\u20101 and CHD incidence Table\u00a0, while 1https://sb452.shinyapps.io/power/) for a PAI\u20101 IV (explaining 0.9% of variance).A genetic variant acts as an IV if it fulfils the following assumptions: 1) the genetic variant is associated with the exposure; and (2) the genetic variant can only influence the outcome through the exposure. the geneSERPINE1). In this step, we selected SNPs in this locus that were associated with PAI\u20101 (P<1\u00d710\u22126) and that were only moderately correlated with each other after iterative stepwise selection (r2<0.5 each round). The correlations between SNPs were obtained from the bioinformatics tool SNiPA using data from the 1000 Genomes phase 3, European reference population.P<5\u00d710\u22128). Four independent SNPs reported from the PAI\u20101 GWAS were used in the IV of blood PAI\u20101 levels is associated with higher risk of CHD incidence compared with the lowest quantile as IV are not simply driven by a single SNP. Similarly, Figure\u00a0Using variants in the SERPINE1 locus alone suggest that an increase of 1\u00a0unit of log\u2010transformed PAI\u20101 level increases circulating fasting glucose levels by 0.08\u00a0mmol/L and refuting (HDL\u2010C) causal links to CHD that mirror clinical trial results.SERPINE1 has been consistently reported to be a functional variant influencing PAI\u20101 expression.Serpine1, a mouse ortholog, creates PAI\u20101 deficiency.SERPINE1 locus SNPs as an IV.A key assumption for the MR approach is that genetic variants employed as the IV can only be associated with the outcome (CHD) through the biomarker (PAI\u20101). The causal effect of PAI\u20101 on CHD suggested by the MR approach should be interpreted under this assumption. In addition, further functional studies are required to understand the mechanism of the causal association between PAI\u20101 and CHD. As a protein biomarker, the genetic locus encoding the PAI\u20101 transcript has clear biological function in determining circulating PAI\u20101 levels. The 4G/5G polymorphism in the promoter region of Our study is the first evidence to suggest a causal association of PAI\u20101 on increased fasting glucose. This indicates PAI\u20101 may play a role in glucose regulation and is consistent with previous population studies that reported positive correlations between circulating PAI\u20101 and glucose levels.Somewhat surprisingly, when addressing the causal effect of PAI\u20101 on measurements of obesity, we find negative trend effects of PAI\u20101 on BMI and waist\u2013hip ratio. Adipose tissue is one of the main tissues expressing PAI\u20101, and population studies have consistently shown positive correlations between circulating PAI\u20101 levels and BMI.SRB1) raises HDL\u2010C and increases CHD risk.Our results suggest a further positive causal effect of PAI\u20101 on HDL\u2010C, which is inconsistent with observational associations in the population study.There are several limitations of the current study. Since we used summary GWAS statistics in the current study, we were unable to address stratified analysis questions such as whether there is a sex or age difference in the PAI\u20101\u2010CHD link, or whether the effect of PAI\u20101 on CHD differs among obese individuals versus nonobese individuals. These are interesting questions for future studies. In addition, our reported observational meta\u2010analysis between PAI\u20101 and CHD is based on PAI\u20101 quantiles, while the causal association is based on log\u2010transformed PAI\u20101 units; therefore, the effect size of PAI\u20101 on CHD in these 2 sets of analysis is not directly comparable.In summary, we applied several approaches to understand the role of PAI\u20101 in CHD. Our results through several analyses support a causal effect of PAI\u20101 on CHD onset, potentially mediated by blood glucose dysfunction. Furthermore, our results and those of others suggest that PAI\u20101 may be interlocked with obesity, and potentially HDL\u2010C in complex feedback relationships. Our study adds to evidence on the role of PAI\u20101 in pathogenesis of CHD and suggests this pathway may be a good target for CHD treatment.Jie Huang, Maria Sabater\u2010Lleal, Folkert W. Asselbergs, David Tregouet, So\u2010Youn Shin, Jingzhong Ding, Jens Baumert, Tiphaine Oudot\u2010Mellakh, Lasse Folkersen, Andrew D. Johnson, Nicholas L. Smith, Scott M. Williams, Mohammad A. Ikram, Marcus E. Kleber, Diane M. Becker, Vinh Truong, Josyf C. Mychaleckyj, Weihong Tang, Qiong Yang, Bengt Sennblad, Jason H. Moore, Frances M. K. Williams, Abbas Dehghan, G\u00fcnther Silbernagel, Elisabeth M. C. Schrijvers, Shelly Smith, Mahir Karakas, Geoffrey H. Tofler, Angela Silveira, Gerjan J. Navis, Kurt Lohman, Ming\u2010Huei Chen, Annette Peters, Anuj Goel, Jemma C. Hopewell, John C. Chambers, Danish Saleheen, Per Lundmark, Bruce M. Psaty, Rona J. Strawbridge, Bernhard O. Boehm, Angela M. Carter, Christa Meisinger, John F. Peden, Joshua C. Bis, Barbara McKnight, John \u00d6hrvik, Kent Taylor, Maria Grazia Franzosi, Udo Seedorf, Rory Collins, Anders Franco\u2010Cereceda, Ann\u2010Christine Syv\u00e4nen, Alison H. Goodall, Lisa R. Yanek, Mary Cushman, Martina M\u00fcller\u2010Nurasyid, Aaron R. Folsom, Saonli Basu, Nena Matijevic, Wiek H. van Gilst, Jaspal S. Kooner, Albert Hofman, John Danesh, Robert Clarke, James B. Meigs, Sekar Kathiresan, Muredach P. Reilly, Norman Klopp, Tamara B. Harris, Bernhard R. Winkelmann, Peter J. Grant, Hans L. Hillege, Hugh Watkins, Timothy D. Spector, Lewis C. Becker, Russell P. Tracy, Winfried M\u00e4rz, Andre G. Uitterlinden, Per Eriksson, Francois Cambien, Pierre\u2010Emmanuel Morange, Wolfgang Koenig, Nicole Soranzo, Pim van der Harst, Yongmei Liu, Christopher J. O'Donnell, and Anders Hamsten.Georg B. Ehret, Patricia B. Munroe, Kenneth M. Rice, Murielle Bochud, Andrew D. Johnson, Daniel I. Chasman, Albert V. Smith, Martin D. Tobin, Germaine C. Verwoert, Shih\u2010Jen Hwang, Vasyl Pihur, Peter Vollenweider, Paul F. O'Reilly, Najaf Amin, Jennifer L. Bragg\u2010Gresham, Alexander Teumer, Nicole L. Glazer, Lenore Launer, Jing Hua Zhao, Yurii Aulchenko, Simon Heath, Siim S\u00f5ber, Afshin Parsa, Jian'an Luan, Pankaj Arora, Abbas Dehghan, Feng Zhang, Gavin Lucas, Andrew A. Hicks, Anne U. Jackson, John F. Peden, Toshiko Tanaka, Sarah H. Wild, Igor Rudan, Wilmar Igl, Yuri Milaneschi, Alex N. Parker, Cristiano Fava, John C. Chambers, Ervin R. Fox, Meena Kumari, Min Jin Go, Pim van der Harst, Wen Hong Linda Kao, Marketa Sj\u00f6gren, D. G. Vinay, Myriam Alexander, Yasuharu Tabara, Sue Shaw\u2010Hawkins, Peter H. Whincup, Yongmei Liu, Gang Shi, Johanna Kuusisto, Bamidele Tayo, Mark Seielstad, Xueling Sim, Khanh\u2010Dung Hoang Nguyen, Terho Lehtim\u00e4ki, Giuseppe Matullo, Ying Wu, Tom R. Gaunt, N. Charlotte Onland\u2010Moret, Matthew N. Cooper, Carl G. P. Platou, Elin Org, Rebecca Hardy, Santosh Dahgam, Jutta Palmen, Veronique Vitart, Peter S. Braund, Tatiana Kuznetsova, Cuno S. P. M. Uiterwaal, Adebowale Adeyemo, Walter Palmas, Harry Campbell, Barbara Ludwig, Maciej Tomaszewski, Ioanna Tzoulaki, Nicholette D. Palmer, Thor Aspelund, Melissa Garcia, Yen\u2010Pei C. Chang, Jeffrey R. O'Connell, Nanette I. Steinle, Diederick E. Grobbee, Dan E. Arking, Sharon L. Kardia, Alanna C. Morrison, Dena Hernandez, Samer Najjar, Wendy L. McArdle, David Hadley, Morris J. Brown, John M. Connell, Aroon D. Hingorani, Ian N. M. Day, Debbie A. Lawlor, John P. Beilby, Robert W. Lawrence, Robert Clarke, Jemma C. Hopewell, Halit Ongen, Albert W. Dreisbach, Yali Li, J. Hunter Young, Joshua C. Bis, Mika K\u00e4h\u00f6nen, Jorma Viikari, Linda S. Adair, Nanette R. Lee, Ming\u2010Huei Chen, Matthias Olden, Cristian Pattaro, Judith A. Hoffman Bolton, Anna K\u00f6ttgen, Sven Bergmann, Vincent Mooser, Nish Chaturvedi, Timothy M. Frayling, Muhammad Islam, Tazeen H. Jafar, Jeanette Erdmann, Smita R. Kulkarni, Stefan R. Bornstein, J\u00fcrgen Gr\u00e4ssler, Leif Groop, Benjamin F. Voight, Johannes Kettunen, Philip Howard, Andrew Taylor, Simonetta Guarrera, Fulvio Ricceri, Valur Emilsson, Andrew Plump, In\u00eas Barroso, Kay\u2010Tee Khaw, Alan B. Weder, Steven C. Hunt, Yan V. Sun, Richard N. Bergman, Francis S. Collins, Lori L. Bonnycastle, Laura J. Scott, Heather M. Stringham, Leena Peltonen, Markus Perola, Erkki Vartiainen, Stefan\u2010Martin Brand, Jan A. Staessen, Thomas J. Wang, Paul R. Burton, Maria Soler Artigas, Yanbin Dong, Harold Snieder, Xiaoling Wang, Haidong Zhu, Kurt K. Lohman, Megan E. Rudock, Susan R. Heckbert, Nicholas L. Smith, Kerri L. Wiggins, Ayo Doumatey, Daniel Shriner, Gudrun Veldre, Margus Viigimaa, Sanjay Kinra, Dorairaj Prabhakaran, Vikal Tripathy, Carl D. Langefeld, Annika Rosengren, Dag S. Thelle, Anna Maria Corsi, Andrew Singleton, Terrence Forrester, Gina Hilton, Colin A. McKenzie, Tunde Salako, Naoharu Iwai, Yoshikuni Kita, Toshio Ogihara, Takayoshi Ohkubo, Tomonori Okamura, Hirotsugu Ueshima, Satoshi Umemura, Susana Eyheramendy, Thomas Meitinger, H.\u2010Erich Wichmann, Yoon Shin Cho, Hyung\u2010Lae Kim, Jong\u2010Young Lee, James Scott, Joban S. Sehmi, Weihua Zhang, Bo Hedblad, Peter Nilsson, George Davey Smith, Andrew Wong, Narisu Narisu, Alena Stan\u010d\u00e1kov\u00e1, Leslie J. Raffel, Jie Yao, Sekar Kathiresan, Christopher J. O'Donnell, Stephen M. Schwartz, M. Arfan Ikram, W. T. Longstreth Jr, Thomas H. Mosley, Sudha Seshadri, Nick R. G. Shrine, Louise V. Wain, Mario A. Morken, Amy J. Swift, Jaana Laitinen, Inga Prokopenko, Paavo Zitting, Jackie A. Cooper, Steve E. Humphries, John Danesh, Asif Rasheed, Anuj Goel, Anders Hamsten, Hugh Watkins, Stephan J. L. Bakker, Wiek H. van Gilst, Charles S. Janipalli, K. Radha Mani, Chittaranjan S. Yajnik, Albert Hofman, Francesco U. S. Mattace\u2010Raso, Ben A. Oostra, Ayse Demirkan, Aaron Isaacs, Fernando Rivadeneira, Edward G. Lakatta, Marco Orru, Angelo Scuteri, Mika Ala\u2010Korpela, Antti J. Kangas, Leo\u2010Pekka Lyytik\u00e4inen, Pasi Soininen, Taru Tukiainen, Peter W\u00fcrtz, Rick Twee\u2010Hee Ong, Marcus D\u00f6rr, Heyo K. Kroemer, Uwe V\u00f6lker, Henry V\u00f6lzke, Pilar Galan, Serge Hercberg, Mark Lathrop, Diana Zelenika, Panos Deloukas, Massimo Mangino, Tim D. Spector, Guangju Zhai, James F. Meschia, Michael A. Nalls, Pankaj Sharma, Janos Terzic, M. V. Kranthi Kumar, Matthew Denniff, Ewa Zukowska\u2010Szczechowska, Lynne E. Wagenknecht, F. Gerald R. Fowkes, Fadi J. Charchar, Peter E. H. Schwarz, Caroline Hayward, Xiuqing Guo, Charles Rotimi, Michiel L. Bots, Eva Brand, Nilesh J. Samani, Ozren Polasek, Philippa J. Talmud, Fredrik Nyberg, Diana Kuh, Maris Laan, Kristian Hveem, Lyle J. Palmer, Yvonne T. van der Schouw, Juan P. Casas, Karen L. Mohlke, Paolo Vineis, Olli Raitakari, Santhi K. Ganesh, Tien Y. Wong, E. Shyong Tai, Richard S. Cooper, Markku Laakso, Dabeeru C. Rao, Tamara B. Harris, Richard W. Morris, Anna F. Dominiczak, Mika Kivimaki, Michael G. Marmot, Tetsuro Miki, Danish Saleheen, Giriraj R. Chandak, Josef Coresh, Gerjan Navis, Veikko Salomaa, Bok\u2010Ghee Han, Xiaofeng Zhu, Jaspal S. Kooner, Olle Melander, Paul M. Ridker, Stefania Bandinelli, Ulf B. Gyllensten, Alan F. Wright, James F. Wilson, Luigi Ferrucci, Martin Farrall, Jaakko Tuomilehto, Peter P. Pramstaller, Roberto Elosua, Nicole Soranzo, Eric J. G. Sijbrands, David Altshuler, Ruth J. F. Loos, Alan R. Shuldiner, Christian Gieger, Pierre Meneton, Andre G. Uitterlinden, Nicholas J. Wareham, Vilmundur Gudnason, Jerome I. Rotter, Rainer Rettig, Manuela Uda, David P. Strachan, Jacqueline C. M. Witteman, Anna\u2010Liisa Hartikainen, Jacques S. Beckmann, Eric Boerwinkle, Ramachandran S. Vasan, Michael Boehnke, Martin G. Larson, Marjo\u2010Riitta J\u00e4rvelin, Bruce M. Psaty, Gon\u00e7alo R. Abecasis, Aravinda Chakravarti, Paul Elliott, Cornelia M. van Duijn, Christopher Newton\u2010Cheh, Daniel Levy, Mark J. Caulfield and Toby Johnson.Aad van der Lugt, Aaron Isaacs, Abbas Dehghan, Afshin Parsa, Alan R. Shuldiner, Albert Hofman, Albert V. Smith, Aldi T. Kraja, Andre G. Uitterlinden, Andre Uitterlinden, Andreas Ziegler, Andrew D. Johnson, Angelo Scuteri, Anne B. Newman, Arne Schillert, Benjamin F. Voight, Ben Oostra, Bolli Thorsson, Braxton D. Mitchell, Bruce M. Psaty, Caroline Hayward, Caroline S. Fox, Charles C. White, Christa Meisinger, Christie Ballantyne, Christopher J. O'Donnell, Cornelia van Duijn, David Altshuler, David M. Herrington, Daniel H. O'Leary, David S. Siscovick, David J. Couper, Edward G. Lakatta, Eran Halperin, Eric Boerwinkle, Eva\u2010Maria Stoegerer, Fernando Rivadeneira, Florian Ernst, Gabriel P. Krestin, Georg Homuth, Gerardo Heiss, Gianluca Usala, Gon\u00e7alo R. Abecasis, Gudny Eiriksdottir, Haiqing Shen, H. Erich Wichmann, Helena Schmidt, Henry V\u00f6lzke, Ingrid B. Borecki, Hugh S. Markus, Jacqueline Witteman, James F. Wilson, Jan L\u00fcdemann, Jeffrey R. O'Connell, Jennifer E. Huffman, Jens Baumert, Jerome I. Rotter, Joanne M. Murabito, Joachim Thiery, Jochen Seissler, Jorma Viikari, Joseph M. Massaro, Joseph F. Polak, Julie Cunningham, Joshua C. Bis, Kari North, Katja E. Petrovic, Kenneth Rice, Kent Taylor, L. Adrienne Cupples, Lawrence F. Bielak, Leena Peltonen, Lenore J. Launer, Mariza de Andrade, Manuela Uda, Marco Orru, Marcus D\u00f6rr, Mary F. Feitosa, Maryam Kavousi, Matthias Sitzer, Matthijs Oudkerk, Michael A. Province, Michael Nalls, Mika K\u00e4h\u00f6nen, Muredach P. Reilly, Nicole L. Glazer, Nora Franceschini, Norman Klopp, Olli Raitakari, Patricia A. Peyser, Philip A. Wolf, Qunyuan Zhang, Philipp S. Wild, Renate B. Schnabel, Roberto Elosua, Ralph B. D'Agostino Sr, Ravi Kumar Chilukoti, Reinhold Schmidt, Renate B. Schnabel, Sekar Kathiresan, Serena Sanna, Sharon L. R. Kardia, Shih\u2010Jen Hwang, Serkalem Demissie, Sigurdur Sigurdsson, Stephen M. Schwartz, Stefan Blankenberg, Steve Bevan, Suzette E. Elias\u2010Smale, Susan R. Heckbert, Tamara B. Harris, Tanja Zeller, Terho Lehtim\u00e4ki, Thomas Illig, Thomas M\u00fcnzel, Thor Aspelund, Timothy D. Howard, Udo Hoffmann, Ulf Schminke, Veikko Salomaa, Vijay Nambi, Vilmundur Gudnason, Yongmei Liu, Yan V. Sun, Wendy S. Post, Wolfgang Koenig, Wolfgang Rathmann, Xia Li and Yu\u2010Ching Cheng.This work was supported by NHLBI Intramural funds to O'Donnell and Johnson. Stephen Burgess is supported by a fellowship from the Wellcome Trust (100114).None.Data S1.Table\u00a0S1. Publications Included in the Observational Meta\u2010AnalysisTable\u00a0S2. SNPs Involved in the Genetic Risk Scores as Instrumental Variable for PAI\u20101Table\u00a0S3. Causal Effect of BMI on PAI\u20101Click here for additional data file."} +{"text": "Necrophagous blowflies can provide an excellent source of evidence for forensic entomologists and are also relevant to problems in public health, medicine, and animal health. However, access to useful information about these blowflies is constrained by the need to correctly identify the flies, and the poor availability of reliable, accessible identification tools is a serious obstacle to the development of forensic entomology in the majority of African countries. In response to this need, a high-quality key to the adults of all species of forensically relevant blowflies of Africa has been prepared, drawing on high-quality entomological materials and modern focus-stacking photomicroscopy. This new key can be easily applied by investigators inexperienced in the taxonomy of blowflies and is made available through a highly accessible online platform. Problematic diagnostic characters used in previous keys are discussed.The online version of this article (doi:10.1007/s00414-017-1654-y) contains supplementary material, which is available to authorized users. The correct identification of necrophagous blowflies is pivotal to their use as evidence in forensic entomology and is aAfrica is home to over a dozen species of necrophagous blowflies, several of which are found on other continents too , 6. The Chrysomya, keys, if available, do not cover the fauna of the whole continent and often are poorly illustrated Eyes of male with sharply demarcated and strikingly large upper facets Fig. d; frontoDistribution: Burkina Faso, Central African Republic, Egypt, DR Congo, Kenya, Mali, Namibia, Nigeria, Rwanda, Senegal, Somalia, South Africa, Sudan, Tanzania, Zimbabwe.Eyes of male without demarcation between dorsal and ventral facets; fronto-orbital plate in female dark at least in upper part Fig. b, c ....7.Chrysomya laxifrons Eyes of male widely separated, frons at its narrowest point measuring 0.5 or more times eye width; frons of female subparallel, fronto-orbital plate with upper part black and lower part bright, reddish Fig. b .......Distribution: Cameroon, Central African Republic, DR Congo, Equatorial Guinea, Namibia, Sierra Leone, South Africa, Sudan, Tanzania, Togo, Uganda, Zimbabwe.Chrysomya inclinata Eyes of male touching Dorsal surface of thorax shining green with little, evenly distributed dusting; gena reddish-yellowish in ground colour Fig. h; lower Distribution: Algeria, Angola, Benin, Botswana, Burkina Faso, Burundi, Cameroon, Central African Republic, Congo, DR Congo, Djibouti, Egypt, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Guinea, Ivory Coast, Kenya, Lesotho, Liberia, Libya, Malawi, Mali, Mauritania, Morocco, Mozambique, Namibia, Niger, Nigeria, Rwanda, Senegal, Sierra Leone, Somalia, South Africa, Sudan, Swaziland, Tanzania, Togo, Tunisia, Uganda, Western Sahara, Zambia, Zimbabwe. The most common necrophagous blowfly in Africa.Dorsal surface of thorax with conspicuous whitish dusting, forming characteristic patterns of dusted and undusted surfaces Fig. j, k; gen9.Chrysomya chloropyga Presutural area of thorax with conspicuous black L-shaped marking on each side of midline, strongly white-dusted median vitta proceeding forwards from suture to front of thorax Fig. j; abdomeDistribution: Angola, Benin, Botswana, Burkina Faso, Burundi, Cameroon, Central African Republic, Congo, DR Congo, Djibouti, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Guinea, Ivory Coast, Kenya, Lesotho, Liberia, Malawi, Mali, Mauritania, Mozambique, Namibia, Niger, Nigeria, Rwanda, Senegal, Sierra Leone, Somalia, South Africa, Sudan, Tanzania, Togo, Uganda, Zambia, Zimbabwe.Chrysomya putoria Presutural area of thorax without conspicuous paired L-shaped markings, but with vague lateral dark spots, white-dusted median vitta extending forwards hardly halfway to front of thorax Fig. k; abdomeDistribution: Benin, Botswana, Burkina Faso, Cameroon, Central African Republic, DR Congo, Gambia, Ghana, Guinea, Eritrea, Ethiopia, Ivory Coast, Kenya, Malawi, Mali, Mozambique, Namibia, Senegal, South Africa, Sudan, Swaziland, Tanzania, Uganda, Zambia, Zimbabwe.10.Calliphora vicina [=C. erythrocephala ]Anterior part of genal dilation yellow to orange Fig. a; basicoMorocco, South Africa. Possibly occur in all countries of North Africa.Distribution: Algeria, Egypt, Anterior part of genal dilation uniformly black Fig. b, c; bas11.Calliphora vomitoria Hairs on genal dilation and postgena orange Fig. b, anteriMorocco. Erzin\u00e7lio\u011flu (1987) gives general information \u201cNorth Africa\u201d. Probably distributed in mountainous areas of North Africa.Distribution: Calliphora croceipalpis Jaennicke, 1867Hairs on genal dilation and postgena predominantly black Fig. c; anteriDistribution: DR Congo, Eritrea, Ethiopia, Malawi, Rwanda, South Africa, Tanzania, Zimbabwe. Widespread from East to South Africa .12.Katatergite Metasternal area setose; posterior slope of humeral callus with 6\u20138 hairs Fig. m; surfacDistribution: Algeria, Egypt, Lesotho, Libya, Mozambique, Namibia, South Africa, Zimbabwe. Possible occurrence in all countries of the North Africa.Lucilia cuprina Metasternal area bare; posterior slope of humeral callus with 0\u20134 hairs Fig. n; surfacDistribution: Botswana, Cameroon, DR Congo, Ethiopia, Kenya, Lesotho, Liberia, Malawi, Mozambique, Namibia, Rwanda, Senegal, Somalia, South Africa, Tanzania, Togo, Uganda, Zimbabwe. Widespread in the Afrotropical Region .15.Hemipyrellia pulchra Third antennal segment bright orange Fig. l; eyes iDistribution: Egypt, Mozambique, Nigeria, Sudan. Widespread West to East Africa .Hemipyrellia fernandica Third antennal segment dark Fig. k; in malBenin, Botswana, Burundi, Cameroon, Central African Republic, Democratic Republic of Congo, Gabon, Gambia, Ghana, Ivory Coast, Liberia, Malawi, Mozambique, Namibia, Nigeria,? Senegal, South Africa, Sudan, Tanzania, Togo, Zimbabwe. Widespread in the Afrotropical Region [Distribution: l Region .Ch. inclinata, Ch. laxifrons, L. infernalis, H. pulchra, H. fernandica) and one obligate parasite of vertebrates (Ch. bezziana) that might affect some forensic cases.*The list of species of forensic importance was prepared for regions with well-studied faunas, usually based on information from human forensic cases or ecological succession studies of large-bodied carrion , 37, 38.Studies on regional African necrophagous faunas are scarce , 38 and L. cuprina and L. sericata and their possible hybrids, which has fortunately been deeply studied [The morphology and taxonomy of adult forms of common necrophagous blowflies is relatively well known, both worldwide and for African species , 30, 32. studied \u201359, espeCalliphora croceipalpis and C. vicina have never been put together in one key dedicated to adult forms [lt forms , 23, 24.lt forms , 6, 60 aChrysomya may also be confusing. In Ch. inclinata, Ch. laxifrons, and Ch. marginalis, the black veins and membrane of the margin of mature adults are obvious, easily observed, and quickly separate these species from other members of the genus, which lack pigment or, in some specimens of Ch. putoria . It is important to mention that two rare East African montane species with a darkened anterior wing margin are not included in the present key: it is likely but not yet certain that Ch. polymita (Villeneuve 1914) and Ch. vanemdeni (Zumpt 1953) breed in carrion [The darkened anterior wing margin in su Zumpt , 23), ha carrion , 30. The carrion .C. croceipalpis), \u201c\u2026 widespread Afrotrop. Reg.\u201d (H. fernandica), or \u201c\u2026 widespread mainland Afrotropical Region\u201d . On the other hand, Verves [Ch. albiceps, Ch. chloropyga, Ch. megacephala, L. infernalis, and H. fernandica) without any mention of the source of this information . Additi putoria , informanal data , 34. GenThis key will assist entomologists on the African continent to use flies in forensic cases and push forward the use of forensic entomology in Africa, as well as the fields of public health and human and veterinary medicine. Further taxonomic research should focus on the alternative morphological methods of identification of adult flies , 62 and ESM 1(PDF 865\u00a0kb)"} +{"text": "Biomedicines would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016. The editors of https://publons.com) to receive recognition. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make. We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (Biomedicines, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Biomedicines in 2016:Abba, KatharineGonz\u00e1lez, V\u00edctor M.Quintarelli, ConcettaAlemany, RamonGunnarsson, AndersRabkin, Samuel DavidAndrianasolo, EricHanson, Robert N.Ram\u00edrez, ManuelAntignani, AntonellaHingorani, DinaRein, AlanArens, RamonHirata, KenjiRovero, PaoloAtkins, Gregory J.Hu, JinmingSamal, SibaBarbieri, FedericaJayant, Rahul DevSchwartz, Jean\u2013LouisBaum, Richard P.Jordan, V. CraigSerda, Rita ElenaBerkhout, BenKasoju, NareshSeymour, Len W.Borlak, J\u00fcrgenKobe, CarstenSherker, Averell H.Busardo, FrancescoKuehnel, FlorianSikora, AndrewCall, MindyKunjachan, SijumonSmerdou, CristianCapasso, RaffaeleLaFace, DrakeSousa, C\u00e9lia T.Casco-Robles, Martin M.Layer, Paul G.Tai, Dar-FuCerullo, VincenzoLeporatti, StefanoTa\u00efeb, DavidChuburu, Fran\u00e7oiseLeung, Chung-HangTanner, Julian A.Chudasama, VijayLi, QingliangTatullo, MarcoCornetta, KennethL\u00f6chelt, MartinV\u00e4h\u00e4-Koskela, MarkusCostantino, LucaLorenzi, VanninaValable, SamuelCrickmore, NeilLoskog, AngelicaVan Den Wollenberg, Diana J. M.Cripe, Timothy P.Lundstrom, KennethVankemmelbeke, MireilleDamour, OdileMacNeill, AmyVassilopoulos, GeorgeDas, SoumenMcfadyen, MoragVillalona-Calero, MiguelDavila, Marco L.Michel, Martin C.Wan, YonghongDelville, Marie-H\u00e9l\u00e8neMirsayar, MirMiladWu, LianfengDingermann, TheodorNakagawa, YoshimiWujcik, EvanDonnelly, OliverNelson, Delia J.Yamada, AkiraGanesan, A.Nu\u00f1o, NataliaYan, GuangmeiGarc\u00eda-Mart\u00edn, Mar\u00eda L.Phyo, Aung PyaeZhou, Heshan SamGirb\u00e9s, Tom\u00e1sPuddu, Paolo EmilioThe following reviewed for"} +{"text": "AbstractClinocerinae and 10 species in subfamily Hemerodromiinae) from the territory of Greece are summarized, including previously unpublished data and data on five newly described species . The new species are described and illustrated, the male terminalia of Clinoceramegalatlantica (Vaillant) are illustrated and the distributions of all species within Greece are listed. The aquatic Empididae fauna of Greece consists of 47 species, with the following described species reported for the first time: Cheliferaangusta Collin, Hemerodromiamelangyna Collin, Clinoceramegalatlantica, Kowarziaplectrum (Mik), Phaeobaliadimidiata (Loew), W. (Chamaedipsia) beckeri (Mik), W. (Philolutra) angelieri Vaillant and W. (P.) chvali Joost. A key to species of aquatic Empididae of Greece is provided for the first time. Information related to the European Ecoregions in which species were found is given. Compared to the other studied countries in the Balkans, the Greek species assemblage is most similar to that of the Former Yugoslav Republic of Macedonia.All records of aquatic dance flies (37 species in subfamily Empididae (Diptera) comprise the subfamilies Clinocerinae and Hemerodromiinae. Larvae mostly live in aquatic habitats and both larvae and adults are predators, primarily feeding on Simuliidae . For the purpose of determination, male terminalia were dissected, boiled in 10% KOH and afterwards neutralized with acetic acid, rinsed in water and identified to species level; or they were macerated in hot 85% lactic acid and stored in 80% ethanol along with the remaining body parts in the same tube. In the genitalia illustrations, only the sockets of the setae are shown on the epandrium; the setae are not drawn. All specimens listed in the material examined sections were collected by Bogdan Horvat, Ignac Sivec, Hans Malicky and Reinhard Gerecke. Taxonomic diversity is considered at the level of subfamily, genus, subgenus and species. The European Ecoregions are those of Limnofauna Europaea ; col. M. Ivkovi\u0107, University of Zagreb, Croatia (UZC); col. Empididae, Slovenian Museum of Natural History, Ljubljana, Slovenia (SMNH). Terms used for adult structures primarily follow those of 1 (as used in 1 (of McAlpine) is termed M4, whereas CuA2 is CuA, the anal cell is cell cua and the anal vein (A1+CuA2) is CuA+CuP. Homologies of the male terminalia follow those of Wiedemannia described herein will not be assigned to a subgenus because we consider current subgeneric concepts confused and mostly not monophyletic . Additional information is included in square brackets. The repository of each type is given in parentheses. Secondary type data are abridged and listed alphabetically. This study is based on material housed in the following institutions: phyletic .Data analysis. A list of species was compiled from all specimen data .Wiedemannia is distinguished by the apically pointed unilobed cercus with small basal projection and a narrow pterostigma on the wings.This species of Male. Body length approx. 3.5 mm (holotype dissected prior to measurement), wing length 3.7 mm . Head in lateral view higher than long; gena narrow, nearly one-third height of eye. Frons short, broader than face. Face wide, with distinct carina on lower margin, bare, lacking setae. One pair of ocellar and one pair of vertical setae; about 5 distinct upper postoculars, subequal in size; lower postocular setae finer and merging PageBreakPageBreakwith longer setae on middle and lower occiput; many setulae present on vertex and between ocellar area. Antenna brownish; postpedicel and stylus minutely pubescent; pedicel slightly longer than scape; scape with complete circlet of subapical setae; postpedicel apically pointed; stylus nearly twice length of postpedicel; scape with setulae dorsally.PageBreaknd dorsocentral seta; 1 strong postpronotal seta and 1\u20134 short setulae; 2 notopleural setae and several setulae; 1 presutural supra-alar seta and many small anterior setulae; 1 postalar seta. Antepronotum with 1 pair of strong setae and 1 pair of smaller setae. Proepisternum with some fine setulae. Laterotergite with several fine, pale setulae. One pair of strong marginal scutellar setae; disc without setae.Scutum with pale central vitta between dorsocentral rows. Mesonotum with 5 dorsocentral setae, with short setulae intermixed. Acrostichal setae small and fine, biserial, extending to 21 and M2 with long stem vein proximal to M1+2 fork. CuA+CuP not visible. Pterostigma elongate, faint. Squama with setulae. Halter pale.Wing membrane clear, veins darker; 1 long basal costal seta, extending almost to humeral crossvein. Cell dm produced anteroapically. MLegs brownish; fore femur with two stronger anterior setae on apical fourth; uniformly covered with rows of small dark setulae. All coxae with longer setae anteriorly; fore coxae with several erect setae. Fore and mid femora ventrally with some longer setulae on proximal half, some longer than width of segment.Abdomen covered in small setae. Terminalia Figs , 7: hypaFemale. Unknown.The species is named after the Greek mythology character Iphigenia, the priestess of the Greek Goddess Artemis.Wiedemanniaiphigeniae sp. n. is known only from the type locality in Greece. The shape of the clasping cercus is similar to that of W.aerea Vaillant, 1967 (Pyrenees), but a distinct basal projection is lacking in the latter species.Taxon classificationAnimaliaDipteraEmpididaeIvkovi\u0107 & Sinclairsp. n.http://zoobank.org/F9A07ACC-BB76-4D11-8736-FDD2414413B739\u00b032'00\"N, 20\u00b012'00\"E.Greece: Epirus, Igoumenitsa, River Thiamis, Soulopoulo, Holotype \u2642 (in 80% ethanol), labelled: \u201cHOLOTYPE/ Wiedemannia// ljerkae IVKOVI\u0106 et SINCLAIR// GREECE, Epirus,/ Igoumenitsa, R. Thiamis,/ Soulopoulo// 39\u00b032'00\"N, 20\u00b012'00\"E, 30.iv.1989,/ leg. B. Horvat, I. Sivec\u201d (UZC). Paratypes: same data as holotype ; 2 \u2642, 16 \u2640, SMNH).GREECE: Central Greece, Etolia, Peristera, Agrinio, 1 km S of Perkos, 300 m, 38\u00b038'00\"N, 21\u00b045'00\"E, 24.iv.1990 (SMNH); Peloponnese, Kato PageBreakKlitoria, 450 m, 37\u00b050'00\"N, 22\u00b010'00\"E, 20.iv.1990 (SMNH); Peloponnisos, R. Kratis, 7 km N of Peristera, 600 m, 38\u00b005'00\"N, 22\u00b014'00\"E, 22.iv.1990 (SMNH); Peloponnese, Aroania Mts., Kastria, 21.iv.1990 (UZC).Wiedemannia is distinguished by the cercus with two long finger-like processes and a rounded pterostigma on the wings.This species of Male. Body length 3.5\u20134.5 mm, wing length 4.0\u20134.3 mm . Head and W.tricuspidata (see 905) see , 1940.Taxon classificationAnimaliaDipteraEmpididaeIvkovi\u0107 & Sinclairsp. n.http://zoobank.org/61BC89BA-016F-43BC-A59F-BA5B5259EAD941\u00b024'24\"N, 24\u00b037'19\"E, 1400 m.Greece: Thrace, north of Dipotama, Holotype \u2642, labelled: \u201cGREECE: Thrace/ N of Dipotama/ 41\u00b024'24\"N, 24\u00b037'19\"E/ 23.v.1994; 1400 m/ leg. B. Horvat, I. Sivec\u201d; \u201cHOLOTYPE/ Wiedemannia/ nebulosa/ Ivkovi\u0107 & Sinclair\u201d . Paratypes: same data as holotype .Wiedemannia is distinguished by the faint clouding about crossveins and base of radial fork, shape of the clasping cercus and position of distiphallus on the phallic shaft.This species of Male. Body length 3.8\u20134.5 mm, wing length 5.2\u20135.3 mm . Head dark with brown frons and vertex, remainder of head with blue pruinescence; head higher than long; gena narrow, one-quarter height of eye. Frons short, broader than face. Face wide, with distinct carina on lower margin, bare, lacking setae. One pair of long ocellar setae and one pair of vertical setae; 6\u20137 distinct upper postoculars; lower postocular setae finer and merging with longer setae on middle and lower occiput; a few small setulae present on vertex and in ocellar area. Antenna brown; postpedicel and stylus minutely pubescent; scape longer than pedicel, with setulae dorsally; pedicel with complete circlet of apical setae; postpedicel apically pointed; stylus twice length of postpedicel.PageBreakseta. Antepronotum with 1 pair of strong setae. Proepisternum with some fine setulae. Katepisternum without setulae. Laterotergite with fine, pale setae. One pair of strong marginal scutellar setae; disc bare.Scutum dark brown with pair of faint black vittae between dorsocentral row and acrostichals and bluish stripe medially; prescutellar depression with blue pruinescence. Pleura clothed with blue pruinescence. Mesonotum with 5 pairs of dorsocentral setae without short setulae interspersed. Acrostichal setae short and fine, biserial, extending onto prescutellar depression; 1 strong postpronotal seta; 2 notopleural setae and several short setae; 1 presutural supra-alar seta and several small anterior setulae; 1 postalar 1 and M2 originating separately from cell dm. CuA+CuP in form of short streak. Pterostigma broad and elongate, very distinct. Squama with setulae. Halter yellowish brown.Wing membrane infuscate with darkening at apex of cell dm, radial fork and r-m crossvein; veins darker; 1 short basal costal seta ending before humeral crossvein. Cell dm produced anteroapically. MLegs mostly brown; fore femur with 2\u20133 strong anterior setae on apical quarter; uniformly covered with rows of small dark setulae. All coxae with longer setae anteriorly; fore coxa with 1\u20132 erect setae. Fore and mid femora ventrally with some longer setulae on proximal half.Abdomen concolourous with thorax, covered in short setae. Pruinescence darker on tergites than sternites. Terminalia Fig. : hypandrFemale. Similar to male. Terminalia: cercus short ovate and minutely pilose.nebulosus , in reference to the clouding about the crossveins.The species name is derived from the Latin Wiedemannianebulosa sp. n. is known only from the type locality in Greece. On the basis of the shape of the clasping cercus, this new species is similar to W.carpathica Vaillant, 1967 (eastern Carpathians), W.pyrenaica Vaillant, 1967 (Pyrenees) and perhaps W.wachtli .Taxon classificationAnimaliaDipteraEmpididaeIvkovi\u0107 & Sinclairsp. n.http://zoobank.org/BD1AFAB9-06BD-4BEC-A08F-F3D80E8FAFE038\u00b023'N, 21\u00b051'E.Greece: Etolia, River Mornos, Nafpaktos, Holotype \u2642 (in 80% ethanol), labelled: \u201cHOLOTYPE/ Wiedemannia// pseudoberthelemyi IVKOVI\u0106// et SINCLAIR/, GREECE, Etolia,// River Mornos,/ Nafpaktos,/ 38\u00b023'N, 21\u00b051'E, 23.iv.1990,// leg. B. Horvat, I. Sivec\u201d (UZC). Paratypes: same data as holotype .GREECE: Central Greece, Panaitoliko Mts., R. Tavropos, Kalesmeno, 300 m, 38\u00b056'N, 21\u00b040'E, 29.iv.1989 (SMNH); Central Greece, Etolia, Agrinio, Agia Soufia, 100 m, 38\u00b036'N, 21\u00b026'E, 24.iv.1990 (SMNH); PageBreakEtolia, Vardousia Mts., R. Evinos, Grammeni Oxia, 800 m, 38\u00b043'N, 22\u00b000'E, 28.iv.1990 (SMNH).Wiedemannia is distinguished by the long gena and the mitten-shaped clasping cercus, which is extremely similar to that of Wiedemannia (Chamaedipsia) berthelemyi Vaillant & Vin\u00e7on, 1987.This species of Male. Body length 3.5\u20134.1 mm, wing length 3.5\u20133.6 mm . Head setulae. Laterotergite with fine, pale setae. One pair of strong marginal scutellar setae with many scattered setae on disc.1 and M2 originating together with short stem vein proximal to M1+2 fork. Vein CuA+CuP extremely faint. Pterostigma elongate, indistinct. Squama with setulae. Halter yellowish.Wing membrane infuscate, veins darker; 1 short basal costal seta ending before humeral crossvein. Cell dm produced anteroapically. Veins MLegs mostly brown; fore femur with 1 strong preapical anterior seta; uniformly covered with rows of small dark setulae. All coxae with longer setae anteriorly. Fore and mid femora ventrally with some longer setulae on proximal half.Abdomen concolourous with thorax, covered in short setae. Pubescence darker on tergites than sternites. Terminalia Fig. : hypandrFemale. Similar to male. Terminalia: cercus short ovate and minutely pilose.Wiedemannia (Chamaedipsia) berthelemyi because of the similarity of the clasping cercus with that of this species.The species name is derived from the name Wiedemanniapseudoberthelemyi sp. n. is known only from parts of Greece. This new species differs from W.berthelemyi on the basis of the truncate posPageBreakterior lobe of the clasping cercus (pointed in W.berthelemyi) and in having only a single preapical seta on the fore femur (2 in W.berthelemyi). The odd stout setae with multi-branched tips on the inner face of the clasping cercus were not noted by W.berthelemyi was not examined.W.angelieri Vaillant, 1967 (Pyrenees), W.vedranae Ivkovi\u0107 & Sinclair, 2014 , and W.queyrasiana Vaillant, 1956 (European Alps).Additional similar species that could be included in this group based on the shape of the clasping cercus include: Taxon classificationAnimaliaDipteraEmpididaeIvkovi\u0107 & Sinclairsp. n.http://zoobank.org/9DE403F2-5A28-4E6F-A485-A4D42308165DGreece: Central Greece, Etolia, Arta, Loutraki.HOLOTYPE \u2642, labelled: \u201cGREECE: Central Greece/ Etolia, Arta, Loutraki/ 16.iv.1990/ leg. B. Horvat, I. Sivec\u201d; \u201cHOLOTYPE/ Chelifera/ horvati/ Ivkovi\u0107 & Sinclair\u201d .A yellow-brown species with distinct, brown and rounded pterostigma, characterized in the male by dark brown cercus with elongate, slender forked process at mid-length, posteriorly tapered epandrium with stout inner setae and membranous distiphallus with two elongate lobes.Male. Body length 4 mm, wing length 3.6 mm. Head dorsoventrally flattened, dark brown; ocellar triangle dark brown; all setae whitish. Eyes iridescent black; narrowly separated on face. Face with thick, whitish pubescence. One pair of postocular setae and scattered fine setae on vertex. Occiput bearing scattered fine setulae; gena with rather dense short, downwardly directed whitish pile. Antenna whitish, with scape and pedicel bearing distinct short dorsal setulae; postpedicel about 1.5\u00d7 as long as wide, stylus much shorter than postpedicel.Thorax elongate; yellow, all setae yellowish. Mesonotum with pair of brown vittae, extending around prescutellar depression; small dark spot posterior to postpronotal lobe and larger dark spot near wing base. Holotype missing most thoracic setae.2+3 arched around it; fork of R4+5 less than 90\u00b0; cell r4 rather long, R5 nearly 2\u00d7 as long as R4. Halter pale.Wing (slightly damaged) membrane transparent, veins yellow; pterostigma dark, rounded, with RPageBreakFore femur with two rows of black ventral denticles and two rows of strong outer brownish-yellow ventral setae, with following chaetotaxy: 20 anteroventral denticles, 6 anteroventral spine-like setae, 21 posteroventral denticles, 6 posteroventral spine-like setae; denticles closely spaced and rows converging distally; posteroventral spine-like setae shorter distally. Fore tibia 0.6\u00d7 as long as fore femur, evenly curved with anteroventral row of short, spine-like setae; with apicoventral dark spur-like seta, longer than width of tibia. Mid and hind femora with anteroventral row of short, slender setae.Legs whitish yellow, apical two tarsal segments on all legs brown. Fore coxa about 8\u00d7 longer than wide with several pale dorsoapical setae. Fore femur slightly longer than fore coxa, more than 4\u00d7 longer than wide, evenly inflated, widest at middle. Abdomen yellow ventrally, brown dorsally, with pale setae most conspicuous on hind margin of posterior sternites. Terminalia Fig. : cercus Female. Unknown.Chelifera Macquart.The new species is named after the late Dr Bogdan Horvat, mentor of the first author, colleague and during his life a leading expert on the genus Cheliferahorvati sp. n. is known only from one site in Greece. The narrow pigmented and sclerotized apex of the distiphallus of C.horvati sp. n. is similar in C.concinnicauda Collin, 1927, C.diversicauda Collin, 1927, C.giraudae Vaillant, 1982 and C.subangusta Collin, 1961 (see 1961 see .Wiedemannia (Philolutra) hygrobia (Loew) is included in the key, although Greek records not confirmed)New records. Thrace, Samothrace, hygropetric zone of stream at the church of Kreminotissa (15).Remarks. This species is newly recorded from Greece. The male terminalia of this species are illustrated ; Epirus, R. Aheron, N of Gliki (115); Central Greece, Etolia, Vardousia Mts., 13 km S of Gardiki (164); Central Greece, Etolia, Panaitoliko Mts., Klepa (170); Central Greece, Etolia, Nafpaktos, Anthofito (174); Central Greece, Etolia, Agrinio, R. Evinos, Kato Hrisovitsa, Diasellaki (183); Central Greece, Etolia, Agrinio, Agia Soufia (191); Central Greece, Etolia, Nafpaktos, Koutsopanneika (203); Peloponnese, tributary of R. Krathis, 7 km N of Peristera (215); Peloponnese, 2 km N of Peristera (216); Peloponnese, Ano Potames, Kalivitis (219).Clinocerastagnalis Literature references. Macedonia, Grevena, stream S of R. Aliakmon by Kamilas Pigi (Agnatha (las Pigi (58); Malas Pigi (61); Malas Pigi (68); Eplas Pigi (94); Ep(Agnatha (105).New records. Thrace, N of Xanthi (18); Thrace, N of Dipotama, 1 (19); Thrace, N of Dipotama 3 (22); Thrace, Dit. Rodopi, Skaloti (29); Thrace, Dit. Rodopi 1 (30); Thrace, Dit. Rodopi, E of Mikromilia (35); Macedonia, Dit. Rodopi, Elatia forest (37); Macedonia, E of Mikroklisoura (38); Macedonia, N of Stavros (39); Macedonia, N of Agios Dimitrios (43); Macedonia, Pieria Mts., S of Elatohori (44); Macedonia, Pieria Mts., E of Fteri (46); Macedonia, Pieria Mts., Fteri (47); Macedonia, Pieria Mts., W of Fteri (48); Macedonia, Pieria Mts., E of Velventos (50); Macedonia, Pieria Mts., 1 (51); Macedonia, Pieria Mts. 2 (52); Macedonia, Pieria Mts., 3 (53); Macedonia, E of Velventos (54); Macedonia, Phalacro Mts., N of Livadero (55); Macedonia, Grevena, Milea (56); Macedonia, Grevena, 6 km S of Milea (57); Macedonia, Kastoria, Nestorio (62); Thessaly, Pieria Mts., S of Livadi (74); Thessaly, 5 km W of Palea Giannitsou (75); Thessaly, Deskati (76); Thessaly, S of Asprokklisia (78); Thessaly, Kalambaka, Agios Nikolaos (80); Thessaly, Trikala, Stournareika (81); Thessaly, Trikala, Kato Palagokaria (82); Thessaly, Trikala, 9 km PageBreakS of Chrisomilea (90); Epirus, Metsovo, Katara Pass (96); Epirus, Metsovo, R. Metsovitikos (99); Epirus, Metsovo, Lakmos Mts., Anthohori, (bellow rapid river) (100); Epirus, Metsovo, Lakmos Mts., Anilio (15 km S influx) (102); Epirus, Metsovo, 14 km W of Milea (103); Epirus, Ioannina, R. Zagoritikos, Karies (106); Epirus, 10 km N of Louros (110); Epirus, Ioannina, R. Voidomatis, Aristi (112); Central Greece, Etolia, Lamia, Ieraklia (145); Central Greece, Oeta Mts., between Kastanea and Katafygio (147); Central Greece, Etolia, Vardousia Mts., 5 km N of Grammeni Oxia (153); Central Greece, Etolia, Vardousia Mts., R. Evinos, Grammeni Oxia (154); Central Greece, Etolia, Vardousia Mts., 9 km N of Grammeni Oxia (155); Central Greece, Etolia, Vardousia Mts., 7 km N of Grammeni Oxia (156); Central Greece, Etolia, Vardousia Mts., 2 km W of Gardiki (166); Central Greece, Tymfristos Mts., R. Sperhios, Lamia (168); Central Greece, Etolia, Panaitoliko Mts., Klepa (170); Central Greece, Karpenisi, Agios Nikolaos (175); Central Greece, Etolia, Nafpaktos, tributory of R. Evinos, 6 km N of Pokista (176); Central Greece, Etolia, Lamia, Pavliani (192); Central Greece, Etolia, Agrinio, Panaitoliko Mts., Palagohori (199); Central Greece, Etolia, Nafpaktos, Koutsopanneika (203); Peloponnese, R. Krathis, 7 km N of Peristera (214); Peloponnese, tributary of R. Krathis, 7 km N of Peristera (215); Peloponnese, R. Krathis, Peristera (217); Peloponnese, Aroania Mts., Zarouhla (220); Peloponnese, Aroania Mts., Xelmos (bellow), Valtos, Zarelia (221); Peloponnese, Pagrati (225); Peloponnese, Aroania Mts., Kastria (226); Peloponnese, Kato Klitoria (227); Peloponnese, Labia Mts., Amigdalia (229); Peloponnese, R. Piro, Elliniko (230); Peloponnese, Panachaiko Mts., tributory of R. Selinous, Leontio (231); Peloponnese, Erymanthos Mts., Lechouri (233); Peloponnese, Panachaiko Mts., Veteika (234); Peloponnese, Erymanthos Mts., Kato Vlasia (235); Peloponnese, Panachaiko Mts., Kounaveika (near village) (236); Peloponnese, Erymanthos Mts., Profitis Ilias (239); Peloponnese, Erymanthos Mts., Stavrohori, Eliniko (241); Peloponnese, Erymanthos Mts., S of Spartia (243); Peloponnese, Stavrodromi (245); Peloponnese, Abelokipi (246); Peloponnese, Panachaiko Mts., Kristalovrisi (stream) (248).Clinocerellasiveci Literature references. Central Greece, Etolia, Panaitoliko Mts., Klepa ; C., Klepa (191); C., Klepa (202); C., Klepa (203); P., Klepa (216); P., Klepa (223); P., Klepa (236); P., Klepa (248); P., Klepa (249).PageBreakDolichocephalacretica Wagner, 1995Literature references. Crete, stream near Kotsifiana (tsifiana (257).Dolichocephalaguttata Literature references. Crete, E of Ierepetra (erepetra (251).New records. Thrace, Sapka Mts. 1 (6); Thrace, Dit. Rodopi, N of Dipotama 3 (26); Macedonia, Pieria Mts., 1 (51); Macedonia, Pieria Mts. 3 (53); Epirus, N of Katarapass, 1 km SW Milea (95); Epirus, Metsovo, Katara Pass (96); Cyclades islands, Andros (206); Peloponnese, 2 km N of Peristera (216); Peloponnese, Aroania Mts., 4 km S of Solos (218); Peloponnese, Ano Potames, Kalivitis (219).Dolichocephalaocellata Literature references. North Aegean islands, Lesbos, 3 km NW of Agiasos ( Agiasos (130); N Agiasos (140); C Agiasos (251).New records. Epirus, 10 km N of Louros (110); Epirus, R. Aheron, N of Gliki (115); Central Greece, Etolia, Agrinio, Agia Soufia (191).Dolichocephalavaillanti Wagner, 1995Literature references. Crete, stream near Sises (ar Sises (252).Dolichocephalazwicki Wagner, 1995Literature references. North Aegean islands, Lesbos, 3 km NW of Agiasos ( Agiasos (130).New records. Cyclades islands, Andros (206).Kowarziabarbatula Literature references. Thrace ; Ma. Thrace (69); No. Thrace (127); N. Thrace (131); N. Thrace (136); N. Thrace (137); N Keramos (138); N Keramos (139); N Keramos (140); C Keramos (142).New records. Thrace, W of Mega Derio (2); Thrace, Lesitse Mts. (3); Thrace, Sapka Mts., 1 (6); Thrace, 3 km N of Alexandroupoli (7); Thrace, Sapka Mts. 2 (8); Thrace, Sapka Mts., Nea Sanda 2 (10); Thrace, Anatoliki Rodopi, E od Drimi (11); Thrace, Dit. Rodopi, N of Dipotama 1 (21); Thrace, N of Dipotama 4 (23); Thrace, N of Dipotama 5 (24); Macedonia, Pieria Mts., 2 streams on Ritini (42); Macedonia, N of Agios Dimitrios (43); Macedonia, Pieria Mts., S of Elatohori (44); Macedonia, Pieria Mts., E of Fteri (46); Macedonia, Pieria Mts., 1 (51); Macedonia, Pieria Mts., 2 (52); Macedonia, Phalacro Mts., N of Livadero (55); Epirus, 10 km N of Louros (110); Epirus, R. Aheron, N of Gliki (115); Central Greece, Etolia, Vardousia Mts., Ano Chora (169); Central Greece, Etolia, Panaitoliko Mts., Klepa (170); Central Greece, Etolia, Nafpaktos, Simos (180); Central Greece, Etolia, Panaitoliko Mts., Prousos (186); Central Greece, Etolia, Panaitoliko Mts., Chaliki, Nerosirtis (188); Peloponnese, Aroania Mts., Kalivia (223); Peloponnese, Erymanthos Mts., S of Spartia (243).Kowarziabipunctata Literature references. North Aegean islands, Lesbos, 2 km N of Akrassi ( Akrassi (132); N Akrassi (134); N Akrassi (135); C Akrassi (250); C Akrassi (253); C Akrassi (254).New records. Thrace, 3 km N of Alexandroupoli (7); Thrace, Sapka Mts., Nea Sanda, 2 (10); Epirus, 10 km N of Louros (110); Epirus, R. Aheron, N of Gliki (115); Central Greece, Etolia, Agrinio, Agia Soufia (191); Central Greece, Etolia, Arta, Loutraki (197); Peloponnese, village Akrata (210); Peloponnese, Aroania Mts., Kalivia (223); Peloponnese, Erymanthos Mts., Stavrohori, Eliniko (241); Peloponnese, Abelokipi (246).Kowarziamadicola New records. Peloponnese, Erymanthos Mts., Stavrohori, Eliniko (241).Kowarziaplectrum New records. Macedonia, Pieria Mts., E of Velventos (50); Macedonia, Pieria Mts., 1 (51); Macedonia, Pieria Mts., 2 (52); Epirus, 10 km N of Louros (110).Remarks. This species is newly recorded from Greece.PageBreakPhaeobaliadimidiata New records. Thrace, N of Dipotama 3 (22); Thrace, N of Dipotama 4 (23); Thrace, Dit. Rodopi, N of Dipotama 2 (25); Macedonia, Pieria Mts., E of Fteri (46); Macedonia, Pieria Mts., Fteri (47); Macedonia, Pieria Mts., W of Fteri (48); Macedonia, Pieria Mts., E of Velventos (50); Macedonia, Pieria Mts., 2 (52).Remarks. This species is newly recorded from Greece.Roederiodesmalickyi Wagner, 1981Literature references. Crete, Xyloskalon .Wiedemannia (Chamaedipsia) aequilobata Mandaron, 1964New records. Epirus, Lakmos Mts., 10 km S of Anilio (101).Wiedemannia (Chamaedipsia) ariadne Wagner, 1981Literature references. Cyclades islands, Naxos, S of Koronis ( Koronis (207); C Koronis (208).Wiedemannia (Chamaedipsia) beckeri New records. Thrace, Rodopi, N of Dipotama 1 (21); Thrace, N of Dipotama 3 (22); Thrace, Rodopi, N of Dipotama 3 (26); Thrace, N of Sidironero 1 (31).Remarks. This species is newly recorded from Greece.Wiedemannia (Chamaedipsia) lota Walker, 1851Literature references. Macedonia, Olympus Mts. above Agios Dyonysos, Prionia ( Prionia (41); Do Prionia (204).New records. Thrace, Anatoliki Rodopi, Drimi (12); Thrace, Anatoliki Rodopi, E of Gratini 1 (13); Thrace, Anatoliki Rodopi, E of Gratini 2 (14); Thrace, 8 km N of Sminthi (17); Thrace, N of Xanthi (18); Thrace, N of Dipotama 1 (19); Thrace, N of Dipotama 3 (22); Macedonia, N of Stavros (39); Macedonia, R. Mavroneri, 10 km W of Katerini (40); Macedonia, S of Agios Dimitrios (45); Macedonia, Pieria Mts., E of Fteri (46); Macedonia, Pieria Mts., 2 (52); Macedonia, E of Velventos (54); Macedonia, Kastoria, Nestorio (62); Macedonia, Kastoria, Grammos Mts., 7 km S Chrisi PageBreak(64); Thessaly, S of Kallithea (73); Thessaly, Pieria Mts., S of Livadi (74); Thessaly, Deskati (76); Thessaly, Trikala, Longiai (77); Thessaly, S of Asprokklisia (78); Epirus, Ioannina, R. Zagoritikos, Karies (106); Epirus, Konitsa, Asimohori (109); Epirus, 10 km N of Louros (110); Epirus, S of Seriziana (111); Epirus, W of Kriopigi (114); Epirus, R. Aheron, N of Gliki (115); Epirus, Mirsini (117); Epirus, R. Kokitos, W of Gardiki (119); Epirus, Igoumenitsa, R. Thiamis, Soulopoulo (122); Epirus, Ioannina, Balndouma (124); Central Greece, Etolia, Lamia, Ieraklia (145); Central Greece, Etolia, Vardousia Mts., Paleovraha (151); Central Greece, Etolia, Nafpaktos, 9 km S of Krokilio (152); Central Greece, Etolia, Vardousia Mts., 5 km N of Grammeni Oxia (153); Central Greece, Etolia, Vardousia Mts., R. Evinos, Grammeni Oxia (154); Central Greece, Etolia, Vardousia Mts., Terpsithea (158); Central Greece, Etolia, Nafpaktos, R. Mornos, Limnitsa (159); Central Greece, Etolia, Vardousia Mts., 6 km S of Lefkada (162); Central Greece, Etolia, Vardousia Mts., 13 km S of Gardiki (164); Central Greece, Etolia, Vardousia Mts., Pougkakia (165); Central Greece, Etolia, Vardousia Mts., 2 km W of Gardiki (166); Central Greece, Etolia, Panaitoliko Mts., R. Evinos, Klepa (171); Central Greece, Etolia, R. Mornos, Nafpaktos (177); Central Greece, Etolia, Agrinio, Panaitoliko Mts., R. Evinos, Agios Dimitros (178); Central Greece, Etolia, Agrinio, Peristra, 1 km S of Perkos (182); Central Greece, Etolia, Agrinio, Panaitoliko Mts. R. Trikeriotis, Dermatio (185); Central Greece, Etolia, Agrinio, Panaitoliko Mts., Potamoula (190); Central Greece, Etolia, Lamia, Pavliani (192); Central Greece, Etolia, Agrinio, Ahlavokastro (196); Central Greece, Etolia, Arta, Loutraki (197); Central Greece, Etolia, Nafpaktos, Koutsopanneika (203); Peloponnese, R. Krathis, Voutsimos (211); Peloponnese, 3 km N of Agia Varvara (213); Peloponnese, R. Krathis, 7 km N of Peristera (214); Peloponnese, tributary of R. Krathis, 7 km N of Peristera (215); Peloponnese, R. Krathis, Peristera (217); Peloponnese, Aroania Mts., Kalivia (223); Peloponnese, Pagrati (225); Peloponnese, Aroania Mts., Kastria (226); Peloponnese, Kato Klitoria (227); Peloponnese, Aroania Mts., Xelmos (above) (228); Peloponnese, R. Piro, Elliniko (230); Peloponnese, Panachaiko Mts., tributory of R. Selinous, Leontio (231); Peloponnese, Panachaiko Mts., Leontio (232); Peloponnese, Erymanthos Mts., Lechouri (233); Peloponnese, Panachaiko Mts., Veteika (234); Peloponnese, Erymanthos Mts., Kato Vlasia (235); Peloponnese, Panachaiko Mts., Kounaveika (near village) (236); Peloponnese, Erymanthos Mts., Profitis Ilias (239); Peloponnese, Erymanthos Mts., Stavrohori, Eliniko (241); Peloponnese, Panachaiko Mts., Souli (242); Peloponnese, Erymanthos Mts., Manesi (244); Peloponnese, E of Olympia (247).Wiedemannia (Eucelidia) zetterstedti Literature references. Thrace ; Ma. Thrace (41); Ep. Thrace (113); N. Thrace (125); N. Thrace (126); Nalochori (129); Nalochori (133); Calochori (142); Calochori (143); Calochori (146); Calochori (201); Calochori (208); Palochori (209); Lalochori (258).New records. Thrace, E of Mega Derio (1); Thrace, N of Avas (5); Thrace, Sapka Mts. 1 (6); Thrace, Sapka Mts. 2 (8); Thrace, Sapka Mts., Nea Sanda 1 (9); Thrace, Sapka Mts., Nea Sanda 2 (10); Thrace, Anatoliki Rodopi, E od Drimi (11); Thrace, Anatoliki Rodopi, Drimi (12); Thrace, Anatoliki Rodopi, E of Gratini 1 (13); Thrace, Miki (16); Thrace, 8 km N of Sminthi (17); Thrace, N of Xanthi (18); Thrace, N of Dipotama 1 (19); Thrace, N of Dipotama 2 (20); Thrace, Dit. Rodopi, N of Dipotama 1 (21); Thrace, N of Dipotama 3 (22); Thrace, N of Dipotama 5 (24); Thrace, S of Dipotama (27); Thrace, S of Silli (28); Thrace, Dit. Rodopi, Skaloti (29); Thrace, W of Sidironero (34); Thrace, Rodopi, E of Mikromilia (35); Macedonia, E of Mikroklisoura (38); Macedonia, N of Stavros (39); Macedonia, R. Mavroneri, 10 km W of Katerini (40); Macedonia, Pieria Mts., 2 streams on Ritini (42); Macedonia, N of Agios Dimitrios (43); Macedonia, S of Agios Dimitrios (45); Macedonia, Pieria Mts., E of Fteri (46); Macedonia, Pieria Mts., Fteri (47); Macedonia, Pieria Mts., W of Fteri (48); Macedonia, W of Daskio (49); Macedonia, Pieria Mts., 1 (51); Macedonia, Pieria Mts., 2 (52); Macedonia, Pieria Mts., 3 (53); Macedonia, Phalacro Mts., N of Livadero (55); Macedonia, Grevena, 6 km S of Milea (57); Macedonia, Kozani, Polilako (Paraveti), Neapolis (59); Macedonia, Smokilas Mts., main stream near the bridge, 2 km E of Agia Paraskevi (63); Thessaly, Ossa Mts., stream Apataniana (71); Thessaly, S of Kallithea (73); Thessaly, Deskati (76); Thessaly, S of Asprokklisia (78); Thessaly, Kalambaka, Agios Nikolaos (80); Thessaly, Trikala, Kato Palagokaria (82); Thessaly, Kalambaka, 5 km E of Paleochori (83); Thessaly, Kalambaka, Trigona (85); Thessaly, Kalambaka, Koridallos (86); Thessaly, Trikala, Arta, Pahtouri (87); Thessaly, Kalambaka, 4 km S of Ambelia (91); Epirus, Metsovo, 14 km S of Milea (92); Epirus, Metsovo, R. Metsovitikos (99); Epirus, Metsovo, Lakmos Mts., Anthohori, (bellow rapid river) (100); Epirus, Ioannina, R. Zagoritikos, Karies (106); Epirus, 10 km N of Louros (110); Epirus, S of Seriziana (111); Epirus, Ioannina, R. Voidomatis, Aristi (112); Epirus, R. Aheron, N of Gliki (115); Epirus, Kanallaki, Skepaston (116); Epirus, Mirsini (117); Epirus, R. Aheron, Gliki (118); Epirus, R. Kokitos, W of Gardiki (119); Epirus, Igoumenitsa, R. Thiamis, Soulopoulo (122); Central Greece, Etolia, Lamia, Ieraklia (145); Central Greece, Etolia, Vardousia Mts., Mousonitsa (149); Central Greece, Etolia, Vardousia Mts., Athanasios Diakos (150); Central Greece, Etolia, Vardousia Mts., Paleovraha (151); Central Greece, Etolia, Nafpaktos, 9 km S of Krokilio (152); Central Greece, Etolia, Vardousia Mts., 7 km N of Grammeni Oxia (156); Central Greece, Etolia, Nafpaktos, R. Mornos, Limnitsa (159); Central Greece, Etolia, Vardousia Mts., Elato (161); Central Greece, Etolia, Vardousia Mts., Pougkakia (165); Central Greece, Etolia, Vardousia Mts., 2 km W of Gardiki (166); Central Greece, Etolia, Vardousia PageBreakMts., Grigorio (167); Central Greece, Etolia, Vardousia Mts., Ano Chora (169); Central Greece, Etolia, Panaitoliko Mts., Klepa (170); Central Greece, Etolia, Panaitoliko Mts., R. Evinos, Klepa (171); Central Greece, Etolia, Vardousia Mts., 3 km W of Kryoneri (172); Central Greece, Etolia, Vardousia Mts., Kato Chora (173); Central Greece, Etolia, Nafpaktos, Anthofito (174); Central Greece, Etolia, Nafpaktos, tributory of R. Evinos, 6 km N of Pokista (176); Central Greece, Etolia, R. Mornos, Nafpaktos (177); Central Greece, Etolia, Nafpaktos, Simos (180); Central Greece, Etolia, Nafpaktos, Pokista (181); Central Greece, Etolia, Agrinio, Peristra, 1 km S of Perkos (182); Central Greece, Etolia, Agrinio, R. Evinos, Kato Hrisovitsa, Diasellaki (183); Central Greece, Etolia, Panaitoliko Mts., Chaliki, Ladikon (187); Central Greece, Etolia, Agrinio, Agia Soufia (191); Central Greece, Etolia, Lamia, Pavliani (192); Central Greece, Etolia, Giona Mts., Sikia (194); Central Greece, Oeta Mts., stream Valorema, Pavliani (195); Central Greece, Etolia, Agrinio, Ahlavokastro (196); Central Greece, Etolia, Arta, Loutraki (197); Central Greece, Etolia, Agrinio, Panaitoliko Mts., Palagohori (199); Central Greece, Etolia, Nafpaktos, Avrorema bridge (200); Central Greece, Etolia, Agrinio, Panaitoliko Mts., 3 km N of Hani Lioliou (202); Central Greece, Etolia, Nafpaktos, Koutsopanneika (203); Peloponnese, Aroania Mts., 2 km S of Zarouchla (212); Peloponnese, Aroania Mts., Zarouhla (220); Peloponnese, Aroania Mts., Kalivia (223); Peloponnese, Kato Klitoria (227); Peloponnese, Panachaiko Mts., tributory of R. Selinous, Leontio (231); Peloponnese, Erymanthos Mts., Lechouri (233); Peloponnese, Panachaiko Mts., Veteika (234); Peloponnese, Panachaiko Mts., Kounaveika (near village) (236); Peloponnese, E of Olympia (247).Wiedemannia (Philolutra) angelieri Vaillant, 1967New records. Central Greece, Etolia, Vardousia Mts., Athanasios Diakos (150).Remarks. This species is newly recorded from Greece.Wiedemannia (Philolutra) chvali Joost, 1981New records. Thrace, N of Dipotama 3 (22); Thrace, N of Sidironero 1 (31).Remarks. This species is newly recorded from Greece.Wiedemannia (Philolutra) fallaciosa Literature references. Macedonia, Olympus Mts. above Agios Dyonysos, Prionia ( Prionia (41); Ep Prionia (113).New records. Thrace, E of Mega Derio (1); Thrace, Miki (16); Thrace, N of Dipotama 1 (19); Thrace, Dit. Rodopi, Skaloti (29); Macedonia, R. Mavroneri, 10 km PageBreakW of Katerini (40); Macedonia, Pieria Mts., S of Elatohori (44); Macedonia, S of Agios Dimitrios (45); Macedonia, Pieria Mts., E of Fteri (46); Macedonia, W of Daskio (49); Macedonia, Pieria Mts., 2 (52); Macedonia, E of Velventos (54); Macedonia, Grevena, Milea (56); Macedonia, Grevena, 6 km S of Milea (57); Macedonia, Kozani, Polilako (Paraveti), Neapolis (59); Macedonia, Grevena, R. Venetikos, Kipourio (60); Macedonia, Kastoria, Nestorio (62); Macedonia, Kastoria, Grammos Mts., 7 km S Chrisi (64); Macedonia, Kastoria, Grammos Mts., 6 km N Pefkofito (65); Thessaly, Deskati (76); Thessaly, S of Asprokklisia (78); Thessaly, Trikala, Moshofito, Avra (79); Thessaly, Kalambaka, Agios Nikolaos (80); Thessaly, Trikala, Stournareika (81); Thessaly, Trikala, Kato Palagokaria (82); Thessaly, Kalambaka, 5 km E of Paleochori (83); Thessaly, Kalambaka, Paleochori (84); Thessaly, Kalambaka, Trigona (85); Thessaly, Trikala, Arta, Pahtouri (87); Thessaly, Trikala, Arta, R. Ahelos, Kapsala (88); Thessaly, Trikala, Arta, Korifi (89); Epirus, Metsovo, 14 km S of Milea (92); Epirus, Metsovo, Lakmos Mts., Anilio (5 km S bellow river) (93); Epirus, Metsovo, 12 km W Milea (98); Epirus, Metsovo, R. Metsovitikos (99); Epirus, Metsovo, Lakmos Mts., Anthohori, (bellow rapid river) (100); Epirus, Lakmos Mts., 10 km S of Anilio (101); Epirus, Ioannina, Megalo Peristeri (104); Epirus, Ioannina, R. Zagoritikos, Karies (106); Epirus, Konitsa, Asimohori (109); Epirus, 10 km N of Louros (110); Epirus, Ioannina, R. Voidomatis, Aristi (112); Epirus, W of Kriopigi (114); Epirus, R. Aheron, N of Gliki (115); Epirus, Kanallaki, Skepaston (116); Epirus, Mirsini (117); Epirus, R. Kokitos, W of Gardiki (119); Epirus, Ioannina, Balndouma (124); Central Greece, Etolia, Lamia, Ieraklia (145); Central Greece, Etolia, Vardousia Mts., Stromi (148); Central Greece, Etolia, Vardousia Mts., Mousonitsa (149); Central Greece, Etolia, Vardousia Mts., Athanasios Diakos (150); Central Greece, Etolia, Nafpaktos, 9 km S of Krokilio (152); Central Greece, Etolia, Vardousia Mts., 5 km N of Grammeni Oxia (153); Central Greece, Etolia, Vardousia Mts., R. Evinos, Grammeni Oxia (154); Central Greece, Etolia, Vardousia Mts., 9 km N of Grammeni Oxia (155); Central Greece, Etolia, Vardousia Mts., 7 km N of Grammeni Oxia (156); Central Greece, Etolia, Vardousia Mts., Terpsithea (158); Central Greece, Etolia, Nafpaktos, R. Mornos, Limnitsa (159); Central Greece, Etolia, Vardousia Mts., Elatovrisi (160); Central Greece, Etolia, Vardousia Mts., Elato (161); Central Greece, Etolia, Vardousia Mts., 6 km S of Lefkada (162); Central Greece, Etolia, Vardousia Mts., Gardiki (163); Central Greece, Etolia, Vardousia Mts., 13 km S of Gardiki (164); Central Greece, Etolia, Vardousia Mts., Pougkakia (165); Central Greece, Etolia, Vardousia Mts., 2 km W of Gardiki (166); Central Greece, Etolia, Vardousia Mts., Grigorio (167); Central Greece, Etolia, Panaitoliko Mts., Klepa (170); Central Greece, Etolia, Panaitoliko Mts., R. Evinos, Klepa (171); Central Greece, Etolia, Vardousia Mts., 3 km W of Kryoneri (172); Central Greece, Etolia, Vardousia Mts., Kato Chora (173); Central Greece, Etolia, Nafpaktos, Anthofito (174); Central Greece, Etolia, Nafpaktos, tributory of R. Evinos, 6 km N of Pokista (176); Central Greece, Etolia, R. Mornos, Nafpaktos (177); Central Greece, Etolia, Agrinio, Panaitoliko Mts., R. Evinos, Agios Dimitros (178); Central Greece, Etolia, Nafpaktos, 2 km N of Pokista (179); Central Greece, Etolia, Nafpaktos, Simos (180); Central Greece, Etolia, Nafpaktos, Pokista PageBreak(181); Central Greece, Etolia, Agrinio, Peristra, 1 km S of Perkos (182); Central Greece, Etolia, Agrinio, R. Evinos, Kato Hrisovitsa, Diasellaki (183); Central Greece, Etolia, Agrinio, Panaitoliko Mts. R. Trikeriotis, Dermatio (185); Central Greece, Etolia, Lamia, Pavliani (192); Central Greece, Etolia, Giona Mts., Sikia (194); Central Greece, Etolia, Agrinio, Ahlavokastro (196); Central Greece, Etolia, Arta, Loutraki (197); Central Greece, Etolia, Agrinio, Panaitoliko Mts., Palagohori (199); Central Greece, Etolia, Nafpaktos, Avrorema bridge (200); Central Greece, Etolia, Agrinio, Panaitoliko Mts., 3 km N of Hani Lioliou (202); Central Greece, Etolia, Nafpaktos, Koutsopanneika (203); Peloponnese, R. Krathis, Voutsimos (211); Peloponnese, 3 km N of Agia Varvara (213); Peloponnese, R. Krathis, 7 km N of Peristera (214); Peloponnese, tributary of R. Krathis, 7 km N of Peristera (215); Peloponnese, 2 km N of Peristera (216); Peloponnese, R. Krathis, Peristera (217); Peloponnese, Ano Potames, Kalivitis (219); Peloponnese, Aroania Mts., Zarouhla (220); Peloponnese, Likouria (under the village) (222); Peloponnese, Aroania Mts., Kalivia (223); Peloponnese, Aroania Mts., Kastria (226); Peloponnese, Kato Klitoria (227); Peloponnese, Aroania Mts., Xelmos (above) (228); Peloponnese, R. Piro, Elliniko (230); Peloponnese, Panachaiko Mts., tributory of R. Selinous, Leontio (231); Peloponnese, Panachaiko Mts., Leontio (232); Peloponnese, Erymanthos Mts., Lechouri (233); Peloponnese, Panachaiko Mts., Veteika (234); Peloponnese, Erymanthos Mts., Kato Vlasia (235); Peloponnese, Panachaiko Mts., Kounaveika (near village) (236); Peloponnese, Panachaiko Mts., Moira (237); Peloponnese, Panachaiko Mts., Moira (after village) (238); Peloponnese, Panachaiko Mts., Souli (242); Peloponnese, Abelokipi (246); Peloponnese, E of Olympia (247).Wiedemannia (Pseudowiedemannia) lamellata Literature references. Thessaly, Karya ; Noy, Karya (128).New records. Thrace, Sapka Mts., Nea Sanda 1 (9); Thrace, Anatoliki Rodopi, E od Drimi (11); Thrace, Anatoliki Rodopi, Drimi (12); Thrace, Anatoliki Rodopi, E of Gratini 1 (13); Thrace, 8 km N of Sminthi (17); Thrace, S of Silli (28); Thrace, Dit. Rodopi, Skaloti (29); Thrace, Dit. Rodopi 1 (30); Thrace, N of Sidironero 1 (31); Thrace, Dit. Rodopi 2 (32); Thrace, N of Sidironero 2 (33); Thrace, W of Sidironero (34); Macedonia, N of Stavros (39); Macedonia, R. Mavroneri, 10 km W of Katerini (40); Macedonia, Phalacro Mts., N of Livadero (55); Macedonia, Kozani, Polilako (Paraveti), Neapolis (59); Thessaly, Trikala, Kato Palagokaria (82); Thessaly, Kalambaka, 5 km E of Paleochori (83); Thessaly, Kalambaka, Paleochori (84); Thessaly, Kalambaka, Koridallos (86); Epirus, Metsovo, Lakmos Mts., Anthohori, (bellow rapid river) (100); Epirus, Ioannina, R. Vardas, Abelos (123); Central Greece, Etolia, Lamia, Ieraklia (145); Central Greece, Etolia, Vardousia Mts., 7 km N of Grammeni Oxia (156); Central Greece, Etolia, Vardousia Mts., 7 km S of Gardiki (157); Central Greece, Etolia, Vardousia Mts., Terpsithea (158); Central Greece, Etolia, Vardousia PageBreakMts., 13 km S of Gardiki (164); Central Greece, Etolia, Vardousia Mts., Pougkakia (165); Central Greece, Etolia, Vardousia Mts., 2 km W of Gardiki (166); Central Greece, Etolia, Agrinio, Panaitoliko Mts., Megali Chora (193); Central Greece, Etolia, Nafpaktos, Avrorema bridge (200); Peloponnese, Aroania Mts., Kalivia (223); Peloponnese, Aroania Mts., Kastria (226); Peloponnese, Panachaiko Mts., tributory of R. Selinous, Leontio (231); Peloponnese, Panachaiko Mts., Leontio (232); Peloponnese, Erymanthos Mts., Lechouri (233); Peloponnese, Panachaiko Mts., Veteika (234); Peloponnese, Erymanthos Mts., Kato Vlasia (235); Peloponnese, Panachaiko Mts., Kounaveika (near village) (236); Peloponnese, Erymanthos Mts., Manesi (244); Peloponnese, E of Olympia (247).Wiedemannia (Pseudowiedemannia) microstigma New records. Thessaly, Trikala, Kato Palagokaria (82); Central Greece, Etolia, Vardousia Mts., Stromi (148).Wiedemannia (Roederella) czernyi Literature references. Macedonia, Chalkidiki, Chlomon Oros., Paleokastron, Vatonia P. 1 (nia P. 1 (66).New records. Thrace, E of Sapka Mts., big stream in the valley (4); Macedonia, Chalkidiki, Chlomon Oros., Paleokastron, Vatonia P. 2 (67).Wiedemannia (Wiedemannia) andreevi Joost, 1982New records. Thrace, S of Silli (28).Wiedemannia (Wiedemannia) bilobata Oldenberg, 1910Literature references. Macedonia, Olympus Mts. above Agios Dyonysos, Prionia ( Prionia (42); Ce Prionia (146).Wiedemannia (Wiedemannia) dinarica Engel, 1940New records. Epirus, Ioannina, R. Voidomatis, Aristi (112); Epirus, R. Aheron, N of Gliki (115); Epirus, R. Aheron, Gliki (118); Peloponnese, Likouria (under the village) (222); Peloponnese, Aroania Mts., Krinofita (224); Peloponnese, Aroania Mts., Kastria (226); Peloponnese, Kato Klitoria (227).PageBreakWiedemannia (Wiedemannia) dyonysica Wagner, 1990Literature references. Macedonia, Olympus Mts. above Agios Dyonysos, Prionia ( Prionia (41).Wiedemannia (Wiedemannia) graeca Vaillant & Wagner, 1990Literature references. Central Greece, Polydrosos (lydrosos (144).New records. Thrace, Rodopi, Skaloti (29); Thessaly, Trikala, Stournareika (81); Thessaly, Kalambaka, 5 km E of Paleochori (83); Thessaly, Kalambaka, Paleochori (84); Thessaly, Trikala, Arta, R. Ahelos, Kapsala (88); Epirus, Metsovo, Lakmos Mts., 2 km S of Anilio (bellow left tributary) (97); Epirus, Metsovo, Lakmos Mts., Anthohori, (bellow rapid river) (100); Central Greece, Etolia, Vardousia Mts., Stromi (148).Wiedemannia (Wiedemannia) tricuspidata New records. Thrace, S of Silli (28); Macedonia, Grevena, R. Venetikos, Kipourio (60); Macedonia, Kastoria, Grammos Mts., 7 km S Chrisi (64); Thessaly, Trikala, Longiai (77); Thessaly, Trikala, Kato Palagokaria (82); Epirus, Konitsa, R. Saradaporos, Drosopigi (108); Central Greece, Etolia, Nafpaktos, R. Mornos, Limnitsa (159); Central Greece, Etolia, Panaitoliko Mts., R. Evinos, Klepa (171); Central Greece, Etolia, Nafpaktos, tributory of R. Evinos, 6 km N of Pokista (176); Central Greece, Etolia, R. Mornos, Nafpaktos (177); Central Greece, Etolia, Agrinio, Panaitoliko Mts., R. Evinos, Agios Dimitros (178); Central Greece, Etolia, Agrinio, Peristra, 1 km S of Perkos (182).Wiedemaniaartemisa Ivkovi\u0107 & Plant, 2012Literature references. Thessaly, Trikala, Kato Palagokaria (226); Peloponnese, Kato Klitoria (agokaria (82); Thagokaria (87); Thagokaria (88); Thagokaria (89); Epagokaria (100); Eagokaria (122); Cagokaria (145); Cagokaria (157); Cagokaria (165); Pagokaria (211); Pagokaria (217); Pagokaria (222); PKlitoria (227); PKlitoria (231); PKlitoria (232); PKlitoria (234); PKlitoria (242).New records. Thessaly, Kalambaka, 4 km S of Ambelia (91); Epirus, Metsovo, Lakmos Mts., 2 km S of Anilio (bellow left tributary) (97); Epirus, Konitsa, Smolikas Mts., Pournia (107); Epirus, Mirsini (117); Central Greece, Etolia, Vardousia Mts., Stromi (148); Central Greece, Etolia, Vardousia Mts., Athanasios Diakos (150); Central Greece, Etolia, Nafpaktos, 9 km S of Krokilio (152); Central Greece, Etolia, Vardousia Mts., R. Evinos, Grammeni Oxia (154); Central Greece, Etolia, Vardousia Mts., 7 km N of Grammeni Oxia (156); Central Greece, Etolia, Vardousia Mts., Terpsithea (158); Central Greece, Etolia, Nafpaktos, R. Mornos, Limnitsa (159); Central Greece, Etolia, Vardousia Mts., 13 km S of Gardiki (164); Central Greece, Etolia, Vardousia Mts., 2 km W of Gardiki (166); Central Greece, Etolia, Vardousia Mts., Grigorio (167); Central Greece, Etolia, Vardousia Mts., Kato Chora (173); Central Greece, Karpenisi, Agios Nikolaos (175); Central Greece, Etolia, Nafpaktos, tributory of R. Evinos, 6 km N of Pokista (176); Central Greece, Etolia, Nafpaktos, Pokista (181); Central Greece, Etolia, Agrinio, Peristra, 1 km S of Perkos (182); Central Greece, Etolia, Panaitoliko Mts., Prousos (186); Central Greece, Etolia, Panaitoliko Mts., Chaliki, Ladikon (187); Central Greece, Etolia, Agrinio, Panaitoliko Mts., Anatoliki Frangista (189); Central Greece, Etolia, Lamia, Pavliani (192); Central Greece, Etolia, Agrinio, Panaitoliko Mts., Megali Chora (193); Central Greece, Etolia, Agrinio, Panaitoliko Mts., Houni (198); Central Greece, Etolia, Nafpaktos, Koutsopanneika (203); Peloponnese, 3 km N of Agia Varvara (213); Peloponnese, R. Krathis, 7 km N of Peristera (214).Wiedemanniaiphigeniae Ivkovi\u0107 & Sinclair, sp. n.Records. Peloponnese, Aroania Mts., Krinofita (224).Wiedemannialjerkae Ivkovi\u0107 & Sinclair, sp. n.Records. Epirus, Igoumenitsa, R. Thiamis, Soulopoulo (122); Central Greece, Etolia, Agrinio, Peristra, 1 km S of Perkos (182); Peloponnese, Aroania Mts., Kastria (226); Peloponnese, Kato Klitoria (227).Wiedemannianebulosa Ivkovi\u0107 & Sinclair, sp. n.Records. Thrace, N of Dipotama 5 (24).PageBreakWiedemanniapseudoberthelemyi Ivkovi\u0107 & Sinclair, sp. n.Records. Central Greece, Etolia, Vardousia Mts., R. Evinos, Grammeni Oxia (154); Central Greece, Etolia, R. Mornos, Nafpaktos (177); Central Greece, Panaitoliko Mts., R. Tavropos, Kalesmeno (184); Central Greece, Etolia, Agrinio, Agia Soufia (191).Cheliferaangusta Collin, 1927New records. North Aegean islands, Lesbos (141).Remarks. This species is newly recorded from Greece.Cheliferabarbarica Vaillant, 1982Literature references. Dodecanese islands, Rhodes, near Archipolis (chipolis (205).Cheliferahorvati Ivkovi\u0107 & Sinclair, sp. n.Records. Central Greece, Etolia, Arta, Loutraki (197).Cheliferaprecabunda Collin, 1961New records. Thrace, Sapka Mts., 1 (6); Thrace, Dit. Rodopi, Skaloti (29); Thrace, Rodopi, E of Mikromilia (35); Macedonia, Pieria Mts., E of Velventos (50); Peloponnese, R. Krathis, 7 km N of Peristera (214).Cheliferaprecatoria Literature references. Crete, Georgioupolis (ioupolis (255).Cheliferastigmatica Literature references. North Aegean islands, Samos, E of Pirgos (f Pirgos (126).New records. Thrace, N of Sidironero 2 (33); Thessaly, Trikala, Kato Palagokaria (82); Epirus, 10 km N of Louros (110); Epirus, R. Aheron, N of Gliki (115); Central Greece, Etolia, Vardousia Mts., Stromi (148); Central Greece, Etolia, Panaitoliko Mts., PageBreakR. Evinos, Klepa (171); Central Greece, Etolia, Agrinio, Peristra, 1 km S of Perkos (182); Central Greece, Etolia, Nafpaktos, Koutsopanneika (203); Peloponnese, Erymanthos Mts., Stavrohori, Eliniko (241); Peloponnese, E of Olympia (247).Cheliferatrapezina Literature references. North Aegean islands, Samos, E of Pirgos (f Pirgos (126).Hemerodromiamelangyna Collin, 1927New records. Epirus, 10 km N of Louros (110); Epirus, R. Aheron, N of Gliki (115).Remarks. This species is newly recorded from Greece.Hemerodromiaoratoria Literature references. Peloponnese, Ano Kastritsi, stream .New records. Thrace, Lesitse Mts. (3); Thrace, Anatoliki Rodopi, E od Drimi (11); Thrace, Anatoliki Rodopi, Drimi (12); Thrace, Miki (16); Thrace, 8 km N of Sminthi (17); Epirus, 10 km N of Louros (110); Epirus, W of Kriopigi (114); Epirus, Mirsini (117); Central Greece, Etolia, Lamia, Ieraklia (145).Hemerodromiaunilineata Zetterstedt, 1842Literature references. Thessaly, Portaria (Portaria (70).New records. Thrace, Anatoliki Rodopi, E od Drimi (11); Thrace, Anatoliki Rodopi, Drimi (12); Thrace, Anatoliki Rodopi, E of Gratini, 1 (13); Thrace, 8 km N of Sminthi (17); Thrace, S of Silli (28); Thrace, W of Sidironero (34); Macedonia, E of Mikroklisoura (38); Macedonia, W of Daskio (49); Epirus, 10 km N of Louros (110); Epirus, R. Aheron, N of Gliki (115); Epirus, Mirsini (117); Epirus, R. Kokitos, Themelo (120); Epirus, Igoumenitsa, Thesprotia, R. Thiamis, Neohori (121).Species richness and assemblage composition. A total of 47 species of aquatic empidids are recorded from Greece , Clinocerella Engel (1 species), Dolichocephala Macquart (5 species), Kowarzia Mik (4 species), Phaeobalia (1 species), Roederiodes Coquillett (1 species) and PageBreakWiedemannia Zetterstedt (22 species). The subfamily Hemerodromiinae is represented by 10 species, in two genera: Chelifera (7 species) and Hemerodromia Meigen (3 species) (Table Clinocerinae genus Wiedemannia is most species rich (46.8%), followed by the Hemerodromiinae genus Chelifera (14.9%) Fig. . The HelEmpididae fauna of Greece is most similar to that of FYR Macedonia followed by Bosnia & Herzegovina, whereas it is the least similar to that of Montenegro beckeri, W. (Philolutra) angelieri and W. (P.) chvali from the subfamily Clinocerinae. They represent new country records. On the other hand, some species that are listed in Wiedemannia (Philolutra) hygrobia (Loew) because its presence has not been confirmed in Greece. However, it is possible that it does occur in Greece as it is present in surrounding countries and Eastern Balkan (Ecoregion 7). The higher species richness is in the Hellenic Western Balkan Ecoregion, but the Eastern Balkan Ecoregion in Greece is much smaller, so this was an expected result. Greece supports at least 47 species, of which 10 are currently endemic to the country graeca, W.iphigeniae, W.ljerkae, W.nebulosa, W.pseudoberthelemyi, Cheliferahorvati). The higher number of species recorded for Slovenia and the far fewer species recorded, for instance, in Montenegro, FYR Macedonia and Bosnia & Herzegovina should be viewed with caution. Slovenia was well studied ariadne, W. (Pseudowiedemannia) microstigma, W. (Wiedemannia) dinarica and W.artemisa). Some species have a small area of distribution, occurring in just one or a few sites graeca, W.iphigeniae, W.ljerkae, W.nebulosa and W.pseudoberthelemyi), and can be considered as Greek endemics.The Greek aquatic Africa) . Most ofClinocerinae and Hemerodromiinae that have not been recorded in Greece and that might be present, as they occur in surrounding countries . Within Greece, most species were reported from the Hellenic Western Balkan Ecoregion; this was expected as this European Ecoregion covers most of the surface area of the country (There are still some genera of country and it i country . The che"} +{"text": "Scientific Reports6: Article number: 36551; 10.1038/srep36551 published online: 11072016 updated: 01112017.This Article contains errors in the affiliations for Xin Qian, Jiao Du and Caiyun Chen, who were incorrectly listed as affiliated to \u201cDepartment of Respiratory Medicine, Taihe Hospital, Hubei University of Medicine, No. 32, South Renmin Road, Shiyan, Hubei, 442000, P.R. China\u201d, \u201cZhongshan Hospital, Xiamen University, 201-209 Hubin Road, Xiamen, Fujian, 361004, P.R. China\u201d and \u201cDepartment of Respiratory Medicine,the First Hospital of Xi\u2032an City, Xi\u2032an, Shanxi, 710002, P.R. China\u201d respectively.The correct affiliation for all authors is given below:Department of Respiratory and Critical Care Medicine, Key Laboratory of Pulmonary Diseases of Health Ministry, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, 430022, China."} +{"text": "Pharmaceutics would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016. The editors of https://publons.com) to receive recognition. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make. We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (Pharmaceutics, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Pharmaceutics in 2016:Ahadian, SamadKelly, Edward J.Popat, AmiraliAnraku, MakotoKhimyak, Y. Z.Rancan, FiorenzaAntipina, Maria N.Kinrys, GustavoRaviv, UriAriga, KatsuhikoKuang, HuihuiRaymond Naxing, XuB\u00e1cskay, Ildik\u00f3Lai, FrancescoRistori, SandraBansal, Arvind K.Lane, MajellaRosania, Gus R.Barcia, EmiliaLaurienzo, PaolaRyan, Michael C.Borup Jensen, SvendLee, JaehwiSandri, GiuseppinaBrandl, MartinLeporatti, StefanoScherlie\u03b2, ReginaBroutin, SophieLiu, FeiShahiwala, AliasgarBurkhart, David J.Loh, Xian JunShi, WenCallahan, Laura SmithLondon, Lucille\u0160kalko-Basnet, Nata\u0161aChauhan, HarshLowry, DeborahSkwarczynski, MariuszCheng, FeixiongLuppi, BarbaraSmolensky, Michael H.Chu, DafengMandal, BivashSugibayashi, KenjiCipolla, DavidMansour, Heidi M.Takeoka, ShinjiClark, MeredithMarte, AntonioTruong Phuoc, NghiaConnor, Thomas H.Matsuda, HiroshiTseng, Ching-LiConway, BarbaraMelucci, DoraUngaro, FrancescaDas, Diganta BhusanMerino, SoniaUpadhyay, Arun KumarDe Rosa, GiuseppeMiki, NorihisaVadlapudi, Aswani DuttElsebai, MahmoudMontenegro, LuciaVan den Mooter, GuyFei, Andrew Chang-YoungMonti, DanielaVani\u0107, \u017deljkaFirer, MichaelM\u00f6schwitzer, Jan P.Waldmeier, FelixFrielinghaus, HenrichNeubert, ReinhardWei, ChangyongFr\u00f6hlich, EleonoreObata, YasukoWeiss, Clemens K.Geyer, JoachimOhsedo, YutakaWillerth, Stephanie M.Hiorth, MarianneOkyar, AlperXi, WeixianHyun, Bae KiOlatunji, OloladeYallapu, Murali M.Jayant, Rahul DevPapadimitriou, Sofia A.Yan, QingJohann, DonaldParikesit, Arli AdityaYiannakopoulou, EugeniaKanaujia, ParijatPerrie, YvonneZhang, LiKathuria, HimanshuPoenie, MartinZucca, PaoloKeck, Cornelia M.Poglayen, GiovanniThe following reviewed for"} +{"text": "Scientific Reports 10.1038/s41598-017-11972-w, published online 18 September 2017Correction to: The original version of this Article contains errors in the spelling of the authors Stefan Sch\u00fclke, Kirsten Kuttich, Sonja Wolfheimer, Nadine Duschek, Andrea Wangorsch, Andreas Reuter, Peter Briza, Isabel Pablos, Gabriele Gadermaier, Fatima Ferreira, Stefan Vieths, Masako Toda & Stephan Scheurer, which were incorrectly given as Sch\u00fclke Stefan, Kuttich Kirsten, Wolfheimer Sonja, Duschek Nadine, Wangorsch Andrea, Reuter Andreas, Briza Peter, Pablos Isabel, Gadermaier Gabriele, Ferreira Fatima, Vieths Stefan, Toda Masako & Scheurer Stephan.These errors have now been corrected in the PDF and HTML versions of the Article, and in the accompanying Supplementary Material."} +{"text": "AbstractBryozoa of the Greek seas had never been published and species records were scattered in several taxonomic and ecological studies. The aim of this paper is to produce a first checklist of marine bryozoan species of Greece, in the framework of the Greek Taxon Information System (GTIS) initiative of the LifeWatchGreece Research Infrastructure (ESFRI), by reviewing the existing literature and following the recent trends in the taxonomy of this group. \ufeffUntil today, a complete checklist of Gymnolaemata (177 Cheilostomatida and 21 Ctenostomatida), while the remaining 39 species are Stenolaemata . Among these species, 12 are considered endemic to the eastern Mediterranean, while another 12 species are non-indigenous.The marine bryozoan fauna of Greece comprises 237 species, classified in 127 genera, 66 families, 3 orders, and 2 classes. The vast majority belongs to the class Bryozoa yielded 101 species, including rare records and new species. Sharing only 47 cheilostomes with Harmelin\u2019s list mentioned above, this study increased the eastern Mediterranean bryozoan diversity by 54 species.Sporadic records of bryozoans from the Aegean Sea can be found in old taxonomic studies, including the descriptions of the cheilostome species e region , based ote 1960s , based oBryozoa however had never been published from Greece. The aim of the present study is to give a first annotated checklist of Bryozoa from the Greek seas.More recently, few taxonomic and ecological studies have focused on the bryozoan fauna of Greece e.g. , while aWorld List of Bryozoa (recent and fossil), the World Register of Marine Species (The checklist presented in this paper was compiled in the framework of the Greek Taxon Information System (GTIS), an initiative of the LifeWatchGreece Research e-Infrastructure aiming to produce a complete inventory of the known biodiversity of Greece Busk, 1884Reptoporellina, probably a mispelling), Antoniadou and Chintiroglou 2005Smitt, 1868Lamouroux, 1812Ganias 1990Waters, 1906Morri et al. 1999Morri et al. 1999Morri et al. 1999Vigneaux, 1949Jullien, 1888Ganias 1990Canu & Bassler, 1927Johnston, 1840\u200bMorri et al. 1999Morri et al. 1999Ganias 1990Johnston, 1840\u200bGanias 1990MacGillivray, 1895Canu & Bassler, 1917Morri et al. 1999Fischer, 1807Chimenz Gusso et al. 2014Canu & Bassler, 1917\ufeffS.rudis has been questioned by Stephanothecawatersi Reverter-Gil, Souto & Fernandez-Pulpeiro, 2012 and Schizomavellaadriatica Reverter-Gil, Souto, Novosel & Tilbrook, 2016 have been erected to allocate some records from the western Basin and the Adriatic, respectively. Nevertheless, records and material from the Aegean were not considered and hence they are provisionally still reported as S.rudis Schizomavella (Schizomavella) asymetricaCalyptothecatriarmata Hayward, 1974 S.auriculata, S.auriculatacuspidata and S.cuspidata possibly belong to this species.Ganias 1990SchizomavellalinearismamillataMorri et al. 1999Vigneaux, 1949Cossmann, 1906Bishop & Hayward, 1989Madurell, Zabala, Dom\u00ednguez-Carri\u00f3 & Gili, 2013Palmiskeneaaff.aviculifera), P.gautieri following Gray, 1848Gray, 1848Levinsen, 1909Oken, 1815NIBCastritsi-Catharios and Ganias 1989Gray, 1848NIBAntoniadou and Chintiroglou 2005\u200bCastritsi-Catharios and Kiortis 1985Gray, 1848NIBNIBGanias 1990Norman, 1903Norman, 1903Canu & Bassler, 1927Gray, 1848Ganias 1990Ganias 1990Harmer, 1926Ganias 1990Ganias 1990Gordon, 1984Morri et al. 1999Canu, 1900Norman, 1903Fernandez Pulpeiro & Reverter Gil, 1993\u200bGanias 1990Osburn, 1940Ganias 1990Brown, 1948Chimenz, Nicoletti & Lippi Boncambi, 1997d'Orbigny, 1851Lamouroux, 1816Simboura et al. 1995Vieira, Spencer Jones & Winston, 2013Ganias 1990Hayward 1974Vieira, Spencer Jones, Winston, Migotto & Marques, 2014Ganias 1990Van Beneden, 1845Harmelin, 1969Ganias 1990Morri et al. 1999Waters, 1897Ganias 1990Castritsi-Catharios et al. 1986aBusk, 1852Morri et al. 1999NIBMorri et al. 1999Fleming, 1828Ellis & Solander, 1786Lamouroux, 1816Ganias 1990Johnston, 1838Heller, 1867Heller, 1867Linnaeus, 1767Gray, 1848Morri et al. 1999Celleporahassalli), Morri et al. 1999\u200bMorri et al. 1999Alder, 1864Alder, 1864Ganias 1990Ryland, 1963Hayward, 1978Morri et al. 1999Gerovasileiou et al. 2015Hayward, 1978Busk, 1884Lamouroux, 1824\u200bMorri et al. 1999Vigneaux, 1949Hincks, 1879\u200bAntoniadou and Chintiroglou 2005Winston, 2005Osburn, 1940Ayari & Taylor, 2008Cigclisulaturrita)Levinsen, 1909Levinsen, 1909NIBHincks, 1879Jullien, 1886\u200bGanias 1990Jullien, 1886\u200bGanias 1990Jullien, 1886Ganias 1990Morri et al. 1999\u200bMorri et al. 1999Harmelin & Aristegui, 1987\u200bMorri et al. 1999Hayward 1974\u200bMorri et al. 1999Morri et al. 1999Vigneaux, 1949Canu & Bassler, 1925Antoniadou and Chintiroglou 2005d'Orbigny, 1851Gray, 1848Lamouroux, 1816Antoniadou and Chintiroglou 2005Gautier, 1954Ganias 1990Gregory, 1893Pieper, 1881\u200bGanias 1990Tilbrook, 2006Milne Edwards, 1836Zabala, Maluquer & Harmelin, 1993\u200bMorri et al. 1999Schizoporellavulgaris), S.vulgaris), Morri et al. 1999Gray, 1848Morri et al. 1999Canu & Bassler, 1917Ganias 1990David & Pouyet, 1978Berning, Tilbrook & Rosso, 2008Escharinaporosa), E.porosa), Berning et al. 2008\u200bHarmer, 1957Smitt, 1868\ufeff\ufeffMorri et al. 1999Duvergier, 1924NIBBassler, 1935Milne Edwards, 1836Celleporacoccinea), Antoniadou and Chintiroglou 2005Fleming, 1828Gray, 1848Barroso, 1949\u200bCastritsi-Catharios and Kiortis 1984Norman, 1903\u200bMorri et al. 1999Gordon in De Blauwe, 2009Levinsen, 1909\u200bMorri et al. 1999Winston, 2005Canu, 1919Gerovasileiou et al. 2015Levinsen, 1909Levinsen, 1909Cosciniopsis sp.), Ganias 1990\u200bNIBVigneaux, 1949Bishop & Hayward, 1989\u200bMorri et al. 1999Canu & Bassler, 1927Gautier, 1962Morri et al. 1999Busk, 1859Lamouroux, 1821Manzoni, 1870Jullien, 1888Levinsen, 1909Ganias 1990Harmer, 1957Harmer, 1957Hayward, 1974Ganias 1990Harmer, 1957Gray, 1843Ganias 1990Hincks, 1879Hincks, 1879Ganias 1990Jullien, 1888Morri et al. 1999Hincks, 1877NIBMicroporellaorientalis could belong to M.coronata This taxon corresponds to a complex of species . RecordeGray, 1848Jullien, 1888Morri et al. 1999Prenant & Bobin, 1966Hayward 1974Gray, 1848Ganias 1990Lamouroux, 1821Morri et al. 1999Morri et al. 1999Hincks, 1882Hincks, 1881Monoporellanodulifera and M.fimbriatacarinifera actually belong to this species, as suggested by Mediterranean specimens of Gray, 1841de Blainville, 1830\u200bGerovasileiou et al. 2015Jullien, 1882Jullien, 1882Ganias 1990\u200bGerovasileiou et al. 2015Neviani, 1895\u200bGanias 1990Jullien, 1882SmittiporaRectonychocella Harmelin 1969Soule, Soule & Chaney, 1991Chimenz-Gusso & Soule, 2003Cleidochasma sp.), Cleidochasmaporcellanum)Busk, 1884Ganias 1990ReteporellagrimaldiiR.septentrionalis Ganias 1990Harmer, 1933Hayward, 1974Ganias 1990Hincks, 1895Ganias 1990Gautier, 1962\u200bGerovasileiou et al. 2015Zabala & Maluquer, 1988sen\ufeffsu Hayward, 1974Gregory, 1893Ganias 1990Ganias 1990Hincks, 1877Ganias 1990Duvergier, 1921Ganias 1990Vigneaux, 1949Jullien in Jullien & Calvet, 1903Ganias 1990Jullien, 1888Gray, 1848Geraci, 1974Norman, 1894Morri et al. 1999Canu & Bassler, 1925Levinsen, 1909Levinsen, 1909Morri et al. 1999Jullien, 1883Canu & Bassler, 1920Morri et al. 1999Hincks, 1877Ganias 1990Ganias 1990Hincks, 1886Ganias 1990Antoniadou and Chintiroglou 2005Levinsen, 1909Hincks, 1877Ganias 1990Levinsen, 1909Osburn, 1952NIBGanias 1990Gautier, 1962Ganias 1990Norman, 1903Porellacervicornis), P.cervicornis), Chimenz Gusso et al. 2014\u200bGanias 1990Antoniadou and Chintiroglou 2005Osburn, 1952Ganias 1990Hayward 1974Antoniadou and Chintiroglou 2005Jullien, 1903Norman, 1869Gordon, Tilbrook & Winston, 2005Levinsen, 1909Canu, 1904Hincks, 1880Hastings, 1944Morri et al. 1999Vigneaux, 1949Neviani, 1896Watersiporasubovoidea probably belong to W.cucullata.Busk, 1852Johnston, 1838Lamouroux, 1813Castritsi-Catharios and Kiortis 1985Prouho, 1892Hincks, 1880Alder, 1857Alder, 1857\u200bGanias 1990d'Hondt, 1983Ehrenberg, 1838Castritsi-Catharios et al. 1986bHincks, 1877Jebram, 1973\u200bMorri et al. 1999Hincks, 1851Hincks, 1851Morri et al. 1999Harmer, 1915Gosse, 1851Ganias 1990Gosse, 1855Morri et al. 1999Osburn & Soule, 1953Soule, 1951Morri et al. 1999Hincks, 1880Lamouroux, 1812Morri et al. 1999NIBGanias 1990Ganias 1990Morri et al. 1999Calvet, 1911Morri et al. 1999Castritsi-Catharios et al. 1986bLamouroux, 1824Ganias 1990NIBConides et al. 1999Hincks, 1880Saville-Kent, 1870Saville-Kent, 1870Castritsi-Catharios et al. 1986bHincks, 1880Fleming, 1823Heller, 1867Morri et al. 1999Ganias 1990Borg, 1926Busk, 1852Hayward & Ryland, 1985Hayward & Ryland, 1985Stomatoporamajor), S.major), Morri et al. 1999\u200bHarmelin, 1976Ganias 1990Harmelin, 1976Harmelin, 1976Johnston, 1838Lamouroux, 1812Ganias 1990Milne Edwards, 1838Castritsi-Catharios et al. 1986bGanias 1990Harmelin, 1990Crisia sp. II), Harmer, 1891Simboura et al. 1995Waters, 1916Simboura et al. 1995Reuss, 1869Canu, 1918Busk, 1875Link, 1807Frondiporagracilis), Gerovasileiou et al. 2015Smitt, 1867Lamouroux, 1821Lamouroux, 1821Simboura et al. 1995Smitt, 1867Gray, 1848D.alboranensis Alvarez, 1992; all records need to be validated. Recorded by Lichenoporahispida), Gray, 1848\u200bAntoniadou and Chintiroglou 2005Ganias 1990Canu, 1918Canu, 1918\ufeff'M\ufefficroecia'occulta See Rosso et al. (2010)Canu, 1918Canu & Bassler, 1922Entalophorarugosa), Ganias 1990Canu & Bassler, 1920Harmelin, 1976Harmelin, 1976Canu, 1918DiplosolenobeliusD.obelius for this species has been proposed by obelium' and 'obelia', used inconsistently in the literature to ensure accordance to the gender of the genus name. The use of the name Morri et al. 1999Canu, 1918Antoniadou and Chintiroglou 2005Harmelin, 1976Ganias 1990Canu & Bassler, 1920Jullien, 1883Johnston, 1838Brood, 1976Harmelinoporaindistincta See Ganias 1990Canu & Bassler, 1920Harmelin, 1976Idmidroneacoerulea See Idmidroneatriforis See Idmidroneaatlantica), I.atlantica)Canu & Bassler, 1920Harmelin, 1976Morri et al. 1999Lamarck, 1816Harmelin, 1976Ganias 1990Ganias 1990Thompson in Harmer, 1898Morri et al. 1999Harmelin, 1976Gymnolaemata, comprising 198 species (177 Cheilostomatida and 21 Ctenostomatida) and the remaining 39 species are Stenolaemata . The families with the highest number of species belong to Cheilostomatida, and are Phidoloporidae (16 species), Celleporidae (14 spp.), Bugulidae (12 spp.), Calloporidae (12 spp.), Smittinidae (11 spp.), Candidae (10 spp.), and Cribrilinidae (10 spp.). These families are the most speciose in the Mediterranean Sea as well and I.coerulea Harmelin, 1976, allocated within the genus Idmidronea Canu and Bassler, 1920 and not Exidmonea David, Mongereau and Pouyet, 1972; 'Microecia' occulta , provisionally left in its former allocation because the characters of the species differ from those of the genus Oncousoecia Canu, 1918 that has been suggested for its allocation . The taxon Rhynchozoon sp. 1 sensu Hayward, 1974 described from Chios Island, was retained in the checklist following extensive lists by All species included in the checklist are recognized in the World List of A number of taxa were omitted from the present checklist Table for diffCheilostomatida, 36.8% of the Ctenostomatida and 52% of the Cyclostomatida species, based on the recent update by The bryozoan fauna of the Greek seas makes up 42.7% of the species, 59.9% of the genera and 71% of the families of the Mediterranean bryozoan fauna, specifically 41.7% of the Adeonellapallasii, Calyptothecarugosa, Celleporaposidoniae, Hippopodinaambita, Hippoporidrapicardi, Monoporellabouchardii, Plesiocleidochasmamediterraneum, Reteporellinadelicatula, Retevirgulaakdenizae, Smittiporadisjuncta, Thereniarosei and Turbicelleporacamera. Of these, 5 species were first described from the island of Chios based on material collected by Hayward , H.picardi was described from the Gulf of Thessaloniki, while R.akdenizae was described from the Turkish coasts of the Aegean Sea. The cheilostome Hippaliosinadepressa, which was described from the Aegean Sea, is considered more typical of the eastern Mediterranean basin, including the Sicily Strait, the western Ionian and south Adriatic seas , also reported from northern Catalonia , also reported from the western Ionian Sea .Interestingly, three of the bryozoans recorded from Greece are typical of the North Atlantic and haveatalonia , Escharinian Sea , and AnaAmathiagracillima and A.verticillata and the cheilostomes Bugulaneritina, Bugulinafulva, Crepidacanthapoissonii, Crisulariaplumosa, C.serrata, Exechonellaantillea, Hippopodinafeegeensis, Microporellacoronata, Parasmittinaraigii, and Scrupocellariascruposa.The recent introduction of non-indigenous species, mostly lessepsian migrants, over the last decades, has considerably increased the number of bryozoans occurring in the Mediterranean Sea . StudiesBryozoans from the Greek seas were reported from a variety of habitats, including soft sediments, seagrass leaves and rhizomes, macroalgae, coralligenous concretions and, to a smaller extent, from marine caves. Further research on bryozoan diversity in understudied habitats, typically species-rich in bryozoans , is expected to increase our knowledge, possibly revealing additional new and non-indigenous species.Supplementary material 1Bryozoa of GreeceChecklist of Marine \ufeffData type: Taxonomic checklistBryozoa known to occur in the Greek seas.Brief description: Taxonomic checklist of File: oo_104057.xlsVasilis Gerovasileiou, Antonietta Rosso"} +{"text": "CrystalPredictor II code: adaptive Local Approximate Models (LAMs). This improvement allows the most efficient use of computational effort to cover a flexible molecule\u2019s conformational space, and is illustrated with a crystal structure prediction (CSP) investigation into the sixth blind test molecule 26.This article describes an important improvement in the CrystalPredictor II [Habgood et al. placement. The entire search space of the relevant molecule\u2019s conformations is initially evaluated using a coarse, low accuracy grid. Additional LAM points are then placed at appropriate points determined via an automated process, aiming to minimize the computational effort expended in high-energy regions whilst maximizing the accuracy in low-energy regions. As the size, complexity and flexibility of molecules increase, the reduction in computational cost becomes marked. This improvement is illustrated with energy calculations for benzoic acid and the ROY molecule, and a CSP study of molecule (XXVI) from the sixth blind test [Reilly et al. methods requires a fine balance between accuracy and computational cost, particularly for the study of large flexible molecules. A major improvement in the accuracy and cost of the intramolecular energy function used in the al. 2015. J. Chem al. 2016. Acta Cr Because of the significant effect that crystal structure has on solid-state properties, such as colour, solubility and hygroscopicity, such a ranked list offers a wealth of information and many opportunities to improve the development of new crystalline materials , and the extent of the search for low-energy minima across the entire free-energy surface. In view of this, most CSP techniques use a broadly two-stage methodology: a first-stage global search that is used to search for low-energy structures on the lattice energy surface using a relatively low-cost, less accurate lattice energy model; and a second-stage refinement that takes the most promising structures from the first stage and re-ranks them via local energy minimization, using a more accurate and computationally demanding lattice energy model. All the successful predictions in the sixth blind test ; therefore, the efficiency of the lattice energy model is very important. Moreover, since only a relatively small proportion of the lowest-energy structures identified will be passed for refinement to the second stage, the lattice energy model employed by the first stage also needs to be sufficiently accurate not to exclude any potential polymorphs from further consideration.In order to identify all potential low-energy polymorphs, the first stage must perform an extensive search of the lattice energy surface over sufficiently wide ranges of the lattice energy model variables an electrostatic term, ab initio calculations, and (b) a repulsion/dispersion term, et al., 1981et al., 1996i.e. in vacuo, with all internal degrees of freedom allowed to vary). To avoid expensive repeated ab initio calculations for the evaluation of the terms CrystalPredictor to obtain a low-cost approximation of these energies at any point. The two versions of CrystalPredictor differ in how the approximation is constructed. In CrystalPredictor II, the intramolecular energy at some value A and C and the vector b are given by from the sixth blind test.A motivating example for the development of an improved algorithm is introduced in \u00a722.CrystalPredictor were deployed by two of the participating groups, in combination with CrystalOptimizer, to identify Z\u2032 = 1 structures. This approach resulted in the identification of the known experimental structures within the predicted energy landscapes in most cases. However, in the case of molecule (XXVI), shown in Fig. 1CrystalPredictor II.The recent blind test on crystal structure prediction methods, organized by the Cambridge Crystallographic Data Centre, sought to evaluate the capabilities of current computational methods in predicting the crystal structures of organic molecules. Five targets were chosen, representing challenges to the crystal structure prediction community. The two versions of et al. contains the common 1,1\u2032-binaphthalene fragment, which can feature axial chirality, although no chiral precursors were present in the synthesis. As reported by Reilly al. 2016, there aet al., 2016CrystalPredictor I and CrystalOptimizer by the Price et al. group successfully led to the identification of form (1) as the lowest energy structure in the final landscape. The use of CrystalPredictor I, however, required making severe assumptions on flexibility to limit the computational cost; as is usually done with CrystalPredictor I when there are many flexible degrees of freedom, the flexible torsion angles were divided into three groups . This approach has been successful in other investigations made use of CrystalPredictor II is to also evaluate the intramolecular energies at the edges of the search space; if these are found to be lower than a user-specified threshold , the search space is expanded. In the case of molecule (XXVI), this investigation identified energies lower than 10\u2005kJ\u2005mol\u22121 on the boundaries of the domains for torsions T3 and T5, and therefore these domains would normally have to be expanded quite significantly. However, a larger regular grid with the domain of the two key torsions extended by the necessary 120\u00b0 would involve 11\u2005858 LAMs, and their construction would require approximately 910\u2005000 CPU\u2005h. As this was impracticable within the time constraints of the blind test, it was decided not to extend the search beyond the domains indicated in Table 1Our normal practice in the applications of As indicated in Table 13.This section presents an adaptive algorithm that automatically positions LAMs at points in the search domain of the independent degrees of freedom, where necessary to ensure the required degree of accuracy. Firstly, the revised algorithm for generating new LAMs is summarized in \u00a73.13.1.The basic idea of the adaptive LAM placement algorithm proposed in this paper is to take an existing set of LAMs placed over the search domain of the independent conformational degrees of freedom Establishing the exact error of the approximation provided by a LAM at a particular point i.e.M, there are two additional conditions we need to consider. First, it is unnecessary to generate a LAM at point M if the latter is unlikely to be inside the region which would be relevant for the purposes of CSP, i.e. if M isA and B are indeed those nearest to point M. If there exists a third LAM C which is nearer to M than either A or B, then of course the accuracy of the approximations provided by the LAMs at A and B at point M is irrelevant: neither of those would be used during the search to determine the quantity M isk other than A and B, where the norm In particular, we assume that the maximum discrepancy between the predictions of two LAMs generated at points A, B), determine its midpoint M, and test criteria (9)\u2013(11)M, and the procedure is repeated until no more new LAMs are found to be necessary.The above ideas provide the basis of the new adaptive algorithm for LAM generation. Given any set of LAMs, we consider each and every pair level of theory.In order to better understand the concept of adaptive LAM placement, we first consider a molecule with a single independent degree of freedom, namely benzoic acid , there is clearly a significant mismatch (9.2\u2005kJ\u2005mol\u22121) in the intramolecular energy contribution predicted by adjacent LAMs at T1 = \u00b1 60\u00b0. This can be corrected by inserting two LAMS at these positions, as illustrated in Fig. 3b). On the other hand, there is no such mismatch at the boundary between the original second and third LAMs at T1 = 0\u00b0, and therefore no new LAM needs to be inserted there. This consistency check, in which different LAM predictions are compared to each other, ensures that the intramolecular energy is described consistently by the LAMs at the given boundary. It does not, however, guarantee that that ab initio accuracy is achieved, although we note that LAMs have been shown to represent ab initio results very well in their locality , as opposed to the 6 LAMs shown in Fig. 3b). Whilst only a small saving is achievable in this simple case, much more marked efficiencies can be achieved for molecules involving multiple independent degrees of freedom, as illustrated by the next example.Overall, achieving the same level of accuracy with a regular grid would require a grid spacing of 3.3.T1 and T2, as shown in Fig. 4T1 The adaptive algorithm is further illustrated for the ROY molecule (5-methyl-2-[(2-nitrophenyl)\u00adamino]-3-thiophenecarbonitrile) Yu, 2010, which ib). The minimum spacing between these LAMs is 14\u00b0; a regular grid constructed over the original domain would require about 163\u2005LAMs to achieve the same minimum spacing (b) also shows the positions of the six known experimental forms of ROY and (b), respectively. It is clear that the low conformational energy regions are not rectangular, i.e. there is significant interaction between the two torsional angles. It can also be seen that the adaptive LAM placement leads to a smoother intramolecular energy surface in these key regions.The intramolecular energy predictions by the original and final sets of LAMs are shown in Figs. 6ab initio over the same range of degrees of freedom at 5\u00b0 increments and shown in Fig. 6c). Visual comparison of the three energy landscapes show that key qualitative features are captured by both LAM-based approximations. A more quantitative comparison is presented in Figs. 7a) and (b), where the differences between the LAM approximation and the ab initio energies are computed at 5\u00b0 intervals. The average absolute deviation for the regular coarse grid scheme is 0.75\u2005kJ\u2005mol\u22121, while for the adaptive scheme it is 0.56\u2005kJ\u2005mol\u22121. More importantly, it is evident that with the regular grid, there are many areas in which the error is more than 5\u2005kJ\u2005mol\u22121, particularly at the edges of LAM validity. This can lead to the generation of a low-accuracy energy landscape during the global search, in which some structures are found to have unrealistically low or high lattice energy. Finally, it can be seen that in the areas surrounding the experimental structures (black triangles), improved accuracy is achieved.The intramolecular energy contribution is also computed 4.cf. \u00a72The proposed algorithm is now applied to molecule (XXVI) from the sixth blind test . The figures show the differences between the value of ab initio value. The underlying data are generated by varying T1 and T7 in 2\u00b0 increments, while keeping the other 5 torsional angles constant at the values T2 = 180.0\u00b0, T3 = 170.0\u00b0, T4 = 70.0\u00b0, T5 = 230.0\u00b0 and T6 = 180.0\u00b0.The accuracy gain achieved by the judicious placement of new LAM points is illustrated in Fig. 8a) shows results obtained using the initial LAM set on a regular grid. The four nearest LAMs used for this purpose are outside the domain shown. As can be seen, the values of \u22121 across the sub-region and a value of 1.01\u2005kJ\u2005mol\u22121 at the experimental values of T1 and T7. On the other hand, Fig. 8b) shows results obtained with the final LAM set which now includes a new LAM placed at the position indicated by the open circle. It can clearly be seen that the addition of this single new point in this sub-region results in very substantial reduction in the error in \u22121, with the error at the experimental values of T1 and T7 being just 0.09\u2005kJ\u2005mol\u22121.Fig. 8As has already been noted in \u00a724.2.CrystalPredictor II, making use of the LAM set determined above. As shown in Fig. 9\u22121 of the global minimum, with 465 and 1413 unique structures being identified within, respectively, 20 and 30\u2005kJ\u2005mol\u22121. The experimental form is identified as the 130th lowest energy structure, with a lattice energy 12.27\u2005kJ\u2005mol\u22121 greater than the global minimum, and a good reproduction of the experimental geometry (RMSD20 = 0.595\u2005\u00c5).A global search over 1\u2005000\u2005000 candidate structures is performed using 4.3.CrystalOptimizer minimizations are performed on the 1413 unique structures that were identified within 30\u2005kJ\u2005mol\u22121 from the global minimum ; thus, refinement using a more accurate lattice energy model and taking account of a higher degree of conformational flexibility has resulted in substantial clarification of the polymorphic landscape. We also note that the geometry of the experimental structure is reproduced with good accuracy (RMSD20 = 0.330\u2005\u00c5), as illustrated in Fig. 12The resulting energy landscape is presented in Fig. 11The computational cost of the CSP study is summarized in Table 45.et al., 2016CrystalPredictor II algorithm, an improvement on the uniform grid scheme which had proved too computationally demanding to apply to molecule (XXVI). A higher density of LAM points is automatically achieved in chemically interesting areas of conformational space, thereby resulting in a more efficient use of expensive ab initio calculations. This, in turn, allows the CrystalPredictor II algorithm to handle larger molecules and to explore larger areas of conformational space, through an effective global search methodology. The successful application of this new approach to molecule (XXVI) realises one of the aims of the blind tests, namely to drive innovation in CSP by providing unique and challenging molecular systems.The 2016 blind test 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322. DOI: 10.1107/S2052520616015122/wf5128sup2.pdfFurther developments. DOI: 1506361, 1506362, 1506363, 1506364, 1506365, 1506366, 1506367, 1506368, 1506369, 1506370, 1506371, 1506372, 1506373, 1506374, 1506375, 1506376, 1506377, 1506378, 1506379, 1506380, 1506381, 1506382, 1506383, 1506384, 1506385, 1506386, 1506387, 1506388, 1506389, 1506390, 1506391, 1506392, 1506393, 1506394, 1506395, 1506396, 1506397, 1506398, 1506399, 1506400, 1506401, 1506402, 1506403, 1506404, 1506405, 1506406, 1506407, 1506408, 1506409, 1506410, 1506411, 1506412, 1506413, 1506414, 1506415, 1506416, 1506417, 1506418, 1506419, 1506420, 1506421, 1506422, 1506423, 1506424, 1506425, 1506426, 1506427, 1506428, 1506429, 1506430, 1506431, 1506432, 1506433, 1506434, 1506435, 1506436, 1506437, 1506438, 1506439, 1506440, 1506441, 1506442, 1506443, 1506444, 1506445, 1506446, 1506447, 1506448, 1506449, 1506450, 1506451, 1506452, 1506453, 1506454, 1506455, 1506456, 1506457, 1506458, 1506459, 1506460, 1506461, 1506462, 1506463, 1506464, 1506465, 1506466, 1506467, 1506468, 1506469, 1506470, 1506471, 1506472, 1506473, 1506474, 1506475, 1506476, 1506477, 1506478, 1506479, 1506480, 1506481, 1506482, 1506483, 1506484, 1506485, 1506486, 1506487, 1506488, 1506489, 1506490, 1506491, 1506492, 1506493, 1506494, 1506495, 1506496, 1506497, 1506498, 1506499, 1506500, 1506501, 1506502, 1506503, 1506504, 1506505, 1506506, 1506507, 1506508, 1506509, 1506510, 1506511, 1506512, 1506513, 1506514, 1506515, 1506516, 1506517, 1506518, 1506519, 1506520, 1506521, 1506522, 1506523, 1506524, 1506525, 1506526, 1506527, 1506528, 1506529, 1506530, 1506531, 1506532, 1506533, 1506534, 1506535, 1506536, 1506537, 1506538, 1506539, 1506540, 1506541, 1506542, 1506543, 1506544, 1506545, 1506546, 1506547, 1506548, 1506549, 1506550, 1506551, 1506552, 1506553, 1506554, 1506555, 1506556, 1506557, 1506558, 1506559, 1506560, 1506561, 1506562, 1506563, 1506564, 1506565, 1506566, 1506567, 1506568, 1506569, 1506570, 1506571, 1506572, 1506573, 1506574, 1506575, 1506576, 1506577, 1506578, 1506579, 1506580, 1506581, 1506582, 1506583, 1506584, 1506585, 1506586, 1506587, 1506588, 1506589, 1506590, 1506591, 1506592, 1506593, 1506594, 1506595, 1506596, 1506597, 1506598, 1506599, 1506600, 1506601, 1506602, 1506603, 1506604, 1506605, 1506606, 1506607, 1506608, 1506609, 1506610, 1506611, 1506612, 1506613, 1506614, 1506615, 1506616, 1506617, 1506618, 1506619, 1506620, 1506621, 1506622, 1506623, 1506624, 1506625, 1506626, 1506627, 1506628, 1506629, 1506630, 1506631, 1506632, 1506633, 1506634, 1506635, 1506636, 1506637, 1506638, 1506639, 1506640, 1506641, 1506642, 1506643, 1506644, 1506645, 1506646, 1506647, 1506648, 1506649, 1506650, 1506651, 1506652, 1506653, 1506654, 1506655, 1506656, 1506657, 1506658, 1506659, 1506660, 1506661, 1506662, 1506663, 1506664, 1506665, 1506666, 1506667, 1506668, 1506669, 1506670, 1506671, 1506672, 1506673, 1506674, 1506675, 1506676, 1506677, 1506678, 1506679, 1506680, 1506681, 1506682CCDC references:"} +{"text": "Scientific Reports6: Article number: 2959010.1038/srep29590; published online: 07142016; updated: 09142016In the original version of this Article, there were errors in Affiliation 2 and 6 which were incorrectly listed as \u2018Department of Nursing, Department of Surgery, Saint Mary\u2019s Hospital Luodong. No. 160, Zhongheng S. Rd., Luodong, Yilan 26546, Taiwan, R.O.C.\u2019 and \u2018Division of Nephrology in Department of Internal Medicine, Department of Surgery, Saint Mary\u2019s Hospital Luodong. No. 160, Zhongheng S. Rd., Luodong, Yilan 26546, Taiwan, R.O.C.\u2019 respectively. The correct affiliations are listed below.Affiliation 2Department of Nursing, Saint Mary\u2019s Hospital Luodong. No. 160, Zhongheng S. Rd., Luodong, Yilan 26546, Taiwan, ROC.Affiliation 6Division of Nephrology, Department of Internal Medicine, Saint Mary\u2019s Hospital Luodong. No. 160, Zhongheng S. Rd., Luodong, Yilan 26546, Taiwan, ROC.These errors have now been corrected in the PDF and HTML versions of the Article."} +{"text": "The author initials were not complete in the original publication .The correct initials should be: \u201cCI Busard, SP Menting, JS van Bezooijen, JM van den Reek, BA Hutten, EP Prens, EM de Jong, MB van Doorn, PI Spuls\u201d."} +{"text": "The thymectomy specimens from the \u201cthymectomy trial in non-thymomatous myasthenia gravis patients receiving prednisone therapy\u201d (MGTX) underwent rigid and comprehensive work-up, which permits analysis of the spatial distribution of histological and immunohistological features. This analysis revealed strong intra- and inter-case variability. While many histological features (e.g. median percent fat content among different specimens) can easily be correlated with clinical parameters, intra-case spatial variability of histological features has yet defied quantification and statistical evaluation. To overcome this gap in digital pathology, we here propose intra-case entropy of measured histological features in all available slides of a given thymectomy specimen as a quantitative marker of spatial histological heterogeneity. Calculation of entropy led to one value per specimen and histological feature. Through these \u2018entropy values\u2019 the so far neglected degree of spatial histological heterogeneity could be fed into statistical analyses, extending the scope of clinico-pathological correlations. The \u201cthymectomy trial in non-thymomatous myasthenia gravis patients receiving prednisone therapy\u201d (MGTX) showed tThe objective of this analysis is to correlate quantitative histological findings with clinical outcome parameters to eventually identify at the time of surgery pathological features with prognostic value in terms of MG outcome. Furthermore, it is hoped that recommendations for an appropriate and economical evaluation of thymectomy specimens will result from the analysis.2 were obtained from defined regions of the right and left thymic lobe above and below the central plane underwent a pre-defined standard diagnostic protocol: First, all sections were hematoxylin-eosin (HE)-stained and evaluated for percentage of fat tissue on the slide; percentage of intra-thymic fat tissue; grading of cortical atrophy; grading of follicular hypertrophy; number of follicles, and proportion of cortical and medullary areas . Second,This process led to 16 histological variables per slidhttp://dx.doi.org/10.11588/data/NWE2JJ).The raw data we are dealing with in this work has been collected in the course of the MGTX trial and is centrally managed by the MGTX Data Coordinating Center , 4. The www.fiji.sc) and automatic image processing in MATLAB and saved in spreadsheets . Furthermore, demographic and clinical data associated with each case were obtained from Dr. Cutter, University of Alabama at Birmingham and submitted in spreadsheets.As described above data werwww.r-project.org) and merged into two main databases: one database with values per slide and another database with summation values per case (on the basis of unique case IDs).All these datasheets were gathered in R (www.r-project.org) by built-in functions or separately loaded libraries , 2019, 2Translating these statistical findings into common clinicopathological terms, it appears that thymectomy specimens with more heterogeneous fat distribution show a trend for higher postoperative prednisone requirements, which is a surrogate for a more delayed clinical improvement. However, due to the great heterogeneity of our data, this correlation is not sufficient to predict clinical outcome.Generally speaking, entropy belongs to the few basic measurable entities in nature. It can be mathematically formulated using different axioms. For example, Shannon\u2019s entropy definition follows a basic additive algorithm (H1+H2 = H3), in contrast to Pincus\u2019s entropy which includes a non-zero additional term dependent upon boundary conditions . Having Basically, the relation of the entropy to the number of measurement points is one possible limitation. However, we could rule out this potential flaw as illustrated in section 8.3: We did not find a significant correlation between the sample sizes and entropy values using our data. However, regarding the strategy of tissue work-up, the strong relation between entropy and the number of sample points argues for an exentsive work-up scheme with sufficiently spaced sampling point: Too few or too closely located sampling points would reduce the meaningfulness of the resulting entropy value. Another possible limitation is the choice of the number of parameter levels compare : For intIn imaging based disciplines the term \u201centropy\u201d has mostly been used in the context of image processing as a textural feature. For instance, in radiology the \u2018textural entropy\u2019 has been used to predict different stages of rectal cancer or the sHowever, since it is a tool to measure any type of system complexity, entropy analysis and its variations (e.g. \u201cminimum spanning tree (MST) entropy\u201d) might be useful wherever heterogeneity plays a diagnostic or biological role, be it in cancer or beyond , 28\u201330: Beyond the analysis of heterogeneity of tissue images, entropy analysis may help to quantify the heterogeneity of RNA-seq data and the Data Coordinating Center: Gary R. Cutter, Inmaculada B. Aban, Greg Minisman, Michelle Feese, Hui-Chien Kuo .Trial Leadership: John Newsom-Davis ; Gil I. Wolfe ; Henry J. Kaminski ; Alfred Jaretzki III, Joshua R. Sonett .Argentina: Claudio Mazia, Valeria Saluto, Moises Rosenberg, Valeria Alvarez, Lisa Rey .Australia: John King, Helmut Butzkueven, John Goldblatt, John Carey ; John Pollard, Stephen Reddel, Nicholas Handel, Brian McCaughan, Linda Pallot .Brazil: M\u00e1rcia Waddington-Cruz, Ricardo Novis, Carlos Boasquevisque ; Elza Dias-Tosta, Rubens Morato-Fernandez, Manoel Ximenes ; Lineu Werneck, Rosana Scola, Paulo Soltoski .Canada: Colin Chalk, Fraser Moore, David Mulder, Lisa Wadup ; Joel Oger, Michele Mezei, Kenneth Evans, Theresa Jiwa, Anne Schaffar ; Chris White, Cory Toth, Gary Gelfand, Susan Wood ; Elizabeth Pringle, Jocelyn Zwicker, Donna Maziak, Farid Shamji, Sudhir Sundaresan, Andrew Seely .Chile: Gabriel Cea, Renato Verdugo, Alberto Aguayo .Germany: Sebastian Jander, Philipp Zickler, Michael Klein ; Alexander Marx, Philipp Str\u00f6bel, Cleo-Aron Weis ; Arthur Melms, Felix Bischof, Hermann Aebert, Gerhard Ziemer ; Wilfred Nix, Bj\u00f6rn Th\u00fcmler, Thomas Wilhem-Schwenkmezger, Eckhard Mayer ; Berthold Schalke, Peter P\u00f6schel, Gisela Hieber ; Karsten Wiebe .Italy: Giovanni Antonini, Alessandro Clemenzi, Vanessa Ceschin, Erino Rendina, Federico Venuta, Stefania Morino, Elisabetta Bucci ; Luca Durelli, Alessia Tavella, Marinella Clerico, Giulia Contessa, Piero Borasio ; Amelia Evoli, Serenella Servidei, Pierluigi Granone ; Renato Mantegazza, Emilia Berta, Lorenzo Novellino, Luisa Spinelli .Japan: Masakatsu Motomura, Hidenori Matsuo, Takeshi Nagayasu ; Hiroaki Yoshikawa, Masaharu Takamori, Makoto Oda, Isao Matsumoto, Yutaka Furukawa, Daisuke Noto, Yuko Motozaki, Kazuo Iwasa, Daisuke Yanase .Mexico: Guillermo Garcia Ramos, Bernardo Cacho, Lorenzo de la Garza .Poland: Anna Kostera-Pruszczyk, Marta Lipowska, Hubert Kwiecinski, Anna Potulska-Chromik ; Tadeusz Orlowski .Portugal: Ana Silva, Marta Feijo, Ant\u00f3nio Freitas .South Africa: Jeannine Heckmann, Andrew Frost, Edward Lee Pan, Lawrence Tucker, Johan Rossouw, Fiona Drummond .Spain: Isabel Illa, Jorge Diaz, Carlos Leon .Taiwan: Jiann-Horng Yeh, Hou-Chang Chiu, Yei-San Hsieh .Thailand: Rawiphan Witoonpanich, Supoch Tunlayadechanont, Sukasom Attanavanich .The Netherlands: Jan Verschuuren, Chiara Straathof, Maarten Titulaer, Michel Versteegh, Arda Pels, Yvonne Krum .United Kingdom: Camilla Buckley, M. Isabel Leite, Angela Vincent, David Hilton-Jones, Chandi Ratnatunga, John Newsom-Davis ; Maria Elena Farrugia, Richard Petty, James Overell, Alan Kirk ; Andrew Gibson, Chris McDermott, David Hopkinson ; Bryan Lecky, David Watling, Dot Marshall, Sam Saminaden, Deborah Davies, Charlotte Dougan, Siva Sathasivam, Richard Page, Dot Marshall ; Jon Sussman, John Ealing, Peter Krysiak .United States: Anthony Amato, Mohammad Salajegheh, Michael Jaklitsch, Kristen Roe ; Tetsuo Ashizawa, Robert Glenn Smith, Joseph Zwischenberg, Penny Stanton ; Alexandru Barboi, Safwan Jaradeh, William Tisol, Mario Gasparri, George Haasler, Mary Yellick, Cedric Dennis ; Richard Barohn, Mamatha Pasnoor, Mazen Dimachkie, April McVey, Gary Gronseth, Arthur Dick, Jeffrey Kramer, Melissa Currence, Laura Herbelin ; Jerry Belsh, Geoge Li, John Langenfeld, Mary Ann Mertz ; Michael Benatar ; Taylor Harrison, Seth Force, Sharon Usher ; Said Beydoun, Frank Lin, Steve DeMeester, Salem Akhter, Ali Malekniazi, Gina Avenido ; Brian Crum, Margherita Milone, Stephen Cassivi, Janet Fisher ; Emma Ciafaloni, Chad Heatwole, Thomas Watson, James Hilbert, Alexis Smirnow ; B. Jane Distad, Michael Weiss, Douglas Wood, Joanna Haug ; Raina Ernstoff, Jingyang Cao, Gary Chmielewski, Robert Welsh, Robin Duris ; Laurie Gutmann, Gauri Pawar, Geoffrey Marc Graeber, Patricia Altemus, Christopher Nance, Ludwig Gutmann ; Carlayne Jackson, Patrick Grogan, John Calhoon, Pamela Kittrell, Deborah Myers ; Henry Kaminski, Ghazala Hayat, Keith Naunheim, Susan Eller, Eve Holzemer ; Bashar Katirji, Amer Alshekhlee, Jason Robke, Brenda Karlinchak ; Jonathan Katz, Robert Miller, Ralph Roan, Dallas Forshew ; John Kissel, Bakri Elsheikh, Patrick Ross, Sharon Chelnick ; Richard Lewis, Agnes Acsadi, Frank Baciewicz, Stacey Masse ; Janice Massey, Vern Juel, Mark Onaitis, James Lowe, Bernadette Lipscomb ; Tahseen Mozaffar, Gaby Thai, Jeffrey Milliken, Veronica Martin, Ronnie Karayan ; Suraj Muley ; Gareth Parry, Sara Shumway ; Shin Oh, Gwen Claussen, Liang Lu, Robert Cerfolio, Angela Young, Marla Morgan ; Robert Pascuzzi, John Kincaid, Kenneth Kesler, Sandy Guingrich, Angi Michaels ; Lawrence Phillips, Ted Burns, David Jones, Cindy Fischer ; Michael Pulley, Alan Berger, Harry D\u2019Agostino, Lisa Smith ; Michael Rivner, Jerry Pruitt, Kevin Landolfo, Demetric Hillman ; Aziz Shaibani, Angelo Sermas, Ross Ruel, Farah Ismail ; Mark Sivak, Martin Goldstein, Jorge Camunas, Joan Bratton ; Rup Tandan, Hill Panitch, Bruce Leavitt, Marilee Jones ; Gil Wolfe, Srikanth Muppidi, Steven Vernino, Sharon Nations, Dan Meyer, Nina Gorham ."} +{"text": "Upon publication of the original article , it was Costello ME, Ciccia F, Willner D, Warrington N, Robinson PC, Gardiner B, Marshall M, Kenna TJ, Triolo G, Brown MA: Brief Report: Intestinal Dysbiosis in Ankylosing Spondylitis. Arthritis Rheumatol 2015, 67:686-691"} +{"text": "AbstractIchneumonidae is revised, based in large part on the collections of the Natural History Museum, London and the National Museums of Scotland, Edinburgh. Distribution records are provided at the country level.The checklist of British and Irish Neorhacodinae is considered to be a separate subfamily rather than a synonym of Tersilochinae. Echthrini is treated as a junior synonym of the tribe Cryptini, not Hemigastrini. Echthrus Gravenhorst and Helcostizus F\u00f6rster are classified in Cryptini rather than, respectively, Hemigastrini and Phygadeuontini.Of the 2,447 species regarded as valid and certainly identified, 214 are here recorded for the first time from the British Isles. Ichneumonidae is one of two families of the superfamily Ichneumonoidea, along with the Braconidae. Given the size of each family in Britain we are publishing the two checklists separately. This is one part of a series of papers revising the British and Irish list of Hymenoptera, that started with Hymenoptera checklists see Ichneumonidae that was not really reflected in his published output. I have made great use of Perkins\u2019s identifications as well as Horstmann\u2019s, Andrey Khalaim\u2019s and many other workers, including my own. Many Irish records are taken from The Hemigastrini and Phygadeuontini - Echthrus Gravenhorst and Helcostizus F\u00f6rster - are transferred to Cryptini and reflecting differences in host use.All additions to and deletions from the British list since Ichneumonidae. A handbook to the British fauna provides an introduction to the biology, classification and identification of this family of parasitoid wasps and will be published soon.Figs Hymenoptera checklist, see online. Conventions and abbreviations are listed below.For a more detailed description of the background and rationale to the species] taxon deleted from the British and Irish list# known introductions occurring only under artificial conditions? status (including uncertain synonymy) or identification in the British Isles uncertainmisident. has been misidentified as this namenomen dubium, a name of doubtful statusnom. dub. nomen oblitum, \u2018forgotten name\u2019, does not have priority over a younger namenom. ob. nomen novum, a replacement namenom. nov. nomen nudum, an unavailable name, with no type specimennom. nud. junior homonym)preocc. name preoccupied stat. rev. unavailable name unavailable under provisions of the ICZN codevar. variety, only available as a valid name under certain provisions of the ICZN codeWhen there are no countries listed for a species, there are two explanations. First, the species has been carried over from the previous checklist and, altHymenoptera checklist, will be kept up to date in a Scratchpad, Hymenoptera of the British Isles.Alternative versions of the checklist can be downloaded here as a Word document or Excel spreadsheet under supplementary materials: Suppl. materials F\u00f6rster, 1869Acaenitinae (formerly Acaenitini and Coleocentrini) were abandoned by Tribes within Latreille, 1809ACOENITES Latreille, 1810ACOENITUS Griffith, 1832Ichneumondubitator Panzer, 1800ScotlandGravenhorst, 1829ASTHENOMERIS F\u00f6rster, 1869SPHALERUS Kriechbaumer, 1878annulicornis synonymised by Varga (2013)Gravenhorst, 1829bifasciatusSphalerus) Macruscroceicornis Gravenhorst, 1829EnglandColeocentrussoleatus was removed from synonymy by Ichneumonexcitator Poda, 1761segmentatorIchneumon) Strobl, 1902Lampronotanotabilis Desvignes, 1856frauenfeldiLissonota) Ichneumonterebrator Scopoli, 1763aratorIchneumon) Kasparyan, 1986ScotlandNMS, det. Shaw, added hereHolmgren, 1857limbatus Thomson, 1888montivagator Aubert, 1976England, Scotland, Irelandchrysopygus (Grav.) referred to by punctulatus Thoms.; chrysopygus is the correct name for the species referred to as granulatus Perkins by The Perkins, 1943EnglandHemiteleschrysopygus Gravenhorst, 1829granulatus Perkins, 1943England, Scotland, Ireland, Isle of ManHolmgren, 1857EnglandNMS, det. Shaw, added hereHemitelesdorsalis Gravenhorst, 1829melanius Roman, 1918insolitusEpitropus) Thomson, 1883England, IrelandShaw & Wahl, 2014England, Scotlandadded by Shaw and Wahl (2014)Thomson, 1888England, Walessome distribution data from Askew (2000)Holmgren, 1857England, Irelandadded by Fitton et al. (1982)Kasparyan, 1986England, Scotlandadded by Kasparyan (1990)Plectiscuspallipes Gravenhorst, 1829ruthei Holmgren, 1857pallidipesPlectiscus) Plectiscustenthredinarum Giraud, 1872nigricornis Thomson, 1888EnglandIchneumontetratinctorius Thunberg, 1824fasciatus Thomson, 1883scabriculus Thomson, 1883England, IrelandSchmiedeknecht, 1911thuringiacus Schmiedeknecht, 1911England, IrelandHaliday, 1838Distribution data from Curtis, 1832CROTOPUS Holmgren, 1859ATOPOTYPUS Chao, 1992Atopotypus synonymised by Bennett (2001)Curtis, 1832abnormisCrotopus) Ichneumondebellator Fabricius, 1775fischeriIchneumon) Ichneumoncruentatus Geoffroy, 1785petiolatumIchneumon) ] brevicollis from Killiecrankie, Scotland, as a species of Agrypon. As this species is now included in Perisphincter ] Listed as a doubtfully placed species of Agrypon by Cremastus. Recorded by J.P. Brock (pers. comm.) has not seen any authentic British material of this species. Only known in Britain from L. Carr material (supposedly from Lichfield) and hence should have been excluded from the previous checklist . See Identified by impressor Grav., based on Morley\u2019s interpretation of Thomson\u2019s interpretation; the species involved is apparently undescribed .Englandadded by Brock (in prep.)F\u00f6rster, 1869DICERATOPS F\u00f6rster, 1869SYZEUCTA Thomson, 1889Syzeuctus excluded from the British and Irish list:Species of irrisorius ] Brock (in prep.) found no British specimens of irrisorius. Recorded from Ireland by Misidentified scalaris are described by Brock (in prep.) as Glypa sp. PU. British specimens identified as teres have proved to be misidentified bifoveolata . Listed as Sinophorusarvensis by [Campoplex excluded from the British and Irish list:species of borealis ] All British specimens in NMS were reidentified as C.caloptiliae by Horstmann On earlier versions of this checklist, C.melanostoma was included based on a reared specimen in NMS, but this was based on a misidentification of C.punctulatus.ScotlandNMS, det. Horstmann, added hereHolmgren, 1859AMORPHOTA F\u00f6rster, 1869ANEMPHERES F\u00f6rster, 1869CAMPOTREPHUS F\u00f6rster, 1869HOROGENES F\u00f6rster, 1869NOTHANOMALON Sz\u00e9pligeti, 1905TROPHOCAMPA Schmiedeknecht, 1907CASINARIODES Aubert, 1960Tschek, 1871IrelandCampoplexalbipalpis Gravenhorst, 1829IrelandThomson, 1887England, IrelandCampoplexmoestus Gravenhorst, 1829maesta Dalla Torre, 1901 preocc.Englandadded by Horstmann (2000d)Holmgren, 1860EnglandBrischke, 1880pallidipes Dalla Torre, 1901England, IrelandMesoleptuspetiolaris Gravenhorst, 1829claviventris Holmgren, 1860EnglandCampoplextenuiventris Gravenhorst, 1829conicaCampoplex) Ichneumoncantator DeGeer, 1778decipiensCampoplex) Campoplexcerophagus Gravenhorst, 1829picticrusOmorga) Campoplexcruentata Gravenhorst, 1829marginellaPorizon) Campoplexdeclinator Gravenhorst, 1829fasciataThymaris) preocc. taken from Distribution data for some species Limneriaaculeata Bridgman, 1889atrumAngitia) Limneriaagilis Brischke, 1880Horstmann, 1969England, ScotlandNMS, det. Horstmann, added hereHorogenesangulator Aubert, 1963England, IrelandNMS, det. Horstmann, added hereAngitiaannulicrus Thomson, 1887Angitiaanura Thomson, 1887England, Scotlandadded by Shaw and Horstmann (1997)Limneriaareolaris Holmgren, 1860IrelandAdded by Horstmann, 2004ScotlandNythobia but subgenera have not been used here.added by Campoplexarmillatus Gravenhorst, 1829tibialeCampoplex) was removed from synonymy by Horstmann, 2013Englandadded by Horstmann (2013)Horstmann, 1969EnglandNMS, det. Horstmann, added hereAngitiabrevivalvis Thomson, 1887EnglandNMS, det. Horstmann, added hereHorstmann, 1993ScotlandNMS, det. Horstmann, added hereIchneumonchrysostictos Gmelin, 1790corsicatorHorogenes) Angitiaclaripennis Thomson, 1887Irelandadded by Limneriaclavicornis Brischke, 1880Campoplexcoleophorarum Ratzeburg, 1852England, ScotlandLimneriacombinata Holmgren, 1860alpinator Aubert, 1970England, Scotland, IrelandHorstmann, 2013Scotlandadded by Horstmann (2013)Campoplexconsumtor Gravenhorst, 1829variansLimneria) Campoplexcrassicornis Gravenhorst, 1829carnifexCampoplex) Angitiacrassiseta Thomson, 1887EnglandBMNH, det. Perkins, added hereLimneriacrassa Bridgman, 1889England, ScotlandHorstmann, 1980England, Scotlandadded by Horstmann (1980a)Limneriacylindrica Brischke, 1880England, IrelandNoted as occurring in England and Ireland by various authors but not listed by Horstmann, 1980England, Scotlandadded by Shaw and Horstmann (1997)Limneriaelishae Bridgman, 1884England, Scotland, IrelandHorstmann, 2013Englandadded by Horstmann (2013)Porizonerucator Zetterstedt, 1838rufipes misident.fumipennisCampoplex) Horstmann & Shaw, 1984England, Scotland, Walesadded by Horstmann and Shaw (1984)Limneriafenestralis Holmgren, 1860Diadegmafenestralegracile ?England, Scotland, Wales, Ireland, Isle of Mandistribution data from Horstmann, 1973EnglandNMS, det. Horstmann, added hereHorstmann, 2008Englandadded by Horstmann (2008b)Mesoleptusgrisescens Gravenhorst, 1829rufiventrisCampoplex) Angitiaholopyga Thomson, 1887England, Scotland, IrelandMeloborishygrobia Thomson, 1887ischnocerumMeloboris) unavailable Ichneumoninsectator Schrank, 1781insectatrixAngitia) Angitialaricinella Strobl, 1904Scotlandadded by Shaw and Horstmann (1997)Campoplexlateralis Gravenhorst, 1829England, Irelandlateralis\u2019 by K. Horstmann in NMS, from the Isle of Coll. and specimens in NMI det. A.W. Stelfox Angitialatungula Thomson, 1887deletumPectinella) Horstmann, 1969England, Scotlandadded by Shaw and Horstmann (1997)Campoplexlitoralis Holmgren, 1856England, IrelandCampoplexmajalis Gravenhorst, 1829England, Scotland, IrelandAngitiamelania Thomson, 1887EnglandAngitiamonospila Thomson, 1887England, Scotland, WalesNMS, det. Horstmann, added hereCampoplexnanus Gravenhorst, 1829England, ScotlandHorstmann, 2008narcyiae misspellingEngland, Scotlandnarcyiae, emended by NMS, det. Horstmann, added here; originally, incorrectly, spelt Horstmann, 1969cerophaga misident.Horstmann, 1969EnglandBMNH, det. Horstmann, added hereMeloborispusio Holmgren, 1860annulipesLimneria) Limneriarufata Bridgman, 1884England, ScotlandLimneriaruficeps Holmgren, 1860gracileCampoplex) preocc. Limneriascotiae Bridgman, 1889ScotlandLimneriasemiclausa Hell\u00e9n, 1949tibialis misident.cerophaga misident.eucerophagum Horstmann, 1969England, Scotland, Ireland, Isle of Mandistribution data from Azidah et al. (2000)Angitiasordipes Thomson, 1887England, Scotland, WalesCampoplexstagnalis Holmgren, 1856England, IrelandHorstmann, 1980England, Scotlandadded by Horstmann (1980a)Angitiatenuipes Thomson, 1887England, Scotland, IrelandLimneriatripunctata Bridgman, 1886England, IrelandAngitiatrochanterata Thomson, 1887England, IrelandCampoplextruncata Thomson, 1887subbuccatumAngitia) Limneriapedella Holmgren, 1860albicoxisSynetaeris) ] K. Horstmann had identified specimens in NMS as limnobia, which appeared on earlier versions of this checklist, but, following the redescription of the species ] Specimens identified in BMNH as Dusonavidua are actually Hyposotertricolor (det. K. Horstmann); H.tricolor. Only included on the British list on the basis that it was described from Carr material, of doubtful origin Limneriaalbonotata Bridgman, 1889melaleucusAnilastus) Limneriaaliena Brischke, 1880IrelandLimneriabarrettii Bridgman, 1881teucriiLimneria) Anilastaboops Thomson, 1887Englandbrischkei.Added by Limneriabrischkei Bridgman, 1882England, Scotland, IrelandCampoplexcaedator Gravenhorst, 1829henscheliAnilastus) Campoplexcarbonaria Ratzeburg, 1844England, ScotlandLimneriaclausa Brischke, 1880England, ScotlandMany specimens in BMNH are only doubtfully identified; material in NMS has been recently identified by K. Horstmann.Anilastacoxator Thomson, 1887EnglandBMNH, NMS, det. Horstmann, added hereIchneumondidymator Thunberg, 1824rotundatorIchneumon) Anilastusdiscedens Schmiedeknecht, 1909IrelandCampoplexdolosus Gravenhorst, 1829rufimanusCampoplex) synonymy by Horstmann (2000d) Limneriafitchii Bridgman, 1881Limneriainquinata Holmgren, 1860ScotlandOne British specimen in BMNH but pointing the other direction, implying erroneous identification (by J.F. Perkins?). Carried over from the 1978 checklist and on the basis of material in UM, det. J.P. Brock.Anilastaleucomera Thomson, 1887tricinctusLimneria) unavailable Anilastalongula Thomson, 1887England, Scotland, WalesLimnerianeglecta Holmgren, 1860varicoxaAnilasta) Campoplexnotatus Gravenhorst, 1829England, Scotland, Wales, IrelandLimneriaobscurella Holmgren, 1860Campoplexorbator Gravenhorst, 1829rufusLimneria) Campoplexplacidus Desvignes, 1856EnglandTryphonrhodocerae Rondani, 1877ebeninus misident.England, IrelandAnilastaruficrus Thomson, 1887EnglandNMS, det. Horstmann, added hereAnilastusthuringiacus Schmiedeknecht, 1909England, IrelandCampoplextricolor Ratzeburg, 1844vidua misident.henaultiiCampoplex) Campoplexvirginalis Gravenhorst, 1829Englanddistribution data from Horstmann (2000d)Limneriavivida Holmgren, 1860albicrusAnilasta) Limneriaclypeata Brischke, 1880sternocerusLathrostiza) synonymy by Horstmann (2004b) Campoplexlugens Gravenhorst, 1829vestigialisCampoplex) Townes, 1965England, Walesadded by Campoplexerrabundus Gravenhorst, 1829Englandadded by Salisbury (2003)Horstmann, 1970Nemeritiscremastoides Holmgren, 1860England, Scotlandpunctulatus (Ratze.) to a synonym of Porizonmoderator (L.).NMS, BMNH, added here; Gravenhorst, 1829Campoplexparvulus Gravenhorst, 1829fusicornisLathroplex) Limneriabucculentus Holmgren, 1860EnglandBMNH, det. Horstmann, added hereHolmgren, 1859ASINAMORA F\u00f6rster, 1869NEPIERA F\u00f6rster, 1869PSEUDOCYMODUSA Habermehl, 1922ANOIXIS Townes, 1970Campoplexalternans Gravenhorst, 1829elachistaeCymodusa) preocc. Ichneumoncollector Thunberg, 1824concinnaLimneria) Pseudocymodusaneglecta Habermehl, 1923Nepieraproxima Perkins, 1942England, Scotland, IrelandBMNH, NMS, det. Horstmann, added hereHolmgren, 1860PSEUDONEMERITIS Sz\u00e9pligeti, 1916Distribution data from Horstmann, 1975EnglandBMNH, det. Horstmann, added hereThomson, 1887rhaphidiae Kriechbaumer, 1892raphidiae Dalla Torre, 1901monticola Habermehl, 1922EnglandHorstmann, 1980EnglandCampoplexfallax Gravenhorst, 1829crassiceps Habermehl, 1922EnglandNMS, BMNH, det. Horstmann, added hereThomson, 1887EnglandCampoplexmacrocentrus Gravenhorst, 1829sordidaCampoplex) preocc. Limneriamandibularis Holmgren, 1860aberrans misident.umbrataCanidia) ] Welsh specimens in BMNH, ex Cephalciaalpina (Hymenoptera: Pamphiliidae) (not a British native), det. K. Horstmann and I.D. Gauld, presumably brought over for biocontrol purposes.[ratzeburgi ] Released in Wales for biocontrol purposes but with no evidence of successful establishment nom. dub.][alienata nom. dub.] Sinophoruspaniscus as British but this name is now a synonym of Macrusfiliventris Gravenhorst, 1829 Ichneumonalbidus Gmelin, 1790hungaricusOmorgus) Limneriumbridgmanii Dalla Torre, 1901distinctusLimneria) preocc. Limneriacostalis Thomson, 1887IrelandLimneriacrassifemur Thomson, 1887IrelandLimneriafuscicarpus Thomson, 1887Englandadded by Sanborne (1984)Campoplexgeniculatus Gravenhorst, 1829nigritellusLimneria) Campoplexjuniperinus Holmgren, 1856ornatusOmorgus) Limneriapleuralis Thomson, 1887Englandadded by Sanborne (1984)Campoplexturionum Ratzeburg, 1844spectabilisLimneria) Campoplexxanthostomus Gravenhorst, 1829pineticolaLimneria) Synetaeriscarbonella Thomson, 1887aterrimumPyracmon) Omorgaexoleta Thomson, 1887geniculatumOmorgus) unavailable Limneriahyperborea Thomson, 1887EnglandNMS, det. Horstmann, added hereGonotypusintermedius Sz\u00e9pligeti, 1916majusGonotypus) Omorgalatiuscula Thomson, 1887England, ScotlandNMS, BMNH, det. Horstmann, added hereOmorganigridens Thomson, 1887striolatumOmorga) Limneriarostralis Brischke, 1880arenicola Thomson, 1887thuringiacumSinophorus) Anilastacitrofrontalis Hedwig, 1939England, Scotland, Wales, IrelandBMNH, NMS, det. Horstmann, Shaw, Broad, added hereLimneriacoxalis Brischke, 1880Englandcoxalis; another British specimen has been labelled 'robusta Wold.' (=Scirtetes) and an English specimen has been labelled as 'interruptus'. Locality data from reared specimens in NMS, det. K. Horstmann.One British specimen in BMNH is probably Ichneumonpraerogator Linnaeus, 1758chrysogasterIchneumon) preocc. Schrottky, 1902IDECHTHIS F\u00f6rster, 1869DEVORGILLA Cameron, 1907NEMERITIS misident.Campoplexcanescens Gravenhorst, 1829frumentariaCampoplex) Ichneumoncoxator Villers, 1789Collyriacoxatorfalcata ?Collyriacoxatorarcuata ?calcitratorBassus) Pachymerustrichophthalmus Thomson, 1877EnglandF\u00f6rster, 1869Distribution data from Gravenhorst, 1829species excluded from the British and Irish list by crassicornis Thomson, 1890][subnasuta ] obfuscator (Villers) as a doubtfully placed species of Trychosis but it was probably misidentified.[stevenii misident.][taschenbergii misident.] Listed as a doubtfully placed species of Hemiteles by Listed as a doubtfully placed species of Hemiteles by pictipes in the BMNH have now been identified as albobasalis and longicauda and there is no evidence that pictipes has ever been found here. Listed as a doubtfully placed species of Trychosis by The type of pilosus was ostensibly British but Schwarz (1995) has excluded this southern European species from the British list. bidentulus were misidentified. Erroneously listed as occurring in the British Isles by Listed as a species of Dichrogaster (Cryptinae: Phygadeuontini) in will be synonymised by Broad & Rose (in prep.) Apparently only recorded as British by Lissonotafunebris) Ichneumonneustriae has traditionally been treated as a species of Rhorus but the species involved has been in doubt (Cotesia (Braconidae: Microgastrinae). According to neustriae auctt. is referable to austriator Aubert, 1988. Known only from males, Klopfstein (2014) was unable to place this taxon but suggested that it may be a colour variant of pallipes. Listed in error by No British or Irish specimens have been seen ; syn. mandibulare ] All British specimens under the name mandibulare Ophionaggressor Fabricius, 1804marginellumMesochorus) Mesochorusalbitarsis Brischke, 1880nigrum Pfankuch, 1921heydeni Habermehl, 1923transsylvanicumPseudacoenitus) Roman, 1909dispersum Schwenke, 1999laricis Schwenke, 1999Englandadded by Riedel (2015)Mesochorusanalis Holmgren, 1860England, Scotlandadded by Riedel (2015)Mesochorusbuccatus Thomson, 1886hamulumMesochorus) Mesochorushirsutus Bridgman, 1883granigerumMesochorus) Mesochorusleucogrammus Holmgren, 1860England, ScotlandNMS, added hereMesochorusnigrocoxatus Strobl, 1904mimulumDemophorellus) Mesochoruspictus Brischke, 1880incidensMesochorus) Mesochorusscutellatus Gravenhorst, 1829festivumMesochorus) Mesochorussplenium Curtis, 1833sericansMesochorus) synonymy by Schwenke (1999) Mesochorustenuicornis Thomson, 1886England, ScotlandSchwenke, 2004Englandadded by Schwenke (2004)Schwenke, 1999England, Wales, Irelandadded by Riedel (2015)Mesochorusvaripes Holmgren, 1860variipes Dalla Torre, 1901England, Scotlandadded by Riedel (2015)F\u00f6rster, 1869PLESIOPHTHALMUS F\u00f6rster, 1869MATER Schluz, 1911TETRAGONALYS Morley, 1913OPHTHALMOCHORUS Roman, 1925Cidaphus species is taken from Cidaphus species. Distribution data for Mesochorusalarius Gravenhorst, 1829thuringiacus Brauns, 1889England, WalesPaniscusareolatus Boie, 1850gigasMeoschorus) synonymy by Horstmann (2002b) synonymy by Horstmann (2002b) Cryptusatricillus Haliday, 1838potanini Kokujev, 1906melanocephalusPlesiophthalmus) have found that Dolichochorus is a rather basal member of the Mesochorinae, and distinct from Astiphromma.Mesochoruslongiceps Strobl, 1904EnglandAdded by Gravenhorst, 1829STICTOPISTHUS Thomson, 1886Mesochorus as W. Schwenke had misinterpreted many names.Mesochorus excluded from the British and Irish list:species of nuncupator ] Horstmann (2006b) Listed as sodalis by Lissonotafunebris), or on the basis of specimens in BMNH identified as sodalis var. moerens, which is now regarded as a separate species. Stenomacrusaffinis of authors was redescribed as S.affinitor Aubert, 1981 as the type of affinis is a species of Hypsicera (Metopiinae), a junior synonym of curvator (Fabricius). Old British records of \u2018Stenomacrusaffinis\u2019 are not valid.[exserens ] Stenomacrusexserens as a British species but the only two specimens purportedly of this species in BMNH, from C. Morley\u2019s collection, are misidentified Eusterinx. There is no other evidence that exserens is a British or Irish species. As discussed in Eclytusornatus from England and Scotland but their identifications were not based on egg characters, used by ornatus might be based on misidentifications. ornatus in NMS. Althouginvolved .Polyblastusangulatus Thomson, 1883Scotland, Isle of ManPolyblastusangustatus Roman, 1909Polyblastusarcuatus Holmgren, 1857antennator Aubert, 1965Englandmarginata sensu Kasparyan.W. Ely has noted that many specimens under this name (including British?) are Kasparyan, 1973Scotlandadded by Polyblastusgenalis Thomson, 1883EnglandAdded by albiventrisPolyblastus) Polyblastusgrossus Brischke, 1871annulicornisPolyblastus) as annulicornis, it was subsequently recorded as Ctenochiragrossa by Listed in Tryphonhaemosternus Haliday, 1839senilisPolyblastus) synonymy by Kasparyan and Tolkanitz (2000) .Some distribution data from stmann\u2019s revised Polyblastusmarginatus Holmgren, 1857fractigenaScopiorus) Tryphonpastoralis Gravenhorst, 1829mutabilisPolyblastus) Tryphonpratensis Gravenhorst, 1829EnglandTryphonpropinquus Gravenhorst, 1829obscuraTryphon) synonymy by Kasparyan and Tolkanitz (2000) Poyblastusromani Pfankuch, 1925pygobarbaScopimenus) Tryphonrufipes Gravenhorst, 1829anilisPolyblastus) preocc. Tryphonsanguinatorius Ratzeburg, 1852EnglandTryphonsphaerocephalus Gravenhorst, 1829bisculptaTryphon) Polyblastusvalidicornis Brischke, 1871added byfusicornisPolyblastus) Polyblastusxanthopygus Holmgren, 1857rivalisPolyblastus) Tryphonrubiginosus Gravenhorst, 1829insidiatorAcrotomus) preocc., synonymy by Horstmann (2006a) unavailable synonymy by Horstmann (2006a) but luteomarginatus. The name praerogator was used by Gravenhorst and Thomson, referring to Linnaeus\u2019s praerogator, which is actually a species of Tranosemella (Campopleginae). These usages of praerogator are unavailable names Tryphonalacer Gravenhorst, 1829xanthopusAcrotomus) Tryphonaurifluus Haliday, 1839geniculosusExenterus) Tryphonbasalis Stephens, 1835connatusExenterus) synonymy by Horstmann (2012a) Exenterusbimaculatus Holmgren, 1856zonellusExenterus) Exenterusconsobrinus Holmgren, 1857IrelandTryphoncurtisii Haliday, 1839England, Scotland, IrelandIchneumondorsator Thunberg, 1824mitigosusTryphon) Tryphonelegans Stephens, 1835aulicusCteniscus) Tryphonflavomaculatus Gravenhorst, 1829praeustusExenterus) Tryphongnathoxanthus Gravenhorst, 1829hachfeldiPolyblastus) Cteniscushofferi Gregor, 1937England, IrelandCteniscuslineiger Thomson, 1883nordstromiCteniscus) Tryphonpachysoma Stephens, 1835coloratorTryphon) Tryphonpictus Gravenhorst, 1829marginatusCteniscus) Cteniscusromani Kerrich, 1952IrelandExenterusrufilabris Holmgren, 1857genalisCteniscus) Exenterusrufonotatus Holmgren, 1857breviventrisCteniscus) Exenterussimilis Holmgren, 1857Englandadded by Ely (2010)Kasparyan, 1985Scotlandadded by Shaw and Kasparyan (2005)Holmgren, 1857ANIAROPHRON F\u00f6rster, 1869TRICHOCALYMMA F\u00f6rster, 1869TRICHOCALYMMUS Thomson, 1887Brischke, 1871England, ScotlandKasparyan, 1973England, Scotland, WalesTryphonbrunnicans Gravenhorst, 1829brunicans Dalla Torre, 1901 preocc.England, ScotlandIchneumoncalcator M\u00fcller, 1776erythropusIchneumon) Ichneumonjunior Thunberg, 1824frenatorExochus) Trichocalymmaplebejus Woldstedt, 1878bipunctatusTrichocalymma) Trichocalymmapunctatus Woldstedt, 1878added bysimplex Thomson, 1883defectivus Strobl, 1903Scotland, Walesadded by Shaw and Kasparyan (2005)Holmgren, 1857nigerAniarophron) Ichneumonzonarius Gravenhorst, 1820obscuratus Habermehl, 1925England, Scotland, WalesDavis, 1897Tryphonapiarius Gravenhorst, 1829obscuratoriusIchneumon) preocc. nom. dub., from England] Listed as a doubtfully placed species of Tryphon by Exenterus following Fitton (1976)[parvulus nom. dub.][Townes & Townes, 1949Thomson, 1888England, Scotland, WalesF\u00f6rster, 1869NEMIOBLASTUS Thomson, 1883Schi\u00f8dte, 1838albicoxa Thomson, 1883British specimens without locality data in BMNH.Holmgren, 1857grammicus Holmgren, 1857lucidus Brischke, 1892England, Scotland, Isle of ManKasparyan, 1973Englandadded by Shaw and Kasparyan (2005)Thomson, 1888pallidicoxa Dalla Torre, 1901England, Ireland, Isle of ManHolmgren, 1857albicoxa Thomson, 1883England, Scotland, Isle of Manalternans Schi\u00f8dte, 1838, of which it is listed as a subspecies by Holmgren, 1857England, ScotlandHartig, 1837Tryphoncancer Hartig, 1837palaemon Schi\u00f8dte, 1838holosericeusTryphon) Tryphoncothurnatus Gravenhorst, 1829drewseni Schi\u00f8dte, 1838unicinctus Bridgman, 1889intermedius Ulbricht, 1916 unavailablehungaricusTrematopygus) Tryphonpedalis Cresson, 1864carbonarius misident.rhenanus Ulbricht, 1926 unavailablerufifemur Hedwig, 1943 unavailableEngland, Scotlandcarbonator Kasparyan, 1970.British specimens belong to the subspecies Ichneumonpinguis Gravenhorst, 1920petryi Schmiedeknecht, 1912Holmgren, 1857ScotlandHabermehl, 1909England, Scotland, WalesTeunissen, 1953Englandadded by Shaw and Kasparyan (2005)Tryphonvaritarsus Gravenhorst, 1829strobilator misident.albovinctusTryphon) Exenterusbohemani Holmgren,1857EnglandExenteruserosus Holmgren,1857EnglandKerrich, 1952Englandsome distribution data from Kerrich (1962)Kerrich, 1952Scotland, IrelandExenterusjucundus Holmgren, 1857EnglandKasparyan, 1976England, Scotlandadded by Shaw and Kasparyan (2005)Kerrich, 1952EnglandIchneumonquinquecinctus Gravenhorst, 1820trianguligena Kerrich, 1952England, ScotlandFall\u00e9n, 1813Distribution data from Tryphon Ichneumonobtusator Thunberg, 1824Tryphon (Stenocrotaphon) obtusatorsubrufus ?consobrinus Holmgren, 1857EnglandHolmgren, 1857EnglandF\u00f6rster, 1869Stephens, 1835incestus Holmgren, 1857incertus Brischke, 1871tricolor Rudow, 1910 preocc.abnormis Habermehl, 1925rufescensErromenus) (but see the note regarding Tryphonduplicatus).Gravenhorst, 1829England, ScotlandSymboethusduplicatus Heinrich, 1953discedensSymboethus) . Townes also regarded \u2018duplicatus\u2019 (=hinzi sensu Townes) as comprising two species, one with red hind femora and one with black hind femora, also differing in characteristics of the egg. However, bidentatus with red hind femora as possibly being synonymous with hinzi. Further clarification is needed.H.K. Townes (pers. comm. to M.G. Fitton) regarded Gravenhorst, 1829connectens Roman, 1909EnglandHolmgren, 1857England, ScotlandAdded by Gravenhorst, 1829bicornutus Holmgren, 1856confinis Holmgren, 1856maculatusSymboethus) unavailable Ichneumonlatrator Fabricius, 1781auricularis Thomson, 1883 synonymy by Horstmann (2001a)England, Scotland, Wales, Ireland, Isle of ManHolmgren, 1857EnglandIchneumonrelator Thunberg, 1824vulgaris Holmgren, 1857erythrogaster Thomson, 1883England, ScotlandIchneumonrutilator Linnaeus, 1761impraegnatorIchneumon) Xylonomuscaligatus Gravenhorst, 1829seticornis Kriechbaumer, 1879England, Scotland, IrelandIchneumonrusticus Geoffroy, 1785striatusOdontomerus) Ichneumondentipes Gmelin, 1790femoratumOphion) Odontomerusquercinus Thomson, 1877liogasterOdontomerus) and Xorides s. str. (containing the others) but Xorides in synonymy.The British species have usually been separated into the subgenera Xylonomusbrachylabis Kriechbaumer, 1889brachylabris misspellingEnglandCl\u00e9ment, 1938EnglandIchneumonfuligator Thunberg, 1824sordatorIchneumon) Xylonomusgravenhorstii Curtis, 1831securicornisXylonomus) Ichneumonirrigator Fabricius, 1793planus \u0160ediv\u00fd, 1958EnglandXylonomusniger Pfeffer, 1913bicolor Cl\u00e9ment, 1938EnglandIchneumonpraecatorius Fabricius, 1793Xoridespraecatoriusarticulatus ?Xoridespraecatoriusfalsatorius ?parvulusXylonomus) preocc. preocc. Xylonomusrufipes Gravenhorst, 1829EnglandXylonomusrusticus Desvignes, 1856EnglandSupplementary material 1IchneumonidaeChecklist of British and Irish Data type: Excel spreadsheetIchneumonidae checklistBrief description: Excel spreadsheet version of the British and Irish File: oo_92300.xlsxBroad, G.R.Supplementary material 2IchneumonidaeChecklist of British and Irish Data type: Word documentIchneumonidae checklistBrief description: text version of the British and Irish File: oo_92298.docxBroad, G.R."} +{"text": "Heliscus lugdunensis, Tetrachaetum elegans, Tetracladium breve, T. marchalianum, and T. nainitalense, against seven plant pathogenic fungi was studied using a dual culture technique. Inhibitory activity of tested aquatic hyphomycetes was determined by measuring the radial growth of plant pathogenic fungi on dual culture plates. Tetrachaetum elegans showed antagonistic activity against Colletotrichum falcatum, Fusarium oxysporum, Pyricularia oryzae, Sclerotium sclerotiorum, and Tilletia indicaHeliscus lugdunensis showed antagonism against only two plant pathogenic fungi, Rhizoctonia solani and Colletotrichum falcatum.Tetracladium breve, T. marchalianum, and T. nainitalense showed no response towards tested plant pathogenic fungi.The antagonistic activity of five aquatic hyphomycetes, viz.,"} +{"text": "The affiliations of Christelle Hano, Giulia Bardino and Michel Saint Jalme are listed incorrectly. The correct affiliations are as follows:Christelle HanoAffiliation: Museum National d'Histoire Naturelle, UMR 7204, M\u00e9nagerie du Jardin des Plantes, Paris, France.Giulia BardinoAffiliation: Museum National d'Histoire Naturelle, UMR 7206, Universita La Sapienza, Rome, ItalyMichel Saint JalmeAffiliation: Museum National d'Histoire Naturelle, UMR 7204, M\u00e9nagerie du Jardin des Plantes, Paris, France.There is also an error in the author contributions. The listed roles for Shelly Masi should read as follows:Shelly MasiRoles: Conceptualization, Formal analysis, Funding acquisition, Investigation, Resources, Supervision, Writing\u2013original draft, Writing\u2013review & editing"} +{"text": "Dear Reader,Drugs\u2014Real World Outcomes for the year, we wish to reflect on another successful year for the journal and for others in the Adis Premier journals portfolio, and to thank all who have contributed to Drugs\u2014Real World Outcomes over the past 12 months.As we approach the end of 2016, and publish our final issue of Drugs\u2014Real World Outcomes in that the journal content is now available on PubMed Central. Another of our open access journals, Drug Safety\u2014Case Reports, is also now available on PubMed Central.An important milestone was reached for Drugs\u2014Real World Outcomes\u2019 top 10 downloaded articles from SpringerLink this year were:As of September 2016, Medicines Management, Medication Errors and Adverse Medication Events in Older People Referred to a Community Nursing Service: A Retrospective Observational Study. Drugs\u2014Real World Outcomes (2016) 3: 13.Elliott, R.A., Lee, C.Y., Beanland, C. et al. Use of Chronic Medications Among Patients with Non-Valvular Atrial Fibrillation. Drugs\u2014Real World Outcomes (2016) 3: 165.Kocis, P.T., Liu, G., Makenbaeva, D. et al. Persistence of Antipsychotic Treatment in Elderly Dementia Patients: A Retrospective, Population-Based Cohort Study. Drugs\u2014Real World Outcomes (2016) 3: 175.Mast, G., Fernandes, K., Tadrous, M. et al.\u00a0\u00ae\u00a0Disposable Insulin Delivery Device for Insulin Delivery in Patients with Poorly Controlled Diabetes at High RiskThe Clinical and Economic Impact of the V-Go. Drugs\u2014Real World Outcomes (2016) 3: 191.Lajara, R., Nikkel, C. & Abbott, S. Traditional Anticoagulants and Hair Loss: A Role for Direct Oral Anticoagulants? A Review of the Literature. Drugs\u2014Real World Outcomes (2016) 3: 1.Watras, M.M., Patel, J.P. & Arya, R. Selective Serotonin Reuptake Inhibitors and Night Sweats in a Primary Care Population. Drugs\u2014Real World Outcomes (2015) 2: 29.Mold, J.W. & Holtzclaw, B.J.\u00a0Drug-Induced Subacute Cutaneous Lupus Erythematosus Associated with Proton Pump Inhibitors. Drugs\u2014Real World Outcomes (2016) 3: 145.Aggarwal, N. 3\u00a0Antagonists Really Contribute to Serotonin Toxicity? A Call for Clarity and Pharmacological Law and OrderCan 5-HT. Drugs\u2014Real World Outcomes (2014) 1: 3.Rojas-Fernandez, C.H. Evaluating the Cost-Effectiveness of Prolonged-Release Tacrolimus Relative to Immediate-Release Tacrolimus in Liver Transplant Patients Based on Data from Routine Clinical Practice. Drugs\u2014Real World Outcomes (2016) 3: 61.Muduma, G., Odeyemi, I. & Pollock, R.F. The Risk of Specific Congenital Anomalies in Relation to Newer Antiepileptic Drugs: A Literature Review. Drugs\u2014Real World Outcomes (2016) 3: 131.de Jong, J., Garne, E., de Jong-van den Berg, L.T.W. et al.\u00a0Drugs\u2014Real World Outcomes over the course of 2016. Their skill and dedication are critical to the continued publication of the journal. The quality of published articles is, similarly, testament to the significant efforts of the peer reviewers, whose commitment ensures that the journal\u2019s content is held to the highest possible standard. We would like to thank the following individuals who acted as reviewers for Drugs\u2014Real World Outcomes in the last 12 months:We offer our sincere thanks to all authors who have contributed articles to Adebowale Dele Ademola, NigeriaKraemer Alwin, GermanyRichard H. Aster, USAPierrick Bedouch, FranceNancy Bernardy, USABenoit Boland, BelgiumMachaon Bonafede, USANeil Brickel, UKMarta Brooks, USAAnette Bygum, DenmarkJohanna Callhoff, GermanyWendy Cheng, USAVictoria Collings, UKRohan A. Elliott, AustraliaBarbara Farrell, CanadaPaula Fresco, PortugalMasahiro M. Fukuoka, JapanChris Gillette, USAB. Joseph Guglielmo, USAZeky Y\u00fcksel Gunaydin, TurkeyMark Haggard, UKJesper Hallas, DenmarkMainul Haque, MalaysiaSwapnil Hiremath, CanadaKeith B. Hoffman, USAChun-Ta Huang, TaiwanKlejda Hudhra, SpainSekwon Jang, USASusan Jick, USAPravin Kamble, USAHarparkash Kaur, UKDonald G. Klepser, USAPaul T. Kocis, USASam Kosari, AustraliaRichard Laing, USACecilie Johannessen Landmark, NorwayMarianne Lisby, DenmarkEleanor Lucas, USAHendrika Luijendijk, The NetherlandsAnke H. Maitland-van der Zee, The NetherlandsLouise Mallet, CanadaG. B. John Mancini, CanadaGloria Manso, SpainJohn F. McCarthy, USANatalie McCormick, CanadaAnthony B. Miller, CanadaAndrew Mosholder, USADomenico Motola, ItalyMarco Mula, UKGiorgio Mustacchi, ItalyPaul N. Newton, UKOnyema Ogbuagu, USAJan Palmblad, SwedenJean-Jacques Parienti, FranceTimo Partonen, FinlandKathryn Peri, New ZealandSathirakorn Pongpanich, ThailandValentin Prieto-Centurion, USANeal Ready, USAJenna M. Reps, UKJohn Robst, USAAlbert Roger, SpainJosea Rono, KenyaSabine Ruths, NorwayAlan Schorr, USATodd Semla, USAPasquale Striano, ItalyRoger E. Thomas, CanadaPhilippe Thuillier, FrancePetra A. Thurmann, GermanyJames E. Tisdale, USAGiuliano Tocci, ItalyAntonella Tosti, USARobert Vander Stichele, BelgiumBastiaan Venhuis, The NetherlandsPa-Chun Wang, TaiwanJuanita Westbury, AustraliaPeter K.K. Wong, AustraliaAntoinette A. Wozniak, USAIn addition, we would like to thank the members of the journal\u2019s Honorary Editorial Board, who have acted as peer reviewers and authors, and have provided guidance on journal content, policy and processes:G.C. Alexander, Johns Hopkins University, Baltimore, MD, USAA. Beresniak, Data Mining International, Geneva, SwitzerlandM.L. Berger, Pfizer, Inc.,\u00a0New York, NY, USAH. Birnbaum, Analysis Group, Inc., Boston, MA, USAJ.M. Bottomley, Amygdala Ltd., Letchworth Garden City, EnglandP. Denig, University of Groningen, Groningen, The NetherlandsJ.E. Fincham, Presbyterian College School of Pharmacy, Clinton, SC, USAB. Godman, Karolinska Institutet, Stockholm, SwedenD. Goldsmith, Goldsmith Pharmacovigilance and Systems, New York, NY, USAS. Karve, AstraZeneca, Gaithersburg, MD, USAN.Y. Kirson, Analysis Group, Inc., Boston, MA, USAC. Kozma, CK Consulting Associates, St. Helena Island, SC, USAT. Lasky, MIE Resources, Baltimore, MD, USAA.A. Mangoni, Flinders University, Adelaide, SA, AustraliaS. Mimica-Matanovic, University Hospital Osijek, Osijek, CroatiaA. Modi, Merck, Whitehouse Station, NJ, USAJ.K. Sluggett, Monash University, Parkville, VIC, AustraliaK.A. Swanson, University of Oklahoma, Oklahoma City, OK, USAJ.E Ware Jr., University of Massachusetts, Worcester, MA, USAQ. Zou, The Lewin Group, Falls Church, VA, USAThe Patient (17.08%), Clinical Drug Investigation (15.99%), the American Journal of Clinical Dermatology (13.17%), Drug Safety (13.5%), and Drugs (12.43%).In other portfolio news, mid-2016 saw the release of the ISI Journal Citation Reports and the latest journal impact factors. The majority of our journals saw a rise in impact factor against the previous year. Most notably, five of our journals saw an increase of over 10% in impact factor \u2013 PharmacoEconomics\u2014Open. This new journal will be fully open access and will focus on the publication of applied research on the economic implications and health outcomes associated with drugs, devices and other healthcare interventions. It joins our other well respected health outcomes publications, PharmacoEconomics, Applied Health Economics and Health Policy, and The Patient: Patient-Centered Outcomes Research.The Adis journals portfolio will expand in 2017, with the launch of We hope that you have found the articles published throughout 2016 to be both interesting and informative. We have appreciated the high quality of content contributed to the journal this year and look forward to keeping you up to date with topical real-world outcomes in 2017.With best wishes from Dene Peters (Editor-in-Chief) and Kathy Fraser (Deputy Editor)."} +{"text": "The editors of Dentistry Journal would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015.We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial decision-making process. Several steps have been taken in 2015 to thank and acknowledge reviewers. Good, timely reviews are rewarded with a discount off their next MDPI publication. By creating an account on the submission system, reviewers can access details of their past reviews, see the comments of other reviewers, and download a letter of acknowledgement for their records. In addition, MDPI has launched a collaboration with Publons, a website that seeks to publicly acknowledge reviewers on a per journal basis. This is all done, of course, within the constraints of reviewer confidentiality. Feedback from reviewers shows that most see their task as a voluntary and mostly unseen work in service to the scientific community. We are grateful to our reviewers for the contribution they make.Ajay Sharma, LavanyaBerron, Brad J.Crowther, MarkArduino, Paolo G.Charalampakis, GeorgiosDalessandri, DomenicoAzuma, KazuoCho, Sang-ChoonDavis, Graham R.Baik, Hyoung-SeonChrcanovic, BrunoDouglass, JoannaBasrani, BettinaChu, Chun-HungEisenbeiss, Anne-KatrinBecker, KathrinCooper, PaulFirth, NormanFleisher, KennethGomes, BrendaG\u00fcldner, ChristianHalazonetis, Demetrios J.Hirshberg, AbrahamHofer, DeborahHorowitz, Robert A.Jaqui\u00e9ry, ClaudeKao, Daniel W.K.Kapellas, KostasKeeling, David M.Keller, Mette K.Khambay, Balvinder S.Kitamura, ChiakiKremer, UrsLang, ChristineLin, Yng-TzerMacEntee, MichaelManfredi, MaddalenaMarsich, EleonoraMazor, ZivMilosevic, AlexMonje, AlbertoNadjmi, NasserNascimento, CassioNibali, LuigiParnanen, PirjoPommer, BernhardPotluri, AnithaSahrmann, PhilippSato, TakuichiSchmidlin, PatrickSchroth, Robert J.Shapira, YehoshuaShimauchi, HidetoshiSimon, Stephane R.J.Sinon, SurayaSuzuki, NaoTadinada, AdityaThikkurissy, SaratTroedhan, AngeloVan Ryn, JoanneWalenga, Jeanine M.Warnakulasuriya, SamanXi, TongYakin, MumammedZaslanky, PaulZhao, Linping"} +{"text": "AbstractGlochidionshanense Gang Yao & Shixiao Luo , is here described and illustrated. The species is morphologically most similar to G.ellipticum Wight, but can be distinguished from the latter by having hairy branchlets, longer pedicels, uniseriate and narrowly triangular sepals of female flowers, 4\u20135-locular ovaries, stout and cylindric persistent style on fruits.Based on morphological studies performed on live plants in the field and specimens deposited in herbaria, a new species, Glochidion J.R. et G. Forst. is the second largest genus in the tribe Phyllantheae Dumortier, Phyllanthaceae Martynov collected some flowers .Glochidion material from herbaria HITBC, IBSC, K, KUN, P, PE and US, as well as consideration of the taxonomic literature of China MYANMAR. Shan State, Pindaya, near the Htwet Ni village, West of Pindaya town, at an elevation of 1396 m, forest understory, in flowering and fruiting, 25 December 2015, Shrubs or treelets, up to 2 m; monoecious; branchlets pubescent. Leaf blade oblong or elliptic, 9\u201313.5 \u00d7 4.5\u20136.5 cm, papery, slightly leathery, with apex acuminate to round and base broadly cuneate, sparsely pubescent along veins adaxially, pubescent abaxially; midvein and 6\u20139-paired lateral veins elevated abaxially. Petiole 3\u20134 mm long, pubescent. Stipules narrowly triangular, 2\u20134 mm long, pubescent. Male flowers: pedicels 6\u201310 mm long, densely tomentose; sepals 6, biseriate, oblong or ovate, densely tomentose; stamens 3. Female flowers: in axillary clusters, pedicels 1.5\u20132 mm long, densely strigose; sepals 6, uniseriate, narrowly triangular, densely strigose; ovary depressed globose, 4\u20135-locular, densely strigose; style connate into a cylinder, ca. 1 mm long, slightly truncate at apex, apex 4\u20135-lobed. Capsules depressed globose, 8\u20139 mm in diameter, ca. 4 mm high, sparsely pubescent, 8\u201310-grooved; persistent style cylindric, ca. 1 mm long; fruiting pedicels 4\u20135 mm long, stout, densely pubescent; seed laterally compressed, orange.Docyniaindica Decne., Schimawallichii (DC.) Korth. and Pinus species.This new species is currently known only from its type locality, Shan State, eastern Myanmar, where it grows in the broadleaved and coniferous dry forest dominated by Glochidionshanense is named after its type locality, Shan State in eastern Myanmar.Glochidionellipticum Wight, a species widely distributed from eastern Himalaya to Taiwan Island, but differs from the latter by its branchlets densely pubescent (Figure G.ellipticum has the branchlets glabrous (Figures The species resembles t Figure , pedicelt Figure , sepals t Figure , ovariest Figure , fruits t Figure , persistt Figure . In cont Figures , pedicel Figures , female Figures , sepals Figures , ovaries Figures , fruits Figures , persist Figures .PageBreakPageBreak"} +{"text": "Behavioral Sciences would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.The editors of https://publons.com) to receive recognition. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make.We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (Behavioral Sciences, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Behavioral Sciences in 2016:Antzoulatos, Evan G.Green, DidoPereira, LianeAvery, AmandaGupta, DishaPeskin, Melissa F.Bard, Kim A.Hilton, DonaldPickett, Scott M.Behnia, BehnamJohnson, Jennifer A.Posner, MichaelBello, Nicholas T.Kass, AndreaPoulos, AndrewBent, StephenKaye, LindaRaine, NigelBetz, AlisonKeeley, JaredReinke, JenniferBuchanan, David R.King, DanielRienecke, ReneeBurghardt, GordonKremling, JanineRinker, Dipali VenkataramanBurrell, LindseyKuan, Wei-LiRosenberg, Stanley D.Carter, GeraldLee, JihyunRussell, DanielCarvalho, PauloLehmann, HugoSamaritter, RosemarieChen, Yu-PingLevy, FlorenceSamsam, MohtashemChung, TammyLogan, CorinaScharoun, Sara MarieCismaru, MagdalenaLoppie, CharlotteSchrepferman, LynnCohen, JerryLuby, JoanSeimon, RadhikaCollins, AdamLynch, GeorginaSheppard, LizzyColombo, MikeMacDonald, SuzanneSkippon, Stephen M.Connolly, JenniferMartin, KarenSlack, Kristen ShookCooper, SimonMasicampo, E. J.Smith, DaleCraft, BaineMason, PeggySorbring, EmmaD\u2019Amato, AlessioMattison, MichelleSprague, JeffreyDaniel, ThomasMccabe, BrendaSteiner, BarbaraDavila-Ross, MarinaMcElwain, AlyssaStriley, Catherine W.Dean, LewisMerlo, EmilianoTabassum, FaizaDevereaux, ChristinaMichael, Kurt D.Taylor, Zoe E.Easton, AlexanderMoffatt, Gregory K.Tennie, ClaudioEl-Sheikh, MonaM\u00f8ller, MetteTrabace, LuigiaFoels, LeonoraNarayan, AngelaVoelbel, GeraldFrancis, LoriNarvaez, DarciaWeedn, Sonnee D.Friedman, Matthew J.Negri, NanetteYearwood, Edilma L.Gabriel, THORENSNobrega, SuzanneYoungstrom, EricGhaemi, S. NassirO\u2019Neill, NinaGirolami, Peter A.O\u2019Sullivan, LuciaThe following reviewed for"} +{"text": "Mouli Chakraborty, Chantal Sellier, Michel Ney, Pascal Villa, Nicolas Charlet-Berguerand, Ruben Artero, Beatriz Llamusidmm032557 (doi: 10.1242/dmm.032557)There was an error published in Dis. Model Mech. 11, The name of the co-author Pascal Villa was presented incorrectly. It has now been corrected and the original article changed correspondingly."} +{"text": "In the original publication the authIncorrect version:Zhang Kaihui, Huang Yan, Dong Rui , Yang Yali, Wang Ying , Zhang Haiyan , Zhang Yufeng , Gai Zhongtao and Liu YiCorrect version:Kaihui Zhang, Yan Huang, Rui Dong, Yali Yang, Ying Wang, Haiyan Zhang, Yufeng Zhang, Zhongtao Gai and Yi Liu."} +{"text": "In the article titled \u201cA Rare Cause of Childhood Cerebellitis-Influenza Infection: A Case Report and Systematic Review of Literature\u201d , Dr. Can\u201cCSF cultures were bacteriologically sterile. Polymerase chain reaction [PCR] assays of CSF for influenza virus, herpes simplex virus 1 and 2, adenovirus, enterovirus, cytomegalovirus, human herpesvirus- 6, epstein-barr virus, and varicella zoster virus were all negative\u201d should be corrected to \u201cMultiplex polymerase chain reaction [PCR] assays of CSF for herpes simplex virus 1 and 2, adenovirus, enterovirus, cytomegalovirus, human herpesvirus-6 and -7, Epstein-Barr virus, varicella zoster virus, parechovirus, parvovirus B19 and influenza virus type A and B, parainfluenza virus, adenovirus, respiratory syncytial virus, human metapneumovirus, human bocavirus, human coronavirus, enterovirus, and rhinovirus were all negative.\u201d\u201cSerologic tests of his blood showed negative results for epstein-barr virus, herpes simplex virus, varicella-zoster virus, cytomegalovirus, measles, mumps, rubella, and mycoplasma pneumoniae. Respiratory viruses such as adenovirus, rhinovirus, respiratory syncytial virus, parainfluenza virus, human bocavirus, human metapneumovirus, and coronavirus were not detected in the nasopharyngeal swab specimen by multiplex PCR. However, we identified influenza A H1N1 virus on the third day of the onset of the symptoms, which was when we started treatment with oseltamivir as 4\u2009\u2009mg/kg orally twice a day. The patient was diagnosed with influenza-associated cerebellitis based on the clinical findings\u201d should be corrected to \u201cSerologic tests of his blood showed negative results for Epstein-Barr virus, herpes simplex virus, varicella zoster virus, cytomegalovirus , measles, mumps, rubella, and mycoplasma pneumoniae . Respiratory viruses including adenovirus, rhinovirus, respiratory syncytial virus, parainfluenza virus, human bocavirus, human metapneumovirus, and coronavirus were not detected in the nasopharyngeal swab specimen by multiplex PCR .\u201dAdditionally, there were errors in the Case Representation section which should be corrected as follows:"} +{"text": "AbstractEmbryopsidae (vascular plants), comprising data collated via the platform http://flora-on.pt/ relating to observation records of vascular plants across mainland Portugal. Observations are uploaded directly to the database primarily by experienced botanists and naturalists, typically on a weekly basis, and consist of geo-referenced data points for species (or infraspecific taxa) along with their date of observation and phenological state.The Flora-On dataset currently includes 253,310 occurrence records for the class The Flora-On project aims to compile and make publicly accessible chorological, ecological, morphological and photographic information for the entire vascular flora of Portugal. The project\u2019s website offers powerful query and visualization capabilities, of which we highlight the probabilistic bioclimatic and phenological queries which operate based on the empirical density distributions of species in those variables.Flora-On was created and continues to be maintained by volunteers who are Associate members of Sociedade Portuguesa de Bot\u00e2nica . Given its focus on research-grade and current data, the Flora-On project represents a significant contribution to the knowledge of the present distribution and status of the Portuguese flora. Flora-On, Interactive Flora of PortugalMiguel Porto (Programmer)The project does not have direct funding from any source, the platform being entirely built and maintained by volunteers. Maintenance costs of the web server are covered by the Associate membership fees of Sociedade Portuguesa de Bot\u00e2nica . However, externally funded projects have contributed through the provision of data.2 and, together with mainland Spain , forms a geographically well-defined territory known as the Iberian Peninsula.Portugal is located at the south westernmost extent of Europe Figure and is bPageBreakvery prominent, including Serra de Montejunto (666 m), Maci\u00e7o Calc\u00e1rio Estremenho (610 m), Serra da Arr\u00e1bida (499 m), and Barrocal Algarvio (479 m).The orography of Portugal is heterogeneous, particularly from north to south, with the Mountains and Plains of the Iberian northwest and of the Iberian Central System dominating the northern parts of its territory . This reAcross mainland Portugal the vegetation is mainly Mediterranean in terms of both its structure and floristic composition. Semi-deciduous and perennial oak woodlands, \u201cmontado\u201d, shrublands, grasslands and silvo-agricultural systems occupy most of this area. Mainland Portugal supports approximately 2,900 native vascular plant taxa , 137 of https://github.com/miguel-porto/flora-on-server/The Flora-On project aims to compile and make publicly accessible chorological, ecological, morphological and photographic information of the entire vascular flora of Portugal. Occurrence data is regularly uploaded to the website by active collaborators, typically on a weekly basis, and consists of geo-referenced data points of species (or infraspecific taxa) along with their date of observation and phenological state. Additionally, other research projects contributed data to the project from their exhaustive sampling campaigns. An open-source version of the platform is currently under development and can be found at PageBreakconduct quantitative probabilistic species queries in relation to bioclimatic distribution, altitudinal distribution and flowering dates. With such queries species can be filtered and ranked by the degree of matching criteria defined by the user for one or more quantitative variables (including flowering date). This innovative feature is based upon empirical density distributions of species that are computed internally for each variable ;The bioclimatic explorer displays jointly the occurrences of the species that match the query in a bioclimatic/environmental space, with the possibility of overlaying multiple queries in the same plots, evidencing the ecological differences between species or groups of species square, e.g. richness of spiny species, richness of summer-flowering species, richness of species occurring in less than five UTM squares, etc. (http://flora-on.pt/#w);The WebGIS displays (with the ability to download the output) the map of the number of species that match the query per http://flora-on.pt/#z);The multi-way interactive identification key allows users to identify species by iteratively narrowing down possible species, freely choosing its way through a set of characters. Displayed characters are adjusted for each iteration according to the list of possible species, and are highlighted according to their discriminant power, to enhance the efficiency of the identification process .http://flora-on.pt:8080/ipt/resource.do?r=flora-onIPT: http://www.gbif.org/dataset/7fe3eb5c-42bd-49d7-a30b-82c353ef6575GBIF: http://flora-on.pt/Website: Embryopsidae. The top orders, comprising 75% of the records, include: Asterales (13.8%); LamialesPageBreakPageBreak(11.3%); Poales (10.3%); Fabales (8.6%); Caryophyllales (6.5%); Asparagales (5.8%); Malvales (4.6%); Apiales (3.7%); Rosales (3.4%); Malpighiales (3.1%); Ericales (3%); and Fagales (2.7%).The Flora-On dataset includes 253,310 occurrence records of the class Asteraceae ; Fabaceae ; and Poaceae ; although some genera are still under-represented. This is probably due to the nature of the dataset, given that the greatest part of the contributions results from non-exhaustive field observations which likely result in the under-representation of the more inconspicuous taxa, or taxa difficult to identify in the field.In total, this dataset includes occurrence records for 150 plant families and 2073 taxa Kingdom: StreptophytaPhylum: EmbryopsidaeClass: Alismatales, Apiales, Aquifoliales, Arecales, Asparagales, Asterales, Boraginales, Brassicales, Buxales, Caryophyllales, Celastrales, Ceratophyllales, Commelinales, Cornales, Cucurbitales, Cupressales, Cyatheales, Dioscoreales, Dipsacales, Ephedrales, Equisetales, Ericales, Fabales, Fagales, Gentianales, Geraniales, Hymenophyllales, Isoetales, Lamiales, Laurales, Liliales, Lycopodiales, Malpighiales, Malvales, Myrtales, Nymphaeales, Ophioglossales, Osmundales, Oxalidales, Pinales, Piperales, Poales, Polypodiales, Proteales, Ranunculales, Rosales, Salviniales, Santalales, Sapindales, Saxifragales, Selaginellales, Solanales, Vitales, ZygophyllalesOrder: Acanthaceae, Aizoaceae, Alismataceae, Amaranthaceae, Amaryllidaceae, Anacardiaceae, Apiaceae, Apocynaceae, Aquifoliaceae, Araceae, Araliaceae, Arecaceae, Aristolochiaceae, Asparagaceae, Aspleniaceae, Asteraceae, Basellaceae, Betulaceae, Blechnaceae, Boraginaceae, Brassicaceae, Butomaceae, Buxaceae, Cactaceae, Campanulaceae, Cannabaceae, Caprifoliaceae, Caryophyllaceae, Celastraceae, Ceratophyllaceae, Cistaceae, Cleomaceae, Colchicaceae, Commelinaceae, Convolvulaceae, Cornaceae, Crassulaceae, Cucurbitaceae, Culcitaceae, Cupressaceae, Cynomoriaceae, Cyperaceae, Cytinaceae, Davalliaceae, Dennstaedtiaceae, Dioscoreaceae, Dipsacaceae, Droseraceae, Drosophyllaceae, Dryopteridaceae, Elaeagnaceae, Elatinaceae, Ephedraceae, Equisetaceae, Ericaceae, Euphorbiaceae, Fabaceae, Fagaceae, Frankeniaceae, Gentianaceae, Geraniaceae, Haloragaceae, Hydrangeaceae, Hydrocharitaceae, Hymenophyllaceae, Hypericaceae, Iridaceae, Isoetaceae, Juglandaceae, Juncaceae, Juncaginaceae, Lamiaceae, Lauraceae, Lentibulariaceae, Liliaceae, Linaceae, Linderniaceae, Lycopodiaceae, Lythraceae, Malvaceae, Marsileaceae, Melanthiaceae, Menyanthaceae, Molluginaceae, Moraceae, Myricaceae, Myrtaceae, Nartheciaceae, Nyctaginaceae, Nymphaeaceae, Oleaceae, Onagraceae, Ophioglossaceae, Orchidaceae, Orobanchaceae, Osmundaceae, Oxalidaceae, Paeoniaceae, PageBreakPapaveraceae, Passifloraceae, Phyllanthaceae, Phytolaccaceae, Pinaceae, Pittosporaceae, Plantaginaceae, Platanaceae, Plumbaginaceae, Poaceae, Polygalaceae, Polygonaceae, Polypodiaceae, Pontederiaceae, Portulacaceae, Potamogetonaceae, Primulaceae, Proteaceae, Pteridaceae, Ranunculaceae, Resedaceae, Rhamnaceae, Rosaceae, Rubiaceae, Ruppiaceae, Rutaceae, Salicaceae, Salviniaceae, Santalaceae, Sapindaceae, Saxifragaceae, Scrophulariaceae, Selaginellaceae, Simaroubaceae, Smilacaceae, Solanaceae, Tamaricaceae, Taxaceae, Thelypteridaceae, Thymelaeaceae, Tropaeolaceae, Typhaceae, Ulmaceae, Urticaceae, Valerianaceae, Verbenaceae, Violaceae, Vitaceae, Woodsiaceae, Xanthorrhoeaceae, Zosteraceae, ZygophyllaceaeFamily: Common names: Vascular plantsUTM square .Sampling Description: A large proportion of the records corresponds to non-exhaustive observations of collaborators, although a significant amount of data results from fieldwork completed as part of other externally funded projects. When possible, plants are identified in the field at least to species level. Otherwise, plant material is collected and identification is confirmed in the lab by the collaborators. Phenological state is recorded if plants are flowering at the time of observation.http://ipt.gbif.pt/ipt/resource.do?r=alfa_checklist_florapt).Taxon nomenclature is fully controlled via use of a reference checklist, allowing neither spelling errors nor outdated synonyms. The reference checklist includes only currently accepted nomenclature which corresponds to an updated version of the \u201cChecklist da Flora de Portugal \u201d . Bioclimatic data are extracted from the climatic variables and bioclimatic indices compiled and developed by Monteiro-Henriques et al. (2015).The Flora-On dataset represents a major contribution to the knowledge of the present distribution of Portuguese and Iberian flora. Despite the lack of information in several parts of the territory, Flora-On dataset constitutes the most complete and up to date source of research-grade occurrence data on the Portuguese flora, since a great concern is put on ensuring the correctness of the data. Other existing nation-wide platforms covering occurrence data of the Portuguese flora have either a partial coverage or do not specifically target validated data. Furthermore, previous data on the Portuguese flora was limited to herbarium and bibliographic sources, which are largely not digitally accessible or accessible only in a very coarse format.Finally, the Flora-On project has been stimulating the collection of new data on the distribution of species, which has resulted in great improvements in the knowledge of many species. Indeed, the voluntary field work conducted by the collaborators has significantly improved the knowledge about the current status of many rare, protected by national and international legislation, or hardly known species, and several new species not known to occur in Portugal have been recently found.Object name: Darwin Core Archive Flora-On: occurrence data of the flora of mainland PortugalPageBreakCharacter encoding: UTF-8Format name: Darwin Core Archive formatFormat version: 1.0Distribution: http://flora-on.pt:8080/ipt/archive.do?r=flora-onPublication date of data: 2016-02-19Language: PortugueseLicences of use: This work is licensed under a Creative Commons Attribution Non Commercial (CC-BY-NC) 4.0 License.Metadata language: EnglishDate of metadata creation: 2014-12-04Hierarchy level: DatasetUsed Darwin Core Terms: id, modified, language, rights, institutionID, collectionID, institutionCode, collectionCode, datasetName, ownerInstitutionCode, basisOfRecord, dataGeneralizations, occurrenceID, catalogNumber, occurrenceRemarks, recordedBy, reproductiveCondition, occurrenceStatus, eventDate, year, month, day, country, countryCode, county, municipality, decimalLatitude, decimalLongitude, geodeticDatum, footprintWKT, footprintSRS, identifiedBy, dateIdentified, scientificName, higherClassification, kingdom, phylum, class, order, family, genus, specificEpithet, infraspecificEpithet, taxonRank, scientificNameAuthorship, nomenclaturalCode."} +{"text": "Yamak D, Pavlicek B, Boltz T, Panse P, Akay M. Coronary calcium quantification using contrast\u2010enhanced dual\u2010energy computed tomography scans. J Appl Clin Med Phys. 2013;14(3):4014.One author of the paper, David Frakes, was mistakenly left off the author list. He should be added in the fifth spot of the author list: Yamak D, Pavlicek B, Boltz T, Panse P, Frakes D, Akay M. His affiliation is:School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA"} +{"text": "High-Throughput maintains high quality standards for its published papers. In 2017, a total of 18 papers were published in the journal. Thanks to the cooperation of our reviewers, the median time to first decision was 23 days and the median time to publication was 50 days. The editors would like to express their sincere gratitude to the following reviewers for their time and dedication in 2017:Abdulmalik, OsheizaMou, HaiweiArany, PraveenNa, HuiminBen-Yoav, HadarNuthikattu, SaivageethiBlomberg, JonasP\u00e9rez, SoledadBorres, MagnusPerumal, DeepakChen, Chun-LiangPi, RongbiaoClifford, GaryPortelius, ErikConesa, AnaPurut\u00e7uo\u011flu, VildaDe Bragan\u00e7a Pereira, Carlos AlbertoRaynal, FlorenceDevine, DeirdreRobertson, DouglasDo, ThuySaikaly, PascalEnguita, FranciscoSinghrao, Sim K.Esguerra, JonathanStafford, PhilipFarlik, MatthiasSumoy, LauroGajula, RajendraTelen, MarilynGilbert, ElizabethTomasetti, MarcoGowans, EricUrbanelli, LorenaHindmarch, CharlieVashist, SandeepHuang, Weei-YuarnVladimirov, VladimirIjiri, DaichiVolinia, StefanoKodzius, RimantasVoss, MatthiasLin, Liang-TzungWang, RongshengLiu, ZhixiaWeng, ChingfengLou, FangfeiWu, HaoMelcher, KarstenXu, WeiM\u00e9tayer-Coustard, SoniaYen, Feng-LinMiernyk, Jan APeer review is an essential part in the publication process, ensuring that"} +{"text": "Scientific Reports7: Article number: 4466710.1038/srep44667; published online: 03202017; updated: 04192017The original version of this Article contained an incorrect affiliation list. The correct affiliations are listed below:Affiliation 1Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, 77030, USA.Sangeetha Mahadevan, Khalied Kaskar & Ignatia B. Van den VeyverAffiliation 2Jan and Duncan Neurological Research Institute, Texas Children\u2019s Hospital, Houston, Texas, 77030, USA.Sangeetha Mahadevan & Ignatia B. Van den VeyverAffiliation 3Century Scholars Program, Rice University, Houston, Texas, 77005, USA.Varsha SathappanAffiliation 4Shared Equipment Authority, Rice University, Houston, Texas, 77005, USA.Budi UtamaAffiliation 5Department of Molecular Human Genetics, Baylor College of Medicine, Houston, Texas, 77030, USA.Isabel Lorenzo & Ignatia B. Van den VeyverAffiliation 6Interdepartmental Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, 77030, USA.Sangeetha MahadevanThese errors have now been corrected in the PDF and HTML versions of this Article."} +{"text": "Jfb would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016. The editors of https://publons.com) to receive recognition. Of course, in these intiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make. We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (JFB, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for JFB in 2016:Allain, Jean PaulJajam, KailashPozzobon, MichelaBarbetta, AndreaJeon, HojeongQuan, TaihaoBardag-Gorce, FawziaJimenez-Acosta, FranciscoQuandt, EckhardBiswas, SouvikKarp, JeffRavindra, NuggehalliCalvo-Guirado, Jos\u00e9 LuisKhadka, DhanRen, DongniChang, JungshanKhandaker, MorshedRico, FelixCheng, XingguoKim, Mee KumRohnke, MarcusCiofani, GianniKirsch, MichaelRose, Austin S.Coleman, NicholaKluger, Petra J.Sarda, St\u00e9phanieCollins, MauriceKong, LingxueSchniepp, HannesDaniell, M.Koren, KlausSilva, Simone S.Darvell, BrianLee, ChiSista, SubhashDe Aza, Piedad N.Lee, Hae-HyoungSnyder, NicoleDias, Ana M.Li, HuiSuzuki, ShukoDias, George JayanthaLoh, Xian JunTakano, KatsuraDinjaski, NinaLoh, Xian JunTanaka, MototsuguDrelich, JaroslawLoo, JoachimTanner, ElizabethDrummond, CarlosMannis, Mark J.Taubenberger, AnnaEdirisinghe, MohanMarchesan, S.Torres Filho, Ivo P.Fan, Pui L.Matsusaki, MichiyaTravagli, ValterFauzi, IlianaMattioli-Belmonte, MonicaTredget, Edward EFemenia, AntoniMemarzadeh, KavehTunesi, MartaGarcia Giralt, NataliaMiri, Amir K.Ulrich, M.M.W.Georgieva, RadostinaMiron, Richard J.Vern\u00e8, EnricaGolkowski, MarkMontesarchio, DanielaVorndran, ElkeGomer, Richard H.Morelli, CatiaWang, Tzu-WeiHahm, Ki BaikMoseke, ClausWang, WenxinHarkin, DamienMotta, AntonellaWelch, TreHedhammar, MyMunoz, XavierWiegand, CorneliaHejazi, VahidMusson, David S.Wininger, MichaelHofmann, SandraNishiyama, NorihiroYamato, MasayukiHsiang, Hsing-IPalumbo, Fabio SalvatoreZehnder, MatthiasH\u00fclsmann, MichaelPascu, IrinaZieske, JamesHung, Kuo-YungPezzella, AlessandroIlmarinen, TanjaPires, Ricardo A.The following reviewed for"} +{"text": "Bacillus strains isolated from the Qinghai-Tibetan plateau. According to their genome sequences, 28 isolates were assigned to 10 Bacillus species. Seventeen strains could not be assigned and are subjects of further research.Here, we report the draft genome sequences of 45 plant-associated Bacillus strains isolated from samples taken from different sites of the Qinghai-Tibetan plateau, known as the Third Pole of the world was used for genome-based species delineation. Formula 2, which is especially appropriate to analyze draft genomes, was used was used to determine the average nucleotide identity based on BLAST+ (ANIb) by pairwise genome comparisons , and the sequencing was done in 300-nucleotide (nt) paired-end mode on an Illumina MiSeq version 3 sequencing platform at LGC Genomics . Reads were trimmed and assembled pipeline . Genome pipeline . The genl., 2013 ). In addparisons . The recBacillus wiedmannii , B. atrophaeus , B. pumilus (PVQT00000000 to PVQX00000000), B. halotolerans , B. subtilis (PVRJ00000000 and PVRK00000000), B. thuringiensis (PVRL00000000 and PVRM00000000), B. velezensis (PVRO00000000 and PVRP00000000), B. paralicheniformis (PVQR00000000), B. safensis (PVQS00000000), and B. toyonensis (PVRN00000000). Seventeen strains could not be assigned down to the species level due to their estimated GGDC (<70%) and ANIb (<96%) values. Most of the strains (15 isolates) are related to B. pumilus . The genome sequence of strain RJGP41 (PVQJ00000000) is distantly related to B. simplex, while strain LLTC93 (PVME00000000) resembles the type strain of B. xiamenensis, HYC-10. Further research is in progress in order to clarify the taxonomic position of these cold-adapted strains.According to their draft genome sequences, we have assigned 28 of the isolates as representatives of PVME00000000, PVQJ00000000, PVQK00000000, PVQL00000000, PVQM00000000, PVQN00000000, PVQO00000000, PVQP00000000, PVQQ00000000, PVQR00000000, PVQS00000000, PVQT00000000, PVQU00000000, PVQV00000000, PVQW00000000, PVQX00000000, PVQY00000000, PVQZ00000000, PVRA00000000, PVRB00000000, PVRC00000000, PVRD00000000, PVRE00000000, PVRF00000000, PVRG00000000, PVRH00000000, PVRI00000000, PVRJ00000000, PVRK00000000, PVRL00000000, PVRM00000000, PVRN00000000, PVRO00000000, PVRP00000000, PVRQ00000000, PVRR00000000, PVRS00000000, PVRT00000000, PVRU00000000, PVWA00000000, PVWB00000000, PVWC00000000, PVWX00000000, PVWY00000000, and PYWP00000000. The versions described in this paper are the first versions.These whole-genome shotgun projects have been deposited at DDBJ/ENA/GenBank under the accession numbers"} +{"text": "Heterosigma akashiwo. These ~160-kb sequences contain 124 protein-, 6 rRNA-, and 34 tRNA-coding sequences. Notable sequence variations were observed among these seven sequenced and two previously characterized strains.We report here the complete chloroplast genome sequences of seven strains of the bloom-forming raphidophyte Heterosigma akashiwo is a eukaryotic, unicellular, bloom-forming alga that belongs to the family Raphidophyceae. It has been identified in the Pacific and Atlantic oceans and in both the northern and southern hemispheres, thus spanning a wide climate range from arctic to tropic of seven H.\u00a0akashiwo strains with different geographic origins: CCAP934/8 , EHUSP1 , CCAP934/4 , CCMP2274 , CCMP3374 , HaFk01 , and CCMP1596 . Total DNA was extracted from H.\u00a0akashiwo cells using the DNeasy blood and tissue kit (Qiagen). The libraries were sequenced with the Illumina MiSeq platform, and the obtained paired-end reads were mapped to the previously published sequences, H.\u00a0akashiwo ptDNA of NIES293 (EU168190) and CCMP452 (EU168191) . The obtU168191) . ProteincfxQs, psaA, psaB, psaC, psaD, psaF, psaL, psb28, two psbAs, psbB, two psbCs, two psbDs, psbE, psbH, psbV, two rbcLs, ycf3, ycf34, and ycf35) were identified in each strain, as reported previously for strains CCMP452 and NIES293. Similarly, 34 previously known tRNA genes, including 2 pseudogenes, were identified in all strains. As previously reported, all strains possessed ~22-kb invert repeats, and the strains CCAP934/8, CCMP2274, and HaFk01 contained an ~8.0-kb inversions, flanked between the tyrC and psb28 genes, compared to those of strains EHUSP01, CCAP934/4, CCMP3374, and CCMP1596. The parts of the H.\u00a0akashiwo ptDNA sequences, between 17.5 and 18 kb and 66 and 66.5 kb, showed notable polymorphisms, which may be utilized as strain-specific markers.The lengths of the ptDNAs of strains CCAP934/8, EHUSP01, CCAP934/4, CCMP2274, CCMP3374, HaFk01, and CCMP1596 were 159,918 bp, 160,150 bp, 160,099 bp, 159,321 bp, 160,152 bp, 159,492 bp, and 159,691 bp, respectively, and G+C contents were 30.5% for all the strains. Twenty-four genes related to photosynthesis (two LC269918 (CCAP934/8), LC269919 (EHUSP01), LC269920 (CCAP934/4), LC269921 (CCMP2274), LC269922 (CCMP3374), LC269923 (HaFk01), and LC269924 (CCMP1596).The sequences reported here were deposited in DDBJ/EMBL/GenBank under the accession numbers"} +{"text": "Journal of Experimental Botany, Vol. 66, No. 19 pp. 6035\u20136045, 2017 doi: 10.1093/jxb/erv318In the original version of this paper, a contributing author\u2019s name was spelt incorrectly.\u201cYing Wang, Liming Cao, Yuexiong Zhang, Changxiang Cao, Fang Liu, Fengkuan Huang, Yongfu Qiu, Rongbai Li and Xiaojin Lou\u201dThe corrected list of authors now reads as follows:\u201cYing Wang, Liming Cao, Yuexiong Zhang, Changxiang Cao, Fang Liu, Fengkuan Huang, Yongfu Qiu, Rongbai Li and Xiaojin Luo\u201d"} +{"text": "Diseases would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015. The editors of We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial decision-making process. Several steps have been taken in 2015 to thank and acknowledge reviewers. Good, timely reviews are rewarded with a discount off their next MDPI publication. By creating an account on the submission system, reviewers can access details of their past reviews, see the comments of other reviewers, and download a letter of acknowledgement for their records. This is all done, of course, within the constraints of reviewer confidentiality. Feedback from reviewers shows that most see their task as a voluntary and mostly unseen work in service to the scientific community. We are grateful to our reviewers for the contribution they make.Amberbir, AlemayehuHolsen, LauraNaeije, R.Avila, Matias A.Hong, Mee YoungNeilson, AndrewBakillah, AhmedHoybye, CharlotteNienaber, Christoph ABrown, Alan S.Humpl, TilmanO\u2019Reilly, CiaraBudzy\u0144ski, JacekIwasawa, TaeOstergaard, John R.Cauli, OmarJeong, Yong-SeobPees, ChristianeChan, Anthony WHJeong, Kyu-ShikPerret, ChristineChao, YeeJohnson, Martin K.Pilolli, RosaChatzigeorgiou, AntoniosJ\u00f8rgensen, Anders Palmstr\u00f8mPregnolato, MassimoChiu, Hsin-HuiKingsley, J. DerekPumpens, PaulChong, Charing Ching-NingKohl, Nancy E.Ran\u010di\u0107, Z.Ciclitera, PaulKusters, JohannesRimassa, LorenzaCuperlovic-Culf, MiroslavaKwon, Dong-YeulRoncalli, Massimoda Costa, Jos\u00e9 Manuel CorreiaLa Vieille, S\u00e9bastienSatokari, ReettaDangardt, Frida.Lammi, AnneScalbert, AugustinDe Backer, JulieLee, YoungJooSkaaby, TeaDe Pinho, Paula GuedesLee, Terence Kin-WahStamm, StefanDeFelice, Amy R.Lionetti, ElenaTang, WeiDelvecchio, MaurizioLove, Brian E.Terzuoli, LuciaEferl, RobertLu, KunTheriault, StevenEinfeld, StewartLundin, SamuelThuesen, Betina H.ElBakri, AliMalnick, Stephen David HowardTorres, M.I.Galli, AndreaMatsunami, KatsuyoshiTsukiyama-Kohara, KyokoGaudreau, LucMoco, SofiaWang, Hee-JungGermano, DomenicoMolinari, MicheleWevrick, RachelGil, AnaMorris, ShaineWingren, Carl JohanHato, TaiMuscatelli, Fran\u00e7oiseYen, EricHe, A. RuthMyl\u00e9us, AnnaYu, Su JongHiratsuka, Masahiro"} +{"text": "The authors\u2019 names are all spelled incorrectly. The correct spelling for each author is:Ben-Chuan Lin, Bo-Kui Chen, Ya-Chun Gao, Chi K. Tse, Chuan-Fei Dong, Li-Xin Miao, Bing-Hong WangThe correct citation is:10.1371/journal.pone.0156756Lin B-C, Chen B-K, Gao Y-C, Tse CK, Dong C-F, Miao L-X, et al. (2016) Advanced Algorithms for Local Routing Strategy on Complex Networks. PLoS ONE 11(7): e0156756. doi:There are two errors in the author affiliations:The affiliation for the second author, Bo-Kui Chen, is incorrect. Bo-Kui Chen is not affiliated with #3 but with #2, School of Computing, National University of Singapore, Singapore, SingaporeThe affiliation for the fifth author, Chuan-Fei Dong, is incorrect. Chuan-Fei Dong is not affiliated with #8 but with: Princeton Plasma Physics Laboratory and Department of Astrophysical Sciences, Princeton University, Princeton, New Jersey, United States of America."} +{"text": "They should have been listed as: Mengdi Wang, MM, Weiwei Sun,MD, Zhenjie Chen, MD, Xiaona Wang, BM, Jie Lv, MD, Quanming Tan, MM, Yaoxian Wang, MD, Jingwei Zhou, MD.In the article, \u201cMultiple aneurysms and gastrointestinal involvement in Behcet's disease: A case report\u201d,"} +{"text": "Toxics would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.The editors of We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make.Toxics, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Toxics in 2016:Anadon, ArturoDrapeau, PierrePeyton, David H.Antunes, MargaridaEvelyn, TalbottPivato, AlbertoAlbuquerque, TeresaFaggio, CaterinaPorsch H\u00e4llstr\u00f6m, IngerAlexander, Laura E. CrottyFinazzi, FrancescoPottinger, Tom G.Aris, AzizFitsanakis, VanessaPowell, CraigBailey, HelenFletcher, John S.Radbruch, LucasBarrett, Emily S.Fujihara, JunkoRainieri, SandraB\u00e4umler, HansGangula, PanduRamesh, Tennore M.Baxter, LisaGeorgieva, RadostinaRogiers, BartBellinger, DavidGreim, HelmutSacks, Jason D.Blukacz-Richards, E. AgnesHarrison, RoySarras, Michael P. Jr.Bodin, JohannaHatch, ElizabethSaunders, David M.V.Boogaard, PeterHendryx, MichaelSchnug, EwaldBouchard, Mich\u00e8leHosgood, Howard DeanSekine, YoshikaBrown, Grant E.Kim, Yong PyoSemple, SeanBury, Nic R.Koehler, RaymondSetou, MitsutoshiChai, TianfengKojima, HiroyukiSilva, L\u00edgiaChan, King MingKwak, Wan-SupSimon, EszterChen, JiangangLachenmeier, DirkSnow, Mathew S.Chen, Te-HaoLai, Chia-HsiangSogorb, Miguel A.Cheng, DelfineLee, Jin HeonSone, HidekoChrzanowski, \u0141ukaszLin, ZhoumengTava, AldoChurchill, David G.Liu, Hui-MingTigini, ValeriaCicero, Theodore J.Liu, Shing-HwaTouboul, DavidConti, BarbaraLooger, LorenUlrich, FranckCrunelle, CleoLuzio, AnaWallace, DavidCyr, Daniel G.Mackinnon, GillianWalton, AnnMarieD\u2019annibale, AlessandroMaricle, Brian R.Wang, WeiDe Gennaro, GianluigiMyridakis, AntonisWard, TonyDe Lourdes Pereira, MariaNasuti, CinziaWorek, FranzDe Oliveira Fernandes, EduardoOh, Jin-WooXu, XiaohuiDevillers, JamesOrford, RobDeWitt, Jamie C.Padilla, StephanieThe following reviewed for"} +{"text": "Journal of the Medical Library Association (JMLA) sincerely thanks our peer reviewers in 2017.The Journal of the Medical Library Association (JMLA) sincerely thanks the 154 reviewers in 2017 who helped vet and improve the quality of work published in our journal.The JMLA is always looking to expand our pool of reviewers who can critically comment on any topic of research or practice in health sciences librarianship. If you are interested in serving as a peer reviewer for the JMLA, please send your CV to the editor-in-chief at jmla@journals.pitt.edu.The Nancy AdamsNancy J. Allee, AHIPKristine M. Alpi, AHIPKatelyn AngellKenning ArlitschNell AronoffCaitlin J. Bakker, AHIPMichael Eliot BalesBecky Baltich NelsonJill Barr-WalkerRobert D. BeckettJoeran BeelChristopher BelterCatherine BodenJill T. Boruff, AHIPPaul BrackeWichor BramerMarci BrandenburgHeather BrownNicole Capdarest-Arest, AHIPAlexander James CarrollThane ChambersDeborah H. CharbonneauYibu ChenNicole ContaxisMarisa ConteI. Diane Cooper, AHIPJoseph CostelloJill Crawley-LowAndrew CreamerVicki F. Croft, FMLA, AHIPPrudence Dalrymple, AHIPKate Daniels, AHIPAriel DeardorffAntonio P. DeRosa, AHIPRobin DesmeulesJo Dorsch, AHIP, FMLAKathel DunnMartha Earl, AHIPErin RB EldermireJonathan Eldredge, AHIPKeith D. Engwall, AHIPJulia M. Esparza, AHIPAlison FarrellLisa Federer, AHIPBarbara FolbErin FosterMargaret Jane Foster, AHIPRick Fought, AHIPSuzanne Fricke, AHIPJulie GlanvilleAbigail GobenSally GoreKelsey Grabeel, AHIPAdelia GrabowskyKaren Elizabeth GutzmanLaura J. HallMargaret Henderson, AHIPJennifer HerronToni Hoberecht, AHIPKristi L. HolmesCarol L. HoweElla HuJeffrey HuberShanda L. HuntEmily Margaret Johnson, AHIPRebecca McKay Johnson, AHIPTimothy P. JohnsonDixie A. Jones, AHIPDouglas JoubertKellie Kaneshiro, AHIPJill R. Kavanaugh, AHIPErin KerbyAlla KeselmanAndrea M. Ketchum, AHIPSujin KimDaniel KipnisStephen Kiyoi, AHIPMolly Knapp, AHIPAmy Knehans, AHIPLaura KoppenPetros KostagiolasFred Willie Zametkin LaPollaJanna Lawrence, AHIPBrenda M. Linares, AHIPAnne M. Linton, AHIPAyaba LoganDiana Nelson LoudenYa-Ling LuMark MacEachernKeith C. Mages, AHIPShaheen MajidLisa MastinSarah McClungKaren McElfresh, AHIPMisa Mi, AHIPElizabeth MoretonMartin MorrisBeverly Murphy, AHIP, FMLABethany Myers, AHIPJoey NicholsonTyler NixRob O\u2019ReillyJessica R. Page, AHIPRobin M. N. ParkerCarol L. PerrymanShenita PetersonJodi L. Philbrick, AHIPElizabeth PienaarJJ PionkeT. Scott Plutchak, AHIP, FMLAKimberly PowellZahra PremjiNeil H. RamboRebecca Raszewski, AHIPRebecca RaworthKevin ReadSophie M. Regalado, AHIPDavid ResnikMelissa L. Rethlefsen, AHIPRebecca Reznik-ZellenStephanie Roth, AHIPSarah SafranekAlexandra SarkozyCathy Sarli, AHIPLou Ann ScartonCynthia SchmidtCarolyn SchubertStephanie J. SchulteJean Shipman, AHIP, FMLAJean SongAnsley Stuart, AHIPAlisa SurkisStephanie Swanberg, AHIPNatalie TaggeMaria TanNancy TanneryMarilyn Teolis, AHIPNicole Theis-MahonLorraine ToewsEfren Torres Jr.Whitney Ann TownsendVedana VaidhyanathanEmily VardellSarah May VisintiniRachel R. WaldenVerma WalkerAmanda Wanner, AHIPErin Watson, AHIPMonique WesselsJulia Charma WhelanJeff D. Williams, AHIPKristen L. Young, AHIPKathy Zeblisky, AHIP"} +{"text": "Email: The original address provided was: MKQURAISHI@doctors.org.ukDepartment of Urology, Medway Maritime Hospital, 5 Miraj Avenue, Sparkhill, Birmingham, West Midlands, UK, B11 4JW; E-mail: The correct affiliation of Dr. Bhavna which is mentioned below:Integrated Rheumatology and Arthritis Centre, Dubai Healthcare City, DubaiThe original affiliation provided was: Department of Rheumatology, Dubai Mall Medical Center, Dubai, UAE"} +{"text": "In the original article, the name of the author Nikita Khmelinskii was missing by mistake. The authors apologize for this oversight.New Author Contribution Statement:Conceived and designed the experiments: IP, JC-L, HC, MA, and JF. Performed the experiments: IP and JC-L. Analyzed the data: IP, JC-L, RC-M, CP, NK, EV-S, and HC. Contributed reagents/materials/analysis tools: IP, RC-M, CP, EV-S, NK and HC. Wrote, reviewed, and accepted the final version of the paper: IP, JC-L, RC-M, CP, EV-S, NK, HC, MA, and JF.These errors do not change the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Journal of Developmental Biology would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015. The editors of We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial decision-making process. Several steps have been taken in 2015 to thank and acknowledge reviewers. Good, timely reviews are rewarded with a discount off their next MDPI publication. By creating an account on the submission system, reviewers can access details of their past reviews, see the comments of other reviewers, and download a letter of acknowledgement for their records. This is all done, of course, within the constraints of reviewer confidentiality. Feedback from reviewers shows that most see their task as a voluntary and mostly unseen work in service to the scientific community. We are grateful to our reviewers for the contribution they make.Andres, Anne-CatherineKappen, ClaudiaNo\u00ebl, Emily S.Barucca, MarcoKashimada, KenichiOakes, SamanthaBelo, Jos\u00e9 Ant\u00f3nioKawamata, ShinPavlov, Youri I.B\u00fcrglin, Thomas R.Kiminobu, SugayaPorcher, CatherineBush, JeffreyKlein, David C.Pusapati, GaneshChen, YipingKmita, MarieRoegiers, FabriceChirumbolo, SalvatoreKouskoff, ValerieRothuizen, Tonia C.Dykes, Iain M.Koyama, TomotsuguShinoka, ToshiharuEl-Bialy, TarekKrum, Susan A.Sima, JianEnzmann, VolkerKusumi, KenroSommerville, JohnFraser, Stuart T.Lafontant, Pascal J.Sparatore, BiancaFukai, TohruLai, Wen-Fu ThomasTawil, Bill J.Greenfield, AndyLi, HongdaThomas-Chollier, MorganeGuehring, ThorstenLien, Ching-LingTuan, Tai-lanHadri, LahouariaLoeken, Mary R.van Beuningen, Henk M.Han, JingjiaMonaghan, James R.Vaughan, MelvilleHan, JinnuoMonte-Alto-Costa, Andr\u00e9aWalsh, William R.Harfe, Brian D.Mukhtar, M. Shahid Yamazaki, JunHeilig, JulianeMuneoka, KenYang, TaoHeissig, BeateMu\u00f1oz-Ch\u00e1puli, Ram\u00f3nYang, Wan-XiHorsley, ValerieNawshad, AliYang, YeHuber, Paul W.Neri, SimonaYano, TohruImmink, RichardNichols, Joan E.Zhang, DonghuiJanuschke, JensNiu, JingwenZhou, JunJa\u017awi\u0144ska, AnnaNiyibizi, ChristopherZorn, Aaron"} +{"text": "Psychologica Belgica have been assessed conscientiously and unselfishly by expert reviewers. The quality of our journal totally depends on their valuable and constructive criticisms to the authors. Both the editors and the authors highly appreciate the input and dedication of all our reviewers. Many thanks.All manuscripts published in Nathalie Aelterman, Ghent University, BelgiumAikaterini \u2013 Aliki Michou, Bilkent University, TurkeyJessica Alleva, Maastricht University, NetherlandsCarryl Baldwin, George Mason University, USAChristine Bastin, University of Li\u00e8ge, BelgiumMoti Benita, Ben Gurion University of the Negev, IsraelRaul Berrios, University of Sheffield, UKWim Beyers, Ghent University, BelgiumFilip Boen, Katholieke Universiteit Leuven, BelgiumPiet Bracke, Ghent University, BelgiumLieven Brebels, Katholieke Universiteit Leuven, BelgiumBernd Carette, Ghent University, BelgiumFabienne Chetail, Universit\u00e9 Libre de Bruxelles, BelgiumElien De Caluw\u00e9, Ghent University, BelgiumKathleen De Cuyper, Katholieke Universiteit Leuven, BelgiumJan De Mol, Universit\u00e9 catholique de Louvain, BelgiumGert-Jan De Muynck, Ghent University, BelgiumEdina Doci, Vrije Universiteit Brussel, BelgiumGesine Dreisbach, Universit\u00e4t Regensburg, GermanyHeiner Drenhaus, Saarland University, GermanyMartin Edwards, The university of Sydney, AustraliaAndrew Elliot, University of Rochester, USAChiedu Eseadi, University of Nigeria Nsukka, NigeriaMariana Falconier, Virginia Tech, USAMarjolein Feys, Ghent University, BelgiumCharlie Frowd, University of Winchester, UKNicolas Gillet, Universit\u00e9 Francois-Rabelais de Tours, FranceLuc Goossens, Katholieke Universiteit Leuven, BelgiumSharon Goto, Pomona College, USALeen Haerens, Ghent University, BelgiumMichel Hansenne, University of Li\u00e8ge, BelgiumWalter Herbranson, Whitman College, USAKineta Hung, Hong Kong Baptist University, Hong KongPeter Iserbyt, Katholieke Universiteit Leuven, BelgiumKonrad Jankowski, University of Warsaw, PolandAnne Joosten, Ghent University, BelgiumTheo Klimstra, Tilburg University, NetherlandsFleur Kraanen, University of Amsterdam, NetherlandsJulie Krans, Katholieke Universiteit Leuven, BelgiumLeah Lefebvre, University of Wyoming, USACraig Leth-Steensen, Carleton University, CanadaMichael Lewis, Cardiff University, UKLisa Linnenbrink-Garcia, University of Michigan, USAKoen Luyckx, Katholieke Universiteit Leuven, BelgiumGenevi\u00e8ve Mageau, University of Montreal, CanadaLars-Erik Malmberg, University of Oxford, UKLennia Matos Fernandez, Pontifical Catholic University of Peru, PeruDora Matzke, University of Amsterdam, NetherlandsAnneleen Mortier, Ghent University, BelgiumGreta Noordenbos, Leiden University, NetherlandsDavid O\u2019Brien, Baruch College, USALauri Oksama, National Defence University, FinlandLeen Oris, Katholieke Universiteit Leuven, BelgiumSoren Ostergaard, Aarhus University, DenmarkDaniele Panizza, University of G\u00f6ttingen, GermanyThea Peetsma, University of Amsterdam, NetherlandsMaria Ranzini, Universit\u00e9 libre de Bruxelles, BelgiumCatherine Ratelle, Universit\u00e9 Laval, CanadaGuy Roth, Ben-Gurion University of the Negev, IsraelWalter Schaeken, Katholieke Universiteit Leuven, BelgiumRachel Seginer, University of Haifa, IsraelCorwin Senko, State University of New York, USADirk Smits, Katholieke Universiteit Leuven, BelgiumBart Soenens, Ghent University, BelgiumArnaud Szmalec, University College London, UKPeter Theuns, Vrije Universiteit Brussel, BelgiumElisabet Tubau, Universitat de Barcelona, SpainJasper Van Assche, Ghent University, BelgiumSara Van Autreve, Ghent University, BelgiumBram Van den Bergh, Erasmus University, NetherlandsHans van der Baan, University of Amsterdam, NetherlandsPieter Van Dessel, Ghent University, BelgiumJulie Vandewalle, Ghent University, BelgiumKim Van Durme, Ghent University, BelgiumJanne Vanhalst, Katholieke Universiteit Leuven, BelgiumKarla Van Leeuwen, Katholieke Universiteit Leuven, BelgiumHubert Van Puyenbroeck, Vrije Universiteit Brussel, BelgiumMaarten Vansteenkiste, Ghent University, BelgiumTim Vantilborgh, Vrije Universiteit Brussel, BelgiumJulie Verstraeten, Ghent University, BelgiumBart Wille, Ghent University, BelgiumKim Willems, Vrije Universiteit Brussel, BelgiumAlex Wood, University of Stirling, UKRalf Wolfer, University of Oxford, UKMingming Zhou, University of Macau, China"} +{"text": "Available on\u2010line atwww.aapm.org/meetings/2013SCM/2013 AAPM Spring Clinical MeetingMarch 16 \u2013 19, 2013Phoenix, AZChairDavid E. Hintenlang, PhDUniversity of FloridaGainesville, FLOrganizersTHERAPY TRACKJoann I. Prisciandaro, PhDRadiation OncologyUniversity of MichiganAnn Arbor, MIDimitris Mihailidis, PhDRad Onc and Med PhysCharleston Radiation Therapy ConsCharleston, WVPROFESSIONAL TRACKDavid E. Hintenlang, PhDUniversity of FloridaGainesville, FLDIAGNOSTIC TRACKRobert A. Pooley, PhDRadiologyMayo ClinicJacksonville, FLYOUNG INVESTIGATOR PROGRAMJessica B. Clements, MSMedical PhysicsTexas Health Presbyterian Hospital DallasDallas, TXBrian Wang, PhDUniversity UtahHuntsman Cancer HospitalSalt Lake City, UTJean M. Moran, PhDDept of Radiation Oncology B2C438Ann Arbor, MIJessica B. Clements, MSMedical PhysicsTexas Health Presbyterian Hospital DallasDallas, TXMAMMOGRAPHY TRACKWilliam Geiser, MSImaging PhysicsM.D. Anderson Cancer CenterHouston, TX"} +{"text": "One of the author names was misspelled in the paper. \u2018Lucia Burgia\u2019 should be amended to \u2018Lucia Burgio\u2019 and the author list should be as follows:Isabelle De Groote, Linus Girdland Flink, Rizwaan Abbas, Silvia M. Bello, Lucia Burgio, Laura Tabitha Buck, Christopher Dean, Alison Freyne, Thomas Higham, Chris G. Jones, Robert Kruszynski, Adrian Lister, Simon A. Parfitt, Matthew M. Skinner, Karolyn Shindler and Chris B. Stringer"} +{"text": "The correct citation is: Mehrvarz Sarshekeh A, Advani S, Overman MJ, Manyam G, Kee BK, Fogelman DR, et al. (2017) Association of SMAD4 mutation with patient demographics, tumor characteristics, and clinical outcomes in colorectal cancer. PLoS ONE 12(3): e0173345."} +{"text": "Scientific Reports7:11915; doi:10.1038/s41598-017-10151-1; Article published online 20 September 2017The original version of this Article contained errors in the spelling of the authors Natalia Marek- Trzonkowska, Karolina Piekarska, Natalia Filipowicz, Arkadiusz Piotrowski, Magdalena Gucwa, Katrin Vogt, Birgit Sawitzki, Janusz Siebert & Piotr Trzonkowski which were incorrectly given as Marek- Trzonkowska Natalia, Piekarska Karolina, Filipowicz Natalia, Piotrowski Arkadiusz, Gucwa Magdalena, Vogt Katrin, Sawitzki Birgit, Siebert Janusz & Trzonkowski Piotr.These errors have now been corrected in the PDF and HTML versions of the Article and in the accompanying Supplementary Material."} +{"text": "Bioengineering would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015.The editors of Aarts, Ronald M.Baigude, HurichaBazylinski, Dennis A.Branchini, AlessioCarothers, JamesCasa\u00f1-Pastor, N.Ching, Congo Tak ShingCinelli, PatriziaCosta, RuiDe Vrieze, JoDe-Juan-Pardo, Elena M.Dijkstra, PaulDoeven, EganEsteves, SandraFeng, YuHanai, TaizoHasegawa, ShinyaHastings, AstleyHeo, Min-SukHorstkorte, R\u00fcdigerHuang, Po-WheiJayant, Rahul DevJiang, NingJing, FuyuanKao, KatyKaviratna, AnubhavKovacs, Korn\u00e9lLan, EthanLazzara, MatthewLeporatti, StefanoLewis, NathanLi, GuanglinLi, HangLienen, TobiasLiu, JingLu, TingMatsumoto, TakeshiMorabito, Francesco CarloNalayanda, DivyaNaseer, NomanNuhn, LutzO'Connor, Jos\u00e9-EnriqueOrellana, GuillermoPantaleo, A.M.Pauss, AndrePoertner, RalfPolacheck, WilliamPolizzi, KarenPusapati, GaneshRagunathan, KaushikRamos, JoseRamos, VictoriaRichardson, James W.Rodriguez, GabrielRuiz-Rodr\u00edguez, Juan C.Saady, Noori M. CataSahm, KerstinSamba, RamonaSchuman, MeredithShah, PratikkumarShimizu, HiroshiShirure, VenkteshSmith, KerryStams, Alfons J. M.Stratakis, EmmanuelSvensson, BoTanaka, KatsunoriTashiro, YoheiThomsen, Sune TjalfeWagner, Andreas OttoWang, YangWiedemann, Philipp Wujcik, EvanYarema, KevinYoon, SeongkyuZengler, KarstenZhang, YaleiZhang, GeZinn, ManfredWe greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial decision-making process. Several steps have been taken in 2015 to thank and acknowledge reviewers. Good, timely reviews are rewarded with a discount off their next MDPI publication. By creating an account on the submission system, reviewers can access details of their past reviews, see the comments of other reviewers, and download a letter of acknowledgement for their records. In addition, MDPI has launched a collaboration with Publons, a website that seeks to publicly acknowledge reviewers on a per journal basis. This is all done, of course, within the constraints of reviewer confidentiality. Feedback from reviewers shows that most see their task as a voluntary and mostly unseen work in service to the scientific community. We are grateful to our reviewers for the contribution they make."} +{"text": "By January 2017, more than 400 patients from 17 mostly European countries have been registered in the ARPKD registry study with significant follow-up data. Due to comprehensive retro- and prospective data collection and associated biobanking, ARegPKD will generate a unique ARPKD cohort with detailed longitudinal clinical characterization providing a basis for future clinical trials as well as translational research. Hence, ARegPKD is hoped to contribute to the pathophysiological understanding of the disease and to the improvement of clinical management.Autosomal recessive polycystic kidney disease (ARPKD) is a rare monogenic disease with a severe phenotype often presenting prenatally or in early childhood. With its obligate renal and hepatic involvement, ARPKD is one of the most important indications for liver and/or kidney transplantation in childhood. Marked phenotypic variability is observed, the genetic basis of which is largely unknown. Treatment is symptomatic and largely empiric as evidence-based guidelines are lacking. Therapeutic initiatives for ARPKD face the problem of highly variable cohorts and lack of clinical or biochemical risk markers without clear-cut clinical end points. ARegPKD is an international, multicenter, retro- and prospective, observational study to deeply phenotype patients with the clinical diagnosis of ARPKD. Initiated in 2013 as a web-based registry ( Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of polycystic kidney disease with early manifestation and substantial morbidity and mortality. ARPKD constitutes one of the most important causes of renal replacement therapy and/or liver transplantation in childhood. Hence, the disease has substantial socioeconomic impact despite its low incidence (polycystic kidney and hepatic disease 1 (PKHD1), encoding the ciliary protein fibrocystin/polyductin .The genotype\u2013phenotype correlation is currently refined to the observation that patients with two truncating mutations in mutation . HoweverRemarkably, even up to 20% of siblings show marked variance in phenotype , indicatThe treatment of renal insufficiency, arterial and pulmonary hypertension as well as the management of the hepatic phenotype with congenital hepatic fibrosis, portal hypertension, and cholangitis are largely symptomatic and opinion based, relying on expert recommendations . DiseaseSeveral landmark studies, e.g., by Guay-Woodford and Desmond , BergmanTo tackle these questions and challenges, the ARegPKD registry study was recently initiated by the German Society for Pediatric Nephrology (GPN) and the European Study Consortium for Chronic Kidney Disorders Affecting Pediatric Patients Network (ESCAPE-Network). Here, we report about the current state of progress of this study.ARegPKD is an international, multicenter, and observational study that follows both pediatric and adult patients with the clinical diagnosis of ARPKD .Clinical/laboratory signs of hepatic fibrosisHepatic pathology demonstrating ductal plate abnormalityAbsence of renal enlargement and/or multiple cysts in both parentsPathoanatomic diagnosis of ARPKD in an affected siblingFamily history consistent with autosomal recessive inheritance.Diagnostic criteria are (a) typical findings on renal imaging and (b) one or more of the following criteria:Exclusion criteria encompass definite genetic, histological, or clinical proof of other cystic kidney disorders.Patient status\u2014baseline evaluation Renal status including symptoms, radiological findings, and biopsy resultsExtrarenal status regarding liver and other organs Laboratory valuesMedications with start and end date, doseTherapy including renal replacement therapy, surgical procedures, and other proceduresFurther developments with inclusion of user-defined comments.Deep phenotypic characterization is ensured by entry of basic data and both retro- and prospective visits. Basic data encompass age and clinical symptoms at primary manifestation as well as perinatal period, genetic testing, and family history. Date of diagnosis and criteria leading to diagnosis are checked for plausibility with other entries. The visits can be entered retro- and prospectively thereby also enabling inclusion of deceased pediatric patients in order to counteract the problem of underreporting of severely affected and early deceased patients. Visits are planned to be entered annually but can be documented at flexible time intervals, e.g., using longer intervals for retrospective entry of adult patients but more frequent prospective data entries of incident patients. In this way, detailed longitudinal information is provided over decades of patient follow-up for the following type of information:www.aregpkd.org) by authorized medical personnel. Subject pseudonymization is performed at the corresponding center. The database is stored on a safe server of the Cologne University Computing Facilities and secured by use of SSL connections.Pseudonymized data are entered into a password-restricted, web-based database consortium, in which clinicians, geneticists, and basic scientists have teamed up to study the clinical and genetic overlap of cystic kidney diseases and establish guidelines for diagnostics and standards of care. Within the frame of NEOCYST ARegPKD will also be evaluated by an external advisory board.The focus and strength of the ARegPKD registry study lies on the stringent collection of detailed longitudinal data in a large patient cohort, which will allow to outline the natural course of the disease and to identify prognostically uniform subcohorts of this heterogeneous disease. Given the observational design of the study, there are obvious weaknesses which include selection bias, incomplete data collection, and operator-dependency of sonographic findings. Yet, the data collected truly represent the \u201creal-life\u201d situation of patients with ARPKD followed in major clinical centers.In summary, since its start in 2013, ARegPKD has made substantial progress with successful international recruitment of ARPKD patients. Given this progress, ARegPKD will soon provide an observational evidence base to recommendations for the care of patients suffering from ARPKD.L. A. Eid, Dubai, United Arab Emirates; N. Ranguelov, Brussels, Belgium; B. Adams, Brussels, Belgium; K. van Hoeck, Edegem, Belgium; A. Raes, Gent, Belgium; D. Mekahli, Leuven, Belgium; L. Collard, Montegnee, Belgium; J. Lombet, Montegnee, Belgium; J. Maquet, Montegnee, Belgium; F. Cachat, Lausanne, Switzerland; G. Schalk, Zurich, Switzerland; T. Seeman, Prague, Czech Republic; N. Ortiz Bruechle, Aachen, Germany; K. Zerres, Aachen, Germany; J. Thumfart, Berlin, Germany; S. Briese, Berlin, Germany; U.\u2009Querfeld, Berlin, Germany; B. Hoppe, Bonn, Germany; M. Feldkoetter, Bonn, Germany; M. Kirschstein, Celle, Germany; G. Gruening, Celle, Germany; B. B. Beck, Cologne, Germany; T. Benzing, Cologne, Germany; R. Buettner, Cologne, Germany; J. D\u00f6tsch, Cologne, Germany; H. Goebel, Cologne, Germany; F. Grundmann, Cologne, Germany; B. Hero, Cologne, Germany; C. Kurschat, Cologne, Germany; L. T. Weber, Cologne, Germany; B. Mayer, Dresden, Germany; J. Weber, Dresden, Germany; B. Ritter, Dresden, Germany; K. Benz, Erlangen, Germany; M. Galiano, Erlangen, Germany; A. Tzschoppe, Erlangen, Germany; B. Buchholz, Erlangen, Germany; R. Buescher, Essen, Germany; A. Buescher, Essen, Germany; K. Latta, Frankfurt, Germany; K. H\u00e4ffner, Freiburg, Germany; M. Pohl, Freiburg, Germany; O. Gross, Goettingen, Germany; J. Kr\u00fcgel, Goettingen, Germany; J. Stock, Goettingen, Germany; L. Patzer, Halle/Saale, Germany; H. Teichler, Halle/Saale, Germany; J. Oh, Hamburg, Germany; R. Schild, Hamburg, Germany; T. Illig, Hannover, Germany; N. Klopp, Hannover, Germany; L. Pape, Hannover, Germany; S. Wahrendorf, Hannover, Germany; W. Bernhardt, Hannover, Germany; A. Doyon, Heidelberg, Germany; E. Wuehl, Heidelberg, Germany; T.\u2009Vinke, Heidelberg, Germany; A. Sander, Heidelberg, Germany; K. Kunzmann, Heidelberg, Germany; C. Bergmann, Ingelheim, Germany; S. Wygoda, Leipzig, Germany; M. Henn, Leipzig, Germany; D. Wiemann, Magdeburg, Germany; K. Blaschke, Magdeburg, Germany; U.\u2009Derichs, Mainz, Germany; R.\u2009Beetz, Mainz, Germany; N. Jeck, Marburg, Germany; G. Klaus, Marburg, Germany; H. Fehrenbach, Memmingen, Germany; T. Hampel, Memmingen, Germany; S. Zoetler, Memmingen, Germany; M. Wallot, Moers, Germany; H. Kyrieleis, Moers, Germany; B. Lange-Sperandio, Munich, Germany; S. Ponsel, Munich, Germany; F. Kusser, Munich, Germany; J. Hoefele, Munich, Germany; B. Uetz, Munich, Germany; M. Benz, Munich, Germany; S. Schmidt, Munich, Germany; C. Huppertz-Kessler, Munich, Germany; B. Kranz, Muenster, Germany; J. Koenig, Muenster, Germany; A. Titieni, Muenster, Germany; M. Boeswald, Muenster, Germany; H. Staude, Rostock, Germany; U.\u2009Jacoby, Rostock, Germany; D. Wurm, Saarbr\u00fccken, Germany; H. E. Leichter, Stuttgart, Germany; M. Bald, Stuttgart, Germany; H. Billing, Tuebingen, Germany; M. Gessner, Tuebingen, Germany; O. Beringer, Ulm, Germany; M.-L. Ilmoja, Tallinn, Estonia; N. A. Soliman, Cairo, Egypt; M. M. Nabhan, Cairo, Egypt; G. Ariceta, Barcelona, Spain; L. E. Lara, Barcelona, Spain; M. A. Garcia-Gonzalez, Santiago de Compostela, Spain; C. Diaz-Rodriguez, Santiago de Compostela, Spain; M. Garcia-Vidal, Santiago de Compostela, Spain; B. Ranchin, Lyon, France; R. Shroff, London, UK; R. Sterenborg, London, UK; T. Davitala, Tbilisi, Georgia; F. Papachristou, Thessaloniki, Greece; S. Stabouli, Thessaloniki, Greece; P.\u2009Sallay, Budapest, Hungary; N.\u2009Hooman, Tehran, Iran; G. Ardissino, Milano, Italy; S. Testa, Milano, Italy; L. Massella, Rome, Italy; F. Emma, Rome, Italy; A. Jankauskiene, Vilnius, Lithuania; R. Cerkauskiene, Vilnius, Lithuania; K. Azukaitis, Vilnius, Lithuania; A. Bokenkamp, Amsterdam, Netherlands; J. van Wijk, Amsterdam, Netherlands; K. Taranta-Janusz, Bialystok, Poland; A. Wasilewska, Bialystok, Poland; I. Zagozdzon, Gdansk, Poland; I. Balasz-Chmielewska, Gdansk, Poland; M. Miklaszewska, Krakow, Poland; K. Zachwieja, Krakow, Poland; D. Drozdz, Krakow, Poland; M. Tkaczyk, Lodz, Poland; M. Stanczyk, Lodz, Poland; P. Sikora, Lublin, Poland; M. Zaniew, Poznan, Poland; M. Litwin, Warsaw, Poland; A. Niemirska, Warsaw, Poland; D. Wicher, Warsaw, Poland; I. Jankowska, Warsaw, Poland; J. Antoniewicz, Warsaw, Poland; J. Lesiak, Warsaw, Poland; P. Lipinski, Warsaw, Poland; M. Szczepanska, Zabrze, Poland; P. Adamczyk, Zabrze, Poland; A. Morawiec-Knysak, Zabrze, Poland; A. Caldas Afonso, Porto, Portugal; A. Teixeira, Porto, Portugal; G. Milosevski-Lomic, Belgrade, Serbia; D. Paripovi\u0107, Belgrade, Serbia; A. Peco-Antic, Belgrade, Serbia; L. Prikhodina, Moscow, Russia; S. Papizh, Moscow, Russia; A. K. Bayazit, Adana, Turkey; A. Anarat, Adana, Turkey; E. Melek, Adana, Turkey; U.\u2009S. Bayrakci, Altindag-Ankara, Turkey; A. Kantar, Altindag-Ankara, Turkey; S.\u2009Cayci, Altindag-Ankara, Turkey; U. E. Baskin, Ankara, Turkey; A. Duzova, Ankara, Turkey; A. Yuzbasioglu, Ankara, Turkey; A. Soylu, Balcova, Izmir, Turkey; S. Kavukcu, Balcova, Izmir, Turkey; S. Kalman, Bestepe-Ankara, Turkey; H. Evreng\u00fcl, Denizli, Turkey; S. Y\u00fcksel, Denizli, Turkey; A. Kara, Firat, Turkey; M. K. Gurgoze, Firat, Turkey; C. Candan, Istanbul, Turkey; L. Sever, Istanbul, Turkey; S. Caliskan, Istanbul, Turkey; N. Canpolat, Istanbul, Turkey; S. Emre, Istanbul, Turkey; A. Yilmaz, Istanbul, Turkey; I. G\u00f6kce, Istanbul, Turkey; H. Alpay, Istanbul, Turkey; N. Akinci, Istanbul, Turkey; S. Mir, Izmir, Turkey; B. Sozeri, Izmir, Turkey; I. Dursun, Kayseri, Turkey; H. M. Poyrazoglu, Kayseri, Turkey; R.\u2009Dusunsel, Kayseri, Turkey; H. Nalcacioglu, Kayseri, Turkey; Z. Ekinci, Kocaeli, Turkey; Y. Tabel, Malatya, Turkey; A. Delibas, Mersin, Turkey; D. \u00d6v\u00fcnc Hacihamdioglu, \u00dcsk\u00fcdar/Istanbul, Turkey; L. Guay-Woodford, Washington, DC, USA; ESCAPE Study Group; GPN Study Group.Main votum: Ethics committee of the Medical Faculty of the University of Cologne. Written informed consent was obtained prior to participation. Informed consent files were reviewed by Ethics committee. Consent by pediatric patients and parents. Age-adjusted consent forms.KE, FS, and ML drafted the manuscript. FS and ML designed the study. KE, FS, and ML contributed to coordinated European establishment of the study. All the authors reviewed and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with one of the authors ML and states that the process nevertheless met the standards of a fair and objective review."} +{"text": "Effective therapeutics exploit common characteristics shared amongst cancers. As many cancers present chromosomal instability (CIN), one possible approach to treat these cancers could be to increase their CIN above a threshold that would affect their viability. Here, we investigated whether causing polyploidy by cytokinesis failure could represent a useful approach. We show that cytokinesis failure caused by depletion of Citron kinase (CIT-K) dramatically decreased cell proliferation in breast, cervical and colorectal cancer cells. CIT-K depletion activated the Hippo tumor suppressor pathway in normal, but not in cancer cells, indicating that cancer cells have evolved mechanisms to bypass this control. CIT-K depleted cancer cells died via apoptosis in a caspase 7 dependent manner and, consistent with this, p53-deficient HCT116 colon carcinoma cells failed to induce apoptosis after cytokinesis failure. However, other p53-mutated cancer cells were able to initiate apoptosis, indicating that cytokinesis failure can trigger apoptosis through a p53-independent mechanism. Finally, we found that actively dividing and, in some cases, polyploid cancer cells were more susceptible to CIT-K depletion. In sum, our findings indicate that inducing cytokinesis failure could be a promising anti-cancer therapeutic approach for a wide range of cancers, especially those characterized by fast cell proliferation and polyploidy. Chromosomal instability (CIN) is a hallmark of many cancers . CIN is Drosophila indicated that proliferating tissues from mutants carrying strong allelic combinations of the CIT-K orthologue were highly polyploid (8N or more), misshapen, and smaller than their wild type counterparts. By contrast, the tissues of animals carrying weaker allelic combinations were tetraploid and normal in shape and size trypan blue (Sigma Aldrich), pipetted into disposable Countess5 cells were stained with annexin V-FITC (BD Pharmingen) for 15 minutes in the dark at RT and then with PI (BD Pharmingen) just prior to analysis on the Cytek FACScan\u2122 Flow Cytometer. 20,000 cells were used in the analysis.Cells were treated with respective siRNAs for 72 hours, harvested using non-enzyme dissociation buffer (Sigma Aldrich) and kept on ice. The media and PBS wash prior to harvesting were collected as apoptotic cells can become buoyant. Dissociated cells were carefully collected, washed twice in ice cold PBS and once in 1X annexin V binding buffer (BD Pharmingen). Approximately 1\u00d710Cells were harvested, washed with PBS and fixed for 30 minutes at 4\u00b0C with ice cold 70% [v/v] ethanol (adding ethanol drop wise to cells whilst vortexing). Fixed cells were washed with PBS and re-suspended in FxCycle\u2122 PI/RNase Staining Solution (Life technologies) for 15 minutes prior to analysis on the Cytek FACScan\u2122 Flow Cytometer. 50,000 cells were used in the analysis, unless stated otherwise.+/+ strain was used) were treated with 4 \u03bcM cytochalasin D (Sigma Aldrich) for \u223c18 hours, washed every 5 minutes for 30 minutes with PBS, stained with 15 \u03bcM Hoescht 33342 for 30 minutes at 37\u00b0C and then FACS sorted for the 8N population (to isolate dividing 4N cells). Cells were grown until near confluent in a T75 flask where they were again sorted for the 8N population . This process was repeated twice more until a near pure population of dividing HCT116 4N cells were achieved. For the parental 2N cell line, cells were sorted for the 2N population following cytochalasin D treatment and cultured under normal conditions.HCT116 cells , the PubMed ID (PMID) was given. Bladder: GSE13507, GSE3167, GSE89, PMID 16432078. Brain: GSE2223, GSE4290, GSE4058, GSE4536, GSE7696, TCGA, PMID 12894235, PMID 11929829, PMID 16357140. Breast: GSE3744, GSE3193, GSE4382, GSE5764, GSE22358, GSE1477, GSE3971, GSE14548, GSE8977, GSE9014, TCGA, PMID 10963602, PMID 22522925. Cervical: GSE7410, GSE6791, GSE9750, GSE7803. Colorectal: GSE20916, GSE9689, GSE20842, GSE9348, GSE20916, GSE8671, GSE5206, GSE6988, TCGA, PMID 12101425. Esophageal: GSE20347, GSE6059, GSE23400, GSE13898, GSE1420. Gastric: GSE27342, GSE13861, GSE13911, GSE19826, PMID 12925757. Head and neck: GSE27155, GSE25099, GSE6631, GSE13601, GSE1722, GSE3524, GSE2379, GSE6791, GSE9844, GSE6004, GSE3467, GSE12452, PMID 12368205, PMID 15833835, PMID 14729608. Kidney: GSE15641, GSE4125, GSE11151, GSE2712, GSE14994, GSE6344, GSE781. Leukaemia: GSE2350, GSE13159, GSE2466, GSE7186, GSE1159, GSE28497, GSE1466, GSE995, GSE5788, PMID 16267031. Liver: GSE6764, GSE3500, GSE14520, GSE14323. Lung: GSE2514, GSE7670, GSE31210, GSE10072, GSE19188, GSE32863, GSE3398, GSE3268, PMID 11707567, PMID 15833835. Lymphoma: GSE6338, GSE2350, GSE3827, GSE1466, GSE12195, GSE14879, GSE12453. Melanoma: GSE7553, GSE3189, GSE6887, PMID 15833814. Myeloma: GSE13591, GSE5900. Ovarian cancer: GSE6008, GSE26712, GSE12470, TCGA, PMID 14760385, PMID 15161682. Pancreatic: GSE16515, GSE15471, GSE3654, GSE1542, PMID 16103885, PMID 15867264, PMID 15548371. Prostate: E-TABM-26, GSE6099, GSE21034, GSE6956, GSE6919, GSE3325, GSE3933, PMID 12873976, PMID 19737960, PMID 22722839, PMID14695335, PMID 11807955, PMID 12086878, PMID 11507037, PMID 12154061. Sarcoma: GSE21122, GSE13861, GSE2719, GSE2712.The following datasets were used to analyse"} +{"text": "Microarrays would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.The editors of We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make.Microarrays, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Microarrays in 2016:Albrecht, SimoneKang, Bum-YongSeo, Kun-HoBorres, MagnusKrishna, SmritiSmrcka, Alan V.Bortoluzzi, StefaniaKukreja, MuskanSpruck, CharlesBosco, GiovanniLee, Sheng-AnSumoy, LauroCalin, George AdrianLian, IanSun, LitaoCervantes, Jorge L.Lu, ShuoSyed, ParvezChai, Han-HaMadsen, OleTaube, JoeCretich, MarinaMaleki, SoheilaThyagarajan, BharatDe Bragan\u00e7a Pereira, Carlos AlbertoMarchetti, PieroTurcanu, VictorDixit, Chandra K.Marguerat, SamuelUsui, KenjiDubey, RaminNagatani, NaokiVan Scherpenzeel, MoniqueDufva, MartinNesterov-Mueller, AlexanderVon Neuhoff, NilsDusinska, MariaPastori, Ricardo L.Wei, HairongEmbers, MonicaPatrinos, GeorgeWhelan, Rebecca J.Enguita, FranciscoPena, Romi N.Wong, Ka-ChunGasparini, MauroPuard, VincentWu, HaoGirod, AndreasPurut\u00e7uo\u011flu, VildaYang, XueGong, FadeRavo, MariaZanella, FabianGuinney, JustinRenaudineau, YvesZhang, JingJingGupta, AditiSamuels, ScottZhang, LeiHirabayashi, JunSapi, EvaZhou, HuaThe following reviewed for"} +{"text": "AbstractPseudacrobasis is reviewed for China. Pseudacrobasisdilatatasp. n. is described as new and compared with Psorosatergestella . Images of adults and illustrations of genital structures are provided.The genus Pseudacrobasis is a monotypic genus established by Roesler in 1975 for the type species Pseudacrobasisnankingella Roesler, 1975 from Nanjing, China. It is widely distributed in China, Korea, Japan, and south of Russian Far East , and transferred tergestella from Psorosa Zeller, 1848 to Pseudacrobasis Roesler, 1975, which eliminated \u201cthe wrong identification leading to the wrong conclusion on a putatively \u2018invasive\u2019 species\u201d. Scalercio (2015) elaborated its biology, ecology, and distribution for the first time.Far East , and its species . In 2014Pseudacrobasistergestella is known only. Here, a second species Pseudacrobasisdilatata sp. n. is described, based on specimens collected from different localities in China, and it is compared with Psorosatergestella .It has been more than 40 years since the genus establishment, and since then the type species Genitalia dissections were carried out following the methods introduced by Taxon classificationAnimaliaLepidopteraPyralidaeRoesler, 1975Pseudacrobasis Roesler, 1975: 100.Pseudacrobasistergestella .Pseudacrobasis is characterized by the combination of the following characters: the male antennal scape with a distal scale projection on the inner side, the several basal flagellomeres slightly incurved, forming a shallow sinus containing a smaller scale tuft, the first and several other flagellomeres beyond the sinus bearing a small spine dorsally Psorosatergestella Ragonot, 1901: 107\u2013108. TL: Italy (Trieste).Pseudacrobasisnankingella Roesler, 1975: 100. TL: China (Jiangsu).Pseudacrobasistergestella : Pseudacrobasistergestella is characterized by the large uncus narrowed from broad base to 3/5, mushroom-like in the distal 2/5; the transtilla distally produced to a stout digitate dorsal process and a curved slender ventral process in the male genitalia , Korea, Japan, south of Russian Far East, France, Portugal, Italy.Pseudacrobasistergestella is widely distributed in China. Its identification in this study is based on the examination of 88 male and 67 female specimens. Scalercio (2015) pointed out \u201cthe currently known [\u2026], the distribution of Psorosatergestella is quite unique with occurrences in the far east and in the far west of the Palearctic region, no records are currently available for Central Asia and East Europe, where suitable habitats are present\u201d. We believe Psorosatergestella is likely to distribute the Central Asian and East Europe region with the depth of the investigation.Taxon classificationAnimaliaLepidopteraPyralidaehttp://zoobank.org/AD43828F-F38B-4D24-929D-4F9EC463A172Psorosatergestella by the following characters: M2 and M3 of the hindwing stalked for approximately 3/5 of their lengths; in the male genitalia by the subtriangular uncus gradually narrowed to truncate apex, the transtilla with its distal part developed into two small horns of nearly equal sizes; in the female genitalia by the posterior margin of the eighth tergite only slightly concave and lacking decoration. In Psorosatergestella , 28 May 1994, leg. Jin Zhou. Paratypes: 1 \u2640, Gansu, Wenxian, Bifenggou, , 10 July 2005, leg. Hai-Li Yu; 1 \u2642, Guizhou, Chishui, Suoluo, , 27 May 2000, leg. Yan-Li Du; 4 \u2640\u2640, Guizhou, Xishui, Linjiang, , 3 June 2000, leg. Yan-Li Du; 1 \u2642, Guizhou, Fanjingshan, Heiwan, , 2 June 2002, leg. Xin-Pu Wang; 3 \u2642\u2642, Guizhou, Daozhen, Dashahe, , Xiannvdong, 28 May 2004, leg. Shu-Lian Hao; 1 \u2642, Guizhou, Daozhen, Dashahe, , Xiannvdong, 17 August 2004, leg. Yun-Li Xiao; 2 \u2642\u2642, Guizhou, Daozhen, , Chengjiashan, 19 August 2004, leg. Yun-Li Xiao; 1 \u2642, Hebei, Jingxing, Mt. Xiantai, , 23 July 2000, leg. Hai-Li Yu; 4 \u2642\u2642, Henan, Huixian, Baligou, , 12 July 2002, leg. Xin-Pu Wang; 3 \u2642\u2642, Henan, Huixian, Guanshan, , 25\u221226 July 2006, leg. Deng-Hui Kuang, Hui Zhen; 2 \u2642\u2642, Henan, Jiyuan, Wangwushan, , 30 July 2006, leg. Deng-Hui Kuang, Hui Zhen; 2 \u2642\u2642, Henan, Yiyang, Huaguoshan, , 1 August 2006, leg. Deng-Hui Kuang, Hui Zhen; 4 \u2642\u2642, 1 \u2640, Hubei, Shennongjia, Bajiaomiao, , 19 July 2003, leg. Shu-Lian Hao; 1 \u2640, Hubei, Shennongjia, , Wenquan, 21 July 2003, leg. Shu-Lian Hao; 1 \u2642, Hubei, Shennongjia, Songbaizhen, , 17 July 2003, leg. Shu-Lian Hao; 1 \u2642, Qinghai, Xunhua, Mengda, , 15 July 1995, leg. Hou-Hun Li, Shu-Xia Wang. 2 \u2642\u2642, 3 \u2640\u2640, Shaanxi, Yangling, , 3\u221211 June 1985, leg. Hou-Hun Li; 4 \u2642\u2642, 6 \u2640\u2640, same data as holotype; 1 \u2640, Shaanxi, Baihe, Qianpo, , 16 May 1994, leg. Jin Zhou; 51 \u2642\u2642, 47 \u2640\u2640, Shanxi, Jincheng, Lingchuan, Xizhashuicun, , 12\u221218 July 2010, leg. Hai-Yan Bai, Lin-Lin Yang; 1 \u2642, Sichuan, Jianyang, Pingquan, , 4 May 1994, leg. Jin Zhou; 1 \u2640, Sichuan, Mabian, Yonghong, , 22 July 2004, leg. Ying-Dang Ren; 2 \u2642\u2642, Sichuan, Tianquan, Lamahe, , 29 July 2004, leg. Ying-Dang Ren; 2 \u2642\u2642, Zhejiang, Mt. Jiulong, , 4\u22125 August 2011, leg. Lin-Lin Yang, Na Chen.Holotype \u2642, China: Shaanxi, Danfeng, Tieyupu, .dilatatus (dilate), referring to the dilated distal part of the transtilla.The specific name is derived from the Latin PageBreak"} +{"text": "Metabolites would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.The editors of https://publons.com) to receive recognition. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make.We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (Metabolites, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Metabolites in 2016:Adrian, LorenzHarshman, Sean W.Reddy, Akhilesh B.Ahn, Woo SukHattori, NobutakaRiccadonna, SamanthaAllen, Doug K.Iorio, EgidioRinnan, \u00c5smundAllen, DouglasIspoglou, TheocharisRoberto, ConsonniAprea, EugenioJensen, J\u00f8rgenRogers, SimonBartels, Else MarieJu, Se-JongRonchetti, SimonaBathe, Oliver F.Kaliszan, RomanR\u00f6ttger, RichardBeauchamp, JonathanKavazis, AndreasSchirra, HorstBingol, KeremKehoe, PatSch\u00f6pf, VeronikaBoccard, JulienKim, JayoungSchumacher, RainerBolognini, DanieleKind, TobiasSeca, Ana M.L.Boros, LaszloK\u00f6falvi, AttilaSeene, TeetBroeckling, CoreyKurland, IrwinSegura, AnaBromage, TimothyLaiakis, EvageliaShipley, PaulBunik, VictoriaLe Moyec, LaurenceSinkkonen, JariChoi, Hyung-KyoonLee, Hsin-ChenSiuszdak, GaryChristos, GeorgiouLeon, CarlosSomerville, Greg A.Collier, JasonLi, WeiStanimirova, IvanaCostantini, SusanLibourel, IgorStefano, CaldaralliDaykin, ClareLiu, XiaojingStein, ThorDe Lima Ara\u00fajo, K\u00e1tia G.Lucarelli, GiuseppeSteinacker, JuergenDettmer, KatjaMaker, GarthStewart, George C.Dias, Daniel A.Maserti, Bianca ElenaSullivan, LucasDon, AnthonyMason, JamesSwiezewska, EwaDuriez, ElodieMillard, PierreTanaka, HirotoshiEbbels, TimMittelbach, MartinToya, YoshihiroEisenreich, WolfgangMotta, AndreaVallini, GiovanniElena-Herrmann, B\u00e9n\u00e9dicteM\u00fcller, Maren LilianVan Der Laarse, Willem J.Eras, JordiMurdaca, GiuseppeVan Der Meer, Marcel T.J.Erny, GuillaumeNadal-Desbarats, LydieVilas, Julia SanchezFanizzi, Francesco P.Neumann, SteffenWebb, Kimberly M.Fiandaca, MassimoNocentini, GiuseppeWesterhuis, Johan A.Freund, DanaParigi, GiacomoWilliamson, MikeGenta-Jouve, Gr\u00e9goryParkinson, Don-RogerWilson, JulieGlenn, Thomas C.Pluskal, Tom\u00e1\u0161Zabaras, DimitriosGregory, StephenRaftery, DanielZhang, BoHaines, Julie ReiszRatcliffe, R. GeorgeThe following reviewed for"} +{"text": "Psychologica Belgica have been assessed conscientiously and unselfishly by expert reviewers. The quality of our journal totally depends on their valuable and constructive criticisms to the authors. Both the editors and the authors highly appreciate the input and dedication of all our reviewers. Many thanks.All manuscripts published in Katarzyna Adamczyk, Adam Mickiewicz University in Pozna\u0144, PolandNathalie Aelterman, Ghent University, BelgiumStefan Agrigoroaei, Katholieke Universiteit Leuven, BelgiumAlejandra Alarcon, Universit\u00e9 Libre de Bruxelles, BelgiumCristina Antunes, University of Tr\u00e1s-os-Montes and Alto Douro, PortugalMatthijs Bal, University of Bath, United KingdomMoti Benita, Ben Gurion University of the Negev, IsraelWim Beyers, Ghent University, BelgiumBoris Bizumic, Australian National University, AustraliaLiesbet Boone, Ghent University, BelgiumMaarten Boudry, Ghent University, BelgiumDries Bostyn, Ghent University, BelgiumPiet Bracke, Ghent University, BelgiumLieven Brebels, Katholieke Universiteit Leuven, BelgiumAsteria Brylka, University of Northampton, United KingdomBeiwen Chen, Ghent University, BelgiumOliver Christ, Fern Universit\u00e4t in Hagen, GermanyElien De Caluw\u00e9, Ghent University, BelgiumKathleen De Cuyper, Katholieke Universiteit Leuven, BelgiumStephanie De Oliveira Laux, University of Osnabr\u00fcck, GermanyEgon Dejonckheere, Katholieke Universiteit Leuven, BelgiumEllen Delvaux, Katholieke Universiteit Leuven, BelgiumKristof Dhont, University of Kent, United KingdomAndrew Elliot, University of Rochester, USAChiedu Eseadi, University of Nigeria Nsukka, NigeriaErnestina Etchemendy, Universidad de Valencia, SpainSarah Galdiolo, Katholieke Universiteit Leuven, BelgiumAlbert Garcia-Romeu, Johns Hopkins School of Medicine, USAPatrick Gaudreau, University of Ottawa, CanadaNicolas Gillet, Universite Francois-Rabelais de Tours, FranceLeen Haerens, Ghent University, BelgiumAlexandre Heeren, Katholieke Universiteit Leuven, BelgiumC\u00e9line Hinnekens, Ghent University, BelgiumMarlies Houben, Katholieke Universiteit Leuven, BelgiumKonrad Jankowski, University of Warsaw, PolandOlivier Klein, Universit\u00e9 Libre de Bruxelles, BelgiumTheo Klimstra, Tilburg University, NetherlandsFleur Kraanen, de Waag, NetherlandsFransciska Krings, Universit\u00e9 de Lausanne, SwitzerlandGiovanna Leone, Universit\u00e0 di Roma, ItalyCraig Leth-Steensen, Carleton University, USAChristophe Leys, Universit\u00e9 Libre de Bruxelles, BelgiumLisa Linnenbrink-Garcia, University of Michigan, USAOlivier Luminet, Katholieke Universiteit Leuven, BelgiumKoen Luwel, Katholieke Universiteit Leuven, BelgiumKoen Luyckx, Katholieke Universiteit Leuven, BelgiumGenevi\u00e8ve Mageau, University of Montreal, CanadaLars-Erik Malmberg, University of Oxford, United KingdomHenri Markovits, Universit\u00e9 du Qu\u00e9bec \u00e0 Montr\u00e9al, CanadaAndrew Martins, The University of Sydney, AustraliaDora Matzke, University of Amsterdam, NetherlandsCecil Meeusen, Katholieke Universiteit Leuven, BelgiumGaetan Mertens, Ghent University, BelgiumAikaterini-Aliki Michou, Bilkent University, TurkeyAnneleen Mortier, Ghent University, BelgiumOana Negru, Babe\u015f-Bolyai University, RomaniaGreta Noordenbos, Universiteit Leiden, NetherlandsSoren Ostergaard, Aarhus University Hospital, DenmarkThea Peetsma, University of Amsterdam, NetherlandsParaskevas Petrou, Erasmus University Rotterdam, NetherlandsMaria Ranzini, Universit\u00e9 libre de Bruxelles, BelgiumCatherine Ratelle, Universit\u00e9 Laval, CanadaGuy Roth, Ben-Gurion University of the Negev, IsraelRachel Seginer, University of Haifa, IsraelCorwin Senko, University of New York, USADirk Smits, Odisee University College, BelgiumMarie Stievenart, Universit\u00e9 de Li\u00e8ge, BelgiumCharles Stoned, John Jay College, USACatia Teixeira, Katholieke Universiteit Leuven, BelgiumKiran Vanbinst, Katholieke Universiteit Leuven, BelgiumJasper Van Assche, Ghent University, BelgiumHans van der Baan, University of Amsterdam, NetherlandsAnja van der Voort, Universiteit Leiden, NetherlandsHilde Van Keer, Ghent University, BelgiumSteven Verheyen, Katholieke Universiteit Leuven, BelgiumJan Verplaetse, Ghent University, BelgiumRalf Wolfer, University of Oxford, United KingdomSofie Wouters, Katholieke Universiteit Leuven, BelgiumVincent Yzerbyt, Katholieke Universiteit Leuven, BelgiumMingming Zhou, University of Macau, China"} +{"text": "Several published checklists of bat species have covered Peninsular Malaysia as part of a broader region and/or in combination with other mammal groups. Other researchers have produced comprehensive checklists for specific localities within the peninsula. To our knowledge, a comprehensive checklist of bats specifically for the entire geopolitical region of Peninsular Malaysia has never been published, yet knowing which species are present in Peninsular Malaysia and their distributions across the region are crucial in developing suitable conservation plans. Our literature search revealed that 110 bat species have been documented in Peninsular Malaysia; 105 species have precise locality records while five species lack recent and/or precise locality records. We retrieved 18 species from records dated before the year 2000 and seven species have only ever been recorded once. Our search of Barcode of Life Datasystems (BOLD) found that 86 (of the 110) species have public records of which 48 species have public DNA barcodes available from bats sampled in Peninsular Malaysia. Based on Neighbour-Joining tree analyses and the allocation of DNA barcodes to Barcode Index Number system (BINs) by BOLD, several DNA barcodes recorded under the same species name are likely to represent distinct taxa. We discuss these cases in detail and highlight the importance of further surveys to determine the occurences and resolve the taxonomy of particular bat species in Peninsular Malaysia, with implications for conservation priorities. Kerivoula krauensis Aethalodes alecto Thomas, 1923: 251. Indrapura Peak, Sumatra, INDONESIA 1923.1.2.1) Vespertilio sphinx Vahl, 1797: 123; Tranquebar, Madras, INDIA Cynopterus spadiceus Thomas, 1890: 235; Baram, Sarawak, MALAYSIA 1890.1.28.4) Macroglossus spelaeus Dobson, 1871: 105, 106; Farm Caves, Moulmein, Tenasserim, MYANMAR Pachysoma ecaudatum Temminck, 1837: 94; Padang, West Sumatra, INDONESIA Cynopterus (Ptenochirus) lucasi Dobson, 1880: 163; Sarawak, MALAYSIA Vespertilio vampyrus Linnaeus, 1758: 31; Java, INDONESIA Pteropus amplexicaudatus Geoffroy, 1810: 96, pl. 4; Timor Island, Lesser Sunda Islands, INDONESIA Pteropus leschenaultii Desmarest, 1820: 110; Pondicherry, INDIA Taphozous saccolaimus Temminck, 1838: 14; Java, INDONESIA 1874.10.26.2) Molossus (Nyctinomus) johorensis Dobson, 1873: 22; Johor, MALAYSIA Vespertilio plicatus Buchannan, 1800: 261, pl. 13; Bengal, INDIA Dysopes mops Blainville, 1840: 101; Sumatra, INDONESIA Rhinolophus armiger Hodgson, 1835: 699; NEPAL Rhinolophus bicolor Temminck, 1834: 19. pl. 1; Anjer Coast, Northwestern Java, INDONESIA Rhinolophus diadema Geoffroy, 1813: 263, pls. 5, 6; Timor Island, INDONESIA Phyllorhina doriae Peters, 1871: 326; Sarawak, Borneo, MALAYSIA Vespertilio pellucidus Waterhouse, 1845: 6; PHILLIPINES Vespertilio (Kerivoula) jagorii Peters, 1866: 399; Samar Island, PHILLIPINES Vespertilio harpia Temminck, 1840: 219, pls. 55; Southeast side of Mountain Gede, Java, INDONESIA Vespertilio suillus Temminck, 1840: 224, pl. 56; Tapos, Java, INDONESIA Vespertilio circumdatus Temminck, 1840: 214; Tapos, Java, INDONESIA Vesperugo tylopus Dobson, 1875: 473; Sabah, north Borneo, MALAYSIA 70.2.10.2) (?)Vespertilios noctula Schreber, 1774: 166, pl. 52; FRANCE Vespertilio brachypterus Temmick, 1840: 215, pl. 53; Padang district, Sumatra, INDONESIA Vesperugo stenopterus Dobson, 1875: 470; Sarawak, Borneo, MALAYSIA Vespertilio tenuis Temminck, 1840: 229; Sumatra, INDONESIA Vesperugo blanfordi Dobson, 1877: 312; Tenasserim, east of Moulmein, south Burma = MYANMAR Vesperus (H.) doriae Peters, 1868: 626; Sarawak, Borneo, MALAYSIA Vespertilio macrotis Temminck, 1840: 218, pl. 54; Padang, Sumatra, INDONESIA Vespertilio pachypus Temminck, 1840: 217; Bantam, west Java, INDONESIA (?)Vespertilio adversus Horsfield, 1824: part 8; Java, INDONESIA Vespertilio ater Peters, 1866: 18; Ternate Island, Moluccas, INDONESIA Vespertilio muricola Gray, 1846: 4; NEPAL Vespertilio hasseltii Temminck, 1840: 225; Bantam, Java, INDONESIA Vespertilio horsfieldii Temminck, 1840: 226; Mount Gede, Java, INDONESIA Pipistrellus ridleyi Thomas, 1898: 361; Selangor, MALAYSIA 1898.3.13.5) Vespertilio siligorensis Horsfield, 1855: 102; Siligori, NEPAL [unknown) .Myotis siligorensis [gorensis .Common English name: Small-toothed MyotisBarcode Index Number: DNA barcodes recorded as M. siligorensis are associated with five BINs, BOLD:AAA9718, BOLD:AAA9719, BOLD:AAA9720, BOLD:AAA9721, and BOLD:ACF1046, but there are no DNA barcodes from Peninsular Malaysia.Remarks: Our NJ analysis suggested that M. siligorensis may be a species complex , M. s. sowerbyi , M. s. alticraniatus and M. s. thaianus . Whether the five BINs correspond to the described subspecies remains to be determined. complex . SimmonsIUCN status: Least ConcernRecorded at: Pahang: Krau Wildlife Reserve [Perlis: Wang Kelian State Park [Kedah: Ulu Muda Forest Reserve [ Reserve , 41, Che Reserve , Tasik C Reserve , Kuantan Reserve ; Perlis:ate Park ; Kedah: Reserve .M. siligorensis has been recorded roosting in rock crevices and fissures in caves, often in small colonies at forest edges, in primary and secondary forests [ forests , 23. Ind forests .S1 Fig(PDF)Click here for additional data file.S2 Fig(PDF)Click here for additional data file.S3 Fig(PDF)Click here for additional data file.S4 Fig(PDF)Click here for additional data file.S5 Fig(PDF)Click here for additional data file.S6 Fig(PDF)Click here for additional data file.S7 Fig(PDF)Click here for additional data file.S8 Fig(PDF)Click here for additional data file.S9 Fig(PDF)Click here for additional data file.S10 Fig(PDF)Click here for additional data file.S1 File(XLS)Click here for additional data file."} +{"text": "Microorganisms would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.The editors of https://publons.com) to receive recognition. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make.We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons Schachter, JuliusDe Barbeyrac, BertilleKr\u00f6mer, Jens OSchembri, MarkDe Sousa, Marta AiresKruppa, MichaelShafer, WilliamDewasme, LaurentKuberski, TimSingh, Om V.Donovan, SharonLeathers, Timothy D.Sinha, RohitaDuh, Pin-DerLee, Chao-HungSintes, EvaEdwards, BethanieMalcolm, Kenneth C.Smith, Jason MichelEllegaard, KirstenMalli Mohan, Ganesh BabuSoultos, NikolaosEyal, YoramMarteyn, Benoit S.Specht, Charles AFierer, JoshuaMatsuguchi, TetsuyaStella, SimoneFilannino, PasqualeMcEvoy, JamesSvensson, Bo H.Fiocco, DanielaMcGenity, TerryThrash, J. CameronFoster, TimothyMcInerney, MichaelTitz, AlexanderFranzetti, AndreaMei, Hui-ChingTolker-Nielsen, TimGaglio, RaimondoMellata, MelhaToyofuku, MasanoriGibbs, Bernhard F.Micangeli, AndreaTurner, Justine M.Gon\u00e7alves, Lu\u00eds GafeiraMusat, FlorinTurton, JaneGonzalez, JuanNagarajan, Uma M.Upadhyaya, InduGreenwood, DavidNagata, YujiVanderhoof, Jon A.Greppi, AnnaNaughton, PatrickVenter, RietieGrosse, StephanNikaido, HiroshiVos, Paul DeHazen, Terry C.O\u2019Gara, James P.Vuorela, PiaHe, FeiOtto, MichaelWells, James E.Heung, LenaPabinger, StephanWood, ThomasHickok, Noreen J.Parikesit, Arli AdityaYoshida, TadashiHolzel, ChristinaPatrone, VaniaYurkov, Andrey MThe following reviewed for"} +{"text": "Journal of Cardiovascular Development and Disease would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015.The editors of We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial decision-making process. Several steps have been taken in 2015 to thank and acknowledge reviewers. Good, timely reviews are rewarded with a discount off their next MDPI publication. By creating an account on the submission system, reviewers can access details of their past reviews, see the comments of other reviewers, and download a letter of acknowledgement for their records. This is all done, of course, within the constraints of reviewer confidentiality. Feedback from reviewers shows that most see their task as a voluntary and mostly unseen work in service to the scientific community. We are grateful to our reviewers for the contribution they make.Aikawa, ElenaGrases, FelixMisumida, NaokiAl-Sheikhly, MohamadHachiya, HitoshiMizobuchi, MasahiroAnderson, Robert H.Hahurij, Nathan DMota-Vieira, LuisaAr\u00e1nega, AmeliaHeideman, WarrenMunshi, Nikhil V.Asirvatham, Samuel JHinton, RobertNemer, GeorgesAtherton, John J.Horowitz, John D.Nichols, Colin G.Bakkers, JeroenHu, Ming-ChangNikus, KjellBilheux, HassinaHurtado, DanielNorris, RussellBirnbaum, YochaiIacoviello, MassimoOhanyan, VahagnBischoff, Joyce E.Jacobs, RogerOhuchi, HideoBrand, ThomasJagla, KrzystofOstergaard, John R.Butcher, Jonathan T.Jost, Christina AttenhoferPadala, MuralidharCai, ChenglengKamai, TakaoPan\u00e1kov\u00e1, DanielaCallewaert, BertKang, Bum-YongPeppelenbosch, MaikelCampione, MarinaKern, Christine B.Postma, Alex V.Cheng, XianwuKrishnamurthy, AdarshPotts, Jay D.Cobbaert, Christa M.L\u00e4nne, TosteShyue, Song-KunCripps, RichardLatif, NajmaSilberbach, MichaelDe La Pompa, Jos\u00e9 LuisLazzeri, ChiaraSnyder, Michelle L.Denvir, Martin A.Le Tourneau, Thierryvan Haaften, GijsDeshmukh, AbhishekLee, Chung-HaoVecoli, CeciliaDhingra, SanjivLi, PeiningVolk, TalilaDykes, Iain M.Liu, AipingXu, Ming-JiangFranco, DiegoMarston, Steven B.Yang, BoGarg, ViduMayer, St\u00e9phanie BYutzey, KatherineGarrity, DeborahMilan, David J."} +{"text": "V. aphrogenes in the first and second paragraphs under the subheading \u201cDescription of Vibrio aphrogenes sp. nov.\u201d in the Results and discussion section. Please see the corrected paragraph below.The strain number is missing in the description of V. aphrogenes sp. nov. .V. aphrogenes tested positive for production of alginase, lipase and DNase, oxidase, catalase, gas production from D-glucose, arginine dihydrolase, and is able to assimilate D-glucose, D-mannitol, D-mannose, D-galactose, maltose, D-gluconate, fumarate, glycerol, acetate, D-glucosamine, pyruvate, L-proline, D-ribose, L-alanine, L-asparagine, and L-serine. The bacteria tested negative for indole production, acetoin production, lysine decarboxylase, ornithine decarboxylase, amylase, agarose, gelatinase and \u03ba-carrageenase productions, and is incapable of assimilating D-fructose, sucrose, melibiose, lactose, N-acetylglucosamine, succinate, citrate, aconitate, meso-erythritol, \u03b3-aminobutyrate, L-tyrosine, Dsorbitol, DL-malate, \u03b1-ketoglutarate, trehalose, gluconate, \u03b4-aminovalate, cellobiose, L-glutamate, putrescine, propionate, amygdalin, arabinose, D-galacturonate, glycerate, D-raffinose, rhamnose, salicine, DL-lactate, L-arginine, L-citrulline, glycine, histidine, and L-ornithine. The G+C content of DNA is 42.1%. Estimated genome size is 3.4 Mb on the basis of genome sequencing. The type strain is JCM 31643T = DSM 103759T = CA-1004T.Gram-negative, facultative anaerobic, non-motile rods isolated from surface of seaweed collected in Mie Prefecture in Japan. Colonies on ZoBell 2216E agar medium were cream or transparent white, round, and smooth on the edge. No flagellum was observed. Sodium ion is essential for growth. Growth occurs at NaCl concentrations of 1.0 to 10.0% and at temperatures between 4 and 40\u00b0C."} +{"text": "Toxics would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015. The editors of Albers, James W.Ale, AlbertArcury, ThomasBadot, P.M.Balayssac, DavidBatteux, Fr\u00e9d\u00e9ricBouris, DimitrisCampbell, Kathleen C.M.Carta, ManoloChen, JiangangChiurchi\u00f9, ValerioChobot, VladimirColoso, ClaudioCory-Slechta, Deborah A.Cuesta, AlbertoDeurwaerd\u00e8re, PhilippeEscher, Beate I.Fabiani, RobertoFreeman, Jennifer L.Fujita, MasayukiGriffith, Darren M.Grisold, WolfgangHadjigeorgiou, GeorgiosHanson, Mark L.Himeno, SeichiroHoyer, Friedrich FelixHuber, Heinrich J.Kanda, IsaoKerchev, PavelKim, Seok JinKim, Jeong-HanKiyama, RyoitiKojima, HiroyukiKrishnan, ArunLaforenza, UmbertoLanvers-Kaminsky, ClaudiaLin, ZhoumengMannelli, Lorenzo Di CesareMartin, Mary BethMayer, Gregory D.Mograbi, BahariaMoretto, AngeloMorfini, GerardoMuggia, FrancoMyridakis, AntonisPanoff, Jean-MichelPark, Susanna B.Dougherty, Patrick M.Paulsen, P.Posthuma, LeoPrado, Rafael dePrice, Timothy JayProzialeck, Walter C.Puddu, Paolo EmilioRobert, JacquesRogers, John M.Ross, M.K.Ruiz, Jos\u00e9Sandalio, Luisa M.Sanz-Medel, AlfredoShafer, Timothy J.Silva, Manori J.So, Hong-SeobStaff, Nathan P.Talbott, Evelyn O.Thewke, Douglas P.Trevisan, AndreaTsuboi, YoshioUgedo, L.Vallero, Daniel A.van Thriel, ChristophVilholm, Ole JakobWallace, DavidWaring, RosemaryWessolek, Gerd.Wolff, MaryZoroddu, Maria AntoniettaWe greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial decision-making process. Several steps have been taken in 2015 to thank and acknowledge reviewers. Good, timely reviews are rewarded with a discount off their next MDPI publication. By creating an account on the submission system, reviewers can access details of their past reviews, see the comments of other reviewers, and download a letter of acknowledgement for their records. Feedback from reviewers shows that most see their task as a voluntary and mostly unseen work in service to the scientific community. We are grateful to our reviewers for the contribution they make."} +{"text": "Scientific Reports6: Article number: 3458910.1038/srep34589; published online: 10072016; updated: 01112017In this Article, Ivo Grosse is incorrectly affiliated to \u201cDepartment of Soil Ecology, UFZ - Helmholtz Centre for Environmental Research, Theodor-Lieser-Str. 4, 06120, Halle/Saale, Germany\u201d. The correct affiliations for Ivo Grosse are listed below:Institute of Computer Science, Martin-Luther University Halle-Wittenberg, Von-Seckendorff-Platz 1, 06120, Halle/Saale, Germany.German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Deutscher Platz 5e, 04103, Leipzig, Germany."} +{"text": "Tor yingjiangensis Chen et Yang 2004, Tor qiaojiensis Wu et al. 1977, Garra qiaojiensis Wu et al. 1977, Garra bispinosa Zhang 2005, and Schizothorax oligolepis Huang 1985, originally described from the upper Irrawaddy (Ayeyarwaddy) River in China, are first reported herein as new records to Myanmar. Counts, measurements, descriptions, photographs, and distributions of the specimens of the five newly recorded species are provided.Freshwater fish from the Putao and Myitkyina areas were collected in three ichthyofaunal surveys of the Mali Hka River and tributaries in and around Khakaborazi National Park and Hponkanrazi Wildlife Sanctuary, Kachin State, from 2014-2016. South and Southeast Asia are among the most speciose areas on the planet, containing 20% of all known freshwater vertebrate species and 25% of all known aquatic plants . There aOreinus cf. meridionalis , Garra aff. dulongensis (=Placocheilus dulongensis), and Pseudecheneis brachyurus.Putao (Hkamti Long) is the northern most district in Myanmar, and contains two protected areas, that is, Khakaborazi National Park and Hponkanrazi Wildlife Sanctuary . Twenty newly recorded species and at least three new species were reported by Oreoglanis hponkanensis was identified and published , Chinese Academy of Sciences (CAS), and Forest Research Institute (FRI) have organized continuous biological surveys in North Myanmar since 2014. After further study in the laboratory, identification of samples was confirmed by comparison with materials in the Kunming Natural History Museum of Zoology, Kunming Institute of Zoology (KIZ), CAS, Kunming, Yunnan, China. A new sisorid catfish species, ublished , and fivTor yingjiangensis putitora: Material examined: SEABRI20140098-100, 3 ex., 70.5\u201381.5 mm SL, main stem of Mali Hka River, Irrawaddy Basin, Wurunga Village, Naung Mun Township, Putao District, Kachin State, Myanmar , collected by Xiao-Yong Chen and Tao Qin, 30 November to 7 December 2014; SEABRI20160086\u2013089, 4 ex., 98.9\u2013174.9 mm SL, from Myitkyina fish market, Myitkyina City, Kachin State, Myanmar, collected by Xiao-Yong Chen, Tao Qin and Shu-Sen Shu, 1 August 2016; SEABRI20160176, 1 ex., 75.5 mm SL, from Putao fish market, Putao District, Kachin State, Myanmar, collected by Xiao-Yong Chen, Tao Qin, and Shu-Sen Shu, 4 August 2016.Comparative material examined: Holotype: KIZ164401, 181 mm SL, paratypes: KIZ704404, KIZ764229, KIZ764235\u2013236, 4 ex., 72.5\u2013162 mm SL, Dayingjiang River (tributary of upper Irrawaddy River), Manyun Town, Yingjiang County, Yunnan, China; KIZ2006004189, 198.9 mm SL, Nanzhang River , Wangzishu Town, Longchuan County, Yunnan, China.Description: According to the original description of Tor yingjiangensis , V-LL 3 (vs. 3\u20133.5), circumpeduncular scales 10\u201312 (vs. 12), caudal-peduncle length 13.4%\u201315.8% SL (vs. 11.3\u201314.8), and caudal-peduncle depth 10.7%\u201312.7% SL (vs. 11.1\u201313.3).Tor (Tor) qiaojiensis Wu & Yao, in Material examined: Tor qiaojiensis, KIZ2014005930\u2013931, 2 ex., 46.1\u201353.7 mm SL, stream near Rat Baw Village, Naung Mun Township, Putao District, Kachin State, Myanmar , collected by Xiao-Yong Chen and Tao Qin, 2 December 2014; KIZ2015006380\u2013381, SEABRI20150277\u2013281, SEABRI20150830\u2013837, 15 ex., 62.8\u2013189.7 mm SL, Zeyar Stream, Irrawaddy Basin, Zeyar Dan Village, Putao District, Kachin State, Myanmar , collected by Xiao-Yong Chen, Tao Qin and Shu-Sen Shu, 9 December 2015; SEABRI20150459\u2013462, 4 ex., 58.2\u201362.8 mm SL, Nam Ru Stream, Irrawaddy Basin, War Sar Dan Village, Putao District, Kachin State, Myanmar , collected by Xiao-Yong Chen, Tao Qin, and Shu-Sen Shu, 17 December 2015; SEABRI20150464\u2013466, 3 ex., 54.1\u2013126.8 mm SL, Patheik Stream, Irrawaddy Basin, Putao District, Kachin State, Myanmar , collected by Xiao-Yong Chen, Tao Qin, and Shu-Sen Shu, 19 December 2015.Comparative material examined: KIZ2006012423\u2013455, 39.9\u2013104.8 mm SL, 33 ex., Guyong River , Guyong Town, Tengchong County, Yunnan, China; KIZ2006012418\u2013422, 86.4\u2013145.5 mm SL, 5 ex., Binglangjiang River , Guyong Town, Tengchong County, Yunnan, China.Description: Based on the literature , circumpeduncular scales 10 (vs. 10\u201312), head length 26.3%\u201331.4% SL (vs. 27.7\u201330.6), body depth 24.7%\u201328.1% SL (vs. 27.3\u201331.4), caudal-peduncle length 15.5%\u201317.4% SL (vs. 13.9\u201318.8), and caudal-peduncle depth 11.1%\u201312.5% SL (vs. 9.7\u201311).Garra qiaojiensis Wu & Yao, in Material examined: SEABRI20140185\u2013193, 9 ex., 76.2\u201394.9 mm SL, main stem of Mali Hka River, Wurunga Village, Naung Mun Township, Putao District, Kachin State, Myanmar , collected by Xiao-Yong Chen and Tao Qin, 30 November to 7 December 2014; SEABRI20150231\u2013234, SEABRI20150414, 5 ex., 118.8\u2013165.9 mm SL, Zeyar Stream, Mali Hka Basin, Zeyar Dan Village, Putao District, Kachin State, Myanmar , collected by Xiao-Yong Chen, Tao Qin, and Shu-Sen Shu, 9 & 14 December 2015; KIZ2016007376-377, SEABRI20160188-190, 5 ex., 60.7\u201373.4 mm SL, from Putao fish market, Putao District, Kachin State, Myanmar, collected by Xiao-Yong Chen, Tao Qin, and Shu-Sen Shu, 6 August 2016.Comparative material examined: KIZ2005002680\u2013694, 49.4\u201372.1 mm SL, 15 ex., Zhina River (tributary of Dayingjiang River), Zhina Town, Yingjiang County, Yunnan, China; KIZ2006011157, 92.9 mm SL, Binglangjiang River (upper Dayingjiang River), Guyong Town, Tengchong County, Yunnan, China; KIZ2006011169\u2013174, 81.1\u2013118.8 mm SL, 6 ex., Longchuanjiang River, Wuhe Town, Tengchong County, Yunnan, China; KIZ2006004475\u2013476, 68.7\u201375.9 mm SL, 2 ex., Minglang River (tributary of Longchuanjiang River), Hehua Town, Tengchong County, Yunnan, China.Description: Specimens examined were identified as Garra qiaojiensis according to the following characters , collected by Xiao-Yong Chen and Tao Qin, 2 December 2014; SEABRI20150036\u2013037, 2 ex., 79.6\u201396.5 mm SL, stream near Upper Chan Khaung Village, Putao District, Kachin State, Myanmar , collected by Xiao-Yong Chen, Tao Qin, and Shu-Sen Shu, 5 December 2015; SEABRI20150125\u2013148, 23 ex., 69.6\u201395.3 mm SL oligolepis: Mo, in Material examined: KIZ2015006382\u2013383, SEABRI20150220\u2013225, 283\u2013291, 17 ex., 61.2\u201391.6 mm SL, Zeyar Stream, Irrawaddy Basin, Zeyar Dan Village, Putao District, Kachin State, Myanmar , collected by Xiao-Yong Chen, Tao Qin, and Shu-Sen Shu, 9 December 2015; SEABRI20150347, 350\u2013351, 355, 362, 364, 375\u2013377, 9 ex., 66.4\u2013152.1 mm SL, upper tributary of Ponyin Stream, Zeyar Dan Village, Putao District, Kachin State, Myanmar , collected by Tao Qin and Shu-Sen Shu, 11 & 12 December 2015; SEABRI20150408\u2013413, 6 ex., 72.6\u201384.4 mm SL, Ponyin Stream, Zeyar Dan Village, Putao District, Kachin State, Myanmar , collected by Xiao-Yong Chen, Tao Qin, and Shu-Sen Shu, 14 December 2015; SEABRI20150497\u2013507, 11 ex., 57\u2013100.5 mm SL, Zan Shaw Stream, War Sar Dan Village, Putao District, Kachin State, Myanmar , collected by Xiao-Yong Chen, Tao Qin, and Shu-Sen Shu, 18 December 2015.Comparative material examined: KIZ2016002803, 905\u2013913, 920, 11 ex., 48.5\u2013132.3 mm SL, Erganya River (tributary of Dayingjiang), Tongbiguan Town, Yingjiang County, Yunnan, China; KIZ2014005075-082, 62.3\u201391.6 mm SL, 8 ex., Dazhupeng River (tributary of Dayingjiang River), Zhina Town, Yingjiang County, Yunnan, China; KIZ2014004705\u2013709, 48.8\u201371.6 mm SL, 5 ex., Zhongling River (tributary of Dayingjiang River), Zhina Town, Yingjiang County, Yunnan, China.Description: Combined with the diagnostic characters from the original description, the examined specimens can be distinguished as Schizothorax oligolepis based on the following characters: Body moderately elongate, head and caudal peduncle compressed, dorsal profile arched more than ventral , Yun-Hong Tan and Bin Yang from the Xishuangbanna Tropical Botanical Garden (XTBG), CAS, and Shwe Lone and Kyi Kyi Khaing from the Forest Research Institute, Forest Department, Ministry of Environmental Conservation and Forestry, Myanmar, for their contribution to the field survey. We especially thank Rui-Chang Quan and Ren Li from XTBG, CAS, for their heartfelt support in the field."} +{"text": "Psychologica Belgica have beenassessed conscientiously and unselfishly by expert reviewers. The quality of ourjournal totally depends on their valuable and constructive criticisms to theauthors. Both the editors and the authors highly appreciate the input anddedication of all our reviewers. Many thanks.All manuscripts published in Baars Martine, Hogeschool Rotterdam, the NetherlandsBaldwin Carryl, George Mason University, USABoen Filip, KULeuven, BelgiumBrebels Lieven, KULeuven, Campus Brussels, BelgiumBrenning Katrijn, Ghent University, BelgiumContent Alain, Free University of Brussels (ULB), BelgiumDe Mol Jan, Universit\u00e9 Catholique de Louvain, BelgiumDe Neys Wim, Universit\u00e9 Paris Descartes, FranceDardenne Benoit, University of Li\u00e8ge, BelgiumDehon Hedwige, University of Li\u00e8ge, BelgiumDelrue Jochen, Ghent University, BelgiumDemeyer Ineke, Ghent University, BelgiumFagnant Annick, University of Li\u00e8ge, BelgiumFeys Marjolein, Ghent University, BelgiumGaudreau Patrick, University of Ottawa, Canada Goossens Lien, Ghent University, BelgiumHansenne Michel, University of Li\u00e8ge, BelgiumHansez Isabelle, University of Li\u00e8ge, BelgiumHellin Joost, AZ Nikolaas, Sint-Niklaas, BelgiumJelicic Marko, Maastricht University, The NetherlandsKalyuga Slava, University of New South Wales (UNSW), AustraliaKlimstra Theo, Univeristy of Tilburg, the NetherlandsLahaye Magali, Universit\u00e9 Catholique de Louvain, BelgiumLens Willy, KULeuven, BelgiumLeunissen Joost, University of Southampton, UKMagis David, University of Li\u00e8ge, BelgiumMikolajczak Moira, Universit\u00e9 catholique de Louvain, BelgiumMonseur Christian, University of Li\u00e8ge, BelgiumMueller Astrid, Medizinische Hochschule Hannover, GermanyNader-Grosbois Nathalie, Universit\u00e9 Catholique de Louvain, BelgiumNelemans Stefanie, Universiteit Utrecht, the NetherlandsPanizza Daniele, Georg August Universit\u00e4t, G\u00f6ttingen, GermanyQuoidbach Jordi, University Pompeu Fabra, Barcelona, SpainReinders Folmer Chris, Erasmus University Rotterdam, the NetherlandsSchaefer Alexandre, Durham University, UK Spronk Marjolein, KULeuven, Belgium Sti\u00e9venart Marie, Universit\u00e9 Catholique de Louvain, BelgiumTan E.S., University of Amsterdam, The NetherlandsTheuns Peter, Free University of Brussels (VUB), Belgiumvan Alphen Bas, Free University of Brussels (VUB), BelgiumVan den Bergh Bram, Erasmus University Rotterdam, the NetherlandsVanheule Stijn, Ghent University, BelgiumVan Overwalle Frank, Free University of Brussels (VUB), Belgiumvan Tiel Bob, Radboud University Nijmegen, the NetherlandsVantilborgh Tim, Free University of Brussels (VUB), BelgiumVerhaeghen Paul, Georgia Institute of Technology, USAVerschuere Bruno, University of Amsterdam, The NetherlandsWillems Kim, Free University of Brussels (VUB), BelgiumWinterstein Gregoire, Universit\u00e9 Paris Diderot, FranceWood Alex, Stirling Management School, UK"} +{"text": "Worldwide jurisdictions are making efforts to regulate pesticide standard values in residential soil, drinking water, air, and agricultural commodity to lower the risk of pesticide impacts on human health. Because human may exposure to pesticides from many ways, such as ingestion, inhalation, and dermal contact, it is important to examine pesticide standards by considering all major exposure pathways. Analysis of implied maximum dose limits for commonly historical and current used pesticides was adopted in this study to examine whether worldwide pesticide standard values are enough to prevent human health impact or not. Studies show that only U.S. has regulated pesticides standard in the air. Only 4% of the total number of implied maximum dose limits is based on three major exposures. For Chlorpyrifos, at least 77.5% of the total implied maximum dose limits are above the acceptable daily intake. It also shows that most jurisdictions haven't provided pesticide standards in all major exposures yet, and some of the standards are not good enough to protect human health. After applied to the environment, pesticides can be transported to four major environmental sinks which include soil, water, air, and biomass. Pesticides could be absorbed by soil partials and rushed away into river, groundwater, and lake by rain water. Some volatile and semi-volatile pesticides can evaporate into the air and disperse through winds. Moreover, pesticides can bio-accumulate and bio-magnitude into crops, plants, animals, and human beings through food chain Pesticides are very common in the environment. Human exposure to pesticides can occur through ingestion, inhalation, and dermal contact Because most pesticides are toxic chemicals, worldwide jurisdictions are taking actions to help manage human health risks caused by pesticides. The actions include regulation of pesticide standard values (PSVs) such as pesticide soil regulatory guidance values (RGVs), pesticide drinking water and air maximum concentration levels (MCLs), and pesticide food maximum residue limits (MRLs). Most jurisdictions regulated PSVs to specify their maximum allowable concentrations in each exposure pathway. PSVs should be regulated and derived based on human health risk model and applied essential toxicological data like acceptable daily intake (ADI) which is the maximum amount of pesticide that can enter human body without adverse health effects. Previous researches have made contributions on regulating worldwide contamination chemical standards. Proctor et al. 2.2.1.The materials needed for this research are worldwide jurisdictions and their PSVs, which include pesticide soil RGVs, pesticide drinking water MCLs, pesticides air MCLs, and pesticide agricultural commodity MRLs. These jurisdictions and PSVs were mainly obtained from online data base. Most governments and environmental departments provided the documents on their official websites. Some materials are collected from other sources such as publication journals, environmental conferences, or news reports. Pesticides from worldwide jurisdictions were identified by Chemical Abstracts Service Registry Numbers (CAS No.). A total of 19,421 soil pesticide RGVs from 174 worldwide soil jurisdictions in 50 nations were identified. Also, a total of 5,474 drinking water pesticide MCLs from 145 worldwide jurisdictions in 95 nations were identified. There are at least 90 worldwide jurisdictions provided agricultural commodity pesticide MRLs. Because only the U.S. regulated pesticide air MCLs, the analysis of air PSVs is omitted. These PSVs references and sources were provided in 2.2.Based on current and historical usage, a total of 25 pesticides have been selected for IMDL analysis . Among t3.3.1.air calculation was omitted.IMDL was introduced in this research to examine the pesticide maximum exposure mass loading based on national jurisdictions PSVs from all major exposure pathways. Pesticide implied dose limits (IDLs) were calculated for each exposure pathway as the following, and because only U.S. regulated pesticide air MCLs, the IDLFor drinking water: For residential soil: For agricultural commodities: All IDLs are based on the following set of exposure scenario coefficient values.EF \u2013 Exposure Factor (1) HW \u2013 Human Weight (70 kg) V \u2013 Volume of water intake rate (2 L/day) 6 mg/kg);CF \u2013 Convert Factor IRAnd IMDL was derived by adding up IDLs from these possible exposures. If a nation regulated more than one PSVs in one of the major exposures, different IMDLs were calculated by combining different IDL with others. 3.2.L), and geometric mean (\u03bcG) were computed for those selected pesticides IMDLs. CDF analysis was applied to illustrate the distribution of IMDLs. IMDL empirical cumulative distribution for each pesticide was shown as follows. The arithmetic mean (\u03bc), median (m), standard deviation correlation coefficient was calculated in i) \u2013 probability calculated from IMDL empirical cumulative distribution;E (IMDLi) \u2013 probability calculated from IMDL theoretical lognormal cumulative distribution.F (IMDL3.4.i \u2212 IMDLi+M) with M non-random values. Binomial probability function expressed in CDF analysis was also applied to find IMDL clusters. IMDL cluster is defined as IMDL interval value which measures the maximum amount of pesticide which can get into the human body without occurring adverse health effects. IMDLs for three pesticides 2,4-D, Chlorpyrifos, and Diazinon were discussed in this study.4.1.The cluster at 7.18 E-03 \u2013 7.81 E-03 mg/kg-day is made up of 33 IMDLs computed from Cambodia, China, Costa Rica, Cuba, Dominican Republic, Honduras, Egypt, Guatemala, Nicaragua, Pakistan, Peru, Philippines, Venezuela, Austria, Cyprus, Denmark, European Union (EU), Finland, France, Germany, Greece, Ireland, Italy, Malta, Morocco, Netherlands, Norway, Poland, Portugal, Slovenia, Spain, Sweden, and Thailand. The cluster at 6.95 E-03 mg/kg-day is made up of 17 IMDLs computed from Algeria, Angola, Bangladesh, Barbados, Bermuda, Belgium, Bulgaria, Estonia, Hong Kong, French West Indies, Iceland, Latvia, Luxembourg, Romania, Switzerland, United Arab Emirates, and Ukraine. The cluster at 8.57 E-04 mg/kg-day is made up of 21 IMDLs computed from Argentina, Tanzania, Albania, Antigua and Barbuda, Belize, Bhutan, Fiji, India, Kazakhstan, Kiribati, Kuwait, Labia, Nauru, Russia, Rwanda, St. Lucia, Syrian Arab, Tonga, Tuvalu, Uganda, and U.S..Only four 2,4-D IMDLs are above the arithmetic mean (2.31 E-02 mg/kg-day) because it is skewed by some extreme values such as 8.66 E-01 mg/kg-day at the high end of the distribution. On the other hand, the median and geometric mean (6.94 E-03 and 2.14 E-03 mg/kg-day respectively) are better measures of vales central tendency. There are 13 2,4-D IMDLs exceeding the 2,4-D ADI which is equal to 0.01 mg/kg-day 4.2.The cluster at 2.86E-06 mg/kg-day is made up of 9 IMDLs from Andorra, Bolivia, Bulgaria, Estonia, Gambia, Labia, Liechtenstein, Ukraine, and Vanuatu. The cluster at 8.57 E-04 mg/kg-day is made up of 14 IMDLs from Antigua and Barbuda, Belize, Bhutan, Fiji, Labia, Kiribati, Kuwait, Nauru, Qatar, Tonga, Tuvalu, Uganda, and St. Lucia. The cluster at 2.09 E-03 \u2013 2.10 E-03 mg/kg-day is made up of 29 IMDLs from Austria, Belgium, Bulgaria, French West Indies, Cyprus, Czech Republic, Denmark, EU, Finland, France, Germany, Greece, Iceland, Latvia, Luxembourg, Ireland, Italy, Malta, Netherlands, Norway, Poland, Portugal, Romania, Slovenia, Slovakia, Spain, and United Kingdom. The cluster at 5.38 E-03 \u2013 5.42 E-03 mg/kg-day is made up of 26 IMDLs from Algeria, Angola, Bangladesh, Barbados, Bermuda, Cambodia, Colombia, Costa Rica, Cuba, Dominican Republic, Honduras, El Salvador, Guatemala, Jamaica, Jordan, Kenya, Lebanon, Netherlands Antilles, Nicaragua, Pakistan, Panama, Philippines, Saudi Arabia, Trinidad and Tobago, Tunisia, and Venezuela.There are 100 Chlorpyrifos IMDLs above the ADI which is 0.001 mg/kg-day 4.3.The data cluster at 2.86 E-06 mg/kg-day is made up of 8 IMDLs from Andorra, Bolivia, Bulgaria, Estonia, Labia, Liechtenstein, Ukraine, and Vanuatu. The cluster at 3.58 E-05 mg/kg-day is made up of 18 IMDLs from the Austria, Cyprus, Czech Republic, Denmark, EU, France, Germany, Greek, Ireland, Italy, Lithuania, Malta, Netherlands, Poland, Portugal, Slovenia, Sweden, and Switzerland. The cluster at 2.59 E-04 \u2013 2.63 E-04 mg/kg-day is made up of 32 IMDLs from Algeria, Angola, Bangladesh, Barbados, Cambodia, China, Chile, Costa Rica, Egypt, Ecuador, El Salvador, Guatemala, Jamaica, Jordan, Kenya, Lebanon, Morocco, Netherlands Antilles, Nicaragua, Pakistan, Panama, Peru, Philippines, South Africa, Thailand, Trinidad and Tobago, Tunisia, United Arab Emirates, Venezuela, Vietnam, and WHO. The cluster at 9.84 E-04 \u2013 1.11 E-03 mg/kg-day is made up of 11 IMDLs from Bahrain, Brunei, Hong Kong, South Korea, New Zealand, Kuwait, Oman, Qatar, Saudi Arabia, and Singapore.Only 22 Diazinon IMDLs are above the arithmetic mean which is 4.26 E-04 mg/kg-day because it is skewed by some extreme values such as 8.90 E-03 mg/kg-day at the high end of the distribution. The median and geometric mean are probably better measures of vales central tendency. Among the 108 Diazinon IMDLs, only two of them were computed from three exposures. There are 20 Diazinon IMDLs above the ADI which is 0.002 mg/kg-day 5.The weighted average Pearson correlation coefficient of selected pesticides IMDLs is 0.926. For some pesticides such as Dieldrin, the correlation coefficient is 0.981. The weighted average order of variance of IMDLs is 6.09. Endosulfan IMDL values have the largest span of 8.29 order of magnitude. It suggests that in general, the IMDLs of selected pesticides are well dispersed over data spans, and worldwide jurisdictions lack the agreement on PSVs regulations in major exposures.Only 105 IMDLs were computed from three major exposures. Most worldwide jurisdictions regulated selected pesticides in either two exposures or one exposure. As those are largely used pesticides and they can move and be transported to the soil, water, air, and biomass. It is necessary for worldwide jurisdictions to regulate PSVs in all major exposures. Glyphosate is top used pesticides over the world, however, only four Glyphosate IMDLs were computed from PSVs in soil, water, and agricultural commodity. Although the use of DDT has been banned, it can still be detected in soil, water, and food because of the wide application in the past.There are 100 Chlorpyrifos IMDLs above the ADI, however, only seven IMDLs were computed from major exposures, indicating that jurisdictions haven't provide safe Chlorpyrifos standard values even in one of the major exposure pathways. Although all IMDLs of Endosulfan are below the ADI value, none of them account for all major human exposures. Above all, it suggests that PSVs in all major exposure pathways should be regulated and comprehensive regulations of PSVs are necessary from human health point of view."} +{"text": "Scientific Reports 10.1038/s41598-017-05682-6, published online 13 July 2017Correction to: In this Article, Affiliation 4 was incorrectly listed as \u2018Institute Theriogenology Department, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, 62511, Egypt.\u2019 The correct affiliation is listed below:Theriogenology Department, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef, 62511, Egypt."} +{"text": "Scientific Reports 10.1038/s41598-017-06727-6, published online 25 July 2017Correction to: The original version of this Article incorrectly listed all author names in reverse. The author list now reads:Chiara Perruchon, Sotirios Vasileiadis, Constantina Rousidou, Evangelia S. Papadopoulou, Georgia Tanou, Martina Samiotaki, Constantinos Garagounis, Athanasios Molassiotis, Kalliope K. Papadopoulou, Dimitrios G. Karpouzas"} +{"text": "AbstractCladocera, Copepoda) of many arctic islands is still unknown and have never been explored. Here we report the results of the first investigation of the zooplankton of the Shokalsky Island .Information on freshwater invertebrates of the Russian Arctic is very scarce, especially concerning insular biota. The species composition of microcrustaceans of many arctic islands is still unknown and have never been explored. Here we report the results of the first investigation of the zooplankton of the Shokalsky Island .Information on freshwater invertebrates of the Russian Arctic is very scarce, especially concerning insular biota. The species composition of microcrustaceans (Cladocera and Copepoda of 21 freshwater habitats located on the south\u00adwestern part of Shokalsky Island. We found 15 species of microcrustaceans in total and all of them are reported for the first time here. Also, the obtained data expand the existing ranges of distribution of some species and report several new taxa for the whole Yamalo\u00adNenets region of Russia.The new records reported here are novel for the region and significantly expand the knowledge of the high\u00ad-latitude aquatic biota. We studied the species composition of Cladocera, Copepoda) of Shokalsky island has never been explored.Shokalsky Island is a small island in the Kara Sea located in the Yamalo\u00adNenets Autonomous Okrug of Russia Fig. . It is sCladocera and Copepoda were recorded. Description of the distributional ranges of the species is also provided in the checklist: AT - Afrotropical, AU - Australasian, ANT - Antarctic, NA - Nearctic, NT - Neotropical, OL - Oriental, PA - Palaearctic, PAC - Pacific oceanic islands.The samples were collected during a hydrobiological survey of the compex expedition of KUBZ (Moscow Zoo young biologist's coterie) in August, 2014. Microcrustaceans were collected from 21 freshwater habitats from south\u00adwestern part of Shokalsky Island, most of them were small thermokarst ponds with the depth of 0.5\u00ad - 1.5 m Fig. ), averagLatreille, 1829Dybowski et Grochowski, 1894Distribution: AT, AU, NA, NT, OL, PA.localities no. 1, 7. Distribution: AT, AU, NA, NT, OL, PA.localities no. 1, 3, 5, 6, 7, 16, 21. Distribution: AT, AU, NA, OL, PA.locality no. 9. Distribution: AT, AU, NA, NT, OL, PAC, PA.localities no. 1-9, 11, 13, 16, 19, 20, 21. Distribution (subsp. testudinaria): AT, AU, NA, NT, OL, PA.locality no. 17. Kurz, 1875 sensu Dumont et Silva-Briano, 1998Lilljeborg 1887Distribution: NA, PA.localities no. 1, 21. Straus, 1820Leydig, 1860Distribution: AT, NA, NT, PA.localities no. 3, 5, 6, 7, 13, 19. Distribution: NA, NT, PA.localities no. 1, 6, 7. Distribution: PA.locality no. 1. Baird 1845 sensu Sars 1865Distribution: : AT, ANT, AU, NA, NT, OL, PAC, PA.localities no. 17, 18. Baird, 1850Distribution: NA, PA.localities no. 21. Baird, 1845Distribution: NA, PAlocalities no. 1-9, 13, 14, 20, 21. Milne Edwards, 1840Burmeister, 1834Rafinesque, 1815Uljanin, 1875localities no. 1, 4, 18, 19.Sars G.O., 1903Baird, 1850Distribution: PA , Greenland, Northern Alaska (Colville River)).locality no. 1. Distribution: NA .localities no. 1-9, 12, 13, 14, 18, 20, 21. Cladocera, and three species in three genera of Copepoda. All of the taxa have not been previously documented on the island. Microcrustaceans were found in 90% of the studied sites. The number of species encountered in each water body varied from one to ten , Polyphemuspediculus and Chydoruscf.sphaericus , they usually dominate in the communities and occured in most of the investigated water bodies.In total 15 species of microcrustaceans were identified, comprising 12 species in 12 genera of Cladocera , Diaptomuscf.castor and Graptoleberistestudinaria . The first two species have never been found on the territory of Yamalo-Nenets Autonomous Okrug, and the third one was only known from waters of lower Ob' River (L.setifera this record is the northernmost finding ever (The distributional ranges of all the species are rather wide, none of them are restricted to the arctic area or more limited region. The areas of the species are noted in the Checklist according to the FADA Databases of ladocera and CopeCopepoda . The mosb' River . All of ing ever ."} +{"text": "This issue marks the conclusion of 10 years of publication of the JACMP and, to note the occasion, I passed my editorial hat to Dr Peter Almond, the first Editor\u2010in\u2010Chief of the JACMP, and invited him to write a guest editorial for this issue of the journal. Before I temporarily relinquish the reins to Dr Almond, however, I want to make note of the fact that this issue of the JACMP is the largest yet published. Consequently, special thanks goes to the authors without whose contributions we would have no journal, the Associate Editors listed below, and the reviewers, listed in a Supplementary File.Associate Editors (including Guest Associate Editors): Nzhde Agazaryan, Salahuddin Ahmad, John Antolak, Peter Balter, Sam Beddar, Pat Cadman, Marco Carlone, Nathan Childress, Geoff Clarke, Laurence Court, Larry DeWerd, Bill Erwin, John Gibbons, Michael Gossman, Rebecca Howell, Ed Jackson, Jennifer Johnson, Stephen Kry, Rajat Kudchadker, Moyed Miften, Robin Miller, Eduardo Moros, Firas Mourtada, Ben Nelms, John Pacyniak, Niko Papanikolaou, Matt Podgorsak, Jerimy Polf, Karl Prado, Jim Rodgers, John Rong, Isaac Rosen, Bill Salter, Mehrdad Sarfaraz, Jeff Shepard, Almon Shiu, Alf Siochi, Eric Siessinger, Tim Solberg, Jason Stafford, Frank Van Den Heuvel, Sastry Vedam, Lu Wang, Chuck Willis, Twyla Willoughby, Al Zacarias, and Ron Zhu.You will hear from me again in February with Vol 11 Number 1.George Starkschall, PhDEditor\u2010in\u2010ChiefNovember 15, 2009Supplementary Material FilesClick here for additional data file."} +{"text": "CVD) among HIV\u2010positive individuals. We investigated whether such differences exist in the observational D:A:D cohort study.There is paucity of data related to potential gender differences in the use of interventions to prevent and treat cardiovascular disease (CVD interventions vs. 2.40 ; ACEIs: 0.88 vs. 1.43 ; anti\u2010hypertensives: 1.40 vs. 1.72 and ICPs: 0.08 vs. 0.30 , and this was also true for most CVD interventions when exclusively considering periods of follow\u2010up for which individuals were at high CVD risk. In fully adjusted models, women were less likely to receive CVD interventions than men , except for the receipt of anti\u2010hypertensives .Women were generally at lower CVD interventions was lower among women than men. Interventions are needed to ensure that all HIV\u2010positive persons, particularly women, are appropriately monitored for CVD and, if required, receive appropriate CVD interventions.The use of most Importantly, there is increasing evidence of delayed or less intensive use of medical and invasive procedures for diagnostic evaluation and treatment of MI and stroke among women compared to men As in the general population, guidelines for the prevention of CVD among HIV\u2010positive individuals generally focus on groups at high CVD risk 2https://www.chip.dk/Portals/0/files/Study%20documents/DAD_MOOP_revised2013.pdf). MIs are classified with a Dundee score using criteria from the WHO MONICA Study www.chip.dk/code) The D:A:D study is a large, prospective cohort study which follows >49,000 HIV\u2010positive persons from 11 collaborating cohorts in Europe, USA and Australia, contributing to >430,000 person years of follow\u2010up (PYRS). The details of the study have been described previously 2.1Men and women were followed from baseline until the earliest of death, six months after last visit or February 1, 2015. CVD interventions considered were ICPs and the use of anti\u2010hypertensives, angiotensin\u2010converting enzyme inhibitors (ACEIs) and lipid lowering drugs (LLDs). Individuals with a previous MI/stroke at baseline (i.e. prior to D:A:D Study entry (n\u00a0=\u00a0654)) were excluded from analyses of the subsequent initiation of interventions as the interventions received by these individuals prior to and after the event could not be ascertained with sufficient accuracy. Rates of initiation of each CVD\u2010related intervention were calculated for the total time of follow\u2010up and for the specific periods of follow\u2010up during which individuals were at high CVD risk according to one or more of the following risk subgroups: TC >6.2\u00a0mmol/L (>240\u00a0mg/dl), TG >2.3\u00a0mmol/L (>204\u00a0mg/dl), hypertension (systolic blood pressure (SBP) >140\u00a0mmHg, diastolic blood pressure (DBP) >90\u00a0mmHg, or reported use of ACEIs/anti\u2010hypertensives), previous (post baseline) MI, diabetes , age >50\u00a0years or predicted 10\u2010year CVD risk score >10% (moderate/high Framingham CVD risk score). As the D:A:D CVD risk score was published in more recent years, the Framingham risk score was chosen as it has been more widely used in participating clinics over the whole study period. Since ACEIs may also be used to treat hypertension, consideration of ACEIs separately to other anti\u2010hypertensives may result in an under\u2010estimation of drugs used to treat hypertension. Thus, we additionally considered a combined drug classification of either ACEIs or other anti\u2010hypertensives.Each individual's follow\u2010up was split into a series of consecutive one\u2010month periods and the clinical, immunologic and virologic status at the start of each period was established. Poisson regression models were then used to assess whether initiation rates of CVD interventions were lower in women compared to men, after adjustment for the following potential time\u2010updated confounders: age, calendar year, body mass index (BMI), TC, TG, hypertension, previous MI, race, smoking status, AIDS, CVD family history, stroke, diabetes and CVD risk score >10%.For each calendar year of follow\u2010up, an individual was considered to have been monitored for TC, TG, HDL and SBP/DBP if there was at least one measure of each within that year. Logistic regression models then assessed whether the probability of being monitored for each measure differed in men and women, after adjustment for calendar year, age, BMI, TC, TG, hypertension, previous MI, diabetes and CVD risk score >10%.Additional analyses were performed in which we adjusted for TC, TG and SBP/DBP as continuous rather than categorical covariates and after excluding those with a mode of HIV acquisition other than heterosexual sex, as the latter is the group in which the comparison between men and women is least affected by other, unmeasured confounders. Where differences between men and women were identified we fitted a series of regression models, progressively adjusting for each of the potential confounders, allowing us to identify the potential mediators of any differences seen. Finally, since our main analyses investigated overall initiation rates both before and after an MI, we performed sensitivity analyses in which post\u2010MI follow up was censored, thus restricting analyses to interventions used only prophylactically and allowing us to investigate whether findings were consistent.33.1Of the 49,049 included participants, 12,955 were women and 36,094 were men. Baseline characteristics of the men and women at study entry are shown in Table\u00a03.2The women in the study contributed a total of 113,821 PYRS to the analyses. Of these, 14.9% were contributed by women with a high TG level, 17.5% were contributed by women >50\u00a0years, and 16.9% were contributed by women with hypertension , although differences were attenuated and became non\u2010significant in adjusted models . In contrast, while no difference in blood pressure monitoring rates were seen prior to adjustment , women were more likely to be monitored for blood pressure in adjusted models .3.4Over the total follow\u2010up period, 1334 (10.3%) women and 6274 (17.4%) men initiated LLD; 944 (7.3%) women and 4016 (11.1%) men initiated ACEIs; 1444 (11.1%) women and 4834 (13.4%) men initiated anti\u2010hypertensives; 1715 (13.2%) women and 6126 (17.0%) men initiated ACEIs or anti\u2010hypertensives; and 89 (0.7%) women and 932 (2.6%) men underwent an ICP. When taking all follow\u2010up time into consideration, women had lower initiation rates than men for all CVD interventions: LLDs (incidence rate (IR) [95% CI]/100 PYRS in women vs. men 1.28 vs. 2.40 ), ACEIs , anti\u2010hypertensives ; ACEIs or anti\u2010hypertensives 1.59 vs. 2.26 and ICPs . To investigate which factors were likely to contribute to the higher likelihood of use of anti\u2010hypertensives by women compared to men, a series of regression models was fitted in which we progressively adjusted for each of the potential confounders in turn. This analysis revealed that this finding was mainly driven by adjustments for hypertension and a CVD risk score >10%.In Poisson regression models, unadjusted rates of initiation for each of the four CVD interventions were lower in women than in men Figure\u00a0. When adAdditional adjustment for TC, TG, and SBP/DBP as continuous covariates, and the exclusion of those with modes of HIV transmission other than heterosexual sex, led to consistent results. Consistent results were also observed when follow\u2010up was censored at the time of an MI, suggesting that our findings could not simply be explained by a higher uptake of secondary prevention interventions post\u2010MI in men.4Women generally have a lower CVD risk than men, particularly at younger ages We identified subgroups of study participants who we believed would be considered to be at higher CVD risk and in whom monitoring and interventions for CVD might be appropriate. Where women were deemed to be at high CVD risk, this was most commonly due to the presence of hypertension and/or triglyceridemia, or because of older age. The relatively high proportion of time that women spent with hypertension likely reflects the higher proportion of those of black African ethnicity, a known risk factor for hypertension In fully adjusted models, women in our study were less likely than men to receive LLDs, ACEIs and ICPs, and of these interventions least likely to receive ICPs. Several other studies from the general population have also demonstrated that women are less likely to receive diagnostic and therapeutic invasive CVD\u2010interventions than men In contrast to the receipt of LLDs, ACEIs and ICPs, women in our study were more likely to receive anti\u2010hypertensives than men. The increased use of anti\u2010hypertensives appeared to be driven by women with hypertension and a CVD risk score >10%. As ACEIs are partly used as anti\u2010hypertensives, the gender difference in the use of ACEIs was expectedly reduced after controlling for hypertension, and the difference between men and women was less marked when the combined class of anti\u2010hypertensives or ACEIs was considered, with the lower uptake in women for ACEIs being counter\u2010balanced by the higher uptake of anti\u2010hypertensives in this group. Supported by the slightly higher monitoring rates for blood pressure that we observed in women, our findings argue that hypertension might have more focus in clinical practice. This may relate to hypertension being one of the more common CVD risk factors in women 4.1While we capture information on many CVD risk factors, some CVD risk factors and preventive CVD\u2010interventions as well as some female\u2010specific factors are not captured in our dataset. For this reason, we did not aim to identify specific individuals in whom interventions would be certain to be recommended or to assess whether any such recommendations were appropriate, but simply used the data to identify groups at higher CVD risk in whom awareness of CVD risk and regular monitoring should be greater. It is possible that some individuals may not have accepted any interventions they were offered, or that provider or health system\u2010related factors, , may have influenced our results, possibilities we are unable to investigate due to the nature of the dataset. Although we believe that our detailed query processes and monitoring activities contribute to minimize ascertainment bias, we cannot exclude the possibility that there may be under\u2010 or delayed\u2010ascertainment of the receipt of CVD interventions or that this information may be less readily available in women than men. A relatively small proportion of follow\u2010up time among women was contributed by those at moderate or high CVD risk, but still represented around 5000 PYRS, and our results suggest that the study is not under\u2010powered to detect effects. Finally, although the differences observed are intriguing, we are unable to investigate the reasons for these gender differences.5In our study, HIV\u2010positive women were less likely than men to receive most CVD\u2010related interventions, with the exception of anti\u2010hypertensive drugs. These findings are mostly consistent with those from the general population.The reasons why women are less likely to receive interventions than men are multiple, but insufficient monitoring and awareness of CVD risk in women, and the more heterogeneous clinical presentations of CVD probably play a major role. As HIV\u2010positive individuals in general are at higher risk of CVD further efforts are needed to ensure that both women and men are appropriately monitored for CVD risk and, if required, receive relevant CVD\u2010related interventions. Furthermore studies are warranted on why these gender related differences exist in the prevention and management of CVD in HIV\u2010positive individuals.Amanda Mocroft has received travel support, honoraria, speaker fees and/or lecture fees from BMS, Gilead, ViiV, Pfizer, Merck, BI and Wragge LLC.Peter Reiss has through his institution received independent scientific grant support from Gilead Sciences, Janssen Pharmaceuticals Inc, Merck & Co, Bristol\u2010Myers Squibb and ViiV Healthcare; he has served on a scientific advisory board for Gilead Sciences and a data safety monitoring committee for Janssen Pharmaceuticals Inc; he chaired a scientific symposium by ViiV Healthcare, for which his institution has received remuneration.Christian Pradier reports non\u2010financial support from JANSSEN, personal fees from GILEAD, non\u2010financial support from VIIV HEALTH CARE, non\u2010financial support from MSD, outside the submitted work.Antonella d'Arminio Monforte has received grants for advisory boards or lectures by Abbve, BMS, Gilead, Janssen, MSD, ViiVMatthew Law has received unrestricted grants from Boehringer Ingelhiem, Gilead Sciences, Merck Sharp & Dohme, Bristol\u2010Myers Squibb, Janssen\u2010Cilag, ViiV HealthCare. Consultancy payments from Gilead Sciences DSMB sitting fees from Sirtex Pty LtdCaroline Sabin has received honoraria for the membership of Data Safety and Monitoring Boards, Advisory Boards and Speaker Panels from Gilead Sciences, ViiV Healthcare and Janssen\u2010Cilag. She has received funding to support the development of educational materials from Gilead Sciences and ViiV Healthcare.Camilla Ingrid Hatleberg, Lene Ryom, Wafaa El\u2010Sadr, Helen Kovari, Francois Dabis, Stephane de Wit and Jens Lundgren have no disclosures to declare.Author contributions: C.I.H, L.R., J.D.L. and C.S. developed the initial analysis protocol. C.I.H and L.R performed study co\u2010ordination and prepared the datasets for analysis, C.S. performed the statistical analysis. C.I.H. prepared the first draft of the manuscript and completed all revisions. L.R, J.D.L and C.S provided critical input at all stages of the preparation of the manuscript. W.E.S, A.M, P.R, S.D.W, F.D, C.P, A.D.M, H.K, M. L provided data and revised the manuscript critically. All authors have provided input at all stages of the project and approved the final version.Grant number DNRF126 from the Danish National Research Foundation (CHIP & PERSIMUNE); \u201cOversight Committee for The Evaluation of Metabolic Complications of HAART\u201d with representatives from academia, patient community, FDA, EMA and a consortium of AbbVie, Bristol\u2010Myers Squibb, Gilead Sciences, ViiV Healthcare, Merck and Janssen Pharmaceuticals.Central coordination: P Reiss*, S Zaheri, M Hillebregt, FWNM Wit;CLINICAL CENTRES (\u00a4 denotes site coordinating physician) Academic Medical Centre of the University of Amsterdam: JM Prins\u00a4, TW Kuijpers, HJ Scherpbier, JTM van der Meer, FWNM Wit, MH Godfried, P Reiss,T van der Poll, FJB Nellen, SE Geerlings, M van Vugt, D Pajkrt, JC Bos, WJ Wiersinga, M van der Valk, A Goorhuis, JW Hovius, J van Eden, A Henderiks, AMH van Hes, M Mutschelknauss, HE Nobel, FJJ Pijnappel, S Jurriaans, NKT Back, HL Zaaijer, B Berkhout, MTE Cornelissen, CJ Schinkel, XV Thomas. A De Ruyter Ziekenhuis, Goes: M van den Berge, A Stegeman, S Baas, L Hage de Looff, D Versteeg. C Ziekenhuis, Eindhoven: MJH Pronk\u00a4, HSM Ammerlaan, E de Munnik . AR Jansz, J Tjhie, MCA Wegdam, B Deiman, V Scharnhorst. Emma Kinderziekenhuis: A van der Plas, AM Weijsenfeld. Erasmus MC, Rotterdam: ME van der Ende\u00a4, TEMS de Vries\u2010Sluijs, ECM van Gorp, CAM Schurink, JL Nouwen, A Verbon, BJA Rijnders, HI Bax, M van der Feltz, N Bassant, JEA van Beek, M Vriesde, LM van Zonneveld. A de Oude\u2010Lubbers, HJ van den Berg\u2010Cameron, FB Bruinsma\u2010Broekman, J de Groot, M de Zeeuw\u2010de Man, CAB Boucher, MPG Koopmans, JJA van Kampen, SD Pas. Erasmus MC\u2013Sophia, Rotterdam: GJA Driessen, AMC van Rossum, LC van der Knaap, E Visser Flevoziekenhuis, Almere: J Branger\u00a4, A Rijkeboer\u2010Mes, CJHM Duijf\u2010van de Ven. HagaZiekenhuis, Den Haag: EF Schippers\u00a4, C van Nieuwkoop, JM van IJperen, J Geilings, G van der Hut, PFH Franck. HIV Focus Centrum (DC Klinieken): A van Eeden\u00a4, W Brokking, M Groot, LJM Elsenburg, M Damen, IS Kwa Isala, Zwolle: PHP Groeneveld\u00a4, JW Bouwhuis, JF van den Berg, AGW van Hulzen, GL van der Bliek, PCJ Bor, P Bloembergen, MJHM Wolfhagen, GJHM Ruijs. Leids Universitair Medisch Centrum, Leiden: FP Kroon\u00a4, MGJ de Boer, MP Bauer, H Jolink, AM Vollaard, W Dorama, N van Holten, ECJ Claas, E Wessels. Maasstad Ziekenhuis, Rotterdam: JG den Hollander\u00a4, K Pogany, A Roukens, M Kastelijns, JV Smit, E Smit, D Struik\u2010Kalkman, C Tearno, M Bezemer, T van Niekerk, O Pontesilli. Maastricht UMC+, Maastricht: SH Lowe\u00a4, AML Oude Lashof, D Posthouwer, RP Ackens, J Schippers, R Vergoossen, B Weijenberg\u2010Maes, IHM van Loo, TRA Havenith. MCH\u2010Bronovo, Den Haag: EMS Leyten\u00a4, LBS Gelinck, A van Hartingsveld, C Meerkerk, GS Wildenbeest, JAEM Mutsaers, CL Jansen. MC Slotervaart, Amsterdam: JW Mulder, SME Vrouenraets, FN Lauw, MC van Broekhuizen, H Paap, DJ Vlasblom, PHM Smits. MC Zuiderzee, Lelystad: S Weijer\u00a4, R El Moussaoui, AS Bosma. Medisch Centrum Leeuwarden, Leeuwarden: MGA van Vonderen\u00a4, DPF van Houte, LM Kampschreur, K Dijkstra, S Faber, J Weel. Medisch Spectrum Twente, Enschede: GJ Kootstra\u00a4, CE Delsing, M van der Burg\u2010van de Plas, H Heins, E Lucas. Noorwest Ziekenhuisgroep, Alkmaar: W Kortmann\u00a4, G van Twillert\u00a4, JWT Cohen Stuart, BMW Diederen, D Pronk, FA van Truijen\u2010Oud, WA van der Reijden, R Jansen. OLVG, Amsterdam: K Brinkman\u00a4, GEL van den Berk, WL Blok, PHJ Frissen, KD Lettinga, WEM Schouten, J Veenstra, CJ Brouwer, GF Geerders, K Hoeksema, MJ Kleene, IB van der Mech\u00e9, M Spelbrink, H Sulman, AJM Toonen, S Wijnands, M Damen, D Kwa, E Witte. Radboudumc, Nijmegen: PP Koopmans, M Keuter, AJAM van der Ven, HJM ter Hofstede, ASM Dofferhoff, R van Crevel, M Albers, MEW Bosch, KJT Grintjes\u2010Huisman, BJ Zomer, FF Stelma, J Rahamat\u2010Langendoen, D Burger. Rijnstate, Arnhem: C Richter\u00a4, EH Gisolf, RJ Hassing, G ter Beest, PHM van Bentum, N Langebeek, R Tiemessen, CMA Swanink. Spaarne Gasthuis, Haarlem: SFL van Lelyveld\u00a4, R Soetekouw, N Hulshoff, LMM van der Prijt, J van der Swaluw, N Bermon, WA van der Reijden, R Jansen, BL Herpers, D Veenendaal. Medisch Centrum Jan van Goyen, Amsterdam: DWM Verhagen, M van Wijk. St Elisabeth Ziekenhuis, Tilburg: MEE van Kasteren\u00a4, AE Brouwer, BAFM de Kruijf\u2010van de Wiel, M Kuipers, RMWJ Santegoets, B van der Ven, JH Marcelis, AGM Buiting, PJ Kabel. Universitair Medisch Centrum Groningen, Groningen: WFW Bierman\u00a4, H Scholvinck, KR Wilting, Y Stienstra, H de Groot\u2010de Jonge, PA van der Meulen, DA de Weerd, J Ludwig\u2010Roukema, HGM Niesters, A Riezebos\u2010Brilman, CC van Leer\u2010Buter, M Knoester. Universitair Medisch Centrum Utrecht, Utrecht: AIM Hoepelman\u00a4, T Mudrikova, PM Ellerbroek, JJ Oosterheert, JE Arends, RE Barth, MWM Wassenberg, EM Schadd, DHM van Elst\u2010Laurijssen, EEB van Oers\u2010Hazelzet, S Vervoort, M van Berkel, R Schuurman, F Verduyn\u2010Lunel, AMJ Wensing. VUmc, Amsterdam: EJG Peters\u00a4, MA van Agtmael, M Bomers, J de Vocht, M Heitmuller, LM Laan, AM Pettersson, CMJE Vandenbroucke\u2010Grauls, CW Ang . Wilhelmina Kinderziekenhuis, UMCU, Utrecht: SPM Geelen, TFW Wolfs, LJ Bont, N Nauta. COORDINATING CENTRE P Reiss, DO Bezemer, AI van Sighem, C Smit, FWNM Wit, TS Boender, S Zaheri, M Hillebregt, A de Jong, D Bergsma, P Hoekstra, A de Lang, S Grivell, A Jansen, MJ Rademaker, M Raethke, R Meijering, S Schn\u00f6rr, L de Groot, M van den Akker, Y Bakker, E Claessen, A El Berkaoui, J Koops, E Kruijne, C Lodewijk, L Munjishvili, B Peeck, C Ree, R Regtop, Y Ruijs, T Rutkens, L van de Sande, M Schoorl, A Timmerman, E Tuijn, L Veenenberg, S van der Vliet, A Wisse, T Woudstra, B Tuk.Coordination: F Bonnet, F DabisScientific committee: M Dupon, V Gaborieau, D Lacoste, D Malvy, P Merci\u00e9, P Morlat, D Neau, JL Pellegrin, S Tchamgou\u00e9, E Lazaro, C Cazanave, M Vandenhende, MO Vareil, Y G\u00e9rard, P Blanco, S Bouchet, D Breilh, H Fleury, I Pellegrin, G Ch\u00eane, R Thi\u00e9baut, L Wittkop, L Wittkop, O Leleux, S Lawson\u2010Ayayi, A Gimbert, S Desjardin, L Lacaze\u2010Buzy, V Petrov\u2010SanchezEpidemiology and Methodology: F Bonnet, G Ch\u00eane, F Dabis, R Thi\u00e9baut, L WittkopInfectious Diseases and Internal Medicine: K Andr\u00e9, N Bernard, F Bonnet, O Caubet, L Caunegre, C Cazanave, I Chossat, C Courtault, FA Dauchy, S De Witte, D Dondia, M Dupon, P Duffau, H Dutronc, S Farbos, I Faure, H Ferrand, V Gaborieau, Y Gerard, C Greib, M Hessamfar, Y Imbert, D Lacoste, P Lataste, E Lazaro, D Malvy, J Marie, M Mechain, P Merci\u00e9, E Monlun, P Morlat, D Neau, A Ochoa, JL Pellegrin, T Pistone, I Raymond, MC Receveur, P Rispal, L Sorin, S Tchamgou\u00e9, C Valette, MA Vandenhende, MO Vareil, JF Viallard, H Wille, G Wirth.Immunology: I Pellegrin, P BlancoVirology: H Fleury, ME Lafon, P Trimoulet, P Bellecave, C TumiottoPharmacology: S Bouchet, D Breilh, F Haramburu, G Miremeont\u2010Salam\u00e9Data collection, Project Management and Statistical Analyses: MJ Blaizeau, M Decoin, C Hannapier, E Lenaud et A Pougetoux; S Delveaux, C D'Ivernois, F Diarra, B Uwamaliya\u2010Nziyumvira, O Leleux; F Le Marec, E Boerg, S Lawson\u2010Ayayi;IT department and eCRF development: G Palmer, V Conte, V SapparrartCentral coordination: M Law*, K Petoumenos, R Puhr, R Huang . Participating physicians : R Moore, S Edwards, J Hoy, K Watson, N Roth, H Lau ; M Bloch, D Baker, A Carr, D Cooper, ; M O'Sullivan , D Nolan, G Guelfi .Central coordination: G Calvo, F Torres, S Mateu (Barcelona);Participating physicians (city): P Domingo, MA Sambeat, J Gatell, E Del Cacho, J Cadafalch, M Fuster (Barcelona); C Codina, G Sirera, A Vaqu\u00e9 .Coordination: S De Wit*, N Clumeck, M Delforge, C Necsoi.Participating physicians: N Clumeck, S De Wit*, AF Gennotte, M Gerard, K Kabeya, D Konopnicki, A Libois, C Martin, MC Payen, P Semaille, Y Van Laethem.Central coordination: J Neaton, G Bartsch, WM El\u2010Sadr*, E Krum, G Thompson, D Wentworth;Participating physicians : R Luskin\u2010Hawk ; E Telzak ; WM El\u2010Sadr ; DI Abrams ; D Cohn ; N Markowitz ; R Arduino ; D Mushatt ; G Friedland ; G Perez ; E Tedaldi ; E Fisher ; F Gordin ; LR Crane ; J Sampson ; J Baxter .Steering Committee: J Gatell, B Gazzard, A Horban, I Karpov, M Losso, A d'Arminio Monforte, C Pedersen, M Ristola, A Phillips, P Reiss, J Lundgren, J RockstrohChair: J RockstrohStudy Co\u2010leads: A Mocroft, O KirkCoordinating Centre Staff: O Kirk, L Peters, C Matthews, AH Fischer, A Bojesen, D Raben, D Kristensen, K Gr\u00f8nborg Laut, JF Larsen, D PodlekarevaStatistical Staff: A Mocroft, A Phillips, A Cozzi\u2010Lepri, L Shepherd, A Schultze, S AmeleThe multi\u2010centre study group, EuroSIDA .Argentina: (M Losso), M Kundro, Hospital JM Ramos Mejia, Buenos Aires.Austria: (B Schmied), Pulmologisches Zentrum der Stadt Wien, Vienna; R Zangerle, Medical University Innsbruck, Innsbruck.Belarus: (I Karpov), A Vassilenko, Belarus State Medical University, Minsk, VM Mitsura, Gomel State Medical University, Gomel; D Paduto, Regional AIDS Centre, Svetlogorsk.Belgium: (N Clumeck), S De Wit, M Delforge, Saint\u2010Pierre Hospital, Brussels; E Florence, Institute of Tropical Medicine, Antwerp; L Vandekerckhove, University Ziekenhuis Gent, Gent.Bosnia\u2010Herzegovina: (V Hadziosmanovic), Klinicki Centar Univerziteta Sarajevo, Sarajevo.Croatia: (J Begovac), University Hospital of Infectious Diseases, Zagreb.Czech Republic: , D Jilich, Faculty Hospital Bulovka, Prague; D Sedlacek, Charles University Hospital, Plzen.Denmark: G Kronborg, T Benfield, Hvidovre Hospital, Copenhagen; J Gerstoft, T Katzenstein, Rigshospitalet, Copenhagen; NF M\u00f8ller, C Pedersen, Odense University Hospital, Odense; L Ostergaard, Skejby Hospital, Aarhus, L Wiese, Roskilde Hospital, Roskilde; LN Nielsen, Hillerod Hospital, Hillerod.Estonia: (K Zilmer), West\u2010Tallinn Central Hospital, Tallinn; Jelena Smidt, Nakkusosakond Siseklinik, Kohtla\u2010J\u00e4rve.Finland: (M Ristola), I Aho, Helsinki University Central Hospital, Helsinki.France: (J\u2010P Viard), H\u00f4tel\u2010Dieu, Paris; P\u2010M Girard, Hospital Saint\u2010Antoine, Paris; C Pradier, E Fontas, H\u00f4pital de l'Archet, Nice; C Duvivier, H\u00f4pital Necker\u2010Enfants Malades, Paris.Germany: (J Rockstroh), Universit\u00e4ts Klinik Bonn; R Schmidt, Medizinische Hochschule Hannover; O Degen, University Medical Center Hamburg\u2010Eppendorf, Infectious Diseases Unit, Hamburg; HJ Stellbrink, IPM Study Center, Hamburg; C Stefan, JW Goethe University Hospital, Frankfurt; J Bogner, Medizinische Poliklinik, Munich; G F\u00e4tkenheuer, Universit\u00e4t K\u00f6ln, Cologne.Georgia: (N Chkhartishvili) Infectious Diseases, AIDS & Clinical Immunology Research Center, TbilisiGreece: , G Xylomenos, K Armenis, Athens General Hospital \u201cG Gennimatas\u201d; H Sambatakou, Ippokration General Hospital, Athens.Hungary: (J Szl\u00e1vik), Szent L\u00e1sl\u00f3 Hospital, Budapest.Iceland: (M Gottfredsson), Landspitali University Hospital, Reykjavik.Ireland: (F Mulcahy), St. James's Hospital, Dublin.Israel: (I Yust), D Turner, M Burke, Ichilov Hospital, Tel Aviv; E Shahar, G Hassoun, Rambam Medical Center, Haifa; H Elinav, M Haouzi, Hadassah University Hospital, Jerusalem; D Elbirt, ZM Sthoeger, AIDS Center (Neve Or), Jerusalem.Italy: (A d'Arminio Monforte), Istituto Di Clinica Malattie Infettive e Tropicale, Milan; R Esposito, I Mazeu, C Mussini, Universit\u00e0 Modena, Modena; F Mazzotta, A Gabbuti, Ospedale S Maria Annunziata, Firenze; V Vullo, M Lichtner, University di Roma la Sapienza, Rome; M Zaccarelli, A Antinori, R Acinapura, M Plazzi, Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome; A Lazzarin, A Castagna, N Gianotti, Ospedale San Raffaele, Milan; M Galli, A Ridolfo, Osp. L. Sacco, Milan.Latvia: , Infectology Centre of Latvia, Riga.Lithuania: (V Uzdaviniene) Vilnius University Hospital Santariskiu Klinikos, Vilnius; R Matulionyte, Center of Infectious Diseases, Vilnius University Hospital Santariskiu Klinikos, Vilnius.Luxembourg: (T Staub), R Hemmer, Centre Hospitalier, Luxembourg.Netherlands: (P Reiss), Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam.Norway: (V Ormaasen), A Maeland, J Bruun, Ullev\u00e5l Hospital, Oslo.Poland: (B Knysz), J Gasiorowski, M Inglot, Medical University, Wroclaw; A Horban, E Bakowska, Centrum Diagnostyki i Terapii AIDS, Warsaw; R Flisiak, A Grzeszczuk, Medical University, Bialystok; M Parczewski, K Maciejewska, B Aksak\u2010Was, Medical Univesity, Szczecin; M Beniowski, E Mularska, Osrodek Diagnostyki i Terapii AIDS, Chorzow; T Smiatacz, M Gensing, Medical University, Gdansk; E Jablonowska, E Malolepsza, K Wojcik, Wojewodzki Szpital Specjalistyczny, Lodz; I Mozer\u2010Lisewska, Poznan University of Medical Sciences, Poznan.Portugal: , Hospital Santa Maria, Lisbon; K Mansinho, Hospital de Egas Moniz, Lisbon; F Maltez, Hospital Curry Cabral, Lisbon.Romania: (R Radoi), C Oprea, Spitalul de Boli Infectioase si Tropicale: Dr. Victor Babes, Bucarest.Russia: (A Panteleev), O Panteleev, St Petersburg AIDS Centre, St Peterburg; A Yakovlev, Medical Academy Botkin Hospital, St Petersburg; T Trofimora, Novgorod Centre for AIDS, Novgorod, I Khromova, Centre for HIV/AIDS & and Infectious Diseases, Kaliningrad; E Kuzovatova, Nizhny Novgorod Scientific and Research Institute of Epidemiology and Microbiology named after Academician I.N. Blokhina, Nizhny Novogrod; E Borodulina, E Vdoushkina, Samara State Medical University, Samara.Serbia: (D Jevtovic), The Institute for Infectious and Tropical Diseases, Belgrade.Slovenia: (J Tomazic), University Clinical Centre Ljubljana, Ljubljana.Spain: (JM Gatell), JM Mir\u00f3, Hospital Clinic Universitari de Barcelona, Barcelona; S Moreno, JM Rodriguez, Hospital Ramon y Cajal, Madrid; B Clotet, A Jou, R Paredes, C Tural, J Puig, I Bravo, Hospital Germans Trias i Pujol, Badalona; P Domingo, M Gutierrez, G Mateo, M Sambeat, Hospital Sant Pau, Barcelona; JM Laporte, Hospital Universitario de Alava, Vitoria\u2010Gasteiz.Sweden: , A Thalme, A Sonnerborg, Karolinska University Hospital, Stockholm; A Blaxhult, Venh\u00e4lsan\u2010Sodersjukhuset, Stockholm; L Flamholc, Malm\u00f6 University Hospital, Malm\u00f6.Switzerland: (A Scherrer), R Weber, University Hospital Zurich; M Cavassini, University Hospital Lausanne; A Calmy, University Hospital Geneva; H Furrer, University Hospital Bern; M Battegay, University Hospital Basel; P Schmid, Cantonal Hospital St. Gallen.Ukraine: A Kuznetsova, Kharkov State Medical University, Kharkov; G Kyselyova, Crimean Republican AIDS centre, Simferopol; M Sluzhynska, Lviv Regional HIV/AIDS Prevention and Control CTR, Lviv.United Kingdom: (B Gazzard), St. Stephen's Clinic, Chelsea and Westminster Hospital, London; AM Johnson, E Simons, S Edwards, Mortimer Market Centre, London; A Phillips, MA Johnson, A Mocroft, Royal Free and University College Medical School, London ; C Orkin, Royal London Hospital, London; J Weber, G Scullard, Imperial College School of Medicine at St. Mary's, London; A Clarke, Royal Sussex County Hospital, Brighton; C Leen, Western General Hospital, Edinburgh.The following centers have previously contributed data to EuroSIDA:Infectious Diseases Hospital, Sofia, Bulgaria.H\u00f4pital de la Croix Rousse, Lyon, France.H\u00f4pital de la Piti\u00e9\u2010Salp\u00e9ti\u00e8re, Paris, France.Unit\u00e9 INSERM, Bordeaux, France.H\u00f4pital Edouard Herriot, Lyon, France.Bernhard Nocht Institut f\u00fcr Tropenmedizin, Hamburg, Germany.1st I.K.A Hospital of Athens, Athens, Greece.Ospedale Riuniti, Divisione Malattie Infettive, Bergamo, Italy.Ospedale di Bolzano, Divisione Malattie Infettive, Bolzano, Italy.Ospedale Cotugno, III Divisione Malattie Infettive, Napoli, Italy.D\u00e9rer Hospital, Bratislava, Slovakia.Hospital Carlos III, Departamento de Enfermedades Infecciosas, Madrid, Spain.Kiev Centre for AIDS, Kiev, Ukraine.Luhansk State Medical University, Luhansk, Ukraine.Odessa Region AIDS Center, Odessa, Ukraine.Central coordination: L Morfeldt, G Thulin, A Sundstr\u00f6m.Participating physicians (city): B \u00c5kerlund (Huddinge); K Koppel, A Karlsson (Stockholm); L Flamholc, C H\u00e5kang\u00e5rd .A d'Arminio Monforte (President), A Antinori, A Castagna, F Castelli, R Cauda, G Di Perri, M Galli, R Iardino, G Ippolito, GC Marchetti, CF Perno, F von Schloesser, P VialeA d'Arminio Monforte, A Antinori, A Castagna, F Ceccherini\u2010Silberstein, A Cozzi\u2010Lepri, E Girardi, S Lo Caputo, C Mussini, M PuotiM Andreoni, A Ammassari, A Antinori, C Balotta, A Bandera, P Bonfanti, S Bonora, M Borderi, A Calcagno, L Calza, MR Capobianchi, A Castagna, F Ceccherini\u2010Silberstein, A Cingolani, P Cinque, A Cozzi\u2010Lepri, A d'Arminio Monforte, A De Luca, A Di Biagio, E Girardi, N Gianotti, A Gori, G Guaraldi, G Lapadula, M Lichtner, S Lo Caputo, G Madeddu, F Maggiolo, G Marchetti, S Marcotullio, L Monno, C Mussini, S Nozza, M Puoti, E Quiros Roldan, R Rossotti, S Rusconi, MM Santoro, A Saracino, M Zaccarelli.A Cozzi\u2010Lepri, I Fanti, L Galli, P Lorenzini, A Rodano, M Shanyinde, A TavelliF Carletti, S Carrara, A Di Caro, S Graziano, F Petrone, G Prota, S Quartu, S TruffaItaly A Giacometti, A Costantini, V Barocci (Ancona); G Angarano, L Monno, C Santoro (Bari); F Maggiolo, C Suardi (Bergamo); P Viale, V Donati, G Verucchi (Bologna); F Castelli, C Minardi, E Quiros Roldan (Brescia); T Quirino, C Abeli (Busto Arsizio); PE Manconi, P Piano (Cagliari); B Cacopardo, B Celesia (Catania); J Vecchiet, K Falasca (Chieti); A Pan, S Lorenzotti (Cremona); L Sighinolfi, D Segala (Ferrara); F Mazzotta, F Vichi (Firenze); G Cassola, C Viscoli, A Alessandrini, N Bobbio, G Mazzarello (Genova); C Mastroianni, V Belvisi (Latina); P Bonfanti, I Caramma (Lecco); A Chiodera, P Milini (Macerata); A d'Arminio Monforte, M Galli, A Lazzarin, G Rizzardini, M Puoti, A Castagna, G Marchetti, MC Moioli, R Piolini, AL Ridolfo, S Salpietro, C Tincati, (Milano); C Mussini, C Puzzolante (Modena); A Gori, G Lapadula (Monza); N Abrescia, A Chirianni, G Borgia, R Orlando, G Bonadies, F Di Martino, I Gentile, L Maddaloni (Napoli); AM Cattelan, S Marinello (Padova); A Cascio, C Colomba ; F Baldelli, E Schiaroli (Perugia); G Parruti, F Sozio (Pescara); G Magnani, MA Ursitti (Reggio Emilia); M Andreoni, A Antinori, R Cauda, A Cristaudo, V Vullo, R Acinapura, G Baldin, M Capozzi, S Cicalini, A Cingolani, L Fontanelli Sulekova, G Iaiani, A Latini, I Mastrorosa, MM Plazzi, S Savinelli, A Vergori (Roma); M Cecchetto, F Viviani (Rovigo); G Madeddu, P Bagella (Sassari); A De Luca, B Rossetti (Siena); A Franco, R Fontana Del Vecchio (Siracusa); D Francisci, C Di Giuli (Terni); P Caramello, G Di Perri, S Bonora, GC Orofino, M Sciandra (Torino); M Bassetti, A Londero (Udine); G Pellizzer, V Manfrin (Vicenza), G Starnini, A Ialungo (Viterbo).Central coordination: C Pradier*, E Fontas, K Dollet, C Caissotti.Participating physicians: P Dellamonica, E Bernard, J Courjon, E Cua, F De Salvador\u2010Guillouet, J Durant, C Etienne, S Ferrando, V Mondain\u2010Miton, A Naqvi, I Perbost, S Pillet, B Prouvost\u2010Keller, P Pugliese, V Rio, K Risso, PM Roger.http://www.shcs.ch/180-health-care-providers).The data are gathered by the Five Swiss University Hospitals, two Cantonal Hospitals, 15 affiliated hospitals and 36 private physicians , CA Fux, HF G\u00fcnthard (President of the SHCS), D Haerry (deputy of \u201cPositive Council\u201d), B Hasse, HH Hirsch, M Hoffmann, I H\u00f6sli, C Kahlert, L Kaiser, O Keiser, T Klimkait, RD Kouyos, H Kovari,B Ledergerber, G Martinetti, B Martinez de Tejada, C Marzolini, KJ Metzner, N M\u00fcller, D Nicca, G Pantaleo, P Paioni, A Rauch (Chairman of the Scientific Board), C Rudin (Chairman of the Mother & Child Substudy), AU Scherrer (Head of Data Centre), P Schmid, R Speck, M St\u00f6ckle, P Tarr, A Trkola, P Vernazza, G Wandeler, R Weber*, S Yerly.The D:A:D study was supported by a grant [grant number DNRF126] from the Danish National Research Foundation (CHIP & PERSIMUNE); the Highly Active Antiretroviral Therapy Oversight Committee (HAARTOC), a collaborative committee with representation from academic institutions, the European Agency for the Evaluation of Medicinal Products, the United States Food and Drug Administration, the patient community, and pharmaceutical companies with licensed anti\u2010HIV drugs in the European Union: AbbVie, Bristol\u2010Myers Squibb, Gilead Sciences Inc., ViiV Healthcare, Merck & Co Inc. and Janssen Pharmaceuticals. Supported also by a grant from the Dutch Ministry of Health, Welfare and Sport through the Center for Infectious Disease Control of the National Institute for Public Health and the Environment to Stiching HIV Monitoring (ATHENA); by a grant from the Agence nationale de recherches sur le sida et les h\u00e9patites virales to the Aquitaine Cohort; The Australian HIV Observational Database (AHOD) is funded as part of the Asia Pacific HIV Observational Database, a program of The Foundation for AIDS Research, amfAR, and is supported in part by a grant from the U.S. National Institutes of Health's National Institute of Allergy and Infectious Diseases (NIAID) [grant number U01\u2010AI069907] and by unconditional grants from Merck Sharp & Dohme; Gilead Sciences; Bristol\u2010Myers Squibb; Boehringer Ingelheim; Janssen\u2010Cilag; ViiV Healthcare. The Kirby Institute is funded by The Australian Government Department of Health and Ageing, and is affiliated with the Faculty of Medicine, The University of New South Wales; by grants from the Fondo de Investigaci\u00f3n Sanitaria [grant number FIS 99/0887] and Fundaci\u00f3n para la Investigaci\u00f3n y la Prevenci\u00f3n del SIDA en Espan\u00e3 [grant number FIPSE 3171/00], to the Barcelona Antiretroviral Surveillance Study (BASS); by the National Institute of Allergy and Infectious Diseases, National Institutes of Health , to the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA); by primary funding provided by the European Union's Seventh Framework Programme for research, technological development and demonstration under EuroCoord grant agreement n\u02da 260694 and unrestricted grants by Bristol\u2010Myers Squibb, Janssen R&D, Merck and Co. Inc., Pfizer Inc., GlaxoSmithKline LLC, ) to the EuroSIDA study; by unrestricted educational grants of AbbVie, Bristol\u2010Myers Squibb, Gilead Sciences, GlaxoSmithKline, Pfizer, Janssen Pharmaceuticals to the Italian Cohort Naive to Antiretrovirals (The ICONA Foundation); and financed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant #148522) and by the SHCS research foundation."} +{"text": "Available on\u2010line atwww.aapm.org/meetings/2015SCM/2015 AAPM Spring Clinical Meeting March 7 \u2013 10, 2015St. Louis, MOChairBrian Wang, PhDUniversity Louisville Louisville, KYVice ChairJessica B. Clements, MSKaiser Permanente Los Angeles, CATrack DirectorsTherapy TrackJean M. Moran, PhDUniversity Michigan Medical Center Ann Arbor, MIKyle J. Antes, MSPresbyterian Healthcare System Dallas, TXProfessional TrackJessica B. Clements, MSKaiser Permanente Los Angeles, CAMichael Howard, PhDSarah Cannon Cancer Center Chattanooga, TNDiagnostic TrackDustin Gress, MSMD Anderson Cancer Center Houston, TXJeffrey M. Moirano, MSUniversity of Washington Seattle, WAYoung Investigator ProgramJean M. Moran, PhDUniversity Michigan Medical Center Ann Arbor, MIBrian Wang, PhDUniversity Louisville Louisville, KYDavid E. Hintenlang, PhDUniversity of Florida Gainesville, FLMammography TrackJessica B. Clements, MSKaiser Permanente Los Angeles, CADustin Gress, MSMD Anderson Cancer Center Houston, TX"} +{"text": "Moran, PhDDept of Radiation Oncology B2C438Ann Arbor, MIDimitris Mihailidis, PhDRad Onc and Med Phys, Charleston Radiation Therapy ConsCharleston, WVPROFESSIONAL TRACKJessica B. Clements, MSMedical Physics, Texas Health Presbyterian Hospital DallasDallas, TXMichael Howard, PhDSarah Cannon Cancer Center, Parkridge Medical CenterChattanooga, TNDIAGNOSTIC TRACKRobert A. Pooley, PhDRadiology, Mayo ClinicJacksonville, FLDustin Gress, MDMD Anderson Cancer CenterHouston, TXYOUNG INVESTIGATOR PROGRAMJessica B. Clements, MSMedical Physics, Texas Health Presbyterian Hospital DallasDallas, TXBrian Wang, PhDUniversity LouisvilleLouisville, KYDavid E. Hintenlang, PhDUniversity of FloridaGainesville, FLMAMMOGRAPHY TRACKWilliam Geiser, MSImaging Physics, M.D. Anderson Cancer CenterHouston, TXJean M. Moran, PhDDept of Radiation Oncology B2C438Ann Arbor, MI"} +{"text": "Journal of Developmental Biology (JDB) would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.The editors of https://publons.com) to receive recognition. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make.We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (JDB, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for JDB in 2016:Alenius, MattiasGao, Wei-QiangNakagawa, YasushiAlvarez-Bolado, GonzaloGoetz, Sarah C.Nilsson, MikaelAndres, Anne-CatherineGordon, JulieNiu, JingwenArtinger, Kristin BrukGreenwold, Matthew J.Oberg, Kerby C.Barucca, MarcoGrieco, FrancescoPaps, JordiBateman, Joseph M.Guo, ShiweiPatek, Sheila N.Bayin, N. SumruHansen, David V.Pavlov, YouriBerendsen, Agnes D.Harwell, CoreyPick, LeslieBergmann, OlafHuang, SumingRubart, MichaelBijlsma, Maarten F.Iwata, JunichiRuiz-Rodr\u00edguez, MagdalenaBlaess, SandraKang, LeiSeo, WooseokBlanchemain, NicolasKappen, ClaudiaSharma, MeghaBoudreau, NancyKapus, Andr\u00e1sThomas-Chollier, MorganeBovolenta, PaolaKmita, MarieTorres S\u00e1nchez, MiguelB\u00fcrglin, Thomas R.Kooyman, David L.Tosato, GiovannaBuscaino, GiuseppaKoyama, EikiVan Berlo, JopCastellone, Maria DomenicaKrumlauf, RobbVukojevi\u0107, VladanaCharron, Fr\u00e9d\u00e9ricLi, QiangWellik, Deneen M.Chaw, Ro CrystalLiu, AiminWestenskow, Peter D.Cheng, JiaLiu, Zhao-junWijnholds, JanCobourne, Martyn T.Loeken, Mary R.Wizenmann, AndreaCrow, Karen D.Logan, Malcolm P.O.Wollesen, TimCullen, PaulLohmann, IngridXu, PengfeiDitzel, MarkLohmann, IngridYang, YeDuman-Scheel, MollyLuu, Doan-trungYano, TohruEstella, CarlosMachon, OndrejYuan, XueFilmus, JorgeMagee, Anthony I.Zalc, BernardFunato, NorikoMartinez, SalvadorZhang, LeiThe following reviewed for"} +{"text": "Abstracthttp://www.waarnemingen.be, hosted by Stichting PageBreakNatuurinformatie and managed by the nature conservation NGO Natuurpunt. Together with the datasets Florabank1 , mainly since 2008. The occurrences are derived from the database orabank1 and the orabank1 , the dat Purpose: Plants have a long history of being recorded by both amateur and professional botanists. Volunteer data from amateur botanists were always an important source of distribution data of plants. The atlas of Flanders and the Brussels Capital region areas. Old notebooks and reports were screened and stored in the database species recorded in Flanders and the Brussels Capital Region. This includes angiosperms (flowering plants), gymnosperms, ferns and allies, but not algae, mosses and lichens. If the observer remarked that the specific individual of this native plant was introduced by man, then this is recorded in the field establishmentMeans.PageBreakKingdom: PlantaeFamilies: Adoxaceae, Alismataceae, Amaranthaceae, Amaryllidaceae, Apiaceae, Apocynaceae, Aquifoliaceae, Araceae, Araliaceae, Asparagaceae, Aspleniaceae, Asteraceae, Athyriaceae, Balsaminaceae, Berberidaceae, Betulaceae, Blechnaceae, Boraginaceae, Brassicaceae, Butomaceae, Buxaceae, Campanulaceae, Cannabaceae, Caprifoliaceae, Caryophyllaceae, Celastraceae, Ceratophyllaceae, Cistaceae, Colchicaceae, Convolvulaceae, Cornaceae, Crassulaceae, Cucurbitaceae, Cupressaceae, Cyperaceae, Cystopteridaceae, Dennstaedtiaceae, Dioscoreaceae, Droseraceae, Dryopteridaceae, Elaeagnaceae, Elatinaceae, Equisetaceae, Ericaceae, Euphorbiaceae, Fabaceae, Fagaceae, Gentianaceae, Geraniaceae, Grossulariaceae, Haloragaceae, Hydrocharitaceae, Hypericaceae, Iridaceae, Juncaceae, Juncaginaceae, Lamiaceae, Lentibulariaceae, Liliaceae, Linaceae, Lycopodiaceae, Lythraceae, Malvaceae, Marsileaceae, Melanthiaceae, Menyanthaceae, Molluginaceae, Montiaceae, Myricaceae, Nartheciaceae, Nymphaeaceae, Oleaceae, Onagraceae, Onocleaceae, Ophioglossaceae, Orchidaceae, Orobanchaceae, Osmundaceae, Oxalidaceae, Papaveraceae, Plantaginaceae, Plumbaginaceae, Poaceae, Polygalaceae, Polygonaceae, Polypodiaceae, Potamogetonaceae, Primulaceae, Ranunculaceae, Resedaceae, Rhamnaceae, Rosaceae, Rubiaceae, Ruppiaceae, Salicaceae, Santalaceae, Sapindaceae, Saxifragaceae, Scrophulariaceae, Solanaceae, Taxaceae, Thelypteridaceae, Typhaceae, Ulmaceae, Urticaceae, Verbenaceae, Violaceae, ZosteraceaeThe number of records (observations) per plant species is shown in Fig. PageBreakGeneral spatial coverage: Flanders and the Brussels Capital Region , urban areas 30%) and woodland (10%) while the Brussels Capital Region mainly consists of urban areas (73%), woodland (12%) and other green areas (10%) . All occ0% and wors using .Coordinates: 50\u00b040'48\"N and 51\u00b030'36\"N Latitude; 2\u00b032'24\"E and 5\u00b055'12\"E Longitude.PageBreakWe show the number of plant observations and the number of plant species per IFBL grid cell Fig. . Figure Temporal coverage: June 30, 1855 - December 31, 2016www.waarnemingen.be in 2008 were recorded by volunteers (citizen scientists). The dataset also includes historical records and datasets imported in waarnemingen.be. The large majority of records (95%) is a casual observation (presence only record). 5% of observations were registered as part of a species checklist. This is also recorded in the field samplingProtocol. The frequency distribution of number of observers per number of records or species is shown in Fig. Quality control description: Recorded data are verified by a group of botanical experts , based on collected specimens, the observer\u2019s species knowledge, added photographs and known species list of locations. The validation procedure from www.waarnemingen.be consists of an interactive procedure in which observers can be asked for additional information by a team of validators, after which the validator manually adds a validation status. Manual validation focuses on rare species, species that are reported outside their known range and observations accompanied by pictures. Records that are not manually validated are additionally checked by an automated validation procedure that takes into account the number of manually validated observations of a species within a specified date and distance range. 12% of the plant records in this dataset are supported by photographs in www.waarnemingen.be. The validation status is indicated in the field identificationVerificationStatus, the link to the original record in references.www.waarnemingen.be. The data were standardized to Darwin Core using a SQL query. The included terms are:The Plant occurrences in Flanders and the Brussels Capital Region, is an export from PageBreakoccurrenceID, type, language, license rightsHolder, accessRights, references, datasetID, institutionCode, datasetName, basisOfRecord, informationWithheld, dataGeneralizations, individualCount, sex, reproductiveCondition, establishmentMeans, samplingProtocol, eventDate, continent, countryCode, stateProvince, municipality, verbatimCoordinates, verbatimCoordinateSystem, verbatimSRS, decimalLatitude, decimalLongitude, geodeticDatum, coordinateUncertaintyInMeters, georeferenceRemarks, identificationVerificationStatus, taxonID, scientificName, kingdom, taxonRank, scientificNameAuthorship, vernacularName, nomenclaturalCode.Generalized and/or withheld information: location information is generalized to 4 \u00d7 4 km\u00b2 IFBL grid cells. Observer name, exact XY-coordinates, toponyms, and photographs are not included in the published dataset, but are stored in the source database. The dataset will be updated on GBIF on a regular basis (currently planned every two year).Object name: Waarnemingen.be - Plant occurrences in Flanders and the Brussels Capital Region, BelgiumFormat name: Darwin Core Archive formatFormat version: 1.0Character encoding: UTF-8Language: EnglishLicense: http://creativecommons.org/publicdomain/zero/1.0/Usage norms: http://www.natuurpunt.be/normen-voor-datagebruikFirst publication date: 2016-12-23Distribution: http://dataset.inbo.be/planten-natuurpunt-occurrencesDOI: https://doi.org/10.15468/fyuklzwww.waarnemingen.be before 2008. Observations are currently mainly presence only records (95%). Presence is certain, absence of data can have multiple reasons: an IFBL grid cell was not visited, the species was not present/seen, the species was present but not registered in the database. For this reason, since the end of 2016, www.waarnemingen.be focusses more on lists and transect registration. During field work, the route can be tracked via the mobile app ObsMapp. At the end of the excursion, observers can indicate different types of lists, depending on whether: (1) the records are opportunistically collected presence only data (some records of some of the species encountered), (2) all individuals of selected species were registered, (3) all species were recorded or (4) all individuals of all species . This additional information allows to account for a better observation effort than currently is the case.Since 2010, the number of plant observations registered annually is larger than all the records available in PageBreakwww.waarnemingen.be is Urticadioica. This species was in Poaannua or Saginaprocumbens should be seen much more than striking species like Cardaminepratensis, Filipendulaulmaria and Anemonenemorosa. This might be explained by the observers\u2019 lack of interest in very common species (The most frequently and widespread observed plant in species . Further species . Samplin species : 1 uneve"} +{"text": "There was a mistake in the authorship. The name of Nima Parvaneh was unintentionally omitted. Dr. Parvaneh has contributed biological specimens and clinical and immunological data from patient P66 included in the manuscript, and as such he should be included in the authorship. The authors apologize for the mistake. This error does not change the scientific conclusions of the article in any way.With the inclusion of Dr. Parvaneh\u2019s name in the authorship, the paragraph of Author Contributions should also be corrected as follows:JM, EM, AM, SP, and LN designed the study, interpreted the data, and wrote the manuscript; KD, GT, EC, OP, PM, SG, and DM performed experiments, acquired and analyzed the data; WA-H, CC, MC, JB, CB, DB, SB, TC, JC, VD-C, LOdB, MTdlM, GM, AF, RG, RKG, AH, SH, C-HH, MK, AlKi, BK, AnKl, TK, BL, VL, MiMa, IM, MeMo, BN, S-YP, NP, AP, SP, IR, JS, RS, TT, Y-JK, JW, AG, and SK contributed patient samples and clinical and immunological data; all authors have revised the work for its intellectual content, have approved its final version and have agreed to be accountable for all aspects related to the accuracy and integrity of the work.This correction does not change the scientific conclusions of the article in any way.Author apologizes for these errors and thank you for your consideration.The original has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Microb Biotechnol 10: 604\u2013611.You, X., Li, R., Wan, K., Liu, L., Xie, X., Zhao, L., In the original publication , the affiliations for two of the authors were incorrect. The affiliations should read as follows:Clinical laboratory, The First Affiliated Hospital of University of South China, Hengyang, 421000, China\u201d\u201cXiaopeng Xie, AndClinical laboratory, Hengyang No.1 People's Hospital, Hengyang, 421001, China\u201d\u201cNing Wu, The authors sincerely apologize for the confusion caused by this error."} +{"text": "Scientific Reports 10.1038/s41598-017-07532-x, published online 10 August 2017Correction to: The original version of this Article contained errors in the spelling of the authors Felice Contaldi, Federico Capuano, Andrea Fulgione, Riccardo Aiese Cigliano, Walter Sanseverino, Domenico Iannelli, Chiara Medaglia & Rosanna Capparelli which were incorrectly given as Contaldi Felice, Capuano Federico, Fulgione Andrea, Aiese Cigliano Riccardo, Sanseverino Walter, Iannelli Domenico, Medaglia Chiara & Capparelli Rosanna.These errors have now been corrected in the PDF and HTML versions of the Article, and in the accompanying Supplementary Material."} +{"text": "Summary of Glaucoma Diagnostic Testing Accuracy: An Evidence-Based Meta-Analysis\u201d, by Saad Ahmed et al, published in Vol. 8, No. 9, 2016, p641-649, doi: http://dx.doi.org/10.14740/jocmr2643w. The authors of this article would like to add an author, Omar Akhtar, who is entitled to authorship, the new author\u2019s list should read as follows.Corrections to article \u201ca, Zainab Khanb, Francie Sia, Alex Maoa, Irene Pana, Fatemeh Yazdic, Alexander Tsertsvadzec, Cindy Hutnika, David Moherc, David Tingeya, Graham E. Troped, Karim F. Damjie, Jean-Eric Tarridef, Ron Goereef, Omar Akhtarg, William Hodgea, g, hSaad AhmedaIvey Eye Institute, University of Western Ontario, London, ON, CanadabFaculty of Medicine, Queen\u2019s University, Kingston, ON, CanadacOttawa Hospital Research Institute, University of Ottawa, Ottawa, ON, CanadadDepartment of Ophthalmology and Visual Sciences, University of Toronto, Toronto, ON, CanadaeDepartment of Ophthalmology, University of Alberta, Edmonton, AB, CanadafProgram for the Assessment of Technology and Health (PATH), and Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, CanadagDepartment of Epidemiology and Biostatistics, University of Western Ontario, London, ON, CanadahCorresponding Author: William Hodge, Ivey Eye Institute, University of Western Ontario, 268 Grosvenor St, London, ON N6A 4V2, Canada"} +{"text": "Scientific Reports 10.1038/s41598-017-00686-8, published online 27 June 2017Correction to: In the original version of this Article, affiliation 2 was inadvertently included. The correct affiliations are listed below:Department of Nephrology, the Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, 330006, P.R. China.Hong-hong Zou, Ping-ping Yang, Tian-lun Huang & Gao-si XuDepartment of Medicine, the George Washington University, Washington, DC20052, USA.Xiao-xu ZhengThis error has now been corrected in the PDF and HTML versions of the Article."} +{"text": "Antibiotics would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016. The editors of https://publons.com) to receive recognition. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make. We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (Antibiotics, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Antibiotics in 2016:Akova, MuratFrenk, StevenMelman, ArtemAlix, Jean-Herv\u00e9Fucini, PaolaMelo-Cristino, Jos\u00e9Anne-Marie, Di GuilmiGillet, ReynaldMengin Lecreulx, DominiqueArenz, StefanGinn, AndrewMissiakas, DominiqueArthur, MichelGottesman, SusanMonte, AaronBabu, MohanGrinter, RhysMoynihan, PatrickBarton, Larry L.Grossman, Trudy H.Naber, KurtBasu, AmitHammerschmidt, SvenNair, Satish K.Bell, AnthonyHan, Sang-MiNicholas, Robert A.Boneca, Ivo GompertsHavrylyuk, DmytroNierhaus, KnudBrooks, Amanda E.Hayward, GailOldach, DavidBr\u00f6tz-Oesterhelt, HeikeHearn, Michael J.Pinho, EvaBryce, AshleyHelld\u00e9n, AndersPinho, Mariana GomesBuchanan, Susan K.Hensler, Mary E.Pon, Cynthia L.Burns, BrendanHerrick, JamesQi, YanfeiCelia, CooperHolmgren, ArneRomby, PascaleCeyssens, Pieter JanIacovides, HarrisRossolini, Gian MariaCheng, Wei-ChiehJaki, BirgitRudenko, NataliiaConstance, Jonathan E.Jeandet, PhilippeSanyal, SuparnaCoque, TeresaJeong, Seok HoonSapi, EvaCronan, John E.Kenny, RachelSperry, JonathanDa Silva, Gabriela JorgeKern, Winfried V.Staerk, KatharinaDavies, ChristopherKieffer, NicolasTommaso, GianiDen Blaauwen, TannekeKrasowski, Matthew D.Trautner, Barbara W.Dessen, Andr\u00e9aLa Teana, AnnaTuomanen, ElaineDevaraj, AishwaryaLaslop, Nora-VazquezVester, BirteDewulf, JeroenLee, Seok-YongVioque, AgustinDinman, JonathanLeung, PollyVollmer, WaldemarDolla, AlainL\u00f8bner-Olesen, AndersWall, Geoffrey C.Dubrovskaya, YaninaLondei, PaolaWeidemaier, ChristopherDuca, MariaLund, BodilWilson, Daniel N.Edwards, Adrianne N.Lutkenhaus, JoeWon, KimberlyFabbretti, AttilioMa, Dik-LungWormser, Gary P.Fern\u00e1ndez, Luc\u00edaMankin, AlexanderYonath, Ada E.Francis, NickMarzaro, GiovanniZitko, JanThe following reviewed for"} +{"text": "AbstractPhlebotomine sand flies are dipteran insects of medical importance because many species are involved in the transmission of pathogens between human and non-human animals. A total of 530 American species of sand flies is presented in an updated checklist, along with their author(s) and year of publication using the classification by Diptera, Psychodidae, Phlebotominae) are medically important insects involved in the transmission of arboviruses, bacteria and protozoan parasites among human and non-human animals , seven sub-tribes , and 24 genera. However, no explicit method was used to group the sand flies, and his classification was not accepted among researchers of this group of insects.Phlebotominae was presented by Idiophlebotomini Artemiev, 1991 was synonymized with Hertigiini Abonnenc & L\u00e9ger, 1976, while the tribe Phlebotomini Rondani, 1840 was maintained. Six subtribes from Idiophlebotomina, Hertigiina, , Sergentomyiina, Australophlebotomina, and Brumptomyiina) and an additional subtribe was created . In addition, one subtribe previously considered synonymous was reinstated . Galati reclassified \"New World\" sand flies into 22 genera. Later, Edentomyia Galati, Andrade-Filho, Silva & Falc\u00e3o, 2003 was proposed as another Neotropical genus in the tribe Phlebotomini; however, this genus was not included in any subtribe ; (ii) Museu de Zoologia da Universidade de S\u00e3o Paulo (MZUSP); (iii) Cole\u00e7\u00e3o de Refer\u00eancia da Faculdade de Sa\u00fade P\u00fablica (FSP\u2013USP); (iv) Cole\u00e7\u00e3o Entomol\u00f3gica do Laborat\u00f3rio de Entomologia em Sa\u00fade P\u00fablica (FSP\u2013USP\u2013LESP\u2013Phlebotominae); (v) Cole\u00e7\u00e3o da Se\u00e7\u00e3o de Parasitologia do Instituto Butantan (IBut); (vi) Cole\u00e7\u00e3o de Flebotom\u00edneos do Instituto Evandro Chagas (COLFlebIEC); (vii) Natural History Museum, London (NHM).The list contains information updated until December, 2016, and data was collated from our own work with sand fly taxonomy, literature surveys, and studies of sand flies deposited in different entomological collections: (i) Cole\u00e7\u00e3o de Flebotom\u00edneos (ICZN) .To be considered valid, and therefore included in this checklist, a species name has to meet the criteria of publication in Articles 8 and 9 of International Code of Zoological Nomenclature . Here, we report one nomem dubium for Nyssomyiasingularis and one species inquierenda for Bichromomyiainornata.There are seven \u201cinformal\u201d taxa that comprise unavailable names since they do not meet the requirements of the Despite the great amount of data on American sand flies and the increased interest in the study of these insects, there has been slow progress in the understanding of taxonomy and systematics of this subfamily. The checklist presented herein aims to give an updated account of which valid species have been recorded in the Neotropical and Neartic regions, as well as provide information on the geographical range of these species by country.PageBreakArthropoda von Siebold, 1848Phylum Hexapoda Latreille, 1825Subphylum Insecta Linnaeus, 1758Class Diptera Linnaeus, 1758Order Psychodomorpha Hennig, 1968Sub-order Psychodidae Newman, 1834Family Phlebotominae Rondani, 1840Subfamily Hertigiini Abonnenc & L\u00e9ger, 1976Tribe HERTIGIINA Abonnenc & L\u00e9ger, 1976Subtribe Hertigia Fairchild, 1949Genus Hertigiahertigi Fairchild, 1949Distribution. Costa Rica, Panama*.Warileya Hertig, 1948Genus Warileyaeuniceae Fern\u00e1ndez, Carbajal, Astete & Wooster, 1998Distribution. Peru*.Warileyafourgassiensis Le Pont & Desjeux, 1984Distribution. French Guiana*.Warileyaleponti Galati & C\u00e1ceres, 1999Distribution. Peru*.Warileyalumbrerasi Ogosuku, Perez, Davies & Villaseca, 1996Distribution. Peru*.Warileyanigrosaccula Fairchild & Hertig, 1951Distribution. Colombia, Panama*.Warileyaphlebotomanica Hertig, 1948Distribution. Ecuador, Peru*.Warileyarotundipennis Fairchild & Hertig, 1951Distribution. Bolivia, Colombia, Costa Rica, Panama*, Peru.Warileyayungasi Velasco & Trapido, 1974Distribution. Bolivia*.Phlebotomini Rondani, 1840Tribe Brumptomyiina Artemiev, 1991Subtribe Brumptomyia Fran\u00e7a and Parrot, 1921Genus Brumptomyiaangelae Galati, Santos & Silva, 2007Distribution. Brazil*.PageBreakBrumptomyiaavellari Distribution. Argentina, Bolivia, Brazil*, Colombia, Panama, Paraguay, Peru, Venezuela.Brumptomyiabeaupertuyi Distribution. Colombia, Venezuela*.Brumptomyiabragai Mangabeira & Sherlock, 1961Distribution. Brazil*.Brumptomyiabrumpti Distribution. Argentina, Bolivia, Brazil*.Brumptomyiacardosoi Distribution. Brazil*.Brumptomyiacarvalheiroi Shimabukuro, Marass\u00e1 & Galati, 2007Distribution. Brazil*.Brumptomyiacunhai Distribution. Brazil*, Honduras.Brumptomyiadevenanzii Distribution. Venezuela*.Brumptomyiafigueireidoi Mangabeira & Sherlock, 1961Distribution. Brazil*.Brumptomyiagalindoi Distribution. Brazil, Panama*.Brumptomyiaguimaraesi Distribution. Argentina, Brazil*, Paraguay.Brumptomyiahamata Distribution. Belize, Colombia, Ecuador, Mexico, Panama*, Peru.Brumptomyialeopoldoi Distribution. Belize, Colombia, Ecuador*, Panama.Brumptomyiamangabeirai Distribution. Brazil*.Brumptomyiamesai Sherlock, 1962Distribution. Belize, Colombia*, Honduras, Mexico.Brumptomyianitzulescui Distribution. Brazil*.Brumptomyiaorlandoi Fraiha, Shaw & Lainson, 1970Distribution. Brazil*.Brumptomyiaortizi Martins, Silva & Falc\u00e3o, 1971Distribution. Brazil*.Brumptomyiapentacantha Distribution. Bolivia, Brazil*, Colombia, Ecuador, Peru.Brumptomyiapintoi Distribution. Argentina, Bolivia, Brazil*, French Guiana, Surinam, Venezuela.Brumptomyiaquimperi Galati & C\u00e1ceres, 1999Distribution. Peru*.PageBreakBrumptomyiaspinosipes Distribution. Brazil, French Guiana*, Panama.Brumptomyiatravassosi Distribution. Brazil*, French Guiana, Panama, Surinam.Brumptomyiatroglodytes Distribution. Brazil*, Peru.Brumptomyiavirgensi Mangabeira & Sherlock, 1961Distribution. Brazil*.Oligodontomyia Galati, 1995Genus Oligodontomyiaisopsi Distribution. Chile*.Oligodontomyiaoligodonta Distribution. Peru*.Oligodontomyiatoroensis Distribution. Bolivia*.Sergentomyiina Artemiev, 1991Subtribe Deanemyia Galati, 1995Genus Deanemyiaappendiculata Distribution. Brazil*.Deanemyiaderelicta Distribution. Brazil*.Deanemyiamaruaga Distribution. Brazil*.Deanemyiaramirezi Distribution. Bolivia, Brazil*.Note. The record for Bolivia is based on specimens collected in Aguas Calientes Department of Santa Cruz and donated by Fran\u00e7ois Le Pont to one of us (EABG).Deanemyiasamueli Distribution. Brazil*.Micropygomyia Barretto, 1962Genus Coquillettimyia) Galati, 1995Subgenus californica Distribution. United States of America*.PageBreakMicropygomyia (Coquillettimyia) chiapanensis Distribution. Costa Rica, El Salvador, Honduras, Mexico*, Nicaragua, Panama.Micropygomyia (Coquillettimyia) stewarti Distribution. Mexico, United States of America*.vexator Fairchild, 1955Series Micropygomyia (Coquillettimyia) apache Distribution. United States of America*.Micropygomyia (Coquillettimyia) oppidana Distribution. Canada, Mexico*, United States of America.Micropygomyia (Coquillettimyia) vexator Distribution. Canada, Mexico, United States of America*.Micropygomyia (Coquillettimyia) vindicator Distribution. Mexico*.Micropygomyia) Barretto, 1962Subgenus absonodonta Distribution. Peru, Venezuela*.Micropygomyia (Micropygomyia) ancashensis Galati & C\u00e1ceres, 2007Distribution. Peru*.Micropygomyia (Micropygomyia) cayennensiscayennensis Distribution. Belize, Brazil, Colombia, Costa Rica, Ecuador, El Salvador, French Guiana*, Honduras, Mexico, Nicaragua, Panama, Peru, Trinidad and Tobago, Venezuela.Micropygomyia (Micropygomyia) cayennensisbraci Distribution. Cayman Islands*.Micropygomyia (Micropygomyia) cayennensiscruzi Distribution. Cuba*.Micropygomyia (Micropygomyia) cayennensishispaniolae Distribution. Dominican Republic*, Haiti.Micropygomyia (Micropygomyia) cayennensisjamaicensis Distribution. Jamaica*.Micropygomyia (Micropygomyia) cayennensismaciasi Distribution. Belize, Guatemala, Mexico*.Micropygomyia (Micropygomyia) cayennensispuertoricensis Distribution. Puerto Rico*.Micropygomyia (Micropygomyia) cayennensisviequesensis Distribution. Puerto Rico*, Virgin Islands.PageBreakMicropygomyia (Micropygomyia) ctenidophora Distribution. Mexico*.Micropygomyia (Micropygomyia) cubensis Distribution. Cuba*, United States of America.Micropygomyia (Micropygomyia) duppyorum Distribution. Jamaica*.Micropygomyia (Micropygomyia) durani Distribution. El Salvador, Honduras, Mexico*.Micropygomyia (Micropygomyia) lewisi Distribution. Venezuela*.Micropygomyia (Micropygomyia) micropyga Distribution. Bolivia, Brazil*, Colombia, Costa Rica, Ecuador, French Guiana, Panama, Peru, Trinidad and Tobago, Venezuela.Micropygomyia (Micropygomyia) schreiberi Distribution. Brazil*.Micropygomyia (Micropygomyia) yencanensis Distribution. Colombia, Venezuela*.pilosa Theodor, 1965Series Micropygomyia (Micropygomyia) chassigneti Distribution. Brazil, Colombia, French Guiana*, Surinam.Micropygomyia (Micropygomyia) mangabeirana Distribution. Brazil*.Micropygomyia (Micropygomyia) pilosa Distribution. Brazil*, Colombia, Costa Rica, French Guiana, Grenada, Panama, Trinidad and Tobago, Venezuela.Sauromyia) Artemiev, 1991Subgenus atroclavata Distribution. Colombia, Costa Rica, Guadeloupe, Martinica, Panama, Trinidad and Tobago*, Venezuela, Virgin Islands.Micropygomyia (Sauromyia) venezuelensis Distribution. Colombia, Venezuela*.oswaldoi Barretto, 1962Series Micropygomyia (Sauromyia) capixaba Distribution. Brazil*.PageBreakMicropygomyia (Sauromyia) dereuri Distribution. Bolivia*.Micropygomyia (Sauromyia) dorafeliciangeli Andrade-Filho, Galati & Brazil, 2009\u2020Distribution. Dominican amber*.Micropygomyia (Sauromyia) ferreirana Distribution. Brazil*.Micropygomyia (Sauromyia) huacalquensis Distribution. Bolivia*.Micropygomyia (Sauromyia) longipennis Distribution. Brazil*, Peru.Micropygomyia (Sauromyia) machupicchu Distribution. Peru*.Micropygomyia (Sauromyia) oswaldoi Distribution. Argentina, Bolivia, Brazil*.Micropygomyia (Sauromyia) paterna \u2020Distribution. Mexican amber*.Micropygomyia (Sauromyia) peresi Distribution. Argentina, Bolivia, Brazil*, French Guiana.Micropygomyia (Sauromyia) petari Galati, Marass\u00e1 & Gon\u00e7alves-Andrade, 2003Distribution. Brazil*.Micropygomyia (Sauromyia) pratti Distribution. Mexico*.Micropygomyia (Sauromyia) pusilla Distribution. Brazil*, French Guiana.Micropygomyia (Sauromyia) quechua Distribution. Peru*.Micropygomyia (Sauromyia) quinquefer Distribution. Argentina*, Bolivia, Brazil.Micropygomyia (Sauromyia) rorotaensis Distribution. Brazil, Colombia, French Guiana*, Peru, Surinam, Panama, Venezuela.Micropygomyia (Sauromyia) saccai Distribution. Venezuela*.Micropygomyia (Sauromyia) trinidadensis Distribution. Belize, Bolivia, Brazil, Colombia, Costa Rica, Ecuador, El Salvador, French Guiana, Guatemala, Honduras, Mexico, Nicaragua, Peru, Panama, Surinam, Trinidad and Tobago*, Venezuela.Micropygomyia (Sauromyia) villelai Distribution. Brazil*.Micropygomyia (Sauromyia) vonatzingeni Galati, 2007Distribution. Brazil*.Micropygomyia (Sauromyia) zikani Distribution. Brazil*.PageBreakSilvamyia) Galati, 1995Subgenus (Micropygomyia (Silvamyia) acanthopharynx Distribution. Brazil*.Micropygomyia (Silvamyia) echinatopharynx Andrade-Filho, Galati, Andrade & Falc\u00e3o, 2004Distribution. Brazil*.Micropygomyiabrandaoi Andrade-Filho, Galati, Falc\u00e3o & Brazil, 2008\u2020Distribution. Dominican amber*.Micropygomyiaxerophila Distribution. United States of America*.Lutzomyiina Abonnenc and L\u00e9ger, 1976Subtribe Sciopemyia Barretto, 1962Genus Sciopemyiafluviatilis Distribution. Brazil, French Guiana*.Sciopemyiamicrops Distribution. Brazil*.Sciopemyianematoducta Distribution. Brazil*, Colombia.Sciopemyiapennyi Distribution. Brazil*.Sciopemyiapreclara Distribution. Bolivia, Brazil, Colombia*, Peru.Sciopemyiaservulolimai Distribution. Bolivia, Brazil*, Colombia, Peru.Sciopemyiasordellii Distribution. Argentina*, Bolivia, Brazil, Colombia, Costa Rica, Ecuador, French Guiana, Panama, Peru, Trinidad and Tobago, Venezuela.Sciopemyiavattierae Distribution. Bolivia*, Colombia, Peru.Lutzomyia Fran\u00e7a, 1924Genus Castromyia) Mangabeira, 1942Subgenus (Lutzomyia (Castromyia) amarali Distribution. Brazil*.PageBreakLutzomyia (Castromyia) caligata Martins, Falc\u00e3o & Silva, 1965Distribution. Brazil*.Lutzomyia (Castromyia) castroi Distribution. Brazil*.Helcocyrtomyia) Barretto, 1962Subgenus caballeroi Blancas, C\u00e1ceres & Galati, 1989Distribution. Peru*.Lutzomyia (Helcocyrtomyia) castanea Galati & C\u00e1ceres, 1994Distribution. Ecuador, Peru*.Lutzomyia (Helcocyrtomyia) ceferinoi Distribution. Colombia, Venezuela*.Lutzomyia (Helcocyrtomyia) erwindonaldoi Distribution. Colombia, Venezuela*.Lutzomyia (Helcocyrtomyia) herreri Galati & C\u00e1ceres, 2003Distribution. Peru*.Lutzomyia (Helcocyrtomyia) imperatrix Distribution. Peru*.Lutzomyia (Helcocyrtomyia) larensis Arredondo, 1987Distribution. Venezuela*.Lutzomyia (Helcocyrtomyia) munaypata Ogusuku, Chevarria, Porras & P\u00e9rez, 1999Distribution. Peru*.Lutzomyia (Helcocyrtomyia) osornoi Distribution. Bolivia, Colombia*, Ecuador, Peru.Lutzomyia (Helcocyrtomyia) quillabamba Ogusuku, Chevarria, Porras & P\u00e9rez, 1999Distribution. Peru*.Lutzomyia (Helcocyrtomyia) rispaili Torrez-Espejo, C\u00e1ceres & Le Pont, 1995Distribution. Bolivia*, Peru.Lutzomyia (Helcocyrtomyia) strictivilla Young, 1979Distribution. Colombia*, Ecuador, Venezuela.Lutzomyia (Helcocyrtomyia) wattsi Fern\u00e1ndez, Carbajal, Astete & Wooster, 1998Distribution. Peru*.peruensis Barretto, 1962Series Lutzomyia (Helcocyrtomyia) ayacuchensis C\u00e1ceres & Galati, 1988Distribution. Ecuador, Peru*.Lutzomyia (Helcocyrtomyia) blancasi Galati & C\u00e1ceres, 1990Distribution. Peru*.Lutzomyia (Helcocyrtomyia) chavinensis P\u00e9rez & Ogusuku, 1999Distribution. Peru*.PageBreakLutzomyia (Helcocyrtomyia) galatiae Le Pont, Mart\u00ednez, Torrez-Espejo & Dujardin, 1998Distribution. Bolivia*.Lutzomyia (Helcocyrtomyia) noguchii Distribution. Peru*.Lutzomyia (Helcocyrtomyia) pallidithorax Galati & C\u00e1ceres, 1994Distribution. Peru*.Lutzomyia (Helcocyrtomyia) peruensis Distribution. Bolivia, Peru*.Lutzomyia (Helcocyrtomyia) pescei Distribution. Peru*.Lutzomyia (Helcocyrtomyia) tejadai Galati & C\u00e1ceres, 1990Distribution. Peru*.sanguinaria Barretto, 1962Series Lutzomyia (Helcocyrtomyia) adamsi Fern\u00e1ndez, Galati, Carbajal, Wooster & Watts, 1998Distribution. Peru*.Lutzomyia (Helcocyrtomyia) botella Distribution. Panama*.Lutzomyia (Helcocyrtomyia) caceresi Le Pont, Mat\u00edas, Mart\u00ednez & Dujardin, 2004Distribution. Bolivia*.Lutzomyia (Helcocyrtomyia) cirrita Young & Porter, 1974Distribution. Colombia*.Lutzomyia (Helcocyrtomyia) gonzaloi Ogusuku, Canales & P\u00e9rez, 1997Distribution. Peru*.Lutzomyia (Helcocyrtomyia) guderiani Torrez-Espejo, C\u00e1ceres & Le Pont, 1995Distribution. Bolivia*, Peru.Lutzomyia (Helcocyrtomyia) hartmanni Distribution. Colombia, Costa Rica, Ecuador, Mexico, Panama*, Peru.Lutzomyia (Helcocyrtomyia) kirigetiensis Galati & C\u00e1ceres, 1992Distribution. Peru*.Lutzomyia (Helcocyrtomyia) monzonensis Ogusuku, Canales & P\u00e9rez, 1997Distribution. Peru*.Lutzomyia (Helcocyrtomyia) sanguinaria Distribution. Colombia, Costa Rica, Ecuador, Honduras, Nicaragua, Panama*, Peru.Lutzomyia (Helcocyrtomyia) scorzai Distribution. Colombia*, Peru, Venezuela.Lutzomyia (Helcocyrtomyia) tolimensis Carrasquilla, Munstermann, Mar\u00edn, Ocampo & Ferro, 2012Distribution. Colombia*.PageBreakLutzomyia (Helcocyrtomyia) tortura Young & Rogers, 1984Distribution. Bolivia, Colombia, Ecuador*.Lutzomyia (Helcocyrtomyia) velezi Bejarano, Vivero & Uribe, 2010Distribution. Colombia*.Lutzomyia) Fran\u00e7a, 1924Subgenus (Lutzomyia (Lutzomyia) alencari Martins, Souza & Falc\u00e3o, 1962Distribution. Brazil*.Lutzomyia (Lutzomyia) almerioi Galati & Nunes, 1999Distribution. Brazil*.Lutzomyia (Lutzomyia) battistinii Distribution. Brazil, Peru*.Lutzomyia (Lutzomyia) bicornuta Distribution. Peru*.Lutzomyia (Lutzomyia) bifoliata Osorno-Mesa, Morales, Osorno & Hoyos, 1970Distribution. Colombia*.Lutzomyia (Lutzomyia) cavernicola Distribution. Brazil*.Lutzomyia (Lutzomyia) cruzi Distribution. Bolivia, Brazil*.Lutzomyia (Lutzomyia) dispar Martins & Silva, 1963Distribution. Brazil*.Lutzomyia (Lutzomyia) elizabethrangelae Vilela, Azevedo & Godoy, 2015Distribution. Brazil*.Lutzomyia (Lutzomyia) falquetoi Pinto & Santos, 2007Distribution. Brazil*.Lutzomyia (Lutzomyia) fonsecai Distribution. Bolivia*.Note. Placement in Lutzomyia based on the study by one of us (EABG) of specimens collected in several caves close to the type-locality of Lutzomyiafonsecai in the Chiquitano seasonally dry forest of Serrania Santiago .Lutzomyia (Lutzomyia) forattinii Galati, Rego, Nunes & Teruya, 1985Distribution. Bolivia, Brazil*.Lutzomyia (Lutzomyia) gaminarai Distribution. Brazil, Uruguay*.Lutzomyia (Lutzomyia) ischnacantha Martins, Souza & Falc\u00e3o, 1962Distribution. Brazil*.Lutzomyia (Lutzomyia) ischyracantha Martins, Falc\u00e3o & Silva, 1962Distribution. Brazil*.Lutzomyia (Lutzomyia) lichyi Distribution. Brazil, Colombia, Costa Rica, Ecuador, French Guiana, Panama, Peru, Trinidad and Tobago, Venezuela*.PageBreakLutzomyia (Lutzomyia) longipalpis Distribution. Argentina, Bolivia, Brazil*, Colombia, Costa Rica, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Panama, Paraguay, Uruguay, Venezuela.Lutzomyia (Lutzomyia) matiasi Le Pont & Mollinedo, 2009Distribution. Bolivia*.Lutzomyia (Lutzomyia) pseudolongipalpis Arrivillaga & Feliciangeli, 2001Distribution. Venezuela*.Lutzomyia (Lutzomyia) renei Distribution. Brazil*.Lutzomyia (Lutzomyia) souzalopesi Martins, Silva & Falc\u00e3o, 1970Distribution. Brazil*.Tricholateralis) Galati, 1995Subgenus araracuarensis Morales & Minter, 1981Distribution. Brazil, Colombia*.Lutzomyia carvalhoi Distribution. Brazil*, French Guiana.Lutzomyia cruciata Distribution. Belize, Brazil, Costa Rica, El Salvador, Guatemala*, Honduras, Mexico, Nicaragua, Panama, United States of America.Lutzomyia cultellata Freitas & Albuquerque, 1996Distribution. Brazil*, Peru.Note. Placement is his subgenus was possible due to the study of specimens provided to us (EABG and PHFS) by Mr. Rui Freitas . We concluded it belongs to the subgenusTricholateralis because among other characters this species presents the ventro-cervical sensillae, setae in the abdominal pleura and lacks the ascoids with posterior spurs.Lutzomyia diabolica Distribution. Mexico, United States of America*.Lutzomyia evangelistai Martins & Fraiha, 1971Distribution. Bolivia, Brazil*, Colombia, Peru.Lutzomyia falcata Young, Morales & Ferro, 1994Distribution. Brazil, Colombia*, Ecuador.Lutzomyia flabellata Martins & Silva, 1964Distribution. Bolivia, Brazil*.Lutzomyia gomezi Distribution. Bolivia, Brazil, Colombia, Costa Rica, Ecuador, El Salvador, French Guiana, Honduras, Mexico, Nicaragua, Panama, Peru, Trinidad and Tobago, Venezuela*.Lutzomyia legerae Le Pont, Gantier, Hue & Valle, 1995Distribution. Nicaragua*.PageBreakLutzomyia maesi Le Pont, Ib\u00e1\u00f1ez\u2013Bernal & Fuentes, 2011Distribution. Nicaragua*.Lutzomyia marinkellei Young, 1979Distribution. Brazil*, Colombia.Lutzomyia sherlocki Martins, Silva & Falc\u00e3o, 1971Distribution. Bolivia, Brazil*, Colombia, Ecuador, Peru.Lutzomyia spathotrichia Martins, Falc\u00e3o & Silva, 1963Distribution. Bolivia, Brazil*, Ecuador, French Guiana.LutzomyiaincertaesedisLutzomyiachotensis Galati, C\u00e1ceres & Zorilla, 2003Distribution. Peru*.Lutzomyiaignacioi Distribution. Colombia, Venezuela*.Note.Psathryromyia as incertae sedis. However, S\u00e1bio, PB (pers. comm.) examined the type material deposited in the Entomological Collection - Smithsonian Institution / Walter Reeed Biosystematic Unit, Suitland, MD - USA) and observed the presence of the ventro-cervical sensillae and the papilla in F3, the setae in the anterior region of the katepisternum is absent, ascoids present reduced posterior spurs and spermathecae are ringed. These characters are synapomorphies shared by some species of Lutzomyia , but this species also lacks characters to placed it with confidence in any of these three subgenera.Lutzomyiainfusca Porter & Young, 1999Distribution. Guatemala*.Lutzomyiamanciola Ib\u00e1\u00f1ez-Bernal, 2001Distribution. Belize*.Note. The insertion of this species in Lutzomyia is provisional. There were no female characters to be observed that could lead to more accurate placement in any genus, nor was the male known. The inclusion of Lutzomyiamanciola in Sciopemyia was suggested by Ib\u00e1\u00f1ez-Bernal (2001). However, Lutzomyiamanciola do not present the head and labrum-epipharynx shorter than the sum of flagellomeres FI + FII, which are diagnostic characters for Sciopemyia.Lutzomyiaponsi Distribution. Venezuela*.Note. The description of this species does not provide sufficient information to place it in any genus; and the similarity of their spermathecae with those of Lutzomyiaignacioi led us to include it together with this species in the genus Lutzomyia.Lutzomyiatanyopsis Young & Perkins, 1984Distribution. United States of America*.Lutzomyiavargasi Distribution. Mexico*.PageBreakMigonemyia Galati, 1995Genus Blancasmyia) Galati, 1995Subgenus (Migonemyia (Blancasmyia) bursiformis Distribution. Brazil, Colombia, Ecuador, French Guiana*, Venezuela.Migonemyia (Blancasmyia) cerqueirai Distribution. Brazil*, Colombia, Peru.Migonemyia (Blancasmyia) gorbitzi Distribution. Colombia, Costa Rica, Ecuador, Panama, Peru*.Migonemyia (Blancasmyia) moucheti Distribution. Brazil, French Guiana*, Peru.Migonemyia) Galati, 1995Subgenus (Migonemyia (Migonemyia) migonei Distribution. Argentina, Bolivia, Brazil, Colombia, Paraguay*, Peru, Trinidad and Tobago, Venezuela.Migonemyia (Migonemyia) rabelloi Distribution. Brazil*.Migonemyia (Migonemyia) vaniae Galati, Fonseca & Marass\u00e1, 2007Distribution. Brazil*.Pintomyia Costa Lima, 1932Genus Subgenus (Pifanomyia) Ortiz and Scorza, 1963evansi Galati, 1995Series Pintomyia (Pifanomyia) evansi Distribution. Colombia, Costa Rica, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Peru, Venezuela*.Pintomyia (Pifanomyia) maranonensis Distribution. Ecuador, Peru*.Pintomyia (Pifanomyia) nevesi Distribution. Bolivia, Brazil*, Colombia, Ecuador, Peru.Pintomyia (Pifanomyia) ovallesi Distribution. Belize, Colombia, Costa Rica, Guatemala, Honduras, Mexico, Nicaragua, Panama, Trinidad and Tobago, Venezuela*.monticola Artemiev, 1991Series Pintomyia (Pifanomyia) misionensis Distribution. Argentina*, Brazil, Paraguay.PageBreakPintomyia (Pifanomyia) monticola Distribution. Argentina, Brazil*, Paraguay, Peru.pacae Galati, 1995Series Pintomyia (Pifanomyia) gruta Distribution. Brazil*.Pintomyia (Pifanomyia) pacae Distribution. Brazil, French Guiana*, Surinam.pia Galati, 1995Series Pintomyia (Pifanomyia) emberai Distribution. Colombia*.Pintomyia (Pifanomyia) limafalcaoae Wolff & Galati, 2002Distribution. Colombia*.Pintomyia (Pifanomyia) pia Distribution. Bolivia, Colombia, Costa Rica, Panama*, Peru, Venezuela.Pintomyia (Pifanomyia) reclusa Distribution. Peru*.Pintomyia (Pifanomyia) suapiensis Distribution. Bolivia*, Peru.Pintomyia (Pifanomyia) tihuiliensis Distribution. Bolivia*, Colombia, Peru.Pintomyia (Pifanomyia) tocaniensis Distribution. Bolivia*, Peru.Pintomyia (Pifanomyia) torrealbai Distribution. Venezuela*.Pintomyia (Pifanomyia) valderramai Distribution. Venezuela*.serrana Barretto, 1962Series Pintomyia (Pifanomyia) boliviana Distribution. Bolivia*.Pintomyia (Pifanomyia) christophei Distribution. Dominican Republic*, Haiti.Pintomyia (Pifanomyia) diazi Distribution. Cuba*.Pintomyia (Pifanomyia) guilvardae Distribution. Bolivia*.Pintomyia (Pifanomyia) novoae Distribution. Cuba*.PageBreakPintomyia (Pifanomyia) odax Distribution. Brazil, Costa Rica, French Guiana, Guatemala, Honduras, Nicaragua, Panama*, Venezuela.Pintomyia (Pifanomyia) oresbia Distribution. Costa Rica, Panama*.Pintomyia (Pifanomyia) orestes Distribution. Brazil, Cayman Islands, Cuba*.Pintomyia (Pifanomyia) ottolinai Distribution. Venezuela*.Pintomyia (Pifanomyia) piedraferroi Distribution. Guatemala*.Pintomyia (Pifanomyia) robusta Distribution. Ecuador, Peru*.Pintomyia (Pifanomyia) serrana Distribution. Belize, Bolivia, Brazil*, Colombia, Costa Rica, French Guiana, Guatemala, Honduras, Mexico, Nicaragua, Panama, Peru, Venezuela.Pintomyia (Pifanomyia) torresi Distribution. Argentina, Bolivia*.townsendi Galati, 1995Series Pintomyia (Pifanomyia) amilcari Distribution. Venezuela*.Pintomyia (Pifanomyia) longiflocosa Distribution. Colombia*.Pintomyia (Pifanomyia) nadiae Distribution. Venezuela*.Pintomyia (Pifanomyia) paleotownsendi Andrade-Filho, Falc\u00e3o, Galati & Brazil, 2006\u2020 Distribution. Dominican amber*.Pintomyia (Pifanomyia) paloetrichia Andrade-Filho, Brazil, Falc\u00e3o & Galati, 2007\u2020 Distribution. Dominican amber*.Pintomyia (Pifanomyia) quasitownsendi Distribution. Colombia*.PageBreakPintomyia (Pifanomyia) sauroida Distribution. Colombia*, Venezuela.Pintomyia (Pifanomyia) spinicrassa Distribution. Colombia*, Venezuela.Pintomyia (Pifanomyia) torvida Distribution. Colombia*.Pintomyia (Pifanomyia) townsendi Distribution. Colombia, Venezuela*.Pintomyia (Pifanomyia) youngi Distribution. Colombia, Costa Rica, Venezuela*.verrucarum Fairchild, 1955Series Pintomyia (Pifanomyia) andina Distribution. Colombia*.Pintomyia (Pifanomyia) antioquiensis Wolff & Galati, 2002Distribution. Colombia*.Pintomyia (Pifanomyia) aulari Distribution. Venezuela*.Pintomyia (Pifanomyia) cajamarcensis Distribution. Peru*.Pintomyia (Pifanomyia) columbiana Distribution. Colombia*.Pintomyia (Pifanomyia) deorsa Distribution. Peru*.Pintomyia (Pifanomyia) disjuncta Distribution. Colombia*.Pintomyia (Pifanomyia) itza Ib\u00e1\u00f1ez-Bernal, May-UC & Rebollar-Tellez, 2010Distribution. Mexico*.Pintomyia (Pifanomyia) moralesi Distribution. Colombia*.Pintomyia (Pifanomyia) verrucarum Distribution. Peru*.Pintomyia) Costa Lima, 1932Subgenus (Pintomyia (Pintomyia) bianchigalatiae Distribution. Argentina, Brazil*.Pintomyia (Pintomyia) christenseni Distribution. Brazil, Colombia, Panama*, Trinidad and Tobago, Venezuela.Pintomyia (Pintomyia) damascenoi Distribution. Brazil*, Colombia, French Guiana, Surinam.PageBreakPintomyia (Pintomyia) fischeri Distribution. Argentina, Bolivia, Brazil*, Paraguay, Peru, Venezuela.Pintomyia (Pintomyia) gibsoni Distribution. Venezuela*.Pintomyia (Pintomyia) kuscheli Distribution. Bolivia*, Brazil.Pintomyia (Pintomyia) mamedei Distribution. Brazil*.Pintomyia (Pintomyia) pessoai Distribution. Argentina, Brazil*, Paraguay.PintomyiaincertaesedisPintomyiaadiketis Poinar, 2008\u2020 Distribution. Dominican amber*.Pintomyiabolontikui Ib\u00e1\u00f1ez-Bernal, Kraemer, Stebner & Wagner, 2013\u2020 Distribution. Mexican amber*.Pintomyiabrazilorum Andrade-Filho, Galati & Falc\u00e3o, 2006\u2020 Distribution. Dominican amber*Pintomyiadiamantinensis Distribution. Brazil*.Pintomyiadissimilis Andrade-Filho, Serra e Meira, Sanguinette & Brazil, 2009\u2020 Distribution. Dominican amber*Pintomyiadominicana Andrade-Filho, Galati & Brazil, 2009\u2020Distribution. Dominican amber*Pintomyiafalcaorum Brazil & Andrade-Filho, 2002\u2020 Distribution. Dominican amber*Pintomyiafilipalpis \u2020 Distribution. Dominican amber*Pintomyiakillickorum Andrade-Filho & Brazil, 2004\u2020 Distribution. Dominican amber*Pintomyiamaracayensis Distribution. Venezuela*.Pintomyiamiocena \u2020 Distribution. Dominican amber*Pintomyianaiffi Distribution. Brazil*.Pintomyianuneztovari Distribution. Venezuela*.Pintomyiapaleopestis \u2020 Distribution. Dominican Republic*.Pintomyiarangeliana Distribution. Colombia, Panama,Trinidad and Tobago, Venezuela*.PageBreakPintomyiasuccini \u2020 Distribution. Dominican amber*Dampfomyia Addis, 1945Genus Coromyia) Barretto, 1962Subgenus (Dampfomyia (Coromyia) aquilonia Distribution. Canada, United States of America*.Dampfomyia (Coromyia) beltrani Distribution. Honduras, Mexico*.Dampfomyia (Coromyia) deleoni Distribution. Belize, Costa Rica, El Salvador, Guatemala*, Honduras, Mexico.Dampfomyia (Coromyia) disneyi Distribution. Belize*, Guatemala, Mexico.Dampfomyia (Coromyia) isovespertilionis Distribution. Colombia, Costa Rica, Panama*.Dampfomyia (Coromyia) steatopyga Distribution. Mexico*.Dampfomyia (Coromyia) vesicifera Distribution. Costa Rica, Nicaragua, Panama*.Dampfomyia (Coromyia) vespertilionis Distribution. Colombia, Costa Rica, Ecuador, Nicaragua, Panama*.Dampfomyia (Coromyia) viriosa Distribution. Costa Rica, Panama*.Dampfomyia (Coromyia) zeledoni Distribution. Costa Rica*, Honduras, Nicaragua.Dampfomyia) Addis, 1945Subgenus (Dampfomyia (Dampfomyia) anthophora Distribution. Mexico, Nicaragua, United States of America*.Dampfomyia (Dampfomyia) atulapai Distribution. El Salvador, Guatemala*, Mexico.Dampfomyia (Dampfomyia) dodgei Distribution. El Salvador, Mexico*.Dampfomyia (Dampfomyia) insolita Distribution. Costa Rica, Panama*.Dampfomyia (Dampfomyia) leohidalgoi Distribution. Mexico*.Dampfomyia (Dampfomyia) permira Distribution. Belize, Guatemala, Mexico*.PageBreakDampfomyia (Dampfomyia) rosabali Distribution. Colombia, Costa Rica, Panama*.delpozoi Young & Fairchild, 1974Group Dampfomyiadelpozoi Distribution. Belize, Guatemala, Mexico*.Dampfomyiainusitata Distribution. Mexico*.Note. The Dampfomyiadelpozoi group shows characters of both the subgenusCoromyia and Dampfomyias.str. and are therefore listed separately.DampfomyiaincertaesedisDampfomyiacaminoi Distribution. Mexico*.Expapillata Galati, 1995Genus Expapillatacerradincola Distribution. Brazil*.Expapillatafirmatoi Distribution. Argentina, Brazil*.Pressatia Mangabeira, 1942Genus Pressatiacalcarata Distribution. Bolivia, Brazil*, Peru, Venezuela.Pressatiacamposi Distribution. Colombia, Costa Rica, Ecuador*, Nicaragua, Panama.Pressatiachoti Distribution. Bolivia, Brazil, Colombia, Ecuador, French Guiana*, Peru, Surinam.Pressatiaduncanae Distribution. Bolivia*, Colombia, Peru.Note. The record of this species for Peru is from the illustrations published by Lutzomyia sp. D) and Young & Morales 1987: 662 (Lutzomyia sp. 1).Pressatiadysponeta Distribution. Brazil, Colombia, Costa Rica, Ecuador, Panama*, Venezuela.Pressatiaequatorialis Distribution. Brazil*, French Guiana.Pressatiatriacantha Distribution. Brazil*, Colombia, Ecuador, French Guiana, Peru, Venezuela.PageBreakPressatiatrispinosa Distribution. Brazil*, French Guiana, Peru.Trichopygomyia Barretto, 1962Genus Trichopygomyiaconviti Distribution. Brazil, Colombia, Venezuela*.Trichopygomyiadasypodogeton Distribution. Bolivia, Brazil*.Trichopygomyiadepaquiti Distribution. Brazil, French Guiana*.Trichopygomyiaelegans Distribution. Brazil, Peru*.Trichopygomyiaferroae Distribution. Colombia*.Trichopygomyiagantieri Distribution. Bolivia*.Trichopygomyialongispina Distribution. Brazil*, Colombia, French Guiana, Venezuela.Trichopygomyiamartinezi Distribution. Colombia*.Trichopygomyiapinna Distribution. Brazil, Venezuela*.Trichopygomyiaratcliffei Distribution. Brazil*.Trichopygomyiarondoniensis Distribution. Bolivia, Brazil*.Trichopygomyiatrichopyga Distribution. Brazil, French Guiana*, Surinam.Trichopygomyiatriramula Distribution. Belize, Colombia, Costa Rica, Ecuador, Guatemala, Mexico, Panama*.Trichopygomyiaturelli Distribution. Peru*.Trichopygomyiawagleyi Distribution. Bolivia, Brazil*, Colombia, Venezuela.Trichopygomyiawitoto Distribution. Colombia*, Ecuador.Evandromyia Mangabeira, 1941Genus Aldamyia) Galati, 1995Subgenus (PageBreakEvandromyia (Aldamyia) aldafalcaoae Distribution. Brazil*.Evandromyia (Aldamyia) andersoni Distribution. Bolivia*, Brazil.Evandromyia (Aldamyia) apurinan Shimabukuro, Figueira & Silva, 2013Distribution. Brazil*.Evandromyia (Aldamyia) bacula Distribution. Bolivia, Brazil*.Evandromyia (Aldamyia) carmelinoi Distribution. Brazil*.Evandromyia (Aldamyia) dubitans Distribution. Brazil, Colombia*, Costa Rica, Panama, Trinidad and Tobago, Venezuela.Evandromyia (Aldamyia) evandroi Distribution. Argentina, Brazil*.Evandromyia (Aldamyia) hashiguchii Le\u00f3n, Teran, Neira & Le Pont, 2009Distribution. Ecuador*.Evandromyia (Aldamyia) lenti Distribution. Bolivia, Brazil*, Surinam.Evandromyia (Aldamyia) orcyi Oliveira, Sanguinette, Almeida & Andrade-Filho, 2015Distribution. Brazil*.Evandromyia (Aldamyia) sericea Distribution. Brazil, Colombia, Ecuador, French Guiana*, Surinam, Venezuela.Evandromyia (Aldamyia) termitophila Distribution. Bolivia, Brazil*.Evandromyia (Aldamyia) walkeri Distribution. Bolivia*, Brazil*, Colombia, Ecuador, French Guiana, Panama, Peru, Trinidad and Tobago, Venezuela.Note. The type locality of Evandromyiawalkeri is along the Abu\u00f1a river, which forms part of the border between Bolivia and Brazil, however it is not clear in which of the countries the exact type locality is located.Evandromyia (Aldamyia) williamsi Distribution. Brazil*, Peru, Venezuela.Barrettomyia) Martins and Silva, 1968Subgenus cortelezzii Distribution. Argentina*, Bolivia, Brazil, Paraguay, Peru, Uruguay.Evandromyia (Barrettomyia) corumbaensis Distribution. Bolivia, Brazil*.Evandromyia (Barrettomyia) sallesi Distribution. Argentina, Bolivia, Brazil*, Ecuador, Paraguay, Peru.PageBreakEvandromyia (Barrettomyia) spelunca Carvalho, Brazil, Sanguinette & Andrade-Filho, 2011Distribution. Brazil*.monstruosa Lewis, Young & Minter, 1977Series Evandromyia (Barrettomyia) monstruosa Distribution. Brazil, Colombia, French Guiana*, Surinam, Venezuela.Evandromyia (Barrettomyia) teratodes Distribution. Brazil*, Paraguay.tupynambai Martins & Silva, 1968Series Evandromyia (Barrettomyia) bahiensis Distribution. Brazil*.Evandromyia (Barrettomyia) callipyga Distribution. Brazil*.Evandromyia (Barrettomyia) costalimai Distribution. Brazil*.Evandromyia (Barrettomyia) petropolitana Distribution. Brazil*.Evandromyia (Barrettomyia) tupynambai Distribution. Brazil*.Evandromyia) Mangabeira, 1941Subgenus begonae Distribution. Brazil, Colombia, Venezuela*.Evandromyia (Evandromyia) bourrouli Distribution. Bolivia, Brazil*.Evandromyia (Evandromyia) brachyphalla Distribution. Brazil*, French Guiana.Evandromyia (Evandromyia) georgii Distribution. Brazil*.Evandromyia (Evandromyia) infraspinosa Distribution. Bolivia, Brazil*, Colombia, French Guiana, Peru, Surinam, Venezuela.Evandromyia (Evandromyia) inpai Distribution. Brazil*, Venezuela.Evandromyia (Evandromyia) ledezmaae Le\u00f3n, Teran, Neira & Le Pont, 2009Distribution. Ecuador*.Evandromyia (Evandromyia) pinottii Distribution. Brazil*, French Guiana, Venezuela.PageBreakEvandromyia (Evandromyia) sipani Distribution. Brazil, Colombia, Peru*.Evandromyia (Evandromyia) tarapacaensis Distribution. Bolivia*, Brazil.rupicola Young & Fairchild, 1974Series Evandromyia (Evandromyia) correalimai Distribution. Brazil*.Evandromyia (Evandromyia) gaucha Andrade-Filho, Souza & Falc\u00e3o, 2007Distribution. Brazil*.Evandromyia (Evandromyia) grimaldii Andrade-Filho, Pinto, Santos & Carvalho, 2009Distribution. Brazil*.Evandromyia (Evandromyia) rupicola Distribution. Brazil*.Evandromyia (Evandromyia) tylophalla Andrade & Galati, 2012Distribution. Brazil*.saulensis Lewis, Young & Minter, 1977Series Evandromyia (Evandromyia) saulensis Distribution. Bolivia, Brazil, Colombia, Costa Rica, Ecuador, French Guiana*, Panama, Peru, Venezuela.Evandromyia (Evandromyia) wilsoni Distribution. Brazil*.EvandromyiaincertaesedisEvandromyiaedwardsi Distribution. Brazil*.Psychodopygina Galati, 1995Subtribe Psathyromyia Barretto, 1962Genus Forattiniella) Vargas, 1978Subgenus (Psathyromyia (Forattiniella) abunaensis Distribution. Bolivia, Brazil*, Colombia, Ecuador, Peru.Psathyromyia (Forattiniella) antezanai Distribution. Bolivia*.Psathyromyia (Forattiniella) aragaoi PageBreakDistribution. Bolivia, Brazil*, Colombia, Costa Rica, Ecuador, French Guiana, Panama, Paraguay, Peru, Trinidad and Tobago, Venezuela.Psathyromyia (Forattiniella) barrettoibarrettoi Distribution. Bolivia, Brazil*, Colombia, Ecuador, French Guiana, Peru, Surinam, Trinidad and Tobago.Psathyromyia (Forattiniella) barrettoimajuscula Distribution. Colombia, Costa Rica, Ecuador, El Salvador, Honduras, Nicaragua, Panama*.Psathyromyia (Forattiniella) brasiliensis Distribution. Brazil*, French Guiana, Peru.Psathyromyia (Forattiniella) campograndensis Distribution. Brazil*, French Guiana.Psathyromyia (Forattiniella) carpenteri Distribution. Belize, Colombia, Costa Rica, Mexico, Panama*.Psathyromyia (Forattiniella) castilloi Distribution. Bolivia, Ecuador*, French Guiana.Psathyromyia (Forattiniella) coutinhoi Distribution. Bolivia, Brazil*, Peru.Psathyromyia (Forattiniella) elizabethdorvalae Brilhante, S\u00e1bio & Galati, 2016Distribution. Brazil*.Psathyromyia (Forattiniella) inflata Distribution. Bolivia, Brazil, French Guiana*.Psathyromyia (Forattiniella) lutziana Distribution. Bolivia, Brazil*, Colombia, French Guiana, Peru, Surinam, Venezuela.Psathyromyia (Forattiniella) naftalekatzi Distribution. Brazil*.Psathyromyia (Forattiniella) pascalei Distribution. Brazil*.Psathyromyia (Forattiniella) pradobarrientosi Distribution. Bolivia*, Brazil.Note. This species has been collected in Brazil in Amap\u00e1 (PHFS) and in Distrito Federal (AJA).Psathyromyia (Forattiniella) runoides Distribution. Brazil, Colombia, Costa Rica, Ecuador, Panama*, Peru.Psathyromyia (Forattiniella) schleei \u2020Distribution. Dominican amber*Psathyromyia (Forattiniella) texana Distribution. Mexico*, United States of America.Psathyromyia) Barretto, 1962Subgenus digitata Distribution. Brazil*.Psathyromyia (Psathyromyia) lanei Distribution. Argentina, Brazil*, Paraguay.Psathyromyia (Psathyromyia) pelloni Distribution. Brazil*.shannoni Fairchild, 1955Series Psathyromyia (Psathyromyia) abonnenci Distribution. Bolivia, Brazil, Colombia, Ecuador, French Guiana*, Panama, Peru, Surinam, Venezuela.Psathyromyia (Psathyromyia) baratai S\u00e1bio, Andrade & Galati, 2015Distribution. Brazil*.Psathyromyia (Psathyromyia) barretti Alves & Freitas, 2016Distribution. Brazil*.Psathyromyia (Psathyromyia) bigeniculata Distribution. Brazil, French Guiana*.Psathyromyia (Psathyromyia) campbelli Distribution. Bolivia, Brazil*, Colombia, French Guiana, Peru, Venezuela.Psathyromyia (Psathyromyia) cratifer Distribution. Belize, Costa Rica, Honduras, Mexico*, Panama.Psathyromyia (Psathyromyia) dasymera Distribution. Belize, Brazil, Colombia, Costa Rica, Ecuador, Mexico, Nicaragua, Panama*, Venezuela.Psathyromyia (Psathyromyia) dendrophyla Distribution. Bolivia, Brazil*, Colombia, Ecuador, French Guiana, Peru, Surinam, Venezuela.Psathyromyia (Psathyromyia) guatemalensis Distribution. Guatemala*.Psathyromyia (Psathyromyia) lerayi Distribution. Bolivia*, Colombia.Psathyromyia (Psathyromyia) limai Distribution. Brazil*.Psathyromyia (Psathyromyia) pifanoi Distribution. Brazil, Colombia, Peru*.Psathyromyia (Psathyromyia) punctigeniculata Distribution. Argentina, Bolivia, Brazil, Colombia, Ecuador, French Guiana*, Panama, Peru, Surinam, Venezuela.Psathyromyia (Psathyromyia) ribeirensis S\u00e1bio, Andrade & Galati, 2014Distribution. Brazil*.PageBreakPsathyromyia (Psathyromyia) scaffi Distribution. Bolivia, Brazil*, Colombia, French Guiana, Peru, Surinam.Psathyromyia (Psathyromyia) shannoni Distribution. Belize, Bolivia, Colombia, Costa Rica, Ecuador, French Guiana, Guatemala, Honduras, Mexico, Nicaragua, Panama*, Peru, Surinam, Trinidad and Tobago, United States of America, Venezuela.Psathyromyia (Psathyromyia) soccula Distribution. Costa Rica, Panama*.Psathyromyia (Psathyromyia) souzacastroi Distribution. Brazil*.Psathyromyia (Psathyromyia) undulata Distribution. Belize, Bolivia, Colombia, Costa Rica, Ecuador, El Salvador, French Guiana*, Guatemala, Honduras, Mexico, Panama.Psathyromyia (Psathyromyia) volcanensis Distribution. Bolivia, Costa Rica, Panama*.Xiphopsathyromyia) Ib\u00e1\u00f1ez-Bernal & Marina, 2015Subgenus (Psathyromyia (Xiphopsathyromyia) aclydifera Distribution. Belize, Bolivia, Colombia, Costa Rica, Ecuador, Guatemala, Honduras, Mexico, Nicaragua, Panama*.Psathyromyia (Xiphopsathyromyia) dreisbachi Distribution. Bolivia, Brazil*, Colombia, Ecuador, French Guiana, Peru, Surinam, Venezuela.Psathyromyia (Xiphopsathyromyia) hermanlenti Distribution. Brazil*.Psathyromyia (Xiphopsathyromyia) ruparupa Distribution. Bolivia, Peru*.PsathyromyiaincertaesedisPsathyromyiamaya Ib\u00e1\u00f1ez-Bernal, May-UC & Rebollar-Tellez, 2010Distribution. Mexico*.Viannamyia Mangabeira, 1941Genus Viannamyiacaprina Distribution. Colombia*, Costa Rica, Honduras, Panama, Peru, Nicaragua.Viannamyiafariasi Distribution. Brazil*, French Guiana.Viannamyiafurcata PageBreakDistribution. Bolivia, Brazil*, Colombia, Costa Rica, Ecuador, French Guiana, Peru, Venezuela.Viannamyiatuberculata Distribution. Bolivia, Brazil*, Colombia, French Guiana, Panama, Peru, Surinam, Venezuela.Martinsmyia Galati, 1995Genus alphabetica Fairchild, 1955Group Martinsmyiaalphabetica Distribution. Argentina, Brazil*, Paraguay.Martinsmyiabrisolai Distribution. Bolivia*, Brazil.Martinsmyiaminasensis Distribution. Brazil*.Martinsmyiamollinedoi Distribution. Bolivia*.Martinsmyiaoliveirai Distribution. Brazil*.Martinsmyiapisuquia Distribution. Peru*.Martinsmyiaquadrispinosa Distribution. French Guiana*.Martinsmyiareginae Carvalho, Brazil, Sanguinette & Andrade-Filho, 2010Distribution. Brazil*.Martinsmyiawaltoni Distribution. Brazil*.gasparviannai Young & Fairchild, 1974Group Martinsmyiacipoensis Distribution. Brazil*.Martinsmyiagasparviannai Distribution. Brazil*.Bichromomyia Artemiev, 1991Genus Bichromomyiaflaviscutellata Distribution. Bolivia, Brazil*, Colombia, Ecuador, French Guiana, Peru, Surinam, Trinidad and Tobago, Venezuela.Bichromomyiainornata Distribution. Bolivia, Brazil*.PageBreakNote. Several authors plus three males from Maranh\u00e3o that were identified as Bichromomyiainornata by the authors of the species, and all specimens have pale rather than dark scutellum, making this species indistinguishable from Bichromomyiaflaviscutellata. authors have menBichromomyiaolmecabicolor Distribution. Brazil, Colombia, Costa Rica, Ecuador, Panama*, Peru, Venezuela.Bichromomyiaolmecanociva Distribution. Brazil*, Peru.Bichromomyiaolmecaolmeca Distribution. Belize, Costa Rica, Guatemala, Honduras, Mexico*, Nicaragua.Bichromomyiareducta Distribution. Brazil, Colombia, Peru, Venezuela*.Psychodopygus Mangabeira, 1941Genus arthuri Barretto, 1962Series Psychodopygusarthuri Distribution. Brazil*.Psychodopyguslloydi Distribution. Brazil*.Psychodopygusmatosi Distribution. Brazil*.chagasi Barretto, 1962Series Psychodopygusbernalei Distribution. Bolivia, Brazil, Colombia*, Venezuela.Psychodopyguschagasi Distribution. Brazil*, Colombia, Peru, Venezuela.Psychodopyguscomplexus Distribution. Bolivia, Brazil*.Psychodopygusdouradoi Distribution. Brazil*.Psychodopygusfairtigi Distribution. Colombia*.Psychodopyguskillicki Distribution. Venezuela*.Psychodopygusleonidasdeanei Fraiha, Ryan, Ward, Lainson & Shaw, 1986PageBreakDistribution. Brazil*.Psychodopygussquamiventrismaripaensis Distribution. Brazil, French Guiana*, Surinam.Psychodopygussquamiventrissquamiventris Distribution. Brazil*, French Guiana, Peru, Venezuela.Psychodopyguswellcomei Fraiha, Shaw & Lainson, 1971Distribution. Brazil*, Venezuela.davisi Barretto, 1962Series Psychodopygusamazonensis Distribution. Bolivia, Brazil, Colombia, Ecuador, French Guiana, Peru*, Surinam, Trinidad and Tobago, Venezuela.Psychodopygusclaustrei Distribution. Bolivia, Brazil, Colombia, French Guiana*, Peru, Surinam, Venezuela.Psychodopygusdavisi Distribution. Bolivia, Brazil*, Colombia, Ecuador, French Guiana, Peru, Surinam, Venezuela.Psychodopygusparimaensis Distribution. Venezuela*.guyanensis Barretto, 1962Series Psychodopyguscorossoniensis Distribution. Brazil, Costa Rica, French Guiana*, Mexico, Panama, Surinam.Psychodopygusdorlinsis Distribution. French Guiana*.Psychodopygusfrancoisleponti Zapata, Depaquit & Le\u00f3n, 2012Distribution. Ecuador*.Psychodopygusgeniculatus Distribution. Belize, Bolivia, Brazil*, Colombia, Costa Rica, Ecuador, French Guiana, Guatemala, Panama, Peru, Nicaragua, Venezuela.Psychodopygusguyanensis Distribution. Belize, Colombia, Ecuador, French Guiana*, Peru, Surinam.Psychodopyguslainsoni Distribution. Bolivia, Brazil*, Peru.Psychodopygusluisleoni Le\u00f3n, Mollinedo & Le Pont, 2009Distribution. Ecuador*.panamensis Young & Fairchild, 1974Series Psychodopygusayrozai Distribution. Bolivia, Brazil*, Colombia, Ecuador, French Guiana, Panama Peru, Trinidad and Tobago, Venezuela.PageBreakPsychodopyguscarrerai Distribution. Bolivia, Brazil, Colombia*, Ecuador, Peru, Venezuela.Psychodopygusfairchildi Distribution. Brazil*.Psychodopygushirsutus Distribution. Bolivia, Brazil*, Colombia, Ecuador, French Guiana, Peru, Surinam.Psychodopygushirsutus Distribution. Bolivia, Brazil*, Colombia, Ecuador, French Guiana, Peru, Surinam.Psychodopygusjoliveti Le Pont, Le\u00f3n, Galati & Dujardin, 2009PageBreakDistribution. French Guiana*.Psychodopygusllanosmartinsi Fraiha & Ward, 1980Distribution. Bolivia, Brazil, Peru*.Psychodopygusnicaraguensis Distribution. Brazil, Panama, Nicaragua*.Psychodopygusnocticolus Distribution. Bolivia, Colombia*, Ecuador, French Guiana, Mexico, Panama, Peru.Psychodopyguspanamensis Distribution. Belize, Brazil, Colombia, Costa Rica, Ecuador, French Guiana, Guatemala, Honduras, Mexico, Nicaragua, Panama*, Peru, Surinam, Venezuela.Psychodopygusparaensis Distribution. Bolivia, Brazil*, Colombia, Ecuador, French Guiana, Peru, Surinam, Venezuela.Psychodopygusrecurvus Distribution. Colombia*, Panama.Psychodopygusthula Distribution. Colombia, Costa Rica, Ecuador, Honduras, Panama*.Psychodopygusyasuniensis Le\u00f3n, Neira & Le Pont, 2009Distribution. Ecuador*.Psychodopygusyucumensis Distribution. Bolivia*, Brazil, Peru.PsychodopygusincertaesedisPsychodopygusbispinosus Distribution. Belize, Brazil, Colombia, Costa Rica, Ecuador, French Guiana, Guatemala, Honduras, Mexico, Nicaragua, Panama*, Surinam.Nyssomyia Barretto, 1962Genus Nyssomyiaanduzei Distribution. Brazil, Costa Rica, French Guiana, Panama, Peru, Venezuela*.Nyssomyiaantunesi Distribution. Bolivia, Brazil*, Colombia, French Guiana, Peru, Surinam, Trinidad and Tobago, Venezuela.Nyssomyiabibinae Distribution. French Guiana*.Nyssomyiadelsionatali Galati & Galvis, 2012Distribution. Brazil*.Nyssomyiaedentula Distribution. Costa Rica, Guatemala*, Honduras, Panama.PageBreakNyssomyiaelongata Distribution. French Guiana*.Nyssomyiafraihai Distribution. Bolivia, Brazil*, Peru.Nyssomyiahernandezi Distribution. Colombia, Venezuela*.Nyssomyiaintermedia Distribution. Brazil*.Nyssomyianeivai Distribution. Argentina, Bolivia, Brazil*, Paraguay.Nyssomyiapajoti Distribution. Brazil, Colombia, French Guiana*, Peru, Surinam.Nyssomyiarichardwardi Distribution. Bolivia, Brazil*, Colombia, Ecuador, Peru.Nyssomyiashawi Distribution. Bolivia, Brazil*, Colombia, Peru.Nyssomyiasylvicola Distribution. Brazil, French Guiana*.Nyssomyiatrapidoi Distribution. Colombia, Costa Rica, Ecuador, Guatemala, Hounduras, Nicaragua, Panama*.Nyssomyiaumbratilis Distribution. Bolivia, Brazil*, Colombia, French Guiana, Peru, Surinam, Venezuela.Nyssomyiaurbinatti Galati & Galvis, 2012Distribution. Brazil*.Nyssomyiawhitmani Distribution. Argentina, Bolivia, Brazil*, French Guiana, Paraguay, Peru, Surinam.Nyssomyiaylephiletor Distribution. Belize, Colombia, Costa Rica, Ecuador, Guatemala, Honduras, Mexico, Nicaragua, Panama*.Nyssomyiayuilli Distribution. Bolivia, Brazil, Colombia*, Ecuador, Peru, Venezuela.Trichophoromyia Barretto, 1962Genus Trichophoromyiaacostai Distribution. Peru*.Trichophoromyiaadelsonsouzai Santos, Silva, Barata, Andrade & Galati, 2013Distribution. Brazil*.Trichophoromyiaarevaloi Galati & C\u00e1ceres, 1999Distribution. Peru*.Trichophoromyiaauraensis Distribution. Bolivia, Brazil*, Colombia, Peru, Surinam, Venezuela.PageBreakTrichophoromyiabeniensis Distribution. Bolivia*.Trichophoromyiabettinii Distribution. Colombia, Venezuela*.Trichophoromyiabrachipyga Distribution. Brazil*, French Guiana.Trichophoromyiacastanheirai Distribution. Brazil*.Trichophoromyiacellulana Distribution. Colombia*, Ecuador.Trichophoromyiaclitella Distribution. Brazil, Peru*.Trichophoromyiadunhami Distribution. Brazil*.Trichophoromyiaeurypyga Distribution. Brazil*, Venezuela.Trichophoromyiaflochi Distribution. Brazil, French Guiana*.Trichophoromyiagibba Distribution. Brazil*.Trichophoromyiahowardi Distribution. Brazil, Colombia*, Peru.Trichophoromyiaincasica Distribution. Peru*.Trichophoromyiaininii Distribution. Brazil, French Guiana*, Surinam.Trichophoromyialopesi Distribution. Brazil*.Trichophoromyialoretonensis Distribution. Brazil, Peru*.Trichophoromyiameirai Distribution. Brazil*.Trichophoromyiamelloi Distribution. Brazil*, Surinam.Trichophoromyianapoensis Distribution. Ecuador*.Trichophoromyianautaensis Distribution. Peru*.Trichophoromyianemorosa Distribution. Peru*.Trichophoromyiaoctavioi Distribution. Bolivia, Brazil*, Peru.Trichophoromyiaomagua PageBreakDistribution. Peru*.Trichophoromyiapabloi Distribution. Colombia*, Ecuador.Trichophoromyiapastazaensis Distribution. Peru*.Trichophoromyiareadyi Distribution. Brazil*.Trichophoromyiareburra Distribution. Colombia, Costa Rica, Ecuador, Panama*.Trichophoromyiareinerti Distribution. Brazil*.Trichophoromyiarostrans Distribution. Brazil*.Trichophoromyiaruifreitasi Oliveira, Teles, Medeiros, Camargo & Pessoa, 2015Distribution. Brazil*.Trichophoromyiaruii Distribution. Brazil*, Colombia.Trichophoromyiasaltuosa Distribution. Colombia*.Trichophoromyiasinuosa Distribution. Peru*.Trichophoromyiaubiquitalis Distribution. Bolivia, Brazil*, Colombia, Ecuador, French Guiana, Peru, Surinam, Venezuela.Trichophoromyiauniniensis Ladeia-Andrade, F\u00e9, Sanguinette & Andrade-Filho, 2014Distribution. Brazil*.Trichophoromyiavelascoi Distribution. Bolivia*.Trichophoromyiaviannamartinsi Distribution. Brazil*.Trichophoromyiawilkersoni Distribution. Ecuador*.Edentomyia Galati, Andrade-Filho, Silva & Falc\u00e3o, 2003Genus Edentomyiapiauiensis Galati, Andrade-Filho, Silva & Falc\u00e3o, 2003Distribution. Brazil*.Nomina dubia in New World PhlebotominaePageBreakNyssomyiasingularis Distribution. Brazil*.Note. This species is only known from the type specimen mounted in Canada Balsam medium. The specimen \u201ccotype\u201d is deposited in the Cole\u00e7\u00e3o Entomol\u00f3gica do Instituto Oswaldo Cruz (FIOCRUZ/CEIOC) (number of the slides: 1436\u20131439). The specimen was collected in 08-VIII-1902 by Adolpho Lutz in Juqueri state of S\u00e3o Paulo, Brazil. One of us (AJA) studied the type and observed that the thorax is damaged, but it is possible to observe the colour of the paratergite and scutum, which is similar to species in the genus Nyssomyia. The spermathecae was dissected, but was not observed in any of the slides, so it is likely the spermathecae has oxized over time. The original description is insufficient for a positive identification, however the spermathecae as illustrated show the same number of rings as Nyssomyianeivai In the absence of evidence positively linking the two species, however, we prefer to consider Nyssomyiasingularis as a nomen dubium.Phlebotomusbreviductus Barretto, 1950Note. Only known from the holotype and five females collected by Trichopygomyia sp. specimen, whereas the thorax and abdomen belong to an anomalous specimen of Nyssomyiaumbratilis.Phlebotomusoliverioi Barretto & Coutinho, 1941Note.Psychodopygus while the wings, thorax and abdomen belong to another specimen, of the genus Psathyromyia.Micropygomyia (Sauromyia) sp. 2 of Araracuara Distribution. Colombia*.Note. Unavailable according to article 11.4 of the ICZN. This species has been described from both males and females, but the authors decided not to name it.Lutzomyia (Helcocyrtomyia) sp. of Pichinde Young, 1979Distribution. Colombia*.Note. Unavailable according to article 11.4 of the ICZN. This species has been described from both males and females. Lutzomyia (Helcocyrtomyia) hartmanni and Lutzomyia (Helcocyrtomyia)PageBreakscorzai, but noted that further studies were necessary before formally naming this species.Pintomyia sp. of Anchicaya Distribution. Colombia*.Note. Unavailable according to article 11.4 of the ICZN. This species has been described form a single male, but Dampfomyia sp. of Suchitepequez Distribution. Guatemala*.Note. This species appears as an illustration in Lutzomyiapiedraferroi. However, Dampfomyia sp. of Suchitepequez, and it awaits formal description.Pressatia #1 Mangabeira, 1942Distribution. Bolivia*, Colombia.Note. Unavailable according to article 11.4 of the ICZN. This species is listed by Evandromyia (Aldamyia) sp. of Baduel Distribution. Brazil, Colombia, French Guiana*, Surinam.Note. Unavailable according to article 11.4 of the ICZN. This species has been described from both males and females. Although this species has been recorded in different publications, no attempt has been made so far to formally describe it.Psychodopygus sp. of Tr\u00e9s Esquinas Distribution. Colombia*.Note. Unavailable according to article 11.4 of the ICZN. This species has been described only from females. Because females of the series guyanensis are indistinguishable in morphology, it is not possible to know if this species has been previously described from a male.Trichophoromyia sp. 1 of Araracuara Distribution. Colombia*.Note. Unavailable according to article 11.4 of the ICZN. This species has been described from both males and females. However, the authors were not sure if it was a variant of Trichophoromyiahowardi Young, 1979, and hence decided not to name it."} +{"text": "Zinaida were assigned to the genus Polytremis, until molecular evidence revealed that the former is a distinct genus. Nine species in Polytremis sensu Evans have since been removed and assigned to Zinaida; however, there is still uncertainty as to the taxonomic status of an additional seven Polytremis species. Moreover, the interspecific relationships within Zinaida have remained unresolved. To further investigate the taxonomic statuses and interspecific relationships within Zinaida, a molecular phylogeny of most species of Zinaida and its allies was inferred based on regions of the mitochondrial COI-COII and 16S and nuclear EF-1\u03b1 genes (3006 bp). The results revealed that Zinaida is monophyletic and consists of four intra-generic clades that correspond to morphological characteristics. Clade A (Z. suprema group) consists of P. kiraizana, Z. suprema, and P. gigantea, with the latter two as sister species. Clade B (Z. nascens group) consists of seven species, and is the sister group of Clade C (Z. pellucida group), which comprises sister species Z. pellucida and Z. zina. In Clade B, Z. caerulescens and Z. gotama, and Z. theca and Z. fukia are sister species, respectively. On the basis of our molecular evidence and morphological features, we have moved P. gigantea, P. kiraizana, P. jigongi, and P. micropunctata to the genus Zinaida as new combinations. We review morphological characteristics and discuss the distribution of each of these groups in the light of our phylogenetic hypothesis, and provide a comprehensive taxonomic checklist.Traditionally, species of the genus Polytremis sensu Evans (1949), has attracted researchers\u2019 attention . Clade C consists of Z. pellucida and Z. zina, and is strongly supported in our analyses. The remaining eight species were included in Clade B, and relationships between some of these species were well resolved; for example, Z. gotama is sister to Z. caerulescens, and Z. jigongi is sister to Z. nascens.Clade A consists of Zinaida and its allies revealed four distinct clades that are consistent with their external features, although the relationships between the four groups were not entirely clarified.The phylogenetic framework including nearly all the species of the genus Z. suprema group is strongly supported. These species share the following synapomorphies: (1) aedeagus with suprazonal sheath bifurcated into serrated symmetrical processes (processes asymmetric in Z. matsuii), and (2) cornuti absent forewing with two cell spots, lower one wedge-shaped, pointing toward wing base , further study is necessary to confirm its association with this clade.In this study, the monophyly of the i absent . Z. supreristics . This sping base : 1\u20134; , the Z. nascens group, within which P. jigongi is also nested. This analysis also revealed that P. caerulescens and Z. gotama are sister species, and placed P. jigongi as a sister to Z. nascens. Accepting the conclusion of Jiang et al. [[1: 144.] Polytremis fukia: Jiang (ed), 2016 [d), 2016 .Zinaida theca fukia: Fan et al., 2016 [Specimens examined: 1\u2642 (He009), Nanling, Guangdong. 2003-VII-13, Min Wang; 5\u26421\u2640, Maoershan, GuangXi, 2003-VII-01, leg. MinWang and Guohua Huang.Distribution: Zhejiang, Anhui, Hubei, Hunan, Fujian, Jiangxi; Guangdong, Guangxi, Sichuan.b. Zinaida fukia macrotheca comb. nov.Polytremis theca macrotheca Huang, 2003: 40 [2003: 40 (Type loDistribution: Yunnan (Nujiang).8. Zinaida gotama Polytremis gotama Sugiyama, 1999: 12\u201314 [9: 12\u201314 , Luguhu, Yunnan, 2003-VIII-13, leg. Xiaoling Fan and Min Wang; 4\u2642, 3\u2640, same data as the former.Specimens examined: 1\u2642 comb. nov.Polytremis jigongi Zhu, 2012 [hu, 2012 comb. nov.Polytremis micropunctata Huang, 2003: 41\u201342 [3: 41\u201342 Pamphila mencia Moore, 1877: 52 [1877: 52 , Lushan, Jiangxi, 2007-VII-24, leg. Xiaoling Fan and Min Wang; 1\u2642, Jiujiang, Jiangxi, 1982-V.Distribution: Jiangsu, Shanghai, Zhejiang, Anhui, Fujian, Hunan, Jiangxi, Sichuan.12. Zinaida caerulescens Pamphila caerulescens Mabille, 1876: 1v [1876: 1v , Baoxing County, Sichuan, 2003-VII-30, leg. Xiaoling Fan and Min Wang; 1\u2642, same data as the former.Distribution: Chongqing, Sichuan, Guizhou, Yunnan, Xizang.Z. pellucida group13. Zinaida pellucida a. Zinaida pellucida pellucida Pamphila pellucida Murray, 1874: 172 [874: 172 , Kumamoto, Japan, 2010-IV-31, leg. Hideyuki Chiba; 1\u2642, Aichi, Seto, Japan, 1999-VIII-13. Leg. Masao Yamanaka.Distribution: North Korea, Japan, Russia.b. Zinaida pellucida quanta Polytremis pellucida quanta Evans, 1949: 445 [949: 445 Polytremis pellucida inexpecta Tsukiyama, Chiba & Fujioka, 1997 [ka, 1997 a. Zinaida zina zina Baoris zina Evans, 1932: 416 [932: 416 , Nanling National Natural Reserve, Ruyuan County, Guangdong, 2003-V, leg. Xiaoling Fan; 2\u2642, 2\u2640, Nanling National Natural Reserve, Ruyuan County, Guangdong, 1997-V, leg. Min Wang; 1\u2642, Yingde, Guangdong, 2003-VI-13, leg. Guohua Huang; 2\u2642, Maoershan, Xinan county, Guangxi, 2003-VII-6, leg. Min Wang and Guohua Huang.Distribution: Heilongjiang, Jilin, Liaoning, Gansu, Shaanxi, Henan, Anhui, Zhejiang, Sichuan, Hunan, Jiangxi, Fujian, Guangxi, Guangdong. North Korea, South Korea, Russia (S. Ussuri).b. Zinaida zina asahinai comb. nov.Polytremis pellucida asahinai Shir\u00f4zu, 1952: 13 [1952: 13 , Taipei, Taiwan, 2014-V; 1\u2642, Taoyuan, Taiwan, 1988-VI-27, leg. Yufeng Hsu.Distribution: Taiwan.S1 Table(DOCX)Click here for additional data file.S2 TableThe best model was selected under a Bayesian Information Criterion (BIC) in W-IQ-TREE.(DOCX)Click here for additional data file.S1 Fig(A) adult; (B) male genitalia.(TIF)Click here for additional data file.S2 Fig(A) upperside; (B) underside.(TIF)Click here for additional data file."} +{"text": "Reason for Corrigendum:The first three authors Naveen Ramalingam, Brian Fowler, and Lukasz Szpankowski contributed equally to this work.Cate Larsen (author) was missed in the original list.Corrected/new list\u2020, Brian Fowler\u2020, Lukasz Szpankowski\u2020, Anne A. Leyrat, Kyle Hukari, Myo Thu Maung, Wiganda Yorza, Michael Norris, Chris Cesar, Joe Shuga, Michael L. Gonzales, Chad D.\u2009Sanada, Xiaohui Wang, Rudy Yeung, Win Hwang, Justin Axsom, Naga Sai Gopi Krishna Devaraju, Ninez Delos Angeles, Cassandra Greene, Ming-Fang Zhou, Eng-Seng Ong, Chang-Chee Poh, Marcos Lam, Henry Choi, Zaw Htoo, Leo Lee, Chee-Sing Chin, Zhong-Wei Shen, Chong T. Lu, Ilona Holcomb, Aik Ooi, Craig Stolarczyk, Tony Shuga, Kenneth J. Livak, Cate Larsen, Marc Unger and Jay A. A. West*Naveen Ramalingam\u2020Equal contribution.The original article has been updated.NR, BF, JS, and JAAW conceived and designed the RNA-based performance test; BF, LS, AAL, JS, and JAAW conceived and designed the single-cell-based performance test; NR, LS, AAL, JS, MLG, CDS, NDA, CG, CTL, IH, AO, CS, and JAAW performed experiments; BF, NSGKD, MZ, EO, and CP were involved in Polaris IFC development; KH, MTM, WY, MN, CC, ML, HC, ZH, LL, CC, and ZS were involved in Polaris system development; RY, WH, JA, and ZH were involved in Polaris software development; NR, LS, JS, CDS, XW, and JAAW analyzed the data; TS edited the manuscript; CL drafted the Polaris user guide; MU and JAAW supervised the project, helped with design and interpretation, and provided laboratory space and financial support; and NR, LS, KJL, and JAAW wrote the manuscript with input from all authors. All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.All authors are employees of Fluidigm Corporation."} +{"text": "Scientific Reports 10.1038/s41598-017-06912-7, published online 27 July 2017Correction to: The original version of this Article contained errors in the spelling of the authors Massimo Moro, Giulia Bertolini, Roberto Caserini, Cristina Borzi, Mattia Boeri, Alessandra Fabbri, Giorgia Leone, Patrizia Gasparini, Carlotta Galeone, Giuseppe Pelosi, Luca Roz, Gabriella Sozzi & Ugo Pastorino which were incorrectly given as Moro Massimo, Bertolini Giulia, Caserini Roberto, Borzi Cristina, Boeri Mattia, Fabbri Alessandra, Leone Giorgia, Gasparini Patrizia, Galeone Carlotta, Pelosi Giuseppe, Roz Luca, Sozzi Gabriella & Pastorino Ugo respectively.These errors have now been corrected in the PDF and HTML versions of the Article, and in the accompanying Supplementary Information file."} +{"text": "Cryptosporidium parvum. PLoS ONE 13(3): e0194058. https://doi.org/10.1371/journal.pone.0194058.The third, fourth, fifth, sixth, seventh, and eighth authors\u2019 names are incorrect. The correct author list is: Jie Bai, Xin Liu, Laetitia Le Goff, Gilles Gargala, Arnaud Fran\u00e7ois, Jean Jacques Ballet, Phillipe Ducrotte, Loic Favennec, Liqianhai Towledahong. The correct citation is: Bai J, Liu X, Le Goff L, Gargala G, Fran\u00e7ois A, Ballet JJ, et al. (2018) Octreotide modulates the expression of somatostatin receptor subtypes in inflamed rat jejunum induced by"} +{"text": "Cohen,a William J. Sandborn,b Gary R. Lichtenstein,c Jeffrey Axler,d Robert H. Riddell,e Cindy Zhu,f Andrew C. Barrett,f Enoch Bortey,f William P. ForbesfDavid T. Rubin,aInflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA bDivision of Gastroenterology, University of California [UC] San Diego and UC San Diego Health System, San Diego, CA, USA cDivision of Gastroenterology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA dToronto Digestive Disease Associates, Toronto, ON, Canada eDepartment of Pathology and Laboratory Medicine, Mt Sinai Hospital, Toronto, ON, Canada fSalix Pharmaceuticals, Raleigh, NC, USA10.1093/ecco-jcc/jjx032doi:n value for patients randomised to treatment in Figure 1.This article has been updated to correct an error to the"} +{"text": "Biomolecules would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016. The editors of https://publons.com) to receive recognition. Of course, in these intiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make. We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (Biomolecules, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Biomolecules in 2016:The following reviewed for Akhtar, NahidMaraia, RichardAndersen, MortenMcDougall, GordonArnhold, JuergenMomparler, RichardAskarian-Amiri, Marjan E.Mondrag\u00f3n, AlfonsoBai, BaoyanMorris, Andrew J.Bailey, Shannon M.Nandi, SaikatBell, AndrewOcampo Daza, DanielBernhardt, Harold S.Parnetti, LucillaBodet, CharlesPashov, AnastasBujnicki, JanuszPayne, AnnetteBurchell, JoyPeitzsch, ClaudiaCabrera-Fuentes, HectorPerego, CarlaCampos, FranciscoPochet, NathalieCarreras Puigvert, JordiPolanco, Juan CarlosChang, Yu-SunPoluektova, LarisaChia, JoannePruijn, Ger J.M.Depamphilis, MelvinPy, BeatriceDeutscher, MurrayRamakrishnan, SadeeshDimitroff, Charles J.Reis, Celso AlbuquerqueDohmen, R. JurgenRibeiro, C\u00e9sar Augusto Jo\u00e3oDunckley, TravisRobbe-Masselot, CatherineFan, ChenguangRomani, AndreaGarbar, ChristianRudiger, StefanGendler, SandraSancho-Bru, PauGerwig, Gerrit J.Sardiello, MarcoGeuns, Jan M.C.Sarkar, SibajiGoodarzi, AaronSaunthararajah, YogenGorgoulis, Vassilis G.Schmidt, ThomasHahn, Noah M.Schmidtke, GunterHan, Dong WookSchmitz, GerdHarrington, CharlesSchoner, WilhelmHartmann, RolandSeligmann, Herv\u00e9Hernandez, FelixShi, PatriciaHirata, AkiraShigi, NaokiHisanaga, Shin-ichiShukla, Shivendra D.Hofmann, Bianca T.\u0160imi\u0107, GoranHoward, Michael J.Soll, DieterIntaglietta, MarcosStathopoulos, ConstantinosJackman, Jane E.Stewart, JasonJacob, FrancisTempera, ItaloJarrous, NayefTigyi, G\u00e1bor J.Jongco, ArtemioT\u00f6r\u00f6k, MariannaKang, Gyeong HoonTran, DuyKang, WeiTsuzuki, TakashiKeegan, Kirk A.Van Vliet, SandraKnepper, JaniceVioque, AgustinKrasilnikov, Andrey S.Wang, Qi-enLagger, SabineWesterlind, UlrikaLamas, Jos\u00e9 Ram\u00f3nWilks, AngelaLaRoque, JanYamashita, KatsukoLehmann, JeanYukl, Erik T.Li, ZhongweiZahr, Natalie M.Lippens, GuyZhao, XiaolanLiu, Chia-ChiZiebuhr, WilmaLu, JianZweckstetter, Markus"} +{"text": "AbstractCynipoidea is revised, considerably updating the last complete checklist published in 1978. Disregarding uncertain identifications, 220 species are now known from Britain and Ireland, comprising 91 Cynipidae (including two established non-natives), 127 Figitidae and two Ibaliidae.The British and Irish checklist of replacement name is proposed, Kleidotomathomsoni Forshage, for the secondary homonym Kleidotomatetratoma Thomson, 1861 ).One Hymenoptera checklists that started with This paper continues the series of updated British and Irish Cynipoidea is a rather diverse superfamily of three British families . The Figitidae and Ibaliidae comprise koinobiont endoparasitoids of other insects whereas the Cynipidae are gall-formers, or inquilines of gall-formers. A summary of cynipoid biology can be found in Figitidae are parasitoids of Diptera larvae although the Charipinae are hyperparasitoids of primary parasitoids in aphids and some other Homoptera and the Anacharitinae are parasitoids of Hemerobiidae (Neuroptera); the small family Ibaliidae are specialised parasitoids of Siricidae larvae; and the Cynipidae are entirely phytophagous, most conspicuously as gall-formers of oaks (Quercus) but with numerous species galling other Rosaceae (and a few other plants) and the tribe Synergini are inquilines of other cynipid galls. A few representative Cynipoidea are illustrated in Figs The Cynipidae checklist was updated comparatively recently have received a certain amount of attention over the years and are studied and recorded under the auspices of the British Plant Gall Society. The numbers of valid, certainly identified Cynipoidea are listed by family and country in Table The British recently and IrisWe reference all additions to and deletions from the 1978 British list and recoBecause the agamic and sexual generations of cynipids are sometimes referred to by different names, these are differentiated in the checklist. The following conventions and abbreviations are used:species] taxon deleted from the British and Irish list and nomina dubia Added by Added by quercusradicis. No recent records. Quercusaegilops, and never established. First recorded from old galls by [quercustozae -a-] Added by Added by Recorded by Both generations reported by quercusfolii. There are no subsequent records and the species requires confirmation as British. Described by Recorded by Galls recorded from Norfolk and Surrey by Aulacideafollioti which also galls Sonchusasper EnglandGalls recorded in Norfolk and Derbyshire by Timaspislusitanica Tavares, 1904Englandadded by Jennings (2005)Latreille, 1802RHODITINI Hartig, 1840Geoffroy, 1762RHODITES Hartig, 1840HOLOLEXIS F\u00f6rster, 1869TRIBALIA Walsh, 1864LYTORHODITES Kieffer, 1902NIPPORHODITES Sakugami, 1949Rhoditeseglanteriae Hartig, 1840rufipesHololexis) Rhoditesmayri Schlechtendal, 1877orthospinaeRhodites) Cynipsnervosa Curtis, 1838centifoliaeRhodites) synonymy by Pujade-Villar and Plantard (2002) Cynipsrosae Linnaeus, 1758bedeguaris Fourcroy, 1785England, Scotland, Wales, Ireland, Isle of ManRhoditesspinosissimae Giraud, 1859rosae-spinosissimaeCynips) Synergusconnatus Hartig, 1840erythroneurusSynergus) ] Added by umbraculus Cynipscrassicornis Curtis, 1838evanescens Mayr, 1872fidelis Tavares, 1920carinulatus Dettmer, 1924England, Wales, IrelandHartig, 1840gallaepomiformis misident.England, Scotland, Wales, IrelandS.gallaepomiformis in Britain but it was shown in Saphonecrus) and the widespread species should be called facialis. gallaepomiformis should be retained as the valid name but did not make an application to ICZN to overturn the type designation of gallaepomiformis.This species has hitherto been known as Hartig, 1840bipunctatus Hartig, 1841crassicornis Hartig, 1843 preocc.England, Scotland, Wales, IrelandHartig, 1841pallidicornis Dalla Torre, 1893England, Wales, IrelandMayr, 1872England, WalesHartig, 1840flavicornis Hartig, 1840nervosus Hartig, 1840nigripes Hartig, 1840albipes Hartig, 1841erythrocerus Hartig, 1841variolosus Hartig, 1841varius Hartig, 1841xanthocerus Hartig, 1841tscheki Mayr, 1872tristis Mayr, 1873hartigi Giraud, 1911fulvipes Dettmer, 1924mutabilis Dettmer, 1924England, Wales, IrelandMayr, 1872EnglandMayr, 1872England, Scotland, Wales, IrelandHartig, 1840England, IrelandCynipsthaumacera Dalman, 1823klugii Hartig, 1840carinatus Hartig, 1841testaceusXystus) Diplolepisumbraculus Olivier, 1791gallaeumbraculataeDiplolepis) PROANACHARITINAE Kovalev, 1979 synonymy by Ronquist (1999)Synonymy follows Haliday in Walker, 1835Fergusson, 1985England, Irelandadded by Fergusson (1985)Cynipsnitidula Dalman, 1823fumipennisAnacharis) Fergusson, 1985England, Scotlandadded by Fergusson (1985)Dalman, 1823MEGAPELMUS Hartig, 1840SYNAPSIS F\u00f6rster, 1869 preocc.PROSYNAPSIS Dalle Torre & Kieffer, 1910tinctus Walker, 1835typica Walker, 1835petiolataCynips) Aegilipsarmatus Giraud, 1860abietinaAegilips) Tenthredoscutellata Villers, 1789ediogasterEvania) Kieffer, 1907 nom. nud. Amblynotusmicrocerus Kieffer, 1903England, IrelandScytodesopacus Hartig, 1840femoralis Cameron, 1883England, IrelandGiraud, 1860rufipes F\u00f6rster, 1869biustaOmalaspis) Tavaresiacarinata Kieffer, 1901WalesDalla Torre & Kieffer, 1910ALLOTRIINAE Thomson, 1862 unavailableALLOXYSTINAE Hell\u00e9n, 1931DILYTINI Kierych, 1979LYTOXYSTINAE Kovalev, 1994Alloxystini was paraphyletic with respect to Charipini. Some Welsh occurrence records from Except where noted, nomenclature follows F\u00f6rster, 1869ALLOTRIA Westwood, 1833 preocc.XYSTUS Hartig, 1840 preocc.PEZOPHYCTA F\u00f6rster, 1869NEPHYCTA F\u00f6rster, 1869ADELIXYSTA Kierych, 1988CARVERCHARIPS Kovalev, 1994Alloxysta species for Britain and Ireland, which Alloxysta excluded from the British and Irish list:species of flavicornis incertae sedis][These species were listed by Alloxysta species of uncertain status:ignorata nom. dub.] Listed by macrophadnus, the type material of ignorata has not been located and it has not been possible to interpret the name Hell\u00e9n, 1963Englandbrachyptera by apteroidea, although the true brachyptera has also been found in Silwood Park.Det. Van Veen, added here. The species identified as Allotriaarcuata Kieffer, 1902minuta misident.ligustri Evenhuis, 1976Scotland, Walesbrevis by Raised from synonymy with Allotriabasimacula Cameron, 1886caledonicaAllotria) Xystusbrachypterus Hartig, 1840England, Scotland, Wales, IrelandAllotriabrevis Thomson, 1862minuta misident.EnglandXystuscastaneus Hartig, 1841melanogaster misident.maculicollisAllotria) preocc. Kieffer, 1902 (rubricepsAllotria) Xystuscircumscriptus Hartig, 1841Englandvictrix by Synonymised under Allotriacitripes Thomson, 1862britannicaAlloxystacitripes var.) Kieffer, 1902 England, WalesCynipsconsobrina Zetterstedt, 1838fuscicornisXystus) synonymy by Ferrer-Suay et al. (2013b) Allotriacrassa Cameron, 1889Scotlandmacrophadnus by Raised from synonymy with Xystuscursor Hartig, 1840castaneaPezophycta) preocc. Xystuserythrothorax Hartig, 1840trapezoidea misident.defectaXystus) Allotriahalterata Thomson, 1862Englandpedestris by Synonymised under Xystusleunisii Hartig, 1841England, Walesadded by Van Veen et al. (2003)Xystusmacrophadnus Hartig, 1841testacea misident.aptera misident.brachyptera misident.fuscipes misident.nigriventris misident.macrophadna misspellingfilicornisAllotria) Kieffer, 1902 Nephyctamarshalliana Kieffer, 1900Scotlandmacrophadna by Synonymised under Allotriamullensis Cameron, 1883Scotlandbrevis by Raised from synonymy with Allotrianigrita Thomson, 1862Walesadded by Baker (2013)Xystusobscuratus Hartig, 1840homotomaAlloxystaullrichi var.) Kieffer, 1904 Cynipspallidicornis Curtis, 1838minutaCynips) Cynipspedestris Curtis, 1838England, Wales, IrelandAllotriapiceomaculata Cameron, 1883Scotland, Walesmacrophadnus by Raised from synonymy with Xystuspilipennis Hartig, 1840flavicornisXystus) synonymy by Ferrer-Suay et al. (2014) has seen English material.Allotriapleuralis Cameron, 1879unicolorAlloxystapusilla var.) Allotriapusilla Kieffer, 1902Englandadded by Sanders and Van Veen (2010)Allotriaramulifera Thomson, 1862minutaXystus) Fergusson, 1986England, Irelandadded by Fergusson (1986)Allotriatscheki Giraud, 1860EnglandExcluded from the British and Irish list by Allotriavictrix Westwood, 1833fulvicepsCynips) nom. nud. Xystustrapezoideus Hartig, 1841xanthocephalaAllotria) synonymy by Paretas-Mart\u00ednez et al. (2011) as a synonym of Phaenoglyphis, it was then raised from synonymy by Phaenoglyphis by Allotriadolichocera Cameron, 1889England, IrelandXystuslongicornis Hartig, 1840WalesAlloxysta, not mentioned by Listed by Hemicrisisruficornis F\u00f6rster, 1869England, WalesPhaenoglyphispubicollis was resurrected as a valid species by pubicollis \u2018is only represented by type material\u2019, implying that the real ruficornis is the widespread one.Allotriasalicis Cameron, 1883forticornis Cameron, 1888England, WalesXystusvillosus Hartig, 1841picicepsAllotria) Eucoilacurta Giraud, 1860EnglandEucoiladepilis Giraud, 1860incrassataCothonaspis) auctt., sensu Cameron .Supposed English specimens in BMNH are all Thomson, 1862Westwood, 1833EUCOELA Agassiz, 1846LYTOSEMA Kieffer, 1901PSILODORA F\u00f6rster, 1869Westwood, 1833boyeniiCothonaspis) Cothonaspismaculatus Hartig, 1840guerini Dahlbom, 1842brevialata Belizin, 1973England, ScotlandF\u00f6rster, 1869Synonymy from Cothonaspisclavipes Hartig, 1841BMNH, det. Forshage, added here.Eucoelafimbriata Kieffer, 1901xanthoneuraEpisoda) sensuQuinlan (1978b) nec preocc. Eucoilaheterotoma Thomson, 1862?mustiXystus) Cothonaspislongipes Hartig, 1841EnglandBMNH, det. Forshage, added here.F\u00f6rster, 1869EPISODA F\u00f6rster, 1869 synonymy by Nordlander (1980)IDIOMORPHA F\u00f6rster, 1869HYPOLETHRIA F\u00f6rster, 1869PSICHACRA F\u00f6rster, 1869ADIERIS F\u00f6rster, 1869PIEZOBRIA F\u00f6rster, 1869PILINOTHRIX F\u00f6rster, 1869ANECTOCLIS F\u00f6rster, 1869TrybliographaCOTHONASPIS auctt. nec Hartig, 1840DIMICROSTROPHIS Ashmead, 1886DUSMETIOLA Tavares, 1924TrybliographaEUCOILA auctt. nec Westwood, 1835PSEUDEUCOILA Ashmead, 1903Trybliographa are present in Britain and several new synonymies will result from MF\u2019s unpublished revision. Some changes have been made in anticipation of this publication as they affect names described from British specimens.Synonymy mostly from Trybliographa excluded from the British and Irish list:species of testaceipes Cameron, 1883] This name will be placed in synonymy. Recorded from Britain in Fauna Europaea Figitesciliaris Zetterstedt, 1838melanopoda Cameron, 1888England, ScotlandTrybliographa but published as a new combination in Kleidotoma by Fauna Europaea Cothonaspisniger Hartig, 1840crassiclava Cameron, 1888nigripes Cameron, 1888brevicornisRhynchasis) Eucoilapygmea Dahlbom, 1842England, IrelandCameron, 1886England, ScotlandCameron, 1880England, ScotlandFigitessubaptera Walker, 1834helgolandicaAgroscopa) . Thomson, 1861 preocc. Name preoccupied by England, Scotland, IrelandEucoilatomentosa Giraud, 1860anisomeraAphiloptera) Cothonaspisheptomus Hartig, 1840biscapusCothonaspis) Cothonaspisvillosus Hartig, 1840England, Wales, IrelandBMNH, det. Forshage, added here.Benoit, 1956BMNH, det. Forshage, added here. Only a single male specimen has been found amongst British material; it is not identifiable to species level with our current state of knowledge, and is listed here as a record of the genus from Britain.Hartig, 1840Melanips has been transferred to Aspicerinae by Synonymy follows Hartig, 1840AMPHITECTUS misspellingSarothrus by Removed from synonymy with Sarothrusareolatus Hartig, 1840dahlbomii Hartig, 1840piceusFigites) nom. nud. Cynipsscutellaris Rossi, 1794ruficornisCynips) Figitesmaculipennis Dahlbom, 1842England, IrelandHartig, 1840Cynipstibialis Zetterstedt, 1838canaliculatus Hartig, 1840silesiacusOmalaspoides) Figitesclavatus Giraud, 1860Wales, Irelandadded by Fergusson (1986)F\u00f6rster, 1869DICERAEA F\u00f6rster, 1869THYREOCERA Ashmead, 1887Figitesurticeti Dahlbom, 1842heteropterusPsilogaster) Ichneumonleucospoides Hockenwarth, 1785cultellatorIchneumon) (Fabricius, 1793, ensiger Norton, 1862suprunenkoi Jacobson, 1899gigantea Yoshimoto, 1970EnglandCresson, 1879drewseni Borries, 1891shirmeri Dalla Torre & Kieffer, 1910England, ScotlandSupplementary material 1CynipoideaChecklist of the British and Irish Data type: formatted textBrief description: Word document version of the checklistFile: oo_124446.docxForshage, M., Bowdrey, J.P., Spooner, B.M., Van Veen, F. & Broad, G.R.Supplementary material 2CynipoideaChecklist of British and Irish Data type: spreadsheetBrief description: Excel spreadsheet version of the checklistFile: oo_124447.xlsxForshage, M., Bowdrey, J.P., Spooner, B.M., Van Veen, F. & Broad, G.R."} +{"text": "Scientific Reports5: Article number: 1537110.1038/srep15371; published online: 10192015; updated: 09072016The original version of this Article contained errors in the spelling of the authors Hiromitsu Shirasawa, Jin Kumagai, Emiko Sato, Katsuya Kabashima, Yukiyo Kumazawa, Wataru Sato, Hiroshi Miura, Ryuta Nakamura, Hiroshi Nanjo, Yoshihiro Minamiya, Yoichi Akagami and Yukihiro Terada, which were incorrectly given as Shirasawa Hiromitsu, Kumagai Jin, Sato Emiko, Kabashima Katsuya, Kumazawa Yukiyo, Sato Wataru, Miura Hiroshi, Nakamura Ryuta, Nanjo Hiroshi, Minamiya Yoshihiro, Akagami Yoichi and Terada YukihiroIn addition, the \u2018How to cite this article\u2019 section quoted an incorrect abbreviation for Hiromitsu Shirasawa. These errors have now been corrected in the PDF and HTML versions of the Article."} +{"text": "Scientific Reports6: Article number: 3904310.1038/srep39043; published online: 12232016; updated: 04052017Affiliation 1 was incorrectly listed as \u2018Group of Clinical Genomic Networks, Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Shanghai 200031, P.R. China\u2019 in the original version of the Article. The correct affiliation is listed below:CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Shanghai, 200031, P.R. China.In addition, an additional affiliation for all the authors was omitted. The correct affiliation is listed below:University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.As a result, the affiliation list and affiliated authors now read:Affiliation 1CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Shanghai, 200031, P.R. China.Christine Nardini, Valentina Devescovi, Yuanhua Liu, Xiaoyuan Zhou, Youtao Lu & Jennifer E. DentAffiliation 2University of Chinese Academy of Sciences, Beijing, 100049, P.R. China.Christine Nardini, Valentina Devescovi, Yuanhua Liu, Xiaoyuan Zhou, Youtao Lu & Jennifer E. DentAffiliation 3CNR IAC \u201cMauro Picone\u201d, Via dei Taurini 19 00185-Roma, Italy.Christine NardiniAffiliation 4Bioinformatics Platform, Institut Pasteur of Shanghai, CAS, Shanghai 200031, P.R. China.Yuanhua LiuAffiliation 5NORSAS consultancy limited, Norwich (NR12 8QP), Norfolk, UK.Jennifer E. DentThis has now been corrected in the HTML and PDF versions of this Article."} +{"text": "European Journal of General Practice (EJGP) would like to express their gratitude to all reviewers who have advised us during the year 2017. 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Ted; Sonnichsen, Andreas; S\u00f8rensen, Kristine; Spiegel, Wolfgang; Spoelstra, Symen K; Sunaert, Patricia; Svab, Igor; Szatkowski, Lisa; Szczesniak, D; Tejedor-Alonso, MA; Terluin, Berend; Thornton, Jane; Tod, Angela; Tomasik, Tomasz; Torloni, Maria Regina; Trappenburg, Jaap; Tvete, Ingunn; Twigg, Michael J; Uijen, Anne-Marie; Uittenbogaart, Steven; Vadiee, Massod; van Achterberg, Theo; van Bokhoven, Marloes; van Boxtel-Wilms, Susanna; van den Berg, Michael; Van Den Broucke, Stephan; Van Den Bruel, An; van den Eijnden, Regina; van der Heide, Iris; van der Horst, Henri\u00ebtte; Van der Weijden, Trudy; van der Wouden, Johannes; van Hunsel, Florence; Van Marwijk, Harm; Van Royen, Paul; van Schayck, Constant; Van Scoy, Lauren; van Weel- Baumgarten, Evelyn; Vannier, Sarah; Varnam, Robert; Verd\u00fa, Fernando; Vermandere, Mieke; Verstappen, Wim; Vicens, Caterina; Vikum, Eirik; Vinyoles, Ernest; Visser, Femke; Vogelsang, Harald; Vollebergh, Wilma; Voltmer, Edgar; Wallace, Emma; Wancata, Johannes; Wandeler, Gilles; W\u00e4ndell, Per; Weinberger, Andrea H; Wensing, Michel; Wermeling, Paulien R; Whatley, Ian; Widhalm, Kurt; Widmer, Daniel; Williams, Pauline; Wojczewski, Silvia; Woo, Jean; Yengil, Erhan; Yuguero Torres, Oriol; Yun, Haesun; Zill, J\u00f6rdis.We want to thank you all for your assistance! Your review reports were valued feedback to the authors and helped us to make our editorial decisions.Although our database of authors and reviewers steadily increases, the Editors do not always find it easy to find referees within the journal\u2019s deadlines. Therefore, we sincerely hope that all reviewers want to continue their review work in the future. We provide a format to facilitate the review.https://mc.manuscriptcentral.com/EJGP and log in to modify your profile. We also invite readers of the EJGP who would like to review manuscripts for this Journal, to visit http://mc.manuscriptcentral.com/ejgp and to register as \u2018new user\u2019, i.e. to complete the details of their expertise. Thank you!If you would like to update your reviewer account, e.g. to specify your expertise, please visit If you have comments regarding the Journal or its peer review process, we invite you to contact the Editorial Office ."} +{"text": "Scientific Reports 10.1038/s41598-018-22209-9, published online 01 March 2018Correction to: In the original version of this Article, there were errors in Affiliation 1 which was incorrectly listed as \u2018IRD, Amap, 34398, Montpellier, France.\u2019 The correct affiliation is listed below:AMAP, IRD, Cirad, CNRS, INRA, Universit\u00e9 de Montpellier, Montpellier, France.These errors have now been corrected in the PDF and HTML versions of the Article, and in the accompanying supplementary material."} +{"text": "Medical Sciences would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.The editors of We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Of course, in these intiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make.Medical Sciences, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Medical Sciences in 2016:Adler, Stuart P.Hardy, MelindaOsborne, BrennaAhmad, AliIsman, MurrayPaganetti, PaoloArmand-Lef\u00e8vre, LaurenceJakubowska, MonikaPani, BibhusitaAzarnia Tehran, DomenicoJampol, LeePeng, Chi ChungBartoloni, AlessandroJenkins, Jill A.Picarelli, AntonioBiunno, IdaJoan, Smith-SonnebornPorta, SeppCaceres, AlejandroKanakkanthara, ArunPrater, M. ReneeCasartelli, LucaKang, YanyongPusapati, GaneshChen, Chiung-TongKasarda, DonRavegnini, GloriaCimanga, KanyangaKashanchi, FatahRemelli, MaurizioCros, G\u00e9rardKasinski, AndreaRephaeli, AdaD\u2019Elia, LanfrancoKundu, AishwaryaSantulli, GaetanoDi Tola, MarcoKyvelidou, AnastasiaSapone, AnnaDias, Lu\u00eds G.Lagasse, BlytheSchauss, AlexDjilali-Saiah, IdrissLakhkar, AnandSchettino, GiuseppeDollard, SheilaLederkremer, Gerardo Z.Shlipak, Michael G.Donnellan, Anne M.Liberti, Sascha EmilieSigafoos, JeffEckel, StephenMariussen, EspenSiltberg-Liberles, JessicaEmond, Claude.Mascaraque, CristinaSimcox, JudithFrancis, JoelMatsumoto, YasuhikoTeixeira Damasceno, N\u00e1gila RaquelFu, SherleenMcmorrow, TaraVan Grevenynghe, JulienGilbert, CarolineMeijles, DanielViggiano, DavideGovoni, Gregory R.Mulder, SasjaVinchi, FrancescaGreco, LuigiNana, Andre W.Wang, KeshengGupta, AditiNath, RajendraYang, XueGutierrez, ClaudioNavarro, FerranZhang, GuozhiHaglin, LenaNenna, RaffaellaZong, Sheng GuoHanson, Nancy D.The following reviewed for"} +{"text": "Scientific Reports7:12200; doi:10.1038/s41598-017-11744-6; Article published online 22 September 2017The original version of this Article contained errors in the spelling of the authors Irene Pierantonelli, Chiara Rychlicki, Laura Agostinelli, Debora Maria Giordano, Melania Gaggini, Cristina Fraumene, Chiara Saponaro, Valeria Manghina, Loris Sartini, Eleonora Mingarelli, Claudio Pinto, Emma Buzzigoli, Luciano Trozzi, Antonio Giordano, Marco Marzioni, Samuele De Minicis, Sergio Uzzau, Saverio Cinti, Amalia Gastaldelli & Gianluca Svegliati-Baroni which were incorrectly given as Pierantonelli Irene, Rychlicki Chiara, Agostinelli Laura, Giordano Debora Maria, Gaggini Melania, Fraumene Cristina, Saponaro Chiara, Manghina Valeria, Sartini Loris, Mingarelli Eleonora, Pinto Claudio, Buzzigoli Emma, Trozzi Luciano, Giordano Antonio, Marzioni Marco, De Minicis Samuele, Uzzau Sergio, Cinti Saverio, Amalia Gastalderi & Svegliati-Baroni Gianluca.These errors have now been corrected in the HTML and PDF versions of the Article, and in the accompanying Supplementary Information document."} +{"text": "There are multiple errors in the Author Contributions. The publisher apologizes for the errors. The correct contributions are:Conceptualization: Carmen Steinborn, Roman Huber, Carsten Gr\u00fcndemann.Data curation: Carmen Steinborn, Amy Marisa Klemd, Manuel Garcia-K\u00e4ufer, Carsten Gr\u00fcndemann.Formal analysis: Carmen Steinborn, Ann-Sophie Sanchez-Campillo, Sophie Rieger, Marieke Scheffen, Barbara Sauer, Manuel Garcia-K\u00e4ufer, Konrad Urech, Carsten Gr\u00fcndemann.Funding acquisition: Roman Huber, Carsten Gr\u00fcndemann.Investigation: Carmen Steinborn, Amy Marisa Klemd, Ann-Sophie Sanchez-Campillo, Sophie Rieger, Marieke Scheffen, Barbara Sauer, Konrad Urech, Marie Follo, Carsten Gr\u00fcndemann.Methodology: Barbara Sauer, Carsten Gr\u00fcndemann.Project administration: Roman Huber, Carsten Gr\u00fcndemann.Resources: Konrad Urech, Roman Huber, Carsten Gr\u00fcndemann.Software: Manuel Garcia-K\u00e4ufer.Supervision: Roman Huber, Carsten Gr\u00fcndemann.Validation: Carmen Steinborn, Amy Marisa Klemd, Ann-Sophie Sanchez-Campillo, Sophie Rieger, Marieke Scheffen, Barbara Sauer, Annekathrin \u00dccker, Gunver Sophia Kienle, Carsten Gr\u00fcndemann.Visualization: Carmen Steinborn, Carsten Gr\u00fcndemann.Writing\u2014original draft: Carmen Steinborn, Konrad Urech, Marie Follo, Carsten Gr\u00fcndemann.Writing\u2014reviewing & editing: Carmen Steinborn, Annekathrin \u00dccker, Gunver Sophia Kienle, Roman Huber, Carsten Gr\u00fcndemann."} +{"text": "Journal of Fungi would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016. The editors of https://publons.com) to receive recognition. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make. We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (Journal of Fungi see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Journal of Fungi in 2016:Agarwal, RiteshGopinath, Shankar P.Pacioni, Giovanni\u00c5hlin, AndersGroll, Andreas H.Pfaller, M.A.Ahmadi-Afzadi, MasoudHage, Chadi A.Ponikau, Jens U.Aimanianda, Vishu KumarHauser, Philippe M.Porollo, AlekseyAlspaugh, AndrewHoenigl, MartinPusateri, AlessandroArabatzis, MichaelHomma, TetsuyaQueener, S.F.Bahn, Yong-SunHoubraken, JosReales-Calder\u00f3n, Jose AntonioBahr, Nathan C.Johnson, John A.Rolfes, RondaBensch, KonstanzeKaditis, Athanasios G.Shor, ErikaBleackley, Mark R.Kameda, HidetoSilva-Vergara, Mario Le\u00f3nBuitrago, Mar\u00eda Jos\u00e9Kidd, Sarah E.Smani, YounesBuzina, WalterKirschner, RolandSpecht, Charles A.Calderone, RichardKonopka, James B.Surup, FrankCoelho, CarolinaKouvelis, Vassili N.Thornton, ChristopherCrous, PerdoLaverty, GarryVatsyayan, PreetyEspinel-Ingroff, AnaLin, Hung-YinVoglmayr, HermannEzra, DavidLivermore, JoanneVoigt, KerstinFalcone, E. LianaMalo, JoshuaWang, ZheFigliuzzi, MatteoMaruyama, Ichiro N.Warris, AdiliaFisher, CynthiaMiceli, Marisa H.Wormley Jr., Floyd L.Freitas, Dayvison F.S.Moore, Margo M.Xue, ChaoyangGarcia-Diaz, JuliaMoreira, Jos\u00e9 A.S.Zaragoza, OscarGarcia-Rodas, RocioMori, MasaakiZhou, ZhichengGasch, AudreyNevez, GillesZutz, ChristophGodet, CendrineObanor, FridayZygadlo, JulioThe following reviewed for"} +{"text": "Due to an oversight, there was an error in the Authors' Contributions statement as published. Author \u201cV\u00edctor Su\u00e1rez-Guti\u00e9rrez\u201d has also contributed towards Experimental setup, code implementation, computational tests, this information went missing in the original article. The correct statement should read as mentioned below. The authors apologize for this mistake. This error does not affect the scientific conclusions of this article in any way.Experimental setup, code implementation, computational tests: CF, VS, IH, MR, \u00d3B, and FAA. Data collecting, cleaning, and pre-processing: VS, IH, AL, FA, MG, and AC. Manuscript preparation: CF, VS, IH, MR, AL, FA, MG, AC, and FAA.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The aim of this biannual meeting was to foster discussion and disseminate the results of the research on natural products that are used for cancer prevention and therapy. During the meeting, the scientific committee members of the meeting who attended the conference had been selected as judges to evaluate all of the oral and poster presentations and the three best oral and poster presentation awards have been granted to the young scientists. The participants were able to network and engage in discussion for potential collaboration to advance our knowledge on utility of natural products for prevention and treatment of cancer. Scientific experts from eight countries gathered to share their views and experience on the latest research on natural products for cancer prevention and therapy. The traditionally used herbal medicines, medicinal plants, plant extracts, fractions, and phytochemicals for cancer prevention and therapy were discussed throughout the meeting. The scientific program comprised of 12 plenary lectures, 23 oral presentations, and 72 posters, providing an opportunity for more than 130 natural product scientists to present their research in three days. Abstracts for plenary talks, oral presentations, and posters were published as proceedings of the meeting in the special issue of Proceedings, Volume 1 and Issue 10 [Growth factors are one of the main factors responsible from the uncontrolled cell progress in cancer. Up to date many scientists have focused on these factors either as the marker or as the targets in several cancer types. Yerer has presented a plenary lecture on the natural products targeting these factors (Nerve growth factor (NGF), epidermal growth factor (EGF), hepatocyte growth factors (HGF), fibroblast growth factors (FGF), vascular endothelial growth factors (VEGF), platelet derived growth factor (PDGF), and transforming growth factor (TGF-\u03b2) (http://www.mdpi.com/2504-3900/1/10/982) [The presentation of Bishayee highlighted studies on cancer preventive and therapeutic attributes of various naturally occurring agents and underlying mechanisms of action, with special emphasis on results reported from our laboratory. Current limitations, challenges, and future directions of research for successful cancer drug development based on natural products will also be discussed (http://www.mdpi.com/2504-3900/1/10/834) [Amr Amin has presented a plenary lecture on the anticancer effects of the saffron\u2019s main active ingredient \u201csafranal\u201d against HCC using in vitro, in silico, and network analyses. In their studies, in addition to the unique and differential cell cycle arrest, safranal showed pro-apoptotic effect through activation of both intrinsic and extrinsic initiator caspases implicating ER stress-mediated apoptosis (http://www.mdpi.com/2504-3900/1/10/972) [This plenary lecture focused on Cardiac Glycosides (GCs) can be considered as pharmacological agents, allowing for cancer cells to switch from one cell death modality to another. All the findings encourage to further explore a potential for CGs in general as cancer cell death modulators alone or in combination with other targeted treatments (http://www.mdpi.com/2504-3900/1/10/977) [Russo et al. has critically reviewed the clinical and pre-clinical studies on the concept that polyphenols, being antioxidant compounds, can fight cancer. They suggest that a clear distinction must be done between the use of polyphenols, such as flavonoids, in cancer treatment versus cancer prevention, starting from adequate and specifically selected cellular models. As an example, he has present data on the potential application of quercetin against chronic lymphocytic leukemia (CLL) (http://www.mdpi.com/2504-3900/1/10/975) [Flavones are abundantly present in common fruits and vegetables, many of which have been associated with cancer prevention. Taking into account that no flavonoid based drugs are clinically used in cancer therapy, Randolph has focused on the flavones\u2014which constitute a subgroup of the flavonoids\u2014show some structural analogy with estrogen, and are known to interact with human estrogen receptors, either as agonist or as antagonist. Thus, whereas epidemiological and pre-clinical data seem to indicate a high potential for flavonoids, from the point of view of the pharmaceutical industry and drug developers, they are considered poor candidates (/10/975) . http://www.mdpi.com/2504-3900/1/10/976) [The relevance of these mechanisms and their translation in clinical therapy has been discussed in Borelli\u2019s plenary lecture. Resveratrol and its mechanism of action has been emphasized by her in cancer cells and in experimental models of senescence, inflammation, obesity, and metabolic diseases. Its molecular targets act at different levels: (1) specific molecular pathways ; (2) epigenetic control of gene transcription through sirtuin activation; (3) cell division cycle and differentiation; (4) apoptosis and autophagy; and, (5) cellular redox homeostasis (http://www.mdpi.com/2504-3900/1/10/974) [Human infection with HCV is currently recognized as the leading cause of hepatocellular carcinoma (HCC), which demands liver transplantation, which was estimated to result in \u223c10,000 deaths in the US only in the year 2011. Elsebai has presented a plenary lecture on cynaropicrin as a potential agent for treatment and prevention of HCC by indirect way through inhibition of HCV and in a direct way evidenced by the many antitumor activities in literature (/10/974) . http://www.mdpi.com/2504-3900/1/10/978) [Many phenolic compounds have been investigated for their potential use as cancer chemopreventive agents. Phenolic compounds consist of one or more hydroxyl substitution on the aromatic ring system. Ko\u015far has emphasized that Cinnamic acid esters, such as caffeic acid phenethyl and benzyl esters, display selective antiproliferative activity against some types of cancer cells. Flavonoids consist of a large group of polyphenolic compounds having a benzo-\ud835\udefe-pyrone structure, and are ubiquitously present in plants. This structure can be responsible from the anticancer acitvities of these compounds (http://www.mdpi.com/2504-3900/1/10/973) [Ulukaya has given a lecture on the pristimerin\u2019s cytotoxic potential on particularly cancer stem cells (CSCs) should be much more important due to the CSCs\u2019 recent role in recurrence of cancer. He has presented their studies on Pristimerin that has been shown to suppress the proliferation of various cancer cell lines at relatively lower concentrations, of which, the IC50 values are around 0.5\u20134 \u03bcM (http://www.mdpi.com/2504-3900/1/10/980) [Curcumin is multi-targeted molecule with pleotropic nature, which inhibits NF-\u03baB and related proteins promoting effectiveness of tyrosine kinase inhibitors (TKIs). Demiray has presented their clinical studies with curcumin on adenoid cystic carcinoma where they have treated patients for 72 months by oral curcumin and eight months by i.v curcumin. Disease control rate was 89.3% (15/17), and no any grade III-IV toxicities was observed related to curcumin reflecting the clinical use of curcumin on adenoid cystic carcinoma patients (/10/980) . http://www.mdpi.com/2504-3900/1/10/981) [Srivastava\u2019s presentation mainly focused on the combination of BRAF inhibitors with Mcl-1 inhibitor such as piperlongumine may have therapeutic advantage to melanoma patients with acquired resistance to BRAF inhibitors alone or in combination with MEK1/2 inhibitors (/10/981) .Oral PresentationsTitleAuthorsLinkEffect of Pomegranate Extract and Tangeretin on Specific Pathways in the Rat Breast Cancer Model Induced with DMBA .H. Fatih Gul et al. http://www.mdpi.com/2504-3900/1/10/983Synergistic Cytotoxic Effects of Resveratrol in Combination with Ceramide Metabolizing Enzymes in Ph + Acute Lymphoblastic Leukemia .Osman O\u011fuz et al. http://www.mdpi.com/2504-3900/1/10/984Characterization of cycloartane-type sapogenol derivatives for prostate cancer chemoprevention .Bilge Debelec-Butuner et al.http://www.mdpi.com/2504-3900/1/10/985Epibrassinolide treatment caused autophagy or apoptosis decision in a time-dependent manner through ER stress in colon cancer cells .P\u0131nar Obakan-Yerlikaya et al. http://www.mdpi.com/2504-3900/1/10/986Determination of Silymarin molecule activity in colon cancer by AgNOR technique .Merve Alpay et al.http://www.mdpi.com/2504-3900/1/10/987Lysimachia savranii on the neuroblastoma cells [The cytotoxic effect of ma cells .Gonca D\u00f6nmez et al. http://www.mdpi.com/2504-3900/1/10/988Autocrine Growth Hormone-triggered curcumin resistance abolished by NF-\u03baB signaling pathway dependent on inflammatory cytokines and active polyamine catabolic machinery in MCF-7, MDA-MB-453 and MDA-MB-231 breast cancer cells .Ajda \u00c7oker G\u00fcrkan et al.http://www.mdpi.com/2504-3900/1/10/989Lysimachia savranii on the migration of the breast cancer cells [The effect of er cells .I\u015f\u0131l Aydemir et al.http://www.mdpi.com/2504-3900/1/10/990Origanum minutiflorum on cancer cells [Investigation of cytotoxic effect of er cells .Oktay \u00d6zkan et al.http://www.mdpi.com/2504-3900/1/10/991Celastrol modulates lipid synthesis via PI3K/Akt/mTOR signaling axis to finalize cell death response in prostate cancer cells .Elif Damla Arisan et al. http://www.mdpi.com/2504-3900/1/10/992Investigation of the Effect of Paclitaxel and Pycnogenol on Mitochondrial Dynamics in Breast Cancer Therapy .Suna Say\u011f\u0131l\u0131 et al. http://www.mdpi.com/2504-3900/1/10/993Effects of curcumin on lipid peroxidation and antioxidant enzymes in kidney, liver, brain and testis of mice bearing Ehrlich Solid Tumor .Mustafa Nisari et al. http://www.mdpi.com/2504-3900/1/10/994Curcumin enhances the efficacy of 5-FU in Colo205 cell lines .Ebru \u00d6zt\u00fcrk et al. http://www.mdpi.com/2504-3900/1/10/995Effect of a New Sapogenol Derivative (AG-07) on Cell Death via Necrosis .Yalcin Erzurumlu et al.http://www.mdpi.com/2504-3900/1/10/996Plantago holosteum Scop [Cytotoxic and Antiinflammatory Activity Guided Studies on eum Scop .Yasin Genc et al. http://www.mdpi.com/2504-3900/1/10/997Continuously monitoring the cytotoxicity of API-1, \u03b1-chaconine and \u03b1-solanine on human lung carcinoma A549 .Ebru \u00d6zt\u00fcrk et al. http://www.mdpi.com/2504-3900/1/10/998The effects of \u03b1-chaconine on ER-\u03b1 positive endometrium cancer cells .Ay\u015fe K\u00fcbra Karabo\u011fa Arslan et al. http://www.mdpi.com/2504-3900/1/10/999Investigation of apoptotic effect of sinapic acid in Hep3B and HepG2 human hepatocellular carcinoma cells .Canan Ero\u011flu et al.http://www.mdpi.com/2504-3900/1/10/1000Cousinia Species of Stenocephalae Bunge. Section [Cytotoxic and Antioxidant Activity of four Section .Leyla Pa\u015fayeva et al. http://www.mdpi.com/2504-3900/1/10/1001Apoptotic effect of Ginnalin A on MDA-MB-231 and MCF7 human breast cancer cell lines .Ebru Avc\u0131 et al.http://www.mdpi.com/2504-3900/1/10/1002Cytotoxic effects of coumarin compounds imperatorin and osthole, alone and in combination with 5-fluorouracil in colon carcinoma cells .Ay\u015fe Eken et al. http://www.mdpi.com/2504-3900/1/10/1003Screening of some Apiaceae and Asteraceae plants for their cytotoxic potential .Perihan G\u00fcrb\u00fcz et al.http://www.mdpi.com/2504-3900/1/10/1004Cyclodextrine Based Nanogels and Phase Solubility Studies of Flurbiprofen as a Chemopreventive Agent .Ay\u015fe Nur Oktay et al. http://www.mdpi.com/2504-3900/1/10/1005Poster PresentationsEffect of a synthesized compound against cancerous cell line and synthesis of copper ion incorporated 1- ethanone-based hybrid nanoflowers .Burcu Somt\u00fcrk Y\u0131lmaz et al. http://www.mdpi.com/2504-3900/1/10/1006Development of effective anticancer drug candidates against breast and colon cancers .Senem Akko\u00e7 et al.http://www.mdpi.com/2504-3900/1/10/1007Synthesis of copper ion incorporated aminoguanidine derivatives-based hybrid nanoflowers .Sevtap \u00c7a\u011flar Yavuz et al.http://www.mdpi.com/2504-3900/1/10/1008Evaluation of anti-proliferative and cytotoxic properties of chlorogenic acid against breast cancer cell lines by real time monitoring .Onur Bender et al. http://www.mdpi.com/2504-3900/1/10/1009Investigation of Apoptotic Effects of Usnic Acid on Hepatocellular Carcinoma .Beste Yurdacan et al.http://www.mdpi.com/2504-3900/1/10/1010In vitro Cytotoxic Effect Evaluation of Dioscorea communis (L.) Caddick & Wilkin Rhizome and Stem Extracts on Hepatocellular Carcinoma Cells [ma Cells .\u00dcnal Egeli et al. http://www.mdpi.com/2504-3900/1/10/1011The Effect of Herbal Medicine on Neuroblastoma Cell Line in Culture .B\u00fc\u015fra \u015een et al.http://www.mdpi.com/2504-3900/1/10/1012The foods containing miR-193b may inhibit the growth of breast cancer cells .Dilek Asci Celik et al.http://www.mdpi.com/2504-3900/1/10/1013Is the dietary miR-193b a novel cell cycle arresting source for breast carcinoma? .Nilgun Gurbuz et al.http://www.mdpi.com/2504-3900/1/10/1014The effects of Wortmannin and EGCG and combined treatments on MDA-MB-231 breast cancer cell lines via inactivation of PI3K signaling pathway .Elgin Turkoz Uluer et al. http://www.mdpi.com/2504-3900/1/10/1015The effects of Paclitaxel and Metformin and combined treatments on TLR signaling pathway on MDA-MB-231 breast cancer cell lines .Melike Ozgul et al.http://www.mdpi.com/2504-3900/1/10/1016Inhibition of telomerase activity by cucurbitacin I in colon cancer cell line, LS174T .Emir Tosun et al. http://www.mdpi.com/2504-3900/1/10/1017Effect of cucurbitacin I on proliferation and migration in colorectal cancer cell line, LS174T .Emir Tosun et al. http://www.mdpi.com/2504-3900/1/10/1018In vitro anticancer and cytotoxic activities of some plant extracts on HeLa and Vero cell lines [ll lines .Fulya Tugba Artun et al. http://www.mdpi.com/2504-3900/1/10/1019Pinus Pinaster on Breast Cancer Cell in Culture [Anticancer Effects of Oleocanthal and Culture .Mahmud \u00d6zkut et al.http://www.mdpi.com/2504-3900/1/10/1020Antiproliferative and Apoptotic Effects of the Medicinal Plants on Breast Cancer Cell Lines .P\u0131nar K\u0131l\u0131\u00e7aslan S\u00f6nmez et al.http://www.mdpi.com/2504-3900/1/10/1021The role of trophoblastic stem cells conditioned media on JAR cell culture .Hilal Kabaday\u0131 et al.http://www.mdpi.com/2504-3900/1/10/1022The effect of pycnogenol and paclitaxel on DNA damage in human breast cancer cell line .H\u00fclya Birinci et al.http://www.mdpi.com/2504-3900/1/10/1023Investigation of the effects of paclitaxel and pycnogenol on inflammatory response in human breast cancer cell line .H\u00fclya Birinci et al.http://www.mdpi.com/2504-3900/1/10/1024Is There Any Protective Effect of Pomegranate and Tangeretin on the DMBA-Induced Rat Breast Cancer Model? .H. Fatih Gul et al. http://www.mdpi.com/2504-3900/1/10/1025Origanum minutiflorum [The neurotoxic effects of tiflorum .\u0130smail Sari et al.http://www.mdpi.com/2504-3900/1/10/1026The Cytotoxic and Apoptotic Effects of Usnic Acid on Prostate Cancer versus Normal Cells .I\u015f\u0131l Ezgi Ery\u0131lmaz et al.http://www.mdpi.com/2504-3900/1/10/1027Linum arboretum on A549 Cells [Antiproliferative Effect of Methanolic Extract of 49 Cells .Ozgur Vatan et al.http://www.mdpi.com/2504-3900/1/10/1028in vitro Cytotoxic Effects of Montivipera xanthina on Healthy and Cancer Human Lung Cell Lines [Investigation of ll Lines .Huzeyfe Huriyet et al. http://www.mdpi.com/2504-3900/1/10/1029Development and Characterization of Paclitaxel-loaded PLGA Nanoparticles and Evaluation of Cytotoxicity on MCF-7 cell line by MTT Assay .Merve \u00c7elik Tekeli et al.http://www.mdpi.com/2504-3900/1/10/1030Effects of Fulvic Acid on Different Cancer Cell Lines .S. 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Extracts on MCF7 Cell Line [Analysis of the Cytotoxic Effects of ell Line .Esra K\u00f6ng\u00fcl et al.http://www.mdpi.com/2504-3900/1/10/1077Abdurrahim Kocyigit, Department of Medical Biochemistry, Faculty of Medicine, Bezmialem Vakif University, Sar\u0131yer, TurkeyAdemi Fahri Pirhan, Department of Biology, Faculty of Science, Ege University, Izmir, TurkeyAdnan Ayhanci, Biology Department, Art and Science Faculty, Eski\u015fehir Osmangazi University, Eski\u015fehir, TurkeyAdriana Borriello, Department of Biochemistry, Biophysics and General Pathology, University of Campania \u201cL. Vanvitelli\u201d, Naples, ItalyAhmet Baysar, Department of Chemical Engineering, Inonu University, Malatya, TurkeyAhmet Cumaoglu, Department of Biochemistry, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyAhmet Savran, Department of Arts and Sciences, Faculty of Medicine, Ni\u011fde \u00d6mer Halisdemir University, Ni\u011fde, TurkeyAjda \u00c7oker-G\u00fcrkan, Department of Molecular Biology and Genetics, Istanbul Kultur University, Atakoy Campus, Istanbul, TurkeyAli Karagoz, Department of Molecular Biology and Genetics, Faculty of Science, Istanbul University, Istanbul, TurkeyAmr Amin, Biology Department, UAE University, Abu Dhabi, United Arab EmiratesAnupam Bishayee, Department of Pharmaceutical Sciences, College of Pharmacy, Larkin University, Miami, FL, USAArzu Atalay, Biotechnology Institute, Ankara University, Ankara, TurkeyAsuman Bozkir, Department of Pharmaceutical Technology, Faculty of Pharmacy, Ankara University, Ankara, TurkeyAyhan Alt\u0131nta\u015f, Department of Pharmacognosy, Faculty of Pharmacy, Anadolu University, Eski\u015fehir, TurkeyAynur I\u015f\u0131k, Department of Molecular Biology and Genetics, Faculty of Science, Gazi University, Ankara, TurkeyAyse Baldemir, Department of Pharmaceutical botany, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyAyse Nalbantsoy, Department of Bioengineering, Faculty of Engineering, Ege University, Izmir, TurkeyAysun Adan, Molecular Biology and Genetics, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri, TurkeyAysun \u00d6k\u00e7esiz, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyAy\u015fe Eken, Department of Pharmaceutical Toxicology, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyAy\u015fe K\u00fcbra Karabo\u011fa Arslan, Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyAy\u015fe Nur Oktay, Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Ankara, TurkeyAy\u015fe Zeynep \u00dcnal, Toxicology Department, Faculty of Pharmacy, Hacettepe University, Ankara, TurkeyAy\u015fenur G\u00f6k, Ankara Un\u0131vers\u0131ty, Faculty of Veterinary Medicine, Ankara, TurkeyBasseem Radwan, Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyBayram Go\u00e7men, Zoology Section, Department of Biology, Faculty of Science, Ege University, Izmir, TurkeyBelma Asl\u0131m, Gazi University, Faculty of Science, Department of Biology, Teknikokullar, Ankara, TurkeyBenjamin-Florian Hempel, Institut f\u00fcr Chemie, Technische Universitat Berlin, Strasse des 17. Juni 124, Berlin, GermanyBeraat \u00d6z\u00e7elik, Department of Food Engineering, Faculty of Chemical and Metallurgical Enginerring, Istanbul Technical University, TurkeyBerrin Tunca, Medical Biology Department, Faculty of Medicine, Uludag University, Bursa, TurkeyBeste Yurdacan, Medical Biology Department, Faculty of Medicine, Uludag University, Gorukle, Bursa, TurkeyBijen K\u0131v\u00e7ak, Deparment of Pharmacognosy, Faculty of Pharmacy, Ege University, \u0130zmir, TurkeyBilge Debelec-Butuner, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Ege University, Izmir, TurkeyBruno Botta, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Roma, piazzale Aldo Moro 5, Roma, ItalyBurak Durmaz, Department of Medical Biochemistry, Ege University, TurkeyBurcu Somt\u00fcrk Y\u0131lmaz, Department of Chemistry, Faculty of Sciences, Erciyes University, Kayseri, TurkeyBur\u00e7in T\u00fcrkmeno\u011flu, Department of Chemistry, Faculty of Sciences, Erciyes University, Kayseri, TurkeyBuse Cevatemre, Department of Biology, Faculty of Arts and Sciences, Uludag University, Bursa, TurkeyB\u00fc\u015fra \u015een, Department of Histology and Embryology, Faculty of Medicine, Celal Bayar University, Manisa, Turkey B\u00fc\u015fra Teke, Faculty of Pharmacy, \u0130stanbul University, Istanbul, TurkeyCanan Ero\u011flu, Department of Medical Biology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, TurkeyCanan T\u00fcrko\u011flu, Department of Biology, Faculty of Art and Life Sciences, Manisa Celal Bayar University, Manisa, TurkeyCarmela Spagnuolo, Institute of Food Sciences, National Research Council, Avellino, Italy\u00c7i\u011fdem Y\u00fccel, Erciyes University Faculty of Pharmacy Department of Pharmaceutical TechnologyDamla Akogullari, Faculty of Medicine, Department of Histology & Embryology, Manisa Celal Bayar University, Manisa, TurkeyDaniel Petras, Institut f\u00fcr Chemie, Technische Universitat Berlin, Strasse des 17. Juni 124, Berlin, GermanyDemetrios A. Spandidos, Department of Toxicology, Medical School, University of Crete, Crete GR, GreeceDidar Tasdemir, Department of Analytical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyDidem \u015e\u00f6hreto\u011flu, Faculty of Pharmacy, Hacettepe Un\u0131vers\u0131ty, Ankara, TurkeyDilek Asci Celik, Department of Medical Biology, School of Medicine, Suleyman Demirel University, Isparta, TurkeyDilek Ceylan, Genome and Stem Cell Center, University of Erciyes, Kayseri, TurkeyEbru Avc\u0131, Department of Medical Biology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, TurkeyEbru \u00d6zt\u00fcrk, Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyEfe Kurtdede, Ankara, TurkeyElgin Turkoz Uluer, Department of Histology & Embryology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, TurkeyElif Damla Ar\u0131san, Department of Molecular Biology and Genetics, Istanbul Kultur University, Atakoy Campus, Istanbul, TurkeyElif D\u00fcndar, Department of Pharmaceutical Botany, Graduate School of Health Sciences, Anadolu University, Eski\u015fehir, TurkeyEmin Sar\u0131p\u0131nar, Department of Chemistry, Faculty of Sciences, Erciyes University, Kayseri, TurkeyEmine Akal\u0131n Uru\u015fak, Faculty of Pharmacy, \u0130stanbul University, Istanbul, TurkeyEmir Tosun, Department of Chemical Engineering, Inonu University, Malatya, TurkeyEngin Ulukaya, Department of Clinical Biochemistry, Faculty of Medicine, Istinye University, Istanbul, TurkeyErcan Kurar, Department of Medical Biology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, TurkeyErc\u00fcment \u00d6lmez, Faculty of Medicine, Department of Pharmacology, Celal Bayar University, Manisa, TurkeyErdal Bedir, Department of Bioengineering, Faculty of Engineering, Izmir Institute of Technology, Izmir, TurkeyErem Bilensoy, Hacettepe University Faculty of Pharmacy Department of Pharmaceutical TechnologyEren Demirpolat, Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyErkan Yilmaz, Biotechnology Institute, Ankara University, Ankara, TurkeyEser Y\u0131ld\u0131r\u0131m S\u00f6zmen, Department of Medical Biochemistry, Ege University, TurkeyEsma Purut, Department of Biology, Faculty of Science, University of Istanbul, Istanbul, TurkeyEsra K\u00f6ng\u00fcl, Department of Pharmacognosy, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyEsra K\u00fcpeli Akkol, Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Ankara, TurkeyEvren Demircan, Department of Food Engineering, Faculty of Chemical and Metallurgical Enginerring, Istanbul Technical University, TurkeyEzgi Balkan, Department of Medical Biochemistry, Faculty of Medicine, Bezmialem Vakif University, TurkeyFatemeh Bahadori, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul, TurkeyFatih \u00c7\u00f6ll\u00fc, Biology, Faculty of Science and Literature, Manisa Celal Bayar University, Manisa, TurkeyFatma Esin K\u0131r\u0131k, Department of Medicinal Microbiology, Faculty of Medicine, Ni\u011fde \u00d6mer Halisdemir University, Ni\u011fde, TurkeyFatma Firat, Department of Histology and Embryology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, TurkeyFeyzan \u00d6zdal Kurt, Department of Biology, Faculty of Art and Life Sciences, Manisa Celal Bayar University, Manisa, TurkeyFulya Tugba Artun, Institute of Science, Istanbul University, Istanbul, TurkeyFunda Karbanc\u0131o\u011flu-G\u00fcler, Department of Food Engineering, Faculty of Chemical and Metallurgical Enginerring, Istanbul Technical University, Sar\u0131yer, TurkeyFunda Kosova, Faculty of Health Science, Celal Bayar University, Manisa, TurkeyFunda Nuray Yal\u00e7\u0131n, Pharmacognosy Dept., Faculty of Pharmacy, Hacettepe University, Ankara, TurkeyGamze G\u00fcney Eskiler, Medical Biology Department, Faculty of Medicine, Sakarya University, Sakarya, TurkeyGian Luigi Russo Russo, Institute of Food Sciences, National Research Council, Avellino, ItalyGonca D\u00f6nmez, Department of Medicinal Biology, Faculty of Medicine, Ni\u011fde \u00d6mer Halisdemir University, Ni\u011fde, TurkeyGorkem K\u0131smal\u0131, Ankara, TurkeyG\u00f6k\u00e7e \u015eeker Karatoprak, Erciyes University Faculty of Pharmacy Department of PharmacognosyG\u00f6zde Girgin, Toxicology Department, Faculty of Pharmacy, Hacettepe University, Ankara, TurkeyGul Ozcan, Department of Biology, Faculty of Science, Istanbul University, Istanbul, TurkeyGulay Melikoglu, Department of Pharmacognosy, Faculty of Pharmacy, Istanbul University, Istanbul, TurkeyGuzide Sat\u0131r Basaran, Department of Biochemistry, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyG\u00fclen Melike Demir, Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Ankara, TurkeyG\u00fcliz Armagan, Department of Biochemistry, Faculty of Pharmacy, Ege University, \u0130zmir, TurkeyG\u00fcl\u015fah Albayrak, Department of Histology and Embryology, Faculty of Medicine, Celal Bayar University, Manisa, TurkeyG\u00fcl\u015fah \u00c7e\u00e7ener, Medical Biology Department, Faculty of Medicine, Uludag University, Gorukle, Bursa, TurkeyG\u00fcl\u015fen Akal\u0131n \u00c7ift\u00e7i, Department of Biochemistry, Faculty of Pharmacy, Anadolu University, Eski\u015fehir, TurkeyH. Fatih Gul, Department of Medical Biochemistry, Faculty of Medicine, Firat University, Elazig, TurkeyH. Gul Dursun, Medical Biology Department, Meram Medical Faculty, Necmettin Erbakan University, Konya, TurkeyH. Seda Vatansever, Department of Histology and Embryology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, TurkeyHakk\u0131 Ta\u015ftan, Department of Biology, Faculty of Science, Gazi University, Ankara, TurkeyHarun \u00dclger, School of Medicine, Department of Anatomy, Erciyes University, Kayseri, TurkeyHasibe Vural, Department of Medical Biology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, TurkeyHatice Bekci, Department of Food Engineering, Engineering Faculty, Erciyes University, Kayseri, TurkeyHatice Kalkan Y\u0131ld\u0131r\u0131m, Faculty of Engineering Department of Food Engineering, Ege University, TurkeyHatice Susar, Department of Anatomy, Faculty of Medicine, Erciyes University, Kayseri, TurkeyHatice Yildirim, Department of Molecular Biology and Genetic, Balikesir University, Balikesir, TurkeyHikmet Memmedov, Department of Medical Biochemistry, Ege University, TurkeyHilal Kabaday\u0131, Department of Histology and Embryology, School of Medicine, Manisa Celal Bayar University, Manisa, TurkeyHulusi Malyer, Botany Department, Faculty of Science and Art, Uludag University, Bursa, TurkeyHuzeyfe Huriyet, Medical Biology Department, Faculty of Medicine, Uludag University, Bursa, TurkeyH\u00fclya Birinci, Department of Histology and Embryology, Faculty of Medicine, Celal Bayar University, Manisa, TurkeyHanifi Ozercan, Department of Medical Pathology, Faculty of Medicine, Firat University, Elaz\u0131g, TurkeyIbrahim Turan, Department of Genetic and Bioengineering, Faculty of Engineering and Natural Sciences, GumushaneUniversity, Gumushane, TurkeyIclal Saracoglu, Department of Pharmacognosy, Faculty of Pharmacy, Hacettepe University, TurkeyIlknur Cinar, Medical Biology Department, Meram Medical Faculty, Necmettin Erbakan University, Konya, TurkeyIsmail Hakki Akgun, Department of Bioengineering, Faculty of Engineering, Ege University, Izmir, TurkeyIsmail Ocsoy, Department of Analytical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyI\u015f\u0131l Aydemir, Faculty of Medicine, Ni\u011fde \u00d6mer Halisdemir University, Ni\u011fde, TurkeyI\u015f\u0131l Ezgi Ery\u0131lmaz, Medical Biology Department, Faculty of Medicine, Uludag University, Bursa, Turkey\u0130brahim \u00c7akir, Department of Food Engineering, Faculty of Engineering and Architecture, Abant \u0130zzet Baysal University, Bolu, Turkey\u0130brahim Tu\u011flu, Department of Histology and Embryology, Medical of Faculty, Celal Bayar University, Manisa, Turkey\u0130lhan \u00d6zer \u0130lhan, Department of Chemistry, Faculty of Sciences, Erciyes University, Kayseri, Turkey\u0130smail Sari, Department of Medicinal Biochemistry, Faculty of Medicine, Ni\u011fde \u00d6mer Halisdemir University, Ni\u011fde, Turkey\u0130smail Tuncer De\u011fim, Department of Pharmaceutical Technology, Faculty of Pharmacy, Biruni University, Topkap\u0131, \u0130stanbul, TurkeyJuana Diez, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, SpainJukka Hakkola, Pharmacology and Toxicology Unit, Institute of Biomedicne, University of Oulu, Oulu, FinlandKaan Adacan, Department of Molecular Biology and Genetics, Istanbul Kultur University, Atakoy Campus, Istanbul, TurkeyKadriye Nur Kasapo\u011flu, Department of Food Engineering, Faculty of Chemical and Metallurgical Enginerring, Istanbul Technical University, TurkeyKamil Vural, Department of Medicinal Pharmacology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, TurkeyKemal \u00d6zbilgin, Department of Histology and Embryology, Faculty of Medicine, Celal Bayar University, Manisa, TurkeyKemal Sami Korkmaz, Department of Bioengineering, Faculty of Engineering, Ege University, Izmir, Turkey Konstantinos Dimas, Department of Pharmacology, Faculty of Medicine, University of Thessaly, Larissa, GreeceK\u00fcbra Uzun, Pharmacognosy Dept., Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyLatife Merve Oktay, Faculty of Medicine Department of Medical Biology, Ege University, TurkeyLeyla Pa\u015fayeva, Department of Pharmacognosy, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyMahmoud F. Elsebai, Pharmacognosy Department, Faculty of Pharmacy, Mansoura University, Mansoura, EgyptMahmud \u00d6zkut, Department of Histology & Embryology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, TurkeyMarc Diederich, College of Pharmacy, Seoul National University, Seoul, KoreaMaria usso, Institute of Food Sciences, National Research Council, Avellino, ItalyMehmet Berk\u00f6z, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Yuzuncu Y\u0131l University, Van, TurkeyMehmet \u0130brahim Tu\u011flu, Department of Histology and Embryology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, TurkeyMehmet Z\u00fclf\u00fc Yildiz, Zoology Section, Department of Biology, Faculty of Arts and Science, Ad\u0131yaman University, Ad\u0131yaman, TurkeyMehtap Nisari, Department of Anatomy, Faculty of Medicine, Erciyes University, Kayseri, TurkeyMelike Ozgul, Department of Histology & Embryology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, TurkeyMeltem Ceylan-\u00dcnl\u00fcsoy, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, TurkeyMert Burak Ozturk, Department of Bioengineering, Faculty of Engineering, Ege University, Izmir, TurkeyMert Ilhan, Department of Pharmaceutical Technology, Faculty of Pharmacy, Biruni University, \u0130stanbul, TurkeyMerve Alpay, Department of Biochemistry, Faculty of Medicine, Duzce University, D\u00fczce, TurkeyMerve \u00c7elik Tekeli, Erciyes University Faculty of Pharmacy Department of Pharmaceutical TechnologyMerve \u00c7elik, Department of Molecular Biology and Genetics, Faculty of Science and Letters, Istanbul Kultur University, Istanbul, TurkeyMerve Karaman, Department of Biology, Balikesir University, Balikesir, TurkeyMerve U\u011fur, Department of Molecular Biology and Genetics, Faculty of Science and Letters, Istanbul Kultur University, Istanbul, TurkeyMetin Y\u0131ld\u0131r\u0131m, Department of Biochemistry, Faculty of Pharmacy, Mersin University, Mersin, TurkeyMiros\u0142aw Kro\u015bniak, Department of Food Chemistry and Nutrition, Medical College, Jagiellonian University, Krakow, Poland Mohamed Mehiri, Nice, FranceMustafa Cengiz, Department of Mathematics and Science Education, Education Faculty, Siirt University, Siirt, TurkeyMustafa Nisari, Department of Nutrition and Dietetics, Faculty of Health Sciences, University of Nuh Naci Yazgan, Kayseri, TurkeyMustafa \u00d6ztatl\u0131c\u0131, Department of Histology and Embryology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, TurkeyMutlu Demiray, Department of Medical Oncology, KTO Karatay University, Konya, TurkeyM\u00fcberra Ko\u015far, Faculty of Pharmacy, Department of Pharmacognosy, Eastern Mediterranean University, Gazima\u011fusa, North Cyprus via Mersin 10, TurkeyM\u00fckerrem Bet\u00fcl Yerer, Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyM\u00fczeyyen Demirel, Department of Pharmaceutical Technology, Faculty of Pharmacy, Anadolu University, Tepeba\u015f\u0131, TurkeyN. Nalan \u0130mamo\u011flu, Department of Basic Sciences, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyNalan \u00d6zdemir, Department of Chemistry, Faculty of Sciences, Erciyes University, Talas Street, Kayseri, TurkeyNar\u00e7\u0131n Palavan-\u00dcnsal, Department of Molecular Biology and Genetics, Istanbul Kultur University, Atakoy Campus, Istanbul, TurkeyNaz\u0131m Bozan, Department of Otorhinolaryngology, Faculty of Medicine, Yuzuncu Yil University, Van, TurkeyNecip Ilhan, Department of Medical Biochemistry, Faculty of Medicine, Firat University, Elazig, TurkeyNeel M. Fofaria, Department of Biomedical Sciences and Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Lubbock, USANeriman \u0130nan\u00e7, Department of Nutrition and Dietetics, Faculty of Health Sciences, University of Nuh Naci Yazgan, Kayseri, TurkeyNevin \u00c7elebi, Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Ankara, TurkeyNevin Ilhan, Department of Medical Biochemistry, Faculty of Medicine, Firat University, Elaz\u0131g, TurkeyNilgun Gurbuz, Department of Medical Biology, School of Medicine, Suleyman Demirel University, Isparta, TurkeyNilufer Cinkilic, Department of Biology, Science and Art Faculty, Uludag University, Bursa, TurkeyNur Selvi, Faculty of Medicine Department of Medical Biology, Ege University, TurkeyNurcan Silahtarl\u0131o\u011flu, Graduate School Natural Applied Science, Erciyes University, Kayseri, TurkeyNurhayat Sutlupinar, Department of Pharmacognosy, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey O. Faruk Kirlangic, Department of Molecular Biology and Genetic, Balikesir University, Balikesir, TurkeyOguzhan Tatar, Department of Medical Biochemistry, Faculty of Medicine, Firat University, Elazig, TurkeyOktay \u00d6zkan, Department of Medicinal Pharmacology, Faculty of Medicine, Ni\u011fde \u00d6mer Halisdemir University, Ni\u011fde, TurkeyOnur Bender, Biotechnology Institute, Ankara University, Ankara, TurkeyOnur Kaya, Graduate School Natural Applied Science, Erciyes University, Kayseri, Turkey Oruc Allahverdiyev, Department of Pharmacology, Faculty of Pharmacy, Yuzuncu Y\u0131l University, Van, TurkeyOsman O\u011fuz, Molecular Biology and Genetics, Faculty of Life and Natural Sciences, Abdullah Gul University, Kayseri, TurkeyOsman Tugay, Department of Biology Program of Botany, Faculty of Sciences, Selcuk University, Konya, TurkeyOsman \u00dcst\u00fcn, Department of Pharmacognosy, Faculty of Pharmacy, Gazi University, Ankara, TurkeyOya Bozda\u011f-D\u00fcndar, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, TurkeyOzer Y\u0131lmaz, Department of Biology, Science and Art Faculty, Uludag University, Bursa, TurkeyOzgun Teksoy, Biology Department, Art and Science Faculty, Eski\u015fehir Osmangazi University, Eski\u015fehir, TurkeyOzgur Tag, Cancer Biology Laboratory, Department of Chemistry, Graduate School of Natural and Applied Sciences, Ege University, Izmir, TurkeyOzgur Vatan, Department of Biology, Science and Art Faculty, Uludag University, Bursa, Turkey\u00d6mer Ta\u015f, Department of Pharmacognosy, Faculty of Pharmacy, Erciyes University, Kayseri, Turkey\u00d6zge Al, School of Medicine, Department of Anatomy, Erciyes University, Kayseri, Turkey\u00d6zge G\u00fczel, Department of Bioengineering, Faculty of Engineering, Izmir Institute of Technology, Izmir, Turkey\u00d6zge Renc\u00fczo\u011fullar\u0131, Atakoy Campus, Department of Molecular Biology and Genetics, Istanbul Kultur University, Istanbul, Turkey\u00d6zlem Temiz-Arpac\u0131, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, TurkeyPelin Ta\u015ftan, Deparment of Pharmacognosy, Faculty of Pharmacy, Ege University, \u0130zmir, TurkeyPelin Toros, Department of Histology & Embryology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, TurkeyPerihan G\u00fcrb\u00fcz, Pharmacognosy Dept., Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyPetek Ballar, Faculty of Pharmacy, Department of Biochemistry, Ege University, Izmir, TurkeyP\u0131nar Atalay D\u00fcndar, Department of Basic Sciences, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeyP\u0131nar \u0130kiz, Pharmacognosy Dept., Faculty of Pharmacy, Hacettepe University, Ankara, TurkeyP\u0131nar K. S\u00f6nmez, Department of Histology & Embryology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, TurkeyP\u0131nar K\u0131l\u0131\u00e7aslan S\u00f6nmez, Department of Histology and Embryology, Faculty of Medicine, Celal Bayar University, Manisa, TurkeyP\u0131nar Obakan-Yerlikaya, Department of Molecular Biology and Genetics, Istanbul Kultur University, Atakoy Campus, Istanbul, TurkeyP\u0131nar \u00d6zden, Department of Medical Biology, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, TurkeyPinar K. S\u00f6nmez, Department of Histology & Embryology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, TurkeyRana Kavurmac\u0131, Department of Advanced Technology, Ahi Evran University, K\u0131r\u015fehir, TurkeyRandolph R. J. Arroo, Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UKRecep Er\u00f6z, Department of Genetics, Faculty of Medicine, Duzce University, D\u00fczce, TurkeyRemzi Soner Cengiz, Faculty of Veterinary Medicine, TurkeyRemziye Kendirci, Department of Histology and Embryology, School of Medicine, Manisa Celal Bayar University, Manisa, TurkeyRenata Francik, Department of Bioorganic Chemistry, Medical College, Jagiellonian University, Krakow, PolandRoderich D. S\u00fcssmuth, Institut f\u00fcr Chemie, Technische Universitat Berlin, Strasse des 17. Juni 124, Berlin, GermanyRojen Geylan, Department of Pharmacognosy, Faculty of Pharmacy, Erciyes University, TurkeyRuziye Da\u015fk\u0131n, Botany Dept., Faculty of Science and Letters, Uluda\u011f University, Bursa, TurkeyS. Kerem Aydin, Sirri Yircali Anatolian High School, Balikesir, TurkeySanjay K. Srivastava, Department of Biomedical Sciences and Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Lubbock, USASeda Duman, Department of Bioengineering, Faculty of Engineering, Izmir Institute of Technology, Izmir, TurkeySeda \u015eirin, Gazi University, Faculty of Science, Department of Biology, Teknikokullar, Ankara, TurkeySedat \u00dcnal, Erciyes University Faculty of Pharmacy Department of Pharmaceutical TechnologySeher Dalgic, Sirri Yircali Anatolian High School, Balikesir, TurkeySeher Y\u0131lmaz, School of Medicine, Department of Anatomy, Bozok University, Yozgat, TurkeySelda Eren, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeySelen \u0130lg\u00fcn, Faculty of Pharmacy, Department of Pharmaceutical Botany, Erciyes University, Kayseri, TurkeySelim Demir, Department of Nutrition and Dietetics, Faculty of Health Sciences, Karadeniz Technical University, Trabzon, TurkeySema Misir, Department of Biochemistry, Faculty of Pharmacy, Cumhuriyet University, Sivas, TurkeySenem Akko\u00e7, Department of Chemistry, Faculty of Sciences, Erciyes University, Kayseri, TurkeySerap Yalcin, Department of Molecular Biology and Genetics, Ahi Evran University, K\u0131r\u015fehir, TurkeySerap Yal\u0131n, Department of Biochemistry, Faculty of Pharmacy, Mersin University, Mersin, TurkeySevil Albayrak, Biology Department, Science Faculty, Erciyes University, Kayseri, TurkeySevin\u00e7 \u0130nan, Department of Histology and Embryology, Faculty of Medicine, Celal Bayar University, Manisa, TurkeySevtap \u00c7a\u011flar Yavuz, Department of Chemistry, Faculty of Sciences, Erciyes University, Kayseri, TurkeySeyhan Altun, Department of Biology, Faculty of Science, University of Istanbul, Istanbul, TurkeySezin Anil, Department of Pharmacognosy, Faculty of Pharmacy, Istanbul University, Istanbul, TurkeySharavan Ramachandran, Department of Biomedical Sciences and Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Lubbock, USASibel Gunes, Biology Department, Art and Science Faculty, Eski\u015fehir Osmangazi University, Eski\u015fehir, TurkeySibel \u0130lbasmi\u015f Tamer, Department of Pharmaceutical Technology, Faculty of Pharmacy, Gazi University, Ankara, TurkeySinem Y\u0131lmaz, Faculty of Pharmacy, Department of Biochemistry, Ege University, Izmir, TurkeySolmaz Susam, Department of Medical Biochemistry, Faculty of Medicine, Firat University, Elazig, TurkeyStefania Moccia, Institute of Food Sciences, National Research Council, Avellino, ItalySuheyl Furkan Konca, Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Erciyes University, Kayseri, TurkeySukran Kultur, Department of Pharmaceutical Botany, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey Sumeyra Cetinkaya, Medical Biology Department, Meram Medical Faculty, Necmettin Erbakan University, Konya, TurkeySuna Sabuncuo\u011flu, Toxicology Department, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey Suna Say\u011f\u0131l\u0131, Department of Histology and Embryology, Faculty of Medicine, Celal Bayar University, Manisa, Turkey \u015eamil \u00d6zt\u00fcrk, Department of Histology & Embryology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, Turkey\u015eebnem Kurhan, Novel Food Technologies Development, Application and Research Center, Abant \u0130zzet Baysal University, Bolu, TurkeyTaner Da\u011fc\u0131, Department of Physiology, Faculty of Medicine, Ege University, \u0130zmir, TurkeyTerken Baydar, Toxicology Department, Faculty of Pharmacy, Hacettepe University, Ankara, TurkeyTevhide Sel, Ankara Un\u0131vers\u0131ty, Faculty of Veterinary Medicine, TurkeyTolga Cavas, Medical Biology Department, Faculty of Medicine, Uludag University, Bursa, TurkeyTolga Ertekin, School of Medicine, Department of Anatomy, Kocatepe University, Afyon, TurkeyTuna Onal, Department of Histology & Embryology, Faculty of Medicine, Manisa Celal Bayar University, Manisa, TurkeyU. Sebnem Harput, Department of Pharmacognosy, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey\u00dcnal Egeli, Medical Biology Department, Faculty of Medicine, Uludag University, Bursa, TurkeyVarol Sahinturk, Vocational School of Health Services, Eski\u015fehir Osmangazi University, Eski\u015fehir, TurkeyVasilis P. Androutsopoulos, Department of Toxicology, Medical School, University of Crete, Crete GR, Greece Veysel Kayser, Faculty of Pharmacy, The University of Sydney, Sydney, AustraliaVildan Bet\u00fcl Yenigun, Department of Medical Biochemistry, Faculty of Medicine, Bezmialem Vakif University, TurkeyYalcin Erzurumlu, Faculty of Pharmacy, Department of Biochemistry, Ege University, Izmir, TurkeyYasemin Tekin, Biology Department, Art and Science Faculty, Eski\u015fehir Osmangazi University, Eski\u015fehir, TurkeyYasin Genc, Department of Pharmacognosy, Faculty of Pharmacy, Hacettepe University, Ankara, TurkeyYe\u015fim Akta\u015f, Erciyes University Faculty of Pharmacy Department of Pharmaceutical TechnologyYuksel Aliyazicioglu, Medicinal Plants, Traditional Medicine Practice and Research Center, Gumushane University, Gumushane, TurkeyY\u00fcksel \u00d6\u011f\u00fcn\u00e7, Department of Biochemistry, Faculty of Pharmacy, Anadolu University, Eski\u015fehir, TurkeyZerrin Seller, Department of Biochemistry, Faculty of Pharmacy, Anadolu University, Eski\u015fehir, TurkeyZeynep Dogan, Department of Pharmacognosy, Faculty of Pharmacy, Hacettepe University, Ankara, Turkey"} +{"text": "AbstractStratiomyinae, Sarginae, Nemotelinae, and Pachygasterinae), and twelve species from five genera have been collected and are recognized in Morocco. Pachygasteratra , Oxycerapardalina , Nemotelusdanielssoni , and Oxyceraterminata are newly recorded to the North African fauna. Nemotelusatriceps and Nemotelusmaculiventris are reported for the first time in Morocco. The present number of soldier flies known from Morocco is 33.A checklist of soldier flies species recorded from the North African countries of Morocco, Algeria, Tunisia, Libya, and Egypt is based on both literature records and material newly collected in Morocco. Four subfamilies ( Diptera that exhibit an extreme array of morphological diversity, as well as a moderate range of life histories, with about 400 genera and about 2,700 species currently recognised worldwide . The soldier flies are found all over the world, but are particularly diverse in tropical regions (Stratiomyids (soldier flies) constitute one of the moderately large families of regions , 2011.The family comprises varied members, ranging from 2.0 to 20.0 mm in length. While some species are entirely slender, others are stout or evidently flattened, with coloration ranging from strikingly patterned dark with a yellow, sometimes white or greenish pattern and frequent metallic reflections , to rathStratiomyidae, Important studies have been done over the world, like those of Stratiomyidae were given by Diptera of Morocco. For the next two decades, they received sporadic study devoted mainly, to the records of Moroccan species amongst the Diptera of Morocco or among the Stratiomyidae of the Palaearctic Region and Nemotelusmaculiventris in Morocco, in addition to Pachygasteratra , Oxycerapardalina , Oxyceraterminata and Nemotelusdanielssoni for the first time not only in Morocco but for the North African continent.In this present study, 12 species of soldier flies have been recorded from 23 sampling sites in Morocco . Photographs of the sampling localities showing Moroccan habitats of the species newly recorded are given (by DY and BB). All the material is deposited in the insect collection of the department of Biology, Faculty of Sciences, University Abdelmalek Essa\u00e2di, T\u00e9touan, Morocco.Preparations of the male and/or female terminalia, as well as the illustrations are given here Figs . SpeciesStratiomyidae Beristunisiae Becker, 1915= North African literature records. Morocco, Algeria, Tunisia: La Calle Stratiomysflauipes Fabricius, 1798= Euparyphuskabylinus Bigot, 1879b= World distribution. Only known in North African from Algeria: Oran, Tebessa Stratiomysauriflua Erichson, 1841= World distribution. Known in North Africa only from Morocco: Middle Atlas and Algeria: Soufouloud Stratiomyssplendens Fabricius, 1787= Ephippiumrufitarse Macquart, 1838= Pycnomallasplendensssp.jordanica Lindner, 1974= North African literature records. Morocco Muscaformosa Scopoli, 1763= Nemotelusflavogeniculatus De Geer, 1776= Muscacicur M. Harris, 1778= Muscaaurata Fabricius, 1787= Sargusaeneus Walckenaer, 1802= Sargusxanthopterus Meigen, 1804= Sargusazureus Loew, 1840= New localities. Morocco, Rif: Taghbalout, 1\u26422\u2640\u2640, 5/IV/2014, sweep net, Coll. Yimlahi and Belqat; Lac Ametrasse . Palaearctic, Austria, Bulgaria, Czech Republic, England, France, Germany, Greece, Italy, Poland, Portugal, Romania, Russia, Slovakia, Slovenija, Spain, Sweden, Switzerland, Turkey, Yugoslavia Muscabipunctata Scopoli, 1763= Sargusreaumuri Meigen, 1804= Sargusreaumurii Fabricius, 1805= Sargussulphureus Meigen, 1822= Sargusbipunctatus O. Costa, 1844= Chrysochromafasciatus Szilady, 1929= Geosargusperpulcher James, 1936= North African literature record. Tunisia ( Tunisia : 221.World distribution. Nearctic: Canada (British Columbia), USA . Palaearctic: Albania, Austria, Belgium, Bulgaria, Croatia, Czech Republic, England, France, Georgia, Germany, Greece, Hungary, Ireland, Italy, Netherlands, Poland, Romania, Serbia, Slovakia, Slovenija, Switzerland Oxyceraannulata Becker, 1906= World distribution. Tunisia: Zaghouan, Tunis Hermionegermanica Szilady, 1932= Hermionedorieri Vaillant, 1950= Hermionedorierivar.barbarica Vaillant, 1950= North African literature record. Algeria: Aur\u00e8s Mountains, Arris Oxyceraranzonii Schiner, 1857= Hermionemuscariaronzonii Vaillant, 1950= Hermionemorrisivar.auresi Vaillant, 1950= Hermionemorrisivar.minuta Vaillant, 1950= North African literature records. Algeria: vicinity of Alger Hermioneochracea Vaillant, 1950= World distribution. Only known in North Africa from Algeria: Aur\u00e8s Mountains, Arris, Constantine Heraclinaorientalis Lindner, 1974= Heraclinastigmosaorientalis = North African literature record. Egypt Oxyceraamoena Loew, 1857= Oxyceraengadinica Jaennicke, 1866= Oxyceracalceata Loew, 1871= Hermionesahunica S\u00e9guy, 1934= Hermionepardalinavar.oldenbergi Lindner, 1938= Hermionepardalinavar.nigrifrons Szilady, 1941= Hermionemorrisivar.bohemica Hrbacek, 1945= Hermionearmata Vaillant, 1950= Hermionepardalinavar.depressa Vaillant & Delhom, 1956= Hermionepardalinavar.alticola Vaillant & Delhom, 1956= New records. Oued Abou Bnar Muscarara Scopoli, 1763= Muscatardigradus M. Harris, 1778= Stratiomysmaculata Geoffroy in Fourcroy, 1785= Oxycerapulchella Meigen, 1822= Hermionepulchellavar.similis = North African literature record. Algeria: Aur\u00e8s Mountains, Arris Hermionetenebricosa Vaillant, 1952= World distribution. Only known in North Africa from Algeria: Atlas de Blida Hermionetorrentium Vaillant, 1950= World distribution. Only known in North Africa from Algeria: Atlas of Bilda, La Chiffa, Aur\u00e8s Mountains Muscagraeca Pontoppidan, 1763= Muscatrilineata Linnaeus, 1767= Muscahypoleon Linnaeus, 1767= Stratiomysfasciata Geoffroy in Fourcroy, 1785= Oxyceraproxima Loew, 1873= Oxyceratrilineatavar.collaris Brunetti, 1889= Hermionetrilineatassp.transfasciata Pleske, 1925= Hermionetrilineatassp.ferghanensis Pleske, 1925= Hermioneucrainica Paramonov, 1926= Hermionebucheti S\u00e9guy, 1930= Hermionetrilineatassp.angustistomata Lindner, 1938= PageBreakHermionetrilineatavar.biroi Szilady, 1941= Hermionetrilineatavar.sajoi Szilady, 1941= Hermionetrilineatavar.algira Vaillant, 1950= New locality. Morocco, Rif: Daya A\u00efn Jdioui Eulaliaalolena S\u00e9guy, 1930= World distribution. Only known in North Africa from Morocco: Casablanca, Tangier, Mahaidja, A\u00efn Leuh Eulaliaangulata Panzer, 1798= Stratiomysangulata Panzer, 1798= Stratiomysvulpina Panzer, 1798= Stratiomyshydropota Meigen, 1822= Odontomyialatifaciata Macquart, 1834= Stratiomysbrevicornis Loew, 1840= Stratiomysbrevicornis Loew, 1840= Stratiomysruficornis Zetterstedt, 1842= Odontomyiahydrophila Loew, 1846= North African literature records. Morocco: Tangier Eulaliadisciclara S\u00e9guy, 1929= World distribution. Only known in North African from Algeria: Touggourt Eulalia (Odontomyia) discolor Loew, 1897= Odontomyialimbata Macquart in Lucas, 1849= North African literature records. Morocco: Tangier Stratiomysflavissima Rossi, 1790= Stratiomysdecora Wiedemann in Meigen, 1822= Stratiomysinfoscata Meigen, 1830= Odontomyiasemiviolacea Brull\u00e9, 1833= Odontomyianigripes Macquart, 1847= Odontomyialimbipennis Macquart, 1847= Odontomyialaufferi Strobl in Czemy & Strobl, 1909= North African literature records. Morocco, Algeria, Tunisia Stratiomyslimbata Wiedemann in Meigen, 1822= Clitellariapacifica Wiedemann in Meigen, 1822= Opseogymnusflavosignata A. Costa, 1857= New locality. Morocco, Rif: Lac Ametrasse, 2\u2642\u26421\u2640, 28/IV/2015; A\u00efn Sidi Brahim Ben Arrif, 4\u2642\u2642, 23/IV/2015; Daya Afrate Eulaliamicrocera S\u00e9guy, 1930= World distribution. Only known in North Africa from Morocco: Mekn\u00e8s Stratiomysviridula Fabricius, 1775= Stratiomyscanina Panzer, 1798= Stratiomysjejuna Schrank, 1803= Muscajejuna Schrank in Gistl, 1837= Odontomyiadentata Meigen, 1804= Odontomyiaholosericea Olivier, 1811= Odontomyialunata Olivier, 1811= Stratiomyssubvittata Meigen, 1822= Stratiomysbimaculata Meigen, 1835= Stratiomysbimaculata Meigen, 1838= Odontomyiapersonata Loew, 1846= Odontomyiainterrupta Loew, 1846= Odontomyiaheydenii Jaennicke, 1866= Odontomyiaatrata Verrall, 1909= North African literature record. Algeria Hirtealongicornis Scopoli, 1763= Muscatenebricus M. Harris, 1778= Stratiomysstrigata Fabricius, 1781= Stratiomystomentosa Schrank, 1803= Stratiomysvillosa Meigen, 1804= Stratiomysnubeculosa Meigen, 1804= Stratiomysthoracica Fabricius, 1805= Stratiomyshirtuosa Meigen, 1830= Stratiomysanubis = Stratiomyiaflavifrons Macquart, 1838= Stratiomysstrigatavar.pallida Loew, 1840= Stratiomyslambessiana : 62Stratiomysflavolimbata : 60Stratiomyiasegnis = Hirteaefflatouni : 58-59Stratiomyia (Hirtea) surcoufi : 64Hirteasurcoufi = Stratiomyialongicornisssp.palaestinensis Lindner, 1937= Stratiomyia (Hirtea) longicornisssp.flavoscutellata Lindner, 1940= North African literature records. Morocco: Casablanca Muscasingularius Harris, 1776= Stratiomysfurcata Fabricius, 1794= Stratiomyspanthaleon Fallen, 1817= Stratiomysriparia Meigen, 1822= Stratiomyspaludosa Siebke, 1863= North African literature record. Egypt = New locality. Morocco, Rif: Daya Afrate . Recently, Mason and Rozko\u0161n\u00fd (2003) have described the female.The species is recorded from Izelfane in Morocco. This finding is very interesting, as it represents the first record from North Africa of a supposed endemic species of Greece.Nemotelusdentatus Becker, 1902World distribution. Only known in North Africa from Egypt: El Alagto Marg = Nemotelusbalearicus Lindner, 1937= Nemoteluszernyi Lindner, 1937= North African literature record. Egypt Muscapantherina Linnaeus, 1758= Stratiomysalbipes Geoffroy in Fourcroy, 1785= PageBreakStratiomysmarginellus Thunberg, 1789= Muscamarginella Gmelin, 1790= Nemotelusnigritus Meigen, 1804= Nemotelusmarginellus Fallen, 1817= Nemotelusnigritus Meigen, 1822= Nemotelus Jraternus Loew, 18 46= Nemotelusgracilis Loew, 1846= Nemotelussatunini Pleske in Lindner, 1937= Nemoteluszelleri Pleske in Lindner, 1937= Nemotelusalbirostris Szilady, 1941= Nemoteluscaucasicus Nartshuk, 1969= Nemoteluspunctirostris Lindner, 1974= North African literature record. Morocco: Tangier ( Tangier : 59, Mor Tangier : 320.World distribution. Albania, Armenia, Austria, Azerbaijan, Belgium, Bulgaria, Cyprus, Czech Republic, Denmark, England, Estonia, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Latvia, Netherlands, Norway, Poland, Romania, Russia, Slovakia, Spain, Sweden, Switzerland, Tajikistan, Turkey, Yugoslavia (goslavia : 320; Sagoslavia : 521.Nemotelusproboscideus Loew, 1846Nemoteluspunctatus Fabricius, 1794= Nemotelusalgericus Jaennicke, 1866= North African literature records. Morocco, Tunisia ( Tunisia : 139; Al Tunisia : 321.World distribution. Italy (n. Italy : 321.Nemoteluspunctiventris Becker 1902World distribution. Only known in North Africa from Egypt (om Egypt : 100\u2013101Nemotelussubuliginosus Rozkosny, 1974World distribution. Only known in North Africa from Morocco: Tangier ( Tangier : 322.PageBreakNemotelusventralis Meigen, 1830World distribution. Only known in North Africa from Morocco ( Morocco : 146, Mo Morocco : 323.Nemotelusnigrinus Fallen, 1817Nemoteluscarneus Walker, 1849= Nemoteluscrassus Loew, 1863= Nemotelusunicolor Loew, 1863= Nemoteluscarbonarius Loew, 1869= North African literature record. Morocco ( Morocco : 326.World distribution. Nearctic: Canada, USA. Neotropical: Mexico. Palaearctic: Afghanistan, Austria, Azerbaijan, Belgium, Bulgaria, China, Czech Republic, Denmark, England, Estonia, Finland, Germany, Hungary, Ireland, Latvia, Lithuania, Mongolia, Netherlands, Norway, Poland, Romania, Russia, Slovakia, Spain, Sweden, Switzerland, Tibet, Ukraine, Yugoslavia (goslavia : 326, Tugoslavia : 110."} +{"text": "The correct spelling of last author's name is provided and replaced online which is mentioned as under:Srisurapanont Manit, Mok Yee Ming, Yang Yen Kuang, Chan Herng-Nieng, Della Constantine D, Zainal, Nor Zuraida, Jambunathan Stephen, Amir Nurmiati, Kalita PranabThe wrong spelling was: Srisurapanont Manit, Mok Yee Ming, Yang Yen Kuang, Chan Herng-Nieng, Della Constantine D, Zainal, Nor Zuraida, Jambunathan Stephen, Amir Nurmiati, Kalita Pranabi"} +{"text": "Non-Coding RNA would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016. The editors of https://publons.com) to receive recognition. Of course, in these intiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make. We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (Non-Coding RNA, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Non-Coding RNA in 2016:Alahari, Suresh K.Gregory, Brian D.Polacek, NorbertAlmeida, MariaGupta, AnkitRiley, Kasandra J.Atianand, Maninjay K.Gupta, Sachin KumarSantulli, GaetanoBaluska, FrantisekHagiwara, KeitaroSaville, BarryBao, GuanhuiHayden, EricShen, XiaopeiBerindan-Neagoe, IoanaHiroshi, NakayamaTang, BenjaminBlanco, EnriqueJaeger, LucTaube, JoeBlin, KaiJiang, WeiUchida, ShizukaCarpenter, SusanKudla, GrzegorzVerjovski, SergioCatapano, Carlo VLiu, YunhuaWilliams, CeciliaCaudron, MaiwenLiu, ChangningXiao, JunDunoyer, PatriceMorris, Kevin V.Xuan, ZhenyuEl-Osta, AssamMoss, WalterYang, JianHuaFabbri, MullerOno, MotoharuYou, Zhu-HongFiannaca, Antonino\u00d8rom, Ulf AnderssonYu, BinGajula, RajendraPatil, DeepakZhang, LeiGao, JianzhaoPeng, YuZhong, GuocaiThe following reviewed for"} +{"text": "Scientific Reports7: Article number: 4088310.1038/srep40883; published online: 01202017; updated: 05262017In this Article, Affiliation 6 is incorrectly listed as \u2018Venomtech, Sophie-Antipolis, 06560, Valbonne, France\u2019. The correct affiliation is listed below:VenomeTech, Sophie-Antipolis, 06560, Valbonne, France."} +{"text": "MEETING PROGRAMAvailable on\u2010line atwww.aapm.org/meetlngs/2016SCM/ChairJessica B. Clements, MSKaiser Permanente Los Angeles, CAVice ChairMichael Howard, PhDSarah Cannon Cancer Center Chattanooga, TNTrack DirectorsTherapy TrackJean M. Moran, PhDUniversity Michigan Medical Center Ann Arbor, MIKyle J. Antes, MSPresbyterian Healthcare System Dallas, TXBrian Wang, PhDUniversity Louisville Louisville, KYProfessional TrackMichael Howard, PhDSarah Cannon Cancer Center Chattanooga, TNBrent C. Parker, PhDUniversity Texas Medical Branch of Galveston Galveston, TXDiagnostic TrackDustin Gress, MSMD Anderson Cancer Center Houston, TXJeffrey M. Moirano, MSUniversity of Washington Seattle, WAMammography TrackJessica B. Clements, MSKaiser Permanente Los Angeles, CAYoung Investigator ProgramJean M. Moran, PhDUniversity Michigan Medical Center Ann Arbor, MIJeffrey M. Moirano, MSUniversity of Washington Seattle, WA"} +{"text": "The affiliation listed for J\u00e9r\u00f4me Bugeon is incorrect. The correct affiliation is: LPGP, INRA, Rennes, France.There are errors in the Author Contributions. The publisher apologizes for these errors. Please view the correct contributions below.Conceptualization: Antti Kause, Marc Vandeputte, Martin Kocour.Data curation: Martin Prchal, Antti Kause.Formal analysis: Martin Prchal, Antti Kause.Funding acquisition: Antti Kause, Marc Vandeputte, Martin Kocour.Investigation: Martin Prchal, Marc Vandeputte, David Gela, Jean-Michel Allamellou, Girish Kumar, Anastasia Bestin, J\u00e9r\u00f4me Bugeon, Jinfeng Zhao, Martin Kocour.Methodology: Antti Kause, Marc Vandeputte, Martin Kocour.Project administration: Antti Kause, Marc Vandeputte, Martin Kocour.Resources: Antti Kause, Marc Vandeputte, David Gela, J\u00e9r\u00f4me Bugeon, Martin Kocour.Supervision: Antti Kause, Marc Vandeputte, Martin Kocour.Validation: Martin Prchal, Antti Kause, Marc Vandeputte, Martin Kocour.Visualization: Martin Prchal, Antti Kause, Martin Kocour.Writing\u2013original draft: Martin Prchal, Antti Kause, Marc Vandeputte, Martin Kocour.Writing\u2013review & editing: Martin Prchal, Antti Kause, Marc Vandeputte, David Gela, Jean-Michel Allamellou, Girish Kumar, Anastasia Bestin, J\u00e9r\u00f4me Bugeon, Jinfeng Zhao, Martin Kocour."} +{"text": "Dr. Kirtan Upadhyaya is not included in the author byline. He should be listed as the sixth author, and his affiliation is 1: Bayes Impact, Technology 501(c)(3) Non-profit, San Francisco, California, United States of America. The contributions of this author are as follows: Conceptualization, Investigation, Validation, and Writing \u2013 Review & Editing.The last five authors, Aleksandr Nisnevich, Everett Wetchler, Sylvia Sudat, Eric Liu, and Kirtan Upadhyaya, should be noted as contributing equally to this work.https://doi.org/10.1371/journal.pone.0181173.The correct citation is: Jamei M, Nisnevich A, Wetchler E, Sudat S, Liu E, Upadhyaya K (2017) Predicting all-cause risk of 30-day hospital readmission using artificial neural networks. PLoS ONE 12(7): e0181173."} +{"text": "Scientific Reports7: Article number: 4076310.1038/srep40763; published online: 01182017; updated: 02232017The original version of this Article contained errors in the spelling of authors Rodolfo Mastropasqua, Lisa Toto, Luca Di Antonio, Enrico Borrelli, Alfonso Senatore, Marta Di Nicola, Giuseppe Di Martino and Marco Ciancaglini, which were incorrectly given as Mastropasqua Rodolfo, Toto Lisa, Di Antonio Luca, Borrelli Enrico, Senatore Alfonso, Di Nicola Marta, Di Martino Giuseppe, Ciancaglini Marco respectively.These errors have now been corrected in the HTML and PDF versions of this Article."} +{"text": "The correct name is: Rachel Joy Jolley. The correct citation is: Xu Y, Li N, Lu M, Dixon E, Myers RP, Jolley RJ, et al. (2017) The effects of patient cost sharing on inpatient utilization, cost, and outcome. PLoS ONE 12(10): e0187096."} +{"text": "Due to an error introduced during typesetting of this article , the aut1. Department of Electrical and Computer Engineering, Seoul National University, 08826 Seoul, Korea.2. R&D Center, Wearable Healthcare, 16954 Gyeonggi-do, Korea.3. Research Division, NanoEnTek, 08389 Seoul, Korea.4. Department of Statistics, Seoul National University, 08826 Seoul, Korea.5. College of Pharmachy, Chung-Ang University, 06974, Seoul Korea.6. Bioinformatics Institute, Seoul National University, 08826 Seoul, Korea."} +{"text": "There is an error in affiliation 1 for authors Hai Sun, Piyush Kalakoti, Kanika Sharma, Jai Deep Thakur, Rimal H. Dossani, Devi Prasad Patra, Hesam Akbarian-Tefaghi, Frank Farokhi, Christina Notarianni, Bharat Guthikonda, and Anil Nanda. Affiliation 1 should be: Neurosurgery, Louisiana State University Health Sciences Center, Shreveport, Louisiana, United States of America. The publisher apologizes for this error."} +{"text": "Journal of Fungi would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015. The editors of the We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial decision-making process. Several steps have been taken in 2015 to thank and acknowledge reviewers. Good, timely reviews are rewarded with a discount off their next MDPI publication. By creating an account on the submission system, reviewers can access details of their past reviews, see the comments of other reviewers, and download a letter of acknowledgement for their records. In addition, MDPI has launched a collaboration with Publons, a website that seeks to publicly acknowledge reviewers on a per journal basis. This is all done, of course, within the constraints of reviewer confidentiality. Feedback from reviewers shows that most see their task as a voluntary and mostly unseen work in service to the scientific community. We are grateful to our reviewers for the contribution they make.Akins, RobertHay, Roderick J.Nevez, GillesAverill, ColinHaydoura, SouhaNouri, KeyvanBarnhart, KirstinHeinz, Werner J.Orlovich, DavidBhatia, NealHoenigl, MartinPapini, ManuelaBubici, GiovanniIdelevich, Evgeny A.Perlin, DavidChao, Sheau-chiouIorizzo, MatildePfaller, Michael A.Chaturvedi, AshokIson, Michael G.Phillips, Lori A.Choi, Jong SooJaijakul, SirayaPullarkat, VinodCogliati, MassimoKhachemoune, AmorRanque, St\u00e9phaneColom, M. FranciscaKouvelis, Vassili N.Reales-Calder\u00f3n, Jose AntonioDaeschlein, GeorgKranabetter, J. MartyRich, PhoebeDaniel, Carlton Ralph C.Lanternier, FannyRoilides, EmmanuelDemirev, PlamenLauto, AntonioSaville, Stephen P.Enk, Claes D.Lavergne, Rose-AnneStarace, MichelaEsper\u00f3n, FernandoLetang, EmilioSturtevant, JoyEspinel-Ingroff, AnaLipner, Shari R.Sukdeo, NicoleFranco-Paredes, CarlosLopez-Llorca, LuisSuz, Laura M.Garcia-Diaz, JuliaMack, MeganTeichtahl, AndrewGhannoum, Mahmoud A.Markinson, BryanTorbett, BruceGiashuddin, ShahMartin, RonnyWainwright, MarkGrim, Shellee A.McKenney, JennieWalsh, Thomas J.Gupta, Aditya K.Morgado, Luis N.Weese, ScottHagen, FerryMorton, Charles OliverZaias, Nardo"} +{"text": "The correct names are provided and replaced online which is mentioned as under:Abraham M Shultz, Sangmook Lee, Mary Guaraldi, Thomas B. Shea, Holly A. YancoThe original names was:Abraham M Shultz, Sangmook Lee, Mary Guaraldi, Thomas B. Shea, Holly C. Yanco"} +{"text": "AbstractActinopterygii, Chondrichthyes, Sarcopterygii) collected in South America, mostly from the Brazilian Amazon. The ichthyology collections of the Museu Paraense Em\u00edlio Goeldi (MPEG: http://www.museu-goeldi.br/) include specimens collected between 1900 and 2014. The dataset is now available for public consultation on the Global Biodiversity Information Facility portal (http://www.gbif.org/dataset/b0059a3a-5cab-4a08-8d14-d92c23378e43), and through Sistema de Informa\u00e7\u00e3o sobre a Biodiversidade Brasileira (http://gbif.sibbr.gov.br/explorador/pt/recurso/62).This dataset contains information on the occurrence of Neotropical fishes ( Museu Paraense Em\u00edlio Goeldi (MPEG), or Goeldi Museum, located in Bel\u00e9m, Par\u00e1, Brazil, is a federal research institution within the Brazilian Ministry of Science, Technology and Communication (MCTIC). The Goeldi Museum is the site of the first Amazonian fish collection in Brazil with specimens dating as far back as the end of the nineteenth century.The MPEG focused on systematics, taxonomy, and biogeography. Due to its wide geographic range and representation of Amazonian fish diversity, over 60 scientific papers have been published over the last ten years based on specimens and types deposited in the Goeldi collections. The MPEG collections are most representative of the Brazilian Amazon, but also contain records of fishes collected in four other neotropical countries . According to The ichthyology collections of the Goeldi Museum receive and preserve material evidence, including specimens and associated data and metadata collected in the field, for research and educational purposes. The collections are a source of information and material used by national and international researchers as well as students of two post-graduate programs at PageBreakalike. More often than not such information is not easily available for policy makers, thus hindering scientifically based management decisions .The aim of this paper is to describe and synthesize information about Amazon fish biodiversity represented in the Goeldi Museum collections, providing summaries about taxonomic coverage and geographical distribution in order to facilitate rapid and dynamic access to the records present at With these factors in mind, the digitization of the Goeldi fish collections began in 2003, and records were initially inserted into Excel software; in 2009, they were transferred to Specify (SPECIFY SOFTWARE 6). All records have now been computerized, and are available to the scientific community and general public in the Sistema de Informa\u00e7\u00e3o sobre a Biodiversidade Brasileira and in GSiBBr and GBIFData published through : http://www.gbif.org/dataset/3bc27e57-a84d-4e0c-ba0d-9dbba8299674; http://gbif.sibbr.gov.br/explorador/pt/recurso/62Project title: Computerization of the ichthyological collection of the MPEG.Personnel: Tim\u00f3teo Monteiro da Silva (student), Marcos Paulo Alves de Sousa (head of informatics), Wolmar Benjamin Wosiacki (curator), Juliana Corr\u00eaa dos Santos (student), Victor Amazonas Viegas Ferreira (student), Lorran Alves da Cruz Ramos (student).Funding: Minist\u00e9rio da Ci\u00eancia, Tecnologia, Inova\u00e7\u00e3o e Comunica\u00e7\u00e3o (MCTIC); Conselho Nacional de Pesquisa (CNPq).General description of taxonomic coverage:MPEG includes 260,000 specimens, distributed in 25,874 lots, representing 28 orders, 102 families, 506 genera, and 1710 species. All species in the collection belong to the classes Actinopterygii, Chondrichthyes, and Sarcopterygii. The three most common orders are Characiformes with 600 species in 13,560 lots, Silurifomes with 389 species in 5,290 lots, and Cichlidae with 211 species in 3,437 lots.The taxonomic organization of the collection followed Among these are found 263 type specimens of which 33 are holotypes and 227 are paratypes. 261 of the 263 type specimens were collected during the last 15 years.PageBreakAll type species found in the collection are detailed below:List of species with holotype and paratype in the collection:Acestridiumtriplax, Archolaemusorientalis, Aspidorasgabrieli, Aspidorasmarianae, Characidiumnana, Characidiumpapachibe, Corydorasurucu, Cyphocharaxaninha, Eigenmanniaantonioi, Eigenmanniadesantanai, Eigenmanniaguairaca, Eigenmanniamuirapinima, Eigenmanniapavulagem, Hemigrammusarua, Hemigrammusdiagonicus, Hyphessobryconmontagi, Hypomasticuslineomaculatus, Hypopygusbenoneae, Ituglanisina, Stenolicmusix, Tatiacaxiuanensis, Tetranematichthysbarthemi, Tometesancylorhynchus, Tometescamunani, Tometeskranponhah, Trichomycterusguaraquessaba, Trichomycterusigobi, Trichomycterusmboycy, Trichomycterusnaipi, Trichomycteruspapilliferus, Trichomycterusplumbeus, Trichomycterustaroba, Xenurobryconvarii.List of species with only paratype in the collection:Adontosternarchusduartei, Anchoviellajuruasanga, Ancistruskrenakarore, Ancistrusranunculus, Apteronotuslindalvae, Apteronotussoneiro, Archolaemusferreirai, Archolaemusjaneae, Archolaemusluciae, Archolaemussantosi, Aspidorasgabrieli, Aspidorasmarianae, Astroblepusnettoferreirai, Baryancistruschrysolomus, Baryancistrusxanthellus, Bryconamericuspinnavittatus, Centromochlusorca, Chaetostomajegui, Crenicichlaanamiri, Cyphocharaxjagunco, Cyphocharaxlundi, Eigenmanniamatintaperera, Eigenmanniameeki, Eigenmanniasayona, Eigenmanniawaiwai, Furcodontichthysnovaesi, Hassargabiru, Hassarshewellkeimi, Hypostomusdelimai, Hypostomushoplonites, Ituglanisgoya, Jupiabacitrina, Leporinusmultimaculatus, Moenkhausiacelibela, Moenkhausiachlorophthalma, Moenkhausiaeurystaenia, Moenkhausiamikia, Moenkhausiapetymbuaba, Moenkhausiaplumbea, Nemuroglanisfurcatus, Parotocinclushalbothi, Peckoltiacompta, Peckoltiafeldbergae, Phallobryconsynarmacanthus, Physopyxisananas, Polycentrusjundia, Scoloplaxbaskini, Synbranchuslampreia, Trichomycterusanhanga, Trichomycterusbalios, Trichomycteruscachiraensis, Trichomycteruscrassicaudatus, Trichomycteruspoikilos, Trichomycterustrefauti, Trichomycterustupinamba, Tyttobryconmarajoara.Kingdom: AnimaliaPhylum: ChordataClasses: Actinopterygii, Chondrichthyes, SarcopterygiiOrders: Atheriniformes, Batrachoidiformes, Beloniformes, Carcharhiniformes, Characiformes, Chimaeriformes, Clupeiformes, Cyprinodontiformes, Elopiformes, Gasterosteiformes, Gobiesociformes, Gymnotiformes, Lepidosireniformes, Lophiiformes, Mugiliformes, Myliobatiformes, Osmeriformes, Osteoglossiformes, Cichliformes, Pleuronectiformes, Pristiformes, Rajiformes, Scorpaeniformes, Siluriformes, Squaliformes, Synbranchiformes, Syngnathiformes, Tetraodontiformes \" and \"Global Biodiversity Information Facility\" (GBIF) using an export tool from Specify Software and \"Integrated Publishing Toolkit\" (IPT) from GBIF which uses the Darwin core Standard version 1.4. The data was imported and published as per the schematic illustration below nets, matapis, dip nets, sieves, harpoons, snorkeling, diving, etc.Quality control description: The most recent taxonomic organization of the collection followed PageBreaksuch that representative groups of the collection, for example, Cichlidae do not belong to Cichliformes. The identification of genus and species still follows the bibliography in Eschmeyeret et al. (2016), but all the data will be updated to 2, air-conditioned to 22\u00b0C. The specimens are fixed in formalin for 50 hours and transferred into a 70% ethanol solution for permanent storage.The curatorial protocol involves receiving material that is identified and labelled, while data and metadata are digitized and deposited in a two story collection room measuring 192 mThe process for the preservation of bone and cartilage samples is based on Object name: Darwin Core Archive Museu Paraense Em\u00edlio Goeldi - ichthyology collectionCharacter encoding: UTF-8Format name: Darwin Core Archive formatFormat version: 11.2Distribution: http://ipt.museu-goeldi.br/ipt/resource?r=museu_paraense_emilio_goeldi_ictiology_collectionand;http://www.gbif.org/dataset/3bc27e57-a84d-4e0c-ba0d-9dbba8299674Publication date of data: 2015-01-21Language: PortugueseLicenses of use: This dataset is licensed under a Creative Commons Attribution Non Commercial (CC-BY-NC) 4.0 License .Metadata language: EnglishDate of metadata creation: 2014-08-01Hierarchy level: Dataset"} +{"text": "The correct names, respectively, are: Henrik Salje, Isabel Rodriguez-Barraquer, and In-Kyu Yoon. Also, the ninth author's name is spelled incorrectly. The correct name is: Bridget Wills. The correct citation is: Hoang Quoc C, Salje H, Rodriguez-Barraquer I, Yoon IK, Chau NVV, Hung NT, et al. (2016) Synchrony of Dengue Incidence in Ho Chi Minh City and Bangkok. PLoS Negl Trop Dis 10(12): e0005188. doi:"} +{"text": "AbstractBrachiopoda from Greece have been included in publications on the Mediterranean brachiopod fauna. These records were mostly based on material collected during marine expeditions in the eastern Mediterranean decades ago, while few recent additional records appear in ecological studies. The aim of this paper was to give the first checklist of brachiopod species of Greece, in the framework of the Greek Taxon Information System (GTIS) initiative of the LifeWatchGreece Research Infrastructure (ESFRI), by reviewing the existing literature.Until today, only scattered species records of Twelve brachiopod species have been found in Greek waters so far. The nomenclature, distribution, fossil records, ecology, and literature sources are discussed for each species. Brachiopoda North Aegean, South Aegean, Levantine Sea, Ionian SeaPleistocene, Pliocene, HoloceneRecorded by NovocraniaturbinataN.turbinata. See discussion. Doubtful species, may be a synonym of South AegeanHoloceneRecorded by Levantine SeaPleistocene, Pliocene, HoloceneRecorded by North Aegean, South Aegean, Levantine Sea, Ionian SeaPleistocene, Pliocene, Miocene, HoloceneMadrepora-Lophelia rudstone, gravel, shells, detritus, coarse sand, muddy sand, mud. Depth: 29-762 m.Recorded by South Aegean, Levantine Sea, Ionian SeaPleistocene, HoloceneRecorded by North Aegean, South Aegean, Levantine Sea, Ionian SeaPleistocene, HoloceneRecorded by North Aegean, South Aegean, Levantine Sea, Ionian SeaPleistocene, Pliocene, HoloceneRecorded by North Aegean, South Aegean, Levantine Sea, Ionian SeaPleistocene, Pliocene, HoloceneRecorded by Levantine SeaHoloceneRecorded by PlatidiadavidsoniP.anomioides. See discussion. Doubtful species, may be a synonym of North AegeanHoloceneRecorded by North Aegean, South Aegean, Levantine Sea, Ionian SeaHoloceneMadrepora-Lophelia rudstone, Lophelia-Madrepora rubble, pelagic mudstone and wackestone, silty sand, sandy mud, mud. Depth: 130-2,133 m.Recorded by North AegeanHoloceneRecorded by Brachiopoda of Greece comprises 12 species classified into 9 genera, 6 families, 2 orders, and 2 classes. Novocraniaturbinata and Platidiadavidsoni have been included in the list as doubtful species. N.turbinata and N.anomala, which had been synonymized for a long period. P.davidsoni with P.anomioides has been also questioned . Thus, we chose to keep the two species in the list until their status is completely clarified.The checklist of Gwyniacapsula to bathyal muddy bottoms and deep-water coral facies.In the Greek seas, Overall, the brachiopod fauna of the Greek seas comprises 85% of the Mediterranean brachiopod species, being considerably richer than in the other countries of the eastern basin: 5 species have been reported to date from Turkey , Cyprus,Supplementary material 1Brachiopoda of GreeceChecklist of Data type: Taxonomic checklistBrachiopoda known to occur in Greek waters.Brief description: Taxonomic checklist of File: oo_97945.xlsVasilis Gerovasileiou, Nicolas Bailly"} +{"text": "Journal of Cardiovascular Development and Disease (JCDD) would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.The editors of https://publons.com) to receive recognition. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make.We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (JCDD, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for JCDD in 2016:Adams, Dany SpencerGarrity, DeborahOcorr, KarenAgopian, A. J.Hachiya, HitoshiOhuchi, HideoAlexander, MarkHarvey, RichardPan\u00e1kov\u00e1, DanielaAndelfinger, GregorHeideman, WarrenPandur, PetraAnderson, RobertHoppler, StefanPasquie, Jean-LucAngelini, PaoloHospital, CentralPeral, Susana CanteroAr\u00e1nega, AmeliaIshikawa, KiyotakePerrin, LaurentBakkers, JeroenIstvan, BaczkoQian, LiBartulos, OscarJacobs, RogerRavichandran, AshwinBlack, Brian L.Jay, Patrick Y.Reim, IngolfBouveret, RomaricJa\u017awi\u0144ska, AnnaRentschler, StaceyBrand, ThomasJoseph, JacobSkinner, JonathanBressan, MichaelKang, Bum-YongStingone, JeanetteCabrera-Fuentes, HectorKasahara, HidekoSullivan, Patrick M.Caputo, MassimoKeller, Bradley B.Swenne, CeesCedars, AriKelly, RobertTan, LarenChen, Wen-PinKrieg, PaulTanios, MagedChirumbolo, SalvatoreLarsen, Lars AllanTomita-Mitchell, AoyCripps, RichardLazzeri, ChiaraVan Eys, Guillaume J.Czubryt, Michael P.Lee, Kyu-HoVolk, TalilaDe Vecchis, RenatoLien, EllenWachten, DagmarDistel, MartinLincoln, JoyWatanabe, MichikoDomian, Ibrahim J.Liu, AipingWaxman, JoshuaDuester, GreggLymperopoulos, AnastasiosWessells, RobertFragata, JoseMartin, InkenYan, BoFranco, DiegoMelkani, GirishYin, LiyaFraser, AlanMilting, HendrikZaffran, St\u00e9phaneFreeman, Jennifer L.Mizobuchi, MasahiroZhang, DonghuiFujimori, KoMuellerleile, KaiFukuda, DaijuNarayanan, AnandThe following reviewed for"} +{"text": "Owing to errors made by the authors, Charles J. Glueck, Kevin Lee, Marloe Prince, Vybhav Jetty, Parth Shah, and Ping Wang, the following article contains errors.J Investig Med High Impact Case Rep. 2016;4(3):1-6. doi: 10.1177/2324709616661833Glueck CJ, Lee K, Prince M, et al. Four Thrombotic Events Over 5 Years, Two Pulmonary Emboli and Two Deep Venous Thrombosis, When Testosterone-HCG Therapy Was Continued Despite Concurrent Anticoagulation in a 55-Year-Old Man With Lupus Anticoagulant. The following correction applies:The fifth author\u2019s name should have been mentioned as \u201cParth Shah\u201d instead of \u201cParth Shah, MD\u201d. The correct author list is given below.Charles J. Glueck, MD, Kevin Lee, MD, Marloe Prince, MD, Vybhav Jetty, MD, Parth Shah, and Ping Wang, PhD."} +{"text": "There is an error in the XML that is causing the first, second, fourth, sixth, seventh, eighth, and ninth authors\u2019 names to be indexed incorrectly. The names should be indexed as: Ribeiro SP, Milush JM, Kallas EG, Passero LF, Hunt PW, Deeks SG, and Nixon DF.INK4a Expression and Immunologic Aging in Chronic HIV Infection. PLoS ONE 11(11): e0166759. doi:10.1371/journal.pone.0166759.The citation is incorrect in the published article. The correct citation is: Ribeiro SP, Milush JM, Cunha-Neto E, Kallas EG, Kalil J, Passero LF et al. (2016) p16"} +{"text": "Figures 5A\u2013D in the results section of Bosch et al. .A sentence in the description of h et al. containeThis modification does not alter any of the results or claims arisen in the original article, while adds coherence across the manuscript.It should read:Figures 5A\u2013D).\u201d\u201cSpine and synapse sizes were distributed with a right-skewed curve, whereas sphericities distributed symmetrically around the means (Designed the project: CB, JD, AMe, ES; performed experiments: CB, AMa, NM, CT, IF, FU, EP, AMe; contributed with reagents/materials/analyses tools: CB, CT, IF, FU, EP, CL, JC, JD, AMe; analyzed the data: CB, AMa, ES; discussed the results and interpreted the data: CB, AMa, NM, CT, IF, FU, EP, CL, JC, JD, AMe, ES; wrote the article: CB, JDF, AMe, ES.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Medical Sciences would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015.The editors of We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial decision-making process. Several steps have been taken in 2015 to thank and acknowledge reviewers. Good, timely reviews are rewarded with a discount off their next MDPI publication. By creating an account on the submission system, reviewers can access details of their past reviews, see the comments of other reviewers, and download a letter of acknowledgement for their records. In addition, MDPI has launched a collaboration with Publons, a website that seeks to publicly acknowledge reviewers on a per journal basis. This is all done, of course, within the constraints of reviewer confidentiality. Feedback from reviewers shows that most see their task as a voluntary and mostly unseen work in service to the scientific community. We are grateful to our reviewers for the contribution they make.Adler, Stuart P.Isman, Murray B.Patel, NimishBaumgartner, StefanJang, Tae-WonPilar Vinardell, Mar\u00edaBrudzynski, KatrinaJellinger, KurtReynisson, J\u00f3hannesCasalino, ElisabettaLee, SangyongRicceri, FulvioChae, HeeyoungLi, Hung-YuanRohe, Benjamin G.Chan, Ding-ChengManu, ManuSaleh, Mahmoud A.Christensen, Kathrine BMao, X. W.Sancho, TeresaChung, Wen-HsinMarano, Kristin M.Schmitt, U.Cimanga, KanyangaMarschalek, RolfSimmons, GrahamDandri, MauraMayer, GerhardTsujita, Takahirode Asmundis, CarloMhaouty-Kodja, STzang, Bor-ShowDollard, Sheila C.M\u00fcller, ThomasVieillard, VincentHerrero, Mar\u00eda Jos\u00e9Ohkura, SatoshiVisioli, FrancescoHsu, Ping-NingOlaku, Oluwadamilola O.Imamura, FumiakiPark, Yong-Ki"} +{"text": "Dear Editor,With great interest we read the article in the recent issue of JBRA by Besides the information on current media usage by IVF laboratories, There is a lot of information and discussions available on the development of modernculture media and its components. Specifically for the G-series media, the fullcomposition of an earlier version of the media has been published ;...\". All media for culture of embryos contain energy sourcessuch as pyruvate and lactate. These are fundamental components in media for embryoculture. There has been discussions on the requirements for glucose, but today there isconsensus that glucose is required and it is present in modern culture media. Morespecifically for the G-series media, the levels of energy sources required for embryoculture at the cleavage stage and blastocyst stage were determined based on measurementsin human oviducts, and uterine fluids collected at relevant time points of the menstrualcycle (Regarding albumin, A final statement we would like to comment on is: \"Salt and ions are present in most ofthem, but in case of Vitrolife...\". Ions are very important in any culture media. Theyhave important roles in different processes but are also the major contributor forobtaining the correct osmotic pressure that is crucial for proper development. As statedearlier, information about all components and thus also ions used in media fromVitrolife is available through different sources.For the sake of completeness, we hereby list in alphabetical order the components ofVitrolife media referred to by G-1: alanine, alanyl-glutamine, asparagine, aspartate, calcium chloride, EDTA,gentamicin, glucose, glutamate, glycine, hyaluronan, lipoic acid, magnesium sulphate,methionine, potassium chloride, proline, serine, sodium bicarbonate, sodium chloride,sodium citrate, sodium dihydrogen phosphate, sodium lactate, sodium pyruvate, taurineand waterG-2: alanine, alanyl-glutamine, arginine, asparagine, aspartate, calcium chloride,calcium pantothenate, cystine, gentamicin, glucose, glutamate, glycine, histidine,hyaluronan, isoleucine, leucine, lysine, magnesium sulphate, methionine, phenylalanine,potassium chloride, proline, pyridoxine, riboflavin, serine, sodium bicarbonate, sodiumchloride, sodium citrate, sodium dihydrogen phosphate, sodium lactate, sodium pyruvate,thiamine, threonine, tryptophan, tyrosine, valine and water G-1 PLUS and G-2 PLUS alsocontain human serum albumin.Studies such as the paper by"} +{"text": "This report profiles the keynote talks given at ISMB03 in Brisbane, Australia by Ron Shamir, David Haussler, John Mattick, Yoshihide Hayashizaki, Sydney Brenner, theOverton Prize winner, Jim Kent, and the ISCB Senior Accomplishment Awardee,David Sankov."} +{"text": "Acta Cryst. (2009), E65, m438.Corrigendum to Acta Cryst. (2009), E65, m438] is corrected.The author list in the paper by Tong, Hung, Wang, Lin & Lo [ Acta Cryst. (2009), E65, m438], the author list was incorrect. The correct author list is given above.In the paper by Tong, Hung, Wang, Lin & Lo ["} +{"text": "Drosophila candidate genes for lipid droplet regulation by RNA interference (RNAi) screening with an image segmentation-based optical read-out system, and show that these regulatory functions are conserved in the mouse. Those include the vesicle-mediated Coat Protein Complex I (COPI) transport complex, which is required for limiting lipid storage. We found that COPI components regulate the PAT protein composition at the lipid droplet surface, and promote the association of adipocyte triglyceride lipase (ATGL) with the lipid droplet surface to mediate lipolysis. Two compounds known to inhibit COPI function, Exo1 and Brefeldin A, phenocopy COPI knockdowns. Furthermore, RNAi inhibition of ATGL and simultaneous drug treatment indicate that COPI and ATGL function in the same pathway. These data indicate that the COPI complex is an evolutionarily conserved regulator of lipid homeostasis, and highlight an interaction between vesicle transport systems and lipid droplets.Lipid droplets are ubiquitous triglyceride and sterol ester storage organelles required for energy storage homeostasis and biosynthesis. Although little is known about lipid droplet formation and regulation, it is clear that members of the PAT protein family coat the droplet surface and mediate interactions with lipases that remobilize the stored lipids. We identified key Drosophila to identify candidate regulators of lipid storage and utilization, and have shown that many of these candidates have functions that are conserved in mammals. We focused our attention on a vesicle-trafficking pathway that we show is required for the modulation of the types of regulatory and enzymatic proteins found on the lipid droplet surface. Interfering with the function of this trafficking system with either RNA interference or small-molecule compounds alters lipid storage. The understanding of this new pathway, as well as the specific reagents we used, may ultimately lead to new therapeutics.Fat cells, and cells in general, convert fatty acids into triglycerides that are stored in droplets for future use. Despite the enormous importance of lipid droplets in obesity and other disease processes, we know very little about how lipid reserves in droplets are formed and how those reserves are drawn down. We have used the model fruit fly Drosophila and mammalian cells.A specific vesicle-trafficking machine is shown to be required for cells to use stored lipid, in both Lipid homeostasis is critical in health and disease, but remains poorly understood (for review see ). Non-esLipid droplets are believed to form in the ER membrane by incorporating a growing TG core between the leaflets of the bilayer, and ultimately are released surrounded by a phospholipid monolayer. Cytosolic lipid droplets possess a protein coat and grow by synthesis of TG at the lipid droplet surface and by fDrosophila melanogaster in addition to the recently proposed strictly standardized mean difference normalization [SSMDi = (xi \u2212 meanj)/square root (2/nj \u2212 2.5 \u00d7 ((nj \u2212 1) \u00d7 SDj2))]. Those related algorithms were supplemented with both a fitted linear model normalization using the Prada package . The samDrosophila lipid regulating gene functions , and results are additionally tabulated ; and Drosophila ), which showed excellent oleic acid feeding characteristics during RNAi assay development but inferior RNAi characteristics as compared to the Kc167 cells. S3 cells showed superior adherence during automated liquid handling in 1,536-well format. We dispensed 4 \u03bcl of cells at 1.25 \u00d7 106 cells/ml into LoBase Aurora COC 1,536-well plates with a bottle-valve solenoid-based dispenser (Aurora) to obtain 5,000 cells/well. A total of 23 nl of compound solution of different concentrations were transferred to the assay plates using a Kalypsis pin tool equipped with a 1,536-pin array containing 10-nl slotted pins . One microliter of oleic acid (400 \u03bcM) was added, and the plate was lidded with stainless steel rubber gasket-lined lids containing pinholes. After 18\u201324-h incubation at 24 \u00b0C and 95% humidity, BODIPY 493/503 (Molecular Probes) was added to the wells to stain lipid droplets, and the Cell Tracker Red CMTPC dye (Molecular Probes) was added to enumerate cell number. Fluorescence was detected by excitation of the fluorophores with a 488-nm laser on an Acumen Explorer (TTP Lab Tech). The total intensity in channel 1 (500\u2013530 nm) reflected lipid droplet accumulation. Cells were detected using channel 3 (575\u2013640 nm) with 5-\u03bcm width and 100-\u03bcm depth filters. The ratio of the total intensity in PMT channel 1 over total intensity of channel 3 was also calculated. Percent activity was computed relative to an internal control (100% inhibited lipid droplet deposition due to the presence of 20 \u03bcM Triacsin C), which was added to 32 wells/plate.Small-molecule compound experiments were performed with embryonic 6 dpm/well, was included as a tracer. In lipolysis experiments, re-esterification of fatty acids in AML12 cells was prevented by including 10 \u03bcM Triacsin C (Biomol), an inhibitor of acyl coenzyme A synthetase [t test (GraphPad software).Measurements of NEFA released from lipid droplets or incorporated into the TG fraction were performed as previously described ,68,83. Bnthetase , in the nthetase , and 10%nthetase . AML12 cRabbit anti-TIP47 and goat anti-ADRP were used as previously published . AntibodCells were plated in four-well Lab-Tek chamber slides (Nunc) and incubated overnight with 400 \u03bcM oleic acid. In compound experiments, wells received vehicle (DMSO) or 5 \u03bcM BFA (10 mg/ml DMSO) treatment for 6 h. RNAi treatment prior to immunocytochemistry is outlined above. For ADRP and TIP47 staining, cells were fixed in 3% v/v paraformaldhyde/PBS for 15 min at room temperature. Staining was performed by published methods ,86. CellEight 100-mm dishes for each condition were treated with 400 \u03bcM oleic acid overnight and further treated with DMSO or BFA (5 \u03bcM) for 6 h on the next day. Cells were washed three times with phosphate buffered saline , scraped into PBS, and then pelleted by low-speed centrifugation. LD isolation was as reported . The lipTable S1(34 KB XLS)Click here for additional data file.Table S2(187 KB DOC)Click here for additional data file.Table S3(273 KB DOC)Click here for additional data file.Table S4(16 MB XLS)Click here for additional data file.Table S5(186 KB XLS)Click here for additional data file.Table S6(72 KB XLS)Click here for additional data file.Table S7(47 KB XLS)Click here for additional data file.Table S8(31 KB XLS)Click here for additional data file.Table S9(1 MB XLS)Click here for additional data file.Table S10(848 KB XLS)Click here for additional data file.Drosophila RNAi screen hits: FBgn0000028, FBgn0000042, FBgn0000114, FBgn0000339, FBgn0000489, FBgn0000547, FBgn0000567, FBgn0001186, FBgn0001204, FBgn0001301, FBgn0002878, FBgn0003048, FBgn0003118, FBgn0003339, FBgn0003380, FBgn0003392, FBgn0003462, FBgn0003557, FBgn0003607, FBgn0003691, FBgn0004167, FBgn0004187, FBgn0004401, FBgn0004587, FBgn0004595, FBgn0004611, FBgn0004652, FBgn0004797, FBgn0004838, FBgn0004856, FBgn0004879, FBgn0005411, FBgn0005626, FBgn0005630, FBgn0010083, FBgn0010215, FBgn0010355, FBgn0010638, FBgn0010750, FBgn0011571, FBgn0011701, FBgn0013746, FBgn0014020, FBgn0015320, FBgn0015818, FBgn0015919, FBgn0016926, FBgn0016940, FBgn0019643, FBgn0020611, FBgn0020908, FBgn0021768, FBgn0022246, FBgn0023143, FBgn0024285, FBgn0024308, FBgn0024555, FBgn0024754, FBgn0025638, FBgn0026206, FBgn0026317, FBgn0026620, FBgn0026722, FBgn0026878, FBgn0027495, FBgn0027589, FBgn0027885, FBgn0027951, FBgn0028360, FBgn0028420, FBgn0028982, FBgn0029123, FBgn0029526, FBgn0029661, FBgn0029731, FBgn0029766, FBgn0029824, FBgn0029850, FBgn0029873, FBgn0029935, FBgn0030075, FBgn0030077, FBgn0030087, FBgn0030093, FBgn0030189, FBgn0030244, FBgn0030390, FBgn0030434, FBgn0030492, FBgn0030608, FBgn0030872, FBgn0030904, FBgn0031008, FBgn0031030, FBgn0031031, FBgn0031074, FBgn0031093, FBgn0031232, FBgn0031390, FBgn0031518, FBgn0031626, FBgn0031673, FBgn0031816, FBgn0031836, FBgn0031888, FBgn0031894, FBgn0032049, FBgn0032340, FBgn0032351, FBgn0032360, FBgn0032363, FBgn0032388, FBgn0032454, FBgn0032622, FBgn0032800, FBgn0032868, FBgn0032945, FBgn0033155, FBgn0033160, FBgn0033541, FBgn0034071, FBgn0034402, FBgn0034646, FBgn0034709, FBgn0034839, FBgn0034946, FBgn0034967, FBgn0035085, FBgn0035136, FBgn0035294, FBgn0035546, FBgn0035569, FBgn0035631, FBgn0036274, FBgn0036374, FBgn0036470, FBgn0036556, FBgn0036734, FBgn0036761, FBgn0036811, FBgn0037024, FBgn0037149, FBgn0037178, FBgn0037250, FBgn0037278, FBgn0037304, FBgn0037568, FBgn0037920, FBgn0037924, FBgn0038168, FBgn0038191, FBgn0038343, FBgn0038359, FBgn0038391, FBgn0038592, FBgn0038633, FBgn0038662, FBgn0039054, FBgn0039941, FBgn0039959, FBgn0039997, FBgn0040279, FBgn0040291, FBgn0040369, FBgn0040534, FBgn0040651, FBgn0040777, FBgn0042693, FBgn0050126, FBgn0050470, FBgn0051313, FBgn0051374, FBgn0051632, FBgn0051814, FBgn0052056, FBgn0052062, FBgn0052112, FBgn0052121, FBgn0052150, FBgn0052202, FBgn0052352, FBgn0052397, FBgn0052440, FBgn0052635, FBgn0052704, FBgn0052710, FBgn0052711, FBgn0052970, FBgn0053207, FBgn0053500, FBgn0053516, FBgn0058413, FBgn0061200, FBgn0083976, FBgn0083992, FBgn0085381, FBgn0086441, FBgn0086674, FBgn0086899, FBgn0243486, FBgn0259162, FBgn0259169, FBgn0259171, FBgn0259217, FBgn0259228, FBgn0259240, FBgn0259243, FBgn0000008, FBgn0000100, FBgn0000116, FBgn0000212, FBgn0000409, FBgn0000492, FBgn0000636, FBgn0000986, FBgn0001133, FBgn0001216, FBgn0001217, FBgn0001218, FBgn0001942, FBgn0002023, FBgn0002590, FBgn0002593, FBgn0002607, FBgn0002906, FBgn0002921, FBgn0003031, FBgn0003060, FBgn0003209, FBgn0003277, FBgn0003279, FBgn0003360, FBgn0003600, FBgn0003687, FBgn0003701, FBgn0003941, FBgn0003942, FBgn0004110, FBgn0004922, FBgn0004926, FBgn0005593, FBgn0005614, FBgn0005630, FBgn0005648, FBgn0008635, FBgn0010078, FBgn0010220, FBgn0010348, FBgn0010352, FBgn0010391, FBgn0010409, FBgn0010410, FBgn0010412, FBgn0010431, FBgn0010612, FBgn0010808, FBgn0011211, FBgn0011272, FBgn0011284, FBgn0011701, FBgn0011726, FBgn0011745, FBgn0011837, FBgn0012034, FBgn0013275, FBgn0013276, FBgn0013277, FBgn0013278, FBgn0013279, FBgn0013325, FBgn0013981, FBgn0014020, FBgn0014857, FBgn0015024, FBgn0015288, FBgn0015393, FBgn0015756, FBgn0015774, FBgn0015778, FBgn0015834, FBgn0016120, FBgn0016694, FBgn0016926, FBgn0017397, FBgn0017545, FBgn0017566, FBgn0017579, FBgn0019624, FBgn0019886, FBgn0019936, FBgn0020129, FBgn0020386, FBgn0020439, FBgn0020910, FBgn0022343, FBgn0022935, FBgn0023170, FBgn0023171, FBgn0023213, FBgn0023531, FBgn0024150, FBgn0024330, FBgn0024733, FBgn0024939, FBgn0025286, FBgn0025582, FBgn0025724, FBgn0025725, FBgn0026262, FBgn0026666, FBgn0026741, FBgn0027321, FBgn0027348, FBgn0027615, FBgn0028530, FBgn0028867, FBgn0028968, FBgn0028969, FBgn0029088, FBgn0029161, FBgn0029504, FBgn0029761, FBgn0029799, FBgn0029822, FBgn0029860, FBgn0029897, FBgn0030025, FBgn0030088, FBgn0030174, FBgn0030259, FBgn0030341, FBgn0030384, FBgn0030386, FBgn0030606, FBgn0030610, FBgn0030669, FBgn0030692, FBgn0030696, FBgn0030726, FBgn0030915, FBgn0030951, FBgn0030990, FBgn0031300, FBgn0031392, FBgn0031545, FBgn0031696, FBgn0031771, FBgn0031842, FBgn0031980, FBgn0032053, FBgn0032215, FBgn0032261, FBgn0032330, FBgn0032400, FBgn0032518, FBgn0032587, FBgn0032596, FBgn0032619, FBgn0032656, FBgn0032675, FBgn0032833, FBgn0032987, FBgn0033029, FBgn0033081, FBgn0033085, FBgn0033282, FBgn0033313, FBgn0033341, FBgn0033368, FBgn0033379, FBgn0033403, FBgn0033591, FBgn0033652, FBgn0033699, FBgn0033902, FBgn0033912, FBgn0034020, FBgn0034258, FBgn0034487, FBgn0034488, FBgn0034537, FBgn0034579, FBgn0034649, FBgn0034751, FBgn0034902, FBgn0034948, FBgn0034968, FBgn0034987, FBgn0035276, FBgn0035315, FBgn0035422, FBgn0035562, FBgn0035563, FBgn0035638, FBgn0035699, FBgn0035753, FBgn0035872, FBgn0035976, FBgn0036135, FBgn0036213, FBgn0036288, FBgn0036343, FBgn0036351, FBgn0036360, FBgn0036398, FBgn0036449, FBgn0036462, FBgn0036492, FBgn0036532, FBgn0036534, FBgn0036576, FBgn0036613, FBgn0036728, FBgn0036820, FBgn0036825, FBgn0036895, FBgn0036990, FBgn0037010, FBgn0037028, FBgn0037093, FBgn0037097, FBgn0037098, FBgn0037102, FBgn0037207, FBgn0037249, FBgn0037270, FBgn0037356, FBgn0037415, FBgn0037429, FBgn0037529, FBgn0037546, FBgn0037559, FBgn0037566, FBgn0037610, FBgn0037637, FBgn0037752, FBgn0037813, FBgn0037912, FBgn0037942, FBgn0037955, FBgn0038049, FBgn0038074, FBgn0038131, FBgn0038281, FBgn0038345, FBgn0038538, FBgn0038628, FBgn0038629, FBgn0038734, FBgn0038760, FBgn0038881, FBgn0038996, FBgn0039205, FBgn0039214, FBgn0039302, FBgn0039359, FBgn0039402, FBgn0039404, FBgn0039464, FBgn0039520, FBgn0039580, FBgn0039857, FBgn0040007, FBgn0040010, FBgn0040233, FBgn0040512, FBgn0040529, FBgn0040634, FBgn0040766, FBgn0040793, FBgn0043001, FBgn0043904, FBgn0050007, FBgn0050290, FBgn0050387, FBgn0051158, FBgn0051284, FBgn0051291, FBgn0051302, FBgn0051354, FBgn0051361, FBgn0051450, FBgn0051453, FBgn0051554, FBgn0051613, FBgn0051754, FBgn0051774, FBgn0051847, FBgn0052050, FBgn0052105, FBgn0052179, FBgn0052193, FBgn0052219, FBgn0052311, FBgn0052600, FBgn0052633, FBgn0052720, FBgn0052733, FBgn0052773, FBgn0052778, FBgn0052797, FBgn0053128, FBgn0053147, FBgn0053256, FBgn0053271, FBgn0053300, FBgn0053319, FBgn0058337, FBgn0062412, FBgn0062413, FBgn0083950, FBgn0085392, FBgn0085408, FBgn0085424, FBgn0085436, FBgn0086710, FBgn0086712, FBgn0086758, FBgn0086904, FBgn0250791, FBgn0250814, FBgn0250834, FBgn0250908, FBgn0259113, FBgn0259212, FBgn0259232, and FBgn0259246.MGI:107807, MGI:107851, MGI:1333825, MGI:1334462, MGI:1335073, MGI:1351329, MGI:1353495, MGI:1354962, MGI:1858696, MGI:1861607, MGI:1891824, MGI:1891829, MGI:1913585, MGI:1914062, MGI:1914103, MGI:1914144, MGI:1914234, MGI:1914454, MGI:1915822, MGI:1916296, MGI:1917599, MGI:1929063, MGI:2385261, MGI:2385656, MGI:2387591, MGI:2388481, MGI:2443241, MGI:3041174, MGI:3694697, MGI:88192, MGI:95301, MGI:98342, and MGI:99431.Mouse genes with a confirmed function in lipid storage regulation:"} +{"text": "The efficacy, safety and tolerability of lumiracoxib, a novel selective cyclooxygenase-2 (COX-2) inhibitor, has been demonstrated in previous studies of patients with osteoarthritis (OA). As it is important to establish the long-term safety and efficacy of treatments for a chronic disease such as OA, the present study compared the effects of lumiracoxib at doses of 100 mg once daily (o.d.) and 100 mg twice daily (b.i.d.) with those of celecoxib 200 mg o.d. on retention on treatment over 1 year.In this 52-week, multicentre, randomised, double-blind, parallel-group study, male and female patients (aged at least 40 years) with symptomatic primary OA of the hip, knee, hand or spine were randomised (1:2:1) to lumiracoxib 100 mg o.d. (n = 755), lumiracoxib 100 mg b.i.d. or celecoxib 200 mg o.d. (n = 758). The primary objective of the study was to demonstrate non-inferiority of lumiracoxib at either dose compared with celecoxib 200 mg o.d. with respect to the 1-year retention on treatment rate. Secondary outcome variables included OA pain in the target joint, patient's and physician's global assessments of disease activity, Short Arthritis assessment Scale (SAS) total score, rescue medication use, and safety and tolerability.Retention rates at 1 year were similar for the lumiracoxib 100 mg o.d., lumiracoxib 100 mg b.i.d. and celecoxib 200 mg o.d. groups . It was demonstrated that retention on treatment with lumiracoxib at either dose was non-inferior to celecoxib 200 mg o.d. Similarly, Kaplan-Meier curves for the probability of premature discontinuation from the study for any reason were similar across the treatment groups. All three treatments generally yielded comparable results for the secondary efficacy variables and all treatments were well tolerated.Long-term treatment with lumiracoxib 100 mg o.d., the recommended dose for OA, was as effective and well tolerated as celecoxib 200 mg o.d. in patients with OA.clinicaltrials.gov NCT00145301 Osteoarthritis (OA) is the most common arthritis in adults, with an estimated worldwide prevalence of 9.6% for men and 18.0% for women aged at least 60 years ) or lumiracoxib 100 mg b.i.d. (n = 2 [0.1%]) compared with celecoxib 200 mg o.d. (n = 3 [0.4]). The incidence of definite or probable upper or lower GI tract ulcer complications was very low . None of the suspected upper GI tract complications were confirmed as definite by the independent safety committee. Probable upper GI tract ulcer complications were reported with lumiracoxib 100 mg b.i.d. and celecoxib 200 mg o.d. . The safety committee adjudicated two lower GI tract ulcer complications as definite .The number of patients with confirmed or probable CV/cerebrovascular events, defined using the APTC endpoint, was 3 (0.40%) with lumiracoxib 100 mg o.d., 6 (0.39%) with lumiracoxib 100 mg b.i.d. and 2 (0.26%) with celecoxib 200 mg o.d. The event analysis by time interval is shown in Table ALT/AST elevations >3 \u00d7 ULN occurred at a higher frequency in patients treated with lumiracoxib 100 mg b.i.d. (twice the recommended dose) (n = 35 [2.3%]) than with lumiracoxib 100 mg o.d. (n = 11 [1.5%]) or celecoxib 200 mg o.d. (n = 3 [0.4%]). The type of injury was usually hepatocellular with some mixed and very few cases of pure cholestatic liver injury. The majority of patients affected were asymptomatic and none were clinically jaundiced. No 'Hy's' cases (ALT/AST >5 \u00d7 ULN and bilirubin >3 mg/dL), which are more predictive for severe liver outcome, were observed with lumiracoxib 100 mg o.d., and one case was observed with lumiracoxib 100 mg b.i.d. after 143 days of treatment. An analysis by time intervals was performed and showed that, after short-term treatment (1\u201349 days), no cases of ALT/AST >3 \u00d7 ULN were observed with lumiracoxib 100 mg o.d. (0.00%) compared with 4 0.26%) with lumiracoxib 100 mg b.i.d. and 1 (0.13%) with celecoxib 200 mg o.d. occurred in 16 patients (2.1%) treated with lumiracoxib 100 mg o.d., 26 patients (1.7%) receiving lumiracoxib 100 mg b.i.d. and five patients (0.7%) treated with celecoxib 200 mg o.d. Notable increases in blood pressure, pulse or weight tended to occur less frequently with lumiracoxib 100 mg o.d. than in the other two groups. Mean changes from baseline in systolic blood pressure were -2.2 mmHg with lumiracoxib 100 mg o.d., 0.1 mmHg with lumiracoxib 100 mg b.i.d. and -0.3 mmHg with celecoxib 200 mg o.d. The corresponding changes from baseline for diastolic blood pressure were -1.1%, -0.5% and -0.1%. No patients in the lumiracoxib 100 mg o.d. group experienced a notable increase in pulse rate compared with 0.2% and 0.3% in the lumiracoxib 100 mg b.i.d. and celecoxib 200 mg o.d. groups, respectively. Weight increases of over 5% from baseline were reported by 10.2% of the lumiracoxib 100 mg o.d. group, 13.8% of the lumiracoxib 100 mg b.i.d. group and 11.2% of the celecoxib 200 mg o.d. group.In the sensitivity analysis excluding data from the centre with major violations of GCP, there were no clinically relevant differences from the total ITT population for any efficacy variable. One-year retention rates for the ITT population excluding the 63 patients from this centre were comparable with those for the total ITT population, and there were no differences between these populations in Kaplan-Meier estimates for the probability of premature discontinuation from the study for any reason.A total of 10 of the 63 patients from the excluded centre reported AEs. Overall, proportions of patients with any AE or with specific AEs were similar to the total safety population. However, two of the patients from this centre were reported to have notable increases in liver function tests. Excluding the centre that was audited, the incidence of ALT/AST elevations (>3 \u00d7 ULN) probably or possibly related to study drug was 1.4% with lumiracoxib 100 mg o.d., 2.3% with lumiracoxib 100 mg b.i.d. (twice the recommended dose), and 0.4% with celecoxib 200 mg o.d.This large, randomised, double-blind study has demonstrated that lumiracoxib 100 mg o.d., the recommended dose for OA, was non-inferior to celecoxib 200 mg o.d. for retention on treatment at 1 year in patients with OA of the knee, hip, hand and spine. As this outcome variable is dependent on the number of treatment discontinuations, which mainly occur for insufficient efficacy and tolerability issues, it indicates that the overall efficacy and safety of lumiracoxib 100 mg o.d. is comparable with that of celecoxib 200 mg o.d. Similar findings were observed with lumiracoxib at the higher dose of 100 mg b.i.d. Previous studies have reported that discontinuation rates are lower with selective COX-2 inhibitors compared with traditional NSAIDs, such as ibuprofen and naproxen ,25. ThesBoth doses of lumiracoxib were associated with improvements similar to celecoxib in all secondary efficacy parameters. At Week 52, approximately 50% of patients in each treatment group assessed their OA target joint pain and disease activity to be reduced, with over half of physicians also reporting lower disease activity. SAS scores were improved in all three treatment groups and there were no statistically significant between-group differences in the use of rescue medication. Although the use of rescue medication was high across all three treatment groups, this would not be unexpected in a 1-year study.Lumiracoxib 100 mg o.d. was also shown to be as well tolerated as celecoxib 200 mg o.d. in this large group of patients with OA over 1 year. The overall incidence and type of AEs for lumiracoxib at both doses were comparable with those observed with celecoxib 200 mg o.d., and as expected given the duration of the study and the population studied.The incidence of adjudicated CV/cerebrovascular events was very low across the treatment arms, supporting previous findings that lumiracoxib has a low risk of CV events that is comparable with NSAIDs. In TARGET, the incidence of non-fatal and silent MI, stroke, or CV death with lumiracoxib 400 mg o.d. was comparable with that observed with traditional NSAIDs, ibuprofen and naproxen . MoreoveLumiracoxib is indicated at a dose of 100 mg o.d. for chronic use in OA, and at doses of 200 mg or 400 mg o.d. for short-term use in acute pain indications. While liver toxicity is a known rare but serious side effect of all COX-2 inhibitors and traditional NSAIDs , there hGiven that OA pain may require treatment over extended periods of time, these findings demonstrating that lumiracoxib is efficacious and well tolerated over 1 year are important. The long-term efficacy, safety and tolerability profile of lumiracoxib 100 mg o.d. compared with celecoxib 200 mg o.d. has also been evaluated previously in a 39-week, double-blind extension to a 13-week, multicentre, randomised, double-blind, placebo-controlled trial of patients with knee OA ,37. CompOne limitation of this study was related to an announcement after the study had started that there may be a possible increase in CV risk with celecoxib. To ensure patient safety, a protocol amendment to patient eligibility was implemented and 17% of randomised patients, who had an elevated CV risk, had to be discontinued. Although this accounted for a significant proportion of treatment discontinuations, similar to that attributed to insufficient efficacy or AEs, supportive analyses showed that this did not affect the relative distribution for retention on treatment across the treatment arms (data not shown). A second limitation of this study was the inclusion of patients from a centre that did not meet the required standards of clinical practice. However, a sensitivity analysis demonstrated that exclusion of data from this centre resulted in the efficacy and safety data similar to that observed for the total ITT population.In conclusion, these data show that lumiracoxib 100 mg o.d. was as effective and well tolerated as celecoxib 200 mg o.d. during long-term treatment of up to 1 year in patients with OA. Hence, lumiracoxib should be considered as a useful treatment option for the relief of OA pain.AEs, Adverse events; ALT Alanine aminotransferase; ANCOVA, Analysis of covariance; APTC, Antiplatelet Trialists' Collaboration; AST, Aspartate aminotransferase; b.i.d., Twice daily; BMI, Body mass index; CI, Confidence interval; COX-1, Cyclooxygenase-1; COX-2, Cyclooxygenase-2; CV, Cardiovascular; CVA, Cerebrovascular accident; DSMB, Data Safety Management Board; ECG, Electrocardiogram; GCP, Good Clinical Practice; GI, Gastrointestinal; ITT, Intention-to-treat; LOCF, Last observation carried forward; LSM, Least squares means; MEDAL, Multinational Etoricoxib and Diclofenac Arthritis Long-term; MI, Myocardial infarction; NSAIDs, Nonsteroidal anti-inflammatory drugs; OA, Osteoarthritis; o.d., Once daily; RA, Rheumatoid arthritis; SAEs, Serious adverse events; SAS, Short Arthritis assessment Scale; SD, Standard deviation; TARGET, Therapeutic Arthritis and Gastrointestinal Event Trial; ULN, Upper limit of normal; WOMAC\u2122, Western Ontario and McMaster UniversitiesNeha P Patel is an employee of, and owns shares in, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Marianne Notter and Peter Sallstig are employees of, and own shares in, Novartis Pharma AG, Basel, Switzerland.Jean-Yves Reginster has received consulting fees from Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed, NPS, Theramex, lecturing fees from Merck Sharp and Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Teijin, Teva, Ebewee Pharma, Zodiac, Analis, Theramex, Nycomed, Novo-Nordisk, and research grant support from Bristol Myers Squibb, Merck Sharp & Dohme, Rottapharm, Teva, Lilly, Novartis, Roche, GlaxoSmithKline, Amgen, Servier.Roy Fleischmann has received research grant support from Novartis, Pfizer, Amgen, Wyeth, Abbott, Centocor, Genentech, Roche, Lilly, USB and TAP. He has been a consultant for Novartis, Pfizer, Amgen, Wyeth, Abbott, Centocor, Genentech, Roche, USB and Lilly, He is a member of the Speakers Bureau for Amgen, Wyeth, Abbott, Genentech and Roche.Hyman Tannenbaum has received lecture and/or consulting fees from Amgen, Bristol Myers Squibb, Merck-Frosst Canada, Novartis Pharmaceuticals, Pfizer, and Wyeth.J-YR, RF and HT were all investigators. PS was the Program Section Leader Phase III , NPP was the study Clinical Trial Leader and was involved in the conduct of the trial, and both were involved in the design of the trial. MN was the Trial Statistican, and was involved in study design and analysis of the data. All authors contributed to the development of the manuscript.Belgium: Dr F. d'Argent, Private Practice, Comines; Dr R. Leliaert, Private Practice, Tielt; Dr G. Mehuys, Private Practice, Tielt; Prof Dr J-Y Reginster, CHU Policlinique L.Brull, Li\u00e8ge; Dr H. Van Aerde, Private Practice, Genk; Dr P. Van Belle, Private Practice, Kraainem; Dr D. Vanroyen, Private Practice, Hasselt; Dr M. Veevaete, Private Practice, Bruxelles; Dr J. Vernijns, Private Practice, Genk; Dr G. Watt\u00e9, Private Practice, Tielt; Dr M. Wouters, CHIREC \u2013 Clinique du Parc L\u00e9opold, Bruxelles.Canada: Dr M. Awde, Murray Awde Medicine Professional Corporation, London, ON; Dr A. Bailey, BioQuest Research, Spruce Grove, AB; Dr A. Beaulieu, Clinique M\u00e9dicale St.-Louis, Ste-Foy, QC; Dr M. Bell, Sunnybrook & Women's College Health Sciences Centre, Toronto, ON; Dr W. Bensen, WynnTech Inc., Hamilton, ON; Dr W. Booth, Antigonish Clinical Trials, Antigonish, NS; Dr L. Breger, Kells Medical Research Group, Pointe-Claire, QC; Dr B. Carlson, North Road Medical Centre, Coquitlam, BC; Dr A. Chow, Credit Valley Prof Bldg, Mississauga, ON; Dr A. Cividino, Mac Research Inc., Hamilton, ON; Dr H. Conter, MSHJ Research Associates Inc., Halifax, NS; Dr D. Craig, Dr Donald Craig, St John, NB; Dr E. Dessouki, ADA Medical Ltd, Oshawa, ON; Dr L. Ferguson, Colchester Research Group, Truro, NS; Dr G. Girard, Novabyss Inc., Sherbrooke, QC; Dr B. Haraoui, Institut de Rhumatologie de Montreal, Montreal, QC; Dr R. Hart, White Hills Medical Clinic, St John's, NF; Dr E. Howlett, Lenore Centre Medical Centre, Saskatoon, SK; Dr C. Hudon, Unit\u00e9 de m\u00e9decine de famille, Chicoutimi, QC; Dr N. Hudson, PCT Networks Inc., Kelowna, BC; Dr S. Jaffer, Dr Shahin Jaffer Inc., Delta, BC; Dr J. Kooy, PCT Networks Inc., Penticton, BC; Dr M. Lafreniere, Clinique Medicale Pierre Bertrand, Vanier, QC; Dr S.Y. Lam, HAWSE Clinic, Calgary, AB; Dr B. Lasko, Manna Research, Toronto, ON; Dr J. Li, G.A. Research Associates Ltd, Moncton, NB; Dr F. Morin, Centre de Recherche Musculo-Squelettique, Trois-Rivieres, QC; Dr W. Olsheski, Albany Medical Clinic, Toronto, OH; Dr M. O'Mahony, London Road Diagnostic Clinic and Medical Centre, Sarnia, ON; Dr M. Omichinsky, Portage Clinical Studies, Portage La Prairie, MB; Dr J.-P. Ouellet, Q&T Research, Inc., Sherbrooke, QC; Dr B. Pynn, Clinical Research Consultant Group, Beaconsfield, QC; Dr B. Ramjattan, First Line Medical Services Ltd, St John's, NF; Dr J. Rodrigues, Dr Jude Rodrigues, Windsor, ON; Dr K. Saunders, McPhillips Medical Clinic, Winnipeg, NB; Dr K. Skeith, Allin Clinic, Edmonton, AB; Dr R. Somani, Dr Rizman Somani, Langley, BC; Dr E. St-Amour, Q&T Research, Inc., Gatineau, QC; Dr H. Tannenbaum, Rheumatic Disease Centre of Montreal, Montreal, QC; Dr J. Tannenbaum, Meadowlands Family Health Center, Ottawa, ON; Dr M. Tolszcuk, Q&T Research, Inc., Sherbrooke, QC; Dr W. Yang, Allergy and Asthma Research Centre, Ottawa, ON; Dr B. Zidel, Malton Medical Centre, Mississauga, ON; Dr M. Zummer, Polyclinique Maisonneuve-Rosemont, Montreal, QC.France: Dr P. Beignot Devalmont, Cabinet du Dr Beignot Devalmont, Rouen; Dr L. Boucher, Cabinet du Dr Boucher, Murs Erign\u00e9; Dr A. Campagne, Cabinet du Dr. Alain Campagne, Tours; Dr B. Chagnoux, Cabinet du Dr Chagnoux, Bourges; Dr J.-B. Churet, Cabinet du Dr Churet, Le Pradet, France; Dr A. El Sawy, Cabinet du Dr El Sawy, St. Martin d'Heres; Dr F. Liotard, Private Practice, Laragne; Dr C. Magnani, Cabinet du Dr Magnani, L'Aigle; Dr S. Musso, Cabinet du Dr Musso, Eaunes; Dr D. Pineau Valencienne, Cabinet du Dr Pineau Valencienne, Nantes; Dr J. Sicard, Cabinet M\u00e9dical; St. Romain/Cher; Dr F. Spilthooren, Cabinet du Dr. Fran\u00e7ois Spilthooren, Evreux.Germany: Dr C. Fleige, Klinische Forschung Berlin Mitte, Berlin; Dr A. Herzner, Klinische Forschung Hamburg, Hamburg; Dr R. Lehmann, Klinische Forschung Berlin-Buch GmbH, Berlin; R. Nischick (Dipl Med), Zentrum Therapiestudien/Dr Nischick, Leipzig; Dr H. Schneider, Praxis Dr. Schneider, Bad Nauheim; Dr M. Schreinert, Klinische Forschung Berlin Mitte, Berlin; Dr V. von Behren, Praxis Dr von Behren, Wiesbaden.Italy: Prof S. Adami, Centro Ospedaliero Clinicizzato di Medicina Riab. e Prev., Valeggio Sul Mincio; Professor E. Ambrosioni, Az. Osp. di Bologna Policl. S. Orsola \u2013 Malpighi, Bologna; Dr S. Bernini, Policlinico \u2013 Universit\u00e0 degli Studi, Modena; Dr G. Bianchi, Az. San. Genovese 3 P.O. Genova Ponente \u2013 S.O. La Colletta, Arenzano; Prof S. Bombardieri, Az. Osp. Ospedali Riuniti S. Chiara \u2013 Universit\u00e0 degli Studi, Pisa; Prof C. Borghi, Az. Osp. di Bologna Policl. S. Orsola \u2013 Malpighi, Bologna; Dr M. Broggini, Ospedale di Circolo Fondazione Macchi, Varese; Prof M. Carrabba, Ospedale Luigi Sacco \u2013 Azienda Ospedaliera, Milano; Prof M. Cipriani, Presidio Ospedaliero della Misericordia, Grosseto; Prof C. Ferri, Az. Ospedal. Univ. di Modena Policlinico Univ. degli Studi, Modena; Prof W. Grassi, Presidio Ospedaliero Ospedale Murri, Jesi; Dr P. Manganelli, Ospedale Maggiore \u2013 Azienda Ospedaliera di Parma, Parma; Prof U. Martorana, Policlinico Universitario, Universit\u00e0 degli Studi di Palermo, Palermo; Prof M. Matucci Cerinic, Azienda Ospedaliera Careggi \u2013 Universit\u00e0 degli Studi, Firenze; Prof S. Minisola, Azienda Policlinico Umberto I\u00b0 \u2013 Universit\u00e0 La Sapienza, Roma; Prof C. Montecucco, Policlinico S. Matteo \u2013 IRCCS Universit\u00e0 degli Studi di Pavia, Pavia; Dr M. Muratore, Presidio Ospedaliero Galateo, San Cesario di Lecce; Prof I. Olivieri, Azienda Ospedaliera S. Carlo, Potenza; Dr L. Punzi, Azienda Ospedaliera di Padova \u2013 Universit\u00e0 degli Studi, Padova; Prof G. Rovetta, Istituto E. Bruzzone, Genova; Dr S. Scarpato, Ospedale Scarlato ASL Salerno 1, Scafati; Prof B. Seriolo, Azienda Osp. Ospedale S. Martino \u2013 Universit\u00e0 degli Studi, Genova; Prof G. Valesini, Azienda Policlinico Umberto I\u00b0 \u2013 Universit\u00e0 La Sapienza, Roma.Switzerland: Dr H. Fahrer, Praxis im Lindenhofspital, Bern; Dr T. Lehmann, Praxis Dr Lehmann, Bern; Dr M. Pellaton, Praxis Dr Pellaton, Neuch\u00e2tel; Dr R. Theiler, Stadtspital Triemli, Z\u00fcrich; Prof A. Tyndall, Felix Platter Spital, Basel; Dr D. Uebelhart, Universit\u00e4tsspital Z\u00fcrich, Z\u00fcrich; Prof P.M. Villiger, Inselspital Bern, Bern.USA: Dr E. Arnold, Illinois Bone & Joint Institute, Morton Grove, IL; Dr A. Aven, Clinical Research Associates, Ltd, Arlington Heights, IL; Dr S. Baumgartner, The Physicians Clinic of Spokane, Spokane, WA; Dr D. Benson, DMI Healthcare Group, Inc., Largo, FL; Dr E. Boling, Boling Clinic Trials, Upland, CA; Dr S. Bookbinder, Ocala Rheumatology Research Center, Ocala, FL; Dr D. Borenstein, Arthritis and Rheumatism Associates, Washington, DC; Dr J. Box, The Arthritis Clinic at Carolina Bone & Joint Center, Charlotte, NC; Dr D. Brandon, California Research Foundation, San Diego, CA; Dr P. Buchanan, River Road Medical Group, Eugene, OR; Dr F. Burch, Radiant Research, San Antonio, TX; Dr. B. Caciolo, St. Louis Center for Clinical Research, St Louis, MO; Dr J. Cato, Dial Research Associates, Nashville, TN; Dr V. Chindalore, Pinnacle Research Group, LLC, Anniston, AL; Dr J. Christensen, Nevada Access to Research & Education Society, Las Vegas, NV; Dr D. Colan, Internal Medicine Associates, Grand Island, NE; Dr J. Condemi, AAIR Research Center, Rochester, NY; Dr B. Corser, Community Research, Cinncinnati, OH; Dr R. Craven, East Coast Clinical Research, LLC, Virginia Beach, VA; Dr A. Dahdul, FutureCare Studies, Springfield, MA; Dr D. Dayon, Adviso Medical Research, LLC, Chicago, IL; Dr M. Dewan, Meera Dewan, P.C., Omaha, NE; Dr A. Dikranian, San Diego Arthritis & Osteoporosis Medical Clinic, San Diego, CA; Dr S. Elliott, MediSphere Medical Research Center, Evansville, IN; Dr R. Ettlinger, Cedar Medical Center, Tacoma, WA; Dr S. Fallahi, Montgomery Rheumatology Associates, Montgomery, AL; Dr F. Farmer, Radiant Research Daytona Beach, Daytona Beach, FL; Dr C. Fisher, Health Research of Hampton Roads, Newport News, VA; Dr D. Fiske, Clinical Research Center of South Florida, Stuart, FL; Dr R. Fleischmann, Radiant Research, Dallas, Texas; Dr S. Folkerth, Clinical Research Center of Nevada/Summit Medical Group, Las Vegas, NV; Dr J. Gresh, Renstar Medical Research, Ocala, FL; Dr M. Grisanti, Buffalo Rheumatology, Orchard Park, NY; Dr W. Harper, Wake Research Associates, Raleigh, NC; Dr E. Harris, E. Robert Harris Medical Corporation, Whittier, CA; Dr D. Haselwood, Med Investigations, Fair Oaks, CA; Dr M. Heick, The Physicians Clinic of Spokane, Spokane, WA; Dr J. Herrod, Cochise Clinical Research, Sierra Vista, AZ; Dr J. Huff, Arthritis Center South Texas, San Antonio, TX; Dr D. Jones III, Alabama Research Center, Birmingham, AL; Dr J. Kaine, Sarasota Arthritis Center, Sarasota, FL; Dr R. Karr, Physicians Pharmaceutical Study Services, Everett, WA; Dr B. Kerzner, Health Trends Research, Baltimore, MD; Dr H. Knapp, Deaconess Billings Clinic Research Division, Billings, NT; Dr M. Kohen, Coastal Medical Research Center, Port Orange, FL; Dr W. Larson, Radiant Research, Lakewood, WA; Dr J. LaSalle, Medical Arts Research Collaborative, Excelsior Springs, MO; Dr D. Lee, Irvine Center for Clinical Research, Irvine, CA; Dr J.D. Lehmann, Ridgeview Research Center, Chaska, MN; Dr R. Lipetz, Encompass Clinical Research, Spring Valley, CA; Dr T. Littlejohn, Piedmont Medical Research Associates, Inc., Winston-Salem, NC; Dr J. Loveless, Intermountain Orthopedics, Boise, ID; Dr B. Lubin, Hampton Roads Center for Clinical Research, Norfolk, VA; Dr N. Lunde, Twin Cities Clinical Research, Brooklyn Park, MN; Dr F. Maggiacomo, New England Center for Clinical Research, Cranston, RI; Dr H. Mcilwain, Tampa Medical Group, P.A., Tampa, FL; Dr J. McKay, Oklahoma Ctr for Arthritis Therapy & Research, Tulsa, OK; Dr E. McPherson, Clinical Research of Winston-Salem, Winston-Salem, NC; Dr K. Miller, Arthritis Associates of CT/NY, LLC, Danbury, CT; Dr S.D. Miller, Northeast Medical Research Associates, Inc., North Dartmouth, MA; Dr V.J. Mirkil, Clinical Research Consortium, Las Vegas, NV; Dr A. Mollen, Southwest Health, Ltd, Phoenix, AZ; Dr M. Morgan, Complete Family Care, Northglenn, CO; Dr D. Moss, Carolinas Research Associates, Charlotte, NC; Dr. N. Neal, Valerius Medical Group and Research Center of Long Branch, Long Beach, CA; Dr T. Nolen, TOMAC, Inc., Columbiana, AL; Dr D. Noritake, Pasadena, CA; Dr D. Petrone, Research Associates of NorthTexas, Dallas, TX; Dr E. Portnoy, Westlake Medical Research, Westlake Village, CA; Dr A. Puopolo, Milford Emergency Associates, Inc., Milford, MA; Dr B. Rankin, University Clinical Research \u2013 DeLand, DeLand, FL; Dr K. Rock, Greystone Medical Research, LLC, Birmingham, AL; Dr S. Rosenblatt, Irvine Center for Clinical Research, Irvine, CA; Dr J. Rubino, Triangle Medical Research Associates, Raleigh, NC; Dr B. Sakran, Southern Illinois Clinical Research Centre, O'Fallon, IL; Dr M. Sayers, Arthritis Associates of Colorado Springs, Colorado Springs, CO; Dr J. Schechtman, Sun Valley Arthritis Center, Ltd, Glendale, AZ; Dr D. Schoenwalder, Mercy Med Group \u2013 Woodlake Research, Chesterfield, MO; Dr. C. Scoville, Insitute of Arthritis Research, Idaho Falls, ID; Dr A. Sebba, Arthritis Associates, Palm Harbor, FL; Dr S. Sharp, Clinical Research Associates, Nashville, TN; Dr Y. Sherrer, CRIA Research, Ft Lauderdale, FL; Dr T. Shlotzhauer, Rochester Clinical Research, Rochester, NY; Dr B. Short, Pinnacle Medical Research, Overland Park, KS; Dr T. Smith, Mercy Health Research, St Louis, MO; Dr C. Strout, Coastal Carolina Research Center, Mount Pleasant, SC; Dr R. Surowitz, Health Awareness, Jupiter, FL; Dr J. Tesser, Radiant Research \u2013 Phoenix North, Phoenix, AZ; Dr H. Thomas, CTT Consultants, Inc., Prairie Village, KS; Dr M. Tonkon, Apex Research Institute, Santa Ana, CA; Dr R. Trapp, The Arthritis Center, Springfield, IL; Dr R. Valente, Arthritis Center of Nebraska, Lincoln, NE; Dr R. Wade, Progressive Clinical Research, Centerville, UT; Dr W. Warnes, Meridian Clinical Research, Omaha, NE; Dr S. Weisman, Boulder Medical Center, Boulder, CO; Dr R. Weltman, Physician's Research Center, Hartford, CT; Dr C. Wiesenhutter, Coeur d'Alene Arthritis Clinic, Coeur d'Alene, ID; Dr M. Wiggins, Clinical Research Coordinating Svc., Loveland, CO; Dr R. Williams, Georgia Clinical Professionals Group, Athens, GA; Dr S. Williams, PharmaTex Research LLC, Amarillo, TX; Dr L. Willis, Lynn Health Science Institute, Oklahoma City, OK; Dr M. Wukelic, Rockwood Clinic, Spokane, WA; Dr D. Zmolek, Central New York Clinical Research, Manlius, NY.The pre-publication history for this paper can be accessed here:"} +{"text": "The affiliations of the second author, Richard Hamelin, are incorrect. First, affiliation number 2 is incorrect. It should read: INSERM, UMRS 938, Paris, France. Second, an affiliation for this author was omitted. Richard Hamelin is also affiliated with Universit\u00e9 Pierre et Marie Curie-Paris 6, Paris, France."} +{"text": "The affiliation for the 12th, 13th, and 14th authors was incorrect. At the time of the study, Laura Bossi, Magali Becker, and Patricia Zerr were affiliated with Faust Pharmaceuticals SA, Illkirch, France. Magali Becker and Patricia Zerr are currently affiliated with Transgene SA, Illkirch-Graffenstaden, France."} +{"text": "Xanthomonas oryzae pv. oryzae PXO99A. BMC Genomics 2008, 9:204' [Following the publication of the article 'Genome sequence and rapid evolution of the rice pathogen , 9:204' , the subSteven L Salzberg, Daniel D Sommer, Michael C Schatz, Adam M Phillippy, Pablo D Rabinowicz, Seiji Tsuge, Ayako Furutani, Hirokazu Ochiai, Arthur L Delcher, David Kelley, Ramana Madupu, Daniela Puiu, Diana Radune, Martin Shumway, Cole Trapnell, Gudlur Aparna, Gopaljee Jha, Alok Pandey, Prabhu B Patil, Hiromichi Ishihara, Damien F Meyer, Boris Szurek, Valerie Verdier, Ralf Koebnik, J Maxwell Dow, Robert P Ryan, Hisae Hirata, Shinji Tsuyumu, Sang Won Lee, Young-Su Seo, Malinee Sriariyanum, Pamela C Ronald, Ramesh V Sonti, Marie-Anne Van Sluys, Jan E Leach, Frank F White and Adam J Bogdanove.A and MAFF. CT and MVS analyzed IS elements. GA and RVS analyzed the adhesin locus. MCS, ALD, and SLS discovered and characterized the 212 kb duplication. FFW carried out the TAL effector analysis, assisted by RK and AJB. CT documented rearrangements in the PXO99A genome relative to MAFF. DDS, SLS and RK investigated the CRISPRs. SeT, AF, and HO validated the MAFF assembly. SLS identified regions of possible lateral gene transfer. DK optimized annotation of hypothetical protein genes. SeT, AF, GA, GJ, AP, PBP, RVS, HI, DFM, BS, VV, JMD, RPR, HH, ShT, SWL, YS, MS, PCR, RVS, MVS, JEL, FFW, and AJB contributed to the manual annotation. SLS and AJB drafted the manuscript, assisted by PDR, SeT, GA, PBP, RVS, RK, MVS, JEL, and FFW. All authors approved the final manuscript.SLS, JEL, FFW, and AJB conceived the project. SLS, PDR, and AJB coordinated and oversaw the project. SLS and PDR managed all genomic sequencing. DP and MCS did the initial assembly of the genome. DR directed the sequence finishing and gap closure activities. MCS, AMP, and ALD created the final assembly. RM was in charge of the initial, semi-automated genome annotation. MCS, CT, and SLS carried out the overall structural analysis of the genome. PBP and RVS performed the whole genome alignments for phylogenetic analysis. DK, CT, DDS, and SLS compared the gene content of PXO99"} +{"text": "The last five authors, Ichiro Saito, Carlo Rivolta, Shiro Ikegawa, Andrea Superti-Furga, and Toshio Hirano, should be noted as joint senior authors on this work."} +{"text": "J Exp Clin Cancer Res 2009, 28:5.Correction to Kleiner HE, Krishnan P, Tubbs J, Smith M, Meschonat C, Shi R, Lowery-Nordberg M, Adegboyega P, Unger M, Cardelli J After publication of the work , we noti"} +{"text": "Molecular evolution of the keratin associated protein gene family in mammals, role in the evolution of mammalian hair. BMC Evol Biol 2008, 8:241.Correction to Wu DD, Irwin DM, Zhang YP: In the publication of our work , in the Table S1 \u2013 KRTAP genes in the human, chimpanzee, rhesus macaque, dog, mouse, rat, opossum, and platypus genomes.Click here for file"} +{"text": "Correction to Bemmo A, Benovoy D, Kwan T, Gaffney DJ, Jensen RV, Majewski J: Gene expression and isoform variation analysis using Affymetrix Exon Arrays. BMC Genomics 2008, 9: 529. After the publication of , we were"} +{"text": "This report profiles the keynote talks given at ISMB02 in Edmonton, Canada, by Michael Ashburner, Barry Honig, Isidore Rigoutsos, Ford Doolittle, Stephen Altschul,Terry Gaasterland, John Reinitz, and the Overton Prize winner, David Baker."} +{"text": "PKD1 gene family in primatesChromosomal evolution of the . BMC Evolutionary Biology 2008, 8:263 (doi:10.1186/1471-2148-8-263)Correction to Kirsch S, Pasantes J, Wolf A, Bogdanova N, M\u00fcnch C, Pennekamp P, Krawczak M, Dworniczak B, Schempp W: After publication of this work , we noteStefan Kirsch, Juanjo Pasantes, Andreas Wolf, Nadia Bogdanova, Claudia M\u00fcnch, Arseni Markoff, Petra Pennekamp, Michael Krawczak, Bernd Dworniczak and Werner SchemppSK performed parts of the molecular phylogenetic analyses and helped to finalize the manuscript, JP and CM performed the FISH experiments, AW and MK performed the statistical analyses and helped to finalize the corresponding sections of the manuscript, NB, AM and PP performed probe identification, preparation and characterization, BD and WS designed the study, and WS drafted and finalized the manuscript."} +{"text": "The Industrialization Workshop Series aims to promote and discuss integration, automation,simulation, quality, availability and standards in the high-throughput life sciences.The main issues addressed being the transformation of bioinformatics and bioinformaticsbaseddrug design into a robust discipline in industry, the government, research institutesand academia. The latest workshop emphasized the influence of the post-genomic era onmedicine and healthcare with reference to advanced biological systems modeling andsimulation, protein structure research, protein-protein interactions, metabolism andphysiology. Speakers included Michael Ashburner, Kenneth Buetow, Francois Cambien,Cyrus Chothia, Jean Garnier, Francois Iris, Matthias Mann, Maya Natarajan, PeterMurray-Rust, Richard Mushlin, Barry Robson, David Rubin, Kosta Steliou, John Todd,Janet Thornton, Pim van der Eijk, Michael Vieth and Richard Ward."} +{"text": "KCNJ11 gene. Ann Saudi Med 2010;30:162-164In Volume 30, Issue 2, in the following article: Al-Mahdi M, Al Mutair A, Al Balwi M, Hussain K. Successful transfer from insulin to oral sulphonylurea in a 3-year-old girl with a mutation in the An additional affiliation for Maria Al-Madhi should have been Pediatric Endocrinology Unit, Pediatric Department, King Abdul-Aziz Medical City, National Guard Hospital, Riyadh, Saudi ArabiaMutaira@NGHA.MED.SAThe corresponding author should be Angham AlMutair, Pediatric Department, Endocrine Division, King Abdul Aziz Medical City, National Guard Hospital, PO Box 22490 Riyadh 11426, Saudi Arabia T: +96612520088 ext. 11630, F: 11641"} +{"text": "The compounds were characterized by melting point, analytical data, IRspectroscopy and magnetic susceptibility. The antimicrobial activity of the compounds was determined bythe disk diffusion method in Mueller-Hinton Agar on Staphylococcus aureus ATCC 6538, Staphylococcus epidermidis ATCC 12228, Escherichia coli ATCC 8739, Klebsiella pneumoniae ATCC 4352, Pseudomonas aeruginosa ATCC 1539, Salmonella typhi, Shigella flexneri, Proteus mirabilis, Candida albicans ATCC 10231. Cu(II)and Ag(I)complexes of II, III and IV showed considerable activity against S. aureus, S. epidermidis, Ps. aeruginosa, S. typhi, Sh. flexneri and C. albicans microorganisms, the ligands themselveshaving no effect.The metal complexes of nine 2-substituted-1H-benzimidazoles"} +{"text": "Correction to: Reprod Healthhttp://dx.doi.org/10.1186/s12978-018-0651-zFollowing publication of the original article , we haveVernon Mochache; email: VMochache@mgic.umaryland.edu;Program Director, Partnership for Advanced Clinical Education (PACE) Kamilisha - Kenya.Center for International Health, Education, and Biosecurity (CIHEB).Institute of Human Virology, University of Maryland School of Medicine, KREP Centre, 6th Floor, Wood Avenue, Kilimani, Nairobi, P.O. Box\u00a0495\u201300606, Nairobi, Kenya."} +{"text": "Scientific Reports 10.1038/s41598-018-35426-z, published online 05 February 2019Correction to: In Figure 1, in the Historic/Modern Samples map, Cambodia, Celebes, Hainan, Laos, Papua New Guinea, Seman, South Moluccas and Vietnam are labelled incorrectly. The correct Figure"} +{"text": "Box: 1712, 11932, Saudi Arabia2 Chemistry Department, Sohag University, Sohag, 82524, Egypt; E-Mail: omran2002@mailcity.comWe found following errors in our paper published in Molecules recently . On page"} +{"text": "The members of The Global Pneumococcal Sequencing Consortium were not correctly acknowledged in the published article. The Acknowledgements should read as shown below.We thank Martin Hunt and the Infection Genomics and Pathogen Informatics groups at the Wellcome Trust Sanger Institute for testing and feedback during development. Furthermore, we wish to thank the authors of PneumoCaT for building the CTV database.We also thank The Global Pneumococcal Sequencing Consortium. Members of The Global Pneumococcal Sequencing Consortium are David Aanensen, Maria-Cristina C. Brandileone, Martin Antonio, Samanta C. G. Almeida, Francisco Campos, P. E. Carter, Stuart C. Clarke, Jennifer Cornick, Nicholas Croucher, Ron Dagan, Dr Sanjay H. Doiphode, Sr. Consultant; Eric S. Donkor, PhD; Egorova Ekaterina, PhD; Ozgen Koseoglu Eser, Dean Everett, Rebecca Ford, Rebecca A. Gladstone, Anne Von Gottberg, Md. Hasanuzzaman, Paulina Hawkins, PL Ho, Waleria Hryniewicz, Andrew J. Pollard, FRCPCH PhD FMedSci Professor of Paediatric Infection and Immunity; Tamara Kastrin, Keith P. Klugman, Brenda Kwambana-Adams, Pierra Law, Deborah Lehmann, Thomas M Lietman, Naima El Mdaghri, Benild Moiane, Helio Mucavele, Stephen K. Obaro, MD Theresa J. Ochoa, Metka Paragi, Tall Haoua PharmD, MPH; Mignon du Plessis, Rama Kandasamy, Nurit Porat, Dr K. L. Ravikumar, Professor Emeritus; Mabel Regueira, Ewa Sadowy, Samir K. Saha, Sadia Shakoor, Assistant professor; Betuel Sigauque, Anna Skoczyoska, Kwan Soo Ko, PhD; Peggy-Estelle Tientcheu, Leonid P. Titov, Paul Turner, Balaji Veeraraghavan, Nicole Wolter, Stephen D. Bentley, Lesley McGee and Robert F. Breiman."} +{"text": "Nature Communications 10.1038/s41467-019-09385-6, published online 01 April 2019Correction to: The original version of this Article contained errors in the author affiliations.Michael W. Sereda was incorrectly associated with the Department of Cellular Neurophysiology, Hanover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany. The correct affiliations for Michael W. Sereda are Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 G\u00f6ttingen, Germany and Department of Clinical Neurophysiology, University Medical Center G\u00f6ttingen, Robert-Koch-Str. 40, 37075 G\u00f6ttingen, Germany.Markus H. Schwab was incorrectly associated with Department of Clinical Neurophysiology, University Medical Center G\u00f6ttingen, Robert-Koch-Str. 40, 37075, G\u00f6ttingen. The correct affiliations for Markus H. Schwab are Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 G\u00f6ttingen, Germany; Department of Cellular Neurophysiology, Hanover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany; and Center for Systems Neuroscience (ZSN), B\u00fcnteweg 2, 30559 Hanover, Germany.Ruth M. Stassart was incorrectly associated with the Center for Research in Biotechnology (CIB), Costa Rican Institute of Technology (TEC), Cartago, Costa Rica. The correct affiliations for Ruth M. Stassart are Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, Hermann-Rein-Str. 3, 37075 G\u00f6ttingen, Germany and Department of Neuropathology, University Hospital Leipzig, Liebigstr. 26, 04103 Leipzig, Germany.These errors\u00a0have now been corrected in both the PDF and HTML versions of the Article."} +{"text": "AbstractPucciniamodiolae, a rust fungus pathogen of Carolina bristlemallow, Modiolacaroliniana , is newly reported from North America, appears to be well established along the Gulf coast and is likely to have been introduced from South America. Its taxonomy, distribution and natural host range are discussed and a lectotype designated for this species. Malvasylvestris and Alcearosea are reported as new hosts for the rust. Additional new records for Malvaceae rusts are made for P.modiolae on Alcearosea from Brazil, P.heterospora on Herissantiacrispa in Florida and P.heterogenea on Malva sp. in Peru. Finally, an identification key for the microcyclic Puccinia species on members of Malvaceae in North America is provided. Neomycetes are alien fungi entering a new area (country or continent), typically as a result of non-intentional human activity, that become established in the new region . The mosPucciniamodiolae P. Syd. & Syd. is a microcyclic rust fungus that was originally reported on Modiolaprostrata A.St.-Hil. (=M.caroliniana (L.) G. Don; Malvaceae) from South America on the basis of specimens from Argentina and Uruguay , the U.S. National Fungus Collections (BPI) and from fresh collections (listed in specimens examined below). Voucher specimens for new material are deposited in PUR. Rust spores and cross sections were routinely mounted in lactic acid in glycerol. Light microscopic analyses were performed using a Nikon Eclipse 80i microscope. Photomicrographs were obtained with a DS-Fi1 Nikon camera. In all studied specimens, thirty spores were randomly selected and measured.Materials studied here were obtained from the Arthur Fungarium and edited in Inkscape v2 . Newly generated sequences are deposited in GenBank, accessions MH742974\u2013MH743006.DNA was extracted and the 5\u2019 end of the nuclear 28S rDNA, amplified with rust-specific primers and sequenced following previous published protocols . SequencPucciniamodiolae along the Gulf coast on Modiolacaroliniana and occurring as far north as Indiana on new hosts Alcearosea L. and Malvasylvestris L. Examination of herbarium material also reveals P.modiolae as far south as Brazil on A.rosea (PUR N15322). Additional new records for Malvaceae rusts are made for P.heterospora on Herissantiacrispa in Florida and P.heterogenea on Malva sp. in Peru. In total, we generated 28S rDNA sequences for 32 collections of Puccinia species on Malvaceae, including ten collections of P.modiolae for phylogenetic analyses 1(3): 478 (1903) [1904]P.malvacearumvar.modiolae Pennington, Anales de la Sociedad Cientifica Argentina 55: 34 (1903). Figures Modiolacaroliniana (as M.prostrata), Argentina, 1880\u20131881, C. Spegazzini, Decades Mycologiae Argentinae No. 10, PUR N6057, named as P.malvacearum (designated here). Isolectotype: BPI 086498.Lectotype: on Spermogonia usually epiphyllous, located on the opposite side of the telia in small groups, globose, 140\u2013150 \u00b5m in diameter, yellowish-brown, with abundant and outward growing periphyses Fig. . TeliospPucciniamodiolae \u2013 ARGENTINA: on Modiolacaroliniana (as M.prostrata), C. Spegazzini, Decades Mycologiae Argentinae No. 10, 1880\u20131881 . USA: Indiana, Tippecanoe Co., Lafayette, Alcearosea L., M.C. Aime, MCA5059, 2012 Nov 05 ; A.rosea, M.C. Aime, MCA5042, 2012 Oct 01 ; West Lafayette, Purdue University Campus, Malvasylvestris L., Amnat Eamvijarn, MCA6961, 2016 Sept 16 ; Louisiana, East Baton Rouge Parish, Baton Rouge, Louisiana State University campus, M.caroliniana (L.) G. Don, Amnat Eamvijarn, U1374, July 2008 ; M.caroliniana, M.C. Aime, MCA3680, 2009 Mar 26 ; M.caroliniana, Don Ferrin, MCA3565, 2008 Mar 14 ; LSU Campus parking lot, M.caroliniana, Don Ferrin, MCA3589, 2008 May 14 ; Baton Rouge, private house, Malvaceae sp., Chris Clark, MCA4228, 2011 May 09 ; Bossier Parish, Red River Research Station, M.caroliniana, M.C. Aime, MCA4719, 2012 Apr 19 (PUR N12551); Evangeline Parish, Mamou, Main Street, Malvaceae sp., M.C. Aime, MCA3523, 2008 Feb 05 (PUR N22676); Tangipahoa Parish, 10 mi East of Independence, M.caroliniana, Charles Rush, MCA3854, 2009 Oct 22 ; St. James Parish, Convent, on the River Road in lawn next to Manresa House of Retreats, M.caroliniana, M.C. Aime & Tom Bruns, MCA3671, 2009 Jan 22 (PUR N12546); Orleans Parish, New Orleans, private residence, Malvaceae sp., Beth Kennedy, U1663, 2017 Mar 03 ; Modiola sp., M.C. Aime, MCA3568, 2008 Mar 23 (PUR N16658); Texas, Harris Co., Shell Station on Rt. 146, Seabrook Waterfront District, M.caroliniana, M.C. Aime, MCA3717, 2009 May 04 . BRAZIL: Sao Paulo, Alcearosea, M. Figueiredo, J. Hennen s.n., 1999 Jan 12 (PUR N15322).Pucciniaheterogenea \u2013 PERU: Cajamarca Provence, Shudall, Malva sp., Jorge Diaz Valderrama, U1568, 2014 Dec 30 .Pucciniaheterospora \u2013 USA: Florida, Monroe Co., Marathon, Herissantiacrispa (L.) Briz., M.C. Aime, MCA2876, 2004 Dec 31 .Pucciniamalvacearum \u2013USA: California, Alameda Co., Berkeley, Alcearosea, M.C. Aime, MCA6367, 2016 Aug 05 ; Idaho, Gem Co., Alcearosea, Krishna Mohan, U888, 2006 May 26 ; Canyon Co., Parma, Alcea sp., Ram Sampangi, U1384, April 2009 ; Malvaneglecta, Krishna Mohan, U1277, 2007 ; TURKEY: Bing\u00f6l Province, Lavateratrimestris, L\u00fctfi Beh\u00e7et, U1562, Jun 21 2014 ; SPAIN: C\u00f3rdoba Province, near Montilla, Malvasylvestris, Walter J. Kaiser, U928, 2006 May 19 ; M.sylvestris, Walter J. Kaiser, U981, 2006 May 19 ; edge of wheat field, M.sylvestris, Walter J. Kaiser, U929, 2006 May 21 ; Cabra, edge of olive grove at Centro de Investigacion y Foirmacion Agraria, M.sylvestris, Walter J. Kaiser, U970, 2006 May 15 ; M.sylvestris, Walter J. Kaiser, U956, 2006 May 15 ; near Carcabury, Alcea sp., Walter J. Kaiser, U1258, April 2007 ; C\u00f3rdoba, Colegio Mayor Universitario, Nuestra Senora de la Asuncion, Avenida Menendez Pidal, Lavateracretica, Walter J. Kaiser, U958, 2006 May 09 ; L.cretica, Walter J. Kaiser, U916, 2006 May 09 ; Malaga Province, outskirts of El Burgo, Alcearosea, U937, 2006 May 27 ; A.rosea, Walter J. Kaiser, U989, 2006 May 27 ; Ja\u00e9n Province, Ba\u00e9za, L.cretica, Walter J. Kaiser, U974, 2006 May 19 ; L.cretica, Walter J. Kaiser, U922, 2006 May 19 ; GERMANY, Thuringia, Weimar, A.rosea, G.R.W. Arnold, U474, 2004 Jun 22 .Pucciniamalvastri \u2013Arizona, Cochise, Cottonwood Canyon, Peloncillo Mountains, Sphaeralcea sp., George Cummins 61265, 1961 Sep 27 .Pucciniasherardiana sensu Sphaeralceagrossulariifolia (Hook. & Arn.) Rydb., Ram Sampangi, U1383, April 2009 ; S.grossulariifolia, Krishna Mohan, U1554, 2009 Aug 18 .Pucciniasphaeralceae \u2013New Mexico, Mesilla Park, Sphaeralceaangustifolia, T. Cockerell 3478, 1896 Aug 01 .P.modiolae, as a new neomycete in the USA.Phytoparasitic Neomycetes have the potential to cause great losses across the world via infestation of crops, ornamental plants and native flora . IntroduModiola compared to those on other members of the Malvaceae. He named the Puccinia species on Modiola as P.malvacearumvar.modiolae, based on material collected from R\u00edo Paran\u00e1, Argentina. Modiola as a separate species based on different material (syntype) collected from Argentina and Uruguay, but designated no holotype for the species. They later considered P.malvacearumvar.modiolae as a synonym of P.modiolae in the appendix of their book . Our phylogenetic analyses show P.modiolae and P.malvacearum are distinct species (Fig. ies Fig. ; designaPucciniamodiolae is a native rust fungus of South America and was most likely introduced in the USA by accompanying its host plant Modiola. The rust species is quite common on Modiolacaroliniana in Louisiana and was also found in Texas, making the Gulf coast a likely site for the original introduction of the rust species in North America. We are unable to pinpoint when P.modiolae was introduced into the USA. However, we were unable to locate any historical North American herbarium material of P.modiolae in BPI or PUR, nor were we able to find records of any rust species on Modiola in the USA, Canada or Mexico in all available literature, making it likely that P.modiolae became established in the southern USA probably no earlier than the second half of the 20th century. Before the present study, P.modiolae was only known from Argentina and Uruguay. In Argentina, Althaeaofficinalis L., Lavateraarborea L. and Malvaparviflora L., in addition to M.caroliniana, have been reported as the natural host range of the rust species; only M.caroliniana is a reported host in Uruguay (Alcearosea and Malvasylvestris as new hosts for this rust species, ranging from southern Brazil to the upper Midwest USA. Uruguay . We haveMalvaceae members (Puccinia spp. on Malvaceae. All studied specimens of P.modiolae in this research produced spermogonia in close connection to telia (Fig. Puccinia species have been reported on Malvaceae in North America thus far.The presence or absence of spermogonia is one of the morphological features for distinguishing microcyclic rust fungi on members . Our stulia Fig. . Eight m"} +{"text": "Correction to: Acta Neuropathol Commun (2019) 7: 95https://doi.org/10.1186/s40478-019-0739-xIn the original version of this article , there wThe updated information is shown in bold.Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.Incorrect affiliation:Department of Experimental Oncology, European Institute of Oncology(IEO), IRCCS, Via Adamello 16, 20139 Milan, Italy.Correct affiliation:"} +{"text": "In the Author Contributions, Peter J. de Jong (PjD) should be listed as one of the persons who contributed to conceptualization, formal analysis, investigation, methodology, project administration, resources, supervision, and writing\u2013review & editing."} +{"text": "Scientific Reports 10.1038/s41598-019-39845-4, published online 01 March 2019Correction to: In the original version of this Article, K. Falk and M. Smid were incorrectly affiliated with \u2018ELI Beamline, Institute of Physics of the ASCR, Na Slovance 2, Prague, 182 21, Czech Republic\u2019. The correct affiliations are listed below.K. Falk:Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstra\u00dfe 400, 01328 Dresden, Germany.Technische Universit\u00e4t Dresden, 01062, Dresden, Germany.Institute of Physics of the ASCR, 182 21 Prague, Czech Republic.M. Smid:Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstra\u00dfe 400, 01328 Dresden, Germany.ELI Beamlines, Institute of Physics of the ASCR, 182 21 Prague, Czech Republic.These errors have now been corrected in the PDF and HTML versions of the Article."} +{"text": "The following information is missing from the Competing Interests section:JBS declares having received grants from 2014 to date from Linde via Hospital Universitario de La Princesa and has participated in speaking activities, advisory committees and consultancies during the period 2014\u22122018 sponsored by Almirall, AstraZeneca, Boehringer Ingelheim, CHEST, Chiesi, ERS, Esteve, GEBRO, Grifols, GSK, Linde, Lipopharma, Mundipharma, Novartis, Pfizer, RiRL, Rovi, Sandoz, SEPAR and Takeda, outside the submitted work. JLLC has received fees for giving conferences, scientific advising, participation in clinical studies or draft of publications for : Almirall, AstraZeneca, Bayer, Boehringer Ingelheim, Cantabria Pharma, Chiesi, Esteve, Faes, Ferrer, Gebro, GlaxoSmithKline, Grifols, Menarini, MSD, Novartis, Pfizer, Rovi, Teva y Takeda. JJSC has received speaker fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Esteve, Ferrer, GSK, Menarini, Mundipharma, Novartis, Rovi, consulting fees from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Esteve, Gebro, GSK, Mundipharma and Novartis and grants from Boehringer Ingelheim, GSK, Chiesi and Novartis. BAN reports personal fees from GSK, Gebro, and Astra- Zeneca; grants, personal fees and non-financial support from Novartis AG and Laboratorios Menarini; and personal fees and non-financial support from Boehringer Ingelheim and Chiesi outside the submitted work. JMRGM has received speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Esteve, GSK, Menarini, and Novartis and consulting fees from Boehringer Ingelheim and GSK. MM has received speaker or consulting fees from AstraZeneca, Bial, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Laboratorios Esteve, Gebro Pharma, GlaxoSmithKline, Grifols, Menarini, Mereo Biopharma, Novartis, pH Pharma, Rovi, TEVA, Verona Pharma and Zambon, and research grants from GlaxoSmithKline and Grifols. MB has received speaker fees from Grifols, Menarini, CSL Behring, and GSK and consulting fees from Novartis, GSK and Gebro Pharma. AstraZeneca has several products in development or marketed products related to COPD."} +{"text": "In Zhang, Xiang, Guo, and Zhang , the Fun"} +{"text": "Dolichospermum planctonicum NIES-80, Planktothrix agardhii NIES-905, and Sphaerospermopsis reniformis NIES-1949, were sequenced. The genome sizes of NIES-80, NIES-905, and NIES-1949 were 4,571,002\u2009bp, 5,512,454\u2009bp, and 6,025,023\u2009bp, and the number of protein-coding genes in each genome was 4,009, 4,925, and 5,408, respectively.Three freshwater planktonic filamentous cyanobacterial strains, Dolichospermum planctonicum NIES-80, Planktothrix agardhii NIES-905, and Sphaerospermopsis reniformis NIES-1949, were sequenced. The genome sizes of NIES-80, NIES-905, and NIES-1949 were 4,571,002\u2009bp, 5,512,454\u2009bp, and 6,025,023\u2009bp, and the number of protein-coding genes in each genome was 4,009, 4,925, and 5,408, respectively.Three freshwater planktonic filamentous cyanobacterial strains, Dolichospermum planctonicum NIES-80, Planktothrix agardhii NIES-905, and Sphaerospermopsis reniformis NIES-1949.Water blooms, also called \u201ccyanobacterial blooms\u201d , are maihttps://github.com/tseemann/shovill). The assemblies were polished using Pilon v1.22 . NIES-80 and NIES-1949 were cultured in 10\u2009ml of CB medium at 22\u00b0C and 20\u00b0C, respectively. NIES-905 was cultured in 10\u2009ml of CT medium and Shovon v1.22 . After rDolichospermum compactum NIES-806, P. agardhii NIES-204, and Sphaerospermopsis kisselevianaNIES-73, respectively, in terms of size and the number of genes. Some strains of Planktothrix agardhii produce a cyanotoxin, microcystin, that is synthesized by the mcy gene cluster , suggesting that this strain can probably synthesize microcystin. The three species used in this study are widely present in freshwater. Thus, the genomes can be used for monitoring using quantitative PCR or droplet digital PCR , 5,512,454\u2009bp , and 6,025,023\u2009bp , respectively . The gen cluster . The NIEDolichospermum planctonicum NIES-80, Planktothrix agardhii NIES-905 (= CCAP 1459/11A), and Sphaerospermopsis reniformis NIES-1949 have been deposited in DDBJ/EMBL/GenBank under the accession numbers BJCF01000001 to BJCF01000201, BJCD01000001 to BJCD01000193, and BJCE01000001 to BJCE01000680, respectively. The genomic raw reads are also available in DDBJ/EMBL/GenBank under the accession numbers DRR172254, DRR172255, and DRR172253, respectively.The draft genome sequences of"} +{"text": "Correction to:npj Breast Cancer4, 26 (2018) 10.1038/s41523-018-0074-6; Article Published online 17 August 2018In the original version of the published article, Constantine Godellas was mistakenly omitted from the Author list and Author Contributions statement. Constantine Godellas has been added as the 29th Author, and is affiliated with Loyola University Medical Center, Maywood, IL, United States. The author contributions statement has been updated as follows: Author Contributions Statement: Judy C. Boughey conducted the review of current protocols, led the effort to establish new I-SPY standards and was the principal author of the manuscript. Laura Esserman co-led the review and standardization processes. Michael D. Alvarado, Rachael B. Lancaster, Fraser Symmans, W, Rita Mukhtar, Jasmine Wong, Cheryl Ewing, David Potter, Todd Tuttle, Tina Hieken, Jodi Carter, James Jakub, Henry Kaplan, Claire Buchanan, Nora Jaskowiak, Husain Sattar, Jeffrey Mueller, Rita Nanda, Claudine Isaacs, Paula Pohlmann, Filipa Lynce, Eleni Tousimis, Jay Zeck, M. Catherine Lee, Julie Lang, Paulette Mhawech-Fauceglia, Roshni Rao, Bret Taback, Margaret Chen, Kevin Kalinsky, Hanina Hibshoosh, Brigid Killelea, Constantine Godellas, and Tara Sanft provided medical and scientific expertise/opinion towards the development of I-SPY standards. Jane Perlmutter provided the patient advocate\u2019s perspective in these discussions. All I-SPY2 trial investigators participated in the review of current standards, had the opportunity to participate in and comment on proposed standards and the final manuscript. Gill Hirst and Smita Asare provided expertise on, conducted and analyzed surveys of I-SPY trial sites. Jeffrey B. Matthews provided significant input and editing throughout the manuscript development process. All authors reviewed manuscript drafts and signed off on the final manuscript. This has been corrected in the HTML and PDF version of the article."} +{"text": "Peer review is an essential part in the publication process, ensuring that Journal maintains high quality standards for its published papers. In 2017, a total of 23 peer-reviewed papers were published in the journal. Thanks to the cooperation of our reviewers, the median time to first decision was 33 days and the median time to publication was 63 days. The editors would like to express their sincere gratitude to the following reviewers for their time and dedication in 2017:Aldred, NicholasLao, Ka UnAljabali, AlaaLee, BruceBertinetti, LucaMessersmith, PhillipBettinger, ChristopherMilford, MichaelBindschedler, SaskiaMustoe, George E.Borges, Jo\u00e3oPalumbo, FabioBreydo, LeonidParisi, CristianBumgardner, Joel D.Reisch, AndreasCarmagnola, IreneRuggeri, FrancescoCicoira, FabioRusso, NinoCirera, JordiScheiner, SteveDel Real, Juan CarlosSchroeder, GrzegorzDhinojwala, AliSlominski, AndrzejDickinson, GarySobolewski, Andrzej L.Drack, ManfredSolano, FranciscoEllinas, KosmasStone, KariFalentin-Daudr\u00e9, C\u00e9lineSturm, ElenaGarc\u00eda-Ruiz, Juan ManuelTaboryski, RafaelGerdon, ArenTaubert, AndreasHarbottle, MikeTavares, AnthonyHess, Dennis W.Thrivikraman, GreeshmaHong, SeonkiVenanzi, MarianoKeil, Matthias S.Webb, BarbaraKimura, ShunsakuWysokowski, MarcinKremer, BarbaraLadavi\u00e8re, Catherine"} +{"text": "Correction to: BMC Bioinformatics 2018, 19 (Suppl 18): 487.https://doi.org/10.1186/s12859-018-2502-xIt was highlighted that the original article containeThe list of authors and submissions for the supplement contained some outdated information and could be improved for readability and clarity. Below is the reformatted and corrected list.CAT: computer aided triage improving upon the Bayes risk through \u03b5-refusal triage rulesNicolas Hengartner, Leticia Cuellar, Xiao-Cheng Wu, Georgia Tourassi, John Qiu, Blair Christian and Tanmoy Bhattacharya.Sparse coding of pathology slides compared to transfer learning with deep neural networksWill Fischer, Sanketh S. Moudgalya, Judith D. Cohn, Nga T. T. Nguyen and Garrett T. Kenyon.Real-time data analysis for medical diagnosis using FPGA-accelerated neural networksAhmed Sanaullah, Chen Yang, Yuri Alexeev, Kazutomo Yoshii and Martin C. Herbordt.High-throughput binding affinity calculations at extreme scalesJumana Dakka, Matteo Turilli, David W. Wright, Stefan J. Zasada, Vivek Balasubramanian, Shunzhou Wan, Peter V. Coveney and Shantenu Jha.Deep clustering of protein folding simulationsDebsindhu Bhowmik, Shang Gao, Michael T. Young and Arvind Ramanathan.CANDLE/Supervisor: a workflow framework for machine learning applied to cancer researchJustin M. Wozniak, Rajeev Jain, Prasanna Balaprakash, Jonathan Ozik, Nicholson T. Collier, John Bauer, Fangfang Xia, Thomas Brettin, Rick Stevens, Jamaludin Mohd-Yusof, Cristina Garcia Cardona, Brian Van Essen and Matthew Baughman.Predicting tumor cell line response to drug pairs with deep learningFangfang Xia, Maulik Shukla, Thomas Brettin, Cristina Garcia-Cardona, Judith Cohn, Jonathan E. Allen, Sergei Maslov, Susan L. Holbeck, James H. Doroshow, Yvonne A. Evrard, Eric A. Stahlberg and Rick L. Stevens.High-throughput cancer hypothesis testing with an integrated PhysiCell-EMEWS workflowJonathan Ozik, Nicholson Collier, Justin M. Wozniak, Charles Macal, Chase Cockrell, Samuel H. Friedman, Ahmadreza Ghaffarizadeh, Randy Heiland, Gary An and Paul Macklin.Scalable deep text comprehension for Cancer surveillance on high-performance computingJohn X. Qiu, Hong-Jun Yoon, Kshitij Srivastava, Thomas P. Watson, J. Blair Christian, Arvind Ramanathan, Xiao C. Wu, Paul A. Fearn and Georgia D. Tourassi."} +{"text": "The error was discovered after publication.The following article: Md. Shakhaoat Hossain, Prantik Roy, Monira Islam, Alamgir Zaman Chowdhury, Zeenath Fardous, Md. Abdur Rahman, ASM Salfullah, Mahmudul Hasan, Md. Mazibur Rahman. Human Health Risk of Chromium Intake From Consumption of Poultry Meat and Eggs in Dhaka, Bangladesh, The authors regret any inconvenience to the scientific community."} +{"text": "Correction to: Arthritis Res Therhttps://doi.org/10.1186/s13075-019-1880-4Following publication of the original article , the autIn Fig.\u00a0In Fig.\u00a0In addition, the authors would like to update the legends of Figure 1, 2, 3 and 4 to the following:a non-adjusted cases and b adjusted cases. Adjusted confounders were baseline sex, age, disease duration, concomitant prednisolone and methotrexate, and number of previously used bDMARDs. ABT = abatacept, ADA = adalimumab, CZP = certolizumab pegol, ETN = etanercept, GLM = golimumab, IFX = infliximab, TCZ = tocilizumab, bDMARDs = biological disease-modifying antirheumatic drugsFig. 1 Drug survival rates due to lack of effectiveness in a non-adjusted cases and b adjusted cases. Adjusted confounders were baseline sex, age, disease duration, concomitant prednisolone and methotrexate, and number of previously used bDMARDs. ABT = abatacept, ADA = adalimumab, CZP = certolizumab pegol, ETN = etanercept, GLM = golimumab, IFX = infliximab, TCZ = tocilizumab, bDMARDs = biological disease-modifying antirheumatic drugsFig. 2 Drug survival rates due to toxic adverse events in a non-adjusted cases and b adjusted cases. Adjusted confounders were baseline sex, age, disease duration, concomitant prednisolone and methotrexate, and number of previously used bDMARDs. ABT = abatacept, ADA = adalimumab, CZP = certolizumab pegol, ETN = etanercept, GLM = golimumab, IFX = infliximab, TCZ = tocilizumab, bDMARDs = biological disease-modifying antirheumatic drugsFig. 3 Drug survival rates due to remission in a non-adjusted cases and b adjusted cases. Adjusted confounders were baseline sex, age, disease duration, concomitant prednisolone and methotrexate, and number of previously used bDMARDs. ABT = abatacept, ADA = adalimumab, CZP = certolizumab pegol, ETN = etanercept, GLM = golimumab, IFX = infliximab, TCZ = tocilizumab, bDMARDs = biological disease-modifying antirheumatic drugsFig. 4 Overall drug survival rates (excluding non-toxic reasons and remission) in The publishers apologise for the errors. The corrected figures are given below:"} +{"text": "AbstractScolytinae) are the most successful group of invasive wood borers worldwide, and the most invasive among them are species in the tribe Xyleborini. This haplodiploid, highly inbred, fungus-farming group is represented by 30 non-native species in North America, of which at least five are serious pests. The few identification resources for Xyleborini that exist are becoming outdated due to new species arrivals and nomenclatural changes. Here we present a new comprehensive key to Xyleborini currently known from the continental United States. Compared to the previous key, the following species have been added to the North American fauna: Ambrosiodmusminor (Stebbing), Ambrosiophilusnodulosus (Eggers), Anisandrusmaiche Kurentsov, Coptoboruspseudotenuis (Schedl), Cyclorhipidionfukiense (Eggers), Dryocoetoidesreticulatus Atkinson, Dryoxylononoharaense (Murayama), Euwallaceainterjectus (Blandford), Xyleborinusandrewesi (Blandford), Xyleborinusartestriatus (Eichhoff), Xyleborinusoctiesdentatus (Murayama), Xyleborusbispinatus Eichhoff, Xyleborusseriatus Blandford, Xyleborusspinulosus Blandford, and Xylosandrusamputatus (Blandford).Bark and ambrosia beetles ( Curculionidae: Scolytinae) are considered one of the most injurious groups of insects in native and planted forests , the Florida State Collection of Arthropods , and/or collected by the authors during various state, regional, and national surveys. Distribution records are as reported in Synonyms listed for each genus and species are cited from BMNHBritish Museum of Natural History, London;CNCICanadian National Collection of Insects, Ottawa;FRI Forest Research Institute, Dehradun;IRSNBInstitut Royal des Sciences Naturelles de Belgique, Brussels;IZM Institute of Zoology at Moscow, Moscow;MCZMuseum of Comparative Zoology, Cambridge, MA;NHMB Natural History Museum Budapest, Budapest;NHMWNaturhistorisches Museum Wien, Wien;NMNHNational Museum of Natural History, Washington, DC;SDEISenckenberg Deutsches Entomologisches Institut, M\u00fcncheberg;UZMCUniversitets Zoologisk Museum, Copenhagen;ZINZoological Institute of the Russian Academy of Sciences, St. Petersburg;ZMFK Zoological Research Museum Alexander Koenig, Bonn; andZMUHZoologisches Institut und Zoologisches Museum, Hamburg.Photographs were taken by JH and DG using an Olympus SZX16 stereomicroscope. Each image is a composite of up to 50 separate images taken with a Canon EOS Rebel T3i camera, and later stacked using the Helicon Focus software .Taxon classificationAnimaliaColeopteraCurculionidaeHopkins, 1915Phloeotrogus Motschulsky, 1863. Synonymy Wood 1966.Brownia Nunberg, 1963. Synonymy Wood 1980.Xyleborustachygraphus Zimmermann.Ambrosiodmus differ from other members of the tribe by the asperities covering the entire surface of the pronotum.Species of Taxon classificationAnimaliaColeopteraCurculionidaeXyleborusdevexus Wood, 1977. Preoccupied Schedl 1977.XyleborusdevexulusX.devexus Wood. Wood, 1978. Replacement name for Xyleboruswoodi Schedl, 1979. Unnecessary replacement name.NMNH.Holotype female; Homestead, FL; North America: Antilles, United States: Florida.A.obliquus, but it is distinguished by its smaller size, lack of declivital granules, and interstriae 1 not elevated. It is only known from southern Florida, Puerto Rico, and the Dominican Republic.This species is very similar to Taxon classificationAnimaliaColeopteraCurculionidaeHopkins, 1915Xyleborusgundlachi Eggers, 1931. Synonymy Wood 1972.Holotype female; Keene, FL; USNM.North America: Antilles, United States: Alabama, Florida, Louisiana, South Carolina, Texas; South America: Brazil.A.tachygraphus.In North America, this species is distinguished by the smaller size and the much deeper, coarser strial punctures compared to Taxon classificationAnimaliaColeopteraCurculionidaeXyleboruslewisi Blandford, 1894.Ozopemontuberculatus Strohmeyer, 1912. Synonymy Beaver and Liu 2010.Xyleborustegalensis Eggers, 1923. Synonymy Schedl 1950.Xyleboruslewekianus Eggers, 1923. Synonymy BMNH.Syntypes female; Japan; Asia; North America (introduced): United States: Alabama, Georgia, Pennsylvania.Ambrosiodmuslewisi was first reported in North America from southeastern Pennsylvania Phloeosinusminor Stebbing, 1909.Xyleboruscrassus Hagedorn, 1910. Synonymy Schedl 1962.FRI.Syntypes female; Assam: labeled Kochujan, printed as Goalpara Sal Forests; Asia; North America (introduced): United States: Alabama, Florida, Georgia, Mississippi.PageBreakA.minor was in Florida in 2011 Pityophthorusobliquus LeConte, 1878.Xyleborusgilvipes Blandford, 1898. Synonymy Wood 1975.Ambrosiodmuslinderae Hopkins, 1915. Synonymy Xyleborusbrasiliensis Eggers, 1928. Synonymy Wood 1975.Xyleborusmexicanus Eggers, 1931. Synonymy Wood 1972.Xyleboruspseudobrasiliensis Eggers, 1941. Synonymy Bright 1985.Xyleborusillepidus Schedl, 1941. Synonymy Wood 1975.Xyleborusmelanarius Schedl, 1978. Synonymy MCZ.Holotype female; Enterprise, FL; Africa; Central America: Costa Rica, Guatemala, Honduras, Panama; North America: Antilles Islands, Mexico, United States: Alabama, Delaware, District of Columbia, Florida, Georgia, Louisiana, Maryland, Mississippi, North Carolina, South Carolina, Tennessee, Texas, Virginia; South America: Brazil, Colombia, Ecuador, Peru.A.devexulus but with less prominent punctures.Similar to Taxon classificationAnimaliaColeopteraCurculionidaeXyleborusopimus Wood, 1974.NMNH.Holotype female; Sebring, FL; North America: United States: Florida; South America: Brazil.A.lecontei in North America, but interstriae 1 armed by several fine granules in A.opimus.Similar to Taxon classificationAnimaliaColeopteraCurculionidaeXyleborusrubricollis Eichhoff, 1875.Xyleborustaboensis Schedl, 1952. Synonymy Xyleborusstrohmeyeri Schedl, 1975. Synonymy IRSNB.Holotype Female; Japan; Asia; Australia (introduced); Europe (introduced): Italy; North America (introduced): Mexico, United States: Alabama, Arkansas, Connecticut, Delaware, Florida, Georgia, Indiana, Louisiana, Maryland, Michigan, Mississippi, Missouri, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Tennessee, Texas, Virginia.Ambrosiodmus by the combination of the red color, the small size, and the equally granulate declivital interstriae.This non-native species, first found in Maryland , is now Taxon classificationAnimaliaColeopteraCurculionidaeXyleborustachygraphus Zimmermann, 1868.MCZ.Holotype female; North Carolina; North America: United States: Alabama, Arkansas, Delaware, District of Columbia, Florida, Georgia, Illinois, Indiana, Kentucky, Louisiana, Maryland, Mississippi, New Jersey, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Tennessee, Texas, Virginia, West Virginia.Xyleborini in North America.Widely distributed in the eastern United States. It is among the largest species of Taxon classificationAnimaliaColeopteraCurculionidaeHulcr & Cognato, 2009Ambrosiodmusrestrictus (Schedl).Ambrosiophilus differ from other members of the tribe by the black and robust body combined with the absence of asperities on a flat pronotal disc, and the rounded edge of elytral declivity.Species of Taxon classificationAnimaliaColeopteraCurculionidaeXyleborusatratus Eichhoff, 1875.ZMUH, lost.Holotype female; Japan. Asia; North America (introduced): United States: Alabama, Delaware, Florida, Georgia, Kansas, Kentucky, Louisiana, Maine, Maryland, Michigan, Mississippi, Missouri, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Tennessee, Texas, West Virginia; Oceania.Ambrosiophilusatratus was first reported in eastern North America from Georgia, Maryland, Tennessee, Virginia and West Virginia Xyleborusnodulosus Eggers, 1941.Xyleboruspernodulus Schedl, 1957. Synonymy Ambrosiophilusperegrinus Smith & Cognato, 2015. Synonymy ZMFK.Holotype female; Fukien ; Asia; North America (introduced): United States: Georgia.A.nodulosus is likely to expand its distribution. Differs from A.atratus by its smaller size and by the presence of evenly spaced tubercles on the declivity.A recent introduction in the U.S. , A.noduTaxon classificationAnimaliaColeopteraCurculionidaeFerrari, 1867Anisandrusdispar (Fabricius).Anisandrus differ from other members of the tribe by the combination of serrations on the frontal edge of pronotum, a tuft of setae at the base of the pronotum, the contiguous procoxae, and an obliquely truncate antennal club with the first segment of club covering the entire posterior side.Species of PageBreakTaxon classificationAnimaliaColeopteraCurculionidaeApatedispar Fabricius, 1792.Bostrichusbrevis Panzer, 1793. Synonymy Eichhoff 1878.Bostrichusthoracicus Panzer, 1793. Synonymy Hagedorn 1910.Scolytuspyri Peck, 1817. Synonymy Hubbard 1897.Bostrichustachygraphus Sahlberg, 1834. Synonymy Eichhoff 1878.Bostrichusratzeburgi Kolenati, 1846. Synonymy Ferrari 1867.Anisandrusaequalis Reitter, 1913. Synonymy Mandelshtam 2001.Anisandrusswainei Drake, 1921. Synonymy Wood 1957.Xyleborusdisparrugulosus Eggers 1922.Xyleboruscerasi Eggers, 1937. Synonymy Schedl 1964.Xyleboruskhinganensis Murayama, 1943. Synonymy Kn\u00ed\u017eek 2011.UZMC.Syntypes female; Germaniae; Asia; Europe; North America (introduced): Canada: British Columbia, New Brunswick, Nova Scotia, Ontario; United States: California, District of Columbia, Idaho, Illinois, Indiana, Maine, Maryland, Massachusetts, Michigan, New Jersey, New York, North Carolina, Ohio, Oregon, Pennsylvania, Rhode Island, Utah, Virginia, Washington, West Virginia.Anisandrusdispar was likely unintentionally introduced before 1817 : United States: Ohio, Pennsylvania, West Virginia, and Wisconsin.Anisandrusmaiche was first reported in the US from Pennsylvania, Ohio, and West Virginia Xyleborusobesus LeConte, 1868.Xyleborusserratus Swaine, 1910. Synonymy Hopkins 1915.Anisandruspopuli Swaine, 1917. Synonymy Schedl 1964.MCZ.Lectotype female; Virginia; North America: Canada: New Brunswick, Ontario, Quebec; United States: Connecticut, Illinois, Kentucky, Massachusetts, Michigan, Minnesota, New Jersey, New York, Ohio, Virginia, West Virginia, Wisconsin.Anisandrus by the presence of a series of tubercles on the posterolateral margin of the declivity.Distinguished from other Taxon classificationAnimaliaColeopteraCurculionidaeHopkins, 1915Xyleborusobesusvar.minor Swaine, 1910. Synonymy Wood 1957.Xyleborusneardus Schedl, 1950. Synonymy Wood 1957.NMNH.Holotype female; Morgantown, WV; North America: Canada: New Brunswick, Ontario, Quebec; United States: Alabama, Connecticut, Delaware, District of Columbia, Georgia, Illinois, Indiana, Iowa, Kentucky, Maine, Maryland, Massachusetts, Michigan, Mississippi, Missouri, New Jersey, New York, North Carolina, Ohio, Pennsylvania, South Carolina, Tennessee, Texas, Virginia, West Virginia.PageBreakAnisandrus in the northeastern U.S. Distinguished from other Anisandrus by the absence of significant sculpture on the elytral declivity. Wood (1957) synonymized A.sayi with X.obesusvar.minor, but Swaine\u2019s name is available and should have priority.This is the most common species of Taxon classificationAnimaliaColeopteraCurculionidaeSampson, 1911Tosaxyleborus Murayama, 1950. Synonymy Browne 1955.Cnestusmagnus SampsonCnestus differ from other members of the tribe by the truncate elytra, which are shorter than the pronotum.Species of Taxon classificationAnimaliaColeopteraCurculionidaeXyleborusmutilatus Blandford, 1894.Xyleborussampsoni Eggers, 1930. Synonymy Xyleborusbanjoewangi Schedl, 1939. Synonymy Kalshoven 1960.Xyleborustaitonus Eggers, 1939. Synonymy BMNH.Holotype female; Japan; Asia; North America (introduced): United States: Florida, Georgia, Kentucky, Louisiana, Mississippi, Pennsylvania, South Carolina, Tennessee, Texas; Oceania.Cnestusmutilatus was first collected in North America from Mississippi in 1999 Xyleboruspseudotenuis Schedl, 1936.Xyleborustenuis Schedl, 1948. Synonymy Wood 1976.NHMW.Holotype female; Brasilien; Schedl Collection in Central America: Costa Rica, Panama; North America: Mexico, United States: Florida; South America: Bolivia, Brazil, Ecuador, French Guiana, Peru, Venezuela.Coptoboruspseudotenuis was first documented in the US based on a reared specimen from southern Florida in 2004 Xyleborusbodoanus Reitter, 1913.Xyleboruspunctulatus Kurentsov, 1948. Synonymy Mandelshtam 2001.Xyleboruscalifornicus Wood, 1975. Synonymy Kn\u00ed\u017eek 2011.NHMB.Syntypes female; Ostsibirien: Sotka-gora; Asia; North America (introduced): United States: Alabama, Arkansas, California, Delaware, Florida, Georgia, Kansas, Louisiana, Maryland, Michigan, Mississippi, Missouri, North Carolina, Ohio, Oklahoma, Oregon, South Carolina, Tennessee, Texas, Washington.Cyclorhipidionbodoanum was first reported in the eastern US in 2000 Xyleborusfukiensis Eggers, 1941.Xyleborusganshoensis Murayama, 1952. Synonymy Xyleborustenuigraphus Schedl, 1953. Synonymy Beaver and Liu 2010.ZMFK.Holotype female; Fukien ; Asia; North America (introduced): United States: Florida, Georgia.C.bodoanum and C.pelliculosum except for body length, with an intermediate size Xyleboruspelliculosus Eichhoff, 1878.Xyleborusseiryorensis Murayama, 1930. Synonymy Kn\u00ed\u017eek 2011.Xyleborusquercus Kurenzov, 1948. Synonymy Kn\u00ed\u017eek 2011.Xyleborusstarki Nunberg, 1956. Synonymy Kn\u00ed\u017eek 2011.ZMUH, lost.Syntypes female; Japan; Asia; North America (introduced): United States: Delaware, Illinois, Kentucky, Maine, Maryland, Massachusetts, Missouri, New Jersey, North Carolina, Ohio, Pennsylvania, Rhode Island, Tennessee, Virginia.Cyclorhipidionpelliculosum was first documented in the US from Pennsylvania in 1987 and from Maryland in 1989 Xyleborusonoharaensis Murayama, 1934.Dryoxylononoharaensum Bright & Rabaglia, 1999 (incorrect subsequent spelling).DryoxylononoharaenseDryoxylononoharaensum Bright & Rabaglia. : Alonso-Zarazaga & Lyal, 2009. Correction for NMNH.Lectotype female; Japan; Asia; North America (introduced): United States: Alabama, Arkansas, Delaware, Florida, Georgia, Louisiana, Maryland, Mississippi, North Carolina, Ohio, South Carolina, Tennessee, Texas, Virginia.Dryocoetini based on tibial characters, but molecular analyses place it within the Xyleborini Xyleborusfornicatus Eichhoff, 1868.Xyleborusfornicatior Eggers, 1923. Synonymy Beeson 1930 (as variety).Xyleboruswhitfordiodendrus Schedl, 1942. Synonymy Xyleborusperbrevis Schedl, 1951. Synonymy Wood,1989.Xyleborusschultzei Schedl, 1951. Synonymy Beaver 1991.Xyleborustapatapaoensis Schedl, 1951. Synonymy ZMUH, lost.Syntypes: Ceylon; Africa; Asia; Central America (introduced): Costa Rica, Panama; North America (introduced): Mexico, United States: California, Florida, Hawaii; Oceania (introduced); South America (introduced): Brazil.This species is a complex of several distinct genotypes, the most common of which are known as the Tea shot hole borer, Polyphagous shot hole borer, and the Kuroshio shot hole borer . The difTaxon classificationAnimaliaColeopteraCurculionidaeXyleborusinterjectus Blandford, 1894.Xyleboruspseudovalidus Eggers, 1925. Synonymy Schedl 1958.BMNH.Holotype female; Japan, China [presumably syntypes]; Asia; North America (introduced): United States: Florida, Georgia, Hawaii, Kentucky, Louisiana, South Carolina, Texas, Virginia.E.validus Bostrichusferrugineus Boheman, 1858. Synonymy Schedl 1960.Xyleborussimilis Ferrari, 1867.Xyleborusparvulus Eichhoff, 1868. Synonymy Schedl 1959.Xyleborusdilatus Eichhoff, 1876. Synonymy Schedl 1959.Xyleborussubmarginatus Blandford, 1896. Synonymy Eggers 1929.Xyleborusbucco Schaufuss, 1897. Synonymy Schedl 1959.Xyleboruscapito Schaufuss, 1897. Synonymy Schedl 1959.XyleborusnovaguineanusSchedl, 1936. Synonymy Xyleborusdilatatulus Schedl, 1953. Synonymy NHMW.Holotype female; \u201cInsula Keeling\u201d. Africa; Asia; North America (introduced): United States: Texas; Oceania; South America (introduced): Brazil.Anodiusdenticulus Motschulsky, 1863 as a synonym of this species (Mandelshtam and Nikitskij 2010) is not considered valid (Alonso-Zarazaga pers. comm.). Wood designated a specimen of Xyleborusperforans as the lectotype of Anodiusdenticulus, not a specimen of X.similis .The designation of Taxon classificationAnimaliaColeopteraCurculionidaeXyleborusvalidus Eichhoff, 1875.IRSNB.Syntypes female; Japan; Asia; North America (introduced): Canada: Ontario; United States: Alabama, Delaware, Georgia, Kentucky, Maryland, Michigan, Mississippi, New Jersey, New York, North Carolina, Ohio, Pennsylvania, South Carolina, Tennessee, Texas, Virginia, West Virginia.Euwallaceavalidus was first collected in the US from Nassau County, New York in 1975 Xyleborusricini Eggers, 1932.Xyleborussolitariceps Schedl, 1954. Synonymy NMNH.Holotype female; \u201cCongostaat\u201d; Africa (introduced); Central America: Costa Rica; North America: Antilles, Mexico, United States: Florida; South America: Brazil, Colombia, Venezuela.It is unclear if this species was introduced from South America or is native to North America. Distinguished by the light-brown color, the short and steep elytral declivity with stout and short interstrial setae, and the smooth posterior face of protibia.Taxon classificationAnimaliaColeopteraCurculionidaeReitter, 1913Bostrichussaxesenii Ratzeburg.Xyleborinus differ from other members of the tribe by the conical scutellum surrounded by setae.Species of Taxon classificationAnimaliaColeopteraCurculionidaeXyleborusandrewesi Blandford, 1896.Xyleboruspersphenos Schedl, 1970. Synonymy Beaver and Brownie 1978.Xyleborusinsolitus Bright, 1972. Synonymy Bright 1985.Cryptoxyleborusgracilior Browne, 1984. Synonymy Beaver 1995.Holotype female; India; BMHN.Africa; Asia; North America (introduced): Antilles, United States: Florida, Hawaii; Oceania.Xyleborinusandrewesi was first reported in the US from Lee County, Florida Xyleborusartestriatus Eichhoff, 1878.Xyleboruslaticollis Blandford, 1896. Synonymy Schedl 1958.Xyleborusrugipennis Schedl, 1953. Synonymy Xyleborinusbeaveri Browne, 1978. Synonymy ZMUH, lost.Holotype female; Asia; North America (introduced): United States: Georgia, Texas; Oceania.Xyleborinusartestriatus was reported for the first time in North America based on specimens from Georgia and Texas Xyleborusattenuatus Blandford, 1894.Xyleborinusalni Niisima, 1909. Synonymy Kn\u00ed\u017eek 2011.BMNH.Holotype female; Nikko, Japan; Asia; Europe (introduced); North America (introduced): Canada: British Columbia, Nova Scotia, Ontario, Quebec; United States: Maine, Maryland, Michigan, New York, Oregon, Pennsylvania, Washington.PageBreakX.saxesenii, but can be distinguished by the larger size and the pointed and hooked tubercles on the declivity Xyleborusgracilis Eichhoff, 1868.Xyleborusaspericauda Eggers, 1941. Synonymy Bright 1985.Xyleborusneogracilis Schedl, 1954. Synonymy Bright 1985.Xyleborusschoenherri Schedl, 1981. Synonymy NMNH.Lectotype; Brasilia; Africa; Central America: Costa Rica, Honduras, Panama; North America: Mexico, United States: Florida, Louisiana, Missouri, North Carolina, South Carolina, Texas; South America: Argentina, Brazil, Colombia, Ecuador, Venezuela.Xyleborinus by the blunt tubercles of declivital interstriae 3.Distinguished from other Taxon classificationAnimaliaColeopteraCurculionidaeXyleborusoctiesdentatus Murayama, 1931.NMNH.Holotype; Kannanri, Korea; Asia; North America (introduced): Alabama, Louisiana, Mississippi, South Carolina.Xyleborinusoctiesdentatus was reported for the first time from North America based on specimens from Alabama and Louisiana Bostrichussaxesenii Ratzeburg, 1837.Tomicusdohrnii Wollaston, 1854. Synonymy Eichhoff 1878.Tomicusdecolor Boieldieu, 1859. Synonymy Ferrari 1867.Xyleborusaesculi Ferrari, 1867. Synonymy Eichhoff 1878.Xyleborussobrinus Eichhoff, 1875. Synonymy Schedl 1964.Xyleborussubdepressus Rey, 1883. Synonymy Bedel 1888.Xyleborusfrigidus Blackburn, 1885. Synonymy Samuelson 1981.Xyleborusfloridensis Hopkins, 1915. Synonymy Wood 1962.Xyleboruspecanis Hopkins, 1915. Synonymy Wood 1962.Xyleborusquercus Hopkins, 1915. Synonymy Wood 1962.Xyleborusarbuti Hopkins, 1915. Synonymy Wood 1957.Xyleborussubspinosus Eggers, 1930. Synonymy Xyleborinustsugae Swaine, 1934. Synonymy Wood 1957.Xyleborinuslibrocedri Swaine, 1934. Synonymy Wood 1957.Xyleboruspseudogracilis Schedl, 1937. Synonymy Xyleborusretrusus Schedl, 1940. Synonymy Xyleborusperegrinus Eggers, 1944. Synonymy Schedl 1980.Xyleborinuspseudoangustatus Schedl, 1948. Synonymy Schedl 1964.Xyleborusparaguayensis Schedl, 1948. Synonymy Xyleborusopimulus Schedl, 1976. Synonymy Xyleboruscinctipennis Schedl, 1980. Synonymy SDEI by Wood and Bright (2007), unconfirmed.Syntypes female; \u201cS\u00fcdlichen Deutschland\u201d; type location is indicated as presumably at Africa (introduced); Asia, Europe (introduced), North America (introduced): Mexico, Canada: British Columbia, New Brunswick, Ontario, United States: Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maine, Maryland, Massachusetts, Michigan, Mississippi, Missouri, New Hampshire, New Jersey, New York, North Carolina, Ohio, Oregon, Pennsylvania, South Carolina, Tennessee, Texas, Utah, Virginia, Washington, West Virginia; Oceania (introduced); South America (introduced): Argentina, Brazil, Chile, Ecuador, Paraguay, Uruguay.X.saxeseni, but saxesenii, with the ii ending. The synonymy stated by X.cinctipennis Schedl, 1980 with X.saxesenii, supported by This species is widely distributed. Taxon classificationAnimaliaColeopteraCurculionidaeEichhoff, 1864Anaeretus Dug\u00e8s, 1887. Synonymy Hagedorn 1910.Progenius Blandford, 1896. Synonymy Hagedorn 1910.Mesoscolytus Broun, 1904. Synonymy Bain 1976.Heteroborips Reitter, 1913. Synonymy Schedl 1934.Boroxylon Hopkins, 1915. Synonymy Schedl 1952.Notoxyleborus Schedl, 1934. Synonymy Bostrichusmonographus Fabricius.Xyleborus differ from most members of the tribe by the truncate antennal club, the first segment of which is corneous. Species of Xyleborus s. str. ; Asia (introduced); Central America: Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panama; Europe (introduced), North America: Antilles, Canada: Quebec, Mexico, United States: Alabama, Arkansas, California, Delaware, District of Columbia, Florida, Georgia, Hawaii, Illinois, Kansas, Kentucky, Louisiana, Maryland, Massachusetts, Michigan, Mississippi, Missouri, New Jersey, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Tennessee, Texas, Virginia, West Virginia; Oceania (introduced); South America: Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Fr. Guiana, Guyana, Paraguay, Peru, Suriname, Trinidad, Uruguay, Venezuela.This widely distributed species can cause economic damage in moist lowland areas of the Neotropics. This species is distinguished by the broadly sloping shagreened declivity and the small denticles in interstriae 1 and 3.Taxon classificationAnimaliaColeopteraCurculionidaeEichhoff, 1868IRSNB.Syntypes female; Brazil; Central America: Belize, Costa Rica, Guatemala, Honduras, Panama; North America: Mexico, United States: Florida, Georgia, Louisiana, North Carolina, Texas; Oceania; South America: Argentina, Bolivia, Brazil, Colombia, Ecuador, Peru, Venezuela.X.ferrugineus by This species was removed from synonymy with Taxon classificationAnimaliaColeopteraCurculionidaeEichhoff, 1868Xyleborusbiographus LeConte, 1868. Synonymy Eichhoff 1878.ZMUH, lost.Syntypes female; \u201cAmerica boreali\u201d. PageBreakNorth America: Canada: Ontario, United States: Alabama, Arkansas, Connecticut, Delaware, District of Columbia, Florida, Georgia, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maryland, Michigan, Minnesota, Mississippi, Missouri, New Jersey, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Texas, Vermont, Virginia, West Virginia.This species is distinguished by its large size and its two pairs of large pointed tubercles on declivital interstriae 1.Taxon classificationAnimaliaColeopteraCurculionidaeBostrichusferrugineus Fabricius, 1801.Tomicustrypanaeoides Wollaston, 1867. Synonymy Schedl 1960.Xyleborusfuscatus Eichhoff, 1868. Synonymy Schedl 1960.Xyleborusconfusus Eichhoff, 1868. Synonymy Schedl 1957.Xyleborusretusicollis Zimmermann, 1868. Synonymy Xyleborusamplicollis Eichhoff, 1869. Synonymy Schedl 1960.Xyleborusinsularis Sharp, 1885. Synonymy Schedl 1960.Xyleborustanganus Hagedorn, 1910. Synonymy Schedl 1960.Xyleborussoltaui Hopkins, 1915. Synonymy Xyleborusnyssae Hopkins, 1915. Synonymy Schedl 1960.Xyleborushopkinsi Beeson, 1929. Synonymy Schedl 1960.Xyleborusargentinensis Schedl, 1931. Synonymy Schedl 1960.Xyleborusrufopiceus Eggers, 1932. Synonymy Xyleborusschedli Eggers, 1934. Synonymy Schedl 1960.Xyleborusnesianus Beeson, 1940. Synonymy Beaver 1991.Xyleborusnotatus Eggers, 1941. Synonymy Schedl 1960.Xyleborussubitus Schedl, 1948. Synonymy Schedl 1960.UZMC.Lectotype female; \u201cAmerica meridionali\u201d; Africa (introduced); Asia; Central America: Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panama; North America: Antilles, Canada: Ontario, Mexico, United States: Alabama, Arizona, Arkansas, California, Delaware, District of Columbia, Florida, Georgia, Hawaii, Illinois, Indiana, Kansas, Kentucky, Louisiana, Maryland, Massachusetts, Michigan, Mississippi, Missouri, New Jersey, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, South Carolina, Tennessee, Texas, Virginia, West Virginia; Oceania (introduced); South America: Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Fr. Guiana, Guyana, Paraguay, Peru, Suriname, Trinidad, Uruguay, Venezuela.X.bispinatus by X.bispinatus by the smaller size, discal interstrial setae sparse or absent, and by its light orange to reddish brown color : United States: Alabama, Florida, Georgia, Mississippi, South Carolina.X.glabratus was first detected in a survey trap near Port Wentworth, Georgia in 2002 (Persea spp.) and other Lauraceae in the southeastern United States Bostrichuspfeilii Ratzeburg, 1837.Bostrichusalni Mulsant & Rey, 1856. Synonymy Hagedorn 1910.Xyleborusvicarius Eichhoff, 1875. Synonymy Schedl 1963.Xyleborusadumbratus Blandford, 1894.Synonymy Schedl 1963.SDEI.Syntypes female; \u201cim L\u00fcneburgschen und in Bayern\u201d; not located, if extant, probably in Africa; Asia; Europe; North America (introduced): Canada: British Columbia; United States: Maryland, Oregon, Pennsylvania, Washington; South America: Brazil.Xyleboruspfeilii was first detected in North America in Maryland in 1992 : United States: Massachusetts.X.seriatus is distinguished from other Xyleborus by the distinctly impressed area adjacent to the scutellum and the alternating series of longer and shorter setae on the elytra : Antilles Mexico, United States: Hawaii, Texas; South America: Argentina, Brazil, Colombia, Ecuador, Guyana, Peru, Venezuela.Xyleborusspinulosus, native to Central America and lowland Mexico, was first found in the US in Texas in 1994 . North America: United States: Alabama, Arkansas, Florida, Illinois, Indiana, Kansas, Maryland, Mississippi, Missouri, Oklahoma, Tennessee, Texas, West Virginia.X.planicollis by the impressed, shining, and tuberculate declivity.Distinguished by the impressed anterior portion of pronotum. Distinguished from Taxon classificationAnimaliaColeopteraCurculionidaeBostrichusvolvulus Fabricius, 1775.Xyleborustorquatus Eichhoff, 1868. Synonymy Wood 1960.Xyleborusalternans Eichhoff, 1869. Synonymy Eggers 1929.Xyleborusbadius Eichhoff, 1869. Synonymy Wood 1960.Xyleborusinterstitialis Eichhoff, 1878. Synonymy Xyleborusguanajuatensis Dug\u00e8s, 1887. Synonymy Wood 1983.Xyleborushubbardi Hopkins, 1915. Synonymy Schedl 1952.Xyleborusschwarzi Hopkins, 1915. Synonymy Xyleborusrileyi Hopkins, 1915. Synonymy Xyleborusgrenadensis Hopkins, 1915. Synonymy Wood 1972.Xyleboruscontinentalis Eggers, 1920. Synonymy Xyleborussilvestris Beeson, 1929. Synonymy Xyleborusvagabundus Schedl, 1948. Synonymy Wood 1972.XyleborusgranularisSchedl, 1950. Synonymy UZMC.Lectotype female; \u201cAmerica ligno Dom v. Rohr (presumably Cuba)\u201d; Africa; Asia; Central America: Belize, Costa Rica, El Salvador, Guatemala, Honduras, Nicaragua, Panama; North America: Antilles, Mexico, United States: Florida, Hawaii; Oceania; South America: Argentina, Bolivia, Brazil, Colombia, Ecuador, Fr. Guiana, Guyana, Paraguay, Peru, Suriname, Trinidad, Uruguay, Venezuela.Distinguished by the slightly convex to flattened declivity bearing prominent tubercles of varying sizes.Taxon classificationAnimaliaColeopteraCurculionidaeBostrichusxylographus Say, 1826.Xyleborusinermis Eichhoff, 1868. Synonymy Eichhoff 1878.Xyleboruscanadensis Swaine, 1917. Synonymy Wood 1957.CNCI.Neotype female; North Carolina; Asia (introduced); North America: Antilles, Canada: British Columbia, Ontario, Quebec; United States: Arkansas, California, District of Columbia, Florida, Georgia, Illinois, Indiana, Iowa, Kansas, Kentucky, Maine, Maryland, Massachusetts, Michigan, Minnesota, Mississippi, Missouri, New Hampshire, New Jersey, New York, North Carolina, Ohio, Oklahoma, Oregon, Pennsylvania, South Carolina, Utah, Virginia, West Virginia, Wisconsin.Distinguished by the lusterless and steep declivity, occupying no more than posterior 15% of elytra.Taxon classificationAnimaliaColeopteraCurculionidaeReitter, 1913Apoxyleborus Wood, 1980. Synonymy Wood 1984.Xyleborusmorigerus Blandford.Xylosandrus differ from other members of the tribe by widely separated procoxae.Species of Taxon classificationAnimaliaColeopteraCurculionidaeXyleborusamputatus Blandford, 1894.Xyleborusmelli Eggers, 1926. Synonymy Beaver 2010.BMNH.Holotype female; Japan: Higo; Asia; North America (introduced): Florida, Georgia.Xylosandrusamputatus was first discovered in the US from Florida in 2010 Xyleboruscompactus Eichhoff, 1875.Xyleborusmorstatti Hagedorn, 1912. Synonymy Murayama and Kalshoven 1962.ZMUH, lost. 1 syntype Schedl Collection NHMW.Syntypes female; Japan; Africa; Asia; North America (introduced): Antilles, United States: Alabama, Florida, Georgia, Hawaii, Illinois, Louisiana, Mississippi, North Carolina, Pennsylvania, Texas; Oceania (introduced); South America: Brazil, Fr. Guiana, Peru, Trinidad.X.compactus was first collected in the US at Ft. Lauderdale, Florida in 1941 Phloeotroguscrassiusculus Motschulsky, 1866.Xyleborussemiopacus Eichhoff, 1878. Synonymy Wood 1969.Xyleborussemigranosus Blandford, 1896. Synonymy Schedl 1959.Xyleborusebriosus Niisima, 1909. Synonymy Choo 1983.Dryocoetesbengalensis Stebbing, 1908. Synonymy Beeson 1915.Xyleborusmascarenus Hagedorn, 1908. Synonymy Eggers 1923.Xyleborusokoumeensis Schedl, 1935. Synonymy Schedl 1959.Xyleborusdeclivigranulatus Schedl, 1936. Synonymy Schedl 1959.IZM.Syntypes female; Ceylon; Africa; Asia; Central America (introduced): Costa Rica, Guatemala, Panama;, North America (introduced): Antilles, Canada: Ontario; United States: Alabama, Delaware, Florida, Georgia, Hawaii, Indiana, Kentucky, Louisiana, Maryland, Michigan, Mississippi, Missouri, North Carolina, Ohio, Oklahoma, Oregon, South Carolina, Tennessee, Texas, Virginia; Oceania (introduced); South America (introduced): Argentina, Brazil, Fr. Guiana, Uruguay.X.crassiusculus has spread in the US along the lower Piedmont region and coastal plain to North Carolina, Louisiana, Florida, and beyond (Xyleborussemiopacus). Distinguished by the confused declivital granules giving the declivity a dull appearance. Causes economic damage in nurseries and stored hardwood lumber Xyleboruscurtulus Eichhoff, 1869.Anisandruszimmermanni Hopkins, 1915. Synonymy Xyleboruscurtuloides Eggers, 1941. Synonymy Xyleborusbiseriatus Schedl, 1963. Synonymy Wood 1973.Xyleborusstrumosus Schedl, 1972. Synonymy Wood 1992.IRSNB.Holotype female: Brazil; Central America: Costa Rica, Guatemala, Honduras, Nicaragua, Panama; North America: Antilles, Mexico, United States: Florida; South America: Argentina, Bolivia, Brazil, Colombia, Venezuela.This species is currently only known from central and southern Florida in the United States. Distinguished by the dark brown body, the small size, and the hairy and shagreened declivity.PageBreakTaxon classificationAnimaliaColeopteraCurculionidaeXyleborusgermanus Blandford, 1894.Xyleborusorbatus Blandford, 1894. Synonymy Choo 1983.BMNH.Syntypes; Japan; Asia; Europe (introduced); North America (introduced): Canada: British Columbia, Ontario, Quebec; United States: Alabama, Connecticut, Delaware, Florida, Georgia, Hawaii, Illinois, Indiana, Kentucky, Maine, Maryland, Massachusetts, Michigan, Mississippi, Missouri, New Hampshire, New Jersey, New York, North Carolina, Ohio, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Vermont, Virginia, West Virginia.X.germanus has now spread across much of North America, including the Northeast, South and Southeast, and the Pacific Northwest (Originating from Asia, orthwest ; it was orthwest . Disting"} +{"text": "Correction to: J Med Case Reports (2018) 12:33510.1186/s13256-018-1876-8In the publication of this article , there iThe error:*, Bakaloudi Dimitra-Rafailia, Giannakidis Dimitrios, Koumpoulas Alexandros, Ioannidis Konstantinos, Tsifountoudis Ioannis, Pappas Dimitrios and Spyridopoulos PanagiotisChatzoulis George, Passos IoannisShould instead read:*, Dimitra-Rafailia Bakaloudi, Dimitrios Giannakidis, Alexandros Koumpoulas, Konstantinos Ioannidis, Ioannis Tsifountoudis, Dimitrios Pappas and Panagiotis SpyridopoulosGeorge Chatzoulis, Ioannis PassosThis has now been updated in the original article ."} +{"text": "Testosterone treatment of men with low testosterone is common and, although relatively short-term, has raised concern regarding an increased risk of prostate cancer (CaP). We investigated the association between modest-duration testosterone treatment and incident aggressive CaP.Retrospective inception cohort study of male Veterans aged 40 to 89 years with a laboratory-defined low testosterone measurement from 2002 to 2011 and recent prostate specific antigen (PSA) testing; excluding those with recent testosterone treatment, prostate or breast cancer, high PSA or prior prostate biopsy. Histologically-confirmed incident aggressive prostate cancer or any prostate cancer were the primary and secondary outcomes, respectively.Of the 147,593 men included, 58,617 were treated with testosterone. 313 aggressive CaPs were diagnosed, 190 among untreated men (incidence rate (IR) 0.57 per 1000 person years, 95% CI 0.49\u20130.65) and 123 among treated men . After adjusting for age, race, hospitalization during year prior to cohort entry, geography, BMI, medical comorbidities, repeated testosterone and PSA testing, testosterone treatment was not associated with incident aggressive CaP or any CaP . No association between cumulative testosterone dose or formulation and CaP was observed.Among men with low testosterone levels and normal PSA, testosterone treatment was not associated with an increased risk of aggressive or any CaP. The clinical risks and benefits of testosterone treatment can only be fully addressed by large, longer-term randomized controlled trials. Serum testosterone declines with age, such that 20\u201340% of men over 40 years old have low testosterone levels, 2 with We used data from the Veterans Health Administration (VHA) to determine if current patterns of testosterone use in Veterans are associated with adverse prostate cancer outcomes. We hypothesized that modest-duration testosterone treatment relative to no treatment is associated with an increase in prostate cancer risk and that, among testosterone users, a larger cumulative dose is associated with a higher risk.We created an inception cohort study of men with low serum testosterone followed for initiation of testosterone treatment and incident aggressive prostate cancer. We utilized data from the United States Department of Veterans Affairs VHA, a large, electronically-integrated health care organization that provides medical care to eligible Veterans. The VHA Institutional Review Board approved this study.Men aged 40\u201389 years with a laboratory-defined, low testosterone measurement who received outpatient care in any VHA facility between January 1, 2002 and December 31, 2011, had at least 2 in-person VA clinic visits in the year prior to cohort entry, and PSA testing within 6 months of the low testosterone level (and prior to testosterone treatment) were eligible to enter the cohort (Appendix A). Cohort entry was the date of the first low testosterone level or the date of the qualifying PSA test, whichever occurred later. We excluded men with any history of testosterone treatment in the year prior to cohort entry, prevalent or past prostate or breast cancer, PSA \u2265 4.0 ng/dL, or a history of prostate biopsy.We required that men survive one year following cohort entry because we assumed that there is increased potential for diagnosis of pre-existing prostate cancer in the first year and thathttps://www.hsrd.research.va.gov/for_researchers/vinci/default.cfm; email: VINCI@VA.GOV).We collected data from two sources: the Corporate Data Warehouse (CDW), and the Veterans Affairs Central Cancer Registry (VACCR) diagnostic and procedure codes, and Current Procedural Terminology (CPT) procedure codes .The records obtained from these databases provided demographics, laboratory results and dates, prescription data, dates of clinic visit and hospitalizations, Serum testosterone tests were identified using the Logical Observation Identifiers Names and Codes . Men were classified as having low serum testosterone if they had a total testosterone, free testosterone, free/total testosterone, free testosterone index, or bioavailable testosterone test flagged as low in the reference range used by the specific testing laboratory and used by ordering providers in day-to-day clinical decision making.Testosterone prescriptions were identified using VA National Drug Internal Entry Numbers (IENs).Data included the testosterone formulation , initial prescription date, refill dates, dose, and amount dispensed (Appendices A and B). Treatment initiation was defined as the first prescription for testosterone following cohort entry. We assessed testosterone levels during treatment by averaging all levels measured after the initiation of treatment in testosterone-treated and after cohort entry in untreated men.delivered that was dispensed in all filled prescriptions.Two methods were used to model the association between time-varying testosterone exposure and prostate cancer risk: 1) Binary exposure where men were regarded as not treated until they received their first testosterone prescription and as treated thereafter, even if treatment was intermittent or later discontinued ; and 2) Time-varying cumulative dose, calculated by summing the amount in mg of testosterone aggressive or any prostate cancer, respectively, between January 1, 2002 and September 30, 2012. All prostate cancers were histologically confirmed in the VACCR which provided cancer histology, Gleason score, clinical stage, and PSA at the time of diagnosis (Appendix C).The primary and secondary outcomes were the first occurrence of Aggressive cancer was defined by the presence one of the following: Surveillance Epidemiology and End Results (SEER) Summary Stage (distant metastases) = 7, American Joint Committee on Cancer Stage Group = 4, any metastasis, tumor grade = 4, Gleason score \u2265 8, or PSA at diagnosis \u2265 20 ng/dL.a priori to characterize medical comorbidity as a dichotomous variable (treated/not treated) with follow-up starting one year after cohort entry; and 2) by cumulative testosterone dose during follow up in 5 categories among new testosterone users , with follow-up starting one year after their first testosterone prescription. We performed baseline adjustment for age, race , site of care, BMI, hospitalization in year prior to cohort entry, and 26 medical comorbidities men remained in the low-testosterone analysis cohort. During follow-up, 56,833 men initiated testosterone treatment and free testosterone (14.5%). The median follow-up time for all men was 3.0 years with 25% of men having follow up for > 5.9 years. Total follow-up time was slightly longer for treated men vs. untreated men .We identified 1,352,977 prescriptions for testosterone, of which 862,344 (63.7%) were intramuscular (IM), 361,644 (26.7%) were topical patches, and 128,989 (9.5%) were topical gels. Of the 56,833 men treated with testosterone, 22,738 (40.0%) were treated solely with IM testosterone, 21,746 (38.3%) solely with topical testosterone, and 12,349 (21.7%) with both. The mean cumulative duration of testosterone treatment was 27.0 (SD 27.3) months. The median cumulative duration of testosterone treatment was 17.3 (interquartile range (IQR) 6.6 to 36.8) months. The median number of PSA tests per year in testosterone treated and untreated men were 0.9 and 0.7 respectively.There was a high burden of medical comorbidities at baseline among cohort members . There wRepeat testosterone testing was more common among testosterone-treated men, with testosterone testing in 15,794 (69.5%) and 14,385 (66.2%) in IM- and topical-treated, respectively, versus 31,540 (35.5%) in untreated men. Untreated men had higher baseline testosterone levels than testosterone-treated men. At follow-up testosterone measurement, testosterone levels were higher among all men, including those who were untreated, and there was little difference in follow-up mean serum testosterone level between untreated and topical testosterone-treated men. However, IM testosterone-treated men had a mean serum testosterone level that was approximately 2-fold greater than that of untreated and topical testosterone-treated men .A total of 313 aggressive prostate cancer events were diagnosed. Among untreated men, there were 190 events (incidence rate (IR) 0.57 per 1000 person years, 95% confidence interval (CI) 0.49\u20130.65); among testosterone-treated men, there were 123 events . With baA total of 1,439 any prostate cancers were diagnosed; 848 were diagnosed among untreated and 591 among testosterone-treated men . In adjusted analyses, there was no difference in risk of any prostate cancer in testosterone-treated versus untreated men: HR 0.90; 95% CI 0.81\u20131.01.In fully-adjusted analyses, there was no association between increasing cumulative testosterone dose and increasing risk of aggressive prostate cancer in testosterone-treated men. However, the highest (\u2265 3200 mg) cumulative dose category was associated with a lower risk for aggressive prostate cancer and for any prostate cancer compared with the lowest dose category (1\u2013399 mg). .Among IM-treated men, there was no increased risk for aggressive or any prostate cancer , relative to untreated men . CumulatAmong topically-treated men, there was no increased risk for aggressive or any prostate cancer relative to untreated men . CumulatSensitivity analyses, considering separately men who at cohort entry were aged under 70 years and men who were aged 70 years or older, yielded results consistent with those of the primary analyses. Sensitivity analyses that extended the survival requirement, commencing follow-up at 3 years and 5 years after cohort entry, also yielded results consistent with those of the primary analyses .In analyses adjusted for time-varying medical comorbidities, repeat testosterone testing, and intensity of PSA monitoring, and that followed men for a median of 3.0 years, we observed that in men with low testosterone levels and normal PSA levels at baseline, testosterone treatment was not associated with increased incidence of aggressive or any prostate cancer compared with untreated men. Among men who initiated treatment, we found no evidence of increased aggressive or any prostate cancer risk with increasing cumulative dose of testosterone treatment, and when our analysis was limited to men who were treated only with intramuscular or topical testosterone.These findings are important given the rise in testosterone treatment and concerns for its potential associated risks. Given the association between testosterone treatment and increase in PSA levels and prostate biopsy, information on the near term risk of prostate cancer among this group of men is important for clinical decision making. In hypogonadal men, testosterone treatment increases prostate size and PSA., 16 ExogObservational studies, 11, 26 Our study cohort was selected to be similar to that of a clinical trial of testosterone treatment: no testosterone treatment in the prior year; no previous diagnosis of prostate or breast cancer; and a serum PSA level < 4 ng/dL. To control for potential differences between testosterone-treated and untreated men, we performed time-varying adjustments for 26 medical comorbidities, repeat testosterone testing, and the intensity of PSA screening as these factors may have affected the likelihood of being treated with testosterone and detecting prostate cancer.We analyzed only men who survived one year after entering the cohort or one year after initiating testosterone treatment because we assumed that testosterone treatment may lead to increased screening and detection of occult prostate cancer in the first year of treatment. We chose aggressive prostate cancer as the primary outcome because it is the most clinically impactful, leading to higher morbidity and mortality than non-aggressive prostate cancer.Our study is the largest pharmaco-epidemiologic study to examine the association between testosterone treatment and prostate cancer. Men were selected for having low testosterone levels and normal PSA levels, a population that is often treated with testosterone, although clinical manifestations of androgen deficiency were not available. A large number of prostate cancers were observed. Data were coded at clinical encounters, not through abstraction. Baseline testosterone and PSA were documented on all men and most treated men had follow-up testosterone and PSA levels. Many subjects received IM testosterone, which has more predictable bioavailability than topical testosterone. All prostate cancers were histologically-confirmed with tumor grade and stage assessment. Furthermore, we adjusted for repeat testosterone testing, PSA screening and changing medical comorbidity over time.minimum of five years were consistent with our primary analyses.There are limitations of the study. Despite extensive adjustments, residual confounding is possible. We approached confounding adjustment in a time-dependent manner using 26 medical conditions. Alternative analytic methods, such as propensity scores that address the imbalance of characteristics in those who did and did not receive treatment, are possible, but with a large number of subjects and events, propensity scores do not to offer advantages over time-dependent multivariable adjustment . It is fAmong men with low testosterone and normal PSA levels who were followed for a median of 3 years, compared with untreated men, men treated with testosterone were not at increased risk of incident aggressive or any prostate cancer. The longer term clinical risks and benefits of testosterone treatment can only be definitively addressed by large, long-term randomized controlled trials.Age at time of cohort entry40 to 89 years at time of first low T testDefined as:AgeSeptember 30, 2012 (end of study)730 days after the last in-person VA clinic visitDate of deathFor the primary outcome of aggressive prostate cancer: diagnosis of non-aggressive prostate cancer Censored from follow-up at the earliest of the following:Defined as:Censoring criteriaInternational Classification of Diseases ninth edition) codes for breast cancer in the year prior to cohort entryICD-9 codes for prostate cancer treatment in the year prior to cohort entryCPT in the year prior to cohort entryHistologically-confirmed diagnosis of prostate cancer in the VACCR laboratory codesLOINC Not updated after baselineDefined as:AgeICD-9 codesVA National Drug Internal Entry Numbers) for alpha-blockers and 5 alpha-reductase inhibitors for BPH in the year prior to cohort entryIENs 2)< 18.518.5\u201324.925.0\u201329.930.0\u201334.9\u2265 355 categoriesDefined as:BMI recorded closest to cohort entry date, with preference for prior to cohort entryUpdated after baseline only with ICD-9 codes for obesityBased on:ICD-9 codes: V85.4x, 278.01Codes used:BMI ICD-9 codesBased on:ICD-9 codes: 428.xx, 398.91Codes used:Chronic Heart FailureICD-9 codesBased on:ICD-9 codes: 456.0, 456.1, 456.2x, 571.2, 571.3, 571.40, 571.41, 571.42, 571.49, 571.5, 571.6, 571.8, 571.9, 572.2, 572.3, 572.4, 572.8Codes used:Chronic Liver FailureICD-9 codesBased on:ICD-9 codes: 491.2x, 492.xx, 493.xx (NOT 493.81 or 493.82), 496.xxCodes used:Chronic Lung DiseaseICD-9 codesIENs for long-acting opiates in the 90 days prior to cohort entryBased on:ICD-9 codes: 338.2xIENs: 142, 154, 15712, 15714, 160, 162, 17264, 20101, 378, 5800, 150, 15361, 156, 159, 21479, 387, 5799, 136, 147, 151, 152, 153, 15362, 155, 15703, 161, 163, 164, 165, 16557, 17697, 394, 396, 5801, 138, 139, 141, 143, 148, 149, 157, 15763, 158, 16556, 377, 5802Codes used:Chronic PainICD-9 codesCPT codesBased on:ICD-9 codes: 36.0x, 36.1x, 36.2x, V45.81, V45.82, 410.xx, 411.1, 411.8, 411.81, 411.89, 412.xx, 413.x, 414.xx (NOT 414.1x)CPT codes: 33510, 33511, 33512, 33513, 33514, 33516, 33517, 33518, 33519, 33521, 33522, 33523, 92980, 92981, 92982, 92984, 92985Codes used:Coronary Artery Disease (includes hard/soft outcomes)ICD-9 codesIENs for oral hypoglycemics and insulin in the year prior to cohort entryLOINC laboratory codes for HbA1c > 6 in the year prior to cohort entryBased on:ICD-9 codes: 250.xx, 362.0xIENs: 22955, 17238, 17239, 14371, 14913, 16264, 16280, 17587, 18029, 19354, 20717, 822, 826, 829, 831, 834, 838, 841, 845, 846, 850, 852, 858, 862, 863, 868, 873, 874, 879, 880, 886, 888, 889, 891, 13113, 13485, 16265, 16466, 16467, 16746, 17588, 18242, 18243, 18690, 823, 824, 828, 836, 837, 842, 844, 853, 856, 867, 869, 871, 875, 882, 885, 890, 13351, 13484, 14591, 14592, 16199, 16200, 16437, 16665, 17851, 18590, 19355, 825, 827, 839, 840, 851, 854, 855, 857, 859, 860, 864, 866, 870, 877, 881, 883, 884, 887, 13352, 13353, 13486, 14476, 14477, 16263, 16370, 17849, 17850, 17894, 19356, 20714, 821, 830, 832, 833, 835, 843, 847, 848, 849, 861, 865, 872, 876, 878, 892, 12469, 12485, 13579, 14537, 15347, 15983, 16137, 17220, 1780, 18086, 18282, 1836, 19238, 2079, 21861, 22043, 22947, 23321, 23629, 23631, 23632, 23638, 23797, 4519, 12369, 12470, 12472, 12483, 12484, 12594, 12766, 13507, 13508, 13580, 13581, 13712, 13713, 13714, 14538, 14620, 15981, 15982, 16125, 16139, 17926, 18281, 1837, 19239, 2078, 20859, 22946, 22948, 22959, 23796, 2877, 576, 12468, 12471, 12592, 12593, 12768, 12901, 12976, 13875, 14539, 14941, 16635, 16711, 1779, 1781, 1782, 17912, 18006, 18009, 20177, 21862, 22042, 22389, 22732, 22733, 22958, 22960, 23333, 23623, 23624, 23630, 23637, 2876, 2879, 2880, 4518, 4520, 4521, 12370, 12767, 12899, 12900, 13509, 14319, 14940, 16124, 16126, 16138, 17191, 17542, 17543, 17925, 17927, 18007, 18008, 18010, 18011, 18085, 19240, 20559, 20561, 20858, 22041, 22731, 23332, 23622, 23628, 23633, 2878, 2881, 577, 21531, 17188, 19123, 19375, 19124, 19125LOINCs: 41995\u20132, 55454\u20133, 4548\u20134, 4549\u20132, 17855\u20138, 17856\u20136, 59261\u20138, 71875\u20139, 62388\u20134Codes used:DiabetesICD-9 codesBMI recorded closest to cohort entry is < 18.5Based on:ICD-9 codes: 728.2x, 783.7x, 797.xxCodes used:FrailtyVeterans Integrated Service Network) listed in the patient\u2019s record closest to cohort entry dateThe \u201cHome VISN\u201d Codes used:MalignancyICD-9 codesBased on:ICD-9 codes: V85.4x, 278.01Codes used:Morbid ObesityICD-9 codesBased on:ICD-9 codes: 733.00, 733.01, 733.02, 733.09Codes used:OsteoporosisICD-9 codesCPT codesBased on:ICD-9 codes: 38.18, 38.19, 38.38, 38.39, 38.48, 38.49, 38.88, 38.89, 39.25, 39.26, 39.28, 39.29, 39.50, 39.90, 433, 433.9, 440.2x, 440.3x, 440.4x, 442.x, 443.x, 445.0xCPT codes: 34800, 34802, 34803, 34804, 34805, 35226, 35256, 35286, 35351, 35355, 35371, 35372, 35381, 35454, 35456, 35459, 35473, 35474, 35482, 35483, 35485, 35492, 35493, 35495, 35546, 35548, 35549, 35551, 35556, 35558, 35563, 35565, 35566, 35571, 35583, 35585, 35587, 35646, 35656, 35661, 35663, 35665, 35666, 35671Codes used:Peripheral Vascular DiseaseICD-9 codesLOINC laboratory codes for HCT > 52 in the year prior to cohort entryBased on:ICD-9 codes: 289.0xLOINCs: 24360\u20130, 4544\u20133, 71833\u20138, 4545\u20130, 48703\u20133, 20570\u20138, 41655\u20132, 71830\u20134, 31100\u20131Codes used:PolycythemiaNot screened in the last 12 monthsScreened in the last 6\u201312 monthsScreened in the last 6 months3 categoriesDefined as:Date of most recent PSA measureLOINC laboratory codesBased on:LOINC codes: 19195\u20137, 19197\u20133, 2857\u20131, 35741\u20138, 10886\u20130, 19201\u20133, 19203\u20139, 12841\u20133, 14120\u20130, 33667\u20137, 15323\u20139, 15324\u20137, 15325\u20134Codes used:PSA (Prostate Specific Antigen) screeningBlackWhiteOther3 categoriesNot updated after baselineDefined as:RaceNo repeat T measureFirst repeat T level lowFirst repeat T level non-low3 categoriesRepeat T levels prior to treatment initiation onlyT level updated only at first repeat T levelDefined as:LOINC laboratory codesBased on:LOINC codes: 14913\u20138, 1639\u20134, 21555\u20138, 2986\u20138, 49041\u20137, 49042\u20137, 55519\u20133, 58835\u20130, 70239\u20139, 51005\u20137, 58716\u20132, 49042\u20135, 49043\u20133, 70240\u20137, 58952\u20133, 2990\u20130, 30123\u20134, 14914\u20136, 25987\u20139, 2991\u20138, 35225\u20132, 24125\u20137, 15432\u20138, 16286\u20137, 17686\u20137Codes used:Repeat T levelsICD-9 codesIENs for PDE5 inhibitors for ED and other ED drugs in the year prior to cohort entryBased on:ICD-9 codes: 302.70, 302.71, 302.72, 302.74, 302.75, 302.76, 607.84, 799.81IENs: 16380, 16384, 12823, 16381, 16385, 16522, 20312, 22644, 12822, 12824, 16520, 16521, 16379, 16382, 16383, 16146, 2956, 2957, 2962, 2963, 2954, 2961, 2964, 16147, 16509, 2955, 2965, 16148Codes used:Sexual DysfunctionICD-9 codesBased on:ICD-9 codes: 780.51, 780.53, 780.57Codes used:Sleep ApneaICD-9 codesIENs for smoking cessation drugs in the year prior to cohort entryBased on:ICD-9 codes: V15.82, 305.1x, 989.84IENs: 17847, 23100, 9697, 9703, 16376, 18746, 18749, 22944, 5095, 9700, 9701, 16375, 17845, 18747, 5096, 9696, 13203, 16685, 17846, 17848, 18748, 22943, 9694, 9695, 9698, 9699, 9702Codes used:SmokingCumulative exposure levelAccumulates at the end of each prescription1\u2013399 mg400\u2013799 mg800\u20131599 mg1600\u20133199 mg3200+ mg5 categoriesBased on IENs for testosteroneBased on pharmacy dataBased on:IENs: 513, 514, 515, 516, 518, 524, 525, 526, 527, 530, 531, 532, 533, 534, 14379, 14380, 14775, 15507, 15508, 16064, 16544, 17475, 17503, 17901, 21468, 21470, 21471, 22219, 22384, 22523, 22526, 22791, 168, 169, 170, 171, 172, 173, 174, 512, 517, 519, 520, 521, 522, 523, 528, 529, 1301, 1302, 1303, 3055, 3637, 3638, 3639, 3795, 4220, 4550, 4551, 4552, 4553, 4554, 4555, 4556, 6577, 6578, 6976, 16141Codes used:Testosterone exposureIENsPharmacy dataBased on:IENs: 513, 514, 515, 516, 518, 524, 525, 526, 527, 530, 531, 532, 533, 534, 14379, 14380, 14775, 15507, 15508, 16064, 16544, 17475, 17503, 17901, 21468, 21470, 21471, 22219, 22384, 22523, 22526, 22791, 168, 169, 170, 171, 172, 173, 174, 512, 517, 519, 520, 521, 522, 523, 528, 529, 1301, 1302, 1303, 3055, 3637, 3638, 3639, 3795, 4220, 4550, 4551, 4552, 4553, 4554, 4555, 4556, 6577, 6578, 6976, 1614Codes used:Testosterone FormulationICD-9 codesBased on:ICD-9 codes: 310.2x, 801.xx, 800.xx, 802.xx, 803.xx, 804.xxCodes used:Traumatic Brain Injury (TBI)ICD-9 codesIENs for blood thinners used for DVT in the year prior to cohort entryBased on:ICD-9 codes: 415.1, 415.11, 415.12, 415.13, 415.19, 453.xxIENs: 11785, 12935, 12938, 13678, 15894, 17111, 18874, 18877, 21208, 21213, 21214, 21215, 22021, 22022, 22575, 22765, 4653, 4654, 4658, 4660, 12362, 12932, 13675, 13676, 15440, 15895, 15896, 17183, 18878, 21207, 21209, 21210, 21212, 22573, 22764, 22766, 4652, 4656, 11784, 11787, 12936, 13624, 13625, 13674, 13677, 13679, 15439, 17110, 17112, 18876, 19109, 21211, 22019, 22020, 4650, 4651, 4657, 4659, 11783, 11786, 12360, 12361, 12933, 12934, 14609, 15480, 22763, 4655, 5592, 5593Codes used:Venous Thrombosis and Pulmonary EmbolismHistologically-confirmed prostate cancer onlyDiagnosed after cohort entrySEER Summary Stage = 7AJCC Stage Group = 4 or IVAny metastasisTumor Grade = 4Gleason Score \u2265 8PSA \u2265 20Must be classified as one or more of the following:Defined as:Aggressive Prostate CancerHistologically-confirmed prostate cancer onlyDiagnosed after cohort entryIncludes aggressive prostate cancerDefined as:Data from VACCRBased on:Any Prostate CancerS1 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file."} +{"text": "Equus caballus) is decribed in detail using high field MRI. The study includes sagittal, dorsal, and transverse T2-weighted images at 0.25 mm resolution at 3 Tesla and 3D models of the brain presenting the external morphology of the brain. Representative gallocyanin stained histological slides of the same brain are presented. The images represent a useful tool for MR image interpretation in horses and may serve as a starting point for further research aiming at in vivo analysis in this species.In this study, the morphology of the horse brain ( Neuroimaging is increasingly important in veterinary large animal neurology. Magnetic resonance imaging (MRI) is more and more used to evaluate intracranial diseases in horses with neurological signs \u201312. HighThe head of an eight years old warm blood horse was examined post-mortem. The animal was euthanized due to a complicated tarsal fracture. The horse was sedated with 0.4 mg/kg xylazin injected in an intraveneous catheter in the jugular vein. General anesthesia was induced with 0.1 mg/kg diazepam (Diazepam AbZ) and 2.2 mg/kg ketamine (Narketan 10). Euthanasia was performed using 0.12ml/kgkg embutramid (T61). No neurological findings were observed at previous clinical examination. Directly after euthanasia the head was dissected between fourth and fifth cervical vertebrae and was trimmed to fit into a standard human knee coil. MRI was performed 90 minutes after death of the animal. Owner consent was obtained for use of the head in scientific research. All data was anonymized.2 field of view (FOV) at 512 x 512 matrix size resulting in 0.25 mm in-plane resolution and 1mm slice distance. Optimum contrast was obtained with 8500 milliseconds (ms) repetition time (TR) and while the echotime (TE) was adjusted to 12 ms. Image acquisition was anisotropic, which is why sagittal and horizontal planes were not recalculated but obtained in consecutive scan sessions. Total scan time was 4 hours and 55 minutes.MRI scans were performed on a 3-Tesla Magnetom Verio scanner using an eight channel phased array human knee coil. Anatomical images of the entire brain were acquired in transverse, sagittal and dorsal planes, using a T2-weighted spin echo sequence. To achieve a sufficient signal-to-noise ratio (SNR), 32 averages were accumulated obtaining slices of 3 mm thickness with 672x672mmImages were reviewed using AMIRA (Mercury Computer Systems) graphical software. This program allows interactive assessment of morphology in all image planes. A 3D model of the outer brain surface was generated based on free hand segmentation of the brain outlines in transverse MR-images. Image segmentation in this context describes the manual tracing of the brain surface. All voxels corresponding to a single anatomical structure in the images are selected and assigned to the same value in the mask. The final mask thus contains information about all selected anatomical structures and, in combination with the original data and polygonal surface reconstruction algorithms, allows the identification of sulci and gyri in 2 D images in association with the produced 3D model. Anatomic structures including the sulci and gyri were identified using a published atlas and by cHistological slides in transverse orientation were obtained to support image analysis. After scanning, the brain was removed and fixed by immersion in 10% formalin for 2 weeks. Due to the large size of the brain, the brainstem with the cerebellum was severed at the level of the rostral pons and the hemispheres were divided. Brain tissue was dehydrated in 96% alcohol and embedded with 8% celloidin for 48 h. The brain together with an excess of 8% celloidin were placed into a big transparent PVC embedding form. The celloidin was concentrated to 16% in a dessicator by a slight vacuum (150 millibar). The 16% celloidin was finally hardened by chloroform vapors and one day prior to cutting with 70% ethanol. The celloidin blocks were serially sectioned on a sliding microtome with section thickness of 350 \u03bcm. Celloidin served as a support, guiding the microtome knife through the tissue block and preventing tangentially cut gyri from floating away during subsequent staining procedures. Slicing of the histology slides was performed perpendicular to the brainstem axis to match the same orientation as the MR transverse image slices. The slices were then stained free-floating in gallocyanin-chromalum quenchedA 3D rendered model demonstrThe lateral rhinal fissure is seen as a thin sheet of brain tissue below the rostrum of the corpus callosum . Fibers coming from the cerebral convolutions converge in the dorsal hemisphere to a great mass of white matter. Dorsal to the lateral ventricles and corpus callosum, it forms the semioval centre lies dorsally to the zona incerta, H2 ventrally to it arching over the dorsal border of the subthalamic nucleus (lenticular fasciculus) [The subthalamus is a region formed by several grey matter nuclei and their associated white matter structures. The subthalamic nucleus : stn is ciculus) : H1, H2 \u201332. The The hypothalamus forms the basal wall of the third ventricle; the hypothalamic sulcus , which is formed by neurons that form a caudal continuation of the diencephalic periventricular nuclei of the hypothalamus. These neuronal masses surround the aqueduct and continue throughout the midbrain. Its shape, as seen in transverse sections, varies at different levels. Scattered throughout the central grey substance are numerous nuclei, which are collectively called the tegmental nuclei. Besides these scattered nuclei the central grey substance contains the nuclei of the oculomotor lobule ending in the contra-lateral red nucleus and the ventral thalamus. The caudal lobe has extensive cortico-pontocerebellar connections via the middle cerebellar peduncles from the ventrolateral pons. The trigeminal ganglion . The facial nerve proceeds upwards and exits the brainstem laterally , and is no longer visible from the outer surface . Little The horse has been referred to as being a macrosmatic mammal . InteresThe descending tracts from the motor and premotor region in the cortex running to the internal capsule and continue to form the cerebral peduncles are not well developed. The pyramids are comparatively small . The bulThe shape of the equine cerebellum has been described as beeing very chracteristic amongst ungulates , 38. In S1 Table(DOCX)Click here for additional data file.S1 FigRfi: rhinal fissure, Sss: suprasylvian sulcus.cin: cingulum, cig: cingulate gyrus, Cor: coronal sulcus, cor: coronal gyrus, Cru: cruciate sulcus, Dia: diagonal sulcus, Ectg: ectogenula sulcus, Ecs: ectosylvian sulcus, Gen: genual sulcus, lot: lateral olfactory tract, mot: medial olfactory tract, olr: olfactory recess, Prr: prorean sulcus, prr: prorean gyrus, Prs: presylvian sulcus, (TIF)Click here for additional data file.S2 Figacn: accumbens nucleus, cc: colossal commissure, cin: cingulum, cla: claustrum, cn: caudate nucleus, cor: coronal gyrus, Cor: coronal sulcus, Cru: cruciate sulcus, cso: centrum semiovale, Dia: diagonal sulcus, ec: external capsule, Ecs: ectosylvian sulcus, fsc: subcallosal fasciculus, gcc: genu of the corpus callosum, Gen: genual sulcus, ic: internal capsule, log: lateral olfactory gyrus, lot: lateral olfactory tract, lv: lateral ventrikel, mot: medial olfactory tract, Prs: presylvian sulcus, put: putamen, Rfi: rhinal fissure, Scl: sulcus of corpus callosum, ssg: suprasylvian gyrus, Sss: suprasylvian sulcus.(TIF)Click here for additional data file.S3 Figacn: accumbens nucleus, Ans: Ansate sulcus, cla: claustrum, cig: cingulate gyrus, cin: cingulum, cn: caudate nucleus, Cor: coronal sulcus, cso: centrum semiovale, ec: external capsule, Ecs: ectosylvian sulcus, Eng: endogenual sulcus, ex: extreme capsule, fsc: subcallosal fasciculus, gcc: genu of the corpus callosum, Gen: genual sulcus, ic: internal capsule, lot: lateral olfactory tract, mot: medial olfactory tract, otb: olfactory tubercle, put: putamen, rcc: radition of corpus callosum, Rfi: rhinal fissure, sl: lateral septal nuclei, sm: medial septal nuclei.(TIF)Click here for additional data file.S4 Figcc: callosal commissure, cho: optic chiasm, cig: cingulate gyrus, cin: cingulum, cla: claustrum, cn: caudate nucleus, cso: centrum semiovale, dbb: diagonal band of broca, Dias: diagonal sulcus , ec: external capsule, ecs: ectosylvian gyrus, Ecs: ectosylvian sulcus, Enrh: endorhinal sulcus, ex: extreme capsule, fsc: subcallosal fasciculus, gp: globus pallidus, ic: internal capsule, icl: islands of Calleja, ins: insular cortex, log: lateral olfactory gyrus, lot: lateral olfactory tract, lv: lateral ventricle, otb: olfactory tubercle, put: putamen, rc: rostral commissure, rcc: radiation of corpus callosum, Rfi: rhinal fissure, Scl: sulcus of corpus callosum, sl: lateral septal nuclei, sm: medial septal nuclei, Spl: splenial sulcus, Sss: suprasylvian sulcus, Syl: Sylvian fissure.(TIF)Click here for additional data file.S5 FigAns: ansate sulcus, ansl: ansa lenticularis, cc: corpus callosum, cho: optic chiasm, cig: cingulate gyrus, cin: cingulum, cla: claustrum, cn: caudate nucleus, cso: supraoptic commissure, ec: external capsule, Ecs: ectosylvian sulcus, ectosylvian gyrus, ex: extreme capsule, fsc: subcallosal fasciculus, gp: globus pallidus, ic: internal capsule, log: lateral olfactory gyrus, lot: lateral olfactory tract, lv: lateral ventricle, Mar: marginal sulcus, mar: marginal gyrus, prpc: prepiriform cortex, put: putamen, rc: rostral commissure, rcc: radiation of corpus callosum, Rfi: rhinal fissure, Scl: sulcus of corpus callosum, smt: stria medullaris thalami, Spl: splenial sulcus, Sss: suprasylvian sulcus, stt: terminal stria, Syl: sylvian fissure, syl: sylvian sulcus, tl: terminal lamina.(TIF)Click here for additional data file.S6 Figab: amygdaloid body,alv: alveus, Ans: ansate sulcus, cc: corpus callosum, cin: cingulum, cig: cingulate gyrus, cf: column of fornix, cfo: corpus of fornix, cn: caudate nucleus, crc: cerebral crus, ec: external capsule, Ecs: ectosylvian sulcus, ecs: ectosylvian gyrus, ex: extreme capsule, fmt: mammilo-thalamic fasciculus, fsc: subcallosal fasciculus, hs: hypothalamic sulcus, ic: internal capsule, ita: interthalamic adhesion, lme: external medullary lamina, lv: lateral ventricle, Mar: marginal sulcus, mar: marginal gyrus, nad: nucleus anterior dorsalis thalami, nrt: reticular nucleus of the thalamus, Obl: oblique sulcus, obl: oblique gyrus, pfc: piriform cortex, put: putamen, rcc: radiation of corpus callosum, Rfi: rhinal fissure, slu: gyrus semilunaris, smt: stria medullaris thalami, ssg: suprasylvian gyrus, Sss: suprasylvian sulcus, stt: terminal stria, syl: sylvian gyrus, Syl: sylvian fissure, 3: third ventricle.(TIF)Click here for additional data file.S7 Figalv: alveus, are: entorhinal area, cam: cornu amonis, cc: corpus calosum, cla: claustrum, cn: caudate nucleus, crc: cerebral crus, dg: dentate gyrus, fh: fimbria of the hippocampus, fsc: subcallosal fasciculus, H1: fields of Forel 1, H2: Fields of Forel 2, ha: habenula, han: habenular nuclei, hf: hippocampal fissure, hit: habenulo-interpeduncular tract, ins: insular cortex, lgb: lateral geniculate body, lme: external medullary lamina, lv: lateral ventricle, mgb: medial geniculate body, ml: medial lemniscus, nrt: reticular nucleus of the thalamus, or: optic radiation, ot: optic tract, pcm: peduncles of the mammillary body, pul: pulvinar nuclei, Rfi: rhinal fissure, Sgs: sagittal sulcus, snr: substantia nigra, sub: subiculum, stt: terminal stria, Syl: sylvian fissure, zi: zona incerta.(TIF)Click here for additional data file.S8 Figare: entorhinal area, alv: alveus, cam: ammon\u2019s horn, CA1: cornu ammonis field 1, CA2: cornu ammonis field 2, CA3: cornu ammonis field 3; CA4: cornu ammonis field 4, cdc: caudal colliculus, cgs: central grey substance, cha: habenular commissure, cn: caudate nucleus, crc: cerebral crus, df: dentate fascia, fh: fimbria of the hippocampus, flv: ventral longitudinal fasciculus, fsc: subcallosal fasciculus, lgb: lateral geniculate body, mgb: medial geniculate body, ml: medial lemniscus, or: optic radiation, ot: optic tract, pb: pineal body, pcm: peduncles of the mammillary body, prs: presubiculum, pta: pretectal area, pul: pulvinar nuclei, Rfi: rhinal fissure, rn: red nucleus, scc: splenium of corpus callosum, scmo: subcommissural organ, snrc: pars compacta of the substantia nigra, snrr: pars reticularis of the substantia nigra, sub: subiculum, vtc: ventral tegmental commissure.(TIF)Click here for additional data file.S9 Figaq: mesencephalic aqueduct, bcc: brachium of the caudal colliculus, cgs: central grey substance, ctt: central tegmental tract, nmt: mesencephalic nucleus of the trigeminal nerve, pb: pineal body, slm: sulcus limitans.(TIF)Click here for additional data file.S10 Figaq: mesencephalic aqueduct, bcc: brachium of the caudal colliculus, cdc: caudal colliculus, cst: corticospinal tract, dtn: decussation of the trochlear nerve, flm: medial longitudinal fasciculus, ftp: transverse fibres of the pons, ipd: interpeduncular nucleus, lal: lateral lemniscus, mcp: medial cerebellar peduncle, ml: medial lemniscus, nII: nucleus of lateral lemniscus, npo: nuclei of the pons, nto: nucleus of trochlear nerves, rcp: rostral cerebellar peduncle, rf: reticular formation, rst: rubrospinal tract, tmnt: mesencephalic tract of the trigeminal nerve, VI: abducence nerve.(TIF)Click here for additional data file.S11 Figcst: corticospinal tract, fld: dorsal longitudinal fasciculus, flm: medial longitudinal fasciculus, IaI: lateral lemniscus, mcp: medial cerebellar peduncle, ml: medial lemniscus, nII: nucleus of lateral lemniscus, npo: nuclei of the pons, ppd: parapeduncular nuclei, rcp: rostral cerebellar peduncle, rf: reticular formation, vst: vestibulospinal tract, V: trigeminal nerve.(TIF)Click here for additional data file.S12 Figdctb: decussation of the trapezoid body, flm: medial longitudinal fasciculus, gnf: genu of the facial nerve, nab: nucleus of the abducent nerve, ncd: dorsal cochlear nucleus, ncv: ventral cochlear nucleus, ndct: superior olivary nucleus, ntsn: nucleus of the spinal tract of the trigeminal nerve, nvl: lateral vestibular nuclei, pyr: pyramidal tract, rcp: rostral cerebellar peduncle, rf: reticular formation, rnf: radix of the facial nerve, rst: rubro-spinal tract, slm: sulcus limitans, tb: trapezoid body, tsnt: spinal tract of the trigeminal nerve, VI: roots of the abducence nerve, VII: facial nerve, VIII: vestibulocochleal nerve.(TIF)Click here for additional data file.S13 Figccp: caudal cerebellar peduncle, dctb: decussation of the fibres of trapezoid body, flm: medial longitudinal fasciculus, li: lingula of the vermis, mcp: medial cerebellar peduncle, ncd: dorsal cochlear nucleus, ncv: ventral cochlear nucleus, ndct: superior olivary nucleus, ntsn: nucleus of the spinal tract of the trigeminal nerve, nvl: lateral vestibular nuclei, nvm: medial vestibular nucleus, pyr: pyramidal tract, rst: rubrospinal tract, slm: sulcus limitans, tac: acoustic tubercle, tb: trapezoid body, tsnt: spinal tract of the trigeminal nerve, VI: roots of the abducence nerve, VIII: vestibulocochleal nerve.(TIF)Click here for additional data file.S14 Figamb: ambiguus nucleus, ccp: caudal cerebellar peduncle, cun: cunetae nucleus, flm: medial longitudinal fasciculus, hypn: nucleus of the hypoglossal nerve, nfl: nucleus of the lateral fascicle, ntsn: nucleus of the spinal tract of the trigeminal nerve, oli: olivary nucleus, pyr: pyramidal tract, sol: nucleus of the solitary tract, soln: nucleus of the solitary trasct, tsnt: spinal tract of the trigeminal nerve, vagn: nucleus of the vagus nerve, X: vagus nerve.(TIF)Click here for additional data file.S15 Figcec: central canal, cst: corticospinal tract, cun: cuneate nucleus, gra: gracile nucleus, hypn: nucleus of the hypoglossal nerve, nfl: nucleus of the lateral fascicle, ntsn: nucleus of the spinal tract of the trigeminal nerve, obx: obex, oli: olivary nucleus, pyr: pyramidal tract, soln: nucleus of the solitary tract, sol: solitary tract, tsnt: spinal tract of the trigeminal nerve, vgn: nucleus of the vagus nerve.(TIF)Click here for additional data file."} +{"text": "Correction to: Implementation Science (2015) 10:2.https://doi.org/10.1186/s13012-014-0193-xFollowing publication of the original article the authAcknowledgementsThe preparation of this manuscript was supported, in kind, through the National Institutes of Health R13 award entitled, \u201cDevelopment and Dissemination of Rigorous Methods for Training and Implementation of Evidence-Based Behavioral Health Treatments\u201d granted to PI: KA Comtois from 2010 to 2015. Dr. Bryan J. Weiner\u2019s time on the project was supported by the following funding: NIH CTSA at UNC UL1TR00083. We would also like to acknowledge the numerous undergraduate research assistants (RAs) who contributed countless hours to this project. Indiana University RAs listed in alphabetical order: Hayley Ciosek, Caitlin Dorsey, Dorina Feher, Sarah Fischer, Amanda Gray, Charlotte Hancock, Hilary Harris, Elise Hoover, Taylor Marshall, Elizabeth Parker, Paige Schultz, Monica Schuring, Theresa Thymoski, Lucia.Walsh, Kaylee Will, Rebecca Zauel, Wanni Zhou, Anna Zimmerman, and Nelson Zounlome. University of Montana RAs (undergraduate and graduate) listed in alphabetical order: Kaitlyn Ahlers, Sarah Bigley, Melina Chapman, May Conley, Lindsay Crosby, Bridget Gibbons, Eleana Joyner, Samantha Moore, Julie Oldfield, Kinsey Owen, Amy Peterson, and Mark Turnipseed.University of North Carolina RAs: Emily Haines and Connor Kaine.In addition, the authors would like to acknowledge Lindsay Crosby (now Dr. Lindsay Meyer) who contributed significant writing portions to this manuscript."} +{"text": "The Acknowledgments contain an error. J. Spencer Johnston should be listed as a member of The International Aphid Genomics Consortium (IAGC).J. Spencer Johnston is affiliated with the Department of Entomology, Texas A&M University, College Station, Texas, United States of America.The Acknowledgements should read:The members of The International Aphid Genomics Consortium (IAGC) are as follows: Sequencing leadership: Stephen Richards, Richard A. Gibbs, Project Leadership: Nicole M. Gerardo, Nancy Moran, Atsushi Nakabachi, Stephen Richards, David Stern, Denis Tagu, Alex C. C. Wilson; DNA sequence and global analysis: DNA sequencing: Sequence Production: Donna Muzny, Christie Kovar, Andy Cree, Joseph Chacko, Mimi N. Chandrabose, Marvin Diep Dao, Huyen H. Dinh, Ramatu Ayiesha Gabisi, Sandra Hines, Jennifer Hume, Shalini N. Jhangian, Vandita Joshi, Lora R. Lewis, Yih-shin Liu, John Lopez, Margaret B. Morgan, Ngoc Bich Nguyen, Geoffrey O. Okwuonu, San Juana Ruiz, Jireh Santibanez, Rita A. Wright; Sequence Production Informatics: Gerald R. Fowler, Matthew E. Hitchens, Ryan J. Lozado, Charles Moen, David Steffen, James T. Warren, Jingkun Zhang; Sequence Library Production: Lynne V. Nazareth, Dean Chavez, Clay Davis, Sandra L. Lee, Bella Mayurkumar Patel, Ling-Ling Pu, Stephanie N. Bell, Angela Jolivet Johnson, Selina Vattathil, Rex L. Williams Jr.; Full length ESTs: Shuji Shigenobu, David Stern, Stephen Richards, Phat M. Dang, Mizue Morioka, Takema Fukatsu, Toshiaki Kudo, Shin-ya Miyagishima, Atsushi Nakabachi; Genome size: J. Spencer Johnston; Genome Assembly: Huaiyang Jiang, Stephen Richards, Kim C. Worley; AphidBase and bioinformatics resources: Fabrice Legeai, Jean-Pierre Gauthier, Olivier Collin, Shuji Shigenobu, Denis Tagu; Gene prediction and consensus gene set: Fabrice Legeai, Lan Zhang, Jean-Pierre Gauthier, Shuji Shigenobu, Denis Tagu, Stephen Richards, Hsiu-Chuan Chen, Olga Ermolaeva, Wratko Hlavina, Yuri Kapustin, Boris Kiryutin, Paul Kitts, Donna Maglott, Terence Murphy, Kim Pruitt, Victor Sapojnikov, Alexandre Souvorov, Fran\u00e7oise Thibaud-Nissen, Francisco C\u00e2mara, Roderic Guig\u00f3, Mario Stanke, Victor Solovyev, Peter Kosarev, Don Gilbert; Phylogenomic Analyses: Toni Gabald\u00f3n, Jaime Huerta-Cepas, Marina Marcet-Houben, Miguel Pignatelli, Don Gilbert, Andr\u00e9s Moya; Gene duplications: Claude Rispe, Morgane Ollivier, Fabrice Legeai, Denis Tagu; Transposable elements: Hadi Quesneville, Emmanuelle Permal, Andr\u00e9s Moya, Carlos Llorens, Ricardo Futami, Alex C. C. Wilson, Dale Hedges; Telomeres: Hugh M. Robertson; U12-Introns and Seleno-Proteins: Tyler Alioto, Marco Mariotti, Roderic Guig\u00f3; Symbiosis: Bacterial and mitochondrial genes in the aphid genome: Naruo Nikoh, John P. McCutcheon, Miguel Pignatelli, Gaelen Burke, Nicole M. Gerardo, Alexandra Kamins, Amparo Latorre, Andr\u00e9s Moya, Toshiaki Kudo, Shin-ya Miyagishima, Nancy A. Moran, Atsushi Nakabachi; Metabolism: Peter Ashton, Federica Calevro, Hubert Charles, Stefano Colella, Angela Douglas, Georg Jander, Derek H. Jones, G\u00e9rard Febvay, Lars G. Kamphuis, Philip F. Kushlan, Sandy Macdonald, John Ramsey, Julia Schwartz, Stuart Seah, Gavin Thomas, Augusto Vellozo, Alex C. C. Wilson; Comparative genomics of Buchnera: Shuji Shigenobu, Stephen Richards, Nancy Moran, Shin-ya Miyagishima, Atsushi Nakabachi; Genome analysis of Regiella insecticola: Bodil Cass, Patrick Degnan, Bonnie Hurwitz, Teresa Leonardo, Ryuichi Koga, Nancy Moran, Stephen Richards, David Stern; Stress and immunity group: Boran Altincicek, Caroline Anselme, Hagop Atamian, Seth M. Barribeau, Martin de Vos, Elizabeth J. Duncan, Jay Evans, Toni Gabaldon, Nicole M. Gerardo, Murad Ghanim, Abdelaziz Heddi, Isgouhi Kaloshian, Amparo Latorre, Carole Vincent-Monegat, Andr\u00e9s Moya, Atsushi Nakabachi, Ben J. Parker, Vicente P\u00e9rez-Brocal, Miguel Pignatelli, Yvan Rahb\u00e9, John Ramsey, Chelsea J. Spragg, Javier Tamames, Daniel Tamarit, Cecilia Tamborindeguy, Andreas Vilcinskas; Development group: Shuji Shigenobu, Ryan D. Bickel, Jennifer A. Brisson, Thomas Butts, Chun-che Chang, Olivier Christiaens, Gregory K. Davis, Elizabeth Duncan, David Ferrier, Masatoshi Iga, Ralf Janssen, Hsiao-Ling Lu, Alistair McGregor, Toru Miura, Guy Smagghe, James Smith, Maurijn van der Zee, Rodrigo Velarde, Megan Wilson, Peter Dearden, David Stern; Germ line group: Chun-che Chang, Hsiao-Ling Lu, Ryan D. Bickel, Shuji Shigenobu, Gregory K. Davis; Epigenetics and Methylation: Jennifer A. Brisson, Owain R. Edwards, Karl Gordon, Roland S. Hilgarth, Stanley Dean Rider Jr., Hugh M. Robertson, Dayalan Srinivasan, Thomas K. Walsh; Wing development: Jennifer A. Brisson, Asano Ishikawa, Toru Miura; JH-related: Toru Miura, Jennifer A. Brisson, Asano Ishikawa, St\u00e9phanie Jaubert-Possamai, Denis Tagu, Thomas K. Walsh; Mitosis, meiosis and cell cycle: Dayalan Srinivasan, Brian Fenton, St\u00e9phanie Jaubert-Possamai; Sex determination: Wenting Huang, Derek H. Jones, Alex C. C. Wilson; MicroRNA and phenotypic plasticity: Fabrice Legeai, Thomas K. Walsh, Guillaume Rizk, Owain R. Edwards, Karl Gordon, Dominique Lavenier, Jacques Nicolas, Denis Tagu, St\u00e9phanie Jaubert-Possamai, Claude Rispe; Aphid Plant Interactions: Chemoreceptors: Carole Smadja, Hugh M. Robertson; Odorant-Binding Proteins: Jing-Jiang Zhou, Filipe G. Vieira, Carole Smadja, Xiao-Li He, Renhu Liu, Julio Rozas, Linda M. Field; Detoxification enzymes: Stanley Dean Rider Jr., John Ramsey, Karl Gordon, Thomas K. Walsh, Martin de Vos, Georg Jander; Salivary glands: Peter D. Ashton, Peter Campbell, James C. Carolan, Angela E. Douglas, Owain R. Edwards, Carol I. J. Fitzroy, Lars G. Kamphuis, Karen T. Reardon, Gerald R. Reeck, Karam Singh, Thomas L. Wilkinson; Neuropeptides: Jurgen Huybrechts, Mohatmed Abdel-latief, Alain Robichon, Jan A. Veenstra, Frank Hauser, Giuseppe Cazzamali, Martina Schneider, Michael Williamson, Elisabeth Stafflinger, Karina K. Hansen, Cornelis J. P. Grimmelikhuijzen, Denis Tagu; Transporters: Daniel R.G Price, Marina Caillaud, Eric van Fleet, Qinghu Ren, Yvan Rahb\u00e9, Angela E. Douglas, John A. Gatehouse; Virus transmission and transcytosis group: V\u00e9ronique Brault, Baptiste Monsion, Marina Caillaud, Eric Van Fleet, Jason Diaz, Laura Hunnicutt, Atsushi Nakabachi, Ho-Jong Ju, Cecilia Tamborindeguy, Ximo Pechuan, Jos\u00e9 Aguilar, Daniel Tamarit; Carlos Llorens, Andres Moya; Dynamins: Atsushi Nakabachi, Shin-ya Miyagishima; Circadian rhythms group: Teresa Cort\u00e9s, Benjam\u00edn Ortiz-Rivas, David Mart\u00ednez-Torres; Cuticular proteins: Claude Rispe, Aviv Dombrovsky, St\u00e9phanie Jaubert-Possamai, Denis Tagu; Chitinase-like proteins: Atsushi Nakabachi, Shuji Shigenobu, Shin-ya Miyagishima; Ion Channels: Richard P. Dale, Thomas K. Walsh, Cecilia Tamborindeguy, T. G. Emyr Davies, Linda M. Field, Martin S. Williamson, Andrew Jones, David Sattelle, Sally Williamson, Adrian Wolstenholme; Protease genes: Peter Campbell, James C. Carolan, Owain R. Edwards, Karl Gordon, Carlos Llorens, Andres Moya, Miguel Pignatelli, Yvan Rahb\u00e9, Claude Rispe, Gerald R. Reeck; AcypiCyc: Augusto Vellozo, Stefano Colella, Ludovic Cottret, G\u00e9rard Febvay, Federica Calevro, Yvan Rahb\u00e9, Angela Douglas, Marie France Sagot, Hubert Charles; Ribosomal Proteins: Claude Rispe, David G. Heckel, Wayne Hunter."} +{"text": "AbstractColeoptera: Coccinellidae) records collected during the last four years across Sindh are reported. A first preliminary checklist of ladybirds from Sindh is presented, consisting of one subfamily, ten tribes, 21 genera, and 29 species including four new records, namely Bulaealichatschovii (Hummel), Exochomuspubescens K\u00fcster, Scymnus (Pullus) latemaculatus Motschulsky, Scymnus (Pullus) syriacus Marseul, and four varieties of the species Cheilomenessexmaculatus (Fabricius).Some new ladybird ( Coccinellidae comprises two subfamilies: Microweiseinae Leng, 1920 and Coccinellinae Latreille, 1807 , Sitobionavenae (Fabricius), Aphisgossypii Glover, Aphisfabae Scopoli, Aphisnerii Boyer de Fonscolombe, Aphiscraccivora (Koch) Rhopalosiphummaidis (Fitch), Therioaphistrifolii (Monell), Hysteroneurasetariae (Thomas), Lipaphiserysimi , Brevicorynebrassicae (Linnaeus), Myzuspersicae (Sulzer), and Hyadaphiscoriandri (Das) (Homoptera: Aphididae); Amritodusatkinsoni (Lethierry)), Amrascabiguttulabiguttula (Ishida), Empoascalybica (Bergevin and Zanon) (Homoptera: Cicadellidae); Bemisiatabaci (Gennadius), Aleurolobusbarodensis (Maskell), Dialeurodescitri (Ashmead) and Aleurocanthushusaini Corbett (Homoptera: Aleyrodidae); Brevipalpuslewisi McGregor , Eutetranychusorientalis (Klein), and Tetranychusatlanticus McG. (Acarina: Tetranychidae) are common pests of wheat, cotton, sugarcane, mango, mustard, vegetables, and fruits in Pakistan. Other works related with the taxonomy, morphology, diversity, distribution and ecology of different coccinellids include Coccinellidae and their role in the field of biological control of important agricultural crop pests such as aphids, mealybugs, scale insects, jassids, and whiteflies.According to The coccinellid fauna of Sindh, Pakistan is insufficiently known, and no checklist exists. The goal of this paper is to contribute to the knowledge of diversity and distribution of ladybirds in Sindh as well as to present the first preliminary checklist of the species recorded previously in the territory of Sindh.Coccinellidae. Specimens were collected during field trips conducted in different parts of Sindh Province, and in reality represent random findings instead of systematic collecting. Beetles were collected in standard ways, including manual collecting, net sweeping, and using light traps. The terminologies for various taxonomic structures including genitalia and procedures used by Ladybird records presented in this paper were collected, identified, and confirmed during the last four years by the authors following the checklists, descriptions, and keys given by Chapin and Ahmad (1966), Pang and Gordon (1986), Coccinellinae only. It includes nine species of the tribe Coccinellini, one species of the Psylloborini, one species of the tribe Bulaeini, five species of the Chilocorini, one species of the Tribe Noviini Mulsant, one species from Tribe Hyperaspini, one species from the Tribe Stethorini, six species of Scymnini, one species of the Tribe Shirozuellini, and three species of the Tribe Sticholotidini. New records are Bulaealichatschovii (Hummel), Exochomuspubescens K\u00fcster, Scymnus (Pullus) latemaculatus Motschulsky, Scymnus (Pullus) syriacus Marseul with four varieties of Cheilomenessexmaculatus (Fabricius).The coccinellids present in this checklist are classified on the basis of the new classification given by Taxon classificationAnimaliaColeopteraCoccinellidaeLinnaeus, 1758India, Nepal, Sri Lanka, Pakistan, Palaearctic. North America (Poorani 2002).Tandojam, Larkana, Mirpur Khas, Thatta, Karachi .Brevicorynebrassicae (L), Lipaphiserysimi , Myzuspersicae (Sulzer), Aphisgossypii (Glover), Hyadaphiscoriandri (Das), Hysteroneurasetariae (Thomas), Schizaphisgraminum (Rondani) (Aphididae: Homoptera); Phenacoccussolenopsis (Tinsley), Ferrisiavirigata (Ckll) (Pseudococcidae: Homoptera); Amrascadevastans (Dist), Amrascabiguttulabiguttula (Ishida) (Cicadellidae: Homoptera); Bemisiatabaci (Gennadius) (Aleyrodidae: Homoptera) on mustard, lucern, cabbage, cauliflower, potato, turnip, bottle gourd, eggplant, okra, wheat, cotton, sugarcane, and rose plants (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeLinnaeus, 1758India, Pakistan. Palaearctic (Poorani 2002).Karachi, Hyderabad, Tandojam, Mirpur Khas and Thatta .Brevicorynebrassicae (L.), Lipaphiserysimi , Myzuspersicae (Sulzer), Aphisgossypii (Glover), Hyadaphiscoriandri (Das), Hysteroneurasetariae (Thomas), Schizaphisgraminum (Rondani) (Aphididae: Homoptera); Phenacoccussolenopsis (Tinsley), Ferrisiavirigata (Ckll) (Pseudococcidae: Homoptera); Amrascadevastans (Dist), Amrascabiguttulabiguttula (Ishida) (Cicadellidae: Homoptera); Bemisiatabaci (Gennadius) (Aleyrodidae: Homoptera) on mustard, lucern, cabbage, cauliflower, potato, turnip, bottle gourd, brinjal, okra, wheat, cotton, sugarcane, and rose plants (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeFabricius, 1781India, Nepal, Sri Lanka, Bangladesh, Indochina, Indonesia, Japan, Australia, New Zealand (Poorani 2002).Hyderabad, Larkana, Mirpur Khas, and Thatta (Ali 2013).Brevicorynebrassicae (L.), Lipaphiserysimi , Myzuspersicae (Sulzer), Aphisgossypii (Glover), Hyadaphiscoriandri (Das), Hysteroneurasetariae (Thomas), Schizaphisgraminum (Rondani) (Aphididae: Homoptera); Phenacoccussolenopsis (Tinsley), Ferrisiavirigata (Ckll) (Pseudococcidae: Homoptera); Amrascadevastans (Dist), Amrascabiguttulabiguttula (Ishida) (Cicadellidae: Homoptera); Bemisiatabaci (Gennadius) (Aleyrodidae: Homoptera) on mustard, lucern, cabbage, cauliflower, potato, turnip, bottle gourd, brinjal, okra, wheat, cotton, sugarcane, and rose plants (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeIndia, Bangladesh, Pakistan, Sri Lanka, Bhutan, Myanmar. Malaysia, Indonesia, Philippines, Vietnam, China, Japan, Australia (Poorani 2002).Hyderabad, Larkana, Mirpur Khas, and Thatta .Aphiscraccivora Koch, A.gossypii Glover, Brevicorynebrassicae (L.), Lipaphiserysimi , Myzuspersicae (Sulzer), Aphisgossypii (Glover), Hyadaphiscoriandri (Das), Hysteroneurasetariae (Thomas), Schizaphisgraminum (Rondani), Ropalosiphummaidis (Fitch), Therioaphistrifolii Monell (Aphididae: Homoptera); Phenacoccussolenopsis (Tinsley), Ferrisiavirigata (Ckll), Centrococcusinsolitus Green (Pseudococcidae: Homoptera), Drosichamangiferae (Green) (Margarodidae: Homoptera) Aleurocanthushusaini Corbett, Aleurocanthuswoglumi Ashby, Aleurolobusbarodensis Mask Amrascadevastans (Dist), Amrascabiguttulabiguttula (Ishida), Amritodusatkinsoni Leth, Evacanthusrepexus Dist (Cicadellidae: Homoptera); Bemisiatabaci (Gennadius) (Aleyrodidae: Homoptera), Pyrillaperpusilla Walk (Fulgoridae: Homoptera), Quadraspidiotusperniciosus Comst (Diaspididae: Homoptera), Diaphorinacitri Kuw (Psyllidae: Homoptera), Tetranychusorientalis Mog (Acarina: Tetranychidae) on mustard, lucern, cabbage, cauliflower, potato, turnip, bottle gourd, eggplant, okra, wheat, cotton, and rose plants (Ali 2013).Common. It is very difficult to compare this species with other taxa because of polymorphism. Six varieties of this species are reported from Pakistan.Taxon classificationAnimaliaColeopteraCoccinellidaeNepal, Pakistan, Afghanistan, Tibet, Mongolia, China, northern and eastern Africa, Palaearctic (Poorani 2002).Hyderabad, Karachi, and Thatta .Brevicorynebrassicae (L.), Lipaphiserysimi , Myzuspersicae (Sulzer), Aphisgossypii (Glover), Hyadaphiscoriandri (Das), Hysteroneurasetariae (Thomas), Schizaphisgraminum (Rondani) (Aphididae: Homoptera); Phenacoccussolenopsis (Tinsley), Ferrisiavirigata (Ckll) (Pseudococcidae: Homoptera); Amrascadevastans (Dist), Amrascabiguttulabiguttula (Ishida) (Cicadellidae: Homoptera); Bemisiatabaci (Gennadius) (Aleyrodidae: Homoptera) on mustard, lucern, cabbage, cauliflower, potato, turnip, bottle gourd, brinjal, okra, wheat, cotton, and rose plants (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeIndia, Nepal, Pakistan, Myanmar, Indonesia (Poorani 2002).Hyderabad, Mirpur Khas, Thatta and Karachi (Ali 2013).Amritodusatkinsoni Teth (Cicadellidae: Homoptera) Quadraspidiotusperniciosus Comst (Diaspididae: Homoptera), Pyrillaperpusilla Walk (Fulgoridae: Homoptera) (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeMulsant, 1866India, Bhutan, Pakistan, Nepal, Myanmar, Thailand, China (Poorani 2002).Hyderabad, Mirpur Khas, Thatta, and Karachi (Ali 2013).Aphiscraccivora Koch, A.gossypii Glover, Brevicorynebrassicae (L.), Lipaphiserysimi , Myzuspersicae (Sulzer), Aphisgossypii (Glover), Hyadaphiscoriandri (Das), Schizaphisgraminum (Rondani), Ropalosiphummaidis (Fitch) (Aphididae: Homoptera), Aleurolobusbarodensis Mask Amrascadevastans (Dist), Amrascabiguttulabiguttula (Ishida), Evacanthusrepexus Dist (Cicadellidae: Homoptera), Tetranychus sp. (Acarina: Tetranychidae) on wheat, mustard, and cabbage (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeIndia, Pakistan, Bangladesh, Japan, China, Europe, North America (Poorani 2002).Hyderabad and Karachi (Ali 2013).Aphiscraccivora Koch, A.gossypii Glover, Brevicorynebrassicae (L.), Lipaphiserysimi , Myzuspersicae (Sulzer), Aphisgossypii (Glover), Hyadaphiscoriandri (Das) (Aphididae: Homoptera), Aleurolobusbarodensis Mask Amrascadevastans (Dist), Amrascabiguttulabiguttula (Ishida), Evacanthusrepexus Dist (Cicadellidae: Homoptera) (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeIndia, Pakistan, Nepal, Bhutan, China, Japan, Taiwan, introduced into North America (Poorani 2002).Hyderabad and Karachi (Ali 2013).Aphiscraccivora Koch, A.gossypii Glover, Brevicorynebrassicae (L), Lipaphiserysimi , Myzuspersicae (Sulzer), Hyadaphiscoriandri (Das), Hysteroneurasetariae (Thomas), Ropalosiphummaidis (Fitch), Therioaphistrifolii Monell, Macrosiphumgranarium (Kirby), Schizaphisgraminum (Rondani) (Aphididae: Homoptera), Amritodusatkinsoni Leth, Idioscopusnagpurensis Pruthi (Cicadellidae: Homoptera); Bemisiatabaci (Gennadius) (Aleyrodidae: Homoptera), Tetranychusatlanticus Mog (Acarina: Tetranychidae), Adelges spp. (Adelgidae: Homoptera) on mustard, lucern, cabbage, cauliflower, potato, turnip, bottle gourd, eggplant, okra, wheat, cotton, and rose plants (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaePakistan, India, Central and West Asia, Afghanistan, Mediterranean region. North and Central Africa .Hyderabad and Karachi (Ali 2013).Aphiscraccivora Koch, A.gossypii Glover, Myzuspersicae (Sulzer), Diaphorinacitri Kuw (Psyllidae: Homoptera) on wheat and mustard.Newly recorded from Pakistan.Taxon classificationAnimaliaColeopteraCoccinellidaeIndia and Pakistan (Poorani 2002).Hyderabad and Karachi (Ali 2013).All the members of this genus are mycophagous (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeAgalega, American Samoa, Burma, Brazil, Ghana, Guam, Hawaii, India, Indonesia, Kenya, Madagascar, Malaysia, Marshall Islands, New Caledonia, Nepal, Oman, Pakistan, Reunion Island, Seychelles, Solomon Islands, South Africa, Swaziland, Society Islands, Tanzania, Togo, Turkey and Zimbabwe .Tandojam, Hyderabad and Karachi (Ali 2013).Aonidiellaauranti (Mask), A.citrina (Coq), A.orientalis Newst, Aspidiotusdestructor Sign, Hemiberiesialatanias (Sign), Leucaspisconiferarum Hall & Williams, Parlatoria spp, Pinnaspisstrachani (Cooley), Quadraspidiotusperniciosus Comst, Tecaspis spp. (Diaspididae: Homoptera) (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeErichson, 1843northwestern India, Pakistan, Palaearctic, Africa (Poorani 2002).Tandojam, Mirpur Khas, Hyderabad, and Karachi .Aphisfabae Theobald, Rhopalosiphummaidis Fitch (Aphididae: Homoptera), Parlatoria spp. (Diaspididae: Homoptera), Ferrisiavirigata (Ckll) (Pseudococcidae: Homoptera). It was recorded on trees and wild plants (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeK\u00fcster, 1848Pakistan, India, Spain, North Africa, Greece, Egypt, Syria, Palestine (Poorani 2002).Karachi (Ali 2013).Parlatoria spp. (Diaspididae: Homoptera). It was found on oak (Ali 2013).Newly recorded from Pakistan.Taxon classificationAnimaliaColeopteraCoccinellidaeIndia, Bhutan, Pakistan, Nepal (Poorani 2002).Tandojam and Hyderabad (Ali 2013).Parlatoria spp., Pinnaspisstrachani (Cooley), Quadraspidiotusperniciosus Comst, Tecaspis spp. (Diaspididae: Homoptera) on wild trees, and shrubs (Ali 2103).Taxon classificationAnimaliaColeopteraCoccinellidaeIndia, Pakistan, Bangladesh, Sri Lanka, Bhutan, Nepal (Poorani 2002).Tandojam, Mirpur Khas, Hyderabad, and Karachi (Ali 2013).Aphiscraccivora Koch, A.gossypii Glover, Brevicorynebrassicae (L.), Lipaphiserysimi , Myzuspersicae (Sulzer), Hyadaphiscoriandri (Das), Hysteroneurasetariae (Thomas), Ropalosiphummaidis (Fitch), Therioaphistrifolii Monell, Macrosiphumgranarium (Kby), Schizaphisgraminum (Rondani) (Aphididae: Homoptera); Phenacoccussolenopsis (Tinsley), Ferrisiavirigata (Ckll) (Pseudococcidae: Homoptera), Drosichamangiferae (Green) (Margarodidae: Homoptera), Amrascadevastans (Dist), Amrascabiguttulabiguttula (Ishida) (Cicadellidae: Homoptera); Bemisiatabaci (Gennadius) (Aleyrodidae: Homoptera), Tetranychusatlanticus Mog (Acarina: Tetranychidae), Adelgesjoshii S.O & S (Adelgidae: Homoptera), Aonidiellaauranti (Mask), A.citrina (Coq), A.orientalis Newst, Aspidiotusdestructor Sign, Hemiberiesialatanias (Sign), Leucaspisconiferarum Hall & Williams, Parlatoria spp, Pinnaspisstrachani (Cooley), Quadraspidiotusperniciosus Comst, Tecaspis spp. (Diaspididae: Homoptera) on mustard, lucern, cabbage, cauliflower, potato, turnip, bottle gourd, eggplant, okra, wheat, cotton, and rose plants (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeMulsant, 1850India, Pakistan, Thailand (Poorani 2002).Karachi and Mirpur Khas (Ali 2013).Iceryaaegyptiaca (Dougl) (Margarodidae: Homoptera). It was found on cotton and roses (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeSicard, 1929Pakistan and India (Poorani 2002).Tandojam, Mirpur Khas, and Karachi (Ali 2013).Centrococcusinsolitus (Green), Naiacoccus sp, Phenacoccussolenopsis (Tinsley), Ferrisiavirigata (Ckll) (Pseudococcidae: Homoptera), Drosichamangiferae (Green) (Margarodidae: Homoptera). It was found on cotton, okra, and trees (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeIndia, Pakistan, Italy, Cyprus (Poorani 2002).Tandojam, Hyderabad, Mirpur Khas and Karachi (Ali 2013).Brevipalpus sp. , Eutetranychuscernus (B&P), E.orientalis (Klein), Tetranychusatlanticus Mog (Acarina: Tetranychidae). It was collected from eggplant, okra, and some wild plants (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeMulsant, 1850Pakistan, India, Bangladesh, Sri Lanka, Nepal, Myanmar, China, Asia Minor (Poorani 2002).Tandojam, Mirpur Khas, Hyderabad, and Karachi (Ali 2013).Aphiscraccivora Koch, A.gossypii Glover, Brevicorynebrassicae (L.), Lipaphiserysimi , Myzuspersicae (Sulzer), Aphisgossypii (Glover), Hyadaphiscoriandri (Das), Hysteroneurasetariae (Thomas), Ropalosiphummaidis (Fitch), Therioaphistrifolii Monell, Macrosiphumgranarium (Kby), Schizaphisgraminum (Rondani) (Aphididae: Homoptera); Phenacoccussolenopsis (Tinsley), Ferrisiavirigata (Ckll) (Pseudococcidae: Homoptera), Drosichamangiferae (Green) (Margarodidae: Homoptera), Amrascadevastans (Dist), Amrascabiguttulabiguttula (Ishida) (Cicadellidae: Homoptera); Bemisiatabaci (Gennadius) (Aleyrodidae: Homoptera), Tetranychusatlanticus Mog (Acarina: Tetranychidae), Adelgesjoshii S.O & S (Adelgidae: Homoptera), Aonidiellaauranti (Mask), A.citrina (Coq), A.orientalis Newst, Aspidiotusdestructor Sign, Hemiberiesialatanias (Sign), Leucaspisconiferarum Hall & Williams, Parlatoria spp, Pinnaspisstrachani (Cooley), Quadraspidiotusperniciosus Comst, Tecaspis spp. (Diaspididae: Homoptera) on mustard, lucern, cabbage, cauliflower, potato, turnip, bottle gourd, eggplant, okra, wheat, cotton and rose plants (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeMotschulsky, 1858Pakistan, India, Bangladesh, Sri Lanka, Thailand, Taiwan. .Tandojam, Hyderabad, and Karachi (Ali 2013).Aphiscraccivora Koch, A.gossypii Glover, Brevicorynebrassicae (L.), Lipaphiserysimi , Myzuspersicae (Sulzer), Aphisgossypii (Glover), Hyadaphiscoriandri (Das), Hysteroneurasetariae (Thomas), Ropalosiphummaidis (Fitch), Therioaphistrifolii Monell, Macrosiphumgranarium (Kby), Schizaphisgraminum (Rondani) (Aphididae: Homoptera); Phenacoccussolenopsis (Tinsley), Ferrisiavirigata (Ckll) (Pseudococcidae: Homoptera), Drosichamangiferae (Green) (Margarodidae: Homoptera), Amrascadevastans (Dist), Amrascabiguttulabiguttula (Ishida) (Cicadellidae: Homoptera); Bemisiatabaci (Gennadius) (Aleyrodidae: Homoptera), Tetranychusatlanticus Mog (Acarina: Tetranychidae) on mustard, lucern, cabbage, cauliflower, potato, turnip, bottle gourd, eggplant , okra, wheat, cotton, and rose plants (Ali 2013).Newly recorded from Pakistan.Taxon classificationAnimaliaColeopteraCoccinellidaeAyyar, 1925India, Pakistan, Bangladesh, Sri Lanka, Malaysia (Poorani 2002).Tandojam, Hyderabad, and Karachi (Ali 2013).Aphiscraccivora Koch, A.gossypii Glover, Brevicorynebrassicae (L.), Lipaphiserysimi , Myzuspersicae (Sulzer), Aphisgossypii (Glover), Hyadaphiscoriandri (Das), Hysteroneurasetariae (Thomas), Ropalosiphummaidis (Fitch), Therioaphistrifolii Monell, Macrosiphumgranarium (Kby), Schizaphisgraminum (Rondani) (Aphididae: Homoptera); Phenacoccussolenopsis (Tinsley), Ferrisiavirigata (Ckll) (Pseudococcidae: Homoptera), Drosichamangiferae (Green) (Margarodidae: Homoptera), Tetranychusatlanticus Mog (Acarina: Tetranychidae) on mustard, lucern, cabbage, cauliflower, potato, turnip, bottle gourd, eggplant, okra, wheat, cotton, and rose plants (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeSicard, 1929Pakistan, India, Bangladesh (Poorani 2002).Tandojam, Hyderabad and Karachi (Ali 2013).Aphiscraccivora Koch, A.gossypii Glover, Brevicorynebrassicae (L.), Lipaphiserysimi , Myzuspersicae (Sulzer), Aphisgossypii (Glover), Hyadaphiscoriandri (Das), Hysteroneurasetariae (Thomas), Ropalosiphummaidis (Fitch), Therioaphistrifolii Monell, Macrosiphumgranarium (Kby), Schizaphisgraminum (Rondani) (Aphididae: Homoptera); Phenacoccussolenopsis (Tinsley), Ferrisiavirigata (Ckll) (Pseudococcidae: Homoptera), Drosichamangiferae (Green). It was found on eggplant, okra, cotton (Ali 2013).Newly recorded from Pakistan.Taxon classificationAnimaliaColeopteraCoccinellidaeIran, Afghanistan, Pakistan (Ali 2013).Hyderabad and Karachi (Ali 2013).Aphiscraccivora Koch, A.gossypii Glover, Brevicorynebrassicae (L.), Lipaphiserysimi , Myzuspersicae (Sulzer), Aphisgossypii (Glover), Hyadaphiscoriandri (Das), Hysteroneurasetariae (Thomas), Ropalosiphummaidis (Fitch), Therioaphistrifolii Monell, Macrosiphumgranarium (Kby), Schizaphisgraminum (Rondani) (Aphididae: Homoptera) (Ali 2013).Newly recorded from Pakistan.Taxon classificationAnimaliaColeopteraCoccinellidaeIndia, Pakistan, China (Poorani 2002).Tandojam, Mirpur Khas, Hyderabad and Karachi (Ali 2013).Aphiscraccivora Koch, A.gossypii Glover, Aphisgossypii (Glover), Hyadaphiscoriandri (Das), Therioaphistrifolii Monell (Aphididae: Homoptera); Phenacoccussolenopsis (Tinsley), Ferrisiavirigata (Ckll) (Pseudococcidae: Homoptera), Drosichamangiferae (Green) (Margarodidae: Homoptera) on on eggplant, okra and cotton (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeAhmad, 1973Pakistan (Poorani 2002).Karachi (Ali 2013).Aonidiellaauranti (Mask), A.citrina (Coq), A.orientalis Newst, Hemiberiesialatanias (Sign), Leucaspisconiferarum Hall & Williams, Parlatoria spp. Pinnaspisstrachani (Cooley), Quadraspidiotusperniciosus Comst, Tecaspis spp. (Diaspididae: Homoptera) (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidae(Mulsant), 1853India, Pakistan, Brazil, and United States (Florida) .Tandojam, Mirpur Khas, Hyderabad, and Karachi (Ali 2013).Aspidiotusdestructor Sign, Hemiberiesialatanias (Sign), Leucaspisconiferarum Hall & Williams, Parlatoria spp, Pinnaspisstrachani (Cooley), Quadraspidiotusperniciosus Comst, Tecaspis spp. (Diaspididae: Homoptera), Coccushesperidium L, Siassetianigra (Nietn) (Coccidae: Homoptera) on wheat and mustard (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidaeAhmad, 1970Pakistan, Thailand (Poorani 2002).Karachi (Ali 2013).Parlatoria spp., Pinnaspisstrachani (Cooley), Quadraspidiotusperniciosus Comst, Tecaspis spp. (Diaspididae: Homoptera), Coccushesperidium L, Siassetianigra (Nietn) (Coccidae: Homoptera) on wheat and mustard (Ali 2013).Taxon classificationAnimaliaColeopteraCoccinellidae(Weise), 1900India and Pakistan (Poorani 2002).Karachi (Ali 2013).Parlatoria spp. Pinnaspisstrachani (Cooley), Quadraspidiotusperniciosus Comst, Tecaspis spp. (Diaspididae: Homoptera), Coccushesperidium L, Siassetianigra (Nietn) (Coccidae: Homoptera) on mustard and wheat (Ali 2013).Coleoptera. Unfortunately, all the specimens were lost during the shifting of Vitoria Museum to National Museum at Karachi. From Pakistan very little taxonomic work has focussed especially on this important family of the order Sindh Province has a rich insect fauna which have diversified into important cities like Karachi, Tandojam, Hyderabad, Larkana, Sukhur, and Mirpur Khas. Coccinellids fauna is still incompletely recorded from Sindh region and has been neglected in the past. All the research findings on coccinellids except Ali (2013) were documentary not taxonomic. No proper collections, identification procedures,or techniques have been used in Sindh to explore the hidden records of insects, including the coccinellid fauna. Ali (2013) worked more comprehensively on the systematics and distribution of ladybirds of Sindh Province with reference to their role in biological control programmes. He tried to highlight the importance of systematic study to make easy their identification as predators of mealybugs, aphids, jassids, whiteflies, and scale insects. This research work may be useful for the entomologists including research students of particularly the Sindh region, but also of Pakistan and other Oriental regions. The geographical distribution and synonyms used in this study for all systematically treated specimens were cited from the findings of Bulaealichatschovii (Hummel), Exochomuspubescens K\u00fcster, Scymnus (Pullus) latemaculatus Motschulsky, Scymnus (Pullus) syriacus Marseul and four varieties of Menochilussexmaculata (Fabricius). All these coccinellids from Pakistan are now placed into the subfamily Coccinellinae and the subfamily Microweiseinae according to the recent classification studies. The coccinellid specimens were deposited in the Natural History Museum, Department of Zoology, University of Karachi, Karachi, Pakistan.The present investigation continues the research carried by Ali (2013), and gives a preliminary checklist of ladybirds from Sindh consisting of only one subfamily, ten tribes, 21 genera, and 29 species including four new records:"} +{"text": "Scientific Reports 10.1038/s41598-018-27084-y, published online 12 June 2018Correction to: In the original version of this Article, there were errors in Affiliations 2, 3 and 7 which were incorrectly listed as \u2018AgriGenome Labs Private Limited, 501, SCK01 Building, Smart City Kochi, Infopark Road, Kakkanad, Kochi, 682 030, India\u2019, \u2018SciGenom Research Foundation, 3rd Floor, Narayana Health City, #258/A, Bommasandra, Hosur Road, Bangalore, 560 099, India\u2019 and \u2018SciGenom Labs Pvt Ltd, Plot no: 43A,SDF, 3rd floor, A Block, CSEZ, Kakkanad, Cochin, Kerala, 682 037, India\u2019 respectively.The correct affiliations are listed below:Affiliation 2AgriGenome Labs Private Limited, 501, SCK01 Building, SmartCity Kochi, Infopark Road, Kakkanad, Kochi, Kerala, 682 042, IndiaAffiliation 3SciGenom Research Foundation, 3rd Floor, Narayana Health City, #258/A, Bommasandra, Hosur Road, Bangalore, Karnataka, 560 099, IndiaAffiliation 7SciGenom Labs Pvt Ltd, Plot no: 43A,SDF, 3rd floor, A Block, CSEZ, Kakkanad, Kochi, Kerala, 682 037, IndiaThese errors have now been corrected in the PDF and HTML versions of the Article, and in the Supplementary Material files."} +{"text": "The author listing above corrects their affiliations in relation to the CholeS study group and recognises the hard work of our Trial Management Team, Collaborators and Data Validators in contributing to this paper.The list of the CholeS management group, Collaborators and Data Validators were omitted from the Acknowledgments. They are listed here as follows:CholeS Study Management TeamRavinder S. Vohra, Consultant Surgeon, Nottingham Oesophago-Gastric Unit, Nottingham University Hospitals NHS Foundation Trust, Hucknall Road, Nottingham, UK;Amanda J. Kirkham, Biostatistician; Cancer Research UK Clinical Trials Unit, The University of Birmingham, Birmingham, UK;Sandro Pasquali, Surgical trainee, Surgical Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy;Paul Marriott, Surgical trainee, West Midlands Research Collaborative, Academic Department of Surgery, The University of Birmingham, Birmingham, UK;Marianne Johnstone, Surgical trainee, West Midlands Research Collaborative, Academic Department of Surgery, The University of Birmingham, Birmingham, UK;Philip Spreadborough, Surgical trainee, West Midlands Research Collaborative, Academic Department of Surgery, The University of Birmingham, Birmingham, UK;Derek Alderson, Emeritus Professor of Surgery, Academic Department of Surgery, The University of Birmingham, Birmingham, UK;Ewen A. Griffiths, Consultant Surgeon, Department of Upper Gastrointestinal Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.CholeS Study CollaboratorsEngland\u2014Stephen Fenwick, Mohamed Elmasry, Quentin M Nunes, David Kennedy ; Raja Basit Khan, Muhammad AS Khan ; Conor J Magee, Steven M Jones, Denise Mason, Ciny P Parappally ; Pawan Mathur, Michael Saunders, Sara Jamel, Samer Ul Haque, Sara Zafar ; Muhammad Hanif Shiwani, Nehemiah Samuel, Farooq Dar, Andrew Jackson ; Bryony Lovett, Shiva Dindyal, Hannah Winter, Ted Fletcher, Saquib Rahman ; Kevin Wheatley, Tom Nieto, Soofiyah Ayaani ; Haney Youssef, Rajwinder S Nijjar, Helen Watkin, David Naumann, Sophie Emesih; Piyush B Sarmah, Kathryn Lee, Nikita Joji, Joel Lambert (Heart of England Foundation NHS Trust); Jonathan Heath, Rebecca L Teasdale, Chamindri Weerasinghe ; Paul J Needham, Hannah Welbourn, Luke Forster, David Finch ; Jane M Blazeby, William Robb, Angus GK McNair, Alex Hrycaiczuk ; Alexandros Charalabopoulos, Sritharan Kadirkamanathan, Cheuk-Bong Tang, Naga VG Jayanthi, Nigel Noor ; Brian Dobbins, Andrew J Cockbain, April Nilsen-Nunn, Jonathan de Siqueira ; Mike Pellen, Jonathan B Cowley, Wei-Min Ho, Victor Miu (Hull and East Yorkshire NHS Trust); Timothy J White, Kathryn A Hodgkins, Alison Kinghorn ; Matthew G Tutton, Yahya A Al-Abed, Donald Menzies, Anwar Ahmad, Joanna Reed, Shabuddin Khan ; David Monk, Louis J Vitone, Ghulam Murtaza, Abraham Joel (Countess of Chester NHS Foundation Trust); Stephen Brennan, David Shier, Catherine Zhang, Thusidaran Yoganathan ; Steven J Robinson, Iain JD McCallum, Michael J Jones, Mohammed Elsayed, Liz Tuck, John Wayman, Kate Carney ; Somaiah Aroori, Kenneth B Hosie, Adam Kimble, David M Bunting, Kenneth B Hosie ; Adeshina S Fawole, Mohammed Basheer, Rajiv V Dave, Janahan Sarveswaran, Elinor Jones, Chris Kendal (Mid Yorkshire NHS Trust); Michael P Tilston, Martin Gough, Tom Wallace, Shailendra Singh, Justine Downing Katherine A Mockford, Eyad Issa, Nayab Shah, Neal Chauhan (Northern Lincolnshire and Goole NHS Foundation Trust); Timothy R Wilson, Amir Forouzanfar, Jonathan RL Wild, Emma Nofal, Catherine Bunnell, Khaliel Madbak ; Sudhindra TV Rao, Laurence Devoto, Najaf Siddiqi, Zechan Khawaja ; James C Hewes, Laura Gould, Alice Chambers, Daniel Urriza Rodriguez (North Bristol NHS Trust); Gourab Sen, Stuart Robinson, Kate Carney, Francis Bartlett ; David M Rae, Thomas EJ Stevenson, Kas Sarvananthan ; Simon J Dwerryhouse, Simon M Higgs, Oliver J Old, Thomas J Hardy, Reena Shah Steve T Hornby, Ken Keogh, Lucinda Frank ; Musallam Al-Akash, Emma A Upchurch ; Richard J Frame, Michael Hughes, Clare Jelley (Harrogate and District NHS Foundation Trust); Simon Weaver, Sudipta Roy, Toritseju O Sillo, Giorgios Galanopoulos ; Tamzin Cuming, Pedro Cunha, Salim Tayeh, Sarantos Kaptanis ; Mohamed Heshaishi, Abdalla Eisawi, Michael Abayomi; Wee Sing Ngu, Katie Fleming, Dalvir S Bajwa ; Vivek Chitre, Kamal Aryal, Paul Ferris ; Michael Silva, Simon Lammy Sarah Mohamed, Amir Khawaja, Adnan Hussain, Mudassar A Ghazanfar, Maria Irene Bellini (Oxford University NHS Trust); Hamdi Ebdewi, Mohamed Elshaer, Gianpiero Gravante, Benjamin Drake ; Arikoge Ogedegbe, Dipankar Mukherjee, Chanpreet Arhi, Lola Giwa Nusrat Iqbal ; Nicholas F Watson, Smeer Kumar Aggarwal, Philippa Orchard, Eduardo Villatoro ; Peter D Willson, Kam Wa Jessica Mok, Thomas Woodman, Jean Deguara ; Giuseppe Garcea, Benoy I Babu, AR Dennison, Deep Malde, David Lloyd, Steve Satheesan, Omer Al-Taan, Alexander Boddy ; John P Slavin, Robert P Jones, Laura Ballance, Stratos Gerakopoulos ; Periyathambi Jambulingam, Sami Mansour, Naomi Sakai, Vikas Acharya ; Mohammed M Sadat, Lawen Karim, David Larkin, Khalid Amin ; Amarah Khan, Jennifer Law, Saurabh Jamdar, Stella R Smith, Keerthika Sampat, Kathryn M O\u2019shea ; Mangta Manu, Fotini M Asprou, Nabeela S Malik, Jessica Chang, Marianne Johnstone ; Michael Lewis, Geoffrey P Roberts, Babu Karavadra, Evangelos Photi ; James Hewes, Laura Gould, Alice Chambers, Dan Rodriguez (North Bristol NHS Trust); Derek A O\u2019Reilly, Anthony J Rate, Hema Sekhar, Lucy T Henderson, Benjamin Z Starmer, Peter O Coe, Sotonye Tolofari, Jenifer Barrie (Pennine Acute NHS Trust); Gareth Bashir, Jake Sloane, Suroosh Madanipour, Constantine Halkias, Alexander EJ Trevatt (North Middlesex Trust); David W Borowski, Jane Hornsby, Michael J Courtney, Suvi Virupaksha (North Tees and Hartlepool NHS Foundation Trust); Keith Seymour, Sarah Robinson, Helen Hawkins, Sadiq Bawa, Paul V Gallagher, Alistair Reid, Peter Wood ; JG Finch, J Guy Finch, J Parmar, E Stirland ; James Gardner-Thorpe, Ahmed Al-Muhktar, Mark Peterson, Ali Majeed ; Farrukh M Bajwa, Jack Martin, Alfred Choy, Andrew Tsang ; Naresh Pore, David R Andrew, Waleed Al-Khyatt, Christopher Taylor Santosh Bhandari, Adam Chambers, Dhivya Subramanium ; Simon K C Toh, Nicholas C Carter, Sophie Tate, Belinda Pearce, Denise Wainwright, Stuart J Mercer, Benjamin Knight ; Vardhini Vijay, Swethan Alagaratnam, Sidhartha Sinha, Shahab Khan ; Shamsi S El-Hasani, Abdulzahra A Hussain ; Vish Bhattacharya, Nisheeth Kansal, Tani Fasih, Claire Jackson ; Midhat N Siddiqui, Imran A Chishti, Imogen J Fordham, Zohaib Siddiqui (Lewisham and Greenwich NHS Trust); Harald Bausbacher, Ileana Geogloma, Kabita Gurung ; George Tsavellas, Pradeep Basynat, Ashish Kiran Shrestha, Sanjoy Basu, Alok Chhabra Mohan Harilingam, Mohamed Rabie, Mansoor Akhtar ; Pradeep Kumar, Sadaf F Jafferbhoy, Najam Hussain, Soulat Raza ; Manzarul Haque, Imran Alam, Rabiya Aseem, Shakira Patel, Mehek Asad ; Michael I Booth, William R Ball, Christopher PJ Wood, Ana C Pinho-Gomes ; Ambareen Kausar, Moh\u2019d Rami Obeidallah ; Joseph Varghase, Joshil Lodhia, Donal Bradley, Carla Rengifo, David Lindsay ; Sivakumar Gopalswamy, Ian Finlay, Stacy Wardle, Naomi Bullen ; Syed Yusuf Iftikhar, Altaf Awan, Javed Ahmed, Paul Leeder ; Guiseppe Fusai, Giles Bond-Smith, Alicja Psica, Yogesh Puri ; David Hou, Fergus Noble, Karoly Szentpali, Jack Broadhurst ; Ravindra Date, Martin R Hossack, Yan Li Goh, Paul Turner, Vinutha Shetty ; Manel Riera, Christina A W Macano, Anisha Sukha ; Shaun R Preston, Jennifer R Hoban, Daniel J Puntis, Sophie V Williams ; Richard Krysztopik, James Kynaston, Jeremy Batt, Matthew Doe ; Andrzej Goscimski, Gareth H Jones, Stella R Smith, Claire Hall ; Nick Carty, Jamil Ahmed, Sofoklis Panteleimonitis ; Rohan T Gunasekera, Andrea RG Sheel, Hannah Lennon, Caroline Hindley ; Marcus Reddy, Ross Kenny, Natalie Elkheir, Emma R McGlone ; Rajasundaram Rajaganeshan, Kate Hancorn, Anita Hargreaves ; Raj Prasad, David A Longbotham, Dhakshinamoorthy Vijayanand, Imeshi Wijetunga ; Paul Ziprin, Christopher R Nicolay, Geoffrey Yeldham, Edward Read ; James A Gossage, Rachel C Rolph, Husam Ebied, Manraj Phull ; Mohammad A Khan, Matthew Popplewell, Dimitrios Kyriakidis, Anwar Hussain (Mid Staffordshire NHS Foundation Trust); Natasha Henley, Jessica R Packer, Laura Derbyshire, Jonathan Porter (Stockport NHS Foundation Trust); Shaun Appleton, Marwan Farouk, Melvinder Basra ; Neil A Jennings, Shahda Ali, Venkatesh Kanakala ; Haythem Ali, Risha Lane, Richard Dickson-Lowe, Prizzi Zarsadias (Tunbridge Wells and Maidstone NHS Trust); Darius Mirza, Sonia Puig, Khalid Al Amari, Deepak Vijayan, Robert Sutcliffe, Ravi Marudanayagam ; Zayed Hamady, Abheesh R Prasad, Abhilasha Patel ; Damien Durkin, Parminder Kaur, Laura Bowen ; James P Byrne, Katherine L Pearson, Theo G Delisle, James Davies ; Mark A Tomlinson, Michelle A Johnpulle, Corinna Slawinski ; Andrew Macdonald, James Nicholson, Katy Newton, James Mbuvi ; Ansar Farooq, Bhavani Sidhartha Mothe, Zakhi Zafrani, Daniel Brett ; James Francombe, Philip Spreadborough, James Barnes, Melanie Cheung (South Warwickshire NHS Foundation Trust); Ahmed Z Al-Bahrani, Giuseppe Preziosi, Tomas Urbonas ; Justin Alberts, Mekhlola Mallik, Krashna Patel, Ashvina Segaran, Triantafyllos Doulias (West Suffolk NHS Trust); Pratik A Sufi, Caroline Yao, Sarah Pollock (Whittington NHS Trust); Antonio Manzelli, Saj Wajed, Michail Kourkulos, Roberto Pezzuto ; Martin Wadley, Emma Hamilton, Shameen Jaunoo, Robert Padwick ; Mazin Sayegh, Richard C Newton, Madhusoodhana Hebbar, Sameh F Farag, ; John Spearman, Mohammed F Hamdan, Conrad D\u2019Costa, Christine Blane; ; Mathew Giles, Mark B Peter, Natalie A Hirst, Tanvir Hossain, Arslan Pannu Yesar El-Dhuwaib, Tamsin E M Morrison, Greg W Taylor .Northern Ireland\u2014Ronald LE Thompson, Ken McCune, Paula Loughlin, Roger Lawther ; Colman K Byrnes, Duncan J Simpson, Abi Mawhinney, Conor Warren ; Damian McKay, Colin McIlmunn, Serena Martin, Matthew MacArtney ; Tom Diamond, Phil Davey, Claire Jones, Joshua M Clements, Ruairi Digney, Wei Ming Chan, Stephen McCain, Sadaf Gull, Adam Janeczko, Emmet Dorrian, Andrew Harris, Suzanne Dawson, Dorothy Johnston, Barry McAree, ; Essam Ghareeb, George Thomas, Martin Connelly, Stephen McKenzie, Krzysztos Cieplucha ; Gary Spence, William Campbell, Gareth Hooks, Neil Bradley .Republic of Ireland\u2014Arnold DK Hill, John T Cassidy, Michael Boland ; Paul Burke, Deirdre M Nally ; Arnold DK Hill, Elmoataz Khogali, Wael Shabo, Edrin Iskandar ; Gerry P McEntee, Maeve A O\u2019Neill, Colin Peirce, Emma M Lyons ; Adrian W O\u2019Sullivan, Rohan Thakkar, Paul Carroll, Ivan Ivanovski ; Paul Balfe, Matthew Lee ;, Des C Winter, Michael E Kelly, Emir Hoti, Donal Maguire; Priyadarssini Karunakaran, Justin G Geoghegan, Frank McDermott, Sean T Martin ; Keith S Cross, Fiachra Cooke, Saquib Zeeshan, James O Murphy ; Ken Mealy, Helen M Mohan, Yuwaraja Nedujchelyn, Muhammad Fahad Ullah .Scotland\u2014Irfan Ahmed, Francesco Giovinazzo, James Milburn ; Sarah Prince, Eleanor Brooke, Joanna Buchan ; Ahmed M Khalil, Elizabeth M Vaughan, Michael I Ramage, Roland C Aldridge ; Simon Gibson, Gary A Nicholson, David G Vass ; Alan J Grant, David J Holroyd, M Angharad Jones, Cherith MLR Sutton ; Patrick O\u2019Dwyer, Frida Nilsson ; Beatrix Weber, Tracey K Williamson, Kushik Lalla, Alice Bryant ; C Ross Carter, Craig R Forrest, David I Hunter ; Ahmad H Nassar, Mavis N Orizu, Katrina Knight, Haitham Qandeel ; Stuart Suttie, Rowena Belding, Andrew McClarey ; Alan T Boyd, Graeme JK Guthrie, Pei J Lim, Andreas Luhmann ; Angus JM Watson, Colin H Richards, Laura Nicol, Marta Madurska ; Ewen Harrison, Kathryn M Boyce, Amanda Roebuck, Graeme Ferguson ; Pradeep Pati, Michael S J Wilson, Faith Dalgaty, Laura Fothergill ; Peter J Driscoll, Kirsty L Mozolowski, Victoria Banwell, Stephen P Bennett ; Paul N Rogers, Brendan L Skelly, Claire L Rutherford, Ahmed K Mirza (Western Infirmary Glasgow).Wales\u2014Taha Lazim, Henry C C Lim, Diana Duke, Talat Ahmed ; William D Beasley, Marc D Wilkinson, Geta Maharaj, Cathy Malcolm ; Timothy H Brown, Bilal Al-Sarireh, Guy M Shingler, Nicholas Mowbray, Rami Radwan ; Paul Morcous, Simon Wood, Abbas Kadhim ; Duncan J Stewart, Andrew L Baker, Nicola Tanner, Hrishikesh Shenoy .Data validators\u2014Shazia Hafiz, Joshua A. De Marchi, Deepak Singh-Ranger, Elzanati Hisham, Paul Ainley, Stephen O'Neill. John Terrace, Sara Napetti, Benjamin Hopwood, Thomas Rhys, Justine Downing, Sam Kanavati, Maria Coats, Danail Aleksandrov, Charlotte Kallaway, Salama Yahya, Beatrix Weber, Alexa Templeton, Martin Trotter, Christina Lo, Ajit Dhillon, Nick Heywood, Yousif Aawsaj, Alhafidz Hamdan, Obuobi Reece-Bolton, Andrew McGuigan, Yousef Shahin, Aymon, Ali Alison Luther, James A Nicholson, Ilayaraja Rajendran, Matthew Boal, Judith Ritchie."} +{"text": "Following publication of the original article , the autAuthor names as originally published:The original publication has been corrected. The initial and corrected names are presented below.Author names corrected:SW Nam, DH Lim, KY Cho, HS Kim, K Kim and T-Y ChungSeung Wan Nam, Dong Hui Lim, Kyu Yeon Cho, Hye Seung Kim, Kyunga Kim and Tae-Young Chung"} +{"text": "Journal of Experimental Botany, Advance Access publication: 05 April 2018, doi: 10.1093/jxb/ery132The original online version of this paper contained an incomplete reference, omitting the name of a lead author. The reference has been updated to read as follows:Silva GFF, Silva EM, Azevedo MDS, Guivin MAC, Ramiro DA, Figueiredo CR, Carrer H, Peres LEP, Nogueira FTS. 2014. microRNA156-targeted SPL/SBP box transcription factors regulate tomato ovary and fruit development. The Plant Journal 78, 604\u2013618."} +{"text": "In the manuscript \u201cELECTROLYTE AND MINERAL COMPOSITION OF TERM DONOR HUMAN MILK BEFOREAND AFTER PASTEURIZATION AND OF RAW MILK OF PRETERM MOTHERS\u201d, DOI:10.1590/1984-0462/;2018;36;2;00015, published in the Rev. paul. pediatr. Fev 22 2018.[Epub ahead of print]Where it reads:a,*, Jamil Pedro de Siqueira Caldasa,Rafaella Regina Alves Peixotoa, Vitor Lacerda Sanchesa, TamaraCristina Guiraldeloa, Solange Cadorea, S\u00e9rgio Tadeu MartinsMarbaaCarla Regina Bianchi CodoaSchool of Medical Sciences, Universidade Estadual de Campinas, Campinas, SP,Brazil.It should read:a,*, Jamil Pedro de Siqueira Caldasa,Rafaella Regina Alves Peixotob, Vitor Lacerda Sanchesb, TamaraCristina Guiraldelob, Solange Cadoreb, S\u00e9rgio Tadeu MartinsMarbaaCarla Regina Bianchi CodoaSchool of Medical Sciences, Universidade Estadual de Campinas, Campinas, SP,Brazil.bInstitute of Chemistry, Universidade Estadual de Campinas, Campinas, SP,Brazil."} +{"text": "The third, fourth, fifth, eleventh, twelfth, and thirteenth authors, Henry Thai, Andrew Fleet, Trevor Morey, Yonathan Brhane, Yuyao Song, and Osvaldo Espin-Garcia should not have been attributed equal contribution to this work. The last two authors, Laurie Ailles and Geoffrey Liu, should be noted as contributing equally to this work."} +{"text": "Author Contributions statement appears below.\u201cElisabeth E. L. Nystr\u00f6m\u201d was not included as an author in the published article. The corrected \u201cGV, AG, MJ, LA, BM-A, EN, PS, NP, PM-B, AP, and CF performed and designed the experiments. GV, AG, MJ, PS, NP, LG, GH, and CF analyzed the data and designed the figures. LG and CF conceived the research. CF wrote the manuscript. GV, MJ, PS, NP, LG, GH, and CF discussed the results, and corrected and approved the final version of the manuscript.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The following information is missing from the Competing Interests statement: JB is a consultant to Novartis, Roche, Merck, Sanofi-Aventis, Verastem, Bayer, Chugai, Exelixis, Onyx and Constellation."} +{"text": "AbstractChromoteleia Ashmead is revised. Twenty-seven species are recognized, of which six species are redescribed: C.congoana (Risbec), C.connectens Kieffer, C.fuscicornis Kieffer, C.longitarsis Kieffer, C.semicyanea Ashmead, C.tricarinata Kieffer; and twenty-one species are described as new: C.aequalis Chen & Johnson, sp. n., C.alternata Chen & Johnson, sp. n., C.bidens Chen & Masner, sp. n., C.copiosa Chen & Johnson, sp. n., C.cuneus Chen & Johnson, sp. n., C.curta Chen & Johnson, sp. n., C.depilis Chen & Johnson, sp. n., C.dispar Chen & Masner, sp. n., C.feng Chen & Johnson, sp. n., C.fossa Chen & Johnson, sp. n., C.ingens Chen & Masner, sp. n., C.levitas Chen & Johnson, sp. n., C.longa Chen & Johnson, sp. n., C.maura Chen & Masner, sp. n., C.parvitas Chen & Johnson, sp. n., C.pilus Chen & Johnson, sp. n., C.plana Chen & Johnson, sp. n., C.rara Chen & Johnson, sp. n., C.robusta Chen & Johnson, sp. n., C.semilutea Chen & Johnson, sp. n., C.sparsa Chen & Johnson, sp. n.Chromoteleiarufithorax Kieffer remains a valid species, but its identity and status are unclear. All species are known only from the Neotropical region except for Chromoteleiacongoana (Resbec) which only occurs in Africa.The genus Chromoteleia was originally described by Chromoteleiasemicyanea Ashmead collected in Saint Vincent. Later, Petalosema for species with expanded metanotum (metascutellum). Petalosema with Chromoteleia by pointing out that C.semicyanea showing a narrow and unexpanded metanotum. Six species were recorded from the New World: C.connectens Kieffer, C.fuscicornis Kieffer, C.longitarsis Kieffer, C.rufithorax Kieffer, C.semicyanea Ashmead, and C.tricarinata Kieffer. One species also was described from the Afrotropical region, C.congoana (Risbec), from what is currently Gabon. One fossil species, C.theobaldi Maneval, is reported from Baltic amber (from 40~60 mya) (The genus ~60 mya) , but the~60 mya) and requChromoteleia has never been comprehensively reviewed. Although there are no host records for Chromoteleia, we suspect that it parasitizes the eggs of Orthoptera based on large size and elongate shape of the parasitoids. A number of scelionine genera of similar habitus, and presumed close relation, are also known to be parasitoids of orthopteran eggs, e.g., Macroteleia Kieffer , Triteleia Kieffer for the individual specimens. The label data for all specimens have been georeferenced and recorded in the Hymenoptera Online database, and details on the data associated with these specimens can be accessed at the following link, hol.osu.edu, and entering the identifier in the form (note the space between the acronym and the number). The electronic version of the paper contains hyperlinks to external resources. Insofar as possible, the external information conforms to standards developed and maintained through the organization Biodiversity Information Standards (Taxonomic Database Working Group). All new species have been prospectively registered with ZooBank (www.zoobank.org), and other taxonomic names, where appropriate, have been retrospectively registered. The external hyperlinks are cited explicitly in the endnotes so that users of the printed version of this article have access to the same resources.In the Material Examined section the specimens studied are recorded in an abbreviated format, using unique identifiers , designed to facilitate the production of a taxon by character data matrices, and to integrate those data with the existing taxonomic and specimen-level database. Data may be exported in both text format and as input files for other applications. The text output for descriptions is in the format of \u201cCharacter: Character state (s)\u201d. Polymorphic characters are indicated by semicolon-separated character states.Data associated with the genus specimage.osu.edu), the image database at The Ohio State University.Images and measurements were made using Combine ZP and AutoMontage extended-focus software, using JVC KY-F75U digital camera, Leica Z16 APOA microscope, and 1X objective lens. Images were post-processed with Abobe Photoshop CS3 Extended. A standard set of images is provided for each species: dorsal habitus, lateral habitus, dorsal and lateral views of the head and mesosoma, and anterior view of head. The individual images are archived in Specimage ; Baryconus Forster, Bracalba Dodd, Chromoteleia Ashmead, Oxyscelio Kieffer); Ashmead, 1893: 209, 211, 219 Type: PetalosemaChromoteleiarufithorax Kieffer, by original description , designated by http://zoobank.org/E5906ABF-3A4D-4005-BFEC-13B2AEBD6E81http://bioguid.osu.edu/xbiod_concepts/8521Length 3.38\u20139.20 mm; body elongate, robust.Head. Head shape in dorsal view: transverse. Vertex: densely punctate to punctate rugose. Hyperoccipital carina: absent. Occipital carina: present, complete or broadly interrupted medially. OOL: lateral ocellus nearly contiguous with inner orbits, OOL < 0.5 OD; lateral ocellus contiguous with inner orbit. Upper frons: convex, without frontal shelf or carina, punctate rugose. Antennal scrobe: broadly convex to concave medially with distinct depression. Submedian carina: absent. Orbital carina: absent. Inner orbits: diverging ventrally. IOS/EH: IOS distinctly less than EH. Interantennal process: short, often excavate medially. Central keel: present or absent. Antennal foramen: oriented laterally on interantennal process. Facial striae: absent. Malar sulcus: present. Malar striae: absent. Setation of compound eye: absent. Gena: broad, convex, distinctly produced behind eye. Clypeus shape: narrow, slightly convex medially, lateral corners not produced. Anterior margin of clypeus: pointed; straight. Labrum: not visible in anterior view. Number of mandibular teeth: 3. Arrangement of mandibular teeth: transverse. Number of maxillary palpomeres: 4. Shape of maxillary palpomeres: cylindrical. Number of labial palpomeres: 2.Antenna. Number of antennomeres in female: 12. Number of antennomeres in male: 12. Insertion of radicle into A1: parallel to longitudinal axis of A1. Shape of A1: more or less cylindrical, not flattened. Length of A3 of female: distinctly longer than A2. Number of antennomeres with basiconic sensilla in female: 5; 6. Number of antennomeres with basiconic sensilla in female: 5; 6. Arrangement of sensilla on female clava: in longitudinal pairs. Number of antennomeres bearing tyloids in male antenna: 1. Shape of male flagellum: filiform.Mesosoma. Posterior apex of pronotum in dorsal view: straight, bifid apically to articulate with tegula. Epomial carina: present. Anterior face of pronotum: oblique, visible dorsally, short. Lateral face of pronotum: weakly concave below position of dorsal epomial carina. Netrion: present. Netrion shape: moderately wide, open ventrally. Anterior portion of mesoscutum: vertical, flexed ventrally to meet pronotum. Mesoscutum shape: pentagonal, excavate at base of wings. Skaphion: absent. Notauli: present, percurrent. Parapsidal lines: absent. Antero-admedian lines: absent. Transscutal articulation: well-developed, narrow. Shape of mesoscutellum: trapezoidal, without spines. Lateral mesoscutellar spine: absent. Median mesoscutellar spine: absent. Axillular spine: absent. Surface of mesoscutellum: convex throughout. Median longitudinal furrow on mesoscutellum: absent. Metascutellum: clearly differentiated. Shape of metascutellum: trapezoidal with broad posterior margin; elongate trapezoidal but with deeply incised apex, forming two spines laterally. Posterior margin of metascutellum: straight; concave; convex. Setation of metascutellum: present. Metapostnotum: fused to propodeum. Lateral propodeal projection: absent. Medial propodeal projection: absent. Mesopleural carina: present. Mesal course of acetabular carina: not separating fore coxae. Setation of subalar pit: present. Mesopleural pit: present. Posterodorsal corner of mesopleuron: rounded anteriorly.Legs. Number of mesotibial spurs: 1. Number of metatibial spurs: 1. Dorsal surface of metacoxa: smooth; punctate. Shape of metacoxa: cylindrical, ecarinate. Trochantellus: indicated by transverse sulcus on femur.Wings. Wing development of female: macropterous. Wing development of male: macropterous. Tubular veins in fore wing: present. Bulla of fore wing R: absent. Length of marginal vein of fore wing: punctiform, R terminating at costal margin. Origin of r-rs in fore wing: basal of point at which R meets costal margin. Basal vein (Rs+M) in fore wing: spectral; nebulous. Development of R vein in hind wing: complete.Metasoma. Number of external metasomal tergites in female: 6. Number of external metasoma sternites in female: 6. Number of external metasomal tergites in male: 7. Number of external metasomal sternites in male: 7. Shape of metasoma: lanceolate. Laterotergites: present, narrow. Laterosternites: present. T1 of female: flat; medially convex as a small hump anteriorly. Relative size of metasomal segments: T2\u2013T3 subequal in length, remaining terga shorter. Metasomal tergites with basal crenulae: T2. Sublateral carinae on tergites: present. Median longitudinal carina on metasomal terga: absent. Shape of female T6: flattened; laterally compressed. Anterior margin of S1: not produced anteriorly, straight. Felt fields on S2: absent. Felt fields on S3: absent. Ovipositor: Scelio-type make it a relatively easy genus to identify. The setation of the metascutellum is found in relatively few scelionine genera, typically among the more robust genera, and is a useful diagnostic character. Chromoteleia appears closest to Bracalba Dodd and Romilius Walker, from which it can be separated by the setation of the eyes (absent in Chromoteleia).The large size and distinctive characters of Chromoteleia in Africa and South America is a phenomenon of biogeographical interest. Dispersal from South America to Africa has been demonstrated in the parasitoid wasp genus Kapala Cameron (Eucharitidae) , suggesting that the extant fauna of this genus is the remainder of a once widespread distribution.The distribution of ritidae) and a siChromoteleia is widespread in continental Mesoamerica, Central America, and South America. It is found as far north as the Mexican state of Jalisco, and in the south extends to Itap\u00faa Department in Paraguay and Paran\u00e1 in southern Brazil. It is noteworthy, though, that it is entirely absent from the Greater Antilles. In the Lesser Antilles, one species, C.semicyanea, apparently is endemic in St. Vincent, and a second, C.aequalis, is known from Dominica (as well as Guyana). This is unusual for scelionines of comparable size and presumed biology: genera such as Scelio, Baryconus, Macroteleia, Triteleia and Opisthacantha are common and richly represented in species throughout the Caribbean.Basiconic sensilla on A12Chromoteleia clearly have two basiconic sensilla on the apical antennomere there may be patch of setae . However, because this is a newly recognized character, it has yet to be examined thoroughly throughout Scelioninae. This character is known to us from Romilius, Bracalba, and Macroteleiapilosa Muesebeck.The presence of setae C.connectens KiefferC.brevitarsis Kieffer= C.copiosa Chen & Johnson, sp. n.C.cuneus Chen & Johnson, sp. n.C.curta Chen & Johnson, sp. n.C.depilis Chen & Johnson, sp. n.C.dispar Chen & Masner, sp. n.C.feng Chen & Johnson, sp. n.C.fossa Chen & Johnson, sp. n.C.fuscicornis KiefferC.ingens Chen & Masner, sp. n.C.levitas Chen & Johnson, sp. n.C.longitarsis KiefferC.longa Chen & Johnson, sp. n.C.maura Chen & Masner, sp. n.C.parvitas Chen & Johnson, sp. n.C.pilus Chen & Johnson, sp. n.C.plana Chen & Johnson, sp. n.C.rara Chen & Johnson, sp. n.C.robusta Chen & Johnson, sp. n.C.rufithorax KiefferC.semicyanea AshmeadC.semilutea Chen & Johnson, sp. n.C.sparsa Chen & Johnson, sp. n.C.tricarinata KiefferTaxon classificationAnimaliaHymenopteraScelionidaeChen & Johnsonsp. n.http://zoobank.org/A91D1FE4-DEF0-4D3F-BC48-3F29A67FC42Ahttp://bioguid.osu.edu/xbiod_concepts/452211Body length of female: 6.88\u20137.27 mm (n = 3). Body length of male: 5.90\u20136.20 mm (n = 3). Color of A1: yellow to orange. A6 in female: distinctly longer than wide. A5 in female: distinctly longer than wide. A6 in male: approximately 2.0\u00d7 longer than wide. Number of basiconic sensilla on A7: 0. Number of basiconic sensilla on A12: 2. Sculpture of dorsal A1: striate. Color of head: black. Sculpture of frons directly above interantennal process: transversely striate to rugose. Central keel: present, interrupted medially. Ventral margin of clypeus: pointed. Granulate microsculpture of dorsal frons: absent. Occipital carina: interrupted medially. Granulate microsculpture of vertex: absent. Sculpture of occiput: smooth. Sculpture of gena: dorsoventrally strigose.Color of mesosoma: black. Sculpture of epicoxal lobe posterior of propleural epicoxal sulcus: densely punctate. Sculpture of lateral pronotal area above pronotal cervical sulcus: smooth dorsally, rugose ventrally. Sculpture of netrion: densely punctate. Microsculpture of mesoscutum: granulate. Macrosculpture of mesoscutal midlobe: densely punctate. Macrosculpture of lateral lobe of mesoscutum: densely punctate. Sculpture of notaulus: foveate. Notaular foveae: discrete. Median mesoscutal carina: present anteriorly, not extending to posterior margin of mesoscutum. Mesoscutellum in lateral view: flat. Sculpture of mesoscutellum: densely punctate rugose. Shape of metascutellum: trapezoidal with broad posterior margin. Median metascutellar carina: absent or indistinguishable from sculpture. Sculpture of metascutellum: areolate. Sculpture of lateral propodeal area: rugose. Mesopleural carina: absent. Sculpture of mesepisternum below femoral depression: smooth directly below femoral depression, otherwise densely punctate. Sculpture of dorsal metapleural area: rugose. Setation of dorsal metapleural area: absent. Setation of area directly dorsal to the metapleural triangle: present. Sculpture of ventral metapleural area: rugose anteriorly, smooth posteriorly. Color of legs: pale yellow with tarsi dark brown to black. Length of hind basitarsus: distinctly longer than remaining segments combined. Sculpture of hind coxa: densely punctate.Length of postmarginal vein: distinctly longer than stigmal vein.Color of metasoma in female: black. Color of metasoma in male: black. Horn on T1 in female: present. Striae of posterior margin of T1 in female: dense. Striae of T1 in male: dense. Transverse sulcus on T2: present. Sculpture of T2: longitudinally punctate rugose. Sculpture of T6 in female: densely longitudinally striate, with fine punctures in interstices. Length of T6 in female: at least 1.5\u00d7 longer than wide. Shape of T6 in female in lateral view: flat. Apical spine on female T6: absent. Sculpture of T6 in male: densely longitudinally striate with fine punctures in interstices. Sculpture of T7 in male: smooth to coriaceous. Posterior margin of T7 in male: straight. Sculpture of medial S2: densely punctate to punctate rugose.This species is easily recognized by its entirely black body both in female and male, densely punctate mesoscutum, and abbreviated median mesoscutal carina.The epithet is inspired by the Latin word for equal, in reference to the black body color shared by males and females, and is intended to be treated as an adjective.http://hol.osu.edu/map-large.html?id=452211][Holotype, male, C.rufithorax var. tricarinata: BELIZE: no date, CAS TYPE9759 (deposited in CAS).Other material: BELIZE: 32 females, 27 males, OSUC556957, 584778\u2013584798, 584800\u2013584804, 584806, 584921, 584932\u2013584934, 586445, 586758, 586870\u2013586871 (CNCI); OSUC186068, 186070, 225287, 232140\u2013232142, 47918\u201347919, 47940, 48011, 48037, 64021, 64026\u201364028, 64046\u201364047, 93534, 93586\u201393588, 94076\u201394077 (OSUC). BRAZIL: 1 female, 2 males, OSUC 56227\u201356229 (OSUC). COLOMBIA: 1 female, OSUC586287 (CNCI). COSTA RICA: 191 females, 340 males, OSUC149653, 149657, 202538 (AEIC); OSUC232992 (BPBM); OSUC232058, 232120\u2013232138, 232188, 232190\u2013232191, 374050, 556994, 556998, 557003, 557007, 557009, 557015, 557017, 557020\u2013557022, 557024\u2013557029, 557046\u2013557047, 557052, 557054\u2013557057, 557059\u2013557060, 557063\u2013557080, 557082, 577894, 577897, 577900\u2013577901, 577905, 577925, 577928, 577930\u2013577931, 577942, 577952, 577956\u2013577961, 577963, 577965\u2013577970, 577972, 578010\u2013578011, 578019, 578023\u2013578024, 578044, 578046, 578053, 578059, 578063\u2013578065, 578067\u2013578070, 578072, 578074\u2013578075, 578077\u2013578078, 578084, 578087\u2013578090, 578093\u2013578096, 578098, 578100\u2013578102, 578105, 583414, 583417\u2013583418, 583421, 583429, 583437, 583460, 583462, 583465\u2013583466, 583470, 583514\u2013583515, 583518\u2013583520, 583709\u2013583715, 583718, 583720\u2013583722, 583724\u2013583730, 583732\u2013583738, 583740\u2013583750, 583754\u2013583755, 583759, 583761\u2013583762, 583766\u2013583767, 583772, 583774\u2013583775, 583777\u2013583783, 583786, 583788\u2013583793, 583795, 583797\u2013583798, 583818\u2013583828, 583830\u2013583833, 583835\u2013583849, 583851\u2013583877, 583883\u2013583885, 583888, 583893\u2013583895, 583899\u2013583900, 583902\u2013583909, 583911\u2013583912, 583914\u2013583915, 583917\u2013583924, 583929\u2013583930, 583939, 583941\u2013583942, 583945\u2013583946, 583950\u2013583951, 583977, 583979, 583983\u2013583987, 583991, 583995\u2013583996, 583999\u2013584002, 584007, 584013, 584015, 584018, 584020\u2013584022, 584024, 584029\u2013584030, 584034, 584036, 584040, 584043\u2013584044, 584046, 584138, 584225, 584227, 584230, 584233, 584240, 584242, 584244, 584250, 584264\u2013584270, 584274\u2013584276, 584281\u2013584283, 584287, 585121\u2013585124, 585126\u2013585144, 586127\u2013586128, 586139\u2013586141, 586152\u2013586156, 586165, 586172, 586174, 586184, 586195, 586197, 586199, 586202, 586204, 586207\u2013586208, 586211, 586215, 586218\u2013586221, 586262\u2013586266, 586270, 586275\u2013586286, 586291\u2013586292, 586296\u2013586301, 586374\u2013586375, 586379\u2013586389, 586391, 586405, 586407\u2013586410, 586414, 586473, 586481\u2013586484, 586486, 586488, 586490\u2013586492, 586495\u2013586497, 586506, 586508, 586511, 586514\u2013586515, 586535\u2013586537, 586540, 586560\u2013586564, 586566, 586569\u2013586571, 586628, 586630, 586632, 586634, 586636\u2013586637, 586642\u2013586643, 586647, 586650\u2013586655, 586657, 586660\u2013586661, 586663, 586665\u2013586666, 586671, 586763, 586765\u2013586768, 586779, 586835, 586872 (CNCI); DPI_FSCA 00010211 (CSCA); SM0810075, SM0810348T (KUNH); OSUC185844, 374051\u2013374054 (OSUC); OSUC320638, 320648\u2013320650 (TAMU); OSUC204982, 204999 (UCDC); OSUC157812 (UCMC). GUATEMALA: 9 females, 16 males, OSUC584920, 584922\u2013584924, 584926\u2013584931, 584935\u2013584936, 584940\u2013584948, 584950, 584952\u2013584953 (CNCI); OSUC317963 (OSUC). HONDURAS: 13 females, 16 males, OSUC584961\u2013584963 (CNCI); OSUC369620, 369622, 369624, 369626\u2013369627, 413758\u2013413759, 413761\u2013413763, 413766\u2013413771, 413773\u2013413782 (MZLU). MEXICO: 14 females, 20 males, OSUC556947, 584937\u2013584939, 584949, 584951, 584954\u2013584960 (CNCI); OSUC268812\u2013268813, 268815\u2013268818, 271011, 271013\u2013271014, 271016, 56230\u201356233, 56235, 56237\u201356241, 56243 (OSUC). NICARAGUA: 1 female, 1 male, DPI_FSCA 00010212 (CSCA); OSUC204951 (UCDC). PANAMA: 68 females, 128 males, OSUC149652, 149655, 202542\u2013202543, 202557, 202559, 202561\u2013202575 (AEIC); OSUC557099\u2013557112, 578054, 583459, 583483, 583501, 583505\u2013583507, 584179\u2013584181, 584183\u2013584224, 584337\u2013584373, 584375\u2013584376, 584383\u2013584397, 586158, 586345, 586373, 586377, 586465\u2013586468, 586477\u2013586479, 586521\u2013586527, 586565, 586613\u2013586617, 586627, 586631, 586682\u2013586692, 586815\u2013586817, 586820\u2013586823, 586825, 586874 (CNCI); OSUC221922\u2013221923, 319208\u2013319209, 320642, 320645\u2013320647, 321353 (TAMU). VENEZUELA: 1 male, OSUC557086 (CNCI)."} +{"text": "In the original version of this article , the refAshworth M, Robinson S, Godfrey E, Shepherd M, Evans C, Seed P, Parmentier H, Tylee A. Measuring mental health outcomes in primary care: the psychometric properties of a new patient-generated outcome measure, PSYCHLOPS . Prim Care Ment Health. 2005;3:261\u2013270."} +{"text": "The authors are listed out of order. Please view the correct author order, affiliations, and citation here:1, Greg Beilman2, John P. Delaney2Alex J. Charboneau1. University of Minnesota Medical School, Minneapolis, Minnesota, United States of America2. Department of Surgery, University of Minnesota, Minneapolis, Minnesota, United States of Americahttps://doi.org/10.1371/journal.pone.0207797Charboneau AJ, Beilman G, Delaney JP (2018) Fucoidans inhibit the formation of post-operative abdominal adhesions in a rat model. PLoS ONE 13(11): e0207797."} +{"text": "Adv. Sci.2019, 6, 1900808TableTableIn the originally published article, To correct these errors, two new entries have been added: QCArchive"} +{"text": "Effect of supplementary zinc on orthodontic tooth movement in a rat model, published at Dental Press J Orthod. 2016 Mar-Apr;21(2):45-50, where it is written:In the article Ahmad Akhoundi Mohammad Sadegh, Ghazanfari Rezvaneh, EtemadMoghadam Shahroo, Alaeddini Mojgan, Khorshidian Azam, Rabbani Shahram, Shamshiri Ahmad Reza, Momeni Nafiseh. Should be written:Mohammad Sadegh Ahmad Akhoundi, Rezvaneh Ghazanfari, Shahroo Etemad-Moghadam, Mojgan Alaeddini, Azam Khorshidian, Shahram Rabbani, Ahmad Reza Shamshiri, Nafiseh Momeni."} +{"text": "Case Report: Imported Melioidosis from Goa, India, to Israel, 2018\u201d (https://doi.org/10.4269/ajtmh.19-0303) by Brosh-Nissimov and others, the name of an additional co-author has been inadvertently omitted. Dr. Shay Weiss has been involved in the culturing of the Burkholderia isolate for its genetic characterization.In \u201cThe new list of authors should therefore be Tal Brosh-Nissimov, Daniel Grupel, Shlomi Abuhasira, Hanna Leskes, Ma\u2019ayan Israeli, Shirley Lazar, Uri Elia, Ofir Israeli, Adi Beth-Din, Erez Bar-Haim, Inbar Cohen-Gihon, Anat Zvi, Shay Weiss, Ofer Cohen, and Theodor Chitlaru."} +{"text": "Body weight was measured annually and participants were categorized as weight regainers, weight cyclers, or continued losers/maintainers based on a \u00b13% annual change in weight from year 1 to year 4. Adjudicated overall fracture incidence was captured from years 4 through 13 (median follow\u2010up duration 11.5 years). Hip and spine BMD was assessed in a subset of participants at baseline, year 4 (n\u2009=\u2009468), and year 8 (n\u2009=\u2009354), using dual\u2010energy X\u2010ray absorptiometry. Cox proportional hazards and linear regression models, adjusted for relevant covariates, were performed for fracture and BMD outcomes, respectively. Fifty\u2010eight percent, 22%, and 20% of participants were classified as weight regainers, weight cyclers, and continued losers/maintainers, respectively; and 217 fractures were recorded during the follow\u2010up period. There were no statistically significant differences in total incident fracture rates for weight regainers or weight cyclers when compared to continued losers/maintainers (p\u2009=\u20090.99). Similarly, follow\u2010up BMD estimates did not significantly vary by weight pattern group, although consistent trends for lowered BMD in the hip region were noted for continued losers/maintainers and weight cyclers compared with weight regainers. Patterns of weight change in the 3 years following 1 year of intentional weight loss were not associated with subsequent fracture or significantly reduced BMD in this cohort of overweight and obese adults with type 2 diabetes. \u00a9 2018 The Authors. JBMR Plus Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.The purpose of this study is to explore the impact of body weight change following intentional weight loss on incident fracture and bone mineral density (BMD) in overweight and obese adults with diabetes. A total of 1885 individuals with type 2 diabetes (baseline age: 58.5\u2009\u00b1\u20096.7 years, 58% women, body mass index: 35.7\u2009\u00b1\u20096.0\u2009kg/m Clinicaltrials.gov Identifier: NCT00017953) study provide a unique opportunity to address this question. Using measured weights over a 4\u2010year period, we aimed to explore associations of three patterns of weight change following intentional weight loss on fracture risk and change in BMD occurring over the next decade.Osteoporotic fracture is a serious and costly clinical problem associated with type 2 diabetes.n\u2009=\u20092290) and had at least two follow\u2010up weights (excluded n\u2009=\u2009301), no fractures prior to year 4 (excluded n\u2009=\u200977), and non\u2010missing covariate data (excluded n\u2009=\u200927).The Look AHEAD Study was a multicenter, randomized controlled trial designed to determine whether intentional weight loss reduces cardiovascular morbidity and mortality in overweight individuals with type 2 diabetes. The study was approved by local Institutional Review Boards and all participants provided informed consent. Details on the study designWeight was measured annually by certified clinic staff, masked to intervention assignment, using a Tanita BWB 800 digital scale . Based on the first 3 years of follow\u2010up (years 1 through 4), participants were classified into three categories: (i) weight regainers, (ii) weight cyclers, and (iii) continued losers/maintainers, using patterns previously employed in the Look AHEAD studyCentrally adjudicated incident fractures included in this analysis occurred between year 4 and the end of the Look AHEAD\u2010Continuation phase, with maximum follow\u2010up time of 13.2 years . As described,n\u2009=\u2009468) or year 8 (n\u2009=\u2009354) regional DXA scans.Total hip, femoral neck, and lumbar spine BMD were assessed at five of the 16 Look AHEAD clinical sites using Hologic fan beam densitometers (DXA), as described.Self\u2010reported characteristics and medical history were assessed using standardized questionnaires. Height was measured in duplicate using a stadiometer and body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. Participants brought current prescription medications to update medication records, with bone negative medications defined as: loop diuretics, selective serotonin reuptake inhibitors (SSRIs), thyroid hormones, oral steroids such as prednisone, tricyclic antidepressants, and thiazolidinedione (TZDs); and bone positive medications defined as: androgens (anabolic steroids), calcium, antacids containing calcium, and antiresorptive agents such as bisphosphonates, calcitonin nasal spray, estrogens, and selective estrogen receptor modulators (SERMs). Fasting blood specimens were analyzed by the Central Biochemistry Laboratory using standardized laboratory procedures for measuring glycated hemoglobin (HbA1c). Depressive symptoms were assessed using the Beck Depression Inventory , with higher scores indicating more symptoms of depression.Descriptive statistics were calculated overall and by weight pattern classification at baseline. Cox proportional hazards models, both unadjusted and adjusted for relevant baseline covariates were performed for incident overall and hip, pelvis, or upper arm fracture outcomes. Because fracture risk is elevated in older women, a formal test of interaction between age, gender, and weight pattern category was conducted to inform whether stratified analyses should be performed. Differences in hip, femoral neck, and lumbar spine BMD at years 4 and 8 were assessed in a subset of participants using linear regression models, adjusting for the same covariates described above plus baseline value of the outcome, and presented as least square means and standard errors. All statistical analyses were executed using SAS version 9.4 .2. Fifty\u2010eight percent, 22% and 20% of participants were classified as weight regainers, weight cyclers, and continued losers/maintainers, respectively. On average, by the year 4 visit, regainers gained 8.3\u2009\u00b1\u20095.5\u2009kg, weight cyclers gained 1.1\u2009\u00b1\u20097.0\u2009kg, and continued losers/maintainers lost 2.9\u2009\u00b1\u20096.0\u2009kg from the year 1 weight. Weight cyclers were more likely to be between the ages of 50 and 59 years, female, Hispanic, and using bone\u2010positive medications, than other categories . Participants in the DXA analyses were more likely to be female (p\u2009<\u20090.01), of ethnic minority (p\u2009<\u20090.01), and slightly younger (p\u2009=\u20090.05) when compared to the main analysis sample; however, the distribution of weight pattern categories within the DXA subset was similar to the larger study sample (data not shown).Baseline descriptive characteristics, detailed by group and overall, are presented in Table n\u2009=\u200963; women n\u2009=\u2009154) were recorded overall. Figure p\u2009=\u20090.99). Similar results were observed for incident hip, pelvis, or upper arm fracture (data not shown). The interaction between age, gender, and weight pattern category was not significant (p\u2009=\u20090.75), thus stratified analyses were not pursued.Over a total of 11.5 years of follow\u2010up, 217 fractures (men 2 (\u22124.5%), \u22120.055\u2009\u00b1\u20090.012\u2009g/cm2 (\u22123.9%), and \u22120.039\u2009\u00b1\u20090.010\u2009g/cm2 (\u22123.0%) in continued losers/maintainers, weight cyclers, and weight regainers, respectively (p\u2009=\u20090.11). Likewise, by year 8, total hip BMD was reduced by \u22120.046\u2009\u00b1\u20090.012\u2009g/cm2 (\u22123.9%), \u22120.042\u2009\u00b1\u20090.012\u2009g/cm2 (\u22123.3%), and \u22120.032\u2009\u00b1\u20090.011\u2009g/cm2 (\u22121.9%) from baseline values in continued losers/maintainers, weight cyclers, and weight regainers, respectively (p\u2009=\u20090.21). No signal was observed for change in lumbar spine BMD .As with incident fracture, no significant associations were observed between weight pattern classification and year 4 and year 8 regional BMD at any site. Trends for lower BMD at the femoral neck and total hip were observed in continued losers/maintainers and weight cyclers compared with weight regainers, yet they did not attain statistical significance. Specifically, by year 8, femoral neck BMD was reduced from baseline by \u22120.050\u2009\u00b1\u20090.012\u2009g/cmThere is increasing interest in understanding the skeletal effects of obesity and diabetes, particularly in the context of weight loss. As reported, randomization to an intensive lifestyle intervention, resulting in weight loss for most participants, was associated with modest bone lossWe are aware of only four studies examining the effect of weight variabilityintentional weight loss on incident fracture; although the effect of weight change following voluntary weight loss on BMD has been assessed in a handful of studies. Some, but not all,To our knowledge, our study is the first to assess the effect of weight patterns dynamics following Strengths of this study include use of objectively measured weights to assess changing weight dynamics following intentional weight loss, as well as adjustment for multiple, relevant covariates. Despite these design strengths, Look AHEAD was not designed to detect differences in incident fracture rates between weight pattern classifications; thus, our analyses may have been underpowered. Certainly, DXA data, which were only available in a subset, are meant to be hypothesis generating, rather than confirmatory. A general limitation in this field of research is the lack of an operational definition for weight cycling. Although we used patterns previously employed in the Look AHEAD studyIn conclusion, in this cohort of overweight and obese adults with type 2 diabetes experiencing intentional weight loss over a year, we did not observe a significant association between subsequent patterns of weight change and incident fracture. Overall, findings temper concerns regarding weight cycling following intentional weight loss on fracture risk, at least in the short term, although certainly more work in this area is needed.All authors state that they have no conflicts of interest.The Johns Hopkins University: Frederick L. Brancati, MD, MHS1*; Jeanne M. Clark, MD, MPH1 ; Lee Swartz2; Jeanne Charleston, RN3; Lawrence Cheskin, MD3; Richard Rubin, PhD3*; Jean Arceci, RN; David Bolen; Danielle Diggins; Mia Johnson; Joyce Lambert; Sarah Longenecker; Kathy Michalski, RD; Dawn Jiggetts; Chanchai Sapun; Maria Sowers; Kathy Tyler.*deceasedPennington Biomedical Research Center: George A. Bray, MD1; Allison Strate, RN2; Frank L. Greenway, MD3; Donna H. Ryan, MD3; Donald Williamson, PhD3; Timothy Church, MD3; Catherine Champagne, PhD, RD; Valerie Myers, PhD; Jennifer Arceneaux, RN; Kristi Rau; Michelle Begnaud, LDN, RD, CDE; Barbara Cerniauskas, LDN, RD, CDE; Crystal Duncan, LPN; Helen Guay, LDN, LPC, RD; Carolyn Johnson, LPN, Lisa Jones; Kim Landry; Missy Lingle; Jennifer Perault; Cindy Puckett; Marisa Smith; Lauren Cox; Monica Lockett, LPN.The University of Alabama at Birmingham: Cora E. Lewis, MD, MSPH1; Sheikilya Thomas, PhD,MPH2; Monika Safford, MD3; Stephen Glasser, MD3; Vicki DiLillo, PhD3; Gareth Dutton, PhD, Charlotte Bragg, MS, RD, LD; Amy Dobelstein; Sara Hannum; Anne Hubbell, MS; Jane King, MLT; DeLavallade Lee; Andre Morgan; L. Christie Oden; Janet Wallace, MS; Cathy Roche, PhD, RN, BSN; Jackie Roche; Janet Turman.Harvard CenterMassachusetts General Hospital: David M. Nathan, MD1; Enrico Cagliero, MD3; Heather Turgeon, RN, BS, CDE2; Barbara Steiner, EdM; Valerie Goldman, MS, RDN2; Linda Delahanty, MS, RDN3; Ellen Anderson, MS, RDN3; Laurie Bissett, MS, RDN; Christine Stevens, RN; Mary Larkin, RN; Kristen Dalton, BS, Roshni Singh, BS.Joslin Diabetes Center: Edward S. Horton, MD1; Sharon D. Jackson, MS, RD, CDE2; Osama Hamdy, MD, PhD3; A. Enrique Caballero, MD3; Sarah Bain, BS; Elizabeth McKinney, BSN, RN; Barbara Fargnoli, MS,RD; Jeanne Spellman, BS, RD; Kari Galuski, RN; Ann Goebel\u2010Fabbri, PhD; Lori Lambert, MS, RD; Sarah Ledbury, MEd, RD; Maureen Malloy, BS; Kerry Ovalle, MS, RCEP, CDE.Beth Israel Deaconess Medical Center: George Blackburn, MD, PhD1* Christos Mantzoros, MD, DSc3; Ann McNamara, RN.*deceasedUniversity of Colorado Anschutz Medical Campus: James O. Hill, PhD1; Marsha Miller, MS RD2; Holly Wyatt, MD3, Brent Van Dorsten, PhD3; Judith Regensteiner, PhD3; Debbie Bochert; Gina Claxton\u2010Malloy RD Ligia Coelho, BS; Paulette Cohrs, RN, BSN; Susan Green; April Hamilton, BS, CCRC; Jere Hamilton, BA; Eugene Leshchinskiy; Loretta Rome, TRS; Terra Thompson, BA, Kirstie Craul, RD, CDE; Cecilia Wang, MD.Baylor College of Medicine: John P. Foreyt, PhD1; Rebecca S. Reeves, DrPH, RD2; Molly Gee, MEd, RD2; Henry Pownall, PhD3; Ashok Balasubramanyam, MBBS3; Chu\u2010Huang Chen, MD, PhD3; Peter Jones, MD3; Michele Burrington, RD, RN; Allyson Clark Gardner, MS, RD; Sharon Griggs; Michelle Hamilton; Veronica Holley; Sarah Lee; Sarah Lane Liscum, RN, MPH; Susan Cantu\u2010Lumbreras; Julieta Palencia, RN; Jennifer Schmidt; Jayne Thomas, RD; Carolyn White; Charlyne Wright, RN; Monica Alvarez, PCT.The University of Tennessee Health Science CenterUniversity of Tennessee East: Karen C. Johnson, MD, MPH1; Karen L. Wilson, BSN2; Mace Coday, PhD3; Beate Griffin, RN, BS; Donna Valenski; Polly Edwards; Brenda Fonda; Kim Ward.University of Tennessee Downtown: Helmut Steinburg, MD3; Carolyn Gresham, BSN2; Moana Mosby, RN; Debra Clark, LPN; Donna Green RN; Abbas E. Kitabchi, PhD, MD (retired).University of Minnesota: Robert W. Jeffery, PhD1; Tricia Skarphol, MA2; John P. Bantle, MD3; J. Bruce Redmon, MD3; Richard S. Crow, MD3; Scott J. Crow, MD3; Manami Bhattacharya, BS; Cindy Bjerk, MS, RD; Kerrin Brelje, MPH, RD; Carolyne Campbell; Mary Ann Forseth, BA; Melanie Jaeb, MPH, RD; Philip Lacher, BBA; Patti Laqua, BS, RD; Birgitta I. Rice, MS, RPh, CHES; Ann D. Tucker, BA; Mary Susan Voeller, BA.St. Luke's Roosevelt Hospital Center: Xavier Pi\u2010Sunyer, MD1; Jennifer Patricio, MS2; Carmen Pal, MD3; Lynn Allen, MD; Janet Crane, MA, RD, CDN; Lolline Chong, BS, RD; Diane Hirsch, RNC, MS, CDE; Mary Anne Holowaty, MS, CN; Michelle Horowitz, MS, RD; Les James; Raashi Mamtani, MS.University of Pennsylvania: Thomas A. Wadden, PhD1; Barbara J. Maschak\u2010Carey, MSN, CDE2; Robert I. Berkowitz, MD3; Gary Foster, PhD3; Henry Glick, PhD3; Shiriki Kumanyika, PhD RD, MPH3; Yuliis Bell, BA; Raymond Carvajal, PsyD; Helen Chomentowski; Renee Davenport; Lucy Faulconbridge, PhD; Louise Hesson, MSN, CRNP; Sharon Leonard, RD; Monica Mullen, RD, MPH.University of Pittsburgh: John M. Jakicic, PhD1; David E. Kelley, MD1; Jacqueline Wesche\u2010Thobaben, RN, BSN, CDE2; Daniel Edmundowicz, MD3; Lin Ewing, PhD, RN3; Andrea Hergenroeder, PhD, PT, CCS3; Mary L. Klem, PhD, MLIS3; Mary Korytkowski, MD3; Andrea Kriska, PhD3; Lewis H. Kuller, MD, DrPH3; Amy D. Rickman, PhD, RD, LDN3; Rose Salata, MD3; Monica E. Yamamoto, DrPH, RD, FADA3; Janet Bonk, RN, MPH; Susan Copelli, BS, CTR; Rebecca Danchenko, BS; Tammy DeBruce, BA; Barbara Elnyczky; David O. Garcia, PhD; George A. Grove, MS; Patricia H. Harper, MS, RD, LDN; Susan Harrier, BS; Diane Heidingsfelder, MS, RD, CDE, LDN; Nicole L. Helbling, MS, RN; Diane Ives, MPH; Janet Krulia, RN, BSN, CDE; Juliet Mancino, MS, RD, CDE, LDN; Anne Mathews, PhD, RD, LDN; Lisa Martich, BS, RD, LDN; Meghan McGuire, MS; Tracey Y. Murray, BS; Anna Peluso, MS; Karen Quirin; Jennifer Rush, MPH; Joan R. Ritchea; Linda Semler, MS, RD, LDN; Karen Vujevich, RN\u2010BC, MSN, CRNP; Kathy Williams, RN, MHA; Donna L. Wolf, PhD.The Miriam Hospital/Brown Medical School: Rena R. Wing, PhD1; Renee Bright, MS2; Vincent Pera, MD3; Deborah Tate, PhD3; Amy Gorin, PhD3; Kara Gallagher, PhD3; Amy Bach, PhD; Barbara Bancroft, RN, MS; Anna Bertorelli, MBA, RD; Richard Carey, BS; Tatum Charron, BS; Heather Chenot, MS; Kimberley Chula\u2010Maguire, MS; Pamela Coward, MS, RD; Lisa Cronkite, BS; Julie Currin, MD; Maureen Daly, RN; Caitlin Egan, MS; Erica Ferguson, BS, RD; Linda Foss, MPH; Jennifer Gauvin, BS; Don Kieffer, PhD; Lauren Lessard, BS; Deborah Maier, MS; JP Massaro, BS; Tammy Monk, MS; Rob Nicholson, PhD; Erin Patterson, BS; Suzanne Phelan, PhD; Hollie Raynor, PhD, RD; Douglas Raynor, PhD; Natalie Robinson, MS, RD; Deborah Robles; Jane Tavares, BS.The University of Texas Health Science Center at San Antonio: Helen P. Hazuda, PhD1; Maria G. Montez, RN, MSHP, CDE2; Carlos Lorenzo, MD3; Charles F. Coleman, MS, RD; Domingo Granado, RN; Kathy Hathaway, MS, RD; Juan Carlos Isaac, RC, BSN; Nora Ramirez, RN, BSN.VA Puget Sound Health Care System/University of Washington: Steven E. Kahn, MB, ChB1; Anne Kure, BS2; Edward J. Boyko, MD, MPH3; Edward Lipkin, MD, PhD3; Dace Trence, MD3; Subbulaxmi Trikudanathan, MD, MRCP, MMSc3; Elaine Tsai, MD3; Brenda Montgomery, RN, MS, CDE; Ivy Morgan\u2010Taggart; Jolanta Socha, BS; Lonnese Taylor, RN, BS; Alan Wesley, BA.Southwestern American Indian Center, Phoenix, Arizona and Shiprock, New Mexico: William C. Knowler, MD, DrPH1; Paula Bolin, RN, MC2; Tina Killean, BS2; Maria Cassidy\u2010Begay, BSND, RND2; Katie Toledo, MS, LPC2; Cathy Manus, LPN3; Jonathan Krakoff, MD3; Jeffrey M. Curtis, MD, MPH3; Sara Michaels, MD3; Paul Bloomquist, MD3; Peter H. Bennett, MB, FRCP3; Bernadita Fallis, RN, RHIT, CCS; Diane F. Hollowbreast; Ruby Johnson; Maria Meacham, BSN, RN, CDE; Christina Morris, BA; Julie Nelson, RD; Carol Percy, RN, MS; Patricia Poorthunder; Sandra Sangster; Leigh A. Shovestull, RD, CDE; Miranda Smart; Janelia Smiley; Teddy Thomas, BS.University of Southern California: Anne Peters, MD1; Siran Ghazarian, MD2; Elizabeth Beale, MD3; Kati Konersman, RD, CDE; Brenda Quintero\u2010Varela; Edgar Ramirez; Gabriela Rios, RD; Gabriela Rodriguez, MA; Valerie Ruelas MSW, LCSW; Sara Serafin\u2010Dokhan; Martha Walker, RD.Wake Forest University: Mark A. Espeland, PhD1; Judy L. Bahnson, BA, CCRP3; Lynne E. Wagenknecht, DrPH1; David Reboussin, PhD3; W. Jack Rejeski, PhD3; Alain G. Bertoni, MD, MPH3; Wei Lang, PhD3; David Lefkowitz, MD3* Patrick S. Reynolds, MD3; Denise Houston, PhD3; Mike E. Miller, PhD3; Laura D. Baker, PhD3; Nicholas Pajewski, PhD3; Stephen R. Rapp, PhD3; Stephen Kritchevsky, PhD3; Haiying Chen, PhD, MM3; Valerie Wilson, MD3; Delia S. West, PhD3; Ron Prineas, MD3; Tandaw Samdarshi, MD3; Amelia Hodges, BS, CCRP2; Karen Wall2; Carrie C. Williams, MA, CCRP2; Andrea Anderson, MS; Jerry M. Barnes, MA; Tara D. Beckner; Delilah R. Cook; Valery S. Effoe, MD, MS; Melanie Franks, BBA; Katie Garcia, MS; Sarah A. Gaussoin, MS; Candace Goode; Michelle Gordon, MS; Lea Harvin, BS; Mary A. Hontz, BA; Don G. Hire, BS; Patricia Hogan, MS; Mark King, BS; Kathy Lane, BS; Rebecca H. Neiberg, MS; Julia T. Rushing, MS; Debbie Steinberg, BS; Jennifer Walker, MS; Michael P. Walkup, MS.Central Laboratory, Northwest Lipid Metabolism and Diabetes Research Laboratories: Santica M. Marcovina, PhD, ScD1; Jessica Hurting2; John J. Albers, PhD3, Vinod Gaur, PhD4.ECG Reading Center, EPICARE, Wake Forest University School of Medicine:1; Charles Campbell 2; Zhu\u2010Ming Zhang, MD3; Mary Barr; Susan Hensley; Julie Hu; Lisa Keasler; Yabing Li, MD.Elsayed Z. Soliman MD, MSc, MSHall\u2010Foushee Communications, Inc.: Richard Foushee, PhD; Nancy J. Hall, MA.Federal SponsorsNational Institute of Diabetes and Digestive and Kidney Diseases: Mary Evans, PhD; Van S. Hubbard, MD, PhD; Susan Z. Yanovski, MD.National Heart, Lung, and Blood Institute: Lawton S. Cooper, MD, MPH; Peter Kaufman, PhD, FABMR; Mario Stylianou, PhD.Centers for Disease Control and Prevention: Edward W. Gregg, PhD; Ping Zhang, PhD.1Principal Investigator.2Program Coordinator.3Co\u2010Investigator.All other Look AHEAD staff members are listed alphabetically by site.Authors\u2019 roles: Study design: KMB, RHN, KCJ, CHD, RC, AVS, CJC, CEL, XP, and SBK. Study conduct and data collection: KJ and AVS. Data analysis: RHN. Data interpretation: KMB, RHN, KCJ, CHD, RC, AVS, CJC, CEL, XP, and SBK. Drafting manuscript: KMB, RHN. Revising manuscript content: KMB, RHN, KCJ, CHD, RC, AVS, CJC, CEL, XP, and SBK. Approving final version of manuscript: All authors approved the final version. KMB and RHN take responsibility for the integrity of the data analysis."} +{"text": "Due to a typesetting error, the author order was changed during the production of the article. The correct order is: Mary A. De Groote, Thale C. Jarvis, Christina Wong, James Graham, Teresa Hoang, Casey L. Young, Wendy Ribble, Joshua Day, Wei Li, Mary Jackson, Mercedes Gonzalez-Juarrero, Xicheng Sun and Urs A. Ochsner.The publisher apologizes for this error. The original article has been updated."} +{"text": "Journal of Intelligence would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.The editors of https://publons.com) to receive recognition. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make.We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (Journal of Intelligence, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Journal of Intelligence in 2016:Abele, StephanFunke, JoachimRast, PhilippeBayen, Ute J.Ganzach, YoavRedifer, JenniBecker, NicolasGignac, GillesRitchie, StuartBeckmann, Jens F.Goldhammer, FrankSchmidt, FrankBenson, Nicholas F.Greiff, SamuelSchmiedek, FlorianBrewer, GeneGrigorenko, ElenaSchneider, W. JoelBriley, Daniel A.Hagemann, DirkSchoppek, WolfgangBurns, NickHorn, SebastianSchweizer, KarlCampbell, Frances A.Kan, Kees-JanStadler, MatthiasChicherio, ChristianKaufman, JamesStevenson, Claire E.Colom, RobertoKretzschmar, AndreTe Nijenhuis, JanConway, Andrew R. A.Kroehne, UlfTroche, Stefan J.De Boeck, PaulLee, James J.Unsworth, NashDickens, William T.Luciano, MichelleVerhaeghen, PaulDoebler, PhilippMolenaar, DylanVoss, AndreasElliott, Julian G.Nettelbeck, TedWeiss, Lawrence G.Fernandez, S\u00e9bastienNisbett, RichardWiernik, Brenton M.Fischer, AndreasPlomin, RobertWoodley, MichaelFlynn, JamesRanger, JochenZu, JiyunThe following reviewed for"} +{"text": "Scientific Data 10.1038/sdata.2018.176 Published online 4 September 2018Correction to: Due to a typesetting error, 25 rows were omitted from Table 3 in the original version of this Data Descriptor. These missing rows correspond to the following sample names:S0315, S0316, S0317, S0318, S0319, S0403, S0404, S0405, S0406, S0407, S0482, S0483, S0484, S0485, S0486, S0543, S0544, S0545, S0546, S0547, S0592, S0593, S0594, S0595, S0596.In addition, a column in the table indicating the total bases for each sample was omitted.Table 3 has been updated to include the missing data."} +{"text": "The correct name is: Limin Li. The correct citation is: Li L, Woo YY, de Bruyne JA, Nathan AM, Kee SY, Chan YF, et al. (2018) Epidemiology, clinical presentation and respiratory sequelae of adenovirus pneumonia in children in Kuala Lumpur, Malaysia. PLoS ONE 13(10): e0205795."} +{"text": "AbstractLophomyra Schaus, 1911 (Noctuidae) is the smaller of two noctuid genera originally described by Schaus that include species recently associated with ferns (Pteridophyta), in this case Polypodiaceae, as larval food plants. Following an examination of type material and reared specimens accompanied by DNA barcode data, Lophomyra is revised to include L.tacita Schaus, 1911, L.santista , and L.commixta , comb. n., the last of which is transferred from Chytonidia Schaus, 1914 . Lophomyra is characterized based on adult and larval morphology, especially that of the male genitalia. Structures associated with the valvae are discussed with reference to dissected and in situ images. Larvae of L.commixta and L.tacita are described from images, and the recorded food plants of both species are discussed in the context of known New World noctuid pteridivores. Lophomyra Schaus, 1911 is one of two noctuine genera (Lepidoptera: Noctuidae: Noctuinae) described by Schaus with larvae recently discovered feeding on fern foliage (Pteridophyta) at \u00c1rea de Conservaci\u00f3n Guanacaste (ACG), northwestern Costa Rica. Because of their age and toxicity, ferns and their associated herbivore faunas have been of interest to plant-insect biologists for decades. In part because some fern-feeding insect groups have only recently become known as such and are in need of systematic treatment, the number of origins of pteridivory has likely been underestimated and the diet breadths of pteridivorous insects oversimplified. Sampling of Lepidoptera larvae during the last four decades in ACG , and figure the larvae of two species while characterizing their host plants at ACG.s in ACG have idePinned specimens were examined with an incandescent light source. Genitalic preparations follow Leucosigma Druce, and our terminology warrants clarification supplementary to that in the parallel review of that genus extracted during the dissection of the type of Lophomyrasantista. That extraction involved an overnight soak of the abdomen in proteinase and sequestration of the lysate prior to soaking the abdomen in KOH per the normal dissection protocol. It is hoped that a more thorough treatment of Lophomyra will be enabled by greater availability of specimens and corresponding sequence data.Provisional (neighbor-joining) analyses of available DNA barcode data helped to guide dissection efforts and taxonomic decisions, and were supplemented by a partial The following abbreviations refer to collections from which specimens form the basis of this work:MNHUKThe Natural History Museum, London, UK (formerly BMNH).USNMNational Museum of Natural History , Washington, District of Columbia, USA.Taxon classificationAnimaliaLepidopteraNoctuidaeSchaus, 1911Iheringia Jones, [1915] 1914.Iheringiasantista Jones, 1908 by monotypy.Lophomyra are most unmistakably diagnosed by the male genitalia, specifically a conspicuous uncus that in situ appears swollen with a silvery or dark-gray sheen of scale-like clusters of setae, each cluster sharing a setal socket and shingled . Forewing variously shaded with moss-green scales; paler scaling, to the extent present, concentrated primarily towards the inner margin; sexual dimorphism discernible with females more darkly colored, their hind wings more uniformly dark gray throughout and forewing pattern elements generally more distinct than in males; males bear a pronounced dorsal tuft on the second abdominal segment.Species of Head. Labial palpi, frons, and vertex scaled with a mixture of whitish, gray brown, and green. Labial palpi upturned, with second segment longer than the other two segments combined. Proboscis with paired lateral rows of small protuberances towards terminus. Eyes smooth. Antennae filiform, finely scaled dorsally with white or a mixture of white and green.Thorax. Vestiture predominantly made up of spatulate scales and simple hairs; a mix of gray-brown, purplish, lime-green scaling and black peppering; paired latero-dorsal tufts of elongate hairs arising at base of metathorax towards abdomen. Wings. Forewing a mix of gray-brown, black, lime- and moss-green, white and cream-colored scales, the green most prominent in the medial and terminal areas and basally along the inner margin; lines generally incomplete, the black postmedial line most visible but broken, bordered with white on both sides; medial veins edged in black towards the PageBreakouter margin. Basal, antemedial and medial costal striae black and white; postmedial striae white only. Pattern element boundaries blurred in part by variably shaded scaling and most particularly by medial streaking in L.tacita and L.santista. Legs. Scaled with a mixture of green and white; a single pair of mid-tibial spurs; two pair on hind-tibiae; 2+ rows of tibial spines on foreleg, three rows on mid- and hind-legs.Abdomen. Scales predominantly grayish tan. Dorsal tuft of brown scales on second abdominal segment of males. Green scales intermixed with grayish tan, darkening towards in terminal segments. Note the complex of dorsal and ventral tufts enclosing and subtending the uncus and valvae, respectively.Male genitalia. Uncus shingled with dark gray or silvery scale-like setal clusters, each representing ~7\u20139 spine-like setae. Saccus blunt. Juxta roughly shield-shaped, the dorsal edge concave, slightly jagged. Each divided valva comprises (1) a weakly sclerotized elongate sacculus; (2) a strongly sclerotized clasper, either a rudimentary beaklike structure or an elongate gently curved and concave spike, fused to the cucullus (3), which is elongate, weakly sclerotized, and may be swollen apically, spatulate or club-like with a heavy covering of setae and slightly recurved, such that the pair of these structures flank the uncus; and (4) a minor, ampulla-like process embedded within the sacculus, with which it may form a crotch that cradles the clasper. Directly beneath this structure on the inner face of the valve is what appears a well-developed editum comprising a raised patch of spine-like setae or, in the larger species, at least 10 fully developed spines directed anteromedially. Vesica unadorned, without cornuti, but a bilobate sub-basal diverticulum, highly bulbous in the larger species.Female genitalia. Papillae anales blunt-tipped, subquadrate; ductus bursae and corpus bursae flask or wineskin shaped, colliculum absent; ductus bursae narrow relative to caudal region of bursa, constricted at juncture of the two, opposite dorsal opening to ductus seminalis; ductus may have small ventral posterior appendicular lobe; corpus bursae without signa.Immature stages. Larvae, known exclusively from images, have predominantly orange or reddish-orange heads with 10 black spots, and paired setose dorsal spines.Taxon classificationAnimaliaLepidopteraNoctuidaecomb. n.Chytonidiacommixta Schaus, 1914. Type locality: French Guiana.Type material. HOLOTYPE \u2642: FRENCH GUIANA: St. Laurent, Maroni, Chytonixcommixta Type Schs, Collection Wm Schaus, Type No. 16530 U.S.N.M., USNMENT01370304, \u2642USNM Dissection 148186. Type at USNM.FRENCH GUIANA : \u2642AOUT, GUYANE FRAN\u00c7AISE St-LAURENT du MARONI COLL LE MOULT, Dognin Collection, USNMENT01437236, Male genitalia imaged in situ; \u2642 JUILLET, Ibid, USNMENT01438844, USNM Dissection 148087; \u2640JUILLET, Ibid, USNMENT01437245; \u2640 JANVIER, Ibid, USNMENT01437277; \u2640 Cayenne, F. Guiana., Collection Wm Schaus, USNM Dissection 148086, USNMENT01370319; \u2640Ibid, Chytonixcommixta Schs., USNMENT01370317; \u2640 S.-Laurent du Maroni Guy. Franc, Dognin Collection, Chytonixcommixta Schs., USNMENT01370327 COSTA RICA : http://janzen.sas.upenn.edu Area de Conservacion Guanacaste, COSTA RICA. Except for those denoted \u201cAlajuela,\u201d all localities are within Guanacaste Province.The following label data precede Santa Rosa National Park (SRNP) identifier codes on all reared and light-trapped specimens examined : Voucher: D.H. Janzen & W. Hallwachs DB: Males: Alajuela: Sector Rincon Rain Forest: Jacobo, 10.94076, -85.3177, el. 461m: larva on Microgrammapercussa: 01/07/2011, ecl. 02/03/2011, Edwin Apu, collector, 11-SRNP-69041, USNMENT01370325, USNM Dissection 148098; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 01/27/2010, ecl. 03/05/2010, Ricardo Calero, collector, 10-SRNP-70532, USNMENT01438818; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 01/27/2010, ecl. 03/06/2010, Ricardo Calero, collector, 10-SRNP-70533, USNMENT01438849; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Polypodiumfraxinifolium: 01/29/2010, ecl. 03/06/2010, Manuel Rios, collector, 10-SRNP-70574, USNMENT01437246; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Polypodiumfraxinifolium: 01/29/2010, ecl. 03/05/2010, Manuel Rios, collector, 10-SRNP-70573, USNMENT01437262; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 01/07/2014, ecl. 02/17/2014, Ricardo Calero, collector, 14-SRNP-70035, USNMENT01438824; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Niphidiumoblanceolatum: 01/25/2010, ecl. 02/27/2010, Ricardo Calero, collector, 10-SRNP-70488, USNMENT01438848, USNM Dissection 148180; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 02/15/2010, ecl. 03/24/2010, Ricardo Calero, collector, 10-SRNP-70810, USNMENT01370328, USNM Dissection 148050; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 02/15/2010, ecl. 03/20/2010, Dinia Martinez, collector, 10-SRNP-70812, USNMENT01437227.Females: Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Niphidiumoblanceolatum: 01/21/2010, ecl. 03/04/2010, Ricardo Calero, collector, 10-SRNP-70495, USNMENT01437182; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 01/24/2010, ecl. 03/02/2010, Ricardo Calero, collector, 10-SRNP-70470, USNMENT01437196, USNM Dissection 148299; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Polypodiumfraxinifolium: 02/03/2010, ecl. 03/17/2010, Ricardo Calero, collector, 10-SRNP-70609, USNMENT01437192; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 11/07/2010, ecl. 12/22/2010, Ricardo Calero, collector, 10-SRNP-73249, USNMENT01437207; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Polypodiumfraxinifolium: 01/29/2010, ecl. 03/11/2010, Manuel Rios, collector, 10-SRNP-70572, USNMENT01437261; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 02/15/2010, ecl. 03/24/2010, Dinia Martinez, collector, 10-SRNP-70811, USNMENT01437202; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Polypodiumfraxinifolium: 01/27/2010, ecl. 03/03/2010, Dinia Martinez, collector, 10-SRNP-70534, USNMENT01437267 USNM Dissection 148187; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 01/23/2010, ecl. 03/02/2010, Ricardo Calero, collector, 10-SRNP-70436, USNMENT01370329, USNM Dissection 148051; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 03/15/2012, ecl. 04/18/2012, Ricardo Calero, collector, 12-SRNP-70644, USNMENT01370326, USNM Dissection 148106.Lophomyra. Overall, we note the more mottled appearance to the forewing than in L.tacita or L.santista. More specifically, the green orbicular spot outlined in cream and the reniform spot outlined in white form a pair of figure 8\u2019s in L.commixta that meet at their posterior edges to form a deformed U-shaped stigma. These pattern elements are less obvious in L.tacita and L.santista, where the fusion of the reniform and orbicular spots is more complete. The male genitalia of L.commixta are distinct from and less robust than those of its congeners by virtue of the clasper\u2019s being less sharply developed, and the cucullus' appearing simple PageBreakand spatulate; the vesica bears a basal diverticular nipple , average 10.6 mm , 11.5 mm . Forewing patterning appearing less blended than in congeners, largely due to visibility of reniform-subreniform complex (see above) and the visibility of the postmedial line; on undersides, green shading confined primarily to forewing terminal areas; post-medial lines present but faint on undersides. Legs. Scaling, tibial spurs, and rows of tibial spines as for genus.Abdomen. Dorsal scales predominantly tannish, except on terminal segments where visibly green; a medial line of dark scaling ventrally. Males with prominent medio-dorsal tuft of brown spatulate scales on A2; dorsal tufts posterior to A2 composed primarily of hairs concolorous with adjacent abdominal scaling.Male genitalia. Structures less robust than those of larger congeners, including the much-reduced sacculus (1), a barely visible ampulla-like structure within it (4); the spines associated with the editum; the clasper (2), which is small and beak-like; and the cucullus (3), which is spatulate or modestly swollen distally, and not strongly recurved. Vesica with a shallow subbasal diverticular bump and a separate, more conspicuous, basal nipple.Female genitalia. Antrum narrow, not more than twice the width of the ductus; ventral appendicular lobe present at caudal end of ductus bursae.Immature stages. Larvae known from images . Eighteen reared individuals used an average of 24 days between the onset of the prepupal stage and adult eclosion in their ACG rain forest habitat. All ACG specimens were reared from wild-caught caterpillars and none light-trapped despite massive ACG-wide light-trapping, and all have the same DNA COI barcode and BIN (BOLD:AAY4740). No barcodes were available for South American specimens.Wild-caught caterpillars were found feeding on leaves of PageBreakFrench Guiana, Costa Rican rain forest.Chytonidia\u201d commixta with Lophomyra. The reared Costa Rican specimens may well represent a species distinct from L.commixta; they are larger than a small series of topotypic specimens from French Guiana . However, in the absence of evidence to the contrary, we have elected to continue to include them under L.commixta, recognizing that additional data may well separate the two, and that it is not un common for South American specimens to be recognized as taxonomically distinct from their Costa Rican look-alikes : VENEZUELA: Aragua Rancho Grande 1100m 1\u20133 IV 1978 blacklight, cloud forest, J. B. Heppner, USNM Dissection 148083, USNMENT01437226 [\u2642]; VENEZUELA: Ar. Rancho Grande July1\u20137 1967 RW Poole 1100m, USNMENT01370311 [\u2642]; Ibid July 15\u201321, USNM Dissection 148084, USNMENT01370316 [\u2640]. COSTA RICA : \u2642Juan Vinas CR, June, Lophomyratacita Schs, gen & sp nov Xylomyges group USNMENT01370323; Turrialba Costa Rica 10 II 1973 V.O. Becker, col. Becker 33420, Lophomyratacita Schs, 1911, USNM Dissection 148143, USNMENT01370321; Ibid, USNM Dissection 148081, USNMENT01438834.http://janzen.sas.upenn.edu Area de Conservacion Guanacaste, COSTA RICA. Except for those denoted \u201cAlajuela\u201d, all localities are within Guanacaste Province.The following label data precede SRNP identifier codes on all reared and light-trapped specimens examined : Voucher: D.H. Janzen & W. Hallwachs DB: Males (16): Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 11/29/2009, ecl. 01/05/2010, Dinia Martinez, collector, 09-SRNP-73925, USNMENT01370314, USNM Dissection 148052; Sector Pitilla: Quebradona, 10.99102, -85.39539, el. 475m: larva on Microgrammapercussa: 01/10/2010, ecl. 03/02/2010, Ricardo Calero, collector, 10-SRNP-70181, USNMENT01437251, USNM Dissection 148188; Sector Pitilla: Quebradona, 10.99102, -85.39539, el. 475m: larva on Pleopeltispolypodioides: 05/03/2011, ecl. 05/29/2011, Petrona Rios, collector, 11-SRNP-70989, USNMENT01370310; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Niphidiumoblanceolatum: PageBreak11/21/2010, ecl. 12/28/2010, Ricardo Calero, collector, 10-SRNP-73286, USNMENT01370301; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 10/21/2010, ecl., Ricardo Calero, collector, 10-SRNP-73135, USNMENT01438813; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 10/21/2010, ecl. , Ricardo Calero, collector, 10-SRNP-70435, USNMENT01437276, USNM Dissection 148202; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 11/29/2009, ecl. 01/01/2010, Ricardo Calero, collector, 09-SRNP-73965, USNMENT01438858; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Polypodiumfraxinifolium: 02/09/2010, ecl. 03/20/2010, Dinia Martinez, collector, 10-SRNP-70707, USNMENT01370287; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Polypodiumfraxinifolium: 01/29/2010, ecl. 03/11/2010, Manuel Rios, collector, 10-SRNP-70571, USNMENT01437222; Sector Pitilla: Calma, 11.00987, -85.39214, el. 412m: larva on Microgrammapercussa: 01/29/2010, ecl. 03/13/2010, Ricardo Calero, collector, 10-SRNP-70569, USNMENT01437252; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 10/21/2010, ecl. 11/20/2010, Ricardo Calero, collector, 10-SRNP-73128, USNMENT01370305; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 02/01/2010, ecl. 03/10/2010, Ricardo Calero, collector, 10-SRNP-70597, USNMENT01438869; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 02/08/2010, ecl. 03/13/2010, Ricardo Calero, collector, 10-SRNP-70719, USNMENT01438854; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Polypodiumfraxinifolium: 01/26/2010, ecl. 03/02/2010, Ricardo Calero, collector, 10-SRNP-70530, USNMENT01438809; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Polypodiumfraxinifolium: 11/26/2010, ecl. 12/03/2010, Dinia Martinez, collector, 10-SRNP-73310, USNMENT01437265, USNM Dissection 148099; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 10/30/2010, ecl. , Dinia Martinez, collector, 10-SRNP-73207, USNMENT01370315.Females (29): \u2640 Costa Rica. Juan Vinas. 2500 ft. June Wm Loxodestacita Schs, NHMUK01606199; Alajuela: Sector San Cristobal: Finca San Gabriel, 10.87766, -85.39343, el. 645m: larva on Campyloneurumgracile: 03/19/2012, ecl. 04/20/2012, Elda Araya, collector, 12-SRNP-1080, USNMENT01370309; Alajuela: Sector San Cristobal: Estacion San Gerardo, 10.88009, -85.38887, el. 575m: 11/21/2006, F.Quesada&H.Cambronero, collector, 06-SRNP-109388, USNMENT01437195; Alajuela: Sector San Cristobal: Estacion San Gerardo, 10.88009, -85.38887, el. 575m: 05/04/2011, R.Franco&S.Rios, collector, 11-SRNP-103237, USNMENT01437212; Alajuela: Sector Rincon Rain Forest: Jacobo, 10.94076, -85.3177, el. 461m: larva on Microgrammapercussa: 01/11/2011, ecl. 02/09/2011, Edwin Apu, collector, 11-SRNP-69085, USNMENT01437180; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 01/19/2010, ecl. 02/23/2010, Dinia Martinez, collector, 10-SRNP-70396, USNMENT01437191, USNM Dissection PageBreakPageBreakPageBreakPageBreakPageBreak148181; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Polypodiumfraxinifolium: 02/02/2010, ecl. 03/04/2010, Ricardo Calero, collector, 10-SRNP-70590, USNMENT01370320, USNM Dissection148189; Sector Pitilla: Coneja, 11.01525, -85.39766, el. 415m: larva on Microgrammapercussa: 06/24/2010, ecl. 07/29/2010, Ricardo Calero, collector, 10-SRNP-71914, USNMENT01370306; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Polypodiumfraxinifolium: 02/09/2010, ecl. 03/17/2010, Dinia Martinez, collector, 10-SRNP-70706, USNMENT01370302; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 10/30/2010, ecl. , Dinia Martinez, collector, 10-SRNP-73205, USNMENT01437237; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 08/17/2010, ecl. 09/24/2010, Ricardo Calero, collector, 10-SRNP-72638, USNMENT01370313, USNM Dissection 148145; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 03/26/2011, ecl. 04/26/2011, Dinia Martinez, collector, 10-SRNP-70741, USNMENT01437210, USNM Dissection 148144; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Niphidiumoblanceolatum: 10/21/2010, ecl. 11/30/2010, Ricardo Calero, collector, 10-SRNP-73136, USNMENT01437215; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 01/23/2010, ecl. 03/06/2010, Ricardo Calero, collector, 10-SRNP-70437, USNMENT01437235; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 11/03/2010, ecl. , Ricardo Calero, collector, 10-SRNP-73225, USNMENT01370322; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 02/26/2010, ecl. 04/01/2010, Ricardo Calero, collector, 10-SRNP-70954, USNMENT01437190; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 01/19/2010, ecl. 02/23/2010, Ricardo Calero, collector, 10-SRNP-70395, USNMENT01437256; Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 01/26/2010, ecl. 03/15/2010, Manuel Rios, collector, 10-SRNP-70493, USNMENT01438828; Sector Cacao: Roca Verde, 10.89354, -85.43603, el. 835m: 08/12/2007, R.Franco&F.Quesada, collector, 07-SRNP-108035, USNMENT01437232; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 11/27/2013, ecl. 01/05/2014, Ricardo Calero, collector, 13-SRNP-71895, USNMENT01370324; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 10/08/2013, ecl. 11/11/2013, Ricardo Calero, collector, 13-SRNP-71692, USNMENT01437185; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 12/04/2010, ecl. 01/17/2011, Ricardo Calero, collector, 10-SRNP-73361, USNMENT01437205; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 11/07/2009, ecl. 12/10/2009, Dinia Martinez, collector, 09-SRNP-73662, USNMENT01437270; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 01/06/2010, ecl. 02/19/2010, Ricardo Calero, collector, 10-SRNP-70072, USNPageBreakMENT01370280; Sector Pitilla: Calma, 11.00987, -85.39214, el. 412m: larva on Niphidiumoblanceolatum: 02/22/2011, ecl. 04/11/2011, Ricardo Calero, collector, 11-SRNP-70494, USNMENT01370312; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Polypodiumfraxinifolium: 01/26/2010, ecl. 03/05/2010, Manuel Rios, collector, 10-SRNP-70496, USNMENT01370308; Sector Pitilla: Amonias, 11.04249, -85.40339, el. 390m: larva on Microgrammapercussa: 08/21/2010, ecl. 09/19/2010, Manuel Rios, collector, 10-SRNP-31891, USNMENT01438853; Sector Pitilla: Coneja, 11.01525, -85.39766, el. 415m: larva on Microgrammapercussa: 01/23/2010, ecl. 03/03/2010, Ricardo Calero, collector, 10-SRNP-70460, USNMENT01437275, USNM Dissection 148053; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 11/27/2013, ecl. 01/05/2014, Ricardo Calero, collector, 13-SRNP-71894, USNMENT01438803, USNM Dissection 148105; Sector Pitilla: Estacion Quica, 10.99697, -85.39666, el. 470m: larva on Microgrammapercussa: 07/02/2010, ecl. 08/07/2010, Ricardo Calero, collector, 10-SRNP-71962, USNMENT01437216.L.commixta as both larva and adult; adult more similar to that of L.santista (below) but can be distinguished by white costal frosting on distal half of forewing, the interruption of the U-shaped stigma by a thin longitudinal white streak which partially encircles a black dot at the base of the reniform, and a variable diffuse gray patch between the dash and a more expansive gray-green patch along the inner margin near the base of the wing. Females lack the appendicular lobe on the ductus bursae, present in both the other species.Readily distinguished from Head. Labial palpus with 2nd segment >2\u00d7 combined length of first and third combined; all segments scaled with a mixture of whitish, black, brown and green. Proboscis with paired lateral rows of ~28 small protuberances at terminus. Eyes smooth. Antennae filiform, dorsally with fine white scales; frons, vertex, and palpi with a mix of white and green scales.Thorax. Thoracic vestiture a mix of green, white, black, and light brown scales. Wings. Forewing length 13.3 mm , average 12.7 mm , 13.2 mm . Forewing patterned with gray, white, black and moss-green scaling, the last predominantly in the subcostal, outer medial, and subterminal areas and along inner margin; basal line confined to a black subcostal spot or a pair of black subcostal spots; the most extensive green scaling forming a uniform green basal patch along the inner margin between CuA2 and the postmedial line; short, black basal dash black along inner edge of M, forming the leading edge of a purplish-gray wedge; an outer medial wedge, predominantly moss green, between CuA1 and M2, the latter of which is also edged in purplish gray, overlaps with the fusion of the reniform and orbicular spots; subterminal line wavy, shadowed by white scaling and punctuated by black dots at the intersections of each vein; orbicular spot elongate, lime green, outlined in gold scaling, converging below the M vein with dumbbell-shaped, moss-green reniform spot, outlined with lime-green scaling, forming a deformed U-shape; white subcostal frosting along distal half of wing; a pale, washed-out patch in the ventro-posterior part of the wing, most conspicuous in PageBreakmales. Hind wing uniformly gray in females, pale basally in males, with discal spot faint but present in both. Underside of forewing terminal area with noticeably green shading; inner margin pale; center of wing gray, paler towards inner margin. Pattern elements on underside less conspicuous in males than females, visible primarily in the terminal area of the forewing and the costal margin of the hind wing, where the discal spot is likewise faint, if present in males, and the postmedial line wavy, brown, outwardly white in costal part and increasingly diffuse towards the inner margin. Legs. Scales primarily a mixture of green and white; tibial spurs and rows of tibial spines as for genus.Abdomen. Tan above; abdominal segments with medio-dorsal tufts of tan spatulate scales, tipped brown on A1 and A2, A2 the most prominent, decreasing in size from A3\u20135; each abdominal segment ringed with an apical ring of elongate, strap-like scales and a basal ring of hairs; medial paired medial tufts of green scales ventrally; terminal tufts elaborate, one pair of lateral tufts arcing medially over uncus, when exposed; recurved, tufted apices of dorsal process of cucullus may direct outwardly when viewed in situ finger-like. Clasper (2) pronouncedly sickle-like and concave. Cucullus (3) especially robust, heavily setose, club-like and recurved apically. Ampulla-like structure (4) embedded within sacculus anterior to a prominent patch of medially directed spines. Vesica with bilobate diverticulum encircling its base.Female genitalia. Appendicular lobe absent from ductus bursae, which is elongate, >\u2153 the length of the corpus bursae; antrum wide and well developed.Immature stages. Larvae known from images . Frons black; antennae orange at base, otherwise black. Dorsum tapers downward from A1 to T3 as in L.commixta. Chalazae black, raised, the dorsal pairs forming robust bisetose spines most prominent on the thoracic and anterior abdominal segments. Integument orange, dorsum spotted black thoracically, thereafter a combination of linear black dashes and black stripes originating dorsally on either side of the orange mid-dorsal line at the caudal end of each segment, giving rise to a striped \u201cherring-bone\u201d pattern and rendering the appearance of bifurcating orange stripes extending forward and down to form a series of slanting alternating black and orange stripes; the orange subspiracular line becoming cantaloupe orange and broader in later instars.ges Figs . OverallMicrogrammapercussa, Niphidiumoblanceolatum, Polypodiumfraxinifolium, Pleopeltispolypodioides, Campyloneurumgracile in ACG rainforest. Thirty-five individuals took an average of 25 days between the observed onset of the prepupal stage and adult PageBreakeclosion, with ranges of 21\u201331 days for males and 19\u201329 days for females. These data are all from their ACG rain forest habitat. Almost all ACG specimens were reared from wild-caught caterpillars and only three light trapped despite massive ACG-wide light trapping, and all have the same DNA COI barcode and BIN (BOLD:AAJ2401). No barcodes were available for other specimens of L.tacita.Larvae found feeding on leaves of Costa Rica, Venezuela.PageBreakPageBreakPageBreakPageBreakTaxon classificationAnimaliaLepidopteraNoctuidaeIheringiasantista Jones, (1915) 1914 Type locality: Brazil.Type material (2\u2642). SYNTYPES: [Brazil] Type, Iheringiasantista type \u2642 Jones, Alto da Serra Santos 800m. 25 Feb. 1913 E.D. Jones, NHMUK01606195; PageBreakAlto da Serra Santos 800m. 9 Mar. 1913, E.D. Jones coll., Brit. Mus. 1919-295., NHMUK01606197. Types at NMHUK.BRAZIL (2\u2642): BRAZIL: Santa Catharina. Blumenau. Neu Bremen. 28 VIII. 1932, Fritz Hoffmann. B.M. 1934-63, NHMUK01606196; Alto de Serra, Sao Paulo February, 1933. (R. Spitz), Rothschild Bequest B.M. 1939-1., NHMUK01606198. FRENCH GUIANA : Juin, Guyane Francse Nouveau Chantier Collection Le Moult, Lophomyratacita Schs [illeg.] 6-2-13, Dognin Collection, USNMENT01438868; St. Jean, Maroni, F. Guiana. Collection Wm Schaus, Lophomyratacita Schs, USNM Dissection 148082, USNMENT01370318.. PageBreakPageBreakL.tacita; ventral hind wing with postmedial line less pronounced than in tacita; male genitalia nearly indistinguishable from those of L.tacita but quite distinct from L.commixta; unlike L.tacita, female genitalia bear the appendicular lobe at caudal end of ductus bursae.Two elongate chocolate brown patches towards base of forewing; apical spot less pronouned than in Head. Antennae filiform, dorsally with fine white scales; eyes naked; scaling on vertex, frons and palpi much like that of L.tacita but greenish scaling faded in available material so direct comparisions difficult except to Costa Rican L.tacita.Thorax. Vestiture similar to that of head. Wings. Forewing length 14.4 mm , average 14.3 mm , 13.9 mm . Underside of forewing variably frosted along costal and outer margins, whitish along inner margin, uniformly pale gray throughout outer part of wing; hind wing underside pale inward, gray-brown and white dusting along costal margin; discal spot faint. Legs. Scaling, tibial spurs, and rows of tibial spines as for genus.Abdomen. Although Jones (1915: 440) describes both the thorax and abdomen as \u201cwithout crests\u201d in the generic description of the monotypic Iheringia, of which L.santista is the type, there are concolorous dorsal tufts on the first 8 abdominal segments of males of this species and L.tacita.Male gentialia. Structures, including vesica, not readily distinguishable from those of L.tacita.Female genitalia. Based on a single French Guiana specimen that diagnoses the genus. What appear to be shingled, dark-gray scales are revealed under high magnification to be palmate clusters of setae.Among the more striking features of Lophomyra represent the phylogenetically narrowest diet breadth of any genus of fern-feeding noctuids thus far documented from ACG. All recorded hosts of Lophomyra are polypodiaceous ferns, which are among the more widespread hosts of known Neotropical pteridivorous noctuoid genera, most of which include species that have been recorded from Polypodiaceae, Dryopteridaceae, or both at ACG. These include the noctuid genera Argyrosticta, Callopistria, Leucosigma, and Phuphena and the erebid genera Dusponera, Mamerthes, Nicetas, Rejectaria, Salia, Scopifera and Tarista. With the exception of Leucosigma, each of these includes species that have been recorded from more than two fern families, and a majority from more than five.The known host plants of PageBreakPageBreak"} +{"text": "Lichen nitidus (LN) is chronic papulosquamous disorder characterized by multiple, 1-2 mm, flesh-colored, shiny, dome-shaped papules. Its incidence is 0.034% in a study of skin diseases in blacks over a 25-years period. Skin lesions classically involves the genitalia, upper extremities, chest and abdomen. Infrequently, the lower extremities, palms, soles, face, nails, and mucous membranes may be affected. Majority of cases are common in children and young adults. Various clinical variants of lichen nitidus are - linear, confluent, vesicular, haemorrhagic, spinous follicular, perforating, generalised, palmar and plantar. We report the observation of a 6-month-old infant who presented translucent papules of the back of the hands whose histological study was in favor of a lichen nitidus."} +{"text": "In Kodaira, Kodama, Kamijo, Kaneko, and Sekijima , an erro"} +{"text": "Geriatrics would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.The editors of https://publons.com) to receive recognition. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make.We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (Geriatrics, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Geriatrics in 2016:Adamis, DimitriosFirmino, HoracioParmelee, Patricia A.Akinwuntan, Abiodun E.Gagnon, SylvainPatel, Kushang V.Ali, Khalid MustafaGardner, Raquel C.Picco, AgneseAntin, Jonathan F.Garrett, Mario D.Putrino, DavidApfeldorf, William JayGauthier, SergeRam\u00edrez-Moreno, Jos\u00e9 Mar\u00edaAtti, Anna RitaGeldmacher, DavidRaval, Amit D.Baeyens, Jean-PierreGeorge, StaceyReidy, PaulBarber, MarkGoldberg, LynetteReliga, DorotaBauer, EvaGrochtdreis, ThomasRike, Per-OlaBellelli, GiuseppeGupta, Vivek K.Roe, Catherine M.Berggren, IngelaGurrera, Ronald J.Root, Martin M.Brouwer, Wiebo H.Haboubi, NadimRoppolo, MattiaBruins Slot, Karsten M. H.Han, Jin H.Ross, Lesley A.Cassavaugh, Nicholas D.Hellstr\u00f6m, IngridSancassiani, FedericaCasutt, GianclaudioHolt, Tim A.Sarabia-Cobo, Carmen Mar\u00edaChan, Mei LengHorvath, Jared CooneySchweizer, Tom A.Chang, DennisHosie, AnnmarieSikes, PatCherniack, E. PaulJongen, Ellen M. M.Stanton, RobertCheung, Karen Siu-LanKales, Helen C.Stavrinos, DespinaChhatbar, PratikKalicinski, MichaelStinchcombe, ArneChhatre, SumedhaKasneci, EnkelejdaStothart, GeorgeChilibeck, PhilKeage, Hannah A. D.Stowe, James D.Collard, Rose M.Killane, IsabelleSurr, ClaireCooper, ClaudiaKupeli, NuriyeTales, AndreaCornish, StephenLai, Shih-WeiTeasdale, NormandDavinelli, SergioLaurin, DanielleThomas, ChristineDe Berardis, DomenicoLeroi, IracemaTse, Mimi Mun YeeDening, Karen HarrisonMartin, SuzanneUnsworth, Carolyn A.Devos, HannesMcGregor, KeithVan Der Voet, GijsbertDezetter, AnneMcPhee, JamieVaucher, PaulDickerson, Anne E.Minetto, Marco AlessandroVellante, MarcelloDombrovski, Alexandre Y.Mohler, JaneWahlin, \u00c5keDonini, Lorenza MariaMontero-Odasso, ManuelWarrington, Kenneth J.Eap, Chin B.Nadkarni, Neelesh K.Wilkie, Richard M.Evans, DavidNogales-Gonz\u00e1lez, CeliaWood, Joanne M.Favrat, BernardPanza, FrancescoThe following reviewed for"} +{"text": "AbstractAprica Goldstein, gen. nov. is described to accommodate Xanthiapatula Druce, 1898. Recent discovery of its larva, which has been recorded eating foliage of species in six families of leptosporangiate ferns, suggest a possible subfamily assignment within the Eriopinae, but this cannot be substantiated based on adult morphology. This species has no obvious close relatives either among the core noctuid pteridivore genera currently recognized in the Eriopinae , nor among genera more recently discovered to be fern-feeders but which remain incertae sedis with respect to subfamily . The recorded foodplant profile is similar to that of another ambiguously placed Nearctic species Fagitanalittera with which it shares no obvious synapomorphies. Xanthiapatula (Noctuidae) from the holotype collected in the Santa Clara Valley, Costa Rica. The species has subsequently been collected in southern Mexico and Central America. Xanthia is otherwise considered a holarctic genus feeding primarily on Salix and Populus . The species patula was placed in in Bagisara by Bagisarinae, a subfamily with larvae associated primarily with Malvaceae, Xanthia by default, remarking \u201cI could not place it to genus, but am sure that the species belongs somewhere in the large assemblage long known as the Amphipyrinae but now probably within the expanded concept of the Hadeninae of recent authors as a tribe within the Hadeninae. The combination Bagisarapatula reappeared only informally among determinations made by Poole in the course of a long-term caterpillar inventory of Area de Conservacion Guanacaste (ACG), northwestern Costa Rica described sta Rica where, iFW) length was measured from the center of the axillary area to the apex of the forewing. Terminology generally follows Pinned specimens were examined with an incandescent light source. Genitalic preparations follow Clarke (1941) in part and The following abbreviations refer to collections from which specimens form the basis of this study:AMNHAmerican Museum of Natural History, NY, USAMNHUKThe Natural History Museum, London, UKUSNMNational Museum of Natural History , Washington, District of Columbia, USAA.patula are consistent with those in Eriopinae, including cephalic striping, oblique lateral striping and false eyespots on the first abdominal segment are not discernible from available images. Two features in the adults consistent with Eriopinae are the expression and configuration of M2 arising from the discal cell in the hind wing derives from the Latin apricus, sunny, open to the light.Aprica may be diagnosed readily both from the appearance of the forewing and by the male and female genitalia. The bisection of the golden-orange FW and similar thoracic coloration from the sunset-reddish HW and similar abdominal coloration is distinctive. Although the male genitalia are unremarkable, the valve simple with a rudimentary, hook-like clasper, the combination of this feature with the absence of abdominal coremata, and the presence of M2 on the HW, differentiates Aprica from other genera with pteridivorous species in which either the clasper is absent and the coremata present ; from genera with the reverse condition , or in which the hindwing M2 is not expressed . In both Apricapatula and Fagitanalittera, the corpus bursae is elongate and the ductus seminalis arises from an appendix bursae located at the posterior end of the corpus, a condition shared by several Eriopinae but usually uninformative at the generic level.Head. Antennae setose, biramous in males, uniramous in females; scaled above, cupreous. Labial palpi upturned, densely scaled. Eyes naked.Thorax. Thoracic vestiture golden orange, concolorous with forewing. Wings. General \u201cbackground\u201d coloration sharply bisected between forewing and hind wing, the former predominantly orange (as the thoracic vestiture) and the latter a reddish russett ; M2 faintly but clearly expressed on hindwing. Legs. One pair mid-tibial spurs, two pair on hind-tibiae; three rows of tibial spines on legs.Abdomen. Coremata absent; without brushes, pockets, or levers.Male genitalia. Uncus heavily setose; dorsal edges of tegumen straight, angled ventrally at roughly 45\u00b0, tegumen widest supra-medially; valvae medially situated, articulating with the vinculum in its dorsal half, setose throughout, of more or less constant width with a minor constriction at the cucullus; corona well developed; baso-costal processes of sacculus robust; clasper medially situated in valve, elongate with a sharply sclerotized apical hook at the cucullus; pleurite fused; juxta shield-shaped; transtilla well developed and paratergal sclerite evident, well fused; sacculus gently rounded.Female genitalia. Papillae anales flanged at postero-basal edge; posterior and anterior apophyses rod-like, not swollen apically, the anterior slightly shorter than the posterior. Antrum well developed; ductus seminalis arising from the appendix bursae, appendix bursae deriving dorsally from the posterior third of the ductus bursae; ductus bursae wide, elongate, tubular, with a 360\u00b0 counter-clockwise torsion immediately posterior to the corpus bursae; corpus bursae, oblong, bearing a single transverse signum.A.patula; see description below.Known from images of Mexico and Central AmericaTaxon classificationAnimaliaLepidopteraNoctuidaecomb. nov.7d2965bd-d088-5235-a7ce-d163d87fea56Xanthiapatula Druce, 1898 in Bagisarapatula : Poole, 1989: 154.Costa Rica, Santa Clara Valley [BMNH].COSTA RICA : The following label data precede individual unique voucher codes of the format yy-SRNP-xxxxxx on all reared and light-trapped specimens from ACG : Voucher: D.H. Janzen & W. Hallwachs DB: http://janzen.sas.upenn.edu Area de Conservacion Guanacaste, COSTA RICA.38\u2642, 16\u2640 All records of \u201con\u201d a given plant species refer definitively to \u201cfeeding on.\u201d Specimens lacking food plant records were light trapped in the forest and have a 6-digit suffix in their SRNP codes, while reared specimens have a 1\u20135-digit suffix.Alajuela Province: Area de Conservacion Guanacaste : Males: Sector Rincon Rain Forest: Estacion Caribe (melina), 10.8956, -85.29558, el. 391m: 11/09/2007, F. Quesada & R. Franco, collector, 07-SRNP-110152, USNMENT01463558; Sector Rincon Rain Forest: Estacion Caribe (melina), 10.8956, -85.29558, el. 391m: 11/10/2007, F. Quesada & R. Franco, collector, 07-SRNP-110402, USNMENT01463615; Sector Rincon Rain Forest: Jabalina, Manta Pizote, 10.97325, -85.31542, el. 288m: 09/30/2008, S. Rios & H. Cambronero, collector, 08-SRNP-107404, USNMENT01463664; Sector Rincon Rain Forest: Jacobo, 10.94076, -85.3177, el. 461m: larva on Salpichlaenavolubilis: 06/16/2014, ecl. 07/19/2014, Edwin Apu, collector, 14-SRNP-80751, USNMENT01463658; Sector Rincon Rain Forest: Manta Hugo, 10.8811, -85.2677, el. 491m: 03/14/2009, H. Cambronero & R. Franco, collector, 10-SRNP-107506, USNMENT01463699; Sector Rincon Rain Forest: Protrero Chaves, 10.93868, -85.32167, el. 433m: 8/19/2009, F. Quesada & H. Cambronero, collector, 09-SRNP-107666, Dissection 148312, USNMENT01441902; Quebrada Bambu, 10.9301, -85.25205, el. 109m: larva on Lomariopsisvestita: 09/18/2012, ecl. 10/13/2012, Cirilo Uma\u00f1a, collector, 12-SRNP-76932, USNMENT01463565; Sector San Cristobal: Estacion San Gerardo, 10.88009, -85.38887, el. 575m: 04/29/2006, H. Cambronero & S. Rios, collector, 06-SRNP-103767, USNMENT01463650; Sendero Carmona, 10.87621, -85.38632, el. 670m: larva on Thelypterisnicaraguensis: 05/16/2005, ecl. 06/07/2005, Gloria Sihezar, collector, 05-SRNP-2726, USNMENT01463665. Females: Sector Rincon Rain Forest: Sendero Rincon, 10.8962, -85.27769, el. 430m: larva on Salpichlaenavolubilis: 03/23/2011, ecl. 04/23/2011, Jose Perez, collector, 11-SRNP-41357, USNMENT01463594; Sector Rincon Rain Forest: San Lucas, 10.91847, -85.30338, el. 320m: larva on Thelypterisnicaraguensis: 6/8/2011, ecl. 6/27/2011, Jorge Hernandez, collector, 11-SRNP-42773, Dissection 148174, USNMENT01463999; Quebrada Escondida, 10.89928, -85.27486, el. 420m: larva on Thelypterisnicaraguensis: 11/16/2010, ecl. 12/16/2010, Anabelle Cordoba, collector, 10-SRNP-44267, USNMENT01463798; Sector San Cristobal: Estacion San Gerardo, 10.88009, -85.38887, el. 575m: 04/30/2006, S. Rios & F. Quesada, collector, 06-SRNP-103899, USNMENT01463696. Guanacaste Province: Area de Conservacion Guanacaste : Males: Sector Cacao: Cuesta Caimito, 10.8908, -85.47192, el. 640m: larva on Pterisplumula: 11/13/2007, ecl. 12/07/2007, Manuel Pereira, collector, 07-SRNP-47084, USNMENT01463600; Sector Cacao: Estacion Gongora, 10.88449, -85.47306, el. 557m: 09/12/2007, R. Franco & S. Rios, collector, 07-SRNP-111179, USNMENT01463585; Sector Cacao: Estacion Gongora, 10.88449, -85.47306, el. 557m: 09/12/2007, R. Franco & S. Rios, collector, 07-SRNP-111178, USNMENT01463617; Sector Cacao: Gongora Bananal, 10.88919, -85.47609, el. 600m: larva on Pterisplumula: 10/25/2005, ecl. 11/19/2005, Manuel Pereira, collector, 05-SRNP-48763, USNMENT01463599; Sector Cacao: Quebrada Otilio, 10.88996, -85.47966, el. 550m: larva on Pterisplumula: 09/17/2007, ecl. 10/11/2007, Manuel Pereira, collector, 07-SRNP-46183, USNMENT01463543; Sector Cacao: Quebrada Otilio, 10.88996, -85.47966, el. 550m: larva on Pterisplumula: 09/17/2007, ecl. 10/08/2007, Manuel Pereira, collector, 07-SRNP-46186, USNMENT01463693; Sector Cacao: Quebrada Otilio, 10.88996, -85.47966, el. 550m: larva on Pterisplumula: 09/17/2007, ecl. 10/07/2007, Dunia Garcia, collector, 07-SRNP-46181; Sector Cacao: Toma de Agua, 10.92956, -85.46512, el. 1160m: 08/09/2010, S. Rios & R. Franco, collector, 10-SRNP-112086, USNMENT01463590; Sector Pailas: Canopy Tours, 10.81262, -85.40248, el. 700m: 9/30/2016, H.Cambronero&R.Franco, collector, 16-SRNP-106142, USNMENT01464165; Sector Pailas: Canopy Tours, 10.81262, -85.40248, el. 700m: 06/11/2008, H. Cambronero & F. Quesada, collector, 08-SRNP-103411, USNMENT01463691; Sector Pitilla: Colocho, 11.0256, -85.41224, el. 390m: 03/19/2007, H. Cambronero & F. Quesada, collector, 07-SRNP-102458, USNMENT01463603; Sector Pitilla: Estacion Pitilla, 10.98931, -85.42581, el. 675m: 03/01/2006, S. Rios & R. Franco, collector, 06-SRNP-102362, USNMENT01463573; Sector Pitilla: Estacion Pitilla, 10.98931, -85.42581, el. 675m: 03/02/2006, R. Franco & F. Quesada, collector, 06-SRNP-102550, Dissection 148362, USNMENT01463556; Sector Pitilla: Estacion Quica, 10.99679, -85.39695, el. 487m: 08/29/2008, S. Rios & R. Franco, collector, 08-SRNP-105409, USNMENT01463651; Sector Pitilla: Estacion Quica, 10.99679, -85.39695, el. 487m: 08/29/2008, S. Rios & R. Franco, collector, 08-SRNP-105410, USNMENT01463621. Females: Sector Cacao: Quebrada Otilio, 10.88996, -85.47966, el. 550m: larva on Pterisplumula: 09/17/2007, ecl. 10/08/2007, Manuel Pereira, collector, 07-SRNP-46187, USNMENT01463536; Sector Cacao: Quebrada Otilio, 10.88996, -85.47966, el. 550m: larva on Pterisplumula: 9/17/2007, ecl. 10/8/2007, Manuel Pereira, collector, 07-SRNP-46182, USNMENT01463895; Sector Cacao: Quebrada Otilio, 10.88996, -85.47966, el. 550m: larva on Pterisplumula: 09/17/2007, ecl. 10/11/2007, Manuel Pereira, collector, 07-SRNP-46185; Sector Cacao: Quebrada Otilio, 10.88996, -85.47966, el. 550m: larva on Pterisplumula: 9/17/2007, ecl. 10/12/2007, Dunia Garcia, collector, 07-SRNP-46180, Dissection 148173, USNMENT01463897; Sector Cacao: Roca Verde, 10.89354, -85.43603, el. 835m: 08/12/2007, R. Franco & F. Quesada, collector, 07-SRNP-108036, USNMENT01463587; Sector Pitilla: Estacion Pitilla, 10.98931, -85.42581, el. 675m: 02/28/2006, S. Rios & H. Cambronero, collector, 06-SRNP-101627, USNMENT01463623; Sector Pitilla: Pasmompa, 11.02666, -85.41026, el. 400m: 07/31/2008, R. Franco & S. Rios, collector, 08-SRNP-104889, USNMENT01463671. Other : Males: COSTA RICA: Juan Vinas, Schaus & Barnes, coll., USNMENT01463893; COSTA RICA: Cartago, Orosi Estacion Tapanti Parque, 9 456\u2019 N, -83 471\u2019 W, 4062\u201d, July 7\u20139 2008, 1275m, J. Bolling Sullivan, collector, Dissection 148364, USNMENT01463654; same data, USNMENT01463683; same data, USNMENT01463630; COSTA RICA: Cartago, Orosi Estacion, Tapanti Parque, LN-559900-194000, 1275 m, February 12\u201317, 2005, J. Bolling Sullivan, collector, USNMENT01463894; COSTA RICA: Cartago, Orosi Estaction, Tapani Parque, LN-559900-194000, 1275 m, February 12\u201317, 2005, J. Bolling Sullivan, collector, Dissection 148371, USNMENT01463577; same data, USNMENT01463681; COSTA RICA: Tuis, May 28\u2013June 4, Schaus and Barnes, collectors, Collection WmSchaus, USNMENT01463564; COSTA RICA: Tuis, June, Schaus and Barnes, collectors, USNMENT01463648; COSTA RICA: San Jose 4000ft, Nov 06, Collection WmSchaus, USNMENT01463535. Females: COSTA RICA: Cartago, Orosi Estaction, Tapani Parque, LN-559900-194000, 1275 m, February 12\u201317, 2005, J. Bolling Sullivan, collector, USNMENT01463571; same data, USNMENT01463641; same data, USNMENT01463568; COSTA RICA: Carillo, Schaus and Barnes, collectors, USNMENT01463572. GUATEMALA : Males: GUATEMALA: Cayuga, May, Schaus and Barnes, collectors, USNMENT01463555; GUATEMALA: Cayuga, Sept, Schaus and Barnes, collectors, Dognin Collection, USNMENT01463529; GUATEMALA: Cayuga, Schaus and Barnes, collectors, Aug., Photo Noc.22, USNMENT01463672. Female: GUATEMALA: Retalhuleu, from L Thiel, S Sebastian, USNMENT01463544. MEXICO (1\u2642): Zacualpan [Veracruz] T21, USNM slide # 59037, USNMENT01463653.supra vide as distinct from Eriopinae and other pteridivorous Noctuidae.The apposition of the forewing and hind wing colors differentiates this species from several unrelated New World species that share superficially similar orange forewing coloration. None of these has a deep reddish hind wing or the laterally bisected contrast in body coloration between thorax and abdomen. The combination of the expressed M2 on the hind wing, the absence of abdominal coremata, and the configuration of the male and female genitalia are summarized in the generic diagnosis Head. Eyes smooth; labial palpi upturned, apex level with antennal base; antennae setose, bifasciculate in males; frons and vertex mix of golden yellow and reddish-orange scales concolorous with those of forewings and thorax.Thorax. Prothoracic vestiture as described for genus. Wings. Forewing length, males, 12.1 mm\u201315.0 mm ; females, 12.1 mm\u201316.1 mm . FW not broadly rounded, outer margin convex; FW scaling golden yellow, suffused with reddish-orange scales, some lilacine at costa; postmedial area less heavily suffused with reddish-orange than antemedial or subterminal areas; antemedial, medial, and postmedial lines distinct and unbroken, the medial line ~2\u00d7 as thick as others; baso-posterior russet patch; reniform spot constricted to form two white stigmata, the antero-costal stigma round and smaller than the other, j-shaped stigma; HW near-uniformly russet-orange, yellowish-orange terminal line unbroken. FW underside russet in center, bounded by paler shading along the costal and posterior margin below the anal vein; pm line jagged, dark gray, fading gradually from costal fascia to the anal vein. HW underside with discal spot present, pm line visible as a series of dark gray spots where it meets the veins; medial lines of both wings diffuse. Legs. As above, for genus. Scales the same mix of golden orange and reddish as on the head and thorax, but more uniformly reddish on the fore-femora.Abdomen. As above, for genus. Vestiture paler than on thorax and concolorous with hind wing.Male genitalia. As above, for genus. Phallus not uniformly sclerotized, weakly so towards the vesica; vesica without cornuti, with a complex of four bubble-like sub-basal diverticula and one larger basal diverticulum; vesica distended baso-medially, recurved clockwise over the phallus before narrowing and everting in a counter-clockwise twist , and both bear false eyespots on the first abdominal segment; the spot is white postero-ventrally, the front half black with a white dot. In the brown form, the head bears a calico pattern, while in the green form the head is more uniformly green; both forms bear a lateral genal stripe. The brown form is predominantly rusty orange, a pair of subdorsal stripes formed by paler orange wedges. Larvae curl their heads under their abdomens when disturbed, emphasizing their false eyespots. This recall\u2019s Pterisplumula Desv. , Pteridiumcaudatum (L.) (Dennstaedtiaceae), Thelypterisnicaraguensis (E. Fourn.) C.V. Morton (Thelypteridaceae), Salpichlaenavolubilis (Kauf.) J. Sm. (Blechnaceae), Lomariopsisvestita E. Fourn. (Lomariopsidaceae), and Nephrolepisbiserrata (Sw.) Schott (Davailleaceae). Recorded hymeopteran parasitoids at ACG include Enicospilusmaculipennis (Ichneumonidae: Ophioninae) and at least one undescribed ichneumonid . The degree to which fern-feeding is more generally conserved phylogenetically has yet to be rigorously tested but see Lithinini (Geometridae). Within the Noctuidaesensu stricto, a precise determination of the number of fern-feeding origins is only now feasible, and enough phylogenetic information exists at least to imply its existence, if not its independent origin, outside the Eriopinae proper. Because of the uncertain placement of several noctuid genera, including Leucosigma , most of the larval characters discussed by Eriopinae are not observed in Apricapatula. Although fern-feeding is phylogenetically localized enough to have flagged this species for examination initially and cast further doubt on its placement in Bagisarinae or Xylenini, it should be noted that Bagisara without the benefit of any life history information, and we detect insufficient evidence among the available data to place it with Eriopinae.In addition to the exercise of circumscribing such genera as well as the Aprica with Fagitana, but these data are not adequate to corroborate their kinship in the absence of other characters, particularly among the larvae. It warrants mention in part because, like Aprica, the phylogenetic placement of Fagitana is uncertain; it is a ditypic genus comprising the well-characterized North American species littera associated with ferns in at least three of the same families as hosts of Aprica and a rather dissimilar Asian species gigantea with an unknown life history. While Aprica and Fagitana share the unusual larval fern-feeding behavior with known Eriopinae, this is insufficient to unite them given the absence of published diagnostic eriopine genitalic features. Although we find it less than ideal to have created a monotypic genus, Aprica, these discrepancies combined with the absence of larval characters and more extensive phylogenetic data render its placement elsewhere difficult to support, and its higher placement at best ambiguous.Provisional DNA barcode analyses suggest a possible kinship of"} +{"text": "Scientific Reports 10.1038/s41598-018-24425-9, published online 18 April 2018Correction to: The original version of this Article contained errors.Affiliations 1, 2, 3, 4 and 5 were incorrectly listed as \u2018Experimental Laboratories of the Department of Dermatology and Allergic Diseases, University of Ulm, Life Science Building N27, James-Frank-Ring, 89081, Ulm, Germany\u2019, \u2018Institute of Experimental Cancer Research, University of Ulm, N27 Life Science Building, James Frank-Ring, 89081, Ulm, Germany\u2019, \u2018Institute for Clinical and Experimental Trauma Immunology (ITI), Ulm University, Helmholtzstra\u00dfe 8/1, 89081, Ulm, Germany\u2019, \u2018Department of Orthopaedic Trauma-, Hand-, Plastic, and Reconstruction Surgery, Ulm University, Albert-Einstein-Allee 23, 89081, Ulm, Germany\u2019 and \u2018Department of Dermatology and Allergic Diseases, Ulm University, Albert-Einstein Allee 23, 89081, Ulm, Germany\u2019 respectively. The correct affiliations are listed below.Affiliation 1:Experimental Laboratories of the Department of Dermatology and Allergic Diseases, Ulm University, Life Science Building N27, James-Franck-Ring, 89081 Ulm, GermanyAffiliation 2:Institute of Experimental Cancer Research, Ulm University, Life Science Building - N27, James-Franck-Ring, 89081 Ulm, GermanyAffiliation 3:Department of Dermatology and Allergic Diseases, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, GermanyAffiliation 4:Institute for Clinical and Experimental Trauma Immunology (ITI), Ulm University, Helmholtzstra\u00dfe 8/2, 89081 Ulm, GermanyAffiliation 5:Department of Orthopaedic Trauma-, Hand-, Plastic, and Reconstruction Surgery, Ulm University, Albert-Einstein-Allee 23, 89081 Ulm, GermanyAdditionally, Benedikt Herold, who had been included as an author on the original version of the Article, did not contribute sufficiently to be listed as an author. He has therefore been removed from the author list.Finally, in the original version of this Article Abhijit Basu and Saira Munir were omitted as equally contributing authors. The author contribution section now reads:\u201cA.B. and S.M. contributed equally to the study design, conducted the experiments, analyzed the results and wrote parts of the manuscript. M.A.M. supported this manuscript by his biometric expertise. K.S. contributed to the study design and performed qRT-PCR experiments. D.C., A.S., N.T., M. H.-L., F.G., and M.W. contributed to the discussion, design and the interpretation of the data in the context of trauma and wound healing. K.S.-K. designed the experiments and wrote the manuscript.\u201dThese errors have now been corrected in the PDF and HTML versions of the paper, and in the accompanying Supplementary Figures file."} +{"text": "Correction to: BMC Biologyhttps://doi.org/10.1186/s12915-018-0605-5Ocean EcoSystems Biology Unit, RD3 GEOMAR Helmholtz Centre for Ocean Research Kiel, Kiel, Germany.Monterey Bay Aquarium Research Institute, 7700 Sandholdt Rd., Moss Landing, CA 95039, USA.Upon publication of the original article , it was"} +{"text": "Positive self-perception of aging has been linked to better physical and psychosocial health outcomes among older adults. Negative self-perception of aging has been associated with poorer health consequences including depression, limited mobility, and mortality. Despite significant findings, the comprehensiveness and quality of self-perception of aging research still warrants further investigation, especially when identifying factors for intervention. Using a large random stratified sample of AARP Medicare Supplement insured members, age\u226565 years, with continuous coverage for \u226512 months, self-perception of aging and various socio-demographic, medical, and psychosocial characteristics were examined using Chi-square and multivariate logistic regression models. Self-perception of aging was measured using the five-item Attitudes Towards Own Aging subscale. Characteristics of interest included age, gender, health status, resilience, purpose, optimism, social network, physical activity, depression, falls, vision, hearing, oral health, and sleep quality. Propensity weighting was used to adjust for potential survey non-response bias. Of weighted survey respondents , 59% exhibited a positive self-perception, while 41% exhibited a negative self-perception. Respondents with a positive self-perception were more likely to be healthier, younger (<75 years), more active (\u22653days), less depressed, have more diverse social networks, higher resilience, and purpose. Negative self-perception was associated with poorer health, older age, depression, and poorer vision, hearing, oral health, and sleep quality. The strongest characteristics associated with positive self-perception were purpose, resilience, physical activity, and social networks. Depression and sleep quality were the strongest characteristics associated with negative self-perception. Interventions targeting these characteristics could be beneficial in promoting positive self-perception of aging and health over time."} +{"text": "Gels would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.The editors of https://publons.com) to receive recognition. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make.We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (Gels, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Gels in 2016:The following reviewed for Abul-Haija, Yousef M.He, WeidongOkada, TomohikoAhadian, SamadHerrera, Raquel P.Pan, LijiaAhearne, MarkIkeda, MasatoParadiso, Vito MicheleAlvarez-Ramirez, JoseJain, GauravRusso, LauraAndrianov, Alexander K.Jajam, KailashSamitier, JosepAppelhans, DietmarJana, SadhanShen, JanaBernards, MattJohn, VijayTabata, MakotoBoluk, YamanJung, Jong HwaTomasini, ClaudiaCallahan, Laura SmithKazakov, SergeyTonelli, Alan E.Carmen S\u00e1nchez, Mar\u00eda DelKharkar, PrathameshTorres, Mar\u00eda D.Corrias, AnnaKiryukhin, Maxim V.Truong, VinhDa Silva, MarceloLenfant, GillesVert, MichelDijkstra, PietLupi, Francesca RomanaVogel, NicolasDostalek, JakubMarchesan, SilviaWang, Hui-LiangDouglas, Jack F.Merino, SoniaWang, LiangDr\u00e4ger, GeraldMeyer, FranckWeon, Byung MookFontaine, MagaliMignon, ArnW\u00f6ll, DominikWinkler, Roland G.Miyatake, TomohiroGohy, Jean-FrancoisNonappa, Nonappa"} +{"text": "Socioeconomic status (SES) is associated with stroke incidence and mortality. Distribution of stroke risk factors is changing worldwide; evidence on these trends is crucial to the allocation of resources for prevention strategies to tackle major modifiable risk factors with the highest impact on stroke burden.We extracted data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. We analysed trends in global and SES-specific age-standardised stroke incidence, prevalence, mortality, and disability-adjusted life years (DALYs) lost from 1990 to 2017. We also estimated the age-standardised attributable risk of stroke mortality associated with common risk factors in low-, low-middle-, upper-middle-, and high-income countries. Further, we explored the effect of age and sex on associations of risk factors with stroke mortality from 1990 to 2017.Despite a growth in crude number of stroke events from 1990 to 2017, there has been an 11.3% decrease in age-standardised stroke incidence rate worldwide . This has been accompanied by an overall 3.1% increase in age-standardised stroke prevalence rate and a 33.4% decrease in age-standardised stroke mortality rate over the same time period. The rising trends in age-standardised stroke prevalence have been observed only in middle-income countries, despite declining trends in age-standardised stroke incidence and mortality in all income categories since 2005. Further, there has been almost a 34% reduction in stroke death rate attributable to modifiable risk factors, more prominently in wealthier countries.Almost half of stroke-related deaths are attributable to poor management of modifiable risk factors, and thus potentially preventable. We should appreciate societal barriers in lower-SES groups to design tailored preventive strategies. Despite improvements in general health knowledge, access to healthcare, and preventative strategies, SES is still strongly associated with modifiable risk factors and stroke burden; thus, screening of people from low SES at higher stroke risk is crucial.The online version of this article (10.1186/s12916-019-1397-3) contains supplementary material, which is available to authorized users. Among 240 causes of death, stroke is globally the second cause of death after ischaemic heart disease , and it Distribution of stroke risk factors in the context of socioeconomic status is changing worldwide 2017, coordinated by the Institute for Health Metrics and Evaluation, as of 19 May 2019 . We repoSES was defined based on the gross national per capita income, as classified by the World Bank , and theThirty-one LICs include Afghanistan, Benin, Burkina Faso, Burundi, Central African Republic, Chad, Comoros, Democratic Republic of the Congo, Eritrea, Ethiopia, Guinea, Guinea-Bissau, Haiti, Liberia, Madagascar, Malawi, Mali, Mozambique, Nepal, Niger, North Korea, Rwanda, Senegal, Sierra Leone, Somalia, South Sudan, Tanzania, The Gambia, Togo, Uganda, and Zimbabwe; 52 LMICs include Angola, Armenia, Bangladesh, Bhutan, Bolivia, Cambodia, Cameroon, Cape Verde, Congo, C\u00f4te d\u2019Ivoire, Djibouti, Egypt, El Salvador, Federated States of Micronesia, Georgia, Ghana, Guatemala, Honduras, India, Indonesia, Jordan, Kenya, Kiribati, Kyrgyzstan, Laos, Lesotho, Mauritania, Moldova, Mongolia, Morocco, Myanmar, Nicaragua, Nigeria, Pakistan, Palestine, Papua New Guinea, Philippines, Sao Tome and Principe, Solomon Islands, Sri Lanka, Sudan, Swaziland, Syria, Tajikistan, Timor-Leste, Tunisia, Ukraine, Uzbekistan, Vanuatu, Vietnam, Yemen, and Zambia; 54 UMICs include Albania, Algeria, American Samoa, Argentina, Azerbaijan, Belarus, Belize, Bosnia and Herzegovina, Botswana, Brazil, Bulgaria, China, Colombia, Costa Rica, Croatia, Cuba, Dominica, Dominican Republic, Ecuador, Equatorial Guinea, Fiji, Gabon, Grenada, Guyana, Iran, Iraq, Jamaica, Kazakhstan, Lebanon, Libya, Macedonia, Malaysia, Maldives, Marshall Islands, Mauritius, Mexico, Montenegro, Namibia, Panama, Paraguay, Peru, Romania, Russian Federation, Saint Lucia, Saint Vincent and the, Grenadines, Samoa, Serbia, South Africa, Suriname, Thailand, Tonga, Turkey, Turkmenistan, and Venezuela; and 58 HICs include Andorra, Antigua and Barbuda, Australia, Austria, Bahrain, Barbados, Belgium, Bermuda, Brunei, Canada, Chile, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Greenland, Guam, Hungary, Iceland, Ireland, Israel, Italy, Japan, Kuwait, Latvia, Lithuania, Luxembourg, Malta, Netherlands, New Zealand, Northern Mariana Islands, Norway, Oman, Poland, Portugal, Puerto Rico, Qatar, Saudi Arabia, Seychelles, Singapore, Slovakia, Slovenia, South Korea, Spain, Sweden, Switzerland, Taiwan, The Bahamas, Trinidad and Tobago, United Arab Emirates, the UK, Uruguay, Virgin Islands, and the USA.Based on the GBD 2017 , the gloIn contrast, stroke prevalence has increased over time from 1990 to 2017, likely because of longer survival and reduced mortality of people experiencing a stroke. In 2017, the crude number of people with a stroke was 104.2 million (UI 98.5\u2013110.1), which has almost doubled, particularly for ischaemic stroke, compared to the number in 1990 , and this rank has remained relatively constant in different regions since 1990 Table .In 2017, stroke has imposed 132.1 (126.5 to 137.4) million DALYs lost globally (34% more than in 1990), 42% of which was related to ischaemic strokes, in particular, 6.8 million DALYs in LICs, 47.1 million DALYs in LMICs, 63.1 million DALYs in UMICs, and 14.2 million DALYs in HICs ; a 1.6-fold difference in stroke prevalent cases ; a 3.4-fold difference in stroke-related deaths ; and a 3.3-fold difference in stroke DALYs .In 2017, 5.2 million stroke-related deaths and 116.3 million stroke-related DALYs lost worldwide were attributable to modifiable risk factors, less than half of which were observed for ischaemic strokes are globally the second leading cause of stroke mortality, irrespective of income levels or SDI Table . HoweverIn addition, dietary risks can worsen the consequences of stroke. In particular, diets low in fruits, low in whole grains, low in vegetables, high in sodium, and high in sugar-sweetened beverages increase the likelihood of global stroke mortality Fig. . WorldwiDiabetes and glucose intolerance-related mortality is globally the third critical risk factor of stroke mortality in 2017 Table . HoweverObesity is globally the fourth most influential indicator of stroke mortality, which varies slightly between different SES Table . AlthougTobacco smoking became the fifth leading predictor of stroke in 2017 Table . From 19Air pollution is globally the sixth leading cause of stroke death with no change in its rank from 1990 to 2017 Table . Its attIn 2017, ambient particulate matter pollution and household air pollution from solid fuels were globally responsible for 10.5 and 5.9 million stroke-related DALYs lost and 444.9 and 231.8 thousand stroke-related deaths, respectively Table . Based oThe global rank of stroke mortality related to alcohol drinking rose from the eighth rank in 1990 to the seventh in 2017 Table . AlthougHypercholesterolemia, particularly high LDL-C, became globally the eighth most important indicator of stroke mortality in 2017 Table . From 19Low physical activity has globally remained the ninth modifiable indicator of stroke mortality since 1990, which is almost constant through the varying SES regions Table . SES canAgeing is regarded as the most important predictor of stroke incidence and mortality, and thus, their rates increase by age Fig. . Older iRisk of stroke and the risk factors differ between men and women, with almost no change in their attributed risk of stroke mortality from 1990 to 2017, particularly for tobacco use, alcohol use, obesity, and air pollution Table .Table 7The results of the current study add to the body of evidence on existing disparities, gaps, and hurdles in stroke research, practice, and educational endeavours in different socioeconomic classes, countries, and regions. It appears that the age-standardised rate of stroke incidence and mortality is decreasing in all regions of varying SES (based on income-level or SDI), although more rapidly in wealthier societies. This influence is largely driven through commonly known modifiable stroke risk factors. In 2017, high systolic blood pressure and dietary risks were the top leading causes of stroke-related deaths and worldwide burden. Among the 11 modifiable risk factors, alcohol had five times higher association with haemorrhagic strokes than ischaemic strokes. Further, the rates of stroke mortality and burden were significantly higher in lower SES regions compared with HICs. Likewise, the age-standardised stroke mortality attributable to potentially modifiable risk factors is declining in almost all regions, except for obesity and alcohol use. LICs hold the worst attributable risk of stroke mortality for hypertension, dietary habits, diabetes, and air pollution, and UMICs hold the worst attributable risk of stroke mortality for obesity, tobacco use, alcohol use, hypercholesterolemia, and low physical activity. Still, HICs have almost threefold lower rates of stroke mortality attributable to modifiable risk factors compared to all other income categories.According to the last report of the global, regional, and national burden of neurological disorders, there has been a significant reduction in the age-standardised prevalence of stroke (10% decrease) and death (30% decrease) from 1990 to 2015 [Based on the results of a meta-analysis of 12 population-based cohorts and case-control studies mainly in HICs, despite some limitations, reduced SES could explain more than 30% of the stroke risk irrespective of classical vascular risk factors . Based oThe disparity between stroke outcomes in LMICs and HICs can be partly explained by a combination of varying levels of general health awareness, access to healthcare, and preventative strategies starting from childhood , 25. StrAccording to the GBD 2015 , there aAlmost half of stroke-related mortality may be attributable to modifiable risk factors , which are mostly the outcome of poor clinical management, limited access to health care, and late detection of underlying risk factors. This necessitates allocation of resources to those modifiable risk factors with the highest impact on stroke in each SES-region. Moreover, social and economic policies to reduce inequalities in stroke care should become a health priority, particularly in less wealthy countries. These policies should focus on treating early predisposing factors and on educational programmes from childhood, which have long-lasting impacts on adulthood health. Likewise, improving worldwide primary healthcare services may have an important impact on post-stroke outcomes. It is essential to improve stroke awareness among socioeconomically deprived individuals and societies and provide equitable post-stroke medical care.Additional file 1:Text S1. Definition of Socioeconomic status; Data gathering and search strategy; Study selection, data extraction, and analysis; Supplements to sections on various risk factors. (DOCX 40\u2009kb)Additional file 2:Table S1. Absolute numbers and rates of stroke mortality and burden attributable to modifiable risk factors. (XLSX 534\u2009kb)Additional file 3:Table S2. Sex differences in stroke-related deaths and burden attributable to modifiable risk factors. (XLSX 501\u2009kb)Additional file 4:Table S3. Age-standardised rates of stroke mortality and burden attributable to behavioural, environmental, and metabolic risks. (XLSX 501\u2009kb)Additional file 5:Table S4. Socioeconomic Status and Stroke Outcome in Low- and Middle-Income Countries. (DOCX 132 kb)"} +{"text": "The first, second, third, fifth, and sixth authors\u2019 names appear incorrectly. The correct author byline is: N Kannan, S Shanmuga Sundar, S Balaji, Arul Amuthan, NV Anil Kumar, N Balasubramanian.https://doi.org/10.1371/journal.pone.0195800The correct citation is: Kannan N, Shanmuga Sundar S, Balaji S, Amuthan A, Anil Kumar NV, Balasubramanian N (2018) Physiochemical characterization and cytotoxicity evaluation of mercury-based formulation for the development of anticancer therapeuticals. PLoS ONE 13(4): e0195800."} +{"text": "The original article has been corrected.The article Reducing chemotherapy use in clinically high-risk, genomically low-risk pN0 and pN1 early breast cancer patients: five-year data from the prospective, randomised phase 3 West German Study Group (WSG) PlanB trial, written by Ulrike Nitz, Oleg Gluz, Matthias Christgen, Ronald E. Kates, Michael Clemens, Wolfram Malter, Benno Nuding, Bahriye Aktas, Sherko Kuemmel, Toralf Reimer, Andrea Stefek, Fatemeh Lorenz-Salehi, Petra Krabisch, Marianne Just, Doris Augustin, Cornelia Liedtke, Calvin Chao, Steven Shak, Rachel Wuerstlein, Hans H. Kreipe, Nadia Harbeck, was originally published electronically on the publisher\u2019s internet portal (currently SpringerLink) on June 29, 2017 without open access.With the author(s)\u2019 decision to opt for Open Choice the copyright of the article changed on January 6, 2019 to \u00a9 The Author(s) 2017 and the article is forthwith distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ("} +{"text": "VOLUME 107107(3) July, page i, page 403, and page 410http://dx.doi.org/10.5195/jmla.2019.563.Haley J, Carlson McCall R, Zomorodi M, de Saxe Zerdan L, Beth Moreton B, Richardson L. Interprofessional collaboration between health sciences librarians and health professions faculty to implement a book club discussion for incoming students. J Med Libr Assoc. 2019 Jul;107(3):403\u201310. DOI: Page i, page 403, and 410: Lisa de Saxe Zerden\u2019s name is misspelled in the table of contents, author byline, and authors\u2019 affiliations.The table of contents entry should be:Jen Haley, Rebecca Carlson McCall, Meg Zomorodi, Lisa de Saxe Zerden, Beth Moreton, Lee RichardsonThe author byline should be:Jen Haley, MSN, RN, CNL; Rebecca Carlson McCall, MLS, AHIP; Meg Zomorodi, PhD, RN, CNL; Lisa de Saxe Zerden, PhD, MSW; Beth Moreton, MLS; Lee RichardsonThe author affiliation should be:Lisa de Saxe Zerden, PhD, MSW, lzerden@email.unc.edu, Senior Associate Dean for Master\u2019s in Social Work Education and Clinical Associate Professor, School of Social Work, University of North Carolina at Chapel Hill, Chapel Hill, NC"} +{"text": "The publisher apologizes for the errors.The authors\u2019 given names and surnames are switched. The correct names are: Abdullah Alzahrani, Maged Mohammed, Hairul-Islam M. Ibrahim, Osama I. Alwassil, Maha Habash, Manal Alfuwaires, Hamza Hanieh. The correct citation is: Alzahrani A, Mohammed M, Ibrahim HM, Alwassil OI, Habash M, Alfuwaires M, et al. (2019) Activation of aryl hydrocarbon receptor signaling by a novel agonist ameliorates autoimmune encephalomyelitis. PLoS ONE 14(4): e0215981."} +{"text": "AbstractPhlebotominae 11 species, Psychodinae 6 species) and Azerbaijan (Phlebotominae 18 species) are summarized. The first records of 18 species of Psychodinae from Armenia and 6 new faunistic records for the fauna of Azerbaijan are listed. The checklist of recent moth flies from Armenia includes now 35 species, and from Azerbaijan, 24 species.All credible and available published records for 17 species of moth flies known so far from Armenia ( As mentioned by The location of this area creates favourable conditions for entomological research. However, several families of flies have not been well studied in the Caucasus, and in particular, in Armenia and Azerbaijan , 2017b.Psychodidae) are represented only by 17 species previously recorded in Armenia (mainly Phlebotominae and Psychodinae .Moth flies papatasi ; P. (Paraphlebotomus) alexandri Sinton, 1928; P. (P.) cucasicus Marzinovsky, 1917; P. (P.) jacusieli Theodor, 1947; P. (P.) mongolensis Sinton, 1928; P. (P.) sergenti Parrot, 1917; P. (P.) similis Perfil\u2019ev, 1963; P. (Larroussius) kandelakii Shurenkova, 1929; P. (L.) perfiliewitranscaucasicus Perfiliew, 1937; P. (L.) perniciosus Newstead, 1911; P. (L.) tobbi Adler & Theodor in Adler, Theodor & Lourie, 1930; P. (Adlerius) balcanicus Theodor, 1958; P. (A.) brevis Theodor & Mesghali, 1964; P. (A.) halepensis Theodor, 1958; P. (A.) simici Nitzulescu, 1931, Sergentomyia (S.) dentata Sinton, 1933; S. (Neophlebotomus) pawlowskyi ; and S. (Parrotomyia) palestinensis ].From Azerbaijan, 18 species of The material presented here comes from two different sampling campaigns. The first campaign collected material by sweep-netting vegetation along streams and lakes in Armenia from August 26 to September 4, 2015 by J. Obo\u0148a, P. Manko and \u013d. Hrivniak; it is preserved in 75% ethanol. A list of 28 sampling sites, with coordinates and altitudes, is given in Table Psychodidae, and catalogue number (cat. no.) of the slide to be included in the NMPCDiptera collection and NMPC = collections of the National Museum Prague, HC = hand collecting, SW = sweep netting, LT = light traps.All material, determined by the first author, is deposited in the National Museum, Natural History Museum, Department of Entomology, Prague, Czech Republic. Slides are numbered by inventory slide number of the family llection . NomenclPhlebotomus (Phlebotomus) papatasi 1. Selected published records.Distribution. Afghanistan, Albania, Algeria, Armenia, Azerbaijan, Baleares, Bosnia and Herzegovina, Bulgaria, Crete, Crimea, Croatia, Cyprus, Egypt, Ethiopia, France, Georgia, Greece, Hungary, India, Iran, Iraq, Israel, Italy, Jordan, Kazakhstan (southern), Kuwait, Libya, Macedonia, Malta, Moldova, Montenegro, Morocco, Oman, Pakistan, Portugal, Romania, Sardinia, Saudi Arabia, Serbia, Slovenia, Spain, Sudan, Syria, Tunisia, Turkey, Ukraine (southern), Yemen.Phlebotomus (Paraphlebotomus) alexandri Sinton, 19282. Selected published records.Distribution. Afghanistan, Albania, Algeria, Armenia, Azerbaijan, Bulgaria, China (western), Crimea, Cyprus, Djibouti, Ethiopia, Georgia, Greece, India, Iran, Iraq, Israel, Kazakhstan (southern), Moldova, Mongolia, Morocco, Pakistan, Romania, Saudi Arabia, Spain, Sudan, Tunisia, Turkey, Ukraine, United Arab Emirates, Yemen; northern Sahara, Caucasus (southern), Near and Middle East, Central and Eastern Asia; Afrotropical and Oriental regions.Phlebotomus (Paraphlebotomus) cucasicus Marzinovsky, 19173. Selected published records.grimmi Porchinskyi, 1876); caucasicus); caucasicus); caucasicus); caucasicus).Distribution. Afghanistan, Armenia, Azerbaijan, Bulgaria, China (not verified), Georgia, Greece, Iran, Kazakhstan, Macedonia, Turkmenistan, Uzbekistan.Phlebotomus (Paraphlebotomus) jacusieli Theodor, 19474. Selected published records.Distribution. Albania, Azerbaijan, Cyprus, Greece, Israel, Jordan, Iran, northern Palestine, Turkey.Phlebotomus (Paraphlebotomus) mongolensis Sinton, 19285. Phlebotomusimitabilis Artemiev, 1974 sergenti Parrot, 19176. Selected published records.sergenti in comparison with subsp. similis Perfil\u2019ev, 1963); sergenti and similis as two bona species); Distribution. Afghanistan, Albania, Algeria, Armenia, Azerbaijan, Baleares, Bosnia and Herzegovina, Bulgaria, Canary I., China, Croatia, Cyprus, Egypt, France (Corsica), Georgia, Greece, India, Iran, Iraq, Israel, Italy, Jordan, Kazakhstan, Lebanon, Libya, Madeira, Macedonia, Mali, Malta, Morocco, Portugal, Romania, Saudi Arabia, Serbia, Slovenia, Somali Republic, Spain, Syria, Tunisia, Turkey, Ukraine, Yemen. Afrotropical and Oriental regions.Phlebotomus (Paraphlebotomus) similis Perfil\u2019ev, 1963 7. Phlebotomus (Paraphlebotomus) sergentisimilis Perfil\u2019ev, 1963Selected published records.sergentisimilis); Distribution.Phlebotomus (Larroussius) kandelakii Shurenkova, 19298. Selected published records.kandelakii); kandelakii and burneyi Lewis, 1967 recognized); burneyi as a species); Distribution. Afghanistan, Armenia, Azerbaijan, Dagestan, Georgia, Iran, Iraq, Lebanon, Turkey, Turkmenistan, Uzbekistan.Phlebotomus (Larroussius) majorsyriacus Adler & Theodor, 19319. Selected published records.major, neglectus Tonnoir, 1921, syriacus Perfil\u2019ev, 1966 and krimensis Perfil\u2019ev, 1966); wui Yang & Xiong, 1965); neglectus as a separate valid species, but taxonomic position of syriacus is unclear due to the missing differential diagnosis in the original description); syriacus as a species).Distribution. Armenia, Azerbaijan, Crimea, Georgia, Greece (Crete), Israel, Italy (Sicily), Jordan, Lebanon, Palestine, Serbia, Syria, Turkey, Ukraine.Phlebotomus (Larroussius) perfiliewitranscaucasicus Perfiliew, 193710. Selected published records.perfiliewi, transcucasicus, and galilaeus Theodor, 1958); Distribution. Azerbaijan, Iran, Iraq, Russia, Uzbekistan.Phlebotomus (Larroussius) perniciosus Newstead, 191111. Selected published records.Distribution. Albania, Algeria, Andorra, Azerbaijan, Baleares, Bosnia and Herzegovina, Bulgaria, Canary I., Corsica, Croatia, Cyprus, France, Germany, Greece, Italy, Libya, Macedonia, Malta, Morocco, Portugal, Romania, Sardinia, Serbia, Sicily, Slovenia, Spain, Switzerland, Tunisia, Turkey.Phlebotomus (Larroussius) tobbi Adler & Theodor in Adler, Theodor & Lourie, 193012. Selected published records.Distribution. Albania, Armenia, Azerbaijan, Bosnia and Herzegovina, Croatia, Cyprus, Georgia, Greece, Iran, Israel, Italy, Jordan, Lebanon, Palestine, Serbia, Sicily, Slovenia, Syria, Turkey.Phlebotomus (Adlerius) balcanicus Theodor, 195813. Selected published records. P.chinensisbalcanicus Theodor, 1958); Distribution. Albania, Azerbaijan, Bosnia and Herzegovina, Bulgaria, Caucasus, Crimea, Croatia, Georgia, Greece, Hungary, Iran (north-western), Macedonia, Romania, Serbia, Turkey, Ukraine.Phlebotomus (Adlerius) brevis Theodor & Mesghali, 19614. 4Phlebotomuschinensisismailicus Perfil\u2019ev, 1966Syn. Published records.P.chinensisismailicus Perfil\u2019ev, 1966); Comments on distribution.Phlebotomus (Adlerius) halepensis Theodor, 195815. Selected published records.Phlebotomuschinensis Newstead, 1916: chinensis, simici Nitzulescu, 1931, longiductus Parrot, 1928, tauriae Perfil\u2019ev, 1966, ismailicus Perfil\u2019ev, 1966, balcanicus and halepensis). tauriae = longiductus, ismailicus = brevis Theodor & Mesghali, 1964); Distribution. Armenia, Azerbaijan, Georgia, Iran, Israel, Kazakhstan, Kirghistan, Russia, Syria, Tajikistan, Turkey, Turkmenistan, Uzbekistan.Phlebotomus (Adlerius) simici Nitzulescu, 193116. Selected published records.chinensissimici, see P.halepensis); Distribution. Armenia, Azerbaijan, Crete, Georgia, Greece, Jordan, Iran, Israel, Kazakhstan, Palestine, Romania, Russia, Syria, Turkey, former Yugoslavia.Sergentomyia (Sergentomyia) dentata Sinton, 193317. Selected published records. Distribution. Azerbaijan, Greece, Iran, Iraq, Kazakhstan, Pakistan, Turkey, Turkmenistan, Uzbekistan.Sergentomyia (Neophlebotomus) pawlowskyi 18. Selected published records.Phlebotomus, Sergentomyia (Rondanomyia) Theodor, 1958; this subgenus was synonymized with Neophlebotomus (ebotomus : 269); Webotomus : 22.Distribution. Afghanistan, Armenia, Azerbaijan, Georgia, Iran, Iraq, Tajikistan, Turkey, Turkmenistan, Uzbekistan.Sergentomyia (Parrotomyia) palestinensis 19. Selected published records. Adler & Theodor (1927) originally described this species in Phlebotomus; Sergentomyia, which was recognized as well by Parrotomyia); Parrotomyia); Parrotomyia).Distribution. Afghanistan, Armenia, Azerbaijan, Georgia, Iran, Iraq, Israel, Jordan, Palestine, Pakistan, Saudi Arabia. Oriental Region.Yomormiapetrovi Je\u017eek, 198520. Material examined. Armenia: Tavush Province, Bldan River, below Jukhtakvank monastery and the mineral water factory/plant, Arm 11, 28.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22537.Comments. This species was known only from the original description from Sandanski, Bulgaria (Limomormia (Limomormia) petrovi 21. Material examined. Armenia: Yerevan, Tigran Mets Avenue, Arm 1, 30.viii.2015, 1 \u2642, O leg., HC, NMPC slide 22575.Comments. This is an expansive, often synanthropic circumtropical and circumsubtropical species , comb. n.22. Comments. This species from Armenia was originally described by Jungiellamonikae. Its generic placement was changed to Parajungiella Vaillant, 1972 by Paramormia (Duckhousiella) ustulata 23. Material examined. Armenia: Lori Province, tributary of Dzoraget River, above Pushkin village, Arm 27, 3.ix.2015, 1M, O Ma H leg. SW, NMPC slide 22541; Ararat Province, above the confluence of Azat and Gekhard rivers, Arm 17, 31.viii.2015,1 \u2642, O Ma H leg. SW, NMPC slide 22582; Lori Province, tributary of Pambak River, at the H24 road switch-backs , Arm 22, 1.ix.2015, 1\u2640, O Ma H leg. SW, NMPC slide 22589; Kotayk Province, Hrazdan River, below Hrazdan Reservoir, Arm 6, 27.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22597.Comments. This is a widespread species or complex of species occurring in the Holarctic region. Paramormia (Paramormia) fratercula 24. Comments.Pericomafratercula from Great Britain. Paramormia (Paramormia), within the tribe Paramormiini, and Parmormiafratercula in tribe Telmatoscopini.Distribution. Denmark, Germany, Great Britain, Hungary, the Netherlands, Sweden polyascoidea 25. Material examined. Armenia: Shirak Province, tributary of Akhurian River, at Torosgyugh village, Arm 25, 3.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22600.Comments. This is a common European and west Siberian species known from Austria, Bosnia and Herzegovina, Czech Republic, Estonia, Finland, Germany, Poland, Abkhazia, and Russia (Novosibirsk region) ( region) . New forPeripsychodaauriculata 26. Material examined. Armenia: Tavush Province, Bldan River, below Jukhtakvank monastery and mineral water factory/plant, Arm 11, 28.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22536; Tavush Province, Bldan River, above Dilijan City, Arm 10, 28.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22527.Comments. This is a large, black, conspicuous European and Transcaucasian species that is very common in lowlands to hilly regions. For detailed distributional data, see Logimaalbipennis 27. Material examined. Armenia: Ararat Province, Gekhard River, at Gerghard monastery (parking place), Arm 14, 30.viii.2015, 1 \u2640, O Ma H leg. SW, NMPC slide 22574. Azerbaijan: Qabala district, S of Durca, light trap near stream, tributary of Qaraschay River, Aze 4, 30.v.2017, 1 \u2640, H leg. LT, NMPC slide 24175.Comments. This is a cosmopolitan species, very common from lowlands to mountains.Distribution. In Europe, it is known from Austria, Azores, Belgium, Bosnia and Herzegovina, Bulgaria, Czech Republic, Denmark, Finland, France, Germany, Great Britain, Greece, Hungary, Ireland, Italy, Luxemburg, Madeira, the Netherlands, Norway, Poland, Portugal, Romania, Russia, Sardinia, Serbia, Slovakia, Slovenia, and Sweden. In Asia from Afghanistan, China, India, Japan, North Korea, Syria and Turkey. In Afrika, from Algeria, the Canary Islands, Gambia, South Africa, Tunisia; also from Australia, New Zealand, South America, USA; Campbell Island, Juan Fernandez Island, Kerguelen Island, Macquarie Island 28. Material examined. Azerbaijan: Qabala district, S of Durca, light trap near stream, tributary of Qaraschay River, Aze 4, 30.v.2017, 1 \u2640, H leg. LT, NMPC slide 24174.Distribution. This is a common Holarctic species. In Europe, known from e.g. Austria, Czech Republic, Ireland, Italy, Norway, Russia, Slovakia, Slovenia, Sweden, the Netherlands, Ukraine and the former Yugoslavia; Canada, USA , Turkey, Iran, Israel, Mongolia, Morocco and the USA 30. Material examined. Armenia: Ararat Province, Gekhard River, at Gerghard monastery (parking place), Arm 14, 30.viii.2015, 1 \u2640, O Ma H leg. SW, NMPC slide 22573; Lori Province, tributary of Dzoraget River, above Pushkin village, Arm 27, 3.ix.2015, 1 \u2640, O Ma H leg. SW, NMPC slide 22543.Distribution. This is a very common cosmopolitan species, in Europe, it is known from Austria, Azores, Belgium, Bosnia and Herzegovina, Bulgaria, Canary Islands, Cyprus, Czech Republic, Denmark, Finland, France, Finland, Germany, Great Britain, Greece, Hungary, Ireland, Italy (including Sardinia), Madeira, the Netherlands, Norway, Poland, Romania, Russia, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey and Ukraine. In Asia, from Abkhazia, Afghanistan, Iran, and Israel. In Africa, from Algeria, Morocco, South Africa, and Tunisia. In the Americas, from Argentina; Brazil, Canada, Chile, Jaun Fernand\u00e9z Island, Puerto Rico, USA. Also known from Australia and New Zealand 31. Material examined. Armenia: Lori Province, tributary of Dzoraget River, above Pushkin village, Arm 27, 3.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22540; Lori Province, tributary of Aghstev River, above M8 road at Lermontov village, Arm 20, 31.viii.2015,1 \u2640, O Ma H leg. SW, NMPC slide 22559; Ararat Province, above the confluence of Azat and Gekhard rivers, Arm 17, 31.viii.2015, 1 \u2640, O Ma H leg. SW, NMPC slide 22581; Kotayk Province, Marmarik district, Marmarik near road H28, Arm 3, 26.viii.2015, 1 \u2640, O Ma H leg. LT, NMPC slide 22583; Ararat Province, Azat River, at Lanjazat village, Arm 19, 31.viii.2015, 1 \u2640, O Ma H leg. SW, NMPC slide 22595; Kotayk Province, Marmarik district, Marmarik Secondary School, Arm 2, 27.viii.2015, 1 \u2642, O Ma H leg. BH, NMPC slide 22608. Azerbaijan: Khizi district, S of Sital\u00e7ay, wetland/pasture near Sumgayit bypass highway, Aze 1, 26.v.2017, 1 \u2640, H leg. SW, NMPC slide 24173.Distribution. This is a cosmopolitan species that is generally very common. In Europe, it is known from Austria, Balearic Islands, Belgium, Bulgaria, Crete, Croatia, Cyprus, Czech Republic, Denmark, Finland, France, Germany, Great Britain, Greece, Hungary, Ireland, Italy, Madeira, Norway, Poland, Romania, Sardinia, Slovenia, Spain, Sweden, Switzerland, the Netherlands, and Ukraine. In Asia, from Afghanistan and UAE. In Africa from Algeria, Cape Verde Islands, Canary Islands, D.R. Congo, Egypt, Gambia, Ghana, Morocoo, Nigeria, the Seychelles, Socotra Island, South Africa, Tanzania, and Tunisia. In Asia from Bangladesh, Borneo, Philippines, India, Jamaica, Japan, Malaysia, Mongolia, North Korea, Ryukyu Islands, Taiwan. From North and South America, including Panama, Puerto Rico, and Trinidad. Also from Australia, Hawaii, and from Micronesia, Macquarie Islands, New Zealand, and Samoa. . Pericoma (Pachypericoma) blandula Eaton, 189333. Material examined. Armenia: Tavush Province, tributary of Gosh River, spring area at parking place and cafeteria, Arm 28, 4.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22546; Lori Province, tributary of the Pambak River, at the H24 road switch-backs, Arm 22, 1.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22588; Tavush Province, tributary of Aghstev River, above Teghut town, Arm 12, 29.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22592; Lori Province, small brook, in valley at road H23 to Pushkin Pass, Arm 26, 3.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22594; Lori Province, Zamanlu River, a tributary of Pambak River, at Vahagnadzor town, Arm 21, 1.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22607. Azerbaijan: Lankaran district, SW of Lankaran, stream with woody vegetation, tributary of Lankaran River, Aze 3, 3.vi.2017, 2 \u2642, H leg. SW, NMPC slides 24171 and 24172.Distribution. This species is widespread in Europe, known from Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, European Turkey, Finland, France, Germany, Great Britain, Greece, Hungary, Ireland, Italy, Macedonia, Montenegro, Norway, Poland, Romania, European Russia, Sardinia, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, the Netherlands and Ukraine. It is also recorded in Transcaucasia, Tunisia, and Morocco bosniaca Krek, 1967); bosnica Krek, 1967); Material examined. Armenia: Ararat Province, small tributary of Azat River, waterfall at road, Arm 16, 31.viii.2015, 2 \u2642, O Ma H leg. SW, NMPC slides 22551 and 22552.Distribution. Bosnia and Herzegovina, Bulgaria, Montenegro, Serbia, Macedonia. New for Armenia.Pericomabunae Krek, 197935. Published records.Pericoma (Leptopericoma) bunae Krek, 1979).Material examined. Azerbaijan: Quba district, Xinaliq village, mountain stream, Aze 2, 27.v.2017, 1 \u2642, H leg. SW, NMPC slide 24170.Distribution: This species is known from Bosnia and Herzegovina, as well as Montenegro. New for Azerbaijan.Pericomaexquisita Eaton, 189336. Material examined. Armenia: Shirak Province, tributary of Akhurian River, in valley below road from above Amasia town, Arm 24, 2.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22530; Tavush Province, tributary of Gosh River, spring area at the parking place and cafeteria, Arm 28, 4.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22547; Ararat Province, Gekhard River, below Garni Temple, Arm 15, 31.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22578; Ararat Province, above the confluence of Azat and Gekhard rivers, Arm 17, 31.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22587; Kotayk Province, Hrazdan River, above Solak town, Arm 5, 27.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22599.Distribution. This species is widespread in Europe, North Africa , and Transcaucasia 38. Material examined. Armenia: Shirak Province, tributary of Akhurian River, in valley below road from above Amasia town, Arm 24, 2.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22534; Tavush Province, tributary of Gosh River, spring area at parking place and cafeteria, Arm 28, 4.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22534.Comments. This is a common European and western Siberian species. In Europe it is known Austria, Belgium, Great Britain, Czech Republic, Denmark, European Turkey, France, Germany, Greece, Hungary, Slovakia, Sweden, the Netherlands and the former Yugoslavia. In Asia, it is known from Turkey, Kyrgyzstan, Afghanistan and China 39. Material examined. Armenia: Kotayk Province, tributary of Marmarik River, above recreation centre, Arm 8, 27.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22606; Kotayk Province, Hrazdan River, above Solak town, Arm 5, 27.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22598; Lori Province, small brook, in valley at road H23 to Pushkin Pass, Arm 26, 3.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22593; Lori Province, small steppe brook, tributary of Dzoraget River, Arm 23, 2.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22591; Kotayk Province, Marmarik River, below Hankavan, Arm 4, 26.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22586; Lori Province, tributary of Aghstev River, above M8 road at Lermontov village, Arm 20, 31.viii.2015, 6 \u2642, O Ma H leg. SW, NMPC slides 22561\u201322566; Shirak Province, tributary of Akhurian River, in valley below road from above Amasia town, Arm 24, 2.ix.2015, 3 \u2642, O Ma H leg. SW, NMPC slides 22531\u201322533.Comments.Satchelliellajoosti.Distribution. This species is known only from Armenia and Transcaucasus 40. Material examined. Armenia: Kotayk Province, tributary of the Marmarik River, above recreation centre, Arm 8, 27.viii.2015, 3 \u2642, O Ma H leg. SW, NMPC slides 22549, 22605 and 22579; Ararat Province, small tributary of Azat River, waterfall at road, Arm 16, 31.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22550; Lori Province, tributary of Aghstev River, above M8 road at Lermontov village, Arm 20, 31.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22560; Ararat Province, Gekhard River, at Gerghard monastery (parking place), Arm 14, 30.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22572; Ararat Province, above the confluence of Azat and Gekhard rivers, Arm 17, 31.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22580; Ararat Province, small tributary of Gekhard River, crossroad at factory, Arm 18, 31.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22603; Gegharkunik Province, Dzknaget River, at Sevan Lake and M14 road, Arm 13, 29.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22604.Comments. This species is distributed throughout almost all of Europe, including Spain, the British Isles and Scandinavia. It is also known from Algeria, Morocco, the Central Caucasus and Tajikistan, but it is relatively sporadic there 41. Material examined. Armenia: Tavush Province, Bldan River, above Dilijan City, Arm 10, 28.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22526; Shirak Province, tributary of Akhurian River, in valley below road from above Amasia town, Arm 24, 2.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22529; Tavush Province, Bldan River, below Jukhtakvank monastery and mineral water factory/plant, Arm 11, 28.viii.2005, 1 \u2642, O Ma H leg. SW, NMPC slide 22535; Lori Province, tributary of Dzoraget River, above Pushkin village, Arm 27, 3.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22539; Tavush Province, tributary of Gosh River, spring area at parking place and cafeteria, Arm 28, 4.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22544; Kotayk Province, tributary of Marmarik River, above the recreation centre, Arm 8, 27.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22548; Lori Province, tributary of Aghstev River, above M8 road at Lermontov village, Arm 8, 31.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22567; Ararat Province, Gekhard River, at Gerghard monastery (parking place), Arm 14, 30.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22571; Lori Province, small steppe brook, tributary of Dzoraget River, Arm 23, 2.ix.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22590; Kotayk Province, Hrazdan River, below Hrazdan Reservoir, Arm 6, 27.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22596.Distribution. This is a very common species, which is recorded from throughout Europe and the Canary Islands. In Europe, it is known from Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, Finland, France, Georgia, Germany, Great Britain, Greece, Hungary, Ireland, Italy, Luxembourg, Macedonia, Montenegro, Poland, Romania, Sardinia, Serbia, Slovakia, Slovenia, Spain, Switzerland, the Netherlands and Ukraine 44. Material examined. Armenia: Lori Province, tributary of Aghstev River, above M8 road at Lermontov village, Arm 20, 31.viii.2015, 1 \u2642, O Ma H leg. SW, NMPC slide 22568.Distribution. This is a common European species known from Austria, Czech Republic, Finland, France, Germany, Great Britain, Italy, Lithuania, Poland, Slovakia, Slovenia and Ukraine ustulata, Psychodochacinerea, Tineariaalternata, Pericoma (Pachypericoma) blandula, Pneumiacanescens, Pneumianubila, or invasive species such as Clogmiaalbipunctata, for the first time from these countries shows that the psychodid fauna is still poorly known.According to erbaijan . In the Knowledge of species distribution is important for studying biogeography and making effective conservation actions. This checklist will provide a baseline for further studies and for initiation of concerted conservation actions in Armenia and Azerbaijan. No doubt that future collecting in Georgia and Azerbaijan, done with the support of the International Visegrad Fund (project No. 21810533), will yield additional faunistic novelties of interest, as shown by similar studies in this region of other dipteran families e.g. ."} +{"text": "In: Jackson D, Wenz K, Muniz M, Abouzahr C, Schmider A, Braschi MW, et al. Civil registration and vital statistics in health systems. Bull World Health Organ. 2018 Dec 1;96(12):861\u201363, on page 861, the name of the sixth author should be Martin W Bratschi."} +{"text": "In Lee, Cho, Lee, Jung, and Heo , the aff"} +{"text": "Scientific Reports 10.1038/s41598-018-31613-0, published online 04 September 2018Correction to: The original version of this Article omitted an affiliation for Khaled Taha-Abdelaziz. The correct affiliations for Khaled Taha-Abdelaziz are listed below:Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.Pathology Department, Faculty of Veterinary Medicine, Beni-Suef University, Al Shamlah, Beni-Suef, 62511, Egypt.This has now been corrected in the HTML and PDF versions of this Article."} +{"text": "In \u201cFactors Associated With Willingness to Use Pre-Exposure Prophylaxis in Brazil, Mexico, and Peru: Web-Based Survey Among Men Who Have Sex With Men\u201d :e13771), the metadata information for author Cristina Pimenta (listed in 8th position) was accidentally overwritten by a duplicate of author Marcos Benedetti (listed in 9th position) when attempting to correct the spelling of Marcos\u2019 surname.Authorship was previously as follows:Thiago Silva Torres, Kelika A Konda, E Hamid Vega-Ramirez, Oliver A Elorreaga, Dulce Diaz-Sosa, Brenda Hoagland, Steven Diaz, Marcos Benedetti, Marcos Bennedeti, Hugo Lopez-Gatell, Rebeca Robles-Garcia, Beatriz Grinsztejn, Carlos Caceres, Valdilea G Veloso, ImPrEP Study GroupThe duplicate name and associated information for the author in 8th position has been adjusted to list Cristina Pimenta, PhD, with affiliation \u201cBrazilian Ministry of Health, Bras\u00edlia, Brazil\u201d, and the spelling of \u201cBennedeti\u201d for the author in 9th position has been corrected to \u201cBenedetti\u201d. Updated authorship is now as follows:Thiago Silva Torres, Kelika A Konda, E Hamid Vega-Ramirez, Oliver A Elorreaga, Dulce Diaz-Sosa, Brenda Hoagland, Steven Diaz, Cristina Pimenta, Marcos Benedetti, Hugo Lopez-Gatell, Rebeca Robles-Garcia, Beatriz Grinsztejn, Carlos Caceres, Valdilea G Veloso, ImPrEP Study GroupThe correction will appear in the online version of the paper on the JMIR website on July 18, 2019, together with the publication of this correction notice. Because this was made after submission to PubMed, PubMed Central, and other full-text repositories, the corrected article also has been resubmitted to those repositories."} +{"text": "Scientific Reports 10.1038/srep37435, published online 25 November 2016Correction to: This Article contains an error where Tariq I. Almundarij is incorrectly affiliated with \u2018College of Agriculture and Veterinary Medicine, Al-Qassim University, Buraydah, Al-Qassim Province, Saudi Arabia\u2019. The correct affiliations for Tariq I. Almundarij are listed below:Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, P.O. Box 6622, Buraidah 51452, Saudi ArabiaDepartment of Biological Sciences, Kent State University, Kent, OH, 44242, US"} +{"text": "Disease Models & Mechanisms (DMM) is delighted to announce that the winner of the DMM Prize 2018 is Wenqing Zhou, for her paper entitled \u2018Neutrophil-specific knockout demonstrates a role for mitochondria in regulating neutrophil motility in zebrafish\u2019 a. The pr Wenqing ZhouWenqing Zhou grew up in a small town in South Central China and received her bachelor\u2019s degree in biotechnology from Central South University, China. In the third year of undergraduate study, she joined Dr Xueduan Liu's lab, where she learned to isolate bacterial strains from the environment and utilize those strains to increase the metal extraction efficiency from mineral. During that time, she was deeply attracted by those \u2018tiny but magic microbes\u2019.Streptococcus pneumoniae, one of the most common pathogens in the respiratory tract, is widely resistant to macrolide antibiotics because of the dissemination of transposon Tn2010, which carries two different macrolide-resistance genes. She identified that transformation is the predominant way to transfer Tn2010 between S. pneumoniae, and that the acquisition of Tn2010 has a negligible fitness cost, which may explain the widespread distribution of the transposon also inhibited neutrophil motility. Furthermore, the research demonstrated that the reduced cell motility resulting from neutrophil-specific knockout of sod1 was rescued by sod1 mRNA overexpression or by treating with scavengers of ROS. Together, their work established the first in vivo evidence that mitochondria regulate neutrophil motility, and provided insights into immune deficiency seen in patients with primary mitochondrial disorders. Technically, the group has used the tissue-specific-knockout approach to discover the function of genes, especially those that are developmentally essential, in neutrophils. This is the first successful example of using this technique to make scientific discoveries. They have further demonstrated the specificity of the knockout by mRNA and chemical rescue 11, dmm033027. doi:10.1242/dmm.033027.Also shortlisted by our Editor team:Bone marrow transplantation corrects haemolytic anaemia in a novel ENU mutagenesis mouse model of TPI deficiency.Ashlee J. Conway, Fiona C. Brown, Elinor J. Hortle, Gaetan Burgio, Simon J. Foote, Craig J. Morton, Stephen M. Jane and David J. Curtis.Disease Models & Mechanisms (2018) 11, dmm034678. doi:10.1242/dmm.034678.Drosophila melanogasteras a function-based high-throughput screening model for antinephrolithiasis agents in kidney stone patients.Sohrab N. Ali, Thamara K. Dayarathna, Aymon N. Ali, Tijani Osumah, Mohamed Ahmed, Tyler T. Cooper, Nicholas E. Power, Dongxing Zhang, Dajung Kim, Rachel Kim, Andre St. Amant, Jinqiang Hou, Thomas Tailly, Jun Yang, Len Luyt, Paul A. Spagnuolo, Jeremy P. Burton, Hassan Razvi and Hon S. Leong.Disease Models & Mechanisms (2018) 11, dmm035873. doi:10.1242/dmm.035873.A novel rabbit model of Duchenne muscular dystrophy generated by CRISPR/Cas9.Tingting Sui, Yeh Siang Lau, Di Liu, Tingjun Liu, Li Xu, Yandi Gao, Liangxue Lai, Zhanjun Li, Renzhi Han.Disease Models & Mechanisms (2018) 11, dmm032201. doi:10.1242/dmm.032201.The class I myosin MYO1D binds to lipid and protects against colitis.William McAlpine, Kuan-wen Wang, Jin Huk Choi, Miguel San Miguel, Sarah Grace McAlpine, Jamie Russell, Sara Ludwig, Xiaohong Li, Miao Tang, Xiaoming Zhan, Mihwa Choi, Tao Wang, Chun Hui Bu, Anne R. Murray, Eva Marie Y. Moresco, Emre E. Turer and Bruce Beutler.Disease Models & Mechanisms (2018) 11, dmm035923. doi:10.1242/dmm.035923.Nmnat mitigates sensory dysfunction in aDrosophilamodel of paclitaxel-induced peripheral neuropathy.Jennifer M. Brazill, Beverley Cruz, Yi Zhu and R. Grace Zhai.Disease Models & Mechanisms (2018) 11, dmm032938. doi:10.1242/dmm.032938.CRISPR-Cas9 human gene replacement and phenomic characterization inCaenorhabditis elegansto understand the functional conservation of human genes and decipher variants of uncertain significance.Troy A. McDiarmid, Vinci Au, Aaron D. Loewen, Joseph Liang, Kota Mizumoto, Donald G. Moerman and Catharine H. Rankin.Disease Models & Mechanisms (2018) 11, dmm036517. doi:10.1242/dmm.036517.Spliceosomal components protect embryonic neurons from R-loop-mediated DNA damage and apoptosis.Shelly Sorrells, Sara Nik, Mattie Casey, Rosannah C. Cameron, Harold Truong, Cristhian Toruno, Michelle Gulfo, Albert Lowe, Cicely Jette, Rodney A. Stewart and Teresa V. Bowman.Disease Models & Mechanisms (2018) 11, dmm031583. doi:10.1242/dmm.031583.Cancer modeling by transgene electroporation in adult zebrafish (TEAZ).Scott J. Callahan, Stephanie Tepan, Yan M. Zhang, Helen Lindsay, Alexa Burger, Nathaniel R. Campbell, Isabella S. Kim, Travis J. Hollmann, Lorenz Studer, Christian Mosimann and Richard M. White.Disease Models & Mechanisms (2018) 11, dmm034561. doi:10.1242/dmm.034561.Cooperation of loss ofNKX3.1and inflammation in prostate cancer initiation.Cl\u00e9mentine Le Magnen, Renu K. Virk, Aditya Dutta, Jaime Yeji Kim, Sukanya Panja, Zoila A. Lopez-Bujanda, Andrea Califano, Charles G. Drake, Antonina Mitrofanova and Cory Abate-Shen.Disease Models & Mechanisms (2018) 11, dmm035139. doi:10.1242/dmm.035139.Neutrophils are fast-moving cells and primarily rely on glycolysis for adenosine triphosphate (ATP) availability. Whether mitochondria regulate neutrophil motility 's group and esta's group a. With tl rescue a.Box 1.Currently, Wenqing is characterizing the stable zebrafish lines that she generated with neutrophil-specific knockout, and trying to provide a full understanding of the pathway regulated by mitochondria in neutrophil migration. She will finish the work in the spring of 2019 and start to look for a postdoctoral position."} +{"text": "Correction to: Eur Rev Aging Phys Act (2019) 16:18https://doi.org/10.1186/s11556-019-0226-1Following publication of the original article , the autJochen Klenk, Raphael Simon Peter, Kilian Rapp, Dhayana Dallmeier, Dietrich Rothenbacher, Michael Denkinger, Gisela B\u00fcchele, the ActiFE Study Group."} +{"text": "Enrique F. Maldonado should be listed as the second author, and his affiliation is 1: Clinical Neuropsychology Laboratory, School of Psychology, University of Malaga, Andalucia Tech, Malaga, Spain. The contributions of this author are as follows: Conceptualization, data curation, investigation, methodology.https://doi.org/10.1371/journal.pone.0209475The correct citation is: Rosel JF, Maldonado EF, Jara P, Machancoses FH, Pallar\u00e9s J, Torrente P, et al. (2019) Intensive longitudinal modelling predicts diurnal activity of salivary alpha-amylase. PLoS ONE 14(1): e0209475."} +{"text": "Following publication of the original article , the cor1*, Yu R2*, Xiong Y3*, Du F4, Zhu S5.Chen Z1Department of Gastroenterology, Second Affliated Hospital, Nanchang University, Nanchang, China.2Department of Endocrinology, Second Affliated Hospital, Nanchang University, Nanchang, China.3Department of Gastroenterology, Second Affliated Hospital, Nanchang University, No. 1, Minde Road, Nanchang, 330006, China.4Department of Gastroenterology, Second Affliated Hospital, Nanchang University, No. 1, Minde Road, Nanchang, 330006, China. 296978043@qq.com.5Department of Gastroenterology, Second Affliated Hospital, Nanchang University, No. 1, Minde Road, Nanchang, 330006, China. 478675878@qq.com.*Equal contributors.Address correspondence toShuiShan Zhu, Department of Gastroenterology, Second Affliated Hospital, Nanchang University, No. 1, Minde Road, Nanchang 330006, China. E-mail: 478675878@qq.comFangteng Du, Department of Gastroenterology, Second Affliated Hospital, Nanchang University, No. 1, Minde Road, Nanchang 330006, China. E-mail: 296978043@qq.com"} +{"text": "AbstractMicrochiritahairulii Rafidah (Gesneriaceae) from limestone hills in Perlis, Peninsular Malaysia, is described and illustrated. Diagnostic characters, description, detailed illustrations, geographical distribution, regional provisional conservation status assessment (Endangered) and ecological observations of the new taxon, as well as an updated key to Microchirita species in Peninsular Malaysia, are provided.A new species, Microchirita (C.B.Clarke) Yin Z.Wang comprises six species with three endemics, M.caliginosa (C.B.Clarke) Yin Z.Wang, M.ruthiae Rafidah and M.sericea (Ridl.) A.Weber & Rafidah and seed characters .Peninsular Malaysia, Perlis, Bukit Manik, 9 February 2017, Microchiritahairulii most closely resembles M.caliginosa and M.sericea in having a branched stem, pale purple corolla and hairy capsule. This new species differs in having ovate leaves , serrate leaf margin , 5\u201310 mm long corolla tube , glabrous anthers and the seed without papillate surfaces .Microchiritahairulii is distinct from M.viola in the length of calyx lobes, 3\u20134 mm long, narrowly lanceolate , corolla lobes very faintly striped or plain (conspicuous dark purple stripes in M.viola), having glandular hairs above the anthers, translucent pale brown Stems pale green or maroon green (in life), erect or sub-erect, if with a single leaf the stem elongated, flowering at c. 10 cm tall, shortly hairy, internodes 3.5\u20136.5 cm long. Leaves opposite, decussate, lowermost solitary; petiole pale green, 0.5\u20131.5 cm long, densely and shortly hairy; lamina ovate, 3.5\u20135.5(\u20139) \u00d7 2\u20132.5(\u20136.2) cm, yellowish green to dark green above, pale green to maroon beneath, thinly leathery (when fresh) or chartaceous (when dried), shortly hairy, base slightly cordate to cuneate, sometimes unequal, margin serrate, apex acute; midrib sunken above, prominent beneath, lateral veins 5\u20136 pairs, sparsely hairy, intercostal veins reticulate. Inflorescence epiphyllous, crested, 1\u20134-flowered, flowering from petiole base; bracts absent; pedicels green to maroon, to c. 1.2 cm long, glandular hairy. Flowers: calyx pale green, lobes almost divided to the base, 3\u20134 \u00d7 1\u20132 mm, acute, narrowly lanceolate, hairy outside, glabrous inside, margin entire; corolla tube very sparsely hairy outside, cream, 5\u201310 mm long, slightly curved, to c. 10 mm wide at the mouth, lobes very faintly striped, spreading, purple, throat cream, glandular hairs above the anthers, translucent pale brown, glistening; stamens 2, filaments whitish, inserted 6\u20138 mm from the base of the corolla, c. 4 mm long, straight, glabrous; anthers yellow, free or connate, without hairs, anther-thecae divergent, 1\u20132 mm long, staminodes 3, pale green, inserted c. 6 mm from the base of the corolla tube, 1.5\u20132 mm long; nectary pale yellow or cream, forming a complete ring, less than 1 mm high; pistil pale green, c. 1 cm long, ovary 2\u20134 mm long, c. 1.5 mm wide at the base narrowing to 0.5 mm below the stigma, shortly hairy, style c. 4 mm long, stigma deeply 2-lobed, c. 1 mm long, c. 2 mm wide, inserted between the anthers, with fine dense papillose hairs towards the tip; ovules cream, less than 1 mm long. Capsules green to maroon, 1.5\u20131.8 cm long, c. 2 mm wide, slender, densely hairy; calyx persistent, pale green or sometimes maroon, hairy. Seeds yellowish cream, many in one row, broadly ovate or elliptic, slightly elongated or rounded, surface without knobs or papillae.Branched herb. The specific epithet honours Mohd. Hairul bin Mohd. Amin, a dedicated field collector who collected the species in the field.Endemic in Perlis, Peninsular Malaysia Fig. . The speProvisionally, the species is assessed as Endangered (EN B1ab(iii)). This endemic species occurs in five localities on the limestone hills. None of the hills lies in Totally Protected Areas, so the hills are potentially vulnerable to be exploited for other commercial uses . Most of the hills are surrounded by paddy fields, rubber plantations and quarrying activities.Microchiritahairulii - PENINSULAR MALAYSIA: Perlis. Bkt. Jernih, February 2017, Rafidah et al. FRI 86671 (KEP); Bkt. Keteri, November 2013, Rafidah FRI 75880 (KEP); Bkt. Mata Ayer, February 2018, Rafidah et al. FRI 90347 (KEP); Kg. Ujong Bukit, May 2017, Rafidah et al. FRI 85902 (KEP).Microchiritacaliginosa - PENINSULAR MALAYSIA: Kedah: Kodiang, Bkt. Kaplu, 6 November 2009, Rafidah FRI 64417 (KEP); Ibid., 27 May 2010, Rafidah FRI 64545 (KEP). Pahang: Bkt. Charas, 15 October 1931, Henderson 25233 (SING); Ibid., 26 November 1984, Kiew RK 1557 (KEP); Ibid., 1 April 2008, Rafidah FRI 55717 (KEP); Bkt. Chintamani, 4 October 1931, Henderson SFN 25033 ; Gn. Jebak Puyuh, 10 February 1986, Kiew RK 2158 (KEP); Ibid., 10 February 1986, Kiew RK s.n. (KEP); Gn. Senyum, 30 July 1929, Henderson s.n. (SING); Ibid., 28 November 1984, Kiew RK 1587 (KEP); Ibid., 2 April 2008, Rafidah FRI 55721 (KEP); Gua Bama, 3 April 2008, Rafidah FRI 55726 (KEP); Gua Cermin R.F., 31 March 2008, Rafidah FRI 55713 (KEP); Ibid., 31 March 2008, Rafidah FRI 55714 (KEP); Gua Kechil, 30 July 2009, Rafidah FRI 64379 (KEP); Kota Glanggi, 4 August 1929, Henderson SFN 22419 (SING); Ibid., 2 April 2008, Rafidah FRI 55724 (KEP); Panching, 26 November 1984, Kiew RK 1571 (KEP); Panching F.R., 15 October 1931, Henderson SFN 25223 (SING); Taman Negara, Batu Subuh, 5 October 1984, Dawn RK 1470 (KEP); Taman Negara, Kuala Keniyam, 29 September 1982, Kiew RK 1202 (KEP). Perak: Batu Kurau, December 1884, Scortechini 1582 (SING); Ipoh, 17 July 1917, Burkill 2558 (SING); Ibid., s.d., Gordon GS 435 (KLU); Ibid., February 1904, Ridley s.n. (SING); Gopeng, 8 March1993, Davison GD 4 (KEP); Gn. Lanno, 16 April 1925, Mills 15061 (SING); Gn. Mesah, 20 April 1962, Burtt B1665 (SING); Ibid., May 1902, Curtis s.n. (SING); Gn. Pipit, 23 April 1987, Kiew RK 2524 (KEP); Gn. Rapat, 21 July 2009, Rafidah FRI 64347 (KEP); Ibid., 9 March 1931, Samsuri SA 560 ; Kinta, August 1898, Curtis 3109 (SING); Ibid., January 1885, King\u2019s collector 7028 (SING); Ibid., 1885, King\u2019s collector 937 (SING); Kuala Dipang F.R., February 1890, Curtis 2359 (SING); Ibid., 1898, Ridley s.n. (SING); Lenggong, Gua Badak, 28 October 2008, Imin FRI 63212 (KEP); Ibid., July 1909, Ridley s.n. (SING); Sg. Siput, 21 May 1985, Anthonysamy SA 842 (KEP); Sg. Siput Utara, 7 January 2015, Rafidah FRI 82007 (KEP). Selangor: Batu Caves, 18 October 1983, Anthonysamy SA 379 (KEP); Ibid., 19 November 1916, Burkill 2253 (SING); Ibid., s.d., Chung 331 (KLU), s.d., Chung 390 (KLU); Ibid., February 1890, Curtis 2359 (SING); Ibid., May 1902, Curtis s.n. (SING); Ibid., s.d., Ding Hou 715 (KEP); Ibid., 23 January 1966, Hardial 477 (SING); Ibid., 1889, Kelsall s.n. (SING); Ibid., 1 May 1981, Kiew RK 1023 (KEP); Ibid., Mohd. Kasim 391 (KLU); Ibid., 14 October 1966, Ng FRI 1629 ; Ibid., 23 June 1889, Ridley s.n. (SING); Ibid., 4 November 1953, Sinclair SFN 40066 ; Ibid., 29 November 1959, Smith KEP 85205 (KEP); Ibid., s.d., Yap SK 26 (KLU); Bkt. Anak Takun, 27 April 2006, Phoon FRI 51570 ; Ibid., 3 May 2005, Sam FRI 50118 (KEP); Kanching F.R., 10 July 1995, Julia JS 26 (KEP); Bkt. Takun, 3 November 1937, Mohd. Nur 34389 (SING); Ibid., 9 March 1988, Saw FRI 36215 (SING); Ibid., 20 November 1962, Sinclair 10732 (SING); Ibid., November 1969, Stone 8934 (KLU); Ibid., 21 September 1969, Stone 8794 (SING); Ibid., 24 June 1933, Symington FMS 30796 (KEP); Ibid., 8 May 1935, Symington 39598 (KEP); Kanching, 16 March 1935, Symington FMS 37431 (KEP). Terengganu: Taman Negara, Batu Biwa, 25 October 1986, Kiew RK 2339 ; Ibid., 22 October 1986, Kiew RK 2284 (SING).Microchiritasericea - PENINSULAR MALAYSIA: Kedah: Gn. Baling, 25 November 1941, Corner s.n. (SING). Perak: Gn. Rapat, 21 July 2009, Rafidah FRI 64347 (KEP); Ibid., 26 May 2010, Rafidah FRI 64544 (KEP); Gn. Tasek, Perak Tong Temple, 21 July 2009, Rafidah FRI 64348 (KEP); Ibid., 23 October 1958, Sinclair 9844 (SING); Ipoh, 4 July 1917, Burkill 2552 (SING); Ibid., August 1898, Corner s.n. (KEP); Ibid., February 1904, Ridley 11952 (SING); Ibid., February 1904, Ridley s.n. (KEP); Ibid., 18 August 1986, Weber UPM 4167 (KEP); Ibid.,18 August 1986, Weber s.n. (KEP); Kuala Dipang F.R., 1898, Ridley s.n. (SING); Tambun, 10 September 1920, Burkill 6284 (SING); Sg. Siput Utara, 29 January 2015, Rafidah FRI 82017 (KEP).Microchiritaviola - PENINSULAR MALAYSIA:Kedah: Gn. Keriang, February 1890, Allen s.n. (SING); Langkawi, 20 November 1941, Corner s.n. (SING); Langkawi, Ayer Hangat, Chung 505 (KLU); Langkawi, Bkt. Malut F.R., 4 November 1968, Keng 80 (SING); Langkawi, Batu Puteh, August 1941, Nauen 38120 (SING); Langkawi, Kuah, 8 November 1968, Chung RC 7 (KEP); Ibid., 5 November 2009, Rafidah FRI 64407 (KEP); Ibid., 1979, Stone 14349 (KLU); Langkawi, P. Langgun, 4 November 2009, Rafidah FRI 64398 (KEP); Langkawi, P. Timun, 1926, Holttum 17433 (SING); Langkawi, Selat Panchor F.R., 19 November 1941, Corner 37832 (SING); Ibid., 21 November 1934, Henderson SFN 28931 (SING); Ibid., November 1934, Henderson SFN 29185 (SING); Ibid., 3 November 2009, Rafidah FRI 64388 (KEP); Langkawi, Tg. Rhu, 21 November 1993, Anthonysamy SA 1144 ; Langkawi, Tg. Sawah, 22 November 1941, Corner s.n. (SING); Langkawi, Tg. Terai, 13 November 1941, Corner s.n. (SING)."} +{"text": "Manuscript: Ursodeoxycholic acid in the prevention of gallstones in patients subjected to Roux-en-Y gastric bypassPublication: Acta Cir Bras. 2019;34(1): e20190010000009DOI: http://dx.doi.org/10.1590/s0102-865020190010000009On Title Page of the original publication, instead of:I, Heladio Feitosa de Castro FilhoII, Rodrigo Feitosa de Albuquerque Lima BabadopulosIII, Hermano Alexandre Lima RochaIV, Jos\u00e9 Lima de Carvalho RochaV, Manoel Odorico de Moraes FilhoVIFrancisco Heine Ferreira MachadoIPhD, Department of Surgery, Universidade Federal do Cear\u00e1 (UFC), Fortaleza-CE, Brazil. Intellectual, conception and design of the study, critical revision, final approval. IIMD, Department of Surgery, UFC, Fortaleza-CE, Brazil. Analysis and interpretation of data, final approval.IIIMD, Hospital Geral Dr C\u00e9sar Cals de Oliveira, Fortaleza-CE, Brazil. Analysis and interpretation of data, final approval.IVPhD, Community Health Department, UFC, Fortaleza-CE, Brazil. Analysis and interpretation of data, final approval.VPhD, UNICHRISTUS, Fortaleza-CE, Brazil. Analysis and interpretation of data.VIPhD, Full Professor, Department of Farmacology, UFC, Fortaleza-CE, Brazil. Manuscript writing, critical revision, final approval.Consider this:I, Heladio Feitosa de Castro FilhoII, Rodrigo Feitosa de Albuquerque Lima BabadopulosIII, Hermano Alexandre Lima RochaIV, Maria da Concei\u00e7\u00e3o Cavalcante CostaV, Jos\u00e9 Lima de Carvalho RochaVI, Manoel Odorico de Moraes FilhoVIIFrancisco Heine Ferreira MachadoIPhD, Department of Surgery, Universidade Federal do Cear\u00e1 (UFC), Fortaleza-CE, Brazil. Intellectual, conception and design of the study, critical revision, final approval. IIMD, Department of Surgery, UFC, Fortaleza-CE, Brazil. Analysis and interpretation of data, final approval.IIIMD, Hospital Geral Dr C\u00e9sar Cals de Oliveira, Fortaleza-CE, Brazil. Analysis and interpretation of data, final approval.IVPhD, Community Health Department, UFC, Fortaleza-CE, Brazil. Analysis and interpretation of data, final approval.VMaster, Servi\u00e7o de Atendimento M\u00f3vel de Urg\u00eancia (SAMU), Fortaleza-CE, Brazil. Analysis and interpretation of data.VIPhD, UNICHRISTUS, Fortaleza-CE, Brazil. Analysis and interpretation of data.VIIPhD, Full Professor, Department of Farmacology, UFC, Fortaleza-CE, Brazil. Manuscript writing, critical revision, final approval."} +{"text": "Following publication of the original article , we wereThe TBI collaborative group: Long K , Rodrigues A , Lozano A , Saxby E , Vargiolu A , Quintard H , Robba C , Sisson A , Allen G , Baro N , Kofler M ."} +{"text": "In Iran, more than 2-3 million people are thalassemia major carrier which from them 25000 people are suffering from the disease , 2. ThisIn this descriptive cross-sectional study, conducted in 2016, the development of minimum datasets was done by extracting data from hospital medical records based on the D55\u2013D59 category of International Classification of Diseases 10th revision (ICD-10). Then, the final questionnaire designed according to the checklist provided by American health information management Association (AHIMA) to develop the minimum data set for EHR in 2006. Finally, by using the Delphi method, the final questionnaire by available sampling sent to 12 specialists including health information management specialists, genetics specialist, hematologists, and general practitioners, so that their views would be collected on the questionnaire. As a result of the Delphi study, data elements at 11 categories were determined.Administrative Data including patient full name, father\u2019s full name, mother\u2019s full name, identifier number, sex, religion, birth date, marital status, education level, occupation, ethnic groups, occupation, place of work, address, blood group, RH Type, Consent, brought or referred by, patient education, comorbidity, and authenticator/signature were determined.Encounter data consist of primary diagnosis, final diagnosis, date/time of admission, kind of admission, admitting physician, admitted from, body mass index, history of hospitalization, the number of hospitalization, length of stay, transfusion information, ward name, date/time of discharge, death data, and authentication/signature after Delphi technique were taken into account.Treatment Plan Data contain Inpatient order, Blood reserve order, Blood transfusion order, consultations orders, lab-tests orders, radiography orders, medications orders, dietary type, order for the following, discharge order, transfer order, time/date of the order, Chelation therapy, surgery order, and authentication/signature.Provider data including provider full name, specialty, provider address, provider telephone, provider role, unique provider identifiers, and authenticator/signature were considered.Examination data were following as; date/time of transfusion, Interval between transfusion, volume of transfused blood, warm blood, transfuse products, patient blood culture, bag culture, complication after transfusion, requested blood volume, iron overload, resistant to hepatitis c, non-resistant to hepatitis c, Desferal pomp type, vital signs before transfusion, vital signs in transfusion, vital signs after transfusion, pre-operative examination, examination during operation, examination post-operative, injectable drugs and solutions during transfusion, adverse reaction to blood transfusion, Desferal side effects, history of unexpected antibody in serum and authentication/signature.History data were detailed as presenting symptom, past disease history, history of blood transfusion reaction, current drug therapy & other addictions, drug or food allergy, family history and authentication/signature.Diagnostic test data contain laboratory test, radiology and radiography report, genetic test, pathology test and authenticator/signature.Event data were considered as the reason for the visit, chief complaint, patient visit information, clinical progress note, and authenticator/signature.Insurance data including authenticator/signature, type of insurance, insurance ID, accident insurance, the total cost of operations, therapies, surgeon, specimen, drugs and special care for insurance data were considered.Follow-up data consists of date/time of follow-up, follow-up visit data, Iron load, chelation associated follow-up, liver function, cardiac function, endocrine function, bone complication, infections, dentition, rehabilitation and Signature/authenticator. Blood product concludes blood type, unit, number, blood group and RH of requested product, blood pack serial number, expired date, and authenticate.This minimum data set is not only applicable in Iran, but it has potential to use in the national and international level. All of the above mentioned will reduce the cost of thalassemia patients. Strategic plan for development infrastructures, standards, and communication tools for integrating such subsystems to electronic health record system (EHRS) is necessary for future research."} +{"text": "The author contributions for Manyando Simbotwe are incomplete. The correct, complete contributions for Manayando Simbotwe are: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing: original draft, and Writing: review & editing."} +{"text": "Regarding the article \u201cJacobson and Truax Method: evaluation of the clinicaleffectiveness of a home care program after prostatectomy\u201d, with DOI number:1518-8345.2249.3003, published in Rev. Latino-Am. Enfermagem, 2018;26:e3003, page 1:Where was written:\u201cEnfermagem Fundamental, Escola de Enfermagem da Universidade de S\u00e3o Paulo, Ribeir\u00e3oPreto, SP, Brazil.\u201dNow Read:\u201cEscola de Enfermagem de Ribeir\u00e3o Preto, Universidade de S\u00e3o Paulo, PAHO/WHOCollaborating Centre for Nursing Research Development, Ribeir\u00e3o Preto, SP, Brazil.\u201dRegarding the article \u201cCoping strategies of people living with AIDS in face of thedisease\u201d, with DOI number: 1518-8345.2284.2985, published in Rev. Latino-Am. Enfermagem,2018;26:e2985, page 1:Where was written:3 PhD, RN, Servi\u00e7o de Atendimento M\u00f3vel de Urg\u00eancia, Prefeitura Municipal deTimon, Timon, MA, Brazil. Adjunct Professor, Departamento de Enfermagem, UniversidadeFederal de Sergipe, Lagarto, SE, Brazil.\u201c4 MSc, Professor, Departamento de Enfermagem, Universidade Federal do RioGrande do Norte, Natal, RN, Brazil.5 Doctoral Student, Universidade Federal do Rio Grande do Norte, Natal, RN,Brazil.6 Doctoral Student, Programa de P\u00f3s-Gradua\u00e7\u00e3o em Enfermagem, UniversidadeFederal do Rio Grande do Norte, Natal, RN, Brazil. RN, Maternidade Professor LeideMorais, Natal, RN, Brazil. Professor, Departamento de Enfermagem, Universidade Federaldo Rio Grande do Norte, Natal, RN, Brazil.\u201dNow Read:3 PhD, Adjunct Professor, Departamento de Enfermagem, Universidade Federal deSergipe, Lagarto, SE, Brazil.\u201c4 MSc, Substitute Professor, Departamento de Enfermagem, Universidade Federaldo Rio Grande do Norte, Natal, RN, Brazil.5 Doctoral Student, Departamento de Enfermagem, Universidade Federal do RioGrande do Norte, Natal, RN, Brazil. Substitute Professor, Departamento de Enfermagem,Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil.6 Doctoral Student, Departamento de Enfermagem, Universidade Federal do RioGrande do Norte, Natal, RN, Brazil. RN, Maternidade Professor Leide Morais, Natal, RN,Brazil.\u201d"} +{"text": "Antibodies would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2016.The editors of https://publons.com) to receive recognition. Of course, in these initiatives we are careful not to compromise reviewer confidentiality. Many reviewers see their work as a voluntary and often unseen part of their role as researchers. We are grateful to the time reviewers donate to our journals and the contribution they make.We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial process. We aim to recognize reviewer contributions through several mechanisms, of which the annual publication of reviewer names is one. Reviewers receive a voucher entitling them to a discount on their next MDPI publication and can download a certificate of recognition directly from our submission system. Additionally, reviewers can sign up to the service Publons (Antibodies, see the link at the bottom of the webpage http://www.mdpi.com/reviewers.If you are interested in becoming a reviewer for Antibodies in 2016:Amengual, OlgaMuyldermans, SergeAndersen, Jan TerjeNayak, Tapan K.Aramaki, YukihikoNugent, KennethBallmer-Hofer, KurtPengo, VittorioBas, de LaatPierce, Grant N.Bizzarri, CarlaPons-Estel, GuillermoCarpentier, R.Reverter, Joan CarlesCassetta, LucaRouet, RomainChauhan, ArunRowley, Merrill J.Chu, Seung Y.Santambrogio, PaoloCorreia, Jo\u00e3o D.g.Schlothauer, TilmanCunningham, Madeleine W.Schrum, Adam G.Di Simone, NicolettaSciascia, SavinoDietrich, UrsulaSerrano, AntonioFavaloro, Emmanuel J.Singh, Satish K.Gummuluru, SuryaramSorice, MaurizioHaynes, Lia M.Steyaert, JanIgawa, TomoyukiTanha, JamshidIzquierdo-Useros, NuriaTaylor, KathrynKelchtermans, HildeTrainer, VeraKisand, K.Trouw, Leendert A.Klasse, Per JohanVan Bergen En Henegouwen, Paul M.P.Knight, Jason S.Van Steenbergen, H. W.Knight, VijayaWillis, Rohan G.Komiyama, TadazumiWozniak-Knopp, GordanaLim, MingXia, HongyanLockshin, Michael D.Zhu, ZhiqiangMitchell, JohnThe following reviewed for"} +{"text": "Antibodies would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2015. The editors of We greatly appreciate the contribution of expert reviewers, which is crucial to the journal\u2019s editorial decision-making process. Several steps have been taken in 2015 to thank and acknowledge reviewers. Good, timely reviews are rewarded with a discount off their next MDPI publication. By creating an account on the submission system, reviewers can access details of their past reviews, see the comments of other reviewers, and download a letter of acknowledgement for their records. In addition, MDPI has launched a collaboration with Publons, a website that seeks to publicly acknowledge reviewers on a per journal basis. This is all done, of course, within the constraints of reviewer confidentiality. Feedback from reviewers shows that most see their task as a voluntary and mostly unseen work in service to the scientific community. We are grateful to our reviewers for the contribution they make.Agadjanyan, MichaelKisand, KaiRakonjac, Jasna \u00c1lvarez-Vallina, LuisKiss, Margaret M.Robinson, MatthewArakawa, TsutomuKnight, Elysse M.Rosenberg, Jacob M.Barelle, CarolineKok, Robbert J.Rouet, RomainBerrih-Aknin, SoniaKristensen, PeterRyba-Stanis\u0142awowska, MonikaBethea, John R.Laborda, JorgeSarafanov, Andrey G.Capito, FlorianLannfelt, LarsSawant, DeepaliChevalier, NinaLeusen, JeanetteSchwab, KarenChu, Seung Y.Liu, JeanSchwimmer, Lauren Chudasama, VijayLood, ChristianShoenfeld, YehudaCorreia, Jo\u00e3o D.g.Morbidelli, MassimoSiegrist, Claire-AnneDe Simoni, MGMoricoli, DiegoSimons, MikaelDeFranco, Anthony L.Moutsopoulos, HaralamposStorkus, WalterDiCara, DanielleMulero, VictorStreltsov, Victor A.Dimitrov, DimiterMuyldermans, SergeTansey, Mal\u00fa G.Drabek, DubravkaNagele, Robertten Brinke, Anja Dumontet, CharlesNallaparaju, KalyanThomas, Helen E.Dumoulin, MireilleNickerson, KevinUrowitz, Murray B.Epstein, Alan L.Niess, Jan Hendrikvan Bergen en Henegouwen, P.Ghiggeri, Gian MarcoNocentini, GiuseppeVan Blarcom, ThomasGoldmana, Ellen R.Panza, FrancescoVilanova, ManuelHendriks, Rudi W.Parodis, IoannisVissink, ArjanHonda, ShinyaPaul, St\u00e9phaneWilliams, Sarah K.Igdoura, Suleiman A.Polito, LetiziaXu, JinJensen, Charlotte H.Quadros, Edward V.Zalutsky, Michael R.Jeong, Ki JunRabuka, David"} +{"text": "Following publication of the original article , the autThe correct names are: Sara Castiglia, Aloe Adamini, Deborah Rustichelli, Laura Castello, Katia Mareschi, Giuseppe Pinnetta, Marco Leone, Alessandra Mandese, Ivana Ferrero, Giulia Mesiano and Franca Fagioli."} +{"text": "Due to an oversight Marina Campos Rocha was not included as an author in the published article. The corrected Author Contributions Statement appears below:FS conceived the study. JS and FS designed the experiments and wrote the manuscript. JS, LB, VC, LG-E, AO, WD, MR, KM, and IM performed the experiments. JS, LB, VC, LG-E, AO, WD, KM, IM, and FS interpreted the results and analyzed the data. LB, VC, LG-E, AO, WD, KM, IM, DAS, FF, DGS, MT, and FS contributed reagents, materials, and analysis tools. All authors read and approved the final manuscript.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Scientific Reports 10.1038/s41598-019-51100-4, published online 22 October 2019Correction to: The original version of this Article contained errors in the spelling of the authors Stefano Pirr\u00f2, Ivana Matic, Arianna Guidi, Letizia Zanella, Angelo Gismondi, Rosella Cicconi, Roberta Bernardini, Vittorio Colizzi, Antonella Canini, Maurizio Mattei & Andrea Galgani which were incorrectly given as Pirr\u00f2 Stefano, Matic Ivana, Guidi Arianna, Zanella Letizia, Gismondi Angelo, Cicconi Rosella, Bernardini Roberta, Colizzi Vittorio, Canini Antonella, Mattei Maurizio & Galgani Andrea respectively.These errors have now been corrected in the PDF and HTML versions of the Article."} +{"text": "Keywords: Common mental disorders, lay counselling, Nepal, randomized controlled trial, task shifting, addendumThe authors of Markkula, et al , would l"} +{"text": "Cristina Tassorelli, Silvano Cristina, and Giorgio Sandrini:Department of Neurorehabilitation, IRCCS Mondino Foundation, Pavia, ItalyArmando Perrotta and Francesco PierelliIRCSS fondazione Don Carlo Gnocchi, Rome, ItalyIn Alvisi et al. , the pre"} +{"text": "Staphylococcus sciuri strain B9-58B, isolated from retail pork. This strain contains a 2,761,440-bp chromosome and a 162,858-bp megaplasmid. The genome contains putative genes involved in virulence, the stress response, and antimicrobial agent and heavy metal resistance.Here, we report the genome sequence of the megaplasmid-bearing Staphylococcus sciuri strain B9-58B, isolated from retail pork. This strain contains a 2,761,440-bp chromosome and a 162,858-bp megaplasmid. The genome contains putative genes involved in virulence, the stress response, and antimicrobial agent and heavy metal resistance.Here, we report the genome sequence of the megaplasmid-bearing Staphylococcus spp. are major foodborne pathogens that cause food poisoning through the production of enterotoxins .Here, we announce the draft genome sequence of Sa442-2 . This is Sa442-2 . This is Sa442-2 for de nS. sciuri B9-58B contained a single chromosome and a megaplasmid, which were 2,761,440 and 162,858\u2009bp, respectively, with GC contents of 32.66% and 31.13%. While it was possible to close the chromosome, the plasmid remained unclosed, with 39 contigs. The B9-58B genome was annotated using the RAST tool kit. The chromosome contained 2,712 protein-coding sequences, 62 tRNA genes, and 16 rRNA genes, while the megaplasmid had 218 coding sequences. Multiple stress response genes, including osmotic, oxidative, heat/cold shock, and periplasmic stress-related genes, in addition to detoxification and carbon starvation genes, were chromosomally located. This strain contained genes conferring resistance to a variety of antibiotics and heavy metals, such as bacitracin, fluoroquinolones, copper, cobalt-zinc-cadmium, and mercury. Interestingly, the chromosome contained a Mycobacterium virulence operon that is involved in protein synthesis and facilitates invasion and intracellular resistance. The megaplasmid contained genes conferring resistance to cobalt, zinc, copper, cadmium, fosfomycin, and chromium.The genome of PRJNA555628. The whole-genome shotgun sequences for Staphylococcus sciuri strain B9-58B have been deposited in GenBank under accession number CP041879 for the chromosome and accession numbers CP041880, CP041881, CP041882, CP041883, CP041884, CP041885, CP041886, CP041887, CP041888, CP041889, CP041890, CP041891, CP041892, CP041893, CP041894, CP041895, CP041896, CP041897, CP041898, CP041899, CP041900, CP041901, CP041902, CP041903, CP041904, CP041905, CP041906, CP041907, CP041908, CP041909, CP041910, CP041911, CP041912, CP041913, CP041914, CP041915, CP041916, CP041917, and CP041918 for the plasmid.The raw sequence reads have been deposited in the Sequence Read Archive (SRA) under accession number"} +{"text": "Author Contributions statement appears below.\u201cPatricia Sampaio Tavares Veras\u201d was not included as an author in the published article. The corrected \u201cConceived and designed the experiments: MA, CT, and CB. Performed the experiments: MA, JC, VA, LdS, MB, MS, and CT. Analysed the data: MA, BA, LF, PV, SK, and CB. Contributed reagents, materials, analysis tools: JV, LF, LG-S, MSS, DMF, BA, CB, and PB. Wrote the paper: MA, PV, CB, and BA.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The third author\u2019s contributions are incorrect. Madhu Mati Goel\u2019s correct contributions are: Conceptualization, Data Curation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing\u2013review & editing."} +{"text": "Burbelo\u201d was not included as an author in the published article. The corrected Author Contributions Statement appears below.\u201cAL, IS, and VR designed research and wrote the paper. AL, C-SW, PY, JN, ER, HM, MS, BL, JS, SR, CV, AR, IM, AP-D, and PB performed research and analyzed data. AL, SP, MA, MM, DP, VR, and IS provided clinical care to enrolled patients\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} diff --git a/PMC_clustering_642.jsonl b/PMC_clustering_642.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..e82ef0ed301b207b1d69315586ee3e9dfeff8e3f --- /dev/null +++ b/PMC_clustering_642.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:91c4cb7950f922d7d56da7a650d3a441b78481d83fe83bb414b0b5ac12f015c7 +size 79893904 diff --git a/PMC_clustering_643.jsonl b/PMC_clustering_643.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..210f6725f4c3ebfedae542d73e6667a17637676a --- /dev/null +++ b/PMC_clustering_643.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:d683df9e5c41eb337b4859e83372d0ada49982cb787d328edd0861d4a3788617 +size 94422724 diff --git a/PMC_clustering_644.jsonl b/PMC_clustering_644.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..d0a7ce40cc446d398dbc9fc739a50da08f03c88d --- /dev/null +++ b/PMC_clustering_644.jsonl @@ -0,0 +1,753 @@ +{"text": "An incorrect version of Fig 2 was published in error. This article was republished on June 16, 2020 to correct for this error. Please download this article again to view the correct version."} +{"text": "The corrected figure is shown here. The authors apologize for any confusion. This error appears only in PDF versions downloaded on or before January 21, 2021.In the initial published version of Figure 8 B, \"PI4KII\" should have been crossed out in all four instances to show that the protein is absent in the"} +{"text": "In the published article, author Kok Soon Phua had a wrong affiliation. Instead of affiliation 4, they should have affiliation 5.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Corresponding editor: John DolanIn the first version of this article, Figures 4 and 5 were mistakenly switched in the text. This has now been corrected. The publisher regrets the error."} +{"text": "This article was republished on March 16, 2020, to correct the author list. Please download this article again to view the correct version."} +{"text": "An incorrect version of Supporting information file S1 Dataset was published in error. The publisher apologizes for this error. This article was republished on February 22, 2021 to correct for this error. Please download this article again to view the correct version."} +{"text": "An incorrect version of Fig 1 was published in error. The publisher apologizes for this error. This article was republished on May 5, 2020 to correct for this error. Please download this article again to view the correct version."} +{"text": "In the original article, we neglected to include the funder NIH/NIA, P30 AG066462 to KM.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The correct and original figure are shown below and both the online full-text and PDF versions of the article have been updated.Fig. 8 (correct image).Fig. 8 .The authors apologise for these errors and any inconvenience they may have caused.This correction does not affect the results in the article or the conclusions of this study."} +{"text": "Tianxin Ye. The correct spelling is Tianxing Ye.An author name was incorrectly spelled as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Dr. Santora will discuss research priorities for the Division of Extramural Activities. He and his team will in addition be available for small group discussions"} +{"text": "An author name was incorrectly spelled as Chooah Qutesh. The correct spelling is Chooah Outesh.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An author name was incorrectly spelled as Lilhong Liu. The correct spelling is Lihong Liu. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Acorus calamus L. should be changed to Colocasia esculenta (L.) Schott. The authors would like to apologize for any inconvenience caused to the readers by these changes.The authors wish to make the following corrections to their paper . The aut"} +{"text": "An incorrect version of S1 Data was published in error. The publisher apologizes for the error. This article was republished on July 20, 2020 to correct for this error. Please download this article again to view the correct version."} +{"text": "Sathypalan. The correct spelling is Sathyapalan.An author name was incorrectly spelled as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Furthermore, they apologize to the readership for any inconvenience caused.The authors have re-examined their data and realized that"} +{"text": "NFIA was incorrectly captured as NIFA. The article title has been updated above and in the original article.Following publication of the original article , an erro"} +{"text": "An author name was incorrectly spelled as Stanziano Mario. The correct spelling is Mario Stanziano. Also, there was an error regarding the affiliations for authors Rosalba Morese and Sara Palermo. This is now corrected in the affiliation list.The authors apologize for these errors and state that they do not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original article, authors Yan Peng and Bigang Mao were not listed as sharing co-first authorship.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The authors wish to make the following corrections to this paper :In Figure 3B, the flow cytometry chart of Dovitinib is the same as that of BA-12 2.5 \u03bcM. This was an error made during figure construction. The corrected Figure 3 is shown below .The authors would like to apologize for any inconvenience caused to the readers by these changes. These changes have no material impact on the conclusions of our paper. We apologize to our readers."} +{"text": "In the published article, the author Tao Xiao was given the wrong affiliation. The author should have affiliation 2 instead of affiliation 3.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An incorrect version of Supporting information file S1 Data was published in error. The publisher apologizes for this error. This article was republished on January 13, 2020 to correct for this error. Please download this article again to view the correct version."} +{"text": "Furthermore, they apologize to the readership for any inconvenience caused.The revised version of"} +{"text": "Qinjun Pan. The correct spelling is Qingjun Pan.An author name was incorrectly spelled as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original article has been updated."} +{"text": "Applied Microscopy. It was published in volume 50 with incorrect citation number.An error occurred during the publication of the below article in In this correction article the old and new citation metadata is published in Table\u00a0The original article has been updated. The publisher apologizes for the inconvenience caused to our authors and readers."} +{"text": "This article was republished on November 8, 2019, to correct a linking error introduced during the typesetting process. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "Burkholderia thailandensis and Francisella tularensis Infection\u201d. We apologize for this error and state that the scientific conclusions are unaffected. The original article has been updated.There is an error in the title. The correct title of the article is \u201cModu"} +{"text": "Xiang-Peng Xiong. The correct spelling is Xian-Peng Xiong.An author name was incorrectly spelled as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "There is an error in the Funding statement. The correct number for Marie Sk\u0142odowska-Curie Individual Fellowship from the European Union's Horizon 2020 is 750200.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Cumming Duan. The correct spelling is Cunming Duan.An author name was incorrectly spelled as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, Zheng-gui Du was not included as a corresponding author.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This article was republished on June 25, 2020, to remove a Supporting Information file that was incorrectly included in the originally published article. The main article text and figures are unchanged. Please download this article again to view the correct version."} +{"text": "Due to an error during the production, the version of this article that was first published contained errors within Figure 3. The figure has now been corrected. The publisher apologises for this error."} +{"text": "An incorrect version of Fig 4 was published in error. The publisher apologizes for this error. This article was republished on August 10, 2020, to correct for this error. Please download this article again to view the correct version."} +{"text": "In the published article, there was an error in the Supplementary Data Sheet S1 as published. The original supplementary data included information which created a small risk of participant re-identification. This data has now been replaced with a fully anonymized file.The authors apologize for this error and state that this does not change the analyzed variables or scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This article was republished on April 17, 2020, to remove Supporting Information files that were incorrectly included in the originally published article. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "In the original published version of this article, the supplementary video showed the patient's identification number. This has now been removed. The authors apologize for this error. Both the HTML and PDF versions of the article have been updated to correct the error."} +{"text": "Co-author Aijun Zhang was not included as a co-corresponding author in the published article.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An incorrect version of Fig 1 was published in error. The publisher apologizes for the error. This article was republished on April 24, 2020, to correct for this error. Please download this article again to view the correct version."} +{"text": "Loss of Jarod Rollins. This mistake has been corrected online.In the version of the microPublication originally published online, the name of the first author was incorrectly spelled. The correct name is"} +{"text": "An incorrect version of S1 Fig was published in error. This article was republished on July 27, 2020 to correct for this error. Please download this article again to view the correct version."} +{"text": "We read with great interest the article by Drs. Robba and Taccone . We agre"} +{"text": "In the original article, we neglected to include the funder \u201cNational Science Foundation REU grant 1756912 to Melanie E. Gucwa\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Furthermore, they apologise to the readership for any inconvenience caused.The authors have re-examined their data and realized that"} +{"text": "An incorrect version of Supporting Information file S1 Data was published. The publisher apologizes for this error. This article was republished on February 9, 2021 to correct for this error. Please download this article again to view the correct version."} +{"text": "Akihiro Matsutmoto. The correct spelling is Akihiro Matsumoto.In the original article, an author's name was incorrectly spelled as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This article was republished on May 15, 2020, to correct errors in the figure captions that were introduced during the typesetting process. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "Mascha Raucher. The correct spelling is Mascha Rauscher.An author name was incorrectly spelled as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This article was republished on July 6, 2020, to remove a paragraph that was incorrectly included in the originally published article. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "WT in Figure 6D, the corrected figure is shown below (The author wishes to make the following correction to this paper . Due to wn below .The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "This article was republished on April 16, 2020, to correct errors in the Introduction and Acknowledgments introduced during the typesetting process. The publisher apologizes for these errors. Please download this article again to view the correct version."} +{"text": "Due to an editorial error, the wrong version of the manuscript was typeset and published. The publisher apologizes for this mistake. The original article has been updated."} +{"text": "The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated.There is an error in the Funding statement of . The cor"} +{"text": "An incorrect version of S1 Data was published in error. The publisher apologizes for the error. This article was republished on October 8, 2020 to correct for this error. Please download this article again to view the correct version."} +{"text": "An author name was incorrectly spelled as Xulian Wang. The correct spelling is Xuelian Wang.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The original version of this article unfortunately contained mistakes.Carsten G. Jungbauer was missing in the author line and the spelling of the name Thomas Fetsch was incorrect.The original article has been corrected."} +{"text": "This article was republished on February 11, 2021, to remove Supporting Information files that were incorrectly included in the originally published article. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "An incorrect version of the Data Availability statement was published in error. This article was republished on April 1, 2019, to correct for this error. Please download this article again to view the correct version."} +{"text": "Due to an editorial error, an outdated version of the manuscript was published. The publisher apologizes for this mistake.The correct article version has now been published."} +{"text": "Furthermore, they apologize to the readership for any inconvenience caused.The authors have re-examined their data and realized that"} +{"text": "In the original article, we neglected to include a funder. This work was also supported by the Engineering and Physical Sciences Research Council [grant number EP/P011454/1].The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An author name was incorrectly spelled as Hyun J. Chong. The correct spelling is Hyun Ju Chong.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original publication of the article, first name and last names of all authors were swapped.The correct author names are published in this version.The original version was updated."} +{"text": "This article was republished on April 8, 2020, to correct an erroneous unicode character in the Materials and methods section. The publisher apologies for the error. Please download this article again to view the correct version."} +{"text": "This article was republished on April 17, 2020, to correct errors in the Funding and Competing interests statements. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "The authors have requested that the following changes be made to their paper .The production process carried out in the pilot plant to obtain the citrus fibre ingredient used in this work had associated intellectual rights that are the property of AZTI. The original authors therefore wish to add the following three authors from AZTI to the paper.The author\u2019s contribution was: \u201cC.T., S.A.-S. and C.B. produced the fibre and physicochemically characterised the citrus fibre ingredient.\u201dWe would like to apologize for any inconvenience caused to the authors and readers by this mistake. The published version will be updated on the article webpage, with a reference to this notice."} +{"text": "The images for all the figures are incorrect. The figure captions are correct and appear in the correct order. Please see the correct Figs"} +{"text": "The original version of this article unfortunately contained a mistake. In the author list, the first and last names were tagged incorrectly. The corrected author list is given above.The original article has been corrected."} +{"text": "Incorrect versions of Fig 3 and the Supporting Information files were published in error. This article was republished on May 18, 2020, to correct for this error. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "In the published article, there was an error regarding the affiliation(s) for Laura Brzoska. As well as having affiliation 1, they should also have affiliation 2.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An incorrect version of S1 Table was published in error. The publisher apologizes for the error. This article was republished on March 18, 2020, to correct for this error. Please download this article again to view the correct version."} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original article has been updated."} +{"text": "In the original published version of this article, an incorrect version of figure 2a was displayed. This has now been corrected as shown below. The author apologizes for this mistake. Both the HTML and PDF versions of the article have been updated to correct the error."} +{"text": "An incorrect version of Fig 10 was published in error. This article was republished on February 28, 2020 to correct for this error. Please download this article again to view the correct version."} +{"text": "An incorrect version of Fig 7 was published in error. This article was republished on August 11, 2020 to correct for this error. Please download this article again to view the correct version."} +{"text": "In the original version of this article, Fig.\u00a03 was published in an incorrect format. The correct figure is published with this correction."} +{"text": "Due to a production error, the graphical abstract was removed from the final version of the article. The graphical abstract and its caption appear below.The publisher apologizes for this mistake. The original article has been updated."} +{"text": "This panel has been replaced with the correct centriole image; the revised Fig. 1 is shown below. All versions of the article have been corrected. This error appears only in PDF versions downloaded on or before June 23, 2020.The authors noticed that an incorrect image had been inadvertently included in the paper. The middle centriole with a cilium in Fig. 1 E is the same electronmicrograph that had been previously used to illustrate a cilium in Sahabandu et al. (2019."} +{"text": "The original version of this article unfortunately contained a mistake. The name of one author is not presented correctly in the author group.The correct name should be Franz Marxreiter."} +{"text": "The correct legend appears below.In the original article, there was a mistake in the legend for Also in"} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original article has been updated."} +{"text": "The authors wish to make the following correction to this paper .The chart element colors were inadvertently mislabeled. Please replace the original figure above with the corrected figure below. Nutrients. The published version will be updated on the article webpage, with a reference to this correction notice.These changes have no material impact on the conclusions of our paper. We apologize for any inconvenience to the readers of"} +{"text": "There is an error in the Funding statement. The correct number for the British Heart Foundation funding is grant no. CH/1/32804.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The authors regret that the authorship of this article was published incorrectly. The above author details are correct, and the online version has been updated.The authors would like to apologise for any inconvenience caused."} +{"text": "In the original article, there was a mistake in the title as published. The first part of the title \u201cSchool Refusal or Truancy?\u201d was missing in the final version. The complete title appears above. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated."} +{"text": "An incorrect version of the running short title was published in error. The publisher apologizes for the error. This article was republished on March 1, 2021, to correct for this error. Please download this article again to view the correct version."} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original article has been updated."} +{"text": "To the Editor,We read the article by He et al.The authors declare no potential conflict of interests."} +{"text": "An incorrect version of the author byline was published in error. This article was republished on May 8, 2020 to correct for this error. Please download this article again to view the correct version."} +{"text": "Medicine has published two,2 articles with protocol mistakenly added to the title. The titles have been updated to remove this.In recent issues,"} +{"text": "The authors wish to make the following corrections to this paper [, regarding an error in Figure 6.is paper , regardiIn the original article, there was a mistake in Figure 6 as published. The aforementioned figure does not display the correct modelled connectivity matrices. The corrected Figure 6 appears below. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The published version will be updated on the article webpage, with a reference to this correction notice."} +{"text": "The Only Way is Essex were incorrect. These have now been corrected.In Table 2, some of the entries for alcohol content in"} +{"text": "In the published article, an author name was incorrectly written as Andrew S. MacElory. The correct spelling is Andrew S. MacElroy.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way."} +{"text": "Incorrect Author NameIn the published article, an author name was incorrectly written as Wengting Wang.The correct spelling is Wenting Wang.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original publication , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "The authors wish to make the following corrections to their paper . Eight s"} +{"text": "In the original publication , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "Due to a production error, in the original article, incorrect files were used for The publisher apologizes for this mistake. The original article has been updated."} +{"text": "In the published article, an author name was incorrectly written as Zhujie Cheng. The correct spelling is Zujie Cheng.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated.In the original publication , there w"} +{"text": "In the original publication, there was a mistake in Figure 3 as published . We obseThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "This article has been corrected to fix a typo incorrectly stating that 325 million Americans suffer from osteoarthritis. The correct number if 32.5 million. Both instances of this error, located in the Abstract and Introduction, have been corrected. The journal regrets that this typo was not identified and corrected prior to publication."} +{"text": "In the original publication , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "In the previously published version of this article, the representative image of the wound healing assay for 5637 cells overexpressing YAP in Figure 1G' is wrong. The updated Figure 1 is as follows. The correction made in this erratum does not affect the original conclusions. The authors apologize for any inconvenience or misunderstanding that this error may have caused."} +{"text": "The following information is missing from the Funding statement: This work was supported by the Soonchunhyang University Research Fund. HJ received this funding under the grant agreement number 2023\u20130067.www.editage.co.kr) for English language editing.The following statement was incorrectly added to the Acknowledgment section: We would like to thank Editage ("} +{"text": "In the published article, there was an error in the Funding statement. No funding statement was inserted. The correct Funding statement appears below.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, there was an error in the author list. Author Abigail A. Scholer was erroneously placed as second from last author, instead of being placed as last author.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, an author name was incorrectly written as Alessandro Michenzi. The correct spelling is Alessandro Michienzi.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Furthermore, they apologize to the readership for any inconvenience caused.The authors have re-examined their data and realized that"} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original article has been updated."} +{"text": "Ziqaing Hong. The correct spelling is Ziqiang Hong.In the published article, an author name was incorrectly written as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This article has been corrected at the request of the authors to include Aron Weingarten as third author. Mr. Weingarten was erroneously omitted from the author list upon initial submission and publication. The authors apologize for this error."} +{"text": "After verifying the source data, the unit has been replaced by ng/mL in both the text and the figure. This has been corrected online.The authors apologize for this error and any confusion it may have caused."} +{"text": "The authors wish to add two authors to the original paper .The authors are requesting a change of authorship for this paper: The paper was published with just Marko M\u00e4kynen and Fernando S. Schlindwein as authors when it should have listed all four authors .The relevant manuscript contributors are not fully listed. After confirming all authors\u2019 detailed contributions. It was decided to correct the authorship to appropriately list the significant contributions to the intellectual content of the manuscript.The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the academic editor. The original publication has also been updated."} +{"text": "It has been over three decades since the thrombin receptor was cloned and its mechanism of action revealed . We now JCI, Denorme and colleagues (In this issue of the lleagues investiglleagues . The A a"} +{"text": "In the published article, an author name was incorrectly written as Robina Josiah Willcock. The correct spelling is Robina Josiah Willock.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, the Funding statement was mistakenly omitted. The correct Funding statement appears below.This work has been partially supported by a grant from the IRCCS Fondazione Stella Maris .The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original publication , there wThe authors state that the scientific conclusions are unaffected. This correction wasapproved by the Academic Editor. The original publication has also been updated."} +{"text": "In the original publication , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "Due to a production error, a note stating that Ke Peng is the first author and Jingjing Jiang is the co-first author was omitted from the original article.The publisher apologizes for this mistake. The original article has been updated."} +{"text": "In the initially published version of our article, we found that there are the errors in Figure 5. Specifically, the survival curve of Figure 5B and 5F are incorrect. The errors occurred during assembling the figures. The correct Figure 5 is provided below. This correction will not affect the results and conclusions. The authors apologize for any inconvenience this may cause."} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "In the original publication , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated with the correct"} +{"text": "The first author's name was incorrectly published in the above article. This has since been corrected. The Publisher apologises for the error."} +{"text": "In the original publication , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updadated."} +{"text": "In the original publication , there wThe authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original article has been updated."} +{"text": "In the original version of our article, there was an error in Fig. 3E. Specifically, the bar chart image of SCC9 Invasion in Figure 3E is incorrect. The correct image is provided below. This correction will not affect the results and conclusions. The authors apologize for any inconvenience this may have caused."} +{"text": "In the original publication . In FiguThe authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "In the published article, there was an error in the Funding statement. We did not introduce or acknowledge the funding source(s) for this research in the article. The correct Funding statement appears below."} +{"text": "In the published article, an author name was incorrectly written as Weili Sai. The correct spelling is Wenli Sai.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated"} +{"text": "Error in FigureFigure 5 as published. The images shown for the control group in 24 h are incorrect; the images for the control group in 48 h were inadvertently inserted because the two images are similar. The corrected Figure 5 appears below. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated.In the original publication , there w"} +{"text": "In the original publication , the figThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "A draft version of the correction notice for this article was mistakenly published. It has now been replaced with the final version. The Publisher apologizes for this error."} +{"text": "Funding statement. Two relevant sources of funding were omitted. The correct Funding statement appears below.In the published article, there was an error in the The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Following publication of the original article, it came to the authors\u2019 attention that the captions of Figs.1 and 2 had been erroneously swapped. The figures have since been corrected in the published article. The authors thank you for reading this correction and apologize for any inconvenience caused."} +{"text": "In the published article, there was an error in the Acknowledgments section. The Coperio Centre was mentioned as an external recruitment site. However, no participants were recruited from the Coperio Centre. The corrected Acknowledgments section appears below:"} +{"text": "The original publication of this article contained erroneous values in tables 3 and 4. The incorrect and correct values are shown in this correction article. The original article has been updated. This does not affect the conclusions of the article."} +{"text": "In the original article , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original article has been updated."} +{"text": "Acknowledgments was mistakenly not included in the publication. A correction has been made to Acknowledgments:In the published article, information in the"} +{"text": "The authors regret that incorrect details were given for ref. 22 in the original article. The correct version of ref. 22 is given below as ref. The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In the published article, there was an error regarding the affiliation for author Anne-Sophie Berthold. Instead of having affiliation 25 they should have 14 .The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The retraction has been agreed given the journal has received evidence confirming that the peer review process of this paper was manipulated. As a result, the conclusions reported in the article are not considered reliable.The following article, published online on {First published: 14 March 2022} in Wiley Online Library {"} +{"text": "In the original publication , there wIn the original publication , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "There was a typographical error in the original publication . A correThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "In the published article, there was an error in the Funding statement. The grant number was incorrect. The correct Funding statement appears below."} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "In the published article, the last name for author \u201cIsrael Rubinstein\u201d was incorrectly written as Rubenstein. The correct spelling is Rubinstein.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "They also apologize to the readership for any inconvenience caused.The authors have re-examined their original data, and realize which data panel should have been included for this experiment in this figure. The corrected version of"} +{"text": "In the original publication , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "In the original publication , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "The authors wish to make the following corrections to this paper: .There was a mistake in Figure 3 as published. Figure 3c must be substituted with the following one. The corrected The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "The online version contains an error. In the author group, the order of authors was incorrect. Mr Dara Kavanagh is the lead author and therefore should be named as the last author. This has now been corrected for all fields.The original article has been corrected."} +{"text": "In the published article, an author name was incorrectly written as Heng-Chi Pan. The correct spelling is Heng-Chih Pan.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Incorrect Author NameIn the published article, an author name was incorrectly written as LiQing Liang. The correct spelling is Liqin Liang.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Huanan Yuan. The correct spelling is Huanran Yuan.In the published article, an author name was incorrectly written as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, an author name was incorrectly written as David Wittenberg. The correct spelling is David Wittenburg.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original publication , The preIn the original publication , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "Due to a production error, the final copyedited version of this manuscript was not used.The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Figure 6 as published. The corrected Figure 6 and its caption appear below.In the published article, there was an error in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original publication , there wIn In The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "The retraction has been agreed given the journal has received evidence confirming that the peer review process of this paper was manipulated. As a result, the conclusions reported in the article are not considered reliable.The following article, published online on {First published: 08 August 2022} in Wiley Online Library {"} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this error. The original article has been updated."} +{"text": "Funding statement as published. The reference for the funding was missing. The correct Funding statement appears below.In the published article, there was an error in the"} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Please download this article again to view the correct version.An incorrect version of Revision 1, Author Response file was published in error. The publisher apologizes for this error. This article was republished on 10"} +{"text": "This article was republished on April 3, 2023, to correct the fourth author\u2019s name in the article PDF. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "In the published article, an author name was incorrectly written as Robert Redjak. The correct spelling is Robert Rejdak.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "DOI was included in the XML metadata.Due to a production error, the wrong The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "The retraction has been agreed given the journal has received evidence confirming that the peer review process of this paper was manipulated. As a result, the conclusions reported in the article are not considered reliable.The following article, published online on {First published: 07 October 2022} in Wiley Online Library {"} +{"text": "Author list. The author \u201cXin Li\u201d was erroneously excluded, and the order of authors was incorrect. The corrected author list appears above.In the published article, there were errors in the Affiliations were erroneously attributed to the incorrect authors. The correct Affiliations appear above.In the published article, some The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, an author name was incorrectly written as Zhangzuo Liu. The correct spelling is Zhangsuo Liu.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original article has been updated."} +{"text": "Due to a production error, The corrected The publisher apologizes for this mistake.The original version of this article has been updated."} +{"text": "Author Contributions. The following sentence was missing. MK performed this work in fulfillment of the requirements for obtaining the degree \u201cDr. med.\u201d.In the published article, there was an error in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The authors also apologize to the readership for any inconvenience caused.A revised version of"} +{"text": "The correct spelling is \u201cKuang-Chao Cheng\u201d. This has been corrected and thereby the citation and author initials in the author contribution section have been corrected.In the published article, an The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, an author name was incorrectly written as Berkley Walker James. The correct spelling is Berkley James Walker.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "They also apologize to the readership for any inconvenience caused.The authors were able to re-examine their original data files, and realized that this figure had been inadverently assembled incorrectly. The revised version of"} +{"text": "This email has been changed to:In the original published version of this article, the corresponding author email (azalomar@ksu.edu.sa\u201d\u201cThe authors apologize for the errors. Both the HTML and PDF versions of the article have been updated to correct the errors."} +{"text": "In the published article, an author name was incorrectly written as Zhifu Shi. The correct spelling is Zifu Shi.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The publisher apologizes for this mistake.The original version of this article has been updated."} +{"text": "Funding statement that we omitted the acknowledgment information in this article. We would like to add this acknowledgment after the conclusion section. The correct funding statement appears below.In the published article, there was an error in the"} +{"text": "There are errors in the Funding section. The correct Funding statement is: This study was supported by a grant from Asan Institute for Life Sciences (grant No. 2016\u20130220)."} +{"text": "The authors wish to make the following change to their paper . Figure \u00a0to:\u00a0The authors would like to apologize for any inconvenience caused to the readers by these changes. The changes do not affect the scientific results. The original publication has also been updated."} +{"text": "Figure 4 as published. Figure 4F was unintentionally duplicated, which was a careless mistake during the revision. Here is the new Figure 4 that has been corrected. The corrected Figure 4 appears below. The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated. We thank an astute reader for their input on this matter.In the original publication , there wThe authors would like to apologise for any inconvenience caused."} +{"text": "Due to a production error, labels for The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Due to a production error, there was a mistake in the legends for The publisher apologizes for this mistake. The original article has been updated."} +{"text": "In Qiong Qin et al.In figure 1, the images on labels e and f were duplicated. The images on label e must be deleted. The authors apologize for the error and any inconvenience it may have caused."} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "In the original publication , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "Due to a production error, the captions did not match the figures correctly.The artwork of Scheme 1 was missed and replaced by Figure 1, causing all subsequent figures to bear the caption of the next figure.The publisher apologizes for this mistake. The original article has been updated."} +{"text": "In the published article, an author's name was incorrectly written as Dhram Singh Meena. The correct spelling is Dharm Singh Meena.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original version of this article, reference 13 in the references list had the incorrect DOI listed against it.10.1177/14687941211065163.This has now been updated to doi: The original article has been corrected online to rectify this error."} +{"text": "The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "Funding statement. The Funding information was missing in the original article. The correct Funding statement appears below.In the published article, there was an error in the"} +{"text": "In the published article, an author name was incorrectly written as Bandar Alosaim. The correct spelling is Bandar Alosaimi.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Due to an error in the editorial process, this article was not proofread before publication. The article has now been proofread and the necessary journal-related corrections have been implemented. The previous version is available in the The article title has also been corrected.The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Adigal Fig. 2 was included in the original article. The correct version of Fig. 2 is presented here.The authors regret that the incorrect caption for Fig. 2 Network architecture.b and d were incorrectly shown in the original manuscript. The corrected list of affiliations is as shown here.The authors also regret that affiliations The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The correct statement is \u201cThe original contributions presented in the study are publicly available. This data can be found here: The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "In Figure 5H a duplication in the images was detected due to an error by the author group. The corrected panel is shown below.The authors regret this error."} +{"text": "The result of the dose calculation is not affected by this. The authors regret the confusion this may have caused.In the article by Gr\u00fcnewald al. 2023, there w"} +{"text": "Both authors should have been listed as co-first authors. The publisher apologizes for this mistake.Due to a production error, there was an error regarding the authorship for The original version of this article has been updated."} +{"text": "Due to a production error, there was a mistake in the figure and table ordering as published in the HTML and XML files. The correct order appears in the final PDF file. Corrections were only required in the HTML and XML files. The publisher apologizes for the mistake. The original article has been updated."} +{"text": "In our original paper, in theAcknowledgments section, one sentence is missing. The complete Acknowledgmentssection is below. This correction does not affect any of the resultsof the work."} +{"text": "The corrected table appears below.Due to a production error, a formatting error was made. In The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Due to a production error, there was a mistake in the figures as published. The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "In the published article, an author name was incorrectly written as Yingkia Li. The correct spelling is Yingkai Li.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, an author name was incorrectly written as Aileen C. Tartaninan. The correct spelling is Aileen C. Tartanian.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In this talk we want to highlight three of these algorithms/approaches. The first is MoSS , a frequuniverses. Each un"} +{"text": "After publication of this article, it came to our attention that an author\u2019s name was misspelled. The correct name is Elise P Jansma.The authors and Publisher apologize to the readers for the inconvenience caused."} +{"text": "There was an error in the name of the first author. The correct name is: Dzmitry A. Kaliukhovich"} +{"text": "There was an error with the presentation of Figure 5. Part C was displayed in black and white. The correct image displays the red and green insulin staining, which is viewable at the following link: ."} +{"text": "This figure should be replaced by the following figure. The previous legend of Figure\u2009\u20094 is correct. The authors would like to make the following correction. In Figure"} +{"text": "There was an error in the sixth author's name. The correct name is James Marion May."} +{"text": "In Figure 2, the top right hand panel in part B is a duplicate of the top panel in part A. The figure legend is accurate.The correct figure can be downloaded from the following link:"} +{"text": "There is an error in the equation. The correct equation is displayed here:"} +{"text": "The version of Figure 2 that appears in the article was incomplete. The correct version is available here:"} +{"text": "There was an error in the author byline. J. Hummers is not an author on this paper."} +{"text": "The version of Figure 6 in the article is incorrect.The correct version is available here:"} +{"text": "In the Materials and Methods section, a formula for the calculation of the relative percent survival is presented incorrectly. A \"-\" (minus) has been replaced with an \"=\" . The correct equation can be viewed here:"} +{"text": "Akin osteotomy is a common component of hallux valgus surgery. Holding the osteotomy in good position with a well placed staple can prove difficult. To aid this, a marker pen is used to apply ink to the tip of the proximal limb of the staple . A hole"} +{"text": "In the Day 2 row, the second image to the right is incorrect. Please view the correct figure here:"} +{"text": "There is an error in the label of Figure 5a. The -/+ symbols underneath the CAT label have been switched. Please find a corrected version of the figure here:"} +{"text": "Clock Gene Variation Is Associated with Breeding Phenology and May Be under Directional Selection in the Migratory Barn Swallow.There is a formatting error in the title. The correct title is:"} +{"text": "Pain Research and Treatment the affiliations have been switched. The affiliations should appear as shown above.In this paper which appeared in Moreover in"} +{"text": "This article was republished on October 23, 2013, because an incorrect version of the article was originally published. Please download this article again to view the correct version."} +{"text": "There is an error in the Correction posted on February 28, 2014. Please view the correct"} +{"text": "Dear Editor,I read with the interest the paper by Jowkar et al. published in a recent issue of Hepatitis Monthly . The aut"} +{"text": "There is an error in the labeling in Figure 2. The figure legend is correct. Please see the corrected figure at the following link:"} +{"text": "Dr. Hua Shen was not included in the author byline. Dr. Shen should be listed as the sixth author and affiliated with institution number 5. The contributions of this author are as follows: Performed the experiments."} +{"text": "This article has been republished to replace Figure 1. If you downloaded the PDF previously, please download it again for the most up to date version."} +{"text": "The incorrect version of Figure 1 appeared in the article. The correct version is available here:"} +{"text": "A Table and it's associated legend were omitted from the article. They are available here:"} +{"text": "Unites must be canged on United. At the first row of the abstract histiocytic lymphadenitis must be canged on histiocytic necrotizing lymphadenitis.Due to a layout error, in the title"} +{"text": "There was an error in Figure 6. The correct version of the Figure is available here:"} +{"text": "Some of the data in Table 2 was not displayed correctly. The full, correct table can be viewed here:"} +{"text": "Errors were introduced during the production process. The placement of some content and text in Figure 4 along the x and y axes is incorrect. The correct version of Figure 4 can be viewed here: . The publisher apologizes for these errors."} +{"text": "David J. Beebe has an ownership interest in Bellbrook Labs LLC, which has licensed technology reported in this publication. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials."} +{"text": "Dear Editor,We read with interest the article by Smyth A about dialysis indications and the modalities of RRT in elderly patients . We woul"} +{"text": "There is a Supporting Information file that is missing from the article. The following is the legend and link to the missing file:File S1. MatLAB code. (ZIP) Click here for additional data file."} +{"text": "The publisher regrets that Fig. 1 was not published completely. The correct version of Fig. 1 is presented below.The publisher would like to apologise for any inconvenience caused."} +{"text": "The original article was initGD carried out the study. YH participated in the design of the study. HW performed the statistical analysis. All authors read and approved the final manuscript."} +{"text": "This article is retracted.The journal editors would like to apologise for the early publication of the original article , which i"} +{"text": "Due to a typesetting error, there was an error in the name of the sixth author.The correct author name is: Ettore C. degli Uberti"} +{"text": "This article was republished on October 23, 2013 due to an incorrect figure. Please download this article again to view the figure."} +{"text": "Due to issues with the typesetting process, there were errors in Table 1. The correct version of the table is available here:"} +{"text": "The version of Figure 1 that appears in the article is incorrect. The correct version is available here:"} +{"text": "In the paper, the authors' names were mistakenly cited in a wrong format . We herein cite the authors' names in the correct format ."} +{"text": "Figure 1 has been removed and was replaced with a lower resolution image. The image was taken by author Ch'ien C. Lee and used with his permission."} +{"text": "The third author was incorrectly indicated as a Corresponding Author of the article. This author should instead be noted as having contributed to the article equally with the first two authors.In addition, the third author's name was spelled incorrectly. The correct name is: Diana Chinyere Anyaogu."} +{"text": "Notice of Republication.This article was republished on February 21, 2014 due to missing figures in the PDF. Please download this article again to view the figures."} +{"text": "An error was introduced during the preparation of this article for publication. In the Methods and Results section, there is error in Equation 1. Please view the complete, correct equation here:"} +{"text": "There is an error in Figure 1. The wrong image was used. The legend is correct. The correct image for Figure 1 can be seen here: [^]"} +{"text": "The version of Table 1 was incomplete.The correct, full version of the table is available here:"} +{"text": "Dear Editor,In reply to the Letter to the Editor by Prof. Wiwanitki concerni"} +{"text": "Searching for active compounds in screening databases is one of the main tasks in chemoinformatics ,2. For t"} +{"text": "This article was republished on Jan 3rd, 2014 due to figures missing in the PDF. Please download the new PDF to view the figures."} +{"text": "There is an error in the column alignment of Table 3. The column labels, as well as items listed under the 'Genome Features' section, should be shifted one column right. A link to the corrected table can be found here:"} +{"text": "There was an error in the first author's given name. The correct name is Fatemeh Heidary."} +{"text": "There was an error in Figure 5. The correct version of the figures is available here:"} +{"text": "There was an error in the Formal Correction posted on December 30, 2013. The name of the seventh author was misspelled in the correction. The correct name is Ding Yin."} +{"text": "This article was republished on January 2, 2014, because of missing and incorrect equations. The publisher apologizes for the errors. Please download this article again to view the corrected version."} +{"text": "We apologize to readers for these errors.There are three errors in the original paper. First, the last sentence of the legend for Figure 3 should have read \u201c"} +{"text": "Kato .A corrigendum to the article by by Kato et al. .Corrections are made to the article"} +{"text": "There was a spelling error in the second author's name. The correct spelling is Il Park."} +{"text": "Dear Editor,This is a study of a Tehran university hospital emergency department with 50,000 annual visits. The researchers are to be complimented for innovating and the amount of effort invested in the changes . A chart"} +{"text": "Dear Editor,We would like to congratulate Dr. Bakhshi and colleagues for being the first group to publish scientific evidence regarding the osteogenic effect of erythropoietin (EPO) in a clinical trial . As you"} +{"text": "A 55 year old male with a history of frequent symptomatic episodes of paroxysmal atrial fibrillation (AF) for four years was referred to us for catheter ablation. He had earlier tried flecainide and sotalol. However he was unresponsive to both of them. The echocardiogram was normal. The role of the pulmonary veins in triggering AF is well established . Increas"} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "The following information is missing from the Funding section: This work was funded in part by a Pennsylvania Department of Health CURE research grant to D. L. Taylor."} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "There is an error in the first name for the co-author listed as Alejandro Aguilar. The correct name for this co-author is Alex Aguilar."} +{"text": "There is an error in Table 1. The codons should be shown in bold. Please view the correct table here. The publisher apologizes for the error."} +{"text": "This article was republished on September 17, 2014, due to the release of confidential or copyrighted information. Please download the article again to view the corrected version."} +{"text": "In the Results section, there is an error in the fourth equation. The publisher apologizes for this error. The correct equation is:"} +{"text": "This article was republished on September 22, 2015, due to the release of confidential or copyrighted material. Please download this article again to view the correct version."} +{"text": "We congratulate Taskapili et al. for their study entitled \u201cThe Effects of Hemodialysis on Tear Osmolarity\u201d . The autWe have read the paper with great interest. We noticed that the authors did not mention the time of HD start in the day. It was reported that there was a diurnal variation of TO for normal subjects, which significantly changes upon awakening and remains relatively constant throughout most of the day . In this"} +{"text": "There is an error in the Background section of the manuscript. The references are swapped. Reference [2] should be [3] and vice versa.There is an error in the subsection Investigation Protocols of the section Object and Methods. The fourth sentence of the paragraph titled \u201cMontreal cognitive assessment (MOCA) scale\u201d is incorrect. The correct sentence is: Details on the specific MOCA are as follows.There is an error in"} +{"text": "This article was republished on June 16, 2014, due to a conversion error resulting in illegible figures in the online version. The publisher apologizes for these errors. Please see this article again to view the corrected figures."} +{"text": "Wallaceophis gujaratensis.There is an error throughout the manuscript. The spelling for the new genus and species is incorrect. The correct spelling should be:"} +{"text": "The data availability statement for this paper is incorrect. Please view the correct statement here.https://github.com/sebmate/OntoImportSuite). In addition we have supplied a demonstration subset of the diverse ontology contents, which is needed to replicate the methodology and the SQL script that was used to generate the source ontology for our Soarian EMR system as described in this paper.The software and source code (licensed under the GPL3) are available on GitHub"} +{"text": "There are several errors in mathematical expressions in theIntroduction under the subheading GWAS Plus: GCTA. In the final sentence of the second paragraph, the expression for the distribution of u is incorrect. The subscript n should be an m and the subscript epsilon should be a u. The correct distribution is:"} +{"text": "This article was republished on July 9, 2015, to replace incorrect figures. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "The correct identifier is: NCT01603147.In the Introduction section, the ClinicalTrials.gov Identifier is incorrect in the 4"} +{"text": "The images for Figs. There is an error in"} +{"text": "In the original manuscript, Hao Yin\u2019s name was misspelled. The correct name is Hao Yin. The incorrect spelling is Hao Lin.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "This article was republished on October 30, 2014, due to an error in the title. The publisher apologizes for this error. The citation has been updated to match the corrected title."} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on March 4"} +{"text": "In the Funding section, the funding statement is incorrect. The authors received no specific funding for this work."} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "Reason for erratum:Due to a misunderstanding the name of the corresponding author was published as Jiayi Luo instead of Rongjun Yu. The contact information is correct as originally published.This error does not change the scientific conclusions of the article in any way. The publisher apologizes for this error. The original article has been updated."} +{"text": "Reason for Erratum:Due to a misunderstanding, the last name of the author Jason S. Jacobskind was published as Jacosbskind. This error does not change the scientific conclusions of the article in any way.The original article has been updated."} +{"text": "Figure 6 is truncated in the PDF version of the article. Please refer to the XML version for the correctly sized figure. The publisher apologizes for this error that occurred while preparing the manuscript for publication.The asterisks in"} +{"text": "The first two authors, Ying Zhang and Yanrong Lv, should be noted as contributing equally to this work. The publisher apologizes for the error."} +{"text": "This article was republished on March 11, 2015, to replace incorrect figures in the PDF that were introduced during the production process. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "This article was republished on June 2, 2014, to replace figures in the online version of the article that had lost color during the production process. The publisher apologizes for the errors. Please view this article again to download the correct figures."} +{"text": "This Correction was republished on September 3, 2015 to correct errors in the reference that were introduced during the typesetting process. The publisher apologizes for the errors."} +{"text": "The authors would like to apologise for not including Tracey P. Koehlmoos as an author on this work . She was"} +{"text": "Critical Care [We read with great interest the article by Fischer and colleagues in a recent issue of cal Care . The autcal Care , we mustcal Care . We appr"} +{"text": "This article was republished on September 25, 2015, due to the release of confidential or copyrighted material. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "Mar. Drugs [We have found the following error in the title of this article, which was recently published in r. Drugs : a word We apologize for any inconvenience caused to the readers."} +{"text": "As a consequence, the surgeon has to rely on the scrub team to provide much-needed retraction with cases such as open appendicectomies. We have found the use of the Alexis setting . It not"} +{"text": "Ever since memory deficits were characterized in patient H.M. during memory acquisition and retrieval .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "This article was republished on April 2, 2015, to correct an error in Dr. Marije aan het Rot\u2019s name. This error affected how the article was indexed in PubMed, as well as the citation and the copyright statement. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "This article was republished on May 19, 2015, to correct the legend for Table 3, which was mistakenly incorporated into the body text during the production process. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "This article was republished on September 30, 2015, due to the release of confidential or copyrighted material. Please download this article again to view the correct version."} +{"text": "Please send all correspondence to plosbiology@plos.org and download this article again to view the correct version.This article was republished on March 15"} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "This article was republished on January 2, 2015, to replace incorrect figures. The publisher apologizes for the error. Please download the article again to view the correct version."} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "There is an error in the correction published on August 19, 2015. The author order on the originally published article is correct."} +{"text": "This article was republished on October 28, 2014, to correct an error in displaying the PDF. Please download the PDF again to view it correctly. The previous version of the PDF is not available because an error prevented it from being viewed."} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "This article was republished on July 31, 2015, due to the release of confidential or copyrighted material. Please download this article again to view the correct version."} +{"text": "This article was republished on July 24, 2015 to correct an error in the author byline and article citation. The first author\u2019s name was spelled incorrectly and should be: Nuno M. Oliveira. Please download this article again to view the correct version."} +{"text": "Mother's smoking during pregnancy has negative consequences in fetus respiratory system's development and asthma's manifestation later in children's life as well.Recording the influence of mother's smoking during pregnancy to the frequency of asthma's manifestation in children.The study was performed at Pediatric Emergency Room and concerns the last two years .Presented in the following table.Smoking during pregnancy is asthma's predisposing factor at all ages. Mothers who smoked during pregnancy were three times more likely to acquire children suffering from asthma than those who did not smoke."} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "The authors made substantive errors in figure images of this article such that the hypotheses were not tested and the conclusions were not supported.On this basis, the Editors formally retract this article from Molecular Vision.Sincerely,The Editors of Molecular Vision"} +{"text": "This article was republished on April 16, 2014, to correct errors in the numbering of equations that were introduced during the production process. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "There is an error in the Correction published on May 8, 2015. The publisher apologizes for the error. The correct figure legends are:"} +{"text": "This article was republished on January 20, 2015, to replace an incorrect figure. The publisher apologizes for the error. Please download this article again to view the corrected version."} +{"text": "This article was republished on June 10, 2014, to replace copyrighted or confidential material and to update the funding statement. Please download the article again to view the corrected version."} +{"text": "This article was republished on May 19th, 2016 to correct poor figure quality in the PDF version, which was introduced during the typesetting process. The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on March 4"} +{"text": "The fourth author\u2019s name is incorrectly spelled in the PDF version of the article. The correct name is: Joanna E. Fr\u0105ckowiak. The publisher apologizes for the error."} +{"text": "In the original Review article, the third author's name was published as \u201cErik M. Giolla\u201d. His name should be Erik Mac Giolla. The author list has been corrected above.The authors apologize greatly for this mistake. This error does not affect the scientific conclusions of the article in any way.The original article has been updated.All three authors worked together to develop the idea about the review paper and how it should be structured. ZV did the majority of the writing and put the manuscript together. ZV received frequent comments and amendments from both PG and EM throughout the writing process. Several meetings were held with all three authors present. The manuscript has been checked by all three authors prior to submitting.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The publisher apologizes for this error.The eighth author and the ninth author, Jie Du and Ming Zhang, should both be noted as corresponding authors of this work. Jie Du can be contacted at"} +{"text": "The publisher apologizes for the error.The last author, Young Chul Yoo, should be noted as Corresponding Author for this work. His email address is"} +{"text": "PLOS ONE apologizes for the error. You can view the corrected table here.There is an error in"} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "The third author\u2019s name is misspelled in the original article and in the correction published on September 14, 2015. The correct name is: Ebraheem O. Alzahrani."} +{"text": "The original version of this article unfortunately contained a mistake. In the author list, the name of author Zhiyi Zhou was incorrectly spelled. The correct spelling has been published in this Erratum."} +{"text": "There is an error in the correction published on August 27, 2015. The image of"} +{"text": "This article was republished on June 24, 2015, to correct an error in the XML that was causing Veronica van Heyningen\u2019s name to appear incorrectly in PubMed. The publisher apologizes for this error. The pdf of the article has not changed."} +{"text": "The publisher apologizes for the error.The URL in the Data Availability statement for this paper is incorrect. The correct URL is"} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "This article was republished on August 19, 2015, due to the release of confidential or copyrighted material. Please download this article again to view the correct version."} +{"text": "Reason for Erratum:Due to a typesetting error, the reviewer Caroline Blais was inadvertently removed from the final published article. The publisher apologizes for this mistake.This error does not change the scientific conclusions of the article in any way.Original article has been updated"} +{"text": "The publisher apologizes for this error.The second author and the fifth author, Qinwei Sun and Ruqian Zhao, should both be noted as corresponding authors of this work. Ruqian Zhao can be contacted at"} +{"text": "This article was republished on August 19, 2015, because part of Table 2 was erroneously omitted during the typesetting process. The publisher apologizes for the errors. Please visit this article again to view the correct version. The PDF of this article was not affected."} +{"text": "After publication of the original article , the autThe corrected versions are given in this erratum. The main findings of the original article are not affected after this correction. The authors apologise for any inconvenience this has caused."} +{"text": "The authors made substantive errors in figure images of this article such that the hypotheses were not tested and the conclusions were not supported.On this basis, the Editors formally retract this article from Molecular Vision.Sincerely,The Editors of Molecular Vision"} +{"text": "In the HTML version of the original publication, the graphical abstract was inadvertently omitted. The graphical abstract is given in this erratum."} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "In this article, one of our funding sources was reported incorrectly as P30 AI078494. The correct funding source is P30 AI078498. This correction does not affect the data or conclusions contained in the manuscript.All authors approve this corrigendum.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "There are errors in the legends for Figs. There are errors in Tables"} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "There is an error in the seventh author\u2019s name. The correct name is: Summer Peterman. The publisher apologizes for the error."} +{"text": "This Correction was republished on May 10, 2016, to correct formatting errors in Table 1 that were introduced during the typesetting process. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "This article was republished on August 21, 2015, due to the release of confidential or copyrighted material. Please download this article again to view the correct version."} +{"text": "Please download this article again to view the correct version. The Data Availability statement has been corrected to read: Due to ethical restrictions imposed by the Queens University Ethics Review Board, IMIAS data are available to external interested researchers upon request. Requests may be sent to the Corresponding Author.This article was republished on May 5"} +{"text": "The original version of this article unfortunIn addition, Fig. The Conclusions and Authors Contributions sections also contain a number of typing and spacing errors that have been updated. Please see the corrected text provided below.Lastly, the reference list has been updated to include all named authors up to the first 30.The original article has been updated to reflect all the above changes."} +{"text": "The affiliation for the eighth author is incorrect. Waleed Arafat is not affiliated with #3 but with #4 The University of Alexandria, Alexandria, Egypt."} +{"text": "The publisher apologizes for these issues with the figure quality. Please download this article again to view the updated version.This article was republished on May 19"} +{"text": "The authors made substantive errors in figure images of this article such that the hypotheses were not tested and the conclusions were not supported.On this basis, the Editors formally retract this article from Molecular Vision.Sincerely,The Editors of Molecular Vision"} +{"text": "After the publication of this article it was brought to our attention that the name of the last author, Andrea F. de Winter had been accidentally misspelt as Andrea F. deWinter in the original publication . This ha"} +{"text": "This article was republished on February 11, 2015, due to the release of confidential or copyrighted material. Please download this article again to view the corrected version."} +{"text": "This article was republished on November 19, 2014, due to the release of confidential or copyrighted information. Please view the article again to download the corrected version."} +{"text": "There are errors in the Funding section. The correct funding information is as follows: Fabio Saracco has been paid by Crisis Lab in the first submission, and Riccardo Di Clemente has been paid by Growthcom Project FP7, Grant Agreement 611272.The publisher apologizes for the error."} +{"text": "N. atra of the varespladib- group in Figure 3a. We provide the correct Figure 3 below (the legend is unchanged):The authors would like to correct an error in the original publication . This erThe authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original publication has also been updated."} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original article has been updated."} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Figure 8 were erroneously duplicated. The corrected Figure 8 and its caption appear below.In the published article, there was an error in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The authors wish to make the following correction to this paper .In the original article, one author Francesca Bandinelli was missing. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated."} +{"text": "In the original article published, the authors Peiliang Wang and Tianwen Yin are co-first authors and have equally contributed to this work.The original article has been corrected."} +{"text": "This article has been corrected to include\u00a0Dr. Jamie Johnston among the list of authors. Per the submitting author, \"Dr. Lowe led the development of the Telehealth module for the training program which was specifically requested by overseas partners. When submitting the paper, we should have included Dr. Jamie Johnston. I did not identify that she was not included and Dr. Lowe did not have knowledge of all of the behind the scenes work Dr. Johnston was doing.\""} +{"text": "Furthermore, they apologise to the readership for any inconvenience caused.The authors have re-examined their data and realized that"} +{"text": "In Fig. 4 the panel labels were ordered incorrectly. In Fig. 5e the same image was used for both the C and C+L groups. This has now been corrected in the PDF and HTML versions of the Article."} +{"text": "In the published version of this article, the accompanying Supplementary Material did not contain figure legends. The Supplementary Material should have included legends, the correct version of this file can be found associated with this corrigendum.The author apologizes for any inconvenience caused.Click here for additional data file."} +{"text": "Due to a production error, the incorrect supplementary material was linked to the article.The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Frontiers in Microbiology.Due to an Editorial error, the article was published in the incorrect journal section. This article's specialty section has been corrected to Microbial Symbioses, a section of the journal The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Furthermore, they apologize to the readership for any inconvenience caused.The revised version of"} +{"text": "Due to a production error, the names of Empedocles and Darwin in the article title were erroneously written in lowercase.The publisher apologizes for this mistake. The original article has been updated."} +{"text": "Missing FundingThe authors wish to make the following correction to this paper .Missingthe supporter and funder, Italian Ministry of Health\u2014Ricerca Corrente 2022, was not included. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated.In the original publication,"} +{"text": "In the original publication , a mistaThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "In the published article, an author name was incorrectly written as Neil Jacobs. The correct spelling is Neil G. Jacobson.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Due to a production error, the figures were incorrectly matched with their captions in the final published article. The correct figures and captions appear below.The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "In the published article, Mingchih Chen was incorrectly included as a corresponding author. The only corresponding author should be Yu-Wei Fang.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This article was republished on June 22, 2022 to remove an unneeded Abstract Teaser. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "In the published article, an author name was incorrectly written as Nicoletta DiSimone. The correct spelling is Nicoletta Di Simone.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original published article, the country name was missing from a co-author's affiliation. This has now been corrected."} +{"text": "Unfortunately, in the original article the figures are wrongly published. The corrected version are updated in the original version."} +{"text": "In this issue of the journal, Koizumi and colleagues have demThere is no doubt that the L-shaped incision provides excellent exposure for total arch replacement . This in"} +{"text": "The authors regret that incorrect details were given for ref. 18. The correct version of ref. 18 is given here as ref. The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Furthermore, they apologize to the readership for any inconvenience caused.The corrected version of"} +{"text": "Mohammad Javed Ansari was linked to affiliations three and four. This should be corrected to affiliation four only.Due to a production error, the author The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "In the published article, an author's name was incorrectly written as Sang-Yi Lin. The correct spelling is Sang-I Lin.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The original articles have both been updated to reflect this change.The reference for Gender API in both of these manuscripts linked to the wrong Gender API tool. The correct URL is <"} +{"text": "The Editor-in-Chief has retracted this article because there are anomalies in the Northern blots shown in Figure 3C. The data reported in this article are therefore unreliable. The authors have been invited to submit a new manuscript for peer review. All authors agree to this retraction. The online version of this article contains the full text of the retracted article as Supplementary Information.Former article version (PDF 5363 kb)Below is the link to the electronic supplementary material."} +{"text": "Correspondence, page 1. The author\u2019s academic email address should have been included. The correct email addresses appear above.In the original article, there was an error in the The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original publication , the BasThe authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "The corrected **** appears below. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated.In the original publication , there w"} +{"text": "In the published manuscript in the RThe authors apologize for any inconvenience. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "Consequently, the article has been retracted with the agreement of the Editorial Board.The authors agree with this retraction."} +{"text": "Due to a production error, there was a mistake in The corrected The publisher apologizes for this mistake.The original version of this article has been updated."} +{"text": "The original version of this article unfortunately contained a mistake. In figure\u00a03, the electrode localizations of all patients do not match the one from the table.The corrected Fig."} +{"text": "Furthermore, they apologise to the readership for any inconvenience caused.The authors have re-examined their data and realized that"} +{"text": "In the original publication , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "In the original published article, one of the affiliations for co-author Tennyson Lee was cited incorrectly. This has now been updated in the online published article.The authors apologise for this error."} +{"text": "In the published article, an author name was incorrectly written as Gaungcai Niu. The correct spelling is Guangcai Niu.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This information is not correct. There are still ways to purchase the Rolimeter, including on the recently launched website"} +{"text": "The authors of Moledina et al. have supOne of the coauthor names was incorrectly spelled in the article \u2018Tim Aubrey\u2019. The coauthor's name is being corrected to \u2018Tim Aubry\u2019.https://doi.org/10.1002/cl2.1154. The authors apologise for the error.The original version is also corrected and can be found on the below link:"} +{"text": "The corrected \u201c appears below. The authors apologize for any inconvenience caused and would like to clarify that the scientific conclusions are unaffected. This correction has been approved by the Academic Editor. The original publication has also been updated.In the original publication , there w"} +{"text": "Sina Neyazii, was misspelt. It should have been Sina Neyazi. The article category should have been Research Article instead of Invited review.In the article by Mawrin et al.,The original article in the online version has been updated.The authors apologize for the errors."} +{"text": "In the original publication, the given and family names of authors were published incorrectly. The correct version is updated in this correction.The original article has been corrected."} +{"text": "The authors wish to make the following changes to their paper . Figure The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "Following publication of the original article , the autZijun Zhou and Yanheng Qiao contributed equally to this work.The correct information has been provided in this Correction.The original article has been"} +{"text": "The authors wish to make the following corrections to this paper :In the original publication, there was a mistake in Figure 2 as published. The same image was mistakenly selected for Figure 2 and Figure 3 during proofreading. The corrected The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "We would like to submit the following correction to our recently published paper .p-value listed for the RADD-2 Expressive Language in In the original publication, there were mistakes in The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "The original version of this article unfortunately contained a mistake. There is a mistake in the abstract.In abstract, second sentence of the result section should read as63 patients were treated using the LCP fixation compared to 40 rTSAs.The original article has been corrected."} +{"text": "This article was republished on July 12, 2022, to remove an erroneous ORCID iD. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "In the original version of this article, the given and family names of all authors were incorrectly structured. The corrected author list is given above.The original article has been corrected."} +{"text": "In the original publication , there wThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "The authors wish to make the following correction to their paper . In the The Grossman-Jacobs rule described also sugThe structures of hyperacmosins A and B are shown below: 1. The Figure 1 should be changed to:2. The Figure 2 should be changed to:3. The Figure 5 should be changed to:The change does not affect the scientific outcome. The manuscript will be updated and the original will remain online on the article webpage. The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "In the publication of this article , in the andThe correct formulae are:andThese have now been updated in the original article.The data calculation used the correct formula.We regret for any inconvenience that this inaccuracy may have caused."} +{"text": "In the original publication, there was a mistake in The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated.Original image (incorrect one):Corrected"} +{"text": "In the original publication , there wThe corrected The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "Acknowledgements statement as Krembil Foundation was accidentally omitted. The corrected statement appears below.In the published article, there was an error in the"} +{"text": "In the original article , there wThe authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "In the previous manuscript,the horizontal axis in Figure 2c was incorrect . It is important to correctthis error in order to correctly present the experimental resultsand the bandwidth of the metasurface. This was simply a typographicalerror and nothing else about the manuscript text has been changed.Corrected figure:"} +{"text": "Ajuga bracteosa and to the writing the original manuscript. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original publication has also been updated.The authors of this paper have agr"} +{"text": "The authors regret that Kenneth E. Gonsalves\u2019 name was spelled incorrectly in the original article. The correct author names are as presented above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Supporting Information with the publishedarticle. The correct file for this paper is provided here.The incorrect PDF file was providedas"} +{"text": "The authors regret that the last name of Dr. Lisa Senzel was captured incorrectly in the original article. It is now corrected in this erratum article.The original article has been corrected."} +{"text": "Vessel Plus [In the original publication , a substsel Plus without The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "The originally published version of this paper was published with incorrect author affiliations listed. This has been corrected and updated in the online article.The Publishers would like to apologise for this mistake."} +{"text": "In the Financial Disclosure, the number for the grant awarded by EPIDNA is incorrect. The correct EPIDNA grant number is 894489."} +{"text": "In the published article, there was an error in the Funding statement. The funding reference 2021J011363 should have not been included in the article.The correct Funding statement appears below."} +{"text": "In the original publication , a formaThe authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "Mental Capacity Legislation was in fact edited by Rebecca Jacob, Michael Gunn and Anthony Holland. We apologise for the error.This book review has an error in the title:"} +{"text": "Due to a production error, there was an error in the title. The corrected title appears above. The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "This has now been corrected. The authors regret this error and apologize for any confusion that it has caused.On examining the online pdf, the authors discovered a mistake in two of the labels in the graphical abstract. The labels \""} +{"text": "In the published article, there was an error in the Funding statement. The reference to the funding was incomplete. The correct Funding statement appears below."} +{"text": "In the published article, an author name was incorrectly written as Wenqian Quan. The correct spelling is Wenqiang Quan.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Figure 6 when published. The experimental data points in the upper diagram were missing. The corrected Figure 6 appears below. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated.In the original publication , there w"} +{"text": "An abstract was missing from the above article. This has since been updated in the online PDF and HTML versions. The authors and Publisher apologise for the error."} +{"text": "The authors wish to make the following corrections to the published paper . FiguresThe authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "Due to a production error, the affiliation linked to Adam Brysiewicz was incorrectly written as affiliation eight. This should be corrected to affiliation six. The publisher apologizes for this mistake.The original version of this article has been updated."} +{"text": "Supplementary Figure S7 as published. In Supplementary Figure S7B , the wrong image was inserted.In the original article, there was a mistake in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Frontiers in Microbiology.Due to an editorial error, the article was published in the incorrect journal section. This article's specialty section has been corrected to Microbial Symbioses, a section of the journal The publisher apologizes for this mistake. The original article has been updated."} +{"text": "In the original publication of the article, the Fig.\u00a03 was published with errors. The correct Fig."} +{"text": "L in L promoter in the E7 open reading frame.In the published review , the HPVThe authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "In the original publication, there was a mistake in Table 2 as published . There wThe authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original publication has also been updated."} +{"text": "The primers in . The corrected In the original publication , there w"} +{"text": "In the original publication of the article, the values in Table 2 were incorrectly placed. The correct Table The abstract was incompletely provided on the website. The complete abstract is updated.The original article has been corrected."} +{"text": "In the original publication, one of the affiliation information was inadvertently missed for the corresponding author Tonya Moen Hansen. It is updated in this correction.The original article has been corrected."} +{"text": "In the original published article, the country name was missing from the author's affiliation. This has now been corrected."} +{"text": "This article was republished on November 11, 2022 to correct a typographical error in the title. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "In the original publication , there wThe author contributions were updated in the newest version to more clearly depict the contributions made by each author to the article . The mod"} +{"text": "They also apologize to the readership for any inconvenience caused.The authors have re-examined their original data, and realize that"} +{"text": "Unfortunately, the headings were not included in the initial version of this article's Abstract section. In this correction, the same was corrected.The original article has been corrected."} +{"text": "No animals were used in this study, and ethical approval for the use of animals was thus deemed unnecessary.The animal ethics statement was missing from this paper. The following statement should have been included:"} +{"text": "There was an affiliation missing in the original article . For theThe authors apologize for any inconvenience caused, and state that the scientific conclusions are unaffected. The original article has been updated."} +{"text": "In the published article, there was an error in the author list, and author Zixun Zhou was erroneously excluded. The corrected author list appears above.In the published article, an author name was incorrectly written as Xiao Pei. The correct name is \u201cPei Xiao\u201d.The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, an author name was incorrectly written as Donlin Lai. The correct spelling is Donglin Lai.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The authors agree with this correction. This correction was approved by the Academic Editor. The original publication has also been updated.We received a complaint from the Universit\u00e9 Catholique de Louvain. In the published version of the article , there w"} +{"text": "Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266.Dear Xinhang Dong et al.,Thank you very much for your thoughts on this study . The hem"} +{"text": "There was an error in the original publication . The fir"} +{"text": "Jeffrey M. Catchmark was not included as an author in the original publication . The cor"} +{"text": "Healthcare [Thank you for your interest and comment on our \u201calthcare in your althcare . Our papalthcare . Questioalthcare . In anotalthcare . This in"} +{"text": "In this correction, the original supplementary files are replaced with the correct final version of the file.The original article has been corrected."} +{"text": "Due to a production error, Supplementary Table 1 was omitted from the article.The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Correction to: PsychopharmacologyIn the published paper, it was found out that the incorrect supplementary materials were uploaded.The original article has been corrected."} +{"text": "This article was republished on February 7, 2022, to correct an error in the author list footnotes. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Stepany C. Paiva. The correct spelling is Stephany C. Paiva.An author name was incorrectly spelled as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original online version of this article the percentage in the second sentence on page 572 was incorrect. The correct value is 45.7%.The original article was corrected."} +{"text": "The authors wish to make the following correction to this paper :Changes in Figure 5, because Figure 5B misprinted as a duplication of Figure 5A by authors mistakenly during the proofreading. The correct The authors would like to apologize for any inconvenience caused to the readers by these changes. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "In the original article , there wThe authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "Due to a production error, Saba Vahdatshariatpanahi was not included as an author in the published article.The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "According to the Dutch legislation on animal experiments , this observational study is not considered an animal experiment. Therefore, no approval from the legal authorities was required.The animal ethics statement was missing from this paper. The following statement should have been included:"} +{"text": "An author name was incorrectly spelled as Yong-Li Zhu. The correct spelling is Li-Yong Zhu.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This article was published in Psychological Medicine with errors in the author affiliations. This has now been corrected online and in the article.The authors apologise for this error."} +{"text": "Due to an error during the final proofing stage, the incorrect version of the article was published.The publisher apologizes for this mistake. The original article has now been updated to reflect the correct version."} +{"text": "During the publication process an error was introduced in the affiliations of two authors.Affiliations 6 and 7 were attributed to Mihajlo Jakovljevic, but these affiliations are for Vijay Kumar Chattu. The publisher apologizes to the readers and authors for the inconvenience caused. The original article has been"} +{"text": "In the original article, there was an error. An author name was incorrectly spelled as Lan Y. Qiao. The correct spelling is Yalan Qiao.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This article has been corrected: The authors recently found that published Figure 11 was an unfinished draft of the final figure. They are now providing the finalized figure referred to in the article. This alteration does not affect the results or conclusions of this work.Figure 11 is presented below.New"} +{"text": "The authors would like to make a correction in a recent published paper . There wOriginal Figure 1b:We would like it to be corrected as shown below.New Figure 1b:Nutrients for this error. The published version will be updated on the article webpage, with a reference to this correction notice.These changes have no material impact on the conclusions of the paper. The authors would like to apologize to the readers of"} +{"text": "In the original article, there was a mistake in the legend for figure 9C as published. Splicing was performed in the image to remove redundant lanes, but this was not originally stated in the figure legend. The band representing ZR-751 t-ERK had also been spliced in wrongly. This error has now been corrected. Figure 9C has now been moved to the supplementary figures and has been uploaded separately. The correct legend appears below.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The authors would like to correct a typographical error in their recently published paper . In the"} +{"text": "The authors regret that Fig. 3 was truncated in the original publication. Here we provide the complete original figure as submitted to the journal during peer-review of the manuscript.The authors would like to apologise for any inconvenience caused."} +{"text": "In addition, Tao Li was not marked as a corresponding author in the author list.Due to a production error, one of the corresponding author\u2019s email addresses was written incorrectly. The correct email address for Liangming Liu is The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "This article was republished on January 7, 2021, to correct errors in the figures. Please download this article again to view the correct version. The publisher apologizes for the errors."} +{"text": "Due to a production error, the latest version of The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "M'an H. Zawati instead of Ma'n H. Zawati.In the published article there was an error. An author name was incorrectly spelled as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Due to a production error, an incorrect version of the article was published. The correct version has now been published and the earlier published version has been included as The publisher apologizes for this mistake. The original article has been updated."} +{"text": "A file unintended for publication was erroneously included in the originally published article. The publisher apologizes for the error. This article was republished on May 3, 2021, to correct for this error. Please download this article again to view the correct version."} +{"text": "This error has been corrected in the online version of the paper. The authors apologize for this error and any inconvenience caused.The accession number for RNA-seq and ATAC-seq data listed in the Key Resources Table was incorrect due to a typographical error. The correct accession number is \u201cGEO:"} +{"text": "The author of the article would like to add a video abstract as a supplementary material for a published article. The supplementary file is published with this correction.The original article has been corrected.Supplementary material 1 (MP4 35289 kb)Below is the link to the electronic supplementary material."} +{"text": "In the original article, there was a mistake published in Figure 2. The figure was published twice in the original published version . The cor"} +{"text": "Author Contributions Statement appears below.Roger A. Kautz was not included as an author in the published article. The corrected The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "After publication of this article it was b The corrected figures and figure legend are shown below. These corrections do not change the results or conclusions of the article. We apologise to readers for these errors.Figure 5 The correct version of Fig.\u00a05a. The full caption and figure are available via the original article.Figure 6 The correct version of Fig.\u00a06a. The full caption and figure are available via the original article.Figure 7 The correct version of Fig.\u00a07a. The full caption and figure are available via the original article."} +{"text": "This article was published in Psychological Medicine with some errors in Table 1. The AFR and EUR case numbers have been swapped and the OUD counts have been corrected to read: and . A reference was also not cited appropriately in the main text and has been fixed.The authors apologise for this error."} +{"text": "Due to a production error, there was a mistake in the author list. Author Mawda Elmhadi was omitted from the author list as the third author.The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "An incorrect version of S1 Dataset was published in error. This article was republished on August 9, 2021 to correct for this error. Please download this article again to view the correct version."} +{"text": "The authors wish to make the following correction to this paper . While t"} +{"text": "An incorrect version of figure 3 was published in the above article. This has now been corrected in both the online PDF and HTML versions of this article. The Publisher apologises for this error."} +{"text": "Figure 3 as published. While image processing, we have grouped few pictures inadvertently in Figure 3. The corrected Figure 3 appears below.In the original article, there was a mistake in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The publisher apologizes for this mistake.Due to a production error, the email address for the corresponding author Wenjuan Wang was not correctly displayed. The correct email address for Wenjuan Wang is The original version of this article has been updated."} +{"text": "Data presented in Figure 4 was misrepresented. This discrepancy was brought to our attention by the corresponding author.On this basis, the Editors formally retract this article from Molecular Vision.Sincerely,The Editors of Molecular Vision"} +{"text": "Unfortunately, the acknowledgment text was incompletely published in the original article. The complete acknowledgment text is provided in this correction."} +{"text": "An author name was incorrectly spelled as Goucerol. The correct spelling is Gourcerol. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Hiroyashi Nishikawa. The correct spelling is Hiroyoshi Nishikawa.An author name was incorrectly spelled as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An incorrect version of Supporting Information file S2 Table was included in the originally published article. The publisher apologizes for the error. This article was republished on April 30, 2021 to correct for this error. Please download this article again to view the correct version."} +{"text": "Funding statement. The correct number for the funder \u201cYouth Project of Anhui Natural Science Foundation\u201d is 2108085QH372, not 2108085QH3720. There was also a mistake in NGR1 is incorrect. The correct In the original article, there was an error in the The authors apologize for these errors and state that this do not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Figure 1 as published. The N positions of the pyridines in the ligand structure are incorrect. The corrected Figure 1 appears below.In the original article, there was a mistake in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Kisho M. Kukuoka. The correct spelling is Kisho M. Fukuoka.An author name was incorrectly spelled as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the recent article by Hardenstine et al. , a spellThis has now been corrected in the article.The authors apologize for this error."} +{"text": "The authors regret that incorrect details were given for ref. 16 in the original article. The correct version of ref. 16 is given below as ref. The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "This statement is incorrect as the company remains a currently viable bio-tech company globally.In the original article, there was a mistake in The authors apologize for this inadvertent error with the statement and a modified"} +{"text": "This article was republished on May 7, 2021 to correct an error in the Acknowledgments section. The corresponding author\u2019s contact email was also updated. Please download this article again to view the correct version."} +{"text": "In the originally published version of this manuscript, there was an error in theFunding section. This has now been corrected online."} +{"text": "An incorrect version of S1 Dataset was published in error. The publisher apologizes for the error. This article was republished on September 7, 2021, to correct for this error. Please download this article again to view the correct version."} +{"text": "In the original publication, the affiliation information of the authors was processed incorrectly. It has been updated in this correction."} +{"text": "The byline for Cristian Montenegro is misspelled in the downloadable PDF for this article. The correct first name is Cristian. The publisher apologizes for the error."} +{"text": "The authors wish to correct the following erratum in this paper .In the original paper , Graeme"} +{"text": "TG should be subtracted from the quotient of DNleaf,T/DNWR_leaf,T . The correct equation is:The authors regret that The error was only in the article text and therefore did not influence the data published. The authors would like to apologise for any inconvenience caused."} +{"text": "Shah and Fredric E. Wondisford . The figThe authors declare that they have no conflicts of interest with the contents of this article."} +{"text": "The authors regret, that the incorrect graph is showing as Figure 5a. The correct graph is shown below.The authors would like to apologise for any inconvenience caused."} +{"text": "It was highlighted that in the original version of this article the wronAdditional file 1. Interview guides."} +{"text": "In the Discussion, subsection Group Authors, a name was incorrectly spelled as Leva Rutkovska. The correct spelling is Ieva Rutkovska.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Funding statement. The correct Name for the Funder is \u201cSpecial Research Project of Traditional Chinese Medicine in Henan Province (Grant No. 20-21ZY1024)\u201d.There is an error in the The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The publisher regrets that at the time the article was published the name of the author N. La Verde was mistakenly abbreviated as N.L. Verde. This has now been corrected.The publisher would like to apologise for any inconvenience caused."} +{"text": "Due to a publisher error, the Editor's note was not included in the original article; this has now been corrected.The original article has been updated."} +{"text": "In the original article there waThe authors would like to apologize for any inconvenience caused. The change does not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage."} +{"text": "The first version of this article displayed Figure 5 incorrectly. This has now been corrected. The publisher apologizes for the error."} +{"text": "The authors wish to make the following corrections to this paper: .Error in Figure\u201d and \u201cCurrent acquisition\u201d are reversed. The corrected appears below.In the original publication, there was a mistake in Missing FundingAuthor would like to modify the funding section to:Funding: This work is supported by State Grid Shaanxi Electric Power Co., Shaanxi Electric Power Research Institute .The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original publication has also been updated."} +{"text": "In the above article, a source of Financial Support was omitted. The Financial Support statement should read as follows:"} +{"text": "This article was republished on October 4, 2021, to remove extra files that were not meant to be included at publication. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "In the original article, there was an error in the Data Availability Statement as published.The revised Data Availability Statement is below.Data Availability Statementhttps://github.com/DianaOaxaca/Weissella_analysis.git.Genome assemblies and raw data are available at GenBank under the BioProject PRJNA642311. Amplicon sequencing data are available under the BioProject number PRJNA648868. The code used for the all bioinformatic analysis and complete results of each are found in: The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the originally published version of this article, the reference list was omitted. This has since been updated to include the reference list."} +{"text": "Due to a production error, the Editor's note was included in the Editor's affiliation. The publisher apologizes for this mistake.The original article has been updated."} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake.The original version of this article has been updated."} +{"text": "The original version of this article unfortunately contained a mistake. We need to add a contributor to Table"} +{"text": "The authors wish to make the following corrections to the published paper . They shMissing FundingPostgraduate Research & Practice Innovation Program of Jiangsu Province, SJCX20_1116 to Henan Zhang and Zhibin Ling was not included. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated.In the original publication, the funder"} +{"text": "It has just started in Japan. We will provide detailed information later. The symposium has experts from 8 countries. We will use an interview and dialog format, instead of presentations."} +{"text": "Due to a production error, a version of the article with grammatical mistakes was published.The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "In the original version of this article, the given name and family name of Graziano Onder were interchanged. The corrected author list is given above. The original article has been corrected."} +{"text": "Due to a production error there were multiple corrections to be made to the reference list. Further minor corrections have been made to the text.The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "After publication of this article, the authors noticed an error in the Discussion and Conclusion section. The incorrect and correct information is shown below. The original article has been"} +{"text": "An author name was incorrectly spelled as Lei Zheng. The correct spelling is Lei Zeng.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original publication of the article, the third author name was published incorrectly. The correct name is Edwin Yuen Hao Tong.The original article was updated."} +{"text": "This article was republished on January 25, 2022, to remove a Supporting Information file that was incorrectly included in the originally published article. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "Due to a production error, PM was listed as an employee for GliaPharm SA in the Conflict of Interest statement. PM is an advisor for GliaPharm SA. The publisher apologizes for this mistake.The original article has been updated."} +{"text": "An incorrect version of Fig 1 was published in error. The publisher apologizes for the error. This article was republished on June 1, 2021, to correct for this error. Please download this article again to view the correct version."} +{"text": "In the original publication a contriThis statement is as followed:Eun Jeong Gong and Li-chang Hsing contributed equally to this work.The original article has been updated. We apologize to the authors and readers for the inconvenience."} +{"text": "An incorrect version of S1 Text was published in error. This article was republished on January 13, 2022 to correct for this error. Please download this article again to view the correct version."} +{"text": "Due to a production error, there was a mistake in The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "In the original publication, the affiliation of all the authors were mixed up and processed incorrectly. It has been updated in this correction.The original article has been corrected."} +{"text": "In the originally published version of the manuscript, there was an error in one of the figures. Figure 5 Panel A showed the wrong curves. The corrected figure is shown here: This error has been corrected online."} +{"text": "In the original article, an author name was incorrectly spelled as Kuwu Yu. The correct spelling is Kunwu Yu.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An incorrect version of Fig 1 was published in error. This article was republished on December 13, 2021, to correct this. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "OT3HL147741 was erroneously included as a funding source.There is an error in the Funding statement. In the original article, The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original article , there wp-value in Table 1 should be corrected to 0.023.In the original article, there was a mistake in Table 1 as published. The The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated."} +{"text": "Furthermore, they apologize to the readership for any inconvenience caused.The authors have re-examined their original data and realized that the Vector and the Rap2c data panels for"} +{"text": "An author name was incorrectly spelled as Elena Diaz-de Cerio. The correct spelling is Elena Rodrigo-Diaz.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Authors would like to correct the error in their publication.Figure\u00a03 contains a part in Italian language which is now removed.The collaborator author names were tagged only in the author group but missed to process in Acknowledgements section. The collaborator author names now updated as Study group in the Acknowledgements section.The original article has been corrected."} +{"text": "There was an error in the original article . In SectMix 100 g PEG 8000 with 400 mL water and mix on a magnetic stirrer until dissolved.The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated."} +{"text": "An incorrect version of Fig 1 was published in the original version of this article. The publisher apologizes for the error. This article was republished on June 7, 2021 to correct for this error. Please download this article again to view the correct version."} +{"text": "Animal domestication was a pivotal point in human history and coincided with a major change in human evolution. The domestication of crops was quickly followed by the domestication of livestock . While a"} +{"text": "The original version of this article unfortunately contained error in author group.The given name and family name of all the authors was swapped and published incorrectly. Now, the correct author names are presented in this correction article.The original article has been corrected."} +{"text": "Due to a production error, the article was published as an Original Research article. The correct article type is Review. The publisher apologizes for this mistake.The original version of this article has been updated."} +{"text": "Due to a production error, the Editor's note was included in the Editor's affiliation.The publisher apologizes for this mistake.The original article has been updated."} +{"text": "The authors would like to make the following corrections to the published paper .There are mistakes in In the original article, S. aureus ATCC 6538 adhesion to human lung A549 cells. However, In the first sentence of the The correct"} +{"text": "During the publication process an error was introduced in the original publication of this article .In Table 1 the value for Concurrent antidepressant use was accidentally changed. In this correction article the incorrect and correct values are published for clarification. The full table is available via the original article. The publisher apologizes to the readers and authors for the inconvenience. The original article has been updated."} +{"text": "In the originally published version of this manuscript, there was a spelling error in the last author's forename. The correct spelling is: Shoaib Saeed. This error has been corrected online."} +{"text": "Due to an editorial error, the article was published as a Review article. The correct article type is Original Research. The publisher apologizes for this mistake.The original version of this article has been updated."} +{"text": "There is an error in the XML that causes the last author\u2019s name to be indexed incorrectly in PubMed. The correct initials are: Oliveira SC. The publisher apologizes for the error."} +{"text": "Ms. Jill Harris has requested that she should be removed from the list of contributing authors. After re-considering her contribution, we wish to remove her from the authorship of our paper and add"} +{"text": "After the publication of our work in BMC Cancer , we becaWe regret any inconvenience that this involuntary inaccuracy in the original data citation might have caused. We wish to thank Dr. Fabio Salamanca for bringing this matter to our attention.The pre-publication history for this paper can be accessed here:"} +{"text": "Jonathan Leo raises issues with the adoption literature on schizophrenia . These sHowever, the salient point in my paper was thatDr. Leo's comments about the treatment of schizophrenia are not within the scope of my paper."} +{"text": "We thank Schofield et al. for their interest in our article and for their comments. We would like to clarify that Our article represen"} +{"text": "We thank Evan Mayo-Wilson for raising the issue on how systematic and exhaustive our search for our recent qualitative analysis was. ThiThank you for drawing our attention to the paper by Klein and Richards . This pa"} +{"text": "Incorrect versions of Fig 1 and Fig 2 were published in error. This article was republished on February 26, 2018 to correct for these errors. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "The funding section was mistakenly not included in this paper. The article has now been updated to include this section. The publisher apologises for this error."} +{"text": "An incorrect version of Fig 4 was published in error. This article was republished on February 6, 2018 to correct for this error. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "In the original publication, the article was published with thecopyright Springer Science+Business Media. However, it has to be published with freeopen access agreement. It has also been updated in the original article."} +{"text": "An author name was incorrectly spelled as Elif I. I Ekinci. The correct spelling is Elif I. Ekinci. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Table 4 was included in the article without full permission. The table was removed from the HTML and PDF versions of this article on July 6, 2017. Please download this article again to view the correct version. Readers can access the MMAS-8 scale through the original publication ["} +{"text": "There is an error in the Acknowledgements section. The paragraph \u201cThis draft manuscript is distributed solely for purposes of scientific peer review. Its content is deliberative and predecisional, so it must not be disclosed or released by reviewers. Because the manuscript has not yet been approved for publication by the U.S. Geological Survey (USGS), it does not represent any official USGS finding or policy.\u201d was erroneously published in the Acknowledgments section. The paragraph should have been removed when the manuscript was accepted for publication. The publisher apologies for the error."} +{"text": "There was a mistake in the writing of the cell growth term in Equation (2a) as published. The correct version appears below.The same mistake is repeated in equation (A2a). The correct version appears below.The authors apologize for these mistakes. This error does not change the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The authors wish to make a change to their published paper . Since 2The change does not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage."} +{"text": "This article was republished on September 22, 2016, as two Supporting Information files were published in error. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "This article was republished on November 8, 2016, as a Supporting Information file was published in error. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "This article was republished on August 25, 2016, to correct an error where an incorrect Fig 1 was published. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "The image for Fig 6 is missing the markers indicated in the figure caption. Please see the complete, correct The image for Fig 8 is incorrect. Please see the complete, correct"} +{"text": "We wish to make the following correction to the published paper . Stewart"} +{"text": "Due to circumstances beyond the journal's control, the database for the above article is no longer accessible. Apologies for the inconvenience."} +{"text": "There is an error in the last sentence of the Results section. The correct sentence is: However, Fig 2D shows there was no muscle damage, and a very slight macrophage infiltrations when Allo was administered.In"} +{"text": "Upon publication of the original article , the autThis has also been updated in the original article.We apologise for the error made."} +{"text": "This article was republished on November 15, 2017, to correct an error in the S1 Text file that was introduced during the typesetting process. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "DataShare and can be found at the following DOI: http://dx.doi.org/10.7488/ds/1563The Data Availability statement for this paper is incorrect. The correct statement is: The authors confirm that all data underlying the findings are fully available without restriction. All the raw data presented within the study is available at"} +{"text": "This article was republished on May 5th, 2015, to correct errors in the figures that were introduced during the typesetting process. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "The author regrets that the second author, Demetrius Evriviades, was inadvertently missed from the author list. The author list has now been updated with the second author.The authors would like to apologise for any inconvenience caused."} +{"text": "In the Funding section, the grant numbers are missing. The grant number for the John Charnley Trust is 2435. The grant number for the MRC CIC is MC_PC_14112 v.2."} +{"text": "The author regrets that in the original version of this article, Dr. Stephen Baylor\u2019s first name was misspelled. Additionally, for All versions of this article have been corrected."} +{"text": "In the publication of this article , the AckAcknowledgementsWe would like to thank Dr. Ahmet Orhan Gurer for his help during the notification process.This has now been included in this correction."} +{"text": "There is an error in the correction published on December 16, 2016. The incorrect figure legend was included in the correction. The correct figure legend and The publisher apologizes for the error."} +{"text": "The authors wish to make the following change to their paper . The perThe bars depicted in"} +{"text": "The authors wish to make the following correction to their paper . The fun"} +{"text": "This article was republished on March 14, 2017, as a Supporting Information file was published in error. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "The Marinovic citation is presented in the final version as:Marinovic and Tresilian 2014This is incorrect and should instead be:Marinovic et\u00a0al. The same citation is also left out in the References list.We apologize for the error."} +{"text": "This has now been acknowledged and corrected in this erratum.After the publication of the original article , discrep"} +{"text": "The authors wish to make the following correction to this paper .The published Figure 3 was incorrect. The correct The authors regret any inconvenience or misunderstanding caused by this error. The manuscript will be updated and the original will remain available on the article webpage."} +{"text": "The original article was corrected. We apologise for any confusion this may have caused.After publication of the original article , it was"} +{"text": "Wei Wang was not originally credited in the byline. Dr. Wang contributed significantly to the study design and writing of the article. The article has since been corrected online.In the article \u201cA Novel Risk Score to the Prediction of 10-year Risk for Coronary Artery Disease Among the Elderly in Beijing Based on Competing Risk Model\u201d,"} +{"text": "This article was republished on December 15, 2016, as a Supporting Information file was published in error. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "The authors regret that the following project number stated in the Acknowledgments section is incorrect. The correct number should have been P 222 48-B17. The corrected text appears below.The authors would like to apologize for any inconvenience this may have caused to the readers of the journal."} +{"text": "An incorrect version of this paper was published. The article was republished on November 11, 2016 to provide the correct version. Please download this article again to view the corrected PDF."} +{"text": "Table 3 was included in the article without full permission. The table was removed from the HTML and PDF versions of this article on July 21, 2017. Please download this article again to view the correct version. Readers can access the MMAS-8 scale through the original publication ["} +{"text": "Sensors2015, 15, 19264\u201319301.The authors wish to make the following correction to their paper : ReferenThe manuscript will be updated and the original will remain online on the article webpage. The authors would like to apologize for any inconvenience caused."} +{"text": "The first two authors, Soo Jung Kim and Shinhee Ye, should be noted as contributing equally to this work. The publisher apologizes for the error."} +{"text": "There is an error in the correction published on November 4, 2016. The incorrect figure was listed in the original correction. The correct figure is The publisher apologizes for the error."} +{"text": "This article was republished on December 5, 2016, as a Supporting Information file was published in error. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "After publication of this work , it was The publisher apologises for these errors.The original article has been updated."} +{"text": "In the original publication of the article, the authors have realized an error in Fig.\u00a01. The corrected version of Fig."} +{"text": "An author name was incorrectly spelled as D. V. Ravi Kumar. The correct spelling is V. Ravi Kumar. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The Original Article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "PLOS ONE article.The Competing Interest statement for this paper is incorrect. The correct statement is: Dr. Allan Darling was involved previously in additional research and testing on HPBCDs with a third party company. This related, unpublished work was performed under a commercial contract for which a confidentiality agreement prevents disclosure of the research details as well as the company and related product names. The authors confirm that this related HPBCD work by Dr. Darling was fully independent from the work published in the https://zenodo.org/record/573845#.Wh9DtkqnGUm).The Data Availability statement for this paper is incorrect. The correct statement is: All relevant data underlying this study are available from Zenodo (The caption for"} +{"text": "After the publication of this work , we notiThe original article was corrected.The publisher apologises for this error."} +{"text": "This article was republished on May 8, 2017, to correct an error where an incorrect Fig 1 was published. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "The authors wish to make the following corrections to this manuscript . The pub"} +{"text": "The publisher apologizes for this error. Please see the corrected There is an error in"} +{"text": "This error, which does not affect the interpretation of our results, has now been corrected in the article online. The authors apologize for the error."} +{"text": "Figure The correct version of Fig. In the original version of this article , publish"} +{"text": "It is among the most common causes, but not the most common. The article has been corrected online ("} +{"text": "Due to issues with the typesetting process, there were errors in the name of the sixth author.The correct name of this author is: Arjan B. te Pas"} +{"text": "This article was republished on January 18, 2017, as a Supporting Information file was published in error. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "We apologise for the inaccuracy.After publication of the article it was b"} +{"text": "The authors wish to make the following correction to their paper . The nam"} +{"text": "When the manuscript was typeset, the wrong URL was used for the \u2018View Article\u2019 link for reference 5. The publisher apologizes for the error. The correct URL for this reference is:"} +{"text": "There are errors in Table 1. The shading is misaligned and certain numbers are out of order. Please see the correct version of"} +{"text": "The authors confirm that they did not have any special access privileges that others would not have.The Data Availability statement for this paper is incorrect. The correct statement is: The data sets generated and/or analyzed during the current study were derived from the The Older Persons and Informal Caregivers Survey Minimum DataSet (TOPICS-MDS) repository. Public sharing of data is restricted per the Data Use Agreement. Data are available by applying to the TOPICS Project Group, who may be contacted at"} +{"text": "The affiliation for the 1st author is incomplete. Andreas Austgulen Westin is affiliated with #1 and #6.There is an error in the caption for"} +{"text": "This article was republished on September 27, 2016, due to the release of confidential or copyrighted material. Please download this article again to view the correct version."} +{"text": "There is an error in the Funding statement. The name of the funder Fondation du souffl\u00e9 is incorrect. The correct name is: Fondation du Souffle. The publisher apologizes for the error."} +{"text": "Matricaria chamomilla instead of Matricaria chamomila in the title and main text of this paper. Besides, the authors wish to remove Affiliation 5 . Affiliation 1 has been changed from \u2018Tangestan Growth and Technology Center\u2019 to \u2018Tangestan Science and Technology Incubator\u2019.The authors wish to make the following corrections to their paper . The chaThe authors would like to apologize for any inconvenience caused to the readers by these changes. The change does not affect the scientific results. The manuscript will be updated and the original will remain online on the article webpage."} +{"text": "In the original article, there was an error: There were a couple of incorrect numbers.A correction has been made to the RESULTS section Paragraph 2.Note that the changes had no further effect on any conclusions.x) was 0.80 for both the conceptual subtest and the factual knowledge subtest.Sinharay for examThe original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The S1 Table was included in the article without full permission. The table was removed from the HTML and PDF versions of this article on May 30, 2017. Please download this article again to view the correct version. Readers can access the MMAS-8 scale through the original publication ["} +{"text": "Due to an error during production, the author, Lavergne S. Lavergne\u2019s name in the published paper was incoWe apologize for any inconvenience caused to the readers by this error. The change does not affect the scientific results. The article will be updated and the original will remain on the article webpage."} +{"text": "An author name was incorrectly spelled as Roland F. Friedel. The correct spelling is Roland H. Friedel. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "We would like to thank Dr. Srinivasan and Dr. Kan for their remarks on our p"} +{"text": "Virology J 2007, 4:92This is a retraction of the article submitted by Zhang et al. Virology Journal on the assumption that the co-authors had agreed to the submission. Since this is not the case, the authors are retracting the article. Mr. Wu is deeply sorry for any inconvenience this may have caused to the editorial and publishing staff. An apology is also extended to the readers.Mr. Wu submitted this article to Virol"} +{"text": "There is an error in the authorship of this paper. Ruben J. Cauchi should be included as an author and is affiliated with institution 1. He should appear between AS and SG in the author list."} +{"text": "Sir,We thank Dr. Mahajan for his comments on our pThe study was planned to focus the beneficial effects of irbesartan in comparison to insulin and thus the relevance of the study remains clear.Suggestion at 2 is well-taken for future studies.We regret the typing error; please read group III for insulin and group IV for irbesartan.It is a printing error. The original Table and 2 su"} +{"text": "In the first five rows of the References column, the numbered citations were incorrect. The corrected Table 2 can be found at"} +{"text": "Dear Sir,We fully agree with the view expressed by Dr. Abdus Salam on our a"} +{"text": "A high accumulation of radioactivity was demonstrated in the tumours, the uptake being the highest in the actively growing parts. The possible mechanism involved is discussed.Autoradiography with"} +{"text": "We appreciate Dr Grant's comments on our dDr Grant focused his comments on 2 aspects of our manuscript. First, he reiterates the similarities between our findings and those by others but critSecond, Dr Grant notes that we failed to suggest a mechanism for the link. As indicated in our discussion , the pre"} +{"text": "We thank Scialli for his interest in our study . As he nScialli posits that there may be a role of reduced plasma or body water volume on the associations observed. As we described in our article , both pr"} +{"text": "The fourth author's name appears incorrectly in the author list and in the citation. It should be P. Jeffrey Conn in the author list and Conn PJ in the citation."} +{"text": "Sir,This is with reference to the comments on our article. The neceHepatitis has been shown as an adverse drug reaction (ADR) to HAART, but some other studies do not report it commonly. We reported hepatotoxicity which includes hepatitis also.3 Out of"} +{"text": "The test depends on sensitization of the patient's lymphocytes to a common antigen apparently present in human tumours. We now offer independent confirmation of these findings, together with methods for improving the test towards its future clinical use.A preliminary announcement of a new"} +{"text": "An incorrect version of S1 Data was published in error. This article was republished on January 10, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "An incorrect version of S1 Text was published in error. This article was republished on September 19, 2018 to correct for this error. Please download this article again to view the correct version."} +{"text": "An incorrect version of S1 File was published in error. The publisher apologizes for this error. This article was republished on December 21, 2018 to correct for this error. Please download this article again to view the correct version."} +{"text": "An incorrect version of Fig 3 was published in error. The publisher apologizes for this error. This article was republished on July 15, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "An incorrect version of Supporting Information S1 File was published in error. The publisher apologizes for this error. This article was republished on September 26, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "The original Supporting Information file Dataset 1 was published in error. The dataset was removed from the HTML and PDF versions of this article on November 15, 2018. The Data Availability statement has also been updated to reflect this change. Please download this article again to view the correct version."} +{"text": "An incorrect version of S1 Dataset was published in error. This article was republished on November 19, 2018 to correct for this error. Please download this article again to view the correct version."} +{"text": "This article was republished on September 7, 2018 to correct an error to the ORCID iD of the corresponding author introduced during the typesetting process. The publisher apologizes for the error. Please download this article again to view the correct version.In addition, the corresponding author\u2019s name has been corrected. The correct name is: Hanna Elizabeth Luke."} +{"text": "The corrected figure appears below.The authors regret that an error appeared in the original version of Fig. 3. In the upper panels of D, the image for Kng1The online HTML and PDF versions of this paper have been corrected. The error remains only in the print version."} +{"text": "In the original article, the reference list was incorrectly numbered and this resulted in mismatched citations. This was fixed and the original article was updated accordingly.The publisher apologizes for this mistake.The original article has been updated."} +{"text": "An incorrect version of Fig 2 was published in error. This article was republished on October 28, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "There is an error in the Correction published on January 31, 2019. The publisher apologizes for this error.The original"} +{"text": "An incorrect version of S2 File was published in error. The publisher apologizes for this error. This article was republished on September 25, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "An author name was incorrectly spelled as Yehdua Pollak. The correct spelling is Yehuda Pollak.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An incorrect version of S1 File was published in error. This article was republished on August 29, 2018 to correct for this error. Please download this article again to view the correct version."} +{"text": "An incorrect grant number was included in the XML of this article. The article was republished on January 13, 2020, to correct for this error. The publisher apologizes for this error."} +{"text": "The corresponding author for this article is now deceased, and the corresponding author information has since been changed from Deepak Narayan to Paul E. Turner."} +{"text": "This missing information, which does not affect our results or conclusions, has now been added in the article online. The authors apologize for the oversight."} +{"text": "Henein's name was incorrectly listed in the article as Henein Y. Michael. The authors apologize for the error."} +{"text": "The correct numbers are provided below. The authors declare that this correction does not change the results or conclusions of this paper. The authors sincerely apologize for this error.100 patients diagnosed with type A AAD and 139 healthy volunteers were registered in the study.Between August 2016 and February 2017,"} +{"text": "PLOS ONE that she had changed her position on the editorial decision in this case. The final paragraph of the retraction notice is hereby updated to the following: AA did not agree with the retraction. KH and FL did not respond.After this retraction notice was post"} +{"text": "Abstract. Instead of \u201cSideroxydans.Due to a typesetting error, there was a mistake in the The publisher apologizes for the error. The original article has been updated."} +{"text": "This article was republished on March 13, 2019 to correct for errors in the Data Availability statement introduced during the typesetting process. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "This article was republished on March 20, 2019, to correct the author list. Please download this article again to view the correct version."} +{"text": "An incorrect version of Fig 1 was published in error. This article was republished on October 18, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "All other relevant data are within the manuscript and its Supporting Information files.The Data Availability statement for this paper is incorrect. The correct statement is: Model data is available from the GBIF database at In the 2.3 Testing accuracy subsection of the Materials and Methods, a reference is omitted from the first sentence. The correct sentence is: To examine the accuracy of the maps based on SDM models relative to the BirdLife maps we downloaded the GBIF data for each species for 2016 and calculated the percentage of these distribution points that fell within the ranges suggested by MaxEnt models and BirdLife range maps, for each species with at least 5 points to test models.https://doi.org/10.15468/dl.cp0csd.The reference is: GBIF.org (07 April 2016) GBIF Occurrence Download"} +{"text": "An incorrect version of Fig 2 was published in error. This article was republished on May 31, 2019 to correct for this error. In addition, an updated Funding statement is included in the republished article. Please download this article again to view the correct version."} +{"text": "E. coli. The authors recently noticed that these black dots might not be the actual nanoparticles as similar dots were also found in the control samples. To verify the results the experiment was repeated, which produced much clearer and convincing images of the Ag NPs. The new images showed that the Ag NPs did penetrate E. coli as shown in the original figure. The authors have provided a corrected version here."} +{"text": "This article was republished on January 2, 2019, to correct errors to Box 1 introduced during the typesetting process. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "An incorrect version of S1 File was published in error. The publisher apologizes for this error. This article was republished on February 6, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "The authors wish to make the following correction to their paper . The firThe authors would like to apologize for any inconvenience caused. The change does not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage."} +{"text": "An incomplete, earlier version of this article was published in error. This article was republished on June 5, 2019 to correct for this error. The publisher apologizes for the error. Please download the article again to view the correct version."} +{"text": "An incorrect version of S2 Raw Data Study was published in error. This article was republished on October 24, 2018 to correct for this error. Please download this article again to view the correct version."} +{"text": "An incorrect version of S2 File was published in error. This article was republished on April 2, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "This article was republished on January 17, 2019 to remove a Supporting Information file that was incorrectly included in the originally published article. The publisher apologizes for the error. Please download this article again to view the correct version."} +{"text": "An incorrect version of S1 File was published in error. This article was republished on July 27, 2018 to correct for this error. Please download this article again to view the correct version."} +{"text": "This article was republished on January 21, 2020, to correct errors in Table 3 that were introduced during the typesetting process. The publisher apologizes for this error. Please download this article again to view the correct version."} +{"text": "An incorrect version of Figure 1 was published in error. This article was republished on November 8, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "Strubbe's second affiliation and funders were omitted from the original manuscript. This has now been amended in the online version.The author apologises for any inconvenience."} +{"text": "The affiliation for the last author is incorrect. Herman Weyenga is not affiliated with #8 but with #1 Ministry of Health, Nairobi, Republic of Kenya. The publisher apologizes for this error."} +{"text": "An incorrect version of the author byline was published in error. This article was republished on October 28, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "Incorrect versions of Figs 1\u20135 were published in error. The publisher apologizes for this error. This article was republished on October 24, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "An incorrect version of S1 File was published in error. This article was republished on June 3, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "An incorrect version of S1 File was published in error. The publisher apologizes for this error. This article was republished on April 1, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "There was an oversight regarding the acknowledgement of funding from the European Research Council, which was a contractual obligation for the funding. Professor Sukhwinder S. Shergill was funded by an ERC Consolidator Award."} +{"text": "In the original article, there was an error. The individual who generated artwork for Figure 1, was not duly acknowledged.Acknowledgements section.A correction has been made to the \u201cThe authors kindly thank Mr. Hans Kek for generating the artwork for Figure 1. We gratefully acknowledge the contribution to this work of the Victorian Operational Infrastructure Support Program received by the Burnet Institute.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An incorrect version of S1 Table was published in error. This article was republished on September 19, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "This article was republished on October 21, 2019, to correct the author list. Please download this article again to view the correct version."} +{"text": "An incorrect version of Fig 12 was published in error. This article was republished on April 19, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "An incorrect version of Figure 4 was published in error. This article was republished on May 20, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "Science leads with the results of a recent gloomy assessment of the cause of global climate change. Nature leads off this week with a story about U.S. attempts to prevent the spread of mad cow disease."} +{"text": "An incorrect version of S1 File was published in error. The publisher apologizes for this error. This article was republished on March 27, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "An incorrect version of Fig 1 was published in error. This article was republished on August 10, 2018 to correct for this error. Please download this article again to view the correct version."} +{"text": "VTTact\u2014reverse contained a false nucleobase. The corrected In the original article, there was a mistake in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An incorrect version of S1 File was published in error. This article was republished on July 31, 2018 to correct for this error. Please download this article again to view the correct version."} +{"text": "An author name was incorrectly spelled as Aylin E. Bilgutay. The correct spelling is Aylin N. Bilgutay. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The original S1 File was published in error. The file was removed from the HTML and PDF versions of this article on October 5, 2018. The Data Availability statement has also been updated to reflect this change. Please download this article again to view the correct version."} +{"text": "An incorrect version of Supporting information file S1 Dataset was published in error. The publisher apologizes for this error. This article was republished on October 8, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "Brewster et al., Chem. Sci., 2019, 10, 5596\u20135602.Correction for \u2018UO We regret that the CCDC number 1893382 was given incorrectly in the original manuscript. The correct CCDC number is 1893882. The crystal structure data file for the original manuscript has been updated to reflect this change.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "In Memoriam list published in the February 2019 issue. The information supplied to us was inaccurate but records have now been updated. We apologise to Dr McBride for this unfortunate error.We included in error Dr Thomas Mary McBride of Carrigawley, Letterkenny, Ireland in the"} +{"text": "An incorrect version of S1 Appendix was published in error. This article was republished on March 29, 2019 to correct for this error. The article\u2019s Data Availability statement has been updated to reflect this change. Please download this article again to view the correct version."} +{"text": "We would like to submit the correction to our published paper . The rea"} +{"text": "The accession number for this data is: GSE63785. The publisher apologizes for the error.In the Data Availability section, the web address for the data available at GEO is listed incorrectly. The correct address is:"} +{"text": "Due to the substantial nature of these edits, many errors were accidentally introduced into this table. We sincerely apologize for this unfortunate error and regret any subsequent confusion. A corrected version of The authors wish to make a correction to the published version of their paper . While rThis change does not impact the overall results or scientific conclusions. The original manuscript will remain online on the article webpage, with a reference to this correction."} +{"text": "Materials Editorial Office would like to report errors in the published paper [The ed paper . The detAffiliation 1 of the authors should be changed to \u201cInstitute of Nanotechnologies, Electronics and Electronic Equipment Engineering, 347922 Taganrog, Russia\u201d.We apologize for any inconvenience caused to the readers by this change. The change does not affect the scientific results. The manuscript will be updated and the original will remain available on the article webpage."} +{"text": "An incomplete, earlier version of this article was published in error. This article was republished on May 1, 2019 to correct for this error. Please download the article again to view the correct version."} +{"text": "An incorrect version of S1 Table was published in error. This article was republished on July 25, 2018 to correct for this error. Please download this article again to view the correct version."} +{"text": "PLOS Neglected Tropical Diseases apologize for this error and the delay in its recognition.The staff is retracting this publication as it is an uncorrected duplicate of pntd.0006993. The editors and staff of"} +{"text": "The authors wish to make the following corrections to their paper . The aut"} +{"text": "An incorrect version of S1 File was published in error. This article was republished on July 18, 2018 to correct for this error. Please download this article again to view the correct version."} +{"text": "An error in the editor name was introduced during typesetting. The correct editor name is Timothy John Hollins.The publisher apologizes for this error and the original article has been corrected. This error does not change the scientific conclusions of the article in any way.The original article has been updated."} +{"text": "There is an error in the second sentence of the fourteenth paragraph of the Results section. The correct sentence is: The GD values for the first and third codon positions are negative, ranging from \u221212.8% to \u221249.1% .In"} +{"text": "The online version was republished to correct an equation that was typeset incorrectly. The PDF version was correct and remains unchanged. The publisher apologizes for the error."} +{"text": "This article was republished on August 12, 2019 to correct an error in the References. The publisher apologizes for this error. Please download this article again to view the correct version."} +{"text": "The authors wish to make the following correction to their paper . The nam"} +{"text": "Nature is on the move. They have a snazzy new home page design and their lead story takes us to San Francisco, where discomfited anthropologists are discussing books at the American Anthropological Association's Annual Meeting. Science stays home and leads with a story about the lagging math and science skills of U.S. students."} +{"text": "The authors would like to make the following corrections to the published paper . The cha(1)\u2003The author\u2019s name should be corrected as follows: Romeo Jacobwith Romeo Iacob(2)\u2003The email address of Adrian Man should be corrected as follows:adrian.man@umftgm.rowithadrian.man@umfst.roThe authors and the Editorial Office would like to apologize for any inconvenience caused to the readers by these changes. The change does not affect the scientific results. The manuscript will be updated and the original will remain online on the article webpage."} +{"text": "In the version of this article originally published online, there was a misspelling of the name Conor Lawless in the author list.This has now been corrected online. The authors apologize for this error."} +{"text": "There are errors in the Funding section. The correct funding information is as follows: No specific funding was received for this work.The publisher apologizes for this error."} +{"text": "This article was republished on February 21, 2019 to correct for errors in the Data Availability statement introduced during the typesetting process. The publisher apologizes for the errors. Please download this article again to view the correct version."} +{"text": "Lotus japonicus was misspelled as Lotus japonius. Please download this article again to view the correct version.This article was republished on January 14, 2019, to correct an error in the title: the species name"} +{"text": "Two Japanese molecular biologists are charged with espionage in a case that could strain scientific relations between the U.S. and Japan, report both Nature and Science in their top stories this week."} +{"text": "Due to a production error, the wrong file was published as Supplementary Table 2. The original article has been updated with the correct"} +{"text": "In the original article, we neglected to include the funder \u201cNational Commission for Scientific and Technological Research REDES No. 180134 (PCI)\u201d to MH.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Due to a production error, the final version of the The publisher apologizes for this mistake. The original article has been updated."} +{"text": "An incorrect version of Fig 3 was published in error. This article was republished on August 17, 2018 to correct for this error. Please download this article again to view the correct version."} +{"text": "This article was republished on January 16, 2020, to remove a Supporting Information file that was incorrectly included in the originally published article. The article\u2019s Data Availability statement has also been updated to reflect this change. The publisher apologizes for this error. Please download this article again to view the correct version."} +{"text": "An incorrect version of Fig 1 was published in error. This article was republished on June 3, 2019 to correct for this error. Please download this article again to view the correct version."} +{"text": "The original version of this article unfortunately contained mistakes.The Tables\u00a01\u20133 were missing. The correct versions of Tables Bettina Standhartinger was unfortunately not correctly named in the acknowledgments of the original version of this article. The correct acknowledgements are as follows: The authors would like to thank Bettina Standhartinger for her valuable assistance in organizing the Wiggers\u2013Bernard Conference.The original article has been corrected."} +{"text": "In the published article, there was an error regarding the affiliations for Stephen W. Porges. As well as having affiliation 2, Dr. Stephen W. Porges should also have affiliation 1. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "PLOS ONE that she had changed her position on the editorial decision in this case. The final paragraph of the retraction notice is hereby updated to the following: AA did not agree with the retraction. KH and FL did not respond.After this retraction notice was post"} +{"text": "Due to an error in the editorial process, this article was not proofread before publication. The article has now been proofread and the necessary language-related corrections have been implemented. The previous version is available in the"} diff --git a/PMC_clustering_645.jsonl b/PMC_clustering_645.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..edcde8015fc5e680addf8e15b0690c7efcd5642c --- /dev/null +++ b/PMC_clustering_645.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:c74894a1d20537a0ff9388e1ec0f41f928adb32dc6d3005ea9d9895e490aee99 +size 65832903 diff --git a/PMC_clustering_646.jsonl b/PMC_clustering_646.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..77db3739391010c1a70e08ebf1b0e0ef754d3b83 --- /dev/null +++ b/PMC_clustering_646.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:e88e0c4f17279b6628f7cf9a30f30c4753b7e66084dca071831f11612ad12782 +size 51579735 diff --git a/PMC_clustering_647.jsonl b/PMC_clustering_647.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..aff3bdd289f24ca2df5c6025d9140bfddfc80577 --- /dev/null +++ b/PMC_clustering_647.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:9f8632d023c11ced81ad14fb753b5a01e7fb752c33fb09f1eaeb9d862f8b31fd +size 54046672 diff --git a/PMC_clustering_648.jsonl b/PMC_clustering_648.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..df2467b73a4603394461f95d42ab63246d146823 --- /dev/null +++ b/PMC_clustering_648.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:0e69e346a9824dcbd834ab1229d170cb2b78f5051f26e0a7dd4f91b730158719 +size 38484082 diff --git a/PMC_clustering_649.jsonl b/PMC_clustering_649.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..0bdca967e5430c25cdac9ca9cd82214f20330d30 --- /dev/null +++ b/PMC_clustering_649.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:d28e43b0eccc9dfb1c5dc701f8a75f23a7be3fd920c3cb814d47a8adbbb92c1b +size 29864388 diff --git a/PMC_clustering_650.jsonl b/PMC_clustering_650.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..37aca248c3af441197c914d5d5178ba13b799398 --- /dev/null +++ b/PMC_clustering_650.jsonl @@ -0,0 +1,689 @@ +{"text": "In the original article there was a mistake in the title. This article deals with \u201cmiR-765\u201d and not \u201cmiR-745.\u201d The correct title is above.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Due to a production error, there was a mistake in The original version of this article has been updated."} +{"text": "Please note that following publication of the original article , two errFirstly, the article has been processed with the wrong article type: it is not a \u2018Review\u2019, but rather a \u2018Research article\u2019.Secondly, the initial of the corresponding author\u2019s middle name is missing in the original article; please see the corrected name in the author list of this Correction."} +{"text": "The authors wish to make the following corrections to this article :Figure 2b,d in the original article were incorrect; the correct images are shown below:At the end of the \u201cLength Control\u201d paragraph (page 6), the sentence \u201dthe lengths of the ZnS nanowires were extended from the original 60 to 330 nm\u2026\u201d should be \u201cthe lengths of the ZnS nanowires were extended from the original ca. 30 to 330 nm\u2026\u201d.Figure S3d in the Supplementary Materials was incorrect; the correct image is shown below:The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "The authors wish to make the following corrections to this paper :The sentence in the abstract \u201cThe ranges reflect variability in body mass index and hence amount of body fat\u201d should be rephrased as \u201cThe ranges reflect variability in body mass index and, more so, variable inhalation patterns\u201d.The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "The Editorial Office of Plants wants to make the following correction to the paper by Saddoud Debbabi, O., et al. (2020) :On page 1, the fourth author\u2019s name should be Mahdi Fendri instead of \u201cMahdi Fendri Fendri\u201d.The manuscript will be updated and the original will remain online on the article webpage.We would like to apologize for any inconvenience caused."} +{"text": "An author name was incorrectly spelled as \u201cFang Ke.\u201d The correct spelling is \u201cKe Fang\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "To the editor,We read the publication on \u201cAssociation between enuresis and obesity in children with primary monosymptomatic nocturnal enuresis\u201d with a great interest. Ma et al. concluded that \u201cObesity is associated with severe enuresis and low efficacy of behavioral therapy in children with nocturnal enuresis .\u201d This r"} +{"text": "OsNAS\u2191instead of OsNAS3\u2191in Defense 3. The corrected In the original article, there was a mistake in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The second sentence of the third paragraph of the Discussion section should have read \u201cOne limitation is that our data were from patients who died during late January 2020, and they may not be representative of later cases of COVID-19.\u201d The article has been corrected.In the research letter titled \u201cClinical Characteristics of Patients Who Died of Coronavirus Disease 2019 in China,\u201d"} +{"text": "The names of the French physician Georges Louis Bardet 1885\u20101966) and the Hungarian pathologist\u2010endocrinologist Artur Biedl 1869\u20101933) are associated with the Bardet\u2010Biedl syndrome (BBS) on which Bardet published in 1920885\u20101966 3 are assAnton (Toni) Mochty was born in the small farmers community of Haindorf, Austria in 1886 and from the age of 10 he was \u201cexhibited\u201d in Europe as \u201cthe fattest boy in the world\u201d and \u201ca wonder of human nature,\u201dAnton/Toni Mochty had several clinical features which are in line with the diagnosis of an autosomal recessive ciliopathy and most probable BBS: bradyphrenia\u2014slow development, truncal obesity, achalasia and polydactyly. However, information on disturbed visual acuity in line with RCD in this case is regretfully lacking. Bardet and Biedl apparently were not aware of his existence and as such, he presented with BBS \u201cavant la lettre.\u201d"} +{"text": "The authors wish to make the following correction to this paper : In the \u201cSolutions were pumped through the syringe at a flow rate of 0.5 mL/h and the rotating speed of the collector was fixed at 1000 rpm.\u201dThe authors would like to apologize for any inconvenience caused to the readers by this change."} +{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, as commented on in the correspondence \u201cComments on \u2018Association of Fc\u03b5RI\u03b2 polymorphisms with risk of asthma and allergic rhinitis: evidence based on 29 case-control studies\u2019\u201d, and therefore has issued an expression of concern to notify readers to potential errors in the conclusions. The authors were invited to respond to the comments made, but have not responded."} +{"text": "In the original article, there was an error. \u201cHpyPIX\u201d was misspelled as \u201cHpyPX\u201d throughout the article. The correct spelling is \u201cHpyPIX\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Abstract. The corrected sentence appears below:In the original article, there was an error in the Abstract. The word \u201ccomplemented\u201d was misspelled as \u201ccomplimented.\u201d A correction has been made to the cmcp-C) was obtained by transforming cmcp to \u0394cmcp.\u201d\u201cA complemented mutant (\u0394The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The article Silver, was not \u201cThe bridge formed by astrocytes is more like a short \u201cdrawbridge\u201d Silver, .\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Our ability to correctly reconstruct a phylogenetic tree is strongly affected by both systematic errors and the amount of phylogenetic signal in the data. Current approaches to tackle tree reconstruction artifacts, such as the use of parameter-rich models, do not translate readily to single-gene alignments. This, coupled with the limited amount of phylogenetic information contained in single-gene alignments, makes gene trees particularly difficult to reconstruct. Opsin phylogeny illustrates this problem clearly. Opsins are G-protein coupled receptors utilized in photoreceptive processes across Metazoa and their protein sequences are roughly 300 amino acids long. A number of incongruent opsin phylogenies have been published and opsin evolution remains poorly understood. Here, we present a novel approach, the canary sequence approach, to investigate and potentially circumvent errors in single-gene phylogenies. First, we demonstrate our approach using two well-understood cases of long-branch attraction in single-gene data sets, and simulations. After that, we apply our approach to a large collection of well-characterized opsins to clarify the relationships of the three main opsin subfamilies. Resolving gene phylogenies is difficult for two reasons. Firstly, single-gene alignments are relatively short and might be poor in phylogenetic signal. Secondly, it is more difficult to counter tree reconstruction artifacts in single-gene alignments, as most approaches used to address these problems have been developed for long superalignments where such artifacts are exacerbated \u2014for examOpsins are G-coupled protein receptors fundamental to light sensitive processes across Metazoa. Opsins are present in almost every animal phylum; including Cnidaria and Ctenophora . Opsin-lcis-photoisomerized state. Together, this combination is known as a visual pigment , but do not affect the relationships inferred for the other sequences in the data set, to identify potentially problematic sequences.We first demonstrate that our approach is able to identify potentially problematic sequences in two classic case studies\u2014recovering a tree displaying Ecdysozoa using the data of The canary sequence approach aims to identify and reduce the number of problematic sequences in an alignment, and thereby reduce topological reconstruction artefacts. The logic underlying the canary sequence approach is based on the identification of sequences that are prone to moving within a phylogeny due to poor clustering signals : The canData set creation: The first step requires the identification of the \u201cfull data set\u201d (the considered data set) and of two additional sub datasets. The first sub dataset is composed of the \u201csequences of interest,\u201d which includes all the sequences that are under examination (these are a set of sequences that we intend to add to a pre-existing gene family data set). The second set is referred to as the \u201cbase data set,\u201d which includes all sequences in the full data set except the sequences of interest. Trees are constructed from both the base data set and the full data set\u2014these are referred to as the \u201cbase tree\u201d and \u201cfull tree,\u201d respectively. The base tree and full tree serve to measure the effect of the sequences of interest on the topology of the gene tree, and allow for an existing gene tree to act as a basis for the application of the canary method. Note that (see the results of our case studies) the method does not assume accuracy of either the base tree or full tree.Measuring the effect of the sequences of interest: In the second step, a series of data sets are generated by separately combining the base data set with each individual sequence of interest. These data sets and the trees from these data sets are referred to as \u201cchecking data sets\u201d and \u201cchecking trees.\u201d The position of each sequence in each checking tree is noted.Identification of sequences for further examination: For each sequence of interest, if the checking tree and the base tree are isomorphic , the sequence of interest is marked as a \u201csequence for further examination.\u201d If, after the removal of the sequence of interest, the checking tree and base tree are not isomorphic the sequence of interest is moved to the \u201cnoncanary sequences of interest data set.\u201dIdentification of canary and stable sequences: As inaccurate phylogenies might emerge because of compositional heterogeneity . Because these sequences do not have sufficient information to cluster firmly in their checking tree, they are more likely to be affected by the presence of \u201cproblematic sequences\u201d when compared with other sequences in the data set. We thus suggest that they can be used as indicators to highlight potentially problematic sequences, which are expected to have the tendency to attract canary sequences.Definition of the \u201ccanary data\u2002set\u201d and \u201ccanary tree\u201d: All canary sequences identified in Step 4 are added to the base data set to generate the \u201ccanary data set.\u201d A tree is inferred from the canary data set, which is referred to as the \u201ccanary tree.\u201d Measuring the effect of the noncanary sequences on the canary data\u2002set: For each sequence in the \u201cnoncanary sequences of interest data set\u201d, a new alignment is generated where a single noncanary sequence of interest is added to the \u201ccanary data set.\u201d These data sets and the trees they generate are referred to as the \u201ccanary checking data sets\u201d and \u201ccanary checking trees\u201d respectively. For each noncanary sequence of interest, if the \u201ccanary checking tree\u201d and the \u201ccanary tree\u201d (of step 5) are isomorphic , the noncanary sequence of interest is identified as \u201cnonproblematic.\u201d All other noncanary sequences of interest are defined as \u201cpotentially problematic.\u201dGeneration of the \u201cMinimal data\u2002set\u201d and completion of the canary pipeline: All \u201cnonproblematic sequences\u201d are added to the \u201ccanary data set\u201d to generate the \u201cminimal data set.\u201d The tree generated from the minimal data set is the final point of the canary sequence approach and is called the \u201cminimal tree.\u201d This is to stress that this gene tree is by definition incomplete and only represents the backbone of the evolutionary history of the family of interest, as it excludes all potentially probelamtic sequences.No canary sequences Identified: Previously identified \u201cstable sequences\u201d from step 3, are identified as potentially nonproblematic. Stable sequences only are added to the base data set to generate the minimal tree.To test the reliability of the canary approach we performed analyses using two data sets We used the Aguinaldo and collaborators 18s rRNA data set to test the performance of the canary method. The original 18s rRNA analysis of Once canary sequences were identified, they were added to the \u201cbase data set\u201d to form the \u201ccanary data set,\u201d which contained 47 sequences, and the sequence that was not determined to be a canary sequence was moved to the noncanary sequences data set. As there was only one noncanary sequence of interest one \u201ccanary checking data set\u201d was constructed, consisting of 48 sequences. The \u201ccanary checking tree\u201d was compared with the \u201ccanary tree\u201d (see point 5 of the \u201cThe Canary Sequence Approach to Identify Problematic Sequences\u201d section) to evaluate whether the noncanary sequence of interest was \u201cpotentially problematic\u201d or not, and whether it was to be excluded from the \u201cminimal data set\u201d and the \u201cminimal tree\u201d that we built to complete the canary pipeline (see point 6 of the \u201cThe Canary Sequence Approach to Identify Problematic Sequences\u201d section).The original 18s rRNA analysis of We started by considering all 15 platyhelminth sequences in the data set as \u201csequences of interest,\u201d as these sequences were the focus of Once canary sequences were identified, they were added to the base data set to generate the canary data set (point 3 of the \"The Canary Sequence Approach to Identify Problematic Sequences\" section), which contained 16 sequences. We identified 14 noncanary sequences of interest , and we thus generated 14 \u201ccanary checking data sets\u201d consisting of 17 sequences each\u2014the canary data set plus one noncanary sequence of interest. The 14 \u201ccanary checking trees\u201d were compared with the \u201ccanary tree\u201d to identify the \u201cpotentially problematic sequences\u201d, generate the \u201cminimal data set\u201d and conclude the canary approach through the inference of a minimal tree (see point 6 of the \"The Canary Sequence Approach to Identify Problematic Sequences\" section).Strongyloides and Caenorhabditis) \u223c10 times longer than the next longest branches in the simulation. For each simulated data set we recovered trees using the JC69 model, to increase chances of recovering an incorrect topology, which we identified as any incorrect arrangement of nematode species . Simulated data sets that did not recover an incorrect topology, where no canary could be identified or where all sequences emerged as canary sequences, were not further considered as we only wanted to evaluate the number of successes in cases in which the full, standard, canary pipeline could be applied (points 1\u20136 of the \u201cThe Canary Sequence Approach to Identify Problematic Sequences\u201d section). A success in the application of the canary approach was defined as the recovery of a monophyletic Nematoda as a memebr of the nonarthropod Ecdysozoa.Fifty simulation data sets were constructed in PAML evolver , using thttps://bitbucket.org/flemingj/canarysequencemethodology .We assembled a data set of 98 well-characterized bilaterian opsins\u2014downloaded from the NCBI website. This data set was assembled to avoid biasing the taxonomic composition of our data set in favor of groups that are overrepresented in sequence databases, such as the Vertebrata in the ciliary opsins, and the Arthropoda in the rhabdomeric opsins see as theseCaenorhabditis and Trichuris. One sequence emerged as \u201cpotentially problematic\u201d: The Strongyloides 18S rRNA sequence. The \u201cminimal tree\u201d that excludes the Strongyloides 18S rRNA sequence recovered monophyletic Ecdysozoa , and the minimal tree derived from this dataset recovered monophyletic Platyhelminthes, and Lophotrochozoa, in accordance with current molecular consensus were rejected in 63.6% of the simulations. 78.8% of the successful simulations reject at least one of these two simulated sequences, with the remaining sequences being able to resolve a correctly positioned monophyletic Nematoda. As the canary sequence approach scales with the capabilities of the models used to resolve the \u201cchecking tree\u201d and \u201ccanary checking tree,\u201d better results could be expected in simulation using more sophisticated models that were not used here to maintain comparability with the original results of With reference to individual sequences, Nematostella vectensis provided the highest number of sequences of interest, but also the highest number of problematic sequences, whereas the anthomedusan Cladonema radiatum and the box jellyfish Tripedalia cystophora provided the largest proportion of nonproblematic sequences. Only two of eight opsins were problematic for C.\u2002radiatum, whereas 5 of 18 opsins were problematic in the case of the box jellyfish as a rhabdomeric opsin, strengthening the evidence for the existence of this opsin type in Cnidaria would still be useful when interpreting phylogenetic results. A practical example of this would be that of mnemiopsis3. Our minimal opsin tree confirms that the three main canonical opsin lineages emerged before the separation of Cnidaria, Ctenophora, and Bilateria . Ctenophevaa015_Supplementary_DataClick here for additional data file."} +{"text": "We appreciate the expressed interest of Chaput et al. in our rChaput et al. asserted that we interpreted our cognitive findings as evidence that prenatal cannabis use is safe in this domain. This is not only untrue but also is a misrepresentation of our meticulously cautious interpretations of the current published literature. The words \u201csafe\u201d or \u201csafety\u201d do not appear anywhere in our article, but they appear at least six times in the critique by Chaput et al. Relatedly, the critique takes exception to our manuscript's title\u2014Totality of the Evidence Suggests Prenatal Cannabis Exposure Does Not Lead to Cognitive Impairments: A Systematic and Critical Review\u2014because, they claim it \u201cimplies evidence for the safety of prenatal cannabis use\u2026\u201d We disagree. A good title should concisely summarize what was done and what was found interpretations of previous findings have frequently overstated the disruptive impact of prenatal cannabis exposure on subsequent cognitive functioning of offspring; and (2) the available empirical database does not support the view that CT prepared the first draft of manuscript. CM-K, KO'M, and CH revised and edited the manuscript until it was completed. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Authors were unable to provide the original dataset to address the concerns raised.The article, \u201cEffectiveness of music therapy with relaxation technique on stress management as measured by perceived stress scale\u201d,"} +{"text": "Instead of the \u201cUniversity of Missouri-Columbia,\u201d the university name should be \u201cUniversity of Missouri-Kansas City.\u201dIn the published article, there was an error in the affiliation The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, the order of affiliation 1&2 were incorrect. Also the affiliation \u201cMudanjiang Medical University\u201d has been added for author Jiahui Wan.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the article, \u201cSearch and Selection of Probiotics That Improve Mucositis Symptoms in Oncologic Patients. A Systematic Review\u201d which ap\u00ae is replaced with the generic name of the formulation, \u201cDe Simone formulation\u201d, following a legal dispute between the distributors of the product VSL#3\u00ae and the formula inventor.As De Simone points oThis change does not affect the study of the paper."} +{"text": "An author's name was incorrectly spelled as \u201cChuangtao Ye\u201d. The correct spelling is \u201cChuantao Ye\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In our recently published article , the refTherefore, we sincerely apologize for missing this important item and we have eliminated the Chandra\u2019s reference from ourWe apologize for this mistake and appreciate the diligence of Jim\u00e9nez-G\u00f3mez and colleagues in spotting this error and helping to maintain the integrity of the science in this field."} +{"text": "The long-term fiscal and economic damage of eurobonds in a rule-based fiscal architecture \u2014 as history corroborates \u2014 would be greater than the historical challenge of the coronavirus pandemic, unless there is a political union in Europe."} +{"text": "We consider a version of Many of the tree forcings on the classical Baire space have various analogues for higher cardinals. Here we are concerned with Miller forcing . In the s. The common interpretation of \u201cs is a splitting node of p\u201d is:For a entclass1pt{minimas is a splitting node of p\u201d is weakened toIn this paper we investigate a version of Throughout the paper we let q is stronger than p.We denote forcing orders in the form t with the singleton function f is also called the length of f. The set of subsets of If superperfect: for each t is a T. A node splitting node if T is denoted by We furthermore require for For For Let For Each of the two forcing orders In this section we consider A family If b of We let If We will apply the following result for Forcing with Forcing with , since it is definable from Since Two forcings Q collapses [If nowhere distributive if there are antichains A Boolean algebra is B be a Boolean algebra. We write dense if density of a Boolean algebra B is the least size of a dense subset of B. A Boolean algebra B has uniform density if for every density of a forcing order Let S. The latter means: in case Suppose that Then(2)Under (a) and (b) [If there is a Lemma\u00a0By Lemma\u00a0If"} +{"text": "In the original article, the reference for \u201cGeorge and Panagiotis, 2008 is incorrect\u201d. It should be \u201cGiatsis and Zahariadis, 2008\u201d. Citations of George and Panagiotis, 2008 have been replaced and it has been removed from the reference list. \u201cGiatsis and Zahariadis, 2008\u201d is already in the reference list.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, there was an error in affiliation 2. The center \u201cCentro de Estudios en Neurociencia Humana y Neuropsicolog\u00eda\u201d was missing.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The original version of this article unfortunately contained a mistake. The sentence within the section \u201cBayesian design and prespecified interim analyses\u201d should read:Due to a Bayesian power prior approach being used, a non-standard parameterization for the ANCOVA model is used to allow for informative prior distributions to be placed separately on the RDN and control arm effects:The original article has been corrected."} +{"text": "In the original article, in The corrected \u201cPrimers sets for qPCR\u201d appears below.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, there was an error in affiliation 4. Instead of \u201cKing Saud University\u201d, it should be \u201cPrince Sultan University.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This commentary sets Caplan\u2019s arguments about food banks and food poverty in the broader context of changes to the welfare state, the \u2018charitization\u2019 of state welfare and the need to address food poverty within a framework of dignity rather than charity."} +{"text": "Due to a production error, the citation for \u201cPiconese et al.\u201d was linked to the wrong article. The publisher apologizes for this mistake. The original article has been updated."} +{"text": "In light of the severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102 or COVID\u201019) pandemic and the possible widespread use of chloroquine and its derivatives ,The authors confirm that there are no conflicts of interest."} +{"text": "To the Editor,I read with great interest the meta\u2010analysis by Kumar et alAdditionally, the authors included a retrospective study by Kolek et alAuthors declare no conflict of interests for this article."} +{"text": "Following the publication of the original article we were The authorship has now been updated in the original article and included in this Correction.The \u2018Author contributions\u2019 section has also been updated to read: \u201cKG and FA: conceived and designed the project; managed the data collection. KG, HG and MT: conducted data analysis and wrote the manuscript. All authors read and approved the final manuscript\u201d."} +{"text": "In the initially published version of this article, the \u201cHeart\u201d image of the RMSNs+Laser group in Figure The corrections made in this erratum do not affect the original conclusions. The authors apologize for any inconvenience or misunderstanding that this error may have caused."} +{"text": "Instead of \u201cRongchong Huang3,\u201d it should be \u201cRongchong Huang1,3.\u201dIn the published article, there was an error in affiliation The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The correct spelling (\u201cLaura Gheuca-Solov\u0103stru\u201d) is presented above.The authors regret that this error was not noticed prior to the publication of their paper, and apologize for any inconvenience caused to the readership of the Journal."} +{"text": "MMWR Editors that some results were inaccurate as a result of a data input error that occurred during an update to the online Alcohol-Related Disease Impact application (Recently, the authors of the report \u201cDeaths and Years of Potential Life Lost From Excessive Alcohol Use \u2014 United States, 2011\u20132015\u201d ("} +{"text": "Due to a production error, there was a mistake in The original article has been updated."} +{"text": "The Society would like to draw the reader's attention to an error in the following supplement:\u201cAbstracts of the 78th Annual Meeting of the Japanese Cancer Association; 2019 Sept 26\u201028; Kyoto, Japan\u201d as Cancer Science, Supplement 1, Vol. 110 (2019).P\u20101295 to P\u20101403 on 26 September 2019P\u20102263 to P\u20102387 on 27 September 2019The following abstracts were not included in the supplement:The supplement has been corrected and the missing abstracts are listed from page 765 onwards.The Society apologizes for this error and any confusion it may have caused."} +{"text": "Portrait of Maria Salviati and Giulia de\u2019 Medici, by reading the historical review article Syphilis in Maria Salviati (1499\u20131543), Wife of Giovanni de\u2019 Medici of the Black Bands, which appears in this issue. This image is also included as Figure 1 in that article.Readers may learn more about this month\u2019s cover image,"} +{"text": "These values also resulted in a wrong calculation of the degree of PDM alignment (\u039b). The corrected In the original article, there was a mistake in"} +{"text": "In the published article, there was an error regarding the contribution of \u201cXinsheng Yao,\u201d who should be a co-corresponding author.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The original publication contained an error in Table\u00a03. The corrected version of Table\u00a03 is shown here;The authors apologise for the error."} +{"text": "This article has been retracted as it includes data\u00a0published without permission from the Get With the Guidelines database, which is property of American Heart Association (AHA). Although the authors' hospital had access to this database and they did\u00a0receive\u00a0IRB approval, the terms of use between the hospital and AHA do not allow publication of the data in a public sphere. The authors were hoping to receive retrospective approval from the AHA but have not been successful in getting this permission thus far.\u00a0 As a result this article has been retracted at the request of the AHA and with full agreement by the authors."} +{"text": "This has been corrected in the HTML and PDF version of the Article.The original version of the published Article contained an error in the \u201cMethods\u201d section and the flow chart depicted in Fig. 3. The statistical test used should be a one sample"} +{"text": "The author wishes to make the following correction to this paper due to mWith the following corrected The reason being that the localization results shown in these figures are not only from ANNs but also from the proposed database (DTB) method and as such it is more appropriate that the label should be \u201cpredicted locations\u201d rather than \u201cANN predicted locations\u201d. This change will not affect any results or findings in the paper.We apologize for any convenience caused by this change."} +{"text": "In the article titled \u201cStay Fit, Stay Young: Mitochondria in Movement: The Role of Exercise in the New Mitochondrial Paradigm\u201d , the aut\u201cThe duration of maximal exercise at which equal contributions are derived from the anaerobic and aerobic energy systems appears to occur between 1 and 2 minutes and most probably around 75 seconds, a time that is considerably earlier than has traditionally been suggested.\u201d"} +{"text": "Following publication of the original article , the autThe collaborators\u2019 names are included in the \u2018Acknowledgements\u2019 section given below. The author group has been updated above and the original article has been"} +{"text": "In the original article, there was a mistake in Figure 1 as published. In Figure 1A as well as in Figure 1B the colors in the bar of the \u201cRed Cabbage Root\u201d were not shown correctly: In Figure 1A the \u201cIndole GLS\u201d in the bar of \u201cRed Cabbage Root\u201d were turquois instead of black. In Figure 1B in the bar of \u201cRed Cabbage Root\u201d the ITCs were orange instead of red and the CNs were dark blue instead of orange (and therefore could be mistaken for ETNs). The corrected The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Inspired by graphic health narratives\u2014or comics as some scholars may define them\u2014my painting \u201cFlashback\u201d shares my experience of recalling a traumatic incident. My aim for this painting was to evoke a visceral reaction of discomfort (particularly with the sharp objects in the character\u2019s eyes) so that viewers may feel some semblance of what I had felt. Flashback was exhibited at the Surgical Humanities Day at the University of Saskatchewan in September 2019."} +{"text": "This action has been agreed because the authors withdrew their article in the year 2016\u20132017 after acceptance, due to non\u2010payment of APC charges. Unfortunately, a technical error in 2019 led to the article\u2019s publication online. The production team of this journal takes full responsibility and apologizes for the technical error that resulted in the publication of this article. The article \u201cIn vitro single\u2010strand DNA damage and cancer cell cytotoxicity of temozolomide ("} +{"text": "There is an error in the article XML causing the eighth author\u2019s name to be indexed incorrectly. The name should be indexed as van der Poll T."} +{"text": "An author's name was incorrectly spelled as \u201cMark Fiecus\u201d. The correct spelling is \u201cMark Fiecas\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original article, we neglected to include the funder the \u201cEuropean Union's Horizon 2020 Research and Innovation Programme under the Marie Sk\u0142odowska-Curie grant agreement, 675610\u201d to Tia Tyrsett Kuo.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The original version of the article unfortunately contained an error in the first name and the surname of one of the authors in the author group. The last author name was incorrectly published as \u2018F. Pecori Giraldi\u2019 and the corrected name is \u2018Francesca Pecori Giraldi\u2019 .The original article has been corrected."} +{"text": "In this paper, we study active learning algorithms for weighted automata over a semiring. We show that a variant of Angluin\u2019s seminal"} +{"text": "In the original article, there was an error in the article title. There was typo in our accepted research article. The title of the article was \u201cGut Microbiota as a Subjective Measurement for Auxiliary Diagnosis of Insomnia Disorder.\u201dThe word \u201csubjective\u201d should be \u201cobjective.\u201d Thus, the correct title is \u201cGut Microbiota as an Objective Measurement for Auxiliary Diagnosis of Insomnia Disorder.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Journal of Global Health published a viewpoint \u201cThe roles of a Grandmother in African societies \u2013 please do not send them to old people\u2019s homes\u201d [Online Supplementary Document we include the letter from the authors, and the original article with authors\u2019 annotations.In the June 2019 issue of the"} +{"text": "The original version of this article unfortunately contained a mistake. First sentence of the second paragraph of the section \u201cDietary and non\u2011dietary assessments\u201d should read as:For the estimation of dietary total polyphenol intake, we used our original database of the polyphenol content of foods; the main values from this database are described elsewhere ."} +{"text": "In the published article there was an error in the Funding statement. The correct number for the Key Research and Development Program of Shaanxi is \u201c2020KWZ-006.\u201d The correct number for the Xi'an Weiyang District Science and Technology Fund is \u201c201927.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Ever since its earliest years, information theory has enjoyed both a promising and complicated relationship with the social sciences. Shannon himself applied his \u201cmathematical theory of communication\u201d to human communication early on, allegedly having his wife Betty estimating word probabilities to calculate the first approximation of the entropy of English . Five yeIt turned out that in the social sciences, this translation process was indeed slow and tedious. After Miller\u2019s famous \u201cmagical number seven\u201d paper and AttnWhile these rather practical and computational limitations have been overcome in recent years due to the \u201cbig data\u201d flood and omnipresent cloud computing, unfortunately, there have also been conceptual reservations to the applicability of information theory to the social sciences, especially during the 1990s and early 2000s. It was argued that information theory was supposedly \u201cinappropriate to represent social processes\u201d as it waReaching the year 2020, the increase in human interactions taking place in digital environments has led to a refound fascination with applying information theory in the social sciences. The new abundance of behavioral \u201cbig data\u201d and our computational resources allow researchers to even calculate measures that converge rather slowly, while, at the same time, the maturation of the social sciences has led to an increased interest in more sophisticated nonlinear methods and measures.This Special Issue compiles 11 creative research articles on innovative uses of information theory and its extensions to better understand human behavior and social processes. The articles in this Special Issue are proof of the abundant opportunities offered by information theory to better understand the nature of humans and its societal systems and dynamics.Hilbert and Darmon use infoUppal, Ferdinand, and Marzen are \u201cInfTwo studies in this Special Issue use MaxEnt and spatial information entropy methods to explore the spatial\u2013temporal evolutionary characteristics of ethnic groups to better understand the different stages of their transition and migration, including \u201cSpatial\u2013Temporal Characteristic Analysis of Ethnic Toponyms Based on Spatial Information Entropy at the Rural Level in Northeast China\u201d and \u201cUsiIn \u201cEconomics of Disagreement\u2014Financial Intuition for the R\u00e9nyi Divergence\u201d, Andrei Soklakov shows hoIn the \u201cSource of Knowledge Dynamics\u2014Transition from High School to University\u201d, Hadad and colleagues make inn\u201cAn Objective-Based Entropy Approach for Interpretable Decision Tree Models in Support of Human Resource Management: The Case of Absenteeism at Work\u201d uses infWiener uses theOf course, Integrated Information Theory\u2019s (IIT) ambition to mathematically model consciousness cannot be missed in a current discussion of information theory for human processes. Popiel and colleagues use the generalized Ising model to calculate \u03a6 as a function of temperature in toy models of fully connected neural networks. In \u201cThe Emergence of Integrated Information, Complexity, and \u2018Consciousness\u2019 at Criticality\u201d , they shThe biggest methodological contribution to the social sciences in this Special Issue comes from Dave Darmon: \u201cDiscrete Information Dynamics with Confidence via the Computational Mechanics Bootstrap: Confidence Sets and Significance Tests for Information-Dynamic Measures\u201d . It solvEntropy is not necessarily nonnegative\u201d , while tEntropy . These a"} +{"text": "There is an error in the title. The correct title of the article is \u201cSurvThere is a typo mistake in the abstract\u2019s conclusion where \u201cis\u201d which follows \u201crepresents\u201d should be deleted so that the sentence can be grammatically correct, as highlighted in the following text: \u201cConclusion: The high hospitalization costs for COVID-19 patients represents The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "Authors were unable to provide the original dataset to address the concerns raised.The article \u201cRandomized controlled evaluation of the effect of music therapy with cognitive-behavioral therapy on social anxiety symptoms\u201d"} +{"text": "In the published article, there was an error regarding the affiliation for \u201cKunhua Wei.\u201d As well as having affiliation \u201c4,\u201d they should also have \u201cGuangxi Key Laboratory of Medicinal Resources Protection and Genetic Improvement, Guangxi Botanical Garden of Medicinal Plants, Nanning, China\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "To the Editor: In the research letter by J. Lu et al. . The authors do not provide evidence that the exhaust fan was not working; they ignored its presence. A simple measurement of air flow would answer this question.The fact that \u201c\u2026 none of the staff or other diners in restaurant X were infected\u201d is another indication that the air conditioner was probably working. Also puzzling is the authors\u2019 conclusion that \u201c\u2026 the smear samples from the air conditioner were all nucleotide negative. This finding is less consistent with aerosol transmission.\u201dThe authors\u2019 conclusion that \u201c\u2026 in this outbreak, droplet transmission was prompted by air-conditioned ventilation\u201d is not supported by the data provided. They further conclude that \u201cThe key factor for infection was the direction of the airflow\u201d but do not follow the airflow to the exhaust fan."} +{"text": "The thirteenth and fourteenth labels in the leftmost column of Figure 3 should have read \u201cQin et al., 2018 Hemorrhagic stroke\u201d and \u201cQin et al., 2018 Ischemic stroke\u201d. The corrected In the original article, there was a mislabeled The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The denominator in the fraction should be (k \u2013 i)! rather than (N \u2013 k)!In the original article, there were two errors in Equation (5). The lower limit of the summation should be A correction has been made to Equation (5). The corrected equation appears below.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original article, the author Xiangming Fan was marked as belonging to affiliation 2. The correct affiliation is 1. In addition, there was an error in the running title as it referred to \u201cFlow Resistance.\u201d The correct running title should be \u201cSimulation of Pressure Difference in the Intraventricular Tunnel.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Unfortunately, the original publication of this article contains an error in table\u00a01. The revised version of Table"} +{"text": "In the original publication of the article, the article note \u201cAshraf A. Dahaba and Zhao Yang Xiao equally contributed to the study and are both first authors.\u201d was published incorrectly. The correct statement should read as \u201cAshraf A. Dahaba and Zhao Yang Xiao equally contributed to the study and are both first authors and are both co-corresponding authors.\u201d"} +{"text": "A biosensor is an analytical device used for the real-time detection and measurement of a chemical or biochemical substance . It is d"} +{"text": "The order of affiliations has been corrected as per the corresponding authorship.The article title read \u201creesonance\u201d this has been corrected to \u201cresonance\u201d.Two errors have been corrected in the original article followinThese errors have been updated in this correction article and the original article. The publisher apologizes to the authors and readers for the inconvenience."} +{"text": "In the article by Wu et al,The correct forward and reverse lnc\u2010MMP2\u20102 primer sequences should be: TCCATCCTGCTGCTCAGTATCTCC and GCTCAGACGTGCCATTCTCAGG.The authors apologize for this error."} +{"text": "There is an error in the entry of the author Constantin von Kaisenberg\u2019s name in the XML of the article, where \u2018von\u2019 is entered as a middle name. The full surname should be \u2018von Kaisenberg\u2019."} +{"text": "In the original article, there was an error in the accession number where the data was deposited. Instead of \u201cGSE75665\u201d it should be \u201cGSE78025.\u201d A correction has been made to the Materials and Methods section, subsection Data Accession:GSE78025.\u201d\u201cThe raw data have been deposited to the Gene Expression Omnibus (GEO) under accession The apologize for this error and declared that this correction does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The authors would like to make a correction to their published paper , Figure On page 9 the legend terms of Figure 6a denoted by a circle \u201c5hmC tumor\u201d and square \u201c5hmC adjacent\u201d were switched by accident and were switched back to where \u201c5hmC tumor\u201d is accompanied by a square and \u201c5hmC adjacent\u201d accompanied by a circle.The original version of Figure 6a is:and should be replaced with the following Figure 6a:We stress that this correction does not change the written portion of the figure legend, interpretation of results, or final conclusion of this manuscript. The manuscript will be updated and the original will remain available on the article webpage. The authors would like to apologize for any inconvenience caused."} +{"text": "BioMed Research International has retracted the article titled \u201cCorrelation of CCNA1 Promoter Methylation with Malignant Tumors: A Meta-Analysis Introduction\u201d [duction\u201d . The artThe article is being retracted with the agreement of the journal and the editorial board due to concerns regarding the reliability of the data. Despite numerous attempts, the authors could not be contacted to provide a response to these concerns."} +{"text": "The gender of S7 is wrongly listed as \u201cM,\u201d where it should be \u201cF.\u201d The corrected In the original article, there was a mistake in The FMA-LE (Pre) of S6 is wrongly listed as \u201c23,\u201d where it should be \u201c21.\u201d The corrected Additionally, there was a mistake in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Acknowledgments statement. The Acknowledgments statement should have been a Funding statement and the grant number \u201c(22SYSX0138)\u201d has further been corrected to \u201c(2022YFSY0034).\u201d The correct Funding statement appears below.In the published article, there was an error in the \u201cThe authors gratefully acknowledge the financial support of the Science and Technology Program of Sichuan, China (2022YFSY0034).\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This article has been corrected to include information on the grant that funded the study and the role of the funder in the Article Information.1In the Original Investigation titled \u201cSkilled Nursing Facility Changes in Ownership and Short-Stay Medicare Patient Outcomes,\u201d"} +{"text": "Instead of \u201cSystematic Review,\u201d it should be \u201cOriginal Research.\u201dIn the published article, there was an error in the The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Results of a randomized controlled trial supported the efficacy of a manualized, Intensive and Brief Psychodynamic Psychotherapy (IBPP) for inpatients with severe depression, but the mechanisms by which the interaction between a psychotherapist and a patient can be involved in a process of change require more direct study.The study aimed to explore how the psychotherapist and the patient interacted to work through the themes of focalization of their therapeutic work and how their work was part of a potential process of change.A pragmatic case study was conducted on two cases selected from the umbrella study with one responder and one nonresponder to treatment (response defined as > 46% decrease in depressive symptoms on the MADRS). For each case, the verbatims of 6 sessions were analyzed, focusing on the themes of the IBPP manual.Becoming the subject of one\u2019s depression\u201d, which includes the following themes: i) \u201cFollowing the Tracks of Pain and Loss\u201d; ii) \u201cNegotiating the Distance to the Cemetery\u201d; iii) \u201cBeginning to Accept\u201d; iv) \u201cInvesting in New Projects \u201c; and 2) \u201cRegaining a sense of support\u201d which includes the following themes: i) \u201cNot Being Beaten Down\u201d; ii) \u201cEmptying a Full Closet\u201d; iii) \u201cFear of Ending Up Alone\u201d. The supportive interactions (regaining a sense of support) were present in a similar way in both cases, whereas the specific interactions (becoming the subject of one\u2019s depression) were more present in the responder case.Two main functions were revealed: 1) \u201cIn the psychotherapy of inpatients with severe depression, specific therapeutic interventions aiming to mobilize internal processes of symbolization, comprehension, and appropriation are necessary to reactivate a previously frozen mourning process. However, such interventions should be carried out in conjunction with interactions aiming to help the patient regain a sense of support. The central role of interactions that serve to build a therapeutic space and to restore epistemic trust was an unexpected result. It invites psychotherapists to pay particular attention to acknowledging a patient\u2019s melancholic suffering, and to continuously seek to adjust their interventions to foster the continuity of emotional contact and the emergence of a sense of support. Theoretical and clinical implications of these findings will be discussed.None Declared"} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Geneva\u201d.The original version of this article has been updated."} +{"text": "The authors regret that in the originally published article, the patient with ovarian cancer was incorrectly identified as \u201cP3\u201d due to an error while renumbering the internal patient identifiers. The patient with ovarian cancer is patient P4. This has been corrected in"} +{"text": "In the published article, there was an error in affiliation [5]. Instead of \u201c\u201d, it should be \u201c.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Geneva\u201d.The original version of this article has been updated."} +{"text": "Funding statement. The grant number for the National Research Foundation of Korea was displayed as \u201c2021M3A9H5020761.\u201d The correct statement is below:In the published article, there was a mistake in the"} +{"text": "In the article by Kwiatkowska et\u00a0al.The first sentence of the 9th paragraph of the Discussion section should read \u2018The figures indicate a current lifetime risk of approximately one in six for NMSC in females and one in four for males.\u2019The authors apologize for this error."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Geneva\u201d.The original version of this article has been updated."} +{"text": "Lid\u00f3n Pru\u00f1onosa Lara, who contributed significantly to the crystallography and should have been included as a co-author.The authors regret the omission of The corrected list of authors and affiliations for this paper is as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Geneva\u201d.The original version of this article has been updated."} +{"text": "In the published article, there was an error in affiliation \u201c1\u201d. Instead of \u201cTianjin People's Hospital\u201d, it should be \u201cTianjin Union Medical Center\u201d.Due to the change of the name of our institution from \u201cTianjin People's Hospital\u201d to \u201cTianjin Union Medical Center\u201d, we propose to correct the original institution name.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, there was an error in the affiliation section .Instead of \u201c\u201d.The affiliations should be corrected as follows:\u201c\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Geneva\u201d.The original version of this article has been updated."} +{"text": "In the published article, an author name was incorrectly written as \u201cNega Brhanie.\u201d The correct spelling is \u201cNega Berhane.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, an author name was incorrectly written as \u201cYanyun Wei.\u201d The correct spelling is \u201cYanyu Wei.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The original version of this article has been updated."} +{"text": "As well as having affiliation 2, they should also have affiliation \u201cThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Materials and methods section at the Paragraph 2.2. Plasmid name was displayed as \u201cA commercially available plasmid pRK793 was used for TEV protease production\u201d.In the published article, there was an error in the The correct statement is \u201cA self-made plasmid pET-TEV was used for TEV protease production\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Geneva\u201d.The original version of this article has been updated."} +{"text": "The authors wish to make the following correction to this paper \u201cDental The study was rightly approved by the DEPARTMENT/ISTITUTIONAL REVIEW BOARD APPROVAL n. 111/2022 Prot. N. 0000867, on 18 May 2022 of Sapienza University of Rome, but in the section Material and Methods of the article and in institutional review board statement section we wrongly wrote that the article was approved by the Ethics Committee.Sentence: \u201capproved by the Ethics Committee of \u201cSapienza\u201d University of Rome\u201d should be replaced with \u201capproved by the Department Review Board Approval of Sapienza University of Rome \u201d. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original publication has also been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The original version of this article has been updated."} +{"text": "Many stereotypes afflict our much-maligned region, and the Jonesborough\u2013Washington County History Museum displays eight of these \u201cmyths of Appalachia.\u201d Here, our Editor-in-Chief suggests a ninth\u2014that the people of Appalachia \u201cdo not care\u201d about their health\u2014and argues that regional health disparities result not from apathy but from a confluence of socioeconomic factors. There are many unique attributes of the small town of Jonesborough, Tennessee. It is the oldest town in Tennessee and was, for a while, the capital of the short-lived State of Franklin.Of relevance to the Journal, however, is the Jonesborough\u2013Washington County History Museum, where there is a display created by the Heritage Alliance, titled \u201cEight Myths About Appalachia.\u201dThe eight myths that they highlight are:The residents of the region are \u201cviolent\u201d;The families of the region are \u201cisolated;\u201dThe culture of Appalachia is \u201cnot innovative;\u201dThe demographics of the region are \u201cnot diverse;\u201dMountain families are \u201cimpoverished;\u201dThe people of the region are \u201cilliterate;\u201dThe culture of the residents is \u201cdefiant;\u201dThe Appalachian region is \u201cbackwards.\u201dstereotypes) started and why they are not necessarily any truer of the people of Appalachia than of those in other parts of the country.The display does a good job of both explaining how these myths will be placed on the slagheap of history."} +{"text": "The order of the last author\u2019s first and last names is switched. It should be written as: Sen Hou."} +{"text": "There was an error in the original publication . In the In Table 1, a correction is needed for the tetracycline resistance breakpoints: \u201c6\u201d should be replaced with \u201c16\u201d.The authors apologize for any inconvenience this change may cause. The authors state that the scientific conclusions are unaffected because the correction involves a typing error that was not caught during proofreading.This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "In the published article, there was an error in affiliation(s) [1]. Instead of \u201cInstitute for Human-Animal Interaction\u201d, it should be \u201cInstitute for Human-Animal Connection.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This article has been corrected at the request of the submitting author to change a minor typo.The last sentence of the introduction has been changed from \u201cOne severe complication of EMH is cord compression, which could result in including motor and sensory impairment\u201d to \u201cOne severe complication of EMH is cord compression, which could result in motor and sensory impairment\u201d.The authors deeply regret that this error was not identified and addressed prior to publication."} +{"text": "In the published article, there was an error in the author list. Author \u201cQun Zhang\u201d was erroneously listed as the second author instead of as the first author. The corrected author list appears below.\u201cQun Zhang, Xianyin Li and Jeffrey Hugh Gamble\u201dAuthor \u201cQun Zhang\u201d was also erroneously listed as the corresponding author. Instead, author \u201cJeffrey Hugh Gamble\u201d should be the only corresponding author.The authors apologize for these errors and state that they do not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, the citation of Author Jaskanwal Deep Singh Sara was incorrectly written as \u201cSingh Sara JD\u201d instead of \u201cSara JDS.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, there was an error in In the published article, there was an error in the Funding statement. The names of the first two funding bodies were incorrectly presented as \u201cFundamental Research Funds for China Agriculture Research System\u201d and \u201cCentral Nonprofit Scientific Institution\u201d. The correct Funding statement appears below."} +{"text": "This is a peer veview of \u201cInformation Technology Ambidexterity, Digital Dynamic Capability, and Knowledge Processes as Enablers of Patient Agility: Empirical Study\u201dThank you for the opportunity to review this paper on the l"} +{"text": "In the published article, there was an error in Also, there is no data regarding clinical studies using tildrakizumab for IBD, so the color has been changed to yellow.The legend has been modified for clarification. The changes include the modification from \u201cGreen: Shown efficacy\u201d to \u201cGreen: approved or shown efficacy in phase 3 clinical trials\u201d.The corrected The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Instead of \u201c[The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "There was a duplication in the case numbers and person-years for the broad definition of depression. This article has been corrected.1In the Research Letter titled \u201cConsumption of Ultraprocessed Food and Depression,\u201d"} +{"text": "In the published article, an author name was incorrectly written as \u201cKatia Capelli\u201d. The correct spelling is \u201cKatia Cappelli\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University Of Geneva\u201d.The original version of this article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding provided by University of Lausanne\u201d.The original version of this article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Geneva\u201d.The original version of this article has been updated."} +{"text": "Applied Bionics and Biomechanics has retracted the article titled \u201cTo Explore the Effects of Acupuncture and Medical Treatment at Different Times on the Gastrointestinal Reaction and White Blood Cell Count of Patients with Lung Cancer Chemotherapy\u201d [therapy\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiThe authors do not agree to the retraction."} +{"text": "In the published article, there was an error in affiliation [1]. Instead of \u201c\u201d, it should be \u201c\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The publisher would like to draw the reader's attention to an error in the article.Table\u00a0The correct Table\u00a0The publisher apologizes for this error and any confusion it may have caused."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Geneva\u201d.The original version of this article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by ETH Zurich\u201d.The original article has been updated."} +{"text": "In the published article, there was an error in the Funding statement. There were two funds not included. They are the \u201cYouth Research Fund of the Beijing Academy of Forestry and Fruit Sciences \u201d. The correct Funding statement appears below."} +{"text": "In the published article, an author name was incorrectly written as \u201cCheeho Kim\u201d. The correct spelling is \u201cC. James Kim\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The original version of this article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding provided by University of Lausanne\u201d.The original version of this article has been updated."} +{"text": "Alveolar Macrophages in Lung Cancer: Opportunities Challenges\u201d, it should be \u201cAlveolar Macrophages in Lung Cancer: Opportunities and Challenges\u201d.In the published article, there was an error in the article title. Instead of \u201cThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Corresponding Author annotation. The corresponding author annotation displayed both \u201cJian Li and Kai Zhou\u201d as corresponding authors. However, \u201cKai Zhou\u201d should be the only corresponding author for the article.In the published article, there was a mistake in the The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original publication of the article, the first and last name of the fourth author was incorrectly published as \u201cLoppi Stefano\u201d. The correct name is \u201cStefano Loppi\u201d.The original article has been corrected."} +{"text": "There is also a provisional version of the BIS\u201311\u2014the BIS\u201311A\u2014that was distributed during development of the BIS\u201311 and that has been more widely disseminated and used than was intended. As the BIS\u201311 and BIS\u201311A only share 24 items in common, it has been recommended that the BIS\u201311A should not be used [The Barratt Impulsiveness Scale (BIS) is one of the most widely used self-report questionnaires for the assessment of impulsivity as a trait. The original BIS was developed by Ernest S. Barratt in 1959 [Complicating matters, abbreviated versions of the BIS\u201311 have been developed in the past decades. These include, for example, the BIS\u2013Brief, which includes 8 of the BIS\u201311\u2019s 30 items . AnotherRecently, Maggi and colleagues reportedWhile I appreciate the effort of Maggi and colleagues to devel"} +{"text": "Materials and methods subsection \u201cGenome assembly and annotation\u201d. The accession number for the complete genome sequence of L. pentosus CF2-10N has been corrected from \u201cERR10150811\u201d to \u201cERR11550479\u201d.In the published article, there was an error in the final paragraph of the The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by ETH Zurich\u201d.The original version of this article has been updated."} +{"text": "In the published article, an author name was incorrectly written as \u201cArash Akbazadeh.\u201dThe correct spelling is \u201cArash Akbarzadeh.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "We also prefer to use \u201ccrowdsourcing\u201d over AI to investigate the type of questions asked in this paper because it can give the researcher the opinion of a very large number of evaluators, like AI, but with the benefit of allowing the gathering of information on the demographics of the evaluators, leading to a much clearer picture of how different groups judge the level of attractiveness.In this Video Commentary, we agree with the authors\u2019 desire to quantify the improvement in \u201cemotion\u201d of varying facelift techniques through artificial intelligence (AI), as a \u201cproof of concept\u201d approach to objectively judging surgical results (Video).ojad049_Supplementary_DataClick here for additional data file."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The original version of this article has been updated."} +{"text": "In the published article, an author name was incorrectly written as Zhou Xu. The correct spelling is \u201cXu Zhou\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Bern\u201d.The original version of this article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Bern\u201d.The original version of this article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The original version of this article has been updated."} +{"text": "In the publishedpaper, thereis a mistake in the structure of the final GO\u2013NPY conjugateboth in"} +{"text": "The term \u201cprognosis\u201d is used inaccurately throughout the article . The corIn the Introduction, a reference has beenPLOS ONE Editors and the authors regret that these errors were not identified prior to publication.The"} +{"text": "A\u201d in \u201cGABAAR\u201d should have been \u201cB\u201d. The corrected caption appears below, along with Due to a production error, there was a mistake in the penultimate sentence of the caption of The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Daniel E. Ford\u2019s middle initial was corrected. This article was corrected.1In the Special Communication titled \u201cLeveraging the Expertise of the CTSA Program to Increase the Impact and Efficiency of Clinical Trials,\u201d"} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The original version of this article has been updated."} +{"text": "In the published article, there was an error in The correct labels for these panels should be \u201cHLA-DR\u201d and \u201cCD38\u201d, respectively. The corrected The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Geneva\u201d.The original version of this article has been updated."} +{"text": "The figure should have shown the mean number of beds adjusted per 10\u2009000 per county by year instead of the sum of all the number of beds adjusted per 10\u2009000 in each county by year. This article has been corrected.1In the Original Investigation titled \u201cTrends in Supply of Nursing Home Beds, 2011-2019,\u201d"} +{"text": "In the published article, there was an error in The correct fetal sex for patient number 1049 is \u201cFemale\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the recent article by Kunde et al.\u00a0, the autOpen Access funding enabled and organized by Projekt DEAL. The publication of this article was funded by the Deutsche Forschungsgemeinschaft \u2013 project number 491292795.The article has been corrected online."} +{"text": "In the published article, there was an error in the article title. Instead of \u201cStudying brains what could neurometaphysics be to NeurotechEU?\u201d it should be \u201cStudying Brains. What could neurometaphysics be to NeurotechEU?\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Affiliations for Yong Li . Instead of \u201c,\u201d it should be \u201c[1]\u201d .In the published article, there was an error in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, there was an error in affiliation [3]. Instead of \u201cKing Saudi University\u201d, it should be \u201cKing Saud University\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University Of Bern\u201d.The original article has been updated."} +{"text": "The authors would like to apologise for an error in the above article. During submission Samantha L Hahn\u2019s name was given as Samantha A Hahn.This has been updated in the original article."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The original version of this article has been updated."} +{"text": "Author name was incorrectly written as \u201cYanqing Zhang.\u201d The correct spelling is \u201cYanqin Zhang.\u201dIn the published article, an The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Due to a production error, there was a mistake in The original version of this article has been updated."} +{"text": "In the original publication, there was a mistake in Figure 1 as published ["} +{"text": "In the published article, an author name was incorrectly written as \u201cLinping Zhou\u201d. The correct spelling is \u201cLiping Zhou.\u201dWe have also checked and ensure that the initials used in the Author contributions section or elsewhere in the article are correct.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Funding statement. The statement was incorrectly written as, \u201cThis work was funded by the Portuguese Foundation for Science and Technology .\u201d The correct Funding statement appears below.In the published article, there was an error in the"} +{"text": "This article has been corrected.In the Original Investigation titled \u201cAssessment of Commercial and Mandatory Discounts in the Gross-to-Net Bubble for the Top Insulin Products From 2012 to 2019\u201d"} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The original version of this article has been updated."} +{"text": "In the published article, an author name was incorrectly written as \u201cChen Xiao\u201d. The correct spelling is \u201cCheng Xiao\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The original version of this article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The original version of this article has been updated."} +{"text": "Funding statement. The grant number for the Sichuan Science and Technology Department Programs was displayed as \u201c2021YFN0021\u201d. The correct Funding statement appears below.In the published article, there was an error in the"} +{"text": "In the original article, there was a typo error in the Author's List section.The author's name was incorrectly written as \u201cWehsin Ko.\u201dThe correct spelling is \u201cWeihsin Ko.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Geneva\u201d.The original version of this article has been updated."} +{"text": "Affiliation 1. Instead of \u201cKey Laboratory of Southwestern Chinese Medicine Resources,\u201d it should be \u201cState Key Laboratory of Southwestern Chinese Medicine Resource.\u201dIn the published article, there was an error in Affiliation 2. Instead of \u201cDepartment of Pharmacy, Affiliated Hospital of Southwest Medical University,\u201d it should be \u201cDepartment of Pharmacy, The Affiliated Hospital of Southwest Medical University.\u201dIn the published article, there was an error in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The original version of this article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University Of Bern\u201d.The original version of this article has been updated."} +{"text": "Funding statement. The grant number \u201c2019XKQYMS57\u201d for Fundamental Research Funds for the Central Universities of China was incorrect. The correct Funding statement appears below.In the published article, there was an error in the"} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201d.The original version of this article has been updated."} +{"text": "Instead of \u201cGI = 100 The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Funding section of the original article was made in error. The following sentence has been added:An omission to the \u201cOpen access funding provided by University Of Bern\u201d.The original version of this article has been updated."} +{"text": "The correct spelling is \u201cHuai-Kang Li\u201d.In the published article, an The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University Of Bern\u201d.The original version of this article has been updated."} +{"text": "A previous version of this article had Diana Barbosa Cunha\u2019s name in the wrong order. The article has since been updated to display the author\u2019s correct name."} +{"text": "Due to a production error, there was an error in the figures as published. The correct \u201cFlexible sensor concept and an integrated collision sensing for efficient human-robot collaboration using 3D local global sensors\u201d.The article title was revised to read The publisher apologizes for these mistakes. The original version of this article has been updated."} +{"text": "Due to a production error, there was a mistake in The original version of this article has been updated."} +{"text": "After this article was publDuring editorial follow up on this issue, the corresponding author stated that the data were correctly reported in Fig 4D, and the Fig 4D SIV panel was erroneously used to represent the Fig 5A SIV+ART panel. The corresponding author also stated that an updated panel cannot be provided and that none of the raw data underlying the article\u2019s results are currently available.An Academic Editor reviewed the concerns and stated that the article\u2019s overall results and conclusions remain s"} +{"text": "This article was incorrectly published as a 'Research Article', it is in fact, a 'Collection Review'. Apologies for any inconvenience caused."} +{"text": "The English term \u201cearly psychosis\u201d was coined in the 1930s to refer to feelings of irritability, loss of concentration, hypochondriac ideas, moodiness, and lassitude that were seen to precede the onset of clear-cut hallucinations and delusions. The history of thinking about \u201cearly psychosis\u201d under names such as \u201clatent,\u201d \u201cmasked,\u201d \u201cmild,\u201d \u201csimple\u201d or \u201csluggish\u201d schizophrenia before World War II and afterwards on the different sides of the Wall and the Iron Curtain reveals \u201cearly psychosis\u201d as a mirror of quite aged international biologist controversies that are still alive today and to the same extent as they are misunderstood, are influential in their implications in today's psychiatry. Bleuler's schizophrenia concept was simply but silently put aside.With the retirement of Schneider from the chief position of the psychiatric university clinic in Heidelberg in 1955, \u201cclassical psychiatry\u201d was said by Walter von Baeyer, his successor, \u201cto have come to its end; the future was for existential analysis in the sense of Heidegger, Husserl and Binswanger\u201d Huber, , 70. In \u201cfailure on the road of life\u201d and the American Psychopathological Association in 1926 in 1922. The most recent form of psychiatric practice, \u201cnamely the set-up of psychiatric welfare units called \u2018dispensaries\u2019 \u201d where \u201cpsychiatrists are facing a material, that usually counts as \u2018healthy\u2019 or \u2018nervous\u2019 and will have to do prophylactic work on it,\u201d is feeding back on the theoretical concepts . Thanks to an invitation of the (East-)Berlin Society for Psychiatry and Neurology at the Humboldt-University, Gerd Huber was among them to present his pneumencephalographic studies in schizophrenia in the year 1958 and is used as \u201can instrument for the assessment of schizophrenia proneness\u201d , was not accidentally dedicated to the etiology of schizophrenia, and defined a clear biologic direction of future research was couched in the clearest possible terms by the American psychologist Paul Meehl in his lecture addressed to the American Psychological Association in 1962: \u201cin the near future\u201d psychology with its new experimental techniques will help \u201cto establish that schizophrenia, while its content is learned, is fundamentally a neurological disease of genetic origin\u201d (Gross et al., \u201cBasic-symptom oriented diagnostic of schizophrenic vulnerability\u201d (Gross et al., compensated\u201d or \u201clatent schizophrenia\u201d? Would \u201cvulnerability for schizophrenia\u201d already be schizophrenia? The oscillation of the conceptualization of the basic symptoms between state or trait markers was of course not entirely innocent for this ambiguity. Moreover, anticipating the objection that the basic symptoms that were used for the diagnosis of schizophrenic vulnerability had not proved to be specific for schizophrenia, Gisela Gross frankly declared that there would not exist any specific psychopathological phenomena at all in psychiatry\u2014and thus made a comment in the direction of an unspecific vulnerability in the sense of a strong \u201cunitary psychosis\u201d model of mental disorder comparable to the Russian \u201clayer-model,\u201d yet continued by arguing that the basic symptoms would not exist in personality or neurotic disorders. Thus she corrected herself to a sort of weak \u201cunitary psychosis\u201d model of affective and schizophrenia disorders. However, as a matter of fact, the work of the Bonn School on early diagnosis has been understood as if there would be a schizophrenia specific cognitive vulnerability that could be identified by the subtle psychopathological examination via the \u201cBonn Scale\u201d and would enable early detection and early treatment (Klosterk\u00f6tter et al., The first prospective study on early diagnosis of schizophrenia has been initiated by Huber and Gross in 1970, was founded by the West-German Ministry for Research and Technology and was later on continued by Joachim Klosterk\u00f6tter under the name of \u201cAt the APA symposium in 1990, Huber and Gross argued for their classic view on early psychosis, basic symptoms and prodromes. Nevertheless, the list of prodromal symptoms was dropped for the DSM-IV in 1994: without any alternative.schizophrenia simplex (World Health Organisation, attenuated psychotic syndrome\u201d as a research category, which may well be seen\u2014just as the originally proposed \u201cpsychosis risk syndrome\u201d\u2014as standing in the tradition of \u201cearly psychosis\u201d or \u201clatent schizophrenia\u201d that the article has recalled.Even if the ICD-10 still knows of The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Dear Editor,Concerning the article \u201cEpidemiology of Pediatric Head Trauma in Guilan\u201d published in one of the previous issues of Archives of Trauma Research , I would"} +{"text": "Alitta virens \u201d and the sentence \u201cWe have recently described the expression of 10 out of 11 Hox genes during postlarval growth of Alitta (Nereis) virens\u201d in the abstract should read as \u201cWe have recently described the expression of 10 out of 11 Hox genes during postlarval growth of Alitta virens (formerly Nereis virens).\u201dAfter publication it was brought to our attention that there is an ambiguity in the title and in the abstract of our paper that cou"} +{"text": "During a general assembly session in a prestigious private hospital, I watched with fascination as all the nominees for the board of directors were above 65 years of age; some were even in their eighties. The homage and tribute to the seniors was so great that the younger doctors were too embarrassed to nominate themselves while the \u201cseniors\u201d competed most fervently for candidacy . Statist"} +{"text": "Optogenetics may be the answer to a search for temporal and spatial specificity in neuroscience. The well-known trade-off between temporal and spatial specificity might be resolved with this \u201ccombination of genetic and optical methods to achieve gain or loss of function of well-defined events in specific cells of living tissue\u201d to which an optical fiber can be attached Figure . Laser lBiological Psychiatry on this topic . This combination has been termed \u201copto-fMRI\u201d or \u201cofMRI\u201d (Desai et al., In sum, optogenetics is a promising tool for cognitive neuroscience and we believe that it might be applied to human subjects in the long run. Although the area still faces many obstacles, the field of optogenetics is growing rapidly and new advances are continuously being made to improve the technique (for a review see Dugue et al.,"} +{"text": "An error was introduced in the preparation of this article for publication. The standalone equation in the Methods section under the subheading \u201cMeasurement of metabolic network modularity\u201d is incorrect. The correct equation is:"} +{"text": "An error led to part of Figure 2 being removed, breaking the red line that should have linked the grey circles \u201cPKC\u201d and \u201cEGFR\u201d. The correct version of Figure 2 is now displayed on both the PDF and HTML versions of the article."} +{"text": "In the paper titled \u201cThe Role of KRAS Mutational Analysis to Determine the Site of Origin of Metastatic Carcinoma to the Lung: A Case Report,\u201d the author's name Ahmad Alkhasawneh was incorrectly listed as Ahmed N. Alkhasawneh; here it is corrected."} +{"text": "There is an error in the Supporting Information file (Text S1) in the first paragraph. The correct sentence is \u201cAn example of pi is demonstrated in Figure S1 for England and Wales and Northern Ireland, for deaths in children aged 15 to 18 years where the death was due to an injury.\u201dThere was a formatting issue in Table 2 the PDF version of this article. The table continues on page 6 and should read \u201cIntentional Injuries\u201d not \u201cTransport accidents.\u201d Please view the correct Table 2 on the PLOS ONE website."} +{"text": "This workshop examines the rise of integrated care as a central component of the UK Government\u2019s current reforms to its health and social care system. In particular, the workshop presents the key debates and conclusions from work undertaken by The King\u2019s Fund and the Nuffield Trust \u2014two key"} +{"text": "The authors wish to make the following correction:In our article, we declared that the study was partly funded by the Swedish Council for Tobacco Research (R\u00e5det f\u00f6r Medicinsk Tobaksforskning). While the authors have received a grant from the Swedish Council for Tobacco Research, this was for a different project. The current study was therefore not funded by the Swedish Council for Tobacco Research and the declaration of funding should not have included a reference to this body."} +{"text": "To the Editor,The study by E\u011fin and Akar entitled"} +{"text": "We believe that we appropriately distinguished the difference between the ortho-phthalates and the polymers, specifically noting that the polymers have \u201cno known toxicity.\u201dWe appreciate Carter\u2019s review of our article and his"} +{"text": "We describe a simple and quick suturing technique that can be used to close arthroscopy portal wounds, resulting in excellent cosmetic appearance. A single suture is seamlessly run in the shape of a \u2018figure of eight\u2019 to give"} +{"text": "Dear Editor,To the Editor \u2013 Rimaz and Colleagues should be congratulated on their report of the effect of Gabapentin on postoperative burn patients . There a"} +{"text": "Sir,This is to request you to kindly make the following addendum to the previous article \u2013 \u201cA position statement by Indian Association of Palliative Care\u201d and to p"} +{"text": "It is well known that the magnitude and dynamics of a neuron\u2019s membrane conductances influence the nature of its response to synaptic input . However"} +{"text": "Sir,I read the recent publication on \u201cnotes to file\u201d with great interest. Hazra noted that \u201cIt is important that all of us stop and think before generating the next NTF, whether it is necessary to do so or can the documentation of this issue be done more appropriate elsewhere.\u201d I would"} +{"text": "In the originally published version of this manuscript, 'tea1\u2206' was sometimes erroneously changed to 'tea1;\u2206\u2019. In the PDF, this resulted in deletion of a small portion of the adjacent text. This issue has now been fixed and the corrected HTML and PDF versions of the manuscript are now shown."} +{"text": "Pneumococcal Conjugate Vaccines and Otitis Media: An Appraisal of the Clinical Trials,\u201d scientific errors were discovered in Table 4. Therefore, an erratum was submitted with corrections to the table.Subsequent to the publication of the previous paper entitled \u201c"} +{"text": "After publication of the original article it was bIt was also noticed by the authors that the image they provided for Figure four panel C Figure\u00a0 here was"} +{"text": "Active Ageing: A Policy Framework that according to the call for papers, has brought active ageing to the forefront of international public health awareness. The 2010 Toronto Charter for Physical Activity: A Global Call for Action was singled out in the call for papers as a key document promoting physical activity one goal of the 2002 WHO active aging policy framework. Media are to report to the public topics of importance to them. We investigated the newspaper coverage of aging well and synonymous terms such as active aging through the lens of the 2002 WHO active aging policy framework and the 2010 Toronto Charter for Physical Activity. As sources we used the following newspapers: China Daily, The Star , two UK newspapers , a database of 300 Canadian newspapers (Canadian Newsstand) and a US newspaper (The New York Times). The study generated data answering the following four research questions: (1) how often are the 2002 WHO active aging policy framework and the 2010 Toronto Charter for Physical Activity mentioned; (2) how often is the topic of active aging and terms conveying similar content discussed; (3) which of the issues flagged as important in the 2002 WHO active aging policy framework and the 2010 Toronto Charter for Physical Activity are covered in the newspaper coverage of active aging and synonymous terms; (4) which social groups were mentioned in the newspapers covered. The study found a total absence of mentioning of the two key documents and a low level of coverage of \u201cactive aging\u201d and terms conveying similar content. It found further a lack of engagement with the issues raised in the two key documents and a low level of mentioning of socially disadvantages groups. We posit that reading the newspapers we covered will not expose the reader to the two key documents and the issues linked to aging well including the need to increase physical activity.As populations continue to grow older, efforts to support the process of aging well are important goals. Various synonyms are used to cover aging well, such as active aging. The World Health Organization published in 2002 the report World Population Ageing 1950\u20132050, the number of older persons in the World will exceed the number of young persons in 2050 for the first time in history and that the reversal in relative proportions of young and old is already a reality since 1998 in the more developed regions [World Population Ageing 1950\u20132050 argues that population aging impacts \u201cintergenerational and intragenerational equity and solidarity that are the foundations of society\u201d, \u201ceconomic growth, savings, investment and consumption, labour markets, pensions, taxation and intergenerational transfers\u201d, \u201chealth and health care, family composition and living arrangements, housing and migration\u201d and \u201dvoting patterns and representation\u201d [According to the 2001 United Nations Report ntation\u201d .Aging well is increasingly discussed as a dynamic process involving use of resources, engagement within contexts and definitions of self . Ageism Active Ageing: A Policy Framework [The World Health Organization published in 2002 the report ramework describiramework . The repTo just give one example, the 2012 Eurobarometer (report of a survey of European citizens) on active aging, active ageing has many facets such as ability of older people to be employed, to contribution actively to society as volunteers and family carers and the ability to live independently made possible through suitable housing and infrastructure [Active Ageing: A Policy Framework [Toronto Charter for Physical Activity: A Global Call for Action as a key document. The Toronto Charter outlines the utility of physical activity to improve the wellbeing, physical and mental health of people, to increase their social connectedness and quality of life [Physical activity is one issue raised in need of improvement in the World Health Organization 2002 ramework . The cal of life , to gene of life . However of life . Many neVarious studies looked at portrayal of aging and the elderly in the media including in newspapers ,16,17,18Toronto Charter for Physical Activity [Both the 2002 WHO Policy framework for active ageing and the Activity mention \u201cOlder people themselves and the media must take the lead in forging a new, more positive image of ageing\u201d ; \u201cWork wThe Toronto Charter in more general terms asks for action to engage the media and to use mass communication and social marketing strategies to promote increased political, community and stakeholder support for physical activity actions .Canadian Newsstand, a database of n = 300 Canadian newspapers from 1980-today has for example n = 20,307 articles that contain the words \u201caging\u201d and \u201celderly\u201d and n = 34,032 articles that contain the terms \u201caging\u201d and \u201cseniors\u201d indicating an interest in the topic of aging. Diffusion of knowledge through printed media is seen for a long time as an essential part of the fabric of society to enable social participation [Wanting to involve media seems to be reasonable. cipation ,28,29 ancipation . Media \u201cChina Daily, The Star , two UK newspapers , a database of 300 Canadian newspapers (Canadian Newsstand) and a US newspaper (The New York Times). Our study answers the following research questions: (1) how often are the 2002 WHO active aging policy framework and the 2010 Toronto Charter for Physical Activity mentioned; (2) how often is the topic of active aging and terms conveying similar content discussed; (3) which of the issues flagged as important in the 2002 WHO active aging policy framework and the 2010 Toronto Charter for Physical Activity are covered in the newspaper coverage of active aging and synonymous terms; (4) which social groups are mentioned in the newspapers covered. Our study adds quantitative and qualitative data to the discourse analysing the Active Ageing: A Policy Framework [Toronto Charter for Physical Activity: A Global Call for Action [The call for papers posits that the 2002 World Health Organization report ramework and the r Action are impoActive Ageing: A Policy Framework [Toronto Charter for Physical Activity: A Global Call for Action [Canadian Newsstand, a database that covers 300 Canadian newspapers from 1980-today as one focus of our study was the Toronto charter. Within this database both Canadian newspapers with national scope and reach are covered . As the WHO report and the Toronto Charter are envisioned to have a global impact we also investigated newspapers outside Canada. We used The New York Times (USA) to add one respected newspaper with national scope and reach from the USA. We also searched two UK newspapers with different political leaning . We also searched two newspapers from Asia as Asia is culturally different from North America and Europe. The two Asian newspapers we chose are published in Asian countries that are different in their political system and the religious background of the country. Both are the leading English language newspapers in their respective country. This selection is not meant to be exhaustive but to give some indication as to global visibility of the documents and the visibility of aging well and the synonyms we covered.To obtain quantitative data on the research question of how often the 2002 World Health Organization report ramework and the r Action are mentThe New York Times, Calgary Herald and The Globe and Mail (1980\u20131 May 2013) for the presence of the phrases \u201cactive aging\u201d, \u201caging well\u201d, \u201csuccessful aging\u201d, \u201cnatural aging\u201d, \u201chealthy aging\u201d and \u201caging well\u201d. The phrases \u201cactive aging\u201d, \u201caging well\u201d, \u201csuccessful aging\u201d, \u201cnatural aging\u201d and \u201chealthy aging\u201d were found in articles of a previous literature reviews on aging well and are often seen as synonyms of aging well. One word on the spelling of the search terms; alternative spellings exist namely aging and ageing. We chose not to use the search term ageing as it gave us less hits in the newspapers then the search term aging. If we use ageing instead of aging our hits for example in the Canadian newsstand go down from 4,569 to 83 hits. Relevant articles were downloaded as PDF and imported into Atlas-Ti for content analysis. To generate data on which social groups are present in the newspaper coverage we used The New York Times, Calgary Herald and The Globe and Mail and the Canadian newsstand as sources.To answer the research question of whether issues raised in the WHO report and the Toronto charter were picked up in the newspapers we first identify newspaper articles from Canadian Newsstand database, Calgary Herald, The Globe and Mail, The New York Times, The Guardian (UK), The Times (UK), China Daily and The Star .To answer the research question of how often aging is used together with elderly or seniors and how often \u201caging well\u201d and its synonyms are mentioned in newspapers we searched the \u00a9, a qualitative data analysis software (CAQDAS) [The Globe and Mail, Calgary Herald and The New York Times covering research question two and three.We used ATLAS.ti(CAQDAS) ,34, for Globe and Mail, Calgary Herald and New York Times articles into ATLAS.ti\u00a9 we performed a content analysis between 1 May 2013 and 27 August 2013 of the imported documents to identify whether any of the issues raised as important in the WHO report and the Toronto charter were dealt with in The Globe and Mail, Calgary Herald and The New York Times through their webpages. The search was performed on 20 October 2013) (result To obtain quantitative data on how often (a) aging was covered linked to elderly or seniors and (b) \u201caging well\u201d and synonyms terms were mentioned we searched ) result .Canadian Newsstand and The New York Times, through the databases accessed through The University of Calgary. The search was performed on 20 October 2013 . As such our findings related to the question of whether newspapers engaged with issues raised in the WHO report or the Toronto Charter do only apply to the two Canadian and the one US newspaper and the findings cannot be generalized beyond the newspapers covered. Another limitation is that our newspapers are English language based and as such we cannot account for coverage in other languages such as French coverage in the Canadian province of Quebec or any non-English language coverage in other countries. Our data can also not be used to judge other media type as we focused on newspapers. However a picture of neglect is evident in the sources we covered which we submit can be used to guide future research in investigating other media sources.We did perform an in-depth content analysis of only three North American newspapers (Canadian Newsstand (n = 300 Canadian newspapers), the China Daily , The Star , The Guardian and The Times for the names of the two key documents. We did not limit this search to articles related to aging or any other prerequisite. We obtained n = 0 hits for the Toronto Charter for Physical Activity in all newspapers. If we looked for variation of the document title no hits were obtained either. As to the WHO Policy framework for active ageing, the exact title also had n = 0 hits in all newspapers covered. Variations of the name generated n = 3 hits in the Canadian Newsstand database . No hits were obtained in the other newspapers even with modifications to the name. The WHO document was mentioned in the three hits as follows.In order to evaluate how often the WHO Policy framework for active ageing and the Toronto Charter for Physical Activity were mentioned in newspapers we searched the full text of all articles of A Policy Framework on Active Aging\u2014and if you can get past the bureaucratese, it was an intriguing undertaking. The UN body solicited participation from 33 cities around the world to provide input into what they could do for their aging populations, and in 2006, Saanich was selected to participate\u201d [\u201cThe trend got a boost more than a decade ago when the World Health Organization launched an initiative \u201cto support communities in developing and strengthening health and social policies in an aging world\u201d. WHO devised what it called icipate\u201d .\u201cThe age-friendly concept was developed by the government within the Elderly Action Strategy, The strategy follows in line with the Active Aging policy framework published in 2002 by the World Health Organization (WHO), to help governments develop and combine health and social policies that take the aging population into consideration and make their environment more friendly and safe\u201d .\u201cThe World Health Organization set out a policy framework on Active Aging at the 2002 Second United Nations World Assembly on Aging. Known to researchers as the Madrid Plan, the policy framework encourages municipalities to make their communities safe and senior-friendly, promoting an active and healthy lifestyle. But Beaulieu said that the Age-Friendly Cities project includes all ages. \u201cIt is important to rethink intergenerational links\u201d, she affirmed\u201d .The quotes of the three articles that mention the WHO document reveal a cursory engagement with the WHO document. They do not reveal the depth of the themes present in the WHO document and what it would mean for the strategies discussed in the three articles.Canadian Newsstand (n = 300 Canadian newspapers), Calgary Herald ; The Globe and Mail , The New York Times , China Daily , The Star , The Guardian and The Times for active aging and related terms . We furthermore searched these sources for articles that covered aging and elderly and aging and seniors. In order to evaluate the frequency of mentioning of active aging and related terms we searched the full text of all articles of Canadian Newsstand has n = 20,307 articles that contain the words \u201caging\u201d and \u201celderly\u201d and n = 34,032 articles that contain the terms \u201caging\u201d and \u201cseniors\u201d. For the Calgary Herald the numbers are n = 815 articles that contain the words \u201caging\u201d and \u201celderly\u201d and n = 2,254 articles that contain the terms \u201caging\u201d and \u201cseniors\u201d; for The Globe and Mail the numbers are n = 1,502 articles that contain the words \u201caging\u201d and \u201celderly\u201d and n = 3,063 articles that contain the terms \u201caging\u201d and \u201cseniors\u201d; for the NYT the numbers are n = 4,026 articles that contain the words \u201caging\u201d and \u201celderly\u201d and n = 4,607 articles that contain the terms \u201caging\u201d and \u201cseniors\u201d. The Guardian has n = 3,897 articles that contain the words \u201caging\u201d and \u201celderly\u201d and n = 334 articles that contain the terms \u201caging\u201d and \u201cseniors\u201d. The Star has n = 97 articles that contain the words \u201caging\u201d and \u201celderly\u201d and n = 28 articles that contain the terms \u201caging\u201d and \u201cseniors\u201d. China Daily has n = 2,025 articles that contain the words \u201caging\u201d and \u201celderly\u201d and n = 588 articles that contain the terms \u201caging\u201d and \u201cseniors\u201d.These numbers indicate that the newspapers cover aging as it relates to the elderly and seniors.The New York Times with the term aging and seniors and \u201caging well\u201d the hit number drops to n = 4. This number and the hit count numbers listed in However if one searches for example Canadian Newsstand database and The New York Times for mentions of physical activity in articles that covered \u201caging\u201c and \u201celderly\u201d or \u201cseniors\u201d and within articles that covered aging well or healthy aging or natural aging or successful aging or active aging.We searched the n = 47,634 in Canadian Newsstand and n = 1,371 in The New York Times indicating an interest in physical activity. Searching Canadian Newsstand 4,613 hits were obtained for articles covering aging well or healthy aging or natural aging or successful aging or active aging. Within these articles n = 362 or 7.8% of the articles covered physical activity. Searching The New York Times 210 hits were obtained for articles covering aging well or healthy aging or natural aging or successful aging or active aging. Within these articles n = 9 or 4.2% of the articles covered physical activity. These numbers indicate a low linkage of physical activity with aging well and synonyms used.Searching for the phrase \u201cphysical activity\u201d by itself we found Canadian Newsstand has n = 20,307 articles that contain the words \u201caging\u201d and \u201celderly\u201d and n = 34,032 articles that contain the terms \u201caging\u201d and \u201cseniors\u201d.Canadian Newsstand the combination search of \u201cphysical activity\u201d and \u201caging\u201d and \u201celderly\u201d generated n = 370 hits or 1.8% . As for the Canadian Newsstand combination search of \u201cphysical activity\u201d and \u201caging\u201d and \u201cseniors\u201d generated n = 893 hits or 2.6% . The New York Times has n = 4,024 articles on \u201caging\u201d and \u201celderly\u201d, n = 663 on \u201caging\u201d and \u201cseniors\u201d and n = 1,371 on physical activity. If we search the articles on \u201caging\u201d and \u201celderly\u201d or \u201caging\u201d and \u201cseniors\u201d for the term \u201cphysical activity\u201d we obtained n = 43 articles in The New York Times for the aging/elderly articles reflecting 1.0% (of the hits of aging/elderly by itself) and n = 11 articles in The New York Times for the aging/seniors articles reflecting 1.6% (of the hits of aging/seniors by itself). This data suggest that physical activity is not much mentioned in relation to aging and the elderly/seniors in general and the low rate of coverage is not just an artifact of the aging well and synonym articles.As for Data so far suggest little coverage or impact that could be explicitly linked back to the WHO Policy framework for active ageing or the Toronto Charter for Physical Activity. However it could be that the issues raised in the WHO Policy framework for active ageing and in the Toronto Charter for Physical Activity are discussed in the newspapers without ever mentioning the two documents. In short we found that most themes and issues raised in the WHO Policy framework for active ageing and in the Toronto Charter for Physical Activity were not even mentioned once increase in mentioning of the two documents; (b) increase of the frequency of coverage of \u201caging well\u201d and synonyms such as \u201cactive aging\u201d and (c) within this coverage of issues raised in the two documents and coverage of socially disadvantaged groups have to be increase. Question is whether one is able to raise the coverage in the newspapers. We submit that newspapers are a difficult route due to lack of influence and lack of consistent coverage. TV and Radio also are difficult and expensive for gaining constant visibility. We submit peer driven news development and topic coverage such as through Facebook which circumvents the printed media as the gatekeeper might be one way out. There are some active aging Facebook pages which we posit might be a good venue and one could make more use of social media. One might want to set up a Facebook pages for the WHO report and the Toronto Charter for increased visibility and grassroots activities. However this strategy of outreach depends on people using the internet which leaves the questions how one reaches people that do not use the internet such as many elderly people especially in low income situations. We posit that the social networking strategy has to be linked to strategies that ramp up local face to face intergenerational interactions and intensify measures that get elderly, especially elderly with disabilities, out of their isolations. As for socially disadvantaged groups the success of the strategy depends on a public that is well educated on the topic especially as it relates to socially disadvantaged groups and that the public believes that the socially disadvantaged groups should be part of it.Toronto Charter for Physical Activity: A Global Call for Action [Diffusion of knowledge through printed media is seen an essential part of the fabric of society to enable social participation ,28,29 anr Action . As suchToronto Charter for Physical Activity: A Global Call for Action [The newspapers covered did not sensitize the reader as to the challenges identified by the World Health organization 2002 Policy Framework on Active Ageing and the r Action . Given tOur work focused mostly on Canadian newspapers and one US newspaper with only two of the four research questions investigating newspapers beyond North American . Future research could look at other media sources to generate empirical data on the other research questions we tackled such as whether newspapers from other cultures covered more the issues raised by the WHO report and the"} +{"text": "This is an erratum to the article \u2018Intranasal Delivery of Chitosan Nanoparticles for Migraine Therapy\u2019 . Unfortunately, all three figures were missing in the published article . The aut"} +{"text": "Over the past two decades the \u201cone drug \u2013 one target \u2013 one disease\u201d concept became the prevalent paradigm in drug discovery. The main idea of this approach is the identification of a single protein target whose inhibition leads to a successful treatment of the examined disease. The predominant assumption is that highly selective ligands would avoid unwanted side effects caused by binding to secondary non-therapeutic targets.In recent years the results of post-genomic and network biology showed that proteins rarely act in isolated systems but rather as a part of a highly connected network . In addiTherefore there is an increasing interest in developing drugs that take effect on multiple targets simultaneously but is concurrently a great challenge for medicinal chemists. There has to be a sufficient activity on each target as well as an adequate pharmacokinetic profile . Early dWe present a new rational approach based on a retrosynthetic combinatorial analysis procedure on appro"} +{"text": "Dear Editor,The frequency of diabetes mellitus is increasing and it is expected that this disorder will affect 300 million people in 2025. It has b"} +{"text": "There is an error in the affiliation for the authors. The correct author affiliation is \u201cthe First Affiliated Hospital of Chongqing Medical University.\u201d"} +{"text": "The 2008\u20132012 French Alzheimer plan aims to implement an integrated services delivery (ISD) called \u201cHomes for Integration and Autonomy for Alzheimer patients\u201d. Alzheimer disease is taken as a model to implement ISD in the whole system. All pilot projects were driven by a \u2018local pilot\u2019 fully dedicated to the ISD implementation.We aimed to analyze factors related to the \u2018local pilot\u2019 in regard of the implementation of the national public health policy. We conducted interviews of all \u2018local pilots\u2019 (n=19) in 2010, their project\u2019s structure managers (n=19) and case managers (17 focus groups). We crossed our results with the external follow-up by the national project team.Main influencing factors of the ISD implementation were: 1) professional autonomy of the pilot; 2) good positioning of the project\u2019s structure manager; 3) project\u2019s management competency of the pilot; 4) support query by the pilot from the national project team; 5) links between case managers and pilot; and 6) the articulation modality of eventual multiple pilots or managers.It was previously shown that it is crucial for ISD implementation to have a dedicated professional for this task. The French national Alzheimer plan gave us an opportunity to analyze factors related to the modality of doing this task."} +{"text": "On page 2087, we missed adding a disclosure statement in the Acknowledgments that \u201cThe findings and conclusions in this article are those of the authors and do not necessarily represent the views of the U.S. Fish and Wildlife Service.\u201d We regret this oversight.The Acknowledgments paragraph should read like the following:"} +{"text": "Sir,et al,[I read with interest the recent case report on \u201cParotid tuberculosis\u201d by Garg et al, and haveThe statement made by the authors \u201cSince 1893, only about one hundred cases of parotid gland tuberculosis have been reported in the literature\u201d is incorrect. The reference cited for the statement is from an article published in 1996 which mentions the total number of cases described till that year. Ideally, the authors should have done an extensive literature search on the number of published cases of parotid gland tuberculosis till date. A search on PubMed with the keywords \u201ctuberculosis\u201d AND \u201cparotid gland\u201d revealed more than 40 cases of parotid gland tuberculosis published after 1996.HIV testing was not done in the case described by the authors. HIV positive patients are more likely to present with extrapulmonary or sputum smear-negative tuberculosis as compared to HIV negative patients. Extrapul"} +{"text": "Parkinson's Disease , the reference citation numbers appearing by the authors' names in the left-hand side column did not match the correct references shown and cited. The reference numbers should appear as follows: for Sinforiani et al., the reference number has been changed from [24] to [25], Mohlman et al., the reference number has been changed from [25] to [26], Sammer et al., the reference number has been changed from [26] to [27], Par\u00eds et al., the reference number has been changed from [27] to [28].In this paper which appeared in"} +{"text": "We have shown that \u03b1 depends on the density and structure of spines and could be a general property of all spiny dendrites , PKC and MAPK is computationally expensive. To address this problem we recently developed a Fractional Integration Toolbox (FIT) does not undergo anomalous diffusion . However"} +{"text": "The following information is missing from the Funding section: The author also received partial financial support from the Bill and Melinda Gates Foundation through the Disease Control Priorities Project .In the Methods section, there are errors in the first and fifteenth equations. In the subsection \u201cRelationship between Income Elasticity and Price Elasticity of Demand,\u201d the variable \u03d6 in In the subsection \u201cStep 2,\u201d the variable \u03d6 in"} +{"text": "There are formatting errors in Secoviridae\u201d. Please see the corrected There is an error in"} +{"text": "After publication of the original article it came to the authors\u2019 attention that there was an error in the \u2018Results\u2019 section of the abstract. The value \u20180.39\u2019 should have been given as \u20180.039\u2019. This error has now been corrected in the original article."} +{"text": "The original version of this article unfortunately contained a mistake. Section \u201cMaterials and methods\u201d subsection \u201cparticipants\u201d was incorrect in the HTML and PDF versions of this article. The original article stated: \u201cParticipants The study for human was approved by Institutional Review Board at Hyogo College of Medicine and informed consent was obtained from all the participants\u201d, this should read: \u201cParticipants The study for human was performed in Tsuna Hospital and informed consent was obtained from all the participants.\u201d"} +{"text": "There is an error in the third sentence of the \u201cWestern blot\u201d section of the Materials and Methods. The correct sentence is: The proteins were transferred onto polyvinylidene fluoride membrane ."} +{"text": "MMWR Summary of Notifiable Diseases \u2014 United States and in the weekly MMWR Notifiable Diseases and Mortality Tables I and II of provisional NNDSS data.CDC\u2019s National Notifiable Diseases Surveillance System (NNDSS) maintains and annually updates information about which Nationally Notifiable Infectious Conditions (NNICs) are considered \u201creportable\u201d in each of the different reporting jurisdictions. NNICs designated \u201cnot reportable\u201d are indicated with an \u201cN\u201d; those conditions that are reportable are recorded with either the number of cases or with a \u201c\u2014\u201d to indicate that no cases were reported for that NNIC. These designations are used in the annual MMWR Summary of Notifiable Diseases \u2014 United States, 2013 and the NNDSS weekly provisional MMWR Notifiable Diseases and Mortality Tables I and II for 2014, respectively. Assessment results for 2015 are being used to populate the \u201cN\u201d indicators in the MMWR weekly provisional tables for 2015.NNDSS staff within the Division of Health Informatics and Surveillance performed assessments with each reporting jurisdiction to ascertain the reportable disease status of each NNIC for the years 2013\u20132015. The assessment results for 2013 and 2014 were used to populate the \u201cN\u201d indicators for NNDSS data in the http://wwwn.cdc.gov/nndss/.When the data for a specified year are reconciled and finalized, NNDSS reporting exceptions (\u201cN\u201d indicators) are summarized by NNIC and reporting jurisdiction in a report that can be found under the Downloads and Resources tab at"} +{"text": "R2 is =0.616. In this erratum we report corrected In the paper titled \u201cReference Values of Pulse Wave Velocity in Healthy People from an Urban and Rural Argentinean Population\u201d there was an error in Figure\u20091. The correct value of In the paper entitled \u201cReference Values of Pulse Wave Velocity in Healthy People from an Urban and Rural Argentinean Population\u201d a mistake was introduced in Figure\u20093. In this erratum we report modified"} +{"text": "Please view the complete, correct equations here:In the Results section, there is an error in the fourth equation in the section titled \u201cPropagule with two dispersal abilities\u201d and in the eleventh equation in the section titled \u201cPropagules with multiple dispersal abilities.\u201d In both equations,"} +{"text": "It has come to our attention that during production of the original article, some of the column headings were missing from Tables\u00a01 and 2. The corrected Tables"} +{"text": "In the \u201cTheoretical Methods\u201d section of the Materials and Methods, there is an error in the second equation. Please view the complete, correct equation here:"} +{"text": "There is a typographical error in Table 2 of this article. Under the \u201cGrower period (22\u201339\u2009days)\u201d section, the body weight gain for the PFA group should have the superscript \u201ca,\u201d instead of \u201cb,\u201d indicating that it is significantly different from the Control and AGP groups.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The Gene Expression Omnibus accession number is missing from the Materials and Methods section, from the last sentence of the \u201cTranscription profiling\u201d subsection. The corrected sentence is: Raw data can be accessed through the Gene Expression Omnibus (GSE65036)."} +{"text": "There is an error in the fourth sentence of the second paragraph under the \u201cMethylation analysis\u201d section of Materials and Methods. The correct sentence is: Supplementary Figure S3 that includes the sequencing of 50 clones illustrates this phenomenon."} +{"text": "In the Materials and Methods section, there is an error in the equation in the section titled \u201cIn Vitro Cleavage Assay.\u201d Please view the complete, correction equation:"} +{"text": "We regret any confusion or inconvenience this error may have caused.In the article \u201cGetting Research to the Policy Table: A Qualitative Study With Public Health Researchers on Engaging With Policy Makers,\u201d a bulleted list was omitted from the Results because of a technical error. The correction was made to our website on May 1, 2015, and appears online at"} +{"text": "There is an error in the first sentence of the \"Imperfect streaks consisting of hot (cold) streaks with up to one miss (hit)\" portion of the \u201cMethod\u201d subsection of the \"Phase 2: How Do the Analyzed Metrics Change in Relation to Streakiness?\" section. The correct sentence is: As hypothesized above, hot (cold) streaks might end with difficult (easy) shot attempts, and a key question about the traditional definition of the hot hand is whether a miss off a difficult FGA is sufficient for a hot streak to be considered as ended in a player\u2019s and an observer\u2019s mind."} +{"text": "Cx. quinquefasciatus chromosomes.\u201d The complete, correct There is an error in the legend for There is an error in the legend for"} +{"text": "In the paper titled \u201cPolyamine regulates tolerance to water stress in leaves of white clover associated with antioxidant defense and dehydrin genes via involvement in calcium messenger system and hydrogen peroxide signaling,\u201d there was a typing error in the section of \u201cIntroduction,\u201d which should be corrected. In the first paragraph in the section of \u201cIntroduction,\u201d \u201cputrescine (Put), spermidine (Spd) and spermine (Spd)\u201d should be corrected to \u201cputrescine (Put), spermidine (Spd) and spermine (Spm).\u201d No other correction is needed.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "We regret any confusion or inconvenience this error may have caused.A change to an author name in the byline of the article \u201cUse of Culturally Focused Theoretical Frameworks for Adapting Diabetes Prevention Programs: A Qualitative Review\u201d has been made. Dr Ana A. Baumann\u2019s name was incorrectly spelled in the original release and has been corrected. The change was made to our website on May 12, 2015, and appears online at"} +{"text": "The article has been updated with a new\u00a0version of the table, and the data have been sorted correctly. The authors regret this error and any confusion that may have resulted."} +{"text": "It has come to our attention that in the work referenced above Figure 7A, B is INCORRECT:The CORRECT one is as follows:"} +{"text": "It has come to our attention that during production of the original article, an error was introduced into Table\u00a01 during copyediting. The corrected Table"} +{"text": "There is an error in the second paragraph of the \u201cTemperature\u201d portion of the \u201cMeasurement of Covariates\u201d subsection of the Methods. The correct paragraph is: For purposes of linking with REGARDS participant data, daily mean air temperature values for 2003\u20132009 were defined as the average of the hourly values for a 24-hour period ending at midnight local standard time. The trailing 1-year mean (\u00b0C) of the NLDAS daily mean temperatures for the grid cell containing the geographic location of the participants\u2019 residence was used to define the temperature exposure for each participant."} +{"text": "The labels in the first equation should read \u201cstate at time There is an error in the second equation. Please see the correct equation here:it, is the probability woodpecker i is alive at the end of time step t.\u201dThe penultimate sentence of the paragraph should read \u201cSurvival probability, denoted \u0424"} +{"text": "A recent letter sent to the Journal of Human Kinetics\u2019 editor warned about a supposed methodology error in the calculation of home advantage in football leagues used in Two teams which obtain the same amount of points as local must have the same HA value.Points obtained as local and HA must have a direct relationship, this is, the more/less amount of points obtained as local team, the more/less value of HA (as long as the number of matches played is constant).The analysis of home advantage (HA) aims to determine the existence of a benefit to the local teams and must meet the following axioms:These axioms meet in the Pollard\u2019s model when thiFor those competitions which do not allow a draw, When first inconsistency lies in the fact that two different competitions with the same number of matches and the same number of points obtained at home can have a different HA value when the Pollard\u2019s model (The \u2019s model is appli\u2019s model by usingsecond inconsistency in the Pollard\u2019s model (The \u2019s model lies in \u2019s model by using"} +{"text": "We have discovered an error in our article on \u201cParental phonological memory contributes to prediction of outcome of late talkers from 20\u00a0months to 4\u00a0years: a longitudinal study of precursors of specific language impairment\u201d . The accThe analyses in the article were computed using this cutoff, and so none of the results or conclusions are altered: the correction is made to ensure that the description of the method in the article matches what was done."} +{"text": "There is an error in the first sentence of the \u201cResults\u201d subsection of the Abstract. The correct sentence is: 274 osteopaths (60% response rate) responded to the survey notice."} +{"text": "There is an error in the first sentence of the final paragraph of the \u201cImpact of ABCB1 1199G>A polymorphism on the intracellular accumulation of Tac and CsA\u201d subsection. The sentence should read:\u201cAs depicted in In Additionally, there are a few errors with some of the figure legends. Please view"} +{"text": "There is an error in the first sentence of the fifth paragraph in the \u201cModel domain and boundary conditions\u201d section of the Materials and Methods. The correct sentence is: The calcium present in the epidermis originates from movement of fluids and calcium across the BM [59], which at steady state must therefore act as a source of extracellular calcium with constant and positive concentration \u03c10.In the \u201cModel domain and boundary conditions\u201d section of the Materials and Methods, there is an error in"} +{"text": "TTCAACCCGAAGCCATCC (position 2830).There is an error in the primer position under the sub-heading \u201cDetection and quantification of VPg in MNV exposed to copper and brass surfaces\u201d in the \u201cMaterials and Methods\u201d section. The correct antisense primer position is In addition, lanes 1 and 3 are labeled incorrectly in the legend for"} +{"text": "It has come to our attention that during production of the original article, an error was introduced into Table\u00a01 during copyediting. The corrected Table"} +{"text": "The legend of The fourth paragraph of the Methods section under the subheading \u201cPhylogenetic reconstruction\u201d is erroneously included in the published article, and should be omitted."} +{"text": "Each individual learns the application of the word through experiences related to injury in early life\u201d. It is n"} +{"text": "There are errors in the article. Please see below for a complete list of the errors and their corrections.In the sixth sentence of the Abstract, \u201ca complex I blocker\u201d should be \u201ca mitochondrial uncoupler.\u201dIn the second sentence of the third paragraph of the Introduction, \u201ccomplex I antagonist CCCP\u201d should be \u201cmitochondrial uncoupler CCCP.\u201dThere is an error in the fifth sentence of the \u201cStress and Control\u201d section of Materials and Methods. The correct sentence is: A subset of slices from WT mice were exposed to 10 \u00b5M CCCP to inhibit mitochondrial function.There is an error in the second sentence of the Conclusion. The correct sentence is: The major observation from this work is that environmental exposure to the toxic mitochondrial uncoupler CCCP is a severe stress in terms of deregulation of energy metabolism and that a response is initiated when ATP levels are irreversibly reduced."} +{"text": "In the paper titled \u201cIonizing Particle Radiation as a Modulator of Endogenous Bone Marrow Cell Reprogramming: Implications for Hematological Cancers,\u201d there was secretarial error made at our end in \u201cFigure 1,\u201d which should be corrected. At some point of the submission in Figure 1, A and B were disarranged in the slide. No other correction is needed as the text and figure legends are correct.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "There is an error in the S1 File from the list of Supporting Information. There is a formula error in the \u2018Total by country\u2019 tab which incorrectly links to the wrong rows. The corrected S1 FileThis file includes supplementary data.(XLSX)Click here for additional data file."} +{"text": "The original version of this article was unfoThe information missing from this section should have noted that this work is a part of the doctoral thesis of main author Sergej Griff, being performed at the Charit\u00e9, University of Medicine in Berlin, Germany."} +{"text": "Dear Sir or Madam,I read with great interest the article by Murphy et al. entitledThe authors provide a comprehensive review of the previous publications in the \u201cDiscussion,\u201d but some of the reference citations are erroneous. The second paragraph of the \u201cDiscussion\u201d starts by focusing on Georgopoulos et al.\u2019s article , which iTo summarize, I think that Murphy et al. investigated a rare but important complication, but our understanding of the relevant pathophysiology would have been aided by providing more detailed clinical and demographic data along with the statistics included in the manuscript."} +{"text": "After publication of this work we deterIn light of this mistake we would ask the reader to disregard the last part of the first paragraph of the Results and Discussion section, beginning with the statement, \u201cIn the present study\u2026\u201d. Also, reference to this experiment in the Methods section can also be omitted (the paragraph beginning with: \u201cTo confirm \u2026\u201d and the sentences through \u201c\u2026as described in the Results and Discussion section.\u201d). Images in the accompanying Figure"} +{"text": "The images for 2, while with transplantation mortality is at a fixed level.\u201d This should refer to In the Discussion section, the third paragraph under the title \u201cTwo easily-confused but different types of \u2018threshold,\u2019\u201d the first sentence states \u201cThat these two types of threshold differ is sketched in Figure 5, which imagines a situation where, with only medical therapy, mortality falls smoothly with rising peak VOAlso in the Discussion section, under \u201cPrognostic studies,\u201d the second sentence of the first paragraph states \u201cFor example, a flexible nonlinear function can be fitted and displayed with confidence bands for incremental log odds over the whole span of the marker; seeking a point such that risk is flat on both sides of that point but the risk on one side is much different from the risk on the other side .\u201d This s"} +{"text": "The ability of animals to count events or objects and its underlying mechanisms \u2013 including the possible existence of a dedicated \u201cnumber sense\u201d \u2013 is a topic of much recent fascination and research interest. A simple computation that frogs execute routinely is counting the number of consecutive sound pulses in a conspecific call that occur with precise and regular timing . Cells s"} +{"text": "There is an error in the third column of the \u201cFalse negatives\u201d row of In addition, the sixth author\u2019s name is incorrect. The correct name is Martin W. Laa\u00df. The publisher apologizes for the error."} +{"text": "A. fluviatilis adults with Wolbachia\u201d of the Results incorrectly refers to The third sentence in the section titled \u201cInfluence of GSK-3 in The legend for"} +{"text": "The authors would like to issue an erratum for this article , and wou"} +{"text": "In the 1620s, Jesuit missionaries living in Peru learned of the healing powers of the bark of \u201cfever trees\u201d that grew in the high forests of Peru and Bolivia.From the Quechua"} +{"text": "The images published for Figs. The name of the first author in the author list was given as \u201cLi Jun Yang\u201d instead of \u201cLiJun Yang\u201d.Unfortunately, the original version of this article containeThe images and the name have been updated in the original article and are also correctly included in full in this erratum."} +{"text": "There is an error in Equation 34 within the subsection \u201cParameter Reduction of the Stability Phase Space\u201d in the Results section. The absolute value notation is incorrect. Please view the complete, correct equation here:"} +{"text": "Annals of General Psychiatry, it was brought to our attention that there was an error in Table\u00a0Following publication of the original version of the a"} +{"text": "BMC Surgery [Following publication of the original version of this article in Surgery it was b"} +{"text": "The formula in the section \u201cSperm Precedence\u201d in the Materials and Methods is incorrectly displayed. The correct formula is shown below."} +{"text": "Dear Editor,We read the latest paper from Torkildsen et\u00a0al.3To our minds, this new more detailed analysis of these existing data provides a compelling illustration of the effects of confounding but do not provide any convincing evidence for an underlying MOB effect in multiple sclerosis."} +{"text": "The article titled \u201cIntravenous Leiomyoma with Extension to the Heart: A Case Report and Review of the Literature\u201d , publish"} +{"text": "In the article titled \u201cSnapshot on a Pilot Metagenomic Study for the Appraisal of Gut Microbial Diversity in Mice, Cat, and Man\u201d, the last"} +{"text": "Paenibacillus exposure\u201d subsection of the Methods section. The second primer in the parentheses should be GAGCAGTTTCTCTCCTTGTTC.There is an error in the penultimate sentence of the \u201cAssay of snail survival after"} +{"text": "There are two formatting errors in this article. The heading \u201cHistological changes at late time post infection cannot be differentiated from PRV induced lesions\u201d in the Results section should be at the same level as the headings above and below; in other words, it should be a subsection of \u201cResults\u201d and not of \u201cSystemic infection of ASCV is reduced by vaccination\u201d.In"} +{"text": "The relationship type_id is \u2018instance_of\u2019, the subject_id is the locus and the object_id is the marker.The publisher apologizes for this error."} +{"text": "Due to a typesetting error the word \u201ctrabeculae\u201d was changed to an incorrect spelling of \u201ctrabecule.\u201d The publisher apologizes for this mistake and the original article has been updated. This error does not change the scientific conclusions of the article in any way."} +{"text": "Malaria Journal[The authors would like to publish a correction article to address the misspelling of co-author Carmenza Spadafora\u2019s name in the original article published in a Journal and also"} +{"text": "Croatian Medical Journal is a general medical journal and although it might seem at first that lacking a specific field is mainly a weakness . One of Croatian Medical Journal can aspire \u201cto move the Earth\u201d of biomedicine. At a new interdisciplinary stage of the biomedical future, the Croatian Medical Journal must be ready to respond to the emerging challenges of the new research pattern and publish relevant science.If multiple disciplinary effort is the right place to stand, then the"} +{"text": "It is important to note that B\u00e9dard and colleagues have also described a method for the single trial extraction of synaptic input (B\u00e9dard et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Next generation sequencing: potential and application in drug discovery\u201d. The correct list of the authors and their affiliations are as shown above.Through this erratum the authors declare that two coauthors were missing in the article entitled \u201c"} +{"text": "Upon publication, it was noticed that in the Acknowledgements section of the original article , \u2018ChikunWe are grateful to the technical team of the medical analysis laboratory of Institut Louis Malard\u00e9 for their contribution in performing the Chikungunya virus molecular testing.In addition, the city \u2018Papeete\u2019 was missing from affiliation 2 in the original article. This has now been corrected."} +{"text": "This is a corrigendum to the article \u2018Inhibition of Key Digestive Enzymes Related to Diabetes and Hyperlipidemia and Protection of Liver-Kidney Functions by Trigonelline in Diabetic Rats\u2019 . Unfortunately,"} +{"text": "Corrigendum:In the article of the Frontiers Research Topic Issue on Models and Estimation of Genetic Effects \u201cDissecting genetic effects with imprinting,\u201d by \u00c1lvarez-Castro , the citThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The article \u201cVascular development and hemodynamic force in the mouse yolk sac\u201d that is part of the research topic \u201cMechanotransduction and Development of Cardiovascular Form and Function\u201d published 20 August 2014, is missing the following Acknowledgment Section:This work is supported by the National Institutes of Health (R01HL120140 and U54HG006348) as well as by the Optical Imaging and Vital Microscopy core at Baylor College of Medicine.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The authors wish to make the following corrections to this paper :On page 683 at the end of Section 3.2. lines 13\u201314, the word \u201cno\u201d is missing. The correct sentence should be:no evidence of false-negative NIPT results so far in the pregnancies included in this study.\u201d\u201cThere has been The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "Geiss's name was incorrectly spelled as Geib. The article has since been corrected online.In the article \u201cQuality of Life Is Related to Fecal Calprotectin Concentrations in Colonic Crohn Disease and Ulcerative Colitis, but not in Ileal Crohn Disease\u201d,"} +{"text": "Due to an error in the publication process, this article (Ramirez et al. BioMed Central have now corrected this error and Figure three Figure\u00a0 here can"} +{"text": "Dr. Kukla's name was also misspelled in the text. The article has since been corrected online.In the article \u201cValidation of Standard and New Criteria for the Differential Diagnosis of Narrow QRS Tachycardia in Children and Adolescents\u201d,"} +{"text": "In their excellent systematic review Meusel et al. put forwDehydration has an important negative effect on cell metabolism (Schliess and H\u00e4ussinger, In contrast to what has been found in the pathophysiology mentioned above, dehydration in healthy humans does not appear to have a great influence on brain volume changes (Kempton et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "After publication of the original article , it was In addition, the authors also noticed minor typos in the Abstract, the \u201cResults\u201d and the \u201cDiscussion\u201d sections. The original article has been updated to rectify these errors."} +{"text": "There are several errors in this article.In the abstract and the Introduction section, the term \u201cchemoembolization\u201d should be \u201cembolization\u201d.Throughout the article, including The correct version of the second sentence in the sixth paragraph of the Results section is: Sixteen patients in period 1 and 19 patients in period 2 received transarterial chemoembolization as a cancer treatment.The correct version of The authors have provided corrected version of"} +{"text": "T\u2019 to the right of the approximate equality sign. The corrected line should be:An error was introduced during the typesetting process. In the fourth line of Equation 13, there should be no dot above the \u2018The publisher apologizes for this error."} +{"text": "Unfortunately, the original version of this article containeThe correct author list and the new \u201cAuthors\u2019 contributions\u201d section have been correctly included in full in this erratum and updated in the original article."} +{"text": "There is an error in the spelling of the sixth author\u2019s name. The correct name is: Ibrahim Omar Ba."} +{"text": "Journal of Mental Health has published an article, \u201cHelp-seeking patterns and attitudes to treatment amongst men who attempted suicide\u201d by Cleary (The y Cleary . The autSuicide in men is a difficult issue and has been described as a \u201csilent epidemic\u201d \u20135. In thLack of help seeking among men is one of the most important issues in the field of men\u2019s mental health . It contAmong men, and young men, especially, masculinity is directly associated with receiving less health care and particularly psychiatric services , 4, 9\u201311The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "BMC Gastroenterology it was brought to our attention that the author\u2019s name has been incorrectly spelt, instead of \u2018Alejuandro\u2019 it should be spelt \u2018Alejandro\u2019.Following publication of the original version of the a"} +{"text": "The formula for \u201cPinkness Index\u201d in the \u201cCorrelation between Reflectance and Anthocyanin Concentration\u201d section of the Materials and Methods is incorrectly displayed. The correct formula, provided by the Authors, is shown below."} +{"text": "It should read bdam. Please view the complete, correct equation here:In the Methods section, there is an error in the third equation in the section titled \u201cStatistical Analysis.\u201d The variable In"} +{"text": "Maximum likelihood estimation of the concentration parameter of von Mises\u2013Fisher distributions involves inverting the ratio However, the general tendency to require even less iterations of the newly established bounds will nevertheless be of interest from a computational point of view if these roots are solved repeatedly, which is required when for example the expectation-maximization algorithm is used to estimate mixtures of von Mises\u2013Fisher distributions (Banerjee et\u00a0al."} +{"text": "In the paper titled \u201cLocalized and Sustained Delivery of Erythropoietin from PLGA Microspheres Promotes Functional Recovery and Nerve Regeneration in Peripheral Nerve Injury\u201d we have found that, in Figure 1(d), one panel is mistakenly a duplication of the adjacent panel. The upper two western blotting results are identical. According to our inspection of the original data sets, this is due to a mistake during the editorial process of the figures. We show here the amended Figure 1(d), with the correct image for the western blotting results of group EPO.y-axis, \u201cAxon count (field),\u201d should read \u201cAxon count (per field).\u201d And a typo was found in the beginning of the second line under Section 3.1 that \u201caws\u201d should read \u201cwas.\u201dDue to the same reason, another mistake was made in the lower left panel of Figure 4. The label of the"} +{"text": "There is an error in the \u201cParticipants\u201d subsection of the Abstract. The correct sentence is: Thirty-nine eyes from 38 patients with active OT."} +{"text": "There is an error in the scheme shown in the \u201cDiscussion\u201d section. Please refer to the correct scheme below:"} +{"text": "The phrase \u201c_ENREF_\u201d mistakenly appears several times in the Introduction and Conclusion. This error was introduced during the typesetting process, and the phrase should not appear."} +{"text": "A recent letter published in the Journal of Human Kinetics falsely The reason why their method makes no sense is that performance at home has to be assessed against performance away from home for a measure of home advantage to be valid. Suppose team A gains 40 points at home and 40 points away from home, and team B scores 40 points at home and 10 away from home. According to The two so-called \u2018axioms\u2019 that the authors state at the start of their letter make it clear that they have no concept of what constitutes home advantage as opposed to home performance which is what they are quantifying. Both their Tables 1 and 2 need an additional column headed \u2018away points\u2019 before home advantage can be calculated. This is what was correctly done by both In their earlier letter to the Journal of Human Kinetics,"} +{"text": "In the Results section, there is an error in the first equation of the subsection titled \u201cSequential imaging using a virtual grid to repeatedly locate a given region of interest.\u201d Please view the complete, corrected equation here: There are errors in the legend for"} +{"text": "We regret any confusion or inconvenience this error may have caused.A correction was made to a sentence in the Methods section of the article \u201cSupermarket and Grocery Store\u2013Based Interventions to Promote Healthful Food Choices and Eating Practices: A Systematic Review.\u201d The sentence describes the calculation of a subscore: \u201cWe used this average as 1 of 2 subscores\u201d was changed to \u201cWe used the sum of these averages as 1 of 2 subscores.\u201d The correction was made to our website on April 30, 2014, and appears online at"} +{"text": "The corrected first name is \u201cYasser\u201d and last name is \u201cAl Omran\u201d. All the authors contributed equally in the manuscript and share equal first authorship where applicable. It is regretted that the first and last names for the author Yasser Al Omran was published wrong for the manuscript entitled"} +{"text": "We have discovered an error in our paper published in Biomolecules , in Figu"} +{"text": "Here, we would like to correct the two points as follows.1) The updated Table 2) Discussion: \u201cSpecifically, compared with the recent developed GraphVar (Kruschwitz et al., We would like to further clarify the description as\u201cSpecifically, compared with the recent developed GraphVar (Kruschwitz et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Reason for Corrigendum:Availability of Source Code and Data\u201d:In the paragraph titled \u201cSUB1015301)\u201d is only a temporary submission ID and is not the permanent accession. This should be replaced with the correct SRA accession number \u201c(SRA SRP061658).\u201dThe published SRA accession number \u201c(SRA Please accept the sincerest apologies from the authors regarding this error. This correction does not impact the scientific conclusions of the article in any way.JR is responsible for composing and submitting this correction.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Review\u201d into \u201cArticle\u201d. The authors would like to apologize for any inconvenience caused to the readers by this change.The authors wish to make the following correction to this paper : The art"} +{"text": "To the Editor\u2014The study by Middelkoop and colleagues [lleagues combininlleagues . This suThe modest effect size in the study by Middelkoop et al may be eMiddelkoop et al also sta"} +{"text": "In the \u201cSeparating normal and abnormal fundus images\u201d section of the Experiments and Results, there is an error in equation 8. Please view the complete, correct equation here:"} +{"text": "In the Funding section, the funder \u201cAmphibian Research and Monitoring Initiative\u201d is incorrectly referred to as the \u201cAmphibian and Reptile Monitoring Initiative.\u201d The correct funding information is as follows: This work was funded by the 2008 USGS Amphibian Research and Monitoring Initiative competitive grant program. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."} +{"text": "In the Original Research Article \u201cOut-of-body experiences associated with seizures\u201d , the Acknowledgment of funding was inadvertently deleted. We wish to acknowledge with gratitude that our work was supported by the Funda\u00e7\u00e3o Bial (grant number 81/08).The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Hypsarhythmia was originally spelled with one \u2018r\u2019 by Drs Frederick and Erna Gibbs when they coined the term in 1952. Hypsarhythmia was originally spelled with one \u2018r\u2019 by Drs Frederick and Erna Gibbs when they coined the term in 1952 . The onePediatric Neurology Briefs prefers the single \u2018r\u2019 spelling in deference to Dr Gibbs, the intended meaning is accepted for both spellings today.Although the Editor of"} +{"text": "Bd and ranavirus in Madagascar.\u201d Please see the complete, correct There are a number of errors in the caption for"} +{"text": "Also, the author's degrees were not given in full in the byline. The article has since been corrected online.In the article \u201cThe Value of U/S to Determine Priority for Upper Gastrointestinal Endoscopy in Emergency Room\u201d,"} +{"text": "There is an error in the final sentence of the paragraph titled \u201cMonomer-dimer equilibrium\u201d in the Results section. The correct sentence is: The dissociation constants with and without MgCl2 can be estimated to 50\u03bcM and 200\u03bcM, respectively ."} +{"text": "There are two incorrect references to Table 2 in the Results section: the last sentence of the section \u201cCardiovascular functional validation of genes from Module 1\u201d and the first sentence of the section \u201cPersonalized representation of gene analysis.\u201d Both of these instances should refer to Table 3.There is one incorrect reference to Table 3 in the Results section of the manuscript: the second sentence of \u201cModifications of PBMC gene expression in hypertensive patients\u201d should refer to Table 2."} +{"text": "Following publication of our article we noticWe would also like to clarify that the data presented in tables 1\u20135 in the article . The rec"} +{"text": "In the paper titled \u201cEvacuation after the Fukushima Daiichi Nuclear Power Plant Accident Is a Cause of Diabetes: Results from the Fukushima Health Management Survey\u201d , the des"} +{"text": "In the Materials and Methods section, there are errors in the first and third equations of the section titled \u201cAnalysis.\u201d The complete, correct first equation is:The complete, correct third equation is:"} +{"text": "After publication of this article , the autPlease find the correct version of the \u2018Acknowledgments\u2019 section below:"} +{"text": "The authors wish to make the following correction to this paper :The author name \u201cXiaoyi Li\u201d should be changed into \u201cXiaoying Li\u201d.The authors would like to apologize for any inconvenience caused to the readers by this change."} +{"text": "During typesetting, errors were introduced into the final row of the \u201cEndogenous system\u201d column of Additionally, there are errors in The publisher apologizes for the errors."} +{"text": "One of the references in this article contained a misspelling of an author name (\u201cShuit\u201d), which we hereby rectify to \u201cSchuit.\u201dThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "There is an error in the sixth to last sentence of the fourth paragraph of the Discussion. The correct sentence should read: The concentration of a drug can never have a value below zero, while the degree of hypothermia may well be negative (for temperatures above 37\u00b0C).20%\u00a0and NT35\u00b0C, that individually were not effective was not neuroprotective indicating that there was no synergistic effect between the two treatments.There is an error in the third to last sentence of the \u201cCombined Experiments of Different Temperatures and Xenon Concentrations with and without delay\u201d section of the Results. The correct sentence should read: Combining the treatments, XeThere is an error in"} +{"text": "Figure 2C of our article the sample traces shown for non-denervated controls and for denervated TNF\u03b1-deficient preparations at 3\u20134 days post lesion (dpl) are identical. Upon re-examination of the original recordings, we found that this sample trace was taken from a denervated dentate granule cell (\u201c3\u20134 dpl group\u201d). The corrected figure showing a sample trace of a non-denervated control is now presented. We apologize for the mistake and for any inconvenience caused to the readers.We noticed that in The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In the original article, we neglected to include the funders \u201cInnovative research team of high-level local universities in Shanghai (SHSMU-ZDCX20210400)\u201d and \u201cShanghai Municipal Key Clinical Specialty (shslczdzk00901)\u201d to the authors.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, there was an error. We inaccurately wrote Materials and Methods, \u201cImage Processing and CVR,\u201d A correction has been made to \u201c\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, there was an error in affiliations 1 and 6. Instead of \u201cThe First Affiliated Hospital of Wenzhou University\u201d, it should be \u201cThe First Affiliated Hospital of Wenzhou Medical University\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "As well as having affiliation(s) 1, they should also have \u201cThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "ApoE\u03b54\u201d, it has been corrected with: \u201cAPOE\u03b54.\u201dIn the original article there was an error in the keyword: \u201cIn the original article, there was an error in the Funding statement as published. The grant number was given as \u201c2018YFC1315300\u201d but should be \u201c2018YFC1315200.\u201d The corrected Funding statement is included below.\u201cThis study was supported by a grant from the National Key R&D Program of China (2018YFC1315200).\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Funding statement. The correct number for \u201cthe National Natural Science Foundation of China\u201d is \u201c 81473215 and 81870276\u201d.There is an error in the Additionally, in the original article, there was a mistake in \u201cThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Computational and Mathematical Methods in Medicine has retracted the article titled \u201cAnalysis of Anesthesia Effect of Dexmedetomidine in Clinical Operation of Replantation of Severed Finger\u201d [ Finger\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiThe authors do not agree to the retraction."} +{"text": "Computational Intelligence and Neuroscience has retracted the article titled \u201cApplication Value of Health Education Combined with Aerobic Exercise in Nursing of Patients with Mastitis Found in Physical Examination\u201d [ination\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiThe authors were unresponsive, and the author Xianglian Sun could not be reached by the publisher using the e-mail address provided to the publisher with the article submission."} +{"text": "In the published article author \u201cHongjiang He\u201d was erroneously not attributed as a corresponding author.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original version of this article, An erroneous following text was included in the \u201cReduced Sexual Activity or Abstinence During Pregnancy and/or Postpartum and PrEP Use\u201d section and this has been removedErratum text:"} +{"text": "The authors regret that the title shown in the original article and several sentences were incorrect due to the use of the word \u201cabsorption\u201d in place of \u201cadsorption\u201d. The correct title is as shown above and all instances of \u201cabsorption\u201d in the text should be \u201cadsorption\u201d. The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Recent arguments in aging and dementia research suggest that \u201cterminal lucidity\u201d\u2014defined as unexpected communication or connectedness occurring shortly before death\u2014is distinct from \u201cparadoxical lucidity\u201d\u2014defined as an episode of communication or connectedness in a person who is assumed to have lost these capacities due to progressive neurodegeneration. We disagree with this distinction and argue that terminal lucidity is a special subtype of paradoxical lucidity. We suggest that specifying the relationship between terminal and paradoxical lucidity is important for investigating the underlying mechanism of lucidity in dementia."} +{"text": "An author name was incorrectly spelled as \u201cZhongxin Jiang\u201d. The correct spelling is \u201cZhongxing Jiang\u201d.There is an error in the Funding statement. Please remove \u201cNatural Science Foundation of China (82000112)\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Journal of Healthcare Engineering has retracted the article titled \u201cExploration of the Curative Effect of Early Enteral Nutrition Nursing on Patients with Severe Acute Pancreatitis and the Improvement of Patients' Mental Health and Inflammation Level\u201d [n Level\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiThe authors do not agree to the retraction."} +{"text": "Vidthiya Jeyananthan\u201d. The correct spelling is \u201cVidthiya Jeyanathan\u201d.In the published article, an author name was incorrectly written as \u201cThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the originally published version of this manuscript, the group author \u201cYoung Persons Advisory Group\u201d was listed sixteenth instead of eleventh.This error has been corrected. The publisher apologizes for the error."} +{"text": "The authors would like to clarify that reference [9], which has been retracted, was included in this review article in error"} +{"text": "Journal of Healthcare Engineering has retracted the article titled \u201cAnalysis of the Effect of Robots in the Treatment of Pancreatic Cancer Based on Smart Medicine\u201d [edicine\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifi"} +{"text": "This article has been corrected at the request of the authors to edit the name of the heart condition in the title from \u201cTakotsubo\u2019s Cardiomyopathy to \u201cTakotsubo Cardiomyopathy\u201d.The authors deeply regret that this error was not identified and addressed prior to publication."} +{"text": "In the published article, there was an error in the article title. Instead of \u201cSTRT1,\u201d it should be \u201cSIRT1.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Due to a production error, there was a mistake in The original version of this article has been updated."} +{"text": "In the article titled \u201cEvaluation of the Mechanism of Modified Lingguizhugan Decoction in the Treatment of Nonalcoholic Fatty Liver Disease\u201d , an incoFuyuan Yang and Jianxiang Zhou made equal contribution to this work."} +{"text": "In the published article, an author name was incorrectly written as \u201cKrista Lentine.\u201d The correct spelling is \u201cKrista L. Lentine.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "It should read \"ABTS\u2022+\".In the abbreviation of the radical cation \"ABTSThe sentence\u201cThe change of DLS was recorded at different time points , showing that the average size and size distribution did not change over time .\u201dshould read\u201cThe change of DLS was recorded at different time points , showing that the average size and size distribution did not change over time .\""} +{"text": "The authors regret that there was a mistake in line 8 of the second paragraph of the right hand column of page 7821 of the original article. The text originally read \u201cindirect band gap was 3.15 eV\u201d. The corrected text should read \u201cindirect band gap was 0.315 eV\u201d.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "This article was published in Psychological Medicine with spelling mistake in its title. In the original the word \u2018psychiatric\u2019 was misspelled as \u2018sychiatric\u2019. This has now been updated.The publisher apologises for this error."} +{"text": "Due to a production error, there was a mistake in The original version of this article has been updated."} +{"text": "The Scientific World Journal has retracted the article titled \u201cCorrelations of Ezrin Expression with Pathological Characteristics and Prognosis of Osteosarcoma: A Meta-Analysis\u201d [nalysis\u201d . This arnalysis\u201d . In addinalysis\u201d .The authors responded to explain that MedChina provided only language editing services on this article and that some mistakes were made due to this being their first systematic review publication. The authors agree to the retraction and the notice."} +{"text": "In the original article, there was a mistake in Results. In the presentation of the mathematical model for FFM estimation, the word \u201cFri\u201d appears instead of the word \u201cSex.\u201dIn the original article, there was an error on page 5 in the section The corrected mathematical model included is presented below:Sex: male = 0; female = 1The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The publisher would like to inform you that during typesetting, a spelling error was made in the title of this article and as a result \u201cgranulomatous\u201d was incorrectly spelled as \u201cganulomatous.\u201dThe publisher apologizes for any inconvenience caused by this mistake."} +{"text": "The word in the title \u2018isolated\u2019 was initially misspelled as \u2018issosslated\u2019. The typo has now been corrected retrospectively both in the article proof and the HTML.The author and the publisher apologize for the error."} +{"text": "The authors declare that these corrections do not change the results or conclusions of this paper. The authors have provided the corrected version of Figs. 2 and 3 here. The authors also would like to correct the description of statistics in the Methodology Statistics section as \u201cThe results are expressed as the mean value\u2009\u00b1\u2009SEM and were interpreted by the The revised Fig."} +{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates. It has been noted that the \u2018Model\u2019 line in the flow cytometry data from Figure 5B would be impossible to attain, as it should not bend to the left in such a way when the X value is increasing"} +{"text": "In the article entitled \u201cRecurrent pericarditis as an extra\u2010intestinal manifestation of ulcerative colitis in a 14\u2010year\u2010old girl,\u201d which was previously published in Volume 6 Issue 8 of Clinical Case Reports, the given statement was published incorrectly. \u201cSulfasalazine was initiated as maintenance therapy of UC. Colchicine was added to the treatment to prevent the recurrence of the pericarditis.\u201dIt has been corrected as follows: \u201cSulfasalazine was initiated as maintenance therapy of UC. Colchicine was added to the treatment to prevent the recurrence of the pericarditis.\u201d"} +{"text": "The rollout of the COVID-19 vaccination program in Portugal was one of the most successful in the world. However, there was still a challenge for Public Health services to determine the health literacy needs of the population in the context of a new vaccine and the uncertainty of the pandemic. The goal of this study was to evaluate the usefulness of Google Trends data to gauge the health literacy needs of the general population during the pandemic.A Google Trends search was performed for Portugal including 5 topics related to health literacy needs of the population between the 28th of december 2019 and the 10th of march 2022. The variation shows the relative popularity of each term referring to the total number of Google searches during that period in a normalized scale of 0-100. The variation was compared to the number of doses administered daily in Portugal and key moments of the vaccination campaign as defined by the Directorate-General for Health in Portugal.The terms \u201cvaccination\u201d and \u201cisolation\u201d had a steady rise in popularity from December 2019 to January 2021. The term \u201cvaccination\u201d was the most popular search term with peak popularity in July 2021 and a downward trend followed by an ascent to a lower peak in popularity in January 2022. The terms \u201cscheduling\u201d and \u201cvaccination certificate\u201d both followed a similar pattern, though at lower popularity levels. The term \u201cisolation\u201d was low on popularity since February 2021, with a significant rise and peak in January 2022. This variation relates to key dates during the Portuguese vaccination campaign.Google Trends data seems to correlate with key events during the Portuguese COVID-19 vaccination campaign. That data might be incorporated in the planning framework of health literacy activities for national and local Public Health services.\u2022\u2002Google Trends might be an important source of information for public health teams.\u2022\u2002There is a need for further research into how Google Trends data can be incorporated with other sources of information to inform health literacy activities."} +{"text": "Computational and Mathematical Methods in Medicine has retracted the article titled \u201cInvestigation of Influencing Factors on the Prevalence of Retinopathy in Diabetic Patients Based on Medical Big Data\u201d [ig Data\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiThe authors do not agree to the retraction."} +{"text": "The creation of future proof infostructures requires a number of efforts on different levels within a health organisation. One important thing that we need to be genuinely realise and grow aware of is that there is an inherent need to move away from Excel Spreadsheets, Access Databases and legacy data tools (including paper) towards interoperable information systems that are focused on high-quality data coordination mechanisms, robust processes and documentation and most of all design of data flows that enable sustainable data collection and analysis. This hands-on session will inform users on the following elements:\u2013\u2002Doing a thorough situation analysis of your current data situation\u2013\u2002Design your health data pipeline - paper and imagination required\u2013\u2002Resources to help you design the ideal infostructure\u2013\u2002Setting your next steps forward\u2013\u2002Being aware of your organisational culture to ensure maximum success"} +{"text": "In the published article, there was an error in the article title. Instead of \u201cLactate and Myocadiac Energy Metabolism\u201d, it should be \u201cLactate and Myocardiac Energy Metabolism\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "After a long moratorium since the Controlled Substances Act was passed in 1970, there has been a resurgence of research on the potential therapeutic benefits of psychedelic (PE) compounds. It has been widely believed that the PE effect is a result of the interaction between the drug and the mindset of the patient (the \u201cset\u201d) with the external physical and social conditions (the \u201csetting\u201d). In order to control non-pharmacological variables and improve therapeutic outcome two types of psychological approaches to PE use have emerged traditionally. One is based on psychoanalytically informed talk therapy with low to moderate doses of a PE agent with the goal of facilitating a discharge of emotionally charged mental contents (psycholytic therapy). The other used one or several high doses of a PE to create an \u201coverwhelming experience,\u201d which was then followed up in integrative sessions (psychedelic therapy).Currently, it is unclear which one is better than another, these two methods are frequently mixed, and all-together carry the name of psychedelic-assisted psychotherapy. There has also been some discrepancy about what is the right \u201cset\u201d and \u201csetting\u201d.To add some anchor points for (and at the same time warn about the limitations of) the reemerging field of psychedelic-assisted psychotherapy the authors refer to anthropological observations in cultures, where PE use has a long practice historically.As part of healing ceremonials PE has usually been administered in a tight community with shared cosmology (\u201cset\u201d) and ritual context (\u201csetting\u201d).These are difficult-to-reach conditions for someone coming from Western tradition.No significant relationships."} +{"text": "Due to a production error, there was a mistake in The original version of this article has been updated."} +{"text": "Dear Editor,We read the letter of Chen et\u00a0al. with interest and we thank the authors for pointing out an inadvertent error in our manuscript . We noti"} +{"text": "In the published article, the first author's name was incorrectly written as \u201cOuyang Shuyi.\u201d The correct spelling is \u201cShuyi Ouyang.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original article, two author names were incorrectly spelled as \u201cJinxing Yang and Pinshan Wang.\u201d The correct spellings are \u201cJingxin Yang and Pingshan Wang.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Computational and Mathematical Methods in Medicine has retracted the article titled \u201cAnalysis of the Mechanism and Safety of Bisphosphonates in Patients with Lung Cancer and Bone Metastases\u201d [astases\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiThe authors agree to the retraction."} +{"text": "In the published article, there was an error in affiliation 1. Instead of \u201cC. Wayne McIlwraith Translational Research Institute,\u201d it should be \u201cC. Wayne McIlwraith Translational Medicine Institute.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Incorrect information was published in the Abstract, second sentence:A correction has been made to \u201cWe systematically assessed the relationship between stroke and three 9p21 loci in this meta-analysis.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, an author name was incorrectly written as \u201cWonhaw Lee.\u201d The correct spelling is \u201cWonhwa Lee.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Epitweetr: Early warning of public health threats using Twitter data\u2019 by Espinosa et al. published on 29 September 2022, the formula for general PPV was wrong in the published article because of a technical error The formula was corrected and replaced on 28 October 2022, and we apologise for any inconvenience this error may have caused.In the article \u2018"} +{"text": "In the published article, an author name was incorrectly written as Marcelo Saliermo. The correct spelling is \u201cMarcelo Salierno\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The above article was published with incorrect terms stating \u2018gender\u2019 when the correct term was \u2018sex\u2019. This has now been updated in the online PDF and HTML versions of the article.The Publisher apologises for the error."} +{"text": "PLOS Neglected Tropical Diseases journal does not condone the use of the term \u201cleper\u201d in describing individuals with leprosy. We apologize to any readers who were negatively affected by the use of this term in the original versions of this article.This article was republished on November 9, 2022 to address a terminology issue that came to light after the article\u2019s initial publication: the term \u201cleper\u201d was removed from the article and replaced by \u201cindividuals with leprosy\u201d or \u201cindividual with leprosy.\u201d We understand that the removed term has negative connotations and has been discussed as contributing to stigmatization of individuals harboring this disease. The The rest of the content remains unchanged in the version of record (listed on the article\u2019s webpage as Version 2) for the republished article.PLOS Neglected Tropical Diseases webpage at the time of republication.The uncorrected proof (Version 1) was removed from the article\u2019s"} +{"text": "Computational and Mathematical Methods in Medicine has retracted the article titled \u201cMeta-Analysis of the Effectiveness and Safety of Intravenous Thrombolysis in Patients with Acute Cerebral Infarction\u201d [arction\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiThe authors do not agree to the retraction."} +{"text": "The text incorrectly read \u201cSequences of primers used for creating modified U7-snRNA\u201d. The correct sentence at the end of the section reads \u201cSequences of primers used in this study are listed in Supplementary Note 3\u201d. Also, in the second sentence of the Methods section \u201cCo-transfection of minigenes and antisense splice modulating oligonucleotides\u201d, the miniTK promoter was wrongly referred to as Minick. These corrections have been made in both the PDF and HTML versions of the article."} +{"text": "Dear Editor, we found that the publication on \u201cGenome characterization and mutation analysis of human influenza A virus in Thailand\u201d in the journal is very"} +{"text": "Computational and Mathematical Methods in Medicine has retracted the article titled \u201cInfluence of MRI on Diagnostic Efficacy and Satisfaction of Patients with Alzheimer's Disease\u201d [Disease\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiThe authors do not agree to the retraction."} +{"text": "The corrected 1) The authors would like to correct mistakes in the title paper \u2019.\u2018Then, the rate of racemization of the methyl (3) In the References section the title of reference [17] contains the misspelled word: \u201cStom\u201d. It should be: \u201cAtom\u201d.The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original publication has also been updated."} +{"text": "This article has been corrected at the request of the authors to edit the name of the PediLoc\u00ae Locking Cannulated Child Blade Plate to the correct name: PediLoc\u00ae Locking Cannulated Infant Blade Plate. In addition, \u201cChild-sized blade plates are made of stainless steel\u201d has been changed to \u201cInfant-sized blade plates are made of stainless steel\u201d.The authors deeply regret that this error was not identified and addressed prior to publication."} +{"text": "Journal of Healthcare Engineering has retracted the article titled \u201cSynergistic Effect of Stereotactic Radiotherapy Combined with Karelizumab on Patients with Advanced NSCLC\u201d [d NSCLC\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiThe authors do not agree to the retraction; the author Beibei Cheng could not be reached by the publisher using the e-mail address provided to the publisher with the article submission."} +{"text": "Experts in neonatal EEG and EEG technicians were also involved to revise the pertaining terminology. Finally, external referees with established experience in the interpretation of the EEG in children and adults revised the entire translation.Most of the terms has been thoroughly translated except those that have already come into common use which have been maintained in English, both single words and acronyms, the full list of which is reported with explanations at the end of the appendix.Dati demografici e anamnesi del pazienteRegistrazioneDescrizioneInterpretazioneAcronimiThe Italian version with facing text of the introduction and glossary of EEG terms as proposed by The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} +{"text": "The authors regret an error in the data processing leading to a swap of information in This mistake also led to a misinterpretation of the literature data reported in this table in the discussion. Indeed, the sentence beginning on line 25 of page 12529 (at the start of the penultimate paragraph of the Introduction section) is incorrect; the corrected text is:\u22123 mol L\u22121 (ref. 26)) and \u2264200 nm agglomerates at lower concentrations\u201d.\u201cThese colloids correspond to 1\u201320 nm particles at high silicate ion concentrations is also incorrect; the corrected text is:4,24,25\u201d\u201cIt is worth noting that no evidence of particle agglomeration was observed; that result is consistent with the results obtained for the other actinide silicate colloids above the silicic acid mononuclear wall.These errors do not affect the overall conclusions of the paper.The authors would like to apologize for these errors and any consequent inconvenience caused.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "This article was updated to correct a typo written in the \u201cDiscussion\u201d:\"Low CBF and CDO2 in the early phase were associated with unfavorable outcome, but this did only hold true for CBF in multiple logistic regressions and not in the vasospasm phase.\"but is supposed to be:CDO2 in multiple logistic regressions and not in the vasospasm phase.\"\"Low CBF and CDO2 in the early phase were associated with unfavorable outcome, but this did only hold true for"} +{"text": "In the article entitled \u201cMeasuring the level of compulsory hospitalisation in mental health care: The performance of different measures across areas and over time\u201d, Hofstad et\u00a0al.,\u00a0The number of compelled inpatients is necessarily less than or equal to the number of events in a period, and the magnitude of geographical variation can differ substantially between the two measures.We apologize for this error."} +{"text": "The authors would like to correct the keyword \u2018bare RNLF\u2019 to \u2018RNFL schisis\u2019 in their prior publication . The worThe authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "In the published article, an author name was incorrectly written as \u201cValentino Maria Merlino.\u201d The correct spelling is \u201cValentina Maria Merlino.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Journal of Healthcare Engineering has retracted the article titled \u201cCervical Spondylopathy and Lumbar Intervertebral Disc Herniation Coexist in Free Radical Metabolism and Focus Separation in the Body\u201d [he Body\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiWe were unable to contact the corresponding author on the email address provided to us."} +{"text": "Delusional idea disorders are a group of syndromes whose main or unique characteristic is the presence of consolidated delusional ideas that usually have a chronic character and do not fit into other diagnoses such as schizophrenia, affective disorder or other organic diseases. On the other hand, Charles Bonnet syndrome is an organ hallucinosis in whose context visual hallucinations may appear in patients with a visual deficit. Historically, it has been considered that the presence of another psychiatric condition is an exclusion criterion for the diagnosis of Charles Bonnet syndrome, although the presence of similar etiological and maintenance factors means that this situation of dignous exclusion must be reconsidered.The objective of the present communication is to study the current state of the topics \u201cdelusional disorder\u201d and \u201cCharles Bonnet syndrome\u201d. Another objective is to reconsider that the presence of previous or concurrent psychiatric pathology is an exclusion criterion for the diagnosis of Charles Bonnet syndrome..A bibliographic review on \u201cdelusional ideas disorder\u201d and \u201cCharles Bonnet syndrome\u201d has been carried out, as well as a discussion on the diagnostic and exclusion criteria, based on the etiopathogenic and maintenance factors.Both in \u201cdelusional ideas disorder\u201d and in \u201ccharles bonnet syndrome\u201d advanced age, social isolation and deficiencies in sense organs constitute etiological factors that facilitate the appearance of these syndromes and make their treatment difficult.Due to this, we consider that the appearance of another previous or present psychiatric illness should not be an exclusion criterion, both can appear in the same patient.No significant relationships."} +{"text": "An author name was incorrectly spelled as \u201cStella Maria Casciofierro\u201d. The correct spelling is \u201cStella Maria Cascioferro\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Computational and Mathematical Methods in Medicine has retracted the article titled \u201cEffect of Application of Treadmill Training on Metabolic Control and Vitamin D Level in Saudi Patients with Type 2 Diabetes Mellitus\u201d [ellitus\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiThe authors do not agree to the retraction; author Lamiaa K. Elsayyad could not be reached by the publisher using the email address provided to the publisher with the article submission."} +{"text": "In Table 3 of this article, the arrows of data under the column \u201cEffects of immediate cord clamping\u201d were missing. The complete Table 3 is shown as follows:The original article has been corrected."} +{"text": "Due to a production error, there was a mistake in The original version of this article has been updated."} +{"text": "Conflict of interest: \u201cThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u201d The correct conflict of interest appears below:In the published article, there was an error in the"} +{"text": "In the original article, there was an error in the Supplementary Material as published. There were spelling mistakes in the English translations of some of the terms in the Supplementary Material (p. 2).A correction has been made to:FlowD1a Je me sens capable de faire face aux exigences \u00e9lev\u00e9es de la situation.[I trust my ablity to meet the high demands of the situation].Correction [I trust my ability to meet the high demands of the situation].A correction has been made to:FlowD1b Je sens que je contr\u00f4le parfaitement mes actions.[I feel completly in control of my actions].Correction [I feel completely in control of my actions].The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original article, there was a mistake in two of the author's names. Two author names were incorrectly spelled as \u201cYu Hwang\u201d and \u201cChuqu Xiao.\u201d The correct spelling is \u201cYu Huang\u201d and \u201cChunqu Xiao.\u201d The original article has been updated.Table 2. Sets, calibrations and descriptive statistics regarding positive and negative rumors.\u201d But should be \u201cTable 2. Sets, calibrations and descriptive statistics after calibrations regarding positive and negative rumours.\u201d The corrected In the original article, there was a mistake in the title of \u201cThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "There was an error in the original publication . In the A correction has been made in the abstract and in the result section (eighth paragraph): the number \u201c12\u201d was changed with \u201c8\u201d. The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "In the published article Nannan Liu was not listed as a co-first author. This has now been rectified.affiliation 2. The name of the hospital just \u201cFuzhou Second Hospital of Xiamen University\u201d and not \u201cFuzhou Second Hospital Affiliated to Xiamen University\u201d.In addition, there was an error in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "There is an error in the Funding statement. The Funding number for \u201cthe National Natural Science Foundation of China\u201d was erroneously given as \u201c8197151950.\u201d The correct number is \u201c81973742\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Sample and Procedure and Descriptives sections in this article as originally published.Placeholders in the form \u201cxxx\u201d erroneously appeared in the The original article has been corrected."} +{"text": "Due to a production error, \u201cZhangfeng Zhong\u201d was not included as an author in the published article.The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "An animal ethics statement was missing from this paper. The following statement should be included: \u201cNo animals were used in this study, and ethical approval for the use of animals was thus deemed unnecessary.\u201d"} +{"text": "Dear Editor2 on the importance of a thorough assessment of the problem and the recognition of probable vaccination\u2010induced diabetes. On the other hand, we would like to add a note about another possible concurrent issue that could cause DKA in a vaccine recipient.We would like to share ideas on the publication \u201cDiabetic ketoacidosis shortly after COVID\u201019 vaccination in a non\u2010small \u2010cell lung cancer patient receiving combination of PD\u20101 and CTLA\u20104 inhibitors: A case reportThe authors confirm that there are no conflicts of interest."} +{"text": "Funding statement. The funding statement for the National Natural Science Foundation of China was displayed as \u201c32071145\u201d.In the published article, there was an error in the the National Natural Science Foundation of China, 32071142, 32271187.\u2019\u2019The correct statement is \u201cThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the originally published version of this manuscript, an incorrect image was used for Figure 5 in error. The \u2018GABA\u2019 circle for flatworms should be blue. This error has been corrected."} +{"text": "Computational and Mathematical Methods in Medicine has retracted the article titled \u201cSingle-Segment Lumbar Intervertebral Disc Nucleus Excision on the Stability of Lumbar Segmental Sagittal Plane\u201d [l Plane\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiThe authors do not agree to the retraction; author Xiaobiao Du could not be reached by the publisher using the email address provided to the publisher with the article submission."} +{"text": "In the published article, there was an error in the legend for 2O2\u201d. \u201cControl\u201d in In the published article, there was an error in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original publication of the article, the initial of Professor Stefan Priebe has been incorrectly published as \u2018P\u2019 instead of\u2019S\u2019. The correct author name is given in this erratum.The original article was corrected."} +{"text": "The authors report a correction of the first equation on page 12 . The \u201cminus\u201d operator should be \u201cplus\u201d in the equation as it shown on the following picture.The authors state that the correction does not affect the results and conclusions of the paper."} +{"text": "The COVID-19 resource centre is hosted on Elsevier Connect, the company\u2019s public news and information\u201d. The references have since been corrected in the published article."} +{"text": "Affiliation(s) [1]. Instead of \u201c,\u201d it should be \u201c.\u201dIn the published article, there was an error in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An author name was incorrectly spelled as \u201cSepideh Babanianmansour\u201d. The correct spelling is \u201cSepideh Babaniamansour\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Journal of Environmental and Public Health has retracted the article titled \u201cAssessment of the Knowledge Level of First Aid among Medical Students in Work Environment\u201d [ronment\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiThe authors do not agree to the retraction."} +{"text": "Computational and Mathematical Methods in Medicine has retracted the article titled \u201cAnalysis of the Role of Comprehensive Treatment Model in the Treatment of Prostate Cancer\u201d [ Cancer\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiThe authors agree to the retraction."} +{"text": "Coban for his interest in our study and for taking the time to express his concerns. The letter has discussed the use of anticoagulants and the method used for measuring mean platelet volume (MPV).In our study entitled \u201cSignificant decrease in plasma D\u2010dimer levels and mean platelet volume after a 3\u2010month treatment with rosuvastatin in patients with venous thromboembolism,\u201d we measured MPV using ethylenediaminetetraacetic acid (EDTA). Studies have shown that EDTA and citrate are similar when the time between blood collection and measurement is less than 1\u2009h which was consistent with our study.Taken all together, we tried to reduce the errors and the factors that may adversely affect our results."} +{"text": "Due to a production error, the corrections requested in the Corrigendum were not implemented in the original article. Furthermore, the title of the original article was listed as \u201cPinocembrin Decreases Ventricular Fibrillation Susceptibility in a Rat Model of Depression,\u201d but should have been \u201cPrognostic Values and Clinical Significance of S100 Family Member\u2019s Individualized mRNA Expression in Pancreatic Adenocarcinoma.\u201dThe publisher apologizes for this mistake. The original version of this article, as well as the original article, have been updated."} +{"text": "In the published article, an author name was incorrectly written as \u201cSimona Bunagu\u201d. The correct spelling is \u201cSimona Bungau\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "A large amount of scientific literature is forcing those who want to study the subject deeply. In general, the number of articles available exceeds thousands. It has become challenging both to dominate the current concept and to see the relationships between the developments that feed the concept. Visualization techniques based on bibliometric data help to gain an overview of the literature on complex research topics. The aim of this study is to examine the topic of \u201cpatient safety\u201d with a bibliometric analysis program. The data of 8372 articles obtained from the Web of Science database were analyzed with SciMAT2 software. Before the analysis, general findings regarding the raw data were brought to the fore. The strategic diagram and thematic development map have been analyzed in terms of 10-year periods covering the past 30 years. Five motor themes were identified in 1990-1999, four motor themes in 2000-2009 and nine motor themes in 2010-2019. The number of motor themes increased during the period and adverse events, which were the active subjects of the early periods, were replaced by new concepts over time. Bibliometric visualization tools make it possible to analyze the literature consisting of a large number of articles. This approach facilitates a person\u2019\u2019s understanding of a complex research topic such as patient safety and ensures that they are aware of new research directions or alternative research priorities. Patient safety is a multifactorial, multidimensional, and interdisciplinary research subject [st century\u201d published in 2001 [ subject . After t subject and the in 2001 , the con in 2001 .Due to its complex character and its relation with other concepts, the number of publications on patient safety has increased over the years. The growing number of publications makes it difficult to look at patient safety literature with a comprehensive overview. When concepts such as equipment safety, safety culture, adverse events, error reporting, and medical errors are searched together in databases along with the notion of patient safety, the search results result in hundreds of thousands of articles.When bibliometric studies on patient safety were examined; it is seen that concepts such as medication errors and adverse errors , the relThe data of the publications analyzed in the study were downloaded from the Web of Science (WOS) Core Collection database. On 25.09.2020, 8372 publications were reached during the search with the term \u201cpatient safety\u201d on the \u201cTitle\u201d tab in the WOS database and the data of these publications were downloaded in plain text format. The downloaded data were uploaded to the SciMAT program for scientific mapping analysis. As a result of the examination, 30 publications that do not contain year information and 44 publications of 1989 and earlier, which do not contain the data required for analysis, were excluded from the analysis. To see the development periodically in the analysis, 8298 publications are divided into the periods 1990\u20131999, 2000\u20132009, and 2010\u20132020. The analysis included 84 publications in the first period, 2009 in the second period, and 6205 in the third period.In the analyzes, words were used as research units. Before the analysis, 9962 keywords used in publications were grouped by considering singular-plural, abbreviation, misspelling, and same meanings. As a result of the analysis, data reduction was made to ensure that the findings can be interpreted. In the analysis, \u201cco-occurrence\u201d in matrix type, \u201cequivalence index\u201d in normalization measurement, \u201csimple centers algorithm\u201d in cluster algorithm, \u201ccore mapper\u201d options were used in the mapping. The h-index and the total number of citations were selected in quality measurement. \u201cInclusion index\u201d options were used in the thematic development map and overlap map.\u2022Approximately 45% of the studies on patient safety have been carried out in the USA.\u2022The most cited three patient-safety-related author/article topics are; communication and information transfer among physicians, information technology, and infection control.\u2022Patient-safety related motor themes have manifested themselves in the last decade as \u201cpatient safety,\u201d \u201ceducation,\u201d \u201cclimate,\u201d \u201csystem,\u201d \u201cmortality,\u201d \u201coperating room,\u201d \u201cvalidity,\u201d \u201cburnout,\u201d and \u201cprimary care.\u201dResearch findings were evaluated visually with strategic diagrams, thematic networks, overlap maps, and thematic development maps. In the strategic diagram, the emerging themes can be located in four different areas according to their centrality and intensity levels: Centrality is related to the outer relations of the theme, and themes shift to the right side in the diagram as the level of relationship with other themes increases. Density is related to the inner relations of the theme, and themes with increasing levels of relationship in themselves move upward in the diagram. The characteristics of the groups with these themes are as follows:\u2022Themes with high centrality and density in the upper right area where motor themes are located\u2022Themes with high centrality but low density in the lower right area where basic and transformational themes are located\u2022Themes with low centrality but high density in the upper left area where developed and isolated themes are located\u2022In the lower left area where emerging or disappearing themes are located, there are themes with low centrality and density.In thematic networks where the relationships between themes in the theme cluster are evaluated, the size of the themes varies according to the number of publications. The thickness of the lines varies according to the degree of the relationship. In the overlap map where the numerical development of the keywords used in the publications is evaluated periodically, the number and percentage of keywords used in the previous period and transferred to the next period, the number of keywords that have just started to be used, and the number of keywords that were used in the previous period but not in the relevant period can be seen. In the thematic development map, the relationships of the themes between periods are evaluated. Straight lines on the map indicate that the same keywords are shared with the theme names. Dashed lines, on the other hand, indicate that common words are shared except for the theme names. The thickness of the lines varies according to the degree of the relationships, and the size of the themes depends on the number of publications \u201315.We evaluated the findings under two headings. Firstly, the number of publications by years, the number of publications by country, the most cited, most productive authors, and the most used keywords in the research are given under the heading of general findings. Secondly, basic themes and strategic diagrams were analyzed according to the results of SciMAT software.General Findings; The distribution of the publications downloaded from the WOS database for analysis by years is presented in th with 51 publications. English, German, and Spanish were the most widely published languages of publications, and Turkish was ranked 10th with 5 publications.The distribution of publications downloaded from the WOS database by country is presented in It was determined that the total number of citations of 8372 publications downloaded from the WoS database was 87,230. This number was 70,889 when self-citations were excluded and h index value of these publications was determined to be 111. The most cited publication information is included in Information on the most productive authors is presented in The strategic diagram for the period 1990\u20131999, which emerged as a result of the analysis, is given in The strategic diagram for the period 2000\u20132009 obtained as a result of the analysis is shown in According to the findings related to the 2000\u20132009 period themes, 202 publications were made related to the theme of \u201cadverse drug events,\u201d one of the motor themes of this period. It was determined that the total number of citations of these publications was 9.521 and the h-index value was 51. After the \u201cAdverse drug events\u201d theme, it is seen that the theme with the most publications, the most citations and the highest h index is the \u201cadverse events\u201d theme.The strategic diagram for the period 2010\u20132020 obtained as a result of the analysis is shown in The numerical development of keywords in publications evaluated in the study by periods is presented in Thematic development map, in which the relationships between themes in the analyzed periods are evaluated, is presented in The theme of \u201cphysicians\u201d in the second period showed a relationship with the \u201cadverse events\u201d and \u201csafety\u201d themes from the first period and the \u201cpatient safety,\u201d \u201ceducation,\u201d \u201cprimary care,\u201d \u201cleadership,\u201d \u201cclaims\u201d themes from the last period, as well as the \u201crisk\u201d theme in the first and last period. There is a strong relationship between the \u201cadministrative data\u201d theme, which is associated with the \u201csurgery\u201d theme from the first period, and the \u201cvalidity\u201d theme from the last period. The \u201coperating room\u201d theme, which is among the basic and transformational themes in the second period and one of the motor themes in the last period, shows a strong relationship between itself. However, it shows relations with the themes of \u201chistory\u201d from the first period, \u201cclimate\u201d and \u201cadverse drug events\u201d from the last period.It is seen that the \u201csurgical care\u201d theme in the second period frequently shared other keywords other than the basic keywords with the \u201cepidemiology\u201d theme from the last period. It is seen that the \u201cnursing home\u201d theme in the second period has a stronger relationship with the \u201clong term care\u201d theme in the recent period and it is also associated with the theme of \u201cnursing.\u201d At the same time, it is seen that the theme of \u201cnursing\u201d is related to the themes of \u201cinformatics\u201d and \u201ccritical incidents\u201d from the second term.The theme of \u201cgeneral practice\u201d that emerged in the second period shares the basic keywords with the theme of \u201cprimary care\u201d and \u201cadverse drug events\u201d from the last period. The \u201cworkload\u201d theme, which is associated with the \u201cenvironment\u201d theme from the first period, also shows a strong relationship with the \u201cburnout\u201d theme from the last period. It is observed that the \u201crisk\u201d theme, which took place in the last period, had a strong relationship with the \u201cvenoes thromboembolism\u201d and \u201cguidelines\u201d themes from the second period, and at the same time, the \u201cguidelines\u201d theme was associated with the \u201cmortality\u201d theme from the last period.It is seen that the \u201cpediatrics\u201d theme, which is associated with the \u201cchildren\u201d theme from the first period, is associated with the \u201csedation\u201d theme from the last period. It is observed that the \u201cadmission\u201d theme in the second period showed a strong relationship in the form of basic keyword sharing with the themes of \u201cevents\u201d and \u201cadverse drug events\u201d from the last period.The results of the bibliometric analysis made through the SciMAT program in the context of patient safety show that there is a stagnation in studies conducted in recent years (2014\u20132018). According to the findings, most of the studies were conducted in the USA and published in English, and \u201cpatient safety,\u201d \u201ccare,\u201d \u201cadverse events,\u201d \u201cquality\u201d and \u201cerrors\u201d were the most used phrases in the studies.According to the findings in this study, the engine themes focused on \u201cadverse event\u201d and \u201csafety\u201d in the 1990s. In the 2000s, it evolved into \u201cinfection control,\u201d \u201chospital-acquired infections,\u201d \u201cadverse drug events,\u201d \u201cculture.\u201d In the 2010s, it emerged as \u201cpatient safety,\u201d \u201ceducation,\u201d \u201cclimate,\u201d \u201csystem,\u201d \u201cmortality,\u201d \u201coperating room,\u201d \u201cvalidity,\u201d \u201cburnout,\u201d \u201cprimary care.\u201d It is seen that the issues that were not included in the studies in the 1990s started to be taken into consideration in the following years and issues such as patient safety, education, system, climate were included in the studies. According to the thematic development map data, it reveals that the adverse event theme has a strong relationship with the \u201cpatient safety\u201d theme.It is seen that studies conducted in the context of patient safety have improved over time, and themes and words that were not previously included in the studies have begun to be taken into account over the years. It is noteworthy that one of the expressions in which the theme of patient safety is most often used together and the strong connection between them is \u201cadvertise event.\u201d However, the theme of \u201cquality improvement\u201d is another theme that has a strong connection with patient safety. Studies conducted in the context of patient safety draw attention to the necessity of efforts to prevent adverse events in health institutions and to improve the quality of health care, and to increase the education and knowledge levels of patients and healthcare professionals. Besides, it was underlined that the risk management mechanisms should be operated by health administrations and the prevention activities should be carried out before the incident occurs in the institutions. The importance of analyzing the incident reports obtained with the security reporting systems to be established, and making the necessary arrangements were emphasized in this study. It should not be forgotten that every precaution to be taken to ensure patient safety can be a means of saving a life.As a result, a large amount of literature can be analyzed using bibliometric data. Visualization of these data using tools such as SciMAT makes it possible to obtain a broad overview of the structure of the literature on a particular topic. This approach can be very useful for better understanding of a complex research topic such as patient safety. Other complex multidimensional research areas can be analyzed similarly. This method of literature analysis can help suggest new research directions or alternative research priorities."} +{"text": "This article was updated to correct Nicol\u00f2 Fabbri's name in the listing of the ERCOLE Study Group (in Acknowledgments)."} +{"text": "Instead of \u201c[The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Some \u2026 may look at the depleted nature of Russia\u2019s military after its invasion of Ukraine and incorrectly surmise that defence spending increases are not that necessary after all."} +{"text": "Funding statement where in the funding source for author \u201cEleanor Longden\u201d was omitted. The correct Funding statement appears below.In the published article, there was an error in the"} +{"text": "On the first publication of MCO273, the authors noted that images of SGC\u20107901 group in Figure"} +{"text": "In the published article, the affiliation of \u201cLiming Cao\u201d was incorrect. Instead of affiliation 5, they should have affiliation 4.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The authors regret that the title of the article that appears in the original article is incorrect. The correct article title is \u201cLoss\u2011of\u2011function manipulations to identify roles of diverse glia and stromal cells during CNS scar formation\u201d which is now captured in this erratum article.The original article has been corrected."} +{"text": "Journal of Healthcare Engineering has retracted the article titled \u201cStudy on the Effect of Combination of Prednisone and Vitamin D in the Treatment of Primary Nephrotic Syndrome in Children\u201d [hildren\u201d due to cFollowing an investigation conducted by the Hindawi Research Integrity team , signifiThe authors do not agree to the retraction."} +{"text": "In the title of this article, there is a typographical error in the word \u201cinvestigation\u201d. The correct title is: An investigation into the epidemiology of chikungunya virus across neglected regions of Indonesia."} +{"text": "Recently, we conducted an examination of our published articles and found that a representative picture Figure E was inc"} +{"text": "Affiliation for Samha Al Ayoubi2. Instead of \u201cSamha Al Ayoubi 2\u201d, it should be \u201cSamha Al Ayoubi1\u201d.In the original article, there was an error in the The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This study aims to identify the trajectories of mental health among older adults and to examine the association between neighborhood characteristics and the identified trajectories. Data came from nine waves of the National Health and Aging Trend Study . Group-based trajectory modeling was used to identify the trajectories of depressive symptoms and anxiety respectively. Multinomial logistic regressions were used to examine the relationship between neighborhood and trajectories. Four trajectories were identified, namely \u201cconstantly low\u201d \u201cincreasing\u201d \u201cdecreasing\u201d and \u201cconstantly high\u201d. Results show that higher levels of social cohesion and the absence of physical disorder in the neighborhood demonstrated beneficial and protective effects on older adults\u2019 mental health trajectories. The findings suggest that social cohesion may be an important social capital to cope with negative mental health experiences. On the contrary, negative physical features may be a stressor that adversely affect older adults\u2019 mental health trajectories."} +{"text": "To the Editor:Dr Jacobs is a Consultant for SpecialtyCare and the American Academy of Dermatology. All other authors reported no conflicts of interest.Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.The https://ipccc.net/) has been seeking to produce such names for the various congenitally malformed hearts, including the bicuspid aortic valve.We congratulate the authors of the recently published \u201cInternational Consensus Statement on Nomenclature and Classification of the Congenital Bicuspid Aortic Valve and Its Aortopathy.\u201dWe also agree that classifications should be based on the English language. In this regard, \u201ccusp\u201d is currently used in a confusing fashion. A \u201cTower of Babel\u201d was identified with regard to whether the moving parts of the aortic root should be described as \u201ccusps\u201d or \u201cleaflets,\u201d with \u201cleaflet\u201d being preferred.The interleaflet triangles, given little attention in this consensus, are described as being \u201cinter-cusp.\u201d,Problems also exist regarding the \u201cannulus.\u201d The consensus, in keeping with the German surgeons, agree this should be represented by the virtual basal ring.Only by using an accurate and descriptive account of the normal anatomy of the aortic root will it be possible to achieve the hoped-for consensus."} +{"text": "The Preface to Volume 1 contains a brief summary of the topic for both issues [This issue is the second part of a two-part issue on \u2018The future of mathematical cosmology\u2019. Volume 1 can be found at"} +{"text": "The initial video did not include the final result after reconstruction. The corrected final Video 2 file has been inserted to replace the incomplete version and is now available online.In the article by Lalonde et al, \u201cSimple Effective Ways to Care for Skin Wounds and Incisions,\u201d published as e2471 in the October 2019 compendium"} +{"text": "As requested by the Editorial Office, the authors remove the scientific consortium \u201cCamille Nous\u201d from the author list and the Author Contributions section in the published paper . To reco"} +{"text": "The authors have noticed an inadvertent error in our article, \u2018\u2018Patterns of Multimorbidity in Adults: An Association Rules Analysis Using the Korea Health Panel\u201d .The published Figure 2b is a result of a network analysis regarding men, but it should be changed to one regarding women. We have attached a corrected version of The authors would like to apologize for any inconvenience caused."} +{"text": "There was a small mistake in the sixth paragraph of the Discussion: the positions of two words (\u201cpositively\u201d and \u201cnegatively\u201d) should be exchanged. The correct expression is \u201cIn aWe apologize for any inconvenience caused to the readers by this mistake."} +{"text": "Behavioural Neurology and the authors have retracted the article titled \u201cPropofol Causes Consciousness Loss by Affecting GABA-A Receptor in the Nucleus Basalis of Rats\u201d [of Rats\u201d , due to of Rats\u201d , 3. The The authors apologize for this error and agree to the retraction of the article, which is also with the agreement of the editorial board."} +{"text": "While the euro officially came into being in 1999, it was the introduction of euro notes and coins 20 years ago in January 2002 that made the common currency a tangible reality for European citizens. The circle of member states has since grown from 11 to 19, and a growing section of the population no longer has any personal experience with a \u201cnational\u201d currency, yet the debate on the legal and institutional framework underpinning the common currency has never gone away."} +{"text": "There is an error in the article title. The correct title\u00a0is\u00a0The Role of NKG2D in Vitiligo.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the title of this article initially published, the spelling of \u2018Traige Tool\u2019 was unintentionally misprinted as \u2018Triage Toll\u2019. The authors sincerely regret this error. The title should be corrected as follows: The effectiveness of the South African Triage Tool use in Mahalapye District Hospital \u2013 Emergency Department, Botswana."} +{"text": "The original version of this article was published with an author missing from the author list., Mark Stoov\u00e9 should have been included. This has now been corrected in the original version."} +{"text": "There is an error in the Funding statement. The grant numbers for the Funding source \u201cThe National Nature Science Foundation of China was incorrectly written as \u201cGrant Nos. 7181101155 and 52002244.\u201d The \u201cGrant No. 7181101155\u201d in the original article is actually an application number rather than a grant number. The correct number for \u201cNational Natural Science Foundation of China\u201d is \u201cGrant Nos. 71961137006 and 52002244.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "In the original publication, the section \u201cAcknowledgments\u201d is not be included. The Acknowledgments section is given in in this correction.Acknowledgments This research was partly supported by AMED under Grant Number JP18ck0106463."} +{"text": "The authors would like to remove the scientific consortium \u2018Camille Nous\u2019 from the author list and the Author Contributions section in the published paper , as sugg"} +{"text": "In the original article, there was a mistake published in In the titles to Figure 2b and Figure 4b, \u201cAntiphase\u201d changes to \u2018anti-phase\u201d (the hyphen is used throughout the text).The last keyword should be \u201cmodel\u201d instead of \u201cnodal\u201d. The authors and editorial office would like to apologize for any inconvenience caused to the readers by these changes and state that the scientific conclusions are unaffected. The original article has been updated."} +{"text": "As well as having affiliations 1 and 5, he should also have \u201cThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Discussion and sub-section TBA and CVD, BAs in Lipid and Glucose Metabolism. The correction has been implemented and the \u201chigh-\u201d was removed from both places.Due to a production error, \u201chigh-\u201d was inserted in the beginning of the first paragraph of The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Figure 3 as published. \u201cThe number in the IRb region of Circaea cordata needed to be corrected.\u201d The corrected Figure 3 appears below.In the original article, there was a mistake in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original publication of the article, the table 1 was published with a misaligned value under the column head \u201cHistory of surgical procedure\u201d. The correct Table The original article has been corrected."} +{"text": "In the published article, the \u201cParameter Sensitivity\u201d formula was erroneously given as:Results section entitled \u201cLocal Sensitivity Analysis\u201d should instead read as:However, the correct \u201cParameter Sensitivity\u201d formula in the first paragraph of the The correct formula has been used to perform the calculations reported in the publication.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The authors wish to make the following corrections to this paper :There is a mistake in a unit of DIP in Surrounding Sea Water provided in Table 1. The unit of DIP in Surrounding Sea Water listed in the original version of the article was \u201cmM\u201d.The correct version should be as follows:The correct unit of DIP in Surrounding Sea Water in Table 1 is \u201c\u00b5M\u201d.The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "In the original publication of the article , in TablPeople with mental illness\u201d, third paragraph, the first sentence was published incorrectly. The corrected sentence should read as \u201cMy Recovery is a peer-led education program developed by Wellways Australia for people living with mental illness and is offered in Darwin through an auspice arrangement with the Northern Territory Mental Health Coalition\u201d.Under the subheading \u201c"} +{"text": "In the published article, there was an error regarding the affiliation superscripts for authors Tao Yang and Xiaohui Xu. For Tao Yang, instead of \u201c4,\u201d It should be \u201c1,\u201d and for Xiaohui Xu, instead of \u201c3\u201d it should be \u201c4.\u201dThe authors apologize for these errors and state that they do not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "In the published version of this article, there was an error in the second sentence of the section \u2018Properties\u2019.The sentence \u2018It is a facultative aerobe that grows via aerobic respiration and anaerobic respiration with nitrate as the terminal electron acceptor.\u2019 should have read \u2018It is a facultative anaerobe that grows via aerobic respiration and anaerobic respiration with nitrate as the terminal electron acceptor\u2019.The authors apologise for any inconvenience caused."} +{"text": "Following the publication of the original article , the autThe \u201cAcknowledgements\u201d section has now been updated to include the following statement: \u201cThe authors thank the Department of Innovation, Research, University and Museums of the Autonomous Province of Bozen/Bolzano for covering the Open Access publication costs\u201d.In the \u201cFunding\u201d section the sentence \u201cThere was no other funding supporting this manuscript\u201d has been replaced by the sentence \u201cThe Department of Innovation, Research, University and Museums of the Autonomous Province of Bozen/Bolzano covered the Open Access publication costs\u201d.The original article has already been corrected as above."} +{"text": "In the published article the authors equal contribution statement is incorrect in the foot note. The correct statement should be read as \u201cChiwei Xu and Zhengwei Yang have contributed equally to this work\u201d."} +{"text": "The Introduction to Part I contains an overview of both issues [This issue is the second part of a two-part issue on \u2018Voice modulation: from origin and mechanism to social impact\u2019. Part I can be found at"} +{"text": "In the article titled \u201cThe Effect of Art Therapy and Music Therapy on Breast Cancer Patients: What We Know and What We Need to Find Out\u2014A Systematic Review\u201d , there w"} +{"text": "In the version of this article initially published, Drienie D. Janse van Rensburg\u2019s first name was misspelled as \u2018Driene\u2019 and the initial omitted. The error has been corrected in the PDF version of the article."} +{"text": "They intended for this citation to reference work from Camp\u00e0s and colleagues but inadvertently included a different Kim et\u00a0al., 2021, study from Style and colleagues in the references instead. This error has now been corrected in the online version of the paper. We apologize for any confusion this may have caused."} +{"text": "Unfortunately in the original version of the article, the Figure\u00a0The original article has been corrected."} +{"text": "In the original article's Funding statement, the stated New Breeding Technologies Development Program Project number (\u201cPJ04781022020\u201d) was incorrect. The correct number is \u201cPJ014781022020\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Due to a production error, there was a mistake in The original article has been updated."} +{"text": "Funding section in the published article has been updated as presented below.In the original article, the authors neglected to acknowledge the funding provided by \u201cStiftung S\u00fcdtiroler Sparkasse\u201d (to Raphael Tiziani). The This work was supported by grants from the Free University of Bolzano (NUMICS TN200E). \u201cThe doctoral fellowship of RT was funded by Stiftung S\u00fcdtiroler Sparkasse.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Due to a production error, there was an error in affiliations 1 and 4. Instead of \u201cThe Second Xiangya Hospital of Central South University,\u201d it should be \u201cXiangya Hospital of Central South University.\u201d The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "In the article titled \u201cPrognostic Role of Serum Amino Acids in Head and Neck Cancer\u201d , authorsThe error was introduced during the production process of the article, and Hindawi apologises for causing this error."} +{"text": "The first sentence of the conclusion in the abstract had a comma instead of a period as shown below \u201c\u2026 without consultation time. but appears unlikely\u2026\u201d. This has now been corrected in both the online PDF and HTML versions of this article. The authors apologise for this error.In the original publication,"} +{"text": "There is an error in S3 FileThis is a TSV file where each line corresponds to all the GenBank assembly accession used in this study for each \u2018species id\u2019 in the NCBI taxonomy.(TSV)Click here for additional data file."} +{"text": "Figure 2 appears below.In the original article, there was a mistake in The authors apologize for this mistake and state that this does not change the article\u2019s scientific discussion and conclusions in any way. The original article has been updated."} +{"text": "The authors did not receive approval for publishing a translated version of the article, which was previously published in Chinese in Chinese Journal of Orthopaedics and Medicine was not informed that the submission was a translated version of a previously published article.The article, \u201cConservative management of avascular necrosis of the metacarpal head: A case report and brief review\u201d,"} +{"text": "Funding Statement. The correct number for \u201cNational Natural Sciences Foundation of China\u201d is \u201c81673817\u201d.There is an error in the The authors apologize for this error and state that this does not change the scientific conclusion of the article in any way. The original article has been updated."} +{"text": "This Commentary describes some upcoming changes to the submission and payment procedures to the Biophysical Society of Japan\u2019s English language journal \u201cBiophysics and Physicobiology\u201d (BPPB) that will facilitate a much easier and cheaper publishing experience for all scientists\u2014whether they be Japan-based or located internationally. The Biophysical Society of Japan (BSJ) runs two publishing vehicles for biophysical content, the Japanese language \u201cSeibutsu Butsuri\u201d and the English language \u201cBiophysics and Physicobiology\u201d (BPPB) BPPB . The latAuthors will be asked to submit their manuscript using a formatting template that can be downloaded from the web page of \u201cInstruction for Authors\u201d BPPB .A manuscript transfer system (B2J) from bioRxiv to the BPPB allows authors to save time by transmitting their manuscript files and metadata directly from bioRxiv to the BPPB (more can be read about this at BioRxiv ).The BPPB submission site which uses the S1M (ScholarOne Manuscripts) system . Then, the manuscript will be published on-line within a week using the service of \u201cAdvance Online Publication\u201d by the J-STAGE.The manuscript, which appears as the Advance Online Publication, is examined by the authors with a request for page proofing. During this final copy editing/page proofing stage, the authors are requested only to confirm the PDF file with typically only a single round for changes to be made by the publication office.From October 2021, the publishing procedures of the BPPB journal have been altered to facilitate more rapid and cheaper publication of each accepted article than before. The full details can be found in the updated \u201cInstruction for Authors\u201d on the web page of the BPPB BPPB and onlyDouble column setting is changed to single column settingThe bibliographic style of the Reference list is slightly changed without using \u201citalic\u201d or \u201cbold-face\u201d fonts.From Volume 19 onwards (published in 2022), each article will be identified by the newly introduced \u201cArticle ID,\u201d not by page numbers.The E-mail address of the corresponding author will not be the main identifier. Instead, the ORCID iD ORCID will be Authors must submit a \u201cGraphical Abstract\u201d except for articles in the category of \u201cEditorial\u201d or \u201cCommentary and Perspective.\u201dThe above procedures will allow BPPB to greatly reduce the publication time and cost. The use of a template will, however, lead to a change in the style of articles published in BPPB as follows:The BPPB Editorial Board Members hope that such simpler and cheaper to the author systems will allow BPPB to continue to attract a broad range of biophysical content submissions, both from nationally based and internationally based researchers. We encourage you to take a look at the journal and the exciting range of original and reviewed content that it offers BPPB ."} +{"text": "Following the publication of the original article it was bAuthor Dairong Cao\u2019s correct affiliation is \u201c3. Department of Radiology of First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China\u201d.This is shown next to the author\u2019s name in the author list of this Correction and has also been updated in the original article."} +{"text": "The decline of \u201cnatural real interest rates\u201d during the last three decades is a common phenomenon in all advanced economies and can be explained by a number of structural factors: the downward trend in potential growth; population ageing, which has led to higher savings rates in many countries; and the rising inequality in the distribution of wealth, which also increases the average savings rate."} +{"text": "The following information is missing from the Funding statement: The publication of this article was funded by the OpenAccess Publication Fund of Freie Universit\u00e4t Berlin."} +{"text": "The following text was removed from the abstract to improve clarity: \u2018enhancer and narrows the diagnostic interval\u2019. The HTML and PDF versions of the Article have been corrected.\u201d"} +{"text": "With the agreement of the handling editor, the corrected version of In the article titled \u201cEvaluation of the Genotoxic Potential against Ha Leaf\u2009\u201d , the inc"} +{"text": "There were mistakes in the calculation of percentage in lines \u201cProportion of HbA1c <7.5%\u201d and \u201cProportion of HbA1c \u22659.0%\u201d and in column \u201cResident\u201d and \u201cMigrant\u201d. The corrected | HbA1c in childhood DM patients in east China appears below.In the original article, there was a mistake in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "In the original article, there was an error in the Funding section. We neglected to include \u201cNational Key R&D Program of China \u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Gon\u00e7alves\u201d.In the original article, we neglected to include the funder The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The authors of the original publication would like to highlight some typographical errors from their article that may potentially cause some problems with interpreting parts of it.\u03bc, \u03c3, \u03b1, \u03b2, and \u03b8 should all be lower case, as should the r describing the negative binomial size. A corrected version of the table is shown belowThe first error is in The second error concerns the likelihood equations (the equations immediately following the text \u201cwith their likelihood given by\u201d). All of the text here is correct, but the last pieces of text in each equation is in the superscript, and should not be. For the first equation, this is everything including and following the word \u201cif\u201d, and for the second equation this is the word \u201cotherwise,\u201d Both of these should be rendered at the same level as the main part of the equation, and not in the superscript. The equations should appear as they do below."} +{"text": "In the article titled \u201cCorrection of a Class III Malocclusion with a Functional Shift and Severe Crowding\u201d , the namAdditionally, in Section 2.2 of the article body, \u201cThe type of anchorage will be minimal in both the upper and lower arches\u201d should be corrected to \u201cThe type of anchorage will be maximum in the upper arch and minimum in the lower arch.\u201dThere were errors in Figures"} +{"text": "Following the publication of the original article , the aut\u201cThe authors would like to acknowledge the support of GE Healthcare and the University of Pisa for proving the MR fingerprinting sequence and analysis software\u201d.The original article has already been corrected as above."} +{"text": "Following publication of the original article , the autThe incorrect author\u2019s name is: Bernarnd Hernandez;The correct author\u2019s name is: Bernard Hernandez;The author group has been updated above and the original article has been"} +{"text": "BioMed Research International has retracted the article titled \u201cConstruction and Immunogenicity of DNA Vaccines Encoding Fusion Protein of Porcine IFN-\u03bb 1 and GP5 Gene of Porcine Reproductive and Respiratory Syndrome Virus\u201d [e Virus\u201d , the artThe authors responded to explain that different shapes in the same lane may be due to the machine and electrophoresis, however, it was determined that this was not a satisfactory response, and the article is therefore being retracted with the agreement of the Editorial Board.The authors agree to the retraction and the notice."} +{"text": "In the Materials and methods section, there is an error in the first sentence of the first paragraph. The correct sentence is: The study and procedures were approved by the Institutional review board at Centro Interamericano de Investigaciones Psicol\u00f3gicas y Ciencias Afines (CIIPCA) [19\u201303]."} +{"text": "This change is marked in bold in the updated table below.In the original published version of the paper of Giallauria Table 1. Characteristics of the trials includedFigureFigureFigureFigureThere were also changes noted in"} +{"text": "RELAFUS\u201d have been amended as this was erroneously applied to the genes and proteins.The italicized terms of \u201cIn the original publication of the article [1] there were errors introduced during the publication process involving the italic emphasis. These errors are as followed:"} +{"text": "An author name was incorrectly spelled as \u201cRoland von Kaenel.\u201d The correct spelling is \u201cRoland von K\u00e4nel.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "On behalf of all authors, I would like to reply as follows:"} +{"text": "In the article titled \u201cImpact of Diabetic Ketoacidosis on Thyroid Function in Patients with Diabetes Mellitus\u201d , the autThe authors and the editorial board agree to the publication of the corrigendum."} +{"text": "Due to a production error, there was a mistake in The original version of this article has been updated."} +{"text": "The correct spelling is \u201cDei Tos AP\u201d.An author name Angelo Paolo Dei Tos was incorrectly spelled in the citation as The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "There is an error in the Funding statement. The correct number for Zhejiang Provincial NaturalScience Foundation of China \u201cNo. Q19H280028\u201d is \u201cNo. LQ19H280007.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Unfortunately, the given name and family name of the third author was incorrectly tagged in the xml data, therefore it is abbreviated wrongly as \u201cDusseldorp IV\u201d in PubMed. The correct given name is Ingeborg and family name is van Dusseldorp."} +{"text": "The name of the second author \u201cNing Zhang\u201d was incorrectly spelled as \u201cNing Zang\u201d in the article when published originally.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original article, we neglected to include the funder \u201cEuropean Union\u2019s Horizon 2020 research and innovation programme under the Marie Sk\u0142odowska-Curie grant agreement No. 847476 to NP.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Funding statement. The correct funding number for \u201cXZ\u201d is \u201c81620108014.\u201dThere is an error in the The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Upon the original publication of this article, errors in \u201cTable 1. Characteristics of habitual and non-habitual nappers from screening week\u201d were noted and list in this erratum.Table 1 has been updated as follows online:The publisher would like to apologize for any inconvenience caused to the reader."} +{"text": "The decision tree boxes \u201cAfrican American OR ACE inh intolerant\u201d and \u201cNot African American AND ACE inh tolerant\u201d were reversed, and the abbreviation \u201cACE inh\u201d instead of \u201cACEi\u201d was used. The corrected appears below.In the original article, there was a mistake in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "This article retracts the publication \u201cAchromobacter xylosoxidans in a child with a polymalformative syndrome: a case report\u201d by Mehdi Borni et al. for instances of image manipulation and plagiarism. It appe\u201cNosocomial Achromobacter xylosoxidans Infection Presenting as a Cavitary Lung Lesion in a Lung Cancer Patient\u201d [Secondly, figure 3 Panel B is similar to Figure 4 in the article Our investigation additionally uncovered other expression of concerns of image manipulation and theft in articles published by author Mehdi Borni ,5.The authors could not provide a reasonable explanation for our findings and do not agree with the retraction. The PAMJ regrets that these grave violations were not identified before publication and sincerely apologizes to the scientific community."} +{"text": "First, far from \u201cdeliberate selection of data,\u201d we followed standard snowball methodology for searNothing in Jenkins\u2019 letter contradicts our conclusion that he and his colleagues presented the data from the 16 Cities Study in a way that conformed to the stated objective of the Tobacco Institute\u2019s \u201cOSHA Projects\u201d to \u201cencourage adoption of a ventilation standard and to discourage adoption of a smoking ban or of a standard that requires separate ventilation for areas where smoking is allowed\u201d . Indeed,"} +{"text": "EHP [Environ Health Perspect 112:A788 (2004)], the need for full disclosure of all potential conflicts of interest by all coauthors contributing to a publication in EHP is commendable and obviously needed. Might I take this one step further and suggest that all reviewers of EHP manuscripts be required to sign a form listing all of their potential conflicts of interest.Concerning your editorial, \u201cEmbracing Scrutiny,\u201d in the October issue of"} +{"text": "We read with great interest \u201cChronic Beryllium Disease and Sensitization at a Beryllium Processing Facility\u201d . We wish3\u201d and sensitization were constant across all the categories of exposure used by a) organization and cleanliness of the workplace; b) control of the upper range of air level exposure using engineering and respiratory protection; c) control of beryllium migration from the work process to the worker, the work area, and outside the facility; d) detailed training of workers; and e) management and worker commitment to effective program implementation. In the facility studied by"} +{"text": "The use of the term \u201cAmericas\u201d in the context of this article could co"} +{"text": "The article \u201cEight Americas: Investigating Mortality Disparities across Races, Counties, and Race-Counties in the United States\u201d reports Consider recent findings that speak to health differences within the nominal category of \u201cAsian.\u201d As a part of the Center for Disease Control and Prevention's Racial and Ethnic Approaches to Community Health (REACH) 2010 program [A 2002 representative survey of Cambodian adults over age 25 in Lowell, Massachusetts found thIn short, existing findings indicate how diverse the health data can be within the overall category of \u201cAsian.\u201d The authors are to be applauded for their recognition of how misleading it can be to treat the categories of \u201cblackness\u201d or \u201cwhiteness\u201d in undifferentiated ways. Unfortunately they have failed to extend that same understanding to the analysis they select for the category of Asians. As researchers and policy makers use the \u201cEight Americas\u201d study to guide their efforts, the result could well be misleading interpretations that do a disservice to those very groups within the \u201cAsian\u201d category who face daily struggles with significant health problems and poor access to health care."} +{"text": "Turner and Tram\u00e8r provide a cogent argument in favor of the ethical use of placebo controls despite \u201cproven effective treatment\u201d . HoweverPLoS Medicine Debate is the value of placebo controls in early \u201cproof of concept\u201d efficacy trials, despite the existence of established treatment. The efficiency of seeking a rigorous efficacy signal before moving on to larger-scale trials (and exposing as few subjects as possible to drugs that might not work or turn out to be toxic) is a valid ethical reason for using placebo controls, provided subjects are not exposed to undue risks of harm from withholding established treatment [Another issue not discussed in this reatment ."} +{"text": "EHP in the past explored two ideas in this regard. In the first article, we (a) that ferritin has a stable magnetic moment of 3.8 Bohr magnetons, and b) that on the basis of reports from The article \u201cMagnetic-Field\u2013Induced DNA Strand Breaks in Brain Cells of the Rat\u201d by icle, we pointed This is an intriguing area of inquiry at the scientific level that may also have health implications."} +{"text": "A preliminary version of a review article was publCardiovascular Ultrasound.The correct version of the article had prevThe authors have agreed that the preliminary version should b"} +{"text": "In their article \u201cAssessing the Reliability and Credibility of Industry Science and Scientists,\u201d Alas, in their haste to condemn public interest groups who wish the government would adhere to the letter and spirit of that law, The"} +{"text": "This error is also present in the main text paragraph \u201cMDGA and NRX Share Binding Interfaces on NL.\u201dThe errors have no effect on any of the conclusions in the paper, and the main text and"} +{"text": "A large set of data suggests that progressive reduction of fitness and senile decay in vertebrates are in correlation with the decline of cell replication capacities. However, the limits in such capacities are hardly explained in evolutionarily terms by current gerontological theories that rule out fitness decline as something genetically determined and regulated, and therefore somehow favored by natural selection.Four theories are tested as possible explanations of the \u201cincreasing mortality with increasing chronological age in populations in the wild\u201d (\u201cIMICAW\u201d[1]), alias \u201cactuarial senescence in the wild\u201d[2], and of the observed negative correlation between extrinsic mortality and the ratio between deaths due to intrinsic mortality and deaths due to extrinsic mortality. Only the theory attributing an adaptive value to IMICAW allows an evolutionary explanation for it and for the aforesaid inverse correlation, while the other three theories even predict a positive correlation.Afterwards, the same theories are tested as possible explanations for the \u201cstate of senility\u201d[3], namely the deteriorated state of individuals in artificially protected conditions at ages rarely or never observable in the wild. With the distinction between \u201cdamage resulting from intrinsic living processes\u201d[4], alias \u201cage changes\u201d[5], and \u201cage-associated diseases\u201d, the same theory explaining IMICAW allows a rational interpretation of the first category of phenomena while another theory, the \u201cmutation accumulation\u201d hypothesis, gives an immediate interpretation for the second category.The current gerontological paradigm explaining the increasing mortality with increasing chronological age as consequence of insufficient selection should be restricted to the \u201cage-associated diseases\u201d. For IMICAW, it should be substituted with the concept of a physiologic phenomenon genetically determined by a balance of opposite selective pressures \u2014 strictly in terms of kin selection \u2014 and, for \u201cage changes\u201d, with the action of the same IMICAW-causing mechanisms at ages when selection becomes ineffective."} +{"text": "Behavioral Sciences [The authors wish to add the following correction to their paper published in Sciences :\u201cMonkey\u201d in the title of the article \u201cCan Rhesus Monkey Learn Executive Attention?\u201d should be \u201cMonkeys\u201d.The authors would like to apologize for any inconvenience caused to the readers by this change. The manuscript will be updated and the original will remain online on the article webpage."} +{"text": "Dear Sir\u201cA Retrospective Cohort Study of Total Colonic Aganglionosis: Is the Appendix a Reliable Diagnostic Tool?\u201d[1] suggest that aganglionosis of the appendix is a reliable tool in the diagnosis of total colonic Hirschsprung\u2019s disease. They base their assumption on a case series of 9 patients with total colonic aganglionosis and the finding of ab-sence of ganglion cells in the appendix.O\u2019Hare et al We would like the authors to note the recent review on the subject in Lane et al. \u201cThe Appendix and Aganglionosis. A Note of Caution-How the Histology Can Mislead the Surgeon in Total Colonic Hirschsprung\u2019s Disease\u201d, [2] This report showed that the appendix is not reliable in determining whether there is Hirschsprung\u2019s disease as many normal appendices have no ganglion cells. When we looked at this question in the reverse for a group of recent cases we found that in our last 4 cases of total colonic aganglionosis there were 3 cases in which ganglion cells were found in the appendix.We believe the readership should recognize that using the appendix alone can mislead surgeons and we strongly caution against using it as a screening tool. We agree with the authors that further studies are needed and a better pathological understanding of the appendix is required. Factors including enterocolitis, inflammation and age can all affect the pathological finding complicating this issue further.Source of Support: NilConflict of Interest: None"} +{"text": "Following the publication of the original article , it was The correct author\u2019s surname is included in the author list of this \u2018Correction\u2019 and has been updated in the original article ."} +{"text": "There is an error in the equation under the subheading \u201cLiquidity\u201d in the Supplementary Analyses section. The correct equation is:There is an error in the third equation under the subheading \u201cInvestor Expectations and Volatility\u201d in the Supplementary Analyses section. The correct equation is:"} +{"text": "There is an error in the first sentence of the \u201cCell Lines\u201d paragraph of the Materials and Methods section. Dr. Uliana de Simone did not provide cell lines for this study. The correct sentence is: Human astrocytoma D384 cells were provided to the authors as a gift."} +{"text": "An error occurred in the process of publishing this article. In the second sentence of the abstract, \u2018synthesiszed\u2019 is incorrect and should read \u2018synthesized\u2019.The Microbiology Society apologizes for any inconvenience caused."} +{"text": "In the article titled \u201cMigration of the Anterior Spinal Rod to the Right Thigh, a Rare Complication of Anterior Spinal Instrumentations: A Case Report and a Literature Review\u201d , the aut"} +{"text": "After publication of the original article , it cameThe correct version of equation (7) is as follows:Equation (7) has also been updated in the original article in order to rectify this publisher\u2019s error."} +{"text": "After publication of the original article it was bSecondly, there was a repetition of the word \u2018deaths\u2019 in the first sentence of the results paragraph.These have both now been corrected on the BioMed Central website."} +{"text": "Following publication of this article , it has Furthermore, it was reported in the Methods section that the ages of patients involved in this study were \u201c8\u201389\u201d when in fact the correct range was 18\u201389. The original version of the article has been revised to reflect this."} +{"text": "In the original article there was a typographic error with the name of the tea cultivar used in our study.We incorrectly used \u201cAnjin Baicha\u201d throughout the manuscript; the correct spelling is \u201cAnji Baicha.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In the published article, the first affiliation was incorrect. Instead of \u201c\u201d, it should be \u201c\u201d. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The incorrect affiliation has been removed and the article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Jacqueline R. Burkholder, PhD, Division of Emergency Operations, Office of Public Health Awareness, CDC.In the report \u201cSafe and Effective Deployment of Personnel to Support the Ebola Response\u2014West Africa,\u201d which was part of the supplement entitled \u201cCDC\u2019s Response to the 2014\u20132016 Ebola Pandemic\u2014West Africa and United States,\u201d the following author was omitted from the listing on the first page:"} +{"text": "Journal of Bacteriology provides us with a timely reminder that all is not as clear as we had previously thought in the general bacterial secretion system. The paper describes a new mode of secretion through the Sec system\u2014\u201cuncoupled cotranslocation\u201d\u2014for the passage of proteins across the bacterial inner membrane and suggests that we might rethink the nature and mechanism of the targeting and transport steps toward protein export.A paper published in this issue of the A collective A itself \u201313. Late itself \u2013.Escherichia coli, it is accepted that the preprotein is shuttled along a cascade involving first SecB, followed by SecA and SecYEG copy 1, 17 for 18\u201321\u2013d SecYEG 28)..EschericJournal of Bacteriology , showed that it was independent of trigger factor and SecB. Moreover, the known interaction of SecB (but not trigger factor) with the nascent chain was showThese new insights compel us to revise the classical overview of bacterial protein secretion and membrane protein insertion to incorporate the action of SecA in cotranslational protein targeting and transport. The authors deal with this neatly by describing a \u201ccoupled\u201d and an \u201cuncoupled\u201d cotranslational activity (The uncoupled cotranslational secretion activity may well preserve some of the features of the posttranslational reaction. For instance, SecA dimer dissociation , 48 coulThe availability of alternative posttranslational and uncoupled cotranslational pathways for preprotein secretion might beThe new results are perhaps a warning that even the classical pathways of yesteryear may need revising. At the same time, they might suggest there are a few more important new aspects of even the Sec machinery that are yet to be revealed."} +{"text": "RNA isolation from human or animal cartilage tissue is necessary when performing mechanical or biotribological applications. Despite no influence on the cells and no alterations in gene expression patterns, enzymatic digestion of tissues should be avoided as it\u2019s known that the expression of collagen 2 can be effected (Hayman et al., 2006"} +{"text": "Unfortunately, the original version of this article was missPlease note that open access for this article was funded by King\u2019s College London."} +{"text": "The retromer cargo\u2010selective complex (CSC) comprising Vps35, Vps29 and Vps26 mediates the endosome\u2010to\u2010Golgi retrieval of the cation\u2010independent mannose 6\u2010phosphate receptor (CIMPR). Or does it? Recently published data have questioned the validity of this long\u2010established theory. Here, the evidence for and against a role for the retromer CSC in CIMPR endosome\u2010to\u2010Golgi retrieval is examined in the light of the new data that the SNX\u2010BAR dimer is actually responsible for CIMPR retrieval. The motif in the CIMPR tail that is required for retromer\u2010mediated endosome\u2010to\u2010Golgi retrieval was identified through a tried\u2010and\u2010tested approach employing CD8 reporters and mutagenesis of the CD8\u2010CIMPR construct. That study identified a sequence comprising Trp\u2010Leu\u2010Met (WLM) in the CIMPR tail as necessary for its retrieval.Over time, the functioning of retromer\u2010mediated endosome\u2010to\u2010Golgi retrieval has become better understood. A major advance by the Cullen laboratory was the identification of SNX5 and SNX6 as retromer components and the demonstration that these two SNX\u2010BAR proteins could associate with dynein by binding to dynactin.4The recent reports from the Cullen and Steinberg labs have suggested that the role of the retromer CSC in sorting the CIMPR for retrieval to the Golgi is questionable because they could not show any mislocalization of the CIMPR when components of the retromer CSC are silenced by RNAi or deleted by targeted knockout. They cite the studies from my lab and that of BonifacinoCould the differences in effects on CIMPR trafficking boil down to different assays\u2014what is the best way to measure the endosome\u2010to\u2010Golgi retrieval of the CIMPR? There is no definitive answer to that question and different labs have employed an array of techniques that are centred on the use of microscopy to visualize the CIMPR. The assay used by Hao et al5The finding that the SNX\u2010BAR dimer can associate with the tail of the CIMPR is undoubtedly a significant advance in the understanding of how the endosome\u2010to\u2010Golgi retrieval of the CIMPR occurs. But does the observation that the SNX\u2010BAR dimer can bind the CIMPR tail negate the role of the retromer CSC? There is sufficient evidence, accumulated by labs operating independently (including studies authored by Cullen and Steinberg"} +{"text": "The patient that is the subject of thereport was unavailable for consent and has since asked that it be removed. All images havebeen removed from the report.The authors of the paper \u201cTransformation of a nonfunctional paraganglioma with I-123MIBG scintigraphy correlation: A case report\u201d,"} +{"text": "It should be corrected as follows:In the article titled \u201cTopography Prediction of Helical Transmembrane Proteins by a New Modification of the Sliding Window Method\u201d , the err"} +{"text": "In the Methods section, there is an error in the fourth equation in the subsection titled \u201c\u2018Example of the calculation\u201d. Please view the complete, correct equation here:"} +{"text": "Table 1 as published. In the row 2 of the Table 1 (Samba Mashuri BPT-5204), the reference was wrongly cited as \u201cKottapalli et al., 2010\u201d. The corrected reference is \u201cSundaram et al., In the original article, there was a mistake in The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In the article titled \u201cSurgical Management of a Giant Adrenal Pseudocyst: A Case Report and Review of the Literature in the Last Decade\u201d , there w"} +{"text": "Following the publication of the original article , it was The full author\u2019s name and surname is included in the author list of this \u2018Correction\u2019 and has been updated in the original article ."} +{"text": "The authors regret that in the original version of this article, author Vincenzo Lariccia\u2019s surname was mispelled.All versions of this article have been corrected."} +{"text": "Nutrients Editorial Office therefore wishes to make these corrections to the paper:Due to a mistake during the production process, there was a spelling error in one of the author names in the original published version . The Nutwinta.yallew@ndsu.edu\u201d was corrected to \u201cwinta.yallew@gmail.com\u201d.The name of the first author \u201cWinta Yellow\u201d was corrected to \u201cWinta Yallew\u201d. The email address of the first author \u201cWe would like to apologize for any inconvenience caused to the authors and readers by this mistake. We will update the article and the original version will remain available on the article webpage."} +{"text": "P. aeruginosa sepsis and found a homozygous LoF mutation in MAP3K9 (MKL1), a gene that was not known to cause PID (22).\u201d The correct form of the sentence should be \u201cThis was recently illustrated by Record et al., who used exome sequencing in a girl with P.\u2009aeruginosa sepsis and found a homozygous LoF mutation in MKL1, a gene that was not known to cause PID (22).\u201dThere was a mistake in the gene name reference to MKL1 on page 6, right column, last sentence of 2nd paragraph. The sentences says: \u201cThis was recently illustrated by Record et al., who used exome sequencing in a girl with The authors apologize for the mistake.This error does not change the scientific conclusions of the article in any way.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "After our manuscript has been published, we have noticed in our acknowledgment section that the name and the code of our funding program were incorrect. Here, we provide the first sentence of the modified acknowledgment using the correct name and code. funded by the Ministry of Education \u201d.\u201cThis study was supported by the BK21 Plus Program"} +{"text": "Animals [The authors would like to add that \u201cS\u00e9bastien Goumon was supported by Grant No MZERO0716 from the Czech Ministry of Agriculture\u201d in the Acknowledgement Section of their paper published in The authors apologize for any inconvenience this change may cause. The changes do not affect the scientific results. The manuscript will be updated and the original will remain online on the article webpage, with a reference to this addendum."} +{"text": "In the Materials and Methods section, there is an error in the equation under the subheading \u201cStatistical methods\u201d. The publisher apologizes for the error. Please view the complete, correct equation here:"} +{"text": "Mycoplasma ovipneumoniae: \u201cProgressive wasting, spasmodic cough, diarrhea and anemia are some of the characteristic symptoms of the disease.\u201d The correct sentence is: \u201cProgressive wasting and spasmodic cough are some of the characteristic symptoms of the disease.\u201dThere is an error in the third sentence of the Introduction. It references the following symptoms of"} +{"text": "We would like to correct the spelling of the last name of the author Saskia Schr\u00f6ter. It was misspelled as \u201cSchroeter,\u201d whereas the correct spelling is \u201cSchr\u00f6ter.\u201d This mistake does not affect the scientific conclusions of the article in any way. The authors apologize for this oversight.The original article has been updated.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "A holistic view of cancer bioenergetics: mitochondrial function and respiration play fundamental roles in the development and progression of diverse tumors\u201d [In this Correction, the authors would like to acknowledge that the original publication of the article \u201c tumors\u201d was supp"} +{"text": "I very much enjoyed reading the contribution by Gordon et al., published on April 3, 2017 . AlthougThe authors state that \u201cthe resolution of TC with DKA treatment, seen as improvement of the ejection fraction and left ventricular motion improvement on echocardiogram, suggests a direct association between the two conditions\u201d and that"} +{"text": "A portion of the figure legend for Table 1 is incorrectly displayed in the text of the Results section in the second and third paragraph of the section headed \u201cComparing the effects of perceived frequency and event valence.\u201d The text in question is \u201cFour of Weinstein\u2019s original items\u2026according to participants\u2019 subjective ratings.\u201d Please see the complete, correct"} +{"text": "The problem of arriving at an \u201caccurate\u201d determination in trace analysis\u2014determining a \u201ctrue\u201d small amount in a large amount\u2014requires the assessment of the performance of the measurement method used to an appropriate detail.235U/238U \u2248 1 (certified to 0.02%) can be used to determine any systematic errors in the \u201cexcitation\u201d or \u201cion\u201d source and correct the observed 233U/235U or 233U/238U ratios. Comparison of the latter to the certified values (given to \u00b10.03%) then provides a means to determine systematic errors of the (sensitive) detectors used in the trace analysis and to determine possible deviations from linearity of the (electronic) measurement equipment used. It is also possible to determine the reproducibility of these systematic errors and/or deviations allowing to correct for them. It is important to point out that the uncertainties of such corrections must be carried on and correctly propagated until the final result in any measurement of unknowns.In the case of \u201cdirect\u201d measurement techniques of trace concentrations, i.e., assaying directly a small amount relative to the large matrix sample, the evaluation should include the assessment of the reproducibility of the linear, or non-linear response of the measurement chain and of the high sensitivity detector over many orders of magnitude down to small concentrations. low signals, i.e., at the trace element level and a first example obtained is given in In the case of measurement techniques which assay small amounts in weighed samples, the \u201cjump\u201d to the trace level is performed through weighing and the problem becomes one of assaying a trace amount with a known, proven, or provable accuracy.Every indication is there that this will have to come from isotope-specific\u2014or should I say nuclide-specific?\u2014methods on the basis of the fact that isotopes are very specific representatives of elements and specificity is an essential key to accuracy.Those which use the property of one nuclide as in a specific nuclear reaction ; the degree of specificity will influence heavily the potential for accuracy; the degree of quantitative knowledge of every parameter concerned will determine the size of the total \u201cinaccuracy.\u201dRx in the sample (\u201cisotope dilution\u201d), by the addition of a \u201cspike\u201d which is a known number of atoms of the same element as the unknown but with another Ry value for the abundance ratio of the same isotopes (an \u201cenriched\u201d stable isotope- or \u201cnuclide\u201d); this spike acts as an almost ideal \u201cinternal standard\u201d and the measurement is reduced to the determination of the new isotope abundance ratio RB in the blend resulting from the change induced by Ry in Rx Of course, proper isotopic homogenization and complete destruction of the matrix (this makes the assay matrix\u2014independent) in a closed system, is an absolute prerequisite for this type of assay.Those which modify an isotope (nuclide) abundance ratio We have at present a few nuclide-specific assay methods in our array of analytical assay methods:Isotope- or nuclide-specific methods do have inherently more potential for accuracy since they measure isotopes and not elements. Isotopic atoms are measured on the basis of properties of the atom nucleus which are shielded from chemical interferences before or during the measurement, by identical outer electron clouds. They can therefore potentially lead to greater accuracy (when the isotopic measurement methods are correctly applied of course). It is to be expected that isotope- or nuclide-specific methods will more and more deliver reference values and methods for elemental trace analysis in the future.Thus the measurement of an element concentration ratio is replaced by the measurement of isotope abundance ratio. The essential step of isotopic homogenization can be guaranteed when properly carried out, because it takes advantage of the fact that the outer electron clouds of both sample and spike isotopic atoms are identical. This ensures that both will behave in the same way and end up in the same chemical forms after chemical destruction of the sample. At the moment of full isotopic homogenization, the end result is in fact \u201cfrozen in.\u201d Any chemical effect in a later stage of the process, e.g., losses in normal purification or separation stages, will therefore affect equally the isotopes of sample and spike in the same way and leave their abundance ratio\u2014the end result\u2014unchanged.The \u201caccurate\u201d values obtained as explained above for trace elements in unknown samples, can now be carried to the field by Interlaboratory Measurement Evaluation Programmes (IMEPs) where measurements on these samples are collected and graphically displayed around the \u201creference value.\u201d One could also call such a programme an \u201cexternal\u201d measurement evaluation.Current work at the Central Bureau for Nuclear Measurements (CBNM) aims at following the route described above to establish reference values for IMEPs. An example of what this yields is given in It must be absolutely transparent how the value intended to be the \u201cclosest approximation of the true value\u201d , is arrived at, based on a detailed explanation of each step in the characterization process which leads from our bank SI units to the value pretending to be able to serve as \u201creference,\u201d andIt must be absolutely transparent how the \u201cuncertainty\u201d or \u201cinaccuracy\u201d of the value is arrived at, based on the establishment of a list of uncertainty contributors which are identified qualitatively and individually quantified by various appropriate procedures so that their component contribution to the total \u201cinaccuracy\u201d is clearly visible; a work model for that is given in The question arises where such \u201creference value\u201d or \u201cbaseline\u201d takes its authority from and why. Since it is very difficult to unequivocally establish these baseline values, this should be done by specialized institutes or laboratories (the \u201cstandards\u201d laboratories in the world) along the following lines:The state of the practice (SOP) which is materialized in the spread of the results and in the (non-)deviation from the established reference values.Same form of the state of the art (SOA) which is materialized in the uncertainty level of the \u201creference values\u201d which must be demonstrated to be reliable enough and usable for such \u201cexternal\u201d QA programmes.Note that such IMEP programmes are result-oriented and not method- or procedure-oriented. In the graphs presenting the results, distinction is clearly made between:It has been shown how the response of measuring equipment can be evaluated for (non-) linearity over many orders of magnitude, this possible error contributor being separated from the contributors located in the \u201csource\u201d or \u201cexcitation\u201d part of the measurement method.Isotope- or nuclide-specific methods have a great potential to serve \u201creference\u201d purposes so badly needed in trace analysis.IMEPs with carefully established baselines should carry references to the field.\u201cStandards-\u201d or \u201cReference-\u201d Institutes should consider it as part of their basic mission to deliver regularly \u201cbaseline-values\u201d for real life samples which are circulated as \u201cblind\u201d samples amongst the laboratories wanting to assess their true measurement capability through an \u201cexternal\u201d evaluation programme."} +{"text": "Contraception and Reproductive Medicine in production, the articles [Due to a technical issue with the set-up of the journal articles \u20135 were particles \u20135, the aarticles \u20135 were pEach article \u20135 has siThe publisher takes full responsibility for this error and sincerely apologises for the inconvenience caused."} +{"text": "Due to an oversight, the data of the last column \u201cVs\u201d in We apologize for any inconvenience this may have caused."} +{"text": "Reason for corrigendumThe statement that \u201cThe MSD y-axis is log scaled\u201d should be added to the end of the figure legend of Figure 1B.The original article has been updated.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In the original article, there were typographical errors in the \u201cMaterials and Methods\u201d under the \u201cPlant Materials\u201d section.The correct version of both instances of \u201c\u201d should be \u201c\u201d.Also, the correct version of \u201c\u201d should be \u201c\u201d.The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In the first paragraph of Section-Materials and Method section and Subsection-Sample, of the original article, it says \u201c(reference omitted to ensure review blindness).\u201d Instead it should say \u201c(Moritz et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Due to a production error the word \u201cFailing\u201d in the title of the article was accidentally published as \u201cFalling.\u201d The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "We regret any confusion or inconvenience this error may have caused.In the article \u201cStrengthening the Connection Between the Supplemental Nutrition Assistance Program and Farmer\u2019s Markets,\u201d the bullets in the key to Panel A in the figure were incorrect. The correction was made to our website on March 10, 2017, and appears online at"} +{"text": "After publication of the original article , it cameIn order to avoid any misunderstanding of the contribution of Dr. Fei Yang, the sentence should be updated to: \u201cYF carried out gas chromatography data and assisted genotyping experiments.\u201d"} +{"text": "Jie Chen's surname was omitted in the byline. The article has since been corrected online.In the article \u201cImpact of Age on the Prognosis of Operable Gastric Cancer Patients: An Analysis Based on SEER Database\u201d,"} +{"text": "In the article titled \u201cDevelopment and Application of a ZigBee-Based Building Energy Monitoring and Control System\u201d , the autAdditionally, there are three figures in article that are"} +{"text": "Ongoing mumpsoutbreak in Israel, January to August 2017\u2019 by V Indenbaum et al., published on31 August 2017, the GenBank accession numbers of the mumps virus sequences were added on 1September 2017 at the request of the authors.In the article entitled \u2018"} +{"text": "This article was repuThe original text under the sub-heading of \u201cPathogenicity measure\u201d in the Materials and Methods was reproduced from Pereira et al. , but notAll authors agree to these corrections and apologize for the errors."} +{"text": "We have been notified by the authors that there was an error in the affiliation of D.T Felsons address (referenced \u2018\u00a7\u2019) of the above article. The correct address is shown above.The authors would like to apologise for any inconvenience caused."} +{"text": "In the original article, there was a mistake in Figure 1 as published. There was a single asterisk placed after the header \u201cMorphologic features of myeloid differentiation in venous blood or bone marrow, body cavity fluid or tissue aspirates\u201d and a double asterisk placed after the header \u201cMyeloid differentiation on flow cytometric analysis.\u201d Both of these symbols referred to more detailed diagnostic criteria provided in Table 1 and are obsolete, since the reader is referred to Table 1 in the legend of Figure 1. The corrected Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Reason for Corrigendum:There was an error in the literature cited for the use of ACTIN as the reference gene for the qPCR analysis in \u201cMaterials and Methods\u201d section. In the sentence \u201cResults were analyzed by using the \u0394\u0394CT method using ACTIN as the internal control.\u201d, \u201cCastanera et al., 2012\u201d should be replaced with \u201cFern\u00e1ndez-Fueyo et al., In addition, in the original article we have neglected to thank the financial support from National Natural Science Foundation of China, grant number 31672123 to TG. The authors apologize for this oversight.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "To the Editor,We have read with great interest the article \u201cThe role of bone resorption in the etiopathogenesis of acquired middle ear cholesteatoma\u201d by Xie et al. . The aut"} +{"text": "Shenzhen healthcare research project\u201d (201505025 to Youde Liang) also contributed to the resources for this research. This has since been formally noted in this correction article.Upon publication of the original article it was h"} +{"text": "Error in Figure/TableUNABLE\u201d should have read \u201cThese advances mean that they might be ABLE\u201d. This typo was solely in the Figure. The correct version of the vignette was presented to participantsThe original Figure . The corrected Figure In the original article, there was a mistake in Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In the article titled \u201cA Rare Anatomical Variation of the Termination of Right and Left Cephalic Veins\u201d , there wIn the Abstract, the text reading \u201cIn this report, we describe a case of an anomalous cephalic vein with a bifid course of terminations on both left and right upper limbs which has not been described by previous literature\u201d should be corrected as \u201cIn this report, we describe a case of an anomalous cephalic vein with a bifid course of terminations on both left and right upper limbs which has not been described by the previous literature.\u201dIn addition, the text reading \u201cDuring routine gross anatomy dissection of the neck, we observed a rare case of variation of the termination of the cephalic vein in both right and left upper limbs, of a male cadaver\u201d should be removed.In the Introduction section, the text reading \u201cIn this report, we describe a case of an anomalous cephalic vein with a bifid course of terminations on both left and right upper limbs which has not been described by the previous literature\u201d should be removed.In addition, the text reading \u201cThe cut-down of cephalic vein in the deltopectoral groove is preferred when superior vena caval infusion is necessary\u201d should be removed.Finally, the text reading \u201cDespite the clinical importance of the cephalic vein, anatomical variations in its course and diameter of the cephalic vein may limit or complicate insertion of one or several leads\u201d should be corrected as \u201cDespite the clinical importance of the cephalic vein, anatomical variations in its course and diameter may limit or complicate insertion of one or several leads.\u201d"} +{"text": "The recent exploratory study of the role of daily reflection on the clinical learning experience by Larsen, et\u00a0al. and its"} +{"text": "Critical Care, it was brought to our attention that there was an error in Table\u00a0Following publication of the original version of our article in Criti"} +{"text": "Amyelois transitella \u201d, the title included an error: the second word in the species name was capitalized. This has now been fixed in the original article.In \u201cImpact of pesticide resistance on toxicity and tolerance of hostplant phytochemicals in"} +{"text": "In the article titled \u201cPotential Extensions of the US FRAX Algorithm\u201d , the autIn the Introduction, FRAX is described as \u201cthe World Health Organization's fracture risk assessment tool\u201d. The Metabolic Bone Diseases Unit at the University of Sheffield that developed FRAX was a WHO Collaborating Centre from 1991 to 2010 and FRAX is based on data generated from that centre. However, the WHO and the University of Sheffield say FRAX was not developed or endorsed by the WHO ["} +{"text": "After the publication of this work an errorHowever, the correct formula for BRI is as follows \u20134.\\docum"} +{"text": "In the Methods section, there is an error in the equation in the \u201cReproducibility of the individual differentiating FC changes\u201d section. Please view the correct equation here:"} +{"text": "When one googles the words \u201cglobal bioethics\u201d and \u201cthe book,\u201d one can see that the author of the greatest number of books with \u201cglobal bioethics\u201d in the title is Henk ten Have. After a handbook and an encyclopedia of global bioethics and after a discussion on bioethics education from a global perspective, Henk ten Have decided to write an introduction to the subject of global bioethics. His latest book, Global Bioethics: an Introduction gives an"} +{"text": "In the article titled \u201cDevelopment of a Rapid and Precise Method of Digital Image Analysis to Quantify Canopy Density and Structural Complexity,\u201d the descThe suite of computer software comprising CanopyDigi is presented here as supplementary material as a zip file. The entire contents of the zip file, including all files and the folder structure, should be extracted to a root directory in the format C:\u2216CanopyDigi (not C:\u2216CanopyDigi\u2216CanopyDigi). The software can run from any root drive, including an external drive."} +{"text": "The original article [1] contains an error whereby all authors\u2019 names are mistakenly inverted; this was an error mistakenly carried forward by the production team that handled this article, and thus was not the fault of the authors. As such, the correct configuration of the authors\u2019 names can be viewed in this Correction article."} +{"text": "Due to an oversight, the name of the author \u201cAhmad M. Alghraibeh\u201d was incorrectly spelled as \u201cAhmad M. Aghraibeh.\u201d The correct version is shown above. The authors apologize for this oversight. This error does not affect the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In the original publication of this article , a formaThe following formula is incorrect:This should have been displayed as:"} +{"text": "In the article titled \u201cTherapeutic Effectiveness and Safety of Mesotherapy in Patients with Osteoarthritis of the Knee\u201d , Dr. Bo"} +{"text": "In the original published version of this article, a typographical error was present in"} +{"text": "In this version of this article that was originally published the authSource (cell line name or tissue type), Type of sample , and Accession code for all ENCODE data analyzed.]"} +{"text": "In the original Commentary article on page 1, the last name of a co-author of the article that was commented on was misspelled as \u201cWinston\u201d instead of \u201cWinton.\u201d The authors apologize for the mistake. This error does not change the scientific conclusions of the Commentary in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "After publication of the original article it was bThe correct spelling of the name is included in the author list of this \u2018Correction\u2019."} +{"text": "In the title of the original article, the name \u201cdel R\u00edo-Hortega\u201d was incorrectly misspelled as \u201cdel R\u00edo Ortega\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In the \u201cACKNOWLEDGMENTS\u201d there was missing information. The information is the following: this study was supported by the grant CPDA123458 (\u201cProgetto di ricerca di Ateneo\u201d) awarded by the University of Padova to Massimo Grassi. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In two separate experiments benzopyrene has been painted regularly on the backs of mice at difference dose levels.2(t \u2014 w)k where t is time from first application, w and k are constants independent of dose, and d is the applied dose.It has been shown that the incidence rate of both tumours and infiltrating carcinomas can be taken as proportional to d"} +{"text": "The mode of cell death was found to depend on both cell type and light dose. \u00a9 2001 Cancer Research Campaign"} +{"text": "We found an error in our paper published in Marine Drugs , in Figu"} +{"text": "EHP. The article \u201cRespiratory and Other Health Effects Reported in Children Exposed to the World Trade Center Disaster of 11 September 2001\u201d appears to be the entity under study."} +{"text": "The association of Crohn's disease (CD) and Sweet's syndrome is rare and the presence of Sj\u00f6gren's syndrome in Crohn's disease is even rarer, with only three reports found in the literature. We describe two cases of Crohn's disease associated with Sweet's syndrome, one of which is the first case of CD and Sweet's concomitantly associated with Sj\u00f6gren's syndrome. Both cases responded rapidly to Infliximab therapy with complete resolution of the skin lesions."} +{"text": "The equation in the fifteenth sentence of the legend for Figure S2 does not appear correctly. Please view the correct equation and related text here: This means that the movement of intermediate B (point \u201cB\u201d) from ground state (point \u201cO\u201d)is not in the same direction as that of intermediate A (point \u201cA\u201d), and intermediate B is not coming any closer tointermediate A starting from the ground state in structural space"} +{"text": "Sir,6 as screening tool in spirometric diagnosis of obstructive airway disease\u2019[The authors would like to thank Lung India for their excellent support. In response to the above letter, the auth disease\u2019 was only"} +{"text": "It appears possible that their relatively consistent finding of an excess of \u201cnumber 16\u201d chromosomes in their largely hyperploid material may be an artefact of their classification scheme, arising from measurement normalization problems, rather than a reflection of a real excess of \u201cnumber 16\u201d or even of \u201cnumber 16-like\u201d chromosomes.Minkler, Gofman and Tandy have recently reported data on the karyotype constitutions of human tissue culture cell lines and human tumours, as gathered by a semi-automatic chromosome analysis system. The data appears to show a relationship between the relative number of \u201cnumber 16\u201d chromosomes and malignancy. We have tested the ability of the \u201ccutting line\u201d approach they used to correctly classify chromosomes from a sample of 723 cells from 100 normal subjects. The cutting line scheme gave very different results from those of an experienced cytogeneticist. The method also failed to give correct average numbers of chromosomes per class. We are thus led to question the conclusions reached by Minkler"} +{"text": "Sir,The paper \u2018Comparison of norepinephrine and dopamine in the management of septic shock using impedance cardiography\u2019 in the D"} +{"text": "Sir,It was extremely heartening to see that the most recent issue of the Indian Journal of Psychiatry carried an Editorial on Sexual Medicine. What wasConsidering that the research in sexual medicine in India had started way back in the 1980s,[Secondly, we must recognise that the positive initiatives taken up by the Indian Psychiatric Society (IPS) in recent years run the That's one small step for man; one giant leap for mankind\u201d.[I am reminded of the famous words of Neil Armstrong- \u201cmankind\u201d. The edit"} +{"text": "The presence of sex chromatin in a metastatic malignant melanoma from a male patient aged 26 who showed no evidence of any constitutional chromosome anomaly is described. A possible association between the apparently \u201cfemale\u201d origin of the tumour and the good response to therapy is considered."} +{"text": "We read with interest the article \u201cProbabilistic Modeling of Dietary Arsenic Exposure and Dose and Evaluation with 2003\u20132004 NHANES Data,\u201d by In our study , we condA key element of our conclusion regardinWe believe that the analysis by"} +{"text": "In the Materials and Methods section, there is an error in the first equation under the section titled \u201cCombination model.\u201d Please view the complete, correct equation here:"} +{"text": "In the original publication of this article, the affiliation of one of the authors was listed incorrectly as \u201cSmithsonian Institute\u201d. The correct affiliation is \u201cSmithsonian Institution\u201d."} +{"text": "A story about a German research group that supplies free genes leads off the news in Nature this week. Science leads with a story about academics who are offended by a recent suggestion by the US government that they disclose \u2018institutional conflicts of interest\u2019 in scientific research."} +{"text": "In the original published version of this article, an error was present in the author list. The 4th author was listed incorrectly as \u201cMelisew Tadele\u201d instead of the correct name \u201cMelisew Tadele Alula\u201d and the 5th author was listed incorrectly as \u201cMinyahil Teferi\u201d instead of the correct name \u201cMinyahl Teferi Desta\u201d. The authors apologize for the mistake. Both the HTML and PDF versions of the article have been updated to correct the error."} +{"text": "Firstly, the penultimate sentence in the \u201cSecondly, TNF-\u03b1 high\u201d, and the labels written as \u201clow and high\u201d in p38MAPK high\u201d, to make them tally with the description of the results in the article and be consistent with the figure legend. The corrected version of Finally, the labels written as \u201chigh and low\u201d in Note that none of these corrections affect the main conclusions reported in the paper. Nevertheless, the authors apologize to the readership of the Journal for any inconvenience caused."} +{"text": "In the article titled \u201cInguinal Herniation of the Urinary Bladder Presenting as Recurrent Urinary Retention\u201d , there w\u201cThe great majorities of significant herniations of the bladder occur in elderly men and are likely to be the result of the need to increase contraction force to overcome distal urinary tract obstruction due to an enlarged prostate [4].\u201d"} +{"text": "Following publication of the original article [1], the author requested this addition to the \u2018Acknowledgements\u2019 section of the article: \u201cDW is funded by the German Federal Ministry of Education and Research \u201d."} +{"text": "Title, first instance of the word \u201cRegulation\u201d should have been \u201cRegulated.\u201dIn the original article, there was an error in the Title:A correction has been made to \u201cGonadotropin Regulated Testicular RNA Helicase, Two Decades of Studies on Its Structure Function and Regulation From Its Discovery Opens a Window for Development of a Non-hormonal Oral Male Contraceptive\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the article titled \u201cAnalysis of the Power of Common Diagnostic Tools in the Management of Acute Pancreatitis\u201d , the nam"} +{"text": "Estimating the \u2018PrEP Gap\u2019: how implementation and access to PrEP differ between countries in Europe and Central Asia in 2019\u2019 by Hayes et al., published on 10 October 2019, the members of the ECDC Dublin Declaration Monitoring group were not listed in the published version. The list of names was added on 14 November 2019.In the article \u2018"} +{"text": "An author name was incorrectly spelled as \u201cAna Pavia.\u201d The correct spelling is \u201cAna Carolina Paiva.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "There is an error in the maximum plasma concentration of niclosamide reported in the \u201cResults\u201d section of the Abstract. The correct concentration range is: 35.7 to 182 ng/mL. This range is correctly reported in the \u201cPharmacokinetic results\u201d section of the article as well as in Table 4."} +{"text": "An author name was incorrectly spelled as \u201cLifang Zhen.\u201d The correct spelling is \u201cLifang Zheng.\u201dAdditionally, in the original article, there was an error. The sentence indicating that two authors contributed equally to the work was erroneously omitted.A correction has been made to the cover page of the article:\u201cThese authors have contributed equally to this work\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the article titled \u201cEffect of Carboxylic Functional Group Functionalized on Carbon Nanotubes Surface on the Removal of Lead from Water\u201d , the nam"} +{"text": "Funding statement. The correct number for the National Project is \u201cAWS14J011.\u201dThere was an error in the The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original article, the reference for Ludwik\u00f3w et al., The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The author\u2019s middle name is missed out in the original publication of the article . The cor"} +{"text": "In the article titled \u201cDifferent Effects of Myoinositol plus Folic Acid versus Combined Oral Treatment on Androgen Levels in PCOS Women\u201d , \u201cCompetPublication was sponsored by ITF Ilac. The company was not involved in the study or the preparation of the article."} +{"text": "In the original article, there is an error in the corresponding author order. The first corresponding author should be \u201cXin You\u201d followed by \u201cYing Tao\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Funding statement. The grant number for \u201cMedical Research Council\u201d is \u201cG9817803\u201d.There was an omission in the The authors apologize for this error and state that this does not change the scientific conclusionsof the article in any way. The original article has been updated."} +{"text": "In the published article, there was an error in affiliation \u201c1.\u201d The affiliation \u201cAffiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China\u201d should be moved to affiliation \u201c7\u201d and should be removed for the first and corresponding authors. Additionally, all subsequent affiliations should move up in order.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "TTCAAGA\u201d the bold part should be changed to \u201cAAGTTC\u201d.The authors wish to make the following corrections to this paper : In TablThe authors would like to apologize for any inconvenience caused to the readers by these changes. The changes do not affect the scientific results."} +{"text": "In the published article, there was an error regarding the affiliation for Maddalena Boccia. Instead of affiliation \u201c5,\u201d it should be \u201c1.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The original version of this article unfortunately contained a mistake. The word post exercise is written twice at the end of the first line of the \u201cIntroduction section\u201d of the abstract.The Introduction should read as:Microcurrent has been used to promote tissue healing after injury or to hasten muscle remodeling post exercise."} +{"text": "Acknowledgments. The correct funding number for the \u201cNational Project\u201d funder is \u201cAWS14J011.\u201dThere was an error in the The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the original article, there was a mistake in Additionally, an author name was incorrectly spelled as \u201cMariaelena Marcocci.\u201d The correct spelling is \u201cMaria Elena Marcocci.\u201dThere was also an error regarding the affiliations for Anna Teresa Palamara. As well as having affiliations 6 and 7, they should also have affiliation 2.The authors apologize for these errors and state that they do not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Due to a production error, 24 references with more than six authors were listed in the Reference list without \u201cet al.\u201d The references affected are Bouaboula et al. , 1996; FThe publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "An error occurred in the article, the name of one author \u201cMohamed Abd El-Radi\u201d was missing.The new version of the article contains the corrected and complete list of authors.The publisher apologizes for this mistake."} +{"text": "At the request of the authors, the article titled \u201cRole of Wheat Based Diet on the Pathology of Necrotic Enteritis in Turkeys\u201d has been"} +{"text": "Gerhardt.\u201d The correct spelling is \u201cAshley N. Gearhardt.\u201d The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.An author name was incorrectly spelled as The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In the original article, we neglected to include the funder \u201cNational Institutes of Health, R01 NS095908\u201d to AJ and \u201cT32 NS062443 and T32 MH020068\u201d to AT.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Corrigendum:Due to uncertainty associated with the identities of the putative antibiotic resistance genes (ARGs), the authors have edited the article\u2019s title and edited the text to focus more generally on the large number of horizontally acquired genes present in Arcobacter cryaerophilus\u2019s genome. The title is now \u201cAccumulation and expression of horizontally acquired genes in Arcobacter cryaerophilus that thrives in sewage\u201d.The authors have also clarified the methodology used to identify potential ARGs and have added a new table (Table S7) that includes the E-value, percent identity and percent coverage for each putative ARG that was detected within the contigs."} +{"text": "The original article containsAs such, the correct and intended title is as follows, and should instead be taken into account:A national survey of the knowledge, attitudes and prescribing practices of doctors regarding antibiotic resistance in a Caribbean country\u201d\u201c"} +{"text": "Over two centuries ago James Parkinson published \u201cAn Essay on the Shaking Palsy\u201d summarizing his experience with neural pathology now known as Parkinson's disease (PD) . NR is new form of vitamin B3 that functions as a precursor to NAD+ and there is growing evidence suggesting that NR may be a potent candidate to protect and improve nigrostriatal complex (Trammell et al., Given the present view of PD etiology, supplementation of key NAD+ intermediates, especially different forms of vitamin B3, can ameliorate a variety of age-associated pathophysiologies generated by metabolic energy decline (Trammell et al., The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "At the request of the authors, the article titled \u201cThe Association between the Parents' Knowledge of Carbohydrate Counting and the Glycaemic Control of the Children with Type 1 Diabetes\u201d ["} +{"text": "In the Preliminaries section, there are errors in the first equation in the section titled \u201cBilinear maps\u201d and the equation in the section titled \u201cAccess structure.\u201d The publisher apologizes for the errors. Please view the complete, correct equations here:"} +{"text": "At the request of the authors, the article titled \u201cChemical Speciation and Potential Mobility of Heavy Metals in the Soil of Former Tin Mining Catchment\u201d has been"} +{"text": "The name was spelt as \u2018Yoshito Ide\u2019, whereas the correct spelling should have been \u2018YoshiThe authors regret that this error was not recognized and corrected prior to the publication of the above article, and apologize for any inconvenience caused."} +{"text": "The title of the article has been changed from \u201cOligodendrocytes: Potential of Discovering New Treatment Targets\u201d to \u201cBiochemical Pathways Triggered by Antipsychotics in Human Oligodendrocytes: Potential of Discovering New Treatment Targets.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Ethical approval is written incorrectly and should be \u201cdifferent indication in term of medical condition than the one described in the authorised product information; a different group of patients than the one described in the authorised product information; a different route or method of administration than the one described in the authorised product information; a different posology than the one described in the authorized product information.\u201dIn the article, \u201cTreatment of a stage III rima glottidis patient with the oncolytic virus Rigvir: A retrospective case report\u201d,"} +{"text": "C and F in In the original article, there was a mistake in"} +{"text": "In the article titled \u201cEffects of Chronic Exposure to Sodium Arsenite on Expressions of VEGF and VEGFR2 Proteins in the Epididymis of Rats\u201d , there w"} +{"text": "In both tables, the sample sizes should not have appeared in the headings for the first 2 data columns, and the word \u201cunweighted\u201d should not have appeared in the spanning heading above those columns because the data are weighted. This article has been corrected.1In the Original Investigation titled \u201cPatterns in Outpatient Benzodiazepine Prescribing in the United States,\u201d"} +{"text": "Instead of \u201c[grant no. (2019) 1209], it should have been written as \u201c[grant no. (2019) The authors apologize to the funders of their research project, and to the readership of the Journal for any inconvenience caused."} +{"text": "There is an error in the penultimate sentence under the subheading \u201cResults\u201d in the Abstract section. The correct sentence is: The numerical increase in fasting insulin was statistically significant only in the fruit group .In"} +{"text": "There is an error in the Funding statement. The correct number for the \u201cNational Project\u201d is \u201cAWS14J011\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "To the EditorI read with great interest the recent article reported by Izumi et\u00a0al.One of the best\u2010known studies regarding the EEG findings during syncope was conducted by Gastaut et\u00a0al.The authors have stated explicitly that there are no conflicts of interest in connection with this article."} +{"text": "We regret that an error occurred in the colorizing of figure 6 in the article \u201cA Primer on Imaging,\u201d by John J. Doria, and"} +{"text": "Raoufy.\u201dAn author name was incorrectly spelled as \u201cMohammad R. Rauofy.\u201d The correct spelling is The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In keeping with the 2019 GSA Annual Meeting theme of \u201cStrength in Age\u2014Harnessing the Power of Networks\u201d, the Biological Sciences Presidential Symposium focuses on cutting edge approaches to understand the biology of aging using network and systems approaches."} +{"text": "In the Author Contributions section, Michaela Gherghiceanu (MG) should have the contribution \u201cFormal analysis\u201d instead of \u201cResources\u201d.The following information is missing from the Funding section: This study was supported by the Rappaport Family Institute for Research in the Medical Sciences [grant number 015.03\u201301]\".The publisher apologizes for the errors."} +{"text": "In the original article, there was an error. The diabetes app \u201cmySugr\u201d was misspelled as \u201cmySugar\u201d throughout the original article.A correction has been made throughout the article to correct this spelling error.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The publisher apologizes to the readers and authors for the inconvenience.In the original publication of article , \u201820 \u00d7 1The original article has been corrected."} +{"text": "In the published article, there was an error in affiliation of the second author, Elzbieta Krajewska-Ku\u0142ak. Instead of affiliation \u201c2,\u201d it should be affiliation \u201c1.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Funding statement. The correct number for \u201cU01-DR116317\u201d is \u201cU01-DK116317.\u201dThere is an error in the The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "India State-Level Disease Burden Initiative Malnutrition Collaborators. The burden of child and maternal malnutrition and trends in its indicators in the states of India: the Global Burden of Disease Study 1990\u20132017. Lancet Child Adolesc Health 3: 855\u2013702019; \u2014The first sentence of the Exclusive breastfeeding section of the Results has been corrected to read: \u201c\u2026with a moderate inverse correlation\u2026\u201d. These corrections have been made to the online version as of Sept 30, 2019, and the printed version is correct."} +{"text": "There is an error in the Funding statement. The correct number for the funder \u201cNational Project\u201d is \u201cAWS14J011.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Due to a typesetting error, the first paragraph and heading of the section \u201cPerceived Role Non-Traditionalism\u201d was incorrectly placed in the section \u201cSweden and Gender Equality\u201d, it belongs in the section \u201cResults\u201d after the second paragraph. The publisher apologizes for this mistake.The original version of this article has been updated."} +{"text": "One of the author's name was incorrect in the Funding Statement. \u201cCecilia Demargasso\u201d should be \u201cCecilia Demergasso.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "There are a number of errors in There are a number of errors in S2 Table(PDF)Click here for additional data file."} +{"text": "In the original article, there was a mistake in the legend for Figure 2 as published. The term \u201cwaiting\u201d in Figure 2 (A) was swapped with the term \u201ctapping\u201d in Figure 2 (B). The correct legend appears below.\u201cActivations in the planning phase of an ongoing action task while tapping (A) and while waiting (B) are shown.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "All items domain of the rating scales between t1 and t2 and showed a significant advantage compared with the CG .There is an error in the second sentence under the heading \u201cResults\u201d in the Abstract. The correct sentence is: The intervention group showed a statistically significant improvement in the In"} +{"text": "A critical analysis of colour\u2014shape correspondences: examining the replicability of colour\u2014shape associations. The authors regret that in this article the SCA restructured data was said to derive from a methodology of analysis and is compared to results from"} +{"text": "In the version of this article initially published, the \u2018how to cite\u2019 indicated Leigh Biagio de Jager\u2019s last name as \u2018De Jager\u2019 but it should be \u2018Biagio de Jager\u2019. The errors have been corrected in the PDF version of the article. The publisher apologises for any inconvenience that this omission may have caused."} +{"text": "There was an error in the Supplementary Material. The order of a few identified taxa did not match their OUT numbers. This does not require further changes in the main text file.A correction has been made to In addition, the phrase \u201csimilarity score\u201d has been replaced with \u201csequence identity score\u201d in the original article and the supplementary material.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Bacillus cereus.In the original article, there was an error in referring to the approved group of Conclusion and Outlook section, \u201c(1) Apathogenicity\u201d:A correction has been made to the B. subtilis species complex including B. velezensis have been listed as risk group in \u2018The Approved List of biological agents\u2019 Apathogenicity: Concerning biosafety issues, no representatives of the The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way."} +{"text": "Funding statement. The correct number for \u201cEPSRC\u201d is \u201c.\u201dThere is an error in the The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The correct sentence is: We consider a sample There are errors in the second and third sentences of the subsection titled, \u201cVirtual biodiversity datasets,\u201d in the Materials and Methods section. The correct sentence is: We assume that the function In the Methods section, there are errors in the first through fifteenth equations. Please view the complete, correct equations here:In the \u201cModelling the functioning of an ecosystem based on its species composition,\u201d section:In the \u201cEvaluating the accuracy of a species clustering,\u201d section:And:And:In the \u201cEvaluating the predictive ability of a species clustering,\u201d section:And:In the \u201cBuilding a hierarchical divisive tree of species clustering,\u201d section:In the \u201cEvaluating the quality of a hierarchical tree of species clustering,\u201d section:And:And:And:In the \u201cEvaluating the optimum number of functional groups,\u201d section:And:In the \u201cVirtual biodiversity datasets,\u201d section:And:The images for Figs"} +{"text": "Panels b' and c' in Figure 4 appear to show the same image, but rotated 180 degrees in c' and shown at a shorter exposurePanels b' and c' in Figure 5 also appear to show the same image, but rotated 180 degrees in c' and shown at a shorter exposurePanel b in Figure 4 and panel b in Figure 5 appear to show an overlap when one of them is rotated 180 degrees .Oxidative Medicine and Cellular Longevity has retracted the article titled \u201cBiomolecular Modulation of Neurodegenerative Events during Ageing\u201d . As raisThe figure comparisons are shown in the supplementary materials. The authors do not agree with retraction, but we consulted our Editorial Board who confirmed the concern."} +{"text": "Please be advised that one of the author names is incorrectly spelled in the published article: \u2018Irene Kyomuhagi\u2019 should be \u2018Irene Kyomuhangi\u2019.The corrected name can be found in the author list of this article."} +{"text": "In Zhi et\u00a0al,The correct figure has been updated in the online version.The authors wished to apologize for any misunderstanding or inconvenience this may have caused."} +{"text": "Henosepilachna vigintioctomaculata\u201d should be \u201cSelection and Validation of Reference Genes for RT-qPCR Analysis of the Ladybird Beetle Henosepilachna vigintioctopunctata.\u201dIn the original article, there was an error in the title. The title \u201cSelection and Validation of Reference Genes for RT-qPCR Analysis of the Ladybird Beetle The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way."} +{"text": "In the original article, the reference for the \u201cEuropean Biostimulant Industry Council\u201d was incorrectly written as \u201c\u201d. It should be \u201c\u201d. It shThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The equation in the subsection of the Methods section titled \u201cPhenotypic Age\u201d is missing a step which makes it impossible to resolve. The equation should read:Where:"} +{"text": "The title of the paper originally entitled \u201cContent Analysis of Online Focus Group Discussions is a Valid and Feasible Mode When Investigating Sensitive Topics Among Young Persons With a Cancer Experience\u201d :e86) was corrected to read \u201cOnline Focus Group Discussion is a Valid and Feasible Mode When Investigating Sensitive Topics Among Young Persons With a Cancer Experience\u201d. The error was introduced by the editor in the final proofreading process to remove a grammatical issue, but the authors feel that \u201ccontent analysis\u201d in the title is incorrect because content analysis was not the method used for analyzing data in the present study. The advantages and disadvantages with the mode of data collection was judged by analyzing characteristics of those who participated, interactions during discussions and the participants\u2019 evaluation of the focus group discussions. Secondly, there was also an incorrect affiliation footnote reading \u201cnull\u201d associated with author Lena Wettergren, which has now been removed from the metadata. These errors have been corrected in the online version of the paper on the JMIR website on May 10 and May 12, 2016, respectively, together with publishing this correction notice. \u00a0There are no changes to the contents of the paper. A correction notice has been sent to PubMed. This was done before submission to Pubmed Central and other full-text repositories."} +{"text": "In the published article, there was an error regarding the affiliations for \u201cEgidio D'Angelo.\u201d As well as having affiliation 2, he should also have IRCCS Mondino Foundation, Pavia Italy. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The first sentence of the fourth paragraph of the Abstract should appear as \u201cWe analyzed 2600 esophagectomy cases of which 956 were open, and 1644 were thoracoscopic surgery.\u201d The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.In the article \u201cEffects of preoperative oral management by dentists on postoperative outcomes following esophagectomy: Multilevel propensity score matching and weighting analyses using the Japanese inpatient database\u201d,"} +{"text": "There was an error in the text in the published article.The abstract states \u2018a child of 4 years of age with retrobulbar uveitis\u2019, this should be \u2018a child of 4 years of age with retrobulbar neuritis\u2019.The author apologizes for any inconvenience caused."} +{"text": "Lai\u201d and \u201cKaiyu Lei\u201d were not included as authors in the published article. Due to the addition of authors, the list of affiliations had been updated accordingly. The corrected Author Contributions Statement appears below."} +{"text": "Following publication of the original article , the autThe correction has been implemented in the original publication of this article as well and the \u2018Authors\u2019 contributions\u2019 section has been updated accordingly there."} +{"text": "Nature Communications 10.1038/ncomms16033, published online 20 June 2017.Correction to: This Article contains an error in the first sentence of the \u2018Data availability\u2019 section of the \u201cMethods\u201d, which incorrectly reads \u2018The authors declare that all the behavioural raw data that were used in this manuscript are included in the Supplementary Information.\u2019 This should read \u2018The authors declare that all the behavioural raw data that were used in this manuscript are included in Supplementary Data 1.\u2019 The error has not been fixed in the PDF or HTML versions of the Article.Additionally, the HTML version of this Article incorrectly omits Supplementary Data 1 file. Supplementary Data 1 can be found as Supplementary Information associated with this Correction.Supplementary Figures"} +{"text": "In the original article, we neglected to include the funder \u201cIran National Science Foundation (INFS), Grant No. 95814261\u201d.Funding statement:A correction has been made to the \u201cThe authors would like to thank the Iran National Science Foundation for the financial support. We would also like to thank the authorities of Tabriz University.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way."} +{"text": "There is an error in the Funding statement. The correct funding number for the \u201cNational Project\u201d is \u201cAWS14J011\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "An author's name was incorrectly spelled as \u201cAmir Aarstehfar.\u201d The correct spelling is \u201cAmir Arastehfar\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the article titled \u201cMeta-Analysis of the Relationship between Deep Brain Stimulation in Patients with Parkinson's Disease and Performance in Evaluation Tests for Executive Brain Functions\u201d , the fir"} +{"text": "In the original article, we neglected to include the funder \u201cEuropean Research Council,\u201d \u201cGrant Number 322749\u201d to GC.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the version of this article published earlier, the surname of the second author, Lena K. von Koch, was inadvertently misspelt as \u2018von Kock\u2019. The second author\u2019s surname should have appeared as \u2018von Koch\u2019 throughout the author list and \u2018how to cite\u2019 information section. This correction does not alter the study\u2019s findings of significance or overall interpretation of the study results. The author apologises for any inconvenience caused."} +{"text": "In the article titled \u201cThe Role of fMRI in the Assessment of Neuroplasticity in MS: A Systematic Review\u201d , the aut"} +{"text": "To the Editor: In a recent study published in the Croatian Medical Journal, \u0160egrt Ribi\u010di\u0107 et al (i\u0107 et al describeWe conducted a series of studies on bubble formation using hydrophobic silicon wafers and sheep blood vessels. On the basis of our findings, we proposed that surface nanobubbles were produced from dissolved gas at active hydrophobic spots on the luminal aspect of blood vessels, and that these may be the source of gas micronuclei from which decompression bubbles develop . 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sha256:0db8a9050351b0ceb66f3e2af84dca0f4ea5515495d5408c69e28d2e941d5ae2 +size 32262416 diff --git a/PMC_clustering_664.jsonl b/PMC_clustering_664.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..538f1f97146d89cbdeca5db8491e0cb22bf85dbf --- /dev/null +++ b/PMC_clustering_664.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:a212b9d1c58b930a8689f9c676d4eb1939cd68f2d116071e4f2993458f52a318 +size 74731573 diff --git a/PMC_clustering_665.jsonl b/PMC_clustering_665.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..c412fc803227c27f36599ad029b64b96627760b9 --- /dev/null +++ b/PMC_clustering_665.jsonl @@ -0,0 +1,883 @@ +{"text": "The data presented in this article are supplementary data related to the research article entitled \u201cThe Copenhagen Tool: A research tool for evaluation of BLS educational interventions\u201d . We present the following supplementary materials and data: 1) a standardized scenario used to introduce the test for gathering data on internal structure and additional response process; 2) test sheets used for rating test participant via video recordings; 3) interview-guide for collecting additional response process data; 4) items deemed relevant but not essential for laypersons, first responders and health personnel in the modified Delphi consensus process; 5) inter-rater reliability values for raters using the essential items of the tool to evaluate test participants via video recordings; 6) main themes from coding interviews with raters; 7) comparison of rater results and manikin software output. The data in this coupled article is important because it presents validation evidence from the domains not covered in the main article.\u2022The data in this coupled article will benefit users of the Copenhagen Tool.\u2022Data illustrate how the Copenhagen tool can be applied in a standard setting. This is illustrated by presenting evidence from the domain \u201cinternal structure\u201d data from raters who rated post-course video recorded standard scenarios of ERC BLS course participants is presented.1The data presented in this article is supplemental data to the study \u201cThe Copenhagen Tool: A research tool for evaluation of BLS educational interventions\u201d 2This data article includes information on tests conducted for collection of validation evidence to support the use of the Copenhagen Tool presented as the main article 2.1To provide additional response process evidence, all six raters were interviewed using a semi-structured interview-guide as presented in 2.2Internal structure evidence was collected by analyzing inter-rater reliability. Raters watched the videos in separate rooms and noted achievements on a list containing all elements from all levels shown in 2.3relations to other variables\u201d presents associations between assessment scores and other measures of the same content. In this study evidence from this domain was collected with the scope of facilitating comparison of research in BLS educational interventions. We have compared the answers of the raters with that manikin data to provide further sources of comparison. In The evidence domain labeled \u201c3The authors note Raw data for this study is attached as supplementary materials. All data is accessible except for the video-recordings of the tested subjects. Video-recordings can be shared upon reasonable request.All experts agreed to participate. The Regional Ethical Committee in the Capital Region of Denmark waived the need for approval .The authors declare no competing interests."} +{"text": "This article was repuSimilarities were noted between images presented in this article and two The schematics of postanal day-3 and adult cochlear sensory epithelia presented in Fig 1A and the The immunohistochemistry images of undifferentiated CGR8 mouse embryonic stem cells in Fig 1B .PLOS ONE articles .\u201dThe authors have provided further details regarding the methodology of the embryotic stem cell experiments. The following information has been added to the Materials and Methods section: \u201cThe authors have indicated that all available data are within the paper and its Supporting Information files and that the individual level data for Fig 7 are still available upon request.S1 File(PDF)Click here for additional data file."} +{"text": "VPS13A\u2013D) are associated with a number of neurological disorders, but little is known about their precise functions or the relevant contact sites affected in disease. In contrast, yeast has a single Vps13 protein which is recruited to multiple organelles and contact sites. The yeast model system has proved useful for studying the function of Vps13 at different organelles and identifying the localization determinants responsible for its membrane targeting. In this review we describe recent advances in our understanding of VPS13 proteins with a focus on yeast research.The conserved VPS13 proteins constitute a new family of lipid transporters at membrane contact sites. These large proteins are suspected to bridge membranes and form a direct channel for lipid transport between organelles. Mutations in the 4 human homologs ( VPS13A) . Mo. Mo56]. ocytosis . The latocytosis suggestiRecent work in yeast and other model systems suggests VPS13 proteins bridge organelle membranes at MCSs to form a direct channel for lipid transport. The localization of the four human VPS13 homologs to different subsets of MCSs could explain why mutations in each are associated with distinct neurological disorders. Understanding the precise function of each homolog at specific organelles or contact sites will thus be important for understanding the cellular basis of these diverse disorders.Additional research using the yeast model is expected to identify new interacting proteins that drive lipid transport or Vps13 membrane recruitment. Although yeast Vps13 is known to localize to a number of organelle membranes, the opposing organelles at these suspected contact sites are largely unknown. Further work is required to determine the organelle pairs tethered by Vps13 and the conditions that regulate its recruitment to each site. Characterizing the interacting partners, membrane targeting strategies and sites of function of yeast Vps13 is expected to inform future research on the human homologs and their roles in disease."} +{"text": "Following the publication and correction of this article , 2, the The same ERK2 data are reported in Figs The lanes 1\u20134 in The corresponding author has indicated that in The PARP panel shown in The ERK2 panel in There is an error in The corresponding author noted that there is an error in the sixth sentence of the second paragraph of the Results. The correct sentence is: \u201cBy contrast, AsPC-1 cells were more resistant to gemcitabine, as evidenced by the absence of p38 MAPK and JNK activation and the appearance of cleaved caspase 3 and cleaved PARP only when the concentration of gemcitabine was increased to 100 ng/mL .\u201dThe corresponding author has provided corrected Figs The raw data underlying the updated versions of Figs PLOS ONE Editors issue this Expression of Concern to notify readers of the above concerns and relay the supporting data and updated figures provided by the corresponding author.The S1 File(PDF)Click here for additional data file.S2 File(JPEG)Click here for additional data file.S3 File(TIF)Click here for additional data file."} +{"text": "Life review therapy, used as part of a comprehensive therapy plan for increasing the quality of life of the elderly, helps them to resolve their past conflicts, and accept their present conditions. This study tested the effectiveness of a structured life review therapy protocol on the life satisfaction of institutionalized older adults. A quasi-experimental design was adopted in this study. Fifty older adults aged 65 or above were recruited from nursing homes in southern Taiwan through convenience sampling. The participants in the intervention group carried out life review therapy for eight weeks in addition to their daily activities. The participants in the comparison group maintained their daily activities. Both groups were evaluated using a life-satisfaction scale including two aspects of life worries and situations in weeks 1 and 8. Data were collected at baseline (T1), immediately post-intervention (T2). Generalized estimating equations were used to examine the effect of the intervention on the outcomes. The overall life satisfaction increased significantly over time for the intervention group compared to the comparison group from week 1 to week 8. The life review therapy programs showed promising effects in improving the life satisfaction of older adults living in nursing homes."} +{"text": "Presenters will describe barriers to psychosocial care and identify which factors increase the odds of experiencing a psychosocial care barrier. Reported major barriers include: insufficient number of nurse aide staff (31%), having to do things other people could do (29%), lack of resources to provide residents with opportunities to leave the nursing home on outings (25%), pressure to admit and discharge post/sub-acute patients takes time away from attending to the social and emotional needs of long stay residents (23%), and not enough social service staff for the number of residents (21%). With data from the 2019 National Nursing Home Social Services Directors Survey, a series of logistic regressions found that significant predictors varied by specific barrier, although devoting more time to short-term residents predicted a greater likelihood of reporting a major barrier in four of the five outcomes. Strategies to address these structural and contextual factors will be discussed."} +{"text": "Correction to: The ISME Journal10.1038/ismej.2016.40Since publication of the original paper the authors realised the following funding body was missing from the article\u2019s Acknowledgements:\u201cFP and this work was also supported by the European Research Council 3687660)\".The authors apologise for any inconvenience caused."} +{"text": "The NH Alliance for Healthy Aging (NH AHA) is a statewide coalition of stakeholders building cross sector partnerships that support and promote healthy aging throughout the state. Formed in 2016, NH AHA works to promote its shared vision to create communities in New Hampshire that advance culture, policies and services which support older adults and their families. As the largest coalition focused on the health and well being of older people in the state, NH AHA currently engages over 300 participants representing more than 185 organizations and/or groups statewide. Participants will hear how this collective power has led to early successes in advancing AHA\u2019s five strategic priorities, including early statewide policy successes. A review of the collective impact model will be provided with discussion on how NH uses this model intentionally to align the work in the aging field of NH. NH AHA\u2019s theory of change starts with changing the conversation around aging across NH\u2019s communities and is the foundation for the efforts to advance Reframing Aging principles and recommendations through the work of NH AHA and statewide. NH AHA\u2019s strategic plans to become a resource and hub of Reframing Aging activity in the state will be reviewed. As a result of the presentation audience members will be able to 1) describe the 5 conditions of collective impact 2) give 2 examples of how NH is utilizing these conditions intentionally and 3) describe NH\u2019s efforts to create common measures for the aging field in NH."} +{"text": "The easy magnetization axis was oriented along the short size of the stripe using deposition in the external magnetic field. Such configuration is important for the development of small magnetic field sensors employing giant magnetoimpedance effect (GMI) for different applications. Microwave absorption of electromagnetic radiation was experimentally and theoretically studied in order to provide an as complete as possible high frequency characterization. The conductor-backed coplanar line was used for microwave properties investigation. The medialization for the precession of the magnetization vector in the uniformly magnetized GMI element was done on the basis of the Landau\u2013Lifshitz equation with a dissipative Bloch\u2013Bloembergen term. We applied the method of the complex amplitude for the analysis of the rotation of the ferromagnetic GMI element in the external magnetic field. The calculated and experimental dependences for the amplitudes of the imaginary part of the magnetic susceptibility tensor x-component and magnetoabsorption related to different angles show a good agreement.Magnetically soft [Ti(6)/FeNi(50)] Microwave techniques is a rapidly growing area of multidisciplinary basic research and practical usage ,2,3. TheThe integration of on-chip sensitive elements with nanoscale components is a hot topic of the day. In this sense thin films and nanostructured multilayers geometry is preferable, being most compatible with semiconductor electronics and existing technologies of electronic circuit fabrication ,14. DespZ, under application of a moderate external DC field when alternating current of high frequency flows through the ferromagnetic conductor:R is resistive and X is inductive components of the total impedance 6 multilayered GMI elements. This configuration is important for sensor applications. Nanostructured GMI elements were obtained by a radio frequency sputtering technique. The broadband FMR measurements were performed in the coplanar configuration of the waveguides in order to extract intrinsic parts of GMI corresponding to the signal of the multilayered element without other test fixture and waveguide contributions. We developed an appropriate model based on the use of the Landau\u2013Lifshitz equation with a dissipative term in the form of Bloch\u2013Bloembergen and applied the complex amplitude method to the Landau\u2013Lifshitz equation in order to provide description the rotation of the ferromagnetic GMI element in the external filed and compare experimental and model results.In this work we discuss both static magnetic properties and angular dependence with respect to external magnetic field of the ferromagnetic resonance parameters in the wide frequency range for [Ti/FeNi]19Ni81(50 nm)]6/Ti(6 nm)/Cu(500nm)/Ti(6 nm)/[Fe19Ni81(50 nm)Ti(6 nm)]6 elements were deposited by magnetron sputtering onto Corning glass substrates, using a background pressure of 3.0 \u00d7 10\u22127 mbar and Ar working pressure of 3.8 \u00d7 10\u22123 mbar 6/Ti/Cu/Ti/[FeNi/Ti]6 multilayered GMI elements installed as a part of the line using highly conductive silver paint adapted for electronics. It was measured for the direction of in-plain applied field along the long side of the element (\u03b1 = 90\u00b0). As the absorption frequencies are well fitted with the Kittel\u2019s equation, we can consider that the absorption of the electromagnetic waves in the sample is a ferromagnetic resonance 6 multilayered GMI element in the range of the angles between the GMI element long side and the applied field 0\u00b0 \u2264 \u03b1 \u2264 360\u00b0 (with the increments of 15 degrees). It is worth mentioning that the employed broadband technique has special advantage of characterization of entire sensitive element which can be used in the detector of small magnetic fields for automatic control, positioning, biodetection, etc.Let us now discuss the experimental and calculated results for angular dependences of the impedance of [Ti(6)/FeNi(50)]\u03b1 = 90\u00b0 peak is much narrower. As the amplitude and frequency dependences were very similar within the error limits in all four quadrants, here we present the first quadrant data only. see also a. One ca6/Ti(6)/Cu(500)/Ti(6)/[FeNi(50)Ti(6)]6 multilayered element in GMI configuration.The calculations were made by the application of the complex amplitude methodology angular dependences of the components of the impedance for [Ti(6)/FeNi(50)]H parallel to h configuration significantly differ from the other angular cases: Both \u0394R and \u0394X show very small signal variations. We therefore show the \u0394R data only as an example. One can clearly see that experimental and theoretical behavior are in a very good agreement in the external field range under consideration. Actually, H parallel to h configuration corresponds to well-known low field non-resonant absorption 6 magnetically soft multilayered structures were deposited by radiofrequency sputtering technique in the shape of elongated stripes. Microwave absorption of electromagnetic radiation was studied in their case aiming to provide high frequency characterization of nanostructured elements in the configuration of giant magnetoimpedance small magnetic filed sensors designed for biomedical applications.[Ti(6)/FeNi(50)]Special attention was paid for comparison of experimental results obtained in the course of the measurements the microwave properties using technique and holders based on the conductor-backed coplanar line maintaining the line impedance at a constant level. To describe the precession of the magnetization vector in uniformly magnetized sample, we use the Landau\u2013Lifshitz equation with a dissipative term in the form of Bloch\u2013Bloembergen and we apply the complex amplitude method to the Landau\u2013Lifshitz equation in order to provide model description of the microwave properties for the rotation of the ferromagnetic GMI element in the external magnetic field.x-component on the intensity of applied magnetic field at different angles between the main axis of the sample and the field direction and the experimental results show good agreement with each other. The proposed way of calculation of demagnetizing fields and magnetic susceptibility tensor can be successfully used for calculations in the course of design of magnetic field sensors and their characterization.The calculated dependences of the amplitudes of the imaginary part of the magnetic susceptibility tensor"} +{"text": "Simultaneous localization and mapping (SLAM), which addresses the problem of constructing a spatial map of an unknown environment while simultaneously determining the mobile robot's position relative to this map, is regarded as one of the key technologies in mobile robot navigation. This data article presents four raw video files, demonstrating the mapping and localization processes of NeuroBayesSLAM, a neurobiologically inspired SLAM system, on two publicly available datasets, namely the St Lucia suburb dataset and the iRat Australia dataset. The cognitive mapping process was recorded by a free screen recorder software on ubuntu Linux system. Neural activities of the head-direction cells and the grid cells, the local view templates of visual scenes, and experience map were included. These data envision the possibility of transferring the multisensory integration mechanism found in the spatial memory circuits of the mammalian brain to develop intelligent cognitive mapping systems for indoor and large outdoor environments as in the research article \u201cNeuroBayesSLAM: Neurobiologically Inspired Bayesian Integration of Multisensory Information for Robot Navigation\u201d Zeng et al., 2020. Specifications TableValue of the Data\u2022The videos presented in this brief demonstrate the performance of a cognitive mapping system, namely NeuroBayesSLAM, on two publicly available datasets.\u2022The conflict between vestibular cue and visual cue is resolved by the competitive dynamics and also explicitly presented in the videos.\u2022The videos provide comparison and benchmark against other brain-inspired SLAM methods.\u2022The dynamic process of neural activities, local view scenes, and experience map over time can help better understand the neural computational mechanisms of head-direction cells and grid cells and their implications for developing intelligent navigation system.1The dataset comprises four raw video files recorded using a free screen recorder software (SimpleScreenRecorder) on ubuntu system when the NeuroBayesSLAM system is demonstrated on two publicly available datasets, namely the St Lucia suburb dataset and the iRat Australia dataset Video S1 shows the mapping process for the St Lucia suburb dataset. Video S2 shows the plastic remapping process when a loop is successfully closed with strong reliability of visual cues. While, weak reliability in visual landmarks fails to complete the loop closure, as shown in Video S3. Video S4 shows the mapping process for the iRat Australia dataset. Supplementary videos are with the article.2The demonstration presented in the video data is based on the NeuroBayesSLAM system In order to demonstrate the competitive dynamics between the integrator cells and the calibration cells of the NeuroBayesSLAM system during the cue conflict resolution process, a loop in the St Lucia suburb dataset is selected to record in finer time resolution. We varied the strength of the injection current from visual cue to show the role of visual cues in plastic remapping process. The injection parameters with smaller energy are for weak/unreliable visual cues. The injection parameters with bigger energy are for strong/reliable visual cues. With strong visual cue, the integration of the visual landmark information generates a loop closure successfully (Video S2). In contrast, weaker visual landmarks fail to create a loop closure (Video S3).The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article."} +{"text": "Panel dataset in this article contains information on the ethical commitment disclosures of Malaysian publicly listed companies. The data presented is related to the research article entitled \u201cEthical Practice Disclosure of Malaysian Public Listed Companies\u201d Specifications Table\u2022The dataset provides preliminary data on various attributes of ethical commitment/practices disclosed by Malaysian companies.\u2022The dataset is useful for companies and policy makers to assess the level of ethical commitment disclosures of companies and implement action plans to improve the ethic practices.\u2022The dataset can be used as part of corporate governance framework and have a potential to be used toward different model in evaluating corporate values.1The dataset contains 223 companies from twelve sector in Main Market of Bursa Malaysia listings as in 2The dataset represents 223 companies randomly selected from Bursa Malaysia main board after excluding financial sectors and missing data and/or annual reports. The dataset consists of 1,115 companies for five year observations from year 2012 to year 2016. Binary scoring method is used to measure each item; whether disclosed or not. One (1) point is given for the disclosure of particular items in annual reports, and zero (0) point if no disclosure is made at all. Binary scoring was chosen due to the nature of the information gathered from each item in ECI that consists of six themes of ethics disclosures. Within each of the themes there are items that represent the detailed information of the themes, thus binary scoring allows information regarding ethics to be examined in depth The authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article."} +{"text": "A number of international safe communities are displaying increasing interest in the United Nations Sustainable Development Goals (UNSDG). The International Safe Communities Certifying Centre is seeking to establish formal relations with the World Health Organization (WHO).A formal review of the UNSDG and WHO General Program of Work 13 \u2013 2019 to 2023 (WHO GPW13) alignment with the international Safe Communities indicators.UNSDGs were formally reviewed by 4 senior ISCCC certifiers and ranked in terms alignment with International Safe Communities Indicators.While injury imposes a considerable cost burden on communities, safety is a critical precondition necessary for the attainment of the productive physical, physical and social environments that communities require to achieve their full potential. Safety provides a dynamic leverage point for communities to achieve their aspiration for sustainable development. There is very strong alignment between the UNSDGs and the International Safe Community Indicators The holistic understanding of injury prevention and safety promotion adopted by the safe communities movement supports the WHO vision to \u201cPromote health, keep the world safe and serve the vulnerable\u201d articulated in its 13th General Program of Work (GPW): 2019 to 2023. Based on the analysis the ISCCC board has identified 7 domains of injury prevention and safety promotion practice that are of high strategic importance8: \u2022 Disaster preparedness \u2022 Prevention of Road Traffic Injuries \u2022 Prevention of Violence against Women \u2022 Prevention Violence against Children \u2022 Suicide prevention \u2022 Falls prevention \u2022 Prevention of workplace injury. All new designation applications submitted after the 1st of July 2019 must provide statistical information regarding the incidence of these issues and to describe how they are addressed in their community. The International Safe Community movement embraces a whole of system definition of injury prevention and safety promotion that aligns easily with the United Nations Sustainable Development Goals (UNSDG) and the WHO General Program of Work 13, 2019 to 2023 (WHO GPW13).United Nations SDGs, WHO General Program of Work, ISCCC"} +{"text": "Following publication of this article , concern- In Fig 1A the 2 h Actin panel for Control cells is a duplicate of the first three lanes of the Actin panel for Control cells in Fig 6A.PLOS ONE article [- In Fig 6B the Actin panel is incorrect and is a duplicate of the 18 h Actin panel for RA cells in Fig 6A of another article reportinThe corresponding author has stated that there were errors in selection of western blot images for Figs 1 and 6 as follows:- In the originally published Fig 1A, the panels for Control cells are not taken from the same replicate experiment as the panels for the RA cells. A revised - In the originally published Fig 6A, the panels for Control cells are not taken from the same replicate experiment as the panels for the RA cells. Additionally, the pSTAT3 and Actin panels for Control cells are incorrect and were taken from blots carried out at an earlier time point than stated (2 h as opposed to 18 h). In the originally published Fig 6B, the Actin panel is incorrect and was taken from a different experiment. A revised The corresponding author has clarified that in revised Figs The available underlying western blot image files for this study are provided as Supporting Information files. They can be viewed below. The original uncropped image files for western blots underlying Figs The corresponding author states that the errors occurred during figure assembly and did not affect any of the associated quantitative data or reported conclusions.Editorial assessment in consultation with a member of the Editorial Board identified a concern that the representative blots for FOXP3 expression in Control cells at 18h in the revised PLOS ONE Data Availability Policy requires that, with few exceptions, all data underlying the findings described in an article are fully available without restriction. While looking into the image issues raised, it came to the attention of the PLOS ONE Editors that the individual-level data underlying the charts in all figures cannot be made available in accordance with the above policy.The PLOS ONE Editors issue this Expression of Concern to alert readers of these concerns about the unavailability of a number of underlying data files. It is additionally noted that in the absence of several original blot images and the individual-level densitometry data, the PLOS ONE Editors are unable to fully resolve queries regarding interpretation of the western blot data.The vecchiar10@gmail.com.There is an update to the corresponding author\u2019s contact information for this article. The corresponding author\u2019s current email address is S1 File(PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file."} +{"text": "American Journal of Respiratory and Critical Care Medicine [European Respiratory Journal [After this article was publMedicine and Euro Journal .Specifically,1) Similarities were noted between the following figures:Scanning electron microscopy (SEM) data in Fig 2A (control) of , Fig 1C SEM data in Fig 2A (LPS) of and Fig Experimental overview diagram in Fig S1 of , and FilFlow cytometry data in Fig S2 of , Fig E2 The authors confirmed that the SEM panels are identical in the three articles. Regarding the supporting information files, the authors noted that the experimental diagram and flow cytometry figures are very similar, though not identical, because the same experimental workflow and strategy to identify neutrophils were used in all three studies.2) Quantitative data reported in histograms for some groups appear similar in \u20133.3) The three related articles \u20133 addresIn responding to these issues, the authors provided the following clarifications about the relationship between the studies reported in \u20133 and reThe studies reported in \u20133 all adThe study reported in aimed atThe study reported in dissecteThe study reported in aimed atThe experiments reported in \u20133 used tAnimal experiments displayed in Figs 1 of all were perThe authors apologize for not having clearly delineated in the relaPLOS ONE study are no longer available.The authors stated that the original underlying data for the PLOS ONE Editors issue this Expression of Concern.In light of the undeclared data reuse across publications and the unavailability of underlying data to support the article\u2019s results,PLOS ONE article [The control and LPS SEM panels in Fig 2A and the images reported in Fig S1 and Fig S2 report material that duplicates or is highly similar to content previously published in by the E"} +{"text": "Further study proposed that the positive geometry for a generic massless scalar theory with polynomial interaction is a class of polytopes called accordiohedra [\u03d5p theories and theories with polynomial interaction correspond to projective triangulations of accordiohedra. Following the very recent development [The story of positive geometry of massless scalar theories was pioneered in in the cdiohedra . Tree-lediohedra , 5 to thelopment we also"} +{"text": "This study aimed to assess the association between social engagement and conversion from Cognitive Impairment No Dementia (CIND) to dementia and to investigate the mediating role of cognitive and physical engagements on that relationship. Data from two waves (2010 and 2014) of the psychosocial and core modules of the Health and Retirement Study (HRS) were used. The sample consisted of 929 people who had CIND in 2010 and participated in the survey in 2014. Latent Class Analysis (LCA) with eight indicators of social engagement found three groups: formal and informal social engagement (20.7%), informal social engagement only (48.9%), and low social engagement (30.5%). Binary logistic regression analysis showed sub groups with higher levels and greater variety of social engagements were associated with lower probability of conversion to dementia in four years. Path analysis with structural equation modeling (SEM) framework showed the relationship between patterns of social engagement and lower conversion to dementia was mediated by having higher engagement in cognitive activities , but not by engagement in physical activities . Results from this study implied (1) promoting active social engagement may be a promising intervention to prevent or delay conversion from CIND to dementia, and (2) promoting social engagement may be a particularly effective and efficient strategy since it promotes other activity engagements that may itself prevent or delay conversion from CIND to dementia."} +{"text": "Bicuspid aortic valve (BAV) is the most common congenital heart defect and may account for more morbidity and mortality than all other congenital cardiac malformations combined. Two theories are commonly discussed for the elevated risk of aortic aneurysm and dissection in patients with BAV: 1) an increased hemodynamic load placed on the proximal aorta results in progressive dilatation and 2) a genetic or developmental abnormality in the proximal aortic tissue leads to weakness of the aortic wall.This study utilizes 4D Flow to collect multidirectional blood flow velocity data in the thoracic aorta of patients with BAV. The goal of the study is to characterize altered flow patterns in these patients and uncover potential hemodynamic contributors to aneurysm and dissection formation.Time-resolved, 3D phase contrast MRI (4D Flow) was employed to assess thoracic aortic blood flow in 12 individuals: 8 patients with bicuspid aortic valve and 4 healthy subjects. The technique, which has been previously validated, was performed with parallel imaging after the standard clinical MR evaluation.1a demonstrates normal flow with streamlines mapped onto a sagittal oblique plane viewed from right and left orientations respectively, 1b shows an eccentric jet resulting in marked right-handed helical flow in a patient with BAV and aortic coarctation but without aneurysm, 1c shows left-handed helical flow in a BAV patient with fusion of the right and noncoronary cusps. Evaluation of aortic flow jets in BAV patients and healthy subjects is included as Figures 2a and b represent systolic vectors from a plane orthogonal to the aorta just above the sinotubular junction in a healthy subject compared to 2c and d which demonstrate an eccentric, right anterior flow jet in a patient with fusion of the right and left coronary cusps; 3a and b show normal flow in a second healthy subject compared to 3c and d which show a left posterior flow jet in a patient with fusion of the right and noncoronary cusps.4D Flow evaluation of the ascending thoracic aorta revealed markedly abnormal systolic helical flow in 6 of 8 patients with bicuspid aortic valve. Five of these patients demonstrated an eccentric right anterior systolic jet and right-handed helical flow; at least two of these patients had fusion of the right and left coronary cusps, and three had aneurysms of the ascending aorta along with aortic stenosis and/or regurgitation. The other patient had a left posterior jet with left-handed helical flow, dilation of the aortic root and fusion of the right and noncoronary cusps. The two BAV patients with normal systolic flow in the thoracic aorta had central flow jets. Normal and abnormal systolic flow patterns are included as Figure Abnormal systolic helical flow is seen in the ascending thoracic aorta of patients with bicuspid aortic valve. Similar helical flow has been described in ascending aortic aneurysms associated with BAV, but we have demonstrated this flow pattern in two patients without aneurysm, suggesting that the pattern is not secondary to the dilated aorta, but may be implicated in the pathogenesis of aneurysm formation. The marked helical flow in the ascending aorta appears to be associated with eccentric flow jets in all 6 of our cases. In the single case of left-handed helical flow, fusion of the right and noncoronary cusps was found, a geometric configuration that may create a left posterior jet as we have demonstrated Figure . Identif"} +{"text": "Individuals are taking more responsibility for their retirement. However, economic stress generated by inadequate planning may pose a grave threat to well-being in retirement. Drawing on stress theory, this study examined how different types of social support mediate the relationship between economic stress and life satisfaction. We used the data from the 2013 and 2014 Korean Retirement and Income Study. Our sample was restricted to older Korean adults in retirement 55 to 96 years of age who were head of household . Confirmatory factor analysis was used to evaluate the measurement model for six latent constructs: 1) economic stress; 2) emotional support; 3) informational support; 4) instrumental support; 5) appraisal support; 6) life satisfaction. Structural equation modeling (SEM) was used to test this hypothesized model. The results revealed that both measurement model and structural model fit the data well. Standardized results from the SEM model adjusting for sociodemographic variables showed that economic stress directly predicted life satisfaction and two of four social support types directly predicted life satisfaction . Analyses demonstrated that economic stress may lead to lower levels of life satisfaction directly and indirectly through its effect on instrumental and appraisal support . These findings will help inform policymakers and institutions of the need to alleviate economic stress and increase particular types of support with potentially more serious impact on the well-being of older adults in retirement."} +{"text": "Despite the vast amount of research focused on neighborhoods within the environmental gerontology, very little attention has been paid to learning how older residents make sense of and describe the changes that have occurred within their communities over the course of their lives. The purpose of this study was to provide a space for residents to tell their stories of what it was like to live through neighborhood decline within Cleveland. Older adults are an ideal group for examining perceptions of neighborhood decline as they have the perspective to address both the historical changes of their neighborhood and the biographical changes of their lives. This study utilized data from 4 years of ethnographic observations with over 30 older (age 60+), African-American adults who have aged in place within Cleveland since their childhood. Additionally, multiple in-depth life history interviews were conducted with 13 long-term residents. Data was analyzed using grounded theory techniques for emergent themes. While each resident had their own unique perspective of neighborhood change, common themes emerged related to 1) institutional decline, 2) changes in safety and crime and 3) changes to the people living in their communities. The findings suggest that resident perceptions can help us better understand how neighborhood dynamics work their way into the lives of long-term residents. The results are particularly important as they provide the foundation for exploring how residents responded to neighborhood decline and why residents remained within their neighborhoods when so many others left."} +{"text": "The figures used in this manuscript contravened the copyright legislations of The United Nations (UN) regarding permissions to reuse images representing their Sustainable Development Goals (SDGs).Fig. 1 incorrectly used the UN\u2019s SDGs imagery as the background to their figure without citation or permission. The figure should have not included the imagery and should have been displayed as follows:Fig. 2 contained an image displaying the UN\u2019s SDGs which non-UN affiliations are not permitted to re-use. The figure should have displayed the following reusable image:The authors apologise for any inconvenience."} +{"text": "We appreciate Dr. Taylor\u2019s thorough review of the history of dipeptidyl peptidase-4 (DPP4) activity measurements. Although dilution of sitagliptin could account for the slightly diminished inhibition of DPP4 activity in controls compared with that previously reported, it could not account for the difference between controls and obese hypertensives reported in the paper, as DPP4 activity was measured using the same methodology in all groups. In addition, we reported an inverse correlation between body mass index and DPP4 activity, suggesting the effect may have been related to the volume of distribution of sitagliptin."} +{"text": "The assay was developed based on the predecessor assay using bradykinin (JPBA 2017). Both neuropeptides are of interest in inflammation and pain research and were thus explored for use with capillary blood and blood cards. Here, we present the protocols and set them in perspective to above neuropeptide assays for serum. Specifications TableThis MethodX article supplements work were we show the use of dabsylated substance P (DSP) as a neuropeptide reporter substance (NRS) for the monitoring of protease activity (PA) in serum The aim of this article is to describe the workflow for the use of a drop of blood, either used fresh or dried on blood cards, and set it in relation to the methods for serum for improved understanding. Validation data are presented in the associated Data in Brief article (1)Incubation of dabsylated neuropeptide with body fluid or other biochemical preparation where PA is of interest;(2)Purification of enzymatic fragments;(3)Thin-layer chromatography (TLC) for separation of enzymatic fragments;(4)Scanning and data analysis.The NRS-PA assay (NRS-PAA) is based on four general steps allowed replicate collection with a defined volume and were emptied into vials or onto blood cards (Whatman 903 Protein Saver Card, For healthy probands, 70\u201390% of DBK1\u20139 were degraded in 60\u00a0min The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} +{"text": "There is an error in the Funding statement. The corrected acknowledgment of the Funder should read \u201cThe scientific research start-up funds for openly recruited doctors (2017RCZX-19).\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "The authors identified a scaling issue with some of the measurements in the manuscript.The length of the scale bar overlain on the microcomputed tomography (\u03bcCT) data in http://cxidb.org/id-93.html). Please see corrected During investigation of this error, the authors realized that the \u03bcCT measurements of muscle length and width that they had used to estimate muscle volume had also been scaled incorrectly in This change in the estimate of muscle mass has a corresponding effect on the specific power and energy calculations.th sentence in paragraph 2 of the subsection of the Results titled, \u201cSnapping organ biomechanics,\u201d corrected text should read: \u201cSpecifically, the rate of change in the kinetic energy of the abdomen during loading implies energy release at a much higher power output than the DLMs and DVMs combined could possibly supply through contraction .\u201dThe fifth sentence in the first paragraph of the subsection of the Results titled \u201cSnapping organ elastic recoil and transformation\u201d should read: \u201cMuscles have previously been suggested to act as springs [10], and here the elastic energy storage is in the range achievable by the muscle cross-bridges [32] if all of the elastic energy were stored in the DLMs , but even the largest of these is an order of magnitude too small to account for the rate of energy release during unloading Click here for additional data file.S1 Methods(DOCX)Click here for additional data file."} +{"text": "The renewal capacity of the heart is extremely limited, with less than 1% cardiomyocyte turnover per year in an adult human heart is an important factor in regulating cardiomyocyte maturation and cardiomyocyte cell cycle activity but also achieve complete regeneration of an adult heart."} +{"text": "GACAL verifies C programs by searching over the space of possible invariants, using traces of the input program to identify potential invariants. GACAL uses the ACL2s theorem prover to verify these potential invariants, using an interface provided by ACL2s for connecting with external tools. GACAL iteratively searches for and proves invariants of increasing complexity until the program is verified."} +{"text": "This study aimed to examine the trajectory of depressive symptoms among Chinese older adults with disabilities and the role of adult children\u2019s support in predicting trajectory classes of depressive symptoms. Data were drawn from three waves of the China Health and Retirement Longitudinal Study (2011-2015). The sample included 1420 disabled older adults age 60+ at the baseline and completed all three waves of the data. Growth mixture model shows two-class depressive symptoms trajectories: the higher risk group (25.49%) and the lower risk group (74.51%). Logistic regression results showed that respondents who received a longer term of adult children\u2019s instrumental support were more likely to be classified in a higher risk group after controlling the covariates , while financial support and the frequency of contacts were not associated with the increased level of depressive symptoms. The policy implications were also discussed in this study."} +{"text": "This data article is related to the research article \u201cComparative life cycle assessment of coffee jar lids made from biocomposites containing poly (lactic acid) and banana fiber\u201d. The article reports the model parameters used to construct each stage and unit process inventory of the life cycle of coffee jar lids, and the subsequent inventories of the investigated system. It also contains details of calculations and descriptions of inventory uncertainties. Primary data were obtained from lab-scale and pilot-scale tests during product preparation. Secondary data collection was based on detailed review of related international and regional literature, databases and recognized web sites. The data presented here can be used by future life cycle assessment studies on natural fiber composites in packaging applications. Specifications table\u2022The data increase transparency of the LCA reported in the main article.\u2022The data can be used by other researchers or by stakeholders that are interested in modelling of natural fiber composites in packaging applications.\u2022The modelling parameters and the unit process inventories can be adapted to generate similar process inventory.\u2022The data has Latin-American relevance, and originates mainly from Colombia.1This article reports the modelling parameters and the life cycle inventory data of stages for manufacturing and landfilling of coffee jar lids made from biocomposites with banana fiber. 2The parameters and inventory data of coffee jar lids were generated in three stages, cultivation of banana, fiber and lid production. Data on the cultivation stage were collected from local government and regional literature. Data on fiber production were obtained from a pilot process using approximately 1.8 tons of pseudostem collected from three farms. The banana fiber was extracted by a fiber decorticator, washed and dried. Data regarding material flows were measured with an industrial balance. Chemical components of fiber and residue were measured through proximate analysis. Transport distances between locations of the different life cycle stages were taken from Google maps and the fuel emissions from regionalized inventories 3g2) underlying uncertainty analysis were described in detail in Rodr\u00edguez et al. (2020) The information given here includes all input and outputs flows from each process throughout the biochar life cycles constructed using model parameters given in"} +{"text": "Recently, increasing demand for the accurate assessment of the structural integrity and fitness-for-service (FFS) analysis of engineering structures has elevated constraint effects to one of the most important issues in fracture mechanics and structural integrity research. In this paper, the effect of crack tip constraints are investigated on the fracture toughness assessment of 9% Ni steel for application in liquefied natural gas storage tanks. Crack tip opening displacement (CTOD) tests were conducted using both conventional standard three-point bending (3PB) and wide plate (WP) specimens at a cryogenic temperature of \u2212196 \u00b0C. The distribution of the stress and strain fields near the crack tip in the 3PB and WP specimens were then obtained by FE (Finite Elements) analysis. Based on both the experimental and numerical results, the parameters of the Weibull distribution were obtained to evaluate the critical Weibull stress at brittle fracture. The equivalent CTOD ratio \u03b2 is defined as the ratio of the CTOD of the 3PB specimen to the CTOD of the WP specimen at the same Weibull stress. The application of the proposed CTOD toughness correction method to the WP results was then demonstrated in the context of a failure assessment diagram (FAD). It was determined that the conventional evaluation yields an excessively conservative result for WP specimens, but can be reasonably reduced by applying \u03b2. Global demand for natural gas is continuously increasing due to its convenience and status as an environmentally friendly energy source with a high energy density. Natural gas can be efficiently stored and transported as liquefied natural gas (LNG) by lowering its temperature below the liquefaction temperature, reducing its volume by 600 times. Technology for transporting and storing LNG has improved immensely over the past 30 years ,2. The pRecently, increasing demand for an appropriate assessment method for the structural integrity and fitness-for-service (FFS) analysis of engineering structures has resulted in constraint effects becoming one of the more important issues in fracture mechanics and structural integrity research. Previous studies have accordingly been conducted to clarify the effect of crack tip constraints in order to ensure the appropriate assessment of engineering structures ,6. Two-pThe present study accordingly focused on the effect of crack tip constraint on the fracture assessment of 9% Ni steel for application in LNG storage tanks using CTOD tests conducted using both conventional standard three-point bending (3PB) and WP specimens under a cryogenic temperature of \u2212196 \u00b0C. The distributions of the stress and strain fields near the crack tip in the 3PB and WP specimens were then obtained through FE analysis. Based on both the theoretical and experimental results, the parameters of the Weibull distribution of the critical Weibull stress at brittle fracture were then obtained. Next, the CTOD fracture toughness value obtained from the 3PB standard specimen was converted to that of the WP standard specimen by applying an equivalent CTOD ratio \u03b2, enabling the fracture assessment of 9% Ni steel by using a constraint-based failure assessment diagram (FAD). Finally, it was demonstrated possible to perform a more carefully adjusted, less conservative assessment by incorporating the CTOD correction for constraint loss in the 9% Ni steel structure of an LNG storage tank.Commercial 33 mm, 37 mm, and 40 mm thick plates of 9% Ni steel were evaluated in this study. The CTOD values of the WP specimens were calculated using the BCS model ,23. All Near crack-tip stress fields play an important role in determining the CTOD value ,24. To eThe crack tip stress fields were analyzed by increasing the CTOD value. The distributions of the crack opening stress w\u03c3 as the fracture driving force of the materials. This paper employs the Weibull stress criterion for the evaluation of the stress distribution and fracture behavior of the 3PB and WP CTOD specimens. The Weibull stress is given by the integration of the near crack-tip stresses in the fracture process zone as follows:The Weibull stress criterion was established for the assessment of the brittle fracture of metallic ferritic materials using the local approach. The local approach employs the Weibull stress Correcting for constraint loss is of critical importance to an accurate evaluation of structural integrity. As shown in The proposed procedure converts the 3PB specimen CTOD fracture toughness to the WP specimen CTOD according to their correlations to the Weibull stress methods ,21,26. TWhen using the conventional evaluation procedure with the CTOD values of the 3PB specimens, the resulting fracture ratios lie in an unsafe area above the curve in (1)WP specimens exhibited a larger CTOD fracture toughness than 3PB specimens. This is due to the fact that the tensile loading mode exerts a smaller constraint effect on the crack tip of the WP specimens than the bending loading mode applied to the 3PB specimens.(2)It was proven that the Weibull stress fracture criterion is a useful fracture parameter for the assessment of brittle fracture of 9% Ni steel when using the local approach. The Weibull stress (3)The conventional fracture toughness evaluation procedure resulted in an excessively conservative result that can be reasonably reduced by applying the equivalent CTOD ratio In this study, an appropriate assessment method for the fracture toughness of a 9% Ni steel for use in an LNG storage tank was proposed and conducted under a cryogenic temperature considering the difference in testing constraint effects on the material CTOD. The utility of this method was demonstrated using the fracture toughness test results, FE modeling, Weibull stress criterion, and FAD analysis. The following conclusions were obtained from this study:"} +{"text": "The aim of the study was to investigate current practice and policies of therapeutic drug monitoring (TDM) service requesting and result reporting in Czechia and Slovakia.All 149 laboratories that measure plasma drug concentrations were given an online questionnaire during a regular external quality assessment TDM cycle. The questionnaire consisted of 17 questions. The optimal TDM practice was defined as the application of all elements needed for reporting a recommendation for further drug dosing (positive response to question number 16).The response rate was 69%, 103 out of 149 laboratories measuring drug concentrations. Only 12% (12 out of 103 laboratories) of the laboratories implemented all elements needed for optimal TDM practice and reported a recommendation. Both paper and electronic request forms were used by 77 out of 103 (75%) laboratories. A total of 69 out of 103 laboratories (67%) specified the type of sampling tube on their request form. Cystatin C was used for prediction of renal drug elimination by 24% (25 out of 103) of participants.Small number of laboratories implemented all elements needed for optimal TDM practice and report a recommendation on further dosing. Further efforts in education on optimal TDM practice as well as harmonization of service are desirable. Therapeutic drug monitoring (TDM) is a part of laboratory medicine that enables correct drug dosing for medications with a narrow therapeutic index cycle of TDM from October 1All responses were taken into consideration and no answers were excluded. The questionnaire had an important educational role to educate laboratory professionals on the importance of pharmacokinetic parameters and their implications for drug dose adjustment. The list of the questions in the questionnaire is displayed in The optimal TDM practice was defined as the application of all elements needed for reporting a recommendation for further drug dosing (positive response to the question number 16).Data were collected to Microsoft Word Office 2007 program . The absolute and relative numbers of responses to particular questions were calculated by Microsoft Excel Office 2007 program .The denominator of all relative proportion calculations of answers to particular questions was the total number of participating laboratories (N = 103).The response rate was 69% (103 out of 149 laboratories). Not all participants responded to all questions. Six questions were answered by all 103 participants of the survey. Other questions were not answered by all laboratories. Both paper and electronic request forms were used by 77 out of 103 (75%) laboratories.Only 12% (12 out of 103 laboratories) of laboratories performed the optimal TDM practice with reporting an interpretative comment. These laboratories are university medical laboratories and laboratories of specialized centers such as a transplant hospital. They also require pharmacokinetic information on their request forms. They measure 10 or more drug concentrations. A total of 71 laboratories measured five or less drug concentrations. A total of 69 out of 103 laboratories (67%) specified the type of sampling tube on their request form. Cystatin C was used for prediction of renal drug elimination by 24% (25 out of 103) of participants. Responses to the questionnaire by participating laboratories are provided in We analysed the request form and reporting of results in therapeutic drug monitoring by medical laboratories in Czechia and Slovakia. Only 12% of laboratories adopted optimal TDM practice according to Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology with request form including all elements needed for optimal TDM practice that enable reporting a recommendation for further drug dosing (positive response to the question number 16) with cystatin C is probably superior compared to creatinine-based eGFR in the prediction of renal drug elimination (Barretto In his review article, Grubb reported a conclusion that cystatin C is indispensable for evaluation of kidney function (et al. described TDM strategy with the collection of all pharmacokinetic information at his university center in patients treated with antipsychotic drugs (Grundmann An Interpretative comment was included among quality indicators in the post-analytical phase (Our study shows the current approach of medical laboratories in Czechia and Slovakia to TDM practice. There is a low number of interpretative comments in TDM reporting. The aim of this study is to improve the harmonization of TDM practice. The presence of an interpretative comment on the TDM report may be used as a quality indicator of the post-analytical phase.Kacirova and Grundmann monitored monthly trough concentrations of gentamicin, amikacin, and vancomycin as an indicator of the quality of medical care and analysed the causes of potentially toxic concentrations (The limitations of the study are incomplete response rate and our inability to verify responses. Some participants did not respond to all questions.In summary, the small number of labs implemented all elements needed for optimal TDM practice and report a recommendation on further dosing. Harmonization of TDM service is desirable. The presence of an interpretative comment on the TDM report may be used as a quality indicator of the post-analytical phase."} +{"text": "The presence of oedema in human tissue increases the observed longitudinal and transverse magnetisation relaxation times (T1 and T2). MRI can therefore be used to assess the extent of cardiac oedema after a myocardial infarction (MI). The oedematous myocardium is considered to be at risk of becoming infarcted. The oedema mass in the left ventricle (LV) may therefore be a useful indicator of prognosis and of the effectiveness of treatment. Current methods of quantifying cardiac oedema are essentially visual in nature, involving either contouring and planimetry or the rating of oedema severity in cardiac segments. Inter- and intra-observer variability reduces the sensitivity of these techniques to small changes in mass.To establish an automated method for the quantification of cardiac oedema and to compare the results with a visual method.Twenty patients were scanned within 48 hours of the onset of MI symptoms and seven were rescanned four weeks later. A triple inversion recovery prepared turbo spin echo sequence was used on a Philips Intera CV 1.5 T system. 2D short-axis images of thickness 10 mm were acquired to cover the entire LV with no inter-slice gaps. Epicardial and endocardial contours were added manually to each slice image.Oedematous regions apparent in the images were manually contoured by a cardiologist who also had access to steady state free precession cine images and late enhancement images. An automated computer segmentation was carried out using the LV contours and triple inversion recovery prepared images. The voxel intensity histogram for the entire LV was clustered by fitting two Gaussian functions to it. An initial segmentation was performed on the basis of a signal intensity threshold set at two standard deviations above the mean of the lower intensity Gaussian. Three-dimensionally connected regions with a mass less than 1 g were discarded, as were those regions that lay further than 2 mm from the endocardium. Finally, the surfaces of the regions were smoothed and holes within them were filled.-3.The oedema masses for the visual and computer segmentations were calculated assuming a density of 1.05 g cmAn example of a triple inversion recovery prepared turbo spin echo image is shown in Figure The computer algorithm described has demonstrated the segmentation of cardiac oedema within images having a T2 weighting. A comparison with a visual segmentation shows no significant bias. The performance of the visual segmentation is limited by the performance of the human visual system, while the computer segmentation is hindered by its lack of anatomical and pathological knowledge. Further work is required to assess whether the computer algorithm can improve scan-rescan variability and make clinically accurate assessments of the severity and progression of cardiac oedema."} +{"text": "As such, improving nanoparticle performance through optimization of their physicochemical properties represents one of the most widely investigated topics in preclinical nanotechnology research. In this issue of Bioengineering & Translational Medicine, a team led by Professor Rangaramanujam Kannan from the Center for Nanomedicine, Wilmer Eye Institute at Johns Hopkins School of Medicine, describes a systematic study to determine how dendrimer size affects targeting of brain tumors in vivo. This work utilized two distinct orthotropic and clinically relevant brain tumor models in both mice and rats to show that Generation 6 dendrimers exhibited ~10\u2010fold higher tumor accumulation at 24\u2009hr as compared to Generation 4 dendrimers. Generation 6 dendrimers were experimentally determined to be ~6.7 nm in diameter whereas Generation 4 dendrimers were\u2009~\u20094.3 nm in diameter, an important distinction that was most likely responsible for the significantly enhanced accumulation of the smaller Generation 4 dendrimers in the kidneys over a 48\u2009hr period in both animal models. The authors associated this enhanced kidney accumulation with higher renal clearance and thus less persistence and shorter circulation in the vasculature, thereby limiting opportunities to interact with the brain tumors and decreasing accumulation. This work clearly demonstrates the importance of considering nanoparticle physical properties for their end application by highlighting how an ~2.3 nm difference in diameter could influence accumulation in brain tumors by ~10\u2010fold.2Phage therapies have recently received considerable interest, in part due to their potential in providing novel and complementary therapeutic mechanisms (as compared to antibiotics) for the treatment of various pathogenic infections. Phages are dominantly protein\u2010based and thus face many of the stability and formulation challenges of biologics. Researchers from the lab of Professor Hak\u2010Kim Chan from the Advanced Drug Delivery Group in the School of Pharmacy at the University of Sydney have developed a spray dried powder formulation of Pseudomonas phage PEV20 that maintains high activity after 250\u2009days of storage. Through the use of plaque assays to evaluate phage titer over time under various temperature and relative humidity conditions and differential scanning colorimetry to determine the glass transition temperature of spray dried formulations, the authors concluded that as the glass transition temperature of the powders approached the storage temperature that the viable storage of phage decreased. Although these results may have been expected, this work highlights the need to develop and validate technologies for the implementation of phage\u2010based technologies.3Recent work from Professor Jordan Green's lab in the Department of Biomedical Engineering at Johns Hopkins University details a nanotechnology capable of enhanced vascular circulation that was applied as a technology to facilitate detoxification in a sepsis model. The author's utilize red blood cell membranes and anisotropic shaped nanoparticles, thereby combining chemical and physical modifications, to improve detoxification as compared to nanoparticles with only a singular modification. Overall, this work highlights the importance of investigating and optimizing both the physical and chemical features of nanoparticles. Moreover, it was demonstrated that physical and chemical modifications to nanoparticles can act synergistically, thereby improving nanoparticle performance beyond what a single modification could afford."} +{"text": "We interrogate whether Foucaldianism contributed, in the past as well today, towards a certain myopia in France regarding biostatistics and its relation to social inequalities in health. One might ask whether this very data could provide an appropriate response to the Foucauldian question: What kind of governance of life is the pandemic revealing to us?In this short paper we analyse some paradoxical aspects of France\u2019s Foucauldian heritage: (1) while several French scholars claim the COVID-19 pandemic is a perfect example of what Foucault called"} +{"text": "The authors wish to make the following corrections to our previously published paper . Because of partially incorrect data plotted by error, replace old Figure 2with new Because of publication of the incorrect figure, replace old Figure 5with new"} +{"text": "The data presented in this paper offer the information needed for assessing the water footprint of steel production. The data provided here are related to the research paper, \u201cAn Improved Water Footprint Model of Steel Production Concerning Virtual Water of Personnel: The Case of Iran\u201d [1]. The data were collected form analysing a case study and reviewing the relevant literature. The case study data were collected from a large steel plant in Iran. All information received from this plant is related to 2017. The primary data were collected by interviewing the head of the research and development of the plant. All relevant formal documents of the plant and information on its web site were also reviewed. For data related to the water footprint of energy and raw materials, used for steel production, the relevant studies were reviewed. Specifications Table\u2022The data are important as they provide an independent reference for steel's water footprint assessment.\u2022Steel's manufactures might benefit these data in assessing their dependence on water resources particularly for developing the current steel plant and for finding the location of a new plant.\u2022Researchers might use these data to compare their findings on water footprint of steel production in different countries with different technological routes.\u2022Researchers might also use these data to evaluate the impact of energy and employees on the water footprint of steel production.\u2022The data help society think about the water footprint of steel production in the short term and develop a sustainable steel production program in the long term.1The data set provided in this section consists of two parts. The first part is related to the steel plant. The second part is related to the water footprint data of energy and raw materials, used in steel plants, collected from the literature.1.11.2The data obtained from the literature comprise water footprints of: (1) natural gas mining and processing; (2) electricity generation; (3) coal mining; (4) iron ore mining; (5) limestone mining; (6) transportation (diesel-based vehicles); and (7) employees' meal. 2The experimental design, materials, and methods are based on a model boundary and a proposed water footprint model from There is no conflict of interest."} +{"text": "Radiation-associated angiosarcoma of the breast (RAASB) is increasingly diagnosed in breast cancer survivors.3We performed a comprehensive analysis of RAASB patients identified from the database of the Finnish Cancer Registry over 25 years.\u2013The evidence from this and previous studies suggests that the primary treatment of a localized RAASB is radical surgery.2Regrettably, a number of RAASB patients later progress into metastatic disease."} +{"text": "Kartal and Collegues from Turkey in this important paper studied the oncological and functional results of open partial nephrectomy (OPN) and laparoscopic partial nephrectomy (LPN) at the T1b clinical stage in 63 patients and compared 41 submitted to OPN and 22 submitted to LPN is considered the gold standard for treating localized renal tumors -6. In la"} +{"text": "Little is known about the unique experiences of sexual and gender minority (SGM) caregivers of people with dementia or their care recipients. We used an electronic survey to assess psychosocial measures within this caregiving population, including measures related to the care recipient. The majority of caregivers (N=285) were gay men (62%). Most respondents were white (80%), with a quarter identifying as Latinx. The majority of caregivers were a spouse/partner (59.3%) and were providing care for someone who identified as LGB (70%), with 20% caring for someone transgender. Half of care recipients did not have an advance directive. The majority of care recipients needed assistance with \u22655 instrumental activities of daily living (83%) and \u22651basic activities of daily living (74%). This study is the first to provide data regarding the unique needs of SGM caregivers of someone with dementia and will support the development of targeted interventions for this population."} +{"text": "Vitamin D seems to be very important for general health but also for athletic performance ,2. InsufThe present special issue on \"Vitamin D and Sport Performance\" included two reviews ,7 and siThe original research articles included studies on soccer ,9,13 andIt is hoped that this special issue will aid to raise the awareness of the current trends of Vitamin D prevalence and supplementation. Practitioners working with athletes should encourage them to be screened regularly for plasma concentration of Vitamin D level. The articles of this special issue are expected to trigger further research about the relationship of Vitamin D with sport performance."} +{"text": "The dark photon with a large wavelength is efficiently produced due to the inflaton motion during inflation and becomes non-relativistic before the time of matter-radiation equality. We compute the amount of production analytically. The correct relic abundance is realized with a dark photon mass extending down to 10"} +{"text": "Our findings have revealed that prior knowledge of hepatic regulation of UGT2B17 expression, mainly derived from the canonical promoter, is not relevant to its expression in B-cells and other cancer cells.cus Fig. .10 with the goal to optimise cancer patient care.It remains to be experimentally demonstrated whether these HERVs play a role in the regulation and shaping of UGT2B17 expression in lymphoid and other cancer cells. Clarifying the in vivo implications of UGT expression and enzyme activity over disease course, induction of UGT expression upon drug treatment and the impact on drug response are also warranted. These aspects are part of our ongoing investigations to gain more insights into how the UGT pathway might impact cancer progression and drug response,"} +{"text": "Uniatrial biventricular connection (UBC) is a rare cardiovascular anomaly characterized by absence of one atrioventricular connection and drainage of the other atrium via a solitary atrioventricular valve into both ventricles. The absent atrioventricular connection may affect either the left or right atrium. Because of the absence of one atrioventricular connection hearts with UBC have been classified among functionally univentricular hearts requiring palliative treatment according to the Fontan principle.We report two further patients with UBC. In one of these patients careful echocardiographic examination of the atrioventricular junction in early infancy revealed the possibility of biventricular repair based on the favorable anatomy of the atrioventricular valve and balanced ventricles in the presence of an inlet ventricular septal defect (VSD).Both patients presented in the neonatal period for evaluation of complex congenital heart disease. The anatomy of the atrioventricular valves in our patients was indistinguishable from atrioventricular septal defects exhibiting the morphology of a common valve with superior and inferior bridging leaflets. The common atrioventricular valve was connected exclusively to the right atrium draining into both ventricles while the left atrium drained into the right atrium via a secundum atrial septal defect. In one of our patients biventricular repair with good longterm-result was performed by reseptation of the atria, patch repair of the VSD and septation of the atrioventricular valve. The second patient underwent univentricular palliation according to the Fontan principle.The echocardiographic findings in our patients suggest that at least some patients with UBC represent a variant of atrioventricular septal defects associated with extreme ventriculoatrial malalignment resulting in fusion of the deviated primary atrial septum with the lateral aspect of the atrioventricular junction. This offers the option of septation of the common atrioventricular valve and biventricular repair in patients with adequate size of both ventricles. Exact echocardiographic analysis of the morphology of the atrioventricular valve is essential to distinguish these patients with a morphologically common atrioventricular valve in early infancy from other variants of absent atrioventricular connection and to select those who are suitable for biventricular repair. Hearts with UBC are characterized by the absence of one atrioventricular connection while the other atrium drains into both ventricles , 2. The Because of the absence of one atrioventricular connection hearts with UBC have been classified among functionally univentricular hearts . In our Our first patient was born at term. Echocardiography in the newborn period showed situs solitus, levocardia and absent left atrioventricular connection. The right atrium drained via a solitary atrioventricular valve into both ventricles. The morphologic left ventricle was dominant while the right ventricle was significantly hypoplastic Fig.\u00a0a. Both vOur second patient presented at the age of 8\u2009days with severe congestive heart failure. Echocardiography revealed situs solitus, levocardia and absent left atrioventricular connection Fig.\u00a0. The atrHearts with UBC represent a rare but distinct cardiovascular anomaly . The larBased on the experience in our patients and on previous reports in the literature we believe that the paradox of one absent atrioventricular connection in the presence of an AVSD does exist. It can be explained as the result of extreme ventriculoatrial malalignment Fig.\u00a0: It is wIt has been suggested to group all patients with UBC among functionally univentricular hearts requiring univentricular palliation since biventricular repair appeared impossible in the presence of a unilateral absent atrioventricular connection . HoweverWhile it has been suggested to address the atrioventricular junction in these patients as solitary and not as common , the morEchocardiographic evaluation of infants with absent right or left atrioventricular connection should include the differential diagnosis of UBC with a morphologically common atrioventricular valve. Univentricular palliation according to the Fontan principle is associated with significant long-term morbidity. If the presence of the common atrioventricular valve is missed on echocardiography the respective patient may be deprived of the option of possible biventricular repair and its associated better long-term prognosis.Additional file 1: Video S1. Apical 4 chamber view in patient 2 showing UBC with absent left atrioventricular connection. Both ventricles are of equal size. Note the atrial septum connecting to the left lateral aspect of the atrioventicular junction and the absence of a primum ASD.Additional file 2: Video S2. The subcostal LAO view in patient 2 reveals a common atrioventricular valve with superior and inferior bridging leaflets."} +{"text": "The following statement in table 3 has been corrected as it erroneously stated that the product label has a black box warning for constipation.\"A retrospective study from October 2018 to January 2020 evaluated 119 patients who took a CGRP mAb. Some monoclonal antibodies such as erenumab caused constipation in more than 20% of the patients and now carries a black box warning.\"This error was the result of mistakenly citing an older version of the article on a health care provider website rather than the up-to-date version on the journal website. As a result, the statement has been amended to the following and reference 28 has been updated to link to the journal website.\"A retrospective study from October 2018 to January 2020 evaluated 119 patients who took a CGRP mAb. Some monoclonal antibodies such as erenumab caused constipation in more than 20% of the patients.\""} +{"text": "Social support networks are an integral component of an individual\u2019s life. This presentation investigates the complementary roles of family and church members as sources of informal social support among African Americans. The analysis utilizes the African American sub-sample of the National Survey of American Life. A pattern variable was constructed that describes four types of church and family networks: 1) received support from both family and church members, 2) received support from family members only, 3) received support from church members only, and 4) never received support from family nor church members. Overall the findings indicated 1) the majority of African Americans received support from both groups, 2) a small group of respondents were socially isolated in that they did not receive assistance from either family or church members, 3) for some African Americans who were estranged from their family members, church members were an alternative source of social support. Part of a symposium sponsored by the Religion, Spirituality and Aging Interest Group."} +{"text": "After this article was publAll data reported in As shown in In Raw data underlying all other results reported in the article are available upon request from the corresponding author, except for four phosphorimager images that are not accessible anymore.The authors apologize for not indicating the splicing junctions clearly in the published article.S1 FileResults shown in (PDF)Click here for additional data file.S2 File(PDF)Click here for additional data file."} +{"text": "This is the case of a 78 years old patient with a history of acute coronary syndrome complicated by rupture of the left ventricle. The ventricular wall defect was closed by tachosyl heamostatic patchs and gluing. Two months after the occurrence of the acute coronary syndrom, computed tomography detected a huge apical pseudoaneurysm of the left ventricle ruptured into the pericardium (A). The patient underwent median sternotomy and cardiopulmonary bypass associated with a moderate hypothermia at 28\u00b0C, then, we performed the DOR technique for the cure of the pseudoaneurysm (B), using a Gore Tex patch and Teflon felt support ."} +{"text": "To evaluate the impact of structural changes in a limited sample of adult preterms with foveal immaturity from optical coherence tomography (OCT) B-scan images and to estimate layer displacement and changes in areal and volume magnification within the inner fovea.Layer thickness was measured in conventional and directional OCT scans from eight preterms with different degrees of foveal immaturity and five controls (20\u201333 years of age). We obtained reflectivity profiles of the outer plexiform layer (OPL) and manual segmentation data of the inner nuclear layer (INL) and the combined ganglion cell layer (GCL) and inner plexiform layer (IPL) at specified eccentricities from 300 to 900\u2009\u00b5m. Displacement of cumulative thickness curves of preterms compared with that of the controls was used to estimate retardation of layer displacement. Changes in areal magnification and layer thickness were used to construct a structural model of redistribution within the fovea of preterms.Retardation of centrifugal layer displacement of OPL and all inner retinal layers (IRL) was marked in both preterm groups with foveal immaturity, whereas retardation was marginal in the preterm group without clinical signs of immaturity. Retarded displacement within the IRL and OPL had a major impact on available space within the central fovea.A marked retardation of displacement was demonstrated for all IRL within the immature fovea of preterms with decreased areal and volume magnification and reduced space available for synaptic communication coupled to the degree of immaturity. Marked changes occur in the human fovea during normal development. Histological studies show that\u00a0towards the latter part of gestation the foveal pit deepens and that neurons within the ganglion cell layer (GCL) and inner nuclear layer (INL) start to disappear from the foveal centre (FC) \u20133. The mCharacteristic persisting signs of immaturity in preterms are increased thickness of the different layers of the inner retina together with presence of a sheet of outer plexiform layer (OPL) covering FC in combination with a reduced foveal depression . An incrWe compared thickness profiles of IRL\u00a0and OPL to estimate the displacement difference of various layers\u00a0in preterms versus controls. Our aim was to analyse the proposal of retarded displacement in preterms. Furthermore, the purpose was to evaluate the structural consequences of immaturity for cells and networks in terms of available space. We considered an estimate of possible retardation of IRL displacement from FC to be of great interest to evaluate possible functional impact of immaturity.It has been estimated that the available space of foveal cone pedicles is increased due to the effect of areal magnification caused by lateral displacement during normal development in monkeys , 16. A sA detailed description of the subjects and the imaging procedure is given elsewhere but is on\u2009=\u20093)\u00a0-\u00a0no clinical signs of foveal immaturity and no ROP, PG2 (n\u2009=\u20093) - incomplete IRL displacement with a shallow foveal pit and no ROP, and PG3 (n\u2009=\u20092) - incomplete IRL displacement with very shallow foveal pit and treated ROP. Inclusion criteria for controls (n\u2009=\u20095) were birth at term, no history of ocular disease and absence of visual complaint.Selected eyes from eight young adults with a history of prematurity and five controls were imaged using conventional and directional SD-OCT with a Cirrus HD-OCT . The preterms were divided into three prematurity groups (PG) after clinical grading of OCT scans based on the signs of reduced FD and the presence of post-receptor layers or IRL at FC as follows: PG1 for each case. Images were registered, averaged and flattened to the posterior retinal pigment epithelium boundary using a semiautomatic custom software written in MATLAB .The temporal side of the SD-OCT B-scan images was selected for analysis to avoid the asymmetry caused by the marked thickening of the retinal nerve fibre layer on the nasal side. Measurements were performed at selected temporal eccentricities defined by the individual distance between FC and the foveal rim for each case. Individual retinal scaling factors were calculated from measurements of axial length to compensate for differences in lateral magnification in all cases except the PG3 group . Layer tThickness profiles of IRL\u00a0and OPL were compared to estimate the displacement difference of various layers in PG versus controls. The displacement of cumulative thickness curves of preterms from that of controls were used to estimate retardation of layer displacement. The area under the curve was calculated using proFit v6.2.16 as the definite integral of a spline curve fit to the data points of mean IRL thickness, mean HFL\u2009+\u2009ONL thickness and mean OPL thickness of C and PG. The lower and upper integral limits for the cumulative curves were values from a minimum eccentricity of zero to a maximum eccentricity defined by selected landmarks. Retardation from a specified temporal eccentricity in controls was obtained by selecting a location along the eccentricity axis, moving vertically to intersect the cumulative function of controls, and measuring the horizontal distance to the corresponding cumulative function index was calculated to relate retardation to severity of immaturity and obtain a quantifiable measure of immaturity at FC. Our FDA index, which is a modification of the macular developmental arrest (MDA) index described by Bowl et al. , was defA structural model based on the areal magnification was estaThe research followed the tenets of the Declaration of Helsinki. All subjects were informed about the goals, consequences and protocol of the study, and then provided their written informed consent.The centrifugal displacement of all inner foveal layers from FC\u00a0towards the foveal rim were retarded compared with controls in all PG Table\u00a0. Group aThe average retardation of all layers was marked within the foveal region (300\u2013900\u2009\u00b5m eccentricity) in PG2 and PG3, i.e. groups with IRL persistence and reduced FD Table\u00a0, whereasLayer displacements of PG2 and PG3 compared with reported values of displacement of ganglion cells and cone pedicles from corresponding cones in normal fovea are pres2 in normals [A model of the structural consequences of a graded retardation of displacement of IRL and OPL was constructed using the parameters retardation, areal magnification and layer thickness ratio Table\u00a0. The siz normals . The aveThe reduction of volume or available space compared with that of the controls was most marked in the different layers of the central part of the fovea and the average reduction within the foveal region ranged from 37 to 62% and from 21 to 40% of that of controls in preterms with mild/moderate immaturity (PG2) and with severe signs (PG3), respectively where it ranged from 15 to 33% in PG2 and 6 to 13% in PG3. An increased thickness ratio responses within the fovea observed in the macula of preterms with and without ROP in a number of recent studies \u201333. SincThe structural consequences of minified cone pedicles and synaptic networks can play a critical role in more complex visual functions where all synaptic couplings need to be optimal. This may explain the discrepancy between the effect on different visual functions with lack of correlation between reduced visual responses and visual acuity. Electron microscopy and immunocytochemical studies in primates have revealed a complex cone pedicle architecture . A markeAccording to our opinion it is therefore too early to state that the foveal pit is of visual insignificance based on the fact that visual acuity and foveal cone inner and OS specialisation is within normal range in spiteThere were limitations to this study. The low number of subjects may limit our conclusions regarding a retarded centrifugal displacement of IRL due to the low statistical power of our analyses. However, the use of characteristic landmarks of the fovea established in the previous study , the groAnother limitation is the measurement and analysis of the OPL, a very thin layer with a thickness of 2\u20135 pixels. A layer thickness measurement difference of one pixel will thus result in large variations. Our observation was that measurements from straight images yielded unreasonable OPL thickness values when compared with data from the literature . A betteIn conclusion, our study of the immature fovea presents evidence for a retardation of normal centrifugal displacement of inner cell structures from FC and the foveal rim. A model of the structural consequences of foveal immaturity indicates that available space for synaptic communication is markedly reduced within the inner part of the central fovea due to the retarded displacement. Further studies of the structural impact of premature birth and foveal immaturity on central visual functions using larger populations of preterms are needed in order to confirm the findings of the present study and elucidate the consequences of arrested foveal development for vision.Characteristic persisting signs of immaturity in preterms are an increased thickness of inner retinal layers in combination with a sheet of outer plexiform layer covering the foveal centre and a reduced foveal depression.An increased thickness of inner retinal layers associated with a decreased foveal depression is still observed at adult age in most preterms born before 28 weeks of gestation.Our study presents evidence of a retarded centrifugal displacement of inner cell structures from the foveal centre in the premature fovea.We present a model of the structural consequences of foveal immaturity for evaluation of decreased available space in the immature fovea."} +{"text": "The penultimate sentence of the first paragraph should have read that devastating rates of suicide attempts for autistic girls and women were found. The last sentence of the fifth paragraph should have read that the highest age-based suicide rate in autism was found for individuals aged 30 to 39 years. This article has been corrected.1In the Invited Commentary \u201cDeath by Suicide Among People With Autism: Beyond Zebrafish,\u201d"} +{"text": "In the initially published version of this article, the representative images of the invasion test of A549 cells overexpressing miR-940 with or without TGF-\u03b21 stimulation in Figure 3C are wrong. The correct Figure 3C is as follows:The correction made in this erratum does not affect the counting results and original conclusions. The authors apologize for any inconvenience or misunderstanding that this error may have caused."} +{"text": "Cyclospora cayetanensis. This species is only known to infect humans and is acquired when oocysts are ingested through food or water contaminated with feces that contain the parasite. The illness was first reported in 1979, and the organism was identified and named in 1994 which were matched to a specific temporal-genetic cluster codeIn Florida, reported numbers of cyclosporiasis cases have been increasing over the last 10 yearsThe Florida Department of Health required that county public health personnel complete the CDC Cyclosporiasis National Hypothesis Generating Questionnaire (CNHGQ)**CDC uses a genotyping tool to aid epidemiologic case linkage in near-real time. Among 211 successfully genotyped specimens from Florida, 153 (73%) were assigned to the same temporal genetic cluster (2022_001), including 43 (96%) of 45 genotyped specimens linked to the bagged salad cluster and 30 (39%) of the 76 persons reporting Caesar salad kits with no further identifying information. This information was shared with the Food and Drug Administration along with source information for the implicated product from the grocery store chain to facilitate traceback of the product; however, the source of the likely contaminated product was not identified.In this investigation, results from genotyping analysis demonstrated strong agreement between the genotyping and epidemiologic data. The combination of the completed CNHGQ and genetic data strengthens evidence for identifying cases potentially linked to the same source of infection and can guide future investigations."} +{"text": "Epidemiological studies shows that exposure to early stress in the form of abuse and neglect in childhood increases the risk for later development of severe mental illneses such as schizophrenia and bipolar affective disorder.\u2022Study the prevalence of childhood trauma in a sample of adult patients diagnosed with schizophrenia and bipolar disorder.\u2022Identify potential differences of types of childhood trauma between both groups.This cross-sectional study was conducted on 200 patients admitted to the inpatient unit at Maamoura psychiatric hospital in Alexandria. Assessment of the history and nature of childhood trauma was done by Arabic version of childhood trauma questionnaire (CTQ).There was no statistically significant difference between the two studied groups regarding past history of childhood trauma (p=0.397). (Table 1) Regarding the nature of childhood trauma, the history of emotional abuse and physical neglect was more commonly associated with developing bipolar disorder whereas the history of physical abuse was sihnficantly more commonamong schizophrenia patients. (Table 2)History of childhood trauma is common among adult patients with schizophrenia and bipolar disorder with no significant difference between both groups. Nature of trauma may be diffirent where physical abuse might be correlated with later development of schizophrenia.None Declared"} +{"text": "A 47-year-old symptomatic male patient with history of idiopathic pulmonary arterial hypertension (PAH) since 2004 was referred to our institution for evaluation. The patient complained of hemoptysis and chest pain since five months ago. On-admission pulmonary artery pressure was 51\u00a0mmHg. Axial A and corPulmonary artery aneurysm associated to PDA and Eisenmenger's syndrome is a very unfrequent clinical entity and only a few cases have been reported in the literature.The author has made substantial contribution to all of the following: (1) provide care to the patient as part of the surgical team (2) write the entire manuscript and edition of the images (3) review the content and final approval of the version. (4) Submit the manuscript to the journal.Informed consent was obtained from the patient for publication of the clinical data and images present in this manuscript.The author declares that he did not receive any fees or funding for the development of the clinical image presented.The author declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} +{"text": "The authors regret some amends to the wording of Supplementary Figure 1 caption were not included in the final version. The correct caption is shown below:Supplement Figure 1.Latimeria mother that shows the cochlear aqueduct (CA) that is ending in the basilar papilla (BP). Unfortunately, the sections of Bernstein (2003) were badly fixed and lead to a different interpretation (B). First, a new end organ (eo) is suggested in a new dorsal or ventral position from the canalis communicans . Neither the nerve fibers nor the position that separates between the cochlear aqueduct and the basilar membrane remain unclear in the description of Bernstein (2003) that indicate a foramen (for) that ended at the BP (compare A and B). A new \u2018end organ\u2019 (B) that most likely belongs to the lagena (L) is shown below the saccule . Not that there is no formation of a \u2018canalis communicans\u2019 that ends in the basilar papilla (compare A and B). Modified after unpublished sections (One ear was well fixed (A) in the littermates of sections and (BerThe authors would like to apologise for any inconvenience caused."} +{"text": "This is a peer-review report submitted for the paper \u201cInformation Technology Ambidexterity, Digital Dynamic Capability, and Knowledge Processes as Enablers of Patient Agility: Empirical Study\u201dMethodsDescribe the study [Move the highlighted (in the reviewed manuscript) content under Data Collection Procedures to a new subsection under subsection heading Study Population (see comments in the reviewed manuscript)The highlighted content should be under a new subsection heading Study DesignProvide content on another two subsection headings:Sampling TechniquesSample SizeSeparate content under Data Collection Procedure into two new subsection headingsData Collection Tool and ProcedureData Analysis and ManagementMove Table 1 to Analyses & Results sectionProvide content under two new subsection headings: Inclusion and Exclusion CriteriaEthics ConsiderationsAbstractDo not begin a sentence with abbreviation of figureUse past tense under Methods See comments in the reviewed manuscriptIntroductionUse physicians in lieu of doctorsUse health care providers not other medical professionalsKeep in-text citation to the end of sentenceAdd health information management professionals among the key stakeholdersConsider reducing the whole of section 2 to 1-2 paragraphs and keep it within the Introduction section just before your study objective. This is to reduce readers\u2019 boredom.Compress the content under research models and hypothesesResultsMake your findings more visible hereMake your writing more readable to known and unknown readersDiscussionPlausible and insightful discussion but not a reflection of the content under the Results. Make the Results section more readable and meaningful to your audience.FigureUse Fig not FigureAcknowledgement It is scientifically necessary that you acknowledge the numerous (n=107) participants, who are the major stakeholders in your research.ReferenceList at least 3 authors before et al Follow the Referencing Style consistentlyOthersUse participants not respondents"} +{"text": "In the original article there are two of the authors have a wrong affiliation. Author Theo Senden has affiliation 3 and author Angelique de Rijk (last author) has affiliation 2 (this is the same as affiliation 6).The updated authors and their affiliation details are given in this erratum.The Original article has been corrected."} +{"text": "Vaccination against SARSCov-19 all over Europe reached over 80% of adult population confronting the pandemic burden on National Health Systems. On the contrary large parts of population remained unvaccinated. These groups are mainly individuals with poor socioeconomic status and psychiatric patientsto determine the ratio of fully vaccinated patients among the hospitalized and outpatient of Psychiatric Hospital of Attika. The reason of vaccination avoidance recorded by the clinicianThe study has done retrospectively and included 2583 psychiatric patients who are hospitalized or are visiting the Outpatient clinic. A concise questionnaire was formed to record the main reason of avoidance 520 out of 2583 (21%) remained not fully vaccinated throughout the pandemic and denial by the patient was the main reason (55%). The reasons recorded at the patient\u2019s file by the physician are shown at table 1.Psychiatric patients belong to a high probability group for vaccine avoidance. In our study the frequency of unvaccinated psychiatric patients found greater than healthy population and the main reason is patient decision not to consent. Loss of information, distrust, inadequate social help are causes of poor decision making and consequent low quality health servicesNone Declared"} +{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates. The authors contacted the Editorial Office regarding a duplication in Figure 3C between the A549 migration vector image and the invasion vector image. A corrected image, which also includes the replacement of the Figure 3C STEAP1 panels, has been provided and is under review by the Editorial Board, and communication remains in progress regarding the western blot data of the figures and the raw data provided by the authors."} +{"text": "Gender incongruence (GI) is a term used to describe a marked and persistent incompatibility between the sex assigned at birth (SAAB) and the experienced gender. Some persons presenting with GI experience a severe psychological distress defined as gender dysphoria (GD).. Although the prevalence of GI is probably underestimated, recently a great increase in numbers of transgender and gender diverse (TGD) youths presenting at the gender clinics has been registered. After a careful multidisciplinary evaluation and upon acquisition of informed consent from the youth and the legal guardian(s), puberty suppression can be started in TGD youths, followed by the addition of gender affirming hormones (GAH) by the age of 16 years. Although Italian specific guidelines are available, their application is often complex because of (among other reasons) lack of specialized centers and healthcare professional with experience in the field and the regional differences within the Italian healthcare system.To investigate the care offered to TGD youths across Italy, we proposed a survey of 20 questions to the directors of the 32 Italian Centers of pediatric endocrinology participating to the Study Group on Growth and Puberty of the Italian Society of Pediatric Endocrinology (ISPED). Eighteen pediatric endocrinologists representative of 16 different centers belonging to 11 different regions responded to the survey. In the large majority of centers TGD youths are taken in charge between the age of 12 and 18 years and at least three healthcare professional are involved. Most of Italian pediatric endocrinologists follow only a very limited number of TGD youths and reference centers for TGD youths are lacking.There is an urgent need for gender clinics where TGD youths can access high standard care.The online version contains supplementary material available at 10.1186/s13052-023-01471-2. Gender incongruence (GI) is a term used to describe a marked and persistent incompatibility between the sex assigned at birth (SAAB) and the experienced gender. Transgender and gender diverse (TGD) persons can feel highly uncomfortable with primary and secondary sexual characteristics and the social role associated to the SAAB and they can experience a severe psychological distress defined gender dysphoria (GD) . The preA recent systematic review estimated the prevalence of GI among children and adolescents between 1.2% and 2.7% (increasing up to 2.5\u20138.4% when a broader non binary concept of gender diversity is investigated) , a unifoAccording to international and national guidelines \u20138, puberWe proposed a survey of 20 questions to the directors of the 32 Italian Centers of pediatric endocrinology participating to the Study Group on Growth and Puberty of the Italian Society of Pediatric Endocrinology (ISPED) to investigate the approach of the Italian pediatric endocrinologists to GI. The questions of the survey are shown in the supplement.Eighteen pediatric endocrinologists representative of 16 different centers belonging to 11 different regions responded to the survey.. Colleagues of 14 centers reported to treat TGD youths, but 64% had in follow-up less than 10 individuals. Only one center reported to have in charge more than 20 TGD youths. According to the experience of 50% of colleagues, GI is more frequent among youths assigned male at birth while according to 36% GI has a higher prevalence in youths assigned female at birth. In 79% of centers TGD individuals receive the diagnosis of GD between 12 and 18 years of age and at least three healthcare professionals are involved . In only 3 centers a bioethicist is part of the team. 79% of the interviewees consider appropriate to start puberty suppression only in selected patients and 50% thinks that puberty suppression should be started between 10 and 12 years of age . According to 50%, gender affirming hormones should be started before the age of 16. Mental health disorders (including eating disorders) are often diagnosed in TGD youths and 50% of centers follow TGD youths who take psychotropic medications (mainly antidepressants). 36% of centers include in the follow-up provided to TGD youths several investigations to evaluate the effect of the treatment and possible side effects, such as the evaluation of glucose metabolism, lipid profile, coagulation profile, bone mineralization and mental health assessment. .Only 21% of centers follow TGD individuals who chose to proceed with gender affirming surgery; however this is most likely due to the fact that surgery is performed after the age of 18, thus after the transition to adult care. Only 12% of interviewees think that surgery should be offered earlier, specifically by the age of 16. In 29% of centers, more than 50% of TGD youths are victims of bullying , while in 43% of centers the percentage is lower (10\u201350%). 29% reports early school drop out in <\u200930% of cases, 21% reports an incidence\u2009>\u200930% and 21% does not estimate a higher incidence of school drop out in TGD youths. 36% of the interviewees affirm that more than 50% of TGD youths is satisfied with the body image obtained with to the treatment, while only 14% refers a satisfaction rate\u2009>\u200990%.Although international and national guidelines for gender affirming treatment in TGD youths are available, not all pediatric endocrinologists are familiar with them or have enough expertise in this specific field. From our survey resulted that most of Italian pediatric endocrinologists offering care to TGD youths follow only a very limited number of individuals while we think that TGD youths should be offered by highly specialized centers where an experienced multidisciplinary team provides care. The care should be homogeneously distributed on the national territory. Our survey has clearly some limitations such as the distribution among a selected study group within ISPED and the lack of involvement of endocrinologists (which in some centers might offer care to both TGD youths and adults). Also we did not investigate in details the adherence to the national guidelines but we aimed to have a general overview on this topic and mainly to sensitize Italian pediatric endocrinologists on the increasing number of TGD youth seeking care and deserving to receive it. We think that the opening of gender clinics with specific focus on youths should be promoted in Italy and uniform protocols of care should be applied.Below is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2"} +{"text": "This statement is also provided in full below:With regard to the article in the February 2022 issue entitled \u201cBlister fluid as a cellular input for Cases with cryogenically stored PBMC and BFC were identified from previous prospective ethically approved studies .With regard to the article in the November 2022 issue entitled \u201cUpregulation of IL-4 receptor signaling pathway in circulating ILC2s from asthma patients\u201d , the ethical/consent statement appeared in the supplemental materials for the article. This statement is also provided in full below:The study protocol was approved by the Institutional Review Board (IRB) of the Keio University School of Medicine . This study was conducted in compliance with the Declaration of Helsinki. All patients provided written informed consent, and patient anonymity was preserved using methods approved by the IRB."} +{"text": "Physicians and pharmacists practicing in the managed care environment.By engaging in this activity, participants will be able to: 1) recognize the symptoms of a woman with depression and develop an appropriate treatment plan while considering unique gender barriers and issues; 2) recognize the need for timely diagnosis by primary care providers for appropriate treatment and entrance into the managed care system to increase optimal outcomes for depression; 3) explain why women are at greater risk for depression than men and describe factors that play a role in developing depressive disorders; 4) acknowledge the complexity of comorbid conditions associated with mental illness and evaluate the importance of adequately diagnosing and treating comorbidities to improve outcomes and manage costs; and 5) integrate best practices into the work environment to ultimately improve patient health and productivity outcomes."} +{"text": "The Academy of Managed Care Pharmacy (AMCP) Format for Formulary Submissions, a template for health plans to use in developing formulary submission guidelines, has been widely adopted since its initial release in 2000. Many health plans request a dossier to provide information for consideration during the formulary decision-making process. While dossier quality has reportedly improved over time, there is no recent research examining the response rate to dossier requests and the quality of dossiers received.To perform an evaluation of pharmaceutical manufacturers' response to a request for a product dossier prepared using the AMCP Format, and to determine if dossier receipt was associated with a favorable formulary placement.The pharmacy and therapeutics (P&T) committee of a mid-Atlantic health plan with approximately 3 million members reviewed 43 drug products from February 2004 through December 2005. A university-based clinical evaluation subcontractor requested dossiers in the AMCP Format by telephone and e-mail from the manufacturers' drug information center about 8 weeks before the committee meeting. A retrospective evaluation of the materials received from the manufacturers was performed. A logistic regression model was developed to determine if dossier receipt increased the likelihood of second-tier copayment formulary placement for new product reviews.Dossiers were requested for 43 products. We received dossiers for 25 products (58%), other drug information for 10 products (23%), a formulary kit for 4 products (9%), and no response for the remaining 4 products (9%). Of the 25 dossiers, 21 (84%) generally followed the AMCP Format. Unlocked interactive budget impact models were included in 5 dossiers (20%), and modeling reports (without an unlocked interactive model) were included in 12 dossiers (48%). Dossiers were more likely to be received when the time between U.S. Food and Drug Administration (FDA) approval and dossier request was 4 months and when requested from a large manufacturer compared with smaller manufacturers . Dossier receipt did not improve a product's likelihood for preferred formulary placement; none of the new products for which dossiers were received were assigned to the second copayment tier compared with 33% of the new products with no supporting dossier. The logistic regression model failed to find any correlation between dossier receipt and preferred formulary placement.Manufacturers met the request for a dossier nearly three fifths of the time. The dossiers were of high quality and generally followed the AMCP Format; the models included in dossiers varied widely in their design and utility. The product manufacturer's size and the time between FDA approval and dossier request influenced the likelihood of dossier receipt. Receipt of a dossier did not appear to influence the likelihood of a product attaining preferred formulary status."} +{"text": "Following the publication of this article , concernThe following The following The following The corresponding author commented that errors were made during figure preparation, due to the similarities in bands and overall underlying images. The corresponding author also clarified that during their post-publication review of the data, they noticed that the following published panels were also incorrect:The corresponding author provided the original underlying data for the blots presented in Figs The authors did not comment on the availability of the remaining data presented in this study.PLOS ONE Editors remain concerned about the number of panels affected by data reporting issues. We issue this Expression of Concern to notify readers of the above concerns and to relay the available data provided by the corresponding author.The provided data and updated figures support the findings reported in , but theS1 File(ZIP)Click here for additional data file.S2 File(ZIP)Click here for additional data file.S3 File(ZIP)Click here for additional data file."} +{"text": "We read with great interest the article by Kil et alThe authors noted that a disadvantage of SF was the high rate of recurring breast symptoms, requiring repeat radiation therapy in 57% of cases.,,Another concern in selecting QS for NBC is whether QS contributes to maintaining cancer-control effects and reducing side effects. The concept of QS first reported by William was intending to maintain the high level of tumor control assuming an \u03b1:\u03b2 ratio of 10 and reduce the expected late complications assuming an \u03b1:\u03b2 ration of 4.We again appreciate the authors\u2019 great effort toward revealing the usefulness of QS for NBC. Although the rate of repeat radiation therapy is high, we believe that SF is also a good option considering the convenience of a one-time procedure. Further studies regarding the proper use of SF and QS in NBC will be needed in the future.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} +{"text": "The sequence (forward and reverse primer) of marker SPGMS1DCAPS was incorrectly published. The corrected ms3 and wms genes in peppers appears below.In the published article, there was an error in The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Techniques included the following: \u2018Go Green IVOST\u2019 posters in key ward areas highlighting benefits of the oral route; targeted pharmacist and pharmacy technician prospective audit and feedback using the electronic prescribing system; presentations to ward and pharmacy teams; staff champions and electronic IVOST prompts displayed when prescribing and administering the targeted agents IV. To measure improvement, oral and IV usage data were measured at baseline and for 24 months post change. Data were displayed on run charts to determine if the QI target was achieved.There was a 44% median reduction in IV defined daily doses (DDDs) in the targeted antimicrobials, surpassing the 20% target . There was a median 10% shift in the proportion of these agents given IV as a percentage of total use The greatest reduction (60%) was in IV metronidazole where usage declined from a monthly baseline of 667 to 267 DDDs. This equates to a median reduction of 1200 IV metronidazole administrations and nearly 600 hours nursing time saved per month. IV fluconazole and IV levofloxacin usage declined from baseline by a median of 35% and 24%, respectively.A QI approach to promote appropriate use of the oral route in antimicrobials with high oral bioavailability resulted in a change in prescribing behaviour and a sustained reduction in IV prescribing of these agents. This is important in terms of improved AS, patient care and safety, healthcare cost and efficiency and environmental sustainability."} +{"text": "The authors have previously requested to correct Figure 6A, and this request was under consideration at the time these additional concerns were raised by readers.The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper, hence has issued an expression of concern to notify readers whilst the Editorial Office investigates. It has been noted that the Western blots of Figure 5C appear similar to those in a retracted publication by a different author group (DOI:"} +{"text": "After this article was publIn response to queries about the experiments in The remaining analyzed and processed data, but not some of the raw unprocessed files, and all individual-level quantitative data underlying article are avaiThe authors apologize for the error in the published article.S1 File(PPTX)Click here for additional data file."} +{"text": "Following the publication of this article , concernThe corresponding author explained that during the initial rounds of revision of this manuscript the incorrect images were accidentally used to prepare the Editorial review of these data raised concerns that the underlying data presented for S1 File(ZIP)Click here for additional data file.S2 File(ZIP)Click here for additional data file."} +{"text": "SpaceOAR is currently the only hydrogel spacer available in Japan and has been actively used in conjunction with radiation therapy for prostate cancer since its introduction in 2018.A multicenter randomized controlled trial involving its use with IMRT showed a significant reduction in the frequency of Grade 2 or higher late rectal toxicities.In this study, the authors report a rare case of gel misplacement into the bladder and the subsequent formation of a bladder stone within a short period.Masashi Morita: Writing \u2013 original draft; writing \u2013 review and editing.The author declares no conflict of interest."} +{"text": "Isolated premature ventricular complexes (PVCs) are the most common arrhythmias observed in patients even if without structural heart disease.The synthesized 18\u2010lead ECGs of 13 consecutive patients who underwent radiofrequency catheter ablation (RFCA) of idiopathic PVCs from near the HIS bundle at the Japan Community Healthcare Organization Osaka Hospital, Osaka General Medical Center, and Nara Prefectural Seiwa Medical Center from January 2018 to December 2020 were included in this retrospective analysis. The origin of the PVCs was identified by a cardiologist using a 3D mapping system . We analyzed the QRS morphology pattern of the synthesized 18\u2010lead ECG analyzed in those patients. This study was approved by the Ethics Committee of each hospital in accordance with the Declaration of Helsinki.The synthesized 18\u2010lead ECG and ECG characteristics in 13 patients with PVCs from near the HIS bundle are shown in Figure\u00a0Several studies have shown that identifying PVCs originating from the vicinity of the ventricular septum remains complicated,A QS pattern recorded in lead V5R of the synthesized 18\u2010lead ECG was characteristic of PVCs originating from near the HIS bundle. This observation might assist in identifying the origin of PVCs during RFCA.H Kida, R Nakanishi, and N Ogasawara participated in the design of the study and coordination and helped draft the manuscript. All authors read and approved the final manuscript.All authors declare no conflicts of interest associated with this manuscript.This study was approved by the Ethics Committee of Japan Community Healthcare Organization Osaka Hospital, Osaka General Medical Center, and Nara Prefectural Seiwa Medical Center in accordance with the Declaration of Helsinki.Since this study was a retrospective study, we used the opt\u2010out system according to the ethics guidelines on human medical research by the Japanese government."} +{"text": "In the published article, there was a mistake in the first paragraph of abstract. Instead of \u201cPoor glycemic control is one of the most determinant factors for type 2 diabetes-related morbidity and mortality. The proportion of type 2 diabetes mellitus patients with poor glycemic control remains high. Yet evidence on factors contributing to poor glycemic control remains scarce. The aim of this study is to identify determinants of poor glycemic control among type 2 diabetes mellitus patients at a diabetes mellitus clinic in University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia Determinants of Poor Glycemic Control among Type 2 Diabetes mellitus Patients at University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia: Unmatched Case-Control Study\u201d, it should be \u201cPoor glycemic control is one of the most determinant factors for type 2 diabetes-related morbidity and mortality. The proportion of type 2 diabetes mellitus with poor glycemic control remains high. Yet evidences on factors contributing to poor glycemic control remain scarce. The aim of this study is to identify determinants of poor glycemic control among type 2 diabetes mellitus patients at a diabetes mellitus clinic in University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia\u201d.The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Incorrect FundingFunding statement was incomplete as funding for the publication cost from another grant was left out. The original text is \u201cRobot development was supported by the Decentralised Gap Fund (DGF 20GAP006) awarded to Ngee Ann Polytechnic from the Singapore Ministry of Education. The survey was conducted pro-bono by the primary healthcare investigators from SingHealth Polyclinics.\u201d The correct Funding statement appears below.In the published article, the Funding statement is \u201cRobot development was supported by the Decentralised Gap Fund (DGF 20GAP006) awarded to Ngee Ann Polytechnic from the Singapore Ministry of Education. The survey was conducted pro-bono by the primary healthcare investigators from SingHealth Polyclinics. The publication cost was supported by Singhealth Polyclinics Centre Grant CG21APR3006 (NMRC/CG3/001/2022-SHP).The correct The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "In the published article, acknowledgement was mistakenly not included in the publication. The missing material appears below:\u201cPreoperative blood samples from 32 study participants with gynecological cancer were provided by the National Cancer Center (NCC) Biobank.\u201dThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "It is extremely rare to come across a single coronary artery during routine interventional cardiology practice. The incidence of single coronary arteries increases\u00a0across congenital heart diseases. We report an extremely rare case of a single coronary artery arising from the left coronary sinus in an octogenarian presenting with anterior wall non-ST elevated myocardial infarction (NSTEMI) secondary to atherosclerotic occlusion of the proximal left main coronary artery (LMCA). It is often difficult to selectively engage a single coronary artery due to anomalous origin from the sinus; nonselective coronary sinus injection often suffices in visualizing the single coronary trunk dividing into left and right coronary arteries besides demonstrating the associated route and atherosclerotic anomalies. Normal coronary blood supply includes the origin of the left main coronary artery (LMCA) from the left coronary sinus, which further bifurcates into the left anterior descending coronary artery (LAD) and the left circumflex artery (LCX) to supply the left side of the heart and the right coronary artery arises from the right coronary sinus to supply the right side of the heart. The anomalous single coronary artery is a rare congenital anomaly reported in 0.024 to 1% of cases across different series . In a siFigure Lipton et al. initially classified the single coronary artery that can arise from the right or left coronary sinus as follows: in the first category, the artery follows the course of either the left or right coronary artery, the second category of single coronary artery includes the aberrant course,\u00a0including an anomalous artery running anterior to the pulmonary trunk, in between the pulmonary trunk and the aorta,\u00a0and the anomalous artery running behind the aorta, and the third category includes the rarest variant with an absent left main coronary artery with the direct origin of the left anterior descending coronary artery and circumflex from the common trunk . A singlWe report an extremely rare case of a single atherosclerotic coronary artery arising from the left coronary sinus in an octogenarian presenting with non-ST elevation myocardial infarction (NSTEMI). It is often difficult to engage the anomalous origin of a single coronary artery from the left coronary sinus; nonselective injection of the left coronary sinus with 10-20 ml of contrast can visualize the same during difficult selective intubation. Although single coronary arteries in the young are commonly nonatherosclerotic, our case is a rare case of the atherosclerotic single coronary artery when it pertains to the elderly population."} +{"text": "Previous studies indicated that mitotic chromosome structure consists of many stacked layers formed by a mononucleosome sheet folded as a helicoid. This multilayer chromatin structure justifies the cylindrical shape of chromosomes and the transverse orientation of cytogenetic bands, and can explain chromosome duplication by the formation of a transient double helicoid that is split into two sister chromatids in mitosis. Here it is hypothesized that the bipolar pulling forces exerted by the mitotic spindle cause the sliding of the layers and facilitate sister chromatid resolution. This hypothesis is supported by three favorable conditions: i) There is no topological entanglement of DNA between adjacent layers; ii) The orientation of the bipolar kinetochore microtubules is adequate to produce layer sliding in opposite directions; iii) The viscous resistance to the sliding caused by the weak interactions between nucleosomes in adjacent layers can be overcome by the microtubule pulling forces. Genomic DNA of eukaryotes is divided into large fragments that are packed within chromosomes. Growing cells replicate their DNA in interphase and the resulting two sets of chromosomes are condensed and precisely distributed into the daughter cells in mitosis . This paThroughout the cell cycle, chromosomal DNA molecules are associated with histone proteins and form long chromatin filaments filled with many nucleosomes. Each nucleosome is composed of a flat cylindrical core particle (11\u00a0nm diameter and 5.7\u00a0nm height) formed by \u223c146\u00a0bp of DNA wrapped around an octamer of core histones . In the 2+ . This in3) . These f3) such as 3) , purifie3) , and DNA3) . Chromat3) , in whic3) . It can It has been shown that the different internucleosome interaction energies in different regions of this multilayer structure provide a consistent physical explanation of the elongated smooth cylindrical shape of metaphase chromosomes and of their mechanical properties . The nucThe multilayer organization of chromosomes provides a structural framework for interpreting cytogenetic results that cannot be justified by other structural models . It was In buffers containing interphase cation concentrations , the chrAccording to Hi-C experiments in interphase, chromatin is organized into topologically associating domains (TADs), which are considered to be the functional subunits of chromatin, and larger compartments . The looDuring the S period of interphase, nucleosomes are temporarily dissociated in many replication origins to allow the interaction of DNA with all the replisome components and eventually two daughter chromatin filaments are produced . As indiScanning electron microscopy results showed that during early-prophase individual chromosomes are not distinguishable; at later stages of prophase chromosomes are long cylindrical structures, usually continuous, but sometimes they are segmented into blocks . The morThe structure and dynamic properties of the mitotic spindle are based on the self-organization of microtubules and motor proteins . In animKinetochores are tightly bound to centromeres . The forNote that the proposed sliding leading to chromatid resolution is not possible if DNA crosslinks the adjacent layers of the two helicoids. The easy sliding of layers in chromatin plates (see above), which was inferred from the frequently observed displacement of the edges of successive layers in chromatin plates emanated from metaphase chromosomes [The proposed mechanism for sister chromatid resolution is based on the sliding in opposite directions of the alternating chromatin layers of the double helicoid produced after chromosomal DNA replication. Further removal of topological links by topoisomerase II (see above) and the spontaneous stacking of the chromatin layers generatein vitro studies performed with purified nucleosome cores showed that the chiral nature of these particles induce the formation of large liquid crystalline columnar phases having a left-handed helical shape (It was suggested that sister chromatids have opposite handedness , but it al shape . Unfortu"} +{"text": "Primary necrosis of the ligamentum teres hepatis (PNLTH) is an extremely rare disease which presents with acute abdominal pain. It has easily been misdiagnosed due to lack of clinical manifestations. Early recognition of PNLTH is crucial for treatment while CT is a good methed to diagnose and differential diagnose PNLTH.Teaching Point: Primary necrosis of the ligamentum teres hepatis (PNLTH) is an extremely rare disease characterized with acute abdominal pain, while computed tomography is the recommended technique to diagnose and differential diagnose this disease. Liver function tests with normal enzymatic profile and bilirubin was plain. The patient was suspected with acute pancreatitis and subsequently received an enhanced computed tomography (CT) scan for further diagnosis. The CT examination of the abdomen showed normal morphology of pancreatic with fewer exudation above the body of pancreas. A hypodensity strip and WBC 21 \u00d7 10CT results suggested the diagnosis of necrosis of the ligamentum teres hepatis and provided a CT volume reproduction of the lesion to show its neighboring relationships (The hepatic round ligament is a remnant of umbilical vein atresia, formed by the embryonic remnants of degenerative atresia of the left umbilical vein, which connects to the left hepatic vein or inferior vena cava through the venous ligament. The clinical incidence of PNLTH is extremely low and the pathogenesis is unclear . In this"} +{"text": "Use of a hybrid type of Ilizarov ring fixator is popular in complex orthopaedic trauma, typically comprising Schanz screws at each ring and tensioned wires. The Schanz screws are cut to the size of the ring but their cut ends may subsequently injure the other leg or damage garments and bed sheets. Custom made protective caps are available but a good alternative is a 22/24Fr Foley catheter, cut and rolled over the sharp ends of screws . These a"} +{"text": "CPE). These generalizations were described by the novel equation which presented parameter Fractional calculus is a mathematical approach dealing with derivatives and integrals of arbitrary and complex orders. Therefore, it adds a new dimension to understand and describe basic nature and behavior of complex systems in an improved way. Here we use the fractional calculus for modeling electrical properties of biological systems. We derived a new class of generalized models for electrical impedance and applied them to human skin by experimental data fitting. The primary model introduces new generalizations of: 1) Weyl fractional derivative operator, 2) Cole equation, and 3) Constant Phase Element ( Application of the mathematics in biology and medicine requires interdisciplinary approach employing the high level of theoretical and experimentally based knowledge in all three disciplines Fractional calculus is a mathematical field extending classical calculus for non-integer order of derivation thus dealing with derivatives and integrals of arbitrary and complex orders Fractional calculus applications in life sciences provides possibility to analytically focus on modeling of biological life processes where fractional order model will span multiple scales . Skin is the largest human organ with extremely high cellular and molecular complexity functioning as the protecting, communication and transfer interface between body and environment Multifrequency measurements and modeling of electrical impedance is an important spectroscopy method in study of complex biological tissues and materials such as human skin. Passive electric properties of human skin were studied by Cole mathematical method employing bioimpedance measurements below 100 kHz CPE) which will be here further mathematically defined and generalized by impedance equations using fractional calculus approach.Biological membranes show a high capacitance and a low but complicated pattern of conductivity We have used fractional calculus approach to construct simple models with unified principles. Without fractional calculus approach it would not be possible to make this generalized type of superior and more precise class of models where Cole model is a special case. Here we report modeling of bioimpedance using fractional calculus approach and experimental data fitting for human skin test system. We have derived new bioimpedance equations introducing one new parameter and corrections for four parameters by employing generalized Weyl fractional derivative operator. Our model and results provide significant mathematical advance for solving complex biosystems when compared to the classical Cole model. Therefore, presented bioimpedance fractional calculus modeling may be useful for further fundamental research with applications in medicine which are related to physiological and pathological analysis of human skin.CPE.Our modeling strategy of the bioimpedance with application to human skin is based on generalization of Weyl fractional derivative operator, generalization of Cole equation, and generalization of Our primary idea was to generalize Weyl fractional calculus because this method is necessary for mathematical analysis of complex periodic functions describing characteristic values of alternating current in electric circuits which are employed in bioimpedance modeling.In 1917 Weyl introduced his new approach of fractional calculus to analysis of periodic functions. In summary the Previously defined operator is linearThe Weyl approach to fractional calculus, can be rigorously treated in the Banach spaces If As described by Butzer and Westphal We now move to more precise definition of Weyl fractional integral. This function will be used as a kernel of the associated convolution integral, so-called Weyl fractional integral Then according to Butzer and Nessel, Moreover, the convolutional theorems for periodic functions (ii)Proof: We should bear in mind the sum member Previous mathematical description is the basis for generalization of Weyl fractional integralProof For Generalization of Weyl fractional integral Proof: The operator Norm of the first element to the right is finite because of the previous lemma.Therefore, if In the case that the operator Supplement to the previous definition is The idea presented in the previous section on non-trivial and non-empty common domain and codomain for all operators that are defined by formula (32) will be used here. By analogy we define domain of the operator This domain is neither equal to Described non-empty set The basic properties of operators in a given domain Proof: For 1\u20133 is obvious and for 4 it can be considered if Because In a similar way proofs are provided for the other three equations.Also, instead The previous operator is analogous to the following oneIf one introduces a non-negative relaxation time parameter If Using appropriate mathematical operations and weakened conditions described in Theorem 3 the Multi Frequency Bioelectrical Impedance Analysis (MF-BIA) is a noninvasive technique for studying biological systems. The complex impedance as a function of frequency of the external alternating voltage source , current passing through the system is 0i. Impedance of the system is given by the equationHere we derive Cole In order to generalize our previous Eq. (2.44) we have used similar principal of mathematical approach as reported by Nigmatullin Formally in By introducing new parameters for resistance It should be mentioned that for small le model ), becausle model and haUsing our model we have tested the effects of CPE, then CPE can be replaced and we can write.If we assume that the change of conducting properties of electrical circuits is only in the Cole model uses linear scaling as seen from the above equation. For generalized CPE (GCPE) we are scaling frequency for dispersion of impedance in non-linear manner. This can be seen from The function CPE (GCPE). The electrical circuit comprising of the element GCPE element with The Using fractional calculus approach we have derived a new class of models for electrical impedance by generalizing Weyl fractional derivative operator, Cole model and constant phase element. These generalizations were described by the novel equation which presented parameter We have derived a new primary model using frOur new parameter Different mathematical approaches for studying electrical properties of human skin were attempted using impedance models based on serially connected reduced Grass EC33 obtained from Grass technologies. This cream is specifically designed for skin resistive and conductive measurements. Cream covered electrodes were gently placed on skin in order to avoid putting excess pressure to skin. Total required time for the frequency sweep measurement was about 10 minutes at 22\u00b0C and 50% relative humidity, thus, minimalizing artifacts production during measurements due to long cream exposure or cream penetration to skin, as well as sweeting. Error of measurements was <0.1%. Twenty series of measurements were taken at each of the 61 different frequencies ranging between 0.1 Hz and 100.0 KHz. The applied voltage of alternating current was of 1.0 V amplitude. Total required time for the frequency sweep measurement was about 10 minutes.Bioimpedance skin measurements were performed at University of Belgrade on upper arm of human volunteers with Solartron Bioimpedance skin measurements were performed at University of Belgrade,University of Belgrade Review Board (IRB) approved specifically use of oral consent for bioimpedance skin measurements on healthy human volunteers for this study. Please note that bioimpendance skin measurements are noninvasive and have been commonly used in public fitness centers for measurements of body fat content without medical or ethic commission authorizations and are thus generally deemed unnecessary for further ethics commission approval.Each volunteers provided oral consent for bioimpendance skin measurements analyzed and reported in our study.2L-norm) C/C++.Levenberg-Marquardt (LM) nonlinear least squares algorithm L2 (left part of the right part of Im (Z)) was plotted versus Z real (Re (Z)). There is a difference in the arc shape for two different electrode sizes. The maximal measured value of Re (Z) is greater for larger electrode surface then the maximal value of Re (Z) obtained for the smaller electrode surface (Im (Z) is smaller for the larger electrode surface then the minimal value of Im (Z) obtained for the smaller electrode surface ; (7) based on one reduced generalized Cole element serially linked to one reduced Cole element (C1GC1) . Although all models were analyzed using LM data fitting, we present in 1\u200a=\u200a1 and n2\u200a=\u200a1). Future experimental electrical biompedance measurements will demonstrate whether the presented seven model types could provide specific description for different organs, tissues and materials.We have used Levenberg-Marquardt (LM) nonlinear least squares algorithm for experimental data fitting with following models: (1) comprised of one Cole element ); 2) ba (C1GC1) , n1\u200a=\u200a1 ba nonlinear least squares algorithm because this model gave best mean square error values as shown in Three serially linked reduced Cole elements had two order of magnitudes higher mean square error and thus is the most inferior quality model.Taking also in account the We have introduced fraction calculus generalization approach in order to be able to cope with complex multi-layered systems with unknown structures which also include simpler structures such as necessary gels and electrodes as additional element influencing and complicating interpretation and analyses of the experimental data.Our GGC1 (one element) and GC2 (two elements) models provide significantly better fitting of the experimental data then Cole model which is actually, as previously explained, a special case for CPE, generalized Cole model and serially connected reduced generalized Cole elements represent a valuable basis for further development of mathematical models for bio-systems and/or any kind of material using the fractional calculus approaches. We propose that this type of powerful modeling tools shall be further applied for noninvasive analysis of complexity of bio-systems and/or any kind of material.Our generalized"} +{"text": "Primary pain amplification syndrome is an important differential diagnosis in patients suspected to have JIA. Secondary PAS may occur within the course of JIA after remission.Characterizing the occurrence of JIA in a group of patients suffering from PAS.Retrospective analysis in 319 patients with PAS admitted to our unit for chronic pain in 2010. Patients` medical histories have been worked up concerning chronic inflammatory diseases. The observed frequencies of JIA subtypes have been compared to frequencies recorded by the national German registry for rheumatic diseases (Deutsches Rheumaforschungszentrum DRFZ 2008).The medical history reported JIA in 61 patients (19%) and chronic multifocal osteomyelitis (CRMO) in 9 (3%) of the patients. (Table More than one third of the histories were not conclusive for the diagnosis of JIA according to the ILAR criteria, mainly because arthritis had not been assured to be present for more than 6 weeks.Polyarticular and Psoriasis JIA seem to have an increased risk to develop secondary PAS. Primary PAS has to be suspected in a number of patients diagnosed as PAS secondary to JIA as arthritis never had been proven conclusively. There are a remarkable number of CRMO patients within the group of secondary PAS patients."} +{"text": "The Author Summary section that follows the Abstract is included in the PDF, but is missing from the online version of the article. The text of the Author Summary is as follows.Author SummaryHomeostasis in the intestine is maintained through regulated interaction between several cell communities: the intestinal epithelium, intestinal immune cells, and the commensal flora living in the gut. A breakdown in the communication network that exists between these three components can lead to a pathologic state, for example inflammation. We have used computational modeling of intracellular and extracellular signaling pathways to determine how intestinal immune cells control the response of intestinal epithelial cells to the inflammatory cytokine tumor necrosis factor alpha (TNF-\u03b1). Cycles of computational modeling and experimental perturbation revealed a network in which epithelial cells communicate with the intestinal immune component via monocyte chemoattractant protein 1 (MCP-1) and the immune cells signal back to the epithelium through interferon gamma (IFN-\u03b3). This extracellular signaling pathway modulates the epithelial apoptotic response to TNF-\u03b1 in order to regain a state of homeostasis. Our study highlights the power of applying systems biology approaches to mouse models in order to characterize complex biological phenomena."} +{"text": "Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children. It is a clinical diagnosis in a child, less than16 years of age with arthritis for at least 6 weeks duration and exclusion of other causes of arthritis.This study was comprised of Iranian children with oligoarthritis and rheumatoid factor negative (RF) polyarthritis subtypes of juvenile idiopathic arthritis (JIA) to determine the association of HLA-DRB1 alleles in Iranian population.HLA-DRB1 alleles were investigated in 33 Iranian children with oligoarthritis and RF negative polyarthritis JIA and compared with 45 healthy controls. HLA typing was performed by PCR with sequence specific primers in either of the two groups and followed by direct detection of HLA polymorphism by sequence analysis in patient group.HLA-DRB1*11 was found to be the most frequent allele associated with oligoarthritis and RF negative polyarthritis JIA in Iran followed by DRB1 *08. The frequencies of HLA-DRB1*04 and *13 were not significantly different in both groups.We concluded that there was a significant difference in allele frequencies between patients and control group that may help in predicting the susceptibility to oligoarthritis and rheumatic factor negative polyarthritis JIA."} +{"text": "No single therapy benefits the majority of patients in the practice of oncology as responses differ even among patients with similar tumor types. The variety of response to therapy witnessed while treating our patients supports the concept of personalized medicine using patients' genomic and biologic information and their clinical characteristics to make informed decisions about their treatment. Personalized medicine relies on identification and confirmation of biologic targets and development of agents to target them. These targeted agents tend to focus on subsets of patients and provide improved clinical outcomes. The continued success of personalized medicine will depend on the expedited development of new agents from proof of concept to confirmation of clinical efficacy. Cancer is a major public health problem in the United States and worldwide . In 2010The development of cancer therapy stems from the design and results of clinical trials. Traditional clinical trial design was primarily developed in the 1970s when few cancer therapies were available , 3. ThisOverall survival (OS) is often acknowledged as the traditional endpoint for phase 3 clinical trials leading to FDA approval \u201311. InitIn this paper we will review how development of targeted agents has changed from the discovery of the first targeted therapy, imatinib, to the approval of new targeted therapies in prostate cancer. We will also discuss potential ways to expedite development of new therapy as the landscape of cancer treatment progresses beyond traditional cytotoxic chemotherapy to improved targeted agents that require biomarker identification and patient stratification that allows matching of the right patients to the right therapy \u201317.The hematologic stem cell disorder chronic myeloid leukemia (CML) was first described in 1845 . ThroughAlmost another ten years passed before the BCR-ABL fusion gene was discovered in 1982 and nearly another decade later was identified as the cause of CML in mice in 1990 . A 2-pheThe first solid organ malignancy to have an FDA approved targeted therapy was breast cancer . The disHER2 overexpression is found on 20% of breast cancer cells, the majority due to gene amplification . This diThe first phase 1 study of trastuzumab began in 1992 followed by additional phase 1 trials and smalThe synergy of trastuzumab with cytotoxic chemotherapy agents seen in early studies , 39, 40 In September 1998 the FDA approved trastuzumab for use in women with metastatic breast cancer whose tumors overexpress the HER-2 protein. FDA-approved indications included treatment of patients as first-line therapy in combination with paclitaxel and as a single agent after prior chemotherapy. This initial approval for trastuzumab was followed in December 2000 by enrollment into phase 3 trials using trastuzumab in the adjuvant treatment of early-stage HER-2-positive breast cancer. These studies were sponsored by the National Cancer Institute and conducted by researchers of the National Surgical Adjuvant Breast and Bowel Project (NSABP B-31) and the North Central Cancer Treatment Group (NCCTG N9831) . A thirdThe results of all three trials were reported in the same edition of the New England Journal of Medicine in 2005. Romond et al. reportedThe most recent approval for trastuzumab in breast cancer came in May 2008 based on the results of the Breast Cancer International Research Group 006 (BCIRG-006) trial that was published earlier in 2011 in the New England Journal of Medicine. This is the fourth large multinational trial evaluating anthracycline chemotherapy alone versus trastuzumab with anthracycline or docetaxel chemotherapy again demonstrating a DFS and OS benefit with combination therapy . The disClinical trial design and momentum has become more streamlined than the cumbersome process experienced with the development of early targeted agents imatinib and trastuzumab. The development, study, and approval process of these drugs were prolonged for many reasons including dependency on newly developed technology, inexperience with the new targeted agents, patients willingness to be involved in clinical trials, and large-scale development requirements on pharmaceutical companies , 4\u20136, 172 was chosen as patients had grade 4 neutropenia at the 25\u2009mg/m2 dosing following the traditional 3 \u00d7 3 \u00d7 3 phase 1 clinical trial design [Taxanes are cytotoxic chemotherapy agents in use for at least the past 20 years for treatment of solid organ malignances as either a single agent or as part of a multiagent regimen . A limitl design . Early rl design . The TROl design . The phaThe second recent prostate cancer therapy to receive approval by the FDA was the immunotherapy sipuleucel-T. The early promise of immunotherapy with autologous dendritic cells was demonstrated in sequential phase 1 and phase 2 studies published in December 2000 after clIn 2011 the oral selective and irreversible inhibitor of CYP17, abiraterone acetate, was approved in combination with prednisone for castrate-resistant prostate cancer after treatment with docetaxel chemotherapy. After preclinical studies demonstrated evidence of 17a-hydroxylation inhibition in the late 1980s and early 1990s, abiraterone acetate was tested for the first time in a series of phase 1 clinical trials in both castrate and noncastrate males demonstrating further suppression of testosterone in castrate males and compensatory hypersecretion of luteinising hormone that overcome testosterone suppression in the noncastrate males . The actThe future of cancer therapy development and expedited drug approval will likely be based to a greater extent on identification of small subsets of patients to whom targeted therapy can be designed and clinical trials tailored to rapid identification of clinical benefit , 17. ThiFrom inception of concept to phase 3 trial design, it took an average of 10 years for FDA approval of these new prostate cancer drugs which is an improvement in providing earlier access to innovative therapy but still indicates that there is continued room for improvement . Factors"} +{"text": "There is an error in the second to last sentence of the \"Introduction\" section. The correct sentence for this section is:\"Downregulation using siRNA and/or inhibition of EPS8 by mithramycin resulted in greater cell growth inhibition in non-EGFR mutant lung cancer cells and a bladder cell line following cisplatin treatment.\""} +{"text": "One of the most discussed and controversial issue in the management of thyroid nodules is the need to perform a routine measurement of serum Calcitonin (Ct) in all cases. The American Thyroid Association guidelines do not recommend in favor or against this procedure since they retain that there are not enough evidences that it can determine an advantage to the health outcomes of these patients. This is not the view of many European experts who met in Lisbon in 2009 at the European Thyroid Association-Cancer Research Network meeting to discuss all the still open controversial issues on the management of medullary thyroid cancer patients.This paper is focused on the routine measurement of serum Ct in all patients with thyroid nodule(s): the evidences, the rational and the benefits of this procedure are deeply analysed following the discussion that was done in Lisbon. The conclusions reached at that time are reported in detail. In 2009 the European Thyroid Association endorsed the American Thyroid association guidelines for the management of medullary thyroid cancer (MTC) affected patients . AlthougThe ATA recommendation 52 of the guidelines for the management of MTC patients defers the recommended approach to thyroid nodules, including FNA and serum Ct testing, to the ATA guideline that addresses thyroid nodules [At variance with the ATA view, the ETA consensus clearly The aim of the discussion in Lisbon was to better clarify the clinical reasons and evidences to sustain the indication to perform the serum Ct routine measurement in thyroid nodules. There is no doubt that many studies demonstrated that routine measurement of serum Ct is the most accurate diagnostic tool for the detection of MTC in patients with thyroid nodules, even more sensitive than cytology -11. HoweTo distinguish these situations, subjects with elevated basal serum Ct should be submitted to a stimulation test which should clarify the origin of the detected Ct, especially when the basal value is low-mild elevated (i.e. between 10 and 100 pg/ml). The Ct deriving from MTC usually increases 3-4 times above the basal value after stimulation while artifactual Ct values due to technical problems or serum Ct produced by non thyroid cells usually do not increase after stimulation Basal serum Ct measurement should never be performed in the absence of thyroid nodules detectable by neck ultrasound; b) Low-medium basal Ct needs to be further analysed by \u201cstimulation\u201d; c) Other causes of increased basal Ct should always be excluded; d) Basal Ct > 100 pg/ml must be considered very suspicious of MTC; e) A stimulated Ct < 60 pg/ml is compatible with normal response to stimulation; f) A stimulated Ct > 60 and < 100 pg/ml can be taken under evaluation by repeating the test 6-12 months later; g) The level of increasing of stimulated Ct with respect to the basal value is of great importance since in MTC it is usually greater than 3-4 times the basal value.Ct: calcitonin; MTC: medullary thyroid carcinoma.No competing interests exist for me and my co-authors."} +{"text": "A 45-year old man presents with stable monomorphic ventricular tachycardia. He had previously been diagnosed with idiopathic fascicular ventricular tachycardia. Intravenous flecainide results in termination of his tachycardia but unmasks a latent type 1 Brugada ECG pattern not seen on his resting ECG. We discuss his subsequent management and the need to consider an alternative diagnosis in individuals with a Brugada type ECG pattern who present with stable monomorphic ventricular tachycardia. A 45-year old man presented with sudden onset palpitations whilst exercising. There was no associated hemodynamic compromise. Electrocardiogram (ECG) showed monomorphic ventricular tachycardia (VT) with a right bundle branch block pattern and a superior axis .He gave a history of 3 prior episodes over the preceding 20 years and had seen an electrophysiologist previously. There was no history of syncope and no family history of sudden cardiac death. Resting ECG was within normal limits and echoOn this occasion he was treated in the Emergency Department with IV flecainide at the instruction of his treating electrophysiologist. This resulted in termination of tachycardia with restoration of sinus rhythm but unmasked a latent type 1 Brugada ECG pattern , not seeHowever, following discussion with the electrophysiology service, a diagnostic EPS with a view to ablation of his idiopathic fascicular VT was recommended. Following administration of intravenous isoproterenol, monomorphic VT (CL 260ms) was easily induced on multiple occasions with programmed ventricular stimulation. This VT had an identical morphology to that seen on arrival at the Emergency Department. An externally irrigated ablation catheter was advanced retrogradely to the left ventricle and a 3 dimensional (3D) left ventricular geometry and activation map was created using Ensite Velocity .Earliest activation of the ventricle was seen at the insertion of the posterior fascicle with centrifugal activation of the rest of the chamber. The catheter was drawn back along the inferior septum to the region of the posterior fascicle until a discrete Purkinje potential could be identified preceding each ventricular electrogram . Ablation was performed (maximum 40W) in the region of the posterior fascicle . FollowiWe present a case of monomorphic VT in a patient with a type 1 Brugada ECG pattern following injection of intravenous flecainide. This raises the possibility of either monomorphic VT as part of the Brugada syndrome or of a latent Brugada ECG pattern in an individual with idiopathic fascicular VT. The common form of idiopathic fascicular VT is characterized by a relatively narrow QRS width with right bundle branch block morphology and a superior axis [Brugada syndrome was first described in 1992 and is characterized by episodes of syncope or unexpected sudden death in patients with structurally normal hearts .In this case although he undoubtedly has a type 1 Brugada ECG pattern he has no other features to indicate he has Brugada syndrome. The ease of inducibility of VT, the intra-cardiac EGMs, the activation map and the site of successful ablation all support a diagnosis of idiopathic fascicular VT as the likely cause for his tachycardia.While monomorphic VT has previously been reported in individuals with Brugada Syndrome it is exThis case highlights the importance of excluding other, potentially treatable causes of idiopathic VT prior to ICD implantation. This is especially true in those with a Brugada type ECG pattern who are considered at low risk of sudden cardiac death, where appropriate ablative strategies can negate the need for a defibrillator."} +{"text": "One of the possible complications following the mitral valve repair is the systolic anterior motion (SAM) of the anterior mitral leaflet. The preoperative echocardiographic examination is essential for the identification of the patients at risk for this situation. The most frequently used indicators are the ratio between the AML and PML (AP ratio) and the distance from the coaptation line to the interventricular septum (C-Sep). When repair of significantly redundant valves is performed additional parameters for SAM risk evaluation might be needed.Objective was to investigate if the length of the mitral leaflets might be considered an additional parameter for the preoperative estimation of SAM risk.From March 2008 till December 2011, 159 patients underwent complex mitral valve repair for degenerative mitral regurgitation. The SAM risk was evaluated using the classically described AP ratio and the C-Sep ; in addition a third parameter was introduced; namely the mitral leaflet length (when longer than 35mm).The prevalence of the postoperative SAM following complex MV repair was 0,012 (two out of 159 pts) which is much lower than the published date over this situation (from about 2 to 16%).The length of the mitral valve leaflets is a valid adjunctive parameter for the prediction and avoidance of postoperative SAM. This information is fundamental for the surgical team as it provides a correct surgical planning."} +{"text": "Hepatitis C is a major health problem affecting more than 200 million individuals in the world. Current treatment regimen consisting of interferon alpha and ribavirin does not always succeed in eliminating the virus completely from patient's body. One of the mechanisms by which virus evades the antiviral effect of interferon alpha involves protein kinase (PKR) eukaryotic initiation factor 2 alpha (eIF2a) phosphorylation homology domain (PePHD). This domain in genotype 1 strains is reportedly homologous to PKR and its target eIF2a. By binding to PKR, PePHD inhibits its activity and therefore cause virus to evade antiviral activity of interferon (IFN). Many studies have correlated substitutions in this domain to the treatment response and lead to inconclusive results. Some studies suggested that substitutions favor response while others emphasized that no correlation exists. In the present study we therefore compared sequences of PePHD domain of thirty one variants of six hepatitis C virus patients of genotype 3. Three of our HCV 3a infected patients showed rapid virological response to interferon alpha and ribavirin combination therapy whereas the remaining three had breakthrough to the same combination therapy. It is found that PePHD domain is not entirely conserved and has substitutions in some isolates irrespective of the treatment response. However substitution of glutamine (Q) with Leucine (L) in one of the breakthrough responders made it more identical to HCV genotype 1a. These substitutions in the breakthrough responders also tended to increase average hydrophilic activity thus making binding of PePHD to PKR and inhibition of PKR more favorable. Hepatitis C Virus (HCV) is a major health concern worldwide with current estimates of more than 200 million affected individuals . In PakiCurrent approved therapy for HCV is interferon alpha in combiAfter death of cells interferon is released and in response neighboring cells release PKR . One of http://www.clcbio.com. Amino acid composition was calculated using MEGA version 4.1.In order to find out whether PePHD region of E2 gene shows any promising results for interferon treatment response of HCV patients we investigated six HCV patients. Baseline serum samples from six HCV patients of genotype 3a subjected to Interferon alpha and ribavirin combination therapy. Three patients after 4 weeks of treatment. Two patients (BT) were breakthrough virological responders characterized by reappearance of HCV RNA at the end of treatment. One of the patients was defined as end of treatment responder (ETR) as characterized by negative HCV RNA at the end of treatment. E2 gene amplified from all these samples was cloned. Five to nine variants from each sample were sequenced and analyzed. Purified PCR product was sequenced by using ABI prism sequencer. Consensus sequences were generated using BioEdit software. PePHD amino acid sequences of all variants were aligned with multiple alignment tools using CLC workbench software The subject is very controversial as some of the investigators reported a correlation between amino acid substitution in PePHD domain of HCV genotype 1, 2 and 3 strains -13 and tTaylor et al reported in vitro inhibition of PKR due to similarity of genotype 1 PePHD domain and phosphorylation domain of PKR and eIF2a . In our Average amino acid composition of polar, non polar and neutral amino acids was compared between samples responding differently to the treatment Table . CompariWe conclude that PePHD domain in our local HCV 3a strains is not totally conserved; it carries substitutions in some samples irrespective of their response to alpha interferon. However substitutions are such that it tend to decrease the average hydrophilic activity of PePHD domain in rapid responders and increase the average hydrophilic activity in breakthrough responders. Additionally the comparative greater similarity of PePHD domain in breakthrough responders with PePHD domain of genotype 1 made it a more efficient candidate for binding to and inhibiting PKR. This leads HCV to persist by evading antiviral activity of interferon alpha.The authors declare that they have no competing interests.SA and MI conceived of the study participated in its design and coordination and gave a critical view of manuscript writing. SA collected samples, epidemiological data, perform all molecular biology assays and analyzed the data statistically. MA,ZA, BK, MA, ZF, SB and AH participated in data analysis. All the authors read and approved the final manuscript."} +{"text": "After the publication of this manuscript we observed inaccuracies in several of the figures. The concerns noted are as below:The right column in The concerns were raised to the attention of King Faisal Specialist Hospital and Research Center which investigated the concerns and established that the first author had made use of the incorrect actin panels in this publication.The authors have repeated the experiments for the affected figures and have supplied corrected figures including the novel data for The data in the corrected figures supports the results and conclusions as originally reported in the article. The authors apologize for the inaccurate representation of the data in the original figures.File S1Raw blots for (ZIP)Click here for additional data file.File S2Raw blots for (ZIP)Click here for additional data file.File S3Raw blots for (ZIP)Click here for additional data file.File S4Raw blots for (ZIP)Click here for additional data file."} +{"text": "Understanding how proteins protect themselves from aberrant aggregation is of primary interest for understanding basic biology, protein biochemistry, and human disease. We discuss the paradigmatic example of ataxin-1 (Atx1), the protein responsible for neurodegenerative spinocerebellar ataxia type 1 (SCA1). This disease is part of the increasing family of pathologies caused by protein aggregation and misfolding. We discuss the importance of protein\u2013protein interactions not only in the nonpathological function of Atx1 but also in protecting the protein from aggregation and misfolding. The lessons learned from Atx1 may lead to a more general understanding of the cell's protective strategies against aggregation. The obtained knowledge may suggest a new perspective for designing specific therapeutic strategies for the cure of misfolding diseases. The increasing realization that protein aggregation plays a predominant role in the development of a number of diseases parallels an increasing interest in the mechanisms that protect proteins from this often unwanted phenomenon. Although much has been said about these protection mechanisms, and several possible strategies that the cell may take in combating protein aggregation have been suggested In this review, we discuss the paradigmatic example of Atx1. This protein provides a unique illustration of how protein\u2013protein interactions can sort the \u2018fate\u2019 of a protein. Atx1 is responsible for SCA1 (OMIM #164400) In the following sections, we review our current knowledge of Atx1 and place these observations within the context of the protection mechanisms against aggregation. We show how the normal function of the protein, together with its unusual structural properties, determine its cellular function/dysfunction and how aggregation is mediated by multiple regions acting in cooperation. We believe that this example may open a new perspective for the study of SCA1 and other misfolding diseases and eventually suggest a strategy for a specific cure.Atx1 is, together with the above mentioned ataxin-3, a member of the family of proteins that contain a polyglutamine (polyQ) tract and are implicated in genetic neurodegenerative diseases Atx1 is a predominantly nuclear, ubiquitous protein well conserved in vertebrates Prediction of the structure of Atx1 based on the amino acid sequence indicates that Atx1 is predominantly an intrinsically unstructured protein The intrinsic tendency of Atx1 to degradation and aggregation even when in its non-expanded form has so far hampered the possibility of expressing and purifying the recombinant full-length protein in an intact mono-disperse form suitable for a structural characterization of its conformational ensemble. However, it was possible to produce the AXH domain in isolation and to investigate its structure both in the crystal and in solution. The crystal structure revealed the open barrel typical of an oligonucleotide-binding (OB) fold, a structural motif involved in nucleic acid and protein recognition SCA1 gene was identified SCA1 showed that gene expression is dysregulated at a very early stage of the disease, when neurological hallmarks are still undetectable DrosophilaNot long after the Using a general read-out assay for repression of transcription it was shown that both full-length Atx1 and the isolated AXH domain repress transcription when tethered to DNA Atx1 has been described as modulating the function of several transcriptional regulators, often by means of direct protein\u2013protein interactions. The partners identified so far include polyQ binding protein-1 (PQBP1) In addition to a role in transcriptional regulation Although polyQ expansion plays a predominant role in disease, it has been demonstrated that polyQ expansion is a necessary but not sufficient condition for disease development and that regions either flanking or sequentially distant from the polyQ tract contribute to protein aggregation in vitro, the domain spontaneously forms fibers even in the absence of destabilizing conditions, whereas in eukaryotic cells its propensity to multimerization positively influences the aggregation of the expanded full-length protein Drosophila Atx1, which lacks the polyQ tract, but different from those observed for polyQ peptides One such region is the AXH domain Therefore, the pathological behavior of Atx1 is a consequence of a complex crosstalk between several different regions. This is not the first example of a protein with multiple aggregation sites comprising both intrinsically unfolded and globular domains Protein aggregation has been suggested to be a competing pathway of normal function and therefore of functional protein\u2013protein interactions As mentioned above, most of the known interactions of Atx1 with its cellular partners have been mapped onto the C terminus of the protein, either on the AXH domain or on short linear motifs around the phosphorylable S776. Phosphorylation of S776, in particular, acts as a molecular switch that allows the protein to discriminate between different binding partners An even more interesting example of how a cellular partner can counteract the intrinsic propensity of Atx1 towards aggregation is that of the transcriptional repressor CIC. This protein forms a stable complex with wild type Atx1 and participates in the formation of a large native complex in mouse cerebellum Recognition between Atx1 and CIC has been mapped onto the AXH domain and a short linear motif located in the N terminus of CIC The minimal CIC sequence necessary and sufficient to recognize AXH with nanomolar affinity was identified in the stretch V34\u2013L44 with W37 and L40 of CIC being the only residues significantly decreasing the peptide affinity when mutated into alanine These results have the potential to be translated into a treatment for SCA1. If what we observe at the level of the isolated domain could be transferred to the full-length protein, the CIC sequence found to bind Atx1 with high affinity could be used directly as a mould to design compounds able to stabilize monomeric Atx1 and prevent aggregation. It would be particularly interesting to design peptidomimetic molecules based on the CIC sequence that would be more suitable to this aim than easily degradable peptides . This stAtx1 provides an interesting example of how proteins are protected from aberrant aggregation. The example stresses once again the importance of protein\u2013protein interactions in determining and diversifying protein function. It also shows the importance of studying the nonpathological function of proteins implicated in misfolding diseases in parallel with the pathological properties. A more general understanding of their cellular role seems indeed to be essential to suggest new, specific strategies for drug development. We thus hope that the message contained in the specific example of Atx1 will be inspirational for other proteins of the misfolding disease family."} +{"text": "Zinc Finger Nuclease (ZFN) technology has provided researchers with a tool for integrating exogenous sequences into most cell lines or genomes in a precise manner. Using current methods, the efficiency of targeted integration (TI) into the host genome is generally low and is highly dependent on the ZFN activity at the genomic locus of interest. It is unknown if the ZFN binding and cutting efficiency is more dependent on the nucleotide recognition sequence or the chromosomal context in which the sequence is located.We have taken a highly efficient ZFN pair (hAAVS1) from human studies and introduced the exogenous DNA sequence into the Chinese Hamster Ovary (CHO) genome in an attempt to improve the efficiency of targeted integration. A \"Landing Pad\" comprised of human AAVS1 sequence has been integrated into the CHO genome at 3 separate loci to determine if the ZFN's will work across species and if the cutting efficiency is affected by chromosomal context. The results of this study will help us to improve the overall efficiency of TI by using Landing Pads, particularly for genomic targets in which suitable ZFN's may not be available.3 CHO Loci were chosen for this study based on previous gene expression studies. Rosa26 and Neu3 show consistent but low levels of expression while Site #1 appears to have no known coding sequence. Additionally, Rosa26 and Site#1 were chosen as potential safe harbor sites in CHO. The ZFN cutting efficiency at the endogenous CHO loci Rosa26, Site #1 and Neu3 are approximately 15%, 30% and 40% respectively. Based on other studies the cutting efficiency of human AAVS1 ZFN's was as high as 50% depending on the human cell line used. A plasmid donor carrying the hAAVS1 ZFN recognition sequence Landing Pad was introduced into CHO Rosa26, Site #1, and Neu3 via targeted integration (Figure Clones carrying the exogenous hAAVS1 Landing Pads at Rosa26, Site #1 and Neu3 were transfected with hAAVS1 ZFN's and the cutting efficiency was measured. We found that the human AAVS1 ZFN's were able to successfully cut at their recognition sequence in the Landing Pad at all 3 CHO loci to varying degrees (Table These results indicate that the chromosomal context of the ZFN recognition sequence has an effect on cutting efficiency. This study shows that TI can be performed with Landing Pads across species with high efficiency and provide researchers with additional tools for cell line engineering. Further development of Landing Pads could create highly engineered and multi-functional platforms that would facilitate more efficient and more tailored CHO cell modifications."} +{"text": "England and Wales recently replaced the 7-valent pneumococcal conjugate vaccine (PCV7) with its 13-valent equivalent (PCV13), partly based on projections from mathematical models of the long-term impact of such a switch compared to ceasing pneumococcal conjugate vaccination altogether.A compartmental deterministic model was used to estimate parameters governing transmission of infection and competition between different groups of pneumococcal serotypes prior to the introduction of PCV13. The best-fitting parameters were used in an individual based model to describe pneumococcal transmission dynamics and effects of various options for the vaccination programme change in England and Wales. A number of scenarios were conducted using (i) different assumptions about the number of invasive pneumococcal disease cases adjusted for the increasing trend in disease incidence prior to PCV7 introduction in England and Wales, and (ii) a range of values representing serotype replacement induced by vaccination of the additional six serotypes in PCV13.Most of the scenarios considered suggest that ceasing pneumococcal conjugate vaccine use would cause an increase in invasive pneumococcal disease incidence, while replacing PCV7 with PCV13 would cause an overall decrease. However, the size of this reduction largely depends on the level of competition induced by the additional serotypes in PCV13. The model estimates that over 20 years of PCV13 vaccination, around 5000\u201362000 IPD cases could be prevented compared to stopping pneumococcal conjugate vaccination altogether.Despite inevitable uncertainty around serotype replacement effects following introduction of PCV13, the model suggests a reduction in overall invasive pneumococcal disease incidence in all cases. Our results provide useful evidence on the benefits of PCV13 to countries replacing or considering replacing PCV7 with PCV13, as well as data that can be used to evaluate the cost-effectiveness of such a switch. Streptococcus pneumoniae was responsible for about 6,000 annual cases of invasive pneumococcal diseases (IPD), with presentations such as meningitis, bacteraemia, sepsis and pneumonia. PCV7 provides protection against 7 serotypes among more than 90 pneumococcal serotypes identified so far. It was introduced into the UK routine childhood immunisation programme in September 2006 for infants at 2, 4 and 13 months with a catch up to children under two years of age. Prior to the introduction of Prevnar 7\u2122, the 7-valent pneumococcal conjugate vaccine (PCV7), in England and Wales, Here we describe an extension of our previous modelling work in order to address these questions. We use a hybrid modelling approach, combining an enhanced version of the previously developed compartmental deterministic model S. pneumoniae in IPD cases was restricted to those identified by culture Key model parameters governing transmission and competition between serotypes were determined by fitting to the same epidemiological data, as was done in our previously published model IPD incidence has been increasing in the years prior to PCV7 introduction, likely reflecting improved ascertainment Two types of pneumococcal transmission dynamical models were developed: a deterministic compartmental model to estimate model parameters using the data described in the previous section, and an analogous individual based model to simulate effects of introducing PCV13 or stopping PCV vaccination entirely. Parameters estimated from the deterministic model were used as inputs for the individual based model. The individual based model was used to implement the heterogeneous vaccine/dose/birth cohort information in those individuals who started vaccination with PCV7 but subsequently switched to PCV13 either post dose 1 or post dose 2 during the immunisation course. This was done because the multitude of possible vaccine status and dose combinations is too complex to capture in a compartmental model framework.Individuals in the population belong to one of eight compartments according to the nature of serotypes they carry in their nasopharynx (deemed an infection): susceptible to any infection (hereafter \u201cSusc\u201d), infected with either VT1, VT2 or NVT serotypes, infected with serotypes from two groups and infected with serotypes from all three groups (\u201cAll\u201d). This is shown graphically in 1, \u03bb2, and \u03bb3) in 3, reduced by the competition parameter C1 .Competition parameters C4 and C5 represent the protection that individuals carrying VT2 or NVT have against acquiring VT1. These parameters do not alter the prevalence of VT2 or NVT after PCV7 introduction since with the elimination of VT1 carriage the respective compartments of multiple carriage disappear. Hence C4 and C5 cannot be estimated using the post-PCV7 data but also the post vaccination epidemiology is insensitive to them. For similar reasons, the competition parameters C6, C7, C8 and C9 also have no significant effect on the post PCV7 and PCV13 epidemiology. We fixed all these competition parameters (C4 to C9) at 0.5.Model parameters governing transmission and coexistence between different groups of serotypes within individuals were estimated by fitting the deterministic model to IPD data in both the pre-PCV7 and post-PCV7 periods in the following way:The model\u2019s goodness of fit is calculated for six age groups among the three serotype groups assuming that the culturing processes only detect the most dominant serogroups amongst the serotypes carried. The order of this dominancy is assumed to follow: VT1>VT2>NVT.The propensity to develop invasive disease given carriage for three serotype groups and 16 age groups is calculated using the trend-adjusted number of IPD cases in 2005/06, assuming carriage prevalence has been stable since 2000/01.The goodness of fit between the number of IPD cases predicted by the model and trend-adjusted post-PCV7 data (measured in terms of Poisson deviance) is calculated.A simplex algorithm determining the minimal overall deviance (FMINSEARCH in MATLAB\u2122) was employed to find the optimal parameter sets for the different scenarios.The dynamics of pneumococcal transmission and the likely impact of changing the valency of the PCV vaccination programme were modelled in an individual based framework that exactly reproduced the deterministic model. The simulations were run with four time steps for each month, with 100 age cohorts from 0 to 99 year olds. As a consequence, the total population size is 48 million, comprising of 10,000 individuals in each of 4,800 birth cohorts. As in the deterministic model each age cohort is weighted based on the population structure of England and Wales in 2006 to estimate the force of infection for three serotype groups at each time step Acquisition and loss of infection, and loss of vaccine protection occur as stochastic processes, with their probabilities determined by the force of infection, duration of infection, and duration of vaccine protection, respectively. Each scenario is repeated ten times in order to estimate the stochastic uncertainty arising from these processes.Only ten repetitions were necessary as the large population size (48 million) limited stochastic variation between repetitions and only their mean is reported here.The effect of each dose of the PCV vaccination programme in the individual based model is shown in Individuals who receive one dose when above the age of one year are fully protected. Those who receive one dose under the age of one year are only partially protected.Individuals who receive two or more doses are fully protected.Individuals who lose vaccine protection by waning are only partially protected.If individuals who are partially protected receive another dose, they then become fully protected.PCV7 vaccination begins in September 2006 and is either changed to PCV13 or stopped in April 2010.When PCV7 is replaced with PCV13, individuals who were scheduled to receive the remaining PCV7 doses receive PCV13 instead and get protection against extra serotypes included in PCV13. For example, if an infant received the first dose with PCV7 and the second dose with PCV13, the infant gets full protection against PCV7 serotypes but only partial protection against extra serotypes in PCV13.The duration of vaccine protection against acquisition of carriage and disease development is assumed to be 5 years For all three scenarios of data adjustment for trend, the model fitted the number of IPD cases as observed in England and Wales well . In all Stopping PCV vaccination altogether in April 2010 is predicted to cause a rebound in the number of IPD cases to the pre-PCV7 equilibrium due to an increase in VT1 IPD as well as decreases in both VT2 and NVT IPD . On the The baseline epidemiological year for calculating the impact of the change in vaccination policy away from PCV7 is assumed to be 2009/10, since PCV13 was only implemented three months before the end of 2009/10. PCV13 replaced PCV7 in the UK\u2019s vaccination schedule in April 2010 following the manufacturer\u2019s decision to cease marketing PCV7 in the UK and only to offer PCV13. At the time of the analysis neither information about multiple carriage episodes nor data on post PCV13 IPD replacement was available. Such information is needed to estimate the competition parameter determining the protection individuals carrying VT2 receive against acquiring NVT infections and the consequent level of NVT replacement expected following the introduction of PCV13. However, we were able to capture this uncertainty and show that even in the case of strong competition between those serotype groups, the corresponding level of serotype replacement is unlikely to offset the benefits in reduction in IPD, which is mainly due to the lower invasiveness of the NVT serotype group among over 65 year olds where the majority of IPD cases occur .The indirect impact of pneumococcal conjugate vaccines is governed by two opposing effects. The beneficial effect is the reduction in the number of vaccine related IPD cases among unvaccinated individuals in the population due to the reduction in pneumococcal carriage and transmission in vaccinated individuals. The detrimental effect is the replacement of vaccine types with non vaccine types: removing the targeted serotypes leaves open an ecological niche for other serotypes to colonise. When there is little propensity for different serotypes to coexist in the host then it is assumed that there is competition between them to colonise the nasopharynx, so carrying one serotype has a protective effect against acquiring another serotype. The stronger the effect of this competition (with a consequent lower propensity to coexist), the more likely it is that individuals will acquire NVT serotypes following vaccination because competition induced by vaccine serotypes is reduced. The existence of such competition is widely accepted The mechanisms driving competition and co-existence between the various pneumococcal serotypes are poorly understood but play a crucial role in determining the effects of vaccination on the transmission dynamics of pneumococcal carriage and disease. The modelling approach we implemented accounts for both these aspects with a mechanistic rather then a causal representation of competition between serotypes. The model promotes co-existence of serotypes trough implicitly assuming serotype group specific immunity for the duration of carriage and thus providing an ecological niche for other serotype groups. Hence, the model is not structurally neutral a priori the effect on IPD of replacing PCV7 vaccination with pneumococcal vaccines of higher valency (PCV13) that captures the transmission dynamics of herd immunity and serotype replacement. In order to capture the effect of giving different vaccines (PCV7 and PCV13) to the same individuals, we used an individual based modelling framework that allowed detailed characteristics of each individual within a model to be tracked. However, the computational requirements of this choice of model structure make it challenging to estimate model parameters in a complex dynamical system. Hence we used a hybrid approach, with a deterministic compartmental transmission dynamic model used to estimate relevant model parameters using pre-PCV7 carriage data, trend-adjusted IPD data between pre- and post-PCV7 periods, age-dependent mixing and PCV7 coverage. Once these parameters had been estimated, we used an individual based model in order to measure the effects of two alternative vaccination programmes on the number of annual IPD cases.In this paper, we present a novel model to estimate One encouraging result is that all the scenarios considered in this study suggest reductions in the overall number of IPD cases following PCV13 introduction, though of varying magnitude. This predicted reduction in the overall number of IPD cases following PCV13 introduction is due to the lower propensity to develop invasive disease given carriage of non-PCV13 serotypes in elderly age groups where most of the IPD cases occur. Similar results were found in a UK study predominantly in children Many high income countries with existing immunisation programmes using PCV7 are replacing or considering replacing PCV7 with PCV13 due to its increased serotype coverage. However, this change will not eliminate the potential for serotype replacement since most of the pneumococcal serotypes causing IPD are not present in PCV13 either. Hence the medium and long term effects of using PCV13 in the context of pre-existing use of PCV7 are still largely unknown. Several models have been developed to estimate this effect This study uses dynamic models to estimate the direct and indirect effects of replacing an existing infant PCV7 vaccination programme with a higher valency vaccine such as PCV13. The transmission model allows more realistic estimation of dynamic effects (indirect protection and serotype replacement) of pneumococcal conjugate vaccines than static models, even when the latter are adjusted using a \u201cdynamic approximation\u201d technique In this study we estimated parameters governing the effect of introducing PCV13 to replace PCV7 or of discontinuing pneumococcal conjugate vaccination through parsimonious dynamic models. Prior to robust data on replacement induced by vaccination with PCV13 and in the absence of information about multiple carriage episodes, a key aspect of the impact of the introduction of PCV13, serotype replacement from the reduced competitive effect of the six additional vaccine serotypes, could not be estimated. However, we show that the possible range of the replacement effect \u2013although substantial- is unlikely to span scenarios where introduction of PCV13 becomes less beneficial than the alternative option of discontinuing conjugate vaccination. Data on multiple carriage would help to reduce the uncertainty of such a priori estimations but would be difficult to obtain because of the large sample size needed to adequately estimate age-dependent carriage prevalence for the compartments of multiple carriage defined in the model. Hence our results provide useful evidence on the possible benefits of PCV13 to countries replacing or considering replacing PCV7 with PCV13, as well as data that can be used to evaluate the cost-effectiveness of such a switch."} +{"text": "Gastric intestinal, skeletal muscle and neurological symptoms are just some of the possible effects of alimentary intolerances that may represent a risk for one's health and may frustrate the athlete's practice benefits and thwart the performance. The immunological tolerance recovery and the re-establishment of a normal diet are generally reached by means of strict dietetic schemes (a turnover or elimination diet) requiring a strong effort into changing one's diet habit. In the elite soccer athlete, an intense competitive schedule including long transfers represents another risk to these dietetic therapies fulfilment that may even worsen the symptomatology once the allergens responsible for the intolerances are again within the diet.The purpose of this study was to objectively estimate an food intolerance in elite soccer players who have foodintolerance symptoms, by arranging a nutritional plan for the immunological tolerance recovery, the symptomatology improvement and to test the effectiveness in terms of nutritional situation by means of the BIVA, assuming a close relation among food intolerances, inflammatory reactions and nutritional status.Eight males 32.5 \u00b1 1.9 years old soccer players and BMI 24.9 \u00b1 1.1 (Average \u00b1 DS) with symptoms of possible food intolerance of an Italian Serie A soccer team were subjected to the ALCAT test before and after eight months of a personalized nutritional treatment. The athletes body composition was basally valued and at the end of the BIVA analysis .The athletes tested, with food intolerance symptoms, were ALCAT test variously positive. The personalized nutritional treatment based on moderation rather than on drastic elimination of reactive foods and complying with the specific nutritional needs of the elite soccer player led to a nearly complete resolution of the first symptoms as the clinical evaluation and the post-treatment ALCAT test results demonstrate. Parallel to these results a significant shift of the mean impedance vector was observed , so indicating a more favourable condition of the soft tissues (hydration and/or mass) with no BMI variation (p<0.05).The ALCAT test seems to be able to detect the food intolerance reactions when it is applied to patients with initial specific symptoms. A personalized and flexible nutritional therapy based on moderation and rational elimination of reactive foods seems to be working and be suitable for the elite athlete whose specific logistic necessities ( for example long travels) discourage the classic dietary regime. An efficient handling of the food intolerances seems to lead to a nutritional condition improvement, maybe reducing the concerned inflammatory situation as observed in body composition changing, which may influence the sports performance."} +{"text": "Various studies report remarkably high maternal mortality rates in northern Nigeria, where maternal mortality rates exceed 1,000 deaths per 100,000 live births and eclampsia contributes approximately 40% of maternal deaths. Across Nigeria, diazepam is routinely used for the management of eclampsia. Prior to February 2008, diazepam was widely used for the management of eclampsia in Kano State (within northern Nigeria) with case fatality rate being over 20%. While magnesium sulphate to 2.3% among eclampsia patients following the MgSO4 therapy with minimal increase in costs when compared to diazepam therapy. Concerted efforts should be focused on properly introducing MgSO4 into emergency obstetric protocols especially within developing countries to reduce maternal mortality and also impact on health system performance.The study found a remarkable reduction in case fatality rate due to eclampsia in those who received MgSO It was reported to have contributed to 46.3% of maternal deaths in Kano State and 43% 4) as a safe and low-cost drug to manage severe pre-eclampsia and eclampsia cases [WHO has recommended the use of magnesium sulphate and an estimated total population of 9,401,288 according to the 2006 Nigerian national census . Kano St4 through a two day training workshop in January 2008. A simple protocol for the use of the drug was developed and then utilized during the training. The participants were taught how to detect MgSO4 toxicity using clinical methods and how to administer the antidote . After the training, MgSO4was supplied by the state government with support from Population Council to the health facilities to replace diazepam as the drug of choice for the management of severe pre-eclampsia and eclampsia. The training of the health workers ensured that all patients with eclampsia across the ten health facilities received similar treatment with MgSO4. In addition, regular supportive supervisory visits were conducted to all the ten facilities to ensure adherence to protocol. Ethical clearance for the intervention was granted by the Kano State Health Management Board as well as Population Council\u2019s Ethical Research Review Committee.Health workers (doctors and midwives) from the ten health facilities were trained on how to use MgSOa1233 eclampsia patients from the baseline period (2006 \u2013 2007) who received diazepam for the management of eclampsia and 996 eclampsia patients from the intervention period who received MgSO4 after presenting to the ten secondary level health facilities selected for the intervention. Similarly there were 49 severe pre-eclampsia patients during the intervention period who also received MgSO4. This makes a total of 1045 (severe pre-eclampsia and eclampsia) patients for the intervention period i.e. between February 2008 and January 2009.The study sample consists of 4 in the ten selected sites during the intervention period. The case fatality rate for eclampsia is defined as the number of deaths with eclampsia as the underlying cause of death per 100 cases of eclampsia that received MgSO4 in the general hospitals. The relative standard error (RSE) was used as a measure of an estimated CFR\u2019s reliability; it was obtained by dividing the standard error of the estimate (SE) by the estimate itself (CFR)*100. RSE\u2009<\u200930% was considered reliable.The case fatality rate of patients who received diazepam during the baseline study period was estimated by analyzing data on case fatality for eclampsia from representative facilities across the state. Similarly the case fatality rate was estimated for patients who received MgSO4 therapy particularly in terms of case fatality rates and also cost implications.Data for the study was obtained from the obstetric records of eclamptic patients. Data collection did not involve collecting data directly from individual patients; however data was collected from the health records of eclamptic patients with no unique identifiers. Data analysis was done using SPSS statistical software version 15. Comparison was made between diazepam and MgSO4 for managing eclampsia cases was calculated by applying the cost per ampoule for both diazepam and MgSO4 to the expected number of ampoules required for managing patients. The cost of managing recurrent convulsions after a loading dose of MgSO4 during the intervention period was estimated. The extra cost of replacing diazepam with MgSO4 as the drug of choice for managing eclampsia per eclampsia patient was also calculated.The estimated cost of using diazepam versus MgSO4 therapy. Table 4 was administered during the intervention period. It shows that more than 90 percent of patients (92.5%) treated with MgSO4 did not have recurrent fits. When a recurrent convulsion occurred, it was treated using 2grammes of MgSO4 administered intravenously. Also about two percent (2%) of the patients who had clinical toxicity were detected by loss of deep tendon reflex using a patellar hammer. All cases of clinical toxicity were treated by stopping MgSO4 and further treatment with 1gramme of 10% calcium gluconate. Table 4 compared with diazepam as well as the cost for treating recurrent convulsions using MgSO4. Expert advice from clinicians working within the state recommends using about 5 ampoules of diazepam/per day for 2\u2009days which is estimated at N1000 (~6.67 US dollars) to manage a patient with eclampsia. The Pritchard regimen with intramuscular maintenance doses has been widely recommended for use in low resource settings [4 within a 24 hour period, estimated at N1600 (~10.6 US dollars), was administered to patients in the health facilities during the intervention period. These figures are calculated based on the assumption that diazepam costs N100 per ampoule while MgSO4 costs N200 per ampoule, but these costs vary widely across Nigeria. In addition, since just about an ampoule will be required to treat recurrent convulsions, the cost for treating any recurrent convulsions was estimated at N200 (~1.33 US dollars). Table settings . A modif4 for the management of eclampsia. This finding reiterates the results of the Magpie trials where MgSO4 reduced the relative risk of eclampsia by half without significant harmful effects on the mother [4 reduced maternal deaths with a risk ratio of 0.59 (95% CI 0.38 to 0.92) [4 over other anticonvulsants for the treatment of severe preeclampsia and eclampsia [This study illustrates a reduction in case fatality rates and the benefits of using MgSOe mother as well to 0.92) . The resclampsia .4 is slightly over 10 US dollars in Nigeria compared with about 7 US dollars if diazepam is utilized. As illustrated by this study less than 1 in 10 patients given a loading dose of MgSO4 will likely get recurrent convulsions. The extra cost per person per episode for managing eclampsia that will be incurred if MgSO4 replaces diazepam is estimated to be between 3 to 4 US dollars. For MgSO4 to be available at cheaper prices, two key strategies are recommended. First, there is need for the Nigerian government to ensure proper price control mechanisms for the drug are put in place while offering market incentives to encourage local production of the drug. Second, there maybe need to introduce subsidies for MgSO4 as presently occurs with anti-retroviral drugs [At present the estimated cost of managing a convulsion and preventing further episodes of eclampsia using MgSOal drugs .4 into health facilities and sustaining its use within the wider health system should progressively reduce, especially if a well organized and efficient supply chain management system for the drug is put in place. Furthermore costs for the procurement of MgSO4, for the management of eclampsia, when applied at national levels, should certainly be manageable, if proper economies of scale are factored into the procurement of the drug.It is expected over time that the cost of introducing MgSO4 intervention provides firm justification for the need to strongly promote the routine use of MgSO4 in health facilities across Nigeria and not just in Kano State. There will be a cumulative impact on the per capita income and gross domestic product (GDP) in Kano State and across the country if this relatively low-cost medication is effectively utilized in the fight against maternal mortality.The significantly better clinical outcomes highlighted through the MgSO4 for eclampsia management, governments in Nigeria and other low income countries should work towards producing clear national guidelines on the use of MgSO4 in concurrence with WHO guidelines. Ministries of Health at state and national levels could also create more awareness about the benefits of using the drug, in collaboration with the World Health Organization as indicated in a previous publication [With clear clinical and economic benefits associated with using MgSOlication . Appropr4 for managing eclampsia by WHO, UNFPA, UNICEF and the World Bank [4 intervention in Kano State by Population Council, the Kano State government has taken over the supply of the drug to its health facilities. Preliminary results indicate clear benefits which should justify the continued use of MgSO4 in the free maternal and child programme currently run by the Kano State government. But a key challenge will be to ensure that there is a steady provision of drugs and supplies to health facilities as well as for patients in need. Freedman and others proposed [4 for eclampsia management may not entirely be a \u201cmagic bullet\u201d but it should be properly integrated into the implementation framework for maternal mortality reduction within the health systems of resource limited countries, for there to be any significant impact on health system performance. As suggested by Nyamtema and others [Following the acknowledgement of the importance of using MgSOrld Bank and the proposed that gov4 therapy reduced the case fatality rate due to eclampsia to a significantly greater extent than the existing diazepam therapy in ten intervention centres in Kano State. There is no significant difference in costs in using both drugs. MgSO4 therapy can be administered by trained health workers who can recognize the side-effects and the necessity for stopping the drug when needed. The continuous supply of the drug by the government is necessary to replace the present day less standard diazepam therapy for eclampsia. Prevention of teenage pregnancy and raising the educational status of women in this region will also help in the long run to reduce maternal mortality due to eclampsia.In conclusion, MgSOaAll the 1233 patients who reported during the baseline/pre-intervention period were recorded and treated as eclampsia patients and received diazepam.bTo introduce MgSO4 into the ten selected health facilities during the intervention period, Population Council incurred expenses that included the costs of training health workers, costs associated with monitoring and evaluation of the MgSO4 intervention as well as cost of procurement of the drug for use in the selected health facilities. However the breakdown of these costs was not included in the costs estimation.*I US Dollar\u2009=\u2009150 Naira.The authors declare that they have no competing interests.EO and SMI jointly participated in the design of the study and the outline for the manuscript. EO and ABO carried out the data collection, data analysis and interpretation of the data. EO developed the first draft of the manuscript. BA, JT and SMI made significant efforts in critically revising the draft for substantial intellectual content. All authors read and approved the final manuscript."} +{"text": "There are obvious problems involved in the accurate description of movement of the intrinsic bones within the foot and ankle. The 26 small bones are difficult, if not impossible to individually represent with standard skin mounted markers for motion analysis ,2. This A number of experimental sessions have been performed at Karolinska Institute. The intracortical pins were inserted by experienced orthopaedic surgeons under sterile conditions and using local anaesthetics Figure . Triads A large range of fundamental data concerning foot and ankle kinematics during walking and running and with various manipulations have been collected and will be presented."} +{"text": "In regards to the error in Figure 2, the authors write:\"In this study, we generated and analyzed 51 mitochondrial genome (mtgenome) sequences of gibbons to reconstruct phylogenetic trees and estimate the divergence times in gibbon evolutionary history. We became recently aware that the sequences of two individuals (J24 and J17) in our dataset of 51 gibbon mtgenomes are partially incorrect and hence the corresponding Genbank records of these two sequences (accession numbers HQ622760 and HQ622786) have been removed from the GenBank database. Here we show the consequences of removing those two sequences from the analysis by examining newly generated phylogenetic trees and Bayesian estimates of divergence times.H. pileatus in the basal position in the Hylobates phylogeny in contrast to the absence of basal species suggested in the previous results . The divergence times were newly estimated with a Bayesian relaxed clock approach using the protein sequences of mtgenomes from 22 individuals , but in which the three tree priors of the previously observed monophylies were no longer set. We obtained somewhat younger estimates with the narrower intervals of 95% highest poster density (HPD) for dating the splitting events compared to the older estimates resulting from the previous analysis (Table 1). Namely, the results of corrected Bayesian estimation suggested that the timings of most splitting events in the Hylobatidae family occurred from the Late Miocene to the Early Pleistocene (11.61-0.78 million years ago) and the Hylobates radiation began some 3.32 million years ago.Using the 49 mtgenome sequences, we reconstructed the phylogenetic trees of gibbons using Bayesian and maximum likelihood methods with three partitions . The revised information on size and characteristics of the partitions are slightly different from those in the previous table (Table 4). While the branching pattern of the gibbon genera remain unchanged, the corrected results place Therefore, accordingly, we would like to replace the Table 4 of partition characteristics with a new revised table, and replace the Figure 2 of phylogenetic tree with a new revised figure as well. Moreover, a new table of corrected Bayesian estimates is also provided to replace the previous Table 1.\"The correct Figure 2 can be seen here: Figure 2. Phylogenetic tree of gibbons and outgroup primates based on the mtDNA concatenated dataset. The phylogenetic relationships among gibbons and six outgroup primates were inferred from the mtDNA concatenated dataset, including three partitioned sets: ribosomal RNA, transfer RNA and protein-coding gene. The maximum likelihood (ML) and Bayesian methods were used to reconstruct phylogenetic trees. Both analyses produced the same topology and their support values are indicated by circles on the nodes of the Bayesian tree shown here. Individuals used in the estimation of divergence times are marked with an asterisk.The correct legend for Figure 2 is:The corrected Table 1 can be seen here: The corrected Table 4 can be seen here:"} +{"text": "A mathematical expression of \"variance\" in the first line immediately below Equation number 6 in the \"Estimation procedure\" of the Materials and Methods is incorrectly given. The correct expression is:"} +{"text": "To explore the clinical experiences of homeopaths participating in an open label pilot study of the homeopathic treatment of children with attention deficit/hyperactivity disorder (ADHD). Specific objectives include to: (1) Explore how treating patients within a clinical trial was similar or different from general practice experiences; (2) Reflect on how clinical practices changed as part of the trial; and (3) Identify issues or lessons for future homeopathic clinical researchers and clinicians.A series of in-person interviews were conducted at month 11 of the clinical trial (2/3 completion) with the two study homeopaths. The clinicians were asked a series of open-ended probing questions to explore their experiences participating in the trial and to reflect on issues they felt significant to the study design.The clinicians described the study participants as having a greater degree of ADHD pathology, more co-morbidities, and as taking more medication than their daily practice patients. The clinical approach to the study patients deviated from the homeopaths\u2019 normal practice in the following ways: a greater reliance on \u201cwater dosing\u201d (giving medication dissolved in water and having the participant dose more frequently) to adapt to concomitant conventional medication; and less dietary advice was given due to the need to establish rapport and the feeling that such advice would overwhelm the families. The homeopaths described challenges in explaining homeopathic treatment concepts such as remedy reaction trajectory and homeopathic remedy aggravations.Homeopathic medications and dietary protocols were found to be easily adapted for use in a clinical trial. These observations provide insights for future research in the area of homeopathic treatment and provide insights for the potential integration of homeopathic practice into conventional settings."} +{"text": "Cancer patients will receive targeting therapy based on knowledge of deregulated genes or signaling pathways. Treatment will be individually designed on genome, transcriptome and proteome data. What a promise! Pathologists will sight with relief as this rids them of the pressing task to identify targets for therapies. Is there still need for old fashioned immunohistochemistry with machinery around providing answers to all questions whether asked or not?One of the current hot targets is the BRAF gene. By far the most numerous BRAF alteration is a single point mutation resulting in an amino acid exchange in position 600 dubbed V600E. The substance PLX4032/RG7204 has showRecently, a monoclonal antibody specifically recognizing the V600E mutation has been developed promisinMoreover, the antibodies ability to identify single cells with the V600E mutation and to provide information on the quantity of mutant protein opens a range of novel opportunities beyond qualitative diagnostic application. Single cell identification allows addressing questions regarding the origin and evolution of tumors. This is of special interest in inhomogeneous tissues such as Langerhans cell histiocytosis with the antibody allowing identifying the neoplastic element , 8. ViceWill there be many more mutation specific antibodies in the future? This very much depends on the recognition of genes exhibiting highly recurrent mutations. In terms of frequency BRAFV600E is the current leader of the pack. IDH1R132H being the dominant mutation in diffuse gliomas and also frequent in AML, chondrosarcomas and cholangiocarcinomas already can be identified by mutation specific antibodies . A very"} +{"text": "The use of HAART during lactation has also been discussed as an approach to reduce postnatal HIV-1 transmission. The benefits and safety of HAART used solely for prevention of postnatal transmission in healthy HIV infected women have not yet been demonstrated in clinical trials. The extension of maternal HAART through the period of breast feeding can be proposed as pivotal strategy to reduce breast milk HIV transmission.To assess the safety of breastfeeding during antiretroviral treatment in terms of virological and clinical outcomes in pregnant HIV-infected women in the Dodoma area of the United Republic of Tanzania. Secondary objective is the study of viral dynamic and therapeutic drug monitoring of antiretroviral drugs into breast milk of HIV-infected women treated with HAART during breastfeeding.The enrolment phase of the AMANI Study started on May 2010 at Makole Health Centre (Makole UHC). After the first two months 68 HIV positive pregnant women (HPW) out of 68(100%) HCWs attending the site were counseled. 50 HPW (73.5%) were enroled in the study and are being followed up at Makole UHC. Of the remaining 16(23.5%) were not eligible and only 2(2.9%) refused to participate. Among the 50 HPW enroled only 6 (12%) have opted not to breastfeed after delivery, 12 HPW have started HAART prophylaxis from the 28 weeks of gestation, 3 HPW were found eligible and started HAART. 1 HPW has given birth on 16th July 2010 with no fetal and maternal complication. No patient reported any side effects to the ARV drugs.At the moment the study is progressing over the expectation. The procedures of the study where well accepted by the local Health Personnel with the totality of the HPWs counseled and by the HPW with only the 2.9% of refusal. Data from the study show that this kind of implementation research is well accepted by the Health personnel in terms of capacity building and by the HPW in terms of compliance and acceptance of the treatment. The benefits of the expanded treatment are well understood and overtake the discomfort of a higher pill burden and the risk of more adverse events."} +{"text": "The prevalence of viral hepatitis in tribal areas of India mostly remains unknown. Saharia is one of the primitive tribes of Madhya Pradesh and live primarily in the Sheopur and Shivpuri districts. The purpose of the present study was to assess the prevalence of hepatitis viruses in Saharia tribal community of central Indian state of Madhya Pradesh.A cross sectional study was carried out to determine the point prevalence of different hepatitis viruses amongst Saharia primitive tribal community of Madhya Pradesh, central India. After obtaining the informed consent, blood samples (5 ml each) were collected from them. Serum was separated on site, aliquoted and transported to the laboratory maintaining the cold chain. The markers of various hepatitis viruses were detected using commercial ELISA kits. The specimens found positive for HBsAg were tested for HBV DNA by Polymerase Chain Reaction (PCR).A total of 173 blood samples were collected. The prevalence of HBsAg and anti HBs was found to be 5% and 33% respectively. The prevalence of anti HCV was 1%. Anti HAV antibodies were present in 165 samples (99%). The prevalence of anti HEV was found to be 40%. 4 samples were found positive for HBV DNA by real time PCR.The findings of the study indicate that viral hepatitis infection is an important problem in saharia primitive tribal community. Control measures including IEC strategies are necessary among them."} +{"text": "In the first sentence of the section \"Plasmid and Lentivirus Preparation\" of the Materials and Methods, some of the sequences are incorrect. It should read: shRNA plasmids were generated by inserting the hairpin oligonucleotides into the FUGW-H1 lentiviral construct as previously described [28]."} +{"text": "H17) cells play a major role by inducing RANKL [The interaction between the immune and skeletal systems has long been acknowledged, but molecular mechanisms linking the two systems have not been demonstrated until recently. Investigation into autoimmune arthritis as well as the various bone phenotypes found in mice deficient in immunomodulatory molecules has highlighted the importance of the dynamic interplay between the two systems and brought about a rapid evolution of the field of osteoimmunology . In boneng RANKL . Maintenng RANKL and inhing RANKL ."} +{"text": "The rs12979860 single nucleotide polymorphism located on chromosome 19q13.13 near the interferon L3 gene (formerly and commonly known as interleukin 28B gene) has been associated in adults with both spontaneous and treatment induced clearance of hepatitis C virus. Although the exact mechanism of these associations remains unclear, it suggests that variation in genes involved in the immune response against the virus favours viral clearance. Limited and preliminary data are available on this issue in children. The aim of the present study was to evaluate, in a representative cohort of children with perinatal infection, the potential association between rs12979860 single nucleotide polymorphism and the outcome of hepatitis C virus infection. Alleles and genotypes frequencies were evaluated in 30 children who spontaneously cleared the virus and in 147 children with persistent infection and were compared with a population sample of ethnically matched controls with unknown hepatitis C status obtained using the 1000 Genomes Project data. The C allele and the C/C genotype showed greater frequencies in the clearance group when compared with both children with viral persistence and with the ethnically matched individuals . Children with the C/C genotype were 2 times more likely to clear hepatitis C virus relative to children with the C/T and T/T genotypes combined . The present study provides the evidence that the rs12979860 single nucleotide polymorphism influences the natural history of hepatitis C virus in children. IFNL3 gene (formerly and commonly known as IL28B) has been associated in adults with both spontaneous and treatment induced clearance of hepatitis C virus (HCV) IFNL1, IFNL2 and IFNL3 reside downstream of the rs12979860 SNP in vitro and in vivo through activation of the JAK-STAT pathway which leads to induction of several IFN stimulated genes which are responsible for antiviral activity IFNL3 gene and clearance of HCV remains unclear, it is evident that variation in genes involved in the immune response against the virus favours viral clearance The rs12979860 single nucleotide polymorphism (SNP) on chromosome 19q13.13 near the There is evidence that the frequency of the C allele of the rs12979860 SNP varies markedly across ethnic groups IFNL3 gene and spontaneous clearance of HCV have been performed in adults. Only two studies on small cohorts of children are available so far on the topic Most of the studies published on the association between rs12979860 SNP of the IFNL3 gene on the outcome of HCV infection in terms of spontaneous clearance and chronic infection in children, this variant was genotyped in an HCV cohort comprised of mono-ethnic children who spontaneously cleared the virus or had persistent infection. Allele and genotype frequencies in this cohort were compared with a population sample of ethnically matched controls with unknown hepatitis C status obtained using the 1000 Genomes Project data To confirm the potential effect of rs12979860 SNP of the This is a cross-sectional study. All the children, born to an HCV-infected mother and older than 30 months evaluated between January 2011 to December 2012 during routine follow-up visits for perinatal HCV infection were recruited. Only children whose parents or guardians provided written informed consent were enrolled and genotyped for the SNP rs 12979860. Retrospective data to define the source and the outcome of the infection were collected at the time of the enrolment. All the children enrolled were negative for hepatitis B surface antigen and for antibodies against human immunodeficiency virus. The ethnic origin of the children enrolled was self-reported by the parents or guardians. The study received the approval of the ethical committee of the Meyer Children's University Hospital of Florence.Mother-to-child transmission of HCV was defined as transmission occurring during pregnancy or in the perinatal period from the HCV-infected mother to the foetus or to the child One hundred and eighty six consecutive children were recruited. Nine of them (4.8%) were not enrolled as the parents did not provide the informed consent. Of the 177 children enrolled (95.2%), 30 consecutive children (16.9%) spontaneously cleared the virus and 133 (83.1%) were chronically infected.http://www.1000genomes.org), October 2010 release Allele and genotype frequencies for the rs12979860 SNP were examined for concordance with the individuals studied in the 1000 Genomes Project and CTGGTTCACGCCTTC (FAM) (Applied Biosystems). Before performing the PCR reactions DNA is added with Allelic Discrimination Assay Mix and TaqMan Universal PCR Master Mix to MicroAmp Optical 96-Well Reaction Plates (Applied Biosystems). Real-Time PCR reactions were performed using the 7500 Fast Real-Time PCR System. After preheating for 10 min. at 92\u00b0C, 40 cycles of 15 seconds at 95\u00b0C and one minute at 60\u00b0C followed. Data were analyzed using the ABI SDS software (Applied Biosystems).Polymerase chain reaction for HCV was performed as previously described 2 test or Fisher's exact probabilities. Odds ratio (OR) and 90% confidence intervals (CI) were calculated. Age was presented as median and interquartile range (IQR). Hardy-Weinberg Equilibrium (HWE) was tested. A deviation from HWE was defined with a criterion of p value <0.05.Data were processed with the SPSSX statistical package . Two tailed P values were used and a p value <0.05 was defined as significant. Differences in frequencies were evaluated by chiThirty children (16.9%) spontaneously cleared the virus and 133 (83.1%) were chronically infected. The characteristics of the children enrolled are summarized in Alleles and genotypes frequencies for the rs12979860 SNP were available in the 1000 Genomes Project database for 1,092 individuals. Rs12979860 alleles and genotypes frequencies according to the ethnic origin are summarized in versus 56.5% among children with chronic infection . The frequency of the C allele among children in the HCV cohort who spontaneously cleared the infection was greater than that observed in the individuals of European ancestry but the difference did not reach the threshold of significance . A significant difference was observed when the frequencies of C alleles of the children with spontaneous clearance and of Italians enrolled in the 1000 Genomes Project database were compared . The T-allele frequency was significantly greater in the chronically infected cohort compared with the European controls .In the HCV cohort, the frequency of the C allele was 76.7% among children who spontaneously cleared the virus Genotypes were in Hardy-Weinberg equilibrium in the cohort of children with HCV infection (p\u200a=\u200a0.63), in individuals of European ancestry and Italians selected from the 1000 Genomes Project database . ChildreIFNL3 gene are associated with spontaneous resolution of HCV infection in Italian children. The results of this study were obtained comparing the frequencies of the C and T allele and of the different genotypes of the rs12979860 SNP of the IFNL3 gene between a cohort of children who spontaneously cleared or where chronically infected by HCV with ethnically matched controls. The rationale for this study was that, if the polymorphism influences natural clearance also in children, we would have obtained a frequency difference in these comparisons, since the children who naturally clear the virus will be excluded from the chronic infection cohort, thereby reducing the frequency of the allele that increases the likelihood of spontaneous clearance. The present results confirm the association demonstrated in adults The present study shows that the C allele and the C/C genotype of the rs12979860 SNP of the IFNL3 gene observed among different European populations studied in the 1000 Genome Project is in line with the gradient of genetic variation described among Europeans following the North-Northwest/South-Southeast geographic axis One of the risks of the interpretation of genome wide association studies is to find spurious associations IFNL3 is a human gene of the host system of innate antiviral defense. The outcome of HCV infection is dependent on the balance between innate immunity of the host and the multiple mechanisms to regulate and evade innate immunity evolved by HCV. Although early studies failed to find altered mRNA expression of IFNL3 associated with different IFNL3 genotypes, since the specificity of real-time PCR primers for IFNL3 has increased (to differentiate between IFN-\u03bb3 and the closely related IFN-\u03bb2), it is now clear that SNPs of the IFNL3 gene affect the expression of IFN-\u03bb3 with the unfavourable allele resulting in less IFN-\u03bb3 expression IFNL3 genotype have depressed innate immune function, particularly with respect to NK cells, suggesting that the decreased expression of IFNL3 affects innate immunity and therefore clearance of HCV The present study contributes to the understanding of the mechanisms of clearance of HCV infection in children with perinatal infection. Spontaneous clearance of HCV in children perinatally infected has been associated so far with a transaminase flare in the first year of life and with HCV genotype 3 infection IFNL3 gene have been associated in adults with both spontaneous clearance of HCV infection and response to treatment with combined dual therapy with pegylated IFN and ribavirin. These results suggest that IFN-\u03bb3 has a key role in determining both treatment-induced and spontaneous clearance of HCV. The association between rs12979860 SNP of the IFNL3 gene and spontaneous clearance in children and the homology of this result with those obtained in adults, supports the hypothesis that IFNL3 gene polymorphisms should be evaluated extensively as pretreatment predictor of virological response also in children.SNPs of the IFNL3 gene are higher in a cohort of children who spontaneously cleared HCV infection when compared to children with chronic hepatitis C and ethnically matched controls. The rs12979860 SNP of the IFNL3 gene influences spontaneous resolution of HCV infection in Italian children.In conclusion, the present result demonstrates that the frequencies of the C allele and the C/C genotype of the rs12979860 SNP of the"} +{"text": "Continuous blood flow from left ventricular assist devices (LVAD) has become an important treatment option for heart failure patients. However, recent reports indicate that the complex geometric alterations of the vascular system associated with LVAD implantation as well as the introduction of constant flow into the aorta may alter blood flow patterns. These can potentially affect perfusion patterns to the supra-aortic vessels or cause structural changes to the aortic root leading to regurgitation and valve dysfunction. The purpose of this study was to evaluate the feasibility of flow-sensitive 4D MRI for the investigation of such blood flow alterations in an in-vitro model simulating 3D blood in a physiological model of the left ventricle, aortic valve and aorta.In a MRI compatible mock loop circuit consisting of a silicon model of an aorta connected to a MEDOS ventricle to simulate the pulsatile flow of the native heart, three different outflow cannula positions and a control model A (without LVAD) were tested. Time-resolved 3D phase contrast MRI with 3D velocity encoding was applied to assess 3D aortic hemodynamics in all three models for a fully ejecting VAD and a reduced cardiac output (CO). 3D blood flow visualization using time resolved pathlines was employed; blood flow velocities and flow volume were quantified in manually positioned 2D analysis planes using home built software .Blood flow patterns in the aorta illustrated the changes in hemodynamic due to LVAD inflow at different positions figure . CompareTime-resolved 3D phase contrast MRI is feasible to model blood flow alterations in the aorta caused by the LVAD. Our preliminary results indicate that the cannula position may influence perfusion of the supra-aortic but has little effect on retrograde flow in the ascending aorta. Future experiments will focus on a more detailed evaluation of the effect on CO on to provide a better understanding of the impact of LAVD support on valve function."} +{"text": "In this study we evaluated sensory alteration in nasal tip and adjacent upper columella after open rhinoplasty. Two groups were randomly selected, each containing 25 patients with thick nasal skin; sensory testing was done preoperatively in all patients; in group one, subdermal soft tissue in tip and supratip areas was removed but in group two no soft tissue removal was done; we compared sensory pressure threshold values 3 weeks and 6 months postoperatively. Results showed no statistical difference between the two groups in nasal skin sensibility at these times; also this study showed that 6 months after rhinoplasty normal sensation of nasal skin will be achieved. Rhinoplasty in patients with thick nasal skin is one of the most challenging operations; regardless of its cause, the thick soft tissue coverage represents a distinct limitation in rhinoplasty because the skin will usually not redrape properly over the nasal skeletal framework , 2.The operative management of such a deformity is controversial and ranges from limited procedures with no soft tissue removal to scoriAn anatomical and histological evaluation of the tissue specimens obtained from the tip and supratip regions showed that collagenous fibrous tissue, adipose tissue, and skeletal muscle were the predominant subdermal tissue type present; fibrous tissue, in fact, comprised the majority of the subdermal tissue so this fibromuscular tissue can be safely resected without violating the dermis thereby decreasing the soft tissue bulk of the bulbous nasal tip and not interfering with the vascular supply to the skin envelope . One of In one study 3 weeks and one year after open rhinoplasty the sensibility of various parts of the external nasal skin was evaluated and it was shown that altered sensibility following open rhinoplasty occurs in the early postoperative period (3 weeks post operatively) in the area of skin supplied by the external nasal nerve ; but sensation became normal after one year; the nerve is probably injured during the subcutaneous dissection as the nerve passes between the nasal bone and the upper lateral cartilage to supply the skin .According to these studies we decided to evaluate sensory alteration in nasal tip and adjacent upper columella , so we randomly selected two groups each containing 25 patients with thick nasal skin; sensory testing was done preoperatively in all patients; in group one we removed subdermal soft tissue, but in group two we did not remove any soft tissue and we compared the sensory recovery in 3 weeks and 6 months postoperatively between these groups with a set of sensory testing monofilaments.This is a prospective study; 50 patients with thick skinned nose were selected and prepared for open rhinoplasty then randomly divided in two groups (group 1 and group 2), each group containing 25 patients. None on the patients had previous facial surgery or trauma prior to the open rhinoplasty procedure. Furthermore, none had developmental delay, a medical history of diabetes, a systemic neurologic impairment, or a syndrome that might impair sensibility. The main indication for surgery was cosmetic improvement of nasal tip. All patients underwent open rhinoplasty using a midcolumellar incision. In group 1 instead of elevating the skin directly over the osteocartilaginous skeleton, in tip and supra tip area, we undermined it under direct vision in a new plane just under the submusculoaponeurotic system extending over collagenous fibrous tissue and adipose tissue that remain attached to the nasal skeleton mostly over the tip and supra tip area, which is dissected off the nasal cartilages and skeleton and discarded; but in group 2 subdermal soft tissue of nasal tip was not touched. All patients underwent tip plasty including resection of the cranial part of the lateral crura of the lower lateral cartilage, interdomal suture, transdomal suture, septal surgery, septal cartilage harvesting, tip graft, and columellar strut graft; most of the patients need spreader graft, all of the patients underwent alar resection. Postoperative recovery was uneventful and no hematoma, infection, or skin necrosis occurred. All patients had subjective questioning and objective testing of nasal sensibility preoperatively, 3 weeks postoperatively, and 6 months postoperatively. Subjectively patients were asked about any alteration of nasal sensibility in tip area; for objective testing two areas were determined as shown in 2) of the lightest filament that evokes perception of pressure is recorded as the pressure threshold, and each area in group one was compared with the same area in group two preoperatively, 3 weeks postoperatively, and 6 months postoperatively. These SW monofilaments are variable in thickness and labeled with numbers ranging from 2.36 to 6.65 as is shown in Figures t-test.For data analysis we used repeated measures \u201cANOVA\u201d test and standard deviations were calculated for pressure threshold values at columella (area 1) and tip (area 2) preoperatively, 3 weeks post operatively, and 6 months after surgery; differences between 2 groups were tested using the independent sampled We had two groups in our study and we compared the role of soft tissue removal in sensory recovery time after open rhinoplasty; in group 1, we performed subdermal soft tissue removal of tip and supratip area and in group 2, we did not remove any soft tissue. Each group contained 25 patients; in group one the patients' ages ranged from 19 to 43 years and mean age was 27.67 years; in group two the patients' ages ranged from 17 to 39 years and mean age was 25.48 years. 6 patients in group one (24%) and 9 patients in group two (36%) were male.3 weeks after surgery all patients had subjective alteration in sensibility of the nasal tip and the adjacent upper columellar skin. This alteration was perceived as heaviness in 19 patients in group one and 17 patients in group two; 6 patients in group one and 8 patients in group two stated that the nasal tip and adjacent columella felt different from remaining nasal skin.Objective testing confirmed the subjective findings and showed higher pressure threshold values 3 weeks after surgery as it is shown in Statistical analysis showed no meaningful differences in pressure threshold values between the two groups 3 weeks and 6 months after operation .In one study they fouOur study confirmed that altered sensibility following open rhinoplasty occurs 3 weeks after surgery in the same area previously reported by Bafaqeeh and Al-Qattan ; these aAlthough risks of nasal tip soft tissue removal such as skin necrosis or skin irregularity should be noted, complication rate will be decreased if you do not violate the dermis and remain in correct plain; on the other hand Garramone et al. showed t"} +{"text": "The binding of SUR2A to Kir6.2 serves a dual purpose: 1) it allows translocation of the channel to the sarcolemma and 2) contributes to the channel regulation earlier opening of KATP channels in response to stress and 2) increased subsarcolemmal ATP due to increased recruitment of creatine kinase and glycolytic enzymes to the KATP channel protein complex. Improved timing of KATP channel opening as well as increased subsarcolemmal production of ATP seems to mediate cardioprotection afforded by SUR2A Development of stem cell therapies to treat cardiovascular disease is limited by the ability to regulate stem cell differentiation and by poor cell survival once grafted to sites of damage in the heart"} +{"text": "Alkaptonuria (AKU) is an orphan inherited homogentisate dioxygenase enzyme deficiency resulting in accumulation of homogentisic acid (HGA). HGA is converted to a black pigment polymer known as ochronosis that causes tissue damage affecting many tissues including joints and heart, with significant poor quality of life. The DevelopAKUre project is a Europe-wide collaboration to study the efficacy and safety of nitisinone as a potential treatment in three clinical studies. The first is a phase 2 dose-response study (SONIA 1) which will determine the optimal dose of nitisinone that decreases HGA levels. The second is a phase III efficacy study (SONIA 2) based on the optimal dose and the third is a cross-sectional study (SOFIA) that will define the age that treatment should begin after determining the onset of ochronosis. Details and rationale of the SONIA 2 design will be described, with special attention to issues arising from the rarity of the disease."} +{"text": "The following scientsts assisted the journal by reviewing manuscripts that were submitted for consideration during the period November 1, 2008 to September 30, 2010. We gratefully acknowledge their critical evaluation and assistance in the selection of papers for publication."} +{"text": "Saccharomyces cerevisiae (yeast) strain National Collection of Type Culture (NCTC) 1071606 as the test organism. From the standard curve the yeast inhibitory potencies of the shampoos in nystatin international unit equivalents were determined from the respective inhibition zones of the test samples of the shampoos. Under test conditions four shampoo samples showed remarkable fungal inhibitory potencies of 10227, 10731, 12396 and 18211 nystatin international unit equivalents/ml while two shampoo samples had extremely feeble inhibitory potencies 4.07 and 4.37 nystatin international unit equivalents/ml although the latter two products claimed antifungal activity. The potency determination method could be applied to any antidandruff shampoo with any one or a combination of active ingredients.A convenient standard microbiological potency determination test for the antidandruff shampoos was developed by adopting the pharmacopoeial microbiological assay procedure of the drug nystatin. A standard curve was drawn consisting of the inhibition zone diameters vs. logarithm of nystatin concentrations in international units using the fungus Malassezia also known as Pityrosporum, which is a tiny yeastShampoos may be classified into three distinct categories. Plain detergent shampoos that are more like soaps in their properties and uses, the cosmetic shampoos with conditioners, dyes or other cosmetic ingredients used for cosmetic purposes and the medicated shampoos, which are formulated to contain any drug substance as in the case of antidandruff shampoos. Each such shampoo category must be dealt accordingly for regulatory purposes. Medicated antidandruff shampoos containing typical drugs such as climbazole1, A2 and A334Saccharomyces cerevisiae as the test organism. It was thought that this procedure could be adopted to screen the shampoos claiming antidandruff activity since a fungus is also responsible for infections associated with dandruff. The proposed microbiological assay method is further justified as both nystatin and the antifungal shampoos are aimed at treating superficial fungal infectionsThe antifungal drug nystatin consists of a mixture of biologically active substances consisting of tetraene molecules ASix brands of shampoos claiming antidandruff activity were procured from the market. Three of them contained zinc pyrithioneSaccharomyces cerevisiae strain NCTC 1071606 was used as the inoculating agent in the Medium F as per the pharmacopoeia. The inoculum was adjusted to contain 10Nystatin standard serial dilutions containing 200, 100, 50 and 25 international units per milliliter were prepared in pH 6 buffer containing 5% dimethylformamide as per the British Pharmacopoeia. The inhibition zones for standard nystatin solutions were determined by incubating the inoculated petri dishes containing 100 \u03bcl nystatin standard dilutions per well at 30\u00b0 for 18 h. Centre well of each Petri dish was filled with 100 \u03bcl of the blank buffer solution as the control. For each dilution inhibition zones were determined in triplicate and three diameters for each inhibition zone were recorded. Prior to the main analysis serial dilutions of the shampoo samples were prepared aseptically with the pH 6 buffer containing 5% dimethylformamide and the dilutions corresponding to inhibition zones falling within the range of the standard curve were determined. Four shampoo samples had to be diluted 250 times and two were tested without diluting. Inhibition zones for each shampoo sample were also determined in triplicate using 100 \u03bcl per well and three diameters for each inhibition zone were recorded. The centre well was filled with 100 \u03bcl of the blank buffer solution as the control. The main potency determination assay was carried out simultaneously for the nystatin standard curve and the appropriately diluted shampoo samples using the same culture media lot under the same conditions.Since the antidandruff shampoos have diverse active ingredients it is difficult to test each one of them requiring different analytical methods. The study was designed to evaluate any of the shampoos with respect to an equivalent in terms of a reference material. Nystatin was selected as the reference antifungal agent since a microbiological antifungal assay for this substance is prescribed in the British Pharmacopoeia. For a given shampoo with any one of the antifungal agents the fungal inhibitory potency will be indicated in terms of Nystatin International Unit Equivalents per milliliter (NIUEqs/ml). In other words it may be assumed that that much nystatin as shown by the number of NUIEqs/ml was found in the particular shampoo in place of the actual antifungal agent facilitating easy comparison of their potencies.NIUEqs value of a shampoo is determined as follows. Find out the log nystatin concentration from the standard curve based on In vitro experimental conditions and the actual usage of the shampoos. Further studies are required to match the antifungal potencies determined here with that of the antifungal effects under actual conditions of usage.The outcome of the assay shows that most antidandruff shampoos are effective fungal inhibitors as claimed but there are others with spurious claims. As expected linearity of the nystatin standard curve fell within the narrow range of log transferred nystatin concentrations of 50 to 200 I.U./ml. Four shampoos had inhibition zones corresponding to the standard curve region after diluting 250 times while two others had barely visible zones when tested undiluted. Under the experimental conditions the six shampoos had highly variable potencies 4.07, 4.37, 10227, 10731, 12396 and 18211 NIUEqs/ml in the brands F, E, C, B, D and A, respectively. It may be noted that the potency of nystatin is expressed in International Units (IU) and that of a shampoo expressed in NIUEqs. An obvious difference exists between the A comparatively simple microbiological potency determination method using NIUEqs based on a pharmacopoeial assay procedure has given successful results. The newly proposed antidandruff shampoo potency parameter NIUEqs harmonize the potency determination irrespective of the diversity of the antidandruff agents found in the shampoos. The method is suitable for the screening of diverse antifungal agents that may be found in the shampoos. Zinc pyrithione appear to be the most effective antifungal agent among the samples screened. Shampoos with false antidandruff action claims may be easily detected by the proposed method."} +{"text": "The structural heterogeneities provide a substrate for triggered activity from which ventricular arrhythmias can be initiated. Pathological alterations in ion channel properties and gap junction intercellular communication lead to changes in the action potential profile and cellular excitability, serving as a trigger for arrhythmias. Although extensive pharmacological therapies have been developed for the treatment of arrhythmias, efficacy of the drugs remains limited due to the complex remodeling processes underlying heart failure.Arrhythmias are a common and often fatal complication of heart failure accounting for 50% to 70% of cardiac deaths due to tachyarrhythmic mechanisms.If) and the hyperpolarization\u2010activated cyclic nucleotide gated (HCN) channels is emerging. The subject has been addressed by Kuwabara et al2 in this issue of Journal of the American Heart Association.Among the ionic mechanisms that contribute to ventricular arrhythmias, the role of the pacemaker or funny current . For instance, increasing cAMP levels via \u03b2\u2010adrenergic stimulation causes a rightward shift in If activation meaning that the current is activated at more positive voltages without affecting the maximum current amplitude. This mechanism participates in the relationship between \u03b2\u2010adrenergic stimulation and regulation of heart rate.3If in nonpacemaker cells and its potential role in triggering ventricular arrhythmias in both patients and various experimental animal models.Over the last 20 years, much attention has focused on If is abundantly present in ventricular myocytes and progressively declines during maturation.4 Thus, in the adult heart, If can be detected only in a minority of ventricular myocytes, and the current is significantly reduced compared with neonatal myocytes. Under certain pathological conditions If is able to recover its \u201cfetal\u201d phenotype with an increase in the numbers of ventricular myocytes in which the current can be recorded and also with greater current amplitude. This has been demonstrated extensively during cardiac hypertrophy in both humans and several animal models of heart failure, such as pressure overload and postmyocardial infarction.6 Interestingly, there is a strong degree of correlation between the severity of hypertrophy and If density in ventricular myocytes; the expression of the HCN channels responsible for If is most pronounced in regions with the greatest overload,7 raising the possibility that this mechanism is mechano\u2010sensitive. The nature of the initial injury also seems a determining factor in this phenomenon. Ischemic cardiomyopathy for example leads to a greater If current density in ventricular myocytes compared with dilated cadiomyopathy.8 Moreover, the link between \u03b2\u2010adrenergic stimulation and If may have a role in these differences and could provide a potential arrhythmogenic mechanism in a setting of enhanced sympathetic drive such as heart failure, with an increased contribution of the current during diastole in ventricular myocytes.During fetal and neonatal development If in both healthy and diseased hearts are the HCN channels responsible for generating the current. There are 4 known isoforms identified in mammals (HCN1 to 4) of which HCN1, HCN2, and HCN4 are differentially expressed throughout the myocardium but with the highest levels in the sinoatrial node. The adult ventricle has low levels of HCN2 and HCN4 which subsequently increase at both the mRNA and protein levels as a result of heart failure.7 The specific overexpression of HCN1 has also been reported recently in heart failure.9 It is possible that increases in the different HCN isoforms that are normally present at low levels could potentially interact and give rise to heterotetramers with unique biophysical and regulatory properties compared with homomers. Posttranscriptional mechanisms may also contribute to HCN expression through microRNA.10 Collectively this increase in HCN subunit expression is likely to be the underlying cause for the gain of function in If recorded from diseased ventricle.The molecular determinants of If and HCN channel expression during cardiac remodeling, yet the precise involvement of If in arrhythmias remains to be fully determined. The paper by Kuwabara et al2 provides insight into the role of If in the initiation of triggered activity in a bradycardic model of heart failure. By using genetically modified mice that express a dominant negative form of the transcriptional repressor neuron\u2010restrictive silencing factor (dnNRSF\u2010Tg), the authors generated a model of heart failure11: NRSF, a regulator of the fetal cardiac gene program, activates the reexpression of HCN2 and HCN4 to induce dilated cardiomyopathy. Kuwabara et al tested the hypothesis that expression of HCN channels predisposes ventricular myocytes to enhanced automaticity. The major findings of the study are the increase in If density and the high incidence of ventricular tachycardia, premature ventricular contractions, and sudden cardiac death in the dnNRSF\u2010Tg mice. \u03b2\u2010adrenergic stimulation increased the susceptibility of myocytes to early after\u2010depolarizations and spontaneous action potentials through increased cAMP production. These findings were confirmed in myocytes from mice with cardiac specific overexpression of HCN2, demonstrating a link between HCN and arrhythmias. These results are also in agreement with another study9 showing that HCN activity increases the proarrythmogenic potential in the failing myocytes through prolongation of the repolarization phase in ventricular action potentials.The majority of studies have focused on the modifications in functional and molecular properties of 2 used ivabradine, a selective heart\u2010rate\u2013reducing agent, to inhibit channel activity. Ivabradine blocks HCN activity by entering the pore of the channels when they are in open state thereby reducing the slope of diastolic depolarization.12 A major clinical trial to demonstrate the beneficial effects of ivabradine is the BEATUTIFUL study treating 10 917 patients with stable coronary artery disease and left ejection fraction <40%. Although ivabradine treatment did not affect the primary composite outcome, it reduced the need for hospitalization due to myocardial infarction and coronary revascularization in patients with baseline heart rates >70 bpm.13 This work was followed by the SHIfT trial (6558 patients), which confirmed that treatment with ivabradine significantly reduced hospital admission for worsening heart failure by 18% and cardiovascular deaths due to heart failure.14 In both trials the favorable effects of ivabradine were greatest in those patients with a higher heart rate. The most striking finding of the SHIfT trial, obtained from the echocardiographic substudy, was the reversal of cardiac remodeling in the left ventricle with pronounced increase in left ventricular ejection fraction and reduced left ventricular systolic volume.15 Effects of ivabradine in preventing arrhythmias were also investigated in a small group of patients (21) with inappropriate sinus tachycardia. Ivabradine reduced 70% of symptoms reported at baseline and in 50% of patients all symptoms were eliminated highlighting its potential use in the treatment of arrhythmias.16 Beneficial effects of chronic treatment with ivabradine have also been shown in rodent models of heart failure with improvements in whole heart systolic and diastolic function, reduction in interstitial and perivascular fibrosis, increase in angiogenesis and myocardial perfusion, improved calcium handling, decreased mortality and ventricular excitability, and reversal of myocardial structural remodeling.19To confirm the contribution of HCN overexpression in the development of arrhythmias, Kuwabara et al20 However, there are studies showing that some of the effects may be mediated by different mechanisms. We have recently shown that the reduction in myocardial fibrosis induced by ivabradine is not due to heart rate reduction, as the \u03b2\u2010adrenergic blocker metoprolol did not reduce fibrosis in a rodent model of heart failure, despite a similar reduction in heart rate.19 Kuwabara et al2 also studied the remodeling effects on arrhythmias independent of heart rate reduction by using a nonbradycardic dose of ivabradine. With this strategy they clearly demonstrated the reduction in If amplitude and occurrence of spontaneous action potentials in the presence of isoproterenol and improved survival rate in the dnNRSF\u2010Tg model. Other effects of ivabradine independent of heart rate include the attenuation of the renin\u2013angiotensin aldosterone system (RAAS) through a reduction in angiotensin\u2010converting enzyme and angiotenisn II type I receptor (AT\u20101) transcript expression.17 All these studies support the notion that ivabradine can have direct effects on ventricular structure and electrophysiology independent of the sinoatrial node.The mechanisms of ivabradine, however, remain controversial. Most clinical and experimental evidence points to a primary role of heart rate reduction. Ivabradine\u2010driven cardiac remodeling has been extensively studied at doses that lower heart rate and the reduction in heart rate is thought to be the likely cause of remodeling by optimizing energy consumption while simultaneously reducing cardiac work load.2 contributes to the significant progress that has been made in establishing the role of If and HCN channels as markers of pathological remodeling and identifying the cardioprotective effects of ivabradine in the failing heart. However, there are key questions that remain unanswered: (1) Is the overexpression of HCN channels and augmented If in the ventricle an adaptive response with specific functional consequences or is it simply part of a global remodeling process? (2) What is the role of the different HCN isoforms and how do the isoforms contribute to the clinical and pathological scenario? (3) What are the effects of ivabradine on the fibrotic pathways, in particular the RAAS system and the local regulation of ECM? (4) Are the effects of ivabradine on arrhythmias secondary to the reversal of remodeling rather than a direct effect on the HCN channels? (5) What are the reasons for the variability in the effects of ivabradine in different HF models and at different stages of disease?The paper by Kuwabara et alPharmacological inhibition of the HCN channels remains a potentially useful strategy in heart failure as there are already significant encouraging results from large clinical trials and accumulating positive laboratory studies. However, more specific clinical trials should address the efficacy on treating arrhythmias in heart failure and it is also essential that the specific mechanisms involved are investigated in the laboratory in order to understand the pathways involved and refine this novel and promising approach."} +{"text": "Brain computer interface (BCI) technology has been proposed for motor neurorehabilitation, motor replacement and assistive technologies. It is an open question whether proprioceptive feedback affects the regulation of brain oscillations and therefore BCI control. We developed a BCI coupled on-line with a robotic hand exoskeleton for flexing and extending the fingers. 24 healthy participants performed five different tasks of closing and opening the hand: (1) motor imagery of the hand movement without any overt movement and without feedback, (2) motor imagery with movement as online feedback passive (the orthosis passively opens and closes the hand without imagery) and (4) active (overt) movement of the hand and rest. Performance was defined as the difference in power of the sensorimotor rhythm during motor task and rest and calculated offline for different tasks. Participants were divided in three groups depending on the feedback receiving during task 2 . Group 1 (n\u200a=\u200a9) received contingent positive feedback (participants' sensorimotor rhythm (SMR) desynchronization was directly linked to hand orthosis movements), group 2 (n\u200a=\u200a8) contingent \u201cnegative\u201d feedback (participants' sensorimotor rhythm synchronization was directly linked to hand orthosis movements) and group 3 (n\u200a=\u200a7) sham feedback (no link between brain oscillations and orthosis movements). We observed that proprioceptive feedback (feeling and seeing hand movements) improved BCI performance significantly. Furthermore, in the contingent positive group only a significant motor learning effect was observed enhancing SMR desynchronization during motor imagery without feedback in time. Furthermore, we observed a significantly stronger SMR desynchronization in the contingent positive group compared to the other groups during active and passive movements. To summarize, we demonstrated that the use of contingent positive proprioceptive feedback BCI enhanced SMR desynchronization during motor tasks. Stroke survivors with chronic hand plegia and low scores in the Fugl-Meyer scale show limited residual muscle activity in the upper arm extensor muscles and no finger extension. Currently, there is no accepted and efficient rehabilitation strategy available in patients with chronic stroke and no residual hand movements. BCI systems could be a solution for those who suffered a stroke and need to rehabilitate a completely paralyzed limb and a damaged brain at the same time On the other hand, it has been widely demonstrated that visual feedback plays a key role in BCI training as in any other skill learning However, with at least some afferent pathways intact, the sensory information to the brain produced by moving the paretic limb engages remaining motor areas in the vicinity of the lesion to control the BCI. Since EEG has a limited spatial resolution it is difficult to separate activity from somatosensory cortex, premotor or motor cortex even using advanced spatial filtering methods 23 healthy volunteers were recruited for the experiment. Participants were sitting in an upright position wearing a 128-channel EEG cap. The experimental protocol was approved by the ethics committee of the University of Tubingen, Medical Faculty. Participants provide their written informed consent to participate in this study. The hand of the participant was fixed to a hand orthosis which could be driven by the participants\u2019 brain oscillations . Participants were asked to perform 5 different tasks following 5 randomly presented auditory cues (the name of the task taped in advance (or from a taped recording of the voice of one of the experimenters):motor imagery without direct control (MIT) of the orthosis i.e. the participant had to imagine to move the hand without moving the hand and with no movement of the orthosis (task1)motor imagery with direct control (MIT&F) of the orthosis i.e. the hand motor imagery related brain oscillations drove the moving orthosis (task2)passive movements of the orthosis i.e. the orthosis opened and closed the participants\u2019 hand. The participant was asked not to perform any mental task. The orthosis movements are not linked to brain activity. (task3)active movement i.e. the participant was required to actively open and close the hand attached to the orthosis and the orthosis followed the movement. (task4)rest (task5)The participants were separated in 3 different groups receiving 3 different feedback contingencies. Only during task2 participants used the EEG-based proprioceptive BCI to control the orthosis with opening and closing the hand motor imagery. The first group received contingent positive feedback (moving the orthosis with SMR desynchronization in task 2: 9 Participants), the second received contingent negative feedback (moving the orthosis with SMR synchronization in task 2: 8 Participants) and the third received sham feedback (the orthosis moved independently from brain activity but participants believed in their control: 7 Participants).Two seconds after the corresponding auditory cue, a \u201cGO\u201d cue was presented and the participant performed the appropriate motor task for 5 seconds terminated by an auditory \u201cend\u201d cue . All audIn www.bci2000.org). EMG data were acquired using 8 bipolar Ag/AgCl electrodes placed on antagonistic muscle pairs; one close to the external epicondyle on the extensor digitorum (forearm extensor), the other on the flexor carpi radialis (forearm flexor), another on the external head of the biceps (upper arm flexor) and the last one placed on the external head of the triceps (upper arm extensor). The EEG and EMG electrodes impedance was always kept under 5 and 20 kOhm respectively.EEG data were acquired using a BrainAmp 128-channel amplifier from Brain Products GmbH, Munich Germany. An EasyCap 128-channel EEG cap (modified 10\u201320 system) from EASYCAP GmbH, Herrsching, Germany was used for EEG data acquisition, referenced to the nasion, and grounded anteriorly to Fz. Only 61 EEG channels over the motor areas on both hemispheres were used recording from pre-motor, motor and parietal areas . AdditioEach finger was moved individually using a DC\u2212Motor M-28 with worm gearhead for each finger. The motor drove a Bowden cable via cogwheel and cograil. A finger holder was mounted on the other side of each Bowden cable . Close tThe BCI system determined the orthosis position and velocity and the device transmitted its actual position and velocity to the host computer upon request. Once the BCI system sends a position and a velocity command, the orthosis would then initiate a movement to the given position with the given velocity. Movement stopped when either the current position was identical to the position command sent by the BCI system (as set in the most recent position command), or when the velocity command was set to zero by BCI system. The direction of the movement was determined by the difference between current and desired position. As a physical connection between orthosis and host computer, a RS232 serial connection was used at a speed of 38400 bps. The BCI2000 two class classifier (motor imagery versus baseline) sent an output every 40 ms and five consecutive outputs for the same class were needed in order to send the orthosis a no-move or a move (positive velocity) command. This time filter was installed to avoid false positives and false negatives. During the sham feedback condition the BCI2000 output changed with a probability of 10%, i.e. when it was sending an output (e.g. moving) there was a probability of 10% that the next output would be the opposite (stop) and vice versa, requiring again 5 consecutive outputs of the same sign to change the movement status of the orthosis. This randomization of the output was identical to the averaged time participants from the contingent positive group achieved to move the orthosis during task 2.The features to be used by the BCI platform were defined through a visual inspection of the R-squared values The BCI software maintained a history of the mean sensorimotor rhythm amplitude estimate from each trial and assigned this to a distribution representing observations for the two classes (rest or motor intention). The classification threshold, defined as the zero mean distance to the two distributions, was adaptive to account for changes in the shapes of these distributions over the course of training.For EEG off-line analysis we performed a time-frequency analysis using a 1.142 s sliding window with an overlap of 26 ms. The event related spectrum perturbation was then calculated using Morlet transforms The EMG data were filtered using a high pass filter at 10 Hz, bipolarized, rectified and visually inspected. Trials presenting muscle activity during the resting task or absence of activity during active opening and closing of the hand were excluded from the event related spectrum perturbation analysis. On average, 8% of the EEG data acquired had to be rejected due to presence or lack of muscle activity during the experiment.One EEG-screening was performed the day before the first training session and was used as a calibration session to identify the best features (electrodes and frequency bins) to be used by the BCI classifier. In this screening session the participants were randomly presented with visual and auditory cues corresponding to 3 different tasks indicating to either relax (task 1), actively open and close the right (task 2) or the left hand (task 3). After a 5 s period performing the tasks a rest cue was presented indicating to stop. The inter-trial-interval time was randomized between 5 and 7 s. The participants underwent 4 to 5 runs of 25 trials. The features to be used by the BCI platform were defined through a visual inspection of the R-square The group matching was performed based on age, handedness and the R-squared values obtained comparing the distribution of data during the screening session rest versus hand motor imagery.After the screening, a cursor control training was performed at the end of the same session, to familiarize the participants with the BCI. For the cursor control training session participants controlled the velocity in the Y axis of a cursor moving from left to right on the screen at a constant speed trying to reach a target presented at the right side of the screen. The participants performed 4 runs containing 12 trials. The participants arrived at 4 consecutive days to perform one session every day. In every session the participants were presented with the 5 different tasks described before.We analyzed how the BCI output changes during the different tasks and investigated the effect of the feedback contingency on BCI control. In addition to the online classification translated into orthosis movements (task 2), we simulated the performance the participants would have obtained if the orthosis would have moved during every motor task in an online setup. For example, how would the brain activity elicited during passive movement have been classified, if the classifier set up for motor imagery (same electrodes and frequency bins) would have been used to move the orthosis. Furthermore, several performance measures indicating different aspects of the SMR modulation were calculated off-line for all the tasks:Percent of time the orthosis was or would have been moved during a trial. This performance measure reflects the ability of the participant to decrease or maintain the decrease of SMR power during a trial.Maximum consecutive time the orthosis was moving per trial. This measure represents the longest period of time the participant was able to decrease or continuously maintain SMR desynchronization within a trial without inetrruption (synchronization in the contingent negative group).Number of orthosis moving onsets switching from not moving to moving per trial. This measure reflects how many times the participant loses and regains control of the orthosis within a trial.Latency to the first onset of orthosis movement per trial. This measure represents the reaction time of the participant in producing an orthosis movement (SMR desynchronization).Classical performance measure of reaching target, i.e. position of the cursor at the end of the trial, considering a successful trial if the cursor was in the upper half of the screen and unsuccesful otherwise.These performance measures were calculated simulating an online scenario before and after EEG and EMG artefact removal to explore the influence of data contamination and the importance of implementing on-line artefact removal filters. We assumed that the proprioceptive feedback is felt by the user as number of times they can make the orthosis switch from not moving to moving (number of orthosis moving onsets), how fast they can start moving the orthosis (onset latency), percent of time the orthosis is moving during the trial and maximum consecutive time they moved the orthosis. We expected to observe learning effects in the contingent feedback groups (negative and positive) during the two tasks involving motor imagery (with and without feedback).For each of the performance measures an ANOVA with two repeated measures (task and session) and three groups (between group factor) was performed to study main effects and interactions .Levene\u2019s tests for homogeneity of error variances among groups were applied for all combinations of tasks and sessions. For all performance measures there were none or only few violations of the Levene-tests. Since the number of participants was less than 10 in each group and the number of performed tests was 20, slight violations were ignored and the error variances were assumed to be homogeneous.Mauchly\u2019s tests for the sphericity were done for the repeated measures factors and in case sphericity was violated significance tests were Greenhouse-Geisser corrected.In this study we furthermore performed several planned contrasts to separately identify effects between the sessions, tasks and groups.To identify learning over the four different BCI sessions we performed an ANOVA of the sessions within each group for each task separately. Mauchly\u2019s tests for the sphericity were done for the repeated measures factors and in case sphericity was violated significance tests were Greenhouse-Geisser corrected.We performed an ANOVA of the tasks for each of the groups and Bonferroni-corrected pairwise comparisons to identify main effects of the factor \u201ctask\u201d and the source of it. The performance measures of the different sessions were combined for this step of the analysis.To study the differences between groups the performance measures of the different sessions were combined and for each task separately we performed an ANOVA of the groups and Bonferroni-corrected multiple comparisons.EEG frequency analysis resulted in very similar event related synchronization and desynchronization (ERS/ERD) maps for all motor tasks when subtracting ERS/ERD power values during rest. A clear contralateral motor and parietal and an ipsilateral pre-motor activation common to most motor tasks and frequency bins was found. The active motor task presented more frequency power differences compared to the other tasks in the 8\u201312 Hz frequency bin . This frA statistical analysis was performed to study session effects (learning) for every motor task. A significant group effect was found for motor imagery alone (task 1) and motor imagery with feedback (task 2) for all performance measures as expected except for the latency to the first orthosis movement onset .When analyzing every feedback group separately (contingent Positive (CP), contingent negative (CN) and sham) for each movement task the only significant session effect \u200a=\u200a4.406, p\u200a=\u200a0.0128) was an increase in number of onsets during motor imagery alone in the contingent positive feedback group only . DespiteThe learning effect was tested for every healthy volunteer independently comparing the first session performance to each of the other sessions using the Kruskal Wallis Test (non-parametric) Bonferroni corrected for multiple comparisons . In the contingent positive feedback group 3 participants showed statistical significant increase in maximum consecutive and percent of time during motor imagery task alone and with proprioceptive feedback. The participants without significant increase (learning) showed high values of performance (ceiling effect). In the sham feedback group (non-contingent) and contingent negative feedback group no significant learning occurred in any of the participants.When comparing group performance measures averaged over sessions for each motor task we observed that during motor imagery without feedback (no movement of the orthosis occurred) (task 1), the percent of time the orthosis would have been moved and the number of orthosis movement onsets were significantly higher (Bonferroni-corrected post-hoc-test) for the contingent positive compared to the contingent negative and sham feedback groups .A, 3.B. During motor imagery with proprioceptive feedback (task 2) and during active movement alone (task 4), the percent of time moving the orthosis, the maximum consecutive time moving the orthosis and reaching target accuracy performance measures were significantly lower for the contingent negative group compared to the contingent positive and sham groups , althougThere was no significant difference during passive movement (task 3) between groups for any performance measure but the number of orthosis movement onsets, which in the contingent positive group showed higher values compared to the other 2 feedback groups .A.We analyzed the difference in the off-line calculated performance for all tasks within each individual feedback group averaging all the sessions. When analyzing the contingent negative group we could not find any significant difference between motor tasks using any performance measure other than the difference between rest and active movement BCI performance difference. The same effect was found in the sham feedback group as well as a significantly higher maximum consecutive and percent of time moving the orthosis during motor imagery with proprioceptive feedback (task 2) when compared with motor imagery task without any feedback.On the other hand, in the contingent positive feedback group, all the performance measures during motor imagery without and with proprioceptive feedback and active movement were significantly different compared to rest as expected.During passive movement, the number of orthosis movement onsets was significantly higher compared to rest indicating that passive movement generated afferent brain activity affects sensorimotor brain oscillations resulting in a significant increase of orthosis movement onsets when using the proprioceptive BCI. Furthermore, a significantly higher number of orthosis movement onsets were found for active movement when compared to passive movement.A significant group effect during imagery with and without feedback (task 1 and task 2) was found for all performance measures except for the latency to the first orthosis movement onset. Contingent positive group showed significantly larger difference between SMR power during rest (increase in power) and motor imagery tasks (decrease in power) and therefore higher BCI performance compared to the other 2 feedback groups. This finding suggests that after the go cue the time needed to move the orthosis was not significantly different between feedback groups and indicates that an initiation based therapy would not show any significant difference in performance between feedback groups.We observed a significant learning effect during motor imagery task with no feedback (task 1) indicating implicit learning (they did not receive any feedback during this task) present in the contingent positive feedback group only. The participants were trained and rewarded for motor imagery and therefore learning was expected to occur during task 2 only (motor imagery task with proprioceptive feedback). We also expected some learning during task 1 motor imagery with no feedback because the same task was repeated although feedback was only present in task 2.As we can see in BCI learning effects (learning of ERD and ERS) were expected to be stronger for percent time and maximum consecutive time moving the orthosis in task 2 because the visual and proprioceptive feedback (orthosis moving) provides maximal information about correct or incorrect control of the BCI. The data indicate that participants of contingent positive group only learned to start moving the orthosis, i.e. to change from ERS to ERD.For all the tasks except rest (motor imagery with and without feedback and active and passive movement), the performance was significantly higher for the contingent positive group in terms of orthosis movement onsets when compared to the other 2 groups. Furthermore, percent of time and maximum consecutive time were significantly higher in the contingent positive group too but only during motor imagery with feedback (task 2) (proprioceptive BCI).In the contingent positive group only significantly higher performance was observed during passive movement when compared to resting BCI performance. These findings suggest that feedback contingency (proprioceptive stimulation paired with EEG SMR desynchronization) influences the motor network enhancing significantly SMR down- regulation. The use of the proprioceptive BCI assists to desynchronize the SMR rhythm during any motor related activity, i.e. the findings indicate that contingent proprioceptive BCI training only operates by priming and engaging a group of ecologically relevant brain regions related to imagery of a task, supporting the proposal of using an online proprioceptive BCI to induce neural changes. These changes could be used as a boosting effect for any passive or active physiotherapy of the same movement. However, although enhancing the SMR modulation during the passive mode, the BCI performance during the use of the online proprioceptive BCI, motor imagery and active movement was significantly higher than during passive movement alone, indicating that the effects would be significantly higher during active engagement in the motor task.All three groups showed significant difference in performance between rest and active movement. However, the significant difference in performance between rest and the other motor tasks (except for active movement) occurs only in the contingent positive feedback group, which underlines the importance of contingent proprioceptive BCI.The results extend experiments of (motor) skill learning to BCI-control, confirming the mechanistic similarity of the two and confirming animal experiments with BCI control of single neurons We investigated an online proprioceptive BCI system linking hand movements and brain oscillations, eliciting implicit learning effects and producing an increase in SMR related neural networks excitation during motor imagery, passive and active movement. We propose the use of the here described proprioceptive BCI as a potential motor rehabilitation tool to be used in paralyzed patients with residual proprioception (e.g. stroke patients)."} +{"text": "There is an error in the \"Results\" section under the subheading \"Divergence Time Estimates.\" The first sentence of the second paragraph should read: With respect to the age of Arvicanthini, a mid-Miocene origin was inferred with ages ranging from 11.29 Ma to 12.13 Ma ."} +{"text": "The association of partial anomalous pulmonary venous connection (PAPVC) with atrial septal defect (ASD) is known, but its prevalence in adult patients with ASD is not well reported in literature. CMR is recognized as excellent method for shunt quantification and assessment of ASD morphology.A total of 53 consecutive patients who were referred for evaluation of ASD by CMR from 2009-2011 were enrolled in the study. The patients with ASD in the setting of complex congenital heart disease were excluded. All patients were being considered for either percutaneous or surgical closure of ASD. The CMR protocol has been described previously and included standard SSFP (steady state free precision) cines to define the LV morphology and function, phase contrast was used to calculate the shunt fraction and define the ASD morphology, and a high resolution contrast enhanced 3-D MR angiograms were performed to assess pulmonary venous anatomy.The total number of patients with ASD was 53. The baseline characteristics and pertinent CMR findings are shown in table The prevalence of PAPVC in this population (n=53) was 6 (11%). The results of which are shown in the table The prevalence of PAPVC in adult congenital ASD patients referred for further evaluation of ASD is 14%. The incidence was higher in women (15%) compared to men (10%).Since the presence of PAPVC will change the clinical decision of closure of ASD from percutaneous to surgical, the comprehensive CMR assessment for ASD can serve as an excellent non-invasive imaging modality not only to define the morphology and quantify shunt severity of ASD but also to identify the presence of PAPVC.None"} +{"text": "In the Results and Discussion section under 'Cell-type Specific Expression Profiling of Medicago Root Nodules' the following sentence was erroneously included: \"Figure 2 summarizes the number of genes that show at least 2 fold enriched expression compared to the average of the other LCM samples.\"Under 'Validation of Cell-type Specific Expression in Medicago Root Nodules', the last sentence of the first paragraph incorrectly refers to Table 2. The corrected sentence is: \"Additionally, we analyzed the expression profile of several selected genes in the nodule .\""} +{"text": "As a part of The Danish Safer Hospital Programme Regional Hospital Horsens introduced the Sepsis package in 2011 in order to reduce unnecessary deaths and harm to patients.With this study we show how the goals defined in the Sepsis package including 5 elements are met in the Emergency Department Regional Hospital Horsens and how this affects the morbidity of septic patients. At the same time we examined which patients with sepsis who didn\u2019t get screened for sepsis.Study design: Cross sectional study.We retrospectively reviewed the journals of all patients with af medical condition age >15 years who were admitted to the Emergency Department Regional Hospital Horsens in April 2012.After thorough review of data from Opus Electronic Patient Journal we found that almost all patients with sepsis (22 of 29) had received all 5 elements of the Sepsis package but only 12 met all goals after 6 hours (the 6 hour bundle). We found 13 patients (45%) with severe sepsis/septic shock out of which 4 died corresponding to 31% of patients with severe sepsis/septic shock.Our data suggests that the implementation of all elements in the Sepsis package are difficult to achieve and that there is place for improval in the Emergency Department Regional Hospital Horsens. To change this a goal directed effort among the staff is needed.The mortality among septic patients doesn\u2019t seem to have been reduced after implementing the Sepsis package, the number of patients in this study is too small to make any final conclusions.By enlarging the study to greater number of patients and including a historical control group it will be possible to evaluate the impact of the Sepsis package.Real time easy registration of observations and treatments are also necessary if better results are to be achieved concerning compliance to all elements of the six hour bundle."} +{"text": "Sterol Response Element Binding Protein 2 (SREBP2) transcription factor is a master regulator of cholesterol homeostasis. Treatment with statins, inhibitors of cholesterol synthesis, activates intestinal SREBP2, which may hinder their cholesterol-lowering effects. Overactivation of SREBP2 in mouse liver was shown to have no effect on plasma cholesterol. However, the influence of activating intestinal SREBP2 on plasma cholesterol is not known. We have generated a novel transgenic mouse model with intestine specific overexpression of active SREBP2 (ISR2) driven by villin promoter. ISR2 mice showed overexpression of active SREBP2 specifically in the intestine. Microarray analysis of jejunal RNA from ISR2 mice showed a significant increase in genes involved in fatty acid and cholesterol synthesis. Cholesterol and triglyceride (TG) in jejunum and liver (mg/g protein) were significantly increased in ISR2 vs wild type mice. Serum Cholesterol was significantly increased in VLDL and LDL fractions whereas the level of serum triglycerides was decreased in ISR2 vs wild type mice. In conclusion, activation of intestinal SREBP2 alone seems to be sufficient to increase plasma cholesterol, highlighting the essential role of intestine in maintaining cholesterol homeostasis in the body. Sterol Response Element Binding Proteins (SREBPs) have been shown to be central regulators of cholesterol and lipid homeostasis Elevated cholesterol level in the plasma is a major risk factor for atherosclerosis and coronary heart diseases The functional roles of SREBPs have been extensively investigated in several cell culture and animal models To understand the physiological and metabolic roles of SREBP2, previous studies mainly focused on the liver To carefully investigate the influence of SREBP2 on intestinal functions and on body cholesterol homeostasis, we have generated a transgenic mouse model with intestine-specific overexpression of the active SREBP2 (460 amino acid NH2-terminus) driven by the villin promoter to investigate its roles in intestine. Microarray analysis in the jejunum revealed a significant increase in the expression of genes involved in cholesterol and fatty acid synthesis as well as other genes responsible for vitamin transport and circadian rhythm. The levels of plasma cholesterol in the transgenic mice were significantly increased in the LDL and VLDL lipoprotein fractions. These data underscore the emerging roles of intestinal SREBP2 in the maintenance of cholesterol homeostasis and provide a novel mouse model for SREBP2 overexpression in the intestine that complements other models previously described in the liver.All animal studies were approved by the animal care committees of the University of Illinois at Chicago and the Jesse Brown VA medical center. A 1380 bp fragment that starts form the ATG codon of the SREBP2 cDNA was amplified from mouse small intestinal RNA using standard PCR methods. This PCR fragment represents the coding region for the first 460 amino acids of the N-terminal of mouse SREBP2. The PCR fragment was then placed downstream of a 9 kb regulatory region of the mouse villin gene .Total RNA was extracted from tissues utilizing RNeasy Mini Kit (Qiagen) according to the manufacturer's instructions. RNA was treated with DNase I to eliminate genomic DNA contamination. Equal amounts of RNA from different samples were reverse transcribed and amplified in one step reaction utilizing Brilliant SYBR Green QRT-PCR Master Mix Kit (Stratagene). Primers used for the current studies are listed in Supporting Information (\u0394Ct(target) gene/2\u0394Ct, where \u0394Ct represents the difference between the threshold cycle of amplification of RNA from different experimental groups for target gene and internal control gene (GAPDH).The results was expressed as a ratio of 2Total cellular protein was extracted from intestinal mucosal scrapings as previously described with minor modifications Sections (5\u201310 \u00b5m thickness) were cut from snap-frozen tissues embedded in OCT medium using a cryostat and were mounted on the slides and preserved at \u221280\u00b0C until further use. For Oil Red-O staining, frozen sections from both wild type and transgenic mice liver were cut at 10 \u00b5m thickness. Sections were air dried and fixed in formalin for 10 minutes, washed with running tap water for 10 minutes and then rinsed with 60% isopropanol. \u03a3\u03b5\u03c7\u03c4\u03b9\u03bf\u03bd\u03c3 were then incubated with freshly prepared working solution of Oil Red-O (Fisher Scientific) for 15 minutes and then rinsed with 60% isopropanol. Nuclei were stained with alum haematoxylin and rinsed with water. Slides were mounted with glycerol and staining was assessed microscopically. For immunofluorescence studies the sections were fixed with 4% paraformaldehyde in PBS for 20 min at room temperature followed by blocking in PBS containing 5% normal goat serum at room temperature. Sections were then incubated with rabbit anti N-terminal SREBP2 antibodies with a dilution of 1\u2236100 (Abcam) and mouse anti-villin with a dilution of 1\u2236100 (Abcam) in the blocking buffer. After PBS washes, the sections were incubated with the secondary antibodies, Alexa Fluor 488-conjugated goat anti-mouse IgG (green), and Alexa Fluor 568-conjugated goat anti-rabbit IgG (red) for 60 min and then washed and mounted with slow-fade DAPI by using coverslips. Microscopy was performed with a 20\u00d7 oil immersion objective of Zeiss immunofluorescence microscope (Observer Z1) equipped with deconvolution software (AxioVision).Total lipid was extracted from intestinal and hepatic tissues essentially as previously described Results are expressed as means \u00b1 SE. Student's t-test or one-way ANOVA were utilized in statistical analysis. P<0.05 was considered statistically significant.Recent studies demonstrated putative roles for SREBP2 in regulating different physiological processes including hepatic autophagy and the expression of intestinal taste receptor and the secretion of cholecystokinin (CCK) To determine the expression profile of the N-terminal SREBP2 transgene, we performed real time PCR using total RNA extracted from jejunum, ileum and colon of ISR2 mice and their wild type (WT) littermates. As shown in To confirm the overexpression of the transgene in the intestine, we performed western blot analysis. As shown in Methods S1). The findings of the microarray analysis show that the expression of several genes is upregulated in ISR2 mice as compared to their wild type littermates and only a few were downregulated. As shown in the Table S2). These data indicate that SREBP2 activation in the jejunum stimulates several pathways that may affect cholesterol homeostasis as well as other processes directly related to intestinal functions.We next examined the effects of SREBP2 overactivation on gene expression in the intestine. As an initial characterization, we focused on the jejunum since it is the major site for nutrient and cholesterol absorption. We performed gene microarray analysis to identify the genes with altered expression in response to constitutively active SREBP2. The methods for microarray analysis are described in Supporting Information . There is a trend for an increase in the levels of blood glucose in ISR2 mice as shown in Since VLDL and LDL cholesterol levels were increased in ISR2 mice, we next investigated lipid content in the liver. As shown in Our studies present a novel transgenic mouse model in which SREBP2 transcription factor is constitutively active in intestinal epithelial cells. It was previously shown that liver-specific overactivation of SREBP2 in mice was not associated with an increase in plasma cholesterol The phosphoenolpyruvate carboxykinase (PEPCK) promoter was previously used to drive liver-specific expression of the first 468 aa of SREBP2 that represent the N-terminal active transcription factor The expression of the transgene in ISR2 mice was assessed using primers specific for the 5\u2032 region of the mRNA encoding for the N-terminal of the SREBP2. Our data clearly showed that the transgene was specifically over-expressed in the small intestine and the colon but not in other tissues such as liver, lung and kidney. Immunofluorescence analysis in the jejunum confirmed the data obtained by PCR and western blotting showing an enhanced staining for SREBP2 along the length of the villus-crypt axis with increased co-localization in the nuclei indicating activation of the transcription factor. In addition, there was no apparent difference in the villus structure between ISR2 mice and their wild type littermates. The expression of the transgene was different along the small intestine with high levels in the jejunum followed by the ileum and colon. This pattern may be due to regional difference in the activity of the villin promoter. This notion is supported by the fact that the protein expression of endogenous villin as judged by western blotting showed high abundance in jejunum followed by ileum and colon. Western blotting analysis further confirmed the results obtained by PCR regarding the expression of the transgene along the GI tract. It is noted that the endogenous active SREBP2 was detected in both jejunum and ileum but not colon. This is inconsistent with previous studies showing more active nuclear SREBP2 in the nuclear extracts from colon and ileum as compared to jejunum The overexpression of SREBP2 in liver and pancreatic \u03b2-cells increases the cellular levels of cholesterol and triglycerides in the liver and pancreas, respectively High levels of free cholesterol in the jejunal mucosa of ISR2 mice were not associated with any significant change in the level of cholesterol ester. This may indicate an overwhelming increase in the loading pathways of free cholesterol (synthesis and/or absorption) to a level that exceeds the capacity of cholesterol esterification pathways mediated by ACAT-2 in the intestine. It is also possible that cholesterol esters did not accumulate in the intestinal epithelial cells due to enhanced secretion of esterified cholesterol from the intestine of ISR2 mice. Indeed, the elevated levels of intestinal cholesterol and triglycerides were associated with an increase in their hepatic levels suggesting that the stimulation of intestinal lipid synthesis and/or absorption caused an overload of lipid in the liver. Although the levels of lipids were increased in the lever, the architecture of the hepatic tissues remained, however, intact and no inflammatory infiltration was observed in livers of ISR2 mice. The Oil Red-O staining confirmed the accumulation of lipids in the hepatocytes and indicated the presence of mild steatosis when mice are fed regular chow diet. It will be interesting in future studies to examine the possible development of steatohepatitis similar to the Non Alcoholic Steatoheptitis (NASH) when ISR2 mice are challenged with high fat diet. The increase in hepatic load triggered normal responses in the liver as judged by the decrease in SREBP2 expression and its target genes Recent studies demonstrated broader roles for SREBP2 beyond controlling the processes of cholesterol homeostasis Our current data presented herein described a novel model of intestine-specific overactivation of SREBP2 in mice that complement previous models of liver-specific alterations in SREBP2 expression Methods S1Methods for RNA microarray.(DOCX)Click here for additional data file.Table S1Sequences for PCR primers.(DOCX)Click here for additional data file.Table S2Altered gene expression in the jejunum of ISR2 mice .(PDF)Click here for additional data file."} +{"text": "Detecting divergence between oncogenic tumors plays a pivotal role in cancer diagnosis and therapy. This research work was focused on designing a computational strategy to predict the class of lung cancer tumors from the structural and physicochemical properties (1497 attributes) of protein sequences obtained from genes defined by microarray analysis. The proposed methodology involved the use of hybrid feature selection techniques followed by Bayesian Network prediction to discriminate lung cancer tumors as Small Cell Lung Cancer (SCLC), Non-Small Cell Lung Cancer (NSCLC) and the COMMON classes. Moreover, this methodology eliminated the need for extensive data cleansing strategies on the protein properties and revealed the optimal and minimal set of features that contributed to lung cancer tumor classification with an improved accuracy compared to previous work. We also attempted to predict via supervised clustering the possible clusters in the lung tumor data. Our results revealed that supervised clustering algorithms exhibited poor performance in differentiating the lung tumor classes. Hybrid feature selection identified the distribution of solvent accessibility, polarizability and hydrophobicity as the highest ranked features with Incremental feature selection and Bayesian Network prediction generating the optimal Jack-knife cross validation accuracy of 87.6%. Precise categorization of oncogenic genes causing SCLC and NSCLC based on the structural and physicochemical properties of their protein sequences is expected to unravel the functionality of proteins that are essential in maintaining the genomic integrity of a cell and also act as an informative source for drug design, targeting essential protein properties and their composition that are found to exist in lung cancer tumors. Oncogenic tumors are the leading cause of death around the world with Lung Cancer bearing the major toll of malignant fatalities Gene expression patterns from microarray analysis enabled the sub-categorization of lung cancer types that related to the degree of tumor demarcation, nature of therapy and victim survival rate In recent research undertakings, several classifiers and data mining models have been used that targeted the appropriate categorization of lung cancer tumors. Forty-one samples characterized by 26 attributes computed from the mass-to-charge ratio (m/z) and peak heights of proteins identified by mass spectroscopy of blood serum samples from lung cancer affected and non-affected patients was utilized to train a classification and regression tree (CART) model The current investigation was focussed on a very recent article by Hosseinzadeh et.al The Gene Set Enrichment Analysis database (GSEA db) The proposed methodology comprised of two phases: The training phase and the prediction phase. The training phase incorporated the data preparation, feature selection and classification process while the prediction phase involved evaluation of the classifier model using Jack-knife cross-validation test based on the performance parameters Feature ranking presented significant features in the order of their contribution to categorizing the samples under the different target classes R), and assuming \u2018F\u2019 to be the set of all features, and SR to be the set of all records, Value is taken to be the value of a specific instance \u2018r <$>\\raster=\"rg1\"<$> S\u2019 for the feature \u2018f <$>\\raster=\"rg1\"<$> F\u2019. Information Gain for the attribute was computed using Gain ratio criterion In order to compute the Intrinsic Value for a test, the following formula was adopted:The Information Gain Ratio The attributes were thus ranked according to their rank in the descending order of the Gain Ratio score and were used for the CFS Subset Evaluator method described below.The CFS hypothesis The attributes filtered by the CFS Subset Evaluator method were added in an incremental manner to identify the optimal set of features that contributed to lung tumor categorization. This methodology is reported below.th feature set could be stated asThe predictor attributes generated by the Gain Ratio and CFS Subset Attribute Evaluator (Hybrid Feature Selection) method were later utilized for Incremental Feature Selection (IFS) o\u2019 was the minimal and optimal feature set that achieved the highest MCC and accuracy.Where M denoted the total number of predictor subsets. On constructing each feature set, the predictor model was constructed and tested through Jack-knife cross-validation method. The MCC and Accuracy of cross-validation was measured, leading to the formation of the IFS table with the number of features and the classification accuracy they were able to generate. \u2018ATIn order to determine the best classification model for lung tumor classification 1, rn}, n \u22651 was the set of input variables. The classification task consisted of classifying a variable V\u200a=\u200av0 called the class variable (NSCLC/SCLC/COMMON) given a set of variables R\u200a=\u200ar1 . . . rn. A classifier C: r \u2192 v was a function that mapped an instance of \u2018r\u2019 to a value of \u2018v\u2019. The classifier was learned from a dataset D that consisted of samples over s, a directed acyclic graph (DAG) over the set of variables R and a set of probability tables The learning phase in this approach incorporated the process of finding an appropriate Bayesian network S and the network represented a probability distribution given by Eq. (8)Where pa(r) was the set of parents of r in BThe inference made from the Bayesian Network Supervised clustering Class impurity, Impurity(X): It was measured by the percentage of marginal examples in the different clusters of a clustering X. A marginal example was an example that belonged to a class different from the most frequent class in its cluster.Number of clusters, k.In this research we have compared the classes to cluster evaluation accuracy of seven clustering algorithms Statistical prediction methods The experimental results are discussed in three sections. The foremost describes the ranking of the structural and physicochemical properties according to their gain ratio. The entire list of attributes was ranked and the file is provided as A total of 1497 attributes were initially loaded as the training data with 113 instances The ranked attributes from the CFS subset evaluator were then input in the descending order of their rank to the classifier. At each attribute entry, the MCC and accuracy of the classifier on Jack-knife test was calculated. The Bayesian Network Learning was found to give the highest prediction MCC of 0.812 and accuracy of 87.6% with 36 features. The IFS curves generated on classifier accuracy and the corresponding MCC is represented in Benchmark classification models that have been reported This study utilized seven clustering algorithms There have been several researches on lung cancer classification The following novel insights on the protein properties were gained from the Random Forest Model with a new set of discriminative features being reported for the first time in discriminating the lung tumor classes.Dipeptide composition was the most discriminating feature among the classes. F1.2 [Dipeptide Composition], F5.3 [Distribution Descriptor], F4.1 [Geary Auto-correlation] and F6.1 [Sequence order coupling number] were the subsequent significant protein properties used by the Random Forest Model to discriminate the lung tumor classes.A low value of the F5.3.2 [Normalized vdW volumes] and F [7.1] pseudo amino-acid composition moved the records into the COMMON class. A high F5.3.1 [distribution of hydrophobicity] and F5.3.3 [distribution of polarity] was found among the genes common in both classes of tumors whereas a lower concentration of the same was found among the NSCLC tumor genes. This directs molecular research to design drugs that would lower the distribution of hydrophobicity and polarity while raising the normalized vdW volumes and pseudo amino-acid composition to target the COMMON classes of tumors.A high dipeptide composition was characteristic of the NSCLC genes and a relatively low value represented the SCLC tumors. A high concentration of F5.3.1 [Distribution of hydrophobicity] and F5.3.7 [distribution of Solvent Accessibility] was evident in the COMMON classes of tumors. These findings suggest designing drugs that raise dipeptide composition to aid in cure of SCLC tumors and drugs that lower the dipeptide composition to cure NSCLC tumors. Moreover design of drugs that lower the distribution of hydrophobicity and solvent accessibility could aid in curing tumors of both kinds.It was evident that a strict demarcation among the tumor categories was a complicated task since many properties were found to exhibit similar composition in both the tumor classes. However the proposed methodology was found to differentiate between the tumor classes with a high MCC of 0.812 and classification accuracy of 87.6%, the highest reported thus far in protein \u2013property based lung tumor categorization.As stated earlier, the only previous computational study on lung tumor categorization based on the protein sequence-based structural and physicochemical properties was reported by Hosseinzadeh et.al The previous work by Hosseinzadeh et.al reported a high accuracy of 86% only on the cleaned data after removal of duplicate records, correlated records and based on the standard deviation values. When considering the same data, our proposed work has achieved a higher accuracy with the original, unmodified data thus saving computational time by the elimination of the data cleaning process. In order to bring out the comparison more clearly we have identified the accuracy of Random Forest with Gain Ratio (previously proposed classifier model) on the original data which was able to generate an optimal accuracy of only 79.6% with 26 features from the Gain Ratio \u2013CFS feature set compared to our proposed method which produced 87.6% accuracy with 36 features from the same feature subset. We believe our proposed methodology can easily be extended to classify and discriminate between other oncogenic tumors since the original data was retained for computational analysis. However the previous method appears to have generated a high accuracy (86%) only on the cleaned data which makes it a limitation when extending the methodology to other cancer datasets. Moreover the previously proposed model would entail additional data pre-processing time when applied to new cancer datasets.We compared three feature selection methods Bayesian Networks have been used in several Bayes net only relates nodes that are probabilistically related by some sort of causal dependency. This eliminates the need to store all possible configurations of states. The algorithm stores and works with all possible combinations of states between sets of related parent and child nodes that greatly reduce computational complexity.Bayes Net utilizes expert knowledge and data to build models dynamically. It allows both backward and forward reasoning.The medical domain is one research area where expert knowledge always has room for improvement and backward reasoning is a definite requirement. Hence application of computational techniques like Bayesian Networks in discriminating and classifying tumor classes based on protein sequence based physicochemical properties is expected to advance the current state of molecular and biological analysis of oncogenic tumor classes for drug design.Research on the utilization of computational techniques and predictions on clinical and biological data has intensified in the recent past owing to the fact that most wet-lab experiments consumed more human expertise, time and capital with irresolute rewards. This research was aimed at identifying the minimal and optimal set of protein sequence based structural and physicochemical properties in lung tumor categorization into NSCLC, SCLC and the COMMON tumor classes. The findings of this study are believed to be both a computational and biological advancement, the former revealing a new combination of feature selection and prediction techniques for categorizing tumor classes with enhanced accuracy and the latter acquiring information on protein properties prevalent in lung tumors that could aid in diagnostic practice and drug design. Possible extensions to this work would involve application of this novel computational framework in categorization of other oncogenic tumors and detecting properties that could be targeted for cancer therapy. Moreover computational advancement would require improving the prediction accuracy of the proposed methodology by possible updations to the existing algorithms.File S1Attribute description file.(DOC)Click here for additional data file.File S2Pre-processed protein based structural and physicochemical data.(TXT)Click here for additional data file.Table S1Hybrid feature selection results.(XLS)Click here for additional data file.Table S2Incremental feature selection results.(XLS)Click here for additional data file."} +{"text": "Health status of aboriginal or indigenous as general is poor compared to the general population all over the world. The increasing trend of non-communicable diseases (NCD)among Orang Asli community became alarming to the health status of this marginalized group. The crude prevalence rate of diabetic and impaired glucose tolerance (IGT) to be 1.3 and 10.7%, respectively among the Orang Asli population living rural area was significantly higher compared to those living in the jungle (0.0 and 3.3% respectively) and the prevalence of hypertension among Orang Asli community was 30.8% which is lower than the National Health and Morbidity Survey. Patient satisfaction towards health care among Orang Asli or aborigines will further determine and discuss the degree of patient satisfaction about healthcare services for this marginalized group especially regarding NCD. Thus this study is conducted to measure burden of NCD among Orang Asli community and patient satisfaction on NCD management at public health facilities. This is essential to ensure the equality and the equity of health services available for this marginalized group.A cross sectional study among the Orang Asli population with chronic diseases will be conducted in September 2012 at selected Orang Asli villages in Selangor, Pahang and Perak. 650 of the respondents will be selected by using Multistage Sampling Technique.Burden of NCD among Orang Asli community and patient satisfaction on NCD management at public health facilities will be measured by using validated patient satisfaction questionnaire with added component of NCD burden.This study outcome will serve as information for the policy makers about the burden and patient satisfaction on NCD management among Orang Asli population towards improvement of health programme planning."} +{"text": "Microarray data from cell lines of Non-Small Cell Lung Carcinoma (NSCLC) can be used to look for differences in gene expression between the cell lines derived from different tumour samples, and to investigate if these differences can be used to cluster the cell lines into distinct groups. Dividing the cell lines into classes can help to improve diagnosis and the development of screens for new drug candidates. The micro-array data is first subjected to quality control analysis and then subsequently normalised using three alternate methods to reduce the chances of differences being artefacts resulting from the normalisation process. The final clustering into sub-classes was carried out in a conservative manner such that sub-classes were consistent across all three normalisation methods. If there is structure in the cell line population it was expected that this would agree with histological classifications, but this was not found to be the case. To check the biological consistency of the sub-classes the set of most strongly differentially expressed genes was be identified for each pair of clusters to check if the genes that most strongly define sub-classes have biological functions consistent with NSCLC. The use of cell lines in biology as a replacement for whole animal studies plays a significant role in reducing the number of animal experiments that have to be carried out in bio-medical research. An important assumption is that gene expression in the cell lines reflects the expression patterns of the tissue from which it was isolated. Recently there has been growing criticism of the use of cell lines in cancer research because of problems with stability, misidentification and contamination The problems with using cell-lines for cancer research are further exacerbated by the diversity within a supposedly single type of cancer. Two recent studies of breast cancer have shown that there is considerable heterogeneity in transcriptomes of tumour cells. A study of the expression profiles from 2000 patients with breast cancer has shown that the data can be used to first discover and then validate subgroups Gene expression data can provide a starting point for the identification of biomarkers although there are considerable challenges to finding a signal amongst noisy data. Existing methods have used microarray data and while these methods are giving way to next generation sequencing technologies, they currently still provide a cheap, accessible and relatively easy to use alternative for gene profiling at the whole organism level A survey of median survival rates for cancer by Macmillan Cancer Support showed that whilst the median cancer survival times had increased for many types of cancers there has been little improvement in the last 40 years in lung cancer survival rates The size of the gene expression studies available for lung cancer is much smaller than that available for breast cancer. Lung cancers can be divided into two major groups, Small Cell Lung Carcinomas and Non-Small Cell Lung Carcinoma (NSCLC). NSCLC can be further classified into three subtypes: Squamous cell carcinoma, Adenocarcinoma, and large cell carcinoma In this paper the transcriptomic datasets from that study are used to look for heterogeneity in gene expression that can then be used to cluster the cell-lines. In the work of Sos and co-workers they combined phenotype screening data to distinguish cell lines that used the PI3K and MAPK pathways to suggest that a broad target therapy that targets both pathways may be an effective treatment across all NSCLC variants The data consists of single arrays collected for each of the cell lines. There are no biological or technical replicates. From a statistical perspective the lack of replicates is a concern as without replicates there is no measure of the variability because of either the experimental conditions or because of biological variation.Improvements in the production of oligonucleotide arrays have suggested that they are now highly reproducible and that there might no longer be a need for technical replicates except in the case of quality control studies Turning to the problem of a lack of biological replicates, it is very important in microarray studies to have biological replicates in order to account for the natural variation in growth and cell populations A lack of biological replicates is far from ideal and without them we do not have a reliable measure of gene expression variance at the gene level for a single cell line. There may be biological variation between individual cells because of the stages in their life cycle this variation will be lost in the experimental samples which pool expression from a population of cells. Pooling of cell line samples has been shown to reduce the number of differentially observed genes between treated and untreated cancer cell lines After clustering members of the same sub-class are assumed to have very similar gene expression profiles and so they then provide pseudo-biological replicates for any subsequent analysis of differential gene expression. In this study this last step is carried out to check for the biological consistency of the results and not in order to identify markers for classification as the study size is too small to allow reliable prediction of markers.An important step in quality control of the raw array data that is often ignored is the visual inspection of the raw array images. If there is contamination this can either result in dark areas where probes are obscured or bright areas where there is excessive signal. Both of these factors will affect the results and also impair normalisation. In this case visual inspection showed that dust contamination was present on one of the arrays, GSM372797.CEL eliminated the outlying expression values for these arrays gcrma was the chosen method of normalisation to have included the data but there has been a study that has shown that gcrma has not performed as well as other methods After normalisation it is important to look at the boxplots for the distributions of expression to see if any of the arrays have outlying expression values which will affect the results of further analysis. These are likely to result from technical problems with some of the probes, this was confirmed by looking at the data for spiked in house keeping genes such as GAPDH. The unusual behaviour of the spiked in probes indicates problems with how the sample has been prepared and applied to the array. There is further evidence for this conclusion as normalisation which takes into account the probe composition as this reduces bias from highly expressed genes. The final boxplots for the log2 expression values of the normalised data are shown in Filtering of the gene sets is necessary to deal with the statistical challenges of dealing with so many different variables and the curse of dimensionality et al. suggested a filtering method that depends on the ratio (r) and the difference (d) between the maximum and minimum values for the expression of a gene across all the arrays farms normalised data exhibits a much lower degree of variation to the other normalisations, but that gcrma has much lower values. The values of r and d are given in table one, along with the actual number of filtered probesets.Golub rd quartile for the arrays was between 8 and 9), second the interquartile range should be about a threshold, third the median of the gene expression should be also be about the third quartile of the expression for the normalised arrays (in this case a cut-off of 600 in absolute units or 9.3 in log2 transformed data). The values of the interquartile ranges for this alternative filtering method and the number of probesets are also given in table one.A more robust measure of variability is the interquartile range, as this is less sensitive to outliers with either higher or lower expression values than usual. Filtering was also carried out using this method which uses a three component filtering. The first is that over 25% of the arrays should be above the third quartile of the expression for the normalised arrays . In this case there are only 50 cases after normalisation, with this data the aim is to show that there are identifiable subsets within the data that have a biological explanation. As NSCLC can be divided into different sub-groups it is expected that the sub-groups should correspond to these classifications from histology. The main concern in clustering is making sure that clusters are not artefacts that arise from the normalisation process, the filtering of the genes or the clustering process itself. The simplest clustering method is agglomerative hierarchical clustering with average cluster distances. By using this method on the data from all three normalisations and the four different sets of gene filters we get twelve trees from which a consensus clustering can be calculated. By looking for clusters that are conserved in all twelve trees we can produce conservative clusters that contain a group of core members, which have very close gene expression profiles. These core clusters of cell lines can then be used to investigate which differences in gene expression distinguish the clusters. An example clustering dendrogram is given in After consensus analysis three clusters were identified. The largest of which contains 16 cell lines, the second largest 11 cell lines and the smallest 7 cell lines. In total 35 out of 50 cell lines can be clustered into these groups. Cell-lines that could not be consistently assigned to a single group were not assigned to any cluster. For example array GSM372762 could be in either cluster 2 or 3 and so because of this ambiguity no cluster can be firmly assigned. By using twelve different normalisation and filtering combinations to generate the data for clustering and only assigning arrays that are consistently in the same cluster, this conservative approach reduces the likelihood of discovering meaningless clusters. Ideally the data should be divided into two groups, one for cluster discovery and the second for cluster validation, but in this case there is insufficient data to take this approach. Using alternative methods to test the robustness of the clusters and their sensitivity to changes in the normalisation and filtering is as much as can be done with such a small dataset.Of the remaining cell lines that could not be clustered three are clear outliers to the rest. These are consistently at the base of the tree in all of the alternative clusterings and so are at some distance from the other cell lines. They are arrays GSM372758.CEL, GSM372779.CEL, GSM372788.CEL. These three arrays are annotated as Neuroendocrine IV, Large Cell Carcinoma, and Unknown respectively. This result suggests that these cell lines are single examples of distinctive expression types that are quite distant from the main grouping of NSCLC cell lines. These lines have been shown to be important in contributing to the gene expression signature used to distinguish lung cancer progression but as only single cell-lines for each type are currently available they are atypical of the existing NSCLC data, and so they are not ideal candidates at this time for testing novel chemical entities that are targeted across a broad spectrum of cases The three final clusters are shown in table three along with their annotations. The largest of these contains 16 arrays. The closest of the other subsets to this group is cluster 3, while cluster 2 is a more distant group. Subset one correspond to adenocarcinoma as an annotation. This is the largest annotated group of cell lines but this has been broken down into subtypes that are not seen in the clustering. There are also a large number of adenocarcinoma cell lines that do not fall clearly into this group. The second subset has a mixture of annotations but Squamous Cell Carcinoma is the most frequent. The final cluster is too small to draw any clear conclusions about annotations but it seems to contain a mixture of histological categories. This suggests that while there is some agreement between the histological classification and the expression profile clustering, the agreement is not perfect and the expression data gives a an additional measure for classification. If we can develop a classifier based on genetic markers this will help to improve NSCLC classification methods.While it is not the aim of this study to find the differentially expressed genes between the clusters identification of the most significant genes responsible for each of the clusters provides further biological support for the sub-groups.limma. gcrma normalisation and IQR filtering for approximately 1000 probes. Heatmaps were generated for differentially expressed genes between all of the clusters for all of the filtering and normalisation methods. While some genes are found in common between methods there is considerable variation.Statistical tests can be carried out to identify the genes that are differentially expressed between the clusters. As there are a large number of tests that are carried out there has to be a correction for multiple testing and the most frequently used correction is that of Benjamini and Hochberg, as Bonferroni correction is too conservative and would mean rejecting all genes that are potentially differentially expressed The filtering method had a dramatic effect on the number of genes identified as differentially expressed between the sub-groups. In the case of clusters 1 and 3 filtered using the IQR method no genes were found to be differentially expressed at a significant level . Cluster three is a sub-group or a branching off from the main subgroup \u2013 cluster one but it was still expected that would be some significant level of differences in gene expression, but this was not the case when IQR is the filtering method. However in the case of using the Golub method for filtering, there are a number of significantly differentially expressed genes. This suggests that either the IQR filtering is losing some of the diversity in gene expression by being too stringent leading to type II errors, or that the Golub filtering method is prone to type I errors by finding signal amongst the noise. This was a consistently identified sub-group and so some feature in the gene expression variation must be responsible for distinguishing this cluster from its neighbours even if this is below the threshold of statistical significance.Most often the 1000 gene sets gave a larger number of statistically significant differentially expressed genes between the clusters than the 300 gene sets. However the ordering of the significance of the genes was different and there was poor agreement between the gene sets identified by both the different filtering methods using the same normalisation method as well as between the normalisation methods (see supplementary data). A small number of genes were conserved as differentially expressed between the clusters in a significant number of the normalisation and filtering variants. A selection of these conserved genes are given in table four. Some are genes often labelled as oncogenes but there are others that are not usually associated. A complete list of the differentially expressed genes between the clusters for the different normalisation methods and different filtering methods as well as their annotations is given in the supplementary materials.The final check on the validity of any microarray analysis is to see if the results make biological sense. Is differential expression of these genes between NSCLC sub-groups reasonable, and have the genes been associated with cancer in other studies? In many cases there is other prior evidence of a connection between the commonly found genes responsible for distinguishing sub-groups and other cancer studies. Of the genes in table four all but one of them has an existing link to cancer in the literature. Trefoil factor one deficiency has already been identified as causing increased tumorigenicity in human breast cancer cells A cause for concern is the inconsistency in genes identified as having significantly different expression levels between the three clusters using the three different normalisation methods. These discrepancies show that in this case normalisation plays a part in determining which genes are identified as significantly differentially expressed between clusters. This should not be true and hampers the reliability of gene expression analysis as well as casting doubt on genetic markers that have been identified using these techniques. Here the differences in expression levels should be small as the arrays are all for similar cell lines and it is possible that this might be an artefact of the small differences being amplified in different ways during the normalisation process, but it does raise questions about objectivity of normalisation methods, and suggests that the use of multiple normalisation methods might improve the reproducibility of gene expression analysis This analysis has shown that there is heterogeneity in gene expression between the NSCLC cell lines, and that this diversity can be used to divide the cell lines into different groups that do not completely agree with the histological annotations. Lung cancer was chosen for this study because of the potential variability in its genetic make-up, which may be responsible for its rapid progression and the difficulty in developing a successful treatment. The variability between sub-classes suggests that it might not be possible to develop a broad ranging treatment, but this also presents an opportunity to develop more specific treatments and for improved molecular diagnostics. By screening new chemical entities against cell-lines chosen from all three sub-classes we can hope to generate a broad specificity drug, or alternatively the focus can be moved to targeting patients who fall into one of the subsets for a more specific treatment.This paper has only used a small of samples where gene expression profiles were available and so it can only provide initial evidence for the existence of at least three sub-groups of NSCLC, although it is likely that with larger datasets more subgroups will be discovered. Considerable effort is required to confirm, and develop these findings in order to advance our understanding of NSCLC, to the same level as breast cancer. As larger studies containing more cell lines and gene expression data from biopsy or single cell samples become available this diversity is likely to increase further. With more biological replicates it will also be possible to identify biological markers for the sub-classes and classification methods in a robust manner. Questions have been raised about the influence of normalisation on the results of gene expression analysis but these could also be addressed by improved experimental designs that include more biological replicates and improvements in normalisation methods.arrayQualityMetrics within Bioconductor to assess the quality of 54 CEL files included in this study Raw data was downloaded from ArrayExpress with accession \u2018EGEOD-14925\u2019 rma, gcrma and farmsNormalisation methods for Affymetrics arrays have been tested as part of Affycomp where spiked in controls are used to evaluate performance et al. which uses differences between the maximum and minimum expression level of a gene as well as a second filtering method based on the interquartile range are given in table one. Filtering was carried out using the genefilter module within Bioconductor The data were then filtered to obtain datasets containing around 1000 and 300 genes which can then be used for cluster analysis and to determine differential gene expression. The cut-offs for filtering were different for the three normalisation methods as the normalised data has a different scale and spread from the different normalisation methods. This is why filtering cut-offs select around a target number of genes rather than an exact number. The values used for filtering using either the method from Golub limma within Bioconductor to carry out multiple testing Clustering was carried out using agglomerative hierarchical clustering for both the 1000 gene and 300 gene datasets. This is perhaps the simplest possible method of clustering. There was a good degree of consistency in the clustering between the three different normalisation methods and the different filtering strategies. One cluster was particularly clearly identified in all cases. This resulted in the identification of 3 main subgroups within the arrays, that were found consistently across all three normalisation methods and the filtered datasets. Arrays that were consistently found in the same cluster regardless of normalisation method make up the core of the cluster. This resulted in 3 conservative groupings containing at least six members and containing 34 out of total of 50 arrays. These clusters were then used for differential gene expression analysis using Figure S1An image of the raw Affymetrix array showing bright lines from dust contamination that span multiple probes.(TIFF)Click here for additional data file.Figure S2Dendrogram for FARMS normalised data using Golub filtering for 300 probes.(TIFF)Click here for additional data file.Figure S3Dendrogram for FARMS normalised data using Golub filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S4Dendrogram for FARMS normalised data using IQR filtering for 300 probes.(TIFF)Click here for additional data file.Figure S5Dendrogram for FARMS normalised data using IQR filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S6Dendrogram for GCRMA normalised data using Golub filtering for 300 probes.(TIFF)Click here for additional data file.Figure S7Dendrogram for GCRMA normalised data using Golub filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S8Dendrogram for GCRMA normalised data using IQR filtering for 300 probes.(TIFF)Click here for additional data file.Figure S9Dendrogram for GCRMA normalised data using IQR filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S10Dendrogram for RMA normalised data using Golub filtering for 300 probes.(TIFF)Click here for additional data file.Figure S11Dendrogram for RMA normalised data using Golub filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S12Dendrogram for RMA normalised data using IQR filtering for 300 probes.(TIFF)Click here for additional data file.Figure S13Dendrogram for RMA normalised data using IQR filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S14Heatmap for the differentially expressed genes between clusters 1 and 2 after Normalisation with FARMS and IQR filtering for 300 probes.(TIFF)Click here for additional data file.Figure S15Heatmap for the differentially expressed genes between clusters 1 and 2 after Normalisation with FARMS and IQR filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S16Heatmap for the differentially expressed genes between clusters 1 and 2 after Normalisation with FARMS and Golub filtering for 300 probes.(TIFF)Click here for additional data file.Figure S17Heatmap for the differentially expressed genes between clusters 1 and 2 after Normalisation with FARMS and Golub filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S18Heatmap for the differentially expressed genes between clusters 1 and 2 after Normalisation with GCRMA and IQR filtering for 300 probes.(TIFF)Click here for additional data file.Figure S19Heatmap for the differentially expressed genes between clusters 1 and 2 after Normalisation with GCRMA and IQR filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S20Heatmap for the differentially expressed genes between clusters 1 and 2 after Normalisation with GCRMA and Golub filtering for 300 probes.(TIFF)Click here for additional data file.Figure S21Heatmap for the differentially expressed genes between clusters 1 and 2 after Normalisation with GCRMA and Golub filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S22Heatmap for the differentially expressed genes between clusters 1 and 2 after Normalisation with RMA and IQR filtering for 300 probes.(TIFF)Click here for additional data file.Figure S23Heatmap for the differentially expressed genes between clusters 1 and 2 after Normalisation with RMA and IQR filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S24Heatmap for the differentially expressed genes between clusters 1 and 2 after Normalisation with RMA and Golub filtering for 300 probes.(TIFF)Click here for additional data file.Figure S25Heatmap for the differentially expressed genes between clusters 1 and 2 after Normalisation with RMA and Golub filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S26Heatmap for the differentially expressed genes between clusters 1 and 3 after Normalisation with FARMS and Golub filtering for 300 probes(TIFF)Click here for additional data file.Figure S27Heatmap for the differentially expressed genes between clusters 1 and 3 after Normalisation with FARMS and Golub filtering for 1000 probes(TIFF)Click here for additional data file.Figure S28Heatmap for the differentially expressed genes between clusters 1 and 3 after Normalisation with GCRMA and Golub filtering for 300 probes(TIFF)Click here for additional data file.Figure S29Heatmap for the differentially expressed genes between clusters 1 and 3 after Normalisation with GCRMA and Golub filtering for 1000 probes(TIFF)Click here for additional data file.Figure S30Heatmap for the differentially expressed genes between clusters 1 and 3 after Normalisation with RMA and Golub filtering for 300 probes(TIFF)Click here for additional data file.Figure S31Heatmap for the differentially expressed genes between clusters 1 and 3 after Normalisation with RMA and Golub filtering for 1000 probes(TIFF)Click here for additional data file.Figure S32Heatmap for the differentially expressed genes between clusters 2 and 3 after Normalisation with FARMS and IQR filtering for 300 probes.(TIFF)Click here for additional data file.Figure S33Heatmap for the differentially expressed genes between clusters 2 and 3 after Normalisation with FARMS and IQR filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S34Heatmap for the differentially expressed genes between clusters 2 and 3 after Normalisation with FARMS and Golub filtering for 300 probes.(TIFF)Click here for additional data file.Figure S35Heatmap for the differentially expressed genes between clusters 2 and 3 after Normalisation with FARMS and Golub filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S36Heatmap for the differentially expressed genes between clusters 2 and 3 after Normalisation with GCRMA and IQR filtering for 300 probes.(TIFF)Click here for additional data file.Figure S37Heatmap for the differentially expressed genes between clusters 2 and 3 after Normalisation with GCRMA and IQR filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S38Heatmap for the differentially expressed genes between clusters 2 and 3 after Normalisation with GCRMA and Golub filtering for 300 probes.(TIFF)Click here for additional data file.Figure S39Heatmap for the differentially expressed genes between clusters 2 and 3 after Normalisation with GCRMA and Golub filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S40Heatmap for the differentially expressed genes between clusters 2 and 3 after Normalisation with RMA and IQR filtering for 300 probes.(TIFF)Click here for additional data file.Figure S41Heatmap for the differentially expressed genes between clusters 2 and 3 after Normalisation with RMA and IQR filtering for 1000 probes.(TIFF)Click here for additional data file.Figure S42Heatmap for the differentially expressed genes between clusters 2 and 3 after Normalisation with RMA and Golub filtering for 300 probes.(TIFF)Click here for additional data file.Figure S43Heatmap for the differentially expressed genes between clusters 2 and 3 after Normalisation with RMA and Golub filtering for 1000 probes.(TIFF)Click here for additional data file.Table S1This contains the annotations that were added to the normalised data in Bioconductor including the clusters.(TXT)Click here for additional data file.Table S2This contains the full list of differentially expressed genes between all of the clusters.(TXT)Click here for additional data file."} +{"text": "Olfactory circuits in both insects and rodents are wired according to a pattern of convergence in which axons from olfactory sensory neurons expressing a single receptor type (SRT) project into the same glomerulus. This permits the representation of individual olfactory receptors in a topographical map in the brain (, 2], , ["} +{"text": "The last row of Table 3 is missing. Please find the complete table 3 here: In the body of the text under the section \"Bacterial Species Associated with Nutrient Enrichment and Herbivore Exclusion in Corals,\" the second to last sentence should read: Read counts ranged from 226 to 365 in all three coral specimens in week 16. In comparison, in all other treatments this OTU was either absent or present in low numbers .In the body of the text under the section \"Bacterial Species Associated with Nutrient Enrichment and Herbivore Exclusion in Corals,\" the sentence, \"It is also interesting to note that this bacterium is aerobic in contrast to the sulfate-reducing bacteria common in hypoxic environments that we identified after week 1 as a result of a combined treatment of nutrient-enrichment and caging.\" should be deleted. This sentence is referring to an OTU that was found after 16 weeks (OTU0223) and not after 1 week (OTU0203)."} +{"text": "EAAT3 (excitatory amino acid transporter 3) mediates the regulation of synaptic transmission by reuptake of glutamate in the synaptic cleft. It is distributed in neuronal membranes and is selectively enriched in the neurons of the hippocampus, cerebellum and the basal ganglia. It belongs to the family of soluble carrier family 1 member 1 (SLC1A1) and is expressed in kidney, a wide variety of epithelial tissues, brain and eyes.Xenopus laevis oocytes. Lanthanide binding tags (LBT) will be inserted into the protein to chelate the lanthanide terbium which serves as the donor element. Cysteines will be reacted to an acceptor dye (bodipy FL).The project utilizes the high-resolution crystal structure of GltPh, the bacterial orthologue to mammalian glutamate transporters. GltPh provides a structural framework for the determination of the helical movement in EAAT3. The structural rearrangement of the protein is caused by the helical movements which will be assessed by distance measurements using the technique of lanthanide resonance energy transfer (LRET). The protein will be expressed in The measured distances will allow us to obtain new insights into the structure-function relationship of the glutamate transporters which can be further investigated using different substrates and inhibitors.The results obtained in this project will allow us to better understand pathophysiological conditions associated with mutations in EAAT3, for instance mutations causing human dicarboxylic aminoaciduria."} +{"text": "A western blot panel in Figure 1 was inadvertently inserted twice to represent both round 16 of MBH + polyanion and round 16 of the HBH + polyanion . The authors requested a correction after reviewing the raw data and incorporating the original blot corresponding to HBH + polyanion. The correct blot does not show any signal besides the migration control of NBH \u2013PK, indicating no spontaneous generation of PrPSc. Therefore, the correction does not change the results or conclusions of this figure or the entire article. The editors have reviewed and agreed to this correction. Please find the corrected Figure 1 here:"} +{"text": "Due to the high prevalence of Bovine Leukemia Virus (BLV) in argentinean dairy herds, classical control based on the individual level of infection do not constitute a feasible strategy. An approach based on selective segregation of animals according to their peripheral-blood proviral load (PVL) could be a practical alternative.We conducted this work to get information about the frequency distribution of PVL under natural conditions with the purpose to describe the proportion of animals that could be selected as potential low transmitters.We analyzed the PVL on 332 cattle from four infected farms with different levels of seroprevalence together with the correlation of PVL with BLV antibody levels.In all farms, more than 50% of the seropositive animals showed a proviral load lower than our internal calibrator sample which corresponds to 1 infected cell in 100 non-infected cells according to: Farm A: 78%, Farm B: 79%, Farm C: 55% and Farm D: 79%.The analysis of antibodies showed that low p24-ELISA reactivity is associated with low PVL in the vast majority of animals.The present study provides biological data that could contribute with the design of a management program that includes a selective segregation policy for BLV control based on the level of proviral load, which represents a measure of integrated viral genome in host cells and a surrogate marker of the level of BLV transmission under natural conditions."} +{"text": "Enterococcus faeciumoutbreak in the medical intensive care unit (MICU). Prompt intervention strategies which were implemented by infection control team facilitated the successful control.Active surveillance which was introduced in 2008 following the Clostridium difficile outbreak in our hospital enhanced early detection of vancomycin resistant th and 30th August 2012, 7 patients in MICU had VRE positive cultures from a variety of samples including blood cultures.A maximum of 10 VRE isolates per year has been the norm between 2008 and 2011 in our 800 bed hospital. These isolates were from the oncology units. Between the 4Sample types and patient clinical data were collected; movement of infected patients within the hospital was traced to identify the possible index patient for patients who were not admitted directly into MICU. Hand washing and contact precautions practises were audited and reinforced as per VRE policy. Environmental cleaning audits were done routinely to minimize the bio burden and the unit was closed for new admission other than VRE positive patients. Infection control monthly reports were reviewed from May 2012 for possible oversight as there were no VRE cases in April. Monitoring and recording of new case is on-going with daily update to the team. One Isolate per patient is stored for molecular characterization.28 patients were identified over 10 months (May 2012 to February 2013). 42% (12/28) patients from MICU, 25% (7/28) were dialysed. The environmental cleaning audit revealed a leaking sewage pipe in the MICU which resulted in a complete closure of the unit and immediate repairs which was followed by terminal cleaning of the whole unit.It is well documented the most transmission of VRE is via contaminated hands of health care workers or environment or patient equipments. The findings in this study suggest that environmental contamination was the source of the VRE.None declared"} +{"text": "During the post-eradication era of Global Polio Eradication, the role of supplementary virological surveillance of groups at risk for the disease increases. The goal of all types of surveillance is to detect possible wild poliovirus importation and evaluate vaccine-derived polioviruses circulation. The large outbreak of poliomyelitis caused by the wild poliovirus of type 1 in Tadjikistan and registration of some cases of poliomyelitis among Tadjik children who have recently arrived in Russia requires the systematic virological surveillance of the children from Tadjik migrants\u2019 families.In 2006-2009 the Sub-national Polio Laboratory investigated the stool samples from 272 children from migrants\u2019 families. The strains of polioviruses of different serotypes were isolated from 10 children including 5 children from Tadjikistan. All strains were classified as vaccine-like strains. The percentage of isolation of polioviruses was higher among the healthy children from migrants\u2019 families (3.7%) than among the patients with acute flaccid paralysis (AFP) and healthy children who had contacts with them (1.9%). More prolonged excretion of polioviruses after vaccination was also demonstrated by the children from migrants\u2019 families.In 2010 the laboratory examined the stool samples from 112 children, including 86 children from Tadjik migrants\u2019 families. Nine polioviruses were isolated from 86 Tadjik children (10.5%). Three strains of polioviruses of type 1 isolated from three healthy Tadjik children were classified as non-Sabin-like according to the results of ELISA-test and PCR with specific primers. The genomic sequencing confirmed that the isolated viruses were wild polioviruses of type 1. The supplementary immunization targeting to avoid the wild poliovirus transmission was held at a nursery school.The systematic virological surveillance of AFP patients and children from the groups at risk for the disease and adequate epidemiological measures are indispensable in order to prevent wild poliovirus transmission and indigenous circulation of wild polioviruses after its importation to polio free countries."} +{"text": "Hearing impairment is the most common sensorineural deficit worldwide. Deafness has a major genetic component, and understanding how genetic variation impacts hearing needs to be extensively studied. The importance of this work is reflected in the review by Lufkin: \u201cthe sense of hearing is one of the most crucial senses endowed to a living organism and its loss can have many ramifications.\u201d This special issue about the Genetics of Deafness contributes to these studies by describing new mutations in genes important in hearing, by exploring the clinical implications of treatment based on genotype as well as reviewing of the literature.Included in this issue are reviews of genetic syndromes where deafness is a significant component. Lassaletta and colleagues set out an important review of the molecular mechanism of vestibular schwannoma. Pillion and colleagues characterize hearing loss in osteogenesis imperfecta. Tomelleri's group explores MELAS. All address molecular pathology of hearing loss and explore treatment options.GJB2.Several papers evaluate the distribution or effect of sequence variation in known hearing loss genes. Leal and colleagues describe novel mutations in two previously identified nonsyndromic hearing loss genes. Mateos et al. describe the effects of noncoding sequence variation in Vilarino and colleagues detail the distribution of mutations in pediatric patients in Portugal. Reports of this type improve our understanding of the mechanisms of hearing and the relevance of sequence variation in gene function.GJB2 are the leading cause of congenital deafness in many countries. Malekpour and colleagues present a large study detailing the performance of cochlear implants in patients with and without GJB2 mutation.Mutations in The complexity of genetic deafness and the tremendous progress associated with inherited hearing loss make it clear to us that the \u201csilence genes\u201d will have a lot more to tell us.Edi L\u00facia SartoratoEdi L\u00facia SartoratoKaren FridericiKaren FridericiIgnacio Del CastilloIgnacio Del Castillo"} +{"text": "The purpose of this study is to quantify right ventricular (RV) motion and surface strain in normal volunteers using 3D cine DENSE MRI.The RV is difficult to image because of its thin wall, asymmetric geometry and complex motion. DENSE is a quantitative MRI technique for measuring myocardial displacement and strain at high spatial and temporal resolutions ,2. DENSEWhole heart 3D cine DENSE data were acquired from two normal volunteers, after informed consent was obtained and in accordance with protocols approved by the University of Virginia institutional review board. The endocardial and epicardial contours were manually delineated to identify the myocardium from surrounding anatomical structures. A 3D spatiotemporal phase unwrapping algorithm was used to remove phase aliasing , and 3D Figure This work presents 3D motion tracking and strain quantification of the RV at a previously unattainable spatial resolution."} +{"text": "There were errors in Figure 1 and Figure 3. The correct Figure 1 can be viewed here: . The correct Figure 3 can be viewed here: Insectivorous birds, the scientific name for the Mariana Swiftlet is listed incorrectly twice in the following sentences:In the Materials and Methods section, under the heading Aplonis opaca), and the Marianas Swiftlet . Aplonis opaca has a localized remnant population of less than 400 birds covering an area of less than 50 km2, and Acrocephalus luscinia has remnant populations numbering around 1100 in three caves in Southern GuamOnly two of the 10 native insectivorous forest bird species remain on Guam: the Micronesian Starling (Aerodramus bartschiThe correct name is"} +{"text": "Rapid 3D-Prototyping is an established technique that converts digital image data of any 3D structure to a physical 3D model. It has been used for a long time in industry for making prototypes of any new products. The state-of-the-art medical imaging facilities such as computed tomography and magnetic resonance imaging (and possibly echocardiography in the future) provide precise digital information of the cardiovascular structures of the human body. The digital information can be used for production of multiple replicas of the human body parts with solid or flexible materials. Virtual visualization of 3D information in the computer screen has revolutionized medical imaging in the last 10-20 years. Although virtual visualization facilitates understanding, it does not allow direct contact or manipulation on the physical model. 3D prototyping of the replicas certainly allows direct visual access to the physical structures and more importantly direct physical manipulation such as practice surgery on the replica of the structure to be operated. The models are excellent teaching materials to all involved in cardiac imaging or surgery. Production of 3D prototypes of various pathologic conditions is even more important as there has been increasing restrictions to keeping human body parts for teaching as well as clinical purposes and pathologic specimens are available only when they are removed at surgery or at autopsy.Rapid 3D-Prototyping is an established technique that converts digital image data of any 3D structure to a physical 3D model. It has been used for a long time in industry for making prototypes of any new products.The state-of-the-art medical imaging facilities such as computed tomography and magnetic resonance imaging (and possibly echocardiography in the future) provide precise digital information of the cardiovascular structures of the human body. The digital information can be used for production of multiple replicas of the human body parts with solid or flexible materials.We have experienced the utility of 3D plastic models in preoperative assessment of the cases with double outlet right ventricle in the last two years,and are convinced that this technology should be further expanded for the following purposes:1)To produce heart models for simulations of surgical procedures in patients with complex surgical anatomy.2)To produce simulated phantoms of various surgical pathways such as Fontan circuit and right ventricle-to-pulmonary artery conduit for assessment of flow through complicated surgical pathways.3)To produce a collection of teaching models for normal and pathological cardiovascular anatomy.4)To develop a technique of image fusion for complete prototyping by using data from multiple imaging modalities.Virtual visualization of 3D information in the computer screen has revolutionized medical imaging in the last 10-20 years. Although virtual visualization facilitates understanding, it does not allow direct contact or manipulation on the physical model. 3D prototyping of the replicas certainly allows direct visual access to the physical structures and more importantly direct physical manipulation such as practice surgery on the replica of the structure to be operated."} +{"text": "Children with moderate/severe Eczema frequently develop sensitisations to several foods leading to specific elimination diets. A positive test to nuts is often considered a potential risk for anaphylaxis. Dietary restriction and a constant fear of potential anaphylaxis has a significant impact on patients of life. Component Resolved diagnosis is not yet widely available in the UK and despite the numerous recent publications in the field the experience in clinical practice remains limited in our population. We have recently introduced this methodology in the evaluation of patients attending our paediatric allergy clinic modifying our diagnostic decision pathway by incorporating the results of these new specific component IgEs. Previously some cases would not have been challenged based on published positive predictive values. We report here our 6 months experience with the use of Ara-h2 and Cor-a8 in the evaluation of children with a positive allergy test to nuts.Amongst all the children investigated 12 mean age 10.5 (range 2-14) tested negative for Ara h2 and or Cor a8. On the bases of the negative test results all underwent food challenges with Peanut and or hazelnut despite having a positive SPT and/or specific IgE to these nuts. All of these children passed a supervised graded challenge with up to 15 grams of the nut as per validated protocols.Eight children had positive allergy test to peanut (mean SPT diameter 4.5mm - range 2-7mm). Eight children had positive Specific IgE to Hazelnuts 4 of them had positive SPT. Post challenge all the 12 children were able to reintroduce the nuts uneventfully in their diet.A mini food allergy quality of life questionnaire was performed pre/post challenge demonstrating a significant improvement in quality of life. Our observation is limited by the very small number of patients involved nevertheless it underlines the usefulness of component resolved diagnosis in the investigation of patients with food allergy."} +{"text": "Cardiovascular disease risks have been documented for active smoking exposures at the higher end of that continuum and for environmental tobacco smoke and ambient air pollution exposures at the lower end. However, there is a distinct lack of information on the cardiovascular risks of exposures in the middle range, which are experienced by hundreds of millions of people who burn biomass and coal indoors. A new commentary analyzes the implications of this crucial knowledge gap .Researchers have examined the effects of fine particulate matter similarly indicated that small PM2.5 dose reductions in populations with relatively low levels of exposure may achieve greater health gains than more drastic reductions in populations with high levels of exposure. Comparing a theoretical population of smokers with the same number of nonsmokers living in a heavily polluted city, this suggests similar numbers of cardiovascular deaths\u2014or possibly more\u2014may be prevented in the nonsmokers by adopting strict ambient PM2.5 reduction measures than by convincing the smokers to quit smoking. This counterintuitive idea could have major policy ramifications, so the authors urge further examination of these relationships.Analysis of three intermediate estimated PMThe gap in studies of exposures greater than those from ETS but less than those from active smoking reflects a dose range of 1\u201320 mg/day. Filling in the missing information for this gap should receive research priority, the authors write, because of the potentially large cardiovascular disease health burden it represents, particularly for the people worldwide who burn biomass for household cooking and heating."} +{"text": "According to the World Health Organization, about 2 billion persons worldwide have been infected with hepatitis B virus (HBV). More than 350 million are chronically infected worldwide with a high risk of developing liver cirrhosis and hepatocellular carcinoma (HCC) (representing 1 million deaths per year). The epidemiology of HCC is peculiar with both geographic and temporal patterns of incidence paralleling exposure to viral etiologic factors. The highest HCC incidence rates are areas endemic for chronic infection with hepatitis B virus (Asia and Africa). Based on sequence divergence in the entire genome of >8%, HBV genomes have been classified into eight groups designated from A to H. The genotypes of HBV have distinct geographical distributions. Although preliminary clinical studies seem to indicate that there is an association between HBV genotype and natural history of infection and/or response to antiviral therapy, further evaluations on larger collectives of patients are necessary to give a clearer picture of the subject. The first paper of this special issue addresses the aetiology and picture of CTNNB1 and TP53 mutations in Thailand patients with HCC and provides a detailed study of the situation in an Asian country. The second paper presents the study on the etiology and viral genotypes in Colombia; these data are not common with South America. The two subsequent papers address the question of HBV variability and HCC in two different countries and continents. Indeed, the third paper is on TP53 mutations and HBx gene of hepatitis B virus status in HCC in Iran. It is bringing interesting discussion about the potential link between HBV genotypes and TP53 mutation R249S. The fourth paper of this special issue presents a fully picture of viral hepatitis viruses and TP53 mutations in HCC from Columbia. The fifth paper describes the evolution of HBV \u201cquasispecies\u201d in a chronic HBV chronic carrier over a 2-year period. The final paper of this special issue proposes an original study on the importance of HBV variability on RNAi strategies.Isabelle CheminIsabelle CheminHel\u00e9ne NorderHel\u00e9ne NorderPatrick SoussanPatrick SoussanRunu ChakravartyRunu Chakravarty"} +{"text": "The advent of combination antiretroviral therapies has altered the clinical course of HIV infection such that successful suppression of HIV replication typically results in sufficient restoration of immune function to protect most patients from the opportunistic complications that have defined AIDS. Yet a substantial proportion of treated HIV infected persons fail to increase circulating CD4 T cell counts to \"normal\" levels and a failure of CD4 T cell restoration predicts increased an increased risk of life threatening events that include malignant, hepatic and cardiovascular morbidities. Recent work suggests that the drivers of immune deficiency and \"non-AIDS\" complications of HIV infection may be intimately linked and in both settings, immune activation and inflammation are central. To this end, we have accused both HIV and the translocation of microbial elements from the damaged gut as drivers of both progressive CD4 T cell depletion and an increased tendency to coagulation and thrombosis formation in HIV infection. The Cleveland Immune Failure (CLIF) study was designed to explore the characteristics and potential drivers of disease pathogenesis among HIV infected persons who failed to achieve robust CD4 T cell increases despite successful suppression of HIV replication with combination antiretroviral therapy. In this study, we find evidence that immune activation, inflammation and increased thrombosis persist even in the setting of \"complete\" control of HIV replication and propose that this is not related to ongoing HIV replication but more likely to translocation of microbial products from the damaged gut."} +{"text": "I read with great interest the recent paper by Ji and Shen . BerberiBerberine inhibits the activation of nuclear factor kappaB by blocking the \u201cmitogen-activated protein kinase\u201d pathway . SimultaThe above examples clearly illustrate the emerging role of berberine in psychiatry and the need for further studies in this regard."} +{"text": "Risk factors for cardiovascular disease including diabetes have seen a large rise in prevalence in recent years. This has prompted interest in prevention through the identifying individuals at risk of both diabetes and cardiovascular disease and has seen increased investment in screening interventions taking place in primary care. Community pharmacies have become increasingly involved in the provision of such interventions and this systematic review and meta-analysis aims to gather and analyse the existing literature assessing community pharmacy based screening for risk factors for diabetes and those with a high cardiovascular disease risk.We conducted systematic searches of electronic databases using MeSH and free text terms from 1950 to March 2012. For our analysis two outcomes were assessed. They were the percentage of those screened who were referred for further assessment by primary care and the uptake of this referral.2 and p values to describe heterogeneity. We found that all included studies suffered from high rates of attrition between pharmacy screening and follow up. We have also identified a strong trend towards higher rates for referral in more recent studies.Sixteen studies fulfilled our inclusion criteria comprising 108,414 participants screened. There was significant heterogeneity for all included outcomes. Consequently we have not presented summary statistics and present forest plots with IOur results show that pharmacies are feasible sites for screening for diabetes and those at risk of cardiovascular disease. A significant number of previously unknown cases of cardiovascular disease risk factors such as hypertension, hypercholesterolemia and diabetes are identified, however a significant number of referred participants at high risk do not attend their practitioner for follow up. Research priorities should include methods of increasing uptake to follow up testing and early intervention, to maximise the efficacy of screening interventions based in community pharmacies. Globally, the prevalence of type 2 diabetes (T2DM) and risk factors for cardiovascular disease (CVD) have seen an upward trend in recent years In 2008 CVD was the primary cause of 17.3 million deaths worldwide and like diabetes, this is expected to rise dramatically to 23.6 million by 2030 The increasing prevalence of T2DM and CVD has seen increased healthcare expenditure focussing on disease detection and early intervention to delay progression and the onset of complications. In both the United Kingdom (UK) and in the United States (US), guidance has been introduced to encourage vascular risk assessment including T2DM risk in adults aged 40 and above. Economic evaluation has shown that screening for T2DM is cost effective and may be cost saving from a health system perspective The vast majority of research in this area thus far has focussed on practice based screening to identify high risk patients to invite for testing. A number of simple risk assessment tools have been developed to pre-screen large numbers of individuals and target high risk individuals with invasive blood tests Community pharmacists are already actively involved in the management of T2DM and CHD and their involvement has shown beneficial effects in patient education and disease management Pharmacists are ideally placed to support existing screening methods by signposting customers to other services run by pharmacy staff for example smoking cessation. Smoking is cited as one factor in reduced health outcomes in groups with higher deprivation Almost a decade ago the paucity of research in the area of pharmacist initiated disease detection and case finding was identified by a review of the literature The purpose of this systematic review is to evaluate current literature focussing on pharmacy based screening interventions for T2DM and CVD. We will evaluate response rates to pharmacy based screening as well as numbers of people either diagnosed or defined as \u2018high risk\u2019 by a pharmacy risk assessment or screening test in order to quantify the level of success of opportunistic pharmacy led screening interventions to better inform the design and delivery of future services.We searched the Cochrane central register of controlled trials, MEDLINE and EMBASE databases from 1950 until April 2012. The search strategy comprised of four layers of search terms relating to T2DM, CVD, pharmacy and screening programmes. Keywords and medical subject headings were used to identify papers reporting uptake or yield of screening programmes, with the first phase of screening taking place at pharmacies. No language restrictions were used in the selection of papers. An example of the review protocol and electronic search strategy used can be found in the online appendix. Studies were reviewed at the title, abstract and full text stage by two independent reviewers (AW and PR), disagreements were resolved through discussion and third party advice from other co-authors was sought where necessary. Authors from the selected full texts were contacted by post and email to provide any missing data relating to the main outcomes considered.We included studies screening people for either T2DM or CVD, whereby the first contact made between the participant and healthcare professional was in a community pharmacy. We defined CVD screening as either calculation of CVD risk based on a validated scoring algorithm or measurement of blood pressure, lipids or triglyceride levels.T2DM screening was defined as calculation of diabetes risk based on a validated scoring algorithm or assessment of known risk factors or measurement by a pharmacist of; blood or plasma glucose (either fasting or non-fasting), HbA1c, or any combination of the aforementioned methods.Risk of bias was assessed independently by two reviewers using the US Preventive Services Task Force (USPSTF) Quality Rating Criteria Two main outcomes were assessed namely i) referral rate to primary care and ii) the uptake to the primary care referral. The referral rate was defined as the number referred divided by the number screened. Uptake was defined as the number attending their general practitioner divided by the number referred.The log odds of referral were calculated as ln(number referred/(number screened-number referred)) with standard error \u221a((1/number referred)+(1/number screened-number referred)). Similar formulae were used for the uptake. We also calculated pooled rates for percentage of the screened population who exceeded cut offs for hypertension, hypercholesterolemia and T2DM. The log odds were pooled using a random effects model to take into account heterogeneity between studies. Outcomes were back transformed by taking exponentials and reported as mean referral and uptake rates with 95% confidence intervals. Analysis was carried out in Stata (version 12).16 individual studies were included in this review All except two of the studies were observational Eleven studies were graded as good Significant heterogeneity was found for both main outcomes (p\u200a=\u200a<0.001), we have therefore presented forest plots showing the two main outcomes reported by the included studies with 95% confidence intervals. We have not presented the calculated summary statistics due to the significant heterogeneity. This is in accordance with previously published guidance 2 statistic showed statistically significant heterogeneity for both outcomes with I2 greater than 75% in all analyses.The percentages of individuals who exceeded diagnostic cut offs for hypertension, hypercholesterolemia and T2DM during a pharmacy based test are shown in Referral cut points for CVD risk factors varied slightly between studies. A blood pressure cut point of \u2265140/90 mmHg was used by the majority of studies Cholesterol cut points used were similar between studies, 3 of the included studies used a cut point for total cholesterol of 200 mg/dl Follow up data from GP confirmatory testing was not routinely reported. Only one study reported data on prevalence of T2DM, impaired glucose tolerance or impaired fasting glucose defined by WHO diagnostic criteria. Krass et al report 2.1% of the screened population subsequently diagnosed as having either Impaired glucose regulation or impaired fasting glucose based on a fasting or random blood test followed by confirmatory oral glucose tolerance test. The same study reported screen detected prevalence rates of 0.2% and 1.7% from the two trial arms Overall, our analysis and results show that typically, less than half of people who take part in studies based on opportunistic recruitment to pharmacy screening for cardiovascular disease risk factors are referred to their general practitioner for a follow up appointment. A significant proportion are not followed up or do not attend their general practitioner.We found evidence of a strong trend towards higher rates of referral in more recently published studies. There was a very high level of heterogeneity for both of these outcomes with values for referral rate ranging from 6.05%\u201373.13% and values for percentage take up of this referral ranging from 12.81\u201383.12%. This heterogeneity could have been caused by a number of factors. It is likely that different methods of measurement of uptake to referral accounted for a significant proportion of the variability.From a health economics perspective higher drop-out rates could increase the cost per case detected from screening interventions The rates reported for the percentage of individuals exceeding diagnostic criteria for: hypertension, hypercholesterolemia and/or diabetes from pharmacy based screening interventions are typically higher than rates for overall diagnosed prevalence of these risk factors. Prevalence of CVD risk factors amongst pharmacy customers is likely to be higher than the general population as a majority will be attending to collect medication for a condition. Data from a UK study It is difficult to compare data on referral and uptake with findings from previous literature. Response rates to a postal invitation to a GP based screening programmes are generally high Comparison is possible between pharmacy and GP initiated screening when considering the percentage of screened participants attending a follow up test. One previous GP initiated T2DM screening intervention reported a 94% uptake of confirmatory testing and 70% of participants completing the screening overall The finding that more recent studies reported a higher percentage of referrals following a screening appointment is perhaps not surprising. The rising global prevalence of CVD risk factors such as obesity The main strength of our study was the use of robust search, review and meta-analysis methods to provide an assessment of the past level of success of previous pharmacy initiated screening interventions. We have also identified a key weakness in past screening interventions which be given greater consideration in the design of future studies.The main weakness of this review and meta-analysis was due to the heterogeneity in selected outcomes. As a result of this, we were unable to calculate and present summary statistics. Research in the area of community pharmacy is sparse, poorly reported and typically of relatively poor methodological quality. It is possible with an increased number of screening interventions in the future which are well evaluated and properly reported; future meta-analysis may have more success in calculating pooled rates which may be of greater use in informing the planning of future interventions.One other potential weakness in our analysis results from the way in which the outcomes included in the meta-analysis were measured. In general, the included papers were of sound methodological quality; however, both of our main outcomes were themselves not major outcomes in any of the included studies. Subsequently there was variation in the method of measurement used. Preferred method of reporting for this outcome was through direct access to practice based medical records following a pharmacy referral. This method was reported in only two of the included studies The results of this study highlight a need for improvement in the implementation of opportunistic pharmacy based screening programmes in order to minimise the drop out of referred patients. The level of drop out from screening programmes for T2DM and CVD risk factors represents a significant waste of investment. Screening interventions delivered by community pharmacists have the potential to increase ease of access to screening in order to reduce health inequalities particularly in the area of T2DM and CVD.The findings of this review show that previous studies of opportunistic pharmacy based screening interventions have been successful in identifying a significant proportion of the population, both suffering from and at high risk of CVD orT2DM. We have shown that more recent screening strategies have identified a higher number of high risk individuals referred to their practitioner for follow up. However the review has also shown that a high proportion of those individuals found to be at high risk of CVD or T2DM do not attend a follow up appointment with their practitioner.It is vital that future screening interventions are designed to minimise this drop out in order to maximise both the financial and health related gains from increased investment and interest in future screening interventions in pharmacies worldwide.Checklist S1PRISMA Checklist.(DOC)Click here for additional data file."} +{"text": "Fasciola hepatica infection\" published in BMC Immunology . The text and figures in this article [The authors would like to retract the article \"The absence of MyD88 has no effect on the induction of alternatively activated macrophage during nology 201, 12:63."} +{"text": "In the second to last sentence of the abstract, the first instance of IHPSS should read EHPSS. The sentence should read: \"...these findings may indicate a causative role for VCAM1 in EHPSS and WEE1 for IHPSS.\""} +{"text": "Although the etiology of varicose veins remains unknown, recent studies have focused on endothelial cell integrity and function because the endothelium regulates vessel tone and synthesizes many pro- and anti-inflammatory factors. The aim of this study was to investigate the evidence involving the endothelium in the development of varicose vein disease. In addition, tissue remodeling was investigated in varicose veins to determine the expression of different types of collagen. Tissue specimens of superficial varicose veins and control saphenous vein were used for immunohistochemical and transmission electron microscope (TEM). \u03b1-smooth muscle actin, and collagen I, III, IV antibodies were applied for immunohistochemical investigation. Findings of this study showed alterations of the intima, such as focal intimal discontinuity and denudation of endothelium; and the media, such as irregular arrangements of smooth muscle cells and collagen fibres in varicose veins. Our findings showed some changes in terms of distribution of types I, III and IV collagen in the intima and media of varicose vein walls compared with controls. These alterations to the media suggest that the pathological abnormality in varicose veins may be due to the loss of muscle tone as a result of the breakup of its regular structure by the collagen fibres. These findings only described some changes in terms of distribution of these types of collagen in the intima and media of varicose vein walls which may result in venous wall dysfunction in varicosis. Varicose vein disease is a disorder of the lower extremities characteAlthough endothelial cells are able to synthesize basement membrane and interstitial collagen, the principal source of collagen in the vessel wall is the smooth muscle cell. Alteration of smooth muscle cells behaviour from quiescent or \u201ccontractile state\u201d typical of the normal vessel phenotype to a proliferative or \u201csynthetic state\u201d characteristic of the atherosclerotic phenotype increases collagen synthesis .vasa vasorum and nerve fibres in the adventitia undergoing long saphenous vein harvesting for coronary artery bypass grafting at the Shahid Modarress Hospital in Tehran, Iran. All patients had some degree of high blood pressure, atherosclerosis and heart disease. Tissue specimens were obtained from 20 patients with superficial varicose veins, undergoing surgery for varicose veins at the Wharfedale General Hospital at Otley. The diagnosis of primary varicose veins was made by the referring surgeon and confirmed by venous duplex scanning. These were defined as clinically evident varicose veins, CEAP grade 3 or above. Appropriate ethical approval and informed consent was obtained in all cases.ImmunohistologyControl and patient saphenous vein was snapped frozen in OCT then 5\u03bcm frozen sections were cut using a Cryostat (LEICA CM 1800), placed onto Poly-L-Lysine (0.1%) (Sigma-Aldrich Company Ltd. UK.) coated slides, and used for immunohistochemical analysis. Immunostaining was carried out as described previously ,23. The Electron Microscopy For electron microscopy the tissue was washed with PBS and then cut into blocks no bigger than 1mm3 . Preparation of sections was carried out as describedpreviously ,25. The ImmunohistologyExpression of \u03b1 -Smooth Muscle Actin\u03b1-SMA antibodies were used to demonstrate the presence of smooth muscle cells. All of the smooth muscle layers in the veins reacted strongly with \u03b1 -SMA. The individual smooth muscle bundles were completely separated and located close to the intima in all of the control saphenous vein specimens. Longitudinal (LM) and circular (CM) smooth muscle bundles in the media were recognisable in thirteen (65%) varicose vein specimens. The LM and CM bundles were not distinguished in seven (35%) varicose veins specimens as separate bundles when compared to other varicose and control saphenous vein specimens .The inneTypes I, III and IV collagenIntensive staining of type I collagen was seen in the subendothelial region of 9 of 20 specimens (45%) of varicose vein. Less intensive staining was seen in the rest of vein wall in the same specimens . A furthDistribution of type III collagen in 3 (15%) varicose vein specimens showed weak staining in the media. In all control saphenous vein, the immunostaining of type III collagen was scattered between smooth muscle cells beneath the endothelial cell layer . Immunolocalisation of type III collagen was found in the subendothelial layer of all varicose vein specimens (100%) and in the media and the adventitia of 16 specimens (85%) Table1)Table1).Type IV collagen staining of control and variIn all the specimens of control and varicose vein (100%), strong staining of type IV collagen was detected in the intimal, medial and adventitial layers. Excepting the intimal layer which stained strongly with type IV collagen, the appearance of type IV collagen staining in the media and the adventitia of all control saphenous vein specimens was the same as \u03b1-SMA staining and demonstrates intact basement membrane around the smooth muscle cells in those areas .Electron microscopyTransmission electron microscopical investigation identified changes in the varicose vein structure compared with control samples. Ultrastructural examination of 3 varicose vein specimens (15%) showed that elastic fibres were as thick as the internal elastic lamina in some areas, in which contrasts with the rest of varicose vein specimens which no internal elastic lamina was detected. In 17 out of 20 (85%) specimens of control saphenous vein an inter Ultrastructural examination of the tunica media in the varicose vein showed disorganization of smooth muscle cells close to the intima in 17 (85%) specimens when compared with normal organized arrangement of smooth muscle cells in 18 (90%) of control saphenous vein specimens. Smooth muscle cells in the control saphenous vein specimens were more closely arranged and showed their regular sheet-like organisation when compared with those varicose vein tissues which showed wide separation of the smooth muscle cells by an increased amount of extracellular matrix and variable bands of collagen fibres .The smooth muscle cells close to the adventitia in 15(75%) varicose vein specimens were not arranged closely and regularly when compared with organisation of smooth muscle cells in the same area in 18 (90%) of control saphenous vein specimens. In two specimens of control saphenous vein (10%) disarrangement of smooth muscle cells close to the adventitia was identified. An accumulation of collagen fibres filled the space between the smooth muscle cells in the media of 16 (80%) varicose vein specimens. These fibres were arranged more irregularly when compared with regularly organized collagen fibres in control saphenous veins . In somevasa vasorum and collagen fibres. The smooth muscle cells in the adventitia of 19 (95%) varicose vein specimens were separated by collagen fibres not as closely packed as in the control saphenous vein. There were no significant differences between the varicose vein and the control specimens with respect to the pattern of endothelial cells and smooth muscle cells in vasa vasorum.The adventitia in varicose and control saphenous veins consists of smooth muscle cells, One of the strongest arguments for varicose vein wall changes is based on the changes observed in the composition of the connective tissue of the varicose vein wall. In the present study, immunostaining showed that bundles of longitudinal and circular smooth muscle cells in all of the control saphenous veins were completely separated, whereas, only in 65% of varicose vein specimens could smooth muscle bundles be recognised in the media. Moreover, among the specimens of varicose veins which show separated longitudinal and circular bundles of smooth muscle cells in the media, the thickness of each bundle appeared to be varied in different parts of the vein wall. This finding confirmed the observation of St\u00fccker et al. that the layer size of circularmuscle in the media was reduced in parts of varicose veins but the staining was weak. Our findings which showed strong staining of type III collagen in both the subendothelial and medial layers compared with type I collagen in varicose veins, do not quantify the level of collagens. Other investigators have quantified the overproduction of type I collagen and decreased production of type III collagen in varicose veins compared with control saphenous veins ,21 35-3-335-37. Our results using both light and electron microscopy studies confirm significant alterations of morphology of the media of varicose veins when compared with control saphenous veins. In addition, collagen fibres were distributed more irregularly in most varicose vein specimens when compared with the regularly organized collagen fibres in the majority of control saphenous veins. These alterations in the distribution of pattern of type collagen to the media suggest that the pathological abnormality in varicose veins may be due to the loss of muscle tone as result of the breakup of its regular structure by the collagen fibres. These findings only described some changes in terms of distribution of these types of collagen in the intima and media of varicose vein walls compared with controls which may result in venous wall dysfunction in varicosis."} +{"text": "There were a number of errors in the y and x axis labels for panels C and D of Figure 1 \"Intraperitoneal insulin tolerance test on Swiss mice and effect of db/db and Swiss conditioned medium (CM) proteins on the in vitro glucose uptake.\" Please see the corrected Figure 1 here:"} +{"text": "Dear Editor,We read with interest the article by Rimaz and coworkers about the beneficial effect of preoperative oral administration of a high single dose 1200 mg) of gabapentin on postoperative pain scores and morphine consumption in patients undergoing surgical debridement of burn wounds 200 mg of. However"} +{"text": "Modeling the mechanisms of astrocytic calcium signals is important, as astrocytes have an essential role in regulating the neuronal microenvironment of the central nervous system ,2. The rWe here study the effect of SERCA pumps and IP3 sensitivity on calcium signals in astrocytes by further exploring the existing deterministic and stoc"} +{"text": "Dear Editor,The report by Yadav et al. concerned 12 patients with abscesses within the prostate which were treated with transrectal ultrasound (TRUS) guided needle aspiration intermittent drainage instead of pure aspiration may have been a more appropriate treatment approach. However, this decision has to be made with consideration of all the patient\u2019s clinical aspects at the time of admittance. Regardless of the intervention a 4-week antibiotic treatment according to the microbiology results is common standard practice."} +{"text": "Direct aortic approach is an attractive alternative technique for transcatheter aortic valve implantation in challenging patients. We report a brief description of this surgical technique and the short term results of our first series.Our group consisted of 35 inoperable patients presenting aortic valve disease unsuitable for transfemoral valve implantation due to extreme peripheral vessel disease. Data were prospectively collected and retrospectively analysed. Using an upper-J mini sternotomy access to the third intercostal space the ascending aorta was exposed. After placing two purse-strings on the ascending aorta at least 7 cm above annulus, the delivery system was inserted and advanced under fluoroscopy to the optimal position and the valve was deployed.Mean age of the patients was 77 years old, mean logistic EuroScore 27 %. Evaluation of the results in these 35 patients treated with the Direct Aortic Approach was made according to the Valve Academic Research Consortium consensus criteria. These include device success endpoints and combined safety endpoints at 30 days. Device success was achieved in 94% of the patients. All cause mortality was 9% at 30 days. One major stroke (3%) and one life threatening bleeding occurred (3%). Pacemaker implantation rate was 9%. The evaluation of the combined efficacy endpoints at 1 year has not been completed yet.These results represent the initial experience of a single centre after adopting the direct aortic approach for TAVI as alternative to the transfemoral route. It is less invasive, fast and safe and can be performed with acceptable mortality and morbidity in high risk patients.Due to the short distance between access point and aortic annulus the positioning of the valve is believed to be more accurate than alternative access route like the transfemoral approach."} +{"text": "Sparse coding accounts for several physiological properties of primary visual cortex V1), including the shapes of simple cell receptive fields and the highly kurtotic firing rates of V1 neurons , includi and sparHere we show that adding a separate population of inhibitory neurons to a recently proposed model of V1 not only"} +{"text": "The use of Chinese Hamster Ovary (CHO) cells for transient gene expression is gaining importance steadily, as it has been shown that both quality and quantity of proteins derived from CHO cells differs from and can even be superior to material derived from Human Embryonic Kidney (HEK293) cells -4. In orAn expression plasmid featuring the EBNA1 gene was transfected into an in-house available CHO wild type cell line by nucleofection and several stable pools were established by antibiotic selection. In a first approach, 133 clones were then isolated by limiting dilution cloning and subsequently expanded for further analysis. The approach aimed at identifying clones showing both the presence of EBNA1 protein and enhanced yields after PEI-mediated transient expression of a reporter protein at the same time.Cell lysates or nuclear and cytoplasmic protein extracts from these clones were tested for presence of EBNA1 protein by Western Blot. An in-licensed cell line, CHO EBNALT85 expressing the full length EBNA1 gene, and the HEK293-6E cell line expressing a truncated EBNA1 gene served as positive controls. A number of commercially available anti-EBNA1 antibodies were tested in Western blotting, but most antibodies failed to detect the EBNA1 protein produced by these positive control cells. Only one antibody was identified that detected the EBNA1 proteins in both positive control cell lines.However, by applying this antibody on the 133 generated clones it became obvious that in most of them the EBNA1 protein appeared to be largely degraded.The functionality of the EBNA1 protein in the cells was probed by PEI-mediated transient transfection of expression plasmids encoding the gene for the reporter protein Secreted Alkaline Phosphatase (SeAP). SeAP expression levels were compared with respect to presence or absence of the EBNA1 interaction sequence oriP on the SeAP expression plasmid. Only one clone showed a twofold enhanced production level of the reporter protein compared to the non-engineered parental CHO cell line. However, in this specific clone no EBNA1 protein could be detected by Western Blot, and the enhanced expression level was independent from the presence or absence of the oriP sequence on the SeAP expression plasmid. We therefore conclude that this clone does not possess a functional EBNA1 protein and an EBNA1/oriP based enhancement of productivity. The mechanism underlying the enhanced yield of the reporter protein in this particular clone remains currently elusive.In an alternative approach flow cytometric cell sorting was applied to generate CHO clones producing a functional EBNA1 protein. Using the EBNA1 positive CHO cell line CHO EBNALT85 it could be shown that expressing eGFP from a transiently transfected expression plasmid with oriP sequence resulted in a 30- to 40-fold increase of highly fluorescent cells in comparison to an expression plasmid lacking the oriP sequence.Thus, the already generated CHO pools stably transfected with the EBNA1 gene were transiently supertransfected with an eGFP expression plasmid containing the oriP sequence. Highly fluorescent cells were collected by cell sorting and expanded. Analysis by Western Blot revealed that this sub-pool was enriched for cells exhibiting the presence of a full length EBNA1 protein besides a major breakdown product. Transient transfection of this sub-pool with SeAP expression vectors led to the conclusion that the pool contained cells with a functional EBNA1 protein capable of enhancing SeAP yields in dependence on the presence of the oriP sequence on the SeAP expression plasmid. Clones were again generated from this sub-pool by limiting dilution cloning and characterized in analogy to the first approach. 9 out of 12 clones that were analyzed further showed increased levels of reporter protein production in dependence on the presence of the oriP element on the expression plasmid. The series of clones exhibiting highest expression levels will now be further evaluated by expression of other protein candidates."} +{"text": "Introduction. Sinus lift procedures are a commonly accepted method of bone augmentation in the lateralmaxilla with clinically good results. Nevertheless the role of the Schneiderian membrane inthe bone-reformation process is discussed controversially. Aim of this study was to prove thekey role of the sinus membrane in bone reformation in vivo. Material and Methods. 14 patients were treated with the minimal invasive tHUCSL-Intralift, and 2\u2009ccm collagenoussponges were inserted subantrally and the calcification process followed up with CBCT scans4 and 7 months after surgery. Results. An even and circular centripetal calcification under the sinus membrane and the antral floorwas detected 4 months after surgery covering 30% of the entire augmentationwidth/height/depth at each wall. The calcification process was completed in the entireaugmentation volume after 7 months. A loss of approximately 13% of absolute augmentationheight was detected between the 4th and 7th month. Discussion. The results of this paper prove the key role of the sinus membrane as the main carrier ofbone reformation after sinus lift procedures as multiple experimental studies suggested. Thusthe importance of minimal invasive and rupture free sinuslift procedures is underlined anddoes not depend on the type of grafting material used. Although subantral augmentation procedures (Sinus lifting) can be considered as an established and highly successful method to multiply bone prior to implant insertion into the lateral maxilla site, the biological mechanisms of subantral bone regeneration are still focus of controversial scientific discussions.While in the eighties and nineties of the past century the discussion on graft material inserted subantrally focused on free autologous bone grafts the mainstream research turned over to heterologous, allogenic, xenogenic and synthetic bone graft materials.Concerning free autologous bone grafts most questions were already answered in the late sixties of the past century by Scandinavian scientists.Puranen proved fThe key role of the periosteum in bone healing and regeneration was proven in other disciplines of medicine for quite a time \u20135 and waLundgren et al. 2004 fouVital periosteum alone initiates bone regeneration and production in absence of any calcified structure or the presence of osteocytes needing only a stable blood coagulum as Srouji et al. were able to prove .Based on the knowledge of the superior atraumaticity of ultrasonic surgery , 13 and The aim of the present study was to verify in vivo the postulated bone regeneration capabilities of the periosteum of the Schneiderian membrane in patients treated with the tHUCSL-Intralift by detecting the origins of the calcification process radiographically on macroscopical level.Within a multicenter study on the success rates of the tHUCSL-Intralift using various radiopaque bone graft materials for subantral augmentation, 14 patients at an average age of 52\u2009yrs (\u00b116\u2009yrs) were selected with vastly pneumatized sinuses on the right side and remaining subantral alveolar crest heights of 4\u2009mm or less. Instead of radiopaque bone graft material only, a radiolucid collagenous sponge of a stable and defined volume of approximately 2\u2009ccm was inserted subantrally to radiographically follow up the origins of new bone growth and calcification processes in CBCT scans to indirectly verify the findings by Lundgren et al. , 10 in hSinus lift surgery on the right maxillary sinus was performed according to the strict tHUCSL-Intralift protocol.The subantral alveolar crest was revealed by either a single or dual 6\u2009mm diameter gingival punch or an 6\u2009mm rectangular top crestal mucoperiosteal flap . A pilotThe sinus floor was opened with the diamond-coated atraumatic TKW 2-ultrasonic tip followedThe sinus membrane then was atraumatically separated from the antral bone with the hydrodynamic ultrasonic cavitational applicator TKW 5 at a floOnce the elevated sinus-membrane was verified to float free and unperforated/unruptured in the traditional unilateral Valsalva check, a form stable radiolucent collagenous sponge of approximately 2\u2009ccm at the entrance site of the Intralift procedure measured intraoperatively.CBCT scans after 4 months revealed an average achieved augmentation height of 16,3\u2009mm in the transversal slides and 16,8\u2009mm in the sagittal slide which was reduced to an average of 14,6\u2009mm in the transversal slides and 14,7\u2009mm in the sagittal slides after 7 months .The calcification process under the sinus-membrane radiologically showed an even centripetal circular distribution under the sinus-membrane and on the antral bone base with calcified tissue thicknesses of 3,6\u2009mm to 4,3\u2009mm .After a healing period of 7 months all CBCT scans showed a completion of the calcification process in the augmented subantral volume except some randomly distributed minor radiolucent spots/areas thus not allowing a precise distinction for measurement between noncalcified areas and calcified tissue .The mean loss of absolute augmentation height of calcified tissue in the CBCT scans between 4 months and 7 months after surgery was 1,9\u2009mm resulting in a final mean overall height of calcified tissue for implant insertion of 14,65\u2009mm .After 4 month approximately a third of the subantral augmented volume in each measurement position related to the total width/height/depth of the augmentation was presented as calcified tissue in the CBCT scans . No precAll patients were successfully treated with two-stage dental implants from various manufacturers after 8 months and prosthetic suprastructure after 11-12 months .Figures The radiological results of the present study confirm the experimental results published by Ortak et al. , LundgreNevertheless a volume stable subantral filling material is needed to stabilize the detached sinus membrane and formation of a blood coagulum in the upmost position to achieve sufficient augmentation heights and widths for implant insertion but the success of Sinus lift procedures does not seem to depend on the type of augmentation material used. The results of this study proved a form stable collagenous sponge to be sufficient in stabilizing the sinus-membrane above the achieved subantral augmentation volume as well as the resulting stable blood clot forming in the collagenous sponge.A general forensic drawback in using collagenous sponges in subantral augmentation procedures might be the inability to prove the successful Sinus lift immediately after surgery since in an OPG, a radiolucent sponge can hardly be detected and onlyIf the reduction of absolute augmentation height of an average of 2\u2009mm between the 4th and the 7th month subsequent surgery could be prevented by the use of calcified bone graft instead of a collagenous sponge still has to be further investigated by a similar study protocol but has to be taken into consideration in the daily routine to prevent finally insufficient augmentation heights when using radiopaque collagenous sponges. Compared to the results of the surgical technique reported by Lundgren et. al. the inseFurthermore the results of this study suggest that after an overall period of 7 months following minimal invasive transcrestal Sinus lift, the calcification process of the augmented subantral site seems to be completed in all cases even at augmentation volumes of 2\u2009ccm. Nevertheless this healing duration might not be applicable to lateral approach of sinus lift procedures or cases of iatrogenic puncture or minor ruptures of the sinus-membrane due to a vaster traumatization of the sinus-membrane and surgical site. This probably might result in longer bone formation and calcification duration due to healing processes and primary repair of the traumatized tissue before the bone formation and calcification process starts.Finally the authors generally suggest to more rely on the osteogenic potential of the periosteum \u20137 and mi"} +{"text": "Dog models with spontaneously occurring mutations in retinal dystrophy genes are an invaluable resource for preclinical development of retinal gene therapy. Adeno-associated virus (AAV) vectors have been most successful; to target the outer retina and RPE they are delivered by subretinal injection, causing a temporary retinal detachment with some potential for retinal morbidity. A recent reporter gene study using an AAV2/8 vector in dogs reported transgene expression beyond the boundary of the subretinal bleb. This could be a desirable feature which increases the area of retina treated while minimizing the retinal detachment and any associated morbidity. We performed a detailed study of the lateral spread of transgene expression beyond the subretinal injection site following subretinally delivered AAV vectors in normal dogs. Vectors expressed green fluorescent protein (GFP) using a small chicken beta-actin promoter. AAV2/2 capsid mutant), self-complementary (sc) AAV2/8 (single Y-F capsid mutant) and a scAAV2/5 were used. We found that in all eyes GFP expression involved retina beyond the initial post-injection subretinal bleb boundary. In all eyes there was post-injection spread of the retinal detachment within the first 3 days post procedure and prior to retinal reattachment. In 11/16 eyes this accounted for the entire \u201clateral spread\u201d of GFP expression while in 5/16 eyes a very slight extension of GFP expression beyond the final boundary of the subretinal bleb could be detected. All 3 AAV constructs induced GFP expression in the nerve fiber layer with spread to the optic nerve. Patients treated by subretinal injection should be monitored for possible expansion of the subretinal injection bleb prior to reattachment. Injections in the para-foveal region may expand to lead to a foveal detachment that may be undesirable. Cell-specific promoters may be required to limit spread of expressed transgene to the brain with these AAV serotypes. Rpe65 gene were pivotal in the development of phase I/II clinical trial programs for treatment of patients with mutations in the RPE65 gene, an important cause of LCA BEST1, CNGB3, rhodopsin, RPGR, PDE6A and PDE6BRetinal dystrophies such as the genetically heterogenous conditions Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are important causes of human vision loss vectors have become a favored gene delivery vehicle for the treatment of retinal dystrophies in both pre-clinical and clinical trials RPE65-LCA patients undergoing retinal gene therapy treatment may be detrimental Subretinal injection of AAV is used when transgene expression is required in the retinal pigment epithelium (RPE) or the photoreceptors. The subretinal injection creates a temporary bullous detachment, separating the photoreceptor outer segments from the RPE layer. Typically the subretinal injection bleb resolves over the following few days both in humans A recent study by Stieger et al. investigating subretinal injection of AAV2/8 expressing green fluorescent protein (GFP) in the dog showed there was spread of GFP expression to retina adjacent to the initial subretinal injection site as well as centrally along the optic nerve to the brain, with the suggestion of trans-synaptic transmission We performed a detailed study of the lateral spread of transduction beyond the initial boundary of the subretinal injection bleb using three different new generation AAV vectors. This showed that the vast majority of reporter gene expression beyond the initial boundary of the subretinal bleb was due to a continued detachment of the retina as the bleb flattened out over the first 3 days post injection.All procedures were in compliance with the ARVO statement for the Use of Animals in Ophthalmic and Vision Research and approved by the Michigan State University Institutional Animal Care and Use Committee .Recombinant AAV vectors were manufactured and purified by previously described methods Eight normal young adult male laboratory beagle dogs were used.11 vg/ml, the injection volume was 250 \u00b5l and the injections were made in the tapetal region of the fundus.Subretinal injections of viral vector were performed as previously described except that a standard three-port 23 gauge vitrectomy was included which allows for greater control in creating the subretinal injection To monitor retinal reattachment and to detect transgene expression, fundus images were taken once daily for ten days and on day 14 and 21 post injection using a Retcam II digital video fundus camera . Both regular color images and images using the fluorescein angiography settings (to detect GFP expression) were captured.Fundus images from the post-operative days were examined to detect any post-injection expansion of the subretinal bleb. Using Photoshop images showing the initial boundary of the subretinal bleb immediately post-injection were overlain by the color images showing the final boundary of the expanded subretinal bleb. Using Photoshop the transparency of the image on the upper layer was reduced to \u223c50% to allow both layers to be visualized simultaneously. The images were moved or rotated as necessary to ensure precise superimposition of the superficial retinal vasculature at all edges of the detached area. Both the area delineated by the initial boundary of the subretinal bleb immediately post-injection and the area delineated by the final boundary of the expanded subretinal bleb was measured on the composite image in pixels using ImageJ NIH The diffTo assess if GFP expression was detectable beyond the expanded subretinal bleb, an image showing the boundary of GFP fluorescence was superimposed on an image showing the final boundary of the expanded subretinal bleb. Again care was taken to ensure accurate superimposition of the retinal blood vessels in both images. The appearance of any GFP expression beyond the final boundary of the expanded subretinal bleb was examined to see if it represented likely spread along the nerve fiber layer towards the optic nerve head or simple expansion of the area of GFP to the adjacent retina.Following euthanasia the globes were removed and fixed in 4% paraformaldehyde as previously described p<0.05.A split \u2013plot ANOVA was used to look for interaction between dog, eye injected, vector type, initial size of bleb, final size of bleb and percentage increase in bleb size . Significance was considered at p>0.05. data not shown).In all 16 eyes the subretinal injection caused a focal area of bullous retinal detachment . This suin-vivo fluorescence of the optic nerve head was apparent once GFP expression in the subretinal bleb became well established (in-vivo fluorescence of the optic nerve head the subretinal bleb contacted the edge of the nerve head. In the four eyes where the bleb did not contact the edge of the optic nerve head GFP expression extended past the final boundary of the expanded subretinal bleb to the optic nerve head in a pattern that suggested it was within the nerve fiber layer (this was confirmed histologically and a representative image is shown in In 15 out of 16 eyes ablished . Subsequablished and sectablished . In 11 oWith the exception of the aforementioned involvement of the nerve fiber layer, GFP expression was isolated to the area delineated by the final boundary of the expanded subretinal bleb in 11 of the 16 eyes.In 5 eyes careful We show in this study that retinal GFP expression extends beyond the boundary of the subretinal bleb immediately post-injection. This supports the findings of Stieger et al. in-vivo fluorescent fundus images with the color images. This extension was very slight, but suggests some lateral spread of vector through the intact retina either by spread though extracellular spaces or even across cells themselves. In separate studies with AAV we have shown transretinal passage of new generation AAV vectors can occur in the dog, with outer retinal reporter transgene expression occurring following intravitreal administration of vectors In 5 of the 16 we noted GFP expression beyond the final boundary of the expanded subretinal bleb on careful comparison of in-vivo fluorescent fundus imaging showed GFP expression within the optic nerve head and on histological sections GFP was detected in ganglion cells and in all 16 optic nerves. Histology also confirmed that GFP expression occurred in the nerve fiber layer and passed over areas in which no GFP expression was detectable (see A second pattern of GFP expression beyond the subretinal bleb was also detected. The pattern of this GFP expression suggested transit within the nerve fiber layer. In 15 of the 16 eyes able see . PotentiThere are a number of important findings from this study. First we found there is progression of the subretinal bleb for up to 3 days following a subretinal injection in the dog. If similar expansion of the subretinal bleb occurs in human patients, injections made to treat parafoveal photoreceptors could lead to post-operative expansion of the detachment to involve the fovea. As it has been suggested foveal detachments from subretinal injections may have deleterious effects"} +{"text": "The Sileye3/Alteino experiment is devoted to the investigation of the light flash phenomenon and particle composition of the cosmic ray spectrum inside the ISS. The particle detector is a silicon telescope consisting of eight planes, each divided into 32 strips. Data acquisition was initiated in 2002 in the Russian Pirs module. The data on nuclei from C to Fe in the energy range above about 60 MeV/n presented here were taken as part of the ESA Altcriss project from lat"} +{"text": "The area of organic photovoltaic materials has elicited great interest in both the scientific and technological communities due to its potential to deliver cheap and highly efficient solar cells . To dateWe present an approach that uses a genetic algorithm to search the space of synthetically accessible molecular wires for those with optimal electronic structures. This approach combines both cheminformatics (SMILES to 3D using OpenBabel) and computational chemistry . Using this method, we have found hundreds of candidates with predicted efficiencies over 8% including many with efficiencies over 10%."} +{"text": "There is now adequate evidence to indicate that liver fibrosis is a dynamic rather than a static process and as effective antiviral and other specific therapies became available, fibrosis and even cirrhosis could become reversible 2]. Effe. Effe2].Several methods have been proposed to noninvasively stage liver fibrosis including a variety of imaging modalities and a range of biochemical tests 11]12].[12].11][.[12].11]In this issue of Hepatitis Monthly, Sporea and colleagues used fibThe accuracy of fibroscan score is excellent for the diagnosis of cirrhosis; it is probably the most accurate noninvasive method for the early detection of cirrhosis. It is a user-friendly technique that can be performed without any preparation in the less than five minutes in clinic or at the bedside, with immediate results and high patient acceptance, it is very likely that in future it will become the most widely used technique for assessment of liver fibrosis 18]. Fur. Fur18]."} +{"text": "Four of them developed LTB and 3 others TBD.No extrapulmonar TB or miliary forms were observed. All patients were PPD negative prior to biological agentsNo significative difference was found between specific anti TNF and the occurrence of LTB or TBD. In 4 pts, the infectious event occurred after 2 ys of exposure and in two earlier as described in the literature. This data highlights the importance of TB surveillance prior to and during anti-TNF therapy."} +{"text": "Large efforts have recently been made to automate the sample preparationprotocols for massively parallel sequencing in order to match the increasinginstrument throughput. Still, the size selection through agarose gelelectrophoresis separation is a labor-intensive bottleneck of theseprotocols.In this study a method for automatic library preparation and size selectionon a liquid handling robot is presented. The method utilizes selectiveprecipitation of certain sizes of DNA molecules on to paramagnetic beads forcleanup and selection after standard enzymatic reactions.The method is used to generate libraries for de novo and re-sequencing on theIllumina HiSeq 2000 instrument with a throughput of 12 samples perinstrument in approximately 4 hours. The resulting output data show qualityscores and pass filter rates comparable to manually prepared samples. Thesample size distribution can be adjusted for each application, and aresuitable for all high throughput DNA processing protocols seeking to controlsize intervals. The new sequencing technologies are reshaping the field of research in genome biologyThe preparation of DNA for next generation sequencing usually consist of four mainoperations, namely; (1) fragmentation, usually performed by mechanical shearing ofthe DNA such as high pressure or ultrasound treatment, (2) repair, modification andligation of adapters, are all enzymatic steps preparing the sheared DNA by additionof universal sequences at the fragment ends thereby enabling amplification andhybridization of the sequencing primers, (3) size selection of DNA molecules with acertain length optimal for the current application or instrument and lastly (4)enrichment for DNA molecules with successfully ligated adapters Protocols of automated library preparation to the new generation of sequencers havebeen described recently In this study an automated protocol for preparation of samples prior to massivelyparallel sequencing is described to prepare DNA for paired end sequencing on theIllumina HiSeq 2000 instrument. The workflow is demonThe initial fragmentation of genomic DNA was performed by Adaptive FocusedAcoustics on a Covaris S2 instrument (Covaris) instead of the standardnebulization method described in the manufacturer's protocol The size selection part of the automated protocol utilizes two PEG solutions toperform sequential precipitations of DNA molecules. The concentration of thefirst PEG solution is chosen so that it, when added to the sample, enablesprecipitation of all molecules longer than the desired upper limit of theinterval to be selected. The beads with the undesired molecules are discardedand the second PEG solution is added to the precipitation reaction solution,still containing all DNA molecules shorter than the upper length cut-off. Thesecond PEG solution is chosen so to that it, when mixed with the supernatantfrom the first precipitation reaction, increases the PEG concentration of thesupernatant enabling precipitation of all molecules longer than the lower limitof the interval to be selected. The beads are washed and DNA molecules withinthe desired size interval are eluted. Different shape and size of selectedintervals can be obtained by varying the PEG concentrations for the twoprecipitation reactions. Following size selection the eluted DNA molecules werePCR enriched as described in the standard protocol and the size distribution andconcentration of the final libraries were evaluated on the Agilent Bioanalyzerelectrophoresis station and Qubit Quant-iTds DNA High Sensitivity(Invitrogen).The range of the automated size selection protocol was assessed by precipitationof six different size intervals from the same pool of fragmented lambda genomicDNA. The PEG concentrations used can be found in All prepared samples started with 3 \u00b5g of DNA and were fragmentedidentically using the Covaris system. Following fragmentation the manual librarypreparations were performed as specified in the standard protocol, excluding thesecond agarose gel separation. Three libraries of spruce genomic DNA wereprepared manually with insert sizes of about 190 bp, 320 bp and 700 bprespectively, for comparison with the automatically generated libraries.The automatic library preparation protocol was used to prepare two spruce samplesas well as three human cancer cell line samples A-431 . Two ofCluster generation of the prepared samples was performed using a HiSeq Paired-EndCluster Generation kit according to manufacturers instructions. Flow cells wereclustered with one library and 1% phiX control library spike inper lane.The 320 bp manual library was prepared with final concentrations of 6, 7 and 8pM and loaded in lane 1\u20133. The concentration of all automaticallygenerated libraries loaded in lane 4\u20138 was 7 pM. The 190 bp, 320 bp and700 bp manual libraries were also used in later instrument runs, withconcentrations varying between 6\u201311 pM.Sequencing of the clustered flow cell was preformed according tomanufacturer\u2019s instructions with settings for generation of 2\u00d776paired end reads.For all lanes the run statistics data such as percentage of passed filterclusters, Phred scores, cluster density and phiX error rates were obtained fromthe HiSeq Control Software. Further, additional data from 25 sequenced lanes ofspruce, with varying insert size and cluster density ,were exThe manual preparation of samples for sequencing is a very work demanding process.Four samples can take several days for a well-trained technician to prepare The automated size selection protocol has been used to select six different sizeintervals during one run . The difAutomatic libraries showed good robustness in terms of size distribution andyield prior to sequencing. The libraries yielded final concentrations with amean of 23.5 ng/\u00b5l and a standard deviation of 0.7 as determined by Qubitmeasurements. Bioanalyzer traces of the libraries show well-defined andreproducible traces of the libraries .The cluster densities of the automatically generated libraries were generallyhigher than the manual ones. This effect can be explained either by a largerproportion of amplifiable molecules in the automated samples or a smalleraverage insert size of the automatic libraries.From the average base call quality per cycle, based on 30 sequenced lanes fromthe same input DNA, we conclude that the variation between automatically andmanually prepared samples are within the normal variation of the system .We findThe 1% phiX spike in all lanes functions as a positive control and shouldnot affect the libraries it is loaded with. The phiX error rate cannot be usedas a direct measure of library quality, it does however give information of therate of accuracy of the sequencing reaction which can be affected by the libraryloaded. All phiX error rates are below the manufacturers threshold and laneswith similar cluster density show similar error rates seemingly independent ofthe type of the loaded library (Data not shown).When mapped to the human genome the samples prepared with automatic sizeselection give an insert size distribution approximately two times wider thanthe ones prepared by the manual procedure showing The automated size selection method described produces flexible and controllablesize intervals, but the distribution obtained is approximately twice as wide asthe manual gel separation. There is a trade off between yield and distributionwidth possible to obtain using this method. In theory, it should be possible tofurther control the distribution with the described method. The traces shownwere the most suitable approach for the workflow needed, combining high yield library preparation. The throughput of thedescribed protocol is currently only limited by the instrument used and a largerliquid handling robot equipped with a 96-tip head could increase the throughputper run to 96 samples or more. This strategy constitutes a general approach tobalance the increasing data throughput of the instruments for the preparation ofsamples for large scale sequencing projects.Figure S1Effect of different clustering parameters and instrument runs.Passed filter rates and percentage of PF read base calls that have qualityscores above 30 for HiSeq 2000 lanes with manually and automatically (rededge) prepared spruce samples. The colors of the markers denote differentinstrument runs. Insert size and concentration used for the clustergeneration can be found in the label for each pair of data points.(TIF)Click here for additional data file.Figure S2Robustness of the automatic size selection method. Two intervals(500 bp and 600 bp) were size selected and repeated five times.(TIF)Click here for additional data file.Table S1PEG concentration of the two solutions used for each size interval in(DOCX)Click here for additional data file.Table S2Parameters and results for the 25 extra lanes included in and (DOCX)Click here for additional data file."} +{"text": "We report on the case of a 54 years old man treating for a metastatic renal carcinoma who had experienced a dermatological toxicity referring to sunitinb intake. The antiangiogenic drug was delivered at a daily dose of 50mg for 4 weeks followed by two weeks of rest. By the second week of treatment the patient presented a nappy erythema evolving towards erosive lesions bleeding at mild friction and extending to the perianal and scrotal area, the process fulfilled the maximal intensity at 4 weeks and improved after the discontinuation of sunitinib. The patient refused the reintroduction of the drug. No skin biopsy was developed seeing that the lesions disappeared 4 weeks later."} +{"text": "The different adhesive types (3 types) could not be mainly responsible for the low shear bond values found for the Ormco bracket. The 3M Unitek combination of the Victory series bracket and Transbond XT adhesive proved to have a high shear bond strength without enamel damage.The purpose of the study was to assess the relative base designs of three different maxillary molar stainless steel brackets with reference to the shear bond strength of three different adhesive resins. The molar brackets used were Victory series (3M Unitek), Upper Molar (GAC) and Optimesh XRT (Ormco). The adhesives used were Transbond XT (3M Unitek), Enlight (Ormco) and Sure Ortho Light Bond (Sure Orthodontics). The human enamel specimens (144) were randomly divided into nine groups and each group (n=16) was allocated to a bracket/adhesive combination. The contact surface of each of the bracket bases was measured three dimensionally using a reflex microscope. The base designs were also subjected to further microscopic investigations. The brackets were bonded to the enamel, temperature cycled and the shear bond strength was measured. The size and design of each of the brackets was different. The base size, surface treatment, mesh strand diameter and aperture size of the bracket base mesh have a significant effect on the shear bond strength at the bracket/adhesive interface. The shear bond strengths of all three Ormco bracket/adhesive resin combinations (5.8-6.8 MPa) were significantly lower ( The num2.It has been demonstrated that retentive surface enlargement improves adhesion but also increases the risk of fracture at the bracket/adhesive interface because of surface variability . This suThe purpose of the study was to assess the relative base designs of three different maxillary molar stainless steel brackets with reference to the shear bond strength of three different adhesive resins.Optimesh XRT Lot: 06D238DVictory Series Lot 998186100Bondable molar attachment Lot B375Maxillary molar stainless steel orthodontic brackets from each of three different manufacturers were obtained. These were:Each of the abovementioned brackets had their 3 dimensional contact surface area measured making use of a reflex microscope . The readings were taken in a mesiodistal direction parallel to the mesh strands from the occlusal to the gingival aspect of the bracket base. The readings were taken to include the undulations of the mesiodistal mesh strands in 3 vertical planes. The floor of each aperture was read in 9 locations . Each vertical mesh strand when encountered had its profile measured in 3 different horizontal locations. The largest of the bases was measured by performing approximately 3000 readings. Each of the bracket types had 2 different specimens measured and the average was taken.The mesh wire diameter of each bracket was measured in microns using the Zwick/Roell ZHV microhardness tester . The aperture dimensions were also measured using the same apparatus and the open space or aperture area was calculated. Each bracket type was measured randomly in five locations for both mesh strand thickness and for the size of the open spaces (apertures). Each of the bracket bases was sectioned in order to measure the average depth of the apertures of each of the brackets.Microscopic images of the adhesive surfaces of the 3 different brackets were captured. This was done by laying the same square millimetre micrometer eyepiece on the mesh surface of each of the brackets. The micrometer was placed upside down in order to have lines of the grid as close as possible to the mesh of the base. The bracket was photographed at 40 and 140 times magnification under the same lighting conditions. The number of apertures in the mesh of each of the bases were calculated and expressed as apertures per square millimetre.These microscopic investigations were performed in order to make comparisons between the 3 base designs.Enlight Transbond XT Sure Ortho Light Bond .The three adhesive resins used to bond each of the brackets were:One hundred and forty four (144) upper extracted human molar enamel specimens were selected. Teeth with caries affecting or undermining the buccal enamel were excluded, as were all teeth exhibiting fluorosis or enamel damage as result of the extraction process.The selected teeth were prepared for bonding by sectioning them in such a way as to remove the roots. This was done by means of a water cooled high speed turbine handpiece. The sectioned crowns were stored in water at four degrees centigrade with a few crystals of thymol added . The teeth were randomly divided into three groups, one group of forty eight specimens for each of the bracket groups. Each group of these assigned teeth was then divided into three subgroups of sixteen teeth each and bottled (9 bottles) separately. Each of these bottles was labeled with the assigned bracket/adhesive resin combination. This was done with a view to ensure that sixteen brackets of each manufacturer would be bonded with each of the three resin adhesive agents (16 \u00d7 3 \u00d7 3 combinations). Each enamel specimen was then checked by a single operator in order to ensure a close fit between the bracket base and the buccal surface of any of the assigned enamel specimens. This was done by placing an example of its assigned bracket with its base positioned in the prescribed position on the buccal enamel. If there was any doubt regarding the closeness of the \u2018fit\u2019 of the base to the buccal tooth surface, the tooth was excluded from any further testing and another specimen was assessed and used if found to be suitable. This was done in an attempt to minimise the variation of the thickness of the adhesive layer as much as possible.All the enamel specimens were gently polished for 10 seconds with an oil free, fluoride free pumice solution to clean the enamel, thus simulating the removal of the pellicle as in the clinical situation.All the brackets to be bonded with the same bonding agent were bonded in one session by a single operator. Each of the three adhesive resins was used in accordance with the manufacturer\u2019s instructions. The bracket was positioned on the buccal surface of each tooth, by means of bracket tweezers, and then a force of four hundred grams was appl2 was used. The intensity of the curing light was checked after every 8 exposures with a Dentsply light intensity meter to ensure this consistent intensity. Each bonded specimen was placed back into the water/thymol solution in its designated bottle and stored for twenty four hours at room temperature and then exposed to a temperature cycling procedure. This entailed each specimen being exposed to 500 cycles of heat and cold. The specimens were exposed to a temperature high of 55\u00b0C as opposed to a low of 5\u00b0C, with a dwell time of 30 seconds.The adhesive resin on each bonded tooth was light cured in three steps for ten seconds at the mesial side, then for 10 seconds at the occlusal side and finally for 10 seconds at the distal side of the bracket with the exit portal of the light curing unit as close as possible to the bracket. A standard tungsten quartz halogen curing light was used to cure the bonding agents. A light intensity range of between 440 and 480 mW/cmFollowing the temperature cycling the enamel specimens were stored in their respective adhesive/bracket combination groups. The bonded enamel specimens were then embedded in plastic cups with cold curing acrylic resin. The specimens were positioned by means of a jig in such a way that the entire buccal enamel surface projected from the embedding material and the plastic tube with the bracket/enamel interface positioned at ninety degrees to the long axis of the plastic tube. The specimens were kept in water between all treatments.The specimens were clamped to the base of the Zwick Universal testing machine . A shear load was applied in an occluso-gingival direction to the attachment, with the debonding force parallel to the bracket/adhesive interface by means of a knife-edged rod at a crosshead speed of 0.5 mm per minute. Care was taken to ensure that the debonding force was consistently applied at the junction between the base of the bracket and the buccal tube on all of the specimens. Shear bond strengths were registered in Newtons to be converted and expressed in mega pascals (MPa) using the contact surface area as reported in Table The average bracket base contact surface area of the 3M, GAC and Ormco brackets as measured with the reflex microscope appear in Table Table The pivot table Table shows avTable rd quartile and the line within the box represents the median value. The region between the 1st and 3rd quartile values is known as the interquartile range.Figure Figures p<0.05; Kruskal-Wallis) than all the other combinations from any of the other 6 bracket/adhesive combinations in this study .It was interesting to note that in association with all three bracket groups Enlight adhesive resin (Ormco) was consistently associated with a lower shear bond strength Figure . Ormco d2) is roughly twenty percent less than that of the GAC bracket base and roughly fifteen percent smaller than the 3M bracket base (Table 2) of either the GAC or the 3M bracket contact surfaces (Table 2), the smallest aperture volume and more apertures per lineal millimetre between the incidence of debonding at the adhesive enamel interface and the adhesive remnant index. The 3M bracket/adhesive combinations showed visible enamel damage in 5 instances after debonding. The GAC bracket/adhesive combinations were associated with 18 incidents of visible enamel damage and it was the only bracket/adhesive combination to remove all the adhesive resin from the enamel surface in 4 instances. The incidence of enamel fracture with GAC brackets was shown to be significant (p<0.05). Chi-square of 62.1438. The apparent stronger bond at the bracket/adhesive interface on the debonding of the GAC bracket may be associated with the larger average aperture volume size. GAC claim (GAC US patent 4889485) the double mesh design enhances the bond at the bracket/adhesive interface as well as it serves to reduce the amount of residual adhesive left on the enamel. The bracket construction is such that the mesh material becomes thicker, the apertures wider and the surfaces rougher toward the adhesive/bracket interface. Mesh design has been found to have an effect on stress distribution at debonding mainly by influencing the flexibility of the base of the bracket (The adhesive remnant index (ARI) analysis Table showed t bracket . Double bracket .et al concluded that single and double mesh bases display similar bond strength and bracket failure modes (Bishara re modes . The resre modes also fouThe 3M Unitek combination of the Victory series bracket and Transbond XT adhesive proved unique in these tests. The 3M bracket/Transbond XT combination was the only bracket/adhesive combination other than the Ormco bracket/ adhesive combinations not to display any visible enamel damage.The size and design of the bracket adhesive surface do play a significant role in bond strength of molar orthodontic brackets.The Ormco bracket has the largest mesh strand diameter, the smallest mesh apertures and aperture area, the smallest aperture volume and more apertures per lineal millimetre.The 3M Unitek combination of the Victory series bracket and Transbond XT adhesive proved to have a high shear bond strength without enamel damage."} +{"text": "The present work exemplifies how parameter identifiability analysis can be used to gain insights into differences in experimental systems and how uncertainty in parameter estimates can be handled. The case study, presented here, investigates interferon-gamma (IFN\u03b3) induced STAT1 signalling in two cell types that play a key role in pancreatic cancer development: pancreatic stellate and cancer cells. IFN\u03b3 inhibits the growth for both types of cells and may be prototypic of agents that simultaneously hit cancer and stroma cells. We combined time-course experiments with mathematical modelling to focus on the common situation in which variations between profiles of experimental time series, from different cell types, are observed. To understand how biochemical reactions are causing the observed variations, we performed a parameter identifiability analysis. We successfully identified reactions that differ in pancreatic stellate cells and cancer cells, by comparing confidence intervals of parameter value estimates and the variability of model trajectories. Our analysis shows that useful information can also be obtained from nonidentifiable parameters. For the prediction of potential therapeutic targets we studied the consequences of uncertainty in the values of identifiable and nonidentifiable parameters. Interestingly, the sensitivity of model variables is robust against parameter variations and against differences between IFN\u03b3 induced STAT1 signalling in pancreatic stellate and cancer cells. This provides the basis for a prediction of therapeutic targets that are valid for both cell types. For the prediction of therapeutic targets and the design of therapies, it is important to study the same pathway across different cell types. This is particularly relevant for cancer research, where several cell types are involved in carcinogenesis. Pancreatic cancer is enhanced by activated pancreatic stellate cells. It would thus seem plausible for an effective therapy to hit stellate and cancer cells. The cytokine IFN\u03b3 is an inhibitor of proliferation in both cell types. Antiproliferative effects of IFN\u03b3 are mediated by STAT1 signalling. An important aspect is to determine those reactions that cause the differences in the initial increase of phosphorylated STAT1 and in the temporal profile of STAT1 nuclear accumulation between the two cell types. We examined this aspect by performing a parameter identifiability analysis for calibrated mathematical models. We calculated confidence intervals of the estimated parameter values and found that they provide insights into reactions underlying the differences. A key finding of sensitivity analysis elucidated that predicted targets for enhancement of STAT1 activity are robust against parameter uncertainty and moreover they are robust between the two cell types. Our case study therefore exemplified how identifiability and sensitivity analysis can provide a basis for the prediction of potential therapeutic targets. Progression of pancreatic cancer (PC) is accelerated by an extended fibrosis, which has been linked to the activation of pancreatic stellate cells (PSC) SOCS1) using global optimization.IFN\u03b3-induced STAT1 signalling was investigated by combining experimental and theoretical systems biology in The present work is motivated by the following consideration: We observed differences in the trajectories of the parameterized models describing the IFN\u03b3-induced STAT1 signalling pathway in PSC and cancer cells. Simulation results agreed with the differences in the experimental time series. The differences can thus be attributed to unequal parameter values of the two models. In general, however, one finds a range of parameter sets leading to a similarly good fit of the model, rather than a unique parameter set. As a consequence it remains unclear which specific model parameters are behind the differences observed for the model trajectories of the two cell types. We therefore focused on the following two questions:Which reactions cause the differences in the temporal profiles of the model simulations between PSC and cancer cells?What are the consequences for therapeutic target prediction?An appropriate method for our first objective is a parameter identifiability analysis. It investigates how accurate the parameter values are determined by the model structure including a mapping of model variables to observables Note that our approach here is different to typical methods of model discrimination used in systems biology that compare for two models with a different number of parameters the quality of the fits to the same experimental data. These methods investigate whether a model with more parameters than a default model describes given data better, without introducing more uncertainty in the parameter values. Such approaches include Akaike Information Criterion In the next part of this work, we investigated the consequences of parameter uncertainties for the prediction of common therapeutic targets in both cell types. We performed a sensitivity analysis to determine those parameters, which sensitively influence protein concentrations during the time of observation. As a quantitative measure for sensitivity we employed what is known as the \u201cmetabolic control coefficient\u201d It is worth pointing out that we confirmed the key findings of the study in a larger panel of pancreatic cancer cell lines and in primary PSC. Finally, we discussed our results from experiments, parameter identifiability analysis and sensitivity analysis in the light of STAT1 nuclear accumulation.The parameters of the two models include reaction constants, delay times, total receptor concentration, Western blot scaling factors and initial conditions of some model variables. Their values were estimated by global optimization from protein and mRNA time series data. We used the experimental findings of reference pwFitBoost of the MATLAB toolbox PottersWheel For parameter value estimation a hybrid approach was applied, which is a combination of a stochastic simulated annealing algorithm, performing a global search, and a deterministic trust region algorithm performing a local search. The hybrid approach is implemented in the routine Due to nonlinearities in the models averages of parameter values do not necessarily lead to a good fit and are thus not appropriate quantities for further analysis. Instead of this, a parameter identifiability analysis provides a confidence interval with a confidence level for each parameter value.A parameter identifiability analysis answers the question of how accurate the parameter values of a given model can be determined by the experimental data. This in turn allows an investigation of which model predictions are possible The value The degrees of freedom for up to 9 hours and fixed in methanol. Immunofluorescence staining of cytoplasmic and nuclear STAT1 and phospho-STAT1 as well as confocal laser scanning microscopy were done as described in The network presented in Rapid initial STAT1 phosphorylation in PSC. Slower initial rise of phosphorylated STAT1 in PC.Nuclear accumulation of STAT1 in PSC. Lack of nuclear accumulation of STAT1 in PC.This raised the question which reactions caused these differences in the model simulations between PSC and PC. To approach this question we performed a parameter identifiability analysis.We performed a parameter identifiability analysis by calculating the profile likelihood estimates (PLE). The PLE for the parameter values of the PSC model are shown in A distinction between the PSC and PC profiles, important for our later discussion, is parameter According to We furthermore plotted the cumulative distribution function in the lower part of Consequences of uncertainties in parameter values on the dynamics can be studied by comparing trajectories resulting from parameter sets within the confidence interval. In the following, we focus on parameters, which based on their position in the biochemical network, could be related to the different experimental profiles of STAT1 and phosphorylated STAT1 between PSC and PC after stimulation with IFN\u03b3.Rapid initial increase of phosphorylated STAT1 time series in PSC in contrast to PC as presented in The estimated value of the parameter The parameter Nuclear accumulation of STAT1 in PSC but not in PC, see \u22121a.u.\u22121 in the PC model. This leads to a broader variability of the The negative correlation between The parameter \u22121 one finds \u22121, which is inside the boundaries of the CI, but for \u22121 one finds \u22121 which is located outside the upper boundary of its CI.The ratio of nuclear versus cytoplasmic STAT1 for PC does not show a nuclear accumulation of STAT1, as depicted in Summarizing our results, we successfully identified reactions that could explain the differences of STAT1 signalling in pancreatic stellate and cancer cells: A larger value of the reaction constant for receptor activation that fit the PSC time series and the parameter sets (including CI) that fit the PC time series. A model variable which is a nonobservable can be influenced by changing a parameter value even within its CI. This includes the amount of phosphorylated STAT1 or to answer the question whether there is more nuclear phosphorylated STAT1 in one of the two cell types. Nevertheless, we positively exploited information from nonidentifiability in our work: The knowledge of one finite confidence interval boundary of a nonidentifiable parameter was sufficient to draw conclusions about reactions which differ between the IFN\u03b3 induced STAT1 signalling pathway in pancreatic stellate cells and pancreatic cancer cells.We used the results of the parameter identifiability analysis to choose parameter sets within the confidence intervals for the sensitivity analysis. The profiles of the time-dependent metabolic control coefficients are very similar for the PSC parameter sets and the PC parameter sets as demonstrated in Our results show that the time dependent metabolic control coefficients can be used for experimental therapeutic studies in cell culture. A similar question was asked by Raia et al., who predicted that the inhibition of STAT5 phosphorylation in IL13 induced STAT5 pathway reduces proliferation in two lymphoma cell types We used mathematical modeling, simulations and parameter identifiability analysis to explain experimentally observed differences of IFN\u03b3-induced STAT1 signalling in pancreatic stellate cells and cancer cells. Parameter identifiability analysis revealed that it is a larger value of the reaction constant for nuclear import of phosphorylated STAT1 Click here for additional data file."} +{"text": "Early feeding with cows' milk (CM) formula may cause CM allergy (CMA). Contribution of CM formula feeding at maternity hospital in the development of CMA was studied.27 children with CMA were retrospectively examined in this study: 12 boys and 15 girls, the median age at the beginning of symptoms was 5 months (range 18 days - 6 years). In 18 children symptoms began quickly after ingesting CM ; in 9 children symptoms began several hours after. All children performed skin prick test and food challenge test.In 12 out of 27 patients (44%) symptoms of CMA appeared after ingestion of the \"first\" meal of CM formula or dairy products at home. Children with rapid reaction had symptoms after the \"first\" meal of CM in 66% of cases. A retrospective examination of neonatal charts revealed that nine out of 12 children who reacted to the \u201cfirst\u201d meal of CM at home had received CM formula at the hospital and were fully breastfed after discharge. Only two out of 12 of these children was born to atopic parents.In our experience feeding of CM formula at the maternity hospital is involved in about one-third of CM allergy. Avoidance of bottles during the establishmet of breastfeeding may give a relevant contribution to the prevention of CMA in children. This measure should be applied to all neonates from atopic and non-atopic parents."} +{"text": "Generation of infectious HIV-1 requires the synthesis of the spliced and the Rev responsive element (RRE)-containing viral transcripts. The former is efficiently processed and rapidly exported to the cytoplasm. The latter retains introns in unspliced and partially spliced forms and does not exit the nucleus until the viral Rev protein mediates its export for the expression of structural proteins and for the production of full-length genomic RNAs. Rev by binding to RRE increases the half- life of unspliced/ partially spliced RNAs and promotes their export to the cytoplasm. Various cellular factors have been reported to contribute to Rev activities but the molecular details of how Rev overcomes the eukaryotic restriction for intron-containing mRNAs remain to be determined.Here we introduced a novel method to explore the proteome associated with the nuclear HIV-1 RNAs. At the core of the method is the generation of cell lines harboring an integrated HIV-1 provirus carrying RNA binding sites for the MS2 bacteriophage protein. Flag-tagged MS2 was then used for affinity purification of the viral RNA.In the proteomic screen we found that the viral RNA is associated with the host nuclear matrix component MATR3 and the polypyrimidine tract-binding protein associated splicing factor (PSF) 1. MATR3 has been recently identified as a cofactor of Rev function and PSF We provide evidence that MATR3 and PSF are novel nuclear cofactors that control Rev activity. We speculate that they are components of a nuclear pathway hijacked by Rev to facilitate the nuclear survival and export of intron-containing viral transcripts."} +{"text": "Pancreas divisum is a frequent congenital anatomical anomaly characterized by the failure of fusion of the ducts of Santorini and Wirsung during fetal development. Although the condition usually remains asymptomatic, it has been reported to be a predisposing factor of chronic and recurrent idiopathic pancreatitis. We report a case of acute non-traumatic pancreatitis in a 54-year-old Caucasian male with pancreas divisum. Diagnosis was established based on the findings from magnetic resonance imaging and magnetic resonance cholangiopancreatography. The patient was managed conservatively and was discharged home having an uneventful clinical course after five days of hospitalization. Although the role of the pancreas in the induction of acute pancreatitis is still a matter of debate, physicians have to be aware about this prevalent pancreatic anatomic abnormality. Timely detection may help in the prevention of potential recurrent pancreatic reaction. The entity has been positively associated with the induction of idiopathic chronic or recurrent pancreatitis [2]. Here we report a case of acute pancreatitis in a previously healthy male.Pancreas divisum, the most common congenital variation of the pancreatic ductal anatomy, occurs in approximately 10% of the population .2). Abdominal ultrasound imaging was normal except for the dilation of the pancreatic duct (d=2.5 cm). A presumed diagnosis of acute pancreatitis was made probably due to a relative outflow obstruction on the pancreatic duct. The patient underwent Magnetic Resonance Imaging (MRI) of the upper abdomen. MRI showed a pancreatic duct abnormality by illustrating two separate pancreatic ducts raising the diagnostic suspicion of pancreas divisum (6).Further investigation with magnetic resonance cholangiopancreatography (MRCP) revealed findings suggestive of the presence of pancreas divisum [3] which at rest has a maximum diameter of 2 mm and is responsible for the drainage of pancreatic secretions derived from cap, body and tail of the gland at the major duodenal papilla [4]. The accessory pancreatic duct (Santorini\u2019s duct) crosses major pancreatic duct and stops on the minor papilla [4]. Minor papilla is located 10-15 cm above the major papilla on the median wall of the 2nd part of the duodenum [4]. Formation of pancreas occurs during embryonic development by the fusion of the ventral and dorsal pancreatic primordia [3] resulting in two \u2018independent glands\u2019 with two separate ducts [5]. The dorsal duct drains the main portion of the pancreas into the minor papilla and the ventral duct drains only a small segment of the pancreas (inferior portion of the pancreatic cap) at the major duodenal papilla [4]. Historically, the condition was first described by Joseph Hyrtl (1810-1894) [6]. Two types of pancreas divisum are described: complete pancreas divisum, which occurs more frequently with total failure of fusion and the incomplete form where the dorsal and ventral pancreatic ducts are joined through small caliber communicating branch ducts [4]. A fusion failure of the ventral and dorsal pancreatic buds occurs in pancreas divisum during the 6th to 8th week of fetal development [3]. However, insufficient drainage of the exocrine pancreatic secretions may result to high intraductal pressure in the duct of Santorini and induce chronic pancreatitis or recurrent episodes of abdominal pain [3]. Almost 2 out of 10 patients with unexplained idiopathic pancreatitis were diagnosed with pancreas divisum [7]. Endoscopic retrograde cholangiopancreatography (ERCP) represents the first choice investigation for a definite diagnosis [3]. The diagnosis of PD is based on ERCP findings, which include the visualization of a short isolated ventral duct or identification of two separate pancreatic ducts [8]. Magnetic resonance cholangiopancreatography (MRCP) is a useful non-invasive technique with high sensitivity and specificity for the diagnosis of pancreas divisum [8] by showing the intersection of the distal common bile duct with the dorsal pancreatic duct. Transabdominal ultrasonography may be used for the determination of the pancreatic duct diameter [9]. A pancreatic duct diameter of more than 1.5 mm for more than 30 minutes following a fatty meal or after secretin infusion is considered abnormal [10]. Pancreatic ducts can be depicted without the injection of iodinated contrast material [3]. Non-communication of the dorsal and ventral pancreatic ducts and the dominance of the dorsal pancreatic duct is visualized [3]. Decompression of the Wirsung\u2019s duct, through sphincterotomy of the minor duodenal papilla represents the basic therapeutic modality for cases with recurrent episodes of pancreatitis [11]. The entity is usually asymptomatic [2], its contribution to the induction of acute pancreatitis is still debatable [2]. A high level of physicians\u2019 awareness is required for this common pancreatic duct anomaly since timely detection may help prevention of recurrent pancreatitis by encouraging patients to follow a healthier dietetic regimen and avoid alcohol consumption. In our case, pancreas divisum was the only predisposing factor for acute pancreatitis. Although pancreas divisum seems to predispose to chronic and recurrent idiopatic pancreatitis [ Consent Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests The authors declare that they have no competing interests."} +{"text": "There is limited data available in the use of soft casting to offload heel ulceration. Heel pressure ulceration is a costly problem in the health board involved in this study with 15% of in-patients having heel pressure ulceration (HPU).This has led to heel ulcers coming under the 1000 lives campaign in Wales. Soft cast is a quick, cost effective treatment modality for foot ulceration which is largely untested on heel ulceration.12 patients with HPU of grade II and above were issued with a soft cast heel protection device and monitored closely. Size and depth of the wound was recorded as was neurological and vascular status and VAS pain scale scores.12 patients were audited, 1 patient died in an unrelated adverse event and of the remaining 11 patients, 2 HPU resolved and the remaining 9 patients ulcers all reduced in size and the wound beds improved. All 11 patients had significantly reduced pain scores with patient stories indicating good compliance and acceptability of the device.The audit results highlight a need for a research project in this area as the indications were that soft cast heel protection was a successful, cost effective modality for this patient group with the potential for reducing hospital stays and staff time costs."} +{"text": "There were errors in the equation directly following Equation 9, and the two equations directly preceding Equation 10. Correct versions of all three equations are available in that order below."} +{"text": "Aneurysmal subarachnoid haemorrhage (aSAH) is associated with a high morbidity and mortality. Although UK Anaesthesia Guidelines advocate early coiling or clipping of the aneurysm within the first 72 hours of admission for all grades of aSAH, the optimal timing of treatment and whether this is linked with better neurological long-term outcome are a subject of debate . We aimeA retrospective analysis of prospective collected data in a tertiary neuroscience centre from January to September 2012. All patients were managed according to the local Guidelines for the management of aSAH. Outcome was assessed at 3 months using the extended Glasgow Outcome Scale (GOSE) defining good recovery as a GOSE \u22657 and poor outcome as GOSE \u22646.A total of 28 patients were included within the study period. Three patients were not expected to survive the first 24 hours and were not included in the study. Seventeen patients were classified as good grade aSAH (WFNS I to III) and eight as poor grade (IV toV). Twenty-two patients underwent successful coiling while the other three required clipping due to unsuccessful coiling. We did not find any correlation between the timing of coiling/clipping and the 3-month GOSE Figure . A totalOverall mortality in patients with aSAH is low when aneurysm is treated early post rupture of aneurysm. We did not find any correlation between the timing of occlusion of aneurysm and the 3-month functional outcome."} +{"text": "Breast cancer is a complex disease which is provoked by a multitude of exogenous and endogenous factors including genetic variations. Recent genome-wide association studies identified a set of more than 18 novel low penetrant susceptibility loci, however, a limitation of this powerful approach is the hampered analysis of polymorphisms in DNA sequences with a high degree of similarity to other genes or pseudo genes. Since this common feature affects the majority of the highly polymorphic genes encoding phase I and II enzymes the retrieval of specific genotype data requires adapted amplification methods. With regard to breast cancer these genes are of certain interest due to their involvement in the metabolism of carcinogens like exogenous genotoxic compounds or steroid hormones. The present review summarizes the observed effects of functional genetic variants of phase I and II enzymes in well designed case control studies to shed light on their contribution to breast cancer risk. FGFR2, CCND1, TOX3, MAP3K1, LSP1, CDKN2A, and 2B , and Methyltransferases. The combined phase I and II metabolism is mainly a detoxification and elimination process, however, both phases bear the risk of formation of toxic and highly reactive compounds which can induce or promote serious health problems such as cancer polymorphism. The human SULT1A subfamily comprises three genes SULT1A1, SULT1A2, and SULT1A3 which are located in close proximity on the short arm of chromosome 16 and share sequence similarities of more than 90% which lead to a decreased activity of the CYP2C19 has been associated with increased risk in Asians causing an ultra rapid metabolizer phenotype leads to a decreased HRT-related breast cancer risk in Europeans and poorly differentiated breast tumors which may be explained by a potential contribution of the variant allele to increased sex hormone levels affects lymph node status of breast cancer patients (Jernstrom et al., CYP2C9*2 allele which is in linkage disequilibrium with CYP2C8*4 cannot be excluded (Jernstrom et al., Only a few well designed studies investigated the association between phase I and II enzymes and histo-pathological characteristics of breast tumors Table . One stuGenetic variations of phase I and II enzymes alter their activity or protein biosynthesis leading to defective detoxification and elimination of carcinogenic compounds. Due to a high degree of DNA sequence similarity among genes of subfamilies accurate genotyping requires elaborated methods and exhaustive quality control. Until now a few well designed studies give insights into the effect of polymorphisms in metabolic enzymes on breast cancer risk and point to their crucial action in steroid hormone catabolism. These finding underline the pivotal role of sex hormones in the regulation of proliferation, differentiation, and apoptosis as critical pathways for onset and progression of breast cancer (Schindler et al., The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The aim of this study is to clarify the effect of acupuncture stimulation on muscular power of isotonic contraction of the elbow flexor.Subjects are 20 healthy males. Maximum Voluntary Contraction (MVC) of elbow flexor was measured using a strain gauge prior to exercise (MVC1). Subjects received acupuncture stimulation before the exercise on their biceps brachii. The stimulation is either deep needling or superficial needling (sACU). The exercise protocol contains 5 sets * 10 repetitions of maximum contraction of elbow flexion at 50% MVC and 90 second intervals between sets. After the exercise subjects were measured for their MVC again (MVC2). The muscle power and the velocity of every contraction was measured using a dynamometer. Electromyogram (EMG) and muscle blood flow (MBF) were also observed during the exercise. Subjects did the same exercise and we measured the same parameter without any stimulation as control. The decrease of MVC between MVC1 and MVC2, muscle power and velocity among sets and repetitions were evaluated.MVC2 was significantly decreased compared to MVC1 in mACU and sACU and control. MVC1 of mACU seemed suppressed compared to control but no difference was observed at MVC2. Muscle power and velocity were also decreased in latter sets and repetitions in every group and the difference between mACU and sACU are under investigation.It is suggested that acupuncture stimulation may have an affect on muscle power and velocity of repeated explosive isotonic contraction. At the field or bedside, acupuncturists should treat athletes carefully before exercise or sports events."} +{"text": "An error occurred in the second row of the second column of Table 1. The acronym \"ACON\" should read \"BACON.\"Errors occurred in the references of this article in the Methods section. The reference numbers were replaced by question marks. In the first sentence of the fourth paragraph of the Methods section, the references should read \"see [18] and [19].\" In the second sentence of the fifth paragraph of that same section, the reference should read \"as in [8].\"An error occurred in Equation 7 in which there is extra white space below the variables between the brackets."} +{"text": "Retrospective single center natural history studies have shown that times to reach disability milestones and ages at which they are reached are similar in primary (PPMS) and secondary (SPMS) progressive multiple sclerosis suggesting that they may be phenotypic variations of the same disease.Here we compared longitudinal disease activity in SPMS and PPMS in the context of international multicenter clinical trials.We analyzed all objective outcome measures that were systematically collected over 2 years for all subjects randomized to placebo arms in one SPMS and one PPMS clinical trial over the last decade. Conventional and exploratory definitions of clinical disease activity were used. Disease activity was analyzed in 3 different categories intermittent activity, progression, and improvement. Conventional MRI measures and one patient reported outcome measure of quality of life were included when available for comparison. Heat maps were drawn for all results followed by hierarchical clustering.There were 101 outcome variables from 206 SPMS subjects and 79 outcome variables from 135 PPMS subjects. The comparison revealed that SPMS and PPMS subjects exhibited similar disease activity over 2 years in all but two of the variables in common worsening in the EDSS sensory system was more common in PPMS while worsening on the 9 hole PEG was more common in SPMS. Intermittent activity was the most common pattern of disease activity in SPMS and PPMS. Clinical worsening and improvement occurred at similar frequency in both.Longitudinal disease activity was nearly identical in SPMS and PPMS subjects in the context of the two multicenter international clinical trials we examined. Although multiple sclerosis (MS) usually begins with a relapsing-remitting course in 85% of patients, over long term follow up the majority of patients develop sustained accumulation of disability referred to as secondary progressive MS (SPMS). About 15% of MS patients develop sustained accumulation of disability from clinical onset without reporting a preceding period of clinical relapses and remissions and are referred to as primary progressive MS (PPMS) Here we studied for the first time differences in disease activity between SPMS and PPMS in the context of multicenter studies. For this we examined all available objective clinical outcome measures that were systematically collected at quarterly scheduled visits over 2 years in subjects randomized to placebo in the IMPACT SPMS All data were from the placebo arms of two large randomized, prospective, double-blinded multicenter clinical trials of progressive MS, IMPACT and OLYMPUS. IMPACT was a 2-year study in North America, Europe, and Israel that evaluated the efficacy of 60 mcg weekly injections of intramuscular interferon beta-1a vs. placebo for the treatment of SPMS We examined all clinical efficacy outcome measures that were systematically collected at the scheduled visits every 3 months for 2 years. These included measures of clinical disability like the EDSS To measure disease activity, 101 variables in the IMPACT study and 79 in the OLYMPUS study were derived by using the original raw data according to pre-specified criteria . There wThe demographic and clinical baseline characteristics of the placebo arms of the IMPACT and OLYMPUS trials were relatively similar except for the expected history of previous relapses that was present only in SPMS . There wFirst we investigated disease activity in SPMS. We did this in 219 subjects randomized to placebo in the IMPACT study and followed for 2 years examining 101 different definitions of disease activity.The analysis revealed that the median percentage of SPMS subjects experiencing intermittent activity over 2 years was \u223c22% . IntermiA similar analysis of disease activity was done for the 147 PPMS subjects randomized to placebo and followed for 2 years in the OLYMPUS study based on the availability of 79 definitions The median percentage of subjects experiencing intermittent activity \u223c20% , about tSPMS and PPMS showed very similar disease activity over 2 years. Only 3 out of the 46 outcome measures in common in the two studies showed significant differences and only one was highly significant: In PPMS there was greater progression in the EDSS sensory system by either definition 1 (p\u200a=\u200a0.008) or definition 2 (p\u200a=\u200a0.04) and in SPMS there was greater progression in the 9HP but only using definition 2 was much higher (37%) in IMPACT It is possible that our clinical definitions of intermittent activity measured examiner and/or subjects\u2019 noise rather than true change. We believe this is unlikely for the following reasons: (1) To minimize false positive findings due to measurement noise we selected robust thresholds, for example \u22652 points increase for the individual EDSS system scores How can one explain the much lower frequency of relapses in PPMS than in SPMS that occurs not only in clinical practice but also in the context of prospective frequent follow up in clinical trials such as OLYMPUS? One possibility is that there are differences in pathophysiology accounting for greater relapsing activity in SPMS. However, our analysis of clinical and MRI measures revealed similar frequency of intermittent disease activity in SPMS and PPMS both clinically and by MRI. An alternative possibility is that there could be under recognition by PPMS subjects and/or their caretakers, relatives, and significant others of symptoms of relapsing activity in the context of sustained disease progression from onset. Another possibility is that patients who end up diagnosed with PPMS are those who underreport intermittent or acute symptoms. This appears unlikely because the detection of MS exacerbations in the OLYMPUS PPMS trial was 9 times lower than in IMPACT despite similar on study monitoring in both trials The remarkable similarities in disease activity between IMPACT and OLYMPUS may be explained because these trials enrolled highly selected patients that are not representative of the general population of SPMS and PPMS patients in the clinic. We believe this is unlikely as the inclusion/exclusion criteria covered a wide segment of the MS population with a wide age range (18\u201360 years old in IMPACT and 18\u201365 years old in OLYMPUS), wide EDSS range (3.5\u20136.5 for IMPACT and 2.5\u20136.5 for OLYMPUS), and wide range of disease duration The traditional tool to measure progression of disability in MS has been the EDSS The finding that the physical components of the MSFC using the definition 2 are sensitive assessors of progression over 2 years allowed us to compare the patterns of disease progression at the individual level in SPMS and PPMS using clustering algorithms and heat map display One limitation on the analysis of patient reported outcomes (PROs) is that information was available only for the subset of English speaking subjects from the IMPACT study . However, the information available was useful to compare the rates of progression and improvement by subject self-report versus objective measurements in the context of SPMS. A comparison of domains represented both in objective measures (e.g. EDSS) and PROs (e.g. MSQLI) showed similar rates of improvement but in some cases higher rates of progression were elicited by subject\u2019s report. For example, progression in bowel and bladder function was 13\u201316% by EDSS system versus 2The findings of this analysis of longitudinal disease activity in the context of multicenter clinical trials support the view that PPMS and SPMS may be viewed as essentially similar. Although we used traditional definitions we also explored several novel definitions of disease activity. Further longer term studies are needed to validate their utility in clinical research and possibly in the clinic. It will also be important to confirm whether our findings are reproducible using different clinical trial data sets. For our analyses we were limited to study subjects with only 2 years of longitudinal follow up. It will also be important to examine clinical trial datasets with longer follow up. The analysis of disease activity at the individual subject level with a machine learning approach and heat map display shows great potential as a tool to study the natural progression and response to treatment of heterogeneous complex diseases like MS."} +{"text": "To the Editor: Except for sporadic cases along the Texas\u2013Mexico border, local transmission of dengue virus (DENV) has not occurred in the contiguous United States since 1946. In 2009, DENV was diagnosed in a vacationer to Key West, Florida were used to amplify products encompassing the envelope (E) gene region and parts of the premembrane and nonstructural 1 genes from the pools collected on June 25 and 30. PCR products were sequenced by using amplification and internal primers to provide double or triple coverage . The sequences from these 2 pools were identical (GenBank accession no. JF519855). We used ClustalX (\u20134 substitutions per nucleotide per year (The analysis showed that American DENV-1 strains clustered by geography and by year of collection , panel BAnalysis of the entire Key West DENV-1 genome may help pinpoint the origin and address the possibility of selective pressure on other genes or recombination events ("} +{"text": "On the other hand, little is known about what kind of factors influence the NIV response in the subacute period. This study aimed to determine the factors influencing PaCO2 levels drop below 50 mmHg in first 24 hours) (group 2) and the nonresponsive group (group 1).In this retrospective study we investigated the differences in NIV strategies and patient characteristics between the responsive group . The home ventilation usage rate was significantly higher in the nonresponsive group than the responsive group.In 34% of the patients, PaCO2 levels, the higher pressure support requirement and prior home ventilation usage are predictors for late and poorer response to NIV.Results of this study showed that, although nocturnal application of NIV in the ICU is associated with a faster drop rate in PaCO"} +{"text": "Diffusion Tensor Imaging (DTI) quantifies the amount of anisotropic diffusion exhibited by biological tissues. Processing DTI images allow a 3D visualization of the fiber architecture by tracking the fiber trajectories within the tissue. Experimental evidence has shown that the myocardium undergoes remodeling as myocardial infarction progresses over time. The aimEx-vivo DTI was performed on an infracted pig heart on 1.5T and 3T MRI scanners. Infarcts were created in the apex region (Fig Fig From this preliminary study we observe that the fibers from both the scanners are consistent in terms of the lengths being short and disarrayed around the infracted region compared to the rest of the LVM. We also observe that in the data from the 1.5T scanner fibers tracked are smoother and more in number compared to the data from the 3T scanner. However, more studies are warranted to confirm our analogy and establish the technique."} +{"text": "There is lack of consensus over what sample size should be used for external pilot trials to inform the design of definitive parallel group superiority randomised controlled trial (RCT). The aim of this research was to investigate the sample size required to precisely estimate the key parameter associated with a continuous outcome, the standard deviation (SD).We use a simulation approach to examine the sampling distribution of the SD for a Normally distributed outcome. We assessed the precision of the estimates by calculating the relative gain in precision through the width of the 95% confidence interval (CI) and the percentage gain in precision per increase in sample size of 5 in each group.The bias in the pooled SD estimate is negligible once the total pilot sample is 60 or above and the relative gain in precision (for each ten subjects added to the pilot) drops to below 10% once the total sample size is 70. When planning the full RCT for a continuous outcome, estimates generated by pilot samples of 70 will have the required power with close to 50% confidence when the true standardised effect size is above 0.2. Adjusting the required sample sizes for the full RCT to deliver the required power with 80% confidence can result in excessively large full planned RCTs.We recommend that an external pilot study needs at least a total of 70 measured subjects (35 per group) to estimate the pooled SD for a continuous outcome."} +{"text": "We justified theoretical and experimental bases of synthesis of new class of highly nanostructured composite nanomaterials based on metal matrix with titanium carbide nanowires as dispersed phase. A new combined method for obtaining of metal iron-based composite materials comprising the powder metallurgy processes and the surface design of the dispersed phase is considered. The following stages of material synthesis are investigated: (1) preparation of porous metal matrix; (2) surface structuring of the porous metal matrix by TiC nanowires; (3) pressing and sintering to give solid metal composite nanostructured materials based on iron with TiC nanostructures with size 1\u201350\u2009nm. This material can be represented as the material type \u201cframe in the frame\u201d that represents iron metal frame reinforcing the frame of different chemical compositions based on TiC. Study of material functional properties showed that the mechanical properties of composite materials based on iron with TiC dispersed phase despite the presence of residual porosity are comparable to the properties of the best grades of steel containing expensive dopants and obtained by molding. This will solve the problem of developing a new generation of nanostructured metal (iron-based) materials with improved mechanical properties for the different areas of technology. This is due to the fact that in most of the proposed methods for the synthesis there are obtained particles characterized by a fairly broad curve of particle size distribution \u201313;necessity of development of precise methods for synthesis of a new generation of composite nanomaterials. If staying, for example, on one type of the composite nanomaterials with the metal matrix, the existing methods for producing such materials often include introduction of nanoparticles or nanowhiskers in the molten metal. Almost always particles in the solid are not evenly distributed in metal matrix volume. This leads to a slight increase in the strength characteristics of composite metal nanomaterials , 15.In the past two decades scientists have paid much attention to obtaining of composite nanomaterials based on nanoobjects with varying dimensions , 2. DuriThus, when considering the preparation of new generation of nanostructured composite nanomaterials, we should talk about the material in whichThe solution of the above problem involves the creation of material with required level of structural organization. In general, we are talking about artificial \u201csuper control\u201d in the solid as an alternative to natural regulation processes, mainly represented by the process of crystallization.the physicochemical aspect includes consideration of composition and crystal (sometimes amorphous) structure;the topological aspect includes consideration of the spatial distribution of the composition and structure ;the electronic aspect concerns electronic states of a solid substance under consideration.The crystal structure of a solid is characterized by two main parameters: structural units (from a single atom to big molecular objects) and ordering degree . Auxiliary parameters are needed for describing artificially synthesized highly organized structures and for characterizing these complex systems. As a rule, the task of any solid-phase synthesis is creation of a certain structure. There are several aspects of understanding the term \u201csynthesis of a solid chemical compound\u201d or its physicochemical analog \u201csynthesis of a certain structure\u201d:The notion of topology implies a complex structure of matter. Therefore, we consider in more detail the notion of topology for highly organized solid compounds. This notion is related to the possibility of various spatial atomic distributions in an artificially synthesized substance \u201316.L > 30\u2009nm), have long been prepared aH denotes an adhesive connection with a layer of silicon with iron layer. The product of 1 cycle of reactions ML-ALD\u2014\u2261Si\u22ef[Fe]a\u2013CH=Ti\u2013(CH3)2\u2014contains titanium-carbon groups (\u2013CH=Ti\u2013(CH3)2) associated covalent bond with surface methyl sites capable to reacting with TiCl4 acco acco4) aThe synthesis was carried out on silicon wafers with a sputtered film of pure iron with thickness of ~10\u2009nm. The sample was alternately treated at 500\u00b0C in a flow-type reactor by carbon tetrachloride and methane.3) on the iron surface the water contact angles were studied. The study of contact angle was conducted by photomicrograph method. Based on a study of water contact angle of samples , regular increase of water contact angle from 43\u00b0 to 76\u00b0 and 94\u00b0 was identified which indicates the transition to higher packing density of surface groups in the case of reactions involving methyl (\u2013CH3) group group . Study o3) group \u20134) was was 3) oData on the chemical analysis of titanium have concluded , that at4 with the surface leads to dissociative process: TiCl4 \u2192 TiCl3 + Cl2, resulting in chlorine chlorinating the surface to form complex C\u2013Cl that blocks it from further reaction with TiCl4.Decline of the titanium content at warming temperature of 450\u00b0C can be associated with the thermal decomposition of surface groups. Apparently, in these conditions the interaction TiClMacrohardness study and thin section structures of the synthesized samples also shoThe study of dependence of titanium content on silicon samples with metallic iron layer from treatment showed that the growth dependence of the titanium content is linear and after 5-6 cycles the titanium content increasing becomes constant. Note that the optimum concentration of the hydrogen significantly increases the rate of titanium carbide formation. This is probably due to the suppression of the reaction of free carbon formation.2/g. Treatment of iron powder in a quartz reactor was performed in a flow of dry argon.Obtaining of titanium carbide on the surface of dispersed iron was carried out on particles with size 40\u201380\u2009nm and specific surface area 6\u2009mTo study the thickness effect of the deposited layer of titanium carbide on the mechanical properties of the samples, obtaining of ultrafine micron films of titanium carbide by chemical vapor deposition (CVD) and nanolayers of titanium carbide by atomic layer deposition (ML-ALD) was investigated. Treatment of iron powder was performed in a quartz reactor in dry argon flow.In gas phase deposition of titanium carbide formation of continuous frame in the pores of metal workpiece begins with the formation of island structures on the surface. This character of the formation is associated with the feature of the reaction of chemical deposition of titanium carbide as surface is energetically heterogeneous. This leads to different rates of growth of the titanium carbide on different sites and forming island structures\u2014three-dimensional nucleus of titanium carbide Figure .Feature of nanolayers obtained by ML-ALD is the absence of phase-formation (nucleation) under maintenance of certain synthesis conditions which allows more fine-tune of the functional properties of the resulting material.As a result of the synthesis there were synthesized examples of iron powder with different quantity of titanium carbide deposited on the surface. The content of titanium-carbon groups in the sample was determined by the titanium content. Analysis of titanium and carbon was performed by chemical method . Data of the chemical composition of samples are given in Observance of conditions of ALD reactions allows obtaining monolayers with certain chemical composition; the number of performed reactions controlled the thickness of the deposited layer of substance. Features of layers produced by chemical assembly are the absence of phase formation (nucleation) under certain synthesis conditions which allows to regulate more fine the functional properties of the obtained material.As it follows from From the X-ray diffraction analysis data there foAnalysis of the compaction and sintering of metallic iron samples nanostructured by nanowires TiC allows finding the conditions for obtaining metallic samples with low porosity. To achieve the lowest porosity (5-6%) the sintering of compacts is necessary to be carried out by heating from 500 to 800\u00b0C for 2 hours with intermediate equalizing at 800\u00b0C in hydrogen for 3 hours.Mechanical properties of nanomaterials essentially depend on the grain size. At large grain sizes a strength and hardness growth with decreasing grain size is determined by introduction of additional grain boundaries that are obstacle to dislocation motion and at small nanoscale grains a strength growth is determined by low density of existing dislocations and the difficulty of formation of new dislocations .\u03c3v) is determined. These studies are presented in To study the mechanical strength of the samples of metal (iron-based) composite materials nanostructured titanium carbide ultimate stress limit-ultimate resistance composite materials nanostructured titanium carbide using surface structuring process is promising for producing of new generation composite materials.Through a nanostructuring process of metal (iron) matrix developed by authors the synthesis of samples of nanostructured metal matrix composite with nanostructural (1\u201350\u2009nm) inhomogeneities on the basis of TiC with the crystal structure in the volume of the iron matrix was reformed.2/g were investigated.The synthesis, pressing, and sintering conditions of dispersed iron nanoparticles (40\u201375\u2009nm) with a surface area of 6\u2009m4, CH4) were studied and it was found that methyl (CH3) groups are most suitable for the synthesis of carbide nanostructures in inert environment compared with hydroxyl (OH) or methoxy (OCH3) groups.The features of the behaviour of surface chemical reactions of functional groups on the metallic iron surface with low molecular substances (TiCl3) functional groups, TiCl4, and CH4 is developed.A method of synthesis of titanium carbide nanostructures on the surface of dispersed iron particles using methyl composite material with low residual porosity with a dispersed phase based on titanium carbide.Mechanical properties of the metal (iron-based) composite material with dispersed phase based on titanium carbide are studied and it is found that it is comparable with the best grades of steel obtained by moulding.The results suggest that the creation of metallic (iron-based) composite materials structured by titanium carbide nanostructures using the process of surface structuring is promising for the preparation of a new generation of composite materials."} +{"text": "The aim of this study was to determine whether reclassifying the Fuhrman grading system provides further prognostic information.We studied the pathological features and cancer specific survival of 237 patients with clear cell cancer undergoing surgery between 1997\u20132007 in a single centre. The original Fuhrman grading system was investigated as well as various simplified models utilising the original Fuhrman grade.The median follow up was 69 months. On univariate analysis, the conventional Fuhrman grading system as well various simplified models were predicative of cancer specific survival. On multivariate analysis, only the three tiered modified model in which grades 1 and 2 were combined whilst grades 3 and 4 were kept separate was an independent predictor of cancer specific survival . Furthermore this simplified model demonstrated a stronger relationship to recurrence than the conventional 4 tiered Fuhrman grading system.A modified, three-tiered Fuhrman grading system has been demonstrated to be an independent predictor of cancer specific survival. In the UK alone, approximately 9000 new cases of renal cancer are diagnosed each year and nearly 4000 die of their disease . OverallCurrently, the TNM stage and tumour grade are the most widely used tools to predict survival. Various grading classifications for clear cell carcinoma based on morphological features have been proposed . Cancer specific survival rates were generated using the Kaplan Meir method. The log rank test was utilised to compare significant differences between subset groups using univariate analysis. Multivariate analysis was carried out based on the results of the univariate analysis. Multivariate Cox regression analysis was performed to identify those factors that were independently associated with cancer specific death. A stepwise backward procedure was utilised to ascertain which of the variables had a significant independent relationship with survival.The patient characteristics are shown in Table\u00a0Univariate analysis of potential predictors of cancer specific survival showed that the majority of the grading models were statistically significant predictors of cancer specific survival Table\u00a0. On multx2 analysis of the various simplified grading models, whilst majority of the grading models demonstrated a positive correlation with T Stage was an independent predictor of cancer specific survival on multivariate analysis. Furthermore, this modified model was also one of only two to correlate to disease recurrence.Several studies have demonstrated that the Fuhrman grading system is capable of predicting cancer specific survival independent of pathological stage (Frank et al. As with most studies examining the modification of the Fuhrman grading system, the present study is limited due its retrospective nature with no analysis of inter or intra observer variability when assigning the Fuhrman grade and no external review of nuclear grade.In the present study, a simplified version of the Fuhrman grading system whereby grades 1 and 2 are combined and grades 3 and 4 were kept separate was shown to be an independent predictor of cancer specific survival and demonstrated a positive correlation to disease recurrence suggesting that this modified model can be considered an option for the purposes of prognosis in those with clear cell renal cancer. Further work is required in terms of a prospective study for validation."} +{"text": "The Thousand Genomes Project has revealed the extraordinary scale of human genetic variation such as each person inherits ~12,000 protein-changing single nucleotide variations (SNVs) including up to 100 premature STOP codons creating an immense challenge to investigate the physiological consequence of this type of genetic variation in experimental animals.de novo mis-sense SNV mutations spread across the genome of individual offspring from ENU-mutagenized C57BL/6 mice [To develop a new strategy to meet this need by using whole exome capture, massively parallel DNA sequencing and computational analysis to sensitively and specifically identify 40-50 L/6 mice .in vivo function is essential for normal processing of MHC invariant chain and terminal B cell and DC maturation.In this presentation we demonstrate how direct sequencing of animals with independent defects in B cell development resulted in the identification of the causative mutation both in genes of previously known and unknown function without meiotic mapping. This approach has resulted in the identification of a new phospholipid transport pathway that is crucial for normal B cell development in the bone marrow and the By sequencing animals from defined strains and also founder animals of ENU mutant pedigrees two generations before the phenotypic screens we have started to build a database of missense mutations containing currently close to 7000 mutations in mouse pedigrees actively breeding and immediately available for experimental analysis. All data is made available from the missense variant database (pb.apf.edu.au/phenbank).This approach transforms mammalian experimental genetics and opens up an unparalleled source for experimental models of human disease and validation of human disease associated SNVs."} +{"text": "MLH1 mutation carriers were found to be at increased risk of disease. A combined analysis of the three datasets was performed to better define this association.For a decade researchers have been searching for modifier genes in individuals with a molecular diagnosis of Lynch syndrome but the task has proven difficult as discordant results seem to be the rule rather than the exception. Recently, two colorectal cancer (CRC) susceptibility loci have been found to be significantly associated with an increased risk of CRC in Dutch Lynch syndrome patients irrespective of which gene was mutated. In a combined study of CRC risk in Australian and Polish Lynch syndrome patients only The three populations combined totalled 1359 individuals from 425 families with a molecular diagnosis of Lynch syndrome. To date, this represents the largest Lynch syndrome cohort examined for modifier genes. Seven SNPs, from 6 different CRC susceptibility loci, were genotyped by both research groups and the data analysed collectively.MLH1 mutations harbouring the CC (variant) genotype of SNP rs3802842 are at increased risk of CRC and develop CRC on average 11 years earlier than individuals with the AA (wild type) genotype. All females carrying the CC genotype of SNP rs3802842 are at increased risk of CRC , while female MLH1 mutation carriers are at highest risk .Individuals with To investigate whether a cluster of risk alleles increases the risk of CRC, SNP rs3802842 was combined with the other six SNPs additively. MLH1 mutation carriers harbouring 3 risk alleles for SNP combination; rs3802842 (11q23.1) + rs16892766 (8q23.3) display an increased risk of CRC and an immense difference in the age of diagnosis of CRC of 28 years is observed compared to individuals with 0 risk alleles. While SNP combination; rs3802842 + rs10795668 (10p14) displays an increased risk of CRC for all females harbouring 4 risk alleles .MLH1 mutations and all Lynch syndrome females are genotyped for two SNPs in each group so that a personalised risk assessment and tailored surveillance program can be offered to patients at increased risk of CRC and therefore likely to develop their CRCs at much younger ages than the average age of disease onset.These results confirm the role of modifier genes in HNPCC. We recommend that Lynch syndrome patients with"} +{"text": "Text was introduced into the second paragraph of the Discussion section. The correct version of the paragraph is available below.\"Our modelling complements that of Williams et al. [15] in exploring ranges for key quantities. We vary changes in HIV incidence independently from ART coverage, allowing for more or less effective control of HIV; we consider a range of effects of ART on immune status [4]; we explore waning protection and different life expectancies on ART, reflecting long-term uncertainties at the individual and programmatic level.\""} +{"text": "Chinese Hamster Ovary (CHO) cells are widely used for the large scale production of recombinant biopharmaceuticals. These cells have been extensively characterised and approved by regulatory authorities for production of biopharmaceuticals. During the last years more and more cell-line engineering strategies have been developed to enhance productivity and quality. CHO cell line engineering work has made remarkable progress in optimizing products or titers by focusing on manipulating single genes and selecting clones with desirable traits. In this work it is shown how cell line engineering approaches enable the expression of a challenging to express \"novel therapeutic protein\". The expression of the \"novel therapeutic protein\" in CHO cells resulted in significant reduced cell growth as well as low productivity.Using customised CHO specific microarrays the gene expression profile of CHO cells expressing the \"novel therapeutic protein\" was analysed. The expression of the \"novel therapeutic protein\" resulted in a significant downregulation of all mitochondria encoded genes. The downregulation was more than 40 fold for some of these genes Figure . This maA variety of cell line engineering approaches were performed to circumvent cell growth inhibition caused by down regulation of mitochondrial encoded genes with the aim to improve expression of the \"novel therapeutic protein\". In the first approach the expression of \"gene A\", which was assumed to trigger the down regulation of the mitochondrial encoded genes, was repressed more than 10 fold using shRNA technique. shRNA is a sequence of RNA that makes a tight hairpin turn that can be used to silence target gene expression via RNA interference. Expression of shRNA was accomplished by delivery of stable integrated plasmids. Cells with reduced expression of \"gene A\" showed an improved cell growth and higher expression of the \"novel therapeutic protein\" Figure . HoweverTo completely eliminate the cell growth inhibition a knockout of \"gene A\" was performed using ZFN technique. ZFNs are artificial restriction enzymes generated by fusing a zinc finger DNA-binding domain to a DNA-cleavage domain. Plasmids encoding ZFNs were transiently transfected in the parental CHO cell line. ZFN cleaves \"gene A\" which is then repaired by non-homologous end joining. This is often error prone and resulted in the generation of mutant alleles. Three clones were identified with mutation in both alleles of \"gene A\" resulting in shifts of the reading frame and therefore only nonfunctional premature termination products are encoded.Knockout of \"gene A\" resulted in complete elimination of cell growth inhibition and the expression of mitochondria encoded genes Figure was restThis example illustrates that transcriptomic analysis can support and facilitate the understanding and solving of specific issues during the expression of therapeutic proteins. Novel cell line engineering methods as ZFN technique are powerful tools to solve definite issues in production of therapeutic proteins in biopharmaceutical industry."} +{"text": "Nobody can forget the devastating 7.0magnitude earthquake that struck poverty-stricken Haiti, Port-au-Prince recently on 12 January 2010. At least 75,000 people were killed and hundreds of thousands became homeless; authorities are worried about sanitation and outbreaks of disease in the region. The camps are full of people and there are not even the most basic facilities for any others. Humanity obliges us to help them in any possible way. I reviewed the literature about the hepatitis E virus infection in Haiti and I would like to draw the scientists\u2019 attention to this important topic in this time of crisis. The Hepatitis E virus (HEV), a small non-enveloped RNA virus, is a causative agent of acute hepatitis especially found in developing countries. HEV is an enterically transmitted viral disease of great importance to public health in the developing countries 2].HEV h.HEV h2].Travelling and increased communication between communities that are living in different countries can facilitate the transmission of different pathogens and the introduction of new pathogens into new geographic areas and exposes non-immune individuals to infection. In 1995 four cases of acute HEV infection with jaundice were identified among Bangladeshi soldiers whose battalion had recently been deployed to Haiti as peacekeepers . This coThe only prophylactic measures against HEV infection that can be currently recommended are improved sanitation and especially sanitary handling of food and water. The starting of educational programs to stress sanitary disposal of feces and careful hand washing after defecation and before handling food is important. The availability of clean water supplies reduces the risk of contraction, and boiling the water appears to inactivate the HEV 19]20].[20].19][.[20].19]"} +{"text": "Mechanistic developmental models of the primary visual cortex V1) in mammals have been able to replicate many of the large-scale spatial features of V1 neurons from experiments, such as their spatial receptive fields and the spatial organization into maps in V1 for LGN and cortThe transient responses of LGN neurons in TCAL are due to lateral inhibition between LGN/RGC cells already present in GCAL, but originally for purposes of contrast gain control. The transient responses at the V1 level are partly inherited from LGN but also reflect lateral connectivity in V1, originally for the purposes of map development. TCAL thus shows how the observed transient response properties can arise from the same mechanisms that lead to map development in mechanistic Hebbian models ["} +{"text": "Cone-beam computed tomography (CBCT) has been accepted as a useful tool for diagnosis and treatment in endodontics. Despite a growing trend toward using CBCT in endodontic practice the CBCT images should be interpreted carefully. This case report presents a case that showed radiolucency inside and around a tooth which was free of pathologic changes under a dental operative microscope and conventional radiographs. A male patient was referred to an endodontic office for evaluation of radiolucency inside and around tooth #21 in his CBCT images. The post and crown over the tooth was removed and the tooth was observed under a dental operative microscope. Clinical examination as well as direct observation under a dental operative microscope showed no pathological lesions inside and around the tooth. The misdiagnosis was based on an artifact on CBCT. Despite the advantages of CBCT images as a great radiographic aid in endodontic practice, in the presence of metallic structures such as post and core the images should be interpreted with caution. The introduction of cone-beam computed tomography (CBCT) has made a revolutionary impact on the diagnosis of complicated cases in endodontic practice. Several investigations and case reports have shown that CBCT is a useful device for diagnosis of periapical lesions, detection of vertical fracture, detection of invasive cervical resorption, investigating root canal anatomy and endodontic mishaps 2]3]4][3][4]2][[4][3][4][3][4]2]6]7].[7].6][7].[7].6][7However, CBCT technology has not been recommended as a routine radiographic aid for all patients in need of endodontic treatment . In a reThis report presents a case with radiolucency inside and around a mandibular premolar tooth that was clinically and radiographically free of pathologic lesion.A 56-year-old male was referred for evaluation of his left mandibular first premolar tooth (#21). His past dental history showed that the tooth had been retreated 11 years previous followedThe patient\u2019s chief complaint when referred to a periodontist office was fracture of the ceramic of the bridge which he wished to replace with two single tooth implants in his edentulous ridge. A CBCT was ordered by the periodontist and during the evaluation of the images a radiolucent lesion was detected around the tooth #21 at both coronal and sagittal views . The briThis case report shows how CBCT can cause artifacts in teeth with intracanal posts; this is a significant disadvantage of CBCT imaging technique. Presence of a metallic artifact in the field of scan will produce streaks and dark bands because a portion of the beam passes through an object at one position making it harder in the other tube positions. Several techniques and equipments have been described to overcome this predicament: filtration , calibraIn our study, the radiolucent lesion around the tooth root was at the coronal third and therefore, should have had some negating effect on the periodontal status of the tooth during clinical/radiographic examination. However, as the pocket depth was normal and so was the periodontal structure and texture, we can conclude that the tooth and its surrounding structures were free of any pathologic changes.In the present case, DOM was used as a diagnostic aid for evaluating the root structure. Direct view by DOM showed no discrepancy at the post space.There is no doubt that CBCT is a valuable aid in endodontic practice; however, AAE and AAOMR have stated that it should not be ordered routinely for all patients in need of endodontic treatment . In factIf the CBCT is retaken after removal of the post and core, the radiolucency around and inside the tooth will disappear showing that it was an artifact. However, assessment of the possible risks and benefits of retaking the CBCT image as well as ethical concerns contraindicated this step. Moreover, Shemesh et al. have reported no significant difference between CBCT and digital periapical radiography for detection of root perforation .Both coronal and sagittal views of the tooth CBCT falsely emulated root perforation image contraindicating the periapical radiograph and clinical findings of the tooth. In our case study, an inappropriate post-space preparation had left an empty space between the post and the root canal filling material which could have mislead the clinician in believing that the CBCT showed a real lesion.In conclusion, the present case has shown that CBCT images should be interpreted with caution especially with post and core restorations."} +{"text": "During production formatting errors were introduced into Table 3, \"Correlations between structural laterality indices of ROIs and language tests in two age groups.\" Every number in the fifth row has been incorrectly moved one cell to the right. The correct version of Table 3 can be found here:"} +{"text": "Intra articular injections are an effective and widely used technique that involes the direct application of a corticosteroid compound such as triamcinalone hexacetonide into a joint with active synovitis. Local IAIs can avoid many of the unwanted adverse effects of sytemic steroids but in children younger than 11 years or those with a polyarticular presentation a general anaesthetic is typically required. Traditional local anaesthetic agents include topical agents such as lignocaine or gaseous agents such as entonox (nitrous oxide). We have introduced an unique form of analgesia for this procedure since the establishment of our national unit in 2006 in form of fentanyl lollipops (Actiq).To evaluate the efficacy & safety of fentanyl lollipops for children with JIA undergoing IAIs.A total of 19 patients were studied . Pain scores an hour after the procedure were recorded using a 0\u201310 cm visual analogue scale (VAS). Parents and patients were reinterviewed at a later date regarding the effectiveness of the lollipops as a form of pain relief and whether they would consider this form of analgesia for their child again.A total of 25 joints were injected in 19 patients . The median patient and parent pain scores were 1.5 and 4.0 respectively. There were no serious adverse events in any patient. All parents agreed that fentanyl lollipops were safe and effective, and over 90% would opt for this form of analgesia again.Fentanyl lollipops are a safe and an effective form of analgesia for intra-articular injections in children. A significant number of parents overestimated pain related to the procedure compared to their child."} +{"text": "UK national HIV testing guidelines were released in September 2008 and disseminated in our trust through emails to consultants and a grand round presentation. These aimed to promote patient HIV testing by all clinicians regardless of specialty and to trigger testing when specific indicator diseases were diagnosed. The guidelines also state that testing should be considered in all general medical admissions in areas where HIV prevalence exceeds 2 in 1000 of the population. Our audit looked at HIV testing at Blackpool Victoria Hospital from October 2007 to September 2009. This represents 1 year before and 1 year after the publication of the new guidelines.We used our laboratory database to identify proven cases of common diseases where HIV testing is indicated. We then cross referenced this against records of HIV tests performed. We also took the total number of HIV tests requested from the medical wards and compared this to the number of acute medical admissions. We found that in the year after guidelines were published and disseminated within the trust the rate of HIV testing for indicator diseases was as followed:- hepatitis B 6%, hepatitis C 28%, tuberculosis 9%, lymphoma 14%. In the case of hepatitis this represented a decrease on previous years. The overall rate of HIV testing in acute medical admissions was 0.5%.Our results demonstrate that in our trust traditional methods of guideline dissemination did not lead to effective implementation on this occasion. We are now assessing alternative methods such as marking all positive laboratory results for indicator diseases with the phrase 'HIV TESTING SHOULD BE CONSIDERED' and the possible implementation of universal opt out screening in our Clinical Decisions Unit for all acute general medical admissions."} +{"text": "Host response to infection with pathogens such as influenza viruses serves to primarily generate immune responses in an attempt to counter the invading pathogens. Consequently, how the host interacts with the virus not only has important influence on its pathogenesis, but also its transmission in a population and dissemination within the infected host. On the other hand, an overly active immune response may actually lead to excessive inflammation, which could be detrimental to the host as many lines of evidence have suggested for human H5N1 infection and the 1918 H1N1 pandemic virus. Macrophages are key orchestrator of the immune response and being one of the most abundant cell types in the respiratory system that can be infected with influenza viruses. Therefore, this study aims utilize high-throughput mass spectrometry to compare time series global proteomic profiles of primary human monocyte-derived macrophages infected with highly pathogenic H5N1 and seasonal H1N1 influenza viruses, in order to allow combinational analysis of proteomic datasets with existing body of transcriptomic datasets to provide further insight into the cellular and molecular host response to influenza virus infection. Global proteomic profiling of influenza virus infected macrophages revealed that many of the proteome changes could not be accounted for by transcriptomic profiling with microarrays. The low concordance of the global proteome profiling results with transcriptomic data indicates that high throughput quantitative proteomic analysis can provide a significant additional dimension to enable combinational analysis with existing datasets from studies using high-throughput genomic platforms. Results from this study suggest proteome changes in infected macrophages that were common to both viruses could be involved in processes that are similar, such as viral replication as both viruses replicate equally well in our macrophage model. On the other hand, pathways derived from analysis of differentially affected proteomes may contribute to the high pathogenic nature of H5N1 viruses. Therefore systematic integrative analysis of datasets from different sources could significantly contribute to detecting differentially expressed genes or pathways that are of relevance during virus infection and allows assessment of heterogeneity. This is likely to contribute to target identification for host-directed treatment of disease caused by influenza viruses."} +{"text": "We present an extremely rare case of late metastases of breast cancer to both suprarenal glands 28 years after mastectomy. The patient originally underwent Patey\u2019s radical mastectomy of the left breast. In the follow-up, metastases were detected in the skin of the thorax and labia majora and were subsequently resected. During the most recent hospitalization metastases to both adrenal glands were detected and removed. In genetic examination the entire coding sequences of BRCA1 and BRCA2 gene were screened for mutation by direct PCR product sequencing as described before by Gorski et al. No BRCA1 and BRCA2 gene mutations were found.Histological examination revealed breast cancer metastasis to the adrenal glands. In our opinion our case can be the latest described metastases of breast cancer. The described case was an early stage of primary cancer (T1N0M0). Patients after breast cancer resection should still be followed up for late metastases. Late metastases including atypical sites should always be suspected regardless of time from initial presentation. The correlations between mutation and metastases of breast cancer needs to be discussed."} +{"text": "There is lack of consensus over what sample size should be used for pilot trials to inform the design of definitive randomised controlled trials. The majority of the existing recommendations focus on estimating the variation of a continuous outcome and relatively little attention is paid to binary outcomes. The aim of this research was to investigate the sample size required to precisely estimate parameters such as event, consent and attrition rates. We assume that the pilot study (and the definitive RCT) will be a two parallel group treatment versus control design.We simulated binomially distributed outcome data with true event rates between 0.1 to 0.5. We examined the variation in estimates, of the event rate, from pilot study sample sizes of 10 to 150 in incremental steps of 5. We assessed the precision of the estimated event rate by calculating the relative a 95% confidence interval (CI) using the Wilson method, and the percentage gain in precision per increase in sample size of 5.The width of the confidence interval plots suggests a sample size that once a sample size of 60 is achieved the relative gain in precision for each additional 5 subjects drops below 5%.If the primary outcome of a planned RCT is a binary outcome then the pilot should contain 60 subjects in each group to estimate the event rate with a reasonable degree of precision. This is substantially larger than the currently common practice regarding continuous outcomes."} +{"text": "In 2010; 12(5):568-571 issue of IRCMJ journal, an article about herpetic encephalitis (HE) in children was published with the following title: Clinical Manifestations, Laboratory Findings and Outcomes of Children with Herpetic Encephalitis in Amirkola Children Hospital, Northern Iran.The authors found that during 2 years 34% (17 cases) of the 50 patients with clinical diagnosis of encephalitis had positive PCR for HSV, only 28% of their HE cases had altered consciousness but they did not say anything about focal neurologic signs and they did not have any disability or mortality and all of the patients were discharged in good general condition.I think that there has been a technical problem with HSV PCR in this research because the incidence of HE was unacceptably high and the prognosis was unbelievably good. Their cases must have been cases of viral meningitis with false positive HSV PCR probably due to contamination.The annual incidence of HE in the whole population was between one in 460000 to 2.2 per million population per year and one-third of all cases occurred in children and adolescents.[2]3] Am Am3] AmiOur experience in Pediatric Infectious Diseases Services of Mashhad and Shiraz which are 2 of the first five big cities of Iran and much bigger than Babol showed that in the past 10 years, the mean number of HSV encephalitis cases has been less than 2 patients per year. We have had the problem of the false positive HSV PCR in Nemazee Hospital (Shiraz) at 2000-2002 period, when we encountered with an outbreak of positive HSV PCR among children with aseptic meningitis that we already had discharged them (at very good condition without giving acyclovir) with clinical diagnosis of viral meningitis, many of them were mumps meningitis."} +{"text": "Rhodiola rosea depends on dietary macronutrient balance\u201d[Longevity & Healthspan. Mahtab Jafari has been removed from the corrected author list above and all authors also agreed to the revised order of the corrected author list.Following publication of the article entitled \u201cLifespan extension and delay of age-related functional decline caused by balance\u201d Mahtab JRhodiola rosea.The authors would like to thank Mahtab Jafari for her help in preparing an earlier version of the manuscript and the arrangement of HPLC analysis for rhizome of Carpathian"} +{"text": "A diagnosis of a second primary breast cancer occurs in between 2-11% of women affected by breast cancer in the general population, but is increased in frequency in women with a family history of breast cancer. We investigated whether the common genomic variants described in breast cancer GWAS studies were determinants of the risk of bilateral breast cancer and compared the effect to that of family history.The Victorian FCC Translational Breast Cancer Cohort consists of the index cases of 1374 families with a high risk family history of breast or ovarian cancer. The cohort has been extensively characterised, including detailed personal and family history and has undergone genetic testing for both high penetrance genes and low penetrance variants associated with breast cancer. 1143 women in the cohort have had at least one breast cancer and 208 women have had multiple primary breast cancers. For this study genotypic data from 22 common genomic variants (SNPs) previously identified in breast cancer GWAS were analysed for each index case and compared to the same set of genotypes from an Australian population based control group . A Polygenic Risk Score (PRS) was calculated using a multiplicative model as the sum of the log odds ratios associated with each allele. Unilateral and bilateral cases were compared on the basis of both the measured polygenic risk and family history parameters.768 women affected by breast cancer were identified in whom BRCA1 or 2 mutation was excluded by sequencing and MLPA. The cohort was followed up an average of 8.8 years since their diagnosis of breast cancer with 135 (18%) women having a diagnosis of a second primary breast cancer. The average Polygenic Risk Score in the group was 1.30 (Log OR) but was significantly increased in the women with a history of bilateral versus unilateral breast cancer (1.40 vs 1.28 p=0.018), with no difference between the groups in follow up (or time to cancer diagnosis) or age of first diagnosis . Measures of the family history including the number of breast cancers in first degree or any relatives, family history of bilateral breast cancer, male breast cancer or ovarian cancer were also examined but showed no significant differences between women with unilateral or bilateral breast cancer.To examine the clinical significance of the difference in PRS the cohort was divided into high, intermediate and low polygenic risk groups. The OR for bilateral breast cancer between the high and low risk groups was 1.9 and survival analysis showed a significantly increased rate of second primary breast cancer in the high versus low polygenic risk group (cumulative hazard to 20 years of 0.39 vs 0.24).Analysis of polygenic risk, determined by common genomic variants, has the potential to stratify women affected by familial breast cancer in relation to their risk of second primary breast cancer, independent of measures of family history."} +{"text": "Staphylococcus aureus (MRSA) antibiogram patterns for 14 antibiotics based on a decade of using the First 100 clinical isolates from inpatients and outpatients tested in participating laboratories. The First 100 isolates provided by 5 Queensland hospitals to AGAR represent inpatient isolates for every second year, 2005 to 2009, and outpatients for every second year, 2000 to 2008. Validity of the resistance patterns idenitfied by the samples is imperative for national surveillance.The Australian Group on Antimicrobial Resistance (AGAR) provide national reports on Methicillin resistant and methicillin sensitive AGAR data were tested for ability to demonstrate resistance patterns similar to the years for full datasets.A percentage point (PP) difference between the antibiograms for the first 100 samples and the corresponding 12-month dataset was estimated as a measure of validity. Robustness of the consecutive sampling of the first 100 isolates was tested using 15 random iterations of 100 isolates from the corresponding full 12-month datasets for inpatients and outpatients. Validity and the effect of phenotypes on the AGAR resistant patterns was tested against 6 antibiotics for inpatients and 5 antibiotics for outpatients.AGAR inpatient data for 2007 and 2009 demonstrated significantly higher resistance levels compared with the full dataset with exception of Clindamycin and Gentamicin for 2009. In the most recent outpatient sampling, 2008, AGAR estimated a significantly lower level of resistance to all 5 antibiotics. Resistance patterns identified from 15 iterations indicated random sampling does not improve the validity of in- or outpatient antibiograms. The resistance patterns for inpatient and outpatient full datasets were driven by AUS-2/3 and EMRSA15 phenotypes with 95% of resistance removed on removal of these phenotypes.Given the small numbers of MRSA isolates and the effect of endemic phenotypes valid antibiograms and annual fluctuations require the entire annual dataset for validity.None declared"} +{"text": "In the Acknowledgments, there are two errors in the first names of members of the NIPPON DATA80/90 Research Group:Hiroshi Kiyohara should be Yutaka Kiyohara; Atsuhi Hozawa should be Atsushi Hozawa.The authors regret these errors."} +{"text": "Sequence variations which affect the peptide binding groove of the major histocompatibility complex (MHC) class I allele HLA-B are strongly associated with viral control in chronic HIV infection. We sought to determine if these differences affect primary HIV infection and establishment of the early viral set point.We longitudinally followed 428 individuals during primary HIV infection. In 110 individuals, we were able to determine the viral set point at six months following diagnosis. Associations between known genetic polymorphisms in HLA class I residues and HIV viral load and viral set point were identified.The identity of the amino acid at position 97 in the peptide binding groove of HLA-B was significantly associated with the level of initial viremia in acute infection (p=0.04) and the viral set point (p=0.025). Individuals with valine at position 97 had a nearly 10-fold lower mean viral set point than those with serine. This association was dependent on presence of the B*57 allele, which was also associated with a lower viral set point. The initial viral load at the time of primary HIV diagnosis was closely correlated with the level of the subsequent viral set point .Control of HIV during acute infection and the viral set point are strongly associated with the amino acid in position 97 of HLA-B. These results provide evidence for genetic predictors of HIV control in primary infection and highlight the importance of sequence polymorphisms in the binding pocket of MHC class I which may be relevant to the development of future HIV vaccines."} +{"text": "In sample surveys, it is usual to make use of auxiliary information to increase the precision of the estimators. We propose a new chain ratio estimator and regression estimator of a finite population mean using linear combination of two auxiliary variables and obtain the mean squared error (MSE) equations for the proposed estimators. We find theoretical conditions that make proposed estimators more efficient than the traditional multivariate ratio estimator and the regression estimator using information of two auxiliary variables. The use of supplementary information provided by auxiliary variables in survey sampling was extensively discussed In this study, we proposed a new chain ratio estimator and regression estimator using linear combination of two auxiliary variates, and obtain the mean squared error (MSE) equations for the two proposed estimators. The proposed estimators, the traditional multivariate ratio estimator and the regression estimator using information of two auxiliary variables were compared at theoretical conditions. And we obtained the satisfactory results.y using one auxiliary information are defined by x is known.The classical ratio estimator and regression estimator for the population mean n is the number of units in the sampleY on X. iy and ix, respectively. iy and ixHereN is the number of units in the population; iy and ix respectively.The MSE of the classical ratio estimator isThe MSE of the regression estimator isKadilar and CingiMSE of this estimator is given as follows:x1 and x2 to estimate the population mean, i\u200a=\u200a1,2) denote respectively the sample and the population means of the variable ix ; Y and Y and The traditional multivariate ratio estimator and regression estimator using information of two auxiliary variables Y and X1, Y and X2, X1 and X2 respectively. The MSE of this traditional multivariate ratio estimator is given by The optimum values of The minimum MSE of The MSE of this traditional multivariate regression estimator is given byThe optimum values of The minimum MSE of We propose the multivariate chain ratio estimator and regression estimator using linear combination of two auxiliary variables as follows: The MSE of this new multivariate ratio estimator is given by The optimum values of The minimum MSE of The MSE of this new multivariate regression estimator is given byWhere The optimum values of The minimum MSE of Where We compare the MSE of the proposed multivariate ratio estimator using information of two auxiliary variables given in Eq. (17) with the MSE of traditional multivariate ratio estimator using information of two auxiliary variables given in Eq.(11) as follows:We compare the MSE of the proposed regression estimators given in Eq. (19) with the MSE of the traditional multivariate regression estimator using information of two auxiliary variables given in Eq.(13) as follows:n\u200a=\u200a70, from N\u200a=\u200a180 using SRSWOR. The MSE of these estimators are computed as given in Eqs.(11), (13), (17) and (19).The comparison among these estimators is given by using a data set whose statistics are given in MSE values of the traditional multivariate ratio estimator and regression estimator using information of two auxiliary variables and proposed chain ratio estimator and regression estimator using linear combination of two auxiliary variables can be seen in From The result shows that the condition (20) and condition (21) are satisfied. Therefore, we suggest that we should apply the proposed estimators to this data set.We develop a new chain ratio estimator and a new regression estimator of a finite population mean using two auxiliary variables and theoretically show that the proposed estimators are more efficient than the traditional ratio estimator and traditional regression estimator using two auxiliary variables in certain condition."} +{"text": "The cortical influence on spontaneous activity of single neurons in the dorsal lateral geniculate (LGN) and perigeniculate (PGN) nuclei were investigated in awake cats by means of reversible cooling of cortical areas 17 and 18 ,3.These results indicate that recurrent inhibition from PGN may play a homeostatic role in the cortico-thalamic loop by restricting thalamic oscillations within their natural functional range . The bufThe BR, FR and IBISI measures of spontaneous activity of PGN cells as a result of cortex cooling increased more than 50% of their original values and more than 20% for SPB while the changes of LGN activity were below 20% for all measures except ISI, which was the only case where the changes were larger in LGN than in the PGN cells Figure . The cha"} +{"text": "Perforation of Meckel's diverticulum by a foreign body represents an unusual and serious clinical occurrence. We present a case of a 4-year-old male who was admitted with symptoms of abdominal pain in the right iliac fossa, raising the suspicion of acute appendicitis. Exploratory laparotomy disclosed normal appendix and perforation of Meckel's diverticulum caused by a wood splinter. Meckel's diverticulectomy was performed and the child had an uneventful postoperative course. Preoperative diagnosis of perforated Meckel\u2019s diverticulum remains a challenging issue. Diagnosis should be considered in the presence of a right lower quadrant abdominal pain or a positive history of ingestion of a sharp foreign body Regarding the gender, although it occurs equally in both sexes, complications appear more frequently among males, with a reported three to four times greater incidence in males [1]. It is formed by incomplete obliteration of the omphalomesenteric duct and is located on the antimesenteric border of the terminal ileum [1]. The structure is usually regressed between the fifth and seventh week of the fetal life [1]. Meckel\u2019s diverticulum contains all three intestinal layers and maintains a separate blood supply from the viteline artery [1]. It is usually asymptomatic in the majority of cases for life [1]. We present an unusual case of perforation of Meckel\u2019s diverticulum in a 4-year-old child caused by a wood splinter. Meckel\u2019s diverticulum represents the most frequent congenital anomaly of the gastrointestinal tract with a reported prevalence of approximately 2% in the general population . Remarkably, in a study among 71 pediatric patients diagnosed with Meckel\u2019s diverticulum, painless rectal bleeding was the most prevalent initial manifestation [3]. Incidence rate of complications due to Meckel\u2019s diverticulum range from 4-16% [1] since the majority of the ingested objects pass through the gastrointestinal tract without problem [4]. Concerning the mechanism of perforation, it has been suggested to be the result of a combined effect of a local bacterial inflammation along with stasis and pressure necrosis to the diverticular wall [5]. In the majority of cases, the patients do not recall the ingestion. Perforation of Meckel\u2019s diverticulum by a wood splinter has been rarely reported in literature [6]. Fish bones, chicken bones [4] and food items are the most common causes of Meckel\u2019s diverticulum perforation [7]. Perforation of Meckel\u2019s diverticulum by a foreign body represents a rare complication [6]. Because clinical, laboratory and imaging features of complicated Meckel\u2019s diverticulum are not pathognomonic [4], the preoperative diagnosis is rarely established. Interestingly, in a study of 600 cases, Yamaguchi et al. reported a preoperative diagnostic rate of only 5.7% [8]. The most frequent initial diagnosis has been reported to be acute appendicitis [6]. This happens since as in our case, right lower quadrant abdominal pain is usually attributed to appendiceal inflammation [6]. Technetium-99m-pertechnetate scintigraphy is considered the most useful non-invasive diagnostic procedure in the pediatric population, for the detection of ectopic gastric mucosa [7], while laparoscopy is a useful diagnostic modality in ambiguous cases [7]. Abdominal tenderness located in the right lower quadrant along with leucocytosis and moderate elevated temperature, are the main clinical features that consist of the initial presentation of a perforated Meckel\u2019s diverticulum [7] along with antibiotics and peritoneal irrigation in case of localized or generalized peritonitis [5]. Early intervention is crucial especially when the patient\u2019s state deteriorates [9]. Controversy exists regarding the management of asymptomatic Meckel\u2019s diverticulum incidentally discovered during surgical operation [7]. Some physicians are supporters of a conservative attitude while others support prophylactic resection in order to minimize the risk of complications [7]. In this direction a number of criteria have been established in favor of diverticulectomy such as age (<40 years old), gender the size of the diverticulum (> 2cm) and the presence of adhesions [10]. Management of complicated Meckel\u2019s diverticulum consists of diverticulectomy in the majority of cases [1]. It usually represents an incidental finding during operation for other abdominal pathology. Symptomatic Meckel\u2019s diverticulum is rare and frequently misdiagnosed, even in developed countries [1]. For this reason, the condition should be considered in the differential diagnosis of right lower quadrant abdominal pain and positive history of a swallowed foreign body. Furthermore, surgeons have to maintain a high level of awareness for the morphological and clinical characteristics of this important anatomical structure in order to appropriately manage its complications. In 1933, Dr Charles Mayo stated that \u2018Meckel\u2019s diverticulum is frequently suspected, often overlooked and seldom found\u2019 [ Consent Written informed consent was obtained from the patient\u2019s legal guardian for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests The authors declare that they have no competing interests."} +{"text": "The CORTICUS trial doubts the value of hydrocortisone replacement for final outcome of septic shock . We hypoRetrospective analysis was made of prospectively collected data for 41 patients with septic shock (ACCP/SCCM 1992 definition) in the past year in two ICUs. Hydrocortisone was infused as suggested [P = NS). Cox regression analysis revealed that the only factor affecting final outcome was early start of hydrocortisone as opposed to appropriateness of antimicrobial treatment .Early start of hydrocortisone was determined by the quartiles of lapsing time as less than 24 hours. The impact of early start is shown in Figure Despite the observational approach, early start of hydrocortisone replacement in septic shock is a critical factor for outcome."} +{"text": "It is however a priori hard to justify that the effect of spikes in only one time bin from the temporal discretization determines the future state of the system. What happens if we use shorter/longer time bins than the characteristic time steps of the network? How do the inferred couplings change if we allow for interactions with memory of multiple past time steps? To answer these questions, we extend the kinetic Ising approach to higher-order Markov chains by introducing time-delayed interactions using (1) a set of couplings derived from scaling the original J and (2) an auxiliary set of couplings K. A model of this sort is closely related to the Generalized Linear Model and its simplicity allows for detailed analysis of the model parameters.Ising models with simple Markov chain kinetics have been recently introduced as a tool for inferring asymmetric interactions in neuronal networks . In suchK particularly improve the identification of these weak excitatory connections; see the right panel of Figure K is in general linearly dependent on J when this connection in the original network is excitatory, but they are less correlated when the connection is inhibitory. This demonstrates that the network has multiple characteristic dynamics which cannot be explained by simple kinetic Ising models.We apply this extended kinetic Ising model to two types of data sets: 1) a realizable case of randomly-connected Ising network with memory of past states and 2) a realistic cortical network simulation with cross-correlated Hodgkin-Huxley dynamics [ a realis a realizThe authors would like to thank John Hertz for providing the key simulations for the cortical column ."} +{"text": "Percutaneous pulmonary valve implantation (PPVI) requires the positioning of a stiff guidewire into one of the pulmonary branch arteries. An infrequent but commonly known complication is the \u201cjailing\u201d of one of the pulmonary branch arteries. However, even without apparent \u201cjailing\u201d of one of the pulmonary branch arteries, we suspect that the technique of stent placements often has an effect on the pulmonary perfusion ratio.The aim of this study was to assess the changes of the pulmonary perfusion ratio and their predictors after PPVI.We studied 47 consecutive patients who received PPVI without jailing of one the pulmonary branch arteries between December 2006 and September 2011. All patients underwent phase-velocity magnetic resonance before and after PPVI. Percent right pulmonary blood (RPA) flow was calculated as follows: percent right pulmonary blood flow = 100 x (RPA net flow volume / (RPA net flow volume + left pulmonary artery net flow volume)).A change of more than +/- 10% in percent RPA flow was considered as a significant change in pulmonary perfusion ratio.The positioning of the guide wire and the balloon during the intervention in respect to the protrusion into one of the pulmonary branch arteries was reviewed.The pulmonary perfusion ratio changed in 17 % of patients significantly by 15 \u00b1 4 %. The direction of the change of percent RPA flow was related in all these patients to the position of balloon during implantation of the most distal stent.PPVI without pulmonary branch intervention leads to a significant change in pulmonary perfusion ratio in 17% of patients. The change in pulmonary perfusion ratio is determined by the location of the balloon during implantation of the most distally situated stent. The clinical relevance of this new observation needs to be determined by prospective studies.No funding."} +{"text": "Peanut Allergy (PA) is one of the major causes for severe allergic reactions. Most children with PA also suffer from atopic eczema (AE). So far strategies for PA prevention are not established. The aim of our ongoing study is to compare if continuous feeding or a strict avoidance of peanut protein may prevent children with AE for the development of PA.Group A parents are advised to feed their children peanut at least three times a week, in Group B participating children strictly avoid peanut in their diet. Children are followed for one year. At the beginning and the end of the study standardized questionnaires are performed, blood samples are collected and medical examination (including SCORAD) is assessed. Children who will develop sensitization to peanut will undergo a double blind placebo controlled food challenge.In an open study design 460 children aged 5 to 30 months with AE and no detectable peanut-specific serum IgE will be divided into two groups. In Group A and 74 parents for Group B. The average age of the children in Group A is 19 months (ranging from 5 to 29 months) and in Group B 22 months (ranging from 6 to 28 months). The SCORAD assessed at the time of the first visit accounted 31 (ranging from 10 to 76) and 26 (ranging from 13 to 81) in Group A and Group B, respectively.So far 142 children are included. 68 parents decided for Many parents reported uncertainty about the current dietary recommendations. Despite the fact that the study is planned as an open study and parents can decide whether to feed peanut or not the decision for either group appears to be equal so far. The finalization of our study will hopefully contribute to improved PA prevention strategies.None declared."} +{"text": "The authors have become aware of concerns over the reliability of some of the results reported in the article.Figure 1 shows orthologs of SaveOBP3 and ApisOBP3 in the multicolored Asian lady bug Harmonia axyridis (HaxyOBP3) and in the marmalade hoverfly Episyrphus balteatus . The cDNAs encoding these proteins were cloned in the Belgium laboratory at the University of Liege and subsequent parts of the work, specifically protein expression, biochemical and biophysical studies and binding assays, were performed in the UC Davis laboratory. Recently, we attempted to re-clone HaxyOBP3 at UC Davis and were surprised that our attempts were unrewarding. We were also unable to clone the HaxyOBP3 cDNA using samples from different locations. Additionally, we performed Western blots using an aphid OBP3 antibody and found no evidence of HaxyOBP3 being expressed in the beetle antennae. We have also tried similar attempts with EbalOPB3 and were unable to clone EbalOBP3 cDNA or find the putative protein band.We therefore conclude that the \"orthologs\" from beetle (HaxyOBP3) and the hoverfly reported in the article are artifacts, probably derived from the template from the European grain aphid, Sitobion avenae.In conclusion, Figure 1 in the article is inaccurate and its results should be disregarded. The expression of the EbalOBP3 recombinant protein and the data presented in Figures 2 and 3 are accurate, however, readers should be aware that the EbalOBP3 gene reported is likely chimeric, and thus that the results do not represent proteins naturally expressed in the antennae of the marmalade hoverfly."} +{"text": "As an alternative to costly phenotypic assays, computational methods aim at predicting virus tropism based on the sequence and structure of the V3 loop of the virus gp120 protein. Here we present a numerical descriptor of the V3 loop encoding its physicochemical and structural properties. The descriptor allows for structure-based prediction of HIV tropism and identification of properties of the V3 loop that are crucial for coreceptor usage. Use of the proposed descriptor for prediction results in a statistically significant improvement over the prediction based solely on V3 sequence with 3 percentage points improvement in AUC and 7 percentage points in sensitivity at the specificity of the 11/25 rule (95%). We additionally assessed the predictive power of the new method on clinically derived \u2018bulk\u2019 sequence data and obtained a statistically significant improvement in AUC of 3 percentage points over sequence-based prediction. Furthermore, we demonstrated the capacity of our method to predict therapy outcome by applying it to 53 samples from patients undergoing Maraviroc therapy. The analysis of structural features of the loop informative of tropism indicates the importance of two loop regions and their physicochemical properties. The regions are located on opposite strands of the loop stem and the respective features are predominantly charge-, hydrophobicity- and structure-related. These regions are in close proximity in the bound conformation of the loop potentially forming a site determinant for the coreceptor binding. The method is available via server under http://structure.bioinf.mpi-inf.mpg.de/.Human Immunodeficiency Virus (HIV) requires one of the chemokine coreceptors CCR5 or CXCR4 for entry into the host cell. The capacity of the virus to use one or both of these coreceptors is termed tropism. Monitoring HIV tropism is of high importance due to the relationship of the emergence of CXCR4-tropic virus with the progression of immunodeficiency and for patient treatment with the recently developed CCR5 antagonists. Computational methods for predicting HIV tropism are based on sequence and on structure of the third variable region (V3 loop) of the viral gp120 protein \u2014 the major determinant of the HIV tropism. Limitations of the existing methods include the limited insights they provide into the biochemical determinants of coreceptor usage, high computational load of the structure-based methods and low prediction accuracy on clinically derived patient samples. Here we propose a numerical descriptor of the V3 loop encoding the physicochemical and structural properties of the loop. The new descriptor allows for server-based prediction of viral tropism with accuracy comparable to that of established sequence-based methods both on clonal and clinically derived patient data as well as for the interpretation of the properties of the loop relevant for tropism. The server is available under The entry of the human immunodeficiency virus (HIV) into human cells is initiated by binding of the viral envelope glycoprotein gp120 to the cellular CD4 receptor It has been shown that in the early, asymptomatic stages of infection mainly R5 viruses are observed, whereas progression towards AIDS is often associated with the emergence of X4 viruses th or 25th residues in the V3 region is indicative of an X4 virus Computational methods for predicting viral tropism based on the sequence of the V3 loop have been developed in silico coreceptor prediction Structures of gp120 including the V3 loop have been determined by x-ray crystallography The work presented here was motivated by the goal of developing a method for genotypic prediction of viral tropism that is at least as accurate as existing structure-based methods, i.e., more accurate than the widely used sequence-based method To meet this goal we present a systematic approach to incorporating physicochemical and structural properties of the V3 loop into the prediction of HIV coreceptor usage. We map 54 amino acid indices representing the physicochemical properties of amino acids onto the V3 loop structure and use methods from statistical learning to extract those features that are most informative of coreceptor usage. The extracted set of features represents a small fraction of the initial feature set and models based on this set attain higher prediction accuracy with decreased computational load. Our structural descriptor affords direct interpretation of the features of the V3 loop relevant for viral tropism by pointing to specific physicochemical properties of amino acids in different parts of the loop being predictive of coreceptor usage. We also applied our method to clinically derived (bulk) data and tested its usability for prediction of the MVC therapy outcome.full model) for coreceptor usage prediction. A training dataset of 1186 phenotyped V3 sequences from the Los Alamos database clonal dataset) was used for model development.The structural descriptor of the V3 loop is based on the published structure of the V3 loop sensitivity for brevity) calculated in a 10\u00d710-fold cross validation as cutoff-independent measures of the prediction accuracy. The radius of 8 \u00c5 yielded the AUC of 0.847 and a sensitivity of 0.587. Smaller or larger radii led to significant reduction of prediction performance . The performances of models with different parameter values are shown in We investigated the average number of residues covered by each sphere and selected the radius of 8 \u00c5 based on predefined criteria see . We testg2p model represents each amino acid as a binary vector of size 20 in which the position of a single 1 indicates the amino acid it encodes. This representation is used by sequence-based approaches, among others by geno2pheno[coreceptor] aaindex model encodes each amino acid as a vector of the 56 amino acid indices used in the structural descriptor.For comparison we implemented two sequence-based descriptors of the V3 loop. The In order to reduce the highly redundant feature vector of the structural descriptor of the full model and to investigate which features are informative for coreceptor usage we applied several feature selection procedures: Random Forest (RF) The sets of features selected by the three feature selection methods show a limited overlap. The initial feature set contains small subsets of highly correlated features that pertain to highly correlated amino acid properties in overlapping structure regions (spheres). These features convey the same information to the prediction method and can be therefore selected interchangeably by each method see . Howeverclonal model and used as the structural descriptor model in subsequent tests code 2QAD) Sander dataset) and the study of Dybowski et al. Dybowski dataset). These datasets have sequence overlap of 19% and 58% with the clonal dataset, respectively. The overlap varies presumably due to different content of the Los Alamos database We compared the performance of our method with the performance of previously published structure-based methods for tropism prediction HOMER dataset). We reran the feature selection procedures on this dataset and selected the best performing model (Lasso) as the clinical model. The clinical model showed AUC 0.774 and the sensitivity 0.463 We additionally tested the method on clinically derived patient data from the HOMER cohort We additionally tested the effect of amino-acid ambiguities on the prediction accuracy of the clinical model and found that the combined information from both types of sequence positions, ambiguous and non-ambiguous is important for tropism prediction see .+ T cell counts. Accordingly, adding such clinical information as additional features to the input of the clinical model significantly improved the predictive performance over that of the clinical model to AUC 0.803 and sensitivity 0.474 . Among the 53 sequences five originate from patients who experienced therapy failure. With the decision cutoff at the 11/25 rule specificity of the HOMER dataset three of these sequences were predicted as X4 viruses in accordance with the patient therapy outcome. The two remaining sequences of patients experiencing therapy failure that were predicted as R5 viruses were also phenotyped as R5 virus, which suggests the presence of undetectable minorities as the potential reason for the classification error.Finally, we tested the prediction performance of the clinical model on a dataset of sequences collected at therapy start from a German cohort of patients undergoing MVC therapy , which quantifies the correlation of the observed and predicted binary classification and is suited for datasets with an unbalanced class proportion. Therapy outcome prediction based on structural descriptor showed overall accuracy of MCC\u200a=\u200a0.34 comparing favorably with g2p model yielding MCC\u200a=\u200a0.29.Phenotypic characterization was only available for a subset of 28 sequences from the MVC dataset (Trofile dataset). In this subset the phenotype appeared to be the best predictor of the therapy outcome with one correctly predicted therapy failure case out of three and 23 correctly predicted therapy successes out of 25 (MCC\u200a=\u200a0.25). The clinical model reported the same number of correctly predicted therapy failure cases and lower number of 20 correctly predicted therapy success cases (MCC\u200a=\u200a0.10). The clinical model scored higher than the g2p method that did not report correctly any of the therapy failure cases and predicted correctly 23 therapy successes (MCC\u200a=\u200a\u22120.10). Additionally, the clinical model correctly classified all X4 sequences in the Trofile dataset reaching MCC of 0.660 and favorably comparing with the g2p showing MCC of 0.352.Overall, the phenotype as well as the structural descriptor model and the g2p model trained on clonal data showed a generally lower capacity of detecting therapy outcome compared to the models trained on clinical data. Detailed results of the MVC dataset analysis are provided in In order to facilitate the interpretation of the large number of selected features we clustered the 56 amino acid indices into four groups using hiBy combining amino-acid indices with specific positions on the V3 loop, the proposed features can be interpreted in terms of physicochemical properties along the structure of the loop. The features selected for the clonal model are informative about the coreceptor usage. Their analysis can therefore provide insights into the physicochemical and structural factors of viral tropism.Features of the clonal model were selected based on two different feature selection methods \u2013 Lasso and SVM. Among 218 features in this model seven were selected by both methods. Three of the features describe electrical charge at positions 319\u2013322. Two of the features are structure-related and related to positions 304 and 305. These amino acid indices based on statistical analysis of 3D structures define propensities of amino acids to form \u03b2-strands Both feature selection methods allow for feature ranking based on the feature coefficients in the respective linear models. We inspected the top-scoring features in both rankings . SVM scoAmong the top-scoring features selected by both methods we found \u201cPositive charge\u201d at the stem position 322 corresponding to the position 25 in the consensus sequence. Highly ranked features in the SVM scoring include also \u201cPositive charge\u201d at the position 321. Additionally SVM scoring pointed to secondary structure propensities and mutability at the loop stem . These indices are based on statistical analyses of secondary structures and statistical models for predicting tertiary structures and define the contributions of different amino acids to the formation of a given structural element Among the high-ranking features in the Lasso scoring we found predominantly charge indices at the loop stem and at the loop base (\u201cNet charge\u201d at position 300). Additionally we found \u201cHydrophobicity factor\u201d at the loop base positions 302\u2013303. Two structure-related features based on \u201cNormalized frequency of turn\u201d and \u201cNormalized frequency of \u03b2-turn\u201d amino acid indices at the base position 305 were also scored high by the Lasso method. Details of the feature ranking are provided as Next, we investigated which clusters of indices were significantly overrepresented among selected features. The only cluster significantly overrepresented among the selected features was cluster 2 (p<0.05). Three out of five features of this cluster are also overrepresented individually in the full set of selected features \u2013 \u201cPositive charge\u201d (22 features), \u201cIsoelectric point\u201d (14 features) and \u201cNormalized frequency of extended structure\u201d (9 features) that describes the propensity of amino acids to form specific secondary structures Next, we inspected which of the amino-acid indices most often appear among the selected features of the clonal model and analyzed the distribution of selected features along the V3 loop in a sliding-window approach . Among icore site (CS) 1 and 2. In the bound conformation of the loop (PDB code 2QAD) CS1 and CS2 are located closer to each other than in the open conformation runtime and software complexity \u2013 which prevents their accessibility via a tool publicly available online \u2013 and (ii) interpretation of the prediction result. Here we present a prediction model of HIV coreceptor usage based on V3 sequence and structure Our clonal model was developed on a sequence set comprising different HIV-1 subtypes. The limited number of sequences of each subtype and the high variability of the V3 loop sequence which obviates a clear subtype classification advocate use of a common model for all subtypes, an approach also applied by other prediction methods Our method shows a moderately but significantly higher prediction performance of approximately 3 percentage points over the model based on sequence only Unlike previously developed structure-based methods We also assessed the capacity of our method to predict MVC therapy outcome. For the purpose of this validation, we used a cohort of patients treated with MVC. This analysis is limited due to the low number of cases in the MVC dataset. With increasing use of entry inhibitors, therapy outcome data are expected to become more abundant and the capacity to train models predicting therapy outcome will improve. The higher performance of the clinical over the clonal model in predicting therapy outcome suggests that comprehensive datasets appropriate for specific prediction goals can produce more reliable models.The analysis of features informative of viral tropism points to two critical sites in the loop stem, comprising residues 304, 307 and 319\u2013322, respectively and to position 324 located more closely to the base of the stem. The charge of amino acids at these sites is known to play role in coreceptor binding The results of other studies of structural features related to HIV tropism are in general accordance with our results. A recently published method http://structure.bioinf.mpi-inf.mpg.de/.Given the considerable structural flexibility and sequence variability of the V3 loop, individual features of this region distinguishing between the two virus phenotypes are hard to define. We performed a comprehensive analysis of a large number of physicochemical residue characteristics in various locations on the loop and pointed to those that are the most informative of tropism. The resulting method offers higher performance than the standard sequence-based approach with a comparable efficiency and a direct interpretation of structural and physicochemical determinants of tropism. The method has been implemented as a server application within the geno2pheno framework under To construct the clonal dataset we screened the Los Alamos database We used the amino-acid indices collected in the AAindex database spheres defining structural neighbors inside the loop structure within which the physicochemical properties of residues are averaged as detailed below. The spheres are positioned along the reference loop backbone and centered at its residues. Specifically, positions of residues were defined as the position of the representative atom of each residue in the structure \u2013 the C\u03b1 atom for Glycine and the C\u03b2 atom for all other amino acid types. Positions of insertions in the alignment relative to the reference structure were inferred based on the positions of representative atoms of the residues at both ends of the insertions (flanking atoms). First, a line connecting the flanking atoms was calculated. Then the inserted residues were placed along the line at equidistant positions. This way we approximate the location of atoms on the loop structure without precise modeling of the structure which is likely to be inaccurate given the flexibility of the V3 loop structure and which would considerably slow down the prediction process. The resulting coordinates of the residues of the V3 loop sequences were used as centers of the spheres defining the structural neighborhoods in the loop structure.The descriptor of the V3 loop was based on the published structure of the V3 loop with PDB In addition to the set of spheres corresponding to alignment positions additional spheres were positioned at the midpoints of lines connecting centers of each pair of consecutive alignment spheres. This way we obtained a set of 99 spheres \u2013 50 corresponding to alignment positions and 49 positioned in-between consecutive alignment positions. Example spheres are illustrated in Each V3 sequence position was mapped to a sphere if the corresponding representative atom was located within the given sphere. The details of the selection of the sphere radius and Gaussian smoothing parameter within the spheres are described and illustrated in The model based on the structural descriptor classifying viruses as R5 or X4 was constructed using a linear SVM We used two classification methods performing feature ranking: Random Forests (RF) clinical model.The HOMER dataset was filtered to contain one randomly chosen sequence per patient, which resulted in a set of 954 sequences out of which 167 comprised X4 viruses. Each sequence in the clinical dataset represents a population of variants genotyped and phenotyped in bulk, an approach used in the routine clinical practice. These sequences contain ambiguous positions with alternative amino acids representing different variants in the population. The ambiguous positions were represented by a balanced average of vectors of indices of all alternative amino acids at a given position. Due to these differences between the clinically and clonally derived data, we repeated the feature selection on this dataset and constructed the Trofile dataset). Summary statistics for all datasets used are presented in The MVC dataset comprises 53 patient cases under MVC therapy whose therapy outcome can be assessed based on the viral load (VL). We define as therapy success an observed 2log decrease in VL with respect to the level immediately before the therapy start or a VL drop below 50 copies/ml measured three months after the therapy start Clustering of the 56 amino acid indices was performed in order to facilitate the interpretation of the large number of selected features. As a similarity score among the indices we used the absolute value of their correlation. This way, indices that express the same affinities among amino acids are considered similar. We performed hierarchical clustering of the 56 amino acid indices and computed silhouette values Figure S1Choice of sphere radius and Gaussian smoothing parameters. Black histograms represent the distribution of the number of residues included in proximities of a radius indicated on the corresponding plot on the left. Red histograms illustrate the sum of Gaussian normalizing factor per each residue. Mean with variance in brackets of each distribution are indicated in legends.(TIFF)Click here for additional data file.Figure S2Performance of models based of structural proximities of different radii. ROCR of models based on different radii are plotted. The selected radius of 8 \u00c5 is traced with a black solid line. AUC and sensitivity at the specificity of 11/25 rule in brackets are indicated in the legend.(TIFF)Click here for additional data file.Figure S3Distance on the 3D structure of features selected by different feature selection methods. Plot in D illustrates the overall distance of spheres of the features of the initial feature set. Plots in A\u2013C illustrate the distance of the highly correlated features as defined above. The highly correlated features can be found among features selected by different methods and they pertain to locations in close proximity on the structure, which is the potential reason for the low overlap of features selected by different methods.(TIFF)Click here for additional data file.Figure S4Correlation of features in the initial feature set. Histograms show distribution of the Pearson correlation of all features of the structural descriptor (left panel), of the features of the clonal model (middle panel) and of the features of the clonal model with the remaining features of the structural descriptor (right panel). Median, percentage of feature pair with correlation >0.5 and >0.75 are indicated in the legend.(TIFF)Click here for additional data file.Figure S5Comparison of the clonal and g2p models in the precision-recall space. The curves show the relationship between true positive rate and positive predictive value (precision). Area under the curve shows a higher predictive performance of the clonal model compared to the g2p model.(TIFF)Click here for additional data file.Figure S6Validation of the clinical model on an external dataset. In order to support the assessment of the performance of the clinical model we used an independent dataset of 760 clinically-derived sequences phenotyped using Enhanced (140 sequences) and standard Trofile (620 sequences). The clinical model shows a visibly better performance compared to the clonal model on the sequences phenotyped using the enhanced Trofile assay and outperforms g2p model train on clinical or clonal data . These differences in performance between the clinical and clonal models are not observed on the subset of sequences phenotyped with the standard Trofile assay (right panel). Nevertheless, in this subset, the structure-based models outperform the corresponding sequence-based models by <2 percentage points.(TIFF)Click here for additional data file.Figure S7Effect of indels on the prediction accuracy of the clonal model. The curves illustrate the prediction performance of the clonal model based on a dataset containing only sequences with indels (black curve) and only sequences with indels (red curve). Similar performance of the clonal model based on both datasets suggests there is a limited effect of the presence of indels on the model accuracy.(TIF)Click here for additional data file.Figure S8Distribution of V3 positions (top panel) and amino acid indices (bottom panel) among the features selected for the clinical model constructed analogous to (TIFF)Click here for additional data file.Figure S9Side-chains of the V3 loop in the unbound and bound conformation. In the bound conformation the residues of CS1 (304 and 307) and CS2 (319\u2013321) are closely located and form bonds between two sides of the loop stem.(TIF)Click here for additional data file.Figure S10Clusters of selected features mapped on the 2B4C structure.(TIF)Click here for additional data file.Figure S11Significantly overrepresented features mapped on the 2B4C structure.(TIFF)Click here for additional data file.Figure S12V3 residue numbering. The numbering of V3 residues used in this manuscript is shown on the 2B4C structure. Top numbers indicate residue position within V3 loop, bottom numbers are assigned according to HXBc2, a numbering used also in the 2B4C annotation (TIFF)Click here for additional data file.Figure S13Hierarchical clustering of amino acid indices. Black dots indicate numbers of clusters, red dots the silhouette values for the consecutive steps of the clustering procedure. Vertical lines indicate the best clustering obtained for 12 clusters and second best with a lower number of clusters (4).(TIFF)Click here for additional data file.Figure S14Separation of amino acid indices into 12 clusters \u2013 the separation that showed the largest silhouette value.(TIFF)Click here for additional data file.Table S1Performance of the clinical model and models derived from the clinical dataset by removing sequences with ambiguities (HOMER-filter), removing sequences without ambiguities (HOMER-ambi) and replacing ambiguities with gaps (HOMER-gap).(PDF)Click here for additional data file.Table S2Therapy outcome prediction using structure-based model.(XLS)Click here for additional data file.Table S3Therapy outcome prediction using g2p model.(XLS)Click here for additional data file.Table S4Ranking and selection of features.(XLS)Click here for additional data file.Table S5AA indices of the selected features.(XLS)Click here for additional data file.Table S6Positions of the V3 loop of the selected features.(XLS)Click here for additional data file.Text S1Selection of model parameters.(PDF)Click here for additional data file.Text S2Overlap of features selected by different feature selection methods.(PDF)Click here for additional data file.Text S3Feature correlation.(PDF)Click here for additional data file.Text S4Combining structure and sequence descriptors.(PDF)Click here for additional data file.Text S5Validation of the clinical model on external dataset.(PDF)Click here for additional data file.Text S6Effect of ambiguities on prediction accuracy.(PDF)Click here for additional data file.Text S7Clonal dataset.(ZIP)Click here for additional data file."} +{"text": "Solanum tuberosum for differences in stomatal behaviour. A large multi-replicated trial of a potato mapping population was used to investigate the consistency in genotypic rankings across different trials and across measurements made at different times of day and on different days. The results confirmed a high degree of consistency between the genotypic rankings based on relative canopy temperature on different occasions. Genotype discrimination was enhanced both through normalising data by expressing genotype temperatures as differences from image means and through the enhanced replication obtained by using overlapping images. A Monte Carlo simulation approach was used to confirm the magnitude of genotypic differences that it is possible to discriminate. The results showed a clear negative association between canopy temperature and final tuber yield for this population, when grown under ample moisture supply. We have therefore established infrared thermography as an easy, rapid and non-destructive screening method for evaluating large population trials for genetic analysis. We also envisage this approach as having great potential for evaluating plant response to stress under field conditions.The rapid development of genomic technology has made high throughput genotyping widely accessible but the associated high throughput phenotyping is now the major limiting factor in genetic analysis of traits. This paper evaluates the use of thermal imaging for the high throughput field phenotyping of Most breeding effort in crop plants has focused on commercially important traits such as yield and traits directly linked to commercially important traits. For further improvements there is a need to extend the range of traits studied. Although many physiological traits are critical for plant growth and development and hence contribute to yield and to tolerance of environmental stresses, they have rarely been used in plant breeding As accurate and elaborate phenotyping is the basis of any plant study for responses to stress, there is a need to develop robust phenotyping systems. A number of laboratory or glasshouse-based phenotyping platforms such as the Keytrack System and Phenofab have been developed recently see . These uOne important physiological trait, especially in water-limited conditions, is stomatal conductance; this plays a crucial role in balancing a need to maximize photosynthesis while minimizing water loss A number of previous studies have demonstrated relationships between stomatal conductance and the commercially critical trait of yield. For example, work on rice has shown that genotypic differences in grain yield in rice were closely related to crop growth rate, which in turn was closely related to higher stomatal conductance during the two\u2013week period preceding full heading These reports suggest that there is therefore good reason to focus on screening for stomatal conductance as a means for improving yield, while the importance of stomatal conductance in controlling water loss suggests that it will be particularly important under water-limited conditions. The work described in this paper aims to explore the reproducibility and sensitivity of canopy-scale thermal imaging (by infra-red thermography (IRT)) as a tool for assessing the genetic variation in stomatal conductance in a diploid potato mapping population. We report the first extensively replicated trials of large scale thermal phenotypic screening under field conditions, with strong evidence for good reproducibility at different times of the day and on different days. We also evaluate and compare methods for processing, assessment and use of images and the requisite statistical methods to eliminate the effect of varying weather conditions over time. We further investigate whether there is any relationship between the observed canopy temperature and yield.Solanum tuberosum group Phureja and Solanum tuberosum group tuberosum (manuscript in preparation). In this study 188 clones from the population together with the two parents and two commercial varieties (Record and Cara) were planted in the field as a replicated trial using an alpha design The work was carried out on a biparental diploid potato population (06H1), derived from a cross between two hybrid clones (99FT1b5 and HB171(13)) each of which are clones derived by crossing Thermal images were obtained using a ThermaCAM P25 infrared camera that operates in the spectral range of 7.5\u201313 \u00b5m and has a focal plane array (FPA) uncooled microbolometer detector with a spatial resolution of 320\u00d7240 pixels. Images were taken from a fork-lift at about 8 m height and covered up to 9 plots horizontally and 3\u20134 rows . ThermalThermal images were processed using ThermaCAM Researcher Pro 2.8 SR-1 software (FLIR systems). To estimate the canopy temperature of each plot (genotype), the acquired images were loaded into the ThermaCAM software and typical areas of canopy for each plot were selected by drawing polygons, avoiding edges and patches of bare ground. Plot temperature was estimated by the mean temperature of the enclosed pixels . As a quPlot canopy temperatures estimated from the thermal images were analysed using GenStat and R statistical software . Two methods of normalizing the plot temperatures were considered, regression analysis (REML) and a simple differencing approach. The significance of differences among genotypes was determined using analysis of variance. REML analysis was performed in GenStat using Trial, Genotypes and Picture temperature as fixed effects with genotypic means and picture temperature means predicted by averaging across trials.In order to find the relationship between the canopy temperature and yield of the genotypes, tuber yield was assessed at physiological maturity. Yield is represented as harvested yield from five plants from Trial 5. To explore the relationship between thermal data and yield before physiological maturity, tuber yield was also measured for Trial 4. Maturity was assessed quantitatively for trial 5 on a scale of 1\u20139, where 9 is less mature and 1 is most mature.The procedure for acquiring the thermal images involved deliberate but non-systematic overlapping and therefore most plots appeared in two or more images . There aThe overlap strategy and the normalisation technique used above assist in analyzing data with more precision and reduction in standard error of the genotype means. This is shown in Thermal images were taken on the 192 genotypes on three different days, during the growing season of the potato plants between stolon initiation and tuber initiation. Data for canopy temperature on each trial measured on different days were analysed separately as 12 independent sets of thermal imaging data . This allows us to assess the consistency and reproducibility of the thermal data .Analysis of variance of NPT for trial 4 shows thThe results on normalised plot temperature data also show good reproducibility in genotype rankings between trials measured at different times of day . Rank co2\u200a=\u200a55%, p<0.001). The yield data for trial 4 were collected roughly 3 months after planting (at the stage of tuber bulking) whereas the yield data for trial 5 were collected at maturity . Previous studies show that evaporation is the main determinant of leaf temperature and there is a direct relationship between leaf temperature, transpiration rate and stomatal conductance The relationships between canopy temperature for different trials and days and growth traits are presented in 2\u200a=\u200a29.2%) and when interacting with maturity it explains nearly 31.6% of the variation and on further addition of plant height, the amount of variation explained is 33%. Thus the results show that stomatal conductance or canopy temperature as measured in these trials play a significant role in determining yield, though there are possibly other morphological and physiological traits that determine yield in interaction with this trait in potato.Stepwise multiple regression using a forward selection approach was used to determine the importance of canopy temperature, plant height and maturity as predictors of yield. Similar results were obtained using best subsets regression (data not shown). The majority of variation in yield was associated with variation in canopy temperature and maturity where maturity is scored on 1 to 9 basis with 9 considered as less mature, thus suggesting that genotypes with higher canopy temperature mature later.The surface temperature of the plant canopy depends on both biological and environmental factors. As our experimental design enabled canopy temperatures to be measured simultaneously for large numbers of genotypes, the normalisation technique employed minimises environmentally-caused temperature variation, leaving primarily the genetic differences. The practice of overlapping different images increases replication, thus allowing more precise estimation of temperature differences and thus reducing the standard error of the plot/genotypic means . IncreasJones et al. (2009) demonstrated that clear genotypic variation can be detected by using normalisation techniques even where substantial variation in soil moisture exists and have given examples of the application of infra-red thermography to phenotyping in the field Although the replication of genotypes within a trial sets the limits to the power of a trial, the errors involved in thermal imaging, including those resulting from environmental variation between images, further degrade the power of any such trial. We have shown that this further error can be minimised by enhanced replication of genotype data either by using \u2018image overlap\u2019 or by increasing the number of images taken. The use of normalised temperatures instead of the raw temperatures is crucial in eliminating the main effect of environmental differences during the day or between days .The matrix of correlation plots in Negative associations of temperature with plant height, similar to those observed in this paper have been observed in wheat, where it was hypothesized that the lower temperature for taller crops was related to a higher boundary layer conductance with taller crops 13C)}. The combination of a mapping approach and the study of genotypic responses to water availability will allow one to quantify the genetic differences in stomatal behaviour. Potentially this will help in breeding genotypes which can close stomata and conserve water under drought conditions but take advantage of any available water. The results described here have identified the extreme genotypes in terms of constitutive stomatal behaviour under well-watered conditions, while the new trials will concentrate on responsiveness to drought allowing mapping of relevant QTLs.Infrared thermography (IRT) is a powerful tool for studying plant responses to environmental stress and for screening plants for differences in stomatal conductance, as changes in canopy temperature are driven by differences in stomatal conductance, which itself is particularly sensitive to water deficit stress The present results also provide evidence for significant negative correlations between yield and canopy temperature as would be expected if increased stomatal opening led to enhanced yield. For example for the trial 5 mean thermal data the correlation with yield was while similar correlations were found for trial 4 data as well.It has been shown in rice S. tuberosum group phureja and S. tuberosum group tuberosum with a limited range of maturity scores (6\u20139), this result is only tentative and needs further evaluation.The present results suggest a negative correlation between canopy temperature and plant maturity, thus the plants which have high transpiration rate have shorter life cycle in this population. However, as this cross is between the hybrids of We conclude that the use of IRT is an easy, rapid and non-destructive method of screening for stomatal behaviour and can be used for evaluating large population trials for genetic analysis. We have also demonstrated a link between high stomatal conductance and high yielding genotypes under favourable growing conditions which suggest that thermal imaging may provide a useful screen in programmes aiming to increase yield under ample water availability and consider that it may have similar potential under stress conditions.Table S1Half-hourly means of meteorological data over the period of thermal measurements obtained at a location around 800 m from the trial site; start times for imaging of each trial are indicated.(DOCX)Click here for additional data file.Table S2Analysis of Variance testing the consistency and significance between different trials on a day.(DOCX)Click here for additional data file.Figure S1Matrix plot showing both the correlations between normalised genotype temperatures (\u00b0C) for different trials on different measurement days and the associated correlation coefficients.(TIF)Click here for additional data file.Figure S2Relationship between normalised genotype temperatures (\u00b0C) for Trial 4 and 5 on 3 days of infra-red imaging and harvest traits represented using regression lines in the plots. The numerical figures on left side of the graphical representation provide the correlation coefficients and the p values for the plotted traits for each plot respectively. Relationships between harvest traits and canopy temperature are also shown for the data on \u201cAverage of All traits\u201d on day 1, day 2 and day 3 and also for data on trial 4 and trial 5 averaged over three days of imaging. Units: Yield in kg/5plants, Plant height in cm.(TIF)Click here for additional data file."} +{"text": "The 2004 Newborn Screening Act has saved a lot of Filipinos from Congenital Adrenal Hyperplasia (CAH). The increase in the number of patients living with CAH challenges us to find the optimal steroid replacement therapy. In the Philippines, there is no locally published data on this. The objectives of the paper are to compare the effect of different hydrocortisone dosing regimen on the 17 hydroxyprogesterone (17 OHP) levels of patients with CAH and to report adverse effects.+11) months. One patient was randomized to HMD, 5 to HED and 3 to EHD. A marginally significant difference in the 17 OHP levels was observed between treatment groups. Adverse effects included increased BMI with concomitant presence of cushingoid facies in 33% (3/9) of the patients and an increased growth velocity in one patient in the HED group.The pilot study is a single-blinded randomized control trial comparing the 17 OHP levels of infants with CAH given higher evening hydrocortisone dose (HED), higher morning hydrocortisone dose (HMD) and equal hydrocortisone dose (EHD) who consulted in a tertiary hospital from January 2011 to July 2011. Nine patients completed the study with mean age of 16 and ACTH levels be included in the outcome measures. Also, the use of oral steroids available in the country such as Prednisone or Dexamethasone as an alternative treatment be investigated."} +{"text": "Due to the increasing emphasis on guiding patient management and revascularisation based on the extent rather than just the presence of ischaemia it is important to understand the relationship between parameters obtained in the catheter laboratory, such as luminal coronary artery stenosis, fractional flow reserve (FFR) and the extent of the ischaemic burden. Classic jeopardy scores estimate the area of myocardium at risk based on luminal stenosis severity without integrating their haemodynamic significance, whereas FFR assesses the impact of a stenosis on flow but is not influenced by the volume of subtended myocardium. Incorporating FFR measurements to a jeopardy score to produce a \"functional jeopardy score\" may provide a rapid method in the catheterisation laboratory to estimate ischaemic burden. The objective of this study is to assess the relationship between classical anatomical jeopardy scores, functional jeopardy scores and the extent of ischaemia identified on cardiovascular magnetic resonance (CMR) perfusion imaging.39 patients with angina and known or suspected coronary artery disease (CAD) referred for coronary angiography prospectively underwent high-resolution CMR perfusion imaging and coronary angiography. Fractional Flow Reserve (FFR) was measured in all vessels with a stenosis of >50%. The APPROACH and BCIS-1 jeopardy scores were calculated based purely on angiographic anatomy using a cut off of both 50% (APP50 and BCIS50) and 70% (APP70 and BCIS70) as well as after integration of FFR (APPFFR and BCISFFR) and compared with the extent of ischaemia identified on CMR perfusion imaging.The correlation between the extent of ischaemia measured by CMR and the anatomical jeopardy score based on a 50 % threshold was moderate see tableAnatomical and functional jeopardy scores overestimate the extent of ischaemia, when compared to CMR. Integrating physiological information from FFR to angiographic lesion characterization to generate a functional jeopardy score improves the estimation of ischaemic burden in the catheterization laboratory.This work was supported by a European Union Grant ; the British Heart Foundation ; the Biomedical Research Centre and the Wellcome Trust and EPSRC ."} +{"text": "Energetic meteorological events such as frontal passages and hurricanes often impact coastal regions in the northern Gulf of Mexico that influence geochemical processes in the region. Satellite remote sensing data such as winds from QuikSCAT, suspended particulate matter (SPM) concentrations derived from SeaWiFS and the outputs (sea level and surface ocean currents) of a nested navy coastal ocean model (NCOM) were combined to assess the effects of frontal passages between 23-28 March 2005 on the physical properties and the SPM characteristics in the northern Gulf of Mexico. Typical changes in wind speed and direction associated with frontal passages were observed in the latest 12.5 km wind product from QuikSCAT with easterly winds before the frontal passage undergoing systematic shifts in direction and speed and turning northerly, northwesterly during a weak and a strong front on 23 and 27 March, respectively. A quantitative comparison of model sea level results with tide gauge observations suggest better correlations near the delta than in the western part of the Gulf with elevated sea levels along the coast before the frontal passage and a large drop in sea level following the frontal passage on 27 March. Model results of surface currents suggested strong response to wind forcing with westward and onshore currents before the frontal passage reversing into eastward, southeastward direction over a six day period from 23 to 28 March 2005. Surface SPM distribution derived from SeaWiFS ocean color data for two clear days on 23 and 28 March 2005 indicated SPM plumes to be oriented with the current field with increasing concentrations in nearshore waters due to resuspension and discharge from the rivers and bays and its seaward transport following the frontal passage. The backscattering spectral slope \u03b3, a parameter sensitive to particle size distribution also indicated lower \u03b3 values (larger particles) in nearshore waters that decreased offshore . The use of both satellite and model results revealed the strong interactions between physical processes and the surface particulate field in response to the frontal passage in a large river-dominated coastal margin. The Mississippi river discharges into the Gulf of Mexico through the birdfoot delta and through a secondary outlet to the west, the Atchafalaya river delta. The combined water and sediment discharge of the Mississippi and Atchafalaya rivers are about 530 \u00d7 109 m3 y-1 and 210 \u00d7 106 tons yr-1 with 70% of the water and 50 to 60% of sediment discharged through the birdsfoot delta into deeper waters of the shelf while the rest discharges through the Atchafalaya River to the west onto a broad shallow shelf that are close to near-infrared bands used for atmospheric correction was downloaded and processed during the period of the frontal passage. This product was evaluated and found to be highly correlated to buoy measurements in the Gulf of Mexico SMP=12.3The Navy Coastal Ocean Model (NCOM) is a hybrid sigma-z vertical coordinate system based on the POM model that uses a nested modeling approach . The hig3.3.1Discharge from the Mississippi-Atchafalaya river system, wind-induced coastal circulation, slope eddies and frontal systems are important physical influences on plume dynamics, optical properties, particle transport and mixing in the northern Gulf of Mexico ; 2007. SDuring winter and early spring the northern Gulf of Mexico is strongly influenced by frontal passages that transfer energy to coastal waters and influence their physical and biogeochemical properties . Frontal3.2-1. -1 at the boundary of the front. The front extended offshore for about 200 km from the coast being strongest nearshore and decreasing offshore. A similar pattern was observed in the COAMPS winds (not shown) that were applied for surface forcing of the MsLaTex coastal model.The prevalent winds observed before the passage of a weak cold front on 23 March 2005 were pre-1 wind speed and 0.2 m significant wave height, respectively. Similarly at NDBC Buoy 42007 located along the Mississippi coast significant wave height increased to 1.43 m following the same frontal passage potentially contributing to resuspension in the region. Effects of the strong offshore winds have also been shown to result in seaward-directed currents that transport suspended sediments and river discharge to the outer shelf March 2005 should be well represented by the model predictions which coFollowing the strong frontal passage of 27 March and the change in wind direction the mode3.3Plume dynamics and transport of dissolved and particulate material are strongly influenced by physical forcing such as circulation in the study region . ModeledA change in the current flow field to a more easterly, southeasterly direction followinEffects of the frontal passage on surface SPM dynamics were further examined using SeaWiFS ocean color derived estimates of the backscattering spectral slope \u03b3 which prFollowing the frontal passage of 27 March, the nearshore low \u03b3 distribution pattern changed to the southwesterly direction, appeared aligned with the flow field and its greater areal extent suggested the potential for the seaward transport of the larger sized particles from the various rivers and bays along the Lousiana-Texas coast . In the 4.The northern Gulf of Mexico receives large amounts of suspended particulate matter from the largest river system in North America that along with energetic meteorological events such as frontal passages strongly impacts the biogeochemical processes in the region ; 2005. T"} +{"text": "Hepatitis A virus (HAV) infection is one of the most common causes of acute hepatitis and it is a serious health problem worldwide. HAV infection is a vaccine preventable disease that can produce the lifelong immunity seen in many developed countries with the vaccination schedule administered to children; however this vaccine is not used in developing countries at the present time. Improvements in food and water hygiene have caused a displacement of hepatitis A infection from children to adults which has increased mortality rates. Therefore evaluation of HAV immunity levels can help health authorities develop polices for prophylaxis especially in developing countries. The hepatitis A virusis a small non-enveloped RNA virus of the Picornaviridae family that causes more than 1.5 million cases of hepatitis throughout the world, and it is one of the most common causes of acute hepatitis as well as being an important worldwide health problem according to Vilibic-Cavlek et al. . On the Hepatitis A virus is transmitted through fecal material with the most common route being orally and outbreaks can occur in closed populations which have crowded living conditions . In deveThe highest number of asymptomatic HAV infection outbreaks occurred in developing countries while symptomatic sporadic infections were seen in developed countries 10]. HAV. HAV10].Hepatitis A infection is a vaccine preventable disease, this vaccine can induce lifelong immunity and is used in many developed countries, but this vaccine is not yet readily available in some developing countries 8]13]. [13]. 8][. [13]. 8Ultimately improvements in the hygiene of food and water have caused the displacement of HAV infections from children to adult populations which has increased the mortality rate. Therefore in conformity with the advice from Vilibic-Cavlek et al. children in developed countries warrant evaluation of their immunity levels as well as those in developing countries until health authorities can suggest a time for prophylaxis. However in developed countries because the seroprevalence of HAV infections is much lower than in children of developing countries, it seems that vaccination against the HAV should be considered for all children."} +{"text": "Dear Editor,High zinc level by promoting the immune system may cause rejection in the allograft organ. So it seems that limitation of zinc supplement and all foods and drugs with high amount of zinc may be effective in prevention of rejection after transplantation.Zinc is an essential micronutrient for human growth, development and immune function.Zinc deficiency was accompanied by the qualities and functional insufficiency of T-cell mediated immunity and by the diminished phagocytic activity of neutrophils.Kabu et al. in July 2006 revealed that zinc was involved in multiple step of FC epsilon RI-induced mast cell activation and required for degranulation of cytokines such as IL-6 and TNF-\u03b1 production and lymphocytes proliferation.[2]In study by Chen et al. (Nov 2005) on the effects of different levels of zinc nutrition status on the immune function of mice spleen lymphocytes showed that zinc status affected the immune function and production of IL-2 in spleen lymphocytes RejectioMoreover transplant rejection has both cellular and humeral components, some of the cytokines produced by T cells and macrophages (TNF-\u03b1) may mediate apoptosis of graft cells. Accordin"} +{"text": "The soluble guanylyl cyclase (sGC) is a key enzyme involved in the production of the second messenger cGMP. Due its cardiovascular relevance, sGC has been the target of numerous drug discovery efforts leading to the development of many different activators and stimulators with pharmaceutical potential. One of such compounds is the sGC activator Cinaciguat (BAY 58-2667) which is in clinical trials for acute decompensated heart failure.We present here our latest structure-function studies related to sGC activation by different sGC activators. The activator complex structures reveal an intriguing mode of heme mimicry by these compounds. The observed activation conformational changes center around the \u03b1F helix that contains the H105 residue normally held in place by the heme moiety in the absence of the activators.The structural insights gained from the complex structures could be used for further optimization and development of sGC activators."} +{"text": "Despite dramatic improvements in the hardware resources and computational power available to pharmaceutical researchers over the past few decades, the methods used for assessing the 2D chemical similarity between two molecules hasn't changed much since the 1960s. Here we report a novel chemical database search method that allows the exact size of the maximum common edge subgraph (MCES) between a query molecule and molecules in a database to be calculated rapidly. Using a pre-computed index, the 50 nearest neighbors of a query can be determined in a few seconds, even for databases containing millions of compounds. This work builds upon the previous efforts of Wipke and Rogers in the 1980s ["} +{"text": "The correct version of Figure 1 is available here: The correct version of the Figure 3 legend is available below:Figure 3. Coronary angiography of modified HypoE mice.The coronary arteries of HypoE mice just before the Paigen diet and 2 weeks after the end of the 7-day Paigen diet intervention ."} +{"text": "The purpose of this study is to select the major tongue diagnosis indicators and evaluate their significance in discriminating the subtypes of Pattern Identification (PI) from stroke patients.Decision tree analysis was carried out using clinical data collected from 1502 stroke patients with same subtypes diagnosed identically by two experts with more than 3 years of clinical experience. Among 9 tongue indicators, 6 major tongue indicators were selected by decision tree analysis. Each PI has a specific combination of tongue indicators which related 6 major tongue indicators.It is suggested that 6 tongue indicators can be used for discrimination of PI in stroke patients, though the combination studies between these tongue indicators and the other PI indicators are left for further study.We could conclude that tongue diagnosis can play a significant role in a differential diagnosis of PI. Namely it can increase the accuracy of diagnosis and simplify the complex process of PI to check important tongue indicators. It is necessary to re-evaluate other indicators in PI by proper ways, and this study is helpful to objectify and be scientific in traditional Korean medicine."} +{"text": "Idiopathic Scoliosis (IS) is a progressive disorder with reduced mobility of the spine. This makes corrections difficult or sometimes even inhibits postural changes. Even when correction of frontal or coronal plane deformity seems successful, sagittal correction mostly is not addressed appropriately. This might be due to functional tethering of the spinal cord or even of peripheral neural structures. This explains the lack of success when trying to correct sagittal plane deformity with the help of stretching exercises. Purpose of this study was to test how the release of these structures may relax lordotic tension in the thoracic area.Finger \u2013 floor distance and sciatic slump was tested in 25 patients before and after a session of physiotherapy using neural tension exercises (Butler) ,2.Significant differences have been achieved with the help of these techniques (16 \u2013 21 cm at the start independent of patient age / 3-0 cm at the end) with improved kyphosation at the same time.While in sole stretching of the hamstrings the sagittal profile cannot be improved, neurodynamics provide an improvement of this deformity. Neurodynamics therefore seem to be a useful add on in the physical treatment of IS."} +{"text": "The familial Mediterranean fever 50 score (FMF50) was recently devised to define response to treatment and as an outcome measure for clinical trials of FMF.To examine the performance of the FMF50 score in a previously published trial of rilonacept for patiWe reanalyzed the data from the controlled trial of rilonacept vs. placebo in 14 patients with colchicine-resistant or intolerant FMF using the FMF50 score as the primary outcome. The FMF50 score required improvement by \u226550% in five of six criteria without worsening of the sixth criterion.In the original trial rilonacept was considered effective according to the primary outcome measure (differences in the attack frequency) with eight analyzable patients considered responders and four as non-responders. According to the FMF50 score, only two participants would have been considered responders to rilonacept, and one to placebo. Only two participants had \u226550% differences between rilonacept and placebo in five criteria. The major explanation for non-response to treatment was that with rilonacept the duration of attack decreased by \u226550% in only 2 participants and 5 participants had no attacks of arthritis either during screening (before randomization) or during treatment with rilonacept.The proposed FMF50 score did not differentiate well between responders and non-responders compared to the a priori defined primary outcome measure in this successful controlled study and should be revisited prior to adoption as a primary outcome measure in multinational FMF trials."} +{"text": "Experimental studies demonstrate a radial bias, wherein radial orientations produce higher activity compared to other orientations with 2 lij,r1r2\u03bc), lateral excitatory and lateral inhibitory weights adapt based on a normalized Hebbian mechanism. In order to develop the retinotopic map, the inputs to the retinal layer consists of centered (assumed to be the point of fixation) rectangular bars of varying dilations and rotations as modelled in [The afferent (elled in . The retA neural activity based model for the development of radially biased orientation maps in V1 is demonstrated."} +{"text": "Acetobacter pasteurianus is among the major bacteria responsible for acetic fermentation and gives the characteristic taste of vinegar, can be found as a contaminant of wine production industry. In industrial fermentation is frequent contamination by lactic acid bacteria such as Lactobacillus fermentum that competes with the yeast for nutrients and inhibiting their growth, slow the fermentation and impair the production of ethanol[f ethanol. (AIM) TThe samples were cultured in a sucrose syrup at 35\u00b0C for 24 hours and subjected to DNA isolation using the protocol of Sambrook et al (1989) [Acetobacter pasteurianus and Lactobacillus fermentum . One of the bacteria showed up as producer of biopolymer, L. fermentum , this drew attention by quantity and rheological properties of a polymer produced molasses medium. The molecular technique used revealed a high degree of conservation of the 16S rDNA gene and comparison of the sequence obtained in this study with sequences deposited in GenBank database resulted in strains of known species showing similarity with the sequences under study.The PCR products of the gene 16S rDNA of the bacteria had a molecular weight of approximately 1500 base pairs . Thus, t"} +{"text": "Additive effects on the energy barrier for synaptic vesicle fusion cause supralinear effects on the vesicle fusion rate. Published 14 April 2015In the published article, minus signs were missing from the exponents in equations 13 and 14:These equations should have read:We apologize for any confusion that may have occurred.The article has been corrected accordingly."} +{"text": "The nasal epithelium with its tight junctions (TJs) represents an important barrier against the penetration of exogenous substances . Damage of the epithelium allows higher amounts of inhaled allergens and pollutants to penetrate the mucosa. Our laboratory has previously used a bronchial epithelial cell line to investigate epithelial damage by various factors [cigarette smoke and cytokines ]. Cultures of primary epithelial cells obtained from nasal epithelium should be superior in resembling the natural situation in the nose and allow a comparison of epithelia from non-allergic and allergic patients. Our aim was to establish primary human nasal epithelial cell culture in a transwell system and to investigate the epithelial barrier function and the properties of the nasal epithelium. Additionally we compared different epithelial cell culture systems to investigate damage and repair in primary human nasal epithelial cells.We obtained nasal tissue samples during routine surgeries and cultured primary human nasal epithelial cells in a transwell system with air-liquid interface as a surrogate of an intact respiratory epithelium. In order to investigate epithelial damage we used the TH1-derived cytokine interferon-\u03b3 (IFN-\u03b3), which has previously been shown to impair the barrier function of the nasal mucosa. Scratch testing was set up as a standard method to investigate the effect of physical damage on cell monolayers. The phenotype of the cells was confirmed by light microscopy, flow cytometry and fluorescence staining of cells cultured on transwell membranes.Primary human nasal epithelial cells gained confluence and displayed high TER after approximately 8 days of incubation in transwell inserts. Incubation of cells with IFN-\u03b3 led to a reduction of TER within 24 hours of incubation. In scratch tests, the untreated cell monolayers gained confluence at the latest after 96 hours hours after performing damage. Repair of cell layers was inhibited by IFN-\u03b3 treatment.We established cell cultures based on primary human nasal epithelial cells and reproducible techniques to investigate the epithelial barrier function. Supported by projects of the Austrian Science Fund and the DK program MCCA."} +{"text": "The following sentence was omitted and should have been included as the last sentence of the first paragraph in the Estimation of Gene Flow section of Because we wanted input dataset for the gene flow analyses of microsatellite data to 1) be comparable for both MIGRATE and BayesAss analyses; 2) avoid as much as possible the use of individuals with large amounts of missing data; and because 3) 15 individuals are recommended (for efficiency) for the MIGRATE analyses , and we wanted each area to be fairly equally represented, we randomly sampled individuals from strata (geographic areas) within each subpopulation, selecting from 26 (WP), 34 (EP) and 60 (CA and SC), depending on the number available for analysis.Please see the correct, complete S1 Supporting Information(DOCX)Click here for additional data file."} +{"text": "On March 6, 2013, the Cook County Department of Public Health contacted the Illinois Department of Public Health regarding a diagnosis of trichinellosis in a patient who had consumed wild boar and deer meat obtained by hunting at a Missouri ranch January 16\u201318. Trichinellosis is a parasitic infection caused by consumption of undercooked infected meat, most commonly from carnivorous or omnivorous animals , and the median incubation period was 16 days (range = 4\u201324 days). All patients reported myalgias, eight had periorbital edema, and seven had both fever and eosinophilia. Trichinella ingestion and the need to inform hunting patrons. The Illinois Department of Public Health recommends posting advisories at hunting ranches that inform hunters of the importance of cooking game meat to the cooking temperature of 71\u00b0C (160\u00b0F) recommended by the U.S. Department of Agriculture and CDC before consuming it (Trichinellosis cases remain infrequent in the United States because of state and federal laws preventing feeding of uncooked swill to commercial swine and public awareness of the danger of eating raw or undercooked game meat. The Missouri Department of Health and Senior Services provided additional education to employees of the ranch about the risk for uming it ."} +{"text": "The authors report an exceptional case of collision tumor comprised of a gastric calcified stromal tumor and a pancreatic adenocarcinoma. The pancreatic tumor was detected fortuitously on the histological exam of resection specimen. The collision tumor is defined as the existence of two different histologic types of carcinoma that are either contiguous or intermingled.The patient was a 70-year-old male who presented with a 6-month history of vomiting, epigastric pain and weight loss. A gastroscopy revealed a large submucosal lesion originating in the fundus of the stomach and the biopsies were inconclusive. CT study revealed a 12x10x9 cm partially calcified mass with heterogeneous contrast enhancement on the fundal region and greater curvature of the stomach . The patCollision tumor has been defined as two histologically differing tumors simultaneously involving the same organ with an equivocal intermediate transitional zone between them . Our patIf collision tumor in the same organ is uncommon and usually discovered incidentally; it is exceptional when it occurs between two tumors of adjacent organs."} +{"text": "Compared with 4 decades ago, more than twice the adults 37%) are voluntarily restricting sleep from 8.5 hours to less than 7 hours per night \u20133. Sleep7% are voIn our modern world, the frequency of meals and snacks is such that each day people are in an absorptive state for most of the hours that they are awake. A study of daily glycemic excursions in persons with type 2 diabetes underscores the potential contribution of postprandial assessment to the understanding of subclinical cardiometabolic pathophysiology . In thosRecent evidence suggests that exposure of the circulatory system to repeated meal-induced waves of metabolic substances and their secondary products over the course of the day may accentuate vascular endothelial pathophysiology . The patAnimal studies have indicated that food deprivation results in a sleep duration decrement , whereas"} +{"text": "The shift by one amino acid position in the mutation column also applies to the iglr-2 mutations indicated in Some ORF names, lengths and mutations in"} +{"text": "The authors consider acute problems in the quality and management of medical services challenging health care systems worldwide. This actuality has motivated the representatives of the European Association of Predictive, Preventive and Personalised Medicine and European Federation of Clinical Chemistry and Laboratory Medicine to consider the efforts in promoting an integrative approach based on multidisciplinary expertise to advance health care. The position paper of EPMA and EFLM providesIn particular, the paper makes following statements:\u27a3 Since chronic pathologies are generally triggered at the molecular level with consequent symptomatic manifestation of the disease, a laboratory based detection of pathology-specific molecular patterns would create a well-founded basis for the desirable predictive medical services giving the opportunity for optimal health care. This requires the application of innovative biotechnologies to predict human pathologies, the devising of appropriate and timely preventive strategies and individualised treatment planning.\u27a3 Multimodal diagnostics represents a model-based examination procedure with several levels of examination resulting in extended patient profiles and medical records which obligate inclusion of an interview with the patient/a questionnaire filled in for relevant information on any known pathology, medical imaging, laboratory diagnostics and evaluation of relevant risk factors. For laboratory diagnostics, it is highly recommended to use minimally invasive validated blood tests for the detection of stage-specific molecular patterns at complementary levels of targeted regulation .\u27a3 Shifting the role of laboratory from the \u2018passive performing\u2019 to the \u2018active advising\u2019 is the next paradigm change in health care. This reconsideration of the laboratory-clinician interface might significantly advance the quality of current medical services, although the implementation of this approach across countries should be adapted to local conditions.\u27a3 The globalisation of markets and laboratory related business requires the comparability, or the unification, of laboratory test values. The mobility of both patients and health care professionals as well as the increasing global data flow require such comparability. Hence, the unification of laboratory tests should be placed at the top of the list of corresponding adapting measures.\u27a3 A new generation of \u2018point-of-care\u2019 monitoring devices is required. These mobile health technologies must enable both the remote management of the analytical process and the active engagement of laboratory professionals at the clinical level.\u27a3 Regarding the promotion of the concepts of \u2018participatory\u2019 medicine, people need to be advised of reliable information sources that are well adapted to a corresponding level of understanding and concrete interests of subpopulations . In the field of education, laboratory medicine may play a leading role providing up-to-date information that is accessible to the layman on laboratory tests and their interpretation for individual health and disease conditions. A professional version will enable for a detailed knowledge about bioactive molecules, enzymatic reactions, molecular and cellular processes which underlie the pathomechanisms of individual predispositions and pathologies as well as medical treatments.\u27a3 A creation of innovative medical records should be considered as a priority for scientific programmes of multidisciplinary character. An integrative bioinformatics is considered as the powerful tool to fulfil this highly ambitious task.\u27a3 Progressing from \u2018disease care\u2019 to \u2018health care\u2019 means a mandated implementation of a new philosophy of the well-being concept tailored to the person as a carefully elaborated spectrum of measures for professional care that promotes the mental and physical health of an individual concept.\u27a3 Considering the sensitive ethical aspects of the laboratory medicine and biobanking, robust information governance of the database and high quality of ethical standards are the prerequisites for the successful implementation of PPPM in health care systems.\u27a3 Currently, bio-banking is facing major viability challenges. These critical problems may be optimally solved by relevant professional groups with complementary expertise such as the International Federations of Laboratory Medicine, EPMA and ESBB followed by adequate decisions of policymakers resulting in the creation of a robust juristic platform.\u27a3 Standardisation of health care services in Europe is a strategic issue for policymakers after detailed consultations with health care professionals.Common Strategic Framework as well as by other global and topic-relevant national programmes.\u27a3 Professional education: we need to develop a new culture among experts in order to promote the multidisciplinary character of predictive, preventive and personalised medicine and concomitantly to advance currently deficient health care services. The innovative PPPM-related educational programmes for professionals should be prioritised in the"} +{"text": "PLOS Biology editorial team would like to warmly thank all those individuals who participated in the peer review process this past year at PLOS Biology. During 2015, over 1,200 reviewers from around the world helped evaluate articles submitted to the journal.The Public Library of Science (PLOS) and the PLOS Biology authors, and for helping us to publish a highly valued open access journal.The names of our 2015 reviewers are listed in S1 Reviewer List(PDF)Click here for additional data file."} +{"text": "The territorial organization of Morocco during administratives division of 2009 is based on 16 regions. In this work we will create a system of recognition of handwritten words (names of regions) using the Amazigh language is an official language by the Moroccan Royal Institute of Amazigh Culture (IRCAM) (2003a) In this context we propose a data set for handwritten Tifinagh regions composed of 1600 image (100 Image for each region). The dataset can be used in one hand to test the efficiency of the Tifinagh region recognition system in extraction of characteristics significatives and the correct identification of each region in classification phase in the other hand. Specifications table\u2022The region is the current highest administrative division of Morocco. The regions are subdivided into a total of 63s-order administrative divisions, which are prefectures and provinces \u2022As part of a 1997 decentralization and regionalization law passed by the legislature 16 new regions of Morocco were created.\u2022We chose a database word contains 1000 words written in marker and that represents the 16 region of Morocco.\u2022Optical Character Recognition (OCR) can be applied on both cases printed or handwritten. In this work we use several efficient techniques in each of the three principal phases forming a the system of recognition which are firstly the pre-processing then secondly the features extraction then finally learning-classification several studies has been done for recognition of Handwritten Tifinagh regions recognition by using in the features extraction phase the square and triangular zoning method in one hand or in the learning-classification phase the support vectors machines (SVM) and the neural networks on the other hand.\u2022Amazigh alphabet is considered as a national language since a new constitution of 2011 is a creative field Value of the dataFor several years, on-line and off-line handwriting character recognition has been considered as a very dynamic field given that its applicability in many different domains such as bank check processing, automatic data entry and postal sorting, The postal automation, bank checks identification, automatic processing of administrative files, etc. In this work we have presented the steps of the recognition system in We chose a database word contains 1000 words written with marker and that represents sixteen region of Morocco \u2022We ask 70 students (in Laboratory of Information Processing and Decision Support) to write the 16 region with Tifinagh characters .\u2022The direction of writing of this character is the left to right in horizontal lines.\u2022The characters are written in a way separated in the text see , Fig. 3.\u2022Each original region image has a size equal to 30\u00d730 pixels , Fig. 17\u2022The number of the square zones in features extraction equal to 4, 6 and 9 zones.\u2022The number of the triangles zones in features extraction equal to 4, 6 and 8 zones.\u2022Each numeral is transformed to a vector of 4, 6 and 9 components for square zoning and to a vector of 4, 6 and 8 components of triangular zoning in features extraction.\u2022The standard deviation of the GRBF kernel function is equal to 0.1 in classification phase with support vectors machines.\u2022a=b=1 in classification phase with support vectors machines.The degree of the Polynomial (POL) kernel function is equal to 10 and their parameters \u2022We realized a variation on the size of the zones in features extraction to find the best performing method.\u2022To do this, we have chosen the values {5, 10, 15} of hidden layer neurons number.The extraction steps were\u03c4r is shown in The graphical representation to recognition rate of each region"} +{"text": "In 2008 the first set of consensus recommendations for performance and interpretation of 24 hours Arterial Blood Pressure Monitoring (ABPM) in children and adolescents have been published . Since t"} +{"text": "Advanced and new technologies within the health sector are aimed to increase efficacy and reduce cost. As a profession, podiatry has seen exponential growth in the use of 3D scanning in the clinical domain. It has been used within orthotic manufacture to improve timely responses in both production and rapid dispensing. It has also been used within research to better understand foot structure and function.3D printing is the next technological step, which will impact the podiatric management of common disorders. This presentation explores its potential uses and describes a new method of prosthetic construction based on 3D printing methodology.The use of 3D printing technology for pre-operative planning is well established at Peninsula Health across multiple surgical disciplines. The 3D-printed models generated from CT (computed tomography) and MRI (magnetic resonance imaging) scans are currently undergoing validation clinical trials. The combination of 2D imaging and 3D haptic models can be useful in podiatry, specifically in the production of custom-made shoe fillers for people who have undergone transmetatarsal amputation or toe amputation. This process is currently being studied within Peninsula Health's High Risk Foot Clinic with the support of Department of Surgery.The use of a shoe filler to improve shoe fitting is a common practice following amputation, however it is associated with a high cost ($500-$800 per patient). We describe the use of a 3D rendered CT image of the foot within the shoe that enables a 3D printed shoe filler to be constructed at an estimated cost of $30. Our assessment of the practical use of these shoe fillers, durability and patient acceptance will be presented.3D printing has a role in podiatry however the application, its advantages and disadvantages are yet to be fully explored. This new and innovative technology introduces exciting future opportunities in the clinical setting."} +{"text": "Treatment of severe chronic hand eczema (CHE) resistant to topical treatment with potent corticosteroids is challenging; in 2013 the Health Technology Assessment Programme released a commissioned call to investigate the most effective treatment for this disease with Alitretinoin specified as the active intervention to evaluate. Existing evidence on systemic treatment options with special focus on Alitretinoin has been summarised in an Evidence Review Group's Report on Alitretinoin for the treatment of severe CHE. The report highlighted that although Alitretinoin has demonstrated efficacy, data are lacking in terms of comparison to other treatment approaches.The brief required applicants to justify the choice of control intervention; we designed a survey to obtain information on currently used treatment pathways in the UK. A total of 194 UK Dermatologists responded and the results indicated that treatment approaches for severe CHE differ widely among UK dermatologists. PUVA(40.2%) and Alitretinoin(30.9%) were identified as the most frequent first line treatment options for hyperkeratotic CHE, whereas oral steroids(37.6%) were identified as the most commonly used for vesicular CHE, followed by PUVA(26.3%) and Alitretinoin(15.5%). In terms of potential side effects of long term or repeated use, Ciclosporine A(58.2%) and oral steroids(41.2%) were reported to cause most concerns among the surveyed dermatologists. The ALPHA team used the survey results to justify the use of PUVA as the control intervention for first line treatment and to evaluate second line treatments as a secondary objective. The ALPHA trial was approved for funding and is due to open to recruitment in October 2015."} +{"text": "Chinese Hamster Ovary (CHO) derived cells are the most commonly used cell lines for the production of biopharmaceuticals. We developed a plug and play method to optimize the growth medium for a given CHO production cell line. The experiment consists of a Mixture Design of Experiments (DOE) approach using different basal media to select the optimized formulations for a specific CHO cell line. The package for media optimization consists of different base media together with the ambr15 high throughput bioreactor and integrated MODDE DoE software.A suspension adapted CHO DG44 cell line expressing a monoclonal antibody was used for the experiments. Media mixes composed of differing concentrations of nutrients were used in a mixture DOE with 20 different media and 3 center points. All conditions were inoculated in the ambr at the same starting density of 2.0xE5 cells/mL. Dissolved oxygen, pH, and temperature control were maintained throughout the batch process. Each bioreactor was sampled for cell count and viability. Metabolites as well as IgG titers were measured. Peak Viable Cell Density (VCD), Doubling Time (DT), and IgG titer results were collected and modeled as responses using MODDE 10 design of experiments (DOE) software to evaluate the optimal media mixtures. Results are shown in Figure The ambr15 and MODDE software used here provided a path to obtain effective media formulations for a given specific CHO cell line. The approach consists of a comprehensive service containing four basal media to prepare the mixes and the ambr15. It is supported by an application specialist to guide the experiments and interpretation of results."} +{"text": "Control of human walking is not thoroughly understood, which has implications in developing suitable strategies for the retraining of a functional gait following neurological injuries such as spinal cord injury (SCI). Bipedal robots allow us to investigate simple elements of the complex nervous system to quantify their contribution to motor control. Human walking can be viewed as a complex programme of reflexes which through the use of feedback and feed-forward processes allows stepping to adapt to a constantly changing terrain or walking environment. Loading and contact information from the feet are important sensory components in producing a walking pattern which is flexible and efficient, and can be measured directly or indirectly by a variety of specific and non-specific receptors which is then fed back to control the stepping. Gait is cyclical in nature with intrinsic muscle properties providing many constraints which can have an influence on individual muscle function and the coordination of multiple muscles to perform the locomotion Many different control strategies have been used within robotics, not only to produce bipeds with a stable and efficient gait pattern, but also for studying biological models and gaining insight into walking control systems that may be present in humans. This allows us to simplify and analyse individual components of a complex system to study their role in generating functional locomotion. From this information, development can be made in the area of rehabilitation engineering with the aim of improving functional gait in individuals with spinal cord injuries (SCI) and other neurological injuries. Rehabilitation technologies for restoring ambulatory function and retraining of a functional gait include devices such as the exoskeleton, ReWalk Classical control strategies employed in bipedal robotics, which have a biomechanic inspired design, include passive dynamic walkers, that are simple and can remain stable while walking down slopes Within a human model, feedback on the current status of the walking process is fed back from different sensory organs located in muscles and tendons and from the peripheral vestibular and visual systems. At high walking speeds, coordination between the sensory input and motor output needs to act efficiently and quickly, which are high dynamic walking demands very difficult to replicate using existing biologically-inspired robotic control systems RunBot is driven by local reflexes without any use of position or trajectory-tracking control algorithms and without using a central pattern generator Central to this paper is investigating the control between the sensor inputs of the robot and its motors. The original RunBot I attempted a biologically inspired approach where the sensor signals were translated into motor signals with the help of a neural network incorporating biologically inspired neuronal functions see . HoweverOur aim was to calculate transfer functions from human walking which translate sensory information into muscle activation signals by recording foot contact data and leg muscle activity (EMG) in healthy subjects as they walked on a speed controlled treadmill. To average out the periodicity in the recorded data, irregular walking patterns needed to be generated. As a treadmill can be viewed as a foreign environment for walking, which may also have an effect on the subjects walking, varying the walking speed in a random fashion should also create an environment which is more closely modelled on natural walking where speed can be changing constantly.The unknown transfer functions which translate the contact information into muscle activation signals were identified using adaptive filtering. The filter was trained by using the heel contact information as an input and ipsilateral (IH) to the leg muscle) and the EMG activity from the Tibialis Anterior (TA), Lateral Gastrocnemius (LG), Rectus Femoris (RF) and Biceps Femoris (BF) as the output.The algorithm converged for the following relationships between the muscle activity and heel contact and generated stable transfer functions: Characteristics within the transfer functions related to flexion or extension of the hip and knee joints in humans were identified and separated to produce transfer functions for controlling RunBot's leg motors and generate stepping. The following transfer functions were applied to RunBot's hip and knee motors and were successful in producing a stable gait cycle: Knowledge of how sensory information from the peripheral nervous system (PNS), in humans, relates to motor actions of the muscles and limbs throughout the gait cycle has potential use in iSCI rehabilitation. Specifically if foot contact information is causally related to muscle activity, then contact information from the feet could be used as a feedback control mechanism for use with FES of leg muscles to generate walking. The idea of this approach is an entirely analogue closed-loop system to generate locomotion using simple reflexes and without central pattern generators. This has potential to provide a minimalistic control system for FES, where the cyclic sequence of joint movements is minimally imposed on the walker, which has an application for producing functional gait in individuals with iSCI without overriding any residual function which may remain. We have shown that transfer functions can be found to translate information from the feet during the gait cycle into muscle activation signals with correct timing to promote flexion and extension of the hip, knee and ankle joints . The long-term aim would be the development of a device which will promote limit cycle walking, allowing the walker to adapt their gait to suit changing loading conditions dependent on terrain or the environment.The investigation was granted ethical approval by the University of Strathclyde ethics committee. Ten subjects, four males and six females with a mean age of 26.5 years (range 23\u201330 years) were recruited at the Department of Biomedical Engineering, University of Strathclyde and gave full informed written consent before taking part in the study.The study involved recording muscle activity and foot contact information during treadmill walking. The muscles recorded were chosen due to their different roles in the gait cycle, two muscles located in the shank and Lateral Gastrocnemius (LG)) and two in the thigh (Biceps Femoris (BF) and Rectus Femoris (RF)), see http://www.linux-usb-daq.co.uk/howto2/bio-sigma/). The device was required to be lightweight and compact so it could be worn by the subject during ambulation. The device has eight channels for recording surface EMG of the four leg muscles in both legs. The device also incorporates amplifier circuitry for force sensing resistors (FSRs) for measuring foot contact information. The FSRs are embedded in standard shoe insoles at four different positions under each of the feet for recording areas of peak pressure distribution during walking (main weight bearing areas); under the first and fifth metatarsals, big toe and heel, as described by Granat et al. To record muscle activity and foot contact information during the treadmill walking, a purpose designed EMG/FSR amplifier was developed were used to create a template of the feet.http://www.linux-usb-daq.co.uk/software2/comedi-record) was used to record the walking data and the output saved in a MATLAB compatible ASCII file for further analysis.All sixteen of the EMG and FSR channels were recorded simultaneously with a sampling frequency of http://monodevelop.com) to produce a pseudo-random sequence of belt speed settings within a desired range. The program was based on the Coscom V3 interface protocol (available from www.coscom.org) enabling the treadmill to be controlled over a RS232 connection to a computer. The belt speed was transmitted via Ethernet and recorded alongside the EMG and foot contact data in Comedirecord.A belted treadmill was taken in a time period of one stride duration before and after heel contact, The next step is to calculate the transfer functions which translate foot contact information into muscle activation signals. These are especially useful in the creation of a human-walking model with potential applications in the development of humanoid robots with locomotion based on human walking and within rehabilitation engineering research.Adaptive filtering was used to derive the transfer function for each of the recorded muscles and implemented using MATLAB . The EMG data for each muscle in the left or right leg, Where Using the Least Mean Squares (LMS) algorithm, the output signal The error signal e(n) is then calculated as the difference between the desired signal The error signal drives the optimisation algorithm which updates the filter coefficients with correction factor Where The transfer function coefficients were calculated using the adaptive filtering method for each of the four leg muscles from each of the ten subjects. A table of the final mean square error (MSE) of the filter coefficients is provided in Applying the coefficients to an FIR filter produces a muscle activation signal when the filter is given an input of a typical FSR heel contact signal. A half Hanning window was convolved with the impulse response of the variable filter to select only the coefficients needed to generate a muscle activation signal one stride duration in length subsequent to the input of a heel contact signal from an FSR. An example of the filter outputs for one subject can be seen in Before the transfer functions can be applied to the RunBot robot the standard operation and mechanical structure need to be understood in terms of how the motors can be controlled by muscle activation signals.RunBot II is the second generation development of a biped, robotic walker which features some adaptions to the robot (RunBot I) described by Geng et al. (2006) RunBot I was designed with stiff knees, which has a disadvantage of causing damage to the gearbox of the motor in the joint due to the impact of the leg on the ground at heel strike. To improve in the RunBot's knee structure and minimise damage to the joint, the motor was moved up to the thigh and three springs were positioned at the joint. This creates a balanced spring-loaded pulley using a robust bearing at the knee joint. The different springs are dominant either during flexion or extension, similar to muscles in the human leg. Using this configuration of springs, there is still a linear relationship between the motor angle and the knee angle but the knee retains an ability to flex to absorb the shock to the joint at heel strike Further development of RunBot II includes using filter functions to generate a coordinated walking behaviour rather than neuronal processing, which was the original control structure employed in RunBot I.Filter functions and real-time processing allow fast tuning of few parameters however, like RunBot I, ground contact information is still used as the main sensory input to promote joint movement and stepping.RunBot II has a height of 0.3 m (foot to hip joint axis) and a total weight of approximately 552 g. Motors at RunBot's hip and knee joints are driven by output signals of a reflexive control program written in C++ (running on a Linux PC) with a sampling rate of The robot has no ankle joint but features flat feet with serrated soles to increase friction with the ground and prevent slipping. RunBot's reflexive control system can be explained through description of three important events in the gait cycle:Ground contactAnterior extreme angle (AEA) of the contralateral hip jointPassive dynamic walking phase(1) Foot contact with the ground triggers the hip and knee of the contralateral leg to begin flexing (swing) and the ipsilateral hip and knee to begin extending (stance), In mathematical terms, the reflexive model of RunBot is a simple system involving convolution of the summed impulse trigger signals, from the leg joints and the ground contact information from both feet, with transfer functions Shown are the general equations for both legs, with \u2018I\u2019 defining the ipsilateral leg and \u2018C\u2019 the contralateral leg:Where The final outputs After having established the transfer functions using the human treadmill walking data and adaptive filtering , which coAs we have discussed, RunBot has push switches in its feet which generate impulses on contact with the ground and knee extension (in the late swing phase and the stance phase). Two separate peaks of activity can be observed in the RF transfer function Where Our aim was to relate muscle activity to foot contact and use this to trigger muscle activation signals with the purpose to attempt to represent the underlying muscle activation dynamics Where, as previously, BF is responsible for hip extension (in the stance phase) and knee flexion (in the swing phase), two motions in different phases of the gait cycle. By taking the transfer functions derived from the BF EMG activity and ground contact information from both feet and knee flexion in pre-swing and initial swing phase. The transfer function relating to contralateral heel contact (In the case of two of our recorded muscles being responsible for the same action (e.g LG and BF in knee flexion) the sum of the two transfer function coefficients is taken. The sum can then be substituted in Eqn. 6c for knee flexion in RunBot's control system:The start point for the transfer functions next needs to be defined. It is important to note that the data is cyclic and thus a start and endpoint of the function needs to be determined.As we have already discussed, the delay between contralateral heel contact and muscle activity related to knee extension at terminal swing , is too lThe springs used in RunBot's knees produce a latency period due to a delay between the motor turning and the springs reacting which can be viewed as equivalent to the delay between heel strike and toe off of the contralateral foot observed in normal human walking during the double support phase (first 10%) of the gait cycle, see Unlike the knee, the hip joint motor in RunBot is directly controlled by the motor so there is no spring latency period. The delay in motor activation between heel strike and contralateral toe off in the transfer functions, summed with RunBot's spring latency period, produces an extended delay causing knee motion uncoordinated to the hip. For this reason, the delay between the trigger and the onset of knee flexor activity was subtracted from the knee flexion transfer functions. As the hip joint motor is not controlled by springs the delay between trigger and muscle activation for hip joint control was not removed.The final stage in data processing before applying the transfer functions to RunBot is curve fitting to remove spurious artefacts in the EMG as the assumption is made that a muscle activation signal should be a smooth increase and decrease in voltage with contraction.The muscle twitch response of muscle has a characteristic shape which closely matches the impulse-response time curve of a damped, linear second-order differential system and models the net result of coupling between the excitation and contraction of the muscle To this purpose we have used the impulse response of a critically damped system to curve fit the muscle excitation of the desired features of the muscle transfer functions using the least mean squares (LMS) algorithm and model optimisation in MATLAB. The resulting transfer functions are to determine the moment for knee extension at terminal swing because for this event there is no causal relationship between heel contact and muscle activity. A stable transition from swing to stance is dependent on the swing leg becoming sufficiently protracted before ground contact. For this reason position of the hip is a suitable candidate for producing an afferent signal regulating swing-to-stance transition Compared to classical control systems used in robotics including, finite-state machines, trajectory tracking, machine learning and CPGs, our controller is based on actual human walking data. We have created a closed-loop system based on the causal relationship between the foot contact information and the muscle activation signals (in humans), which translates to motor activation at the limbs in the robot. The result is so-called limit cycle walking which is defined by Hobbelen and Wisse (2007) as a nominally periodic sequence of steps which although not locally stable at every instant in time, is stable as a whole The precise function of load dependent reflexes and the extent to which reflex responses generated by sensory input from peripheral receptors contribute to human bipedal gait in comparison to other mammals is not thoroughly understood. It is still unclear how significant spinal networks are in the generation of human walking and whether the functional effect of load receptors and reflexes play a similar role in human muscle activation as in the animal models.Neurophysiological studies have revealed in different animal species that during locomotion , motor neurons are being driven by CPGs. These central networks have been observed to work independent of sensory or descending inputs carrying specific timing information and generate the rhythm and pattern of the locomotor bursts of the motor neurons Unlike a CPG, a reflex is a local motor response to a local sensory input. In the locomotion of human and animals, various reflexes act together to control the limbs and their integration contributes to the regulation of the locomotor gait cycle Within a human model, feedback on the current status of the walking process is fed back from different sensory organs located locally in muscles and tendons and peripherally from the vestibular and visual systems. At high walking speeds, coordination between the sensory input and motor output needs to act quickly with efficiency and these high dynamic walking demands are currently not possible using existing artificial robotic control systems We believe that our controller demonstrates that complex behavioural patterns can result from a simple model for locomotion and gait control based on reflexes. An achievement where much of the biological complexity within the true human motor control system has been omitted.A reflexive controller based on human data has implications for locomotor training after spinal cord injury. Functional electrical stimulation (FES) is commonly recruited as a rehabilitation strategy for SCI to exercise and strengthen weakened muscles as well as artificially replace muscle activation that is missing or lacking as an alternative for push button control, using a pre-programmed multi-channel electrical stimulation system for stroke patients Closed-loop control has been studied using two different forms of sensory feedback; biological signals generated by the individual and signals derived from artificial sensors. Research involving gait event detection have traditionally been based on a single type or an integration of different body-worn sensors typically positioned on the thigh, shank or foot to measure ambulation and have included accelerometers A study by Kojovic et al. (2009) compared the automatic FES control system, proposed by Popovic et al. (2005) The main difference between the previously discussed control schemes and ours presented here is that our approach uses linear transfer/filter functions which do not require any thresholding. Although bipedal robots featuring finite-state machines can exhibit a stable limit cycle In the future we would like to adapt the simple reflexive control system employed by RunBot into an FES controller for gait rehabilitation, which could assist stepping and promote limit cycle walking in patients with spinal cord injuries.In summary, the results presented here demonstrate a simple method for controlling walking by establishing the underlying relationship between ground contact information from the feet and muscle activity, which could be of great importance and has significant potential in the development of bipedal robotics and in rehabilitation strategies.Table S1The final mean square error result for each subject for each muscle transfer function from the adaptive filtering. The transfer functions were calculated using the EMG activity recorded from the subject's right leg with heel contact information from both the right and left foot. Transfer functions related to the Lateral Gastrocnemius (LG), Rectus Femoris (RF) and Biceps Femoris (BF) are given, contralateral heel contact are labelled (CH) and ipsilateral heel contact (IH).(EPS)Click here for additional data file.Table S2Values for the extreme angle of each joint .(EPS)Click here for additional data file.Table S3The gain of the motor amplifier .(EPS)Click here for additional data file.Video S1Experimental set-up. Video demonstrating the experimental set-up used to record muscle activity (EMG) and foot contact information from the human test subjects.(MP4)Click here for additional data file.Video S2EMG and foot contact recording during human treadmill walking.(MP4)Click here for additional data file.Video S3RunBot walking using transfer function set 1A.(MP4)Click here for additional data file.Video S4RunBot walking using transfer function set 1B.(MP4)Click here for additional data file.Video S5RunBot walking using transfer function set 2A.(MP4)Click here for additional data file.Video S6RunBot walking using transfer function set 2B.(MP4)Click here for additional data file.Video S7RunBot walking using transfer function set 3A.(MP4)Click here for additional data file.Video S8RunBot walking using transfer function set 3B.(MP4)Click here for additional data file.Video S9RunBot walking using transfer function set 4A.(MP4)Click here for additional data file.Video S10RunBot walking using transfer function set 4B.(MP4)Click here for additional data file.Video S11RunBot walking using transfer function set 5A.(MP4)Click here for additional data file.Video S12RunBot walking using transfer function set 5B.(MP4)Click here for additional data file.Video S13RunBot walking using transfer function set 6A.(MP4)Click here for additional data file.Video S14RunBot walking using transfer function set 6B.(MP4)Click here for additional data file.Data S1File information for (GZ)Click here for additional data file.Data S2Subject A.(GZ)Click here for additional data file.Data S3Subject B.(GZ)Click here for additional data file.Data S4Subject C.(GZ)Click here for additional data file.Data S5Subject D.(GZ)Click here for additional data file.Data S6Subject E.(GZ)Click here for additional data file.Data S7Subject F.(GZ)Click here for additional data file.Data S8Subject G.(GZ)Click here for additional data file.Data S9Subject H.(GZ)Click here for additional data file.Data S10Subject I.(GZ)Click here for additional data file.Data S11Subject J.(GZ)Click here for additional data file.Data S12Subject A.(GZ)Click here for additional data file.Data S13Subject B.(GZ)Click here for additional data file.Data S14Subject C.(GZ)Click here for additional data file.Data S15Subject D.(GZ)Click here for additional data file.Data S16Subject E.(GZ)Click here for additional data file.Data S17Subject F.(GZ)Click here for additional data file.Data S18Subject G.(GZ)Click here for additional data file.Data S19Subject H.(GZ)Click here for additional data file.Data S20Subject I.(GZ)Click here for additional data file.Data S21Subject J.(GZ)Click here for additional data file."} +{"text": "There is an error in paragraph nine of the Discussion section. The authors incorrectly summarized the findings of the cited paper. The correct sentence is: Previous studies have also indicated a broad role for HoxA5 during embryonic development and 50% of homozygous null HoxA5 mice die at birth or shortly thereafter."} +{"text": "The use of 3D prototyping in medical practice is becoming increasingly important, due to the development of 3D printing and the recent rapid advances in relevant techniques and equipments. The use of 3D model is especially important in the field of paediatric cardiology and congenital cardiovascular disease, where there is a clear advantage over conventional 2D images in demonstrating complex anatomies and relationships between different structures.The authors have selected a few paediatric cardiovascular diseases, and hope to share their initial experiences in 3D prototyping in this presentation.Different cases are included to illustrate the use of 3D prototyping in management of congenital cardiovasclar diseases.The departments of radiology and paediatrics of a local teaching hospital and the department of medical engineering of a local university have started the first collaboration in Hong Kong, which pioneered the use of 3D printing in paediatric cardiovascular diseases."} +{"text": "Oriens-lacunosum moleculare (OLM) cells are a major subclass of hippocampal interneurons involved in controlling synaptic plasticity in Shaffer collateral synapses . An immunohistochemistry study has also shown that adult animals exhibit larger number of identified somatostatin positive cells in stratum pyramidale of all recorded/filled cells in the CA1 of these mice could be classified as OLM and little or no Cre activity was observed in the dentate gyrus or CA3 . Hence, it seems that the variability in bacterial artificial chromosome (BAC) transgene technology restricted Cre expression to a very specific subpopulation of Chrna2+ cells. Notably, two other GENSAT BAC lines attempting to use the chrna2 promoter appear to have a less restricted expression of Cre .We recently described a transgenic mouse line that expresses Cre predominantly restricted to OLM cells of the CA1 and subiculum Figure . In our In addition to the restricted expression in the OLM cells of the CA1/subiculum, Cre expression in Tg(Chrna2-cre)1Kldr was observed to be more significant in the intermediate and ventral hippocampus Figure . In summThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Dear Sir,-4Pediatric flexor pollicis longus (FPL) injury is an uncommon entity with scarce literature pertinent to the results of repair. Although much has been inferred from the study of long flexor tendons of the other 4 digits, the FPL's unique anatomy has been cited as justification for its independent study. The largest case series of 16 patients has reported outcome analysis using a modification of the otherwise complex Buck-Gramcko and Tubiana assessment scales.1In a quest to propose a more practical pediatric assessment tool for FPL repair outcomes, we conducted a retrospective review of our practice. Seven children ranging in age from 9 months to 14 yeReview of the hand therapy assessment charts showed challenges faced by both clinicians and hand therapists with documenting the complex joint measurements required by the existent assessment scales. We thus collaborated with specialist hand therapists to develop a functional assessment scale for more reliable and practical documentation of outcome measures in the pediatric population.The 10-point Kapandji scale of thumb opposition was simplified to include 3 of its reference points and thenThe hand therapy chart notes at 3 months after surgical repair were extrapolated into the assessment proposed by our scale. We did not observe any postoperative tendon ruptures in our series. Four repair outcomes were graded as excellent, 2 as good, and 1 as fair in a year-old boy who required tenolysis following suspected rupture. This was consistent with the functional outcome seen on long-term follow-up of the patients, demonstrating our modified scale to be both practical and reliable in our small cohort of patients. Our preferred outcome assessment enables hand therapists and doctors evaluating repairs in clinic to use the hand as its own frame of reference. The use of stickers on Kapandji reference points and everyday props in functional assessment make this an effective assessment tool that is both child- and user-friendly."} +{"text": "The authors would like to give readers the following update: Due to the mislabeling of a plasmid used for HeLa cell transformation the authors mistakenly claimed that SA2 protein devoid of two putative C-terminal nuclear localization signals found between amino acids 1071 and 1140 had a nuclear localization . In fact, the unpublished results corroborate the data of Kong et al., (2014) indicating that both those C-terminal NLSs are required for the nuclear localization of the C-terminal fragment of SA2 [2]. Other conclusions of the work are unaffected. The authors regret any inconvenience this error may have caused."} +{"text": "Cervical cancer and Pancreatic ductal adenocarcinoma , were used contrary to the Publication Guidelines at The authors and the TCGA agreed that a republication of the article with those data sets removed would resolve this, and the Academic Editor and PLOS staff are satisfied that the results and conclusions of the article stand without these two data sets. We are republishing the article to report the results obtained from the 14 permitted data sets.The summary of the results in the abstract was previously:We carried out GISTIC2 analysis of TCGA datasets spanning 16 cancer subtypes and identified 486 genes that were amplified in two or more datasets. The list was narrowed to 75 cancer-associated genes with potential \u201cdruggable\u201d properties. The majority of the genes were localized to 14 amplicons spread across the genome. To identify potential cancer driver genes, we analyzed gene copy number and mRNA expression data from individual patient samples and identified 42 putative cancer driver genes linked to diverse oncogenic processes.The summary of the results in the abstract is now:We carried out GISTIC2 analysis of TCGA datasets spanning 14 cancer subtypes and identified 461 genes that were amplified in two or more datasets. The list was narrowed to 73 cancer-associated genes with potential \u201cdruggable\u201d properties. The majority of the genes were localized to 13 amplicons spread across the genome. To identify potential cancer driver genes, we analyzed gene copy number and mRNA expression data from individual patient samples and identified 40 putative cancer driver genes linked to diverse oncogenic processes."} +{"text": "There are errors in the raw data presented in Table S9Proportions still attached in cattle coat after a certain time [min] for up to five repetitions (rep.) for the 64 species in table S10. We standardized the measured values by subtracting the minimum value and dividing by the range of the measured values.(DOCX)Click here for additional data file."} +{"text": "Substance use disorders (SUDs) and traumas frequently co-occur. A recent German study found that 66% of the women with a diagnosis of opioid dependence also reported sexual abuse, whereas the figure for men was 11% and 10% (OR 3.2), respectively. Conversely, about 35% of people diagnosed with PTSD also have an alcohol use disorder all treatment-seeking SUD patients should been screened for PTSD; 2) all treatment-seeking PTSD patients should be questioned about their alcohol and drug use; 3) all patients with PTSD and/or SUD should be screened for the presence of early childhood trauma; 4) the presence childhood trauma should always be validated and possibly treated; 5) the relationship between PTSD symptoms and substance use should be assessed and monitored; 6) the patient's preference for abstinence or controlled use should be taken into account because both drug use and withdrawal can worsen the course of PTSD symptoms; 7) all patients with PTSD and SUD should be screened for sleeping disorders; 8) it is preferable to treat PTSD and SUD simultaneously either with one or two different therapists; 9) cognitive behavioural therapy with exposure is preferred (including eye movement desensitisation and reprocessing), possibly in combination with pharmacotherapy for addiction and/or PTSD; 10) there is no role for benzodiazepines or tricyclic antidepressants in the treatment of patients with SUD and PTSD; and 11) there might be a role for topiramate, prazosin, or gabapentin in the treatment of nightmares in patients with PTSD and SUD."} +{"text": "Col2a1 has previously been studied in the mouse and our mutant phenotype closely resembles mutations made in the Col2a1 locus.Phenotype-driven mutagenesis experiments are a powerful approach to identifying novel alleles in a variety of contexts. The traditional disadvantage of this approach has been the subsequent task of identifying the affected locus in the mutants of interest. Recent advances in bioinformatics and sequencing have reduced the burden of cloning these ENU mutants. Here we report our experience with an ENU mutagenesis experiment and the rapid identification of a mutation in a previously known gene. A combination of mapping the mutation with a high-density SNP panel and a candidate gene approach has identified a mutation in These alleles represent powerful models of human development and disease. Multiple laboratories have shown the power of ENU mutagenesis over the past several years. These screens were initially aimed at general morphological and organogenesis defects We recently performed an ENU mutagenesis experiment in the mouse as part of our continuing efforts to understand the genetic basis of congenital malformations affecting the forebrain and craniofacial tissues. Similar to our previous efforts, this breeding strategy included a genetic outcross to combine a genetic mapping component with our exome analysis MC13 mutants were readily identifiable from control littermates by their abnormally shaped heads and limbs at E18.5 mapping across the mouse genome. We submitted three mutant DNA samples to the MEGAMUGA mouse SNP panel. This is a commercial panel of 77,800 SNPs spaced throughout the genome at an average distance of 33 Kb. Given the ENU treatments were administered to the B6 mice , we follCol2a1. Sequencing of the Col2a1 locus (ENSMUSG00000022483) identified a mutation (G>A) in the intron between exons 21 and 22, five nucleotides from the end of exon 21 (Col2a1.A survey of known phenotypes in the region showed a high similarity between our MC13 mutant and previous ablations of exon 21 . We iden exon 21 . We nextCol2a1 transcript (ENSMUST00000023123) in MC13 mutants similar to those we describe here in our MC13 mutants. The random nature of ENU mutagenesis does raise the possibility that another, closely linked, gene may theoretically be mutated to cause this phenotype. However, the phenotypic resemblance of our mutants to known Col2a1 alleles, the 100% concordance between the Col2a1 mutant genotype and phenotype to date, and the predicted effects of this mutation lead us to conclude this is indeed the most likely causal mutation. The definitive proof of this would be a complementation test between our MC13 allele and known allele of Col2a1. We, however, believe the evidence for this being the causal mutation is strong enough that we have not conducted this experiment for formal proof of our model.We originally identified COL2A1 mutations in humans have been identified in a number of skeletal dysplasias . Given that our analysis of the mutant transcript does indicate the normal variant is produced at some level, we suggest that some aberrant RNA is likely degraded but truncated peptides are produced. These then ultimately prevent the normal production and function of collagen fibrils and recapitulate aspects of both the null phenotype Col2a1 locus. This represents a new mouse model of human disorders associated with collagen mutations.This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Institutional Animal Care and Use Committee of the Cincinnati Children's Hospital Medical Center (protocol numbers 1D05052 and IACUC2013-0068). All euthanasia and embryo harvests were performed after isoflurane sedation to minimize animal suffering and discomfort. Animal euthanasia was via cervical dislocation and thoracotomy.SNP mapping on the MEGAMUGA panel was performed by the Neogen Corporation .Embryos were dissected, examined and photographed with a Zeiss Discovery.V8, Axiocam MRc5and AxioVision software. Skeletal preparations to highlight bone and cartilage were done according to standard, published methods TCGGCCCTCATCTCTACATC). Transcripts were PCR amplified with primers for exons 19 and exon 23 and Sanger sequencing was performed at the CCHMC DNA Sequencing and Genotyping Core Facility. Quantification of the cDNA was done with the GelAnalyzer 2010a software.RNA was prepared from whole heads of E16.5 MC13 mutants and wild-type control littermates using the TRIZOL reagent and manufacturer's protocols . cDNA was prepared using the SuperScript III First Strand cDNA Synthesis kit (Life Technologies) and gene specific primer ("} +{"text": "Medical training in the UK has now changed with the development of Foundation Programmes providing two years of experience in a range of disciplines that may include acute medicine and 3 months Basic training in ICM . The ICMThe aims of this audit were to reinforce the benefits and practicalities of basic level ICM training from a Medical trainee's perspective and summarize the key competencies for the assessment of the technical skills required to deal with acutely unwell patients in ward needing intensive Care.A questionnaire was sent out to all the Registrars and SHOs working in Medical Specialities in West Midlands and Manchester region including ST and Staff grade level. 147 Registrars and SHOs in total responded to the questionnaire, 68 in Manchester and 79 in West Midlands. The questionnaire sought info about the prior involvement of the Registrars in formal 3 months Competency based ICM training at Basic Speciality level and the level of confidence in doing ICU procedures like Central line, Arterial line and managing invasive Ventilation, tracheostomy care and non invasive Ventilation and use of Vasopressors and Inotropes etc.The registrars who had done ICM preliminary training for 3 months demonstrated a significant difference in being confident in inserting Central lines with Ultrasound guidance (p = 0.046) and non invasive Ventilation management (p = 0.009) than the group who did not do a formal ITU training . There was no significant difference in Confidence levels between the Medical trainees of various specialities .There was a significant difference in ease of using Inotropes and Vasopressors in the ICM trained group as compared to the non trained group with P = 0.008.5. The confidence of dealing with ward patients is better in registrars who have completed competency based ICM basic training and helps in reducing burden on Intensive care registrars.It should be mandatory to do 3 months basic ICM competency before beginning Medicine Registrar position"} +{"text": "Child abuse is widely prevalent in the Netherlands, and the strong social and political focus now put on the issue is fully warranted. Prevalence studies have estimated that around 3% of all Dutch children experience some form of abuse or neglect Do the parents acknowledge that their child has problems? (2) Do they acknowledge the part that they themselves have played in the onset of the problems? (3) Are they motivated in any way to try to change the situation? (4) Are the parents capable of recognizing experts as people that can truly help? (5) Do the parents themselves have mental health problems that complicate the treatment? Some situations are simply too unsafe, and some parents are utterly incapable of bringing up their child or children. That necessitates the placement of children away from home.Once a safe environment has been created, the next question is whether the traumatized child should receive trauma-focused treatment right away or whether the first priority should be to ensure a degree of stability. There is considerable debate about this in the adult literature (e.g., De Jongh & ten Broeke,"} +{"text": "Four years\u05f3 behavioral data of thin-film single junction amorphous silicon (a-Si) photovoltaic (PV) modules installed in a relatively dry and sunny inland site with a Continental-Mediterranean climate are presented in this article. The shared data contributes to clarify how the Light Induced Degradation (LID) impacts the output power generated by the PV array, especially in the first days of exposure under outdoor conditions. Furthermore, a valuable methodology is provided in this data article permitting the assessment of the degradation rate and the stabilization period of the PV modules.Further discussions and interpretations concerning the data shared in this article can be found in the research paper \u201cCharacterization of degradation and evaluation of model parameters of amorphous silicon photovoltaic modules under outdoor long term exposure\u201d Specifications TableValue of the data\u2022The shared data may be useful to understand the behavior of thin film single junction amorphous silicon (a-Si) photovoltaic modules based technology deployed under outdoor conditions.\u2022Understanding the behavior and the characteristics of the a-Si PV modules are essential to improve the reliability of this PV modules based technology and selecting the best technology for the appropriate climatic conditions.\u2022The methodology used in this data article is valuable for determining the performance and estimating the degradation period of PV modules.1The shared data describes the behavior of the amorphous silicon (a-Si) thin film PV modules deployed under outdoor conditions from July 2011 to December 2014.G\u2265700\u00a0W/m\u00b2), delimited by two boundaries defined as initial and stable PV array DC output powers for the second semester of each year along the experimental campaign are presented in The actual DC output power generated by the PV array versus filtered values of irradiance due to the Staebler\u2013Wronski effect (SWE) The degradation rate assessment can be based on the comparison of the monitoring outdoor performance with initial indoor measurements taken as references The data presented in this article were analyzed using the technique proposed by Hussin et al. To avoid problems of uncertainties caused by low values of irradiance due to the presence of shading, a data filtering process is needed, as explained in G), module temperature (Tc), and can be calculated by using the following equations:Pdcinit is the predicted array DC power referred to initial (W), Ns and Np are the number of modules connected in series and parallel respectively, Pminit is the initial measured peak power of PV module (Wp), kv and ki are the voltage and current temperature coefficients respectively provided in the manufacturer\u2019s data sheet (1/\u00b0C), Pdcstab is the predicted array DC power referred to stabilized (W), Pmstab is the stabilized peak power of the PV module found in the manufacturer\u05f3s data sheet (Wp), \u03b7 is the efficiency referred to all general system losses which changes between 0.89 in summer and 0.86 in winter months, Gn and Tn are the reference irradiance and cell temperature respectively under STC .The predicted initial and stabilized data values depend on the measured plane-of-array irradiance (The empirical equations presented in"} +{"text": "The complex activity of the human brain makes it difficult to get a big picture of how the brain works and functions as the mind. We examine pertinent studies, as well as evolutionary and embryologic evidence to support our theoretical model consisting of separate but interactive layers of human neural activity. The most basic layer involves default mode network (DMN) activity and cardiorespiratory oscillations. We propose that these oscillations support other neural activity and cognitive processes. The second layer involves limbic system activity accompanied by corresponding changes in cardiorespiratory oscillations. The third layer consists of corticothalamic processing and involves higher cortical functions including awareness, cognition, and consciousness. These layers interact to form the complex neural activity of the human brain. Examining the origins and relationships of various neural and physiologic oscillations may provide better understanding of human neurophysiology and consciousness.A number of EEG and fMRI studies in mammals indicate spontaneous low frequency oscillations in cerebral activity at <0.1 Hz represent a fundamental component of brain activity have been detected in infants between 20 and 36 gestational weeks the default mode network and cardiorespiratory oscillations, (2) limbic activity Figure , and (3)The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Retrospective study of patients with chronic tension headache (CTH) and chronic migraine (CM).To compare the efficacy of biofeedback (BFB) compared to only prophylactic therapy in these primary headaches \u20134.Headache diary to assess days per month with headache;Analgesic consumption and/or triptans;Score of the visual analogue pain scale (VAS);SEMG parameter for patients who carried out BFB training.We evaluated a total of 8 patients with CTH and 8 patients with CM. All patients had a history of primary headache and had never undergone prophylactic therapy. The observation period lasted 90 days. Four CTH patients and 4 CM patients underwent only prophylactic therapy (amitriptyline 20 mg daily), the remaining 4 CTH and 4 CM prophylactic therapy and BFB training sessions. Assessment tools outcome measures were:At the end of the 90 day observational period there was a significant improvement in CTH and CM patients that had undergone both BFB training and prophylactic therapy when compared to the group of patients treated only with prophylactic therapy drug.The overall data confirmed the efficacy of the BFB training in the prophylaxis of primary headaches, further supporting the benefits already possible with the therapy of only pharmacological prophylaxis Table . The datWritten informed consent to publication was obtained from the patient(s)."} +{"text": "A 13-year-old girl presented with swelling and tenderness of the digits of the hand. She had undergone prior excision of similar lesions. These lesions have been present since approximately the age of 4, are bilateral, and have become progressively troublesome and painful. She was noted to have an asymmetric gait and unequal extremity lengths.What is the typical age at which onset of symptoms occurs?What is the risk of malignant degeneration of the bony lesions?What are characteristic features seen on hand x-ray in this disease?What is the pattern of inheritance of Maffucci syndrome?,Maffucci syndrome typically begins to manifest around 4 to 5 years of age and progresses throughout life.2It is important to recognize the diagnosis and differentiate Maffucci syndrome from the clinically similar Blue Rubber Bleb Nevus (BRBN) syndrome because of the significant risk for malignant degeneration of enchondromata.5The characteristic features of Maffucci syndrome seen on hand x-ray are the multiple acral enchondromata that progress over time. These radiographs should be followed by a Hand or Orthopedic surgeon to assess for malignant degeneration. Because of the multiple spindle cell hemangiomas present in the hands, characteristic calcific phleboliths may also be visualized within the vascular malformations.Maffucci syndrome is a rare, sporadically inherited genetic disorder that does not display any sexual or racial predilections. Because of the rarity of the disease, specific genetic markers have long eluded association with this syndrome. However, a link with somatic mosaic mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and 2) genes have been associated with both Maffucci syndrome and Ollier disease. A recent study found that roughly 80% of patients studied with both Ollier disease and Maffucci syndrome had heterozygous somatic mutations of the IDH1 or 2 genes in their tumors.6Maffucci syndrome had long been a clinical diagnosis. There is no hereditary transmission and no etiological predilections. Recently, a link with mutations in the IDH1 and 2 genes has been associated with this process. It is important to distinguish this syndrome from BRBN syndrome due to the roughly 30% risk for malignant degeneration of the cartilaginous lesions over time into chondrosarcomas. Symptoms of this syndrome may range from asymptomatic soft tissue swelling to painful lesions that hemorrhage causing anemia or pathologic fractures that deform the bony skeleton and impair function."} +{"text": "The search for natural sources of molecules that exhibit biological activity has intensified in the last 20 years. The andiroba (Carapa guianensis) oil is known for its medicinal actions , and bio"} +{"text": "In a previous study on 15 AIS patients, we demonstrated the feasibility of a brace design technology combining Computer Aided Design and Manufacturing (CAD/CAM) and finite element modeling (FEM) for the treatment of scoliosis. The braces showed an equivalent correction to standard braces, but were 61% thinner and had 32% less material. A Randomized Control Trial (RCT) was undertaken to pursue the validation and further assess the effectiveness of braces issued from this technology as compared to standard brace design approaches.Patients who received a brace treatment prescription were randomized into two groups: 1) TLSO fabricated using a scan of patient's torso and a CAD/CAM approach (Rodin4D) (StandardBrace); 2) TLSO additionally designed using Finite Element Modeling (FEM) built from 3D reconstructions of the trunk skeleton from bi-planar radiographs and optimization (NewBrace). The latter approach allowed to simulate the scoliosis correction and the applied pressures on the torso, and to iteratively design the brace up until the simulated correction was considered maximal and its contact surface with the torso minimal. It was then fabricated using Computer Numerical Controlled technology. StandardBrace and NewBrace effectiveness was assessed using radiographs and compared to the simulations.36 patients were consecutively enrolled and to date, 24 patients received their brace. The average Cobb angle prior to bracing was 32\u00b0 and 30\u00b0 for the main thoracic and lumbar curves respectively. The preliminary results showed that the NewBrace reduced Cobb angles by 47%, which was simulated with a difference inferior to 5\u00b0. The StdBrace reduced the Cobb angles by 40%. The NewBrace had 32% less covering surface than the StdBrace. The highest pressures were located on the thoracic and lumbar regions and at the axillary and the trochanter extensions.So far, a novel design scheme combining CAD/CAM and 3D FEM simulation allowed the fabrication of braces more efficient and lighter than standard TLSO. The study is ongoing to fully compare and validate the effectiveness of the novel design platform.Written informed consent was obtained from the patient for the image(s) used in this study. A copy of the written consent is available for review by the Editor of this journal."} +{"text": "The Data Availability statement does not appear on the paper. The correct Data Availability statement is: The authors confirm that all data underlying the findings are freely available without restriction. Data are included in the paper and structural data can be found in the Protein Data Bank under PDB IDs: 4NTA,4NTB and 4NTF.The publisher apologizes for this error."} +{"text": "The Critical Care Outreach services are considered to be an essential part of a hospital wide approach in improving the early identification and management of deteriorating patients.Original recommendations made during the modernisation and improvement programme for Critical Care Services within England in 2000 led to different models of the service introduced but they remained mainly nurse led, with mixed approach to service delivery.We aimed to compare the difference in patient outcomes on a outreach service with consultant intensivist versus a nurse led outreach service. The CCOT at Queens hospital expanded in September 2013 to include consultant intensivist and the service also had extended the hours of provision from 8 hours /5 days to 7 days/12 hours.Retrospective cohort study of prospective collected data at a teaching university hospital of adult critical care patients admitted from January to June 2012 and January to June 2014.Outcomes measured were:Emergency admissions to critical care. (from ward areas only)Critical care readmission:- early < 48hrs; Late >48hrsICU length of stayPatients seen by CCOT before admissionNumber of cardiac arrest calls.15% reduction on number of Cardiac Arrest calls, .5.7% reduction on Length of Stay with a 75% increase in early discharges121% increase in CCOT visits for critical care admissions.10% increase in Emergency admissions> Critical care admitted sicker patients with higher acute physiology score with 91% reduction on admissions requiring zero organ support0.9%increase in Critical Care readmission In our critical care unit (ICU/ HDU) there has been an increase in the number of occupancy over a period of time (Graph 1). The extension of the critical care outreach service to longer hours and to include a consultant has allowed for early discharges leading to a higher turn over in the number of critical care patients. The reduction in cardiac arrest calls could be attributed to an increase in the \u00b4Not for Resuscitation\u00b4 decisions initiated by the consultants as well as an increase in service provision. The total cost effectiveness of the service is an area of future research."} +{"text": "Whilst the use of the mannitol/lactulose test for intestinal permeability has been long established it is not known whether the doses of these sugars modify transit time Similarly it is not known whether substances such as aspirin that are known to increase intestinal permeability to lactulose and mannitol and those such as ascorbic acid which are stated to be beneficial to gastrointestinal health also influence intestinal transit time.Gastric and intestinal transit times were determined with a SmartPill following consumption of either a lactulose mannitol solution, a solution containing 600 mg aspirin, a solution containing 500 mg of ascorbic acid or an extract of blackcurrant, and compared by doubly repeated measures ANOVA with those following consumption of the same volume of a control in a cross-over study in six healthy female volunteers. The dominant frequencies of cyclic variations in gastric pressure recorded by the Smartpill were determined by fast Fourier transforms.The gastric transit times of lactulose mannitol solutions, of aspirin solutions and of blackcurrant juice did not differ from those of the control. The gastric transit times of the ascorbic acid solutions were significantly shorter than those of the other solutions. There were no significant differences between the various solutions either in the total small intestinal or colonic transit times. The intraluminal pHs during the initial quartiles of the small intestinal transit times were lower than those in the succeeding quartiles. This pattern did not vary with the solution that was consumed. The power of the frequencies of cyclic variation in intragastric pressure recorded by the Smartpill declined exponentially with increase in frequency and did not peak at the reported physiological frequencies of gastric contractile activity.Whilst the segmental residence times were broadly similar to those using other methods, the high degree of variation between subjects generally precluded the identification of all but gross variation between treatments. The lack of any differences between treatments in either total small or large intestinal transit times indicates that the solutions administered in the lactulose mannitol test of permeability had no consistent influence on the temporal pattern of absorption. The negatively exponential profile and lack of any peaks in the frequency spectra of cyclic variation in gastric intraluminal pressure that were consistent with reported physiological frequencies of contractile activity profile suggests that the principal source of this variation is stochastic likely resulting from the effects of external events occasioned by normal daily activities on intra-abdominal pressure.ACTRN12615000596505Australian New Zealand Clinical Trials Registry The lactulose mannitol (LM) test is well established in the clinical investigation of intestinal permeability \u20133. Latte13C labelled octanoic acid . Th. Th48]. The mean small bowel transit times over all treatments was 4.63 h, a value that is well within the overall range (3\u20136 h) reported by other workers for healThe overall pattern of rise in ambient pH in consecutive quartiles of total small intestinal transit time following ingestion of the placebo fits in with reports that the capacity for the buffering in chyme increases distally along the small intestine . Hence tThe mean overall colonic transit time (53.59 h) was within the range reported for healthy individuals, i.e. between 24\u201360 h . The dife(sum of amplitude x number of contractions + 1)/time) may be inappropriate in ambulant or mobile subjects. We suggest that the use of the capsule to detect and analyse gastrointestinal motility may lack fidelity and needs further investigation [The spectral density profile of pressure recordings taken whilst the WMC was in the cavity of the stomach, did not peak at or around the known frequencies of antral slow wave associated contractions ,45. The tigation .The similarity of the gastric residence time to that reported during phase III MMC indicateTogether the data indicate that the administration of the solutions in the expanded lactulose mannitol test does not change the temporal characteristics of transit through any particular segment. Hence, it is likely that the administration of any of these solutions will not result in significant delay or hurry of the passage of chyme and thus will not displace the peak time of excretion so as to influence the absorption of lactulose or mannitol at a given time after dosage.S1 File(DOC)Click here for additional data file.S2 File(PDF)Click here for additional data file.S3 File(PDF)Click here for additional data file.S4 File(PDF)Click here for additional data file.S5 File(PDF)Click here for additional data file.S6 File(PDF)Click here for additional data file.S7 File(PDF)Click here for additional data file.S8 File(DOCX)Click here for additional data file."} +{"text": "In Canada and the US, omalizumab is indicated for adults and adolescents (>12 years of age) with moderate to severe persistent allergic asthma. In the EU, omalizumab has been approved for children (age 6 \u2013 11 years) since 2009. The pediatric population within Canada and the United States has very few treatment options available for severe asthma. Current treatments options can lead to other health concerns such as adrenal insufficiency and osteoporosis. These cases demonstrate that early treatment of moderate to severe asthma with omalizumab is an effective treatment and can help to prevent or reverse damage done by long-term use of other treatment options.1, inhaled corticosteroid (ICS) and oral corticosteroid (OCS) use.A retrospective chart review of our database was performed and patients \u2264 17 years of age receiving omalizumab treatment were evaluated. Data was collected on FEV12 patients were identified as 17 years old or younger at the start of treatment with omalizumab. After the first 6 months of treatment, all 12 patients showed an increase in FEV1 results and a decrease in ICS dose. Results also indicated a decrease in OCS use for those patients taking daily dose as well as those who required periodic bursts to control asthma exacerbations.Early treatment of moderate to severe asthma with omalizumab in adolescent/pediatric patients may improve quality of life and help prevent health concerns associated with side effects and/or long term use of ICS and OCS in growing children. Juvenile osteoporosis can be a significant problem because it occurs during the prime bone-building years and may lead to reduced peak bone mass and increased risk for osteoporosis later in life. Regular re-evaluation of the treatment regime to ensure the use of the lowest effective dose of corticosteroids and consideration of other treatments would also be beneficial."} +{"text": "Single coronary arteries are rare congenital anomalies in which the whole heart circulation is supplied by a coronary artery arising from a single ostium. Single left coronary artery with right coronary artery (RCA) originating from distal left circumflex artery (LCX) is a very rare anomaly with only few cases reported in the literature. We report a 44 years old male presenting with anterior myocardial infarction who was found to have a single left coronary artery during angiography. RCA had an abnormal origin arising from distal of a dominant LCX that retrogradely followed the course of a normal RCA to the base of the heart. A brief review of the reported cases with emphasis on the clinical significance of this unusual anomaly is presented. A 44 years old man was referred to our hospital for coronary angiography. He had a history of anterior myocardial infarction four days earlier for which he had received streptokinase in another hospital and had been referred to our center for coronary angiography for recurrent ischemic symptoms. His past medical history was otherwise unremarkable. He didn\u2019t report a history of smoking. He had developed recurrent chest pain on the third day of his admission that had been refractory to intensification of anti-ischemic therapy. Transthoracic echocardiography showed a left ventricular ejection fraction of 45%, hypokinetic anterior and apical segments and trivial mitral regurgitation. Right ventricular (RV) size and function were normal. He was scheduled for coronary angiography. During catheterization only one coronary ostium originating from left coronary cusp could be cannulated and several attempts with different catheters to identify the right coronary artery (RCA) ostium failed. Injection of contrast medium didn\u2019t show any coronary artery originating from right coronary cusp. The patient had a single coronary artery arising from left coronary cusp. RCA had an abnormal origin arising from distal of a dominant left circumflex artery (LCX) that retrogradly followed the course of a normal RCA to the base of the heart . Left an2222 This anomaly is compatible with L1 type of extensively used Lipton classification of coronary anomalies in which a single coronary artery from left sinus of valsalva divides to LAD and LCX, and distal LCX continues its course beyond the crux in to the atrioventricular groove and follows the course of a normal RCA to the base of the heart.12 Right coronary ostium is congenitally absent. Though single coronary arteries are often associated with other congenital anomalies12 and could be associated with the development of cardiac ischemia, cardiomyopathy, sudden cardiac death and congestive heart failure14, this particular anomaly has been reported to have a clinically benign course unless there are significant atherosclerotic lesions compromising the coronary flow.20 Majority of reported cases had a benign course and negative ischemic work up in the absence of coronary lesions.21 Choi et al. report a similar patient who presented with atypical chest pain. They attributed her chest discomfort to possible myocardial ischemia from abnormally slow coronary flow to the RCA and successfully treated the patient with calcium channel blocker and nitrates.13 On the other hand a 30 years old male with chest discomfort had mild posterolateral ischemia on perfusion imaging in the absence of any atherosclerotic lesion.4 Association with atrial fibrillation (AF) and severe mitral regurgitation (MR) have also been reported.18 Ma et al. report a similar patient who presented with right ventricular infarction and was treated with coronary stenting in distal LCX.19 Incidental finding during coronary CT angiography for the evaluation of atypical chest pain has been described.20 Ghaffari et al. described a patient with prolonged hemodynamic instability following a massive pulmonary embolism who was found to have a single left coronary artery. They attributed the prolonged and disproportionate RV dysfunction to its insufficient perfusion in the setting of acute pulmonary hypertension and absence of proximal RCA.15Single left coronary artery with anomalous origin of right coronary artery arising as a continuation of distal left circumflex artery is a very rare congenital coronary anomaly with few reported cases in the literature.15 or RV infarction since collateral circulation from proximal to distal RCA are not developed.19 Associated conditions are extremely uncommon and only one case of AF and one patient with severe MR are described in the literature. However coronary lesions could be of more critical significance because of the dependence of the heart\u2019s circulation on a single coronary. Coronary artery bypass grafting and PCI have been described in a few cases with associated coronary atherosclerosis.Our patient similar to most of the reported cases didn\u2019t have objective evidence of ischemia in the territory of RCA. Anomalous origin of RCA from distal continuation of LCX though extremely rare, seems to be an isolated and benign congenital anomaly in the absence of atherosclerotic lesions and it is unlikely that the anomaly causes myocardial ischemia. Actually left ventricular perfusion in these patients is very similar to that of normal subjects with LCX dominant coronary system. The main difference could be RV perfusion through RV branches. We postulated that the most vulnerable segments to ischemia in these patients could be in RV as described in few case reports of acute RV strain in the setting of pulmonary embolismThe study was approved by the Ethics Committee of the University.Authors declare no conflict of interest in this study."} +{"text": "This study investigates the asymptotic performance of the Quadratic Discriminant Function (QDF) under correlated and uncorrelated normal training samples. This paper specifically examines the effect of correlation, uncorrelation considering different sample size ratios, number of variables and varying group centroid separators ( Discriminant analysis (DA) as a topic in Multivariate Statistical Analysis has attracted much research interest over the years, with the evaluation of discriminant functions when the covariances matrices are unequal with moderate sizes being well explained by Wahl and Kronmal . Linear Marks and Dunn approachW and Z formed under the assumption of independent training observation. Asymptotic expected error rate for W under the model when the covariance matrices are heterogeneous with the data of interest being correlated, sample size ratios being unequal, considering different number of variables and varying values of group centroid separator (To evaluate the performance of QDF for correlated and uncorrelated training samples of distributions, we considered a Monte Carlo study with multivariate normally correlated random data generated for three populations with their mean vector Mean vector separator which is set at Sample sizes which are also specified. Here 14 values of The number of variables for this study is also specified. The number of variables are set at 4, 6 and 8 following Murray who consThe size of population 1 Factors considered in this study were:Series of subroutines were written in MatLab to perform the simulation and discrimination procedures on QDF. Below are the important ones.Generalization of classification procedure for more than two discriminating groups (ie from 2 to Allocate mentclass2pt{minimSuppose that the ith population is defined asThe constant d in Eq. , since ix to the population mean The quadratic score x to Allocate In practice, the Suppose that the joint densities of mentclass2pt{minimThis function is easily extended to the 3 group classification where 2 cut off points are required for assigning observations to the 3 groups (Johnson and Wichern This section presents the performance of QDF when the training data are correlated and then when they are uncorrelated.Evaluating the effect of sample size on QDF with respect to the correlated normal distribution for mentclass2pt{minimmentclass2pt{minimFrom Table For the uncorrelated distribution from Table entclass1pt{minimaThe coefficients of variation generally increased exponentially and stabilized with increasing total sample size and number of variables in The coefficients of variation in correlated normal distribution in Fig.\u00a0The effect of number of variables on the QDF under the correlated and uncorrelated normal distribution are discussed under this subsection.The graphs of the results for sample size ratio 1:1:1 of the situations of 4, 6 and 8 variables are shown in Fig.\u00a0The coefficients of variation in this distribution for ratio 1:1:1 in Fig.\u00a0From Fig. The coefficients of variation shown in Fig.\u00a0This section presents the results of our investigation on the effect of the Mahalanobis distance on QDF for correlated normal distribution. Considering the correlated normal distribution in Fig.\u00a0The coefficients of variation of sample size ratio 1:1:1 with increasing total sample size in Fig. From Fig. mentclasspt{minimaThe study focussed on the asymptotic performance of the QDF under correlated and uncorrelated normally distributed training samples. Under this distribution, the performance of the QDF under varying sampling ratios, selected number of variables and different group centroid separators were extensively studied. The QDF recorded minimum misclassification error rates and high variability as the sample size increased asymptotically under correlated normal distribution, thereby increasing the accuracy of classification of observations with the function. The performance of the QDF deteriorated when the sample size ratio was 1:2:3 as f Lawoko where th"} +{"text": "Sepsis remains a leading cause of death in intensive care units. Administration of appropriate antibiotics within the first hour of diagnosis has been found to be the most effective intervention associated with a reduction in mortality . CurrenThis survey aimed to determine how many intensive care units in England currently use extended and continuous infusions of time dependent antibiotics in the treatment of sepsis.One ICU in each acute trust in England was contacted via telephone in June 2014. A doctor working on the unit grade CT1 or above was then interviewed about antibiotic prescribing in sepsis.Of the 148 acute trusts with critical care facilities in mainland England 123 replied to the survey, 23 were unable to be contacted and 2 declined to respond; a response rate of 83.1% was achieved. Of the trusts that responded antibiotic infusions were never used as a clinical strategy in the management of septic patients in 66 (54%). Of the 57 (46%) trusts that did consider using antibiotic infusions for the management of septic patients only 11 (7%) used both continuous and extended infusions of antibiotics, 27 (18%) used continuous infusions only and 19 (15%) used extended infusions but not continuous infusions . Of the 57 trusts that used infusions of antibiotics; Vancomycin was administered by infusion in 48 (84%) trusts and beta-lactams in 16 (28%).There remains disagreement regarding the clinical benefit of continuous and extended infusions of time dependent antibiotics in the management of septic patients in ICU. This is despite a large body of theoretical evidence based on pharmacokinetic studies. We suggest further, larger trials powered towards mortality are indicated for consensus to be achieved."} +{"text": "Genetic and environmental factors contribute to the pathogenesis of type 2 diabetes. Epigenetic changes link environmental exposures with potentially heritable disease mechanisms. Pancreatic beta cell failure is central in the pathogenesis of type 2 diabetes. The gold standard for elucidating the underlying mechanisms is the study of human islets of Langerhans. We performed the first comprehensive DNA methylation profiling of islets from type 2 diabetic and non-diabetic donors . We iden"} +{"text": "The management of complex high risk patients (pts) is always a challenge for the cardiac surgeon.This paper describe our experience using an alternative surgical option in the treatment of concomitant valve disease and myocardial revascularization (CABG) in high risk patient with Ejection Fraction (EF) below 30 %.From July 2013 up to September 2014 four high risk patients with low EF below 30 %, concomitant mitral valve disease (3 pts), ventricular aneurism (1 pt), and severe coronary artery disease were operated using on pump beating heart technique. Al pts were first connected to the IABP through the femoral artery and then put on CPB machine with a double venous cannula in the superior and inferior vena cava, aortic cannula, ventricular vent through the right superior pulmonary vein and cannula for the retrograde perfusion in the coronary sinus. At first was completed the myocardial revascularization with beating heart on pump, using the LIMA on the LAD in all patients and a segment of the saphenous vein or radial artery as a T graft from the left internal mammary artery (LIMA) for the lateral or posterior wall. Then the aorta was cross-clamped, leaving the heart beating while the coronary were perfused through the retrograde perfusion and through the composite grafts. The procedure was completed harvesting a mitral ring in three cases and in one case with an aneurismectomy of the left ventricle.All patients were discharged 8 to 11 day after the operation, with an improved EF: Pt 1 EF pre op: 28%; post op EF 35%; Pt 2 EF pre op 30%; post op EF 40%; Pt 3 EF pre op 38%; post op EF 45%; Pt 4 pre op EF 30%; post op EF 40%.Even if the study involve just a little number of patients, the technique can improve the post op ejection fraction without changing the in hospital stay. It can be proposed for that patients with a low EF in which there is a disease associated with CAD or in patient that have had a previous CABG with an heart disease different than a CAD."} +{"text": "This article contains epidemiological, demographic and other data used for estimating health and economic burden of neurocysticercosis (NCC)-associated active epilepsy in India Specifications Table\u2022The data and the code can be adapted to estimate health and economic impact of NCC in other countries.\u2022The data demonstrate the importance of input variables such as prevalence, per capita income, proportion of people seeking medical attention and case fatality on changing the disability adjusted life years (DALY) for NCC in India.\u2022The data demonstrate the importance of input variables such as prevalence and per capita income on economic losses occurring due to NCC in India.1Demographic and epidemiologic data along with the associated R code used for estimating the health and economic impact are presented in R-code. The data indicating the effect of changing prevalence and per capita income on economic losses for NCC are presented in 2http://www.r-project.org). To compute 95% uncertainty interval (UI) (defined as 2.5\u201397.5th percentile), the authors ran Monte Carlo simulations for 10,000 iterations. The R code along with associated data The demographic and epidemiologic data were collected by review of the national and international peer reviewed literature as well as sourced from government agencies"} +{"text": "Reason for Erratum:Due to a typesetting error the spelling of a few terms was incorrect in \u201cNotch Signaling\u201d Section, paragraph 4. This error does not change the scientific conclusions of the article in any way. The publisher apologizes for this error and the correct text appears below:A tantalizing hypothesis for the mechanism underlying Notch function in stem cell quiescence comes from embryonic data showing that the levels of Hes proteins and proneural bHLHs oscillate in neural precursor cells (Imayoshi et al., The original article has been updated."} +{"text": "The myriad of mouse genetic alterations that result in a lupus-like phenotype and the >100 genes now known to be involved in human lupus are all probably only a hint at the potential complexity of the many mechanisms that lead to systemic lupus erythematosus (SLE).We have applied exome sequencing to 24 SLE patients and their parents (trios) in an effort to conquer the data analysis and to identify candidate genes that may contribute when the activity of their gene products were substantially altered.de novo mutations in RAD54B that was predicted to change ARG to GLN and to be severely damaging to protein product activity by multiple algorithms. A second much more conservative de novo mutation in DOCK8 was not predicted to be consequential. RAD54B is a component of the homologous recombination DNA repair pathway. Cells from the SLE proband were unusually sensitive to ionizing radiation by the colony survival and comet tail assays. Ionizing radiation selectively induced interferon responsive genes in cells from this patient and not from controls. Transfection of the wild-type gene into the cells from this patient led to overexpression of the RAD54B gene product and returned ionizing radiation resistance toward normal.The proband of one of our SLE trios had TREX1, RAD51B, XRCC1, XRCC3, and XRCC4) implicate base excision repair, nonhomologous end joining, and homologous recombination. These results suggest that multiple DNA repair mechanisms contribute to SLE susceptibility.These data in addition to the other five other genes directly or indirectly involved in altering risk of SLE by influencing DNA repair ("} +{"text": "Allergen challenge chambers expose allergen-sensitive subjects to a predetermined concentration of allergen in a closed, controlled environment and provide a mechanism to induce clinical symptoms and measure the effect of medication.TM was performed. The theatre is a 4-zone facility holding up to 99 seats in a series of elevated rows. Grass (Phleum pratense) and ragweed (Ambrosia artemisiifolia) pollens were injected into the air supply and blown into the facility through ducts located across the top of the front wall. Grass and ragweed pollen concentrations were measured on impact samplers set at face level in 5 sections of a T-shaped quadrant. Concentrations were measured every 30 minutes for 150 minutes. Continuous pollen counts were also read by a laser particle counter (LPC) set to read particles > 5\u00b5m and positioned 5 feet above floor level.A technical evaluation of the capabilities of the Red Maple Trials Allergen Challenge Theatre3. Concentrations for the quadrant were consistent at each 30-minute measurement with means ranging from 3648 to 4523 and SDs from 678 to 1105. Pollen concentrations were consistent in each of the 5 sections of the quadrant over time with means ranging from 3112 to 5268 and SDs ranging from 308 to 926. Pollen counts measured by LPC remained consistent at 4000 per m3 during the experiment. There was a linear relationship between the LPC pollen readings and the impact sampler readings.The impact sampler pollen concentration for the theatre quadrant during the entire 180-minute exposure was 3992 \u00b1 975 grains mThe Red Maple Trials allergen exposure theatre demonstrated the capacity to achieve and maintain a concentration of pollen grains at a magnitude consistent with the literature and associated with the ability to induce symptoms of appropriate intensity upon allergen challenge. The use of an LPC provided a significant advantage by monitoring pollen counts on a continuous basis. The chamber with a seating capacity of 99 places has the ability to evaluate large test groups at a time."} +{"text": "Metal matrix composites (MMCs) exhibit improved strength but suffer from low ductility. Metal particles reinforcement can be an alternative to retain the ductility in MMCs Specifications Table\u2022The FSP parameters presented here lead to defect free stir zone and provide a processing window for incorporating Ni particles in 5083 Al to make composites by FSP.\u2022Similar parameters can be used to process other Al or Mg based composites with variety of reinforcement particles.\u2022Other researchers may use the data as guidelines to select suitable parameters without going through rigorous trials and errors.\u2022The data will also help in selectively enhancing the properties at desired locations on the surface offering possibility of a new kind of surface engineering.Value of the data1Process parameters for friction stir processing (FSP) of 5083 Al alloy for a defect free processed zone (stir zone) and for incorporating metal particles to make composites. The parameters are the rotation speed (rpm) and the traverse speed (speed of forward motion of the tool). The particle size and the micrographs depicting the structure of the composite are the other parts of the data presented here.2A friction stir processing setup, which was obtained by modifying a milling machine, was used. In order to incorporate the particles, a groove of 1\u00a0mm in width and 2\u00a0mm in depth was cut precisely on the 5083 Al plate. The groove was first filled with Ni particles of average size 70\u00a0\u03bcm and FSP was carried out over the groove with a cylindrical tool. More details can be found in the parent article The heat input into the material during FSP depends on the ratio of rotation to traverse speeds with higher ratio giving rise to higher heat input"} +{"text": "There is an error in the last sentence of the Abstract. The correct sentence is: These observed differences contribute to our understanding of how genetic ablation of GSTP causes different levels of myeloproliferation and migration.There is an error in \u2212/\u2212Gstp1/p2 bone marrow cell populations\u201d of the Results should have cited references 15 and 18 instead of 26. The correct sentence should read: These results support our previous publication that ablation of GSTP either genetically or pharmacologically results in the over-production of lymphoid, erythroid and myeloid lineage cell lineages as well as platelets .The last sentence of the subsection \u201cIncreased DNA synthesis in"} +{"text": "This case report describes our first clinical experience of a previously described new surgical technique for the treatment of unstable simple elbow dislocations. The technique utilises a central strip of the distal triceps tendon which is harvested proximally at the musculotendonous junction and left attached at its insertion on the olecranon. The strip is the passed through the olecranon fossa and attached to the coronoid process to stabilise the joint. We encountered an early postoperative complication that led to a modification of our technique and ultimately an excellent recovery of a stable pain free joint with a full range of movement. The incidence of simple elbow dislocations is 5\u20136 per 100,000 . A smallA 73-year-old lady presented to the Accident & Emergency (A&E) department immediately after a fall from standing height with a painful deformed right elbow. Initial radiographs demonstrated a dislocation of the elbow with no associated fractures . The joiThe patient had significant medical comorbidities: ischaemic heart disease with previous coronary stents; left ventricular failure; complete heart block with a permanent pacemaker; type 2 diabetes; a BMI\u00a0>\u00a035 and emphysema treated with long-term steroids. She was discussed in the departmental trauma meeting and due to her high anaesthetic risk, poor soft tissues and general frailty she was assessed as not suitable for our standard operative treatment with collateral ligament repair and stabilisation with a hinged external fixator. The options suggested by the consultant body at the trauma meeting were to offer either non-operative treatment (pain control medications and a brace) or percutaneous trans-articular pinning. Both these options have significant drawbacks in terms of functional outcome. We have previously described a new operative technique that we proved to be technically feasible in a cadaveric study [The surgery was performed under regional anaesthetic. The elbow was reduced and stressed to assess the competence of the collateral ligaments. The radial collateral ligament and both the medial and lateral ulnar collateral ligaments were completely disrupted such that the joint did not remain congruent even in flexion beyond 90\u00b0. Dislocation occurred with both external and internal rotation of the fore arm. The triceps tendon reconstruction described above was performed with an operative time of 45\u00a0min. There were no technical difficulties or complications and a congruent stable reduction was achieved . The patThis case report documents our experience and the outcome of the first clinical use of our novel technique for the stabilisation of a simple elbow dislocation. According to O\u2019Driscoll et al. this wasThe treatment of grossly unstable elbow dislocations in elderly patients with significant comorbidities is a difficult surgical challenge. In spite of the initial failure of our new surgical reconstruction, the subsequent modified technique achieved an excellent result. This first case report establishes the grounds for further research to investigate the potential role our new technique in comparison to more traditional stabilisation techniques for the treatment of unstable elbow dislocations.The authors declare no conflict of interest in relation with this paper."} +{"text": "The endoplasmic reticulum (ER) is the central intracellular organelle responsible for proper folding, localization, and post-translational modifications of proteins in eukaryotic cells. During conditions of cellular stress, incorrectly folded proteins can accumulate in the ER and trigger the unfolded protein response (UPR), which involves the activation of signal transduction pathways designed to restore correct protein folding and recovery from ER stress . In rapiWe have recently unveiled an unexpected role for the tumor suppressor p53 in regulating ER function via the IRE1\u03b1/XBP1 pathway . The CDIThe loss of p53 function in relation to ER stress is likely to have important consequences for the sustenance of cancer cell proliferation. Previous studies have demonstrated that the activation of p53 suppresses mTOR activity and consequently inhibits protein translation . The eliMalignant transformation occurs through a combination of oncogenic pathway activation and the loss of tumor suppression. Understanding the consequences and identifying vulnerabilities caused by such changes can provide promising opportunities to selectively target cancer cells. Mutation in the p53 gene is the most frequent genetic alteration found in human cancer and inactivation of p53 is known as one of the strongest driving factors in cancer development and chemoresistance . The new"} +{"text": "This paper presents data related to the research article entitled \u201cEffects of cell\u2013cell contact and oxygen tension on chondrogenic differentiation of stem cells\u201d Specifications tableValue of the data\u2022Data can be helpful to the readers when designing a pattern with appropriate spatial distribution of microdomains of different microisland numbers to enhance efficiency to examine the effects of microisland numbers in microdomains on cell behaviors.\u2022Data emphasizes the importance of keeping the same microisland density in a basic repeated unit in cell studies in order to rule out the interference of other factors such as difference of paracrined soluble factors.\u2022The sequences of primers can be employed by other researchers in sequence design of targeted genes detected by quantitative real-time polymerase chain reaction (qRT-PCR) to study the chondrogenic induction of mesenchymal stem cells (MSCs) derived from bone marrow of Sprague Dawley (SD) rats.1The data provided here are bright-field micrographs of three sets of micropatterns with a similar microisland density and prim1.1The method to prepare micropatterns had been reported previously by our group 1.2The characteristic genes for the chondrogenic differentiation Original mRNA and genomic sequence was obtained from NCBI, then pasted into PerlPrimer"} +{"text": "Establishing nutrition support is a priority in the management of the acutely unwell patient. Administration of proprofol by infusion is commonly used for sedation. This can significantly contribute to the total calorific input due to the lipid content. We investigated the total calorific input received in a cohort of patients in the first 7 days of nutrition support during their critical care stay.We examined the current practice of our intensive care unit (ICU) looking at the total calorific input including the proportion of calories contributed from profolol infusions.We collected retrospective data from 50 consecutive ICU patients from July to November 2014. We included patients that received \u22657 days of enteral/parenteral feeding. Data collected included; patient demographics, type and amount of feed given and total propofol administered in the same period. We then calculated the proportion of calories from propofol given to the 50 patients.In the 50 patients established on feed,10% of the 7 day total calorific input came from propofol.One patient (patient 2) received the highest calories from profolol at 4169 kcals.Patient 16 had the highest proportion of calories from propofol at 33%.Use of propofol for sedation makes a significant contribution towards a patient's energy requirements. Although in situations such as traumatic brain injury (patient 2) deeper sedation may be required, care is still required over both prescription of propofol, and nutrition support to take account of the additional calories provided as Intralipid with the propofol."} +{"text": "Analysis and identification of competitive antagonist in the co receptor binding of HIV is a challenging task towards overcoming the tropism of HIV. Hence analyzing the structure activity relationship between CCR5 and the derivatives of carboxamide is an initiation towards discovering the future inhibitors of CCR5.We have identified the interaction between CCR5 and existing sulphonyl derivatives of carboxyl amine and it was followed by construction of various derivatives of carboxamide with trans confirmation of carboxyl phenol. Further, the constructed molecules were screened on the basis of various molecular descriptors. The potential derivates were identified using molecular dynamics simulations in 1 nano second using Discovery Studio software suite (version 2.0).Regression Analysis of various molecular descriptors showed a threefold increase in the competitive binding of carboxamide derivatives with CCR5 and the increased activity of existing sulphonyl derivatives is single fold. Binding Energies of carboxamide derivatives were less than 2 KCal of sulphonyl derivatives. Conformational analysis using Molecular Dynamics Simulation of sulfo carboxamide derivatives confirms a twofold increased stability when compared with sulphonyl derivatives of piperidine.In silico analysis of these piperidine based Sulfo carboxamide derivates show a better competitive inhibition than existing sulphonyl derivatives of carboxyl amine. Further in vivo tests are required to analyze the effective concentration for constructing effective derivatives of carboxamide based piperidine as potential antagonists of CCR5 in future.Construction of analogs based on sulfo carboxamide using chemsketch generated fourteen compounds."} +{"text": "Human infertility is the incapacity of a couple to conceive after one year of unprotected sexual intercourse. Selection of the best gametes for subsequent steps of fertilization and embryo transfer was shown to be the crucial step in infertility treatment procedure ,2. OocytSeven 7) patients with informed consent were selected for ovarian stimulation, ICSI (intracytoplasmic sperm injection) and subsequent embryo transfer at day 3 at the IVF clinic of Bonn University Medical School. Cumulus-oocyte complex (COC) were retrieved 36 to 38 h after HCG administration and washed. While cumulus cells (CCs) of each oocyte were individually collected and put at -80\u00b0C for subsequent RNA extraction , the metaphase II (MII) oocytes were completely denuded by hyaluronidase followed successively by automatic ZP birefringence assessment ; Figure . After I patientsPossible correlation between 7 biomarkers differentially expressed in the CCs of good quality oocytes and the Weak correlations between the 7 gene biomarkers of oocyte developmental potential and the ZP birefringence score. It looks that the ZP morphology is associated to a transcriptomic gene pattern that is not directly related to the developmental competence pathway. Further studies using larger lists of candidate markers are required to identify suitable genes that are highly correlated with the morphological criteria, and therefore able to reinforce the accuracy of oocyte selection. Together, the combination of these two approaches should offer a reliable prognostic tool of the best oocyte allowing efficient infertility treatment and successful pregnancy."} +{"text": "The input to the retinal layer consists of rectangular bars of varying dilation and rotation; since images on the retina could be considered as different projective transforms of the objects seen. The outer boundary of the V1 layer is also constrained to simulate the flattened V1 surface area (see Figure The afferent \u03bcij,rr2, laterA neural activity based model for the development of retinotopic map along the dorsoventral axis is demonstrated and the final map developed is compared with experimental results approximated by the complex log map equations."} +{"text": "This special issue features articles offered by contributors to a session on that subject at the Society of Experimental Biology Annual Meeting in Prague in 2015 which was sponsored by European Union project called EURoot and its homeologue RUL1 (RUM1-like 1), both of which are regulators of auxin signalling. While both genes have similar molecular properties, the expression of RUL1 is much lower than that of RUM1 while the authors reveal a RUM1-associated protein 1 (RAP1) that specifically interacts with RUM1 but not with RUL1 suggesting that RUM1 and RUL1 are at least partially associated with different molecular networks.Researchers from the same laboratory as above detected for root system architecture traits. In RUM1 and RTCS . In durum wheat, The gene Meloidogyne graminicola revealing 11 QTLs and some notable candidate genes. They also discovered two rice landraces with complete resistance to the nematode which was confirmed in separate, large-pot experiments in two independent laboratories, providing excellent breeding strategies for improving resistance to this soil-borne pest that severely impacts root growth and function.Genome-wide association mapping was used in rice for the final two papers of this special issue. A total of 196 accessions were assessed for root and shoot growth under low phosphorus by Together these reviews and original research papers provide a glimpse into some of the issues and methodologies that are occupying root scientists at the current time."} +{"text": "Flow cytometry, and the more recently introduced imaging flow cytometry, are ideal tools for following the cell cycle in mammalian cells. One of the first applications of flow cytometry was looking at DNA content via single parameter fluorescence of a DNA-binding dye such as propidium iodide or DAPI but this only provides a snapshot of cells at one point in time. More sophisticated techniques are needed to investigate multiple rounds of division and these include the addition of a nucleotide analog such as bromodeoyurdine (BrdU) which can follow cells through 1-2 rounds of cell division; the BrdU-Hoechst quenching technique which can follow 3-4 rounds of cell division or the use of a dye dilution technique using protein binding dyes such as CFSE or the CellTrace dyes or lipid-binding dyes such as the PKH dyes. We recently developed a method to study cell cycle analysis in multiple rounds of division using a combination of CellTrace Violet for round of division, propidium iodide for DNA content and staining for phoshpoH3 to identify mitotic cells ["} +{"text": "Experimental studies demonstrate a radial bias, wherein radial orientations produce higher activity compared to other orientations with 2 lij,r1r2\u03bc), lateral excitatory and lateral inhibitory weights adapt based on a normalized Hebbian mechanism. In order to develop the retinotopic map, the inputs to the retinal layer consists of centered (assumed to be the point of fixation) rectangular bars of varying dilations and rotations as modelled in [The afferent (elled in . The retA neural activity based model for the development of radially biased orientation maps in V1 is demonstrated."} +{"text": "Streptococcus agalactiae) complicated by embolic arthritis of the right hip. Initial echocardiography revealed moderate aortic insufficiency developed on a tricuspid aortic valve with a small vegetation (5 mm \u00d7 4 mm) on the left coronary cusp. Furthermore, an aneurysmal dilatation of the ascending aorta was noted. Other heart valves and left ventricular function were considered normal. The patient completed a 4 weeks course of antibiotherapy, and the right hip arthritis was treated by drainage and synovectomy. The patient was subsequently referred to surgery on an outpatient basis for the aneurysm of the ascending aorta. Preoperative computed tomography showed localized aortic dissection of the tubular ascending aorta characterized by an intimal tear without medial hematoma but excentric bulging of the aortic wall. This lesion was initially considered a penetrating ulcer of the aortic wall The operative specimen allowed to make differential diagnosis with a penetrating aortic ulcer by showing that the lesion did not develop within an atherosclerotic plaque. However, downstream extension of the dissection was probably limited by the presence of transmural calcifications on its distal side. The patient underwent successful complete aortic root replacement using a stentless Freestyle bioprosthesis with Dacron graft extension as reported previously.TWe present the case of a 64 years old male patient who had recently suffered an infective aortic valve endocarditis ( Initial echocardiography revealed moderate aortic insufficiency developed on a tricuspid aortic valve with a small vegetation (5 mm \u00d7 4 mm) on the left coronary cusp. Furthermore, an aneurysmal dilatation of the ascending aorta was noted. Other heart valves and left ventricular function were considered normal. The patient completed a 4 weeks course of antibiotherapy and the right hip arthritis was treated by drainage and synovectomy. The patient was subsequently referred to surgery on an outpatient basis for the aneurysm of the ascending aorta.We present the case of a 64 years old male patient who had recently suffered an infective aortic valve endocarditis . The ope7 In patients with a classic intimal flap, detection of the presence of aortic dissection by available imaging techniques is very accurate, with a reported sensitivity of 97% to 100% for both transesophageal echo (TEE) and MRI.7There are two well-recognized forms of aortic dissection: dissection of the aortic wall, resulting in the classic septum associated with an intimal tear (class 1), and the less common intramural hematoma-type dissection of the aortic wall in which the dissection is usually filled with blood clot without a detectable intimal tear (class 2).The importance of variants such as intramural hematoma (class 2) dissections and penetrating ulcer (class 4) sometimes present some diagnostic difficulties.6For patients with an intramural hematoma-type dissection, the sensitivity for detection of dissection is difficult to document accurately because it is not known how many patients are missed . Furthermore, noninvasive and invasive testing may overestimate the incidence of this type of dissection because a tear is often found at the time of surgery or autopsy.The variant class 3 of aortic dissection is characterized by a stellate or linear intimal tear associated with exposure of the underlying aortic media or adventitial layers but without the progression and separation of the medial layers, but only extensive undermining of the intimal layers. And the class 5 is about iatrogenic or traumatic aortic dissection.5The patient underwent successful complete aortic root replacement using a stentless Freestyle bioprosthesis with Dacron graft extension as reported previously.The authors have obtained all permission before using any data and patient images.Authors declare no conflict of interests in this study."} +{"text": "PLOS Medicine editorial team would like to warmly thank all those individuals who participated in the peer review process this past year at PLOS Medicine. During 2014 over 900 reviewers from around the world helped evaluate the 194 articles we published, and offered valuable input and advice for those authors whose papers we did not publish.The Public Library of Science (PLOS) and the PLOS Medicine authors, and for helping us to publish a highly read and highly regarded open access medical journal.The names of our 2014 reviewers are listed in S1 Reviewer List(PDF)Click here for additional data file."} +{"text": "The aim of this study is to identify HTLV-1 minor strains that change the bind sites for transcriptional factors in the LTR promoter region. For this purpose 28 patients samples were analyzed, being 14 with TSP/HAM and 14 health carriers. The LTR fragments were submitted to the deep sequencing using the Ion Torrent methodology for a 200bp read in a 314 chip. We found 172 variations in these 28 patients samples. The single nucleotide polymorphisms (SNP) screening showed minor variants strains in the previously described transcriptional factor bind sites . In addition a SNP in the TATA box from an asymptomatic carrier sample was found in 90% of the sequences changing the site from TATAAA to TCTAAA (depth of 2632 nucleotides). Two asymptomatic carriers samples showed a 9 and 11 base pair deletion in all the sequences, being the 9 base pair deletion between the first and second TxRE and the 11 base pair deletion in the second TxRE. The number of minor variants was not constant (0 to 19) and was not related to proviral load or clinical status. An in silico analyze has being done in order to identify the motifs for transcriptional bind factor in those minor variants. The site directed mutagenesis followed by a luciferase assay will be performed to analyze the LTR activation in those strains."} +{"text": "Whereas some studies infer a role of professional APCs present in the lymph nodes draining the site of parasite injection by the mosquito, others argue in favor of the liver as a primary organ and hepatocytes as stimulators of na\u00efve parasite-specific T cell responses. This review aims to critically analyze the current knowledge and outline new lines of research necessary to understand the induction of protective cellular immunity against the malaria parasite.While the role of malaria parasite-specific memory CD8 Identification of the essential site for priming of malaria liver stage-directed CD8+ T cell responses of broader antigen specificity as well as mimicking the conditions of the natural exposure to the uninfected mosquito vector will pave the way for the optimal design of T cell-based vaccines. We hope that experimental approaches suggested above in the context of the reviewed original data both DCs and hepatocytes can prime na\u00efve malaria parasite-specific CD8nal data , 34, 39 The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "PLOS Neglected Tropical Diseases (PLOS NTDs) editorial team would like to express our tremendous gratitude to all individuals who participated in the peer review process for PLOS NTDs this past year. As a community run journal, we depend on the participation of active and expert members of the field to communicate the best work. 2015 was great year for PLOS NTDs; this year, over 2,400 reviewers from around the world helped evaluate over 1,200 articles.The Public Library of Science (PLOS) and the PLOS NTDs community. Your efforts are an important part of making the journal a highly read, highly cited and highly regarded open access resource created by and for the benefit of the scientific community.The names of our 2015 reviewers are listed in S1 Reviewer List(PDF)Click here for additional data file."} +{"text": "Cosmopolites sordidus but does not reduce its damage to the banana plants\u201d Cosmopolites sordidus, and the abundance of the earwig Euborellia caraibea were affected by the addition of a cover crop. The field data set is made publicly available to enable critical or extended analyzes.The data presented in this article are related to the research article entitled \u201cCover cropping reduces the abundance of the banana weevil Specifications TableValue of the data\u2022The data is valuable for other researchers working on this pest or in similar scientific field.\u2022This data offers the opportunity to other researchers to compare with their own datasets.\u2022This data enables other researchers to independently verify or extend statistical analyses.1Cosmopolites sordidus and the predator Euborellia caraibea in banana plots with or without the cover crop Paspalum notatum. The dataset provided in this article gives information on the abundance of the banana pest 2P. notatum was planted in three of the plots (CC soil type plots) while the other three plots were maintained with bare soil (BS soil type plots) through the use of herbicide (glyphosate). Banana weevil and earwig abundances were estimated with pseudostem traps deposited at the basis of each banana plant. We discriminated between teneral adult weevils and mature weevils based on exoskeleton color The experiment was conducted in six plots were established, each with an area of 361\u00a0m\u00b2 and with 49 banana plants (Cavendish Grande Naine cultivar). The cover crop Cosmopolites sordidus but does not reduce its damage to the banana plants\" The data presented in this article are related to the research article entitled \"Cover cropping reduces the abundance of the banana weevil"} +{"text": "The authors of \"Usage of Multilingual Mobile Translation Applications in Clinical Settings\" ; 1(1):e4) inadvertently omitted Regina Schmeer from the list of authors during the submission process. The author Schmeer should have been added after Marianne Behrends in the originally published manuscript. The footnote \"all authors contributed equally\" extends to the omitted author. The omitted author certified that there are no conflicts of interests to add. This error has been corrected in the online version of the paper on the JMIR website on August 7, 2013, together with publishing this correction notice. This was done before submission to PubMed or Pubmed Central and other full-text repositories."} +{"text": "To the Editor: In an article that reviews evidence of a plot to use plague to break the siege of Candia during the Venetian\u2013Ottoman War of the 17th century, Dr. Thalassinou and her colleagues (Danish historian Karl-Erik Frandsen conducted a careful study of the plague outbreak affecting the Baltic area during 1709\u20131713 and found no evidence to support this allegation (Intentional introduction of disease has been rare ("} +{"text": "To determine the prognostic and predictive value of tumor infiltrating lymphocytes (TIL) in colon cancer in a cohort of patients who previously took part in a trial on adjuvant Active Specific Immunotherapy (ASI).Vermorken et al. conducteHere we determined the number and location of CD3+ and CD8+ cells in archival tumor samples of 106 MSS colon cancers. Disease specific survival (DSS) and recurrence free interval (RFI) were evaluated in detail at the 5 year post-treatment time point. First, we investigated the prognostic value of stromal and intraepithelial T cell infiltrates independent of treatment arm. Second, we investigated the predictive value of stromal and intraepithelial T cell infiltrates for clinical outcome after ASI treatment. For the analysis we used continuous data on T cell counts comparing the treatment effect of adjuvant Active Specific Immunotherapy in patients with high TIL to the treatment effect in low TIL.Based on the data presented we concluded that 1) high numbers of stromal CD3 T cells have positive prognostic value measured as DSS for patients with stage II MSS tumors, and 2) high numbers of epithelial CD8 positive T cells have positive prognostic value measured as RFI for the group of patients with stage II MSS tumors as well as for the whole group (stage II plus stage III together). Furthermore we concluded that high numbers of preexisting stromal CD3 positive T cells are of positive predictive value in adjuvant ASI treatment measured as DSS as well as RFI.ASI therapy contributes to an improved DSS and RFI in patients with MSS colon tumors harboring high numbers of preexisting stromal CD3+ TIL."} +{"text": "Next generation sequencing (NGS) data analysis pipelines are frequently described in literature. NGS data is relatively easy to acquire from national data repositories and most software used in the pipelines are open source. This study extends research on the causal relation between changes in the ataxia telangiectasia and Rad3 related (ATR) pathways and melanoma.To study the effects of mutations in the ATR region on melanoma, we downloaded the Melanoma Genome Sequencing Project dataset (dbGaP Study Accession: phs000452.v1.p1) from the dbGaP repository[Though analysis and validation of the results are still ongoing at the time of this report, we can share that we identified five previously unreported somatic missense or splice site SNP mutations in the ATR gene region in melanoma patients. Results will be further validated by analysis of NGS data from melanoma cell lines.The main goal of this abstract was to describe a methodology that we used to identify novel genetic markers in publicly available data. This methodology offers a cost effective way to test hypotheses drawn from laboratory research on human genome data."} +{"text": "The authors would like to clarify that the controls previously depicted in Figs The correct control for The correct control for the original p values.We have also taken this opportunity to provide new versions of several figures Figs , 5, 6, 7The text in the Results section titled \u201cUCP2 Levels Increase in Food-Deprived Mice\u201d has been edited to accommodate the removal of the original ad libitum. Importantly, we found an increase in levels of UCP2 protein in starved mice compared with fed mice . The level of Sirt1 protein in starved pancreas is roughly comparable to fed controls (unpublished data). These findings suggest that changes in NAD levels in the pancreas regulate Sirt1 activity and insulin secretion in response to diet."} +{"text": "The purpose of this study was to evaluate the effects of custom-made insoles based on the foot pressures and electromyography (EMG) activities in a subject group of idiopathic pes cavus which the term used to describe a foot type with an excessively high medial longitudinal arch -3. The sCurrent Controlled Trials ISCRTN73824458"} +{"text": "The aim of this study was to develop a three-dimensional (3D) computational model to justify the effect of myoelectric stimulation in preventing ankle inversion ligamentous sprain injury.The subject who sustained a grade 1 anterior talofibular ligamentous sprain injury on his right ankle during our previous case report [The model is validated. Stimulation with a delay time of 25 milliseconds could successfully prevent the ankle inversion sprain when the lower threshold of 300 or 400 degrees per second was identified.This study is indispensable and crucial for evaluating the actual effect of myoelectric stimulation on peroneal muscles in preventing ankle inversion sprain injury. Meanwhile, this study would also contribute to the research on the intelligent anti-sprain system, which in turn would boost sports participation with more effective protection for the general public."} +{"text": "AR) gene were associated with differences in the clinical or humoral immune manifestations of lupus in a cohort of female subjects. We found that shorter AR CAG repeat lengths in lupus subjects correlated with a higher Systemic Lupus Erythematosus Disease Activity Index score, higher ANA levels, and expression of a broader array of IgG autoantibodies. Our findings of more severe clinical manifestations and more exuberant humoral autoimmunity in women with a shorter AR exon 1 CAG repeat length suggest a role for genetically determined sensitivity to androgens as a modulator of autoimmune processes.Clinical and experimental evidence support a role for gonadal steroids in modulating the expression and course of autoimmune diseases such as lupus. Whether or not inherited variation in sensitivity to circulating androgenic hormones could influence the manifestations of such disease is, however, unknown. We sought to determine whether differences in androgen sensitivity conferred by variation in the exon 1 CAG repeat region of the androgen receptor ( Androgenic gonadal steroid hormones exert effects on both human autoimmune disease and the corresponding animal models. In an experimental mouse model of human systemic lupus erythematosus, females acquire fatal renal disease while males are generally spared; treatment of females with androgens prevents the progression of nephritis while castration of males results in disease progression and mortality AR) gene affects androgen action. Deleterious mutations in AR can result in syndromes ranging from mild abnormalities to total failure of normal male phenotypic development AR gene also includes a CAG repeat region of variable length that encodes a polyglutamate tract in the N-terminal region of the protein n sequence in the protein) is inversely related to the capacity of the receptor to activate a target gene in vitroAR signaling capacity in vitro diminishes by an average of 1.7% for each additional CAG repeat within the range from 16 to 35 AR CAG repeat lengths has been found to be associated with phenotypic features of men with Klinefelter's syndrome AR CAG repeats were associated with more exuberant expression of IgG autoantibodies in males with lupus AR CAG repeat length and disease activity in women with rheumatoid arthritis Inherited variation in the androgen receptor ), and assessments of the overall breadth of humoral autoimmune reactions by autoantigen microarrays.We reasoned that, as women have much lower circulating levels of endogenous androgens, inherited variation in sensitivity to these hormones might play an even more significant role in modulation of immune reactivity when compared with men. We genotyped a cohort of women with lupus for variation at the Study samples and de-identified clinical data are obtained from normal female volunteers and from female patients seen in clinics at the Penn State Milton S Hershey Medical Center. The study was approved by the Institutional Review Board of the Penn State College of Medicine and the M S Hershey Medical Center, and all subjects gave informed consent. De-identified subject samples included serum for autoantibody analyses and DNA for genotyping. Clinical data on individuals with lupus included age, number and type of lupus diagnostic criteria Genomic DNA was isolated from peripheral whole blood or from buffy coat cells using the QIAamp DNA Mini Kit (Qiagen) following the manufacturer's protocol. DNA was quantitated using a Nanodrop 2000c spectrophotometer.AR exon 1 CAG repeat length was measured for both alleles in each subject using a PCR-based technique as described previously xl Genetic Analyzer in the Penn State College of Medicine Molecular Genetics Core Facility. Determination of the sizes of the PCR products was performed using the GeneMapper Software (Applied Biosystems).The AR allele using the CpG methylation-sensitive restriction endonucleases HpaII and HhaI Methylation analysis was carried out to detect the degree of inactivation of each The percentage of each allele that was unmethylated (active) was determined by calculating the ratio of the respective peak areas in the enzyme-digested samples. As individual alleles usually do not amplify with equal efficiency, we used a correction based on the amplification of each allele in the undigested samples AR CAG repeat length was calculated A weighted mean (a) peak area of allele 1 in digested samples(b) peak area of allele 2 in digested samples(c) peak area of allele 1 in undigested samples(d) peak area of allele 2 in undigested samples(e) number of CAG repeats in allele 1(f) number of CAG repeats in allele 2These variables were used in the following equations:Fractional inactivation of allele 1:Fractional inactivation of allele 2:AR CAG repeat length:Weighted mean AR CAG repeat length was the average of these two determinations.Samples were analyzed in this fashion with both HpaII and HhaI (Promega). The results were uniformly concordant and the final weighted mean Levels of ANAs were measured in serum samples using the ELISA technique . A positive result in this assay is defined as >20 ELISA units. ANA results using this technique correlate with those obtained by immunofluorescence assays s.d. of the values observed. For the lupus subjects, values above this level were scored as positive tests for each respective autoantibody.Individual serum samples (5\u200a\u03bcl) were analyzed for IgG and IgM autoantibodies directed against the components of an 84-component autoantigen array described previously AR CAG repeat lengths for alleles and for weighted mean AR CAG repeat values based on methylation analysis were determined in the study populations by a t-test. The Gaussian curve fitting for the frequency distribution of AR CAG repeat lengths was done using the GraphPad Prism 6 Software . The same software was used to determine linear correlations between individual AR CAG repeat lengths and measures of disease activity. Hierarchical cluster analysis of normalized microarray data was carried out using Cluster 3.0 and the results were prepared for visual presentation as heat maps using Tree View 1.6. Fisher's exact test was used to analyze autoantigen microarray data as discrete variables in individuals with short (\u226419) AR CAG repeats compared with those with long (>19) AR CAG repeats.Differences in mean AR CAG repeat lengths differed between healthy individuals and subjects with lupus, we genotyped 25 healthy female volunteers and 39 women with a diagnosis of lupus who are subjects in a registry at the Milton S Hershey Medical Center. No difference was observed in the average length of the AR exon 1 CAG repeat in all alleles between the healthy control group and the lupus subjects do not play any primary role in the predisposition to the development of autoimmunity in individuals with lupus.X chromosomal inactivation could conceivably alter effective AR alleles of greater or lesser length might be more prevalent in the lupus subjects. Skewed X inactivation can be defined by a variety of criteria \u2013 usually ranging from >70 to >90% inactivation (methylation) of one allele. We noted such skewed methylation in 7.8\u201332.8% of individuals have been reported to occur more frequently in individuals with autoimmune disease ividuals based onAR CAG repeat length might be related to differences in clinical features of lupus or in the manifestations of humoral autoimmunity that characterize the disorder. Of the 23 subjects with lupus, 13 had been treated with hydroxychloroquine, nine had received treatment with a pharmacological dose of glucocorticoids, and two had received mycophenolate mofetil. There was no difference in the weighted mean AR CAG repeat length among the groups who had received different therapies, and none of them differed from the mean for the total subject population.While there was little reason to expect that the genetic determinants of androgen insensitivity could influence overall susceptibility to autoimmune disease, we hypothesized that inherited variation in sensitivity to hormone action might affect aspects of the course, severity, or breadth of autoimmune reactivity. We examined in detail a subset of individuals to test whether the AR CAG repeat length in the lupus subjects. The number of lupus diagnostic criteria observed for each patient at the time of entry into the registry failed to show a linear correlation with the AR CAG repeat length when analyzed as a continuous variable . The SLEDAI showed a significant inverse correlation with the weighted mean AR CAG repeat length used to assess disease activity both showed evidence of an inverse correlation with the weighted mean AR CAG repeat length in our cohort of lupus subjects against individual antigens and showed more numerous autoantibody specificities than did the lupus subjects with longer AR CAG repeat lengths. A similar qualitative trend appeared for IgM autoantibodies (AR CAG length as a dichotomous variable (\u226419 vs >19) revealed a statistically significant increase in the number of autoreactive IgG antibodies in individuals with a shorter AR CAG length that are generally believed to result in diminished efficiency of hormonal signaling are associated with decreased severity of clinical and serological parameters of autoimmunity. Conversely, females with lupus who had shorter AR exon 1 CAG repeats were found to have greater disease activity and more robust humoral autoimmune responses. Our current data are also similar to the observations in women with rheumatoid arthritis \u2013 in whom a shorter AR CAG repeat length was noted to be associated with earlier onset and more aggressive disease course AR CAG repeat length was inversely correlated with the SLICC/ACR index of disease damage AR CAG repeat variation in women do not appear to be compensated by alterations in circulating hormone levels. While longer AR CAG repeats are associated with higher levels of circulating androgens in men AR CAG repeats have previously been found to have lower testosterone levels Since the time of Talal's seminal experiments in the NZB/W mouse, the preponderance of evidence has been that androgenic signaling in the immune system was generally suppressive AR allele CAG repeat lengths and their enrollment in the Hershey Medical Center lupus registry was not biased for any particular manifestation of disease, for severity of manifestations, or for specific therapy. The study is limited by its cross-sectional design. Our clinical data (diagnostic criteria and SLEDAI score) were based on disease manifestations present at the time of each subject's enrollment in the study and further longitudinal data on the relationship of AR genotype to the course of disease would certainly be of interest. Finally, our data are from DNA samples derived from whole blood samples or buffy coat cells. Obviously, while this would not affect the genotyping of the individual AR alleles, the presence of different patterns of X chromosomal inactivation in different cell types could affect the calculation of the weighted mean AR repeat length. It might be argued that specific subsets of B cells at different points during the lymphopoiesis pathway or even bone marrow stromal cells Some limitations of the present study might be noted. First, a relatively small number of subjects have been evaluated, and the possibility of some unrecognized unique characteristics of our study population cannot be excluded. Our subjects exhibited normal distribution of their AR are, in fact, responsible for the observed effects, and several candidate genes on the X chromosome have been identified as susceptibility factors for the development of lupus. Interleukin 1 receptor-associated kinase 1 and toll-like receptor 7 are both such X chromosomal genes for which both human association studies and mechanistic experiments in mice support roles in lupus pathogenesis AR gene (at Xq12) would certainly seem to preclude such linkage disequilibrium. A number of other X chromosomal genes, including that encoding CD40 ligand, have been found to be overexpressed in T cells of women with lupus as a consequence of gene demethylation on an otherwise inactivated X chromosome CXCR3, OGT, and MIR421 (on X q13), are in closer proximity to the AR gene.Our current studies do not explain how attenuation of androgen action could result in amelioration of features of the autoimmune phenotype in women with lupus. It is possible that X chromosomal genes in linkage disequilibrium with AR CAG repeats, both estrogen and androgen levels are increased AR CAG repeat lengths have been reported to have lower circulating androgen levels A second possibility is that inherited differences in androgen sensitivity might alter the steroid hormonal milieu of an individual by altering feedback regulation of gonadotropins or other mechanisms. In men with long Nod1 mouse has now been shown to interact with the animal's hormonal milieu \u2013 with consequent impact on the expression of autoimmunity It is also possible that interactions between an individual and the environment might account for the relationship between inherited androgen sensitivity and the manifestations of autoimmunity. The microbiotic environment of the A variety of mechanisms have been proposed to account for the remarkable sexual dimorphism of most human autoimmune diseases"} +{"text": "We offer dose response in order to derive the concentration causing either 50% or 200% of expression of the biomarker gene. These records revealed to be a valuable end-point to predict in vitro the embryotoxicity of chemicals There is a necessity to develop Specifications TableValue of the data\u2022in vivo embryotoxicity potency.We offer to the readers examples of widely used chemicals with different \u2022We offer to the readers the primer sequence and their respective annealing temperatures to assay using Power SYBR Green methodology the quantitative real time PCR the expression of 6 different genes (5 biomarkers of differentiation plus a house-keeping).\u2022We show as the treatments do not affect the expression of the house-keeping gene, which is an unavoidable requirement for validating the quantification of gene expression.\u2022We show doses\u2013responses of model chemicals that allow deriving the concentrations causing either 50% or 200% of expression of the biomarker genes.1in vitro methods for testing embryotoxicity We needed to select model chemicals with different embryotoxicity in order to develop a cellular method for testing embryotoxicity based on the alterations of the differentiation of D3 mouse embryonic stem cells. We finally selected our model chemicals among thWe needed to assay the effect of the selected chemicals on the aIn order to check if the chemicals alter the expression of the house-keeping gene (\u03b2-actin) we determined that there were no statistical significant differences among the number of thermal cycles of control samples and samples exposed to all the tested concentrations of all model chemicals listed in We determined the effect of gene expression of biomarker genes of all the selected model embryotoxicants . The dos2\u2212\u0394\u0394Ct calculations p<0.05 in Dunnett test; **=statistically different form control for at least p<0.01 in Dunnett test.)D3 cells cultured on monolayer under spontaneous differentiation were exposed to several concentrations of the strong embryotoxicants 5-fluorouracil and reti"} +{"text": "It is often discussed whether patients with juvenile idiopathic arthritis (JIA) should wear orthopedic insoles or not. The functions of insoles are to minimize pain or to assist foot deformities. JIA often goes along with foot impairments ,2 descriThe aim of the study was to analyze the peak plantar pressure distribution of a well described cohort of JIA patients with an active symmetrical ankle joint arthritis and no history of foot involvement. This setting enables to study joint loadings on healthy tissue (foot joints) due to arthritis in a superior joint (ankle joint).2 pressure distribution plate . For analysis the foot was divided into eleven regions of interests.Twenty two patients with a symmetrical ankle joint arthritis with the subtypes sero-negative polyarticular JIA (n = 16) and systemic JIA (n = 6) and a cohort of healthy subjects are included in this retrospective study design. Each subject had to walk five times on each side over a four sensors/cmThis abstract shows the loading of each metatarsal-head - MH5 ) (Tab.1). Patients have statistical significant higher peak pressure values in the forefoot except under MH3. Further on patients have a deviating pressure distribution along the transversal arch with the highest loads under MH5. (Table The patients included in this study suffer from an active ankle joint arthritis. They have significant higher joint loading under healthy tissue of the foot in comparison to the controls. This might be a reason for prescribing orthopedic insoles during a period of an active arthritis. The lateral shift of the peak pressure distribution within the patients in the transversal arch indicates that it is important to control the foot function and pressure distribution not only in patients with a history of foot impairment. Orthopedic insoles might be a valuable therapeutic treatment to protect healthy tissue during a period of active arthritis.None declared."} +{"text": "There are errors in S2 FigThe spatial distribution of activity centers was influenced by the distribution of traps across the study area and the locations of observed bear detections.(TIF)Click here for additional data file."} +{"text": "Women with BRCA1 gene mutations have about 30 to 40 times higher risk of ovarian cancer compared to the population risk (the lifetime risk of BRCA1-dependent ovarian cancer is about 40 percent). Because of the high risk BRCA1 mutations carriers at the age of about 40 are recommended prophylactic salpingo-oophorectomy (after completion of reproductive plans). After the surgery there is still a risk of peritoneal cancer which histologically resembles ovarian cancer, but it is much lower than the risk of ovarian cancer before salpingo-oophorectomy: the cumulative risk of developing cancer of the peritoneum is about 4 percent during 20 years from the removal of ovaries and fallopian tubes.We are going to present a case of long lasting diagnosis of pericardial metastases from BRCA1-associated peritoneal cancer."} +{"text": "There are errors in the legend for Figure 1, \u201cWorkflow for the validation of POPI.\u201d The complete, correct legend for Figure 1 is:*An item involving codeine was removed subsequent to the validation of the propositions included in POPI, following the revelation of new contraindications for this drug in children under 12 years old [19]. Another item involving permethrin for lice was removed due to new recommendations to use dimeticone first instead of insecticides [20]. N: Number of items; n: number of panelists"} +{"text": "The escalating cost of pharmaceuticals is a global challenge and major hindrance to access to medicines in developing countries. Half of the Ugandan population lacks reliable access to essential medicines and out of pocket expenditure by patients is as high as 80% . GenericIt was a cross sectional descriptive study employing two data collection tools; a structured questionnaire administered to dispensers in a random sample of community pharmacies and simulated patients presenting with prescriptions developed and validated by the research team.Up to 133 community pharmacies in Kampala city were included in the study. Almost all community pharmacies practised drug substitution. The most common forms of drug substitution were innovator medicine to generic medicine (85%) and generic medicine to other generic medicine (82%). Up to 92% of the pharmacies substitute \u201cover the counter\u201d drugs while 56% substitute medicines on prescription. Only 24% of the pharmacies did not consult the prescriber before drug substitution and majority (75%) considered the price of the drug before drug substitution. Knowledge of drug substitution policy was low and many (61%) dispensers thought Uganda has no national policy on drug substitution.Drug substitution involving both innovator medicine to generic medicine and generic to generic medicines is wide spread in community pharmacies in Kampala city.The drug regulatory authority should focus on therapeutic equivalence studies and safety profile of approved generic products to better protect the public from substandard medicines."} +{"text": "DNA methylation is a repressive epigenetic mark vital for normal development. Recent studies have uncovered an unexpected role for the DNA methylome in ensuring the correct targeting of the Polycomb repressive complexes throughout the genome. Here, we discuss the implications of these findings for cancer, where DNA methylation patterns are widely reprogrammed. We speculate that cancer-associated reprogramming of the DNA methylome leads to an altered Polycomb binding landscape, influencing gene expression by multiple modes. As the Polycomb system is responsible for the regulation of genes with key roles in cell fate decisions and cell cycle regulation, DNA methylation induced Polycomb mis-targeting could directly drive carcinogenesis and disease progression. Epigenetic systems modulate the interpretation of the information contained in genomes by regulating DNA dependent processes. Many different epigenetic pathways act in mammalian cells and recent work has highlighted extensive interactions between them DNA methylation and the Polycomb repression system are two epigenetic pathways that play key roles in cancer formation and progression. Here, we focus on recent evidence that links DNA methylation to the genomic targeting of Polycomb repressive complexes (PRCs), the effectors of the Polycomb system. In light of this evidence, we discuss how widespread reprogramming of DNA methylation patterns in cancer could drive the relocation of PRCs on chromatin, and contribute to carcinogenesis through alterations in gene expression.Mammalian genomes exhibit widespread DNA methylation that is acquired during early development DNA methylation is classically implicated in gene regulation at promoters, where it is proposed to repress transcription initiation by attenuating the binding of transcription factors, and recruiting repressor complexes through the attraction of methyl-CpG binding proteins Two radical differences exist between normal mammalian DNA methylation landscapes and those found in cancer: many CGIs become aberrantly hypermethylated in cancerous cells, and large amounts of DNA methylation are lost from other genomic regions In addition to aberrant CGI hypermethylation, cancer genomes exhibit widespread loss of DNA methylation . Work ovDNMT3BExperiments in transgenic animals have demonstrated that genomic hypomethylation can either inhibit or promote carcinogenesis depending on the cellular context Despite the application of the latest genomic approaches to cancer DNA methylomes, we still have a limited understanding of the causes of DNA methylation reprogramming and its impact on cancer phenotypes. The picture is complicated by heterogeneity caused by differences in cellular origin or stochastic clonal evolution In addition to methyl-CpG binding proteins, we now know that an eclectic variety of proteins exhibit DNA methylation-modulated binding to chromatin Rasgrf1 locus where one allele is marked by DNA methylation and the other by H3K27me3 It has emerged that DNA methylation plays an unexpected role in restricting the genomic targeting of Polycomb repressor complexes (PRCs) (see Box The Polycomb system is a highly conserved epigenetic mechanism that contributes to the stable repression of thousands of target genes outside of their normal expression domains Recent studies have addressed the cause-consequence relationships involved in establishing these patterns by perturbing either DNA methylation or H3K27me3 and asking what happens to the other mark. In multiple organisms and experimental systems, the removal of DNA methylation has a profound influence on the distribution of the H3K27me3 mark throughout the genome While the majority of studies have focused on the influence of DNA methylation on the PRC2 complex, it is likely that PRC1 localization is also affected. Canonically, PRC1 is recruited to genomic loci by the H3K27me3 mark laid down by PRC2 Dnmt3a mutant neural stem cells, levels of DNA methylation are reduced within the body of some actively transcribed genes, leading to PRC2 binding and repression of their transcription As PRCs are involved in transcriptional repression, their redistribution upon loss of DNA methylation can have significant effects on the transcriptome. For example, in Many interesting questions remain concerning the relationship between DNA methylation and the Polycomb system and its implications for genome regulation. Despite the fact that in vitro experiments have suggested that PRC2 is able to directly read CpG methylation states In addition to changes in the DNA methylome, H3K27me3 patterns are subject to reprogramming in cancer cells Based on frequently observed changes to the DNA methylome in cancer, multiple putative effects on PRC-mediated gene regulation can be envisaged . One sucGenomic hypomethylation in cancer is also likely to impact on the transcriptome. The de novo formation or exacerbation of PMDs in cancer, due to the processes underlying hypomethylation, could uncover binding sites for PRC2, allowing the formation of new H3K27me3 domains and causing the repression of multiple adjacent genes B 3. The In addition to de novo gene repression, loss of PRC restriction by DNA methylation in cancer could paradoxically result in the de-repression of Polycomb-target genes, as observed in DNA methylation mutant MEFs In differentiated cells part of the barrier to transformation is precise partitioning of the genome into active and repressed domains; epigenetic reorganization of these domains is a feature of both cellular and cancer reprogramming. Understanding the cause and functional impact of epigenetic reprogramming is a major goal of both basic and clinical research. The action of PRCs is fundamentally important to many types of cancers as exemplified by the recurrent mutations of PRC components uncovered by cancer re-sequencing studies The functional consequences of DNA methylation mediated PRC redistribution as described here are also likely to be important in other biological systems. Large-scale hypomethylation and the formation of PMDs are now known to be a feature of aging cells In cancer, this mechanism could potentially impact genome regulation in many ways, leading to a transcriptome that facilitates cancer formation, plasticity, and progression, or influences how cancers respond to therapy. We are just beginning to comprehend the epigenetic heterogeneity that exists in cancer"} +{"text": "It has been long known that somatosensory deafferentation can produce a dramatic reorganization of the somatotopic map, characterized by the retraction of the deafferented body part representation followed by expansion of unaffected body part representations (Pons et al., The apparent absence of corticocortical mechanisms driving cortical receptive field reorganization in these experiments is very intriguing. Simultaneous recordings from the normal chin and deafferented body representation of S1 demonstrated the expansion of the chin area in animals with dorsal column lesions (Kambi et al., The hand representation in area 3b receives inputs from M1 (Liao et al., Dendritic spine loss has also been described in deafferented cortical neurons after spinal cord injury (Ghosh et al., Finally, differences in mechanism driving cortical reorganization after deafferentation may also correlate with manifestation of phantom limb pain. It has been proposed that this phenomenon is caused by a maladaptive plasticity in the somatosensory cortex (Ramachandran, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The development of direct acting antiviral agents against the hepatitis C virus has revolutionized treatment paradigms for hepatitis C. In 2011 the first HCV protease inhibitors boceprevir and telaprevir were approved, which still needed to be combined with pegylated interferon and ribavirin and were only usable in patients with genotype 1. However, the new triple therapy achieved successful cure rates of hepatitis C in almost 70% of treatment na\u00efve patients and immediately became the new gold standard of HCV therapy. With the development of further agents, in particular the recent licensing of sofosbuvir and simeprevir, two further DAA\u2019s have become available. Thereby, for the first time Interferon free regimens are already available for genotype 2 and 3 patients allowing cure rates approaching 90% after 12 weeks of sofosbuvir and ribavirin for genotype 2 treatment na\u00efve as well as treatment-experienced patients and 24 weeks of all oral therapy for patients with genotype 3 (again treatment-na\u00efve or experienced). For genotype 1 the combination of sofosbuvir with pegylated interferon and ribavirin allows curing over 90% of patients after 12 weeks of triple therapy and therefore has become the preferred HCV therapy for this particular patient group. Also combination of sofosbuvir with other agents have been presented in particular simeprevir or daclatasvir leading to high success rates above 90% even in patients who failed previous triple therapy with one of the first HCV protease inhibitors. Therefore, where available, 2 DAA combinations \u00b1 ribavirin are rapidly becoming the new HCV treatment standard for more difficult to treat patient groups. In the near future combinations of antiviral agents with no cross resistance and improved safety profile will further reduce treatment durations and will become the new recommended HCV regimens making HCV the first viral infection to be possibly eradicated worldwide."} +{"text": "Updated information from the World Health Organization confirms that the neglected tropical diseases (NTDs) exert an important and adverse impact on human development in the Group of 20 (G20).The NTDs represent a group of at least 17 chronic parasitic and related infections that comprise the most common afflictions of the world\u2019s poorest people. Recent information released by the Global Burden of Disease Study (GBD) confirms the high disease burden from NTDs worldwide. For example, the GBD 2010 found that the NTDs affect more than 1 billion people and were associated with 26.06 million disability-adjusted life years (DALYs) .,18.17,18Previously, I suggested that the concept of blue marble health should be linked to accountability. If the G20 and Nigeria took greater responsibility for their own autochthonous NTDs, most of the world\u2019s NTD burden could be controlled or eliminated ,19. SuccThe new data presented here and their links to worm indices for human development reinforce this concept and the urgency to bring NTDs to the attention of the leaders of the G20 countries. While it is too late to put such ideas on the agenda for the 2015 G20 summit in Turkey, an emphasis for the anticipated 2016 summit in China could be paradigm shifting and a major breakthrough in global public health."} +{"text": "Real\u2010time electrode material displacement is captured in 3D allowing degradation mechanisms such as delamination of the electrode from the current collector and electrode crack formation to be identified. Continuum DVC of consecutive images during discharge is used to quantify local displacements and strains in 3D throughout discharge, facilitating tracking of the progression of swelling due to lithiation within the electrode material in a commercial, spiral\u2010wound battery during normal operation. Displacement of the rigid current collector and cell materials contribute to severe electrode detachment and crack formation during discharge, which is monitored by a separate DVC approach. Use of time\u2010lapse X\u2010ray computed tomography coupled with DVC is thus demonstrated as an effective diagnostic technique to identify causes of performance loss within commercial lithium batteries; this novel approach is expected to guide the development of more effective commercial cell designs.Tracking the dynamic morphology of active materials during operation of lithium batteries is essential for identifying causes of performance loss. Digital volume correlation (DVC) is applied to high\u2010speed operando synchrotron X\u2010ray computed tomography of a commercial Li/MnO Synchrotron radiation sources can provide the high photon flux and brilliance necessary to achieve high resolution 3D images over short periods of time2 electrode material in a commercial primary Li/MnO2 lithium battery during a high rate, constant resistance discharge. As Li/MnO2 cells have a high discharge rate capability (they are often used for high drain applications), we use the high speed imaging capability of beamline ID15A2 electrode in 3D as lithiation\u2010induced dilation occurs. 3D displacement fields generated using continuum DVC are used to derive 3D strain profiles of the electrode material throughout operation. Additionally, the electromechanical effect of the dilating electrode on the structural integrity of the cell architecture is assessed. The extent of unraveling of the current collector is quantified using a separate DVC approach and related to the temporal continuum strain field evolution. The importance to commercial cell designs of accommodating the changes in cell architecture during operation is highlighted, and this new approach of combining high speed tomography and DVC is demonstrated as an effective technique for identifying causes of performance loss within commercial batteries.In this study, we capture the evolution and quantify the strain in the bulk architecture of the MnO22.1This study focuses on a commercial, spiral wound, Duracell CR2 batteryFigureThe Duracell CR2 battery was imaged in a 76 keV monochromatic X\u2010ray beam with a field of view (FOV) of 8.6 mm \u00d7 8.7 mm and a pixel size of 10.87 \u03bcm (794 \u00d7 800 pixels), corresponding to half of the cell built into the ID15A rotation stage whereby the 3D images could be separated into 2D planar slices, as shown in Figure 2.2Figure2 is reduced from tetravalent to trivalent state to form LixMnO2 (where 0 \u2264 x \u2264 1) as the Li+ ion inserts into the MnO2 lattice.In this study, the CR2 cell is discharged from its fully charged state (3 V) to below 2 V, as shown in A regular 3D grid of nodes was defined over the CT image volume, and a \u201ccorrelation window\u201d was centered on each node for the correlation analysis. In the current study, the grid spacing of the nodes was 5 voxels in each direction and the correlation window had a volume of 15 \u00d7 15 \u00d7 15 voxels.The displacement for each node was derived by identifying the 3D translation that maximizes the cross\u2010correlation of the gray\u2010level data within the correlation window in the nondeformed image and the translated correlation window in the deformed image. The displacement field so determined had a precision of 1 voxel in each direction.Subvoxel resolved translation vectors were determined based on the maximum of the interpolated correlation coefficient for a range of displacements around the initial integer voxel value.Calculation of the strain tensor was based on the gradient of the displacements over eight\u2010point cubic elements of neighboring nodes.The DVC approach can be described briefly as having the following main steps:xMnO2 electrode architecture was quantified in 3D by correlating successive tomograms. Tomograms were captured every 40 s during discharge and increments between sequential tomograms which showed significant material displacement were chosen for correlation. The discharge profile of the CR2 battery in Figure Following the above continuum DVC approach, the evolution of the LixMnO2 material was >0.97 ; whereas poor correlation was observed for all other materials. DVC analysis points that gave a normalized cross correlation coefficient of less than 0.97 were filtered out.For each volume correlation the correlation coefficient of the Li2.3As a separate measurement, the DVC methodology was used to determine the deformation of the collector mesh during battery discharge. The current collector is a metallic mesh of diamond pattern, embedded within the electrode material, and spirally wound within the battery case. The mesh contains distinct nodes where individual wires meet, creating unique features that can be tracked as deformation occurs. Three layers of 176 nodes were identified within the battery, and their centers located approximately by standard imaging methods. Each point formed the center of a rectangular 40 \u00d7 40 \u00d7 80 voxel subvolume, large enough to contain the complete connection, but small enough to prevent interaction between layers of the scroll. Subvolumes were extracted from imaging of a charged battery and tracked within imaging of the discharged state. Subvoxel translational and rotational degrees of freedom were activated for a zero normalized sum of square difference objective function with tricubic spline interpolation and a typical coarse\u2010fine search strategy was employed. Convergence tolerance was tightened until all points tracked successfully and displacement values stabilized. Deformations were visualized with 3D vector plots showing motion of points within the three layers of junction points.33.1xMnO2 can cause severe mechanical degradation on both the micro and macro scale. The exact volume expansion of the LixMnO2 is difficult to determine via threshold segmentation due to the change in attenuation of LixMnO2 as it lithiates and the overlapping grayscale of different materials within the cell. Additionally, individual crystallites tend to break up during dischargexMnO2 particles. However, an estimate of 20% volume expansion due to lithiation was determined by comparing the quantity of the grayscale threshold associated with the electrode material before and after discharge. Over a single discharge at low operating voltages (2\u20133 V) it is not expected that dissolution of LixMnO2 has any significant effect on the observations in this work.The volume expansion observed during lithiation of LiFigurexMnO2 spiral wound layer expands and the thickness of the lithium region is seen to diminish during the lithiation process. The battery casing is included in these movies to observe any interaction between the evolving active materials and the casing.xMnO2 from the current collecting mesh, as evidenced by the cracks emanating in the anticlockwise direction in Figure xMnO2 electrode causes a slight degree of unraveling of the spiral wound materials, a consequence of the mechanical energy associated with the electrode\u2010active material.Detachment of the LixMnO2 from the current collecting mesh results in a significant reduction in interfacial area between the current collecting mesh and the active material. The inset in Figure The internal unraveling of the electrode layers further contributes to crack propagation via the strain induced from the movement of the current collecting mesh against the active material, explaining the increased severity of cracking with distance from the center of the cell observed in Figure xMnO2 and the formation of cracks within the LixMnO2 material may also benefit the performance of the cell by exposing additional LixMnO2 surface area to Li\u2010ion transfer. The experiment was repeated for a slower discharge with a constant resistance of 4.5 \u03a9; the time\u2010stamped slices show similar behavior but over a longer period of time. The discharge plot and evolution movies are provided in Figure S10 and Movies S3 and S4, Supporting Information.Delamination of electrode materials from the current collector is a well\u2010known cause of increased cell impedance and capacity fade in commercial cells.DVC was applied to consecutive images to determine the 3D strain profiles caused by lithiation of the electrode and to explore the electrochemically induced strain that causes unraveling of the current collecting mesh.3.2FigurexMnO2, binder and conductive material, and electrolyte\u2010filled pore phase). The correlation window was set as a cube of 15 voxels which, with a voxel resolution of 10.87 \u03bcm, tracks grain detail up to 163 \u03bcm3. The distance between nodes was set as 5 voxels or 54.35 \u03bcm.Continuum displacement DVC between consecutive tomographs was applied to plot the evolution of 3D displacement and strain profiles. Consistent grain detail is required between consecutive images to measure continuum displacement with a high correlation coefficient. An example of the fine detail present in the tomography images is shown in xMnO2 will be observed as bulk deformation of the active electrode layer on the submillimeter scale via interaction and displacement of the LixMnO2 active crystallites, binder and the conductive carbon substrate. The continuum DVC provided averaged displacement profiles between 3D images which were 200 s apart during discharge. Displacements were plotted in 3D and the associated strain maps were generated by differentiating the vector displacements with respect to the X, Y, and Z directions. FigurexMnO2 electrode measured between 200 and 400 s into discharge. Correlation windows shows the evolution of volumetric strain of the xMnO2 decreases. This results in nonuniform insertion stresses on the microscale.xMnO2 crystallites.As lithiation progresses deeper into the active material, the dilation front progresses toward the center of the electrode layer, and hence the strain in this region begins to increase, which is already evident between 400 and 600 s in Figure xMnO2; however, the strain observed on the inner side of the electrode layer being different on each side of the current collecting mesh.A significant difference in strain is evident between both sides of each electrode layer, as identified in the twin peaks at these locations in Figure xMnO2 material it is expected that the local current density and hence activity would be lower, which is consistent with a lower strain on the outside of the LixMnO2 layers in Figure In battery modeling the current density is given by the reaction current density at the surface of the electrode particles, which is determined by the surface lithium diffusion flux. The surface area of the outer side of the electrode layer is greater than the surface area of the inner side of the electrode due to its larger radius of curvature. If the current density is assumed to be uniform on both sides of the current collecting mesh, then with the increased surface area on the outer side of the LixMnO2 layer the one\u2010sided activity in FigurexMnO2. At this location, lithium diffuses into the LixMnO2 in one direction only, radially inward. The progression of lithiation can be seen from the strain front traveling through the electrode material during operation, as shown in Figure xMnO2 from the outer surface. As the lithiation progresses, the strain front travels deeper into the active material. The observed strain decreases near the end of discharge as the LixMnO2 becomes increasingly concentrated with lithium and the rate of lithiation (and particle dilation) slows down. The traveling strain front is indicative of the progressing lithium concentration distribution within the electrode during discharge, which emphasizes the potential for DVC as a model validation technique for evolving lithium concentration in active materials during operation.On the outer end of the Li3.3xMnO2 architecture displaces the rigid current collecting mesh which detaches from the electrode material. This leads to increased contact resistance between the electrode and current collector which can significantly affect the performance of the cellxMnO2 electrode is seen to expand against the shell of the casing on one side only ; consequently, the spiral wound layers shift toward the vacant side of the cell. The shift of the current collecting mesh was quantified by using a point tracking method developed by Bay et al.FigureXY plane, whereas very little displacement is observed in the vertical Z direction. Figure XY plane where displacements up to 0.8 mm are observed. As seen in Movie S1 (Supporting Information), the spiral wound layers are only in contact with one side of the casing; as the electrode expands during lithiation the contents of the cell are pushed in the opposite direction, as shown in Figure xMnO2 electrode material resulting from displacement of the current collector can cause electrically isolated electrode sections as a result of loss of direct electrical contact with the current collector.The measurements above have demonstrated that the evolving Li4DVC software has been applied to high speed operando X\u2010ray CT of commercial primary lithium batteries during discharge. By quantifying the movement of discrete sections of the electrode material between sequential images during discharge, a spatial and temporal map of material activity and strain profiles was generated. The progression of the lithiation front has been tracked by measuring the local displacement of electrode material during dilation for the first time which has provided valuable insights into the transient structural mechanics that take place within commercial cells during operation. For example, relatively inactive regions were identified and large concentration gradients within the electrode layers could be deduced from the evolving strain patterns, giving the capability to pinpoint inefficiencies and identify means through which the performance of the cell could be improved.+ transport and dilation between sides of the electrode layer causing an uneven distribution of activity and strain. The cell was identified as being limited by Li+ transport since throughout the discharge the material dilation progressed from the surface of the electrode toward the current collector. This technique could also provide empirical evidence for whether optimum electrode thickness is achieved for particular operating conditions and assess the tension and compression effects associated with thick spiral wound electrodes.Although this cell is a primary cell, this novel diagnostic approach has provided a means of identifying numerous sources of performance loss, which may also be applied to rechargeable cells. The placement of the current collecting mesh to one side of a thick electrode during manufacturing has resulted in a significant variation in LiThis DVC approach also provides valuable information for multiphysics modeling of operating lithium batteries by providing real\u2010time, structural, and strain information in 3D. As demonstrated here, the interaction between evolving materials and their environment is imperative to accurately predict the performance of a particular cell design during operation, as crack formation and delamination can have a significant impact on the rate of aging and degradation of cells. Internal mechanics of a cell can also be elucidated and used to determine the tendency of a cell to incur capacity loss via breakage and isolation of electrode material. The extent of expansion, cracking, and delamination observed during discharge of the cell affects the local ionic diffusivity and electrical conductivity of the material.To date, very few experimental studies have quantitatively captured the temporal local activity of electrode material within lithium batteries; in this work, the combination of the high\u2010resolution, high\u2010speed imaging capabilities of synchrotrons, and image correlation techniques, has been demonstrated as a powerful tool for identifying local strain, material displacement, and degradation within an operating cell. This approach could also be applied on the microscale to extract 4D strain profiles of individual electrode particles and be used as a tool for strain model validation. Information about local lithiation could be extracted from the correlation volumes by observing the material displacement fronts. The elucidation of the evolving active materials and their interaction with commercial mechanical designs is expected to guide the optimization of material use and commercial cell designs.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re\u2010organized for online delivery, but are not copy\u2010edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file."} +{"text": "There is an error in the last sentence of the \u201cValidation on factual statements\u201d section of the Results. The sentence should read: With this method we estimate that, in the four subject areas, true statements are assigned higher truth values than false ones with probability 95%, 98%, 100%, and 95%, respectively.For each confusion matrix depicted in Fig 3 we compute ROC curves where true statements correspond to the diagonal and false statements to off-diagonal elements. The red dashed line represents the performance of a random classifier."} +{"text": "Early Warning Scores (EWS) are used in UK hospitals to identify patients who are acutely unwell or needing urgent review. The National EWS (NEWS) was implAll patients scored as 'high risk' by NEWS (with a score of 6 or more) in a snapshot audit of patients in our 500-bed acute district general hospital were identified and reviewed clinically. All of these patients were then recategorised using ViEWS. The clinical safety of this recategorisation was then assessed.Forty-six patients were identified in our hospital at the time of the snapshot as being high risk according to NEWS. After recategorising this cohort of patients using ViEWS, 36 were classified as high risk (in this instance meaning a score of 5 or more). Subjectively the authors did not have any clinical concerns created by moving 10 patients out of the high-risk classification.ViEWS is more specific without being less sensitive. We have replaced NEWS with ViEWS and feel that this is clinically safe."} +{"text": "TP53 gene is known as the \u201cguardian of the genome\u201d as it plays a vital role in regulating cell cycle, cell proliferation, DNA damage repair, initiation of programmed cell death and suppressing tumor growth. Non uniform usage of synonymous codons for a specific amino acid during translation of protein known as codon usage bias (CUB) is a unique property of the genome and shows species specific deviation. Analysis of codon usage bias with compositional dynamics of coding sequences has contributed to the better understanding of the molecular mechanism and the evolution of a particular gene. In this study, the complete nucleotide coding sequences of TP53 gene from eight different mammalian species were used for CUB analysis. Our results showed that the codon usage patterns in TP53 gene across different mammalian species has been influenced by GC bias particularly GC3 and a moderate bias exists in the codon usage of TP53 gene. Moreover, we observed that nature has highly favored the most over represented codon CTG for leucine amino acid but selected against the ATA codon for isoleucine in TP53 gene across all mammalian species during the course of evolution. TP53 gene encodes tumor protein p53 which is known as the \u201cguardian of the genome\u201d as it plays a vital role in maintaining genomic stability by preventing mutation in the genome is the expected number of codon occurrences given the nucleotide distribution at three codon positions (b1b2b3) [Gene expression was estimated through RCBS which can be defined as the overall score of a gene indicating the influence of relative codon bias (RCB) of each codon in a gene . The RCB(b1b2b3) .Otot is the total number of codonsWhere, TP53 genes in different mammalian species. All statistical analyses were carried out using the SPSS software. Cluster analysis (Heat map) of correlation coefficient of codons with GC3 and the RSCU values of codons among the eight mammalian species were clustered using a hierarchical clustering method implemented in NetWalker software [The above mentioned genetic indices were estimated in a PERL program developed by SC (corresponding author) to measure the CUB on the selected coding sequences of software ."} +{"text": "The importance of imaging in establishing the focus of infection is recognised in current guidelines for the management of severe sepsis , with deThe study cohort was composed of 50 consecutive patients who met the criteria for severe sepsis attendinCXR was performed as the initial investigation in 49 of the 50 patients (98%). The median time from arrival at the ED to initial imaging was 1 hour:00 minutes (range 0 hours:04 minutes to 4 hours:25 minutes). Initial investigations in the ED of CXR and urine dip identified a septic focus in 30 of 50 patients (60%). Fourteen of the remaining 20 went on to have one or more further imaging studies. Figure Our results indicate that simple bedside investigations are able to identify a focus of infection in 60% of patients presenting to the ED with severe sepsis. Our results support the continued use of CXR as the initial imaging modality in severe sepsis, but also demonstrate the benefit of further imaging in confirming the focus of infection and to guide definitive treatment. Instances where further imaging was delayed by several days highlight the need for guidelines detailing which investigations should be done and in what time frame."} +{"text": "The issue of acquired resistance to breast cancer regimes such as tamoxifen continues to negatively affect clinical outcomes. While many mechanisms of resistance have been discovered ,2, thereReal time PCR examines the gene expression profile of the LY2 cells under various treatments including oestrogen, tamoxifen and a mixture of both.It was found that the normal oestrogen receptor target genes PS2 and GREB1 display reduced expression without the presence of the receptor. However EGR3 signals excessively despite having the receptor stably knockdown.As a result these data provides evidence that EGR3 is involved in the adaptation of the oestrogen receptor and that global signalling of common target genes does not occur when the receptor adapts. Hence it demonstrates an initial clue of the process of adaptation in resistant tumours that have changed their receptor status."} +{"text": "Percutaneous tracheostomy is one of the most commonly operative procedures performed in Intensive Care Unit (ICU) patients . CiagliaAim of this study is to present a simple procedural modification of Ciaglia Blue Rhino PDT in order to avoid the potential difficulty in carrying out initial dilation and greatly reduce the chance of seeing the posterior tracheal wall or create a false route during the dilation. After a preliminary experience with this new technique that showed its safety and in fact we replaced the standard CBR technique with the new one from January 2014.A retrospective cohort study in a medical/surgical ICU was carried out over a 24-month period: patient undergoing PDT between January 2014 to December 2014 (Group A: 70 patients) were retrospective analyzed and compared with patient who were undergoing PDT between January 2013 to December 2013 (Group B: 65 patients). In the Group A PDT was performed by using the modified CBR technique: the modification consist of a transverse cut practiced, under guided light given by flexible bronchoscope trans illumination, before the trachea was punctured with a 14-gauge Teflon catheter introducer needle. In the group B we use the standard CBR technique [One hundred and thirty five patients were entered into the study. Patient data and complications recorded are reported in table The simple modification we propose made the initial dilation easier to perform and prevented a prolonged procedure time. In addiction appears to reduce the incidence of complications such as lesions of the posterior tracheal wall and fractures of the tracheal rings."} +{"text": "Following publication, the authors learned that the \u201cDiscovery Study\u201d section of the originally published version of The discrepancy stemmed from use of the originally released version of the Discovery Study data set GEO GSE45330 for production of the original The statistical analysis syntax used in the production of the corrected S3 File(PDF)Click here for additional data file."} +{"text": "Predicting species potential and future distribution has become a relevant tool in biodiversity monitoring and conservation. In this data article we present the suitability map of a virtual species generated based on two bioclimatic variables, and a dataset containing more than 700,000 random observations at the extent of Europe. The dataset includes spatial attributes such as: distance to roads, protected areas, country codes, and the habitat suitability of two spatially clustered species (grassland and forest species) and a wide-spread species. Specifications tableValue of the data\u2022This data brings an insight on factors that might affect species distribution models.\u2022This data is valuable in the study of uncertainty related to species distribution models.\u2022This data can be used as a tool to identify differences among species distribution modelling approaches.1There are two types of data provided:A map of habitat suitability for a widely spread virtual species, based on two bioclimatic variables, annual temperature (Bio1) and annual precipitation (Bio12). The map has a spatial resolution of 1\u00a0km .A table of 768,234 random observations with spatial coordinates (Mollweide projection), suitability score for the virtual species previously described and three species with varying habitat preferences extracted from the ESA CCI landcover map 22.1The habitat suitability map presented here was created using the package virtualspecies 3The 768,234 random observations were generated using GRASS GIS Distance from major roads was computed by generating a raster cost surface based on Euclidean distance from the Global Roads Open Access Data Set (gROADS) The column with the country location per point was extracted from the map of Europe at NUTS2 level with countries presented using ISO3 codes. The columns with species suitability were extracted for one species from the suitability map described above, and for the other three species based on the reclassification of the CCI land cover map"} +{"text": "PLOS Biology editorial team would like to warmly thank all those individuals who participated in the peer review process this past year at PLOS Biology. During 2014, over 1,250 reviewers from around the world helped evaluate articles submitted to the journal.The Public Library of Science (PLOS) and the PLOS Biology authors, and for helping us to publish a highly valued open access journal.The names of our 2014 reviewers are listed in S1 Reviewer List(PDF)Click here for additional data file."} +{"text": "In addition, Tables 2 and 3 presented values for silicon in nanograms per cubic meter. The figures have been corrected, and the values for silicon in the two tables have been rescaled to micrograms per cubic meter.In the original online version of \u201cCharacterizing Spatial Patterns of Airborne Coarse Particulate (PMThe authors regret the errors."} +{"text": "The following scientists assisted the journal by reviewing manuscripts that were submitted for consideration during the period January 1, 2008 to October 31, 2008. We gratefully acknowledge their critical evaluation and assistance in the selection of papers for publication."} +{"text": "A 14 year old girl was referred for CMRI following an echo demonstrating Left Ventricular hypertrophy and pulmonary stenosis. She presented to Cardiology with atypical chest pain at 13 years and had an exercise tolerance test that induced chest pain. She had a history of a murmur at 6 weeks of age, which was followed up with an echo at 6 months which showed mild pulmonary stenosis.Steady-state free precession (SSFP) imaging was performed to assess ventricular function, along with tagging. Black blood T1 and T2 weighted fast spin echo sequences were acquired for tissue characterisation and phase contrast imaging was used to quantify blood flow. First pass perfusion imaging was performed during the administration of gadolinium and finally Late Gadolinium Enhancement (LGE) imaging was acquired.SSFP imaging showed a marked asymmetrical hypertrophy of the crest of the intraventricular septum which was eccentric in nature and protruded extensively into the right ventricle where it caused to a degree of subinfundibular and infundibular narrowing. The Pulmonary Valve appeared a little thickened and domed and without functionally significant stenosis. There was no evidence of systolic anterior motion (SAM) or LVOT obstruction. Black blood imaging did not show any obvious oedema or signal change in the area of hypertrophy. First pass perfusion indicated the area of hypertrophy enhanced relatively normally without any microvascular dysfunction. LGE showed minor patchy scar within the area of maximal hypertrophy and there was no myocardial scar elsewhere. The patient is being treated medically with monitoring for rhythm disturbances and further imaging will be performed at a later dateWe report an unusual case of severe mass like asymmetric hypertrophy of the septum consistent with Hypertrophic Cardiomyopathy (HCM). Right Ventricle involvement in HCM is uncommon and has been described previously by Matsunga et al in 1985, Basarge et al in 1996, Kerekes et al in 2003 and Gullumser et al in 2013.None."} +{"text": "The molecular and cellular mechanisms of the primary brain dysfunction leading to the onset of a migraine attack and to susceptibility to cortical spreading depression (CSD), the neurophysiological correlate of migraine aura and a likely trigger of the headache mechanisms, remain largely unknown and major open issues in the neurobiology of migraine. Our approach to these open questions is the study of the functional consequences of mutations causing familial hemiplegic migraine type 1 and type 2 (FHM1 and FHM2). FHM1 is caused by gain-of-function mutations in the neuronal CaV2.1 channel, a voltage-gated calcium channel that plays a dominant role in controlling neurotransmitter release at brain excitatory and inhibitory synapses. FHM2 is caused by loss-of-function mutations in the glial alpha2 Na/K-ATPase, an isoform that is thought to have specific roles in K+ and glutamate clearance by astrocytes and in astrocyte Ca2+ homeostasis. Knockin (KI) mouse models carrying FHM1 or FHM2 mutations show a lower threshold for CSD induction and a higher velocity of CSD propagation. We have investigated the cortical mechanisms underlying the facilitation of experimental CSD in FHM1 and FHM2 KI mice by studying synaptic transmission at cortical excitatory and inhibitory synapses and the rate of glutamate and K+ clearance by cortical astrocytes in acute cortical slices. Our findings are consistent with the conclusion that increased activation of NMDA receptors due to enhanced cortical glutammatergic synaptic transmission in FHM1 and to reduced rate of glutamate clearance at cortical excitatory synapses in FHM2 contributes to the facilitation of CSD in FHM KI mice. The data from FHM mouse models support the view of migraine as a disorder of brain excitability characterized by dysregulation of the excitatory-inhibitory E/I balance, and point to episodic disruption of the E/I balance and neuronal hyperactivity due to excessive recurrent glutammatergic transmission as the basis for vulnerability to CSD ignition in FHM."} +{"text": "TrkB is a high affinity receptor for the brain derived neurotrophic factor (BDNF) and its phosphorylation stimulates activation of several intracellular signalling pathways linked to cellular growth, differentiation and maintenance. Identification of various activators and inhibitors of the TrkB receptor and greater understanding their binding mechanisms is critical to elucidate the biochemical and pharmacological pathways and analyse various protein crystallization studies. The data presented here is related to the research article entitled \u201cBrain Derived neurotrophic factor is involved in the regulation of glycogen synthase kinase 3\u03b2 (GSK3\u03b2) signalling\u201d Specifications TableValue of the data\u2022Three dimensional molecular model of the cyclic peptide cyclotraxin B was generated for the first time to determine its interactions with the TrkB receptor.\u2022Future studies to determine pharmacological, biochemical or interaction studies of TrkB receptor or related molecules will be facilitated by the interaction and binding parameters reported here.\u2022Binding interactions of CTXB with TrkB will determine its potential usage in pharmacological studies and development of new derivatives and ligands.1The data shown here elucidates molecular modeling of cyclic peptide cyclotraxin B which is a TrkB inhibitor. Active site of the extracellular D5 domain of the TrkB receptor which is primarily involved in this interaction was also modelled. Finally the cyclic peptide inhibitor was also identified and docking carried out with the extracellular D5 domain of TrkB. The interacting amino acid residues that are involved in docking are identified and various interaction parameters provided in detail using a combination of molecular modeling and molecular docking computational tools.22.1via MOPAC method Cyclotraxin B (CTXB) is a cyclic peptide chain of 10 amino acid linked by a disulphide bridge 2.2The primary structure of TrkB receptor and its various domains were examined 2.3in silico assessment of the potential binding of selected CTXB residues to different regions on the TrkB D5 surfaces. This binding interactions were assessed in terms of probability of CTXB participating residues binding to the TrkB D5 receptor surface and theoretical scores determined using the PepSite2 server The protein motif was subjected to PepSite2 is a computational tool that scans the surface of a given protein for patches or grooves that are likely to influence binding of individual amino acid residues or peptides up to ten amino acids and provides a score that reflects the propensity of the peptide to bind to that region. The PepSite score is expressed in relative units and the higher scores reflects superior binding. We applied PepSite in a sliding window of 10 residues to assess the binding of the TrkB-D5 domain and CTXB peptide sequence (CNPMGYTKEG). The scores of the CTXB binding to different regions of TrkB D5 domain are presented [1].2.4The protein-peptide docking was performed with the PatchDock software available in the public domain"} +{"text": "Examination of the lungs of adult sheep with chronic respiratory diseases was readily achieved using both 5\u2009MHz linear and sector scanners. Superficial lung abscesses in eight sheep appeared as anechoic areas containing multiple hyperechoic dots bordered distally by a broad hyperechoic capsule. Unilateral fibrinous pleurisy (2 sheep) appeared as an anechoic area containing a hyperechoic latticework. Ovine pulmonary adenocarcinoma (OPA) lesions appeared as sharply demarcated hypoechoic areas in the lung parenchyma initially in the cranioventral lung lobes (21 sheep) with lesions also present in the caudodorsal diaphragmatic lobe (11 sheep); abscesses and areas of calcification within the OPA tumour mass were also identified. Daily treatment with procaine penicillin for 30 consecutive days was successful in both sheep with unilateral fibrinous pleurisy and six sheep identified with superficial lung abscesses measuring 2\u20138\u2009cm in diameter; only one of two sheep with more extensive lesions recovered. Auscultation of the chest failed to detect adventitious sounds in any of the ten sheep with lung abscesses; normal breath sounds were reduced over the area of fibrinous pleurisy; no pleuritic rubs were heard. Wheezes and crackles auscultated in some OPA cases and did not correlate well with lesions detected ultrasonographically. An aetiological approach to the diagnosis, treatment, and control of respiratory diseases affecting sheep is often adopted in review articles and bookIndividuals with chronic respiratory diseases are in poorer body conditions and have a higher respiratory rate than other sheep in the group . The accPublication of auscultated sounds recorded over specific respiratory tract pathologies, defined during simultaneous ultrasonographic investigation, has allowed clinicians to assess the value of auscultation of the chest performed as part of the standard veterinary clinical examination of sheep , 7 and cWhile ultrasonographic examination of the chest in cattle and sheep has been routinely undertaken in some veterinary schools for many years , this adThis paper describes the antibiotic treatment response in sheep with chronic lung diseases where the diagnosis was based upon ultrasonographic examination of the lungs using 5\u2009MHz linear and sector scanners; no account was taken of auscultation findings. Lung pathologies were confirmed in those animals that failed to respond to treatment and were euthanased for welfare reasons. Necropsy examinations allowed comparison between sonographic findings and pathological changes.The thirty one sheep included in this study originated from the University of Edinburgh's first opinion ambulatory practice and cases were referred by local veterinary practices. This study covered a two-year period (October 2011\u2013October 2013 inclusive). To mimic the time constraints faced by farm animal practitioners, ultrasonographic examination of both sides of the chest, including skin preparation, totalled no more than 5 minutes for each type of ultrasound scanner and often took less time. Ultrasonographic examination of the chest was undertaken using both 5.0\u2009MHz sector and linear transducers connected to a real-time, B-mode ultrasound machine (Aloka and BCF Technology Miniscan).A 5\u2009cm wide strip of skin was shaved on both sides of the thorax extending in a vertical plane from the point of the elbow to the caudal edge of the scapula corresponding to the 6th or 7th intercostal spaces. The prepared skin overlying the chest wall can be freely moved 3\u2009cm which allowed examination of the caudal aspect of the lung field. The skin was soaked with warm tap water then ultrasound gel liberally applied to the wet skin to ensure good contact. The transducer head was firmly held at 90\u00b0 to the skin overlying the intercostal muscles of the 6th or 7th intercostal spaces and the thorax was examined in the longitudinal plane. The relatively large linear probe head was held on the chest wall at a slight angle to represent the angle of the intercostal spaces. It was important to visualise the echogenic (white) line of the normal visceral pleura at the most dorsal margin of the lung field before scanning the ventral areas of the chest. The visceral pleura was followed down the chest wall to identify the junction between normal lung and pathology where present.The diagnosis of respiratory disease was confirmed at gross necropsy in 22 sheep. Bacteriology examinations were not undertaken because of prior antibiotic therapy. Ultrasonographic examination of 31 adult sheep with respiratory diseases associated with weight loss included OPA (21), fibrinous pleurisy (2 cases), and superficial lung abscesses (8 cases).The sonograms are presented with the probe head at the top of the image; dorsal is to the left and ventral to the right of the image. Centimetre dot markers are displayed on the margin of the images and should be consulted to ascertain the depth of field presented. The chest wall of adult sheep was approximately 1\u20131.5\u2009cm thick. An air interface, created by aerated lung parenchyma reflects sound waves and appears as a bright white (hyperechoic) linear echo. The sonogram below the white linear echo may contain equidistant reverberation artefacts which are of no clinical significance. The area visualized below the linear echo, including the reverberation artefacts, does not represent lung parenchyma; thus the initial ultrasound machine setting with a 5\u2009MHz sector transducer was 8\u2009cm which examined approximately 1\u20131.5\u2009cm of chest wall then pleurae and superficial lung parenchyma. The 5\u2009MHz linear transducer used had a field depth of 7\u20139\u2009cm.The surface of normal aerated lung was characterized by the uppermost white linear echo with equally-spaced reverberation artefacts below this line . CarefulThe hyperechoic linear echo representing the normal visceral pleura was lost with superficial lung abscess which appeared as an uniform anechoic area containing many hyperechoic dots representing gas echoes bordered by a broad concave white abscess capsule Figures and 4. TThe visceral pleura appeared broader and more hyperechoic than normal in one sheep due to acoustic enhancement by the pleural exudate with fibThe first indication of change in the lung parenchyma caused by OPA was the abrupt loss of the bright linear echo formed by normal aerated lung tissue to be replaced by a large hypoechoic area in the ventral margins of the lung lobes at the 5th or 6th intercostal spaces Figures and 8. TConsecutive daily treatment with procaine penicillin for 30 days was successful in all six sheep identified with pleural/superficial lung abscesses measuring 2\u20138\u2009cm in diameter; only one of two sheep with more extensive lesions recovered.Chronic bacterial infection of the respiratory tract in sheep usually presents with weight loss over several weeks/months and an increased respiratory rate . A wide Arcanobacterium pyogenes [ Arcanobacterium pyogenes was the most common bacterial isolate from chronic suppurative pneumonia cases in cattle and such chronic infections were treated with a 4\u20136-week course of procaine penicillin with reasonable success [Ultrasonographic examination of the chest accurately defined superficial lung pathology in agreement with previous work , 17. Ultpyogenes , 18. Arc success . Other aLesions of ovine pulmonary adenocarcinoma (OPA) were sharply demarcated sonographically from normal lung where the hypoechoic areas extended 6\u20138\u2009cm into the lung parenchyma in the cranioventral lung lobes and had the sonographic appearance of liver (hepatoid change). Such lesions cannot be accurately delineated by auscultation findings alone , 6. The Accurate identification and distribution of pleural and superficial lung pathology necessitated ultrasonographic examination; auscultation failed to identify common lesions including OPA. With some experience, systematic ultrasound examination of the ovine chest takes no more than 5 minutes. Long-term penicillin therapy was successful in 7 of 8 cases of pleural/superficial lung abscesses."} +{"text": "Aedes japonicus Population Genetics in Germany.The word \" japonicus\" is misspelled in the article\u2019s short title. The correct short title is: Additionally, the following paragraph was incorrectly placed as the last paragraph of the Materials and Methods section. It should appear as the last paragraph of the Results section:The distribution of nad4 haplotypes matches to some extent the distribution of the two genotypes. Specifically, haplotype H5 occurs exclusively and is highly abundant in populations with a predominant genotype 2 signature ."} +{"text": "The aim of this study is to assess the performance of 18F-FDG whole body PET/MRI in comparison with PET/CT based on SUV. Anatomical location of lesion with Dixon MRI and additional value of advanced MRI technology such as diffusion weighted MR imaging in diagnosis of malignant disease will also be investigated."} +{"text": "There is a typographical error in page 4, line 21. The reference of \"protein IV\" should be changed to \"protein VI\". The sentence should read: This capsid destabilization causes detachment of the fibers and exposure of protein VI [18]."} +{"text": "There are errors in There are errors in the second sentence in the Results subsection titled \u201cAchievement of conservation goals in the current protected area system.\u201d The correct sentence is: Reptiles, butterflies, and plants are the groups less satisfactorily protected with 50%, 42%, and 36%, of their species under protected, respectively."} +{"text": "Diabetic foot is an invalidating complication of diabetes mellitus that can lead to foot ulceration and amputations. While experimental analyses are limited solely to measurements of interfacial variables, three-dimensional (3D) patient specific finite element models (FEMs) of the foot can provide both the interfacial pressures and insight into internal stresses and strains tolerated by the plantar tissue . FEMs al2) while the other ten did not .Foot biomechanical analysis was carried out as in on 16 diIn order to obtain the internal stresses and the simulated plantar pressures Figure , a recenK-means and hierarchical cluster analysis were performed as in with simThe hierarchical method (Ward\u2019s linkage) which led to the definition of three clusters Table gave theA longer follow up is needed in order to verify whether the neuropathic subjects in cluster 2 and 3 will develop ulcers. A larger dataset is needed to further validate this methodology. Besides these limitations, results showed that combined FEMS and cluster analysis allowed to infer useful informations on the risk of ulceration even five years prior to the wound evolution."} +{"text": "In the original article on page 4, there is an error in the following sentence:\u201c[\u2026] Liver sinusoidal endothelial cells are efficient scavenger cells strategically located in the sinusoids and able to clear low-density lipoprotein (LDL) and capture particulate antigens and immune complexes circulating via the blood and deliver them to hepatocytes and capture small particles (<200 nm) circulating via the blood (Sorensen et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "FBN1 during adipogenesis: relevance to the lipodystrophy phenotype in Marfan syndrome and related conditions\u201d FBN1, the gene encoding the extracellular matrix protein fibrillin-1, during adipogenesis in vitro and in relation to adipose tissue in vivo. The encoded protein has recently been shown to produce a short glucogenic peptide hormone, FBN1 and coexpressed genes were examined in mouse strains and in human cells undergoing adipogenesis. The data show the genes that were coexpressed with FBN1, including genes coding for other connective tissue proteins and the proteases that modify them and for the transcription factors that control their expression. Data analysed were derived from datasets available in the public domain and the analysis highlights the utility of such datasets for ongoing analysis and hence reduction in the use of experimental animals.This article contains data related to the research article entitled \u201cExpression of Specifications TableValue of the data\u2022 Adipogenesis involves the downregulation of generic mesenchymal extracellular matrix (ECM) genes and upregulation of those genes encoding proteins specific to adipose tissue. The data provide a comprehensive list of the genes whose expression is altered during adipogenesis, which will assist in finding gene networks that are up- and downregulated during this process.Fbn1 mRNA varies between strains and the data present a list of genes whose expression is correlated with that of Fbn1 in vivo (in mice). These data provide insight into the function of fibrillin-1 in adipogenesis and can be used also to determine the appropriate mouse strains for further experiments on obesity.\u2022 The mouse data focus on fibrillin-1, the precursor of a newly described glucogenic hormone. In the mouse, \u2022 The data also show how transcription factors are altered during the process of adipogenesis in human cells, which allows researchers to determine the regulatory molecules that are likely to control expression of key genes.in vivo data from humans and other animals.\u2022 These data will be useful in determining key genes downregulated during adipogenesis and can be compared with other experiments and 1Fbn1 in different mouse strains. The second list shows all the clusters derived by BioLayout Express3D for the differentiation of mesenchymal stem cells to adipocytes. Each cluster represents a different pattern of expression, which is described in the table. The patterns show a transition from generalised mesenchymal extracellular matrix to a specialised adipose extracellular matrix, with high expression of mitochondrial and lipid processing genes by the end of the time course. The third list shows the clusters of transcription factors derived from the same experiment. A similar transition in transcription factor expression was observed as adipogenesis progressed.The main data consist of gene lists. The first list contains genes whose expression was correlated with that of 21.Fbn1. A high correlation coefficient indicates that the gene had a very similar expression pattern, that is it was high in epididymal fat of mice where expression of Fbn1 was also high.Mouse gene expression data were obtained as described in 2.Express3DFBN1 is located in the centre of Cluster 06 (pink). Histograms show expression patterns of these nodes. Human gene expression during the transition from mesenchymal stem cells to adipocytes in culture was obtained from a publicly available time course of adipogenesis available from the FANTOM5 website, as described in 3.A separate file containing gene based transcription factor expression levels was downloaded from the FANTOM5 website for clustering of transcription factor expression patterns. A Pearson correlation coefficient of 0.62 with an MCL inflation value of 2.2 was used to cluster the transcription factors. This ensured that all 1380 available transcription factors were included in the analysis. There were 73 clusters with four or more nodes and 209 genes whose expression pattern did not cluster with at least 3 other genes."} +{"text": "Rehabilitating atrophied mandible with two-implant supported denture is a common treatment modality for implant retained removable overdenture in mandible. This paper aims to design a treatment modality where single implant reinforced overdenture is fabricated for a severely atrophied mandibular ridge with early loading protocol. Results of studies have shown that a single implant mandibular overdenture significantly increases the satisfaction and quality of life of patients with edentulism. Midline fracture of the prosthesis is the most common complication related to single implant and two-implant retained mandibular overdentures. To manage such complication, a thin metal mesh is used to reinforce the overdenture and also to make the prostheses lighter and cost effective as compared to conventional cast metal framework. Edentulism is a chronic condition and therapy is palliative, aimed to improve function and quality of life . AccordiA single implant supported mandibular overdenture significantly increases the satisfaction and quality of life of patients with edentulism . StudiesThe aim of this study is to present the fabrication of mandibular implant overdenture by using single dental implant and early loading protocol.A 50-year-old female patient visited our Dental College and Hospital with a chief complaint of loose, ill-fitting, and broken mandibular denture. She was wearing conventional maxillary and mandibular denture for the past 10 years. Clinical examination revealed a highly resorbed mandibular alveolar bone, which was later confirmed with an orthopantomograph. Radiographic examination showed that mandibular bone was atrophic and 10\u2009mm of bone height was there, between the mental foramens for implant placement.Amongst the various treatment alternatives suggested to the patient were the conventional complete dentures with option of implant supported removable overdenture with varying number of implants. Depending on the patient's expectation, cost consideration, and diagnostic information, the treatment chosen was metal mesh-reinforced upper and lower single implant with locator attachment.One root form implant was placed into the parasymphyseal region of mandibular alveolar bone perpendicular to occlusal plane, after anaesthetizing the region with the local anesthetic agent , and a mid crestal incision was made with relieving incision and the mucosa was reflected and the selected implant was placed after preparing the osteotomy as prescribed by the manufacturer. The implant achieved an insertion torque of 35\u2009Ncm. The reflected flap was later sutured using vicryl suture. A postoperative radiograph was taken to confirm the position of the implant placement . Postope(1) After 6 weeks of healing, preliminary impression was made with irreversible hydrocolloid using rim lock perforated edentulous trays (ADA specification number 87), and the primary cast was poured with high strength dental stone (Type III).(2) Over the primary casts, wax spacers were adapted, and custom trays were fabricated using self-cure acrylic resin (ADA specification number 139).(3) Custom trays were border-moulded with addition silicone and a pick up impression using closed tray technique was made.(4) Locator implant analog was attached to the impression coping and secondary impression was poured with high strength dental stone (Type III).(5) Resin record bases were fabricated with the transfer coping as a guide for accurate position of locator housing in the final denture base.(6) Wax occlusal rims (modelling wax) were fabricated to average dimension, and jaw relation was recorded.(7) Bilateral occlusion was achieved during teeth arrangement.(8) Assessment of the trial dentures was done clinically. Aesthetics were accepted by the patients.(9) Trial dentures were waxed up and flasking and dewaxing were carried out in the same fashion.(10) Additional retentive grooves were given on the acrylic teeth (ADA specification number 15) after dewaxing.(11) Metal mesh was adapted on the secondary casts after dewaxing procedure, and three drops of self-cure acrylic resin were used as stops and applied to the model .(12) The reinforced mesh was positioned and the resin is allowed to harden as long as the resin has a highly viscous consistency. If reinforcing mesh does not adhere to the model prior to pressing, in that case a cyanoacrylate adhesive can be used, and stops created a 0.5 to 1\u2009mm space between mesh and tissue surface which helped the heat cure resin to flow through the pores and fill the space which makes mesh completely embedded inside the denture resin.(13) After refining the contour, it was packed and processed with heat cure polymerized resin .(14) The dentures were then finished and polished.(15) The yellow transfer coping was still present in the denture which was trimmed and the final locator female housing was picked up in the denture from that position with the help of self-cure acrylic resin and patient was instructed to bite in centric relation.(16) The black nylon processing ring from the male housing was removed with an appropriate tool and blue dual retention locator male processing ring was inserted as per patient's expectation of amount of retention required .(17) Posttreatment therapy included 24\u2009hrs, 1 week, and 6 weeks of evaluation involving evaluation of occlusion, oral hygiene, and comfort .(18) No posttreatment complications were seen and patient was followed up every six months for 2 years.The two-implant supported overdenture has been a very popular treatment option and has been widely accepted . Recent Within the limitations of this study, it appears that early loaded single implant overdenture reinforced with metal mesh is reliable treatment option in prosthetically maladaptive edentulous patients and patients for whom cost is a major issue of concern; it can provide a beneficial outlay over a 2-year observation period."} +{"text": "One behavioral paradigm for investigating decision making in relation to an earlier reference is the delayed motion direction discrimination task (DMD) [clockwise (CW) or anticlockwise (ACW) rotated in relation to the reference direction . In thisn Figure . AlthougCW (or ACW) rotated with respect to the reference direction and the latter guarantees the feasibility of the network under variable references. The simulations demonstrate that the proposed network is indeed capable of solving the DMD task a"} +{"text": "In vivo Cardiac Diffusion Tensor Imaging (cDTI) offers the potential to calculate the mean intravoxel myocyte helical angle (HA) and assess the degree of average myocyte organisation with fractional anisotropy (FA). However it is not known how these parameters compare between different phases of the cardiac cycle.We recruited 46 healthy volunteers for cDTI at 3T. T-3mm2/s; p < 0.001).Two of the original 46 volunteers were excluded due to ECG irregularities. Data from one further volunteer was incomplete and therefore excluded from the final analysis. Results from the remaining 43 volunteers are in table The MD measurement with this sequence is expected to be independent of the phase at which it is sampled. Our finding of a significant difference between systole and diastole may therefore be as a consequence of strain effects which have been reported to distort the diffusion tensor when acquired out with the cardiac 'sweet spot'. The finNIHR cardiovascular BRU of Royal Brompton Hospital & Imperial College."} +{"text": "Genetic predisposition to rheumatoid arthritis related to the presence of specific polymorphic HLA sequences has been frequently reported ,2. HLA cIn order to understand the influence of variation in HLA DRB genes on rheumatoid arthritis sequence comparison of 21 allelic variants of HLA DRB gene was carried out.Although a lot of variation was observed in the 5\u2019 ends, almost all sequences showed alignment scores of above 200 for 30-40% of the sequence towards the 3\u2019 end. High levels of variations were however observed in two alleles; HLA-DRB1- 1318 and HLA-B*5904. Both these alleles have been recently reported as novel variants of HLA [Our results strongly support the shared epitope hypothesis presenting an explanation for the susceptibility to rheumatoid arthritis. Yet considering the length of similar sequence at the 3\u2019 end and the hyper variable region at the 5\u2019 end, we conclude the hypothesis may not completely explain the course of disease severity and emphasize the need to develop superior biomarkers to predict the course of the disease."} +{"text": "Myocarditis is a common inflammation of the myocardium with variable symptoms, which is in daily clinical routine quite difficult to diagnose. Cardiac magnetic resonance imaging assumes an increasingly important role in the diagnosis of myocarditis by their exact functional analysis and the possibility of representation of tissue changes. The aim of this clinical trial consists in the examination of the validity of cardiac biomarkers and cardiac function parameters in the context of magnetic resonance T2 signal intensity in myocarditis.This retrospective study includes the collection of data from 39 patients (n = 39) with a confirmed myocarditis by magnetic resonance imaging (MRI). In addition, next to the main criterion of radiologically diagnosed myocarditis, elevated cardiac biomarkers (troponin or creatine kinase), increased CRP or increased NT-proBNP were regarded as an inclusion criterion.The maximum deflection of cardiac biomarkers showed a significant correlation with the T2 relaxation times in patients with myocarditis in the acute stage . The correlations between myocardial functional parameters and T2 relaxation times missed the statistical correlation level.In summary, the obtained results show that calculated T2 relaxation times in MRI are directly related to the biochemical severity of myocarditis. T2-mapping in MRI represents a stable method of detection of myocardial edema in myocarditis.Nothing to declare."} +{"text": "PLOS Medicine editorial team would like to warmly thank all those individuals who participated in the peer review process this past year at PLOS Medicine. During 2015 over 630 reviewers from around the world helped evaluate the 144 articles we published, and offered valuable input and advice for those authors whose papers we did not publish.The Public Library of Science (PLOS) and the PLOS Medicine authors, and for helping us to publish a highly read and highly regarded open access medical journal.The names of our 2015 reviewers are listed in S1 Reviewer List(PDF)Click here for additional data file."} +{"text": "To the editors of the Canadian Journal of Gastroenterology and Hepatology, We read with greatinterest the article \u201cYield of Screening Colonoscopy in Renal TransplantCandidates\u201d by AlAmmel and colleagues. This study about the results of screeningcolonoscopy in a cohort of 169 renal transplant candidates over 50 years old showed aprevalence of colorectal polyps of 24%, 4 advanced adenomas, and 1 adenocarcinoma. Theauthors conclude that colorectal cancer screening is indicated in renal transplant candidatesover 50 years old and that the choice of the screening test should be individualized based onpatient's preference and risk benefit ratio [We previously published a retrospective study about the results of pretransplantcolonoscopies in renal transplant recipients from January 2007 to December 2009 at the CentreHospitalier de l'Universit\u00e9 de Montr\u00e9al [Our results are in accordance with the results from AlAmmel and colleagues, reinforcing theneed of colorectal cancer screening among renal transplant candidates, even if aged less than50 years. It has indeed been proven that the incidence of colorectal cancer is higher amongsolid organ recipients as soon as two years after transplant, notably in individuals less than50 years old , 4. The"} +{"text": "The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa. Published 8 January 2015TGF-\u03b2 was incorrectly spelt out as \u2018tumor growth factor beta\u2019 both in the title and in the Digest. The correct title is: The transforming growth factor beta signaling pathway is critical for the formation of CD4 T follicular helper cells and isotype-switched antibody responses in the lung mucosa. The title and Digest have been corrected accordingly."} +{"text": "Anterior uveitis is a well-known threatening comorbid condition of JIA and affects around 10 to 20 % of the patients depending on JIA subtype. A large proportion of children with JIA develop uveitis in the first year of disease and 73 to 90% do so after four years of the arthritis onset. Uveitis can progress into the adulthood and usually occur as \u201cwhite uveitis\u201d which is not associated with symptoms like redness and pain as opposed to JIA related to the enthesitis subtype that is symptomatic. Factors associated to lower uveitis remission rate are: JIA diagnosis, findings of 1+ or more vitreous cells at presentation and initial visual acuity of 20/200 or worse. The Standardization of Uveitis Nomenclature (SUN) Group took the first step to define outcome measures for uveitis, but it was established just for adults. The Multinational Interdisciplinary Working Group for Uveitis in Childhood (MIWGUC) proposed outcome measures for JIA associated uveitis incorporating the Standardization of Uveitis Nomenclature (SUN) criteria in 2011.None declared."} +{"text": "Pediatric acute liver failure (PALF) is an aggressive clinical syndrome in which a previously healthy child rapidly loses hepatic function and can become critically ill within days ,2. The mThe goal of the present study was to investigate the prognostic accuracy of the commonly used mortality prediction score known as pediatric index of mortality 2 (PIM2). PIM2 uses 10 variables on admission to the pediatric intensive care unit (PICU) to assess risk of mortality and in the UK is used as a measure of the quality of service. All children who were admitted to the PICU at King\u2019s College Hospital between 2003 and 2013 and who had PALF as defined by the PALF study group [One hundred and three children were included. Forty-three received a liver transplant; of these, five died . Of the 60 who were not transplanted, 20 died . A receiver operating characteristic (ROC) curve was developed by using the study population and their outcomes. An area under the curve (AUC) of more than 0.75 was considered clinically useful [Thus, we conclude that PIM2 is not fit for use in PALF as it neither predicts mortality nor identifies children in need of liver transplantation. It may also bias the quality assessment of PICUs in liver centers. As such, the quest for a better predictive score in PALF continues."} +{"text": "A method for Red Blood Corpuscles (RBCs) counting has been developed using RBCs light microscopic images and Matlab algorithm. The Dataset consists of Red Blood Corpuscles (RBCs) images and there RBCs segmented images. A detailed description using flow chart is given in order to show how to produce RBCs mask. The RBCs mask was used to count the number of RBCs in the blood smear image. The blood smear has been illuminated by 50\u00a0W halogen lamp and the image focused by normal microscopic focusing system in order to capture high resolution image of the stained blood smear.The acquired images subjected to segmentation process as a part of the date reduction stage involves the partitioning of the image plane into meaningful parts"} +{"text": "The worldwide depletion of major fish stocks through intensive industrial fishing is thought to have profoundly altered the trophic structure of marine ecosystems. Here we assess changes in the trophic structure of the English Channel marine ecosystem using a 90-year time-series (1920\u20132010) of commercial fishery landings. Our analysis was based on estimates of the mean trophic level (mTL) of annual landings and the Fishing-in-Balance index (FiB). Food webs of the Channel ecosystem have been altered, as shown by a significant decline in the mTL of fishery landings whilst increases in the FiB index suggest increased fishing effort and fishery expansion. Large, high trophic level species have been increasingly replaced by smaller, low trophic level fish and invertebrates . Declining trophic levels in fisheries catches have occurred worldwide, with fish catches progressively being replaced by invertebrates. We argue that a network of fisheries closures would help rebalance the trophic status of the Channel and allow regeneration of marine ecosystems. The field of historical marine ecology has introduced a different perspective to our understanding of marine ecosystems; it has revealed that overfishing has had profound effects on coastal ecosystems worldwide for centuries Fisheries typically remove top predators first and as a result their direct competitors and prey are able to prosper, affecting the overall productivity and ecological stability of the ecosystem In the present study, we used a 90-year dataset of international catch statistics from the English Channel marine ecosystem, a region that has numerous important fishing ports and where finfish landings now make up a far smaller proportion of the catch than they did historically . This da2 and narrows to ca 30 km wide at its easternmost point; the Channel is relatively shallow, with an average depth of around 100 m in the west gradually decreasing to 40 m depth in the east The English Channel (\u2018La Manche\u2019 in French) is a narrow strait between England and France . It coveth century fishing effort increased substantially due to the advent of motorised fishing vessels. Monitoring of fish populations has revealed reductions in mean length and length at maturity of demersal communities Squatina squatina, Squatinidae) and common skate which is now commercially extinct in the Channel; whereas small, commercially undesirable species such as the small-spotted catshark have increased in abundance Today the UK and France account for 98% of the total landings from the Channel jTL is the \u2018non-integer\u2019 trophic level of prey j and ijDC is the fraction of j in the diet of iy:iyY is the catch of species i in year y, and iTL is defined as in The trophic level (TL) of an organism denotes its position within a foodweb and it can be estimated from diet observations, nitrogen isotope measurements or models of trophic fluxes from the equation:Additionally, Will maintain a value of zero when a decrease or increase in TL is accompanied by an ecologically balanced increase or decrease in catches;Will increase (>0) if bottom-up effects have occurred or if the fishery has expanded beyond its traditional ground;Will decrease (<0) if the fishery has contracted geographically or if it has taken so much biological productivity from the ecosystem that has impaired its natural functioning.y by:yY is the catch at year y; yTL is the trophic level of the catch in year y; 0Y and 0TL are the catch and trophic level of the catch at the beginning of the series analysed and TE is the energy transfer efficiency between TL estimated to be 0.1 (\u200a=\u200a10%) in several marine ecosystem studies It is defined for any year Catch statistics for the English Channel were obtained from ICES There was a clear increase in landings from the English Channel between 1920 and 2010 . These iThe mTL of fish landed from the English Channel has declined from 4.0 in 1920 to 3.0 in 2010 and therWe decided to use the concept of \u2018Granger causality\u2019 Galeorhinus galeus, Triakidae) landings declining considerably after the 1980s while small-spotted catshark landings increasing significantly , ling and European hake . Landingcciidae) .Cancer pagurus, Cancridae), European lobster and Great Atlantic scallop have increased considerably .It is now well known that fishing removed populations of species that were common around Britain and Ireland a century ago. Large and long-lived species of elasmobranch, such as the common skate and the angel shark, have proved to be particularly vulnerable as they have low fecundity rates and are slow to mature Conger conger, Congridae) and monk fish , have declined since the 1960s as also documented in the Celtic Sea by When fishing pressure eased off during World Wars I and II stocks of demersal fish such as \u2018cod, hake and haddock\u2019 built up around the UK but recent decades of overfishing have brought these stocks to historic lows The removal of high trophic level species can have a \u2018cascading effect\u2019 on lower trophic levels Socioeconomic factors are also known to influence the composition of landings. These include consumers\u2019 income and preferences, catching restrictions, fuel prices and technological innovations. These factors are in turn reflected in the price placed on a certain product. Generally as a resource become scarcer its price increases. In the Celtic Sea and in Portugal high trophic level species have become more expensive than low trophic level ones The recent recognition of a global fishery crisis has induced many governments and fishery scientists to question current strategies used in fisheries management. Since the 1950s, the concept of Maximum Sustainable Yield (MSY) and annual catch allowances has been at the foundation of all fisheries management There have been moves to improve the ecological status of the English Channel. In 2012, the UK Government approved 31 of 127 conservation areas recommended by an extensive stakeholder consultation, representing 3.7% of the marine area under English jurisdiction The community-level changes observed in the English Channel reflect those that have occurred in other heavily-fished systems around Europe and the rest of the world Table S1Estimated mean trophic level (TL) for aggregated taxa.(DOCX)Click here for additional data file.Table S2UK Fisheries Statistics list of species by group.(DOCX)Click here for additional data file.Table S3List of species arranged into ISCAAP groups.(DOCX)Click here for additional data file.Supporting Information S1Detrended mTL against Detrended FiB with statistical tests.(DOCX)Click here for additional data file."} +{"text": "In recent years, our knowledge surrounding mammalian mitochondrial DNA (mtDNA) damage and repair has increased significantly. Greater insights into the factors that govern mtDNA repair are being elucidated, thus contributing to an increase in our understanding year on year. In this short review two enzymes, tyrosyl-DNA-phosphodiesterase 1 (TDP1) and aprataxin (APTX), involved in mitochondrial single strand break repair (SSBR) are discussed. The background into the identification of these enzymes in mtDNA repair is communicated with further deliberation into some of the specifics relating to the import of these enzymes into the mitochondrion. With the discovery of these enzymes in mitochondria comes the probability that other mechanisms underlying mtDNA repair are yet to be fully understood, suggesting there is much left to discover when shaping our understanding of this relatively undefined subject. These organelles have retained their own genome (mtDNA) in most species, which is present in multiple copies, is often maternally inherited, and in man (the focus of this review) is approximately 16.5\u00a0kb Initial investigations of mtDNA repair reported the absence of pyrimidine dimer resolution following ultra violet (UV) irradiation of mammalian cells, which may have led to the general assumption within the field that mitochondria did not possess any DNA repair capabilities 2The process of SSBR is required in response to DNA damage caused by a multitude of sources with the most common source being reactive oxygen species (ROS) DNA cleavage is not only initiated by ROS-induced damage. For example the mitochondrial topoisomerase (TOP1MT) ordinarily forms a transient nick in mtDNA which is thought to have a role in regulating mtDNA replication APTX and TDP1 have been reported to cause both ataxia with oculomotor apraxia type 1 TDP1) Failure to repair these lesions could have implications in genome stability as SSBs may progress to double strand breaks (DSBs), which could cause DNA instability and/or impaired replication and gene expression from the mitochondrial genome 3Despite any debate over whether defective SSBR in the nucleus or mitochondrion is the primary cause of AOA1 and SCAN1, the identification of APTX and TDP1 as factors also found in mitochondria predicts novel members of the mtDNA repair network. One intriguing aspect surrounding TDP1 activity in mitochondria is how it is imported into the mitochondrion given that no N-terminal presequence is apparent, and there is little evidence to suggest a mitochondrial-specific isoform.in silico analyses identified more than 150 putative mitochondrial proteins with similar sequences; most of which had not yet been identified in mitochondria Unlike TDP1, an alternatively-spliced isoform of APTX was found to contain a 14 amino acid (14-aa) N-terminal sequence with a high relative potential of being a mitochondrial targeting sequence (MTS) Year on year, novel mitochondrial proteins are identified that have a variety of functions, some of which include those implicated in mtDNA repair/maintenance. The recent publications regarding the alternative translation initiation sites suggest\u00a0that prediction of mitochondrial localisation for a protein maybe more complex than thought 4When reflecting on the mechanisms of mtDNA repair; is it likely that all the major players have been identified? Almost certainly no, but to what extent does mtDNA repair, or absence of it, impact in disease and ageing? One consideration when pursuing the study of the involvement of TDP1 and APTX in mitochondria was that mutations in the genes encoding both these proteins are linked to diseases that include ataxia In\u00a0vitro analyses into the ability of the mitochondrial DNA polymerase (polymerase \u03b3) indicated that the bypass of UV-induced cyclobutane thymine dimers was possible Another point for consideration with reference to mtDNA maintenance is the capability of the organelle to tolerate damage to its genome without necessarily requiring the active repair of the DNA itself. One final point with regard to the discovery of novel mtDNA repair/tolerance mechanisms in mitochondria is to echo some of the comments made by our colleagues in relation to a comparative long/short range PCR based method to measure mtDNA damage"} +{"text": "To assess the utility of Mangled Extremity Severity Score in the injured lower limb.This study was done in the Accident & Emergency Centre of a tertiary hospital in India.This is a descriptive study assessing the validity of the MESS score in predicting limb salvage.The study included patients older than 18 years with open injuries/crush injuries of the lower extremities up to the level of the ankle (Gustilo and Anderson type III B / III C injuries).Patients were divided into those who presented within 6 hours and those after 6 hours of injury. The final study consisted of 50 patients with 51 lower limb injuries. The study was conducted over a span of 18 months.\u2022 The MESS mean score in the salvaged group were 4.36 and in the amputated group were 8.42.\u2022 Thus the sensitivity was 75%, specificity 92.31%, positive predictive value 75% and negative predictive value 92.31%.\u2022 After calculation of the receiver operator characteristic (ROC) curves and calculation of area under the curves (AUC) as 0.935, a score of 7 or greater predicted amputation with the highest sensitivity and specificity.As this is a prospective study in a limited time frame, the long term follow up is not known. It is also not known from our study nor from other previous studies whether the MESS distinguishes between functional and nonfunctional salvage.A total score of \u22657 is significantly associated with amputation both in the primary amputation group as well as in the combined primary and delayed amputation group.Thus the utility of MESS as a tool in assessing limb salvage following open and crush injuries to the lower extremity has been validated."} +{"text": "Ultrasound is already a major technique to study focal liver lesions. Particularly since the arrival of the ultrasound contrast agents which allows a sensitivity greater than 90% for characterizing incidentally detected focal liver lesions in adults in whom an unenhanced ultrasound scan is inconclusive or with inconclusive MRI/CT. However the role of ultrasound will probably rise even more in the near future because of rapid software and hardware developments.Future prospects are:1) The development of image fusion and navigation technology combining US and CT or MRI to improve the possibility to perform difficult percutaneous ultrasound guided biopsy or thermo ablation procedures with a higher rate of success.2) The development of 3D imaging technology in ultrasound to improve liver tumour response assessment particularly by means of a combination with ultrasound contrast agents. The challenge will be to be able to reach a real time 3D imaging through matrix technologies also capable of handling contrast agents enhanced modes in order to get enhancement curves of the whole tumour with a adapted temporal resolution.3) The development of targeted imaging through targeted microbubbles against a variety of targets located on the vessel wall. Indeed contrast enhanced ultrasound is probably the second more sensitive technique to the presence of a small amount of targeted contrast compound after PET. Many feasibility studies on animal models have already been conducted and currently a hypo allergenic targeted microbubble that includes in its membrane a heterodimer peptide having a high affinity to VEGFR2 (BR55) is being tested in humans.Beside CT and MRI, US must be also considered as a major technique that has much to offer particularly in liver imaging and the near future of ultrasound is undoubtedly exciting."} +{"text": "In the case report titled \u201cHiatal Hernia Repair with Gore Bio-A Tissue Reinforcement: Our Experience,\u201d the corrThe first and last names of the authors were reversed. The correct names in order have been shown in the front matter of the paper."} +{"text": "The present study was undertaken to reveal the effects of chronic arsenic exposure on mitochondrial functions and oxidative stress in male Wister rats. Chronic arsenic exposure resulted in decrease in the activities of the mitochondrial complexes. There was increased generation of ROS followed by decrease in MnSOD activity. The generation of oxidative stress was associated with increased protein oxidation and lipid peroxidation in rat brain as evident by FTIR spectra. The RT-PCR analysis of NRF 1, NRF 2 and PGC 1\u03b1 revealed decrease in gene expression suggesting decreased biogenesis following chronic exposure in rat brain. Thus, the findings of the present study reveal that arsenic induced decrease in mitochondrial biogenesis may be responsible for the decreased metabolic response that may be further involved in the generation of oxidative stress and neurodegeneration in rat brain."} +{"text": "The prediction of sites and products of metabolism in xenobiotic compounds is key to the development of new chemical entities, where screening potential metabolites for toxicity or unwanted side-effects is of crucial importance. In this work 2D topological fingerprints are used to encode atomic sites and three probabilistic machine learning methods are applied: Parzen-Rosenblatt Window (PRW), Naive Bayesian (NB) and a novel approach called RASCAL (Random Attribute Subsampling Classification ALgorithm). These are implemented by randomly subsampling descriptor space to alleviate the problem often suffered by data mining methods of having to exactly match fingerprints, and in the case of PRW by measuring a distance between feature vectors rather than exact matching. The classifiers have been implemented in CUDA/C++ to exploit the parallel architecture of graphical processing units (GPUs) and is freely available in a public repository.It is shown that for PRW a SoM (Site of Metabolism) is identified in the top two predictions for 85%, 91% and 88% of the CYP 3A4, 2D6 and 2C9 data sets respectively, with RASCAL giving similar performance of 83%, 91% and 88%, respectively. These results put PRW and RASCAL performance ahead of NB which gave a much lower classification performance of 51%, 73% and 74%, respectively.2D topological fingerprints calculated to a bond depth of 4-6 contain sufficient information to allow the identification of SoMs using classifiers based on relatively small data sets. Thus, the machine learning methods outlined in this paper are conceptually simpler and more efficient than other methods tested and the use of simple topological descriptors derived from 2D structure give results competitive with other approaches using more expensive quantum chemical descriptors. The descriptor space subsampling approach and ensemble methodology allow the methods to be applied to molecules more distant from the training data where data mining would be more likely to fail due to the lack of common fingerprints. The RASCAL algorithm is shown to give equivalent classification performance to PRW but at lower computational expense allowing it to be applied more efficiently in the ensemble scheme. The prediction of sites and products of metabolism for xenobiotic and endogenous compounds is an important avenue of research, playing an influential role in the development and use of pharmaceuticals, cosmetics, nutritional supplements and agrochemicals. Toxicity of metabolites can play a major role in the withdrawal of new drugs or black-box warnings, contributing to the high attrition rates in the development of new chemical entities.The cytochrome P450s (CYPs) are a family of heme-containing enzymes involved in the phase-I metabolism of over 90% of drugs on the market ,2. The CThe most common reactions catalysed by CYPs involve the insertion of a single oxygen into an organic molecule giving rise to C=C epoxidation, aromatic C oxidation, S oxidation and C-H hydroxylation reactions, the last example often leading to N-dealkylation or O-dealkylation if oxidation occurs on a suitable leaving group in an amine or ether moiety.A host of computational approaches to predict SoMs have been developed as an alternative or aid to the resource and time consuming nature of experimental investigation. These approaches can be either ligand-based, where the structures and properties of known substrates or non-substrates are modelled to develop structure-activity relationships, or structure-based, where the structure of the metabolising CYP enzyme and its interactions with ligands are modelled. The reader is referred to the many comprehensive review papers -7 for anMany methods consider reactivity and accessibility factors since a SoM must be sufficiently reactive and also able to come into close proximity to the reactive heme centre. One such example is SMARTCyp , a Java-Other methods take the accessibility consideration further and employ docking techniques to refine the predictions from reactivity approaches. Examples of these methods include IMPACTS , which cIn contrast to these approaches the methods described in this work do not require the explicit modelling of ligand binding or reactivity, but make use of machine learning techniques applied to an appropriate, representative data set. Various machine learning methods have been applied to the problem of SoM metabolism with some of the major contributions summarised below.An example of a data-mining approach is MetaPrint2D , an onliMany methods employing machine learning techniques generate a wide-range of descriptors for each atomic site in the data set often including quantum chemical and electronic descriptors. An example is RegioSelectivity (RS)-predictor ,15 whichAnother study combinesA further method with relThe computational expense of using quantum chemical descriptors is addressed by FAME , a metabA recent publication describeThis paper takes a similar approach using the 2D topological circular fingerprint ,28 of atThe kernelised nature of the PRW and RASCAL algorithms allied with the ensemble approach lends itself to a parallel implementation exploiting the massively parallel processing capability of Graphical Processing Units (GPUs). The computing industry is moving towards a parallel model as the limitations and capabilities of modern semiconductor manufacturing mean that ever increasing performance from a single processor is no longer possible . In receRecent developments in GPU accelerated classification tools include implementations for support vector machines -32, neurIn the Methods section the data sets and descriptors are presented, along with the three probabilistic classifiers and a discussion of the CUDA implementation. In the Results and discussion section the classification performance of the different methods is presented in terms of the Matthews Correlation Coefficient (MCC), area under the ROC curve and the percentage of the data sets where a SoM is identified in the top k positions. The effect of varying the size of the circular fingerprints used to describe atomic sites is investigated and a benchmarking analysis comparing the speed performance of the CUDA implementation on a Tesla C2075 GPU and a GeForce GT640 GPU to reference is presented. The important inferences from this work are presented in the Conclusions section.To emphasize the benefits and novel aspects of this work it is important to point out that the SoM prediction models are built from 2D topological circular fingerprints without the requirement for complex quantum chemical and 3D descriptors. RASCAL combines the classification performance of the PRW with greater computational speed and hence could be applied to other much larger data sets. The data sets employed here are relatively small and show that SoMs can be identified within data sets of the order of 100\u2019s of molecules being of potential interest to pharmaceutical companies with limited data on a specific series of molecules.The machine learning approaches used in this study have been applied to the publicly available CYP 3A4, 2D6 and 2C9 data sets that originate from those initially released in the supporting information of the RS-Predictor paper but furtThe feature vectors used to describe the atomic sites in each molecule are 2D topological circular fingerprints ,28 basedMethods section was assessed for each isoform data set using feature vectors calculated at each of the bond depths ranging from 0-8. These methods have been implemented on an ensemble subsampling methodology, hence as described previously the length of the subsample, q, needs to be optimised. Therefore, for each classification model q was varied from an initial value of 5 to the full number of features L in increments of 5, with the Matthews Correlation Coefficient (MCC) but but,[15]q\u226aL (where q is the subsample length and L is the full length of the feature vector) and in these situations the benefits from using RASCAL are likely to become more compelling.RASCAL gives similar classification performance to PRW but at lower computational expense making it suitable for use on large data sets and particularly for the ensemble schemes outlined in this paper. The speed boost from using RASCAL is likely to become more apparent for classification problems where The suitability of using CUDA/C++ to exploit the parallel capabilities of GPU hardware for classification problems has been demonstrated and it is hoped that the source code will be of use to other researchers in the field. Further enhancements to the implementation could include maximising the use of faster memory , implementing task parallelism using streams and implementing code to run on multiple GPUs, all of which should further improve the speed-up in performance compared to the reference.In summary it has been shown that probabilistic classifiers implemented using randomly selected subclassifiers on an ensemble basis using 2D topological circular fingerprints as descriptors can give strong SoM predictive performance. However, as with all machine learning methods, the models are likely to be most relevant within their domain of applicability and are likely to perform less well against novel molecules that are very different from those in the training set.The authors declare that they have no competing interests.JDT wrote the programs in C++ and CUDA, produced the data sets of circular fingerprints to represent the atomic sites and generated the results; HYM provided the theoretical ideas behind the probabilistic classifiers; MJW provided guidance with the programming and implementation and assistance with optimising the code; JK and RCG provided overall scientific guidance in the development of this work particularly around the use of atomic fingerprint descriptors. All authors read and approved the final manuscript.Topological circular fingerprints for atomic sites in the 3A4 data to a bond depth of 4.Click here for fileTopological circular fingerprints for atomic sites in the 3A4 data to a bond depth of 5.Click here for fileTopological circular fingerprints for atomic sites in the 3A4 data to a bond depth of 6.Click here for fileTopological circular fingerprints for atomic sites in the 2D6 data to a bond depth of 4.Click here for fileTopological circular fingerprints for atomic sites in the 2D6 data to a bond depth of 5.Click here for fileTopological circular fingerprints for atomic sites in the 2D6 data to a bond depth of 6.Click here for fileTopological circular fingerprints for atomic sites in the 2C9 data to a bond depth of 4.Click here for fileTopological circular fingerprints for atomic sites in the 2C9 data to a bond depth of 5.Click here for fileTopological circular fingerprints for atomic sites in the 2C9 data to a bond depth of 6.Click here for fileLigands in the 3A4 data set in mol2 format.Click here for fileLigands in the 2D6 data set in mol2 format.Click here for fileLigands in the 2C9 data set in mol2 format.Click here for file"} +{"text": "Prolapse of the fallopian tube after hysterectomy is a rare but known complication. Cases of prolapse of the fallopian tube through the vaginal vault have been reported after abdominal, vaginal or laparoscopic hysterectomies. This is the first case report to the best of our knowledge on the prolapse of a fallopian tube through an abdominal wound after caesarean section.We report a case of the prolapse of the fimbrial end of a fallopian tube through an abdominal scar after caesarean section mimicking scar endometriosis. A 24-year-old primipara South Asian woman of Punjabi ethnicity presented to our institute with a fleshy mass protruding through her abdominal scar and bleeding from the mass during menstruation for the past 5 months. She underwent a caesarean section 6 months earlier for breech presentation. Her history revealed she had wound dehiscence on the sixth postoperative day. The major portion of her wound healed in 1 month leaving a 2 cm area in the middle of her vertical scar. An abdominal examination revealed a 2\u00d72 cm fleshy mass protruding through the middle part of her infraumbilical abdominal scar. At the time of the surgery we found that the fimbrial end of her left fallopian tube was protruding through her abdominal scar.Awareness of this complication may prevent improper management of wound dehiscence and such complication causing prolonged agony to the patient. Prolapse of the fallopian tube after hysterectomy is a rare but known complication. Cases of prolapse of the fallopian tube through the vaginal vault have been reported after abdominal, vaginal or laparoscopic hysterectomies \u20133. We reA 24-year-old South Asian woman of Punjabi ethnicity presented with fleshy mass protruding through midline vertical abdominal scar and bleeding from the mass during menstruation for the past 5 months. She was primigravida; she underwent a caesarean section 6 months earlier at term gestation for breech presentation in a local hospital. She delivered a normal healthy baby boy and the immediate postpartum period was uneventful. On the sixth postoperative day she noticed serosanguinous discharge from her abdominal wound and wound dehiscence was diagnosed. She was managed conservatively and the wound was left for secondary healing by the attending physician. Her history revealed that she was given antibiotic coverage during this time. The major portion of her wound healed in 1 month leaving a 2 cm area in the middle of her vertical scar. An investigation at the time of her caesarean section revealed that she was anemic (hemoglobin 8 gm %). Peripheral blood film revealed microcytic hypochromic anemia. On admission to our institute she was emaciated, thin built, anemic and her vital signs were normal. An abdominal examination revealed a 2\u00d72 cm fleshy mass protruding through the middle part of her infraumbilical abdominal scar. On per vaginal examination her uterus seemed attached to the anterior abdominal wall at the scar site and with cervical movement the mass was getting retracted into her abdomen. With her history of menstruation through the abdominal wound a provisional diagnosis of scar endometriosis/uterocutaneous fistula was made and ultrasonography (USG) and fistulogram were suggested. USG showed normal uterus and adnexa and fistulogram showed communication with intraperitoneal cavity. A tissue biopsy revealed granuloma. She was planned for excision of the fistula tract and repair. On an operating table methylene blue dye was injected through the wound to mark the fistulous tract and dye was found to be escaping through her vagina confirming communication with uterine cavity. An elliptical incision was made around the fleshy mass and on entering the abdominal cavity, the left side of her uterus was adherent with her anterior abdominal wall at the scar site and the fimbrial end of her left fallopian tube was found to be protruding through the abdominal scar. A probe (dilator) was passed through the tube and diagnosis was confirmed (Fig.\u00a0et al. [Pozzi in 1902 described the first report of postoperative prolapse of fallopian tube after vaginal hysterectomy . Since tet al. did a syet al. ; howeverPrevention of tubal prolapse can be achieved by improving the general condition of the patient and treating anemia and infections during the pregnancy, using a proper technique of wound closure at the time of primary surgery and careful inspection in the case of wound dehiscence for burst abdomen. Awareness of this complication may prevent inadequate treatment of wound dehiscence and such complication causing agony in the patient\u2019s life.Written informed consent was obtained from our patient for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."} +{"text": "In the section Shared Error and Complex Dosimetry Systems for Dose Reconstruction under the subheading \u201cIncorporating multiple realizations of dose into dose-response analysis,\u201d the first sentence of the seventh paragraph incorrectly refers to equation 6 and equation 7. This should instead should refer to Eqs The second sentence in the final paragraph of the Discussion incorrectly refers to equation 6. This should instead refer to The publisher apologizes for these errors. Eqs"} +{"text": "Limited evidence exists on how systematic reviews are used in the design of new trials. A study by Jones (2013) showed that 11 out of 48 applications made no reference to a systematic review. Of the 37 trials referencing a systematic review 20 reported their use in the design of the trial.To replicate and verify Jones' study and explore the reasons why some trials do not refer or use a systematic review. The study also included an updated cohort of NIHR HTA trials to identify any improvements over time.Two cohorts of NIHR HTA randomised controlled trials were included. Cohort I included the same trials as Jones (2006-2008). Cohort II included NIHR HTA trials funded in 2013. Data extraction was undertaken independently by two reviewers and results were presented using descriptive statistics.Justifying the need for new primary research using a systematic review is not always feasible. Our study found nine (19%) and three (9%) trials from cohort I and II respectively where a systematic review was not referenced. Although our findings were similar to Jones, we found all nine trials had a justifiable reason for not referring to a systematic review.The results of this study demonstrate how 85% of NIHR HTA trials use systematic reviews to inform the design and planning of a new trial. Systematic reviews play an important role in the development of clinical trials and the implications of this will be discussed."} +{"text": "Dear SirPure esophageal atresia (EA) constitutes around 6-7% of all congenital anomalies of oesophagus and is associated with a long gap between the upper and lower ends which make primary repair almost impossible [1]. But in literature there are isolated reports where the two esophageal ends were joined either by a membrane or when the upper pouch is longer than the usual .A (2.4 Kg) female full-term baby admitted with respiratory distress and frothing from the mouth since birth. The infantogram with the nasogastric tube in situ revealed the position of the tube was at T7-T8 vertebral level and there was no gas in the abdomen . There was no other associated anomaly. At operation, the upper and lower pouches were almost in continuity but there was a 1cm long atretic segment between them, without tracheo-esophageal fistula . The atretic segment was excised and primary anastomosis was done between the two ends with nasogastric tube in place. The patient was put on ventilator in postoperative period because of the pneumonitis. The chest tube was removed on 5th day and the patient was weaned off the ventilator; the nasogastric tube was removed on 10th day. The histopathological examination of atretic segment show fibromuscular layer without mucosa. Kluth has described ten types of EA in his atlas; pure atresia is classified as type II in which the proximal and distal segments are atretic without a tracheo-esophageal fistula [4]. In this condition the gap between two pouches makes primary anastomosis impossible and management options remain either delayed primary repair or oesophageal substitution. However variation to this typical pure EA is also reported [2]. Loosbroek et al described a new type of pure EA that included double membranes with 2cm gap between them [3]. The present case resembles that of pure atresia reported by Lall [2] as well as by Loosbroek [3]; where the two ends were joined together by a membranous structure but was managed by thoracotomy and primary repair. At times it is challenging to make a preoperative differentiation between a pure EA or a blocked distal fistula [5]. Preoperative endoscopic examination or a contrast study via gastrostomy ascertains the length of distal esophagus as well as the status of fistula [5].Source of Support: NilConflict of Interest: None"} +{"text": "Rationale. The development of IVF techniques has diminished the importance of tubal infertility but recent discoveries shed a new light on reproductive tubal surgery prior to any IVF cycle.Objective. To adapt current state of the art recommendations concerning tubal factor infertility to actual possibilities in Romanian healthcare system and to grow the awareness of fellow fertility specialists and general practitioners to the improved outcomes of novel management and treatment modalities.Methods and results. 67 free full text articles centered on the subject of management in tubal infertility were identified in international databases. Four articles described general diagnosis using data from medical history, 21 works approached the diagnosis through hysterosalpingography, 14 papers introduced the use of different sonographic procedures, 8 files analyzed the importance of exploratory laparoscopy and 20 articles reviewed different treatment modalities.Discussions. Current data show that active implementation of the large scale use of tubal surgery prior to any IVF cycle will reduce up to 30% the costs associated with obtaining a viable pregnancy in cases with tubal factor sterility. As seen in many guidelines the gold standard end point of care when speaking about infertility are the IVF techniques, but these are still expensive and present low accessibility in many countries and needless to mention that in some instances there is the barrier of culture and religion that needs to be broken [2]. Main causes of tubal factor infertility are: tubal obstruction or occlusion [3], endosalpingeal destruction [4], periadnexal adhesions [5], pelvic inflammatory disease [6], endometriosis [7], ectopic pregnancy [8], abdomino-pelvic surgery, use of intrauterine devices, induced surgical abortion [9], etc.The problem of fertility is growing nowadays not only in western countries but also in other areas as even in developing countries the couples postpone childbirth well over the age of 30 in order to focus on their careers and financial stability .In case of suspected tubal infertility women who are not known to have comorbidities should be offered hysterosalpingography as initial screening test; alternatively hysterosalpingography should be replaced with hysterosalpingo-contrast-ultrasonography if available and in case of associated comorbidities the patient should be subjected to laparoscopic chromopertubation [11]. Tubal spasm is the culprit for lower accuracy of this diagnostic imaging technique but with the use of intravenous scopalamin and rotation of the patient it has been reduced to a minimum [12]. HSG has two contraindications: PID and pregnancy , and a history of allergic conditions requires premedication with methylprednisolone 32mg for 12h and 2h in advance [13]. Moreover HSG with an oil-based contrast media has been proven to have a somewhat therapeutic role through flushing of tubal debris [14].Hysterosalpingography is the fluoroscopic visualization of the uterine cavity and fallopian tubes by injection of a radio-opaque contrast media and is credited with 84% sensitivity and 74.5% specificity [15]. Hysterosalpingo-contrast sonography evolved from using a negative contrast which is saline water to a positive contrast agent that is microbubble agent and from 2D to 3D and even 4D imaging [16]. HyCoSy is advantageous as patients exhibit a better pain tolerance, avoidance of iodinated contrast medium and preventing the use of ionizing radiation [17].Sonohysterography and hysterosalpingo-contrast sonography are credited with 84.6% sensitivity and 99.7% specificity in detecting hydrosalpinx [Fig. 1) [18]. Through the injection of diluted indigo carmine into the uterine cavity with simultaneous laparoscopy in order to visualize the tubal fill and spill into the abdomen [19]. The disadvantages of this procedure are: expensive, invasive and requires anesthesia [20].Unfortunately laparoscopic chromopertubation remains the gold standard in evaluating the tubal sterility (21].For proximal tubal disease other macroscopic anastomosis surgeries have been abandoned in favor of selective salingography and transcervical tubal cannulation. Although observational studies have credited this procedure with up to 85% success, there are still no RCTs compared with no active treatment, and the rate of ectopic pregnancy was of 9% and the risk of tubal perforation of 2% [22].In cases with distal tubal disease is offered the option of a neosalpingostomy which can be technically upgraded till the level of laparoscopy with CO2 or yttrium aluminum garnet laser used for performing a cruciate incision at the distal end of the tube [23].There are still some unclear aspects concerning the association between hydrosalpinx and tubal sterility but the introduction of salpingectomy prior to IVF procedures has improved overall outcome of IVF procedures and thus proved 2.4 fold increase in the delivery rate [24].Any diagnostic laparoscopy should be immediately followed in the same session by the lysis of adhesions and that this simple procedure is followed by a 60% conception rate in the following 6 to 12 months [25].A distinct group of patients with tubal infertility is that requiring sterilization reversal through tubal reanastomosis. It has been proven that the outcome of such a procedure is foreseen by the initial sterilization method used thus laparoscopically sterilized patients had 50% chances of conception as laparoscopic sterilization requires minimal injury to the tube [Reproductive surgery has the objective of restoring the natural procreation in couples with tubal factor infertility. At worldwide level, there is still need for a randomized control trial comparing the benefits and costs for IVF versus reproductive tubal surgery. Unfortunately, in Romania the expertise chain needed for a complete fertility clinic is broken at the level of diagnosis through sonography as in the evidence of the Romanian Society for Ultrasonography in Medicine and Biology there are registered only 3 healthcare specialists able to perform hysterosalpingo-contrast sonography. Given the fact that nowadays a single IVF cycle costs around 2600 U.S. $ and the estimated cost of a reproductive tubal surgery prior to IVF is of 1000 U.S. $ and that it was established that reproductive tubal surgery can half the number of IVF cycles needed, one can simply imagine a minimum of 30% cost reduction by associating reproductive tubal surgery with a follow-up of 6 months prior to first IVF cycle. DisclosuresNone"} +{"text": "Metagenomic sequencing has contributed important new knowledge about the microbes that live in a symbiotic relationship with humans. With modern sequencing technology it is possible to generate large numbers of sequencing reads from a metagenome but analysis of the data is challenging. Here we present the bioinformatics pipeline MEDUSA that facilitates analysis of metagenomic reads at the gene and taxonomic level. We also constructed a global human gut microbial gene catalogue by combining data from 4 studies spanning 3 continents. Using MEDUSA we mapped 782 gut metagenomes to the global gene catalogue and a catalogue of sequenced microbial species. Hereby we find that all studies share about half a million genes and that on average 300 000 genes are shared by half the studied subjects. The gene richness is higher in the European studies compared to Chinese and American and this is also reflected in the species richness. Even though it is possible to identify common species and a core set of genes, we find that there are large variations in abundance of species and genes. Our bodies are home to a myriad of microbial cells and our intestinal tract is especially densely populated with bacteria. Alterations in the composition of the gut microbiota have been associated with common human diseases. By sequencing the genomes of the microbes, the metagenome, detailed information about who is there and their capabilities can be obtained. In this paper, a method for analyzing metagenomic data is presented together with an analysis of gut metagenomes from 4 different studies and 3 different continents. We identify a core set of genes and species were identified but the abundance of core components differs between study populations. A catalogue of gut microbial genes from the 4 studies was constructed containing more than 11 million genes. The analysis also involves preprocessing such as quality assessment and filtering out human reads.Metagenomic sequencing of the human microbiome has contributed to our understanding of the microbial communities that live in symbiosis with humans and their genomic capabilities de novo assembly. The de novo assembly tools are important because the available genomic databases do not yet include complete genomes for many organisms present in metagenomic samples. Tools for taxonomic assignment of metagenomic reads have been developed and these include Phylophytia Several methods exist for either performing de novo assembly of the metagenomic data to predict gene sequences from longer contigs such as SOAPdenovo To address the problem of quantitative characterization of a metagenome data set, we have developed a tool for quality control, filtering reads and counting alignments to reference genomes and a gene catalogue database in one step. Furthermore, downstream tasks such as handling a large number of samples and annotating the alignment counts to taxonomic and functional databases are handled. Handling an abundance table of several hundred samples and millions of gene features puts special requirements on efficient implementation. This requires a machine with a large amount of RAM and efficient data management codes. We have tested MEDUSA on four gut metagenomic datasets from three continents and evaluate its performance by mapping to two databases, one reference genome catalogue made up of 1747 bacterial and archaeal genomes and a gene catalogue constructed in this study.One important question in the field of the human gut microbiome is whether there is a common core of species and genes and how variable the microbiome is between different individuals. A core of gene functions was identified in an American population of 18 individuals but using 16S rRNA sequencing on 154 individuals did not identify a core at the species level MEDUSA is an integrated pipeline for analysis of short metagenomic reads, it contains modules for mapping reads to reference databases, combining output from several sequencing runs and manipulating the tables of read counts and testing for differential abundance . Python In this study, four of the largest published gut metagenomic datasets to date were included and compared. The subjects are from United States of America A non-redundant catalogue of species genomes was constructed based on the results of a method using 40 universal single copy phylogenetic marker genes used for clustering prokaryotic genomes into species streamAligner. This function can take a number of compressed fastq files as input and will produce a count file for each input file and reference database. The function produces a log file for each input file with mapping statistics and output from the various software used in the stream such as fastx and Bowtie2. The function streamAligner can easily be parallelized by starting many instances of the function; each instance will look in the list of files supplied and start working on unprocessed files given that all instances have access to the same file system. The input number of reads for each study were on average 40\u00b112, 102\u00b128, 45\u00b118 and 31\u00b118 million single end reads per sample for the studies China, HMP, MetaHIT and Sweden, respectively. Most of the sequencing runs have a high quality with almost 98% of the reads passing the quality cutoff . MEDUSA makes use of standalone tools such as FASTX, bowtie2 http://www.metabolicatlas.com/medusa.MEDUSA was implemented in python programming language and requires the numpy package between the first and third quartiles and the line within denotes the median; whiskers denote the lowest and highest values within 1.5 times IQR from the first and third quartiles, respectively. Circles denote data points beyond the whiskers.(PDF)Click here for additional data file.Figure S2Boxplot of the 20 most abundant genera and their abundance by study. The definitions of boxplots are the same as in (PDF)Click here for additional data file.Figure S3Bacteroides, Parabacteroides and Alistipes) or Firmicutes species .Heatmap of relative abundance of the 30 most abundant species across 782 samples. Clustering was done using hierarchical clustering and complete linkage and Spearman correlation distance. Two clusters appear that are dominated by either Bacteroidetes species ((PDF)Click here for additional data file.Figure S4Heatmap of relative abundance of the 20 most abundant genera across 782 samples. Clustering was done using hierachical clustering and complete linkage and Spearman correlation distance.(PDF)Click here for additional data file.Figure S5Species core size as a function of the relative abundance cutoff shows that the pan size is more dependent on the cutoff than the core size.(PDF)Click here for additional data file.Figure S6http://enterotype.embl.de/ were used for the analysis. 73 genera with a mean abundance above 0.01% were used in the analysis. A) The clustering strength measured by Calinski-Harabasz index and the Silhouette index were calculated for a range of number of clusters. B) Between-class analysis using the R package ade4 for representing the genera abundance data together with the cluster identity as instrumental variable.Enterotype analysis of the samples. The recommended methods from (PDF)Click here for additional data file.Figure S7Abundance of three genera suggested being driver of each enterotype. Definitions of boxplots are the same as in (PDF)Click here for additional data file.Figure S8Bacteroides and Ruminococcus do not show a bimodal abundance distribution whereas Prevotella does.Histograms of abundance of three genera suggested to be drivers of enterotype separation. (PDF)Click here for additional data file.Figure S9Number of genes from each study. A) Number of genes predicted from contigs of each study. Genes from individual assemblies and global assemblies of unassembled reads are shown separately. B) Number of non-redundant genes in each study.(PDF)Click here for additional data file.Figure S10Relative abundance of genes grouped into how they are shared in the Venn diagram and norm(PDF)Click here for additional data file.Figure S11Number of gene in each sample using A) all data and B) data rarefied to 11 million aligned reads.(PDF)Click here for additional data file.Table S1List of species and genomes included in the species catalogue.(XLSX)Click here for additional data file.Table S2MEDUSA statistics for each sequencing run.(XLSX)Click here for additional data file.Table S3Pearson correlation between MEDUSA and Metaphlan genus abundance.(XLSX)Click here for additional data file.Table S4Identified core species in 50% and 90% of the individuals.(XLSX)Click here for additional data file.Table S5Enterotype distribution in each study.(XLSX)Click here for additional data file.Table S6Comparison of enterotypes assignment between this study and Arumugam et al (XLSX)Click here for additional data file.Table S7Sample and repeated visit information.(XLSX)Click here for additional data file.Table S8Genus assignment of genes using the KEGG database. All refers to all 11 million genes in the gene catalogue while core refers to the core genes.(XLSX)Click here for additional data file.Table S9KO assignment of genes using the KEGG database. All refers to all 11 million genes in the gene catalogue while core refers to the core genes.(XLSX)Click here for additional data file."} +{"text": "Inherited retinal disease leading to death of the photoreceptor cells affects around 1 in 3000 people and includes the retinal ciliopathies which disrupt the function of proteins associated with the photoreceptor cilia. We are interested in the potential for repair of the retina and preservation of sight via cell transplantation. This approach could be broadly applicable across a range of inherited retinal dystrophies. Our work has identified an optimal donor cell population from the developing retina, that following subretinal transplantation in adult mice generates large numbers of new functional rod photoreceptors . Thus, p"} +{"text": "Supporting Information files S1 TableEstimates of the number of undiagnosed HIV cases among MSM in King County stratified by ethnicity. * Sum of cases thought to reside in King County based on HIV surveillance data and the estimated number of undiagnosed cases.(PDF)Click here for additional data file.S1 ExampleThis example uses a very simple case to show the logic behind the constant incidence calculation.(PDF)Click here for additional data file.S1 DetailsThis provides more detail on the basic backcalculation algorithm, accounting for limited surveillance windows, and the quadratic smoothing penalty.(PDF)Click here for additional data file."} +{"text": "A 40-year-old woman was seen at our outpatient clinic because of episodes of palpitations that lasted several hours. She reported no syncopal episodes or family history of sudden cardiac death and was not on any medication. The resting ECG and ECG recorded during the palpitations are shown in Fig.\u00a0You will find the answer elsewhere in this issue."} +{"text": "The problems associated with the ageing immune system coupled with possible solutions were discussed recently at the British Society for Immunology Annual Congress in Harrogate in December 2004. The session \"Ageing and the Immune System in vivo\" dealt in details with the immune risk phenotype and the potential methods of reversing the problems of an ageing immune system. This is a commentary on that session. From an early age our immune system is introduced to a variety of infectious agents through contact with infected individuals. We also deliberately present our immune responses either to attenuated organisms or to components of infectious pathogens in order to provoke a response. A successful response to these organisms when first encountered provides us with immunological memory to enable our immune systems to make more rapidly responses to the same potentially infectious agents at a later date. In theory the longer we live the better our memory responses and our ability to cope with any potential pathogen seen previously. Since there are no completely sterile environments, individuals who have survived to reach a ripe old age must have combated many possible infectious agents, and have an immune system with a prodigious memory component. Only part of this is true. As we age the memory component of our immune system, as measured by the number of memory cells, does increase. Unfortunately this is not accompanied by improved immunity even to infectious agents that have been overcome earlier in life -4.The problems associated with the ageing immune system coupled with possible solutions were discussed recently at the British Society for Immunology Annual Congress in Harrogate in December 2004. The session \"Ageing and the Immune System in vivo\" dealt in details with the immune risk phenotype and the potential methods of reversing the problems of an ageing immune system.+CD28- cells (or CD8+CD28-CD27- in the very old), low numbers of B cells and the presence of CD8 T cells which were cytomegalovirus (CMV) tetramer positive. Within both the OCTO and NONA groups Dr Anders was able to show that the immune risk phenotype had some predictive input towards morbidity. This was even more apparent when cognitive impairment was included in the calculations.The concept of the immune risk phenotype was described by Dr Anders Wikby (J\u00f6nk\u00f6ping University) who carried out a longitudinal immunological study in order to establish predictive factors for longevity. Dr Anders first worked on a group of normal octogenarians in the OCTA study in Sweden which later became the NONA study as these individuals entered their nineties. Within this group he was able to describe the immune risk phenotype which he characterised by a CD4:CD8 ratio of <1, poor in vitro T cell proliferation, an increase in the number of CD8+ and show an increased incidence with age, so far it seems that clonal expansion is not due to malignant transformation but may follow antigen stimulation. The control of CMV within the body is mainly attributed to CD8+ T cells and Professor Moss revealed that in older individuals up to 50% of CD8+ T cells may be specific for CMV as judged by tetramer staining. It is possible that this increased response to CMV may lead to the impairment of responses to other viruses in the aged. This theme of CMV infection and ageing was then continued by Professor Graham Pawelec (University of Tuebingen) who introduced the use of the KLRG-1 marker as a marker of senescence. T cells which are KLRG-1+ do not proliferate in vitro when provided with a stimulus which would induced proliferation in T cells which lack this marker. In elderly individuals fewer CMV tetramer positive CD8+ T cells secreted interferon-\u03b3 in Elispot assays when compared with similar cells from younger individuals. Furthermore between 96 and 99%of the CD8+ T cells which stained with the CMV tetramer also expressed the KLRG-1 marker. The theme of CMV infection in the elderly was further continued by Professor Arne Akbar (University College London) whose research group has recently been analyzing telomere lengths in different T cell subsets using a fluorescent staining technique. In this method telomeres are stained with a fluorescently labeled probe and the brighter the fluorescent labeling the longer the telomere. Using this technique Professor Akbar reported that CMV specific CD4+ T cells in older individuals had very short telomeres indicating their limited replicative capacity and that more of these CMV specific CD4+ T cells expressed interferon-\u03b3.The effect of CMV infection on the immune system in the elderly was also discussed by Professor Paul Moss (University of Birmingham) with particular emphasis on the clonal expansion of T cells. Clonally expanded T cells are usually CD8This view of a bleak future for displaying the immune risk phenotype was countered by the last two presentations which discussed different approaches to reversing the defects seen in the immune system with age. Both of these methods centered around reversing the atrophy of the thymus seen with age. Dr Jayne Sutherland, currently at the Anthony Nolan Research Institute, detailed her work carried out whilst with Professor Richard Boyd (Monash University) on reversing age associated thymic atrophy by surgical or chemical castration. Studies in mice revealed that reversal of thymic atrophy followed surgical castration and in humans chemical castration produced changes in the TREC levels which indicated improved thymic output. Functional studies showed that this treatment improved immune function in the treated aged subjects. This theme of improved immunity following reversal of thymic atrophy was carried further in work reported by Dr Richard Aspinall . He showed how therapeutic intervention with interleukin 7 and derivates could reverse atrophy of the thymus in old animals and also lead to improved immune function compared with age and sex matched controls. In addition he described work done in the Gambia which suggested a link between the development and enlargement of the thymus after birth and the level of interleukin 7 in breast milk.Two speakers from the posters presentations were also chosen to present their results. K. Wang from Professor Janet Lord's group (Birmingham) presented work on dehydroepiandrosterone, (DHEA). This steroid hormone declines with age and treatment of NK cells with DHEA increases NK cytotoxicity and further analysis shows that DHEA induces PKC-\u03b2 translocation and upregulates perforin expression in these cells. D. Silva from Donald Palmers laboratory presented work on the expression of neuropeptides in epithelial cells from the thymuses of different species.The meeting revealed that much needs to be done in characterizing the changes in the immune system which are associated with ageing, and members of the audience were asked whether they were interested in receiving more details about the newly formed \"Differentiation and Immunosenesence Affinity Group\" associated with the BSI."} +{"text": "The authors admitted the error and agreed to retract the article.The article \u201cIntegrative analysis of the characteristic of lipid metabolism-related genes for the prognostic prediction of hepatocellular carcinoma,\u201d"} +{"text": "Food environments influence food preferences, in particular among children. Besides their homes, children spend most of their time in and around the school. This study mapped changes in retail food environments around primary and secondary schools in Flanders between 2008 and 2020. In addition, associations between those indicators and children's weight status were assessed.The food environment near primary and secondary schools was mapped using three spatial indicators: 1) The density of different types of food retailers within 1000m road distance from the school entrance, 2) the percentage of schools with at least one food retailer of a certain type within 1000m road distance from the entrance, and 3) the median walking distance from the school entrance to the nearest food retailer of a certain type. Associations between the density of convenience stores, as well as fast food outlets around the schools and the weight status of the schools\u2019 children were assessed using generalized linear models adjusted for level of urbanization, socio-economic status of children at school level and sex.Food environments near schools in Flanders were found to be unhealthy, with a significant increase in fast-food outlets and convenience stores between 2008 and 2020. Food environments near schools with a higher proportion of children from a poor socio-economic background were found more unhealthy than those near schools with a lower proportion of such children, regardless of the urbanization level. A significant positive association was found between the density of fast food outlets as well as convenience stores around primary schools and the weight status of children aged <6 years and 6-12 years.Food environments around schools in Flanders became more unhealthy over time and were associated with children's weight status. The government therefor has the responsibility to create healthy food environments near schools to protect children's health.\u2022\u2002The food environment near schools became more unhealthy between 2008 and 2020.\u2022\u2002The food environment near schools was associated with younger children's weight status."} +{"text": "Youth integrated care services were developed to overcome common barriers to mental health treatment. Satisfaction is key for services utilization and engagement.To study users satisfaction with youth integrated care service, \u201cHeadspace\u201d, throughout the course of treatment and its correlation with clinical and demographic characteristics and service utilization.A sample of 112 participants ranging between ages 12-25 who attended the Headspace clinic between March 2016 and June 2018 were assessed in the middle (after 7 sessions) and end of treatment (n=71).Participants expressed high levels of satisfaction across all service aspects at the middle and end of treatment. The highest rate of satisfaction was with the centre\u2019s staff and the lowest with personal outcomes. A repeated measures ANOVA analysis revealed that only satisfaction with personal outcomes improved significantly over time Length of wait to begin treatment and parental engagement y were negatively correlated with youth satisfaction.Satisfaction rates of Headspace among youth are high from the start and with their outcomes increase over time. Youth satisfaction with the staff\u2019s attitude and approach and satisfaction with accessibility suggest the service achievement in addressing barriers of help seeking in youth.No significant relationships."} +{"text": "Dear Editor, CFI and ARMS genes and their association with exudative age-related macular degeneration in Algerian patients [CFI and ARMS2 genes by disclosing for the first time the allelic and genotypic frequencies of these genes' polymorphisms that define the Algerian population [We would like to share ideas on the publication \u201cCharacterization of polymorphisms in patients .\u201d Accordpulation . Exudatipulation . Future None"} +{"text": "Nonsyndromic craniofacial clefts are relatively common congenital malformations which could create a significant negative effect on the health status and life quality of affected individuals within the pediatric population. Multiple cleft candidate genes and their coded proteins have been described with their possible involvement during cleft formation. Some of these proteins like Homeobox Protein BarH-like 1 (BARX1), Distal-Less Homeobox 4 (DLX4), Forkhead Box E1 (FOXE1), Homeobox Protein Hox-B3 (HOXB3), and Muscle Segment Homeobox 2 (MSX2) have been associated with the formation of craniofacial clefts. Understanding the pathogenetic mechanisms of nonsyndromic craniofacial cleft formation could provide a better knowledge in cleft management and could be a possible basis for development and improvement of cleft treatment options. This study investigates the presence of BARX1, DLX4, FOXE1, HOXB3, and MSX2 positive cells by using immunohistochemistry in different types of cleft-affected tissue while determining their possible connection with cleft pathogenesis process.Craniofacial cleft tissue material was obtained during cleft-correcting surgery from patients with nonsyndromic craniofacial cleft diagnosis. Tissue material was gathered from patients who had unilateral cleft lip (n=36), bilateral cleft lip (n=13), and cleft palate (n=26). Control group (n=7) tissue material was received from individuals without any craniofacial clefts. The number of factor positive cells in the control group and patient group tissue was evaluated by using the semiquantitative counting method. Data was evaluated with the use of nonparametric statistical methods.Statistically significant differences were identified between the number of BARX1, FOXE1, HOXB3, and MSX2-containing cells in controls and cleft patient groups but no statistically significant difference was found for DLX4. Statistically significant correlations between the evaluated factors were also notified in cleft patient groups.HOXB3 could be more associated with morphopathogenesis of unilateral cleft lip during postnatal course of the disorder. FOXE1 and BARX1 could be involved with both unilateral and bilateral cleft lip morphopathogenesis. The persistence of MSX2 in all evaluated cleft types could indicate its possible interaction within multiple cleft types. DLX4 most likely is not involved with postnatal cleft morphopathogenesis process. Craniofacial clefts are characterized as abnormalities of the facial region development in which the process of facial prominence fusion has been defective and incomplete during the embryogenesis . CraniofThe formation of craniofacial clefts can be affected by multiple factors. Factors from the external environment like physical factors, chemical factors, biological factors have been previously described as contributing agents which could increase the likelihood of incorrect development of the facial region . GeneticOrofacial clefts can be classified by their location. Clefts which affect the lip can be classified as unilateral or bilateral cleft lip. Clefts which affect the palatal region can be described as isolated cleft palate or a combination of cleft palate with cleft lip. Multiple classification systems have been used to classify orofacial clefts , 6. The Homeobox Protein BarH-like 1 (BARX1) is a transcription factor involved with the development and positioning of mesenchyme in multiple organs like the stomach, the spleen and the branchial arch region while also affecting the differentiation of the endodermal surface epithelium in stomach and tooth development process , 10. BARDistal-Less Homeobox 4 (DLX4) protein is a transcription factor involved with the differentiation of cranial neural crest cells, cranial mesenchyme and together with other DLX transcription factors are involved with the development and patterning of the craniofacial region tissue and organs like the teeth and the developing jaw region , 13. DLXForkhead Box E1 (FOXE1) protein is a transcription factor involved with the development of thyroid gland and the craniofacial epithelium formation . FOXE1 iHomeobox Protein Hox-B3 (HOXB3) has been described as a factor involved with the development of craniofacial region epithelium like the pharyngeal epithelium and also regulates neural crest cell migration in the craniofacial region , 20. HOXMuscle Segment Homeobox 2 (MSX2) has been described as regulatory factor for pluripotent stem cell differentiation into mesodermal tissue, regulates epithelial and mesenchymal tissue interactions and the development of the limbs and the craniofacial region . The rolBARX1, DLX4, FOXE1, HOXB3, and MSX2 are transcription factors which regulate the development of the orofacial region and patterning process within craniofacial tissue. BARX1, DLX4, HOXB3 and MSX2 proteins contain a homeodomain , 22, 23,The aim of this study is to determine the presence of BARX1, DLX4, FOXE1, HOXB3, and MSX2 proteins in the epithelium and the underlying connective tissue within the postnatal cleft affected tissue groups in comparison to controls and to evaluate the correlations between the factors within the nonsyndromic cleft affected tissue. This specific combination of cleft candidate gene proteins and their possible interactions has not been described in previous studies within human cleft affected tissue. These specific proteins have been chosen for this study because of their previously described role in formation of orofacial cleft as cleft candidate gene coded proteins and to better understand their presence in cleft affected tissue and to determine their possible representation differences and similarities between the tissues of different cleft types.All patient and control group tissue samples which were analyzed in this study were donated with a voluntary agreement from the parents of the patients and the parents of the controls. Both the control group and the patient group tissues were acquired in Cleft Lip and Palate Centre of the Institute of Stomatology of Riga Stradins University (RSU). The analysis and study of said tissue material was performed in the RSU Department of Morphology. The approval of the study protocol was received from the RSU Ethics Committee . This study was conducted in accordance with the Declaration of Helsinki of 1964.The evaluated patient study groups were split based on the type and location of the cleft affected tissue. Unilateral cleft lip tissue group, bilateral cleft lip tissue group and cleft palate tissue group were formed. The tissue material obtained from the cleft correcting surgery from cleft affected tissue group patients contained oral cavity surface epithelium and the underlying connective tissue.The inclusion criteria for each patient group were the diagnosis of cleft lip or cleft palate, surgery performed to repair said orofacial cleft, no presence of any other orofacial pathology during the time of surgery, the age of the patients during the surgery restricted to a time frame before the moment of primary dentition (from age of 3 months to age of 18 months).Based on the available tissue material the patient groups were split into 36 patients with unilateral cleft lip , 13 patients with bilateral cleft lip and 26 patients with cleft palate .The tissues of the control group were taken from 7 patients who received surgery for the correction of enlarged upper lip frenulum. The control group contained 4 male and 3 female patients with an age from 8 years to 11 years. The inclusion criteria for the control group were the diagnosis of upper lip frenulum hypertrophy, no clefts found during clinical investigation , no orofacial clefts found in the patient anamnesis or in family anamnesis, no other pathological process like inflammation, fibrosis, malignancy, atrophy present within the collected tissue sample.Due to the very limited amount of control tissue material available for immunohistochemical evaluation BARX1, FOXE1, HOXB3, MSX2 immunoreactivity could be analyzed only from 5 control tissue group patients while DLX4 immunoreactivity could be evaluated from the tissue material of 7 patients within the control group.The main technique used to prepare and assess the tissue samples for this study was the standard streptavidin and biotin immunohistochemical method, which was utilized to provide the detection of BARX1, DLX4, FOXE1, HOXB3, MSX2 proteins . The conLeica DC 300F digital camera was used to provide the visualization of slides. Image Pro Plus software allowed to process and analyze the collected images.The relative frequency of BARX1, DLX4, FOXE1, HOXB3, and MSX2 containing cells within the patient and control group slides stained with the biotin-streptavidin immunohistochemical method was obtained by using nonparametric slide evaluation with the semiquantitative counting method , 28, 29.s) value was understood with the following: very weak correlation (rs=0.0\u20130.2), weak correlation (rs=0.2\u20130.4), moderate correlation (rs=0.4\u20130.6), strong correlation (rs=0.6\u20130.8), very strong correlation (rs=0.8\u20131.0). The semiquantitative count of immunopositive cells within the patient group and control group tissues is conveyed as median values. The calculation of statistical significance between the number of immunopositive structures in each research group was accomplished with the Mann\u2013Whitney U test and Kruskal\u2013Wallis H test. SPSS Statistics program was utilized for data statistical analysis. Statistical significance of all statistical calculations was accepted with a p-value of <0.05.Descriptive and analytical statistical methods were employed for analysis of data. The count of immunopositive cells within each visual field and descriptive statistics calculations were utilized. Spearman\u2019s rank correlation coefficient calculation was applied to the data. The strength of correlation for Spearman\u2019s rho and it ranged from no BARX1 positive cells (0) to 0 positive cells. In the control group connective tissues the median number of BARX1 positive cells was no immunopositive structures (0) and it ranged from no BARX1 positive cells (0) to barely detectable (0/+) positive cells .In the unilateral cleft lip group epithelium, the median number of BARX1 positive epitheliocytes was no positive cells (0) and no BARX1 positive epitheliocytes were found within any slide of the unilateral cleft lip tissue group. The median number of BARX1 positive connective tissue cells was a few (+) positive cells and it ranged from no positive cells (0) to few to moderate (+/++) number of BARX1 immunopositive connective tissue cells, mainly macrophages .The median number of BARX1 positive epitheliocytes in the bilateral cleft lip tissue group was no positive cells (0) and no BARX1 positive epitheliocytes were found in any slide of the bilateral cleft lip affected tissue group. The median number of BARX1 immunopositive structures in the connective tissues of the bilateral cleft lip group was few to moderate (+/++) and it ranged from no BARX1 positive structures (0) to few to moderate (+/++) positive structures .In the cleft palate affected tissue group, the median number of BARX1 positive epitheliocytes was no positive cells (0) and no BARX1 positive epitheliocytes were found in any slide of the cleft palate affected tissue group. In the connective tissues, the median number of BARX1 positive structures was barely detectable to a few (0/+ - +) and ranged from no BARX1 positive cells (0) to few to moderate (+/++) positive structures .The Kruskal\u2013Wallis H test revealed that no statistically significant difference was present in the number of BARX1 immunopositive surface epitheliocytes among all four groups . This test indicated a statistically significant difference in the number of BARX1 positive structures in the connective tissue among all four tissue groups .The Mann\u2013Whitney U test indicated no statistically significant difference in the number of BARX1 immunopositive surface epitheliocytes between the controls and the unilateral cleft lip tissue group . This test revealed a statistically significant difference in the number of BARX1 immunopositive connective tissue cells between the controls and the unilateral cleft lip tissue group .The Mann\u2013Whitney U test indicated no statistically significant difference in the number of BARX1 immunopositive surface epitheliocytes between the controls and the bilateral cleft lip tissue group . This test revealed a statistically significant difference in the number of BARX1 immunopositive connective tissue cells between the controls and the bilateral cleft lip tissue group .The Mann\u2013Whitney U test revealed no statistically significant difference in the number of BARX1 immunopositive surface epitheliocytes between the controls and the cleft palate tissue group . This test indicated no statistically significant difference in the number of BARX1 immunopositive connective tissue cells between the controls and the cleft palate tissue group .The median number of DLX4 positive epitheliocytes in the control group epithelium was a few (+) and it ranged from no positive cells (0) to moderate to numerous (++/+++). The median number of DLX4 positive connective tissue cells was a few (+) and it ranged from barely detectable (0/+) to moderate to numerous (++/+++) .In the unilateral cleft lip tissue group the median number of DLX4 positive epitheliocytes was few to moderate (+/++) and it varied from no positive structures (0) to numerous (+++) in the epithelium. The median number of DLX immunopositive structures in the unilateral cleft lip connective tissues was a few (+) positive structures and it varied from no positive structures (0) to moderate to numerous (++/+++) immunopositive structures .The median number of DLX4 positive structures in the epithelium of the bilateral cleft lip tissue group was few to moderate (+/++) and it ranged from no positive structures (0) to moderate to numerous (++/+++) immunopositive structures. The median number of DLX4 positive connective tissue cells of the bilateral cleft lip group was few to moderate (+/++) and it ranged from a few (+) positive structures to few to moderate (+/++) immunopositive structures .In the cleft palate tissue group the median number of DLX4 positive epitheliocytes was few to moderate \u2013 moderate (+/++ - ++) and it ranged from no positive cells (0) to moderate (++) number of DLX4 immunopositive cells. The median number of DLX4 positive cells in the connective tissues of the cleft palate tissue group was a few (+) immunopositive connective tissue cells and it ranged from no positive cells (0) to few to moderate (+/++) immunopositive cells .The Kruskal\u2013Wallis H test indicated that a statistically significant difference was not present in the number of DLX4 immunopositive epitheliocytes among all four tissue groups . This test also revealed that a statistically significant difference was not present in the number of DLX4 positive cells in the connective tissues among all four tissue groups .The Mann\u2013Whitney U test indicated no statistically significant difference in the number of DLX4 immunopositive surface epitheliocytes between the controls and the unilateral cleft lip tissue group . This test revealed no statistically significant difference in the number of DLX4 immunopositive connective tissue cells between the controls and the unilateral cleft lip tissue group .The Mann\u2013Whitney U test indicated no statistically significant difference in the number of DLX4 immunopositive epitheliocytes between the controls and the bilateral cleft lip tissue group . This test indicated no statistically significant difference in the number of DLX4 immunopositive connective tissue cells between the controls and the bilateral cleft lip tissue group .The Mann\u2013Whitney U test revealed no statistically significant difference in the number of DLX4 immunopositive epitheliocytes between the controls and the cleft palate tissue group . This test indicated no statistically significant difference in the number of DLX4 immunopositive connective tissue cells between the controls and the cleft palate tissue group .In the control group the median number of FOXE1 positive epitheliocytes was few to moderate (+/++) and it ranged from barely detectable immunopositive epitheliocytes (0/+) to moderate (++) number of FOXE1 immunopositive cells. The median number of FOXE1 positive control group connective tissue cells was a few (+) and ranged from a rare occurrence (0/+) to few to moderate (+/++) number of FOXE1 immunopositive connective tissue cells .In the unilateral cleft lip tissue group the median number of FOXE1 positive epitheliocytes was moderate (++) and it ranged from a few (+) to numerous (+++) number of FOXE1 positive surface epitheliocytes. The median number of FOXE1 positive connective tissue cells in the unilateral cleft lip tissue group was moderate (++) and it ranged from a few (+) positive cells to numerous to abundant (+++/++++) FOXE1 positive cells .In the bilateral cleft lip tissue group the median number of FOXE1 positive cells in the surface epithelium was moderate to numerous \u2013 numerous (++/+++ - +++) and it ranged from a few (+) to numerous (+++) number of immunopositive epitheliocytes. In the bilateral cleft lip group connective tissue, the median number of FOXE1 structures was moderate to numerous (++/+++) and it ranged from no immunopositive structures (0) to numerous to abundant (+++/++++) immunopositive structures .In the cleft palate tissue group the median number of FOXE1 positive surface epitheliocytes was few to moderate (+/++) and it ranged from a few (+) to numerous (+++) immunopositive epitheliocytes. In the cleft palate group connective tissues, the median number of FOXE1 positive structures was a few to moderate (+/++) and it ranged from a few (+) to numerous (+++) immunopositive connective tissue cells .The Kruskal\u2013Wallis H test revealed that there was no statistically significant difference among all four tissue groups in the number of FOXE1 immunopositive surface epitheliocytes . This test revealed that a statistically significant difference was present in the number of FOXE1 positive cells in the connective tissues among all four tissue groups .The Mann\u2013Whitney U test indicated no statistically significant difference in the number of FOXE1 immunopositive surface epitheliocytes between the controls and the unilateral cleft lip tissue group . This test revealed a statistically significant difference in the number of FOXE1 immunopositive connective tissue cells between the controls and the unilateral cleft lip tissue group .The Mann\u2013Whitney U test indicated no statistically significant difference in the number of FOXE1 immunopositive epitheliocytes between the controls and the bilateral cleft lip tissue group . This test indicated no statistically significant difference in the number of FOXE1 immunopositive connective tissue cells between the controls and the bilateral cleft lip tissue group .The Mann\u2013Whitney U test revealed no statistically significant difference in the number of FOXE1 immunopositive epitheliocytes between the controls and the cleft palate tissue group . This test indicated a statistically significant difference in the number of FOXE1 immunopositive connective tissue cells between the controls and the cleft palate tissue group .In the control group the median number of HOXB3 positive epitheliocytes was a few (+) and it ranged from a few (+) to moderate (++) number of HOXB3 immunopositive cells. The median number of HOXB3 positive connective tissue cells in the control group was moderate (++) and ranged from few to moderate (+/++) to moderate (++) number of immunopositive connective tissue cells .In the unilateral cleft lip tissue group the median number of HOXB3 positive epitheliocytes was moderate to numerous (++/+++) and it ranged from a few (+) to numerous to abundant (+++/++++) HOXB3 positive surface epitheliocytes. The median number of HOXB3 positive connective tissue cells in the unilateral cleft lip tissue group was moderate (++) and it ranged from a few (+) positive cells to numerous to abundant (+++/++++) HOXB3 positive cells .In the bilateral cleft lip tissue group the median number of HOXB3 positive cells in the surface epithelium was moderate (++) and it ranged from a few (+) to moderate to numerous (++/+++) number of immunopositive epitheliocytes. In the bilateral cleft lip group connective tissues, the median number of HOXB3 structures was moderate (++) and it ranged from a few (+) to moderate to numerous (++/+++) immunopositive structures .In the cleft palate tissue group the median number of HOXB3 positive surface epitheliocytes was few to moderate to moderate (+/++ - ++) and it ranged from a few (+) to numerous (+++) immunopositive epitheliocytes. In the cleft palate group connective tissues, the median number of HOXB3 positive structures was few to moderate (+/++) and it ranged from a few (+) to numerous (+++) immunopositive connective tissue cells .The Kruskal\u2013Wallis H test revealed a statistically significant difference among all four tissue groups in the number of HOXB3 immunopositive surface epitheliocytes . This test also revealed that a statistically significant difference was present in the number of HOXB3 positive cells in the connective tissue among all four tissue groups .The Mann\u2013Whitney U test indicated a statistically significant difference in the number of HOXB3 immunopositive surface epitheliocytes between the controls and the unilateral cleft lip tissue group . This test indicated no statistically significant difference in the number of HOXB3 immunopositive connective tissue cells between the controls and the unilateral cleft lip tissue group .The Mann\u2013Whitney U test indicated no statistically significant difference in the number of HOXB3 immunopositive epitheliocytes between the controls and the bilateral cleft lip tissue group . This test indicated no statistically significant difference in the number of HOXB3 immunopositive connective tissue cells between the controls and the bilateral cleft lip tissue group .The Mann\u2013Whitney U test revealed no statistically significant difference in the number of HOXB3 immunopositive epitheliocytes between the controls and the cleft palate tissue group . This test indicated no statistically significant difference in the number of HOXB3 immunopositive connective tissue cells between the controls and the cleft palate tissue group .In the control group the median number of MSX2 positive epitheliocytes was no positive structures (0) and no MSX2 positive epitheliocytes could be found in any control group slides. In the connective tissues of the control group the median number of MSX2 positive structures was no positive structures (0) and it ranged from no positive structures (0) to a rare occurrence (0/+) of MSX2 positive cells .In the unilateral cleft lip tissue group the median number of MSX2 immunopositive epitheliocytes was moderate (++) and it ranged from no positive cells (0) to numerous (+++) MSX2 positive epithelial cells. In the unilateral cleft lip group connective tissues, the median number of MSX2 positive structures was a few (+) and it ranged from no positive structures (0) to moderate to numerous (++/+++) .In the bilateral cleft lip tissue group the median number of MSX2 positive cells in the surface epithelium was a few (+) and it varied from no immunopositive structures (0) to moderate to numerous (++/+++) immunopositive structures. The median number of MSX2 immunopositive structures in the bilateral cleft lip group connective tissues was a few (+) and it varied from no positive structures (0) to few to moderate (+/++) positive structures .In the cleft palate tissue group the median number of MSX2 positive surface epitheliocytes was a few (+) and it varied from no positive cells (0) to moderate (++) number of MSX2 positive epitheliocytes. The median number of MSX2 positive connective tissue cells in the cleft palate tissue group was a few (+) and it ranged from no positive cells (+) to few to moderate (+/++) MSX2 immunopositive connective tissue cells .The Kruskal\u2013Wallis H test revealed a statistically significant difference among all four tissue groups in the number of MSX2 immunopositive surface epitheliocytes . This test also revealed that a statistically significant difference was present in the number of MSX2 positive structures in the connective tissues among all four tissue groups .The Mann\u2013Whitney U test indicated a statistically significant difference in the number of MSX2 immunopositive surface epitheliocytes between the controls and the unilateral cleft lip tissue group . This test indicated a statistically significant difference in the number of MSX2 immunopositive connective tissue cells between the controls and the unilateral cleft lip tissue group .The Mann\u2013Whitney U test revealed a statistically significant difference in the number of MSX2 immunopositive epitheliocytes between the controls and the bilateral cleft lip tissue group . This test indicated no statistically significant difference in the number of MSX2 immunopositive connective tissue cells between the controls and the bilateral cleft lip tissue group .The Mann\u2013Whitney U test revealed a statistically significant difference in the number of MSX2 immunopositive epitheliocytes between the controls and the cleft palate tissue group . This test indicated a statistically significant difference in the number of MSX2 immunopositive connective tissue cells between the controls and the cleft palate tissue group .The semiquantitative evaluation of BARX1, DLX4, FOXE1, HOXB3, and MSX2 immunoreactivity is summarized in Spearman\u2019s rank correlation coefficient calculation allowed to find multiple statistically significant correlations between the number of factor positive cells for BARX1, DLX4, FOXE1, HOXB3, MSX2 in the surface epithelium and the underlying connective tissues within each of the cleft affected tissue groups.No statistically significant correlations between the evaluated factors were found in the control group.Multiple statistically significant positive correlations were calculated within the unilateral cleft lip tissue group.s=0.6\u20130.8) were notified between the number of HOXB3 immunopositive epitheliocytes and the number of HOXB3 immunopositive connective tissue cells .Statistically significant strong correlations (rs =0.4\u20130.6) were identified between the number of FOXE1 immunopositive connective tissue cells and the number of HOXB3 positive connective tissue cells , between the number of FOXE1 immunopositive epitheliocytes and the number of FOXE1 immunopositive connective tissue cells , between the number of DLX4 immunopositive epitheliocytes and the number of HOXB3 immunopositive epitheliocytes , between the number of FOXE1 immunopositive connective tissue cells and the number of HOXB3 positive epitheliocytes , between the number of MSX2 immunopositive epitheliocytes and the number of MSX2 immunopositive connective tissue structures , between the number of FOXE1 immunopositive epitheliocytes and the number of HOXB3 immunopositive connective tissue cells , between the number of HOXB3 containing connective tissue cells and the number of MSX2 containing connective tissue cells .Statistically significant moderate correlations (rs =0.2\u20130.4) were notified between the number of HOXB3 containing epitheliocytes and the number of MSX2 containing epitheliocytes , between the number of BARX1 immunopositive connective tissue cells and the number of MSX2 containing epitheliocytes , between the number of DLX4 containing epitheliocytes and the number of FOXE1 containing connective tissue structures , between the number of FOXE1 containing epitheliocytes and the number of HOXB3 containing epitheliocytes .Statistically significant weak correlations were notified between the number of FOXE1 containing connective tissue cells and the number of HOXB3 containing epitheliocytes , between the number of HOXB3 containing epitheliocytes and the number of MSX2 containing epitheliocytes , between the number of FOXE1 immunopositive connective tissue structures and the number of MSX2 immunopositive epitheliocytes , between the number of DLX4 containing epitheliocytes and the number of DLX4 containing connective tissue cells .Statistically significant strong positive correlations (rs =0.4\u20130.6) were notified between the number of SHH immunopositive connective tissue cells and the number of WNT3A immunopositive epitheliocytes , between the number of FOXE1 containing epitheliocytes and the number of FOXE1 containing connective tissue cells , between the number of MSX2 immunopositive epitheliocytes and the number of SHH immunopositive epitheliocytes , between the number of DLX4 containing epitheliocytes and the number of FOXE1 immunopositive connective tissue structures , between the number of FOXE1 immunopositive connective tissue structures and the number of WNT3A immunopositive epitheliocytes , between the number of SHH immunopositive epitheliocytes and the number of SOX3 immunopositive epitheliocytes , between the number of BARX1 immunopositive connective tissue cells and the number of DLX4 immunopositive connective tissue cells .Statistically significant moderate correlations were identified between the number of BARX1 immunopositive connective tissue cells and the number of MSX2 immunopositive connective tissue cells , between the number of BARX1 immunopositive connective tissue structures and the number of DLX4 immunopositive epitheliocytes .Statistically significant strong negative correlations were identified between the number of HOXB3 containing epitheliocytes and the number of HOXB3 positive connective tissue cells , between the number of DLX4 containing epitheliocytes and the number of FOXE1 containing epitheliocytes , between the number of FOXE1 positive epitheliocytes and the number of MSX2 positive epitheliocytes .Statistically significant moderate correlations difference in the number of BARX1 positive connective cells within the postnatal mucosal connective tissue. BARX1 (the gene encoding BARX1 protein) expression has been previously described in orofacial mesenchymal tissue, mainly within the mesenchyme of the developing maxillary and mandibular regions and later in the dental papilla of developing molars , 32. TheFor DLX4 no statistically significant differences were notified between the controls and any of the cleft affected tissue groups. While DLX4 did not show statistically significant differences in immunoreactivity between the tissue groups, its involvement with the formation of orofacial cleft could not be excluded because of its regulatory role during the development of the craniofacial region , 13.The assessment of FOXE1 notified statistically significant differences in the number of FOXE1 containing connective tissue cells between the controls and the unilateral cleft lip tissue group and between the controls and cleft palate tissue group, but not between the control group and the bilateral cleft lip tissue group. Statistically significant differences for the number of FOXE1 containing cells were not found in the epithelium between the controls and any cleft tissue group epithelium. These results could indicate that FOXE1 might play a similar regulatory role within the developing connective tissue of the palatal region and the lip and the disruption of FOXE1 regulation could have a similar impact on the formation of cleft palate and unilateral cleft lip. FOXE1 gene expression previously has been described in the epithelium of the secondary palate which implies its regulatory purpose during palatogenesis process and the After evaluation of HOXB3 immunoreactivity the only statistically significant difference was notified in the number of HOXB3 containing surface epitheliocytes between the control group and the unilateral cleft tissue group. No other statistically significant differences for HOXB3 were notified. While HOXB3 gene involvement with the development of the craniofacial region has been previously described in mice , data abAssessment of MSX2 immunoreactivity indicated statistically significant differences in the number of MSX2 positive cells in the epithelium between the controls and each of the cleft affected tissue groups while statistically significant differences were also found in the number of MSX2 containing connective tissue cells between the controls and the unilateral cleft lip tissue group and between the controls and the cleft palate tissue group but not between controls and bilateral cleft lip tissue group. This implies the possible role of MSX2 in formation of multiple orofacial cleft types. MSX2 is involved with the formation of orofacial structures like tooth development and affects the differentiation of the oral cavity epithelium into the tooth enamel organ , 37. TheIn the unilateral cleft lip patient group multiple statistically significant positive correlations were notified.A statistically significant strong correlation was identified between the number of HOXB3-containing cells in the epithelium and connective tissue. HOXB3 gene involvement with craniofacial region morphogenesis has been previously described in mice and togeMultiple statistically significant moderate correlations were identified in the unilateral cleft lip tissue group. The correlation between the number of FOXE1-containing epithelial cells and FOXE1-containing connective tissue cells could be an indication that FOXE1 might provide a regulatory role during the formation of the lip. FOXE1 has been previously described as a regulatory factor during craniofacial morphogenesis process and more information has been found about its regulatory role in other regions like in the development of the thyroid gland and thyroid gland pathologies with disrupted cell proliferation like thyroid cancer .Other correlations have been found between FOXE1 and other factors. Some correlations between FOXE1 and HOXB3-containing cells could show a possible molecular interaction between these two factors in unilateral cleft lip tissue, for example, the correlation between the number of FOXE1-containing connective tissue cells and the number of HOXB3-containing connective tissue cells and the correlation between the number of FOXE1-containing epitheliocytes and HOXB3-containing connective tissue cells, between the number of FOXE1-containing connective tissue cells and HOXB3-containing epithelial cells. FOXE1 together with HOXB3 has been described as a transcription factor which plays a regulatory role in formation of craniofacial organs and tissues, for example, during the development of the thyroid gland where FOXE1 has a more direct role in regulation of thyroid gland growth and formation, while HOXB3 has a more indirect role during thyroid gland and craniofacial structure development process . DisruptA statistically significant weak correlation involving FOXE1 was identified between the number of FOXE1-containing connective tissue cells and DLX4-containing epitheliocytes. The weak correlation between FOXE1 and DLX4 might be incidental but the regulatory role of both transcription factors is important for the craniofacial region in general. DLX genes help to determine the patterning of the developing mandible and maxillary region in mammals , 40 whilA statistically significant moderate correlation was found between the number of DLX4-containing epitheliocytes and HOXB3-containing epitheliocytes. DLX4 and HOXB3 are involved with the developing pharyngeal arch region but their exact role is relatively unclear due to simultaneous activity of other homeobox transcription factors within the developing orofacial region . This inA moderate correlation was found between MSX2-containing epitheliocytes and MSX2-containing connective tissue cells in unilateral cleft lip tissue. MSX2 involvement with the formation of orofacial clefts has been previously described and MSX2Some other statistically significant moderate and weak correlations involving MSX2 were identified \u2013 between the number of MSX2-containing connective tissue cells and HOXB3-containing connective tissue cells, between MSX2-containing epitheliocytes and HOXB3-containing epitheliocytes, between MSX2-containing epitheliocytes and BARX1-containing connective tissue cells. MSX2 has been previously described as transcription factor which can regulate cell proliferation in some pathological conditions like oral squamous cell carcinoma in which increased MSX2 activity has been associated with decreased cell proliferation and a tumor suppressor-like effect . HOXB3 hMultiple statistically significant correlations were identified in the bilateral cleft lip patient group.A statistically significant very strong correlation was found between FOXE1-containing epitheliocytes and MSX2-containing epitheliocytes. Both FOXE1 and MSX2 have been associated with the development of craniofacial malformations , 45. FOXMultiple statistically significant strong correlations were identified in bilateral cleft lip tissue. Interestingly there were statistically significant strong correlations involving FOXE1 \u2013 between the number of FOXE1-containing connective tissue cells and the number of HOXB3-containing epitheliocytes, and between the number of FOXE1-containing connective tissue cells and MSX2-contatining epitheliocytes. A statistically significant correlation was seen also between the number of HOXB3-contating epitheliocytes and MSX2-contatining epitheliocytes. This could indicate a close interaction between three factors \u2013 FOXE1, HOXB3, and MSX2 within bilateral cleft lip tissue. All three transcription factors are involved with each other indirectly within a network of signaling pathways like WNT, BMP and SHH signaling during craniofacial development , 47. TheA statistically significant strong correlation was identified between the number of DLX4-containing epitheliocytes and DLX4-containing connective tissue cells. DLX4 dysregulation has been associated with changes in cell proliferation in pathological tissue in the craniofacial region like nasopharyngeal carcinoma . There cSome statistically significant moderate correlations were notified. The correlation between the number of FOXE1-containing epitheliocytes and FOXE1-containing connective tissue cells in the bilateral cleft lip tissue was alike to the same correlation seen in unilateral cleft lip tissue. This could mean that the pathogenetic role of FOXE1 might be quite similar in both types of lip clefts. FOXE1 has been mainly described as a transcription factor which regulates cell differentiation and proliferation specifically in the thyroid gland but FOXEAnother statistically significant moderate correlation was found between the number of DLX4-containing epithelial cells and FOXE1-containing connective tissue cells in bilateral cleft lip tissue. A similar statistically significant weak correlation was found between the number of DLX4-containing epithelial cells and FOXE1-containing connective tissue cells in unilateral cleft lip connective tissue which could indicate that both DLX4 and FOXE1 interactions could be similar in both types of cleft lip with a more significant interaction being present within bilateral cleft lip tissue. The possible action of DLX4 and FOXE1 on the development of the craniofacial region most likely could be the regulation of cell differentiation and proliferation , 49.The statistically significant moderate correlation between the number of BARX1-containing connective tissue cells and the number of DLX4-containing connective tissue cells could indicate that the underlying connective tissue is the main possible location of BARX1\u2013DLX4 interactions. Previous studies have shown that BARX1-containing cells and BARX1 activity has mainly been found in mesenchyme-derived tissue during oral cavity development , 32 and Interestingly, our study revealed that there were statistically significant negative correlations in the bilateral cleft lip tissue which were notified between BARX1 in the connective tissue and MSX2 in the connective tissue and between BARX1 in the connective tissue and DLX4 in the epithelium. BARX1 and MSX2 could possibly interact with each other during facial development. Both BARX1 and MSX2 are affected by the WNT signaling pathway during the development of the maxilla and this pathway could be inhibited by Dickkopf-related protein 1 (DKK1) which afterwards downregulates BARX1 and MSX2 genes . InteresSome statistically significant moderate correlations were identified in the cleft palate group.A statistically significant moderate correlation was found between the number of HOXB3-containing epithelial cells and HOXB3-containing connective tissue cells in cleft palate tissue. A similar but stronger correlation was seen also in unilateral cleft lip tissue which could imply some similarities of HOXB3 regulatory role in the developing of both lip and palate. This correlation involving HOXB3 could mean that HOXB3 might affect tissue growth and cell migration in the craniofacial region which has been previously described and thesA statistically significant moderate correlation was found between the number of FOXE1-containing epithelial cells and DLX4-containing epithelial cells. This seems to imply that the epithelium could be an important location for molecular interactions between FOXE1 and DLX4 during cleft palate formation. Both FOXE1 and DLX4 regulate craniofacial region development and inteA statistically significant moderate correlation was found between the number of FOXE1-containing epithelial cells and MSX2-containing epithelial cells. Interestingly, a similar but a very strong correlation was seen in bilateral cleft lip tissue which might imply some similarities in possible pathogenetic mechanisms between the two cleft types. This could also indicate that FOXE1 and MSX2 could interact with each other within the oral cavity epithelium. FOXE1 and MSX2 could interact with each other through different signaling pathways like BMP and SHH signaling , 47.in situ hybridization and gene amplification could contribute more information for this specific study. Genetic studies could be a valuable addition to complement and elaborate our study results while possibly providing more definite conclusions on the involvement of evaluated factors in cleft formation. An important limitation for the effective use of genetic studies is the fact that it is difficult to find and follow up specific cleft patients over a long period of time because the tissue material has been gathered over a period of two decades since the start of cleft morphological research in our departments and additional agreements would be necessary for the implementation of genetic research. The application of other additional study techniques for the evaluation of cleft candidate genes and their coded proteins is planned in the foreseeable future. Another limitation which could impact the results is the size of the control tissue group which is rather small due to the difficult access to available tissue material because of ethical concerns regarding the collection of said tissue material. An additional possible limitation in our research has been the control group collected from older individuals than the cleft patient groups which complicates the assessment and the comparison between the evaluated groups. The tissue from children of patient groups was gathered before the age of primary dentition while controls had mixed dentition. Factors, including aging changes in tissue endotypes, changes in protein expression and location due to tissue growth in older children, could possibly affect the differences in tissue evaluation between the groups. Difficulties with obtaining control tissue from relatively healthy children with the same or similar age like the patient groups have limited and complicated our assessment of exact differences between the controls and patient groups. Practically it is very difficult to obtain relatively healthy oral cavity tissue not affected by clefts from a significant number of healthy children of such age due to the previously established ethical aspects including permissions from parents and the presence of significant surgical indications to obtain any tissue at all.One of the main limitations of this specific study is the application of only immunohistochemistry for the detection of BARX1, DLX4, FOXE1, HOXB3, and MSX2 proteins in control and cleft affected tissue groups. The application of additional methods like The evaluation of postnatal cleft affected tissue can describe the characteristics and specifics of craniofacial tissue growth and development after birth, but it cannot clearly describe morphopathogenetic changes in mechanisms which have occurred prenatally. The problematic aspects of obtaining prenatal cleft affected tissue is a limitation of this study and a possible comparison between prenatal and postnatal cleft affected tissue morphophatogenesis could be future research topic.The statistically significant increase of transcription factor HOXB3 within unilateral cleft lip affected tissue signifies their association with this specific type of cleft.Transcription factors BARX1, FOXE1 are probably involved with the formation of both unilateral cleft lip and bilateral cleft lip morphopathogenesis processes within the postnatal cleft affected tissue.The statistically significant increase of MSX2 containing cells in all evaluated cleft patterns might indicate its role in the formation of different cleft types.Interactions between transcription factors BARX1, DLX4, FOXE1, HOXB3, and MSX2 within the postnatal cleft affected tissue types indicates the presence of similar pathogenetic signaling mechanisms within different cleft type variations with some variations which could be affected by other unknown factors regulating gene expression within the postnatal cleft affected tissue."} +{"text": "Raising concerns is an important part of being a doctor and part of the GMC \u2018Good Medical Practice\u2019 guidelines, however as a trainee it often comes with specific challenges. Historically trainees are often left feeling that their concerns are not taken seriously and there is no resolution to problems raised. Here we present the findings of a scoping exercise undertaken as part of a Quality Improvement project exploring these issues within a large mental health Trust.Trainees across all training grades from Foundation doctors to higher trainees were invited to engage in virtual focus groups specific to their training programme. Contributions were analysed anonymously using a thematic analysis approach by two independent coders. Quantitative data were also gathered using an online survey to capture trainees who had been unable to attend a focus group.A total of 6 focus groups were attended by more than 35 trainees, with high turnout particularly within Foundation trainees and CT1 doctors.Three key themes were identified from the qualitative data: difficulties with the process of raising concerns, fear of the consequences and challenging the culture of the organisation.It was noted that senior trainees felt more comfortable with the process of raising concerns compared with junior colleagues but were more apathetic about the impact of doing so.12 trainees completed the online survey. Of these, 6 (50%) reported having had patient safety concerns and 7 (58%) had had concerns about their training.The most common reported barriers to raising concerns were the impact on working relationships (67%), lack of support (50%) and fear of repercussions on their training (50%). 42% of respondents were unsure of how to raise concerns.Trainee suggestions for change included improved information for trainees and trainers about the process for raising concerns, sharing of feedback about concerns raised more widely and regular opportunity to meet with key stakeholders.Key results included:The majority of trainees had experienced concerns about either patient safety or training issues. It will be necessary to address the multiple barriers highlighted to enable trainees to feel more confident and able to raise concerns. Increasing awareness of escalation processes, improving the processes themselves and fostering a supportive environment which encourages and supports trainees to raise concerns will be important given the implications for patient safety and trainee well-being."} +{"text": "Following the publication of this article [1], concerns were raised regarding similarities between the pFyn immunoblot image presented in Fig 2D (pFyn416) and the pFyn immunoblot image presented in The corresponding author explained that the incorrect blot was inadvertently used to present the The corresponding author provided underlying data for the western blots presented in this article in PLOS ONE Editors issue this Expression of Concern to notify readers of the above concerns and relay the supporting data and updated figure provided by the corresponding author.The S1 File(PDF)Click here for additional data file.S1 Fig(TIF)Click here for additional data file."} +{"text": "The Editorial Office has been made aware of potential issues surrounding the scientific validity of this paper hence has issued an Expression of Concern to notify readers whilst the Editorial Office investigates. A duplicated, modified region has been identified between the miR-145 mimic and siHOXA1 panels of Figure 4C, as well as concerns raised regarding the western blots in Figures 6 and 7."} +{"text": "After publication of this article , concernPLOS ONE Editors followed up with the authors, who have provided the following additional information:The The last author stated that a single lane has been spliced from all blots of the upper and lower panels of Raw data underlying the remaining results reported in the article are available from the corresponding author.S1 File(PDF)Click here for additional data file."} +{"text": "Joint Action Health Equity (JAHEE) was a Joint Action financed by the Third Health Programme 2014-2020 of the European Union. It was developed in the period June 1, 2018 - November 30, 2021, and involved 24 countries. It represented an important opportunity for member states to work together to address health inequalities and achieve greater equity in health outcomes across all groups in society in all participating countries and in Europe at large. The results of JAHEE show that almost all participating countries have increased their level of action to address health inequalities and strengthened their capacities in some important policy domains. 76 actions to contrast health inequalities were started during the Joint Action and a final Consensus Policy Document was produced including a set of cross-cutting recommendations. The proposed workshop will discuss the 3-year JAHEE project in the European region and through presentations and active participation review JAHEE actions, results of internal and external evaluations and discuss the main lessons learned. The session will go beyond sharing information and disseminating results and focus on what the JAHEE evaluation has taught us and how it can help improve health equity interventions in the future.We plan to have:a) Presentations1. Short introduction to JAHEE and Actions2. Presentation Internal Evaluation3. Presentation External EvaluationAfter the presentations there will be opportunity for interactive sessions with the participants to further explore the case studies and issues raised around evaluation and equityb) Interactive Group Discussion\u2022\u2002What do the JAHEE evaluations findings add?\u2022\u2002What aspects of the evaluation were missing? What could have been improved?\u2022\u2002How can the lessons learned from the evaluation be applied to interventions in equity/ migrant health?3) Feedback from Groups4) Summary and Conclusions\u2022\u2002No data no progress.\u2022\u2002Apply an equity lens: Evaluation in health equity actions is important for the sustainability of actions and contributes to the implementation of good practices."} +{"text": "Alteration of GABergic neurotransmission is accused to be sharing in the cognitive impairment in schizophrenia. Exploring the relation between the neuronal expression of GABergic genes and cognitive impairment in living patients through modeling of schizophrenia is an important step to know more about the core of the pathophysiology of this disorderAltered genetic expression of GAD 67 may have an important role in the pathophysiology of cognitive impairment in schizophrenia. Reprogramming of human fibroblasts into human induced pluripotent stem cells (hIPSc) then neuronal differentiation was performed in 20 patients presenting with schizophrenia and 20 matched controls. Real time Polymerase chain reaction was done for measurement of genetic expression of GAD 65, GAD 67 and GABA beta 2. The Digit Symbol task, block design, block design task and similarities tasks from the Wechsler Adult Intelligence Scale., Trail A and Trail B making tests in addition to Rey-Osterrieth Complex Figure Test (ROCF) were applied to measure cognitive functions .There were lower means of GAD65, GAD67 and GABA beta2genetic expression in the patients group with significant statistical difference between the 2 groups. The down regulation of GAD 67 in patients presenting with schizophrenia is positively correlated with impairment in executive functions.GAD 67 gene expression had the most significant correlations with the cognitive assessment in both patients and controls. The presence of those statistically significant correlations in both groups points to the possible role of GAD 67 gene functioning in the pathophysiology of cognitive impairment in schizophreniaNo significant relationships."} +{"text": "This calculation was performed with an assumed population size of 100 using Epi Info software (Power calculations showed that 70 dogs would be needed to estimate the prevalence of a disorder that occurred in 20% of dogs with 5% acceptable margin of error at a 95% confidence interval."} +{"text": "The authors regret that the affiliations for the second (Rodrigo Tart\u00e9) and corresponding author (Nuria C. Acevedo) were incorrectly shown in the original article.The correct affiliations are given here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "The retraction has been agreed following an investigation based on allegations raised by a third party, which revealed inappropriate and unexplained duplications between this and another article [The above article published online on 13 October 2016 in Wiley Online Library ("} +{"text": "The scale has 11 items and is based on the patient\u2019s subjective report of his or her clinical condition 3-Drug Attitude Inventory:consists of a questionnaire that is completed by the patient, pertaining to various aspects of the patient\u2019s perceptions and experiences of treatment.1-There is a positive correlation between the mean score of Young mania Rating scale in 1st episode manic patients and the mean score of DSM5 Anxious Distress specifier Interview 2-The presence of high score of DSM5 Anxious Distress Specifier Interview is positively correlated to the mean score of Drug Attitude Inventory during the follow up visits after controlling the 1st episode maniaThe presence of high levels of Anxious Distress in the 1st episde mania affected the symptoms severity and medication adherenceNo significant relationships."} +{"text": "Congenital anatomical variations of the terminal aorta are rare. Given the increasing number of endovascular and laparoscopic procedures, such variations are likely to assume greater clinical significance. A 15-year-old male sustained a pelvic vascular injury following a stab to the left gluteus. Computed tomographic angiography and digital subtraction angiography demonstrated a left superior gluteal artery pseudoaneurysm and absence of the common iliac arteries consistent with congenital quadrifurcation of the terminal aorta. The patient was subsequently treated with endovascular coil embolisation with a good angiographic and clinical outcome.Terminal aortic variants are rare and given the increasing number of interventional endovascular procedures performed in the aorta, an awareness of the potential anatomical configurations of the distal aortic branches is of increasing relevance. The authors describe the imaging findings of one such anatomical variant. Bleeding was controlled with two inflated wound-track Foley\u2019s catheters and urgent pelvic CT angiography was performed. This demonstrated a traumatic pseudoaneurysm of the left superior gluteal artery and incidental absence of the common iliac arteries with the abdominal aorta terminating as bilateral internal and external iliac arteries at the superior margin of the L5 vertebral body .The patient was then referred for endovascular coiling of the pseudoaneurysm by our trauma surgery team. Arterial access was obtained in the right common femoral artery under sonographic guidance. Subsequent digital subtraction angiogram of the distal abdominal aorta was performed to guide selective catheterisation of the left internal iliac artery. Super-selective catheterisation of the posterior division of the left internal iliac artery demonstrated a superior gluteal artery pseudoaneurysm, which was successfully embolised using three pushable coils (one 4 mm \u00d7 14 cm and two 4 mm \u00d7 5 cm). There was good preservation of the remaining left internal iliac branches .The wound-track Foley\u2019s catheters were deflated in the angiography suite and there was no further haemorrhage. The patient was discharged from hospital by our trauma team 2 days later.2 The abdominal aorta forms by the fusion of the paired dorsal aorta in the 4th week.2 Subsequently, four paired dorsal segmental arteries originate from the abdominal aorta to form the upper lumbar arteries and the fifth lumbar artery gives rise to the bilateral common iliac arteries.2 At 3 months gestation definitive vascularisation is achieved.1The embryological development of foetal vascularisation begins in the 3rd week by a process of vasculogenesis and angiogenesis.5 The two common iliac arteries then course anterior and slightly to the left of the L5 vertebral body before bifurcating into the internal and external iliac arteries at the level of the pelvic inlet.1The normal distal aorta bifurcates into the left and right common iliac arteries at the lower border of the L4 vertebral body in most individuals.7 The incidence of distal aortic and iliac anomalies is unknown, however, a study of 8000 patients performed by Grebe and colleagues revealed only six cases with iliofemoral anomalies.9Variations to the configuration of the terminal aorta and iliac arteries are far rarer than the thoracic aorta and complete failure of bilateral common iliac arteries formation is extremely rare.6 emergent surgical ligation of the internal iliac arteries to arrest intra-operative haemorrhage5 and selection of pelvic host vessels in renal transplantation.This rare anatomical variation is often found incidentally but carries clinical implications in several open and endovascular interventions, such as the selection of distal stent landing zone in endovascular aortic aneurysm repair,10Pham et al. describe a novel endovascular approach to preserve internal iliac artery flow during endovascular aortic aneurysm repair in a patient with bilateral absence of the common iliac arteries by using an iliac branched aortic graft device to repair the aneurysm. They describe selective preservation of a single internal iliac branch to perfuse the pelvis and embolisation of the contralateral internal iliac branch prior to graft deployment.With the increasing number of endovascular and laparoscopic pelvic procedures performed, such variations are likely to be encountered with greater frequency and interventionists should be prepared to tailor their procedural approach to accommodate such anomalies. This is to the best of our knowledge the first case report demonstrating the diagnostic imaging features of this anatomical variation on the African continent. Reporting of this finding when encountered is encouraged.Consideration of this rare anomaly in the planning and execution of open surgical and endovascular arterial procedures is recommended."} +{"text": "Informed by the Ecological and Health Belief models, the manualized Stroll Safe program addresses the unmet need of a targeted outdoors falls prevention program. We examined the efficacy of the program in partnership with eight Naturally Occurring Retirement Community program sites in one U.S city (N=86). Participants age 60 and older with a history of falls or a fear of falling were recruited. Community sites were randomly assigned to the treatment or wait list control group. Results of independent samples t-tests reveal a statistically significant improvement in knowledge of outdoor fall risks and safe community mobility strategy use for the treatment group as compared to the wait list control group on the Outdoor Falls Questionnaire (OFQ) and Falls Behavioral Scale for the Older Person (FaB) . Improvements were retained at 6-week follow up. Implementation strategies are being developed to facilitate program adoption by other occupational therapists."} +{"text": "While volunteers are the foundation of service agencies in rural communities, they are difficult to recruit. This study aims to understand the characteristics of volunteers in a rural community that could aid in recruitment. All volunteers (N=127) for an organization providing services to keep older adults in their homes in rural Michigan were approached to participate in the study. Data were gathered via telephone-interview survey (N=76) and in-person focus groups (N=14) in the summer of 2021 to understand demographic factors as well as benefits and community factors contributing to volunteer participation. Most volunteers were female (61%), married (71%), over age 70 (M=71), and lived with others (72%). In the past year, 49% volunteered 1-5 hours per week and with multiple organizations (70%). They identified the primary benefits from volunteering as getting to know new people (66%). Volunteers agreed that they feel they contribute to the community (97%), have a strong attachment to the community (91%), and have the ability to make a difference in the community (95%). Volunteers were less aware of what could be done to meet the needs in the community (54%) and understand the needs and problems facing the community (59%). Focus group data suggest that volunteers desire information about community needs and aging in place. Due to the lack of centralized locations, social and educational hot spots such as coffee shops could attract new volunteers. Having a sense of community is an important component of volunteering and should be fostered when recruiting new volunteers."} +{"text": "Clinical practice in psychiatry is shifting toward personalized approach. In other words, clinicians aim to help patients based on their individual characteristics. It\u2019s known that testosterone play a crucial role in the regulation of the emotions specially in men. The problems of hypogonadism and its possible role as an etiological factor in the development of depression in men are available in detail. But there is no solid date about the features of depression in men with testosteron defficency and theraputic approach including testosterone replacement therapy and antidepressants.\u0410ssessment of efficiency of different pharmacological approaches in the treatment of depression in men with testosterone deficiencyThe main group included 37 men with a depressive episode that arose against the background of a decrease in testosterone levels (\u226412.1 nmol / L). A depressive episode was diagnosed based on the ICD-10 criteria for a depressive episode (F32). Patients were randomized into 3 treatment groups, depending on the received treatment: 1) sertraline; 2) testosterone gel; 3) sertraline + testosterone gel. The control group consisted of men (n = 40) aged 18 to 65 years, suffering from depression in accordance with the ICD-10 criteria with normal testosterone levelsAn insufficient effectiveness of antidepressant monotherapy in relation to sexual dysfunction was found in main group, while testosterone monotherapy did not give statistically significant improvements in depression indicators.Combination therapy was most effective for the main symptoms and can be regarded as the most appropriate algorithm for the treatment of depression in men with low testosterone levelsNo significant relationships."} +{"text": "Loneliness is a stressor that has been found to increase the likelihood of poor health and dementia. Few studies have focused on this association among men and even fewer studies have examined racial disparities in loneliness and cognitive functioning among this group. The purpose of this study was to examine racial differences in the association between loneliness and cognitive functioning among national sample of men aged 50 years and older.Data were drawn from Black and White men in the 2016 Health and Retirement Study who completed the Leave Behind Questionnaire (n=2226). Cognitive function was the primary outcome and was measured by a dichotomous variable derived from a modified version of the Telephone Interview for Cognitive Status. Loneliness was the primary independent variable and was derived from the 3-item UCLA Loneliness Scale.Black men made up 18.5% of the study sample; however, the proportion of this group with scores indicating cognitive impairment or dementia (35.9%) doubled the corresponding percent of white men (17.6%). Findings from race-stratified modified Poisson regression models indicated that loneliness was associated with a higher prevalence of cognitive impairment or dementia for White men , but Black men .Results from this study raise important questions about the salience of pooled analyses and suggest a need for tailored approaches to mitigate cognitive decline. Additional studies focusing on Black men are needed to develop effective interventions preserving cognitive functioning among this population."} +{"text": "Following publication of the original article , a typesThe article title was incorrectly published as: Molecular brain (micro report) oxytocin ameliorates impaired social behavior in a mouse model of 3q29 deletion syndrome.The article title should read: Oxytocin ameliorates impaired social behavior in a mouse model of 3q29 deletion syndrome.The error has been corrected and the original article has been updated. The publisher apologises to the authors and readers for the inconvenience caused by this mistake."} +{"text": "The dataset published contains all the raw data used in the statistical analysis (Table 1) in order to make them available for any further study. The table contains soil properties, observations on land use, and theoretical coordinates. Real coordinates cannot be made publicly available because they are considered personal data by GDPR and French law\u2013only anonymized data can be shared publicly. The anonymization technique used here is to give theoretical coordinates corresponding to the centre of the 16 km by 16 km grid cell used for the sampling strategy of the RMQS network.The Data Availability statement for this paper is incorrect. The correct statement is: All raw data sets are publicly available in the EBI database system (in the Short Read Archive) under project accession no PRJEB21351. The complete soil characteristics are publicly available in the Data INRAe deposit under project DOI:"} +{"text": "Soil movements produced around deep excavations are one of the main issues to be addressed during design and construction of underground structures in urban environment. Several methods to predict ground movements are currently available. Semi-empirical methods correlate displacements and simple geometrical features of the excavation; these methods predict separately transversal and longitudinal settlement troughs or at least provide a conservative envelope of them and they are mainly based on empirical data of excavations in clay. Numerical methods based on the solutions of FEM or DFM models usually provide prediction of the green field subsidence. In this paper existing 2D semi-empirical methods are first shortly reviewed. Some of these methods are then modified and combined into a new 3D analytical description of the subsidence trough around a deep excavation. The proposed two variable subsidence function depends on several parameters: four independent parameters defining the overall shape and the maximum settlement acting as a scale parameter. Settlement fields reproduced by a 3D FEM nonlinear parametric study of deep excavations inspired by real case studies are thus presented and discussed. The newly proposed 3D analytical description is applied to fit the FEM results and some fundamental relationships among geometrical features of the excavation pit and the 3D shape function parameters are identified. These relationships are validated via the application to three case studies of deep excavations in sand where the subsidence was controlled by the deformation of the retaining structures finding a satisfactory and encouraging agreement. For the prediction of movements around excavations various proposals are available and rely on different approaches. The first and the simplest one, the semi-empirical approach, is based on the experience gained by interpreting data from case histories where displacement around excavation were measured and related to simple geometrical parameters such as the depth of the excavation The settlement around a deep excavation in urban environment are among the main construction issues to be addressed by the design because of the likely damages to nearby buildings and structuresmentclass2pt{minim4 and proposed empirical methods have been tested at least partially on this extensive basis. Among the others reference can be made to the semi-empirical methods by Ou5, Clough and O\u2019Rourke6 and Bowles7 for the transversal settlement trough and to the method by Roboski and Finno8 for the longitudinal settlement trough . Some more specific alternative has been proposed more recently for 2D transversal settlement trough in case of multipropped excavations in clay10. In the following section 2D empirical methods for the prediction of longitudinal and transversal settlement trough are first shortly reviewed. A combination of existing but slightly modified 2D methods was recently proposed by Russo et al.11 to analytically describe the full 3D subsidence trough around a rectangular deep shaft and is further developed in \u201cLarge databases on deep excavations case histories are available since relatively long time12, Finno and Harahap13, Whittle et al.14. As a matter of fact, a 2D simulation of the shaft excavation under plane strain assumption is currently a typical and nearly routinely design step15. Since the aim of the analysis is not only predicting bending moment and shear force acting on diaphragm wall but also the settlement trough behind the wall, extreme attention should be paid when selecting an appropriate constitutive soil model and simulating even apparently minor construction details16. L\u2019Amante et al.16 for instance showed the importance of modelling the very initial stage of the construction of a reinforced concrete (i.e. r.c) diaphragm wall because of its large influence on both soil-structure interaction and on displacement field around the excavation compared to the simpler wish-in-place modelling option. The large computational resources available have recently pushed forward the frontier of numerical simulation capabilities allowing a relatively easy access to large 3D models. This has occurred more frequently with reference to the prediction of tunnelling settlement trough18 but contributions in the field of deep excavation are also available20. These latter contributions aimed mainly at describing 3D corner effects with reference to the horizontal displacement profile of the diaphragm walls.The second approach, the numerical one, consists of the numerical prediction of the green field subsidence trough by means of a FEM or DFM model. Early and significant contributions on numerical analysis are those proposed by Clough and HansenIn this paper 2D semi-empirical methods are reviewed and briefly compared in \u201cIn \u201c22. Displacement fields around deep excavations have been studied in the past via 3D FEM analysis, but the research focussed on the horizontal displacement profile of the deformed supporting wall20. For the settlement prediction at ground surface simple 2D semi-empirical methods are more popular and more diffused in the engineering practice. For this reason, a brief review of semi-empirical methods for 2D settlement prediction around an excavation shaft is here proposed. The settlement field is generally considered strictly linked to the horizontal displacement profile of the retaining wall. The prediction of the surface settlement field is generally divided in two separate subproblems: i.e., the prediction of settlement troughs along two horizontal directions, respectively normal and parallel to the retaining wall. There are quite evident similarities between this methodology and the usual procedure adopted to manage the same issue with reference to a tunnel construction; the evolution of the 3D tunnelling excavation process is generally simply linked to the partial development of the transversal gaussian curve while the longitudinal settlement trough is considered less important and is simulated, if needed, with a cumulative error function. Similarly, in the case of open excavations research has paid more attention to the prediction of the settlement profile along the wall normal direction nearly neglecting the problem of settlement trough along the direction parallel to the wall. This probably occurred also because of the usually adopted assumption of analysing the excavation as a 2D plane strain problem. In the frame of this assumption the plane strain normal settlement trough is simply assumed to be invariable along the side itself. On the contrary the displacement field around a deep excavation is a full 3D problem.The deformation field around deep excavations is three-dimensional. The possibility of a simplified but reliable prediction by means of a two-dimensional model depends mainly on the two geometrical ratios 23 or the subsequent proposals by Bowles7 and Clough and O\u2019Rourke6 are still widely adopted in the preliminary design step of many deep excavation. However, all these works only suggested a conservative envelope of the expected settlement trough. Ou5 and Ou and Hsieh25 proposed on purely empirical bases two different shapes of the settlement trough using discontinuous functions and established a clear dependence of those shapes on the vertical profile of the diaphragm wall horizontal displacements. They divided the settlement trough into a Primary Influence Zone (PIZ) adjacent to the excavation, where large settlements occur, followed by a Secondary Influence Zone (SIZ) where settlements fade away. The SIZ and the PIZ were assumed with equal extension 11)) it i28 focused on 3D effects on horizontal displacement of the diaphragm walls indicating even a 40\u201350% reduction of the displacement close to the corner compared to the plain strain condition. However, if the focus is on settlements, the function Equation allows tmentclasspt{minimamentclasspt{minimaTo test the and to c29 the calibration of the parameters is carried out by fitting data collected from case histories. On one hand these data are certainly very valuable but on the other hand they are often limited to readings performed along simple 2D alignment and furthermore they do not allow for the separate evaluation of the influence of various details. Settlement troughs obtained via numerical parametric analyses allow to look for 3D trends and to effectively separate the contribution of several different factors. In the present study the basic FEM model is inspired by several case histories of stations of the underground network in the urban area of Napoli34. It is worth recalling that the case history and the monitored behaviour were already successfully back-analysed by35 with a similar FEM model and also mentioning the fact that several station boxes have been constructed in recent years with similar geometry and procedure and many others will be in the close future.For empirical methodsThe deep shaft to be excavated has a rectangular plan with dimensions L\u2009\u00d7\u2009B\u2009=\u2009100\u00a0m\u2009\u00d7\u200925\u00a0m and a depth H\u2009=\u200925\u00a0m. see Fig.\u00a0; the modIn Fig.\u00a0Neapolitan Yellow Tuff)37. The depth of the bedrock, Hardening Soil Small Strain Model38 was selected to model the behaviour of layers A and B whilst the Mohr\u2013Coulomb Model was optioned for the layer T. The physical and mechanical parameters overlying a thick soft-rock stratum. The three layers sketched in the profile are: layer A, made ground; layer B, granular silty/sandy layer; layer T, soft rock bedrock on the excavation temporary bottom. The diaphragm walls were modelled as wish in place. For this reason the computed displacements do not include movements generated by the excavation and the subsequent construction stage of the r.c. diaphragm walls. L\u2019Amante et al.16 provided simple tools to evaluate this type of movements. However, two different construction processes were analysed. In the former one, indicated in the following as Top-Propped case (TP), the first prop was installed just after a preliminary, very shallow, excavation (1\u00a0m below the prop axis). In the latter case, called Top-Unpropped case (TU), the first prop was installed after a deeper excavation ; this latter procedure was in fact used in many sites in Napoli and in other historical cities to allow for the mandatory preliminary archaeological checks. The properties of the anisotropic plates adopted for modelling the r.c. diaphragm walls are in Table A classical A plan view of the computed settlement at the ground surface is reported with coloured contour maps in Figs.\u00a0A plot of the results along the transversal sections is reported in Fig.\u00a05 and confirm the validity of this ratio as a predictor of a spandrel shape of the transversal 2D settlement trough at the ground surface. Also in the case TP is reported in Fig.\u00a0mentclasspt{minimaThe settlement data resulting from the 3D FEM analyses were fitted using the function show a very good agreement with suggested values with the only exception of the very unrealistic case corresponding to 25 is either confirmed (for propped cases) or at least conservative (for unpropped cases).To complete the description of the transversal profile in Fig.\u00a025. According to the discussed results it can be simply concluded that the validity of the predictor is here confirmed: all the propped cases (i.e. TP) have a pronounced concave shape with the only exception of the case The values of the two areas In Figs.\u00a08 for an Roboski and FinnoIt was based on the measured performance of a couple of excavations in clayey subsoils. The trend of the parameter A in Fig.\u00a0\u03bb).As regards the parameter In this case the presence of the opening on the long side L play a very important role (full circles cases). In such a case the decreasing trend of \u0394 with the excavation depth is confirmed but the relationship is significantly different from the general equation found above. In Table Three case studies of excavations in sand carried out in the city of Napoli are here presented to be used in the validation of the functions Montedidio underground car park built with top-down procedure in the historical city center. The second one is referred to another underground car park build in the Fuorigrotta borough for the San Paolo mall. The third one is referred to an underground metro station excavated in the fashion district of Chiaia. In all the cases the excavations were carried out in sand overlying a bedrock. In the first two cases the groundwater table was deeper than the excavation depth while for the third case the low permeability of the bedrock and the presence of the sea very close to the excavation inhibited the groundwater lowering outside the excavation. Hence the settlements outside the excavation shaft were in all the cases governed by the retaining system deformations.The first one is the case of Montediddio hill. The excavation reached a maximum depth 39.A multi-storey underground parking was built in a site very close to existing masonry buildings in the historical centre of the city of Napoli at the top of the 25 and obtained by FEM computations presented in the paper are reported in Fig.\u00a0A plan view of the site is shown in Fig.\u00a0mentclass2pt{minimSan Pasquale along the downtown stretch of line 6 close to the sea. The main excavation is supported by T-section reinforced concrete (RC) diaphragm walls. The presence of valuable historical edifices on one side of the excavations suggested the selection of a top-down construction procedure. The reinforced concrete intermediate slabs were used as permanent struts and two large central openings were needed to allow for soil removal during the excavation stages. Full settlement troughs were observed along two different alignments. As a matter of fact, none of the monitored alignments could be interpreted exactly as a normal or a parallel settlement trough. A shape function based on the complementary error function was thus proposed to fit the observed settlement data in the plane considering both the distances x and y respectively parallel and normal to the excavation11.A 27\u00a0m deep excavation in a pyroclastic sand was constructed in the urban area of Napoli to be used as station named 11. Along the sea side, the horizontal displacement profile of the diaphragm walls, reported in Fig.\u00a0quasi longitudinal settlement profiles with the function quasi longitudinal settlement profile indicates that San Pasquale station A plan view of the site is shown in Fig.\u00a0y of Eq. b \u201cpredicAfter a careful review of the existing literature on semi-empirical indications for separate 2D transversal and longitudinal surface settlement pattern around a deep excavation a new two variable function to describe the overall 3D settlement profile behind sides of a rectangular deep excavation has been built and discussed. That is a combination of two separate functions f(y) and g(x). The new two variables function depend on four independent shape parameters and one scale parameter which is the maximum settlement. As widely reported in the scientific literature while the maximum settlement depends on soil mechanical parameters the shape of the settlement trough is mainly dependent on geometry and constraints.Matlab was used to carry out the least square regressions with the proposed new two variable function applied to the subsidence trough produced by Plaxis 3D and adequately sampled via a Python script.The quantitative relationships among the shape parameters and the main geometrical features of the excavation pit or the type of the supporting structural system have been explored using settlement computed by solving several 3D FEM models inspired by typical and repetitive underground station boxes of the transportation network recently developed in the city of Napoli and embedded in pyroclastic sandy layers overlying the bedrock of the yellow tuff formation without groundwater table. The fitting toolbox by 2 coefficient and a random distribution of the residuals. This success clearly indicates the potentiality of the function to be the main element on which to build a semiempirical method. In this paper several preliminary but sound indications on how to fix the shape parameters of the 3D function have been obtained and proposed, verifying, modifying, and integrating previous suggestions by Ou and Hsieh25 and Roboski and Finno8 separately provided for the 2D transversal and longitudinal settlement profiles. With regard to the transversal function f(y) it has been shown that:i.the shape of the horizontal displacement profile of the diaphragm wall summarized by the ratio ii.25 which compared to the FEM computations revealed either exact or at least conservative; the same does not hold true for the spandrel shapes (roughly corresponding to the top unpropped cases).all the shape parameters of the transversal settlement profile, i.e. the slope e/Hg; He/L; L/B of the excavation shaft. Previous indications by Roboski and Finno8 on the parameter A have been integrated and modified recognizing that:Regarding the two shape parameters iii.the value of A for all the analysed propped cases fall in the narrow range [0.1\u20130] while for all the analysed unpropped cases the range is [\u2212\u00a00.1 to 0]; for such a reason the parameter A can be set to 0 as first approximation when using the suggested empirical approach, while more detailed suggestions are available in Table iv.the value of The 3D surface fitted successfully on all the data sets from the cases computed via the FEM code showing high values of the RThe above findings obtained via a careful scrutiny of the FEM computed results have been applied on three case studies of excavations in sand where the settlements at the ground surface are only influenced by the retaining walls deformations, resulting in a general rather satisfactory and encouraging agreement. It is worthy to remark that case studies of excavations in sand with good quality monitoring data are by far rarer in the scientific literature and as a matter of fact most of the empirical methods recalled at the beginning of the paper are often oriented towards excavations in clay. This paper has also contributed to show that this distinction is not that important at least in the cases where the excavation in sand does not involve seepage inside the excavation shaft."} +{"text": "Relapse prevention is a key objetive for patients with a First Episode Psychosis (FEP) and the low adherence to antipsychotic (AP) treatment is the main reason for relapse after a FEP.There are no clear recommendations about the early use of long-acting injectables (LAIs) in FEP. We review the impact on hospitalization rates of the early use (earlier than 1 year after the inclusion in our Early Intervention Service \u201cLehenak\u201d) of LAI paliperidone in a FEP sample.We evaluated in a naturalistic study a sample (N=384) of patients with a FEP. We carried out a mirror-design study to compare the numer of hospitalizations before and after the introduction of LAI paliperidone (1 and 3 monthly) in early users (<1 year) vs late users (>1 year).A total of 384 FEP patients with LAI paliperidone were assessed.There was no difference between the early and late introduction of LAI Paliperidone in the number of hospitalizations after treatament. There was a trend to present more previous hospitalizations and days in hospital in late users. This could support an earlier use of paliperidone LAI to prevent an excess of hospitalizations due to late introduction.The presenting author has received honouraria for lectures or advisory boards from Janssen, Otsuka, Lundbeck and Angelini in the last five years."} +{"text": "The Importance of the appendicular skeleton in the conformation, shape and physiology of wild animals especially carnivores for adaptation and survival cannot be overemphasized, as limited and obsolete information on the bones of the forelimb necessitated this study. Matured adult African lions that weighed 173\u2009kg and 112\u2009kg were obtained at different times after post mortem examinations of their carcasses. Bone preparation was achieved via cold water maceration after proper skin and muscle removal to a barest minimum.The acromion process of the scapula consisted of a ventral hamate and caudal suprahamate processes. The Clavicle was absent in this species. The musculospiral groove of the humerus was more or less absent while its supracondyloid foramen and crest were positioned above the medial condyle and lateral condyle respectively. The radio-ulna presented a twisted appearance with the radius slightly curved thereby creating an extensive interosseous space that spanned its entire length. The seven (7) carpal bones were uniquely arranged in two rows while the 5 metacarpals anchored 5 digits with 3 phalanges except the first with 2 phalanges each. Two sesamoid bones were located on the ventral surface of each Metacarpophalangeal joint. None was seen on its dorsal surface. The 3rd phalanx had a unique appearance with a crescent plate projecting from the ventral cavity. The average total number of bones constituting the pectoral limb was 80.Panthera leo leo) have added some valuable literature to science. This further serves as a baseline data for future scientific exposition on this species.Numerical information and detailed anatomical features of the pectoral limb bones of the African lion ( Panthera leo leo), a member of the family Felidae, order Carnivora and suborder Feliformia [The rapid decline of the African lion weighing 173\u2009kg and 112\u2009kg with estimated ages of 6 and 4\u2009years respectively were obtained as post-mortem carcasses at different periods from the Department of Veterinary Pathology, University of Ilorin, Nigeria. Bone processing was achieved through cold water maceration\u00a0[Two adult African Lions , Arm (Humerus), Fore arm (Ulna and Radius), and Manus . The clavicle was absent in this species. The bones contained morphological features that resembled and differed from other domestic animals studied. The total number of pectoral limb bones in this species was investigated to be 80 as represented in Table\u00a0The Scapula Fig.\u00a0 presenteThe Humerus Fig.\u00a0 presenteThe Ulna and Radius Fig.\u00a0 were fusThe Carpus Fig.\u00a0 presenteFive 5) Metacarpal Fig. bones we MetacarpThis study presented unique morphological features of the African Lion\u2019s pectoral limb that appeared similar and different from other feline and canine species. The Scapula\u2019s presentation of a straight caudal border, convex cranial, convex dorsal border and two surfaces with the lateral divided into two equal halves by the scapula spine was similar to that of the dog and cat The musculospiral groove which is usually present in the humerus of the horse, pig and ruminants was moreThe features of the radio-ulna bone which included the olecranon, anconeal process, coronoid process, medial and lateral styloid processes were all similar to those of the cat and dog . HoweverThe presentations of the seven (7) carpal bones uniquely arranged in two rows and five (5) metacarpals with the first anchoring 2 phalanges while the remaining anchored 3 phalanges were similar to those of the cat and dog . HoweverPanthera leo leo) pectoral limb skeleton presented numerical, detailed anatomical information and elucidated some similarities and differences when compared to the canine and feline species. While adding some valuable literature to science, it further serves as a baseline data for future scientific exposition on this species.This study on the Numerical and Morphological features of the African Lion\u2019s ("} +{"text": "There was apparently some minor arithmetic error involved in the calculation of the nominal mass percentage of TiO2 which was deposited on carbonaceous carbon materials. The nominal mass percentage of TiO2 deposited on carbonaceous carbon materials was calculated incorrectly (should be 20.9 wt% TiO2 instead of 25 wt% TiO2). It should be recognized that this error does not affect any discussion and conclusions reported in this publication. However, this correction is necessary to determine the nominal mass percentage of TiO2 which was deposited on carbon materials and improve the quality of this scientific publication.The authors regret that the Experimental section (2.2 Preparation of hybrid TiOThe Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Administrative data are primarily collected for operational processes and these processes can lead to sources of bias that may not be adequately considered by researchers. We provide a framework to help understand how biases might arise from using linked administrative data, and hopefully aid future study designs.We developed the conceptual framework based on the team\u2019s experiences with the 100 Million Brazilian Cohort (100MCohort) which contains records of more than 131 million people whose families applied for social assistance between 2001 and 2018, linked to other administrative data sources. We provide examples from the 100MCohort of where and how in the linkage process different forms of bias could arise. We make recommendations on how biases might be addressed using commonly available external data.The conceptual framework covers the whole data generating process from people and events occurring in the population through to deriving variables for analysis. The framework comprises three distinct stages: 1) Recording and registration of events in administrative systems such as Brazil\u2019s Mortality Information System (SIM) and the Hospital Information System (SIH); 2) Linkage of different data sources, for example using exact matching via the Social Identification Number (NIS) in Brazil\u2019s Cad\u00danico database or linkage algorithms; 3) Cleaning and coding data used both for analysis and linkage. The biases arising from linkage can be better understood by applying theory and making additional metadata available.Maximising the potential of administrative data for research requires a better understanding of how biases arise. This is best achieved by considering the entire data generating process, and better communication among all those involved in the data collection and linkage processes."} +{"text": "Frail older adults particularly need transitional care between hospital and home due to physical function decline and psychological instability after discharge. This study aimed to develop a transitional care for frail older adults in Korea who are discharged home following hospitalization. The Returning Home (Rehome\u00a9) program was established through the three phases according to the Medical Research Council\u2019s 2013 guidelines. 1) Identifying the evidence base phase included a systematic review of literature and needs assessments from interviews with frail older adults. The core intervention components were determined. 2) At the phase of identifying theory, the transition theory was selected and modified to fit the target population in the context of the Korean healthcare system. 3) Phase three was for the modeling process and outcomes. Based on the result from phases 1 and 2, the Rehome program was developed considering clinically applicable strategies. The final Rehome program consisted of a comprehensive geriatric assessment at admission; structured discharge/transitional care planning at discharge; a home visit and six phone follow-up calls up to 12 weeks after discharge; and emotional support and engagement of the family during the entire period. The Rehome program showed good content validity. The Rehome as a frailty-focused transitional care program could improve the transition through implementing a tailored intervention that meets the care needs of these vulnerable populations."} +{"text": "In the original publication, there was a mistake in The investigation by Holbert et al. aimed to examine the effectiveness of a hydrogel burn dressing as an analgesic adjunct to burn first aid in acute paediatric burn patients. No significant between-group differences in pain scores were found between paediatric burn patients who received hydrogel dressings and those who received standard care (2). A clear benefit of hydrogel dressings as an analgesic adjunct to burn first aid was not identified in the investigation (2). The corrected The authors state that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "After publication of this article , concernLane 1 appears similar to lane 2.When levels are adjusted to visualize background details, there appear to be vertical discontinuities on either side of lane 2.The first and corresponding authors stated that an error was made in assembling this figure panel and the wrong blot was included. They further stated that they have not been able to recover the original data for the top left western blot panel in question.The authors provided a corrected version of The first and corresponding authors stated that the correction of the upper left western blot of panel F of PLOS Biology concluded that the results reported for the PLOS Biology Editors issue this Expression of Concern.S1 File(TIF)Click here for additional data file.S2 File(ZIP)Click here for additional data file.S3 File(XLSX)Click here for additional data file."} +{"text": "The dynamic changes in the rate of H2O2 production were in a reciprocal relationship with the respiration rate and in a direct relationship with the mitochondrial membrane potential and other indicators studied. The pre-incubation of mitochondria with Ca2+(Sr2+)-dependent phospholipase A2 inhibitors considerably suppressed the accumulation of free fatty acids, including palmitic and stearic acids, and all spontaneous Sr2+-induced cyclic changes. These data suggest that the mechanism of ion efflux from mitochondria is related to the opening of short-living pores, which can be caused by the formation of complexes between Sr2+(Ca2+) and endogenous long-chain saturated fatty acids that accumulate due to the activation of phospholipase A2 by the ions. A possible role for transient palmitate/Ca2+(Sr2+)-induced pores in the maintenance of ion homeostasis and the prevention of calcium overload in mitochondria under pathophysiological conditions is discussed.Mitochondria are capable of synchronized oscillations in many variables, but the underlying mechanisms are still unclear. In this study, we demonstrated that rat liver mitochondria, when exposed to a pulse of Sr The futile cycles of the ion mediated by MCUC and Pal-mPT pore functioning in mitochondria may lead to a mild uncoupling accompanied by a significant decrease in ROS production. As shown in this work, there is a direct relationship between the dynamic changes in the rate of H2O2 production by mitochondria and the value of the mitochondrial membrane potential and Sr2+. The data obtained allow us to suggest that the transient palmitate/Sr2+(Ca2+)-induced pore is a tool for the rapid release of calcium ions from mitochondria, which may be involved in preventing mitochondrial calcium overload and regulating cell ion homeostasis. Studies of the Pal/Ca2+(Sr2+)-induced lipid pore hold promise for understanding the mechanism of the oscillatory mode of mitochondrial function under physiological and pathological conditions.In this work, it was found that, during prolonged ion oscillations in response to a Sr"} +{"text": "The worldwide SARS-CoV-2 pandemic has forever altered the manner in which the world and various health agencies will deal with such epidemics and pandemics in future. The synthesis of the COVID-19 vaccinations and the various immunization drives which are underway, mainly garnish and confer protection to the adult populous; namely those aged above 18 years in age . The fruThe Centre for disease control (CDC) recommends 2 doses of Pfizer vaccine separated by 21 days in those aged 5 to 11 years, with an additional third booster in immunocompromised children .The WHO has published a list of all the recognized as well as vaccines undergoing the WHO EUL/PQ evaluation process. What is vitally important to understand is that all vaccines are not the same and do not confer the same level of immunity and protection. The majority of the vaccines are developed for those 18 years of age and above. The various vaccines within the WHO EUL/PQ list are in different levels of testing and are under different phases of study. Among the list of 13 vaccines whom have applied for the WHO approval only 17 thus far have attained the final level of acceptance. These vaccines namely being:BNT162b2/COMIRNATY Tozinameran (INN)AZD1222 Vaxzevria Covishield (ChAdOx1_nCoV-19) [EMA], mRNA-1273COVID-19 Vaccine (Vero Cell)Inactivated/ CoronavacSARS-CoV-2 Vaccine Inactivated (Vero Cell)/ COVAXINNVX-CoV2373/CovovaxNVX-CoV2373/NuvaxovidThe earliest acceptance being Pfizer Biotech with its first site approved on the 31st of December 2020. Pfizer\u2019s vaccine was quickly followed by the likes of AstraZeneca, Covishield, Janssen and Moderna Biotech. Bharat Biotech India received the approval for its Whole-Virion Inactivated Vero Cell vaccine on the 3 of November 2021, in contrast to the initial mRNA based vaccines which received earlier approval. It is widely accepted that the mRNA based vaccines have a greater efficacy and therefore have been more widely used by developed nations in their national rollout of vaccinations. The importance of the above list is the fact that only 2 of the above vaccines (Pfizer and Moderna) have received the necessary licenses and have undergone the necessary studies to be approved for the administration in the younger age group. If one looks at the timeline above, it is evident that both Pfizer and Moderna are both mRNA vaccines and were among the first two companies to bring the vaccine to market. This first to market advantage has allowed for the collection of further data as well as funding for greater research to best produce enhanced vaccines for both the adult and now younger paediatric age group and it is thus only sensible that these two pharmaceutical giants are at the forefront of developing these immunizations which are being targeted towards the younger paediatric age group .As with all new drugs and vaccines, strict trials and studies must be undergone before the medicament can be applied and acceptably used on the general populous. The same regulations apply for the COVID-19 vaccinations. The initial release of the first vaccines were strictly for groups aged 18 years and above. It is now stated by the WHO that all of the vaccines which have received the WHO EUL are safe for the majority of individuals aged 18 years and above including individuals with pre-existing conditions. The younger age groups were also not naturally targeted in the first round of vaccinations due to the illness causing milder symptoms in the young. It has however now been concluded by the World Health Organizations SAGE (Strategic Advisory Group of Experts) that the Moderna vaccine can be safely used in children aged 12 years and above. The WHO\u2019S SAGE has also concluded that the Pfizer vaccine can be administered safely to children aged 5 years and above..The developing nation of Nepal has received both consignments of COVAX as well Moderna vaccines. The national immunization stratagem aims to vaccinate 1.74 million children aged 12 to 17 years with the Moderna vaccine and used the COVAX vaccine for those aged 18 years and above. This planning and forethought will ensure a rapid rise in herd immunity again the virus via vaccinating from the proverbial \u201ctop\u201d and \u201cbottom\u201d of the demographic populous, thus conferring coverage to both the elderly and the young ,15.Pfizer is currently undergoing a phase 1, dose-finding study in combination with an ongoing phase 2\u20133 randomized trial which are being used to study the safety and efficacy of a two-dose regimen of the BNT162b2 vaccine. It is a trial on children between 6 months to 11 years old with a 2-dose regimen of 10, 20 and 30 microgram injections. The doses being given at an interval of 3 weeks. The study concluded that a vaccine regimen of two 10 microgram doses of BNT162b2 administered 21 days apart was found to be safe and immunogenic in children 5 to 11 years of age. Pfizer is also under taking a study using immune-bridging techniques in the younger age group between 6 months to 5 years. The study testing a 2-dose regimen of 3 microgram injections; equating to a dose one tenth of that used in adults. The doses being given at an interval of 3 weeks. Early reports suggest that the immune-conversion and response in the younger patients is insufficient and thus may call for a 3-dose regimen. More data is needed in order to categorically determine the efficacy of the vaccines in those under 5 years of age. It is however evident that vaccinations in the younger paediatric age group namely 6 months to 5 years will materialize and it is now a question of when and not if; the premise of vaccinations being accepted in this age group relies on the data which will be produced via the trials currently underway .The efficacy of the COVID-19 vaccines is evident and their role is vital in combatting the mortality, morbidity and development of new mutations. The role of approved vaccines such as Pfizer and Moderna in the younger age groups namely 12 to 18 years of age and 5 to 12 years of age is vital and shows a categorical increase in immunity and protection. It is thus advised for the 5 to 18 year old cohort to receive their COVID-19 vaccinations. The efficacy of such vaccines in those aged between 6 months and 5 years is still in question and further scientific data and research will need to be undertaken so as to establish the benefits of COVID-19 immunization in the younger paediatric populous."} +{"text": "During the preparation of The label of the color scale in The available data underlying the PLOS ONE Editors sincerely regret that this case was not resolved much sooner after the prior correspondence.The authors provided updated versionsS1 File(PPT)Click here for additional data file."} +{"text": "The retina encompasses several cone and rod photoreceptors at fovea region i.e., 90 million cells of rod photoreceptors and 4.5million cells of cone photoreceptors. The overall photoreceptors determine the vision of every human. An electromagnetic dielectric resonator antenna has been presented for retina photoreceptors in order to model them at fovea and its peripheral retina with the respected angular spectrum. Three coloring primary system of human eye can be realized based on the model. Three miscellaneous models i.e., simple, graphene coated, and interdigital models have been presented in this paper. The nonlinear property of interdigital structures is one of the best advantages to use for creating the capacitor. The capacitance property helps improving the upper band of visible spectrum. The absorption of light for graphene as an energy harvesting material and its conversion into electrochemical signals is making it one of the best models. The mentioned three electromagnetic models of human photoreceptors have been expressed as a receiver antenna. The proposed electromagnetic models based on dielectric resonator antenna (DRA) are being analyzed for cones and rods photoreceptors of retina in the human eye by Finite Integral Method (FIM) utilized by CST MWS. The results show that the models are so fine for vision spectrum due to its localized near field enhancement property. The results indicate fine parameters of The electromagnetic modeling of retina photoreceptors is the best way to realize this vital procedure. Photoreceptors in a normal eye are being located at the outer layers of retina containing photopigments which they are responsible for phototransduction to generate the electrochemical neuronal signals in the presence of light stimuli. These signals can be passed and processed by some neurons at the middle layers of the retina before reaching the retinal ganglion cells (RGC) within the inner layers of retina and the central nervous system (CNS) by optic nerve. Vision restoration of blind people can be achieved by creating devices such as retinal prostheses which they can receive the light and process it. After processing the light, the information can be transmitted in the form of electrical impulses to the remaining inner retinal layers for the visual function. One of the big electromagnetic challenges is analysis and modeling of retina and its optic nerve in order to replace a prosthesis as a bionic eye. Many good endeavors for realizing commercial prosthesis are being done so far Two modes of array antenna have been investigated in this paper. Finite array with 9 (3 \u00d7 3) elements and infinite array (unit cell boundary conditions). There are three different models: simple, graphene coated and interdigital one. The dielectric constant of photoreceptor (cone or rod shapes) and its media to 1 \u03bcm (end point). Every simulated rod photoreceptor array has the equal length of 100 \u03bcm and the diameter is 2 \u03bcm. The results of the output to input ratio obtained by numerical method of the mentioned arrangement for photoreceptors array have very good conformance with mfERG ones of a normal subject with a valid interpretation of the signal to noise ratio of the experiments.The following sections illustrate the response and electromagnetic fields at one frequency sample of each three models.23 \u00d7 3 array of simple cone photoreceptor model has been illustrated in 33 \u00d7 3 array of simple rod photoreceptor model has been illustrated in 4The unit cell boundary condition provides criterion which it equals to infinite array. Simple cone photoreceptor infinite array (unit cell) has the equal length and diameters as shown in 5Simple rod photoreceptor infinite array (unit cell) has the equal length and the diameter as shown in 63 \u00d7 3 array of graphene coated cone photoreceptor model has been illustrated in 73 \u00d7 3 array of graphene coated rod photoreceptor model has been illustrated in 8Graphene coated cone photoreceptor infinite array (unit cell) has the equal length and the diameter as shown in 9Graphene coated rod photoreceptor infinite array (unit cell) has the equal length and the diameter as shown in 103 \u00d7 3 array of interdigital cone photoreceptor model has been illustrated in 113 \u00d7 3 array of interdigital rod photoreceptor model has been illustrated in 12Interdigital cone photoreceptor infinite array (unit cell) has the equal length and the diameter as shown in 13Interdigital rod photoreceptor infinite array (unit cell) has the equal length and the diameter as shown in 14The multifocal ERG responses for a normal subject with a valid interpretation of signal to noise ratio are being shown in 15\u2218 to 5\u2218). The distribution of cones decreases from 5\u2218 to 15\u2218 meanwhile the distribution of rods increases in this area. The rods distribution will be maximum around 20\u2218-27\u2218 and afterwards it begins to decrease upto 30\u2218 and 70\u2218. The maximum input power (intensity) of incidence into photoreceptors is 0.5 The E and H fields of dielectric photoreceptors for every model can be presented here as these fields have been shown with maximum probability location for both conveying and receiving (on Z axis) the signals in the previous figures. There are E and H fields for simple cone and rod photoreceptors array in The impedance bandwidth parameter of DRA severely depends on its permittivity. Decreasing the dielectric constant of the model results in the decrement of the Q-factor and consequently increases the bandwidth of the resonant modes. Moreover, the resonant frequencies of low dielectric constant are higher than those of with the high permittivity one As one single cone photoreceptor is connected with one nerve through optic nerve, there is a comparison on Z axis for output to input ratio of interdigital cone model (the best suited model) by two numerical methods i.e. FIT (CST MWS) and FEM (COMSOL Multiphysics) at the determined sample frequency, 565 THz . Fig. 20The aim of this research for showing these results is the inquiry of phototransduction process of photoreceptors mainly the received signals with respect to the input ones. So, dielectric transmission line can be more suitable for using in this note as well.16In this paper, electromagnetic dielectric resonator antenna (DRA) was presented for retina photoreceptors as a receiver antenna concept based on three models i.e., simple, graphene coated and interdigital structure at outer segment (OS) in order to model them at fovea with the respected angular spectrum. The proposed electromagnetic models based on dielectric resonator antenna (DRA) was analyzed for cones and rods of retina photoreceptors in human eye by utilizing the Finite Integral Method (FIM) associated with CST MWS. The results showed that these models were so fine for vision spectrum with a proper field enhancement in cone photoreceptors due to its sensitivity to light by the localized near field enhancement property. The results indicated fine properties of The study followed the tenets of declaration of Helsinki and was approved by the Farabi eye hospital/Tehran University of Medical Science's Institutional Review Board (IRB) and written informed consents were obtained from patients (Ethics committee reference number: ERC/R/332).None.Informed consent was taken from all individual participants.Mahdi Norooz Oliaei: Conceived and designed the experiments; Analyzed and interpreted the data; Contributed reagents, materials, analysis tools or data; Wrote the paper. Hamid Riazi Esfahani: Conceived and designed the experiments; Performed the experiments; Contributed reagents, materials, analysis tools or data; Wrote the paper. MohammadSadegh Abrishamian: Contributed reagents, materials, analysis tools or data; Wrote the paper.None declared."} +{"text": "Study on ovarian maturation stages were carried out using external morphological assessment of ovarian colourations and histological assessment of Oocyte structure for broodstock selection purpose. Stage 1 to Stage 4 of female shrimps broodstock were sampled from Kuala Muda, Kedah, Malaysia. Four obvious colourations of ovary stages were identified which are: yellow (Stage 1), green yellowish (Stage 2), light greenish (Stage 3) and dark green (Stage 4) through the morphological assessment. The Gonadosomatic Index (GSI) showed significant increment as the gonad reach advance stages. Histological assessment of Stage 1 ovary identified perinucleolar oocyte (PO) with small size oocytes. Stage 2 ovary was identified with yolkless oocyte (YO), Stage 3 ovary was identified with late stage of yolky globules and Stage 4 ovary was identified with fully yolky globules. From the results achieved, it can be concluded that the ovarian colourations and GSI can be applied to identify the ovarian maturation stages, meanwhile, the histology assessment is the most precise method to determine the ovarian maturation stages in more details and accurate for each of the ovarian maturation stages. Maturation stages were identified; yellow (Stage 1), green yellow (Stage 2), light green (Stage 3) and dark green (Stage 4).A histological assessment of ovarian maturation stages was really valuable in the identification of the ovary development for female shrimp broodstock.Additional knowledge generates on the ovarian maturation stages in the broodstock management and selection technique in aquaculture.Penaeus merguiensis is one of the most valuable penaeid shrimp in the marine crustacean group for the identification of ovarian stage instead of histology analysis that gives more precise results. Thus, this study really useful to be applied in identifying the ovarian maturation stages of female broodstock. Ultimately, this study can also be used to identify the reproductive biological change during maturation stages for breeding programs of any marine shrimp broodstock in the future.The details study on the biological of penaeids shrimp is still require and inadequate information and data on the reproduction, spawning seasons and maturation of these shrimps remains scanty . The samThe ovarian maturation stages were distinguished by the colouration of the ovary based on observations from previous studies by Nikon eclipse 80i) and labeled for it ovarian maturation stages for further data analysis.The small lobes of ovary were fixed in the Davidson\u2019s solution for 24 h in the GSI value according to respective stages . The data were presented as mean \u00b1 standard deviation.One-way ANOVA (SPSS version 20.0) with post-hoc and Tukey test was carried out to identify the significant difference , Stage 2 (green-yellow), Stage 3 (light green) and Stage 4 (dark green). The ovary which in Stage 4 (dark green) was clearly visible through the top body of the p = 0.009; p < 0.05) between the GSI to respective stages.In P. merguiensis. For the immature Stage 1 ovary, the perinucleolar oocyte (PO) and small size oocytes were identified from the sectioning of ovary to 31.11 (Stage 4) showed that precise development of the ovarian maturation stages of the female broodstock which is also less similar with the studied done by P. merguiensis shrimp and also can be practically utilised to identify other type of penaeid marine shrimp.Previous study conducted identified that the early ripe which was Stage 3 and the ripe stage which was Stage 4 females can be reliably separated only by identification through histological ovary examination shrimp cannot be reached during the sampling from wild. The results achieve through histology analysis is more reliable as the reproductive biology can be recognised and identified instead of the colourations of each stage of the ovary respectively. This study was really helpful in determining the ovarian maturation stages and can be referred for broodstock management and selection purpose in the future."} +{"text": "Ambulatory care sensitive hospitalizations are widely considered as important measures of access to as well as quality and performance of primary care. In our study, we investigate the impact of spending, process quality and continuity of care in the ambulatory care sector on ambulatory care sensitive hospitalizations in patients with type 2 diabetes. We used observational data from Germany's major association of insurance companies from 2012 to 2014 with 55,924 patients, as well as data from additional regional data sources. We conducted negative binomial regression analyses with random effects at the district level. To control for potential endogeneity of spending and physician density in the ambulatory care sector, we used an instrumental variable approach. In doing so, we adjust for a number of known risk factors for hospitalizations among this patient group. We undertook a Shorrocks-Shapley decomposition to investigate the relative contribution of groups of regressors to the pseudo R2. The results of our analysis suggest that spending in the ambulatory care sector has weak negative effects on ambulatory care sensitive hospitalizations. We also found that continuity of care was negatively associated with hospital admissions. Patients with type 2 diabetes are at increased risk of hospitalization resulting from ambulatory care sensitive conditions. The results of the decomposition analysis for groups of variables indicate that ambulatory care characteristics account for 9.8% of the pseudo R2, morbidity of patients (including gender and age groups) for about 85.5%, and system-related factors of health provision for 4.7%. Our study provides some evidence that meso-level factors such as increased spending and improved continuity of care while controlling for process quality in the ambulatory care sector may be effective ways to reduce the rate of potentially avoidable hospitalizations among patients with type 2 diabetes."} +{"text": "This cycle has been intensively studied over the 50\u2009yr since it was elucidated, and it is highly conserved across nature, from cyanobacteria to the largest of our land plants. Eight out of the 11 enzymes in this cycle catalyse the regeneration of ribulose\u20101\u20105 bisphosphate (RuBP), the CO2 acceptor molecule. The potential to manipulate RuBP regeneration to improve photosynthesis has been demonstrated in a number of plant species, and the development of new technologies, such as omics and synthetic biology provides exciting future opportunities to improve photosynthesis and increase crop yields.The Calvin\u2013Benson\u2013Bassham (CBB) cycle is arguably the most important pathway on earth, capturing CO ImproviuBP Fig.\u2009. A majorBox 1et\u2009al.,\u2009There is a pressing need to increase the yield of crop plants in order to feed our growing population, and this needs to be achieved within the next 20\u2009yr without increasing land area used, or increasing water or nutrient inputs. The yield potential is the maximum yield attainable from a crop when the best adapted crop variety is grown, in optimal conditions with no biotic or abiotic stress. Yield potential is determined by a combination of the availability of light, the ability to capture the available light, conversion of the fixed energy into biomass, and plant architecture in terms of harvest index. Energy conversion is the only one of these four components that is well below its potential maximum, and this parameter is determined by photosynthetic efficiency cycle) comes from studies with a range of plants grown in field conditions under elevated CO2 utilizing ATP and NADPH from the light reactions. The biochemical steps in the regenerative phase of the cycle use this GAP, and through the action of eight enzymes catalysing 10 reactions produce RuBP. In the 1990s antisense technology was used as an empirical approach to identify which of these enzymes exert control over the flow of CO2 in this pathway , fructose 1,6\u2010bisphosphate aldolase (FBPA) and transketolase (TK) as promising targets for overexpression and improvement of photosynthesis , has also resulted in improved CO2 assimilation and growth was increased when the expression of the Brassinole resistant 1 transcription factor (BZR1) was increased and enhanced photosynthetic capacity was observed, suggesting that simultaneous overexpression of these proteins may stimulate the CBB cycle system and the CP12 protein. Increasing the expression of these regulators in conjunction with their CBB cycle targets has yet to be explored as a strategy but could be a viable option given the indications from overexpression of trx on its own approaches to be incorporated into strategies to improve RuBP regeneration and CO2 fixation.The RNA abundance of CBB cycle enzymes changes during plant development, in response to light conditions and the accumulation of sugars; however, the detailed molecular mechanisms underlying the regulation of individual genes have not been elucidated, and even less is known about the coordination of expression of the whole pathway (Wang et\u2009al.,\u2009et\u2009al.,\u2009Metabolite profiling of CBB cycle intermediates from C3 and C4 species revealed specificity and diversity in the CBB cycle between C3 species (Stitt et\u2009al.,\u20092 fixation pathway to operate in parallel with the endogenous cycle (Erb & Zarzycki,\u2009et\u2009al.,\u2009Advances in kinetic flux and multiscale modelling have provided novel predictions on how to further enhance RuBP regeneration. Testing these outputs will require the application of rapid high\u2010throughput and iterative approaches to identify the best candidates with which to achieve improvements in photosynthesis (Benes"} +{"text": "Medically complex older adults from underserved communities experience multiple barriers to obtaining necessary health care and services. Often these individuals are largely unable to leave their homes due to a lack of community resources facilitating travel to and from provider appointments. Rush@Home is a home-based primary care program that focuses on the 4Ms by incorporating patient navigation and social work services for medically complex older adults. The majority of the patients enrolled in the Rush@Home program identify as Black and/or Latino (>50%) and reside on the West Side of Chicago which is historically underserved in terms of health care access. To date, Rush@Home has enrolled n=234 participants with n=176 patients who are currently active in the program. Among participants there less than a 10% readmission rate and an ED visit rate of approximately 5%. This presentation will discuss the Rush@Home data and the importance of community engagement."} +{"text": "Living WHO guideline on therapeutics and COVID\u201019. This trustworthy continuously updated guideline serves as a highly useful decision aid for Nordic anaesthesiologists caring for patients with COVID\u201019.The Clinical Practice Committee of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine endorses the The individual domain totals were: Scope and Purpose 94%; Stakeholder Involvement 84%; Rigour of Development 94%; Clarity of Presentation 91%; Applicability 83%; Editorial Independence 76%; Overall Assessment 94% is available in the Supporting information.4Agreement between the SSAI CPC appraisers was high and the overall assessment of the guideline was very good. The guideline can be used in daily clinical practice in Nordic countries without adaptation or modification. Of note, the effects of the proposed therapeutic agents may to some extent be sensitive to the specific settings they are used in, including the baseline disease severity of COVID\u201019.Living WHO guideline on therapeutics and COVID\u201019https://app.magicapp.org/#/guideline/nBkO1E).The 5Living WHO guideline on therapeutics and COVID\u201019.The SSAI CPC endorses the No Clinical Practice Committee member had direct or indirect conflicts of interest.Supplementary MaterialClick here for additional data file."} +{"text": "There was an error in the original publication . Amount A correction has been made to Section 4. Highly Processed Food Withdrawal, Paragraph Number 1:The minimum daily amount of sodium required by the body is 500 mg; 1500 mg of sodium is an adequate daily intake amount; increased chronic disease risk is associated with an intake of more than 2300 mg of sodium; and the average American consumes 3400 mg of sodium a day [32]. The author states that the scientific conclusions are unaffected. This correction was approved by the Academic Editor. The original publication has also been updated."} +{"text": "The authors regret that the original version of this paper unfortunately contained an inappropriate representative image of Boyden chamber assay. An inappropriate image was inadvertently used for the HSC-LX2 Ligu+GW9662 during the assembly of this figure. The authors confirm that the correction of Figure 4F does not affect the original conclusions. The authors sincerely apologize for any inconvenience or misunderstanding that the error may have caused. The corrected image is shown below."} +{"text": "A need to improve the transitions of care between a small rural emergency department, a residential care facility and a primary care practice emerged early on in our work to become a level 2 accredited emergency department. One challenge is bringing together 3 partners all with distinct types of health records, unique foci of care and a variety of disciplines and workforce. This paper will focus on our journey of creating an individualized plan of care to help mitigate problems of poor communication with a focus on the 4Ms framework including: What Matters Most, Mobility, Medication and Mentation."} +{"text": "In 2019 Dartmouth-Hitchcock Medical Center (DHMC) was recognized by the Institute for Healthcare Improvement as a level 2 Age Friendly Health System (AFHS). Over the past two years DHMC leveraged the strengths of the AFHS to become a level 1 American College of Emergency Physicians (ACEP) accredited geriatric emergency department. Leveraging the paradigm of 4M care including: What Matter\u2019s Most, Mobility, Medication and Mentation, DHMC achieved alignment between the geriatric emergency department accreditation and the AFHS framework. Pathways focusing on the 4Ms have been identified as a model to improve transitions of care post ED. This talk will focus on lessons learned and outcome data specific to the creation of the 4M pathways and transitions of care,"} +{"text": "P<0.01 vs the LPS vehicle group, but not the LPS vehicle group vs the Con. The histogram images of mRNA expressions of TGF-\u03b2 and ICAM-1 in Fig.The authors regret that the original version of their manuscript unfortunately contained some typo and incorrect images. The statistical significance for Nuc p65 between the control and LPS vehicle groups was incorrect in Figure The authors confirm that the corrections made in this erratum do not affect the original conclusions. The authors apologize for any inconvenience that the errors may have caused."} +{"text": "This article has been retracted: Aging has completed its investigation of this paper. We found overlap between some of the transwell assay images used for Figures 3E and 5E and data published by other authors. We also found that images of exosomes isolated from the medium of NEEC and EC18 cells in Figure 4B duplicate exosome images from different cells published in unrelated papers. The authors reply that they \u201care unable to provide satisfactory data in relation to these figures and were unable to support the integrity of the research.\u201d Consequently, all authors agreed that the article should be retracted."} +{"text": "In this research, we have considered the convective heat transfer analysis on peristaltic flow of Rabinowitsch fluid through an elliptical cross section duct. The Pseudoplastic and Dilatant characteristics of non-Newtonian fluid flow are analyzed in detail. The Rabinowitsch fluid model shows Pseudoplastic fluid nature for Siddiqui and Schwarz provided analytical study of the Second-grade fluid flow through axisymmetric tubes with sinusoidally vibrating walls2. Eytan et al. described the peristaltic flow via narrowed conduit under the application of embryo transport within the uterine aperture3. Tsiklauri and Beresnev had considered the flow of Maxwell fluid across a circular channel with peristaltic movement of the boundary4. Rao and Mishra explained the asymmetric channel flow in addition to viscous effects and without neglecting the curvature effects5. Reddy et al. analyzed fluid flow due to fluctuating walls of rectangular shape channel by considering long wavelength approximation6. The fractional model of Maxwell fluid is utilized to study the visco-elastic fluid flow inside a sinusoidal wavy conduit by Tripathi et al.7.The process in which fluid flows across a conduit by the sinusoidal fluctuating boundaries is known as Peristalsis. The fluid propels by the means of deformation of the walls parallel to the axis of channel in peristaltic flow. The wide applications of peristaltic flow in the industrial area, physiological and engineering fields like corrosive fluid transport, blood pumps in heart lungs machines, blood flow in small vessels makes it much important. Due to these many applications numerous researchers has been studying the peristaltic flow via various conduits. Bohm and Friedrich studied the flow of viscoelastic fluids under peristaltic wall deformation of channel by considering an assumption of small Reynold number8. Akbar et al.9 examined the entropy generation and MHD influences on peristaltic flow. Maraj and Nadeem10 interpreted the curved channel peristaltic flow of non-Newtonian Rabinowitsch fluid. Hayat et al.11 explained the entropy interpretation of peristaltic flow of nanofluid in a rotating frame. Rashid et al.12 explained the Williamson fluid flow via curved conduit under the influence of magnetic and peristaltic effects. Saleem et al.13 studied the Casson fluid to highlight the non-Newtonian nature of fluid via duct with elliptical cross section and fluid flows due to peristaltic effects. McCash et al.14 provided the analysis of Newtonian fluid flow through elliptical duct affected by cilia. Asha and Beleri15 highlighted the nanofluid effects on non-Newtonian Carreau model for an axially symmetric inclined conduit by contemplating the Joule heating effect. Riaz et al.16 gave the analysis of solid particles influence on the peristaltically flowing Jeffery fluid across eccentric annuli. Vaidya et al.18 studied the influence of variable liquid and rheological characteristics on peristaltic flow of Rabinowitsch fluid across an inclined channel. The variables properties and application of peristaltic flow of non-Newtonian Rabinowitsch fluid under various effects is discussed by many researchers22.Ali et al. provided the analysis of temperature distribution within a curved wavy conduit23. Akbar and Butt24 provided the analytical study of nanofluid flow in curved tube with vibrating walls. Bibi and Xu25 presented the heat transfer in a nanofluid flow through a horizontal conduit with MHD effects. Raza et al.26 gave the study of water-based nanofluid for various shaped nanoparticles in an asymmetric conduit having permeable boundary under magnetic effects. The influence of heat flux and endoscope on non-Newtonian Jeffery fluid movement across concentric symmetric tubes due to peristaltic motion of walls is discussed by Abd-Alla and Abo-Dahab27. Abbasi et al.28 examined the nanofluids flow under the peristaltic and electroosmotic effects via asymmetric narrow channel. Li et al.29 studied the peristaltic movement of non-Newtonian nanofluid by utilizing Jeffery fluid model under the hall effects and viscous dissipation. Some of the recent literature work that highlights the peristaltic flow, pseudo plastic flow characteristics, MHD impacts and chemical reactions on a channel flow problem are given as33.The heat transfer effects on fluid flowing through different channels are studied by many researchers. The peristaltic flow of heated magnetohydrodynamic fluid under partial slip influence is analyzed by Nadeem and AkramIn this research, we have studied the heated Rabinowitsch fluid flow across a duct of elliptical cross section. The published literature and researchers clearly highlight that there is no research on Peristaltic flow of heated Rabinowitsch fluid inside an elliptic duct. The non-Newtonian fluid flow is studied through a channel with sinusoidally fluctuating boundary walls. The velocity and heat transfer effects on fluid flow are analyzed. A unique polynomial is involved to obtain the solution of temperature. The dilatant and pseudoplastic characteristics of the Rabinowitsch fluid are examined.34 and the geometrical model is given by Fig.\u00a0Consider the flow of a heated Rabinowitsch fluid through a duct having elliptical cross section. The elliptic shape conduit is studied with sinusoidally fluctuating walls. The mathematical study in completed by utilizing cartesian coordinates mentclass2pt{minimThe governing equations of incompressible fluids areThe boundary conditions corresponding to above equations are17The Rabinowitsch fluid stress tensor is provided asThe transformations relate the fixed (unsteady) and wave (steady) frames are given followingThe dimensionless variables to transform the equations into non-dimensional forme is known as the eccentricity of the ellipse such that By applying long wavelength approximation together with the transformation given in (9) and non-dimensional variables by ignoring dash notation provided in (10), Eqs. -7) take take7) tThe corresponding dimensionless boundary conditions areThe expression and 1-b1-b take The dimensionless form of extra stress tensor for Rabinowitsch fluid isThe following Eq.\u00a0 represenThe velocity solution is obtained by using Eq.\u00a0 and direThe volumetric flow rate is attained by integrating the Eq.\u00a0 over ellThe mathematical expression for pressure gradient is attained by utilizing the equation The expression for pressure rise is obtained as35. It is obtained by utilizing the following polynomialThe solution of temperature is attained by using the method provided inBy setting the polynomial in Eq.\u00a0 and takiMoreover, using boundary condition and comparing the coefficients of The solution of temperature is acquired by solving the Eqs. \u201334) sim sim34) sThe graphical analysis of analytically attained results in earlier fragment is presented in this section. This analysis provides an effective study and better understanding of the physical aspects of peristaltic motion of Rabinowitsch fluid flow across elliptic duct. The effect of different physical constraints on the flow velocity, temperature distribution, pressure gradient and pressure rise are discussed. The three-dimensional graphs of velocity and temperature distribution are provided in this graphical examination. Figure\u00a0The Fig.\u00a0Figure\u00a0Figure\u00a0The velocity of flow has same magnitude on the axis of conduit.The flow velocity decreases rapidly in neighboring of walls for Dilatant fluid than Pseudoplastic fluid.The temperature has opposite behavior for Pseudoplastic and Dilatant fluids.Our major task was to solve the complex partial differential equation involved in convection heat transfer and we have provided an exact solution for temperature equation by considering a polynomial of order six with ten constants. Such a polynomial is considered first time in this work to solve the energy equation exactly.The pressure gradient shows the periodic behavior.The pressure rise nature of Dilatant fluid opposes the behavior of pressure rise of Pseudoplastic fluid.The velocity and temperature profiles are parabolic in nature for Pseudoplastic fluid.The streamlines analysis unfolds that size of trappings reduces with rise in flow rate for Pseudoplastic fluid but has opposite behavior for Dilatant fluid.In this study, we have considered the flow of heated Rabinowitsch fluid across an elliptical cross section duct. The flow is studied with sinusoidally vibrating walls of the conduit. The impact of physical constraints on Pseudoplastic and Dilatant fluids through elliptic duct is analyzed. A novel mathematical technique is introduced to solve the partial differential equation that includes the heat transfer in present analysis. A polynomial of order six with ten constants is introduced first time in such analysis to solve the temperature equation. The major outcomes of our study are following:"} +{"text": "Bioscience Reports at the request of the authors due to technical reasons that they feel unable to address. This Retraction also takes place following receipt of a notification from a reader alerting the Editorial Office to similarities in figure panels across other published papers with no common authors. Figure panels of concern include 2C (common images across papers), 4F and 5C/F (common images across papers). The authors are unable to correct the article and wish to retract the article. The Editor-in-Chief and Editorial Board agree with the Retraction.This article is being retracted from"} +{"text": "Patients with an MEN1 genetic mutation nearly all present biochemical evidence of primary hyperparathyroidism (pHPT) in their teens. By definition these patients have unpredictably metachronous multiple gland parathyroid disease. Since nearly all pHPT patients are young there can be no doubt that a parathyroidectomy is indicated to counter the long-term deleterious effects of the excess parathyroid hormone on the bone, renal and cardiovascular systems [The issue of timing of the parathyroid surgery is debated because whilst early intervention limits the risk of end organ damage it tends to be associated with macroscopically more subtle disease and a longer life span for recurrence to occur. Earlier intervention also provides a longer length of patient life to live with the any adverse surgical outcome, in particular hypoparathyroidism. The accepted consensus appears to be that surgery should ideally happen before end organ damage is present, before the biochemistry becomes severe and before a pregnancy in female patients. Once the decision to perform a parathyroidectomy has been taken, usually a joint decision between the patient, the endocrinologist and the surgeon, the optimal surgical strategy in MEN1 patients has also to be agreed.The surgical approach to MEN1 parathyroidectomy has changed over the past decades. A total parathyroidectomy with or without thymectomy and parathyroid autotransplantation in the brachioradialis muscle was popular in central Europe but appears to have lost favour because of the variable efficacy of parathyroid autotransplantation. It has been largely replaced by a subtotal parathyroidectomy with removal of 3 or 3.5 glands often with a cervical thymectomy . The arrThis systematic review of the 2 currently most practiced parathyroidectomy strategies by Dr Bouriez and colleagues highlights the advantages and disadvantages of a LSTP and subtotal parathyroidectomy in MEN1 patients . The LSTThe advantages of a unilateral approach in MEN1 parathyroidectomy can only be obtained if the truly unilateral dominant disease can be reliably identified. The parathyroid dominance can be functional\u2014sestamibi or Choline PET\u2014or based on size using US or CT. However sestamibi scans tend to be negative in multiple gland disease so does the presence of a positive alternative imaging modality make a LSTP wise?The 2 approaches discussed in this manuscript are not mutually exclusive and it seems clear that an approach tailored to each patient circumstance is appropriate . Minimis"} +{"text": "The 2019 coronavirus epidemic (CoViD-19) in Italy originated in Lombardy, on February 21, 2020. Crowding has been defined as a worldwide problem as cause of reduced quality of care and patient satisfaction. It is due and identified by three orders of factors: those at the access (input); those related to the patient\u2019s process (throughput); and those at the exit from the ED (output).We evaluated all the population who went to ED for intossication and substance abuse. Due to the high level of care needed by these, an excessive duration of LOS (length of Stay) can be counterproductive.We evaluated all patients accessing our ED for intossication and substance abuse from February 22 to May 1, 2020 and during the same period of the previous year.We enrolled 142 patients. The Crowding input factors are lower in the pandemic period: reduced attenders (41 vs 101) and reduced average waiting times (59 min vs 86 min). The Crowding throughput factors have instead worsened: LOS for both the visit rooms (810 vs 544 min) and the holding area (1205 min vs 947 min). The Crowding output factors also worsened: the percentage of access block is higher during the pandemic (10% vs 5%). The Total Access Block Time is significantly higher in the CoViD period for the holding area (1053 vs 930 min).The pandemic period presented a worsened crowding for these patients due to the Access Block."} +{"text": "Numerical treatment of singularly perturbed parabolic delay differential equation is considered. Solution of the equation exhibits a boundary layer, which makes it difficult for numerical computation. Accurate numerical scheme is proposed using Stability and uniform convergence of the proposed scheme is investigated. The scheme is uniformly convergent with linear order of convergence before Richardson extrapolation and second order convergent after Richardson extrapolation. Numerical examples are considered to validate the theoretical findings. Singularly perturbed delay differential equation (SPDDE) is a differential equation in which its highest order derivative term is multiplied by small perturbation parameter and involving at least one delay term. Such type of equations have variety of applications in modelling of neuronal variability , in contNotation: In this paper, the symbols We consider a singularly perturbed parabolic delay differential equation of the formSolution of \u20132) exhi exhi2) eFor the case is valid . Since, mentclass2pt{minimb(x) and a(x) respectively. We assume also For small values of mentclass2pt{minimument}\u03b4, \u20134) are are \\docThe derivatives of the solution u of \u2013 is bounded aswhere C a positive constant independent of the parameter of \u20134) is b is bThe T] into M intervals as We sub-divide the time domain iThe global error estimate up totime step is given by To construct exact finite difference scheme, we follow the procedure in . ConsideN is the number of mesh intervals. We denote the approximate solution of u(x) at mesh point Let mentclasspt{minimaN is the number of mesh intervals. Using the discretization in Suppose there exist Solutionof the discrete scheme in satisfies the bound(Uniform stability estimate.) heme in satisfieLet us construct a barrier functions as Let us define the differences operators in space as The solutionof satisfies the truncation error boundWe consider the truncation errormentclass2pt{minimFor a fixed mesh N, and forwe obtainUsing Lemma Solution of the scheme in satisfies the uniform error boundheme in satisfiThe uniform error bound of the scheme follows from the results of Theorem N and M number of mesh points by including the mid points We apply the Richardson extrapolation technique in spatial direction to accelerate the rate of convergence of the scheme. Let We considered two numerical examples of the form in \u20132) from from2) fThe exact solution of the examples are not known. We use the double mesh procedure to calculate maximum absolute error as Solution of Examples mentclass2pt{minimIn this paper, second order uniformly convergent numerical scheme is developed for solving singularly perturbed parabolic delay differential equation. The developed scheme is based on non standard FDM. Stability of the scheme is investigated using construction of barrier function for the solution bound. Uniform convergence of the scheme is proved. Applicability of the scheme is investigated by considering two test examples. Effects of the perturbation parameter on the solution is shown using figures and tables. The scheme is accurate, stable and uniformly convergent.The proposed scheme is not layer resolving method (i.e. there is no sufficient number of mesh points in the boundary layer region)."} +{"text": "The authors regret that the image wrongly attached due to their carelessness in integrating figures in the Figure 2A, Figure 9A and Supplement figure 1. The correct versions are shown below. These images substitution would not affect any results presented in the originally-published version, nor the corresponding text description and the conclusion of the paper. The authors apologize for any inconvenience or misunderstanding that this error may have caused."} +{"text": "The authors wish to make the following corrections to this paper :In the original article, there were mistakes in Figure 6 due to our data storage system encountering an unknown hardware error. Some image files were accidentally duplicated into other, inappropriate folders. We previously sent the wrong (old) version of the manuscript with incorrect images in Figure 6B (panel 10), 6C (panel 1) and 6D (panel 2) because the paper was undergoing a process of multiple revisions at the time of the data storage system error occurring. Now we want to correct these mistakes. However, these changes do not impact the scientific value of the article. The corrected The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated."} +{"text": "We describe a 65-year-old woman with a retinal vein exiting via the pit of the optic nerve (PON). The patient did not report any history of ocular or systemic problems.A temporal congenital pit of the optic nerve (CPON) was detected in the right eye of a 65-year-old woman on routine examination. A retinal vein was noted to exit directly through the optic pit. The vein possibly continued as a choroidal vessel visible in continuity with the retinal vein [Figure 1a]. The left optic nerve was normal [Figure 1b]. Horizontal and vertical sections of the spectral domain optical coherence tomography (SD-OCT) scans of the right eye showed cavitation in the disc stroma [Figures 2a and 2b]. Horizontal sections of the SD-OCT scans showed the relationship of the PON with the retinochoroidal vein [Figure 3]. OCT angiography demonstrated cavitation in the disc stroma and a retinochoroidal vein that emerged through the PON at the level of the superficial capillary plexus in the right eye [Figure 4]. Fundus fluorescein angiography showed filling of the retinochoroidal vein in the early and late phases [Figures 5a and 5b]. Magnetic resonance imaging with contrast of the brain and optic disc showed no venous malformation or vascular anastomosis.,2 CPONs are typically temporal. Acquired disc pits occur in association with myopia and glaucoma. CPON is usually asymptomatic and diagnosed incidentally; however, serous retinal detachment (SRD) or cystoid retinal edema are potential complications.,3,4Pit of the optic nerves can be congenital or acquired and consists of the presence of a crater-like depression in the optic nerve head.To the best of our knowledge, this is the first report of a retinal vein exiting the eye via an optic pit. We propose that the vein is retinochoroidal as it seems to continue as a choroidal vein. That retinal vein may also be a retina\u2013pial vein connecting the retinal circulation to the pial vessels of the optic nerve dura through the pit. However, there is no clear evidence of an anastomosis between the pial or posterior ciliary vessels of the optic nerve with the retinal vein.Informed consent was obtained from the patient included in the study.Nil.The authors declare that there is no conflict of interest regarding the publication of this paper."} +{"text": "This presentation will summarize the extant published studies on the translation of proven family care programs for dementia in different care settings. This review is the first to our knowledge to examine the specific implementation efforts deployed in care settings for different family caregiver programs. In this review, we sought to answer three basic questions: (1) What theory base(s) or conceptual framework(s) guided the implementation of evidence-based family care programs?; (2) What implementation strategies were used to support translation into practice?; and (3) What were the identified drivers of and barriers to organizational change required for adoption of an evidence-based program? Understanding the frameworks and strategies deployed in translational studies published to date can help guide future translation efforts, inform the design of new family caregiver support programs that optimize their implementation potential, and ultimately help to minimize the \u201cfamily care gap.\u201d"} +{"text": "The Editor-in-Chief has retracted this article due to cThe bottom left two panels of Figure 4F of appear tThe TAC panel in Figure 4G of TAC imagThe data reported in this article are therefore unreliable Changsheng Ma agrees to this retraction. The other authors have not responded to correspondence regarding this retraction.The online version of this article contains the full text of the retracted article as electronic supplementary material.Former article version"} +{"text": "The transforming growth factor \u03b21 (TGF\u03b21), whose level may depend onthe polymorphism of the TGFB1 gene, is involved in the formation of myocardialfibrosis. Myocardial fibrosis in a cardiac allograft may lead to aheart\u2019s structural and functional remodeling and subsequent dysfunction.The frequency of occurrence of alleles and genotypes of the TGFB1 genepolymorphic regions rs1800469, rs1800470, and rs1800471 in heart transplantrecipients and their association with graft myocardial fibrosis were analyzed.Carriers of the CC genotype ,and more often the G allele of rs1800471 , were found among heart transplant recipients less frequentlythan among healthy individuals. In patients with ischemic heart disease (IHD),the GG genotype was less common , while the A allele of rs1800469 was found more frequently than in patients with dilatedcardiomyopathy (DCM). In heart transplant recipients with the AA genotype ofrs1800470, myocardial fibrosis, verified by endomyocardial biopsy, was detectedmore often than in carriers of the G allele . The revealed differences suggest a relationshipbetween TGFB1 gene polymorphism and graft myocardial fibrosis. Studies on alarger group of patients would make it possible to characterize the influenceof genetic factors on the formation of myocardial fibrosis in heart transplantrecipients. The number of patients with heart failure is constantly on the rise as the meanlife expectancy increases, while mortality due to acute medical conditions inyoung and middle-aged individuals declines. Heart transplantation is anefficient method for treating end-stage heart failure that improves theprognosis and quality of life of patients. The recently observed increase inthe longevity of heart transplant recipients has been achieved mainly thanks toa reduction in the mortality rate during the early posttransplant period.Myocardial fibrosis, whose development is accompanied by structural andfunctional remodeling of the cardiac graft, is among the factors with anunfavorable impact on the long-term outcome of heart transplantation .Graft myocardial fibrosis is a multifactorial process, with a number ofcellular and molecular factors predisposing one to it . Recent The finding that the TGF\u03b21 level in the peripheral blood is geneticallydetermined is now a fact. Some genetic polymorphisms of the TGFB1 gene wereshown to be associated with the severity of coronary artery atherosclerosis andgenetic predisposition to myocardial infarction; this association varies fordifferent ethnic groups , 5.The TGF\u03b21 protein is encoded by the TGFB1 gene residing on chromosome 19.Eight single nucleotide polymorphisms and a deletion/insertion polymorphismaffecting the expression and activity of TGF\u03b21 have been identified thusfar . ResearcThis study aims at uncovering any association between the rs1800469, rs1800470,and rs1800471 polymorphisms of the TGFB1 gene and myocardial fibrosis incardiac allograft in heart transplant recipients.A total of 110 randomly selected heart transplant recipients who had undergonecardiac allograft transplantation at the Shumakov National Medical ResearchCenter of Transplantology and Artificial Organs in 2017\u20132019 wereenrolled in the study. All study participants were ethnic Russians; of those,99 (84%) patients were males: the recipients\u2019 mean age was 44 \u00b1 14(range: 16\u201370) years. The reason for the development of the end-stageheart failure responsible for the indications to transplantation was dilatedcardiomyopathy (DCM) in 57 patients and ischemic heart disease (IHD) in 53patients. The duration of the follow-up period after heart transplantationextended up to 4 (2.3 \u00b1 1.3) years.The patients were examined and treated in compliance with the clinicalguidelines of the Russian Transplant Society. Endomyocardial biopsy for hearttransplant recipients was performed according to the protocol during scheduledclinical laboratory examination or if there were respective indications.Endomyocardial biopsy specimens were assessed based on the histological andimmunohistochemical data. Thin sections of endomyocardial tissue were subjectedto Masson\u2019s trichrome staining to confirm fibrosis in a cardiac allograft.\u2122 amplification system . The probesfluorescently labeled using VIC /FAM channels weredetected at each amplification cycle. The resulting data were analyzed usingthe BioRad CFX manager 3.0 software.Genomic DNA was isolated from peripheral blood in accordance with the protocol,using a commercial QIAamp DNA Blood Mini Kit on a QIAcube\u2122 automatedanalyzer . The rs1800469, rs1800470, and rs1800471polymorphisms of the TGFB1 gene were analyzed by real-time polymerase chainreaction using TaqMan probes on aCFX96The statistical analysis was carried out using the suite of applied softwarefor research and engineering computations IBM SPSS STATISTICS 20 . In order to prove an independent distribution of alleles in theanalyzed polymorphisms, their compliance to the Hardy\u2013WeinbergEquilibrium was tested . ThefreGenomic typing of the rs1800469, rs1800470, and rs1800471 polymorphisms of theTGFB1 gene in heart transplant recipients was conducted. No deviations in thedistribution of the alleles and genotypes from the Hardy\u2013WeinbergEquilibrium were revealed in the sex- and age-matched control group, consistingof healthy individuals (43). Compliance with the Hardy\u2013WeinbergEquilibrium was detected in none of the heart transplant recipients for allthree polymorphisms .The deviation from the Hardy\u2013Weinberg Equilibrium in the heart transplantrecipient group can be associated with a cardiovascular pathology, although theeffect of a small sample size should not be ruled out; so, a larger sample isneeded for testing.A comparative analysis of the distribution of the genotypes and alleles of thers1800469 and rs1800470 polymorphisms of the TGFB1 gene detected no differencesbetween healthy individuals and heart transplant recipients. However, somedifferences in the distribution of the alleles and genotypes of the rs1800471polymorphism of the TGFB1 gene were found.Carriers of the CC genotype of the rs1800471 polymorphism of the TGFB1 genewere found among heart transplant recipients less frequently than among healthyindividuals , while carriers ofthe G allele were found more often (within the GG and GC genotypes) .An analysis of the association between the frequencies of distribution of thestudied polymorphisms and the demographic and clinical characteristics of theheart transplant recipients revealed statistically significant associationswith sex, diagnosis, and myocardial fibrosis in a cardiac allograft.The distribution of the alleles and genotypes of the rs1800470 polymorphism ofthe TGFB1 gene differed significantly among male and female heart transplantrecipients .Male heart transplant recipients were less likely to carry the GG genotype thanfemales (p \u2264 0.05). A comparison of the frequencies of individual allelesshowed that the frequency of the A rs1800470 allele of the TGFB1 gene is higherin males . No differences inthe distribution of the genotypes and alleles of the rs1800469 and rs1800471polymorphisms of the TGFB1 gene among males and females were revealed.A comparison analysis of the frequencies of the alleles and genotypes of thepolymorphisms in the TGFB1 gene depending on the disease responsible for theheart failure and subsequent cardiac allograft transplantation revealed thatpatients with DCM carried the GG genotype of rs1800469 more frequently thanpatients with IHD did .The frequency of the A allele among patients with IHD was higher than thatamong patients with DCM .Examination of the endomyocardial biopsy specimens showed that myocardialinterstitial fibrosis in cardiac allografts was verified in 49 out of 110transplant recipients. Staining made it possible to clearly discern theconnective tissue, which was colored in various shades of blue (depending onits maturation state) and differed from other cardiac muscle tissues. Allfibrosis types were taken into accountduring the analysis.A comparative analysis of the frequency and genotype distribution revealeddifferences in the frequency of the AA genotype of the rs1800470 polymorphismof the TGFB1 gene in heart transplant recipients with and without myocardialfibrosis .Heart transplant recipients carrying the AA genotype of the rs1800470polymorphism of the TGFB1 gene were more likely to have fibrosis than thosecarrying the G allele .This study has analyzed the distribution of the alleles and genotypes of threefunctionally significant polymorphisms of the TGFB1 gene in heart transplantrecipients. In heart transplant recipients, differences in the frequency ofoccurrence of genotypes and alleles of the rs1800471 polymorphism of the TGFB1gene were found in comparison with healthy individuals. A number of studieshave shown that the G allele of the rs1800471 polymorphism is associated with ahigher level of gene expression and elevated blood level of TGF\u03b21.Dysregulation of the TGF\u03b21 signaling pathway caused by a mutation can beassociated with an increased risk of cardiovascular diseases , 13.When analyzing the genetic predisposition to the primary disease that had beenresponsible for the end-stage heart failure and had made it necessary toperform heart transplantation, we observed a significant association betweenischemic heart disease and the rs1800469 single nucleotide polymorphism.Similar data were obtained by Barsova et al. . Liu et Having analyzed the genetic predisposition to myocardial fibrosis in hearttransplant recipients, we found significant associations between this trait andthe rs1800470 polymorphism. The A allele of this polymorphism is known to beassociated with a high level of TGF\u03b21 in peripheral blood. TGF\u03b21 is apotent stimulator of extracellular matrix production; its hyperproduction isassociated with fibrotic disorders and the development of myocardial fibrosis.Leask showed tThis study has revealed the differences in occurrence of the alleles andgenotypes of the TGFB1 gene: the rs1800471 polymorphism in heart transplantrecipients and healthy individuals, the rs1800469 polymorphism in patients withDCM and IHD, and the rs1800470 polymorphism in patients with and withoutmyocardial fibrosis in a cardiac allograft. The findings give grounds forassuming that the TGFB1 gene and its polymorphic variants are involved in theformation of genetic predisposition to myocardial fibrosis in heart transplantrecipients. Further studies using a larger cohort of patients would providemore specific characteristics of the impact of single nucleotide polymorphismson the development of fibrosis in a cardiac allograft."} +{"text": "The author wishes to make the following correction to this paper :In the original publication, there was a mistake in Figure 2. During manuscript preparation, the Figure 2B CDK4 blot was erroneously duplicated with CDK2. The authors did minor changes in statistical analysis in corresponding western blot quantification. These changes do not affect the conclusion and findings of the research article. The corrected The authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original publication has also been updated."} +{"text": "The authors wish to make the following corrections to this paper :The commercial human cardiomyocytes used in the study were believed to be derived from human induced pluripotent stem cells during the studies. After the studies had been completed and published, short tandem repeat testing by NCardia determined that Cor.4U\u00a9 cardiomyocytes have the genetic background of the human embryonic stem cell line RUES2. The different provenience of these well-characterized cardiomyocytes changes neither our findings nor the interpretation of our data.The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "This article was published in Psychological Medicine with some errors regarding table 5. The first version of this article incorrectly described the models in table 5 as logistic regression models, when in fact they are linear probability models.The authors apologise for this error."} +{"text": "Following the publication of this article , concernIn The Y79 siTiam 1 treated panel of The Y79 siScrambled treated panel of The 0Hr-Y79 C1199 Tiam 1 panel of The corresponding authors indicated that errors were made during the compilations of Figs In addition, the corresponding authors explained that the partial overlap of panels presented in The raw data underlying all other results reported in the article are available upon request from the corresponding authors.PLOS ONE\u2019s Editorial Board advised that the updated figures support the results and conclusions reported in the original article. However, the PLOS ONE Editors issue this Expression of Concern due to the number of panels and figures affected and concerns regarding the overall reliability of the data presented in the original article.Updated Figs"} +{"text": "The FlourishCare Model (FCM) transforms primary care sites by addressing all determinants of health and focusing on helping patients to flourish. The FlourishCare Index (FCI) is a clinical measure to assess the effectiveness of the FCM to address all determinants of health. We will present data on the effectiveness of the FCM serving 159 older adults with MCCs. The sample was mostly female (77%), White (64%), retired (54%), married (30%) or widowed (20%) and living in urban areas (64%). The mean age was 69 (SD=15), with 13 years education (SD=3). Patients changed significantly over time on total FCI scores . Results show significant growth over time for individual health behaviors , health care access and social determinants with psychological determinants and environmental determinants showing a trend to significance. Interaction effects with time show that the FCM supported patients with lower education attainment to improve at a higher rate than those with higher education attainment, for the total FCI score and health care access . Receiving mental health counseling resulted in more improvement in psychological determinants than those who did not receive counseling . The FCM was able to support rural patients at a higher rate than urban patients to gain access to health care . The FCM supported Hispanic patients the most in improving social determinants of health . This study showed the importance of a systems approach to care using measures that focus on what matters most to older adults who value quality-of-life outcomes."} +{"text": "Alam The authors regret that in the published version of the above article the position of the footnote symbol (\u2020) indicating three authors who contributed equally to the paper was incorrect. The footnote symbol should be positioned after the first three authors Israt S. Alam,\u2020 Rory L. Arrowsmith,\u2020 and Fernando Cortezon-Tamarit\u2020 as shown above.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Early Infant Male Circumcision (EIMC) is part of sustainable HIV prevention strategies in Kenya. The goals of the national EIMC program are to circumcise at least 40% of all newborn male infants delivered at hospitals offering the service and keep the rate of moderate and adverse events below 2%.To determine the proportion of early male infants (age less than 60 days) born at hospitals in four counties of western Kenya who got circumcised and document the prevalence of adverse events (AEs) among those circumcised.A retrospective descriptive study involving all records for EIMC from 1st March 2014 through 31st March 2018 in four counties of western Kenya. Data analysis was done using EXEL to document proportion of facilities offering EIMC and compare EIMC uptake and outcomes in the four counties against the national goals for the program.A mean of 4.3% of total health facilities offer EIMC in the region. Siaya had the highest proportion of facilities offering EIMC while Migori had the lowest proportion. Uptake of EIMC was low at 17.4% for all male infants born, far less than the anticipated target of 40%. Average adverse event rates were 0.3%.EIMC uptake remains low in this region of Kenya due to small number of health facilities offering the service. The proportion of circumcised early male infants born at the target health facilities is below the national target of 40% even though the rate of adverse events among those circumcised is acceptable. Voluntary Male Medical Circumcision (VMMC) was introduced as a component of the national HIV prevention program in Kenya in the year 2008 after three randomized controlled trials in African men demonstrated that male circumcision reduces the risk of HIV acquisition by approximately 60%The aim of EIMC program in Kenya was to circumcise at least 40% of all early male infants who come into contact with EIMC providing facilities within 60 days after birth by 2019The aim of this study was thus to describe the uptake and outcomes of EIMC services in the four high-priority VMMC counties of western Kenya. The study mainly focused on the male infants born within the counties' health care facilities in the four counties who return for EIMC within 60 days after birth. The results of the study were compared against national program set targets as outlined in the Second Kenyan VMMC strategic plan (2014\u20132019)Study was conducted in four (4) counties of western Kenya, which were classified as high priority because of high HIV prevalence and inhabited by traditionally non-circumcising community. These counties are affiliated to the CDC western Kenya branch office.The target group was male infants born at the health care facilities in four counties and received EIMC within 60 days of birth at the EIMC accredited facilities within the four counties. Records of clients who were born at the EIMC accredited facilities in the four counties during a 4-year period.The study included all male infants who received EIMC at 60 days after birth. Excluded were all male infants who received EIMC after 60 days of age, those with incomplete records (i.e. missing data) plus those born at home as well as outside the health care facilities in the four counties.Data was collected by review of EIMC records from March 2014 up to March 2018. The study had two sets of records 1) the total health facilities in each of the four counties plus the total accredited facilities certified to offer EIMC in these counties during the four-year period, and 2) EIMC data in the four counties for four years. Data was collected by two trained research assistants (RAs), one covering two counties. Each RA identified the relevant data sets for EIMC for their counties and obtained relevant data on a standard structured data collection sheet. The data was then forwarded via e-mail to the statistician at CDC office in Kisumu for entry, cleaning and analysis.Collected data was cleaned, coded and entered into an EXEL sheets for data analysis. The study variables of interest included:Number of male infants born at the EIMC target facilities in the four countiesNumber of male infants (aged less than 60 days) accessing immunization services who got circumcisedNumber of early male infants circumcised who developed AEsTotal number of health care facilities in each of the four countiesNumber of health facilities offering EIMC in each of the four countiesYear of circumcision Percentages and proportions of health care facilities offering EIMC against total health care facilities in each county were determined. In addition, proportions of early male infants circumcised against total number of early male infants born at the EIMC target facilities were determined. The values generated were measured against the national strategic objective targets of circumcising at least 40% of all male infants born at the EIMC providing facilities within 60 days after birth. The rate of occurrence of AEs was determined by summing up all the reported cases of AEs against the total number of circumcisions performed. A table and graphs were generated to show the trends in uptake and outcomes of the various EIMC interventions in the four counties over the 4-year period.The study was approved by institutional ethical research committee (IREC) at Moi University and permission to review ministry of health data base obtained from EIMC implementing partners before data collection began. The study did not have informed consent processes since there was no direct contact with patients and personally identifiable information was de-identified before analysis. It was a less than minimal risk study, the only possibility being breach of confidential patient information, and so utmost care was taken to safeguard privacy and anonymity of client data. Data sharing was only among the study team members plus the sponsors of research.The study sample was the total number of male infants born at the healthcare facilities in the four counties of western Kenya over a four-year period. Their mean age at the time of EIMC was 22.6 days. In Although the Kenyan VMMC strategic plan (2014\u20132019) had indicated that EIMC roll-out would begin in 2014 and proceed till 2019 According to Another factor that could have led to low uptake of EIMC services is lack of access. The results show that the number of health facilities offering EIMC represents a very small proportion of the total health facilities in the counties (range=4.9\u20135.8%). The trend in EIMC uptake also showed that this number of health facilities offering EIMC remained fairly constant in all the counties during the study period and there were few new facilities being upgraded and accredited to offer EIMC from 2015 to 2018. These reasons could have contributed to the low uptake of EIMC services in this regionThe EIMC uptake in this program is still low against the expected program target, even though the rate of AEs among those who received EIMC is below the expected cut-off of 2%. More efforts, therefore, have to be put in place to enhance uptake of this service. The study had a number of limitations. First of all, this being a retrospective study, there was the inherent weakness of missing and/or incomplete data. Therefore, all patient records with missing data were excluded and data analysis was adjusted according to completeness of information obtained."} +{"text": "Inaccurate description of results in the main text and figure legends;Inconsistencies between the descriptions of results and figures;Overlap between images in Figs.\u00a04a, b (western blot) and 6a, b (cell images);Issues with western blot images presented in Figs.\u00a03 and 4.The Editor has retracted this article after concerns were raised regarding the figures and the contents of the article, including:The Editor no longer has confidence in the results and conclusions presented.None of the authors have responded to correspondence from the editor or publisher about this retraction."} +{"text": "A technical error that occurred during the production process resulted in this article\u2019s peer review history publishing incorrectly; the publisher apologizes for the error. The full Responses to Reviewers from the peer review history can be found below.S1 FileThis file includes the authors\u2019 response to reviewers for the first round of revisions.(PDF)Click here for additional data file.S2 FileThis file includes the authors\u2019 response to reviewers for the second round of revisions.(PDF)Click here for additional data file."} +{"text": "Etheostoma caeruleum) is a member of this ichthyofauna and has a disjunct distribution in glaciated and unglaciated environments west of the Mississippi River. Based on glacial history of the region, there are different expectations on the observed spatial genetic structure of populations in these environments. The aim of this study was to utilize genome\u2010wide SNP data to compare the population genomic structure of the rainbow darter in river networks with disparate glacial histories; the Volga River in the glaciated upper Mississippi River basin and the Meramec River in the unglaciated Ozark Plateau. Individuals were sampled from localities within each river system at distances dictated by the organismal life history and habitat preferences. Riverscape analyses were performed on three datasets: total combined localities of both rivers and one for each river independently. The results revealed a lasting influence of historic glaciation on the population genomic structure of rainbow darter populations. There was evidence of population expansion into the glaciated northern region following glacial retreat. The population genetic signature within the Volga River did not fit expectations of the stream hierarchy model, but revealed a pattern of repeated colonization and extirpation due to cyclic glaciation. The population within the unglaciated Meramec River adhered to the stream hierarchy model, with a directional order of genetic diversity based on the life history and habitat preferences of the species. These results demonstrate the importance of considering the geologic and climatic history of a region as well as the life history of an organism when interpreting spatial genetic patterns.Periodic glaciation during the Quaternary period shaped the contemporary riverscape and distribution of freshwater fishes in the Mississippi River drainage of central North America. The rainbow darter ( The aim of this study was to compare the population genomic structure of the rainbow darter in river networks with disparate glacial histories. The results support the hypothesis that historical glacial cycles during the Quaternary period influenced the observed genetic signature of rainbow darter populations in drainages of central North America. They support the prediction that the populations in the glaciated environment in the north does not fit expectations under the stream hierarchy model. Understanding the influences on the evolution of spatial genetic structure of populations in riverine environments is a unique problem that involves a specific set of questions, which are described as riverscape genetics and Meramec rivers were selected as systems for comparison. Both waterways are historically known to contain abundant resident populations of E.\u00a0caeruleum individuals . A two\u2010adapter process was utilized to create DNA libraries from the digested samples, with 10\u201315 individually barcoded samples allocated to each Illumina library pool. P1 adapters with unique barcodes were ligated to the specific SbfI overhang sequence exposed during the digestion process. Samples were then pooled, sheared using a sequence of cyclic sonication (Diagenode Bioruptor), and size selected into approximately 300\u2013400 base pair (bp) lengths using magnetic beads in PEG/NaCl buffer was run to create a consensus sequence catalog, generate SNP loci, and formulate candidate alleles for individual fish as an optimization target and filtering step to ensure only SNP loci shared by a minimum of 80% of all individuals in a population are retained . The Bayesian assignment test was performed using the software package Jombart, .fastStructure makes use of efficient algorithms to employ a Bayesian framework model for the inference of the total genetic clusters (K) within the data, and assignments of fish to a cluster based on individual genotypes without a priori definitions following Rousset than the Volga River localities among all 10\u00a0localities in the combined river dataset showed a substantial amount of genetic distance between the Meramec and Volga River localities with values ranging between 0.3453 and 0.4345 and an average of 0.4083 ; Data curation ; Formal analysis (lead); Writing \u2013 original draft (lead). Tony Gamble: Data curation (supporting); Formal analysis (supporting); Writing \u2013 original draft (supporting). Peter B. Berendzen: Conceptualization (lead); Data curation ; Formal analysis (lead); Funding acquisition (lead); Writing \u2013 original draft .Table S1Click here for additional data file.Table S2Click here for additional data file.Table S3Click here for additional data file."} +{"text": "This audit aimed to assess to what extent patients being referred for assessment of memory problems were receiving appropriate screening for reversible causes. We considered the blood tests recommended by the National Institute for Clinical Excellence (NICE).Research into \u2018reversible dementias\u2019 identified numerous common underlying causes. As a result of this NICE complied comprehensive guidance on investigations which should be performed in the initial stages of assessing patients with memory problems, ideally at a primary care level. These investigations are also crucial at the point of secondary care assessment in order to make a confident diagnosis.Details of patients referred by their GP to the Older Adult CMHT with memory problems over a one month period were collected. We then used the local laboratory database to note whether each of the eight recommended blood tests had been performed in the preceding 6 months. We measured this against an agreed standard of 95%.After the first cycle of data collection we prepared business-card sized \u2018aide memoirs\u2019 for GPs that could serve as a quick reminder. These were sent out to all GPs in the area along with a letter outlining the audit findings.Overall 31 patients were included in the first cycle. 15 patients had all 8 dementia blood screens (48%), 13 (42%) had some of the recommended tests and 3 patients had no screening tests at all (10%). On average patients had 76.6% of the recommended bloods completed. The most commonly completed tests were Full Blood Count (FBC) and Urea & Electrolytes (U&Es), with blood Glucose being the most frequently omitted.In cycle 2, 20 patients were included. Of these patients, 10 had the full complement of screening bloods (50%); 8 had some tests completed (40%) and 2 patients had no screening tests complete (10%). On average 76% of tests were completed. There was an improvement in the rate of completion of both Glucose and Liver Function Tests from cycle1.This audit demonstrated that current practice does not meet the national standard in general. Our intervention produced a modest improvement in the proportion of patients who received a full complement of dementia screening tests, as well as increasing the rate of patients receiving a blood glucose as part of their screening. It would likely be beneficial to consider further intervention and a 3rd audit cycle in due course."} +{"text": "This study examined the mediating effects of facilitating conditions (FC) on the association between types of social support providers and attitude toward using gerontechnology (AUG) or between types of social support and AUG. The sample was 256 older Koreans having a partner and children . The dependent variable was AUG in terms of an exoskeleton robot for exercise. There were two kinds of independent variables: 1) four types of social support provider , and 2) four types of social support . Mediating variable was calculated as the mean of FC from five questions. There were two analytic steps: 1) structural equation modeling with four latent variables about types of social support provider, and 2) path analysis with four types of social support if only for significant providers at the first analysis. The results from the first step of analysis showed that only social support from spouses had a significant effect on AUG via FC to use gerontechnology. In the second step of analysis, emotional support from spouses was associated with the higher level of AUG via FC to use gerontechnology. The findings could shed light on the salience of emotional support from spouses in terms of the positive attitude on technology usage in later life through enhancing FC for technology acceptance."} +{"text": "Many of the 1.8 billion Muslims across the world observe the fast of Ramadan .The peak of the first wave of the COVID-19 pandemic in the UK coincided with the start of Ramadan which took place between April \u2013 May 2020 and occurred during a period of lockdown with no communal activities. In the UK where nearly 3 million Muslims fast during Ramadan, the Muslim community has been shown to have disproportionately suffered from the health impacts of COVID-19 over the first wave of the pandemic [Leading up to Ramadan there was concern that observing fasting, with its calorific and water restriction, could either exacerbate or predispose people to COVID-19 and cause harm. A rapid evidence review undertaken prior to Ramadan found no evidence against fasting in healthy individuals , which wWe explored the impact of Ramadan fasting on COVID-19 mortality using England as a case study. Data were compiled from the Office for National Statistics (ONS) data sets which were publicly available.We identified 17 local authorities (LAs) in England where the Muslim population as measured at the 2011 census made up at least one-fifth of the population. Muslim populations in these LAs ranged from 20% in Rochdale to 42% in Newham. Apart from 2 LAs (Redbridge and Slough), these LAs were amongst the most deprived quintile of LAs in the country as measured by the Index of Multiple Deprivation 2019.We restricted our analysis to these 15 LAs in the most deprived areas in the country to allow us to make a simple comparison against similarly deprived areas with low Muslim populations. The total population across these 15 LAs was approximately 5 million people 1.35 million of whom were Muslim.A control group of 5 million people was formed by combining the populations of the remaining LAs which were in the most deprived quintile and with the lowest proportions of Muslims in their populations. Muslim populations in this control group of 29 LAs ranged from 0% in Blackpool to 6% in Greenwich.We aggregated COVID-19 deaths by week and plotted these as rates per 100\u2009000 population for the two groups for weeks 10 through 30 of 2020 both as raw death rates as well as indirectly age-standardised death rates (The results show that deaths were falling steadily in both Muslim areas and control areas over the Ramadan period. Furthermore, this trend continued in both sets of areas post-Ramadan suggesting that there was no lagged detrimental effect of fasting in the Muslim areas. Age adjusted death rates were higher than raw death rates in the Muslim areas due to their younger than average populations. These age-adjusted death rates suggest that if anything death rates fell faster in the Muslim areas than the control areas over Ramadan albeit from a higher intial peak level (Our findings suggest that the practices associated with Ramadan did not have detrimental effects on COVID-19 deaths. There has been much commentary suggesting that the behaviours and cultural practices of minority communities explain their increased exposure to the pandemic . These c"} +{"text": "In this paper, we present a Kane-Mele model in the presence of magnetic field and next nearest neighbors hopping amplitudes for investigations of the spin susceptibilities of Germanene layer. Green\u2019s function approach has been implemented to find the behavior of dynamical spin susceptibilities of Germanene layer within linear response theoryand in the presence of magnetic field and spin-orbit coupling at finite temperature. Our results show the magnetic excitation mode for both longitudinal and transverse components of spin tends to higher frequencies with spin-orbit coupling strength. Moreover the frequency positions of sharp peaks in longitudinal dynamical spin susceptibility are not affected by variation of magnetic field while the peaks in transverse dynamical susceptibility moves to lower frequencies with magnetic field. The effects of electron doping on frequency behaviors of spin susceptibilities have been addressed in details. Finally the temperature dependence of static spin structure factors due to the effects of spin-orbit coupling, magnetic field and chemical potential has been studied. The low energy linear dispersion and chiral property of carbon structure leads to map the nearest neighbor hopping tight binding hamiltonian which at low energy to a relativistic Dirac Hamiltonian for massless fermions with Fermi velocity 2.A lot of theoretical and experimental studies have been performed on Graphene as a one-atom-thick layer of graphite since it\u2019s fabrication5. Also, 2D materials could be used for a extensive applications in nanotechnology7 and memory technology8. While the research interest in Graphene-based superlattices is growing rapidly, people have started to question whether the Graphene could be replaced by its close relatives, such as 2 dimensional hexagonal crystal of Germanene. This material shows a zero gap semiconductor with massless fermion charge carriers since their 9. Germanene as counterpart of Graphene, is predicted to have a geometry with low-buckled honeycomb structure for its most stable structures in contrast to the Graphene monolayer10. Such small buckling as vertical distance between two planes of atoms for Germanene comes from the mixing of 12. The behavior of Germanene electronic structure shows a linear dispersion close to K and K\u2019 points of the first Brillouin zone. However ab initio calculations indicated that spin-orbit coupling in Germanene causes to small band gap opening at the Dirac point and thus the Germanene has massive Dirac fermions13. Also the band gap due to the spin orbit coupling in Germanene is more remarkable rather than that in Graphene14. The intrinsic carrier mobility of Germanene is higher than Graphene15. The different dopants within the Germanene layer gives arise to the sizable band gap opening at the Dirac point an the electronic properties of this material are affected by that17. In a theoretical work, the structural and electronic properties of superlattices made with alternate stacking of Germanene layer are systematically investigated by using a density functional theory with the van der Waals correction18. It was predicted that spin orbit coupling and exchange field together open a nontrivial bulk gap in Graphene like structures leading to the quantum spin hall effect20. The topological phase transitions in the 2D crystals can be understood based on intrinsic spin orbit coupling which arises due to perpendicular electric field or interaction with a substrate. Kane and Mele21 applied a model Hamiltonian to describe topological insulators. Such model consists of a hopping and an intrinsic spin-orbit term on the Graphene like structures. The Kane-Mele model essentially includes two copies with different sign for up and down spins of a model introduced earlier by Haldane22. Such microscopic model was originally proposed to describe the quantum spin Hall effect in Graphene21. Subsequent band structure calculations showed, however, that the spin orbit gap in Graphene is so small24 that the quantum spin Hall effect in Graphene like structures is beyond experimental relevance.Recently, the hybrid systems consisting of Graphene and various two-dimensional materials have been studied extensively both experimentally and theoretically25. Moreover, microwave magneto transport in doped Graphene is an open problem26.In-plane magnetic field affects the magneto conductivity of honeycomb structures so that the results show the negative for intrinsic gapless Graphene. However the magneto-resistance of gapless Graphene presents a positive value for fields lower than the critical magnetic field and negative above the critical magnetic28 and experimentally29. However there are no the extensive theoretical studies on doped bilayer systems.The many body effects such as Coulomb interaction and its dynamical screening present the novel features for any electronic material. The collective spectrum and quasiparticle properties of electronic systems are determined form dynamical spin structure factors. These are applied to imply the optical properties of the system. Moreover a lot of studies have been done on collective modes of monolayer Graphene both theoretically30. We can readily express the inelastic cross-section of scattering of neutron beam from a magnetic system based on correlation functions between spin density operators. In other words the differential inelastic cross section 31. The results of this study shows there is no remarkable angle dependence for imaginary part of polarizability around the van Hove singularity, i.e, t implies nearest neighbor hopping integral.The frequency dependence of dynamical spin susceptibility has been studied and the results causes to find the collective magnetic excitation spectrum of many body system. It is worthwhile to explain the experimental interpretation of imaginary part of dynamical spin susceptibilities. Slow neutrons scatter from solids via magnetic dipole interaction in which the magnetic moment of the neutron interacts with the spin magnetic moment of electrons in the solid33. In this references, the optical absorption of Graphene structure in the presence of spin-orbit coupling and magnetic field has been theoretically studied. Optical absorption rate corresponds to the charge transition rate of electrons between energy levels. However in our work, we have investigated the dynamical spin susceptibility of Germanene structure due to spin-orbit coupling. In other words we have specially studied the transition rate of magnetic degrees freedom of electrons. Such study is a novelty of our work so that there is no the theoretical work on the study of magnetic excitation modes in Germanene structure due to spin-orbit coupling. These studies have been performed for Graphene like structures and the most important difference between our results and the spin susceptibilities of Graphene structure is the effects of overlap function in Germanene structure compared to Graphene lattice. In fact overlap function has considerable impact on the frequency position of excitation mode and also on the intensity of scattered neutron beam from Germanene structure.It is worthwhile to add few comments regarding the comparison Germanene and Graphene like structure. As we have mentioned, the most important difference between Germanene structure ad Graphene one arises from the nonzero overlap function between nearest neighbor atoms in Germanene structure. Response functions of Graphene in the presence of spin-orbit coupling have been studied recentlyThe purpose of this paper is to provide a Kane Mele model including intrinsic spin-orbit interaction for studying frequency behavior of dynamical spin susceptibility of Germanene layer in the presence of magnetic field perpendicular to the plane. Using the suitable hopping integral and on site parameter values, the band dispersion of electrons has been calculated. Full band calculation beyond Dirac approximation has been implemented to derive both transverse and longitudinal dynamical spin susceptibilities. We have exploited Green\u2019s function approach to calculate the spin susceptibility, i.e. the time ordered spin operator correlation. The effects of electron doping, magnetic field and spin-orbit coupling on the spin structure factors have been studied. Also we discuss and analyze to show how spin-orbit coupling affects the frequency behavior of the longitudinal and transverse spin susceptibilities. Also we study the frequency behavior of dynamical spin susceptibility of Germanene due to variation of chemical potential and magnetic field. Also the effects of spin-orbit coupling constant and magnetic field on temperature dependence of both transverse and longitudinal static spin susceptibilities have been investigated in details.21 (H) for Germanene structure includes the tight binding model (BA(B) in unit cell index i. The operators fulfill the fermionic standard anti commutation relations B refers to strength of applied magnetic field. g and 21 of the KM Hamiltonian in Eq. (i to its next-nearest neighbor j. Moreover A,\u00a0B in the unit cell, ith unit cell in the crystal and i th unit cell on sublattice index The crystal structure of Germanene has been shown in Fig.\u00a0entclass1pt{minimaentclass1pt{minimas is the overlap between orbital wave function of electron respect to the nearest neighbor atoms, ab initio calculations has been determined the hopping amplitudes and overlap values 18T introduces the time ordering operator and arranges the creation and annihilation operators in terms of time of them without attention to the their algebra. The Fourier transformation of each Green\u2019s function element is obtained byThe small Buckling in Germanene causes to the considerable value for 2NN and 3NN hopping amplitude. Moreover we have considerable values for overlap parameters of electron wave functions between 2NN and 3NN atoms. The band structures of electrons with spin mentclasspt{minimaz direction. The solid angle 30. In order to study the general spin excitation spectrum of the localized electron of the systems, both transverse and longitudinal dynamical spin-spin correlation functions have been calculated. Linear response theory gives us the dynamical spin response functions based on the correlation function between components of spin operators. We introduce N is the number of unit cells in Germanene structure. In order to calculate the correlation function in Eq.\u00a0(34 asz component of spin operators asThe correlation function between spin components of itinerant electrons in Germanene layer at different times can be expressed in terms of one particle Green\u2019s functions. The frequency Fourier transformation of this correlation function produces the dynamical spin susceptibility. The frequency position of peaks in dynamical spin susceptibility are associated with collective excitation of electronic gas described by Kane-Mele model Hamiltonian in the presence of magnetic field. These excitations are related to the spin excitation spectrum of electrons on Honeycomb structure. In the view point of experimental interpretation, the dynamical spin susceptibility of the localized electrons of the system is proportional to inelastic cross-section for magnetic neutron scattering from a magnetic system that can be expressed in terms of spin density correlation functions of the system. In other words the differential inelastic cross section n in Eq.\u00a0 should bStatic transverse spin structure factor (We turn to a presentation of our main numerical results of imaginary part of dynamical structure factors of Germanene layer at finite temperature in the presence of magnetic field and spin-orbit coupling. Also the temperature dependence of static structure factors has been addressed in this section. Using the electronic band structure, the matrix elements of Fourier transformations of spin dependent Green\u2019s function are calculated according to Eq.\u00a0. The imaing Eqs.\u00a0, 33.The frequency behaviors of both the transverse and longitudinal dynamical spin susceptibilities have been addressed in this present study. Also the spin structure factors behaviors have been investigated for Germanene structure.The optimized atomic structure of the Germanene with primitive unit cell vector length mentclass2pt{minimz direction of magnetic moment of electrons and neutron beam. Another novel feature in Fig.\u00a0In Fig.\u00a0The frequency dependence of imaginary part of longitudinal dynamical spin structure factor of undoped Germanene layer in the presence of spin polarization for different magnetic field values In Fig.\u00a0z components of spins improves with spin-orbit coupling. Another novel feature is the non zero value for static structure factor The behavior of longitudinal static spin structure factor The temperature dependence of static longitudinal spin structure factor of doped Germanene layer for various chemical potential has been studied in Fig.\u00a0z direction perpendicular to the plane causes long range ordering of z components of spins of electrons which increases the longitudinal static structure factor at low temperatures below 0.5.The effect of longitudinal magnetic field on the behavior of We have also studied the dynamical and static transverse spin structure factors of Germanene layer in the presence of magnetic field and spin-orbit coupling. Our main results for imaginary part of dynamical transverse spin susceptibility of undoped Germanene layer for different spin-orbit coupling strengths at fixed temperature In Fig.\u00a0Figure\u00a0The behavior of transverse static spin structure factor mentclasspt{minimamentclasspt{minimaThe temperature dependence of static transverse spin structure factor of doped Germanene layer for various chemical potential in the absence of magnetic field has been studied in Fig.\u00a0mentclasspt{minimaz direction perpendicular to the plane causes long range ordering of components of spins parallel to the plane of electrons which increases the longitudinal static structure factor at low temperatures below 0.25.The effect of longitudinal magnetic field on the behavior of"} +{"text": "Black men experience high levels of social and psychological stress and religion has been a coping strategy. The purpose of this study was to examine the association between religious service attendance and mortality among Black men. Data were drawn from the NHANES III (1988-1994) sample linked to the 2015 public use Mortality File. The analytic sample (n=2300) was restricted to Black men. All-cause mortality was the primary outcome and religious service attendance was the primary independent variable. Findings from Cox proportional hazards models indicated participants who attended at least once per week were 18% less likely to die than their peers who did not attend a religious service at all . The robust association between religious service attendance and mortality among Black men suggest that prospective studies are needed to further examine the influence of religion on health among this population."} +{"text": "Strongyloides fuelleborni infections from Australia made in this paper was incorrect, as those samples in fact originated in Guinea-Bissau and Senegal.All errors found in this paper are due to six samples included in the paper incorrectly assigned as being from Queensland, Australia. The report of There is an error in S1 FigThis file serves as an aid for (PDF)Click here for additional data file.S1 FileThe details in this supplementary file have been updated in accordance with the corrections in (XLSX)Click here for additional data file.S2 FileSome of the fasta sequence headers in this file were updated according to the corrections detailed in (FASTA)Click here for additional data file.S3 FileSome of the fasta sequence headers in this file were updated according to the corrections detailed in (FASTA)Click here for additional data file."} +{"text": "ALDH2*2 is a loss of function mutation common in East Asian populations associated with facial flushing on exposure to alcohol and increased risk of certain cancers. Conversely, absence of the ALDH2*2 mutation is associated with increased risk of hypertension and cerebral microbleeds, and two recent studies report a higher frequency of ALDH2*2 alleles in nonagenarians compared to population control samples. We used survival analysis to investigate the association between ALDH2*2 and risk of cognitive impairment and death after controlling for midlife alcohol consumption and other covariates. Participants are 621 Japanese-American men (72 to 92) enrolled in the Honolulu Asia Aging Study (HAAS) and assessed for cognitive impairment for up to 20 years. Impairment was defined as crossing below a threshold score of 74 on the Cognitive Assessment Screening Instrument (CASI). Age at death was determined by Hawaii state death certificate. Ounces of ethyl alcohol consumed per month was assessed by structured interview conducted 25 years prior to baseline cognitive assessment. Persons heterozygous for the ALDH2*2 variant have reduced risk of cognitive impairment and reduced risk of death, compared to homozygote non-carriers. Covarying by alcohol exposure had no effect on observed associations. This study replicates previous findings associating ALDH2*2 with longevity, and provides evidence the protective effect extends to cognition. This poster details the statistical analysis carried out to obtain these results."} +{"text": "The world is tantalizingly close to eradicate the second human disease in the history of global health. Compared to late 1980s when the Global Polio Eradication Initiative (GPEI) was launched, incidence of wild poliovirus (WPV) cases has been reduced by more than 99.9%, two of three serotypes of WPV have been certified eradicated and all but two countries \u2013 Pakistan and Afghanistan \u2013 have successfully interrupted endemic WPV transmission. However, an uptick of WPV type 1 cases in these two endemic countries in the recent past combined with a rise in circulating vaccine-derived poliovirus (cVDPV) spreading across more than twenty countries in Africa have proved to be issues of major concern in the final phase of the eradication battle In addition to overcoming the evolving challenges of persistent WPV type 1 circulation in the two endemic countries and the expansion of cVDPV circulation in the African continent, safeguarding post-eradication risks of re-introduction of poliovirus transmission is a key strategic focus of the GPEI. In the post-eradication era, accidental leakage of WPV from vaccine manufacturing plants could lead to community exposure and paralytic outbreaks. Applying containment strategies and maintaining high population immunity through routine immunization with inactivated poliovirus vaccine (IPV) are expected to minimize such risks and the fallout in vitro in the recent past. Also, in December 2020, Sabin IPV manufactured at LG Chem received WHO Prequalification paving the way for boosting IPV supplies in low and middle income countries vs three dose regimen trial, study participants were randomized to receive either 3 doses of sIPV at 2,3 4 months, or 2 doses at 4 months and at 8\u201311 months. Seroprotection rates achieved one month after the last vaccination, 5 months in the 3 dose and 9\u201312 months in the 2 dose groups, was greater than 98% for all three polio serotypes in both schedules while median titers were significantly higher in the 2 dose group for all serotypes. Enhanced immunogenicity of the delayed 2-dose regimen with longer interval between doses is consistent with our understanding of impact of maternally-derived antibodies on IPV when administered early in infancy.Sabin strain IPV (sIPV) formulations have been in development for almost a decade, with on-going use in China and Japan These results should encourage similar studies with other Sabin IPV vaccine candidates in infant immunization schedules with less than 3 doses. The tradeoffs across delayed, dose sparing schedules with cost and supply advantages have to be carefully balanced out with any potential risk of vulnerability of young infants from on-going polio transmission in high-risk areas. Non-inferiority of delayed, SAGE recommended schedules of Salk IPV \u2013 either in full or fractional doses \u2013 have also been demonstrated in randomized controlled trials All strategies aiming to improve biosafety measures of polio vaccine production with the promise of further cost saving through dose sparing are important to strengthen the chances of success to complete and maintain polio eradication. This study is a valuable addition to the evidence base around the option of reduced number of sIPV doses infant inmunization schedules and should therefore expand the supply possibilities of IPV produced from safer sources in the final phase of polio eradication and beyond.We declare no competing interests."} +{"text": "Students enrolled in Psychology of Aging and Consumer Behavior combined efforts during an 8-week course to create marketing plans focused on proposing a product or service targeting older adults. The goal of the project was to 1) infuse aging content into the curriculum 2) increase awareness of older adult consumers and 3) decrease aging stereotypes. Student teams were engaged in this project one day each week over 8 weeks. Instructors created weekly tasks to break down components of the project and each student group was required to turn in evidence of their completed task. During the 2020-2021 academic year, participants used Microsoft Teams and recorded their tasks for instructors to grade. A rubric was used to facilitate grading of weekly team tasks and similar weights/points were used in both classes to create similar levels of student \u201cbuy in.\u201d Suggested implementation tips for both face-to-face and online modalities will be discussed."} +{"text": "The original publication of this article containeIncorrectPXD00008293.The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium [16] via the PRIDE partner repository with the dataset identifier CorrectPXD008293.The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium [16] via the PRIDE partner repository with the dataset identifier IncorrectPXD00008293.The SILAC mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (16) via the PRIDE partner repository with the dataset identifier CorrectPXD008293.The SILAC mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (16) via the PRIDE partner repository with the dataset identifier"} +{"text": "Therefore, the Oxidative Medicine and Cellular Longevity 13 contribution of other SIRT families such as SIRT1 was not taken into account.\u201dDue to an error introduced during the preparation of the manuscript, the IR DAPI panel of Due to an error introduced during the preparation of the manuscript, in In the article titled \u201cDexmedetomidine Ameliorates Hippocampus Injury and Cognitive Dysfunction Induced by Hepatic Ischemia/Reperfusion by Activating SIRT3-Mediated Mitophagy and Inhibiting Activation of the NLRP3 Inflammasome in Young Rats\u201d , a numbe"} +{"text": "A 5\u2013year-old boy presented with a history of sudden onset of asymptomatic dark patchy pigmentation over his right hand for a duration of 2 days which could not be washed off with soap and water. The child gave history of playing in the fields along with his friends catching insects and butterflies. The parents explained the presence of similar kind of lesion among his play mates. On examination, right palm showed black patchy pigmentation as discrete macules of varying sizes as ink splatter appearance which to spread along the dermatoglyphics . DiagnosChilocoris assmuthi) has been reported in various parts of India. Cynidae fall under the superfamily pentatomoideae with a common name of \u201cburrowing bugs\u201d because of its natural habitat of staying underground, feeding on roots of plants.,Cutaneous pigmentation because of cynidae bugs are mostly underreported may either be due to its transient nature or self-awareness of its innocuousness by the people belonging to the indigenous locality. The occurrence of burrow bugs (Asymptomatic exogenous pigmentation may simulate many dermatologic ailments but a careful history and examination points us toward the cause. The tip off in this case would be prevalence of the bug in India, definite history of outdoor activity before the onset of lesions and its characteristic pigmentation."} +{"text": "Background: The recently introduced Tigertriever XL Device for treatment of cerebral vessel occlusions combines manual adjustability and maximum length in one device. In this study, we report our initial experience with the Tigertriever XL in terminal ICA occlusions. Methods: Retrospective multicenter analysis of acute terminal ICA occlusions treated by mechanical thrombectomy using the Tigertriever XL Device. Results: 23 patients were treated using the Tigetriever XL due to an acute occlusion of the terminal ICA. The overall successful reperfusion rate after a median of two maneuvers using the Tigertriever XL Device was 78.3% (mTICI 2b-3). In 43.5% (10/23) additional smaller devices were applied to treat remaining occlusions in downstream territories, which resulted in a final successful reperfusion rate of 95.7%. Device related complications did not occur. Two symptomatic intracerebral hemorrhages (sICH) were observed. Conclusions: The Tigertriever XL Device might be a helpful tool in the treatment of ICA terminus occlusions with large clot burden resulting in high reperfusion rates. This is mainly related to the manual adjustability of the device combined with the maximum length. Ischemic stroke due to an occlusion of the terminal internal carotid artery (ICA terminus) accounts for 20\u201330% of large vessel occlusions (LVO) within the anterior circulation . PatientFor LVOs within the anterior circulation, mechanical thrombectomy (MTE) using either a stent-retriever in combination with aspiration or aspiration alone is safe and effective ,7. With A recent study demonstrated higher successful reperfusion rates achieved with a manually expandable stent-retriever compared to conventional devices following a comparative analysis of MTE in acute LVOs within the anterior circulation . The novWith this retrospective observational multicenter analysis of acute ICA terminus occlusions treated with the Tigertriever XL Device on an intention to treat approach we thought to evaluate our initial angiographic and clinical experience.We performed a retrospective analysis of the prospectively maintained stroke databases at the four participating neurovascular centers. All patients treated by MTE using the Tigertriever XL on an \u201cintention to treat approach\u201d due to an acute occlusion of the ICA terminus between July 2020 and June 2021 were included. An underlying proximal stenosis of the ipsilateral ICA treated by implantation of a stent prior to MTE (tandem lesion) was not an exclusion criterion in this analysis.The diagnosis was confirmed by multimodal computed tomography (CT) including non-enhanced CT and CT-angiography, while CT-perfusion studies were not routinely performed. All pre-procedural non-enhanced CTs were retrospectively classified according to the Alberta Stroke Programme Early CT Score (ASPECTS). The clinical status of each patient was evaluated by the attending stroke neurologist according to the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS) on admission and at discharge. A postprocedural non-enhanced CT was routinely performed within 24 h following the procedure. Patients that arrived within 4.5 h of symptom onset received intravenous thrombolysis (IVT), if eligible. The decision to perform MTE resulted from an interdisciplinary consensus of the neurological and neuro-interventional team members based on the 2015 guidelines of the American Heart and Stroke Association and the guidelines of the German Society of Neurology . The finThe following data were analyzed in retrospect: successful reperfusion achieved using the Tigertriever XL Device only defined by the modified Thrombolysis in Cerebral Infarction scale score (mTICI) 2b and 3; the final mTICI (2b and 3) after additional thrombectomy maneuvers in downstream vascular territories were performed with suitable devices and the first pass effect (defined as mTICI 3) . FurtherThe indication to use the Tigertriever XL is restricted to the treatment of ICA terminus occlusions due to its size. Therefore, additional occlusions in the downstream branches of the anterior or middle cerebral artery (whether preexistent or in the context of an ENT) were treated with different suitable devices.The statistical analysis of all variables was performed independently using Excel 2019 and IBM SPSS Statistics 27 . Continuous variables are given as the median and range and independent variables are described as percentages.The fundamental technical concept of the Tigertriever XL Device does not differ from the remaining Tigertriever Devices, whose design consists of a braided mesh of nitinol wires with the distal end connected to an inner wire . A contrProcedures were performed under general anesthesia by experienced stroke interventionalists (at least five years of experience in endovascular stroke treatment) on different biplane angiographic systems at the contributing centers. After confirmation of the suspected ICA terminus occlusion by digital subtraction angiography a combination of an 8 and 6 French (F) guiding and aspiration catheter was placed within the target cervical ICA. Guiding and aspiration catheters were applied according to the institutional standard of the participating centers without a predefined technical setup. In cases of an accompanying cervical ICA stenosis reconstruction of the affected segment by balloon dilatation and a self-expandable stent was carried out prior or following the MTE procedure. The decision whether to perform the stent angioplasty before or after the MTE was left upon the operator\u2019s decision. Placement of the Tigertriever XL Device does not differ from that of conventional stentretrievers, while the desired position was the terminal ICA with the distal end of the mesh reaching into the M1 segment. The device was then expanded stepwise until the mesh was assumed to cover the entire circumference of the ICA based on the information obtained from the previously performed CTA or a relevant deformation of the mesh occurred. The aspiration catheter was pushed upwards guided by the wire of the Tigertriever XL. Then, the device was gently pulled back under continuous aspiration. In the event of resistance recognized by the operator during retrieval the expansion of the mesh was reduced accordingly. Once a sufficient reperfusion (mTICI 2b-3) was obtained, the procedure was terminated. The maneuver was repeated in cases of a remaining occlusion of the ICA terminus using the Tigertriever XL or alternative devices, while the decision of which device to use was made by the operator.In cases of successful reperfusion of the ICA terminus but a remaining or additional occlusion in the downstream arteries, the procedure was continued using standard devices appropriate for these downstream arteries of smaller caliber (MCA M1 or M2 and ACA A2). The decision whether to continue or to cease the procedure in these situations was made by the operator. However, the fundamental goal was a final mTICI 2b-3 result.Between July 2020 and June 2021, 23 patients were treated using the Tigetriever XL Device due to an acute occlusion of the ICA terminus at the participating centers.tandem lesion).Time median intervals from symptom onset to reperfusion and from groin puncture to reperfusion were 223 min and 41 min (range 115\u2013348 min and 13\u2013137 min), while in 9 of the 23 cases (39.1%) the exact time of symptom onset remained ambiguous (wake-up stroke). In 8 of the 23 patients (34.8%), IVT was initiated prior to the endovascular procedure. In 26.1% (6/23) of all cases, an accompanying ipsilateral extracranial ICA stenosis was treated prior to the MTE procedure (The median NIHSS and ASPECTS on admission was 16 (range 2\u201342) and 8 (range 5\u201310). The overall successful reperfusion rate (mTICI 2b-3) in the entire series was 95.7% (22/23 cases). The primary endpoint (successful reperfusion using the Tigertriever XL only) was accomplished in 18 of the 23 cases (78.3%) after a median of two attempts with the Tigertriever XL . An overview of the additional devices applied including the alteration of the TICI grades thereby is given in Technical failures of the Tigertriever XL Device or procedure-related complications as dissections or vessel ruptures did not occur. The postprocedural CT was without evidence of SAH in all of the cases. Two of the 23 patients experienced a sICH following the successful reperfusion observed on the postprocedural CT (8.7%). At discharge the median NIHSS was 11 (range 1\u201342) and the rate of mRS 0\u20132 was 26.1%. Five patients died related to the stroke but not the procedure itself .With this retrospective analysis, we evaluated the safety and efficacy of MTE in ICA terminus occlusions using the Tigertriever XL Device. The overall successful reperfusion rate achieved with the Tigertriever XL alone and in combination with additional devices used for further occlusions in downstream arteries was 95.7%. This rate is slightly higher compared to those known from the randomized clinical trials (RCT) that were not restricted to ICA terminus occlusions but included LVOs within the anterior circulation in general, with successful reperfusion rates up to 86.0% [ICA terminus occlusions are known for their poor clinical prognosis due to the large infarct volume with an unsatisfactory response to IVT, which is presumably related to a higher clot volume compared to more distally located occlusions within the Circle of Willis . With thfibrin-rich white clot) [More than one-half of the cases included in our series were treated beyond the 4.5 h time window , which might potentially indicate cases of larger and fibrinogen richer clots. It is known that intracranial thrombus morphology and composition undergoes time-dependent changes, which include proximal and distal apposition as well as a progressive fibrin network propagation (te clot) . Fibrin-te clot) ,20.However, the median revascularization (symptom onset to reperfusion) and procedure time of 223 and 41 min found in our series is lower compared to the 317 and 71 min in the series described without cases in the late time window [The lower overall procedure times found in our series might indicate the high efficacy of the Tigertriever XL Device. These findings are in line with those within the recently published Tiger Trial, with reduced procedure times using the Tigertriever in LVOs compared to results achieved with either Solitaire or Trevo devices. This potentially higher efficacy of the Tigertriever might be explained by the technical specifications of the device namely the manual adjustability of the radial force and with this the possibility to interact with the clot in combination with the larger size of the Tigertriever XL Device .Interestingly, larger vessel diameters (>2 mm) were associated with a lower successful reperfusion following a subgroup analysis of the Tiger Trial that was carried out with standard versions of the Tigertriever without the Tigertriever XL, which might serve as a further argument for the value of device size in occlusions of larger vessels with higher clot burden .Among ischemic strokes caused by LVOs ICA terminus occlusions are caused by longer thrombi with a larger thrombus volume as described above. Longer and larger thrombi are generally more difficult to retrieve, requiring more attempts and prolonging procedure time according to a study of Dutra et al., who analyzed 408 patients treated within the MR CLEAN Registry . The radLonger stent-retrievers proved to be more efficient in an unselected group of LVOs treated with different stent-retrievers according to the study of Zaidat et al. . In the The first pass effect of 34.8% found in our series is promising especially with regard to the subgroup of ICA terminus occlusions. Zaidat et al. performed a subgroup analysis of 354 acute ischemic stroke patients within the North American Solitaire Acute Stroke registry. They identified an overall first pass effect of 25.1%, while the first pass effect in the subgroup of ICA terminus occlusions was only 10.1%. The first pass effect was associated with improved angiographic, clinical, and safety outcomes, while ICA terminus occlusions were associated with lower rates of first pass effect .tailored approach is in line with the increasing trend towards MTE in distal medium vessel occlusions (DMVO) [A potential criticism of the strategy applied in this series might be the requirement of additional smaller devices to treat occlusions in downstream vessels since the Tigertriever XL Device is rather unsuitable for smaller caliber arteries. However, this s (DMVO) .Our study has several limitations that are mainly related to the retrospective design without fixed inclusion criteria whether to use the Tigertriever XL Device or alternative standard devices. Furthermore, the small sample size of this analysis does not allow for a reliable (matched pair) comparison of ICA terminus occlusions treated with different devices. Additional factors with a potential influence on the angiographic and clinical success of the procedure were not analyzed.MTE of ICA terminus occlusions seems to be safe and effective using the Tigertriever XL Device. The technical properties together with the large size of the device allow for the successful removal of larger and longer clots. In some instances, additional smaller thrombectomy devices are helpful to treat remaining occlusions in downstream smaller arteries. Further prospective studies are needed to confirm the findings of this observational retrospective analysis."} +{"text": "Table 7 have been inserted twice. The corrected Smoke emission of unmodified PU and polyurethane foams with APP or HGOA system appears below.In the original article , there wA).There was an error in the Section 3.5 of the original article. The wrong name of the sample was used of all samples was 6 s or less. Reduced thermal inertia of foams with lower density may lead to decreased TTI values [38], as in the case of PU/10HGOThe authors apologize for any inconvenience caused and state that the scientific conclusions are unaffected. The original article has been updated."} +{"text": "Lyu et al used natI would suggest that the study might be enhanced by including additional keyword searches for vaccination synonyms identified by a method such as the Continuous Bag of Words (CBOW) word2vec model [gensim implementation of the CBOW word2vec model [rtweet package [I identified synonyms for \u201cvaccination\u201d commonly used on Twitter by using the ec model . This mo package . The keyrtweet, 94,768 contained at least one of the words searched for in the study by Lyu et al [Out of the 503,862 COVID-19\u2013related tweets downloaded with I would propose that researchers performing keyword searches on social media chatter consider using the CBOW word2vec model to enhance their studies by expanding the number of comments they capture and to reduce geographic or population bias that may occur from the preselection of terminology. The CBOW word2vec model can help capture more completely the full range of word choices used by social media users."} +{"text": "Mismatch between demands of work and workers\u2019 ability to meet those demands may play an important role in retirement decisions. This presentation extends earlier work using Health and Retirement Study data linked to O*NET to develop measures of discrepancy between individual\u2019s own reports of physical and mental abilities and 1) their perceptions of the physical and mental demands of their jobs and 2) O*NET ratings of the physical and mental demands of their jobs. In particular, we utilize newly available linked information using 2010 Census codes and 2019 O*NET ratings that reflect more current jobs. We then examine the impact of each type of mismatch (subjective and objective) on retirement timing. Overall, we find a stronger connection between subjective mismatch relative to objective mismatch. We discuss implications of this finding in terms of the value of the O*NET linkage and potential interventions aimed at extending working lives for positive aging."} +{"text": "Dear Editor,The correct placement of V1 and V2 pericordial leads of the electrocardiogram (ECG) is on the fourth intercostal space to the right and the left margins of the sternum Walsh, . MisplacHerein, we present three ECG examples done in the preassessment clinic at Spire Fylde Coast Hospital for patients undergoing elective surgical procedures where misplacement of V1 and V2 leads generated false\u2010positive findings (Figure\u00a0In conclusion, the main learning point of presenting these ECG examples is to raise the awareness of the importance of careful and correct pericordial leads placement when performing the ECG as pericordial leads misplacement has negative consequences which could affect accurate ECG interpretation and the quality of care delivered to the patients. Furthermore, the morphology of P wave in V1 and V2 is a useful tool to detect pericordial leads misplacement so physicians can avoid ordering further investigations or interventions unnecessarily.The authors declare that they have no conflict of interest."} +{"text": "There has been an increasing recognition of the lack of clinical validity of different types of ICD10 personality disorder.The prevalence was established among patients in a high secure hospital in England of those with either a primary or secondary diagnosis of personality disorder and its recorded type according to ICD10 and then ICD11.The new ICD11 classification increased the validity of diagnosis of personality disorder as well as its severity.ICD 11 has proposed the dropping of the classification of personality disorder based on particular types of personality disorder and instead adopting a diathesis model based on 2 dimensions: presence of personality disorder and three levels of severity and the option of specifying one or more prominent trait domain qualifiers and also specify a Borderline Pattern qualifier.The electronic medical records were used to establish the presence and type of personality disorder using the criteria of ICD10 and ICD11.The researchers assured reliability by rating some vignettes using the Schedule for Personality Assessment from Notes and Documents (SPAN-DOC) before rating actual cases.From a total population of 208 patients, 64(30.8%) were classified as having either a primary or secondary diagnosis of personality disorder according to the ICD 10.30 (47%) had dissocial personality disorder (DSPD), 19(30%) emotionally unstable personality disorder (EUPD) and 8(13%) paranoid personality disorder. 20 (31%) had a comorbid diagnosis of mental illness and about a tenth had diagnoses of multiple personality disorders. These types of personality disorder diagnosed by the researchers using ICD 10 did not always match the types of personality disorder diagnosed by clinicians at the hospital.All patients met the criteria of personality disorder under ICD 11 but the number with a borderline specifier was greater than those with an ICD10 diagnosis of EUPD. Using the trait domain qualifiers in ICD 11, patients with ICD 10 diagnoses of EUPD or DSPD showed dissociation and disinhibition, with those with a DSPD showing low and those with EUPD high negative affectivity.The results confirm that while psychiatrists in a high secure hospital reliably diagnose the presence of a personality disorder, they are much less able to make an accurate diagnosis as to the actual type of personality disorder. The new ICD 11 classification will increase the clinical validity of the diagnosis of personality disorder and its severity."} +{"text": "Non-union of the radius and ulna is a major complication of forearm fractures, accounting upto 10% of all forearm fractures. Multiple modalities are available for the treatment of non-union. Vascular grafts are a less sought-after surgical choice owing to the need of expertise and skills of surgeons. We discuss a case of gap non-union of fracture shaft radius treated with vascular fibula graft.We describe a case of 45yr old lady with closed fracture of both bones of left forearm.She underwent open reduction and internal fixation with 3.5 small DCP (6 hole) two days following trauma. On subsequent follow up in 6 months the radius fracture showed signs of infected non-union with osteolysis at screw sites while the ulnar side showed signs of satisfactory union. The patient underwent debridement with implant removal and osteosynthesis with vascularised fibula for gap non-union as second stage. 3 and 6 months follow up showed improvement in DASH score as well as VAS score and fair return of regular activity.In management of gap non-union of Shaft radius with gap (>6cm) vascularised fibular graft provides excellent functional outcome with far less donor site complications.None declared Non-union rates after screw and plate fixation of diaphyseal fractures of forearm are upto 10%.It has been concluded in studies that technique of bone block grafting to correct diaphyseal defects of the radius or ulna is relatively easy to perform and has a high success rateA 45yr old lady suffered from a road traffic accident and sustained a closed diaphyseal fracture of both the bones forearm on left side. She underwent Open reduction and internal fixation of both the bones after 2 days following trauma with 3.5 Small DCP(6 hole). On subsequent follow up at 6 months with her primary surgeon it was found that there was osteolysis at the radius site while the ulna showed good signs of union. She was complaining of persistent pain (VAS Score-4) and unable to do routine activities with the involved limb. We evaluated her radiographs and did routine haematological tests. The parameters suggested there is some deep tissue infection (Raised Erythrocyte Sedimentation Rate {ESR} and C-reactive protein {CRP}) but the wound was healthy with healthy scar.The patient was planned for staged surgery. First stage for implant removal with debridement, lavage of fracture site with culture sensitivity studies. Second stage for osteosynthesis with FVFG with plate once the acute phase reactants settled down. After a period of 2 months we again admitted the patient and did the routine investigations. As it was expected there was near normalcy of the parameters of infection like ESR, CRP. We diagnosed this as a case of gap non-union of shaft radius as evident from radiological investigation and descrd taken as a pedicle with the peroneal artery, which arises from the posterior tibial artery, 3 to 4 cm distal to its bifurcation into the anterior and posterior tibial arteries (We approached the radius through the previous incision site and freshened the atrophic ends of radius and finally found the gap to be 8cm . The ipsarteries , 2C. It arteries . With thPost-operative slabs were given both in upper and lower limb.The patient was followed up monthly with radiographs and serum parameters of infection. She was allowed to do free range of movement exercise for elbow and wrist but non weight lifting. At 6 months there is satisfactory movement in elbow and wrist and the Non unions of both bone of forearm is not so uncommon and among that gap non-union of any single bone is very rare. While iliac crest grafting is mostly preferred by surgeons it is associated with a lot of donor site morbidities. Other methods such as Radialisation of Ulna in Post Infective Gap Non-union Radius leads to limitation of movements due to single bone construct.Though a procedure of expertise free vascularised fibular grafting should always be borne in mind while treating gap non unions of forearm to give satisfactory movement and function to the patient's affected limb."} +{"text": "There is currently no treatment for Alzheimer disease (AD). However, the Icelandic mutation in the APP gene (A673T) has been shown to confer a protection against the onset and development of AD . This single nucleotide mutation in APP exon 16 reduces the cleavage of the APP protein by the beta-secretase by 40% thus preventing the development of AD even in persons more than 95 years old. Our research group has initially shown that the presence of the A673T mutation in an APP gene reduced the secretion of beta-amyloid peptides even if there is also a FAD mutation in the gene. This is the case for 14 different FAD mutations. We have used CRISPR/Cas9 base editing and PRIME editing technologies to insert the A673T mutation in the APP gene. We have compared several different cytidine base editor complexes to achieve the most effective and accurate genome modification possible in HEK293T cells and in SH-SY5Y neuroblastomas. The insertion of the A673T mutation in cells containing the London mutation reduced the secretion of beta-amyloid peptides. We are currently using lentiviral vectors to infect neurons from a mouse model and human neurons induced from fibroblasts of a patient with the London mutation. The insertion of the protective Icelandic mutation in the APP gene using these editing technologies opens a new potential therapeutic avenue not only for Familial Alzheimer\u2019s diseases but also for sporadic Alzheimer\u2019s disease."} +{"text": "The health profile of African Americans clearly shows that stress works to worsen chronic conditions. To improve the health of aging African Americans, interventions need to address how effects of stress are reduced by individual resilience factors and exacerbated by anxiety or other traits. We will characterize the effects of stress by measuring rate of biological aging (RBA) over thirty years in a Black cohort (aged 18-30 at baseline) of approximately 2,000 individuals from the longitudinal CARDIA study. Biological aging (BA) captures premature physiological aging beyond that predicted by an individual\u2019s chronological age. RBA will be characterized by within person change in BA over 30 years. We will measure the association between RBA and anxiety and will further measure the extent to which various forms of individual resilience factors mitigate the effects of anxiety on BA. We will also explore how intersectionality is evinced in sex differences in RBA."} +{"text": "VOLUME 19 (2020) PAGES 540-553There was an error in the grant information in which a grant acknowledgment was omitted. The Partnership for Clean Competition should be added to this section."} +{"text": "Careful intraoperative management of the artery of Adamkiewicz minimizes the risk of spinal cord ischemia.32.See Article page Plotkin and colleaguesCerebrospinal fluid drain placement in endovascular aortic aneurysm repair is not without risks. Although at our center we have had minimal morbidity, there are reports of 2% intracranial hemorrhage rate and 2% paraplegia rate secondary to spinal hematoma.Postoperative collateralization of blood flow to the great anterior radiculomedullary artery after TEVAR has been studied. In a series of 32 patients, the artery of Adamkiewicz was perfused by a segmental artery distal to the stent graft landing zone in 53%, branches of the left subclavian artery in 33%, and a branch of the external left iliac artery in 13%.The patient described by Plotkin and colleagues"} +{"text": "The DVLA has strict guidelines regarding how long a driver should stay off driving when they have certain mental health illnesses or severity of symptoms. It is difficult to give such advice if we are unaware of the patients\u2019 that drive; especially when they do not volunteer this information for various reasons.This audit was aimed at identifying people who have been admitted to the Ward 3 at the Mount Hospital and if they were asked about driving. The audit also looked at whether there were discussions around the driving requirements and DVLA guidelines in terms of their mental health diagnosis. The expected outcome of this project was to improve information gathering when clerking in a new patient and to ensure that elderly patients\u2019 who drive are made aware of the DVLA guidelines.This audit retrospectively examined the care of 50 patients on Ward 3 at the Mount Hospital, a mixed acute psychiatric ward for older people, between 1st April 2020 and 11th November 2020. All patients\u2019 aged 65 years and over who were on admission within that period were audited. Data collection took place between 17th November and 17th December 2020; this involved reviewing patient records throughout their inpatient stay including paper notes and electronic records (on Care Director). Results were compiled using a pre-determined data collection tool and analysed using Microsoft Excel. The audit used the standards within the DVLA Guidance- Psychiatric Disorders: Assessing fitness to drive.Only 1 (2%) patient had sufficiently documented evidence around driving and the impact of psychotropic medication on driving. DVLA information was given verbally in 3 (9%) patients and only 2 patients had this information passed on to their General Practitioner (GP). Only 3 (6%) patients were made aware of the DVLA guidelines and 2 (4%) patients made aware of their obligation to inform the DVLAGenerally, the compliance of psychiatrists in identifying all patients\u2019 who drive is poor and seems even worse with elderly patients\u2019. There was little documented evidence that patients were asked about their driving status on or during their admission, were given verbal or written information, had discussions around the impact of medication on driving or informed about their obligation to notify the DVLA. This study provides opportunity to improve practice by educating the medical workforce and raising awareness within the wider team. There also needs to be greater involvement and communication with GPs when completing discharge summaries."} +{"text": "This comparative effectiveness study evaluates aerosol particle leak and standard surgical mask fit with 3 elastomeric harness designs tested on mannequin heads and human participants using US Occupational Safety and Health Administration N95 fit factor requirements. Written informed consent was obtained from all study participants. The study followed the International Society for Pharmacoeconomics and Outcomes Research (6 We designed 3 harnesses with Illustrator software (Adobe), with an emphasis on improving the seal around the nasal sidewalls, around the cheeks, and under the chin and a cancer center (The University of Texas MD Anderson Cancer Center). Through flyers sent to the Rice University Graduate School of Engineering network and to health care professionals at The University of Texas MD Anderson Cancer Center, we recruited participants between the ages of 21 and 65 years who did not present symptoms of or have a positive COVID-19 test result. The 8026 Particle Generator (TSI Inc) was used to supplement the ambient particle count in the room. The quantitative fit tests were recorded using the 830 PortaCount Pro Respirator Fit Tester (TSI Inc).Health care workers were given a survey to complete after using the harness to provide feedback on the harness and user comfort. The fit factor data from all participants wearing different harness designs were computed and plotted in MATLAB (MathWorks). Mean fit factors were also calculated in MATLAB.Among 18 participants from Rice University, 11 were women and 7 were men. Among 21 participants from The University of Texas MD Anderson Cancer Center, 11 were women and 10 were men. Data on participant age were only collected at 1 site and are therefore not reported.Infrared imaging showed hot spots around the eyes and nasal sidewalls when the mannequin heads were wearing only the surgical masks, indicating significant air leakage. This air leakage was reduced when harness design 1 was worn over the standard surgical mask B. InfrarFit tests for designs 1 and 2 were performed at Rice University and feedback was obtained. As expected, none of the 18 participants wearing the surgical mask alone met the OSHA N95 FFR score of 100 A. When fBased on the feedback from health care workers, design 2 was modified to reduce the amount of material along the nasal sidewalls to prevent disruption of the user\u2019s field of view while also reducing air leakage (design 2.1). Design 2.1 was tested on 21 perioperative hospital staff members at at The University of Texas MD Anderson Cancer Center. Ten participants (47.6%) passed the fit test while wearing the surgical mask and harness design 2.1 B. The ad5The results of this comparative effectiveness study suggest that a low-cost, easy-to-manufacture elastomeric harness may improve the fit and protection of a standard surgical mask. Infrared imaging and OSHA-approved fit testing were used to improve the harness design and optimize both fit and user comfort. The use of rubber-band harnesses with surgical masks has been reported, but they lack the consistency and comfort that can be achieved with manufactured harnesses.A limitation of this study is that we did not evaluate surgical mask fit without a harness for all participants. This study highlights how multidisciplinary short-run manufacturing capability within academic institutions accelerates the application of engineering solutions to health care challenges. Future work should explore other manufacturing techniques such as injection molding, which can make the nasal sidewall seal more comfortable and easier to assemble."} +{"text": "Adult Day Service (ADS) centers play an important role in community services that help families keep a person living with dementia (PLWD) at home. We interviewed 33 family caregivers about their experience during the COVID-19 Pandemic and the shutdown of the ADS centers where the PLWD attends. All 33 (100%) reported that the ADS center was shut for a period of time (range: 2 weeks \u2013 remain closed). Caregivers reported a decline in their physical health and mental health and an increase in feelings of loneliness . For the PLWD, the caregivers noted, a decline in physical and mental health and an increase in behaviors . The shutdown of most ADS centers across the country due to the COVID-19 pandemic has had implications not only for the ADS sites but for the families that entrust them with the care for a family member."} +{"text": "Acute traumatic abdominal wall hernia (TAWH) is a rare type of hernia that occurs after a low or high velocity impact of the abdominal wall against a blunt object with few cases reported. Perforations of the hollow viscera commonly follow abdominal trauma and likely require surgery for hemorrhage and sepsis source control. We report a case where a high velocity impact of the abdominal wall against the stump of a felled tree caused a TAWH with concomitant gastric perforation in a 20-year-old male patient who required exploratory laparotomy with primary repair of the stomach and fascia. The physical examination findings without previous history of abdominal hernia and pneumoperitoneum in the chest X-ray made suspect our diagnosis and it was confirmed intraoperatively. At 3\u00a0months postoperatively the patient has a strong abdominal wall. It is imperative to emphasize the importance of the physical examination goal of not losing diagnosis of TAWH. Traumatic abdominal wall hernia (TAWH) is a rare clinical entity, with only a few cases reported since1906. Most cases are caused by an injury of falling on or hitting an angled or curved material, less common causes are high-energy type traumas like motorcycle accidents, fall from a height, seat belt injuries, pedestrian accidents and larger deceleration forces . The incA 20-year-old male, farmer presents to the emergency room of the hospital with 5\u00a0h of severe abdominal pain after he felt prone from a tractor impacting his abdomen against the stump of a felled tree; the pain was of sudden onset and constant and the site of the impact started to swell progressively. There was no personal history of abdominal wall hernias or chronic diseases.His physical examination revealed a slight abdominal distention with a swelling located above the umbilicus of ~10 by 10\u00a0cm with the presence of bruises and abrasions on the left side of the skin; the mass was partially reducible with the presence of subcutaneous emphysema extended to the left flank and hypochondrium ; the resAn exploratory laparotomy was performed through an incision in the supra and infraumbilical midline, as we advanced we found food debris in the subcutaneous tissues and a defect with poorly defined borders of ~3\u00a0cm in the rectus muscle fascia with exposure of the abdominal content and 3; AIn the literature, there is consensus that this kind of hernia occurs at anatomically weak points of the abdomen with a blunt trauma. An obvious fascia defect may exist with or without reducible hernia and it iThe appropriate timing and approach of surgical treatment for TAWH depend on a case-by-case basis and represent a diagnostic and therapeutic challenge . Open suTAWH should be suspected when patients present with an abdominal swelling following blunt abdominal trauma especially high-energy injuries to the abdomen. A good history and physical examination are of exceptional value in making an early diagnosis of traumatic hernia, being a challenge if there are concomitant intra-abdominal injuries where the use of CT scan will confirm it and help with the surgical management decision. Management typically involves surgical intervention to prevent complications."} +{"text": "With the advent of the COVID-19 Pandemic the NHS long term Plan commitments of January 2019 to improve crisis care nationwide became all the more pressing. The aim of this study was to thematically investigate what mental health crisis presentations might be diverted from the Emergency department to external crisis hubs in order to reduce the COVID-19 contamination risks.All referrals made to the Homerton University Hospital (HUH) mental health liaison service were looked at between 1/3/20-11/6/20 (n = 846), coinciding with the first peak of the COVID-19 Pandemic.Referral data was anonymised and sorted independently into naturally emerging thematic classes by two junior liaison doctors.Cases that did not clearly fit any of the 14 themes generated were further looked into to determine outcome of referral and discussed to try and match to an appropriate class.14 frequent themes for mental health crisis referrals were identified. The distribution of these ranged from most common to neurocognitive presentation and identified shifts in themes over the course of the pandemic peak such as increases of low mood, anxiety and intoxication requiring medical attention over the three month period.Although themes for presentations may be identified in acute referrals to mental health liaison services it is problematic determining how these may be parsed safely to crisis hubs without risking overlooking cases that may require medical attention. The most common theme that was identified and remained throughout the first wave of the COVID-19 Pandemic was acute suicidal presentation. The remaining themes would require careful consideration around risk thresholds for what a service may wish to accept in devolving the emergency department liaison and balance these against future risks of repeat COVID-19 waves."} +{"text": "I have read with interest this retrospective study that reviewed the results of fluoroless endourological treatment of 183 cases of complex renal and ureteric stones. All cases were performed by an experienced single surgeon without using fluoroscopy at all [The rational of omitting fluoroscopy to decrease X-ray exposure for the patient and the operating room staff is valid. Some retrospective studies reported radiation-free flexible ureteroscopy ,3. HowevThe conclusions of this manuscript must be taken with great caution because an experienced surgeon may sometimes accomplish extraordinary techniques because his high level of expertise enables him to achieve a high success rate with minimal complications. Therefore, it is unsafe for generalisation to all cases or all surgeons depending on the results of anecdotal experience ."} +{"text": "To establish rates of pregnancy testing on admission of women within a blended secure service.Women with psychiatric illness are known to be at increased risk of pregnancy, often due to engagement in risky sexual behaviours such as having a higher numbers of sexual partners and engaging in sexual activity whilst under the influence of drugs or alcohol. Awareness of pregnancy at the point of admission to psychiatric hospital would inform ongoing care plans to manage the pregnancy in the safest, least restrictive environment and inform future prescribing decisions, to minimise the risk of teratogenicity associated with some psychotropic medications. Ardenleigh in Birmingham is a blended female secure unit. No pregnancy screening guidelines for this population currently exist. This audit sought to establish current rates of pregnancy testing at the point of admission with a view to developing future guidelines.A retrospective case note audit of electronic records of all patients admitted to Ardenleigh blended women's service as of 1st September 2019 (n = 26). The expected standard for pregnancy testing within one month of admission was set as 100%.The majority of patients (67%) were aged under 35 years (range 20\u201356). The most common ethnicities were Caucasian (42%) and African-Caribbean (38%). Almost half (46%) had a primary diagnosis of paranoid schizophrenia.Two women were known to be pregnant at the point of admission. Only 54% of women with an unknown pregnancy status were screened for pregnancy within one month of admission.Rates of screening were particularly poor in women aged under 25 years (43%) and between 36 and 45 (0%).Women not screened for pregnancy were typically admitted from other hospital settings, including AWA services (27%) or other medium secure units (55%). 2 women admitted from prison were not tested (29%)Of those tested, the majority were checked using urine hCG (92%).None of the women tested were found to be pregnant.Key results include:Overall pregnancy testing on admission to the unit was poor, with only 54% of service users screened. Less than 100% compliance could result in serious consequences for both the woman and unborn baby if a pregnancy is not discovered. Updating the admission checklist for Ardenleigh to include pregnancy testing may prove beneficial. It is recommended that a re-audit is completed 6 months following checklist introduction."} +{"text": "Convective systems dominate the vertical transport of aerosols and trace gases. The most recent in situ aerosol measurements presented here show that the concentrations of primary aerosols including sea salt and black carbon drop by factors of 10 to 10,000 from the surface to the upper troposphere. In this study we show that the default convective transport scheme in the National Science Foundation/Department of Energy Community Earth System Model results in a high bias of 10\u20131,000 times the measured aerosol mass for black carbon and sea salt in the middle and upper troposphere. A modified transport scheme, which considers aerosol activation from entrained air above the cloud base and aerosol\u2010cloud interaction associated with convection, dramatically improves model agreement with in situ measurements suggesting that deep convection can efficiently remove primary aerosols. We suggest that models that fail to consider secondary activation may overestimate black carbon's radiative forcing by a factor of 2. Deep convection efficiently removes particles at and above the cloud baseThe default convective scheme in climate model overestimates middle and upper tropospheric aerosol by a factor of 10\u20131,000The default convective transport scheme overestimates black carbon's radiative forcing by a factor of 2 Wet scaConvective transport schemes vary in different climate and regional models. In the National Science Foundation/Department of Energy Community Earth System Model (CESM), deep convection is parameterized following Zhang and McFarlane and shalA number of in situ measurements of the aerosol vertical distribution in the upper troposphere and lower stratosphere have been made in recent years. For this study we include the Atmospheric Tomography Mission (ATom) from 2016 to 2017 , coupled with the CESM to investigate convective transport of aerosols and trace gases to study aerosols transport aerosols upward from the cloud base to 9\u201318\u00a0km in one time step . A recent field study near the tropopause and dominates (over 80%) for pressures lower than 400\u00a0hPa Figure\u00a0e. The to6Recent field campaign data suggest that the concentrations of global primary aerosols including sea salt and BC drop by 1 to 4 orders of magnitude from the surface to the upper troposphere and lower stratosphere. The default convective scheme in CESM transports aerosol from the surface to the upper troposphere too efficiently and leads to an overestimation of primary aerosol by a factor of 10\u20131,000 in the global middle and upper troposphere, especially in the tropics. Our study modifies the convective transport scheme following Wang et al. by consiSupporting Information S1Click here for additional data file."} +{"text": "We investigate damage inside the bulk of borosilicate glass by a single shot of IR picosecond laser pulse both experimentally and numerically. In our experiments, bulk damage of borosilicate glass with aspect ratio of about 1:10 is generated. The shape and size of the damage site are shown to correspond to an electron cloud with density of about 10 Ultrafast lasers are ubiquitous in a wide range of applications such as micro-welding , waveguiIn this paper, we target to gain fundamental insights of how ultrashort pulses interact with bulk glass, particularly how initial electrons are generated at the very beginning of the process. Specifically, we focus on understanding the contribution of electrons from different ionization channels such as multiphoton ionization and avalanche ionization during the exposure of a single picosecond laser pulse focused in the bulk of borosilicate glass. We demonstrate experimentally the bulk modification of borosilicate glass with high aspect ratio damage tracks by a single shot of picosecond laser pulse. We present a beam propagation model that tailored to our experiments to extract ionization constants and electron density distributions. The shape and size of the inner dark damage center match an electron density of about 10The experimental setup used in our study is shown in The borosilicate glass plate used in our experiments has a thickness of about 1 mm, with density 2.38 E in cylindrical symmetry coordinates around the propagation axis Z. The electrical field envelop To understand the mechanism of damage formation, we numerically model the pulse propagation and electron generation inside the borosilicate glass plate. The model used in our study has been widely applied for propagating intense pulse in fused silica , air 2121, and lessed by ,(1)E\u2202E\u2202zThe propagation equation is described in the reference frame moving at the group velocity Equation describe16cm2/W is the nIn our study, the maximum intensity used is eUi/eE=2 . When \u03b3>The electron excitation by the laser pulse from valence band to conduction band can be described through a rate equation ,(3)\u2202\u03c1\u2202tThe first term on the right hand side describes the electron promotion through multiphoton ionization and the second term describes electron generation through avalanche ionization, where in glass .The experimental results of damage inside borosilicate glass are shown in We measure the length as well as the inner and outer width of the damage track for each of the energy cases shown in \u2212Eth,i)3Douter=c2The simulation results of beam propagation and electron density at input pulse energy of The relative role of electron contribution from multiphoton ionization and avalanche ionization is shown in as well ,26. At tIn conclusion, we demonstrated generating damage tracks in the bulk of borosilicate glass by a single shot of IR picosecond laser pulse. Particularly, we generated extended damage tracks with an aspect ratio of 1:10 under our focusing geometry. The positions of the damage track are shifting away from the geometrical focus towards the incoming laser beam driven by the plasma expansions and nonlinear effect such as self-focusing. The shape of the damage track shows distinct features at different energy levels, specifically, we observed smooth damage channel at low input pulse energy levels, while beaded hollow structures were found at higher input pulse energy levels. We modeled the beam propagation and electron generation numerically. Our simulation results shows the size and shape of the inner dark damage track in the experiments match very well with electron density of"} +{"text": "The overarching aim of the session was to address and reduce stigma around Borderline Personality Disorder among doctors. The three main objectives were:To increase empathy and understanding around Borderline Personality Disorder by exposing junior doctors to service user perspectives outside a clinical setting;To address knowledge gaps identified by junior doctors in a self-reported questionnaire disseminated prior to the teaching session;To offer junior doctors a basic psychological framework to base their assessment and formulation of service users with personality disorders.\u2018Borderline Personality Disorder: The Person Behind the Label\u2019 was the title of the first co-produced teaching session in the Leeds and York Partnership Foundation Trust (LYPFT). Prior to the teaching session, an online questionnaire was sent out to trainees. The results highlighted three key issues:Negative attitudes towards service users with personality disorders;Poor subjective knowledge of the psychological models of personality disorders;Perception among trainees that they do not receive adequate training to deal with the challenges service users with personality disorders present.A teaching session was co-produced by a team of two service users, a principal clinical psychologist within the Leeds Personality Disorder Network (PDN) and a core Psychiatry trainee. It was delivered in a 75 minute session to 40 attendees consisting of both trainee doctors and consultants.Feedback was collected immediately after the session through the use of anonymous feedback forms. The response to the training was overwhelmingly positive with all 28 respondents rating the session as 4/5 or 5/5 on a satisfaction scale ranging from 1 (poor) to excellent (5). Key themes from the feedback included appreciation for the service user perspective and teaching on psychological theory. The fourth question in the questionnaire: \u201cHow will this teaching impact your work?\u201d produced the highest number of responses (25/28) and provided evidence that the above listed objectives of the session were met.Co-produced teaching has great potential to address negative attitudes around highly stigmatised conditions by bridging the gap that often exists between service users and mental health professionals."} +{"text": "There is an error in the Author summary section in the first bullet point under the heading \"What did the researchers do and find?\" The correct sentence should read: \"This study assessed breech outcomes of 27,825 term births before and after the introduction of a third trimester screening ultrasound, which increased the proportion of pregnancies screened from 39% to 99%\"."} +{"text": "A new cell line (CAL51) was isolated from a malignant pleural effusion of a woman with metastatic breast cancer. These cells grow in continuous culture and exhibit the morphological, ultrastructural and immunohistochemical features of epithelial cells of mammary origin. They are tumorigenic in nude mice and clone in soft agar. Oestrogen receptors are not detected. CAL51 consists of a homogeneous population of cells with normal chromosomes even after the use of high resolution banding. Cytogenetic analysis of the cells from the tumour induced by CAL51 in the nude mouse confirmed the normality and the stability of the karyotype. All breast cancer cell lines established to date present abnormal karyotypes; CAL51 cell line may be more informative than cell lines with aberrant karyotypes for investigating essential genetic differences between normal and malignant mammary gland cells."} +{"text": "The effects of cellular glutathione depletion by buthionine sulfoximine on the development of thermotolerance and synthesis of heat stress protein was studied. Cellular glutathione levels were found to increase rapidly following an acute heat treatment of either 12 min at 45.5 degrees C or 1 h at 43 degrees C and remain elevated for prolonged periods. Glutathione depletion and prevention of glutathione synthesis by buthionine sulfoximine resulted in inhibition of the development of thermotolerance and a decrease in total protein as well as specific heat stress proteins. While the degree of inhibition of thermotolerance was similar for both glutathione depletion protocols, inhibition in heat stress protein synthesis was greater when glutathione was depleted to low levels prior to heating. The possible role of glutathione and the cellular redox state to thermotolerance and synthesis of heat stress protein is discussed."} +{"text": "We thank Kolanz for his careful reading of our article . An erra3 and sensitization occurred with exposure below the Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) of 2 \u03bcg/m3 than we 3 to characterize not only the central tendencies of the exposures but also their extreme excursions.We stand by our statement thatThe inclusion of genetic data combined with exposure data may better define which individuals in this cohort are at a particularly high risk of development of CBD and/or sensitization and may account for the absence of typical exposure\u2013response seen with other environmental or occupational toxins.It is also important to note that both peak exposure and the different chemical and physical forms may be important factors in the risk of development of CBD but are not part of the current OSHA standard .Finally, Kolanz states that \u201c"} +{"text": "The effect of low (0.08 microU g-1 body wt min-1) and high (0.16 microU g-1 body wt min-1) rates of vasopressin infusion on blood flow to normal liver tissue and to liver metastases derived from azoxymethane induced colorectal carcinomas was studied in 36 male Wistar rats. Portal venous flow was measured by electromagnetic flowmetry and blood flow to normal and metastatic liver tissue by the clearance of xenon-133 injected directly into the liver parenchyma or metastasis. The low rate of vasopressin infusion decreased portal venous flow but increased blood flow to normal and metastatic liver tissue while at the higher rate of infusion these effects were reversed. Hepatic artery ligation (HAL) immediately following a low rate of vasopressin infusion abolished the observed increase in blood flow to both normal liver tissue and metastases. HAL immediately following the higher rate of vasopressin infusion further reduced blood flow to metastases but did not further alter blood flow to normal liver tissue. HAL prior to the infusion of the vasoactive drug significantly reduced blood flow to metastatic liver tissue, increased portal venous flow and was without effect on blood flow to normal liver tissue. Following HAL, blood flow to metastatic liver tissue was not further altered by either the low or high rates of vasopressin infusion. However, blood flow to normal liver tissue after HAL was reduced by a low rate of infusion of vasopressin and increased by the higher rate of infusion. The results of this study indicate that blood flow to normal or metastatic liver tissue can be increased or decreased by differential rates of infusion of vasopressin. These observations may have important implications in the treatment of liver metastases in man where different rates of vasopressin infusion may potentiate the effects of hepatic artery ligation or cytotoxic therapy."} +{"text": "A cohort comprising 11678 women who had undergone cholecystectomy in the period 1964 through 1967 for a benign gallbladder disease was investigated. They represented almost a total ascertainment from a defined geographic area. Follow-up during 11-14 completed years of observation revealed a total of 202 breast cancer cases after the cholecystectomy. This number was close to the expected incidence of 199.1 (relative risk 1.0). Further analysis of the risk in relation to duration of observation and age at operation did not reveal any trend or subgroup with a significantly increased or decreased risk. It was concluded that despite the many epidemiologic observations indicating that in Western Countries dietary habits are particularly important determinants of the high incidence of both gallstone disease and breast cancer, our results contradict the idea that the diseases share common aetiologic factors."} +{"text": "We have compared the response to a number of cytotoxic drugs of cells treated either within intact multicellular spheroids or as isolated cells following spheroid disaggregation. The cells used were of the EMT6/Ca/VJAC mouse tumour line and spheroids were treated or disaggregated at a mean diameter of 250 micron. The response of cell to nitrogen mustard (HN2) or CCNU was similar under the two exposure conditions and we conclude that factors related to spheroid structure do not influence the initial response to these agents. Recovery of potentially lethal damage occurring over 24 h, however, greatly modifies the level of cell killing in intact spheroids. EMT6 cells were found to be extremely resistant to vincristine under all exposure conditions. For adriamycin (ADM), cells were always initially more sensitive when exposed to the drug in suspension rather than in intact spheroids. When ADM exposure was prolonged beyond 1 h, however, delaying spheroid disaggregation for 24 h led to increased cell kill and reduced differential between the two conditions of exposure. The data suggest that both drug penetration problems and other factors related to spheroid structure are involved in determining the response of cells in small spheroids to ADM."} +{"text": "Environ Health Perspect 114:1186\u20131192 (2006)], the average daily weight of food should have been in grams instead of milligrams.In Table 1 of the the article by Gulson et al. [The authors regret the error."} +{"text": "A human bladder carcinoma cell line was irradiated at high and low dose rates and exposed to camptothecin and VP16, inhibitors of topoisomerase I and topoisomerase II respectively. Although camptothecin substantially modified the cytotoxic effects of high dose rate irradiation, abolished low dose rate sparing and inhibited the repair of sublethal and potentially lethal damage, VP16 had no effect on the survival curves even at highly cytotoxic doses. Thus, it is argued that there is a role for topoisomerase I but not topoisomerase II in the repair of DNA damage induced by ionising radiation."} +{"text": "In hepatocellular carcinoma, mutation within the p53 gene occurs mainly at codon 249 and its frequency has been associated with exposure to aflatoxin. As Senegal is a country where liver cancer incidence is one of the highest in the world and where people are highly exposed to aflatoxin, we screened 15 liver cancer samples from this country for mutation at codon 249 of the p53 gene. Non-tumoral DNA from the patients showed a wild type genotype. Mutation at codon 249 of the p53 gene was detected in 10 of the 15 tumour tissues tested (67%). This frequency of mutation in codon 249 of the p53 gene is the highest described. These results confirmed that there is an association between countries of high aflatoxin intake and a high frequency of mutation in codon 249 of p53 gene, and that HBV alone does not contribute to these base changes."} +{"text": "The human gene sequences encoding the translation-associated functions of alpha-subunit of elongation factor 1 and the ubiquitin carboxyl extension protein (HUBCEP80) have been isolated by differential cDNA screening, and found to have significantly higher levels of expression in fibroadenomas (benign) compared with carcinomas of the breast. These data parallel our previous findings that the acidic ribosomal phosphoprotein P2 also has higher expression levels in the benign breast tumours . In situ hybridisation has shown these genes to be expressed predominantly in the epithelium of breast tumours."} +{"text": "The effects of tumour cells (Colon 26) on the development and response of new blood vessels to different vasoconstrictors have been investigated. Sponge implants in mice were used to host tumour cells while washout of 133Xe was employed to assess local blood flow in the implanted sponges. By 14 days after implantation the response of vessels in tumour-bearing implants to the various vasoconstrictors generally was decreased compared to that obtained in control sponge implants or adjacent normal skin. Thus at this time point the t1/2 for 133Xe washout from control sponges treated with adrenalin (0.5 micrograms) was 30 +/- 4 min whereas in tumour-bearing sponges it was 5 +/- 1 min. This decreased sensitivity in tumour vessels was probably not due to a complete lack of contractile elements since actin was demonstrated by immunohistochemistry around blood vessels in both types of implant. The results of the present study have shown that the pharmacological responses of blood vessels in a growing tumour, Colon 26, differed from the responses of vessels of a similar age in non-neoplastic tissue. These results appear to suggest that the different angiogenic stimuli released from tumour tissue may markedly influence pharmacological reactivity of newly formed blood vessels."} +{"text": "The phenotype of peripheral blood lymphocytes of 27 renal cell carcinoma patients before and at the end of subcutaneously given rIL-2 therapy was determined by two colour flow cytometry. Therapy induced changes in peripheral blood leucocyte composition and phenotypes were comparable to those reported for intravenously given rIL-2. The present paper shows a correlation between the 'activation status' of the patient before therapy and eventual response."} +{"text": "A prospective randomised study was carried out to compare the effect of mesna (2-mercaptoethane sulphonate sodium) with that of forced diuresis in preventing cyclophosphamide induced haemorrhagic cystitis in marrow transplant recipients. Sixty-one consecutive BMT recipients were randomised for treatment with forced diuresis or mesna. The incidence of macroscopic haematuria was significantly lower in the mesna treated group . No specific side effects of mesna were detected. The lymphopenia induced by cyclophosphamide in the aplastic recipients was similar in the mesna and forced diuresis groups suggesting that mesna has no effect on the lymphocytotoxic activity of cyclophosphamide, although 6 out of 7 episodes of graft failure documented in the study occurred in mesna treated patients. As a result of this study our present policy is to use mesna in all BMT recipients but to continue careful documentation of the incidence of graft failure."} +{"text": "Human topoisomerase II enzymes are targets for a number of widely used anticancer agents. We have analysed a lung adenocarcinoma cell line CALU3, which has co-amplified topoisomerase II alpha and ERBB2 sequences, for the structure of the amplicon and for expression of both topoisomerase II alpha and beta. The region of chromosome 17q amplified in CALU3 also includes the retinoic acid receptor alpha locus and is therefore similar to the amplicon observed in breast cancers carrying amplified topoisomerase II alpha and retinoic acid receptor sequences. The use of fluorescence in situ hybridisation localises the amplified topoisomerase II alpha sequences to a cluster on one chromosome with single copies localised to others. CALU3 express high levels of topoisomerase II alpha is determined by Western blot, immunofluorescence and enzyme activity. The enzyme activity extracted from CALU3 is sensitive to inhibition by the topoisomerase II poison etoposide. Topoisomerase II beta expression was observed in three lung cancer cell lines including CALU3 and was confined to the nucleoli. Thus, the CALU3 cell line is an ideal model to study the amplification and expression of topoisomerase II alpha in adenocarcinomas."} +{"text": "Flavone acetic acid (FAA) is extremely active against subcutaneous transplantable tumours in mice, but disappointingly there has been no demonstrable clinical activity. Previous studies have shown that lung tumour deposits are less responsive than the same cells implanted subcutaneously. The aim of this study is to examine the tissue disposition of FAA in an attempt to explain this site-dependent activity. The data show clearly that FAA clearance curves are influenced by the presence of MAC 15A tumours growing either subcutaneously or systemically. The decreased clearance of FAA from MAC 15A tumour bearing animals does not however explain the resistance of lung deposits. Neither can this be explained by differences in metabolism in these different sites. Cytotoxic metabolites have not been detected either in vitro or in vivo and their role in the mechanism of action of FAA is questionable."} +{"text": "Thirty permanent and more than 60 primary tumour cell lines were established from pleural and pericardial exudates or wedge biopsies from human bronchial carcinoma. The permanent cell lines have their origin in 6 small cell, 5 large cell, 9 squamous and 5 adeno carcinomas of the lung. Tumour cells were purified from non tumour cells by direct cloning in fluid cultures or by soft agar cloning. In vitro secretion of ACTH, bombesin, calcitonin, and neurotensin was demonstrated for lung tumour cells belonging to the four major histological types. Cell suspensions of peptide hormone secreting permanent cell cultures were grown to solid tumours after xenotransplantation into nude mice. Comparative ultrastructural examination of the primary tumour and of cells grown in tissue culture and in xenografts demonstrated the preservation of most tumour type specific structural criteria in the ex vivo/in vitro systems. The present data show that not only tumour cells from small cell carcinoma but also from other histological types are capable of synthesizing a broad spectrum of immunoreactive peptide hormones. This result might be interpreted as indicating a common expression of hormone biosynthesis and secretion by all lung tumours."} +{"text": "Tumour cords have been measured in 33 cases of squamous cell carcinoma (SCC) of the bronchus and 19 cases of SCC of the uterine cervix. The overall mean cord radius for SCC in both sites was 104 microns, similar to the overall mean for various tumours in rodents. For tumour cells adjacent to blood vessels in cords of SCC, the mean Mitotic Index was 2.1% and from this value a rapid potential doubling time could be inferred (approximately 31 to 66 h). The proportion of dead cells within cords of cervical SCC was higher than in animal tumours. Using measured values for cord radius and published equations that describe the diffusion and consumption of oxygen in metabolising tissue, an attempt was made to calculate the oxygen partial pressure in vessels of cords of these SCC."} +{"text": "The biodistribution of radiolabelled SWA11, a mouse monoclonal antibody recognising the cluster w4 group antigen associated with small cell lung cancer (SCLC) was studied in patients with SCLC. Five patients were injected intravenously with approximately 5 mCi of 131I conjugated to 1 mg of SWA11. The half-life of the radiolabel in blood was short but there was a prolonged second phase of clearance with a half-life of about 40 h. Tumour was detected by gamma camera imaging two patients. However, most of the whole body radioactivity was located in the bone marrow. At least 35% of the radioactivity in blood 18 h after injection was bound to circulating granulocytes and this probably accounted for the unusual biodistribution of the radiolabel in man. This study shows that the biodistribution of radiolabelled SWA11 in man differs from human tumour xenograft models and that the antibody in unsuitable for targeting therapy to SCLC in man."} +{"text": "The finding that human papillomavirus (HPV) genes can immortalise breast epithelial cells has led to suggestions that HPV could be involved in the pathogenesis of breast cancer. Using the polymerase chain reaction (PCR) we have been unable to demonstrate the presence of HPV DNA in a series of 80 breast carcinomas."} +{"text": "BMC Public Health 2006, 6:251) we found an error in the equation of our measurement of trait anxiety.In review of our article differed between the two sub-samples.That is to say that the response alternative \"almost never\" was coded as \"1\" in the first sub-sample whereas in the second sub-sample it was coded as \"4\". Therefore we can also deduce that the responses of the participants from the different sub-samples were coded into the different direction.This error is corrected by recoding the variable so that in both sub-samples the higher score indicates higher trait anxiety. We re-conducted the analyses and found only minor differences compared to the original figures given and we also found that the error did not alter the main results or conclusions drawn.The following corrections should be incorporated into any future analysis of our original article .Trait anxiety), the Cronbach's Alpha for Trait Anxiety should be 0.85 instead of 0.88.Within the Methods section, paragraph 10 , the last sentence should now read as \"The associations with trait anxiety and magnitude of changes in work were weaker.\" rather than \"In contrast, the associations with trait anxiety and magnitude of changes in work were much weaker.\"Within the Results, paragraph 6 , the 3rd sentence should read \"Further adjustment for personality trait anxiety attenuated the association in both sexes, but the results remained statistically significant.\" rather than \"Further adjustment for personality factor trait anxiety had no effect on the associations.\"Within the Results, paragraph 7 can indicate that the construct of social capital might be more than an aspect of an individual's personality.\" rather than \"The significant association in multilevel models together with the substantially weak association with one personality measure (trait anxiety) can indicate that the construct of social capital might be more than an aspect of an individual's personality.\"And finally, within the discussion, paragraph 5 (paragraph beginning \"We assessed criterion\") The 3The pre-publication history for this paper can be accessed here:"} +{"text": "Deer antlers are the only mammalian organs that can fully regenerate each year. During their growth phase, antlers of red deer extend at a rate of approximately 10 mm/day, a growth rate matched by the antler nerves. It was demonstrated in a previous study that extracts from deer velvet antler can promote neurite outgrowth from neural explants, suggesting a possible role for Nerve Growth Factor (NGF) in antler innervation. Here we showed using the techniques of Northern blot analysis, denervation, immunohistochemistry and in situ hybridization that NGF mRNA was expressed in the regenerating antler, principally in the smooth muscle of the arteries and arterioles of the growing antler tip. Regenerating axons followed the route of the major blood vessels, located at the interface between the dermis and the reserve mesenchyme of the antler. Denervation experiments suggested a causal relationship exists between NGF mRNA expression in arterial smooth muscle and sensory axons in the antler tip. We hypothesize that NGF expressed in the smooth muscle of the arteries and arterioles promotes and maintains antler angiogenesis and this role positions NGF ahead of axons during antler growth. As a result, NGF can serve a second role, attracting sensory axons into the antler, and thus it can provide a guidance cue to define the nerve track. This would explain the phenomenon whereby re-innervation of the regenerating antler follows vascular ingrowth. The annual growth of deer antler presents a unique opportunity to better understand the factors involved in rapid nerve regeneration. Nerve Growth Factor (NGF) is involved in many aspects of nerve growth. This small secreted dimeric protein, originally identified by its ability to promote neurite out-growth, exerts its biological actions primarily on cells of the nervous system NGFR and p75NTR receptors for NGF present on Human Umbilical Vein Endothelial Cells NGF has also been found to have non-neuronal functions NGF is synthesized as a prohormone of 22 kDa which undergoes proteolytic cleavage. The three dimensional structure of NGF is determined by the presence of six cysteine residues involved in disulphide bond formation. These are important in defining the backbone structure of the protein Deer antlers are elaborate bony structures that are shed and then completely regenerate each year. This cycle of antler casting and regeneration is controlled by seasonal fluctuations of testosterone with antler growth beginning in early spring when testosterone decreases below threshold levels Antler is a valuable model for the study of nerve growth and regeneration as the repetitive renewal of a highly innervated, developmentally regulated organ is not observed in other mammals. Very little is known, however, about nerve regeneration and antler innervation during antler renewal. A previous study from our group In the present study, we showed that NGF mRNA was expressed in the arterial smooth muscle of regenerating antlers. Using these data we proposed a model of antler innervation whereby axons grow into the regenerating antler using NGF expressed by the vascular smooth muscle as a guidance cue to define the nerve track. Full or partial denervation of the regenerating antlers significantly increased NGF mRNA expression in the antler arterial smooth muscle, indicative of a causal relationship between nerve ingrowth and NGF expression. Our model explains the phenomenon whereby reinnervation of the regenerating antler follows vascular ingrowth.Prior to commencing this work the sequence for deer NGF was unknown. Partial sequence coding for the mature protein was obtained from deer genomic DNA using PCR primers designed from exon IV of the bovine NGF gene. This deer sequence has been deposited in GenBank (Accession number AF145043). We obtained this sequence by analyzing multiple clones (7) from four individual animals. Deer NGF showed 97%, 92% and 88% homology to bovine, human and mouse NGF sequences respectively The expression of NGF in the antler tip was investigated using Northern blot analysis. Northern blots consisting of mRNA from different layers within the antler tip and fromEarlier studies provided information describing nerves in the shaft of the antler but did not give a clear indication of where axons terminated distally Antler tip samples were divided into longitudinal sections from each side of the tip and a central section which spanned from the apex into the core of the antler. Axons with diameters ranging from 0.5\u20133 \u00b5m were found mainly in the reserve mesenchymal layer in the aImmunohistochemistry was employed to characterize axon patterns in antlers following severing of the zygomaticotemporal and infratrochlear branches of the trigeminal nerve and the auricular palpebral branch of the facial nerve. Contrary to our expectations, 3 weeks after denervation we found the number of immunopositive profiles greatly increased in two oTo identify cells expressing NGF in the growing antler tip, and to determine whether a feedback mechanism exists between the ingrowing sensory nerve axons and the expression of NGF mRNA, the tips of both denervated and contralateral control antlers were subjected to in situ hybridization using a riboprobe for deer NGF. NGF mRNA was found to be expressed in smooth muscle cells surrounding the arteries and arterioles at the interface between dermis and reserve mesenchyme in the intact antler tip , in closet alet alThis study has identified nucleotide sequence for deer NGF. PCR and cloning techniques were used to generate a consensus sequence for part of the deer NGF mRNA, and this showed strong homology with NGF of other species. Northern blotting showed an NGF transcript of approximately 6 kb. This message was larger than the expected 1.3 kb size suggested by Scott Localization of NGF mRNA expression was consistent between our Northern blot analysis and in set alComparison of axon density in the distal region with that in the shoulder region of the antler revealed that the shoulder region was more densely innervated than the tip region. The most distal tissues in the antler are those that formed within the last few hours and presumably axons have not yet grown into these newly formed regions. The cellular localization of NGF mRNA suggests that blood vessels at the interface of the reserve mesenchyme and the dermis act either as the peripheral targets or specify the pathway for axons innervating the antler. Gibran The developmental expression of NT-3 correlates well with the density and pattern of innervation in the antler et alin vivo without a cell body for up to three weeks. Elevated NGF levels may maintain sensory axons in a denervated antler, however, the prospect of these axons growing with the antler for a further 10 cm over a three week period is difficult to rationalize.Antler denervation was followed by up regulation of NGF mRNA expression in the antler tip and, in this case, resulted in an increase in the number of axon profiles present near the tip, even when there were few axon profiles remaining at the base of the antler. Surgical axotomy of branches of the trigeminal and facial nerves which provide sensory innervation to antlers is unlikely to have affected autonomic axons which travel with the antler arteries. The over expression of NGF in response to the loss of sensory nerves would stimulate sprouting of parasympathetic axons. Localized over expression of NGF mRNA at the base of the antler following denervation surgery may also explain why two of the experimental animals exhibited an increased number of immunopositive axonal profiles. Alternatively, the high level of NGF mRNA produced in response to denervation may aid the survival of sensory axons in the absence of a cell body. This phenomenon has been observed in the frog by Humphrey et alet alet alNGF has also been associated with biological functions other than nerve growth and survival. It has been shown to promote wound healing In summary, we have shown that NGF mRNA is expressed in the smooth muscle of the arteries and arterioles in the growing antler tip. Axon pathways in the antler have been shown to follow the major blood vessels supplying this structure. This vascular bed lies at the interface between the dermis and the reserve mesenchyme. The positional relationship between NGF expressed by the blood vessels and the most distal growth of the axons shows NGF mRNA closer to the apex of the antler than the majority of nerve endings. We have also demonstrated that a feedback mechanism exists between NGF mRNA expression in arterial smooth muscle and sensory axons in the antler tip. We therefore propose that axons growing into the antler use NGF expressed by the vascular smooth muscle as a guidance cue to define the nerve track. This means that innervation of the antler follows and is shaped by vascular ingrowth. We suspect that for the sensory axons to form terminals with their sensory target requires a second signal, such as an intrinsic timing mechanism, to complete their development. This model of NGF utilization is most closely aligned to regenerative nerve growth rather than that which occurs during embryonic nerve generation. Therefore, the annual growth of deer antler provides a unique opportunity to better understand the factors involved in rapid nerve regeneration.Cervus elaphus) 60 days after casting of the previous year's hard antler. Local anaesthetic (bromacaine) was injected around the junction of the pedicle and the skull before each antler was removed above the pedicle. The distal 5 cm from each antler was collected for this study. Following the established methods Velvet antler was collected from red deer (C. elaphus) stags were selected at 10\u201320 days post casting of their previous year's antlers. At this stage antlers were between 6 and 8 cm in length. Animals were anaesthetized with Fentazin (1.8 ml/100 kg). The zygomaticotemporal and infratrochlear branches of the trigeminal nerve and the auricular palpebral branch of the facial nerve innervating one of the antlers were cut using the procedure reported by Li et alDenervation experiments were carried out, following approval by the AgResearch Invermay Animal Ethics Committee, to determine whether there exists a causal relationship between nerve ingrowth and NGF mRNA expression level. Three 2-year-old red deer . The forward primer sequence was 5\u2032-GGGGAGTTCTCGGTGTGCGA-3\u2032 and the reverse primer was 5\u2032-CACACGCAGGCCGTGTCGAT-3\u2032. PCR products were A/T cloned into the pGEM-T\u00ae Easy vector containing the SP6 and T7 RNA polymerase promoters flanking the multiple cloning site. DNA was sequenced using primers to the SP6 and T7 promoters and fluorescent dye terminator chemistry on an ABI 377 automated cycle sequencer .32P]dCTP and the probe purified using a NICK\u2122 Column . Hybridization was performed at 42\u00b0C overnight in 50% formamide Isolation of mRNA from antler tissues or whole E17.5 mouse embryos used the MicroPoly(A)Pure mRNA purification kit . Approximately 5 \u00b5g of mRNA was subjected to formaldehyde gel electrophoresis and capillary transferred onto Hybond N+ nylon membrane . Twenty five ng of deer NGF DNA was labeled by random priming with 10\u00b5Ci/\u00b5l [\u03b1et alThe immunohistochemical protocol for nerve staining followed that described by Li et alSacII or SalI to give sense and antisense probes respectively. Single stranded sense and antisense riboprobes were labeled by transcription with 10\u00b5Ci/\u00b5l [\u03b133P] UTP as per manufacturers instructions . Sections were counter stained with Gills Hematoxylin and viewed on an Olympus BX50 microscope using both bright and dark field illumination.The in situ hybridization protocol was based on the methods described by Clark"} +{"text": "This study has investigated two of the main problems with radiolabelled antibody imaging, the formation of circulating immune complexes (I.C.) and the non specific binding of radiolabel to the antibody molecule. Patients undergoing immunoscintigraphy with 111In labelled monoclonal antibody ICR2 were divided into three groups who received either the radiolabelled antibody alone , the radiolabelled antibody which was incubated with the chelating agent diethylene triamine pentacetic acid (DTPA) prior to size exclusion chromatography (n = 6) or whose injectate was treated with DTPA and cold MAb administered intravenously prior to radiolabelled MAb administration (n = 6). Radiolabelled antibody uptake in abdominal organs was measured by region of interest analysis using a gamma camera with online computer and that in tumour and normal tissues by gamma well counting of biopsies. Circulating antigen and immune complex was measured by high pressure liquid chromatography (HPLC). The sensitivity of tumour imaging and the tumour uptake of radiolabelled antibody was not significantly different between the groups. Patients with high circulating antigen levels developed high levels of circulating immune complex but also had high tumour uptakes of radiolabelled antibody. Administration of cold MAb increased the splenic, but did not effect the tumour uptake of radiolabelled antibody and only minimally reduced levels of circulating immune complex. Chelate administration reduced the urinary excretion of radioactivity but increased the liver uptake of radioactivity. These results have shown that successful antibody imaging can be carried out despite high levels of circulating antigen, that large doses of unlabelled antibody are required to prevent immune complex formation and that removal of non specifically bound 111In does not reduce the liver uptake of radioactivity."} +{"text": "The ability of cancer cells to survive at a distance from blood vessels should be dependent on the local supply of nutrients to each vessel. The corded growth of tumour cells around blood vessels within regions of necrosis in the RH carcinoma in the mouse allows the limit to which cells can be supported by individual vessels to be observed. The thickness of individual tumour cords was measured in conventionally stained tumour sections using a scanning technique to determine the distance between the blood vessel wall and the most distant viable cell adjacent to necrosis. Cord radius was found to vary with the oxygen supply conditions. Control animals had a mean radius of 105 +/- 2 microns while animals that had breathed 10% oxygen had significantly narrower cords (93 +/- 3 microns after 48 h) and animals breathing 100% oxygen had significantly wider cords (117 +/- 3 microns after 24 h). Mice made anaemic (mean hct. 28%) by phlebotomy and plasma transfusion had cord radii that were not significantly different from controls at any time up to 48 h. We conclude that this relatively slow growing mouse tumour is capable of rapid morphological adaptation (less than 3 h) to changes in nutrient availability and that oxygen is probably the limiting substrate."} +{"text": "The ability to detect photosensitisers in tissue at a microscopical level is important when studying photodynamic therapy (PDT) in both normal and malignant tissue. We have studied the fluorescence distribution of aluminium sulphonated phthalocyanine (A1SPc) in the normal rat bladder using a cooled CCD (charge coupled device) imaging system with computerised image processing. This system makes it possible to carry out a quantitative assessment of photosensitiser fluorescence in the various layers of the bladder wall. The highest fluorescence intensities were obtained within 1 h of intravenous administration but there was little selectivity of uptake between layers. A1SPc was eliminated from the deeper muscle layers more quickly than from the superficial layers of the bladder wall so that by 24 h a 4:1 ratio of fluorescence intensity was apparent which persisted at least until 72 h, although the absolute amount of photosensitiser declined. Following irradiation by red light (675 nm), photobleaching of the sensitiser in the deeper layers further increased this ratio. Direct absorption of A1SPc by the bladder wall following intravesical administration proved unreliable."} +{"text": "The expression of the c-erbB-2 oncogene has been evaluated using an immunohistochemical technique with the 21N polyclonal antibody in paraffin embedded tissue from 465 patients treated between the years 1975-1981 for Stage I and II breast cancer. One hundred and four (22%) patients exhibited positive staining. This was not associated with any other variables. Expression of the oncogene was associated with significantly poorer survival which was independent of other tumour variables."} +{"text": "The alpha 6/beta 4 integrin complex has been shown to be expressed in murine tissues at the basolateral aspect of most epithelial cells including the mammary epithelium, thus suggesting that this heterodimer may interact with components of the basement membrane. Because transformation of mammary epithelium frequently results in disappearance of basement membranes and loss of cell polarisation we have analysed in the present study whether expression of the alpha 6/beta 4 complex is altered in human breast tumours. The results of the present study confirm that in human mammary gland alpha 6 and beta 4 subunits colocalise at the basolateral aspect of the epithelium. While in benign breast lesions this distribution pattern remains mostly unchanged, in primary carcinomas the expression of both chains is either redistributed over the cells surface or significantly reduced. This altered pattern of expression is paralleled by the lack of detection of basement membrane laminin and collagen type IV. In metastatic lesions the expression of the heterodimer is maintained in most of the lymphnodal foci, but less frequently detected in metastasis localised in the pleural cavity and in parenchymal tissues. These findings indicate that in breast epithelium expression of the alpha 6/beta 4 heterodimer is modulated by the presence of basement membrane and is possibly influenced by microenvironmental factors as suggested by the different pattern of alpha 6/beta 4 expression in nodal and extranodal metastatic foci."} +{"text": "Overt liver tumour was induced in Fisher rats by intraportal administration of 1.6 x 10(7) Walker carcinosarcoma cells. Control groups of rats received similar volumes of dead cells or saline intraportally. All animals were studied at 3 weeks when overt tumour was present. The Hepatic Perfusion Index (HPI) was significantly raised in rats with overt tumour compared to both groups of control animals. Portal flow and portal venous inflow were significantly reduced in the presence of overt tumour but hepatic arterial flow did not alter. These observations suggest that the alteration in the HPI in the presence of overt tumour results from an alteration in portal venous flow and inflow even though the blood supply to the tumour is principally derived from the hepatic artery. The changes in hepatic haemodynamics in the presence of tumour were accompanied by a reduction in portal pressure, an increase in splanchnic vascular resistance and an increase in the degree of arteriovenous shunting through the liver. Portal vascular resistance was unchanged. These findings indicate that the presence of overt hepatic tumour results in gross derangements of hepatic blood flow. These changes must be taken into consideration when attempting to potentiate the delivery of cytotoxic drugs to hepatic tumour by manipulation of hepatic haemodynamics."} +{"text": "Neurofilaments (NFs) are specific intermediate filaments to neural cells. Mammalian NFs are protein triplets composed of three major subunits with respective molecular weights of approximately 70, 150 and 200 kD. Using an immunohistochemical method, 13 carcinoid tumours from different sites were examined for the presence of these three subunits by means of monospecific antisera. All tumours contained cells that were positive for the 70 Kd subunit; nine cases contained cells immunoreactive for the 150 Kd subunit and only three of them for the 200 kD subunit. The results indicate that the 70 kD subunit is a good overall marker of carcinoid tumours. The 150 and 200 kD subunits are more likely to be absent in carcinoids, both typical and atypical."} +{"text": "Immunoglobulin (Ig) could not be detected on the surface or in the cytoplasm of neoplastic cells from five cases of follicle centre cell lymphoma with centroblastic/centrocytic follicular histology when examined by immunohistology of frozen or wax embedded sections. Examination by fluorescein labelled antibodies of cells in suspensions prepared from the biopsies revealed a monotypic surface Ig positive population in one case and a surface or cytoplasmic Ig kappa:lambda light chain imbalance in a further two cases consistent with neoplastic B cell involvement: in all cases the proportion of cells failing to express Ig or T cell markers ranged from 24 to 75%. The monoclonal antibodies B1 (Pan B cell), FMC4 (HLA class II) and J5 (cALL antigen) stained the majority of cells in suspension with residual cells staining with UCHT1 or OKT11 . In frozen sections, neoplastic follicular cells did not stain with UCHT1. However, in the one case tested these cells stained with the antibodies B1 and FMC4. In paraffin sections J chain could be demonstrated in the cytoplasm of three out of five cases. Cells from four cases were cultured in vitro for Ig production: two failed to produce Ig and monotypic light chains were the sole Ig product of the remaining two cases. The failure to express Ig by the majority of the neoplastic cells from the cases described in this report is at variance with the follicular histology of these neoplasms. Mechanisms responsible for this failure are discussed with reference to current models of B cell differentiation."} +{"text": "We determined the circulating level of bioactivity for skeletal muscle proteolysis-inducing factors (PIF) in the blood samples from cancer patients whose body weight loss was greater than 10%. The level of bioactivity was estimated by measurement of tyrosine release from isolated 1at diaphragm muscles incubated with an ultrafiltered fraction of plasma or serum proteins containing molecules from 0 to 25 kDa in molecular weight. Significant levels of bioactivity were detected in 25 of the 50 cancer samples. No activity was found in 18 of the samples from healthy human blood donors. The ability of 13 of the cancer samples to induce muscle proteolysis was significantly inhibited by incubation of muscles in presence of indomethacin (10 microM). The neutralisation of 12 of the cancer samples with the antibodies to recombinant human interleukin-1 (IL-1), alpha and beta forms, partially abrogated the activity in five samples. These results suggest that the accelerated breakdown of proteins induced by the cancer plasma factors is at least in part mediated by IL-1 in cooperation with other active factors not yet defined. Additionally, we have shown that the increased breakdown of proteins induced by PIF in the crude supernatant derived from activated mouse peritoneal macrophages is prevented by the treatment of muscles with either indomethacin or quin-2 (1 microM). These observations provide indirect evidence for a possible causal relationship between the production of PIF and the body-weight loss of cancer patients."} +{"text": "Two monoclonal murine antibodies have been raised against a delipidated extract of human cream. These antibodies were detected by immunohistological screening of hybridoma culture supernatants on sections of human breast tissue. One of those antibodies (E29) was subsequently screened against a range of normal and neoplastic human tissues and shown to react with a wide variety of human epithelia and with mesothelial cells. Antibody E29 was unreactive with other cell types, with the exception of occasional plasma cells. Antibody E29 is suitable for use on paraffin embedded tissue and represents a valuable reagent for the identification of tumours of epithelial origin."} +{"text": "Aminolaevulinic acid (ALA) is the first committed step in haem synthesis. In the presence of excess ALA the natural regulatory feedback system is disrupted allowing accumulation of protoporphyrin IX (PP IX) the last intermediate product before haem, and an effective sensitiser. This method of endogenous photosensitisation of cells has been exploited for photodynamic therapy (PDT). We have studied the fluorescence distribution and biological effect of induced PP IX in normal and tumour tissue in the rat colon. Fluorescence in normal colonic tissue was at a peak of 4 h with a rapid fall off by 6 h. The fluorescence had returned to background levels by 24 h. All normal tissue layers followed the same fluorescence profile but the mucosa showed fluorescent levels six times higher than the submucosa, with muscle barely above background values. At 6 h the ratio of fluorescence levels between normal mucosa and viable tumour was approximately 1:6. At this time laser treatment showed necrosis of normal mucosa and tumour with sparing of normal muscle. There was good correlation between the fluorescence distribution and the biological effect of ALA-induced photosensitisation on exposure to red light. ALA may be superior to conventional sensitisers for tumours that produce haem as the PP IX is synthesised in malignant cells while the other sensitisers mainly localise to the vascular stroma of tumours. There is also a greater concentration difference between the PP IX levels in tumours and in normal mucosa and normal muscle than with the other photosensitisers raising the possibility of more selective necrosis in tumours."} +{"text": "DNA-synthetizing lymphocytes were identified in the lymph nodes regional and more distal to the site of developing P-815 tumours by incorporation of [3H]-thymidine followed by autoradiography of lymph node sections. It appeared that not only T but also B cell areas of draining and to a lesser extent of distal lymph nodes were stimulated by the growing tumour. This result was unexpected since neither humoral nor tumour cell-bound antibody could be identified so far as a functional correlate of B cell stimulation. In general the proliferative response of lymphocytes followed a biphasic pattern with an early peak of reactivity on days 2-3 and a second peak around day 12-15 after tumour cell inoculation. In the draining (axillary) lymph node the second peak of reactivity was suppressed, possibly as a consequence of metastatic tumour cells in this node when tumour cells were inoculated in the flank. The pattern of lymphocyte stimulation revealed larger individual variations after tumour cell inoculation in the flank than the foot pad. These results were associated with a slower and less regular drainage of carbon particles from the flank to the axillary and exceptionally the brachial lymph node than from the foot pad to the popliteal node after injection of India ink."} +{"text": "Anticipatory nausea and vomiting (ANV) after repeated cycles of cytotoxic chemotherapy is thought to be a conditioned response to a conditioning stimulus. Good control of acute and delayed emesis may result in a lower incidence of ANV. We have analysed data from 574 chemotherapy patients who received granisetron as their antiemetic treatment during repeat cycle chemotherapy. Per treatment cycle, less than 10% of patients displayed symptoms of anticipatory nausea and 2% or less had symptoms of anticipatory vomiting. It is concluded that the use of granisetron as an antiemetic during the acute phase of chemotherapy may result in a lower incidence of ANV in patients undergoing repeat cycle chemotherapy."} +{"text": "In this study 125 primary lung tumours have been immunostained with a panel of 5 anti-p53 antibodies . These antibodies recognise different epitopes over the full extent of the p53 gene. It is generally believed that immunolabelling identifies only mutant p53 proteins due to the short half life of the wild type protein. The aims of this study were to confirm earlier studies of p53 positivity in human lung tumours and to establish whether or not this bore any relationship to survival. Immunostaining was demonstrated within the nuclei of affected cells in 54% of the 125 lung tumours . This confirms previous smaller studies of p53 protein expression in human lung tumours. Survival curves have been drawn for all of the cases considered together and for squamous and adenocarcinomas separately. No differences in survival between p53 positive and negative cases were seen for any group of tumours. This indicates that although p53 may be of considerable importance in the initiation of malignancy it is probably of little significance once a tumour has developed."} +{"text": "We measured tumour cellular DNA in 102 patients entered into two phase III trials of chemotherapy for end stage squamous carcinoma of the head and neck. The median survival of untreated patients with aneuploid tumours was 55 days compared with 224 days for patients treated with cisplatinum. This difference was highly significant. In contrast the median survival of untreated patients with diploid tumours was 74 days compared with 118 days for treated patients. Although this difference is statistically significant, the increased survival of 6 weeks is of no clinical benefit compared with the prolongation of survival of 6 months in patients with aneuploid tumours. Multivariate analysis showed that the significant predictors of survival were Karnofsky status, response to chemotherapy and ploidy."} +{"text": "Study of U waves exemplifies important clinical role of noninvasive electrocardiography in modern cardiology. Present article highlights significance of U waves with a clinical case and also summarizes in brief the history of the same Study of U waves has been more of academic importance rather than clinical application. Negative U waves when present may be of immense clinical importance. We describe here one such case where U waves were not only an early noninvasive marker for acute ischemia but they also disappeared after successful revascularization.The U wave, named by Einthoven in 1903, is still a subject of debate with respect to its origin and clinical importance . U wavesNegative U waves have low sensitivity but high specificity for heart disease and they are recorded in approximately 1% of all electrocardiograms in general hospital . NegativThe present case exemplifies the significance of negative U waves as the important sign of acute ischemia. We believe that clinical utility of U waves remains underutilized and more clinical studies are needed to exactly define their significance in the spectrum of coronary artery disease."} +{"text": "Young women presenting with breast cancer are more likely to have a genetic predisposition to the disease than breast cancer patients in general. A genetic predisposition is known to increase the risk of new primary breast (and other) cancers. It is unclear from the literature whether genetic status should be taken into consideration when planning adjuvant treatment in a young woman presenting with a first primary breast cancer. The primary aim of the POSH study is to establish whether genetic status influences the prognosis of primary breast cancer independently of known prognostic factors.st June 2001 to 31st December 2007. Written informed consent is obtained at study entry. Family history and known epidemiological risk data are collected by questionnaire. Clinical information about diagnosis, treatment and clinical course is collected and blood is stored. Follow up data are collected annually after the first year. An additional recruitment category includes women aged 41 to 50 years who are found to be BRCA1 or BRCA2 gene carriers and were diagnosed with their first breast cancer during the study recruiting period.The study is a prospective cohort study recruiting 3,000 women aged 40 years or younger at breast cancer diagnosis; the recruiting period covers 1Power estimates were based on 10% of the cohort carrying a BRCA1 gene mutation. Preliminary BRCA1 and BRCA2 mutation analysis in a pilot set of study participants confirms we should have 97% power to detect a difference of 10% in event rates between gene carriers and sporadic young onset cases. Most of the recruited patients (>80%) receive an anthracycline containing adjuvant chemotherapy regimen making planned analyses more straightforward. Less than 5% of breast cancers diagnosed in the UK are diagnosed in women aged 40 years or younger although there is a rapid increase in the incidence from about 35 years of age.Published retrospective studies suggest that early age at onset of breast cancer below 35 years) is a poor prognosis factor; high grade and oestrogen receptor (ER) negative tumours appear to be more frequent in younger women,3. Breas5 years iCertain tumour characteristics are characteristically seen in breast cancers due to a BRCA1 gene mutation and also to a lesser degree in BRCA2 gene carriers -12. For There are several areas of important clinical uncertainty regarding the management of hereditary breast cancer. It is not clear whether the prognosis for women with BRCA1 and BRCA2 related breast cancers differs compared to sporadic tumours with similar pathological prognostic indices. Current publications variously suggest that overall survival for BRCA1 gene carriers is better,14, the Both BRCA1 and BRCA2 are involved in cellular DNA repair mechanisms . FurtherBRCA1 and BRCA2 gene carriers are at increased risk of developing contralateral breast cancer and appear, in the longer term, to have an increased rate of new primary tumours in the affected breast (reviewed in). The roThe uncertainties surrounding the most appropriate treatment of breast cancer in BRCA1 and BRCA2 gene carriers is of critical importance and must be resolved in order that clinicians can better tailor treatment in hereditary breast cancer. There is a need for robust unbiased data to provide clear answers to the question of risk of death from the presenting cancer diagnosis versus risk of a future new primary cancer in an individual with hereditary breast cancer. Genotype and tumour phenotype should be considered so that questions of future risk reducing strategies can be given appropriate weight and timing by both patient and the treating oncologist.We describe here the design and progress of a prospective study established to provide reliable answers to questions about the influence of genotype on tumour phenotype and prognosis.In addition, since young onset breast cancer is uncommon, the prospective design of this very large cohort study presents many opportunities for exploring how inherited genetic traits affect tumour biology and treatment outcomes. Studies exploring how lower penetrance genes, radiological features and obesity and weight gain relate to prognosis in this cohort are some of the sub-studies currently in progress. The steThe Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) is a large, prospective cohort study. This design was chosen to minimise ascertainment bias, facilitate identification of controls that could be matched for all potential confounding factors and ensure accurate standardised and high quality data collection.The primary aims of the study are to determine whether:(1) The prognosis of patients with breast cancer who harbour BRCA1 or BRCA2 gene mutations differs from non carrier patients after adjustment for age and other major prognostic indicators.(2) Breast cancers occurring in patients with an inherited mutation in the same predisposing gene have a consistent and distinct tumour phenotype.(3) There are differences in the pattern of distant breast cancer recurrence between patients with BRCA1 or BRCA2 gene mutations and matched non carrier patients.(1) To develop a validated set of pathological criteria that improve the specificity and sensitivity of methods for identifying carriers of germ-line BRCA1/2 mutations to facilitate future clinical trials based on genotype.(2) To determine whether inherited genetic variants influence tumour biology (3) To describe the radiological features in a large cohort of young breast cancers and correlate these with genetic factors, tumour pathology and prognosis.This study received approval from the South and West Multi-centre Research Ethics Committee (MREC 00/6/69). Recruiting centres across England, Scotland, Wales and Northern Ireland. Recruitment began in April 2001. Recruitment was initially through the Southampton Breast Centre and all eligible individuals diagnosed from January 2000 were approached to participate since we could be sure that there had been no deaths of eligible women diagnosed between January 2000 and June 2001 when recruiting started in this centre. On joining the study each new centre was instructed to approach all patients as early as practical within 12 months of diagnosis, to ensure recruitment would be as complete as possible and not compromised by a failure to recruit patients who relapse early. Centres were given leave to invite patients diagnosed over the previous year provided they could be certain that no potentially eligible patients had died and could therefore not be invited to participate.Study recruitment is supported by the National Cancer Research Network All patients giving written informed consent to the study are asked to complete a short family history and epidemiology questionnaire and co-investigator (P Simmonds) to ensure consistent data entry. The data files for recruits who die during the period of follow up are systematically checked for accuracy and consistency of data entry.A blood sample (30 mls) is collected from each recruit. Whole blood (for DNA) and serum are stored. Peripheral Blood Lymphocytes (PBL) are stored of cases where sample quantity and transit time permit (currently 75% of cases). Tumour tissue from paraffin blocks is collected centrally for formal pathology review and assembly of tissue micro arrays.\u00ae which implements the BRCAPRO carrier probability algorithm since this is widely used in genetics services in the UK in particular[A family history questionnaire is completed by each recruit. Reported diagnoses in the family are accepted as stated, no attempt is made to verify these diagnoses since ethical permission was not granted for this. The family history is used to rank genetic risk for each individual using the commercially available software Cyrillicarticular. This soarticular. In a siarticular it proviarticular,28. MutaThe power estimates depend critically on the prevalence of mutation carriers. The initial power analyses were based on a cohort of 2000 patients and looked at a variety of possible BRCA1 prevalence rates since we intend to analyse by each gene. In a cohort of 2000 women, if the prevalence rate of BRCA1 gene carriers is 10%, a study with 200 BRCA1 gene carriers has 97% power to detect a difference in 2 year event rate of 20% in gene carriers compared with 10% for sporadic cases. If the prevalence rate of carriers drops to 5%, the number of carriers would be 100 (estimate for BRCA2) and the power drops to 78% to detect the same difference in event rates.Approximately 30% of the participants report some family history in first or second degree relatives of breast or ovarian cancer. Preliminary mutation testing in 120 study participants revealed 1/38 (3%) of women with no documented family history of cancer had a pathogenic BRCA1 mutation and 32/81 (39.5%) of recruits with a family history of breast (or ovarian) cancer had a pathogenic mutation \u2013 22/81 (27%) in BRCA1 and 10/81 (12%) in BRCA2. The target for recruitment was revised to 3,000 in 2006. From our preliminary mutation testing, we expect to find 260 BRCA1 gene carriers amongst women presenting with a family history (about 30% of the cohort) + 63 BRCA1 gene carriers amongst young women with no family history. We would expect 108 BRCA2 gene carriers amongst the recruits with a family history.We will in addition have a cohort of know gene carriers but their treatment choices may differ in light of their known genetic status. The difficulty of \"confounding by indication\" whereby the prognosis partly determines the choice of treatment, is potentially a significant problem for non randomised trials such as this . This prDemographic data and features of the primary tumour will be compared using the two-sample t-test or the Mann-Whitney test, as dictated by the distribution of the response variable. Treatment modalities will be compared using the chi-squared test. Follow up data will be compared using Kaplan-Meier survival curves, with the log rank test being used to compare the distribution of recurrence-free times. Analysis comparing outcomes for patients treated differently will be adjusted for patient characteristics using logistic or Cox regression.In the UK at present most young women diagnosed with breast cancer have not had a genetic test. Technical challenges and cost have limited the ability to perform rapid molecular genetic testing until quite recently. Thus most newly diagnosed breast cancer cases will be treated on the basis of tumour prognostic features and without knowledge of the patient's genetic status although family history is often recorded. As technology moves on and genetic testing becomes more readily available, treatment decisions may be increasingly influenced by knowledge of the patient's genetic make-up. At present such genotype directed management strategies would be premature since the published evidence is based on inherently unreliable information from small retrospective studies . The POSH study will provide unique and important data about modern breast cancer treatment in a large group of women with unusually young onset disease. It will give important insights into the underlying influences of genetic variation on disease aetiology, host response to disease and treatment effects as well as long term outcomes for early onset breast cancer.The author(s) declare that they have no competing interests.DE is the Chief Investigator for the POSH study, devised the study and wrote the paper. PS is co-investigator and helped design the study and database fields and co-wrote the manuscript. SG is responsible for data collection and entry and day to day management of the study. SE provided advice on data abstraction and analysis for the study, VH carried out a pilot BRCA1 and 2 mutation analysis in the cohort to verify the power estimates. DGA is involved in the planning of the study design and data analyses and advised on presentation of the manuscript.POSH Steering GroupAdditional members of the steering group for the POSH study involved in monitoring study progress and in aspects of the study design and who contributed valuable comments during the preparation of this manuscript are Dr Paul Pharoah (genetic epidemiology), Strangeways Research Laboratories, Cambridge; Professor Louise Jones (pathology), Tumour Research Laboratory, John Vane Cancer Centre, St Bartholomews Hospital, London; Professor Sunil Lakhani (pathology), University of Brisbane, Australia; Dr Ros Eeles, (Cancer Genetics Group), The Institute of Cancer Research & Royal Marsden NHS Foundation Trust; Professor Gareth Evans, (Cancer Genetics), St Mary's Hospital, Manchester; Professor Alastair Thompson (Surgery), Dundee University; Professor Shirley Hodgson (Cancer Genetics), St Georges Hospital, London; Mr Hisham Hammad (Surgery), Guy's Hospital, London; Dr Ruth Warren (Radiology), University of Cambridge; Professor Fiona Gilbert (Radiology), University of Aberdeen;The pre-publication history for this paper can be accessed here:Family history questionnaire format. This shows the questions asked to elicit family history data for each recruit.Click here for fileLifestyle questionnaire format. This shows the questions asked to elicit epidemiological risk data for each recruit.Click here for filePOSH diagnosis information. This shows the clinical trials form for collecting data about the initial patient diagnosis.Click here for filePOSH surgery. This shows the clinical trials form for collecting data about the surgical management of each recruit.Click here for filePOSH additional treatment information. This shows the clinical trials form for collecting data about adjuvant treatment for each recruit.Click here for file"} +{"text": "Abnormalities of the EGF receptor and/or the related ERBB2 receptor occur in a significant proportion of cases of human breast cancer and are important influences in the behaviour of this tumour type. In this report we demonstrate by nucleic acid analysis and immunohistochemistry that the recently recognised third member of this gene family, ERBB3, shows a wide range of expression in breast cancer, and shows stronger immunoreactivity than that observed in normal tissue in 43 out of 195 cases (22%) of primary breast cancer. Overexpression of ERBB3 appears to result from increased levels of gene transcription since in none of the cell lines or primary cancers analysed did we find evidence of gene amplification. High expression of ERBB3 is positively associated with the presence of lymph node metastases, but there was no demonstrable relationship with patient survival in this series."} +{"text": "Arabidopsis gene APETALA3 (AP3). Previous work has demonstrated that the ancestral paleoAP3 lineage was duplicated at some point within the basal eudicots to give rise to the paralogous TM6 and euAP3 lineages. This event was followed in euAP3 orthologs by the replacement of the C-terminal paleoAP3 motif with the derived euAP3 motif. It has been suggested that the new motif was created by an eight-nucleotide insertion that produced a translational frameshift.The evolution of type II MADS box genes has been extensively studied in angiosperms. One of the best-understood subfamilies is that of the AP3 homologs to the existing dataset has allowed us to clarify the process by which the euAP3 motif evolved. Phylogenetic analysis indicates that the euAP3/TM6 duplication maps very close to the base of the core eudicots, associated with the families Trochodendraceae and Buxaceae. We demonstrate that although the transformation of paleoAP3 into euAP3 was due to a frameshift mutation, this was the result of a single nucleotide deletion. The use of ancestral character state reconstructions has allowed us to demonstrate that the frameshift was accompanied by few other nucleotide changes. We further confirm that the sequence is evolving as coding region.The addition of 25 eudicot This study demonstrates that the simplest of genetic changes can result in the remodeling of protein sequence to produce a kind of molecular 'hopeful monster.' Moreover, such a novel protein motif can become conserved almost immediately on the basis of what appears to be a rapidly generated new function. Given that the existing data on the function of such C-terminal motifs are somewhat disparate and contradictory, we have sought to synthesize previous findings within the context of the current analysis and thereby highlight specific hypotheses that require further investigation before the significance of the euAP3 frameshift event can be fully understood. APETALA3 (AP3) lineage of type II MADS box genes.An increasing body of research has demonstrated that changes in gene regulation play a major role in the evolution of morphological form (reviewed -3). ThatMembers of the type II MADS box family control many important aspects of plant development (reviewed ). ExtensAPETALA3 (AP3) and PISTILLATA (PI) gene lineages, which include the Arabidopsis petal and stamen identity genes of the same names. These two lineages are sister groups within the larger MIKC MADS gene family . The PI Motif-derived region is boxed in green; paleoAP3 motifs, in blue; and euAP3 motifs, in purple. Residues showing chemical conservation with the consensus for each of these regions [28] are shaded in grey. Red arrows at the right indicate the loci that appear to have experienced independent frameshift mutations.Click here for fileAPETALA3 nucleotide alignment NEXUS format file of complete APETALA3 nucleotide alignment used in current phylogenetic analyses.Click here for fileComparison of position-by-position nucleotide diversity values for paleoAP3 and euAP3 motif containing loci. Complete dataset of nucleotide diversity values of paleoAP3 and euAP3 containing loci. Region spans the entire C-terminal motif. The yellow bars indicate the values for a dataset including all TM6 lineage members and basal eudicot paleoAP3 loci. The codon positions of each nucleotide are indicated by vertical hash marks and the corresponding amino acids are shown immediately below the chart. Note that the last four nucleotides in the paleoAP3 alignment are 3' UTR. The blue bars indicate the values for a dataset including all euAP3 lineage members. The codon positions of each nucleotide are indicated by vertical hash marks and the corresponding amino acid are shown at the bottom. The position of the euAP3 frameshift is represented by a dash mark. n/a = not applicable.Click here for filePaleoAP3 alignment for nucleotide diversity calculation Alignment of paleoAP3 encoding regions of Pachysandra loci, TM6 orthologs and basal eudicot paleoAP3 representatives. Indels were removed from the alignment.Click here for fileEuAP3 alignment for nucleotide diversity calculation Alignment of euAP3 motif encoding regions of euAP3 lineage members. All indels were removed except for the single nucleotide deletion corresponding to the euAP3 motif frameshift.Click here for file"} +{"text": "We have examined the proliferative response (DNA synthesis) of primary thyroid epithelial cultures to serum and a defined serum-substitute. These cultures were derived from normal human thyroid and from thyroid adenomas and carcinomas. All normal cultures showed a dose-dependent response, with a maximum 3H-thymidine labelling index of around 50%. Three out of the four adenomas demonstrated a much reduced or delayed response under the same conditions. In two carcinomas, labelling was never more than 5% and in one case was undetectable. This inverse relationship between the degree of in vivo malignancy and proliferative response in vitro has important implications for the interpretation of tissue culture models of epithelial neoplasia and also offers the potential for isolating novel growth factors specific for thyroid cancer cells."} +{"text": "Four established human breast tumour cell lines with different biologic properties were selected for study and requirements for their clonogenic growth in semisolid cultures were identified. The conventional conditions were modified by factors that enhanced colony formation of 3 or more of these cell lines. The modified culture conditions were then applied to the growth in agar of primary breast tumours. A 5-fold improvement in plating efficiency was observed when cultures of 105 primary tumours grown under these modified conditions were compared to those of 52 tumours grown earlier under conventional conditions, and a 4-fold improvement resulted from the addition of hormones and conditioned medidum in 26 tumours cultured simultaneously under both conditions. The biologic relevance of these clonogens recovered in vitro was substantiated by a 70% concordance of in vitro and in vivo tumour sensitivity to anticancer drugs."} +{"text": "Suspensions of syngeneic sarcoma cells were injected into the Peyer's patches of rats from which the mesenteric nodes had been removed. By later cannulating the thoracic duct of such rats it was possible to collect peripheral intestinal lymph that had come directly from the tumour bearing area without being filtered through a regional node. The number of viable tumour cells in the lymph coming from the tumours was monitored by culturing the whole lymph cells in a limiting dilution assay. The tumours grew to a diameter of approximately 1 cm in 25 days and during this time tumour cells were present in the lymph at a ratio of approximately 1 tumour cell per 10(5) lymph cells. In euthymic rats this number declined as the immune response developed. In athymic rats the number increased by approximately 10 fold during the experiments. It was concluded that the shedding of viable cells parallels the linear, not the volumetric dimensions of the tumour."} +{"text": "The practical usefulness of a panel of monoclonal antibodies recognising epithelial and lymphoid antigens has been evaluated on a series of 10 routinely processed thyroid tumours of uncertain origin. All 6 small cell tumours were shown to be of lymphoid origin whereas of the 4 large cell tumours two were lymphomas and two carcinomas. Two of the tumours, one large cell and one small cell, were undiagnosable due to technical reasons and emphasized the value of immunohistology in this context. Clinical follow-up of all 10 cases indicated that these distinctions are of both prognostic and therapeutic value. It is concluded that immunocytochemistry using a carefully selected panel of monoclonal antibodies is a valuable and convenient means of making an objective distinction between anaplastic thyroid tumours of epithelial or lymphoid origin."} +{"text": "The importance of host immune status on the spontaneous metastasis of cloned cell lines of the 13762NF rat mammary adenocarcinoma was examined. Cell lines MTLn3 , MTF7 and MTLn2 and MTC were subjected to a series of in vivo assays designed to assess how manipulation of the immune system in the syngeneic F344 host would affect the ability of these cells to metastasise. Treatment of tumour bearing rats with the immunosuppressive agents cyclosporin A or cyclophosphamide had little influence on metastasis in this system. Growth of tumours in congenitally athymic nude rats resulted in reduction of observed metastases. In addition, humoral immune response was not detectable during a 23-day period of tumour growth in F344 rats. Excision of the tumour growing in situ reduced the number of metastases when the tumours were resected early (less than 10 days), but at later times tumour resection did not influence the incidence of metastasis. The importance of initial lymphatic rather than haematogenous routes of dissemination was confirmed in experiments where the draining inguinal and axillary lymph nodes were removed at different times either before, or after, subcutaneous mammary fat pad injection of metastatic tumour cells."} +{"text": "The limitations of case review as a means of identifying errors in death certificates among breast cancer patients in a non-randomised trial of screening are illustrated by the findings of this large study. Records of 928 out of 990 deaths were available for review but were very variable in quality. Definite errors were found in 1%, errors were suspected in a further 5% and uncertainty about the cause of death, despite review, was recorded for 27%. The overall bias in reporting breast cancer deaths was less than 1%. It was concluded that the certified underlying cause of death without review provides an adequate endpoint for evaluating breast cancer screening programmes in the UK."} +{"text": "Three types of natural immune responses against malignant cells were studied in vitro: Cytotoxicity mediated by splenic NK cells; cytostasis mediated by splenocytes and binding of naturally occurring antibodies to various tumour targets. These responses were studied in untreated 3 and 12 month old mice and in mice of both age groups inoculated with B16 melanoma cells. The results showed that in normal mice NK activity decreases with age, cytostatic activity remains unchanged and the titre of natural antibodies increases. Twelve-month old mice were shown to be appreciably more resistant than 3 month old mice to the development of tumours from subthreshold numbers of B16 tumour cells. In mice injected with threshold amounts of the B16 tumour, there was no change in any of the responses in the tumour-free period, but there was a decrease in NK activity and an increase in cytostatic activity when a large tumour mass developed. An increase in the titre of natural antibodies in young mice injected with the tumour was also seen. The correlation between these changes and tumour appearance and development is discussed."} +{"text": "The relationship between colony numbers and concentration of cells plated is an important parameter of clonogenic assay systems. The cloning efficiency for an ideal sample should be independent of cell concentration, thus giving a straight line through the origin when colony numbers are plotted against cell concentration. A simple statistical method has been developed to test if this is the case for individual tumour samples. Colony data from 51 freshly obtained tumour samples, which had sufficient cells to plate 3 or more dilutions and gave at least 20 colonies per plate at one or more of the dilutions, were tested. The results indicated that colony formation was linear for 27 (53%) of the samples. The remaining 24 samples could be classified into 2 groups: type I, in which cloning efficiencies increased with increasing cell concentration and type II, which had reduced cloning efficiencies at high cell concentrations. Fifteen (29%) of the samples had type I non-linearity and 9 (18%) exhibited non-linearity of type II. These findings indicate that the relationship between colonies and cells plated should be examined for each biopsy sample particularly in each experiment where the effects of cytotoxic drugs are tested."} +{"text": "Three\u2010dimensionally ordered macroporous (3DOM) hydrogels prepared by colloidal crystals templating display highly reversible shape memory properties, as confirmed by indirect electron microscopy imaging of their inverse replicas and direct nanoscale resolution X\u2010ray microscopy imaging of the hydrated hydrogels. Modifications of functional groups in the 3DOM hydrogels result in various materials with programmed properties for a wide range of applications. Hydrogels are synthetic or natural polymer networks crosslinked either chemically or physically to maintain 3D structures that are able to absorb and retain large amounts of water.2 capture.Macroporous hydrogels prepared by colloidal crystal templating have attracted much attention in recent years due to their unique structural features, holding immense promise as responsive materials for detection,stem) gels can be programmed, depending on the applied chemistry. Thus, the functional hydrogels represent a robust platform for constructing well\u2010defined functional materials with preselected properties targeting a wide range of applications.Herein, we analyze the reversible 3DOM porous structures in colloidal crystal templated macroporous hydrogels through two approaches: one procedure is electron microscopy imaging of their inverse replicas and the other is noninvasive and nondestructive nanoscale resolution X\u2010ray microscopy (nano\u2010XRM) imaging of the hydrated hydrogels. Thus, one focus of this work is the development of two novel methods for the characterization of 3DOM structures in hydrogels. This work also demonstrates for the first time the intrinsic shape memory properties of 3DOM hydrogels. The additional aim of this work is further modification of functional 3DOM hydrogels. The properties of such structurally tailored and engineered macromolecular ; however, no pores were observed in the SEM images Figure b. NevertIn order to prevent collapse of macropores, more rigid water\u2010soluble monomers were used, and the 3DOM hydrogels were synthesized by controlled radical polymerization , see Supporting Information, Figure S3),A facile method was developed to resolve this problem and indirectly characterize the 3DOM structure by SEM. The porous hydrogels were soaked in an acetone solution of a crosslinker ), which was then thermally polymerized to form arrays of crosslinked DVB spheres inside the macropores of the hydrogels Figure . The resThe macroporous structures of the 3DOM hydrogels were retained and highly reversible through repeated collapse and reformation cycles. The original 3DOM structures stayed intact as the 3DOM hydrogels were repeatedly dried under vacuum and then swollen by solvents for ten cycles. This was confirmed by the ordered sphere arrays in the SEM images of their inverse replicas . This demonstrated the intrinsic reversible shape memory nature of the 3DOM structures in the hydrogels.FigureIn addition, a direct approach was employed to resolve the 3DOM structure in the presence of water by nano\u2010XRM in Zernike phase contrast mode.stem gels that can evolve into materials with final properties and function that can be programmed, depending on the chemistry applied for modification. By the esterification of the hydroxyl groups of the 3DOM hydrogels with dodecanoyl chloride, the surfaces of hydrogels modified with the long alkyl chains became hydrophobic. The alternation of the hydrophilicity/hydrophobicity was verified by water contact angle measurements. Water droplet was absorbed by the pristine hydrogels, while it stayed on the surface of the modified hydrogels (PNIPAM) was then grafted from the pore walls by ATRP and the resulting copolymer showed temperature\u2010responsive surface properties due to the lower critical solution temperature (LCST) of PNIPAM (32 \u00b0C). As shown in Figure In addition, ATRP initiators were anchored onto the surface of the pores by reaction between hydroxyl groups of the 3DOM hydrogels and \u03b1\u2010bromoisobutyryl bromide. Poly . While the use of enzyme immobilized inverse opals as heterogeneous biocatalysis has been demonstrated in previous reports,N\u2010\u03b1\u2010benzoyl\u2010l\u2010arginine ethyl ester hydrochloride (BAEE) as the substrate molecules. For instance, trypsin was grafted onto the pores of the 3DOM hydrogels by the reaction of trypsin amino group with carboxylic acid groups from the hydrogels. The resulting 3DOM hydrogels with pore immobilized trypsin displayed bioactivity for tryptic digestion of bovine serum albumin (BSA) Figure4b and 3 by NaBH4 on the surface of 3DOM hydrogels modified with the carboxylic acid groups to form Au nanoparticles (NPs) with an average diameter of 7.1 nm that were uniformly distributed on the pores. The distribution of the formed AuNPs can be observed in the transmission electron microscopy (TEM) images of a thin\u2010section of the sample NPs with an average diameter of 3.1 nm were decorated onto the positively charged pore surfaces of 3DOM hydrogels containing quaternary ammonium groups, affording magnetic 3DOM hydrogels molecules, and inorganic particles generates materials with new properties into the structured 3DOM hydrogels and result in novel composites for (bio)catalysis and separation applications. The unique 3DOM structures with well\u2010controlled pore size and excellent pore interconnectivity can also serve as models for systematic studies of the influence of pore size and pore interconnectivity on the properties of the resulting materials . This work suggests that functional 3DOM hydrogels represent a versatile platform for a wide range of applications and there are even more multifunctional materials based on 3DOM gels to be explored.As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re\u2010organized for online delivery, but are not copy\u2010edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file.SupplementaryClick here for additional data file."} +{"text": "The first version of this article published online included errors in Figure 4 that occurred during production. The graph in Both the HTML and PDF versions of the article have been corrected. This error appears only in PDF versions downloaded on or before January 22, 2018. Rockefeller University Press apologizes for this regrettable error."} +{"text": "This paper explores the question of whether school drug testing is an effective solution to tackle adolescent substance abuse problems. Research studies in major academic databases and Internet websites are reviewed. Several observations are highlighted from the review: (1) there are few research studies in this area, particularly in different Chinese contexts; (2) the quality of the existing studies was generally low; and (3) research findings supporting the effectiveness of school drug testing were mixed. Methodological issues underlying quantitative and qualitative evaluation studies of the effectiveness of school drug testing are also discussed."} +{"text": "In the Austral summer of 2014\u20132015 we surveyed visitors at the popular marine tourism destination of Koombana Bay, Bunbury, Western Australia to investigate resident and visitor attitudes towards the provisioning of the wild dolphins and their knowledge about the legal, social and environmental repercussions arising from the unregulated provisioning of the dolphins. We report the data collected in our survey along with our preliminary statistical analyses and the survey instrument we utilized to collect the data. Specifications TableValue of the data\u2022Data and survey instrument questions can be compared with or inform other studies.\u2022Outcomes of statistical analyses highlight trends in data.\u2022Provides simple statistical techniques (with exemplars), which may assist other studies.1n=80 and Males n=36). Numerical data for participant responses to categorical, five point Likert scale and ranking questions appear in We had 116 analyzable questionnaires returned from the 216 we distributed at Koombana Bay in the regional city of Bunbury, Western Australia and the local Dolphin Discovery Centre (DDC) are important drawcards for this marine tourism destination The resident wild population of Indio-Pacific Bottlenose Dolphins (2.2We collected our data on two field trips to Koombana Bay during the Austral summer of 2014\u20132015 by opportunistically sampling visitors using self-report pencil and paper questionnaires in a cross sectional survey research approach. Our survey instrument appears in 2.3\u00ae 2010 spreadsheets.Our data analysis primarily utilises chi-squared analysis of categorical data. We use the Marascuilo Procedure for post-hoc testing when statistically significant differences are identified"} +{"text": "We report a case of massive associative visual agnosia. In the light of current theories of identification and semantic knowledge organization, a deficit involving both levels of structural description system and visual semantics must be assumed to explain the case. We suggest, in line with a previous case study [1], an alternative account in the framework of (non abstractive) episodic models of memory [4]."} +{"text": "Healthy mobile phone users aged 18\u201330\u00a0y.o. provided exfoliated buccal cells samples from the right and left inner cheeks. A total of 2000 cells per subject were screened for the presence of micronuclei as a sign of genotoxic damage, according to the mobile phone use profile of each user. Specifications TableValue of the data\u2022Data was collected from members of an important share of mobile phone users . Establishing the effects of mobile phone use in this population can contribute to an overall perception of how such devices affect the majority of its users \u2022Improved perception of the effects of mobile phone electromagnetic radiation in humans can contribute to improved safety guidelines for the use of this device and help combat long standing misconceptions on mobile phone radiation \u2022Establishing the relevance and efficacy of exposure levels and of the biomarker assessment method herein described can help in the determination of a genotoxicity-based model of observation and thus promote the development of new methods.1Overall micronucleus frequency in the study population (2.02 (\u00b11.65) per 2000 cells) was found to be within currently accepted physiological ranges 2Buccal exfoliated cells were collected using sterile endobrushes followed by a smearing technique on histological slides. Cells were fixated with an ethanol-based solution, air-dried and stained according to Feulgen's method"} +{"text": "Data files present information on the quantitative distribution of the polycystine radiolarian species in the Quaternary marine sediments from the subarctic areas. Dataset on the open North Atlantic north of 43\u202f\u00b0N contains percentages of 35 abundant (> 1%) species in 145 samples of five sediment cores. Dataset on the Sea of Okhotsk contains percentages of 31 abundant (> 1%) species in 794 samples of seven sediment cores. Dataset on the bottom surface sediments of the North Atlantic contains percentages of 35 abundant (> 1%) species in 78 grab and core-top samples. For the microscopic radiolarian analysis, the sediment fraction of > 40/50\u202f\u03bcm was used. Specifications TableValue of the data\u2022data on the distribution of the microfossils in the oceanic bottom sediments provide an information on the development of the environments and climate as the marine microorganisms are valuable environmental indicators\u2022we publish the detailed micropaleontological datasets on the subpolar areas of the Northern hemisphere where the long- to short-term climatic changes exhibit a high magnitude\u2022our micropaleontological data are obtained according the standard analytical technique so that they can be used without significant modification by other specialists\u2022main research output from use of our datasets is a reconstruction of paleoenvironments , such as water temperature, to define trends and possible cycling of the paleoclimatic changes1Data files contain the quantitative information on the relative content (%) of the abundant (> 1% of concentration) species of the polycystine radiolarians in the Quaternary sediments of the subarctic North Atlantic and Sea of Okhotsk. Polycystine radiolarians as protists with silica skeleton are one of major groups of the marine microplankton. They can be accumulated in great numbers on the oceanic floor, and then extracted from sediments for the biostratigraphic and paleoceanographic studies. The Quaternary sediments contain diverse lithophysical, geochemical, and micropaleontological information on the glacial to interglacial paleoclimatic changes. We provide detailed micropaleontological data mostly on the last glacial cycle in 5 sediment cores from the northern North Atlantic (35 radiolarian species in 145 samples) and 7 sediment cores from the Sea of Okhotsk (31 radiolarian species 794 samples) ; Table 12The laboratory treatment of sediment samples (1\u20132\u202fg of dry bulk sediment) and preparation of the radiolarian slides for the microscopic analysis was made the standard technique : cleanin"} +{"text": "Most sampling in phyllosphere research has focused on the collection of microbiota without the use of a control, so the opportunity to determine which taxa are actually driven by the biology and physiology of plants as opposed to introduced by environmental forces has yet to be fully realized. To address this data gap, we used plastic plants as inanimate controls adjacent to live tomato plants (phyllosphere) in the field with the hope of distinguishing between bacterial microbiota that may be endemic to plants as opposed to introduced by environmental forces. Using 16S rRNA gene amplicons to study bacterial membership at four time points, we found that the vast majority of all species-level operational taxonomic units were shared at all time-points. Very few taxa were unique to phyllosphere samples. A higher taxonomic diversity was consistently observed in the control samples. The high level of shared taxonomy suggests that environmental forces likely play a very important role in the introduction of microbes to plant surfaces. The observation that very few taxa were unique to the plants compared to the number that were unique to controls was surprising and further suggests that a subset of environmentally introduced taxa thrive on plants. This finding has important implications for improving our approach to the description of core phytobiomes as well as potentially helping us better understand how foodborne pathogens may become associated with plant surfaces.An important data gap in our understanding of the phyllosphere surrounds the Salmonella\u2013tomato associated outbreaks occurred between the years of 1990 and 2014, causing thousands of illnesses . All metadata has been submitted according to MIMARKS (minimum information about a marker gene sequence).S1 FigMost abundant bacterial families identified using 16S rRNA gene amplicons for all independent replicates of control (C) and phyllosphere (P) at all time-points. Taxonomy was assigned using the RDP classifier trained on the GreenGenes database.(TIF)Click here for additional data file.S2 Figpermutest in Vegan package). No significant differences in dispersions among time-points within each environment were identified (most likely due to limited group sizes).Permutation-based tests of dispersion homogeneity were performed using the Vegan R package (betadisper). Significant differences in dispersion were identified between T0 compared to T1 and T1 compared to T2 Click here for additional data file.S1 TableFull report of pre-processing and quality screening of sequences used for downstream analyses.(XLSX)Click here for additional data file."} +{"text": "The dataset helps the readers to understand and evaluate the potential of POFA though a waste material can be used as a replacement of Portland cement in having durability properties at an acceptable range.Datasets contained in this article are outcomes of the durability properties carried out on Palm Oil Fuel Ash (POFA) concrete specimens to determine the effect of acid attack, Sulphate resistance, water absorption and rapid chloride permeability. Specimens were immersed in 1% hydrochloric acid (H Specifications TableValue of the data\u2022The data contained herein can be used to solve some of the problems of durability of concrete in the cement industries.\u2022The data can be used to determine durability behaviour of self compacting concrete (SCC) \u2022The employed approach can serve as benchmark to other methods in testing properties of SCC.\u2022The dataset can be used to determine performance required for concrete structure.\u2022The dataset can serve as an experimental framework for the analysis of other basic properties of concrete.1In this dataset article, durability test, acid attack, sulphate, water absorption test, rapid chloride permeability test on POFA self-compacting concrete test were carried out while the test results are as contained in 22.1The results of acid attack in terms of weight loss after 90 days for all the concrete are shown in 2.2External sulphate attack to cementious matrix is a complex process that involves the movement of sulphate ions through the pores by means of different mechanisms of transportation and the interaction of aggressive solution with some compounds of cements paste to form expansive compounds (gypsum) that produce cracking, strength loss and softening. After 28 days of curing the test was conducted by measuring the weight losses of the specimen at 28, 56 and 90 days. 2.3The result of Saturated Water Absorption (SWA) tests of various self-compacting concrete mixes at the ages of 28, 56 and 90 days are given in 2.4In the text, SCC and NC denote self compacting concrete and normal concrete (without POFA) respectively.It was observed that the incorporation of palm oil fuel ash in self-compacting concrete enhanced the Sulphate and acid attack. The rapid chloride and water absorption showed a reduction in weight. It can also be seen that both normal concrete as well as SCC palm ash have all been following the same trend. In"} +{"text": "Drosophila ortholog of NR5A1, is expressed and required in the secretory cells of the spermatheca, the female exocrine gland that ensures fertility by secreting substances that attract and capacitate the spermatozoids. We here identify a direct regulator of Hr39 in the spermatheca: the Gcm transcription factor. Furthermore, lack of Gcm prevents the production of the secretory cells and leads to female sterility in Drosophila. Hr39 regulation by Gcm seems conserved in mammals and involves the modification of the DNA methylation profile of mNr5a1. This study identifies a new molecular pathway in female reproductive system development and suggests a role for hGCM in the progression of reproductive tract diseases in humans.NR5A1 is essential for the development and for the function of steroid producing glands of the reproductive system. Moreover, its misregulation is associated with endometriosis, which is the first cause of infertility in women. Hr39, the In mammals and insects, the process of spermatozoid maturation occurs first in the male before copulation and second after copulation where molecules secreted by the female reproductive tract epithelium preserve and capacitate the spermatozoids123691011121314NR5A1 gene is hNR5A1 and mouse ortholog is mNr5a1 throughout the text)1418202122Several insect species have developed specific structures called spermathecae that preserve the spermatozoids well after copulation in the female reproductive tract. The molecules that attract, store and capacitate the spermatozoids in the spermatheca are produced by a layer of secretory cells (SC)16Hr39 during Drosophila spermatheca development. While the complete lack of Gcm leads to embryonic lethality due to the loss of glia25262728hNR5a1 locus as those observed in endometriosis.In this study, we identify the zinc finger transcription factor Glial cells missing as a major transcriptional regulator of Drosophila spermatheca and the conserved regulation of Hr39 and NR5A1, which represents the first evidence of the functional conservation of the Gcm transcription factors. Understanding the regulation of Hr39 expression may shed light on the physiopathological mechanisms of the major cause of infertility in women.Collectively, our data reveal the regulatory pathway underlying SC differentiation in the Drosophila, the complete lack of the Gcm protein leads to embryonic lethality due to the transformation of glial cells into neurons2430gcm mutant animals at later stage243132gcmrA87 allele is due to the insertion of a P-element containing the LacZ gene in the promoter of gcm and the gcmGal4 allele has been produced upon replacement of the LacZ by the Gal4 gene243132gcmGal4 homozygous and the transheterozygous gcmGal4/gcmrA87 animals reach adulthood and display fertility defects. To assess whether the defects are sex specific, we crossed wild type males with gcmGal4 homozygous or with transheterozygous females and found a significantly reduced number of offspring compared to that obtained in control crosses expressing the Runt-domain transcription factor Lozenge (Lz), which is essential for the development of the whole spermathecaTwo elegant studies14gcm conditions , the SC layer is completely absent, leaving the dark cuticular structure relatively unaffected using the gcmGal4 as a driver 132 strain in which the gcm gene is completely deleted33gcm hypomorphic but lethal mutation induced by P-element mutagenesis, gcm34\u2009rd instar larval stage prior to spermatheca differentiation. WT clones contain both cell types (SC and LEC), whereas Df(2L)132 and gcm34 mutant clones contain LEC but completely lack SC. Thus, Gcm is necessary for the differentiation of SC. Given the strong phenotype observed in loss of function gcm alleles, we assessed the consequences of overexpressing Gcm in its own territory of expression in WT animals (gcm\u2009>\u2009gcm GOF). In these gain of function (GOF) animals, the dark cuticular structure and the LEC are present but the morphology of the spermatheca is altered , which is active in the MP. Like in hypomorphic conditions and in gcm\u2009>\u2009gcm KD animals, RNAi-mediated down-regulation of Gcm in the MP leads to the decrease of the number of SC in the adult spermatheca . We then proceeded to overexpress Gcm under the control of the lzGal4 driver (lz\u2009>\u2009gcm GOF) and found that this leads to severe spermatheca defects including a deformed and almost absent cuticular structure. This phenotype is stronger than the overexpression of Gcm using the gcmGal4 driver (gcm\u2009>\u2009gcm GOF) in which the cuticular structure can still be observed , after the division of the MP, the SUP co-expresses Gcm and Hnt leads to a decrease in SC number at adult stage and those of mNR5A1 and mNR5A2 in mouse embryonic fibroblasts (MEF) upon transfection of mGCM1 and mGCM2 expression vectors. While the levels of expression of hNR5A2/mNr5a2 are not modulated by the mGCM proteins, the expression levels of the hNR5A1/mNr5a1 transcripts significantly increase when either mGCM proteins are expressed until the 3rd exon (nd exon and the TSS was estimated by bisulfite sequencing in MEF transfected with an empty vector (Control) or with expression vectors of mGCM1 or mGCM2. The three CpG located around the TSS are demethylated in the presence of mGCM1 or mGCM2 proteins compared to that observed upon transfecting the control plasmid is expressed early during photoreceptor differentiation but needs to be switched off for normal eye developmentA second common feature between the three developmental events is the transient and early expression of Gcm. In the spermatheca, Gcm is expressed during the differentiation of the SC but no longer present in the adult SC. Similarly, Gcm is expressed early in the glial and in the hemocyte lineages but its transcripts are not detected in the mature cells343657gcm expression and prevents the production of glial cells; accordingly, lack of Notch induces gcm expression and the production of glia at the expense of neurons613436A third common feature between the three systems is the participation of the Notch pathway. In the spermatheca, the production of the SC from the initial MP encompasses three cells divisions. The first and third divisions involve the Notch pathway and trigger the differentiation of the LEP and the SC respectively14eyeless master gene induces the formation of ectopic eyes on wings, legs and antennaeOur work also highlights the cell-specific nature of the Gcm differentiation pathways: while the Gcm transcription factor is required to induce several cell identities, its downstream factors are cell-specific. Repo expression is absent in the spermatheca and Hr39 expression is absent in glial cells. Moreover, the overexpression of Gcm in the spermatheca does not activate Repo expression in those cells nor does Gcm overexpression in the embryonic nervous system activate Hr39 expression in that territory (data not shown). Thus, although \u2018master regulators\u2019 are considered as simple molecular switches, this represents an oversimplified view of cell differentiation. The activity of such potent transcription factors rather relies on the history of a given cell, that is, its specific transcriptional and epigenetic asset. For example, the ectopic expression of the famous gcm mutant animals display supernumerary crystal cells and in addition ectopic Gcm expression in the crystal cell precursors using the lzGal4 driver prevents the expression of Lz and converts cells into plasmatocytes36lz locus and the known role of Gcm as an activator of transcription prompt us to speculate that Gcm represses Lz expression indirectly. The transcriptional repressor Tramtrack (Ttk)66396970Finally, the expression profile of Gcm gives an important insight on spermatheca differentiation. Our study shows that Gcm and Lz are co-expressed in the MP and that Gcm remains expressed exclusively in the SUP following the asymmetrical division of the MP whereas Lz is repressed in the SUP3437Drosophila)1314mGcm1 and mGcm2 genes inducing mNR5A1 expression in MEF cells and being expressed in the reproductive system. This represents the first evidence of functional conservation for GCM proteins in similar biological systems of Drosophila and mammals.Hr39 and NR5A1 transcription factors were proposed to share similar functions and to target similar genes for the development of specific secretory glands of the reproductive system were counted from the stack of six focal plans taken at 3\u2009\u03bcm interval in the middle of the spermatheca (the plan giving the largest cross-section of the spermatheca). This was repeated in at least six independent spermathecae for each genotype. The average number of SC and the s.e.m. are represented in et al.The transfection of S2 cells, the quantitative PCR (qPCR) and the luciferase assay were performed as described in Cattenoz in situ hybridisation with digoxigenin-labelled probes for mGcm2 transcripts was performed as described in Vernet et al.C57BL/6 mouse uterus RNA extracted from 3 different animals with TRI reagent.RNA et al.HeLa cells transfection was performed as described in Cattenoz mNr5a1 locus. The procedure is detailed in MEF cells transfected and sorted as described above were used to analyse the methylation profile of How to cite this article: Cattenoz, P. B. et al. An evolutionary conserved interaction between the Gcm transcription factor and the SF1 nuclear receptor in the female reproductive system. Sci. Rep.6, 37792; doi: 10.1038/srep37792 (2016).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."} +{"text": "The other important component is the illustration on pollen grains traits under light microscopy (LM) and scanning electron microscopy (SEM). Pollen grains of 56 species are extracted from voucher specimens from the PE herbarium at the Institute of Botany. It is worth noting that these species own special distribution patterns in China. The distribution maps are plotted using the Google Maps and the species distribution data at the county level supplied by the Chinese Virtual Herbarium ( Specifications TableValue of the Data\u2022The dataset includes pollen morphological characteristics and distribution patterns of 56 dominant species among the desert vegetation in eastern ACA.\u2022The pollen descriptions with related illustrations could be used to identify pollen grains at the generic or species level.\u2022The distribution maps could be used to interprete distribution patterns of 56 dominant species among the desert vegetation in eastern ACA.1The dataset of this article provides information on the diversity of pollen features of the dominant species in the eastern ACA desert and the distribution patterns of these species in China. 1.1See plates 1.2See 1.3See 22.1Here, we attempt to 1) depict a pollen spectrum of the dominant species in desert vegetation to improve the resolution and accuracy of pollen identification in the eastern ACA, and 2) plot distribution maps of each dominant species for a better understanding of the distribution patterns of these desert plants 2.2http://www.cvh.ac.cn/).Pollen grains of 56 species were extracted from voucher specimens from the2.3Pollen grains were acetolyzed by the standard method P/E ratio values. The P/E ratio of each pollen grain was calculated using the polar axis diameter (P) and equatorial diameter (E). Hesse et al. The pollen morphological terminology follows the overview of Hesse et al."} +{"text": "Interstitial ectopic pregnancy is a rare type of tubal pregnancy that poses diagnostic challenge. It is associated with the highest risk of massive, uncontrollable bleeding and can result in uterine rupture in the second trimester. This is a rare case of unruptured interstitial ectopic diagnosed in the first trimester by ultrasonography and managed medically with systemic methrotrexate and serial ultrasound monitoring.` Ectopic pregnancy is the implantation of a fertilized ovum outside the uterine cavity and it's thought to affect 1-2% of pregnancies. 93-97% of ectopic pregnancies are tubal with the interstitial type constituting only 3-4%. This shows interstitial ectopic pregnancy is rare. It is associated with high rate of complications and diagnostic challenge [th day post methotrexate injection. While, on day 10, the gestational sac has been completely disappeared.A 39 year old gravid 4 para 1 + 2 non alive who was referred to our department for obstetric ultrasound on account of bleeding per vaginum at EGA of 9 weeks 2 days and a provisional diagnosis of threatened abortion She booked at 6 weeks gestation after the pregnancy was confirmed by ultrasound which revealed gestational sac with a diameter equivalent to 7 weeks 1 day and devoid of fetal pole. No associated abdominal pain, trauma, vaginal instrumentation or use of abortifacient. She had two previous spontaneous abortions at EGA of 10 and 8 weeks respectively and was managed by using manual vacuum aspiration. She also had a spontaneous vaginal delivery of a female still birth at 40 weeks with macrosomic baby. She was diagnosed to be diabetic after delivery 2 years ago. She was also diagnosed of multicystic nodular goiter 2 months prior to presentation. She was placed on insulin at booking. Ultrasound at presentation revealed a gestational sac devoid of fetal pole located high at the fundus adjacent to the superior margin of the endometrial plate on longitudinal scan and eccentrically located at the right cornual end on transverse scan . The gesnd trimester and massive hemorrhage. While all ectopic pregnancies are associated with a risk of hemorrhage, interstitial pregnancies are associated with the highest risk of massive, uncontrollable bleeding [Interstitial ectopic pregnancy is a rare and atypical type of tubal ectopic with a high risk of rupture and haemorrhage compared to other types and it is of increase incidence . It is ableeding . There wbleeding . This pableeding . The latInterstitial type is an uncommon type of tubal ectopic pregnancy and delay in diagnosis result in high maternal morbidity and mortality. However, early diagnosis using ultrasonography at early stage of pregnancy prior to rupture and prompt treatment as in this present case can prevent complications like massive hemorrhage and uterine rupture. This case also emphasizes the role of non invasive medical management with serial ultrasound monitoring in the treatment of unruptured ectopic pregnancy.The authors declare no competing interests."} +{"text": "PLOS ONE article, short excerpts of text were duplicated verbatim from the sources listed below. In each case where the original source is a previously published journal article or book, the original publication was properly cited in the PLOS ONE article. However, the authors acknowledge that the text from these sources should have been either reworded or reproduced with quotation marks. The authors declare that the text overlap has no effect on the results and conclusions of the study and apologize for these instances of overlap.In this The following sentence in the Introduction section overlaps with the text from Reference 7 in the original article:\u201cBoth the pelvic and abdominal diaphragms should be examined and treated since ptosis of the viscera may be a problem in constipation.\u201dThe following sentence in the Methods section overlaps with the text from Reference 10 in the original article:\u201cThoracic respiration is responsible for 50% of the lymph movement in the thorax and diaphragmatic movements especially are essential for enabling the lacunae on the undersurface to absorb the abdominal fluid, the gut being the largest lymphoid organ in the body.\u201dThe following portion in the Methods section overlaps with the text from Reference 9 in the original article:\u201cTo find the pylorus, the practitioner looked for its approximate projection on the stomach wall. For this purpose, the practitioner had to move from the navel about one finger width cranially. From there fingers were placed slightly next to the right, next to the median line. At this point, fingers slowly slid posteriorly into the abdomen. Once palpation advanced deeply enough, a lens-sized solidification could be palpated. Small circulations, vibrations or inhibitions on this point were applied until the tonus and sensitivity were clearly reduced.\u201dThe following sentences in the Discussion section overlap with the text from Reference 22 in the original article:\u201cIn a prospective randomized trial preterm infants received moderate pressure massage and were compared to control with light pressure massage.\u201d\u201cThe moderate massage stimulated the vagal nerve leading into increased gastric motility.\u201d"} +{"text": "Corrigendum on Supplemental Table 2.In the original article, description of helper plasmids in C58C1 (pGV2260) and GV3101 (pMP90) were missing. The correct information of these two strains appears below. The authors apologize for the missing information. This error does not change the scientific conclusions of the article in any way.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The effects of adenosine A2A receptors on the cells and tissues of healing wounds have only recently been explored. Here we summarize the evidence indicating that adenosine and selective adenosine agonists, acting at A2A receptors, promote the salutary functions of inflammatory cells, endothelial cells and fibroblasts in stimulating wound healing.Recent studies have demonstrated that application of topical adenosine A2A receptor agonists promotes more rapid wound closure and clinical studies are currently underway to determine the utility of topical A"} +{"text": "Metformin is a most widely used medication all around the world to treat Type 2 diabetes mellitus. It is also found to be effective against various conditions including, Prediabetes, Gestational diabetes mellitus (GDM), Polycystic Ovarian Syndrome (PCOS), Obesity, Cancer, etc. It is a cationic drug and it depends Organic Cation Transporters (OCTs) and Multidrug and Toxin Extruders (MATEs) mostly for its pharmacokinetics movement. The probability of drug interaction increases with the number of concomitant medications. This article focuses the drug interactions of metformin and most of them are linked to the inhibition of OCTs and MATEs leading to increased plasma metformin concentrations and subsequent elevation of risk of Metformin Associated Lactic Acidosis (MALA). By identifying the drugs inhibiting OCTs and MATEs, the healthcare professionals can predict the drug interactions of metformin. Metformin is a popular drug and is used by millions worldwide to treat various conditions including Type 2 diabetes mellitus, Prediabetes, Gestational diabetes mellitus (GDM), Polycystic Ovarian Syndrome (PCOS), Obesity, Cancer, etc.3\u00a0It is postulated that the antihyperglycemic action of Metformin results from decreased hepatic glucose production largely by inhibiting gluconeogenesis5 and increased glucose utilization.6 The activation of AMP-activated protein kinase (AMPK) by Metformin is required for the inhibition of hepatic glucose production and induction of skeletal muscle glucose uptake.7Metformin is primarily used as a first line drug for the treatment of type 2 diabetes mellitus in overweight patients.8 The oral absorption and hepatic uptake of Metformin are mediated possibly by Organic cation transporters (OCTs) (OCT1 and OCT3) and renal excretion of Metformin is largely mediated by Metformin transporters such as Multidrug and Toxin Extruders (MATEs) MATE1 and MATE2-k and Organic cation transporter 2 (OCT2).9 Metformin is not metabolized and excreted unchanged in urine10 and the patients with moderate and severe chronic renal impairment (CRI) should not be administered with metformin.11 As Metformin is not metabolized, it is not expected to be involved in many drug\u2013drug interactions (DDIs).Metformin is a cation at physiological pH, as it is a strong base. Hence, the absorption, distribution and excretion of Metformin depend on the transporters such as Organic Cation Transporters (OCTs), Multidrug and Toxin Extruders (MATEs) and Plasma membrane Monoamine Transporter (PMAT).12 The drugs inhibiting the Metformin transporters (MATEs and OCTs) could decrease the elimination of Metformin and increase it\u2019s plasma concentrations leading to elevated risk of Metformin Associated Lactic Acidosis (MALA).Metformin administration should be stopped and urgent medical attention given to the patients developing first signs of MALA such as severe vomiting and diarrhea.13Metformin use is associated to Lactic Acidosis probably due to the accumulation of lactate through the inhibition of hepatic glucose production from lactate molecules.14 Hence, the risk of toxic accumulation of Metformin and subsequent Lactic Acidosis may be higher in patients taking Metformin who undergo procedures using Iodinated contrast material (ICM). The risk is further increased in patients with renal impairment and it is recommended to stop Metformin while using ICM in patients with renal impairment.16Iodinated Contrast Materials (ICMs) used widely and successfully during many procedures including angiography, urography, etc. Administration of iodinated contrast media (CM) would result in Contrast-induced nephropathy (CIN).18 Concomitant use of Metformin and Cimetidine decrease the excretion of Metformin, resulting in increased exposure of Metformin and elevated risk of Metformin Associated Lactic Acidosis (MALA).20 It is recommended to reduce the dose of Metformin when Cimetidine is co-prescribed.21Cimetidine is a potent inhibitor of Multidrug and toxin extruder 1 (MATE1) of proximal tubular epithelial cells and it is a broad-spectrum inhibitor of transporters including Organic Cation Transporter 2 (OCT 2).22Ranitidine is a potential inhibitor of Multidrug and Toxin Extruder 1 (MATE1) and hence the renal clearance of Metformin decreased.23Famotidine may be suitable H2 blocker in patients taking Metformin, as it is a selective inhibitor of MATE1 and increasing the therapeutic efficacy of Metformin by significantly increasing the estimated bioavailability of Metformin. In addition, Famotidine enhances the renal clearance of Metformin compared to Cimetidine or Ranitidine which decrease it's elimination.24 It is recommended to monitor the concomitant use of Proton pump inhibitors with Metformin.25Proton pump inhibitors may inhibit Multidrug and toxin extruder (MATE) and OCT2 transporters and increase plasma metformin exposure.2 receptor blockers and Metformin. The malabsorption of vitamin B12 promoted by additive effects of Proton pump inhibitors or H2 receptor blockers and Metformin. Concomitant use of these drugs should be monitored for the consequences such as peripheral neuropathy and megaloblastic anemia.28 It is recommended for Vitamin B12 replacement in patients taking Metformin and PPIs/ H2 receptor blockers to prevent cobalamin deficiency.29The risk of Vitamin B12 deficiency was found to be elevated by the combination of Proton pump inhibitors or H30Trimethoprim inhibits Metformin elimination moderately through the inhibition of OCTs and MATEs, but the co-administration of both the drugs should be carried out carefully in patients with renal dysfunction or patients taking higher doses of Metformin.31 and it reduces the elimination of Metformin resulting in accumulation.32Cephalexin is a zwitterionic substrate of MATE133Hepatic uptake of Metformin might be elevated by the administration of Rifampin due to increased expression of OCT1.36Dolutegravir is used as the first-line antiretroviral agent in the treatment of HIV infection and it is an inhibitor of both OCT2 and MATE1 transporters within the renal tubules. Concomitant use of Dolutegravir and Metformin may result in increased adverse effects of Metformin such as hypoglycemia and GI intolerance caused by increased plasma concentrations of Metformin occurred due to the inhibition of OCT2 and MATE1 transporters. Prescribers may adjust the Metformin dose to prevent intolerable ADRs while prescribing Dolutegravir and Metformin concurrently.37 Co-administration of Pyrimethamine with Metformin results in elevated plasma concentrations due to decreased renal clearance of\u00a0Metformin induced by the inhibition of OCT2 and MATE transporters by Pyrimethamine.38Pyrimethamine is an antiparasitic drug and is used to treat toxoplasmosis\u00a0and\u00a0cystoisosporiasis. Pyrimethamine is an inhibitor of both OCT2 and MATE transporters.39 The plasma concentrations of Metformin may be elevated by the co-administration of Ranolazine which may decrease the Metformin elimination through the inhibition of OCT2 transporter. This interaction is dose dependent and it is recommended that the daily dose of Metformin should not exceed 1700\u2009mg in patients taking Ranolazine 1000\u2009mg two times daily.40Ranolazine is approved to treat chronic angina. Ranolazine blocks sodium channel of pancreatic \u03b1 cells and decreases electrical activity to inhibit glucagon release.41 and its co-administration with Metformin may result in increased plasma concentrations of Metformin due to decreased elimination as it is the substrate of MATE1 and MATE2K transporters. The patients receiving the combination of Vandetanib and Metformin should be monitored carefully for Metformin toxicity.42Vandetanib is used in the treatment of medullary thyroid cancer. Vandetanib is a potent inhibitor of MATE1 and MATE2K transporters43Tyrosine kinase inhibitors such as Imatinib, Nilotinib, Gefitinib, and Erlotinib may reduce the elimination of Metformin by inhibiting OCTs and MATEs transporters, at clinically relevant concentrations.44The plasma concentration of Metformin may be elevated due to reduced elimination induced by Atenolol as it reduces the renal blood flow and inhibits OCT2 competitively.45The plasma concentration of Metformin can be decreased by Metoprolol by increasing the hepatic uptake of Metformin through the induction of OCT1, increasing the renal uptake of Metformin by reducing the expression of MATE1 and increasing the uptake of Metformin in thigh muscle through the induction of OCT3.Most of the possible drug interactions of Metformin occur through the inhibition of OCTs and MATEs as it is not metabolized and excreted through urine as such. Iodinated Contrast Materials (ICMs) and the drugs such as Cimetidine, Ranitidine, Proton Pump Inhibitors (PPIs), Trimethoprim, Cephalexin, Dolutegravir, Pyrimethamine, Ranolazine, Vandetanib, Imatinib, Nilotinib, Gefitinib, Erlotinib and Atenolol inhibit either OCTs or MATEs or both leading to decreased elimination and increased exposure of Metformin. The risk of Metformin Associated Lactic Acidosis (MALA) enhances with the rise of plasma concentrations of Metformin. Metformin administration should be stopped and urgent medical attention given to the patients developing first signs of MALA such as severe vomiting and diarrhea. The prescribers and pharmacists should be aware of the medications inhibiting OCTs and MATEs transporters, before considering them for the patients taking Metformin.Not applicable.Authors declare no conflict of interest in this study."} +{"text": "We have investigated the role of bidirectional interactions between the dopamine reward and motivation system and executive function in addicted individuals, with a particular focus on the intersection between the role of D2 receptor (D2R) signaling in the striatum and perturbations in prefrontal brain activity.Using brain imaging we have studied these interaction for various types of addiction and explored how their involvement affect behavior including impulsivity and compulsiveness. We have also investigated the mechanisms associated with vulnerability to drug use disorders as linked with disrupted executive function including the effects of genetics and physiological factors such as circadian rhythms, sleep deprivation and obesity.We found that: a) chronic drug use reduces striatal levels of D2R and perturbs metabolism in frontal brain regions, emotional reactivity and executive control; b) that higher-than-normal striatal D2R availability in nonalcoholic members of alcoholic families appear to play a protective role against alcoholism by regulating circuits involved in inhibiting behavioral responses and in controlling emotions; c) that chronic sleep deprivation is associated with increased striatal dopamine, lower D2R availability, and metabolic changes in several cortical brain regions; and, d) that newly characterized variable number tandem repeat (VNTR) polymorphisms in the genes coding for PER2 and the AKT1 proteins (a kinase that has been implicated in schizophrenia and psychosis) appear to modulate striatal D2R availability in the human brain.Although the studies have focused on the effects of drugs, the DA striato cortical pathway is of direct relevance to schizophrenia as well as that of other psychiatric disorders. We will discuss the implications of our findings as they relate to the prevention and treatment of substance use disorders and schizophrenia."} +{"text": "Cardiac arrhythmias are the most common cause of mortality and sudden cardiac death worldwide. In the past decade, genetic factors underlying arrhythmogenic diseases have been revealed and given novel insights in to the understanding and treatment of arrhythmias predisposing one to sudden cardiac death.We conducted a pilot genetic screening of two patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) and 14 patients with ventricular tachycardia (VT) for genetic variants in the human ryanodine receptor gene 2 (hRYR2). The most relevant 45 hot-spot exons of hRYR2 were amplified by polymerase chain reaction (PCR) and directly sequenced.One novel mutation in a CPVT patient and a novel mutation in a VT patient were identified. Both variants are located at phylogenetically conserved positions and predicted pathogenesis. Three known synonymous SNPs were detected in the study group. No further variants within the target regions were detected in the study group.The results of study can be applied to risk asssessment for life-threatening arrhythmias and assist in development of appropriate strategies for prevention of sudden cardiac death. The implementation of these strategies would assist in the management of patients with genetically determined arrhythmias in Kazakhstan."} +{"text": "The data presented in this article are related to the research article entitled \u201cThe succession of the plant community on a decontaminated radioactive meadow site\u201d Specifications TableValue of the data\u2022Data presented allows to follow the meadow community formation in the north taiga subzone under technogeneous contamination.\u2022A process of appearance and exclusion of high plant species from the pioneer step of succession up to stable community formation is shown.\u2022The structure and the composition of meadow community in the North taiga zone on territories with the enhanced and natural radioactivity background could be compared with plant communities formed in other ecological conditions.1226Ra production plant activity; detailed description of radiation situation during the whole observation period presented in 226Ra. Then in 1962 the area was deactivated with filling with sand and gravel mixture. Short-term decrease in dose rate of \u03b3-irradiation in the air and activity concentration of radionuclides in the root-inhabited soil layer up to background level had happened, but gradual increase in those values observed with vegetation cover development.Data on high plant species presence/absence during long time observation of overgrowing of the radioactively contaminated site are given in de novo with surrounding area characterized the background radiation level.Following observations of the community formation with plants from adjacent area were performed up to 2012 year. The list of species presented on the site at time of observation is given in Figures show the pattern of dominating vascular plant species on the studied site in 1965 , 1967 F and 197022.1The development of plant community under dynamic radiation background was observed for 50 years. Registrations were performed in 1962, just before the deactivation and then in 1965, 1967, 1970, 1976, 1992, 2007 and 2012 years. Intervals among examinations depended on the succession steps. Also activity concentrations of radionuclides in soil and plants were traced during the observation period, detailed data presented in 2 sampling plots at the former radium production plant and natural vegetation sites with background concentrations of radionuclides in the soil.An auxiliary grid net containing 55 cells (5 \u00d7 10\u2009m each) was made for the experiment on the contaminated site. Vascular plants were listed for each cell. Plant cover was mapped based on the data on dominating plant species in every square meter of the cell. A life form of each species from the list was assigned according to Raunki\u00e6r"} +{"text": "The computational nature of memory modification. Published 15, March 2017A reader recently pointed out two errors in the originally published article.after conditioning, not at the time of retrieval. The schematic has been corrected. The error does not substantively change the scientific conclusions. The caption of Figure 10 has been corrected as follows:In Figure 10, the schematic incorrectly described the experiment and simulation. The protein synthesis inhibitor was injected \u201cThe amnestic affect of PSI administration after conditioning can be reversed by readministering the PSI at the time of test.\u201dLikewise, the text incorrectly stated that the protein synthesis inhibitor was injected at the time of retrieval. The text has now been corrected as follows:\u201cAs in previous studies, the authors found that post-conditioning PSI administration disrupted the CR at test; the novel twist was that administering the PSI both immediately after conditioning and immediately before test eliminated the disruptive effect.\u201dThe corrected Figure 10 is shown here:The originally published Figure 10 is also shown for reference:Owing to a production error the following sentence after equation 10 was erroneously omitted from the published version:\u201cwhere This sentence has now been added back.The article has been corrected accordingly."} +{"text": "It is found that sensitivity of ZnO-In2O3 composite to H2 nonmonotonically depends on the oxides\u2019 content. The optimal ratio between the components is chosen. The new mechanism of nanocrystalline ZnO-In2O3 sensor sensitivity to H2 under illumination by green light is proposed. The mechanism considers the illumination turns the composite into nonequilibrium state and the photoconductivity change in the H2 atmosphere is linked with alteration of nonequilibrium charge carriers recombination rate.The possibility of reducing the operating temperature of H Nanocrystalline metal oxides are widely investigated as sensitive materials for gas sensors working at high temperature (300\u2013500 \u00b0\u0421). High operating temperature leads not only to high power consumption but also to the fire and explosion risks and impossibility of gas sensor embedding in the electronic boards of mobile devices. In this regard, considerable research efforts have been devoted to reduction of the gas sensor operating temperature.2 ago but investigations of the influence of illumination on sensor response began only in the last decade. Most of the studies are devoted to the influence of ultraviolet (UV) illumination on the sensor properties of nanocrystalline metal oxide to oxidizing gases6. However UV light emitting diodes (LEDs) have lower efficiency and are much more expensive than visible LEDs. Therefore the utilizing of visible LEDs for the sensor response activation is more effective from a practical point of view.The effect of molecules adsorption on photoconductivity of semiconductors was known a long time10). In addition, proposed explanations of the illumination effect on the sensor response of metal oxides (to both oxidizing and reducing gases) don\u2019t consider that the illumination realizes non-equilibrium condition. Therefore, the description of the electronic processes under the illumination should be in terms of photoconductivity instead of conductivity. Photoconductivity, in its turn, strongly depends on the charge carriers recombination and generation. And the observed effects of gases adsorption on the surface of metal oxides under illumination can be determined by generation-recombination processes.Much less attention is paid to the effects of visible illumination and mainly effects of irradiation on response to gases-oxidizing agents are investigated. Number of researches studying the photo-activation of the sensor response to reducing gases is much smaller, and there is no definitive interpretation of the observed processes was shown in nanocrystalline In2O324.Excitation of nonequilibrium carriers under illumination should be monopolar, as the energy of green light photons is smaller than band gap values of ZnO and In2O3 film containing 10 wt.% ZnO during exposure to air with hydrogen and pure air is shown in Fig.\u00a0The gas sensing of composite films under the illumination was determined by the following procedure. Firstly, the samples were illuminated for several hours while the photoconductivity reached the steady state. Afterwards the mixture of pure air and hydrogen was supplied into the chamber for 25\u2009minutes and then the pure air flowed through the chamber for the sample recovery. The cycle of exposure of sample to air with hydrogen and pure air was repeated to demonstrate the reproducibility of the results. The photoconductivity alteration of composite ZnO-InTo facilitate the analysis the photoconductivity in Fig.\u00a025, the stationary photoconductivity is determined by the relaxation time According toThe relaxation time of photoconductivity is determined by the processes of the electrons recombination in the sample. Since the kinetics of photoconductivity for all samples is described by a simple exponential dependence (equation ), the re27. In our samples the defects like dangling bonds (indium and zinc vacancies)29 and oxygen molecules can be such recombination centers. In our previous work23 we showed that the photoconductivity of nanocrystalline indium oxide strongly depends on the oxygen molecules adsorbed on the surface.In nanocrystalline and polycrystalline materials recombination centers are often assumed to be located at the boundaries of the nanocrystals32. In addition, the oxygen molecules adsorbed on the surface of oxides can form a chemical bond with hydrogen and desorb34. The concentration of recombination centers decrease results in increase of photoconductivity relaxation time and, in accordance to equation . This electrons release can increase the dark conductivity. However, initially in nanocrystalline In2O3 and ZnO (in the pure atmosphere before hydrogen adding) free charge carriers concentration is very high22 and the change in concentration during the hydrogen adsorption is negligible. Therefore, the electron concentration change in the air with hydrogen at room temperature practically does not affect the value of the dark conductivity, which leads to the absence of gas response.Thus, we can assume that the change of photoconductivity in hydrogen atmosphere is determined by a significant change of the charge carriers recombination rate. It should be noted that the desorption of oxygen can result in increase of the electrons concentration the highest response to H2 was observed for ZnO-In2O3 composites containing 20 wt.% and 80 wt.% ZnO16. The difference between the relative fractions of ZnO in the composite, at which the maximum gas response was observed, confirms different H2 sensitive properties of the composites under illumination and heating.The dependence of the sensor response on relative fraction of ZnO in the ZnO-In2 gas sensor based on ZnO-In2O3 down to room temperature under green illumination. It is found that sensitivity of ZnO-In2O3 composite to H2 nonmonotonically depends on the oxides\u2019 content, which allows to choose the optimal ratio between the components to achieve the highest sensitivity. The maximum sensitivity to 970 ppm of H2 is observed for the nanocomposite films based on 65 wt.% ZnO and 35 wt.% In2O3. It should be noted that the studied composites did not exhibit the sensitivity to hydrogen at room temperature without illumination.In conclusion, we have shown the possibility of reducing the operating temperature of H2O3 sensor sensitivity to H2 under illumination by green light. The mechanism considers the illumination turns the composite into nonequilibrium state. In this regard the photoconductivity of the ZnO- In2O3 composite change in the H2 atmosphere is largely determined by recombination processes. The recombination processes determine the photoconductivity relaxation time which in turn determines the photoconductivity of the composite. It is shown that the photoconductivity relaxation time is linked with the response of the ZnO-In2O3 composites to H2. The possible recombination mechanisms of non-equilibrium charge carriers in the studied structures are discussed. The proposed mechanism links the response of the ZnO-In2O3 composites to H2 under illumination with change of the nonequilibrium charge carriers recombination rate.We proposed the new mechanism of nanocrystalline ZnO-In2O3 and ZnO . The average nanocrystal size of the oxides in the original powder is 50\u201380\u2009nm.Nanocrystalline composite films were synthesized from commercial nanopowders In2O3 were mixed and triturated in an agate mortar with a small amount of distilled water until a homogeneous suspension with pre-determined mass proportion of constituent oxides was obtained. The resulting slurry was screen printed on a dielectric alumina substrate equipped with platinum contacts and a heater. The resulting layer was heated during 3\u2009hours at 120\u2009\u00b0C and then annealed in air, the temperature was gradually raising up to 550\u2009\u00b0C and was kept at this value until a constant resistance value of the resulting nanocomposite film was obtained.Nanocrystalline composite films were prepared using aqueous suspensions of nanopowders. The certain amounts of ZnO and In16. The resulting nanocomposite films are a mixture of nanocrystals of the corresponding oxides with variety of shapes and wide particle size distribution from 40 to 80\u2009nm, which practically coincides with the sizes of the original commercial nanopowders claimed by the manufacturers.The structure and particle size were examined by transmission electron microscopy using the device JEM-2100 . Detailed analysis was described elsewhere\u03bbCu\u2009=\u20090.154056\u2009nm)). A typical X-ray diffraction pattern of the nanocomposite metal oxide film ZnO-In2O3 is shown in Fig.\u00a0The phase composition of the metal oxide films was determined by X-ray diffraction on Ultima IV (CuK\u03b11 (X-ray wavelength 2. The photoconductivity \u03c3d:Experiments were carried out at room temperature. Illumination of the samples was performed by green LED with a maximum intensity at 525\u2009nm. The intensity of light incident on the sample was 5\u2009mW/cmFor sensor properties investigation the samples were placed in chamber with mounted LED and pure air or air containing 970 ppm of hydrogen flowed through the chamber.The datasets analysed during the current study are available from the corresponding author on reasonable request."} +{"text": "Neopicrorhiza scrophulariiflora) is wrongly mentioned as CITES listed species. The correct version of the sentence in the second paragraph of \u201cThreats and conservation challenges\u201d can be found here:In the original publication the specTaxus wallichiana).Illegal trade of NTFPs from the landscape often includes some of the CITES Appendix listed species such as Sunakhari (Orchids) and Lauth salla ("} +{"text": "This article presents the multilayered complex network formulation for three different supply chain network archetypes on an urban road grid and describes how 500 instances were randomly generated for each archetype. Both the supply chain network layer and the urban road network layer are directed unweighted networks. The shortest path set is calculated for each of the 1 500 experimental instances. The datasets are used to empirically explore the impact that the supply chain's dependence on the transport network has on its vulnerability in Viljoen and Joubert (2017) Specifications TableValue of the data\u2022The dataset can be used to empirically test a number of complex network phenomena such as targeted attack & random error, spreading and synchronisation on three supply chain network archetypes layered on the urban road grid.\u2022The shortest path sets open up opportunities for research pertaining to supply chain optimisation and city planning.\u2022The dataset is a first example of a multilayered complex network that combines a supply chain with an urban road network and can be used as a prototype for modelling other parts of the supply chain.1http://www.matsim.org/files/dtd/multilayerNetwork_v1.dtd.The data accompanying this article include the Extensible Markup Language (XML) files required to construct the 1500 unique multilayered complex network instances (500 instances for each of three supply chain archetypes). Each XML file contains all the information pertaining to one specific multilayered instance. It also contains the shortest path sets calculated for each instance. All datasets are publicly available from Mendeley 22.1The generic multilayered network formulation is based on the notation presented in 2.2multilayer network is a pair The interlayer connections while elements of intralayer connections.Therefore the elements of 2.3logical layer. The second layer shows how the associations are randomly generated to produce Algorithm 2:Random generation of The algorithm used to generate Algorithm 3:Random generation of Finally the algorithm used to generate The experiments conducted in We therefore generated 500 instances for each archetype with 1.Node set and edgelist of 2.Node set and edgelist of 3.The association between nodes in 4.The shortest path sets unique to each instance (discussed in the next section).The data required to reconstruct each instance is contained in an XML file. The datafile includes the following:A template of the .xml file structure is shown in 2.3.2The shortest path sets of an instance of To explain how the shortest path sets were calculated, we use the example of a Double Hub instance of 0*2=120) f. The shMetrics pertaining to shortest path sets refer to a specific instance of Enumerating and storing"} +{"text": "Bone morphogenetic protein 2 (BMP2), differentially regulates the developmental lineage commitment of neural stem cells (NSC\u2019s) in central and peripheral nervous systems. However, the precise mechanism beneath such observations still remains illusive. To decipher the intricacies of this mechanism, we propose a generic mathematical model of BMP2 driven differentiation regulation of NSC\u2019s. The model efficiently captures the dynamics of the wild-type as well as various mutant and over-expression phenotypes for NSC\u2019s in central nervous system. Our model predicts that the differential developmental dynamics of the NSC\u2019s in peripheral nervous system can be reconciled by altering the relative positions of the two mutually interconnected bi-unstable switches inherently present in the steady state dynamics of the crucial developmental fate regulatory proteins as a function of BMP2 dose. This model thus provides a novel mechanistic insight and has the potential to deliver exciting therapeutic strategies for neuronal regeneration from NSC\u2019s of different origin. Bone morphogenetic protein 2 (BMP2), a pleotropic cytokine, is crucial to determine the developmental fates of neural progenitor cells in central and peripheral nervous systems. Telencephalic neural progenitor cells acquired from central nervous system (CNS) switch from neuronal to gliogenic developmental fate under transient exposure of BMP2113412467Undoubtedly, the underlying gene regulatory network organizing the developmental event in the nervous system is extremely complex. Activities of various basic helix\u2013loop\u2013helix (bHLH) transcription factors such as Mash1 and Ngn (neurogenin) control the lineage specific neuronal cell fate in CNS and PNS123416101679Keeping these complexities in mind, one can presume that mathematical and computational modeling approaches might provide some initial insight to disentangle the underlying regulatory dynamics of this complex network. No wonder, in last few decades, mathematical and computational modeling studies were used extensively to understand the dynamic regulation of few of these important transcription factors (such as Hes1) either in isolation, or taking a part of the gene regulatory network organizing the developmental events1314We divide the entire gene regulatory network controlling the BMP2 driven differentiation of NSC\u2019s in CNS and PNS into three simple gene interaction modules. By using extensive bifurcation analysis, we integrated the mathematical models of the individual modules one by one systematically to build up the overall model of BMP2 driven neural stem cell differentiation for CNS. An exhaustive list of mutant and overexpression studies available in the experimental literature are utilized to establish the mathematical model that qualitatively describes how BMP2 alters the cell fate decision during development of neural progenitor cells in CNS. To this end, we employ a systematic sensitivity analysis on the model parameters and predict the possible routes to obtain a PNS like behavior using the same model developed for CNS. Our model predicts several mutant and over-expression phenotypes for NSC\u2019s acquired from PNS and importantly unveils more than one possibility to efficiently transform the NSC\u2019s into neuron in a lineage specific manner. Existing experimental literature corroborates well with these model predictions1617SI Appendix), comprised of three individual modules that describes how BMP2 controls the process of development in the NSC\u2019s of CNS and PNS. BMP2 is known to regulate the transcription of Mash1 and Id1 proteins through direct and indirect mechanisms12182021222367122514SI Appendix. There we have more comprehensive schemes for modules 1\u20133 in SI Appendix with detail description of each module in terms of precise molecular interaction curated from available experimental literature. Although the simplified scheme shown in The model, depicted in The overall model can be r1527282930SI Appendix for details) but now in the total model both the lower and upper steady states are unstable. The saddle node SN1 in 2) that makes the dynamics beyond this value of BMP2 oscillatory. Although BMP2 controls the transcription of Mash1, Id1 and Hes5 genes, initially when BMP2 level is very low it affects the Mash1 transcription by up regulating the E47 mediated Mash1 transcription more than the Id1 and Hes5 transcriptions.To understand the characteristic dynamical transitions under the influence of BMP2, we first perform the bifurcation analysis for the nd switch in the process with saddle nodes SN3 (BMP2\u2009~\u200958.14 s.u.) and SN4 (BMP2\u2009~\u20096.71 s.u.) (4) at BMP2\u2009~\u2009895.7 s.u.Thus, for low values of BMP2 the system quickly attains high levels of Total Mash1 protein . Once there is enough accumulation of Id1 and Hes5 proteins in the system, they start to affect the Mash1 level by initiating its degradation (Id1 mediated) as well as sequester the E47 protein to inhibit the Mash1 positive feedback to its own transcription. This will make sure that the Mash1 level starts dropping after BMP2\u2009=\u20090.827 s.u. and cause the 271 s.u.) . The lowAt this point, we define BMP2\u2009=\u20092 s.u. as one of the representative low dose of BMP2 and BMP2\u2009=\u200920 s.u. as high dose of BMP2 to observe the expression levels of different proteins in the network under high and low doses of BMP2. Although this definition seems arbitrary to begin with, it is a reasonable one and we stick to this definition through out our study as in the experimental papers the high dose of BMP2 (~80 ng/ml BMP2 dose used in experiments) is considered to be at least 10 times higher than the low dose1327On the contrary, if we initialize the dynamical system similarly for BMP2 close 0) and suddenly employ BMP2\u2009=\u200920 s.u., the system preferably leans towards a gliogenic phenotype indicated by low levels of pro-neural proteins and higher levels of gliogenic protein had revealed that stem cells can exist in mixed clonal populations after a certain period of incubation with certain dose of a specific growth factor. This clearly indicates that a bi-stable mechanism underlies the cell fate decision-making process during stem cell differentiation in CNS and PNS.Our proposed model cruciallHes1 mRNA oscillation with 2\u20133\u2009hour cycle in various cultured cells like fibroblasts (C3H10T1/2), myoblasts (C2C12), neuroblastoma cells (PC12) and teratocarcinoma cells (F9) and there exists a time delay of the order of 15\u201330\u2009minutes between Hes1 protein and Hes1 mRNA oscillationsHes1 mRNA whereas Mash1 mRNA does not show any significant difference up to 6\u2009hours of BMP2 additionIn our model the time delay comes in automatically because an appropriate molecular mechanism is used mulation . Hirata Mash1 mutant for low dose of BMP2 as seenn \u0394Mash1 predictsId1 gene inhibited neurogenesis1241Id1 condition leads to gliogenesis with a very low expression level of Mash1 protein or not? We begin to address this question with a hypothesis elucidated in 1 and SN4 critically control the dynamics of the overall system as a function of BMP2 dose. If one manages to tune the dynamics of the overall system in such a way that the total system can be represented by a slightly altered bifurcation diagram shown as dashed red line in From kbmp2, kbmp21 and kbmp22 in the model. Our proposed model predicts that by reducing both kbmp2 (~20 times) and kbmp22 (~400 times) from the values used to describe the WT type case of the CNS, we can have the bifurcation diagrams will not give the desired PNS like feature. What is the reason behind such an observation? Can we have a situation where by only changing any one of the parameters related to the system, we can alter CNS like dynamics to a PNS like one? Can we predict more such possibilities to tune the dynamics? To answer these intriguing questions, we performed a systematic sensitivity analysis (1 and SN4 (1 and SN4) in the opposite direction. Essentially, increasing one kind of parameters individually will take both the saddle nodes (SN1 and SN4) away from each other. The saddle nodes will eventually approach each other due to individual increment made in the other kind of parameters. Unfortunately, neither of these situations will help us to realize a PNS like feature. This immediately indicates the fact that by only changing one of the parameters of this system will not allow to transform the CNS like system to a PNS like situation.Interestingly, changing analysis of all t and SN4 separatekbmp2 and kbmp22) we can have a PNS like behavior (SI Appendix and 1 and SN4) for the two concerned parameters kbmp2 and kbmp22. From 1 is more sensitive with respect to parameter kbmp2 than the saddle node SN4, whereas the situations are just the opposite when we compare the sensitivities of SN1 and SN4 as a function of kbmp22. This gives an immediate hint that tuning these two parameters can modify the dynamics of the system and we eventually get the PNS like features by reducing both of them as described earlier.We have already shown that by varying two parameters even in presence of low level of BMP2 can transiently take the Mash1 protein to a high level very quickly ensured the onset of inhibition of neuronal differentiation by degrading the Mash1 protein with increasing doses of BMP2 in NSC\u2019s in CNS that also complies with the experimental findings in literature1161746In accordance with the observation made by Kim quickly and can kbmp2 (can be correlated with a low expression level of Sox10) and kbmp22 will delay the BMP2 driven sudden activation of total Mash1 protein level by pushing the saddle node SN1 for relatively higher values of BMP2 and keep the system in the gliogenic state (low Mash1 level) as shown in 13451847On the contrary, relatively lower values of Despite some inherent differences that exist between NSC\u2019s obtained from CNS and PNS, it is believed that in these NSC\u2019s of slightly different origin, similar kind of mechanism regulates the cell fate decision-making process during development3301234SI Appendix) where we analyzed each module with the help of bifurcation analysis to obtain certain experimentally observed features1234272671620Hes1 mRNA and protein oscillatory period as well as the amplitude of oscillations of Hes1 almost remain unaltered in both neuronal as well as in the gliogenic state corresponding to low and high BMP2 doses to understand the crucial control parameters of the systems. This will allow one to circumvent the complex non-trivial bifurcation features that may arise due to the high dimensional model proposed by us and will permit us to study the system in more detailed manner through low dimensional bifurcation analysisSecondly, experiments in literature do suggest that stochastic fluctuations play a significant role in differential cell fate regulation1234We believe more experiments in these directions will be crucial to understand the stochastic dynamics in a better way and will allow us to explore possible therapeutic strategies to minimize unwanted gliogenesis that results as the aftereffect of nerve injury and neural stem cell implantation. More importantly it will throw new challenges to the proposed mathematical model that has shown a lot of potential to generate exciting questions both in terms of experiments and theory. We hope that in future stochastic version of this deterministic model will help us to progress systematically to decipher the influence of stochastic fluctuations in these complex systems and will pave the way to find an efficient route for neuronal regeneration from NSC\u2019s.SI Appendix) were expressed in terms of 13 and 34 ordinary differential equations respectively. The deterministic models (SI Appendix and SI Text) were encoded as.ode files and the deterministic simulations were performed using freely available software XPP-AUT. The bifurcation diagrams were drawn by the AUTO facility available in XPP-AUT software. The bifurcation diagrams and time profiles were drawn in OriginLab and MATLAB using the data points generated by XPP-AUT.The complete gene regulatory network was expr1 and SN4. The bar diagrams were drawn in MATLAB. Orange bar signifies movement of the saddle nodes towards higher BMP2 and dark green bar signifies movement of the saddle nodes towards lower BMP2 than the WT CNS case.In the sensitivity analysis section parameters were increased individually at an amount of 20% of the model parameters (SI Text) keeping all other parameters constant and the bifurcation diagrams were drawn by the AUTO facility available in XPP-AUT software. Sensitivity analysis of the model parameters (SI Text) was done on the saddle nodes SNHow to cite this article: Sengupta, D. and Kar, S. Unraveling the differential dynamics of developmental fate in central and peripheral nervous systems. Sci. Rep.6, 36397; doi: 10.1038/srep36397 (2016).Publisher\u2019s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."} +{"text": "In There were computational errors in generating Figures 9 and 10 of the These errors resulted in incorrect depiction of the perceptual depth distortion from viewer\u2019s perspective, where the disparity differences between the real-world 3D viewing and S3D viewing should be increased in negative (uncrossed) direction (as shown in This corrected depiction indicates a depth expansion (not compression) in the viewer\u2019s peripheral field, which makes any motion in depth in the peripheral area to be perceived slower than it should be.The same errors also affected a few panels in Figure 10 of the Although the direction of peripheral depth distortion has been reversed and the amount of the distortion caused by viewer\u2019s lateral head shift have been corrected, these changes are not affecting the general conclusion of the paper, that the peripheral depth distortion and viewer\u2019s position shift while viewing S3D may induce non-rigidity of the depicted world, and it may be a likely source of the visually induced motion sickness."} +{"text": "The explanations summarize the example contents from which the CIPROS checklist was created.The data presented relates to the publication \u201cEnhancing Requirements Engineering for Patient Registry Software Systems with Evidence-based Components\u201d Patient registries are a crucial part of medical research. High quality registries use efficient information systems software selected from a wide variety of existing software solutions.An efficient selection process requires focused selection criteria. The evidence-based CIPROS checklist CIPROS was developed in a multistep procedure: (1) A systematic literature review provided an exhaustive collection of relevant publications (64 articles), (2) a catalogue of relevant criteria was derived by a qualitative content analysis, and (3) the checklist containing 72 items was composed which provides a minimal appraisal standard.The data presented per checklist item provide the relevant textual information (examples) and a first qualitative summary (explanation). The examples and explanations provide the background information on CIPROS. They elucidate how to implement the checklist items in other projects. The literature list and the selected texts serve as a reference for scientists and system developers. Specifications TableValue of the data\u2022A collection of references and examples how patient registries are implemented and used in the medical research community.\u2022Examples and explanations represent a wide range of practices, and provide the practical background how to implement CIPROS items in projects.\u2022The examples provide the raw data used to derive the CIPROS checklist.\u2022The structured collection of examples supports decision makers and developers to formulate project requirements and explain how to implement CIPROS.\u2022The data presented are a reference book for scientists and system developers on how to implement the features in their own projects.1CIPROS is the result of a qualitative text analysis. This paper presents the qualitative data used for this process. It was created via a systematic review see which id21)A systematic literature review2)A qualitative content analysis3)Creation of an early version of the checklistFor the development of the CIPROS checklist we used qualitative content analysis (QCA) methods developed by Mayring 2.1\u201c(registry or registries) AND (eCRF or EDC or CDMS or CTMS or web) AND (software or open-source or open source or Java)\u201d. It was updated at 15st of February 2015.A systematic literature review was performed in PubMed to find papers on patient registry software systems. This guarantees that the software systems are used in real-life medical research projects. The following search in PubMed was performed at 17th of January 2014: The search terms were chosen in an iterative process: We are interested in registries with electronically Case Report Forms (eCRFs) or Electronic Data Capture (EDC) technology or Clinical Data Management Systems (CDMS) or Clinical Trial Management Systems (CTMS). We were mainly interested in software systems or open-source systems. We also included Java in our search terms.2.2A qualitative content analysis according to Mayring 2.3To create the checklist we performed the step model of deductive category application described by Mayring The CIPROS checklist consists of 72 items organized within 12 topics which relate to features in system components (S), functional aspects (F), or design steps (D).2.4The data are presented in For some items, we do not provide a reference and cannot provide an example, as these items were not discussed in the literature that we found in our SLR. However, they are considered relevant based on our own experience and theoretical reasoning ."} +{"text": "Construction of highway pavements or high rise structures over the expansive soils are always problematic due to failures of volume change or swelling characteristic experienced in the water permeability of the soil. The data in this article represented summary of Specification tableValue of the data\u2022The data provided detailed experimental procedures on how common salt could be used to stabilize expansive soil thereby reducing its swelling properties.\u2022The data provided an insight into cost effective method of stabilizing expansive soil.\u2022The data could be useful in research that involves studying of expansive soil for the construction of highway pavement and high rise building.\u2022The data experimental procedure is detailed and it can be adopted or modified for further study or to compare the results of this data.1Several studies has been done on the available additives to stabilized expensive soil due to its change in moisture contents and problematic in nature that causes soil to either shrink or swell under loading The data presented in 2The sample of expansive soil used for this data was gotten from highway pavement (subgrade) works at Oniyale, Ifo, Ewekoro Local Government Area, Ogun State, Nigeria. The experimental procedure were carried out in three stages. Firstly, sample gotten from the study area was air dried because the sample was gotten during the raining season. Secondly, the sample was sieved through 4.75\u202fmm sieve to dispose rock division and the sieved soil was put into water/air proof compartments for stability. Thirdly, sample kept for stability was blended with common salt and distilled water at different percentages ranging between 0%, 0.5%, 1.0%, 1.5%, 2.0%, and 2.5%. The test conducted were classified into two Swelling parameters: and Strength parameters: . However, various experimental procedures conducted on engineering properties of expansive soil was in accordance with British Standard codes , shrinkage restrict drastically reduced the swelling parameters with an increase in percentage of sodium chloride content The variety of swelling restrain with sodium chloride content on the expansive soil are shown in Fig. 2"} +{"text": "The force analyses on surfaces with three different crystal orientations revealed that the TiO2 (110) surface has unique characteristics for adsorbing glycine molecules showing different features compared to those on TiO2 (001) and (100). To examine this difference, we investigated thermal desorption spectroscopy (TDS) and the interaction between the PEG cross-linker and the three TiO2 surfaces. Our data suggest that the different single crystal surfaces would provide different chemical evolution field for amino acid molecules.Surface force analysis with atomic force microscope (AFM) in which a single amino acid residue was mounted on the tip apex of AFM probe was carried out for the first time at the molecular level on titanium dioxide (TiO Understanding the interaction of biomolecules with TiO2 surfaces is important for many areas of modern technology, including photocatalysis, dye-sensitized solar cells, and biological implants used in dental and orthopedic applications used in this study showed specific interactions with the glycine-modified AFM tips, whereas no adhesion was observed on pyrite. The surface force results were in good agreement with the TDS measurements in which glycine showed a desorption peak on the TiO2 surfaces, whereas no desorption was observed on mica and pyrite.In this work, we studied the interaction between glycine and three different TiO2 surfaces was attributed to the shape of force curves on the TiO2 (110) surface. The adhesion forces and the shapes of the force curves on TiO2 (001) and (100) surfaces were similar. However, the TiO2 (110) surface showed a different feature of adhesion in both the AFM force results as well as in the TDS measurements. We assume that the PEG cross-linker may interact with the TiO2 (110) surface before the glycine adsorption. Therefore, the crystal orientation of TiO2 may influence the amino acid adsorption pathway; however, how the surface structure of this crystal attaches the organic molecules is still under investigation.The difference in adsorption on the TiO2 surfaces is also studied for use in many technological and medical applications. In origins of life studies, a fundamental level of understanding of the role of minerals in chemical evolution can be achieved by studying how molecules interact with TiO2 surfaces in a way similar to that applied to other candidate catalysts. Our results may contribute to the chemical evolution studies by adding to the knowledge of how biomolecules interact with the TiO2 surface, which is considered as one of the host inorganic catalysts in prebiotic evolution studies. Moreover, knowledge of these interactions might also facilitate the use of TiO2 in biotechnological applications.As outlined in the introduction, the biomolecule adsorption on TiO"} +{"text": "The data in this article are related to the research article titled \u201cFlexural Strength determination of Reinforced Concrete Elements with Waste Glass as Partial Replacement for Fine Aggregate\u201d [1]. The article provides information on reinforced concrete beam elements with the fine aggregate partially replaced with waste glass in proportions of 0%, 10%, 20% and 30%. The beam elements were cured and subjected to flexural load after 7, 14, 28 and 90 days. Three samples were tested for each conditions and the average value computed. The tests records include deflection at each gradual increase in the flexural load and the load at final failure. Specifications tableValue of the data\u2022The data presented shows the response of reinforced concrete elements to flexural load with waste glass as replacement for fine aggregate.\u2022The data allows for the assessment of the possibility of replacing fine aggregate with waste glass particles.\u2022The reported data gives information on the effect of waste glass in the reinforced concrete elements on the workability, flexural strength, alkali-silica reaction etc.1\u2022Deflection value at points of flexural load application on the beam.\u2022Failure load of reinforced concrete beams with fine aggregate replacement at 7, 14, 28 and 90 days of curing.The data presented information on flexural strengths of reinforced concrete element:2The aggregate materials and cement used for this research were collected from different locations in Lagos state, Nigeria . Waste glass particles . collect"} +{"text": "Retinal dysfunctions have been integrated in cognitive models of visual hallucinations in several pathologies such as Parkinsonian syndromes or eye diseases. Besides, structural abnormalities of the retinal ganglion cells are documented in schizophrenia and have been associated to visual hallucinations (VH) in neurological disorders. We aim to study functional abnormalities of retinal ganglion cells in schizophrenia patients with VH.We measured the activity of retinal ganglion cells using electroretinogram according to ISCEV criteria. We compared the amplitude and implicit time of the P50 and the N95 waves of the pattern electroretinogram in schizophrenia patients with VH , Auditory Hallucinations or no hallucination and controls (n = 30).Preliminary findings show a significant increase of the N95 implicit time in the HV group compared with controls (p = .05). No difference was found between the HV and HA/NH groups but a gradient appeared to emerge between the 3 groups.Functional impairment of the retinal ganglion cells appears to be more pronounced in schizophrenia patients with HV. The increase of N95 implicit time may be interpreted as a dysfunction of retinal ganglion celles rather than a cell loss. These preliminary results need to be confirmed with a larger sample."} +{"text": "Ollier\u2019s disease is a non-hereditary, benign bone tumor which is usually characterized by presence of multiple radiolucent lesions (enchondromas) in the metaphysis of long bones with unilateral predominance. The disease is a rare clinical entity with 1/100000 occurrence in early childhood. Patients mostly present with multiple hard swellings and deformity of the tubular bones specially hands and feet with leg discrepancy and pathologic fractures.We present two cases of Ollier\u2019s disease in a 13\u00a0years old female and 8\u00a0years old boy which had no specific symptoms. The girl had multiple hard swellings and deformity in the fingers of both hands and left toes with left leg deformity and discrepancy. Her plain radiographs demonstrated multiple expansile enchondromas in the phalanges of hands, left toes and metaphyses of upper humeri as well as left leg bones. The enchondromas were also noted in the left iliac bone and anterior end of ribs. The boy had bowing deformity and shortage of left leg with multiple enchondromas in the metaphyses of left femur, left tibia and fibula as well as left iliac bone in his radiographic images.Ollier\u2019s disease is usually diagnosed by clinical signs and typical location of enchondromas across skeleton in conventional radiography. It usually does not need specific treatment. Well understanding of the clinical manifestation and radiographic features can prevent unnecessary application of other imaging modalities; while other diagnostic imaging modalities like MRI, ultrasound and scintigraphy can be used in complicated and painful conditions. Multiple enchondromatosis is a rare bone disease with six subtypes. Ollier\u2019s disease is a non-hereditary subtype of the disease which for the first time was introduced by Ollier in 1899 . It is cA-13\u00a0year old girl was referred to the radiology department of French Medical Institute for Mothers and Children (FMIC) for taking plain radiographs of the axial and appendicular bones. The patient had short left leg with abnormal swelling and deformity of fingers and left toes. The swelling were hard in palpation however no pain was noticed. The overlying skin appeared normal. In radiographic images, multiple expansile lytic lesions (enchondromas) were noted in the metacarpi and phalanges of hands with sparing of the index finger of right hand associated with multiple lytic lesions in the distal ulna and radius of both hands with sparing of left distal ulna Fig.\u00a0. EnchondAn 8\u00a0year- old boy was referred to our radiology department for taking radiographs of left leg and pelvis bones. The patient had left leg discrepancy with bowing deformity without specific pain. The lateral radiograph of the left leg demonstrates bowing deformity with enchondromas in the distal femur as well as proximal and distal ends of left tibia and fibula Fig.\u00a0. The antThe etiology of Ollier\u2019s disease is not well known however abnormal signaling pathways in the proliferation and differentiation of chondrocytes have been proposed which results in the development of intraosseous cartilaginous foci. Some authors have indicated genetic aberrations like heterozygous mutations of PTHR1, IDH1 and IDH2 genes as the pathogenesis of the disease . The dis"} +{"text": "The tear film cytokine profiling data in this article was obtained from a prospective case-control study with a sample size of 34 dry eye disease (DED) patients with HIV infection and 32 DED patients without HIV infection, see \u201cA distinct cytokines profile in tear film of dry eye disease (DED) patients with HIV infection\u201d Specifications TableValue of the data\u2022This is the first dataset of tear film cytokines in HIV patients with dry eye disease and its comparison with dry eye disease patients without HIV infection \u2022The data show the significantly increased levels of cytokines epidermal growth factor (EGF) and IFN-gamma-inducible protein 10 and decreased levels of growth-regulated oncogene (GRO) in HIV patients with DED and explains the possible role of these 3 cytokines in HIV associated ocular inflammation in DED pathogenesis \u2022None of the cytokine concentrations in HIV patients with DED correlated with the clinical parameters indicate that the levels of these 3 cytokines in these patients are independent of clinical severity of the disease and mainly mediated by HIV \u2022The data presented in this report will help researches to study the disease pathogenesis and mechanisms of DED associated with HIV infection.1The tear film cytokine profiles data obtained from DED patients with and without HIV infection using Lu2\u00ae MAP human cytokine/chemokine magnetic bead panel \u22121 kit following the manufacturer\u05f3s instructions. In each group the cytokine differences were analyzed using logistic regression models and the cytokine levels were correlated with clinical parameters.Tear samples were collected from 34 DED patients with HIV infection and 32 DED patients without HIV infection with prior informed consent"} +{"text": "The data contained in this article was acquired from the automatic gauge control system for a steel cold rolling mill production line in Nigeria. Accuracy is the one of the most important indices of productivity during a milling process. A total of 486 data points were obtained from selected feedback sensors located on the rolling mill machine via the control panel Human Machine Interface (HMI). The selected rolling parameters were gathered at different time intervals for different sample coils strips during the different milling stages. The data shows parameters such as actual thickness measured, x-ray gauge temperature, mill speed at both entry and exit and the mill power. This dataset could be used to analyze and improve the accuracy of the Automatic gauge control system and reduction in error in thickness variation. Specifications TableValue of the Data\u2022The dataset for the thickness measurements can be analyzed to determine the efficiency of the rolling mill automatic gauge control system.\u2022The dataset can be used to investigate the direct effect of change in temperature of the X-ray gauge on the thickness variation at both sides of the mill.\u2022The dataset can be used to determine the accuracy level of the cold rolling mill production line.\u2022The dataset could be used to predict the most significance rolling mill process parameters.1The following parameters were selected from the 6-high cold rolling mill of a steel cold rolling plant; located in Abeokuta, Ogun State, Nigeria. For each pass via the operators Human Machine Interface (HMI).The Supervisory Control and Data Acquisition system (SCADA) provides a detailed real time monitoring of the numerous feedback parameters"} +{"text": "The data presented in this article support the research article entitled \"Development of a rationale for decoupling osmotic coefficient of electrolytes into electrostatic and nonelectrostatic contributions\"\u00a0 Specifications TableValue of the data\u2022The linear regions in the osmotic coefficient-molality plots of several aqueous solutions of single electrolytes have been marked. The existence of these linear regions provides supportive evidence to the analysis presented in the main paper \u2022The primary molar hydration volumes and primary hydration numbers obtained in this article would be useful for estimation of nonelectrostatic contribution to the osmotic coefficient of aqueous solutions of single and mixed electrolytes using the procedure described in Ref. \u2022These data would also allow estimation of electrostatic contribution to the osmotic coefficient of aqueous solutions of electrolytes using the procedure described in Ref. 1The data are provided in two parts. Part-1 contains plots of osmotic coefficient versus molarity of solutions of single electrolytes. The linear regions are marked on the plots. Slopes of these linear regions are listed below the plots. Part-2 lists the data of the primary molar hydration volume and primary hydration numbers.Part-1: Plots of Osmotic coefficient-molality data for single aqueous electrolytes.a. 1-1 electrolytes spectrometry has been present in our main paper 2Slope The primary hydration number The molar hydrated volume of electrolyte, where the molar hydrated volume of the cation, In Eqs. Solving Eqs. The pressure in the hydration shell is calculated using equation given by Desnoyers et al. The values of We have provided the equation to be used for estimation of the excess nonelectrostatic contribution to the osmotic coefficient in our main paper The nonelectrostatic contribution is given byMoreover, the Fig. 3 of our main paper shows the excess nonelectrostatic contribution to the osmotic coefficient for NaCl at 25\u2009\u00b0C. It is seen that the excess nonelectrostatic contribution varies approximately linearly with the electrolyte concentration."} +{"text": "Haematuria and pelvic pain are recognized and documented adverse reactions related to Cabazitaxel use. To date there has not been any documentation of imaging findings in patients with this presentation.We report a case series of five patients who experienced these symptoms while on Cabazitaxel and were all found to have very similar urothelial changes on CT. The patients were noted to have ureteric and renal pelvic dilatation along with urothelial enhancement (in those who had post contrast imaging). All of these changes were noted to be reversible in those who had follow up imaging after cessation of Cabazitaxel and initiation of a short course of steroids.This case series helps demonstrate the pathological reversible urothelial inflammatory changes that may be occurring in patients experiencing haematuria and pelvic pain on Cabazitaxel therapy. These changes may relate to direct toxic effect of drug metabolites, a radiation recall type phenomenon or a combination of both. Cabazitaxel is an antineoplastic agent currently indicated for the treatment of adult patients with hormone refractory metastatic prostate cancer, who have previously been treated with a Docetaxel containing regime. It works primarily through disruption of the microtubular network in cells which in turn inhibits mitotic and interphase cellular functions. Once administered intravenously Cabazitaxel is primarily metabolized in the liver (>95%) by mainly CYP3A isoenzyme (up to 90%). The majority of excretion is in faeces as numerous metabolites with less than 4% of the dose excreted by the kidneys .The incidence of haematuria and pelvic pain with Cabazitaxel therapy is estimated to be 16.7% and 1.9% respectively [We report a series of five cases of Cabazitaxel induced pelvic pain and microscopic haematuria with characteristic pattern of urothelial inflammatory changes on CT at the time of symptoms. All patients had a history of prior pelvic radiotherapy, uncomplicated treatment with Docetaxel and exclusion of urinary tract infections at the time of presentation.All patients in our series tolerated at least 5\u00a0cycles of Cabazitaxel prior to onset of symptoms, which included a varying description of pelvic pain with microscopic haematuria. Table Four of the patients in the series cases 1\u20134) had whole pelvis radiotherapy and one patient case 5) had radiotherapy only to the right hemi-pelvis . Corresponding to this, cases 1\u20134 were able to be restarted on Cabazitaxel therapy without recurrence of significant symptoms.Follow up imaging was conducted on two of the patients (cases 3 and 4) after resolution of pelvic pain and haematuria. These scans revealed significant improvement in the urothelial inflammatory changes supporting the reversible nature of these effects both clinically and radiologically.Through this case series we are providing imaging based evidence of reversible urothelial inflammatory changes occurring in patients experiencing pelvic pain and haematuria while on Cabazitaxel therapy.While reversible side effects such as pelvic pain and haematuria have been documented related to the use of Cabazitaxel , to our We hypothesise these changes to be due to either direct toxic effect of Cabazitaxel (or its metabolites) on the urothelium or the provocation of radiation recall syndrome or a combination of both.The reversibility of inflammatory changes following Cabazitaxel cessation is compatible with both drug toxicity and radiation recall syndrome . Very liWe feel that the unilateral nature of urothelial inflammatory changes in case 5 (corresponding to the side of hemi-pelvic radiation) also further supports the possibility of a radiation recall syndrome rather than drug toxicity .Although the timing of symptom onset to beyond 5\u00a0cycles of treatment and involvement of the entire urothelium rather than just the radiated pelvic regions is atypical for radiation recall syndrome, it is still possible for such a presentation to occur , 3, 6. CThere is at least one case series we are aware of that has histologically shown urothelial inflammation from Cabazitaxel induced radiation recall syndrome . Whilst It must be noted that if this is indeed a radiation recall syndrome while successful re-initiation is possible (as in our case series), there is also the possibility of severe symptom recurrence at re-initiation and cautWe hope our observations will help to improve assessment and management of patients experiencing pelvic pain and haematuria while on Cabazitaxel treatment."} +{"text": "Arabidopsis thaliana seedlings is explored. A protocol for the immunopurification of ectopically expressed green fluorescent protein (GFP) from Arabidopsis thaliana seedlings using a GFP-binding nanobody is developed, and through GC-MS analysis of protein hydrolysates it is established that constitutively expressed GFP reports accurately on the labelling of total protein in root tissues. It is also demonstrated that the constitutive expression of GFP does not perturb metabolism. The principal obstacle to the implementation of the method in tissues with cell-type specific GFP expression is the sensitivity of the GC-MS system.Stable isotope labelling experiments are used routinely in metabolic flux analysis (MFA) to determine the metabolic phenotype of cells and tissues. A complication arises in multicellular systems because single cell measurements of transcriptomes, proteomes and metabolomes in multicellular organisms suggest that the metabolic phenotype will differ between cell types. In silico analysis of simulated metabolite isotopomer datasets shows that cellular heterogeneity confounds conventional MFA because labelling data averaged over multiple cell types does not necessarily yield averaged flux values. A potential solution to this problem\u2014the use of cell-type specific reporter proteins as a source of cell-type specific labelling data\u2014is proposed and the practicality of implementing this strategy in the roots of The purified nanobody was coupled to NHS-activated Sepharose to produce an antibody resin which was then used to purify GFP from root extracts from liquid-cultured Arabidopsis seedlings. The purity of the GFP was confirmed by SDS-PAGE and the identity of the protein was verified by peptide mass fingerprinting. The typical yield of GFP from the roots of 30\u201350 seedlings was about 0.7 \u00b5g.A His-tagged GFP binding protein derived from a Camelidae single heavy chain antibody or a mixture of unlabelled glucose and 20% [13C6]glucose. Each dataset shows the same trend with large variations in the measured 13C fractional abundance for fragments with low ion counts, and with the expected fractional abundance only being observed reliably for fragment ion counts of at least 105 they report accurately on the isotopomer distributions in the amino acid pools that are used for the synthesis of total cellular protein; and (ii) the use of the reporter protein does not perturb primary metabolism in tissues expressing GFP.A. thaliana roots were compared with the MIDs obtained from the total protein fraction from the same tissue by fitting labelling data obtained from total biomass to a model in which the metabolic network is duplicated , and undE. coli where it was shown that the labelling patterns for the total protein fraction and purified GFP were equivalent, thus showing that the GFP was synthesized from the same pool of amino acids as the rest of the protein glucose. Carbohydrate is the principal respiratory substrate in roots and glucose is therefore commonly used as a source of 13C label in steady-state MFA. However, flux maps of plant tissues obtained with this labelling strategy should be interpreted within the context of the increasing evidence for the potential signalling effects of carbohydrates glucose and 20% [13C6]glucose were determined using the \u201cTracer simulation\u201d function. Mass isotopomer datasets were obtained for a range of networks in which internal and output fluxes were varied either independently or in combination (Analysis of the canonical non-compartmented network of core metabolism was based on mass isotopomer measurements using the model described in bination . Flux dibination . The 95%"} +{"text": "InvGE and BMY-8/2 and in the forward primer of PWD shown in Table\u00a0After the publication of this work , we deteAdditional file 2:Solanum tuberosum Group Phureja with the SNP alleles and SNP positions in the potato reference genome (version 4.03) . The sequences were retrieved from the SPUD data base [44]. Primer sequences are underlined, markers with associations are highlighted in blue and SNPs previously reported for tetraploid potatoes are shown in italics. The numbers indicate the position of the sequence and the SNPs in the chromosomes (chr). Exonic regions are represented with red letters while introns are represented in black letters according to the gene models from the SPUD data base [44]. (DOCX 23\u00a0kb)Amplicon sequences of candidate genes with associations to sugar contents and frying color in Additional file 3:Solanum tuberosum Group Phureja with the SNP alleles and SNP positions in the potato reference genome (version 4.03) . The sequences were retrieved from the SPUD data base [44]. Primer sequences are underlined and the SNPs previously reported for tetraploid potatoes are highlighted in yellow. Exonic regions are represented with red letters while introns are represented in black letters according to the gene models from the SPUD data base [44]. (DOCX 26\u00a0kb)Amplicon sequences of additional candidate genes studied in"} +{"text": "This article describes initial and final configurations of methane hydrate structure I as PDB file at various cage occupancies and different temperatures. Cage occupancies from full occupancy to 75% at three temperatures of 290\u202fK, 300\u202fK and 310\u202fK are presented. Dissociation behavior of gas hydrate structure I at the temperature of 300\u202fK is shown in changing the potential energy and radial distribution function. Specifications TableValue of the data\u2022The present data will help in construction the methane hydrate gas structure I at various cage occupancies.\u2022The present data will help in understanding the dissociation behavior of gas hydrate structure when cage occupancy decreases.\u2022The data will aid the discussion of molecular dynamics simulation parameters changes during the structure dissociation.\u2022Data presented here provides initial and final condition of simulation at the beginning and end of the simulation at different temperatures.1The PDB files that are provided as supplementary data for this article show the initial and final structure of methane gas hydrate structure I at various cage occupancies and temperatures see .22.1To construct the hydrate structure, the initial positions of oxygen atoms of water molecules were determined using crystallography data obtained from the literature The PDB files of gas hydrate structure I at various cage occupancies are provided as supplementary data see .2.2MD simulations were performed using Gromacs 4.5.5 package The final structure of gas hydrate structure I at the cage occupancy of 80% after 10\u202fns of the simulation is shown in"} +{"text": "There is an error in how protein XCV0537 is referred to in the fourth sentence of the \"Does a Broad Range of Pathogens Recruit Nudix Effectors?\" section and in the penultimate sentence of the Figure 1 legend.In the fourth sentence of the \"Does a Broad Range of Pathogens Recruit Nudix Effectors?\" section, the word \"putative\" should be added so that the sentence instead reads:Xanthomonas campestris pv. vesicatoria, the putative T3SS Nudix effector XCV0537 was identified [11].\"\"In In the Figure 1 legend, the penultimate sentence should instead read:\"Hpx26 is a type III secretory effector from vascular wilt bacteria [8] and XCV0537 is a putative type III secretory effector from pepper or tomato leaf spot bacteria [11].\""} +{"text": "Alphanodavirus and Betanodavirus (Family Nodaviridae) were comparatively analyzed and the data of their evolutionary origins and relatedness are reported. The nucleotide sequence alignment of the complete genomes from all species and their deduced evolutionary relationships are presented. High sequence similarity within the genus Betanodavirus compared to the genus Alphanodavirus was revealed in multiple sequence alignment of the Nodaviridae genomes. The amino acid sequence similarity for both RNA1 and RNA2 ORF is more conserved in Betanodavirus, compared to Alphanodavirus. The conserved and variable regions within the virus genome that were defined based on the multiple sequence alignments are presented in this dataset.In this article, nine complete genomes of viruses from the genus Specifications TableValue of the data\u2022Nodaviridae genomes are essential to study the virus evolution and the virus diversity.Multiple sequence alignment established the conserved and variable regions within the \u2022Nodaviridae complete genome defined by multiple sequence alignment allowed the design of sequence specific primers that can be used for virus detection and identification.The conserved and variable regions in the \u2022Nodaviridae is applicable in subsequent downstream research.Virus identification and classification inferred based on phylogenetic analysis of sequence conservation in 1Nodaviridae species available in NCBI database were aligned using MEGA7 software Complete genomes of nine 2Nodaviridae were retrieved from NCBI (http://www.ncbi.nlm.nih.gov/). Nine Nodaviridae species in the family of alphanodavirus and betanodavirus were selected of genomic RNA1 and RNA2 were identified using ORF Finder (http://www.ncbi.nlm.nih.gov/orffinder/) and the deduced amino acid sequences were aligned using MEGA7. Phylogenetic trees based on virus genomes and deduced amino acid sequences of ORF were constructed by Neighbor-Joining and Maximum Likelihood respectively (The complete genome data of selected for aligectively ."} +{"text": "The two right-sided difference topography visualizations (upper and lower) of the grand average of the N400 effect (incongruent minus congruent condition) for the two turn-taking modes were exchanged. The shown N400 effect plot for Listening is the N400 effect plot for Reading aloud, whereas the N400 effect plot shown for Reading aloud is the N400 effect plot for Listening. This only affects the visualization of the two difference topographies. The corrected Figure In the original article, there was a mistake in Figure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Allosteric signalling in the outer membrane translocation domain of PapC usher. Published October 01, 2014In the published article there was an error in the schematic representation of residues involved in the allosteric signalling to control PapC gating , showing the wrong shape (corresponding to the cellular phenotype) for two residues (C327 and K427).The figure has been adjusted to show the correct shape, consistent with the results presented in the paper.The corrected Figure 7 is shown here:The originally published Figure 7 is also shown for reference:The article has been corrected accordingly."} +{"text": "This data article describes the experimental data used in the research article \u201cIncorporating individual differences in human reliability analysis: an extension to the virtual experimental technique\u201d Specifications TableValue of the data\u2022The data serve as a benchmark for human performance in emergency situations.\u2022The data allow objective assessment of human reliability rather than subjective assessments that rely on expert judgement.\u2022The data enable investigating the effects of different PSFs on human performance.\u2022The data provide the information that each human is different and the effect of PSFs on performance can vary from individual to individual.\u2022Analysis of the data can provide direction towards adaptive training.1Human performance data for 36 individuals in 4 testing scenarios are associated with this article. The testing scenarios were created in AVERT. Two PSFs - visibility and complexity \u2013 were varied in the scenarios. Details of the 4 testing scenarios can be found in Table 3 in Performance metrics recorded during the scenarios include: time to muster, time spent running, interaction with fire doors and watertight doors, interaction with hazards, and reporting at different muster locations.The 4 supplementary text files summarize the performance metrics of 36 individuals in the 4 simulated emergency scenarios.2The data presented in this article were originally collected during an experimental study presented in A total of 36 participants took part in the study with a goal to learn how to perform a successful offshore emergency evacuation. The participants were na\u00efve concerning any detail of the experimental design, they were not employed in the offshore oil and gas industry, and therefore they were not familiar with the offshore platform. Each participant was assigned to one of two groups for training: 1) G1: high level training and 2) G2: low level training. Participants in both groups received basic offshore emergency preparedness training. Participants in G1 received additional training tutorials and practice scenarios on alarms and hazards.Once a participant was assigned to a group, his/her training level remained static (either low or high) for the rest of the study. The PSFs visibility and complexity, on the other hand, were set to different levels to investigate how these PSFs influence each participant. The schematic diagram of the experimental design can be found in"} +{"text": "Temperature and relative humidity (RH) are two major external factors, which affect equilibrium moisture content (EMC) of wood-plastic composites (WPCs). In this study, the effect of different durability treatments on sorption and desorption isotherms of southern yellow pine (SYP)-high density polyethylene (HDPE) composites was investigated. All samples were equilibriumed at 20 \u00b0C and various RHs including 16%, 33%, 45%, 66%, 75%, 85%, 93%, and100%. EMCs obtained from desorption and absorption for different WPC samples were compared with Nelson\u2019s sorption isotherm model predictions using the same temperature and humidity conditions. The results indicated that the amount of moisture absorbed increased with the increases in RH at 20 \u00b0C. All samples showed sorption hysteresis at a fixed RH. Small difference between EMC data of WPC samples containing different amount of ultraviolet (UV) stabilizers were observed. Similar results were observed among the samples containing different amount of zinc borate (ZB). The experimental data of EMCs at various RHs fit to the Nelson\u2019s sorption isotherm model well. The Nelson\u2019s model can be used to predicate EMCs of WPCs under different RH environmental conditions. The model is of the form:Different durability treatments had only slight effects on the EMC of the composites. The moisture uptake is almost a constant when the amount of wood fibers in WPCs is fixed. In this study, the wood content was 55% by weight for all material types while the maximum content of ZB or UV stabilizers was only 2%, which is so small that the effects of them on the moisture sorption property of WPCs could be ignored. In other words, the sorption isotherm of WPCs in the study was dominated by wood fibers.A and Mv were different for various materials. These parameters can be used in Equation (3) to predict the EMC of different materials at a given RH level. The magnitude of Mv was higher in desorption than in absorption for all materials tested at a given RH. Among all these materials, WPCs showed the lowest magnitude of Mv both in absorption and desorption, averaging at 16.70 for absorption and 16.81 for desorption. Composite panels and solid wood had higher Mv values than WPCs. The regression analysis data on sorption isotherm for various materials is shown in The additives such as ZB and UV stabilizers at the loading levels used have little effect on the EMC of WPCs under various RHs at 20 \u00b0C;The experimental data of EMC at various RHs fit to Nelson\u2019s sorption isotherm model well and the model can be used to predict EMCs of WPCs under different RH environmental conditions;The EMC of WPCs is significantly lower than solid wood and other wood-based composites due to less wood content and partially encapsulation of the wood fiber by plastic in WPC.Within the scope of this study, the main conclusion is that WPCs demonstrate sorption and sorption hysteresis phenomena similar to wood and other wood-based composites. The other conclusions can also be drawn as follows:"} +{"text": "Scientific Reports 10.1038/s41598-017-12740-6, published online 09 October 2017Correction to: The original version of this Article contained an error in the Abstract.\u201cAlthough these rearrangements are ascertained by junction PCR, we describe here a variety of anticipated structural changes often involving reintegration of the region demarcated by the gRNAs in the vicinity of the edited locus.\u201dshould read:\u201cAlthough these rearrangements are ascertained by junction PCR, we describe here a variety of unanticipated structural changes often involving reintegration of the region demarcated by the gRNAs in the vicinity of the edited locus.\u201dThis error has now been corrected in the PDF and HTML versions of the Article."} +{"text": "There are errors in the third paragraph under the subheading \"Molecular dynamics simulations and analysis\" in the Methods section. The publisher apologizes for the errors. Please view the complete, correct paragraph and equation here:ith and jth filament was calculated and averaged over all three filament pairs:Analysis of the resulting trajectory was performed using the AmberTools suite [54]. In order to determine the torsion angle \u03d5 between two filament axes, the vectors"} +{"text": "The outcome for patients diagnosed with facial palsy has been shown to be linked to rehabilitation. Dense 3D morphable models have been shown within the computer vision to create accurate representations of human faces even from single 2D images. This has the potential to provide feedback to both the patient and medical expert dealing with the rehabilitation plan. It is proposed that a framework for the creation and measuring of patient facial movement consisting of a hybrid 2D facial landmark fitting technique which shows better accuracy in testing than current methods and 3D model fitting. We have investigated landmark fitting methods using state-of-the-art techniques and proposed a hybrid 2D landmark fitting method incorporating these which provides better accuracy when measured against the ground truth 2D images.To realise the potential of an application for facial palsy rehabilitation measurement there two key areas of further work. The first is that although the hybrid method proposed provides a high degree of accuracy on landmark fitting a significant level of error resides in fitting mouth landmarks specifically in facial palsy patients when there is a large range of asynchronous movement. This level of error could negatively impact the accuracy of the rehabilitation tracking and therefore further study of asymmetrical motion in the face needs to be captured with 2D landmark fitting systems. The second is to develop available datasets of facial palsy specifically graded 3D models which can be used as ground truth to fully support the proposed framework in its entirety."} +{"text": "We suggest and analyze this iterative scheme under some appropriate conditions imposed on the parameters such that another strong convergence theorems for the SFP are obtained. The results presented in this paper improve and extend the main results of Tian and Zhang of the related matrix, based on Moudafi\u2019s viscosity approximation method for solving the C and Q be closed convex subsets of two real Hilbert spaces H and K, respectively with inner product and norm are denoted by split feasibility problem (SFP) which was first introduced by Censor and Elfving )LetandAssume thatCandQsatisfy the conditions (H1) and (H2), and define the halfspacesandas algorithm in CorollaryFor anyand for eachwe haveand(A projection point problem)u and satisfies the following system of linear equations:Let u and u and the different starting points Let mentclass2pt{minim(A split feasibility problem)LetLet and Xiu , and Li and Xiu , which aentclass1pt{minima(A convex feasibility problem) Let u and Let (A convex minimization problem)Find minimize of Define the Lagrange function \u03bb, which depends on the zero point and \u03f5 to 10\u22124 for the verification to the our solution. Let split common fixed point problem (SCFP) for two firmly nonexpansive mappings and also solving the split feasibility problem (SFP) such that other strong convergence theorems for the SCFP and the SFP are obtained.In this paper, we obtain an iterative scheme using the gradient projection method with a new step size, which is not depend on the related matrix inverses and the largest eigenvalue of the related matrix, based on Moudafi\u2019s viscosity approximation method for solving the"} +{"text": "In this data, the statistical analyses of silicon microwire (SiMW) solar cells are presented for the research article entitled \u201cElectrical and optical properties of Si microwire solar cells\u201d [1]. This article shows the statistical analyses on performances of the various SiMW solar cells. The accuracy of solar cell parameters is discussed on the basis of data sets. Specifications TableValue of the data\u2022The data presents the variations of solar cell parameters with the statistical analyses.\u2022The variations of solar cell performances were measured by changing of contact positions.\u2022The data is useful to analyze the accurate solar cell performances by error bars.1ocV) for scJ) for FF) values for n) values for The datasets were acquired from the each SiMW solar cell. The repeating measurements (10 times) were performed on each solar cell to provide the accuracy of parameters. The measurement was obtained by an interval time of 1\u00a0min by changing of contact position. The accuracy of data is given for the open circuit voltage values were obtained by different contact position. Repeating of 10 times, the obtained data was calculated in terms of the median value and the absolute error. These statistical analyses may provide a scheme of the accuracy for solar cell performances.Four different shapes of microscale Si structures were fabricated for solar cells"} +{"text": "Some numbers regarding the stage of overall rectal cancer patients and year of diagnosis of newly diagnosed rectal cancer patients in the original Table\u00a01 were incorrect. The authors apologize for the error."} +{"text": "Cannabis use remains the most widely used recreational drug worldwide. Following from several USA states legalisation policies, European countries are reconsidering their cannabis laws. While a significant amount of Epidemiological evidence has reported that cannabis use increases the risk of psychosis it is still unclear: 1) what underpins individual differences in developing a psychotic disorder following cannabis use; 2) if variations in availability of cannabis have affected rate of Psychotic disorders across Europe.Using detailed data on lifetime pattern of cannabis use from the EUGEI first episode case-control study (N=2300) and the available Incidence rates of Psychosis calculated for each European site of the same study, we aim 1) to estimate if differences in age at first use, especially of high potency cannabis among cannabis users resulted in differences in their probability to develop psychosis across the study sites; 2) to calculate the proportion of new cases of psychosis attributable to early adolescence-high Potency cannabis in the 5 countries; 3) to relate data on prevalence of cannabis use in each study site with the corresponding Incidence rates for psychotic disorders.Cannabis users starting using cannabis at age 15 and younger who live in those EU countries where high potency cannabis is available have the highest probability to develop psychosis, compared to never users . Moreover, the proportion of new cases of Psychosis attributable to heavy use started in adolescence was between 20% and 37%.Finally, the correlation between lifetime use of cannabis in population controls from the study sites was significantly correlated with the corresponding incidence rates for Psychosis Before Europe rushes into the USA legalisation \u201cmoda\u201d more public education effort might need to be invested in reducing the use of high potency type of cannabis among young adolescents. The latter could lead to a significant reduction in the proportion of new cases of psychosis across Europe."} +{"text": "Finding dense spanning trees (DST) in unweighted graphs is a variation of the well studied minimum spanning tree problem (MST). We utilize established mathematical properties of extremal structures with the minimum sum of distances between vertices to formulate some general conditions on the sum of vertex degrees. We analyze the performance of various combinations of these degree sum conditions in finding dense spanning subtrees and apply our approach to practical examples. After briefly describing our algorithm we also show how it can be used on variations of DST, motivated by variations of MST. Our work provide some insights on the role of various degree sums in forming dense spanning trees and hopefully lay the foundation for finding fast algorithms or heuristics for related problems. In the case that G is weighted, the classic problem of finding the minimum spanning tree (MST) seeks the spanning tree with the minimum weight (sum of edge weights on the spanning tree). Because of its extensive applications such as network design and cluster analysis, numerous studies have been published on the algorithms , the Steiner tree problem 19].S1 File(PDF)Click here for additional data file."} +{"text": "Nature Communications7 Article number: 1212310.1038/ncomms12123 (2016); Published 06302016; Updated 09122016An incorrect version of the Supplementary Information was inadvertently published with this Article in which the image for Supplementary Fig. 7 was missing. The Article has now been updated to include the correct version of the Supplementary Information."} +{"text": "Caenorhabditis elegans gene orthologues of the genes are obtained from WormBase, the online biological database of C. elegans. This dataset has not been uploaded to a public repository yet.The data presented in this article are related to the review article entitled \u2018Unravelling the role of fatty acid metabolism in cancer through the FOXO3-FOXM1 axis\u2019 Specifications TableValue of data\u2022The dataset shows the extensive overlap in the signaling pathway and molecules involved in the FOXO3-FOXM1 axis and FA metabolism. The assessment of this interaction can be of value for research group from related fields.\u2022The dataset allows integration of researches in oncology and metabolic diseases.\u2022The dataset opens up new approaches to study the roles of FOXO3-FOXM1 axis and FA metabolism in breast cancer initiation, progression and metastasis and drug resistance.\u2022These data also be useful for researches in all cancer types where lipid and energy metabolism is implicated.1C. elegans orthologues of mammalian forkhead box (FOX) proteins, FOXO3 and FOXM1, and also the primary factor essential for enhancing the expression of gene networks involved in regulation of fatty acid (FA) metabolism et al., we selected a list of FA metabolism regulatory genes that are downstream of DAF-16/FOXO3 www.wormbase.org), and their roles in lipid and energy metabolism are summarized in Based on literature reviews, we observed that the DAF-16 is the"} +{"text": "In this data article, morphological and optical data of AgNW encapsulated between ITO layers are presented to get insights into our article [1]. SEM images for the formation of AgNWs networks by number of spin coating are also presented. SEM photographs showing the surface morphologies before and after rapid thermal treatment of prepared samples have been presented. Apart from morphological data set, optical characteristics of this type of samples are given. The comparison plots of optical reflectance from AgNW encapsulated between ITO layers and bare ITO are given between the wavelength ranges from 300 to 1100\u00a0nm. At the end, transmittance and reflectance curves of native glass substrates used in this study are presented. Specifications TableValue of the data\u2022Analyzed surface morphologies of AgNW and AgNW encapsulated between ITO layers before and after Rapid Thermal Processing (RTP) would be useful for tunning the required morphological characteristic of various TCO materials.\u2022The number of spin coatings can be treated as a function to modulate the packing density of nanostructures (like AgNW) on the substrates.\u2022Remarkable improvement in the reflectance property of AgNW encapsulated ITO layer between the wavelength ranges from 320 to 510\u00a0nm suggest a route to selectively improve the optical characteristics of particular TCO material.\u2022The data will be useful in understanding the role of AgNW in transparent conducting contacts and designing of solar cell.1The morphological and optical data sets are acquired from the fabricated samples. 22.1The sample preparation included the experiments for deposition of AgNW on and in between ITO layers followed by post annealing through RTP technique. A uniform 100\u00a0nm thick ITO layer was first deposited on Si and soda lime glass substrates using DC sputtering 2.2Surface morphologies of the newly architecture TCO (AgNW embedded ITO) and dispersed AgNWs on ITO surface are shown in 4 pallets. The transmittance and reflectance characteristics of bare glass substrate are given in Reflectance data for the fabricated samples between the wavelength range of 1100\u2013300\u00a0nm are presented in"} +{"text": "MMWR.The 2016 Compendium of Animal Rabies Prevention and Control was released in the March 1, 2016 issue of the Journal of the American Veterinary Medical Association dogs and cats that have never been vaccinated should either be euthanized immediately or vaccinated within 96 hours of the exposure and placed in strict quarantine for 4 months (a reduction from 6 months in previous recommendations); 2) dogs and cats that are overdue for a booster vaccination (and have appropriate documentation of prior rabies vaccination) should receive a booster vaccination within 96 hours of rabies exposure and be kept under owner observation for 45 days; and 3) dogs and cats that are overdue for booster vaccination (and do not have documentation of prior vaccination) may be treated as unvaccinated or undergo serologic monitoring to document an anamnestic response after receipt of a rabies booster vaccination."} +{"text": "The use of transdermal scopolamine to solve methodological issues raised by gender differences in susceptibility to simulator sickness\u201d The data presented in this article are related to the research article entitled \u201c Value of the data\u2022Performing an item-by-item analysis helps to better characterize which specific symptoms involved in simulator sickness are the most prominent in each population/condition. This profiling can be used to personalize solutions to reduce feelings of discomfort. The authors present these data in order to suggest that the restriction of analysis to total SSQ scores or to the three subclasses of symptoms might not be representative of the whole phenomenon of simulator sickness.\u2022The use of a radar chart visualisation shows, in one straightforward and clear picture, which symptoms and to what extent these symptoms are implied in the genesis of the simulator sickness. Such a methodology might be a useful tool to simplify comparisons between results obtained in further studies.\u2022Using this method of assessing the increasing item score between two subsequent driving sessions highlights the relevance of the methodology used to evaluate the relationship between time and simulator sickness intensity.1Initial scores obtained during a pre-exposition simulator sickness questionnaire SSQ0; as well 2Experiment 1 involving 48 participants) and one pharmacological solution to solve the methodological issues raised by gender differences in susceptibility to simulator sickness and of the use of transdermal scopolamine (Experiment 2), on simulator sickness intensity, SSQ scores reported before and after each driving sessions were compared. Following the methodology proposed by Kennedy et al. i.e. Oculomotor symptoms, Disorientation and Nausea). Nevertheless, a reproduction of the initial study from Kennedy et al. Fig. 1a) and Experiment 2 as well as the evolution of scores across time during Experiment 1 (Before the first exposition and after each of the two expositions, participants filled a simulator sickness questionnaire (riment 1 ."} +{"text": "C4 photosynthesis in the wheat seed provides an adaptation to heat and moisture stress and is an efficient mechanism for minimizing carbon loss due to respiration during grain filling through re-fixation of carbonAnalysis of the transcriptome revealed the expression of a complete set of enzymes specific for a C4 photosynthetic genes in the genome (Rangan et al., 4 photosynthetic genes being optimal during early to mid-grain filling. This illustrates the power of genomics in providing novel perspectives in plant biology (Abberton et al., 3 plant. Careful analysis of the literature over a long period of time reveals extensive but highly fragmented evidence for C4 photosynthesis in developing wheat grains. Elaborate explanations have often been offered to explain away the results due to the clear evidence for C3 photosynthesis in the leaves and the dogma of a requirement for Kranz anatomy for C4 photosynthesis to be accomplished. Different pathways may be found in different parts of the same plants or in different environments (Hibberd and Quick, New technologies often provide novel perspectives that modify long standing assumptions. The widespread application of modern sequencing (Rossetto and Henry, 4 photosynthesis in the pericarp of cereals has been controversial because of uncertainties due to the difficulty of demonstrating flux of carbon through the pathway and the carbon isotope discrimination (Farquhar et al., 4 leaves. The complex pathway of carbon to the pericarp via photosynthetic fixation in C3 photosynthesis in the leaves and respiration in the endosperm before arriving at the pericarp explains these issues. Isolated pericarp tissues have been used to demonstrate the flux of carbon into malate and then sugars in barley (Nutbeam and Duffus, Evidence for C4 photosynthesis was discovered around 50 years ago and has been associated with adaptation to low carbon environments within the plant often due to high temperatures and the associated management of water loss in dry environments. Plants have been categorized as C3 or C4 based upon leaf anatomy. Wheat is clearly a C3 plant on this basis. However, different photosynthetic pathways have been reported in different organs of plants; and the possibility of C4 photosynthesis without Kranz anatomy supports the possibility of grain specific photosynthetic pathways.C4 leaf displays Kranz anatomy allowing the different parts of the C4 pathway to be compartmentalized in different cells within the leaf. The inner pericarp of the developing wheat grain has two distinct cell layers, cross cells, and tube cells, that correspond anatomically with the mesophyll and bundle sheath cells of the C4 leaf. We propose here that this seed anatomy be described as \u201cBose\u201d anatomy in honor of the early photosynthesis researcher Jagadish Chandra Bose who reported that C4 acids are involved in carbon fixation in Hydrilla verticillata during summer (Bose, 3 pathway of carbon fixation was described in 1957 (Calvin, The classical Cer Bose, and not 4 pathway have been detected in the wheat genome and are expressed in the developing wheat grain at the relative levels required to support C4 photosynthesis with appropriate subcellular compartmentalization (Rangan et al., Genes encoding a complete NAD-dependent C2 release. This suggests a role for seed photosynthesis in recapture of CO2 generated in the endosperm. Early work by Kriedemann (Seed photosynthesis is necessarily unique as the seed is a major carbon sink while most photosynthetic tissues are a net source of carbon. This complicates the interpretation of macromolecule assembly may involve significant COiedemann showed tGenetic improvement of wheat is critical to the food demands of a growing human population. Targeting selection for enhanced seed photosynthesis may contribute significantly to improving wheat yields. This may be especially important under harsh environmental conditions late in the growth of the crop. Stress late in crop development is often encountered in wheat production and may become increasingly important as a result of climate change (Henry et al., All authors conceived, wrote, and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "To the EditorElevated levels of inflammatory mediators have been identified in patients with heart failure (HF) with a reduced ejection fraction (HFrEF) in direct relation to worsening New York Heart Association (NYHA) class . HoweverWe measured circulating levels of the biomarkers in 120 controls (EF>55%) and 120 cases with NYHA class I\u2013IV HFrEF EF<40%) from the Washington University Heart Failure registry [0% from tWe conclude that although classical DAMPs such as HMGB1 and calprotectin are elevated in HFrEF patients, they do not track with NYHA class, and therefore are not likely to explain the increased levels of inflammatory mediators observed in HF, nor are these DAMPs as accurate for diagnosing HF as traditional markers of cell injury, such as troponin T."} +{"text": "This data article contains complementary results related to the paper \u201cCharacterization of monovarietal olive oils obtained from mills of Calabria region \u201d Specifications TableValue of the data\u2022The data provides some additional data on composition of Carolea oils in Calabria.\u2022The data denoted different olive growing practices and processing in this region of the Southern Italy, manifested for ethyl ester quantification by the showed high standard deviations.\u2022This data could serve as a benchmark for other researchers, evidencing the peculiar characteristics of this olive cultivar and the environmental influences.12P<0.05) were applied to the data by using of SPSS Software . Different letters indicate significant differences among samples.The sampling of olive oils in different areas of Calabria region was conducted as illustrated by Piscopo et al."} +{"text": "These data are made publicly available to enable critical or extended analyses.The data presented in this article are related to the research article, \u201cThe Use of End-Tidal Carbon Dioxide (ETCO These data include those studies that were considered to be most relevant in the determination of the utility of end-tidal carbon dioxide (ETCO2) measurement in the management of cardiac arrest in any setting. These data have been reported as the results of this effort to describe the use of ETCO2 in adult cardiac arrest, and are provided in a summary article describing their utility for adult patient experiencing cardiac arrest in any clinical setting 2 and ROSC. 2 levels and survival to hospital discharge. 2 level higher or lower than 10- or 20-mmHg for predicting outcome following cardiac arrest.These data report findings determined through the 2015 Consensus on Science and Treatment Recommendations process, managed by the International Liaison Committee on Resuscitation (2This review includes information on resuscitation questions developed through the 2015 Consensus on Science and Treatment Recommendations (CoSTR) development process, managed by the International Liaison Committee on Resuscitation (ILCOR)"} +{"text": "The goal of controlled ovarian hyperstimulation (COH) is to supply enough oocytes with normal maturation to insure the consequent biological procedures. A variety of different stimulation protocols have been suggested and an individual selection of the correct stimulation protocol is mandatory. The aim of the present study is to evaluate the correlation between number of retrieved oocytes and clinical pregnancy rate (CPR) after IVF or intracytoplasmic sperm injection (ICSI) procedures. We reviewed 1017 cycles in a total of 975 patients. The study results clearly demonstrate that the aspiration of less than 5 oocytes significantly reduced pregnancy rate. The aspiration of a large number of oocytes (>15) does not lead to an increase of the treatment effect and, at the same time, increases the risk of ovarian hyperstimulation syndrome. The major goal is to obtain 5\u201415 oocytes as a \u201cgold standard\u201d, connected to optimal pregnancy rate after assisted reproduction (ART).The implementation of safe and maximally effective ovarian stimulation is a major aim for"} +{"text": "The enzyme phosphodiesterase 10A (PDE10A) is highly expressed in the striatum where it modulates both dopamine D2 and D1 dependent signaling. Its inhibition leads to a suppression of D2 mediated signaling \u2013similar to effects of D2 antagonists - and an enhancement of D1 dependent signaling. D1-dependent signaling has been implicated in reward based learning. Its deficient activation may be a key factor underlying deficient reward functions including reward anticipation and reward based learning that have been implicated as major drivers of negative symptoms of schizophrenia. Therefore, inhibition of PDE10 could be a way to ameliorate such deficits and consequently negative symptoms. In healthy volunteers the PDE10 inhibitor RG7203 indeed enhanced performance in tasks that probed reward functioning suggestive of its potential utility to treat negative symptoms in schizophrenia. We therefore tested the hypothesis that it should enhance imaging and behavioral markers of reward functions in patients with moderate negative symptoms in order to establish mechanistic proof of its utility as treatment of negative symptoms.In a three-way cross-over study we investigated the effects of two doses of RG7203 (5 mg and 15 mg) and placebo given as adjunctive treatment to stable background antipsychotic treatment on reward functioning and reward-based effortful behavior using the monetary incentive delay (MID) task during fMRI and the effort choice task in patients with chronic schizophrenia and moderate levels of negative symptoms (PANSS negative symptom factor score \u2265 18 points). Each treatment period lasted three weeks followed by a 2 week washout period. fMRI and behavioral tasks were administered at the end of each treatment period. Key outcome measures were the differential BOLD during reward anticipation and overall BOLD activity during the MID task and the percentage of high-effort high-reward choices when the probability of reward was 100% during the effort choice task.Thirty-three patients with schizophrenia at screening) were recruited at three study centers in the US. Twenty-four subjects finished the entire study. RG7203 at 5 mg significantly increased differential BOLD activity during reward anticipation in the MID task. However, this enhancement occurred in the context of a significant decrease of BOLD activity across all conditions during the MID task under treatment with RG7203. RG7203 significantly worsened reward-based effortful behavior in the effort choice task (the high-effort high-reward choice: 67% for both doses of RG7203 versus 73% for placebo). Multiple regression revealed that the decrease in effortful behavior was significantly related to the decrease in overall BOLD activity during the MID task and not related to the difference of BOLD activity during reward anticipation versus the control condition.In contrast to our expectation and previous results in healthy volunteers, RG7203 worsened indices of reward functions which we hypothesize may be due to a further enhancement of D2 antagonistic activity. The results do not support the utility of a PDE10 inhibitor as adjunctive treatment for negative symptoms in patients with schizophrenia. Given the previous observation that RG7203 enhanced reward functions in healthy volunteers who were not treated with D2 antagonist, the results of our study point to potentially deleterious effects of D2 blockade on reward functions and by extension on negative symptoms of schizophrenia. They raise the question if the presence of D2 antagonistic treatment curtails the potential effects of any adjunctive treatment for negative symptoms."} +{"text": "The data presented in this article are related to the research article entitled \u201cThe Voluntary Coffee Standard Index (VOCSI). Developing a composite Index to Assess and Compare the Institutional Strength of Mainstream Voluntary Sustainability Standards in the Global Coffee Industry\u201d in press) Specifications TableValue of the data\u2022Our database currently presents the most detailed comparison of all major VSS that exist in global coffee production.\u2022It will assist further research on the effectiveness of VSS.\u2022Especially, it may serve researchers to better explain impacts related to VSS and to better understand how impact and institutional characteristics are correlated.\u2022The database may also assist consumers and further stakeholders in business, politics and civil society to differentiate between VSS with stronger and weaker institutional designs.\u2022Standard setters may use the database to benchmark and improve their institutional designs.1The following table (Table 1) contains a comprehensive list of regulatory topics related to sustainability transformations in the global coffee sector. The numbers show how strictly each VSS addresses each of these regulatory topics .2The creation of this dataset is based on an extensive document analysis of all standard catalogues and attached enforcement documents that the different standard setters have set up through its financial support of the research group TRANS SUSTAIN.This work was supported by the"} +{"text": "In this paper, we presented the datasets generated using Chose Game representation (CGR) and Choase Game Representation of Frequencies (FCGR) of bacterial and archaeal 16S rRNA sequences. The data in the form of graphical representations was yielded with the help of ENDMEMO tool. The computational representation of these data datasets is useful for studies and interpretation of microbial sequences. Based on a technique from chaotic dynamics, the method produces a picture of any gene (DNA and RNA) sequence which displays both local and global patterns. Eukaryotes and prokaryotes can be identified merely based on their generated visual representation/DNA structures. Specifications TableValue of the data\u2022Data generated in this study permits the representation and investigation of patterns in any type of sequences which visually revealed previously unknown pattern.\u2022The generated graphical data by means of sequences using a new tool derived from the \"chaotic dynamical systems\" which allowed the depiction of frequencies of oligonucleotides in the form of images.\u2022Data on CGR and FCGR are the main factors explaining the variability observed among sequences. The distance between images helpful for measurement of phylogenetic proximity.1This paper describes data on 16S rRNA sequence of bacterial and archaeal species isolated from Soda Lakes such as Sambhar Lake and Chilka Lake (India). The data generated in the form of graphical representations contains information on their oligonucleotides distribution and numbers.2115 bacterial and archaeal 16S rRNA sequences (both short and long) were obtained in FASTA format from NCBI repository . These s"} +{"text": "A programme of Continuous Ambulatory Peritoneal Dialysis has been in progress at the Gloucester Royal Hospital since January 1988. After 2 years patient and technique survival was 81% and 73% respectively, very similar to that in established British Renal Units. Management of end stage renal failure at the local District General Hospital has meant that patients no longer have to travel long distances to the Regional Renal Unit."} +{"text": "The meaning should be clear that in previous work, rag1\u2212/\u2212 zebrafish were compared to heterozygous rag+/\u2212 while in the present work they were compared to homozygous rag1+/+. The authors sincerely apologize for those inaccurate statements. These errors did not change the scientific conclusions of the article in any way.In the original article there were two inaccurate statements, in the introduction and method sections, which may lead to misunderstanding the way previous microarray profiles of uninfected rag1The correct version of the introduction 3rd paragraph, statement on line 25 should more accurately read:\u2212/\u2212 zebra fish, their gene expression profiles in response to viral infection, has yet to be compared to rag1+/+.Probably, due to the difficulties encountered when breeding rag1Danio rerio) section, statement on line 13 should now be more accurate as:The correct version of the materials and methods, zebra fish .These difficulties may explain why few people could make experiments with them and why only comparisons of rag1The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In this paper, we investigated the effect of elemental powder size on the foaming. The powder size of Ni and Ti affected the ignition temperature of the combustion reaction, cell morphology and microstructure of the foams. The cell morphology of the foams was also modified by the powder size of TiB2.Nickel titanium (NiTi) foams were made by combustion synthesis of powders with the help of ZrH Hch foams . The hea2 powder size on combustion foaming process of NiTi is not known. Therefore we investigated that in this study. Besides, the elemental powder size affects the cell morphology of AlTi foams made by the combustion foaming process ,8. Howev2) and a foaming agent powder were used in this study. The sizes of these powders are given in 2 and 0.5mass% ZrH2 were added in the NiTi mixture. Cylindrical compacts in comparison to the use of coarse Ni powder (as well admixed to fine Ti and TiB2) powders as can be seen in cle size . Accordicle size , Ti phas2) releases H2 gas strongly above 773 K [2 gas is lost before the combustion foaming starts. ve 773 K . Therefo2). Fractured at outer cell wall and nonspherical shaped pores existed in relatively high porosity samples with fine Ti and fine Ni, fine Ti and intermediate Ni and intermediate Ti and fine Ni powders.2 powder. i.e., fine TiB2. These values are the sum of three samples. 2 has the positive effect of reducing the pore size of foams. This effect is more obvious in the high porosity foams. Thus the finer endothermic agent not only reduces the pore size but also stabilizes NiTi foams by preventing the collapse of outer cells probably because the finer solid TiB2 particles can stabilize better the foam in the liquid state. Previous studies support the observation that the addition of suitable solid particles increases the stability of metal foams and the stability increases by reducing the size of solid particles [2) powder is effective not only for absorbing the heat generated during the combustion reaction but also for stabilizing liquid NiTi foams in the liquid stage of combustion foaming.articles . From th2Ni and Ni3Ti) appear in the microstructure of all samples. However, the amount of these intermediate products in the sample made with coarse Ni and fine Ti powders was larger than that of the sample made by fine Ni and fine Ti powders. The larger amount of intermediate products on the sample prepared with coarse Ni powder occurred because the reaction to form NiTi is more incomplete due to the lower reactivity of Ni phase. As the Ti phase has a higher reactivity than Ni phase, the effect of Ti powder size on the micro structure is less remarkable.From these results, it seemed that applying homogenization treatment by heating after the combustion foaming or using finer elemental powders than the elemental powders used in this work were needed to eliminate the intermediate products from the final products.2 powder size on foaming behavior of NiTi alloy made by combustion synthesis was investigated: The effect of Ti, Ni and TiB(1) Ignition temperature of combustion reaction of the samples increases with increasing powder size of both Ni and Ti, but the effect of Ni is more pronounced. In this regard, no significant change in the temperature profile was observed by changing the powder size of endothermic agent.2. The reason for that is that solid fine TiB2 particles stabilize more effectively than coarse ones NiTi foams in the liquid state during combustion foaming.(2) Porosity and pore diameter of samples decrease by increasing the powder size of Ni and Ti. The effect of Ni powder size is also more remarkable because the use of coarse powders, especially coarse Ni powder, increases the ignition temperature above gas emission temperature of the foaming agent thus producing gas losses before foaming starts. Fractured outer cell walls and nonspherical shaped pores, and large pore diameter can be prevented by using finer endothermic agent TiB2Ni and Ni3Ti appear in the microstructure of all samples. However, the amount of these non-desirable intermediate products is reduced by using fine Ni powder which helps complete the reaction to form NiTi. (3) The intermediate products Ti"} +{"text": "Penile injuries are relatively uncommon[1]. The crush injury mediated by entrapment of the skin between the teeth and fastener of a zipper mechanism has been described. It is seen more commonly in uncircumcised children than adults[4]. A number of treatment methods have been mentioned in the literature. An adult case presentation and novel method of management using two small needle holders is illustrated."} +{"text": "The integrity of the genome is maintained by specific DNA repair pathways. The main pathway removing DNA lesions induced by exposure to UV light is nucleotide excision repair (NER). The DNA damage response at chromatin is accompanied by the recruitment of DNA repair factors to the lesion site and the deposition of specific histone marks. The function of these histone marks in NER stays for the most part elusive. We have recently reported that the methyltransferase MMSET catalyzes the dimethylation of histone H4 at lysine 20 (H4K20me2) at the lesion site. The deposition of H4K20me2 at DNA damage sites elicits the recruitment of the NER factor XPA providing evidence for an H4K20me2-dependent DNA repair factor recruitment mechanism during lesion recognition in the global-genomic branch of NER. Here we discuss how H4K20me2 might impact on the chromatin conformation and the DNA damage response. One of the unanswered questions in nucleotide excision repair concerns the specific recruitment of DNA repair factors to chromatin. Many reports have addressed the sequential recruitment of factors, but not much is known about the role of histone modifications in this process. The Repair-Prime-Access model suggestsWe have recently reported that a specific chromatin mark, H4K20me2, promotes the recruitment of XPA to the DNA damage site . Our preThis study raises several interesting avenues for future investigation. XPA has been shown to play a role in positioning and formation of the repair bubble . The decIn conclusion, the elucidation of chromatin based XPA recruitment mechanisms might provide important new insights into the regulation of the chromatin landscape during DNA damage repair. It could also serve as a potential link between chromatin structure and the universal DNA damage response."} +{"text": "Around 35,000 patients undergo emergency laparotomy surgery in the UK each year with an in-hospital 30-day mortality estimated as between 11 and 15\u00a0%. The recent publication of the First Patient Report of the National Emergency Laparotomy Audit (NELA) has provided a detailed description of individual hospital performance against national standards of care in emergency laparotomy in England and Wales. Although the standards used for audit purposes in NELA are based upon the best currently available evidence, none of the source data derives from randomised controlled studies. This commentary explores the evidence base for the standards evaluated by NELA and highlights recent and forthcoming studies that may substantially contribute to improving the evidence base in this area, thereby improving patient care and strengthening the validity of the NELA audit standards. The First Patient Report of the National Emergency Laparotomy Audit (NELA) was launched on 30 June 2015 NCEPOD , two areFor example, chapter seven in the First Patient Report of NELA contains the auditable standard that \u201cPatients admitted as an emergency should be seen by a consultant at the earliest opportunity. Ideally this should be within 12\u00a0hours and should not be longer than 24\u00a0hours\u201d. This standard is taken directly from the NCEPOD Emergency Admissions report from 2007 guidance CQUIN ; and thePart of the problem restricting the current evidence base underpinning the NELA standards is the difficulty of conducting trails in emergency laparotomy patients specifically or in critically ill patients in general. Patients undergoing emergency laparotomy are a heterogeneous group with a range of surgical pathologies and exposed to a variety of clinical care processes: large numbers of patients may be required to separate signal from noise. The emergency context brings particular challenges to the consent process, but recent large trails in critical care show that these are not insurmountable. Randomisation of individual emergency laparotomy patients to different packages of care may be substantially undermined by washover of care practices within hospital wards and teams over time. The solution to this last problem may lie in less conventional research trial designs (see below).Despite the complexities of doing clinical studies in patients undergoing emergency laparotomies, the evidence base is growing with one recent important publication and two other studies close to reporting results. None of these studies uses a classical parallel group randomisation of patients to intervention or control. A non-randomised \u201cbefore and after\u201d evaluation of implementation of best practice guidelines, the Emergency Laparotomy Pathway Quality Improvement Care (ELPQuiC) bundle, recruited 726 patients in four centres and published results in 2014 demonstrating a mortality reduction in the implementation phase (Huddart et al. The current evidence base underpinning national standards around the care of patients undergoing emergency laparotomy is weak, in terms of both the quantity and grade of evidence. However, this situation is rapidly improving. The next 24\u00a0months will see important evidence emerging from EPOCH and the ELC. Clearer definition of what is best practice in this patient group will be of great value to clinicians and healthcare providers and may also pave the way for financial incentives for Trusts Murray , in a si"} +{"text": "Although policies and procedures for sharing H3Africa genomic data and biospecimens have been combined, this article will address the process developed to enable the ethical and efficient sharing of the biospecimens and associated data. To this end, biorepositories have been established in Nigeria (HVN H3Africa Biorepository [I-HAB]), Uganda (Integrated Biorepository of H3Africa Uganda [IBRH3AU]), and South Africa . The biorepositories will preserve the consortium's DNA and other sample collections and also facilitate their distribution to support additional research efforts by African scientists and eventually the global biomedical community.2 Each H3Africa principal investigator (PI) has agreed to donate a portion of the DNA collected in his/her H3Africa study while retaining the rest for his/her own future research. All biospecimens to be made available for distribution from the H3Africa biorepositories were collected under appropriate informed consent with institutional and regional or national ethical review.A 3 Fundamental concepts were drawn from existing biorepository best practice documents,4\u20136 which were used to inform the policies developed by investigators and biorepository experts across the H3Africa Consortium.Consortium working groups were established to develop polices for biospecimen sharing and access that respect the interests of all stakeholders. H3Africa stakeholders include the biospecimen donors and their community; the PI and his/her team collecting the specimens and primary data; the institutional, local, and regional ethics committees; the local or national government where samples were collected and stored; the scientists who are granted access to shared biospecimens for additional research; and the eventual consumers of biomedical knowledge to be gained from these studies.Key Elements of the H3Africa Biospecimen Sharing Policy\u2022\u2002Samples deposited in the H3Africa biorepositories are not owned by the biorepositories, but rather retained under the custodianship of the H3Africa biorepositories until they are approved for future research by the Data and Biospecimen Access Committee (DBAC).\u2022\u2002The Data and Biospecimen Access Committee must approve all requests to access the H3Africa biospecimens.\u2022\u2002The DBAC may consult donor PIs regarding caveats in appropriate use of the donated collections.\u2022\u2002Researchers on the African continent or who collaborate with African scientists will have priority access to samples.\u2022\u2002An embargo period for access to the biospecimens by outside investigators will allow time for publication of the H3Africa study for which the samples were initially collected;\u2022\u2002Commercialization of the biospecimens themselves is prohibited.www.ebi.ac.uk/ega/home) through H3Africa-approved requests.7 An interactive searchable catalog is under development by H3ABioNet (the informatics resource of H3Africa) to allow public viewing of available biospecimen collections.The H3Africa biorepositories will adhere to international standards for the implementation of standard operating procedures related to biospecimen processing, storage, shipping, tracking, and quality assurance/quality control. A set of minimum essential data elements determined by the H3Africa working groups will accompany each sample from the central collection laboratory to the H3Africa biorepositories for future shared distribution. Additional phenotypic, clinical, and genomic data for each sample will be available from the European Genome-phenome Archive (http://h3africa.org/consortium/documents). The process for requesting biospecimens from the H3Africa Consortium is illustrated in Procedures for sample access were drafted to ensure optimal use of the limited amount of DNA available for each biospecimen. These procedures and the above policy elements were then integrated with information governing release of H3Africa genomic data sets to form the H3Africa Data and Biospecimen Access Guidelines. The guidelines were reviewed and approved by the H3Africa Steering Committee and posted on the consortium website must be completed, describing the proposed research question and methodology; evidence of funding and local ethics review; a description of the biospecimens requested; benefits of the research to Africa; the investigator's experience, expertise, and resources; and a plan for the disposal or transfer of unused biospecimens.\u2022\u2002Evaluation criteria are scientific merit of the request, conformity of the proposed research with the informed consent signed by the biospecimen donor and the donor's country laws, as well as the local ethics committee stipulations on biospecimen sharing, and compliance with H3Africa goals in specific biomedical research funding areas; potential for publication of the research and translation to biomedical practice; requestor's research expertise; and funding and resources.\u2022\u2002A commitment by the recipient scientist to return newly generated data from the biospecimens, e.g., additional genotyping and sequencing data, to H3ABioNet or EGA in order to make it widely accessible.Key points related to biospecimen access are presented here:If the request for access to biospecimens is approved, the DBAC will send an approval letter to the requestor, who must then contact the host H3Africa biorepository to sign a Biospecimen Release Material Transfer Agreement and arrange for biospecimen shipment. Users must agree to furnish the DBAC with the citations for future publications resulting from shared resources. If a request is denied, the DBAC will correspond with the requestor regarding the reason for denial.Achieving a fair, equitable, and efficient process for sharing of H3Africa biospecimens is expected to involve numerous challenges. One challenge is the limited amount of material from available biospecimens (mostly DNA isolated directly from whole blood). While whole-genome amplification has been discussed as the best way to provide an infinitely renewable DNA resource, the initial cost of such an approach will likely require the discovery of new funding sources. Therefore, the DBAC must balance the merit of the scientific question and the data that will be generated, and the appropriateness of the proposed methods with the remaining amount of sample to maximize the utility of resource.Another challenge may involve differences in emerging biobanking policies across institutions and countries and over time. Ongoing tasks of the H3Africa Consortium will be to evaluate the effectiveness of the DBAC guidelines and implementation process, to track the use of biospecimens to evaluate whether meritorious science and the generation of valuable additional data are being facilitated, to maintain a feedback loop on the quality of the biospecimens, and to stay engaged in regional and international discussions around biobanking policy development, keeping an eye on maintaining policies and procedures that are balanced with the rights and intentions of stakeholders. Perhaps the greatest challenge to any biorepository is sustainability beyond the initial funding period. Solutions will require hard choices and innovative thinking by the H3Africa Consortium and biorepositories. Providing state-of-the-art, fee-based biorepository services to projects outside the H3Africa Consortium is critically important for long-term sustainability.The H3Africa Consortium has developed a robust and comprehensive foundation to build genomic research capacity and excellence across the African continent. It is the intent of the biorepositories to contribute to this endeavor by providing genomic researchers with high-quality biospecimens that advance the goals of the H3Africa Consortium."} +{"text": "We are pleased to announce the publication of a special issue on major research challenges and achievements in the physiology, pharmaceutical drug therapy, and management of \u201chemorrhage stroke.\u201d The call for papers on this topic resulted in a significant amount of interest from researchers all over the world. A total of 27 articles were submitted for review. Our editorial team selected 14 basic and clinical search articles for publication and rejected the remaining 13 (an acceptance rate of 52%). Half of the accepted manuscripts are review articles which summarize current literature on diseases such as cervical artery dissection, hydrocephalus after subarachnoid hemorrhage, intracranial atherosclerosis, or hypertensive intracerebral hemorrhage. We are confident that this special issue will advance the understanding and research of the broad range of disorders referred to as \u201chemorrhagic stroke.\u201d"} +{"text": "Functional double dissociation within the entorhinal cortex for visual scene-dependent choice behavior. Published 07, February 2017Two of the visual stimuli in Figure 2A were used in the SNSC task, but not in the SSC task. We have corrected this error by replacing those two images with correct ones (bamboo and mountain patterns). Please note that this correction does not affect the results and conclusions of the original paper.The Corrected Figure 2 is shown here:The originally published Figure 2 is also shown for reference:The article has been corrected accordingly."} +{"text": "Genetic variations among humans occur both within and among populations and range from single nucleotide changes to multiple-nucleotide variants. These multiple-nucleotide variants are useful for studying the relationships among individuals or various population groups. The study of human genetic variations can help scientists understand how different population groups are biologically related to one another. Sequence analysis of hypervariable regions of human mitochondrial DNA (mtDNA) has been successfully used for the genetic characterization of different population groups for forensic purposes. It is well established that different ethnic or population groups differ significantly in their mtDNA distributions. In the last decade, very little research has been conducted on mtDNA variations in the Indian population, although such data would be useful for elucidating the history of human population expansion across the world. Moreover, forensic studies on mtDNA variations in the Indian subcontinent are also scarce, particularly in the northern part of India. In this report, variations in the hypervariable regions of mtDNA were analyzed in the Yadav population of Haryana. Different molecular diversity indices were computed. Further, the obtained haplotypes were classified into different haplogroups and the phylogenetic relationship between different haplogroups was inferred. Specifications TableValue of the data\u2022The present data is highly useful for the identification of individuals hypervariable involved in mass disasters, missing person cases and criminal cases in the Yadav population of Haryana.\u2022This data will help assess matches in mtDNA sequences in forensic casework in Haryana, and will be useful for population analyses based on specific sequence polymorphisms in the Yadav population of Haryana.\u2022The data report will provide baseline information for genetic studies based on the control region of mtDNA for tracking families related to the Yadav population of Haryana.\u2022This report is important for anthropological and evolutionary research, as well as for phylogenetic studies on the Yadav population of Haryana.\u2022This report could also be used by evolutionary biologists to study genetic variations in order to understand the possible relationships of the Yadav population with other populations.\u2022The data presented here can be used as reference material for future genetic studies on the Yadav population of Haryana.\u2022The mtDNA haplogroups generated in this data report can be used for tracing the migration and ancestry of the Yadav population of Haryana.\u2022The present data will contribute to the DNA database for the Yadav population of Haryana, which can be used for calculating the probability of matches based on mtDNA.1\u2022Table 1: Primers used for amplification of the hypervariable regions . Nucleotide position, primer name, sequence, length and melting temperature of the primers are mentioned.\u2022Table 2: Constituents of the PCR reaction mixture for each reaction volume of 25 \u00b5l per sample for amplification of the HVI, HVII and HVIII regions.\u2022Table 3: PCR cycling conditions for amplification of three hypervariable regions of mitochondrial DNA.\u2022Table 4: Molecular diversity indices for the HVI region, HVII+HVIII region & HVI+HVII+HVIII region.\u2022Table 5: Frequency distribution of the mtDNA haplotypes in the Yadav population.\u2022Table 6: Sequence polymorphism of the three hypervariable regions and their respective haplogroups in the Yadav population.\u2022Table S1: GenBank accession numbers for the mtDNA polymorphisms identified in the Yadav population.\u2022Figure 1: Phylogenetic tree of haplogroups including all related polymorphisms relative to the rCRS for Yadav population22.1Blood samples were collected from 66 maternally unrelated individuals belonging to the Yadav population of Haryana from nearly all districts of Haryana. A sample of 2\u20135\u202fml of venous blood was drawn into 5\u202fml EDTA vacutainer tubes . A consent form was signed by each participating individual at the site of collection. DNA was extracted using the phenol-chloroform-isoamyl (PCI) method 2.2The three hypervariable regions were amplified by using two sets of PCR reactions. The primers F15900 and R00159 were used to amplify the HVI region. The primers F00015 and R00599 were used to amplify the HVII and HVIII regions 2.3The cleaned PCR product was sequenced by commercial DNA sequencing service . Both the strands were sequenced with the ABI BigDye Terminator Cycle Sequencing Kit on the ABI 3700 Genetic Analyzer (Applied Biosystems). All the samples were sequenced with the same primers used in PCR amplification of the HVI, HVII and HVIII regions. An additional primer (16410R-GAGGATGGTGGTGGTCAA) was used in cases where there was slippage due to \u2018C\u2019 stretch in hyper variable region 1.2.4A total of 66 mtDNA sequences was obtained, which included all the base pairs from nucleotide positions 16021\u221216365, 69\u2212576\u202fbp. Sequence data files were edited and aligned with the revised Cambridge reference sequences (rCRS)"} +{"text": "In this article, we provide the data analysis between controllable variables and the performance of CuS crackle based electrode, there are four important factors which could influence the formation of cracks, the colloid concentration, drying temperature, colloid dosage and ambient humidity. We carried out and summed nineteen controlled data experiments below and other variates which could affect the performance were discussed in this article. Specifications TableValue of the data\u25cfThe relationship between the colloid concentration and the performance of CuS crackle based electrode was exhibited by controlled experiments.\u25cfThe relationship between the colloid dosage and the performance of CuS crackle based electrode was exhibited by controlled experiments.\u25cfThe relationship between the drying temperature and the performance of CuS crackle based electrode was also exhibited by controlled experiments.\u25cfOther variates which could affect the performance of CuS crackle based electrode were also displayed in this data in brief.1See 22 based crack and TiO2 based crack were displayed in 2 based crack shows greater order property than SiO2 based crack in this work. Rs) of Cu film reaches its minimum value. The relationship between the stability testing time in ambient condition and the resistance increasing is shown in The data analysis for controllable variables versus the performance of CuS transparent conducting electrode(TCE) is provided here: first, four important factors could influence the morphology of cracks, they are the colloid concentration, drying temperature, colloid dosage and ambient humidity, respectively"} +{"text": "The Therapeutic Status for Tremelimumab in Table 1 was incorrect. In the original article it was: FDA approved in malignant mesothelioma (2015)Corrected: Tremelimumab was granted orphan drug status in 2015 for the treatment of malignant mesothelioma but is not FDA approved yet.In the original article, there was an error: The indications of immune checkpoint inhibitors (ICIs) are set to rise further with the approval of newer agents like tremelimumab and atezolimumab for use in patients with advanced stage mesothelioma and urothelial carcinoma respectively.Corrected sentence: The indications of immune checkpoint inhibitors (ICIs) are set to rise further with the approval of newer agent like atezolimumab for use in patients with advanced stage urothelial carcinoma.Original Article: Ribas et al. on Tremelimumab in grade >3 toxicities Endocrine adverse effects is 6(2)Corrected: Not reported (NR)Original Article: Massard et al. on Durvalumab in grade >3 toxicities Diarrhea is NRCorrected: 0 (0).The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article and supplementary material has been updated with these corrections.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Error in TableTABLE 1 | Derivation of human immunodeficiency virus (HIV) knowledge items with correct responses noted and descriptive statistics and TABLE 2 | Derivation of HIV-related stigma items and descriptive statistics as published. The citations of scale items were misplaced such that they do not match the citation numbers in the reference section. The corrected TABLE 1 | Derivation of human immunodeficiency virus (HIV) knowledge items with correct responses noted and descriptive statistics and TABLE 2 | Derivation of HIV-related stigma items and descriptive statistics appear below. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.In the original article, there was a mistake in The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In Secondly, we report an incorrect value (N = 57) for the control colony #11 in The corrected text and \u201cAfter only 150 paired foraging bouts, a large proportion of each of the test colonies\u2019 forager population learnt to string pull, whereas none of the control colony foragers learnt to pull the string .\u201dThese corrections do not change the results or conclusions of the paper."} +{"text": "The data presented herein are compiled of the research summary of \u201cCharacterization of High-Volume Fly-Ash Cement Paste for Sustainable Construction Application\u201d [1]. This data article provides general information about the ASTM Class C and Class F fly ash cement paste composites composed of silica fume, lime, water reducing admixtures in three different level of workability . The dataset here also helps the readers to understand the links with the basic properties of the ingredients, for example, how can porosity be predicted based on the mixture design? how can the strength of the material be linked with the basic strengths of the constituent ingredients?. Specifications TableValue of the data\u2022The data presented herein can be used to investigate the effects of high volume fly ash on mixture proportions\u2022The dataset can be used by others to construct mix design monograph for cement pastes\u2022The data presented herein may be used to develop new methods for controlled low strength applications\u2022The data may be concerned with the effect of different fly ash content in pore volume of cement paste.\u2022The research data may be helpful for manufacturing commercially sustainable building products1The dataset presented herein were obtained from the physical and mechanical tests of various amounts of ASTM Class C and Class F fly ash, silica fume, lime and water reducers to produce high volume fly ash (HVFA) cement paste composites. The data provides in this article composed of pure cement paste composites. The detailed of the dataset presented here can be found in 2The water-to-binder (w/b) ratio was adjusted to attain the required workability. This article investigates three workability range and seven mixture groups. The groups are all optimized in a previous researches"} +{"text": "E. Exhaustive protein sets and protein abundances before and after depletion are presented in tables and figures. Also, the core protein set and the unique proteins for each sample collection method previously described Complete blood protein profiles of 4 different blood sample collection methods were investigated and the data presented herein is an extension of the research article in Ilies et al. Specifications TableValue of the data\u2022Data shows a comprehensive evaluation of the different blood sample collection methods on 6 high abundant proteins and their depletion efficiency using immunoaffinity MARS6 column which can be used for future investigations on blood high abundant proteins and depleted fractions.\u2022Individual protein abundances, their presence and variance in the samples collected with different methods after depletion are of potential value to determine which sampling method to be used for proteomics investigations.\u2022Data presents an all-inclusive set of information on the methods applied to evaluate the impact of different blood sample collection methods on protein profiling studies and can be used as benchmark for future blood protein profiling studies.1E method and standard search parameters were employed. Detailed description of methods can be found in Ref. In this Data in Brief article we provide detailed information on blood protein profiling as an extension of the results reported in Ref. 2Experimental design and the materials and methods have been reported previously"} +{"text": "The data presented herein are results of the research summary of the investigation for pozzolanic activity in coconut shell ash (CSA) towards a sustainable construction. The data article provides information on the properties of Coconut Shell Ash that are indicative of pozzolanic activity as stated in ASTM C618-15 (2015) [1], BS EN 197-1 (2011) [2] and Joshua et al. (2018) [3]. The data are the physical property of the sand used in determining the binder strengths and the chemical and physical properties (oxide composition and Strength Activity Indices respectively) of the pulverized, calcined and sieved Coconut Shell Ash. Cement is classed as a non-green and non-environmental friendly material that contribute to global warming and other ills associated with it \u2022This data will contribute to other materials that can be used to produce more durable concrete due to the advantage pozzolanic effect imputes to concrete durability.\u2022This data contributes to the list of materials that are otherwise wastes (agro-waste) that is recycled to better use in concrete production .\u2022This data may be helpful in the manufacturing of commercially sustainable building products.1One of the indices used in measuring the level of development of a nation is the volume and level of specification of buildings and other civil structural facilities within that nation. New York and other cities in the United States, Dubai in the United Arab Emirates (thriving tourism industry) and other major cities in the world are characterized by multiple high-rise buildings that are interconnected by roads, bridges and other civil facilities. The major materials used in these buildings and facilities are Portland cement concrete and other cement based-materials. Over 90% building structures in Nigeria are made of reinforced concrete 2) emission, this is a major factor in global warming with negative worldwide consequences. 5% of CO2 global emission occurs in concrete production with the manufacture of cement being the major contributing factor PC is a non-environmentally friendly material due to its very high greenhouse gas , 42.5\u202fN Dangote cement brand, drinkable borehole water and sand prepared to satisfy the standard sand specified in The tests wherein the data was generated are the setting times on the 0% and 15% blends of CSA with cement and mortar strength performed according to The standard sand in accordance to fluorescence (XRF) spectrometer to evaluate for possible pozzolanic activity and classification of the CSA , see N\u2019 if the sum of SiO2, Al2O3, and Fe2O3 is greater than 70%, SO3 content is less than 4% and when LoI is less than 10%. The measure of pozzolanic activity is confirmed by the Strength Activity Index (SAI), which is the ratio of the 28-day strengths at 20% cement replacement with a pozzolan and the control (0% replacement). When pozzolans are blended to cements, the fresh mix is usually less workable that when cement alone is used at constant water/cement ratio According to If SAI is equal to or greater than 75%, pozzolanic activity may be inferred"} +{"text": "During the 2016 Zika virus outbreak in Brazil, we detected Zika virus RNA in urine samples collected from Zika virus\u2013positive pregnant women during different stages of pregnancy. Women had positive and negative intervals of viruria; 3 newborns had adverse outcomes. Further research is needed to clarify the relationship between viruria and outcomes for newborns. Zika virus is a reemerging flavivirus that was first isolated in Uganda in 1947 during the course of a yellow fever virus survey was <38.5\u00a0and negative if the Ct was >38.5, as described previously (Pregnant women who were Zika virus positive by quantitative reverse transcription PCR (RT-qPCR) . The maximum period of detection was 7 months (patient no. 2). The number of collections varied depending on when during the pregnancy the patient started treatment at the facility and when the last urine sample was collected before delivery. Of the 12 newborns for which outcomes were known, 3 (25%) had adverse outcomes: 1 had subependymal cysts and 2 had unilateral abnormal otoacoustic emissions was likely due to the sensitivity of the test. More studies are necessary to understand the dynamics of the replication of Zika virus in fetal tissues and its connection to viruria in pregnant women.We report findings of long-term viruria among Zika virus\u2012positive pregnant women, with Zika virus RNA being detectable in urine during different stages of pregnancy. Plasma and serum are considered the biologic fluids of choice for the molecular diagnosis of Zika virus for Urine, semen, and saliva have been described as specimens that can be used in the molecular detection of Zika virus after the clearance of viremia and can be taken >5 days after the onset of clinical symptoms (Considering that some mothers had viruria just before delivery and newborns without adverse outcomes, the adverse outcomes of the 3 newborns might or might not have been related to the viruria. Because microcephaly and fetal abnormalities have been attributed to Zika virus, continuing to monitor women who had Zika virus infections during their pregnancies will be essential to manage adverse fetal outcomes. The monitoring of Zika virus viruria in pregnant women through the regular collection of urine samples over the course of the pregnancy proved to be a workable approach; however, the meaning of viruria and the consequences for newborns will need to be evaluated further. Whether virus replicates in fetal tissues and uses them as reservoirs remains to be determined."} +{"text": "SCC curves obtained from the test were analyzed to derive SCC parameters such as rate of steady state elongation, the time required for set-in of tertiary region, and time to complete fracture. The fracture surfaces of SCC samples were examined using Scanning Electron Microscope to reveal the mode of fracture. Super 304HCu stainless steel being used as construction material for super heaters and reheaters of advanced ultra super critical boilers, this data will be an addition to the design data available for material selection in design of power plants.Hot tensile test data of Gas Tungsten Arc Welded (GTAW) autogenous joints of Super 304HCu tubes tested at their operating temperature are presented along with the microstructure of the weld joint. The GTAW joints exhibited lower tensile strength than the parent metal and the failure occurred in the weld metal region for all test temperatures. Constant load Stress Corrosion Cracking (SCC) test data of the GTAW weld joints tested in boiling MgCl Specifications tableValue of the data\u2022Microstructural variation in the autogenous GTA weld joint of super 304HCu with details of micro segregation in the weld metal\u2022High temperature tensile test data of cross weld samples of autogenous GTA welded joints of super 304HCu can be used in accessing the structural integrity of the welded joint\u2022SCC rate of steady state elongation can be used to predict the remaining time to failure of the components in service\u2022Provided data can be used to determine the cracking mechanisms associated with the SCC failure12 solution using constant load SCC and their respective corrosion elongation curves are presented. The structural integrity of the autogenous joint evaluated at their operating temperatures using high temperature tensile tests are presented.Super 304HCu (Cr-Ni-Cu-N-Nb-B) austenitic stainless steel tubes with distinct addition of 2.3 to 3 (% wt) of copper is a candidate material for use in super heaters and reheaters of advanced ultra super critical nuclear power plants 2Super 304H tubes of 57.1\u202fmm diameter and 3.5\u202fmm thick were used as base material in this investigation. The chemical composition of the tubes in as-received condition is given in The joints with square butt edge preparation were welded using PC-GTAW processes with argon as the shielding and purging gas. The welding parameters used in this investigation are shown in The weld joints were inspected for full penetration and the test samples are extracted using wire-cut electric discharge machining.2.1\u22123 s\u22121 as per ASTM E21 standard The dimensions of tensile specimen along with the photograph of the specimen after test is shown in The engineering stress-strain curves of autogenous GTAW joints of Super 304HCu at various test temperatures are shown in 2.23) for 5\u201310\u202fs to reveal the general structure of parent metal and with boiling Murakami's reagent to reveal \u03b4 ferrite and carbides in the weld metal. The microstructural examination of the samples were carried out using light optical microscope (OM), scanning electron microscope (SEM) and compositional variation within the weld regions are determined using energy dispersive spectroscopy (EDS) attached with SEM.The metallographic samples were prepared using standard metallographic techniques and etched with Glyceregia from secondary to tertiary region, representing the rate of steady state elongation, tss is the time required for set-in of tertiary region, tf is the time to complete fracture. The ratio of tss to tf is used to determine the most prominent mode of degradation active in their respective test conditions.From corrosion elongation curve, parameters such as iss/tf tends to increase with decrease in applied stress which implies that the time in tertiary region i.e. the time to fracture after crack initiation decreases steadily with decrease in applied stress level, whereas the steady state elongation rate (iss) decreases with increase in tf and decrease in applied stress. SCC is rapid at 0.8\u00d7YS of applied stress indicated by its corrosion elongation curve which does not reveal region of steady state elongation. Hence, the SCC test is not carried out at applied stress of 1.0\u00d7YS.The value of tf) is shown in The relationship between applied stress and time to failure in corrosion dominant region are shown in"} +{"text": "An adult patient with a Fontan circulation because of a complete atrioventricular septal defect Fig.\u00a0a and a d4D Flow MRI-derived streamline visualization showed a complex three-dimensional (3D) inflow pattern from the common atrioventricular valve with the formation of vortical flow around the ventricular part of the septal defect Fig.\u00a0b. MathemKnowledge on the consequences of intracardiac deformations on hemodynamic vortex formation and viscous energy loss might be useful in unraveling the pathophysiological mechanisms leading to circulatory failure, one of the main causes of morbidity and mortality in Fontan patients."} +{"text": "The data presented in this article provide supporting information to the related research article \u201cComparison of ten different DNA extraction procedures with respect to their suitability for environmental samples\u201d Specifications TableValue of the data\u2022The data on the gel sample load are valuable to serve as indirect control for DNA quantification with fluorescence stain called PicoGreen.\u2022This data provide additional gel images of crude DNA and PCR of the tested DNA extraction procedures.\u2022The cost analysis of the DNA extraction procedures provided are valuable for further economical comparison.1The visual DNA quality control of crude DNA extracts and PCR of procedures B, C, D, E, H, I and J is presented in The results for the crude DNA extracts of procedure D and E (method according to The results of the crude DNA extracts of procedure H and I (method according to The results of the crude DNA extracts of procedure J are presented in The cost analysis of the ten DNA extraction procedures and the two commercial DNA extraction kits is presented in detail in 2x represents all low cost calculations and the letter y represents all high cost calculations. The individual cost per chemical needed for every DNA extraction was calculated either with Eqs. mextraction is the chemical weight required for a single DNA extraction and mtotal,fix cost is the total weight corresponding to the fix cost. The individual cost for additional consumables such as gloves, tubes and/or tips was calculated either with Eqs. The sample preservation, DNA extraction, PCR performance and gel electrophoresis were described elsewhere The cost for the lab staff was calculated either with Eqs. The sum of total costs of chemicals was calculated either with Eqs. 2.1See"} +{"text": "Cosmopolites sordidus damage in plantain fields as affected by intercropping\u201d Zea mays), cocoyam (Xanthosoma sagittifolium) and bottle gourd (Lagenaria siceraria) intercropped in the plantain fields in Cameroun modify ant community structure and damages of banana weevil Cosmopolites sordidus. The field data set is made publicly available to enable critical or extended analyzes.The data presented in this article are related to the research article entitled \u201cAnt abundance and Specifications TableValue of the data\u2022The data presents the abundance of sampled ants in each crop associated to plantain and could be used by others researchers.\u2022The weevil damages on the banana bulb were measured by using the Vilardebo method and could be compared to others weevil damage studies.\u2022This data allows other researchers to extend the statistical analyses.1The dataset of this article provides information on the abundance of ant taxa in the cultivated plants intercropped with the plantain and the weevil damages. The 22.1The experiments were carried out during two periods: the rainy season and the dry-season in Cameroon. Three crops and theirs combinations were intercropped with the plantain. In each experimental unit, to measure the abundance of ants, we used the attractive traps placed at 0.5\u00a0m of each plantain plant and alternated the side at each plantain plant CIRAD, France (AIRD grant) and the C2D project.This work is part of a Ph.D. thesis of Anicet Dassou and was funded by"} +{"text": "This article provides supporting data for the research article \u2018Microbial Signatures of Oral Dysbiosis, Periodontitis and Edentulism Revealed by Gene Meter Methodology\u2019 [1]. In that article, we determined the microbial abundance signatures for patient with periodontics, edentulism, or health using Gene Meter Technology. Here we provide the data used to make the DNA microarray and the resulting microbial abundance data that was determined using the calibrated probes and the 16S rRNA genes harvested from patients. The first data matrix contains two columns: one is the GenInfo Identifier (GI) numbers of the 16S rRNA gene sequences and the other is the corresponding oral bacterial taxonomy. The probes were then screened for redundancy and if they were found to be unique, they were synthesized onto the surface of the DNA microarrays. The second data matrix consists of the abundances of the 576 16S rRNA genes that was determined using the median value of all individual calibrated probes targeting each gene. The data matrix consists of 16 columns and 576 rows, with the columns representing the 16 patients and the rows representing 576 different oral microorganisms. The third data matrix consists of the abundances of 567 16S rRNA genes determined using the calibrated abundance of all aggregated probes targeting the same 16S rRNA gene. The data matrix of the aggregated probes consists of 16 samples and 567 rows. Specifications TableValue of the data\u2022The data matrix could by used by scientists to design their own DNA microarrays.\u2022Scientists could use the gene abundance data to further examine differences in clinical status among patients with periodontitis, edentulism, caries or health.\u2022Scientists could use the data to benchmark future studies.12The study design and sample collection methods have been previously published"} +{"text": "In vitro, co-culture systems that mimic microenvironmental stimuli are necessary to sustain tumor cells. In vivo, engraftment of CLL cells in immunocompromised mice depends on the presence of autologous CD4+ T cells. In patients, the effects of the TME on tumor biology have been characterized by gene expression profiling [Cumulative evidence points to the importance of the tumor microenvironment (TME) in chronic lymphocytic leukemia (CLL) pathogenesis . In vitrrofiling . Periphe2H) is a nonradioactive isotope that can be safely administered in the form of deuterated water (2H2O) and incorporated into the deoxyribose (dR) moiety of replicating DNA [2H enrichment. Deuterated water labeling was first applied in CLL to study the rates of cell birth in PB [Deuterium together with bright expression of CD5 on flow cytometry identifies a fraction of CLL cells in the PB that are activated and thought to have recently emigrated from the LN. Using deuterium labeling, we found the highest proportion of newly divided cells within the CXCR4Deuterium labeling has also been used to study lymphocyte kinetics during treatment with ibrutinib. Ibrutinib therapy decreased the cell birth rate and accelerated the disappearance of cells from the PB of patients with CLL . These f"} +{"text": "GCNT2 locus in PKCC215, we examined the whole-exome data of three affected individuals, which revealed the absence of variants at chromosome 6 interval harboring GCNT2. A search of variants in proximal and distal regions of GCNT2 identified two SNP\u2019s rs35318586 and rs3756954 in exome data defining the proximal and distal boundaries of the deletion.There are errors in the fourth paragraph of the Results section. The correct paragraph is: To further investigate the possibility of a deletion mutation at the"} +{"text": "The dataset of physical properties for the proposed CIGS solar cell with Cd-free AlGaAs buffer layer has been depicted in this data article. The cell performance outcome due to different AlGaAs buffer layer band gap is reported along with optimum solar cell performance parameters for instance, open circuit voltage Specifications TableValue of the data\u2022The dataset for physical and electrical properties of various semiconductor materials used to manufacture the proposed CIGS solar cell is defined in \u2022This numerical data can be utilized by scientific community to model and simulate another CIGS solar cell.\u2022The rationality of other simulation process and design can be associate and confirm by evaluating these datasets.\u2022The future simulated model of CIGS solar cell can take suggestion from the numerical values of material parameters.1The input data of electrical properties and material parameters for different layers of the proposed CIGS photovoltaic solar cell have been described in 22.10.9Ga0.1As/CIGS materials stack on the molybdenum coated soda-lime glass substrate for more effective cell performance.The basic diagram of the proposed CIGS solar cell in the simulation study is denoted in 2.2x; a. band gap ADEPT 2.1 2.3J\u2013V characteristic curve of cell, the performance parameters such as From the"} +{"text": "Immunotactoid glomerulopathy (IGN) is a rare immunoglobulin deposition disease. It is often mistaken for cryoglobulinemia or amyloidosis due to the similarities on biopsy findings. The disease progresses to end-stage renal disease (ESRD) within 7 months to 10 years. This is the first case reported of a patient with a diagnosis of IGN who developed acute kidney injury (AKI) and ESRD within 1 week of initial presentation."} +{"text": "Birdsong and human vocal communication are both complex behaviours which show striking similarities mainly thought to be present in the area of development and learning. Recent studies, however, suggest that there are also parallels in vocal production mechanisms. While it has been long thought that vocal tract filtering, as it occurs in human speech, only plays a minor role in birdsong there is an increasing number of studies indicating the presence of sound filtering mechanisms in bird vocalizations as well.Taeniopygia guttata) to song structures we identified beak gape and the expansion of the oropharyngeal-esophageal cavity (OEC) as potential articulators. We subsequently manipulated both structures in an experiment in which we played sound through the vocal tract of dead birds. Comparing acoustic input with acoustic output showed that OEC expansion causes an energy shift towards lower frequencies and an amplitude increase whereas a wide beak gape emphasizes frequencies around 5 kilohertz and above.Correlating high-speed X-ray cinematographic imaging of singing zebra finches (These findings confirm that birds can modulate their song by using vocal tract filtering and demonstrate how OEC and beak gape contribute to this modulation. Birdsong is a complex vocal behaviour often considered to show striking developmental and structural similarities with human speech In humans, voiced speech is produced by vibrations of the vocal folds which are subsequently filtered in order to produce different speech sounds that form an important part of our phonetic repertoire In contrast to this source-filter theory of human speech Zonotrichia albicollis), swamp sparrows (Melospiza georgiana) Taeniopygia guttata) Serinus canaria) Some of the first evidence derives from experiments showing that both songbirds and non-songbirds singing in heliox exhibit deviating vocal characteristics Streptopelia risoria) Cardinalis cardinalis) Myiopsitta monachus) also seem to have a filtering effect on the sound produced Other studies indicate that expanding the oropharyngeal-esophageal cavity (OEC) plays a role in vocal tract filtering as well by tuning it to the fundamental frequency of the vocalizations in doves .We used five male and two female zebra finches for the X-ray cinematographic imaging and five male zebra finches for the experiment in which we replaced the syrinx by a mini-loudspeaker. The female birds only served as stimulus birds in the X-ray setting to stimulate the males to sing. During X-ray recordings male birds were individually transferred into a small cage (30 cm wide \u00d720 cm high \u00d710 cm deep) built from wood with plexi glass on both long sides. The small size of the cage allowed to optically focus on the birds, but still allowed the typical dancing movements during singing \u22121, shutter speed 1/500 s by replacing the original camera of the X-ray apparatus by the Kodak system. The images which had a resolution of 512\u00d7240 pixels were loaded into the camera's onboard memory. The maximum recording time of the Kodak Motion Corder which was triggered manually is 8.7 s at 500 fields s\u22121, making it necessary to save the video sequences immediately on digital video for permanent storage \u22121 we played back the video sequences from the Kodak system with 25 frames s\u22121 to prevent data loss while re-recording. We continuously applied an X-ray dose of 56 kV, 60 mA. The videos were captured either from the Mini DV tapes or from the DVDs using Adobe Premiere Pro software version 7.0 for Windows. Due to a distinct tone produced by the X-ray apparatus only while the shutter was open it was possible to align sound and video using the frame-matching features of Adobe Premiere with an accuracy of 2 milliseconds. In order to accurately follow and quantify the movements of certain articulators we also glued several lead markers (ca. 0.5 mm3) on head and beak of the birds using tissue adhesive . In two birds we implanted additional lead markers into the tongue and larynx. These procedures were conducted under anesthesia using isoflurane .A Philips Optimus M 200 X-ray apparatus was combined with a Kodak Motion Corder Analyzer SR- 500 s that records at 500 field sTo quantify beak gape and OEC expansion we measured the distance between the tips of mandible and maxilla and the distance between the most ventral point of the OEC and the midpoint of the neck of the bird for several note types per song and always at the temporal midpoint of those notes as identified on song spectrograms. These measurements were taken from still images using AviDigitiser (\u00a9 Peter Ch. Snelderwaard) which provides the coordinates of manually selected points within each video frame and from which distances can be calculated. Only X-ray images in which the birds kept their head in a perfect lateral position towards the camera were used, so that in the end we obtained measurements from at least 8 songs for every measured note type. Although we recorded with a high frame rate, the stereotyped dancing movements of zebra finches allowed sampling of only a few notes per song per bird, namely those in which the bird's head was perfectly lateral to the camera. This method is well suited for comparing beak gape and OEC expansion for various elements within a song, as well as for qualitative comparison between birds, but not for quantitative comparisons between birds. Furthermore, due to the small size of zebra finches it was not possible to identify structures such as single vertebrae, but the overall shape of OEC and neck was used to obtain measurements.Afterwards we carried out a direct discriminant function analysis using beak gape and OEC expansion as predictors for determining which note types were produced. Since zebra finches produce several different and complex note types we did not relate our articulation measurements to signal analytic features such as fundamental or peak frequency as has been done in other studies www.praat.org) Prior to the X-ray cinematography we recorded the songs of each bird in a sound-attenuating chamber (ca. 1.80 m \u00d71.20 m \u00d72.00 m) that was lined with acoustic foam to reduce sonic reflections from the walls. From these recordings we later took amplitude measurements using the software PRAAT in the pectoral muscle. Afterwards a small incision was made posterior from the lower jaw to expose the urohyal bone We obtained sufficient video data from four male birds and measured beak gape and OEC expansion of different note types within each song per individual. For every bird separately a direct discriminant function analysis was carried out \u20133 with In all four birds beak gape is weighted heavier in the first discriminant function whereas OEC expansion is weighted more in the second, as shown by the standardized coefficients and the correlation between each variable and any discriminant function .The classification results show thaWhile it is difficult to compare note types between individuals since the four males sing different note types, it is possible to detect some similarities between birds that produce comparable note types. Bird 498 for instance produces a frequency modulated note (note 4) with an upwards sweep in the second half of the note which is comparable to note 5 in bird 705. In both cases these notes show a relatively high OEC expansion and a similar beak gape. Another comparison can be drawn in individuals 499 and 498 since they produce a rather dense harmonic stack and in both birds these elements are produced with a relatively large beak gape, although OEC expansion varies remarkably . This agAnother factor that might be influenced by beak gape and OEC expansion is amplitude and indeed three out of four birds produce the loudest note measured with the largest OEC expansion and in two cases also with a wide beak gape ; Table 4Generally speaking the results indicate that beak gape as well as OEC expansion might act as vocal tract articulators to generate different note types within each zebra finch song. However, no clear picture concerning the specific effects of these articulators on sound modulation is emerging yet and the speaker experiment was carried out to directly address the role of beak gape and OEC expansion.The results of this experiment are displayed in The overall frequency and amplitude modulation pattern is rather similar in all five individuals indicating a fairly specific effect of the mentioned articulators on the sound signal. The clearest and most consistent effect is given by the expansion of the OEC leading to an amplitude increase especially in the frequency region around 5 kHz which is particularly obvious at a wide beak gape, but also clearly visible when the beak is only slightly open. The total amplitude increases on average 10.9 dB when the beak is only slightly open and 8 dB when the beak is wide open. With a closed beak this effect is not so clear since amplitude first increases with OEC expansion but at a certain point drops again; in three birds even below the intensity level that was gained at position 0. Also at the other two beak gapes amplitude first increases rapidly, but drops again at a certain point although it clearly remains above the intensity level at the beginning of a series. Furthermore OEC expansion causes an energy shift towards relatively lower frequencies which again is especially obvious with a wide beak gape, but also visible in the two other conditions.Beak gape has a strong effect on amplitude too. The wider the beak opens the louder the sound becomes with an average amplitude increase of 5.8 dB compared between a closed and a wide beak gape.Regarding frequency range it seems that a closed beak filters frequencies above 6 kHz whereas a wide beak gape emphasizes high frequencies above 5 kHz and over a broader frequency range.All of the nine subplots show a low prominent formant around 1.5 kHz probably mostly influenced by the resonating trachea, the dimensions of which do not change under the different articulator configurations tested in this experiment.In the current study we combined observational and correlational data on song production in zebra finches with findings derived from experimental manipulations of beak gape and OEC expansion to provide insight into the mechanisms of vocal tract filtering in this species. Based on our results it seems clear that zebra finches can use both beak gape and OEC expansion as vocal articulators to filter the sound produced by the syrinx. However, while some of our results support conclusions drawn by other studies and are in line with some of the hypotheses formulated earlier, not all our findings confirm what has been discovered regarding vocal tract filtering in other bird species.Our X-ray cinematographic imaging of singing zebra finches revealed that the expansion of the OEC is caused by a cyclical posterior-ventral movement of the hyoid skeleton which is comparable to northern cardinals Melospiza melodia) Branta leucopsis) Beak gape has been shown to essentially influence frequency patterns of bird vocalizations although different studies arrive at different conclusions. The general picture emerging from the literature is that wider beak gapes correlate with higher frequencies whereas smaller beak gapes correlate with lower frequencies. This has been shown in several songbird species such as the white-throated sparrow, the swamp sparrow Pipilo erythrophthalmus) the hypothesis that beak gape articulation causes significant modulation of the vocal tract filtering function. In this species frequencies between 4 and 7.5 kHz are attenuated when beak gape width is reduced. Furthermore the authors propose that towhees in particular and songbirds in general might vary beak gape as a mechanism to exclude or concentrate energy in distinct frequency bands which often results in the production of narrow-band or pure-tone sounds.Another study Based on the results of our speaker experiment it seems that on the one hand large beak gapes indeed sustain high frequencies and therAnother observation made in song sparrows is that coordinated beak movements develop rather late during song learning and appear to correspond with improved tonal quality of the sound produced whereas they are not necessary for producing the acoustic fine structure of notes A different study found a strong positive correlation between beak gape and fundamental frequency as well as peak frequency in zebra finches in most of the individuals tested although the relationship between beak gape and fundamental frequency did not apply to harmonic stacks Phonygammus keraudrenii) exhibit elongated tracheas which are assumed to lower the pitch of the vocalizations Other structures that might be involved in vocal tract filtering include the trachea itself and glottal opening. Whereas the role of glottal opening has not been examined yet there are indications that zebra finches actively shorten the trachea at the beginning of a song bout In any case it has become clear that vocal tract filtering in birds can enhance vocal complexity and serve to code biologically relevant information such as size In summary we have shown that zebra finches can use both beak gape and OEC expansion to modulate their vocalizations to a substantial degree. However, the wide variety of different note types that these birds produce does not seem to be solely based on the interaction of these articulators but is likely to be affected also by other factors related to the sound source.Video S1X-ray video of a singing zebra finch(5.69 MB WMV)Click here for additional data file."} +{"text": "C5adesArg generated in vitro by yeast incubation of autologous plasma stimulates PMN chemotaxis and oxidative metabolism but has no effect on enzyme release. Preincubation of whole blood with C5adesArg causes aggregation and changed oxidative burst activity of the isolated PMN. These changes are similar to those found in cells from patients after haemodialysis with cuprophane membranes. So the elevated plasma levels of C5adesArg after haemodialysis explain some of the changes in PMN functions, but additional mechanisms have to be assumed.Cuprophane membranes during haemodialysis significantly increase the plasma levels of C5a"} +{"text": "C. parvum 3 days after antigen had a variable effect. Nevertheless in a number of cases it significantly increased the primary response to all 3 antigens. It also inhibited the growth of the CBA fibrosarcoma but was without effect on the A/HeJ fibrosarcoma.The effect of transplanted syngeneic methylcholanthrene induced fibrosarcomata on the primary immune response of CBA and A/HeJ mice to standard doses of alum BSA, SRBC and SIII has been investigated. In animals with established fibrosarcomata the responses were (with one exception) either normal or elevated. Cell transfer studies in sublethally irradiated syngeneic recipients confirmed that the spleens from tumour bearing mice were capable of responding effectively to all 3 antigens. In animals simultaneously challenged with viable sarcoma cells and antigen the response to alum BSA was suppressed while those to SRBC and SIII were often enhanced. Furthermore the secondary response of A/HeJ mice to BSA was also suppressed by the simultaneous injection of viable fibrosarcoma cells. The administration of"} +{"text": "The pharmacokinetics of ciprofloxacin excretion have been studied in 54 patients undergoing biliary andpancreatic operations with and without obstruction of the common bile duct. High concentrations wereachieved in common duct bile within 20 minutes of intravenous injection and persisted for over 3 hoursafter 100 mg and for over 8 hours after 200 mg. The concentration of ciprofloxacin in the bile of functioninggall bladders was much greater than that in the common duct bile. Remarkably, it was identified intherapeutic concentrations in the bile of obstructed ducts. This and the rapid fall from initially high venousconcentrations probably reflect diffusion from the circulation as a result of the exceptional tissuepenetration. A unique feature of this study was the finding of clinically significant concentrations in thebile of obstructed ducts. 90 for most biliary pathogens for more than 8 hours.Two patients developed wound infection and no side effects were observed. The broad spectrumantibiotic ciprofloxacin has potential as a useful agent for prophylaxis in biliary surgery maintaining biliaryand venous concentrations in excess of the MIC"} +{"text": "Leucoraja erinacea) and compared to the published Hoxa cluster of the Horn Shark (Heterodontus francisci) and to available data from the Elephant Shark genome project.The chondrichthyan or cartilaginous fish occupy an important phylogenetic position as the sister group to all other jawed vertebrates and as an early lineage to diverge from the vertebrate lineage following two whole genome duplication events in vertebrate evolution. There have been few comparative genomic analyses incorporating data from chondrichthyan fish and none comparing genomic information from within the group. We have sequenced the complete Hoxa cluster of the Little Skate found between Skate and Horn Shark, compared to three between human and marsupials. We have also identified novel potential non-coding RNAs in the Skate BAC clone, some of which are conserved to other species.We find that the Little Skate Hoxa cluster is remarkably similar to the previously published Horn Shark Hoxa cluster with respect to sequence identity, gene size and intergenic distance despite over 180 million years of separation between the two lineages. We suggest that the genomes of cartilaginous fish are more highly conserved than those of tetrapods or teleost fish and so are more likely to have retained ancestral non-coding elements. While useful for isolating homologous DNA, this complicates bioinformatic approaches to identify chondrichthyan-specific non-coding DNA elements Additionally, a Little Skate (Leucoraja erinacea) genome project has been approved by the National Human Genome Research Institute. However, there is currently little information available on patterns of genome evolution within the cartilaginous fish. To start to rectify this omission, we undertook the sequencing and analysis of a complete Hox cluster from the Little Skate.The Chondrichthyes (cartilaginous fish) are one of the three extant major clades of jawed vertebrates and comprise two sister-groups; the elasmobranchs and the holocephalans have been fully sequenced from a chondrichthyan , a member of the oldest extant lineage of Elasmobranchs [The Hox genes play important roles in determination of anterior-posterior patterning during embryonic development . Their cand Hoxd ) as a reand Hoxd -11. Furtand Hoxd . Two Hoxrancisci ,4). Becaenegalus ) - a memobranchs . TogetheFJ944024) contains the full Hoxa cluster as deduced by comparison to the published Horn Shark and Elephant Shark clusters [Hoxa14 gene, we do not believe that this gene is present in either Skate or Horn Shark because of the distribution of conserved non-coding elements between the three species. Thus a conserved element found 5' to Hoxa14 in coelacanth is present 5' to Hoxa13 in Little Skate and Horn Shark. The distance from the start codon of Hoxa13 to the stop codon of Hoxa1 comprises 104,602 bp, strikingly similar to the 105,289 bp figure for the Horn Shark despite the genome size of the Horn Shark being around twice the size of that of Little Skate from the Toarcian Stage of the Early Jurassic [Within the Little Skate Hoxa cluster, only 9522 bp codes for protein (compared to 9525 bp in Horn Shark). Hox gene coding sequence is typically around 95-98% identical at the amino acid level between the two species. Turning to non-coding DNA, an alignment of the Little Skate Hoxa cluster with the orthologous regions of other vertebrates Figure reveals Jurassic . A compaet al. [et al. [et al. [Polypterus). This very high degree of conservation of ultraconserved elements between Little Skate and Horn Shark is surprising given the length of time that has passed since the divergence of these two elasmobranchs. By comparison, there are only three UCEs conserved absolutely between the Hoxa clusters of human and marsupials (both Platypus and Opossum), species that have been separated for approximately the same period of time. If the Elephant Shark genome is taken to be approximately 75% complete [Xenopus tropicalis); species which have been separated for at least 330-350 million years and in which only a single Hoxa ultraconserved element at 100% over \u2265 100 bp is found. If the conservation threshold is lowered to 90%, then there are still only nine elements conserved between human and frog, five of which overlap with Hox coding sequences.Ultraconserved elements (UCEs) were originally defined as regions of 200 bp or more conserved at 100% identity between human and rodent genomes . Recentl [et al. found thcomplete one woulcomplete ). A compHoxa7 in the mouse through a reduction of protein level, rather than mRNA destabilisation [Hoxa7 gene. There are four potential mir196b binding sites in the 3' UTR of Horn Shark Hoxa7 [Hoxa7 3' UTR. Bioinformatic identification of microRNA targets is complicated by the fact that the miRNA-target binding can include mismatches and gaps and often involves only a small part of the mature miRNA [Polypterus senegalus HoxA cluster has retained mir196b despite the loss of the Hoxa7 gene, lending support to the suggestion that mir196b has other targets within vertebrate Hox clusters [Hoxa13 and is found only in the Little Skate. The third is located within the intron of Hoxa10 and is conserved between Little Skate, Horn Shark, Elephant Shark and Indonesian Coelacanth, but not in teleosts or tetrapods. The final predicted ncRNA is more problematic, having an unusual secondary structure in skate and an even more unusual structure in Elephant Shark (not shown). Closer examination of this RNA suggests that it may not be functional, since it is located near to several repetitive elements as well as a very large number of hits to the Elephant Shark genome sequence. It is possible that this prediction actually reflects two repetitive elements in opposite orientations suggestive of a stable stem-loop structure.Vertebrate Hox clusters are known to contain several microRNAs which are known to be involved in anti-sense regulation of Hox genes both within and across clusters . The miclisation and has rk Hoxa7 and thesre miRNA . Interesclusters . We haves Figure in both Hoxa11 and Hoxa10 which shows high (84%) identity to the Deu-domain and 3'-tail region of SacSINE1 identified by Nishihara et al. [Squalus acanthias). SacSINE1 is a 463 bp tRNA-derived SINE related to the SINE3 family of zebrafish and thought to be derived from the L2 clade of LINEs. The Little Skate SINE fragment lacks the 5' promoter for transcription by RNA III polymerase, indicating that it is a non-functional retroposon although it may have accumulated some other function which accounts for the degree of sequence conservation to SacSINE1. Alternatively, the Little Skate SINE may represent a recent retroposition into the Hox cluster which has been inactivated by the loss of the 5' promoter region. The orthologous region of the Horn Shark Hoxa cluster shows no sequence similarity to the Little Skate SINE fragment and it will be interesting to trace the evolution of this SINE within other members of the Rajidae. Repeatmasker [HoxA1 and HoxA13. The same region of the Horn Shark Hoxa cluster contains only 1205 bp (1.14%) of repetitive DNA, despite the larger genome size of Horn Shark. Aside from the SINE fragment in the Little Skate cluster, the rest of the repeats are simple-sequence elements such as mononucleotide tracts (see below) or microsatellites with a repeating unit of 2-6 bp. It seems likely therefore that the constraining force on repetitive DNA in vertebrate Hox clusters is not the preservation of precise intergenic distances (since microsatellites are known to expand and contract by strand slippage during DNA replication) but rather the exclusion of alternative transcriptional start sites in LINE or SINE promoters which may disrupt the tightly controlled expression of Hox genes during development.Vertebrate Hox clusters are usually free of complex repeats. However, the Little Skate Hoxa cluster contains a 109 bp region between a et al. in the datmasker identifiHoxa13 and Hoxa1. The orthologus region in Horn Shark contains 14 such sequences and although some relative positions appear to be conserved (such as between Hoxa9 and Hoxa10 and a doublet between Hoxa4 and Hoxa5) these do not appear to be homologous based on conservation of both the G4 quadruplex and surrounding sequences. Because of this, it appears unlikely that G4 DNA plays an ancestral role in Hoxa gene regulation, although it is still possible that there are some cell- or species-specific requirements for the G4 structures in non-embryonic Hox expression.Both the Skate and Horn Shark Hoxa clusters contain a number of guanine-rich sequences Figure . RegionsCallorhinchus milii) genome project suggests that the Hoxa cluster of this species is also highly conserved with respect to the Skate and Horn Shark despite having been separated from them for around 375 million years. Comparisons of the human Hoxa cluster to those of marsupials and amphibians reveal a much lower level of sequence conservation over similar periods of time, indicating either a faster rate of molecular evolution in the tetrapod and mammalian lineages or a slower rate of evolution in the cartilaginous fish. This finding echoes the suggestion of Wang et al. [The Little Skate Hoxa cluster is strikingly similar to that of the Horn Shark in terms of both sequence conservation and intergenic distances despite the two lineages having been separated by at least 180 million years. The available data from the ongoing Elephant Shark ) filters from the Clemson University Genomics Institute (CUGI). The BAC was shotgun sequenced to 9.3\u00d7 coverage by contract to the Genome Center at Washington University, resulting in 14 major contigs in 4 scaffolds. Remaining gaps were filled using a combination of direct sequencing on BAC DNA or by cloning and sequencing of PCR products from primers designed to cross gaps in the scaffolds. Genes were annotated by comparison to published Horn Shark genes (from BAC sequences described by implemenJFM carried out the experiments, JFM, YFZ and PWHH analysed the data and JFM and PWHH wrote the paper. All authors read and approved the final manuscript."} +{"text": "Mycophenolate mofetil has been tried in 20 cases of chronic relapsing erythema nodosum leprosum reaction where long use of systemic steroid produce complications or are contraindicated. Excellent results have been observed in all the cases to arrest the reaction followed for a period of six to eight months duration. Progressive knowledge of leprosy over the last few decades sometimes fall short in the understanding of many a subsequent complication and aftermath of this disease even after a full multidrug therapy (MDT) schedule. Treatment of reactional and post reactional episodes often pose a therapeutic challenge to leprologists of our country and some times drug therapy with routine anti-inflammatory and immunomodulator agents fail to produce desired response.1The present study attempts to evaluate the role of a yet not so routinely used agent Mycophenolate Mofetil in reactions in leprosy where systemic corticosteroid therapy is not viable.In this study profile 20 patients of erythema nodosum leprosum (ENL) between the age group of 30 to 50 years were selected out which 16 patients were of lepromatous leprosy (LL) type and 4 patients of borderline lepromatous leprosy (BL) type. These patients had intractable ENL reactions of severe grade refractory to routine conservative treatment and having contraindications for systemic corticosteroid therapy like hypertension, diabetes mellitus and peptic ulcer and history of melena.All the patients had erythematous evanescent, tender skin nodules with pyrexia and joint pains as the commonest clinical findings.These patients were started with Mycophenolate Mofetil at dose of 1 gram per day and in a few cases dosage increment to 2 grams per day were necessary for control and subsequent maintenance. The liver function, kidney function and routine blood counts were done during the course of therapy. These patients were monitored for a period of six to eight months. In two patients treatment was discontinued within a month due to the systemic side-effects of the drug like nausea and vomiting and other gastro intestinal symptoms and drug did not produce desired results. Maintenance dosages of 500 mg per day was effective to control the ENL in most cases.Out of the 20 cases under going treatment 14 cases were males and 6 females mostly of the middle age group. Most of the cases (18) showed significant subsidence of lesions within a month although low dose maintenance with 0.5 gram per day was necessary for 4 to 6 months for complete remission The name ENL given by Japanese Dr. Murata 1912 is used in most parts of Asia alternatively lepromatous lepra reaction is also used as it commonly occurs at the bacilliferous end of the leprosy spectrum. It is common in treated lepromatous patients 50% developing by the end of the first year of treatment.3Mycophenolate Mofetil is used. In dermatology and documented in the treatment of SLE, pemphigus, steroid resistant idiopathic thrombocytopenic purpura and other autoimmune diseases. Its use in ENL as a steroid sparing agent has not so commonly being put to test. Efficacy of Mycophenolate Mofetil in diffuse proliferative lupus nephritis and in stable renal transplant recipients has been commonly put to practice by the medical fraternity.45Immunopharmacology of Mycophenolate Mofetil is vital in understanding its clinical usage. Prodrug Mycophenolic acid acts as a inhibitor of inosine mono phosphate dehydrogenase (IMPDH) which is the rate limiting enzyme in denovo synthesis of guanosine nucleotide. T and B lymphocytes are more dependent on this path way that alters cell types. Mycophenolic acid (MPA) is five times more potent inhibitor of type (ii) isoform of IMPDH which is expressed in activated lymphocytes than type (i) isoform. MPA has cytostatic effect on lymphocytes than on other cell types (mechanism by which MPA exerts immunosuppressive effects).Efficacy of MPA occurs mainly due to induction of apoptosis of activated T cells, eliminating clones of cells responding to antigenic stimulation. Depleting guanosine nucleotides, MPA suppresses glycosylation and expression of some adhesion molecules. By depleting guanosine nucleotides, MPA also depletes tetrahydrobiopterin (cofactor for inducible form of nitric oxide synthetase - INOS).The common dosage schedule followed was the routine 0.5 gram twice in a day with dosage reduction over period of 4 to 6 months and further follow-up for another two months.Mycophenolate Mofetil may be an important steroid sparing agent for ENL reactions where systemic cortisone is contraindicated for producing quick control of symptoms and remission lasting over 6 to 8 months."} +{"text": "Combinatorial regulation of gene expression is ubiquitous in eukaryotes with multiple inputs converging on regulatory control elements. The dynamic properties of these elements determine the functionality of genetic networks regulating differentiation and development. Here we propose a method to quantitatively characterize the regulatory output of distant enhancers with a biophysical approach that recursively determines free energies of protein-protein and protein-DNA interactions from experimental analysis of transcriptional reporter libraries. We apply this method to model the Scl-Gata2-Fli1 triad\u2014a network module important for cell fate specification of hematopoietic stem cells. We show that this triad module is inherently bistable with irreversible transitions in response to physiologically relevant signals such as Notch, Bmp4 and Gata1 and we use the model to predict the sensitivity of the network to mutations. We also show that the triad acts as a low-pass filter by switching between steady states only in response to signals that persist for longer than a minimum duration threshold. We have found that the auto-regulation loops connecting the slow-degrading Scl to Gata2 and Fli1 are crucial for this low-pass filtering property. Taken together our analysis not only reveals new insights into hematopoietic stem cell regulatory network functionality but also provides a novel and widely applicable strategy to incorporate experimental measurements into dynamical network models. Hematopoiesis\u2014blood cell development\u2014has long served as a model for study of cellular differentiation and its control by underlying gene regulatory networks. The Scl-Gata2-Fli1 triad is a network module essential for the development of hematopoietic stem cells but its mechanistic role is not well understood. The transcription factors Scl, Gata2 and Fli1 act in combination to upregulate transcription of each other via distal enhancer site binding. Similar network architectures are essential in other multipotent cell lines. We propose a method that uses experimental results to circumvent the difficulties of mathematically modeling the combinatorial regulation of this triad module. Using this dynamical model we show that the triad exhibits robust bistable behavior. Environmental signals can irreversibly switch the triad between stable states in a manner that reflects the unidirectional switching in the formation and subsequent differentiation of hematopoietic stem cells. We also show that the triad makes reliable decisions in noisy environments by only switching in response to transient signals that persist longer than the threshold duration. These results suggest that the Scl-Gata2-Fli1 module possibly functions as a control switch for hematopoietic stem cell development. The proposed method can be extended for quantitative characterization of other combinatorial gene regulatory modules. Appropriate spatiotemporal control of gene expression is central to metazoan development. Unraveling the dynamical properties of GRNs will be the key to understanding their functionality. Throughout development, cells progress through a succession of differentiation steps from stem cells via immature progenitors to fully differentiated mature cells, and each of these subtypes is associated with a unique regulatory state of the GRN Various computational approaches have been used for regulatory network analysis in the past. Boolean models provide qualitative information about network behavior such as the existence of steady states and network robustness and are most useful for large networks or when experimental information is scarce Gata2-3 and Fli1+12 enhancers contain multiple Gata2 (GATA), Fli1 (ETS) and Scl (E-BOX) binding motifs. The Scl+19 enhancer contains ETS and GATA binding motifs. Scl, Gata2 and Fli1 are all essential for normal hematopoiesis in mice The hematopoietic system has long served as a powerful model to study the specification and subsequent differentiation of stem cells lacZ reporter vector and tested using stable transfection of hematopoietic progenitor cell lines The triad architecture is very It has been suggested that the dense connectivity and positive feedback loops within stem cell GRN modules play important roles in stabilizing the stem cell phenotype Scl+19 enhancer; the full model is derived in the Full quantitative characterization of the combinatorial nature of transcriptional regulation requires measurements of binding affinities between the DNA and TRs as well as interaction strengths among TRs. Moreover, the contribution of each individual TR and each possible combination to the transcriptional rate must be assessed. This information is extremely tedious to measure due to the combinatorial multiplicity of TR configurations and does not exist for the majority of experimental systems. Experimental data for synthetic libraries of transcriptional reporters that contain the gene regulatory elements is more readily available. We develop thermodynamic methods to characterize the combinatorial transcriptional regulation by distal enhancers based on this type of data and apply it to model the Scl-Gata2-Fli1 triad - a core module of the GRN of hematopoietic stem cells. Recently this system has been experimentally characterized Scl+19 enhancer is only revealed upon integration of the enhancer-promoter construct into chromatin and that the activity of the enhancer is independent of its position (upstream or downstream) relative to the reporter gene Scl+19 enhancer.We assume that the distant enhancers increase the transcriptional rate via modulation of chromatin remodeling rather than through direct interaction with transcriptional machinery. This assumption is motivated by the observations that activation of the te ; see . This waScl+19 enhancer contains binding sites for Gata2 and a Fli1 dimer and therefore can exist in closed and four different open states .The cumulative probability of all open state configurations is then given by s denotes the the Scl+19 enhancer: e.g. for the Gata2-bound state Scl+19 enhancer and the superscript to specify the binding configuration (cf. The Direct measurements of the binding free energies in this expression may be tedious but these can be straightforwardly computed from the ratios of the transcription rates from synthetic reporter libraries with full or mutated enhancer sites. Ratios of the reporter expression levels of cell lines with wild-type (wt) and mutated (mut) enhancers can be used as constraints on the values of the binding free energies.Scl, Gata2 and Fli1 form an interconnected triad of positive interactions and play an important role in hematopoietic differentiation Assuming first-order degradation kinetics, deterministic rate equations for the change in TR concentrations take the formGata2-3 enhancer):Scl+19 and Fli1+12 enhancers respectively). These equilibrium constants are dimensionless quantities characterizing the maximum possible fold enhancement of gene expression by the respective enhancer. The partition functions are used to compute Gata2 synthesis rate In addition to distant enhancers, Notch and Bmp4 are known to serve as activators of the promoters of Gata2 and Fli1, Gata2 respectively Conversion to dimensionless form can greatly simplify the model allowing easy interpretation of simulation results. We normalize the species concentrations of Scl, Gata2 and Fli1 as OFF state and a high expression ON state (ON state. This irreversible progression switch behavior is expected from the triad module which has been reported to play a significant role in the specification of HSCs in the hemogenic endothelium. We use the above-described approaches to estimate the parameters for our model. Equations (25)\u2013(27) relate the gene expression results from the Scl+19 enhancer to the chromatin equilibrium constant Gata2-3 and Fli1+12 enhancers are estimated based on the experimental results and We use the model developed in the preceding sections to analyze the steady state response of the triad to Notch and Bmp4. By varying ates see . For cerON state . This swIn addition qualitative information about system behavior, namely its switchability as a response to physiologically relevant Notch and Bmp4 signals, places an upper bound on chromatin equilibrium constants values. For a different set of y states . As a reOFF to ON (data not shown). The calculated free energies are shown in We expect the triad to be switchable in response to both Notch and Bmp4. Therefore we choose the chromatin equilibrium constants from within the narrow ranges shown above and calculate the TR-enhancer binding free energies using these chosen values. For this chosen set of parameter values the model shows an irreversible bistable response to Notch and Bmp4 . Bmp4 coGata2-3 enhancer. Through competition for binding sites and subsequent chromatin remodeling Gata1 can switch the triad from high expression back to the low expression state. We represent the chromatin remodeling effect of Gata1 by including a factor 02 fold change in the callus tissues to the set of genes that are preferentially expressed in embryonic stem cells (ESCs) The final set of studies were directed at validating the expression of two different candidate genes Nanog and Methyl-CpG binding domain protein 2. The data related to Nanog is first presented since it has been shown to be a central component in maintaining pluripotency of ESC and is related to repression of ESC response to BMP signaling Since the marrow ablation and fracture callus tissues from which the RNAs were purified contain complex mixtures of multiple cell types, it was unclear if Nanog expression would be representative of populations of cells that contribute to skeletal tissue formation or would be found in stem cells that give rise to other cell lineages. In order to further address this question, the expression of Nanog was examined over the time course of induction of osteogenesis of marrow stromal cells in vitro . MessengThe final data that is presented is for the Methyl-CpG binding domain protein 2 Gene expression . This geA number of previous studies have used transcriptional profiling approaches to identify novel candidate genes expressed during fracture healing The various tissue types, major biological processes , and varWhile it was anticipated that skeletogenic processes would predominate during fracture healing, the number of genes associated with vasculogenesis and neurogenesis associated processes were five times more prevalent than those associated with skeletogenesis. Genes associated with these biological processes also appeared to be expressed earlier during fracture healing than those associated with skeletogenesis and overlapped into the genes sets that were identified to be common with ESC. While it may be speculated that many of the developmental genes that control neurogenesis and vasculogenesis will overlap with the subset of genes associated with skeletogenesis, it is noteworthy that large numbers of the expressed genes seen in the neurogenic ontologies were unique structural elements associated with axon formation and neural signal transduction. Such data suggest then, that neurogenic tissues are also regenerated during fracture healing, which has considerable implications in terms of using this model to study specific aspects of post natal neural regeneration.The early temporal expression of large numbers of genes associated with vascular and neurogenic tissue formation during fracture healing is consistent with the very early and concurrent development of these tissues during embryogenesis. In this context, salamander limb regeneration does not occur in the absence of accompanying neural tissue development Several studies have shown that bone and marrow tissues contain both myelinated and non-myelinated fibers that enter the bone along with blood vessels from the central feeding vessel along with many smaller branches from the periosteum that all terminate in the marrow space Fracture healing is generally believed to recapitulate embryological mechanisms that formed the skeletal tissue. This raises the question whether the post natal stem cells that contribute to this repair process would express genes common with ESC or other types of stem cells. In this regard, it is noteworthy that almost a third of all genes that are preferentially expressed in ESCs are seen in fracture callus tissues and that three of these genes Oct4, Sox2, and Nanog, which play central regulatory roles in ESC maintenance Lastly, we observed expression of large numbers of genes associated with gametogenesis and gonad function during fracture healing. While this observation is surprising, it is noteworthy that spermatogonia arise in the only known post natal stem cell niche that maintains a pluripotent stem cell population In summary, these data present the first temporal analysis of the transcriptome of an endochondral bone formation process that takes place during fracture healing. Major observations include: the extensive involvement of neurogenesis and vasculogenesis during injury induced bone repair; the overlap in genes that are upregulated to those that are preferentially expressed in ESC; and the characterization of the temporal expression patterns of genes known to be associated with various skeletal dysplasia during fracture healing.Figure S1Comparison of Expression Profiles of Runx2 By Two Methods of Normalization. An example of the set of splice variants seen for the Runx2 is shown in Figure S1. These results are used to provide a demonstration of how copy number values can be extrapolated from the externally normalized expression values. A comparison of the temporal expression of the four unique Runx2 transcripts based on the normalization of the expression data to either day 0 no fracture or the in spike alien control is presented. These data demonstrate the differences in the expression profile data based on the two different approaches of expression normalization. As can be seen from the data in which the values were externally normalized to the alien control, the two mRNA transcripts expressed in cluster twenty one were quantitatively the most prevalent. Based on the oligonucleotide sequences and their position in the genomic sequence four separate model sequences for the Runx2 mRNA were predicted. The primary splice differences in the exon arrangements for this mRNA were seen in variations in the mid to 3 prime regions of the mRNA. Interestingly the model prediction for the expressed transcript seen in clusters 21 and 35 were similar. In contrast the predicted model structure for the mRNA seen in cluster 32 showed an alternate initiation site for the coding sequence. Top panel are expression values based on normalization to the in spike alien oligonucleotide. Bottom panel are expression values based on normalization to day 0 no fracture. The legend denotes the expression profile lines for each of the four unique oligonucleotides used to assess splice variants for the Runx2 gene.(0.04 MB PDF)Click here for additional data file.Table S1Identified Biological Ontologies Used To Define the General Percentages of Functional Activities Across Fracture Healing. Table S1 presents the individual biological processes that were grouped together for presentation in (0.08 MB XLS)Click here for additional data file.Table S2Identified Biological Ontologies Used To Define the Percentages of Functional Activities Seen in Commonly Expressed Genes Between Fracture Healing and Those that Are Preferentially Expressed in ESCs. Table S2 presents the individual biological processes that were grouped together for presentation in (0.08 MB XLS)Click here for additional data file.Table S3Tabular Summary of the Expressed Genes Across the Time Course of Fracture Healing. Expressed gene sets are arranged by numeric cluster from the CAGED analysis. Unigene number, short letter gene name and gene name are denoted. Two sets of values are presented: Log ratio intensity values based on normalization to Day 0 no fracture: Log ratio intensity values based on normalization to the in spike alien sequence control. The sequence of each oligonucleotide is presented for assessments of nature of splice variants. These data are broken down to identify the subsets that was filtered and used for the clustering analysis. The externally normalized expression values to the co spotted alien sequence can be used to extrapolate copy number of expressed genes in the bone tissues. Approximately \u223c10% of the gene descriptors in the array represent multiple splice variants that can be deduced from the nucleotide sequences (Table S3). The major biological themes that tracked with individual clusters may be identified by self examination of the clusters by assessments of the expressed genes in the cluster with DAVID. As one example, all of the major extracellular matrix proteins associated with cartilage tissue formation tracked in cluster one. Table S3A: Tabular list of those genes that were spotted on the array which met inclusion criteria for use in the cluster analysis. Table S3B: Tabular list of gene expression data that did not meet criteria for inclusion in the cluster analysis but which were shown to have met the criteria for measurable expression. Table S3C: Tabular list of those genes that were spotted on the array but which did not meet inclusion criteria for measurable expression.(8.49 MB XLS)Click here for additional data file.Table S4Expression Characteristics of Known Genes Associated With Skeletal Disorders During Fracture Healing (0.13 MB XLS)Click here for additional data file.Table S5Summary of the Expression of FGF Morphogenetic Family and Receptors Across the Time Course of Fracture Healing. The FGF morphogens and the FGF receptor are summarized based on clusters in which they are associated. Expressed genes are arranged by numeric cluster from the CAGED analysis. Unigene number, short letter gene name and gene name are denoted. Two sets of values are presented: Log ratio intensity values based on normalization to Day 0 no fracture: Log ratio intensity values based on normalization to the in spike alien sequence control. The sequence of each oligonucleotide is presented for assessments of nature of splice variants. Groupings of clusters are arranged by their temporal profiles in a similar manner as described for (0.03 MB XLS)Click here for additional data file.Table S6Tabular Summaries of the Expressed Genes across the Time Course of Fracture Healing Showing Overlap With Those Preferentially Expressed in ESC, Embryonic MSCs or Post Natal MSCs. The overlap of those genes showing differential expression during the time course of fracture healing to three published gene sets of those showing preferential expression in ESCs and MSCs (0.35 MB XLS)Click here for additional data file."} +{"text": "Eleven patients suffering from intra-abdominal malignancy were treated with various doses of intraperitoneal mitomycin C adsorbed onto activated carbon particles. Seven of the patients underwent resection of their primary gastric tumour and all developed potentially life-threatening severe complications that proved to be fatal in four patients. The pattern of complications seen in these patients was unusual in patients undergoing gastrectomy and must be presumed to be secondary to the intraperitoneal mitomycin C. Intraperitoneal mitomycin C at a dose of 25 mg and 50 mg in the presence of an anastomosis or other suture line does not appear to be safe."} +{"text": "The purpose of this study was to evaluate the significance of liver volumetry as a parameter for hepatic functional reserve in cirrhotic patients with hepatocellular carcinoma. Liver volume was calculated from preoperative computed tomograms of 44 cirrhotic patients who underwent elective hepatic resections for hepatocellular carcinoma. The liver volume per body weight of non-alcoholic cirrhotics was significantly smaller than that of alcoholic cirrhotics . The values for alcoholic cirrhotics was comparable with normal values. The liver volume per body weight of the cirrhotic patients demonstrated correlation with the preoperative serum albumin (p<0.01) and indocyanine green clearance (p=0.02). We conclude that the determination of hepatic atrophy by volume try can serve as a parameter for the assessment of hepatic reserve but not as a predictor of postoperative complications in elective liver surgery for cirrhotic patients."} +{"text": "The tumour response was essentially the same for both the single and fractionated dose schedules.The effects of one large single dose of 5-fluorouracil (FU) have been compared to the same amount given in divided doses daily over a 3- or 5-day period. Comparison of the effects of single There were marked increases in animal mortality from drug toxicity following fractionated doses of FU compared to one large single dose. Mortality in animals with Tumour 3924A increased from 10% following one large single dose to 60% for animals given daily fractionated doses for 3 days, and 80% for animals given daily fractionated doses for 5 days. Total marrow reserve was measured by the total DNA content of tibial marrow. The nadir of 6 days for loss of total tibial marrow DNA following one large dose of FU was increased to 9 days for both fractionated schedules of FU. The 3-day delay in recovery of the marrow prevented recovery within the time frame necessary for animal survival. The inference from these experimental cancer-treatment studies is that daily fractions of chemotherapeutic agents such as FU result in increased morbidity and mortality, without benefit in the control of the solid tumour. The results question the advisability of the clinical practice of initially giving small daily \u201cloading doses\u201d of proliferation-dependent agents such as FU.These results emphasize the need for more precise information on the temporal relationship between the response and recovery of the host and the response and recovery of the solid tumour. They also emphasize the need for a better clinical understanding of the time sequence of solid-tumour recovery in relation to the time sequence of marrow recovery."} +{"text": "The present study of the effect of heparin and dextran 1000 on the metastasis formation after i.v. tumour cell injection in dextran non-sensitive rats using a syngeneic 20-methylcholanthrene induced fibrosarcoma showed that heparin treatment decreased with formation of pulmonary metastases in animals both untreated and treated with dextran 1000. Treatment with dextran 1000 increased the formation of pulmonary metastases in animals both untreated and treated with heparin and the effect of dextran 1000 was thus not affected by heparin treatment. Heparin did not have any direct action on the tumour cells, which influenced metastasis formation. The data suggest that heparin acts as an anticoagulant with decreased microthrombus formation around lodged cells and that dextrax 1000 stimulates metastasis formation primarily by mechanisms other than intravascular coagulation."} +{"text": "We report the results of a case-control study of oral contraceptive use and breast cancer conducted in London, Oxford and Edinburgh between 1980 and 1984. One thousand one hundred and twenty-five women aged 16-64 years with newly diagnosed breast cancer and a like number of matched controls were interviewed and asked about their past due use of oral contraceptives (OCs). Among women aged 45 years or more at diagnosis there was no evidence of an association between OC use and breast cancer. Among the 351 pairs of women aged under 45 years at diagnosis there was a significantly elevated risk associated with increasing duration of use before first full term pregnancy . Since this result is at variance with the findings in some other studies we have investigated the nature of this association with particular emphasis on possible bias, pill type and a latent effect."} +{"text": "A sensitive single-stranded hybridisation probe for the oestrogen receptor mRNA was synthesised using T3 polymerase from oestrogen receptor cDNA cloned in the Bluescript vector. This probe was used to measure oestrogen receptor mRNA in total RNA extracted from breast tumours. Oestrogen receptor mRNA was detected in 41 of 47 (87%) tumours whereas cytosolic oestrogen receptor protein was detected in only 18 out of 39 (46%). There was a significant correlation between the levels of the oestrogen receptor, as measured by 3H-oestradiol binding, and the oestrogen receptor mRNA. Oestrogen receptor mRNA was detected in 15 of the 21 tumours that did not contain detectable oestrogen receptor protein. This suggests that detection of the mRNA is a more sensitive means for establishing oestrogen receptor status than the radioligand oestrogen receptor assay. Oestrogen receptor mRNA was found in all histological tumour types examined. Its level was related to tumour differentiation. All the tumours that did not contain oestrogen receptor mRNA and most of the tumours that contained only low levels of oestrogen receptor mRNA were classified as grade III according to Bloom and Richardson: the median of the oestrogen receptor mRNA levels was significantly lower in this group."} +{"text": "The present study was carried out to determine the variation in DNA content between multiple fine needle aspirates (FNA) of the same tumour from patients with breast cancer. Analysis of different aliquots of the same FNA showed good reproducibility in terms of cell cycle distribution and DNA index. Duplicate FNAs taken from different sites in nine of 11 excised tumours showed similar reproducibility. However, two of the aneuploid tumours displayed substantial variations in the distribution of cell populations between the duplicate samples. Sequential FNAs with no intervening therapy were obtained from the same tumour in 17 patients; one at the time of diagnosis and the other at biopsy 1-3 weeks later. Only five cases showed no variation between the sequential FNAs; the remaining 12 displayed different DNA profiles. A further 13 patients were studied before and during systemic therapy. While there was no variation between sequential FNAs in four patients, marked differences in the DNA profile were observed in the remaining nine patients undergoing treatment, the changes not necessarily being associated with clinical response to therapy. It is concluded that the monitoring of cellular changes by DNA analysis of sequential FNAs may be complex and subject to problems associated with heterogenecity."} +{"text": "In vivo study of various plant parts extracts of Morinda morindiodes (Bak.) was conducted to evaluate their antiplasmodial properties and effects on the liver using chloroquine sensitive Plasmodium berghei in mice. Water extract of the root was observed to significantly reduce parasitaemia compared to the activities of other plant parts and the untreated control. A mean survival time of 19 days observed in the root extract supported its antiplasmodial activities compared with other plant parts. The antiplasmodial activities of the plant extracts when administered twice daily were not significantly different (P > 0.05) compared with those treated once daily. The chemosuppression produced by the extracts were significantly different compared to untreated control. Liver function tests (LFT) of uninfected mice administered with the plant extracts showed that extracts of the leaf and stem in 'fermented maize starch extract' altered the function of the liver significantly compared to normal mice. This study shows that Morinda morindiodes possess antimalarial properties and the root may be used as a prophylaxis where western medicine is not easily accessible and affordable. Tables 4"} +{"text": "Results of the functional assays have been compared with direct sequencing of all 11 exons of the p53 gene. The results show good agreement between the two functional assays and between them and sequencing. No false-positives or negatives were seen with either functional assay although the apoptotic assay gave one borderline result for an individual without a mutation. As an initial screen the apoptotic assay is not only rapid but inexpensive and very simple to perform. It would be expected to detect any germline defect that leads to loss of p53 function. The apoptotic assay could be ideal as a means of prescreening large numbers of samples and identifying those that require further investigation. The FASAY detects mutations in exons 4\u201310, is rapid and distinguishes between functionally important and silent mutations. \u00a9 2000 Cancer Research CampaignWe have tested two rapid assays of p53 function, namely the apoptotic assay and the FASAY as means of detecting germline"} +{"text": "Dear Editor,et al. on nuclear management with Blumenthal technique[I read with interest the article by Malik technique and in tBlumenthal had elegantly described the use of anterior chamber maintainer in extracapsular cataract extraction and manual small-incision cataract surgery (SICS).\u20134 In theBlumenthal has described use of smooth round-tipped Blumenthal cannula for hydrodissection which is very different from the conventional sharp-tipped hydrodissection cannula. The original hydrodissection technique described by Blumenthal entails the hydrodissection of superior 12 o'clock pole through side port incision by Blumenthal cannula followed by supplemented hydrodissection at 3 o'clock and 9 o'clock pole which facilitates superior pole of the nucleus to pop out of the bag which is subsequently pushed out into the anterior chamber followed by maneuvering out the remaining nucleus with the help of the Blumenthal canula only. At no step is the use of viscoelastic agent advocated.[Similarly, during removal of the cortex Blumenthal has again described the use of single-port cannula along with anterior chamber maintainer and has not advocated use of viscoelastic agent. The diagrammatic representation showing the frown incision in Fig. 1 is also not described by Blumenthal, he has advocated the use of straight incision of maximum size 5 mm with back cuts on either side of straight incision of length up to 1.5 mm, with 100-110 degrees angulation with straight incision, and further dissection of the tunnel under anterior chamber maintainer only without using viscoelastic agent.I have been practicing and teaching the original Blumenthal technique since the last six years and have been fairly successful in using the originally described Blumenthal technique."} +{"text": "Since August 1989, we have seen 4 patients with leukoplakia of the renal pelvis associated with a longstanding renal stone. In 2 of them, excretory or retrograde pyelography revealed multiple filling defects in the left renal pelvis as well as a renal stone, although urine cytological examination was negative. One of the other 2 patients underwent extracorporeal shock wave lithotripsy (ESWL) for the renal stone, but this was not followed by the passage of stone fragments. The renal stone in the remaining patient was associated with staghorn calculi. For stone extraction as well as endoscopic evaluation of the intrapelvic lesion, percutaneous nephroscopy was performed. A small to large amount of tissue-like white debris in sheets characteristic of leukoplakia was found in the renal pelvis with stones embedded in it and was removed directly by forceps or suction and then by irrigating with saline. We propose that 1) the endourological approach should be recommended for patients with renal pelvic lesions associated with longstanding renal stones or for patients who show difficulty in passing stone fragments after ESWL and 2) this entity of leukoplakia should be kept in mind for the differential diagnosis of renal pelvic lesions associated with renal stones."} +{"text": "The need for a multiple-target compound selectivity programme led to the establishment of a single robotic system that produces a compound's serial dilution and its distribution to multiple replicate assay plates. A Genesis RSP 150 integrated into a Zymate Laboratory Automation System XP produced the serial dilutions, and the subsequent replicate assay plates were produced quickly and accurately by an efficient use of the carousels and rapid plate. Currently, this process allows for the production of over 200 serial dilution assay plates in a workday."} +{"text": "Serum-free supernatants from in vitro maintained gastrointestinal cancer and melanoma cell lines inhibit the generation of lymphokine (IL-2) activated killer (LAK) cells in a time and dose-related manner. Concentrations as low as 5% can inhibit the generation of LAK cytotoxicity but inhibition of proliferation is not observed until higher concentrations are included in the culture system. Inhibition is not observed with supernatants from a breast cancer cell line nor with supernatants from normal cells. There was complete concordance between the capacity of the tumour cells themselves to inhibit LAK generation and the presence of inhibitory activity in the corresponding supernatant. The inhibitory factor(s) is stable after heating to 44 and 56 degrees C. Production of the inhibitory factor(s) is sensitive to metabolic inhibitors and has a molecular weight greater than 25 kD. The inhibition of LAK cell stimulation by tumour cells may partially explain the failure of adoptively transferred LAK cells and IL-2 therapy to cause tumour regression in man."} +{"text": "Chromosomal loss is a characteristic feature of the myelodysplastic syndromes (MDS). A method is described which detects chromosomal 7 loss in MDS by DNA analysis using a specific hypervariable region gene probe which has been cloned from a human DNA fingerprint. Loss of one of the chromosomal 7 homologues was demonstrated in 10/118 MDS patients; the ten patients include all the five patients which had previously been shown to have monosomy 7 by cytogenetic analysis. This technique makes it feasible to study serial samples from large numbers of patients for loss of chromosomal material and could be readily applied to the study of other human malignancies."} +{"text": "Trans acting loci are much harder to detect than cis acting loci and their effects are much more sensitive to genetic background.Differences in gene expression may be caused by nearby DNA polymorphisms for differential expression, whereas trans regulated genes were associated with values 0.005 < p < 0.05. The genes differentially expressed between congenics and controls were not a subset of those that were differentially expressed between the founder lines, showing that these were dependent on genetic background. For example, the cholesterol synthesis pathway was strongly differentially expressed in the congenic mice by indirect trans regulation but this was not observable in the parental mice.To quantify trans and strongly influenced by genetic background, suggests that pathways that are modified by an allelic variant, may only exhibit differential expression in the specific genetic backgrounds in which they were identified. This has significant implications for the interpretation of any QTL mapping study.The evidence that most gene regulation is There is a trivial sense in which all genes are expected to be both trans regulated by multiple transcription factors and cis regulated by transcription factor binding sites and this has been confirmed experimentally in yeast [cis and trans regulation is only useful when the gene is differentially expressed between two conditions; then we can ask whether that difference is due to differences in the transcription factor binding region (cis regulated) or due to differences in structure or abundance of transcription factors (trans regulated) or both.There is considerable interest in discovering polymorphic loci that regulate differences in gene expression since this information can help us understand not only how genes are regulated but also how they interact. Genetic polymorphisms may regulate genes that are physically close to them on the chromosome (in yeast . Howevercis and trans acting genes is to use gene expression as a phenotype and to map associations between thousands of markers and the expression of thousands of genes in hundreds of samples to discover expression quantative trait loci (eQTL) [cis regulatory loci since it is only necessary to test a few markers around each gene, but its statistical power to detect trans regulatory loci is limited by the large multiple testing correction that is required when correlating the genotype of thousands of genome wide markers with the expression of thousands of genes. The proportions of trans regulated genes discovered in these studies vary widely depending on the significance threshold used. Furthermore it has been argued that polymorphisms in transcription factors that cause extensive phenotypic effects are likely to be rare and rapidly purged from populations [trans regulators that effect multiple genes might have small individual effects making them hard to detect by genetic mapping and give the misleading impression that cis regulation is the dominant form. These problems make eQTL studies an unsatisfactory platform for discovering the relative contributions of cis and trans regulation to the observed differences in gene expression.One strategy for the discovery of i (eQTL) ,3. This ulations ,5. Conseulations ,6. Therecis effects to differential expression. Importantly this strategy also makes it possible to objectively identify a threshold p value at which there is a significant association between haplotype differences and gene expression. This value can then be used to quantify the contribution of cis regulation to differential regulation.The availability of data for 8 million single nucleotide polymorphisms (SNP) in inbred mouse strains has been used to construct a comprehensive haplotype map of the mouse genome . This matrans regulation independently using expression data from a panel of congenic mice and their controls that had been developed for other purposes. Since congenic mice have a small region of donor genome introgressed into the host genome, any differential expression that is outside the introgressed congenic region can be assumed to be trans regulated by that region, permitting a direct estimate of the proportion of trans regulated genes. These trans regulated genes were highly enriched for cholesterol synthesis genes. This suggested that the congenic region was altering cholesterol flux and this in turn was causing changes in cholesterol gene transcription a process we call indirect trans regulation. Indirect trans regulation is likely to be even more sensitive to environmental and genetic effects than direct trans regulation by a transcription factor. It is therefore important to be aware of the extent of this effect.We estimated the contribution of 2 difference in expression > 0.5 and a pplr less than the value indicated in the text . The expression ratio and pplr for all relevant comparisons, together with the number of upstream SNP and the assigned haplotype is shown in Additional File Gene expression data were obtained for the parental and congenic lines for a total of 12 conditions . Furthermore 49% more genes were over-expressed in A/J than C57BL/6; the opposite direction to any effect that would be expected to be caused by SNP modifying expression. Consequently the data could be used with confidence that observations were not a simple consequence of SNP causing expression differences . This provided persuasive evidence that low pplr values are associated with haplotype differences.The \u03c7cis regulated may be reflected by the excess of those genes that are both differentially expressed and on different haplotypes over the number that would be expected to be on different haplotypes by chance. In the parental mice 30% of all genes were on different haplotypes in the two strains, but 55% of genes that were differentially expressed in at least one tissue were also on different haplotypes . Applying Bayes theorem shows that approximately 36% of genes that are differentially expressed in any one tissue can be attributed to haplotype difference and hence putatively cis-regulated of genes that were differentially expressed in at least one tissue and on different haplotypes (putatively cis regulated) were differentially expressed in all three tissues, whereas only 7/214 (3%) of genes that were differentially expressed in at least one tissue and on the same haplotype (putatively trans regulated), were differentially expressed in all three tissues . This suggests that cis effects were five times less sensitive to tissue environment than trans regulated genes.Genes that were potentially The number of genes that were differentially expressed in each condition or in relevant combinations of conditions are summarised in figure trans effect of genes within the congenic interval on genes outside the interval is not detectable in the parental mice. Microarray studies to detect pathways that cause the difference in phenotype between strains are based on the assumption that the difference in expression of those pathways will be substantial enough to be observable. In this case there was no observable difference in the parental strains in any of the pathways that were regulated by the QTL in the congenics and therefore expression data from the parental strains may not be a reliable resource for identifying the pathways that regulate the phenotype.Surprisingly however, there was relatively little overlap between the sets of genes that were differentially expressed in the congenic strains and in the parental strains from which they were derived Fig. . In the trans regulated. In the congenic liver in the liver between Tir1CC and Tir1AA mice but no difference in this pathway was observed between the parental or the Tir3NN strains differentially expressed genes were outside the congenic interval and therefore putatively ver Fig. 41/48 . This was interpreted as evidence that the variance of expression of cis regulated genes is much lower than that of trans regulated genes. Although the 1 kb upstream region may contain the highest density of regulatory elements it does not contain all of them, they can be spread throughout the gene and its 3' region as well as going tens to hundreds of kilobases upstream. Therefore we are likely to have underestimated the numbers of cis regulated genes using this strategy. However SNP in the upstream region will frequently be markers for larger haplotypes that extend into or through the whole gene region so these regions will not have been completely excluded from the analysis. By selecting the region with the highest density of regulatory elements we have maximised our power to detect an association between SNP and gene expression, which would have been more difficult in the presence of higher proportions of non-functional SNP distributed through the rest of the gene region.The availability of high-density genotype data for mice has made it possible to quantify the relationship between haplotype structure and differential gene expression. A relationship between SNP in the 1 kb upstream region and differential expression was only observable when using a stringent test of differential expression by changing the rate of absorption or excretion from cells or the body. There are at least two genes in the Tir1 region that are directly involved in cholesterol metabolism but cho as well ,24, any indirect trans regulation to distinguish it from direct trans regulation of a target gene by a transcription factor. Cholesterol synthesis is a particularly well-known example of indirect trans regulation [We describe this mechanism of regulation by multiple intermediates such as metabolites as gulation .trans regulated genes goes well beyond the lack of statistical power of eQTL studies for this purpose. Expression differences in cis regulated genes were found to have lower variances than those of trans regulated genes in this study, and several eQTL studies have found that cis regulated differences in transcription are larger than trans regulated differences [trans regulated genes are likely to have a much larger number of intermediates involved in their effect on expression. Firstly there is usually a complex of gene products and metabolites that bind to a given regulatory factor binding site, eg a mean of 3.1 loci have been found to regulate each trans regulated gene in radiation hybrid cells [trans acting eQTL were not enriched for transcription factors and that a wide range of gene classes could cause trans differences in expression [indirect rather than direct (transcription factor mediated) trans effects. Each interaction in the regulatory cascade is likely to introduce an element of noise and hence the effect of a trans acting regulatory factor polymorphism on gene expression is likely to have much higher variance than a cis polymorphism. Therefore indirect trans regulation is likely to have even larger variance than direct trans regulation. These higher variances will make trans regulated differences in expression between conditions much harder to detect than cis regulated differences and indirect trans harder than direct trans. We do not know the proportion of genes that were indirectly trans regulated in the congenic mice; there are several zinc finger proteins with unknown targets in the congenic region that might be direct trans regulators. Indirect trans regulation relationships are likely to be less well known because they are more complex and harder to discover experimentally by methods such as chromatin immunoprecipitation. But if the cholesterol synthesis pathway is representative of the main mode of trans regulation in the congenic mice, most regulation was indirect.Almost completely different sets of genes were found to be differentially expressed between the congenic mice and their controls and between the parental inbred mice, as has been observed before . This suferences . This isid cells . Secondltrans regulated expression to experimental conditions than cis regulated genes may make it even harder to detect those genes that are subject to both polymorphic trans and cis factors. Since the penetrance of the cis acting factors is usually likely to be higher than the trans factors only the strongest trans effects will be observable in the presence of concurrent cis effects.The greater sensitivity of trans regulated genes is important because their regulation appeared to be less stable under different conditions and consequently gene expression based approaches to the discovery of genes regulating a phenotype are likely to be exquisitely sensitive to the particular experimental conditions used. There was almost no overlap between genes that were differentially expressed between congenics and controls and outside the congenic regions, and genes that were differentially expressed between the parental inbred mice strains, even when comparing the same tissue, and this is consistent with previous observations [trans regulation of gene expression is highly context dependent; the context in this case being genetic background. A study of recombinant inbred strains of mice estimated that 1500 genes differed between conditions and 1200 were sensitive to genetic background and hence presumably trans regulated [The large proportion of rvations . This inegulated . The senegulated .Daxx) in the Tir1 QTL region that is not differentially expressed, but was subsequently found to have an amino acid indel, on the basis of its membership of a differentially expressed KEGG pathway in the parental strains [The sensitivity of both expression and phenotype to genetic background has profound implications for the interpretation of expression data for a range of purposes. For example, the use of expression arrays is a common strategy for following-up QTL mapping studies with the objective of identifying the genetic polymorphism underlying a QTL. Gene expression is typically measured in the parental lines that are used to generate the mapping populations in order to infer the genes regulated by the QTL. The candidate quantative trait gene(s) (QTG) causing the phenotypic difference may be identified because they are differentially expressed in at least one tissue. Candidate genes can be selected from these long lists by identifying those that participate in networks that are differentially expressed and that intersect with the QTL region. We have previously identified a candidate gene , presumably because the close coupling of the polymorphic regulatory region to the gene leads to much lower variances in expression. There was a ratio of approximately 2:1 of trans:cis regulated genes and the cis regulated genes were more likely to be differentially expressed in multiple tissues than trans regulated genes. The fact that genes that are regulated by a congenic region were not observably regulated in the parental mice, means that expression studies in the parents of a mapping population are unlikely to detect many of the trans regulated expression differences caused by the QTL genes. This will make it much harder to identify the pathways regulated by a QTL. The Tir1 region of chromosome 17 regulated the cholesterol synthesis pathway, but this was probably because this region modifies cholesterol flux and not because it contains transcription factors that regulate cholesterol metabolism. This mode of indirect trans regulation may be the most common form of gene regulation but also the hardest to detect except in well defined genetic backgrounds such as congenic mice. Consequently only the cis and largest direct trans regulatory relationships will be amenable to discovery and the large fraction of indirect trans regulation will be missed by most high throughput experimental strategies.We have found that post mortem animals that had not been subject to any prior treatment.All mouse work was conducted at the International Livestock Research Institute in Nairobi and approved by their Internal Animal Care and Use Committee. In the UK no project licence would be required for the procedures described here since they were all conducted on Tir1 and Tir3 QTL for Trypanosoma infection response [Trypanosoma infection response (Tir) loci; Tir1 and Tir3 on chromosomes 17 and 1, respectively. The progeny at each backcross generation were genotyped with microsatellite markers defining the genetic intervals containing the QTL using the following markers: D17Mit29, D17Mit16 and D17Mit11 (Tir1); D1Mit60, D1Mit217 and D1Mit87 (Tir3). At the seventh generation of backcrossing each line was typed with a series of markers at approximately 2 cM intervals flanking the Tir loci. The individuals with the shortest donor haplotype extending beyond the QTL interval were used for breeding the next generation by intercrossing a single heterozygous male with full or half sib female carriers of the C57BL/6 donor region. The progeny of these were genotyped and those individuals homozygous for the alternative haplotypes were used as founders to propagate each line, which were denoted either TirnAA or TirnCC for homozygotes at the QTL for recipient A/J haplotype and the donor C57BL/6 haplotype, respectively. Thus in total 4 lines were produced; these are Tir1AA and Tir1CC; Tir3AA and Tir3CC. The Tir1CC line is homozygous for a C57BL/6 haplotype spanning 10 cM interval between marker D17Mit84 and D17Mit177 on Mmu17. Tir3CC individuals have a C57BL/6 haplotype spanning approximately 10 cM between markers D1Mit49 and D1Mit139 on Mmu1.Two congenic lines were created to cover the response ,9 as preresponse . Two conTir1 and A.B6-Tir3. However there is no recommended nomenclature for the control lines, so for clarity the TirnAA and TirnCC style will be used in the following description.The recommended names for the test lines according to the Mouse Genome Informatics would be A.B6-The use of controls derived from the same line as the congenic mice is critical since even the small amount (<1%) of non target C57BL/6 remaining can have profound non-specific effects on phenotype through heterosis. The homozygous congenic mice lines were genotyped at the Wellcome Trust Clinical Research Facility, Edinburgh, UK using the Illumina Mouse Medium Density Linkage Panel on an Illumina BeadStation 500 instrument, with the Illumina 1536 murine SNP panel. 959 markers were informative between A/J and C57BL/6 with a mean spacing of 2.61 Mb. Using this data it was possible to identify the approximate boundaries of the introgressed regions and also to identify non-target regions of C57BL/6 origin that had also been carried through into the congenic lines.trans effects from these loci, however since they were present but not fixed in both test and control mice we would have had very low power to detect trans effects from the non-target loci, therefore we have disregarded possible effects from these loci in the subsequent discussion.This showed that Tir1CC congenic mice carried a region of C57BL/6 between 26.0-43.9 Mb (NCBI36) on Mmu17 in the A/J background, this region includes the major histocompatibility complex (MHC). The Tir3CC mice carried a region of C57BL/6 origin between 93.3-123.6 Mb on Mmu1. The SNP genotyping data showed that approximately 0.75% of the genome outside the congenic regions was of C57BL/6 origin in both TirNAA and TirNCC mice . The nonThe initial cross and the first three backcrosses were reciprocal between the sexes, the fourth backcross was of congenic females to A/J males to eliminate residual C57BL/6 Y chromosomes. Subsequent backcrosses were of a single congenic male to multiple A/J females. The Y chromosome was not assayed in the SNP genotyping so the Y chromosome genotype has not been independently verified.Trypanosoma congolense [ad libitum for 4 weeks to acclimatise before killing. Tissues for hybridisation were selected iteratively and different sets of tissues were hybridised for each pair of strains and further purified on RNAeasy columns (Qiagen). RNA was quantified and checked for integrity on an Agilent Bioanlyser and extractions were repeated for any degraded samples. The samples were then mixed into four or five pools of five samples for each strain, most pools comprised of samples of a single sex. The pooling strategy that we used is predicted to give the same power to detect differential expression as over fifteen individual samples hybridised separately . Sex waspplr as a confidence value, for ease of comparison and ranking of genes such that a value close to zero indicates significant confidence in differential expression. PPLR makes use of the probe-level measurement error across replicated experiments and may be most appropriate where there are a variable number of probes per probeset, as is the case with probesets obtained from AffyProbeMiner. The data is available through ArrayExpress under accession numbers E-MEXP-1190 for the parental strains and E-TABM-865 for the congenic strains.Chips were initially assessed using DChip criteria and PCA to screen for outliers. Data from outlier chips were discarded and hybridisations were repeated with the same or fresh RNA samples from the same batch of mice until complete sets of chips for each condition were obtained. Sets of 25 mer probes for each gene represented on the array were identified using AffyProbeMiner . Normali2 fold difference between strains >0.5 and pplr values for a difference in expression below the thresholds indicated in the text.The Perlegen SNP dataset was downBoundaries of haplotypes identified within the Perlegen SNP data set were downloaded from the UCLA Perlegen Mouse SNP Browser Mouse, strainsBayes theorem was used to estimate the proportion of differentially expressed genes that were putatively differentially expressed because of difference in haplotype.h/E) \u00d7 (Nhd/Nh))/( Gd/E)) where Nh is the number of differentially expressed genes for which haplotype data was available; Nhd is the number of differentially expressed genes on different haplotypes; Gd Number of genes for which C57BL/6 and A/J have different haplotypes; E is the Number of Ensembl genes with haplotype data. Values for each variable and condition are shown in Additional File Bayes Theorem: ((NPathways that were overrepresented amongst the differentially expressed genes were identified using KEGG, DAVID and GeneGO and are shown in Additional File eQTL: expression quantative trait locus; KEGG: Kyoto Encyclopaedia of Genes and Genomes.HN did the SNP analysis and drafted the manuscript; MA managed experimental work on the mice; SA managed microarray work; AA participated in study design and supervised microarray work; AB analysed microarray data and interpreted the analyses; JG designed mouse breeding and supervised mouse work; LH did microarray hybridisations and quality control; HH analysed microarray data, SJO data interpretation, SJK conceived of the study, interpreted data, redrafted manuscript, supervised study. All authors read and approved the final manuscript.pplr values for all conditions for all genes with numbers of upstream SNP and Haplotype block assignment for A/JExpression ratios and .Click here for fileCounts of SNP under each probeset and calculations of their effect on observed expression differences.Click here for fileNumbers genes with each number of SNP in their upstream region and the correlation with expression differences.Click here for fileCalculations of number of differentially expressed genes attributable to haplotype differences.Click here for fileGO and KEGG classifications of differentially expressed genes.Click here for fileDescription of how allele numbers were assigned to haplotype blocks.Click here for fileAllele assigned to each strain at each haplotype block.Click here for file"} +{"text": "A case of Cholangitis Glandularis Proliferans (CAGP) in association with a cholangiocarcinoma of thecommon bile duct as described. This is the eighth case of CAGP described and the second associationwith cholangiocarcinoma."} +{"text": "A recent flurry of publications and media attention has revived interest in the question of how many genes exist in the human genome. Here, I review the estimates and use genomic sequence data from human chromosomes 21 and 22 to establish my own prediction."} +{"text": "Some clinical studies involving several histological types of cancer have suggested that high vascular density in the primary tumour promotes metastasis. Other studies have suggested that a high incidence of metastases is associated with low oxygen tension in the primary tumour. The purpose of the study reported here was to search for correlations between incidence of metastases and oxygen tension or vascular density in the same population of patients. Thirty-eight consecutive patients with squamous cell carcinoma of the uterine cervix were included in a prospective study. Pelvic, iliac and retroperitoneal lymph node metastases were detected by magnetic resonance imaging at the time of initial diagnosis. Oxygen tension was measured polarographically using the Eppendorf pO2 Histograph 6650. Vascular density was determined by histological examination of tumour biopsies. The primary tumours of the patients with metastases (n = 19) were more poorly oxygenated than those of the patients without metastases (n = 19). Thus, the fractions of the pO2 readings resulting in values below 5 mmHg and 10 mmHg were significantly higher for the former group of patients than for the latter (P = 0.03 and 0.02 respectively). In contrast, the vascular density of the primary tumour was not significantly different for the two groups of patients. The present study suggests that a high incidence of metastases in squamous cell carcinoma of the uterine cervix is associated with poor oxygenation of the primary tumour and not with a high vascular density."} +{"text": "Electron spin resonance (ESR) studies were made on frozen samples of 7,12 dimethylbenzanthracene (DMBA)-induced rat breast tumours both before and after lyophilization. The primary purpose of these studies was to determine the relationship between ESR spectra under these two conditions and thereby hopefully resolve an apparent conflict as to the experimental findings and clinical implications of these findings. In contrast to the other system which we studied by a similar method, in the DMBA-induced tumours we found a close parallel between the ESR spectra before and after lyophilization. In both cases free-radical levels were elevated about two-fold in all tumours and showed little dependence on the age of the tumour. Studies of blood and liver before the development of tumours showed no change in free radicals levels in either nonlyophilized or lyophilized samples. In animals with tumours, the level of free radicals in the liver increased approximately 17%. Manganese (2+) levels were increased in breast tumours but the changes did not closely follow those of free radicals and were much more variable in the lyophilized samples. We conclude that: (1) there seems to be no general relationship between ESR spectra of tumours before and after lyophilization; (2) there appears to be no general pattern of ESR changes in lyophilized samples of tumours."} +{"text": "Of 193 CBA mice kept under prolonged observation after excision of small intradermal transplants of a non-immunogenic tumour (CBA Carcinoma NT), 27 (14%) presented with local recurrence, 19 (10%) with regional lymphnodal metastasis (RNM) and 72 (37%), with pulmonary metastasis +/- other systemic metastases. When mice were exposed to sublethal whole-body irradiation (WBI) before tumour transplantation, the incidence of RNM rose to approximately 80% and the latent period was reduced from approximately 60 days to approximately 40 days after tumour transplantation. This enhancement of RNM by WBI was undiminished when the interval between WBI and tumour transplantation was increased from 1 to 90 days. An explanation for this effect in terms of immunosuppression by the WBI is unlikely for the following reasons: the tumour was non-immunogenic by standard quantitative tests; the effect persisted long after the expected time for recovery of immune reactivity; and i.v. injection of normal marrow and lymphoid cells after WBI failed to reduce the effect. That the effect was systemic was proved by failure of local pre-irradiation of the tumour bed or regional node to enhance RNM. The effect was not observed when WBI was given 4 days after excision of tumours. These and other experiments failed to indicate the mechanism of the effect of WBI, but its long persistence suggests that it may relate to stored lethal radiation damage in migrating cells of slow turnover tissues."} +{"text": "A library of six characteristic spectra served to scan the cells and reconstruct new images depicting the nuclear area occupied by each spectrum. Fifteen cases of infiltrating ductal carcinoma and six cases of lobular carcinoma were examined; nine of the infiltrating ductal carcinoma and three of the lobular carcinoma showed an in situ component. The spectral morphometric analysis revealed a correlation between specific patterns of spectra and different groups of breast carcinoma cells. The most consistent result was that lobular carcinoma cells of in situ and infiltrating components from all patients showed a similar spectral pattern, whereas ductal carcinoma cells displayed spectral variety. Comparison of the in situ and the infiltrating ductal solid, cribriform and comedo carcinoma cells from the same patient revealed a strong similarity of the spectral elements and their relative distribution in the nucleus. The spectrum designated as number 5 in the library incorporated more than 40% of the nuclear area in 74.08% of the infiltrating lobular cells and in 13.64% of the infiltrating ductal carcinoma cells (P < 0.001). Spectrum number 2 appeared in all infiltrating ductal cells examined and in none of the lobular cells. These results indicate that spectrum number 5 is related to infiltrating lobular carcinoma, whereas spectrum number 2 is characteristic for infiltrating ductal carcinoma cells. Spectral similarity mapping of central necrotic regions of comedo type in situ carcinoma revealed nuclear fragmentation into defined segments composed of highly condensed chromatin. We conclude that the spectral morphometric features found for lobular and ductal cell populations may serve future automated histological diagnostics. \u00a9 1999 Cancer Research CampaignThe spectral morphometric characteristics of standard haematoxylin and eosin breast carcinoma specimens were evaluated by light microscopy combined with a spectral imaging system. Light intensity at each wavelength in the range of 450\u2013800 nm was recorded for 10"} +{"text": "Despite encouraging results from recent studies, there is still no consensus to undertake mass screening using the Haemoccult test in the general population. The success of mass screening for colorectal cancer depends among other things on Haemoccult test properties. In on-going screening programmes, the Haemoccult test consists of six slides and a test is considered positive if at least one slide is coloured. The aim of this work was to study the influence of the type and number of positive slides on the Haemoccult test's positive predictive value and characteristics of screened lesions. This work focuses on 63,958 first tests in a mass screening programme in Calvados (France) among people aged 45-74 years. There was a linear relation between the positive predictive value for cancer or an adenoma larger than 1 cm and the number of positive slides (P < 10(-4)). The positive predictive value for cancer or large adenoma was significantly higher when 4-6 slides were positive (44.3%) than when only 1-3 were positive (19.1%) (P < 10(-4)). In this latter group, the subjects in whom tumours were detected were younger and had significantly less extensive cancers. Borderline tests (no slides positive and at least one slide with a blue coloration confined to the edges) had a positive predictive value for cancer or an adenoma larger than 1 cm no different to that of tests with 1-3 positive slides. Subjects with borderline results were markedly younger than the others and had less extensive cancers and rectal localisation more often than the others. Our results suggest that (1) increasing the number of positive slides required to declare a test positive leads to an increase in the positive predictive value but is not to be recommended because of the sensitivity of the test and (2) considering borderline Haemoccult tests as positive in on-going and future mass screening campaigns would allow an increase in the sensitivity of the test, especially for rectal cancer and low extensive tumours without any decrease in its positive predictive value."} +{"text": "The acetylator phenotype was determined in 100 patients with breast cancer and 100 control female subjects using isoniazid. The proportion of fast acetylators in the breast cancer patients (43%) was not significantly different from the control group (43%). We conclude that acetylator phenotype is unlikely to be an important determinant of the risk of developing breast cancer."} +{"text": "In 1993 we became aware of a worrying increase in apparent errors in the histopathological diagnosis of musculoskeletaltumours in our Unit. As a result all cases seen over the past 8 years were reviewed by an independent panel. Of the 1996cases reviewed there was an error in 87. In 54 cases (2.7%) this had led to some significant change in the active managementof the patient. The main areas where errors arose were in those very cases where clinical and radiological features were nothelpful in confirming or refuting the diagnosis. The incidence of errors rose with the passage of time, possibly related to adeterioration in the pathologist\u2019s health. The error rate in diagnosing bone tumours in previously published series rangesfrom 9 to 40%. To ensure as accurate a rate of diagnosis as possible multidisciplinary working and regular audit are essential."} +{"text": "The patterns of early and late relapses (those occurring later than 3 years after diagnosis) in 432 patients achieving complete remission after treatment for stage I and II Hodgkin's disease at the Royal Marsden Hospital between 1964 and 1983 were studied to identify factors predicting for late relapse. The incidence of early relapse has fallen progressively in recent treatment eras as staging procedures and management have improved but in contrast there has been no decrease in the risk of late relapse. The incidence of late relapse was greater in patients treated with radiotherapy rather than combined modality therapy (P less than 0.05). However, patients who were clinically staged and treated with combined modality therapy retained as high a risk of relapse between 3 and 6 years as in years 2 and 3. The risk of late relapse was also greater in patients with stage II disease and in those without B symptoms at presentation. Patients falling into the higher risk categories for late relapse require continued close follow-up beyond 3 years to monitor for possible relapse."} +{"text": "Twenty patients with ultrasonographic or computed tomographic diagnosis of pancreatic pseudocyst werereferred for endoscopic retrograde cholangiopancreatography (ERCP). Two of these were found atlaparotomy not to have pseudocysts and were excluded. Pancreatography was successful in 15 out of 18cases (83%) and cholangiography in 12 out of 18 cases (67%). Three types of pseudocysts were noticedaccording to the communication of the pseudocyst to the main pancreatic duct and the presence ofpancreatic duct stensosis. Successful treatment included two spontaneous resolutions, two internaldrainages and three left pancreatic resections. In the eight percutaneous external drainages fourrecurrences (50%) occurred, one after closure of temporary pancreatocutaneous fistula. All therecurrences occurred in Type III pseudocysts with communication of the pseudocysts to stenotic mainpancreatic duct. In these cases internal drainage would have been the preferable treatment method. Webelieve that by ERCP one can identify pseudocysts not suitable for external drainage."} +{"text": "Since publication of our article , we haveIn Figure 2 (Figure In addition in Figure 7 Figure 1]..1].These errors inadvertently occurred during the preparation of these figures from the images of the fluorescent microscope. We sincerely apologize for the error and any inconvenience or confusion it may have caused."} +{"text": "A central component of type 2 diabetes and the metabolicsyndrome is insulin resistance. Insulin exerts a multifacetedand highly integrated series of actions via its intracellularsignaling systems. Generation of mice carrying null mutationsof the genes encoding proteins in the insulin signalingpathway provides a unique approach to determining therole of individual proteins in the molecular mechanism ofinsulin action and the pathogenesis of insulin resistance anddiabetes. The role of the four major insulin receptor substrates(IRS1-4) in insulin and IGF-1 signaling have beenexamined by creating mice with targeted gene knockouts.Each produces a unique phenotype, indicating the complementaryrole of these signaling components. Combined heterozygousdefects often produce synergistic or epistatic effects,although the final severity of the phenotype dependson the genetic background of the mice. Conditional knockoutsof the insulin receptor have also been created using theCre-lox system. These tissue specific knockouts have provideunique insights into the control of glucose homeostasisand the pathogenesis of type 2 diabetes, and have led to developmentof new hypotheses about the nature of the insulinaction and development of diabetes."} +{"text": "A polyurethane intraurethral catheter (IUC) was used in 27 patients with benign prostatic hypertrophy who were unfit for surgery, or were awaiting surgery. All of them had previously had a periurethral catheter inserted. The IUC was inserted with a cystoscope under fluoroscopic control. Spontaneous voiding through the IUC resumed in 25 patients (93%) in the immediate postprocedure period. At the end of 6 months follow-up, the peak flow rates and the residual volumes estimated in 22 patients were satisfactory. Immediate complications included incontinence due to distal displacement in 2 patients and hematuria in one patient; long-term complications included mild encrustation of the IUC in 2 patients and calculus formation on the IUC in 1 patient. None of the patients had clinically significant urinary tract infection. The presence of the IUC did not compromise the subsequent transurethral resection of the prostate gland. We recommend the use of an IUC for up to 6 months in patients with urinary retention who are awaiting surgery or are unfit for surgery as an alternative to an indwelling urethral catheter."} +{"text": "Dual ventricular response to a single supraventricular impulse is an interesting possibility in the presence of dual atrioventricular nodal physiology. Double His bundle and ventricular responses to a single atrial impulse caused by a simultaneous fast and slow pathway conduction is the hallmark of this condition. One of the earliest descriptions of simultaneous conduction through both atrioventricular (AV) nodal pathways was by Csapo G , who desThe major determinants of simultaneous anterograde fast and slow pathway conduction during sinus rhythm are: 1) Retrograde unidirectional block in both pathways 2) Critical conduction delay in the slow pathway and a long enough His-A interval to allow sequential conduction of impulse from both pathways . The criA mistaken diagnosis of atrial fibrillation may be entertained if the dual response is intermittent. Dixit S et al found thNon-reentrant supraventricular tachycardia due to 1:2 AV conduction has been described between 44 - 74 years of age and with duration of symptoms of up to 7 years . It may Even tachycardiomyopathy secondary to non-reentrant atrioventricular nodal tachycardia has been described recently . TreatmeIn this issue of the journal Laszlo R et al describe"} +{"text": "Laparoscopic minilaparotomy in 6 patients using the Maher abdominal elevator facilitated both quicker enucleation and morcellation of the myoma and suture of the myoma cavity. Myoma reduction in 12 patients by electrosurgery resulted in a 60% reduction in myoma diameter with failure in 2 patients. This technique may avoid myomectomy and be particularly useful in patients with infertility or near menopause."} +{"text": "Serum inhibition of autochthonous lymphocyte cytotoxicity for tumour cells has been studied in 112 cases of colonic carcinoma. Addition of patient's serum to the lymphocyte tumour cell reaction mixture resulted in decreased cytotoxic reactivity of lymphocytes from 8 of 39 cytotoxic positive cases. It was also shown that sera could inhibit if separately preincubated with the lymphocytes (4 cases) or the target cells (2 cases). A tumour antigen preparation inhibited only when incubated with the lymphocytes. Inhibition by serum or antigen appeared to be specific for colon carcinoma. Four cases were specially studied to determine the mode of lymphocyte killing of tumour cells: in 3 it was mediated largely if not entirely by T lymphocytes, and in the fourth by both T and non-T cells. The findings support the view that T lymphocytes lose their anti-tumour reactivity in vivo in the presence of circulating antigen or antigen-antibody complexes such as would occur with progressive tumour growth."} +{"text": "Early \u201cprophylactic\u201d oophorectomy and adrenalectomy has been performed on 12 patients with carcinoma of the breast. The patients selected were considered to have a very bad prognosis on account of axillary node involvement associated with internal mammary chain deposits (9 patients), supraclavicular nodes (2 patients) and a parasternal mass (1 patient). Five patients had evidence of spread beyond the primary lymph drainage area , and all had died within 4 years. In 7 patients the disease was confined to the primary lymph drainage area and 4 lived for more than 10 years, 3 being alive and well at 11 to 12 years. This is a higher proportion than in a control series but does not quite reach the level of statistical significance. In the 7 patients with disease confined to the axillary and internal mammary nodes prognosis was not apparently related to malignancy determined histologically, but did have an association with the extent of invasion of the axillary nodes. Urinary oestrogen estimations performed in 4 patients did not give any evidence that outcome was related to persistence of oestrogen production. Details of the patients' management and replacement therapy are given and from prolonged personal follow-up of these patients it is concluded that women who have undergone oophorectomy and adrenalectomy are able to lead full and active lives."} +{"text": "Traumatic anterior dislocation of the hip is rare. Bilateral traumatic anterior dislocation is an even rarer injury; indeed, only 5 cases have been reported in the English literature. We describe a case of a bilateral traumatic anterior dislocation of the hip and a concomitant unstable lumbar burst fracture following a mechanism of injury distinctly different from other reports. Hip dislocations are orthopaedic emergencies because of the possible complications. The usual direction of a hip dislocation is posterior and the rate of posterior dislocations is 90%.A 60-year-old man who was working in a squatting position at a construction site was struck by a 600 lb H-beam falling from 2 m over his lower back and buttocks area. When he arrived at our hospital 3 hours after the injury, he already had been diagnosed with a bilateral anterior dislocation of the hip and a spDislocation of the hip joint represents 2% to 5% of all traumatic dislocations.7)Motor vehicle accidents were the cause of bilateral traumatic anterior dislocations of the hip in all reported cases.Except for an unreduced bilateral anterior dislocation,9)A hip joint dislocation is an orthopaedic emergency. Delay in the reduction of a dislocated hip joint increases the incidence of avascular necrosis, which develops in 26% of hip dislocations.This case report is without precedent and illustrates that a rare bilateral anterior dislocation of the hip can occur following unusual mechanisms of injury."} +{"text": "Animals treated with a sufficiently high dose of busulphan die about 14 days later from bone marrow failure. A single, appropriately timed injection of cyclophosphamide can save these mice. The nature of this protection is shown to be the cyclophosphamide induced elaboration of a humoral factor which stimulates haemopoietic recovery."} +{"text": "These results might in part explain the observed difference in metabolism of chlorambucil by the resistant and sensitive strain of Yoshida ascites sarcoma cells.Drug uptake into the body tissue was rapid, with a high level of radioactivity being associated with the plasma and ascitic fluid during the initial 6-hour period after treatment. Previous studies"} +{"text": "The relationship between early and late radiation damage has been analysed by comparing the early skin reaction (desquamation in the first month) with the late foot deformity seen at 6 months, for mice from a wide variety of different fractionation experiments. A close correlation was observed between the early and late reactions in each experiment and the relationship was the same for all the experiments except for 17-64 fractions given over a short time. The fractionation schemes included single doses and 2-64 fractions, and the overall times ranged from 1 day to 6 months. This close correlation for such a wide variety of treatments suggests that the two end points are not necessarily independent responses of different tissues and that late damage in the mouse foot can result secondarily from depletion of the basal layer of the epidermis. Late foot deformity is therefore not a reliable model for the response of a slowly proliferating tissue."} +{"text": "Inhibitory activity was overcome at PHA concentrations 2-3 times greater than the concentration which allowed maximum discrimination between NHS and leukaemia sera.Sera from 16 of 20 patients with AML at some stage of the disease inhibited the PHA transformation of washed lymphocytes obtained from AML patients before treatment and when receiving induction or consolidation (cytoreductive) chemotherapy was reduced only when cultures contained a high proportion of primitive cells. Even in primitive cell contaminated cultures significant responses to PHA could be measured if conditions were modified to prevent increasing acidity.in vitro immunological reactions in pretreatment and poor prognosis patients may therefore be due to the presence of primitive cells in culture, and in treated patients to the failure of chemotherapy to reduce the circulating primitive cell count. Serum inhibitory factors may have a significant immunosuppressive effect in vivo, but the accurate assessment of the role of immune mechanisms in AML should attempt the measurement of specific immunity.Reports of reduced"} +{"text": "The stereochemical factors that influence the tendencies for sequence specific binding ofplatinum antitumour drugs to DNA are examined. The NHs of the platinum-amine moietycan form hydrogen bonds to the O6 of guanine or to a phosphate oxygen of DNA. Modellingthe stereochemistry of the NH atoms can lead to compounds with a strong preference forforming one type of adduct with DNA."} +{"text": "Forty Africans from Nigeria and 89 American negroes with colorectal polyps were analysed by age, sex and type of polyp. The Nigerians were much the younger group and far fewer of their polyps were truly neoplastic (7.5% compared with 87% of the Americans). These differences may be partly due to the American negro population being older than the Nigerian, and partly to environmental factors like those previously postulated to account for the difference in colon cancer incidence between these populations."} +{"text": "Placental site trophoblastic tumour (PSTT) is a rare form of gestational trophoblastic disease (GTD). We have conducted an analysis of all cases of PSTT managed at the Trophoblastic Disease Screening and Treatment Centre, Sheffield, from 1984 to 1996. During this time we received 4988 registrations for GTD and managed seven cases of PSTT. A large range of interval between antecedent pregnancy and presentation was observed \u2013 the most common presenting symptoms being irregular vaginal bleeding with or without preceding amenorrhoea. Three out of seven patients had disease confined to the uterus at diagnosis and were successfully treated by hysterectomy alone. Two out of seven patients had pulmonary metastases in addition to uterine tumour and were treated with combination chemotherapy \u2013 both are alive and well. Of the remaining two patients one had distant and the other loco-regional metastases and both died despite numerous therapeutic interventions. \u00a9 2000 Cancer Research Campaign"} +{"text": "The subcloning of a DNA fragment from an entry vector into a destination vector is a routinely performed task in molecular biology labs.We here present a novel benchtop procedure to achieve rapid recombination into any destination vector of choice with the sole requirement of an endonuclease recognition site. The method relies on a specifically designed entry vector and the combined action of type II and type IIs endonucleases with ligase. The formulation leads to accumulation of a single stable cloning product representing the desired insert carrying destination vector.The described method provides a fast single step procedure for routine subcloning from an entry vector into a series of destination vectors with the same restriction enzyme recognition site. One of the most routinely performed tasks in molecular biology labs around the world undoubtedly is the subcloning of a given DNA fragment from one plasmid vector into a different one. The reasons to do so are as numerous and diverse as are the applied methods. We here describe a further such technique involving the orchestrated action of a typeII and a typeIIs endonuclease (\"outside cutter\") with ligase. This procedure achieves the speed of recombinase based methods without the need for unusual recognition elements in the target vector.In an example experiment we subcloned a 1166 bp long DNA fragment* from an entry vector into a NheI site of a destination vector . The method relies on a specifically engineered entry vector which comprises two key elements flanking the insert to be subcloned Figure . To testWe combined entry vector, destination vector, Esp3I (Fermentas), NheI (Fermentas) and T4 ligase (Promega) in a buffer allowing all three enzyme actions (**) and incubated at room temperature for 1 hour Figure . We tranIn three independent tests we found between 40 and 73 colonies on the kanamycin plate (indicating pEGFP-N1) and no colonies at all (in two tests) or 10 colonies (in one test) on the ampicillin plate (harbouring pGEM-Teasy). Of 10 colonies per kanamycin plate tested for the presence of the subcloned insert in pEGFP-N1 by restriction analysis all proved to be the desired product. Noteworthy the two different resistance markers on entry and destination vector are not necessary for the procedure to function but were used for the sole purpose of easy discrimination between products in our tests. Following this proof of principle the procedure can certainly be further refined.The entry vector once constructed can only serve to subclone into one selected restriction site. Further limitations of this technique are the inapplicability for directional cloning and the dependence on absence of the utilized endonuclease recognition sites on both vector backbone and insert. We feel, however, that the speed of this single-step benchtop procedure makes up for this when routinely cloning PCR products into a variety of destination vectors all containing the same restriction site. Our group for instance is interested in cloning certain promoter elements upstream of several different reporter genes and conversely, cloning a given open reading frame behind a series of different promoters. An even broader application can be envisaged in the field of engineering improved enzymes by gene shuffling approaches or, more generally, as one instrument in the molecular toolbox enabling the construction processes that essentially constitute synthetic biology.AY523564 from BglII site at base position 2325 to BglII site at 3491.* Genbank ** Y+/tango-buffer supplemented with 5% (w/v) PEG, 10 mM DTT and 1 mM rATP in a final volume of 10 \u03bcL. Enzyme amounts: 7.5 units Esp3I, 10 units NheI, 3 weiss units T4 ligase.The author(s) declare that they have no competing interests.TF devised the described procedure, conducted all experiments and drafted the manuscript. MK provided the tangible base and technical expertise in refining this method and assisted in drafting the manuscript. Both authors read and approved the final version of this manuscript."} +{"text": "When the reactant is cis-[Pt(NH3)2(OH2)2]2+ no such differences are observedsuggesting that outer-sphere interactions between the reactant and the oligonucleotide mayplay a substantial role in determining the rates. Rates of closure to the bifunctional adductsare similar to those observed for cisplatin. Studies of the adduct profiles formed by stericallybulky and/or optically active complexes reveal that steric interactions play a major role inmediating the binding of Pt(ll) to DNA but that hydrogen bonds play less of a role. In vitro cytotoxic activities for these complexes do not always follow the trends that would beexpected on the basis of the adduct profiles.Studies directed at establishing the structural features that control Pt/DNA interactions andthe anticancer activity of Pt drugs are described. ["} +{"text": "In this study we show that heterologous expression of annexin VI in A431 squamous carcinoma cells caused a marked suppression of tumour cell growth when cells were cultured subcutaneously in nude mice. The tumours formed by the annexin VI+ A431 cells were morphologically and histologically similar to those formed by the wild-type cells."} +{"text": "Co-culture in agar of normal bone marrow cells from different individuals gave granulocyte macrophage colony counts that were expected from counts made when the marrows were cultured separately. Co-culture of normal marrow with normal peripheral blood leucocytes (which did not themselves give rise to colonies) caused inhibition of colony growth only when the ratio of peripheral blood to bone marrow cells was of the order of 4 : 1. Peripheral blood or bone marrow cells from 7 of 9 patients with acute myelomonocytic leukaemia, which did not give rise to colonies, caused a marked reduction in the number of colonies obtained from normal marrow cells when cultured with them. This inhibitory effect of leukaemic cells was found when ratios of leukaemic to normal cells were as low as 1 : 4. Additional evidence that the inhibition of normal colony formation was related to the leukaemic process was obtained from follow-up studies on one of the patients whose cells lost the capacity to inhibit normal colony formation during remission and became inhibitory again on relapse."} +{"text": "Intact human bone marrow cells from 7 patients with myelomatosis were inoculated intravenously into adolescent CBA mice rendered immunologically deficient by thymectomy followed by total body irradiation (600 rad). Each inoculum of human myeloma marrow cells and subsequent passages of intact mouse marrow and spleen cells resulted in the presence of morphological changes in the marrow, spleen and peripheral blood of a proportion of these mice which were closely similar to those seen in the human donor. A substantial amount of human immunoglobulin (IgG and IgA) was detected in the sera of some of the mice showing morphological changes. Mice prepared identically but remaining uninoculated or receiving intact human bone marrow cells from 3 patients with no evidence of haematological malignancy showed none of these changes when examined after similar intervals.There are at least 3 possible explanations for these findings: in mice receiving human myeloma marrow cells they might be accounted for by the persistence and replication of these cells in an immunologically deficient host. In mice receiving a first, second or third passage of abnormal mouse marrow and spleen cells they might similarly be accounted for by the survival and multiplication of a stem cell secreting both mouse and human immunoglobulins. Alternatively, the mouse stem cells may in some way have been transformed following infection by a transmissible agent originally present in the myeloma donor marrow cells."} +{"text": "Sir,et al, 2003 brings to the fore new evidence for correlations between radiosensitivity and the initial DNA damage in the form of double-strand breaks (dsb). The conclusion is at variance with a previous paper by the same group where the nonrepaired DNA dsb were identified as indicators of radiosensitivity and nonrepaired dsb in another showing a correlation between initial damage and radiosensitivity in human tumour cell lines are in agreement with three earlier investigations . A relationship between repair fidelity and radiosensitivity mainly based on a plasmid transfection assay and recovery of restriction cuts has also been reported would underline the principal uncertainties associated with the 24\u2009h repair marker and early damage responses in general. The p53 status of the tumour lines used by El-Awady et al (2003) was not identified further, but inspection shows that the cell lines are heterogeneous some being wild type, some being mutant and some being dysfunctional. It is clear therefore that the check point and S-phase arguments would apply differently to the tumour cell lines analysed by El-Awady et al (2003).Events measured after 20\u201324\u2009h of repair when compared and correlated with cell survival measured after 7\u201310 days have to deal with the problem that nonrepaired and repaired dsb in fact are early consequences of the irradiation insult. At 20\u201324\u2009h postirradiation, the repaired DNA would be found in the total envelope of undamaged DNA, but may be functionally compromised by misrepair and say little about the performance of the restituted DNA strands in subsequent rounds of cell division. It seems likely therefore that determination of nonrepaired dsb underestimates the full biological damage that manifests itself only after 7\u201310 cell divisions when mitotic integrity can be recognised and quantitated from the surviving clonogens. The induced dsb (or the induced DNA damage), on the other hand, measured at zero time and in the absence of any repair conceivably represents initial damage that would depend on cell type and dose alone, hence not incorporating any time-dependent variables affecting the comparison with cell survival. That broad variations found in the amount of dsb remaining after 24\u2009h of repair in tumour cells may arise from apoptosis, and cell cycle progression as suggested irrespective of the radiosensitivity , whereas slopes in the damage induction curve between 11 cell lines analysed by the FADU method operating at low dose vary by a factor of 6.3 . It could also be a reflection of the superior ranking of initial DNA damage as a determinant for cell survival. More measurments using the fluorescent unwinding technique could help to clarify.A methodological distinction worth noting is that the fluorescent analysis of DNA unwinding (FADU) method also generate such a relationship in fibroblast cell lines. The observed correlations thus would depend upon methodology and other unknown factors. The fact that DNA dsb are a nonuniform group of lesions and diff"} +{"text": "Cytoplasmic changes were investigated in livers of rats at various intervals up to 50 weeks during primary induction of hepatoma by thioacetamide feeding.Microsomal Glucose-6-phosphatase and ATPase activities were shown to decrease progressively with increased period of thioacetamide feeding the fall in activities being more pronounced during the first 15 weeks.Hormonal induction of tryptophan pyrrolase and tyrosine transaminase activities was shown to undergo a significant decrease of 65% and 55% respectively at the end of 50 weeks feeding.The substrate induced tryptophan pyrrolase activity was decreased to 50% during the 50 weeks period whereas the substrate induced tyrosine transaminase activity gradually increased to 200%. The latter is attributable to differences in the optimal induction dose of tyrosine in normal and carcinogen fed rats.The m-RNA template lifetime for tryptophan pyrrolase was shown to be exceeding 24 hours in normal rats as against that of 13 hours in rats fed with carcinogen for 30 weeks. On the other hand the m-RNA template lifetime for tyrosine transaminase was 3 hours in control rats while it was 7 hours in the carcinogen fed rats.The observed changes were shown to occur long before the onset of malignant transformation.The alterations in terms of decreased Glucose-6-phosphatase and substrate induced tryptophan pyrrolase activities were shown to be reversible when the carcinogen was withdrawn from the diet after 30 weeks of feeding.The significance of these observations is discussed in relation to damage to endoplasmic reticulum during hepatocarcinogenesis."} +{"text": "It consists of introducing small fragments of heat-coagulated hen egg white into the subcutaneous tissue of mice. After 14 days, animals challenged with purified ovalbumin into the footpad presented an immediate swelling of the paw peaking at 30 min, followed by two peaks of swelling at 6 and 24 h. Histological examination of the paws showed a massive eosinophil infiltration (more than 800 cells/5 microscopic fields). This intense infiltration persisted for more than 14 days after the challenge. Furthermore, in mice immunized with coagulated egg white the delayed swelling of the paws and eosinophilic infiltration were significantly higher than in mice immunized with the classical protocol of ovalbumin in alumen adjuvant. Transfer of lymph node cells obtained from mice implanted with heat-coagulated hen egg white induced footpad swelling and eosinophil infiltration in response to ovalbumin. High levels of ovalbuminspecific IgG1 but not of IgE were detected in the serum of these animals. The advantages of this model for the experimental study of late-phase reaction"} +{"text": "Our experience of 90 hepatectomies (HE) and examinations of 64 cadaver livers resulted in the elaborationof a simplified technique for the exposure of hepatic pedicles (HP) and the rapid selective ligationwithout significant normothermal ischemia of the retained parts of the liver. The method comprises 4consecutive steps: 1) a superficial T-shaped incision of Glisson's capsule at the site of HP projectionon the liver's inferior surface, 2) introduction of the surgeon's forefinger into the liver parenchyma,controlled by clamping the hepatoduodenal ligament, the fingertip finding a tubular structure well distinguishedby its smooth elastic surface from the friable parenchyma and bending the finger to hookthe pedicle, 3) drawing the hooked pedicle downwards through the slit in the capsule and temporarilyclamping it, while releasing the hepatoduodenal ligament so as to restore blood supply to the retainedparts of the liver, 4) checking for correct ligature position on the HP before its final ligation by matchingthe actual ischemic area with the intended line of resection and moving the clamp proximally or distallyalong the exposed pedicle for the release or clamping of lateral branches as necessary. Whereuponresection can be performed by any of the known methods. This method has been used in 8 major HE, allowing to reduce intraoperative blood loss from2200\u00b1247 ml to 1000\u00b1225 ml and reducing general liver ischemia from 10 minutes and more to 2\u20133minutes."} +{"text": "The membrane fractions retained tumour specific antigenic determinants and exhibited an increased antigenic activity over other subcellular membrane fractions, as defined by their capacity to quantitatively neutralize the membrane immunofluorescence staining of viable hepatoma D23 cells by antibody in tumour immune serum. In contrast, no antigenic activity was found to be associated with purified hepatoma D23 nuclei or nuclear membranes as evaluated by the The two methods described for the isolation of hepatoma D23 membranes have been developed for the large scale fractionation of tumour homogenates in order that further studies upon the nature and immunogenicity of membrane associated tumour specific antigens may be resolved using defined membrane preparations of increased antigenic activity."} +{"text": "To estimate the prevalence of TP53 mutations in familial breast cancer, constant denaturant gel electrophoresis (CDGE) was used to screen exons 5-8 of the TP53 gene for germline mutations. Genomic DNA from 128 breast cancer patients belonging to 109 families with familial cancer were screened. No germline mutations were found in any of the patients. We also studied TP53 mutations in tumour DNA from 51 of the same individuals and found mutations in 14%. This is similar to what has been reported in sporadic breast cancer."} +{"text": "A total of 155 samples from 101 patients with ovarian cancer were investigated using flow cytometry to evaluate the DNA index and the percentage of cells in the various cell cycle phases. Thirty-four samples were DNA diploid tumours, while the other 121 were DNA aneuploid tumours. The DNA index was very stable in different sites and over time in the same patient. Tumour stage and ploidy were significantly associated: stages III and IV tumour stage were more likely to be DNA aneuploid. Patients with residual tumour size at first surgery greater than 2 cm had a significantly larger number of DNA aneuploid than DNA diploid tumours. The DNA index was also related to the degree of differentiation of the tumours. The percentage of cells in the S phase of the cell cycle was significantly higher in DNA aneuploid and in poorly differentiated tumours than DNA diploid and well differentiated tumours. Multivariate analysis using the Cox model showed that the DNA index and the percentage of cells in S phase were not independent prognostic variables in this study. Prospectively collected data should be accumulated before assigning the DNA index an important role as a biological prognostic factor in ovarian cancer."} +{"text": "Thirty-one consecutive patients with advanced epithelial ovarian cancer entered a phase II study with cisplatin and etoposide combination chemotherapy. None of them had received prior chemotherapy or radiotherapy. Most patients had advanced (88%) or far advanced (61%) disease. All 31 patients are evaluable for toxicity which was significant and led to removal of five (16%) patients from the study. Of the 23 patients evaluable for response there were four clinical complete (CR) and eight partial (PR) responders for a total clinical response rate of 52% of evaluable patients and 39% of all patients. Eight patients have undergone second look laparotomy with pathological CR in one of the clinical CR patients. Median survival time for responders and non-responders is 19 and 8 months respectively. The results obtained appear to be inferior to other cisplatin based combinations. Although this could be attributed to the unusually high proportion of patients with bulky disease and stage IV patients, we feel that the study suggests that etoposide did not add any benefits for this patient population to cisplatin as a single agent."} +{"text": "Thus, a solitary pulmonary tumour nodule model with lymph node metastasis approximates clinical lung cancer and may provide a useful basis for lung cancer research. \u00a9 1999 Cancer Research CampaignThis study is designed to establish a pulmonary tumour model to investigate the biology and therapy of lung cancer in mice. Current methods for forming a solitary intrapulmonary nodule and subsequent metastasis to mediastinal lymph nodes are not well defined. Lewis lung carcinoma (LLC) cell suspensions were orthotopically introduced into the lung parenchyma of C57/BL6 mice via a limited skin incision without thoracotomy followed by direct puncture through the intercostal space. The implantation process was performed within approximately 50 s per mouse, and the operative mortality was less than 5%. Single pulmonary nodules developed at the implanted site in 93% of animals and subsequent mediastinal lymph node metastasis was observed in all mice that formed a lung nodule after intrapulmonary implantation. The size of tumour nodule and the weight of mediastinal lymph node increased in a time-dependent manner. The mean survival time of mice implanted successfully with LLC cells was 21 \u00b1 2 days (range 19\u201324 days). Histopathological analysis revealed that no metastatic tumour was detectable in the mediastinal lymph nodes on day 11, but metastatic foci at mediastinal lymph nodes were clearly observed on days 17 and 21 after implantation. Other metastases in distant organs or lymph nodes were not observed at 21 days after the implantation. Comparative studies with intrapleural and intravenous injections of LLC cells suggest that the mediastinal lymph node metastasis by intrapulmonary impantation is due to the release of tumour cells from the primary nodule, and not due to extrapulmonary leakage of cells. An intravenous administration of"} +{"text": "We studied the effect of dietary factors and a variety of other risk factors on the development ofcholelithiasis through a case control study. The study involved 96 cases and 118 age and sex matched controls. All cases and controls wereinterviewed with regard to a variety of risk factors and frequency of consumption of over 100 fooditems. Analysis was done both by chi square and a multiple logistic regression model. From all thedietry factors the only ones that showed a positive statistically signficantly (p<0.05) association wasconsumption of animal fat as expressed by eating all visible fat on the meat and using butter on thetable. Interestingly high consumption of olive oil had a negative (protective) association with thedisease. A negative association was also found with smoking and holding a job demanding hardlabor."} +{"text": "Transgenic mice expressing the E7 protein of HPV16 from the keratin 14 promoter demonstrate increasing thymic hypertrophy with age. This hypertrophy is associated with increased absolute numbers of all thymocyte types, and with increased cortical and medullary cellularity. In the thymic medulla, increased compartmentalization of the major thymic stromal cell types and expansion of thymic epithelial cell population is observed. Neither an increased rate of immature thymocyte division nor a decreased rate of immature thymocyte death was able to account for the observed hypertrophy. lo population. We therefore suggest that mature thymocytes that would normally die in the thymus gradually accumulated in E7 transgenic animals, perhaps as a consequence of exposure to a hypertrophied E7-expressing thymic epithelium or to factors secreted by this expanded thymic stromal cell population. The K14E7 transgenic mouse thus provides a unique model to study effects of the thymic epithelial cell compartment on thymus development and involution. Thymocytes with reduced levels of expression of CD4 and/or CD8 were more abundant in transgenic (tg) mice and became increasingly more so with age. These thymic SP and DP populations with reduced levels of CD4 and/or CD8 markers had a lower rate of apoptosis in the tg than in the non-tg mice. The rate of export of mature thymocytes to peripheral lymphoid organs was less in tg animals relative to the pool of available mature cells, particularly for the increasingly abundant CD4"} +{"text": "P > 0\u00b705), while in the cervix series (4817 patients) a small excess of breast tumours was found over a period of 15 years.Index sites of breast and cervix uteri were selected from populationbased data held at the West Midlands and Birmingham Regional Cancer Registry, and the expected numbers of second primary cancers in cervix and breast were computed . In the breast series a small deficit of cervical tumours was observed . Complementary analysis indicated that there was no excess of women with the 2 primary tumours and that cancers of the breast and cervix uteri are not aetiologically related."} +{"text": "All of 10 patients with colonic carcinoma and 5 with malignant melanoma of skin showed no sign of immunoreactivity against the cultured tumour cells by the lymphocyte populations residing within the tumours. More than half of these patients did show cytotoxic reactivity by their blood lymphocytes. Possible cytotoxic reactivity by the regional lymph node lymphocytes was also investigated in 57 tumour cases . One third of the cases showed positive blood lymphocyte immunoreactivity, but in only 4 tumours (3 colonic) did the node lymphocytes show any cytotoxicity against the tumour cells. This state of anergy of intrinsic and regional lymphocytes is presumably acquired during the development of the cancer and would permit local tumour spread and metastasis to lymph nodes. Its cause has not been identified but appears to be lymphocyte inhibition rather than selective change in lymphocyte population. In particular, no special pattern can be seen in the relative proportions of T and B cells in patients' blood, lymph node or intrinsic carcinoma lymphocytes."} +{"text": "The evolution of bone lesions in transplantable C57BL/KaLwRjj 5T mouse myeloma (MM) has been followed in vivo. Mice were anaesthetised and a radiograph of the pelvis and hind legs was performed by a radiograph dedicated for mammography. This is the first description of an in vivo technique under experimental conditions whereby the development of bone lesions owing to the MM growth was demonstrated."} +{"text": "Liposarcoma of the thyroid gland is rare with only 3 cases reported in the English literature. We present a further two patientswhom we have recently treated: a 49 year old lady with a myxoid liposarcoma and a 71 year old man with a pleomorphicliposarcoma. Both underwent macroscopic excision of tumour but had positive margins, so were then treated with externalbeam radiotherapy. The former patient died from metastases 10 months after presentation, the latter remains alive but hasdeveloped metastatic disease on follow up at 24 months. We recommend the use of high dose radiotherapy following radical surgery as margins of excision are usually narrow inthis most difficult region. The role of chemotherapy is yet to be established."} +{"text": "The incidence of type 1 diabetes (T1D) shows a worrying tendency for a steady increase in Western countries. Along the line of the hygiene hypothesis, evidence accumulates to suggest that this increase is explained by the decrease of infections due to improved hygiene and medical care. This article presents a review of epidemiological data and of the main putative underlying cellular and molecular mechanisms."} +{"text": "We have investigated the use of the antibody MIB1 as a proliferative and prognostic marker in breast cancer and whether changes in proliferative activity could account for differences in prognosis of premenopausal women operated on during different phases of the menstrual cycle. MIB1 expression was strongly correlated with S-phase fraction and histological grade. There was no difference in MIB1 scores between different phases of the menstrual cycle. Both MIB1 score and timing of surgery correlated significantly with duration of survival, while the two together were even stronger predictors of overall survival. Women with slowly proliferating tumours surgically removed in the luteal phase had a very good prognosis, whereas women with rapidly proliferating tumours excised at other times of the cycle had a worse prognosis."} +{"text": "During the routine serial passage of over 30 human tumour xenografts in athymic (nu. nu.) mice over a period of 6 years the induction of murine fibrosarcomas at the site of transplantation has been observed on three occasions. In two cases it has been possible to follow the development of these tumours over successive transplant generations. These sarcomas had growth rates, tumour karyotypes and isoenzyme patterns which clearly distinguished them from the original human xenografts."} +{"text": "We report a rare case of a limited chronic dissection of the ascending aorta that was accidentally discovered at operation performed for severe aortic stenosis and moderate to severe dilatation of the ascending aorta. Preoperative investigations such as transoesophageal echocardiography and cardiac catheterization missed the diagnosis of dissection. Intraoperative findings included a 3.5 cm eccentric bulge of the ascending aorta and a 5 mm circular shaped intimal tear comunicating with a limited hematoma or small dissection of the media layer. of the ascending aorta). Aortic dissection is defined as the separation of the lamellae of the aortic wall. The extent of undermining of the intimal layer by dissection can vary from being only a few millimetres to extending to all the aorta itself. The dissecting process creates a false lumen that may vary from only a few millimetres to the larger classic false lumen . ChronicA 83 years-old woman was referred to our department for surgical treatment after being diagnosed a severe aortic stenosis associated with a dilatation of the ascending aorta.The patient had recently been hospitalized for congestive heart failure. Patient history included permanent atrial fibrillation and no previous episodes of chest or back pain suggestive of aortic dissection.2) together with moderate aortic and tricuspid valve regurgitation. Cardiac catheterization showed a markedly calcified aortic valve with moderate to severe insufficiency and a 4.5 to 5 cm dilatation of the ascending aorta above the sino-tubular junction without any other pathologic findings including the presence of an eccentric bulge; coronary arteries were normal cardioplegia was obtained. The aneurysm of the ascending aorta was resected and inspected: there was a 5 mm circular shaped intimal tear comunicating with a limited hematoma or small dissection of the media layer porcine bioprostheses was inserted. The ascending aorta was then replaced with a 30 mm dacron tube graft, the proximal anastomosis being at the level of the sino-tubular junction and the distal anastomosis being just below the innominate artery. The patient was weaned off the cardiopulmonary bypass easily and made an uneventful recovery. Aortic cross clamp and cardiopulmonary bypass time were respectively 85 and 91 minutes.Cardiopulmonary bypass was instituted and cardioplegic arrest with selective antegrade Custodiol Figure. . The aorTransthoracic echocardiograms and general examination performed three and nine months after operation were unremarkable.Hystologic examination of the aortic wall showed dissection associated with thrombosis of the media layer while chronic inflammation and fibrosis of the adventitia were detected.According to the classification proposed by L.G. Svensson in 1999 there are five variants of aortic dissection: classic type ; intramural hematoma class 2); intimal tear without hematoma (limited dissection) and eccentric aortic bulge (class 3); atherosclerotic penetrating ulcers (class 4); iatrogenic/traumatic dissection (class 5) [; intimalWe want to focus our attention to class 3 variant in which the intimal tear is associated with exposure of the aortic media or adventitial layer but without extensive separation of medial layers.Because of this limited pathology the current imaging techniques may be inadequate for the diagnosis of this type of dissection. Svensson, in his article regarding intimal tear without hematoma, reported that all the 9 patients with limited dissection in a series of 181 consecutive patients were not diagnosed preoperatively. A careful review of preoperative investigations revealed the presence of an eccentric aortic bulge on the aortography in 5 of the nine patients while this bulge was not noted on the transoesophageal studies . In patiThis type of dissection may propagate to become the classic type 1 dissection as described by Svensson and Gott. These authors reported older healed class 3 intimal tears associated with acute dissections, particularly in Marfan patients .Our report is consistent with the up to date literature because our limited dissection was not diagnosed preoperatively, too. Therefore we speculate that if the patient was not taken to theatre because of the severe aortic stenosis, then probably the very thin adventitia would have ruptured or an acute dissection would have occurred. As a matter of fact we know that at least one third of the patients with aortic dissection are not diagnosed before death .In conclusion our small limited dissection eluded two of the most current imaging modalities yet have catastrophic consequences if unrecognized. Newer tridimensional imaging techniques could be helpful in the diagnosis and treatment of aortic aneurysms.Each author contributed equally to the paper. All authors read and approved the final manuscript.Written informed consent was obtained from the patient for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."} +{"text": "Arginase activity was found to be increased in precancerous nodules and mammary tumour when compared with the mammary gland. Proline inhibited the mammary tumour arginase and up to 30 mmo1 concentration the inhibition follows first order kinetics. Hill analysis of the inhibition of arginase by proline showed that proline inhibits the arginase activity by competing directly at the active site without conformational change. The inhibition may be of regulatory importanec, involving a feedback mechenism in mammary tumours."} +{"text": "The isotope is released if labelled cells or their progeny die. Consequently the rate of 125I excretion from mice can be used to follow the fate of labelled cells in vivo. Using these principles we show:The compound in vitro into both fresh and cryopreserved human leukaemic myeloblasts, in non-toxic concentrations, to allow their survival in mice to be estimated by whole-body counting;(1) Sufficient label can be incorporated in vivo ;(2) The release of isotope from labelled cells is sufficiently slow to offer reasonable expectation that this technique can be used for assessing the sensitivity of myeloblasts to cytotoxic agents 125Iexcretion from mice injected with myeloblasts from different donors varies. This probably reflects different rates of spontaneous death of injected myeloblasts;(3) The rate of (4) Active rejection of myeloblasts starts within 48 h of their injection into mice;(5) Indirect evidence that phagocytic cells may be active agents in myeloblast destruction in mice;(6) Various methods of immunologically depriving mice were assessed to see if they would result in a useful increase in survival of injected human myeloblasts. We conclude that there is little advantage and some limitations in using mice thus deprived;125I loss from mice injected with labelled killed myeloblasts. This experience emphasizes the importance of including the killed-cell control in this assay.(7) One of the agents used for immunological deprivation\u2014silica powder\u2014markedly decreased the rate of"} +{"text": "The effects of combretastatin A4 prodrug on perfusion and the levels of 31P metabolites in an implanted murine tumour were investigated for 3 h after drug treatment using nuclear magnetic resonance imaging (MRI) and spectroscopy (MRS). The area of regions of low signal intensity in spin-echo images of tumours increased slightly after treatment with the drug. These regions of low signal intensity corresponded to necrosis seen in histological sections, whereas the expanding regions surrounding them corresponded to haemorrhage. Tumour perfusion was assessed before and 160 min after drug treatment using dynamic MRI measurements of gadolinium diethylenetriaminepentaacetate (GdDTPA) uptake and washout. Perfusion decreased significantly in central regions of the tumour after treatment. This was attributed to disruption of the vasculature and was consistent with the haemorrhage seen in histological sections. The mean apparent diffusion coefficient of water within the tumour did not change, indicating that there was no expansion of necrotic regions during the 3 h after drug treatment. Localized 31P-MRS showed that there was decline in cellular energy status in the tumour after treatment with the drug. The concentrations of nucleoside triphosphates within the tumour fell, the inorganic phosphate concentration increased and there was a significant decrease in tumour pH for 80 min after drug treatment. The rapid, selective and extensive damage caused to these tumours by combretastatin A4 prodrug has highlighted the potential of the agent as a novel cancer chemotherapeutic agent. We have shown that the response of tumours to treatment with the drug may be monitored non-invasively using MRI and MRS experiments that are appropriate for use in a clinical setting."} +{"text": "The roles of a self-completed symptom questionnaire and four biochemical markers of disease were assessed to determine risk for gastric and colorectal cancer from within a hospital population and a random population. Eight-six patients with cancer, 168 subjects with benign conditions of the stomach and large bowel and 720 individuals from the community at large were investigated. Multivariate analyses of the questionnaire and biochemical data were performed individually and in combination using a data set comprising 54 cancer subjects, 80 patients with benign disease and 200 random individuals. The most favourable predictive equation derived was then applied to the remaining data set to determine its efficacy. In the primary analyses the questionnaire data identified 32 (60%) cancers successfully and using the biochemical markers alone 36 (67%) patients were also correctly classified as cancer bearing. However, the combination of the questionnaire and marker data improved the sensitivity for cancer to 50 cancers detected (92%) (P less than 0.02). Using the predictive equation from this combination of data to identify risk in the second data set 28/32 (88%) cancers were correctly identified with only an 11% false positive rate. An 18 month follow-up for the non-cancer group has to date revealed only one cancer (ca. pancreas). In this limited study, multivariate analysis of questionnaire and biochemical marker data does successfully identify individuals at \"high risk' of harbouring gastric or colorectal cancer within a symptomatic population and may have a role in determining priority for investigation for a symptomatic individual."} +{"text": "We documented available information concerning incident cases of gastric cancer in part of Kenya's Eastern Province between 1991 and 1993. By reviewing the records of all major health facilities in the area, 200 cases of gastric carcinoma were found giving an annual average crude incidence rate of 7.01 per 100\u2008000 males and 3.7 for females . There is likely to be underascertainment of cases especially among those aged over 65 years. Previous incidence estimates for the same area of Kenya were reviewed and a 10-fold increase in the recorded indirectly standardised incidence rate between the periods 1965\u201370 and 1991\u201393 was noted but this may be due to improved diagnostic facilities. The recent rates in this part of Kenya are comparable to Eastern European rates and similar to those recorded in other highland regions of Africa. \u00a9 2001 Cancer Research Campaign"} +{"text": "The quenching of the rhod fluorescence is proportional to the strength of the Cu(II)-complex-rhod interaction and therefore provides a quantitative measurement of the \u201cintercalating\u201d capacity of the quinolones and their copper complexes. These results agree well with the theoretical total adduct formation energies.Theoretical electronic Structure methods have been employed to study the structure and activity of certain (free) quinolones and the interaction of their Cu(II)-complexes on a DNA model (Rhodamine 6G (rhod)). As a manner of assessing the generated geometries, the nalidixic acid geometrical parameters obtained were tested against the crystallographic ones and it was found that the average error in the calculated geometries is small. The present study allows us to (1) Rationalize the observed differences in antibiotic activities through their electronic hardnesses. (2) Suggest a plausible mechanism of action for these drugs through formation of a reactive intermediate (or carrier) which would consist of a quinolone anion coordinated to an adequate metal center (Cu(II) in this study). (3) We find that, through this model of DNA (modeled with rhod) the interaction seems to be mediated by an effective \u03c0-\u03c0 stacking. (4) Finally, an"} +{"text": "C3H mice were implanted with pieces of spontaneous mammary carcinoma which were irradiated or removed surgically when they had grown to 6\u00b75 mm mean diameter. The incidence of lung metastases was determined from samples taken at various times up to 6 months later. Single x-ray doses and fractionated schedules up to 15 fractions in 18 days were used, no significant difference being observed in the results for all these schedules.On the major question of whether radiation caused an increase in the number of lung metastases the study is inconclusive. The incidence of metastases was found to be 8% if the implanted tumour was cured by the radiation, whereas if the radiotherapy did not cure the tumours the incidence was 35%. This difference between the two groups was significant. If tumours recurred locally after radiotherapy and were then removed surgically, the incidence of lung metastases was significantly greater than that after surgery of unirradiated tumours. The incidence of metastases was similar after curative surgery and after curative radiotherapy."} +{"text": "TP53 mutation. The regions of chromosomal gain and loss identified in this study indicate the location of genes that are potentially important in the development and progression of childhood adrenocortical tumours. Finally, the copy number changes identified in childhood tumours are distinctly different to those seen in adult cases Cancer Res56: 4219\u20134223), and we propose that this indicates that childhood tumours are of embryonal origin. \u00a9 1999 Cancer Research CampaignWe have examined 11 cases of childhood adrenocortical tumours for copy number changes using comparative genomic hybridization (CGH). The changes seen are highly consistent between cases, and are independent of tumour type (carcinoma versus adenoma) or the presence of a germline"} +{"text": "Death appeared to be due to hypoglycaemia and the ability to induce this condition correlated with the differences in malignancy between the sublines; WBP1 (X) and WBP1 (V), the more malignant sublines, inducing hypoglycaemia earlier and more rapidly than the least malignant subline WBP1 (A). Possible mechanisms whereby the tumour produces these effects are discussed.A possible basis for the differences in malignancy between three closely related sublines of the WBP1 ascites tumour of the rat has been studied by examining the biochemical changes in rat sera during tumour growth"} +{"text": "Alterations in the hMLH1 gene were found only in colorectal tumours with a large presence of microsatellite instability. None of the pancreatic tumours showed any alteration in the two genes analysed. Our results demonstrate that microsatellite instability is unlikely to play a role in the tumorigenesis of sporadic pancreatic cancers and confirm the presence of mismatch repair gene alterations only in sporadic colon tumours with a highly unstable phenotype. \u00a9 1999 Cancer Research CampaignGenomic instability has been proposed as a new mechanism of carcinogenesis involved in hereditary non-polyposis colorectal cancer (HNPCC) and in a large number of sporadic cancers like pancreatic and colon tumours. Mutations in human mismatch repair genes have been found in HNPCC patients, but their involvement in sporadic cancer has not been clarified yet. In this study we screened 21 pancreatic and 23 colorectal sporadic cancers for microsatellite instability by ten and six different microsatellite markers respectively. Microsatellite alterations were observed at one or more loci in 66.6% (14/21) of pancreatic cancers and in 26% (6/23) colon tumours, but all the pancreatic and half of the colon samples showed a low rate of microsatellite instability. All the unstable samples were further analysed for mutations in the"} +{"text": "Important differences exist in the responses to photodynamic agents of normal and tumour-derived pancreatic acinar cells. In the present study amylase release has been used to assess the mechanisms by which the photodynamic drugs tetra- and disulphonated aluminium phthalocyanine act on pancreatic cells via energy and calcium-dependent activation and transduction pathways. The photodynamic release of amylase was found to be energy dependent and inhibited by the chelation of free cytoplasmic calcium but not by the removal of extracellular calcium. In contrast to their effects on normal acinar cells, the photodynamic action of A1PcS4 and A1PcS2 was to inhibit amylase secretion from pancreatoma AR4-2J cells. Removal of extracellular calcium reversed this inhibitory effect on AR4-2J cells and produced a significant increase in amylase release, but chelation of free cytoplasmic calcium did not affect the inhibitory photodynamic action of the phthalocyanines on amylase release from the tumour cells. Overall, these results demonstrate further important distinctions between the photodynamic action of sulphonated aluminium phthalocyanines on normal versus tumour exocrine cells of the pancreas and indicate that calcium plays an important role in photodynamic drug action, since these agents affected intracellular calcium mobilisation at some distal point in the membrane signal transduction pathway for regulated secretion. Furthermore, the photodynamic inhibition of constitutive secretion in tumour cells may involve a calcium-dependent membrane target site or modulation of membrane calcium channels by activation of protein kinase C."} +{"text": "Tumour necrosis factor (TNF) inhibits the accumulation of acetyl CoA carboxylase (ACC) mRNA by decreasing the rate of ACC gene transcription. The ACC mRNA species found in 30A5 cells are generated from promoter II and TNF inhibits the accumulation of class 2 type mRNAs. By using 5' deletion mutants of promoter II fused to the bacterial chloramphenicol acetyltransferase (CAT) gene, the DNA mobility shift assay and the DNase I footprinting assay, the authors have identified the 30 bp from \u2212389 to \u2212359 as the TNF responsive element in promoter II. TNF treatment causes a decrease in the binding activity of nuclear protein(s) specific to the TNF responsive element. When the fragment containing the TNF responsive element was incorporated into the thymidine kinase promoter, the chimeric gene exhibited TNF induced inhibition of expression."} +{"text": "Forty-seven cases of biliary tract infection with septic shock are presented. The sepsis was caused byempyema of the gallbladder in 23 cases and by cholangitis in the remainder. Gallstones were mostfrequently the cause of the sepsis. An appropriate diagnostic description of the syndrome of biliary tractinfection and septic shock should therefore include a description of the underlying biliary disease as wellas the term acute biliary shock. In this series, emergency surgical management by removal of gallstonesand drainage of suppuration was felt to be the most appropriate treatment. There was a high incidenceof gallbladder rupture (10.6%) and intrahepatic stones (53.2%). Of the 13 patients who died, 8 mighthave survived if early operation had been performed after the diagnosis of acute biliary septic shock wasestablished."} +{"text": "The prostate cancer cell lines PC3 and LNCaP have been shown to lack expression of the tumour suppressor gene MMAC1/PTEN, in contrast to the immortalized non-tumorigenic epithelial lines PNT1a and PNT2. We have measured the effects of reintroduction of wild type (wt) and mutant MMAC1 genes on to these genetic backgrounds, using gene constructs expressing either wt MMAC1 or various mutants deficient in the dual specificity phosphatase domain of the protein. Over-expression of wild type PTEN protein induced cell shrinkage and rounding, but did not result in increased levels of classical apoptosis. Permanently transfected lines containing the MMAC1 gene could only be obtained from the PNT cells, as PTEN expression resulted in rapid loss of both tumour lines. In contrast, mutation of the phosphatase domain resulted in partial attenuation of the phenotypic effects of MMAC1 after transient transfection, and also allowed the derivation of permanent tumour cell lines containing the mutated MMAC1 gene. The results suggest that re-expression of wt PTEN is incompatible with survival of human prostate cancer cells in vitro, and that the full biological activity of this common tumour suppressor requires functions additional to the established protein and lipid phosphatase activities in epithelial systems. \u00a9 2000 Cancer Research Campaign"} +{"text": "Diethylnitrosamine (DENA) at 10 mg/kg was fed to adult rats either continuously or for periods ranging from 1 to 10 weeks. Survival correlated inversely with the duration of carcinogen feeding. Less than 4 weeks of DENA feeding produced only preneoplastic foci that persisted indefinitely; 4 weeks were found to be necessary for the transformation of preneoplastic lesions into liver cancers; after 6 weeks, the incidence of hepatomas was 100%. The process of liver cancerization appeared to be identical whether DENA was fed for 8 weeks or continuously up to the time of death. These results are discussed in the light of the evolution of the homoeostatic control of liver-cell division during DENA feeding, in order to distinguish the different successive roles played by the carcinogen."} +{"text": "Reticuloendothelial (RE) phagocytic and circulating plasma opsonic activity was evaluated in rats transplanted with the Walker 256 carcinoma tumour in an attempt to evaluate the role of opsonic protein in governing the functional state of the macrophage system. Animals transplanted intramuscularly with 2 X 10(4) viable tumour cells manifested 2 peaks of RE stimulation at 6 and 14 days post-transplantation with a subsequent decline in the phagocytic activity over the 14-30 day period. Increased phagocytic activity as determined by colloid clearance was primarily a reflection of hepatic K\u00fcpffer cell hyperphagocytosis while the decline in phagocytic activity was related to a decrease in K\u00fcpffer cell function. The initial peak of RE stimulation was associated with an elevation in the blood opsonin level and no significant enlargement of the liver and spleen. In contrast, the second peak of RE stimulation at 14 days was associated with both an elevation in opsonin levels and an associated hepatic and splenic enlargement. The decline in phagocytic activity over the 14-30 day interval was associated with a progressive decline in the plasma opsonic activity, a return of the spleen to its normal size in relationship to the body weight, and a persistent hepatomegaly. These findings suggest that the alterations in macrophage function during tumour growth may be mediated in part by changes in the opsonic or phagocytosis promoting capacity of plasma. Since opsonic protein contributes to the discriminatory capacity of macrophages, it is suggested that changes in the blood opsonin level may condition the anti-tumour capacity of the macrophage system with respect to host defence aginst malignant disease."} +{"text": "The Proteomics Standards Initiative (PSI) aims to define community standards for data representation in proteomics and to facilitate data comparison, exchange andverification. Rapid progress has been made in the development of common standardsfor data exchange in the fields of both mass spectrometry and protein\u2013protein interactionssince the first PSI meeting [1]. Both hardware and software manufacturershave agreed to work to ensure that a proteomics-specific extension is created for theemerging ASTM mass spectrometry standard and the data model for a proteomicsexperiment has advanced significantly. The Protein\u2013Protein Interactions (PPI) groupexpects to publish the Level 1 PSI data exchange format for protein\u2013protein interactionsby early summer this year, and discussion as to the additional content of Level2 has been initiated."} +{"text": "We have developed chimeric Fab fragments of MAb A7 (chA7Fab) and have reported on their potential usefulness as a carrier of neocarzinostatin (NCS). However, a large amount of chA7Fab accumulates in the kidneys which might cause renal failure. This was one of the major side-effects of the chA7Fab-NCS immunoconjugate administered to humans. To decrease the kidney accumulation of chA7Fab, chA7Fab was biotinylated and administered with a subsequent injection of avidin to nude mice with pancreatic cancer. The accumulation of biotinylated chA7Fab in the blood and the kidneys decreased significantly after the injection of avidin. In a separate experiment with biotinylated chA7Fab-NCS, the blood and kidney accumulation decreased significantly after the injection of avidin. These findings suggest that the injection of biotinylated chA7Fab complexed with NCS followed by avidin may be safer and may permit the administration of larger doses of NCS without the subsequent development of renal failure."} +{"text": "A modified Mantel-Haenszel analysis of data from the Oxford Survey of Childhood Cancers has shown that cases associated with foetal irradiation (X-rayed cases) accounted for a higher proportion of deaths between 5 and 10 years than of earlier or later deaths. This finding is compatible with somewhat later origins for the cancers actually caused by the radiation exposures (radiogenic cases) than for other (idiopathic) cases which proved fatal before 10 years of age. Therefore the usual time for incurring congenital anomalies could be the commonest time for initiating childhood cancers. The theoretical implications of this and other findings of the Oxford Survey are discussed within the framework of a theory which assumes that all mutant cells have cancer potentialities and that defects in the immune surveillance mechanism favour multiplication of these cells (or endogenous sources of self-replicating foreign proteins) as well as live pathogens (or exogenous sources of self-replicating foreign proteins)."} +{"text": "The relationship between DNA double-strand break rejoining rates, inherent radiation sensitivity and tumour response to radiation therapy was determined for a group of 25 squamous cell carcinoma (SCC) and eight sarcoma (SAR) tumours. DNA double-strand break frequencies were measured by neutral filter elution in first passage following explant tumour samples after in vitro exposure to 100 Gy of 60Co gamma-rays. There was no significant difference between SCC and SAR tumour cells in their sensitivity to break induction, but in a 1 h time period SAR tumour cells rejoined significantly fewer breaks than SCC tumour cells, consistent with the greater sensitivity of SAR and suggesting that differences in rates of break rejoining account for the different distributions of radiosensitivities seen when different tumour types are compared. The percentage of breaks rejoined in 1 h in these tumour samples correlated well with D(o) and with the beta component of the survival curve, measured in vitro by clonogenic assay in tumour cell lines established from the tumour samples, but not with SF2 or the alpha component of the survival curve. The rates of DNA double-strand break rejoining therefore appear to influence the exponential portion of survival curves and probably the interactions between breaks. The percentage of breaks rejoined in 1 h was higher in SCC tumours that subsequently failed radiotherapy and, although the differences were not significant, they suggest that rates of break rejoining are an important component of tumour response to radiation therapy."} +{"text": "Control and streptozotocin induced diabeticWistar rats were infused with [U14C]-glucose and[3H]-2-deoxyglucose (2DG). The fetal side of the placentawas perfuseci with a cell free medium and glucoseuptake was calculated in the adjacent fetuses.Despite the 5-fold higher maternal plasma glucoseconcentration in the diabetic dams the calculatedfetal glucose metabolic index was not significantlydifferent between the 2 groups. Placental blood flowwas reduced in the diabetic animals compared withcontrols but reduction of transfer of [U14C]-glucose and [3H]-2-deoxyglucose and endogenously derived[14C]-Lactate to the fetal compartment, could not beaccounted for by reduced placental blood flowalone. There was no significant net production oruptake of lactate into the perfusion medium thathad perfused the fetal side of the placenta in eithergroup. The plasma lactate levels in the fetuses adjacentto the perfused placenta were found to be higherthan in the maternal plasma and significantlyhigher in the fetuses of the diabetic group comparedwith control group. In this model the in situ perfusedplacenta does not secrete significant quantitiesof lactate into the fetal compartment in eitherthe control or diabetic group.Placental transfer of lactate, glucose and 2-deoxyglucosewas examined employing the"} +{"text": "The management of neovascular age-related macular degeneration (nAMD) has been transformed by the introduction of agents delivered by intravitreal injection which block the action of vascular endothelial growth factor-A (anti-VEGF agents). One such agent in widespread use is bevacizumab which was initially developed for use in oncology. Most of the evidence supporting the use of bevacizumab for nAMD has come from interventional case series and this clinical trial was initiated because of the increasing and widespread use of this agent in the treatment of nAMD (an off-label indication) despite a lack of definitive unbiased safety and efficacy data.\u00ae (bevacizumab) for choroidal neovascularisation (ABC) trial is a double-masked randomised controlled trial comparing intravitreal bevacizumab injections to standard therapy in the treatment of nAMD. Patients are randomised to intravitreal bevacizumab or standard therapy available at the time of trial initiation . Ranibizumab treatment was not included in the control arm as it had not been licensed for use at the start of recruitment for this trial. The primary outcome is the proportion of patients gaining \u2265 15 letters of visual acuity at 1 year and secondary outcomes include the proportion of patients with stable vision and mean visual acuity change.The AvastinThe ABC Trial is the first double-masked randomised control trial to investigate the efficacy and safety of intravitreal bevacizumab in the treatment of nAMD. This trial fully recruited in November 2007 and results should be available in early 2009. Important design issues for this clinical trial include (a) defining the control group (b) use of gain in vision as primary efficacy end-point and (c) use of pro re nata treatment using intravitreal bevacizumab rather than continuous therapy.Current controlled trials ISRCTN83325075 Age-related macular degeneration (AMD) is the leading cause of visual loss in patients over the age of 50 years in Europe and North America . There aHistorically the prognosis for patients with subfoveal nAMD has been poor with the established treatment of verteporfin photodynamic therapy (PDT) only showing modest efficacy in reducing visual loss in patients with well-defined (predominantly classic or classic no occult) sub-types of nAMD . Until tOne of the key mediators implicated in the pathogenesis of CNV in nAMD is vascular endothelial growth factor-A (VEGF). New treatments have targeted VEGF with the introduction of agents administered by injection into the vitreous cavity with high binding specificity to VEGF (anti-VEGF agents). There are three agents which block the action of VEGF-A currently in clinical use. These agents are administered by intraocular injections with repeated injection necessary every 4\u20136 weeks depending on the agent.\u00ae, Pfizer Inc, New York, NY). This agent is an oligonucleotide with high binding specificity for the 165 isoform of VEGF. The pivotal phase III randomised controlled trial reported a benefit in stabilising vision over sham treatment but disappointingly only 6% of treated patients improved vision by 15 letters or more at one-year follow-up [The first drug developed and licensed for use was pegaptanib sodium . This full-length monoclonal antibody binds to and blocks the action of all isoforms of VEGF. It was initially developed as an intravenous agent in the treatment of metastatic colorectal cancer [Another agent which has gained favour with ophthalmologists is bevacizumab is an antibody fragment developed from the bevacizumab molecule with increased binding affinity for all isoforms of VEGF. It has been shown to be more efficacious than sham treatment (placebo) in treating minimally classic or occult CNV [Ranibizumab . In addition to perceived better efficacy, repackaging pharmacies provide intravitreal bevacizumab for a fraction of the cost of pegaptanib, verteporfin or ranibizumab. However there are no large scale prospective, double-masked, randomised controlled trials supporting the use of bevacizumab for nAMD and there was therefore a need to design a clinical trial to investigate the efficacy and safety of intravitreal bevacizumab injections to standard therapy (PDT or pegaptanib) in the treatment of nAMD.The current trial is designed to investigate whether intravitreal bevacizumab injections are an effective and safe treatment for nAMD when compared to standard therapy. It will also provide exploratory data on the efficacy of bevacizumab when compared to either PDT, pegaptanib or sham treatment alone.Double-masked, randomised, controlled trial with 2 parallel treatment groups. Eligible patients were randomised in a 1:1 ratio to receive either intravitreal bevacizumab or standard therapy . Only one eye per patient was included in the study and this was selected prior to randomisation. Standard therapy was determined prior to trial enrolment at which point patients were allocated to treatment groups by minimisation \u2013 a dynamic process which reduces the imbalance between trial arms with respect to standard treatment eligibility and site. During trial recruitment, patients with well-defined were funded for PDT in line with National Institute for Health and Clinical Excellence (NICE) guidance. However there was no national funding in place for patients with poorly defined forms of nAMD as PDT had not shown efficacy over natural history for these lesion subtypes and the new anti-VEGF agents (pegaptanib and ranibizumab) had not been subject to appraisal by NICE. National Health Service (NHS) treatment was delivered on a case by case basis with many patients not funded for NHS treatment. Eligible patients with minimally classic or occult no classic CNV were either randomised to pegaptanib or sham treatment (based on funding of pegaptanib therapy). A summary of the enrolment and randomisation process in shown in Figure During the later stages of trial recruitment, after ranibizumab had been introduced into clinical practice, if patients were funded for ranibizumab, they were excluded from enrolment to this clinical trial. At the time of recruitment for this trial, since many patients who were refused public funding of treatment did not have medical insurance and could not afford the costs of private treatment, a significant proportion of patients remained untreated and therefore would consider involvement in a trial in which they were randomised to active treatment or to a sham arm. Previous precedents for such active treatment versus sham or no treatment trial included the pegaptanib VISION trial or the LTo test the hypothesis that in patients being treated for choroidal neovascularisation (CNV) due to age-related macular degeneration (nAMD), intravitreal bevacizumab injections can improve visual acuity (defined as a gain of \u2265 15 letters) in the treated eye in a greater proportion of patients than standard therapy after 12 monthsTo test the hypothesis that in patients being treated for CNV due to age-related macular degeneration (nAMD):1. Intravitreal bevacizumab injections are not associated with increased ocular and systemic adverse events compared to standard therapy after 12 months2. Intravitreal bevacizumab injections can stabilise visual acuity in a greater proportion of patients than standard therapy after 12 months3. Intravitreal bevacizumab injections can improve visual acuity (defined as a gain of \u2265 10 letters) in a greater proportion of patients than standard therapy after 12 months4. Intravitreal bevacizumab injections can improve visual acuity in a greater proportion of patients than standard therapy at the 6 month time-point5. Intravitreal bevacizumab injections can improve mean visual acuity when compared to standard therapy at the 12 month time-point6. Intravitreal bevacizumab injections can lead to a greater reduction in macular thickness than in patients receiving standard therapy at the 6 and 12 month time-points7. Intravitreal bevacizumab injections can lead to a greater reduction in leakage from CNV than in patients receiving standard therapy at the 12 month time-point\u2022 Age >50 years\u2022 Primary subfoveal CNV lesions secondary to AMD in the study eye\u2022 An occult CNV must have presumed evidence of disease progression, defined as one or more of the following:1. Deterioration of best corrected vision by 1 Snellen line or 5 letters on Early Treatment of Diabetic Retinopathy Study (ETDRS) charts within the past 3 months due to progression of CNV2. Presence of sub or intraretinal blood3. Growth of lesion size on fluorescein angiography by more than 10% in the past 3 months\u2022 Evidence of central macular thickening assessed using optical coherence tomography (OCT)\u2022 Total lesion size < 12 optic disc areas including all contiguous lesion components.\u2022 Area of fibrosis < 25% of the total lesion area\u2022 Area of subretinal blood less than 50% of total lesion area\u2022 Best corrected visual acuity, using ETDRS charts of 6/12 to 6/96 in the study eyeOnly one eye is assessed in the study. If both eyes are eligible, the one with the better visual acuity will be selected for treatment and study unless, based on medical reasons, the investigator deems the other eye the more appropriate candidate for treatment and study.Prior treatment with external-beam radiation therapy, transpupillary thermotherapy (TTT), thermal laser, or PDT in the study eyeTreatment with verteporfin in the non-study eye less than 7 days preceding Day 0,\u2022 Previous participation in a clinical trial (for either eye) involving anti-angiogenic drugs \u2022 Previous intravitreal drug delivery in the study eye\u2022 History of vitrectomy surgery in the study eye\u2022 History of greater than mild non-proliferative diabetic retinopathy or any diabetic maculopathy\u2022 History of retinal vascular occlusions \u2022 History of glaucoma filtering surgery in the study eye\u2022 History of corneal transplant in the study eye\u2022 History of submacular surgery or other surgical intervention for AMD in the study eye\u2022 Previous participation in any studies of investigational drugs within 1 month preceding Day 0 \u2022 Current or intending use of warfarin or known abnormal blood clotting\u2022 Subretinal haemorrhage in the study eye that involves the centre of the fovea, if the size of the haemorrhage is either >50% of the total lesion area or >1 disc area in size\u2022 Subfoveal fibrosis or atrophy in the study eye.\u2022 CNV in either eye due to causes other than AMD, such as ocular histoplasmosis, trauma, or pathologic myopia\u2022 Retinal pigment epithelial tear involving the fovea in the study eye\u2022 Any concurrent intraocular condition in the study eye that, in the opinion of the investigator, could either require medical or surgical intervention during the 12 month study period to prevent or treat visual loss that might result from that condition, or if allowed to progress untreated, could likely contribute to loss of at least 2 Snellen equivalent lines of best corrected visual acuity over the 12 month study period\u2022 Active intraocular inflammation (grade trace or above) in the study eye\u2022 Current vitreous haemorrhage in the study eye\u2022 History of rhegmatogenous retinal detachment or macular hole in the study eye\u2022 History of idiopathic or autoimmune-associated uveitis in either eye\u2022 Infectious conjunctivitis, keratitis, scleritis, or endophthalmitis in either eye\u2022 Aphakia or absence of the posterior capsule in the study eye. Previous violation of the posterior capsule in the study eye is also excluded unless it occurred as a result of YAG posterior capsulotomy in association with prior, posterior chamber intraocular lens implantation.\u2022 Spherical equivalent of the refractive error in the study eye demonstrating more than -8 diopters of myopia or signs of pathologic myopia with a refraction of 4\u20138 dioptersFor subjects who have undergone prior refractive or cataract surgery in the study eye, the preoperative refractive error in the study eye cannot exceed -8 diopters of myopia.\u2022 Intraocular surgery (including cataract surgery) in the study eye within 2 months preceding Day 0\u2022 Uncontrolled glaucoma in the study eye (defined as intraocular pressure >30 mmHg despite treatment with anti-glaucoma medication)\u2022 Premenopausal women not using adequate contraception\u2022 History of other disease, metabolic dysfunction, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect interpretation of the results of the study or render the patient at high risk for treatment complications\u2022 Current treatment for active systemic infection\u2022 Recent stroke, or cardiac event in the last 6 months, uncontrolled angina or hypertension.\u2022 History of allergy to fluorescein\u2022 Inability to obtain fundus photographs or fluorescein angiograms of sufficient quality to be analyzed and graded by the central reading centre\u2022 Inability to comply with study or follow-up proceduresAll patients referred to the Trial Centres with active CNV due to AMD were informed of the clinical trial and were given patient information sheets. Those patients who were keen to participate were screened with those meeting the eligibility criteria invited to enrol. The study is conducted according to ICHGCP , as set out in the European Union Clinical Trials Directive (2001) and associated UK Regulations (2004), which adhere to the principles of the Helsinki Declaration.Figure Bevacizumab was administered by six weekly intravitreal injections (dose of 1.25 mg in 0.05 ml per injection) and a treatment strategy of 3 treatments with further injections as needed based on investigator driven retreatment with standardised retreatment criteria was used reflecting the real world use of this agent at the time of the trial . The bevacizumab injections were prepared by Moorfields Pharmaceuticals in line with UK pharmaceutical regulatory standards.These were given as per the product license with a dose of 0.3 mg of pegaptanib in 0.09 ml given as continuous therapy by intravitreal injection every 6 weeks for 1 year (9 injections in 54 weeks). This reflects the dosing and frequency of treatment used in the pivotal VISION randomised controlled trial reporting the efficacy and safety of pegaptanib in the treatment of nAMD [2 of body surface area) in 30 ml of 5% dextrose after calculating body surface area from a nomogram based on the height and weight of the patient. Intravenous infusion of the solution is given over 10 minutes after covering the infusion line and pump to maintain masking (the solution is green). Fifteen minutes after the start of the infusion, the unmasked ophthalmologist applies laser light (diode laser 689 nm) for 83 seconds to the CNV lesion through a fundus contact lens of known magnification. The laser spot size for each treatment is determined by measuring the greatest linear diameter of the CNV lesion on fluorescein angiography and adding an addition 1000 \u03bcm in order to provide an additional margin of 500 \u03bcm around the lesion. After the treatment the patient is advised to avoid bright sunlight for 48 hours to prevent possible photosensitive reactions.Verteporfin PDT is performed as described elsewhere . BrieflyIn line with previous randomised controlled trials ,8, sham This is used for patients randomised to bevacizumab in cases in which standard care is PDT. The procedure is identical to that used for active verteporfin PDT except 5% dextrose is used as placebo with no verteporfin added. This is in line with previous studies . Care waAs the treatment of patients randomized to bevacizumab or pegaptanib involves the comparison of a pro re nata treatment (bevacizumab) to a treatment given continuously , to maintain masking, sham treatments were given to patients randomised to bevacizumab not requiring intravitreal treatment at that visit (weeks 18 to 48) based on the standardised retreatment criteria. This was to maintain masking as pegaptanib was delivered as continuous therapy (as per the product license) whereas bevacizumab was given as 3 initial injections with further retreatment as necessary using standardised retreatment criteria.Adequacy of masking was assessed by means of a questionnaire to patients and the masked investigator when the patient left the study to determine views on treatment allocation1. Visual acuity scoreAn improvement in visual acuity is defined as a gain of 15 letters or more (3 lines) of best corrected visual acuity score at the 12 month time point compared with baseline, using ETDRS visual acuity charts and visual acuity measurement at a starting distance of 4 metres.1. Other visual acuity based outcomesIn addition to the conventional end-point of 15 or more letter gain in visual acuity, more recently a clinical trial visual acuity end-point of 10 or more letters has been suggested and so t2. Optical Coherence Tomography based retinal thickness measurementStratus OCT was used to obtain retinal thickness measurements using fast macular thickness mapping scan protocol. Radial line scanning was used to determine the presence or absence of macular fluid at each visit. The mean change in macular thickness in the bevacizumab and standard therapy groups at the 6 and 12 month time-points will be reported.3. Contrast sensitivity measurementPelli-Robson charts were used to measure contrast sensitivity .4. Reading ability measurementMinnesota Reading (MNREAD) charts were useThese will be documented and serious adverse events will be reported to the Medicines and Healthcare Products regulatory Agency (MHRA). Both ocular and systemic adverse events will be noted. There will also be a specific report of any adverse events meeting the Antiplatelet Trialists' Collaboration (APTC) criteria . As thisRandomisation and treatment occur up to 14 days after a screening visit (or on the same day). After baseline treatment, patients attended again at week 1 for a safety visit (no treatment given). Further follow-up visits with repeat treatment occurred at week 6, 12, 18, 24, 30, 36, 42 and week 48. The study exit visit occurs at week 54 (1 year). This gives 9 treatment visits with the first 3 intravitreal bevacizumab treatments compulsory with further treatments as needed based on standardised retreatment criteria . Safety assessments consist of recording all adverse events, monitoring of blood pressure and pulse at every visit with blood tests at baseline, week 24 and study exit (week 54).Study assessments include functional outcome measures including best-corrected visual acuity assessments, contrast sensitivity measurement and measurement of reading ability (using MNREAD acuity charts). Structural outcome was assessed at every visit using OCT measures of retinal thickness and qualitative features of CNV activity. Fundus fluorescein angiography was performed at baseline and weeks 6, 12, 24, 36 48 and week 54 visits to allow assessment of any change in CNV size and leak. The trial visits are summarised in Figure 1, of 0.300 and a Group 2 proportion, \u03c02, of 0.060 when the sample size in each group is 57. To allow for a potential 12% loss to follow-up we plan to recruit 65 patients per treatment group. or more in each group at 12 months will be provided with 95% confidence intervals computed by the exact binomial method. A Fisher's exact test will be conducted to assess whether or not any observed difference in these proportions is statistically significant. Odds ratios will be reported together with 95% confidence intervals to illustrate the contrast between bevacizumab and standard treatment. If any imbalance in prognostic factors is detected, logistic regression will be conducted to assess the impact of any imbalance and adjusted odds ratios reported. Data will be analysed according to the group to which patients were originally assigned (i.e. intent to treat). In addition to the intention to treat analysis, a per protocol analysis will be carried out.The proportion of patients in each group who at 6 and 12 months havea) gained 5 letters of BCVAb) gained 10 or more letters of BCVAc) lost fewer than 15 letters of BCVAwill be reported with 95% confidence intervals together with a description of the average change in OCT determined central macular thickness and BCVA at 12 months. Comparative results (odds ratios and mean differences) will also be reported with 95% confidence intervals. These form part of the secondary end-points for the trial.Kaplan Meier plots will be constructed to examine rates of improvement of BCVA and Cox regression or log rank tests conducted. Adherence to the proportional hazards assumption will be assessed.Adverse events will be tabulated by treatment group.The trial centres and investigators are listed in Table 1The Trial Steering Committee monitor and supervise the trial and comment on any proposed major protocol amendments Table .The data monitoring committee (DMC) includes 2 independent ophthalmologists with a specialist interest in retinal disease and an independent statistician with clinical trials experience Table . No formAn operations committee consisting of the Chief Investigator, the Principal Investigator at the co-ordinating centre and the Trial Manager meet every week. During these meetings, the committee reviews the progress of the study identifying any problems or issues at all 3 sites.The trial is centrally co-ordinated from the Clinical Trials Unit (CTU) at Moorfields Eye Hospital. This provides the telephone randomisation service (which uses minimisation) and is responsible for data management.All trial centres are supplied with a Protocol, Standard Operating Procedures guidance, Source Documentation and Case Report Forms. Serious adverse events are reported to Moorfields Eye Hospital and to the MHRA.Applications to UK Main and Local Research Ethics Committees (REC) have received favourable opinions and a Clinical Trials Authorisation has been issued by the MHRA.The results of this trial will be submitted for publication to peer-review medical journals regardless of whether the outcome is in favour of the trial intervention.August 2006November 2007December 20082 years, 5 months1 year (54 weeks)\u00ae (bevacizumab) for CNV trial will be the first definitive, prospective, double-masked, multi-centre, randomised controlled trial reporting unbiased efficacy and safety data for intravitreal bevacizumab in the treatment of nAMD with results expected in early 2009.Since the first reports of the efficacy of bevacizumab in treating nAMD, there has been increasing use of this drug for this unlicensed indication and bevacizumab is probably the most widely used drug worldwide to treat nAMD because of its low unit cost despite the availability of alternative licensed therapies. However, most of the evidence supporting its use comes from interventional case and in this age of evidence-based medicine, there is no data from prospective, double-masked, multi-centre randomised controlled trials comparing the efficacy and safety of intravitreal bevacizumab to other therapies in the treatment of nAMD. The AvastinIn addition, the trial will provide information about the effect of treatment on structural and other functional outcome measures (including contrast sensitivity and reading ability). Exploratory analyses including possible prognostic indicators will also be of interest.\u00ae (bevacizumab) for CNV trial incorporates several novel features in the trial design. In contrast to previous multi-centre randomised controlled trials in the field [The Avastinhe field ,4,8,9, tTreatment in the comparator or control arm is determined by funding of standard therapy. This may be viewed as both a strength and a weakness of the study. Though not allowing comparison with a single agent, the choice of a comparator arm with one of 3 different treatments (2 active and one sham) reflects the usual treatment of patients in the NHS at the time of recruitment. It does not undermine the analysis of results as all treatments in the comparator arm have shown to offer patients a similar chance of improvement in vision (a maximum proportion of 0.06 improving vision with either comparator treatment at one year ). RanibiAnother novel design feature is the use of pro re nata treatment with bevacizumab (based on investigator determined retreatment with standardised retreatment criteria) after three initial treatments. This approach reflects clinical practice with clinicians using retreatment criteria to determine further treatment with anti-VEGF agents and should make the results more translatable into clinical practice. However this is distinct from the approach taken in the pivotal anti-VEGF agent trials in which a continuous treatment strategy was used. The use of continuous pegaptanib (reflecting the product license for pegaptanib) in the comparator arm is identical to the dosing used in the phase III trial comparing pegaptanib to sham treatment .The ABC trial is the first multi-centre randomised controlled trial to use OCT in all patients both using retinal thickness data to assess outcome and to use qualitative interpretation of scans in deciding on retreatment of patients with AMD. Previous randomised trials have used OCT only in a sub-set of patients with no use of OCT based retreatment criteria.In summary, the ABC trial uses a pragmatic yet high-quality trial design to evaluate the efficacy of intravitreal bevacizumab in the treatment of nAMD. The treatment strategy used reflects the clinical use of bevacizumab in treating nAMD and should help clinicians in translating the results from the trial into clinical practice. The trial aims to augment the evidence base for therapeutic options in the treatment of nAMD.The authors declare that they have no competing interests.PJP participated in development of the trial protocol and the trial design, coordinated the trial's set-up at Moorfields Eye Hospital and facilitated the set-up of the other study sites in London; prepared the trial's manual of operations, study documentation and publicity and drafted the manuscript. CB participated in development of the trial protocol, setup the trial's randomisation procedure and coordinates statistical analyses. AT conceived and designed the trial, secured trial funding and led its set-up at Moorfields Eye Hospital and helped to draft the manuscript."} +{"text": "The Ames Seralyzer uses solid phase chemistry coupled withreflectance spectroscopy to measure levels of serum alanineaminotransferase (serum ALT). The study reported here wascarried out to evaluate the performance of the Seralyzer methodcompared to conventional analyses carried out on a Coulter Dacosdiscrete random access analyser using Boehringer (BCL) reagentsconforming to SCE specications at 37\u00b0 C. Clinically acceptableaccuracy and precision were obtained. The effect of bilirubin andhaemoglobin on the test was investigated. Increased levels ofbilirubin in sera did not affect the estimation but the presence ofhigh haemoglobin levels produced significant interference. Theoverall practicality of the Seralyzer was assessed and the methodwas found to be particularly suitable for the estimation of urgent orhigh risk samples in the laboratory or for use by suitably trainedpersonnel in other clinical areas."} +{"text": "Cytokines play an important role in the development and persistenceof the inflammatory lesions seen in Crohn's disease and ulcerativecolitis. This review discusses the current thinking of the role ofcytokines in chronic intestinal inflammation including theinvolvement of immunoregulatory cytokines within the Th1 and Th2subsets."} +{"text": "The respiratory burst could be completely abolished by decomplementation and preincubation with rabbit antihuman C5a antibodies. Observation of human omentum using electron microscopy showed intravascular aggregation of PMNs, with capillary thrombosis and diapedesis of the cells through endothelial junctions 90 s after exposure to ZAP. PMNs caused disruption of connections between the mesothelial cells. After 4 min the mesothelium was completely destroyed, and connective tissue and fat cells exposed. Native plasma and minimum essential medium did not induce any morphological changes. These data support the concept that C5a activated PMNs can cause endothelial and mesothelial damage in man. Even though a causal relationship between anaphylatoxins and organ failure cannot be proved by these experiments C5a seems to be an important mediator in the pathogenesis of changes induced by severe sepsis and trauma in man.Activation of polymorphonuclear granulocytes (PMNs) by C5a is thought to be important in the pathogenesis of multiple organ failure during sepsis and after trauma. In our experiment exposure of human PMNs to autologous zymosan activated plasma (ZAP) leads to a rapid increase in chemiluminescence. Heating the ZAP at 56"} +{"text": "A retrospective survey has been made of 58 patients with recurrent and advanced male breast cancer treated with oral diethylstilboestrol. Fifty-five patients were suitable for assessment. Fourteen patients had an objective response and 7 had a partial response giving a total response of 21/55 patients (38%). The median remission for the objective responders was 7 years. Three patients are alive and free of disease; one has now been in remission for 13 years. It is suggested that diethylstilboestrol is a useful treatment in patients with soft tissue disease ."} +{"text": "In patients with disseminated malignant melanoma an optimal method of immunization with irradiated tumour cells was developed by reference to an in vitro assay for circulating specific serum inhibitors of cell mediated cytotoxicity. This immunization protocol consisted of the intradermal inoculation of 2 times 10(7) irradiated allogeneic melanoma cells admixed with 50 mug of percutaneous BCG. This method of immunization induced a significant but transient fall in the specific inhibitory effects of the sera on tumour directed cytotoxic activity of the patients' lymphocytes. In a pilot group of 30 patients with disseminated malignant melanoma being treated with chemotherapy (DTIC and vincristine) the immunotherapy was given midway between courses of the cytotoxic drugs. There was a correlation between the effects on circulating inhibitor and clinical outcome. The number of objective regressions occurring in this small pilot group was surprisingly high (17/30) and these clinical effects, although obtained in a series without concurrent controls, are presented for discussion. We suggest that the approach illustrated by this study, employing in vitro assays of tumour directed immune responses, may provide a suitable rational basis for the use of active immunotherapy as an adjunct to chemotherapy in the treatment of malignant disease."} +{"text": "Between 1977 and 1993, 384 breast cancer patients were followed up post-operatively every 4 or 6 months with a serum tumour marker panel (CEA-TPA-CA15-3) and the usual imaging techniques. Twenty-eight patients were treated 13.5 +/- 10 months (mean +/- s.d.) before the clinical and/or radiological occurrence of distant metastases that were suspected because of an increase in the tumour markers (patients treated 'early'). Their outcome was compared with that of 22 similar patients who were treated only after a definite radiological diagnosis was achieved (patients treated 'not early'). The median survivals from mastectomy and salvage treatment were also compared for the two groups. The groups were similar for all the major prognostic factors . In the group treated 'early', the lead time from the tumour marker increase to the clinical and radiological signs of metastases was significantly longer than that of the group not treated 'early' . For patients treated 'early', the survival curves up to 30 months after salvage treatment and up to 72 months after mastectomy showed greater survival than those for the patients treated later . These data suggest that treatment triggered by rising tumour markers before clinical and/or radiological appearance of distant metastases can be useful in prolonging both the asymptomatic interval and the duration of response of some relapsed patients. Randomized prospective trials must be encouraged to confirm these data and to better evaluate the effect on the disease-free survival (DFS) and overall survival (OS) of 'early' salvage treatment protocols."} +{"text": "The behaviour in vivo of tight and loose variants of murine melanoma cells is further characterized. In vitro clonal morphology is reproduced on a variety of substrates. Results suggest that repeated selection of loose cells can co-select for cells with high metastatic and colonization potentials. Measurement of cell motility shows that 1G3 (loose) cells are more motile than 1G8 (tight) which are restricted to movements within clonal boundaries. Studies of adhesive properties show that loose cells are more easily detached from the substrate with trypsin or EDTA and that both cell lines attach more quickly to monolayers of loose cells than to tight ones. No gross differences are found either in attachment rates to plastic and ECM or in aggregation and disaggregation rates. Analysis of the cell surface has not revealed any differences between 1G8 and 1G3 in the sialylation of terminal galactose and N-acetylgalactosamine residues or in neuraminidase releasable sialic acid. The binding patterns of iodinated lectins to SDS-PAGE separated proteins are similar for both lines except for one 85/90 KD protein which is more abundant in 1G3 than 1G8 cells after neuraminidase treatment. The results show enhanced differences in metastatic potential of tight and loose clones after selective cloning and that there may be important differences in motility and cell-substrate interactions."} +{"text": "Serum activity of alpha-N-acetylgalactosaminidase , the extracellular matrix-degrading enzyme that appears to be produced exclusively by cancer cells, was measured in mice bearing SCCVII tumours (squamous cell carcinoma). The NaGalase levels in these mice increased with time of tumour growth and were directly proportional to tumour burden. After exposure of SCCVII tumours to a single X-ray dose of 20 Gy, the serum NaGalase levels gradually decreased during the first 10 days after treatment and then began to increase. The decrease in serum NaGalase activity was more rapid after the treatment of SCCVII and EMT6 tumours by photodynamic therapy (PDT) and was dependent on the PDT dose. The treatments (based on photosensitizers Photofrin or mTHPC) that were fully curative resulted in the reduction of NaGalase activity to background levels within 2 or 3 days after PDT. A slower decrease in NaGalase activity was found after PDT treatments that attain an initial tumour ablation but are not fully curative. The regrowth of PDT-treated SCCVII tumours was preceded by an increase in serum NaGalase levels, which was detected as early as 8 days before the visible tumour reappearance. These findings ascertain the validity of serum NaGalase measurement for the assessment of tumour response to different treatments and support the concept that the NaGalase measurement could serve as a diagnostic and prognostic index that might allow oncologists to design the dosage or nature of treatment."} +{"text": "Rapid hydrolysis of both the carboxylate and cyclopentadienyl ligands inCp2TiX2 occurs in DMSO to give biologically inactive species. Therate of these reactions are concentration dependent as dilution of these samples with saline orwater to give the therapeutic conditions of 10%DMSO/90%H2O slows the hydrolysis chemistry. Incontrast, samples of Cp2TiX2 , dissolved in water give solutionscontaining the presumed antitumour active species in which the halide or glycine ligands havebeen hydrolysed but the Cp rings remain metal bound.The rate of hydrolysis of the aromatic rings of Cp"} +{"text": "The ABO(H) and Y antigen status of epithelial cells from 45 breast carcinomas, 14 benign breast lesions and 7 normal breasts have been assessed using an indirect immunoperoxidase histochemical assay and a series of blood group specific monoclonal antibodies. All 20 A, AB and B group tumours had lost the A and B isoantigens, 13 of these tumours were however found to express H and Y antigens. Of 25 group O tumours 17 expressed the expected H and Y antigens. These findings were not dependent on the histological nature or the invasive characteristics of the tumour. Similar results were obtained when 28 metastases from breast carcinomas were examined, the H and Y antigens being identified in the tumour elements in 24 lymph nodes while we failed to identify either the A or B antigens. The development of breast malignancy appeared therefore to correlate best with the deletion of A and B glycosyl transferases. Normal breast tissue consistently expressed the expected blood group isoantigens. Areas of benign breast disease showed a more varied pattern of antigen expression. Seven of 14 lesions lacked ABH antigens, the loss of blood group structures could not however be correlated with any specific histological features and was not limited to the loss of A and B substances."} +{"text": "A mutation at codon 974 of the dihydropyrimidine dehydrogenase (DPD) gene was previously described in a cancer patient with undetectable DPD enzyme activity who experienced severe toxicity when treated with 5-fluorouracil. We have studied the frequency of this mutation in 29 Scottish subjects with low DPD enzyme activity and in 274 American subjects. We detected no mutations in the 606 alleles studied and conclude that mutations at codon 974 are a rare event."} +{"text": "We have studied various factors involved in the optimal use of a tetrazolium (MTT) based colorimetric assay for cell growth and chemosensitivity. The assay is dependent on the ability of viable cells to metabolise a water-soluble tetrazolium salt into a water-insoluble formazan product. We have found that DMSO is the best solvent for dissolving the formazan product, especially where a significant amount of residual medium is left in the wells of the microtitre tray used for the assay. A reaction occurs between medium and a solution of MTT formazan in DMSO which changes the shape of the absorbance spectrum of the solution. The resulting optical density is not however greatly dependent upon the volume of added medium in the range 1-10 microliters. Between 10 and 40 microliters of added medium results in a gradually lower optical density than that produced by the smaller volumes. Above 40 microliters, the optical density increases again due to turbidity as protein precipitation occurs. When cells are incubated with MTT, the resulting optical density of the formazan product is dependent upon both the concentration of MTT and the incubation time. The optical density is stable for several hours after solution of the formazan in DMSO. A linear relationship is seen between optical density and cell number for incubation times of 2, 4, 6 or 24 h with 20 microliters of MTT (5 mg ml-1) added to 200 microliters medium. We have adopted 4 h as the standard incubation time for the assay. Only a small amount of MTT formazan product can be detected in the growth medium of wells in which cells have been exposed to MTT. Comparative chemosensitivity data for EMT6 mouse tumour cells show good agreement between results obtained using the MTT assay and results based on total cell count after a fixed period of growth."} +{"text": "A loading dose of MPA employing a regimen of 1,000 mg six hourly for 8 doses can achieve plateau levels above 100 ng ml-1 within the first 36 h of treatment, without any untoward toxicity. This raises the possibility of shortening the time to response for this agent. The additional factor of the time required to achieve adequate serum levels may explain the apparent contradictions between reports correlating response rates and dose and those correlating serum level and response."} +{"text": "Tak Tent is a cancer support organisation consisting of 14 groups of which 11 are based in Scotland. In 1985, a survey was conducted among those attending the Scottish groups. 146 (79%) of the groups' members completed survey questionnaires. The results showed that Tak Tent's membership mainly comprised cancer patients (36%), relatives of patients (34%) and professionals involved in cancer care (21%). Women outnumbered men 3 to 1 and most of the membership belonged to social classes I, II or III. The groups appeared to be meeting their members' expectations of them to varying degrees. Respondents were satisfied that group membership had allowed them to make new friends, find out more about cancer and meet others facing similar difficulties. They were less certain that participation in a group had enabled them to learn how to cope better with cancer, share their problems with others or provide support for others to the extent they had anticipated."} +{"text": "The natural course of untreated posterior lateral rotatory instability of the elbow is unclear. A case of elbow arthrosis with progressing deformity and flexion contracture after an episode of elbow dislocation about 20 years ago presented the possibility the long term outcome of untreated posterior lateral rotatory instability of the elbow. The lateral collateral ligament complex of the elbow is the main stabilized of posterolateral rotatory instability and was described by O'Driscoll at 1991. The lonA 46-year-old, right-hand-dominant male presented with left ring and little fingers numbness and hand weakness that had been aggravated over the previous 4 months. He had chronic pain and progressive deformity of lateral elbow, and lost extension after one episode of elbow dislocation about 20 years ago. He was transferred to our office for further assessment with above symptoms. Tracing back his trauma history revealed that he noted a daily sensation of painful slip in and out on the lateral elbow joint after a dislocation underwent a closed reduction by a bonesetter. His elbow symptom didn't improve or got a diagnosis after visiting three orthopedic surgeons for the first 6 months. Although his elbow symptom was persisting but he was tolerable at eating, dressing, carrying or pulling of daily activity or working ability except lifting or push-up and he didn't visiting any physician for further help since then until this new symptom of hand numbness occurred.Physical examination revealed the elbow with flexion arc from 20\u00b0 to 120\u00b0 and full forearm rotation compared with contra lateral side, and grip strength 105 lb (125 lb on the right side). Palpation revealed the deformed elbow with prominent radial head not lateral epicondyle on the lateral of the elbow. The result of neurologic examination was abnormal including paresthesias in the ulnar half of ring finger and little finger and dorsal ulnar wrist with positive Tinnel sign and nerve compression test of the ulnar nerve at elbow, little finger abduction weakness but without claw hand deformity. Plain radiographs showed arthrosis of the elbow joint with the radiohumeral joint more sever than ulnohumeral joint, radial head deformity including lost normal concave shape and hypertrophic marginal osteophyte with lateral subluxation and some chip bone or ectopic bone over lateral epicondyle . Post-operative plain radiographs showed the deformed radial head still subluxation at anterior-posterior view but no progressing arthrosis of the elbow joint in the wrist with scapholunate advanced collapsed degeneration is well known; we need more clinical studies of posterolatreal rotatory instability of the elbow and biomechanical investigations of the pivot-shift test of lateral collateral ligament complex to establish this relationship and understanding the natural course of posterolateral rotatoy istability of the elbow. The radiographic findings of this case with elbow arthrosis more severs on the radiohumeral joint than ulnohumeral joint and the radial head hypertrophic deformity and subluxation may be to characterize a neglected ligament injury with rotatory instability.Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The author declares that they have no competing interests."} +{"text": "Solanum lycopersicum) is being sequenced by an internationalconsortium of 10 countries as part of a larger initiativecalled the \u2018International Solanaceae Genome Project (SOL): Systems Approachto Diversity and Adaptation\u2019. The goal of this grassroots initiative, launched inNovember 2003, is to establish a network of information, resources and scientiststo ultimately tackle two of the most significant questions in plant biology and agriculture:(1) How can a common set of genes/proteins give rise to a wide range ofmorphologically and ecologically distinct organisms that occupy our planet? (2) Howcan a deeper understanding of the genetic basis of plant diversity be harnessed tobetter meet the needs of society in an environmentally friendly and sustainable manner?The Solanaceae and closely related species such as coffee, which are includedin the scope of the SOL project, are ideally suited to address both of these questions.The first step of the SOL project is to use an ordered BAC approach to generate ahigh quality sequence for the euchromatic portions of the tomato as a reference forthe Solanaceae. Due to the high level of macro and micro-synteny in the Solanaceaethe BAC-by-BAC tomato sequence will form the framework for shotgun sequencingof other species. The starting point for sequencing the genome is BACs anchoredto the genetic map by overgo hybridization and AFLP technology. The overgos arederived from approximately 1500 markers from the tomato high density F2-2000genetic map (http://sgn.cornell.edu/). These seed BACs will be used as anchors fromwhich to radiate the tiling path using BAC end sequence data. Annotation will beperformed according to SOL project guidelines. All the information generated underthe SOL umbrella will be made available in a comprehensive website. The informationwill be interlinked with the ultimate goal that the comparative biology of theSolanaceae\u2014and beyond\u2014achieves a context that will facilitate a systems biologyapproach.The genome of tomato ("} +{"text": "The aim of this study was to evaluate the role of colour-coded and spectral Doppler sonography to predict the benign or malignant nature of breast lesions. A total of 112 women with mammographically suspicious breast lesions were investigated prior to surgery. Thirty-nine breast carcinomas and 73 benign lesions were evaluated for the resistance index, pulsatility index and the flow velocity. A resistance index of > or = 0.70 was characteristic of malignant tumours with a sensitivity of 82% and a specificity of 81%. The positive predictive value was 70% and the negative predictive value 89%. Doppler sonography offers one possible method for further investigation of patients with mammographic abnormalities."} +{"text": "The MAC 16 is a transplantable murine carcinoma of the colon producing extensive weight loss in tumour-bearing animals. The weight loss is proportional to the size of the tumour and occurs without a reduction in food intake when compared with non tumour-bearing control mice. Weight loss produced by the MAC 16 tumour is accompanied by hypoglycaemia which becomes more extensive as the tumour mass increases. In order to understand the mechanism of the cachexia produced by the MAC 16 tumour the rate of substrate utilization and CO2 formation from both glucose and palmitate has been compared in vitro, with other colon carcinoma cell lines known not to produce cachexia as well as a range of murine and human tumour cell lines. The rate of glucose consumption, lactate production and CO2 formation from both glucose and palmitate is much higher for the MAC 16 than for the other tumour cells. For all cell lines in vitro the consumption of glucose exceeds that of palmitate by a factor of 10(3). Excessive consumption of glucose by the MAC 16 tumour may account for the hypoglycaemic effect on the host. The level of 3 oxo acid CoA transferase, an initiator of ketone body utilization, was found to be much lower in the MAC 16 tumour than non-involved colon. This suggests that the tumour may not be able to metabolize ketone bodies effectively."} +{"text": "Detection of bone marrow infiltration by lymphoma with low field strength magnetic resonance imaging (MRI) has been assessed. Measurements of spin lattice relaxation time (T1) were made in 31 patients with lymphoma and compared with the results of bone marrow biopsy and with T1 measurements made on 90 healthy volunteers. The sensitivity of MRI was excellent in patients for whom the microscopic pattern of marrow infiltration was diffuse, but poor in those with microscopically focal infiltration."} +{"text": "Serum sialyl transferase (SST) was measured in 49 female patients with advanced breast cancer and 60 female controls. The mean SST level was significantly raised in patients with advanced breast cancer. There was no correlation between specific sites, or numbers of sites of metastatic disease and SST levels. The patients with advanced breast cancer were all treated with chemotherapy; in 13/21 responders there was a significant fall in SST and in 2 responders a significant rise in SST. The 6 patients who died after one course of chemotherapy had a significantly higher mean SST than those surviving longer. SST appears to lack sufficient specificity to be of practical value as a marker of response in patients with breast cancer treated by chemotherapy, though constant measurement of changes in SST may be of use in monitoring drug response. Raised SST at the commencement of chemotherapy may signify poor prognosis."} +{"text": "A cluster of 22 imported malaria cases, 21 caused by Plasmodium falciparum, was observed among illegal Chinese immigrants in northern Italy in the summer of 2000. The rate of severe disease was high because the patients were not immune and they sought health-care services late in their illness because of their clandestine status. Recognition of the outbreak was delayed because no regional alert system among infectious diseases hospitals was in place."} +{"text": "By measuring peripheral drug levels in plasma, the effect of combining albumin microspheres with angiotensin II on systemic exposure to 5FU when administered by bolus injection into the hepatic artery in patients with advanced colorectal liver metastases has been assessed. The results suggest that despite hepatic arterial administration of 5FU, there was no reduction in systemic exposure when compared with that associated with intravenous injection of the same dose. Neither albumin microspheres nor angiotensin II appeared to improve the regional advantage. There have been a number of reports relating the plasma levels of cytotoxic agents with pharmacodynamic parameters. We have shown significant direct correlations between 5FU clearance and 1 week post treatment platelet and white cell counts, and an inverse relationship between the area under the 5FU plasma concentration-time curve (AUC) and 1 week post treatment platelet count and white cell count respectively."} +{"text": "A control system based on a combination of the gain-schedulingcontrol method and an adaptive PID controller was designed forthe production of xylose from hardwood hemicellulose using astirring tank reactor. Different operating conditions have beenconsidered for estimating the adjustable parameter (\u03b8) to take intoaccount the changes of energy of the system. The performance ofthe control system was studied first by numerical simulation, andafter implementation in the stirred tank reactor where the controlleractually works."} +{"text": "Sir,Asthma and other atopic conditions such as eczema and hay fever are often treated with corticosteroids and have been found by some epidemiologic studies to be associated with a reduced risk of many types of cancers, although these findings are not consistent l . Consequet al suggests the possibility of such confounding. Table 1A reanalysis of data pertaining to oral glucocorticoid use presented in the paper by Karagas Crude odds ratios with accompanying 95% confidence intervals were calculated to measure the association between risk of BCC and SCC and oral steroid use (Table 2"} +{"text": "Antioxidant properties of three Curcumin derivatives in which the 1,3-diketone system isappended with nitrogen and sulfur donors and their copper conjugates are examined for the first time. Metalconjugation seems to offer distinct advantages in radical scavenging activities of curcumin compounds."} +{"text": "Breast cancer in men is rare and is clearly due in some cases to an inherited predisposition. A total of 28 male breast cancer patients were tested for BRCA2 mutations; two frameshifts and one putative missense mutation were identified. One of the frameshifts was detected in the same position as a mutation estimated to be responsible for 40% of all male breast cancer cases in Iceland."} +{"text": "An animal model of experimental testicular teratoma has been established to study how a teratoma affects the host testis and how the host testis reacts against the teratoma. 129/SvJ-mice were used as experimental animals. To induce the experimental testicular teratoma, male gonadal ridges from 12-day-old 129/SvJ-mouse fetuses were grafted into the testes of adult mice for 1\u201312 weeks. The developing tumour was analysed by light and electron microscopy and by immunocytochemical localization of transcription factors SOX9 and c-kit, glial fibrillary acidic protein (GFAP) and type IV collagen. Testicular teratoma was observed in 36 out of 124 testes with implanted fetal gonadal ridges (frequency 29%). One spontaneous testicular teratoma was observed in this material from 70 male mice (1.5%). One week after implantation intracordal clusters of cells were seen in embryonic testicular cords of the graft as the first sign of testicular teratomas. Four weeks after implantation the embryonic testicular cords had totally disappeared from grafts with teratomas, and the tumour tissue had enlarged the testis and invaded the interstitium of the host testis. It consisted of solitary pieces of immature cartilage as well as of glial cells and of primitive neuroepithelium. Six to eight weeks after implantation the tumour tissue had expanded so that the enlarged testis could be detected by macroscopic enlargement of the scrotum. The testicular tissue of the host had practically disappeared, and only solitary disrupted seminiferous tubules of the host were seen surrounding the teratoma. Neuroepithelial structures of some teratomas cultured for 8 weeks had cells with a granular nucleus as a sign of obvious apoptosis. Eleven to 12 weeks after implantation the growth of the teratoma had stopped, and the histology corresponded to that of a mature cystic teratoma. GFAP, SOX9 and type IV collagen were strongly positive in some parts of the tumours cultured for 4 and 8 weeks, while only occasional c-kit-positive areas were observed in tumours cultured for 8 weeks. As conclusions: (1) the metastasizing capacity of the experimental testicular teratoma is very low during 12 weeks, but the behaviour of the tumour in the testicular tissue of the graft is invasive; (2) the growth of experimental testicular teratomas cease 6\u20138 weeks after implantation of the fetal gonadal ridges with the obvious apoptosis of the immature tissue components; (3) the model of experimental testicular teratoma in the mouse is suitable for studying how the teratoma affects the host testis and how the host testis reacts to teratoma. \u00a9 1999 Cancer Research Campaign"} +{"text": "Few data are available on the circadian rhythmicity in cancer patients. Since monitoring the disease usually implies the follow-up of blood concentrations of a number of biological variables, it would be of value to examine the profile of the circadian variations of serum cortisol and tumour marker antigens. This we did in 33 cancer patients (13 breast cancer patients and 20 ovarian cancer patients). The profiles of serum cortisol were documented, since this hormone is considered as a strong marker of circadian rhythms. This study shows that 8 out of 13 breast cancer patients and 15 out of 20 ovarian cancer patients had deeply altered cortisol circadian patterns. The modifications were either high levels along the 24 h scale and/or erratic peaks and troughs and/or flattened profiles. Within 24 h, variations of tumour marker antigens as large as 70% were observed but no typical individual circadian patterns could be found. No relationship between cortisol subgroups and concentration of tumour marker antigens at 8 h could be observed (Kolmogorov-Smirnov's test). The question thus arises as to the origin of these alterations, and whether they are related to a cause or a consequence of the disease, and their possible incidence upon therapeutic designs."} +{"text": "The aim of this study was to examine the possibility of predicting anxiety and depression 6 months after a cancer diagnosis on the basis of measures of anxiety, depression, coping and subjective distress associated with the diagnosis and to explore the possibility of identifying individual patients with high levels of delayed anxiety and depression associated with the diagnosis. A consecutive series of 159 patients with gastrointestinal cancer were interviewed in connection with the diagnosis, 3 months (non-cured patients only) and 6 months later. The interviews utilized structured questionnaires assessing anxiety and depression [Hospital Anxiety and Depression (HAD) scale], coping [Mental Adjustment to Cancer (MAC) scale] and subjective distress [Impact of Event (IES) scale]. Patient anxiety and depression close to the diagnosis were found to explain approximately 35% of the variance in anxiety and depression that was found 6 months later. The addition of coping and subjective distress measures did little to improve that prediction. A model using (standardized) cut-off scores of moderate to high anxiety, depression (HAD) and intrusive thoughts close to the diagnosis to identify patients at risk for delayed anxiety and depression achieved a sensitivity of 75% and a specificity of 98%. Levels of anxiety and depression at diagnosis predicted a similar status 6 months later. The results also indicated that the HAD scale in combination with the IES intrusion subscale may be used as a tool for detecting patients at risk of delayed anxiety and depression. \u00a9 1999 Cancer Research Campaign"} +{"text": "Thirteen cases of falciparum malaria acquired by Europeans in the Dominican Republic occurred from June 1999 to February 2000. The cases were identified by the European Network on Imported Infectious Disease Surveillance (TropNetEurop)."} +{"text": "Interviews were obtained with 106 patients with adenocarcinoma of the renal parenchyma, 33 patients with carcinoma of the renal pelvis and 139 individually matched control patients. Comparison of the cancer patients with the control patients showed no evidence of a positive association between either type of renal cancer and coffee or animal protein consumption. Carcinoma of the renal pelvis was associated positively with cigareete consumption (relative risk estimate 1-8) and the daily consumption of analgesic tablets was more frequent in patients with cancer of the renal parenchyma than in their matched controls . It appeared likely that the latter relationship was non-causal."} +{"text": "We have used bisulphite genomic sequencing to examine the detailed sequence specificity of DNA methylation in the CpG island promoter/exon 1 region in the p16 gene in DNA from a series of human breast cancer specimens and normal human breast tissue (from reductive mammaplasty). The p16 region examined was unmethylated in the four normal human breast specimens and in four out of nine breast tumours. In the other five independent breast tumour specimens, a uniform pattern of DNA methylation was observed. Of the nine major sites of DNA methylation in the amplified region from these tumour DNAs, four were in non-CG sequences. This unusual concentration of non-CG methylation sites was not a general phenomenon present throughout the genome of these tumour cells because the methylated CpG island regions of interspersed L1 repeats had a pattern of CG methylation similar to that found in normal breast tissue DNA and in DNA from tumours with unmethylated p16 genes. These data suggest that DNA methylation of the p16 gene in some breast tumours could be the result of an active process that generates a discrete methylation pattern and, hence, could ultimately be amenable to theraputic manipulation. \u00a9 1999 Cancer Research CampaignThe"} +{"text": "The proliferation characteristics of vascular endothelium have been studied in 131 individual experimental tumours, representing 18 transplanted tumour lines. The labelling index (LI) is high in most tumours, with a mean value of 0.9%, regardless of the growth rate of the tumours, or whether different tumour types are considered or individual tumours from within one line are studied in detail. A similar high LI value has been found by others for a human tumour. These high LI values may even underestimate the proliferation in new capillary buds. The high proliferative index of tumour endothelium is in marked contrast with the previously reported low 3HTdR uptake into normal tissue blood vessels. It seems likely that it is the type of new vessels formed that will influence tumour growth rates more than the simple rate of endothelial-cell proliferation. The large difference between the proliferation characteristics of tumour endothelium and normal tissue endothelium, recently identified as a possible approach for tumour therapy, has now been confirmed for a range of animal tumours and a human tumour."} +{"text": "P. falciparum-infected erythrocytes (IEs) express a unique member of the PfEMP1 family named VAR2CSA, which is associated with the ability of the IEs to adhere to chondroitin sulphate A (CSA) in the placenta [In pregnant women, We have shown that full length recombinant VAR2CSA binds with high affinity to CSA . To defiStructural analysis of theVAR2CSA recombinant proteins shows that the protein is structured with a large compact head structure where the minimum CSA binding region is also located.The minimum CSA binding region ofVAR2CSA spans several single domains; this is in line with data showing that several single domains can induce adhesion blocking antibodies. It remains to be investigated if the minimum binding region is a better vaccine construct than the proposed single domains."} +{"text": "Sir\u2014I have read with interest the article by Dr. Apelqvist et al. In their well-performed study they did not find pneumatic wound compression to reduce the need for blood transfusion after hip fracture surgery. In the discussion the authors mention several explanations for not receiving positive results found in two previous studies concerning the same wound compression device used after elective total hip arthroplasty in the compression group and to 85 (55%) in the non-compression group."} +{"text": "Levels of the nucleotide pathway enzyme thymidine kinase (TK) were assayed in the mononuclear leukocytes and serum of 70 female patients with breast cancer and 98 male and 77 female non-cancer hospital patients. The total TK levels in both mononuclear leukocytes and serum from patients with breast cancer were significantly higher than in controls. The serum TK levels showed a significant correlation with cancer stage. No such correlation was observed with mononuclear leukocyte TK levels. Serum TK from 20 patients with breast cancer and 19 control patients was further assayed to ascertain the relative contributions of the thymidine kinase isozymes TK1 and TK2 to total TK levels. The increase in serum TK from breast cancer patients appears to be due to an increase in both TK1 and TK2 levels."} +{"text": "A study of the thymidine labelling index (TLI) of bone marrow blast cells in 58 untreated patients with acute myelogenous leukemia showed no correlation with remission rate but there was a strong correlation between labelling index and remission length in the 21 patients who achieved remission. The median remission length of the patients was 33 weeks. Of the 12 patients with initial labelling indices greater than 10%, only 2 had remissions longer than 33 weeks whereas 8 of the 9 patients with labelling indices less than 10% had remissions longer than 33 weeks. No correlation could be found between the degree of cytological differentiation and remission induction, remission length or survival. No correlation was found between the TLI and the degree of cytological differentiation. Age and initial platelet count were confirmed to be important factors influencing complete remission rate, but these factors did not correlate with remission length. Sixteen patients had their pretreatment sera assayed for mouse marrow colony stimulating activity and inhibitor levels but there was no correlation with subsequent response to treatment, although the number of patients examined was clearly too small for any definite conclusions to be drawn."} +{"text": "Objectives To clarify the underlying mechanism for the highrestenosis rate after the coronary angioplasty for the chronictotal occlusion by using the coronary angioscope. BackgroundCoronary angioplasty for the chronic total occlusion is associatedwith higher restenosis rate than for highly stenotic lesion.However, the difference in the restenosis rate has not beendiscussed from the angioscopic observation.Methods and Results The lesion morphology after coronaryintervention were classified into 4 grade . Coronary angioscopic observation was performed in 46patients with stable angina. Most of the lesion morphology afterangioplasty in 13 patients with chronic total occlusion was grade3. On the other hand, none of grade 3 was observed in 36 patientswith severe coronary stenosis.Conclusion The various protrusions into the lumen shown by the angioscope might be areason for higher restenosis and reocclusion rates compared with those after the angioplastyfor the severe stenotic lesion."} +{"text": "No bacteria were detected in 10 of the 13 patients in the control group. In the other three control patients the bacterial count was 2.2 log CFU/ml or less. The mean bacterial count was significantly higher in patients with recurrence than in those without recurrence. Cholescintigraphy revealed a trend toward a higher number of isolates and a higher bacterial count in bile in patients with delayed bile passage than in those with good passage. The results suggest that an increased number of biliary isolates and an increased bacterial count indicate decreased bile flow in patients with choledocholithiasis who are being followed up after EST. These variables may potentially serve as indicators of the risk of stone recurrence. Especially when the bacterial count is higher than 7.0 log CFU/ml, the risk of a decrease in bile flow and an increased stone recurrence would be possibly found.Bacteria have been implicated in recurrent choledocholithiasis associated with endoscopic sphincterotomy (EST). This study was designed to clarify whether bacterial examination of bile provides information useful in predicting the risk of recurrence of choledocholithiasis in patients undergoing EST. Bacteria in bile collected via a duodenoscope before cholangiography were cultured. We compared bacterial isolates and quantity among 41 patients with choledocholithiasis (7 with and 34 without a history of recurrent choledocholithiasis) who had undergone EST more than 3 months previously and 13 control patients with no evidence of pancreatobiliary disease. The bile samples were cultured under aerobic and anaerobic conditions. The bacterial quantity was expressed as the mean logarithm of the number of colony forming units (CFU)/ml. Furthermore, cholescintigraphic studies of bile flow were performed with the use of"} +{"text": "To estimate the effectiveness of pneumococcal polysaccharide vaccine, we serotyped isolates submitted to the Pneumococcal Sentinel Surveillance System from 1984 to 1996 from 48 vaccinated and 125 unvaccinated children 2 to 5 years of age. Effectiveness against invasive disease caused by serotypes included in the vaccine was 63%. Effectiveness against serotypes in the polysaccharide vaccine but not in a proposed seven-valent protein conjugate vaccine was 94%."} +{"text": "Proprotein convertases mediate the production of a variety of peptidic mitogens by limited proteolysis of their precursors. These proteases may also participate in the autocrine production of such mitogens by cancer cells and thus contribute to the unchecked proliferation of these cells. As a step towards defining this contribution, we have examined the levels of four convertase mRNAs in human lung neoplasms using semiquantitative Northern blot analysis. Furin mRNA was expressed in all the tumours; its level in squamous cell carcinomas and adenocarcinomas was on average about threefold higher than in small-cell lung carcinomas (SCLCs). PACE4 transcripts were detected in eight of 14 adenocarcinomas and in seven of 17 squamous cell carcinomas; they were detectable in only two of seven SCLCs. PC1 mRNA was undetected in squamous cell carcinomas and in all but two adenocarcinomas; it was present in four of six SCLCs. PC2 mRNA was found in two adenocarcinomas, in one squamous cell carcinoma and in five of seven SCLCs. This preliminary survey indicates that SCLCs often carry more mRNA for the endocrine convertases PC1 and PC2 and less mRNA for the more ubiquitous furin and PACE4, suggesting inverse roles of these convertases in the development of this neoplasm."} +{"text": "A monoclonal antibody raised against the high molecular weight melanoma antigen was labelled with indium-111 and injected intravenously into 25 patients with malignant melanoma. The results obtained from images at 24 and 96 h post i.v. administration of the antibody were compared with results obtained from computerised tomography studies with regard to detection of previously unrecognised sites of metastatic disease and apparent false positive localisation. Detailed study of the patients' clinical condition and detection rates using the two methods suggest that both methods detect approximately 80% of clinically and pathologically confirmed metastases. Of 62 known metastases, the antibody detected 50 (81%), with 17 false positive results. False negatives were most common in the lung. In eight patients the two methods were considered of equal value, in 10 the monoclonal gave a greater amount of clinically relevant information, and in seven the CT was superior. In three patients clinically significant metastatic lesions were detected by the radiolabelled monoclonal and had not been previously recognised either by CT scanning or on clinical grounds. No patients had any adverse reaction to the antibody and in the course of our study the dose of antibody was reduced from 20 mg to 200 micrograms with no apparent loss of sensitivity. In at least two patients uptake of the labelled monoclonal into tumour sites would have been adequate for effective targeted radiotherapy."} +{"text": "Purpose of this study was to evaluate the functional outcome of spinal accessory to suprascapular nerve transfer (XI-SSN) done for restoration of shoulder function and partial transfer of ulnar nerve to the motor branch to the biceps muscle for the recovery of elbow flexion (Oberlin transfer).This is a prospective study involving 15 consecutive cases of upper plexus injury seen between January 2004 and December 2005. The average age of patients was 35.6 yrs (15\u201352 yrs). The injury-surgery interval was between 2\u20136 months. All underwent XI-SSN and Oberlin nerve transfer. The coaptation was done close to the biceps muscle to ensure early recovery. The average follow up was 15 months (range 12\u201336 months). The functional outcome was assessed by measuring range of movements and also on the grading scale proposed by Narakas for shoulder function and Waikakul for elbow function.Good/Excellent results were seen in 13/15 patients with respect to elbow function and 8/15 for shoulder function. The time required for the first sign of clinical reinnervation of biceps was 3 months 9 days (range 1 month 25 days to 4 months) and for the recovery of antigravity elbow flexion was 5 months (range 3 1/2 months to 8 months). 13 had M4 and two M3 power. On evaluating shoulder function 8/15 regained active abduction, five had M3 and three M4 shoulder abduction. The average range of abduction in these eight patients was 66 degrees (range 45\u201390). Eight had recovered active external rotation, average 44 degrees (range 15\u201395). The motor recovery of external rotation was M3 in 5 and M4 in 3. 7/15 had no active abduction/external rotation, but they felt that their shoulder was more stable. Comparable results were observed in both below and above 40 age groups and those with injury to surgery interval less than 3 or 3\u20136 months.Transfer of ulnar nerve fascicle to the motor branch of biceps close to the muscle consistently results in early and good recovery of elbow flexion. Shoulder abduction and external rotation show modest but useful recovery and about half can be expected to have active movements. Two patients in early fifties also achieved good results and hence this procedure should be offered to this age group also. Surgery done earlier to 6 months gives consistently good results. In upper brachial plexus avulsion injuries loss of abduction and external rotation at shoulder and flexion at elbow are the main functional deficits. Spinal accessory nerve has been the most commonly used donor for restoration of shoulder abduction and external rotation with varying results in different centers. -9. On avRecent literature and our This was a prospective study of 15 consecutive cases of upper plexus injury with good hand function who presented to us within 6 months of injury during the period of January 2004 and December 2005. The average age of patients was 35.6 yrs (15\u201352 yrs). There were 14 males and one female. In all the cases mode of injury was road traffic accident. All the patients were right hand dominant and 14 had injury to the dominant side. The surgery was done between 2 and 6 months after the accident. The average follow up was 15 months (range 12 to 36 months). Spinal accessory to suprascapular nerve transfer (XI-SSN) and transfer of ulnar nerve fascicle to the motor branch to biceps (UNF-BrBi \u2013 Oberlin transfer) was done in all of them.A detailed preoperative assessment was done in all the case and documented as the base line. Elbow flexion, shoulder abduction, and external rotation range of motion were 0 degree in all the cases. Deltoid, teres minor, supraspinatus, infraspinatus, biceps, and brachioradialis muscle were all paralyzed and scored M0 on Medical Research Council (MRC) scoring. In two cases triceps scored M0 (case no. 5 and 6), others had M4\u2013M5 score. Trapezius muscle was scored M5 and grip and pinch strength in the hand was normal in all the cases.With a minimum follow up of 12 months, all of them were evaluated for range of movements at shoulder and elbow; motor power and functional improvement.Strength of muscle was graded using MRC scoring and range of movements was recorder with Goniometry. The range of elbow flexion was measured as the angle formed between the long axis of the arm and the forearm. The range of abduction was recorded by measuring the angle formed between the arm axis and parallel to the spinal cord axis. External rotation was measured with the patient standing with the shoulder fully internally rotated and forearm placed transversally over the abdomen. Any rotation from this position was measured and noted as the range of external rotation.Shoulder and elbow function were graded using the scale proposed by Narakas and WaikAll patients were operated under general anesthesia in the supine position with head and trunk turned to the opposite side. The supraclavicular part of the plexus was exposed through a transverse incision 2 cm above the clavicle at the root of the neck and the C5 and C6 roots were identified. Avulsion of the C5\u20136 roots and absence of usable stump proximally was confirmed intra-operatively. Nerve transfer was performed in the following manner.The spinal accessory nerve was identified along the superior border of the trapezius and confirmed with electrical stimulation. Suprascapular nerve was then identified as it emerged from the roots in the scar. The proximal branches of the spinal accessory to the upper part of the trapezius were preserved and the terminal branch was dissected and divided as far distally as possible. It was then transposed and coapted to the suprascapular nerve under microscopic magnification with 10-0 Ethilon average range of abduction was 66 degrees (range 45\u201390). Figures All regained active flexion at the elbow. 13 of 15 patients recovered full flexion 140 degrees); one had 90 degree and other 100 degree of anti-gravity flexion. The average time required for clinical reinnervation of biceps (flicker of movement) was 3 months 9 days (range 1 month 25 days to 4 months). 13 patients had M4 power and 2 had M3+. The average time taken for the recovery of antigravity elbow flexion was 5 months (range 3 1/2 months to 8 months). Figures 0 degreesThe details of the patients and the final grading of their elbow and shoulder function are detailed in Table The incidence and severity of brachial plexus injury has been increasing world wide mainly because of rapidly growing number of motor cycle accidents. Most of these injuries are high velocity injuries resulting in root avulsions. Although Carlstedl et al have triNerve transfer by reinnervating most functionally important nerves using intact neighboring nerves has become widely accepted since it was reported by Seddon in 1963 . Since tNerve transfer gives good results in restoring simple function like flexion of elbow but results are not as good when done for complex function like shoulder abduction and finger flexion . Allieu Success rate of intercostals to musculocutaneous reported in literature is 33\u201387% . The sucIn 1994 Oberlin introduced a new technique for restoration of elbow flexion . They trDelay in the surgery is known to result in poor results in brachial plexus surgeries. In our study all the cases were operated within 6 months of injury. When dividing the patient in two groups, less than 3 months and more than 3 months of injury to surgery duration, no significant difference in the results was noted in the present study Table . Althoug\u2022 Nerve transfer is an effective treatment option for restoration of elbow and shoulder function in brachial plexus injury and multiple nerve transfers help in early restoration of function\u2022 Nerve transfer close to target muscle without any intervening nerve graft allows faster and better recovery.\u2022 Use of ulnar nerve fascicles to restore elbow flexion is reliable technique and the ulnar nerve function is not downgraded.\u2022 Although the functional improvement in shoulder is not as dramatic as elbow, patient satisfaction is phenomenal.\u2022 Age of the patient shall not be criteria to deny the procedure especially till late fifties, and if done within 6 months good results are regularly obtained.The authors declare that they have no competing interests.HR and SRS were the main operating surgeons and designed the study, PB and SRJ performed data collection and analysis of the results, HR and PB were involved in sequence alignment and drafting of the manuscript, SRS edited the manuscript. All the authors have read and final manuscriptWritten informed consent was obtained from the patients for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal."} +{"text": "A single injection of testosterone into neonatal female rats causes a higher uptake of 32P in adult life, while a single injection of oestradiol into male neonates lowers the incorporation in adult life. Gonadectomy at 4 weeks of age has only a small effect on the subsequent incorporation of 32P into nuclear RNA either in control rats or in rats injected with sex hormones immediately after birth, showing that this effect of liver metabolism is mainly determined by the hormanal pattern at about the time of birth. The possible relevance of this sex difference in RNA metabolism to the different sex incidence of spontaneous or induced liver cancer is discussed.Fifteen minutes after the intraperitoneal injection of"} +{"text": "At low concentrations of DMBA (\u00bd% and 1%) twice as many sarcomas and carcinomas of the salivary glands are induced in male as in female rats. Additional oestrogens reduce neoplasms in males by one half while testosterone doubles them in females. The sex difference disappears at the higher dose levels of the carcinogen (2%).Females are more sensitive than males to the toxic effects of DMBA, though less sensitive to the carcinogenic action.Carcinomas rise to a single peak within 240 days while sarcomas appear as late as 770 days with secondary and tertiary peaks. This difference in pattern of induction may be due to the formation of a fibrous capsule separating persisting DMBA-deposits from the epithelial structures and thus protecting them from carcinogenic risk."} +{"text": "This study showed frequent cross-hemisphere virus movement, which can affect the risk posed to poultry and humans. The spread of highly pathogenic avian influenza virus (AIV) (H5N1) underlines the potential for global AIV movement through birds. The phylogenies of AIV genes from avian hosts usually separate into Eurasian and North American clades, reflecting limited bird migration between the hemispheres. However, mounting evidence that some H6 sequences from North America cluster with Eurasian subtype H6 sequences calls the strict hemispheric divide into question. We conducted a comprehensive phylogenetic analysis of the extent and timing of cross-hemisphere movements by the H6 gene. Results suggested that Eurasian H6 subtype has invaded North America several times, with the first invasions occurring 10 years before the first detection of invading isolates. The members of the North American clade decreased from 100% in the 1980s to 20% in the 2000s among H6 isolates from North America. Unraveling the reasons for this large-scale gene movement between hemispheres might identify drivers of global AIV circulation. The transboundary expansion of highly pathogenic avian influenza virus (AIV) (H5N1) in 2005 increased the interest in global AIV spread by wild birds AIV infection occurs frequently in wild and domestic birds in Asia, America, and Africa for all descendents in the new hemisphere . These 2TMRCAs were obtained by fitting a coalescent process to the gene sequence data, by using the Bayesian Monte Carlo Markov Chain package BEAST 1.4 (f(t) of the time of invasion t was determined from all sampled pairs of the time of the earlier node and later node, eit and lit, respectively:i, I denotes an indicator variable that equals 1 if eit99% ee reagent >99% ee 52]. Bo. Bo8b in13 analogous to lactate-based chiral iodoarenes . Th. Th18 asTo conclude, throughout this review we have seen substantial growth in the field of chiral hypervalent iodine reagents. This review points a number of striking chiral hypervalent iodine reagents used in stoichiometric or in catalytic fashion for quite a number of useful organic transformations. Most importantly the oxidative chemistry can be done using catalytic amounts of chiral hypervalent iodine reagents in the presence of an external oxidant. For convenient reading, we have only highlighted the optimized chiral catalysts or reagents used in the mentioned transformations. We hope that these new classes of reagents can achieve synthetically more challenging and application-oriented conversions that can be applied for the total synthesis of natural products as well as in industry related to pharmaceutical and medicinal chemistry.These environmentally friendly, cheap and readily available reagents will surely attract the attention of scientists towards a sustainable replacement of transition metals. The application of chiral hypervalent iodine reagents is expected to pave the way for new reactions and reagent design in the field of asymmetric synthesis and catalysis."} +{"text": "Letter to the editorDisseminated intravascular coagulation (DIC) is a relatively common complication of sepsis. The pathophysiology of septic DIC is associated with neutrophil extracellular trap (NET) formation which reThere is increasing interest in the classification of sepsis for pers"} +{"text": "Purtscher\u2019s retinopathy and sixth nerve palsy are often seen following head trauma. However, both are rarely seen coexisting together in the same patient. We present a rare case of both these entities occurring simultaneously in opposite eyes of the same patient following head trauma. Purtscher\u2019s retinopathy is a rare form of retinal disease seen after head trauma or chest compression injuries and was first described by Othmar Purtscher in 1910 . HoweverA 30-year-old male patient came with chief complaint of diplopia on right gaze and decreased vision in the left eye of 20 days duration following a road traffic accident. He had a fall from a two-wheeler which he was riding without a helmet. There was a history of loss of consciousness and epistaxis and he was admitted in a general hospital for four days. Computerized tomography (CT) scan of the brain showed minimal extradural bleed over the right frontal lobe with minimal subarachnoid bleed along the basal cisterns. CT scan of the orbits showed a minimally displaced fracture of the right supraorbital bone extending into the frontal bone along with a linear undisplaced fracture of the anterior and lateral walls of the right maxillary sinus. The left orbit showed an undisplaced fracture of the lateral wall along with a linear undisplaced fracture of the anterior wall of the left maxillary sinus with a hypodense collection in both maxillary sinuses. On ocular examination, his best corrected visual acuity was 20/20 in the right eye and 20/60 in the left eye. Anterior segment examination showed enophthalmos with restricted abduction in the right eye Figure 1 and a noPurtscher\u2019s retinopathy was first described following blunt head trauma. It is mostly bilateral, however unilateral cases have also been reported . PurtschThe authors declare that they have no competing interests.Informed consent was obtained from the patient for publishing his case including the photographs."} +{"text": "The anterior scrotal nerve is a cutaneous nerve that branches from the ilioinguinal nerve after it leaves the superficial inguinal ring.\u00a0However, we identified a cadaveric specimen with an anterior scrotal nerve arising from both the femoral and ilioinguinal nerves.\u00a0This anatomic variation should be considered with anesthetic blockade of this region or during surgical procedures nearby. The anterior scrotal nerve provides cutaneous innervation to a portion of the penis and the upper scrotum in males.\u00a0It arises from the ilioinguinal nerve after the aforementioned nerve passes through the superficial inguinal ring .\u00a0Both thDuring routine dissection of the thigh, a variant anterior scrotal branch was found in an African-American fresh-frozen male cadaver whose age at death was 79-years-old. The anterior division of the femoral nerve gave rise to two cutaneous nerves, the medial femoral cutaneous nerve of the thigh (MFC) and the intermediate cutaneous nerve of the thigh (ICN). The MFC was traced and found to supply three branches to the skin of the anterior and medial thigh. The MFC then traveled medially and superiorly to join the anterior scrotal branch of the ilioinguinal nerve which coursed superficial to the spermatic cord Figures , 2. The Although prior anatomical studies have been performed with regard\u00a0to the femoral and ilioinguinal nerve branches, none have focused on the origin of the anterior scrotal nerve.\u00a0Gustafson et al. dissected femoral nerves and observed alternate branching patterns of its cutaneous subdivisions . Rab et The anterior scrotal nerve has historically originated from the ilioinguinal nerve; however, we report a unique case study in which the anterior scrotal nerve originates from both the ilioinguinal and femoral nerves. This finding is significant as it provides insight for surgeons and anesthetists alike, especially when performing procedures such as cutaneous nerve blocks."} +{"text": "The alteration of the carbon isotope composition of contaminants along the groundwater flow path indicates microbial degradation processes and can be used as an indicator for in situ biodegradation. The Rayleigh equation was applied to calculate the percentage of the in situ biodegradation (B[%]) using the change in the isotopic composition of contaminants (Rt/R0) along the ground water flow path and a kinetic carbon isotope fractionation factor (\u03b1C) derived from defined biodegradation experiments in the laboratory. When the groundwater hydrology is known and a representative source concentration (C0) for a groundwater flow path can be determined, the extent of in situ biodegradation can be quantified.A concept to assess"} +{"text": "Eyprepocnemis plorans to Locusta migratoria and Eyprepocnemis monticola to Eumigus monticola in the following paragraph:The authors wish to make the following modification in their review . Change Locusta migratoria) B chromosomes was determined [19]. The \u2018satellitome\u2019 in the grasshopper Eumigus monticola consists of 27 satellite DNAs [6], less than half of the migratory locust, where 62 were found [19].\u201d\u201cWith the RepeatExplorer and RepeatMasker programs, the satellite DNA composition of the migratory locust (The changes do not affect the scientific results. The manuscript will be updated, and the original will remain online on the article webpage, with a reference to this Correction."} +{"text": "Apolipoprotein E is a glycoprotein mediator and regulator of lipid transport and uptake. The APOE4 allele has been associated with higher risk of Alzheimer\u2019s disease and of mortality, but the protective effect of the less prevalent APOE2 allele is less well established. This symposium will bring together experts in epidemiology, molecular biology, neurology and systems biology to clarify the role of APOE2 in longevity and cognitive health, to describe molecular targets of APOE alleles, and to suggest mechanisms of protection conferred by APOE2 using IPSc derived systems. Dr Seshadri will show the strong association between APOE2 and human longevity using data of 38,537 individuals of European ancestry. Mr Sweigart will examine longitudinal trajectories of cognitive function in participants of the Long Life Family Study and the New England Centenarian Study and show that carriers of the homozygote genotype of APOE2 have a significant slower rate of decline of their cognitive function compared to carriers of other genotypes. Dr Monti will present an association analysis of APOE genotype data with 4137 human proteins in serum of 222 New England Centenarian Study participants. The analysis discovered a signature of 16 proteins that associated with different APOE genotypes, and replicated in 3 independent studies. Dr. Ellerby will summarize her recent analyses that used transcription analysis of isogenic iPSCs with APOE2 and APOE4 homozygote genotypes differentiated into inhibitory GABAergic neurons to show that E2 inhibitory GABAergic neurons regulate genes involved in nuclear division, DNA integrity and DNA damage checkpoint."} +{"text": "After publication in volume 54, issue 7, page 571\u2013586 the Japanese Society of Gastroenterology requested that the article be Open Choice to make the article an open access publication. Post-publication open access was funded by the Japanese Society of Gastroenterology. The article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (The original article has been updated."} +{"text": "When a patient enters the end stage of life threatening disease like cancer, treatment of pain and other symptoms must be considered to preserve quality of life Specifications tableValue of the data\u2022Data and survey instrument questions can be compared with or inform other studies.\u2022Data emphasize the need for developing palliative care services in Iran.\u2022Nurses have a prominent role in end of life care. Palliative care needs to become a part of nursing and medical school curricula as well as continuing nursing and medical education program offerings.1Socio-demographic characteristics of nurses were summarized in 2A cross-sectional study was conducted with nurses at 2 Hospitals related to Neyshabur University of Medical Sciences in Neyshabur city, northeastern Iran, from January 2016 to May 2016. The nurses who working in outpatient departments and clinical wards of the hospitals were recruited to participate in the study with at least 1 year job experience. However, nurses working in the central sterilization supply department, operating room and delivery rooms were excluded. The sample size according to the similar study"} +{"text": "Relevance to Wider Literature.Following publication of the original article , the autThe sentence currently reads:The trial experienced recruitment difficulties (only six patients were randomised) and therefore had limited power to investigate the impact of the intervention on the trial\u2019s primary outcome\u2014depression.The sentence should read:The trial experienced recruitment difficulties and therefore had limited power to investigate the impact of the intervention on the trial\u2019s primary outcome\u2014depression."} +{"text": "Staphylococcus aureus phage genomes and have been shown to interact with the Stl repressor protein of S. aureus pathogenicity island SaPIbov1. In the present work we set out to characterize the interactions between these proteins based on a range of biochemical and biophysical methods and shed light on the binding mechanism of the dimeric \u03c6NM1 phage dUTPase and Stl. Using hydrogen deuterium exchange mass spectrometry, we also characterize the protein regions involved in the dUTPase:Stl interactions. Based on these results we provide reasonable explanation for the enzyme inhibitory effect of Stl observed in both types of complexes. Our experiments reveal that Stl employs different peptide segments and stoichiometry for the two different phage dUTPases which allows us to propose a functional plasticity of Stl. The malleable character of Stl serves as a basis for the inhibition of both dimeric and trimeric dUTPases.The dUTPase enzyme family plays an essential role in maintaining the genome integrity and are represented by two distinct classes of proteins; the \u03b2-pleated homotrimeric and the all-\u03b1 homodimeric dUTPases. Representatives of both trimeric and dimeric dUTPases are encoded by Staphylococcus aureus are hazardous for both humans and livestock especially since S. aureus strains develop resistance and adapt to the new hosts rapidly via horizontal gene transfer (HGT).,41.26,41erodimer [6,9,26,"} +{"text": "The firm\u05f3s suppliers are in most social responsibility literature considered a branch of the firm\u05f3s stakeholders that may not necessarily benefit directly from the firm\u05f3s social responsibility practices. However recent studies on CSR from the developing country\u05f3s perspective has highlighted the importance that needs to be placed on supply chain improvement. Thus, this article presents data on the effect of supply chain improvement as a construct of corporate social responsibility on operational competency. The study employed a descriptive quantitative research design survey method. The study population consists of 1748 employees from four top oil and gas firms quoted in the Nigerian stock exchange. A sample size of 350 employees were selected. Data was analysed using statistical Package for Social Sciences (SPSS). Regression analysis was employed as the statistical tool of analysis. The field data set is made widely accessible in this article. Further studies can review this stance in other industries.\u2022The provided data also shows statistics on CSR from the developing country\u05f3s perspective. Considering the limited available data on CSR that goes beyond philanthropy from the developing country\u05f3s perspective, future studies might consider expanding their investigation into other aspects of CSR beyond philanthropy.\u2022Considering the limited available data on employees\u2019 perception of the firm\u05f3s commitment to supply chain improvement, as well as lack of data set on this area of corporate social responsibility, the provided data opens up avenue for future studies focused on the creating shared value concept of CSR.1A total of three hundred and fifty copies of questionnaire were administered to respondents from the top four listed oil and gas firms in Nigeria\u05f3s stock exchange. 1.1Given that the correlation co-efficient measures the degree to which two things vary together, this model correlated two variables: supply chain improvement and operational competency.R square is called the coefficient of determination and referred to as R2. The R Square tells how much of the variance in the dependent variable is explained by the independent variable (supply chain improvement). The F statistic tests the overall significance of the model. In this case, the value for each firm is expressed as a percentage, this means that the independent variable (supply chain improvement) explains Firm 1 (92%), Firm 2 (60.1%), Firm 3 (51%) and Firm 4 (57.9%) of the variance in operational competency scaled , promotion of local suppliers scaled . Statistically, this means that honesty in contracts with suppliers makes the strongest unique contribution in influencing operational competence.The result in 2The data presented a quantitative research based on a descriptive research design to assess the effect of supply chain improvement on operational competency of oil and gas firms within the confines of corporate social responsibility and from a developing country\u05f3s perspective. Survey method was considered appropriate for data gathering.The population of the study consists of the stakeholders of four (4) top oil and gas firms listed on the Nigerian stock exchange. The choice of these firms is in support of previous studies The data was coded and keyed into the statistical package for social sciences (SPSS) version 22. Data was described using inferential statistical tests involving multiple regression analysis.The researchers ascertained that respondents were well informed about the background and the purpose of the research. Every respondent was entitled to the opportunity to stay anonymous and their responses treated with utmost confidentiality. Permission was obtained from the appropriate authorities in the firms where copies of the research instruments were distributed."} +{"text": "A 15-day-old female newborn presenting nasal obstruction since birth underwent computed tomography of the paranasal sinuses in our department due to clinical suspicion of choanal atresia. The patient presented no other complaints. Pyriform aperture stenosis becomes particularly significant during the first two months of life when infants are mandatory nose breathers.Computed tomography allowed 1 PyriThe lateral margins of the pyriform opening are defined by the nasal processes of the maxilla and its lower margins by the junction of the horizontal processes of the same bone.(-)Pyriform aperture stenosis is believed to be due to embryological malformations of the primary palate, which are associated with a hard triangular-like palate and the bone overgrowth of the nasal process of the maxilla. This set of findings narrows the pyriform aperture, which is particularly important since the pyriform aperture is one of the narrowest nose areas. Even small decreases in the pyriform aperture area cause significant increase in airway resistance.-4The clinical presentation is indistinguishable from choanal atresia, although it can be safely diagnosed by paranasal sinus computed tomography scan when the imaging reveals a diameter of the pyriform aperture below 1.1cm.,5Often there are additional malformations associated, mainly the triangular-shape palate and the single central megaincisor, which is found in up to 75% of these patients.,5The initial treatment of this condition is usually conservative. Surgical interventions are reserved for cases of persistent symptoms after conservative treatment.,6"} +{"text": "Dear Editor,1 A case of a 53-year-old man with a solitary kidney is reported after previous gunshot injuries who presented with left flank pain and renal failure. Subsequent imaging revealed a hydronephrotic left kidney with a 1.5\u2009cm calcification in the left pelviureteric junction (PUJ), which was deemed to be a stone encasing a bullet and an atrophic kidney. The operative management comprising stent insertion, delayed definitive treatment necessitating holmium laser tripsy, and eventual extraction of the bullet fragment with graspers is described.1 The case is notable as the clinical sequelae of delayed gunshot injury are illustrated as 10 years elapsed between injury and eventual presentation because of delayed migration of the bullet fragment into the PUJ. The authors do not state whether any follow-up imaging was undertaken or whether delayed ureteral stricturing occurred.We read with interest the recent article by Jhaveri and D'Angelo.The rarity of such cases is alluded to by the authors and they further acknowledge the difficulty in diagnosing late urologic complications of gunshot injury.2 and Gawande et al. have also described a case of spontaneous passage of a gunshot pellet 2 hours after injury.3 The passage of multiple spontaneous pellets has also been described.4The authors should recognize the heterogeneity of presentations that exist with gunshot injuries and the upper urinary tract. Spontaneous passage per urethra of a shell fragment 23 years after initial injury has been described6A 5-month interval between initial injury necessitating open surgical repair and delayed presentation to a urologic service with colic has been described with one case passing the pellet spontaneously and one case requiring nephrostomy and eventual ureteroscopic extraction with a grasper.7 Effective use of the holmium laser through a percutaneous approach to shatter a bullet fragment thus permitting basket extraction8 has also been described with a 4-month stricture-free follow-up. Finally, all urologists who encounter delayed gunshot injuries should be aware of the fact that bullets may not follow anatomical routes as described by Kollias and Kyriakopoulos9; although the entry point was the supraclavicular area, the bullet was eventually removed from the urethra!Gutman and colleagues have reported a case of delayed colic caused by gunshot occurring 7 years after injury."} +{"text": "The dataset presented in this data article was compiled from 100 published and unpublished empirical studies that employed Lintner\u05f3s dividend payout model or related extensions over the period 1957\u20132016. Besides the reported degree of dividend smoothing and its estimation precision the data include a wide set of underlying study design characteristics such as the time period of analysis, the type of firms investigated or the econometric estimator employed. The data are related to the research article \u201cWhat drives dividend smoothing? A meta-regression analysis of the Lintner model\u201d . Specifications tableValue of the data\u2022The dataset provides an extensive overview of the empirical literature on dividend smoothing.\u2022Researchers can gain holistic insights on dividend smoothing and the factors that drive its degree.\u2022The importance of research design characteristics for the resulting degree of dividend smoothing can be evaluated using this dataset.\u2022The dataset can serve to detect publication biases across the empirical literature on dividend smoothing.\u2022The dataset can provide a useful benchmark and/or starting point for meta-analysis based on further issues of payout policy such as stock repurchases.1Our dataset comprises 998 estimated dividend smoothing coefficients derived from 100 published and unpublished empirical studies that employed Lintner\u05f3s dividend payout model or related extensions over the period 1957\u20132016. For each dividend smoothing coefficient, the standard error is included as a measure of estimation precision and a wide set of underlying study design characteristics such as the type of publication, the econometric specification used to generate the coefficient as well as the analyzed period, sector and region are added. 2This dataset was compiled based on a survey of the literature that focuses on the empirical estimation of Lintner\u05f3s dividend payout model or related extensions. The literature search followed the Meta-Analysis of Economics Research Reporting Guidelines provided by p-, or t-values were reported those were converted to standard errors.To ensure a consistent and uniform interpretation of dividend smoothing across the dataset we converted all speed of adjustment coefficients to dividend smoothing coefficients as defined in Each dividend smoothing coefficient relates to a unique combination of underlying study design characteristics. The dataset therefore also comprises an extensive set of variables that were selected to reflect in a best possible way the set of study design characteristics used to generate each smoothing coefficient."} +{"text": "Concerns have been raised about results presented in several figures of this article . SpecifiFig 1 Sucrose water intake and Fig 2 Immobility timeFig 4 Complex III and Fig 6 TNF\u03b1Fig 4 Complex IV and Fig 5 Serum corticosteroneFig 5 Serum corticosterone and Fig 8 BDNFPLOS ONE\u2019s Editorial Board and an external reviewer with statistical expertise expressed concerns that the same fold changes were observed between the indicated datasets for all groups, and advised that the degree of correlation between variates appears to exceed considerably what would be expected in such experiments given the assays used, the number of animals per group, and that different groups of animals were used for the different experiments.A member of The corresponding author commented that the results in these figures are from different experiments expected to yield opposite results. The underlying data supporting the results are not available.PLOS ONE Editors retract this article in light of concerns about the validity of the data reported in these figures.The PR, AK, and SG do not agree with retraction."} +{"text": "The raw densitometry data underlying the graphs in The authors would like to correct an image duplication error in The original Western blots from which the PLOS ONE\u2019s Editorial Board has reviewed the replication data provided and confirmed that they support the published findings.A member of In addition, the authors clarify that in Fig 9, the blot images presented for different antigens are from distinct Western blot experiments using the same protein samples; the blot images were grouped within the respective panels in preparing the figure.S1 File(TIF)Click here for additional data file.S2 File(TIF)Click here for additional data file."} +{"text": "Neural therapy utilizes the regulatory mechanisms and plastic properties of the nervous system. The generation of targeted mechanical stimuli (through the needle) and the selective extinction of other stimuli affect both the organization of the nervous system and tissue perfusion, thereby disrupting positive feedback actions in the pain cycle .\u201dIn the Discussion section it should instead read:\u201cThe purpose of this technique is not primarily to achieve local anesthesia , 26. Neu"} +{"text": "Following publication of this article , the folThe authors explain that an error during figure preparation led to duplication of figures and apologise for this oversight. The authors provide the uncropped and unadjusted images underlying all panels in The data underlying other figure panels in the article are available upon request from the corresponding author.A member of the Editorial Board reviewed the updated S1 File(ZIP)Click here for additional data file."} +{"text": "Concerns have been raised regarding partial duplication of some images in this article . SpecifiThe corresponding author stands by the accuracy of the results presented in fro +oxLDL, fro +TNF-\u03b1 and fro +stauro) are replaced with replicates collected at the time of the original study. All original image files underlying these replacement figures are provided as Supporting Information.Replacement Figs An investigation conducted by the Research Integrity Office of INSERM confirmed that some original images from these experiments are no longer available, and the laboratory computer was unsecure at the time of the original study. An image in The corresponding author has further clarified that the majority of the original data files underlying the rest of the article are also unavailable due to the fact that the study was completed more than 10 years ago; files have been lost or corrupted and some of the original investigators have left the institution. However, the corresponding author states that all the materials are available in their laboratory for investigators interested in replicating this work.PLOS ONE Editors have been unable to determine how the middle and bottom panels of PLOS ONE Editors issue this Expression of Concern.The S1 File(ZIP)Click here for additional data file.S2 File(ZIP)Click here for additional data file.S3 File(ZIP)Click here for additional data file.S4 File(ZIP)Click here for additional data file.S5 File(ZIP)Click here for additional data file.S6 File(ZIP)Click here for additional data file."} +{"text": "Telfairia occidentalis (Fluted pumpkin) fruit rind and poultry manure both of which currently constitute an environmental nuisance in the localities where they are found. The data presented in this article is on the use of combined heat and power (CHP) system to assess the energy and economic feasibility of applying thermo-alkali pretreatment procedures to one of the substrates (Fluted pumpkin) prior to anaerobic digestion. Also, the microbial characterization and succession pattern of important microbes during the anaerobic digestion process was evaluated and the data reported in this paper.The data described in this article was obtained in an experiment designed for the generation of biogas from the anaerobic co-digestion of Specifications tableValues of the data\u2022Telfairia occidentalis (Fluted Pumpkin) and Poultry manure for biogas generationThe data presented in this article reveals the energy and economic evaluation of the anaerobic co-digestion of fruit rind of \u2022The data will serve as a precursor for further research on the economic assessment of biomass pretreatment prior to anaerobic digestion processes\u2022The data give further exposure on the necessity and feasibility of pretreatment of biomass prior to anaerobic digestion.\u2022More robust heat and power systems can be used to further explore the generated data from this study in order to apply the processes in industrial scale experiments.1T. occidentalis fruit rind using a 50 and 30% thermal and electrical efficiencies respectively system was used to assess the energy balance and the economic feasibility of applying thermal and alkaline pre-treatment to ectively . TherefoTo assess the electrical energy, only the electric energy used for the substrate mixing was considered neglecting the energy used during mechanical treatment since this was also done for the experiment without thermal and alkaline pre-treatment Telfairia occidentalis fruit rind and poultry manure, various aerobic and anaerobes bacteria, fungi and methanogens were isolated and characterized into the pretreatment procedure through the sale of additional energy gained.Data was obtained from the evaluation of pretreatment application to fruit rind of 2.2-1 TS for raising the temperature of one ton TS of T. occidentalis fruit rind from 25 to 55\u202f\u00b0C during pre-treatment A simple computational equation was used to first determine the thermal energy required (TER) in kWh\u202ft2.3The aerobic organisms (Bacteria and fungi) associated with the fermenting substrates were isolated and enumerated weekly using standard methods 2.4The paired sample t-tests were conducted to determine the significant difference in the means of three replicates."} +{"text": "This descriptive associative study focused on the attitudes of selected adolescents toward the involvement of grandparents in childcare. Specifically, it aimed at determining the rate of closeness of these adolescents toward their own grandparents; their attitudes toward the involvement of their grandparents; and the relationship between the students\u2019 closeness with their grandparents and their attitudes toward grandparents\u2019 involvement. A survey was administered to 185 adolescents aged 16 to 22 from the University of the Philippines. Results showed that most of the respondents (43.38%) are either very close or close to their grandparents, especially their maternal grandmother (n = 126). The attitudes of the respondents toward grandparents\u2019 involvement were measured by looking at their rate of agreeableness on 17 statements. Results showed that most of the respondents either agree or neither agree nor disagree (M = 2.60) on grandparents\u2019 involvement. The correlation analysis showed a moderate to high positive linear association between MGM closeness and MGM involvement (r=.72); MGF closeness and MGF involvement (r=.74); PGM closeness and PGM involvement (r=.63); and PGF closeness and PGF involvement. This implies that perceived closeness increases with perceived involvement. The findings of this study emphasized on the role grandparents play in the lives of adolescent grandchildren. Some implications of this study with regards to future research in this field are described."} +{"text": "The data for effective diameter and zeta potential was generated using the particle size analyser and zeta potential analyser respectively. The measured data for effective diameter and zeta potential was processed to generate the data for sedimentation velocity and stability factor. The ultra-sonication time with maximum value of stability factor was used for sample preparation of Cu/Al2O3 single particle nanofluid and hybrid nanofluid in the related research article \u201cOn trade-off for dispersion stability and thermal transport of Cu-Al2O3 hybrid nanofluid for various mixing ratios\u201d [1].The data presented in this data article comprises the critical parameters of dispersion stability such as the particle effective diameter, zeta potential, sedimentation velocity and stability factor for Cu/Al Stability factor for Cu nanofluid is not presented in The data on particle effective diameter (22O3 single particle nanofluid and hybrid nanofluid synthesis using ultra-sonication bath and characterization using particle size analyser and zeta potential analyser are discussed in the related research article The experimental design and detailed methodology of Cu/Al"} +{"text": "Informed consent is one of the most important processes during the implementation of a clinical trial; special attention must be given to meeting the needs of persons with dementia in nursing homes who have impaired decision making capacity. We overcame several challenges during enrollment and consent of potential participants in a pilot clinical trial including: (1) the consent document was designed for legally authorized representatives however some potential participants were capable of making their own decisions; (2) the written document was lengthy yet all seven pages were required by the IRB; (3) the required legal wording was difficult to understand and deterred potential participants; and (4) the primary mode of communication was via phone. We tailored assent and informed consent procedures to persons with dementia and their legally authorized representative/surrogate decision maker to avoid risking an incomplete trial and to improve generalizability of trial results to all persons with dementia."} +{"text": "This article presents data that examined the modeling of nexus between entrepreneurs\u05f3 commitment and business performance in a developing country. 315 copies of questionnaire were retrieved from 400 copies that were administered to Nigerian Association of Small Scale Industrialists (NASSI) Southwest chapters which comprised of six states. In addition to descriptive analysis of part of the data, correlation and regression analysis were used to present the data through structural equation model (SEM). The SEM path analysis shows the estimates of the interconnectedness of the major constructs in the data. Specifications TableValue of the data\u2022The data present the relationship and its impact of entrepreneurs\u2019 commitment on business performance.\u2022The demographic nature of the entrepreneurs was highlighted by the data.\u2022The data shows the level of impact each of the commitment variables had on business performance.\u2022The data will aid further discourse on the interconnectedness of entrepreneurs\u2019 commitment towards business performance.1The data contained 315 copies of questionnaire retrieved from 400 copies administered to entrepreneurs in six states of Southwest Nigeria. The data shows the correlation estimate between affective commitment and market share (0.151), affective commitment and customers\u2019 satisfaction (0.191), continuance commitment and business performance (0.172), continuance commitment and market share (0.155) and continuance commitment and customers\u2019 satisfaction (0.196).2This data presentation adopted survey method. The questionnaire is structured and it is designed to gather information from respondents about the influence of commitment"} +{"text": "Misra, Pascal Maisonobe, Savary Om on behalf of the INTEREST IN CD2 study group, was originally published electronically on the publisher\u2019s internet portal (currently SpringerLink) on 09 Septembr 2019 without open access. With the author(s)\u2019 decision to opt for Open Choice the copyright of the article changed on 13 September 2019 to \u00a9 The Author(s) 2019 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (The original article has been corrected."} +{"text": "In \u2018Satellite observations and modeling to understand the Lower Mekong River Basin streamflow variability\u2019 Specifications tableValue of the data\u2022The satellite dataset benefits hydrologic modeling at poor spatial in-situ data regions such as the Lower Mekong River Basin.\u2022The dataset can assist to understand the water balance in the Lower Mekong River Basin.\u2022The dataset is essential in hydrological modeling in the Mekong region since it contains new developed land cover land use, and soil characteristics layers.1https://swat.tamu.edu/) to simulate hydrological fluxes in the LMRB and explore the streamflow regime changes as a result of expected upstream flow changes . This paper reports various hydrological time series and remote sensing data that was used to model and understand the streamflow variability in the Lower Mekong River Basin (LMRB) http://www.mrcmekong.org/). Interpolation was carried out using a recent observed level data acquired from the Asian Preparedness Disaster Center (ADPC) geospatial and climate resilience teams (http://www.adpc.net/) to update and fill the gaps of the streamflow time series data we present. The dam data we report here was obtained from the Greater Mekong Consultative Group for International Agricultural Research (CGIAR) Program on Water, Land and Ecosystems The LMRB streamflow data reported is observed and collected by various agencies in the Lower Mekong Region. The LMRB streamflow time series data that we present here was obtained from the Mekong River Commission (MRC) hydrological respiratory product. We also report precipitation data obtained from the IMERG dataset. The IMERG dataset presented here is the Global Precipitation Mission (GPM) Level 3 IMERG *Final* Daily 0.1 \u00d7 0.1 degree (GPM_3IMERGDF) data product, which is derived from the half-hourly data product (GPM_3IMERGHH). The derived result represents the final estimate of the daily accumulated precipitation in millimeters.The precipitation data we report here was obtained from the Tropical Rainfall Measurement Mission (TRMM) https://disc.gsfc.nasa.gov/.Minimum and maximum daily air temperature data we describe here was calculated from air temperature record retrieved from the Global Land Data Assimilation System (GLDAS) simulation data products The land cover land use data we present was produced from multiple 2010 land cover land use maps at a spatial resolution of a 0.25\u2009km for the Lower Mekong Basin The soil data we report here was processed from the Harmonized World Soil Database (HWSD) 2The streamflow time series data is presented with this paper as a spreadsheet in 2 are reported in this paper. Dams within the Lower Mekong River Basin that are either already commissioned or still under construction and have a maximum reservoir area greater than or equal to 280\u2009kmThe precipitation data for the whole LMRB is presented with this paper as a spreadsheet named \u2018Precipitation\u2019 in The air temperature data for the whole LMRB is presented with this paper as spreadsheets named \u2018Tmin\u2019 and \u2018Tmax\u2019 in The MODIS monthly NDVI images used to produce the land cover land use map presented were derThe soil data reported here was produced to meet the hydrological modeling needs in Mohammed et al.,"} +{"text": "The purpose of the data was to determine excess lifetime cancer risk (ELCR) and risk of lung cancer from inhalation of radon in radiotherapy staff at Tehran radiotherapy Centers in 2015.The concentration of radon gas was extracted from a study done at Tehran radiotherapy centers, and then ELCR and risk of lung cancer were calculated in all centers by standard equations. The excess lifetime cancer risk and risk of lung cancer were 1.89 and 8.46 cases per 100,000 people in radiotherapy centers in Tehran City. The data indicate that the excess lifetime cancer risk and risk of lung cancer in radiotherapy centers are lower than the standard values which presented by UNSCEAR 2000. Specifications tableValue of the data\u2022Data showed that the excess lifetime cancer risk and risk of lung cancer in radiotherapy centers are lower than the standard values which presented by UNSCEAR 2000. That means the possible hazards from radon concentration are low compared to UNSCEAR 2000.\u2022Data can be used to demonstrate that the risk of lung cancer is greater than excess lifetime cancer risk in radiotherapy centers in Tehran City i.e., for the current population radon concentration should also be considered a potentially significant cause of lung cancer which is exposed through contamination of indoor air by radon from surrounding materials.\u2022The data can be used to compare ELCR and the risk of lung cancer with other studies in radiotherapy centers.1The excess lifetime cancer risk and risk of lung cancer were calculated in eight radiotherapy centers in Tehran . The ELC2The concentration of Radon-222 was extracted from a study, which was carried out at eight radiotherapy centers in Tehran, Iran 2.1\u22121) = 0/057\u2009Sv\u22121. [8]To calculate the excess lifetime cancer risk due to gamma-ray radiation the following equation was used 2.2The probability of annual lung cancer cases per million people (CPPP) caused by effective dose received from Radon-222 was assessed by [11]"} +{"text": "This research aims to combine the effects of nanosilica and glass powder on the properties of self-compacting mortar at normal and at higher temperatures. The fine aggregate was replaced by waste glass powder at various percentage levels of 10%, 20%, 30%, 40% and 50%. The mechanical properties of self-compacting glass mortar (SGCM) were studied at elevated temperatures of 200, 400, 600 and 800 \u00b0C. Furthermore the effect of sudden and gradual cooling technique on the residual strength of glass mortar was also investigated In order to enhance the behavior of SCGM the nanosilica of 3% by weight of cement was added. From the results it was obtained that the glass powder replacement effectively contributed towards the thermal performance while the addition of nanosilica enhanced the mechanical performance. The enhanced physical properties were obtained mainly at the glass transition temperature thus showing the active participation of glass powders during high temperatures. Moreover the gradually cooled specimens exhibited improved strength characteristics than the suddenly cooled specimens. Today\u2019s world is moving towards the phase of sustainable construction. The attempts to utilize the waste materials in construction are being extensively carried out not only from the economic point of view but also from the social and ecological view . Waste gThough concrete structures are highly resistant to temperatures they suffer from a serious threat due to fire ,15. The Nano-technology is also emerging as a popular field in the construction industry and has Numerous research works have already been done by the replacements of waste glass powder and also as partial substitutes for fine aggregates in normal and self-compacting concrete at normal ,6,7,8,9 The effect of elevated temperatures by using recycled glass powder on the self-compacting concrete was already done by Poon et.al . This reOrdinary Portland cement of grade 43 conforming to BS EN197-1 is used.The fine glass powder was used a partial replacement for fine aggregate and the obtained particle size distribution is shown in Nano silica was added 3% by weight of the cement for all the self-compacting mortar mixes. This range was chosen as established in previous works that at this level the properties of cement was very much enhanced .Natural river sand was used as fine aggregate confirming to EN 12620-2002 . The resSuper plasticizer which is a naphthalene based under the trade name of Enfiiq was used to achieve required workability. The dosage of super plasticizer was constant at ~1.5% of weight of cement throughout the mix.The self-compacting mortar was prepared by CEM method as folloThe self-compacting glass mortar was then prepared by substituting the sand by glass powder at various dosages by the weight of fine aggregate. Nano silica was added 3% by weight of the cement in the glass powder replaced mixes.The fluidity of the SCGM was evaluated using the mini-cone test and the V funnel flow time test immediately within 5 min mixing of the mortar as shown in 3 and for compression testing and prisms of size 160 \u00d7 40 \u00d7 40 mm3 for flexural testing procedure. These samples were left in the mold for 24 hours after which they were demolded and placed under water for curing up to 28 days. After 28 days the specimens were then tested for compression and flexure to determine the mechanical strength of the mortars at normal temperatures.The self-compacting mortars after conducting the fresh state tests were then cast into cubic specimens of size 50 \u00d7 50 \u00d750 mmThe specimens with and without the glass powder replacement were then heated in a muffle furnacecoupled with a digital controller which can attain a maximum temperature of 1000 \u00b0C atuniform heating rate of 20 \u00b0C per minute. The heating of the specimens were done at a range of 200 \u00b0C to 800 \u00b0C in increments of 200 \u00b0C. The inbuilt thermostat in the muffle furnace automatically regulates the temperature and rate of heating of the specimens. After the oven has reached the target temperature the specimens were left to remain in the oven for about 1 hour and so that the specimens may undergo stabilized heating throughout their cross section The heated samples were then subjected to two types of cooling regimes in which a part of the specimens were cooled in air and the other part were suddenly cooled by immersing in water. For each test three specimens were casted and the results were reported as the average of the three specimens. The produced self-compacting glass mortar specimens are shown in The bulk densities of self-compacting mortar with and without the glass powder replacements were determined after 28 days water curing of the samples. The variation of the bulk density was determined for all mortars with and without the partial replacement of sand by glass powder after subjected to various elevated temperatures of 200 \u00b0C, 400 \u00b0C, 600 \u00b0C and 800 \u00b0C.The porosity was also determined knowing the saturated mass of the samples and mass of cubic samples which were oven dried. The dried mass was obtained after drying saturated samples in an oven at 60 \u00b0C until the specimens achieved constant weight. The apparent volumes of the samples were determined using pycnometric method.The cube compression tests were conducted as per EN 1015 -11: 1999 in whichThe compressive strength was calculated from the relation3 according to ASTM standards C 348-14 [The flexural strengths were done on the prisms of size 160 \u00d7 40 \u00d7 40 mmC 348-14 . The fleThe mass losses of the specimens after exposure to various temperatures were measure accurately using a weighing balance. The mass loss was recorded as a percentage of initial mass of the specimen before exposure to temperature. The porosity studies indicate that the porosity values decreased for the specimen with the glass powder replacement. However the porosity values were increasing for the specimens prepared with glass powder with smaller proportions. This may be due to the fact that the lesser cement glass powder caused a perfect bending of the cement and glass powders whereas the mortars with the greater glass powder proportion caused a negative influence on the porosity values as shown in However the decrease in flowability caused by the addition of nanosilica was nullified by the increasing glass powder content due to the weak inter molecular cohesive force between finer glass particles and due to their smooth surface texture . FurtherThe density of the self-compacting glass mortars decreased with increased glass content as shown in The porosity studies indicate that the porosity values decreased for the specimen with the glass powder replacement. However the porosity values were increasing for the specimens prepared with glass powder with smaller proportions. This may be due to the fact that the lesser cement glass powder caused a perfect binding of the cement and glass powders whereas the mortars with the greater glass powder proportion caused a negative influence on the porosity values as shown in Compressive strength results of all mortar samples that were prepared by the partial replacement of fine aggregates by the glass powder are shown in The residual compressive strengths of the mortar specimen after subjected to high temperatures were shown in The compressive strength values at higher temperature are also shown in The residual compressive strength of the self-compacting glass mortar specimens after heated to 200 \u00b0C were higher than the reference specimens for all concentration of glass powder. This observed increase in strength variation at this temperature was due to the addition of nanosilica which caused an increase in the compressive strength due to the hydration of unhydrated particles in the cement and due to the improvised mechanical properties of calcium silicate hydrate gel. These increased compressive strength results obtained at 25\u2013200 \u00b0C were contrary to the results obtained by Poon et al. . This shThe air cooled specimens exhibited a little strength variation than the water cooled specimens and this may be due to the gradual cooling of the specimens rather than the sudden cooling which may have caused this strength variation. The relative residual compressive strength of gradually cooled self-compactingglass mortar at high temperature was shown in The variation of flexural strength with various amounts of glass powder was shown in The residual flexural strength of the self-compacting mortar with various percentage of glass powder replacement after heating to four stages 200 \u00b0C, 400 \u00b0C, 600 \u00b0C and 800 \u00b0C were shown in The flexural strength decrease was almost similar to the earlier research works and proved that nanosilica showed insignificant contribution to the self-compacting glass mortar at elevated temperatures.The air cooled specimens showed a little disintegration than the water cooled specimens by visual observation. It was very difficult to measure the flexural tests for the 800 \u00b0C specimens since they were completely disintegrated. The relative residual flexural strength of gradually cooled self-compacting glass mortar at high temperature was shown in When the fresh state properties were taken into account the glass powder replaced self-compacting mortars provided acceptable values in the mini-cone and mini v funnel values. Thus the observed changes in the values obtained with comparison to the reference values were acceptable. Thus the influence of glass powder as a complete substitution of sand do not cause any detrimental effects on the fresh state characteristics which is the most important property taking into account of the practical applications.The compressive strength result of the glass powder replaced mortars showed a fact that the glass powder has a detrimental effect on the compressive strength. Though the values decreased with increase in the glass powder proportion the values show that specimen do not suffer a significant strength loss and thus the strength achieved is more or less acceptable to a certain margin. However the nanosilica coupled glass powder replacement more or less balanced the negative influence caused by glass powder on the compressive strength of self-compacting mortar.The water absorption and porosity values shows glass powder has a positive effect on the performance in self compacting mortar. Thus it can be concluded that the self-compacting glass mortar can be applied in areas especially subjected to humid condition.The temperature variations also concluded the fact that the glass powder though weak in compression and normal temperature exhibited a greater positive effect when subjected to higher temperature. Thus the incorporation of glass powder can be used to enhance the thermal properties of self-compacting mortar.The flexural strength results also showed that the flexural strengths do not increase due to glass powder replacement but the temperature increase causes a little positive influence.The final conclusion can also be drawn that the perfect replacement in self compacting mortar for sand is glass powder when all the properties of fresh and hardened state were taken into account. The observed disadvantages in the strengths due to the addition of glass powder were almost nullified by the addition of 3% nanosilica. The air cooled specimen exhibits a greater performance than sudden cooling by water. The further studies can be done to analyze the crystalline nature of the products formed due to the glass powder substitution and temperature effects on the properties with the changes in the microstructure. However these mechanical tests performed brings in the conclusion that glass powder which is a waste product causing a great disposal problem can effectively be incorporated into the construction industry especially to enhance the self-compacting nature of concrete and an enhanced fire resistance property."} +{"text": "After publication of this article , severalIn DR4 TRAIL panel and DR5 Resveratrol panel DR5 Resveratrol panel and DR5 TRAIL panel DR4 Resveratrol panel and DR5 TRAIL panelThe authors provide here an updated version of In There appears to be a region of overlap between the The authors noted that the quantitative data shown in the published Figures were obtPLOS ONE\u2019s Editorial Board reviewed the updated figure panels and confirmed that the overall conclusions of the study are supported by the new data.The authors apologize for these errors and provide here the underlying image files supporting results in Figs The authors confirm that the underlying data supporting other figures in the published article are avaiPLOS ONE Editors issue this Expression of Concern to notify readers of the issues with the published figures and to provide the additional supporting data for the affected results.The S1 File(ZIP)Click here for additional data file.S2 File(ZIP)Click here for additional data file.S3 File(ZIP)Click here for additional data file.S4 File(ZIP)Click here for additional data file.S5 File(ZIP)Click here for additional data file."} +{"text": "The original version of this article unfortunately included a mistake in Fig.\u00a02b where the images of mice in the tumour control group (right), day 30 (bottom) should be removed as the wrong images (duplicate of day 17) were inserted by mistake. At this time point the tumour control mice were no longer alive and the images were replaced by black areas.The revised Fig."} +{"text": "To evaluate the impact of National Institute for Health and Care Excellence (NICE) head injury guidelines on deaths and hospital admissions caused by traumatic brain injury (TBI).All hospitals in England between 1998 and 2017.Patients admitted to hospital or who died up to 30 days following hospital admission with International Classification of Diseases (ICD) coding indicating the reason for admission or death was TBI.An interrupted time series analysis was conducted with intervention points when each of the three guidelines was introduced. Analysis was stratified by guideline recommendation specific age groups .The monthly population mortality and admission rates for TBI.An interrupted time series analysis using complete Office of National Statistics cause of death data linked to hospital episode statistics for inpatient admissions in England.The monthly TBI mortality and admission rates in the 65+ age group increased from 0.5 to 1.5 and 10 to 30 per 100 000 population, respectively. The increasing mortality rate was unaffected by the introduction of any of the guidelines.The introduction of the second NICE head injury guideline was associated with a significant reduction in the monthly TBI mortality rate in the 16\u201364 age group .In the 0\u201315 age group the TBI mortality rate fell from around 0.05 to 0.01 per 100 000 population and this trend was unaffected by any guideline.The introduction of NICE head injury guidelines was associated with a reduced admitted TBI mortality rate after specialist care was recommended for severe TBI. The improvement was solely observed in patients aged 16\u201364 years.The cause of the observed increased admission and mortality rates in those 65+ and potential treatments for TBI in this age group require further investigation. This study is the first to use complete national data and the robust quasi-experimental method of interrupted time series analysis to evaluate the impact of the National Institute for Health and Care Excellence head injury guidelines.We adjusted our analysis for seasonality, autocorrelation and demographic changes using standard statistical techniques.Inpatient mortality was assessed at a population level as national data on emergency department attendance for traumatic brain injury (TBI) was unavailable and the guidelines acted to change the admission threshold for TBI identified by CT imaging.There are approximately 2.5\u2009million cases of traumatic brain injury (TBI) annually in the European Union and TBI is a leading cause of death and disability.One of the important health service challenges is identifying the small proportion of patients with life-threatening TBI among the large number of patients who attend emergency departments (EDs) following head injury (blunt trauma to the head) and then ensure they receive specialist care, including neurosurgery, within a time critical period.In England, since 2003, three National Institute for Health and Care Excellence (NICE) head injury guidelines have been introduced in order to improve the ED identification and subsequent management of TBI online .3 5\u20137 Th10.1136/bmjopen-2019-028912.supp1Supplementary dataWe describe the first study to use complete national data and interrupted time series analysis to evaluate the impact of early TBI management guidelines on patient outcomes and admission rates for all severities of TBI.Hospital episode statistics (HES) are collected on all inpatients in England. The Office for National Statistics (ONS) has computerised International Classification of Diseases (ICD) coding of cause of death information recorded on death certificates.We used individual patient level HES data provided by NHS Digital on all emergency inpatient hospital admissions in England from April 1998 to April 2017. Reason for admission is recorded using ICD10 coding. For patients with ICD10 diagnostic codes: S00\u2013S09 (indicating TBI) or T04.0 and T06.0 (crushing injury to the head) who died up to 30 days from discharge ONS cause of death was also provided.(CDC) as indicating a death attributable to TBI analysis was conducted assessing the impact of the NICE guidelines using the ITSA package in STATA V.14.The ITS model included three intervention time points corresponding to the introduction of each guidelines in: June 2003, September 2007 and January 2014. Analysis was conducted separately for the 0\u201315, 16\u201364 and 65+ age groups. A segmented regression model predicting the mortality rate and hospital admission rate for TBI per 100 000 population in each age group per month was estimated.To adjust for potential changes in the composition of the TBI population that could possibly affect the risk of mortality a further ITS model predicting the TBI mortality rate adjusted for % male, median age and mean Charlson comorbidity index score of patients admitted with TBI was fitted. Stratification by age group and intervention points were identical to the previous analysis.In all analyses, autocorrelation of the residuals was assessed using the Durbin-Watson and Rho statistic. Throughout we used the Prais-Winsten transformation adjustment for auto-correlation due to improved fit of the model, deviation from a Durbin-Watson statistic of 2 and a non-statistically significant Rho statistic.The Hull and East Yorkshire NHS Trust Trans-Humber Consumer Research Panel and Hull branch of the Headway charity were consulted in the initial stages of developing the research questions addressed in this study. These patient groups highlighted that although national head injury guidelines seemed evidence based, there appeared to be little evidence to show they had achieved their aims.The trends in mortality rate and impact of the guidelines varied between age groups. In the 65+ age\u2009group the monthly TBI mortality rate increased from around 0.5 to over 1.5 per 100 000 population over the time period . This waThe second guideline was found to be associated with a large reduction in mortality in the 16\u201364 age group . Before In the 0\u201315 age group the mortality rate fell continuously over the time period from around 0.05 to 0.01 per 100 000 population . There wAdjustment for the monthly median age, mean Charlson Score and proportion of male admissions for TBI did not materially alter the estimates associated with the introduction of guidelines in any of the age groups online . In the In the 0\u201315 age group TBI admissions steadily fall over the study period from around 20 per 100 000 to 10 per 100 000 , and is A sensitivity analysis for implementation lags in which the 12 months following the introduction of a guideline were removed from the analysis did not materially change the estimates associated with the introduction of the guidelines in any age group online .To our knowledge this is the first study to use national population based data and interrupted time series analysis to evaluate the impact of the NICE head injury guidelines in England. The second NICE guideline was associated with a reduction in the admitted TBI mortality rate in the 16\u201364 age group at a population level . We founThere was a continual and significant increase in TBI mortality and admission rates in the 65+ age\u2009group and a contrasting falling trend in mortality and admission rates in children . Both trIncreased imaging was intended to reduce hospital admissions by reducing diagnostic uncertainty but the first NICE guideline coincided with the introduction of the 4\u2009hour target.Later guidelines were associated with a reduction in hospital admissions rates in both adult populations assessed . FurtherWe used complete national data for England to assess the impact of the NICE head injury guidelines on mortality after admission for TBI at a population level. We have used individual level patient data to define TBI deaths and admissions. We controlled for seasonal factors and auto-correlation using established techniques.Ideally, we would have estimated the impact of the guidelines on case fatality, as this better measures the impact on the population at risk. The impact on case fatality of those attending ED with TBI could not be estimated because ED data were not collected until 2007. The impact on case fatality of those admitted with TBI could be estimated but because the guidelines resulted in changes in admissions policies and rates, the rate of deaths per admission is difficult to interpret. Instead we analysed the impact on the population TBI mortality rate, as this represents the best available unbiased measure of the guidelines\u2019 impact. This outcome may be affected by changes in the underlying population TBI rate that we are unable to account for, although annual attendances to the ED for head injury gradually smoothly increased over the study period online . We wereONS linked HES data is based on routinely collected administrative data; these can suffer from poor accuracy of injury coding.The impact of guidelines is limited by how well they are implemented. The NICE head injury guidelines have been found to be well implemented,The reconfiguration of the trauma network in England in 2012 is a co-intervention which could affect the TBI mortality rate.Few previous studies assess the impact of the NICE head injury guidelines see .9 A cohoA paediatric study analysing English HES data from 2000 to 2011 found a reduction in annual mortality during admissions for head injury after the introduction of 2007 NICE guideline.An economic evaluation of the NICE guidelines found them to be cost effective due to a reduction in hospital admissions predicted from early single centre studies and improved outcomes.Other studies using TARN data have found increases in TBI in patients 65+ disproportionate\u2009to population changes and it has been suggested that better case ascertainment due to increased CT imaging in older patients may account for this.We are unaware of comparable national evaluations of the impact of head injury guidelines. Evaluations of International Brain Trauma Foundation guidelines, particularly in the USA, have utilised evidence from single centre studies or subsets of patients.We found evidence that only the second NICE head injury guideline was associated with a change in population-based TBI mortality. This guideline contained a recommendation for increased management of severe TBI in specialist centres. Much research has focused on determining which head injured patients require CT imaging.This first national evaluation suggests that the introduction of the second NICE head injury guideline was associated with a reduction in the admitted TBI mortality rate in the 16\u201364 age group and a reduction in TBI admissions in England. The guidelines were not associated with significant changes in the secular trend for TBI admissions and subsequent mortality in children and those aged 65+. Research is needed to identify clinically and cost-effective management approaches for TBI in older patients."} +{"text": "We provide additional information relevant to our previous publication on the quality of reports of investigations of research integrity by academic institutions. Despite concerns being raised about ethical oversight of research published by a group of researchers, each of the four institutional investigations failed to determine and/or report whether ethics committee approval was obtained for the majority of publications assessed. Recently, we reported that four institutional investigations of the integrity of publications between 1996 and 2013 by a single research group were of low quality [In the reports of their investigations, none of the institutions addressed the concerns about ethics oversight. In correspondence with one of us (AG), institution 1 stated that 4 of 38 papers it assessed had been approved by its ethics committee but did not report whether the other papers had received ethics committee approval. Neither institution 2 nor institution 4 mentioned evaluation of ethics oversight for any papers. Institution 3 reported the findings of its investigation after submission of our paper. It assessed 40 publications, but did not mention ethics oversight in its report or correspondence with us.Overlapping the institutional investigations, two journals which had published research by the group in question between 1996 and 2001 that claimed ethics committee approval established that there was no ethics committee in place at that time at either institution 3 or one of the hospitals at which research was conducted by staff affiliated to institution 3 \u20136. Thus,Unethical conduct of research is a serious breach of research integrity and grounds for retraction . Ethics"} +{"text": "The aberrant expression of CD5 in both hairy cell leukemia (HCL) and HCL-variant (HCL-v) is very rare; only 26 such cases have been reported in the literature . SimultaHCL is an indolent small mature B lymphoid malignancy accounting for 2% of lymphoid leukemias . The thrIn conclusion, this case posed a diagnostic challenge as the patient had no cytopenias or splenomegaly along with CD5 positivity. This case is important because it creates awareness of this uncommon presentation of HCL and emphasizes that the best approach in diagnosing HCL is to give careful attention to morphological details while interpreting peripheral blood, as in our case, which can prompt detailed evaluation of bone marrow with immunophenotyping in such cases for early diagnosis and management of the patient."} +{"text": "Passive samplers were used in a sampling campaign for the detection of weekly mean ozone concentrations in 15 sites over a domain of 80 x 40 km on the southern side of the European Alps from May to August 1998. The area is characterized by vast natural terrain of complex topography, with conifer and broadleaf forests. It is difficult to access and monitor air quality there with continuous analysers. By applying geostatistical techniques (ordinary kriging), and correcting the interpolated ozone concentrations according to the altitude of each single grid cell (2 x 2 km), maps of weekly ozone concentrations were produced. The weekly ozone data were used to assess daily and hourly data by means of an iterative procedure based on a functional dependence of ozone concentrations both on altitude and on the time of day. This allowed the estimation of values with an exposure index such as AOT40 (accumulated exposure over the threshold of 40 ppb) in all 800 cells of the domain. This also allowed the mapping of risk assessment related to the effects of ozone on the regional forest vegetation. Results obtained show values that exceed the exposure standards adopted in the Kuopio protocol (1996). Excess exposure values also match values calculated over a wider territorial domain by using hourly data on ozone concentration derived from continuous automatic analysers."} +{"text": "BioMed Research International would like to express concern with the article titled \u201cCrocus sativus L. (Saffron) Stigma Aqueous Extract Induces Apoptosis in Alveolar Human Lung Cancer Cells through Caspase-Dependent Pathways Activation\u201d published in BioMed Research International in 2013 [As noted on PubPeer, there are indications of duplication of figure elements in each panel of Figure 2 and in Figure 7B. The authors said they were unable to provide the original high-resolution underlying images for Figures 2 and 7, any replicates, and the individual data points behind Table 1 and Figures 1 and 4 due to a laptop failure, and they offered to replicate the work. The Editorial Board agreed to allow the authors to attempt to replicate this work under the supervision of their institution. This notice may be updated or replaced based on the outcome of the replication attempt and institutional investigation."} +{"text": "Phosphorescent iridium(iii) complexes bearing two carbon chains are able to distinguish between endogenous and exogenous analytes when serving as luminescent cellular probes. iii) complexes as phosphorescent probes that are partially retained in the cell membrane during their cellular uptake. The utilization of the probes for sensing and distinguishing between exogenous and endogenous analytes has been demonstrated using hypoxia and hypochlorite as two examples of target analytes. The endogenous analytes lead to the luminescence response of the intracellular probes while the exogenous analytes are reported by the probes retained in the cell membrane during their internalization.Many luminescent probes have been developed for intracellular imaging and sensing. During cellular luminescence sensing, it is difficult to distinguish species generated inside cells from those internalized from extracellular environments since they are chemically the same and lead to the same luminescence response of the probes. Considering that endogenous species usually give more information about the physiological and pathological parameters of the cells while internalized species often reflect the extracellular environmental conditions, we herein reported a series of cyclometalated iridium( Many of the probes exhibit a sensitive response towards specific analytes and are used to determine their intracellular location and concentration via laser-scanning confocal microscopy, no matter whether the targets are produced inside the cells or internalized from extracellular environments. However, it is very difficult to distinguish between endogenous and exogenous species, because both of them lead to the same luminescence response of the probes. Since endogenously generated species usually give more information about the physiological and pathological conditions of the cells while internalized species often reflect the conditions of extracellular environments, it is of great importance to develop probes that are able to distinguish the origin of the analytes.Molecular probes showing a luminescence response toward specific analytes have been widely used for the detection of intracellular species related to physiological and pathological processes.iii) polypyridine complexes are selected for this study because of their advantageous photophysical propertiesiii) complexes are tunable via structural modification of the ligands. The utilization of iridium(iii) complexes to stain the cellular membrane,Endogenously generated and internalized species are chemically the same. The difference is that the internalized species must pass through the cell membrane while endogenously generated ones need not. Thus, we aim to develop luminescent probes that are partially retained in the cell membrane during their cellular uptake so that the internalized probes can report endogenously generated species while the retained probes are capable of monitoring the internalization of extracellular species . Phosphoiii) polypyridine complexes 1\u20134 (1H and 13C nuclear magnetic resonance (NMR), matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS), infrared (IR), and ultraviolet-visible (UV-Vis) absorption spectroscopy (see in the ESIsn-glycero-3-phosphocholine (DSPC) and the iridium(iii) complexes 1\u20134, respectively according to the literature method.In this work, phosphorescent iridium assay revealed that HeLa cells maintained more than 80% viability after incubation with the complexes even at a high concentration of 100 \u03bcM for 24 h complexes that show efficient cellular internalization1\u20134 were partially retained in the cell membrane. The internalized complexes were localized in the cytoplasm surrounding the cell nuclei (1\u20134 with CellMask (32\u201386%) increased progressively with the length of the carbon chains, while a reverse trend was observed for the co-localization coefficients with MitoTracker (74\u201337%). These results reveal that the carbon chains partially inhibit the internalization of the complexes into living cells owing to the lipophilic\u2013lipophilic interaction with the bilayer cell membrane and that the complexes with longer carbon chains exhibit a stronger affinity to the cell membrane. These results are in line with the luminescence spectra of complexes 1\u20134 in DSPC vesicles solution under an atmosphere containing different oxygen contents were recorded. Complex 3 exhibited phosphorescence enhancement by about 1.7 fold with lifetime elongation from 269 ns to 377 ns upon reduction of the oxygen content from 21% to 0 (Table S1KSV) was determined to be 0.027%\u20131. To eliminate the possible dynamic concentration variation of the complex in the cell membrane and the cytoplasm, the living cell imaging was performed via photoluminescence lifetime imaging microscopy (PLIM) owing to the independence of the lifetime values relative to the complex concentration. Living HeLa cells incubated with complex 3 exhibited moderate phosphorescence from both the cytoplasm and the cell membrane (2 and 95% N2 into the culture medium with a flow rate of 5 mL min\u20131 gave rise to luminescence enhancement and lifetime elongation in both the cytoplasm and the cell membrane. Such a luminescence response reached an equilibrium after 30 min bubbling (3 was less affected by exogenous hypoxia compared to the complex retained in the cell membrane. This is in accordance with our previous finding that the sensitivity of luminescent iridium(iii) complexes toward exogenous hypoxia was reduced upon their internalization into living cells.3, living HeLa cells were first treated with CoCl2 , which is a hypoxia inducer.3 led to intense luminescence from both the cytoplasm and the cell membrane did not reveal noticeable luminescence due to the weak emission of the complex , which is an anticancer drug that induces oxidative stress by triggering production of RONS including hypochlorite.3a resulted in bright luminescence in the perinuclear region with the cell membrane being non-emissive complexes that stain both the cytoplasm and the cell membrane. The amounts of the complex retained in the cell membrane can be easily tuned by shortening or elongating the carbon chains in the complex structure. Incorporation of recognition units into the new luminescent probes not only allow to sense exogenous and endogenous analytes but also enable to distinguish them from each other. Since endogenous species usually reflect physiological and pathological parameters of the cells while exogenous species are more related to extracellular environmental conditions, these probes are of great importance and helpfulness in improving the accuracy and precision in disease diagnosis. However, these probes cannot be used for distinguishing when the endogenous analytes are produced in the cell membrane or can undergo exocytosis through the cell membrane.To conclude, we have developed a series of phosphorescent iridium(There are no conflicts to declare.Supplementary informationClick here for additional data file."} +{"text": "This data article presented the effect of the Big Five Personality traits on entrepreneurs\u2019 commitment. 400 copies of questionnaire were administered to practicing entrepreneurs whom were members of a business guild in their annual end of year meeting and award day. 369 copies were duly filled and returned for use. Using statistic package for social science (SPSS 20) and Amos 22, correlation and regression analysis were used to find out the relationship between the two constructs and the strength of the relationship respectively. The Amos path diagram revealed the standardized estimates of the regression coefficient. Specifications TableValue of the data\u2022This data present a robust analytical and statistical technique to establish the interconnectedness that exists between entrepreneurs\u2019 personality traits and commitment towards business performance.\u2022The data describe the demographic structure of the entrepreneurs which can help in government formulation of non-discriminative policy towards gender, age and level of education.\u2022The data contributes to the body of literature on entrepreneurs\u2019 personality traits and commitment towards business performance.\u2022The data will aid academy discourse on the role of personality traits on the commitment of the entrepreneur.\u2022Our data can be compared with others collected from another part of the country or other part of the world.1The data for this article emanated from 400 copies of questionnaire administered to SMEs owners in six states of south west Nigeria. Each of the state received percentage of its total registered member over all the total registered members in South West Nigeria. 369 copies which were 92.2% of number administered were returned and satisfied useful for analysis. 21)Cluster Sampling as it included all the six states branches in south west Nigeria2)Purposive sampling as only registered member were used, and3)Convenience Sampling Technique as registered members that attended the monthly meeting.Multi- stage sampling technique was employed and it was made up of;The questionnaire was the instrument used to gather this data. There were 32 items in the questionnaire 8 statements on the bio-data, 9 statements on entrepreneur commitment and its factors"} +{"text": "The data survey focused on building control measures which are critical in attaining sustainable built environment. The data examined the public and private professional\u05f3s performance of building control measures and its barriers in Lagos. The targets consist of sixty (60) construction experts in public and private construction firms operating in Lagos. The sample size was generated from the pool of registered construction professional\u05f3s from private and public construction organizations in Lagos using random sampling technique. Descriptive statistics and inferential tests which include Kruskal-Wallis and Mann-Whitney U tests were performed on the dataset generated. The data harvested will avail the construction expert\u05f3s in public and private construction industry on the need for partnership in a bid to enhance building control measures performance in Lagos. Specifications tableValue of the data\u2022The data when analyzed compared with existing data on building control can help identify the sustainable ways of achieving sustainable building control measures.\u2022The dataset can help construction experts to ascertain the state of building control practices in a bid to enhance their performance and preserve the built environment \u2022The dataset will avail the public and private construction institutions of the need for partnership in order to enhance building control measures and manage the barriers to its effective performance.1The deficit in housing provisions due to the alarming increase in cities population has led to the prevalence of abuse of the built environment in a bid to meeting the housing challenge 22.1A well-structured questionnaire was used to generate the data by targeting a pool of registered construction experts operating in the study area. Random sampling technique was used in selecting the sample size. The contents (variables) of the questionnaire was sourced from the review of literatures and is designed to capture the datasets. A similar method of data exploration includes 2.2The data gathered was analyzed using percentages, mean item score and descriptive statistics as indicated in"} +{"text": "After publication of this article , concernThe Flag-RanBP9 Cortex panel in Figure 3A appears to be identical to the Flag-RanBP Hippocampus panel in The Flag-RanBP9 Hippocampus panel in Figure 3A appears to be identical to the Flag-RanBP Cortex panel in The Chromogenin Cortex panel in Figs The inset image in the The authors acknowledge that they mistakenly re-used and mis-labeled some images during figure preparation that resulted in similarities between individual panels. Although the flag-RanBP9 blots in the Figure 3A cortex and Insets in An Academic Editor reviewed the updated figure(s) and underlying original data files and confirmed that they support the results and conclusions reported in the published article.https://figshare.com/s/7a05b8d2bebef5410bae. The authors were unable to locate the actin blot for hippocampus in The authors apologize for the errors in the published article and confirm that all the primary data underlying other figures in the article are available in Figshare at the following link:"} +{"text": "In rodents, anatomical connections have been observed from all three of these candidates . In the To determine what kind of visual information is integrated in auditory cortex, Finally, a key result of The discovery of a subpopulation of visually-responsive cells in L6 suggests that this layer may serve as a gateway for contextual information from other modalities. Two recent studies in V1 further support this hypothesis. The recent burst of work on multisensory enhancement in sensory cortex and on L6 pyramidal cells make this an exciting time for unraveling the circuit mechanism underlying crossmodal integration."} +{"text": "The data presented here are related to the research article \u201cEnergy-environmental efficiency and optimal restructuring of the global economy\u201d Specifications TableValue of the data\u2022A combination of a theoretical framework and a computer program forms a tool for the analysis and development of environmentally friendly policies.\u2022The computer program estimates the energy-environmental efficiency of the global economy and determines the ways of its optimal increase.\u2022The computer program allows for analysis of the group efficiency of different economic systems.1This article presents an R program that utilizes and further develops a novel stochastic data envelopment analysis with a perfect object method (SDEA PO) introduced in Vaninsky 2This program advances a novel SDEA PO method introduced in"} +{"text": "The original article [1] contains a spelling error in the authorship; the authors would like to note the correct spelling of the second author, Jiajia Xi."} +{"text": "Data for six electric vehicle WOT interior sound measurements and eight enhanced sound signatures are presented. The measurement of electric vehicle interior sound signature data and the enhancement of these stimuli are documented in this data article. The procedures and equipment that were used to record the data, as well as the transposition, harmony and order addition, frequency filtering and modulation enhancement techniques that were applied to these stimuli are explained in detail. The transient frequency content of the 12 sound stimuli is presented in acoustic spectrograms along with the audio files in.mp3 format. Specifications tableValue of the data\u2022The Wide Open Throttle (WOT) interior sound signatures of several electric vehicles (EV\u05f3s) and one hybrid electric vehicle are presented.\u2022The sound signatures include the binaural sound pressure levels as a function of time for the driver position, during WOT acceleration of the different vehicles.\u2022The data provide researchers with accurate binaural sound recordings of commercial electric vehicles, which can be used for future jury evaluations of electric vehicle psychoacoustics.\u2022Additional enhanced stimuli are presented that were created as potential future sound signatures.\u2022The enhanced stimuli provide industry with realistic variations in sound signatures that enrich different components of electric vehicle sound character.1Six vehicle sound signatures were recorded in the interior of standard production electric/hybrid electric vehicles on public secluded asphalt roads. The measurements were opportunistic and vehicles were assessed during test drives from vehicle dealerships. The sound signatures were acquired during WOT acceleration, which involves accelerating the vehicle from rest to a maximum speed of 120\u202fkm/h in the shortest time possible (Avg. 18.7\u202fs). WOT acceleration provokes the maximum response of the electric motor and vehicle drive-train, which augments different aspects of the vehicle sound character during the run-up.22.1Six standard production EV/HEV\u05f3s were evaluated with details as shown in 2.2Several concepts were explored to add character and variation to the acoustic vehicle recordings. In the process a further six enhanced stimuli were created in order to evaluate their potential to evoke known sound quality attributes. The full description of enhanced stimuli data is provided in Sound stimuli B and D were enhanced from the original BWM i3 stimulus (Sound A). The harmony and order additions of these two stimuli were generated in Matlab using the chirp function, sweeping from 20\u2009Hz to the respective frequencies within the 10\u2009s stimulus period. The addition of these enhancements can be seen in Sound stimulus E was generated in Matlab by isolating several lower electric motor orders and enhancing the stimuli with reverberation in the GarageBand software before finalizing the length and level of the stimuli in Audacity.Sound J was created in Matlab using a Shepard\u05f3s Risset Glissando with a fundamental frequency of 110\u2009Hz, sample frequency of 44.1\u2009kHz and a cycle time of 2\u2009s Sound K was developed in an attempt to make the enhanced sound E more realistic by adding simulated road and tyre noise. Sound l was developed to improve the warning characteristics of the base stimulus (Sound A), through the addition of frequency modulated pink noise, which improves the localization and differentiation of similar sounding stimuli 2.3In order to analyze and visualize the differences between the sound stimuli with respect to the spectral and temporal content, spectrograms (FFT versus time) of the stimuli were created and are shown in"} +{"text": "To the editor,We read with interest the recent paper by Ochoa - L\u00f3pez et al. examining the incidence of genitourinary malignancies in renal transplant patients . An imprSpecific to the urothelial carcinoma subgroup, all were non muscle invasive tumours managed with endoscopic resection alone but 1 had nephroureterectomy of the graft performed for upper tract neoplasia.The authors proceed to discuss risk factors for post - transplant malignancy identifying tobacco use and immunosuppression as predominant ones. Importantly the difficulty in treating transplant patients with bladder cancer is further highlighted due to concerns over intravesical chemotherapy but the authors acknowledge that cystectomy remains an option although no patient in this series underwent radical cystoprostatectomy.The authors should acknowledge that geographical variations exist in the development of transitional cell carcinoma following transplantation with higher incidences noted in Taiwan . A 34 - Shum et al. reported a case of lymphoproliferative disease of the adrenal gland in a transplant recipient treated with rituximab and also a case of bladder cancer treated with radical cystectomy 9 years following cystectomy although the patient succumbed 8 months postoperatively .We reported a case of a 63 year old transplant patient with a triumvirate of genitourinary malignancies occurring 41 years following a live donor transplant (Chakera et al. have reported a case of renal cell carcinoma of the graft occurring 8 years post transplantation treated with partial nephrectomy and high intensity focussed ultrasound .Weinstein et al. have further reported a case of a 29 year old kidney transplant patient who had undergone conversion of a ureterosigmoidostomy to an ileal conduit and subsequently developed adenocarcinoma of the colon.Therefore, as the incidence and complexity of genitourinary tumours in transplant recipients increases due to improved immunosuppression and increasing numbers of transplants being performed it is necessary for non - transplant urologists to be aware of the potential uropathological presentations that are unique to this patient cohort."} +{"text": "In studies of probiotic use in neonates the phenomenon of cross contamination (cross colonization) of the control group neonates with the probiotics administered to the study group was observed and a hypothetical reanalysis of the presented data after statistically controlling this phenomenon unveils significant benefits resulting from probiotic therapy. This article discusses the putative pathogenesis of this phenomenon and its clinical and research implications. Lactobacillus species, bifidobacterium species, streptococcus thermophilus and saccharomyces boulardii are the probiotic strains that have been used in neonates . Meta-anMechanism of cross-contamination of probiotics in neonatal intensive care units (NICU)The bacterial probiotics used in the studies in neonates are gram-positive viable organisms and are prepared from lyophilized powder form in sachets. Hand washing and alcohol-based gels are the mainstays of prevention of cross-infection in the current neonatal units. It has not been mentioned in the UK and Australian probiotic studies whether gloves were uniformly used during preparation of probiotic dosage for administration.Lyophilized sachet reconstitution process can result in a significant environmental contamination. Although we could not find any study that explores this in the context of bacterial probiotics used in neonates, there is one published study that has investigated this phenomenon with the non-bacterial probiotic Saccharomyces boulardii. The mere opening of sachets of lyophilized saccharomyces boulardii leads to significant environmental contamination (probiotic blast) that included air at 1-meter distance, simulated patient surface and hands of the sachet opening operator, the last being the heaviest that persists even after hand washing. It was recommended in this article that preparation of saccharomyces boulardii for clinical use should be done outside the patient care area using gloved hands . It is pThe next question is whether a single sentinel event of feco-oral transmission is enough for \u2018contamination\u2019 of the control group. The answer to this question is probably negative as it has been known that gram-positive probiotic bacteria are only transient colonizers of the\u00a0gut . Hence tHowever, this phenomenon of cross contamination occurred to a lesser extent in the Australian study as well wherein the preparation of the probiotic was by the hospital pharmacist and the entire clinical team was blinded . A criti1.\u00a0Stool and environmental samples were collected for molecular DNA fingerprinting evidence for probiotic bacteria colonization at two predefined time points, one during the study period (Point A) and second six\u00a0months after the first time point during off the study period (Point B).2.\u00a0Forty-three stool samples and 19 environmental samples (12 from rooms where probiotic-administered infants were there and seven from other rooms) were obtained during point A.3.\u00a0Forty-four stool samples and eight environmental samples were obtained during point B.4.\u00a0At point A\u00a0all five of five probiotic group stool samples were positive, two of seven in the placebo group and one of 31 in the non-study group were also colonized thus giving the cross-colonization rate of three of 38 (7.9%). This is well and way below the stool colonization frequency of placebo group in the PiPS study (around 40%). This implies that the more distant the probiotic preparation site (non-involvement of nursery personnel) from the infants lesser the chance of cross-colonization.5.\u00a0At point A, four of 12 environmental samples from rooms wherein probiotic administered infants were cohorted were positive which effectually means that the probiotic bacteria in the environment are indeed sourced from the stools of the probiotic-administered infants via intermediaries healthcare workers. None of the seven in non-probiotic administered rooms was positive.6.\u00a0At point B, none of the environmental samples were positive whereas one of 44 stools sample was positive. The latter is intriguing as probiotic administration had been stopped at least three months before and environmental samples were negative. The inference that is deduced from this is that it is from healthcare workers who were still harboring the probiotic bacteria. This buttresses our previous argument that probiotic bacteria bear the characteristics of resident skin flora and are not easily removed by the usual hand disinfection routines of the\u00a0nursery.However, absolute safety with probiotic use in preterm neonates has been demonstrated in both these trials and cross contamination was in effect a welcome phenomenon that extended the benefits of probiotics to the control group neonates as well masking the true benefits of probiotic administration , 11.Putative mechanisms of probiotic bacteremiaThere have been about five reported cases of bacteremia and systemic sepsis during probiotic therapy (four with lactobacillus and one due to bifidobacterium) and these have been mainly in patients with open intestinal malformations like omphalocele . TherapyIt can be logically deduced from this article that cross-contamination (as termed by PiPS Study) or cross-colonization (as termed by ProPrems study group) does exist with probiotic bacteria , 4. BothTherapeutic and research implications of the cross-colonization phenomenon of probiotic bacteriaColonization of the gut with gram-negative enteric pathogens and subsequent translocation has been proposed as the causative factor in a majority of blood-stream infections in neonates , 16. In Efficacy of the standard nursery disinfection routines and hand hygiene standards are not consistent across different centers which is reflected in the lower cross-colonization rate observed in the Australian units who follow the State of Victoria Cleaning Standards for Health facilities . This,\u00a0wCross colonization phenomenon of probiotic bacteria does exist and by virtue of it even the control group neonates in the well designed large randomized trials of probiotic use in neonates derive the advantages that were thought to accrue to the study group infants only.\u00a0Both environmental factors and healthcare workers\u2019 hand hygiene are contributory factors in the genesis and existence of this phenomenon.\u00a0Probiotic bacteria are resilient to eliminate by the currently recommended disinfection routines and hand hygiene routines.\u00a0It is probable that this phenomenon can be an effective weapon in our fight against multi-drug resistant pathogenic neonatal bacteria."} +{"text": "In 1973, Corsellis and colleagues presented their findings of neuropathological changes in retired boxers in their seminal paper entitled \u2018The Aftermath of Boxing\u2019 . The neuOur findings indicate that seven of the 14 cases (mean age 69) fulfilled current CTE diagnostic criteria Below is the link to the electronic supplementary material."} +{"text": "The area under the receiver operating characteristic curve that appeared corresponded to the results for digital single-lens reflex camera images, whereas the specificity corresponded to the results for iPhone images. The area under the receiver operating characteristic curve for those images was 95.8%. This article has been corrected.1The Original Investigation titled \u201cAssessment of Accuracy of an Artificial Intelligence Algorithm to Detect Melanoma in Images of Skin Lesions,\u201d"} +{"text": "Wastewater minimization in phenylacetaldehyde production by using indirect electrochemical oxidation of phenylethane instead of the seriously polluting traditional chemical process is described in this paper. Results show that high current efficiency of Mn(III) and high yield of phenylacetaldehyde can be obtained at the same sulfuric acid concentration (60%). The electrolytic mediator can be recycled and there will be no waste discharged."} +{"text": "To the editor,We read with interest the recent paper by Zhong et al. examining the variety of endourological strategies available for the management of urinary tract stone disease in patients following urinary diversion .The authors report a retrospective study involving 26 patients who underwent urinary diversion and who subsequently presented with stone related problems and allude to the variety of techniques available .Specific to the lower tract it is stated that 3 patients underwent orthotopic neobladder surgery and were subsequently treated for vesical calculi with neobladder lithotripsy and in select cases a second look procedure was performed 3-5 days later .The authors list the treatment modalities mentioned: PCNL, SWL, Percutaneous antegrade and retrograde ureteroscopy and open removal but shou"} +{"text": "Melanoma, the deadliest form of skin cancer, is often characterized by mutations of genes involved in the MAP Kinase signaling pathway leading to a hyperactivation of the pathway and thereby uncontrolled cellular proliferation and survival of the malignant cells. In recent times drugs specifically targeting the MAP Kinase signaling pathway were therefore developed. These so called \"targeted therapies\" like BRAF or MEK inhibitors are very powerful in the beginning of treatment but are limited due to the occurrence of resistance . TherefoThe Signal transducer and activator of transcription 3 (STAT3) was shown to play a central role in resistance towards targeted therapies . MoreoveSOX2 was demonstrated before to be a cancer stem cell marker and its expression is increased in melanospheres which showed a higher resistance towards the BRAF inhibitor vemurafenib , 7. InteIt appears that for melanoma cells CD24 upregulation constitutes an escape mechanism by which the cells survive the initial and toxic exposure to the BRAF inhibitor. The surviving cells are then able to acquire additional long-term mechanisms of drug resistance. Our results suggest that this escape mechanism can be blocked by using Src or STAT3 inhibitors. Hence, the use of these inhibitors even in the more resistant SOX2 and CD24 overexpressing cells lead to a higher sensitivity towards the BRAF inhibitor treatment . STAT3 pThis mechanism of adaptive resistance in melanoma cells helps to understand how some of the cancer cells manage to escape the cytotoxic activity of BRAF inhibitors and are able to acquire long-term mechanisms of resistance resulting in cancer relapse in the patients. Thus, we highly recommend to proof if the use of Src and STAT3 inhibitors can help patients to delay the onset of resistance or in best case prevent resistance towards BRAF inhibitors."} +{"text": "Data presented in this article are supplementary materials to our article entitled \u201cCatheter Ablation for Fascicular Ventricular Tachycardia: A Systematic review\u201d . The current article provides additional procedural data regarding the catheter ablation for fascicular ventricular tachycardia (FVT) performed in the patients enrolled in our analysis. Furthermore, we provide data regarding the quality assessment of the studies included in our systematic review. Specifications tableValue of the data\u2022These data can be used for defining the scientific quality of the most relevant published series of patients undergoing catheter ablation for FVT.\u2022These data also provide useful information for guiding the ablation strategy for FVT, by defining the timing of the pre-Purkinje potentials at the successful ablation site and the incidence of fascicular block after ablation.1The data presented in this article are supplementary material to our systematic review on catheter ablation for FVT 2We performed a systematic electronic search of the published studies including patients who underwent catheter ablation for FVT"} +{"text": "Malaria remains one of the most important infectious diseases in the world today, infecting 300 to 500 million people yearly and resulting in 1 to 2 million deaths, primarily of young African children[1]. The most severe form of this disease is caused by infection with the mosquito borne protozoan parasite Plasmodium falciparum. This parasite lives by invading and multiplying within the red blood cells of its host, causing disease through anemia resulting from red cell destruction, and also through modifications made to the surface of infected red cells. These modifications make infected cells cytoadherent or \u201csticky\u201d, allowing them to adhere to the walls of blood vessels, leading to obstruction of blood flow and such clinical manifestations as the often fatal syndrome of cerebral malaria[2]. In addition, parasites are capable of undergoing antigenic variation, a process of continually changing the identity of proteins on the surface of infected cells and thus avoiding the immune response mounted by the host[3]. This process promotes a long term, persistent infection that is difficult to clear."} +{"text": "Routine childhood immunization remains an important strategy for achieving polio eradication and maintaining a polio-free world. To address gaps in reported administrative coverage data, community surveys were conducted to verify coverage, and guide strategic interventions for improved coverage.We reviewed the conduct of community surveys by World Health Organization (WHO) field volunteers deployed as part of the surge capacity to Kaduna state and the use of survey results between July 2015 and June 2016. Monthly and quarterly collation and use of these data to guide the deployment of various interventions aimed at strengthening routine immunization in the state.Over 97,000 children aged 0\u201311\u2009months were surveyed by 138 field volunteers across 237 of the 255 wards in Kaduna state. Fully or appropriately immunized children increased from 67% in the fourth quarter of 2015 to 76% by the end of the second quarter of 2016. Within the period reviewed, the number of local government areas with <\u200980% coverage reduced from eight to zero.The routine conduct of community surveys by volunteers to inform interventions has shown an improvement in the vaccination status of children 0\u201311\u2009months in Kaduna state and remains a useful tool in addressing administrative data quality issues. Childhood Immunization is a critical cost effective strategy used globally to reduce infant and under 5-year-old mortality rates . In a biNigeria marked 2\u2009years without a case of paralytic Wild Polio Virus (WPV) until the recent isolation of three cases in Borno state in 2016 as it prepared for a post-polio immunization system and its recent removal and consequent reversal from the list of polio-endemic countries , 9. To aKaduna state, located in northwest Nigeria is one of the 11 high-risk states for polio transmission and has recently enacted a primary health care under one roof (PHCUOR) law and established the state primary health care agency with a primary mandate to improve primary health care services.A total of 1094 health facilities provide routine immunization (RI) services to a targeted population of 326,118 infants; delivering all vaccines based on the national immunization schedule. The Nigeria Demographic Health Survey (NDHS) 2013 reported routine immunization coverage of 43.7% for the third dose of Diphtheria-Pertussis-Tetanus (DPT) vaccine and 44.4% for Oral Polio Vaccine (OPV3) in Kaduna state . Data quGuidelines have been reviewed with strategies proposed to address the impact of data quality on program implementation with guidance documented in the country multiyear plan (cMYP) 2016\u20132020 . ImmunizKaduna state has over the years experienced various degrees of outbreaks of measles and cerebrospinal meningitis (CSM) despite very high administrative coverage data of routine antigens. In line with the surge in health worker capacity of WHO in Nigeria, personnel and field volunteers have been deployed to various communities.These personnel supervise RI services and conduct surveys of children aged 0\u201311 monthly using standard program tools and checklists and document vaccination status at sub-district levels to be used to guide and support program interventions.This study reviews the surveys conducted across Kaduna state involving more than 90,000 children between 2015 and 2016 and its use to guide the implementation of various RI interventions at LGA and state levels. It also reports on survey documentation as a best practice regarding polio legacy and its use in transition planning [We conducted a retrospective study to review the trends of community surveys conducted across various communities in Kaduna state across four quarters between July 2015 and June 2016 of children <\u20091\u2009year of age who were fully or appropriately immunized for age in Kaduna state.Quantitative data showing various vaccination status variables including the number of settlements and wards was analyzed, and we also reviewed the routine immunization administrative coverage data reported by LGA and state within the same period.A total of 138 field volunteers had been deployed across 255 wards of the 23 LGAs of Kaduna state based on the World Health Organization (WHO) Nigeria surge capacity to improve program implementation. These levels of staff were mandated, as documented in their terms of reference (TOR), to conduct a minimum of one community survey per month in any settlement in the catchment area of the health facilities in the ward of assignment using a community survey checklist. The adherence to this task was ensured by the WHO accountability framework and quarterly administrative action from the Office of the WHO Representative (WR) in Nigeria with all assigned responsibilities accessed accordingly .A total of 9557 surveys involving 96,597 children aged 0\u201311\u2009months were conducted across the 23 LGAs between July 2015 and June 2016.The sample size for each survey was 10 children per selected settlement was based on the standard protocol of the WHO Nigeria field volunteer\u2019s checklist and field guide for staff.All survey data with complete information for 10 children sampled with complete information on all variables as shown on the field volunteer\u2019s checklist. Children in households where mothers were not at home at the time of visits, consent not given by caregivers or selected households with children aged greater than 12\u2009months or incomplete documentation on the checklist were discarded. The study utilized the weekly submissions of field volunteer survey checklists which was transferred to a simple Microsoft Excel\u00ae template for collation with the capture of details showing the date of survey, settlement name, ward and classification of children according to vaccination status. This was done monthly at the LGA level and quarterly in the state. Data was measured in proportions of vaccination status of all children surveyed and also displayed as simple quarterly trends to show the pattern of various vaccination statuses.The average number of settlements and wards per quarter were documented. A review of routine immunization administrative coverage data for first and third doses of Pentavalent and oral polio vaccine (OPV) was also shown at LGA and state levels.All designated WHO staff at quarterly program review meeting were re-sensitized and reoriented on the process for community surveys using the field volunteer\u2019s checklist. The identified template for collation and capture of surveys was also discussed and shared with all LGA facilitators (first line supervisors of the field supervisors) for monthly collation and timelines for quarterly submission to the state level monitoring and evaluation (M&E) Officer. The template included various validation checks to reduce entry errors as well as automatically generated graphs to show simple analysis of vaccination status by ward and LGA.Surveys were conducted by the staff after community entries and permission by village gatekeepers, mainly the village head and consent by caregiver sort and given, in selected households to participate in the survey. Vaccination status was documented using vaccination cards with an assessment of vaccination status for the current age of child based on the current EPI schedule for Nigeria.Sampling technique for surveys included skipping 1 or 2 households in settlements with less than 10 or greater than 20 Households respectively. A selected household without an eligible child was skipped and the next household with a child sampled.Collated data were reviewed and proportions of various vaccination status category including \u201cfully or appropriately immunized,\u201d \u201cpartially immunized\u201d and \u201cnot immunized\u201d and shared at the state emergency operations center (sEoC) and comparison with administrative data. LGA and ward survey reports were reviewed and interventions best suited deployed. These interventions deployed based on best fit are outlined in Table\u00a0At the LGA level, these survey reports were shared with the local immunization officer, director of health and displayed at the government office by ward conspicuously. This data set was also discussed at the monthly review meetings with routine immunization providers for all health facilities in the LGA with clear directives on action points to address issues in a settlement with low levels of appropriately immunized children including supportive supervision.A total of 97,007children aged 0-11\u2009months were surveyed between July 2015 and June 2016 by 138 field level staff in Kaduna state and Penta 3 was 90 and 92% respectively in quater1 2015, OPV3 94% and Penta 3 91% in quater2 2015, 100% in quater3 2015, and 107% in quater4 2016 conducted by the state in 2015 with an over-reporting factor of 10%).The summary of children surveyed and their vaccination status was documented across four quarters Table\u00a0. The proIn our reviews of the outputs of the surveys conducted in Kaduna state involving >\u200990,000 children between July 2015 and June 2016, we found an increasing trend of fully or appropriately immunized children from 67% in quarter 3 2015 to 76% in quarter 2 2016.The use of these routine surveys results to guide various routine immunization intensification activities has also shown to have a positive impact on routine immunization coverage in Kaduna with an increase of Penta 3 coverage data from 90% before the use of these survey data to 134% by the end of June 2016.This result is similar to documented variance with survey data seen to be less than administrative values in South Sudan .The impact was also seen at lower levels of an increase in the number of LGAs with Penta 3 coverage from 65 to 100%. We have also shown a reduction in variance between OPV3 and Penta3 coverage, antigens scheduled at the same hospital visit, a simple method for data quality check. We have also shown increases in surveys conducted in quarter 1 and quarter2 of 2016 compared to those done in 2015. We attribute this to increasing awareness of the importance of the surveys and more interest by the Local authorities\u2019 staff to support the process.Not all 255 wards in Kaduna state were surveyed within the study period. The survey scope was highest in Q1 2016 and lowest in Q4 2015.This variance in surveys in wards are linked to the decision by field staff to focus on settlements they consider as poor performing regarding routine immunization based on information from the Health facility supervisory visit. We, however, note that some data submissions with quality issues or surveys not done based on guidelines were discarded. Even though we also see variation in numbers of settlements, we have noted that some settlements were surveyed more than once within the period of the survey. These repeat surveys were only conducted in specifically highlighted settlements with clear risks such as disease outbreaks of VPDs or validation visits of interventions already deployed.Even though a huge number of children were sampled in these surveys, our study was limited by the fact that not all the wards and settlements in the state were surveyed, and surveys were mainly conducted around communities close to a health facility. This limitation is based on the current staff deployment of 138 field officers in the state. This limitation can be addressed by the push for the involvement of by LGA and state Health personnel which could then ensure sure complete state coverage. The limitation of surveys around health facilities is based on transportation cost as the personnel are also not provided with any means of transportation or entitled to transportation reimbursements. With increasing government buy-in and participation, health department vehicles may subsequently be available for the conduct of settlement surveys far from the health facilities but within the reaching every ward (REW) catchment area of the health facility.This study has shown that routinely administered community of surveys in Kaduna has been used effectively to guide the various routine immunizations intervention activities in the state with a resultant increase in state and LGA level administrative data and with high-level coordination support shown improvement inappropriately immunized children.We recommend the continuous routine conduct of household surveys by local government, other partner and all field staff at regular intervals and use of vaccination status of children under 1\u2009year to routine immunization activities across Nigeria and other developing countries with administrative data management challenges. These surveys can also be useful in strengthening immunization systems and PHC delivery. Tao W et al. have suggested that reported routine immunization coverage may be lower than reported . SustainCommunity surveys are a very effective tool to guide implementation of routine immunization services at community levels with a noticeable increase in proportion of fully immunized children. The use of simple tools to track vaccination status of children and provide regular feedback to program authority at local levels remain critical in the push to reach all eligible children with vaccines and improve coverage."} +{"text": "Following publication of this article concernsIn In In the western blot in Fig 7, there are horizontal discontinuities in the background shading above and below the band in lane 5 of the cleaved caspase-3 panel.In the western blot in Fig 7, there are similarities between bands in lanes 1\u20133 compared to lanes 4\u20136 of the \u03b2-actin panel.The corresponding author has clarified that the original flow cytometry experiments were carried out by a technician in another laboratory within the same institution. The corresponding author stands by the flow cytometry dot plots in The underlying raw data files for the repeat experiment are provided as Supporting Information .The corresponding author stands by the western blot images in Fig 7 as accurate; however, the original uncropped blot images are not available.The underlying data for the other parts of the article remain available upon request.PLOS ONE Editors issue an Expression of Concern to inform readers about the concerns regarding the accuracy of the western blot and flow cytometry image data in the original article, which could not be fully resolved due to the unavailability of the original raw data files.The S1 File(RAR)Click here for additional data file.S2 File(ZIP)Click here for additional data file."} +{"text": "The dataset and toolbox presented in this article are related to the research article entitled \"Modeling potential tree belt functions in rural landscapes using a new GIS tool\" Specifications TableValue of the data\u25cfThe input dataset could be used to assess the degree of potential tree belt function availability in the north-west part of the Gen. Dezydery Ch\u0142apowski Landscape Park in Poland.\u25cfThe data can be used for testing the TBM toolbox by a potential user and serve as a reference for the structure of any other dataset to be used in the toolbox.\u25cfOpen access to the TBM toolbox internal structure allows researchers to further develop it by adding new parameters, modules or incorporating the TBM toolbox into other GIS tools and software.1This article presents a dataset over the Gen. Dezydery Ch\u0142apowski Landscape Park in Poland. It includes input data acquired from Head Office of Geodesy and Cartography in Warsaw and output data received from the Tree Belt Modeling (TBM) toolbox processing. The first part of the dataset contains vector layers (format: ESRI shapefile): polylines layer and polygon layer (land cover). The digital elevation model (Geo Tagged Image File Format) is also added to the first part. The second part contains the output vector layers obtained from all the five analysis modules described in the related article. The result of the TBM final analysis situated in western Poland. This part of the park was selected based on the assessment of the density of linear structures over the entire park. To reliably test the TBM tools, the area with the highest density of linear structures was selected. It was assumed that the dense network of linear objects concentrated within a small area is appropriate for checking the efficiency of the TBM tools because of higher probability of detection of possibly untypically distributed linear structures. The selected part of the park covers 5460.95\u202fha of agricultural area (90.93%) and 495.19\u202fha of forested area (9.07%). The total length of linear objects as potential places for linear woody features is 1023.12\u202fkm.The presented toolset was based on the Model Builder . MB facilitates the development of spatial models without the necessity of combining the typical developing software programs and advanced programming skills of a user Select by attributes tool and the Field calculator tool in ArcMap. To prepare the Digital Elevation Model (DEM) on the basis of Airborne Laser Scanning data (density of point cloud: 4\u20136 points/m\u00b2), the LAS dataset toolbar and the LAS dataset to raster tool (Conversion tools in ArcMap) were used. In the second part of the TBM toolbox, Python scripts were developed for the solar conditions analysis tool (The input data preparation tool from the first part of TBM toolbox was usedsis tool and the sis tool . In thessis tool , the plosis tool and the sis tool . The thisis tool used for"} +{"text": "Molecular evidence for the existence of multiple receptors for CGRP has been rather difficult to obtain. Over 10 years after suggesting the existence of at least two classes (CGRP1 and CGRP2) of CGRP receptors on the basis of pharmacological data[1], molecular data on the CGRP2 receptor subtype are still lacking as well as potent and selective antagonists. The situation is somewhat different for the functional CGRP1 subtype which is likely composed of diverse subunits CRLR, RAMP1 and possibly RCP[2]. Moreover, BIBN 4096BS was recently reported as the first nonpeptide highly potent CGRP1 receptor antagonist[3]. However, in situ hybridization and receptor autoradiographic data have clearly shown the existence of major mismatches between the discrete localization of CRLR, RAMP1, and specific CGRP binding sites supporting the existence of CGRP receptor subtypes. Functional studies have also provided evidence in that regard (for a recent review: [4]). Accordingly, additional studies aiming at cloning additional CGRP receptors are certainly warranted. Similarly, recent evidence from various laboratories including ours suggests the existence of more than one class (CRLR and RAMP2) of adrenomedullin receptors at least in the rat brain. In contrast, most evidence suggests the existence of a single class of amylin receptors. In brief, it appears that multiple receptors or receptor complexes do exist for CGRP and related peptides but their composition is apparently unique among the GPCR super-family and additional data are needed to fully establish the molecular organization of each subtype. Supported by CIHR of Canada."} +{"text": "This paper examines the extent to which critical gerontology has raised awareness of the heterogeneity of rural ageing in High Income Countries (HICs) and compare this to our knowledge of the issues that are associated with rural ageing in Low to Middle Income Countries (LMICS). We will draw on Nancy Fraser\u2019s social justice framework to summarize key issues around: (1) Demography ; (2) Resources ; (3) Recognition ; (4) Representation . We argue that an intersectional approach that takes into account location and context alongside other dimensions of oppression and/or privilege can provide a better understanding of the experience of ageing in rural areas."} +{"text": "There is a numerical error that appears in the Abstract, Additionally, there are citation errors in the Methods section. The fourth sentence of the third paragraph should have cited reference 25 instead of 26. The third sentence of the fifth paragraph should have cited reference 20 instead of 18."} +{"text": "The wrong file was uploaded for the Supporting Information Supplementary text. Please view the correct supplementary text file below. The publisher apologizes for the error.S1 TextSupplemental text giving a more detailed description of the RSEC framework and its implementation, as well as information about the analysis of the datasets.(PDF)Click here for additional data file."} +{"text": "High mountain areas have recently been observed to be polluted by organochlorine compounds (OC) despite their isolation. These persistent pollutants arrive at these remote regions through atmospheric transport. However, the mechanisms involving the accumulation of these compounds from the atmospheric pool to the lacustrine systems still need to be elucidated. These mechanisms must be related to the processes involving the transfer of these pollutant from low to high latitudes[1] as described in the global distillation effect[2]."} +{"text": "Very long baseline interferometry (VLBI) scheduling is a challenging optimization problem. With the development of the new VLBI global observing system (VGOS) consisting of smaller but very fast slewing antennas, new opportunities arise. In this work, we give a deep insight into optimized VGOS scheduling using a newly developed VLBI scheduling software called VieSched++, and we show how different scheduling parameters and approaches affect the precision of geodetic results. Therefore, the results of over one thousand generated schedules and over one million simulated sessions are analyzed. The simulations reveal that the most important parameters to optimize VGOS schedules with VieSched++ are the so-called weight factors. A proper selection of individually optimized weight factors can improve the quality of a schedule significantly. It is shown that the values of the weight factors used to generate the schedule are highly correlated with the expected precision of the geodetic parameters. We highlight the benefit of selecting schedules based on large-scale Monte Carlo simulations and show why scheduling statistics like the number of observations or the sky-coverage are not necessarily the best metric to evaluate schedules. The very long baseline interferometry (VLBI) has been developed by radio astronomers in the 1960s and was soon after used for geodesy as well. Today, it plays an important role in the realization of the terrestrial reference frame as the next-generation VLBI system is necessary to reach the goal of the Global Geodetic Observing System (GGOS) for one session and compare the results. Fortunately, this work is highly automated in VieSched++ and VieVS making this process very efficient, e.g., scheduling 100 VGOS sessions with a fixed observing duration of 30\u00a0s and simulating each session 1000 times takes less than 30\u00a0min on a desktop computer with AMD RYZEN 7 2700X processor."} +{"text": "S3 TableMetadata defining column headers for the data file that includes the aligned coordinates and centroid sizes for both dorsal and lateral landmark configurations for all specimens used in this study.(CSV)Click here for additional data file.S3 FileThe data file that includes the aligned coordinates and centroid sizes for both dorsal and lateral landmark configurations for all specimens used in this study.(TXT)Click here for additional data file."} +{"text": "This results the under- or overestimation of net ecosystem exchanges of CO2. We propose a technique for nighttime filtering (and correction) of CO2 fluxes to eliminate (and replace) those significantly affected by horizontal advection: the modified moving point test method. This was developed by merging the friction velocity filtering and van Gorsel methods. It is based on an approach using moving windows for time and friction velocity, allowing a nighttime CO2 flux correction that includes an assessment of CO2 drainage at midnight. We tested the method using datasets from two flux towers in forests in hilly and complex terrains, where the application of generic nighttime filtering methods is difficult because CO2 drainage is generated earlier than the time assumed by the generic methods. The method produced carbon budgets consistent with previous research results, while showing improved applicability.The measurement of carbon dioxide (CO\u20222 flux filtering method for hilly and complex terrain that combines the friction velocity filtering and van Gorsel methods.We propose a nighttime CO\u20222 drainage at midnight based on an approach using moving windows for time and friction velocity.This method determines the friction velocity threshold and the significance of CO\u2022The method produced consistent results and shows improved applicability. Specifications Table2) can be expressed as . 2 budgets from the three traditional nighttime correction methods with and without applying the site-specific filter, and those from use of the modified MPT method. We already knew that the site-specific filter improved on the discrepancies (see the standard deviation among the results) between the three nighttime correction methods and the underestimation of ER . There 2 fluxes is that two existing methods were merged to produce a new method. The u* filtering and van Gorsel methods have been merged to produce the modified MPT method. Such a strategy enhances the strengths and makes up for the weakness of the original methods. There are other examples of such improvements; the lookup table method and mean diurnal variation method were merged into the marginal distribution sampling method for flux gap-filling [2 fluxes near sunset using u* and (2) salvage the omitted data from most of the nighttime when using the van Gorsel method. Notably, the modified MPT method for nighttime CO2 flux correction substantially improves its applicability, leading to the expectation that it will contribute to the standardization of eddy covariance data processing.The distinctive feature of the new technique proposed in this study for nighttime flux filtering (and correction) of eddy CO-filling , and the-filling ) The mod"} +{"text": "After publication of this article , concernWith this Correction, the authors provide updated Figs A member of PLOS ONE\u2019s Editorial Board confirmed that the new Figures and provided data support the results and conclusions of the published article.The authors apologize for the errors in the published article.S1 FileAll underlying data for this study.(ZIP)Click here for additional data file."} +{"text": "Idiopathic ventricular arrhythmias originating from the aortic sinus of Valsalva often show preferential conduction to the right\u2010ventricular outflow tract, which may render radiofrequency ablation more difficult. We describe a patient with symptomatic premature ventricular contractions of left\u2010ventricular outflow tract origin presenting with a variation of QRS morphology during ablation. The correlation between the characteristics of local voltage potentials and the real origin site of the ventricular arrhythmia is discussed. The QRS morphology of the PVCs was characterized by an r pattern with a notch in lead I, an rS pattern in leads V1 and V2, a QS pattern in leads aVR and aVL, and a precordial transition in lead V3 features suggested that the PVCs originated from the right\u2010ventricular outflow tract (RVOT). Activation mapping was performed in the RVOT during the PVCs. At the earliest ventricular activation (EVA) site in RVOT, the local ventricular potential was recorded for 42\u2009milliseconds before the earliest start of the QRS complexes during clinical PVCs; this was preceded by a slow, low\u2010amplitude, far\u2010field potential which was recorded for 53\u2009milliseconds before the earliest start of the QRS of the aortic sinus of Valsalva origin and breakout sites in the RVOT.dV/dt of the unipolar electrogram and the maximal amplitude of the bipolar electrogram) must be performed to define the real origin of the VA.Di Biase et al reported that RFCA may be unsuccessful at the site of the earliest local ventricular activation when the bipolar electrogram is far field. Activation mapping (using the maximal negative Bloch Thomsen et alIn short, this case suggests that distinguishing near\u2010field from far\u2010field potentials is helpful for identifying the real site of origin of ventricular arrhythmia. The phenomenon of preferential conduction to multiple exit sites may occur in the LVOT when conduction is impaired and during anisotropic conduction of the muscle surrounding the site of origin.Video 1. Fluoroscopic documentation: Radiofreqency catheter was close to the ostium of the left main coronary arteryClick here for additional data file.Video 2. Video from carto system: The PVCs with the second QRS morphology was eliminated, the spontaneous PVCs changed to the third formClick here for additional data file."} +{"text": "Dietrich and Anais Riggs, was originally published electronically on the publisher\u2019s internet portal (currently SpringerLink) on 31 May 2018 without open access. With the author(s)\u2019 decision to opt for Open Choice the copyright of the article changed on 16 July 2018 to \u00a9 The Author(s) 2018 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (The original article has been corrected."} +{"text": "The following sentence was not included correctly in the original Notice of Retraction: \u201cThe authors provided some replication data in support of the results, but the original uncropped images underlying the published figures are no longer available.\u201dThe publisher apologizes for the error. The Notice of Retraction was republished on August 1, 2019 to correct this error. Please download the notice again to view the correct version."} +{"text": "The data sets in this article are related to a Placket Burman (PB) design of experiment (DOE) made on a wider range of uncertainties such as: reservoir, operational and reservoir architecture parameters that affect oil rim productivities. The design was based on a 2 level PB-DOE to create oil rim models which were developed into reservoir models using the Eclipse software and configured under the best depletion strategy of concurrent oil and gas production. Approximate solutions to the models was developed to forecast oil production using the least square method. The Monte-Carlo simulation approach was used in estimating 3 production forecasts for the oil rim reservoirs. This will help to create a probabilistic variety of forecasts that can further be used in making decisions. Specification TableValue of data\u2022This data incorporates a wider range of parameters such as reservoir architecture (dip), operational parameters and extra reservoir parameters in describing the nature of oil recovery in oil rim reservoirs.\u2022A response surface model can be developed from the given data to represent oil and gas recovery for all the models and a Pareto analysis can made to distinguish significant parameters that affect oil and gas recovery\u2022The models generated from the data can be used to derive decline curve equations using the linear regression method of an Excel Program from which probability production forecasts can be estimated using Monte-Carlo.\u2022The models generated from the data can also be classified based Pareto analysis and subjected to secondary and enhanced oil recovery schemes.\u2022A 3 level design of experiment can be carried out on the outcomes of the Pareto analysis to scientifically reduce quantify (and reduce where possible) uncertainties thus making the outcome more effective.1Parameters affecting oil rims have been highlighted by Ref. 22.1R2 values and profile equations to the production profiles for some of the models were used to develop decline curve based models. R-squared value of the straight line fitting, the production rate,\u2217, when the straight line is extrapolated to time zero were estimated.With the linear regression method of an Excel program, the calculations of the continuous decline rate constant, q\u204e and continuous decline rate constants used in analyzing the decline plots are shown in The time of plateau production, initial production rates The values of the selected models are shown in"} +{"text": "The experimental work was performed using a macrocalorimeter to measure the combustion heat, and the sublimation enthalpy was determined via the measurement of the vapor pressure at equilibrium with the vapor phase at different temperatures resorting to the Clapeyron-Claussius equation. Theoretical calculations were performed using semiempirical AM1 and PM3 methods as well as"} +{"text": "Pyrus) is one of the oldest temperate fruit crops, of which at least 22 primary species are recognized. This article documents the public availability of the partial draft genome sequence data of the Taiwanese pear \u2018Hengshanli\u2019 that is less dormant during the winter season. This dataset may be used to prepare molecular markers for the breeding of new cultivars that are subjected to chilling at low temperatures to overcome endodormancy. This data will also help analyze the process of evolution in the Pyrus species. We sequenced paired-end libraries using Illumina HiSeq. 2500 and generated approximately 210M reads. Data on the draft genome obtained in this study has been deposited to the DNA Data Bank of Japan (DDBJ). The read data were submitted to the DDBJ Read Archive .Pear (genus Specifications TableValue of the data\u2022Pyrus species.This dataset may be used to compare between the genomic data of other \u2022It will also be useful to prepare molecular markers for the breeding of new cultivars that are subjected to chilling at low temperatures for breaking endodormancy, because Taiwanese pear Hengshanli is less dormant during the winter season.\u2022Pyrus plants.This data will further be valuable for more detailed study of evolutionary processes occurring in 1Pyrus spp.) belongs to the family Rosaceae, and is generally divided into two groups: Occidental pears (European pears) and oriental pears (Asiatic pears) Pyrus species by providing genomic data for a comparative analysis with Chinese pear Pear protocol 2.2The extracted genomic DNA was subjected to preparation of a paired-end library for genome sequencing using the Illumina HiSeq. 2500. Genomic DNA libraries were constructed using the TruSeq Nano DNA Library Prep Kit according to the manufacturer\u05f3s protocol.2.3The read data were submitted to the DDBJ Read Archive ."} +{"text": "Pyrus pyrifolia), a member of the family Rosaceae, is one of the most important fruit trees in Japan. This article documents the public availability of the partial draft genome sequence data of the Japanese pear strain TH3, which is the S1 of \u2018Osa-Nijisseiki\u2019 and is homozygous for the S4sm gene. This dataset may be used to prepare molecular markers for breeding of new cultivars having a crisp texture and feel. This data will also help research on physiological disorders affecting Japanese pear fruit. We sequenced paired-end libraries using Illumina HiSeq. 2500 and generated approximately 212M reads. Data on the draft genome obtained in this study has been deposited to the DNA Data Bank of Japan (DDBJ). The read data were submitted to the DDBJ Read Archive .The Japanese pear ( Specifications TableValue of the data\u25cfPyrus plants, this dataset may be used to compare between the genomic data of other Pyrus species.In study of evolutionary processes occurring in \u25cfThis data will be useful to prepare molecular markers for breeding of new cultivars having a crisp texture and feel because the flesh of the Japanese pear has many stone cells.\u25cfThis data will further be valuable for more detailed study on physiological disorders affecting Japanese pear fruit.14sm gene Pyrus species by providing genomic data for a comparative analysis with Chinese pear The Japanese pear, one of the most important fruit trees in Japan, is also widely distributed in China and Korea 22.1Genomic DNA was extracted from the young leaves of the Japanese pear strain TH3, using a modified version of the cetyltrimethylammonium bromide (CTAB) protocol 2.2The extracted genomic DNA was subjected to preparation of a paired-end library for genome sequencing using the Illumina HiSeq. 2500. Genomic DNA libraries were constructed using the TruSeq Nano DNA Library Prep Kit according to the manufacturer\u05f3s protocol.2.3The read data were submitted to the DDBJ Read Archive ."} +{"text": "For the latter presence of water vapour in the gas stream leads to noticeable corrosion. Combining the experimental results with the chemical bonding analysis and first-principles calculations, the relationships among the chemical nature of the compounds, their reactivity and catalytic performance towards epoxidation of ethylene are investigated.The ethylene epoxidation is a challenging catalytic process, and development of active and selective catalyst requires profound understanding of its chemical behaviour under reaction conditions. The systematic study on intermetallic compounds in the Ca\u2013Ag system under ethylene epoxidation conditions clearly shows that the character of the oxidation processes on the surface originates from the atomic interactions in the pristine compound. The Ag-rich compounds Ca Ton oxides ,33.2 and CaAg to oxygen strongly depends on the crystal structure and chemical bonding features , [Ag6] and [Ca2Ag4] slabs along [001]. Further dilution of Ag by Ca leads to the formation of CaAg2 (KHg2 type) are separated by Ca atoms , [010] and [001] have very close cleavage energies crystallographic direction. This surface is also able to form stable, ordered and dense CaO-based layer under ethylene epoxidation conditions . This la5Ag3 and Ca3Ag are characterized by a significant electron transfer from calcium to silver atoms the different oxidation behaviour is not only determined by thermodynamic properties and the affinity of Ca towards oxygen, (ii) the chemical bonding mainly determines the chemical behaviour of the Ca\u2013Ag compounds and (iii) each component of the system plays an important role in the oxidation of Ca\u2013Ag compounds and thereby in their catalytic properties."} +{"text": "The original article containsin vivo inspite of low readthrough levels observed in vitro. One explanation could be a lower efficiency of the nonsense mediated mRNA (NMD) pathway in the cells of these patients, which can not be revealed with the dual reporter system.The corrected Table"} +{"text": "This study examined the trajectories of depression and cognitive function in the transition to widowhood and investigated the temporal and causal relationship between these two closely related constructs. Respondents were 1,822 widowed adults aged 51 to 91 from a restructured data set (Wave 3 to Wave 12) of the Health and Retirement Study. The results of cross-lagged panel analysis indicated a bidirectional relationship between depressive symptoms and cognition decline, but the effects of cognitive impairment at earlier time points on later depression were larger than the effects of previous depressive symptoms on later cognition. The latent growth curve analysis showed that the cognitive function declined over time, whereas the initial level of depressive symptoms first increased following widowhood and gradually decreased over time. Significant negative associations were found between the initial levels of depression and cognitive function (p < .001) and between the rates of change of these two variables (p = .025). Older adults tended to have lower initial level of cognitive function and they showed faster cognitive decline over time. Female respondents were more likely to report more depressive symptoms and higher cognitive function. White respondents were more likely to report fewer depressive symptoms and higher levels of cognitive function. Higher levels of education were protective for one\u2019s cognitive function but not for depressive symptoms. The study highlighted the reciprocal relationship between depression and cognitive function following widowhood and pointed out that accelerated cognitive decline may precede elevated levels of depression."} diff --git a/PMC_clustering_666.jsonl b/PMC_clustering_666.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..a6acb17b4ec19e7a559e627be61180506d35bfe3 --- /dev/null +++ b/PMC_clustering_666.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:6b9a9b0f5cd305390eec2e054a3e395f389b1df19f26b92525d33222848464c8 +size 55341980 diff --git a/PMC_clustering_667.jsonl b/PMC_clustering_667.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..9ce1f23420f6d1de5473ac3c623c69d9ff153d2f --- /dev/null +++ b/PMC_clustering_667.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:60494e86fa021451e8f60a5f07fc0f4d1fddaec902a6654ced3019d5cc5db8f9 +size 68929690 diff --git a/PMC_clustering_668.jsonl 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These conditions can pose a diagnostic dilemma and difference of opinion among clinicians. Erythromelanosis follicularis faciei et colli (EFFC) is one of these rare conditions that may be difficult to pick up especially at early stages. The condition was described for the first time by Kitamura et al and is clinically characterized by the presence of well-demarcated reddish brown patches of hyperpigmentation and erythema along with follicular papules present on the face, extending down to involve the neck ,2. It isEight consecutive patients with features suggestive of EFFC presented to the outpatient department and were enrolled and subjected to relevant history and clinical examination after taking informed consent. Criteria for diagnosing EFFC included the presence of hyperpigmentation, erythema, and follicular papules involving mainly the face extending to sides of the neck. Patients who met the clinical criteria were subjected to dermoscopic examination using a handheld dermoscope . Histopathological confirmation was performed in cases where diagnosis was doubtful.The clinico-demographic profile and dermoscopic findings of the patients are summarized in Dermoscopic examination revealed whitish scales and numerous follicular keratotic plugs against a reddish brown background in all the patients. Gray-blue dots and granules present in the perifollicular and interfollicular areas were seen in most of our patients, especially in subjects with longer duration of disease. Telengiectasias were present in 5 patients. White shiny structures (rosettes) were observed under polarized light in 4 patients. A coiled-up or twisted hair retained inside a follicular prominence with an inflamed follicular papule overlying it was observed in all patients .Histopathology was performed in only 3 cases and revealed hyperkeratosis, dilated infundibula with follicular plugging, and increased pigmentation in the basal membrane along with a mild perivascular and periadnexal chronic inflammatory infiltrate .EFFC is a rare disorder with limited cases reported across the globe. Multiple contributing etiologies have been proposed . Many stThe dermoscopic finding of EFFC was reported by Errichetti et al for the first time and our findings were consistent with their study . Mouni eSo far, no treatment of EFFC has proven satisfactory. Various options that have been explored include topical keratolytic agents such as ammonium lactate 12%), tretinoin cream , salicylic acid 2%, metronidazole, topical tacalcitol and hydroquinone 4%. Intermittent oral isotretinoin, chemical peel, and long-pulsed dye laser are other treatment options being considered %, tretin. We adviDermoscopy can play a vital role in improving the diagnostic accuracy of EFFC, evade the need for an invasive procedures like skin biopsy, and help us to differentiate it from close mimics. Polarized dermoscopy revealing white rosettes in EFFC further supports the existing literature that rosettes are not specific to any particular condition. They are the result of the optical effect of crossed polarization in the follicular and perifollicular structures."} +{"text": "This review aims to discuss (1) the refinement of mammalian visual cortical circuits and the maturation of visual functions they subserve in primary visual cortex (V1) and other visual cortical areas, and (2) existing evidence supporting the notion of differential rates of maturation of visual functions in different species. It is well known that different visual functions and their underlying circuitry mature and attain adultlike characteristics at different stages in postnatal development with varying growth rates. The developmental timecourse and duration of refinement varies significantly both in V1 of various species and among different visual cortical areas; while basic visual functions like spatial acuity mature earlier requiring less time, higher form perception such as contour integration is more complex and requires longer postnatal time to refine. This review will highlight the importance of systematic comparative analysis of the differential rates of refinement of visual circuitry and function as that may help reveal underlying key mechanisms necessary for healthy visual development during infancy and adulthood. This type of approach will help future studies to establish direct links between various developmental aspects of different visual cortical areas in both human and animal models; thus enhancing our understanding of vision related neurological disorders and their potential therapeutic remedies. Cortico-cortical networks undergo significant refinement and reorganization in the postnatal period; humans , monkeysNeural circuit formation and functional maturation in the developing brain follows a pattern of either hierarchical maturation or synchAlthough other reviews have focused on the development of (1) Ocular dominance columns in ferrets, cats and monkeys , (2) RF Developmental remodeling of visual cortical circuits spans over successive stages of postnatal development in various species, (1) Corticocortical connections in ferrets , 2014; hThe ferret has emerged as a promising model system in the study and characterization of visual circuit and function, particularly for early developmental mechanisms. This can be mainly attributed to the fact that ferrets are born at an early stage of brain development with delayed eye opening, which does not occur until about postnatal day 30 . The perIn addition to being important for studying developmental events, ferrets are also useful subjects for comparative studies. Comparative studies can reveal which physiological or anatomical aspects are present in all mammals, and which are unique to a particular species, For instance, it has been shown that the arrangement of ocular dominance domains in the ferret visual cortex exhibits a high degree of regional variation in size and shape, compared to that in primates and cats . This haNeural circuits underlying the maturation of visual functions are programmed to follow a hierarchical or synchronous pattern of maturation that is species dependent. While hierarchical maturation refers to the sequential development of basic physiological properties or anatomical circuits followed by the maturation of complex ones , synchroOne of the earliest reports supporting the notion of hierarchical development revealed that cortical connections linking somatosensory, primary motor, auditory and visual cortical regions were the very first to undergo myelination during the early stages of postnatal life in humans . SimilarAn open question remains as to why it is adaptive for feedforward connections to mature earlier than feedback connections. At the outset, feedforward and feedback connections in the visual cortex show strong differences in their anatomical features and connectivity patterns . FurtherIn contrast, there are reports which demonstrate concurrent development in the visual cortex. For instance, in ferrets, feedback neurons projecting from extrastriate areas to area 17 are already present prior to eye opening and refinement of the topography of feedback projections in these visual cortical areas occur in a synchronous manner . AdditioA conspicuous feature of the neocortex is the horizontal arrangement of neurons within cortical areas . HorizonIn the adult brain, neurons in the visual cortex respond to stimuli in a circumscribed region in visual space referred to as the receptive field center (RF). Visual stimuli presented in the surrounding region (surround) do not elicit a response, but can suppress or facilitate a cell\u2019s response to simultaneous presentation of visual stimuli in its RF center . The disThe emergence of mature RF tuning properties during development is thought to arise from the refinement of cortical circuits that underlie these tuning properties. Converging evidence suggests that the developmental timecourse varies markedly for different response properties of visual cortical neurons. Moreover, the variability in development is reflective of the maturational state of cortical circuits that presumably mediate specific neuronal response properties. The functional maturation of the mammalian visual system appears to be slower in higher-order visual areas than in V1. Moreover, the maturation of neuronal response properties in the visual cortex is dependent on the maturation of cells at lower levels of the visual system . The matGenerally, complex neuronal response properties in higher order visual areas require a relatively protracted period of maturation in comparison to basic response properties in lower order visual areas which mature early in life and require less time to mature. For instance, in the ferret, basic RF properties such as orientation selectivity of cells in area 17 are immature at birth, but improve in the days after eye-opening and become adultlike at 42 days postnatal . SimilarAn important question in developmental neuroscience is how early sensory experience contributes to the functional development and maturation of an adult brain. Visual experience differentially affects neuronal response properties, even among different species. Direct dependence of brain regions and their underlying mechanisms on visual experience may contribute to the observed differences in RF maturation among species. For example, spatial frequency tuning increases independently of visual experience in cats during the first 3 weeks of life, but is required for further improvement . DirectiEarlier studies in cats discussing the effect of light on the maturation of RF properties of cells in area 17 have shown that cells in dark reared animals were immature for orientation selectivity and direction preference stimuli . A compaVisual function at birth is relatively poor in human and non-human primates and gradually matures in the following months or years. Behavioral assessment of visual function in infants reveals that receptive field properties of neurons appear more developed than a behaviorally elicited response . The firIn humans, the progressive enhancement of visual functions such as visual acuity, orientation preference, contrast sensitivity, and motion detection is necessary for the development of higher order visual functions that require complex cognitive processing. Interestingly, none of these basic visual functions attain adultlike characteristics at the initial stages of development . For insHigher order visual functions involving more complex form cues exhibit delayed maturation, requiring longer postnatal time to become adult like. Orientation sensitivity is one of the first visual functions to appear after birth in humans, monkeys and ferrets. In humans, some orientation discrimination capabilities are present at birth and orientation-selective responses are first detected around 6 weeks of age . HoweverAlthough studies focusing on the development of direction preference in cats and ferrets have mostly resulted in physiological data , behavioSpatial contrast sensitivity including peak contrast sensitivity and spatial resolution are poor in both humans and monkeys at birth. Assessment of spatial contrast sensitivity in monkeys has revealed rapid development during the first 10\u201320 weeks, followed by a gradual more protracted period of development to adult levels over the remainder of the year . A similMoreover, temporal contrast sensitivity appears to mature ahead of spatial contrast sensitivity in both human , and nonGlobal motion sensitivity, a complex visual function that depends on extrastriate cortical processing requires considerable postnatal time to mature. It is important to distinguish between low-level mechanisms that provide local motion signals from higher-level mechanisms that integrate motion information across space and time. For instance, young monkeys are sensitive to global motion as early as 3\u20135 weeks postnatally, however, the complete maturation of this visual function continues up to 3 years of age . SimilarBehavioral studies in humans have similarly documented the protracted period of maturation of global visual functions. Global motion responses are more prevalent than global form responses in 4 month olds, although the activation patterns were different in infants compared to adults , These fThe visual system\u2019s ability to group discrete elements with similar orientation into a continuous contour that can be detected is known as contour integration . Neural Behavioral evidence supporting mechanisms of contour detection suggest that this function is present in the early stages of development , howeverFull maturation of contour integration abilities results from developmental remodeling of cortical circuits that mediate contour detection and integration. Analysis of human brains ranging from 24 weeks of gestation to 5 years of age has revealed that although the basic anatomical structure of V1 is seen very early in development, however, anatomical features of vertical and horizontal connections in the visual cortex continue to refine throughout development . HorizonIn the present review, we provided a comprehensive discussion on the development of visual cortical circuits and function in three mammalian species , in an effort to highlight the importance of comparative analysis of the differential rates of development. This is immediately relevant to our understanding of human visual perception as it may help reveal common mechanisms necessary for healthy visual development during infancy and adulthood. Although a large volume of experimental data suggests that basic RF properties and visual functions across species mature earlier than complex ones, few studies have focused on revealing mechanisms that can explain the differential rate of development among species, and how response properties evolved to serve species-specific adaptive behavior. It is clear that rudimentary RFs are generated early in life through interactions between molecular cues and spontaneous activity, while visual experience fine tunes circuits to improve the selectivity of neuronal response properties. However, further studies are needed to establish why visual experience differentially affects the development of neuronal response properties and functions among species. This will likely require an integrated view of visual system development and evolution of adaptive behavior in mammals.Permission must be obtained for use of copyrighted material.Permission to adapt Permission to reproduce CD and RK contributed to writing and editing of the manuscript. RK contributed to the conception and organization of the manuscript. CD and RK approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Older adults\u2019 perceptions of the presence and quality of neighborhood resources provide important information about the potential benefit of those resources but are not necessarily concordant with the actual physical resources available in that environment. There is debate about whether subjective perceptions of local context are more important for individual behavior and well-being than objective indicators of resources. However, little research has examined how cognitive function is related to differences in the perceived availability and quality of neighborhood resources among older adults. We found that subjective reports of neighborhood safety and adequacy of parks were positively associated with objective measures of property crime and park density. Cognitive function was associated with higher subjective neighborhood evaluations, but adults with lower cognitive function reported more discordance between objective and subjective measures of neighborhood resources. These findings inform how neighborhood resources may have different consequences for older adults experiencing cognitive decline."} +{"text": "The underlying theme of my research is to advance our understanding of cognitive aging through early detection of cognitive decline and the promotion of positive lifestyle factors. I will present my past and recent work that uses new perspectives to predict and modify cognition with older age, specifically focusing on intraindividual variability in cognitive speed, and lifestyle activity engagement. This includes examining the utility of variability in cognitive speed, usually a predictor of decline, instead as a predictor of cognitive plasticity following activity interventions. Further, the association between activity engagement and later cognitive ability and dementia risk is more complex than first appears. I will present research that looks at critical issues about the activity-cognition relation from a different perspective, including unique frameworks investigating the ideal way to measure activity, and the duration of how long past activity can potentially impact cognition. Finally, I will discuss my future research directions."} +{"text": "In support of our older adult community and in alignment with Age Friendly University principles, the University of North Georgia Center for Healthy Aging promotes wellness and disease prevention through active research and intervention, promotes leadership through mentorship and partnerships, fosters an environment of healthy aging through interdisciplinary service and research with community partners, and supports healthy aging through innovative interprofessional collaboration and research. This presentation offers insight into the ways we have engaged retired faculty and staff, with particular focus on a collaboration with The Wisdom Project, a community organization of adults 55+ interested in using their skills and talents to benefit their community through action and advocacy projects. While aligned with Principle 9, this presentation also offers insight regarding how the university supports additional AFU Principles."} +{"text": "Although veterans typically have better health and lower mortality risk than nonveterans earlier in life, a crossover occurs in later life, resulting in comparatively poorer health and higher mortality risk in older age. Alterations in biomarkers of physical health could be an initial indicator of this crossover. The current study uses data from the second wave of the Midlife Development in the United States (MIDUS) survey. Previously validated cortisol profiles were used to categorize participants into normative and non-normative groups, that were examined in relation to veteran status. Results revealed a significant age by veteran interaction , indicating that older veterans were less likely to belong to the normative profile group than non-veterans and younger veterans. Results demonstrate the need to explore underlying physiological mechanisms linking military service with poorer health in later life. Part of a symposium sponsored by the Aging Veterans: Effects of Military Service across the Life Course Interest Group."} +{"text": "Recent work suggests that the prefrontal cortex is recruited during complex walking as a form of cognitive compensation to maintain performance in aging and neurodegenerative diseases. Evidence from fNIRS studies is accumulating on different patient groups demonstrating the utility of this method and its sensitivity to neural dysfunction. However a direct comparison that explores the specificity of prefrontal activation patterns has not been conducted. This process is essential towards implementing the use of fNIRS at the individual level. Data collected from four different cohorts; young adults, older adults, PD patients at different stages of the disease, and patients with Multiple-Sclerosis during challenging tasks will be presented. Overlap, commonality, disparity and variability between groups and conditions will be presented and modifiers and moderators that can affect individual performance will be discussed. Understanding individual differences in fNIRS response will enhance data interpretation and promote translation of this technology to clinical care applications."} +{"text": "Stigma represents one of the biggest barriers to living well with dementia following diagnosis. Social isolation is common as roles, friendships and opportunities to participate in the broader community disappear. An intergenerational dementia choir is a joyful activity that offers opportunities for learning, friendships and purposeful engagement towards common goals . Data collection involved surveys and interviews with 32 dyads comprised of persons with dementia (PwD) and caregivers, as well as focus groups with 29 high school students. Results illustrate the development of a choir community across weeks of participation with far reaching benefits. Both caregivers and PwD experienced reductions in health risks and improvements in quality of life. Students\u2019 understanding of dementia became more positive over time and new friendships developed. The discussion focuses on the need for meaningful and inclusive community activities for PwD and their caregivers."} +{"text": "Telemedicine, the use of electronic information and communication technologies to deliver care, has grown substantially over the past few years, potentially benefiting older adults who have difficulty accessing and traveling to care locations. Given that providers and interprofessional staff with training in geriatric medicine often practice in urban rather than rural areas, older adults\u2019 access to quality geriatric care is limited. Prior experiences with telemedicine adoption for geriatric team consultation, though limited in scope, were well accepted by older adults and demonstrated benefits such as identifying and meeting care needs for older adults. Bringing geriatric team care to large regions across the country requires further consideration of population needs, local contexts and training and enhancement of an interprofessional workforce to deliver geriatric care through telemedicine. The Veteran healthcare system has been a pioneer in telemedicine care and considers the use of telemedicine necessary for all providers in its system. This symposium aims to discuss approaches to identify and target older adults who may benefit from geriatric consultation, how care delivery is scaled through identifying common approaches and local adaptations, what the important elements are for providers and teams to deliver care effectively for the older adult population, especially those with multiple complex chronic conditions and functional limitations, and considerations for training the next generation of providers to provide care for older adults with complex conditions, particularly in rural areas with limited access."} +{"text": "Being able to progress on and accomplish personal goals is an important source of satisfaction and meaning across the adult lifespan and into old age. This study focuses on the importance of close others, such as spouses, for facilitating goal progress when individual resources may no longer suffice. We used multilevel modelling to analyze data from 119 couples . Participants reported their personal goals at baseline and subsequently provided simultaneous ratings of goal pursuit, effort, and partner involvement three times daily over 7 days. Our findings show that more effort and spousal involvement indeed go hand in hand with better goal progress. More in-depth follow up analyses will pinpoint the role of individual and partner effects as potential mechanisms underlying contributions to everyday goal pursuit as well as address stress related processes."} +{"text": "Escherichia coli associated diarrhea in children as medicinal biological therapeutics. This is driven partly by increases in antibiotic resistance in pathogenic bacteria as well as an increasing awareness of the importance of the commensal microbiomes. Indeed, regarding their high species specificity, phages fully respond to the Ehrlich's magic bullet concept Heynick, , and repBretaudeau et al.).Future personalized medicine approaches may necessitate distributed, near-patient manufacturing of phages. The need to scale-up production to multiple manufacturing sites or nearer to the patient within healthcare settings may require novel manufacturing approaches that are compliant from a regulatory point of view. Flexible modern scalable production approaches following the standards of current Good Manufacturing Practices (cGMP) are needed to supply clinicians with stable phage products of suitable quality, safety, and efficacy. Moreover, personalized medicine implies development of new designs for future randomized clinical trials, which remain mandatory to demonstrate the considerable potential of phage therapy . Overall, the need for consistent manufacturing processes with a rigorous Quality Assurance (QA) system in place is deemed essential and experience in the field of vaccines for human and veterinary use may be a useful future guide. An important manufacturing consideration relies on the selection of suitable bacterial production strains that preferably should be devoid of virulence determinants and of potential contaminant temperate phages and formulation challenges to ensure future medicinal phage drug products meet quality, safety and efficacy criterion.DM and GR were joint co-editors of this special issue and co-wrote the editorial. Both authors contributed equally to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Availability and accessibility of nutritious foods can vary according to the food outlets present within a neighbourhood or community. There is increasing evidence that community food environments influence food choice, diet and the risk of diet-related chronic disease, however contemporary community food environments assessments may be too simplistic to accurately summarise the complexities of their impacts on food choice. This study protocol describes the development of the Food Outlets Dietary Risk (FODR) assessment tool for use by local government in Perth, Western Australia.Similar to food safety risk assessment, the FODR assessment tool rates the potential harmful public health nutrition impact of food outlets by identifying and characterising the issues, and assessing the risk of exposure. Scores are attributed to six public health nutrition attributes: 1) availability of nutrient-poor foods; 2) availability of nutritious foods; 3) acceptability and appeal; 4) accessibility; 5) type of business operation; and 6) complex food outlet considerations. Food retail outlets are then classified as having a low, medium, high or very high dietary risk based on their total score.A local government administered tool to rate the public health nutrition risk of food outlets requires data which can be collected during routine assessments or sourced from the internet. The ongoing categorical classification of foods available within food outlets as either unhealthy or nutritious will require nutrition scientists\u2019 input. An objective risk assessment of the dietary impact of food retail outlets can guide local government planning, policies and interventions to create supportive community food environments. It is intended that locally relevant data can be sourced throughout Australia and in other countries to apply the local context to the FODR assessment tool. Utility and acceptability of the tool will be tested, and consultation with environmental health officers and public health practitioners will inform future iterations.The online version contains supplementary material available at 10.1186/s12937-020-00641-w. There is increasing evidence that food environments influence food choices and diet, therefore improving food environments to reduce the risk of diet-related chronic disease is a public health priority \u20133. The aTo date, community food environments assessment has mainly focused on identifying and mapping a limited number of food outlet types using supermarkets or greengrocers as a proxy for healthy food access, and fast food or takeaway outlets as a proxy for unhealthy food access , 9. For The role supermarkets play within community food environments is unclear . AustralSome anomalies also exist in fast food outlets and takeaways. Studies conducted in the United States (US) and United Kingdom (UK) indicate fast food is energy-dense and nutrient-poor compared to home prepared food , 24, andTwo Australian studies which developed detailed classifications of healthy and unhealthy food outlets have recognised these limitations , 29. ThoPublic Health Act 2016 [The commonly used risk assessment approach, adopted by the Codex Alimentarius system of international food standards , 31 compAct 2016 . Public Act 2016 . The risThe aim of this protocol is to describe development of the Food Outlet Dietary Risk (FODR) assessment tool which incorporates public health nutrition issues. The FODR assessment tool is intended to be used to rate the potentially harmful public health nutrition impact of individual food outlets (i.e. food businesses with a consumer-facing retail or food service component), to inform surveillance and planning.Public health nutrition includes the determinants of health that relate to a safe, nutritious, affordable, accessible, secure and environmentally sustainable food system . EnvironThe risk assessment principles applied to the protocol include: using the best available evidence, recognising the inherent uncertainty in risk assessment, and using an iterative process .The WA Department of Health delivers health services to the Perth metropolitan population via three area health services, including East Metropolitan Health Service (EMHS). EMHS provides tertiary, secondary, specialist, and community health care services that aim to maintain and improve the health of one-third of the WA population . ThirteeThe Standard Protocol Items: Recommendations for Interventions Trials (SPIRIT) checklist was used to guide this protocol and food service outlets , food preparation businesses , charitable food provision (e.g. food pantries), and institutional food was developed . The ability to source data and the practical effort required will be assessed. The scores generated by the FODR assessment tool for all food outlets present in the selected community food environment will be spatially mapped using Geographical Information System (GIS) technology. Statistical analysis will be conducted including: an average risk assessment score, number of food outlets scoring high or very high public health nutrition risks, and kernel density analysis of all food outlets (which estimates the density of referenced points rather than the proximity). Interested and affected groups, including LGA environmental health officers and public health practitioners, will be consulted and further analyses identified during the consultations will be incorporated into the pilot testing phase. Results from pilot testing, and input received during consultations, will inform future iterations of the FODR assessment tool. Validation of the risk rating scores will be conducted, to identify whether the scores allocated by the FODR tool accurately indicate the community exposure to public health nutrition risk.The aim of this protocol was to describe development of a food outlets risk assessment tool which can be used to rate their public health nutrition impact. The FODR assessment tool was developed to assist LGAs within the EMHS area to identify food outlets that have a high or very risk to public health nutrition, by replicating the approach recommended by the WA Department of Health for food safety risk assessment. The risk is rated by inputting data to the tool, to provide an objective assessment of the food outlet\u2019s impact on food safety (part A) and public health nutrition (part B). The tool is suitable for use throughout Australia, and could also be adapted for use in other countries.The FODR assessment tool requires robust data for six public health nutrition attributes for each food outlet: 1) availability of discretionary foods; 2) availability of nutritious food; 3) acceptability and appeal; 4) accessibility; 5) type of business operation; and 6) complex food outlet considerations. For food safety risk assessment, data is usually obtained during the new business registration process with LGAs, and environmental health officer assessments of food outlets. Additional data related to rating the public health nutrition risk could also be collected during these processes, including whether the food outlet is licensed to sell alcohol, offers a takeaway or drive-through service, provides children\u2019s toys or a play area, provides an all-you-can-eat buffet, delivers foods (including via a delivery service such as Uber Eats), or is co-located with a bottle shop or within a food court. Routine LGA data collected from registered food businesses could also capture whether the food outlet is independently operated or part of a franchise or chain, and details of the parent company. However, classification of available foods according to the recommendations of the Australian Dietary Guidelines requires nutrition or dietetics expertise, and it is not practical to advise environmental health officers to assess all products in each food outlet to determine the proportions of discretionary and nutritious foods. Published peer-reviewed surveys which describe the availability of discretionary and nutritious foods in different types of food outlets can be used instead, where available. For example, an audit of Australian supermarket packaged foods (not fresh foods) found that half were classified as discretionary , which cAn alternative but more time-intensive method to determine availability of discretionary and nutritious foods is to conduct audits of the food outlets using a validated tool such as the Nutrition Environment Measures Survey for supermarkets or restaurants whiFrequency of food outlet assessment of dietary risk can be pragmatically guided by established processes for monitoring food safety risk by local government environmental health officers. In WA, the Department of Health recommends an approach which considers the risk profile of each food business (refer to Fig. To improve the healthfulness of community food environments, LGAs will need to develop appropriate policies and interventions based on the dietary risk assessment of food outlets. In WA, the requirements of the Public Health Act provide a legal mechanism for encouraging action by LGAs. The FODR tool could be used to establish baseline scores for all food outlets in an LGA\u2019s geographic area, with actions to improve ratings provided in public health plans. The \u2018Nourishing\u2019 framework of food policies to promote healthy diets and reduce non-communicable diseases recommends setting incentives and rules to create healthy food environments, for example setting limits on the number of fast food or takeaway outlets allowed near schools . HoweverThis FODR assessment tool protocol is the first to rate the risk of food outlets to public health nutrition using objectively derived data, to the authors knowledge. Use of the FODR tool will assist in ensuring categorisation of dietary risk of specific food outlets is based on transparent and consistent criteria. In addition, the FODR assessment tool replicates the approach recommended by food regulators for risk assessment of food safety. There are limitations to its current use, which requires food outlet data to be collected for six public health nutrition attributes. Some of this data can be sourced using information obtained from the internet, including the food outlet websites and photographs posted to the Google search engine. The authors have provided two supplementary tables which include a summary of the literature describing public health nutrition impacts of food outlets (Supplementary Table\u00a0This protocol describes development of a food outlet risk assessment tool that incorporates six public health nutrition attributes. The risk assessment approach applied in this tool aims to assist LGAs to identify the healthfulness of food outlets and their potential impact on community food environments, and is the first to do so using objectively derived data. Although it was developed to assist the 13 LGAs within the EMHS area in Perth WA, the tool can also be applied throughout Australia and adapted for use in other countries. LGAs and public health practitioners will be able to use the FODR assessment tool to assist with making planning decisions, and to inform policies and interventions to improve the healthfulness of community food environments.Additional file 1:Supplementary Table 1. Completed SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*.Additional file 2:Supplementary Table 2. Food business classification framework.Additional file 3:Supplementary Table 3. Summary of public health nutrition impacts of consumer-facing food outlets.Additional file 4:Supplementary Table 4. Market data to inform the public health nutrition risk rating tool for food outlets."} +{"text": "Lasionycteris noctivagans populations suggest they could be genetically isolated, but this has rarely been assessed using genetic data. Here, we evaluate this possibility by sequencing the complete mitochondrial genome of four silver-haired bats from eastern and western populations. The three usable mitogenomes were closely associated with other Vespertilionid bats and the phylogenetic tree revealed the two western individuals grouping together to form their own clade. Our results support the idea of small but significant genetic differences between eastern and western populations of these bats, but this should be tested further.The geographic distributions of eastern and western Qiagen DNeasy blood tissue extraction was performed and was sequenced using Illumina NovaSeq. DNA is currently stored at the Museum of Biological Diversity at The Ohio State University . Raw reads were trimmed using Trimmomatic , one possible explanation for the differentiation is sex-biased migration. Whitaker and Hamilton state th"} +{"text": "Sense of purpose is related to many positive physical and mental health outcomes . Unfortunately, sense of purpose declines as adults age and particularly with retirement . Retirement is often measured dichotomously, however, many people are retiring gradually and do not fit clearly as retired or not retired. Moreover, people retire for different reasons ranging from seemingly non-negative reasons to more negative reasons . The current study used data from a Hawaiian sample in which participants completed self-report surveys on retirement status and activity engagement, as well as a measure of purpose . We examined whether the role of retirement on sense of purpose differed by form of or motive for retirement. Results indicated the fully retired population reported significantly lower sense of purpose than both the still working and the partially retired populations, but these two groups did not differ. Participants who retired for negative reasons reported significantly lower sense of purpose than those who retired for non-negative reasons. Greater activity engagement was significantly related to sense of purpose for all retirement statuses. However, this relationship was stronger for the partially retired population. Future research should examine further the role of partial retirement for maintaining sense of purpose in older adulthood."} +{"text": "This article describes the initial impacts of COVID-19 on beef supply chains and beef product markets. An overview of major beef market segments of retail grocery, food service, and exports is provided, including a focus on ground beef markets.COVID-19 caused massive and unprecedented impacts on beef supply chains for food service and retail grocery.The shutdown of food service and the corresponding surge in retail grocery demand provoked a first wave of product shortages due to bottlenecks and rigidities in food service and retail grocery supply chains.A second wave of impacts resulted from COVID-19-induced reductions in cattle slaughter and beef production. This resulted in additional product shortages in retail grocery.COVID-19 revealed both the efficiencies and rigidities of specialized food service and retail grocery supply.Dramatic and varied market price reactions across beef product markets helped rebalance markets and restore equilibrium.One of the many factors that make the U.S. cattle and beef industry an extremely complex set of markets is the disassembly of the beef animal into thousands of different products. These products are marketed in a vast array of final markets including retail grocery, food service and exports . In the Beef packers provide the animal harvest and the primary fabrication of beef carcasses into wholesale products. Typically, packers fabricate several hundred basic wholesale products, which are marketed as several thousand products representing unique customer specifications. Subsequently, the majority of wholesale beef products move through a diverse and specialized set of further processing activities that further expand the set of products by several thousand additional products into largely separate supply chains. Following sections provide a brief overview of beef market sectors to better understand the impacts of COVID-19 on beef markets.Retail grocery is responsible for a large amount of beef sales and grocery sales are generally recognized as the main driver of total beef sales. Retail grocery typically sells a core set of products that is rather broad but also has considerable flexibility to adjust and feature different products when market conditions are favorable. Many supermarkets no longer have butchers or do any meat cutting in the store. Some independent stores and at least one regional grocery chain are exceptions to this. The majority of supermarkets receive case-ready product from further processors, many of which are owned by major packing companies. Further processing for retail grocery involves cutting, packaging, and labeling for retail, including ground beef retail packaging. Ground beef is discussed separately in more detail below. Retail grocery increasingly may include premarinated, ready to cook \u201cmeal kits\u201d or similar value-added products. Retail grocery uses almost entirely fresh beef products with beef features following a standard calendar in which advertising and purchasing are planned several weeks to several months in advance.Food service includes facilities sometimes referred to as HRI, meaning hotels, restaurants, and institutions . Restaurants represent a wide range of establishments including quick service restaurants (QSR or fast food), fast casual, cafeterias/buffets, casual dining, midlevel, and fine dining. Individual restaurants or chains typically have limited and fixed beef product needs that are very specific and quite rigid. Collectively, restaurants utilize a wide range of beef products from ground beef to Prime steaks. The majority of food service beef products originate from further processing facilities in which products are trimmed, sized for portions, tenderized, marinated or otherwise processed according to specifications. Food service further processing often produces additional beef products as primals and subprimals are further fabricated into multiple products including bench trim that is used for cooked ingredients in other processed products. Although most food service facilities use fresh beef products, some restaurants may utilize frozen portion-control steaks or other products that can be thawed on demand.Ground beef represents an estimated 45% of total U.S. beef consumption and playGround beef for food service is typically provided by specialized grinders that utilize a diverse set of inputs including fresh 50% (or similar) fatty trimmings,Beef exports frequently originate with packers that produce export products according to unique specifications that are typically different from domestic products; or from exporting companies that may do additional fabrication/processing for export. Growing exports in recent years and expanded demand for specific products have significantly changed domestic markets. For example, various chuck products are popular in some Asian markets and have increased prices relative to other products and changed seasonal price patterns. Food service grinders, that can and have used these chuck items in ground beef now find that these products are effectively priced out of the ground beef market. Most exports are frozen and products are typically staged in cold storage prior to shipment.The United States has long been a major beef importing country, despite being the largest beef producing country and a major beef exporter. Beef imports are driven by the demand for lean trim to support ground beef production with over 70% of imports estimated to be processing beef. It is estimated that imported lean trimmings accounts for over 25% of the total trim used for ground beef production in the United States. Imported beef also includes some muscle cuts from Canada and Mexico. Beef trade with Canada includes some bilateral trade of similar products that are economically motivated by north\u2013south transportation efficiencies (compared to east\u2013west shipping in both countries). Beef imports from Mexico have grown dramatically in recent years and largely represent retail grocery and food service products targeted to Hispanic markets in the United States.The first wave of impacts, which began in mid-March, resulted from the near total shutdown of food service. Abruptly, food demand at retail grocery nearly doubled. The surge in retail grocery demand was further aggravated by panic buying as consumers attempted to stockpile food at home. Retail grocery demand quickly overwhelmed the retail grocery supply chain resulting in localized and temporary shortages in retail stores. It is important to recognize that there was no actual shortage of product during the first month of the shutdown, but rather bottlenecks in the supply chains. The shutdown affected various beef products differently according to their primary use. The contrasting impacts in retail grocery and food service ground beef supply chains are demonstrated in The second wave began in April when COVID-19 affected the labor force of harvest and processing installations and severely reduced output. Never before have so many packing and processing plants been affected simultaneously by reductions in capacity. Some harvesting plants completely shut down for up to 2 wk and others curtailed output due to labor force reductions. Cattle slaughter decreased weekly through the month of April, reaching a peak reduction of 34.8% down year over year the end of April, and then slowly recovered through May. Total beef production over a 9-wk period of these effects was down 17.9% compared to the same period 1 yr earlier . This reRetail beef prices, which reflect retail grocery prices (as opposed to food service), responded as expected but with some difference in timing. The monthly retail all-fresh beef priceThe impact on and perception of consumers to these two waves of impacts was similar due to the lack of product in grocery stores in both cases. The reality of those impacts was very different\u2014one due to bottlenecks and rigidities in the supply chain and the other the result of actual reductions in product availability. The combined impacts of the shutdown and packing plant disruptions were unprecedented volatility in beef product markets. The focus of this article is on beef products and supply chains from packers downstream. However, upstream cattle production is broadly part of the beef supply chain and cattle markets were significantly affected by the packing plant disruptions in April and May and beyond. The reductions in packing plant operations effectively cleaved beef product markets from cattle markets for several weeks. During this period, beef product markets generally moved in opposite directions from fed cattle markets. The lack of packing capacity created beef shortages that led to immediate and dramatic price spikes for beef products while that same lack of packing capacity created an immediate excess supply of fed cattle relative to packer demand and led to lower fed cattle prices. Many concerns were voiced about the disconnect between fed cattle markets and boxed beef cutout prices when there was, in fact, an unavoidable temporary physical disconnect that caused prices to move in opposite directions above and below the packing level of the industry. Although this was an extremely unusual situation, the market reactions at all levels were exactly what is expected and helped support a remarkably rapid recovery in beef product markets.The initial impacts of the food service shutdown and packing plant disruptions were largely past by the end of June. Beef production returned to year earlier levels by mid-June . HoweverMajor impacts on fed cattle markets extended well beyond June. Reduced cattle slaughter in April and May resulted in a large backlog of fed cattle that took many weeks over the summer and fall to work through. No cattle were depopulated and delayed feedlot marketings resulted in excess supplies of fed cattle that pushed fed cattle price lower into July before recovering into the fall. Delayed fed cattle slaughter resulted in heavier carcass weights, higher quality grading percentages and other lingering impacts on beef supplies and product mixes.Beef exports also dropped sharply in May and June before recovering in July and by August exceeded year earlier levels. Beef imports spiked higher with a delay, jumping sharply in July and remaining well above year earlier levels in August. Beef imports increased in the summer in response to strong ground beef demand from the recovery of QSR restaurants. Large supplies of fatty trimmings resulting from heavy carcass weight in domestic fed cattle and stimulated additional lean demand.The beef production disruptions and product shortages resulting from COVID-19 provoked questions about the availability and use of beef in cold storage to supplement fresh beef supplies. Most beef marketed in food service and retail grocery is fresh and moves to final consumption in a matter of a few days to a few weeks at most. Cold storage inventories are frozen stocks of products held more than 30 d and does not typically consist of a complete set of beef products. Beef in cold storage includes products staging for export, which are mostly frozen and imported beef products until they are used. Cold storage beef supplies typically increase in the fall and winter and include supplies of domestic lean trimmings resulting from seasonally higher cow culling in the fall of the year. These lean trimmings are used to support ground beef production for seasonal grilling demand the following summer. Occasionally, unique market situations result in commercial firms putting other products into cold storage. This is not a regular or preferred practice as cold storage adds cost and frozen beef is often marketed at a discount to the fresh product.In 2020, beef in cold storage increased counter-seasonally in March before declining seasonally in April and May, likely as a result of the abrupt loss of food service demand. Cold storage was not available to offset retail grocery product shortages because it consists of the wrong set of products and because the quantity of cold storage holding is small. Monthly beef cold storage inventories averaged 458 million pounds in 2019. This represents less than 1 wk of beef production, which averaged over 513 million pounds per week in 2019. This means that even if all cold storage beef was pulled out at once, it would represent less than 1 wk of beef supply and, as noted previously, would not match the mix of products needed in food service and retail grocery markets.As noted previously, the majority of the initial COVID-19 shocks were resolved by the end of June. Certainly, there were continuing impacts after June and additional recovery will occur for many months. Ripple effects on beef quality, product mixes, beef exports and imports, and feedlot dynamics will extend beyond 2020. Moreover, at the time of writing in October 2020, the public health crisis and the macroeconomic impacts of COVID-19 in the United States and globally were continuing and could lead to new or renewed impacts going forward. Food service is still significantly diminished with a slow recovery that will last many more months. Clearly, recovery is a moving target as 2020 moves into the fourth quarter.Many questions have been raised about likely permanent or very long-lasting effects of COVID-19 on food industries, beef supply chains, and the cattle industry. Given the on-going nature of the situation, it is premature to say anything definitive about permanent impacts. There are clear indications of several changes that will affect food industries; including the likely loss of food service establishments (which may rebuild or be replaced over time); changes in travel, especially business travel in a world of Zoom meetings; a larger role for take-out, drive-thru, and home delivery food service; and the extent to which home food preparation results in a long-term reduction in food service demand. Only time will provide the perspective to understand the types of changes and long-term impacts on food industries.COVID-19 also exposed rigidities and lack of agility of beef supply chains to respond to this type of shock. Questions have been raised about the likelihood of fundamental changes to increase the resilience of beef supply chains. Certainly, it seems likely that individual firms may assess some business practices and make some changes. Firms may consider a wider range of procurement practices, such as contracts and other means to enhance both supply reliability and manage price risk. Many firms may devote additional resources to management planning with such things as supply chain mapping and other activities that will help identify supply chain redundancies and contingency plans to reduce the impact of future supply shocks. However, the current structure of food service and retail grocery supply chains evolved in response to efficiencies and economic returns to specialized facilities and have contributed to reducing the cost of food in the United States. Less specialized multifunction facilities that operate simultaneously in food service and retail grocery chains would be less efficient and more costly. Marginal changes in management and operational flexibility to increase the tactical agility of firms are more likely than massive reinvestment in new beef supply chain infrastructure.COVID-19 has revealed both strengths and weaknesses in beef supply chains. It has also revealed much about market economics. Under normal, stable market conditions, markets coordinate resource and product allocation with such efficiency and subtly as to be largely unrecognized. Only in the face of abrupt and unexpected shocks are the reactions of markets to rebalance and restore equilibrium revealed. Freely operating markets react with dramatic, sometimes surprising, and confusing responses to massive and unprecedented shock such as COVID-19. Consumers, producers, companies, and policymakers all learned much about how beef supply chains and the market-based economy works as a result of COVID-19."} +{"text": "When planning extraction of teeth with poor prognosis especially lower first permanent molars, it is important to consider the timing of tooth removal and its effect on future occlusion to avoid interventions. Timing of mandibular first molar extraction if not planned well can lead to complications like space loss, tilting, and lingual rolling of mandibular second molar and supra\u2010eruption of maxillary first molar. Hence, the timing of mandibular first molar extraction in mixed dentition must be planned according to the status of the existing dentition to avoid any complications. SKM: involved in proof reading."} +{"text": "The changes or updates in ocean biogeochemistry component have been mapped between CMIP5 and CMIP6 model versions, and an assessment made of how far these have led to improvements in the simulated mean state of marine biogeochemical models within the current generation of Earth system models (ESMs).The representation of marine biogeochemistry has progressed within the current generation of Earth system models. However, it remains difficult to identify which model updates are responsible for a given improvement. In addition, the full potential of marine biogeochemistry in terms of Earth system interactions and climate feedback remains poorly examined in the current generation of Earth system models.Increasing availability of ocean biogeochemical data, as well as an improved understanding of the underlying processes, allows advances in the marine biogeochemical components of the current generation of ESMs. The present study scrutinizes the extent to which marine biogeochemistry components of ESMs have progressed between the 5th and the 6th phases of the Coupled Model Intercomparison Project (CMIP).The online version of this article (10.1007/s40641-020-00160-0) contains supplementary material, which is available to authorized users. Our review confirms that the current generation of marine biogeochemical models are still struggling to reproduce the major features of the oceanic iron distribution although the observations of dissolved iron in the ocean are growing rapidly and are An expanded array of biological taxa may also be expected in the next generation of ocean biogeochemical models. A potentially important change in the ocean ecosystem modelling paradigm is the inclusion and integration of mixotrophs which are an important grazer of bacterioplankton, and which also feed on phytoplankton, microzooplankton and (sometimes) mesozooplankton. Mixotrophic bacterivory among the phytoplankton may be important for alleviating nutrient stress and may increase primary production in oligotrophic waters. Some modelling studies indicate that mixotrophy has a profound impact on marine planktonic ecosystems and may enhance primary production, biomass transfer to higher trophic levels and the functioning of the biological carbon pump .This expanded array of biological taxa may take the concept of the marine biogeochemical model up to the marine ecosystem model, which will enable the representation of feedbacks of the marine trophic food web on marine biogeochemical cycles. The work of Lefort et al. providesA third important step change is related to the couplings between Earth system components and ocean biogeochemistry. Our review highlights that models have evolved toward a more comprehensive treatment of biological boundary conditions but that these latter are currently largely represented using climatological data rather than dynamic connections. Progress toward more complete couplings between Earth system components such as rivers, ice sheet/iceberg calving and ice shelves or atmospheric aerosols can help to better simulate interactions between marine biogeochemistry, biogeochemical cycles and climate.2O and CH4 is much less developed compared with CO2. Therefore, better treatment of biophysical and biogeochemical feedback requires a larger array of observational data sets in order to improve our understanding of the processes underlying these ocean emissions.In the same manner, a more comprehensive treatment of biophysical and biogeochemical feedback could be realized in the next generation of marine biogeochemical models. The latter involves, for instance, ocean emissions of greenhouse gases or biogenic volatile organic compounds (BVOCs) that are already simulated by a small number of models . Indeed, when confronting model complexity against model mean state performance, our work suggests that complex models do not necessarily outperform simple models. This is consistent with the earlier study of Kwiatkowski et al. , which dESM 1(XLSX 11927 kb)"} +{"text": "The intestinal epithelial monolayer forms a transcellular and paracellular barrier that separates luminal contents from the interstitium. The paracellular barrier consists of a highly organized complex of intercellular junctions that is primarily regulated by apical tight junction proteins and tight junction-associated proteins. This homeostatic barrier can be lost through a multitude of injurious events that cause the disruption of the tight junction complex. Acute repair after injury leading to the reestablishment of the tight junction barrier is crucial for the return of both barrier function as well as other cellular functions, including water regulation and nutrient absorption. This review provides an overview of the tight junction complex components and how they link to other plasmalemmal proteins, such as ion channels and transporters, to induce tight junction closure during repair of acute injury. Understanding the components of interepithelial tight junctions and the mechanisms of tight junction regulation after injury is crucial for developing future therapeutic targets for patients experiencing dysregulated intestinal permeability. The intestine is lined with a monolayer of columnar epithelium that maintains two critical functions: 1) selectively filtering luminal contents, including nutrients, water and electrolytes, to allow for their translocation into the circulation and 2) forming a barrier to prevent the translocation of luminal toxins, commensal or pathogenic microorganisms, and foreign antigens into the circulation . Th. Th80]. occludin . Specifiassembly . FurtherInjury of intestinal epithelium affects both the epithelial cells and the junctional structures that link them. A great deal of attention has been focused on mechanisms of epithelial restitution, but a lesser level of attention has been paid to the reassembly of tight junctions within repairing epithelium. This intriguing process appears to be intimately associated with ion channels, which in the case of NHE2 and ClC-2, is facilitated by a close association with tight junction regulatory proteins. With ClC-2 in particular, the mechanism of ion channel-facilitated tight junction reassembly has been linked to endosomal recycling of tight junction proteins, with evidence of restoration of the positioning of tight junction integral membrane proteins during the reparative process, and increased membrane expression of sealing claudins with cellular over-expression of ClC-2. However, how precisely ion channels interact with structures such as endosomes, and how this facilitates insertion of sealing tight junction proteins at the repairing tight junction will require further study. Nonetheless, it does appear that ion channels such as NHE2 and ClC-2 have a greater cellular function than ion transport alone. It is conceivable that the transport of select ions accompanies a structural change that sets off a series of signaling events associated with tight junction reassembly, but this will require additional mechanistic work. Ultimately, further studies to uncover the relationship between ion channels and reassembly of tight junctions has the potential to lead to novel therapeutic targets for patients with increased intestinal paracellular permeability."} +{"text": "Phase III clinical trials in adults (HAVEN 1) and children HAVEN 2) have shown significant overall bleed reduction compared to prophylaxis with classical bypassing agents such as recombinant activated factor VII (rFVIIa) or activated prothrombin complex concentrate (aPCC) in patients with haemophilia A and inhibitors have sho. This moSeveral other novel agents are in different stages of development and will probably also have a major impact on the care of haemophilia patients. A new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions (MarzAA)), has increased catalytic activity and prolonged half-life which allows subcutaneous dosing . Other nEmicizumab and the other agents described above will certainly have a major impact, as described below, in the care of patients with inhibitors. This is summarized in the 10 revised principles of inhibitor management originally proposed in 2018.The bispecific antibody, emicizumab, has the potential to modify the natural history of inhibitor development in some patients, especially in previously untreated patients (PUPs) treated with this agent early in life to avoid exposure to exogenous FVIII. More data shall become available about the role, safety and efficacy of emicizumab in PUPs \u201310 as weThe importance of early recognition and accurate diagnosis of patients developing inhibitors remains of high importance, regardless of the availability of these new agents. It is recommended for patients with inhibitors to have their inhibitor titre checked regularly, at least once per year and, most importantly, before any invasive procedure. Appropriate assays for inhibitor detection and quantification should be used in patients treated with emicizumab .Availability of a bispecific antibody and other novel agents will most likely impact significantly on how care of inhibitor patients is organised. As stated jointly by the European Haemophilia Consortium (EHC) and European Association for Haemophilia and Allied Disorders (EAHAD), supervision of patients on novel treatment products should be exclusively conducted in European Haemophilia Comprehensive Care Centres (EHCCCs) or European Haemophilia Treatment Centres (EHTCs), thus increasing the necessity of good communication between healthcare professionals involved. The frequency of visits of inhibitor patients to their treating specialists will probably diminish due to the less intensive treatment regimens and subcutaneous administration of the novel products. Measures should be taken to avoid negative impact of changes related to these treatment innovations on the patient-doctor relationships, in particular regular multidisciplinary follow-up by the EHCCCs with the crucial support and involvement of patients\u2019 organisations. A major responsibility for these expert centers will also be to carefully monitor potential adverse events which may be different from those seen with rFVIIa and aPCC .While inhibitors can be eradicated in patients who have access and a positive response to immune tolerance induction therapy, the inhibitors persist in many patients. These patients standardly require regular treatment with bypassing agents, ideally administered prophylactically. The bispecific antibody and other novel agents should be readily available, when licensed, especially for patients with persistent inhibitors. Clear protocols should be put in place for the management of breakthrough bleeds, as well as for the co-administration of clotting factor concentrates or bypassing agents in case of invasive procedures , 13.Inhibitor eradication by immune tolerance induction (ITI) remains the best option for patients with inhibitors . TreatmeAvailability of the bispecific antibody and other novel therapies currently evaluated in trials has a substantial impact on access and modalities of invasive procedures and surgery for people with inhibitors. Minor invasive procedures, e.g. dental extraction or central venous access device insertion, can be successfully performed with the bispecific antibody without FVIII and tranexamic acid, given that there is a close collaboration between the haematologist and the specialist performing the procedure. Careful planning and timing of major elective surgery is mandatory, along with well-designed protocols for co-administration of bypassing agent(s) during surgery . The current inhibitor titre at the time of surgery should be properly determined in order to evaluate whether replacement therapy with FVIII or FIX concentrates represents an alternative to the use of bypassing agents.It is crucial to provide nurses with continuous and practical education about the bispecific antibody and other emerging therapies, including awareness and understanding of their respective mode of action, the precautions of use, situations requiring co-treatments with factor concentrates or bypassing agents, skills for intravenous and subcutaneous infusions \u2026The use of the bispecific antibody allows inhibitor patients to engage in various types of physical activities and for those already disabled has the potential to convert them into ambulatory patients, as reported previously with aPCC given prophylactically and combined with active physiotherapy . RegularThe new perspectives opened by a life with much fewer bleeds and less treatment burden require major individual mental, physical and social adaptation that could benefit from the support of psychosocial experts within the multidisciplinary team.Clinical data on the use of the bispecific antibody and other novel products in the real life remain scarce, especially in the cohort of inhibitor patients. Thus, it is essential to collect treatment and outcome data regularly in the frame of international registries and/or pharmacovigilance programs. Further international, multicentric and collaborative studies and research initiatives exploring the impact and modalities of use of the novel therapies in patients with inhibitor should be encouraged and promoted.As described above, adoption of novel non-replacement therapies for haemophilia will have a major impact on each of the 10 principles of inhibitor management published in 2018. This amendment of the 10 principles appears as a very important advocacy tool and framework in order to promote access and proper use of these revolutionary therapies for all stakeholders actively involved in the care of patients with inhibitors."} +{"text": "Loneliness is a key indicator of exclusion from social relations. Its prevalence among older people is of increasing global concern given the powerful impact of loneliness on health and wellbeing. To date, empirical and theoretical advancements in understanding loneliness have been focused on the micro contexts of networks of social relationships surrounding older people. Yet these relationships occur within broader socio-cultural, political and geographical settings that may help us better understand the experiences and manifestations of loneliness. In this presentation we draw on our research on loneliness on three continents. Findings from Canada show how ageing in a foreign land can truncate social connections. Research across Europe reveals differences in values and expectations about social connections. South African findings illustrate the long-term impact of dislocation resulting from political ideologies. We draw together these findings to create an ecological model of contexts that may lead to cumulative disadvantage in social relations."} +{"text": "Reducing the burden of unsafe abortion rests considerably on women\u2019s ability to access appropriate and timely treatment or services. A critical component of that care relies on a functional supply chain to ensure availability of abortion drugs and supplies within the health system. Disruptions in the supply of medical abortion drugs delay provision of abortion services and can increase the risks to a woman\u2019s health. We examine the ways in which supply chain management (SCM) affects women\u2019s ability to access safe and timely abortion to meet their reproductive health needs and highlight the gap in evaluation research on which SCM interventions best improve access to safe abortion care.SCM comprises a critical component of efficient and sustainable abortion service provision and is a requisite for expansion of services. Furthermore, governments are responsible for safeguarding links in the abortion supply chain, from registration to distribution of abortion drugs and supplies. Strategic public\u2013private partnerships and use of innovative local or community-based distribution mechanisms can strengthen supply chain systems. Finally, alternatives to the pull-based models of distribution could alleviate bottlenecks in the final steps of abortion supply chains. Programs aimed at increasing access to safe and comprehensive abortion care must include SCM as a foundational component of service provision. Without access to a sustainable and affordable supply of abortion drugs and equipment, any attempt at providing abortion services will be critically limited. More implementation research is needed to identify the most effective interventions for improving SCM. Unsafe abortion accounts for 7 million annual cases of abortion-related complications and accounts for 8% of maternal deaths worldwide . While aStudies of supply chain management (SCM) as relating to contraceptive security have demonstrated its impact on women\u2019s ability to utilize modern contraception to meet their reproductive health needs , 6. InefThere is a current lack of research on how supply chain management impacts abortion services. Although needed commodities overlap significantly with maternal health programs, abortion care may be overlooked or ignored in government\u2019s planning for peripartum supplies. Intervention studies in this domain are lacking, yet some descriptive studies suggest that proper management of the abortion supply chain facilitates provision of timely, necessary and life-saving abortion services, while poor management at best delays services and at worst results in unsafe abortion practices. We examine the ways in which SCM affects women\u2019s ability to access safe and timely abortion care to meet their reproductive health needs.Direct, small-scale abortion supply provision can result in critical shortages once program funding ends. Providers in Malawi and Cameroon faced significant declines in MVA kit availability following initial training or piloting of interventions due to a lack of follow-up funding and capacity for supply management, forcing a reversion to use of dilation and curettage, a practice associated with greater rates of maternal morbidity and pain , 15. In From initial registration of abortion drugs to price negotiation for affordable procurement and maintenance of distribution channels, governments are the lynchpin in effective abortion SCM initiatives . GovernmNon-governmental organizations (NGOs) and private sector partners play an important role in abortion supply management, especially in settings where legal indications for abortion are restricted. Partnerships between private and public sectors or NGOs and governments, can be effective in registration, procurement and distribution of misoprostol . PrivateA study of community-based advocacy for misoprostol in Tanzania and Kenya demonstrated the significance of local strategies for innovative misoprostol delivery . In KenyTraditional pull-based distribution models\u2014which rely on complex and time intensive systems of stock record-keeping and procurement requests\u2014may be exacerbated further in the context of abortion drugs and supplies where off-label misoprostol use, clandestine service provision or consumption underreporting due to stigma may occur . Daff etSCM is a critical component of abortion service programming, yet no current studies evaluate the impact of abortion SCM programming on abortion access. The lack of any peer-reviewed or grey literature articles testing interventions to improve abortion SCM, despite its importance in delivering quality abortion care, demonstrates a significant dearth of attention on abortion SCM in the reproductive health and rights field. Providers repeatedly point to supply chain barriers as one of the primary challenges to abortion service provision, yet few abortion service training programs directly address SCM. Abortion supplies may be subject to additional legal and social barriers that limit their availability within traditional supply chain systems, further highlighting the importance of additional research in this area. Furthermore, none of these programs evaluate the unique challenges of ensuring a robust supply chain for quality abortion drugs and equipment. Evidence from such studies could greatly facilitate the planning and development of effective SCM interventions for abortion service delivery programs.Timely access to affordable abortion drugs and supplies forms the foundation upon which provision and expansion of abortion services rest. Although some abortion commodities may overlap with maternal child health programming, the parallel abortion services are more likely to be short-changed in the face of scarcity. Research is needed to identify interventions which meaningfully improve supply chain systems for abortion commodities as well as their effect on women\u2019s health outcomes to fully understand the impact of SCM on safe abortion care. Such evidence could be used to rally governments and strategic partners around interventions to strengthen supply chain systems, and to advocate for inclusion of SCM interventions within abortion programming.The onset of COVID-19 has exacerbated issues in global and local abortion supply chains, further limiting access to safe and timely abortion for millions around the world. Delays in production and export for distribution of abortion medication and supplies from counties which closed their borders during the pandemic highlight upstream issues in manufacturing that will require more widespread effort in our field to address. However, the pandemic has also encouraged significant innovation, particularly through telemedicine and mailing of abortion drugs, which has helped ensure access during the crisis. How we respond to emerging issues today may offer additional reproductive health choices, or may even expand access to some women and girls, moving forward beyond the pandemic."} +{"text": "Limited research has been conducted regarding the perspectives of caregivers of persons with dementia (PWD) regarding preparing for emergencies. The purpose of this study was to understand dementia caregivers\u2019 perceptions of burden, emergencies, and emergency preparedness through the caregiving lens. Fourteen semi-structured interviews were conducted with a purposive sample of dementia caregivers who reside in Hillsborough County, Florida, to gain participants\u2019 perspectives. Data were analyzed using the thematic analysis method. Caregivers discussed emergencies in terms of medical issues, mostly related to the PWD\u2019s health, as well as natural disasters such as hurricanes. Caregivers discussed their perspectives of caregiving and burden as centered around their roles and experiences with the PWD, including ways in which they would deal with emergencies such as natural disasters. Caregivers reported that they were physically prepared for emergencies but not mentally prepared for coping with or helping their loved ones cope with the stress of an emergency related event. The interviews presented opportunities to raise awareness of emergency preparedness resources and provide information specific to each caregivers\u2019 situation. The results suggest the caregiver role may be essential to mitigating the adverse effects of emergencies on PWDs. Recommendations for practice include providing person-centered care, individualized emergency planning, and interprofessional collaboration."} +{"text": "Family caregiving is associated with social isolation, but the role of geographic distance between caregiver and receiver in caregiving experience is unclear with mixed research findings. This study examined the relationship between geographic distance and caregiver social isolation (CSI), and explored the interaction between geographic distance and caregiving intensity in association with CSI. Based on the Ecological Model of Caregiver Isolation, hierarchical linear regression and ANCOVA analyses were applied to conduct data analysis with the 2012 Canadian General Social Survey . Caregivers living a short distance from receivers reported the lowest CSI than coresident, moderate and long distance caregivers. Being involved in higher intensity caregiving as the primary caregiver, undertaking more caregiving tasks, and providing care more frequently resulted in higher CSI scores. Additionally, long and moderate distance caregivers reported greater CSI than coresident and short distance caregivers only when providing higher intensity caregiving. Geographic distance is a salient contextual factor affecting CSI, and longer distance creates environmental barriers for caregiving provision. Employing a granulated measure of geographic distance positioned within an ecological framework facilitates an understanding of the nuanced association between geographic proximity and CSI. Furthermore, the identified interactive effects between geographic distance and caregiving intensity on CSI further reveal the complexity of caregiving experience. The findings are relevant for programs supporting caregivers in different contexts, especially physical distance."} +{"text": "The authors incorrectly denoted ATCC 25923 as a methicillin resistant control strain in the penultimate sentence of the Antibiotic Susceptibility subsection of the Methods. The correct sentence is: ATCC 29213 (methicillin sensitive control strain) and ATCC 25923 were used as a control for micro broth dilution and disk diffusion assay, respectively.The authors would like to acknowledge the importance of using a genuinely positive MRSA control strain in phenotypic testing and interpreting results.There are errors in"} +{"text": "Information and communication technology are playing a major role in ensuring continuity of healthcare services during the COVID-19 pandemic. The pandemic has also disrupted healthcare quality improvement (QI) training and education for healthcare professionals and there is a need to rethink the way QI training and education is delivered. The purpose of this rapid evidence review is to quickly, but comprehensively collate studies to identify what works and what does not in delivering QI training and education using distance learning modalities.Three healthcare databases were searched along with grey literature sources for studies published between 2015 and 2020. Studies with QI training programmes or courses targeting healthcare professionals and students with at least one component of the programme being delivered online were included.A total of 19 studies were included in the review. Most studies had a mixed methods design and used blended learning methods, combining online and in-person delivery modes. Most of the included studies reported achieving desired outcomes, including improved QI knowledge, skills and attitudes of participants and improved clinical outcomes for patients. Some benefits of online QI training delivery include fewer required resources, reduced need for on-site instructors, increased programme reach, and more control and flexibility over learning time for participants. Some limitations of online delivery modes include limited learning and networking opportunities, functional and technical problems and long lead time for content adaptation and customisation.The review highlights that distance learning approaches to QI help in overcoming barriers to traditional QI training. Some important considerations for those looking to adapt traditional programmes to virtual environments include balancing virtual and non-virtual methods, using suitable technological solutions, customising coaching support, and using multiple criteria for programme evaluation.Virtual QI and training of healthcare professionals and students is a viable, efficient, and effective alternative to traditional QI education that will play a vital role in building their competence and confidence to improve the healthcare system in post-COVID environment. The COVID-19 pandemic is rapidly transforming the landscape of the healthcare system and virtual healthcare solutions are playing a key role in this change . QI prinRather than viewing COVID-19 as a disruption to healthcare QI education and training, it can be considered as an opportunity to improve distance learning techniques and benefit from digital hyper-connectivity to enhance education delivery that can extend into the post-pandemic environment . ApplicaOnline learning platforms have the potential to bring healthcare professionals together to share knowledge and collaborate in QI teaching, learning and education . Beyond What distance learning modalities are being used to train healthcare staff and students in QI methods?What is the efficacy of distance learning QI programmes?What were the advantages and limitations in delivering QI programmes using distance learning modalities?The review aims to answer the following questions:By answering these questions, we aim to synthesise guidelines and recommendations for those who are dealing with the challenge of adapting and delivering QI training to healthcare professionals through distance learning modes.Three databases were searched to identify studies published between 2015 and 2020. The inclusion criteria were QI training programmes or courses targeting healthcare professionals and students with at least one component of the programme being delivered online. Only studies with primary data were included. Conference proceedings, editorials, protocols, and book sections were excluded. Studies that did not explicitly teach QI principles in the programme were excluded. Papers with no full text available or no English translation available were also excluded. Reference lists of included papers and grey literature search of Google Scholar was also conducted to identify further papers. The search and screening processes are documented in Fig.\u00a0The summary of the 19 studies included in this evidence synthesis is presented in Table Although, the overarching aim of the included studies was to improve QI skills of healthcare professionals and students, the studies differed in design, evaluation, and analytical methods used. Most studies had a mixed methods design and 17 of the 19 studies were based in the United States. Design of the interventions was also variable; most studies used a blended learning method combining online and in-person modes while only six studies , 30, 32 All included studies were deemed to be of good quality even though some studies did not report on all areas evaluated by the QI-MQCS tool. All studies discussed the rationale behind the intervention, organisational motivation, description of the intervention and implementation approach. Some studies included limited information about describing sustainability or the potential for sustainability of the interventions and explicitly naming the study design. None of the studies were excluded based on quality assessment and a detailed quality assessment is attached in Additional file The online delivery modes used by studies included online modules , 28\u201331, Only a few studies discussed the tools/software used to deliver the online QI training components. One study used Adobe Connect and Blackboard for delivering a web-based QI curriculum while foStudies used various evaluation methods; some focused on programme level factors such as course completion rates , 27, leaMost of the included studies reported achieving desired outcomes such as improved QI knowledge and skills , 27, 28,This shows that majority of the interventions were successful in demonstrating the desired results. However, there was scant information around the role played by mode of delivery in the attainment of these outcomes. One study using a control group concluded that use of online content in conjunction with in-person sessions as being more effective in improving QI knowledge than only relying on online content . The fliAn online QI programme can virtually connect users and provide them with an environment that balances training and practice . Online Participants in online QI programmes have more control over their learning time , allowinAnother advantage of online programmes using innovative methods such as digital story telling is that it engages the participants in learning a new skill and creates a level playing field in terms of the anxiety associated with a new experience . VirtualParticipants were generally positive about features of online programmes such as open discussion forums, closed groups, private messaging, and feedback submission forms . Using tOpen communication, stakeholder buy-in, and continuous feedback were necessary in developing a shared vision and QI site ownership . EducatiEvidence suggests that mobile and asynchronous educational technologies have the potential to overcome barriers related to teaching QI methods . HoweverCustomising didactic materials to suit programme and participant needs is a time-intensive task . DevelopWith blended learning programmes, a major challenge was group session scheduling so that participants could attend without disruption of clinical responsibilities . Some paThe training modalities discussed in the included studies can be broadly categorised into e-learning programmes and blended learning programmes. A previous systematic review comparing online with face-to-face education for healthcare professionals concluded that online programmes had comparable knowledge gains and benefits to onsite or face-to-face training . HoweverThe review highlights that distance learning approaches to QI help in overcoming barriers to traditional QI training such as shortage of trained faculty and deficiencies in organisational structure to support QI education . AdditioAnother recommendation for those considering online delivery of QI programmes is to build relationships with institutional QI units to identify resources and link the programme to an institutional network of QI education . InsteadCoaches play an important role in the success of the initiatives and should connect with teams early on to provide supplemental support through coaching calls . In term.There is a need for curriculum and training designs to evolve to the needs of the new generation of healthcare professionals with an increasing emphasis on technological tools to overcome the generational difference between educators and learners . The rev3This rapid evidence review aimed to synthesise research and recommendations quickly and comprehensively to adapt traditional QI programmes for online delivery in response to the COVID-19 pandemic which has disrupted healthcare systems and QI training programmes. The review employed a systematic search strategy with robust and transparent screening processes. Owing to the time and resource constraints, only one reviewer was involved in the screening process. However, two additional reviewers critically reviewed the study synthesis to ensure quality. It is recognised that a systematic review is neither appropriate nor possible in every situation . This raThe findings of this review have important implications for those looking to adapt traditional QI programmes to a virtual environment. Virtual training environment holds great potential in delivering standardised training remotely, which will be of utmost importance in the post-COVID environment. However, caution should be practised, and a realistic evaluation of capabilities and needs should be conducted before making adaptation decisions. Factors such as programme design, mode of delivery, technical skills, implementation support and contextual factors are important considerations. Virtual QI and training of healthcare professionals and students is a viable, efficient, and effective alternative to traditional QI education that will play a vital role in building their competence and confidence to improve the healthcare system in post-COVID environment.Additional file 1: Search strategy.Additional file 2: Quality assessement of included studies."} +{"text": "The symposium will highlight the reciprocal relationship between aging and sleep and circadian rhythms. Circadian rhythms and sleep deteriorate with age, but at the same time, disruptions in these processes can contribute too aging. Presenters will show how work in model organisms is providing insight into this relationship"} +{"text": "The current study explores the association between grandparent caregiving by Chinese American elders and their perceived receipt of filial support from their adult children, called filial piety (xiao). Many studies find a correlation between grandparent caregiving and filial behaviors from their adult children, which is notably higher among minority families, especially among Asians than among white families, stimulated by the norm of reciprocity, familism, and extended kinship. Drawing from the theory of intergenerational relationships, social exchange theory, and the role theory, this study questions whether a more active engagement in grandparenting renders higher levels of filial piety returns from adult children. It uses the PINE data, a survey on the wellbeing of Chinese American elders in Chicago. The results show that more hours of grandparent caregiving relate to higher returns of filial piety perceived by older parents. Correspondingly, though with a marginal significance, more pressures to take care of a grandchild from adult children reduce the elders\u2019 perception of filial piety receipt. No interaction effect is found between the grandparenting hours and the pressure from adult children. Additionally, Chinese American elders possessing higher levels of education, mastery, and longer stays in the US perceive lower levels of filial piety receipt from adult children. Discussion will focus on how grandparent caregiving can be mutually beneficial and strengthen intergenerational relationships among Chinese American families."} +{"text": "The negative consequences of caregiving disproportionately impact women, as women make up the majority of informal caregivers and spend more time doing caregiving duties than men. The competing demands inherent in being a caregiver while working can increase levels of stress and burden that these individuals may experience. However, the nuances of the challenges of working female caregivers are still not salient. This review synthesizes the extant literature on working female caregivers to clarify the dilemmas they face and factors that impact their ordeals. Thirty studies on working female caregivers met inclusion criteria. Findings indicate common themes that emerged across the studies. These themes indicate the need to more comprehensively support the multifaceted nature of working female caregivers\u2019 experiences in the workplace and outside of work. Furthermore, this review identifies areas in which informed policy can have a meaningful impact on working female caregivers\u2019 lives."} +{"text": "Age-related hearing loss is prevalent in two-thirds of older adults and reflects progressive impairments in cochlear function leading to impoverished peripheral neural encoding of sound. Research has demonstrated the broader implications of hearing loss for the health and functioning of older adults, particularly with respect to brain aging and dementia. This presentation will summarize current epidemiological and neuroimaging evidence for how hearing loss in older adults affects cognitive load and brain structure/function and relate this contemporary research with previous psychological studies proposing \u2018information degradation\u2019 and \u2018sensory deprivation\u2019 hypotheses of how hearing may affect cognitive function. Finally, the design of an ongoing NIA-funded randomized controlled trial that will determine if hearing treatment reduces the risk of cognitive decline, dementia, and brain aging in adults will be discussed. Part of a symposium sponsored by Brain Interest Group."} +{"text": "Motor decision-making processes are required for many standard neuropsychological tasks, including the Trail Making Test (TMT), that aim to assess cognitive functioning in older adults. However, in their standard formats, it is difficult to isolate the relative contributions of sensorimotor and cognitive processes to performance on these neuropsychological tasks. Recently developed clinical tasks use a robotic manipulandum to assess both motor and cognitive aspects of rapid motor decision making in an object hit (OH) and object hit and avoid (OHA) task. We administered the OH and OHA tasks to 77 healthy younger adults and 59 healthy older adults to assess age differences in the motor and cognitive measures of performance. We administered the TMT parts A and B to assess the extent to which OHA performance is associated with executive functioning in particular. The results indicate that after controlling for hand speed, older adults performed worse on the OH and OHA tasks than younger adults, performance declines were far greater in the OHA task, and the global performance measures, which have been associated with cognitive status, were more sensitive to age differences than motor measures of performance. Those global measures of performance were also associated with measures of executive functioning on the TMT task. These findings provide evidence that rapid motor decision making tasks are sensitive to declines in executive control in aging. They also provide a way to isolate cognitive declines from declines in sensorimotor processes that are likely a contributing factor to age differences in neuropsychological test performance."} +{"text": "Intensive measurements of individuals\u2019 experiences allow for identifying patterns of functioning that may be markers of resilience, and whether such patterns differ across the life span. Using 8 daily diary reports collected in the second burst of the National Study of Daily Experiences , we examined whether positive emodiversity (Shannon\u2019s entropy) attenuated the association between cumulative stressor exposure and depressive symptoms, and age-related differences therein. Results indicated age moderated the extent to which positive emodiversity attenuated the association between stress and depressive symptoms . The attenuated association was strongest for younger adults with higher positive emodiversity, compared to those with lower positive emodiversity. For older adults, the association between stress and depressive symptoms was relatively similar regardless of their positive emodiversity. Implications pertain to for whom and in what contexts specific types of dynamic emotion experiences may promote optimal functioning and resilience."} +{"text": "Older people who live alone may benefit more from using electronic communication than those who live with others. Although living alone has been linked to a higher risk of depression and social isolation, few studies examined the effect of using electronic communication separately by living arrangements. The current study examines the effect of electronic communication use by living arrangements for people aged 65 and older. Using the 2011-2018 National Health and Aging Trends Study (NHATS), we examine how the frequency of emails/texts is associated with changes in psychological well-being and depressive symptoms accounting for sociodemographic, health, social network characteristics . Multilevel growth curve models showed that those living alone or with others were more likely to have fewer depressive symptoms at baseline if they used electronic communication, but the use did not affect their trajectory of depression. Those living alone or with others who used electronic communication did not have higher psychological well-being at baseline, nor did it affect their trajectory. The overall findings raise a question on the effectiveness of promoting electronic communication technology as a substitute for in person interaction for older adults living alone in the community."} +{"text": "Medications are one of the pillar 4Ms of an age-friendly healthcare system. Ensuring that benefits of a medication regimen outweigh the risks and that medications are not contributing to meaningful outcomes such as functional or cognitive decline is a challenge for our healthcare system, particularly for older persons experiencing adverse social determinants of health, health disparities or uncoordinated care. More fully engaging pharmacists in the older person\u2019s health care team is one strategy to improve clinical, humanistic and economic outcomes. This workshop reports findings on medication management capacity among older residents of five low-income apartment buildings in urban Richmond, VA, indicating that this population experiences challenges in managing medications as measured by MedMaIDE. The second presentation describes a pilot partnership between an independent community pharmacy and a local area agency on aging to provide medication coaching to residents of six affordable housing buildings in Seattle, WA, demonstrating feasibility of engaging pharmacists in the healthcare team and resulting in an average of five interventions per resident. The third presentation describes an interprofessional educational intervention based in two low-income apartment buildings for older persons in underserved West Baltimore, MD involving pharmacy students, to better prepare pharmacists to engage in interprofessional team care and meet the needs of a low income culturally diverse older adult population. Discussion will focus on barriers and opportunities to more fully engage pharmacists to support urban residents of low-income housing buildings to optimize medication outcomes and reduce medication-related harm."} +{"text": "Optical antennas are key elements in nano-optics, bridging the gap between the dimension of an optical wavelength and the size of elementary quantum emitters such as single atoms, molecules, etc. (a few nanometers to below 1 nm). Nanoantennas have been under examination for the past few decades in view of their attractive fundamental properties, while the rapid development of nanofabrication techniques has opened up possibilities to create more and more sophisticated shapes and configurations with increasing control over their optical performance 57]. In the emisThe contributions collected in this Thematic Issue thus highlight current and emerging directions in the fast-moving field of optically and electrically driven nanoantennas. In the current age of photonics, such elements may prove essential in further expanding the functionality of electrical devices by integration with photonic functionalities. We sincerely thank all colleagues who contributed to this Thematic Issue with their time and research results.Monika Fleischer, Dai Zhang and Alfred J. MeixnerT\u00fcbingen, September 2020"} +{"text": "Inadequate food intake is common among hospitalized older adults and is linked to negative hospitalization outcomes, including functional decline and mortality. Depression is a well-established risk factor in inadequate food intake in the community but its role in food consumption during hospitalization is poorly studied. To examine the associations between depressive symptoms, appetite and the quantity of food consumed by older inpatients, we conducted a secondary data analysis of 724 hospitalized adults aged 69 to 95 using a prospective cohort dataset: Hospitalization Process Effects on Functional Outcomes and Recovery. Depression was evaluated with Tucker\u2019s Short Zung Instrument at time of admission. Food intake and appetite were examined daily for three consecutive days, using self-reports of food consumed at breakfast, lunch and supper, based on the nDay Express Questionnaire. Approximately 40% of respondents reported eating half or less than half of each meal. The risk of depression was prevalent among a third of respondents, 54% of whom were identified at high risk of depression. The association between depression and inadequate food intake was found to be negative . Low appetite was significantly linked to reduced food consumption and made a considerable contribution to the explained variance of food consumed . Finally, decreased appetite partially mediated the association between depressive symptoms and food intake during hospitalization . These findings contribute to the understanding of inadequate food intake during hospitalization and indicate the importance of screening for depression among hospitalized older adults."} +{"text": "Wetlands among all terrestrial ecosystems have the highest carbon density and are found to store up to three to five times more carbon than terrestrial forests. The current study was undertaken to quantify carbon stocks of two carbon pools: aboveground biomass (AGB) and belowground biomass (BGB). Chosen study sites; Kolonnawa wetland and Thalawathugoda wetland park are distributed within the Colombo wetland complex. Colombo was recognized as one of the 18 global Ramsar wetland cities in 2018. A combination of field measurements and allometric tree biomass regression models was used in the study. Stratification of the project area was performed using the normalized difference vegetation index (NDVI).The occurrence of climate change at an unprecedented scale has resulted in alterations of ecosystems around the world. Numerous studies have reported on the potential to slow down climate change through the sequestration of carbon in soil and trees. Freshwater wetlands hold significant potential for climate change mitigation owing to their large capacity to sequester atmospheric carbon dioxide , has the potential to enhance the net sink of AGB carbon in these non-mangrove wetlands. However, further studies are essential to confirm if enhanced carbon sequestration by Annona glabra is among the unexplored and unreported benefits of the species.In conclusion, the study reveals that tropical freshwater wetlands contain considerable potential as carbon reservoirs. The study suggests the use of tropical freshwater wetlands in carbon sequestration enhancement plans in the tropics. The study also shows that Primary data collected from Thalawathugoda wetland park. This database contains data that were used in the study - Estimation of aboveground and belowground carbon stocks in urban freshwater wetlands of Sri Lanka. The database particularly contains data obtained from Thalawathugoda wetland park which is one of the study sites included in the study. Each sheet contains data belonging to 7 fields: Local name of the species , scientific name, species ID (as assigned by the authors), wood density, height, diameter at breast height (DBH) and biomass of the tree. Wood density values used for calculating biomass were obtained mainly from [nly from and 44]Additiona"} +{"text": "Older adults are often stereotyped in a paternalistic manner , deserving of assistance regardless of their need. We have examined the veracity and malleability of this paternalistic stereotype using an experimental vignette with both male and female targets. Younger adults (N = 717) deemed it more necessary and appropriate to offer unnecessary help to older adults in a grocery store scenario. Additionally, competence was malleable for both older adult male and female targets if the older adults denied the offer of help. Interestingly, older women were viewed as warm, which did not change as a function of their response, whereas older men were initially viewed as colder, but their warmth ratings increased. In light of these findings, we will discuss the intersection of age and gender when considering the malleability of the warmth and competence dimensions of the paternalistic older adult stereotype."} +{"text": "The Native Hawaiian and Other Pacific Islander (NHOPI) older adult population remains understudied and are disproportionately affected by diabetes and heart conditions. Research has shown that participating in physical activity is a protective factor for many of the health conditions experienced by older adults. Yet, the link between physical activity, diabetes, and heart conditions among the NHOPI older adult population is limited. The purpose of this study is to identify the characteristics of NHOPI older adults and to explore the association between physical activity levels and diabetes/heart conditions. Methods and findings Using data from the 2014 Native Hawaiian and Pacific Islander National Health Interview Survey (NHPI NHIS), which is considered to have a representative sample of NHOPI, the study explores the associations between physical activity and diabetes/heart conditions. A total of 1,045 older adults ages 50 years and older were included for analyses. Weighted multivariate analyses with multiple imputation techniques were used. The NHPI NHIS is the first federal survey focusing on the NHOPI population of the United States with rich information on health. Results and Implications Those with who were engaged in a sufficient physical activity had lower odds of having diabetes or heart conditions than their counterparts without physical activity while controlling for other sociodemographic characteristics. Findings highlight the importance of physical activity promotion intervention in preventing cardiovascular disease. Research and practice addressing health disparities and cardiovascular conditions should leverage efforts to provide culturally relevant physical activity types and resources to NHOPI older adults."} +{"text": "Existing scholarship in social gerontology has surprisingly paid little attention to broader loving emotions, such as compassionate and altruistic love, as potentially meaningful mechanisms for improving later life psychological well-being. This study examined the influence of feeling love toward other persons and experiencing love from others on later life psychological well-being. We conducted a 3-wave longitudinal study of a representative sample of 340 ethnically heterogeneous community dwelling older residents of Miami, Florida. The increase in feeling of being loved and love for others led to decline in odds of reporting greater level of depressive symptoms over time. The odds of reporting higher level of positive affect were significantly greater for older adults who reported feeling loved by others and expressed love for other people . Older adults who felt loved had 0.92-point lower ordered log odds of reporting higher negative affect than those who reported lower level of love. The impact of compassionate love on depressive symptoms and negative affect remained statistically significant even after adjustment for altruistic attitudes and emotional support. The influence of loving emotions on positive affect was, however, explained by altruistic attitudes and emotional support. Our findings underscore the powerful influence of both receiving and giving love for the maintenance of later life psychological well-being. We offer support for the expectation that love is a significant force in the lives of older adults that transcends intimate relationships."} +{"text": "There is consensus that the heart is innervated by both the parasympathetic and sympathetic nervous system. However, the role of the parasympathetic nervous system in controlling cardiac function has received significantly less attention than the sympathetic nervous system. New neuromodulatory strategies have renewed interest in the potential of parasympathetic motor output to treat cardiovascular disease and poor cardiac function. This renewed interest emphasizes a critical need to better understand how vagal motor output is generated and regulated. With clear clinical links between cardiovascular and metabolic diseases, addressing this gap in knowledge is undeniably critical to our understanding of the interaction between metabolic cues and vagal motor output, notwithstanding the classical role of the parasympathetic nervous system in regulating gastrointestinal function and energy homeostasis. For this reason, this review focuses on the central, vagal circuits involved in sensing metabolic state(s) and enacting vagal motor output to influence cardiac function. It will review our current understanding of brainstem vagal circuits and their unique position to integrate metabolic signaling into cardiac activity. This will include an overview of not only how metabolic cues alter vagal brainstem circuits, but also how vagal motor output might influence overall systemic concentrations of metabolic cues known to act on the cardiac tissue. Overall, this review proposes that the vagal brainstem circuits provide an integrative network capable of regulating and responding to metabolic cues to control cardiac function. While sympathoexcitation may be widely accepted as a hallmark of the pathogenesis of cardiovascular disease, decreased parasympathetic, or vagal, tone is linked to a broad spectrum of diseases, including cardiac arrhythmias, coronary heart disease, and heart failure, and is an accurate predictor of morbidity and mortality in humans and animals . ExperimSignificant clinical evidence also implicates metabolic diseases as independent risk factors for the development of cardiovascular disease . NotablyAlthough a large scale clinical investigation suggested that chronic vagal stimulation did not improve cardiac function in patients with heart failure , this stThis review then will focus on autonomic function in the context of cardiometabolic physiology, particularly as it relates to vagal motor output. Therefore, it will aim to define basic brainstem circuits and the influence of metabolic signaling on plasticity within these circuits. It will hopefully compel more investigations into how vagal motor output is both affected by and an effector of metabolic cues.Ever since the first description of cardiac innervations in the 19th century , signifiVagal motor innervation of cardiac tissue is comprised of cholinergic, preganglionic motor neurons whose cell bodies are located in the brainstem . These pThese preganglionic cardiac vagal motor neurons originate from two brainstem regions: the nucleus ambiguus (NA) and the dorsal motor nucleus of the vagus (DMV) . The vasLittle is known, however, about the innervation arising from the cardiac-projecting neurons residing within the DMV. Retrograde tracing studies indicate that cardiac motor neurons do originate in the DMV , providiWe also know relatively little in terms of the electrophysiological properties and upstream signaling network governing the activity of cardiac-projecting DMV neurons. While cardiac NA neurons have low resting membrane potentials and are silent when devoid of synaptic input, DMV neurons with other visceral organ targets exhibit a slow pace-making current . The preRegardless of the location and electrophysiological properties of cardiac vagal motor neurons, upstream central brainstem signaling is critical to their final motor output. Centrally-mediated autonomic motor control of the cardiovascular system is sensitive to various sensory afferent information carried in large part by peripheral neurons located in the intrathoracic nodose ganglia, which synapse in the nucleus tractus solitarius (NTS) . First aHowever, there is considerable overlap in visceral organ-based topography within the NTS with sensory afferent innervations from other organ systems is an independent risk factor for the development of cardiovascular disease . While mThe nuances surrounding different diets and their relationship to cardiovascular disease are best reviewed elsewhere . HoweverIn animal models, diets high in saturated fats can induce tachycardia , even ifUnfortunately, the mechanism(s) responsible for vagal circuit reorganization of the brain regions involved are still largely unknown. There are now substantial data implicating vagal afferents and the NTS as important sites in the effects of high fat diet in the context of feeding regulation , suggestThe case for early inhibition of the vagal motor system can only be made through longitudinal evaluations of consumption of high fat diets (that includes earlier timepoints in the feeding paradigms). While a significant amount of research is appropriately dedicated to investigating the role of long-term high fat diet and ultimately the obesity that follows long term consumption of these diets, there is increasing evidence that consumption of high fat for a few days can affect neuronal function. Part of this reevaluation includes the emerging concept that metabolic challenges lead to neural adaptions, rendering the brain insensitive to future metabolic cues . ImportaChronic inflammation is also considered a significant risk factor for the development of cardiovascular disease . Of partAnother emerging modulator of central cardiovascular regulatory networks is the most abundant glial cell in the central nervous system, the astrocyte . OriginaIndirect pathways of neuroinflammatory activation are also implicated in cardiovascular (dys)function. The renin-angiotensin system (RAS) is classically considered an endocrine regulator of the cardiovascular system. However, it is now recognized that components of the RAS system are present within the brain, including the brainstem , and RASTo fully understand the role of perturbations in metabolic cues on cardiac function, it is important to understand the role of autonomics in mediating the concentrations and sensitivities of metabolic hormones with known cardiac modulatory abilities. It is worth mentioning that much of our understanding of the role of metabolic signaling perturbations has been insulin-centric. However, it is becoming evident that metabolic diseases come with a complex hormonal milieu. As such, there have been calls for a more diverse focus, such as on glucagon . TherefoFirst discovered more than 100 years ago, insulin is secreted from pancreatic beta cells in response to high blood glucose concentrations and its role in metabolic dysregulation is well established. Insulin receptors are widely expressed throughout the cardiovascular system, including cardiac tissue . InsulinThe parasympathetic nervous system also plays an important role in the secretion of insulin. Preganglionic vagal innervation to the pancreas originates from the DMV, with little known contribution from the NA . These DServing in opposition to insulin , glucagoin vivo glucagon measures also suggest that inhibition of DMV motor activity increases glucagon concentrations is an incretin hormone produced from L-cells within the intestine and released during digestion of fat and carbohydrates . Upon rein vivo and in vin vitro .However, the action of GLP-1 in cardiac regulation may be more complex . There iGiven the long history of both basic science and clinical investigations into cardiac autonomic function, it can be easy to assume that we fully understand how these systems work. While we know a great deal about the anatomy of these circuits, how they process the wide variety of complex signals they receive and ultimately integrate and relay this information to peripheral organs, such as the heart, is still under active investigation. Despite the scarcity of studies investigating the effect of metabolic signaling on cardiac vagal motor neuron physiology, reports have confirmed the therapeutic potential\u2014although varied in magnitude\u2014of activating vagal pathways, most notably through vagal stimulation. Although these results may provide a mechanistic rationale for the importance of cardiac-related vagal tone and health, more studies investigating the plasticity within autonomic regulatory circuits related to various metabolic cues are needed to better understand the fundamental role of vagal signaling in metabolic and cardiovascular physiology.During this discussion, it is also important to consider that the plasticity associated with a disease may not simply be an exaggeration of normal physiology. Therefore, considerable work must be done to determine the role of the brain in mediating cardiometabolic integrative homeostasis in both health and disease. These examinations into autonomic contributions to cardiometabolic function need to include time courses throughout disease progression. This will determine when important neuronal remodeling occurs, revealing important biological milestones for intervention. Continued investigation into these autonomic pathways will not only increase our understanding of these circuits, but will develop a more informed perspective that will influence current clinical treatment guidelines for patients to provide early and reliable detection markers of autonomic dysregulation, as well as a more complete management of a patient\u2019s disease and the prevention of cardiac-related morbidity and mortality.LE, SF, and CB wrote and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Tight metabolic regulation is essential to maintain stem cell homeostasis and support healthy aging. With age, metabolic alterations cause neural stem cell (NSC) dysfunction and are associated with a decline in neurogenesis, but the underlying mechanisms are not known. Aged stem cells display defects in the autophagy-lysosomal pathway that may disrupt mitochondrial dynamics, resulting in metabolic disruptions that alter self-renewal and differentiation potential. We have used genomic and functional approaches to investigate the metabolic mechanisms that support NSCs throughout aging. We found that mitochondrial and mitophagy gene networks as well as mitophagy dynamics are differentially regulated between the quiescent and activated states and become dysregulated with age. This work provides new insight into the metabolic regulation of NSCs and may lead to strategies to enhance neurogenesis in the context of aging and neurodegenerative disease."} +{"text": "Neglected tropical diseases (NTD) comprise a group of infectious viral, bacterial, and parasitic diseases with high endemicity in tropical and subtropical regions, disproportionately affecting the developing countries . The WHOS. japonicum infection. Their results suggest that this protein promotes the progression of liver fibrosis, through alternative activation of macrophages. Immunological research is also important in the development of clinical tools available to address such diseases: vaccines, diagnostics, and drugs. In this issue, Bernardes and colleagues intend to investigate an antigen of S. mansoni as a target for vaccine development. This manuscript relates a complete analysis concerning humoral and cellular responses investigation and also the worm burden after vaccination and infection in murine model. Regarding the diagnostic based on immunological tools, Takeuchi and colleagues measure serum total and specific anti-Ascaris IgE to evaluate wheezing in children. They cluster these kids and investigate the relationship between wheezing and Ascaris infection. When it comes to leishmaniasis, Aleka and colleagues monitored visceral leishmaniasis treatment efficacy by measuring the production of cytokines before, during, and at the end of treatment. Their work presents a unique cohort study using a novel methodology to discriminate active from cured leishmaniasis patients.The control and elimination of NTD involve both the comprehension of immune mechanisms during parasite establishment in the host and the development of better tools to improve detection and minimize transmission. Research in this field is critical to comprehend each organism that causes these diseases and to develop new treatment for them. The immune response to NTD agents was previously investigated over the last decades. The new discoveries in this field enabled NTD researchers to better understand parasite evasion, modulation of host immune responses, and the immunopathology of infections. In this special issue, we present two manuscripts providing new insights on these topics. Quental and colleagues evaluate puerperal colostrum, discover that maternal Zika infection increases colostrum viscosity, and also modify cytokine concentrations. The altered levels of cytokines are possibly what changes colostrum viscosity, which represents a possible mechanism of adaptation of breastfeeding against Zika virus. In another original research, Duan and colleagues find that CCAAT/enhancer-binding homologous protein (CHOP), a transcriptional regulator induced by endoplasmic reticulum stress, plays a critical role in liver pathology associated with In summary, this current special issue publishes five original research articles on recent findings about NTD immunology. The few number of papers published in this special edition reflects the major difficulties among NTD research and also the limited interest of the scientific community to this topic. Although the content of this special issue only covers a few topics, it reports the newest discoveries on the field and provides new data that enhance the knowledge in the field and stimulate researchers to keep investigating the NTD in the future. These diseases take many lives yearly and challenge many researches around the world, so the works published here enhance the understanding of NTDs and help experts in this inspiring field.Barbara Castro-Pimentel FigueiredoCarina Silva PinheiroFabio Vitarelli MarinhoNestor Adrian Guerrero"} +{"text": "In Japan, death from colorectal cancer has become the second leading cause among cancer deaths, and there were 50,628 deaths from colorectal cancer in 2018. Liver metastasis is a necessary determinant of colorectal cancer patients, and many studies have clarified prognostic factors associated with survival after resection of liver metastasis. They can be grouped into three categories, namely, tumor factors , patient factors , and treatment factors .(1). They concluded that histologic features expressed in the primary tumor predict oncological outcome after resection of liver metastasis and are useful for identifying high-risk patients with early relapse after hepatic resection.In this issue, Ueno et al. added another information to prognostic factors of colorectal liver metastasis and showed that survival after resection of liver metastasis from colorectal cancer is not associated with T or N stage but with primary tumor histology, including poorly differentiated clusters and desmoplastic reaction (2). In his study, the CPL classification was associated with the prognosis of patients who underwent resection of gastric and uterine cancers.Interaction between tumor and host is a necessary aspect of host defense against tumor and must be emphasized from a viewpoint of surgical pathology. In 1960, Imai of Kyushu University paid attention to advancing margin of the tumor and proposed a novel prognostic classification abbreviated as CPL: C refers to cirrhotic sprouting (invading mode expressed by the extent of sprouting tumor cells); P refers to progressive sprouting (invasion without reactive fibrous tissue in their surroundings); and L refers to lymphatic and blood vessel permeation (4). In 1976, Watanabe et al. demonstrated that the presence of nondesmoplatic stroma infiltrated uniformly with abundant lymphocytes and plasma cells throughout the entire area of tumor showed high survival rate among 1,041 patients undergoing gastrectomy for cancer. In 1986, Jass evaluated 447 specimens of rectal cancer and showed that 5 year survival rates for pronounced, moderate, and little lymphocytic infiltration were respectively 92%, 65%, and 36%. His study first clarified that lymphocytic infiltration affected survival independent from other pathologic variables.Another stromal aspect of host defense mechanism against tumor is exudative reaction, such as lymphocytic infiltration or lymphoid stroma In the era of molecular biology or genetic pathology, researchers were prone to investigate the tumor pathology by the novel and evolving technology rather than the classical histologic examination.(5).Our great seniors reminded us that tumor tissue observation and evaluation simply via optical microscope is necessary in cancer study. In this sense, traditional histologic study based on hematoxylin-and-eosin stained slides by Ueno et al. is essential and suggestive for young readers of this journal, including researchers, pathologists, surgeons, and clinicians. Open your eyes, and look up to the skies and see (excerpt from Bohemian Rhapsody by Freddie Mercury) NoneMasaki Mori is one of the Associate Editors of JMA Journal and on the journal\u2019s Editorial Staff. He was not involved in the editorial evaluation or decision to accept this article for publication at all."} +{"text": "Bacillus thuringiensis subspecies israelensis (Bti) is the most popular of these alternatives, although it can also have direct effects on lowering environmental biodiversity and indirect effects on food-web relationships in the ecosystems where it is deployed. In addition, microbial control agents that impede pathogen development or transmission from mosquito to human are under investigation, including Wolbachia and Asaia, but unexpected interactions with mosquito gut bacteria can hinder their effectiveness. Improved characterization of mosquito gut bacterial communities is needed to determine the taxa that interfere with microbial controls and their effectiveness in wild populations. This mini-review briefly discusses relationships between mosquito gut bacteria and microbial forms of control, and the challenges in ensuring their success.Mosquitoes are one of the deadliest animals on earth because of their ability to transmit a wide range of human pathogens. Traditional mosquito control methods use chemical insecticides, but with dwindling long-term effectiveness and negative effects on the environment, microbial forms of control have become common alternatives. The insecticide Bacillus thuringiensis subspecies israelensis (Bti) has been a popular alternative to chemical insecticides and is the most common microbial form for controlling mosquitoes today as three distinct crystals that become lethal once ingested by mosquito larvae. Enzymes present in the larval gut activate these protoxins to a toxic state, form pores in the gut epithelial membrane, and lead to larval death. In certain environmental conditions, Bti toxins can persist for months after application, possibly exposing mosquito larvae to low concentrations of toxin for a prolonged period that could favor resistance development, but with the combination of all four toxins this is not a likely outcome . Bti tolNew York and an Ane-Alpes , with none-Alpes with theAnopheles stephensi with sterile guts show increased susceptibility to Bti compared to those colonized with bacteria, wherein the microaerophilic conditions of the normal larval gut might promote the degradation of Bti toxins via bacteria using them as a nitrogen source , inhabit insect reproductive organs to cause cytoplasmic incompatibility between sperm and egg, and inhabit the insect gut, which is a key environment for the replication and maturation of many human pathogens will enable development of microbial control agents with higher success rates against disease transmission, but might require a combination of sequencing techniques and biochemical tests for species level resolution and isolation . This bacterium can prevent dengue virus and Plasmodium falciparum infection in lab-reared A. aegypti and A. gambiae, respectively, by rapidly colonizing the mosquito gut, prompting expression of host immune factors, and maintaining an effective level of host innate immunity gene sequencing, but inconsistencies in species profiling exist due to variations in experimental designs and analytical methods that introduce biases, preventing direct comparisons of microbial communities across studies (as reviewed by Anopheles albimanus microbiomes and resistance to the organophosphate insecticide fenitrothion (Anopheles immune factor on the microbiota, revealing immune factor APL1 to have homeostatic control on the abundance of specific Cedecea and Klebsiella species in the gut (D. melanogaster has a direct impact on the gut bacterial community but at a more general level, as this gene is responsible for repressing expression of antimicrobial peptide genes in the digestive tract (Some of the limitations of 16S sequencing can be addressed using whole metagenome sequencing because of the information acquired from other regions in bacterial genomes. While this can be more costly and challenging, metagenomics offers advantages over 16S sequencing in its ability to profile bacterial genes and to both detect and identify a greater diversity of bacterial species . For exatrothion . The com the gut . Similarve tract . ExploitDD conceived, designed, and wrote the manuscript. FC critically reviewed the manuscript. Both authors approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Cancer is a leading cause of death and poor quality of life globally. Even though several strategies are devised to reduce deaths, reduce chronic pain and improve the quality of life, there remains a shortfall in the adequacies of these cancer therapies. Among the cardinal steps towards ensuring optimal cancer treatment are early detection of cancer cells and drug application with high specificity to reduce toxicities. Due to increased systemic toxicities and refractoriness with conventional cancer diagnostic and therapeutic tools, other strategies including nanotechnology are being employed to improve diagnosis and mitigate disease severity. Over the years, immunotherapeutic agents based on nanotechnology have been used for several cancer types to reduce the invasiveness of cancerous cells while sparing healthy cells at the target site. Nanomaterials including carbon nanotubes, polymeric micelles and liposomes have been used in cancer drug design where they have shown considerable pharmacokinetic and pharmacodynamic benefits in cancer diagnosis and treatment. In this review, we outline the commonly used nanomaterials which are employed in cancer diagnosis and therapy. We have highlighted the suitability of these nanomaterials for cancer management based on their physicochemical and biological properties. We further reviewed the challenges that are associated with the various nanomaterials which limit their uses and hamper their translatability into the clinical setting in certain cancer types. Figure .Cancer is a leading cause of death and a global health burden. It was estimated that there would be 18.1 million new cancer cases and 9.6 million cancer-related deaths by 2018Genetic mutations can cause changes in the synthesis of certain biomolecules leading to uncontrolled cell proliferation and ultimately cancerous tissuesIn the past few decades, the application of nanoparticles in cancer diagnosis and monitoring has attracted a lot of attention with several nanoparticle types being used today for molecular imaging. Due to their advantages including small size, good biocompatibility, and high atomic number, they have gained prominence in recent cancer research and diagnosis. Nanoparticles used in cancer such as semiconductors, quantum dots and iron oxide nanocrystals possess optical, magnetic or structural properties that are less common in other molecules For cancer diagnostics, imaging of tumor tissue with nanoparticles has made it possible to detect cancer in its early stages. In lung cancer, the detection of metastases can be determined by developing immune superparamagnetic iron oxide nanoparticles (SPIONs) that can be used in MRI imaging with the cancer cell lines as the target for the SPIONs in vitro studies using nanosystem for positron emission tomography (PET) have also been developed based on self-assembled amphiphilic dendritic molecules. These dendritic molecules spontaneously assemble into uniform supramolecular nanoparticles with abundant PET reporting units on the surface. By taking advantage of dendritic multivalence and the enhanced penetration and retention (EPR) effect, the dendritic nanometer system effectively accumulates in tumors, resulting in extremely sensitive and specific imaging of various tumors while reducing treatment toxicities.Magnetic powder imaging has also been used in tomographic imaging technology where it has shown a high resolution and sensitivity to cancer tissuesIn current research, nanotechnology can validate cancer imaging at the tissue, cell, and molecular levelsThe lack of ability to penetrate objects limits the use of visible spectral imaging. Quantum dots that emit fluorescence in the near-infrared spectrum have been designed to overcome this problem, making them more suitable for imaging colorectal cancer, liver cancer, pancreatic cancer, and lymphomaAnother commonly used nanotechnology application is the use of nanoshells. Nanoshells are dielectric cores between 10 and 300 nanometers in size, usually made of silicon and coated with a thin metal shell Figure . When the energy exceeds 80kev, the mass attenuation rate of gold becomes higher than alternative elements like iodine, indicating a greater prospect gold nanoparticles Gold nanoparticle (AuNPs) is a good contrast agent because of its small size, good biocompatibility, and high atomic number. Research shows that AuNPs work by both active and passive ways to target cells. The principle of passive targeting is governed by a gathering of the gold nanoparticles to enhance imaging because of the permeability tension effect (EPR) in tumor tissuesCancer biomarkers are biological features whose expression indicates the presence or state of a tumor. Such markers are used to study cellular processes, to monitor or identify changes in cancer cells, and these results could ultimately lead to a better understanding of tumors. Biomarkers can be proteins, protein fragments or DNA. Among them, tumor biomarkers, which are indicators of a tumor, can be tested to verify the presence of specific tumors. Tumor biomarkers ideally should possess a high sensitivity (>75%) and specificity (99.6%)In general, protein profiling tests would remove the high molecular weight proteins such as albumin and immunoglobulins. However, the removal of these proteins also removes the low molecular weight protein biomarkers conjugated to them, resulting in the loss of the biomarkers of interest. These low molecular weight proteins represent a potential biomarker-rich populationAnother method to improve screening with nanocarrier is to improve the sensitivity of mass spectrometry. The unique optical and thermal properties of carbon nanotubes enhance the energy-transfer efficiency of the analyte, contributing to the absorption and ionization of the analyte, and eliminate the interference of inherent matrix ionsThe development of nanotechnology is based on the usage of small molecular structures and particles as tools for delivering drugs. Nano-carriers such as liposomes, micelles, dendritic macromolecules, quantum dots, and carbon nanotubes have been widely used in cancer treatment.Table . For instance, liposomal forms of adriamycin have been used for the management of metastatic ovarian cancer where they have shown appreciable clinical benefitLiposomes are one of the most studied nanomaterials, which are nanoscale spheres composed of natural or synthesized phospholipid bilayer membrane and water phase nucleiin vitro and in vivo for cancer treatmentBased on the structure and the diameter, Carbon nanotubes (CNTs) can be categorized into two kinds, the single-walled CNTs (SWNTs) and the multiwalled CNTs (MWNTs)Polymeric nanoparticles (PNPs) are the inventions that relate to a solid micelle with a particle size range of 10-1000 nmThe advantages of the higher thermodynamic stability and the smaller volume make the PNPs a suitable drug carrier with good endothelial cell permeability while avoiding kidney rejectionThe dendrimers are nanocarriers that have a spherical polymer core with regularly spaced branchesin vivo, can be used to target tumors and make possible their potential applications in cancer imaging and treatment. Some studies combine QDs with prostate-specific antigen to label cancer, while others use QDs to make biomarkers that speed up the process with such immune markers having a more stable light intensity than traditional fluorescent immunomarkersin vivo and can also be used to detect ovarian cancer marker cancer antigen 125 (CA125) in different types of specimens Quantum dots (QDs) are small particles or nanocrystals of semiconductor materials between 2 and 10 nanometers in sizeNanotechnology has shown a lot of promise in cancer therapy over the years. By their improved pharmacokinetic and pharmacodynamic properties, nanomaterials have contributed to improved cancer diagnosis and treatment. Nanotechnology allows targeted drug delivery in affected organs with minimal systemic toxicities due to their specificities. However, as with other therapeutic options, nanotechnology is not completely devoid of toxicities and comes with few challenges with its use including systemic and certain organ toxicities, hence, causing setbacks with their clinical applications. Given the limitations with nanotechnology, more advancements must be done to improve drug delivery, maximize their efficacy while keeping the disadvantages to the minimum. By improving the interactions between the physicochemical properties of the nanomaterials employed, safer and more efficacious derivatives for diagnosis and treatment can be made available for cancer management. In sum, we sought to highlight the key advantages of nanotechnology and the shortfalls in their use to meet clinical needs for cancer. Adding to that, the therapeutic benefits of nanotechnology and future advancements could make them a therapeutic potential to be applied in other disease conditions. These may include ischemic stroke and rheumatoid arthritis which would require targeted delivery of a suitable pharmacologic agent at the affected site."} +{"text": "Throughout the centuries, humankind has relentlessly searched for ways to live longer and healthier lives. From the \"fountain of youth\" quest to novel senolytics, from alchemical recipes to modern diets, different approaches have been pursued to fulfil the human desire of prolonging life while maintaining good shape. Among all anti-aging interventions, calorie restricted diets and periods of fasting stand out as the most compelling and robust methods to prolong life and health span and to reduce the risk of diabetes, neurodegeneration, autoimmune disorders, spontaneous tumours and cardiovascular disease . FurtherPlanarians -better known for their impressive regenerative capacities- can be deprived of food for more than 3 months without showing an impairment in either physiology or activity levels. They handle prolonged periods of starvation or fasting by shrinking in size. Around 25% of the cells in their parenchyma are adult stem cells, which are kept in a constant ration respect their body size. Interestingly, refeeding allows fasted planarians to grow back to their original size [in situ on whole planarians we found that fasted planarians present a higher percentage of stem cells with the longest telomeres, indicating that fasting rejuvenates the stem cell pool [We have recently reported the effect of fasting on planarian stem cells regarding telomere length . Telomerell pool . Having Our data shows that the enrichment of stem cells with long telomeres during fasting occurs through the inhibition of mTOR signalling , a pathwBoth activation of telomerase and long telomere length are known to positively correlate with stem cell pluripotency. Interestingly we find that the stem cell population is highly heterogeneous for telomere length, correlating with their known heterogeneity with regards to potency and lineage commitment . We also"} +{"text": "Modifying health behaviors can be difficult, especially for older adults who are challenged by multiple chronic conditions, reduced functional and/or cognitive capacity, and limited social support. Although much attention has been given to the theories, skills, and resources behind initiating and achieving behavior change, less work has focused on maintenance of health behaviors over time. This presentation will showcase pilot research inspired by RCCN\u2019s first workshop, Achieving and Sustaining Behavior Change. Specifically, this pilot brings together an interdisciplinary team of behavioral scientists and health services researchers working at the intersection of intervention science and implementation science to better understand the construct of maintenance and discuss emerging methods for intervention development and evaluation. The presentation will utilize physical activity as an example behavior to demonstrate the value of interdisciplinary research, including recommendations on how some of the six NIA research centers can make unique contributions to understanding health behavior maintenance."} +{"text": "The primary cilium, a microtubule based organelle protruding from the cell surface and acting as an antenna in multiple signaling pathways, takes center stage in the formation of the cerebral cortex, the part of the brain that performs highly complex neural tasks and confers humans with their unique cognitive capabilities. These activities require dozens of different types of neurons that are interconnected in complex ways. Due to this complexity, corticogenesis has been regarded as one of the most complex developmental processes and cortical malformations underlie a number of neurodevelopmental disorders such as intellectual disability, autism spectrum disorders, and epilepsy. Cortical development involves several steps controlled by cell\u2013cell signaling. In fact, recent findings have implicated cilia in diverse processes such as neurogenesis, neuronal migration, axon pathfinding, and circuit formation in the developing cortex. Here, we will review recent advances on the multiple roles of cilia during cortex formation and will discuss the implications for a better understanding of the disease mechanisms underlying neurodevelopmental disorders. The cerebral cortex contains dozens of different types of neurons . This diPrimary cilia are small protrusions from the cell surface and act as signaling hubs in neural development. Harboring the cell surface receptors for multiple signaling pathways, this tiny organelle receives the signals controlling corticogenesis and converts them into cellular responses, for example into changes in gene expression and/or alterations in the migratory behavior of cells and axons. Astonishingly, the cilium can even influence axon pathfinding decisions by the axonal growth cone which is separated from the cilium by large distances, in case of the corticospinal motor neurons by several centimeters . MoreovePrimary cilia are microtubule based cell organelles that function as sensors for chemical and mechanical cues from the cellular environment. Nine outer microtubule doublets emanate from the basal body at the ciliary base to form the ciliary axoneme which protrudes from the cell surface Fisch a. PrimaryGli2 mutant mice while Gli3 null mutants present with severe morphological and molecular defects in the dorsal telencephalon . These feriments . In cont mutants . InteresGpr161 encodes an orphan G protein coupled receptor (GPCR) that acts as a negative regulator of Shh signaling by controlling cAMP levels and thereby Gli3 processing and repressor formation cause dwarfism, microcephaly and intellectual disability and Filamin A genes abolished hotspot formation and resulted in defective centrosome dynamics and altered nucleokinesis. Interfering with the centrosomal localization of PKA phenocopied these migratory defects strongly suggesting a direct link between the primary cilium and the centrosome through cAMP signaling. Interestingly, the authors found a similar cAMP hotspot in migrating cortical projection neurons. While this raises the interesting possibility that cAMP signaling is similarly involved in somal translocation of cortical projection neurons, it remains to be seen whether other signaling pathways and in particular Reelin signaling which is critical for correct cortical layering and epilepsy . A majoral axons . Arrivinal axons . In addial axons . These fircuitry .Arl13b conditional inactivation in interneurons caused alterations in interneuron morphology and electrophysiological properties with reductions in synaptic buttons density and synaptic size (In models, single neurons are often depicted with their primary cilium protruding from the surface of the neuronal soma at a distance from dendrites and synapses. However, projection neurons and interneurons are very densely packed in the developing and adult cortex and as such cilia will be in close contact with other neurons, their dendrites and axons. This raises the interesting possibility that due to their position cilia represent excellent candidates as modifiers of neuronal circuitry. This certainly is an area much to learn about in the developing cerebral cortex but we are starting to gain insights into ciliary roles in other forebrain neurons in shaping neuronal connectivity. In addition to cortical interneurons, the medial ganglionic eminence generates striatal interneurons that regulate the activity of medium spiny neurons in the striatum and thereby striatal output . It was tic size . Moreovetic size accumulatic size .In this review, we have summarized our current knowledge on the role of primary cilia during corticogenesis. This tiny organelle plays multiple and remarkably varied roles at various steps of cortical development. A major focus in the future will be to elucidate how a combination of defects in ciliary controlled signaling pathways contribute to this variability in phenotypes. Throughout this review, we have emphasized the importance of ciliary mediated processing of Gli3 for cortical patterning and stem cell development reflecting a strong requirement to suppress Hedgehog signaling in these early steps of corticogenesis. In contrast, Hedgehog signaling becomes increasingly more active at later stages to control the formation of olfactory bulb interneurons and of glial cells and estaKH-T and TT conceived the idea and wrote the manuscript. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Recent research demonstrates burnout prevalence rates as high as 76% in emergency medicine (EM) residents. In 2017 the Accreditation Council for Graduate Medical Education (ACGME) required that all training programs provide dedicated wellness education for their trainees as a requirement for accreditation. We aimed to conduct a systematic review of published wellness interventions conducted in EM residency programs following the implementation of the 2017 ACGME Common Program Requirements change in order to characterized published intervention and evaluate their effectiveness.We applied a published approach to conducting systematic reviews of the medical education literature. We performed a search of the literature from January 1, 2017\u2013February 1, 2020. Studies were included for final review if they described a specific intervention and reported outcomes with the primary goal of improving EM resident wellness. Outcomes were characterized using the Kirkpatrick training evaluation model.Eight of 35 identified studies met inclusion criteria. Most described small convenience samples of EM residents from single training programs and used the satisfaction rates of participants as primary outcome data. Only quantitative assessment methods were used. Studies addressed only a limited number of factors affecting resident wellness. The majority of interventions focused on personal factors, although a few also included sociocultural factors and the learning and practice environment.There is a relative dearth of literature in the area of research focused on interventions designed to improve EM resident wellness. Furthermore, the studies we identified are narrow in scope, involve relatively few participants, and describe programmatic changes of limited variety. Future directions include an increase and emphasis on multi-institutional studies, randomized controlled trials, qualitative methodology, and opportunities for funded research. Emergency medicine (EM) is a high-stakes, fast-paced specialty requiring quick decision-making with limited information and often with critically ill patients. High anxiety and concern for poor outcomes influences emotional exhaustion and burnout among emergency physicians.4Residency is one of the most physically and mentally taxing periods of a physician\u2019s career. Compared with attending physicians or medical students, residents score significantly lower on measures of self-care including sleep, exercise, seatbelt use, and overall wellness.In addition, residents have cited that these factors negatively impact their interactions and relationships with patients and have increased frequency of conflict with colleagues.10In 2017 the Accreditation Council for Graduate Medical Education (ACGME) implemented common core program requirements focusing on the psychological, emotional, and physical well-being of residents.We conducted a systematic review of published studies that describe interventions to mitigate burnout or improve wellness in EM training programs in order to characterize the published interventions and evaluate their effectiveness as measured by outcomes. Understanding the current state of the literature and remaining gaps is crucial as educators seek to design and implement programs intended to meaningfully combat burnout and improve wellness among trainees. In this systematic review, we focused our investigation on wellness interventions conducted in EM residency programs following the implementation of the 2017 ACGME Common Program Requirements.Using the methodology described by Cook and West,Articles identified through these search methods were screened by two authors and included for final review if they described a specific intervention and reported a primary outcome that addressed the need for supporting resident well-being in accordance with the ACGME Common Program Requirements Section VI.C.We identified 35 articles on our initial search of the literature. No additional studies meeting the inclusion criteria described above were found after a review of references cited. Eight published studies were included for final review based on our inclusion criteria .An additional six articles described specific wellness interventions but did not provide outcome data, and although these were not considered in our analysis, we have provided them for reference .The majority of studies (6 of 8) took place in a single residency program using a convenience sample ranging from 24\u201358 with an average of 34 residents.The most commonly encountered wellness intervention (5 of 8) was a formal, classroom-based initiative.21Included studies used a variety of previously published measures with existing validity evidence to assess the impact of wellness interventions . Two stu18A diverse array of interventions were described in our literature review. Overall, participant satisfaction rates for changes aimed at improving resident wellness were high across all of the studies included for analysis, regardless of the specific intervention employed. Although the specific assessment tools varied, none of the authors demonstrated statistically significant differences between rates of wellness and/or burnout before and after the intervention period. Lastly, none of the studies included in our final analysis received grant support or other funding.While EM as a specialty has responded with large-scale wellness initiatives, such as the American College of Emergency Physicians\u2019 Wellness Week and the formation of dedicated wellness committees within major national organizations, there is still a paucity of understanding about interventions employed for individual programs and learners. In our review of the literature since 2017, when the ACGME mandated that programs include wellness-specific programming, we found eight published studies that describe implementation of interventions designed to improve resident wellness in EM residency programs. The majority of studies describe small convenience samples of EM residents from single training programs and used the satisfaction rates of participants as primary outcome data. While the majority of outcomes are modest in size and limited in impact, these studies demonstrate encouraging pilot data to inform larger scale studies.Expert consensus supports the development of a more comprehensive model in order to effect positive change. One such model proposed by the National Academy of Medicine Model of Clinician Well-Being describes seven important factors: society and culture; rules and regulations; organizational factors; learning and practice environment; healthcare responsibilities; personal factors; and skills and abilities.Our review of the literature suggests a need for a more diverse field of interventions that aim to mitigate the risk of burnout and promote resident engagement. The current literature supports a comprehensive and longitudinal focus on physician well-being that begins in residency training and emphasizes environmental factors, more specifically the following: that programs create and employ interventions to promote well-being; enact systems to better recognize depression, stress and burnout among residents; and fortify trainees in building resilience. Supportive experiences and healthy coping skills learned during training produce resilient residents and pave the way for career longevity and professional satisfaction.High-quality published research studies of measurable outcomes with large samples of learners are needed to inform educators about which wellness interventions improve trainee outcomes. These studies are time and labor intensive, and would be supported and facilitated by dedicated grant funding for wellness research from national organizations and local entities. Our systematic review of wellness initiatives suggests that the next steps toward understanding how to meaningfully impact trainee wellness are to support multi-institutional studies, randomized controlled trials, and qualitative studies to further explore the phenomenon of wellness in medical education, and opportunities for funded research.The search window of articles published since January 1, 2017, is narrow and we may not have captured relevant wellness interventions published prior to that date. However, this date is significant as it marks the year when the ACGME Common Program Requirements began to mandate wellness initiatives for residency program accreditation. The goal of this literature review was to identify the highest quality published evidence and is not meant to be a comprehensive review of all interventions. We did not include a review of abstracts or the gray literature, such as conference proceedings, reports, or dissertations, as we wished to capture the best-studied and most effective interventions as reflected in peer-reviewed manuscript publication.The methodology described within this small pool of literature is limited; thus, we were unable to draw definitive conclusions regarding the overall effectiveness and generalizability of interventions. Although the Kirkpatrick model is widely accepted as a method of categorizing educational outcomes, the level of outcome that matters may vary depending on the study aim. For educational concepts where learner reactions and perceptions are the outcome of interest, Level 1 outcomes may be the \u201cbest\u201d outcomes to measure; thus, Kirkpatrick levels are not a definitive hierarchy of quality. The majority of studies described small convenience samples of EM residents from single training programs and used the satisfaction rates of participants as primary outcome data. Additionally, none of the studies we identified primarily used qualitative methods of assessment, which offer a richer understanding of resident experiences and can serve to guide the focus of quantitative studies.Despite the increased attention to EM resident wellness, there currently exists only a modest number of published studies describing wellness interventions for EM residents with variable outcome data primarily focused on participant satisfaction. This review of the literature reflects a need for scholarship of EM resident wellness to extend beyond the current focus on individual factors to an emphasis on environmental factors, and rigorous evaluations of outcomes-driven interventions."} +{"text": "In the absence of approved treatments to repair damage to the central nervous system, the role of neurosurgeons after spinal cord injury (SCI) often remains confined to spinal cord decompression and vertebral fracture stabilization. However, recent advances in bioelectronic medicine are changing this landscape. Multiple neuromodulation therapies that target circuits located in the brain, midbrain, or spinal cord have been able to improve motor and autonomic functions. The spectrum of implantable brain-computer interface technologies is also expanding at a fast pace, and all these neurotechnologies are being progressively embedded within rehabilitation programs in order to augment plasticity of spared circuits and residual projections with training. Here, we summarize the impending arrival of bioelectronic medicine in the field of SCI. We also discuss the new role of functional neurosurgeons in neurorestorative interventional medicine, a new discipline at the intersection of neurosurgery, neuro-engineering, and neurorehabilitation. A century of medical research and clinical practice has transformed the management of patients with spinal cord injury (SCI). The standards of good clinical practice for a traumatic SCI consist of stabilizing spine fractures, decompressing the spinal cord, and maintaining optimal hemodynamics to avoid hypotension and secondary spinal cord damage. As soon as possible, the patient is transferred to a specialized SCI center where expert clinical teams deploy intensive rehabilitation programs and educate patients in the management of their bladder, bowel, and general body condition.These surgical procedures, supportive measures, and rehabilitation programs have ameliorated neurological outcomes and decreased morbidity in patients with SCI simplified into two main functions: provide monoaminergic modulation and glutamatergic excitation. The interruption of descending pathways from the brainstem thus deprive spinal circuits from these essential sources of modulation and excitation. While executive centers residing in the spinal cord are intact, they fail to produce leg movements. This understanding triggered the development of neuromodulation therapies that seek to replace these missing sources of modulation and excitation to reactivate spinal circuits, and thus enable motor control.1A, 5HT2A/C and 5HT7 receptors subtypes\u2014for example with Quipazine and 8-OHDPAT over the lumbar spinal cord immediately reestablished intentional control over the activity of previously paralyzed leg muscles, even more than a decade after the occurrence of the SCI. Continuous EES also restored full weight-bearing standing and facilitated stepping of electrical spinal cord stimulation with anatomically realistic models of the main afferent and efferent circuits located in the spinal cord revealed that the electrical fields elicited by EES do not penetrate the spinal cord EES. Two patients with motor complete SCI but partially preserved sensory function followed intense locomotor training for more than 1 year. Both recovered the ability to walk overground with assistive devices during continuous EES .Deep brain stimulation (DBS) of basal ganglia nuclei is a well-established treatment for movement disorders such as Parkinson\u2019s disease, essential tremor, and inherited dystonias (Lozano and Lipsman The nucleus raphe magnus (NRM) has also been targeted with electrical stimulation in rodent models of SCI in order to augment the release of serotonin. Indeed, this region is the main source of serotonin to the spinal cord Fig. . PreviouActivity leads to the functional and anatomical reinforcement of the repeatedly activated neural connections applied over the human motor cortex augmented the transmission along descending neural pathways. This increase in conductivity improved motor functions and reduced spasticity (Tazoe and Perez The role of the functional neurosurgeon in SCI medicine is currently restricted to the occasional treatment of spasticity or chronic pain in the chronic stage of SCI. Acute treatments are usually performed by spine surgeons. The advent of bioelectronic technologies will transform the role of functional neurosurgeons in spinal pathology (Borton et al. SCI remains a challenging disease to treat. Despite having significant impacts on lives of patients across the world, years of research into improving neurologic outcomes after injury have yet to find a cure. Relatively recently, there has been a surge in bioelectronic technological developments including spatiotemporal epidural spinal stimulators, brain-spine interfaces, and deep brain stimulation paradigms for various locomotor diseases including SCI. With these developments, there have been clinical improvements in human SCI patients never seen before. The potential promise of these new technologies for SCI has significant implications for clinicians treating SCI patients, especially neurosurgeons. Traditionally, spinal surgeons have been at the forefront of generating guidelines for spinal trauma. However, the increasing involvement of functional neurosurgery in treating SCI will likely parallel the development of new technologies for improving function after SCI. As bioelectronic technologies continue to advance, close collaboration and dialogue between multiple professions including surgeons, neurologists, and engineers will be a necessity more than ever before."} +{"text": "Macular holes have attracted significant interest over the last few years due to the progress made in imaging and pharmacological and surgical therapies. The tractional interaction between foveal tissue and the vitreous has been extensively studied to identify vectorial forces, as well as the role of different cell subtypes in the pathogenesis and repair of retinal alterations . At the This special issue encompasses cutting-edge research and review articles focusing on new perspectives on macular hole diagnosis and therapy. It includes novel research articles and reviews describing new insights into different types of macular holes, new instrumental OCT imaging, histopathology evaluations, and therapy. The main topics of the included manuscripts are summarized below to better classify and underline each topic.idiopathic macular hole, it is demonstrated that the dynamic forces caused by mobile posterior cortical vitreous with fluid currents exist already at early stages of macular hole development. A macular hole with a diameter of less than 250\u2009\u03bcm may have more chance of closing spontaneously. In addition, these spontaneously closed macular holes possess some distinctive OCT characteristics. Metamorphopsia is significantly related to the deterioration of visual quality of life and can be used as an independent index to evaluate visual function before and after surgery. A systematic literature search was conducted to identify and review studies comparing SF6 to C3F8 gases as a tamponade agent in the intraoperative management of macular holes, with no evidence found to support C3F8 gas as the tamponade agent of choice for macular hole surgery. Finally, several clinical studies evaluated different approaches applying the inverted flap technique for recurrent and large idiopathic as well as myopic macular holes [In ar holes .lamellar macular hole, a clinical study which evaluated the two different subtypes of LMH found peculiar functional aspects due to their morphological features; tractional lamellar macular holes revealed higher visual acuity and retinal sensibility due to the relative preservation of the outer retinal layers compared to degenerative lamellar macular holes. Another clinical study demonstrated that an accurate diagnosis of full thickness macular hole, lamellar macular hole, and myopic macular hole is important to determine the most appropriate surgical treatment of these lesions. Different options may be selected according to the OCT and fundus autofluorescence imaging findings [In findings .traumatic macular hole, a review on its etiology and management discusses about the role of tangential and anteroposterior vitreomacular traction. This macular hole may also result from foveal photoreceptor atrophy following commotio retinae. Spontaneous closure can occur; however, vitrectomy combined to the induction of posterior vitreous detachment and inner limiting membrane (ILM) peeling (with or without an ILM flap to cover the macular hole) is associated with anatomic success rates of up to 100%. Another research paper evaluated the outcome of surgery with and without an ILM flap, underlining the benefits of the ILM flap technique.In myopic macular hole, an interesting review on surgical techniques underlines how myopic eyes still remain a challenge for vitreoretinal surgeons. Several and complex tractional mechanisms are implicated in the development of macular holes. The introduction of significant innovations for the treatment of myopic macular holes has allowed vitreoretinal surgeons to perform safe and effective surgery in these complicated eyes. Another research article on ILM peeling and inverted flap, which investigated the microstructural changes after successful myopic macular hole surgery, underlines that the inverted ILM flap technique did not affect the myopic macular hole healing processes compared to complete ILM removal [In removal . Thus, t removal , 9.the histology of epiretinal proliferative tissue, the authors investigated the morphological characteristics and cell composition of various types of surgically excised proliferative membranes and internal limiting membranes. Cell components such as myofibroblasts, macrophages, and polymorphonuclear cells were recognized as the expression of cell migration and differentiation that induced an inflammatory process and a fibroproliferative repair process. The detection of pigments in specific types of epiretinal membrane suggested that retinal pigment epithelium cells might have a role in the development of these vitreoretinal disorders.In a research article on new experimental approaches in autologous cell transplantation as a new therapy, the application of mesenchymal stem cells (MSC) described an adjuvant treatment for refractory and late-stage macular holes to be considered a promising direction. The combination of pars plana vitrectomy and MSC injections or MSC exosome application appears feasible, but the evidence regarding their safety needs to be expanded. Long-term clinical trials featuring control groups are still required in order to compare the efficacy of MSC applications with pars plana vitrectomy and other adjuvant techniques.In a review evaluating In summary, this special issue offers an overview of different types of macular holes, as well as providing new findings that may offer directions for new research in this important field."} +{"text": "Artificial intelligence (AI) is becoming more commonplace in all aspects of the developed world, where robots might help with tasks as diverse as hospital operations to defusing explosives and novel technologies may result in widely unknown and unpredictable risks. Researchers have already noted the lack of data about public health aspects of sex robot use and Francois Rabelais' obscene Gargantua and Pantagruel (1530-40) boosted the early printing press . No ANPRMs have been issued for sex toys. The unmet safety needs for sex toys may offer useful insight in navigating the complex landscape of risks represented within sex robots.In addition to enhancing conventional risks, internet-enabled sex toys and sex robots also pose new cybersecurity risks that cannot be fully addressed under existing regulatory processes for other products. Such risks including lax security measures that allow uninvited parties to collect and store usage information or videos, or the potential hacking of remotely operated sex toys Hern, . With thExisting regulations for sex toys fall under both the Consumer Product Safety Commission (CPSC) and the Food and Drug Administration (FDA). The CPSC oversees sex toy sales, but does not mandate or implement any labeling standards or testing, and the FDA has regulatory control over a small number of vibrators still archaically classified as obstetrical and gynecological medical devices. The remainder of sex toys, constituting the market's vast majority, are currently sold under the label \u201cfor novelty use only,\u201d which exempts them from regulation or mandatory safety testing. As Stabile documentMeanwhile, sexualized chatbots have already launched in several domains Ellis, . The staMore data are needed to characterize risks for sex robots and their AI capabilities, but government agencies must actively engage in gathering, analyzing, and acting upon the data. The drivers of the privacy shroud for sex-based technologies should be examined and in some cases challenged in order to forecast and responsibly manage future risks. AI innovation of sex robots may further expose people to the harms of sex toys while spurring the development of machine learning products. Regulators need to place this topic in the light and examine it with the same professional dispassionate objectivity that is granted to other consumer products.IL and CH formulated the problem statement for the paper, and SG gathered sources and conducted the research under guidance from CH, BT, and SG framed the argument, and SG drafted the paper, which was revised and finalized by CH, BT, and IL.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Cancer and its treatment can induce accelerated aging changes in physiological and behavioral processes. In studies of cancer associated cognitive decline, subjective reports of cognitive impairment are often many times greater than performance deficits on objective tests of neurocognitive functioning. In an Ecological Momentary Assessment study of 47 breast cancer patients (M age = 53.3 years), subjective ratings of cognitive performance and the occurrence of memory lapses assessed at the end of day were predicted by cognitive performance and ratings of fatigue and depressed mood throughout the day. Results indicated that poorer subjective cognition was significantly associated with elevated fatigue throughout the day. Slower processing speed, elevated ratings of fatigue, and depressed mood throughout the day were associated with a greater likelihood of memory lapses. Subjective ratings of cognitive deficits are related to objective performance, as well as common quality of life decrements among cancer survivors."} +{"text": "Research has consistently reported the association between intergenerational relationship quality and mental health outcomes in later life. However, few studies have examined the link among very old parents and their older children, and even fewer studies investigated whether the relationship quality matters similarly to parents and children. Employing a dyadic approach, this study examined how one\u2019s own and partner\u2019s perceptions of relationship quality are associated with depressive symptoms among very old parents and their children. Data from 105 dyads of parents and their children in South Korea were used. Results showed that parents tended to report significantly higher levels of intergenerational support and lower levels of intergenerational conflict, compared to their children. Regarding the actor effects of relationship quality, one\u2019s own perceptions of intergenerational conflict were positively associated with depressive symptoms for both parents and children , whereas intergenerational support was not significant. In terms of the partner effect, intergenerational support (reported by parents) was negatively related to depressive symptoms only for children , but the partner effect of conflict was not significant. The findings highlight the centrality of perceptions of intergenerational relationship in understanding well-being in later life. Further, children\u2019s depressive symptoms were susceptible to how their parents view the relationship. Findings were discussed in the context of Intergenerational Stake Theory."} +{"text": "Thailand is among few developing countries that have provided universal social pension for its older adults since 2009. Analyzing nationally-representative data from the Surveys of Older Persons in Thailand, we address the extent to which older Thais have benefited from the policy and describe the socio-demographic correlates of older persons who primarily rely on OAA as their main income source. Importantly, we examine how reliance on OAA may have implications for intergenerational exchanges between older parents and adult children as well as the well-being of older Thais. Results show significant changes over the last decade in the patterns of old-age income sources and filial economic support for older parents, particularly after the universalization of the OAA policy. We find the declining importance of children and rising significance of OAA as the primary income source. Older persons whose main income source was OAA were considered socially and economically vulnerable, although it was men rather than women who were more likely to depend on OAA as the main income source. Results further indicate that reliance of OAA as the main income source is not associated with a reduction in non-monetary familial support for aged parents. Nevertheless, we find that older parents whose main income was OAA were consistently less likely to report income adequacy and psychological well-being compared to others. This evidence suggests that while the OAA scheme may have tackled old-age poverty issues, it has little impact in dampening economic and social inequality among older Thais."} +{"text": "Persistent stress of external or internal origin accelerates aging, increases risk of aging related health disorders, and shortens lifespan. Stressors activate stress response genes, and their products collectively influence traits. The variability of stressors and responses to them contribute to trait heterogeneity, which may cause the failure of clinical trials for drug candidates. The objectives of this paper are: to address the heterogeneity issue; to evaluate collective interaction effects of genetic factors on Alzheimer\u2019s disease (AD) and longevity using HRS data; to identify differences and similarities in patterns of genetic interactions within two genders; and to compare AD related genetic interaction patterns in HRS and LOADFS data. To reach these objectives we: selected candidate genes from stress related pathways affecting AD/longevity; implemented logistic regression model with interaction term to evaluate effects of SNP-pairs on these traits for males and females; constructed the novel interaction polygenic risk scores for SNPs, which showed strong interaction potential, and evaluated effects of these scores on AD/longevity; and compared patterns of genetic interactions within the two genders and within two datasets. We found there were many genes involved in highly significant interactions that were the same and that were different within the two genders. The effects of interaction polygenic risk scores on AD were strong and highly statistically significant. These conclusions were confirmed in analyses of interaction effects on longevity trait using HRS data. Comparison of HRS to LOADFS data showed that many genes had strong interaction effects on AD in both data sets."} +{"text": "Combining health programs with microfinance is gaining more recognition as apathway for improving health and increasing access to health services amongthe poor, especially women living in low-income countries. Recentlypublished reviews have summarized the changes in health behaviors and healthoutcomes due to the effective layering of health interventions withmicrofinance initiatives. However, a large gap remains in defining andunderstanding the organizational strategies for implementing effectivehealth programs and services that improve the health and social well-beingof women and their families.As microfinance organizations and the global health community recognize thelargely untapped potential of developing effective multidimensional channelsof providing access to a variety of health interventions through amicrofinance platform, there is a need for more evidence to guideorganizational strategies that are feasible, sustainable and produceresults. We developed a framework and classification scheme for identifyingorganizational arrangements between microfinance and health, outlined thecriteria for article identification and selection, and reviewed originalarticles that included a discussion on organizational strategies publishedin peer-reviewed journals to better inform future research and effectiveprogram development.Our review found that most MFIs operate in cooperative and collaborativepartnerships for expanding health and social services with health educationas the leading intervention. The extreme ends of the integration-partnershipcontinuum, ie, no partnership on one end and complete merger on the other,are rare if they exist.The drivers of organizational strategy are related to the context, healthneeds of the clients, and individual capacities of MFIs to develop effectiveservices. However, approaches to establishing these processes anddecision-making for effectively structuring and delivering health andmicrofinance services is an inadequately explored area. Future progressdepends on bridging public health, microfinance, and organizational researchsilos to study how different organizational arrangements affectimplementation and outcomes. The expansive reach of microfinance to more than 200 million households globally throughmore than 3,000 MFIs \u201chealth\u201d that appeared anywhere inthe title or abstract were used in the advanced search features to identifyarticles. We limited our key search words to \u201cmicrofinance\u201d and\u201chealth\u201d attempting to include programs or interventions that werecomparable. Our focus was to review the published research containing strategiesthat have been rigorously evaluated and therefore providing evidence-basedrecommendations for organizing health programs in microfinance institutions. Weincluded studies that focused on access and delivery of different health programswith microfinance and explicitly described the intervention, were full-text articlesbased on original research and published in peer-reviewed journals. Studies thatfocused on health outcomes of microfinance as a stand-alone intervention or dealtwith microfinance as an intervention tool in existing health programs were excluded.Articles that explicitly described the institutional arrangements and processes ofproviding direct services or forms of linked health services and products throughmicrofinance organizations and partnerships were used in the final analysis for complete details of thesearticles.The individual articles included in our review are synthesized using a framework thatteases out organizational arrangements for delivery of the interventions to classifythem as \u2013 Integrated, or Partnerships. We present the articles along withtheir health themes and services, but the focus is on understanding theorganizational arrangement used for microfinance-health combined services. Ananalytical look at these organizational arrangements provides insights on the choiceof organization strategy used by the MFI based on their context \u2013 setting,client health needs, the scale of operations and financial sustainability. Thechallenges and enabling factors for the MFI-Health organization briefly mentioned inthe discussion section of some articles, provide valuable insights for deciding onthe appropriateness, feasibility, scalability, and replicability of the MFI-Healthinterventions in other settings. These challenges, as well as enabling factors, arediscussed separately after the findings section. We summarize the articles scheme to provide healthcare directly to their clients by establishing healthcenters along with paying for their coverage. The bank sold an annuallyrenewable prepaid insurance card to the poor, both members and non-member, ofthe MFI with the delivery of curative services at reduced medical consultationfees, discounts on drugs and test, hospitalization benefits, and free annualhealth checkup and immunization , was adapted for preparing thetraining curriculum had received health loans was integrated into loan meetings and delivered through aseparate training team. Microfinance services were implemented by the SmallEnterprise Foundation (SEF), Tzaneen, South Africa. The intervention alsoinvolved a phase of wider community mobilization through partnerships with localinstitutions along with the establishment of committees targeted at intimatepartner violence such as crime and rape. The intervention led to reductions inthe level of intimate partner violence and thereby the risk of HIV were integrated into MFI loan meetingsdelivered by field agents. The field staff was trained in collaboration withnational malaria control programs and health professionals. The MFI was linkedto distribution networks of ITNs and antimalarial providers to ensure access tothese products. The intervention led to the enhanced knowledge of malariaprevention and use of ITNs among pregnant women partnership model. SKS, an MFI in India,partnered with ICIC-Lombard, a private insurance company, to launch a bundledmandatory health insurance product along with microfinance loans. Clients hadthe option to seek care from various approved health facilities for cashlesstreatment or pay out-of-pocket at other facilities to be reimbursed later. Thepolicy only covered hospitalization and maternity expenses. The MFI was alsoinvolved in administering enrollment and initial processing of claims while theprivate insurance company provided back-end insurance. The uptake of theinsurance product was low due to low insurance demand in the community.Microfinance clients were even found to give up microfinance to avoid purchasinghealth insurance. Later the product was made voluntary but led to a breakdown ofthe partnership due to this unilateral decision by the MFI andcommitment to launch health interventions that impact outcomes (The practice of integrating health interventions and microfinance has progressedand many organizations have implemented such interventions. This review hasevaluated only published literature and therefore has two limitations \u2013publication bias and missing experiences of health-microfinance interventionsthat have not been published or exist as grey literature. We also had narrowinclusion criteria and therefore may have missed some studies. However, weintended to review only rigorously evaluated interventions to identifyevidence-based strategies and therefore accepted these biases. As the focus ofpublished studies was on the outcome and not organizational arrangements, manydetails are lacking in the structure, conditions, and governance that specifieshow the organizational arrangements were developed and operationalized. Someauthors do not provide sufficient evidence to distinguish between differenttypes of organizational arrangements, so it was sometimes difficult to separatestudies into our structured categories especially as boundaries were not clearon the partnership continuum.This review identified the importance of multi-sectoral partnerships as anorganizational strategy to build effective linkages of MFIs with the health sector.Coordination and collaboration partnerships are central to the delivery of servicesand have also been frequently cited as critical strategies for enhancing theeffectiveness of health and human service systems (Given the increasing demands of multi-organizational partnerships to address complexproblems, resources must be allocated to develop shared partnership processes andnurture partnership relations (Despite calls for more robust evaluation frameworks with methodological innovations("} +{"text": "Management of any disaster event is a complicated task. An important and frequently overlooked aspect of efficient disaster response is effective information exchange among emergency managers, aging and social service providers, and those impacted by the disaster. Breakdowns in communication are regularly cited as failures in actual emergency situations. Older adults have unique challenges to effective communication during a disaster event. Further, messaging platforms may be inaccessible to older adults. Given the lack of data collected on the role of effective communication for older adults in a disaster event, we developed this symposium to highlight lessons learned for facilitating disaster communication among older community members and discuss how policy can further disaster communication efforts. The first presentation highlights the advantages of using targeted marketing communication channels to encourage older adults to prepare and recover from a disaster, as well as the value of collaborative partnerships in this communication. The second presentation introduces results from research collected from older adults on their use of social media to stay informed before and after Hurricane Matthew. The third presentation explores whether assisted living communities in Florida\u2019s affected counties evacuated or sheltered in place in the context of emergency management communications concerning evacuation. The fourth presentation highlights the experiences of older persons in Houston\u2019s communication post-Hurricane Harvey from an aging service provider\u2019s perspective. The final presentation discusses disaster literacy and how this model can be used to enhance outcomes at all phases of a disaster. Disasters and Older Adults Interest Group Sponsored Symposium."} +{"text": "INTERpersonal synchrony leads to increased empathy, rapport and understanding, enabling successful human-human interactions and reciprocal bonding. Research shows that individuals with Autism Spectrum Disorder (ASD) exhibit difficulties to INTERpersonally synchronize but underlying causes are yet unknown. In order to successfully synchronize with others, INTRApersonal synchronization of communicative signals appears to be a necessary prerequisite. We understand INTRApersonal synchrony as an implicit factor of INTERpersonal synchrony and therefore hypothesize that atypicalities of INTRApersonal synchrony may add to INTERpersonal synchrony problems in ASD and their interaction partners. In this perspective article, we first review evidence for INTERpersonal dissynchrony in ASD, with respect to different approaches and assessment methods. Second, we draft a theoretical conceptualization of INTRApersonal dissynchrony in ASD based on a temporal model of human interaction. We will outline literature indicating INTRApersonal dissynchrony in ASD, therefore highlighting findings of atypical timing functions and findings from clinical and behavioral studies that indicate peculiar motion patterns and communicative signal production in ASD. Third, we hypothesize that findings from these domains suggest an assessment and investigation of temporal parameters of social behavior in individuals with ASD. We will further propose specific goals of empirical approaches on INTRApersonal dissynchrony. Finally we present implications of research on INTRApersonal timing in ASD for diagnostic and therapeutic purposes, what in our opinion warrants the increase of research efforts in this domain. Terms such as interactional synchrony, non-verbal mirroring, shared rhythmicity, motor mimicry or chameleon effect embrace the underlying dimension of coordination between two or more individuals in the domain of nonverbal action\u201d control participants as a standard diagnostoc tool targets the coordination of communication channels as a symptom of ASD in terms of relational signal onsets, durations and end points. Thereby one may gain insights into the temporal composition of individual signal streams. On the background of findings of enhanced motor variability with children with ASD revealed positive effects, as robots attract attention and elicit novel behavior while social complexity can be controlled for . Socially interactive robots generally need to be able to recognize communicative signals and exhibit appropriate reactions (Breazeal et al., There exist a number of aspects that need to be considered when planning approaches on INTRApersonal dissycnhrony in ASD. One potentially confounding factor when measuring INTRApersonal synchrony lies in the distinction between spontaneously and voluntarily produced behavior, as different cognitive processes are thought to underlie these processes (Frith and Frith, Further research should broaden this approach to other psychiatric disorders that entail INTRApersonal coordination peculiarities like schizophrenia (Walther et al., In accordance with theoretical discussions with CF-W and KV, CB wrote the first manuscript version. AG contributed literature and theoretical ideas. All authors read and modified the manuscript several times. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Insisting people are equally worthy of aging in place is a radical but challenging idea. Scenes of homelessness texture the contemporary city, manifesting broader issues of inequality. This qualitative study explored material with twenty-two housed and unhoused San Franciscans born in 1950 or earlier, who participated in semi-structured in-depth interviews and chronicled their everyday lives using disposable cameras. Theoretical work on social and spatial practices was drawn upon to help understand their aging in place experiences. In interpreting themes, informants elucidated a moving tension between the daily interiority of identity and the negotiation of a changing environment that produces a sensation characterized as the uncanny. The vicissitudes of life and precariousness of their positionalities exposed tactics for \u201cpassing\u201d as creative forms of resistance to their expulsion from society. Utilizing visual methods helped reveal assumptions and contributed to gerontological discourse and critical theorizations about aging in place inequalities. Part of a symposium sponsored by the Qualitative Research Interest Group."} +{"text": "By graduation most high school students have negative feelings about aging, the idea of working with older people is unappealing, and few choose to study aging. When non-traditional students of any age enroll after gaining experience in the workforce, they experience ageism and may not persist to degree completion. The value of Ageism First Aid (AFA) as an internal and external AFU tool is supported by Bronfenbrenner\u2019s Ecological Theory and Rogers\u2019 Diffusion of Innovation theory. AFA utilization during high school can increase traditionally-aged student enrollments. Its use for professional development on campuses can improve the campus climate for all constituents and ensure graduates will know how to avoid contributing to aging stigma. AFA use by providers of aging services and support can reduce the aging stigma older people experience. Attendees will receive handouts with a variety of dissemination models and information on how to gain institutional access to AFA. Part of a symposium sponsored by Age-Friendly University (AFU) Interest Group."} +{"text": "An early, problematic symptom of aging, exacerbated by cognitive problems such as Alzheimer\u2019s disease, is difficulty finding one\u2019s way. Long term care (LTC) communities are especially challenging for wayfinding. This study compares three different tools to evaluate spatial complexity within eight LTC communities. The tools included computation of space syntax integration values using axial lines to determine how connected wayfinding routes are within the community. The Wayfinding Checklist tool (revised) rates the quality of signage, complexity of a building floor plan, and use of decorative elements. The Calkins Route Assessment tool evaluates route complexity using both plan and vertical visual field information . The results of the analysis showed that the buildings varied with respect to integration, with some very well integrated floorplans and routes, and some that were very complex, with multiple jogs, turns, and limited integration. The Wayfinding Checklist echoed the variety of complexity of floorplans, but lowered scores for poor existence and design of signage and mostly substandard lighting for visibility. The Calkins Route Assessment tool added greater specificity to the space syntax analysis and Wayfinding Checklist, showing how visual elements can compensate for plans with low-integration. These study findings indicate that each tool was valuable for measuring wayfinding complexity, but measured different aspects of building and route complexity. Tools like these can be used to identify challenging wayfinding routes and buildings so that designers and clinicians can improve the overall design for wayfinding."} +{"text": "Plasmodium vertebrate life cycle stages to investigate antimalarials mode of actions and underlying complex host-parasite interactions. Also, we discuss current limitations as well as make several practical suggestions for methodological improvements which could drive metabolomics progress for malaria from a comprehensive perspective.Advances in research over the past few decades have greatly improved metabolomics-based approaches in studying parasite biology and disease etiology. This improves the investigation of varied metabolic requirements during life stages or when following transmission to their hosts, and fulfills the demand for improved diagnostics and precise therapeutics. Therefore, this review highlights the progress of metabolomics in malaria research, including metabolic mapping of Excellent reproducibility alone with non-destructive property for NMR allows all kinds of sample analysis in a short period, making it an ideal candidate in large-scale metabolomics screening. With the growing demand for capturing low-abundance metabolites to meet the requirement of obtaining metabolic patterns as detailed as possible, the MS platform coupled with chromatography could be another powerful and complementary platform for simultaneous analysis of hundreds of compounds in complex biosamples with sufficient resolution, sensitivity, and reproducibility. Until now, the development trend of analytical platforms still mainly focuses on acquiring more metabolic information in a minimized sample, developing high throughput approaches with improved qualitative and quantitative accuracy.Analytical Scope\u2022Untargeted metabolomicsAs a hypothesis generating strategy, it mainly focuses on the global assessment of a broad range of both known and unknown compounds to offer either comprehensive or unbiased approaches to investigate unanticipated perturbations. Using this unbiased strategy, changes of metabolic profiles subjected to different conditions can be revealed, leading to the identification of novel metabolites or metabolic pathways. Then subsequent analysis can be performed to structural or functional characterization of these candidates.\u2022Targeted metabolomicsAs a hypothesis driven strategy, it mainly emphasizes the detection of clearly defined compounds which holds the advantages in obtaining a comprehensive understanding of the kinetic profile in specific pathways.\u2022Functional metabolomicsin vitro and in vivo assays including cell biology and clinical platform. It is able to increase the reliability for metabolomics study and contributes novel knowledge about previous findings.Functional metabolomics, as one kind of emerging concept, spans from the discovery of differential metabolites to investigate the actual function of specific compounds. Based on untargeted and/or targeted approaches, it further characterizes the functional role of selected metabolites as well as the enzymes in related pathways through both Plasmodium-infected erythrocytes. Analysis of metabolic profiles for both intracellular and extracellular metabolomes from different life stages is capable of reflecting the perturbations of specific pathways during culture. As clarified, after infection, the parasite will massively convert host metabolome into essential molecules to maintain survival during the erythrocytic asexual stage, leading to the excretion of products of erythrocyte lysis and parasite metabolism. Actually, this could have a significant effect on the host response, including events at the cellular or molecular level occurring in both host and parasites displayed distinct metabolic patterns, confirming the feasibility for acquiring unique metabolic perturbation rather than non-specific variance. For example, as a cytochrome bc1 complex inhibitor, disrupted de novo pyrimidine synthesis resulted from mitochondrial membrane potential loss has been confirmed by targeting the detection of carbamoyl-L-aspartate and dihydroorotate, the precursor and substrate of affected dihydroorotate dehydrogenase . For example, neither rare homogeneity during Plasmodium research is to be integrated with traditional system biology strategies routinely used in parasitological studies. More system biology approaches will be generate growing interest from genomics, transcriptomics, proteomics, and metabolomics. These combinatorial strategies will allow for better understanding of the biological events from a more global perspective, yielding a detailed view of its intricate networks. Such approaches can undoubtedly inform many aspects of malaria research including, but not limited to, building basic parasite biological models, development of therapeutics, identification of diagnostic biomarkers, and establishment of human pathophysiology models.One current trend toward standardization of varied metabolomics workflows is a practical way to make the technology and the data more accessible. We believe the future of metabolomics in QZ and JC were responsible for providing the idea and framework of the whole work. XY wrote the first draft of the manuscript. GF did critical revision of the article. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "These studies could help us understand the interplay between homeostatic regulation of energy and taste perception to guide proper feeding behaviors.Feeding is essential for survival and taste greatly influences our feeding behaviors. Palatable tastes such as sweet trigger feeding as a symbol of a calorie-rich diet containing sugar or proteins, while unpalatable tastes such as bitter terminate further consumption as a warning against ingestion of harmful substances. Therefore, taste is considered a criterion to distinguish whether food is edible. However, perception of taste is also modulated by physiological changes associated with internal states such as hunger or satiety. Empirically, during hunger state, humans find ordinary food more attractive and feel less aversion to food they usually dislike. Although functional magnetic resonance imaging studies performed in primates and in humans have indicated that some brain areas show state-dependent response to tastes, the mechanisms of how the brain senses tastes during different internal states are poorly understood. Recently, using newly developed molecular and genetic tools as well as Food intake is essential for survival and the neural processes mediating hunger information guide animals to initiate appetitive food seeking and subsequent consummatory feeding. Taste is important for animals to evaluate the value of food or electrophysiology studies have discovered brain areas including the OFC, the amygdala, the InsCtx, and the lateral hypothalamus (LH) that respond to taste cues in a hunger/satiety-dependent manner. Neuroimaging research in humans has shown that sated participants reported attenuated subjective pleasantness of a specific taste, suggesting that satiety has a negative effect on the taste perception motivational and anticipatory process before the start of feeding (appetitive behavior), (2) taste perception and execution of feeding (consummatory behavior), and (3) termination of feeding . In receHunger promotes motivation for appetitive behaviors to seek food and evokes feeding behaviors to trigger feeding behaviors.LH neurons preferentially encode aspects of appetitive or consummatory behaviors contribute to the modulation of appetitive and aversive taste, respectively. The LS and the LHb are parts of mesolimbic reward system, indicating that the LH may modulate the reward value of the taste (LH neurons that encode satiety serve as a brake to terminate consummatory behavior during hunger state (Stamatakis et al., LH neurons could promote consummatory behavior to meet the emergent caloric need.An electrophysiological study (Li et al., he taste . While VNotably, the OFC is connected both directly and indirectly with the LH (\u00d6ng\u00fcr and Price, Feeding behaviors are regulated by homeostatic and hedonic feeding systems. Taste perception from the brainstem to the gustatory cortex serves as a regulator and driving factor for feeding by interacting with the hypothalamus and with the mesolimbic reward system. The brain integrates sensory information and interoception to guide proper feeding behaviors for survival. Understanding the mechanism by which the brain senses taste and reward modalities in different physiological states may be beneficial in therapeutic treatment of overeating in the future.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Oryza glaberrima Steud) is one of the two independently domesticated rice species, the other one being Asian rice (Oryza sativa L.). Despite major progress being made in understanding the evolutionary and domestication history of African rice, key outstanding issues remain controversial. There appears to be an underlying difficulty in identifying the domestication centre and number of times the crop has been domesticated. Advances in genomics have provided unprecedented opportunities for understanding the genetic architecture of domestication related traits. For most of the domestication traits, the underlying genes and mutations have been identified. Comparative analysis of domestication genes between Asian and African rice has revealed that the two species went through an independent but convergent evolution process. The genetic and developmental basis of some of the domestic traits are conserved not only between Asian and African rice but also with other domesticated crop species. Analysis of genome data and its interpretation is emerging as a major challenge facing studies of domestication in African rice as key studies continue giving contradictory findings and conclusions. Insights obtained on the domestication of this species are vital for guiding crop improvement efforts.African rice ( Plant domestication is a key evolutionary event where humans modify plant characteristics genetically by selecting for some preferred and favourable traits. Domestication has had a huge impact on food and nutrition security as it involves changes in important traits affecting productivity, adaptability and diverse quality aspects. Knowledge of the domestication process is important for guiding crop improvement efforts mapping and linkage analysis have played pivotal roles in studying genetic mechanisms underlying domestication traits. In African rice, these studies are being aided by the availability of extensive genetic resources conserved in genebanks , a zinc-finger transcription factor gene which was found to be under strong positive selection. As will be highlighted here, in addition to PROG7, there could be additional genetic factors controlling plant architecture in African rice.Plant architecture was a key target during the domestication process, with the main change being transition from prostrate to erect growth. The main differences between the two phenotypes is in the number of tillers and tiller angle, both of which significantly affect other agronomic traits. Through its potential role in enhancing photosynthetic efficiency and increasing planting density, this transition had a major impact on plant productivity, with the erect growth being associated with higher grain yields than prostrate growth which has been shown to have foot prints of strong positive selection locus on chromosome 7 which contains a tandem repeat of zinc genes some of which have been shown to control plant architecture. A selective sweep spanning both PROG 1 and the deletion in both cultivated species suggests that both were targets of human selection.In Asian rice, the key gene responsible for plant architecture is O. barthii, its putative progenitor grains over the red (pigmented) ones found in wild rice and RAE2 . RAE1 was found to be identical to An-1 which had been reported earlier as being responsible for regulating awn formation, grain size and grain number gene locus has been found to control plant architecture in both species from its presumed progenitor, green foxtail (S. viridis) (Wu et al. There has recently been growing evidence of phenotypic convergence of the same traits across different crop lineages (Pickersgill Oryza genome species and the South American AA species O. glumaepatula (Stein et al. Most of the genetic resources that are found in ex situ and in situ conservation were collected in areas that have been disturbed through human activity and may have lost their original genetic makeup. Significant introgressions has for example been reported between African AA O. barthii populations and possible genetic drift in remaining populations (Cubry et al., The coincidence of African rice domestication with the southward expansion of the Sahara desert may have led to loss of important The analytical tools used in studying domestication especially at the genome scale and the interpretation thereof may present significant challenges in accurately inferring the evolutionary and demographic history of cultivated species. Despite great advances in DNA sequencing and increased availability of whole genome data, analysis and interpretation of this data still remains a complicated and non-trivial exercise. Various technical and methodological challenges are now emerging particularly when dealing with large data sets (Cubry and Vigouroux O. barthii, Veltman et al. (After analyzing a total of 206 whole genome sequences of African rice and n et al. did not n et al. have foun et al. is that n et al. identifin et al. . It therIt is expected that advances in genomics will continue reshaping our understanding of domestication. Epigenetics, archaeogenetics and genome editing are novel approaches that have potential for great application in domestication research (Schreiber et al."} +{"text": "Transitions of care involve multifaceted considerations for patients, which can pose significant challenges if factors like oral health are overlooked when evaluating medication management. This article examines how oral health factors should be considered in medication management of patients who may be at risk for hospital readmission. This article also explores successes and challenges of a pharmacy consult service integrated into a dental clinic practice, and the opportunities within that setting to improve overall patient outcomes including those related to care transitions. Transitions of care can be challenging times for patients in ensuring they are well-informed and practicing health behaviors to prevent hospital readmissions. Access to follow-up care after hospitalization can be equally challenging to obtain and fraught with barriers. Approximately 17% of adults in the United States do not have a usual source of health care, including a primary care provider (PCP), and these statistics are less among racial and ethnic minorities ,3,4. TheChronic diseases such as cardiovascular disease, chronic obstructive pulmonary disease (COPD), and diabetes have been associated to both leading causes for hospital readmission and oral health-related complications ,10,11,12Specifically, in cardiovascular disease, the association between atherosclerosis and periodontal infection exists ,13. SystIn regards to pulmonary diseases, like COPD, cytokines produced by periodontal inflammation can penetrate into the systemic circulation and can increase inflammatory burden in the lungs, worsening COPD ,13. FurtWhat may be best defined and studied to date is the bidirectional relationship between diabetes and periodontal disease . HyperglTherefore, in consideration of the associations described, great attention should be given to the medications used to treat not only these chronic conditions but review of medications that increase risk of dental caries and oral disease. Xerostomia is a common adverse effect of numerous medications that leads to impact on saliva production, changes in oral microbiome, and serves as a risk factor for caries and periodontal disease . The micIt cannot be discounted that medication management for chronic conditions related to hospital readmissions can also be challenging for these populations due to access, affordability, lack of education, and lack of follow-up. Medication-related problems occur at a higher rate during care transitions . These fThe University of North Carolina (UNC) Adams School of Dentistry (ASOD) has sought to better address these barriers within its practice clinics through clinical partnerships with the UNC Eshelman School of Pharmacy (ESOP) to offer clinical pharmacy services as it has identified patients in North Carolina who come from 74 out of the 100 counties that are dental provider shortage areas, and 59 of these counties are primary care and behavioral health shortage areas as well . PharmacPlacement of a clinical pharmacist in the dental practice clinics at UNC ASOD originated out of a dental student research project that focused on diabetes care of patients coming to the dental school for treatment. The intent of the project was to provide more wholistic education to the patients about diabetes given the link to periodontal disease as described. In usual care, the dental students provided cleanings, procedures, and counseling on appropriate oral hygiene in between appointments such as use of proper brushing and flossing technique, interdental cleaning aids, and oral irrigators ,32,33. TSupport from ESOP and ASOD in 2016 led to creation of a clinical pharmacist faculty position to provide more in-depth consultation services to help bring awareness to gaps stated above. As services expanded, consult services were conducted by three pharmacists and additional Doctor of Pharmacy students that included reviewing patient medication histories and profiles, providing medication and disease state education, documenting on medications impacting oral health, counseling on prevention and treatment of medication-related oral manifestations, and answering medication-related inquiries.A pharmacy consultation guidance document was also created to help dental providers and students recognize when a pharmacist should be consulted and included six types. In describing the six types, it is important to note that consultations primarily occurred in conjunction with dental appointments. Patients received their dental care and education on preventative oral hygiene practice from the dental team as described above, while pharmacy consultations were integrated based on consult type. Consult type one involved a full medication history verification and reconciliation by a pharmacist and pharmacy student. Generally, this was for patients on complex regimens who were coming for initial diagnosis and treatment planning dental appointments. Consults for patients who could not recall what medications they were taking were also requested through this category. The patient\u2019s dispensing pharmacy was identified and contacted to verify their regimen and clarify missing or incorrect doses. Additionally, medication regimens were evaluated for oral health implications, including but not limited to medications causing xerostomia that increases caries risk and medications that increase bleeding risk for invasive procedures. Patient and provider education was provided at point of consult and documented in the electronic health record. Consult type two involved in-depth assessment of high risk medications including anticoagulants and insulin. Indications and last doses taken of anticoagulants were confirmed to ensure safety of procedures prior to oral surgery.Consult type three consisted of evaluation of patients with chronic conditions of hypertension, diabetes, asthma, COPD, and/or smoking to determine overall disease control and safety for procedures. Opportunities to educate on lifestyle management to help in prevention and maintenance were also provided.Consult type four consisted of evaluation of patients with other significant conditions or medications that directly impact oral health including bisphosphonate use, gastroesophageal reflux disease (GERD), antimicrobials, antipsychotics, antineoplastic medications, and history of radiation. Education on administration and adverse side effects were primarily provided to help promote understanding and reduce risk of oral health complications. Consult type five involved providing patient education for any new medications prescribed within the scope of the dental care. This primarily included discussion of antibiotics, antifungals, analgesics, anesthetics, saliva modifiers, and anxiolytics with dental providers and students. Thorough review of a patient\u2019s existing medication list was conducted to identify potential drug-drug interactions and adverse effects. Medication education was offered to patients prior to end of appointment to provide overview of dosing instructions and adverse side effects. Consult type six involved responding to any specific drug information questions related to medications requested by dental providers or students or voiced by a patient directly. Verbal or written responses were provided and documented in the electronic health record.The clinical pharmacy consultation service continues to expand and evolve, and there have been many successful endeavors and teaching opportunities to overall improve patient care and understanding of links between oral health and systemic health. The initial pilot of pharmacy consult services included collecting dental student perspectives on roles of pharmacy personnel in dental care and interprofessional communication. Focus groups with students also highlighted an increase in integration of clinical discussion of medications and complex cases within the didactic curriculum.Involvement of pharmacy students has also expanded. Additional toolkits were developed to help with flow of the consult process within the clinic space for pharmacy students rotating through the clinical environment as part of their experiential curriculum. A sit-down rounds model with pharmacy and dental students was also implemented to provide clinical teaching and deeper discussion of patients with complex medication regimens. Increased focus on opioid prescribing in dental pain management and antimicrobial stewardship have also garnered more significant attention within the clinical settings to address optimizing current and future prescribing behaviors.Incorporation of a clinical pharmacist faculty position within the dental school faculty has also served as a framework for other health disciplines to integrate into the dental practice clinics including a social worker and nurse practitioner to provide enhanced team-based patient care.While there has been significant success in integration of a pharmacy team within the dental practice clinics, challenges still exist to further optimize patient care. Electronic health records (EHRs) are not linked to many primary care or health care centers. Progress is being made in implementing a broadly accepted EHR system within the dental school that is linked to the larger health system nearby. This still poses challenges for patients who travel from rural communities or far distances and do not have PCPs or routine medical care. Many patients without dental insurance coverage are also older adults with more complex health histories. The dental practice clinics serve as an entry point to the health care system, and strides are being made to better connect those patient populations with health care access back in their local communities. While oral health has been historically siloed from overall medical care, due to the links between chronic conditions and oral diseases, increased focus and attention should be made to incorporate oral health assessment, especially in patients recently discharged from hospitalizations or transitioning between other care environments like long-term and skilled nursing care facilities. Patients with poor oral health may be in jeopardy of increased risk of hospital readmission. Better coordination of care between these environments is crucial. Future expansion of services to include not only pharmacy but social work and advanced practice nursing will aid in this endeavor."} +{"text": "Millions of older adults are admitted to an intensive care unit (ICU) every year. Many of these patients have preexisting impairment in hearing or vision, but sensory impairment is rarely addressed in the ICU. This talk will present recent work evaluating the association of sensory impairment with functional outcomes among older ICU patients, and discuss barriers to and potential strategies for addressing sensory impairment in the ICU."} +{"text": "The transition between healthcare settings is a complex process presenting challenges for effective and consistent communication between older adults, their caregivers, and healthcare providers. These challenges often result in adverse health events and re-hospitalizations. Further, once transitioned to home, older adults often need ongoing care management and support and evidence for models remains unclear as to the precise parameters of supports needed for comprehensive care. This symposium will provide an overview of the evidence for both interdisciplinary care management models and transitional care programs, present the implementation of a care management program for low income older adults at one social service agency, and provide evidence-based tools for older adult functional assessment and decision-making for transitional care. The speakers will present new tools from the American Physical Therapy Association home health toolbox that promote patient-centered health care decision-making to facilitate successful transitions that reduce resource use and hospital readmission. The speakers will also discuss the implementation of a care management program for older adults in a care gap . An implementation framework for the needs assessment will be highlighted and 1-year program outcomes will be presented. Attendees will learn strategies for interprofessional collaboration, enhanced communication, and advocacy within the interprofessional team to facilitate improved care management and transitional services for older adults."} +{"text": "The field of tissue engineering and regeneration constantly explores the possibility of utilizing various biomaterials\u2019 properties to achieve effective and uneventful tissue repairs. Polyrotaxanes (PRXs) are supramolecular assemblies, which possess interesting mechanical property at a molecular scale termed as molecular mobility. This molecular mobility could be utilized to stimulate various cellular mechanosignaling elements, thereby altering the cellular functions. Apart from this, the versatile nature of PRXs such as the ability to form complex with growth factors and peptides, numerous sites for chemical modifications, and processability into different forms makes them interesting candidates for applications towards tissue engineering. This literature briefly reviews the concepts of PRXs and molecular mobility, the versatile nature of PRXs, and its emerging utility towards certain tissue engineering applications. The search and designing of new biomaterials that can impart unique bio-interface functions and cellular modulations are never ending , 2. It hPolyrotaxanes are molecular assemblies resembling a beaded-chain but at molecular scales , 17 (PIPAAm) polymeric networks, thereby yielding a thermoresponsive and extremely stretchable hydrogel, which could be used for muscle tissue engineering [PRXs can be processed into scaffolds with controllable pore sizes. This helps to widen the utility for tissue engineering applications. PEG hydrogel scaffolds were produced by crosslinking hydrolyzable PRXs and also with cholesterol functionalized PRXs which were explored for cartilage regenerative applications. Hydrolyzable PRX-scaffolds containing hydroxyapatite particles were also synthesized and were suggested to exhibit promising outcomes for bone tissue engineering. PRXs can be utilized as crosslinkers for the poly. Culturing iPSCs on PRXs with high mobility lead to the higher expression of Rac1 and N-cadherin expression indicating the strong cell-cell interactions when compared to cells cultured on gelatin-coated surfaces. The number of beating colonies indicating the successful cardiomyogenic commitment was higher on the high mobile PRX surface. Furthermore, the cardiomyocyte genes such as \u03b1-MHC, TnT2, and HCN4 were highly expressed in iPSCs cultured on high mobile PRXs confirming that PRX surface with high mobility could be effectively utilized to induce cardiomyocyte commitment from iPSCs .Nanog and Oct4. Further, when these MSCs were collected and replated onto regular tissue culture polystyrene plates, only the cells grown on high mobile S-PRX surfaces with bFGF were able to differentiate into osteoblasts.Recently, it was reported that molecular mobility of PRXs could alter the stemness and differentiation capability of bone marrow-derived MSCs even during a short culture span . It was Biomaterials for bone tissue engineering and enhancing osteogenic differentiation are of great importance as bone is the most widely transplanted tissue next to blood transfusions . AlthougCartilage regenerative therapies mainly focus on finding suitable biomaterial scaffolds to support the growth of chondrocytes and aid the secretion of extracellular matrix proteins in a spatiotemporally controlled pattern for matching the native healthy tissue as close as possible . Lee et Cellular adhesion is one of the most important requirements for biomaterial interfaces in the tissue engineering approach. It has been found that the molecular mobility of PRXs could be used to alter the cellular adhesion patterns. Generally, PRXs with low mobility tend to enhance the cellular adhesion and spreading of adherent cells such as fibroblasts, MC3T3-E1, and MSCs . This coFormation of microvascular networks in implanted biomaterials is one of the key events for a successful tissue regeneration, as these microvessels are necessary for the efficient transport of cells, nutrients, and removal of the wastes . It was The effect of molecular mobility of S-PRXs on hepatocyte functions has also been explored by using HepG2 cells . HeparinThe molecular mobility of polyrotaxane surfaces also affected collagen fibrillogenesis. Although the extent of molecular mobility was independent of the absorbing amount of collagen, higher mobility of polyrotaxane surfaces preferentially induced rearrangement of adsorbed collagen and caused collagen fibrillogenesis. When PRX-coated substrates were implanted subcutaneously in rats, it was observed that the recruitment of macrophages at the implant site was suppressed by polyrotaxane surfaces with higher mobility. These results suggest that the molecular mobility of polyrotaxane helps suppress inflammation and promote regeneration in vivo .As briefly reviewed above, we could see that PRXs are a novel class of supramolecular assemblies which exhibit mechanical movements at a molecular scale. It has also been shown that these mechanical signals from the molecular mobility of PRXs could be harnessed and utilized for modulating various mechanosignaling pathways and thereby driving specific gene expressions Table . One of"} +{"text": "Choral singing is a novel approach to reduce dementia stigma and social isolation while offering participants a sense of purpose, joy and social connection. The pervasiveness of stigma surrounding dementia remains one of the biggest barriers to living life with dignity following a diagnosis . This paper examines how a social inclusion model of dementia care involving an intergenerational choir for people living with dementia, their care partners and high school students can reduce stigma and foster social connections. Multiple methodologies are used to investigate the effects of choir participation on cognition, stress levels, social connections, stigma, and quality of life. Results demonstrate the positive impact of choir participation and indicate that this socially inclusive intervention offers an effective, non-pharmacological alternative for older adults living with dementia in the community. Discussion focuses on the importance of instituting meaningful and engaging dementia-friendly activities at the community level."} +{"text": "Antibiotic stewardship aims to tackle the global problem of drug-resistant infections by promoting the responsible use of antibiotics. Most antibiotics are prescribed in primary care and widespread overprescribing has been reported, including 80% in dentistry. This review aimed to identify outcomes measured in studies evaluating antibiotic stewardship across primary healthcare. An umbrella review was undertaken across medicine and a systematic review in dentistry. Systematic searches of Ovid Medline, Ovid Embase and Web of Science were undertaken. Two authors independently selected and quality assessed the included studies . Metrics used to evaluate antibiotic stewardship programmes and interventions were extracted and categorized. Comparisons between medical and dental settings were made. Searches identified 2355 medical and 2704 dental studies. After screening and quality assessment, ten and five studies, respectively, were included. Three outcomes were identified across both medical and dental studies: All focused on antibiotic usage. Four more outcomes were found only in medical studies: these measured patient outcomes, such as adverse effects. To evaluate antibiotic stewardship programmes and interventions across primary healthcare settings, measures of antibiotic use and patient outcomes are recommended. Antimicrobial resistance is a serious global public health problem responsible for increased healthcare costs and poorer clinical outcomes . The WorWhile antimicrobials include antibiotic, antiviral and antifungal medicines, most antibiotic prescribing occurs in primary healthcare ,6, with Antibiotic stewardship programmes (ASPs) in primary care are essential to try to curb antibacterial resistance . AntibioThis review aimed to identify a suite of outcome measures used in published studies to evaluate ASPs and interventions across primary care medicine and dentistry. An umbrella review (systematic review of systematic reviews) was used to identify outcome measures from the numerous studies across primary care medicine and a systematic review was used to determine the metrics from dentistry, where fewer studies have been published . CompariThe protocol for this two-part systematic review was registered in PROSPERO . Both reIn May 2020, three databases were searched from their earliest dates: Ovid Embase, Ovid Medline and Web of Science. The search strategies and terms were developed in consultation with an information specialist at the University of Melbourne. The search terms and strategy for both reviews are shown in Research studies published in peer-reviewed journals were included if they reported measurement of ASP or interventions to optimise antibiotic use in non-specialist primary medical or dental care. Studies related to specialist care delivered in primary care settings and/or primary care services delivered in hospital settings were excluded. Studies which did not include antibiotic prescribing were also excluded.After performing the search using each database, the titles and abstracts were extracted into Endnote X9 and duplicates were removed. Separate Endnote libraries were created for the umbrella review and the systematic review. Two authors (LT and WT) screened all titles and abstracts independently for potential inclusion. Full text of all the shortlisted studies were assessed independently for eligibility by LT and WT. Discrepancies were resolved through discussion. Summaries of the selection processes used for the umbrella and systematic reviews are shown in The Critical Appraisal Skills Programme (CASP) Checklist for Systematic Reviews was used assessing the quality of studies included in the umbrella review 19]. Th. Th19]. Measures used to evaluate ASPs and interventions in both the umbrella review in primary medical care and the systematic review of primary dental care were extracted by two authors (LT and WT) independently. Disagreements were resolved through discussion. Categories were developed by one author (LT) to group the outcome measures and checked independently with another author (WT). Outcomes that did not relate to the aims of this review were excluded from the extraction process.After completion of extracting and categorising the measures used to quantify the ASP outcomes, these metrics were compared and contrasted across both settings .For the umbrella review across primary medical care, 3052 studies were identified for possible inclusion in the review. After duplicates were removed, 2355 were screened, 21 eligible for full text review, and eleven of these excluded with reasons. This resulted in ten articles that met the inclusion criteria and were of adequate quality .For the systematic review across primary dental care, 4234 studies were identified for possible inclusion in the review. After duplicates were removed, 2704 were screened, 11 eligible for full text review, and six of these excluded with reasons. This resulted in five studies that met the inclusion criteria and were of adequate quality .The characteristics of the included studies in the umbrella review are shown in The characteristics of the five studies included in the systematic review across primary dental care are shown in Eight ASPs and intervention outcomes were identified , rate and quality (including appropriateness).Four outcome measures were unique to primary medical care and related to patient outcomes and experiences: re-consultation rates, adverse effects, severity of symptoms, and patient reported outcomes such as satisfaction. One outcome measure was unique to dentistry: The confidence and attitude of dentists towards the intervention .An extensive list of outcomes measured in studies of primary medical and dental care to evaluate ASPs and interventions has been collated. It presents options for researchers testing new interventions in primary medical and dental care as well those wishing to evaluate the implementation of ASPs across primary healthcare. It should also enable the translation of existing metrics to other primary care settings, including from medicine to dentistry. While most ASPs have focused on various healthcare settings ,16,36,37Whilst antibiotic stewardship was introduced as a way to tackle antibiotic resistance , this reBy contrast antibiotic usage is relatively easy to measure and various international studies have demonstrated that a reduction in antibiotic use can result in changed patterns of resistance to antibiotics. A Cochrane systematic review has demonstrated that the prescribing of an antibiotic in primary care for a respiratory or urinary infection results in patients developing bacterial resistance to that antibiotic that may persist for up to 12 months . At the Antibiotic usage as expressed as quantity, rates, percentage and relative ratios was commonly used across both medical and dental primary care. As these outcome measures are easy to interpret and monitor, they are used widely across healthcare settings . A systeA key finding of this study was that none of the dental studies employed clinical or patient outcome measures, such as adverse effects to evaluate ASPs. A study of antimicrobial stewardship in outpatient settings drew similar conclusions, that most of the metrics related to antibiotic usage rather than patient or clinical outcomes . IncorpoInfections of the head and neck may rapidly become life-threatening if they spread into and along the oropharyngeal fascia, such as the pharyngeal space . With thWith rates of antibiotic resistance differing between places and over time, and as there is wide variety in the way clinical services are provided in different parts of the world, including between high and low-middle income countries, selecting the right outcome measures for the context is vital. One set of metrics will not suit all primary healthcare settings and so it is recommended that this suite of clinical and patient outcome metrics be used or adapted when evaluating future ASPs and interventions. Whilst many of the clinical and non-clinical factors that influence antibiotic prescribing by clinicians in primary medical and dental care (including patient expectations and workload), there are also differences between the contexts . FurtherMeasures of quantity are crucial as they provide baseline measures for monitoring and tracking antibiotic use, but they do not provide insight into the quality of patient care. Reduced antibiotic usage does not always correlate with improved clinical outcomes and the significance of changes in antibiotic prescription rates is not well understood . For thiInterestingly whilst all of the studies in this review measured quantity of antibiotic use, only four of the systematic reviews across medical care ,26,29,30Incorporating clinical outcomes in addition to antibiotic use and quality antibiotic use is important to provide further insight to the effectiveness of the ASPs and interventions on individual patient care. For example, a recently published dental intervention pre\u2013post study showed a decrease in antibiotic use and an overall decrease in inappropriate prescribing, but a significant number of prescriptions were still for inappropriate indications . CliniciPublication bias and the possible exclusion of studies in languages other than English are limitations for both the umbrella and systematic review. However, it is unlikely that this would have provided other outcome measures as most studies already used overlapping metrics. Since most studies in the dental systematic review comprised of multifaceted interventions, it is not possible to separate the individual components of the intervention and relate them to a specific metric. The broad range of methodologies in both reviews and heterogeneity of trial designs made it difficult to directly compare the utilisation and choice of specific outcome metrics. Some reported outcomes were subjective such as severity of symptoms, belief in the effectiveness of antibiotics, and thus at risk of reporting bias . OutcomeTo maximise benefits from implementing an intervention to change prescribing behaviour, interventions need to be tailored to the specific context to target the specific delivery method that is best for the specific group of clinicians . NonetheA suite of clinical and patient outcome measures used to evaluate ASPs and interventions in primary medical and dental care has been collated. This will be a useful resource for those selecting appropriate measures to monitor and evaluate the delivery of ASPs in primary healthcare contexts across medicine and dentistry. Employing a mix of clinical and patient outcomes, and quantitative and qualitative measures is recommended. The outcomes selected for measurement should address both delivery of the intended benefits as well as avoidance of negative unintended consequences."} +{"text": "Cellular adaptation to stress and metabolic cues requires a coordinated response of different intracellular compartments, separated by semipermeable membranes. One way to facilitate interorganellar communication is via membrane contact sites, physical bridges between opposing organellar membranes formed by an array of tethering machineries. These contact sites are highly dynamic and establish an interconnected organellar network able to quickly respond to external and internal stress by changing size, abundance and molecular architecture. Here, we discuss recent work on nucleus-vacuole junctions, connecting yeast vacuoles with the nucleus. Appearing as small, single foci in mitotic cells, these contacts expand into one enlarged patch upon nutrient exhaustion and entry into quiescence or can be shaped into multiple large foci essential to sustain viability upon proteostatic stress at the nuclear envelope. We highlight the remarkable plasticity and rapid remodelling of these contact sites upon metabolic or proteostatic stress and their emerging importance for cellular fitness. Adaptation to changing environments is key to maintaining cellular and organismal survival. For microbial cells, evolutionary success depends on their ability to sense and rapidly adapt to fluctuating availability of nutrients or exposure to stress. Cellular metabolism needs to be adjusted to allow growth and division in times of plenty and to sustain homeostasis and stress response when nutrients are limiting . OptimalSaccharomyces cerevisiae represents a prime model organism for studies on the molecular architecture of contact sites and their regulation and multifaceted functions. Several processes and proteins associated with different contacts have been first described in yeast, followed by the identification of the mammalian counterparts biogenesis under stress .The interaction between the principle NVJ tethering pair, the perinuclear ER-resident protein Nvj1 and the palmitoylated protein Vac8 on the vacuolar membrane, represents a prerequisite for NVJ formation Pan et\u00a0. Nvj1 anper se. In our recent work, we identified the integral ER protein Snd3 as a novel component of NVJs . Using mutants deficient in the assembly of NPCs, multi-subunit complexes composed of several nucleoporins that facilitate nucleocytoplasmic transport, the authors could show that NVJs are critical to sustain cellular fitness upon perturbation of NPC assembly (Expansion of the contact region between the nucleus and the vacuole is not limited to nutritional stress but also occurs upon exposure to other stresses, in particular ER stress . Establiassembly (Lord anassembly . In contassembly . As NPC assembly , it mighLord and Wente demonstrated that a mutant form of Nup116, a nucleoporin suggested to promote NPC biogenesis by stabilizing assembly intermediates (mediates , is defemediates . ProteosMdm1, which coordinates LD biogenesis at NVJs upon nutrient limitation , decoratUpon metabolic stress, NVJs serve as platforms for the organisation and biosynthesis of a specific LD subpopulation . LDs budThus, the LD population decorating the periphery of the ER-vacuole contact zone might be in a prime position to sequester misfolded proteins from the ER and facilitate efficient microphagic removal due to the close proximity to the vacuole. Accordingly, not only LD biogenesis and NVJ formation but also Atg1 as key autophagy regulator were required for degradation of NPC assembly intermediates . One migAccumulating studies on the dynamic remodelling and physiological relevance of NVJs highlight these contact sites as hubs to integrate metabolic cues and stress responses to determine cellular fate . While cThis might be the case for other scenarios of cumulative cellular damage, for instance during cellular ageing . Though While global responses to general nutrient deprivation are in place to regulate entrance into quiescence, cells also possess genetic programs specifically tailored to starvation of distinct macronutrients . Not onlIn sum, NVJs emerge as hubs that integrate distinct cellular stress signals and metabolic cues to regulate cell fate. The molecular machineries driving NVJ remodelling and tailoring NVJ molecular composition to the respective cellular needs are far from being understood and represent an exciting challenge for further research."} +{"text": "Education and mentorship of undergraduate students extends beyond the classroom and clinical setting into research. This presentation will discuss the experience of the student and research mentor as well as provide findings from an important qualitative research study. Through a university funded grant, a student nurse partnered with faculty to investigate the needs and experience of caregivers of recently hospitalized older adults with diabetes. Caregivers play a vital role in caring for older adults, often they do not receive the education necessary to achieve optimal health outcomes. Qualitative interviews of 20 caregivers were conducted. The main themes that emerged from the data were: the role itself, challenges, preparation, and additional comorbid diagnoses. These findings provide an understanding of experience, tasks, and needs of caregivers for older adults with diabetes. This research experience provided exposure and education that is essential to developing future aging research scientists."} +{"text": "This paper examines the evidence to support the need to translate current research into health care practices about social isolation and loneliness (SIL) among older adults. The health care system may be in the best position to identify those at highest risk\u2014namely, older adults, whose only interactions are with members of the health care system. This paper reviews recommendations related to periodic assessments, including the use of validated tools to identify those at highest risk. Through this identification, clinicians and health care researchers may be able to use these findings to better target meaningful clinical and public health interventions. Additionally, a critical step toward preventing, mitigating, or eliminating negative health impacts will be to improve awareness about the problem and impact of SIL within the older adult population. This paper reviews recommendations for improving overall awareness by including SIL in national health strategies and public campaigns. Part of a symposium sponsored by Loneliness and Social Isolation Interest Group."} +{"text": "Despite increasing acknowledgement that social integration/isolation is an important determinant of health in later life, relevant evidence for older adults in less developed social contexts is still limited. Data derived from 2015 and 2018 waves of a longitudinal study of 976 older adults, aged 60 and older, living in rural areas of Anhui Province, China. We analyzed how the level of social integration/isolation (measured as family and friendship ties) impacted depressive symptoms of older adults. Our results showed that more than half of older adults in our sample were either isolated from family or friends. Further analysis demonstrated that older people who were isolated from friends were more depressed in comparison with those who were closely integrated into friendship ties, while no such association was found in relation to family ties. Assessments of social integration among older adults should account for both family and friendship ties."} +{"text": "Biopolitical paradigms are frameworks that specify how concerns about health and the body are made the simultaneous focus of biomedicine and state policy . As aging and urbanization trends converge, developing \u201cage-friendly community initiatives\u201d (AFCIs) has become a global movement and important policy area. To prompt critical questioning, situational analysis was used as a theory-methods package to compare AFCI conceptual frames with perspectives of thirteen AFCI experts and seventeen older San Franciscans. Preliminary analysis suggests AFCIs form a biopolitical paradigm because they not only seek to rework boundaries between bodies and environments, they operate as modes of individual and population governance for the sake of health; yet, struggle to find ways to preserve the inclusion of older people in the ongoing social system. Understanding how AFCIs place social and physical environments squarely in view within the biomedical arena of the gerontological gaze has theoretical and policy implications."} +{"text": "Gastric varices are often associated with formation of spontaneous portosystemic shunts that arise to relieve portal hypertension. Balloon retrograde transvenous obliteration (BRTO) is a procedure indicated to prevent recurrent gastric variceal bleeding. Its advantage is diverting blood flow towards the liver, but this can also worsen portal pressure and increase risk for ascites or esophageal variceal bleeding. Patients with gastric varices and concomitant hepatocellular carcinoma (HCC) usually have more advanced cirrhosis and lower possibility of treatment of HCC. BRTO is thought to preserve hepatic function from increased blood flow, possibly allowing better chances of treatment and survival in these patients. Gastric varices account for 20% of all variceal bleeding, and the one-year risk of bleeding is around 16% ) and one large gastric varix with a gastrorenal shunt Figure . ImportaInitially, left-sided TIPS was attempted, but multiple attempts to pass from left portal vein to left hepatic vein were unsuccessful due to challenging anatomy. The patient required multiple blood products. Eventually, the patient underwent BRTO. His left renal vein was accessed via the right internal jugular vein, the balloon was inflated and a sclerosing agent was injected into the bleeding varix. This was followed by coiling of the same varix, resulting in occlusion of the portosystemic shunt Figure . The patIn the American Associated for the Study of Liver Diseases (AASLD) guidelines, BRTO is indicated primarily for prevention of recurrent gastric variceal bleeding . It can A prospective study showed that patients with gastric variceal bleeding and concomitant HCC usually have more advanced cirrhosis and lower possibility of HCC treatment, due to bleeding-related hepatic decompensation. Another study showed that patients with HCC and esophagogastric varices have overall poorer liver functional reserve . AlthougPatients with variceal bleeding and HCC have worse outcomes compared to those without HCC, and death is most commonly related to hemorrhage. Variceal bleeding is known to be an independent risk factor for overall survival in newly diagnosed HCC and an important component in prognosis .\u00a0The role of BRTO for primary prevention for gastric variceal bleeding in HCC patients is still obscure.\u00a0Investigating the benefit of BRTO could be important if there is a possibility of improving survival in these patients. Lack of experience with this procedure could be a limiting factor, but we expect BRTO to be increasingly used in the United States."} +{"text": "A suboptimal diet and nutritional deficiencies can have important influences on health with significant impact among older adults. This study aims to assess the presence of suboptimal dietary intake among older Americans and identify risk and protective factors influencing diet quality. For this study, data from a nationally representative sample of 5,614 community-dwelling older adults over age 54 in the Health and Retirement Study \u2013 Health Care and Nutrition Survey were used. Descriptive analyses were conducted to assess average intake of 17 food groups and nutrients and the percentage of respondents who consumed an optimal amount of food and nutrients. Differences in diet quality by sociodemographic, psychosocial, environmental, and geographic factors were assessed using chi-square and OLS regression was used to identify risk and protective factors for good quality diet. Overall, only 10.7% of respondents had a good quality diet (HEI score 81 and above); the majority had diets considered poor or needing improvement. Less than 50% of respondents met dietary guidelines and nutritional goals for most individual food groups and nutrients. Respondents with low socioeconomic status, fewer psychosocial resources, and those who had limited access to healthy food outlets were more likely to have a diet of suboptimal quality. Efforts to remove identified barriers that put older adults at risk for poor nutrition and to provide resources that increase access to healthy food should be made to encourage healthy eating and enhance diet quality."} +{"text": "Italy is the first European country in which the COVID-19 epidemic outbreak has spread, starting from two regions in Northern Italy, Veneto, and Lombardia. The outbreak poses a relevant burden on hospital resources, with a marked increase in the intensive care unit (ICU) occupancy rates [It has been hypothesized that the proportion of severe infections that need intensive care could be affected by the testing strategy. At the beginning of the epidemic outbreak 21 February), an extensive testing strategy of both symptomatic and asymptomatic subjects has been adopted in Veneto and Lombardia. However, soon after the starting of the outbreak (27 February), the Italian Ministry of Health introduced restrictions in testing asymptomatic/mild symptomatic subjects. Such a recommendation has been a topic of debate among Italian scientists and policymakers since it has been suggested that also asymptomatic patients seem to transmit the infection February, in lineTo compare such two testing strategies, we assessed the relationship between the percentage of ICU admissions on the resident population and the percentage of asymptomatic/mild symptomatic subjects tested on the resident population, in Lombardia and Veneto.Analyses are based on official data . The asyThese findings suggest that testing also asymptomatic/mild symptomatic patients would help reduce the proportion of most severe cases eventually requiring ICU and thus limiting the risk of saturation of ICU units."} +{"text": "This study investigates whether intergenerational relationships and social support improve the psychological well-being of Korean older adults. We examine whether intergenerational relationships and social support directly influence psychological well-being and the extent to which they mediate the distressing consequences of life events such as declining health and recent widowhood. Using longitudinal data from the 2006 to 2016 Korean Longitudinal Study of Aging, we explore depression trajectories among individuals who are 60 or older with at least one living adult child at baseline. Specifically, we converted data from 5,383 older adults into a person-period file with 24,726 observations over a ten-year period. Then we estimated linear growth curve models of depression trajectories separately for men and women using the Center for Epidemiologic Studies Depression Scale (CES-D). Results from the hierarchical linear models indicate that declining health and recent widowhood are positively related to depressive symptoms. Satisfactory intergenerational relationships and social support in the form of personal interactions and proximate living arrangements with adult children decrease depressive symptoms of older parents, especially among women. We conclude that the psychological benefits of intergenerational relationships and social support are contingent upon the vulnerability of older adults and discuss the implications for public policy."} +{"text": "Despite the fact that religiosity and spirituality are commonly cited as essential elements of physical and mental health functioning in old and very old age, the conceptualization of religiosity and spirituality continues to present a quandary in contemporary gerontological inquiry and assessment. Identification of variables that best capture and truly define religious and spiritual constructs has remained relatively inconclusive over the past few decades. Recently, there has been a renewed interest among gerontologists to identify underlying religious and spiritual variables using alternative qualitative and quantitative methods of evaluation. Such methods have been used to further disentangle and understand the uniqueness of religion and spirituality as variables for studying human aging. This symposium will be used to communicate empirical results, methodological procedures, and conceptual insights concerning the identification of understudied and under-represented variables often absent within modern gerontological inquiry of religion and spirituality. Four presentations representing qualitative and quantitative studies will be used to report key religious and spiritual variables stemming from the context of personal narrative, oral storytelling, self-improvement behavior, and the disposition to seek forgiveness. Recommendations pertaining to future gerontological inquiry in the science of religion and spirituality, as well as applications within geriatric and gerontological practice will be highlighted and discussed."} +{"text": "In Ethiopia, poor infant and young child feeding practices and low household dietary diversity remain widespread. The Government has adopted the National Nutrition Programme that emphasizes the need for multi-sectoral collaboration to effectively deliver nutrition-sensitive and nutrition-specific interventions. The Sustainable Undernutrition Reduction in Ethiopia (SURE) programme is one such Government-led initiative that will be implemented jointly by the health and agriculture sectors across 150 districts in Ethiopia. Prior to the design of the SURE programme, this formative research study was conducted to understand how the governance structure and linkages between health and agriculture sectors at local levels can support implementation of programme activities.Data were collected from eight districts in Ethiopia using 16 key informant interviews and eight focus group discussions conducted with district and community-level focal persons for nutrition including health and agriculture extension workers. A framework analysis approach was used to analyze data.Few respondents were aware of the National Nutrition Programme or of their own roles within the multi-sectoral coordination mechanism outlined by the government to deliver nutritional programmes and services. Lack of knowledge or commitment to nutrition, lack of resources and presence of competing priorities within individual sectors were identified as barriers to effective coordination between health and agriculture sectors. Strong central commitment to nutrition, increased involvement of other partners in nutrition and the presence of community development workers such as health and agriculture extension workers were identified as facilitators of effective coordination.Federal guidelines to implement the Ethiopian National Nutrition Programme have yet to be translated to district or community level administrative structures. Sustained political commitment and provision of resources will be necessary to achieve effective inter-sectoral collaboration to deliver nutritional services. The health and agriculture extension platforms may be used to link interventions for sustained nutrition impact. Ethiopia is primarily an agrarian society. The economy relies heavily on rain-fed agriculture, employing 76% of the workforce and accounting for 41% of the national GDP . UndernuAgriculture is a major livelihood for nutritionally vulnerable people in developing countries . AdvanceEthiopia has a decentralized platform of community-based nutrition service delivery with an emphasis on district and local level management . The heaThe Ethiopian National Nutrition Programme provides a framework for multi-sectoral collaboration to effectively deliver nutrition interventions (both nutrition-specific and nutrition-sensitive) . To implThe Sustainable Undernutrition Reduction in Ethiopia (SURE) programme is a government-led intervention that will be implemented in 150 districts from 2017 to 2019. The programme aims to reduce stunting and to increase prevalence of minimum acceptable diet through counselling on child feeding practices and dietary diversity to be jointly delivered to caregivers by health and agriculture extension workers. SURE also aims to strengthen multi-sectoral coordination committees at district and community levels.This formative research study was conducted to understand how governance structures and linkages between the health and agriculture sectors might support implementation of programme activities at local levels. Findings from this study are intended to inform the design of the SURE programme and other integrated interventions that depend on effective multi-sectoral coordination for nutrition.This aim of this qualitative study was to identify barriers, facilitators and opportunities for local level coordination between health and agriculture sectors to deliver nutritional services in Ethiopia.This study was conducted in August 2015 in four agrarian regions of Ethiopia: Oromiya, Amhara, SNNP and Tigray regions.active sites and those without were designated inactive sites and 8 kebeles (4 active and 4 inactive) selected across the four regions.All woreda (districts) and kebeles in the four regions were eligible for inclusion and samples were selected using purposive sampling method. In order to ensure heterogeneity of study participants, we selected woreda and kebeles according to the known presence or absence of effective multi-sectoral coordination committees. Those with functional multi-sectoral coordination committees in place were designated tes Fig. . These cSectoral focal points for health and agricultureFocal point for Community-Based Nutrition programme (CBN), a set of nutrition-sensitive interventions delivered to women and children under 2 years by the Health Extension PlatformFocal point for Agriculture Extension ProgrammeOther health/agriculture district officialsHealth and agriculture extension workers and community leadersStudy participants represented various institutions listed below:active and inactive districts and kebeles.Data was collected using 16 key informant interviews (KIIs) at woreda level and 8 focus group discussions (FGDs) at kebele level. Participants were asked about existing functionality of local level multi-sectoral coordination and about barriers, facilitators and future opportunities for effective multi-sectoral coordination to deliver integrated nutrition services to the community. The number of interviews and focus group discussions depended upon reaching a theoretical saturation point in each category of Data collectors were selected using pre-defined criteria by their educational background and previous experience on qualitative data collection. They were given 4 days of training by investigators at the Ethiopian Public Health Institute (EPHI) on principles of qualitative research, the study topic guide, and interviewing and facilitation skills. As part of their training, data collectors were involved in pilot testing and also given in-field supervision by EPHI staff. Interviews and group discussions were conducted using local languages. Prior to interview data collectors arranged separate, conducive rooms. Key informant interviews were conducted for about 30\u00a0min and group discussions lasted on average 60\u00a0min. All sessions were recorded using digital audio recorders. Audio recordings were kept in a safe lockable cabinet while on field and transferred to the head office at EPHI and only the principal investigator had access to the data.Audio recordings were transcribed by EPHI staff. Specific themes were identified and coded. We identified facilitators using data from the active districts and kebeles with functioning coordination mechanisms, whereas the barriers were identified from inactive sites.Framework analysis approach was used to analyze collected qualitative data. The five stages of framework analysis approach were followed: 1) familiarization (reading through the transcribed data), 2) identifying a thematic framework (start coding), 3) indexing , 4) charting (create charts representing the data) and 5) mapping and interpretation . Qualitative data analysis software Nvivo version 10 was used to code and construct thematic areas from the collected data.In total, there were 45 participants from the agriculture sector and 38 participants from the health sector. At woreda level, there were 16 key informant interviewees, and at kebele level, there were 67 participants in the focus discussions Nutrition interventions such as raising awareness about complementary feeding and dietary diversity were delivered to the community using existing government structures and community networks in the active sites, and were supported by the coordination mechanisms.\u201c\u2026 we gave pictorially supported training to the community on how to prepare food for the children. For example, we showed them how to prepare a soup using the following recipes: 3 cups of water, 1-cup flour, \u00bd coffee cup of oil all mixed in a bowl. We also trained mothers on how to prepare foods using locally available fruits and vegetables; such as kale, pumpkin, potato and others\u2026we informed mothers that if they prepare diversified food using locally available food items, their children will not be malnuritioned.\u201d Strong leadership and commitment to nutrition within the local government structure was the main facilitator to establish and support effective inter-sectoral coordination between the health and agriculture sectors.\u201cYes, there is strong commitment and supportive supervision from the district officials \u2026 on the role of committee, timing of the meeting, type of participants and the like.\u201d The presence of extension workers who were actively engaged in nutrition also facilitated the successful delivery of nutritional services to the community. A focus group discussion participant from the agriculture sector in an active site described how the committee functions:\u201cThe government structure itself ties both sectors together. It consists of health extension worker, agriculture development agent, administration personnel and also representatives from the education sector. Therefore, when we meet for a certain issue, the health extension workers are with us to update one another about local nutritional programmes\u2026\u201dThe presence of community networks with reach at household level and the increasing engagement of development partners in nutrition such as NGOs were also reported as strong facilitators for good health and agriculture linkages at community level.\u201c\u2026 NGOs support us by working at the grass roots level. They provide us with the necessary training and support our activities, so their contribution to nutrition has been valuable\u201d In the active woreda and kebeles, there was evidence of an established and functioning nutrition coordination committee. Participants reported regular participation in an established local nutrition committee represented by multiple sectors, and demonstrated awareness of the National Nutrition Programme and of their responsibilities under the subsequent guideline for multi-sectoral coordination.\u201cThere is lack of awareness on the importance of collaboration among committee members, the health extension workers and agriculture development agent\u201d In districts with no effective linkages between the health and agriculture sectors (inactive sites), participants reported that each sector focused only on its own priorities rather than working in collaboration to achieve local nutrition objectives.\u201cThere is an established committee but it is poor in supporting sectors to work together. Every sector is running by itself and all sectors are not working in collaboration\u201d Other barriers reported were lack of logistics and supply, workload and presence of natural emergencies such as drought, which draw resources away from routine work.Lack of nutrition knowledge was cited by participants as a major barrier against establishing effective coordination structures at both woreda and kebele levels. Poor awareness of the nutrition problem and lack of commitment by local government structures hindered effective inter-sectoral collaboration between the health and agriculture sectors.\u201cWe, as health and agriculture extension workers, are responsible for a lot of households in our kebele and deliver various services. We used to travel a long distance before, but currently we have health development armies who are helping us to provide nutrition services nearer to mothers and children in their home\u201d Health and agriculture sector participants also reported willingness to collaborate to provide nutritional services when aligned with a favorable political environment and increasing government commitment to nutrition.\u201c\u2026there is a government guideline from above and we are the implentors. Only the two health extension workers can not do all the job in nutrition. They should rather work in coordination with the kebele administer, agricultural extension workers and health development armes. Therefore, even if the idea is new for me, we are willing to work together\u2026\u201d Other opportunities to link services include the presence of key infrastructure such as farmer demonstration sites and training centers and other facilities used to show food preparation and gardening.Participants reported that the presence of professional community-level health and agriculture extension platforms represented a clear opportunity to collaborate to link service delivery for improved community nutrition outcomes. The health and agriculture extension workers who provide key services are well-established professionals supported by volunteer community leaders.While functional multi-sectoral committees were identified in some localities, we found that few respondents at local levels of government were aware of the Ethiopian National Nutrition Programme. Facilitators of collaboration included the existence of strong local government commitment to nutrition and the presence of community networks. Barriers of effective coordination included poor awareness of the nutrition problem or of mandated coordination structures, weak political commitment, competing priorities, and lack of resources. Prior investments in community-level health and agriculture platforms and infrastructure provide a key opportunity to accelerate both coordination and the delivery of nutritional services.There is little evidence to date on multi-sectoral coordination for nutrition , 14. HowOur results confirm that key challenges to effective coordination of nutrition activities include insufficient political commitment and the presence of competing priorities in non-health sectors. In agriculture, the ability to integrate nutrition and other intra-sectoral aims into a single framework may be poor . SpecialCascading multi-sectoral nutrition structures from central to local levels will depend on improved awareness, leadership and continued political commitment . ProvisiThis is the one of the first studies to explore the existence and functioning of nutrition coordination mechanisms at district and community levels. The study benefitted from local participant members of both active and inactive nutrition coordination committees. The findings are not generalizable to all districts or communities and this remains one of the key limitations of the study. However, the results provide context to support the establishment and function of local level committees to govern integrated nutrition interventions such as the SURE programme.Collaborations between health and agriculture sectors were not adequate at woreda and kebele levels. Federal guidelines to implement the Ethiopian National Nutrition Programme have yet to be translated to relevant administrative structures. Sustained commitment will be necessary to achieve effective inter-sectoral collaboration to deliver nutritional services. The health and agriculture extension platforms may be used to link interventions for sustained nutrition impact."} +{"text": "This session identifies common misconceptions about identity for persons living with Alzheimer\u2019s disease and related dementias (ADRD). Going beyond diagnostic brain imaging and neurocognitive testing, case studies and research in creativity from around the United States highlights consciousness of persons living with ADRD. Reviewing and discussing artworks is aimed to set dialogue in the question of where memory deposits emerge when engaged in creativity. Through art therapy techniques, this type of self-expression may provide new avenues in treatment for dementia care. Exploring the arts from those with Mild Cognitive Impairment to late stage Alzheimer\u2019s and other forms of dementia, such as frontotemporal dementia, consciousness seems to remain intact despite neural death. This session aims to discourage poor spending allocations and establishing meaningful care. From clinical research trials to creativity of self-expression, the importance of why the arts and sciences matter are demonstrated as effective modalities that enhance quality of life."} +{"text": "In vivo cartilage is subjected to mechanical stimuli that are essential for cartilage development and the maintenance of a chondrocytic phenotype. Cartilage damage caused by traumatic injuries, ageing, or degradative diseases leads to impaired loading resistance and progressive degeneration of both the articular cartilage and the underlying subchondral bone. Since the tissue has limited self-repairing capacity due its avascular nature, restoration of its mechanical properties is still a major challenge. Tissue engineering techniques have the potential to heal osteochondral defects using a combination of stem cells, growth factors, and biomaterials that could produce a biomechanically functional tissue, representative of native hyaline cartilage. However, current clinical approaches fail to repair full-thickness defects that include the underlying subchondral bone. Moreover, when tested in vivo, current tissue-engineered grafts show limited capacity to regenerate the damaged tissue due to poor integration with host cartilage and the failure to retain structural integrity after insertion, resulting in reduced mechanical function. The aim of this review is to examine the optimal characteristics of osteochondral scaffolds. Additionally, an overview on the latest biomaterials potentially able to replicate the natural mechanical environment of articular cartilage and their role in maintaining mechanical cues to drive chondrogenesis will be detailed, as well as the overall mechanical performance of grafts engineered using different technologies.Articular cartilage is a highly specialised connective tissue of diarthrodial joints which provides a smooth, lubricated surface for joint articulation and plays a crucial role in the transmission of loads. Osteochondral defects are areas of damage that involve both the articular cartilage and the underlying subchondral bone and can be caused by ageing, diseases (such as osteoarthritis and osteochondritis dissecans) or trauma. Osteoarthritis (OA) is a degenerative joint disease that affects over 250 million people worldwide , type II collagen and chondrocytes. Mechanical properties of articular cartilage largely depend on ECM composition and organisation, however, mechanical stimulation is essential for cartilage development as well as maintaining cartilage homeostasis are tightly packed and aligned parallel to the articular surface to protect deeper layers from shear stress , inflammatory mediators is a synthetic plug designed to be used with microfracture in order to improve the mechanical stability of the defect. Initial studies showed positive results with the regeneration of cartilage in a goat model, however, clinical studies revealed that 70% of patients required reoperation and the plug failed specifically in restoring the subchondral bone . Several types of membranes and scaffolds have been developed for MACI procedures such as Novocart\u00ae3D a collagen-chondroitin-sulphate based membrane, CaRes\u00ae\u2013Cartilage Regeneration System a collagen type I matrix and Cartipatch\u00ae a monolayer agarose-alginate hydrogel and/or a combination of bioactive molecules such as growth factors and cytokines. Autologous chondrocyte implantation (ACI) is a procedure for the regeneration of cartilage introduced by Brittberg et al. , where ain vitro, chondrocytes undergo dedifferentiation exhibiting a flattened, fibroblast-like morphology. In these conditions they produce a higher amount of collagen type I and collagen type X inducing the formation of fibrocartilage. An advantage of growing spheroids of chondrocytes isolated from biopsies is that the cartilage phenotype is better maintained than when cells are grown on flat tissue culture plastic. However, all of these approaches fail to fully repair the lesion in severe osteochondral defects, where both subchondral bone and articular cartilage are damaged ] and tensile modulus (0.02\u20133.5 MPa) similar to articular cartilage. Steinmetz et al. exerts biphasic behaviour similar to normal articular cartilage under compression and it is currently under clinical trial for first metatarsophalangeal joint hemiarthroplasty but due to its relatively hydrophilic nature and instability in aqueous solution loses its mechanical integrity between two and four weeks in vivo, but also to provide environmental mechanical cues to selectively guide stem cell differentiation into the appropriate osteochondral phenotypes.PCL is an FDA approved biodegradable aliphatic linear polyester and it is one of the most investigated polymers for tissue engineering applications due to its adjustable mechanical strength. PCL can be used to produce porous scaffolds as well as electrospun nanofibers , which will eventually lead to cartilage mineralization. There is increasing evidence that environmental (such as low oxygen tension) and mechanical cues control stem cell fate. In particular . Interestingly dynamic stimulation also affects MSC differentiation and the quality of ECM synthesised. A study from Thorpe et al. revealedIn vivo HP varies between 2 and 10 MPa with peaks of 18 MPa during intense activities such as jumping or running . One of the major limitations of cartilage tissue engineering is the formation of fibrocartilage, which has inferior mechanical properties compared to articular cartilage. HP appears to affect hypertrophic genes, increasing Col I, Col X and MMP13 have also been defined. Despite these biological and clinical evaluation there are no specific requirements for mechanical testing, and there is uncertainty as to whether articular cartilage implants are classified as partial joint replacement implants and should therefore be subject to mechanical characterisation as implantable medical devices that as defined in ISO 13485, 2016, are implanted into the human body via surgical intervention and are intended to remain in place after the procedure. ISO 14630:2012 specifies the general requirements for non-active surgical implants, whereas ISO 21536:2007 is the level 3 standard referring more specifically to knee joint replacement implants. These standards include performance, design, materials, evaluation and sterilisation and the tests needed to demonstrate compliance with these regulations. More specific standards relating to tissue engineered cartilage constructs include the quantification of sulfated glycosaminoglycans (sGAG) (ISO 13019: 2018), and the evaluation of tissue morphology including collagen fibre orientation and anisotropy in vivo animal studies (that will be discussed later in this review) and various in vitro mechanical tests. It states that \u201cmechanical testing should address the following: the ability of the implant to withstand expected in vivo static and dynamic loading ; analysis of fixation method ; and propensity to generate wear debris.\u201d It is also recommended that static mechanical behaviour such as the maximum recoverable compressive strain, the aggregate modulus (HA), the shear modulus (G), and permeability (\u03ba) as well as the dynamic complex shear modulus are included. Degradable scaffolds should also include assessment of failure properties over time and some examples of confined or unconfined compression and indentation are suggested for analysing the mechanical properties of implants.In contrast, the FDA provides more specific mechanical testing criteria for the use of tissue engineered cartilage constructs, which highlights inconsistencies with regard to global standardisation. The FDA guidance document for products intended to repair or replace knee cartilage includes specifications for in vitro test are usually biological assays to evaluate the biocompatibility (ISO 1099), cytotoxicity (ISO 10993-5), gene expression and matrix deposition and under loading conditions of compression, tension, and shear. Analysis of fixation within the defect is also required and assessment of the bioreactivity of any device-generated wear debris.In addition to the standard mechanical tests previously mentioned, implants need to be tested after periods In vivo animal models are crucial preliminary studies to assess the safety and efficacy of newly developed cartilage TE implants. However, currently there are no exact guidelines for the comparison of animal models, assessment of defect size/location and description of appropriate mechanical tests for the assessment of implantable devices such as osteochondral grafts to repair and regenerate articular cartilage. The FDA recommends using combined animal studies with appropriate mechanical testing to assess biological response, durability and toxicology are mainly used for \u201cproof of concept\u201d studies as a translational step between Mechanical push-out tests are useful pre-clinical studies to evaluate the maximum forces needed for graft failure and for assessing integrative repair with host cartilage over time (Theodoropoulos et al., in vitro whole joint simulations can be used to assess the tribological performance of osteochondral grafts, taking into consideration the interactions and biomechanical properties of the joint as a whole under physiological loading conditions. These types of test are relevant for comparing the efficacy of osteochondral grafts to other surgical interventions such as scaffolds and cell-based approaches (Bowland et al., in situ compressive loading. Whole joint simulation models highlight the importance of restoring the congruence of articular surfaces during an experimental setting that mimics more closely the physiological environment of joint articulation. However, the use of cadaveric tissue with diluted serum replicating the joint's synovial fluid is a useful approach but it fails to replicate large numbers of walking cycles due to limitations regarding the continual sterility and viability of the tissue.In contrast, Chondrocytes in the superficial layer produce lubricin that maintains low coefficients of friction of joints. Maintaining a low frictional interface is essential to prevent mechanical wear and erosion of the articular surface. The application of frictional shear stress has been shown to cause damage such as cracking and peeling in cartilage TE constructs, which are not seen in native cartilage controls (Whitney et al., Despite tremendous advances in the field of tissue engineering, an optimal biomaterial system for osteochondral defects that is able to direct stem cell differentiation into chondrocytes for the cartilage and osteoblast for bone without the use of exogenous stimuli is elusive. Material selection is essential for creating a graft able to withstand the multiple forces that cartilage is subject to. Synthetic materials not only provide high tensile stress and compressive modulus, but they are easily modified, facilitating the creation of layered scaffolds which is a requirement for osteochondral grafts. However, the lack of cellular binding sites require them to be combined with natural materials, which are highly biocompatible and can provide biochemical cues for stem cell differentiation. The natural architecture of cartilage and the impermeable subchondral plate enhances the development of hydrostatic stress in the cartilage which promotes and maintains the chondrocytic phenotype, however few osteochondral implant designs replicate this sub-chondral barrier.in vivo, the optimal range of stiffnesses is yet to be determined. Conflicting results have been reported, as to whether high stiffness could enhance chondrogenic differentiation of MSCs or upregulate hypertrophic markers. The use of dynamic stimulation, such as hydrostatic pressure or dynamic loading, could promote a stable differentiation of MSCs into chondrocytes and enhance matrix deposition, thus preventing the use of TGF-\u03b2 which lead to the formation of hypertrophic cartilage.Although suitable mechanical properties are essential for ensuring graft stability in vitro are essential to ensure graft stability in vivo, however, the lack of standardised procedures questions the reliability of the published data in providing an understanding of the long term endurance and suitability of osteochondral grafts. In addition, only a small fraction of studies on cartilage constructs tests all of the mechanical properties requested from the FDA or the ICRS and this might, in part, explain why many scaffolds fail when tested in vivo.Mechanical testing of TE constructs SD and TR completed a literature search, wrote the manuscript and critically revised the manuscript. MR, GB, and GT contributed ideas, content to the manuscript, and critically revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Objectives: To investigate whether caregiver neuroticism has an effect on subsequent occurrence of elder abuse and whether change in the level of caregiver perceived burden alters this relationship. Methods: Using two-year longitudinal data, we analyzed a consecutive sample of 800 Chinese family caregivers and their care recipients with dementia recruited from the geriatric and neurological departments of three Grade-A hospitals in People\u2019s Republic of China (PRC). All the participatory dyads were assessed between September 2015 and February 2016 and followed for two years. Results: Significant increase in the prevalence was found for physical and psychological abuse, caregiver neglect, and financial exploitation. Caregivers high in neuroticism were more likely to engage in subsequent physical and psychological abuse, however, change in the level of caregiver perceived burden altered this association. Specifically, absence and alleviation of care burden during the two-year observation prevented the subsequent occurrence of physical and psychological abuse. Although caregiver neuroticism was also associated with subsequent caregiver neglect, caregiver perceived burden did not appear to have an impact on this relationship. Discussion: This study provided evidence that caregiver neuroticism was associated with subsequent physical and psychological abuse, while change in the level of caregiver perceived burden may alter this trajectory. These findings suggest the importance of implementing caregiver-centered intervention and prevention programs for elder abuse by specifically targeting at caregivers\u2019 behaviors related to their neurotic personality trait and cognitive appraisal of caregiving stressors associated with such personality trait."} +{"text": "Open dislocations of the midfoot and subtalar joints are extremely rare injuries. Understanding the anatomy of these joints and the various injury patterns is imperative to obtain stable concentric reduction and provide good functional outcome. We present a report of a 26- year old male who was involved in a road traffic accident and sustained open dislocations of the calcaneocuboid, naviculocuneiform and subtalar joints. He initially underwent external fixation in view of the severe soft tissue injury. After improvement of the soft tissue condition, he underwent K-wiring of the calcaneocuboid joint, buttress plating of the talonaviculocuneiform joint, peroneal tendon reconstruction using hamstring allograft and defect coverage with a free anterolateral thigh flap. With appropriate rehabilitation protocols, patient recovered well and was allowed to weight bear as tolerated by 10 weeks. His wounds healed completely by 4 months. We report this case considering the rarity of the combined calcaneocuboid, naviculocuneiform and subtalar dislocations which were successfully managed. Dislocations of the midfoot and subtalar joints are extremely rare injuries, with only a handful of cases being reported in the literature [1e4]. Knowledge of the anatomy and biomechanics of these joints as well as understanding of the injury pattern is essential for the treating surgeon to provide the patient a good functional outcome. We present a rare case of an open dislocation of the calcaneocuboid, naviculocuneiform and subtalar joints, and discuss the diagnosis and management of such an injury.A 26-year-old otherwise healthy man presented to the Emergency Department following a road traffic accident. He was a motorcyclist who was hit by a taxi. He complained of severe right ankle and foot pain. Clinical examination revealed an open wound over the lateral aspect of his ankle with gross ankle deformity noted . PosteriIn view of the absent dorsalis pedis pulse, attempted reduction was performed in the emergency department prior to obtaining radiographs. Post-reduction radiographs revealed dislocations of the calcaneocuboid, naviculocuneiform and subtalar joints . A compuThe patient underwent emergent open reduction and external fixation with Shanz pins placed in the tibia, calcaneus and first metatarsal. The foot was maintained in dorsiflexion and eversion, a position of maximum stability . IntraopA CT scan was performed post-external fixation to evaluate for congruency of reduction and to better characterize the injuries. The calcaneocuboid, naviculocuneiform and subtalar joints were still identified to be unstable, with partial extrusion of the navicular . In addiThe patient underwent definitive fixation at a delayed setting after improvement in the soft tissue condition. The subtalar joint was reduced by removing the interposed soft tissues. The talonaviculocuneiform joint was reduced and held with a dorsal medial buttress plate, and the calcaneocuboid joint was held with 1.6 mm Kirschner wires and 6. TThe patient recovered well post-operatively. The external fixator and K wires were removed at 6 weeks after adequate healing has occurred. At 10 weeks, there was no more pain or tenderness at the surgical site, and he was allowed weight bearing as tolerated. Serial radiographs revealed no implant loosening with the naviculocuneiform, calcaneocuboid and subtalar joints well-reduced . At 4 moMidfoot dislocations are extremely rare injuries. Main and Jowett reported 71 cases of midtarsal injuries with only 10 involving midfoot dislocations . IsolateIt is important to recognize the anatomy and biomechanics of the midfoot and subtalar joints and the injury patterns associated with such dislocations so as to obtain stable concentric reduction and provide good functional outcomes.Articulation of the navicular bone with the three cuneiform bones consists of three facets with a common synovial capsule . The surThe calcaneocuboid articulation has its stability conferred by the firm ligamentous attachment to adjacent bones, its relationship to the peroneus longus and brevis tendons, its rigid fibrous capsule and its saddle-shaped joint surface . The staFor midfoot dislocations, anatomical realignment of the axes and columns is crucial because a reduction of column length or a shift in foot axis will significantly alter gait biomechanics and increase the risk of midfoot arthritis in the future .The subtalar joint consists of the anterior, middle and posterior facets, through which the talus articulates with the calcaneus, permitting foot inversion and eversion. The joint is stabilized by its inherent bony configuration and the supporting soft tissue structures. The talocalcaneal interosseous ligament within the sinus tarsi and capsular structures around each facet, strengthened medially by the superficial deltoid ligament and laterally by the calcaneofibular ligament, constitute the main ligamentous support . StudiesMidfoot dislocations are usually sustained after high energy trauma, such as road traffic accidents as shown in our case report. Such injuries usually involve both osseous and ligamentous components, involve both medial and lateral columns and are almost always associated with significant soft tissue injury.Kollmannsberger et al. postulatMain and Jowett classified their cases based on the direction of deforming forces . Their cSubtalar dislocations are usually classified by the direction the foot takes in relation to the talus ,15. MediEarly accurate diagnosis and appropriate treatment is important to prevent long term complications and functional impairment. A high index of suspicion is important in such high energy injuries and radiographs should be obtained early. In our case, radiographs were only obtained after the initial reduction due to the fact that this occurred in a trauma activation setting where other scans were being prioritized first and also the concern about vascular compromise. We acknowledge this as a limitation and do not recommend routinely attempting reduction without prior radiographs identifying the exact injuries. Signs and symptoms of compartment syndrome should also be monitored for, in view of the severe soft tissue compromise.Initial radiographic evaluation should consist of anteroposterior, oblique and lateral views of the foot. Ebraheim et al recommended routine medial oblique views to best visualize the calcaneocuboid joint line . FurtherAlthough it is generally agreed that such cases of midfoot dislocations require reduction, there is a general lack of consensus in the literature as to which is the recommended method of fixation. Previous cases have been treated with K wires , plate fSimilarly, closed reduction is successful in most cases of isolated subtalar dislocations . HoweverOur principles of managing such a complex injury consists of initial soft tissue management, interval definitive fixation to restore medial and lateral column length, definitive soft tissue stabilization and eventual skin coverage. In accordance to the principles of management of open fractures, we elected to apply an external fixator in the emergent setting in view of the large open wound and the severe soft tissue trauma.Plate fixation has been shown to provide rigid fixation without further articular damage as compared to transarticular screws . Plate fRedfern and Myerson previously described a treatment algorithm for combined tears of the peroneus longus and brevis, based on a validated protocol . SurgicaOpen dislocations of both the calcaneocuboid and naviculocuneiform joints are rare injuries. Understanding the anatomy of the midfoot joints is of utmost importance in treating such injuries. Principles of management include initial soft tissue management, interval definitive fixation and soft tissue reconstruction and repair to restore medial and lateral column length for good clinical and functional outcome."} +{"text": "The current coronavirus outbreak may provide an illustrative analogy for sustainability challenges, exemplifying how challenges such as climate change may become wicked problems demanding novel and drastic solution attempts. The current coronavirus pandemic is causing an unprecedented worldwide economic and social disruption. The rate of infected people is steadily on the rise (Dong et al. Both the coronavirus crisis and climate change, although occurring on different temporal scales, represent surprisingly similar problem and response dynamics. To this end, the coronavirus pandemic and climate change both feature traits that are characteristic of what has been termed \u201csuper wicked problems\u201d (Levin et al. The coronavirus crisis is threatening to rapidly overwhelm the capacities of health care systems of severely affected countries around the globe . Disrupthttps://www.nature.com/nclimate]. Still, many experts agree that to date the global reaction to climate change has been insufficient and policy proposals would need to better account for the effect of culture as a mediator in societal reactions to climate change (Adger et al. It is becoming evident that the world community was ill prepared for the coronavirus pandemic, although experts flagged the problem early on (World Health Organization Responses to the coronavirus crisis demand urgent measures to minimize further spread, and despite unprecedented global measures already in place, halting the outbreak\u2019s momentum is challenging. As with the coronavirus crisis, urgent actions to tackle anthropogenic climate change are now required as the impacts of changing climate are increasing in both scale and pace Pittock . The futBoth challenges demand solution-oriented action with multiple interventions that address the systemic causes of the crises. Furthermore, the changing nature of the crises means that a single specific solution may not be possible and interventions need to be continually adjusted and reassessed to changing conditions. Behavior change represents a crucial component in addressing both crises [Fischer ]. Arrest"} +{"text": "Repetitive transcranial magnetic stimulation (rTMS) is implemented to treat many clinical diagnoses. The most common clinical patients receiving rTMS are those suffering from treatment resistant depression (TRD). As a treatment for TRD, rTMS is thought to modulate circuits dysregulated by the disease , the research topic is ripe for investigation or the medial prefrontal cortex (mPC). Preclinical models of optogenetic stimulation helped motivate these stimulation sites of the participant facilitate the effectiveness of the treatment? Stramba-Badiale et al. outlinedThe articles included in this special issue brought us closer to developing an understanding of how to move forward in using rTMS as a therapeutic intervention for addiction. There are promising results and tantalizing effects to drive thorough research into uncovering more known unknowns. Generally, rTMS used to treat SUDs was tolerated by a wide range of patients. Applying chronic rTMS as a treatment also proved feasible and generally effective at modifying the targeted behavior. Higher frequency stimulation produced greater benefits to the patient. This is all good news and is in line with a recent consensus paper outlining steps toward developing an rTMS treatment for SUDs develop and integrate preclinical models to clinical applications of rTMS, (2) elucidate effective combinations of rTMS and other treatments, (3) identify individual differences with respect to inducing excitation and inhibition with rTMS. Recent coil technology allows focal stimulation in rodents (Meng et al., VRS conceived and wrote this commentary.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Given the importance of understanding the underlying dynamics of physical and mental health in old age, the present study explored the roles of physical health constraints in predicting subjective health perception and psychological distress among older Asian Americans. Guided by the Health Belief Model, we also examined whether subjective health perception would function as a mediator in the link between physical health constraints and psychological distress. Using data from 533 Asian Americans aged 60 and over in the 2016 Asian American Quality of Life Study, the direct and indirect effect models were tested with multivariate linear regressions and the PROCESS macro. Advanced age, unmarried status, lower levels of acculturation, and more chronic physical conditions were significant predictors of psychological distress. When subjective health perception was added to the model, an additional 5% of the variance was accounted for, resulting in 25% of the total variance explained by the estimated model. Negative health perception was a significant predictor of increased level of psychological distress. Supporting the mediation hypothesis, all direct paths among physical health constraints, subjective health perception, and psychological distress were significant. The indirect effect of physical health constraints on psychological distress through subjective health perception status was significant, as evidenced by the 95% bootstrap confidence interval for the indirect effect not containing zero . The findings not only help better understand the psychological mechanisms that underlie physical health constraints and psychological distress but also suggest avenues for interventions."} +{"text": "Eye-movement recording has made it possible to achieve a detailed understanding of oculomotor and cognitive behavior during reading and of changes in this behavior across the stages of reading development. Given that many students struggle to attain even basic reading skills, a logical extension of eye-movement research involves its applications in both the diagnostic and instructional areas of reading education. The focus of this symposium is on eye-movement research with potential implications for reading education.Christian Vorstius will review results from a large-scale longitudinal study that examined the development of spatial parameters in fixation patterns within three cohorts, ranging from elementary to early middle school, discussing an early development window and its potential influences on reading ability and orthography. Ronan Reilly and Xi Fan will present longitudinal data related to developmental changes in reading-related eye movements in Chinese. Their findings are indicative of increasing sensitivity to lexical predictability and sentence coherence. The authors suggest that delays in the emergence of these reading behaviors may signal early an increased risk of reading difficulty.Jochen Laubrock\u2019s presentation will focus on perceptual span development and explore dimensions of this phenomenon with potential educational implications, such as the modulation of perceptual span in relation to cognitive load, as well as preview effects during oral and silent reading --and while reading comic books.Video stream:https://vimeo.com/362645755"} +{"text": "The aim of this presentation is to reveal the importance of engaging older refugee community members in creating partnerships with local healthcare providers to implement culturally responsive interventions. Such engagement invites older refugees\u2019 participation and encourages continued connection to country of origin beliefs and culture, particularly within the sphere of healthcare and medical family therapy. Cambodian and Laotian refugee families in coastal Alabama were interviewed via qualitative community-based participatory research and ethnographic, in-depth interviews focused on familial and communal processes. Local healthcare providers engaged in focus group discussions regarding cultural processes associated with health beliefs and behaviors and in periodic outreach through culturally responsive health fairs. We found that older adults play important roles in refugee populations as community leaders, problem-solvers, and legacy-carriers upholding traditional values and cultural continuity. They also maintain and promote continuity by employing traditional, complementary, or alternative medicine (TCAM). Recursive processes also emerged as older individuals sought care from younger community members in times of sickness, including having younger generations provide language translation and transportation to local healthcare centers and hospitals and in navigating the United States healthcare system. In addition, community members joined with local healthcare providers to aide in health and healthcare literacy among refugees and to educate local physicians on culturally responsive interventions. Implications include the inclusion of older adults in health decisions and the promotion and maintenance of community partnerships with health agencies that both encourage TCAM utilization and also allow for access to ongoing, appropriate treatment within the US healthcare system."} +{"text": "Nations globally are facing the fiscal consequences of being aging societies, including the redistribution of wealth resources across sectors that influence generational relations . Political differences or clashes between youth and older adults is not a new phenomenon. However, questions are being raised about whether current political systems, governing structures, and social trends are eroding generational solidarity which traditionally has a role in promoting equity and protecting vulnerable individuals from rapid social change. Reflecting on the 2020 national election results and political opinion surveys, we explore the meaning of age or generational differences in political attitudes in an increasingly partisan society. We suggest that the use of a generational location or habitus lens, which focuses on the distinct sociohistorical realities that shape age groups and their interrelations, may offer insights into current political debates and divides."} +{"text": "The Clinical Research Experience Internship Program (CREST) provides participants with foundations in scientific research appropriate for high school students interested in clinical careers in health-related disciplines . The overall program goal is to provide research and career experiences to individuals from disadvantaged backgrounds, racial/ethnic minorities, and others who are underrepresented in these fields. The focus of this presentation is that part of the CREST program that has been ongoing since 2013. One program mentor has provided an internship experience to 22 high school students training in and work experience with community-based programs designed to improve health for older adults (identified as \u2018community gerontology\u2019). This poster presentation describes some of these experiences . Students have worked with older adults in senior housing facilities, supported housing complexes for veterans, and congregate meal sites for older adults. Because of the program experience, the CREST program helps dispel common stereotypes about older adults and encourages students exploring possible clinical career options to consider focusing on older adults as client populations. Program components are described which can allow conference participants to decide on the applicability of this type of programming for their own communities. Qualitative data are presented that provide insights into these experiences as these influence choice of college major and projected career paths and attitudes about working in community-based healthcare with older people."} +{"text": "Understanding the ecology of rodent-borne hantaviruses is critical to assessing the risk of spillover to humans. Longitudinal surveys have suggested that hantaviral prevalence in a given host population is tightly linked to rodent ecology and correlates with changes in the species composition of a rodent community over time and/or habitat composition. We tested two hypotheses to identify whether resource addition and/or habitat composition may affect hantavirus prevalence among two sympatric reservoir hosts in a neotropical forest: (i) increased food resources will alter the rodent community and thus hantaviral prevalence; and (ii) host abundance and viral seroprevalence will be associated with habitat composition. We established a baseline of rodent\u2013virus prevalence in three grid pairs of distinct habitat compositions and subjected one grid of each pair to resource augmentation. Increased rodent species diversity was observed on grids where food was added versus untreated control grids during the first post-treatment sampling session. Resource augmentation changed species community composition, yet it did not affect the prevalence of hantavirus in the host population over time, nor was there evidence of a dilution effect. Secondly, we show that the prevalence of the virus in the respective reservoir hosts was associated with habitat composition at two spatial levels, independent of resource addition, supporting previous findings that habitat composition is a primary driver of the prevalence of hantaviruses in the neotropics. Hantaviridae, Genus Orthohantavirus) are maintained by transmission within reservoir rodent species across complex ecosystems in diverse landscapes and habitats across the globe )c Forest ,41. Howe"} +{"text": "Molossus) as our model system. Many species within this genus have low-levels of genetic variation within and between morphologically distinct species, and the relationships among them remain unresolved using traditional Sanger sequencing methods. Given that both de novo and reference genome pipelines can be used to assemble next generation sequences, and that several tree inference methodologies have been proposed for single nucleotide polymorphism (SNP) data, we test whether different alignments and phylogenetic approaches produce similar results. We also examined how the process of SNP identification and mapping can affect the consistency of the analyses. Different alignments and phylogenetic inferences produced consistent results, supporting the GBS approach for answering evolutionary questions on a macroevolutionary scale when the genetic distance among phenotypically identifiable clades is low. We highlight the importance of exploring the relationships among groups using different assembly assumptions and also distinct phylogenetic inference methods, particularly when addressing phylogenetic questions in genetic and morphologically conservative taxa.\u2022 Herein we propose a framework for assembling and analyzing Genotype by Sequencing (GBS) data to better understand evolutionary relationships within a group of closely related species using the mastiff bats (\u2022 The method uses the comparison of several filter settings, alignments, and tree inference approaches on Genotype by Sequencing data.\u2022 Consistent results were found among several approaches.\u2022 The methodology successfully recovered well supported species boundaries and phylogenetic relationships among species of mastiff bats not hypothesized by previous methods. Specification TableGenotyping by Sequencing (GBS), which involves sequencing genomic regions flanking restriction sites. Using GBS, many sequences of short length are obtained, vastly increasing the size of the overall data set in comparison to traditional Sanger methods. This technique provides sequence data for thousands of single nucleotide polymorphisms (SNPs), allowing the detection of small, but consistent genetic variation among genetically similar groups not revealed by standard gene sequencing approaches. GBS has been successfully used in studies of population genetics Advances in genomics technology have allowed the generation of large numbers of molecular markers across the genome, which increases sample sizes and provides additional data to help resolve interpretation of the ecology and evolution of traditionally poorly understood species groups Molossus), a genus with a complex taxonomic history and low levels of genetic variation de novo and reference genome pipelines are often used to assemble next generation sequencing (NGS) data, and that several tree inference methodologies have been proposed for SNP data, we also test if different alignments and phylogenetic approaches produce similar results. These data offer a useful framework for other comparative studies of ecology and evolution using the GBS approach.In this context, we propose a framework for assembling and analyzing GBS data to better understand evolutionary relationships among species of mastiff bats pipelines, available as part of the TASSEL 3.0 software We assessed the quality of the paired GBS-tags using FastQC. The likelihoods of the possible genotypes were estimated for both pipelines, and the Genotype quality (GQ), which is the difference between the most likely and the second most likely genotype, was calculated also using FastQC. The data were then imported into TASSEL where samples were demultiplexed and filtered. The amount of missing data acceptable for phylogenetic estimates still lacks a consensus. The identification of minimum values for these filters is still debatable and may ultimately depend on the dataset in hand and the question that needs to be answered Similarly, the optimum value for minimum allele frequency (MAF) is not universally agreed upon and there is a trade-off between the use of MAF and the loss of rare alleles. The increase of the MAF value may cause an under-calling of heterozygotes with the loss of biological information, instead of the removal of sequencing errors de novo alignments using VCFtools, and then we simulated how the depth could affect the number of SNPs in both alignments by removing sequences with lower and higher depths than the mean in the TASSEL software. For this simulation we looked at the number of SNPs removed and the agreement between final topologies using the optimum MAF value found for each dataset.Low depth sequences are sequences recovered by relatively few reads and, if not removed, they might lead to serious bias (2014) Molossus and the low percentage of tags that aligned to the Myotis genome (2.5%), precluded use of this method for our dataset. Each tag produced by the GBS method has 64 bp, and therefore we have tried to overcome this problem by removing SNPs that were separated by less than 128 bp in the genome.GBS sequences are short, which decreases the chance of intragenic recombination. However, if the SNPs are closely linked on the same chromosome, they might not be independent. Some studies suggest mapping the SNPs in a reference genome to confront this issue Molossus using the Maximum Likelihood approach (ML) implemented in FastTree To test for divergence in tree inference approaches we removed invariant sites in both alignments and reconstructed the phylogenetic relationships within the genus de novo pipeline identified 418,810 SNPs after error curation in the standard network error remover of TASSEL. The alignment using the reference genome discarded 96.6% of tags that did not align with the Myotis genome and 0.9% of the tags that aligned multiple times, keeping only 2.5% of the short length sequences. After removal of invariant sites, the reference genome alignment produced 55,350 SNPs. Of the 189 specimens included in the Illumina library, 23 were discarded in the de novo pipeline and 16 were discarded in the reference-based pipeline because they had low numbers of raw reads and few loci (>90% of missing data), probably because of low DNA quality. The quality of the isolated DNA depends on the quality of the tissue sample. Fresh tissues produce the highest DNA yield and quality and samples should be stored under conditions that preserve DNA integrity. In addition, repeated freezing and thawing of frozen tissues might reduce the size and quality of DNA. For compromised samples, the initial concentration was lower than required by GBS library preparation (>100 ng/ul), and multiple DNA concentration procedures were required to archive the required DNA quality. After this procedure, thirty microlitres of each sample were sent to sequence, but the remaining DNA aliquot were less than thirty microlitres per individual, too low for repeating the GBS library preparation.After merging the Illumina paired-end sequences, more than nine million tags remained. The Both alignments behaved similarly for all filters. In our dataset, the removal of 10% missing SNPs decreased the total number of markers by less than half. The number of SNPs decreased further when removing 20% to 90% of missing data . Our finde novo and 49% with the reference genome approaches) , which ide novo alignment in comparison with the reference genome data set. When set to 0.01, this filter discarded approximately two-thirds of the SNPS in the de novo alignment and half of those in the reference genome alignment and species relationships compared to the linked dataset. However, the relationships within some populations changed slightly, which might indicate a higher effect on population structure analyses.More than half of the SNPS were closely aligned in the genome, which could indicate linked loci. We removed SNPs that were 128 base pairs apart, twice the length of a single tag, to decrease linked SNPs in the dataset . Linkagede novo and reference genome alignments were seven and six respectively, which is consistent with our analysis that shows a plateau in the number of SNPs after setting missing data depth less than six and seven for each respective data set , and this high proportion of low depth tags suggests a high degree of uncertainty about the homology of those sequences The average depth in the data set . The depde novo and reference alignment, respectively. After data filtering, the de novo pipeline yielded 71,801 SNPs and the reference genome pipeline yielded 27,323 SNPs. To remove unlinked and uncertain SNPs, sites with more than 50% of missing data were discarded as were sites less than 128 bp apart. The final data set with unlinked SNPs had 29,448 SNPs for the de novo pipeline and 15,569 SNPs for the reference genome dataset. In addition, we also used more and less conservative filtering values to test for differences in accuracy and consistency in tree topologies.According to the previous results, the sequences were filtered for missing data < 50%, minor allele frequency (MAF) >0.02, heterozygosity >0.01, and depth coverage lower than seven and six for the de novo and the reference genome alignments are congruent when the optimum filtering settings are used, recovering the same clades and the same relationships among species Molossus start to lose support; although, the relationships among them do not change. This outcome is consistent with loss of true rare polymorphic sites, which should not be removed from the dataset. The removal of markers with less than 50% of missing data did not change supports in the phylogenetic trees. However, if markers with more than 50% of missing data are removed and less conservative filtering setting values are used , the topologies between de novo and reference genome alignment lose agreement and relationship among some clades within Molossus are no longer supported by both alignments. These results are consistent with incorporation of sequencing errors. Using the optimum filtering values (The ML and SVDquartets trees with both the g values , the besde novo and reference-based alignments. In our study, relationships within terminal clades with low bootstrap support were affected by the choice of the pipeline, which could have resulted from the difference in number of SNPs retained from both alignments. However, the use of the reference genome in the alignment does not seem to be essential for recovering a robust overall phylogenetic tree, since both phylogenies, de novo and with the reference genome, were similar at the species level when optimal filtering settings values were used.The greater power of next-generation sequencing approaches compared to Sanger methods for answering phylogenetic questions is well established We highlight the importance of exploring the relationships among groups using different assembly assumptions and also distinct phylogenetic inference methods, particularly when addressing phylogenetically conservative groups. All models of molecular evolution are a simplification of the actual evolutionary process, and the inappropriate choice of filters during alignment or tree inference can lead to systematic bias in the phylogenetic reconstruction"} +{"text": "The influences of neighborhood characteristics remain understudied in relation to oral health, especially within the context of immigration. Acculturation exerts influences on the oral health of immigrants. This study investigated the relationship between neighborhood cohesion and oral health problems among older Chinese American immigrants and examined the moderating role of acculturation in such a relationship. The working sample included 3,157 older Chinese American immigrants aged 60 years or older from the baseline of the Population Study of Chinese Elderly in Chicago. Stepwise logistic regression models with interaction terms were conducted. Individuals experiencing higher levels of neighborhood cohesion reported a lower likelihood of having oral health problems. The protective effect of neighborhood cohesion against having oral health problems was stronger when individuals resided in ethnic enclaves such as Chinatown. To promote optimal oral health, interventions need to account for individuals\u2019 perceptions and levels of integration into their neighborhoods and communities."} +{"text": "Contemplative practices such as meditation, yoga, and prayer had been used as coping resources to reduce the adverse impacts of stressful life experiences. Despite emerging scholarship on the benefits of contemplative practices for cognitive health, scant research has examined the influence of such practices on both episodic and working memory among women in later life. While the use of private prayer outside of church or temple has been shown to have statistically significant positive effect on episodic memory among older adults, previous studies have relied on measures that fail to capture various aspects of meditative practices . Drawing from the Study of Women\u2019s Health Across the Nation (n=2245) conducted during 2006-2008, this study investigates the effect of contemplative practices on episodic and working memory. Multivariate regression model estimates suggests women who either used meditation, imagery or relaxation techniques had significantly better episodic and working memory as compared to those who did not use those methods. Surprisingly, the influence of prayer on episodic memory was negative , while the influence of yoga on memory was not statistically significant. Our findings underscore the need to incorporate meditative practices in non-pharmacological interventions that are designed to improve later life memory."} +{"text": "DigestiFlow that focuses on the management of Illumina flow cell sample sheets and raw data. It allows for automated extraction of information from flow cell data and management of sample sheets. Furthermore, it allows for the automated and reproducible conversion of Illumina base calls to sequences and the demultiplexing thereof using bcl2fastq and Picard Tools, followed by quality control report generation.Management of raw-sequencing data and its pre-processing (conversion into sequences and demultiplexing) remains a challenging topic for groups running sequencing devices. They face many challenges in such efforts and solutions ranging from manual management of spreadsheets to very complex and customized laboratory information management systems handling much more than just sequencing raw data. In this article, we describe the software package https://github.com/bihealth/digestiflow-server. The client software components are available via Bioconda.The software is available under the MIT license at Bioinformatics online. Although there is no clear consensus of what comprises a Laboratory Information Management System (LIMS), the term LIMS is often used to describe systems supporting these step. Simple \u2018pure peopleware\u2019 implementations consist of spreadsheets on network shares while comprehensive commercial packages such as Illumina BaseSpace Clarity LIMS offer highly adjustable but very expensive solutions. A number of academic and open solutions fall in between, offering a variable number of features and degrees of customizability.Laboratories operating modern-sequencing facilities face a multitude of challenges. These include sample tracking, The general lack of agreement of what a LIMS should cover or not cover stems from the fact that sequencing laboratories alone differ greatly. Areas of difference include the types of samples accepted , and the type of data generated , sequences, aligned reads or bioinformatics analytical reports). In addition, the surrounding information technology (IT) infrastructure varies greatly as does the degree of integration with such additional IT systems.DigestiFlow (DF) that addresses the different needs of organizations by focusing on a small, well-defined subset of tasks: management of Illumina flow cell and sample sheet information and orchestrating the step converting BCLs to sequences and demultiplexing pooled sequencing runs. To the best knowledge of the authors, in this domain DF offers unparalleled functionality. Flow cells can be filled with an arbitrary combination of libraries using any combination of index and molecular barcode reads. DF also supports the barcode being part of the template sequence. DF provides extensive features for sanity checking and comparison of expected indexing reads with those actually seen in the raw BCL data.In this article we present our approach This is particularly important in an era where technologies such as single cell and low input sequencing require an ever-growing complexity of barcoding and indexing schemes and the amount of sequencer throughput is growing dramatically. We have encountered flow cells with more than 600 libraries and expect this to grow with increasing sequencer throughput.A fundamental link to central IT is the integration with existing authentication infrastructure via directory servers, e.g. Microsoft ActiveDirectory (AD). DF supports linking accounts to central AD instances as well as using user accounts that only exist within the system. Beyond this, the system provides its functionality through a REST API such that other services can be easily integrated. Instead of covering all possible functionality and sample tracking schemes, DF avoids the complexity of a monolithic system and can be integrated as a part of a modular system. However, it can also just be standalone without integration with any other system.DF consists of three major components. The architecture of the system is shown in DF Serverugh being out of scope of this article, we note that DF could be integrated with other software packages as long as they provide an API with additional code. The integration with Parkour LIMS appears particularly appealing as it is based on the same technology as DF (Python/Django) and has few other dependencies itself. Based on practical experience, we greatly appreciate the automated comparison of observed adapter sequence content and sample sheet. Unexpected sequence in either set is an indication for possible errors. DF Server provides fine-grained control to acknowledge and suppress inconsistency warnings (after either fixing errors or accepting errors and then excluding corresponding data). Furthermore, common artifacts such as PhiX sequence are automatically recognized and show up as information rather than warnings or errors. The DF Client and Demux components are available from Bioconda as Conda packages and Docker images, thus allowing for future proof installations and creating reproducible workflows. By offering REST APIs and two useful client applications, DF greatly supports sequencing and demultiplexing operators in automating their work. Further automation can be added later as the APIs are open. Automated quality control using FastQC and aggregation using MultiQC also allows users to spot problems earlier (together with the sample sheet adapter checks described earlier). In our experience this allows for the early detection of many common issues. For example, from time to time, it occurs that the same adapter was used for two different libraries in the same lane. This error might be hard to spot on paper or in spreadsheets but applications such as DF Server can easily detect and report such problems similar to the example shown in btz850_Supplementary_DataClick here for additional data file."} +{"text": "Studies in natural ecosystems show that adaptation of arbuscular mycorrhizal (AM) fungi and other microbial plant symbionts to local environmental conditions can help ameliorate stress and optimize plant fitness. This local adaptation arises from the process of multilevel selection, which is the simultaneous selection of a hierarchy of groups. Studies of multilevel selection in natural ecosystems may inform the creation of sustainable agroecosystems through developing strategies to effectively manage crop microbiomes including AM symbioses. Field experiments show that the species composition of AM fungal communities varies across environmental gradients, and that the biomass of AM fungi and their benefits for plants generally diminish when fertilization and irrigation eliminate nutrient and water limitations. Furthermore, pathogen protection by mycorrhizas is only important in environments prone to plant damage due to pathogens. Consequently, certain agricultural practices may inadvertently select for less beneficial root symbioses because the conventional agricultural practices of fertilization, irrigation, and use of pesticides can make these symbioses superfluous for optimizing crop performance. The purpose of this paper is to examine how multilevel selection influences the flow of matter, energy, and genetic information through mycorrhizal microbiomes in natural and agricultural ecosystems, and propose testable hypotheses about how mycorrhizae may be actively managed to increase agricultural sustainability. The sustainable agriculture movement aims to enhance environmental quality, maintain soil fertility, reduce erosion, and sustain the economic viability of farm operations . ManaginEvolution: The Modern Synthesis. It is time to update the modern synthesis to include microbiomes.The traditional narrow focus on individuals as the only unit of selection has beenin situ management of mycorrhizas in agroecosystems:To reduce fertilizer inputs, develop mycotrophic crop varieties that substitute symbiotic uptake of nutrients for fertilizer supplements.Maintain soil P at levels that encourage selection of mutualistic mycorrhizae which optimize trading of minerals for photosynthate but do not limit crop yield.Provide sufficient N to prevent N-competition between plants and AM fungi.Maintain soil water availability so that mycorrhizal enhancement of drought tolerance can be manifested, but not so low that AM fungi are chronically water limited.Reduce tillage to maintain the fine-scale spatial structure necessary for intact hyphal networks to evolve over time through multilevel selection.Maintain host plant continuity through planting mycotrophic cover crops or perennial crop varieties.Add spatial or temporal diversity through crop rotation, intercropping or other polyculture practices.Mechanistic insights informing the development of sustainable agricultural systems may be gained through systematic testing of hypotheses related to the mycorrhizal phenotype model . The focField-based studies in many different environments are necessary to sufficiently test whether or not these hypothesized principles maximize mycorrhizal mutualism and to develop strategies to enhance their value for crop production and other ecosystem services.Managing biological soil fertility in general and mycorrhizal symbioses in particular is environmentally sustainable, but it may not be economically sustainable under current market conditions . Many coThe original contributions presented in the study are included in the article/supplementary material; further inquiries can be directed to the corresponding author/s.NJ drafted the initial version of the manuscript. KG contributed critical ideas and created The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The brain continuously receives diverse information about the external environment and changes in the homeostatic state. The attribution of salience determines which stimuli capture attention and, therefore, plays an essential role in regulating emotions and guiding behaviors. Although the thalamus is included in the salience network, the neural mechanism of how the thalamus contributes to salience processing remains elusive. In this mini-review, we will focus on recent advances in understanding the specific roles of distinct thalamic nuclei in salience processing. We will summarize the functional connections between thalamus nuclei and other key nodes in the salience network. We will highlight the convergence of neural circuits involved in reward and pain processing, arousal, and attention control in thalamic structures. We will discuss how thalamic activities represent salience information in associative learning and how thalamic neurons modulate adaptive behaviors. Lastly, we will review recent studies which investigate the contribution of thalamic dysfunction to aberrant salience processing in neuropsychiatric disorders, such as drug addiction, posttraumatic stress disorder (PTSD), and schizophrenia. Based on emerging evidence from both human and rodent research, we propose that the thalamus, different from previous studies that as an information relay, has a broader role in coordinating the cognitive process and regulating emotions. Complex sensory inputs about the external world and constant update of the internal state are fed into our neural system at every moment. The ability to capture the most relevant information from the noisy background is critical to both learning and survival. The saliency of a stimulus is not only determined by its physical properties but also influenced by different behavioral context and motivational states . TherefoA variety of neuroimaging studies have revealed the cortical nodes of the salience network, the dorsal anterior cingulate cortex (dACC), and anterior insula (AI) . SubcortEarly ideas about thalamic anatomy and function were derived from classic studies of the LGN . LGN neuThalamocortical projections exhibit interesting anatomical features, which support the role of the thalamus in orchestrating cortical activities and regulating cognitive functions. For example, single neurons in the mediodorsal thalamus (MD) send axons to multiple prefrontal areas and form patchy axon arbors. This organization allows MD neurons to recruit a specific set of cortical neurons in distant cortical regions, compatible with the role of the MD in coordinating task-relevant cortical representations. In addition, thalamic axon arborizations are found not only in the relay layer (layer4) but also in the superficial layers of the cerebrocortex , which aAltogether, the thalamus is in position to detect and orientate neural resources toward behavioral relevant stimuli. This view is further evidenced by myriad functional imaging studies . On top Salience processing is often associated with amplification of certain sensory inputs and enhanced functional connectivity, whereas arousal also requires enhanced brain excitability and connectivity, but at a more general scale . TherefoMidline thalamic nuclei receiving hypothalamic and brainstem inputs connect with widespread cortical areas . Hence, The majority of thalamic neurons are glutamatergic; however, neurons in the reticular thalamus (TRN) are primarily GABAergic and exert inhibitory control over thalamic nuclei . SpontanNeurocircuits regulating pain and reward have been considered as part of the system orientating attention toward various salient stimuli . Thalamiin vivo single-unit recording, Zhu et al. showed that posterior PVT neurons could be activated by both rewarding and aversive stimulus and the cues predicting those outcomes, indicating that the pPVT encodes stimulus salience irrespective of valance and the MD, contribute to attention control primarily via their connections with limbic structures . The ATNAccumulating evidence from human and animal studies have indicated that disruption of the MD impairs cognitive processes . AnatomiDynamic control of salience is also reflected in the process of cognitive switching, which is important for action selection and behavioral flexibility. Thalamic nuclei are involved in cognitive switching primarily through connections with the striatum and PFC . The cenWithout adequate assignment of salience, stimuli that typically trigger mood and emotions can no longer attract one\u2019s interest to act and react. Thus, it is not surprising that aberrant functional connectivity in the salience network is frequently observed in depressed patients . FunctioThalamic nuclei modulate both innate fear and conditioned fear responses . Fear exOn the other hand, augmented observational fear responses have been demonstrated in socially related conspecifics . Social Given the essential role of the thalamus in salience processing, it is perhaps not surprising that altered connectivity patterns and responses of thalamic nuclei have been poised to contribute to the aberrant salience attribution in neuropsychiatric disorders. Below, we will describe the engagement of thalamic dysfunction in three distinct mental disorders, in which dysregulation of salience processing is often observed.Drugs of abuse profoundly modulate neural response toward previous neutral stimuli which become associated with drugs. The development of incentive salience of drug-paired context or cues is an essential component of drug addiction . As discThe phenomenon that drug-seeking behaviors progressively increase after abstinence is termed incubation of craving . In addiPosttraumatic stress disorder (PTSD) is a long-lasting and recurring mental disorder triggered by traumatic experience. Trauma recollection is associated with enhanced connectivity in the salience network, while salience connectivity is reduced following effective treatment in PTSD patients , b. PTSDPsychotherapeutic strategies for treating PTSD often involve reassignment of salience and modulation of attentional processes . For exaSchizophrenia is a mental disorder involving a range of problems in cognition, emotion, and behaviors. One influential theory about schizophrenia is that positive symptoms including hallucination and illusion could be attributed to aberrant assignment of salience to a certain experience or internal representation .Abnormalities in structure and function of the thalamus have been associated with schizophrenia . AccordiAs discussed above, thalamic neurons could encode salient features of stimuli, contributing to cognitive process and emotional regulation. However, it remains unknown how the information of salience is integrated from distinct pathways in single thalamic neurons. Also, it is worth further investigating the role of the neuromodulatory system on salience control in the thalamus. Stress induces perturbations in the structure and function of the brain, which present a major risk factor for many neuropsychiatric disorders. Future studies describing the molecular and circuitry adaptations in acute and chronic stress, would help us to analyze the contribution of the thalamus to salience allocation under pathological conditions.KZ, LZ, and GH contributed equally to the writing of this review article. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Personality pathology and emotion dysregulation are associated with impaired psychological and functional outcomes in adults. However, much less is known about their relationship with depression, social functioning, and suicidal behaviors among older clinical samples. The aim of this study was to examine how the two impact depression, social adjustment, and suicidal behavior in an inpatient sample of depressed adults 55 to 89 years of age (N=52). Personality (agreeableness and neuroticism) and suppression strategies (expressive and thought suppression) were first investigated individually and then jointly as a combined predictive model. Results found lower agreeableness predicted poorer social adjustment , while higher neuroticism and greater use expressive suppression each predicted more severe depressive symptoms. Individuals high in neuroticism also evidenced greater use of both thought suppression and expressive suppression, while those who were more depressed endorsed poorer social functioning. Although not reaching the point of statistical significance, lower agreeableness, higher use of suppression strategies, and poor social functioning were found to be moderately associated with experience of recent suicidal ideation. Our findings demonstrated personality pathology and ineffective emotion regulation are promising potential pathways in the detection and intervention of psychological and functional impairments in depressed older adults. Our study also highlighted the need for more research examining the effects of personality pathology and emotional dysregulation from a functional perspective, which could enhance the focus of target problem areas in interventions for severely depressed older adults."} +{"text": "This symposium presents data from three applied clinical research projects that involve intergenerational interaction as one component of effective treatment. The first paper describes learner outcomes in an intergenerational art therapy and reminiscence program provided in an adult day service facility. Results show that, in comparison with students in a didactic psychology of aging course or an introductory psychology course, learners in the experiential learning course demonstrated increased empathy, as well as better attitudes toward and increased interest in working with persons with dementia (PWD). The second paper focuses on observed outcomes for older PWD participants in this art therapy and reminiscence program, showing that intergenerational communication engagements exceed engagements with art. Mixed method data across time indicated that PWD benefitted from the treatment, facilitated by undergraduate student learners. The third paper focuses on cultural humility and the importance of racial diversity in providers conducting behavioral health screening in an integrated geriatric primary care clinic. Training issues and behavioral health outcomes regarding assessment of cognitive status, cultural mistrust, and test validity are considered. The fourth and final paper considers how intergenerational dynamics facilitated group cohesion and allowed for increased normalization of common challenges in mindfulness practice. Training issues for graduate student therapists are described. Consideration of level of behavioral health integration in each site, treatment efficacy, and the impact of intergenerational relationships are the foci of discussion. This symposium will show why age matters in behavioral health training."} +{"text": "Retinal degenerative diseases (RDDs) are a group of diseases contributing to irreversible vision loss with yet limited therapies. Stem cell-based therapy is a promising novel therapeutic approach in RDD treatment. Mesenchymal stromal/stem cells (MSCs) have emerged as a leading cell source due to their neurotrophic and immunomodulatory capabilities, limited ethical concerns, and low risk of tumor formation. Several pre-clinical studies have shown that MSCs have the potential to delay retinal degeneration, and recent clinical trials have demonstrated promising safety profiles for the application of MSCs in retinal disease. However, some of the clinical-stage MSC therapies have been unable to meet primary efficacy end points, and severe side effects were reported in some retinal \u201cstem cell\u201d clinics. In this review, we provide an update of the interaction between MSCs and the RDD microenvironment and discuss how to balance the therapeutic potential and safety concerns of MSCs' ocular application. Retinal degenerative diseases (RDDs), including age-related macular degeneration (AMD), retinitis pigmentosa (RP), Stargardt disease (STGD), and Leber congenital amaurosis (LCA), are some of the leading causes of irreversible vision loss worldwide , and stem cell therapy\u2014have the potential to delay vision loss or even to restore vision are multipotent cells isolated from a variety of tissues, such as adult bone marrow , adipose tissue , and dental pulp , and extracellular vesicles (such as exosomes and microvesicles) that contain reparative molecules survived in rat eyes with chronic hypertension and protected retinal and optic nerve function and structure from MSCs promote photoreceptor cell survival can also protect photoreceptors. Intravitreally injected autologous bone marrow\u2013derived lineage-negative hematopoietic stem cells prevented cone loss in two murine models of retinitis pigmentosa (rd1 and rd10) in the RCS rat model of retinal degeneration can preserve photoreceptors and visual function into STZ-induced diabetic athymic nude rats in mouse MSCs may obtain optimal therapeutic effects in vivo without using immunosuppressant have not observed obvious rejection . The common sources of MSCs for clinical trials of retinal degeneration therapy are bone marrow (BM) stem cells -derived MSCs have been proposed as an unlimited source of cells for therapeutic applications in regenerative medicine. These cells possess better cell quality with batch-to-batch consistency and higher proliferative potential and display stronger immunomodulation effects (Zhang et al., Another strategy to overcome MSC product heterogeneity is using primed MSCs or boosting the innate therapeutic efficacy by other bioengineering methods (Levy et al., A pre-clinical study indicated that systemically administered MSCs did not migrate to the injured eyes and had no effects on RDDs, as they are trapped in lung capillary beds (Johnson et al., Subretinal injection allows direct contact of the host and MSCs, but the injection procedure may disturb the retina. There are two main surgical approaches, internal and external. The internal approach requires an initial vitrectomy, after which a small-gauge needle is introduced into the eye via the pars plana and is passed through a retinotomy at the injection site and the cell suspension is deposited in the subretinal space near the fovea. The external approach involves subretinal delivery of cells via a cannula delivered outside the eye through the suprachoroidal space. This technique avoids exposure of the cells to the vitreous cavity but can induce retinal perforation and detachment (Ho et al., The intravitreal delivery approach is straightforward and widely used in anti-VEGF therapy in the ophthalmic clinics. The MSCs are injected as a suspension into the vitreous cavity via a needle through the pars plana. The cells do not gain access to the subretinal space and remain in the vitreous. Cellular cluster formation in the vitreous occurred in some cases of MSC intravitreal injection (Tzameret et al., in vitro (Levy et al., Both intravitreal and subretinal injection can disturb the host BRB and expose the grafted cells to the host retinal immune system and thus raise concerns about long-term donor cell survival. Indeed, both the retention and survival of MSCs following local administration are important factors affecting the therapeutic outcome (Levy et al., Retinal degeneration diseases are a leading cause of blindness worldwide and there is no effective treatment. MSCs can be easily isolated from multiple tissues and have shown promise in treating many diseases by restoring organ homeostasis in inflamed, injured, or diseased tissues. Pre-clinical animal studies suggested that their trophic and immunomodulatory properties can protect retinal neurons and enhance the function of retinal pigment epithelium cells from an array of retinal degeneration diseases. Recent clinical trials have demonstrated promising safety profiles for the application of MSCs in retinal diseases and have provided valuable data for future exploration. However, significant complications that arise from poorly designed clinical trials, questionable practices or regulatory shortcuts could substantially hinder research in MSC-based retinal therapies. Nevertheless, MSCs have great therapeutic potential for the treatment of retinal degeneration. A better understanding of the interaction between MSCs and host retinal degenerative environments is the key to yield an optimal benefit. Overcoming the heterogeneity in the MSC product and optimizing ocular surgical delivery to avoid adverse sequela are major challenges to translational use of MSCs to treat retinal degeneration.YL and DC were involved in the concept and design. YL and XR wrote the first version of the manuscript. YL, YC, and DC reviewed and revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Current, literature has found a negative relationship between caregiving responsibilities and paid employment. There are two possible causal explanations; people with low employment prospects self-select into care and caregiving is time-consuming therefore, it require carers to accommodate this by reducing work. While there is considerable work on the influences of caregiving on work, there is limited research investigating how employment influences informal caregiving decisions. We investigated longitudinal associations between work status preferences and informal caregiving among older adults in New Zealand. The present study also explored whether gender and perceived health moderated the relationship between work status preference and caregiving. The study used data provided by three waves of the New Zealand Health, Work and Retirement Study. The findings suggest that underemployed and overemployed participants were more prone to taking up caregiving compared to participants who were satisfied with their work status. Regression analyses revealed that females with poor self-reported health were most vulnerable to experience incongruent work status preferences. The direct effects of work status preference on willingness to care may imply conflict between policies promoting full time labour force participation and social welfare policies that are continuing to rely on family carers to support the community. This evidence has implications for care policy given the importance of informal care in sustaining ageing in place policies."} +{"text": "As access to computers and use of technology becomes more common in older adults, the incidence of online financial fraud increases. Law enforcement officials and fraud experts predict this trend to continue as aging baby boomers increasingly become targets. One reason this population might be at risk for financial fraud is due to subtle, undetected decline in cognitive abilities that have been associated with decline in financial capacity. Many cases of incipient cognitive decline go undetected. Further, those with early cognitive decline often have poor insight to its potential impact on daily functioning. Assessment of Activities of Daily Living Skills (ADLs) is paramount to determine early decline in daily activities. The ORCATECH Life Lab was designed to evaluate subtle neurological and other health changes and their relation to changes in daily functioning. Older adults participating in the Life Lab complete annual ADL and neurocognitive assessments. Additionally, 97 participants completed an online technology questionnaire where 64 participants reported participating in online financial activity. Results revealed that within the online financially active group, some assistance in ADL\u2019s was required. However, inconsistencies in ADL change over time highlight the challenges of screening for early signs of mild cognitive impairment (MCI) in patients that fall between normal cognition and MCI. In-home information technology may help overcome these challenges. Defining subtle changes in ADLs is a crucial step to enable early diagnosis of neurocognitive disorders and assist health care providers in improving disease management and to prevent incidents of financial fraud in this vulnerable population."} +{"text": "The use of telemedicine in pediatric rheumatology has been historically low. The current COVID 19 global pandemic has forced a paradigm shift with many centers rapidly adopting virtual visits to conduct care resulting in rapid expansion of use of telemedicine amongst practices.This commentary discusses practical tips for physicians including guidance around administrative and governance issues, preparation for telemedicine, involving the multidisciplinary care team, and teaching considerations. We also outline a standard proforma and smart phrases for the electronic health record. A proposed variation of the validated pediatric gait arms legs spine examination (pGALS) called the video pGALS (VpGALS) as a means of conducting virtual pediatric rheumatology physical examination is presented.This commentary provides a starting framework for telemedicine use in pediatric rheumatology and further work on validation and acceptability is needed. This commentary describes practical creative approaches based on our experiences and discusses the potential for telemedicine to address unmet needs in the wider context of pediatric rheumatology.The COVID-19 pandemic has forced rapid changes in the way that medical care is delivered worldwide. Virtual care models with remote clinics and video visits (e-visits or telemedicine) have become widespread practice overnight. The adoption of telemedicine in pediatric rheumatology has been limited historically . Furthercredentialing of providers to provide telemedicine is entrusted to the remote site where they are physically located [originating site (where the patient is located) [Patient privacy and confidentiality is paramount and needs to be addressed in the technological requirements with access (at both originating site and remote sites) restricted to individuals essential to facilitate patient care. This may include an in person telepresenter, multiple virtual support staff to help coordinate after visit care, and, other specialists and members of the multidisciplinary team (MDT). Many electronic health record (EHR) systems have compliant telehealth modules and General Data Protection Regulation (EU). For circumstances in which an EHR module is not available, several commercial vendors offer \u2018standalone\u2019 privacy compliant video platforms. Issues related to data ownership and security vary in different regions of the world, depending upon whether telemedicine is considered to be a healthcare service or an information service. It is important to review the contract for services, as different vendors may also have different policies. Both standalone telemedicine platforms and EHR modules offer the ability to capture still images (photographs) or have the capacity for asynchronous communication. The billing systems used for in-person visits are also used for telemedicine visits. Limitations in the observed physical examination make time-based billing more rewarding in many circumstances, but the complexity of pediatric rheumatology medical decision make it a viable alternative in our specialty.Guidance for telemedicine clinics is available Table\u00a0 albeit g located , 4 and plocated) . ConsentPreparation is essential and includes provider related tasks, incorporating the broader MDT and ensuring that family are supported with the requisite equipment and information. We provide resources and practical tips in Table Patient selection for video visits will be influenced by individual site and situational factors. Generally speaking most established patients can be seen by video visits at least on an intermittent basis. Young patients (<\u20093\u2009years) are more challenging to keep on task with a virtual joint exam, but a care-giver only visit to discuss symptoms or medication side effects is often feasible. Guidance for consideration of urgent in-person evaluations during the ongoing pandemic is available and include new patient evaluations when the consulting or referring provider indicates urgency, acute flare or ongoing disease activity of a known disease.The Virtual Exam Section requires creativity depending on the location of the family/patient, consideration of the exam sequence, technical issues and how to cue the family and child to gain optimal views . At the start of the visit, obtaining consent is important and a brief scaffolding statement helps to ease anxiety and set expectations. Documentation of discussions with the family and mechanisms to ensure follow up tasks are coordinated and carried through is critical. We provide suggested EHR Dot Phrases and a recording proforma or other key persons .Teaching opportunities. Telehealth clinics provide novel educational opportunities (Practical Tips - Table The COVID-19 pandemic has provided an opportunity to expand telerheumatology and address workforce challenges around the world , 11. Tel"} +{"text": "The tumor extended to the symphyseal portion of the mandible and fungated through the skin in the submental area. After bilateral selective neck dissections and composite floor of the mouth, partial tongue, and mandible resections, the residual defect measured 168 cmWhat is the epidemiology of invasive head and neck cancers?What are the goals of head and neck reconstruction?What are common options for reconstruction of mandibular defects?What impact does peripheral vascular disease have on flap selection?Globally, head and neck tumors comprise the sixth most common cancer, with squamous cell carcinoma representing nearly 90% of diagnoses.Invasive head and neck cancers are advanced in nature and often extend beyond the primary site to disrupt local anatomical integrity.,For extensive mandibular defects, free tissue transfer is ideal to bring in healthy, vascularized tissue and for improved structural integrity. The most common options include the free fibular flap (FFF), iliac crest free flap, scapular or parascapular free flap, and radial forearm free flap. All of these flaps provide the opportunity to reconstruct both bony and cutaneous defects simultaneously. The FFF and the iliac crest flap offer large amounts of available bone as well as adequate vascular pedicles, allowing for variability in flap sizes. However, the peroneal vessels used in the FFF are commonly narrowed in patients with peripheral vascular disease and incidences of disfiguring scars and chronic gait disturbances following iliac crest flaps have been reported in as high as 20% of patients.6Given the aforementioned causes of these cancers, a majority of patients expectedly reveal a long-standing history of peripheral vascular disease. In addition to causing technical difficulties with vascular anastomoses, it influences the choice of reconstruction. Our patient expressed an extensive history of smoking up to 4 packs per day; preoperative angiography revealed severely reduced diameter of the peroneal artery, precluding the possibility of using an FFF. The bony defect spanned the entire mandible, excluding the use of a scapular flap. Alternatively, the decision was made to perform bony reconstruction with a titanium plate. Next, recreation of soft-tissue bulk was achieved by sandwiching the plate between a latissimus dorsi myocutaneous free flap . This fl"} +{"text": "The coronavirus pandemic has impacted medical education globally. As universities seek to deliver medical education through new methods of modalities, this continuing of education ensures the learning of the future workforce of the NHS. Novel ways of online teaching should be considered in new medical curricula development, as well as methods of delivering practical skills for medical students online. The coronavirus disease COVID-19) pandemic has had a worldwide impact on the population, global economy and heath care systems. Whilst the spread of the virus has resulted in far-reaching consequences, the closure of schools and universities has led to innovative methods of delivering education, ensuring that students continue to receive teaching, albeit different methods of modality. A national effort by UK medical schools in graduating early nearly 5,500 final-year students will allow for these interim Foundation Year doctors to support the NHS during the pandemic [9 pandemiThe coronavirus pandemic has seen the introduction of novel methods of delivering education to medical students. Lectures have rapidly been developed to be delivered online as webinars using various platforms such as Zoom, with such technologically enhanced approaches already being proven to have high levels of engagement with medical students . With inThe transition to online medical education has also seen a change in examination methods. Following on from the recent success of Imperial College London\u2019s first ever online exam for final years , other mTo ensure the future workforce of the NHS are qualified, continuing education is vital and this can be achieved by medical school staff continuing to engage regularly with medical students using online teaching platforms. The current success of online teaching and OBEs provides an initial insight into new and innovative ways of teaching for medical education. Consideration is encouraged as to how such online methods may be adapted to deliver teaching on clinical and practical skills remotely that would otherwise have been developed during clinical placements."} +{"text": "False ideas about the physical and psychosocial characteristics of older adults exist in America. It is especially important that nurses are not susceptible to myths and stereotypes as these myths can affect the quality of patient care. For example, some people stereotype older adults as forgetful, disabled, ill, and unable to understand new information. Misconceptions and negative stereotypes are also present in first year nursing students. It is vital that students assess their own attitudes about older adults to form positive attitudes and gain knowledge about aging and health care needs. To achieve this goal, the older adult lecture in a first semester theory and fundamental course begins with a PowerPoint slide presentation asking students to distinguish truths and myths. The truth or myth topics include a) developmental tasks; b) common physiological changes; c) a comparison of delirium, dementia, and depression; and d) addressing health concerns of older adults. Active discussion follows the activity. Seventy to ninety percent of students correctly answered nine of ten questions related to older adult content on the final exam. Considering the increasing number of older adults in the health care setting, nurse educators must dismantle negative stereotypes with creative teaching strategies."} +{"text": "A better understanding of the molecular evolution of myofilament proteins in the context of physiological functions of invertebrate and vertebrate flight muscles can help explore novel approaches to enhance the performance and efficiency of skeletal and cardiac muscles for the improvement of human health.The powered flight of animals requires efficient and sustainable contractions of the wing muscles of various flying species. Despite their high degree of phylogenetic divergence, flight muscles in insects and vertebrates are striated muscles with similarly specialized sarcomeric structure and basic mechanisms of contraction and relaxation. Comparative studies examining flight muscles together with other striated muscles can provide valuable insights into the fundamental mechanisms of muscle contraction and energetic efficiency. Here, we conducted a literature review and data mining to investigate the independent emergence and evolution of flight muscles in insects, birds, and bats, and the likely molecular basis of their contractile features and energetic efficiency. Bird and bat flight muscles have different metabolic rates that reflect differences in energetic efficiencies while having similar contractile machinery that is under the selection of similar natural environments. The significantly lower efficiency of insect flight muscles along with minimized energy expenditure in Ca Insecta (insects) and Aves (birds) and in the Chiroptera order of mammals (bats). It is interesting to investigate how flight muscles of these phylogenetically distant species have evolved to meet the requirement of highly efficient and sustainable contractions to power their wings during flight. Insect and vertebrate flight muscles are both striated muscles with similar sarcomeric structure, and myofilament motor and regulatory proteins. To compare their similarities as well as unique features together with non-flight muscles for convergent evolutionary selections can help provide insight to the molecular basis of the contractility and energetic efficiency required for flight muscles.Flying is an energetically demanding activity for animals. Muscle-powered flights have evolved in the classes of The flight capacity of insects, birds, and bats is a typical example of convergent evolution. These animals have independently evolved from different ancestors at different times with analogous functionality of powered flight as results from similar natural selective pressures .Certain common environmental factors might have been critical to the emergence and convergent evolution of animal flight. Geophysical data indicate that dramatically elevated atmospheric oxygen level occurred twice in the history of Earth . The firWingless insects emerged 395\u2013390 Mya, and although the origin of flying insects is unclear, the ancestor was likely a pterygote hexapod (winged insect) as indicated by the earliest fossils dated from \u223c325 Mya Nelson . The mor2) compensated for the diffusional limits in insect tracheal systems during respiration, reducing constraints on maximum body size, and the atmospheric hyperoxia may have played a role in the evolution of gigantism have much larger body sizes compared to Microchiroptera (microbats). Microbats evolved the ability of echolocation using high frequency sounds to detect small preys such as insects, while megabats are nectarivores and dragonfly (Odonata), which have wing beats at lower frequencies (<100 Hz). Similar to the actions of avian pectoral muscles, contraction of elevator muscles in the thorax lift the wings, and depressor muscle contractions power the wings to power high frequency wing beating via deformation of the thoracic exoskeleton rather than directly driving the movements of wings . With conous IFM .Bird flight is primarily powered by the pectoralis muscles that move the humerus bone of the wing around the shoulder. The pectoralis muscles of most adult birds take up approximately 8\u201311% of the total body mass . The priTo produce sufficient aerodynamic power to sustain flight, avian flight muscles need to continuously contract at high frequencies with substantial work and with high energy costs. The fiber-type compositions of avian flight muscles vary in different species. The pectoralis contains mainly fast-oxidative fibers (\u223c85% in pigeons) and a small portion of fast-glycolytic fibers, while in supracoracoideus, the proportions of fast-glycolytic fibers and fast-oxidative fibers can be very different among species .Like in most flying birds, bats have a keel on the sternum where the large pectoral muscles attach . Gross aUnlike the flapping wings of birds and insects, bats have evolved unique wing structures that are more like the patagia of gliding animals. Bat wings are formed with membranous skin called plagiopatagium covering the bones of forelimb and connecting the areas between the limb, digits and even the tail. The majority of the surface area of bat wings is skin that varies in thickness between 27 and 270 \u03bcm depending on the species. The skin of a bat wing is complex and unique, and is composed of bundles of elastin and embedded tiny skeletal muscles named plagiopatagiales . The ela2+-activated or stretch-activated contractions indicate adaptations to specific selective pressures for a particular type of flight activity , the inhibitory subunit troponin I (TnI), and the thin-filament anchoring subunit troponin T (TnT) . The increase in cytosolic [Ca2+] promotes the binding of Ca2+ to TnC and induces a series of conformational changes in Tn and tropomyosin, allowing the myosin heads to form strong cross bridges with the actin thin filament to activate myosin ATPase and generate power strokes. Muscle relaxation occurs when free Ca2+ decreases by the work of SR and plasma membrane Ca2+ pumps that remove Ca2+ from the cytosol resulting in Ca2+ dissociation from TnC . When thfrom TnC .Based on the conserved subcellular structures, biochemical basis and functions, unique features of the contractile and regulatory mechanisms of insect, avian, and bat flight muscles can provide insights into the evolution of their contractility and energetic efficiency.The fact that the flight muscles of lower insects such as locusts and dragonflies with wing beating frequency slower than 100 Hz have synchronous flight muscles that function like the non-flight muscles of insects and vertebrate striated muscles suggests2 + influx that induces the release of larger amounts of Ca2+ from the SR. The rising free Ca2+ binds to TnC, which induces conformational changes in the Tn complex and tropomyosin in the actin thin filaments, leading to activation of myosin ATPase. ATP hydrolysis generates a power stroke of the myosin head to shorten the sarcomere and contract the muscle. During relaxation, the cytosolic Ca2+ is pumped back to SR and extracellular space. With this mechanism, the rate of Ca2+ cycling is limited by the rates of Ca2+ diffusion and SR Ca2+ pumps, restricting the wing beat frequency of insects with synchronous flight muscles to <100 Hz , which ile cells . A hypotMeasuring wingbeat kinematics as mechanical power and metabolic power (oxygen consumption) estimated that the efficiency of avian flight muscle is between 13% and 23% in small birds . Avian pUnlike insects and mammals, flying birds exhibit a high daily energy turnover and have a longer lifespan compared to mammals of similar body mass. Because of chronically elevated blood glucose and insulin resistance, avian flight muscles predominantly use lipid oxidation to power locomotion, which yields more energy than carbohydrate metabolism. To prevent free radical production under the high metabolic rate, mitochondria of sparrow pectoralis muscle have a much higher capacity of oxidizing fatty acids than mitochondria of rat hindlimb muscles. In addition, avian flight muscle has a high electron transport chain/oxidase ratio, indicating a low redox potential for the production of reactive oxygen species .Migrant birds can sustain long distance flight non-stop without food or water intake. The metabolic rate of migrating birds is adjusted in real-time by their migration needs. They primarily use lipids and a minimal amount of protein as fuel during flight . During N-terminal variable region .Similar to birds, bats have a high metabolic rate and relatively small body size but an exceptional longevity. Unlike birds, bats do not use triacylglycerol as oxidative fuel due to the lack of efficient transport enzymes in mammals . TherefoThe high metabolic rate of bats is essential for their flying ability but also results in a systemic accumulation of harmful free radicals. Genomic studies found that bats evolved genetic variants to counter the toxicity of free radicals generated during flight . It has A proposed mechanism of energetic efficiency in bats is the trade-off with maneuverability. Wind tunnel experiments showed that while bats are less energetically efficient than birds in cruising flight, they have the edge over birds when it comes to maneuvering . While bN-terminal Glu-rich region of avian pectoral muscle fast TnT, whereas its overall structure is conserved similar to that of avian leg muscle fast TnT and mouse fast skeletal muscle TnT (To investigate whether the analogous Glu-rich segments evolved in insect and avian pectoral muscle TnT had alsoscle TnT .By comparing the flight muscles of insects, birds, and bats for their evolution of contractile features and mechanisms for energetic efficiency, the data summarized in this focused review show that while these phylogenetically diverse animals independently evolved flight abilities at different times from different ancestral lineages, natural selection has yielded analogous flight functions. While many hypotheses and debated viewpoints remain for the origins of flight, the existing evidence provides informative insights into the understanding of muscle contractility and energetic efficiency. To achieve and sustain flight, all flying species need to balance flight performance and energy saving, which is also important in other muscles especially when the treatment of muscle weakness and heart failure is considered.A better understanding of the molecular evolution of myofilament proteins in the context of physiological features of invertebrate and vertebrate flight muscles can help explore potential mechanisms and translational applications for improving human health. One intriguing point is the underlying molecular mechanisms for bird and bat flight muscles to function with very different metabolic rates reflecting different energetic efficiencies, although they have similar contractile machinery and under the selection of similar natural environments.2+ handling system that is a major ATP consumer in vertebrate striated muscles (2+ handling vs. that of myofilament myosin motors in mammalian striated muscle is an attractive direction to increase the energetic efficiency for the treatment of muscle weakness and heart failure.Another attractive direction for future research is that the low contractile efficiency of insect asynchronous IFM is sustained by minimizing the work and energy expenditure of the Ca muscles . Past anBoth authors contributed to the literature review, data analysis, compose figures and table, draft and revision of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Rapid technology evolution has led to new challenges for the anesthesiologist in neurosurgical practice. This trend resulted in training in neuroanesthesiology to adapt to the changes. Neuroanesthesiology fellowship training has increasingly received the auspicious attention of graduates from anesthesia residency programs. Competency in neurological surgical procedures requires a multidisciplinary approach with anesthesiologists that hold profound knowledge in neurological sciences. Enhanced learning experiences in neuroanesthesiology and neuro critical care are a part of the changing sphere of clinical neurosciences training . AdaptatNeurosurgical procedures are extremely delicate and require a collaborative effort to ensure safety and success. Technologically fueled interventional neuroradiology is particularly challenging for anesthesiologists to practice in new settings and demandingly complex procedures . The devTherefore, multidisciplinary collaboration between neurosurgery and anesthesia during training has become critical for anesthesia practitioners. Furthermore, the success and strength of any neuroanesthesiology program can only be enhanced through collaboration among faculty from the departments of neurosurgery, neurology, anesthesiology, and critical care medicine . Such coCapacity enhancement continues to be a trend in graduate medical education\u00a0at teaching hospitals. After clinical residency training, anesthesiologists encounter\u00a0dilemma of whether a subspecialty fellowship is necessary to strengthen her skill sets and competitiveness in the job market. Pursuing a fellowship is yet another training commitment after lengthy residency training. The debate continues if a year or even three more years of subspecialty fellowship training is necessary in today\u2019s challenging and rapidly advancing medical careers.How critical is neuroanesthesia fellowship?Anesthesia for neurological procedures requires an advanced understanding of anatomy and physiology of the central nervous system and the pathophysiology of related diseases that are likely to change in response to other diseases, such as space-occupying lesions, trauma, and infection . AnestheConditions such as vasogenic and cytotoxic cerebral edema require an extensive understanding of pathophysiological reasoning and must be treated accurately and appropriately. The anesthesiologist is required to provide optimal operating conditions and to be capable of early detection and proper management of intraoperative events and complications. As such, any disturbances must be corrected to ensure a smooth operational intervention. Emergence should be well and rapidly controlled to establish assessment immediately after the procedure.Neurosurgery is meticulous and microscopically complex. Anesthesiologists who specialize in this field should understand the fundamentals of neurosurgical procedures and be familiar with critical aspects of the surgery . CommuniWhat is the goal of neuroanesthesia fellowship?The goal of neuroanesthesiology fellowship is to provide advanced technological and clinical training in anesthesia related to neurological diseases, including advanced understanding of neurological related physiology, pharmacology, and pathophysiology . ClinicaAt the end of the neuroanesthesiology fellowship program, the graduate will become skilled in performing preoperative assessment of patients with neurological and neurosurgical diseases. Graduates will be competent in developing and executing an appropriate anesthetic plan that includes monitoring techniques and provides perioperative patient management. Graduates will participate in the neurosurgical patients\u2019 perioperative care and will function as part of a contemporary multidisciplinary neurocritical care team . FellowsFellowship market in anesthesiaThe mission of fellowship training is to produce advanced-level competence in clinical subspecialties. The ACGME introduced competency-based milestones for resident and fellowship education necessary for independent practice in some specialties. Thus, fellowship programs are established to provide research and educational experience to enhance trainees\u2019 clinical and teaching skills. During the 2019 academic year, the ACGME tabulated there were 1442 anesthesiology senior residents and 1070 fellows in the training pipeline . EstimatMilestone developmentThe Council on Perioperative Neuroscience Training (ICPNT) stated, it is critical for fellows to master the cognition and skills to utilize various monitors, such as fiberoptic intubations, intracranial pressure monitoring, regional cerebral oxygenation monitoring, placement of jugular bulb catheters, and transcranial doppler ultrasonography . FellowsThe ACGME commissioned the Society for Neuroscience in Anesthesiology and Critical Care (SNACC) to adapt the ACGME anesthesiology milestones for use in neuroanesthesiology graduate medical education and training milestones. Since then, 12 neuroanesthesiology-specific milestones in five major ACGME domains are recommended. These milestones include medical knowledge, practice-based learning and improvement, and interpersonal and communication skills [In the international sphere, developed countries such as Japan and Canada also have a structure adaptive process in advanced neuroanesthesiology training ,13. AlthOver the last two decades, growth in the neuroscience field has been exponential. The care of neurosurgical patients requires specialized neuroanesthesiologist. Advanced and complex neurosurgical procedures require the understanding of disease pathology and procedure-specific knowledge. Anesthetic techniques may influence neuropathological conditions, and anesthesia care for neurological related surgeries mandate a thorough preoperative assessment, as these are often pathologically complicated. Participation and spending extra time in subject-specific neuroanesthesiology training is critical. Fellowship provides confidence and skills required to deal with advancements in technology and increased complexity of care. Such training also grants trainees the credentials for team building and patient care."} +{"text": "We are grateful for the insightful comments in regardinWe also agree that the associations between occupational noise exposure of maritime workers and the development of hypertension or other cardiovascular diseases, such as coronary heart disease, require further investigation. The fact that noise exposure is not mentioned in existing summaries of occupational cardiovascular risk factors of seafarers and thatTo prevent not only sensorineural hearing loss but also cardiovascular diseases, such as arterial hypertension, occupational physicians and technicians in all affected industries should promote appropriate technical, organizational and personal protective measures to reduce the level of occupational noise exposure."} +{"text": "For the growing population of older immigrants in the United States, both age at immigration and familial relationships are important factors affecting psychological well-being. This study explores how age at immigration and contemporary relationships with adult children combine to explain older immigrants\u2019 depressive symptoms. This study uses 2014 Health and Retirement Study data from a sample of 759 immigrants age 65 and older who have at least one adult child age 21 or older. A series of ordinary least squares regressions and mediational analyses were conducted. Findings indicate that two aspects of familial relationships, associational solidarity and structural solidarity, significantly mediate the association between age at immigration and depressive symptoms. Specifically, immigrating in later-life was associated with a lower level of depressive symptoms through its relationship with structural solidarity. Immigrating in later-life was also associated with a higher level of depressive symptoms through its relationship with associational solidarity. In addition, giving monetary support to children and providing care for grandchildren may alleviate depressive symptoms for older immigrants. This study suggests that relationships with adult children may differ with age at immigration. The types of support that older immigrants provide to their adult children may be crucial because such support may instill a sense of obligation and reciprocity that may be beneficial to the psychological well-being of older immigrants."} +{"text": "Health inequity is linked to societal and social determinants that constrain health promoting opportunities for older adults. From birth to death, many older adults contend with the prevailing social and health effects of discrimination in employment, education, and housing. As a consequence, middle-aged Black Americans are experiencing accelerated aging, and living with and dying from preventable chronic health conditions typically diagnosed at older ages. Despite these conditions, there is much variation in health outcomes among older Black Americans. Professor Karen Lincoln will share her approach to research that explores heterogeneity within the Black American population to discover factors that promote healthy aging. She will describe her unique outreach and health education program that serves older adults in underserved communities, and her roles as an aging advocate and public scholar. She will discuss how these experiences led to the development and testing of an innovative intervention to reduce Alzheimer\u2019s disease disparities."} +{"text": "Using data from older participants from the 2015 Asian American Quality of Life survey (n = 533), the present study assessed direct and interactive effects of life stressors and social capital. The sample includes diverse Asian ethnic groups . Among all groups, high levels of mental distress were found in Koreans and Vietnamese. In the multivariate analyses, Korean ethnicity (compared to Chinese) was found to be a significant predictor to mental distress. As significant risk factors to mental distress, all stressor variables accounted for 9% of the variance of mental distress. Social capital variables explained the variance by 4%. None of the interaction terms reached statistical significance. Findings confirmed the negative effects of stressors and the positive effects of social resources across older Asian Americans. However, it was interesting to note that ethnic variations disappeared when stressors and social capitals were taken into considerations."} +{"text": "Teamwork and communication are recognised as key contributors to safe and high-quality patient care. Interventions targeting process and relational aspects of care may therefore provide patient safety solutions that reflect the complex nature of healthcare. Team reflexivity is one such approach with the potential to support improvements in communication and teamwork, where reflexivity is defined as the ability to pay critical attention to individual and team practices with reference to social and contextual information.To systematically review articles that describe the use of team reflexivity in interprofessional hospital-based healthcare teams.Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, six electronic databases were searched to identify literature investigating the use of team reflexivity in interprofessional hospital-based healthcare teams.The review includes articles investigating the use of team reflexivity to improve teamwork and communication in any naturally occurring hospital-based healthcare teams. Articles\u2019 eligibility was validated by two second reviewers (5%).Fifteen empirical articles were included in the review. Simulation training and video-reflexive ethnography (VRE) were the most commonly used forms of team reflexivity. Included articles focused on the use of reflexive interventions to improve teamwork and communication within interprofessional healthcare teams. Communication during interprofessional teamworking was the most prominent focus of improvement methods. The nature of this review only allows assessment of team reflexivity as an activity embedded within specific methods. Poorly defined methodological information relating to reflexivity in the reviewed studies made it difficult to draw conclusive evidence about the impact of reflexivity alone.The reviewed literature suggests that VRE is well placed to provide more locally appropriate solutions to contributory patient safety factors, ranging from individual and social learning to improvements in practices and systems.CRD42017055602. Traditionally, measurement of and intervention for patient safety have focused on learning from specific harm events. The effectiveness of this approach is limited, relying, as it does, on retrospective reports and producing recommendations for practice based on unrealistic views of in-situ clinical work.\u2018the interrelatedness of the components within a system\u2019,By definition, complexity concerns Reflexivity is seen as a way to frame individual actions and behaviours with reference to the effect of the actions and behaviours of others, and the context in which these actions occur.Reflexivity as a collective practice in healthcareA more novel approach to team reflexivity is video-reflexive ethnography (VRE).This review therefore aims to collate the literature exploring the use of reflexivity in interprofessional healthcare teams, specifically attempting to understand the use of reflexivity in interprofessional teams working in the provision of hospital-based healthcare and how these tools might impact patient safety.The review will focus on the following questions:How has reflexivity been used with interprofessional healthcare teams?How do staff respond to different methods of supporting team reflexivity?Does team reflexivity work to effect change in teamwork and communication?This review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement see ,31 and t10.1136/bmjqs-2019-009921.supp1Supplementary data10.1136/bmjqs-2019-009921.supp2Supplementary dataThe inclusion criteria are outlined in Study quality was assessed using the Quality Assessment Tool for Studies with Diverse Designs (QATSDD).All data were extracted by a single researcher (SKM) using predefined data extraction points . Followi10.1136/bmjqs-2019-009921.supp3Supplementary dataThe search strategy yielded 2566 articles excluding duplicates. In total, 15 articles met the inclusion criteria and were included in the review . Article10.1136/bmjqs-2019-009921.supp4Supplementary dataThe quality of studies was variable, with total scores ranging from 40% to 83% (mean=60%; 10.1136/bmjqs-2019-009921.supp5Supplementary dataLimited detail regarding specific elements of team reflexivity made it difficult to determine how reflexive feedback was delivered. This was particularly true of the facilitation of feedback and how the feedback session itself was structured.Three methods currently promoting reflexive practice in interprofessional healthcare teams were identified from the reviewed articles: team debrief postsimulation,In seven studies, team reflexivity was embedded in simulation training programmes as collective debriefing. Teams were asked to participate in simulated practices replicating regularly occurring real-world emergenciesIn eight studies, reflexive discussion was prompted following in-situ observation. Seven of these studies employed VRE to effect reflexive discussion.Reviewed studies generally lacked information about the role of the facilitator in prompting reflexive discussion. Studies refer to the facilitator as being a researcher or an independent healthcare professional, but there is no exploration of their role within the reflexive feedback session.et alStudies included in this review generally lacked theoretical underpinning, making it difficult to gain insight into the active components of reflexivity. Although most studies used videos to prompt reflexive discussion, only four studies engaged briefly in the theory of this, suggesting that viewing routine practice can promote individual and collective learning.Reflexive feedback appears to be accepted as successful in allowing staff to explore the intrinsic complexities of their daily work and develop technical and non-technical skills.et alThe use of video in prompting reflexive discussion is less well defined in terms of staff acceptability and research feasibility. Iedema Communication during interprofessional teamworking was the most prominent focus of improvement methods,The following sections identify the main areas of improvement reported in the reviewed studies and how they were measured.et alet alet alet alet alEleven reviewed articles identified communication within interprofessional teams as a specific area of focus.et alThe remaining articles identified improved discourse within teams relating to changes in process or structure. Two studies identified development of discourse about the complexities of existing processes and collective rethinking of routine communication practices.et alet alRoss et alet alIedema et alet alTwo studies reported reflexive practice as a catalyst for improvement of safety. Fransen Improvement in collective clinical confidence was reported following team debrief focused on the effectiveness of teamwork as well as technical skills.The current systematic review explores how reflexivity has been used to target factors contributing to patient safety within interprofessional healthcare teams. Although we focus on team reflexivity as a tool for the improvement of teamwork and communication in interprofessional healthcare teams, it is evident that the impact of team reflexivity also extends to improvements in specific clinical routine practices and clinical processes and to specific patient safety outcomes.\u2018team debrief\u2019 or \u2018team feedback\u2019. Nevertheless, collective discussion sessions across all methods aligned with accepted definitions of reflexivity in healthcare research.The use of reflexivity within interprofessional teams in healthcare research is becoming more widespread, reflecting the increasing complexities of safe and high-quality care. Three methods of prompting team reflexivity were identified in this review\u2014team simulation training, reciprocal peer review and VRE\u2014although papers differed in the way reflexivity was defined. Team reflexivity embedded within a wider simulation training or peer-review programme was often referred to as Going forward, a more detailed understanding of how team reflexivity works will be important in relation to learning and improvement in healthcare. Continued professional education methods, including simulation training and peer review, are grounded in an extensive body of theoretical literature, exploring situated learning through interaction as social psychological determinant of collective learning.Interpreting VRE methods through the lens of complexity theoryUnderstanding how team reflexivity works must also extend to the role of the facilitator in prompting collective learning. There is limited reference to the role of the facilitator within the reviewed literature, despite good evidence from other research that the role of the facilitator is linked to successful reflective practice and collective learning.Finally, there is no exploration in the reviewed literature of whether the impact of reflexivity differs between teams and the factors that might affect the process of collective reflexive discussion. Exploration of the relevant literature suggests that high levels of psychological safety are significantly associated with more creative team performance and help teams to engage in learning behaviours due to reduced anxiety and a greater willingness to honestly share knowledge that requires risk.The majority of studies in this review explored the impact of team reflexivity or evaluated the methods used. Few studies investigated the acceptability of team reflexivity among staff, and it is unclear from the reviewed literature whether there are any issues of feasibility with reflexive methods in hospital-based healthcare teams. It is also uncertain whether the limited number of studies in this field reflects the infancy of the concept or the difficulty of using this approach within acute healthcare environments.Two divergent observations emerged in this review regarding outcomes of team reflexivity. Studies of simulation training, by design, excised elements of complexity to focus specifically on the improvement of specific clinical procedures and the NTS aligned with such procedures. Conversely, improvement methods capturing in-situ practices and interactions, such as VRE, operate within the inherent complexities of healthcare provision. As such, articles focused on simulation training methods were of higher quality, predominantly due to the level of methodological and analytical detail provided, resulting in well-defined measures of change or improvement. However, evaluation of the reflexive feedback component was not isolated from other elements of the training; thus, any reported improvement in NTS could not be attributed solely to reflexive feedback.Establishing the effectiveness of more adaptive, sociocultural interventions like VRE is more complex, with conventional approaches to evaluation less likely to be appropriate. Reviewed studies generally relied on ethnographic observations and unstructured discussions with staff to identify change or improvement; evaluation methods better placed to capture and account for complexity. Current literature suggests encouragement of methods prompting the development of flexible and locally appropriate goals and solutions should be embraced.Poorly defined methodological information relating specifically to the reflexive elements of reviewed studies made it difficult to draw conclusive evidence about the impact of reflexivity alone. It is possible that simulation training, peer review and VRE would trigger individuals to reflect privately on the social and contextual underpinning of collective processes even in the absence of structured team reflexivity. The nature of this review only allows assessment of team reflexivity as an activity embedded within these methods.Despite the application of an inclusive search strategy, relevant articles may not have been identified. Articles may not have referred to team reflexivity, specifically where collective feedback was embedded within wider improvement methods.Healthcare professionals are often best placed to suggest change or improvement to working practices. Intuitively, it makes sense for staff to be empowered to identify and make these changes. The reviewed literature suggests that simulation training imposes simplicity on complex practices,Importantly, the reviewed literature has highlighted particular areas for improvement relating to the study of team reflexivity in healthcare and the reporting of findings. It is important that future studies aim to justify their use of team reflexivity with reference to the theoretical foundations of the specific tool or intervention to be used, allowing authors to account for and provide detail of methodological and analytical choices. Studies must consider the acceptability of such methods in varied healthcare environments and must account for any issues of feasibility where they arise. Authors must focus on providing adequate description of the reflexive element of any study, including the context of the reflexive session and the level of facilitation. Analytical methods used must not only be detailed within the study method, but authors must also provide clear justification for their choices. Future studies should focus on analysis of the specific impact of reflexivity on NTS so that stronger conclusions can be made about the link between teams having the time and space to practise reflexivity, and subsequent improvements in these contributory patient safety factors.Reflexivity has been identified as a practice that encourages healthcare professionals to focus on improvements in the process and relational aspects of care, with high-fidelity team simulation training, team peer-review methods and VRE gradually becoming documented as improvement methods. The reviewed literature, combined with supporting literature in non-hospital-based care,"} +{"text": "The importance of postsecondary education for economic vitality and individual opportunity has received increased focus with over 40 states embracing postsecondary attainment goals for their populations in alignment with Lumina Foundation\u2019s goal that 60% of individuals ages 25-64 have a recognized credential by 2025. Credentials that both meet the needs of an aging society and move the country towards achieving attainment goals are widely available at community colleges. Community colleges are not only important sources of training and education for adult learners, they also work closely with employers to meet their workforce needs. However, adult learners face many barriers to college enrollment, including poor pre-enrollment advising and lack of understanding of financial aid options. Examples of successful strategies to facilitate enrollment will be discussed, including navigators who serve as holistic advisors and work with students from pre-enrollment to graduation, and also guide the prospective student through the financial aid process. Part of a symposium sponsored by the Community College Interest Group."} +{"text": "This review illustrates the relevance of shamanism and its evolution under effects of psilocybin as a framework for identifying evolved aspects of psychedelic set and setting. Effects of 5HT2 psychedelics on serotonin, stress adaptation, visual systems and personality illustrate adaptive mechanisms through which psychedelics could have enhanced hominin evolution as an environmental factor influencing selection for features of our evolved psychology. Evolutionary psychology perspectives on ritual, shamanism and psychedelics provides bases for inferences regarding psychedelics\u2019 likely roles in hominin evolution as exogenous neurotransmitter sources through their effects in selection for innate dispositions for psychedelic set and setting. Psychedelics stimulate ancient brain structures and innate modular thought modules, especially self-awareness, other awareness, \u201cmind reading,\u201d spatial and visual intelligences. The integration of these innate modules are also core features of shamanism. Cross-cultural research illustrates shamanism is an empirical phenomenon of foraging societies, with its ancient basis in collective hominid displays, ritual alterations of consciousness, and endogenous healing responses. Shamanic practices employed psychedelics and manipulated extrapharmacological effects through stimulation of serotonin and dopamine systems and augmenting processes of the reptilian and paleomammalian brains. Differences between chimpanzee maximal displays and shamanic rituals reveal a zone of proximal development in hominin evolution. The evolution of the mimetic capacity for enactment, dance, music, and imitation provided central capacities underlying shamanic performances. Other chimp-human differences in ritualized behaviors are directly related to psychedelic effects and their integration of innate modular thought processes. Psychedelics and other ritual alterations of consciousness stimulate these and other innate responses such as soul flight and death-and-rebirth experiences. These findings provided bases for making inferences regarding foundations of our evolved set, setting and psychology. Shamanic setting is eminently communal with singing, drumming, dancing and dramatic displays. Innate modular thought structures are prominent features of the set of shamanism, exemplified in animism, animal identities, perceptions of spirits, and psychological incorporation of spirit others. A shamanic-informed psychedelic therapy includes: a preparatory set with practices such as sexual abstinence, fasting and dream incubation; a set derived from innate modular cognitive capacities and their integration expressed in a relational animistic worldview; a focus on internal imagery manifesting a presentational intelligence; and spirit relations involving incorporation of animals as personal powers. Psychedelic research and treatment can adopt this shamanic biogenetic paradigm to optimize set, setting and ritual frameworks to enhance psychedelic effects. Set normally refers to factors related to the person, idiosyncratic personality dynamics, mood and expectations that influence individual experience. Setting is concerned with the social environment, including the broader cultural beliefs regarding the substances and their effects, which contribute to the experience. Set and setting have been considered personal and social influences, respectively, and like ritual, are generally considered to be relatively arbitrary, individual and cultural.However, concepts of ritual, set and setting must include our evolved dispositions that shape mood, personality, expectations and experiences under the effects of psychedelics. Similarly, setting features include not just cultural features, but also the innate factors which contribute to certain kinds of experiences through the neurophenomenological dynamics produced by psychedelics . This neurophenomenological experiential dynamics is embodied in the concept of entheogens, where these substances are experienced as producing encounters with internal and external spiritual entities.There are features of optimal psychedelic ritual, set and setting derived from of our evolved psychology. For example, most prefer psychedelic sessions at night and would feel it strange to start a ceremony at midday. Singing, drumming and dancing are frequent aspects of psychedelic rituals, but not wrestling, swimming or mountain climbing. Feeling compelled to sing a song or heal is normal in psychedelic sessions but explaining a mathematical solution or football strategy is not. Why?The natural aspects of set and setting reflect an evolutionary relationship between our evolved psychology and the effects of psychedelics as exogenous analogues of neurotransmitters. Consumption of mind-altering plants enhanced human adaptations across evolution . EvolutiPsychedelics shaped human evolution as a significant source of serotonin analogues that enhanced active stress response mechanisms. The 5 HT2 psychedelics (those that bind at the serotonin receptors) stimulate 5-HT2AR, a serotonin receptor characterized by enhanced plasticity that enables an active coping strategy that addresses stress sources through changes in perspective and behavior . ShamaniThe deep evolutionary roots of collective rituals reveal a psychosocial dynamic that has characterized hominins for millions of years . The co-But there is little recognition in pharmacology, psychiatry or ethnopharmacology of the significance of millions of years of enabling relationships of psilocybin-containing mushrooms with humans\u2019 evolved psychology of ritual healing but see . These rBut little literature exists on the nature of the shamanic set and setting that characterized most of humanity\u2019s relationships with psychedelic fungi but see . This shThere is a deep evolutionary relationship between humans and plant drugs . There wHuman use of psilocybin and other psychedelics provided exogenous analogues for neurotransmitters that are limited by dietary intake. Our ancestors accrued fitness benefits through utilization of exogenous sources of neurotransmitters, with ancient environmental exposures to these exogenous sources of neurotransmitters stimulating human evolution. Hominin access to psychoactive fungi would have been regulated by the highly seasonal dynamics of fungi growth . Nonetheless, exposure to these and other botanical sources of neurotransmitter analogues was sufficient for hominins to undergo positive selection for CYP2D6 (Cytochrome P450 2D6), a gene that encodes an enzyme that facilitates metabolization of plant toxins , reducinSubstances with effects on serotonin are important in the context of human evolution because \u201cserotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. . . Active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signaling and characterized by enhanced plasticity (defined as capacity for change). . . . [This] 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics\u201d , p. 1091This evolution of the hominin serotonergic system involving modifications of 5-HT2AR signaling enhanced the capacity to actively address sources of stress through changes in perspectives and behavior, rather than passive tolerance of stressors. The ability of psilocybin to functionally modulate 5-HT2A receptor signaling provides enhanced neuroplasticity, a fitness enhancing effect supporting an active coping strategy with heightened flexibility in both unlearning and learning, particularly creating new models of adaptation.How do psychedelics enhance the creation of new perspectives and behavior and what is the basis of the new perspectives they produce?The role of serotonin in the inhibition of dopamine is central to neurochemical balance in the brain, involving the right hemisphere\u2019s serotonergic and noradrenergic systems inhibiting the dopamine system and the left hemisphere . SerotonPsychedelics lock into serotonin receptors but are resistant to normal serotonin reuptake mechanisms that remove neurotransmitters from the receptor to increase synaptic firing frequency. This psychedelic resistance causes habituation of receptor firing, and eventually reduces the regulatory role of the serotonergic system because receptor sites become locked out. The resulting loss of serotonin control results in a release of the dopamine system normally repressed by serotonin, causing a variety of visual experiences and modifying control of major brain subsystems.These psychedelic effects in altering consciousness are illustrated by This enhanced availability of information from ancient brain areas normally repressed results in a flood of information that overwhelms the frontal cortex, altering experience of self, others, and environment and promoting a focus on the internal world of psychological projections. Psychedelics also stimulate the visual system and limbic system areas that manage emotional information and mediate personal relations and social bonding as well as the range of innate brain modules. In addition to the 5HT2 psilocybin and psilocin effects on serotonin receptors, they also have effects on dopamine receptors . PsilocyThe effects of the deregulation of these brain areas caused by serotonin saturation and dopamine disinhibition have direct effects on experience, manifested in the release of normally unconscious sensory, personal and emotional dynamics. The bottom-up brain dynamic induced by psychedelics liberates aspects of the unconscious mind. Phenomenal evidence indicates that the brain\u2019s innate intelligences, modular structures and cognitive operators are liberated by psychedelics, with their integration producing supernatural thought and experiences .Psychedelic stimulation of innate brain structures was discovered a century ago in mescaline-induced visual phenomena called entoptics. Subjective reports of mescaline-induced experiences revealed recurring visual patterns, form constants such as geometric shapes, lattice structures, tunnels, funnels, and cones; and their super-imposition and integration into larger complex flowing patterns that typify psychedelic experiences. The release of these and other innate cognitive aspects by psychedelics make these cognitive structures part of the intrinsic features of set and setting, a manifestation of the structures of the human brain.Evolutionary psychology proposes human cognitive evolution involved acquisition of independent modular cognitive structures providing specialized innate capacities for specific survival functions, automatic processors operating unconsciously to provide specific cognitive responses that affected adaptation in the environment of evolutionary adaptedness . These iPsychedelics produce animism, an entheogenic mind set where the natural world is humanized and personalized with traits that derive from humans\u2019 innate social and cognitive intelligences . PsychedCognitive science explanations of religion also proThese combinations of innate cognitive capacities is how supernatural experiences and beliefs contributed to new forms of intelligence, creating symbols from the integration of operations from distinct cognitive modules that normally operate independently . ASC havAnimism, a view that that nature involves sentient entities that interact with humans, is fundamental to shamanism and entheogenic perspectives. Animism reflects operations of innate processing modules for \u201canimacy detection,\u201d for being hyper-sensitive to the presence of an animate agent. The religious presumption of an unseen agent, a hyperactive sensitivity and automatic tendency to project an active agent responsible for the cause of unexplained phenomena, reflects functions acquired for detection of predators and prey. These tendencies were expanded across human evolution because of survival benefits of detecting predators, and subsequently linked to other capacities to understand the most important and dangerous animals in the environment\u2014other humans. Consequently, our animistic thinking also emphasizes human-like mental, personal and social qualities.Spirit beliefs extend animism and agency detection with Gardner\u2019s intrapersonal and interpersonal intelligences, integrating capacities for self-awareness and mind-reading. Intrapersonal intelligence provides a meta-cognitive operator that uses its capacity for self-awareness and representing one\u2019s own mental states to model and infer the contents of others\u2019 minds. The need for human cooperation requires knowledge of their mental states, a \u201ctheory of mind\u201d that infers others\u2019 intentions and beliefs. Our tendency to attribute our mind states, internal dispositions and purpose to spirit entities reflects this adaptive tendency to infer the mental states of others to predict and adapt to their behavior. Our evolved psychology for modeling the cognitive and emotional world of others also produces the imagined entities of the spirit world, extending social adaptations .A fundamental human capacity for socialization involves process for modeling self development based on internalization of others\u2019 roles. This process can be extended to internalization of spirit others as personal models for development. This process is also extended in the use of natural symbols for representations of self and social groups (totemism).Our naturalist intelligence provides for recognition and classification of animal species in similar systems found in cultures worldwide that parallel the scientific Linnean classification system. Humans in different cultures parse the natural world of animal species similarly through our innate intelligence. This animal intelligence provided templates for analogical reasoning, for creating meaning in animal metaphors. This intuitive biology was subsequently extended as a natural system for creating personal identity and social identity (totemism).Totemism. Totemism involves a metaphoric relationship between the natural history domains of animals and domain of social groups, conceptualizing humans\u2019 social organization through analogical reasoning processes that attribute a homology between animal species and human groups.A prominent feature of shamanism involves animal allies that takes the social capacity to incorporate the models of the social other\u2014to internalize qualities of others into our self-identity\u2014and extends this capacity by using animals as representations of self. The characteristics of animals are used to structure individual psychodynamics and social behavior modeled on the natural symbols of animals. A similar model of identity is exemplified in totemism, where an animal species represents the identity of a group, as manifested in totemic ancestor worship where group deities are represented by an animal species. The significance of totemism as symbolic cognition was illustrated in Psychedelic disinhibition of the dopaminergic system through reduction of serotonergic control results in ascendance of the dopaminergic systems which produce a variety of visual syndromes, typified by hallucinations and dreaming . The infPsychedelics increase blood flow in the visual cerebral cortex and expand functional connectivity in the primary visual cortex, reflecting an enhanced activity in visual areas from increase in contributions from other areas of the brain to the visual processing centers . PsychedThese forms of thought presented in psychedelic experiences involve what Psychedelic-induced visionary phantasy reflects a latent human cognitive capacity underlying all experience that manifests through the visual system used for organizing information in the external world. These internally produced visual experiences evoked by diverse conditions are symbols\u2014presentational symbolism\u2014an ancient modality of cognition see .Academia has recognized this intuitive mode of knowing for centuries, but it is seldom studied because of difficulty in sharing these internal experiences. This illusive capacity is reliably elicited by psychedelics, which are unparalleled tools for examination of the phenomenology and operation of this intrinsic system of the human brain-mind and a source of unconscious cognitive processes. This visual thinking capability involves the innate intelligence of spatial-temporal reasoning, an ability to think though visualizing patterns and performing mental manipulations with them. The visual thinking provides the working space for organizing constructs, assimilating information and creating new ideas by synthesizing spatial information. This capacity was central to human evolution.A cognitive niche is how we adapt to diverse environments, a uniquely human capacity involving reliance upon complex cognitive systems of representation that mediate relations with the natural world . This reThe model of psychedelic instrumentalization derived from the drug instrumentalization paradigm indicateEarly hominins evolved traits from selection pressures for abilities to live in a cognitive niche, a virtual social reality, for functioning and survival. Beginning with the incidental ingestion of psychedelic fungi in an opportunistic diet, and eventually their deliberate inclusion in rituals, our ancestors\u2019 use of psilocybin could have contributed to the evolution of our unique survival mode by imposing a systematic bias on the selective environment via the enhanced visual information processing and integration induced by psychedelics. Psychedelic consumption thus could have had significant consequences on the selective forces that drove hominin cognitive and behavioral evolution.These adaptations involving construction of new models of the environment were enhanced by psychedelic effects on visual thinking and globally integrated cognition. The enhanced availability of information is a central feature of psychedelic effects, a result of increased global connectivity in the brain that results from psychedelic interference with the integrity of the Default Mode Network (DMN). Disabling the DMN results in increased levels of functional connectivity between normally disconnected brain networks and morePsychedelics consequently produce a higher level of brain integration with a greater diversity of functional connectivity networks. This enhanced modeling provided a meta-context for possible further selection of related traits and competencies that facilitated adaptation to the socio-cognitive niche. Individual differences in enhanced cognitive processes provoked by psychedelics provided variations in fitness in ancient hominin populations, variation upon which selection could act because they contributed to enhanced ability to operate in a cognitive niche.Ancient hominin societies developed social institutions, represented in the practices of shamanism, to manage the therapeutic and other adaptive effects that can be obtained by using psychedelics to integrate information in consciousness. The deliberate, intentional self-administration of psychoactive compounds that significantly enhance mental functions and access to unconscious material is typified in shamanic practices, which exhibit hominins\u2019 unique capacities for constructing a cognitive niche through adaptively instrumentalizing these mind-altering substances to produce sociality-enhancing models of spirits.Shamanism represents a cross-cultural concept derived from recognition of a similar complex of spiritual healing practices in pre-modern cultures around the world. Europeans first developed this concept from reports by explorers, traders, missionaries, colonists, administrators and military personnel. Their sensationalistic exaggerations and misunderstandings, filtered through Christian religious biases, were incorporated into the literary and cultural life of elite Renaissance Europe during the 18th century as an understanding of the foreign \u201cother\u201d . These csaman in the Tungusic language, took this widespread Siberia cognate and applied it cross-culturally to premodern spiritual healing practices.This European view of shamans as theatrical performers who deceived their gullible community only began to shift as professional understandings emerged with 19th and 20th century anthropological studies. Studies on Siberian groups already substantially changed by Russian colonization were soon augmented with ethnographies that attested to a similar cross-cultural phenomenon manifested in European, Asian, Austronesian and American indigenous cultures. The modern concept of the shaman, based on the term Shamanism: Archaic Techniques of Ecstasy, where this comparative religion specialist described these recurrent practices found across the globe. This contributed to the 20th-century emergence of the shaman as a legitimate comparative (etic) concept in academia and subsequently its revitalization and popularization in Western society. Eliade characterized the core of shamanism as \u201ctechniques of ecstasy\u201d\u2014ritually-induced altered states of consciousness (ASC)\u2014used in community ritual interactions with the spirit world for purposes of healing and divination. This nighttime ceremony attended by all members of the local group was an unparalleled social gathering, a \u201cspectacle unequaled in the world of daily experience\u201d . This dramatic ritual provoked powerful emotions as the shaman recounted battles with spirits while excitedly beating drum, imitating animals, singing, chanting, and dancing. Eventually the shaman reclined or collapsed exhausted into a ecstatic state \u201ca trance during which his soul is believed to leave his body and ascend to the sky or descend to the underworld\u201d (The concept of shamanism began its scientific basis in Mircea Eliade\u2019s (1951/1964) erworld\u201d , p. 5 toPreeminent leader in the group\u2019s ecological, political, spiritual and healing activities;Performance of a communitywide nighttime ritual to engage and enter the spirit world;Ritual preparations involving fasting and water deprivation, sexual abstinence and austerities;Training and rituals involving alteration of consciousness produced though extensive drumming, dancing, collective chanting and singing, and often use of plant drugs;Experiences conceptualized as soul flight, similar to modern astral projection, out-of-body and near-death experiences, in which the shaman travels into the spirit world;Ritual healing of soul loss, the extraction of intrusive objects, and sorcery;Selection from encounters with spirits in visions, illness, and dreams;Training involving prolonged solitude in the wilderness, a vision quest for spirit allies that empowered the shaman;An initiatory experience of personal death, often involving experiences of being attacked, killed, and devoured by animals;A rebirth experience in which the animals reconstruct and revive the initiate by incorporating their powers into the initiate;Experience of a personal transformation into an animal; andCausing magical harm through intrusive darts and soul theft.While some have questioned Eliade\u2019s claims that shamanism was cross-cultural because of his loose comparative methods, the broad patterns he noted are confirmed by formal cross-cultural studies . ForaginThis complex of ritual activities and beliefs found worldwide in foraging societies establishes shamanism as an empirical reality of the premodern world, not something created by the Western imagination. The cross-cultural distribution of the shamanic features reflects a cultural universal: all societies have ritual practices involving alterations of consciousness for spirit communication, divination and healing, what Biogenetic structural approaches reveal shamanism has roots in hominid communal displays . CollectThese origins of human ritual are identified in these comparative analyses revealing parallels of shamanism with the chimpanzee maximal display. This reveals a generalized hominid trait involving bipedal displays by the alpha male and collective hand and foot drumming and chorusing by the group . The maxThis maximal display is the basic mechanism for group integration in chimpanzee society by producing an auditory beacon to reunite the dispersed troop . These nnighttime group reunification displays;aggressive alpha-male enactments (\u201cdancing\u201d);emotional group vocalizations (chorusing and singing) and drumming; andindividual and group emotional integration.This common dynamic of great apes indicates these behaviors characterized our hominid ancestors and consequently, our uniquely human ancestors, the hominins. These pre-adaptations for hominin ritual include:Synchronous group vocalizations are central to both hominid displays and shamans\u2019 rituals, an expressive system for communicating emotional states and enhancing group integration. Their functional adaptations include : an audievolution of capacities for extended drumming, dancing, song and music;expansion of the ritual capacities for more prolonged conspicuous displays;rituals of healing;beliefs regarding spirits, particularly animals as personal powers and identity;prominent alterations of consciousness and their cognitive properties;diagnosis and divination of information;mythic systems of explanation.The similarities between chimpanzee maximal displays and shamanic rituals indicate a hominid biogenetic behavior pattern which was a pre-adaptation for shamanism. This involved collective nighttime group vocalizations and drumming with vigorous attack displays by alpha males . The feaThe capacities of music and dance depend on mimesis, an innate modular intelligence and a central feature of hominin evolution which emerged 1\u20132 million years ago . MimesisMimetic processes are based in the activity of mirror neurons, brain cells that are activated by performance of a specific intentional and goal directed behavior, as well as when one observes a conspecific engaging in that same specific intentional movement require inhibition of normal impulses and visibly demonstrate excessive fitness and commitment. The ability to endure these painful and exhausting rituals both signals social commitment and elicits such commitment . Costly Homologies between chimpanzee collective displays and shamanic healing rituals indicate communal ritual was the context within which hominins experienced selection for enhanced capabilities related to endogenous healing responses . These pMusic is a modular intelligence and an aspect of mimesis that provides healing mechanisms through its innate ability to affect emotions . Music eMusic manifests emergent properties that communicate basic emotions and transform them into expressions of complex feelings through the coordination of biological, physical, psychological, cognitive and social processes . ConsequThis synchrony contributes to enhanced well-being through effects on social emotional systems related to mammalian and group bonding. The mimetic capacities of music and dancing provided technologies that enhanced synchrony and group formation, with coordinated rhythmically repeated motions exemplified in dance extending the mechanisms of social cooperation. By providing a system of coordinated expression of intentions in observable body actions, dance contributed nonverbal communication mechanisms for the creation a shared group consciousness. Mimetic engagements of rhythmic dancing, clapping and chanting provide powerful socialization effects, an engagement of the motor and somatosensory systems in a way that produces powerful affective linkages of the individual with the group and development of social ties and group identity beyond the biological family.The dramatic displays of the shaman evoke two innate healing principles or processes, the holistic imperative and shamanic projection . The holThe parallels of chimpanzee displays and shamanic rituals reveal a hominid core of collective ritual behaviors that was necessarily the social context within which psychedelics were institutionalized into ancient hominin cultures. Mimesis and costly displays can explain some features of the chimpanzee-shaman ritualization gap . But many features are not explained by mimesis such as beliefs regarding spirits, animals as personal powers and identity, alterations of consciousness, divination and mythic systems of explanation.A notable gap between hominid and shamanic ritual involves ASC and spirit world experiences that are at the focus of communal shamanic healing practices. Notably, all three\u2014communal relations, shamanic ASC and healing\u2014are stimulated by psychedelics, exemplified in the concept of entheogens. Cultures around the world have expressed beliefs about the effects of psychedelics that are entheogenic\u2014inherent sources of stimulating internal spiritual experiences . The empAn entheogenic experience of entering a spiritual world;a visionary experience of the separation of one\u2019s soul from the body;a death-and-rebirth experience producing self-transformation;healing, especially through ritual and singing;acquiring information through divination;an encounter with animal spirits and an experience of transformation into an animal;a cosmological system involving an animated nature, animal and plant spirits.Psychedelics produce experiences directly related to the chimpanzee-shamanism gap from :An entheThese differences between chimpanzee displays and shamanic ritual indicate a zone of proximal development where psychedelics could have acted as a selective force in evolutionary developments leading to the emergence of shamanism. Shamanic evolution may be explained in part by psychedelics\u2019 effects of stimulating our innate cognitive structures as discuThe sociality enhancing effects of psychedelics indicate they could have been key elements in selection for communal ritual healing capacities though Baldwinian processes see . PsychedThis psychedelic enhancement of sociality suggests that they exercised influences in selection for those same dispositions in early hominins. The environmentally induced changes on brain function exerted by psychedelics could have become genetically heritable over time as a result of the selective pressure exerted by their physical and psychological effects. The reproductive advantages derived from instrumentalization of psychedelics could have enabled selection for supportive traits that further enhanced exploitation of psychedelic effects .Psychedelic healing was necessarily at first incidental rather than deliberate. This occurred through their effects in enhancing serotonin mediated coping responses, diverse dopamine mediated healing responses, as well as enhancing core aspects of sociality. This treatment became deliberate as hominins learned that psilocybin\u2019s effects on emotions and social relations could be enhanced through ritual in ways that contributed to fitness through their renowned ability to evoke a variety of healing responses permits emergence of a new identity as a healer. These reformulations of the self are guided by innate drives toward integration derived from the psychointegration produced by ASC. Holistic imperatives toward psychointegration restructure the ego through integration of repressed and dissociated cognitive structures, alleviating psychosomatic and emotional problems through enhancing self-actualization.The cross-cultural characteristics of shamanic practices reveal features indicative of our evolved psychology; practices that incorporate these biological bases should enhance psychedelic effects by optimizing set and setting. The homologies of shamanism with key features with chimpanzee maximal displays emphasize the features of the hominid baseline from which shamanism emerged. Furthermore, many core features of shamanism and its ritual set and setting are homologous with typical psychedelic effects, indicating the need to consider shamanic principles as important for structuring contemporary psychedelic therapy.Features of shamanic setting have homologies with features exhibited in the chimpanzee maximal display, indicating both the hominid baseline and the deep evolutionary roots of shamanism. These hominid features are: high energy nighttime displays with group unification; enactments of costly displays, the precursors to dancing; dramatic emotional vocalizations (chorusing and singing) by group members; collective hand and foot drumming; and individual and group emotional expression and integration. A significant feature of hominid ritual setting is the collective ritualization that integrates all members of the local community.Shamanism emerged through the exploitation of the mimetic capacity through ritualized enactment, dancing, singing and vocal imitation . The shaThe significance of mimesis for psychological well-being is illustrated in This habitus engrains at deep emotional levels not only adaptive behaviors, but also those derived from stressed and pathological social relations. This unconsciously acquired habitus is the basis of one\u2019s orientation to the environment, an embodiment that produces consciousness within the subjectivity derived from the visceral responses of the body. The activities of dance as well as mime and enactment, are the expressions of this habitus. Dancing may be an exceptional modality for both expressing and reprogramming this mimetic-inscribed habitus see . The bodMusic, a core feature of shamanic ritual, is part of the mimetic capacity with numerous adaptive psychophysiological effects that both produce psychological and social integration and elicit healing responses. Hominins evolved music and other mimetic modalities because they extended social bonding through the release of endogenous opioids. Music is an innate intelligence that provides a capacity for evoking a range of endogenous healing mechanisms, addressing health problems through eliciting emotional states and concerns and transforming them. The myriad of physiological and therapeutic effects of music make it a natural adjunct for ritual healing, especially psychedelic-induced healing states.The core role of dance in shamanism and the therapeutic use of dance in cultures around the world reflects its mimetic basis, as well as the diverse mechanisms of action of dance on the body and mind, including contributing to the altering consciousness . The rolWoods proposes that dance exercises intrinsic therapeutic effects derived from the elicitation of emotional reactions that facilitate catharsis. ASC produced through dance facilitate experiences of different aspects of the self in personal expressions that liberate repressed emotions in nonverbal expressions of unconscious dynamics. This expression is exemplified in possession phenomena where dance performances manifest participants\u2019 dissociated and repressed desires that are expressed in behavior and utterances attributed to possessing entities. The effects of dance as exercise produces cycles of sympathetic stimulation followed by relaxation (parasympathetic collapse phase), providing an intrinsic ability to both provide energetic stimulation and revitalization, as well as relief of tension and stress. Woods reviews evidence that dances also engage processes similar to hypnotic induction and a release of ego control, which allows for emergence of ancient body-based expressive modalities that promote psychological integration and self-actualization.Set effects of healing involve elicitation of endogenous healing responses through placebo effects, hypnotic susceptibility and psychointegration of unconscious material. Group ritual dynamics with dramatic authoritative performances enhance hypnotic and placebo responses. The conspicuous displays typical of shamanism should play an important role in conveying these dynamic performances that elicit confidence and contribute to well-being. The collective rituals typified in contemporary raves parallel these collective dynamics of shamanism .Shamanic ASC and psychedelics produce a cognitive set by stimulating innate thought processes, particularly intrapersonal and interpersonal awareness and mimetic and musical intelligences. Innate modular thought also structures setting in naturalistic intelligences and spiritual and existential intelligences that produce spirit experiences and cosmological explanations. Entheogenic (and shamanic) perspectives engage a natural neuropsychological set structuring our relationship to nature, especially in animals that have human-like qualities. Ritual engages our reptilian brain\u2019s behavioral communication systems and our paleomammalian brain\u2019s analogical reasoning and emotional, social, and personal processes. The effects of psychedelics in disabling higher-level integrative centers and reduction of serotonergic inhibitory control results in ascendence of these reptilian and paleomammalian brain activities . The norPre-modern psychedelic experience was entheogenic\u2014an experience of spiritual beings activated by the plant and within the self. This encounter with an active social agent exemplifies functions of innate modular cognitive intelligences and cognitive operations that are at the core of shamanism. The animistic worldview reflects an enhanced sociality with a natural world imbued with human qualities. Shamanic relations embody the entheogenic perspective that external entities can enter the person and manifest as spiritual powers, as well as become guides and allies. Shamanism incorporated the influences from these spirits as fundamental to self, producing an ecopsychology based in perceptions of nature as personal, intelligent, spiritual and human-like. Shamanism and entheogenic encounters emphasize a set involving the incorporation of others\u2019 as self, reflecting an extension of the social mind\u2019s inference system beyond normal limitations because spirits are presumed to have fuller access to strategic information.Shamanic ASC have both personal and collective dimensions, emphasizing their role as both set and setting. The shamanic set for ritual involved various methods of inducing ASC, beginning with preliminary fasting or dieting, sexual abstinence and sleep deprivation, conditions that produce biological and psychophysiological changes . These pVarious ASC result in breakdown in higher cognitive processes and self-structures, exemplified in the disintegration of functions of the prefrontal cortex and Default Mode Network, and in the phenomena of soul flight and the death-and-rebirth archetype, a significant set for psychedelic personal transformation. Some shamanic dynamics such as death-and-rebirth and soul flight reflect disarticulation of neurognostic systems. This breakdown of the normal unity of innate modules supporting consciousness produces new forms of consciousness. ASC manifests our innate animistic and social psychology involving the integration of innate thought modules . ShamaniShamanic practices include dream incubation as a set preparation prior to rituals and during performance of overnight rituals during normal dream cycles, enhancing the integration of normally unconscious processes into consciousness. Dreams provide a natural extrapharmacological influence for shamanic and psychedelic experiences, an enhanced capacity for accessing and integrating information from the unconscious, especially in visual forms. These normal physiological processes are integrated into conscious awareness by the enhanced features of consciousness produced by ritual . The innate processes of dreaming involving enhanced learning and memory integration makes these features important adjuncts for an enhanced capacity to integrate unconscious material into waking consciousness. This integration facilitates the resolution of trauma and conflicts and provides new possibilities in the processes of virtual scenario construction created by the dream functions.The phantasy imagery present in dreams and produced by psychedelics has a direct relationship to the processes of \u201cactive imagination\u201d proposed by Carl The process of active imagination focuses on the images that emerge from the unconscious mind, exemplified in dreams and other processes such as fantasy that manifest material from subconscious and unconscious processes. By allowing for an emergence of unconscious material with focused consciousness and attention, the active imagination techniques produce psychological integration of the fragmented self and dissociated functions, identities and complexes. A focus on this material, particularly interpretation of the images through the narrative exploration of their meanings, enhances their integration with ego awareness. This parallels the post-session integration activities typical of contemporary psychedelic retreats. These processes not only produce personal integration but also open the potential for the integration of material from the collective unconscious .The ASCs of shamanism and psychedelics give rise to experiential properties of a spiritual self, embodied in a soul flight, astral body or similar concept of the self apart from the physical body. This epitome of the entheogenic experience, an experience of an in-dwelling spiritual entity, takes various forms in shamanism, including the death-and-rebirth experience involving the disintegration of physical identity as a prelude to natural processes of rebirth and self-transformation.An initiatory experience of death, typified in shamanic traditions as being killed, and devoured by animals, has many manifestations, an archetype of self-disintegration. This disintegrative dynamic undoubtedly underlies the frequent reports of psychedelic users that they are going to die. Shamanic traditions emphasized facing death rather than running, overcoming one\u2019s fears in confronting experiences that could lead to rebirth as a more powerful person.The set and setting of shamanic practice are spiritual and collective, with the expectation of a transformative healing encounter through intimate contact with spirit powers. Shamanic healing is communal, attended by all in the local group. The shamanic setting extends the social dynamic of ritual, incorporating non-physical social entities in the cognitive orientation of animism and relationality with the powers of nature, animals and the Universe. A setting in nature was typical for many shamanic activities, and an intimate contact with nature was part of most pre-modern settings. Even modern psychedelic users occasionally experience animal contact during their sessions . The socShamanic ASC engage the visual system, a key source of shamanic and psychedelic information. A deliberate internal engagement with the visionary images enhances consciousness by accessing intensified visual information and the novel forms of knowledge created by interregional and global brain connectedness. As is the case with supernatural agents, psychedelics and other vision producing processes expand human abilities at scenario building, producing thoughts independent of actual circumstances or perceived limitations. The imagestic scenarios typify unconscious manifestations and the operation of decoupled cognition, with innate inference systems and intelligences operating independent of normal environmental input. The adaptive niche construction capacity depended on many evolved brain structures. Two crucial innate intelligences that Gardner added to the original eight in his update (2000) were: Spiritual intelligence, a desire to engage spiritual, noetic and transcendent experiences; and Existential intelligence, concerned with cosmic issues, the meaning of life and death and manifested in mythology and pantheons.One powerful quality of psychedelic experiences is the certainty of one\u2019s beliefs that may result. This reflects a modular intelligence, an \u201cexistential operator [which] gives a sense of reality to beliefs, regardless of whether they are non-contradictory or contradictory, or counterintuitive, according to neocortical operators\u201d , p. 33. This transdisciplinary synthesis incorporating insights from anthropology, evolutionary psychology, psychopharmacology, and the clinical sciences and the neurosciences of psychedelics provides an enhanced understanding of the biological bases of shamanic psychedelic practices. Understanding these bases provides insights into our evolved psychology and how to incorporate these features into post-modern best practices approaches to the set and setting for enhancing therapeutic utilization of psychedelics. These can help guide the application of traditional ethnomedicinal wisdom in the interest of psychedelic-mediated improvements in the mental health of post-modern populations.The recent clinical research on the objective effects of psychedelics provides an empirical basis to make inferences regarding the likely effects of an environmental factor\u2014psychedelic mushrooms\u2014in shaping selection for core features of hominin psychology, sociality and cognition. Psychedelics have deep evolutionary roots with our ecopsychology through action on our nervous system, particularly serotonin and dopamine. Their effects enhance stress responses in producing active modes of adaptation through changing stressor or our responses to them, as well as enhancing environmental and personal awareness and sensitivity to social rituals and their roles in emotional regulation and healing.Humanity\u2019s evolved psychology involves enhanced capacities that could have resulted from stimulation with these exogenous neurotransmitter analogues and knowledge of these biopsychosocial bases can an optimize psychedelic effects. These biocultural adaptations are manifested in the cross-cultural patterns of shamanistic ritual preparations and ceremonial activities that incorporate a distilled wisdom regarding set and setting features that help enhance the efficacy of the therapeutic experiences by a grounding in an orientation to innate intelligences and their integration and interaction.The principal interpretative framework provided by this multidisciplinary approach to shamanic and psychedelic set and setting is neurophenomenological , where eThis neurognostic approach to adapting the structuring of psychedelic experience to our evolved psychology also accommodates principal aspects of pre-modern indigenous practices for optimal utilization of psychedelics. The scientific application of this traditional knowledge is supported by this interdisciplinary synthesis that reveals the biogenetic origins of shamanic ritual activities that prepare the mind-set of users. These involve extrapharmacological effects of ritual practices that enhance the dynamics of psychedelics."} +{"text": "The 85+ population is the fastest-growing age segment in the United States. Understanding attitudinal and behavioral trends among adults ages 85 and over is of increasing importance to researchers and practitioners alike. This symposium will present findings drawing on mixed methods across multiple domains of research with the Lifestyle Leaders, a bimonthly panel study of adults ages 85 and older at the MIT AgeLab, which began in September 2015. Each presentation in this symposium will highlight a different focus of research conducted with the Lifestyle Leaders, ultimately offering insights about physical health, social engagement, and civic engagement at age 85 and beyond. The first presentation in this symposium will frame Lifestyle Leaders\u2019 resources and how these resources affect their perceptions of risks, their worries, and their well-being. Diving deeper, the second presentation will center on how Lifestyle Leaders perceive and utilize different transportation options and how these options have changed for them over time. The third presentation will focus on civic engagement and Lifestyle Leaders\u2019 perspectives on technology as enabling or inhibiting their civic engagement and participation. The fourth presentation will examine Lifestyle Leaders\u2019 attitudes toward medication, medication management, and technology-enabled medication management devices. This symposium will deepen attendees\u2019 understandings of the attitudes and experiences of active octogenarians and nonagenarians."} +{"text": "Religious communities are uniquely able to serve the needs of older adults, yet very little aging related training exists for lay people and clergy within religious congregations. This talk will discuss the needs of older adults in faith communities, intergenerational interventions, and formal educational training programs such as the Specialist in Aging Ministries program (SAM) developed by Concordia University Chicago as a way to educate and support caregivers and older adults in real world settings. The speaker will also discuss the ways gerontology curriculum has personally impacted her applied work with elders in faith communities including next steps for building and implementing curriculum and training for caregivers, older adults, and the community at large. Sociocultural implications and future directions will also be discussed."} +{"text": "Geropsychologists are well-suited to assess dementia, assist caregivers in understand the disease and associated behavioral changes and ways to cope with their loved one\u2019s disease. However, majority of these services are offered during in-person clinic appointments in urban settings. This study aims to describe the utilization and potential benefits of providing dementia education telehealth services to Veterans and their families residing in rural mountain and plain areas of Colorado. Psychological intervention was provided via telehealth from the primary VA hospital to small community clinics or to Veterans homes via video mobile application. The present study provides demographics of participants who elect this service and discusses how these challenge ageism and other biases relate to technology use. Further, we examined how engagement in this intervention may impact utilization of geriatric and extended care services as well as use of primary care, emergency room visits, and use of anti-psychotic medications."} +{"text": "Cholinergic modification by anticholinergic medication can produce adverse effects in central nervous system (CNS) and cyclopentolate is an antimuscarinic agent widely used for ophthalmologic management. We demonstrate a rare case of hyperactive delirium caused by topical administration of cyclopentolate in a patient with amnestic mild cognitive impairment (MCI) due to Alzheimer's disease (AD).A 74-year-old man showed acute confusion after preparation for cataract operation in day surgery clinic. The patient became confused and agitated after instillation of topical cyclopentolate drop into the eye and the symptoms persisted over several hours.18F-flutemetamol positron emission tomography scan demonstrated multifocal amyloid deposition in the brain.Previously the patient had been diagnosed with amnestic MCI with the finding of bilateral medial temporal atrophy on brain magnetic resonance imaging. The patient was closely observed with the supportive management.The patient began to recover 5\u200ah after the onset of symptoms and the cognitive function was reverted to previous state within 24\u200ah.It is well known that several drugs with anticholinergic effects used in perioperative periods make the patients susceptible to delirium, but even the topical administration of cyclopentolate for cataract surgery also produce adverse CNS effects in a vulnerable patient who is diagnosed with MCI due to AD in this case. Cholinergic modification by anticholinergic medication can result in anticholinergic syndrome in central nervous system (CNS) that includes cognitive decline, psychosis, seizure, and a variety of neurologic signs. Cyclopentolate is an antimuscarinic agent as mydriatics and cycloplegics and widely used for ophthalmologic examination and surgery with the benefit of rapid onset and recovery. Although CNS adverse event of topical anticholinergic agents is not common, several cases related CNS manifestation after instillation of topical eye drops have been reported.218F-flutemetamol positron emission tomography (PET) scan performed 2 months after the event demonstrated multifocal amyloid deposits in bilateral frontal lobes, the left precuneus, and the right lateral temporal cortex of the brain showed atrophic changes in the whole brain and bilateral medial temporal lobes and focal chronic infarction in the right cerebellum (Fig. 3The transient manifestations of the patient which developed after receiving eye drops of cyclopentolate include confusion, agitation, and aggressiveness and lead to diagnosis of hyperactive delirium. The patient had been diagnosed with amnestic MCI which is a syndrome defined by clinical, cognitive, and functional criteria. The amount of anticholinergic burden in the normal elderly is closely related to cognitive impairment in memory and executive functions and brain atrophy measured by whole brain cortical volume, temporal cortical thickness, and lateral inferior temporal volume. Cyclopentolate is a synthetic anticholinergic agent which produce mydriasis and cycloplegia with the benefit of rapid onset and recovery. Cyclopentolate eyedrops pass readily through nasolacrimal duct and are well absorbed locally as well as systemically via conjunctiva and nasal mucosa. Systemic toxicity includes inappropriate behavior, visual and auditory hallucinations, and cerebellar dysfunction that has been reported mostly in a group of children and adolescents and depends on the dose administered. It has been reported that instillation of several drops of a solution of cyclopentolate produced mental deterioration in an elderly patient with dementia. In this case, we demonstrated the exact neurological status of the patient who suffered mild cognitive decline and showed amyloid accumulation in the brain on PET imaging which suggests underlying pathophysiologic process. Cholinergic deficit can make the elderly with MCI or dementia more vulnerable than the cognitively normal persons to cognitive impairment. Nonetheless, there may be some possible limitations in this study. The causal relationship between delirium and the drug and the exact mechanism may not be clear. The lowest available concentration of the cyclopentolate should be applied for prevention of systemic toxicity especially in patients with cognitive decline.It has been well known that anticholinergics has a detrimental effect on cognitive functions. Cholinergic deficiency is recognized as a likely contributing feature to all cause of delirium.MCI has been known to be transitional state between the cognitive changes of normal aging and dementia but is a heterogeneous clinical condition with several subtypes and multiple etiologies. But the patient showed PET evidence of A\u03b2 deposition in the brain and structural MRI findings for neuronal injury that suggest AD pathophysiological processes in cognitive decline which led to the diagnosis of MCI due to AD. It is well known that several drugs with anticholinergic effects used in perioperative periods make the patients susceptible to delirium, but even the topical administration of cyclopentolate for cataract surgery also produce adverse CNS effects in a vulnerable patient with prodromal AD in this case.Conceptualization: Hak Young Rhee.Data curation: Yu Yong Shin.Writing \u2013 original draft: Yu Yong Shin.Writing \u2013 review & editing: Jin San Lee, Key-Chung Park, Hak Young Rhee."} +{"text": "Knowledge of the deeper meaning of how growing older alongside companion animal dogs affects men\u2019s perspectives of aging is limited. This study employed qualitative research methods utilizing individual interviews and panel discussions with older adult men in order to investigate the dynamic phenomenon of their personal experience of growing older alongside their aging companion animal dogs. Individual audio-recorded and in-depth interviews and repeated panel discussions with a sub-group of participants, convened as a panel over a three-month period, explored behavioral and emotional manifestations of aging along with a companion animal. Analysis involved open, axial, and selective coding of transcripts to reveal underlying patterns within the data. Outcomes included insight into the role of dogs in the men\u2019s perspectives of attitudes toward aging, toward not only themselves as older adult men, but also toward their aging dogs. Findings reveal that the older adult men felt empathy for their aging dogs, which translated to feeling empathy for themselves as well as other older adults. The men revealed attitudes of being sympathetic and understanding of the aging process simply as a result of aging alongside their aging dogs. A prominent idea that emerged was a feeling of grace toward oneself, others and their aging dogs. This study offers insight into the deeper understanding of one effect caring for older companion animals has on older adult men\u2019s attitudes toward aging. This study provides movement toward a theory of the role of dogs in the development of older adult men\u2019s attitudes toward aging."} +{"text": "Older adults who receive home- and community-based services (HCBS), such as home-delivered meals and personal care assistance, are at particular risk for falls due to their extremely high prevalence of fall risk factors. HCBS organizations and their staff are well-positioned to implement fall risk screens with HCBS clients and then refer older adults to fall prevention services as needed; however, the extent to which HCBS organizations manage fall risk has yet to be systematically examined. The purpose of this qualitative study was to explore the barriers to and facilitators of implementing fall risk screens and fall prevention service referrals in HCBS organizations. A total of 26 HCBS staff members and administrators participated in semi-structured interviews and focus groups. Qualitative data were examined using directed content analysis guided by the Consolidated Framework for Implementation Research. HCBS staff expressed that strong rapport with clients allowed for them to address fall risk proactively but were concerned that their lack of fall prevention training precluded them from effective fall risk management. HCBS administrators perceived their organization to have reliable internal communication procedures which enhanced fall prevention care coordination but believed their limited connections with fall prevention service providers served as a barrier to referring at-risk clients to appropriate care. Accordingly, HCBS stakeholders are encouraged to develop strategies, such as providing fall prevention coaching and building a network of fall prevention service providers, that account for these barriers and facilitators in future efforts to support effective fall risk management with HCBS clients."} +{"text": "The variation in Latino older adults\u2019 conceptualizations of positive aging across studies suggests greater attention should be paid to within-group factors. The purpose of the current study was to identify which factors are important to positive aging from the perspective of Latino older adults, and whether the importance of these factors varied based on participant characteristics. A second aim of this study was to examine whether there are differences in views of successful aging between Latino older adults and service providers who support aging Latinos. The current study was conducted as part of a broader research project investigating Latino older adults\u2019 perceptions of positive aging. Latino older adults (n = 93) and aging services providers (n = 45) rated the importance of a series of statements related to positive aging. Mixed-methods analysis of the statements identified nine distinct dimensions . Latino older adults rated Positive Outlook and Spirituality highest on importance, and ratings differed based on gender and other individual difference characteristics. For example, men placed greater relative importance on Independence and Support for Others compared to women, and younger participants rated Independence higher on importance compared to older participants. In addition, Latino older adults (vs. providers) placed greater importance on all aspects of positive aging, with greatest mean differences related to providing Support for Others and Spirituality. These findings have implications for wellness programs for Latino older adults and training for service providers."} +{"text": "Autophagy is a mechanism of lysosomal proteolysis that is utilized to degrade damaged organelles, proteins, and other cellular components. Although key studies demonstrate that autophagy functions as a mechanism of tumor suppression via the degradation of defective pre-malignant cells, autophagy can also be used as a mechanism to break down cellular components under stress conditions to generate the required metabolic materials for cell survival. Autophagy has emerged as an important mediator of resistance to radiation, chemotherapy, and targeted agents. This series of articles highlight the role of autophagy in cancer progression and drug resistance and underscores the need for new and more effective agents that target this process. Autophagy is an evolutionarily conserved protein degradation process that is characterized by the formation of double-membraned vesicles (autophagosomes) that envelop bulk cellular material and/or organelles. Autophagosomes subsequently fuse with lysosomes and the degradation of their cargo is mediated by lysosomal proteases ,2. AutopThe roles of autophagy in normal and malignant cells can be strikingly different. In normal cells, autophagy functions as a mechanism of tumor suppression by eliminating damaged organelles and proteins to promote cellular homeostasis. However, cancer cells preferentially utilize autophagy to drive metabolic reprogramming that degrades cellular components to generate the necessary energy needed for cell survival during periods of stress such as hypoxia, starvation, and during chemotherapeutic treatment . In addiMost studies have focused on inhibition of autophagy at the distal point in the process through interference of lysosomal degradation using drugs such as hydroxychloroquine (HCQ) . Indeed,In addition to these research articles, several excellent reviews summarizing key aspects of the field were published in this Special Issue. It has been well established that autophagy is an important mediator of therapeutic resistance to diverse classes of anticancer agents. Two outstanding articles discuss the mechanisms underlying autophagy-mediated treatment resistance and strategies to enhance chemosensitization through inhibition of autophagy ,12. An aBesides being a facilitator of drug resistance, upregulation of autophagy has been identified as a contributing factor that accelerates disease progression and metastasis in a multitude of tumor types. Saxena et al. review the roles of autophagy in esophageal squamous cell carcinoma and esophageal adenocarcinoma pathogenesis . They alThe articles in this Special Issue mesh perfectly with each other to highlight the significance of autophagy as a key mechanism that cancer cells utilize to drive malignant progression and drug resistance. The articles comprehensively discuss the rationale for developing novel autophagy-modulating agents and combining them with standard therapeutic regimens to improve clinical outcomes. They also establish the framework for further studies aimed at delineating the differences between inhibiting autophagy at proximal vs. distal points. Hopefully, the development of specific and more potent compounds will enable optimized precision targeting of autophagy in future clinical studies."} +{"text": "As cases of Alzheimer\u2019s disease and related dementias (ADRD) continue to rise, informal caregivers are critical resources in providing dementia care, yet caregiving is associated with high levels of burden, stress, anxiety and depression. Caregiving can be a prolonged and stressful experience, and impaired cognitive functioning in caregivers could impact their own health and quality of life and compromise the quality of care provided to their care-recipient. Thus, the purpose of the current study is to use the Stress Process Model as a guiding theoretical framework to identify whether primary stressors or secondary stressors predict performance across seven domains of cognition in 50 primary ADRD caregivers. Hierarchical regression analyses were used to examine which primary and secondary stressors emerge as predictors of cognitive performance. Results indicated that primary stressors significantly predicted working memory performance and secondary stressors significantly predicted implicit memory performance. Additionally, higher levels of caregiver burden predicted worse performance on executive functioning and implicit memory measures. Overall, the findings of this study indicate that the stress associated with caregiving may have adverse effects beyond psychosocial outcomes, and findings can be used to inform policies and practices with regard to caregiver health and well-being."} +{"text": "Sexual transmission of Ebola virus (EBOV) is well established and has been implicated in multiple resurgences during the West African Ebola epidemic. Given the persistence of viral RNA in semen, guidelines from the World Health Organization (WHO) recommend abstinence or condom use for at least 1 year or until two semen PCR tests are negative. To better understand the impact of semen testing on sexual behavior, male EVD survivors were surveyed regarding their sexual behavior before and after semen testing. Of the 171 men who enrolled, 148 reported being sexually active following discharge from an ETU with 59% reporting episodes of condomless sex. At least one semen sample for testing was provided by 149 men and 13 of these men had EBOV RNA detected in their semen. When comparing sexual behaviors before and after semen testing, a positive semen test result had limited impact on behavior. Of those with seminal EBOV RNA detected, 61% reported no change in behavior pre- and post-semen testing with 46% engaging in condomless sex before and after testing and only 1 adopted safer sex behaviors following receipt of a positive result. Similarly, among men with undetectable EBOV in their semen, 66% reported no change in sexual behaviors with semen testing, with 55% forgoing condoms during sex. In only 11% was a negative semen result followed by abandoning condoms. There were no known sexual transmission events of Ebola virus in this cohort despite viral presence in semen during periods of condomless sex. This highlights the need to better understand the infectious potential of viral RNA persistence and determine what constitutes effective counseling for survivors and their partners. Ebola virus (EBOV) is established as a sexually transmitted infection, however there is limited information on the sexual behaviors of Ebola survivors. We surveyed a cohort of male Ebola survivors regarding sexual activity and condom use and offered semen testing to assess EBOV persistence in semen. We found that a large majority of men who were sexually active prior to contracting Ebola Virus Disease remained sexually active after their recovery with most reporting only intermittent condom use. Semen testing for the presence of Ebola virus had limited impact on sexual behaviors, with most continuing to report engaging in condomless sex whether EBOV was detected or not. This finding has implications for use of semen testing for outbreak control as well as counseling for Ebola survivors and their partners. The development of acute Ebola Virus Disease (EVD) among female sexual partners of male EVD survivors and the persistence of detectable Ebola virus (EBOV) RNA in semen demonstrate the potential of Ebola as a sexually transmitted infection (STI)\u20134 which In the midst of the Ebola epidemic in West Africa, the World Health Organization (WHO) issued guidance for the prevention of sexual transmission of Ebola and recommended semen testing for male survivors beginning three months after recovery and continuing monthly while engaging in safe sexual practices with condom use or abstinence from sex until semen testing is negative on two consecutive occasions. Where sWhile numerous studies have highlighted the duration, patterns, and significance of viral RNA detection in semen, there have been comparably few studies that have characterized the sexual behavior of survivors. This stMen, women and children who were survivors of EVD were enrolled into the Liberian Longitudinal Ebola Survivor Cohort between June 2015 and June 2016. The cohort was created at the Eternal Love Winning Africa (ELWA) Hospital in Monrovia, Liberia, the site of two large Ebola Treatment Units (ETUs) to assess the longer-term physical and emotional consequences of EVD as well as the persistence of EBOV RNA in male and female genital secretions. The study is supported by the National Institute of Allergy and Infectious Diseases (NIAID) at the US National Institutes of Health (NIH). Participants were recruited to the cohort from an Ebola Survivor Clinic established at ELWA Hospital and from the surrounding communities via word of mouth. Cohort entry required written documentation of prior EVD as evidenced by an ETU discharge certificate containing the name of the participant and verified by photo identification. Participants underwent a comprehensive interview every three months to assess physical symptoms, mental health, and stigma. Additionally, individuals 12 years and older were asked questions about sexual behavior and men aged 18 years and older were invited to provide semen specimens for analysis of viral RNA persistence. All study visits and interviews occurred at the UNC-ELWA research site in Monrovia, Liberia.Questions related to sexual behavior were selected and adapted from a survey developed by FHI360 to assess HIV risk among youth in Liberia . ParticiAll surveys and pre- and post-test counseling were conducted in private rooms in Liberian English by research assistants who had received training on Good Clinical Practice (GCP) and at least four hours of training on survey administration. Additionally, they all successfully completed Collaborative Institutional Training Initiative (CITI) ethics and compliance certification.Detailed information on semen collection and analysis has been described previously . BrieflyAt baseline, sexual practices since discharge from the ETU and condom use in the prior 30 days were assessed. For men who provided semen for EBOV testing, we assessed sexual behavior in the 30 days prior to semen testing and in the 30 days prior to their subsequent survey, which occurred a median of 90 days later (range 57\u2013146 days).This study was approved by the Institutional Review Boards of the University of North Carolina at Chapel Hill and the University of Liberia\u2014Pacific Institute of Research (UL-PIRE). All participants provided written informed consent, with assent obtained for minors and consent from their parent/guardian. As per above, participants had to be at least 18 years of age to be eligible for semen analysis.Of the 326 people enrolled in the Liberia longitudinal Ebola survivor cohort, 180 (55%) were male. Demographic characteristics of the male participants are shown in At the time of study entry, 23 of the 171 male participants reported not being sexually active since leaving the ETU with 5 of these reporting never having had sex. Among those who were sexually active prior to EVD the most common reasons for abstinence were \u201cI have had no interest\u201d followed by \u201cI wanted to but did not have a partner\u201d. No participants cited difficulty achieving erection, feeling too tired or sick, partner refusal, or fear of transmitting Ebola to their partner. Five of these 23 men (22%) reported wanting to engage in sexual activity but were told not to by a healthcare provider because they previously had Ebola.Semen was donated at least once by 149 men and all but 7 participants provided 2 or more samples for analysis. The median time from ETU discharge to first semen donation for all men was 659 days (range 272\u2013822 days). Thirteen (9%) of those who donated semen provided at least one specimen that tested positive for EBOV RNA. At the time of study entry, 12 of the 13 men whose semen had detectable EBOV at any time point during study follow-up reported being sexually active since their discharge from the ETU and 6 (50%) of these sexually active men with detectable EBOV RNA in semen reported episodes of condom-less sex since ETU discharge.At the time of the first semen donation (median 288 days from study entry), all 13 participants reported being sexually active. Comparisons of reported sexual activity during the periods immediately prior to positive semen testing and immediately following receipt of a positive result are shown in Of the 136 men who provided at least one semen sample and never had EBOV RNA detected, the majority reported no change in sexual behavior, with most of these men reporting episodes of condomless sex both before and after testing negative . FifteenIn this large cohort of male Ebola survivors in Liberia we found that the majority of those who were sexually active prior to EVD continued to be sexually active after their discharge from the ETU and that more than half reported having sex without a condom. Importantly, in this study semen testing for the presence of EBOV had limited effect on condom use whether EBOV was detected or not detected. In particular, 6 of the 13 men who had EBOV detected in their semen reported condomless sex both before and after testing positive. Two men who were using condoms prior to testing positive stopped using them after receipt of their test result, suggesting a positive result did not encourage condom use. For 5 of the 13 men with detectable EBOV RNA in semen, consistent condoms or abstinence was practiced, however many of these men reported sexual activity without a condom on prior surveys suggesting they did not all consistently adhere to the recommendations. Collectively, this highlights the challenges in dissemination and implementation of guidance on the prevention of sexual transmission of EBOV and emphasizes the need to develop effective strategies to mitigate the risk of sexual transmission of EBOV.Similarly, most of the men whose semen testing did not reveal EBOV RNA also reported little change in sexual behavior, with most reporting condomless sex both before and after semen EBOV testing. Only 15% either abandoned condoms or became sexually active after being abstinent following the testing, perhaps influenced by the negative results despite the caveats that accompanied the test report detailing the limitations of the assay.Our finding of a limited impact of semen testing on sexual behavior stands in contrast to a report detailing the results of the Liberian national semen testing program for EVD survivors. That stIn our cohort, a small number of men reported being sexually abstinent at study entry and lack of desire was the most commonly cited reason. We did not probe as to the underlying reason for lack of desire or if this impacted participants\u2019 quality of life, however it is possible that ongoing symptoms or mental health post-EVD may play a role in sexual health. It is notable that on study entry only 5 participants reported not engaging in sexual activity on the advice of healthcare personnel given their history of EVD, despite 75 of 171 men being less than 1 year from ETU discharge. None of the men reported abstaining from sex due to concerns for transmitting EBOV. This finding underscores the importance of developing sexual health strategies and survivor guidance that acknowledges that most men will remain sexually active. Such strategies should be developed with active input from the survivor community and implemented in a manner that does not add additional stigma to this already marginalized group. Traditional approaches to reducing the risk of STIs, may be a useful starting point to prevent EBOV infection of the partners of male survivors, particularly early in convalescence when the risk of transmission appears to be greatest. Studies conducted to enhance condom use to prevent HIV infection have shown success with interventions targeting heterosexual men through group and individual counseling, peer educators, and mass national communication campaigns; however The continued sexual activity of male survivors and inconsistent use of condoms we observed has a number of implications. Foremost, the risk of transmission posed by the persistence of EBOV RNA in semen requires greater scrutiny. While viral RNA has been detected in the semen of men two years or more out from acute EVD, in all the documented cases of sexual transmission of the virus, the male source was within 16 months from ETU discharge[As discussed, real-time semen testing for EBOV RNA was not found to generally influence behavior in our study but may have an impact when offered as part of routine care and when coupled with other interventions such as counseling and the provision of condoms, as had been shown in other settings. CounselWhile the relatively large sample size, and standardized surveying and semen testing for EBOV RNA are strengths of our study, there were several limitations that should be considered when interpreting our findings. Questionnaires were administered in-person and although conducted by trained staff, there is the possibility of social desirability and/or recall bias. Despite this potential for under-reporting of risk behavior, more than half of the participants reported condomless sex. Additionally, questions on condom use assessed if there were any episodes of condomless sex since ETU discharge and in the past 30 days. This approach may have missed more complex patterns and trends in condom use over time. We also did not determine if participants with more than one sexual partner were using condoms differently with each partner, for example less commonly using condoms with their primary partner but consistently using them with casual partners, as has been found in prior studies related to condom use and other STIs.\u201321 LastlWhile there has been considerable investigation of the dynamics of EBOV in genital compartments, considerably less attention has been paid to the sexual behaviors of EVD survivors. We found that most men in this cohort of EVD survivors remained sexually active with high rates of condomless sex after discharge from ETU and that testing semen for the presence of EBOV had limited impact on condomless sex, including among those with positive EBOV detected. The continued sexual activity of men who survive EVD underscores the importance of determining their actual potential to transmit the virus. Such data are critical to developing evidence-based recommendations and policy to prevent sexual transmission of Ebola and approaches to counseling that will allow survivors and their partners to make informed decisions."} +{"text": "Vector surveillance provides critical data for decision-making to ensure that malaria control programmes remain effective and responsive to any threats to a successful control and elimination programme. The quality and quantity of data collected is dependent on the sampling tools and laboratory techniques used which may lack the sensitivity required to collect relevant data for decision-making. Here, 40 vector control experts were interviewed to assess the benefits and limitations of the current vector surveillance tools and techniques. In addition, experts shared ideas on \u201cblue sky\u201d indicators which encompassed ideas for novel methods to monitor presently used indicators, or to measure novel vector behaviours not presently measured. Algorithms for deploying surveillance tools and priorities for understanding vector behaviours are also needed for collecting and interpreting vector data.The available tools for sampling and analysing vectors are often hampered by high labour and resource requirements (human and supplies) coupled with high outlay and operating costs and variable tool performance across species and geographic regions. The next generation of surveillance tools needs to address the limitations of present tools by being more sensitive, specific and less costly to deploy to enable the collection and use of epidemiologically relevant vector data to facilitate more proactive vector control guidance. Ideas and attributes for Target Product Profiles (TPPs) generated from this analysis provide targets for research and funding to develop next generation tools.More efficient surveillance tools and a more complete understanding of vector behaviours and populations will provide a basis for more cost effective and successful malaria control. Understanding the vectors\u2019 behaviours will allow interventions to be deployed that target vulnerabilities in vector behaviours and thus enable more effective control. Through defining the strengths and weaknesses of the current vector surveillance methods, a foundation and initial framework was provided to define the TPPs for the next generation of vector surveillance methods. The draft TTPs presented here aim to ensure that the next generation tools and technologies are not encumbered by the limitations of present surveillance methods and can be readily deployed in low resource settings. Vector surveillance will increasingly be critical to the success of national malaria control and elimination programmes in designing, planning and monitoring vector interventions as the number of World Health Organization (WHO) recommended vector control strategies increases beyond insecticide treated nets (ITNs), indoor residual spraying (IRS) and larval source management (LSM) , 2 The WA recent analysis of the capacity of NMCPs to conduct vector surveillance programmes was conducted . On averIn this study, surveillance methods consist for both field sampling tools to collect vectors (i.e. traps) and laboratory techniques to analyse specimens ; CDC light trap (with or without lights or lures including placement near an occupied bed net) ; human-bThe HLC was the most frequently used technique Table\u00a0. It was The potential exposure of collectors to vector borne diseases limits the use of HLC in some countries . The HLCCDC light traps were the second most frequently used tool for monitoring biting vectors Table\u00a0. CDC lig2, near human under bed net or other), lure source and sampling site location (inside and outside of houses) making comparisons uncertain across geographic locations.Identified weaknesses of light traps are logistics in accessing necessary supplies (lures and batteries) and their initial outlay or running costs. The lure often includes carbon dioxide, usually supplied by dry ice which is not universally available. The cost of batteries, and availability, can also significantly limit light trap use. Collection efficacy varies by species and geographic area . Light traps also catch a lot of non-target insects which damages mosquito specimens while held in the collection bags which reduces the reliability of morphology-based specimen identifications. Community acceptance of CDC-LT indoors is not universal. There is also not a standard operation procedure for the CDC-LT, with deployment varying by light source , lure .Human and animal-baited traps were used less frequently in studies of biting mosquitoes and were limited to providing data on biting rates and times Table\u00a0. Human-bBoth human and animal baited traps were limited by labour, costs and ease of use. The relationship of the number of sporozoite positive mosquitoes captured when attracted to animal baited traps to the sporozoite rate in mosquitoes attracted to humans was uncertain to informants and thus concerning, as was the relative attractiveness of mosquitoes to animals and humans; thereby making the calculation of the EIR based on these techniques problematic without area specific comparisons to HLC collections.Two basic surveillance categories sampled resting mosquitoes: sampling natural resting habitats with aspirators and knockdown spray catches and the construction of sites from which resting mosquitoes are collected sprays were the most common tools for sampling indoor resting mosquitoes. None of these tools were considered to be particularly effective Table\u00a0. These tThe second approach is to create or provide suitable resting habitats prior to collection through building of pit traps, provision of resting boxes and clay pots and consBarrier screens differ from both pit traps and resting boxes and pots in that the barrier screen intercepts mosquitoes in transit to likely resting habitats or when transitioning between behaviours . Barrier screens are inexpensive to construct from locally sourced materials, and community members are easily trained to construct and operate barrier screens. Barrier screens are labour intensive to operate and involve some effort to transport and assemble materials in remote sites.There was not a preferred tool for sampling resting adults. The barrier screen, the most recently developed tool, measured more indicators associated with resting mosquitoes but was used by only 15% of informants. The need for a new more efficient and less labour-intensive tool for sampling resting mosquitoes was universally expressed.Dipping and emerWhile dipping for larvae can determine species presence, a significant limitation includes the uncertain relationship of larval numbers to epidemiologically relevant indicators as the density or prevalence of dips positive for larvae to larvae numbers by surface area, total larvae numbers in the habitat or the number of biting adults is unknown. A confounding factor for interpretation of results is that the consistency of dipping by species will vary by species-specific larval behaviours and the efficiency of the collector.Emergence and gravid traps provide data on mosquito species presence and density but were not used by vector control experts as they do not provide much information on other entomological indicators. These sampling tools are not easy to use and require training before use.Adult mosquito samples were most often analysed for species identification, malaria parasite species infection and adult mosquito age structure. While all the analysis techniques are potentially compatible with in-country analyses, almost all of the techniques require well trained staff, have complex protocols, have significant costs and associated logistic constraints, as well as requiring specimens in good condition. The interpretation of results from these laboratory techniques are susceptible to variability, which can arise from the variation in the technical consistency of the laboratorian performing the test Table\u00a0.Table\u00a07SThirty-eight percent of vector control experts commented on vector identification techniques.Morphological mosquito identification is less expensive than molecular-based identifications, and countries have this capability. However, the training and retention of staff to use complex taxonomic keys are drawbacks. Morphological-based identifications are often only to species complexes even for good condition specimens or a high identification error rate can result (varies by site/person). Hence, morphological identifications almost always require molecular confirmation for members of species complexes. Ethanol storage for ease of molecular identifications, unfortunately, increases the difficulty of morphological identifications.Polymerase chain reactions (PCR) for mosquito identifications can be done in some countries and PCR based analyses is compatible with multiple storage conditions and has high sample throughput . HoweverTen vector control experts critiqued the circumsporozoite enzyme-linked immunosorbent assay (CS-ELISA) and PCR to identify malaria parasites in mosquitoes. Both techniques share the need for a high level of training, have high laboratory establishment costs, are labour intensive techniques with complex analyses protocols. However, both techniques are compatible with multiple mosquito storage methods prior to analyses.The CS-ELISA strengths are species specificity, lower laboratory establishment and sample run costs relative to PCR and compatibility with analyses of pools of mosquitoes . Once esPCR can identify sporozoites to species and is cThe PCR for sporozoite detection is more costly than the CS-ELISA to process samples and to establish the laboratory. The technique is species but not stage specific, so, like the CS-ELISA, mosquito heads and thoraxes need to be separated from abdomens before analysis. There is also the potential for interference by blood contamination if abdomens are not removed prior to analyses.The current techniques to age grade field collected mosquitoes are dissections for parity and ovarian dilatation counts . A thirdThe advantage of ovarian dilatations for age grading mosquitoes is the sensitivity of age determinations based on the number of oviposition events which provides epidemiology relevant data Table\u00a0. OvarianParity dissections are easier to perform than ovarian dilatation dissections and parity determination is thus a field friendly technique, enabling a skilled technician to age-grade many mosquitoes by distinguishing parous from non-parous mosquitoes. Weaknesses of parity dissections were the lack of specificity (mosquitoes either have never laid eggs or they have laid eggs), a microscope is required, and live mosquitoes must be dissected (limitations shared with the ovarian dilatation technique). While easier than ovarian dilations, experience and practice are required; the technique is labour intensive and needs a dedicated team.The relatively new technique of using near infra-red scanning to age-grade mosquitoes has advantages of being compatible with high throughput, is inexpensive to analyse mosquitoes and is compatible with species identification . HoweverCurrent techniques for measuring insecticide resistance phenotypes in mosquitoes were discussed by 15 vector control experts. Training requirements, protocol complexity, logistics including transporting specimens to laboratories and the need to rear larvae from field collections to adult mosquitoes were key weaknesses for both the WHO tube test and the CDC bottle bioassay. Updated and more detailed SOPs are needed. Instructional videos would help in consistently defining live and dead mosquitoes.The WHO tube test is the historical gold standard and is compatible with both laboratory and field-based analyses . The exiThe CDC bottle bioassay measures shifts in population insecticide resistance phenotypes and is more adaptable to local conditions than the WHO tube test. The available SOPs lack sufficient detail and would benefit from videos on defining live and dead mosquitoes. Assays using the PBO synergist are challenging in that they require a 1-h pre-exposure to PBO before exposing mosquitoes to pyrethroids, which damages mosquitoes and thus impacts survival. Errors are easily made in the dilution series and acetone procurement is difficult in some countries.The current technique to determine biologically active insecticide concentrations on treated surfaces is the WHO cone test attached to a wall or ITN . WeaknesTwenty-three vector control experts provided ideas and attributes for Target Product Profiles (TPPs) for seven next generation vector surveillance tools based upon the identified strengths and limitations of current surveillance tools, as summarized above. Overall, it was expressed that the next generation of surveillance field tools and surveillance techniques should be simple to deploy with minimal training and manpower and have low establishment and operational costs to collect and process specimens. Sampling tools should be applicable for both indoor and outdoor applications and be amenable to a standardized deployment strategy. New tools should sample populations using representative sampling algorithms to measure epidemiologically relevant parameters that can be quickly and easily interpreted by programme managers for decision-making and insecticide monitoring .HLC alternatives Alternatives to the HLC are needed to sample human host-seeking adult vectors that can be calibrated to historical HLC data without placing trap operators at risk and are safe for use in or near human dwellings. Any new method must maintain the functionality of the HLC with operational costs below current costs to determine surface insecticide concentrations as well as molecular or biochemical resistance markers in adult mosquitoes that reduces human and budget resources over current WHO tube and CDC bottle assays is needed . Thus, there is a need to develop next generation vector surveillance tools to monitor these behaviours. The resulting data will then better inform interventions targeting these behaviours. The following priority areas were identified as critical for improving vector surveillance.More information is needed on the movement of adult vectors from emergence to blood feeding and oviposition sites to inform representative sampling over a geographic area and not biased to areas with high densities. Such representative sampling can then be used to optimize intervention deployment more effectively. Improved surveillance would benefit from understanding (1) where and when mosquitoes are exposed to control tools, (2) the distribution of daytime biting mosquitoes; (3) host attractancy/biting rates of mosquitoes to different blood meal hosts, (4) novel attractants to replace carbon dioxide, human odours and other blood seeking lures to improve trap performance, (5) receptivity (its definition and measurement), (6) outdoor resting site characteristics by species to improve interventions targeting exophilic adults, (7) larval habitat characteristics by species to improve larval source management. Detailed understanding of the biology of vectors will improve both vector surveillance and malaria control programmes.Faster data entry systems with uniform formats for data capture and recording across locations will enable vector surveillance data to guide programme decisions in real time to improve vector surveillance.Historically the need to maximize mosquito collection samples sizes encouraged sampling bias to collect maximum numbers of mosquitoes with minimal effort. Algorithms for representative sampling across geographic areas for adults and larvae as well as defining/stratifying receptivity are essential.Representative sampling methods for resistance testing of mosquito populations are needed. More spatially explicit representative sampling for resistance phenotypes are required along with guidance on interpreting results for resistance management . Algorithms are needed to correlate vector insecticide resistance bioassay and genetic data to intervention impact and to correlate hut data to intervention efficacy at scale.Surveillance encompasses the field sampling tools, their deployment strategies and the laboratory techniques to analyse captured vectors. Vector surveillance provides critical data for decision-making to ensure that malaria control programmes remain effective and responsive to threats such as insecticide resistance, behavioural resistance, changes in species composition and invasive species , 36\u201339. The assessment presented here summarizes how global vector control experts have been using the currently available vector surveillance tools and techniques to evaluate new vector control strategies and/or to monitor malaria control programmes. Overall, this analysis identified several consistent strengths and weaknesses shared by both the field tools and laboratory analysis techniques that constrain the scope and scale of vector surveillance undertaken by NMCPs. These weaknesses included high labour and resource requirements (human and supplies) coupled with high outlay and operating costs and variable tool performance across species and geographic regions. The strength of this assessment is that it was based on 40 semi-structured interviews with global control experts and the interviews were coded against a standardized framework of indicators that defined the utility, strengths and weaknesses of the tools. This was a fundamentally different methodological process to previous landscape analyses and as such the results summarize how the community utilizes current methods as opposed to presenting a summary of the potential applications of surveillance methods [Defining the strengths and weaknesses of the current vector surveillance methods provided a foundation to define draft TPPs for the next generation of vector surveillance tools; ones that will not be encumbered by the limitations of our present surveillance methods. Any new tools and techniques will need to be assessed against a standardized framework to ensure non-inferiority relative to present tools as regards both the logistics of deployment and performance (sensitivity and specificity) in a manner analogous to evaluations of new vector control products . Vector More efficient sampling methods which are less dependent on human resources and less expensive will facilitate increased surveillance (both frequency of sampling and number of sampling locations). Vector surveillance is fundamental to deploying more effective vector control , in partPrioritization and investments in new surveillance tool development should be shared by the entire malaria community including but not limited to NGOs, government agencies, research institutes and commercial companies. The challenges and risks associated with the successful development and implementation of new tools are acceptance and recognition for the use of alternative surveillance technique by global health authorities and NMCPs, and (2) the potential that new surveillance techniques may not have broad spectrum effectiveness across disease vectors or ecosystems which may limit the usefulness globally.More efficient surveillance tools and a more complete understanding of vector behaviours and populations will provide a basis for more cost effective and successful malaria control by better enabling interventions to be selected that align with vulnerabilities in vector behaviours and thus enable more effective control. Vector surveillance methods, as has been said for vector control interventions, are imperfect tools applied imperfectly, but present vector surveillance methods have been useful in assessing the potential of new control methods and for guiding the implementation of recommended malaria vector control strategies. The draft TTPs presented here aim to ensure that the next generation tools and technologies are not encumbered by the limitations of present surveillance methods and can be readily deployed in low resource settings. Improvements in the quality, quantity and availability of entomological data will no doubt facilitate more proactive vector control guidance and support the global progress towards malaria eradication.Additional file 1. Semi-structured interview guide.Additional file 2. Nextgen vector surveillance draft TPPs."} +{"text": "Genetic technologies such as gene editing and gene drive create challenges for existing frameworks used to assess risk and make regulatory determinations by governments and institutions. Insect genetic technologies including transgenics, gene editing, and gene drive may be particularly challenging because of the large and increasing number of insect species being genetically modified and the degree of familiarity with these organisms and technologies by biosafety officials charged with making containment decisions.An anonymous online survey of biosafety professionals was distributed to the membership of ABSA International, a global society of biosafety professionals, to investigate their perspectives on their preparedness to meet these new challenges.Existing guidance used to make containment decisions for nongenetically modified insects was widely seen as adequate, and most respondents thought the available guidance for making containment decisions for genetically modified insects with and without gene drives was inadequate. Most respondents reported having less confidence in their decisions concerning containment of genetically modified insects compared to decisions involving genetically modified microbes, (noninsect) animals, and plants.These results reveal a need for additional support for biosafety professionals to improve the quality of and confidence in containment decisions regarding genetically modified insects with and without gene drive. These needs might be addressed by increasing training, updating existing guidance, creating new guidance, and creating a third-party accreditation entity to support institutions. Sixty percent of the respondents said they either would or might use a voluntary third-party accreditation service to support insect containment decisions. To date, more than 40 species of insect already have been genetically transformed using transposon-based gene vectors,13 and 26 species have successfully undergone germline genetic modification using CRISPR/Cas9 gene editing technology, a technology that has only been available since 2013.19 The rapid pace with which insects are being genetically modified is expected to continue, and as methods improve for using these genetic technologies in a growing number of insect species, the pace with which genetically modified insects are developed will accelerate.Genetic technologies for creating transgenic organisms and precisely modifying genomes are being developed and are evolving rapidly, as are the number of ways in which these technologies can be applied to address problems in medicine, public health, and agriculture. These technologies and their applications create challenges for government and institutional decision makers relying on existing frameworks to assess risk and make regulatory and containment determinations.20 Gene drive technologies are a powerful set of new genetic technologies that are now easily assembled in the laboratory and introduced into insect genomes. Synthetic gene drive systems have the properties of selfish genetic elements, capable of being preferentially transmitted to the next generation during sexual reproduction.21 These systems could serve as platforms on which to build specific, sustainable, self-propagating insect population-suppression and -modification technologies capable of addressing some of the world\u2019s most intractable public health and agricultural problems caused by insects.22 Insects containing these technologies present new containment challenges since active synthetic gene drive systems are designed to persist and increase in frequency in target populations as well as spread under certain conditions to other conspecific populations.26 In some cases, such as so-called threshold-independent gene drives, spread of the gene drive construct can be initiated with the release of a single gene drive\u2013containing insect.Genetic technologies are being widely adopted by insect scientists because they enable difficult questions in insect biology to be addressed as well as the development of new insect control technologies such as those based on gene drive.31 Recently, recommendations for the laboratory containment and management of synthetic gene drive systems in arthropods were published in which the authors recognized that special considerations regarding containment and insectary management may be needed for this class of genetically modified organisms.32 Similarly, a large multidisciplinary working group of scientists and other professionals developed recommendations for the safe and ethical testing of synthetic gene drive\u2013containing mosquitoes intended for use as public health tools to reduce or eliminate mosquito-transmitted diseases such as malaria and dengue fever. This working group concluded that international harmonization of standards for the minimum containment requirements for gene drive\u2013containing mosquitoes would be beneficial to researchers, developers, and containment decision makers.33 Similarly, in the report Editing Biosecurity, the authors identified a need for improving oversight of gene drive research and development and suggested that this might include updating standards for research and development as well as enhancing the creation and dissemination of best practice guidance coming from research communities and professional societies.34The expanded use of insect genetic technologies, including gene drives, has elicited concerns within research communities and among environmental and biological safety experts that escape or release of genetically modified and gene drive\u2013containing insects, especially threshold-independent drives, could result in unintended changes to the environment and significantly erode public trust in the research.Given the rapidly evolving use of insect genetic technologies and the challenges they present, the perspectives of biosafety professionals and other front-line containment decision makers regarding their preparedness to meet these challenges are of interest since they are well placed to identify gaps and needs that should be addressed. Here we report the results of a survey of biosafety professionals experienced in dealing with genetically modified insects in which they were asked about sources of guidance used in making risk assessments and containment recommendations, the adequacy of that guidance, their confidence in making insect-related containment and biosafety decisions as well as that of their institutional biosafety committee when considering projects involving genetically modified insects, including those containing gene drives. Respondents were also asked about their use of neutral third-party accreditation services in general and the likelihood they would consider voluntarily using a third-party accreditation entity to support their work with genetically modified insects. The results revealed areas in which application and harmonization of regulations and guidelines for the containment of genetically modified insects could be enhanced to increase confidence both within and outside institutions that insect genetic technologies are being managed safely and responsibly. There was clear evidence that institutional biosafety professionals would benefit from additional support when dealing with genetically modified insects.https://www.wufoo.com/) and titled A Biosafety Needs Assessment\u2014Genetically Modified & Gene Drive\u2013Containing Insects was created consisting of 5 parts with a total of 25 questions and requiring approximately 10 minutes to complete . In collaboration with ABSA International, the Association for Biosafety and Biosecurity (https://absa.org/), an invitation to participate in the online survey was delivered to its members via email, followed by a second invitation approximately 2 weeks later.An anonymous online survey using a commercial survey tool the responsibilities of respondents and their experience with genetically modified insects, (2) a partial inventory of insects housed at the respondents\u2019 institutions, (3) the sources used by respondents for guidance in assessing risk and containment requirements for insects , (4) the level of confidence of respondents and their institutional biosafety committees in assessing risk and containment requirements for genetically modified insects with and without gene drives, and (5) the familiarity of respondents with third-party laboratory accreditation services and their willingness to use such services that specialized in insect biosafety and containment.Wufoo.com to Microsoft Excel and processed by removing (1) duplicate entries, (2) those who indicated they were not responsible for biosafety compliance, (3) those whose current and prior institutions did not maintain insects or who were uncertain about the insect status of both their current and previous positions and therefore unlikely to have relevant experiences with genetically modified insects, and (4) those who did not complete the entire survey.The data were downloaded from Supplemental File 2).An invitation to participate in the survey was emailed to the approximately 1700 members of ABSA International. A total of 145 responses were received, which after removing duplicate responses, responses from those who indicated they were not responsible for biosafety compliance, responses from those whose current and prior institutions did not maintain insects, and responses from those who did not complete the entire survey, resulted in 76 unique completed surveys from respondents with relevant experiences and who had responsibilities that included laboratory safety and/or compliance. Based on the respondents\u2019 self-identification, there were 56 biosafety officers, 7 manager/director/administrators, 5 academic titles, 2 consultants, 2 entomologists, and 4 other. All but 9 of the respondents were in the United States ; USDA Containment Guidelines for Nonindigenous, Phytophagous Arthropods and their Parasitoids and Predators; USDA Containment Guidelines for the Receipt, Rearing and Display of Nonindigenous Arthropods in Zoos, Museums, and Other Public Displays; NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules; specifications and conditions associated with a permit; national/regional/state/local requirements or guidelines; and advice and recommendation of the principal investigator.39 There was little difference between responses regarding genetically modified and nongenetically modified insects with the exception that the NIH guidelines on recombinant DNA were used much more frequently when considering genetically modified insects of respondents thought existing guidance for nongenetically modified insects was adequate . When coFifty-seven percent of the respondents rated their level of confidence in assessing risks and containment requirements for laboratories working with genetically modified insects as much less or significantly less confident compared to when they were making similar assessments of other genetically modified organisms such as microbes, animals, and plants . About tWhen asked to estimate the collective level of experience of their institutional biosafety committee (IBC) in assessing risks and containment requirements for laboratories working with genetically modified insects compared to those working with other genetically modified organisms, 40% rated the experience of their institutional biosafety committee as low, whereas 19% rated their IBC\u2019s level of experience as high .Similarly, the IBC\u2019s level of confidence in assessing risks and containment requirements of laboratories working with genetically modified insects compared to those working with other genetically modified organisms was estimated to be much less or somewhat less by 60% of the respondents whose institutions had a biosafety committee .A large majority, 68%, of the respondents reported having no experience using third-party conformity/assessment entities for any of their official responsibilities, whereas 15% reported having experience with such entities . When as22 Other synthetic gene drives unrelated to homing endonucleases that use different mechanisms and strategies for their effective self-propagation in populations have also been successfully assembled and tested in the laboratory.22 The accelerated pace with which scientists are now adopting transgenic technologies is presenting challenges to investigators, institutional biosafety officers, and institutional biosafety committees as they consider the containment requirements of novel genetically modified insects.Advances in the development of insect genetic technologies, including germline transformation and gene editing, are democratizing insect genetic modification, resulting in their increased application in basic and applied insect research. Interest is growing in the potential application of genetic biocontrol strategies for insect disease vectors and agricultural pests. Novel synthetic gene drives with exceptional capabilities of persisting and spreading within natural populations and resembling homing endonucleases found in some organisms such as yeasts can now be readily assembled in the laboratory using RNA-guided DNA endonucleases such as those from the CRISPR/Cas9 gene editing system.For these reasons, we conducted a survey of institutional biosafety officials and experts who are members of ABSA International to obtain their opinions regarding the adequacy of existing guidelines relevant to their making insect containment decisions.In the United States, containment standards for insects currently used in research are largely described in voluntary guidelines, most of which have very little specific information on transgenic insects. Furthermore, containment facilities are usually not inspected by central authorities such as the National Institutes of Health, the Centers for Disease Control, or the United States Department of Agriculture (USDA). Notable exceptions are USDA-certified quarantine facilities that house and test nonindigenous insects for potential biological control applications and ad hoc USDA inspections of containment facilities that are requesting permits to receive certain genetically modified insects through international importation or interstate movement.Arthropod Containment Guidelines of the American Committee of Medical Entomologists, which were written to cover vectors of human pathogens/parasites and included some consideration of transgenic insect vectors.36 The reference Biosafety in Microbiological and Biomedical Laboratories, which does not explicitly cover transgenic insects, was consulted by about the same fraction of respondents (\u223c70%).35 When dealing with genetically modified insects, 83% of the respondents reported using the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules.39 Section III D-4 of the NIH Guidelines cautions that \u201cspecial care should be used in the evaluation of containment conditions of some experiments with transgenic animals,\u201d but no specific guidance is provided other than suggesting increased containment when the transgenic host animal has \u201cundesirable traits.\u201d Under these circumstances, appropriate containment is expected to be determined by IBCs (Section III D-4-b).Respondents reported relying heavily on the advice of a project\u2019s principal investigator in their decision making. Less than 70% reported using the The results of this survey revealed that respondents mostly agreed that existing guidance used by biosafety officials and IBCs is largely inadequate for their evaluation of genetically modified insects, including those containing synthetic gene drives. The perceived inadequacies of existing guidance and the estimated low levels of experience and confidence of IBCs in assessing risk and containment requirements of projects involving genetically modified insects likely result in great variability in containment standards for genetically modified insects among institutions.34 Concerned researchers and relevant professional societies may have an important role to play here, as previous efforts have already demonstrated.40 For example, the Arthropod Containment Guidelines written by the American Committee of Medical Entomology within the American Society of Tropical Medicine and Hygiene were drafted to address a perceived lack of guidance for arthropod vectors of human and other animal pathogens and parasites.36 These guidelines could form the basis for an enlarged set of guidelines that encompass all insects and specifically address insect genetic technologies such as gene drive. International organizations could also play a key role in developing and promulgating appropriate guidance.41Satisfying the needs identified in this survey could involve any number of strategies. Updating applicable standards and best practices guidance documents has been recommended.Increased training could improve understanding by researchers and biosafety professionals of insect genetic technologies and familiarity with existing best practices within the insect research community. Online learning modalities have enhanced delivery of biosafety knowledge and training and would be well suited to satisfying some of the needs revealed in this study.42Finally, an external entity with experts familiar with relevant regulations and guidance documents as well as the norms and best practices of the research community could serve as a periodic resource for institutions to support their efforts to meet their biosafety objectives. Third-party accreditations can be voluntary peer assessments intended to enhance quality, ensure that prescribed standards and guidelines are being followed, assure funders and supporters that every effort is being made to conduct research responsibly, and engender public confidence in researchers, their institutions, and their results. AAALAC International is an example of a voluntary third-party accreditation service that has served to harmonize compliance standards and foster public confidence in the commitment of institutions to the responsible conduct of laboratory research involving animals.In this study, survey participants were asked about their experience with third-party accreditation services and the likelihood of their using such a service that could support their compliance efforts associated with genetically modified insects. Approximately 60% of the survey\u2019s respondents said they either certainly would or might avail themselves of a voluntary third-party accreditation service for insect containment facilities and management practices. As with other third-party accreditation services, this could serve to raise and harmonize transgenic insect containment standards.Appropriate and consistent containment of genetically modified insects is important not only to protect against possible harms that might result should certain genetically modified insects unintentionally enter the environment but also to protect against the erosion of public trust in scientists and institutions as well as possible legal repercussions that could occur following the unintended release of genetically modified insects. Such an erosion in public trust, reputational harm to individuals and institutions, as well as possible legal and financial liability could significantly impede research and development involving the use of insect genetic technologies and their applications to improve public health and food security. This study revealed how biosafety professionals are being challenged by insect genetic technologies and that existing resources may need to be augmented to further support decision making."} +{"text": "DNA barcoding based on mitochondrial (mt) nucleotide sequences is an enigma. Neutral models of mt evolution predict DNA barcoding cannot work for recently diverged taxa, and yet, mt DNA barcoding accurately delimits species for many bilaterian animals. Meanwhile, mt DNA barcoding often fails for plants and fungi. I propose that because mt gene products must cofunction with nuclear gene products, the evolution of mt genomes is best understood with full consideration of the two environments that impose selective pressure on mt genes: the external environment and the internal genomic environment. Moreover, it is critical to fully consider the potential for adaptive evolution of not just protein products of mt genes but also of mt transfer RNAs and mt ribosomal RNAs. The tight linkage of genes on mt genomes that do not engage in recombination could facilitate selective sweeps whenever there is positive selection on any element in the mt genome, leading to the purging of mt genetic diversity within a population and to the rapid fixation of novel mt DNA sequences. Accordingly, the most important factor determining whether or not mt DNA sequences diagnose species boundaries may be the extent to which the mt chromosomes engage in recombination. Neutral models of mitochondrial evolution predict mitochondrial DNA barcoding cannot work for recently diverged taxa, but mt DNA barcoding accurately delimits species across a wide spectrum of bilaterian animals. I propose that the tight linkage of genes on mt genomes that do not engage in recombination could facilitate selective sweeps whenever there is positive selection on any element in the mt genome, leading to the purging of mt genetic diversity within a population and to the rapid fixation of novel mt DNA sequences. If selective sweeps play a key role in generating mt DNA barcode gaps, then the most important factor determining whether or not mt DNA sequences diagnose species boundaries within a taxon would be the extent to which the mt chromosomes of individuals within that taxon engage in recombination."} +{"text": "Due to rapid technical advancements, many devices in the Internet of Things (IoT) environment, such as embedded systems, mobile devices, actuators, and sensors , can receive huge amounts of information through data exchanging and interconnection. In this context, it is important to preserve individual privacy and secure shared data. Thus, privacy and security has attracted a great deal of attention and research interest in recent decades. Hundreds of security solutions have recently been discussed for the IoT environment. Since many criteria and parameters must be considered with regard to privacy and security issues, it is critical to discuss and develop new methodologies and techniques by adopting evolutionary computations. The objective of this Special Issue on \u201cSecurity and Privacy Techniques in IoT Environments\u201d was to compile recent research efforts dedicated to studying and developing security and privacy issues related to IoT devices and the IoT environment. The Special Issue solicited high quality, unpublished work on recent advances in new methodologies for security and privacy solutions, as well as theories and technologies proposed to defend IoT-oriented applications against adversarial or malicious attacks. The number of selected/accepted papers for publication was 15, and their main contributions are described below.The first paper proposesThe second paper proposesThe third paper analyzedThe fourth paper proposesThe fifth paper proposesThe sixth paper proposesThe seventh paper proposesThe eighth paper aimed toThe ninth paper focuses The tenth paper introducThe authors of the eleventh paper carried The twelfth paper proposesThe thirteenth paper first ovThe fourteenth paper proposesThe fifteenth paper summariz"} +{"text": "Until now, mixed empirical evidence in experimental and natural studies still leaves many questions about the generality of any single relationship pattern and the underlying mechanisms. Plants are sessile and an enormous portion of their life is located belowground, in particular for herbaceous communities abundance of saprotrophic fungi is likely to promote plant richness and productivity through increases in mineralization and resource partitioning is definitely the way forward in understanding how soil\u2010inhabiting communities affect plant community dynamics and functions. However, typically, roughly half of the sequenced fungal operational taxonomic units (OTUs) can be assigned reliably to species level and for even fewer, function can be assigned. In order to overcome this limitation, efforts to improve databases using cultivation and morphological observation\u2010based methods, and by adding sequences of known functional groups, are needed.With the results of"} +{"text": "The Engaged Health Sciences Library Liaison assembles case studies from US and Canadian academic and medical institutions that highlight the unique yet diverse roles and responsibilities of a health sciences library liaison. Each case study showcases a library's innovative approach to customizing liaison services to patron needs and leveraging liaison staff as stakeholders in, and contributors to, curriculum planning and execution. This text helps early career librarians explore the options available to them in the specialty of health sciences librarianship and is ideally suited for experienced health sciences librarians or administrators who are seeking to expand the breadth and depth of services that their libraries and institutions offer.The text is tight but readable, and each case study provides reference lists for additional reading opportunities. Figures interspersed throughout the text are a welcome addition, but some are too small to be legible (p. 33 and p. 103). The index does a good job identifying the libraries and organizations that are represented in the case studies, though readers might appreciate more expansive subject indexing.The Engaged Health Sciences Library Liaison offers a variety of approaches and best practices to a targeted audience. Whether describing high school enrichment programs (chapter 2), undergraduate and graduate medical student instruction , systematic review research support (chapter 6), or resident boot camps and clinical rounding (chapter 11), The Engaged Health Sciences Library Liaison demonstrates that health sciences library liaisons have the potential to impact decades of student years, health research, and clinical practice.Just as health sciences libraries serve an assorted, yet specialized patronage, Evolution of Library Liaisons, SPEC kit 349 [Health Sciences Librarianship by M. Sandra Wood, FMLA [The Engaged Health Sciences Library Liaison focuses on its subject matter, revealing facets of health sciences library liaisons and their work that readers will find invaluable and inspiring.Unlike the 2015 Association of Research Libraries"} +{"text": "Sleep problems are prevalent among older adults. It is evident that sleep duration, as an important indicator of sleep quality, is closely associated with life satisfaction. However, it remains unclear as to whether sleep duration influences life satisfaction, or whether lower levels of life satisfaction increase the likelihood of sleep duration decline. This study examined the directional relationship between life satisfaction and sleep duration among Chinese older adults. Data were derived from the China Health and Retirement Longitudinal Study . A cross-lagged panel model with three time points was used to jointly examine the longitudinal reciprocal effects between life satisfaction and sleep duration. This model achieved acceptable indices of goodness of fit. The results revealed that sleep duration were positively associated with life satisfaction at all time points , and life satisfaction also positively predicted sleep duration across timepoints .These associations remained unchanged when taking demographics, and noontime napping into account. The findings indicate that the relationship between life satisfaction and sleep duration is bidirectional. Sleep duration may present as a mechanism for the relationship between life satisfaction and health, and suggests that effective treatment of sleep duration may improve life satisfaction."} +{"text": "It is often during transitions between health services that many issues arise for older adults, such as care that is poorly coordinated, additional burden placed on family and friend caregivers, and inappropriate placement in nursing homes. The Home Again program delivered by the provincial health authority in Nova Scotia, Canada, provides transitional care through providing additional support beyond what is normally provided through home care services to help older adults transition home after a hospital admission. The purpose of this research was to identify what factors contribute to older adults being placed unnecessarily in a nursing home when they could receive care through the Home Again program. Through using a retrospective multiple case study design, we analyzed interviews for five cases including older adult patients, their family or friend caregivers, and healthcare professionals in each case. Results indicate all hospitalized patients experienced a major health event or rapidly declining health. All family and friend caregivers experienced burnout and frustration from the lack of sufficient home care supports and quality of services available, such as services provided throughout the night. Healthcare professionals discussed that patients were placed on a waiting list for nursing homes due to lack of home care supports and resources for caregivers. This study contributes to our knowledge about better processes to ensure that hospitalized older adults are not unnecessarily admitted to nursing homes which can result in reduced healthcare costs and improved delivery and quality of care to older adults and their family and friend caregivers."} +{"text": "These resident immune cells also shape the nervous system by actively pruning synapses during critical periods of learning and engulfing excess neurons. In neurodegenerative diseases, aberrant microglial activity can impede the proper formation and prevent the development of appropriate functional properties of adult born granule cells. Ablating microglia has been presented as a promising therapeutic approach to alleviate the brain of maladaptive immune response. Here, we review key mechanisms through which the immune system actively shapes neurogenic niches throughout the lifespan of the mammalian brain in both health and disease. We discuss how interactions between immune cells and developing neurons may be leveraged for pharmacological intervention and as a means to preserve adult neurogenesis.Microglia regulate neuronal development during embryogenesis, postnatal development, and in specialized microenvironments of the adult brain. Recent evidence demonstrates that in adulthood, microglia secrete factors which modulate adult hippocampal neurogenesis by inhibiting cell proliferation and survival both Neurodegenerative diseases such as Alzheimer's and Parkinson's disease impair both longevity and quality of life. Hallmarks of these diseases are distinct pathology that cause irreversible damage or death to neurons and result in progressive cognitive and often physical decline. The progressive nature of neurodegenerative diseases is attributed largely to immune system dysregulation and chronic inflammation resulting in neuronal death and the subventricular zone (SVZ) lining the lateral ventricles , currently the most prevalent cause of dementia. It involves two major pathologies\u2014amyloid beta plaque accumulation and neurofibrillary tangles\u2014both of which contribute to neurodegeneration and cognitive decline , a model of injury-induced neurodegeneration, Willis and colleagues address the dynamics of microglial input on neural damage and subsequent repair. TBI itself results in deficits in learning and memory concomitantly with decreased doublecortin (DCX)-expressing cells (Willis et al., The restorative effects of microglial replenishment create a permissive environment for survival of doublecortin cells which are implicated in forms of learning and memory attributed to spatial navigation and working memory (Blaiss et al., Depletion studies have elucidated key aspects of the immune response to brain injury. First, cognitive deficits are not necessarily caused by aberrant microglia activity but rather loss-of-function of microglia that would normally support survival of neuroblasts with injury or other inflammatory conditions (Elmore et al., Under homeostatic conditions, the neurogenic pool is able to regulate and self-maintain despite microglial depletion (Kreisel et al., Microglia dysfunction has been implicated in most neurological diseases which affect adult neurogenesis. Proper function of microglial signaling is crucial during development for healthy nervous system formation. This signaling is important for the patterning of the stem and progenitor pools that eventually shape the neurogenic niches in adulthood. Disruptions of appropriate microglial signaling due to genetic defects during development can result in long lasting effects on adult neurogenesis. Perturbations in microglial input to cells that have committed to a neuronal fate greatly affects neuroblast survival, ultimately leading to decreased neurogenesis. Defects at this stage may explain cognitive deficits associated with immune activation in many neurodegenerative diseases. Immune activity is therefore a potential target to modulate pathological outcomes and ameliorate the effects of inflammation on adult neurogenesis. Microglial turnover appears promising as a method of using endogenous repair mechanisms to bolster adult neurogenesis. As many immune molecules have opposing effects on different stages of neurogenesis and different areas of the brain, the timing and localization of microglial turnover to key timepoints in neurogenic niches may act to preserve and potentially enhance adult neurogenesis in health and disease.SC and FI drafted manuscript. SC generated figure. SC and SK edited manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The daily lives of family caregivers of persons with dementia (PwD) often require that they manage multiple competing demands in a context of unpredictability. Memory and behavior changes associated with dementia can cause PwD to act in random and irrational ways that create stress and influence all aspects of caregivers\u2019 everyday life. Supportive others, including informal helpers and formal service professionals, should provide relief to primary caregivers; however, help may not alleviate caregiver stress and can sometimes compound the burden of care. This symposium draws on daily diary surveys and face-to-face interviews to focus on four aspects of managing everyday care of PwD among family caregivers in rural areas. Brandy Renee McCann explores how caregivers\u2019 vigilance on behalf of PwD care quality interacts with service use. Karen Roberto examines the ways in which caregivers manage PwD resistance to help, including their use of forceful care strategies. Rosemary Blieszner focuses on competing caregiver roles and demands that may contribute to or alleviate caregiver stress. Tina Savla addresses the unexpected, and often hidden, challenges involved in using formal services. Collectively, the four presentations provide in-depth insight into the complicated daily lives of families coping with dementia and the ways in which they meet the demands of full-time caregiving under often difficult and challenging circumstances. Discussant Steve Zarit considers the efficacy of these management strategies for various aspects of everyday care and offers suggestions for future research and person-centered programs and interventions to reduce health disparities among caregivers in rural areas."} +{"text": "Age is a social constructions. The treatment of people on the basis of their age, imposes serious psycho-emotional, social and economic costs on society and older people. The experiences of ageism may be exacerbated when other forms of acute and chronic forms of oppression are experienced due to racism, sexism, etc. The first paper looks at the impact of ageism on older people\u2019s health. Their systematic review of studies showed that ageism detrimentally and consistently impacted older individuals in 11 health domains, with the prevalence of significant findings increasing over time. Informed by NIA\u2019s Health Disparities Framework, the second paper examines the relationships between discrimination and protective factors on cognitive functioning. Their analyses of the Health and Retirement Survey data reveal, among other things, that everyday experiences of ageism significantly worsen older adults cognitive functioning. Using survey data of adults throughout the life-span, our third presenter examines how multiple identities (such as age and gender) influence employees\u2019 perspectives on workplace fairness in hypothetical situations. The findings are informative to human resource departments in ensuring workplace fairness within the context of a multigenerational workforce. The final paper examines two efforts to disrupt ageism, specifically interventions that target students in an intergenerational program and staff members of senior living communities. Results from these evaluations point to an increase in positive attitudes among students and a reduction in ageist behaviors among staff members. All presenters will discuss policy, practice and research implications of their studies."} +{"text": "In advanced years of life comorbidity of chronic illnesses is a common phenomenon. While chronic illnesses have been documented to impact overall quality of life, morbidity, and mortality, older adults may develop psychological resources in the years of coping and managing their illnesses. These psychological resources can be influenced by individual perceptions and context as people age, and include concepts such as psychological resilience, inner strength, subjective age, and illness perception. This symposium brings together emerging health science scholars\u2019 work on exploring and leveraging these psychological resources to improve care. Amy Ketcham will present a systematic review of psychological resilience and depression in adults with cardiac disease. Brianna Morgan will present a concept analysis exploring the nature of inner strength in people aging with serious illness and cognitive impairment. Anyah Prasad will present results examining the association between chronic illnesses and subjective age and discuss its clinical relevance. Eleanor Rivera will explore illness perception phenotypes in a longitudinal cohort study of older adults with chronic kidney disease. Together, the perspectives shared in this symposium improve understanding of and indicate ways to move toward person-centered and contextual clinical models of care in the management of chronic illnesses among older adults. In addition, the discussant will engage in a dynamic conversation about psychological resources in later life and the role these projects have played in advancing the presenters along their academic trajectories."} +{"text": "The CAZy database, and associated bioinformatics tools, organize all known CAZymes into the following classes; glycoside hydrolases (GHs), glycosyl transferases (GTs), polysaccharide lyases (PLs), carbohydrate esterases (CEs), and auxiliary activities (AAs) encompasses all enzymes involved in the modification, degradation, or biosynthesis of carbohydrates and their derivatives. Especially the CAZymes acting on glycosidic bonds have proven to be crucial for the significant biotechnological advances within sectors that include bioenergy and biobased industries. The concept of CAZymes and their organization into families, based on similar structurally related catalytic or functional domains, was established in the late 1990'ties, and in 1999 Lombard et al. launchedBiorefinery has received increasing relevance in the last decades, fueled by the significant drawbacks of unsustainable fossil fuel-based production and its negative effect on the global climate showed that they possessed different temperature optima and regioselectivity. The addition of both enzymes to a commercial Trichoderma reesei enzyme cocktail was found to boost plant biomass saccharification. Machado et al. studied the exoproteome of two white-rot fungi, Phanerochaete chrysosporium and Trametes versicolor, cultured in microcrystalline cellulose (Avicel). The most predominant enzymes in both secretomes corresponded to cellobiohydrolase I (CBHI). The enzymatic cocktails produced by both fungi were further compared to commercial lignocellulolytic cocktails and provided an alternative for enzymatic cocktail formulations.Secretomics analysis (exoproteome) is another approach that can provide valuable insights into the versatile CAZyme arsenal deployed by microorganisms during biomass degradation. In the study by Li et al. heterologously produced and characterized four new fungal enzymes belonging to the CE family, three showing acetyl xylan esterase activity and one presenting both feruloyl esterase and acetyl xylan esterase activities. The enzymes displayed promising properties, including high pH stability, thereby showing their potential for biotechnological applications. Underlin et al. characterized 14 feruloyl esterases from different subfamilies using synthetic and plant cell wall-derived substrates. The study revealed unique enzymatic profiles and diverse applicability of the various feruloyl esterases in the biorefinery context. On the other hand, Zeuner et al. report on the activity of four different pectin lyases from Aspergilli on different substrates and finds that the enzymes only displayed subtle differences in activity and product formation profiles. The highest reaction rate was found on apple pectin, while the lowest efficiency was observed for sugar beet pectin. A finding that are of high relevance for the biotechnological industries that utilize pectin lyases for food and biorefinery processes. Finally, a very interesting review concerning carbohydrate-binding modules (CBMs) and CAZymes were prepared by Sidar et al. CBMs are found in many CAZymes and are known to increase the proximity of the enzyme to its substrate, especially for insoluble ones. The review emphasizes cellulases and amylases produced by the filamentous microorganisms from the genera of Streptomyces and Aspergillus known as efficient secretors of polysaccharide degrading enzymes.Three original papers focus on specific CAZyme families. Two articles report on carbohydrate esterases (CE) and feruloyl esterases (FEA), which are vital accessory enzymes for hemicellulose deconstruction. Collectively, the included articles provide a broad introduction to the major experimental strategies currently utilized to further the biorefinery field via a better understanding of CAZymes.FC designed and wrote the Editorial with contributions from AD and RF. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Drosophila has garnered increasing attention and many studies have been dedicated to elucidate its circuitry. In this review we will summarize the recent advances in mapping and characterizing LH-specific cell types, their functional properties with respect to odor tuning, their neurotransmitter profiles, their connectivity to pre-synaptic and post-synaptic partner neurons as well as their impact for olfactory behavior as known so far.Sensing olfactory signals in the environment represents a crucial and significant task of sensory systems in almost all organisms to facilitate survival and reproduction. Notably, the olfactory system of diverse animal phyla shares astonishingly many fundamental principles with regard to anatomical and functional properties. Binding of odor ligands by chemosensory receptors present in the olfactory peripheral organs leads to a neuronal activity that is conveyed to first and higher-order brain centers leading to a subsequent odor-guided behavioral decision. One of the key centers for integrating and processing innate olfactory behavior is the lateral horn (LH) of the protocerebrum in insects. In recent years the LH of Animals are constantly exposed to an infinite number of complex odor blends in their natural habitat. The identity and specific composition of these odors convey crucial information about food availability, threats from predators or pathogens, mates, and sites for oviposition. Therefore, based on their information content, odors initiate and drive appropriate behavioral responses in animals of highly divergent species. Chemically, these odorants are small, volatile molecules that bind to their cognate olfactory receptors (ORs) expressed in the dendrites of olfactory sensory neurons (OSNs) in the peripheral olfactory organs and therefore raised the possibility that each LHN might be highly sparsely and narrowly tuned in its response profile representing the third-order olfactory processing center. In addition to the SLP, two other nearby neuropils, called the superior intermediate protocerebrum (SIP) and the superior medial protocerebrum (SMP), were also target regions of LHONs few LHNs are synapsing directly onto MBONs and (2) LHONs and MBONs converge onto the same downstream neurons which therefore function as \u201cconvergence neurons,\u201d which often represent a feedback neuron (FBN) that gives direct input onto modulatory neurons have been dissected in great detail and have been shown to be crucial for odor mixture processing, gain control, discrimination abilities, and signal boosting which connects the first and second olfactory centers in the fly brain (Coates et al.\u00a0It would be important to address in future studies the identity of the postsynaptic partner neurons of these identified LHNs in order to understand how these LHNs modulate the activity of these neurons in the next processing level. Altogether the knowledge of the neurotransmitter profile of various LHNs opens up the opportunity to study the complex network in the LH and its underlying neuronal circuit function in order to decode the incoming olfactory information from second-order neurons.Since the higher brain regions possess distinct anatomical and physiological properties, it is likely that their neurons might have distinct functions with regard to olfactory behavior. The majority of studies that have employed direct functional manipulations were exclusively limited to the understanding of the function of the MB and were lacking for the circuitry of the LH until recently. Using split-GAL4 lines it could now be demonstrated that the activity of LHNs can be stereotyped depending upon the odor category and different aspects for odor-guided behavior (Frechter et al.\u00a0Although earlier studies indirectly implicated a function of the LH regarding solely innate olfactory behavior (de Belle and Heisenberg\u00a0The LH has emerged as the center for integrating innate behavioral responses and shares many similarities with the mammalian cortical amygdala, since it receives spatially stereotyped input from individual glomeruli of the olfactory bulb and is also involved in processing odor information that directs innate odor-guided behavior (Miyamichi et al."} +{"text": "To perform histopathologic analysis of tissue manifesting meibomian gland dropout on noncontact infrared meibography in a dog.A 14\u2010year\u2010old intact male Cairn terrier was evaluated at Triangle Animal Eye Clinic for dense corneal opacity of the right eye. A complete ocular examination was performed, including slit\u2010lamp biomicroscopy, tonometry, and noncontact meibography. Pigmentary glaucoma with elevation of intraocular pressure was diagnosed, and meibography revealed morphological changes suggestive of gland dropout in the middle of the upper right eyelid.The globe was enucleated by the transpalpebral method, and palpebral tissue was subjected to histopathologic analysis. The analysis revealed an almost complete loss of meibomian gland structure accompanied by slight enlargement and proliferation of fibroblasts as well as by infiltration of plasma cells and lymphocytes.Meibomian gland dropout as detected by meibography can be associated with chronic inflammation. Their primary function is to produce oily components of the lipid layer of the tear film, with these components being secreted along the margins of the eyelids. The lipid layer of the tear film facilitates smooth blinking and attenuates the evaporation of lacrimal fluid. Meibomian gland dysfunction (MGD)2A 14\u2010year\u2010old intact male Cairn terrier was brought to Triangle Animal Eye Clinic for ophthalmologic testing of the right eye. General ophthalmologic findings included mucoid ophthalmic discharge, mild hyperemia of the upper and lower conjunctiva, eyelid swelling, extensive corneal pigmentation, and dense vascularization with corneal ulcer (Figure Histopathologic analysis of the tissue area corresponding to the site of gland dropout detected by NIM revealed meibomian gland atrophy with minimal lobular tissue remaining near the duct Figure A. Chroni3The most severe finding of meibography is gland dropout, which is characterized by an apparent complete loss of gland structure. Sites of gland dropout appear dark on meibographic images, likely as a result of the loss of the oily material produced by meibomian glands. In the present case, histopathology revealed the loss of lobular and ductal tissue at the site of gland dropout. This site included chronic inflammation, characterized by the presence of slightly enlarged and proliferating fibroblasts and by infiltration of plasma cells and lymphocytes. Although this inflammatory response may have been the result of a foreign body reaction to oil remaining in the meibomian gland duct or of the effects of ocular surface inflammation on the eyelid margin, its cause could not be discerned from our histological findings.We previously performed histopathologic analysis at the site of meibomian gland dropout in a 15\u2010year\u2010old miniature dachshund without evident ophthalmologic disease. The results revealed destruction of the lobular and ductal structure of the gland and multiple vacuolar lesions in connective tissue not accompanied by inflammatory cell infiltration.None declared."} +{"text": "Risk aversion determines how people make decisions and is known to predict a wide array of economic outcomes. This study assessed whether there are veteran status differences in risk aversion utilizing the Health and Retirement Study. Risk aversion is based on hypothetical financial gambles and self-reported risk attitudes on selected topics . Results from multivariate analyses reveal that veterans were more likely to be risk averse than nonveterans in financial matters, occupation, and health, but veteran status is not statistically significant in explaining risk taking in driving and leisure, and sport risk. Further research is needed to discern the role of military service-related experiences in determining levels of risk aversion among veterans and the extent to which risk aversion accounts for veteran status differences in later-life economic outcomes. Part of a symposium sponsored by the Aging Veterans: Effects of Military Service across the Life Course Interest Group."} +{"text": "Prior research has demonstrated that ageism, specifically negative attitudes and behaviors about growing old, can be barriers to delivering high-quality long-term care (LTC), but little is known about how ageism may be related to job satisfaction \u2013 an important driver of workforce retention in LTC. Hence, the purpose of this study was to examine the role of ageism in job satisfaction in LTC. Our cross-sectional study used data collected from 265 staff members of aging services organizations representing the continuum of job types in LTC. The study examined the relationship between ageist attitudes and ageist behaviors, and job satisfaction when controlling for socio-demographic and employment-related variables . Results of a regression analysis showed that lower internalized aging anxiety and higher affinity for older people were significantly associated with higher levels of job satisfaction. Findings suggest addressing ageism to improve job satisfaction in LTC and provide some evidence for incorporating ageism screening and training into recruitment and onboarding of staff to enhance job satisfaction and to mitigate turnover."} +{"text": "Use of lay health workers for the treatment of common mental disorders is an expanding, yet still underutilized, opportunity for closing the behavioral health treatment gap globally. In this commentary, we describe how \u201cmutual capacity building,\u201d an equal exchange of ideas between low and middle-income countries (LMICs) and high-income countries (HICs) to promote shared learning, could promote the development and scale-up of therapies using lay health workers. We propose ways that task sharing models for behavioral health can inform and be supported by bidirectional learning across HICs and LMICs. As HIC healthcare systems aim to reduce healthcare costs and expand access to care, they are increasingly looking to LMIC innovations in both HICs and LMICs. LHWs are people with minimal formal training who often share a diagnosis (peer provider) or community with the patients whom they treat. A recent systematic review described the characteristics of LHW interventions for behavioral health in both LMICs and HICs and found that the majority of interventions took place in LMICs (Barnett et al. CHWs are typically from the community they serve, and therefore, bring cultural and community expertise through their familiarity with cultural practices, social structures, local social determinants of health, and community understandings of disease (Magidson et al. One HIC response to the behavioral health treatment gap has been use of peer providers Kent ; for insThere are several lessons from CHW interventions in LMICs that could contribute to mutual capacity building. First, LHWs may help mental health treatment programs develop a better understanding of culturally appropriate care and engage stigmatized groups. In South Africa, CHWs have expanded access for the maintenance of antiretroviral therapy and provided care with outcomes similar to physicians, possibly by making HIV care more acceptable for people who feel stigmatized and shamed by their disease (Myers et al. Adapting these lessons from LMICs is most ethically and effectively done collaboratively. Mutual capacity-building could take a variety of forms. More concretely, many HIC universities have contributed to or led research in LMICs, but these efforts could involve intervention testing and implementation in both settings. Funders can put out calls for mutual capacity building to address behavioral health problems that are high priority in both HICs and LMICs (DePasse and Lee As the evidence on outcomes of LHW programs in LMICs expands and both LMICs and HICs continue to face a behavioral health treatment gap, now is the time for mutual capacity building. Mutual capacity building provides an opportunity to begin reshaping the power dynamics of global and community health research, making the research more collaborative, and providing a mechanism for elevating the voices of peers and community members in care delivery."} +{"text": "The persistence of health disparities demonstrates the need for more comprehensive research to better understand key methodological approaches and intervention leverage points among the complex relationships between psychosocial, environmental, and biological factors influencing patterns of health among older adults. Growing empirical evidence implicates differential exposure to chronic stressors that are rooted in the social environment and related social inequities in premature aging and development of chronic diseases among socially marginalized groups. This, in turn, leads to health disparities within the older adult population. Mechanisms linking stressors and health, however, remain poorly understood. This symposium assembles research examining challenges associated with measuring exposure to stressors, relationships between stressors and health outcomes, and the insight provided by stress-based frameworks for understanding mechanisms of health disparities. Allen and colleagues use comprehensive measures of exposure to stressors to identify stressor characteristics most closely associated with diurnal cortisol dysregulation and Black-White disparities, which are risk factors for adverse cardiometabolic health outcomes. Kalesnikava and colleagues will introduce methods for exploring relationships between self-reported stress and another cortisol stress biomarker\u2014cortisol reactivity to an acute stress event. Byrd and colleagues round out the symposium with a presentation on the directionality of relationships between perceived stress and depressive symptoms contributing to health disparities among Blacks. Discussant Jackson will explore implications of these studies for more nuanced research related to mechanisms of health disparities and for more targeted approaches to the prevention of health disparities among older adults."} +{"text": "Morbillivirus genus are enveloped, negative-strand RNA viruses that include a number of highly contagious pathogens important to humans and animals. They are known to be transmitted via the respiratory route and cause febrile diseases that can be fatal. Despite the availability of attenuated vaccines against several members, these viruses remain responsible for significant morbidity and mortality in their natural hosts worldwide. The development of molecular biology techniques over the past decades has helped increase the understanding of morbillivirus pathogenesis and explore the possibility to engineer their genomes as viral vectors. This Special Issue of Viruses explores recent advances in recombinant morbilliviruses platforms, especially measles virus (MV) and canine distemper virus (CDV), for novel vaccine development and oncolytic virotherapy against cancers. Topics in this special issue include parameters involved during the viral vector production, strategies of viral vector engineering, and the underlying mechanisms of the therapeutic effects exhibited by these vectors.Members of the Loewe et al. performeWith the above studies, we hope that this Special Issue will provide further insights into the development of vaccine and therapeutic applications using viral vectors in the morbillivirus family."} +{"text": "This paper examines trends in elder abuse cases by using longitudinal data (2012-2018) collected by Japan\u2019s Ministry of Health, Labour and Welfare since its enforcement. Considering these trends, this paper then compares the Elder Abuse Prevention Law to the Child Abuse Prevention Law to assess differences in policy and program provisions and how those relate to successful prevention outcomes. For example, while reports for both elder abuse and child abuse cases have been increasing, governmental actions taken in response have varied. The Child Abuse Prevention Law has been modified 6 times since its enactment based on abuse cases, but no amendments have been made for Elder Abuse Prevention Law based on case or evaluation data. Moreover, there have been many public awareness campaigns for child abuse prevention, but none for elder abuse prevention. These efforts appear to have positive outcomes including increased reporting of child abuse to police. This analysis aims to compare abuse data, abuse laws and public health efforts for children and older adults in Japan. Findings seek to identify disparities and areas where the public approach to child abuse can inform and strengthen elder abuse policies and programs."} +{"text": "Fidelity in complex behavioral interventions is underexplored. This study examines the fidelity of the INFORM trial and explores the relationship between fidelity, study arm, and the trial\u2019s primary outcome\u2014care aide involvement in formal team communications about resident care.A concurrent process evaluation of implementation fidelity was conducted in 33 nursing homes in Western Canada (Alberta and British Columbia). Study participants were from 106 clinical care units clustered in 33 nursing homes randomized to the Basic and Enhanced-Assisted Feedback arms of the INFORM trial.F = 4.27, p = .042).Fidelity of the INFORM intervention was moderate to high, with fidelity delivery and receipt higher than fidelity enactment for both study arms. Higher enactment teams experienced a significantly larger improvement in formal team communications between baseline and follow-up than lower enactment teams (enact the core components of an intervention. Greater attention to fidelity assessment and publication of fidelity results through studies such as this one is critical to improving the utility of published trials.Overall fidelity enactment was associated with improvements in formal team communications, but the study arm was not. This suggests that the intensity with which an intervention is offered and delivered may be less important than the intensity with which intervention participants Contributions to the literatureAlthough comprehensive models of fidelity assessment exist, recent systematic reviews indicate fidelity frameworks are rarely used and fidelity receipt and enactment are poorly reported.By providing a comprehensive, theory-based examination of fidelity in a complex, behavioral intervention , this study enhances understanding of how health service interventions are implemented and why they succeed or fail.enact a complex intervention than to the intensity of intervention delivery.Study findings underscore the need for comprehensive fidelity assessment and suggest more attention needs to be paid to how, and how well, intervention participants can Concurrent rather than retrospective process evaluations are needed, including concurrent fidelity studies. Concurrent process evaluations ensure the theory behind the design of interventions is considered when interventions are evaluated form and content with responsivity to context\u201d encapsulThis paper assesses fidelity quantitatively, although qualitative approaches can give a greater depth of understanding and reveal important aspects of complex organizational environments for interventions. We conducted focus groups only across teams, preventing analysis at the team level.Assessing fidelity is key to understanding care delivery interventions, revealing how and why interventions succeed or fail , 39. Howenact the core components of the intervention. The fidelity-outcome relationship has been examined in only a few settings [Our concurrent fidelity analysis helps us interpret the main results of the INFORM trial. Our results enhance understanding of impact mechanisms in complex trials. Our findings raise questions about the relative importance of intervention intensity and intensity with which participants settings , and thesettings , but a ssettings . The firsettings in how sThis concurrent fidelity evaluation demonstrates (1) implementation of the INFORM trial largely as intended, with few differences across study arms and (2) lower levels of fidelity enactment than fidelity delivery and receipt across study arms. Our evaluation highlights the relationship between fidelity enactment and intervention outcomes, and the need for additional research on how best to support intervention enactment. Our findings help explain the main INFORM trial results, strengthening conclusions on INFORM\u2019s effectiveness, and helping to make clearer its mechanisms of impact. This is valuable for replication. Future work on fidelity assessment would ideally combine quantitative and qualitative approaches for both breadth and depth of understanding on ways that interventions are delivered, received, and enacted. Fidelity to core components of interventions is important, but further research must answer precise questions about how, when, and what type of intervention adaptation can positively influence trial effectiveness. Greater attention to fidelity assessment, fidelity measurement, and publication of fidelity results through studies such as this one is needed in the literature to improve the utility of published trials."} +{"text": "Covid laid bare the structural inequities and systemic challenges facing LTC, both in terms of risk and neglect. Lost in the daily tally of new cases and mortality rates are the stories of essential workers who have neither degree nor stature in the field, yet who fulfill an awesome responsibility\u2014caring for older adults no longer visible behind locked doors. Suddenly, these full-time students and part-time workers found themselves employed in one of the most dangerous occupations in the country\u2014providing direct care in nursing homes and assisted living communities. This award lecture highlights their voices and lessons learned."} +{"text": "Acting is fascinating from psychological and neuroscientific perspectives, as it involves an individual creating an endogenously generated, accurate physical and verbal performance of another's emotional and cognitive states. However, despite the popularity of acting, the practice has received limited interest from cognitive neuroscience What are the neural mechanisms that allow actors to produce realistic performances of characters other than themselves? (ii) What long-term impact does acting training have on neurocognition? Following Goldstein and Winner , we explDebate over which techniques allow actors to produce realistic performances has a long history, with numerous schools theorizing and prescribing methods for acting practice has been defined as sharing or mirroring the feelings of another, while being aware that the emotion originates from another person inducing changes in cortical morphology (Valk et al., Based on these initial findings, we propose that actors, by repeatedly engaging the first-person fictional perspective required to produce a character, may induce changes to the cortical networks underlying social cognition. Such changes could occur as the result of Hebbian learning mechanisms which involve the strengthening of neural network functional and effective connectivity due to frequent network engagement (Keysers and Gazzola, Taken together, these initial behavioral studies suggest that engagement in acting training may indeed improve aspects of social cognition. Given that many mental disorders involve impairments in social cognition (Gallagher and Varga, BM, TG, and PK contributed to the conception and writing of this review. BM prepared the draft for submission. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Chemical probes have been instrumental in microbiology since its birth as a discipline in the 19th century when chemical dyes were used to visualize structural features of bacterial cells for the first time. In this review article we will illustrate the evolving design of chemical probes in modern chemical biology and their diverse applications in bacterial imaging and phenotypic analysis. We will introduce and discuss a variety of different probe types including fluorogenic substrates and activity-based probes that visualize metabolic and specific enzyme activities, metabolic labeling strategies to visualize structural features of bacterial cells, antibiotic-based probes as well as fluorescent conjugates to probe biomolecular uptake pathways. Mycobacterium tuberculosis bacteria, demonstrating its causality for tuberculosis and clarifying a matter of contentious scientific debate at that time )Technological innovations have always been pushing the frontiers of (micro)biological research, but the bleak reality of the emerging antimicrobial resistance (AMR) crisis forces us to revisit research topics that were nearly considered done with decades ago: The development of new and improved antimicrobial treatment strategies is back on top of the research agenda of the microbiology community. One potential future scenario to control the AMR crisis relies on the development of sustainable personalized medicine strategies that break the vicious circle of antibiotic exposure and resistance development: targeted narrow-spectrum treatment strategies that prevent pathogenesis or increase antibiotic susceptibility by modulating bacterial physiology rather than killing them. For such a scenario to become reality, it is necessary to improve understanding of bacterial physiology, virulence and AMR within the host and translate this knowledge to develop new precision chemical tools to manipulate bacterial physiology and as point-of-care diagnostic tools. Chemical probes can provide such high-level biological validation of target-engagement or drug uptake in increasingly complex physiological environments. Furthermore, thanks to the continuous improvement of reporter fluorophores and luminophores, chemical probes have great potential to yield sufficient sensitivity and specificity to serve as diagnostic tools for in vivo and ex vivo assessment of clinically relevant parameters such as AMR and virulence to inform treatment strategies.The single-cell frontier and the assessment of cellular phenotypic heterogeneity is another area where chemical probes are instrumental . BacteriThese developments are further supported by progress along the frontier of synthetic chemistry, where methods are emerging for the facile production of entirely new probes, linkers and bioconjugation strategies, providing a steadily expanding chemical biology toolkit that will allow microbiologists to study and manipulate biological systems with unprecedented versatility and precision."} +{"text": "Failed surgical treatment of anterior shoulder instability should be treated according to clinical principles similar to primary stabilization by addressing risk factors related to the damaged static glenohumeral stabilizers . In relatively rare conditions when failed primary surgery involves patients with functionally low demands, conservative treatment by strengthening dynamic muscular stabilizers might be considered; otherwise, surgical revision should be strongly considered aimed at improving quality of life. Although the overall failure rate following primary and revision surgery is expected to be below 4%, it is clear that revision surgery is technically demanding. Therefore, the initial recognition and correction of the exact pathology causing glenohumeral instability is crucial to avoid failure of primary surgery and to facilitate the success of the revision procedure, if necessary. Primary surgery for anterior shoulder stabilization fails in up to 30% of patients, but the reported failure rate can be as low as 3%.4Interestingly, a similar failure rate is reported by several authors after primary and revision surgery, following failed primary shoulder stabilization, either open or arthroscopic.Accordingly, with the aim of understanding the mode and source of a failed primary surgery and predicting and avoiding recurrent surgical failure, heavy emphasis has been placed on understanding and defining the risk factors of anterior shoulder stabilization failure.To improve decision-making in planning revision surgery, several scoring systems have been developed that take into consideration demographic and anatomic factors. The highly popularized ISIS (Instability Shoulder Index Score), which takes into consideration age, sports involvement, joint laxity, and bony damage, was validated to predict surgical outcome and accordingly determine the decision-making for the preferred surgical approach and technique.Recognizing the risk factors might explain the reason for the failure of primary stabilization surgery and could help in planning revision surgery and predict the risk of its failure. The risk factors include demographic and behavioral factors, type of surgical techniques used, and extent of anatomical damage.A consensus exists that young age is a factor that highly increases re-dislocation rate following stabilization surgery. Patients younger than 20 years have a two-fold higher risk of postsurgical shoulder dislocation.8A highly controversial risk factor is involvement in contact sports. A patient usually returns to sports activity when the treating surgeon is convinced of sufficient recovery following stabilization surgery and the rehabilitation program. It is logical to assume that in this case the anatomical etiology for the shoulder instability has been resolved, therefore the new shoulder dislocation might be considered a new injury, independent of the previous reason for treating the shoulder instability. Thus, the decision regarding the sports activity factor should be considered cautiously, providing that the surgeon and the patient are convinced of the success of the initial surgery.Surgical pitfalls and errors in primary surgery probably have a crucial effect on the risk of failure. Anatomical deficiencies left untreated in primary surgery is probably the most important reason for the failure. Regarding the soft tissue, insufficient balancing of the redundant anterior capsule when the stabilizing anchors are placed incorrectly on the anterior glenoid rim , insufficient repair avulsion of the anterior glenoid labrum, and unfixed thorn humeral side of capsule leave insufficiency of the static stabilization of the capsule unsolved and highly susceptible for re-dislocation. The number of anchors that are desirable for soft tissue stabilization has recently become a subject of debate. The dogmatic rule of the required use of at least three anchors for anterior labral stabilization, which had been previously well established,One important reason for primary surgery failure is the technical errors of bone block placement that cause its malunion or non-union on the anterior glenoid rim or hardware penetration into the glenohumeral joint. When bone block placement fails, in addition to the unsolved problem of glenohumeral instability, pain and stiffness of the shoulder due to non-union and/or joint surface damage become part of the surgical failure risk factors.Bony deficiencies, either glenoid or humeral, become an important risk factor for surgical failure when they exceed a critical size, mainly according to their three-dimensional configuration. Posterolateral humeral head impression (Hill\u2013Sachs lesion) becomes a significant risk factor for anterior shoulder instability when it exceeds 20%\u201325% of the humeral head spherical surface,15The combination of engaging Hill\u2013Sachs lesion with anterior glenoid deficiency is considered a significant risk factor for anterior shoulder instability according to the \u201coff-track\u201d concept of glenohumeral instability.When the failure of primary anterior stabilization surgery is determined by functional scoring following estimation of the increased risk of re-dislocation after primary stabilization surgery, e.g. by the WOSI scoring, according to clinical examination of shoulder range of movements and stability, it should be expected that the pathophysiology of the remaining glenohumeral instability is identified based on the risk factors and predictive scoring (ISIS system). Subsequentially, further patient management planning is required in order to address specifically the cause of the initial surgery failure, with the foreseen expectation of the final successful shoulder stabilization.Since shoulder instability, pain on exhort, and stiffness are of less functional importance in patients with functionally low demands, palliative non-surgical treatment following failure of primary shoulder stabilization might be of value if the severity of the disability due to the unstable shoulder can be controlled in part by pharmacological means and physiotherapy to strengthen the dynamic shoulder muscle stabilizers. Obviously, this solution cannot be applied to patients with functional demands, regardless of their age.Therefore, in most clinical circumstances, revision shoulder stabilization surgery is necessary following failure of primary surgery. Revision surgery is primarily directed at resolving glenohumeral instability and pain, but the revision stabilization procedure could compromise the extent of shoulder range of movements as a secondary outcome; this should be discussed with the patient, especially in regard to his/her future physical abilities. A substantial arsenal of surgical solutions exists for different underlying causes of primary surgery failure, and revision surgery should be planned accordingly.Anterior labral repair with or without capsular plication is highly effective for shoulder stabilization in patients with ligamentous laxity. When primary soft tissue repair fails due to suboptimal anchor placement, unbalanced capsule redundancy, humeral side ligamentous damage, and small non-engaging Hill\u2013Sachs lesion of less than 20% anterior glenoid deficiency, the anterior labrum repair (Bankart repair) and capsule balancing by arthroscopic approach should suffice for functional outcome. Using this approach, shoulder stability with a good range of painless movement is expected to be achieved with revision surgery.When the inferior glenoid deficiency is less than 20%, a bony procedure is not always considered,The consideration for tricortical bone graft implantation is logical as an alternative technique for treating glenoid deficiency after a previous coracoid transfer that failed due to its malunion or non-union, but it is expected to have a less favorable functional outcome due to the high risk of postoperative shoulder stiffness.19In rare cases when bone loss exceeds 45% of the glenoid surface, prosthetic replacement of the glenohumeral joint should be considered since treatment by bone grafting for extensive glenoid damage is not enough for mechanical glenohumeral stabilization.A decision-making uncertainty exists if glenoid bone deficiency is in the intermediate range of 20%\u201330%. Under such circumstances, there is lack of substantial reported clinical information for the favored surgical treatment, either by the less extensive soft tissue procedure or by bone block implantation. In this \u201cgray zone\u201d of uncertainty, the relevant demographic data and personal risk factors might help in making the surgical decision.If the primary surgical stabilization failed because of significant bone loss in the humeral head and/or the glenoid, a more complicated surgical technique is required during revision surgery.In the case of primary stabilization surgery failure due to large humeral head bony damage (Hill\u2013Sachs lesion) that involves more than 20% of the surface, especially if the bony lesion is of an \u201cengaging\u201d type, autologous bone grafting with or without a \u201cremplissage\u201d procedure (filling the defect with infraspinatus tenodesis and posterior capsulodesis) is the favored surgical method, preferably using the arthroscopic approach that is expected to prevent glenohumeral dislocation by preventing the engaging mechanism of humeral impression on a glenoid rim.Failure rate of revision surgery following failed primary shoulder stabilization is below 20%,"} +{"text": "People who plan ahead typically fare better during the response and recovery phases of a disaster. However, problems arise when the needs, wants, abilities, and resources of vulnerable people are not adequately considered. The lack of alignment between the literacy demands of existing materials and the literacy skills of many vulnerable subgroups limits their ability to understand and effectively use potentially life-saving information. Existing health literacy models that have demonstrated effectiveness in changing health behaviors and improving outcomes is a first step to reducing disaster-related morbidity and mortality in low resource and low literacy areas. This presentation will 1) describe how interdisciplinary collaborations can be used to address this public health issue, 2) explain how health literacy techniques can be applied when developing disaster materials, and 3) present research data on a social marketing campaign to improved disaster preparedness of older adults. Part of a symposium sponsored by Disasters and Older Adults Interest Group."} +{"text": "The world of concussion and traumatic brain injury (TBI) entered a new dimension with the advent of the Iraq and Afghanistan wars, which have persisted over the past 2 decades . This waThe first area of unmet need \u2013 namely improved detection and diagnosis of acute concussion \u2013 is critical to prevent additional closely spaced, additive concussions , especiaThe second area of unmet need is the wider, more aggressive use of simple, therapeutic visual interventions in the severe TBI population . Vision The aforementioned areas are two important fields in which we, as vision care professionals, can better serve the concussion and TBI populations. As our knowledge and technology improve, additional diagnostic and therapeutic paths will become available to assist with these and other future unmet needs in the patient with concussion/TBI."} +{"text": "The author mistakenly used the word \"screws\" instead of \"holes\" throughout the article, including the title. These incorrect instances of \"screws\" have been replaced with the correct word (\"holes\"). In addition, the following sentence was removed as it was also mistakenly included by the author: \"Furthermore, retentive holes were made and screws were placed into the dentin to retain the fragment in position.\"The Cureus editorial team deeply regrets that these errors were not caught prior to publication."} +{"text": "The National Association for Geriatric Education (NAGE) has maintained consistent education and advocacy efforts since 2006. In recent years NAGE has implemented formal and grassroots advocacy strategies. At the federal level NAGE has increased collaboration with other aging advocacy organizations and coalitions. At the request of Congress, NAGE leadership and stakeholders have testified before Congress and regularly submit testimony to the House and Senate. NAGE staff maintain strong working relationships with congressional staff. Strategies for effective grassroots education and advocacy have been taught to members, and membership has mobilized to educate elected officials about the essential work of the Geriatric Workforce Enhancement Programs across the country. This presentation will provide a thorough review of NAGE\u2019s advocacy work over the past 4 years."} +{"text": "Older persons are frequently identified as more vulnerable during natural disasters due to age-related changes and chronic conditions. Over the last decade, the use of social media has grown, even among the older adult population. While many communities and organizations have utilized social media as a platform to communicate news and information about natural disasters among the public, little is known regarding how older adults utilize social media to plan, evacuate, and recovery from natural disaster events. This study examined the experiences of 23 older adults (n=23) use of social media following Hurricane Matthew. Individuals were able to speak about what they perceived as helpful in the information communicated, and recommendations they had for how such communications could be improved. The presentation will conclude with recommendations on how individuals helping with evacuation and recovery can utilize social media as a communication resource for older adults during disasters. Part of a symposium sponsored by Disasters and Older Adults Interest Group."} +{"text": "Delay in closure of ductus arteriosus in postnatal life may lead to serious consequences and complications in an extremely premature neonate secondary to hemodynamic alterations in regional blood flow pattern in various organs. Despite the widespread recognition amongst neonatologists to identify a hemodynamically significant patent ductus arteriosus (hsPDA) early in the postnatal course, there is lack of consensus in its definition and thus the threshold to initiate treatment. Echocardiographic assessment of PDA shunt size and volume combined with neonatologists' impression of clinical significance is most frequently used to determine the need for treatment of PDA. Common clinical signs of hsPDA utilized as surrogate for decreased tissue perfusion may lag behind early echocardiographic signs. Although echocardiogram allows direct assessment of PDA shunt and hemodynamic alterations in the heart, it is limited by dependence on pediatric cardiologist availability, interobserver variation and isolated time point assessment. Electrical cardiometry (EC) is a non-invasive continuous real time measurement of cardiac output by applying changes in thoracic electrical impedance. EC has been validated in preterm newborns by concomitant transthoracic echocardiogram assessments and may be beneficial in studying changes in cardiac output in premature newborns with hsPDA. Alterations in perfusion index derived from continuous pulse oximetry monitoring has been used to study changes in cardiac performance and tissue perfusion in infants with PDA. Near infrared spectroscopy (NIRS) has been used to objectively and continuously assess variations in renal, mesenteric, and cerebral oxygen saturation and thus perfusion changes due to diastolic vascular steal from hsPDA in preterm neonates. Doppler ultrasound studies measuring resistive indices in cerebral circulation indicate disturbance in cerebral perfusion secondary to ductal steal. With recent trends of change in practice toward less intervention in care of preterm newborn, treatment strategy needs to be targeted for select preterm population most vulnerable to adverse hemodynamic effects of PDA. Integration of these novel ways of hemodynamic and tissue perfusion assessment in routine clinical care may help mitigate the challenges in defining and targeting treatment of hsPDA thereby improving outcomes in extremely premature neonates. Ductus arteriosus is an important and necessary structure for the fetus. It allows communication between the pulmonary artery and descending aorta during fetal life facilitating majority of right ventricular output to bypass the pulmonary vascular bed and enter the descending aorta supporting systemic oxygenation. Delay in its postnatal closure as commonly encountered in extremely premature infants born <28 weeks gestation can resuThe clinical consequences depend on the degree of left-to-right shunting through the PDA and ductal steal. The increase in pulmonary blood flow in the setting of prematurity can lead to pulmonary edema, pulmonary hemorrhage, respiratory deterioration, pulmonary hypertension, left atrial and ventricular overload and dilation followed by left ventricular dysfunction , 4. DimiPersistent patency of hsPDA is indisputably associated with increased morbidity and mortality in premature neonates. However, there is debate whether early medical or surgical closure of PDA improves outcomes. Hence, in the last decade, approach to PDA has shifted from early treatment to watchful waiting for spontaneous closure . A recenCurrently echocardiographic measurements of a PDA are considered as gold standard for assessing the magnitude and relevance of left to right shunting in premature newborns . Many auArterial blood pressure (BP) is one of the commonly used physiologic signals for evaluating hemodynamic status associated with any clinical condition. Invasive arterial catheter is the gold standard for measuring arterial BP in the initial course of premature newborn followed by oscillometric monitoring. There are technical concerns with inaccurate and under or over estimation of BP with either methods in this population , 18 howeEchocardiography is the gold standard of predicting and diagnosing hemodynamic significance of PDA. hsPDA may go clinically unnoticed in initial postnatal course of a preterm neonate as clinicals signs of hsPDA lag behind echocardiographic measurements by mean of 2 days . PerformThe European special interest group for Neonatologist Performed Echocardiography describeVarious scoring systems, incorporating measurements from fECHO have been published to standardize the assessment of hemodynamic severity of the PDA , 38. TheAssessment of the hemodynamic status particularly cardiac function is crucial for understanding the hemodynamic impact of hsPDA in preterm neonates. In neonatal practice, invasive blood pressure is routinely and continuously monitored in initial days of life for premature infants followed by intermittent non-invasive oscillometric blood pressure monitoring. Assessment of cardiac output (CO) by interpretation of indirect variables like blood pressure can be unreliable in premature and sick neonates . Other rElectrical Cardiometry has been proposed as a safe, well-tolerated, practical, non-invasive, continuous method of measurement of cardiac output that is reproducible in neonates of various gestational maturity, weight and body surface area , 47. EC Authors have established the validity of EC by demonstrating that stroke volume and cardiac output measured by EC are comparable with echocardiogram with estimated similar bias, precision and acceptable percentage error in neonates , 54, 57.Despite the accumulating evidence of clinically advantageous and acceptable values between EC and echocardiogram in hemodynamic assessment of hsPDA, it is important to note that reference values of premature neonate cardiac function on EC is yet under research and not clinically established . Also la2) in multiple organs particularly cerebral (cRSO2), renal (rRSO2), and splanchnic beds (sRSO2) necessitating physiological increase in fractional tissue oxygen extraction (FTOE) to maintain tissue oxygen requirement in premature neonates. Use of NIRS has progressed from being a research tool to clinical bedside device for non-invasive, continuous assessment of this changing oxygen dynamics in presence of hsPDA is a non-invasive method of objectively measuring peripheral perfusion from the plethysmography signal generated by pulse oximeters and represents the ratio of light absorbed by pulsatile elements such as arteries and non-pulsatile elements such as blood in venous or capillary bed, bone, connective tissue etc. , 84. PI Studies have examined PI values in healthy and sick term neonates as well Decrease in superior vena cava (SVC) flow may be a novel marker of compromised systemic circulation in neonates with hsPDA . PI has Other authors reported that the PI of the lower extremities is decreased compared to the right arm in preterm infants with hsPDA which measured by delta PI of a certain cut off value strongly correlated with the echocardiographic diagnosis of hsPDA . In anotThe review of physiologic alterations secondary to hsPDA would be incomplete without discussion of certain biomarkers that have been studied and incorporated in clinical practice for assessment of hemodynamic significance of PDA. Cardiac peptides such as B-type (Brain) natriuretic peptide (BNP) and N-terminal pro-BNP(NT-proBNP) have been studied extensively for early detection as well as monitoring therapy of hsPDA. NT-pro BNP is a marker of heart failure that increases due to ventricular volume and pressure overload in hsPDA. Normative values for this peptide in plasma in first week of life has been studied at various gestational ages, with lower normal values noted in term infants compared to preterms . VariousAlterations of organ perfusion associated with hsPDA can lead to production of ischemia modified albumin, serum levels of which were found to be elevated in cohort of preterm neonates with hsPDA . RelatioElevated nucleated red blood cell (NRBC) count at birth is related to chronic uterine hypoxia which may predispose to PDA. A recent prospective study of preterm infants, showed differences in absolute NRBC count with ductal size and hemodynamic significance of PDA as measured by echocardiogram. The authors proposed cut off absolute NRBC levels to predict hsPDA .There is ambiguous data on association of thrombocytopenia with hsPDA and its influence on response to treatment. Presence of low platelet count and high platelet distribution width in preterm neonates is shown to be associated with hsPDA . There iThe definition of hsPDA and the population it applies to, continues to develop and unfold with accumulation of further evidence of novel ways of assessment and outcomes. This review discusses the role of various continuous modes of tapping and analyzing physiologic variables resulting from a hsPDA beyond the cardiologist's echocardiogram as summarized in AP conceived the idea for the article, reviewed the current literature, and wrote the manuscript. PT reviewed the literature and assisted in writing various sections of the manuscript. MM and HB critically reviewed the manuscript. All authors reviewed the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "To support the rising need for testing and to standardize tumor DNA sequencing practices within the U.S. Department of Veterans Affairs (VA)\u2019s Veterans Health Administration (VHA), the National Precision Oncology Program (NPOP) was launched in 2016. We sought to assess oncologists\u2019 practices, concerns, and perceptions regarding Next-Generation Sequencing (NGS) and the NPOP.Using a purposive total sampling approach, oncologists who had previously ordered NGS for at least one tumor sample through the NPOP were invited to participate in semi-structured interviews. Questions assessed the following: expectations for the NPOP, procedural requirements, applicability of testing results, and the summative utility of the NPOP. Interviews were assessed using an open coding approach. Thematic analysis was conducted to evaluate the completed codebook. Themes were defined deductively by reviewing the direct responses to interview questions as well as inductively by identifying emerging patterns of data.Of the 105 medical oncologists who were invited to participate, 20 (19%) were interviewed from 19 different VA medical centers in 14 states. Five recurrent themes were observed: (1) Educational Efforts Regarding Tumor DNA Sequencing Should be Undertaken, (2) Pathology Departments Share a Critical Role in Facilitating Test Completion, (3) Tumor DNA Sequencing via NGS Serves as the Most Comprehensive Testing Modality within Precision Oncology, (4) The Availability of the NPOP Has Expanded Options for Select Patients, and (5) The Completion of Tumor DNA Sequencing through the NPOP Could Help Improve Research Efforts within VHA Oncology Practices.Medical oncologists believe that the availability of tumor DNA sequencing through the NPOP could potentially lead to an improvement in outcomes for veterans with metastatic solid tumors. Efforts should be directed toward improving oncologists\u2019 understanding of sequencing, strengthening collaborative relationships between oncologists and pathologists, and assessing the role of comprehensive NGS panels within the battery of precision tests. Approaches to systemic cancer treatment are evolving with the widespread growth of precision oncology. Particularly among patients with metastatic disease, the use of targeted therapies and immunotherapy have improved outcomes for a growing number of cancers while mitigating the toxicities often associated with traditional cytotoxic chemotherapy . The likOf the varying forms of precision testing, next-generation sequencing (NGS) of multi-gene panels is increasingly becoming the standard modality for tumor DNA sequencing. NGS panels provide opportunities to assess the mutational status of a large number of genes and carry the potential to routinely conduct sequencing of a patient\u2019s whole exome or entire genome, simultaneously. The number of molecular targets and biomarkers that may be determined by a multi-gene NGS panel is exponentially greater than with other forms of precision testing, namely quantitative polymerase chain reaction (QPCR), which facilitates single mutation detection, and immunohistochemical staining (IHC), but the cost and required time to complete an expansive NGS panel is far greater. The resources and personnel to complete NGS of tumor samples is also often unavailable at many hospitals.Though multi-gene NGS panels output a large amount of molecular information, which is considered comprehensive within the growing arena of precision oncology, the vast majority of identified mutations are not amenable to available treatments at this time. In fact, the utility of conducting multi-gene NGS panels across all advanced tumor types has been questioned previously. The concerns are secondary to the costs of tumor DNA sequencing despite limited evidence supporting its use. A few studies have evaluated the benefits of conducting multi-gene NGS panels in a widespread fashion \u20136. A limFor these reasons, The National Comprehensive Cancer Network (NCCN) provides recommendations for conducting tumor DNA sequencing via multi-gene NGS panels on a case-by-case basis . The disTo facilitate the rising demand for testing and to standardize tumor DNA sequencing practices within the U.S. Department of Veterans Affairs (VA)\u2019s Veterans Health Administration (VHA), the National Precision Oncology Program (NPOP) was launched in 2016. The NPOP provides opportunities for veterans throughout the country to have access to targeted cancer care by supporting the completion of NGS through an external vendor molecular laboratory and by facilitating consultative guidance from experts in cancer genomics based upon the results of testing. Oncologists serving within VHA practices from diverse settings may submit tumor samples for sequencing and prescribe targeted therapies thereafter with the aid of the vendor\u2019s automated interpretive summaries and the program\u2019s national consult service. Over 6000 samples from veterans have undergone NGS . VHA oncPrevious qualitative studies have assessed the perceptions of tumor DNA sequencing among patients and providers. A substantial number of unintended real-world consequences have been discovered with the accumulating use of comprehensive NGS panels. Patients are increasingly asked to handle complex genetic findings, which may be unrelated to their primary malignancies but convey greater risk for other tumors or non-malignant conditions \u201312. GeneAs such, we designed and deployed semi-structured interviews to assess the concerns, practices, and perceptions regarding tumor DNA sequencing and the NPOP among VHA oncologists who have participated in the program. Though the oncologists included in our study were uniquely employed by the VHA, the implications of our findings are relatable to providers in other settings. The indications for tumor DNA sequencing and the associated external vendor molecular laboratories are similar for oncologists serving within University-based medical centers and private cancer practices.A semi-structured interview protocol was created following discussions with expert oncologists and included the authors\u2019 previous experiences with ordering tumor DNA sequencing and overseeing the NPOP. Questions were constructed to assess the following domains: expectations for the NPOP, procedural requirements to complete tumor DNA sequencing, applicability of testing results, and the summative utility of the NPOP. An experienced specialist (VP) within the field of qualitative investigations guided the development and flow of questions. Prior to conducting recorded interviews with recruited participants, two pilot interviews were completed to assess the quality and delivery of questions.The inclusion criteria for invited participants specified that each interviewee (1) was a specialist in the field of medical oncology, (2) practiced within the VHA at the time of interview, and (3) had submitted at least one sample for tumor DNA sequencing through the NPOP. The exclusion criteria restricted other providers within the field of oncology from participating. Purposive sampling was undertaken with a total population sampling approach. Invitations were disseminated via e-mail and by communication with VHA oncologists at the annual meeting for The Association of VA Hematology and Oncology (AVAHO) in 2018. In total, 105 medical oncologists were requested to participate from all geographical areas of the country and from practices of varying sizes.The background of the interviewer was an experienced fellow in the fields of hematology and oncology. Semi-structured interviews, both in-person and telephonic, frequently lasting between 15 and 30 minutes with a mean duration of 17 minutes and 10 seconds, were scheduled and completed with interested oncologists. Participants were interviewed individually between September 2018 and January 2019. Informed consent was obtained verbally from all included participants prior to conducting interviews. Interviewees were often asked to expound on their opinions and attitudes from their structured responses by specifically describing their previous experiences with tumor DNA sequencing. Audio of all interviews was recorded and professionally transcribed by a transcriptionist who was not associated with the study team. Prior to conducting interviews with recruited participants, two pilot interviews were completed to assess the quality and delivery of questions.Data organization, management, interview question response tracking, and coding was performed using Microsoft Excel. Five representative verbatim transcripts were initially reviewed and responses were assessed by two study team members through open coding. All team members reviewed the five coded transcripts to identify differences among codes between the two sets of transcripts and to reach a consensus for each difference. The remaining interviews were coded thereafter by one study team member under the consideration of previous recommendations from all team members for nuanced excerpts of transcripts. Following review of all transcripts, thematic analysis was undertaken as previously described byBraun and Clarke et al. . PatternThis qualitative analysis was conducted within the realm of clinical operations\u2019 quality improvement of the VHA. Permission to publish the study\u2019s findings was obtained from a VHA employee with supervisory authority to approve completed investigations.Twenty interviews were conducted, by a single interviewer (VV), with oncologists treating patients at VHA practices geographically distributed across the U.S. The response rate was 19% (20/105), which is not unusual for busy oncologists. Following review of five transcripts by two study team members (VV and PP), the remaining study team members compared the designated codes between each author, and a consensus for the differences was reached through discussion. The remaining 15 interviews were then conducted by a single study team member (VV). With the use of open coding and a deductive approach to thematic analysis, the following four recurrent themes were identified: (1) Educational Efforts Regarding Tumor DNA Sequencing Should be Undertaken, (2) Pathology Departments Share a Critical Role in Facilitating Test Completion, (3) Tumor DNA Sequencing via NGS Serves as the Most Comprehensive Testing Modality within Precision Oncology, and (4) The Availability of the NPOP Has Expanded Options for Select Patients. A final theme, (5) The Completion of Tumor DNA Sequencing through the NPOP Could Help Improve Research Efforts within VHA Oncology Practices, was identified inductively. Quotations indicative of each theme are conveyed in Nearly all interviewees discussed their desire to develop a greater understanding of at least one of three key facets of tumor DNA sequencing. First, oncologists raised concerns that they were unsure of the optimal forms of tumor samples and the necessary steps to prepare samples to conduct NGS , Quote FFourteen (70%) interviewees accentuated the value of their relationships with pathologists who are affiliated with their local VHA sites to facilitate and expedite the completion of testing through the NPOP. Interviewees felt that requests for multi-gene NGS assessments were efficiently conducted when their associated pathologists believed in the utility of tumor DNA sequencing for those respective cases interviewees reported that conducting tumor DNA sequencing through the NPOP has led to changes in systemic treatment for patients managed at their respective VHA practices. A few interviewees shared experiences with prescribing targeted therapies in the frontline setting based upon the results of sequencing , 18. TheExternal to the VHA, two investigations have quantitatively assessed oncologists\u2019 perceptions of tumor DNA sequencing via NGS for patients with metastatic solid tumors. First, Gray et al. surveyed 160 physicians at an academic institution between 2011 and 2012 prior to the center making a 41 gene panel routinely available to clinicians . InteresAs conveyed by Theme 1, the participants in our study shared a wide range of concerns related to their understanding of the steps required to conduct and implement tumor DNA sequencing, ranging from the procedural requirements to efficiently conduct NGS to interpreting the reported results on behalf of their patients. As of now, centers are integrating advisory support panels into their precision oncology programs with the hopes of addressing these widespread queries among oncologists \u201325. SimiOur second theme suggests that the traditional distinction between the roles of clinicians and those of pathologists may need to be reconsidered in this modern era of precision oncology. Generally, diagnostic testing is managed by pathologists while systemic treatments are administered by medical oncologists. The separation between the two disciplines may now be blending with the rapid integration of molecular testing into routine clinical practice. Medical oncologists are desiring a greater knowledge regarding the modalities of precision testing, and pathologists are seeking an enhanced understanding of the clinical relevance for the recent rise in requests for tumor DNA sequencing . StrengtTheme 3 conveys a common interest among our interviewees for a more streamlined approach to precision testing. As of now, the number of assessments related to precision oncology can be significantly complex for clinicians . NGS of The fourth and fifth themes that were observed in our study illustrate the interviewees\u2019 level of confidence in the summative utility of tumor DNA sequencing. Previous work has shown that the rate of actionable somatic mutations associated with FDA-approved therapies among patients with solid tumors is relatively low depending on the cancers assessed . DespiteIn accordance with the expansion of NGS practices, further clinical studies will be required to validate the widespread use of tumor DNA sequencing among patients with metastatic solid tumors. Such studies could assess survival outcomes, changes in treatment practices, and/or enrollment in ongoing clinical trials. These studies are needed to validate our interviewees\u2019 perceptions that outcomes are improved with tumor DNA sequencing and the number of completed clinical trials has grown with incorporating multi-gene NGS panels into practice.A few key limitations of our qualitative study must be discussed. First, our interviewees solely included medical oncologists who served veterans within the VHA. Though many of the perceptions and concerns surrounding tumor DNA sequencing are likely similar between oncologists within the VHA and those employed elsewhere, the familiarity of sequencing may vary across practice settings, and the availability of consultative support similar to that provided by the NPOP is potentially unavailable to oncologists external to the VHA. Therefore, the implications of our findings may not be universally applicable. Second, our purposive sampling approach only sought participants who had requested at least one sample for sequencing through the NPOP. Oncologists who have never requested testing may have a lesser understanding of the indications and benefits of tumor DNA sequencing, and their input could have been valuable to further highlight the need for specific educational initiatives. In addition, oncologists who had not previously ordered testing may have felt that completing multi-gene NGS panels was simply not beneficial, and their perceptions regarding the utility of tumor DNA sequencing could have been critically missed. Third, though our interviewees provided important information about the vital role of pathologists towards the completion of molecular sequencing, we excluded providers who were not medical oncologists from our study, and consequently, the perceptions of pathologists were not included. A separate qualitative analysis is warranted to assess the opinions and concerns regarding the rising number of requests for multi-gene NGS panels among this critical group of physicians.In this qualitative study, we found that medical oncologists serving within the VHA commonly believe that tumor DNA sequencing through the NPOP leads to an improvement in outcomes for patients suffering from metastatic solid tumors. Though the oncologists participating in this study expressed positive feelings regarding the utility of tumor DNA sequencing, no clinical data has confirmed improvements in survival with widespread NGS practices. Furthermore, oncologists desire more education from technicians and genomic experts to better understand the requirements for sample preparation and to comfortably interpret the findings from NGS reports. The process to efficiently conduct testing for a large volume of patients is optimized through effective working relationships between medical oncologists and pathologists. Ideally, all of the clinically relevant biomarkers within the field of precision oncology may be identified by ordering a comprehensive large NGS panel, but currently, NGS is an additional diagnostic assessment within the battery of precision tests. As the use of tumor DNA sequencing continues to grow, these findings should be taken into consideration as oncologists are chiefly responsible for ordering NGS panels and prescribing treatments based upon the results."} +{"text": "Gopherus agassizii) is a threatened species occupying a variety of habitats in the Mojave and Colorado Deserts. Desert tortoises have been referred to as corridor-dwellers, and understanding how they move within suitable habitat can be crucial to defining corridors that will sustain sufficient gene flow to maintain connections among populations amidst the increases in human development.Preserving corridors for movement and gene flow among populations can assist in the recovery of threatened and endangered species. As human activity continues to fragment habitats, characterizing natural corridors is important in establishing and maintaining connectivity corridors within the anthropogenic development matrix. The Mojave desert tortoise that have been integrated into land management decisions in the Ivanpah Valley.Tortoises avoided areas of high slope and low perennial vegetation cover, avoided moving near low-density roads, and traveled along linear barriers (fences and flood control berms).We found that mitigation corridors designated between solar facilities should be wide enough to retain home ranges and maintain function. Differences in home range size and movement resistance between our two natural mountain pass corridors align with differences in genetic connectivity, suggesting that not all natural corridors provide the same functionality. Furthermore, creation of mitigation corridors with fences may have unintended consequences and may function differently than natural corridors. Understanding characteristics of corridors with different functionality will help future managers ensure that connectivity is maintained among Mojave desert tortoise populations. Maintaining genetic connectivity between animal populations is a crucial step in ensuring the long-term viability of species \u20134. TypicCharacterizing animal movement, which directly links a species\u2019 ecology to connectivity, has been considered one of the optimal methods for describing functional or dysfunctional corridors , 13, 14.Gopherus agassizii) is a terrestrial, herbivorous reptile native to the Mojave and Colorado Deserts of the southwestern United States. The majority of Mojave desert tortoise habitat falls in bajadas and valleys, though some populations exist in rugged mountainous terrain, and mountain passes between neighboring valleys may serve as important natural corridors between major populations \u2009<\u20091\u2009km, Hromada et al. unpublished data). With continued monitoring of tortoises within these populations, we will be able to better describe how these different mountain passes influence dispersal patterns and the potential for tortoises to cross unsuitable habitat during dispersal movements.We developed our model of tortoise movement using movements of adult tortoises within established home ranges. Recent studies have demonstrated that movements of animals during dispersal events may not be subject to same selection criteria as movements within home ranges. Rather, many species (including other tortoise species) often disperse through habitat unsuitable for long-term occupancy , 107\u2013109 deserts , 32, pophabitats , 113. Gehabitats . SeveralAlthough our model was fitted using movement data from tortoises living within plots whose habitat characteristics varied considerably, we are limited in that we cannot observe or parameterize the response of tortoises to things they do not encounter . Hence, our prediction of poor movement quality in areas such as the dry lakes in the Ivanpah Valley and areas of different vegetation communities, such as the blackbrush-Joshua tree scrub and pinyon-juniper woodlands present in higher elevations of our study area, are based on the positive linear relationship we found between tortoise habitat quality and tortoise movement propensity. While we do not have information on tortoises using all habitat types, we think our tortoises provide a reasonable sampling of the use of available habitat within this area, and their exclusion of using features (e.g. dry lakes and steep mountainous regions) is still valuable information toward evaluating their movement preferences. As the climate changes in the future, conditions for tortoise movement may be further degraded within the areas they currently inhabit while altering vegetation and climate conditions in higher elevations \u2013116. It Maintaining connectivity of animal movement through the conservation of corridors is crucial to maintaining tortoise populations across landscapes and assisting in the recovery of the species. Based on our results, the mitigation corridors left between utility scale solar (roughly 2\u2009km wide) and the edge of tortoise habitat in the Ivanpah Valley Fig. are likeWe provide characterization of natural corridors for desert tortoise population connectivity using movement resistance and home range estimation. These natural corridors differ in general patterns of movement resistance, and tortoise home ranges are smaller in the mountain pass with more areas of higher movement resistance, indicating that these passes likely function differently in terms of movement connectivity. We also demonstrate that tortoise movement is influenced by anthropogenic disturbances\u2014movement resistance increases in the presence of roads but decreases dramatically in the presence of hard barriers to tortoise movement. Mitigation corridors left on the landscape of our study area seem to be sufficiently wide to contain tortoise home ranges and allow for movement across the landscape, as long as habitat within them does not degrade in quality from further anthropogenic impacts. The use of fencing to create the edges of these mitigation corridors may have unintended consequences to individual tortoise fitness due to alteration of tortoise movements; continued monitoring could determine if this may undermine long-term connectivity and viability of tortoise populations."} +{"text": "Cannabis use during the critical neurodevelopmental period of adolescence, may lead to brain structural, functional, and histological alterations that may underpin some of the longer-term behavioral and psychological harms associated with it. The endocannabinoid system performs a key regulatory and homeostatic role, that undergoes developmental changes during adolescence making it potentially more susceptible to the effects of exposure to cannabis during adolescence. Here, we synthesize evidence from human studies of adolescent cannabis users showing alterations in cognitive performance as well as in brain structure and function with relevant preclinical evidence to summarize the current state of knowledge. We also focus on the limited evidence that speaks to the hypothesis that cannabis use during adolescence, may pose a greater risk than use during adulthood, identify gaps in current evidence and suggest directions for new research. Existing literature is consistent with the association of cannabis use during adolescence and neurological changes. Adolescence cannabis users show altered functional connectivity within known functional circuits, that may underlie inefficient recruitment of brain regions, as largely increased functional activation has been observed compared to controls. This disruption in some cases may contribute to the development of adverse mental health conditions; increasing the chances or accelerating the onset, of their development. Preclinical evidence, further supports disruption from cannabis use being specific to the developmental period. Future studies are required to better investigate adolescent cannabis use with more accuracy using better defined groups or longitudinal studies and examine the permanency of these changes following caseation of use. Furthermore, research is required to identify heritable risk factors to cannabis use. There is a need for caution when considering the therapeutic potential of cannabis for adolescence and particularly in public discourse leading to potential trivialization of possible harm from cannabis use in adolescence. Current evidence indicates that adolescence is a sensitive period during which cannabis use may result in adverse neurocognitive effects that appear to show a level of permanency into adulthood. Cannabis is the most used illicit drug worldwide, with those who go on to become habitual users most commonly beginning use during adolescence , 2. AttiAdolescence is a critical period of neural development and a lavia cannabinoid 1 (CB1) receptors, its main central receptor relevant to the central issue under examination here are summarized under different sub-sections below and also presented in Human studies and right putamen (extending to the striatum and insula) . These rDespite being limited, functional imaging studies have also investigated whether early and late-onset cannabis users differed in their brain activity \u201394 whileOther studies have investigated alteration in the functional connectivity between different regions of the brain in the context of cannabis use to complement and help better understand the differences in brain activation seen in cannabis users . A longiDirect comparison of adolescent exposure with comparable exposure during adulthood is challenging to address in human studies. Preclinical studies have further advanced current understanding of the effects of cannabinoids in adolescence, with experimental designs allowing for systematic investigation and better control of potential confounding factors Efficacy and Mechanism Evaluation scheme (UK).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Danio rerio) is an excellent model to study a wide diversity of human cancers. In this review, we provide an overview of the genetic and reverse genetic toolbox allowing the generation of zebrafish lines that develop tumors. The large spectrum of genetic tools enables the engineering of zebrafish lines harboring precise genetic alterations found in human patients, the generation of zebrafish carrying somatic or germline inheritable mutations or zebrafish showing conditional expression of the oncogenic mutations. Comparative transcriptomics demonstrate that many of the zebrafish tumors share molecular signatures similar to those found in human cancers. Thus, zebrafish cancer models provide a unique in vivo platform to investigate cancer initiation and progression at the molecular and cellular levels, to identify novel genes involved in tumorigenesis as well as to contemplate new therapeutic strategies.Zebrafish ( Xiphophorus maculatus and the green swordtail Xiphophorus helleri spontaneously develop malignant melanomas . . 233]. OTHOR .Oncogene expression through transgenesis via the injection of transgenes into one-cell stage embryos implies that these oncogenes will be expressed from early embryogenesis, with potentially deleterious effects during development. To bypass this possible limitation, Richard White and colleagues implemented a method called TEAZ (Transgene Electroporation in Adult Zebrafish) to deliver transgenes driving oncogene as well as CRISPR/Cas9 components expression, directly into somatic tissues of adult zebrafish using electroporation . One intThen, the continuous progress in the improvement of conditional transgenesis approaches in zebrafish has generated an immense toolbox for controlling oncogene and tumor-suppressor gene activities in specific cells and a given time. This set of tools offers a variety of modelling possibilities in the field of cancer research.Over the past two decades, the progresses accomplished in the implementation of sophisticated genetic and reverse genetic tools allowed the emergence of a remarkable diversity of genetically engineered zebrafish cancer models. The precision of the reverse genetic toolbox enables the generation of zebrafish lines carrying genetic modifications that are identical to the alterations found in patients. Transcriptomic and oncogenomic comparisons between human and zebrafish tumors reveal common molecular signatures and potentially lead to the discovery of novel genes involved in tumorigenesis ,240,241."} +{"text": "In the anatomical sciences, it has long been recognized that the human body displays a range of morphological patterns and arrangements, often termed \u201canatomical variation\u201d. Such variations are quite common and often have no noticeable impact on patient health. However, some variations may cause or contribute to significant medical conditions. An understanding of normal anatomical variation is vital for performing a broad range of surgical treatment modalities and other medical procedures. However, despite their importance for effective diagnosis and treatment, such variations are often overlooked in medical school curricula and clinical practice. Recent advances in imaging techniques and a renewed interest in variation in dissection-based gross anatomy laboratories have facilitated the identification of many such variants. This Special Issue of Diagnostics includes invited and contributed papers that highlight previously under-recognized anatomical variations and discuss them in a clinical context. In particular, the Issue focuses on variants that have specific implications for diagnosis and treatment and explores their potential consequences.Several studies in this Special Issue present new information that has implications for surgical procedures, especially of the head and neck. Degaga and colleagues described variations in the pneumatization and septation of sphenoid sinus diagnosed using computed tomography (CT) scans, which have implications for trans-sphenoidal surgery . Wang anOther studies presented implications for surgical and other invasive interventions of the pelvis and extremities. Palomo-Lopez and colleagues documented the anatomic and histological features of the insertion of the extensor digitorum longus tendon on the proximal phalanx of the second toe . They deA number of studies revealed anatomical and developmental bases for various pathologies and clinical presentations. Lee and colleagues described longitudinal changes in the tibiofibular relationship in patients with hereditary multiple exostoses . A previFinally, Petto and colleagues presented a case of a rare anatomical variant, musculus sternalis . They deThese papers present a variety of intriguing, clinically relevant anatomic variants, and explain their implications for surgical interventions, developmental understanding, and diagnoses. They emphasize the wealth of information that is still unknown about human anatomy. These studies also highlight the important contributions of body donors to medical education and the advancement of medical treatments, as many studies were conducted using cadaveric specimens. It is our sincere hope that the information in this Special Issue will be applied to advancing the diagnosis and treatment of patients with anatomic variants."} +{"text": "Data need to be collected to establish their full prognostic significance. As a better understanding is developed, the prognostic significance of these histopathological factors may influence decision-making of multidisciplinary teams involved in looking after gastric cancer patients. Surgery and lymphadenectomy continue to be the key components for treating gastric cancer patients. However, the future lies in tailoring treatment specifically to patients and their tumour biology to minimise unnecessary interventions and their side-effects and ensure an optimum therapy."} +{"text": "Organizations in seven states have been participating in the Center for Medicare and Medicaid Innovation (CMMI) initiative aimed at reducing potentially avoidable hospitalizations among long-stay nursing home (NH) residents. The purpose of this study was to identify market and policy factors that may have affected the initiative in those states. Forty-seven interviews were conducted with key stakeholders in the seven states and qualitatively analyzed to identify themes across states. Few policies or programs were found that may have affected the initiative; only New York (NY) was found to have state policies or programs specifically aimed at reducing hospitalizations. Market pressures reported in most states were similar. For example, stakeholders reported that the increased availability of home and community-based services and the growing presence of managed care are contributing to higher acuity among both long and short stay residents and that reimbursement rates and staffing have not kept up. Stakeholders suggested greater presence of physicians and nurse practitioners in NHs, better training around behavioral health issues for frontline staff, and more advance care planning and education of families about end of life may help further reduce NH hospitalizations. We also found that all states, except NY, had regional coalitions of health care related organizations focused on improving some aspect of care, such as reducing hospital readmissions. These coalitions may suggest ways that organizations can work together to reduce hospitalizations among NH residents."} +{"text": "Standard induction rules induct over only the top-level structure of data, leaving any data internal to the top-level structure untouched. By contrast, deep induction rules induct over all of the structured data present. We give a grammar generating a robust class of nested types (and thus ADTs), and develop a fundamental theory of deep induction for them using their recently defined semantics as fixed points of accessible functors on locally presentable categories. We then use our theory to derive deep induction rules for some common ADTs and nested types, and show how these rules specialize to give the standard structural induction rules for these types. We also show how deep induction specializes to solve the long-standing problem of deriving principled and practically useful structural induction rules for bushes and other truly nested types. Overall, deep induction opens the way to making induction principles appropriate to richly structured data types available in programming languages and proof assistants. Agda implementations of our development and examples, including two extended case studies, are available.This paper introduces"} +{"text": "Recent advances in preventive and lifestyle medicine in conjunction with improvements in pharmacological and surgical treatments have prolonged the life expectancy with a significant increase in the number of patients 65 years of age and older . HoweverHeart disease and metabolic diseases are common disorders in the elderly population and represent a major health problem worldwide causing high hospitalization and mortality as well as elevated costs . NeverthElderly subjects show multi-organ impairment with metabolic dysfunction as well as a slow and progressive decline in adaptive homeostasis . HoweverMetabolomics is an emerging powerful technology that allows for the profiling of several metabolites in biofluids and tissues. Using a metabolomic focused approach not only allows identifying altered metabolites and circulating prognostic biomarkers during disease but also provides insight into the pathophysiological mechanisms involved.Animal studies have confirmed that aging itself is characterized by impaired function and metabolic changes in different organs including liver, muscle and adipose tissue, resulting in a peculiar plasma metabolic profile (e.g. changes in fat and amino acid metabolism) ,4. This Plasma metabolomics studies have shown altered circulating metabolite levels in patients with HF (e.g. increased long-chain acylcarnitines and impaired levels of circulating metabolites involved in fatty acid oxidation) . Of noteOur group has recently confirmed the circulating metabolic footprint of aging and has demonstrated that myocardial ischemic injury does not affect the plasma metabolomic signature in either young or old mice . This fiRoberts and collaborators performed a metabolomic study in serum samples from two ethnically distinct cohorts of elderly patients (from the United Stated and Japan) and evaluated the effect of the metabolic syndrome . The autFurther studies will elucidate how different metabolic disorders affect tissue and circulating metabolome in older subjects with heart disease. Translational studies will be instrumental to comprehend the pathophysiological mechanisms involved and will clarify the specific contribution of hyperglycaemia, insulin resistance and dyslipemia to the metabolic disturbances occurring in elderly patients with HF."} +{"text": "The patient was a 33-year-old man with a medical history significant for autism and congenital agenesis of bilateral optic nerves who presented with progressive enlargement of the right malar region. Maxillofacial computed tomographic scan revealed bony hypertrophy involving the right inferolateral orbit, lateral maxilla, and zygoma consistent with fibrous dysplasia.What is the etiology of fibrous dysplasia?What are the associated signs and symptoms of fibrous dysplasia?What are the goals and methods for treating craniofacial fibrous dysplasia?What methods were used in this case and what were the outcomes?GNAS1 gene that leads to excess production of interleukin 6.Fibrous dysplasia is a relatively uncommon, benign condition in which normal bone is replaced by fibrous connective tissue and poorly formed trabecular bone. This occurs due to an activating mutation of the Lesions most commonly occur in a single bone (monostotic) but may involve multiple bones (polyostotic). While fibrous dysplasia can affect any bone in the body, it most frequently involves the maxilla, mandible, and bones of the skull.The treatment goals are to eliminate or reduce symptoms and achieve aesthetic improvement. Radiotherapy is contraindicated for treatment due to the 400-fold increase in risk for malignant degeneration.b). Temporary reconstruction was performed using titanium mesh and plates for the orbit and Medpor for the zygomatic arch and maxilla. After final pathology confirmed clear margins, a second surgery was performed for definitive reconstruction. The titanium plates, mesh, and Medpor were removed and replaced with autologous bone from fifth and sixth ribs. The autologous bone reconstruction with rib grafts provided an acceptable aesthetic result that remains stable (d).In this patient, a surgical approach with staged reconstruction was done. The areas of involvement were identified as irregular, pinkish invasion of the bone and were resected. The resection included a portion of the zygomatic arch, the zygoma, inferior and lateral orbital wall, and the lateral maxilla on the right b. Tempors stable d.Craniofacial fibrous dysplasia often presents as facial deformity. In the fronto-orbito-malar region, treatment with excision and bone grafting can achieve aesthetically and functionally acceptable results. This case demonstrates that fibrous dysplasia involving the orbit and midface can be adequately treated with resection and staged reconstruction with autologous bone."} +{"text": "Purpose is to review the pathogenic mechanism for ocular hypertension and glaucoma development after pars plana vitrectomy. Both acute and chronic causes are considered, and special attention is paid to the theories and clinical evidence on the risk of developing Open Angle Glaucoma (OAG) after Pars Plana Vitrectomy (PPV). Most existing scientific literature on the issue agree on the role of ascorbate as an oxygen scavenger within the vitreous chamber. Oxygen tension in the vitreous and anterior chamber is maximum inn proximity of the retinal surface and endothelium, respectively and steeply decreases toward the lens, on both sides, and trabecular meshwork. Vitreous removal and, to a lesser extent, liquefaction, greatly reduces oxygen tension gradient in vitreous chamber while cataract extraction has similar effects on anterior chamber oxygen gradients. Oxygen derivatives originated from the cornea and retina are actively reduced by the vitreous gel and/or the crystalline lens. Vitreous removal and cataract extraction reduce drastically this function. Most reported clinical series confirm this hypothesis although protocol difference and follow-up length greatly impact the reliability of results. The vitreous proteome indeed is acquiring increasing importance as more information regarding its component in normal and pathologic states gets unraveled. Even neurodegenerative diseases may be heralded by specific proteins in the vitreous and reseThe vitreous indeed plays a pivotal role in the anatomy and physiology of the eye , acting Pars plana vitrectomy (PPV) is a common surgical procedure aimed at removing the vitreous gel, performed for a variety of indications includinVitreous removal and replacement, in fact, may cause significant intraocular pressure (IOP) increase and glaucoma by means of different mechanisms including tamponade hyper-filling, aqueous misdirection, lens diaphragm shifting, zonular weakness, ciliary body edema, trabecular meshwork damage, vortex vein damage, neovascular stimulation only to Moreover, vitreous removal and its replacement with gas or silicone oil induce a myriad of changes even from the bio-mechanical standpoint and may alter the measure of intraocular pressure itself, compromising our capability to understand fluid behavior and balance within the eye : particuWe will briefly illustrate the most prevalent and important acute and chronic mechanisms for IOP increase both in the short and long term and will focus on what is possibly the most interesting and misunderstood: open angle glaucoma occurring years after uncomplicated pars plana vitrectomy without recurring to long last tamponades and even when no tamponade at all has been used. Interestingly, although the potential for PPV to alter ocular pressure homeostasis had been hypothesized in the very early stages of vitrectomy development the fullThe role of PPV in the development of successive open angle glaucoma (OAG) up to several years after gel removal has been lengthy debated in the past years as clinical the proposed pathogenic mechanism gained acceptance and clinical series have been published.Acute peri- or post-operative IOP rise recognizes mechanism related to surgery, inflammation and/or tamponade use and their physical and chemical properties see .The risk for optic nerve and retinal damage related to intraoperative ocular pressure correlated to pars plana vitrectomy start from the very beginning as is nowadays understood that intraoperative IOP management is as important as long-term control. IOP peak during surgery may in fact result in long-term damage to the optic nerve and many other ocular structures .Intraocular pressure (IOP) increase over 30 mmHg has been found in over 43% of all eyes undergoing uncomplicated PPV and someOther frequent mechanisms of acute IOP rise include anterior shifting of the iris-lenticular diaphragm, more often in phakic eyes, especially highly myopic eyes due to weakness of the zonular ligament that allows forward movement of the entire crystalline lens under the buoyancy force of both silicone oil and gas bubbles used as tamponades. Effective treatment for such conditions often is based on limiting unnecessary surgical maneuvers to minimize inflammation, and posturing. In case of iris and lens anterior shifting, the suspicion index must be particularly high and in case posturing fails evaluate the need for making the patient pseudo-phakic as soon as possible since malignant glaucoma mechanism may ensue.Post-operative choroidal hemorrhage, especially if annular and extended 360\u00b0 around may be another cause for anterior shifting of the ciliary body, iris and lens and drainage may be necessary to re-establish a deep anterior chamber .Aqueous misdirection syndrome is a well-known cause of acute post-operative IOP increase in phakic eyes undergoing many different types of surgery, mostly trabeculectomy. The same pathogenic mechanism has also been observed in phakic eyes following pars plana vitrectomy as aqueo6, C2F6, C3F8) may lead to expansile concentrations leading to acute, often disastrous, IOP rise that may result in ophthalmic artery occlusion [Excessive filling of the vitreous chamber with silicone oil at the time of fluid injection may also determine acute intraocular pressure rise after surgery, as well as expansile gas injection dilation. Inaccurate estimate of tamponade gas mixtures where is2O by the action of catalase. In this scenario, the vitreous would act as a barrier to oxygen derivates strategically interposed between the highly vascularized and metabolically active retina and the delicate anterior structures extremely sensitive to oxidative stress: the lens and trabecular meshwork meshwork. Why is so much ascorbate needed within the vitreous chamber? Shui et al. proposedSiegfried et al. confirmeShui et al. also noticed that the liquified vitreous contains less ascorbate and consumes oxygen at a much lower rate than vitreous gel . Until tThis may suggest a role of vitreous liquefaction in the development of nuclear cataract, as liquified gel current increase oxygen levels close to the lens altering the physiologic gradient acting as consecutive barriers protecting the crystalline transparency. Oxygen and oxidative stress are well-known risk factors for cataract development. Oxygen has been linked to apoptosis in trabecular meshwork cells which woThe very first to report OAG increase after PPV were probably Stangos et al., in 2004 who obseLuk et al. confirmeNot all data concurred: Yu et al. in 2010 retrospeKoreen et al. in 2012 Govetto et al. in 2014 Yamamoto found a Miele at al. in 2018 conducteMansukhani et al. also repOcular pressure homeostasis is a precious and delicate equilibrium actively pursued through a number of precisely tuned mechanism and vitreous removal is a gross maneuver, literally an amputation that cannot but have profound consequences on many of those intricate metabolisms.The prevention and management of intraocular pressure alterations related to pars plana is a multifaceted and articulate issue: dealing with acute ocular hypertension is more straightforward and usually effective. For what concerns the development of open angle glaucoma with or without silicone oil emulsion the problem is virtually ineludible and intrinsic to the surgical procedure.Although the seeds of potential chronic harm secondary to vitreous removal were planted at the very beginning of the vitrectomy era, the lengthy latency and complex pathogenesis delayed the acquisition of full consciousness until much later on.From the very moment a vitrectomy starts, the surgeon takes a somewhat illusory control of intraocular pressure but must pay extreme attention to leave it as much unaltered as possible. When surgery ends, the injection of tamponades, both gas and liquids will inevitably have marked repercussions on pressure short and long-term control: oil emulsification leads to macrophage and monocyte phagocytosis and activation and even leaving aqueous in the vitreous chamber will forever destroy the ascorbate-based oxygen scavenging mechanism. This will de facto open the door to future inevitable events such as progressive and consecutive crystalline lens and trabecular meshwork meshwork oxidation as a ticking bomb. This unless game-changer vitreous substitutes appear at the horizon.In the meantime it is imperative to counsel post pars plana vitrectomy patients appropriately as to the risk of developing secondary open angle glaucoma even years after the surgical procedure and more likely so after cataract removal if performed at a later time. For many surgeons used to combine phacoemulsification to pars plana vitrectomy almost irrespective of patients age, or at least in patients in their fifties or early sixties it may be wise to reconsider this approach until an overt cataractous lens develops as this is actually protecting the trabecular meshwork from a much less repairable damage. It is unclear at the moment if the subgroup of patients at risk for glaucoma for many reasons and glaucoma suspects are more prone than the remainder of the population to develop post pars plana vitrectomy open angle glaucoma but it seems likely and wise to suspect it and behave accordingly.Most surgical series reported after the enlightening Jackson Lecture given by Stanley Chang on this issue in 2006, proposing the oxidative pathogenic mechanism, have been largely confirming (with a few exceptions) the oxidation theory and the role of the crystalline lens. The only available meta-analysis pointed out the lack of standardization and the need for longer follow-up on similar series in order to be able to shed more light on the issue and acquire solid data that may help us understand the numbers and entity of the problem.There is today enough convincing experimental evidence to believe that the vitreous gel plays a pivotal role in oxygen gradient maintenance throughout the vitreous chamber and that vitreous liquefaction and more overtly vitreous removal determine an abrupt loss of such gradient. There also is evidence that after vitrectomy the crystalline lens itself, if present, acts as an oxygen scavenger paying the price of speeding the cataract process. After cataract removal in previously vitrectomized eyes, both barriers resisting to oxygen derivatives spreading throughout the eye , fail to work and the trabecular meshwork becomes a very likely target for oxidation triggering an intricate metabolic cascade that leads to trabecular cell apoptosis, trabecular function decline and glaucoma. While the role of ocular hypertension in causing optic nerve head hypoperfusion thus promoting oxidative stress derived damage in ganglion cell axons is known , at the Effective countermeasures are difficult to imagine at the time being, except for the development of an entirely new generation of vitreous substitutes capable of keeping the oxygen gradient within the vitreous chamber, something difficult even to imagine with the present level of insight on this specific topic. Biomimetic gels with tunable mechanical properties have been developed with lengthy research and the All tested hydrogels, no matter how promising, may mimic the ascorbate system keeping the oxygen gradient within the vitreous chamber. For this reason and possibly for a long time still to come, the risk of OAG should be overtly discussed with patients especially because PPV indications since the very first cases from Machemer have now"} +{"text": "As part of a randomized control trial for deprescribing opioids and benzodiazepines (BZD) to reduce falls (funded by Centers for Disease Control), we conducted a virtual focus group and surveys to evaluate opioid and BZD prescribing practices among healthcare providers in four primary care clinics in North Carolina. Survey and focus group questions measured providers\u2019 confidence in their abilities to weigh benefits and harms of opioids and/or BZDs in older adults; determine alternative interventions; create a safe dosing plan; and incorporate patient preferences. A validated pre-intervention survey, adapted from a survey by the Canadian Deprescribing Network, was administered to providers in control and intervention clinics (n=29). Providers expressed high confidence in their abilities to weigh risks and benefits of deprescribing opioids and BZDs, but low confidence in deprescribing under impeding circumstances . Results were similar across opioids and BZDs. A focus group was conducted among seven providers from the two intervention clinics. Barriers to deprescribing identified included patient resistance, lack of knowledge of deprescribing best practices, and lack of time to discuss deprescribing during regular clinic visits. Providers also expressed concerns about deprescribing medications initiated by or managed by other prescribers. Key facilitators of deprescribing included patient trust in physician, patients being agreeable to reduce medications, and use of gradual tapering rather than abrupt discontinuation. Barriers and facilitators were subsequently used to optimize training and provider resources for the deprescribing intervention, which is currently being implemented."} +{"text": "The aim of the current study was to understand how to integrate digital home assistant technologies and smart appliances into older adults\u2019 homes by developing supportive user guides that facilitate adoption and continued use. We conducted a series of interviews among older adults, with and without mobility disabilities, to understand their attitudes towards digital assistants and to identify needs for instructional support and user guides. Subsequently, we developed and tested specific user guide modules for older adults aimed at addressing the identified concerns and desired instructional support. Specifically, we developed and field-tested user guides for the initial Amazon Echo device setup, basic device use , and separate modules for other domestic use cases . Our results provide guidance for implementation of smart voice technologies to support older adults with long-term mobility disabilities."} +{"text": "Although the implications of family care regime, social location, and stress process factors for the mental health of family caregivers have been well-documented individually, there is a lack of research that integrates these factors. Yet, linking family care regime and intersectionality approaches to stress process theorizing provides us with one possible explanation of the mechanisms potentially linking family care regime and intersecting structural inequalities to mental health outcomes. This paper draws on pooled data from the 2012 and 2016 European Quality of Life Surveys to assess direct and indirect associations between family care regime and the self-reported mental health (SRMH) of family caregivers, together with the additive and interactive associations involving social location , and stress process factors (stressors and resources). The results of a series of weighted least squares regression analyses reveal that family care regime has a direct association with SRMH and that social location and stress process factors partially mediate this association. Additionally, the results suggest that additive and interactive social location factors have direct associations with SRMH and that stress process factors also partially mediate the association. Lastly, stress process factors are associated with SRMH as expected. Overall, our findings provide initial support for the value of linking family care regime, intersectionality and stress process frameworks for an understanding of the mental health implications of family caregiving."} +{"text": "Financial security is critical to overall well-being in retirement. Life course disruptions in work due to unemployment or disability may have lasting impacts on financial security in later life, and these effects may or may not be ameliorated by old age security programs and retirement benefits. Women are known to be particularly vulnerable for financial hardship in later life, making their life course experiences especially important in understanding financial well-being in retirement. We examine the Canadian Longitudinal and International Study of Adults (LISA) to assess later life financial insecurity in retirement, including 20 years of data on labor force experiences across adulthood drawn from linked tax records . The Canadian context is a useful complement to studies in the US due to its diverse and relatively generous public support programs, in addition to personal savings options for retirement. We find that among men, financial insecurity is tied to years reporting unemployment, where for women this outcome is more strongly linked to reports of disability and income assistance across adulthood. Although public and private retirement benefits do not offset these associations for either gender, receipt of income supplements reduce subjective financial insecurity among women. Among men, personal savings have the most robust effect in reducing financial insecurity. Our results suggest that in Canada, with its relatively generous provision of retirement support, life course work and health instability have lasting but differential effects for men and women in retirement."} +{"text": "Lesbian, gay, bisexual, transgender, and queer (LGBTQ) elders have shown considerable strength while aging in a society predicated on heteronormative and binary expectations for gender and sexuality. The life trajectories of LGBTQ older adults are shaped by discrimination and stigmatization, and the embodied resistance that comes with demanding their full participation and recognition in society. This symposium highlights the innovative scholarship of emerging scholars in the field of LGBTQ aging who are engaging in diverse substantive and methodological investigations. The first study takes a comparative cohort approach to explore differences in stressors and depressive symptomatology between younger and older sexual minorities, highlighting the significance of cohort effects among LGBTQ people. The second paper uses data from the Health and Retirement Study to examine anticipated nursing home placement needs between LGB and heterosexual adults with suggestions to better prepare aging service networks. The third describes the influence of state legislature mandating LGBTQ-sensitivity training by examining differences in provider baseline knowledge and attitudes toward LGBTQ older adults in two states, one mandating LGBTQ-sensitivity training and one not. The final paper highlights findings from a multi-methods study that explores how long-term care workers, managers, and administrators respond when staff, visitors, or residents challenge LGBTQ rights for religious and moral reasons. Although substantively and methodologically varied, these studies all demonstrate the importance of applied scholarship that builds knowledge in support of policies and practices that promote equity among LGBTQ individuals across the life course. Rainbow Research Group Interest Group Sponsored Symposium."} +{"text": "The contribution of PET/CT is significant to primary focus detection in metastatic diseases of unknown primary origin that presented gastrointestinal bleeding. In addition to its use in staging of testicular carcinoma, PET/CT provides significant benefit in evaluating patients with increased levels of tumor markers and in detecting recurrence.Gastric metastasis of choriocarcinoma is rarely reported in the literature. This case report presents the case of multiple metastatic testicular choriocarcinoma mimicking gastric cancer, with melena as the initial symptom. In this case,"} +{"text": "Although not standard of care, Cystic Fibrosis patients with recurrent hemoptysis occasionally have coil embolization of bronchial arteries. In the event of recanalization of these arteries in this specific subset of patients, the presence of indwelling coils makes the prospect of conventional particle embolization more difficult, preventing both adequate catheterization of the coiled segment and reflux of the particles.In this report, we describe a case of bronchial artery embolization of a complex Cystic Fibrosis patient with massive hemoptysis from recanalized coiled bronchial arteries utilizing a Scepter Balloon Catheter\u00ae in administration of the liquid embolic agent Onyx\u00ae .The Scepter occlusion balloon catheter allowed for careful placement of the tip within the interstices of the pre-existing coils, allowing for Onyx injection directly into the coil mass without reflux, reconfirming the benefits of Onyx embolization in bronchial artery embolization and providing evidence that the Scepter occlusion balloon catheter should be added to the armamentarium of devices used in complex bronchial artery embolization for Cystic Fibrosis patients with massive hemoptysis. Intercostal and bronchial artery embolization with particles is a commonly used procedure to treat massive hemoptysis in patients with Cystic Fibrosis (CF). Occasionally, while not standard of care, coils may be used but prevent repeat embolization when needed. Patients with coils and recurrent hemoptysis may have recanalized arteries making the prospect of conventional particle embolization more difficult due to inability to safely catheterize the coiled segment and retreatment. Liquid embolic agents such as Onyx\u00ae , often used in neuro-interventional procedures . Following DMSO injection, the balloon was inflated and Onyx 18, using common preparation technique (Guimaraes and Wooster At this point, the balloon catheter was deflated by aspirating the balloon port and removed uneventfully. Postembolization arteriography demonstrated no residual flow to the diseased portion of the lung from the targeted feeding pedicle Fig.\u00a0 and an ONext, the right fifth intercostal artery was selected and further diagnostic arteriography was carried out. Although coils were present, a proximal branch could be embolized in the conventional fashion with 700\u2013900 microspheres. Post embolization selective arteriography demonstrated no residual flow from the fifth intercostal artery and appropriate pruning of embolized vessels. The catheters and wires were then removed from the patient and hemostasis was achieved using manual compression. Follow up at 6 and 12\u2009months revealed no evidence of further hemoptysis or other complications. The patient later underwent successful bilateral lung transplantation.Hemoptysis is a common complication of CF, and occurs in approximately 9.1% of patients (Flume et al. In general, two different types of materials are used in endovascular embolization: solid and liquid agents. Currently, solid agents including Polyvinyl alcohol particles and coils, all lead to mechanical obliteration of the vessel through flow deceleration and subsequent thrombosis (Brassel and Meila Within the realm of BAE, particles or microspheres are the most commonly used embolic agents Corr . Coil emIn this case, the presence of indwelling recanalized coils in the bronchial artery caused reflux of PVA particles during the attempted embolization of the fourth intercostal artery. Since adequate control could not be obtained and superselective catheterization showed multiple tortuous vessels feeding the diseased portion of the right upper lung distal to the coils, a decision was made to embolize with a liquid embolic agent. While other liquid embolic agents such as NBCA are increasingly being used in BAE (Woo et al. Since Onyx is a liquid agent, a rapid administration may result in reflux and some retrograde embolization, which can compromise normal vasculature and lead to entrapment. Attempting to pull the microcatheter can lead to catheter stretching, rupture, and occasionally rupture of the feeding vessel, causing further hemorrhage (Paramasivam et al. In this case, in order to minimize reflux of Onyx, a Scepter balloon catheter was used. Since the 1970\u2019s, balloon catheters have been used in neurointerventional procedures allowing for distal fluid delivery while the balloon remains inflated which forms a proximal plug and prevents reflux of the embolization agents Kerber . More reIn this example, we reconfirm the benefits of Onyx embolization in BAE, especially in attempts to embolize recanalized coils. It also provides evidence that the Scepter occlusion balloon catheter should be added to the armamentarium of devices used in complex BAE for CF patients with massive hemoptysis."} +{"text": "Modernisation of the workforce, together with an ageing population, has seen increased participation rates of middle-aged and older women in industrialised countries . With goResearchers have called for menopause to be considered as a work, health, and safety (WHS) issue in an effort to retain female workers by supporting them through the menopause transition . HoweverThe hot flush usually begins as a sudden hot sensation that spreads from the chest to the neck, head, and arms. Physiologically, the flush begins with significant increases to peripheral skin blood flow, sometimes accompanied by an increased heart rate and/or followed by localised sweating of the upper body. Normally, an increased heart rate accompanies increased skin blood flow requirements to ensure adequate cardiac output for the maintenance of blood pressure. The potential acute effects of a hot flush on heart rate may be further aggravated with increased physical work and/or environmental heat exposure as seen in occupational heat stress profiles . As oestAnother acute effect of the hot flush could arise from the increased peripheral skin blood flow response, directly impacting cognitive performance. Unpleasant warmth can reportedly impact complex cognitive performance, affecting people's ability to concentrate and complete complex cognitive tasks when they perceive themselves to be uncomfortably hot ,12. In tWomen experiencing night sweats have their normal sleep-wake cycles acutely disrupted, sometimes with chronic consequences. The neurobiological processes which govern sleep can become dysregulated by consistent waking and sleep deprivation, such that decrements in cognitive performance can occur when awake . Sleep dThe workplace can also impact upon the experience of menopausal symptoms; factors such as employment status or loss of pay can contribute to the frequency of hot flush occurrences in menopausal women ,6. The aIn conclusion, the retention of menopausal female workers is important to ensure age diversification and expertise remains within the modern workforce. For older women, menopause and hot flushes represent a potential occupational safety issue. Employers should consider menopausal symptoms within physiological contexts, rather than solely within a comfort framework, to emphasise the importance of female worker health. The experience of menopause in the workplace would benefit from research further exploring the physiological mechanisms of hot flushes, the thermal comfort requirements of women, and practical mitigation strategies to offset the negative effects associated with hot flushes. The objective of such research should be to enhance the ability of women in the menopause transition and beyond to optimise their workplace performance."} +{"text": "World Health Organization data show that approximately 800,000 persons die by suicide each year . MoreoveThe presence of positive future thinking such as hope is a clear correlate of indicators of mental well-being in a variety of samples . Russel,Although a broad framework such as IMV may inform suicide prevention efforts, unique resilience factors exist in underrepresented populations . The intThe three investigations noted above attempt to inform the suicide resilience research literature. Despite a disparity in work that investigates suicide resilience compared to suicide risk , researcFinally, suicide-specific care such as suicide safety planning is not always needed in treating patients presenting for mental health concerns. Thus, although suicide prediction appears to be a difficult pursuit , suicideInternational Journal of Environmental Research and Public Health details new investigations into factors that relate to suicide resilience in samples of adolescents and adults. This research indicates a need for the further refinement of our knowledge of how positive thinking styles relate to each other and thus suicide resilience, the need for upstream suicide prevention efforts that target not only risk of STBs but broader mental well-being, and the utility of incorporating identity considerations into theoretical frameworks of suicide risk and resilience. This research could inform the refinement and creation of suicide-specific interventions. This work, however, should be aware of important implementation considerations identified by providers using suicide safety planning. It is possible for behavioral healthcare providers to feel confident in their utilization of these interventions but demonstrate varying indicators of using these practices with fidelity. Finally, suicide risk assessment is needed to identify the level of suicide-specific care a patient may need. The use of natural language processing and machine learning techniques may enhance the identification of the level of care needed.In summary, this Special Issue of the"} +{"text": "Emergency measures including social distancing and program restrictions during COVID-19 has reduced supports for people living with dementia and family/friend caregivers in the community. Consequently, these reductions in dementia services and resources have added to existing challenges and (in)equities for this stigmatized population. The objectives of this study were to identify how community-based resources and services for people with dementia and their caregivers are impacted by public health emergency measures enacted during COVID-19 and other infectious pandemics and secondly, use an intersectional health equity perspective to explore how supports for people and families living with dementia are affected by social determinants of health. A scoping review using JBI methodology was conducted. Academic databases searched included Embase, Medline, CINAHL and PAIS. Grey literature was searched using the CADTH tool. English articles published after 2000 in high-income countries were included. Data was extracted by two reviewers using an adaptation of the Health Equity Impact Assessment tool to explore factors related to health equity. Findings included articles discussing the COVID-19 pandemic (N=15). Most alterations to dementia services included switching to telehealth platforms with some advantages/disadvantages of this method discussed. Limited information on how different populations experienced service changes was identified and more research is needed to address issues of (in)equities for people living with dementia and their caregivers during public health emergencies. Information on how health emergency responses affects dementia services and their users will provide important information on resources for current and future efforts to analyze and assess their impacts."} +{"text": "Premature preterm rupture of membranes (PPROM), rupture of fetal membranes before 37 weeks of gestation, is the leading identifiable cause of spontaneous preterm births. Often there is no obvious cause that is identified in a patient who presents with PPROM. Identifying the upstream molecular events that lead to fetal membrane weakening presents potentially actionable mechanisms which could lead to the identification of at-risk patients and to the development of new therapeutic interventions. Functional genomic studies have transformed understanding of the role of gene regulation in diverse cells and tissues involved health and disease. Here, we review the results of those studies in the context of fetal membranes. We will highlight relevant results from major coordinated functional genomics efforts and from targeted studies focused on individual cell or tissue models. Studies comparing gene expression and DNA methylation between healthy and pathological fetal membranes have found differential regulation between labor and quiescent tissue as well as in preterm births, preeclampsia, and recurrent pregnancy loss. Whole genome and exome sequencing studies have identified common and rare fetal variants associated with preterm births. However, few fetal membrane tissue studies have modeled the response to stimuli relevant to pregnancy. Fetal membranes are readily adaptable to cell culture and relevant cellular phenotypes are readily observable. For these reasons, this is now an unrealized opportunity for genomic studies isolating the effect of cell signaling cascades and mapping the fetal membrane responses that lead to PPROM and other pregnancy complications. Preterm birth remains a major public health challenge affecting 10% of pregnancies in the United States . The leaFunctional genomics assays aim to define the relationships between the human genome and epigenome; the environment; and molecular, cellular, and organismal phenotypes. The past decade has been transformative for functional genomics, owing largely to high-throughput short read sequencing providing quantitative and genome-wide readout for many functional genomic assays. Such assays are particularly adept at identifying differential activity that may result from changes in the environment, such as hormone exposures or immune insults . Today,For the purposes of this review, we define functional genomic assays as those that scan large fractions of the genome for evidence of regulatory activity. In the context of human disease studies, such regions are a promising starting point for subsequent efforts to discover causative biological mechanisms. Follow-up is then needed to evaluate the biological consequences of identified regulatory regions, both in terms of the effects on cellular and organismal phenotypes and also in terms of the effects of non-coding genetic variation on their activity.Functional genomics studies have primarily focused on immortalized cell models, ostensibly because they are highly proliferative and robust. However, recent advances in the adaptation of functional genomics protocols for use on limited primary cells and tissues have created the potential to study more physiologically relevant cell models . In theFunctional genomic assays on fetal membrane samples have been completed both by large genomics consortia such as ENCODE and Roadmap Epigenomics , as wellRNA-seq typically measures mRNA transcript levels that can be compared among tissue types to identify tissue specific transcription . BisulfiAdditional studies have investigated the gene expression of healtTo further define healthy gene regulation in fetal membranes, microarray-based gene expression studies compared activated amnion from late term non-laboring elective Cesarean-sections, defining activation as high NF-\u03baB protein levels similar to the levels observed in post-delivery samples . That acFunctional genomic studies are particularly powerful for identifying molecular differences between different cell states, such as between fetal membrane tissues from healthy pregnancies and those with pregnancy complications. Differentially regulated genes from these studies can identify molecular pathways that may be either causal or a downstream consequence, and in the best cases can nominate new therapeutic targets. In fetal membrane tissues, such comparative studies have been done to compare healthy tissues to those from patients with preterm birth, recurrent early pregnancy loss, and preeclampsia.Due to the integral role fetal membranes play in maintaining pregnancy or stimulating parturition, a substantial amount of research has been devoted to understanding changes in gene regulation that occur during the onset of parturition. RNA-seq analyses have revealed hundreds of gene expression changes that occur between the site of membrane rupture and distal membrane sites in term spontaneously ruptured membranes. For example, Because signaling cascades leading to fetal membrane rupture can be informative in identifying the causes of membrane rupture, directly comparing the gene expressed at the site of rupture in preterm and term deliveries can give more direct insight into the cause of PPROM. The gene expression patterns of term membrane samples are more internally consistent whereas preterm samples are more variable . The varFunctional genomic studies can also identify genes of interest for specific causes of preterm birth. In one example, comparisons of gene expression in fetal membranes between preterm labor with intact membranes and membranes from PPROM patients identified Proteinase Inhibitor 3 (PI3) having significantly decreased expression in PPROM samples . ImmunohFunctional genomic studies have also identified differential epigenetic states which may contribute to or result from such gene expression differences. Differential DNA methylation in amnion between term and preterm pregnancies in labor and term pregnancies not in labor show the majority of changes in methylation occur at the onset of labor. A large portion of the differentially methylated genes are associated with non-coding RNA and imprinted genes . Of the MicroRNAs, another layer of control, regulate gene expression post-transcriptionally through binding to and destabilizing mRNA molecules . AlthougEarly embryonic arrest affects approximately 10% of pregnancies with rates increasing as the age of couples trying to conceive increases . PregnanPreeclampsia is a common disease that is the leading cause of pregnancy associated mortality and morbidity for both the mother and child . Shallowin vitro stimulus response studies to in vivo studies that examine the progression of labor. Such in vitro studies can circumvent the limitation that observational studies are necessarily correlative and thus cannot differentiate between the cause and consequence. Additionally, in vitro stimulus-response studies can identify intermediate steps leading to the onset of phenotype that observational studies miss due to strict limits on tissue collection during pregnancy. For example, in vitro functional genomic studies of fetal membranes cells responding to inflammatory stimuli can reveal the direct effects of those signals on pathways related to cell proliferation, adhesion, or apoptosis that may impact the timing of membrane rupture. Indeed, studies of cultured amnion mesenchyme cells exposed to an IL1\u03b2 challenge for up to 8 h showed transcriptional dynamics reflecting an immediate immune challenge compared to sustained response. The early responsive genes showed signatures of NF-\u03baB activity, a well-documented effector of IL-1 signaling (in vitro exposures. However, many of the common signals in pregnancy such as hormonal changes, oxidative stress and mechanical force changes remain to be investigated.Understanding signaling events that cause membrane rupture can suggest specific pathways misregulated in PPROM. Testing specific response pathways can connect early signaling events from ignaling . Later rignaling . Similarignaling . While dTranscriptomic and DNA methylation studies can take on additional informative power when combined with genetic association studies. Most variants identified in genome wide association studies are found in non-coding regions . IntegraThe combination of epigenomic data and genome wide association studies has also been employed for other pregnancy complications affecting the fetal membranes, including preeclampsia. A genome wide association study that incorporated both maternal and fetal DNA variants identified a variant near the gene FLT1 from the offspring of pregnancies associated with preeclampsia . The eviWhile many genome wide association studies detect common non-coding variants from large populations, rare coding variants can also contribute to disease. In these cases, whole exome sequencing is often employed to detect these variants. A whole exome sequencing study of PPROM cases and healthy term controls in an African American population identified 10 rare variants more common in PPROM cases than term controls in native regulators of innate immunity, LPS detoxifying enzymes and antimicrobial protein genes . An addiin vitro tissue models in addition to cellular models to replicate the structural complexity of fetal membranes and cellular interaction can help add to a more complete understanding of the signaling that leads to PPROM, preterm birth, preeclampsia or early pregnancy loss.While the number of studies comparing regulation between healthy and pathological membranes is growing, the data available remains sparse. Published studies have largely focused on comparing transcriptomic data or DNA methylation between cases and controls, often using microarray measurements that are noisier and have less dynamic range than sequencing-based methods . In addiSC wrote the manuscript with supervision from TR. TA and LF edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Living with dementia causes increasing dependence on the surrounding physical and social environment. There is limited information on environmental interactions of persons with cognitive impairment. Based on participant observation and repeated interviews with both members of nine dyads (primary care partner and person with cognitive impairment) in situ in their homes, a theoretical model depicting environmental interaction was developed. The model illustrates parallel and interwoven environmental experiences of each member of the dyad as they negotiate progressive cognitive impairment. Evolution of the dyad is situated within nested layers of the physical and contextual environment including physical structures, social norms, and political environments. Experiential elements for each member of the dyad are described. Elements include cognitive status, trial and error associated with care provision, adverse behavior linked with onset of caregiver burden, onset of a significant event leading to altered living situations, and maximum dependence on environmental factors prior to end of life. Evidence collected suggests that both persons of the dyad become increasingly susceptible to environmental influences with progression of the disorder. Implication of these findings offer a theoretical framework describing dyadic experiences of environmental interactions when living with dementia. This theoretical model provides a basis for clinical and social intervention to enhance the well-being of both members of the dyad. Interventions associated with environmental interactions may slow socially discordant behavioral manifestations associated with dementia and significantly improve quality of life for both members of the dyad."} +{"text": "Evidence from human genetics supporting the therapeutic hypothesis increases the likelihood that a drug will succeed in clinical trials. Rare and common disease genetics yield a wide array of alleles with a range of effect sizes that can proxy for the effect of a drug in disease. Recent advances in large scale population collections and whole genome sequencing approaches have provided a rich resource of human genetic evidence to support drug target selection. As the range of phenotypes profiled increases and ever more alleles are discovered across worldwide populations, these approaches will increasingly influence multiple stages across the lifespan of a drug discovery programme. Over the past 75 years, the development of new therapeutic drugs for serious illness has had a major impact on improving lifespan and quality of life. Early successes were mostly characterised by chance observations and application of emerging chemistry on successful folk medicines . Over tiThese productivity gains are increasingly being driven by improvements in understanding of the causes of rare disease, cancer and, more recently, common complex disease provided by genetics and genomics. Identifying genes underlying rare genetic disease has opened many of them to effective therapeutic development, with much higher average development success rates than seen in most other clinical areas . DiagnosRare genetic diseases are usually attributed to protein-coding mutations affecting a single gene (monogenic). Their pathological mechanisms tend to be better understood facilitating translation of these insights into drug development. Examples include mutations in the CFTR gene in cystic fibrosis, in the beta-globin gene in sickle cell anemia, and in Huntington gene HTT in Huntington\u2019s disease. Advances in technology including access to whole exome and genome sequencing have revolutionised our understanding of the genetic basis of a broad spectrum of rare diseases and interpretation of their clinical consequences ..28].An allelic series refers to a set of naturally occurring rare and common variations within the same gene with different effects on phenotype severity. This can help estimate the quantitative relationship between gene function and the clinical phenotype generating a dose-response curve approximating that of a potential drug Figure . For insBy combining rare and common variant signals from whole exome sequencing (WES) and GWAS data in half a million UK Biobank participants, Regeneron scientists recently identified that rare variant associations were often found near a GWAS signal for the same trait and the majority remained significant after conditioning on the common signal suggestiGrowing evidence for genetic support as a positive prognostic indicator for clinical drug trials and increased investment of pharmaceutical companies in genetics (and geneticists) suggestsThe increased number of hypotheses to test will require higher throughput approaches to target validation. Genetics and genomics approaches can assist here with increasingly sophisticated techniques including high throughput gene editing and single cell analysis to unpick the relevant biological mechanisms. Initiatives such as the Human Cell Atlas and the We anticipate continued advancements in machine learning technology, particularly applications of deep neural networks, to have an increasing impact on our ability to integrate vast, multi-modal genetic and genomic data to better understand how genes and the molecular pathways they encode affect disease . Just asCurrent genetics studies primarily examine the onset of disease. However future studies will focus on disease progression either through collections of specific patient populations, or availability of longitudinal imaging datasets such as that recently announced by UK Biobank. It is very likely that clinical trials will increasingly collect genetic information, particularly if there is a genetic biomarker for patient stratification. However the size of clinical trials is such that power to detect an effect in a single trial is low. More likely, identifying genetic effects on drug efficacy/response will come from large scale analysis of the EHRs in the large biobanks .In addition to implicating targets, genetics can stratify the disease population. In the future we will see many more diseases treated on the basis of single biomarkers or more likely collections of genetic markers derived from polygenic risk analysis . This vi"} +{"text": "Considerable attention has been given to the sustainability of adolescent health programs as federal funds have become limited. This article describes important steps and lessons learned in seeking buy-in from stakeholders to promote sustainability and secure non-federal funds to maintain the Minnesota Student Parent Support Initiative (MSPSI) after federal funding ended.MSPSI was established in 2010 to address the academic and health needs of expectant and parenting postsecondary students. MSPSI provided coordinated case management and referrals to health, education, and social services for expectant and parenting adolescents, as well as for their children, through Student Parent Centers (SPCs). Six important actions sustained the SPCs after the Office of Population Affairs (OPA) grant funds ended in November 2017: (1) preparing and planning for sustainability, (2) creating and engaging a sustainability committee, (3) assessing sustainability needs and creating a sustainability plan, (4) creating a data system to collect relevant data, (5) building capacity to support communication with decision makers, and (6) sharing data and success stories.The implementation of the sustainability plan resulted in ongoing communications and data sharing with key partners that helped secure additional funds for continuing the program after OPA funding ended.Implementing the MSPSI sustainability plan developed from OPA\u2019s sustainability framework was effective in sustaining the SPCs after federal funding ended. The sustainability planning, the ability to secure funds, the attempt at passing legislation, and the lessons shared in this article provide valuable guidance to organizations seeking strategies to sustain adolescent health programs. What is already known on the subject: Much emphasis has been placed on assessing the efficacy of adolescent health programs, but little attention has been paid to sustaining the programs after federal funding ends. To our knowledge, there has been no comprehensive discussion in literature on how building community partnerships and early planning can sustain adolescent health programs, particularly student parent programs.What this study adds: This paper illustrates how selecting the right stakeholders, early sustainability planning, and development of strategic steps could be useful for sustaining adolescent health programs.Expectant and parenting college and university students are part of a growing population of nontraditional students, and they are often referred to as postsecondary student parents (PSSP). According to a National Postsecondary Student Aid Study, 22% of all college students are parents, and the majority (51%) of PSSP are students of color, compared with students without children was funded through the Pregnancy Assistance Fund (PAF) authorized through the 2010 Patient Protection and Affordable Care Act (The Minnesota Office of Higher Education (MOHE) reported that, during the 2014\u20132015 academic year, 31,392 undergraduate students across Minnesota were parents ; academic needs assessment ; and health screenings . Upon completing health screenings and educational needs assessments, the SPC staff referred PSSP to campus or community-based health ; education; and social services. Furthermore, the SPC provided direct or referral services to material supports and child health supports to PSSP, their children, and immediate family members. The SPC staff also hosted parent education classes, workshops, and other activities designed to meet participants\u2019 health and education needs.Maintaining the operations of the SPC required staff with expertise from various professional backgrounds. Social workers, counselors, psychologists, and program coordinators with knowledge of social services or higher education served as the SPC coordinators or managers. MDH planned and hosted more than 15 professional development training courses based on biannual surveys that assessed the SPCs\u2019 staffs\u2019 training needs. MDH offered a variety of training courses on health, education, and social service topics to help staff develop all the necessary skills required to serve PSSP and promote the services offered at the SPC. All SPCs were required to send at least one staff member to each professional development training. If an SPC\u2019s staff missed a training, MDH distributed the accompanying handout materials.At the end of the 2016\u20132017 academic year, the majority of participants had plans to reenroll for classes and to continue receiving services through the SPC. However, OPA\u2019s grant funding was to end in November 2017. The strategic activities to support SPC sustainability we discuss here were very meaningful in maintaining the SPC through funds secured primarily from MOHE after OPA\u2019s grant funding ended. We identify six critical steps secure alternative funding sources and continue the PSSP program on the nine IHE campuses after federal funding ended; (2) open SPCs at additional community colleges, technical colleges, and private and public universities; (3) connect SPCs statewide to advocate for PSSP; (4) increase public, employer, and legislature awareness of the barriers PSSP face; and (5) create infrastructure to conduct research studies on the needs of PSSP. The strategic activities of the committee informed other agency staff of the essential needs of PSSP, which led to opportunities to identify continuation funding.Data collection was an integral part of the sustainability process because it ensured relevant information was gathered to evaluate activities and advocate for funding to sustain the SPCs. The sustainability activities discussed in this paper were not based upon clinical study or patient data.MDH ensured all data privacy protocols were met before proceeding with data collection. The MSPSI team obtained approval from MDH\u2019s Institutional Review Board (IRB) to proceed with MSPSI as an evaluation of a public health program. Participating IHEs submitted letters of agreement to MDH indicating they were working with their respective IRBs.MDH created a data system to support individual SPC evaluation and program sustainability strategies. All SPCs used the same data system to collect OPA required performance measures and other information suggested by the Sustainability Committee. The data systems included four data tools Table designedNew participants completed the intake form during enrollment. The form allowed the SPCs to collect baseline data such as demographics, family structure, living situation, and academic information. The information collected on the intake form was incorporated into the MSPSI database. This baseline information provided a foundation for monitoring student progress and the effectiveness of MSPSI that supported the efforts to sustain the program.MDH designed the MSPSI database to track program participants longitudinally, to enhance its ability to evaluate relationships between program measures and outcomes. The database automatically generated identification numbers for all participants across the nine IHEs. The unique identification numbers assigned to participants helped track their progress and departures from the program, their employment status, high school or General Education Diploma status, screenings and referrals, support services, and reenrollment during the grant period without personally identifying the student. More and more, decision makers are demanding that programs demonstrate how they are improving the lives of people they serve and how these changes have a real impact on their communities. The ability to track program participants helped MDH and SPCs use data to inform stakeholders and future funders about the impact of the program.MDH staff analyzed the data from the MSPSI database using SAS software and end (post) of each grant year. Analyzing the pre and post assessments helped identify the SPC\u2019s progress and barriers to sustainability. MDH used the capacity assessment results to organize training about basic program sustainability concepts to increase the SPCs\u2019 staffs\u2019 capacity to engage in sustainability activities.MDH and the SPCs hosted several multipurpose training events to build SPCs\u2019 staff\u2019s capacity to discuss alternative funding solutions with their institutions\u2019 decision makers and other prospective funders, including private organizations. MDH trained SPC staff on OPA\u2019s eight sustainability factors and framework . MDH\u2019s decision to support the IHEs\u2019 individual and unique program sustainability strategies by sharing the database with SPCs proved to be invaluable. Distributing the database infrastructure and the software application to IHEs guaranteed that the database was available to collect and store data by SPCs after the grant ended. Sharing the database infrastructure with the SPCs ensured their ability to collect data, store data, and communicate the progress of the programs with potential private and public funders and decision makers.This article describes lessons learned from the implementation of the MSPSI sustainability process. The lessons we shared are real-life implementation experiences peculiar to the MSPSI sustainability process, so the findings may not be necessarily generalizable to implementers in other settings.The MSPSI sustainability process demonstrates the importance of leveraging multiple community partners in securing local funds once federal funding ends. We found that getting buy-in on strategies to sustain MSPSI from multiple stakeholders serving the PSSP population, such as state agencies and the colleges and universities who operated SPC early in the program implementation phase, was critical in securing state and university funds. All nine SPCs benefited from early sustainability planning as well as relationships with multiple agencies and organizations serving expectant and parenting youth. These relationships contributed to MOHE\u2019s decision to allocate state funds to maintain operations at eight SPCs immediately after federal funding ceased in November 2017. Even though MOHE funding was available for all SPCs, one SPC did not receive this funding because it had already secured funding from the university. As of June 2019, at least four of the funded SPCs creatively secured alternative funding through the state, colleges, and universities to maintain some components of their SPCs\u2019 activities and services. Although the lessons learned from the field are specific to MSPSI, they can be beneficial to the broader federally funded adolescent health programs seeking diverse financial opportunities.Adolescent health programs should start sustainability planning early in the implementation planning phase and bring together multiple agencies and organizations, policy makers, and stakeholders with interests in promoting adolescent health and well-being. Student parents have several unique needs that one institution cannot address. Linking student parent programs with a broader network of state and local organizations and policy makers will raise the public\u2019s awareness about the benefits of these programs. Given the limited research on how to sustain programs, the lessons learned provide useful guidance on how to leverage community partners to sustain adolescent health programs, particularly student parent programs."} +{"text": "Bioethics is an interdisciplinary field that uses critical and empirical tools to explore and make recommendations concerning uncertainty about duties to others, including socially marginalized populations. In the context of social science or biomedical research involving people living alone with dementia, practical challenges in conducting research with capacity-impaired participants have ethical dimensions concerning informed consent and other aspects of research conduct. The underrepresentation in dementia research of the voices and perspectives of people living at home with dementia raises normative questions. Using data from a recent National Institute on Aging bioethics supplemental grant, this paper explores how thinking like a bioethicist can strengthen gerontological research. This paper examines areas such as precarity of housing, poverty and social interactions from a bioethicist\u2019s critical analysis/perspective and provides a framework for others to apply to their own research."} +{"text": "A decades-long policy impasse has crippled our national capacity to finance long-term care (LTC) sufficiently or equitably, leaving large swaths of the US population at risk of going broke paying privately for LTC or having unmet LTC needs, while also draining state and federal budgets. By reviewing past LTC financing policy efforts\u2014from the passage of the Social Security Act and the enactment of Medicaid and Medicare, to the LTC financing proposals advanced by 2020 presidential candidates\u2014the political interplay of budgetary concerns in government spending and social justice concerns regarding access to care emerged as a primary LTC policymaking issue. Establishing national consensus on the prioritization of these fiscal and social justice concerns, and their respective values, could help lawmakers craft policy capable of generating the political will needed to overcome political gridlock. Clarifying how LTC benefits would be paid for appears to be a relatively straightforward technical task in comparison."} +{"text": "Disparities in health care information and access often experienced by rural residents exacerbate health risks of older adults. The purpose of this symposium is to highlight efforts in varied rural settings to develop new information that contributes to identifying, assessing, and addressing the causes of these disparities, thus informing and strengthening advocacy and intervention. Mi and Ma address an unmet need for the description of challenges related to the extensive migration of Chinese rural workers and their families (46 million increase since 2011) that has exacerbated disparity of Social Security access. They describe barriers to establishing eligibility of these newly urban families for social services as they change from rural farmers to urban householders. Asman and Sisofo discuss barriers to working successfully with an alliance of diverse city, county, and state organizations to meet perceived needs of three categories of rural older adults: 1)active but denies aging, 2)adapting to aging and achieving satisfaction; and 3)dependent aging. Using a novel measure to determine true needs of their rural older communities resulted in benchmarks, which the alliance used in creating their strategic plan. Ford and colleagues tested a church-based program in a rural African American setting to facilitate chronic disease management. They tested the efficacy of utilizing online resources in underserved settings. Wiese and Williams investigated stakeholder perceptions/knowledge regarding dementia at six diverse rural sites. Although 71% of participants believed heart disease and poor diet increased dementia risk and were willing to be screened, only 15% had been tested for memory loss."} +{"text": "The papers in this symposium explore different aspects of social ties and how they act as critical coping mechanisms in the face of negative circumstances in later life. Using data from diverse settings, including China, Singapore, and the U.S., these papers underscore the importance of strong family and friendship ties, as they offer older adults with strong protection against social isolation and adverse health outcomes. Gupta and Pilai explore the similarity and differences in coping strategies/resilience among a diverse group of 30 U.S. older adults. Results point to the saliency of support from friends, regardless of race/ethnicity. Visaria addresses the relationship between the expression of loneliness and objective measures of social networks among older adults in Singapore. The findings shed light on how meaningful companionship and desired social connection offer powerful buffers against isolation in later life. Ruan and Chen explore which types of social ties offer the strongest protection when Chinese older adults are coping with the aftermath of negative life events. Findings point to the need to look beyond filial obligations and to consider the interplay among various forms of social support, including family, friends and the broader community. Zhang et al. examine the role of family and friendship ties in a rural Chinese community where many older adults were left behind by migrant children. The results suggest that those who are isolated from friends experience more depressive symptoms while those with close-knit friendship ties are the most resilient."} +{"text": "Early detection of cognitive decline and mild cognitive impairment (MCI) during the pre-symptomatic phase of Alzheimer\u2019s disease is particularly important for maximizing effectiveness of clinical trials and efficiency of resource allocation. However, it is difficult to distinguish early signs of decline and impairment from normative aging, especially with biomarkers and clinical-based assessments that are expensive and challenging to apply widely. Ambulatory assessments in naturalistic settings provide opportunities to capture everyday markers of cognitive decline and offer cost-effective tools for sensitive, early detection of transitions to MCI in community-dwelling older adults. In this symposium, we present four studies that use ecological momentary assessment (EMA) data from the Einstein Aging Study to showcase how everyday markers of behavioral and social functioning assessed up to six times a day for 14 consecutive days can facilitate early detection of cognitive difficulties. Zhaoyang et al. examine whether older adults with intact cognition versus MCI differ in patterns of daily social interactions. Hyun et al. investigate how the diversity of daily activities is associated with ambulatory cognitive deficits. Cerino et al. compare the sensitivity of everyday markers of stress versus global trait-based stress measures to detect MCI. Roque et al. use completion time from EMA surveys as a reliable and unobtrusive way to measure cognition and distinguish those with and without MCI. Stacey Scott will integrate insights gained from these four papers, and discuss the opportunities and challenges faced when combining ambulatory assessments of everyday markers with traditional methods to better detect cognitive decline and impairment."} +{"text": "Chronic stroke survivors with spastic hemiplegia have various clinical presentations of ankle and foot muscle spasticity patterns. They are mechanical consequences of interactions between spasticity and weakness of surrounding muscles during walking. Four common ankle and foot spasticity patterns are described and discussed through sample cases. The patterns discussed are equinus, varus, equinovarus, and striatal toe deformities. Spasticity of the primary muscle(s) for each deformity is identified. However, it is emphasized that clinical presentation depends on the severity of spasticity and weakness of these muscles and their interactions. Careful and thorough clinical assessment of the ankle and foot deformities is needed to determine the primary cause of each deformity. An understanding of common ankle and foot spasticity patterns can help guide clinical assessment and selection of target spastic muscles for botulinum toxin injection or nerve block. About 80% of chronic stroke survivors have varying degrees of abnormal gait and impaired locomotion capability . SpasticJoint abnormalities in the hip, knee, ankle, and foot joints observed in post-stroke hemiplegic gait are mechanical consequences of the interactions among muscle spasticity, weakness, and disordered motor control during locomotion . DependiAmong the spectrum of treatment options for ankle and foot deformities and gait disorders, interventions such as botulinum toxin (BoNT) injection and phenol neurolysis are commonly used to manage spasticity of the ankle and foot muscles ,4,11,12.An equinus ankle and foot deformity in stroke survivors with spasticity is a condition where the ankle and foot is held in the plantarflexed position, and there is difficultly with voluntary dorsiflexion of the ankle. This is primarily caused by spasticity of the ankle plantarflexors (gastrocnemius and soleus muscles) with or without toe flexor spasticity. The difference in the resting ankle joint angle and MAS scores for the ankle plantarflexors with the knee joint flexed and extended revealed that the spasticity of the gastrocnemius muscle was the primary cause of the equinus deformity. The gastrocnemius muscle spans across both the knee and ankle joint, while the soleus muscle crosses the ankle joint only. Therefore, knee joint position does not affect soleus muscle spasticity. However, the contribution of the spasticity of the soleus muscle to the equinus deformity cannot be definitively ruled out. Intramuscular needle electromyography (EMG) was utilized to further evaluate muscle spasticity. Spontaneous motor unit firing has been commonly observed in spastic muscles ,17,18. TA varus ankle and foot deformity is a condition where the ankle and foot complex is held in the varus position, i.e., inversion. This abnormal joint position is primarily caused by coexistence of spasticity in both the tibialis anterior muscle and the tibialis posterior muscle in spastic hemiplegia. As shown in An equinovarus deformity is the most common deformity of the ankle and foot complex in spastic hemiplegia. It is part of the \u201ctypical\u201d hemiplegic gait pattern in stroke survivors ,4. This The striatal toe deformity describes a condition of hyperextension of the great toe . It is sThis was a 64-year-old female with a medical history of a patent foramen ovale and right middle cerebral artery stroke 15 months prior, with residual left hemiplegia and abnormal gait. She presented with a one-year complaint of hyperextension of her left great toe with associated pain. She regained the ability to walk several weeks following her stroke with subsequent development of great toe hyperextension. She had two previous injections to her left extensor hallucis longus (EHL) at an outside facility without improvement. The patient was referred to our clinic for possible phenol neurolysis for EHL spasticity. On exam, the patient had hyperextension of her left great toe of ~60 degrees in a resting supine position .The above ankle and foot deformities are commonly seen in clinical practice. These common spasticity patterns usually present with different levels of severity. Proximal knee and hip muscles also have different degrees of weakness and spasticity that may alter the ankle and foot deformities over time. In addition, other rare presentations may be seen, for example, focal spasticity of the extensor digitorum longus or toe curling from intrinsic foot muscle spasticity . TherefoThe standard algorithm to treat ankle and foot deformities and gait disorders can be found elsewhere ,11. UndeUnderstanding the different ankle and foot spasticity patterns and their underlying primary causes is helpful to guide the intervention plan. Tibialis anterior muscle spasticity is a primary contributor of the varus deformity, while its role is negligible in the equinovarus deformity. However, management of tibialis anterior muscle spasticity has been controversial. Targeting this muscle is included in the treatment decision-making algorithm by one group of clinicians , but it It is important to understand the mechanical consequences of spastic muscles during functional tasks, i.e., gait. The striatal toe deformity is anothClinical presentations of ankle and foot spasticity are various. There are mechanical consequences of interactions between spasticity and weakness of surrounding muscles during walking. Careful and thorough clinical assessment of the ankle and foot deformities is needed to determine the primary causes of each deformity. Understanding common ankle and foot spasticity patterns is helpful to guide clinical assessment and selection of target spastic muscles for botulinum toxin injection or nerve block."} +{"text": "We provide graded extensions of algebraic theories and Lawvere theories that correspond to graded monads. We prove that graded algebraic theories, graded Lawvere theories, and finitary graded monads are equivalent via equivalence of categories, which extends the equivalence for monads. We also give sums and tensor products of graded algebraic theories to combine computational effects as an example of importing techniques based on algebraic theories to graded monads."} +{"text": "Institutionalisation of mental healthcare users was a prevalent treatment approach in the apartheid era in South Africa. The introduction of community-based mental healthcare is aimed at improving mental healthcare services. The integration into primary healthcare improves access to mental health services. This integration is implemented by professional nurses working in the primary healthcare clinics.The aim of this study was to explore and describe experiences of professional nurses regarding integration of mental health into primary healthcare at the iLembe district of KwaZulu-Natal.This study was conducted at a public hospital in the iLembe health district of KwaZulu-Natal province.An explorative, descriptive and contextual qualitative research study was conducted. Semi-structured interviews were conducted with 15 professional nurses. Data were transcribed verbatim, organised into codes and finally analysed thematically using Tesch\u2019s method of data analysis.This study revealed that majority of participants experienced and faced challenges regarding integration of mental health into primary healthcare. Professional nurses stated that they require support from the management and training to equip themselves with knowledge and skills to render effective mental healthcare services.The integration of mental healthcare into primary healthcare is pivotal to ensure easy and accessible mental healthcare services to its users. This strategy requires planning and implementations of available policies and guidelines regarding mental healthcare. Furthermore, adequate funding is required to secure human and material resources to aid the integration of mental healthcare into primary healthcare. After permission was granted by gatekeepers, the researcher approached participants. The information letter and consent form were given to all participants. To address the ethical issues related to participants, three fundamental ethical principles were taken care of throughout the research process: respect of persons, beneficence and justice , staff supervision and monitoring of the process of integrating mental healthcare into primary healthcare to limit relapse in mental healthcare patients.Proper assessment and evaluation of mental healthcare users\u2019 readiness to be shifted from mental healthcare hospitals to primary healthcare should be done by a multidisciplinary health team.The study was conducted at a level 1 public hospital and its various clinics situated in iLembe district. If the study was extended to other districts in KwaZulu-Natal province, it would have yielded different findings.The integration of mental healthcare into primary healthcare is an initiative aimed at rehabilitating mental healthcare users back into the mainstream of the society. This strategy needs proper planning and implementation with the support of administration to ensure that professional nurses are adequately trained and motivated to implement the integration process. This should include regular holding of in-service training to capacitate professional nurses on how to render services to mental healthcare users at primary healthcare level. Furthermore, proper infrastructure suitable for consultation and holding rehabilitation programmes for mental healthcare users should be available, including enough psychotropic drugs to avoid relapse in mental healthcare users because of unavailability of treatment. Moreover, policies and guidelines should be implemented correctly regarding the referral system and the care rendered by professional nurses to mental healthcare users."} +{"text": "Multifactorial complexity and heterogeneity challenge the care of older adults and research into the pathophysiology of common geriatric syndromes. Multicomponent interventions matching intervention components with individual risk factors are grounded in precision medicine by ensuring that interventions may be offered to those who will more likely bene\ufb01t, sparing expense and side effects for those who will not. Nonetheless, the development of mechanism-guided interventions has been hampered by failure to identify single mechanisms for effective targeting within this multifactorial complexity, a problem worsened by historical barriers between research disciplines and silos. Geroscience-guided interventions target biological hallmarks of aging representing mechanisms that geriatric syndromes share with aging. We will present examples of multidisciplinary bench-to-bedside translational science seeking to transform the care of common geriatric conditions as diverse as frailty, voiding disorders and immunization against influenza and pneumococcal infections via geroscience-guided therapies applied with a greater emphasis on heterogeneity of aging and targeting."} +{"text": "Effective exercise training and regular physical activity (PA) practice are important for healthy aging and are key modalities for chronic disease management. Approaches that enhance exercise prescriptions and adherence for older adults should be innovative and based on evidence. Thus, the exercise prescription should be tailored accordingly to the person\u2019s health status, functional capacity, and living arrangements. To properly achieve the desirable health outcomes, the PA should be performed at higher intensity, greater frequency, and longer duration. National PA Guidelines recommend at least 150 minutes of moderate-intensity aerobic activity or 75 minutes of vigorous-intensity aerobic activity and at least two days of muscle-strengthening activities per week. Each prescribed modality has unique benefits. Therefore, it is critical to investigate and integrate novel techniques and tools to ensure adherence to the recommended PA guidelines. One of the presentations in this symposium, will highlight the research that has been evaluating for the last 15 years the effectiveness of the exercise randomized trial for older adults with/out cognitive impairments. The second presentation will introduce a novel technology paradigm designed to improve guidelines for exercise training as well as our understanding of how technology may motivate exercise behavior for older adults. The last presentation will discuss the design and methodological flaws that impact the outcomes of the exercise intervention by addressing the interpretations of non-findings and key factors affecting the desirable outcomes."} +{"text": "The livestock sector requires a significant amount of natural resources and has animportant role in global greenhouse gas emissions. The most important greenhouse gasesfrom animal agriculture are methane and nitrous oxide.Mitigation strategies aimed at reducing the emission intensity of this sector areneeded to meet the increasing demand for livestock products driven by populationgrowth.To increase the effectiveness of mitigation strategies, the complex interactionsamong the components of livestock production systems must be taken into account toavoid environmental trade-offs.According to the United Nations , theworThe most important greenhouse gases from animal agriculture are methane and nitrous oxide.Methane, mainly produced by enteric fermentation and manure storage, is a gas which has aneffect on global warming 28 times higher than carbon dioxide. Nitrous oxide, arising frommanure storage and the use of organic/inorganic fertilizers, is a molecule with a globalwarming potential 265 times higher than carbon dioxide. The carbon dioxide equivalent is astandard unit used to account for the global warming potential .In addition to greenhouse gases arising from enteric fermentation and manure storage, feedproduction together with the related soil carbon dioxide and nitrous oxide emissions isanother important hot spot for the livestock sector. Soil carbon dioxide emissions are dueto soil carbon dynamics , the manufacturing of synthetic fertilizers and pesticides,and from fossil fuel use in on-farm agricultural operations . NitrousAs shown in Feed production includesEnteric fermentation is a natural part of the digestive process of ruminants wherebacteria, protozoa, and fungi contained in the fore-stomach of the animal (rumen), fermentand break down the plant biomass eaten by the animal. Plant biomass in the rumen isconverted into volatile fatty acids, which pass the rumen wall and go to the liver throughthe circulatory system. This process supplies a major part of the energy needs of theanimal and enables the high conversion efficiency of cellulose and semi-cellulose, whichis typical of ruminants. The gaseous waste products of enteric fermentation, carbondioxide and methane, are mainly removed from the rumen by eructation. Methane emission inthe reticulorumen is an evolutionary adaptation that enables the rumen ecosystem todispose hydrogen, which may otherwise accumulate and inhibit carbohydrate fermentation andfiber degradation . The emiManure acts as an emission source for both methane and nitrous oxide, and the quantityemitted is linked to environmental conditions, type of management and composition of themanure. Organic matter and nitrogen content of excreta are the main characteristicsinfluencing emission of methane and nitrous oxide, respectively. Under anaerobicconditions, the organic matter is partially decomposed by bacteria producing methane andcarbon dioxide. Storage or treatment of liquid manure (slurry) in a lagoon or tankpromotes an anaerobic environment which leads to an increase in methane production. Longstorage periods and warm and wet conditions can further increase these emissions . On the Almost 60% of the global biomass harvested worldwide enters the livestock subsystem asfeed or bedding material . GreenhoThe extreme heterogeneity of the agricultural sector needs to be taken into account whendefining the overall sustainability of a mitigation strategy, which can vary acrossdifferent livestock systems, species, and climates. Generally, no measure in isolation willencompass the full emission reduction potential, while a combination selected from the fullrange of existing options will be required to reach the best result . It is aMitigation may occur directly by reducing the amount of greenhouse gases emitted, orindirectly through the improvement of production efficiency. The main strategies to mitigategreenhouse gas emissions in the livestock sector have been investigated and are summarizedin Decreasing methane emissions from ruminants is one pressing challenge facing the ruminantproduction sector. Strategies for reducing this source of emissions focus on improving theefficiency of rumen fermentation and increasing animal productivity. A large number ofmitigation options have been proposed with different efficiencies in reducing entericmethane as shown in Forage quality and digestibility affect enteric methane production. Lignin contentincreases during plant growth, consequently reducing plant digestibility. Therefore,harvesting forage for ensiling at an earlier stage of maturityincreases its soluble carbohydrate content and reduces lignification. According to Physical processing of forages, such as chopping, grinding, and steam treatment, alsoimproves forage digestibility and mitigates enteric methane production in ruminants . HoweverImproving diet digestibility by increasing concentrate feeding is another effectivemitigation strategy, reducing by 15% methane emissions per unit of fat protein correctedmilk . HoweverAddition of fats or fatty acids to the diets of ruminants can decrease enteric methaneemissions by both decreasing the proportion of energy supplied from fermentablecarbohydrates and changes in the microbial population of the rumen . AlthougFeed additives have also been tested for their ability to decrease methane emissions . HoweverIncreased animal density together with continuous inflow of nutrients from imported feedsis likely to increase volumes of manure to be managed. Stored manure accounts for arelatively small amount of direct agricultural greenhouse gases , and it As methane production increases with the temperature of stored manure, a reduction ofstorage temperature has been reported to drop these emissions by 30\u201350% . HoweverFrequent removal of manure to an outside storage facility is an effective practice thatcan be accomplished using grooved floors combined with regular scraping of manure,especially for pigs and some cattle production systems. Indeed, if the channels underneaththe stable are emptied regularly, and the manure/slurry are transported to an outsidestorage facility, this practice has the potential to reduce methane and nitrous oxideemissions by 55% and 41%, respectively . On poulSolid-liquid separation is a processing technology that partially separates the solidsfrom liquid manure using gravity or mechanical systems such as centrifuges or filterpresses. As shown in Anaerobic digestion is a biological degradation process, which in the absence of oxygen,produces digestate and biogas (mainly methane and carbon dioxide) from manure. Biogascollected from the system is often used to generate electricity, to fuel boilers orfurnaces, or to provide combined heat and power. Taking into account the greenhouse gasemissions arising from the use of the digestate as fertilizer, and the credit for therenewable energy produced, anaerobic digestion has been reported to yield more than 30%reduction in greenhouse gas emissions when compared with traditional manure handlingsystems . HoweverDiet severely affects excretion of nitrogen in most farm animals, therefore groupinglivestock on the basis of their feed requirements can help in reducing this source ofnitrous oxide in the excreta. Although a low-protein diet could effectively mitigatenitrous oxide emissions from cattle manure storage , some atThe diet for all animal species should be balanced for amino acids to avoid a depressionin feed intake and a decrease in animal productivity. Manufactured amino acids areroutinely used to balance the diet of monogastrics (pigs and poultry), but theenvironmental impact associated with the manufacturing of these supplements must beconsidered when including amino acids as a greenhouse gas mitigation strategy. Inruminants, supplementation of free amino acids results in fast degradation in the rumen,without a significant increase in animal productivity. On the contrary, rumen-protectedamino acids resist chemical alterations in the rumen and can reach the intestine wherethey are absorbed, improving milk yield in dairy cows. Overall, feeding protein close tothe animal\u2019s requirement is recommended as an effective mitigation strategy to reduceammonia and nitrous oxide emissions from manure .The timing, quantity, and method of fertilizer applications are important factorsinfluencing soil nitrous oxide emissions. The nitrogen fertilizer applied is susceptibleto loss by leaching and denitrification before crop uptake. Therefore, ensuring thatappropriate amounts of nitrogen get to the growing crop and avoiding application in wetseasons or before major rainfall events, are valuable practices which could help inoptimizing biomass production and reduce soil greenhouse gas emissions.As lower methane emissions occur after manure land application, decreasing storage timecan effectively help in reducing greenhouse gas emissions . HoweverAdequate storage facilities can provide greater flexibility in choosing when to applymanure to fields, while the use of on-farm manure analysis could help the farmer develop anutrient management plan and minimize environmental impacts .The use of nitrification inhibitors has the potential to reduce nitrogen leaching byinhibiting the conversion of ammonia to nitrate. However, this beneficial effect isweakened by a reported increase in indirect nitrous oxide emission that can result fromincreased ammonia volatilization . This hiIntensive rotational grazing systems are being promoted as a good way to increase forageproduction and reduce nitrous oxide emissions . These sThere is a direct link between greenhouse gas emission intensities and animal efficiency.The more productive the animal is, the lower the environmental impact will be (on a perunit of product basis). Both management quality and expression of full genetic potentialare necessary to increase production efficiency.Breeding for more productive animals can lead to a reduction of the nutrient requirementsneeded to reach the same level of production. This is a valuable greenhouse gas mitigationstrategy . A more Poor fertility means that more breeding animals are required in the herd to meetproduction targets, and more replacements are required to maintain the herd size, which inturn increases greenhouse gas emissions. Improved fertility in dairy cattle could lead toa reduction in methane emissions by 10\u201324% and reduced nitrous oxide by 9\u201317% . NeverthPoorer livestock health and welfare are associated with behavioral and metabolic changes,which can effect greenhouse gas emissions in several ways. Animals fighting an infectionwill need more energy for maintenance. A recent study in the United Kingdom investigatedcost-effective ways to reduce greenhouse gas emissions by improving cattle health. Thesestudies found that cattle diseases can increase greenhouse gas emissions up to 24% perunit of milk produced and up to 113% per unit of beef carcass . A diseaAgriculture in general, and livestock production, in particular, contributes to globalwarming through emissions of methane and nitrous oxide. To meet future needs of an expandingpopulation, animal productivity will need to increase and greenhouse gas emission intensityper unit of product will need to decrease. One of the principal ways to achieve thisenvironmental standard is to adopt effective mitigation strategies. To increase theeffectiveness of these strategies, complex interactions among the components of livestockproduction systems must be taken into account to avoid environmental trade-offs.Unfortunately, there is not a standard procedure to follow. Mitigation practices should notbe evaluated individually, but as a component of the entire livestock production system. Themajority of these strategies aim to increase productivity ,which in most cases cannot be achieved without good standards of animal health and welfare.Optimizing animal productivity has a powerful mitigating effect in both developed anddeveloping countries; however, the size of the effect will also depend on factors such asthe genetic potential of the animal and adoption of management technologies."} +{"text": "With enhanced challenges to maintain social connections especially during times of social distancing due to the COVID-19 pandemic, the need for technology solutions grow. Technologies have become interwoven into the daily lives for many older adults. The Technology Use in Later Life (TILL) study investigated how the perceptions and use of technology both can foster new and leverage existing intergenerational relationships. Through a mixed methods study engaging older adults aged 70 years of age and greater across rural and urban sites in Canada and the UK (N=37), participants described how the interconnection between technology and intergenerational relationships was an integral component to social connectedness with others. Through a qualitative descriptive approach, it was noted that older adults leveraged intergenerational relationships with family and friends to adjust to new technologies and to remain connected to adult children and grandchildren especially when there is high geographic separation between them. Especially during times of COVID-19, younger family members can play an important role to introduce and teach older adults how to use, technologies such as digital devices, computers, and social networking sites. Participants emphasized the benefits of intergenerational connections to adopt and use technology in later life noting flexibility and willingness to overcome barriers to technology adoption and remain connected across the generations. The adoption and uptake of technologies may continue as viable options during times of social distancing to support older persons to remain independent, age in place, in both age-friendly cities and across rural geographies during and post COVID-19."} +{"text": "Babax waddelli, adults consume and even contest the feces of nestlings by adopting cheating strategies , whereas the relative abundances of the other 3 groups were significantly lower in nestlings than in adults .During the nestling period, a provisioning adult usually ate the fecal sacs of nestlings. The fecal consumption behavior of dominant females and helpers was significantly negatively correlated with the nestling age (Supplementary Table S3). Dominant females and helpers tended to transport the nestling feces rather than eating them when the nestlings grew to fledge ; whereasOur findings concerning the temporal variation of fecal consumption and contest behaviors of giant babax provide no further evidence for the current hypotheses about fecal consumption in altricial birds. Although there may be residual nutrients or water in the feces of nestlings owing to their lower digestion efficiency , the amoFinancial support was provided by the National Natural Sciences Foundation of China .The authors declare no conflicts of interest to any other institutions.https://academic.oup.com/cz. Supplementary material can be found at"} +{"text": "The limitations of challenge models for evaluating ASFV vaccine candidates are also discussed.African swine fever is a major concern due to its negative impact on pork production in affected regions. Due to lack of treatment and a safe vaccine, it has been extremely difficult to control this devastating disease. The mechanisms of virus entry, replication within the host cells, immune evasion mechanisms, correlates of protection, and antigens that are effective at inducing host immune response, are now gradually being identified. This information is required for rational design of novel disease control strategies. Pigs which recover from infection with less virulent ASFV isolates can be protected from challenge with related virulent isolates. This strongly indicates that an effective vaccine against ASFV could be developed. Nonetheless, it is clear that effective immunity depends on both antibody and cellular immune responses. This review paper summarizes the key studies that have evaluated three major approaches for development of African Swine Fever virus vaccines. Recent immunization strategies have involved development and Asfarviridae family, genus Asfivirus pfu was protective against virulent wild type OURT88/1 challenge when administered intranasally, but not when administered intramuscularly at the same doses and bush pig (Potamochoerus larvatus) genomes to better understand mechanisms of tolerance to ASFV infection, and how the disease burden is reduced in these swine species compare to domestic swine (African swine fever virus causes acute hemorrhagic fever in pigs that results in high mortality and lack of a vaccine limits control to test and mass slaughter of infected and in-contact pigs. Sequencing genomes of attenuated and virulent strains, and targeted gene deletions from virulent strains have revealed genes encoding some of the factors involved in virulence and immune evasion, and with increasing spread of the disease, there is an impetus to sequence genomes of more isolates to identify relevant genes. It is clear that effective immunity depends on both antibody and cellular immune responses. Pigs immunized with naturally low virulence isolates or attenuated viruses produced by targeted gene deletions can induce protection against challenge by wild type virulent viruses. Virus antigens that are potential targets for inducing neutralizing antibodies have been identified and immunization with some of these antigens has been shown to confer partial protection. However, antigens that can elicit protective immunity, especially CD8ic swine . This daWM, SL, RB, and SW planned and wrote the paper. HS, GM, and NS conducted literature review and wrote the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Many countries in Sub-Saharan Africa (SSA), did not achieve the Millennium Development Goal 4 target of reducing under-five mortality by two-thirds between 1990 and 2015. A large proportion of under-five deaths in SSA and other developing regions have been attributed to undernutrition and poor household environmental conditions. Failure to address nutritional deficit and household environmental pollution in SSA will therefore likely result in many countries not meeting the Sustainable Development Goal (SDG) 3.2 target which aims to reduce under-five mortality to less than 25 deaths per 1000 livebirths by 2030. This paper pinpoints the nutritional and environmental threats to child health in SSA, and identify interventions that will work best to improve child survival in countries. It is important to broaden the spectrum of interventions for improving child survival beyond health systems strengthening to enable countries meet the SDG 3.2 target. The following interventions are thus proposed: strengthening child welfare clinics through digital technologies; investment in school feeding programmes; addressing household air pollution; and improving water, sanitation and hygiene (WASH) services in basic schools. There are certainly barriers to effective implementation of the proposed interventions in countries but are surmountable with strong political will and involvement of the private sector. Gains in child survival have long being recognized as an important proxy indicator of improvements in overall population health and socioeconomic development . Several4A large proportion of under-five deaths in SSA and other developing regions have been attributed to undernutrition and poor household environmental conditions. Childhood illnesses with high mortality burden such as malaria, gastroenteritis, pneumonia and acute lower respiratory infections are all linked to household environmental exposures . UndernuFailure to address nutritional deficit and household environmental pollution in SSA will thus likely result in many countries not meeting the SDG 3.2 target. It is against this background that this paper pinpoints the nutritional and environmental threats to child health in SSA, and identify interventions that will work best to improve child survival in countries. In many SSA countries interventions for improving child survival has focused predominantly on health systems strengthening and it is important to broaden the spectrum of interventions if countries are to meet the SDG 3.2 target.Growth monitoring assures early detection of growth faltering, improved nutrition, and reduction in childhood morbidity and mortality. A review found children who undergo growth monitoring coupled with their mothers receiving nutrition and health education as part of the process to have better nutritional status and/or survival rate . The finBreastfeeding confers survival throughout the entire continuum of childhood. Optimal breastfeeding prevents around 12% under-five deaths annually in low- and middle-income countries . All-cauComplementary feeding is important for child growth and development. Provision of complementary foods with and without nutrition education and counselling has been associated with weight and height gain, increased linear growth, and decreased incidence of respiratory infections especially in food insecure populations 1314.13Household air pollution from solid fuel use has been associated with risk of childhood pneumonia, acute lower respiratory infections, stunting, underweight, childhood anemia, and neonatal and child mortality 1617. In 16Poor water, sanitation and hygiene (WASH) conditions have detrimental effect on child growth and development owing to continual exposure to enteric pathogens, and associated wider social and economic complexities . There iIn many developing countries, community health workers (CHW) are responsible for provision of health services in rural and remote communities. This is because primary healthcare centers are usually several kilometers away from these communities thereby making access a challenge for residents of these communities. CHWs in these countries are trained to administer a compendium of care with provision of nutrition-specific advice a key component of the care. CHWs, however, have limited training in nutrition which hampers the nutrition advice they are expected to provide to enhance child growth and development.Smartphone technology should be leverage to improve child welfare services through the development of mobile applications for effective triage of nutrition care and provision of accurate, reliable, consistent, timely and up to date nutrition advice tailored toward the needs of children. The mobile applications can also be used to advise mothers and caregivers during the triage about environmental conditions that adversely impacts child health and survival. The mobile applications can also be used to send short SMS messages on nutrition and environmental health tips in the dominant language of the child welfare service coverage area to mothers and caregivers on regular basis. A study assessing the feasibility of mobile health technology for the provision of maternal and child health services in a deprived region of Ghana found the intervention to have the potential of eliminating barriers to equitable access to maternal and child healthcare services in rural areas . A studyThere is compelling evidence on the benefits of SFPs for child health and nutrition 2627. Wel26There is limited evidence from randomized cookstove intervention trials conducted in Ghana, Nigeria, Malawi, and Nepal on the benefits for child health and survival of the use of liquefied petroleum gas (LPG), ethanol and improved cookstove for cooking 293031. M2930Another source of HAP in SSA countries is the open burning of solid waste in households owing to limited and irregular waste collection services in many neighbourhoods.Guarding against open burning of waste in households also demands private sector involvement to ease the burden on municipal authorities, as well as ensuring universal waste collection and curtailing the proliferation of informal dumpsites.Creating awareness on the dangers of solid fuel use and open burning of waste through community durbars and religious fellowships could also help to address HAP. Governments and their development partners should support local non-governmental organizations and community-based organizations to take up the task.WASH remains an essential intervention for improved child health and development, and is very fundamental to sustainable development . Improve34WASH content should be incorporated into the curriculum of basic schools at all levels to assure increased WASH knowledge of pupils for enhancing proper attitudes and practices. Ministries of Education should encourage the formation of health clubs in basic schools to provide a platform for promoting proper WASH attitudes and practices in schools and communities. Through meetings of the health club, the capacity of pupils in WASH promotion can be developed to enable them become effective change agents.Sustained use of veronica buckets Figure , a key iLocal governments should also invest in the construction of toilets facilities in schools and provide access to improve water sources through the construction of mechanized boreholes and payment of water utility bills of schools.In conclusion, improving child health and survival in Sub-Saharan Africa and achieving the SDG targets will require a package of interventions beyond health system strengthening. There is ample empirical evidence on the effectiveness of the proposed interventions. Governments should therefore invest in these interventions by resourcing and strengthening the appropriate ministries, departments and agencies to act. There are barriers to effective implementation of the proposed interventions in countries but are surmountable with strong political will and involvement of the private sector."} +{"text": "A high percentage of older adults engages with games; however research about impacts of gaming on older adults is focused almost exclusively on games intended to strengthen cognitive health or slow age-related cognitive decline, very little relates gaming to exercise. Rural \u2013dwelling older adults are underrepresented in this as in other health-related research. Nonetheless, recent developments that explore effectiveness of embedding positive health behaviors (including exercise) in established games such as Bingo hold great promise for addressing the endemic social isolation and chronically debilitating conditions often associated with rural aging. Using recent research with a challenging population group as an anchor for discussion, this paper describes the state of the art of such interventions and, through a multinational lens, finds that these suggest a new direction for gaming design that could enhance effectiveness of the use of gaming to improve health and happiness of rural adults. Part of a symposium sponsored by the Rural Aging Interest Group."} +{"text": "Advances in computational algorithms and the availability of large datasets with clinically relevant characteristics provide an opportunity to develop machine learning prediction models to aid in diagnosis, prognosis, and treatment of older adults. Some studies have employed machine learning methods for prediction modeling, but skepticism of these methods remains due to lack of reproducibility and difficulty understanding the complex algorithms behind models. We aim to provide an overview of two common machine learning methods: decision tree and random forest. We focus on these methods because they provide a high degree of interpretability. We discuss the underlying algorithms of decision tree and random forest methods and present a tutorial for developing prediction models for serious fall injury using data from the Lifestyle Interventions and Independence for Elders (LIFE) study. Decision tree is a machine learning method that produces a model resembling a flow chart. Random forest consists of a collection of many decision trees whose results are aggregated. In the tutorial example, we discuss evaluation metrics and interpretation for these models. Illustrated in data from the LIFE study, prediction models for serious fall injury were moderate at best (area under the receiver operating curve of 0.54 for decision tree and 0.66 for random forest). Machine learning methods may offer improved performance compared to traditional models for modeling outcomes in aging, but their use should be justified and output should be carefully described. Models should be assessed by clinical experts to ensure compatibility with clinical practice."} +{"text": "Much of the existing work around implementation of cancer optimal care pathways (OCP) has either focused exclusively on the clinical elements of care or has targeted individual stages in the cancer trajectory, rather than using a patient-centred or service delivery lens to inform the integration of care across the continuum. This review aimed to identify and summarise the available literature on lung cancer OCP.A scoping review was conducted, with literature across multiple databases and grey literature searched. Articles were included if the OCP was being used to manage adult patients with lung cancer and reported on either the development process and outcomes and/or barriers and facilitators associated with optimal care pathway development and/or uptake.Of the 381 references screened, 32 articles were included. The lung cancer pathways reviewed varied significantly. A number of themes were identified including the development and implementation of the OCP; the use of quality indicators to audit the OCP; and studies on outcomes of the OCP incorporating timeliness of care delivery, patient experiences and health care utilisation and costs.The limited number of relevant articles found in this review may suggest that an OCP for lung cancer is still in its preliminary stages across the broader health systems. Lung cancer is a significant cause of morbidity and the leading cause of cancer mortality in Australia . In 2016345689Cancer patients utilise a wide range of services from multiple providers at various points during their cancer journey, including oncologists, primary care physicians, nurses, pharmacists, physiotherapists and social workers . They fr12Optimal care pathways are structured, multidisciplinary care plans for a specific clinical condition, which describe the tasks to be pursued, their timing, sequence and the professionals involved 16. Imple2025262728However, there is currently only limited consensus around the definition of the optimal care pathway, and there are various terminologies used interchangeably in the literature 21. LittlAs part of developing our own lung cancer pathway to cater for our population, this review aims to identify and summarise the available literature on lung cancer pathways. A scoping review was conducted in order to explore the key components of lung cancer care pathways, identify the facilitators and barriers associated with their use and to examine the outcome measures that have been determined to assess their impact.This review of the literature used the scoping review methodology as defined by Arksey and O\u2019Malley . ScopingOur research question was refined to: \u2018What is known from the existing literature about the implementation and evaluation of optimal care pathways for people with lung cancer?\u2019Published articles were identified from electronic literature databases including MEDLINE, PubMed, Embase, and Google Scholar. Hand searching of reference lists and grey literature, including Cancer Institute publications, government websites, websites of cancer societies and cancer foundations was also done. The literature search was done using key search terms; AND (\u2018lung cancer\u2019 or \u2018lung neoplasm\u2019). Only articles in the English language were selected.Two authors (ZO and AB) independently reviewed and screened the abstracts for selection, using the following inclusion criteria:Articles were included if,The optimal care pathway was being used to manage adult patients with lung cancer.The article reported on either the development process and outcomes and/or barriers and facilitators associated with optimal care pathway development and/or uptake.Articles were excluded if:The optimal care pathway was used for management of cancers other than lung cancer.The articles were concerned with only screening and prevention of lung cancer.The articles purely focusing on treatment algorithms of specific sub-specialities.The process of selection of articles for the final review is depicted in Figure Reasons for excluding full text articles included the following: articles dealing only with post-operative care (six), studies looking at systemic therapy in lung cancer (five), articles that included other types of cancers apart from lung cancer (four), articles dealing with molecular pathways (four) and articles that consisted of systematic review (three).Two authors independently reviewed the results and categorized the studies into sub-themes. Final themes were developed through consensus between authors and as follows:Development and implementation of lung cancer pathwaysUse of quality indicators to audit lung cancer care pathwaysStudies on outcomes of lung cancer pathways:Improved timeliness of care deliveryStudies on patient experiencesStudies on health care utilisation and costsData are summarised under each category in Table 2 .A total of 421 references were retrieved and from these, 32 articles were selected for the final review. Out of these, six were guidelines published by professional organisations on implementing optimal care pathways for lung cancer, in their respective countries , straight-to CT pathway (44), automatic referral for CTs when an abnormality was found on CXRs (44), and immediate reporting of CXR by radiographers. In terms of management and multidisciplinary stage, One-Stop Clinics, where the patients are seen by multiple specialists on the same day and multiple investigations are organised have also been successfully trialled . HoweverIn terms of patient information management, electronic and web-based platforms seem to be more widely used to implement lung cancer pathways 232426. W2324Some of the studies in this review have utilized quality indicators that were used by other centres for research on lung cancer pathways 272829. T272838Despite investment by governments on lung cancer pathways, clinicians, patients and system managers face many barriers to implementing the lung cancer pathways. Some example of barriers include the following: inadequate support from clinicians because of concerns of increased-workload (28), limited integration between primary care and tertiary care (47), slow referral processes, limited resources and administrative support, lack of training for providers regarding the pathway and inadequate information technology support (32). While larger teaching hospitals have put significant resources into fast tracking diagnosis, diagnostic and staging technologies and molecular genotyping of lung cancer , this maOur review has some limitations. To manage scope, we excluded studies examining the pathways in other cancers that might have solutions applicable to lung cancer. We identified only a few studies on implementing care pathways in predominantly rural populations that face many of workforce and resource related barriers . HoweverThe limited number of relevant articles found in this review may suggest that an optimal care pathway for lung cancer is still in its preliminary stages across the broader health systems. Clinical leadership, involvement of multidisciplinary clinicians and managers, dedicated administration or nursing support, innovative solutions, integration of pathways into user-friendly IT platform, and quality improvement mechanisms seem to be important components for successful implementation of a lung cancer care pathway. Smaller centres could take advantage of telehealth technologies to connect to larger centres and acquire workforce capabilities remotely. Depending on the geographical location and resource constraints, the optimal lung cancer pathway needs to be adapted for local setting with inclusion of innovations to overcome deficiencies. Since different health services have different types of referral patterns for lung cancer, local workflow issues must be considered and problems with the lung cancer pathways need to be solved at the local health service level.The additional file for this article can be found as follows:10.5334/ijic.5438.s1Appendix Table 2.Table of themes and related studies."} +{"text": "The vestibular ocular reflex is responsible for stabilizing the eyes in space (known as gaze stability) and the body in space during head motion. This is achieved initially by generating exceptionally short latency vestibular oculomotor reflexes (~10 ms) of the same magnitude and velocity, but in the opposite direction of the sensed head motion. The head motion signal also descends via the vestibulo-spinal system for postural and gait stability. Knowledge of this reflexive function has spawned the development of tests and measures that assay the behavioral relevance of vestibular sensation, without measuring the physiologic performance . The focus of this special topic is on the diagnostic accuracy and rehabilitative efforts using novel tests and measures of vestibular behavior.Millar et al. illustrate that vestibular rehabilitation improves gaze stability and other functional outcome measures, but that such recovery correlates with residual otolith function not change in semicircular canal function. Similarly, Allum et al. report that balance rehabilitation can restore normal balance 3 months after acute bilateral semicircular canal loss as long as otolith function is spared.Romano et al. report that athletes of different sports have different gaze stabilization performances when tested at the highest head angular accelerations. van Dooren et al. compared the fHIT with dynamic visual acuity during gait on a treadmill and quantify the oscillopsia in patients with bilateral vestibular hypofunction to report that the fHIT correlates with experienced oscillopsia as measured by the Oscillopsia Severity Questionnaire. Sj\u00f6gren et al. investigated nine patients with total unilateral vestibular loss using passive and active head impulses and the fHIT. They report normal VOR performance toward the affected side during active head impulses and that visual acuity as measured by the fHIT correlated with the latency of covert saccades.Using the novel functional head impulse test (fHIT), Ramaioli et al. compared dynamic visual acuity during translational and angular head motion in a group of normal subjects and report that the well-known under-compensatory translational VOR gains are correlated with worse DVA scores during translational head motion.Figtree and Migliaccio propose an interesting low-cost motion tracking system for posturography based on a stereo vision system that tracks a body-fixed pattern of markers. Coupled to a force plate it represents an affordable alternative for functional assessment of balance abilities.Dasgupta and Ratnayake conducted a retrospective review of superior canal dehiscence (SCD) in children and correlated functional (audiometry), behavioral (eye movements), and anatomical (computed tomography scan) findings to reveal that children with SCD show phenotypes different from those reported in adults.Fu et al. studied the high acceleration VOR in a set of 47 patients with acute vestibular neuritis using the video head impulse test and the dizziness handicap inventory (DHI). At 6 months follow-up, the patients had significant reduction in compensatory saccades (overt and covert), but also that the patients with normal to mild DHI scores (DHI \u2264 30) had higher VOR gain and lower number of covert saccades.per se . The plasticity of our nervous system indeed is challenged by vestibular failure. The brain expends a fascinating repertoire of mechanisms to ensure functional navigation of everyday life, be it via recalibration or substitution.Taken together, this collection of papers underlines the importance of functional testing for quantifying the ecological ability of patients with vestibular hypofunction, and reveals the importance of how errant vestibular information impacts quality of life. Functional testing appears especially useful for assessing the effectiveness of rehabilitation programs, where the functional ability of the patient is more concerning and may be more informative than the objective measurement All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Metastases from primary solid organ cancers are the most common central nervous system (CNS) tumor type and their incidence is increasing with improved control of systemic disease. Multidisciplinary treatment with personalized therapeutic strategies is required for these patients in order to optimally balance oncological and quality of life outcomes. This comprehensive textbook brings together experts across many fields to produce a concise resource on all important and current topics regarding the care of CNS metastasis patients.1\u20133 Therefore, a multidisciplinary resource summarizing the contemporary approaches to diagnosis and management of these lesions is very timely. Accordingly, in May of this year, Springer published a textbook entitled Central Nervous System Metastases: Diagnosis and Treatment that is a comprehensive multi-disciplinary resource on the management of CNS metastases.4As metastases comprise the majority of central nervous system (CNS) tumors and are increasing in incidence due to enhanced treatment strategies that improve systemic cancer control, management is becoming increasingly complex and personalized.The editors Rohan Ramakrishna , Rajiv S. Magge (Department of Neurology), Ali A. Baaj , and Jonathan P.S. Knisely (Department of Radiation Oncology) from the New York-Presbyterian Hospital/Weill Cornell Medicine in New York, New York, United States worked with over 130 contributors to create this concise 718-page, 7-part textbook. Contributors included leaders with clinical and research expertise in neurosurgery, radiation oncology, medical oncology, medicine, neurology, neuroradiology, plastic surgery, pain medicine, palliative care, neuropsychology, psychiatry, physical medicine & rehabilitation, and neuropathology.The section orients the reader to the epidemiology of CNS metastases and summarizes the mechanistic biology underlying the process of cancer metastasizing to the CNS. Implementation of clinically relevant translational models is highlighted as a significant component in the development of novel targeted therapies. Important principles of neuropathological diagnosis are described along with molecular alterations and corresponding targeted treatments. Finally, the utilization of clinical decision-making tools and advanced imaging techniques in the care of these patients is described. Overall, the initial section of the textbook succinctly introduces the reader to the field and provides context for the following sections on the evaluation and management of CNS metastatic disease.Here, the reader encounters a summary of the clinical manifestations of CNS metastases and a concise outline of the systemic therapies available for CNS metastases by cancer type. Dedicated chapters describe additional considerations for the evaluation and management of leptomeningeal disease, mood disorders, and pediatric patients. This section also includes chapters focusing on paraneoplastic neurological disorders (PNDs) and cerebrovascular lesions that can occur in cancer as additional CNS manifestations. Not only does this section provide great detail regarding the evaluation of CNS metastases, the all-encompassing nature of the textbook is highlighted here by the inclusion of content regarding other CNS complications of cancer like PNDs that may develop in cancer patients without CNS metastases.The radiotherapy section of this book nicely summarizes the physics and biology foundations for radiation treatments that provide context for the understanding of the various options used to manage CNS metastases. In particular, the roles for whole-brain therapy (WBRT) and stereotactic radiosurgery (SRS) along with approaches to reduce the side effects and complications of radiotherapy are discussed. Finally, the dilemma of diagnosing radiation necrosis or pseudoprogression from tumor recurrence as well as the use of reirradiation after recurrence are outlined. Within this section, the authors very effectively distill down the evidence for each therapeutic option with clear and comprehensive tables containing relevant studies and trials. Clinical case reports were nicely used throughout to highlight the role for various radiotherapy approaches in both important and challenging scenarios.The content of the textbook then nicely flows into the role for surgical resection of brain metastases and approaches to deciding between surgery and definitive radiotherapy in various clinical settings. Strategies to improve surgical outcomes are discussed including the utilization of advanced imaging techniques along with intraoperative mapping. New techniques are outlined as well ranging from intraoperative brachytherapy to laser interstitial thermal therapy (LITT) as a minimally invasive technique to ablate tumors. Finally, important considerations in managing cranial wound complications are summarized. Altogether, this section outlines how surgical treatment fits within the framework of multi-disciplinary care for brain metastasis patients and describes exciting new minimally invasive strategies with the evidence for them.This section expands on the fundamental CNS metastasis content in Part I with specific foundational principles related to spinal lesions from clinical factors to imaging and treatment considerations. Additionally, readers will encounter detail regarding bone metabolism and antiresorptive treatments for bony metastases, principles for managing spinal cord compression, and the application of advanced imaging techniques to spinal metastases. This section ends with a discussion of algorithms that guide decision-making regarding the treatment of spinal metastasis patients which effectively consolidates the content here for the reader and highlights important concepts.Part VI nicely complements Part IV that focuses on surgical management of brain metastases. After an introduction to spinal biomechanics, spinal stabilization techniques are summarized. Indications for surgery versus radiotherapy are discussed with specific considerations for the roles of vertebrectomy and intraoperative radiotherapy. Minimally invasive approaches are outlined including separation surgery with concomitant stereotactic body radiotherapy (SBRT), minimally invasive decompression and fixation, vertebroplasty/kyphoplasty, and LITT. Additional content concisely summarizes post-surgical complications with focus on the management of wound healing issues. Overall, this section provides a detailed description of the role for surgery with effective use of diagrams depicting biomechanical properties and radiographical images showing important fixation principles.Finally, the authors discuss approaches to managing CNS metastasis pain including a well-organized outline of all the available pharmacological agents along with resective and ablative spinal procedures, intrathecal agents, and spinal cord stimulation as approaches to manage refractory pain. Finally, palliative and supportive care strategies along with available alternative complementary and integrative therapies are discussed. As with other sections, this section continues to be a comprehensive guide and the inclusion of alternatives treatments that are being increasingly considering by patients is notable.This textbook is a comprehensive and well laid out resource that provides succinct descriptions of all topics relevant to the management of CNS metastasis patients from classical approaches to novel treatment strategies. Leaders in the field from a wide range of disciplines have come together to create an invaluable resource for multidisciplinary providers managing CNS metastasis patients as well as for researchers aiming to improve their care."} +{"text": "Growth in the network of Age-Friendly Universities (AFU) signals the importance of making higher education more age inclusive. Commitment to AFU principles creates opportunities for universities to develop new initiatives and activities that embody them. However, changing academic culture can present unique challenges as well as opportunities. Theories of organizational change help in developing strategies promoting greater involvement of older adults in communities traditionally focused on younger adults. The University of Rhode Island\u2019s experience in continuing to develop as an AFU illustrates the complex challenge of transformation in institutions typically slow to change. This presentation focuses on the following three elements. First, uncovering and confronting ageism in academic settings is a critical first step in opening up the campus community to students of all ages. Second, identifying champions who can advocate for change in different institutional segments is an essential element in expanding the AFU movement. Third, promoting intergenerational programs helps to build bridges between traditional age and older students, particularly emphasizing the contributions that older adults can make to the academic enterprise. Implications for expanding the AFU network while focusing on individual institutions include the following: (1) using theory to drive practice in an intentional and strategic fashion; (2) identifying factors opposing change, particularly since they are usually hidden and not widely recognized; (3) developing a strategy to address these barriers, especially one tailored to the unique institutional context; and (4) recognizing the larger social, economic, and political forces generally in higher education that establish the context for AFUs."} +{"text": "Visual methods, like photovoice and photo-elicitation, have attracted modest attention in gerontological inquiry with diverse and vulnerable community-dwelling older adults. Visual methods are based on the idea of inserting images, produced by informants or not, into research interviews, allowing informants to be the experts of knowledge and meaning-making while the researcher becomes the student. The empowerment of informants as subject-collaborators in the research process is a distinctive feature of visual methods. Benefits include revealing unique insights into diverse phenomena by evoking elements of human consciousness, feelings, and memories that words may not easily express and surveys may not easily capture. This symposium presents qualitative research using visual methods to illuminate the lived experiences, voices, and perspectives of diverse and vulnerable older adults living in New Jersey, Connecticut, and California. Reyes\u2019 research critiques how the operationalization of mainstream notions of civic participation becomes exclusionary and provides a more inclusive understanding of how civic participation is enacted and performed through the practices of Latinx and African American older adults living in New Jersey. Versey\u2019s research with homeless older adults subverts the attention often focused within cities by interrogating the meaning of place with informants whose needs and desires are often overlooked or obscured by residing in a small, rural town in central Connecticut. Yeh\u2019s research on aging in place inequalities chronicles the everyday lives of housed and unhoused older San Franciscans to reveal their tactics for negotiating a moving tension between the daily interiority of identity and contingencies of a changing environment. Qualitative Research Interest Group Sponsored Symposium."} +{"text": "Older adults with serious illness residing in the community are at risk for decline and death. Homecare Registered Nurses (RNs) are in an ideal position to recognize serious illness and engage older adults and their caregivers in discussions about goals for care, while guiding transitions to supportive care services such as palliative or hospice care. However, little is known about this process, or how homecare RNs act upon this information. Using a grounded theory approach, data were collected through focus group interviews with 35 RNs working in homecare. A social process rooted in relationship-based care over time was identified using the constant comparative method. RNs recognize serious illness and support care transitions by identifying changes in illness trajectories and assessing the impact of such changes on quality-of-life, adapting and accommodating care to support older adults in the home for as long as possible, communicating with the care team, engaging stakeholders, and maneuvering through complex systems of care; ultimately relinquishing care to other providers and settings. Our findings also reveal that RNs feel inadequately prepared and frustrated with a fragmented healthcare system and lack of collaboration among the team in supporting the best care transition for older adults and their caregivers. Our findings reinforce the importance of promoting care continuity in homecare settings whenever possible, suggesting a critical need to develop training and team processes that support and empower RNs, so that they may lead care transitions as changing needs emerge during serious illness management of older adults."} +{"text": "Globally, as people expect the longer life expectancy than ever before, people have increasing concerns about their health and aging. Although what people believe regarding aging can affect their health behaviors, limited research has investigated which beliefs regarding aging influence health behaviors. Previous research has shown that essentialist beliefs about aging reflect beliefs that the aging process is fixed, while nonessentialist beliefs about aging reflect the beliefs that the aging process is rather malleable. Since beliefs in nonessentialism regarding aging imply the benefits of health-promoting behaviors, we examine if manipulating nonessentialist beliefs about aging could contribute to intentions to engage in health behaviors. We also investigate if age and income might moderate the effect of nonessentialist beliefs. We conducted an experiment with a sample of American participants of varied ages (n = 599). The results showed that compared to essentialist beliefs, nonessentialist beliefs regarding aging significantly increased an intention to eat healthy food but they did not improve intentions of other health-promoting behaviors in terms of regular exercise and consumption of fruits and vegetables. Income moderated the effect of essentialist beliefs on an intention to eat fruits and vegetables. Specifically, nonessentialist beliefs had a positive effect among high-income people but rendered a negative effect among low-income people. Together, the present findings provide initial evidence that nonessentialist beliefs have a potential to promote health behaviors and call for the further investigation of the effects of educating nonessentialist beliefs on actual health behaviors and the boundary conditions of the effects."} +{"text": "Outbreak of some diseases such as HIV/AIDS, Severe Acute Respiratory Syndrome (SARS), and Ebola Virus has created a demand for making appropriate policies and diplomatic coordination in the international level and has turned international health to the core component of foreign policy in the recent decades . Peter BIn recent decades, some health policies have succeeded in increasing political reputation or improving relations between states and political actors. Among these programs as soft power, some countries as China and Cuba send a large number of physicians to the African countries. Establishment of hospitals and health care centers in these countries is another type of soft power policies . Given t"} +{"text": "Pain is the number one reason for seeking medical attention, and a top contributor to healthcare costs in the United States. Considerable evidence highlights racial/ethnic disparities in pain with Latinx communities being disproportionally affected at higher rates. Compared to other ethnic minority groups, Latinx older adults are more socioeconomically disadvantaged and experience higher rates of disability and frailty . Given the rapidly growing population of Latinx, it is anticipated that the incidence of pain and its associated impact will adversely affect the quality of life of many older adults. The public health focus on improving pain management with non-opioid treatment options also highlights the need to provide culturally responsive care for Latinx older adults. However, limited efforts have addressed this important target for intervention. Following the biopsychosocial model of pain, this presentation will provide an overview of biological, psychosocial and cultural factors influencing pain disparities among older adults. Findings from experimental and clinical settings will be discussed. The presenter will also review current evidence highlighting the preference for self-management strategies for pain management among Latinxs, as well as the need to increase accessibility to psychosocial treatments for chronic pain, such as cognitive behavioral therapy for pain (CBT-pain). Furthermore, preliminary findings from a qualitative study will be presented to illustrate the need to offer culturally adapted treatments for pain management . Future research is needed to study sociocultural factors influencing pain disparities to help identify modifiable targets for intervention."} +{"text": "While it is recognized that caregiver engagement can improve processes and outcomes of care in gerontology, there are barriers to caregiver centered communication, including limited resources for health systems to devote services specifically to families, geographic distance and lack of time. Digital tools such as social media platforms and video-conferencing introduce opportunities for remote and often asynchronous communication. In this presentation, we discuss findings from two randomized clinical trials that explored digital tools to empower family caregivers. In the first we examined ways to use video-conferencing to enable family caregivers to become virtual team members during hospice interdisciplinary teams, and in the second trial we examine the use of secret Facebook groups to meet informational and emotional needs of family caregivers during episodes of care that are often linked to increased social isolation and loneliness. We discuss challenges and opportunities in designing digital tools to facilitate caregiver engagement and empowerment."} +{"text": "Xenobiotics are released into the environment by human activities, and they often cause problems such as environmental pollution, since most such compounds cannot be readily degraded, and have harmful effects on human beings and the natural ecosystem. However, some microorganisms that degrade man-made xenobiotics have been isolated. Most of these aerobic xenobiotics-degrading bacterial strains use xenobiotics as their sole source of carbon and energy, and thus they are excellent models for studying the adaptation and evolution of bacteria in the environment.Recent genome analyses of bacterial strains that degrade xenobiotics have strongly suggested that they indeed emerged relatively recently by gathering genes for the degradation of xenobiotics, and mobile genetic elements played important roles in the recruitment of the genes . HoweverThis issue gathers 13 articles dealing with various aspects of the microbial degradation of xenobiotics. Four of them deal with the bacterial strains that degrade monocyclic phenolic compounds , polylac"} +{"text": "There are some indicators that there are signs of improvement in thequality care for some groups, however the quality measures of disparities related toage, race/ethnicity, and income have not demonstrated the same levels ofimprovement. Research has shown that individuals from minority groups in the United States haveinferior health, experience added problems accessing care, have an increased likelihoodof being uninsured and even when insured will more often receive lower quality healthcare than non-minorities. Maternal and child health, cancer screening, diabetes andaccess to care are examples in which disparities persist in the minority and low-incomepopulations. There rovement. . The positive impact of increasing nursing workforce diversity reverberatesacross education, research and clinical areas. Nursing has the capability to be the leading force in reducing health inequities.Increasing the racial and ethnic diversity of the nursing workforce has been proposed asa significant strategy to bring equality into health care access and delivery and thereis strong supportive evidence across the United States to support this assertion. Whilecultural proficiency is important for all nurses to attain, the importance of anethnically and racially diverse nursing workforce remains. Racial and ethnic minoritiesare more likely to return to and serve their underrepresented communities, bridge thecultural and linguistic gaps inpatient education, and provide a broad and differentcultural prospective to all conversations within nursing. The poThe role of academia in addressing the nursing workforce diversity ismultidimensional. As an institution seeks to improve diversity and inclusionefforts, it seems appropriate to define diversity and inclusion within thatcommunity and/or environment. While there are standard definitions for diversity, itshould be articulated what the expected outcomes are by achieving diversity and howdiversity will be supported once this new and diverse community has been developed.Building an inclusive environment must often come before the goal ofdiversification. In order to create an inclusive environment, is critical toestablish processes that nurture difficult conversations, address mindsets towardsdiversity and develop training/educational resources which support and enhance ourability to create an inclusionary culture. The conditions academia creates should strengthen all student\u2019s knowledge of how toassess vulnerable populations for social determinants, disparities and inequities.The curriculum should include foundational tools that will promote the student\u2019sdevelopment and ability to address health disparities through leadership developmentand health policy mechanisms. Pipeline programs which seek to identify and supportunderrepresented minority faculty and students should be created and integrated intothe fabric of the school. With the development of pipeline programs, it isimperative to address barriers that commonly hinder the admission, matriculation andsuccessful graduation of underrepresented students by developing academic, financialand mentorship support interventions. Some important components that contribute tostudent success once they are enrolled in the nursing program are resources such astutoring, language resources for English as a second language students, cultureguides (peer guides), faculty advisors, social and emotional support and financialsupport. It is also important to prepare these students for future leadership andencourage participation in student organizations. Students may also need assistanceto create professional development plans or mind maps to help them envisionthemselves achieving higher level education and in leadership roles. Facultypipeline programs should include pedagogical and socialization mentorship componentsand if tenure track, research support. Nursing education programs should identify creative ways to Increase the number ofracially and ethnically diverse research scientists that represent the growingdiversity of the United States. Development of pipeline programs early inundergraduate programs that focus on mentoring the next generation of researchers isessential to achieve this aim. Similarly, to other pipeline programs, it is alsonecessary to address barriers to graduate level education including support forentrance requirements, financial resources, and socialization to another possiblynew environment..There is a goal for increasing the number of minority researchers who have interestin addressing unsolved problems that disproportionately affect minority populations.It is more likely that minority researchers will create community participatoryresearch, broaden the clinical and health services research agenda to includeproblems specific to minority populations, and develop culturally sensitiveinterventions which are customized for underrepresented populations.Clinical nursing workforce diversity is also multidimensional. Health systems musttake initiative to connect with community partners to understand the needs andissues of importance within the community in order to better understand theresources which are needed to improve access to care. Returning to our socialmission roots in community orientated health care delivery models and increasingnurse-managed primary care will help to increase access for vulnerable populations. Future of Nursing Report, the primaryfederal agency that is tasked with improving access to health care services for theuninsured, isolated or medically vulnerable, has long recognized the importance ofdiversity and created nursing workforce diversity grant programs to enhance theunderstanding of barriers to achieving these goals and strategies to address. Ittakes support from these high-level organizations and from the institutionalleadership to elevate the charge of increasing nursing workforce diversity. We allmust address this initiative with fervor and dedication in order to have an impacton eliminating health disparities and achieving health equity.The Institutes of Medicine (IOM) OM, 2010 recommeCampaign. The He"} +{"text": "Gait variability is a marker of cognitive decline. However, there is limited understanding of the cortical regions associated with gait variability. We examined associations between regional cortical thickness and gait variability in a population-based sample of older people without dementia. Participants were randomly selected from the electoral roll. Variability in step time, step length, step width and double support time (DST) were calculated as the standard deviation of each measure, obtained from the GAITRite walkway. MRI scans were processed through FreeSurfer to obtain cortical thickness of 68 regions. Bayesian regression was used to determine regional associations of mean cortical thickness and thickness ratio with gait variability. Smaller overall cortical thickness was only associated with greater step width and step time variability. Smaller mean thickness in widespread regions important for sensory, cognitive and motor functions were associated with greater step width and step time variability. In contrast, smaller thickness in a few frontal and temporal regions were associated with DST variability and the right cuneus was associated with step length variability. Smaller thickness ratio in frontal and temporal regions important for motor planning, execution and sensory function and, greater thickness ratio in the anterior cingulate was associated with greater variability in all measures. Examining individual cortical regions is important in understanding the relationship between gray matter and gait variability. Cortical thickness ratio highlights that smaller regional thickness relative to global thickness may be important for the consistency of gait."} +{"text": "Angiogenesis requires coordinated endothelial cell specification, proliferation, and collective migration. The orientation of endothelial cell division is tightly regulated during the earliest stages of blood vessel formation in response to morphogenetic cues and the controlled orientation of the mitotic spindle. Consequently, oriented cell division is a vital mechanism in vessel morphogenesis, and defective spindle orientation can perturb the spatial arrangement of daughter cells and consequently contribute to several diseases related to vascular development. Many factors affect endothelial cell proliferation and orientation and therefore blood vessel formation, with the relationship between improper spindle orientation in endothelial cells and various diseases extensively studied. Here we review the molecular mechanisms driving the orientation of endothelial cell division, particularly with respect to the mitotic spindle, and how these processes affect vascular development, disease pathogenesis, and their potential as novel targets. Blood vessel development, which includes vasculogenesis and angiogenesis, is crucial for the formation of the cardiovascular system and blood vessel regeneration after injury. The vasculature is one of the first organ systems to develop during vertebrate embryogenesis . AngiogeSpindle orientation determines the fate and position of daughter cells during mitosis and playOxygen and nutrient transport in developing embryos depends on the formation of vascular networks , and manThe correct separation of chromosomes into daughter cells of different sizes or cell fates requires precise spindle orientation to control cell fate choices, tissue architecture, and tissue morphogenesis . Blood vAmong the already identified pro-angiogenic molecules, vascular endothelial growth factor (VEGF) is established as the key angiogenic growth factor , by reguIn the process of forming new blood vessel branches through angiogenesis, endothelial tip cells, which lead nascent vessels , likely in vivo, and this process is regulated through increased expression of VEGF in muscle cells signal transduction to enhance the barrier function of endothelial monolayers, which can promote vascular stability . It has The orientation of the cell division axis determines the positions of daughter cells in a tissue and is therefore crucial to tissue morphogenesis and cell fate decisions . Recent Firstly, human retinopathy of prematurity (ROP) has been linked to altered spindle orientation. aberrant mitotic spindle orientation causes ROP by changing endothelial cell cleavage plane and further increasing vessel tortuosity and dilation . Secondlin vivo mechanism of plane spindle orientation and its involvement in blood vessel development.Cell division orientation plays an essential role in tissue morphogenesis and cell fate decisions. This is achieved through the formation of the mitotic spindle . The VEGAberrant spindle orientation is hypothesized to contribute to tissue disorganization . TargeteXW wrote the manuscript and drew the figures. JZ revised the manuscript. DL conceived the study and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Over fifteen million older adults in the United States rely on the means-tested Medicaid program for healthcare coverage . With the older adult population growing exponentially, there has been concern that steadily rising Medicaid spending will skyrocket among this group and that there may be a need to reconfigure coverage of the program. However, few studies have longitudinally examined which factors are related to utilization of the program over time among older adults in order to better understand how any future coverage changes might impact this group. This study used the 1998 to 2014 waves of the Health and Retirement Study to analyze a representative sample of those 50 and older regarding demographic, health, and economic trends associated with Medicaid utilization over a sixteen-year period. Descriptive analyses showed stable longitudinal patterns such that those who utilized Medicaid had significantly poorer health and fewer financial resources compared to those who never accessed Medicaid. Multivariate analyses further revealed those who were older, female, minority race/ethnicity, less educated, in poorer health, below the federal poverty line, and with lower net wealth had a higher proportional risk of utilizing Medicaid during the observed time period than their counterparts. The findings from this study highlight the importance of monitoring changes in the documented risk factors over time in terms of their impact on Medicaid utilization and underscore the need to consider how these factors may be interrelated."} +{"text": "As Americans have become increasingly indebted over time, understanding the factors influencing indebtedness is increasingly important and can help policymakers design policies that discourage debt, thus enhancing private retirement savings so that retirees become less dependent on Social Security benefits. The paper uses data from a major credit bureau of a nationally representative 2 percent random sample from more than 250 million consumer records to examine the financial health and indebtedness of older adults. The data cover the years 2010 through 2018 and follow the same consumers over time. They are supplemented with the zip-code level information from the American Community Survey on neighborhood characteristics, including racial and ethnic composition, education, median income, and poverty. Our preliminary findings suggest that, while the proportion of older adults in serious financial distress is not substantial, their indebtedness is increasing and the growth of unsecured debt has been especially fast. Part of a symposium sponsored by the Economics of Aging Interest Group."} +{"text": "Neurology International was launched in 2009 and it has been published over the past eleven years by PAGEPress Publications [ications . Dr. MicNeurology International from PAGEPress and continue the legacy of this journal, and ensure that we serve well the neurosciences communities. Neurology International complements very well the MDPI portfolio of neurosciences journals, especially Neuroglia [NeuroSci [Brain Sciences [We are delighted to take over the publication of euroglia , NeuroScNeuroSci and BraiSciences .MDPI will publish the fourth quarterly issue of 2020, and thereafter publish four quarterly issues as of 2021.Neurology International [Looking forward to publishing your research work in national !"} +{"text": "Physical resilience, generally defined as the ability to recover or resist functional decline following a stressor, holds promise for clinicians to identify patients who are likely to benefit from a planned stressor (such as an elective procedure) or deteriorate after an unplanned stressor (such as heart failure). This symposium will present innovative research approaches that enhance understanding of the constructs of resilience from human and animal models. The symposium will include presentations from leading experts addressing issues in the study of resilience including choices of definitions, study design, comparator groups, and considerations of underlying latent factors. Data from population-based cohort studies and animal models will be presented to inform the discussions. This interdisciplinary symposium will address recommendations for advancing resilience knowledge through elucidating biologic, clinical and environmental influences and optimizing definitions, designs, and analyses. Epidemiology of Aging Interest Group Sponsored Symposium."} +{"text": "Trigeminal neuralgia is often misdiagnosed at initial presentation due to close connotation with dental pain and is often over diagnosed for the very same reasons leading to numerous unnecessary surgical procedures such as peripheral neurectomy and alcohol injections, while the actual cause may remain elusive for decades. Evaluation of the neurosensory system may disclose the correct anatomical location of the etiology. The neurological examination may be clouded by the sensory deficits subsequent to previous peripheral surgical procedures. The corneal and blink reflexes are integral measures of the trigeminal and facial neurosensory assessment, and their abnormal function may facilitate the identification of intrinsic disease of the brain stem. These reflexes can be employed to discover pathological lesions including intracranial space-occupying trigeminal, lateral medullary, cerebral hemispheric lesions, and degenerative diseases of the central nervous system. Dental surgeons and oral and maxillofacial surgeons should consider corneal reflex in neurological assessment of patient presenting with trigeminal neuralgia-like symptoms. Failure to evaluate corneal sensitivity may lead to delayed or inaccurate diagnosis and unsuitable or redundant treatment interventions. This simple noninvasive reflex can be performed by chair-side and may provide significant information regarding the origin of facial pain and is an invaluable part of clinical methods especially in remote and peripheral healthcare center practitioners where sophisticated radiographic investigations such as computed tomography and magnetic resonance imaging may not be available. The human eye is covered by a thin and transparent layer of tissue called cornea which contains the highest number of nerves in the whole body . These nCorneal and blinks reflexes have several common features, and each results in excitation of orbicularis oculi motor units and lid closure. The nasociliary and supraorbital branch of the ophthalmic division of the trigeminal nerve gives origin to the afferent innervation for the corneal and blink reflexes, respectively, while the efferent motor response is interceded via branch of the facial nerve to the orbicularis oculi muscle. Hence, these reflexes are essential instruments for assessment of the integrity of the trigeminal and facial cranial nerves which comprise the reflex arc Figure .Trigeminal neuralgia, also known as tic douloureux, is a bursting painful condition that is characterized by agonizing, piercing paroxysms, inflicting one or more divisions of the trigeminal nerve, with less than 5% of the cases involving the ophthalmic division, while the mandibular division is affected in 70% of the cases. The attack can transpire suddenly as brief electric current-like contraction lingering for a few seconds to few minutes, or conversely, it is triggered by slight stimuli touching the facial skin including mild wind or even sound vibration rendering the patient unable to chew, eat, drink, shave, or brush their teeth for fear of impending attack. Trigeminal neuralgia is not characterized by objective sensory or motor deficits, but the patient may present with a subjective hypesthesias or numbness over the facial skin in the distribution of trigeminal nerve branches. The diagnosis is based on history alone; however, primary disorder must be differentiated from similar symptoms secondary to other more ominous causes. Documenting the age of commencement of symptoms is significant in such cases as the advent of trigeminal neuralgia in a young patient should raise the suspicion of secondary causes including multiple sclerosis or intracranial space-occupying lesions that may lead to compressive demyelination of the trigeminal root entry zone at the lateral pons , 7. In tThe corneal and blink reflexes are not only integral measures of the trigeminal and facial neurosensory assessment, but the abnormal function may facilitate the identification of intrinsic disease of the brain stem as well. These reflexes can be employed to discover a range of different pathological lesions including intracranial space-occupying trigeminal, lateral medullary, cerebral hemispheric lesions, and degenerative diseases of the central nervous system , 4, 5 T.Measurements of delays in these reflexes have been reported as reliable in localization of supranuclear, nuclear, or peripheral nerve lesions. Trigeminal nerve may become compressed anywhere in the region brain-stem nuclei, the gasserian ganglion, or in the root entry zone at the cerebellopontine angle region and reveal symptoms of diminished sensations on the facial skin in association with hearing loss, facial muscle weakness, and complete loss or delay in reflex Figure .The provoked reaction permits measurement of the delay in reflex after the stimulation of the afferent or the efferent nerve and noting the time taken by orbicularis oculi muscle contraction bilaterally .Lightly touching the surface of the cornea with a delicate material such as a cotton swab or wisp induces a rapid bilateral blink. Corneal reflex evaluation can be made while the patient looks to the side and the cornea is mechanically stimulated approaching from the temporal direction with a saline-soaked cotton tip or a droplet of saline or air ejected with an empty disposable syringe tip. The direct gaze on the oncoming object may cause the patient to blink in response to visual threat and may lead to misinterpretation of the reflex , 7. The The blink reflex is considered the electronic equivalent of the corneal reflex that is utilized to serve the same diagnostic purpose. An electrical stimulus is applied to the supraorbital nerve, and evoked responses are recorded over various muscles innervated by the facial nerve. The blink reflex requires the electromyographic or nerve conduction study machine with at least two-channel recording capabilities and recording and dispersive electrodes . The catAll of the trigeminal reflexes and sensations of touch, two point discrimination, pressure, temperature, and pain are reported to be unaffected in classic or typical trigeminal neuralgia cases unlike the secondary type; therefore, the neurophysiologic examination and trigeminal reflex testing represents the paramount and the most valuable and dependable measure for the diagnosis and differentiation of primary and secondary TN . This diThere are various conditions and situations that may alter corneal innervation and sensation which may subsequently limit the utility of corneal reflex in differentiation of primary and secondary trigeminal neuralgia .Mycobacterium leprae, and fungal infections can harm both the parenchyma and nerves of the cornea which subsequently alter the corneal reflex and limit its use in such situations.Various infections including type 1 herpes simplex virus and varicella zoster virus, Herpes zoster virus affecting the ophthalmic region is an agonizing and overwhelming situation arising due to reactivation of virus in the trigeminal ophthalmic division. Ophthalmic involvement may involve any portion between the conjunctiva and the optic nerve and is accompanied by a wide variety of inflammations causing ulceration and corneal perforation. Numerous research studies have observed the physical damage of nerves of the cornea due to infection of zoster virus, associated with reduced sensation which can consequently hamper the utilization of corneal reflex in postherpetic neuralgia cases . SimilarLeprosy has been reported to be associated with variations in nerve density of the stroma, abnormalities in epithelial nerves, and swelling, twisting, and convolution of the corneal nerve, supplemented by reduced sensations .Several studies have reported a significant reduction in corneal sensation many years subsequent to transplantation. The most common corneal corrective surgical procedures include laser-assisted in-situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) that utilize excimer photoablation for tissue removal. The magnitude of postsurgical corneal sensation reduction depends on the amount of tissue removal during the procedure , 18. LasReduction in sensation is documented in patients on glaucoma medication particularly with topical beta-adrenergic antagonists, specifically with a preservative benzalkonium chloride .Corneal sensation appears to decrease with age including thermal sensitivity to a cooling stimulus . HoweverDiabetic neuropathy involving the unmyelinated C and A delta-fibers contribute to paresthesias and may reduce corneal sensation in diabetics , 23. ThiAny thyroid gland dysfunction especially Graves' disease may present with thyroid-related ophthalmological pathology that may lead to abnormal function of corneal nerve and associated reflexes .This condition can compromise corneal nerve function as it causes distortion of microscopic architecture of the nerve. However, there is disagreement in literature, whether this distortion leads to corneal sensation reduction or causes increased sensitivity, which may affect the validity of various testing modalities used to assess the corneal sensitivity \u201327.As the trigeminal neuralgia pain appears to be originating from structures of the face and oral cavity, patient primarily pursue a general dentist for pain relief. When such patients finally present at tertiary care centers seeking relief of pain, they have already endured multiple dental procedures that have caused irreversible damage. In contrast, vast majority of dental practitioners lack knowledge of facial pain due to various other causes and have a tendency to over diagnose trigeminal neuralgia, being the only other cause of pain apart from toothache with which they are acquainted. For general dentists and maxillofacial surgeons, thorough history and meticulous clinical examination with a special emphasis on comprehensive appraisal of cranial nerves are indispensable in eluding erroneous diagnosis and inappropriate interventions in patients presenting with facial pain. Dental surgeons and oral and maxillofacial surgeons should consider corneal reflex in neurological assessment of patient presenting with trigeminal neuralgia-like symptoms. Failure to evaluate corneal sensitivity may lead to delayed or inaccurate diagnosis and unsuitable or redundant treatment interventions. This simple noninvasive reflex can be performed by chair-side and may provide significant information regarding the origin of facial pain and is an invaluable part of clinical methods especially in remote and peripheral healthcare center practitioners where sophisticated radiographic investigations such as computed tomography and magnetic resonance imaging may not be available. Its use may be limited in some local and systemic conditions of corneal hypoesthesia."} +{"text": "The concept of isoinertial training using flywheel devices has been developed in the recent past with the first evidence supporting its efficacy as conditioning method only dating back to the early 1990's can be confidently used to enhance the subsequent sport-specific tasks, such as vertical and horizontal jumps and change of direction are recommended to obtain acute enhancements on athletic performances are generally recommended to induce chronical adaptations and enhance the athletic performances and repetitions (from 6 to 8) are reasonably implementable to ensure chronic adaptations and performance enhancements outputs exercise intensity (inertias), volume (sets and repetitions), rest interval, all possibly contributing to optimally enhance athletic performances. These aspects may be addressed by implementing well-designed randomized controlled trials (RCT) investigating the comparative effects of flywheel training and traditional resistance training methods both used in isolation or combined within an integrated approach.Studies design: the scientific literature clearly supports the utilization of flywheel training to induce adaptations in strength, muscle power, muscle mass, running speed, and sport-specific capabilities are progressively increased to greater ones , particularly with novices and with athletes at high risk due to previous injury history or involved in return to sport programs.This commentary provides practical recommendations about flywheel training in sports. The contemporary literature suggests flywheel training as a valid alternative to traditional resistance training methods without clear evidence about its superiority among elite athletes. Flywheel exercise offers unique physiological responses compared to other resistance exercise modalities; therefore, practitioners should integrate both flywheel and traditional resistance training in their daily routine in order to optimize the benefits for their athletes. Future research is warranted to determine robust guidelines and construct objective consensus about the methodological aspects of flywheel training so to help researchers, practitioners and athletes for its implementation in their daily practice. In conclusion, this commentary supports the utilization of flywheel exercises implementation for both acute- and long-term athletic performance enhancements and provides researchers and practitioners with practical guidelines.MB and AD have contributed equally to the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared past co-authorship with one of the authors, AD."} +{"text": "Cognitive control of walking may change with aging and is associated with poorer mobility and greater fall risk. The prefrontal cortex function is important for cognitive control of walking, and functional near-infrared spectroscopy (fNIRS) provides the primary means for assessing prefrontal activation during walking. Growing interest in fNIRS to assess cognitive control of walking has led to advancements in the methodologies for processing and analyzing the data, a greater sophistication of experimental protocols and participant samples, and implementation within intervention studies. These advancements will be highlighted in five presentations from an international group of researchers at the forefront of the field. First, Meltem Izzetoglu will provide direct comparisons of various data processing methodologies, demonstrating comparability across approaches. Three talks will demonstrate the range of applications of fNIRS to studying walking in older adults. Nemin Chen will present data on task-related patterns of prefrontal activation across walking tasks in relation to performance, cognitive function, and structural brain health. Sarah Fraser will present results from stair climbing, a critical task for daily function which also presents a fall risk. Inbal Maidan will examine how individual differences affect prefrontal activity during walking across older adults, younger adults, and patients with Parkinson\u2019s disease or multiple sclerosis. Finally, David Clark will demonstrate the use of fNIRS in assessing outcomes from an intervention that combined walking with non-invasive frontal brain stimulation. Roee Holtzer will lead a discussion of the results and the future of fNIRS in assessing cognitive control of walking in older adults."} +{"text": "Standardized Antimicrobial Administration Ratios or SAARs are representations of antimicrobial use data and were first provided to hospitals voluntarily participating in the National Health Safety Network Antimicrobial Use (NHSN AU) option in 2015. Submission to the AU module will be mandatory per CMS effective 2024. AU module data is reported back as a SAAR report, with the goal of facilitating risk-adjusted inter- and intra-facility antimicrobial use benchmarking and monitoring antimicrobial use trends over time at the local and national levels. Our health-system implemented optimized SAAR dashboard at its largest hospital and are now expandingCumulative percentage of facilities reporting at least one month of data to NHSN\u2019s AU OptionTo optimize our use of this module, we created dashboards for adult and pediatric SAAR antimicrobial categories and consolidated representations of antimicrobials of the corresponding categories and SAAR-reporting locations. Optimization and validation of these dashboards took place at our largest of ten hospitals in the health-system and required collaboration between informatics specialists, infection prevention and antimicrobial stewardship clinicians. To help facilitate implementation, a guidance document was created. Collaboration with informatics specialists, infection prevention and ASP clinicians will occur as these optimized dashboards are adapted to the individual site\u2019s needs, as spelled out in the guidance document.Optimized Default Dashboard LayoutOptimized Default Dashboard Layout for Antimicrobial Category BSHOBased on the experience of the pilot implementation at the largest of the ten hospitals, the remaining nine hospital\u2019s site, antimicrobial stewardship leads are implementing these optimized dashboards into their antimicrobial stewardship program.Optimized Dashboard for BSHOPictured are two units classified as the same NHSN location type, visualized on the BSHO dashboard.Optimized Dashboard With Antimicrobial and NHSN Location Groupers Selected, AU Data sectionPictured is the DOT for BSHO antimicrobials. The only input to see data was selecting the \"department\". The remaining information is prepopulated to the antimicrobial dashboard selected.Optimized Dashboard With Units and Antimicrobial Grouper Selected, AU Data sectionPictured is same dashboard but manipulated to show the two units that make up the NHSN grouper. Additionally, antimicrobials with negligible DOT's have been deselected.We anticipate after the dashboards are fully implemented across the system, antibiotic stewardship site leads can integrate SAAR data into their stewardship program, giving SAAR a defined role in our health system's antimicrobial stewardship program management. As none of our configuration required changes to the module's source code, the EHR provider could have our optimized dashboards incorporated into the module's standard configuration. As more institutions receive SAAR reports, more stewardship programs will seek how to interpret and act on their SAAR data.All Authors: No reported disclosures"} +{"text": "Effective blood pressure reduction reduces cardiovascular risk and prevents later complications.To consider the pharmacoeconomic benefits of antihypertensive therapy.Every managed care pharmacist should consider the balance of cost and benefit of antihypertensive therapies, ensuring that best treatment options for patients with the lowest cost to the health care system are available and implemented. Pharmacists must also evaluate the direct and indirect cost associated with risk reduction for stroke and cardiovascular disease.Using an interdisciplinary approach to hypertension treatment, pharmacists can assume a major role in detection, management, and control of hypertensive patients. As the medical teams' drug expert, they will be expected to recommend best treatment options for effective blood pressure control and cardiovascular risk reduction."} +{"text": "The integration of pharmacogenomic (PGx) tests into daily clinical practice has gained significant momentum in recent years . These tTo address these challenges and promote the widespread acceptance of computational approaches in PGx analysis within clinical settings, this Research Topic focuses on highlighting real-world clinical cases that benefit from bioinformatics tools, algorithms, and other computational and statistic methods. The submitted articles encompass a range of themes, including the role of computational genomics in pharmacogenetics and pharmacogenomics, the advantages of bioinformatics tools and statistical analysis for running clinical pharmacogenomic tests, genomic data management and optimization, and the direct translation of computational analysis of pharmacogenomic test results and genetic-derived therapy into routine clinical practice. Furthermore, the articles also discuss the challenges and future needs in utilizing clinical pharmacogenomic tests as part of daily clinical practice, as well as the attitude and willingness of local pharmacists to train such tests in their routine clinical settings.Yu et al., the authors investigate the regulatory effects of alternative splicing (AS) events and RNA binding proteins (RBP) on the efficacy of histone deacetylase inhibitors (HDACi) in treating cutaneous T-cell lymphomas (CTCLs). Through computational data analysis and network mapping, the study identifies specific events and proteins that are associated with HDACi resistance or sensitivity, providing insights into potential targeted treatment strategies for CTCLs .Alternative splicing is a fundamental process that plays a crucial role in gene regulation, and its dysregulation has been implicated in various diseases, including cutaneous T-cell lymphomas. In the article of Naimat et al., the authors explore the value and appeal of precision medicine to community pharmacists in Malaysia. It assesses their knowledge levels, perceptions, and willingness to integrate precision medicine into their daily practice. The study highlights the positive perceptions and high willingness among community pharmacists to adopt precision medicine, emphasizing the need for additional training and exposure to pharmacogenomics during pharmacy education .As mentioned before, personalized medicine has emerged as a promising approach in healthcare. Understanding community pharmacists\u2019 perceived value, desired training components, and exposure during pharmacy education is essential for assessing their readiness to incorporate this innovative practice into their professional roles and responsibilities. In the article of Zhu et al., the authors use Mendelian randomization analysis to assess the causal effect of endogenous and exogenous antioxidants on the risk of six different cancers. The findings reveal potential protective effects of specific antioxidants, such as serum albumin, on prostate cancer risk. The study provides insights into the genetic factors influencing cancer risk and offers potential targeted interventions for cancer prevention, again through the advancement in computational approaches and technologies .The investigation on the impact of endogenous and exogenous antioxidants on the risk of multiple cancer types through a Mendelian randomization study, shedding light on the broader role of these compounds in cancer prevention and providing insights into their potential as preventive strategies. In the article of Simona et al., the authors provide a review on the use of polygenic risk scores (PRS) in PGx. PRS have emerged as a promising tool to account for the complex interplay of genetic factors affecting drug response. The review discusses the general pipeline for PRS calculation and highlights the remaining barriers and challenges in integrating PRS research into clinical care. It emphasizes the need for collaboration between bioinformaticians, treating physicians, and genetic consultants to ensure the transparent and effective implementation of PRS results in real-world medical decisions . It must be noted, however, that development of PRS is presently only a promising research discipline and under no circumstances can be implemented in clinical reality, not even for clinical decision support, as they clinical evidence is poor and regulatory approval not available.Polygenic risk scores in PGx present both promising opportunities and unique challenges. They offer not only a potential avenue for personalized medicine by predicting individual responses to medications based on genetic factors, but also require careful consideration of the complexities involved in their development, interpretation, and implementation within clinical practice. In the article of The studies published in this Research Topic contribute to the advancement of PGx analysis in clinical practice. They provide valuable insights into the potential applications of computational tools and algorithms, the challenges faced in implementing computational approaches, and the future needs in utilizing pharmacogenomics for personalized patient care. By showcasing real-world clinical cases and highlighting the translation of computational analysis into routine practice, these studies will help for the widespread acceptance and integration of pharmacogenomic analysis into healthcare systems worldwide."} +{"text": "To the Editor,Fragmented QRS (fQRS) on electrocardiography (ECG) is a predictor of myocardial scar and fibrosis and is significantly associated with adverse outcomes in patients with cardiovascular diseases (CVD) . RecentlThe association of fQRS with LVH in patients without hypertension has been previously reported . MoreoveIn conclusion, presence of fQRS on ECG may be useful in the clinical evaluation of patients with acromegaly. However, some types of QRS fragmentation may not be associated with myocardial damage. Hence, localization of fQRS on ECG and number of leads with fQRS should be considered in order to define the exact association of fQRS with impaired cardiac structure and LVH parameters."} +{"text": "Psychosis and dissociative disorders are both described in the DSM-5 as different diagnostic categories. However, a high comorbidity of these diagnoses has been observed in different studies, perhaps due to the overlapping of symptoms between them.A systematic review about overlapping symptoms in psychotic spectrum and dissociative disordersPresentation of the case of a patient and review of the existing literature on the differential diagnosis between dissociative disorder and other psychotic spectrum disorders.Both similarities and differences have been found between both diagnoses. Patients with dissociative disorder experienced more dissociative and positive symptoms while those on the psychotic spectrum experienced more negative symptoms. The literature reflects that the two entities overlap on many of their diagnostic symptoms. On some occasions, more dissociation has been detected in patients diagnosed with the psychotic spectrum than those with a diagnosis of dissociative disorder.Despite the fact of being different diagnostic entities, the literature does not reflect clear boundaries between psychosis spectrum symptoms and dissociative disorder.None Declared"} +{"text": "In response to herbivory, most plant species adjust their chemical and morphological phenotype to acquire induced resistance to the attacking herbivore. Induced resistance may be an optimal defence strategy that allows plants to reduce metabolic costs of resistance in the absence of herbivores, allocate resistance to the most valuable plant tissues and tailor its response to the pattern of attack by multiple herbivore species. Moreover, plasticity in resistance decreases the potential that herbivores adapt to specific plant resistance traits and need to deal with a moving target of variable plant quality. Induced resistance additionally allows plants to provide information to other community members to attract natural enemies of its herbivore attacker or inform related neighbouring plants of pending herbivore attack. Despite the clear evolutionary benefits of induced resistance in plants, crop protection strategies to herbivore pests have not exploited the full potential of induced resistance for agriculture. Here, we present evidence that induced resistance offers strong potential to enhance resistance and resilience of crops to (multi-) herbivore attack. Specifically, induced resistance promotes plant plasticity to cope with multiple herbivore species by plasticity in growth and resistance, maximizes biological control by attracting natural enemies and, enhances associational resistance of the plant stand in favour of yield. Induced resistance may be further harnessed by soil quality, microbial communities and associational resistance offered by crop mixtures. In the transition to more sustainable ecology-based cropping systems that have strongly reduced pesticide and fertilizer input, induced resistance may prove to be an invaluable trait in breeding for crop resilience. In addition to a constitutive first layer of chemical and morphological defences, virtually all plant species perceive and respond to risks of herbivore attack provide the emitting plants themselves with enhanced resistance or ii) reduce herbivory on related plant individuals in the neighbourhood (an inclusive fitness benefit) Kessler . HerbivoEach of the hypotheses on the evolutionary drive behind induced resistance should be placed in a community perspective to fully understand how benefits of induced resistance outweigh costs. The primary costs associated with induced resistance are not the metabolic costs, but so-called ecological costs that arise through the effect of the induced phenotype on ecological interactions with community members Heil .Inducibility of resistance traits does allow plants to save metabolic costs of resistance in the absence of herbivores, but also creates costs due to a lag time between recognition of herbivore attack and the mobilisation of effective resistance Karban . During Nicotiana are defensive against generalist herbivores. However, specialist herbivores use these compounds in food plant recognition and acceptance -\u03b2-caryophyllene in response to root feeding by the western corn rootworm attract entomopathogenic nematodes that infect and kill the root pest. These interactions could be restored through transformation breeding of this trait into North-American varieties that had lost the ability to produce (E)-\u03b2-caryophyllene , maximizing the impact of biological control, and making crops resilient to changes in the environment. Using induced resistance in agriculture clearly has implications for farming practices and requires in depth understanding of both the physiological regulation of inducible traits as well as its role in ecological interactions (Chr\u00e9tien et al. Perhaps the most prominent challenge may be that inducibility could reduce uniformity in growth and ripening of the crop, enhancing variation in crop quality. This directly affects harvesting strategies as well as the marketing of the crop that needs to be sold with a larger distribution over quality classes. In depth understanding of how induced resistance is traded-off or coupled to growth and phenological trajectories of plants may provide breeders with opportunities to decouple growth-defence responses (Bourke et al. Matching induced resistance traits with the local community of herbivores, challenges by abiotic conditions as well as landscape context that determines availability of natural enemies will require knowledge on local species interactions. Farmers themselves may need to increase the monitoring of crops when these are under attack by more numerous pest species. Such a monitoring challenge may to an extent be overcome by apps for species identification, although such apps could be improved by taking host plant into account in the search scope. At the same time, breeders may have to incorporate the context of community dynamics on a specific farm to advise for the use of induced resistance and/or combination of crop accessions or species that result in a resilient cropping system to local conditions. Soil quality and microbial community composition may prove to be critical in harnessing the vigour of inducible resistance (Cameron et al. To start breeding for induced resistance and understand the community consequences of inducibility in a crop, we may learn from wild plants. We require understanding of how inducibility matches with other life-history traits of plants. For example how mating system, constitutive defence, lifespan, or growth-defence trade-offs correlate with inducibility will identify the potential to select for inducibility in specific crops (Garcia et al."} +{"text": "The goal of perioperative pain management is to optimize patient experience, reduce distress, and to facilitate recovery and rehabilitation following surgeryThe evidence that RA reduces postoperative complications and mortality is sparse, with few supporting data, except in high-risk surgical populationsRA may reduce the use of opiates and other drugs with adverse risk profiles, particularly in patients who are at risk of developing significant perioperative morbidity associated with respiratory or gastrointestinal side-effects, such as the elderly and frail with hip fracture,TAP block and rectus sheath catheters have gained popularity as effective pain relief for patients undergoing intra-abdominal surgery. Their value lies particularly in their ability to provide effective relief of pain in those presenting for emergency laparotomy, and is the subject of ongoing clinical trialsRA attenuates the surgical stress response by blocking afferent neuronal transmission and preventing transmission to the central nervous systemRecent preclinical evidence indicates that the systemic inflammatory response and immune disequilibrium following surgery can allow growth of metastases, highlighting the potentially important role of drugs used in the perioperative periodAs the focus of perioperative research has moved away from merely survival after surgery to survivorship, the emphasis of perioperative analgesia has also changed from reducing pain to improving quality of recovery and promoting function. RA is not appropriate for all patients. Some find the altered sensation associated with the onset and recovery from RA more distressing than the pain avoided. Hence, a technically successful block will not always translate to enhanced patient satisfaction. RA techniques are considered to be partially or completely opiate-sparing. They serve to not only reduce unpleasant opiate related experiences, such as nausea and itching, but may also accelerate the trajectory towards the DREAMing paradigmThere are important methodological issues to be considered in clinical trials of RA. There is growing frustration about the heterogeneity of clinical trials of perioperative analgesic effectiveness and efficacy,There is a lack of robust methods to identify patients who will benefit and therefore should receive RA. The varied practice of RA highlights that decision-making around the anaesthetic and analgesic technique is often chosen driven by the preference, habit, and expertise of the anaesthetists and surgeons rather than by patient preferenceDisclosure. JY is Director of UK Perioperative Medicine Clinical Trials Network."} +{"text": "Drug risks may be ignored or under appreciated, overemphasized, misinterpreted, or in some cases presented in ways that do not wholly reflect the evidence base and clinical experience. Often the available evidence pertaining to drug interactions is grounded upon theoretical concerns, very small trials, or case reports, and thus it is often very challenging to balance the potential risks and benefits of a particular therapy when drug interactions are present. While prescribers and pharmacists may fail to heed interaction alerts provided by decision support systems, it is also possible that the overstatement of risks can cause providers to avoid utilizing a clinically beneficial therapy. The case of the interaction between triptan antimigraine medications and selective serotonin reuptake inhibitor/selective serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI) antidepressants provides an example of how the presentation of drug risk may unduly influence the utilization of drug therapy."} +{"text": "Deep brain stimulation (DBS) of brain circuits involved in mood regulation is a novel tool that is being investigated as a potential treatment for some of the most severe patients with mood disorders. At UTHealth Houston, we have had an ongoing clinical trial with DBS of the medial forebrain bundle (MFB).Our preliminary results suggest effects in alleviating depressive symptoms in this very severe, refractory patient group.In this presentation, we will review our latest findings, and will also discuss the potential effects of the MFB stimulation on measures of suicidality in this patient population.None Declared"} +{"text": "Early life experiences may impact the development, affecting neural, behavioral, and psychological domains analyses; A preliminary report, Ayyash et al. explored adversity-related changes using an innovative approach to brain imaging analysis, that combines functional and structural connectivity, the awFC. Compared to controls, children whose mothers had poor mental health and/or low socioeconomic status during the perinatal period exhibited lower connectivity in some cortical and limbic networks, but increased connectivity in the ventral attention network. The awFC approach highlighted the importance of accounting for structural aspects when assessing functional connectivity in developmental networks. This study provides further support that early life stress impacts the course of brain maturation, specifically the developmental tuning of functional and structural connectivity.Two studies examined exposure to early adversities in children. In Variation in maternal sensitivity and the development of memory biases in preschoolers by Rifkin-Graboi et al. explored whether insensitive care predicts subsequent memory biases for threatening stimuli in preschoolers, and if such relations could influence different forms of memories and hippocampal volume. Using data from the Two Wave Study, the authors showed that exposure to insensitive caregiving predicted the difference between emotional memories which were associated with hippocampal body volumes. The study highlights that lower levels of maternal sensitivity when children were four and a half years of age predicted better relational memory when angry stimuli were involved.Early life experiences are the basis of a child's health during development and early life caregiving adversity may influence future negative memory biases. The study These studies underline the need for additional research focusing on the effects of stress during early developmental stages, when brain circuits are still maturing and adapting, in order to better understand how stress imprints into neural circuits and changes their functioning throughout life. In the future, this understanding of the mechanisms associated with early life adversity may help to better establish protective strategies. In addition, filling the knowledge gap on sexual dimorphism in the neurobiological mechanisms of early life stress, as well as how protective strategies may reverse several of those effects will allow the development of more accurate treatments for a set of psychiatric disorders.RMSL, NSCP, CD, and DMA wrote, reviewed, and edited the editorial manuscript. All authors contributed to the article and approved the submitted version."} +{"text": "Generalized anxiety disorder (GAD) is a highly prevalent mental illness that is associated with clinically significant distress, functional impairment, and poor emotional regulation. Primary functional magnetic resonance imaging (fMRI) studies of GAD report neural abnormalities in comparison to healthy controls. However, many of these findings in the primary literature are inconsistent, and it is unclear whether they are specific to GAD or shared transdiagnostically across related disorders.This meta-analysis seeks to establish the most reliable neural abnormalities observed in individuals with GAD, as reported in the primary fMRI activation literature.We conducted an exhaustive literature search in PubMed to identify primary studies that met our pre-specified inclusion criteria and then extracted relevant data from primary, whole-brain fMRI activation studies of GAD that reported coordinates in Talairach or MNI space. We then used multilevel kernel density analysis (MKDA) with ensemble thresholding to examine the differences between adults with GAD and healthy controls in order to identify brain regions that reached statistical significance across primary studies.Patients with GAD showed statistically significant neural activation in various regions of the cerebral cortex and basal ganglia across a variety of experimental tasks.These results inform our understanding of the neural basis of GAD and are interpreted using a frontolimbic model of anxiety as well as specific clinical symptoms of this disorder and its relation to other mood and anxiety disorders. These results also suggest possible novel targets for emerging neurostimulation therapies and may be used to advance our understanding of the effects of current pharmaceutical treatments and ways to improve treatment selection and symptom-targeting for patients diagnosed with GAD.None Declared"} +{"text": "The pathophysiological processes underlying the phenotypic spectrum of severe forms of epidermolysis bullosa (EB) are complex and poorly understood.To use burden mapping to explore relationships between primary pathomechanisms and secondary clinical manifestations in severe forms of EB and highlight strengths and weaknesses in evidence regarding the contribution of different pathways.Literature searches were performed to identify evidence regarding the pathophysiological and clinical aspects of JEB/DEB. Identified publications and clinical experience were used to construct burden maps to visually communicate plausible connections and their relative importance by subtype.Our findings suggest that most of the clinical consequences of JEB/DEB may result from an abnormal state and/or faulty skin remodeling driven by a vicious cycle of delayed wound healing, predominantly mediated through inflammation. The quantity and quality of evidence varies by individual manifestations and disease subtype.The burden maps are provisional hypotheses requiring further validation and are limited by the published evidence base and subjectivity in clinical opinion.Delayed wound healing appears to be a key driver of the burden of JEB/DEB. Further studies are warranted to understand the role of inflammatory mediators and accelerated wound healing in patient management. Despite inherent issues of subjectivity, this approach shows promise in consolidating and corroborating heterogenous evidence to generate hypotheses on the clinical relevance of underlying disease mechanisms in rare diseases.Literature searches were performed in PubMed through to March 2022 to identify all consequences of the disease. A review of relevant publications was used to construct draft conceptual maps that visually linked specific complications, deformities, and symptoms with shared pathomechanisms. Structured discussions were then undertaken to obtain clinical expert feedback on the structure and components of the maps from six EB health care professionals across geographies . This included input on: pathological drivers of disease and organ systems affected; direction and nature of the relationships between primary pathomechanisms and downstream clinical manifestations; and disease impact on patient health outcomes and HRQoL. Interim maps were modified and validated based on repeated clinical input. Clinical authors were also asked to rate the frequency of pathophysiological changes and clinical manifestations in each of the most common subtypes of JEB and DEB on a 5-point scale of 0 (absent) to 4 (very high).A burden map of severe forms of EB identified JEB and DEB as being largely associated with cutaneous involvement and to a lesser extent the digestive, cardiovascular, nephrourological, respiratory, and visual systems . While eThe pathomechanisms linking cutaneous blistering/wounding to clinical manifestations in JEB and DEB was then investigated in a more detailed burden map focusing on cutaneous involvement . WidesprInflammation is a constant in nonhealing wounds and is implicated, either directly or indirectly, in the majority of the clinical manifestations associated with severe forms of EB . CompromThe implications of these clinical manifestations were highlighted in the identified published literature and corroborated by the clinical experts. Wound burden and care were reported to have a significant impact on daily activities and HRQoL of patients. Painful blistering/wounding on the soles of the feet and/or complications of significant hyperkeratosis/scarring/fibrosis can impact an individual\u2019s ability to walk or functionA) and clinical manifestations (B) found that overall, these occurred more frequently in severe subtypes, with some notable differences within JEB and between JEB and DEB. JEB-S was less frequently associated with pubertal delay and SCC compared with intermediate JEB, despite a higher reported incidence of underlying pathomechanisms. This finding reflects the fact that most patients with JEB-S die in infancy, meaning there is insufficient time to develop these clinical features. Hypergranulation was most frequently reported for JEB-S. Granulation tissue bleeds easily and profusely making infants more susceptible to anemia, serious infections, and loss off body fluids/essential nutrients. Additionally, a build-up of granulation tissue in airways can cause difficulty in breathing. The highly fibrotic environment reported in RDEB versus JEB is consistent with higher ratings for downstream SCC and joint contractures/pseudosyndactyly in RDEB, in particular RDEB-S.Clinical expert assessments of the main pathomechanisms , A and cstations , B foundA) and DEB-S (B) through proportionately shaded boxes.Clinical expert ratings of the frequency of the main pathophysiological changes and clinical manifestations can be superimposed onto the burden map of cutaneous involvement to produce dedicated burden maps for each subtype. nd DEB-S , B throuThe pathophysiological processes underlying the phenotypic spectrum of severe forms of EB are complex and poorly understood. In this study, we used burden mapping as a means of gaining valuable insight into possible connections between primary pathomechanisms and secondary clinical manifestations . Our findings propose a role for delayed wound healing in the burden of severe forms of EB \u2013 predominantly mediated through inflammation. Much of the evidence is available in the published literature but this tends to focus on individual clinical features or a given EB subtype, rather than considering the common pathomechanisms underlying the range of clinical manifestations and/or the relative contribution of different pathways by subtype. We suggest burden mapping as a useful tool in understanding and building consensus among clinical experts on the etiology and severity of different diseases. This is particularly important in the context of often poorly understood and under-researched rare diseases, where defined and validated outcome measures are frequently lacking. Having generated plausible links through this approach based on published literature and clinical experience, further research efforts can be directed to yield evidence where this may be limited or where uncertainties remain. This in turn should help in the design of clinical trials and the advent of new therapies.P\u00a0=\u00a0.013) within 45\u00a0days.,P\u00a0=\u00a0.002).In the absence of approved EB-specific therapies, patient care has centered on protection from minor trauma and friction, bandaging, and prevention of infection.,LAMB3.KRT5 in EBSCOL7A1 in dominant DEB.A number of further therapeutic interventions are being explored.Our study has several limitations, which should be considered when interpreting the findings. First, evidence for the clinical manifestations of JEB and DEB that we consider largely reflects published literature and hence may not include those that have potentially not been described. From our clinical experience of managing these patients we believe that most of the major drivers of disease burden have been reported, but given the interpatient diversity, it is possible that some features seen in a minority of patients have not been captured. Second, our study relies on the subjective assessment of the 6 clinical authors involved in the study. Involvement of a larger panel of clinicians may have helped ensure that the findings are relevant for all patients with JEB and DEB. However, the panel included clinicians from specialist centers in the US, Germany, Spain, and the UK and therefore is broadly representative of the clinical experience in Europe and the US. Finally, our findings are provisional hypotheses; further studies are needed to validate the role of delayed wound healing in the burden of JEB and DEB.In the present study, we used clinical expert opinion along with published evidence to link pathomechanisms underlying clinical manifestations in severe forms of EB. Our resultant burden maps suggest delayed would healing as a key driver of the burden of JEB and DEB, underpinned by dysregulated inflammation.Jemima E. Mellerio has undertaken paid consultancy and speaker for Amryt Pharmaceuticals DAC and Krystal Biotech Inc. Dimitra Kiritsi has undertaken paid consultancy for Amryt Pharmaceuticals DAC, Rheacell GmbH and FibRx Derm Inc; is a founder at Crowd Pharma GmbH. M. Peter Marinkovich has undertaken paid consultancy for Amryt Pharmaceuticals DAC; and is an investigator for Krystal Biotech Inc, Abeona Therapeutics Inc and Castle Creek Biosciences, through funding administered by Stanford University Office of Sponsored Research. Natividad Romero Haro has undertaken paid consultancy for Amryt Pharmaceuticals DAC, Kellie Badger has undertaken paid consultancy for Amryt Pharmaceuticals DAC, Meena Arora is an employee at Amryt Pharmaceuticals DAC. Marc A. Dziasko has undertaken paid consultancy services to Amryt Pharmaceuticals DAC. Mansi Vithlani has undertaken paid consultancy services to Amryt Pharmaceuticals DAC. Anna E. Martinez has undertaken paid consultancy for Amryt Pharmaceuticals DAC."} +{"text": "In their article, Mowitz et al investigated the burden of comorbidities and healthcare resource utilization among extremely premature infants enrolled in Medicaid, laying a foundation for further policy action. The authors analyzed data from publicly available Medicaid databases of 6 US states from 1997 to 2018, which included information on 26.6 million Medicaid beneficiaries. The incidence of EP births is correlated with low socioeconomic status (SES) and Medicaid enrollment. EP infants possessed a relatively high burden of comorbidities, with more than 70% having at least 1 comorbidity. Additionally, EP infants were observed to require considerably higher use of medical resources, which involved more frequent admissions to hospitals, intensive care units, and surgeries. Disparities in care for vulnerable patient populations such as EP infants and their families underscore the need for focused interventions to engender favorable outcomes.Preterm birth is the leading cause of infant mortality worldwide.The higher proportion of EP births among Medicaid-insured patients in the 6 examined states may be linked to their lower SES, given that 5 of these 6 states have a median household income ranking in the bottom half of all US states. Despite quality improvement networks that have created more detailed recommendations for respiratory support in the EP population, Mowitz et al denote that premature infants with comorbidities who require extensive use of healthcare resources typically induce high-cost burdens upon their respective families. We suggest that the standardization of care mentioned by the authors include socioeconomically tailored approaches to meet the needs of a diverse patient population. These interventions can include (but are not limited to) patient navigators and social work methodologies.Patients not enrolled in Medicaid are more likely to have higher educational attainment, elevated SES, and greater access to quality prenatal care compared with Medicaid patients.Serving the EP infant population requires comprehensive support. Social work case management programs must include well-trained medical professionals and support staff who have expertise with neonatal intensive care unit (NICU) patients and are familiar with the major challenges faced by this patient population.Managed care organizations (MCOs) continue to play a vital role in mitigating healthcare costs. In a study of 365 parents of premature infants, only 26% of parents whose newborns were hospitalized in the NICU discussed costs of care with NICU staff and only 19% of parents discussed costs of care with their pediatrician.The current standard of care does not include many strategic clinical therapies and procedures capable of minimizing the occurrence of preterm comorbidities. Sammour and colleaguesBlack newborns constitute a disproportionate share of preterm births and are born at a lower gestational age than White infants in aggregate. In a study conducted by Karvonen et al,EP infant comorbidities, alongside the corresponding costs of relatively high use of healthcare resources, may be successfully reduced by strategies that are socioeconomically tailored. Skilled and empathetic patient navigators, social workers, case managers, and MCOs all have an important role to play in minimizing patient costs and ensuring the delivery of high-quality healthcare. We commend Mowitz and colleagues for their rigorous approach, nuanced analysis, and contribution to the field of health economics via their research of the premature infant population. Their findings are supported by robust statistical evidence and provide an excellent foundation for further policy action and future investigation into socioeconomic disparities among Medicaid-enrolled EP infants and vulnerable patient populations writ large."} +{"text": "Okolo and Wen empiricaTwo opposing groups have continued to discuss how natural hazards influence technological innovation in emergency management. One group has advocated the negative role of natural hazards in technological innovation, as in the case of Okolo and Wen , Chen etThe other group has strongly suggested a positive role of natural hazards in technological innovation. These researchers agree that the occurrence of natural hazards has caused both human loss and huge economic damage to human society. Nonetheless, when examining the number of patents or other disaster data in advanced nations, natural hazards eventually spur technological innovation in the region (Miao and Popp Similarly, researchers have maintained that the occurrence of multiple natural hazards has formulated incentives and opportunities for technological innovation in the field Khitrun . After cThere are at least 18 types of natural hazard, each with unique characteristics; however, they are no longer fundamentally natural (Arosio et al. Considering that researchers have faced tremendous difficulties in making a single generalization on research topics due to the complicated aspects of natural hazards, the necessity of case studies has been constantly maintained (Grynszpan et al. In addition, heterogeneous research is required to address the need for multidisciplinary information for effective natural hazard management (Shams et al."} +{"text": "Significant gaps in quality pervade U.S. health care, leading to suboptimal care and rising costs. One key factor driving the apparent quality gaps and rising costs in the current health care system is the issue of nonadherence to prescription medications.To describe quality gaps in managed care that are driven by nonadherence to prescription medications and characterize the components of successful pharmacy management strategies for overcoming nonadherence.Collaborative networks and medication therapy management (MTM) programs are 2 pharmacy management initiatives that are useful in reducing medication nonadherence among plan members. The Pharmacy Quality Alliance has laid the foundation for developing useful pharmacy quality metrics, aggregating data, and reporting to both consumers and pharmacies. At the same time, the National Committee for Quality Assurance has developed MTM measures to monitor pharmacy quality. Both organizations have used Medicare Part D as an impetus for these initiatives in an effort to assess the value of the high-cost investment in prescription drugs resulting from the government mandate.Managed care stakeholders should strive toward a value based health care system by investing more on appropriate medication use, including initiatives to reduce nonadherence and avoid the high costs of treating severe disease in the future."} +{"text": "Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and worse survival, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression.Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer\u2013one of the deadliest malignancies\u2013have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1, in pancreatic cancer cells, which led to faster tumor growth and worse survival in mice and enhanced chemotherapeutic resistance to standard chemotherapy agents used in the treatment of pancreatic cancer. Collectively, our findings establish human pancreatic cancer as having clock dysfunction and clock dysfunction causing a more aggressive cancer.The circadian clock is a regulator of human homeostasis. Dysfunction of the clock can lead to the development of diseases, including cancer. Although several cancers have been shown to have a dysfunctional clock which may alter prognosis or change treatment, this has been suggested but not demonstrated in pancreatic cancer. Investigation of this link is important because pancreatic cancer is highly lethal with few effective treatment options. Here we use recently pioneered bioinformatics approaches to assess clock functionality in human pancreatic cancer specimens, where we demonstrate that the clock is dysfunctional relative to normal pancreatic tissue. We then knocked out the core clock gene,"} +{"text": "Cancer is a global health challenge that continues to affect millions of people, despite extensive research efforts. The Special Issue on \"Frontiers in Pathogenesis and Therapeutics of Cancer\" presents a collection of research articles that aim to advance our understanding of cancer pathogenesis and develop targeted therapies to improve patient outcomes. In this Editorial, we provide a summary of the key insights and findings from these articles, highlighting their broader implications for cancer research.The articles in this Special Issue address different aspects of cancer pathogenesis, such as the role of microRNAs in cancer progression and the influence of the tumor microenvironment on tumor growth and metastasis. They also explore the use of genetic and epigenetic markers for predicting cancer prognosis and developing diagnostic tools for early cancer detection. Additionally, several studies delve into the molecular mechanisms underlying cancer stem cell self-renewal and differentiation, as well as the development of targeted therapies that can selectively eliminate cancer stem cells.Targeted therapies that selectively target cancer cells while sparing healthy cells have emerged as a promising approach for cancer treatment. This Special Issue highlights several innovative targeted therapies, including the use of engineered T cells to target cancer cells, the development of nanoparticles that can selectively deliver anticancer drugs to tumor cells, and the use of immunotherapy to activate the immune system against cancer. Moreover, precision medicine is another area of active research, with several studies focusing on developing personalized approaches for various types of cancer.In conclusion, the articles in this Special Issue provide significant contributions to cancer research. They offer important insights into cancer pathogenesis and showcase novel approaches for cancer diagnosis and treatment. The development of targeted therapies and precision medicine approaches holds enormous potential to transform cancer treatment and improve patient outcomes. We hope that the findings presented in this Special Issue will inspire further research and ultimately lead to better cancer therapies and patient care."} +{"text": "Nutrients, \u201cFood Intake and Adipose Tissue Metabolism\u201d aims to create a collection of scientific papers that explore how the relationship between food intake and adipose tissue metabolism influence general health, including chronic disease risk and longevity. Furthermore, enhancing our ability to navigate the complex interactions existing between food intake and adipose tissue has important implications for public and personalized health.The quality and quantity of the food we consume have a major impact on our general health and longevity. Western dietary trends include an abundance of calories and refined sugars that contribute to adipose tissue accumulation, dysregulated adipose tissue function, and an increased risk of chronic disease . AdiposeThe macronutrient composition of food has a strong influence on adipose tissue metabolism. High-carbohydrate diets, especially those rich in refined sugars, can lead to insulin resistance and adipose tissue inflammation. Conversely, diets emphasizing unsaturated fats and whole grains promote adipose tissue health . ProteinTo further advance our understanding of the relationship between food intake and adipose tissue, it is important to consider the concept of na\u00efve substitution proposed by Waters . Na\u00efve sBrown adipose tissue (BAT) is another classification of adipose tissue that accumulates above the clavicle and in the posterior subscapular region but typically declines with advancing age . Brown aBone marrow adipose tissue (BMAT) is found mostly in long bones, vertebrae, and the iliac crest. This unique classification of adipose tissue displays characteristics of both WAT and BAT; however, the exact function of BMAT remains uncertain . In factTo summarize, there is considerable complexity in adipocyte function between and within adipose tissue classifications that are influenced by body composition and nutritional challenges. As we delve deeper into the molecular processes governing these interactions, novel therapeutic strategies and dietary interventions will undoubtedly emerge. This Special Issue aims to collate scientific papers that contribute to further understanding how adipocytes from diverse adipose tissue classifications function in response to different nutrients and/or dietary strategies with the intention of moving in the direction of a healthier future."} +{"text": "The emergence of awake functional imaging in small animals has revolutionized our ability to examine the intricate relationship between brain activity patterns and specific task components or sequences of stimuli. In contrast to traditional anesthetized imaging, awake imaging provides a more natural and behaviorally relevant context for investigating brain activity. While anesthesia has been widely used in small animal neuroimaging studies to mitigate motion artifacts and physiological stress during functional imaging, it has become apparent that anesthesia can significantly impact brain metabolism, neuronal activity, and neurovascular coupling. Consequently, this limits the translatability of findings to humans has emerged as the gold standard for identifying task-dependent local activity patterns by recording hemodynamic responses to neuronal activity through the blood oxygenation level-dependent (BOLD) MRI contrast and most contributions in the current Research Topic deal with this method. Miranda et al., who established imaging studies in awake freely moving and interacting rats in the PET scanner provides functional neuroimages using injectable radioactive and biologically active tracers to map brain metabolism and brain perfusion or to monitor neurotransmitter-receptor binding in small laboratory animals. However, investigating transient changes in brain neurotransmitter levels upon behavior, in response to external stimuli or tasks cannot be achieved in anesthetized animals and requires the use of awake and preferentially freely moving animals. In a recent study by Russo et al. implemented a gradual acclimatization procedure during scanning, reducing stress levels and improving imaging quality. However, the current state of research has neglected the investigation of potential sex differences in the habituation response of small animals, although it is widely recognized that male and female rodents exhibit differing responses to stressors and Non-REM (Deffieux et al., In summary, the above investigations published in this Research Topic addressed the challenges and underscored the great potential of awake functional imaging in small animals to improve the translation from preclinical to clinical functional MRI. The field and methods are at a point where open data bases for awake fMRI rodent data start to emerge (Liu et al., All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "Lung cancer is the third most common cancer in the United States, after female breast cancer and prostate cancer. It accounts for more cancer-related deaths in both men and women than any other types of cancer . The incMultiple studies have shown that older patients are more likely to be undertreated because of their chronological age, even after accounting for their comorbidities and socioeconomic status. Common reasons for this disparity are insufficient study evidence, lack of appropriate resources and support, patient factors such as socioeconomic status, as well as variations in individual physician practices and preferences. Even though the median age of lung cancer diagnosis is 71 years, and more than two-thirds of patients are older than 65 years , older pMajority of older patients receive their cancer care in the community where access to clinical trials is limited CommunitWith the majority of lung cancer patients being older than 65, it is imperative that actions are taken to encourage and facilitate clinical trials among older patients. Creative and adaptive clinical trial designs with stepwise dosing approach should be encouraged . Apart fTo facilitate recruitment of a more representative group, academic institutions should be incentivized to collaborate with private practices to conduct clinical trials in the community . Social Although there is now increasing effort and guidance by major cancer societies and regulatory groups to increase inclusion of older patients, better conscious collaboration between the stakeholders is necessary for effective implementation of the strategies discussed and to enhance enrollment and retention of older cancer patients."} +{"text": "Endogenous opioid peptides and their receptors are critical mediators of various physiological and psychological processes, including motivation, affect, pain processing, cognition, stress-responsivity, and autonomic function. These opioid systems are embedded in neuronal circuits that subserve specific aspects of such processes and play a pivotal role in finely tuning behavioral outcomes. This is of relevance as dysfunction in endogenous opioid systems has been implicated in a plethora of neuropsychiatric disorders characterized by alterations in several of symptom clusters. To date, opioid receptor systems remain a promising therapeutic target for a variety of neuropsychiatric disorders and are an area of on-going development.As a field, we have achieved significant advancements in our understanding of the cellular and molecular underpinnings of endogenous opioids in regulating cellular activity and behavior. However, there remain critical knowledge gaps in our understanding of how endogenous opioid systems are embedded in neuronal circuits and how these systems regulate emergent properties of brain function. Recent advances in technology have permitted a thorough dissection of endogenous opioid systems with cell type, pathway, and subcellular resolution. Accordingly, progress has provided us with a better understanding of endogenous opioid system engagement in regulating neuronal systems that subserve the aforementioned physiological and psychological processes. Despite those critical breakthroughs, further efforts are necessary to unravel the precise granularity with which endogenous opioid systems dysregulation alters pathways necessary for the development and maintenance of pathophysiological states in mental health disorders.With the present collection of articles in this Research Topic, we provide recent advancements in our understanding of endogenous opioids from receptor signaling to neuronal circuits and highlight future avenues and opportunities for research aiming at elucidating novel targets and approaches to treat neurological and psychiatric disorders.Gamble et al. highlight recent advancements in uncoupling cellular mechanisms mediating beneficial pharmacological effects such as treatment of pain and receptor signaling that leads to various unwanted effects such as analgesic tolerance, physical dependence and activation of reward circuitry. They discuss the relatively unappreciated interaction of mu opioid receptors (MOR) with receptor tyrosine kinases (RTKs), including RTKs transactivation of MOR, and the potential therapeutic implication for targeting RTK to enhance the safety and analgesic profile of MOR agonists. There is a strong case to be made that RTK inhibitors may be a co-treatment therapy that will allow opioid mediated analgesic properties with attenuated negative outcomes associated with chronic opioid pharmacotherapies.Adhikary and Williams provide a synthesis of the recent advancement on cellular tolerance induced by chronic opioid receptor activation. In addition, they present insights into how tolerance can be manifested at the neuronal systems level. One highlight in their article is that tolerance is not mediated by a single regulatory mechanism but rather by various adaptations in cellular processes and circuits. In their review they discuss pre- and post-synaptic mechanisms underlying cellular tolerance to chronic morphine in multiple brain regions, and how the pharmacological properties of opioids, including their potency and efficacy, produce distinct adaptations that lead to tolerance.Lubejko et al.), or conditioned pain modulation . McPherson and Ingram review the importance of the opioid systems in descending pain modulation and how opioids contribute to the cellular and circuit diversity within the PAG implicated in pain transmission and opioid analgesia. The granularity on the description of circuit afferent, cell type specificity, and cellular signaling provides a cohesive summary of our current knowledge on this specific area of research. One of the important messages for future direction in this area is the potential for optimizing novel target drug development by taking advance of our knowledge of cellular heterogeneity in the PAG and other regions implicated in descending pain modulation.The ventrolateral periaqueductal gray area (PAG) is well recognized for its importance in descending modulation of pain , spinal cord stimulators, vagal nerve stimulation and transcranial direct current stimulation (tDCS). This paper highlights evidence supporting the effectiveness of various neurostimulation techniques and how they may engage opioid systems to produce their beneficial effect in pain management. The authors also provide a comprehensive overview of the various brain regions and circuits where pain transmission is processed and modulated by opioids, as well as a future outlook of the next generation of safe, effective, and technologically-innovative clinical treatments.The manuscript by Limoges et al. provide us with a detailed description of the architecture and function of the dynorphin kappa-opioid receptor system, specifically in amygdala circuits. This review presents evidence from current literature demonstrating that the dynorphin kappa-opioid receptor system plays a pivotal role in controlling many aspects of behavior, including aversive learning, pain-related, and alcohol and drug-seeking behaviors. Embedded in this article are comprehensive illustrations of the various neural circuit inputs onto dynorphin kappa opioid receptor expressing cells within the basolateral and central amygdala as well as targets of these neurons, providing a framework for how the kappa opioid system may contribute to neuropsychiatric disorders.Reeves et al. provide a comprehensive overview of the role of opioid systems in regulating synaptic transmission and intrinsic excitability across the nervous system. In their review they summarize the current literature to present a detailed description of how endogenous opioids finely tune information flow in discrete circuits, providing a cellular basis wherein opioid-mediated transmission may shape circuits at the systems level.Adding to this article, Higginbotham et al. provide a review on how pain or prolonged opioid exposure modifies reward circuitry and changes in opioid receptor function. There is strong evidence that persistent pain negatively impacts reward sensitivity and mood. Together, pain modulation of reward sensitivity and mood contributes to susceptibility in initial opioid misuse and the development of opioid use disorder. They provide a strong message that the ability to curb the opioid crisis will require more understanding of how pain and opioid-induced adaptations alter functional neurocircuitry. Indeed, much of this research is still in its infancy. Complementing this review is another by Rysztak and Jutkiewicz that comprehensively describe the mechanisms by which enkephalin peptides and enkephalin-expressing neuronal circuits mediate reward function, focusing on the modulation of mesolimbic dopamine circuitry. The authors further discuss alterations in those enkephalinergic systems in models of opioid use disorder.There is a pressing need to understand how opioids produce reinforcement and drug seeking behaviors, especially in the context of pain treatment, as chronic pain has been identified as a risk factor for developing an opioid use disorder. Maletz et al. share a compelling study in which they identify non-overlapping neuronal populations, expressing or lacking MOR, activated by morphine and hypoxia/hypercapnia in the Nucleus Tractus Solitarius. This original data report provides a deeper understanding of the circuits and neuronal populations involved in opioid-induced respiratory depression and may lead to further advancement for prevention and recovery of such events.Lastly, Overall, this compilation of papers recognized various future directions that need to be further explored. While there has been significant advancement in our understanding of cellular and synaptic level mechanisms that mediate opioid-regulated behaviors, there is much to be gained by furthering our understanding of how opioids regulate the activity of defined synapses and excitability to shape the activity of large-scale networks and emergent properties of the brain. Emerging research has shown that opioid receptor signaling is diverse and much more complex than what was previously appreciated . However, how nuanced signaling by endogenous opioid systems regulate information flow in neuronal circuits is in large part unresolved. Further, future research is needed to develop a model that integrates opioid systems with other signaling modalities . This provides a basis for diversity of gene expression across cell types of the brain to influence not only where opioids may act, but also their function effect on circuits. Additionally, while the rapid rise in technology development has facilitated swift progress in the neuroscience field, further tools are needed to precisely dissect the functional anatomy and activity of the opioid systems. Those will be critical to delineate the effects of endogenous opioids on circuits with high spatiotemporal resolution helping us to better understand and solve essential questions. For instance, revealing activity dynamics of not only neurons expressing opioid peptides, but subsequent opioid peptide release and receptor-mediated signaling in models of affective pain or analgesia tolerance will help elucidating potential steps where endogenous opioid system dysfunction occurs. Together, this will provide critical insight necessary to develop novel opioid therapeutics for safer treatment for both the sensory and emotional experiences associated with pain. Another exciting trajectory of the field will be to understand the role of opioids in the context of other treatment modalities such as neuromodulation or rapid-acting antidepressants, which may in part exert their function via endogenous opioids or can synergize with opioid-based treatments. In conclusion, here we present a collection of articles focused on opioid systems in the context of systems neuroscience, which highlights developments and provide insights to the future of opioid research in this setting.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "The Asia Pacific Society of Infection Control launched the Infection Prevention and Control Guidelines in July 2022. This document describes the guidelines and recommendations for safe practices in dental setting. It aims to highlight practical recommendations in a concise format designed to assist dental facilities at Asia Pacific region in achieving high standards in infection prevention and control practices, staff and patient safety.The guidelines were developed by an appointed workgroup comprising experts in the Asia Pacific region, following reviews of previously published international guidelines and recommendations relevant to each section.It recommends standard precautions as a minimal set of preventive measures to protect staff and prevent cross transmission. Surgical aseptic technique is recommended when procedures are technically complex and longer in duration. Only trained staff are eligible to conduct reprocessing of dental instruments. The design, layout of the dental facility are important factors for successful infection prevention. The facility should also have a Pandemic Preparedness Plan.Dental facilities should aim for excellence in infection prevention and control practices as this is part of patient safety. The guidelines that come with a checklist help dental facilities to identify gaps for improvement to reach this goal. Surgical aseptic technique is demanded when procedures are technically complex, and longer in duration. The concept of a main critical aseptic field is considered and hence, sterile gloves and protective barriers (e.g. drapes) are required. A surgical hand scrub is required prior to any aseptic task or procedure.The principles of IPC and standard aseptic technique must be applied to all dental procedures, specifically those which are technically simple and short in duration (approximately\u2009<\u200920\u00a0min). [AI1]The principles of IPC and surgical aseptic technique must be applied to all surgical dental procedures, particularly those where there is a planned penetration of the oral mucosa. [AI1]Effective hand hygiene is an essential part of aseptic technique. [A1]A surgical hand scrub using an antimicrobial handwashing solution, or an alcohol based hand rub (ABHR) approved for surgical hand decontamination, is required for surgical aseptic technique [A1]Sterile gloves must be used for surgical aseptic technique [A1]An aseptic field is necessary to provide a controlled aseptic working space to help maintain the integrity of asepsis during surgical procedures. [AI1]Recommendations on asepsis and surgical management include:The facility is divided into two zones: clean and contaminated zones, where the clean zones are where there is no patient care activities e.g. staff room, office area, waiting and reception areas, storage supply area and sterilized instruments and equipment; and the contaminated zones are determined by what is touched and where the droplets, splash or spatter has spread. Clinical contact surfaces in the contaminated zone not barrier protected must be cleaned after each patient.Routine cleaning of the clinical area is necessary to maintain safe environment because dust soil and microbes on the environment surfaces can transmit infection.The environment should be clean, free from dust, dirt and body fluid stains and spillages. Compliance with safe care and safe working environment is the key to quality care. The use of audit check list to conduct regular audits help identify discrepancies between standards and the actual practices among the team.Management of medical and related waste must conform to national and institution regulations. It is recommended that the dental facility develop a waste management program according to the national and institutional regulation and guide.Most dental unit waterlines contain biofilm, which acts as a reservoir of microbial contamination. It is recommended that dental unit waterline systems must be regularly maintained, via water treatment and monitoring, and performed according to the manufacturer\u2019s instruction.If surface barriers are used to protect clinical contact surfaces change surface barriers between patients.Clean and disinfect clinical contact surfaces that are not barrier-protected with approved hospital grade disinfectant at the start of the day and after each patient. [BIII]Establish policies and procedures for routine cleaning and disinfection of the environmental surfaces in dental healthcare settings. [AIII]Select EPA-registered disinfectants or detergents with label claims for use in health care settings. [AIII]Follow manufacturer instructions for use of cleaners and EPA-registered disinfectants . [BIII]Follow national and institutional regulation on managing different types of waste. [BII]Use water that meets the CDC recommended limit for dental procedural water for routine dental treatment output water. Adopt appropriate infection control procedures for dental unit waterlines. These include flushing dental unit waterline, use of germicidal product, biofilm prevention and monitoring of water quality from the dental unit waterline. [AII]Use only sterile saline or sterile water as a coolant/irrigant when performing surgical procedures. [AII]Recommendations for safe dental environment include:Potential occupational exposures at the dental facility may occur arising from grinding, polishing or other aerosol generating procedures at laboratories, surgeries, etc. Standard precautions including appropriate environment/equipment hygiene would help ensure all health activities are carried out in a safe and healthy environment for both dental health care professionals (DHCPs) and patients.All impressions and appliances should be thoroughly cleaned and rinsed of all debris before being handled in the on-site laboratory or sent to an off-site laboratory. [BII]The dental on-site laboratory staff should wear appropriate PPE to perform disinfection. [AII]Heat-tolerant items used in the mouth must be cleaned and heat sterilized before being used on another patient. [AII]Environmental surfaces should be barrier-protected or cleaned and disinfected with low-level disinfectants [AII]Appliances and prosthesis delivered to the patient should be free of contamination. New and old dentures should be disinfected and rinsed by treated water . [AII]In radiography room, when the surface is visibly contaminated with blood or saliva, intermediate level disinfectant should be used. [AII]Radiography equipment should be cleaned and disinfected with low level disinfectant after each patient use or should be protected with surface barriers. [BII]In heavy aerosol environment, high volume evacuation must be used as routine practices, and preventable by routine practices [BII]Critical OPD surgery should have pre-procedural mouth rinses for patients to decrease the number of microorganisms during invasive dental procedures. [AII]Recommendations for special procedures include:The dental instrument reprocessing cycle includes the vital steps of cleaning and disinfection, inspection, packaging, sterilization, documentation and before they are reused on the next patient. These are assigned to DHCPs with training in the required reprocessing steps to ensure reprocessing results in a device that can be safely used for patient care, including the appropriate use of PPE necessary for safe handling of contaminated equipment.Pre-cleaning is strongly recommended before disinfection to improve the safety and effectiveness of instrument reprocessing. It ensures the removal of organic remnants that the microbes are embedded in. If this organic layer is not removed properly, it can shield the microorganisms and potentially compromise the disinfection or sterilization process. If cleaning is delayed, the soiled instruments can be kept in liquid solution which could be any proprietary product for pre-cleaning. Drying out of the uncleaned debris will make subsequent cleaning more difficult. Separation of dirty and clean zones must be clearly demarcated to ensure no mixing of contaminated instruments from cleaned/disinfected instruments before sterilization.Cleaning verification by users must be performed to assess level of cleanliness of instrument surfaces. This can be done by mainly visual inspection with the aid of lighted magnifying lens if needed. Other verification methods if deemed necessary can also be used.Regular monitoring of the sterilization cycle is necessary to ensure the sterility of reprocessed instruments. Where there is a sterilization failure, a product recall must be activated and the use of the sterilizer stopped immediately. The process of sterilization must be reviewed to rule out the possibility of operator error. If there is any procedural error/failure identified, this should be rectified and subsequently retest the sterilizer, performing the physical, biological and chemical monitoring.Proper cleaning, disinfection and sterilisation processes must be clearly stated in all dental clinics and preferably be carried out by trained dental healthcare professionals. [BII]Proper sterilisation of dental handpieces and all dental instruments is important and should follow the manufacturer instructions. It is important that proper sterilisation is performed to prevent transmission of microorganisms. [AII]Recommendations on instrument handling and reprocessing include:Exposure to blood or saliva by percutaneous injury with sharp injury is the greatest risk for acquiring a blood-borne pathogen in the dental health-care setting. The dental facility should have a post-exposure management protocol where staff is immediately evaluated to assess the potential to transmit an infectious disease. An outbreak, if any, will need to be investigated and risk assessment done to evaluate possible environmental exposures.There should be a process of notification of supervisors, senior management and IPC. [AIII]A procedure should be established for the recall of improperly reprocessed medical equipment/devices. [AIII]Recommendations on managing incidents and outbreaks include:IPC education and training, such as hand hygiene, use of PPE, appropriate to their position and responsibilities is provided upon hire, at least annually, and whenever new equipment or processes are introduced.Education on the basic principles and practices for preventing the spread of infections should be provided to all DHCPs.Training should include both DHCP safety and patient safety Regular refresher training is also appropriate to ensure the necessary infection control measures are being complied with and understoodRegular continuing education is required and be supported, as well as encouragedThere are regular documented internal audits to assess the competency of staff involved in IPC proceduresIPC policies are reviewed by all staff members and updated at least annually.Infection prevention education and training with ongoing program for DHCPs are critical for ensuring that infection prevention policies and procedures are understood and followed. The supervisor needs to ensure:There is a written policy regarding immunizing DHCP, with immunization program. [CI]Develop and maintain regularly updated immunization/health records for dental staff. [BI]Provide job- or task-specific infection prevention education and training to all DHCPs. [BI]Provide training during orientation and at regular intervals . [BI]Maintain training records according to state and national requirements. (IB)Recommendations on education and training include:Following the 2009 influenza H1N1 and the 2020/21 COVID-19 pandemics, it is clear that dental care services and clinics should have a pandemic preparedness plan. Such plans shall be reviewed periodically with reference to the most updated scientific evidence and the local health authority.Travel to areas with known epidemic of potential concern (EPC) within the known or suspected incubation periodPossible Occupational exposure to pathogens of potential concern (O)Unprotected Contact with those with the EPC within the known or suspected incubation periodBeing part of a rapidly spreading Cluster of patients with the infection of unknown cause, including exposure to household members with the EPC.Patients suspected with a pandemic associated infection should be isolated in separate room as far as possible. Consider postponing elective procedures and non-urgent patient visits when client reports signs and symptoms of the pandemic infection and positive history of epidemiological clues (acronym TOCC), i.e.Dental care services clinics should have a pandemic preparedness plan with reference to the local health authority. [BII]Early identification through client triage process in pandemic situations is key to prevent spread of infectious disease in clinic settings. [AII]Consider if elective procedures and non-urgent patient visits be postponed when patient reports signs and symptoms of the pandemic infection and positive TOCC history. [BII]Avoid AGP as far as possible. If unavoidable, AGPs should be carried out in negative pressured rooms. [BII]Use fourhanded dentistry, high evacuation suction and dental dams to minimize droplet spatter and aerosols. [AII]DHCP should wear appropriate PPE for standard precautions and transmission base precautions according to pandemic guideline recommendations. [BII]Practices should ensure physical distancing. Good hand and respiratory hygiene measures are followed at all times throughout the practice. [BII]Recommendations on pandemic preparedness include:There should be clearly defined clean and contaminated zones. [AII]It is highly recommended that the operatory be in single room [BII]Alcohol-based hand rub (ABHR) dispensers should be installed at every operatory at the point of care to facilitate easy access to hand hygiene. [AII]Receiving, cleaning and decontaminationPreparation and packagingSterilisation andStorage. [AII]The reprocessing area must be divided into distinct areas for:The design, layout of dental surgery and treatment areas are important factors for successful infection prevention. Work areas should be well lit and ventilated with sufficient uncluttered and easily cleaned bench space to contain dental equipment. There must be a defined area for clean and contaminated zones in the dental operatory and instrument reprocessing rooms. All dental staff must understand the purpose of and requirements within each zone, and adhere to the protocols.We recommend all dental facilities to aim for excellence in IPC practices. COVID-19 pandemic had expedited rapid changes in many dental practices globally but these changes should be long-lasting with regular reviews for strategic revisions towards achieving staff and patient safety. A checklist for self-assessment is included in the guidelines to help in identifying gaps for improvement. The APSIC guideline not only gives timely guidance on safer practices at dental facilities during the COVID-19 pandemic but its continual implementation will certainly assist dental facilities to ensure appropriate safe practices are in place to mitigate healthcare associated infections.Hong Kong Infection Control Nurses Association (HKICNA), Hong KongInfection Control Association of Singapore (ICAS), SingaporeJapanese Society for Infection Prevention and Control (JSIPC), JapanKorean Society of Health-associated Infection Control (KOSHIC), South KoreaNational Nosocomial Infection Group of Thailand, ThailandNursing Association for Prevention & Control of Infection, Thailand (ThaiNAPCI)Philippine Hospital infection Control Society, (PHICS), PhilippinesInfection Control Society of Taiwan (ICST)Malaysian Society of Infection Control and Infectious Disease (MyICID), MalaysiaIndonesian Society of Infection Control (INASIC), Indonesia"} +{"text": "Plasma zonulin is acknowledged to be a biomarker for intestinal permeability. Previous studies have demonstrated significant relationships regarding potential effects of zonulin in several major psychiatric conditions including attention deficit and hyperactivity disorder, autism spectrum disorder and depression, however its role in schizophrenia still remains unclear.We aimed to identify the alterations of plasma zonulin levels between the different periods of the illness and we strive to reveal the associations between plasma zonulin levels and symptoms in patients with chronic schizophrenia.30 patients with schizophrenia and 29 healthy controls participated in the study. Sociodemographic data form and Positive and Negative Syndrome Scale (PANSS) were administered. Blood sampling was performed for patients who are in exacerbation and following treatment response periods along with the healthy controls. ELISA method was utilized to measure plasma zonulin levels.The groups did not differ in plasma zonulin level comparisons. Plasma zonulin did not fluctuate between the symptom exacerbation and treatment response periods of the patients. Besides, plasma zonulin level was found to be associated with passive/apathetic social withdrawal, active social avoidance, and somatic concern items of the PANSS in a negative direction.This is the first follow-up study in the literature that assesses plasma zonulin in patients with schizophrenia. The measurement of plasma zonulin may not be a convenient parameter in distinguishing symptom exacerbation and treatment response periods in chronic schizophrenia, nevertheless it may have implications on reduced social interaction and somatic symptoms. Our study can provide better insight for future studies to be more cautious while interpreting the associations of plasma zonulin levels with psychiatric disorders.None Declared"} +{"text": "One of the most striking findings in this research is the increased abundance of circMLL in paediatric leukaemia compared with controls when quantified from neonatal blood spots (Guthrie cards) 1\u20137\u00a0years prior to disease onset.0, which The ability of circMLL to inhibit the proteasome signifies an intriguing facet of this newfound phenomenon. The proteasome, a cellular juggernaut responsible for protein degradation, is a focal point in the context of cancer biology. Inhibiting the proteasome catalyses the accumulation of proteins with the propensity to induce DNA breaks and chromosomal translocations, well\u2010acknowledged drivers of cancer.3Biomarkers for early diagnosis: The presence of these oncogenic circRNAs could serve as novel biomarkers for early leukaemia diagnosis. Profiling the abundance of specific circRNA signatures in patients' samples might permit the detection of leukaemia at earlier stages, prior to symptom onset, particularly in paediatric populations where early intervention is paramount to boost patient survival.Prognostic indicators: The abundance of specific circRNAs may aid in predicting disease progression and therapeutic response. In paediatric cases, where personalised treatment approaches are critical, circRNAs could guide physicians in stratifying patients into risk groups, ensuring tailored interventions. Changes in circRNA profiles throughout the course of treatment might provide real\u2010time feedback on how patients are responding to therapies, enabling physicians to adjust treatment strategies as needed. This would be particularly useful for cancers requiring costly imaging, or invasive procedures including brain or colorectal cancer.Personalised therapeutic targets: By designing treatments that disrupt the oncogenic interactions between circRNAs and their targets and the proteasome), or that target the circRNA for destruction clinicians might offer more precise therapies with reduced side effects compared with standard frontline chemotherapies. Specifically, avoiding the use of topoisomerase inhibitors, like etoposide, that have been linked to recurrence of MLL\u2010rearranged leukaemias,Engineering circRNA for enhanced protein production: Their unique circular structure provides enhanced stability and resistance to degradation, making them promising candidates for the delivery of therapeutic proteins.This discovery raises a number of questions and research opportunities. These include do circRNAs shape other genetic rearrangements that could contribute to cancer or other diseases? Can we harness the potential of circRNAs for assisting patients? The most exciting prospect stemming from the interactions of circRNAs and leukaemia is the potential for clinical translation. circRNAs may revolutionise how we diagnose, prognosticate and treat paediatric leukaemia.4MLL gene, have ushered circRNAs into the forefront of leukaemia research and cancer research, at large. These circRNAs can no longer be considered passive transcripts but active participants in the intricacies of genetic instability and oncogenesis. Moreover, this finding may potentially shape future therapeutic landscapes to transform clinical practice in diverse malignancies. Indeed, a number of companies are undertaking clinical trials for therapeutic circRNAs in cancer and other human diseases.The revelation of circMLL and its interplay with DNA, especially within the"} +{"text": "Gestational weight gain (GWG) should be tracked at all antenatal consultations, and pregnant women should gain weight according to pre-established guidelines. The recommendation on weight gain varies according to the pre-pregnancy nutritional status (body mass index \u2013 BMI).Pre-pregnancy weight can be obtained from medical records, reported by the pregnant woman, or measured at the beginning of pregnancy. Maternal height should be obtained at the beginning of pregnancy. The two measures are used to calculate the pre-pregnancy BMI and classify the nutritional status as underweight, normal weight/eutrophic, overweight or obesity.Until 2022, there was no weight gain curve for the Brazilian population and the Ministry of Health recommended the adoption of two tools for nutritional monitoring during pregnancy: Atalah\u2019s gestational BMI curve (Chile) and GWG recommendations from the Institute of Medicine \u2013 IOM (United States).Based on data from 7,086 women participating in 21 studies that are part of the Brazilian Maternal and Child Nutrition Consortium (Portuguese acronym: CONMAI), specific GWG curves and recommendations were created for Brazilian pregnant women.The new GWG curves and recommendations were discussed and endorsed by specialists in a workshop held in Bras\u00edlia in June 2020, and adopted by the Ministry of Health as of 3 August, 2022.The new system includes a single instrument that allows tracking and making recommendations on gestational weight gain.In antenatal care, guidelines on optimal weight gain should be based on the new GWG recommendations for Brazilian pregnant women.Insufficient or excessive weight gain is associated with the occurrence of adverse maternal and neonatal outcomes.The use of specific weight gain curves for Brazilian women presented in this document is the current recommendation of national guidelines.Ranges of GWG according to pre-pregnancy BMI can also be used and should include the different guidelines for cumulative weight gain per trimester of pregnancy.Gestational weight gain is a modifiable factor, so it must be carefully tracked in order to reduce risks associated with weight gain out of the range.Weight gain during pregnancy is natural and necessary for the growth and development of the fetus. Gestational weight gain (GWG) includes the following: fetus, placenta and amniotic fluid, uterus and breast growth, expansion of blood volume and extracellular fluid, and maternal body fat reserve.Gestational weight gain out of recommended ranges is associated with maternal complications and adverse perinatal and infant outcomes.Since the early 2000s, the Ministry of Health has recommended the adoption of two methods for assessing the nutritional status of pregnant women during antenatal care: the Chilean curve by Atalah et al.Although there is no global recommendation on ideal GWG values, since the 1990s, the recommendations proposed for certain countries consider different weight gain ranges according to the pre-pregnancy BMI.Given the aforementioned limitations, these tools have to be updated considering different populations and cultures, as well as the local epidemiological scenario. Parameters also have to be established so that health professionals can guide pregnant women. Between 2021 and 2022, Brazilian researchers developed specific GWG curves and recommendations for the Brazilian population, adopted by the Ministry of Health from 2022 onwards.To avoid errors arising from the use of curves based on anthropometric data and perinatal outcomes from other populations, Brazilian GWG curves were created based on data from the Brazilian Maternal and Child Nutrition Consortium (Portuguese acronym: CONMAI), a collaborative research network created in 2019 to investigate issues of maternal and child health and nutrition.The GWG curves represent an important advance for monitoring the behavior of this indicator in Brazil. However, they do not answer the most common question asked by pregnant women during antenatal care: what is the recommended weight gain until the end of pregnancy? The percentiles on curves associated with higher/lower risk of adverse outcomes also needed to be identified. Thus, optimal GWG ranges were defined based on values that would reduce the occurrence of births of SGA and LGA children, premature children and excessive weight retention at 6 and 12 months postpartum. Data from CONMAI and the Food and Nutrition Surveillance System were used in this analysis. Details on data and methods used in the definition of these ranges will be published soon.The optimal GWG ranges were proposed by researchers from the Nutritional Epidemiology Observatory of the Universidade Federal do Rio de Janeiro (UFRJ) and discussed with technicians from the Ministry of Health, health professionals who perform antenatal care and specialist researchers from various regions of Brazil in a workshop held in June 2022, in Bras\u00edlia. The new guidelines agreed upon in this workshop were incorporated into the curves and into the new pregnant woman\u2019s record card Chart. TherefThe GWG curves and guidelines were created for adult pregnant women (over 18 years old) in low-risk singleton pregnancies. There are still no specific guidelines for different degrees of obesity. The recommendation ranges were defined based on the best evidence available to date and considering the current epidemiological scenario. This scenario needs to be monitored and the ranges may be revised in the future.Health professionals who will monitor the pregnant woman and advise on GWG should adopt the following guidelines:2. The pre-pregnancy weight used in this calculation must be the one reported by the pregnant woman. When the pregnant woman cannot inform this value, the weight measured at the beginning of pregnancy (up to 8 weeks) or the usual weight of the pregnant woman should be considered.In the first consultation, the pre-pregnancy BMI should be calculated using the formula pre-pregnancy BMI = pre-pregnancy weight (kg)/height (m)The pre-pregnancy BMI must be classified according to cutoff points proposed by the WHO After obtaining the weight at the consultation, the GWG (kg) must be calculated using the formula: GWG = weight at the visit \u2013 pre-pregnancy weight. This value must be marked on the chosen curve . From the marking, it is possible to assess if the gain is within recommended ranges (darker areas on the graph) or above/below recommendations.The professional should advise the pregnant woman on maintaining adequate weight gain or on the need to increase/reduce gain, so that she reaches the recommended values.The weight gain schedule until the next appointment, until the end of the trimester or up to 40 weeks can also be calculated.Three tools were created to facilitate the adoption of the new curves and guidelines by health professionals performing antenatal care and pregnant women:An interactive panel available in English and Portuguese that allows the use of curves and guidelines online (https://observatorioufrj.shinyapps.io/GPG_app/);An Excel calculator that allows calculation of the z score and exact percentile of a pregnant woman or a database, including multiple measurements by pregnant women and several pregnant women (https://dataverse.nutricao.ufrj.br/dataverse/curvas_openaccess/);An Android/iOS application (PesoGestBR) including curves, recommendations and nutritional guidelines based on the Food Guide for the Brazilian Population . Although created specifically for pregnant women, it can be used by health professionals, as the registration of more than one pregnant woman is allowed. This app will be available for free download until December 2022.Following the proposed recommendations for weight gain during pregnancy is important for the woman and for the outcome of the pregnancy. Thus, the curves and recommendations should be widely disseminated and used by health professionals. Following recommendations and adapting weight gain is not an easy task at any stage of life, and it is no different during pregnancy. Pregnancy brings several physical and emotional demands that must be considered by the team of professionals performing antenatal care. The pregnant woman needs to be served with cordiality and without judgments or stigmas because of her nutritional condition. This way, she will be more likely to monitor her weight gain, adhere to recommendations and reduce the risk of maternal and child adverse outcomes.National Commission Specialized in Antenatal Care of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Fernanda Garanhani de Castro SuritaVice-president:L\u00edlian de Paiva Rodrigues HsuSecretary:Adriana Gomes LuzMembers:Eliana Martorano AmaralEugenia Glaucy Moura FerreiraFrancisco Herlanio Costa CarvalhoJoeline Maria Cleto CerqueiraJorge Oliveira VazJose Meirelles FilhoLuciana Silva dos Anjos Fran\u00e7aMarianna Facchinetti BrockMary Uchiyama NakamuraPatricia Gon\u00e7alves TeixeiraRenato AjejeSergio Hecker LuzNational Commission Specialized in High Risk Pregnancy of the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo)President:Rosiane MattarVice-president:Alberto Carlos Moreno ZaconetaSecretary:Mylene Martins LavadoMembers:Arlley Cleverson Belo da SilvaCarlos Alberto MaganhaElton Carlos FerreiraFelipe Favorette CampanharoInessa Beraldo de Andrade BonomiJanete VettorazziMaria Rita de Figueiredo Lemos BortolottoFernanda Santos GrossiRenato Teixeira SouzaSara Toassa Gomes SolhaVera Therezinha Medeiros Borges"} +{"text": "This graphical review provides a concise overview of indole alkaloids and chemical reactions that have been reported to transform both these natural products and derivatives to rapidly access new molecular scaffolds. Select biologically active compounds from these synthetic efforts are reported herein. Natural products have played an essential role in medicine due to their abilities to bind to and modulate biological targets critical to disease. Vincristine, vancomycin, morphine, and paclitaxel are complex natural products with unique molecular architectures enabling exquisite drug\u2013target interactions and therapeutic benefit to humankind. Many drug discovery programs have focused on utilizing synthetic chemistry to optimize the inherent biological activity, or pharmacology, of natural products as disease treatments; however, this graphical review focuses on synthetic transformations of indole alkaloids and relevant derivatives that would be expected to significantly alter, or re-engineer, their biological activity profiles.Our group is developing a ring distortion platform to re-engineer the biological activities of readily available indole alkaloids using a combination of ring cleavage, ring rearrangement, and ring fusion reactions to rapidly generate diverse collections of small molecules bearing high stereochemical complexity. We hypothesize that dramatically altering the inherently complex molecular architectures of indole alkaloids will lead to new biologically active small molecules with activity profiles distinct from the parent indole alkaloid and alternative derivatives with diverse scaffolds.Upon scanning the literature, one can find a diversity of exciting synthetic transformations that have been applied to numerous indole alkaloids and related indole-based molecules. Although these transformations have been used in total synthesis or methodology development, we view these precedented reactions as potential launching points for ring distortion chemistry. The overarching goals of this graphical review are to provide an overview of useful synthetic transformations of indole alkaloids (and related derivatives) by reaction type and for select indole alkaloids .This graphical review will begin with some basic background information related to a diversity of biologically active indole alkaloids . Then, we will transition the graphical review to published ring cleavage and ring rearrangement transformations on indole alkaloids and derivatives. Finally, we will focus on reported transformations of select indole alkaloids that have been used, or could be useful, to generate novel scaffolds for drug discovery and chemical biology."} +{"text": "Although homopositivity, the attitudinal acceptance of homosexuality, has generally increased across Western societies, there remains considerable homonegativity across certain regions of the world as well as certain demographic and socioeconomic groups. Although previous cross-national research has successfully identified the key factors affecting homopositive attitudes, the literature neglects both potentially key mediation pathways and moderating interactions between those factors that may unlock more nuanced understanding of these variations in homopositive attitudes across individuals and places. In response, the present study innovatively applied a multivariate structural equation modelling approach to the latest Wave 9 (2018 data) of the large-scale cross-national European Social Survey data in order to shed new light on these currently neglected predictors, pathways, and moderating influences on homopositive attitudes. It used a three-item latent variable to measure the homopositive attitudes outcomes construct. Its explanatory variables were focused across three key sets of factors identified in theoretical and empirical literature alongside various wider controls. Our analyses made several innovative methodological and empirical contributions to existing debate. Key innovative findings include the original identification of important indirect effects of religious beliefs on homopositive attitudes via religious practices, important indirect effects of education on homopositive attitudes via household income, and the role of national welfare regimes to homopositive attitudes (and with its effects interestingly not moderated by household income). Although homopositivity, the attitudinal acceptance of homosexuality, has generally increased across Western societies there remains considerable homonegativity across certain regions of the world including Africa, Eastern Europe, and parts of Asia framework to bring the exploration of key mediation pathways to the heart of the analysis. The exploration of such mediation pathways is important to understand the indirect as well as direct effects of key explanatory variables as well as to shine a light on the processes at play in shaping homopositive attitudes.Secondly, previous research pays relatively little attention to the potential moderation of key explanatory factors, with some notable exceptions a general question asking to what extent respondents agree with the statement that gay and lesbian individuals should be free to live their life as they wish. Instead, the present study acknowledges that homopositivity should instead be treated as a latent concept with multiple dimensions and whose nature and strength of feeling may vary dependent upon the specific dimension in question of the European Social Survey (ESS) released in late 2019 and relating to data collected during 2018. The ESS has been collected bi-annually since 2001 and has well-established survey sampling, data collection, and weighting procedures as well as detailed documentation ESS, . The RouAlthough not used in previous in studies in the literature, SEM offers a flexible statistical framework to incorporate our theoretical innovations around the examination of homopositivity as a latent concept, mediation pathways, moderation, and moderated mediation .Figure\u00a0In the socioeconomic theoretical block, explanatory variables relating to education, income and, in later modelling, national welfare regimes.A final theoretical block relates to basic human values and, in later modelling, its potential moderation by the national legislative and policy framework regards homosexuality. Basic human values of universalism, conformity, tradition, self-direction, hedonism, and power are included in our analyses. Each is coded one to six where higher scores correspond to a greater reporting of that value by the individual. The country\u2019s legal and policy regulation of homosexuality is incorporated as the 2019 Rainbow Europe Country Index (RECI) score single indicator to measure its outcome indicator, the present study encourages greater explicit consideration and debate of this key specification. The present study embraces its ability to readily incorporate latent factors into its SEM framework to instead measure the inherently latent concept of homopositivity from three distinct yet equally plausible underlying indicators. Model comparisons show that the main messages from the findings remain broadly consistent across all specifications of the outcome indicator. However, differences in effect sizes and in reduced model power are evident when single indicators as used as the outcome measure.Religiosity has been found in numerous previous studies to be a key factor in explaining homopositive attitudes in terms of religious beliefs, practices, and faith groups. Our analyses include all three and findings make two main contributions in this area. Firstly, our models allow a mediation pathway between religious beliefs and religious practices for the first time in the literature and this highlights the strong role of religious beliefs in driving religious practices. This illustrates a key process through which beliefs affect homopositive attitudes via their influence on religious behaviours. It also highlights that the total effect of religious beliefs on homopositive attitudes\u2014by which is meant its direct effects plus its indirect effects mediated via religious practices\u2014are notably larger than previous studies have identified via direct effects alone. Secondly, our analyses include detailed interaction terms between religious beliefs and religious denomination in order to explore the potential for varying effects of beliefs across denominations, in contrast to existing scholarship which assumes uniform effects. Our analyses show that although religious beliefs are important to homopositive attitudes in all faith groups their effect size differs across denominations. Specifically, other things equal Eastern Orthodox and especially Islamic faith show notably less positive attitudes towards homosexuality at low levels of religious belief while individuals of Protestant, Eastern Orthodox, and Other denominations show larger expected increases homonegative attitudes as strength of belief increases compared to other faith groups.In terms of the socioeconomic drivers of homopositive attitudes our findings make three contributions to the literature. Firstly, they newly illustrate that education has marked indirect effects on homopositive attitudes mediated through household income in addition to the direct effects of both education and household income on homopositivity evidenced in previous research. Secondly, our analyses bring new insights into the role of welfare regimes in affecting homopositive attitudes directly as well as in moderating the effects of low income. The Nordic regime shows the largest positive association with homopositive attitudes and the Eastern European regime the least positive association, other things equal, with Liberal, Corporatist, and Southern European regimes falling in between those extremes. Thirdly, our analyses highlight that household income shows a positive association with homopositve outcomes and that this effect does not vary across welfare regimes despite their markedly differing propensities to mitigate financial risks and losses, particularly at lower income levels. Taken together these findings suggest that welfare regimes do matter to the shaping of homopositive attitudes and hence should be included into future research in the field. However, and perhaps contrary to initial expectations, these findings suggest that they do so less as a moderator of material financial and instead as a reflection of their differing cultural and ideological regimes.Finally, our analyses confirm the relevance of key basic human values to homopositive attitudes, with Universalism showing a particularly strong positive association with homopositive attitudes. Compared to previous research findings however (Kuntz et al., Taken together the analyses add a range of valuable new insights to our understanding of the key predictors, pathways and moderators of homopositive attitudes. Despite general strides towards greater acceptance of homosexuality homonegativity continues to be a challenge in many regions of the world and within certain demographic groups of all nations. It is our hope that this development in the literature of these richer understandings of homopositive attitudes beyond the identification of headline predictors can help to support continued progress towards equality and acceptance of homosexuality across all people and places."} +{"text": "Perinatal maternal depression and anxiety are associated with adverse maternal outcomes, and nutrition may play an important role in their emergence. Previous research shows that certain micro and macronutrients found in different dietary patterns may influence perinatal mood disorders.This study aims to explore relationships between nutrition during pregnancy and perinatal maternal depression and anxiety symptoms using network analyses.Using data from the French EDEN mother-child cohort, the sample consisted of 1438 women with available perinatal mental health outcomes and nutritional markers collected from food frequency questionnaires. Four networks were constructed to explore the relationships between prenatal nutrient status, dietary patterns, and perinatal mental health, while accounting for important confounders.The Healthy dietary pattern was associated with the presence of vital micronutrients, while the Western dietary pattern was consistently associated with poorer intake of vital micronutrients and contained an excess of certain macronutrients. Western dietary pattern and symptoms of postnatal depression were connected by a positive edge in both the macronutrient and micronutrient networks. Lower education levels were associated with higher Western dietary pattern scores, from which a positive edge linked to postnatal depression symptoms in both models.A Western dietary pattern was associated with increased symptoms of postnatal depression in our adjusted network models; The Healthy dietary pattern was associated with essential micronutrients but not with symptoms of depression or anxiety. Perinatal mental health might be impacted by specific dietary patterns in the context of psychosocial and physical stress associated with pregnancy.None Declared"} +{"text": "Breastfeeding has incontestable proven health benefits for mothers and babies , yet lesMost mothers and babies do not need medical treatment, but do require professional support during the first hours of the baby\u2019s life. The absence or suboptimal provision of such support potentially leads to avoidable harm with crucial consequences, such as mothers who cannot feed their own babies.The Lancet breastfeeding Series likewise states parents and health professionals frequently misinterpret normal baby behaviours, such as crying and short night-time sleep durations, as signs of milk insufficiency or inadequacy . ResearcActions are needed for improving the education of health workers and families on breastfeeding practices and beliefs, and toward the adoption and effective implementation of evidence-based recommendations for improving quality of care for mothers and newborns in Romania. This will require changing practices and behaviours. Addressing the shortage of midwives and their undervalued role is key in this task . Indeed,"} +{"text": "Professional attitudes and ethics skills of physicians are influenced in part by the lessons of medical training. Still, few medical schools and postgraduate training programs introduce a formal curriculum. There is also the hidden curriculum which is influenced by instructions that are implicitly learned by observation of others, the cultural climate, and the social norms. The hidden ethics curriculum in psychiatry resident programs was investigated with qualitative interviews. Patient autonomy and ethical problems that arise during the management of difficult patient populations were the most common themes. Psychiatric residents perceive a need for more education on ethical issues. The speaker will present the available knowledge on psychiatry residents\u2019 perspectives and the current programs addressing ethics training. This talk is hoped to elicit discussion in preparation for future action and inform a roadmap for addressing ethics training and subsequent educational events during psychiatry undergraduate and postgraduate education.None Declared"} +{"text": "As the demand for more advanced artificial intelligence becomes increasingly urgent, scientists gradually realize that von Neumann computers still lag behind the human brain in terms of adaptability, fault tolerance and generalization capabilities. The continuous exploration of the working mechanism of the human brain has given rise to research on efficient neuromorphic computing. The realization of this goal can be achieved by neuromorphic electronics, which aims to realize computing functions by simulating neural behavior with neuromorphic devices. With the iteration of semiconductor technology, neuromorphic devices such as memristors have brought researchers the dawn of efficient neuromorphic computing. Owing to the extensive selectivity of materials and technologies, developing memristors and other neuromorphic devices has been a very promising option to meet the request for future electronics. There still exist challenges in designing high-performance memristors and neuromorphic devices and it is hoped that more novel working mechanisms and devices with functional materials can be found.This Focus Issue on \u2018Materials and Technologies for Memristors and Neuromorphic Devices\u2019 organizes very high-quality review articles on the latest progresses in neuromorphic computing. Memristors and synaptic transistors have been widely studied in neuromorphic devices. Recent research interests include finding suitable materials and structures for mimicking biological nervous systems and developing low-power brain-like algorithms. With the combination of hardware, the functional simulation of the human brain neural network can be realized at the lowest power consumption and cost.Li et al. from HuaAs guest editors, we would like to thank all authors and reviewers who have contributed to this Focus Issue. We believe that the nine review papers in this STAM Focus Issue can provide the latest advancements in memristors and neuromorphic devices. We hope this Focus Issue can inspire numerous outstanding developments and new ideas in the neuromorphic computing research area and offer some strategies for the future development of memristive materials in neuromorphic electronics."} +{"text": "Despite studies pointing to the important role of relational and community factors in influencing mental health during times of crises such as the current pandemic, little research has examined protective factors at the relational/community level that serve protective factors against mental health impairment in response to the current pandemic.This study aims to address this gap and examines protective factors against adverse mental health consequences related to the pandemic at the relational and community levels among individuals residing in high-risk marginalized low-resourced settings in Guatemala at one and a half years post onset of the pandemicTelephone surveys were administered to 100 participants to assess sociodemographic characteristics, psychosocial functioning, and protective factors against psychological distress. . Multiple linear regressions were used to examine predictors of mental health impairment.Our findings demonstrate that only psychoeducation serves a protective factor against psychological distress.Interpersonal support was found to predict increased levels of anxiety and depression and adaptive coping was found to predict increased levels of anxiety, depression, and burnout. No significant relationship between community resources and any type of mental health impairment was found.Public mental health efforts should capitalize on the effectiveness of psychoeducation to promote strategies for managing symptoms of psychological distress as well as providing information regarding resources and services. In the context of complex emergencies that have an immediate effect on already scarce resources at a personal, community, and institutional levels, psychoeducation has the advantage of a low-cost intervention, easily transferable between communities, providing immediate support as well as sustainability over time.None Declared"} +{"text": "Emerging epidemiological data have indicated associations between maternal smoking during pregnancy and a range of negative outcomes in children. Nevertheless, there is scant evidence reporting adverse effects on lower academic performance during adolescence.To examine the association between maternal smoking during pregnancy and the risk of lower academic performance in adolescent children.Data were obtained from the New South Wales (NSW) Perinatal Data Collection, which included all live births in the Australian state of NSW from January 2003 to December 2005. This was linked with NSW admitted data collection and National Assessment Program for Literacy and Numeracy (NAPLAN). A total of 168, 528 mother-offspring pairs were involved in the final analysis. Maternal smoking during pregnancy was assessed using self-reports of smoking during pregnancy. NAPLAN was used to assess the educational performance of the offspring. A logistic regression model was used to explore the association.The findings show that exposure to cigarette smoke in utero was associated with an increased risk of poor academic performance in adolescent offspring in all domains, including numeracy , reading , writing and spelling . In our sensitivity analysis by gender, maternal smoking during pregnancy demonstrated stronger effects on the academic achievements of females in all domains.The results show that exposure to cigarette smoke in utero was associated with an increased risk of lower educational achievements in adolescent children with greater effects in female than male children in all domains. The findings suggest the potential for targeted screening and early intervention of academic performance in exposed offspring.None Declared"} +{"text": "Neurodevelopmental Disorders (NDDs) represent a broad class of conditions characterized by difficulties in cognitive, communicative, behavioral or adaptive skills that manifest early in development and persist across the lifespan. Considerable research attention has been dedicated to understanding the causes and early emerging developmental profiles of different NDDs, but there is a striking paucity of research focused on disease progression through adulthood.FMR1), people with Down Syndrome, and individuals with Cerebral Palsy. Our goal is to heighten awareness of the unique and diverse needs of adults living with an NDD.These large gaps are particularly salient in the context of findings showing strong associations between NDDs and risks for both health issues tests. FMR1 premutations are associated with multiple subclinical and clinical issues during adulthood, including Fragile X-associated Tremor and Ataxia Syndrome (FXTAS), Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and Fragile X-associated Neuropsychiatric Disorder (FXAND) are now well-documented, so factors that can mitigate declines in cognitive and memory abilities are critical for slowing disease progression. Physical activity may be a feasible target for this purpose because it has been shown to be effective in improving memory function and lowering risk for dementia in neurotypical adults , Whitney et al. provided a prospective review assessing the extent to which well-established clinical measures predicting health outcomes for the general population may not apply to adults with Cerebral Palsy (CP). CP is associated with multiple disease-specific anatomical and physiological changes that confound clinical guidelines during translation. For example, lower body masses common to adults with CP lead to lower body mass index (BMI) scores despite high rates of obesity in this population. Bone mineral density (BMD) and glomerular filtration rate (GFR) are additional metrics useful for risk assessments of bone fracture and kidney dysfunction that may require separate consideration when interpreted with adults with CP. This prospective review emphasizes the need for differential interpretation of health metrics for adults with CP and other forms of NDDs. The authors also make the case that applying clinical standards to NDD populations requires integrating the unique characteristics of the individuals being evaluated.Articles in this Research Topic each highlight the urgent need for greater research attention on the unique needs and challenges of individuals with NDDs as they enter adulthood. As seen in childhood, outcomes associated with different NDDs show high levels of variability across individuals. Impairments caused by NDDs also appear to change significantly across the lifespan, indicating that new support strategies will be needed, and approaches for clinically monitoring individuals with NDDs as they age will need refinement. This refinement process should be based on rigorous and comprehensive studies of the natural history of different NDDs across the full lifespan, and the incorporation of measurements of the environmental and neurobiological factors that may affect individuals beyond childhood. We thank all authors for their significant contributions and reviewers for their constructive feedback. We hope that this Research Topic stimulates fruitful discussion and vigorous research to promote better understanding of and supports around aging-related changes in individuals with NDDs.ZW drafted the editorial. MM revised the editorial. All authors have made a direct contribution to the work and approved it for publication."} +{"text": "In response to the growing incidence of opioid dependence, guidelines have been created, and new treatments are being developed to assist physicians in treating dependence and withdrawal of opioids.To review treatment modalities and guidelines utilized in opioid dependence.Guidelines for the treatment of opioid dependence have been developed by organizations such as the American Society of Interventional Pain Physicians (ASIPP) and the American Psychiatric Association (APA). Current guidelines recommend comprehensive treatment with pharmacological agents such as methadone, buprenorphine, or buprenorphine combined with naloxone as well as psychosocial therapy. These guidelines stress the need for an integrated approach to treatment. Office-based opioid treatment is currently being utilized to treat opioid dependent patients in a physician's office setting with buprenorphine/naloxone replacement therapy as an alternative to entering patients into a methadone clinic. These office-based programs offer a breakthrough in access to care for dependent patients.Physicians need to be aware of and adhere to currently accepted guidelines and recommendations for treating opioid dependent patients, including integrating psychosocial treatments and behavior modification strategies for optimal results. Clinicians must be educated on the new treatment modalities and regulations surrounding the use of these therapies."} +{"text": "Sea level rise is expected to be rapid and extremely damaging to coastal communities and infrastructure, with unavoidable losses and coastal protection costs in the tens of billions per year. Retreat of the Thwaites and Pine Island Glaciers is likely already in an unstable regime as their oceanic fronts are ablated by deep intruding layers of relatively warm seawater. Warm water can be blocked from reaching the grounding line by thin flexible buoyant curtains anchored to the seabed. The consequent reduction in ice shelf melting could result in increased ice sheet buttressing as the shelf makes contact with seabed highs. Flexible curtains are less costly than solid artificial barriers, more robust against iceberg collisions, and easier to repair or remove in the event of unforeseen side effects. We illustrate the technical viability of this approach by considering curtain design concepts that should withstand oceanographic forces, and feasible methods of installation. Suitable materials are commonly available. Installation of a seabed curtain in temperate ocean waters would be entirely within the capabilities of existing offshore and deep ocean construction techniques. Installing in polar waters presents severe challenges from icebergs, harsh weather, and brief working seasons, which can however, be overcome with present-day technology. An 80\u2005km long curtain installed in 600\u2005m deep waters on alluvial sediments could help stabilize Pine Island and Thwaites glaciers over the next few centuries at much lower cost ($40\u201380 billion + $1\u20132 billion/yr maintenance) than the global coastline protection (\u223c$40 billion/yr) needed due to their collapse. Sea level rise is probably the single biggest impact of climate warming and difficult to prevent given the huge reservoir of heat in the global ocean. The largest concern for rapid sea level rise is the collapse of parts of the West Antarctic ice sheet where ocean melting has already destabilized the equivalent of a meter or more of global sea rise. We propose a system of flexible barriers to limit access of warm deep ocean currents that would allow the vulnerable ice shelves to thicken, reground, and buttress the inland ice. Despite the difficulties and risks resulting from severe ice conditions, these barriers could be installed with existing technology at lower cost, and better globally equity than coastal protection.Concern that a warming climate could destabilize the primarily marine-based West Antarctic Ice Sheet (WAIS) began in the 1970s . Under MOcean thermal forcing controls both the onset and the rate of MISI collapse and refe). ImportMethods of blocking warm water and increasing buttressing have been proposed , 17, howWe explore conceptual design and installation approaches at the scale of a large but achievable civil engineering project, with the potential to prevent, delay, or even gradually reverse marine ice sheet collapse of the Pine Island and Thwaites glaciers Fig. . We consWhile this preliminary analysis supports the basic feasibility of the concept, much further detailed study will be needed to investigate fluid-structural interactions and changes in ocean circulation and sea ice resulting from curtain deployment, in parallel with engineering design and development of installation techniques.Seabed anchored curtains will be buoyantly tensioned, flexible barriers to block the progress of deep warm water towards the grounding line. They will not provide any buttressing of ice fronts. The curtains are attached to the seabed and stretched upward in the water column by their own buoyancy Table of rubbeThe curtains include two main components: their foundation, and the curtain itself Fig. . The fouThe seabed curtain panels are designed to tilt and bend in response to changing ocean loads. As tides and currents change, the curtain will passively adjust its lean angle and curvature so that the horizontal forces dictated by oceanographic conditions are balanced by the vertical buoyancy force produced by the curtain itself. The curtains are flexible and will passively lean closer to the horizontal under heavier loads from stronger ocean currents or steeper density stratification, avoiding catastrophic failure. Higher loads would cause a gradual reduction in effectiveness as increasing volumes of warm water are mixed over the curtain, which can rebound when those loads are reduced. There must be enough buoyancy in the curtain to keep it sufficiently upright to effectively block enough warm water under realistic ranges of oceanographic loading. The vertical buoyancy force must thus support the typical oceanographic forces on the curtain at its target height above the seabed. Larger oceanographic forces would require increased curtain buoyancy to achieve a desired height, while increased buoyancy in turn requires greater curtain tensile strength and stronger foundations. The curtain panels must bend frontally under changing oceanographic loading and potentially, iceberg collisions, either by flexure or by mechanical hinges between the panels and the foundations Fig. C.The oceanographic forces on the curtain include differential hydrostatic pressure resulting from contrasting vertical density gradients on opposite sides of the curtain, and hydrodynamic drag resulting from fluid flow across or along the curtain. As the curtain will be resisting overflow from the deeper and higher density CDW ocean layer, the hydrostatic and hydrodynamic loads will both typically be directed towards the ice front across the curtain. Once the seabed anchored curtain has been installed, the vertical density contrasts and resulting hydrostatic loads are expected to increase due to freshening on the sheltered glacier side of the curtain. At the same time, hydrodynamic loads from flow across the curtain will be changed as reductions in the melt rate reduce the driving force for the overturning circulation in front of the glacier, and volumetric exchange flows would be reduced by curtain blocking action while local currents may be increased in the constricted aperture above the curtain. Thicker winter sea ice may also be expected because of reduced heat release from CDW import.The stratification between the cold meltwater-freshened surface layer and the deeper layer of relatively higher temperature and salinity leads to a pycnocline, typically 200\u2013300\u2005m thick Fig. . There wThe dominant flow pattern over the curtain will be the exchange flow between deeper seawater overflowing the curtain toward the glacier front, and an outward surface flow of lower density seawater freshened by meltwater and floating ice. This exchange flow is driven from the glacier side by the buoyant plume of subglacial drainage turbulently entraining seawater and meltwater from the glacier front, and from the continental shelf margin by variations in upwelling related to changing wind forcing and Ekman pumping. The exchange flow is resisted by form drag across seabed obstacles, seabed skin friction, shear friction between the exchange flow layers, wave drag from internal wave generation, and dissipation from turbulent mixing.The steady drag force across the curtain will largely result from flow separation on its lee side, with a minor contribution from skin friction on the curtain front. The drag force will be approximately quadratic with current velocity and linear with curtain height. This drag force is self-limiting for the following reasons: (1) while the drag varies quadratically with flow velocity, the volumetric flow itself is opposed and thus reduced by greater drag, (2) successful blocking of deeper warm water intrusion will reduce the volume of meltwater buoyantly forcing the exchange flow circulation, and (3) a curtain will reduce the density contrast driving the buoyant meltwater plume.\u22121 and mostly less than 20\u2005cm\u2005s\u22121 by such measures as (1) simply raising curtain height with more buoyant tensioning, (2) installing two parallel curtains approximately a Rossby radius (\u223c5\u2005km) apart, or (3) installing short \u201ctraining wall\u201d curtain segments orthogonal to the main curtain at suitable intervals to suppress eddy-generated tangential flows.Fluid-structural interactions will include multiple oscillatory and traveling wave modes, and possible resonant or chaotic instabilities. Excessive oscillations could cause progressive degradation by flexural fatigue, chafing damage between panels, and bearing wear. Such oscillations and consequent degradation modes may be mitigated by several possible strategies such as (1) adjusting panel tension by changing net buoyancy; (2) optimizing the vertical distribution of curtain buoyancy and the resulting curtain curvature; (3) adjusting panel flexural stiffness and/or damping; (4) rounding panel tops to delay hydrodynamic separation; (5) shaping panel tops with spoilers to disrupt vortex shedding; (6) adding slots near the top of the curtain for boundary layer control; (7) adding textured drag elements to the curtain to increase damping and added mass; and (8) configuring buoyancy elements at the top of the curtain to act as dynamic vibration absorbers .Curtain construction and changes to ocean circulation patterns will impact regional marine ecology, but these will also be impacted by dramatic retreat of the ice sheet. Although the objective is to maintain the ocean and glacier system at the status quo, the possible deployment will be governed by the Madrid Protocol (At this stage, engineering design concepts for subsea anchored curtains are insufficiently developed and too little is known about seabed conditions for total costs of fabrication and installation to be estimated with great confidence. However, hypothetical installation of structures similar to our seabed curtains in temperate ocean waters is within the capabilities of present offshore and deep ocean construction techniques. Pipelines are laid and heavy platform foundations are installed in much deeper water than here contemplated, while massive structures are routinely moved to or from the seabed. Complex tasks are performed by remote operated submersible vehicles. While surface and subsea research and reconnaissance missions are increasingly performed in arctic waters, the extension of full ocean engineering capabilities to the margins of the polar ice sheets will be very challenging. Specialized equipment including icebreakers with heavy lift and submersible deployment capabilities will be needed. Polar night, adverse weather and iceberg movements will disrupt work.\u00b0 S latitude (Fig. Simultaneous stabilization of both Thwaites and Pine Island Glaciers may be achieved by a long subsea curtain installation taking advantage of existing partial sills in Pine Island Bay, located either on a dissected ridge across the inner bay near the present ice shelf front, or in a mid-shelf location of Pine Island Trough at approximately 73ude Fig. \u2014and see ude Fig. .The seabed at the mid-shelf location is glacially sourced sedimentary deposits making for easier engineering design and installation than on the glacially carved bedrock of the inner bay route. Allowing for the costs of curtain and foundation materials, fabrication costs, the engineering and manufacturing costs of necessary specialized equipment, construction of icebreakers and robustly ice-reinforced heavy lift ships, seabed geotechnical investigations, seabed preparation using remotely operated subsea machinery, and installation of foundations and curtains during short and frequently interrupted working seasons, the decade of construction for a mid-shelf subsea curtain protecting both Pine Island and Thwaites Glaciers may cost $4\u20138 b/yr with ongoing maintenance in the range of US $1\u20132 b/yr . This reThere is a real risk of multi-meter sea level rises over the next few hundred years. The feasibility of coastal protection depends on individual country wealth and tends to be more expensive as a fraction of GDP for relatively poorer countries, meaning that inequalities are likely to be exacerbated by sea level rise . The DevWe recommend the seabed anchored curtain concept for high priority feasibility evaluation and development . The outUnlike rigid underwater barriers, curtain flexibility allows them to deform around impinging icebergs, and their modularity facilitates installation and maintenance. They can be installed using ballast controlled from the surface, and then unfolded once they are attached to the seabed. They can be removed if the intervention produces unanticipated side effects. Preliminary consideration of hydrostatic and hydrodynamic oceanographic loads indicates that simple curtain designs with available materials will be capable of providing the buoyancy and tensile strength necessary to withstand those loads. It will take considerable effort by the scientific and engineering communities to refine and demonstrate an implementable design. Without deep greenhouse gas emission cuts, it is probable that warming atmospheric temperatures would eventually destroy their effectiveness. The hundreds of years commitment to maintenance and long-term governance of sea level rise management means that governance, funding and social licence must go far beyond the 29 consultative parties to the Antarctic Treaty System .pgad053_Supplementary_DataClick here for additional data file."} +{"text": "It is wForest soil is an important living repository of biodiversity, with interactions between microorganisms, fauna, and plants providing multiple functioning and services to human health . Soil biForests distributed in the tropical and subtropical regions are highly concentrated habitats of the Earth\u2019s terrestrial biodiversity . However2Cunninghamia lanceolate plantation greatly increased the abundance of plant parasite nematodes, consequently threatening soil and plant health in subtropical China of soil organic matter were higher in the natural ecosystem than in the managed ecosystems in North Eastern India, indicating protecting natural ecosystems is very important to mitigate climate warming. Thirdly, natural forests exhibit higher water use efficiency and soil organic matter storage compared to planted forests . The conTherefore, it is generally believed that natural forests can assist to relieve the negative impact of global warming by conserving biodiversity, as well as supporting multiple ecosystem functions and services . In the 3Comparatively little is known about the responses of soil biodiversity, with most climate warming experiments concentrating on the aboveground ecosystems . Soil or13C isotope identification, and network analysis, have been increasingly applied for the characterization of the soil food web and biodiversity (This is a research area receiving little attention in forest ecosystems but could potentially have a tremendous impact on combating global warming in the future. However, disentangling soil food webs and biodiversity in the forest soil may be a daunting task, because of the enormous phylogenetic variety in the soil . Traditiiversity .4Overall, to mitigate the adverse impacts of global warming on soil biodiversity, we urge the restoration community, forestry specialists, and legislators to emphasize natural forest regeneration over various tree-planting approaches, thus maintaining soil biodiversity and improving multiple ecosystem functions. Additionally, we call for new theories and technologies to preserve soil biodiversity based on the soil food web to combat global warming in the future. This perspective will emphasize the necessity of strengthening natural regeneration rather than planted forests for maintaining soil biodiversity and ecosystem functioning.JW contributed ideas to the study and drafted the manuscript. XS contributed ideas to the study and improved the draft. All authors contributed to the article and approved the submitted version."} +{"text": "Using recent nationally representative survey data from New Zealand, multivariate regression models estimate the effects of reading engagement on earnings, health, social trust, political efficacy and civic engagement. Reading engagement has statistical and substantial positive effects on each of these outcomes with the effects of literacy proficiency, education and other important variables held constant. Although these results do not imply a causal relationship between reading engagement and the outcomes, they have important implications for policy and practice in adult education as well as for future research about the role of reading engagement in wellbeing more generally.Education and literacy have long been associated with a range of economic and social outcomes in industrialized societies. Recent research based on large-scale national and international surveys has examined effects of education and literacy on individuals\u2019 social and economic outcomes. This paper takes a further step in understanding the importance of literacy for individuals\u2019 economic and social outcomes by disentangling the effects of two different aspects of literacy, This paper examines the role of literacy in individual wellbeing using data from New Zealand\u2019s 2014 Programme for the International Assessment of Adult Competencies (PIAAC) survey. Although there are many possible indicators of individual wellbeing, two variables measured in PIAAC\u2013earnings and overall health status\u2013are widely accepted wellbeing indicators and are core elements of the Organisation for Economic Cooperation and Development (OECD) global Better Life Index )Although the increases across levels of reading engagement are statistically significant for both the earnings and social outcomes, they are relatively modest for the social outcomes. The regression-adjusted percentage of adults reporting a high health status increases from 51% among adults in the lowest quintile of life-wide reading engagement up to 62% among those in the highest quintile; the corresponding increases for social trust are from 20% to 27%; for political efficacy from 36% to 45%; and for civic engagement from 15% to 18%. For each of these social outcomes, the increases seen across levels of life-wide reading engagement are evident across only the lower quintiles of the reading engagement scale, in contrast with the substantial earnings gains evident across the entire scale of reading engagement at work.The significant effects of reading engagement found in the cross-sectional models of earnings and social outcomes do not, of course, imply causal relationships between reading engagement and those outcomes. Additional research is needed to identify causal mechanisms that may underlie the relationships observed here, including instrumental variable models of cross-sectional data and panel models of longitudinally measured outcomes. As noted before, previous research has found literacy to have a causal relationship with both earnings and health status, suggesting that both literacy proficiency and reading engagement may have such causal relationships as well. Previous research has not yet identified causal relationships between literacy and the other social outcomes examined in this paper.A second important limitation is encountered in trying to interpret the robust and substantial effects of reading engagement at work on monthly earnings. As measured in PIAAC, reading engagement at work is an attribute of the job as well as of the individual who performs the job. In contrast with literacy proficiency, which is conceptualized as an attribute of the individual that moves from job to job (context to context), reading engagement at work is shaped by the design, requirements and affordances of the job and workplace. Research is needed that compares the earnings of workers holding a given job who use different levels of reading engagement in performing their work. Multi-level surveys\u2014in which both firms and jobs are sampled and employees are sampled within those firms and jobs\u2013would be a promising source of needed data.Subject to these limitations, the findings in this paper have important implications for programmes, policy and future research. The findings, considered in the context of previous research, suggest that effective adult literacy programmes may not only improve adults\u2019 literacy abilities, they may help improve key economic and social dimensions of their lives as well. Strong quasi-experimental comparisons of high school dropouts in the United States who participate or do not participate in adult literacy programmes found that participation leads to substantial gains in long-term earnings and other outcomes . The CanFor many adults, reading engagement is more malleable across the lifespan than either literacy proficiency or educational attainment , 31, 49.Instructional interventions might be designed to increase reading engagement directly rather than literacy proficiency. Such practice-centred instruction has long been considered a promising approach to adult literacy education in numerous countries . The preThe findings of this study also suggest that initiatives and programmes that connect reading engagement with political efficacy and civic participation may increase both reading engagement and these social outcomes. Contextualising reading engagement in programmes fostering political efficacy and civic engagement\u2013a cornerstone of Freire-inspired pedagogies\u2014has a long tradition in adult education around the world. The findings also have implications for education, training and wellbeing policy in New Zealand. The goals and designs of adult literacy programmes and interventions should be formulated in terms of both literacy proficiency and reading engagement. Given the increasing evidence for PET, programme evaluations should measure shorter-term impacts on reading engagement and longer-term impacts on literacy proficiency. This may help policymakers recognize the importance of complex skill formation processes underlying wellbeing frameworks and funding priorities, as called for by Cochrane and colleagues . As evidFurther research is needed to better understand and address the ubiquitous effects of gender observed in these economic and social outcomes. As widely found in previous research, fulltime female workers experience substantial earnings penalties in the current study even with controls for work experience, education, literacy and other variables. At the same time, women appear to attain better social outcomes than men with these variables controlled.In addition to exploring interventions that foster reading engagement, several lines of additional research will enhance our understanding of how practice engagement is related to social and economic outcomes. Linkages available between New Zealand\u2019s PIAAC data and its national administrative database, the Integrated Data Infrastructure, may provide an opportunity to identify causal relationships between reading engagement and longitudinal earnings and health data . InterveIn addition to reading engagement, the PIAAC data include information about adults\u2019 engagement in writing, maths and ICT practices. Engagement in these additional types of practices may also have important effects on social and economic outcomes. Examining the effects of these practice engagement measures on wellbeing outcomes will be useful, both in cross-sectional analyses and in potential longitudinal studies within the Integrated Data Infrastructure.This study contributes to the literature on the relationship between cognitive skills and wellbeing, focusing on the relationship between literacy and adults\u2019 economic and social outcomes as measured in New Zealand\u2019s PIAAC survey. The study adds to the literature by showing that two distinct aspects of literacy\u2013literacy proficiency and reading engagement\u2013are positively associated with monthly earnings, general health status, social trust, political efficacy and civic engagement. These associations remain statistically significant after controlling for other variables including education, work experience, age, gender, ethnicity, native language and birthplace.These observed associations do not imply causal relationships between literacy and the outcomes. When considered in relation to other research, the findings suggest that both literacy proficiency and reading engagement are likely social determinants of earnings, general health status and possibly the other social outcomes examined here. Further research is needed to confirm the causality and mechanisms underlying the observed relationships between reading engagement and these economic and social dimensions of wellbeing.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file."} +{"text": "Central hypovolemia is accompanied by hemodynamic compensatory responses. Understanding the complex systemic compensatory responses to altered hemodynamic patterns during conditions of central hypovolemia\u2014as induced by standing up and/or lower body negative pressure (LBNP)\u2014in humans are important. LBNP has been widely used to understand the integrated physiological responses, which occur during sit to stand tests (orthostasis), different levels of hemorrhages (different levels of LBNP simulate different amount of blood loss) as well as a countermeasure against the cephalad fluid shifts which are seen during spaceflight. Additionally, LBNP application is useful in understanding the physiology of orthostatic intolerance. The role seasonal variations in hormonal, autonomic and circulatory state play in LBNP-induced hemodynamic responses and LBNP tolerance as well as sex-based differences during central hypovolemia and the adaptations to exercise training have been investigated using LBNP. The data generated from LBNP studies have been useful in developing better models for prediction of orthostatic tolerance and/or for developing countermeasures. This review examines how LBNP application influences coagulatory parameters and outlines the effects of temperature changes on LBNP responses. Finally, the review outlines how LBNP can be used as innovative teaching tool and for developing research capacities and interests of medical students and students from other disciplines such as mathematics and computational biology. We subject our body to orthostatic challenge every time we stand up , following aspects must be considered when applying LBNP:Depending on the magnitude of suction, LBNP induced vascular pooling in the legs leads to decreases in venous return, central venous pressure, and stroke volume Baisch . The onsLBNP also causes an increase in total peripheral resistance; this is dependent on the magnitude of LBNP applied. Low levels of LBNP cause increases in sympathetic tone leading to vasoconstriction in the forearm and in the splanchnic area , environmental conditions , and in-laboratory conditions should be considered.As changes in environmental temperature lead to changes in the generalized systemic responses, it is not surprising that LBNP tolerance is influenced by changes in temperature. Just as greater incidence of collapse and syncope during the hot seasons is reported , conducting, implementing and interpreting experimental data.LBNP induces responses , which vary widely across persons. When carrying out LBNP studies, confounding variables such as selection criteria, LBNP protocol to be used and the laboratory- and environmental\u2014conditions should be carefully accounted for. The call out box summarizes the potential changes in coagulation that could occur during LBNP as well as how temperature changes during LBNP application influence the physiological responses."} +{"text": "Climate change threatens the health of all Australians: without adaptation, many areas may become unlivable, in particular the tropical north. The Northern Territory (NT) health workforce is already under colliding operational pressures worsened by extreme weather events, regional staff shortages and infrastructure that is poorly adapted to climate change. The H3 Project explores nature-based interventions in the NT health sector aiming to strengthen the resilience and responsiveness of health infrastructure and workforce in our climate-altered future. The H3 Project engaged the health workforce, climate researchers and the wider community, in recognition that meaningful and timely climate action requires both organization-led and grassroots engagement. We recruited campus greening volunteers and sustainability champions to Royal Darwin Hospital (RDH) to develop strategies that enhance climate adaptation, build climate and health literacy, and incentivize active mobility. We implemented low-cost biophilic design within the constraints of legacy healthcare infrastructure, creating cool and restorative outdoor spaces to mitigate the impacts of heat on RDH campus users and adapt to projected warming. This case study demonstrated substantial cooling impacts and improved local biodiversity and hospital campus aesthetics. We collaborated with Indigenous healers and plant experts to harness the synergy between Aboriginal people\u2019s traditional knowledge and connectedness to land and the modern concept of biophilic design, while seeking to improve hospital outcomes for Indigenous patients who are both disconnected from their homelands and disproportionately represented in NT hospitals. Australia faces widespread impacts from climate change. The frequency and intensity of heatwaves, flooding and other extreme weather events is increasing, posing acute and compounding risks to human health in the foreseeable future . The NorChronic exposure to heat, humidity and seasonally poor air quality has well-known impacts on population health, contributing to cardiovascular deaths, some cancers, respiratory illness and mental health problems ,6. TheseThe H3 Project was initiated by members of NT Health\u2019s Sustainable Healthcare Committee in September 2021 in response to the exhaustion and low morale of front-line healthcare workers that stemmed from a prolonged COVID-19 response, staffing shortages, hospital overcrowding and workplace aggression. The period was marked by a rise in patient complaints and critical incidents which included numerous episodes of emergency department nursing staff being assaulted while providing care. Patient complaint themes included long wait times and a lack of privacy imposed by \u201cdouble bunking\u201d in cubicles .At this time, it was observed that the Royal Darwin Hospital (RDH) precinct was failing to provide the hospital campus users with restorative and climate-resilient green spaces to recover from these challenges, particularly for Indigenous patients who preferred to be outdoors. The precinct was prone to the urban heat island effect due to a paucity of tree canopies and an abundance of paved terrain , resultiThe RDH campus is predominately occupied by buildings and carparks, which results in warmer surface temperatures than the natural landscapes within the adjacent Casuarina Coastal Reserve. This results in a greater risk of heat stress, particularly for the vulnerable population groups that commonly frequent hospital campuses . Figure The expansive car parking at RDH reflects the dominant culture of motor vehicle commuting to work, with 74% of workers commuting by car and more than 60% of commutes being 10 km or less . In contThe H3 Project\u2019s launch coincided with significant national debate about lagging Australian efforts to mitigate the health sector\u2019s own contribution to environmental pollution and its carbon footprint, which is estimated to be 7% of total national emissions ,28. AustRDH is the largest of the NT\u2019s five hospitals, providing direct services to the Top End Region, and a tertiary referral service for the remaining regions and the remote Kimberley region of Western Australia. First Nations people comprise 30% of the NT population yet constitute 70% of hospital inpatients , a trendSeventy-five percent of Indigenous Territorians live in remote and very remote communities and continue to engage in traditional healing practices including the use of bush medicines . These pAn attempt in 2017 to develop an Indigenous healing garden to improve Indigenous cultural safety at RDH was unable to reach its potential due to underfunding, attrition of project champions and issues with site accessibility ,38. The aim of this paper is to outline specific efforts undertaken to create climate-resilient, culturally safe spaces for staff and patients at RDH and to examine how successful responses have been developed through a staff-led process.This case-study focused on grassroots sustainable healthcare initiatives and volunteer-led campus greening at Royal Darwin Hospital in the Northern Territory of Australia. Volunteer participation was essential to mobilize the hospital workforce at a time of fiscal austerity, while alleviating climate anxiety in the workforce and community members by creating opportunities for local climate action.Phase 1 launched volunteer working bees within 2 months, targeting some zones accessible to all campus users and others used predominantly by hospital staff. We launched a volunteer recruitment and literacy-building program, consisting of internal staff communications and a social media presence to reach the precinct\u2019s multi-agency staff and the wider community. We commenced design of a sustainable healthcare intranet site intended to communicate progress and build engagement in future sustainability initiatives. Phase 2 and 3 consolidated and expanded the vegetation planting zones over the subsequent twelve months, accompanied by further efforts to recruit volunteers and engage health executives. We co-hosted a \u201cChalk the Campus\u201d heat mapping event with the Darwin Living Lab on 26 May 2022. Over twenty participants representing a diverse range of staff and visitors were led on a 1-h tour of the precinct\u2019s main walking routes and were asked to identify heat-prone areas and share their perception of how heat affects their activities and their health while using these areas. Participants marked these \u201chot spots\u201d on maps and on the pavement, then outlined the cooling interventions that they believed should be applied in these locations. We launched a synergistic active mobility campaign, scheduled for the cooler dry season to maximize participation. Multi-agency staff and medical students were targeted, highlighting the environmental and wellness-promoting benefits of cycling to work, and of spending time and volunteering in the project\u2019s nascent green spaces. Surface temperatures have been widely accepted as an indicator of urban heat across different land surfaces . HoweverThe relative cooling impacts of the greening interventions were assessed with land surface temperature measurements using a thermal imaging camera that also recorded image geolocation and orientation. Microclimate monitoring was also undertaken using the Scarlet TWL-1S heat stress meter . This device measured air temperature, relative humidity, radiant temperature and wind speed, and calculated wet-bulb globe temperature as an indicator of heat stress conditions. Prior to planting, we performed two sets of baseline surface temperature measurements , the firFollow-up measurements were taken in Planting Zones 2 and 14 to determine the effect of planting in reducing land surface temperature and heat stress as the trees established. Biodiversity impacts were documented by conducting bird surveys on the hospital campus, including in the vicinity of a significant banyan tree that had been scheduled for removal. Volunteer bird enthusiasts used a Google Drive document to record data from five biodiversity surveys which they conducted between April and November 2022. Personal correspondence detailing native bird sightings in other locations on campus were also included. We also collated the number and variety of native plant species that were introduced to the campus during the project and the plant death rate eighteen months after the start of planting. Qualitative data on perceived wellbeing and engagement impacts were informally gathered by collating personal correspondence and social media posts from volunteers, health workers, patients and the community. Formal data collection was outside the project\u2019s resource capabilities.Vegetation planting zones are shown in Eucalyptus miniata) and many species of grevillea which produce nectar-rich flowers and hollows to support native bees which in turn are key plant pollinators and food species for other native animals [Croton habrophyllus) and the Atlas moth plant (Pittosporum moluccanum) [We postulated that replanting predominantly regional native plants would have numerous ecological, therapeutic and spiritual benefits. \u201cTop End\u201d plantings would pay homage to the original flora that had been cleared during colonization, be most likely to thrive in the soil and microclimates of the site and would best encourage the return of native fauna through the replanting of suitable food plants and habitat. Examples include the Darwin woollybutt . A varieErythrophleum chlorostachys), or \u201cMindilima\u201d in the Larrakia language, owing to its foundational role in smoking ceremonies. When burned during the iconic Larrakia \u201cWelcome to Country\u201d ceremony, ironwood leaves emit a fragrant smoke that is believed to impart cleansing, protective and healing effects on participants as they walk through or waft the smoke about their bodies. We argue that offering our Indigenous inpatients\u201470% of all inpatients\u2014greater opportunities to participate in smoking ceremonies and other complementary traditional healing practices may enhance the cultural safety of healthcare at RDH.We consulted with Senior Larrakia Elders who endorsed the project\u2019s merit in seeking to enhance Indigenous health outcomes and wellbeing. They provided ethnobotanical expertise including a list of thirty-eight native Australian plants which were favored as bush foods and those associated with an ongoing practice of Larrakia ceremony and traditional healing. Of note was their recommendation to include ironwood which had been scheduled for removal northwest of Planting Zone 7, at the site of the hospital\u2019s new mental health development in Planting Zone 6 and on a cycle path in close proximity to Planting Zone 8 [Sightings of eleven Australian native bird species were documented at the site of this banyan tree during five separate surveys that werg Zone 8 ,50. At the time of writing, more than 260 individuals have joined the RDH Campus Greening Volunteers social media group . MembersFeedback universally expressed gratitude, encouragement and congratulations for improving the physical conditions and aesthetics of the campus . Many stTwenty-four \u201cworking bees\u201d were held over the first fourteen months of operation and were attended by between five and thirty volunteers, who were aged between three and sixty-five years old. Since the start of the project, many individuals, local businesses and non-government organizations have offered their support. These have included donations of seeds, mulch and plants, funding for planting activities in Zones 12 and 13 and notification of the availability of community grants. Participants and contributors emerged following promotion of the project though internal hospital channels, mainstream media reports and presentations at national climate health forums. The appearance of executive staff members and ministers at working bees is also likely to have stimulated interest. The \u201cChalk the Campus\u201d event played a key role in building engagement in the workforce, executives of the precinct\u2019s multiple agencies and in the community . A diverOur campaign to conserve the established banyan tree elevated discourse regarding the interconnected priorities of cultural safety, wellness-promotion through biophilic design and biodiversity preservation amongst stakeholders for health infrastructure design. There is ongoing discourse with the NT Department of Infrastructure to improve active mobility infrastructure on the health campus ,60.The H3 Project spearheaded the successful campaign to recruit the Northern Territory\u2019s first Director of Sustainability Action. By the time of writing, the newly appointed executive had commenced mapping grassroots initiatives, recruiting additional sustainability officers and drafting a roadmap for environmental sustainability within NT Health. Hospital operations managers have modified their teams\u2019 work plans to support the project. A greenhouse project has also been established at RDH to facilitate propagation activities on-site.Areas frequented by staff, patients and visitors were successfully planted, including active mobility thoroughfares, gathering places and highly industrialized zones where non-clinical support staff perform manual work outdoors. The outdoor seating infrastructure that was installed in the shade of Planting Zones 3 and 15 continues to generate positive feedback and is being utilized regularly by staff. Staff feedback obtained during the \u201cChalk the Campus\u201c heat-mapping workshop allowed \u201chot-spots\u201d to be specifically identified and targeted. Participants represented the major healthcare, research and educational institutions operating on campus. Hibiscus sabdariffa) and passion fruit (Passiflora edulis) which have been interplanted in several zones. Crop gathering encourages hands-on interaction with the green spaces while the self-sowing rosella species will provide sustainable harvests in the future.Staff and visitors have enjoyed multiple harvests of edible rosella flowers (Syzygium suborbiculare) was a strong favorite for the Larrakia, West Arnhem and Tiwi Islander peoples we interviewed. We included a pink cultivar of S. suborbiculare which is endemic to the Tiwi Islands and prized for its unique taste. Other popular requests included green plum (Buchanania obovata), billy goat plum and \u201can-binik\u201d (Allosyncarpia ternata). The distinctive boab (Adansonia gregorii) was planted to acknowledge Indigenous patients from remote areas of the Northern Territory and Western Australia who also receive care at RDH. Importantly, five specimens of ironwood (Erythrophleum chlorostachys) are now growing on campus whose leaves will be harvested for on-site Larrakia smoking ceremonies. We have successfully planted seventeen of the thirty-eight species and region-specific cultivars that were recommended by our Larrakia plant experts and Indigenous consumers. Red bush apple featured comprehensive shade infrastructure and green spaces via a network of external and courtyard gardens. Tree canopies reflect and absorb solar radiation, which reduces the absorption and re-emittance of heat from surfaces such as roads and footpaths. The inclusion of well-irrigated green spaces can also provide cooling benefit through evapotranspiration . The cooIn addition to cooling healthcare precincts, the broader restorative benefits of green spaces have become well established in recent decades ,68. One Responding to warming predictions by simply providing access to more airconditioned refuges is inconsistent with emissions reduction, unless it is powered with renewable energy. It is also impractical due to prohibitive capital and operating costs and the potential return of social distancing restrictions in the future .With the scientific evidence for global warming accumulating , the disThe H3 Project identified the omission of the RDH campus from two major climate adaptation strategies that sought to improve resilience to the impacts of climate change in the region ,78. DespInvestment in healthcare green spaces can offer significant protection from the current heat stresses that prevail in the Australian tropics and is paramount given the extreme warming predictions for the region . ClimateFirst coined by Fromm in the 1960\u2019s, biophilia is the innate human instinct to connect with nature and other living beings . The conResearch in the past decade compels the health sector to implement biophilic design from staff, patient and organizational perspectives. Observed patient benefits include reduction in blood pressure, post-surgical recovery time and the need for pain medication, while improving mood and satisfaction with health services . EmerginImportantly, biophilic encounters in the healthcare setting are most restorative when they assist individuals to contemplate the existence of a reciprocal, nurturing relationship with nature . These eThe native landscapes developed by this project satisfy the conditions that may trigger this contemplation of nature. These include offering a spectrum of visual and non-visual stimuli, a variety of far and near visual perspectives and both ordered and complex stimuli . NotableWorking in healthcare is inherently stressful, with one pre-pandemic study revealing 40% of staff had felt unwell as a result of work-related stress within the previous 12 months . The samHealthcare staff also desire access to green spaces that are reserved solely for their use, where they can be assured of being \u201coff the clock\u201d and out of the eye of patients and carers . LocatioAccessibility for sight- and mobility-impaired users should also be considered, as well as infrastructure that promotes security and safety. Our project sought to overcome local barriers to accessing healthcare green spaces. Champion- and consumer-led assessment of hot spots, focusing on active mobility thoroughfares and consideration of typical staff, patient and visitor journeys at RDH resulted in site selection that maximized opportunities for biophilic encounters. On a basic level, our greening interventions improved the amenity of a health campus that was impacted by weeds, soil erosion and lack of irrigation. Importantly, healthcare staff and the community were encouraged to participate in local land care activities whose known social, cultural and learning benefits are summarized in Ficus virens [The project\u2019s early biodiversity impacts are worth highlighting. Enthusiastic social media posts, participation in bird surveys and reports of Gouldian finch sightings point to strong community and health workforce interest in implementing conservation activities on the RDH health campus. The results of our biodiversity survey and the Indigenous cultural significance of s virens were keyThe H3 Project continues to consult with Larrakia Elders who represent the traditional custodians of the land on which RDH stands. We noted that older campus plantings consisted mostly of exotic ornamental species which provided no link to Indigenous culture and were unsuccessful due to improper species selection, pest incursion and unmet demands for water and maintenance. This partnership identified native plant species that are favored by the Larrakia people, such as bush foods, and for traditional healing and ceremony. We showcased ironwood due to its foundational role in smoking ceremonies. Offering our Indigenous inpatients\u201470% of all inpatients\u2014greater opportunities to participate in smoking ceremonies and other complementary traditional healing practices will enhance the delivery of culturally safe healthcare. The RDH also treats patients from many distinct Indigenous groups across the NT as well as the Kimberley region of Western Australia. A concerted effort was made to plant native species from these areas wherever permitted by the climate and soil conditions of the campus. Informal feedback from Indigenous patients and their escorts supported the planting of familiar and regionally specific species to help provide a connection to Country during prolonged separations. Our project\u2019s scope includes the curation of online resources and physical signage to highlight the Larrakia names and traditional uses of significant species. This component aims to promote awareness and respect for Indigenous culture in staff, patients and visitors. In turn, it makes the health campus more welcoming to Indigenous people.After fourteen months of operation, only preliminary heat mapping and qualitative wellbeing impact data have been obtained. Several years\u2019 vegetation growth and dedicated research funding is required for the cooling, aesthetic and wellbeing impacts to be fully evaluated. Similarly, the biodiversity impacts of the project to date are qualitatively assessed and likely to be underestimated. While the H3 Project achieved a significant visual transformation of the RDH campus, any further expansions and nurturing of existing plants to maturity requires dedicated funding and support from an employed workforce.We plan to install a weather station on RDH campus to facilitate ongoing data collection for heat stress measurements, which will provide reference points for localized climatic conditions. We intend to install additional seating, drinking water outlets and campaign for the installation of additional shade infrastructure in areas regarded as \u201chot spots\u201d by participants in the Chalk the Campus event. We are exploring mobile application-based interactivity for campus users to foster relatedness to nature.Further plantings are being planned in the Indigenous accommodation precinct of RDH to improve thermal comfort and offer a \u201cconnection to Country\u201d during prolonged separations. We plan to install ethnobotanical signage and establish a series of walking paths that will be promoted to staff and patients as \u201cnature prescriptions\u201d. We are looking for opportunities to collaborate with Larrakia ethnobotanists to conduct harvesting activities and eco-cultural tours. As plants mature, we intend to facilitate regular practice of on-site Indigenous ceremony and traditional healing. It will be vital to seek ongoing feedback on the wellbeing impacts of these curated landscapes on First Nations people and quantify any effect on the rates of leaving hospital before treatment is complete. We intend to facilitate engagement of healthcare workers with a volunteer land care group that operates in the coastal reserve adjacent to the RDH campus. This may encourage recruitment to local land care efforts while offering health workers opportunities to combat eco-anxiety and environmental generational amnesia.Quantitatively assessing the full health, environmental and economic benefits of this case-study would assist health services to further understand and rationalize investment in similar projects in the NT and other jurisdictions.Health campuses have the potential to alleviate the hardship of delivering and receiving care in the face of colliding operational and climatic pressures. Biophilic design offers low-cost adaptation of legacy health infrastructure to climate change that promotes biodiversity, wellbeing and a relationship of reciprocal nurturing between campus users and the environment.This case study set in the harsh climatic environment of the Northern Territory provides a platform for improving cultural safety and hospital health outcomes for First Nations Australians, while promoting Indigenous knowledge and leadership in climate adaptation and mitigation efforts in the healthcare system."} +{"text": "Objectives: We noted moisture in Thompson retractor sets after steam sterilization in our hospital. Moisture can cause severe problems leading to potentially contaminated instruments that carry infection risk to patients and cause procedure delays, wasted time and effort, greater workload, and higher costs. We sought to reduce the number of retractor sets with moisture to zero. Methods: The central sterile supply (CSS) team discussed the cause of the problem. We hypothesized that temperature difference between the sterilizer chamber and inside the container might create condensation and thus moisture in the final surgical set. We collected and analyzed data and proposed an experiment to improve the sterilization process. We performed a trial of sterilization process improvements pertaining to proper loading technique and the packaging process. We also evaluated the appropriate drying time for rigid containers. We then rearranged the process and adjusted the cooling time from 30 to 60 minutes after steaming. Results: Moisture in Thompson retractor packs occurred because of thicker, rigid containers. We removed the previous type of lining material to separately steam the rigid surgical instrument, and we extended the cooling time to 60 minutes. We updated standard operation procedures and continued to monitor and re-evaluate the process. Conclusions: We identified the primary cause of moisture in Thompson retractor sets after steam sterilization. We illustrated that avoiding sterilizer overload, avoiding contact with fabric wrapping materials, and proper cooling time kept the pack moisture free. Occurrences of moisture in surgical packs after sterilization should be reported and handled efficiently by CSS personnel to preserve quality and avoid waste."} +{"text": "I was fortunate to meet Professor Herman Paul Schwan a couple of times. Unforgettable scenes took place during the X ICEBI, held in Barcelona back in April 1998. At the end of most presentations, in a gentle and elegant manner, Professor Schwan used to highlight that similar studies (mostly more advanced ones!) were previously performed by himself together with other emblematic figures of the field. Hence gaining new insights into an electrical bioimpedance (EB) topic appears highly challenging if not erroneous.However, recent technological advancements concerning both instrumentation and data analysis as well as combining EB with other methods led to sensitive quantitative tools to assess bacteria, and the related antimicrobial susceptibility testing (AST), bringing the topic of Rapid Assessment of Pathogenic Bacteria back into a well-deserved spotlight.th Century [The first electrical impedance assay to assess microorganism growth was described at the end of the 19Since electrical assays lack specificity, EB microbial assessments are generally affected by low throughput, lengthy assays, have to be performed on previously isolated cultures or in conjunction with a method allowing target microbe separation from the sample. High-throughput, automation and specificity are nowadays enabled via immunomagnetic capturing and combination with magnetophoresis and microfluidics.Microbial identification, and quantitation as well as rapid AST can be achieved based on EB in conjunction with periodic magnetophoresis, as reported by my group ,3. MicroEB measurements are simultaneously performed at two radiofrequencies chosen to assess the impedance decrement (related to the beta dispersion) of magnetically tagged live microbes to derive the electrical opacity of the specimen as the ratio of impedance amplitude at the higher versus the one at lower frequency .EB monitoring of the AMbMs periodic magnetophoresis between two electrodes allows quantitative assessment of microbial load (quantitation) since microbial load relates to the weight of the electrode coverage by AMbMs .Bacterial viability is revealed by electrical opacity of the magnetically tagged microbes (membrane integrity is a marker of cell viability). Since susceptibility/resistance to bactericidal antimicrobials directly relates to microbial viability, EB provides an effective tool for cost effective AST assays.Besides the suitability to multiplexing, allowing AST of various antimicrobials be performed in parallel, such assays allow for rapid measurements since a relevant amount of magnetically trapped microbial cells could be simultaneously analyzed.Examples based on microfluidic impedance cytometry were recently reported by Hywel\u2019s group in whichWhile the whole bacterial population can be addressed at once, single cell EB analysis cannot be attained due to the limited spatial resolution of the electrical assays, inherently linked to the electrode size.Thus, another game changer is provided by combining EB and optical methods e.g., by AC electrically modulated light microscopy assays, as the ones highlighted by recent reports ,6.These approaches empower EB assays with the spatial resolution needed to allow single cell analysis without the limitations related to electrode size and microelectrode arrays dimensionality. Single-cell resolution is currently limited to analysis of cells adhered to the sensing electrode, yet access to (the dynamics of) of both electrical and the complementary optical parameters of cellular structures is expected to provide new insights into living cell machinery. These advancements are expected to open up renewed challenges to Electrical Bioimpedance supporting countless applications of Rapid Assessment of Pathogenic Bacteria, so exciting to witness and contribute to."} +{"text": "Introduction: As demand for healthcare continues to grow, public health systems are increasingly required to drive efficiency improvement (EI) to address public service funding challenges. Despite this requirement, evidence of EI strategies that have been successful applied at the whole-of-system level is limited. This study reports the development, implementation and evaluation of a novel taxonomy of EI strategies used in public health systems to inform systemwide EI models. Materials and methods: The public health system in New South Wales, Australia, operates a centralised EI model statewide and was the setting for this study. An audit of EI strategies implemented in the NSW Health system between July 2016 and June 2019 was used to identify all available EI strategies within the study timeframe. A content management approach was applied to audit the strategies, with each strategy coded to an EI focus area. Codes were clustered according to similarity, and category names were assigned to each cluster to form a preliminary taxonomy. Each category was defined and examples were provided. The resulting taxonomy was distributed and evaluated by user feedback survey and pre\u2013post study to assess the impact on EI strategy distribution. Results: A total of 1127 EI strategies were identified and coded into 263 unique strategies, which were clustered into nine categories to form the taxonomy of EI strategies. Categories included the following: non-clinical contracts and supplies; avoided and preventable activity; clinical service delivery and patient outcomes; finance and operations; recruitment, vacancies and FTE; staffing models; leave management; staff engagement and development; premium staffing; and clinical contracts and supplies. Evaluative findings revealed a perceived reduction in the duplication of EI work, improved access to EI knowledge and improved engagement with EI processes when using the taxonomy. The taxonomy was also associated with wider use of EI strategies. Conclusions: Whole-of-system EI is an increasing requirement. Using a taxonomy to guide systemwide practice appears to be advanta-geous in reducing duplication and guiding practice, with implications for use in health systems internationally. Despite great focus on efficiency improvement (EI) in public health systems, there has been a lack of focus on establishing processes to support EI at a whole-of-system level internationally . A generKnowledge in the context of organisations is defined as information which adds value, supports decision-making or is useful in delivering outcomes ,5. A knoA taxonomy represents a solution for providing structure for reporting and sharing unstructured data elements by organising them into categories which are closely related according to their requirements, purpose and/or focus area ,8. This In the current environment of ongoing increases in demand for healthcare amidst ongoing economic uncertainty, the increasing requirement for public health systems to maximise service outcomes achieved for resource investment is likely to persist. A gap in the literature exists regarding the design and delivery of centralised EI models, with a review of the recent literature noting a lack of comprehensive frameworks for driving EI at the whole-of-system level . This stThis study is set in New South Wales (NSW), a large Australian state with its own public health system, NSW Health. This system operates a systemwide EI model coordinated by a central program management office. The presence of this centralised approach in NSW is the rationale for selecting this setting. Through this model, each NSW Health service is required to achieve a mandated EI target each financial year by delivering EI strategies, with the EI strategy plans held and monitored by the central office in a database. These strategies aim to reduce the cost of delivering services while also improving or maintaining quality and experience outcomes, supporting public health organisations to meet service demand within allocated budgets and maximise outcomes achieved for resources invested . Common A taxonomy development process was undertaken following an established intuitive content management approach to audit and form clusters of similar EI strategies ,15.The EI strategy database held by the NSW Health central EI office as outlined in the setting for this study was the source of data, making this study an audit of explicit knowledge as the study material existed in electronic format as formally documented information . As thisTo be eligible for inclusion, EI strategies must have been undertaken within the most recent three Australian financial years and held in the central NSW Health EI database. Only strategies which proceeded to implementation were included in this study, but the performance of these strategies is beyond the scope of this study.To undertake the audit, data were extracted from each eligible EI strategy in the database, including financial year, the NSW Health organisation in which the improvement initiative was implemented, objectives, key metrics and financial assumptions. For each EI strategy, a one-sentence summary of the specific improvement focus area was derived to serve as a code for further analysis in alignment with content management methodology . The metIn order to develop the EI taxonomy, the corresponding author systematically examined all one-sentence summary codes developed during the audit, clustering codes together in categories according to common areas of improvement focus using a content management approach ,15. WherAn inductive method was applied to guide the categorisation process, with the units of analysis being the codes created through the knowledge audit procedure . For eacThe taxonomy was used to create a resource document to serve as a user guide for NSW Health EI stakeholders for the purpose of summarising and distributing EI knowledge across NSW Health.Using the structure provided by the taxonomy categories, the EI strategy codes and performance measurement metrics for each unique EI strategy were listed to create a resource document which summarised the collective body of EI strategic knowledge from the sample data. Due to the clustering approach that was taken for classification, with all EI strategies grouped together underneath their respective taxonomy labels with duplicates removed, the structure for this resource was readily apparent and was set out according to the categories constructed during taxonomy development . The resDesign: Following two and a half years of EI resource use, in March 2022, the impact of the EI resource was evaluated via a mixed-methods approach synthesising qualitative and quantitative data.A series of free-text questions were developed to test the EI knowledge sharing concepts identified in the literature and to test the extent to which the EI resource had improved access to EI knowledge.Modification for the existing ethics approval for the study was obtained through the University of New South Wales .A purposive sample of the population of designated NSW Health EI key stakeholders was the study group, which numbered 26 at the time of evaluation. This sampling approach aligns with the key informant technique . ParticiFree-text data were collected using MS Forms and extracted in MS Excel format, which was used to aggregate the responses for each question along with total number of responses received.Responses were clustered together but separated into individual statements to identify any recurring concepts, with responses also explored for potential linkages between themes . An estaObservational pre/post study design was employed, using the body of NSW Health organisations as the study cohort and incidence of EI categories as the measure of comparison ,19.The existing data extract used for the knowledge audit sample included all EI plans from the most recent financial year prior to EI resource implementation. As such, this subsample was used as the baseline for the study (July 2018\u2013June 2019). At the conclusion of the intervention financial year (July 2019\u2013June 2020), the process used to audit and code EI plans for the creation of the taxonomy was repeated for all improvement plans within that period to create the comparison sample.p-values for pre\u2013post analysis both at the NSW Health organisation level and for overall EI strategy numbers were tested for statistical significance.Audit data for the pre/post financial years were combined in Microsoft Excel, with NSW Health organisation, financial year and taxonomy category compared using pivot tables. Through the comparison of results before and after the resource document was made available in the categories in which each NSW Health organisation reported at least one improvement plan, this pre\u2013post comparison sought to establish whether providing the resource was linked to an increase in the number of organisations reporting improvement plans in each taxonomy category. This study also compared overall improvement plan numbers in each category before and after the taxonomy implementation. The pre\u2013post difference of means and The taxonomy development process resulted in eight categories. Of the 1127 EI strategies audited in this study, a total of 263 unique approaches were identified. Nine categories were identified with between 9 and 59 unique approaches in each category. Taxonomy labels were listed alphabetically. The eight categories within the taxonomy fit within three broader domains: employee-related expenditure, clinical services and non-clinical business. The list of unique strategies is provided in the taxonomy user guide resource document attached as Each of the eight classifications within the taxonomy are explored as follows.EI strategies within this classification relate to the procurement and use of goods, consumables and commercial arrangements which are directly involved in the delivery of healthcare. This classification covers approaches such as reducing waste, changing to more cost-effective products or services and renegotiating contracts. Only EI strategies which focused on items, technologies and logistics required in the processes of healthcare were included in this category. Opportunities to improve efficiency represented by better-value products and providers were found to be a common area of opportunity across all NSW Health organisations. Examples include improving stock management to reduce waste, changing to more cost-effective service providers, working toward targeted reduction in high-cost consumables use and consolidating stock ordering by introducing standardised product catalogues.The remainder of the EI strategies within the clinical services domain focus on the processes of providing clinical care. With patient experience and patient outcomes included within the concept of value in healthcare, EI strategies in this classification also address opportunities to achieve patient-focused improvements while also reducing cost. This classification is distinct from the products and consumables approaches included in the previous classification in that the included approaches focus on reducing service time, reducing wasted time, improving asset utilisation and reviewing service provider arrangements. Examples include reducing unwarranted diagnostic procedures, improving patient transport scheduling to reduce out-of-hours transport requirements, improving appointment scheduling to minimise missed appointments and replacing paper forms with digital forms.Due to the requirement for health services to maintain minimum staffing levels often at short notice, a range of options to deploy staff at short notice are available; however, these are more costly than deploying regular staff. EI strategies include working additional or overtime hours, creating temporary contracts with medical staff and using staffing agencies to provide contingent workers. While these options provide flexibility and assure service capacity, EI strategies in this classification aim to reduce reliance on these options. Examples include reviewing billing practices of external providers, replacing contingent staff with permanent staff, implementing central staffing pools and improving overtime governance processes.EI strategies in this classification focus on ensuring appropriate and effective use of paid absence entitlements. This includes reducing sick leave, reducing accrued leave balances which would otherwise be paid out and reducing costs associated with replacing staff on planned leave. Common elements of these EI strategies include monitoring leave balances, monitoring utilisation rates and planning staff replacement in advance. Examples include reducing sick leave by targeting performance management, reducing excess annual leave liability, enhancing leave planning to minimise coverage costs and avoiding backfilling positions for short-term vacancies.Health services typically have flexibility in how they deploy a mix of staff types to safely meet the demand for clinical services. EI strategies in this classification aim to reduce the cost of staffing while ensuring services are delivered to an appropriate level of safety, quality and accessibility. Such EI strategies include improving rostering practices, maximising use of role-delineated skillsets and aligning shift hours with service demand. Examples include increasing staffing hours to reduce after-hours callbacks, restructuring services to maximise skill mix utilisation, changing skill mix and seniority needed and improving governance to align staffing levels with activity.The remaining EI strategies in this domain relate to the establishment and filling of positions. While previously discussed contingent workforce options exist to meet short-term staffing pressures, most routine service staffing is achieved through the planned hiring and deployment of regular staff. This is measured in full-time equivalent (FTE). Delaying recruitment to established positions to match reduced demand or role redesign, streamlining recruitment to address increased demand and improving staff retention are common EI strategies in this classification. Examples include improving recruitment to reduce overtime, reviewing vacant roles for ongoing requirements, delaying recruitment to vacant positions where services are not required, employing medical staff to reduce locum requirements and establishing training positions to enhance recruitment.Although the primary purpose of healthcare services involves clinical care, a range of business functions are required to support health service operations. Asset management, asset maintenance and consumables not involved in patient care are routine considerations and as such also offer opportunities for improved efficiency. Examples of EI strategies in this category include reducing utilisation of fleet vehicles, consultants and stationery along with renegotiating commercial arrangements and changing to more cost-effective service providers.The finance and operations classification provides a catch-all for the range of improvements achieved through enhanced business management practices, strategic decision-making and streamlined day-to-day business activities. This classification encompasses improvements in the delivery of overall business functions which are essential for supporting the core activities and processes of delivering frontline healthcare. Examples include removing low-value equipment, reducing discretionary spending and improving routine maintenance practices.Eight responses were received from the population of 26 invitees, giving a response rate of 30.7%. A number of conclusions were able to be drawn from the survey responses as discussed below.1.Please describe how you have used the NSW Health \u201cSummary of expenses improvement strategies\u201d resource document to support your work in efficiency improvement.Eight out of nine respondents addressed Question One. Responses included using the EI resource for EI ideas (two), reviewing opportunities, identifying EI strategies not currently being undertaken, promoting networking through discussion (two), supporting future planning and informing EI strategy development. Two respondents indicated that the categorisation approach was of benefit, specifically in \u201cconducting a gap analysis to determine which categories should be investigated for further opportunities\u201d and to \u201cinform the category strategy development for the savings leadership program and inform our value-based procurement framework\u201d.2.Please describe your thoughts on the benefits, strengths and weaknesses of this resource document.Eight out of nine respondents addressed Question Two. Responses included using the EI resource for identifying EI strategy opportunities (two), for exploring and validating current EI strategies as well as for providing visibility of all EI strategies across NSW Health without having to \u201cre-invent the wheel\u201d. It was stated that the resource was a \u201cvery important tool to identify further opportunities\u201d. Other respondents reported using the EI resource as a guide and comprehensive outline. Two respondents requested additional details, including implementation, financial management and process details.3.Please outline your thoughts on how this resource document could be improved.Eight out of nine respondents addressed Question Three. Improvement suggestions included the provision of consistent high-level impact calculation methodologies, provision of hyperlinked examples for highly successful EI strategies, sharing of case studies and provision of further guidance on factors required for EI strategy success such as governance, process mapping and a culture of continuous improvement. Two suggestions related to further information on capturing, reporting and sharing EI strategy benefit measures.4.What have been the impacts of the resource document on understanding and engagement with efficiency improvement within your organisation?Seven out of nine respondents addressed Question Four. Responses included providing EI strategy guidance to refer to (three), enabling EI discussions and supporting management framework development. The EI resource was again described as supporting NSW Health organisations to avoid \u201creinventing the wheel\u201d while sharing and scaling knowledge as a \u201creference guide\u201d, \u201cproviding clarity on EI plans\u201d and \u201cinitiating positive conversations\u201d.The taxonomy evaluation found a 43% increase in the number of EI strategies implemented, as well as an improvement in EI category uptake in six of eight categories. This indicates that the taxonomy was associated with an increase in EI category implementation across NSW Health organisations as well as in overall volumes of EI strategies implemented. Three categories showed the most significant increase in uptake: non-clinical contracts and supplies; avoided and preventable activity; and clinical service delivery.Results are shown in p-value of 0.0429, which demonstrates a statistically significant result. ANOVA or ANCOVA on gain scores were not deemed suitable due to sample size limitations.The difference of means for pre\u2013post changes in EI strategy numbers in each taxonomy category was 13, with a The complexity of identifying and evaluating the impact of EI strategies on health services is a common challenge . Due to The findings of this study reaffirmed the breadth of various approaches to EI in public health systems. While it may therefore be expected that similar initiatives would be implemented across multiple locations within a public health system, this study demonstrated the extent to which this occurs with only one in four audited EI strategies being unique. This is indicative of the high level of duplication in EI strategies occurring across the system, thereby validating efforts aimed at reducing the amount of avoidable effort invested in such duplication. This study adds further evidence of the utility of taxonomies in promoting EI strategies within the current theoretical construct of value-based care . In thisThe EI resource was also associated with an increase in the number of NSW Health organisations implementing EI strategies across taxonomy categories. This can be linked with its benefits in supporting users to identify EI opportunities and well as promoting a comprehensive EI approach which includes EI strategies across all taxonomy categories. As the largest improvement in EI distribution by category was identified in non-clinical contracts and supplies, namely, avoided and preventable activity and clinical service delivery and patient outcomes, these categories may potentially represent areas for further investigation for additional EI strategies across all public health systems. While the implementation of the taxonomy cannot be established as the sole causal factor in these improvements, these findings are suggestive of an association between sharing knowledge of improvement approaches and an increase in the number of EI strategies developed, in addition to an increase in the number of organisations addressing opportunities across each of the taxonomy classifications.This study highlighted the varying diversity in EI strategies across the different taxonomy categories. Two out of every five unique approaches were related to contracts and supplies, distributed close to evenly between clinical and non-clinical areas. This is likely to be reflective of the wide range of healthcare products and contracted service providers prevalent in large, complex health services. Conversely, only limited numbers of unique EI approaches focused on position creation, hiring and leave, which is potentially related to the rigid and regulated nature of industrial relations in the public health sector. The potential to scale successful EI strategies from their original setting across other similar settings within the same healthcare system is highlighted by these findings, with such efforts having the potential to result in the realisation of benefits achieved by the original initiative in similar settings. This provides new evidence for the utility of an EI taxonomy for public health systems internationally. As the policy imperative for improved efficiency continues to be reflected in the strategic priorities and performance management frameworks of public health systems, the EI taxonomy presented in this study is highly relevant to contemporary policy directions.This study was impacted by a number of limitations. The unique setting in which the study was undertaken limited the scope and scale of investigations, while the small sample size across qualitative and quantitative evaluations limited the potential for application of complex statistical methods. The use of MS Forms limited qualitative data to free-text responses only. These limitations were overcome by clearly articulating the relevance of the study context to international settings and by using validated analysis techniques appropriate to the sample sizes.Undertaking a systemwide audit of EI strategies can enable the mobilisation of this knowledge across a public health system, supporting EI stakeholders to address the challenge of identifying opportunities for EI initiatives and methods to measure their impact. Importantly, this has the potential to reduce repetition in the development of highly similar improvement initiatives across different areas of the system, allowing EI planners to rededicate this time to applying the shared knowledge in their individual settings to suit specific local requirements while also supporting the scaling and application of successful EI strategies . This alThe development and distribution of an EI resource provides evidence for the role of a centralised, whole-of-system approach to EI support in managing EI knowledge distributed across the system. Access to systemwide EI information, the creation of networks with EI stakeholders across the system and the ability to align EI with broader system management frameworks are key enabling benefits of a centralised EI approach. Such centralised approaches to EI are therefore well-positioned to manage the collective EI knowledge distributed across the broader system, providing structured knowledge management services and leading efforts to make this knowledge accessible and user-friendly for key EI stakeholders across the system. This can support the replication of EI success originating in a single health facility or organisation across similar settings elsewhere within public health systems internationally.With the requirement to address demand and funding challenges expected to continue, public health systems will increasingly stand to benefit from centralised approaches to improving efficiency. This study finds that significant duplication of EI strategies exists across the organisations within the NSW public health system, along with significant effort unnecessarily invested in recreating EI strategies already developed elsewhere within the system. By applying audit and content management methodology as a foundational step in managing the collective body of EI knowledge in NSW Health, this study developed a categorisation system for EI strategies along with a detailed catalogue of EI strategies and their measurement approaches. The resulting taxonomy and EI resource provide vehicles for knowledge mobilisation to increase accessibility of collective EI knowledge and experience with the aim of supporting EI stakeholders to address common challenges. This study highlights the potential for centralised EI models to support public health systems to drive EI by consolidating and sharing distributed EI knowledge to address ongoing resource and demand pressures."} +{"text": "Professional religious specialists centralised religious authority in early human societies and represented some of the earliest instances of formalised social leadership. These individuals played a central role in the emergence of organised religion and transitions to more stratified human societies. Evolutionary theories highlight a range of environmental, economic and social factors that are potentially causally related to the emergence of professional religious specialists in human history. There remains little consensus over the relative importance of these factors and whether professional religious specialists were the outcome or driver of increased socio-cultural complexity. We built a global dataset of hunter\u2013gatherer societies and developed a novel method of exploratory phylogenetic path analysis. This enabled us to systematically identify the factors associated with the emergence of professional religious specialists and infer the directionality of causal dependencies. We find that environmental predictability, environmental richness, pathogen load, social leadership and food storage systems are all correlated with professional religious specialists. However, only food storage is directly related to the emergence of professional religious specialists. Our findings are most consistent with the claim that the early stages of organised religion were the outcome rather than driver of increased socio-economic complexity. Social media summary: Food storage systems enabled professional religious specialists to emerge in hunter\u2013gatherer societiesAt the start of the Holocene, the world's religious landscape consisted of a diverse range of religious systems, each closely linked to local context Bellah, . Today, Religious specialists refer to individuals with a greater knowledge of, or ability to engage with, the supernatural than other community members. Broadly defined, religious specialists can include healers, mediums, shamans, priests and priestesses . This suggests that both vertical and horizontal processes of transmission are potentially important forms of non-independence within our sample. We note that the phylogenetic and geographic distances between societies are correlated with one another , making it challenging to disentangle these two forms of non-independence. High rates of horizontal transmission can lead to inaccurate inferences when using phylogenetic methods to infer ancestral states of traits or the mode and tempo of trait change . To provide a preliminary test of these hypotheses, we use phylogenetic generalised least squares to identify the cultural and environmental factors associated with professional religious specialists . These aThe results of our bivariate phylogenetic generalised least squares analyses indicate that pathogen load , environmental predictability and environmental richness were significantly associated with professional religious specialists . ContrarSocial leadership and food storage were also positively associated with professional religious specialists . These bWe developed a novel method of exploratory phylogenetic path analysis to test for directional dependencies between professional religious specialists, and social, economic and environmental variables. This method builds on the frequentist model comparison functions implemented in the R package phylopath in hunter\u2013gatherer societies often focus on explaining and controlling existentially threatening and unpredictable life events. For example, !Kung healers used trance dances to heal individuals and communities Lee, , NortherThis study shows how comparative historical data and phylogenetic causal modelling can help untangle the complex pathways in human cultural evolution. Our findings are the most consistent with hypotheses in which the early steps towards the evolution of organised and hierarchical religions were primarily the result of, rather than driver of, changes in socio-economic complexity. Specifically, food storage may have been a catalyst of religious, economic and social change in hunter\u2013gatherer societies. This possibility is corroborated by qualitative descriptions in ethnographies and previous theoretical literature, as well as the finding that food storage is the single strongest predictor of professional religious specialists within our bivariate analyses.We note several ways in which future research could help develop and expand our research findings. First, we note that this study uses a broad classification of professional religious specialists that collapses a diverse range of religious roles. This helps identify common paths towards religious specialisation, and potentially means that these pathways generalise to other forms of specialisation. This breadth also comes at the costs of overlooking factors associated with specific forms of religious specialisation (Lightner et al., These limitations notwithstanding, the method of exploratory path analyses developed here offers and additional tool for comparative research on both biological and cultural evolution. Our findings help clarify the complex pathway to the emergence of religious organisation and contribute to the growing recognition of the complexity of religious and social systems in hunter\u2013gather societies (Boyd & Richerson,"} +{"text": "Prostate cancer (PC) is the second-most prevalent malignancy affecting the male population worldwide . The gloRecent studies have shown that immunotherapy can enhance the immune system\u2019s ability to recognize and target cancer cells, leading to improved clinical outcomes in patients with mCRPC . VaccineVenkatachalam et al.\u2019s article In Bansal et al.\u2019s review on the use of immunotherapy combinations to enhance treatment in mCRPC the authOverall, both articles provide valuable insights into the use of immunotherapy in prostate cancer and highlight the potential of these therapies to improve outcomes for patients with lethally advanced PC. The articles also underscore the need for further research on the tumor microenvironment (TME) to optimize the use of immunotherapy in this setting and to identify biomarkers that can predict response to treatment when selecting therapies for patients. Taken together, immunotherapy and combination immunomodulatory strategies incorporating vaccine-based therapies, ICIs, and CAR T cells represent a promising approach for the treatment of mCRPC. However, further research and, more importantly, clinical trials are needed to optimize these therapies and improve clinical outcomes for patients with this disease, along with the need for scientists and clinicians to collaborate to design highly valuable clinical trials using novel therapies. Regardless of these requirements, the future seems to point toward accelerated development for treating this dreaded disease."} +{"text": "Neuromodulating the locomotor network through spinal cord electrical stimulation (SCES) is effective for restoring function in individuals with gait deficits. However, SCES alone has limited effectiveness without concurrent locomotor function training that enhances activity-dependent plasticity of spinal neuronal networks by sensory feedback. This mini review discusses recent developments in using combined interventions, such as SCES added to exoskeleton gait training (EGT). To develop personalized therapies, it is crucial to assess the state of spinal circuitry through a physiologically relevant approach that identifies individual characteristics of spinal cord function to develop person-specific SCES and EGT. The existing literature suggests that combining SCES and EGT to activate the locomotor network can have a synergistic rehabilitative effect on restoring walking abilities, somatic sensation, and cardiovascular and bladder function in paralyzed individuals. By activating the locomotor network, spinal cord electrical stimulation (SCES) can be utilized to restore gait in patients who have suffered from the effects of spinal cord injuries (SCI) . This mePowered exoskeletons have been extensively developed to offer new opportunities for people with significant gait impairments . New conIn this review, we focus on the treatment approach that combines EGT with neuromodulation of the spinal pattern generation networks using SCES. We evaluate the available evidence for the benefits of combined interventions. Given that SCI is a heterogeneous condition and that the spinal cord is a neural structure capable of plastic changes, a special emphasis is placed on the role of functional assessment of the spinal circuitry for developing personalized EGT + SCES therapies. We consider recent research that utilizes this approach to investigate the foundations of such interventions, the suitability of combining EGT and SCES treatments for individuals with SCI, and the potential for therapeutic benefits.In recent years, significant advancements have been made in the development of wearable powered exoskeletons designed to aid in walking and promote motor recovery. This has led to the creation of several solutions for gait assistance and rehabilitation . ExoskelDespite significant progress in exoskeleton technology in recent years, fully functional and optimal assistive device still have to emerge from this research. Moreover, there are still challenges that need to be addressed before lower limb exoskeletons can be utilized in practical settings . In addiThe growing interest to restoring and enhancing gait control in individuals with neurological disabilities has led many researchers to pursue innovative approaches that aid in activating the spinal circuits for locomotion. A significant method for facilitating locomotion involves neuromodulation of the central pattern generation (CPG) circuitry with the stimulation of the spinal cord. It has been shown that stepping-like movements in humans can be elicited when spinal locomotor circuits are activated by relatively non-specific stimuli such as vibratory stimulation of muscle receptors , electriWhat are the benefits of combining SCES with EGT? While EGT provides a unique opportunity for SCI patients to experience overground weight bearing stepping and to be used in real walking scenarios, its effectiveness in severely paralyzed individuals is very limited . On the Walking in an exoskeleton while SCES is applied allows coupling of continuous sensory feedback with activity-dependent plasticity of spinal neuronal networks, which represents a great therapeutic potential. The exoskeletons are designed to bear the full body weight and provide full loading of the body weight on the feet during the stance phase of assisted walking. It is also worth noting that overground EGT typically involves walking with crutches and allows to use the upper body and arm muscles to assist leg movements and balance control by coordinating arm, trunk and lower limb motion and thus promoting connections between lumbosacral and cervical enlargements . To engaNeuromodulation of the spinal cord appears to be beneficial for promoting the locomotor function and could result in some immediate effects, within a single day, on motor activities after motor complete paraplegia before they can receive the combined EGT and SCES treatment . This trThe other important aspect for developing locomotor and CPG-modulating therapies is physiologically relevant assessment of the state of the spinal circuitry when using person-specific SCES. The rationale is the following. The spinal cord normally possesses a notable degree of plasticity , redundaTo effectively use CPG-modulating therapies, it is crucial to understand how to evaluate the functional state of the spinal network and its response to modulatory inputs. Since SCI affects people differently, it is important to examine and study the distinct variations in the spinal cord condition. Some research has been done to analyze the individual physiological state of spinal multisegmental reflex pathways in relation to CPG-modulating therapies . Even inThe specific procedures used to stimulate the spinal cord and to train SCI patients are instrumental for activation of the spinal CPG network and its restoration. In several studies, neuromodulation tools have been developed and tested in both neurologically intact individuals and patients. For instance, non-invasive SCES has become widespread for both basic and clinical research . The effCombining SCES with EGT is an efficient approach to rehabilitation of patients paralyzed after SCI. This method enacts sensorimotor functions while increasing the activity in spinal networks. Although EGT and SCES techniques have advanced significantly in recent years, further improvements are still needed, particularly in understanding how SCES modulates the excitability of spinal circuitry. Although promising immediate effects of SCES in enabling voluntary control of leg movements, more research is needed to determine its effects when combined with EGT, as well as long-term effects of this treatment. To develop clinical treatments, a range of factors should be considered, including individual differences in spinal cord physiology, personalized CPG-modulating therapies during EGT, and accumulating evidence of their therapeutic potential.All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication."} +{"text": "Mwenezi district is a drought prone area characterised by high temperatures, droughts, rainfall deficit, crop failures and chronic food deficiencies. Rainfed agriculture can no longer be sustained without any innovations. The study explored the impacts of climate change on household food security among the vulnerable populations of Matande communal lands, Mwenezi district in Zimbabwe. The study is guided by the Sustainable Livelihoods Framework (SLF). An exploratory sequential research design was adopted, and a total of 78 respondents were selected from the population of 371 households using purposive and cluster sampling techniques. Data collection was triangulated through the use of household survey, focus group discussions, key informant interviews and observations. The thematic approach and SPSS software were used to analyse qualitative and quantitative data, respectively. Results demonstrated that climate change propelled increases of pests and diseases for both livestock and crops, reduction of meals uptake per day, biodiversity loss and dwindled crop production. Livestock increases were recorded despite the changing climate shows a nexus with food insecurity. The research called for the adoption of drought-tolerant crops, capacity building through climate change resilience programmes, livestock centric in diversification, improved formal markets for livestock and tapping of underground water for irrigation and other purposes to complement existing water bodies to prevent them drying up early.There is deepening aridification in Mwenezi district because of climate change resulting in the continuous obliteration for the worst of agro-ecological regions iv and v reclassified into a and b. This confirmed the heterogeneity of various climatic conditions and variability within the same geographical context. However, vulnerability continues to be generalised into regions. The study investigates the impacts of climate change typical to Matande communal lands with the view to generate knowledge relevant to review adaptation practices specific to the researched area in order to escalate community resilience. The effects of climate change are ever growing and tremendously increasing vulnerability to all the populations of the world and Mavhura, Manatsa & Matiashe extrapol and MavhClimate change burdens the already at-risk populations Alam . ZimbabwThere is also increased aridification in Mwenezi district because of climate change in which agro-ecological regions iv and v were further reclassified into a and b . Sustainable Livelihoods Framework provides a comprehensive theoretical framework for understanding the impacts of climate change on household food security in Matande communal lands. This framework encompasses five key components: livelihood assets, livelihood activities, livelihood strategies, livelihood outcomes and the vulnerability context DFID . By applThe investigation focused on the impacts of climate change in Matande communal lands, Ward 2, Mwenezi district in the southeast of Zimbabwe see . The disThe area has Savannah type of vegetation and dominated with sand soils. Livelihoods are largely agrarian with maize as a staple crop. Farmers rely on subsistence livestock rearing; growing small grains, legumes, mbambara nuts; and migration into South Africa Mutopo . The majYin :19 averrPopulation refers to the totality of subjects under study , Rutavo (157 households) and Mashindi (60 households); hence, it was easier to cluster respondents. Cohen et al. :112 postThe researchers triangulated the data collection tools in which in-depth interviews, key informant interviews, FGDs, observation and a questionnaire were used. Triangulation is defined as a process of using multiple perceptions to clarify meaning, verifying the repeatability of an observation or interpretation and 35\u201345 years (44.2%) reside in the rural areas and relied on subsistence agriculture for their living. In terms of marriage status, 69.8% of respondents were married, an indication that the community values the marriage institution. Study respondents (67.4%) depend on manual labour for survival. Manual labour jobs are not highly paid, and hence, the population is in poverty. Many of respondents attained secondary education (46.5%). The high rate of literacy among the population influenced the completion of questionnaires by the study respondents.Research revealed have dire consequences on household food security. Climate change has resulted in the changing of food consumption patterns such as the reduction in the number of meals per day. During one of the sessions of FGDs, one respondent extrapolates:\u2018Now I resolved that we ate one meal per day so that I force my food reserves to take us through to the harvesting time.\u2019 The Riparian ecosystem along Runde River had been altered by environmental degradation caused by flooding and gold panning. On the other hand, droughts negatively affected the production of wild fruits, where some species of fish and wild animals have changed their habitat, thereby compromising food security. A key informant said:There is a lot of environmental degradation along Runde River mainly caused by gold panning. Look there are pits everywhere as people were searching for gold. Due to low rainfall, the water flow along Runde River was reduced and some seasonal pools have dried up. Tourists and locals used to come here at Chirote to see hippopotamus and sometimes bought tiger fish as well as gathering wild fruits such as makudende along Runde River but now there is none.\u2019 Crops and animal pests as well as diseases wreaked havoc in Ward 2, Mwenezi district because of climate change leading to a highly diminished crop yield. Another small-scale farmer who used solar-powered borehole to irrigate his horticultural plants cited that at one point in November 2022, he had to uproot and burn 8000 plants of tomatoes because they were attacked by an uncontrollable disease. Maize crop was the most affected one bouts of arm worms. One of the interviewed officials reported:\u2018Our early assessment of the maize crops planted so far indicated that army worms have already reduced the maize crop by more than half plants per hector.\u2019 (AGRITEX officer)One respondent also confirmed:\u2018Some of us who planted maize with the early rains have realised that we made a huge mistake. A yellow worm is wiping out the maize crops. Now we are planting again. I should have planted small grains; the worms would not have destroyed much of them because they germinated in large numbers.\u2019 There were perpetual crop failures recorded year in and year out because of erratic and often unpredictable rainfall patterns resulting in truncated crop yield. A small-scale farmer where field day commemorations were usually done at his homestead espoused that:\u2018I used to have bumper harvests here because of good rains. Look there on the ground, those are marks of a heavy vehicle which got stuck in 2002 when it was loaded with 30 tonnes of maize I have produced and destined for the Grain Marketing Board. Now things have changed, I can no longer able to produce surplus maize, it usually wilted due to prolonged dry spells and heat waves when it is almost mature.\u2019 Another confirmed that in the year 2021/2022 farming season, their crop failed and they could not harvest legumes (groundnuts and roundnuts) that are drought resistant because the field had formed a hard crust because of prolonged dry spells:\u2018If government failed to provide food aid, by January 2023, we are likely to record death due to food shortages at household level. We had done our homework very well but the weather patterns failed us. I even failed to harvest my ground nuts because the ground was too dry. I just dig a few to get seeds for this season and later quitted.\u2019 Livestock increases were reported despite the negative consequences of climate change. High numbers were found among goats because they are drought tolerant. A general increase was also recorded in the number of cattle in Mwenezi district particularly because of the fact that there was no market for cattle necessitated by sporadic disease outbreaks in the area. People feared that they might buy contaminated meat and get infected. Numbers keep on growing as he indicated:\u2018Mwenezi is officially classified under region iv and v which is suitable for animal husbandry.This year, there was no market because the movement of livestock across districts was banned by government to avoid the spread of foot and mouth which was reported in Chivi district. Their numbers keep on increasing day by day. Over the years, our farmers have resisted destocking, they preferred their animals to die during droughts than culling them.\u2019 The researchers made observations during field work on the impacts of climate change, adaptation and mal-adaptation practices. The mal-adaptation practices witnessed were the rampant cutting down of thorn bushes and indigenous trees for fencing of homesteads, fields and household gardens to protect crops from wild animals, and livestock was causing environmental degradation. The gold panning along Runde River caused siltation and drying up of seasonal pools leading to the migration of animals and marine species. The practice of lending cattle to relatives within the same community to spread the risk was not working, small-scale farmers were recorded colossal loses during droughts as they are often trapped in the same disaster. Mandimo dam that was destroyed by cyclone Eline in 2000 was not repaired. It was observed that the area of the study is mountainous, and there was relief variability in the same area; the western sides of the Dungungwi Mountains were already having crops, while the eastern side of the mountains did not receive any rains by 25 November 2022. The researchers observed that the majority of household small dams used as water harvesting techniques, which were around a few homesteads in Matande communal lands, had dried up.The negatives of climate change were overwhelming in the researched area, which is in agreement with studies by Filho and Nalau , SibandaPersistent bouts of army-worm were also found to be retarding crop production and yields. Brazier and USAIClimate change alters suitable habitats for different wild animals and marine species because of the decline in fresh water and drying up of some seasonal pools. The findings made by the researchers on environmental degradation of the riparian ecosystems concurred with Kupika and Nhamo , Mwera, Livestock increases recorded despite the changing climate interestingly, the increase in livestock points to a nexus with food insecurity. Livestock diseases often erupted in the area posing as the main challenge affecting the sale of cattle, which resulted in the quarantine and prohibition of the sale of cattle through formal systems. Similar findings were recorded by Paenda et al. in the MAs households were threatened by climate change, the research shows that they deployed a number of copying strategies. The SLF recognises the importance of human skills, knowledge and capabilities in livelihood strategies. Climate change and its associated challenges, such as unpredictable rainfall patterns and pests, require farmers to possess adaptive agricultural techniques and pest management skills. The inhabitants of Matande communal lands responded to hunger by reducing the number of meals uptake per day in line with postulations by Gukurume and ZvomPoverty among locals precipitated mal-adaptation practices. Filho and Nalau viewed mThe study conducted in Matande communal lands, Mwenezi district, Zimbabwe, provides valuable insights into the impacts of climate change on household food security. The findings highlight the challenges faced by the vulnerable populations in the area, including reduced crop yields, changes in food consumption patterns, increased pests and diseases affecting crops and livestock, lack of livestock markets and biodiversity loss. These findings call for urgent actions to enhance community resilience and address the adverse effects of climate change.To mitigate the impacts of climate change and improve household food security in Matande communal lands, the following recommendations are proposed:Cultivation of drought-tolerant crops: Promote the adoption and cultivation of drought-tolerant crop varieties that are better suited to withstand the challenges of erratic rainfall patterns and prolonged droughts. This can help ensure more stable crop yields and enhance food security in the face of climate uncertainties.Tapping underground water sources: explore and utilise underground water sources for irrigation and other purposes to supplement existing water bodies. This will alleviate the pressure on limited water resources, especially in arid regions, and prevent their premature drying, enabling sustained agricultural production and livelihoods.Livestock-centric diversification: Encourage a livestock-centric approach to diversification in drought-prone areas. This can involve promoting sustainable livestock-rearing practices, improving livestock management and disease control, and facilitating access to formal livestock markets. Enhancing livestock-based livelihoods can provide alternative sources of income and food security for communities.Strengthening climate resilience programmes: Implement and scale-up climate resilience programmes that equip farmers with knowledge, skills and resources to build resilience in the face of climate change impacts. These programmes should focus on sustainable farming practices, climate-smart agriculture and adaptive strategies tailored to the local context.Enhancing formal livestock markets: Improve the functioning of formal livestock markets by addressing market inefficiencies, providing market information and infrastructure, and supporting fair trade practices. This will enable small-scale farmers to sell their livestock at fair prices, improving their economic opportunities and food security.Introduction of climate tax to finance and repair damaged critical infrastructure: The fund helps to mobilise resources to finance adaptation, mitigation and resilience programmes rather than waiting for external interventions. Some of the community dams destroyed by cyclones in the early 2000 were not repaired because of the lack of funding by the government.Addressing the impacts of climate change on household food security requires a holistic approach, involving collaboration between government agencies, local communities and relevant stakeholders. It is essential to prioritise sustainable practices, build adaptive capacities and promote resilience at individual, community and institutional levels. By implementing these recommendations, Matande communal lands can work towards a more sustainable and food-secure future, even in the face of a changing climate.The opportunities presented by the impacts of climate change as they may present opportunities of innovation and investment.The possibility of passing the management of livestock and related infrastructure from government to its owners."} +{"text": "Promoting physical activity, such as habitual walking behaviors, in people with cognitive impairment may support their ability to remain independent with a good quality of life for longer. However, people with cognitive impairment participate in less physical activity compared to cognitively unimpaired older adults. The local area in which people live may significantly impact abilities to participate in physical activity. For example, people who live in more deprived areas may have less safe and walkable routes.To examine this further, this study aimed to explore associations between local area deprivation and physical activity in people with cognitive impairment and cognitively unimpaired older adults (controls).87 participants with cognitive impairment (mild cognitive impairment or dementia) and 27 older adult controls from the North East of England were included in this analysis. Participants wore a tri-axial wearable accelerometer on their lower backs continuously for seven days. The primary physical activity outcome was daily step count. Individuals\u2019 neighborhoods were linked to UK government area deprivation statistics. Hierarchical Bayesian models assessed the association between local area deprivation and daily step count in people with cognitive impairment and controls.Key findings indicated that there was no association between local area deprivation and daily step count in people with cognitive impairment, but higher deprivation was associated with lower daily steps for controls.These findings suggest that cognitive impairment may be associated with lower participation in physical activity which supersedes the influence of local area deprivation observed in normal aging. Approximately 50 million people are living with dementia worldwide, making the condition a global public health priority . The WorEvidence suggests that people with dementia participate in lower volumes of physical activity, such as taking fewer steps per day compared to normal ageing . AdditioThe local area in which a person lives becomes an increasingly important influence on physical activity during aging, as reduced income, health, and mobility limit geographical movements . People To gain an initial understanding, this analysis aimed to explore associations between local area deprivation in the North East of England and the volume of physical activity in people with cognitive impairment and cognitively unimpaired older adults (controls). Our secondary aim is to explore associations between area deprivation and metrics relating to pattern of physical activity, as this may provide contextual information . We hypothesized that both people with cognitive impairment and controls living in more deprived areas would have a lower volume and different patterns of ambulatory physical activity compared to those living in less deprived areas.n\u200a=\u200a87; including probable mild cognitive impairment and dementia due to Alzheimer\u2019s disease, vascular dementia, dementia with Lewy bodies, and Parkinson\u2019s disease dementia) and community-dwelling cognitively unimpaired older adults . Diagnosis of cognitive impairment and associated dementia disease conditions were verified by consensus clinical review; two clinicians independently reviewed participants\u2019 clinical notes and study assessments to verify their clinical diagnosis. Where disagreements occurred, a third clinician reviewed participants\u2019 notes and assessments to provide a consensus. Formal diagnostic criteria for Alzheimer\u2019s disease and the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University [BH152398/PD0617]. Dr. R\u00edona Mc Ardle is funded by the National Institute for Health Research (NIHR) for her fellowship (NIHR 301677). The research was also supported by the National Institute for Health and Care Research (NIHR) Newcastle Biomedical Research Centre based at The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle University and the Cumbria, Northumberland and Tyne and Wear (CNTW) NHS Foundation Trust, and by the NIHR Research Capability Funding (NU-004071) for North East and North Cumbria. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.The authors have no conflict of interest to report.The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions."} +{"text": "Psychiatric admissions of elderly subjects with mental disorders is a difficulty in management and treatment. This problem is essentially related to somatic comorbidities of this population.To compare the demographic characteristics, comorbid conditions and functional status of younger and older individuals with major mental illnesses admitted to psychiatry.Using the records of patients admitted between 2015 and 2020 to the psychiatric department \"G\" of Razi Hospital, we collected the demographic characteristics, comorbid conditions and functional impairments for patients admitted to psychiatry and aged over 65 years. We compared these characteristics to those collected in the total population of admitted patients.The study population consisted of 75 elderly patients. Compared to the youngest patients there was a greater male majority, a higher rate of severe cognitive impairment, higher rates of chronic medical illnesses, such as congestive heart failure.Our findings suggest an urgent need for integrated psychiatric and medical care for elderly subjects with major mental illness. Future research is needed to adapt evidence-based integrated models of collaborative mental health care.None Declared"} +{"text": "Depression is a painful, functionally impairing, and frequently recurring condition. A costly illness for employers, depression contributes to reduce functioning, decreased work productivity, and absenteeism. In addition, costs associated with comorbidities in people who have depression are higher when they are compared with the costs in people who do not have depression. In patients with either coronary or cerebral vascular disease, depression significantly increases the risk of cardiovascular morbidity and mortality.To highlight some of the challenges faced by primary care providers when they deliver mental health services and to provide an overview of an integrated behavioral health and medical benefit plan implemented as one solution to improve overall depression outcomes and reduce associated depression costs.Because of the high prevalence and significant impact of depression, the U.S. Preventive Services Task Force recommends screening adults for depression in clinical practices that have systems in place to ensure accurate diagnosis, effective treatment, and follow-up. However, depression appears to be only partially recognized and inadequately treated in primary care due somewhat to several challenges that primary care practitioners face when they manage a mental health diagnosis along with comorbid medical illnesses.Integrating the medical and behavioral health benefits in a health plan allows for depression screening and the opportunity to direct patients to seek treatment when needed. Preliminary results of this effort in one managed care plan show reduced use of hospital services, days gained at work, and improved adherence to antidepressant therapy. A different component of this plan design includes patient care coaching as well as support of primary care's efforts by providing expert telephone consultation about treatment plans and allowing billing for adequate time spent with depressed patients."} +{"text": "Anticoagulant therapy is suggested for patients with acute symptomatic or incidentally-detected PVT without active bleeding or other contraindications. Conversely, a careful evaluation of the risks and benefits of anticoagulation is suggested in patients with chronic thrombosis. The aims of this narrative review are to discuss the available data and to identify the correct timing for anticoagulant therapy in patients with liver cirrhosis and PVT.A recent guidance paper from the International Society of Thrombosis and Haemostasis suggested that the stage of thrombosis and significantly lower rates of thrombus progression as compared to untreated patients, and a significant reduction of both major bleeding and gastroesophageal variceal bleeding risks .,13 These results were also observed in a large prospective cohort of cirrhotic patients with splanchnic vein thrombosis, with significantly higher bleeding rates in never treated patients as compared to treated patients, probably due to PVT-related hemodynamics. If the need for anticoagulant treatment in patients with cirrhosis-associated PVT is supported by increasing evidence, the optimal timing for starting treatment remains controversial, evidence is lacking, and individual patient\u2019s characteristics solely drive the decision. A small retrospective study including 66 patients with liver cirrhosis-related PVT reported that the time between diagnosis and starting of treatment was not associated with vein recanalization. However, no information was provided about the stage of thrombosis and about half of anticoagulated patients stopped treatment prematurely, mostly due to patients\u2019 decision or minor bleedings. Another retrospective study including 55 cirrhotic patients with acute or recurrent PVT reported that anticoagulant treatment started within 14 days from diagnosis was associated with higher rates of vein recanalization than a delayed treatment strategy. Data on a longer time interval between PVT diagnosis and treatment administration were conflicting possibly due to the different methodology for the estimation of thrombosis occurrence time., 17, 18 For example, the presence of symptoms, the analysis of previous radiological imaging, and the radiological characteristics of the thrombus at diagnosis were taken into account in two studies, while any information regarding the methodology to assess the stage of thrombosis were reported in a latter study., 17, 18 Consequently, it should be acknowledged that the proportion of patients with acute/recent or chronic PVT differed across these studies., 17, 18 This lack of knowledge hampers clinical decision that remains guided by experts\u2019 opinion and mainly based on patients\u2019 characteristics and prognosis.Acute or recent PVT is less common than a chronic thrombosis in cirrhotic patients but may cause an increase in portal pressure and an higher risk of portal hypertension-related bleeding. However, the presence of esophageal varices should not represent an absolute contraindication to anticoagulant therapy as most of patients with PVT and liver cirrhosis are already receiving prophylaxis.,20 Data from a recent retrospective study comparing the outcomes of varices endoscopic treatment in PVT patients receiving low molecular weight heparin and in patients receiving no therapy showed that anticoagulation did not increase the risk of both post-procedural bleeding and mortality . Of note, 65% of treated patients were receiving therapeutic dose anticoagulation and 95% had high risk varices. Rates of post-procedural variceal bleedings (9%) were higher in a more recent retrospective study, but about one third of patients were on vitamin K antagonists and no information was provided on drugs and dosages associated with bleeding events.The presence of esophageal varices may pose some concerns about the safety of a prompt starting of anticoagulant treatment, early esophagogastroduodenoscopy is not always feasible, and anticoagulant therapy may complicate this latter procedure.i.e., prophylactic or half therapeutic dose) within 14 days from PVT diagnosis in the absence of active bleeding or other contraindications. The dose of low molecular weight heparin may be increased to therapeutic doses, or oral anticoagulant therapy may be started after a proper endoscopic and/or pharmacological prophylaxis for esophageal varices has been achieved.Based on this limited evidence, experts have suggested to start treatment with a reduced dose of low molecular weight heparin . The need and dose of anticoagulant therapy should be periodically reassessed to ensure a favorable risk to benefit profile.Chronic PVT is generally characterized by signs of longstanding thrombosis including the presence of intra-abdominal venous collaterals or cavernous transformation of the portal vein.Anticoagulant therapy provides beneficial effects in portal hemodynamics of patients with both acute and chronic PVT. A prompt start of therapy should be considered for most patients, specifically in whom thrombotic risk exceeds the bleeding risk. In patients with high-risk varices, adequate pharmacological and/or endoscopic prophylactic strategies should be implemented as soon as possible. When indicated, anticoagulation should be started within the first 2 weeks from the diagnosis of acute PVT, possibly starting with reduced doses of low molecular weight heparin that may be increased or switched to oral anticoagulation based on patients and thrombosis characteristics."} +{"text": "Patterns of species diversity have been associated with changes in climate across latitude and elevation. However, the ecological and evolutionary mechanisms underlying these relationships are still actively debated. Here, we present a complementary view of the well-known tropical niche conservatism (TNC) hypothesis, termed the multiple zones of origin (MZO) hypothesis, to explore mechanisms underlying latitudinal and elevational gradients of phylogenetic diversity in tree communities. The TNC hypothesis posits that most lineages originate in warmer, wetter, and less seasonal environments in the tropics and rarely colonize colder, drier, and more seasonal environments outside of the tropical lowlands, leading to higher phylogenetic diversity at lower latitudes and elevations. In contrast, the MZO hypothesis posits that lineages also originate in temperate environments and readily colonize similar environments in the tropical highlands, leading to lower phylogenetic diversity at lower latitudes and elevations. We tested these phylogenetic predictions using a combination of computer simulations and empirical analyses of tree communities in 245 forest plots located in six countries across the tropical and subtropical Andes. We estimated the phylogenetic diversity for each plot and regressed it against elevation and latitude. Our simulated and empirical results provide strong support for the MZO hypothesis. Phylogenetic diversity among co-occurring tree species increased with both latitude and elevation, suggesting an important influence on the historical dispersal of lineages with temperate origins into the tropical highlands. The mixing of different floras was likely favored by the formation of climatically suitable corridors for plant migration due to the Andean uplift. Accounting for the evolutionary history of plant communities helps to advance our knowledge of the drivers of tree community assembly along complex climatic gradients, and thus their likely responses to modern anthropogenic climate change. Latitudinal and elevational gradients of species diversity have captured the attention of biologists for centuries . HoweverOne of the most prominent historical mechanisms proposed to explain the assembly and diversity of communities along large-scale environmental gradients is the tropical niche conservatism hypothesis (TNC) ,11. ThisThe simplicity of the tropical niche conservatism hypothesis makes it a very attractive mechanism to explain the ubiquity of large-scale diversity gradients. However, most real-world communities and regional biotas integrate species from multiple lineages with diverse evolutionary and biogeographic histories ,14,15. FIn this study, we tested the TNC and the MZO hypotheses using laTo test the predictions from the TNC and MZO hypotheses, we used a combination of computer simulations to evaluate theoretical predictions and empipbtree function available in the phytools R package . In. In40]. Quercus humboldtii, Weinmania pubescens, Podocarpus montana, etc.) can help explain why tropical highlands can show similar aboveground carbon productivity to tropical lowlands [A remaining open question is to define the main evolutionary traits that characterize functional differences between tropical and temperate lineages. Along the elevational gradient, lowland tropical taxa may have had to reduce total mass and size to survive in the colder, more seasonal, and less productive highlands. In contrast, large temperate species that have migrated to colder and more seasonal tropical environments such as highlands do not seem to have reduced their size in tropical highlands ,42. The lowlands . We hypolowlands and incllowlands .In conclusion, the multiple zones of origin (MZO) hypothesis highlights the importance of the bidirectional historical dispersal of lineages between tropical and temperate biomes shaping plant phylogenetic diversity along latitudinal and elevational gradients in the Andes. The historical exchange of lineages along latitude and elevation may have been fostered by the formation of climatically suitable corridors for plant migration along with mountain uplift. The observed increase in phylogenetic diversity with elevation and latitude found in both the simulated and the empirical datasets does not support the idea that broad-scale diversity gradients are generated primarily through a single ecological zone of origin centered in the tropical lowlands and thus questions the generality of the tropical niche conservatism hypothesis in its current form . The tro"} +{"text": "Millions of children living with severe neurological impairment have a limited ability to connect with the world, depriving them of fundamental rights. Brain-computer interfaces (BCIs) are a rapidly evolving potential solution. Despite progress in BCI technology and design and a well-defined need, children have been almost entirely neglected from BCI research. This is changing and this Research Topic provides concrete examples of how fundamental issues are being addressed in the rapidly emerging field of pediatric BCI.Rowley et al. identify power mobility as one common goal for families of children living with severe neurological disabilities. They demonstrate the ability of a clinical pediatric BCI program to organize a pilot clinical trial, combining simple, practical BCI systems with established power mobility training techniques. Endorsed by participant families, their results demonstrate the feasibility of such approaches and provide evidence of functional performance that promises to drive future studies.Patient-oriented approaches are critical to the design of BCIs that address the needs of pediatric populations. Keeping with patient-oriented design, Floreani, Mussi and Adams conducted a broad review of hybrid EEG-based BCI systems viewed from the perspective of children with complex needs and their families. Including >40 relevant studies, they describe multiple strategies for the design of hybrid BCIs, including selection of system and paradigm elements, that promise to inform future research efforts and could help bring modern hybridization approaches to pediatric BCI.Hybridization of BCIs with other assistive technologies is a well-considered strategy to maximize performance and practical impact. Although compelling uses for such techniques are easily imagined, research to date for children has been limited. To fill this gap, Jadavji et al. confirm the ability of children with large brain lesions to operate simple BCI systems and favorable tolerability of pairing motor EEG signals with execution of functional movements in the paretic limb. Phase 2 clinical trials appear to be on the immediate horizon.The use of BCIs for clinical rehabilitation is a rapidly advancing area of research that has particular relevance to pediatric populations. For example, all the research on BCIs for rehabilitation of stroke-induced hemiparesis has focused on adult populations even though a comparable burden is found in children with hemiparetic cerebral palsy. An initial step toward closing this gap is the first pilot trial of combining BCI with functional electrical stimulation (BCI-FES) in a group of children with perinatal stroke and hemiparesis. Warschausky et al. describe an important advancement on this issue, evaluating a BCI-adapted version of a standardized test in young people. In demonstrating a strong correlation between the standard and modified versions of the Peabody Picture Vocabulary Test they provide early evidence supporting the psychometric properties of BCI-assisted cognitive assessments. Supplemented by consideration of fundamental challenges of BCI use in children, Huggins et al. further explore specific issues around BCI-based cognitive assessments in an accompanying perspective. Challenges addressed include the design of BCIs for participants with limited alternative communication strategies and practical issues of evaluation design, environmental factors, and interpersonal interactions. These efforts highlight some of the greatest differences between designing BCIs for adult populations, where cognition is often predictably intact, and strategizing BCIs for the more complex brains of children with severe disabilities since birth.Recognizing and liberating the hidden cognitive potential of children with severe physical disabilities is a primary aim of pediatric BCI development. A major challenge is the inability to apply age-appropriate developmental evaluations in children with limited communication abilities. Floreani et al. explored the ability of functional near infrared spectroscopy (fNIRS) to detect emotional valence in typically developing school-aged children. Testing and validating a technique that is well-established in adults like fNIRS-BCI in the developing brain makes fundamental progress toward the use of BCIs by children. Even more innovative and clinically relevant is the concept of capturing and using emotional states. Such paradigms remain unexplored in children despite the high proportion of pediatric BCI candidates who have limitations in communication and cognition where such approaches may be impactful. Their initial validation of the concept merits further investigation while their technique of simultaneously expanding technological and methodological approaches serves as an example for pediatric BCI researchers.Establishing fundamental design guidelines for BCIs in children will accelerate the adoption of these technologies in pediatric populations. The examples contained here suggest that the unique needs, methods, and opportunities for BCI to impact the lives of children with complex needs are beginning to be defined. Examples are myriad but may include adapting adult approaches to truly unlock BCIs for communication beyond spellers and for those with alternatively developed communication pathways, bidirectional BCI for improving child-centered feedback, how BCIs could be presented and taught for \u201cintuitive\u201d use by children, how current standards of BCI stimuli could be more appealing for kids, how to address attention and fatigue to enable extended use by young users, BCI opportunities for unique pediatric goals such as play, music, art, and social networking, and many others. The number of opportunities for BCI to positively impact the lives of children with severe neurological disabilities would appear unlimited.All authors contributed to the editorial and have approved the final version."} +{"text": "Screening and treatment guidance for somatic sequalae of eating disorders typically include specifics such as laboratory testing, observable physical signs, and treatment interventions. Oral health guidance is notably sparse or absent from many guidelines. Often, the only mention of oral health is the potential erosion caused by self-induced vomiting and suggests a referral to an oral health professional. The guidelines generally do not include information about education and training of oral health professionals.The objective of this research was to explore the literature on eating disorders and oral health including the effects of eating disordered behaviors on oral health and training of oral health professionals to increase their capacity to recognize and appropriately address clinical care needs of individuals with eating disorders.A comprehensive scoping review was conducted to investigate what is known about the relationship between eating disorders and oral health and training provided to oral health professionals in recognition and treatment of individuals with eating disorders. The search was completed using PubMed, Embase, Science Direct, Google Scholar, and the Journal of the American Dental Association.Of 178 articles returned in the initial search, 72 full texts were read, and 44 were included based on eligibility criteria. The retained articles were categorized thematically into articles related to (1) oral health professional education and training, (2) the oral health effects of eating disorders, and (3) patient experiences of oral health care.Most of the research on the relationship between eating disorders and oral health examines the impact of eating disordered behaviors. There is a significantly smaller literature on the knowledge and training of oral health professionals related to eating disorders and individuals with eating disorders\u2019 experiences of oral health care. Research on education and training of oral health professionals should be expanded globally, taking into consideration the suitability of interventions for diverse models of oral health education and service delivery. Further, there is an opportunity for eating disorder professionals and professional organizations to improve understanding and care of eating disorders by building relationships with oral health providers and professional organizations in their local communities. Oral health professionals, including dentists and dental hygienists, are well positioned to observe signs of eating disordered behaviors during routine oral health care. To gain an understanding of what is known about the relationship between eating disorders and oral health, we reviewed research studies that discussed any aspect of this relationship. We identified 44 studies meeting our criteria. Most of the extant research focuses on the impact of eating disorders on oral health. Smaller portions of the literature discussed education and training of oral health professionals and patients\u2019 oral health behaviors . Educational interventions to increase oral health professionals\u2019 knowledge of eating disorders and confidence in raising concerns with patients are effective, but evidence about whether they are being implemented in training programs is lacking. Further, many studies indicated the need to connect oral health professionals to eating disorder treatment providers. Additional research is needed to develop guidance and best practices for collaboration between fields. Eating disorders are serious psychiatric illnesses with substantial morbidity and mortality, causing significant disturbances in somatic health and psychosocial functioning \u20133. ReseaAcross health conditions, it is widely understood that early identification and intervention leads to better health outcomes. The same is true for people with eating disorders. The paucity of guidance regarding the link between oral health and eating disorders means that health conditions are not addressed until the impact is severe. A significant benefit of early intervention is that it decreases the time of untreated illness , which iGiven the particular effects of eating disorders on oral health, and the opportunity for oral health providers to play an instrumental role in early detection of eating disorders, the purpose of this study was to assess the status of research on clinical implications and provider education about eating disorders for oral health providers. Additionally, as the reported rates of eating disorders education and training are generally low, the question remains whether such training is provided for OHPs given the high rates of oral health symptoms that individuals with eating disorders experience. Presently, there is limited research on oral health and eating disorders, with existing systematic reviews focusing on clinical presentation. The primary aim of this study is to examine the literature on eating disorders and oral health broadly to capture clinical research and topics such as dental education and training.A scoping review was conducted to identify key concepts, sources of evidence and research gaps at the intersection of eating disorders and oral health. Scoping reviews are appropriate in cases where there is uncertainty about the breadth of the literature on a topic. Accordingly, the study was conducted with the methodology and guidance in Peters et al. and from PRISMA , 18. A sAn initial 178 articles were identified from the search terms Fig.\u00a0. Of thesThe 17 articles about oral health professionals fell into three overarching categories: knowledge, education, and practices.Seven of the articles assessed OHPs\u2019 knowledge of the oral health signs of eating disorders, symptoms of eating disorders, how to raise concerns with a patient, and where to refer a patient for treatment if necessary. Of these seven articles three studies included dentists and dental hygienists , 27, thrAdditional studies addressed education provided to oral health students about eating disorders and interventions to improve student and provider knowledge. The study populations included deans of dental schools and directors of dental hygiene programs , dentistThe final category of articles relates to specific practices of OHPs when working with patients who have eating disorders. Of the four articles in this category, three are case studies providing insight into procedures OHPs used to address specific effects of eating disorders on oral health. In a 2014 paper, Lee et al. present two cases of adolescents who restricted food intake as a result of wearing braces that led to hospitalization for eating disorders . The twoThe largest numbers of articles generated by the scoping review focused on the oral health effects of eating disorder behaviors. One study examined the prevalence of erosive lesions in a cross-section of Polish 18-year-olds and found that lesions were significantly associated with eating disorders .\u00a0Eleven Two articles described the impact of eating disorder behaviors in individual cases. One study described a patient who\u2019s self-induced vomiting led to necrotizing sialometaplasia and significant dental erosion . The othA final study designed and tested a questionnaire to identify oral health risk factors and symptoms in individuals with anorexia nervosa. A 26-item questionnaire was assessed and found have moderate reliability when administered as a self-report form. The ten most reliable items from the original questionnaire were recommended as a risk assessment in patients with anorexia nervosa .The remaining seven articles evaluated dental fear and anxiety, oral hygiene knowledge and attitudes, and oral health behaviors in individuals with or at-risk-for eating disorders. Three articles identified elevated dental fear and anxiety among individuals with or at risk for eating disorders compared to those without \u201362. ThesTwo papers evaluated oral health concerns, sources of information about oral health effects of eating disorders, and willingness to see OHPs in people with eating disorders , 57. BotConviser et al. and Dynesen et al. also evaluated oral care behaviors following self-induced vomiting. Conviser et al. asked whether participants rinsed the mouth with water or a mouth rinse (84%) or brushed their teeth immediately after (33%) purging. Dyneson et al. study summarized the findings of participants\u2019 oral health behaviors following SIV as neutralizing acid in the mouth (34%) and avoiding toothbrushing (29%). Both studies, along with Wilumsen et al. , and JohAdditionally, Dynesen, Willumsen, and Johanssen asked participants about frequency of visits to an OHP. Dynesen et al. framed the question in terms of frequency, with 33% reporting visiting the dentist more than twice per year . WillumsThe last study examined differences in behaviors in individuals with eating disorders at different clinical presentations in their eating disorders. They compared participant responses when symptoms were relatively absent (defined as ED-good) and when they were more \u201cactive\u201d or highly symptomatic (defined as ED-bad) . They foThis scoping review investigated the state of evidence about oral health and eating disorders. In addition to literature on the oral health sequalae of eating disorders, included articles addressed (1) eating disorder knowledge and education of OHPs, (2) interventions OHPs use to treat effects of eating disorders, and (3) patient attitudes and behaviors related to oral health care. Across the different categories of studies, a consistent finding was that OHPs do not receive sufficient education and training to address eating disorders in practice\u2014inhibiting early identification, treatment, and referral.OHPs\u2019 insufficient knowledge of eating disorders is evidenced by an absence of or minimal educational content on eating disorders and lack of clinical exposure to patients with eating disorders in training programs. The insufficient training received in OHP training programs is similar to medical training programs \u201316, 63. Research examining methods to educate OHPs about eating disorders found promising results. Knowledge about eating disorders and their presentation was increased, and the interventions were considered acceptable to participants. While both a static e-learning training and an interactive training improved participants\u2019 knowledge of eating disorders, the interactive training was superior at reducing OHPs\u2019 perceived barriers to secondary prevention, increasing perceived benefits of secondary prevention, and increasing perceived self-efficacy to perform secondary prevention behaviors . The smaOne major area of note across the included studies was the assertion that OHPs need to be connected to eating disorder professionals. No studies were identified that examined mechanisms for connecting OHPs and eating disorder professionals. The eating disorders field has an opportunity to build relationships with local and national oral health provider organizations and with local providers to increase awareness of referral resources and offer support to OHPs who may be among the first providers to observe an eating disorder. Increasing OHPs awareness of resources for eating disorder treatment and eating disorder treatment providers\u2019 knowledge of oral health risks and referral resources presents an opportunity for research into methods to incorporate OHPs in eating disorder treatment teams. The clearly stated need for these relationships and the noted lack of research indicates an important area of study for researchers across the globe.A small portion of the research in this review examined eating disorder patients\u2019 oral hygiene behaviors and feelings about oral health procedures. The findings in these studies indicate that many individuals do not disclose their eating disorder to OHPs and may engage with oral health care less frequently than clinically recommended. Future research should evaluate whether and how eating disorder treatment professionals can contribute to patient engagement with oral health care. In addition to the potential for engagement between eating disorder professionals and OHPs, there is an opportunity for eating disorder professionals to encourage patients to disclose to OHPs and to address fear and anxiety about oral health procedures. There is also an opportunity to examine the ways that OHPs can be formally included in the American Psychiatric Association practice guidelines for the treatment of eating disorders as members of the multi-disciplinary research team\u2014and whether doing so increases engagement with OHPs.A final note on the findings of this scoping review is that the majority of work on oral health and eating disorders is on the oral health sequalae of eating disordered behaviors. This body of literature has been the subject of previous systematic reviews \u201367. One This research has a number of limitations. First, articles were only included if they were available in English. Several studies returned in the search were excluded based on language that may address some of the topics that were less well represented in this study. Additionally, we did not evaluate the quality of the research. The quality of evidence for oral health sequalae of eating disorders has been previously reviewed. Future research should consider the quality of studies evaluating provider education and training and patient experiences.This scoping review sought to assess the state of research on eating disorders and oral health. While there has been significant research on the impact of eating disorders on oral health, there is a need for research in all other aspects of the intersection between eating disorders and oral health. In addition, there is a clear need to establish relationships between oral health professionals and eating disorder treatment professionals. These relationships would improve patients\u2019 referral to specialty care when symptoms are observed in an oral health setting and increase the potential for improved oral hygiene and clinical outcomes for individuals with eating disorders."} +{"text": "Objectives: To quantify the microorganism burden of rehabilitation gym equipment surfaces as well as to assess the effectiveness of patient\u2019s practice of hand hygiene and our current disinfection methods to reduce burden and transmission of microorganisms during rehabilitation sessions. Methods: A prospective study of environmental contamination using microbiology culture in Khoo Teck Puat Hospital Geriatric Medicine Outpatient Rehabilitation Gym. Results: For both the control and intervention group, the total aerobic bacterial count on the gym equipment after patient use is significant and increase up to 360 CFU per swab. In the control and intervention groups, the total aerobic bacterial counts on the gym equipment before patients\u2019 use were negligible (<10 CFU per swab). The total aerobic bacterial count of the equipment remained negligible (<10 CFU per swab) after patient use and immediate disinfection. We detected discrepancies between the results of the total aerobic bacterial count after patient use between the control and intervention groups. Conclusions: Outpatient rehabilitation gyms are potential reservoirs of microorganisms, which may further contribute to the transmission of healthcare-associated pathogens. In this study, an intervention in which cleaning equipment was wiped with alcohol wipes was effective in reducing microorganism transmission in the rehabilitation gym environment and should be considered as part of our infection control strategy. The additional step of involving our patients in using hand rub before the start of their therapy sessions can provide additional benefit in reducing microorganism transmission only if patients adhere to the World Health Organization (WHO) recommended 7 steps of proper hand rub. Good patient education on hand hygiene is equally as important as that for healthcare professionals to control environmental contamination."} +{"text": "Novel approaches to prevent and treat intracellular bacterial infections\u201d, highlighting common themes that emerge from the research.Infectious diseases caused by intracellular bacterial pathogens present a considerable health threat, requiring innovative strategies to overcome the limitations of traditional antibiotics, which cannot easily penetrate and accumulate inside host cells. This Research Topic brings together a collection of papers that explore \u201cZhong et al. investigate the activity of essential oil from satsuma mandarin against Aeromonas hydrophila, showing that it disrupts the extracellular membrane permeability, while Sawicki et al. explore the impact of propolis treatment on the metabolic pathways and cell envelope of Mycobacterium tuberculosis.Two studies focus on the discovery and evaluation of alternative antimicrobial agents from natural products. Zhou et al. provide an extensive review of various targets within the cell wall, highlighting their significance in bacterial growth and virulence. The authors emphasize the need for innovative methodologies to discover new antibiotics that target the cell wall components effectively.Targeting the bacterial cell wall is another common theme. Hou et al. review the use of non-antibiotic compounds for preventing and suppressing chlamydial infections. This approach aims to identify alternative strategies beyond traditional antibiotic treatments, considering the potential risks of antibiotic resistance.Addressing the challenges of antibiotic resistance and treatment failures, Zhang et al. develop composite nanoparticles loaded with cellulase and levofloxacin, combined with ultrasound irradiation, to target Mycobacterium tuberculosis biofilms. Du et al. investigate the effectiveness of silver nanoparticles in treating multidrug-resistant Escherichia coli infections in mice. Both studies highlight the potential of nanotechnology-based approaches for improved bacterial infection management.Two studies explore the utilization of nanoparticles for intracellular infection treatment. Overall, the findings presented in this Research Topic have the potential to shape the future of intracellular bacterial infection management and contribute to the global fight against antimicrobial resistance. We commend the authors for their valuable contributions and invite readers to delve into these exciting research findings.VB wrote the first draft of the manuscript. All authors contributed to the manuscript revision and have read and agreed to the published version of the manuscript."} +{"text": "The gut microbiome has emerged as a key regulator of response to cancer immunotherapy. However, there is a gap in our understanding of the underlying mechanisms by which the microbiome influences immunotherapy. To this end, we developed a mathematical model based on i) gut microbiome data derived from preclinical studies on melanomas after fecal microbiota transplant, ii) mechanistic modeling of antitumor immune response, and iii) robust association analysis of murine and human microbiome profiles with model-predicted immune profiles. Using our model, we could distill the complexity of these murine and human studies on microbiome modulation in terms of just two model parameters: the activation and killing rate constants of immune cells. We further investigated associations between specific bacterial taxonomies and antitumor immunity and immunotherapy efficacy. This model can guide the design of studies to refine and validate mechanistic links between the microbiome and immune system."} +{"text": "Dicer 1 (gene encoding microRNA processing enzyme) in intestinal epithelial cells exhibit marked changes in the epithelium with reduced number of goblet cells, increased crypt cell apoptosis and inflammation and impaired barrier patients is responsible for a compromised heart function observed in UC subjects. The importance of intestinal exosomal microRNAs in systemic and local tissue injury has also been highlighted in the excellent review by Park et al. Using sepsis as the disease model and aging as the aggravator of septic injury Park et al., hypothesize that basolaterally secreted gut exosomal microRNAs migrate to distant tissues to alleviate septic injury. It is fascinating to imagine how targeting gut exosomal machinery or microRNAs can help mitigate deregulation of peripheral tissue function that is induced by the disturbances in gut homeostasis.Since their discovery in 1993 , microRNng cells . These eng cells . EnumeraLiu et al., in their original research article have explored the TCGA database for differentially expressed Lnc RNAs in colorectal cancer patients identifying 6 Lnc RNAs of prognostic relevance. All articles covered in this Research Topic indicate the significance of studying non-coding RNAs. These RNA species not only can be therapeutic targets but also serves as efficient biomarkers of disease status. Intensive research on these applications, however, is needed to determine their clinical relevance. We hope you share our excitement in reading these articles enumerating some of these research efforts.The role of Lnc RNAs in intestinal disorders is gradually gaining prominence. Due to the added complexity of interaction of Lnc RNAs with microRNAs and RNA binding proteins and their tissue specific effects, the progress on deciphering role of Lnc RNAs in intestinal and other diseases is slow . Non-eth"} +{"text": "Viderman et al. undertook this systematic review with the intent of providing evidence on the potential application of remote monitoring in chronic critically ill patients post-hospital discharge . HoweverFirstly, the research protocol submitted to PROSPERO is about the utilization of devices in the context of brain injuries. Curiously, the authors broaden their research question to encompass critically ill patients. This shift becomes more questionable given that the database search was conducted on 15 May 2021, while the protocol submission followed on 18 June 2021 without apparent alignment with the search strategy. Notably, the keywords and terms for these two topics are quite different, so it is unclear how conclusions can be drawn about remote monitoring of critically ill patients while their original focus was on brain injuries.On the other hand, while the focus of this study centers on the utilization of remote monitoring devices post-discharge; the included papers mainly address deployment of these devices in inpatient settings and their validation in healthy individuals. A notable gap in this systematic review is the lack of papers addressing the utilization of remote monitoring in patients after their hospital discharge. While this review does highlight significant aspects of the remote monitoring and biometric devices era, it is constrained by the questionable validity of its literature search. As a result, it leans more toward a literature or scoping review that addresses remote patient monitoring as a broader health-related concern, rather than a meticulously conducted systematic review. Readers should be mindful of these limitations when interpreting these findings and applying them to their future research.Also, further systematic reviews with more rigorous search strategies and stricter inclusion and exclusion criteria are imperative to address this crucial healthcare issue."} +{"text": "Chronic diseases have a significant impact on life expectancy, quality of life and healthcare costs . The manWingenbach and Zana investigated the potential of encouraging physical activity and social activities through augmented reality games such as Pok\u00e9mon Go. They found that an increase in physical activity and social relationships related to playing Pok\u00e9mon Go augmented participants\u2019 quality of life, providing empirical evidence that augmented reality games can foster social connectedness and overall wellbeing. However, the limitations of these games include the need for ongoing engagement and the potential for overuse or addiction. Despite these challenges, the findings emphasize the importance of integrated programs that encourage lifestyle changes to reduce the risk of chronic diseases and improve mental health by promoting physical activities and social symbiosis.Su et al. identified a subgroup of metabolically healthy obese (MHO) individuals who seemed healthy but still faced an increased risk of developing metabolic disorders and cardiovascular diseases. This review article emphasized the critical role of physical activity in preventing and treating chronic diseases, particularly for MHO individuals, to correct abnormal micro-metabolic pathways of the MHO, regulate metabolic homeostasis, and enhance metabolic flexibility. The study highlighted that MHO individuals may have a normal metabolic profile but still have an increased risk of developing chronic health problems. The review emphasizes the need for healthcare professionals and researchers to be aware of the unique challenges faced by MHO individuals and to develop targeted intervention strategies that incorporate physical activity and other lifestyle modifications to prevent the onset of chronic disease and improve overall health. Sarcopenia, a decrease in muscle mass, strength, and function because of aging, gives rise to declined physical performance and an increased risk of chronic diseases. Kim et al. investigated a method that uses the circumference of calves as a tool for detecting sarcopenia early among healthy Korean adult men. The measurement of calf circumference was found to be an effective tool for assessing muscle mass in the diagnosis of sarcopenia, which enabled effective intervention and improved health results. By using a simple, non-invasive and cost-effective method such as calf circumference measurement, healthcare professionals and researchers can quickly and easily identify individuals at risk of sarcopenia and implement targeted interventions such as tailored exercise programs and dietary counseling. This practical approach can help individuals maintain their muscle mass, strength and overall functional capacity, ultimately improving their quality of life and reducing the burden on healthcare systems.Obesity is a major contributing risk factor in various chronic diseases. Miura et al. observed that the progression of NAFLD in mice could be delayed with the rescue of p62/Sqtsm1 protein in skeletal muscles through the management of muscle health in mice fed with a high-fat diet. This finding highlights the importance of the muscle-liver axis in the management of NAFLD and suggests a novel strategy involving the improvement of p62/Sqtsm1 activity by exercise and dietary intervention. Exercise can improve insulin sensitivity in skeletal muscle, reduce lipid accumulation in the liver and promote the secretion of myokines that can modulate liver metabolism. These factors contribute to the prevention and management of NAFLD. By focusing on the muscle-liver axis and incorporating exercise and dietary interventions, healthcare professionals and researchers can develop more effective strategies for managing NAFLD and reducing its associated health risks. Parkinson\u2019s disease (PD) is a progressive neurodegenerative disorder that impairs motor, cognitive, and behavioral abilities, ultimately reducing overall quality of life. Wang et al. conducted a comprehensive review of the long-term effects of various exercise interventions in healthy older adults and those with PD. The study emphasized the practical application of different exercise methods and demonstrated that tailored exercise programs can have a significant impact on reducing the symptoms and progression of PD. The results showed that these exercise programs led to positive functional and structural changes in the brain, improving exercise performance and daily functioning in participants with PD. In addition, the study highlighted the importance of individualized exercise programs that meet the unique needs of each person with PD, considering factors such as disease severity, physical ability and personal preferences.Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease closely related to obesity and metabolic disorders. The muscle-liver axis plays a crucial role in the development and progression of NAFLD, as skeletal muscle influences liver function through various metabolic pathways. The aforementioned studies underscore the potential of lifestyle change in preventing and managing chronic diseases. Researchers can develop evidence-based interventions that improve wellbeing and prevent chronic diseases by uncovering new diagnostic tools, identifying crucial proteins, or implementing a program of various exercise interventions. However, to optimize the outcome of any lifestyle change strategy, social determinants impacting our health need to be addressed. Medical experts need to recognize that a one-size-fits-all approach to lifestyle change cannot accommodate the vast differences in individuals. These experts need to be vigilant in personalizing the interventions to specific populations and individual needs. Therefore, providing comprehensive and personalized treatments to individual patients requires participation from medical experts and researchers."} +{"text": "Lipid metabolism is pivotal in controlling energy homeostasis. Impaired lipid metabolism is a hallmark of numerous health problems, including adiposity, cardiovascular diseases, diabetes, and several types of cancers . This SpGrowing evidence demonstrates that the lipid metabolism of peripheral tissues is modulated by peptide hormones . LeciejeThere is growing evidence that the metabolism of lipids is influenced by genetic variability, different miRNAs, and epigenetic modifications ,6. AlanbThis Special Issue also includes two review articles. Our research group discussed the potential role of selected peptide hormones discovered in the present century in controlling the formation and biology of white and brown adipocytes . FurtherIn conclusion, the experimental data published in this SI significantly improved our knowledge of the role of peptide hormones in controlling lipid metabolism in adipose tissue and other peripheral tissues such as muscles. This SI also sheds light on the importance of miRNAs expression and epigenetic mechanism in controlling lipid metabolism, adipose tissue development, and its endocrine and metabolic activity. We believe the published results will play a key role in future research aiming to identify new diagnostic and therapeutic tools in lipid metabolism abnormalities and adipose dysfunction."} +{"text": "The emerging field of advanced imaging technologies in biology and medicine is paving the way for novel applications. Advanced imaging employs sophisticated detection schemes that combine one or more complementary imaging modalities with cutting-edge image analysis. Such multimodality leads to significant improvement in data interpretation and new possibilities of real-time applications in biology and medicine. The aim of this Research Topic is to shed light on recent progress and trends in the development of imaging methods and approaches in biomedicine.in vivo imaging of complex vessels and nerves using computed tomography and widefield imaging. Relaxation and contraction dynamics of vessels and nerves can be monitored by specific labelling methods after intravenous administration of a contrast agent that can be easily imaged. However, detection of specific biomarkers indicating changes in cancer tissue metabolism is often done by immunostaining. With the advanced technique of multiplex immunohistochemistry, multiple parameters can be used to generate large image datasets. These datasets from different modalities can be further analyzed using machine learning methods, leading to new predictive tools for bioimaging.Imaging of blood vessels may reveal significant vascular dysfunction. In particular, the hypoxic state affects not only red blood cells and haemoglobin oxygen saturation but also endothelial cell dysfunction. Monitoring of altered cellular metabolism can be performed by label-free methods such as atomic force microscopy and Raman imaging of specific proteins or by The current Research Topic in Frontiers in Cell and Developmental Biology includes six articles from 58 authors, covering a wide range of advanced imaging technologies, analysis approaches, and applications. The authors have shed light on the use of advanced imaging approaches for recent and ongoing research efforts in biology and medicine. A total of five original research and one data report articles in this research area have been accepted. The collection encompasses different areas of investigations as further detailed by the sections below.Angom et al. investigated nanomechanical changes in the membrane and analyzed in detail the morphological and structural changes of endothelial cells by atomic force microscopy under hypoxia-induced senescence. Their work identified vascular endothelial growth factor and Yes-associated protein of the Hippo pathway as important in the signaling pathways in this condition. These signaling pathways and nanomechanical changes in endothelial cells may therefore be important targets in age-related disease models.Cellular hypoxia has been hypothesized to play an important role in the ageing process. Endothelial cell dysfunction may be responsible for the development of various diseases. Hypoxic conditions acting on cells can change their phenotype to senescence and affect the expression of vascular endothelial growth factor in these cells. Abramczyk et al. studied the oxidized and reduced forms of cytochrome c in sperm cells using Raman imaging. They identified cytochrome c as the key molecule that determines the life and death of human male reproductive cells. In this work, Raman imaging represents a label-free technique that has been shown to be a useful tool for rapid fertility testing based on the redox status of mitochondria.Cytochrome c redox balance plays an important role in mitochondrial state and cellular respiration. Kronsteiner et al. used microcomputed tomography and three-dimensional reconstructions to visualize the topography and anatomy of cardiac vagal autonomic innervation in rabbits and pigs from the cervical level down to the heart. Their findings on species-specific cardiac branching highlighted the need for further characterization of cardiac autonomic innervation and new in silico models to improve stimulation patterns for selective cardiac vagus nerve stimulation.Neuro-modulation strategies for peripheral nerves could reduce the extensive use of pharmacological drugs that cause adverse effects in patients. Vagus nerve stimulation may be useful in cardiovascular medicine. Proper knowledge about the morphology of the cardiac vagus nerve is important for selective stimulation. Fujimoto et al. evaluated relaxation/contraction dynamics by imaging a new parameterized model of erectile dysfunction. They visualized analyses of sinusoidal dynamics in the mouse model using Patent Blue dye. The model system they studied provides unique information to further investigate the regulation of erectile dysfunction.Blood vessels and nerves should be coordinated in the proper erectile function of male reproductive organs. Therefore, the penile microcirculatory system and erectile responses might be related. Zhao et al. developed an algorithm to predict haemoglobin concentration and screen for anemia using ultra-widefield fundus images in large datasets of patient samples. The proposed algorithm focuses on the blood vessels in the optic nerve head and macular region with special attention given to the vessels in the periphery of the fundus. The distribution of peripheral vessels is an important parameter than can be enhanced with the deep learning mode. It provides a comprehensive, sensitive, and non-invasive approach for screening and predicting anemia in a large population study.Deep learning algorithms are machine learning techniques that have attracted much interest in recent years due to the rapid detection of selective patterns. Jiang et al. represents the comprehensive study of cell composition, cell functions, and cell-cell interactions in situ. Samples from a liver cancer were analyzed using multiplex staining and then evaluated using machine learning methods for tissue segmentation, cell segmentation, and phenotype.Cancer exhibits different pathological features and metabolic landscapes at different stages, so liver cancer can be diagnosed using serological tests, diagnostic imaging, and histology. Multiplex immunohistochemistry provides a tool to analyze multiple biomarkers in a single tissue section. The work of In summary, this Research Topic gathered a wide spectrum of high-quality articles demonstrating the impact of advanced imaging in the fields of biology and medicine. We acknowledge all authors who contributed to this Research Topic, and we hope that this Research Topic will serve to inspire the scientific community by providing new routes for understanding biological process and human diseases."} +{"text": "Prescription drugs constitute an important component of health care. However, drugs can benefit patients only if they are used appropriately. Drug use evaluation (DUE) can detect inappropriate and/or unnecessarily costly drug therapy and thereby promote the rational use of drugs. Because DUE programs are rarely conducted in Chinese hospitals today, there is a paucity of information on the quality of prescribing, and there is no organization that advocates the conduct of DUEs in China."} +{"text": "Patients with epilepsy (PWE) may experience seizure emergencies including acute repetitive seizures despite chronic treatment with daily antiseizure medications. Seizures may adversely impact routine daily activities and/or healthcare utilization and may impair the quality of life of patients with epilepsy and their caregivers. Seizures often occur at home, school, or work in a community setting. Appropriate treatment that is readily accessible for patients with seizure urgencies and emergencies is essential outside the hospital setting. When determining the best acute antiseizure therapy for PWE, clinicians need to consider all of the available rescue medications and their routes of administration including the safety and efficacy profiles. Benzodiazepines are a standard of care as a rescue therapy, yet there are several misconceptions about their use and safety. Reevaluating potential misconceptions and formulating best practices are necessary to maximize usage for each available option of acute therapy. We examine common beliefs associated with traditional use of acute seizure therapies to refute or support them based on the current level of evidence in the published literature. For patients with epilepsy (PWE), seizure urgencies and emergencies include acute repetitive seizures initially approved rectal administration of diazepam for treatment of seizure clusters Myths and misbeliefs regarding the limitations of acute rescue therapies may contribute to antiseizure medication (ASM) usage that is not approved by the FDA for this indication In this consensus report, we explore misconceptions that exist about the use of acute seizure therapies. Furthermore, we sought to address safety limitations involving both FDA-approved use and off-label use of rescue therapies available for PWE. The objective of this report is to identify potential pitfalls and misconceptions associated with acute seizure therapies and provide clinical pearls about treatment based on evidence obtained from the current treatment landscape.Potential misconceptions about acute seizure therapies were identified from expert consensus comprising authors within the United States (U.S.), focusing on misconceptions and misbeliefs that were selected based on treatment agents for acute seizure urgencies and emergencies. The focus of this paper does not examine misconceptions associated with this type of treatment in the European Union (E.U.) or other areas of the world, which may differ. Viewpoints and perspectives from additional countries and global regions, although valuable for global inclusivity, are not directly aligned with the focus and scope of this U.S.-centered paper. For example, buccal and intranasal midazolam formulations are approved for prolonged acute convulsive seizures in the E.U. Here, common myths and misconceptions in U.S. practice were stratified by the authors; a narrative review of the literature was performed to obtain a broad perspective. The most relevant ones were selected based on the frequency of occurrence. These misconceptions were then categorized according to patient populations, formulation, route of administration, efficacy, or safety. To dispute or ratify concepts, published literature on treatment of seizure emergencies was accessed using PubMed to support or refute each concept. Using current evidence from selected literature, each concept was designated as either supported or refuted . As the These concepts address respiratory depression, clinical tolerance, and nasal irritation associated with intermittent use of acute seizure therapies.Overall, use of benzodiazepines in patients with epilepsy may be associated with concern for cardiorespiratory events such as respiratory arrest and hypoventilation In open-label clinical trials for the evaluation of intermittent use of benzodiazepine acute seizure therapies in epilepsy, treatment-related respiratory depression was not reported Clinical tolerance does not develop during acute intermittent benzodiazepine therapy and was not observed in clinical trials. With rectal diazepam, there was no evidence that higher doses resulted in tolerance nor altered the effectiveness of diazepam Respiratory depression and clinical tolerance over time are NOT characteristic of benzodiazepine acute seizure therapies.Nasal discomfort may be a concern for intranasal acute seizure therapies due to previous experience with use of atomized IV formulations or prior investigational nasal formulations. For example, in a study evaluating intranasal use of an injectable midazolam solution (pH of\u202f\u223c\u202f3) when used by this route to abort seizures, patients reported considerable pain immediately after administration The assumption that mucosal irritation should be expected with intranasal administration of medication stems from use of formulations not approved by the U.S. FDA for this use. Recently available FDA-approved intranasal formulations of acute seizure rescue medications were specifically designed and developed to reduce the potential for nasal irritation Substantial mucosal nasal irritation should NOT be expected with intermittent use of acute intranasal seizure therapies.Benzodiazepines as ASMs have an important role in epilepsy management. The successful use of chronic benzodiazepines, such as clobazam in patients with Lennox-Gastaut syndrome A phase 3 study of diazepam nasal spray permitted patient use of benzodiazepines as chronic maintenance therapy Concomitant use of chronic benzodiazepines does NOT appear to have an impact on the safety profile of intermittent use of diazepam nasal spray for acute seizure therapy .These concepts are associated with age groups of patients experiencing seizure emergencies.Acute seizure therapy is prescribed at a different rate for children and adults with epilepsy. One cross-sectional observational study surveyed 100 families that included a child with epilepsy aged\u202f\u2264\u202f21\u202fyears The prevalence of epilepsy is 2.6 to 6 million people in Europe and >3 million in the United States Untreated seizure emergencies can have devastating consequences. Therefore, treatment in the form of an acute ASM is needed to interrupt seizures and prevent progression to acute repetitive seizures or status epilepticus that would require emergency care utilizing accessible healthcare resources and facilities Intermittent use of acute seizure therapy is needed NOT ONLY for children with epilepsy, but also for adults.Written treatment plans are often a requirement for children with epilepsy who attend public schools in case medication needs to be administered by school personnel For other chronic medical conditions that require emergency treatment , self-management, education, and action plans demonstrate that written plans are beneficial for patients of all ages Seizure action plans for children with epilepsy have shown benefits for patients and caregivers. One study looked at the effects of a new standardized SAP form in a pediatric neurology clinic and found that SAPs increased parental knowledge and confidence about their child\u2019s epilepsy treatment compared with those who did not receive a plan Guidelines and templates for SAPs allow standardization Written SAPs are useful NOT ONLY for school-aged children, BUT ALSO for adults with epilepsy.These concepts are associated with comparisons among medications and appropriate usage of different formulations for acute seizure therapies.The limitations of IV and rectal administration of ASMs for seizure emergencies led to investigation of potential fast-acting intranasal therapy that could be easily administered by nonmedical individuals Potential shortcomings of intranasal administration of solutions designed for IV use include inadvertent swallowing of medication, nasal irritation, and variable absorption and bioavailability (absolute levels and time to reach therapeutic levels) These limitations are less likely to be associated with formulations that are specifically designed for intranasal administration When used as an intranasal rescue therapy, all benzodiazepine formulations DO NOT work the same way.Oral ASMs have been used predominantly in adult patients as a common route of administration and are more socially acceptable than rectal administration The potential shortcomings of orally administrated tablets and oral formulations include aspiration risk, delayed time to efficacy, first-pass metabolism, and incomplete ingestion limited by swallowing Intranasal formulations of acute rescue medication provide advantages over limitations imposed by rectal administration and the ability to overcome those associated with oral agents Oral benzodiazepines DO have shortcomings as an acute seizure therapy in adults.These concepts are associated with who can administer acute seizure therapy and when these therapies should be administered.Intravenous administration is the gold standard therapy for aborting seizure emergencies including status epilepticus The time and access required to secure IV administration contributes to the need for developing an intermittent acute seizure rescue therapy for use outside the hospital setting Acute seizure rescue therapies for seizure clusters that occur in the home or community setting should be easy to use by lay personnel, including caregivers PWE in a phase 3 open-label safety study of diazepam nasal spray and their caregivers completed survey questionnaires about usage of the study therapy; 27 of the 163 patients who used intranasal diazepam spray reported self-administering medication Non-parenteral formulations of acute seizure rescue therapy, including rectal gels and nasal sprays, CAN be administered by nonmedical individuals such as care partners and school personnel and in some cases self-administered by patients themselves.status epilepticus. Because the majority of seizures are brief, if seizures last longer than 5\u202fmin they are likely to continue. Therefore, benzodiazepine treatment for convulsive status epilepticus is begun at 5\u202fmin to minimize risks of seizure prolongation and the consequences of overtreatment In 2016, the Guideline Committee of the American Epilepsy Society provided guidelines for the treatment of convulsive status epilepticus in children and adult patients with epilepsy Acute repetitive seizures, like status epilepticus, are a medical emergency Two specific situations arise that deserve special consideration. First, patients with a history of a prolonged seizures or status epilepticus are at higher risk to have a subsequent future episodes of prolonged seizures and status epilepticus Data obtained from patient diaries in a phase 3, open-label, repeat-dose safety study of diazepam nasal spray was evaluated in a post hoc analysis to examine the time to administer medication and the time until seizures ceased For patients with a history of prolonged seizures and for those who experience recurrent seizure clusters, waiting 5\u202fmin or until a second seizure occurs to initiate treatment is NOT appropriate for patients with an established pattern.These concepts are associated with clinical results based on the route of administration and use of pharmacokinetic characteristics for assessing the effectiveness of acute seizure therapies.Oral, rectal, and intranasal formulations for acute seizure rescue therapy allow for a variety of routes of administration.max) and to clinical seizure cessation max than intranasal and rectal diazepam; however, use of oral diazepam with food would be expected to result in greater pharmacokinetic variability The rate of absorption for medication used for intermittent acute seizure rescue therapy varies based on pharmacologic and pharmacodynamic factors as well as pharmacokinetics including the route of administration Use of intranasal formulations may reduce time-to-treatment delays in drug delivery Clinical endpoints results are NOT the same irrespective of the route of administration for an acute seizure rescue therapy.max of a medication is equivalent to the onset of action for its use as intermittent acute seizure rescue therapy.There is a belief that the Tmaxmax and instead was shown in an animal model to become effective with a minimal steady-state plasma level of medication to cause seizure threshold elevation to function as an acute antiseizure treatment peri-ictal and interictal diazepam plasma concentrations in the first 6\u202fh following intranasal administration were sustained above the minimal concentration shown to elevate the seizure threshold In the recent literature, the time to effectiveness for medications that are used for acute seizure urgencies and emergencies was not shown to be directly proportional to the TThe time to an acute seizure rescue therapy\u2019s effectiveness CANNOT be determined using pharmacokinetic characteristics.Seasonal allergies may cause inflammation that has the potential to tighten airway mucosa and reduce nasal absorption of topically deposited molecules of medication For intranasal midazolam, patients with allergic rhinitis have not yet been formally evaluated Seasonal allergies and rhinitis do NOT appear to have a clinical impact on the effectiveness of intermittent intranasal drug delivery for acute seizure termination.Current priorities for treating patients with epilepsy should include an up-to-date SAP. Plans for patients who experience seizure urgencies and emergencies should include directions for intermittent use of acute seizure rescue therapies. An array of therapeutic options are currently available, to provide acute seizure rescue treatment for a wide range of patients with epilepsy. Clinicians should be aware of how to distinguish the practical benefits and limitations of each formulation and route of administration so that using acute seizure rescue therapies maximizes effectiveness and safety. This necessitates understanding misconceptions associated with intermittent use of acute seizure rescue therapies to provide the best practices in epilepsy management.Dr Tatum received a stipend from Elsevier as immediate past Editor-in-Chief of Epilepsy & Behavior Reports and is on the Editorial Board of Journal of Clinical Neurophysiology. He has received grant funding from Eisai Inc., Martin Family Foundation, Mayo Clinic, and McElvey Fund, and industry research support from Cerevel, Engage, LivaNova, UCB and Xenon. He has served as a consultant for Bioserenity; Neurelis, Inc.; Natus and Zimmer-Biomet. He has received royalties from Demos, Springer Publishers, and Wiley. He has patents/patents pending on intraoperative monitoring devices . Dr Glauser is a consultant for Clarigent Health and Neurelis, Inc. He receives research support from the National Institutes of Health. Dr Peters has served as a speaker and consultant for Neurelis, Inc.; SK Life Science; and Jazz Pharmaceuticals. Dr Verma is a consultant and member of the speakers bureau for Aquestive Therapeutics; Neurelis, Inc; SK Pharmaceuticals, and UCB. Dr Weatherspoon is a consultant and speaker for Neurelis, Inc. Dr Benbadis is a consultant or member of an advisory board for Eisai Inc.; Jazz Pharmaceuticals; Neurelis, Inc; SK Life Science; Sunovion; Takeda; and UCB. He is a member of the speakers bureau for Aquestive; Eisai Inc.; Jazz Pharmaceuticals; SK Life Science; Sunovion; and UCB. Dr Becker is a consultant/speaker for Neurelis, Inc; SK Life Science; Supernus Pharmaceuticals; and UCB; is a speaker for Jazz Pharmaceuticals; and received research support from SK Life Science. Dr Puri is a consultant for Eisai Inc. and a speaker and consultant for Neurelis, Inc. Dr Smith is a consultant for Azurity Pharmaceuticals and a consultant and speaker for Neurelis, Inc., and SK Life Science. Dr Misra and Dr Rabinowicz are employees of and have received stock options from Neurelis, Inc. Dr Carrazana is an employee of and has received stock and stock options from Neurelis, Inc.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} +{"text": "Intertwined for millennia with the human experience, fungi perform vital functions in our daily life. Without fungi we would not have bread or beer, sake or soy sauce, tofu or miso. Fungi secrete enzymes that deconstruct the world around them into nutrient building blocks which they then absorb for nutrition. For example, the number of enzymes for carbohydrate assimilation continues to expand (Garron and Henrissat, Below I outline a selection of current challenges in fungal biotechnology. The list of challenges and the examples cited are not meant to be exhaustive.Aspergillus niger citric acid process in the US (Currie, A. niger had displaced lemons as the source of citric acid (Neushul, Fungi are a rich and diverse source of metabolic pathways. Through history there are examples of fungal production hosts for several different types of metabolites. One of the early fungal metabolites to be produced on an industrial scale was citric acid. The industrialization of fungal organic acid production arguably began when USDA researcher James Currie published and patented the Currie, . By the Neushul, . Over 10Neushul, . IndustrAnother success for fungal metabolite production occurred during the World War II when teams of researchers from academia, government and industry discovered new fungal strains and developed processes leading to greatly increased production of penicillin, which had been discovered in 1928 by Alexander Fleming Fleming, . PhylogeAspergillus oryzae, a koji fungus, was among the first filamentous fungal genomes to be sequenced; this achievement laid the foundation for genome scale based insights into domestication of fungi for these processes (Machida et al., Saccharomyces cerevisiae are shedding light on domestication and specialization within this species (Gallone et al., S. cerevisiae has been modified to produce the terpene involved in the hoppy flavor so prevalent in IPA style beer (Denby et al., Food and beverage production that involves fungi is also a platform for biotechnological innovation. Not only are they able to derive nutrition from a broad range of building block molecules, fungi secrete a massive array of enzymes to digest complex substrates into building block nutrient compounds. As such, fungi have long been utilized as hosts for protein production. Indeed, recognizing the enzyme production potential of fungi, Jokichi Takamine was granted one of the first biotechnology patents in 1894 for development of a fungal derived digestive enzyme mixture (Takamine, Genome sequencing and molecular analysis continues to provide insight into how fungi regulate their secretome in response to different types of biomass (Benocci et al., Once primarily the domain of model organisms, genetic tractability has been democratized by CRISPR-cas9 methods (Satish et al., The chemical diversity present in the fungal kingdom makes fungi attractive synthetic biology chassis. Understanding the dynamic nature of metabolic pathways and cell signaling is essential for both understanding and designing biosystems. The development of metabolic and regulatory models for a variety of fungi is made tractable by the rapid generation of new genome sequences and genome scale data (Swift et al., The last century has seen great advances in fungal biotechnology from production of enzymes and organic acids to genome sequencing, engineering and modeling. Despite these advances there are still many aspects of fungal biology with potential applications in biotechnology we still do not fully understand. The future will see research focused on translating genomes into functional and phenotypic information that will inform design of fungal biotechnology based solutions to grand challenges in human health, nutrition, sustainable energy, and the environment.SEB conceived and wrote the manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Case Report. Following multidisciplinary discussion, transcervical tracheal resection with limited manubriectomy was successfully performed, without the need for cardiopulmonary bypass, in an adolescent male on ERT with the severe airway manifestations of Morquio A syndrome. His trachea was found to be under significant compressive forces at surgery. On histology, chondrocyte lacunae appeared enlarged, but intracellular lysosomal staining and extracellular glycosaminoglycan staining was comparable to control trachea. At 12\u2009months, this has resulted in a significant improvement in respiratory and functional status, with corresponding enhancement to his quality of life. The primary cause of death in Morquio A syndrome (mucopolysaccharidosis (MPS) IVA) is airway obstruction, brought about by an inexorable and pathognomonic multilevel airway tortuosity, buckling, and obstruction. The relative pathophysiological contributions of an inherent cartilage processing defect versus a mismatch in longitudinal growth between the trachea and the thoracic cage are currently a subject of debate. Enzyme replacement therapy (ERT) and multidisciplinary management continue to improve life expectancy for Morquio A patients by slowing many of the multisystem pathological consequences of the disease but are not as effective at reversing established pathology. An urgent need has developed to consider alternatives to palliation of progressive tracheal obstruction to preserve and maintain these patients' hard-won good quality of life, as well as to facilitate spinal and other required surgery. This addressing of tracheal/thoracic cage dimension mismatch represents a novel surgical treatment approach to an existing clinical paradigm and may be useful for other carefully selected individuals with MPS IVA. Further work is needed to better understand the role and optimal timing of tracheal resection within this patient cohort so as to individually balance considerable surgical and anaesthetic risks against the potential symptomatic and life expectancy benefits. The ubiquitous nature of these proteins means that many organ systems are generally affected [Morquio A syndrome (mucopolysaccharidosis IVA) is a rare autosomal recessive lysosomal storage disease caused by an aberration or total deficiency of the enzyme N-acetylgalactosamine-6-sulphate sulfatase (GALNS). This deficiency leads to the accumulation of partially degraded metabolites of two ubiquitous glycosaminoglycans (GAGs: chondroitin-6-sulphate (C6S) and keratan sulphate (KS)) within lysosomes and the extracellular matrix , individuals with Morquio A syndrome are living longer after earlier initial diagnosis and treatment . The benWe report the novel and successful application of transcervical tracheal resection and limited manubriectomy as a surgical technique for severe airway obstruction in Morquio A syndrome, performed without the need for cardiopulmonary bypass.A 17-year-old male patient with Morquio A syndrome, under the long-term care of the inherited metabolic disorders (IMD) service at Manchester University NHS Foundation Trust (MFT), was referred to the Manchester Paediatric Otolaryngology (ENT) service in November 2019 for airway assessment due to progressive dyspnoea and opisthotonos. At the time of referral, the patient had received ERT for 10\u2009years, having commenced treatment aged 78\u2009months, and his quality of life was otherwise good, attending college, studying drama, and relying only on nocturnal BiPAP for respiratory support. Progressive fatigue due to increasing work of breathing over time left the patient unable to sustain a full school timetable, increased his reliance on powered mobility aids especially outside of home, and limited his sentences to 1 to 2 words.Postpubertal CT imaging demonstrated characteristically tortuous multilevel airway obstruction with a focal segment of severe collapse at the level of the thoracic inlet . Airway After multidisciplinary discussion involving local ENT, respiratory, physiotherapy, and IMD services, robust consensus was reached to pursue active treatment options for the patient rather than palliation, and the UK's National Tracheal service at GOSH was contacted regarding possible tracheal resection or airway stenting. Airway stenting was felt not to provide enough radial force to alleviate his airway stenosis and risked tracheal wall erosion by the stent. Localised resection of tracheal tortuosity at the thoracic inlet was felt likely to provide sufficient symptom relief without the need for cardiopulmonary bypass.n-of-one\u201d nature of the procedure which has not previously been described in literature, and finally, the unpredictability of how underlying Morquio A disease might affect wound healing, with risk of surgical dehiscence or anastomosis failure. Further advice and input were also sought from the GOSH Clinical Ethics Committee, where an opinion in favour of proceeding with the planned procedure was reached [Several challenging factors needed consideration, and a series of collaborative multidisciplinary meetings were undertaken with the patient and his parents. These factors were as follows: the highly technical and challenging nature of the procedure, the patient's extremely high-risk spinal and respiratory comorbidities, the \u201c reached in June Transcervical surgical resection of the most affected proximal tracheal segment was performed in July 2020 . A midliGiven the need for prolonged neck extension with the incumbent risk of spinal cord compression throughout the procedure, spinal neuro-monitoring with motor and sensory evoked potentials was performed at the start of the procedure to determine baseline readings without neck extension as well as the maximal neck extension available without spinal cord compression, and this was actively rechecked throughout the case.The resected tracheal segment was analysed by histology and immunohistochemistry for CD68 (macrophage marker) and LAMP1 . GAG depThe patient was transferred to the paediatric intensive care intubated and ventilated. On the first postoperative day (POD), he developed bilateral pneumothoraces and chest drains were sited. Over subsequent days, sedation was gradually weaned, although the teenage patient found the difficulties associated with an inability to communicate extremely distressing; multidisciplinary input from physiotherapy and psychology were instrumental in his immediate postoperative recovery. He was successfully extubated on POD 4 onto noninvasive ventilatory support (NIV) as a bridging therapy.It is our practice as the National Tracheal Service to use early postoperative endoscopic microlaryngobronchoscopy rather than CT as a measure of postsurgical change, as it is more clinically relevant with regards to the degree of luminal obstruction, enables interventional capability in the case of postsurgical granulations or insertion of luminal stents, and does not confer any additional radiation load. This was performed on POD 7 confirming that the tracheal anastomosis was healing well with no dehiscence or granulation formation quality of life score ).This case illustrates some new key concepts in the pathophysiology and management of Morquio A syndrome airway manifestations. It is generally thought that Morquio A syndrome's pathognomonic tracheal defects arise from (1) mediastinal and thoracic inlet crowding due to the brachiocephalic artery and the manubrium and (2) a longitudinal size mismatch of the trachea . Others In our National Morquio A cohort, we have found no specific risk factor for the development of tracheal narrowing in some patients with MPS IVA and not others, and indeed one sibling with Morquio A may be affected to a far greater extent than another. The main indication for surgical intervention is based on a life-limiting respiratory obstruction alongside objective clinical markers compatible with tracheal narrowing as the primary cause. Patients all go through individualised MDT discussion (which fully include the patient and their family) as to whether their symptoms warrant the risk of surgical intervention.We found that this patient's tracheal rings were under significant compressive forces, in contrast to a normal airway where the proximal and distal portions of the airway separate under tension when transected, which rendered a primary tension-free anastomosis straightforward. On histology, CD68 staining for macrophages did not show the foam cell phenotype or florid cartilage invasion reported in other cases, but tracheal staining patterns for GAGs for our patient were very similar to those seen in normal trachea using established protocols for mucopolysaccharidosis histopathology . IncreasAlthough there have been other cases reported in the literature of successful use of tracheal resection to ameliorate Morquio A syndrome's airway manifestations \u201315, thesIn this case, we have shown tracheal resection via a transcervical approach without the use of cardiopulmonary bypass to be safe and effective in significantly improving the burden of airway symptoms associated with Morquio A syndrome. In the right multidisciplinary and holistic setting, this could open the technique up as an option for other similarly affected patients in the future."} +{"text": "Necessity and fairness require that health plans limit the products and services they cover. The basis for these decisions refers to population averages and related population parameters. However, individuals vary and may not be accurately represented by the parameters used to establish coverage policies. Health plans, therefore, are obligated to anticipate and manage heterogeneity among their member groups. This commentary offers considerations for managing heterogeneity in prescription drug benefits."} +{"text": "It is predicted that the growth in the U.S. elderly population alongside continued growth in chronic disease prevalence will further strain an already overburdened healthcare system and could compromise the delivery of equitable care. Current trends in technology are demonstrating successful application of artificial intelligence (AI) and machine learning (ML) to biomarkers of cardiovascular disease (CVD) using longitudinal data collected passively from internet-of-things (IoT) platforms deployed among the elderly population. These systems are growing in sophistication and deployed across evermore use-cases, presenting new opportunities and challenges for innovators and caregivers alike. IoT sensor development that incorporates greater levels of passivity will increase the likelihood of continued growth in device adoption among the geriatric population for longitudinal health data collection which will benefit a variety of CVD applications. This growth in IoT sensor development and longitudinal data acquisition is paralleled by the growth in ML approaches that continue to provide promising avenues for better geriatric care through higher personalization, more real-time feedback, and prognostic insights that may help prevent downstream complications and relieve strain on the healthcare system overall. However, findings that identify differences in longitudinal biomarker interpretations between elderly populations and relatively younger populations highlights the necessity that ML approaches that use data from newly developed passive IoT systems should collect more data on this target population and more clinical trials will help elucidate the extent of benefits and risks from these data driven approaches to remote care. Age is arguably among the most significant health determinants and is a risk factor for various human pathologies, especially those concerning the heart. Cardiovascular Diseases (CVD), which includes coronary heart disease, stroke, heart failure and peripheral artery disease, are leading causes of morbidity and mortality in U.S. adults and is expected to continue to rise in the future . During Technological advantages within the category of \u201cInternet-of-Things\u201d (IoT) has enabled passive and remote monitoring of data collected across various industries and applications due to ubiquitous internet connectivity, advances in the miniaturization of wireless hardware technologies, and improvements in a wide variety of sensor technologies. Naturally, these advancements have started to emerge in healthcare-specific applications . These tThe adoption of home health technologies among the elderly population has been increasing in recent years . This isThe digitization and consumerization of healthcare is taking disease management along a new paradigm, whereby advanced data analysis techniques that use ML enable more personalized and real-time lifestyle and disease management care in addition to new applications altogether like predictive insights of pending events. These advances come as a consequence of an increase in device connectivity, portability, and tracking passivity which leads to an increase in more data followed an increase in ML capabilities and model training across wider healthcare applications . For exaPrimary risk factors for CVD include diabetes, dyslipidemia, hypertension, and obesity . The prepassivity refers to the degree to which sensors can collect data without user intervention and can range from items with small active interventions like stepping on a scale to devices that have eliminated user intervention such as mains-powered connected smart furniture. This mini review examines the passivity of IoT technologies because the high-frequency, long-term data collection advantages of passive devices enable more sophisticated ML approaches to biomarker discovery and support throughout the treatment journey, especially among the geriatric population where active use of technology can be more challenging [Sensor llenging .Wearable technologies are now available with a wide array of miniaturized sensors that are capable of collecting high-frequency data and used for CVD risk classification, prevention, diagnosis, and treatment management and haveContinuous glucose monitors are growing in use among individuals with diabetes as a means for passive blood sampling and have improved care for many Type 1 and Type 2 diabetics . HoweverSmartwatches and other wrist-borne devices offer some of the most widely tested and adopted technologies for health and wellness monitoring . In addiClothing represents an opportunity for passive monitoring and can provide localized sensor placement beyond the wrist. For example, smart socks have been tested for peripheral neuropathy , as wellIntegrating sensors into furniture and other structures used within the home is another increasingly explored area of passive IoT biomarker monitoring with significant potential for CVD monitoring. For example, chair-shaped systems that measure blood pressure biomarkers using similar technologies in smartwatch systems have been prototyped and tested . Sleep mIn this section, we will explore the prevalent techniques used in analyzing longitudinal health trajectories of geriatric patients, which involves examining patient data during extended durations of time to identify patterns and forecast health trends. Within the context of CVD and hypertension prevention, we will discuss how artificial intelligence (AI) and ML techniques can be used to extract meaningful insights from observed data, and the implications of data security and ownership. This is typically viewed through a 4-layer IoT architecture model whereby the perception layer is responsible for collecting data from sensors and devices, the transport layer moves the data from the perception layer to the processing layer, the processing layer is where the data is analyzed and transformed into useful insights, which are then made available to end-users through the application layer . AdditioSupervised learning: This type of algorithm can be used to predict the onset of chronic diseases and heart issues based on patterns in physiological biomarker data that is pre-labeled before training [training . For exatraining presenteUnsupervised learning: Unsupervised learning algorithms are more exploratory . They can be used to identify patterns, clusters, and anomalies in unlabeled physiological biomarker datasets that may indicate the onset of a chronic disease or heart issue. In European Heart Journal - Digital Health [l Health , a revieReinforcement learning (RL): An RL algorithm learns to make decisions based on feedback from the environment. The algorithm interacts with the environment and learns by receiving rewards or penalties based on its actions [ actions . The goa actions showed hSemi-supervised learning: This type of algorithm combines elements of supervised and unsupervised learning and can be used to make predictions based on a combination of labeled and unlabeled data. Semi-supervised learning has proven to be useful in medical imaging analysis where data availability is often sparse [ed data) .Transformers: Transformers are a type of deep learning algorithm designed to analyze and process large amounts of sequential data, such as natural language text and physiological biomarker data. Transformers use an attention mechanism to focus on different parts of the input sequence when processing each element in the sequence. This allows the model to capture long-range dependencies and relationships between words in a sentence or words in different sentences. Some well-known applications include language translation, question answering, and sentiment analysis. A study published in the IEEE Journal of Biomedical and Health Informatics [ormatics used a TIntegrating AI and ML with IoT has greatly impacted the way passive monitoring of older populations is conducted. AI and ML algorithms can analyze large amounts of data generated by wearable devices, sensors, and health records to identify patterns and predict the onset of disease . This haThe elderly population is particularly vulnerable to having difficulty adopting new technologies due to their age-related physical and cognitive impairments . ReducedWith the rise of remote care services, connected devices, and other digital tools that can now be used in the home setting, there is a heightened need for adequate data protection for seniors who might not have the technical knowledge necessary to safeguard their protected health information. While it is possible for healthcare providers to ensure patient data is legally secured through HIPAA compliance regulations and other standards of responsible practice, there are still additional risks associated with using home health technologies that need to be addressed. For instance, if an elderly patient\u2019s personal device is hacked or stolen then their sensitive medical information could become compromised. Additionally, if an elderly person transfers ownership of their technology device or equipment to someone else, either intentionally or unknowingly, then they could lose control over who has access to their medical history which can result in exploitations and medical identity theft . Recent Despite the many opportunities presented by IoT passive monitoring, there are also challenges that must be addressed. Ethical concerns related to data privacy and confidentiality remain one of the biggest challenges to IoT health data collection and use. Careful consideration must be given to protect sensitive patient data collected from unauthorized access and breaches.Another challenge that must be addressed is the potential for bias in the data collected by IoT passive monitoring systems. The data collected by these systems can be affected by factors such as the type of device used, the location of the device, and the demographics of the patient population. If not carefully monitored and adjusted for, this bias can result in inaccurate and potentially harmful healthcare decisions. Thus, it is crucial for healthcare providers to carefully consider the limitations of IoT passive monitoring systems and develop methods to mitigate these biases. By addressing these challenges, healthcare providers can fully realize the benefits of IoT passive monitoring while ensuring patient privacy and safety.IoT passive monitoring has improved healthcare and medical management for U.S. geriatric populations in a variety of ways that include, but not limited to early detection of chronic diseases, prompt medical assistance, telehealth visitations, and a reduction in human errors . The treThere are opportunities for advancing the field of IoT passive health monitoring by improving the breadth of physiological biomarker detection technologies. The majority of data collection is performed via smartwatches and other wearables that all use a handful of similar sensor modalities. Additional sensor modalities would provide richer data that could improve the accuracy of existing methods or create entirely new applications. Increasing passivity is another significant area of opportunity. For example, current approaches like smartwatches may improve battery performance to eliminate battery recharge burden, or more seamless integration of IoT sensors into furniture, clothing, and home appliances could create more zero-burden data collection platforms. There are significant opportunities in the application of ML algorithms for both novel digital biomarker discovery and better interpretation of health status and personalized health trajectories. The strength and relevance of ML algorithms come from the datasets they are built on and emphasizes the need for more data collection specifically from elderly populations. This will improve accuracy of models within these populations .The adoption of digital health tools such as telemedicine and wearables among the elderly U.S. population is a positive trend that demonstrates an increase in perceived value among the elderly and has significant potential to improve remote geriatric care either directly or through increased datasets used for improving current and future systems that will result in better personalized treatments."} +{"text": "This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) provides an overview of cancer and increased body fat.The scientific information for this CPS is based upon published scientific citations, clinical perspectives of OMA authors, and peer review by the Obesity Medicine Association leadership.Topics include the increased risk of cancers among patients with obesity, cancer risk factor population-attributable fractions, genetic and epigenetic links between obesity and cancer, adiposopathic and mechanistic processes accounting for increased cancer risk among patients with obesity, the role of oxidative stress, and obesity-related cancers based upon Mendelian randomization and observational studies. Other topics include nutritional and physical activity principles for patients with obesity who either have cancer or are at risk for cancer, and preventive care as it relates to cancer and obesity.Obesity is the second most common preventable cause of cancer and may be the most common preventable cause of cancer among nonsmokers. This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) on cancer is one of a series of OMA CPSs designed to assist clinicians in the care of patients with the disease of obesity. Patients with obesity are at greater risk of developing certain types of cancers, and treatment of obesity may influence the risk, onset, progression, and recurrence of cancer in patients with obesity. Encoura10\u2022Short-term weight reduction interventions may favorably affect cancer prognosis 5\u201310\u2009years later.\u2022Preclinical studies support a beneficial effect of calorie restriction and weight loss on both chemically induced and spontaneous tumors\u2022Caloric restriction increases the life span of rodents and dogs and extends the life span and delayed cancer development in rhesus monkeysWhile unintentional weight reduction suggests poor cancer prognosis, intentional weight reduction may be beneficial for patients with obesity/pre-obesity who are at risk for cancer or who have cancer :\u2022Short-t\u2022Reduce the risk for future cancer ,119,120.\u2022Reduce cancer cell multiplication ,121.\u2022Enhance cancer cell death ,121.\u2022Reduce inflammation ,123.\u2022Improved body metabolism with increased insulin sensitivity and lowered cancer-promoting sex hormones .\u2022Bariatric surgery may reduce the risk of cancer and cancer-related mortality , especiaThe cancer-reducing benefits of weight reduction in patients with obesity somewhat mirrors the benefits found with healthful nutrition and physical activity. Weight reduction in patients with pre-obesity or obesity may:11Attaining healthy body weight is a primary goal for nutritional and physical activity-based cancer management in patients with obesity. Given the adiposopathic consequences of obesity that lead to hyperinsulinemia, and given that hyperinsulinemia (a growth factor) may increase cancer risk , then re12A dietary intervention sometimes used in management of patients with obesity is implementation of the ketogenic diet . Given t13\u2022Breast cancer screening\u2022Gynecological exam with Pap smear (which may include assessment of human papilloma virus)\u2022Testicular and prostate cancer screening\u2022Colorectal cancer screening\u2022Skin cancer surveillanceIndividuals with obesity often do not receive the same preventive standards of care as those without obesity. This can be especially relevant to certain types of cancer with increased risk associated with obesity and adiposopathy. Examples of cancer-related preventive medical care (depending upon gender and age) that patients with obesity may not adequately receive include :\u2022Breast A prior Obesity Medicine Association Clinical Practice Statement provided guidance how clinicians may address potential obesity bias within the health care setting, with practical recommendations regarding people-first language, waiting room furniture, medical equipment, and medical devices . With sp14This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) on Obesity and Cancer is designed to help clinicians manage their patients with the disease of pre-obesity/obesity. Patients with obesity are at greater risk of developing cancer. When weight reduction in patients with obesity is achieved by safe and effective interventions such as healthful nutrition and routine physical activity , anti-obThis manuscript was largely derived and edited from the 2021 Obesity Medicine Association (OMA) Obesity Algorithm. Beginning in 2013, OMA created and maintained an online Adult \u201cObesity Algorithm\u201d that underwent yearly updates by OMA authors and was reviewed and approved annually by the OMA Board of Trustees. This was followed by a similar Pediatric \u201cObesity Algorithm,\u201d with updates approximately every two years by OMA authors. Authors of prior years\u2019 version of the Obesity Algorithm are included in Over the years, the authors of the OMA Obesity Algorithm have represented a diverse range of clinicians, allied health professionals, clinical researchers, and academicians. The authEL and HEB reviewed, edited, and approved the document.Potential dualities or conflicts of interest of the authors are listed in the Individual Disclosure section. Assistance of a medical writer paid by the Obesity Medicine Association is noted in the Acknowledgements section. Neither the prior OMA Obesity Algorithms, nor the publishing of this Clinical Practice Statement received outside funding. The authors of prior OMA Obesity Algorithms never received payment for their writing, editing, and publishing work. Authors of this Clinical Practice Statement likewise received no payment for their writing, editing, and publishing work. While listed journal Editors received payment for their roles as Editors, they did not receive payment for their participation as authors.EL and HEB report no disclosures.The content of the OMA Obesity Algorithm and this manuscript is supported by citations, which are listed in the References section.This OMA Clinical Practice Statement manuscript was peer-reviewed and approved by the OMA Board of Trustee members prior to publication. Edits were made in response to reviewer comments and the final revised manuscript was approved by all the authors prior to publication. This submission did not involve human test subjects or volunteers.This Clinical Practice Statement is intended to be an educational tool that incorporates the current medical science and the clinical experiences of obesity specialists. The intent is to better facilitate and improve the clinical care and management of patients with pre-obesity and obesity. This Clinical Practice Statement should not be interpreted as \u201crules\u201d and/or directives regarding the medical care of an individual patient. The decision regarding the optimal care of the patient with pre-obesity and obesity is best reliant upon a patient-centered approach, managed by the clinician tasked with directing an individual treatment plan that is in the best interest of the individual patient.It is anticipated that sections of this Clinical Practice Statement may require future updates. The timing of such an update will depend on decisions made by Obesity Pillars Editorial team, with input from the OMA members and OMA Board of Trustees.Both the OMA Obesity Algorithms and this Clinical Practice Statement were developed to assist health care professionals in providing care for patients with pre-obesity and obesity based upon the best available evidence. In areas regarding inconclusive or insufficient scientific evidence, the authors used their professional judgment. This Clinical Practice Statement is intended to represent the state of obesity medicine at the time of publication. Thus, this Clinical Practice Statement is not a substitute for maintaining awareness of emerging new science. Finally, decisions by practitioners to apply the principles in this Clinical Practice Statement are best made by considering local resources, individual patient circumstances, patient agreement, and knowledge of federal, state, and local laws and guidance.EL and HEB report no disclosures."} +{"text": "Falls and frailty in the older adults are a considerable public health and socioeconomic problem. Physical activity has an important role in delaying degenerative ageing processes and preserving the neuromuscular system\u2019s plasticity. Multicomponent exercise programmes could improve strength (stability), balance, mobility (flexibility) and walking speed; especially if they are carried out for at least some extend of time. Exercise programmes for fall and frailty prevention in community-dwelling older adults should include muscle performance, balance challenging and functional exercises. Slovenia has a long tradition of implementing community organized and structured exercise programmes in Health promotion centres and Healthy clubs. We are establishing new approach of frailty and falls prevention in our elderly population.With the collaboration of professionals in the field of sport recreation, health and fitness we constructed new exercise approach called vAdBeCeDa\u00ae. According to the WHO guidelines of physical activity and sedentary behaviour and the latest World guidelines for fall prevention and management for older adults, the programme is an addition to the existing Slovenian functional exercise programme called Health Promoting Sport Program ABC\u00ae. ABC programme focused especially on developing strength in fundamental movement patterns and influencing aerobic capacity. The supplement includes warm-up exercises adapted to the specific needs and functional status of the elderly, progressive balance-training programme for 12 training units and a set of static stretching exercises with support, due to poor balance. Functional and physical fitness is assed pre and post intervention with Slovenian version of senior fitness test . Programme will be implemented in existing network of Health promotion centres (HPC) and in Healthy clubs (HC) all over the country, where all elderly population could practice on the Slovenian health insurance costs.The results from many longitudinal studies on effects of multicomponent exercise programmes are encouraging, given that maintenance of physical fitness has a successful, prolonged effect on fall and frailty prevention in older adults. All countries should pursue a lifelong physical activity for elderly, which is achievable with community approach and good collaboration between health and sport sector."} +{"text": "Sudden Unexpected Death in Epilepsy (SUDEP) is the unexpected death of a person with epilepsy who was otherwise healthy and no other cause of death was found mechanisms could disrupt brainstem regions important for breathing and/or cardiac function in epilepsy. Original research by Wenker et al. refute the hypothesis that cortical neurons directly drive apnea in the Scn8a mouse model of epilepsy. They found that silencing forebrain neurons could reduce seizure threshold but did not prevent apneas during the tonic phase of seizures. They propose that brainstem circuitry most likely drives tonic phase apneas that are thought to contribute to SUDEP. Different mechanisms (or combinations of risk factors) may be engaged in different people, necessitating additional research using a variety of approaches and animal models.Several hypotheses have been proposed to explain how epilepsy could disrupt the control of breathing. Hampson et al. use functional magnetic resonance imaging (fMRI) to examine changes in brain activity during increased CO2 exposure in persons with epilepsy compared to healthy controls. They show enhanced activation of the dorsal raphe (which contains CO2 sensitive serotonergic neurons) as well as altered functional connectivity between the brainstem and adjacent subcortical areas in persons with epilepsy. These results suggest that the respiratory system may be less able to handle respiratory challenges in persons with epilepsy. Ciumas et al. review the current methods to use fMRI to investigate central respiratory control in human patients. The authors discuss the challenges associated with studying the brainstem nuclei involved in breathing and summarize the various methods that can be used to overcome these challenges. They review examples of studies that have used fMRI to study breathing in various conditions, including epilepsy. Functional imaging is a promising tool that may be useful for identifying individuals that are most at risk for SUDEP as well as probing the mechanisms leading to SUDEP.There are currently no established biomarkers to identify individuals that are vulnerable to SUDEP. Potential predictors of SUDEP under investigation include impaired chemosensory responses, depressed arousal/resuscitation responses, altered brain activity, abnormal respiratory patterns, or altered neurotransmitter release. For example, prior studies have shown that some epilepsy patients have a decreased ability to respond to increased levels of carbon dioxide in the blood, which correlates with longer episodes of respiratory depression following a seizure specific brain regions implicated in SUDEP as well as methods to prevent initiation or propagation of spreading depolarizations. Two original research articles describe potential novel treatment targets: Collard et al. work indicates that the neurotransmitter Galanin holds promise as a potential future treatment because either systemic or central nervous system delivery of galanin analogs could prevent seizure induced respiratory arrest in mouse electroshock seizure models. Fukushi et al. show that inhibition of microglia activation with minocycline delayed seizures induced by hypoxia and reduced the incidence of post-seizure respiratory arrest.There are currently no therapeutic approaches to prevent SUDEP and research in this area presents many challenges, including difficulty assessing which patients are at risk, insufficient understanding of the underlying mechanisms, a lack of animal models to recapitulate all aspects of SUDEP, and the diversity of patients at risk for SUDEP. Epilepsy patients may undergo a vicious cycle whereby seizures impair respiratory responses and impaired breathing increases the incidence or severity of seizures. The complicated interactions between epilepsy and breathing control indicate that collaborations between researchers and clinicians investigating epilepsy and experts on the control of breathing could advance our understanding of SUDEP and accelerate prevention.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "During the early stage of the COVID-19 pandemic, the World Health Organization recommended including risk communication and community engagement (RCCE) as part of national public health emergency responses . This cross-sectional analytical study was conducted in 12 Latin American countries during the pandemic and shows that populations in multiple action scenarios experienced poor pandemic management. The results acknowledged that the most perceived inadequate control mechanisms established by a government were in Honduras, highlighting the unignorable health inequalities during the pandemic. Evidence on the associated factors would also help design effective mitigation plans for future pandemics and other emergencies.Various health control mechanisms and public perceptions of inadequate health control in Latin American countries were examined in the study by researchers from the Universidad de Buenos Aires and the Emergency Organizations-Emergency Information Release Matters (EOs-EIRMs) 2-mode network constructed in the research could help explain the driving factors and implementation mechanism of the temporal evolution characteristics of the collaborative emergency information release model and would help improve the efficiency of information release in other countries during a pandemic.Naqvi et al.). The results highlight the important role that social media plays in vaccine hesitancy as well as identify enabling factors, such as a desire to travel and positive public health messages that can increase vaccine uptake among ethnic minority groups in the UK. Tailored public health messaging to address the concerns of marginalized communities by policymakers was also recognized as a critical issue.Some mitigation and containment measures have unintended consequences, particularly for historically marginalized racial and ethnic groups and health professionals. These communities would face disproportionate impacts of the pandemic , just asGhirotto et al. from Azienda USL-IRCCS di Reggio Emilia investigated the opinions of Italian healthcare professionals who were part of categories affected by the country's mandatory COVID-19 vaccine regulations. The author considered the scientific evidence that drives ethics-related decisions and noted the epidemic of confusing and incorrect information affecting professionals. Increasing disaffection with the healthcare system and professional conflicts also highlights the fundamental role of RCCE in responding to emergencies, especially among healthcare professionals.Through a qualitative online survey, Wang et al.). They reported key material supply problems, including a lack of procurement channels, insufficient material reserves, and insufficient transportation capacity, and provided tips and lessons learned on how to better manage the preparation, dispatch, and transportation of basic necessities that were in shortage for vulnerable populations during the city-wide lockdown in Shanghai.Wang and Wu from Fudan University shared an empirical case on providing basic necessities to vulnerable populations during the COVID-19 pandemic in Shanghai . They presented an empirical study of the effect of a flood event caused by extreme rainfall on COVID-19 prevention behaviors and found that the individual's flood risk perception and response behaviors were significantly correlated with the individual's COVID-19 prevention behaviors. They proposed that community risk preparedness behavior and social capital can moderate the above relationship to a certain extent. These findings would guide risk communication under the complex risk scenario and reduce risky public behaviors during a pandemic.Zhang and Liu from Beijing Normal University put forward a new perspective on RCCE under the compound risk scenario (As we read the articles included in this Research Topic, governments in different countries have adopted a range of strategies for RCCE, with profound consequences, both positive and negative. This Research Topic demonstrates that there are learning opportunities for countries to improve RCCE during a pandemic, and how vulnerable groups were affected and their perceptions varied. It also brought to our attention the complex risk scenario during emergencies and how to balance containment efforts with potentially unintended consequences. The contributions by authors and reviewers to this critical and timely topic are greatly appreciated. We hope this Research Topic will be useful to researchers and policymakers as it shares evidence-based insights on the COVID-19 pandemic from multinational academic research.GH, ZC, JW, and SH contributed to the conceptualization and design of the Research Topic and the editorial. GH wrote the first draft of the editorial. All authors contributed to the manuscript revision and approved the submitted version."} +{"text": "Neuroinflammation is an important biological process induced by complex interactions between immune cells and neuronal cells in the central nervous system (CNS). Recent research on the bidirectional communication between neuronal and immunological systems has provided evidence for how immune and inflammatory processes are regulated by nerve activation. One example is the gateway reflex, in which immune cells bypass the blood brain barrier and infiltrate the CNS to cause neuroinflammation. We have found several modes of the gateway reflex in mouse models, in which gateways for immune cells are established at specific blood vessels in the spinal cords and brain in experimental autoimmune encephalomyelitis and systemic lupus erythematosus models, at retinal blood vessels in an experimental autoimmune uveitis model, and the ankle joints in an inflammatory arthritis model. Several environmental stimulations, including physical and psychological stresses, activate neurological pathways that alter immunological responses via the gateway reflex, thus contributing to the development/suppression of autoimmune diseases. In the manuscript, we describe the discovery of the gateway reflex and recent insights on how they regulate disease development. We hypothesize that artificial manipulation of specific neural pathways can establish and/or close the gateways to control the development of autoimmune diseases. The central nervous system (CNS), which includes the brain and spinal cord, is a unique system with neural connections across several organs and physiological systems barrier and the blood-brain barrier (BBB) -23, which is required for the survival of TH17 cells is a widely used model for multiple sclerosis (MS), which is a neuroinflammatory disease characterized by focal lymphatic infiltration and demyelination in the CNS followed by the development of neurological and psychiatric disorders axis releases glucocorticoids systemically upon psychological stresses; these hormones suppress immune cell functions at the fifth lumbar spinal cord (L5) spinal cord are innervated by sensory neurons of the soleus muscles. Gravity stimulation can constantly activate the neighboring spinal cords of dorsal vessels through the innervation of sensory neurons from the L5 DRG to create the gravity gateway reflex via the sympathetic pathway from L5 sympathetic ganglions.H17 cells mice are a mouse model that spontaneously develops rheumatoid arthritis in which joint inflammation is amplified by the IL-6 amplifier mice spontaneously develop autoimmune cell infiltration and systemic inflammation in multiple organs (Theofilopoulos and Dixon Systemic lupus erythematosus (SLE) is an autoimmune disease attributed to the loss of immunological tolerance with many symptoms including skin rash, arthritis, nephritis, hematologic abnormalities, and inflammation in the CNS Tsokos . About hThe gateway reflex describes neuro-immune interactions at specific boundaries between the CNS and adjacent blood vessels during inflammatory and immune events. Several types of environmental stimulations, including gravity, pain, psychological stress, and light, activate specific neural pathways to establish immune cell gateways at specific blood vessels including the CNS and cause tissue-specific inflammatory diseases. From a clinical point of view, the manipulation and control of the gateway reflex are potential management strategies for some inflammatory diseases. Recent advances in techniques for the artificial control of neural activation, such as chemogenetics and optogenetics, may be used to activate specific neuronal projections leading to neurological and psychological manifestations Roth , raising"} +{"text": "Pharmacists have been shown to positively impact the outcomes of care for treatment of many different kinds of disease states. In particular, pharmacist-run lipid clinics have enjoyed varying degrees of success, depending on the outcome assessed. At our hospital, when a patient is transferred to the pharmacist coordinated lipid clinic, the primary care pharmacist is responsible for ordering and interpreting labs and prescribing and monitoring lipid-altering therapy.This study was designed to assess if there is a statistically significant difference between the magnitude of serum cholesterol reduction for patients receiving lipid-altering pharmacotherapy when clinically trained pharmacists are actively prescribing and adjusting the drug therapy compared to other health care practitioners .Patient records from the hospital computer databases were retrospectively and randomly selected for analysis. Following evaluation for inclusions and exclusions, 41 patient records remained for statistical analysis for the cohort group, and 47 records remained from the group of patients managed by a clinical pharmacist.Management of dyslipidemia by a clinical pharmacist was associated with a significant reduction in overall mean low-density lipoprotein compared to the cohort that did not have a clinical pharmacist as the primary manager of dyslipidemia . This suggests improved clinical outcomes, defined as greater LDL reduction, when clinical pharmacists participate in lipid management, including drug prescribing. The magnitude reduction in LDL was found to be related to the number of clinical pharmacy visits , compared to the usual care group . These results occurred even though the group of dyslipidemic patients managed primarily by a clinical pharmacist contained a statistically greater number of patients with 2 or more risk factors and high-density lipoprotein (HDL) levels less than 40 mg/dL.Interdisciplinary medical teams that include clinical pharmacists who are actively prescribing and adjusting lipid drug therapy may achieve greater reductions in LDL for patients who have been assessed with multiple risk factors compared to patients managed without clinical pharmacists. Active participation by clinical pharmacists in lipid management for patients with elevated LDL resulted in improved treatment success as measured by the magnitude reduction in LDL. The reduction in LDL was between 5% and 22% per visit greater for patients being treated by clinical pharmacists versus usual care, even in a patient population with more risk factors. These intermediate outcomes may translate into long-term outcomes in fewer cardiovascular events, improved quality of life for patients with dyslipidemia, and lower costs associated with sequelae of dyslipidemias."} +{"text": "Reducing avoidable healthcare-associated harm is a global health priority. Progress in evaluating the burden and aetiology of avoidable harm in prisons is limited compared with other healthcare sectors. To address this gap, this study aimed to develop a definition of avoidable harm to facilitate future epidemiological studies in prisons.Using a sequential mixed methods study design we first characterised and reached consensus on the types and avoidability of patient harm in prison healthcare involving analysis of 151 serious prison incidents reported to the Strategic Executive Information System (StEIS) followed by in-depth nominal group (NG) discussions with four former service users and four prison professionals. Findings of the NG discussions and StEIS analysis were then synthesised and discussed among the research team and study oversight groups to develop an operational definition of avoidable harm in prison healthcare which was subsequently tested and validated using prison patient safety incident report data derived from the National Reporting and Learning System (NRLS).Analysis of StEIS incident reports and NG discussions identified important factors influencing avoidable harm which reflected the unique prison setting, including health care delivery issues and constraints associated with the secure environment which limited access to care. These findings informed the development of a new working two-tier definition of avoidable harm using appropriate and timely intervention, which included an additional assessment of harm avoidability taking into the account the prison regime and environment. The definition was compatible with the NRLS incident report narratives and illustrated how the prison environment may influence identification of avoidable harm and judgements of avoidability.We have developed a working definition of avoidable harm in prison health care that enables consideration of caveats associated with prison environments and systems. Our definition enables future studies of the safety of prison healthcare to standardise outcome measurement. Improving patient safety in healthcare is a global priority, and there is evidence that patients are frequently exposed to avoidable, healthcare- associated harm \u20134. WhilsThe Royal College of General Practitioners and Care Quality Commission have advocated for the concept of equivalence between primary care in the community and within secure environments including the prison estate. This means people in secure environments should have access to services and treatment that is consistent in range and quality as that available in the community and to tDelivering safe and effective healthcare in the secure prison environment is challenging and requires consideration of factors unique to this context. For example, people in prison have poorer physical health, higher rates of mental illness and communicable diseases than the general population, with an ageing population that brings increasingly complex care needs , 13\u201315. Core healthcare services commissioned by the National Health Service (NHS) in prisons are based on the primary care delivery model and their aim is to be equivalent to those cared for outside of prison . OutsideA critical step in the improvement of safety is adequate understanding and measurement of the problem(s) , 25. Whi\u201cA patient safety incident could have been probably, or totally, avoided by the timely intervention of a healthcare professional and/or an administrative process in accordance with accepted standards of evidence-based practice and/or clinical governance and/or the Bolam test*.\u201dThe Bolam test refers t.*However, it remains unclear what types of healthcare-associated harm patients in prison experience that are unique to the setting, how these harms affect or change the existing definition in primary care , 29, whaThis study was conducted as part of the \u2018Avoidable harm in prison healthcare\u2019 project (NIHR: PR-R20-0318-21001). This is a multi-phase project that aims to understand the frequency, burden and nature of avoidable harm in prison healthcare in order to improve patient safety.A sequential mixed-methods approach comprising two main phases was used to develop and test the validity of an operational definition of avoidable harm in prison healthcare. This two phase process is summarised in Since 2002 serious incidents occurring in NHS organisations in England have been required to be reported and investigated . These aEach report contains categorical information and a free-text commentary of what occurred, what immediate action was taken and a summary of the case. The reporting organisation is later required to complete further free-text fields detailing the investigation carried out, root causes identified, and lessons learned following the incident. A description of the database and the content of reports has been documented previously .Fig 1 in The Nominal Group (NG) technique was used to explore consensus on what kinds of avoidable harm related to prison healthcare occur, why and under what circumstances. This is a mixed methods consensus-building approach which has been described in detail elsewhere , 33. ConWhat patient harms are most likely to occur in a prison healthcare setting and how avoidable and severe are they?\u2019. Participants then individually generated thoughts and ideas in response to the nominal question, before calling out their ideas for the facilitators to display to the group in \u2018round robin\u2019 fashion. A discussion of these ideas was then facilitated for approximately one hour, where ideas were clarified, refined, and grouped into themes by the facilitators. Finally, participants were asked to select and rank their \u2018top five\u2019 resulting ideas, presented in order of importance.Data collection took place during December 2019 in private meeting rooms at The University of Manchester, and each NG discussion lasted three hours. In total, eight participants took part across the two groups: four former service user participants and four professionals . All participants in the service user group were also members of a service user stakeholder oversight group for the wider \u2018Avoidable harm in prison healthcare\u2019 project. Professional participants comprised a prison healthcare manager, prison pharmacist and nursing and commissioner representatives for health and justice services in England. Four authors were present during one/both of the NG discussions, with RNK leading the sessions and CS taking field notes. Following a general introduction and setting of ground rules in accordance with established NG methodology , 37\u201340, Anonymised transcripts of NG discussion recordings were triangulated alongside typed researcher field notes and data generated by participants (ranking and sticky notes) for thematic analysis . AuthorsThematic frameworks generated from the StEIS and NG analyses in phase one were reviewed by the authors in order to establish what prison healthcare related harms are , characterise the types of harms and explore what makes them avoidable. The author team includes a diverse group of health professionals , pharmacist, forensic psychiatrist) and academics with backgrounds in patient safety and psychology. The nature of these avoidable harms were then assessed to determine the extent of alignment to our established primary care definition of avoidable harm , 29, witFindings arising from this assessment by the authors were then presented and discussed in a stepwise process as follows with wider teams in order to develop and agree the final avoidable harm definition for prison healthcare. At all times the discussions focused on how the unique prison context was different to primary care, and how this influenced judgements on harm avoidability in relation to the established primary care definition.The wider \u2018Avoidable harm in prison healthcare\u2019 project team, a multi-disciplinary group comprising academics specialising in patient safety, forensic psychiatrists, GPs, sociologists, substance misuse specialists, psychologists, pharmacists, and mental health professionals. Patient and public representation was also present in the group;Study oversight stakeholder groups. This includes a service user group comprised of four former prisoners recruited via existing networks, social media and third sector organisations alongside a study advisory group of 23 individuals comprised of prison GPs, prison policy makers/commissioners, senior prison leaders/managers, prison quality leads and academics with backgrounds in health economics, patient safety and criminology. These groups convene independently at quarterly intervals throughout the project to monitor and evaluate the progress of the wider study and to both hold the study team to account and help problem solve as issues arise.The research project funder )/Department of Health and Social Care. As the funder and policy customer who commissioned the wider study, the research team liaise with representatives from these organisations to provide regular updates on the study and to monitor and evaluate progress according to key milestones. In addition, representatives for both the funder and DHSC attend the stakeholder advisory group.The agreed operational definition of avoidable harm in prison healthcare was then applied to anonymised patient safety incident reports identified from the National Reporting and Learning System (NRLS), now called the Learn from Patient Safety Events (LFPSE) service. The NRLS database was established in 2003 and has been integral in supporting improvements within patient safety. NRLS data has been, and will continue to be, extensively utilised for investigating patient harm across the healthcare continuum \u201346. Prisin vivo approach in order to determine themes and patterns to understand the context, event sequence and incident antecedents.An analysis of incidents occurring in English prisons and remand centres reported to the NRLS between April 2018 and March 2019 which contained contributory factors were used as the dataset for applying the avoidable harm definition. These incidents were first coded by two clinical academics (JM and KD), and codes were assigned from the classification system outlined by the Primary Care Patient Safety (PISA) Research Group which has been utilised previously \u201350. CodeThe avoidable harm definition generated by the research term was then applied to the thematic data and incident narratives to consider (a) whether it could be used to clearly identify instances of avoidable harm, and (b) whether the influence of the prison regime and/or environment informed judgements concerning the avoidability of harm. Examples of incident report classification using the new avoidable harm definition were discussed amongst the research team and an iterative process followed to refine classification criteria until consensus was reached.For the StEIS and NRLS data analysis, a data sharing agreement was created between Cardiff University and NHS Improvement/England (DSA 5131) and ethical approval was provided by the Cardiff University School of Medicine Ethics Committee (SMREC 20/83). For the NG discussions, ethical approval was provided by the University of Manchester Research Ethics Committee (2019-7330-11582).The NG discussion and StEIS analysis identified a range of avoidable harms in prison health care, including examples relating to both physical and psychological harm, for example arising from delayed medical appointments or medicines issues related to bullying or diversion. The StEIS analysis key themes with supporting vignettes and illustrative participant quotes, alongside supporting key themes from the NG discussions are presented Table 1 and Box 1 in Prison health care delivery issues were reported in StEIS data (n = 80) as failure to follow evidence-based practices (n = 27), deficient initial assessments when entering prisons (n = 23) and when risks or changes in patient behaviour prior to suicide were not detected (n = 15). NG discussions also identified how complex/vulnerable patient factors may have impacted on how they were perceived and given care by prison staff; for example how behavioural/medical issues that were perceived as negative by staff drove responses to how it was dealt with at the time. NG thematic analyses also revealed cultural issues concerning a perceived lack of standard of equivalence with community services with health care needs being seen as secondary to security.Prison environmental constraints were a reported antecedent to avoidable harm events across the StEIS (n = 13) and NG data sets, including issues relating to staffing levels, experience and continuity alongside rigid prison rules which contributed to limited access to treatment for example through delayed appointments or access to medication. Other themes reported included medication incidents arising from StEIS data (n = 45) which were reported to commonly arise due to the timely access to prescribed medications (n = 29) and issues with methadone prescribing or administration (n = 13).the staff/prison could have done no more\u201d in reaching their decision on whether the harm was, on the balance of probability, avoidable.Following initial discussions of the phase one study findings by the authors, the types of avoidable harm in prison health care were considered to be adequately identified and described using the existing definition of avoidable harm for community-based primary care settings developed previously by the authors and how this could influence the ability of staff to intervene and therefore influence judgements on harm avoidability. Therefore, following further discussion and contextualisation of these findings by the wider \u2018Avoidable harm in prison healthcare\u2019 study team, study oversight groups and the study funder, it was agreed that judgements on the avoidability of patient harm should therefore be made on a two-tier basis:Tier 1: assessment of whether more could have been done, with equivalence to how community cases would be assessed input, a further assessment should be made about whether or not the prison could have done more, considering the restrictions imposed by the regime and environment .In rating the avoidability of harm, it was decided that a six-point system developed to assess the preventability of deaths in English acute hospitals Unavoidable (Slight to modest evidence of avoidability)Possibly avoidable Probably avoidable Probably avoidable (Strong evidence of avoidability)Totally avoidable Differences compared to the primary care setting definition related harm must never be classified as unavoidable due to the prison setting alone and should be judged on the basis of Tier 1 presented above. The additional information gathered as part of Tier 2 is designed to help users of the definition to understand prison specific constraints/explanations for the harm that may help inform decision-making processes of avoidability. This definition and guidance builds on the definition of avoidable harm in primary care in In the context of this working definition, harm was agreed across the StEIS and NRLS analysis along with the NG discussions to constitute either physical or psychological nature with the latter including emotional distress as a result of a healthcare issue. For instance, former service users spoke about how inappropriate prescribing could lead to issues of violence and bullying, giving examples of prisoners swapping medications between themselves or having their medication taken from them by other prisoners. The research team also concluded that Specifically, 1529 patient safety incidents from the NRLS dataset were retrospectively reviewed and the avoidable harm definition conceptually applied. Vignettes were created and discussed as a team to show the clear delineation between both tiers, drawing on prison experiences and knowledge to consider Tier 2 differences. The working definition was found to be compatible with the incident report narratives, both in identifying cases of avoidable harm and in capturing the context of the prison environment in facilitating judgements concerning incident avoidability according to the Tier 1 and Tier 2 model. To illustrate this, Tables 2\u20134 in The operational definition for avoidable harm in primary care developed for community settings 29] was was29] wContexts and barriers unique to, or aggravated by, a prison setting compared to community settings identified in this study included issues at a micro, meso and macro/systemic level Click here for additional data file."} +{"text": "Gap junctions (GJs) are not static bridges; instead, GJs as well as the molecular building block connexin (Cx) proteins undergo major expression changes in the degenerating retinal tissue. Various progressive diseases, including retinitis pigmentosa, glaucoma, age-related retinal degeneration, etc., affect neurons of the retina and thus their neuronal connections endure irreversible changes as well. Although Cx expression changes might be the hallmarks of tissue deterioration, GJs are not static bridges and as such they undergo adaptive changes even in healthy tissue to respond to the ever-changing environment. It is, therefore, imperative to determine these latter adaptive changes in GJ functionality as well as in their morphology and Cx makeup to identify and distinguish them from alterations following tissue deterioration. In this review, we summarize GJ alterations that take place in healthy retinal tissue and occur on three different time scales: throughout the entire lifespan, during daily changes and as a result of quick changes of light adaptation. The mammalian retina is a sheet of nervous tissue that covers the posterior aspect of the eye. Its neurons are organized into three cellular layers incorporating the light-sensitive photoreceptors (PRs), three interneuron populations including bipolar cells (BCs) horizontal cells (HCs) and amacrine cells (ACs), as well as the retinal ganglion cells (RGCs) that provide the sole output of the retina towards the brain. Neurons in the retina like in other brain areas communicate via chemical and/or electrical synapses. Following the initial descriptions ,2,3,4, eGJs serve as conduits allowing for the free transcellular diffusion of ions and small molecules up to 1 kD , which pGJs are abundant in all brain areas including the mammalian retina , where aCx36 has been found in both plexiform layers of the rOver 50 years ago, Potter and his colleagues providedBesides the above two prevalent Cx subunits, Cx30.2 is also expressed in some RGC connections , whereasDuring the daily darkness/brightness cycle, the retina operates over a ~50-billion-fold change in illumination and maintains a broad dynamic range. This involves a tremendous capacity of light adaptation including several different mechanisms. One of these involves a shift of signaling between the rod and cone photoreceptor-initiated pathways. This rerouting of visual signals within the retina happens slowly during dusk and dawn but also occurs more quickly when one enters a dark room during daylight (or exits from a dark room to a bright exterior). For the smooth transition between signaling systems, the retina utilizes an intermediary route, called the secondary rod pathway, which relies on Cx36 GJs between rods and cones. The Cx protein subunit turnover takes only a few hours, leaving an effective time window for a potential light adaptation-induced Cx transcript and protein expression change . HoweverPrevious sections described how retinal GJs and their Cx building blocks endure expression changes throughout the lifespan of an organism and summarized how quick environmental changes affect the intracellular milieu and corresponding GJ gating in various retinal cells. The responses of the retinal tissue to changes on these two timescales overlap considerably. For example, adaptation to altered light conditions initially involves only the on- or offset of intracellular signaling mechanisms and the corresponding change in GJ gating. However, as pointed out in the previous section, longer lasting light adaptation eventually exerts Cx expression changes as well ,58. ThusAlthough the observed Cx36 mRNA level changes were not robust (and were not significant), they may correspond to the increasing GJ gating and Cx36 protein need in the coming dusk and dawn periods (note that mRNA expressions should precede protein level elevations thus mRNA transcript levels peak hours prior to when protein expression needs a boost). It is unknown, however, how and to what extent external diurnal and internal circadian factors contribute to these changes. Future work will enlighten these details along with those describing how other retinal Cx transcript and protein levels are controlled by the daily rhythm and if circadian mechanisms partake in that process. It has also been demonstrated that when the retina is treated with a GJ blocker, the circadian period of each layer-specific oscillator increases significantly compared to the normal circadian period of the whole retina (93). This thus reflects that GJs and Cx building blocks are not just under the control of daily cyclic changes but also partake in the functioning of the circadian clock. This indicates that an important mutual interaction exists between GJ coupling and the retinal circadian rhythm.In this present review, we summarized latest advances in the field of GJ signaling in the mammalian retina with a focus on the expression alterations of GJ-forming retinal Cx subunits as a response to intrinsic and environmental changes. Such changes include the cyclic modulation of the intracellular molecular milieu driven by the circadian clock as well as cyclic diurnal and monotonous alterations throughout the postnatal life of an organism. While the Cx mRNA and protein expression alterations appear more prominent, changes occur on a longer timescale and they also seem to follow quick changes of the internal and external environment, including circadian rhythmicity and diurnal light level alterations, respectively. By demonstrating these changes in GJ signaling as well as expression levels of the Cx building blocks, this work exemplifies how signaling through a sensory organ adapts to the altered environmental conditions. In addition, this converging evidence also pinpoints the importance of the standardization of experimental conditions, such as the age of the animal models, the timing of experiments and also the light conditions."} +{"text": "The Opportunity Atlas project is a pioneering effort to trace social mobility and adulthood socioeconomic outcomes back to childhood residence. Half of the variation in adulthood socioeconomic outcomes was explainable by neighborhood-level socioeconomic characteristics during childhood. Clustering census tracts by Opportunity Atlas characteristics would allow for further exploration of variance in social mobility. Our objectives here are to identify and describe spatial clustering trends within Opportunity Atlas outcomes.We utilized a k-means clustering machine learning approach with four outcome variables each given at five parental income levels to create clusters of census tracts across the contiguous United States (US) and within each Environmental Protection Agency region.At the national level, the algorithm identified seven distinct clusters; the highest opportunity clusters occurred in the Northern Midwest and Northeast, and the lowest opportunity clusters occurred in rural areas of the Southwest and Southeast. For regional analyses, we identified between five to nine clusters within each region. PCA loadings fluctuate across parental income levels; income and low poverty neighborhood residence explain a substantial amount of variance across all variables, but there are differences in contributions across parental income levels for many components.Using data from the Opportunity Atlas, we have taken four social mobility opportunity outcome variables each stratified at five parental income levels and created nationwide and EPA region-specific clusters that group together census tracts with similar opportunity profiles. The development of clusters that can serve as a combined index of social mobility opportunity is an important contribution of this work, and this in turn can be employed in future investigations of factors associated with children's social mobility. Children's opportunity for upward social mobility is a potential driver of health and well-being, as it will likely influence access to care, ability to respond to adverse exposures, in addition to general resource availability.The Opportunity Atlas could be a potential data source for researchers; however, the complexity of the data and potential variation across US regions make working with the full datasets an enormous challenge. The Opportunity Atlas is not a composite indicator of children's social mobility, but a collection of many different variables at different parental incomes levels with different levels of national coverage and geographic resolution, along with some variables that are only applicable to specific types of individuals. Across this variety of data, dimension reduction techniques can be used to create a single composite indicator of children's social mobility from the Opportunity Atlas variables.Clustering techniques have been used for dimension reduction across many areas of research, including epidemiology , environOur objectives here are to identify and describe spatial clustering trends within Opportunity Atlas outcomes, and to develop a composite index of spatially distinct clusters for future explorations of predictors of children's social mobility. To do this, we selected four main outcomes at five parental income levels of the national distribution and used these as inputs in a k-means clustering algorithm such that census tracts with similar magnitudes of variables were clustered together. Because of potential variability across areas because of underlying structural differences, clustering was also performed individually for each of the 10 US Environmental Protection Agency (EPA) Regions to provide greater detail on which census tracts were most similar.22.1We created social mobility clusters of US census tracts using the US Opportunity Atlas dataset, which estimates social mobility outcomes for those who grew up within specific census tracts based on 1978\u20131983 US birth cohorts using ea2.2opportunityatlas.org) .The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} +{"text": "These platforms have been applied to different infectious diseases and in the future should target prevalent and emerging infectious diseases with novel algorithms.The opinion flows from Introduction to the immunological quantum that requires a historical perspective, to Quantum vaccine algorithms supported by a bibliometric analysis, to Quantum vaccinomics describing from our perspective the different vaccinomics and quantum vaccinomics algorithms. Finally, in the Discussion and conclusions we propose novel platforms and algorithms developed to further advance on quantum vaccinomics. In the paper we refer to protective epitopes or immunological quantum for the design of candidate vaccine antigens, which may elicit a protective response through both cellular and antibody mediated mechanisms of the host immune system. Vaccines are key interventions for the prevention and control of infectious diseases affecting humans and animals worldwide. Biophysics led to quantum biology and quantum immunology reflecting quantum dynamics within living systems and their evolution. In analogy to quantum of light, immune protective epitopes were proposed as the immunological quantum. Multiple quantum vaccine algorithms were developed based on omics and other technologies. Quantum vaccinomics is the methodological approach with different platforms used for the identification and combination of immunological quantum for vaccine development. Current quantum vaccinomics platforms include Vaccines are one of the most important achievements in human history. From classical 3Is (isolate-inactivate-inject) to recombinant vaccines and recent vaccinomics approaches, vaccines have prevented millions of deaths worldwide \u20134. HowevQuantum biology was proposed by Pascual Jordan in 1932 based on the dynamics of biological living systems to maintain the non-equilibrium state , 5. Thenhttps://pubmed.ncbi.nlm.nih.gov; January 16, 2023), the results provided 14 references. The recent origin of these algorithms starts with advances in deep sequencing and structural studies applied to protective candidate antigens to develop safer and more efficacious vaccines and in silico methods provide candidate immunological quantum for vaccine antigen design .\u201338.36\u201338n design , 30 use of commensal bacteria to produce and secrete protective antigens to interfere with pathogen infection or serve for vaccine delivery , (b) comBoth authors listed have made substantial, direct and intellectual contributions to the work and approved it for publication."} +{"text": "Autism spectrum disorder (ASD) is a heterogenous groups of neurodevelopmental conditions characterized by difficulties in social communication and the presence of restricted interests and repetitive behaviors. Autistic traits are distributed along a continuum in the general population and are negatively associated with social functioning also in non-autistic subjects. Several studies have evaluated the association between autistic traits and the quantity of social interaction; however, evidence on the relationship between autistic traits and quality of social interaction is still scarce.To evaluate the association between autistic traits and the quality of social interactions in daily life in youths from the general population using the experience samplic method (ESM).During a six-day experience sampling period, 349 twins and 248 of their siblings aged between 15 and 34 reported the quality of their everyday social interactions. Autistic traits were assesed using the Autism Spectrum Quotient (AQ). The association between autistic traits and quality of social interaction was tested in separate multilevel linear and logistic regression models.When participants were alone, higher autistic traits were associated with a sense of being less safe . When participants were in company, higher autistic traits were associated with a higher preference for being alone and higher sense of being judged . Moreover, while in company, higher autistic traits were associated with a decreased pleasure of being in company , a lower sense of being safe in company , and a lower sense of belonging to a group .The preliminary results of the present study showed that autistic traits may influence the quality of social interactions in daily life. Future studies may clarify the mechanisms underlying this association. Assessing autistic traits in youth may help improve the outcome of psychosocial interventions of youths presenting difficulties in social interactions.None Declared"} +{"text": "Ventilator-associated pneumonia (VAP) is associated with substantial health care costs that place a significant burden on scarce hospital resources. Preventative measures and appropriate management strategies can be effective in reducing the incidence of VAP and in improving VAP related resource utilization.To provide an overview of the economic costs associated with VAP and of strategies that can be used to meet the goals of improving the efficiency of resource utilization without negatively impacting clinical outcomes.The substantial costs attributed to VAP are mainly due to the prolonged hospital length of stay (LOS) associated with these patients. Initial appropriate antimicrobial therapy is critical in achieving successful outcomes\u2014including reducing LOS, mechanical ventilation days, and mortality. Initial treatment includes combination therapy when a multidrug-resistant pathogen or Pseudomonas aeruginosa is suspected. Once microbiologic results are available, de-escalation of therapy should be considered to reduce the unnecessary use of antimicrobials without impacting clinical outcomes. VAP prevention programs can also be an effective means to improve resource utilization in hospitals, although it is important to adopt a multidisciplinary team approach for acceptance of such programs and adherence to them.In the current health care environment of increased transparency and accountability, renewed efforts must be made to not only prevent VAP but also to appropriately manage patients with VAP. All health care personnel involved in the management of patients with VAP must take a proactive role in reducing its incidence."} +{"text": "Cascade genetic testing is the process of extending genetic testing to at-risk blood relatives of individuals found to carry cancer predisposition germline pathogenic gene variants. Cascade testing is critical as relatives found to carry a pathogenic gene variant have the opportunity to pursue targeted cancer risk reduction and early detection, decreasing cancer-associated morbidity and mortality , 2.\u00a0The It is possible that there are differences in uptake of cascade testing between racial and ethnic groups; it is already known that there is disproportionate under-recognition of hereditary cancer syndromes amongst racial and ethnic minorities , 7. To fIn summary, the uptake of cascade genetic testing for hereditary cancer syndromes by racial and ethnic minority groups is not well elucidated. Among eight trials currently evaluating interventions for cascade testing registered on clinicaltrials.gov, six (75%) do not include the influence of race and ethnicity on uptake of cascade testing as a primary or secondary objective. The American Society of Human Genetics published guidance to improve representation of racial and ethnic minorities in genomics research, highlighting the need to recruit and engage historically disadvantaged and underrepresented communities . Our fin"} +{"text": "Although registered under Hong Kong's legislative framework, chiropractors are not able to certify sick leave, restricting the effectiveness of their services for patients with musculoskeletal issues requiring time away from work. This paper explores the evolution of chiropractic regulation in Hong Kong, the growth of the profession, and the tardy recognition of chiropractors' power to issue sick leave certificates. The chiropractic profession and its patients have long lobbied for this authority, but the government has been slow to respond. This document presents a comprehensive analysis of the benefits and restrictions of allowing chiropractors prescriptive authority for sick leave and requests that this change in policy be considered. Developing responsible criteria for chiropractors to prescribe sick leave within their scope of practice could legitimize chiropractic's position in the population's health and interdisciplinary pain care while lowering the burden on injured workers. Not all statutorily registered healthcare professionals in Hong Kong can certify sick leave. According to Hong Kong\u2019s labor laws, under the Medical Registration Ordinance Cap. 161), only medical doctors or registered Chinese medicine practitioners have this authority 61, only . DespiteThe history of chiropractic in Hong Kong precedes the outbreak of World War II . The enaChiropractors in Hong Kong have long advocated for the authority to certify sick leave. Since being formally recognized in 1993, the profession has grown, but chiropractors' sick leave certificates remain unrecognized. By contrast, registered Chinese medicine practitioners have been able to certify sick leave since 2006 . The HonThe criteria for recognizing sick leave certificates likely considers the scope of practice and training of the prescribing profession. Responsibility for these criteria is likely to fall under the relevant government department responsible for overseeing each profession. Given that the Employees' Compensation Ordinance was made for a complete employee compensation system, it approves chiropractic treatment for work injuries . HoweverChiropractic service has been widely used in Hong KongChiropractors in Hong Kong are trained to diagnose and treat musculoskeletal and neurological conditions amenable to chiropractic care . ChiroprWhile greater awareness and understanding of chiropractic would facilitate broader acceptance, policy changes could also further legitimize the profession. People are educated about the efficacy of chiropractic care through a variety of channels, including social media, advertisements, informational seminars, and online resources -31. ChirThe evidence of chiropractic's acceptance in Hong Kong lies in its inclusion in major insurance plans and government health programs. Most private insurance companies cover chiropractic services, with injured employees permitted to claim chiropractic treatment under the Employees' Compensation Ordinance. In fact, chiropractic services accounted for 2.3% of total claims in this area in 2019 . The facChiropractic as an effective and low-risk therapyChiropractors in Hong Kong utilize manual techniques such as spinal manipulation and soft tissue mobilization to address musculoskeletal dysfunction and reduce pain -23. AccoChiropractic care offers a non-drug-oriented approach to pain relief that could reduce the reliance on prescription analgesics, including opioids . ConsideHow issuing sick leave certificates would enhance chiropractic's roleThe ability of chiropractors to certify sick leave would affirm chiropractic as an essential medical treatment and establish chiropractors as the primary spine and joint care providers. Chiropractors cannot currently officially authorize time needed away from work for musculoskeletal recovery, which limits the recognition of the value of chiropractic care. Were they granted the prescriptive power to indicate incapacity and authorize necessary sick leave, chiropractors would have a formal means of validating the importance of the treatment they provide. This authority could elevate the status of chiropractic as a profession, supporting its growth and integration into the healthcare system. Wider acceptance of chiropractic's role in managing back and joint conditions could increase patients\u2019 access to the important conservative techniques this discipline offers.The ability to certify sick leave would allow chiropractors to more comprehensively oversee patient treatment and recovery . By indiThus, the ability to certify sick leave would elevate the status of chiropractic care and potentially increase its use. With this legally recognized authority, chiropractors would have a formal means of demonstrating the medical value of their services. This could build public confidence in chiropractic and dispel misconceptions regarding its legitimacy and effectiveness. For the chiropractic profession, the ability to prescribe sick leave would underscore the role of chiropractors as spine and joint specialists and would help to attract high-quality practitioners to the field. If more people seek chiropractic treatment for musculoskeletal conditions, this may reduce their reliance on medications, advanced imaging, or surgery. Granting chiropractors sick leave authorization could thus benefit both public health as a whole and the chiropractic profession itself.Potential concerns and recommendations to addressWhile an interdepartmental working group was appointed to evaluate recognizing chiropractors' sick leave authority, it has not yet recommended this change . The worChiropractors in Hong Kong have long fought for the right to certify sick leave, arguing that this authority would legitimize their role as spine and joint specialists. However, the government is cautiously evaluating this proposal due to concerns about the potential overuse or misapplication of sick leave certification given chiropractors' focused scope of practice . A workiLack of International PracticesWhile practices regarding chiropractors' roles in labor systems vary internationally , this shFewer Reported Employees Managed by ChiropractorsWhile relatively few injured employees have sought chiropractic treatment that is covered under Hong Kong's compensation system , this reNo Tertiary Institutions Providing Chiropractic TrainingWhile Hong Kong lacked tertiary chiropractic education and neutral certification authorities beyond the chiropractic profession itself in 2005 , the McTNew Legal ObligationsBefore recognizing chiropractors' ability to grant sick leave certificates, the government and other stakeholders should understand the conditions that chiropractors treat and the relevant criteria for determining necessary time away from work. This understanding would clarify chiropractors\u2019 responsibilities and obligations, thereby minimizing the likelihood of disputes. Through education on chiropractic's conservative approach to treating musculoskeletal conditions, appropriate sick leave could be prescribed for conditions within the scope of chiropractors' expertise. Rather than denying chiropractors the authority to grant sick leave due to current limitations in stakeholder knowledge , the govSick leave guideline for chiropractorsTo ensure responsible use of certified sick leave, chiropractors could be authorized to only certify time away from work relating to musculoskeletal conditions within their officially recognized scope of practice . The ChiShould chiropractors be granted the authority to certify sick leave, guidelines should ensure the evidence-based application of this responsibility. With parameters grounded in the conservative scope of chiropractic practice and training, chiropractors can effectively support recovery from common musculoskeletal conditions through safe, patient-centered care. By objectively defining when incapacity necessitates time away from occupational tasks, the misapplication or overutilization of sick leave authority can be minimized. With appropriate oversight and professional accountability, chiropractors can make a valuable contribution to Hong Kong\u2019s healthcare system and public health overall through the administration of prudent sick leave certification. This can be an important aspect of focused specialty care for spinal and joint conditions.Recognizing chiropractors' authority to certify sick leave would merit considering strategically expanding access to conservative musculoskeletal care. Although concerns regarding the overuse or misapplication of this authority are valid, responsible guidelines can help enable chiropractors to accurately prescribe the necessary time away from work for conditions within their scope of practice. With appropriate professional standards and levels of oversight, this certification power could legitimize chiropractic's role in serving population health and providing multidisciplinary pain management. Rather than denying chiropractors an opportunity to formally support patient recovery through officially authorized sick leave and augmenting the burden of the injured workers, policymakers could trial this change by confining chiropractors' certification ability to specific, evidence-based clinical criteria."} +{"text": "Bone augmentation grafts may act as space-maintaining devices to allow coronal migration of periodontal progenitor cells. The idealbone replacement graft should be able to trigger osteogenesis, cementogenesis and formation of a functional periodontal ligament. Ithas been theorized that bioactive glass, which is a ceramic has bioactive properties that guide and promote osteogenesis allowingrapid formation of bone. Bioactive glass consists of sodium and calcium salts, phosphates and silicon dioxide for dental applications.When this material comes into contact with tissue fluids, the surface of the particles becomes coated with hydroxy carbonate apatite,incorporates organic ground proteins such as chondroitin sulfate and glycosaminoglycans and attracts osteoblasts that rapidly formbone. Periodontal regeneration is defined as the reproduction/reconstitution of a lost / injured part so that form and function of loststructures are restored AAP 1992). Bone augmentation grafts may act as space-maintaining devices to allow coronal migration ofperiodontal progenitor cells. The ideal bone replacement graft should be able to trigger osteogenesis, cementogenesis and formation ofa functional periodontal ligament. It has been theorized that bioactive glass, which is a ceramic has bioactive properties that guideand promote osteogenesis allowing rapid formation of bone. Bioactive glass consists of sodium and calcium salts, phosphates andsilicon dioxide for dental applications. When this material comes into contact with tissue fluids, the surface of the particlesbecomes coated with hydroxycarbonate apatite, incorporates organic ground proteins such as chondroitin sulfate and glycosaminoglycansand attracts osteoblasts that rapidly form bone Use of bone-inductive graft materials[2] Guided cell repopulation using barrier membranes.[3] Coronally positioned flap procedures in which the flap margin is secured an appreciable distance from healing site.Indications for periodontal regenerative therapy[1] To obtain root coverage in order to improve esthetics and reduce root sensitivity.[2] Furcation-involved teeth[3] \"Hopeless\" teeth with deep vertical defects, increased tooth mobility or through and through furcations can be successfullytreated with regenerative periodontal therapy .Loss of alveolar bone is one of the characteristic signs of periodontal disease and is generally considered to represent theanatomic sequela to the apical spread of periodontitis. A clear understanding of the topography of bony defects associated withperiodontal destruction is essential for diagnosis, prognosis and management. Classifications are generally based upon specificmorphological criteria and are aimed at guiding clinicians with their diagnosis, treatment and prognosis.Bone grafting has been used for almost 100 years in attempts to stimulate healing of bony defects .The firBio-glass is composed of SiO2, Na2 O, P2 O5 and are resorbable or not resorbable depending on the relative proportion of thesecomponents. When bio-glasses are exposed to tissue fluids, a double layer of silica gel and calcium phosphate is formed on theirsurface. Through this layer the material promotes absorption and concentration of proteins used by osteoblasts to form extracellularbone matrix which theoretically may promote bone formation . All bioStudies have found out that the use of bioactive glass allowed the regeneration of a normal periodontium and that it was effectivein retarding epithelial down growth than other materials like hydroxyapatite and tricalcium phosphate. The two properties of bioglassthat appeared to contribute to these favorable results seem to be first, the increased rate of reaction in vivo that it possesses incomparison to the other materials as a result of its release of silicon and secondly, that it appeared to bond with connective tissuecollagen. Because of its high bioactivity, the reaction layers appear to form within minutes of its implantation and the osteogeniccells freed by the surgery can rapidly colonize the particles. This process supplements the bone, which grows by osteoconduction fromthe alveolus, and these two processes combined have been termed osteoinduction . ThisreImmediately after implantation, fibroblasts lay down collagen above the level of the particulate, and this collagen appeared toattach to the superficial particles, immobilizing them in the soft tissue and restoring the transeptal connections of the periodontium.This appeared to prevent epithelial down growth, which only occurs to the point at which it meets adherent collagen fibres overlyingthe restoring bone. Beneath this layer, the particles induced a production of bone and cementum, and by 9 months the particles wereseen within the repairing bone and cementum. A normal periodontal ligament was seen between these tissues.An organic bovine mineral, natural and converted corals, and other materials appear to be suitable as a carrier vehicle for rhBMP2 or otherThe biologic rationale behind the use of bone grafts or alloplastic materials in periodontal regenerative surgery is the assumptionthat these materials[1] Contain bone-forming cells [osteogenesis][2] Serve as a scaffold for bone formation [osteoconduction][3] That matrix of grafting material contains bone inductive substances [osteoinduction]The various criteria for periodontal regeneration are epithelial exclusion, wound stabilization and use of mechanical and chemicalmeans to promote favorable root surface characteristics. Bone augmentation grafts have been successfully used to increase the heightof periodontal attachment apparatus. Regenerative therapy with bone replacement grafts did not gain acceptance as predictable therapyuntil the 1980's. Controversy still remains as to whether new [attachment] at a coronal level is achieved or whether primarily a longjunctional epithelium [repair] occurs as with flap debridement surgery alone.Among the various methods used for assessing periodontal regeneration, histology remains the ultimate standard. Although routineclinical assessment such as probing or simple measurements from radiographs will be adequate to assess relatively large amounts ofregeneration in practice, newer methods such as digital radiography, provide the higher precision needed to detect small differencesbetween different treatment modalities. The two important properties of bioactive glass are first, the increased rate of reaction invivo that it possesses in comparison to other materials as a result of its release of silicon and secondly, that it appeared to bondwith connective tissue collagen.The shelf life of Perioglas was found to be 3 years and it was resorbable. The mode of breakdown was through leaching anddissolution. Zamet et al. found ouA randomized controlled trial done by El-Haddad et al. in 2014 compared the efficacy of bioactive glass (BG) grafting materialversus autogenous bone grafting in the treatment of Grade II furcation involvement. The study concluded that BG and autogenic bonegraft had better regenerative attachment gain in the treatment of grade II furcation when compared with open mouth debridement. A meta Stavropoulos et al. in 2012 histological evaluated the healing Trans alveolar maxillary sinus augmentation with bioglass andautogenous bone and concluded that the Sinus augmentation with a bioglass and autogenous bone composite is compatible with boneformation . Koller The ultimate aim of periodontal therapy is to achieve periodontal regeneration. The value of using bone grafts or alloplasticmaterials for regeneration has mainly been examined in case reports, while histologic evidence of new attachment and controlledclinical studies is limited. Bioglass is preferred for its high bioactivity, because of which the reaction layers appear to formwithin minutes of its implantation and the osteogenic cells freed by the surgery rapidly colonize the particles. Use of bioactiveresults in more rapid filling of the defects, which may result from more rapid accumulation of bone morphogenic proteins and othergrowth factors on the surface of bioactive glass. The prevention of epithelial down growth is probably the main advantage of usingbioactive glass. At present, bone substitutes are finding increasing use in conjunction with guided tissue barriers. Growing interestperiodontal and other bone regeneration will encourage the development of improved materials."} +{"text": "Sharks, rays, and chimaera form the clade Chondrichthyes, an ancient group of morphologically and ecologically diverse vertebrates that has played an important role in our understanding of gnathostome evolution. Increasingly, studies seek to investigate evolutionary processes operating within the chondrichthyan crown group, with the broad aim of understanding the driving forces behind the vast phenotypic diversity observed among its constituent taxa. Genetic, morphological, and behavioral studies have all contributed to our understanding of phenotypic evolution yet are typically considered in isolation in the context of Chondrichthyes. In this viewpoint, I discuss why such isolation is prevalent in the literature, how it constrains our understanding of evolution, and how it might be overcome. I argue that integrating these core fields of organismal biology is vital if we are to understand the evolutionary processes operating in contemporary chondrichthyan taxa and how such processes have contributed to past phenotypic evolution. Despite this, the necessary tools to overcome this major limitation already exist and have been applied to other taxa. Major knowledge gaps exist regarding Chondrichthyan trait evolution. Lack of integration between key fields of organismal biology is the main driver of this uncertainty. Increase in research effort and application of methodologies used frequently in other clades may be sufficient to overcome this lack of integration."} +{"text": "We commYoung people bear a disproportionate burden of HIV globally yet continue to have the worst outcomes in both treatment and prevention cascades . CompareAddressing the slow rate of decline in new HIV infections among key populations of youth remains critical to controlling the HIV pandemic, especially in adolescent girls and young women in Africa and sexual and gender minority youth globally. Despite global guidelines recommending tenofovir\u2010based oral pre\u2010exposure prophylaxis (PrEP) for adolescents at substantial risk, HIV prevention efforts are severely undermined by profound inequalities in PrEP access for key youth populations . For exaLAED products offer tremendous promise to curb the challenges of medication adherence by simplifying regimens and decreasing daily pill burdens. LAED products also provide an increased level of privacy that can ameliorate concerns regarding stigma and unintentional disclosure associated with sexual activity and/or sexual identity for PrEP users. The availability of safe, efficacious LAED options for youth continues to grow and expands the choices youth have for products that fit their needs and circumstances make it increasingly difficult if not impossible to access essential sexual and reproductive health services. The Joint United Nations Programme on HIV/AIDS (UNAIDS) reports that among 141 countries with available data, 75% require adolescents to obtain parental/guardian consent for HIV testing . Similarregardless of whether the product is LAED or not. Integrated strategies must incorporate social and structural components to provide the support young people (and their parents/guardians) need for effective and sustained sexual and reproductive health. Almost 20 years ago, the World Health Organization issued recommendations for HIV services to be based around five adolescent\u2010friendly principles: accessible, acceptable, equitable, appropriate and effective [In sum, the implementation of wholistic HIV prevention and treatment services is much more than administering a biomedical product, ffective . HoweverLS\u2010C received travel support from ViiV to attend the International Workshop on HIV and Adolescence 2022, Cape Town, South Africa. SH has no conflicts to declare.SH and LSC contributed equally to researching, writing and editing this manuscript."} +{"text": "Rapid Arctic warming may increase erosion and stream channel formation, which alters the flux of sediments, carbon, and nutrients in these sensitive ecosystems. Yet, understanding landscape change is hampered by a lack of predictive tools applicable to permafrost settings. However8. These collapse features remove protective vegetation and expose easily erodible soils to concentrated surface runoff leading to new channels with flow paths that closely follow the degrading ice wedge network8.In non-permafrost watersheds, erosional gullies commonly develop in response to increases in erosive capability of surface water, decreases in the resisting forces of the land to erosion, or a combination of both. In these systems, gullying may be triggered by land use, climate change, or by natural cycles of erosion and deposition. In permafrost settings, gully formation by surface water flow commonly occurs by melting of ice wedges rather than erosion of the ground surface. Melting of ice wedges by flowing water creates tunnels that in turn collapse7 show that the development of channels within such settings is spatially discontinuous and independent of both topographic steepness of the valley and grain size of the channelized material, two common predictors for channel development in non-permafrost settings. Chartrand et al.7 further note the sources of water driving the melting of ice wedges are strongly influenced by thaw of permafrost and changing hydrology, such as snow melt magnitude and timing. All these factors make this type of channelization difficult to predict and require new models developed for these systems.Documented in high-resolution topographic data, Chartrand et al.9, where ground ice may be more distributed and less predictable in location than the ice wedge complexes of Muskox Valley7. In these settings, subsurface flow also accelerates the melting of ground ice and physically erode soils from beneath the overlying, and often intact surface vegetation. Where pipes reconnect to the ground surface, large volumes of sediment and eroded organic matter may be deposited on top of undisturbed ground downslope6. Once sufficient volumes of ice melt and soil are excavated, the ground surface may collapse and drive channel development through coalescing disturbances7. Such channelization appears most commonly along valley axes where converging topography concentrates surface runoff.These challenges are not limited to settings with ice wedges. Subsurface erosion of soils due to water flowing through tunnels or pipes has also been observed in more southerly and discontinuous permafrost settings7, but they also document gullies, landslides, and linear surface water flow features called water tracks that all may play a role in expanding channel networks in permafrost watersheds. Along hillslopes across the Arctic, shallow landslides and deeper failures accelerate erosion and increase sediment and carbon delivery to streams and rivers11. Similar to ice wedge melt, these landslides tend to be isolated and generate local channel development rather than an integrated watershed-scale expansion of drainage networks. Attempts to predict the location and timing of these landslides with tools developed for temperate watersheds have met with limited success6. Results to date suggest that failures appear to be strongly connected to local ground ice conditions and seasonal warming, rather than topographic slope and hydrology5.Rapid channelization along ice wedges is the most dramatic change highlighted in the Chartrand et al. study7 shows numerous linear water track features. Water tracks are ubiquitous features in the Arctic that preferentially route water down hillslopes. The origin of water tracks is not well understood12 but it has been hypothesized that they may represent incipient drainage networks that will facilitate channel expansion in response to warming-induced erosion13. Erosion within water tracks have recently been observed and may be increasing14. However, a widespread integration of erosion along water tracks that would cause widespread channel expansion has not yet been documented. At present, the occurrence of water track erosion appears to be largely related to local ground collapse due to melting of ice12 rather than a systematic or predictable shift in processes governing channel development.Figure 2 of the Chartrand et al. study7 provide a watershed-scale picture of diverse processes that influence the flow of water and erosion. These processes range from failures on hillslopes to rapid erosion of ice wedge complexes along the valley axis. This study also highlights the complex interactions of ground ice, permafrost thaw, rapid warming, sediment grain sizes, and even stochastic flood events on channel formation. At present, we have very few tools for predicting where and how individual erosional processes occur in permafrost settings, let alone the ability to integrate these processes to predict channel network evolution across entire watersheds. The presence of ground ice strongly influences the vulnerability of permafrost landscapes to erosion and channel formation. Despite recent advances in the automated detection and mapping of ice wedge polygons15, we still lack the ability to map more distributed ground ice or predict which polygons may be vulnerable to surface water infiltration and melting.To address these research gaps, in their study of Muskox Valley, Canada, Chartrand et al.7, that identify patterns and timing of channel expansion and link these changes to climatic and hydrological drivers, will be needed to develop mechanistic models of landscape evolution in permafrost settings. These models will need to incorporate thermal controls on landscape responses to warming and couple hillslopes to channels. Integrated models that capture hillslope and channel coupling will allow for predictions of how increased disturbance and erosion of permafrost soils will alter the storage, transport rates, and release pathways of sediment, carbon, and nutrients across watersheds in a rapidly warming Arctic.More detailed watershed studies, such as the Muskox Valley study by Chartrand et al."} +{"text": "Complex regional pain syndrome (CRPS) is a rare condition associated with chronic pain. It is an inflammatory and neuropathic disorder principally characterized by involvement of the autonomic nervous system. The etiology of the syndrome is not clear and the known treatment modality is also very complicated.Extant literature has shown the relationship between CRPS and suicidal behaviours in adults but less data are available in adolescents. This literature review aims to synthesize and evaluate the existing studies assessing suicidality in CRPS adolescents.A narrative review of the literature focusing on CRPS and chronic pain in adolescents and their associations with suicidal behavior including suicidal ideations, suicide attempts and death by suicide.The studies of suicidality factors in adolescents evaluated chronic pain in general. Those who studied CRPS specifically did not look for its association with suicide risk. In fact, adolescents who suffer from chronic pain present increased risk for suicide ideations and suicidal attempts. Furthermore, no available data have demonstrated the association between chronic pain and suicide. Additionally, among adolescents with CRPS, the risks of somatization, anxiety, and depression are higher. The duration of pain, depression and eating disorders has been shown to be associated with increased suicidality.Our findings suggest that CRPS is associated with higher risks for suicidal ideation, suicidal attempts compared to the general population. The risk factors underlying suicidal behavior in CRPS patients are not studied enough and require further investigation.None Declared"} +{"text": "Cerebral palsy (CP) is a non-progressive motor condition that hinders the development of movement and posture. One of the common problems faced in CP is spastic hips, which can cause discomfort, deformity, and functional restrictions. This review article seeks to offer a thorough summary of the most recent methods for treating spastic hips in cerebral palsy patients. Additionally, it describes the success and potential risks of various conservative and surgical procedures. It also looks at new treatments and potential avenues for managing this complicated ailment. Cerebral palsy (CP) is a neurological condition that affects the development of a large number of children around the world. Among the various manifestations of CP, spasticity in the hip joint poses significant challenges in terms of management and overall quality of life for affected individuals . The spaEtiology and pathophysiologySpastic hip in cerebral palsy is caused by injury or abnormality of the developing brain, which typically manifests in infancy or early childhood . Hip spaAssessment and diagnosisCerebral palsy patients with spastic hips should have a thorough evaluation and diagnosis to determine the full scope of their problem and how it affects their daily functioning. There are often several stages.Medical HistoryCollecting a thorough medical history is crucial for diagnosing and treating cerebral palsy and hip problems since it provides insight into the patient\u2019s overall health, developmental milestones, and past interventions .Physical ExaminationIt is essential to perform a complete physical examination of the hip. This includes assessing the range of motion, muscle tone, and any signs of spasticity, contractures, or dislocations .Radiological ImagingX-rays and other imaging techniques may be used to assess the alignment of the hip joint, detect any abnormalities, and determine the degree of bone deformities or hip dislocation . X-rays Gait AnalysisObserving the patient\u2019s gait can provide valuable insights into their functional limitations and reveal compensatory movements or imbalances caused by the spastic hip .Spasticity EvaluationThe assessment of spasticity involves identifying the muscle groups affected and measuring the severity of spasticity using standardized scales, such as the Modified Ashworth Scale .Functional AssessmentThe assessment of a child with CP and a spastic hip should encompass evaluating the impact on the patient's quality of life. This assessment may include the use of standardized questionnaires or functional tests . HoweverMultidisciplinary Team EvaluationCollaboration between various healthcare professionals, such as orthopedic surgeons, physiotherapists, occupational therapists, and neurologists, is vital for a comprehensive evaluation and accurate diagnosis .After all of the data has been collected, a diagnosis can be made that takes into account factors such as the patient\u2019s level of spasticity, the existence or absence of contractures or dislocations, and the severity of any associated sequelae. . This inHip surveillanceCerebral palsy patients with spastic hips, in particular, benefit greatly from regular hip monitoring. This process involves frequent clinical and radiological evaluations to closely monitor the development of the hips and identify any irregularities at an early stage. By catching potential issues early on, healthcare professionals can intervene promptly, which may help prevent serious complications like hip dislocation. Physical examinations by medical professionals trained to evaluate hip motion, muscle tone, and overall hip health in people with cerebral palsy are a standard part of routine clinical assessments. X-rays and other forms of radiological analysis are used to capture high-resolution images of the hip joint for a more thorough analysis of the joint\u2019s anatomy and alignment ,15. Hip ManagementConservative ManagementIn order to enhance hip function and prevent further difficulties, conservative therapy of the spastic hip in cerebral palsy employs non-invasive techniques . PhysicaBotulinum Toxin InjectionsBotulinum Toxin A (Botox) injections are used to temporarily weaken spastic muscles around the hip joint. Muscles such as the hip adductors, flexors, and abductors are commonly targeted for Botox treatment due to their involvement in hip spasticity. They work by blocking the release of a chemical messenger called acetylcholine, which is responsible for muscle contractions. This treatment can help relieve muscle tightness and improve joint alignment ,19. AfteSurgical InterventionsSurgical interventions play a crucial role in addressing hip subluxation or dislocation when conservative treatments prove inadequate or when the condition becomes severe. In cases where non-surgical approaches do not yield satisfactory results, surgical procedures become necessary to improve joint stability and functional outcomes. A frequently employed surgical technique is soft tissue release, which specifically targets the commonly affected tight or contracted muscles and ligaments around the hip joint in cerebral palsy. For instance, the hip adductors and flexors are often the focus of this approach. In soft tissue releases, these muscles and ligaments are meticulously cut or lengthened through surgical procedures. This intervention is designed to significantly enhance joint mobility and effectively alleviate pressure on the hip. By precisely addressing these tight structures, the ultimate goal is to restore proper alignment and functional capability. The selection of muscles for release and the method used are based on a thorough assessment of the individual's condition and the expertise of the surgical team. This tailored approach ensures the best possible outcomes for the patient's unique hip spasticity profile . Bony reEmerging therapies and novel approachesIn the field of cerebral palsy management, emerging therapies and novel approaches have been paving the way for more effective treatments for the spastic hip. Surgical procedures that can selectively target and block neural pathways responsible for spasticity, such as selective dorsal rhizotomy (SDR), have gained popularity in recent years . AdvanceRehabilitation and postoperative careThe care of the spastic hip in cerebral palsy is greatly aided by rehabilitation . To imprFuture directionsFuture directions in the care of the spastic hip in cerebral palsy show promising promises as research and technology advance. Innovative treatments, such as regenerative therapies using stem cells or growth factors, may offer the potential to promote tissue repair and functional recovery . To helpSpastic hips in cerebral palsy must be treated using a comprehensive and interdisciplinary approach. Early diagnosis and timely surgical correction of spastic hip displacement can prevent hip dislocation and the need for more extensive surgery. We advise building the screening program utilizing the GMFCS Level. Ongoing research and innovation will influence the future of spastic hip care, with the ultimate goal of improving the quality of life for people with cerebral palsy."} +{"text": "While translated as two-eyed seeing, the term refers to explanatory pluralism and invites a respectful dialogue among cultures as equals.Psychiatry has historically had difficult relationships with Indigenous people, tending to dismiss their views on mental health and illness as superstitious or primitive. Indigenous people have responded by refusing to come for services, missing appointments, and dismissing treatment offered. Canadian Mi\u2019qmak elder Albert Marshall introduced the term, We implemented a two-eyed seeing research in Indigenous communities to explore the differences of some Indigenous North American cultures in their view of mind and mental health from conventional Euro-American psychiatry and how their cultural practitioners negotiated those differences. We wondered how perception of services would change if mental health practitioners were aware and were more respectful of those differences.We engaged in a series of discussions with traditional knowledge keepers about their views on mind and mental health. We used constructivist grounded theory methods to identify what was common among these views. We developed a training program to engage mental health clinicians in understanding and responding to these differences. We engaged community members receiving services in a discussion about their perception in the change in the quality of the services. We summarized their responses.Differences between Indigenous views and those of conventional psychiatry included (1) greater emphasis on the role of community and socio-environmental influences on mental health, (2) inclusion of spirituality and spiritual beings in their expectation for cause of problems and treatment, (3) greater emphasis on inter-generational trauma and historical trauma in addressing mental health. After inclusion of practitioners in the mental health services who had been oriented to these differences and integration of ceremony into the mental health services, ninety-four percent of respondents asked if the service had improved responded in the positive. Attendance at scheduled appointments increased from 56% to 81%. Adherence to recommendations increased from 27% to 67%, which were significant.Awareness of cultural differences in beliefs about causes of mental illness and acceptable types of treatment increased client satisfaction with services offered, improved attendance rates, and improved adherence rates to treatments offered among Indigenous people. These results could generalize to other populations who hold different views than those of conventional psychiatry. The concept of two-eyed seeing, or explanatory pluralism, holds heuristic value for psychiatry by allowing multiple points of view to be true at the same time.None Declared"} +{"text": "Medicare covers costs far more than 50% of all cancer patients, and most private payers follow Medicares lead on coverage and benefits for cancer care. Medicare and private payers are legally required by federal statute to cover anticancer chemotherapeutic products based on U.S. Food and drug administration-approved labeling and indicate how off-label uses are covered.To review reimbursement issues unique to Medicare with regard to oncology drugs.Currently, the Centers for Medicare and Medicaid Services (CMS) recognizes 2 compendia for purposes of evaluating off-label uses of drugs. Coverage determinations can be pursued nationally, locally, and case by case. Because of the impact and scope of colorectal cancer on the national budget, CMS initiated a process to establish national coverage determinations. This and other such Medicare reforms will have significant repercussions for clinicians who work with oncology patients. Major administrative and access challenges for both health care providers and beneficiaries include a diverse array of plan choices. In terms of Medicare Part d, the 25% of patients who are chronically ill and prescribed expensive therapies (including antineoplastics and supportive care agents) may find the coverage gap (\"donut hole\") challenging and even prohibitive in their access to appropriate care. Lack of coverage could potentially affect therapy compliance, and managed care must pursue additional payment or coverage support mechanisms. Evaluating formularies will be critical for cancer patients and those who use specialty drugs as they select their Part d plans in the future.Oncologists and their patients are left with difficult choices regarding not only the clinical efficacy of a treatment but also the financial considerations of the treatment."} +{"text": "The omentum is the predominant site of ovarian cancer metastasis, but it is difficult to remove the omentum in its entirety. There is a critical need for effective approaches that minimize the risk of colonization of preserved omental tissues by occult cancer cells. Normal saline (0.9% sodium chloride) is commonly used to wash the peritoneal cavity during ovarian cancer surgery. The omentum has a prodigious ability to absorb fluid in the peritoneal cavity, but the impact of normal saline on the omentum is poorly understood. In this review article, we discuss why normal saline is not a biocompatible solution, drawing insights from clinical investigations of normal saline in fluid resuscitation and from the cytopathologic evaluation of peritoneal washings. We integrate these insights with the unique biology of the omentum and omental metastasis, highlighting the importance of considering the absorptive ability of the omentum when administering agents into the peritoneal cavity. Furthermore, we describe insights from preclinical studies regarding the mechanisms by which normal saline might render the omentum conducive for colonization by cancer cells. Importantly, we discuss the possibility that the risk of colonization of preserved omental tissues might be minimized by using balanced crystalloid solutions for peritoneal washing. The omentum comprises two fatty structures. One apron-like structure drapes from the greater curvature of the stomach and extends to the transverse colon and splenic hilum, whereas the other thinner structure extends from the lesser curvature of the stomach to the liver ,2. SevenOmentectomy is the standard of care for metastatic ovarian cancer, but it is difficult to remove the omentum completely because of its anatomic location . PotentiThere has been a lack of consensus about how much grossly normal omental tissue should be removed in ovarian cancer patients who present without overt metastasis, and the benefit of total omentectomy in these patients has been questioned by several investigators ,9,10,11.A caveat that needs to be considered is that disseminated ovarian cancer cells have a proclivity to implant on the omentum, and there are no effective strategies that minimize the risk of colonization of preserved omental tissues by occult cancer cells. Peritoneal washing using normal saline (0.9% sodium chloride) is commonly performed during ovarian cancer surgery, but the impact of this procedure on the disease has not been questioned. This review article focuses on the importance of reconsidering the use of normal saline for peritoneal washing in patients with ovarian cancer. Firstly, we discuss preclinical and clinical studies of the use of normal saline in fluid resuscitation and in pNormal saline is the most widely utilized crystalloid solution in medical practice and is commonly used for fluid resuscitation and lavage. It is thought that the medical use of saline solutions started during the cholera epidemic in the 1830s, but the composition of these early solutions did not resemble that of normal saline . The earFluid resuscitation with normal saline has been investigated in a number of clinical trials and observational studies in a variety of settings ,23,24,25Hyperchloremic acidosis in patients infused with normal saline is associated with an increased risk of renal and vascular dysfunction . PreclinBecause of the adverse renal and vascular effects of hyperchloremic acidosis caused by normal saline, extensive clinical efforts have been directed to evaluating balanced crystalloids in fluid resuscitation. The two most-studied balanced crystalloids are lactated Ringer\u2019s solution and Plasma-Lyte A. These solutions contain physiological concentrations of chloride and are buffered . LactateNormal saline is administered into the peritoneal cavity for diagnostic aspiration and is aIt has been commonly thought that mesothelial cells are stripped by peritoneal washing due to shear stress from the procedure ,42. HoweWhereas previous studies of peritoneal lavage have largely focused on the effects of normal saline on the mesothelial lining, the impact of this procedure on underlying tissues is poorly understood. This merits investigation as more than one liter of solution is typically used for intraoperative washing and apprThe omentum is often termed an adipose tissue but has important protective functions, giving rise to its moniker the \u2018abdominal policeman\u2019 by Morison in 1906 . The omeWhereas metastasis of many other types of cancers occurs through hematogenous or lymphatic routes, metastasis of ovarian cancer is predominantly transcoelomic and occurs through the transport of cancer cells by interstitial fluid in the peritoneal cavity ,54. CancGrowth and invasiveness of ovarian cancer cells that implant on the omentum are stimulated by a repertoire of factors that mediate cross-talk between cancer cells and stromal cells. Omental adipocytes provide energy for tumor growth by transferring lipids to ovarian cancer cells through the lipid trafficking protein fatty acid-binding protein 4 . OvarianBecause of the absorptive ability of the omentum and its proclivity for transcoelomic metastasis, agents that are administered into the peritoneal cavity need to be evaluated for their impact on the omental microenvironment and for potentially stimulatory effects on metastasis. In a recent study using mouse models , we idenThere are two ontogenically and phenotypically distinct types of macrophages that reside in the peritoneal cavity. It is thought that large peritoneal macrophages (LPM) arise from the yolk sac, whereas small peritoneal macrophages (SPM) derive from monocytes ,65. LPM CX3CR1+ monocytes/macrophages have been found to mediate wound healing in various types of tissues ,67. OmenNormal saline decreases pH and low pH increases NF-\u03baB activity in macrophages , but theIn view of the findings that normal saline can render the omentum conducive for implantation of ovarian cancer cells, what other lavage solutions might be suitable for peritoneal washing? Several potential alternative solutions are listed in Conventional peritoneal dialysis solutions have been considered unsuitable for peritoneal lavage because these solutions contain glucose that generates glucose degradation products (GDPs) and advanced glycation end products (AGEs) . ExposurLactated Ringer\u2019s solution and Plasma-Lyte A have been found in a number of independent clinical studies to cause fewer adverse effects than normal saline when used for fluid resuscitation ,30,31,32Although no adverse effects were observed following the administration of lactated Ringer\u2019s solution into the peritoneal cavity of mice , it remaFor several decades, normal saline has been used for peritoneal washing in patients with ovarian cancer. However, this practice needs to be reconsidered. The presence of exfoliated mesothelial cells in peritoneal washings of patients with ovarian cancer and the difficulty in distinguishing reactive mesothelial cells from cancer cells have presented significant challenges for accurate cytologic evaluation. The use of balanced crystalloids instead of normal saline for peritoneal washing could potentially minimize the exfoliation of mesothelial cells and thereby improve the accuracy of cytologic assessment.The use of normal saline for peritoneal washing in patients with ovarian cancer also needs to be carefully reconsidered in view of the potential impact of this procedure on the disease. Greater appreciation of the prodigious absorptive ability of the omentum is required. The administration of normal saline into the peritoneal cavity may elicit changes in the omentum that render its microenvironment conducive for colonization by occult ovarian cancer cells in the peritoneal fluid. Further investigation is needed to characterize changes in gene expression and signaling pathway activation in both immune and non-immune cell populations in the omentum following exposure to normal saline. Importantly, the possibility that the risk of omental colonization could be minimized by repurposing readily available and clinically used balanced crystalloids for peritoneal washing in patients with ovarian cancer merits further investigation."} +{"text": "Female cancer survivors who received gonadotoxic cancer treatment are at risk for profound diminished ovarian reserve and/or primary ovarian insufficiency with resulting infertility, which can be associated with distress and decreased quality of life.. Despite prioritizing future parenthood, many survivors are unsure of the impact of their treatment on their future fertility, and little is known about the perceived reproductive health needs and factors associated with receipt of a fertility status assessment (FSA). There is a lack of developmentally appropriate reproductive health decisional support interventions available for emerging adult cancer survivors. This study will explore the perceived reproductive health needs of emerging adult female survivors of childhood cancer and to identify decisional and contextual factors that influence pursuit of FSA using an explanatory sequential quantitative to qualitative mixed methods design.This study will enroll 325 female survivors from four cancer centers in the United States. Sociodemographic and developmental factors, reproductive knowledge and values, decisional needs, and receipt of an FSA will be assessed through a web-based survey. Informed by survey findings, a subset of participants will be recruited for qualitative interviews to explore decisional factors associated with uptake of an FSA. Clinical data will be abstracted from the medical records. Multivariable logistic regression models will be developed to identify factors associated with FSA and qualitative descriptive analysis will be used to develop themes from the interviews. Quantitative and qualitative findings will be merged using a joint display to develop integrated study conclusions and direct future interventional research. Cancer treatment has improved such that survival rates overall for childhood and adolescent cancer now surpass 80% . There aThe ability to conceive and have children is a priority among patients and families from the time of cancer diagnosis into lonThere are no definitive tests that predict fertility among cancer survivors, as fertility can be affected by various factors which are unrelated to previous gonadotoxic treatments including the partner\u2019s health, sperm quality/quantity, health problems that impact fecundity, lifestyle/behavioral factors, and others. Assessing the risk for infertility among cancer survivors includes consideration of prior gonadotoxic exposures and other medical history, gonadal assessment, and counseling regarding family building options, which can broadly be described as a fertility status assessment (FSA). An FSA for females typically includes a medical history, assessment of menstrual-cycle specific laboratory hormones and a pelvic ultrasound with antral follicle count. This testing should be followed by discussion of ovarian reserve and the risk of infertility and/or premature ovarian insufficiency, and available treatment options. These consults are typically completed by reproductive endocrinologists . Among sReproductive health and consideration of FSA is particularly relevant to the emerging adult population. This is because emerging adulthood (18\u201325 years of age) represents a developmental period of transition from adolescence to adulthood . EmerginWhile potential infertility is a top concern among young cancer survivors, little is known about the perceived reproductive health needs and factors associated with uptake of a FSA among female cancer survivors. The purpose of this two-phase sequential quantitative to qualitative mixed methods study is to explore the perceived reproductive health needs of female cancer survivors and to identify decisional and contextual factors that influence receipt of an FSA. The goal of the first, quantitative study phase is to establish a knowledge base of the reproductive health needs of this population and identify sociodemographic, developmental, and reproductive-health factors that are related to receipt of an FSA. This will be achieved by surveying 325 survivors recruited from four cancer centers across the United States. The goal of the second, qualitative phase, is to build on the quantitative results and elucidate patient experiences with FSA and preferences for a decisional support intervention by interviewing 32 survey participants purposefully selected based on their reported receipt/interest in an FSA. The rationale for integrating quantitative and qualitative methods in this study is to expand our understanding of the factors that influence survivors\u2019 receipt of reproductive health services and to inform the development of a decisional support intervention for survivors interested in an FSA. Quantitative, qualitative, and mixed methods research questions to guide the study are:Quantitative: What are the reproductive health values, behaviors, and knowledge gaps of young adult female survivors of childhood cancer? Which sociodemographic, developmental, and reproductive health factors are related to receipt of an FSA?Qualitative: How do contextual factors influence female cancer survivors\u2019 decision to pursue or not pursue an FSA? What are barriers or facilitators to accessing an FSA and/or reproductive health services?Mixed Methods: What components, grounded by the quantitative and qualitative results, should be incorporated into reproductive health and decisional support interventions to address barriers and increase decisional satisfaction for young adult females considering an FSA?While there have been independent quantitative and qualitative investigations in this area, a mixed methods approach is necessary to fully understand survivor perspectives regarding reproductive health and FSA, with a focus toward future intervention development and testing. Mixed methods research involves the collection of both quantitative and qualitative data, with a key feature of integrating findings to determine meta-inferences or integrated study conclusions . A two-pThis study is informed by the Ottawa Decision Support Framework that purports an individual\u2019s decisional needs will affect decision quality, behavior, and emotions regarding the decision . The conThe population of interest for this study is female survivors of childhood cancer, 18 through 29 years of age. A sample of 325 survivors will be identified and recruited from four cancer centers throughout the United States. The participating sites have established fertility clinical services, are active members of the Children\u2019s Oncology Group, and have a history of collaboration through the Pediatric Initiative Network of the Oncofertility Consortium . These sParticipants are eligible for this study if they are (1) 18.00 to 29.99 years of age, (2) diagnosis of cancer < 21.00 years of age, (3) female sex, and 4) received gonadotoxic cancer treatment , surgeries, history of hematopoietic cell transplant, and date of cancer treatment completion will be abstracted from participant\u2019s medical records using an adapted version of the Children\u2019s Oncology Group Summary of Cancer Treatment Template .Data for the qualitative phase will be collected through semi-structured interviews. Participants will be contacted and invited to complete a 45-minute semi-structured interview over the phone or using Zoom web conferencing (HIPAA compliant) with a trained qualitative interviewer. Consistent with a sequential design, the interview guide will be developed and informed by descriptive results from the quantitative phase . We antith, 2022 at the coordinating center, with all participating sites actively recruiting by January 11, 2023. Qualitative data collection is planned to begin in summer 2023.Study recruitment and quantitative data collection began April 4Descriptive statistics will be examined using means and standard deviations, medians and interquartile ranges, or percentages and frequencies, as appropriate. For the primary outcome variable , multivariable logistic regression models will be developed to identify factors related to receipt of an FSA. Final multivariable results will be guided by the bivariable associations and determined using backward selection procedures, as well as any clinically relevant variables.Interviews will be audio-recorded and professionally transcribed verbatim and checked for accuracy . InductiTo assure quality in this mixed methods study, we will use strategies associated with the quantitative phase, qualitative phase, and strategies that support mixed methods meta-inferences , 58. StrStrategies to enhance credibility and trustworthiness for the qualitative phase include the use of field notes and reflexive journaling throughout the interview and analysis process . After tTo enhance the quality of the mixed methods meta-inferences we will focus on addressing veracity, consistency, applicability, and neutrality . The quaIn addition to the points of connection between the survey phase and interview phase, the quantitative results and qualitative findings will be mixed to generate meta-inferences or integrated study conclusions regarding factors that contribute to FSA and factors to be addressed through a decisional support intervention. This will involve identifying critical content and resources to include in the decisional support intervention and refining measurement tools and outcomes for the testing of the intervention. Qualitative findings will be integrated with the quantitative descriptive and multivariable model results to further describe decisional satisfaction and associated concepts . This wiA joint display will be used to assist with integrative analysis . This wiQualitative data will be summarized, with illustrative quotes, into matrices by site and FSA status of participant to further identify patterns . Data wiThis study has been approved by the coordinating center institutional review board (Emory University IRB #00003083) and will be approved by all participating site institutional review boards prior to recruitment of participants. Informed consent will be obtained from participants prior to completing any aspect of the study. All data will be collected and stored through the password protected and secure REDCap database; audio recordings for qualitative interviews will be stored in password protected files on the secure Emory University server. At each participating site, access to data will be restricted to approved study team members and study-related files will be stored in password protected files. Data will be deidentified whenever possible through the use of assigned study identification numbers. Findings from this study will be disseminated through presentation at academic and professional conferences and in peer-reviewed journal.Little is known about the perceived reproductive health needs and factors associated with receipt of an FSA among emerging adult female cancer survivors. Overall, prior research has been limited by small sample sizes and lacking in comprehensive assessment of clinical and treatment characteristics, sociodemographic, developmental, and psychological factors related to FSA, all aspects that will be addressed through this study. Through a mixed methods approach, this study will allow for a better understanding of the of factors association with FSA uptake and the decisional processes amongst both survivors who have and have not received an FSA.This study will use a developmental framework to identify factors related to an FSA among female cancer survivors in emerging adulthood. Studies of reproductive health among cancer survivors have traditionally included a very wide age range without accounting for the unique developmental features and milestones that occur during emerging adulthood. There is a lack of developmentally appropriate reproductive health and fertility-related psychoeducational and decisional support interventions available for emerging adult cancer survivors. By focusing on a distinct population of cancer survivors during a developmental period that is ripe for fertility-related distress and family building, results of this study have a strong translational application for survivors who are in their reproductive years. Furthermore, this work will inform future interventions to promote uptake of FSA among interested female cancer survivors.S1 File(PDF)Click here for additional data file."} +{"text": "Hypoglycaemia is a common problem with significant adverse influence on neurodevelopment in childhood and lasting impact in adult life with consequent neurodisability. Hypoglycaemia is often incompletely understood and inadequately treated. This research topic collates various manuscripts along diverse strands but is unified on the common theme of hypoglycaemia to enrich our current understanding of disease pathways, therapeutic targets and patient impact centred around patient need Figure\u00a01Kristensen et\u00a0al. gets to the heart of the health consequences of hypoglycaemia but concludes that Health related Quality of Life (QoL) studies are infrequent, inconsistent in their reports and often generic to chronic illness, thereby failing to capture disease specific nuances and family perspectives, for example in the case of Congenital Hyperinsulinism (CHI), a disease of severe and recurrent hypoglycaemia in early childhood. The present generation of generic instruments are not sensitive to individual family distress and are therefore unlikely to capture everyday parental anxiety and feelings of despair and helplessness. There is a case to develop CHI specific QoL instruments and apply these to individual aetiologies to draw out meaningful change and derive valid comparisons.Maiorana et\u00a0al. discuss gene panel testing in the context of metabolic causes of hypoglycaemia whilst including hyperinsulinism and CHI. Delineating specific genetic association or causation is important to provide certainty of diagnosis without complex and often uncertain biochemical investigations for optimal pharmacologic therapy and for anticipation of prognosis or disease behaviour. Hewat et\u00a0al. also round up various genetic aetiologies for CHI but suggest caution in simplistic interpretation; phenotypes are variable and a genetic reporting strategy based on previously recognized gene variants may fail to account for the wide variety of seemingly disparate genetic aetiologies and ignore nuances in appreciating pathogenic behaviour. The authors argue for an informed genetic investigational approach utilizing the experience and interpretive abilities of well-established and research active genetic laboratories.Genetic technology has changed rapidly over the past decade and genetic investigation of hypoglycaemia is no exception. Zenker at al. The authors explore the strength of association, some being tenuous while others having closer correlation and some having distinctive pancreatic histopathological changes, for example those with Beckwith Wiedemann syndrome. The diversity of genetic aetiology reiterates the heterogeneity of hyperinsulinism in CHI in a nod to Wieland et\u00a0al. who question traditional understanding of differential gene expressions in the well-recognized form of focal CHI. The authors explore the possibility of integrating pancreatic gene transcript expression to enrich understanding of focal lesional pathobiology. While the recognition of novel genetic correlates may appear to diversify existing heterogeneity, it may promote deeper understanding of pathways for regulation of insulin and potential therapeutic windows in hypoglycaemia.Understanding of genetic aetiology is important not just for the diagnosis of specific forms of hypoglycaemia, such as focal CHI but also for dissecting syndromic forms of CHI described by + channel (K-ATP) targeted by diazoxide. van Albada et\u00a0al. describe alternative therapeutic paradigms in the somatostatin pathway regulating insulin secretion. While somatostatin receptor activation may modulate excess insulin in patients with severe genetic forms of CHI, therapy remains off-label both for short and long-acting forms, although with the promise of newer therapies targeting somatostatin receptor subtypes.At present, medical therapies for CHI, a leading cause of childhood hypoglycaemia, are suboptimal; the mainstay of CHI therapy with diazoxide is not applicable to those with mutations in the ATP sensitive KDanowitz and de Leon. The authors describe the physiology of GLP1 and a similar peptide glucose-dependent insulinotropic polypeptide (GIP), setting the scene for potential therapy with GLP1 receptor antagonists for CHI and post prandial forms of hyperinsulinism. It remains to be seen if such insulin modulating mechanisms have sufficient disease modifying ability to enter the hypoglycaemia treatment repertoire.Glucagon like peptide 1 (GLP1) as another molecular target and pathway in CHI amenable to therapeutic modulation, has been reviewed by Lithovius and Otonkoski. The authors discuss current use of pluripotent stem cells (PSCs) with predicted technical advances leading to the conversion of differentiated PSCs into pancreatic islets to serve as a paradigm changing model exploring novel mechanisms, beta-cell glucotoxicity and novel therapies. While stem cell technologies emanating from research in hyperinsulinism may benefit the understanding of CHI in the first instance, it is likely that collateral information will strengthen our understanding of beta-cell biology and have wider application in other beta-cell disorders such as diabetes.A radical departure from traditional investigational methods is described in a paper by Rossi et\u00a0al. dynamic methods to characterize hypoglycaemia have been discussed. These range from traditional techniques such as functional in vivo testing to more modern in vivo metabolic profiling using Continuous Glucose Monitoring (CGM). The paper also discusses the value of isotope tracing to dissect aetiologies in inherited errors of metabolism through the interrogation of metabolites and pathways, for instance in glycogen storage disorder type 1 (GSD1).While molecular technologies advance at pace providing exciting new aetiologies of hypoglycaemia, phenotypic exploration using current investigational tools must also continue, if only to understand the link between abnormal genetic mechanisms and disease manifestations. In the paper by Kolker et\u00a0al.) and more specifically in CHI , a hypoglycaemia disorder with significant family impact. Patient reported data in carefully curated registries are excellent platforms to characterize phenotypic detail that supplement clinician gathered information. As such datasets mushroom, encompassing different groups of patients in different countries, critical evaluation of disease trajectories will no doubt lead to cross correlation of multi-sourced information to build a multidimensional, enriched and individualized model of health need.There is no substitute to natural history studies in hypoglycaemia, mirroring real-world patient information. Although imperfect with inherent data variability, natural history studies of hypoglycaemia captured in global registries are valuable sources of information to design clinical studies and novel therapies. The topic features a narrative of the development of registries in rare diseases as a whole (Auckburally et\u00a0al. take up the patient side to explore the often-unheard voices concurring and dissenting in the use of rapidly emerging technologies such as CGM in hypoglycaemia. Their focused thematic analysis provides a clarion call to adapt and innovate on patient need for optimal health outcomes tailored to the individual. Their manuscript reinforces the increasing importance of the patient perspective in the design of studies and clinical services as joint collaborative enterprises between different disciplines and patient groups, all working harmoniously towards a common goal to alleviate morbidity from debilitating hypoglycaemia.A crucial component of the health need in hypopglycaemia is the patient voice, which is often neglected in the face of rapidly expanding technologies and medical opinions. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "Mental health problems are increasingly prevalent among students, necessitating adequate mental health support both for those who with or at risk of developing a mental health disorder.This systematic review examined the efficacy of psychological interventions delivered to student populations and whether interventions with some form of adaptation to the content or delivery of the intervention for students could improve outcomes compared to interventions which had no such adaptation.Randomised controlled trials of interventions for students with or at risk of mental health problems were included. Specific adaptation for students (or whether they utilised a student population as a convenient sample) was recorded. Meta-analyses were conducted and multivariate meta-regressions explored the effect of adaptation on the pooled effect size. Eighty-four studies were includedPromising effects were found for both treatment and preventative interventions for anxiety disorders, depression and eating disorders. PTSD and self-harm data was limited, and did not demonstrate significant effects. Relatively few trials adapted intervention delivery to student-specific concerns, and overall adapted interventions showed no benefit over non-adapted interventions. There was some suggestion that adaptions based on empirical evidence and provision of additional sessions, and transdiagnostic models may yield some benefitsInterventions for students show benefit though uncertainty remains around how best to optimise treatment delivery and content specifically for students. It would be beneficial to understand how intervention content which is specific to underlying mechanisms of problems experienced by students as well as more transdiagnostic approaches could further support recovery and prevention of mental health problems while at university.None Declared"} +{"text": "Host-Pathogen Interactions Interplay and Cancer: Understanding Mechanisms and Beyond\u201d, established under the section Molecular and Cellular Oncology of the Frontiers in Oncology.This editorial summarizes the contributions to the Frontiers Research topic \u201cRole of microbes in cancer is evident through several recent studies. It is apparent that microbes play multifaceted and complex role in the oncogenesis ranging from development of cancer to its prevention. The role of several virus and bacteria are established in the oncogenesis , on the This Research Topic encompasses multidisciplinary articles focusing on diverse aspects of microbial involvement in oncogenesis mediated through host-pathogen interactions. Overall, the authors of every manuscript covered different aspects of microbial involvement in cancer development. The research topic consists of article related to basic research using computational approaches along with review articles discussing novel aspects of microbial involvement in cancer development through unique host-pathogen interactions. These manuscripts are ranging from specific role of individual microorganism to collective involvement of microbiome in the cancer development.Suhail et\u00a0al.).The role of hepatitis C virus in hepatocellular carcinoma was discussed with emphasizing the interactions of viral proteins with host cells leading to impairment of normal signaling pathways, inflammation and oxidative stress ultimately contributing to carcinogenesis. In addition, the role of hepatitis C virus in neurological diseases was also discussed as some patients with hepatocellular carcinoma also developed neurological complications. This article tried to gather the details about advancements in the field of hepatitis C virus mediated hepatocellular carcinoma including diagnosis, mechanisms and antiviral therapies related to hepatitis C virus mediated hepatocellular carcinoma (Ozdemir and Nussinov).The articles included in the research topic also discussed structural biological insights to the pathogen mediated cancer. The 3D structure of host-pathogen interaction complexes can help to understand the importance of these interactions in microbial pathogenesis including their involvement in pathogen mediated cancer. It also provides an idea about importance of host-pathogen interaction predictions and the gaps in computational approaches for host-pathogen protein-protein interaction prediction. At the end the article discusses about how these approaches can be beneficial in the field of cancer research and provides details for utilization of these approaches in understanding pathogen medicated cancer .In addition, the role of tumor microbiome in tumor microenvironment was also discussed in the research topic by the authors. This article focuses on the composition of tumor microenvironment and the studies pertaining to understanding tumor microbiome in different solid tumors. Moreover, this article tries to cover clinical application of microbiome based approaches for cancer management. In conclusion, the article provides comprehensive information about tumor microbiome and its contribution in tumor microenvironment .The research article included in Research Topic encompasses novel approaches for drug repurposing using biological interaction data. The authors demonstrated the use of this approach for cervical cancer which is almost exclusively associated with human papillomavirus (HPV) infection. The authors used certain conditions to screen important host proteins from interaction networks. These conditions were (i) differential expression of host proteins, and the author screened transcriptomic datasets using gene expression omnibus (GEO) for identifying differentially expressed genes with cervical cancer. (ii) the relationship of host proteins and cervical cancer was evaluated using statistical significance by adjusted p-value. (iii) Along with that, the authors also screened number of interactions between host and viral proteins and used the rationale that the host targets with more interactions with viral proteins will affect virus more effectively and thus increase the chances of preventing disease progression. In addition, the host target should have low numbers of interaction with human proteins in order to display fewer side effects on the host. (iv) Moreover, the host protein expression level in cervical cancer was taken as another parameter to evaluate is efficacy as a host drug target. Using this approach, the authors identified novel drug candidates and targets for HPV16 and 18 those are majorly involved in the cases of cervical cancer. The approach devised in this manuscript can be used to identify drug candidates for several other infectious diseases including pathogen associated cancer (in silico, in vitro and in vivo approaches for leveraging translational potential of the findings and their replication in several other diseases including pathogen medicated carcinogenesis.From the application perspective, the manuscripts included in the research topic generate thought provoking space for the readers and generate ideas for using the information for understanding the mechanistic enigma of pathogen associated cancer and the role of host-pathogen interactions in this process. The findings presented in research article can help in the development of novel investigational Altogether, the research article and reviews compiled in this Research Topic provides an important resource for understanding the diverse insights about pathogen mediated cancer and the role of host-pathogen interactions in this process. The review articles highlight the major milestones achieved so far in understanding role of microbes and microbiome in cancer development and using recent approaches to understand this association. On the other hand, the research findings elaborate the strategy for identification of therapeutic targets and drug repurposing for such pathogen mediated cancer using host-pathogen interactions data. Current approaches are generating high throughput host-pathogen interaction data which is being compiled in several dedicated databases and the articles collected in this research topic provides avenues for their utilization in understanding pathogen mediated cancers and their management strategies. We expect our readers deify the noticeable collection of research on cancer related host-pathogen interactions.AAK and EA prepared and finalized the manuscript. All authors contributed to the article and approved the submitted version."} +{"text": "Failure in treating opioid dependence is costly to the patient, the employer, managed care organizations, and the overall health care system. Opioid dependent patients tend to be less productive at work and in society and utilize a great many health care resources. Optimizing outcomes is essential.To introduce the benefit of integrated strategies and patient support in the treatment of opioid dependence.Health Analytics is currently studying the benefit of HereToHelp, a behavioral support program in which registered nurses or addiction treatment counselors with specialized training in addiction education provide information and encouragement to patients receiving pharmacologic treatment for opioid dependence. A total of 470 physicians in 41 states have been enlisted to participate in this patient support study. The study hypothesis is that patients who receive behavioral support and encouragement will be more compliant with their opioid replacement therapy, leading to better outcomes. Additional treatment strategies are also being developed to minimize the risk of abuse and diversion. Prodrugs and vaccines are also being investigated.A coordinated team approach is essential in treating pain patients and opioid-dependent patients. Offering behavior modification in addition to pharmacotherapy and utilizing strategies such as prescription monitoring programs, pain contracts, and screening are all vital components necessary for positive outcomes."} +{"text": "However, not all patients who may be eligible for local treatment are offered this option. This is due to the absence of transparent and validated criteria for local treatment as well as the inability to keep up with local treatment possibilities by improving surgical techniques such as ablation and liver augmentation in non-liver expert centres. Previous studies have shown that the use of online liver expert panels may increase the number of patients who may benefit from local treatment.6 In this RCT, patients with initially unresectable colorectal cancer liver-only metastases were randomised between the currently most effective induction regimens consisting of chemo- and targeted therapy. The analysis of 1149 evaluations of 496 patients showed disagreement between panel surgeons in 50% of resectability assessments, and surgeons proposing different local treatment plans in 77% of patients. The most pronounced inter-surgeon differences concerned the advice to proceed with a major hepatectomy versus parenchymal-preserving approaches involving local resection and ablation strategies.This study assessed the variability in resectability assessments and local treatment planning among 17 surgeons participating in the Dutch Colorectal Cancer Group (DCCG) liver expert panel from the randomised controlled phase III CAIRO5 study (NCT02162563).7 Lastly, most studies in patients with initially unresectable CRLM only report on the percentage of patients in whom local treatment was achieved, and not on the long-term outcome of these patients.8 More efforts should be made to identify patients in whom local treatments result in a clinically meaningful benefit. Therefore, further research is needed to explore whether resectability assessments can be supported by other biological resection criteria such as the consensus molecular subtypes and/or circulating tumour DNA. In addition, it is important to examine whether the different technical treatment plans as proposed by the panel surgeons are associated with differences in survival and postoperative morbidity.Several steps should be taken to reduce this unwarranted variability and to ensure that every patient who is eligible for local treatment is given the opportunity to undergo such treatment. First, all patients with CRLM should be evaluated by a multidisciplinary team involving at least one liver surgeon, and preferably by a panel of multiple surgeons considering the high rate of disagreement. The implementation of online liver expert panels within oncological networks can help to improve the consistency and quality of care. These panels allow multiple experts to review patients, reducing variability and ensuring that every patient, including those with multiple CRLM, is evaluated for local treatment before and after systemic therapy. This is particularly important given the success of induction therapy in CRLM. Second, consensus guidelines on resection criteria and technical approaches should be further developed to enhance the standardisation of local treatment. Current local treatment evaluation of initially unresectable CRLM remains primarily a technical anatomical decision. Existing clinically available tumour biomarkers fall short in predicting early recurrence after local treatment of CRLM, i.e., selecting patients who will and will not derive benefit from local treatment."} +{"text": "Green logistics has recently received considerable attention because of its practical benefits to businesses and the environment, particularly in developing countries. However, there is a lack of empirical evidence regarding the motivations behind green logistics practices and environmental performance. This study explores the impact of green logistics knowledge exploitation on green logistics management practices and green logistics performance. In addition, this study explains the moderating role of green intellectual capital in the relationship between green logistics knowledge exploitation and green logistics management practices. Based on responses from 142 Vietnamese logistics business managers, the data were analyzed using partial least squares structural equation modeling. To our knowledge, this is the first study to confirm 1) the influence of green logistics knowledge exploitation on green logistics performance through the mediating role of green logistics management practices, and 2) the moderating effect of green intellectual capital on the relationship between green logistics knowledge exploitation and green logistics management practices. These results have implications for environmental management practices in logistics operations and could help promote green logistics practices through green logistics knowledge exploitation and its subsequent enhancement of green logistics performance."} +{"text": "The Asia Pacific Society of Infection Control launched the APSIC guide for prevention of catheter associated urinary tract infections in July 2022. It aims to highlight practical recommendations in a concise format designed to assist healthcare facilities in the Asia Pacific region to achieve high standards in infection prevention and control practices during the management and care of patients with a urinary catheter.The guidelines were developed by an appointed workgroup comprising experts in the Asia Pacific region, following reviews of previously published guidelines and recommendations relevant to each section.It recommends that healthcare institutions have a catheter associated urinary tract infection prevention program that includes surveillance and the use of the insertion and maintenance bundles. Implementation of the bundles is best done using a quality improvement approach with a multidisciplinary team.Healthcare facilities should aim for excellence in care of patients with urinary catheters. It is recommended that healthcare facilities have a catheter associated urinary tract infection prevention program as part of their Infection Prevention and Control program. The members of this workgroup are the authors of this paper.For the APSIC guideline, the workgroup reviewed previously published guidelines and recommendations relevant to each section and performed computerized literature searches using PubMed. Some examples of keywords used in search include catheter associated urinary tract infection, CAUTI, infection prevention and control.The workgroup met on four occasions in addition to discussion via email correspondences to complete the development of the guideline. Criteria for grading the strength of recommendation and quality of evidence are described in Table Among urinary tract infections (UTIs) acquired in the hospital, 75% are catheter-associated UTIs (CAUTI) . It is eEnsure staff have an understanding of the pathogenesis and risk factors for CAUTIs in order to develop and implement appropriate infection prevention measures. [IA]Undertaking risk assessments will identify modifiable risk factors to reduce CAUTI. [IA]Recommendations for initial steps to the prevention of CAUTI includeGenerally, the diagnosis of CAUTI is made based on the presence of bacteriuria with signs and symptoms consistent with UTI in a catheterized patient or in a patient who had the catheter removed within the past 48\u00a0h. Signs and symptoms compatible with CAUTI include new onset or worsening of fever, rigors, altered mental status, malaise or lethargy. Local symptoms include flank pain, costovertebral angle tenderness, acute hematuria, pelvic discomfort and in those whose catheters have been removed, dysuria, urgent or frequent urination, or suprapubic pain or tenderness may occur.Bacteriological urine culture is essential for the diagnosis of CAUTI. Urine collection for culture must be done using aseptic technique to avoid contamination and unnecessary antimicrobial treatment. Ideally urine samples for culture should be obtained by mid-stream collection after removal of the indwelling urine catheter. In patients with a long-term indwelling catheter where removal is not possible, the preferred method of obtaining a urine specimen for culture is to replace the catheter and collect the specimen from the freshly placed catheter. Alternatively, urine should be obtained from the catheter access port in the drainage system. The collection port must be disinfected with an appropriate disinfectant such as 70% alcohol and allow to dry for at least 30\u00a0s prior to accessing the port. Urine culture should not be taken directly from the drainage bag.5\u00a0CFU/ml. [IA]Microbiological confirmation of urine culture is needed for diagnosis of CAUTI. Urine culture must have no more than 2 species of organisms, at least one of which has bacterial growth of\u2009>\u200910.Urine collection for culture must be done using aseptic technique to avoid contamination. [IA]Recommendations for diagnosis of CAUTI includeProvision of evidence-based guidelines for catheter use, insertion, and maintenanceStaff education and periodic training in insertion and removal technique, maintenance procedures, complications, infection prevention and alternatives to indwelling urinary cathetersSupervised practice and competency assessment of staff to ensure only trained and competent staff insert urinary cathetersAdequate supplies and equipment to ensure aseptic technique during catheter insertion and maintenance requirementsDocumentation systems that record medical order for catheter placement, indications for catheter insertion, name of person inserting catheter, date, time, daily maintenance care and assessment of the ongoing need for catheter and planned date of removalAdequately trained staff to support surveillance and feedback of catheter use and outcomesWhere surveillance identifies opportunities for improvement, support for the implementation of evidence prevention strategies with ongoing surveillance and feedback.Recommendation:A CAUTI prevention program should be developed [IA]The primary outcomes for CAUTI prevention programs are to reduce unnecessary catheter placement and minimize the duration catheter remainis in place. Organizations should develop CAUTI prevention programs that ensure:Surveillance of CAUTI is important to monitor trends for detection of outbreaks and the assessment of efficacy of CAUTI prevention programs. Performing surveillance for CAUTI is best based on a facility\u2019s risk assessment and/or local regulatory requirements. The facility should consider identifying patient groups or units at risk for CAUTI through reviews on frequency of urinary catheter use and other potential risk factors, such as genitourinary surgery, obstetrics, critical care to develop a targeted surveillance program.Infection Prevention and Control (IPC) leadership is responsible for ensuring that an active program to identify HAIs is implemented and that HAI data are analyzed with timely feedback to those who can use the information to improve the quality of care , and that evidence-based practices are incorporated into the program.Use standardized methodology for performing CAUTI surveillance [IA]Routine screening of catheterized patients for asymptomatic bacteriuria is not recommended. [IIB]When performing surveillance for CAUTI, regular feedback of unit specific CAUTI rates to nursing staff and clinical care staff. [IIB]Reporting of outcome measures to senior administrative, medical, and nursing leadership and clinicians who care for patients at risk for CAUTI. [IIB]Recommendations for surveillance of CAUTI include:Successful results have been seen when healthcare institutions adopt a quality improvement approach to reduce healthcare associated infections (HAIs). The Comprehensive Unit-based Safety Program (CUSP) is one successful example . A multiImplementation of CAUTI insertion and maintenance bundles is best done using a quality improvement approach with a multidisciplinary team. [IA]Recommendation:We recommend healthcare facilities to have a CAUTI prevention program as part of their IPC program.Endorsed by:Hong Kong Infection Control Nurses Association (HKICNA), Hong Kong, ChinaHo Chi Minh City Infection Control Society (HICS), VietnamIndonesian Society of Infection Control (INASIC), IndonesiaInfection Control Association (ICAS), SingaporePersatuan Kawalan Infeksi dan Antimikrobial Kota Kinabalu Sabah (PKIAKKS), Borneo, MalaysiaMalaysian Society of Infection Control and Infectious Diseases (MyICID), MalaysiaNational Nosocomial Infection Control Group (NNIG), ThailandVietnam National Infection Control Society (VNICS), Vietnam"} +{"text": "The central and peripheral nervous systems are two separate yet connected domains characterized by molecularly distinct cellular components that communicate via specialized structures called transition zones to allow information to travel from the CNS to the periphery, and vice versa. Until recently, nervous system transition zones were thought to be selectively permeable only to axons, and the establishment of the territories occupied by glial cells at these complex regions remained poorly described and not well understood. Recent work now demonstrates that transition zones are occupied by dynamic glial cells and are precisely regulated over the course of nervous system development. This review highlights recent work on glial cell migration in and out of the spinal cord, at motor exit point (MEP) and dorsal root entry zone (DREZ) transition zones, in the physiological and diseased nervous systems. These cells include myelinating glia , exit glia, perineurial cells that form the perineurium along spinal nerves, as well as professional and non-professional phagocytes . Summary: Until recently, the nervous system boundaries were thought to be permeable only to axons. This review highlights recent work that illustrates glial cell transgression of nervous system transition zones. Although commonly thought of as two separate domains known as the central nervous system (CNS) and peripheral nervous system (PNS), the vertebrate nervous system functions as one unit.The CNS is composed of the brain and spinal cord, while the PNS includes ganglia and nerves that connect the CNS to various parts of the body. Bi-directional communication between the CNS and the PNS is essential and is possible at transition zones, specialized regions punching the cover of the spinal cord at regular intervals, where central and peripheral neural tissue intimately meet. Spinal cord transition zones are comprised of motor exit points (MEP) ventrally, and dorsal root entry zones (DREZ), dorsally. These regions are traversed by bundles of nerve fibers as well as central and peripheral non-neuronal components of the nervous system. Motor neurons, located in the ventral spinal cord, project their axons through MEP transition zones in order to innervate their target muscles in the periphery. Conversely, sensory axons that relay information such as touch and pain from the periphery toward the brain, enter the spinal cord at DREZ.Glial cells, or glia, are an essential non-neuronal constituent of the nervous system. Both in the CNS and in the PNS, glial cells provide neurons and axons with metabolic and trophic support, enable saltatory conduction by producing myelin, but they also shape, remodel, and synchronize neural circuits. Glial cells were originally described as residents of either the CNS or the PNS, that are not capable of freely crossing the CNS/PNS boundaries. The CNS and the PNS are two separate yet connected domains in which distinct cell types often carry out similar biological functions. For example, oligodendrocytes are glial cells restricted to the CNS and Schwann cells are glial cells limited to the PNS, and both glial subtypes function to myelinate axons .During embryonic development, neural crest cells give rise to many structures of the PNS including peripheral glial cells, while the neural tube contributes to structures that build the CNS. There is growing evidence indicating interactions between glial cells residing in distinct domains of the nervous system and demonstrating their transgression of nervous system boundaries in physiological and pathological conditions . How cerNervous system transition zones have historically been explored in a wide array of species that include the lamprey, rat, cat, grass hopper, human, and were originally described by using methods such as autoradiography, immunohistochemistry and electron microscopy . These sin vitro preparations of dissected tissue and allowed for a better understanding of CNS/PNS cellular segregation. In vitro models of astrocyte/Schwann cell interactions have revealed that astrocytes exclude Schwann cells from the CNS by limiting their migration via N-cadherin-mediated adhesion and that Schwann cells are expelled when transplanted into the glia limitans in the spinal cord through contact-mediated communication glia, were recently described at motor nerve roots . These gIn chick and mouse embryonic development, a population of glial cells known as boundary cap (BC) cells, associates with ventral roots and contributes to the establishment of the CNS/PNS transition zone . BC cellin situ hybridization in fixed tissue, discrete populations of BC cells might have escaped detection. A more recent piece of data illustrating BC cells extending long projections into the spinal cord at MEP transition zones brings a new perspective and does not rule out the possibility of a CNS origin for a subset of BC cells, reappraising the traditional lineage of this understudied glial cell type and Putative Serine Protease 56 (Prss56) reported that BC cells migrate from the neural crest and arrive at MEP transition zones at E10.5 in mouse embryos, and were last observed at E16.5, when they contribute to the production of Schwann cells and other derivatives . By usinell type . The tecSuch tools have recently contributed to the identification of a novel role for a traditional neural-crest-derived cell population. During nervous system development, programmed cell death naturally occurs in both the CNS and the PNS to regulate cell number and tissue sculpturing. In a study using live imaging in larval zebrafish, it was discovered that migratory neural crest cells respond quickly to dying cells and engulf cellular debris around the neural tube until 36\u2005h post fertilization, which corresponds to the arrival of professional phagocytes . In thisRecent work has demonstrated that the boundaries of the nervous system are a dynamic and plastic interface, and we are now starting to understand the cellular and molecular mechanisms underlying bidirectional cell migration across these barriers. Transition zones are unique regions where central and peripheral tissue meet and where CNS and PNS glial cells occupy non-overlapping territories. These territories are well defined along myelinated spinal axons, where oligodendrocytes produce layers of fatty membrane to myelinate the central portion of the fibers, and Schwann cells and MEP glia myelinate the peripheral segments. Damage to myelin sheaths results in axonal degeneration and loss of neuronal function and can be restored through a repair mechanism called remyelination. In the CNS, remyelination involves the presence of healthy OPCs and their differentiation into mature myelin-forming oligodendrocytes.in vivo imaging in zebrafish, a recent remyelination study demonstrated that new oligodendrocytes exhibit more abundant and accurate myelin regeneration than those that survive demyelination rats, their presence is mostly limited to discrete areas near the spinal dorsal root entry zone and motor exit points (Although spontaneous invasion of the CNS by Schwann cells was described in the demyelinated spinal cord and in rodent mutants where oligodendrocytes fail to make myelin such as the t points . In thest points .in vitro and in vivo over the past decades (in vivo and ex vivo study led by Garcia-Diaz et al. not only revealed that Schwann cells use the vascular scaffold as their preferred route to infiltrate the demyelinated spinal cord and override the central inhibition created by CNS myelin, but also identified the signals regulating this migration (Numerous studies have focused on using Schwann cells to repair myelin lesions in the adult CNS. However, while Schwann cells efficiently remyelinate CNS axons and restore axonal function, they do not migrate far and subsequently only remyelinate limited areas within the spinal cord. This poor migration into the spinal cord has been investigated both decades . Results decades . Contemp decades . The in igration . The autThe past two decades have shed light on molecular mechanisms that regulate Schwann cell migration into the spinal cord as well as oligodendrocyte progenitor cell migration into the PNS, and have paved the way for the development of innovative therapeutical approaches for the treatment of neurodegenerative disorders and injuries . Future"} +{"text": "Editorial on the Research TopicCongenital craniofacial deformities: genetic and clinical aspectsThe Research Topic \u201cCongenital Craniofacial Deformities: Genetic and Clinical Aspects\u201d is a Frontiers Research Topic aimed to provide an opportunity for researchers and clinicians from different perspectives and areas to publish recent advances in investigating the genetic etiology and the treatment options for different congenital craniofacial deformities.Caused by genetic diseases, chromosomal mutations, or abnormal embryonic development, congenital craniofacial deformities refer to the inborn anomalies of the skull, orbits, zygomatic bones, maxilla, and mandible. Facial soft tissue defects, including craniosynostosis, craniofacial fissure, dilated orbital distance, and craniofacial microscopic anomalies are also considered craniofacial deformities. In severe cases, they can even lead to intellectual disability and visual impairment. Craniofacial deformities are often accompanied by anomalies of the spine, trunk, limbs, and visceral transposition. The treatment of congenital craniofacial deformities is complex, and satisfying outcomes are still missing. Furthermore, the patient's psychological state and related social behavior also need more attention. Even though a lot of research has been carried out in the field of craniofacial development, the genetic etiology of congenital craniofacial deformities needs more investigation to reveal the role of specific genes and their synergistic effect during the development of the craniofacial skeletal system.Cleft lip and palate is one of the most common congenital craniofacial deformities. For repairing cleft lip and palate, team approach should be carried out. Restorations of primary deformities and secondary dysfunctions are the main purposes in the treatment of cleft lip and palate.Yin et al. Outcomes by three dimensional evaluation of presurgical nasoalveolar molding (PNAM) therapy in patients with non-syndromic complete unilateral cleft lip and palate (UCLP) were presented. Their results demonstrated that PNAM therapy could help decrease the difficulties of cleft lip repair.In this Research Topic, presurgical intervention of primary cleft lip repair is focused by Wei et al. developed an algorithm for surgical method selection for repairing narrow nostrils in patient with secondary cleft lip nasal deformities. It demonstrated that the width of the nasal floor and the length of the alar rim are critical elements for selecting the appropriate surgical method. Meanwhile, a review by Xu et al. focusing on the growth patterns of the nasolabial region following unilateral cleft lip primary repair was also included in this Research Topic.Rhinoplasty for patients with cleft lip is always a challenge to the surgeons, and narrow nostril deformities are the most troublesome. The study by Fan et al. compared the velopharyngeal morphology of patients with hard and soft cleft palate after Furlow and Sommerlad palatoplasty, and Mao et al. presented a review to introduce specific problems that are currently under-recognized in the diagnosis and treatment of marginal velopharyngeal inadequacy and provides guidelines for further exploration of standardized and reasonable intervention protocols for marginal velopharyngeal inadequacy.The purpose of cleft palate repair is to reconstructing a normal velopharyngeal function of the patient. In this Research Topic, the study by Wu et al. which concluded and updated probable causes underlying the association between cleft lip and palate and poor oral health.A review about poor oral hygiene and high susceptibility to dental caries and periodontitis in patients with cleft lip and palate was presented by Feng et al. A case with hereditary sensory autonomic neuropathy was also reported by O\u2019hagan-Wong et al. which demonstrated extensive oral trauma as one of the early signs of hereditary sensory autonomic neuropathy that should provoke a timely referral for neurological assessment.Meanwhile, application of vertical transposition flap in closure for large facial soft tissue defects in children was reported by This Research Topic targets the acquisition and dissemination of knowledge regarding to congenital craniofacial deformities to share knowledge from both the basic and clinical sciences. Briefly, this Research Topic provided researchers and clinicians from different perspectives and areas with a platform to discuss recent advances in the understanding of congenital craniofacial deformities. It also will provide readers with new insights and different viewpoints to stimulate further investigations in this broad research field."} +{"text": "Editorial on the Research TopicAdvances in the use of neuromonitoring in newbornsNeonatal neurocritical care is a rapidly evolving subspeciality with the goal of implementing neuroprotective strategies and identifying new therapies to care for babies at risk of or with existing brain injury in order to improve long term neurodevelopmental outcomes. Brain-focused care is a desired development following decades of focus on survival and extending the limits of viability. Neonatal neurocritical care and Neuro-NICUs seek to better address the sizable population at risk of or with brain injury by integrating intensive care practices with focused neurologic care. Bedside continuous neuromonitoring has a significant role in this ambitious endeavor with specific focus on near-infrared spectroscopy (NIRS), continuous electroencephalography (cEEG), and amplitude integrated electroencephalography (aEEG) as well as the combined use of these and other techniques called multimodal neuromonitoring . This coVariane et al. comprehensively describe the current uses of neuromonitoring in Neuro-NICUs focusing on aEEG, cEEG, and NIRS. Multimodality monitoring simultaneously with aEEG or cEEG and NIRS is likely to improve understanding of the physiology of both functional and hemodynamic changes and the resulting risk of cerebral injury. The incorporation of other time-synchronized physiologic vital signs will enhance the development of neuroprotective strategies. The available options, as well as challenges of data integration and processing, are described and the power of artificial intelligence and machine learning to significantly benefit vulnerable critically ill neonates is highlighted. The authors conclude that the broader use of brain monitoring with analysis of large amounts of clinical data available in an intensive care setting has the potential to significantly change care and improve outcomes.Chock et al. provide a comprehensive review of continuous measures including cEEG, aEEG, NIRS, and heart rate variability as well as serial measures including cranial ultrasound and somatic and visual evoked potentials in newborns with HIE undergoing therapeutic hypothermia. cEEG and aEEG are promising predictors of adverse outcome with high specificity and sensitivity. The higher specificity seen with cEEG is offset by its greater complexity and cost for placement and interpretation. Mutli-modality use of both cEEG or aEEG with NIRS along with physiologic vital signs is appealing as it allows for continuous bedside assessment of both cerebral function and cerebral oxygenation and correlates them with alterations in other physiologic parameters.Given the significant risk for adverse outcomes in newborns with HIE, including death and neurodevelopmental impairment, a wide range of neurodiagnostic modalities have been evaluated to provide critical diagnostic and prognostic information on brain injury and prediction of outcome. Greisen et al. provide a perspective on the state of NIRS monitoring for the preterm infant. The authors compare cerebral oximetry to other monitoring modalities that may be used in the neonatal intensive care setting despite minimal empiric evidence of clinical benefit, including pulse oximetry, non-invasive electric cardiometry, and invasive blood pressure monitoring. Future research may require a focus on more granular effects of a targeted cerebral NIRS algorithm on the brain and clarify timing and conditions for which NIRS monitoring may best optimize care for the premature infant.NIRS monitoring has been investigated in premature infants in different situations including the transitional period after birth \u20134, for dHoffman et al. describe the utility of both cerebral and somatic NIRS monitoring with relation to carbon dioxide tension in 178 infants with hypoplastic left heart syndrome following Norwood palliation. Increasing arterial carbon dioxide tension was associated with increased cerebral but decreased renal oxygenation. Along with this differential response to carbon dioxide, the magnitude of these responses was greater in the early 18\u2005h post-operative period. Given the sensitivity of the brain to hypocarbia with resulting cerebral vasoconstriction, strict attention to carbon dioxide levels may be an important strategy to optimize cerebral blood flow. The authors speculate that normalization of cerebral hemodynamics may be achieved in the early post-operative period with dynamic manipulation of carbon dioxide levels through directed ventilator approaches such as permissive hypercapnia.Neuromonitoring with NIRS may further have utility in infants with CHD, particularly in the peri-operative period and may reduce the need for intubations in select infants with CHD , 13. CerVariane et al. describe 10 additional cases including cardiopulmonary disorders, circulatory disorders, and abdominal disorders, where multimodal monitoring with multi-site NIRS and in some cases with aEEG provided earlier recognition of the underlying hemodynamic status and its impact.Continuous neuromonitoring using NIRS and aEEG or cEEG allows for bedside assessment of brain, renal, and splanchnic/mesenteric oxygenation and perfusion as well as cerebral function and seizure detection. Further combination with vital sign monitoring including blood pressure, pulse oximetry, heart rate and temperature is described as multimodal monitoring and provides further understanding of physiology. These approaches have been previously described in premature infants and in newborns with HIE , 17, 18.Leon et al. review various modalities to assess cerebral blood flow and specifically cerebral autoregulatory capacity in these conditions. Doppler ultrasound, magnetic resonance imaging, and NIRS are techniques that have advantages and limitations for use in the fetal and neonatal period. The authors emphasize that future assessment of cerebral autoregulation will require an individualized approach and use of multiple synchronized monitoring modalities and predictive analytics.Impairment of cerebral autoregulation may lead to alterations in cerebral blood flow, particularly in vulnerable populations including neonates with HIE, preterm infants, and those with congenital heart disease. Sandoval et al. acknowledge that high cost is a factor limiting more widespread use of cEEG. In comparison, aEEG is recognized as often helpful when used together with cEEG, as it allows bedside providers to review the simplified tracing without the need for neurophysiologists. However, short, low amplitude seizures or seizures in areas of the brain not monitored by aEEG will be missed, and a high skill level with aEEG interpretation is required. Future uses of cEEG include centralized cEEG interpretation, automated seizure detection, and prenatal EEG use.Several uses for cEEG in the neonatal population have been described, including seizure diagnosis and management, identifying neonates at risk for seizures, and prognostication by assessment of background activity. It is the standard of care for seizure diagnosis as designated by the World Health Organization (WHO), International League Against Epilepsy (ILAE), and American Clinical Neurophysiology Society (ACNS) \u201321. SandThis collection of original articles and reviews on neonatal neuromonitoring adds to our current understanding of the techniques available to non-invasively assess the newborn brain. While EEG and NIRS have been mainstays of neuromonitoring, newer indications for these techniques including applications in different neonatal populations have been described. Research studies have also refined the optimal timing of monitoring and highlight an outcomes-based focus. The approach to combined or multimodal neuromonitoring with time-synchronized vital signs has been evolving with the potential for remote-monitoring and automated detection of concerning events such as seizures or cerebral hypoxia. Future advances may incorporate additional physiologic parameters such as heart rate variability or point-of-care imaging and utilize artificial intelligence and machine learning to interrogate multiple bedside data streams. Progress in the field of neuromonitoring will continue to improve predictive capabilities and guide clinical management with the goal of optimizing brain health and development in the newborn."} +{"text": "Toxoplasma gondii benefit from, antagonize, or exploit host ESCRT machinery to preserve their intracellular niche, gain resources, or egress from infected cells. Here, we review how intracellular pathogens interact with the ESCRT machinery of their hosts, highlighting the variety of strategies they use to bind ESCRT complexes using short linear amino acid motifs like those used by ESCRTs to sequentially assemble on target membranes. Future work exposing new mechanisms of this molecular mimicry will yield novel insight of how pathogens exploit host ESCRT machinery and how ESCRTs facilitate key cellular processes.The Endosomal Sorting Complex Required for Transport (ESCRT) machinery consists of multiple protein complexes that coordinate vesicle budding away from the host cytosol. ESCRTs function in many fundamental cellular processes including the biogenesis of multivesicular bodies and exosomes, membrane repair and restoration, and cell abscission during cytokinesis. Work over the past 2 decades has shown that a diverse cohort of viruses critically rely upon host ESCRT machinery for virus replication and envelopment. More recent studies reported that intracellular bacteria and the intracellular parasite Table 1 summarizes the interactions of complexes that mediate the assembly of the ESCRT machinery. However, other ESCRT functions do not require ESCRT-0 for initiation and instead depend on different adaptors for the initiation of assembly. This is the case for the role of ESCRTs in plasma membrane repair, in which the ESCRT adaptor apoptosis linked gene-2 interacts with ESCRT components for the repair of injured membranes AP late domain motif in HIV-1 Gag and its interaction with TSG101 preceded the realization that these motif were present in HRS and ALIX and that retroviruses were \u201cmimicking\u201d intercomplex interactions to make use of the host ESCRT machinery ,166. Wit"} +{"text": "To review data supporting the integrated airway hypothesis. Allergic rhinitis, rhinosinusitis, and asthma are common conditions associated with significant morbidity and health care costs. A theory has been developed suggesting that these conditions may be manifestations of an inflammatory process within a continuous airway rather than fully separate diseases. Based on this theory, the presence of upper airway symptoms may negatively influence the natural course of lower airway disease. Controlling upper airway inflammation and symptoms among asthma patients may help improve health and economic outcomes.Further clarifying and understanding the relationship between diseases of the upper and lower respiratory tracts are important because of the prevalence of allergic rhinitis, rhinosinusitis, and asthma and the resulting burden on patients and the health care system. Recent progress in understanding the biology of airway disease has identified inflammation as playing a critical and integrating role in these diseases; however, other important questions remain, including factors that determine the clinical phenotype in allergic airway disorders and optimal treatment approaches.Several recent studies have suggested that allergic rhinitis, rhinosinusitis, and asthma may be manifestations of a common underlying pathology, but there are many unanswered questions. More studies are needed to better define all the underlying pathologic mechanisms as well as treatments to optimize outcomes for patients with allergic rhinitis, rhinosinusitis, and asthma."} +{"text": "Medicare is one of the largest health care payers in the United States. As a result, its decisions about coverage have profound implications for patient access to care. In this commentary, the authors describe how Medicare used evidence on heterogeneity of treatment effects to make population-based decisions on health care coverage for implantable cardiac defibrillators. This case is discussed in the context of the rapidly expanding availability of comparative effectiveness research. While there is a potential tension between population-based and patient-centered decision making, the expanded diversity of populations and settings included in comparative effectiveness research can provide useful information for making more discerning and informed policy and clinical decisions."} +{"text": "According to reactivation theory, increasing the use of affected body parts through motor execution may reactivate relevant cortical motor representations and increase excitability, improving sensorimotor function , the mental simulation of actions in the mind in the absence of overt motor output and environmental constraints in movement in a way that represents real-world situations, potentially increasing the individual's ability to adapt their movements under changing environments. In an ecological dynamics perspective on motor skill development, the emergence of cognitive states that support motor execution require an individual to be continuously coupled to the environment but under conditions requiring varied movement execution to encourage degeneracy to skill acquisition, Taberner et al. proposedA key benefit of MIT is that it affords rehabilitation practitioners the ability to reintegrate more complex movements with limited risk of reinjury and may allow early activation of motor pathways during periods where movement may be limited or not possible. Subsequently, MIT provides a unique tool to supplement physical training approaches to rehabilitation like the CCC, potentially serving to prime motor pathways and psychologically prepare individuals for more chaotic movement situations and encourage them to explore alternative movement solutions (expressed as movement variability) that match individual motor capabilities (Renshaw et al., The aim of this paper was to provide some considerations for practitioners in sport and rehabilitation settings incorporating movement variability in MIT for motor skill development. We propose that MI may enable safe engagement with movement variability, potentially supporting adaptation of movement patterns to changing environmental constraints. Informed by a CLA and a CCC framework, MIT may facilitate psychological and neural preparation early in rehabilitation that could contribute to enhanced motor recovery. Practically, the CLA and CCC framework provide key training principles that practitioners can adapt to MIT in moving activities from low variability to high variability and catering to individual constraints in rehabilitation. Practitioners are encouraged to consider MIT as a low-risk strategy for incorporating movement variability into the rehabilitation process and developing adaptable movement skills.RL and MS contributed to original conception and structure of this article. RL, SS, and MS contributed to the first draft of the manuscript. All authors were involved in manuscript revision, reading, and approval of the submitted version."} +{"text": "Autonomic adjustments of the cardiovascular system are critical for initiating and sustaining exercise by facilitating the redistribution of blood flow and oxygen delivery to meet the metabolic demands of the active skeletal muscle. Afferent feedback from active skeletal muscles evokes reflex increases in sympathetic nerve activity and blood pressure (BP) and contributes importantly to these primary neurovascular adjustments to exercise. When altered, this reflex contributes significantly to the exaggerated sympathetic and BP response to exercise observed in many cardiovascular-related diseases, highlighting the importance of examining the reflex and its underlying mechanism(s). A leading risk factor for the pathogenesis of cardiovascular disease in both males and females is aging. Although regular exercise is an effective strategy for mitigating the health burden of aging, older adults face a greater risk of experiencing an exaggerated cardiovascular response to exercise. However, the role of aging in mediating the exercise pressor reflex remains highly controversial, as conflicting findings have been reported. This review aims to provide a brief overview of the current understanding of the influence of aging on cardiovascular responses to exercise, focusing on the role of the exercise pressor reflex and proposing future directions for research. We reason that this review will serve as a resource for health professionals and researchers to stimulate a renewed interest in this critical area. Aging adversely affects cardiovascular health, contributing to an increased risk of developing and dying from cardiovascular disease (CVD) with each decade of life in both males and females . Indeed,Epidemiological evidence suggests that healthy older adults are more likely to experience an exaggerated BP response to sub-maximal and maximal large-muscle mass dynamic exercise when compared to healthy young adults . FurtherAlthough multifactorial, alterations in autonomic nervous system regulation likely play a role. Indeed, appropriate autonomic adjustments of the circulation mediated by feedforward signals from higher brain centers and feedback signals from the contracting skeletal muscle are vital to increasing BP and matching metabolic demand and supply in the contracting skeletal muscles . In receDue to conflicting findings, the effects of aging, independent of pathology and physical activity levels, on the exercise pressor reflex are unclear and controversial. Indeed, reports have suggested that the BP response to reflex activation is blunted , preservTransitioning from rest to exercise dramatically increases skeletal muscle metabolic activity, causing an immense integrative challenge. The body meets this challenge primarily through cardiovascular adjustments mediated by neural control mechanisms. These mechanisms mainly include feedforward signals evoked by central command and feedback signals evoked by the exercise pressor reflex. Moreover, resetting the arterial baroreflex allows continued regulation of BP during exercise . AcknowlThe exercise pressor reflex is defined as \u201call the cardiovascular changes reflexively induced from contracting skeletal muscle that is responsible for the increase in arterial BP\u201d . In brieVarious protocols are utilized to study the exercise pressor reflex and its two components in humans and animals. Blood flow occlusion to enhance or trap the metabolic stimuli during or after exercise , is a standard procedure to isolate the metaboreflex component. Passive movement or stretching of the skeletal muscles or rhythmic contractions provides a robust mechanical stimulus without substantial production of metabolites. It is, therefore, commonly used to assess the mechanoreflex component. It is worth noting that studying the complete exercise pressor reflex (mechanoreflex + metaboreflex), independent of central command, is difficult in humans and requires sophisticated invasive techniques. In this regard, the current approach is to compare BP responses before and after the injection of lumbar intrathecal fentanyl, which temporarily attenuates muscle afferent feedback from the contracting muscle while preserving force-generating capacity.It is fairly well-described in the literature that older male and female adults exhibit a greater BP response to large and smaller muscle-mass dynamic exercise than their younger counterparts . AlthougThe following section reviews the current evidence to decipher the contradictory results regarding the role of the exercise pressor reflex in mediating an exaggerated BP response to exercise with advancing age. Due to the limited space and studies available, we primarily focus on human studies attempting to isolate the reflex component of the exercise pressor response. We have organized the discussion based on the direction of the BP response (primary outcome) in older compared to younger adults and include supporting material on muscle sympathetic nerve when available. See The initial studies investigating the effect of age on the exercise pressor reflex suggested healthy older adults have a blunted reflex-evoked BP and MSNA response compared to young adults. For example, Several studies also suggest that aging does not alter the exercise pressor reflex. Two early studies reported similar metaboreflex-evoked BP and MSNA responses following fatiguing isometric handgrip exercise (40% MVC) in healthy older and young adults , with noStudies have also provided convincing evidence of an exaggerated exercise pressor reflex in older adults compared to their young counterparts . For exaversus older adult group), their physical activity or fitness levels, mode of exercise or limb involved , or intensity at which the exercise was being performed. It is also worth considering that the effect size of aging on the exercise pressor reflex may be on the smaller side, requiring larger sample sizes and/or a greater exercise stimulus .When comparing study outcomes, it is essential to consider the differences in methods, protocols, and participant characteristics. Interestingly, sex was not equally represented in the studies mentioned, possibly contributing to variable findings from study to study . Other pOne possible explanation for study divergence warranting discussion is the magnitude of age-related alterations in skeletal muscle characteristics. Significant structural and functional skeletal muscle changes occur with aging , contributing to decreased physical strength and metabolic alterations . The magIt is important to consider that aging may affect the exercise pressor reflex arc at multiple levels, including the concentration of stimulants present around the afferent endings , afferent sensitivity , central processing in the brainstem, as well as the efferent activity. Although one study suggested a lower metabolite production during muscle contraction could contribute to the blunted metaboreflex observed in older compared to younger adults , other sAnother notable change with aging is increased insulin resistance, which appears to influence the exercise pressor reflex . For exaAppropriate autonomic adjustments are critical for initiating and sustaining exercise by increasing BP and facilitating the redistribution of blood flow and oxygen delivery to meet the metabolic demands of the active skeletal muscle. Aging may negatively affect this ability, as highlighted by an exaggerated BP response and attenuated maximal oxygen uptake . Given tFurthermore, evaluating the impact of reflex activation on the components determining BP during exercise may provide additional insight. As defined by Ohm\u2019s law, the BP response to exercise is the product of cardiac output and total peripheral resistance (TPR). Aging results in a dramatic shift in the contribution of these two components to BP in both males and females, which is exacerbated during exercise. Specifically, cardiac output contributes less to BP with increasing age due mainly to decreased stroke volume and heart rate . ConversThe literature reviewed highlights a complex relationship between age and sex regarding the reflex control of cardiovascular responses to exercise. Sex is a well-known, crucial biological determinant of neurovascular control . Indeed,Although speculative, the augmented exercise pressor reflex observed in post-menopausal females may impair contracting muscle blood flow, which could further amplify reflex activation, ultimately resulting in a positive feedback loop. This hypothesis is supported by studies showing that post-menopausal females exhibit a greater decrease in peripheral vascular conductance during mechano- and metaboreflex activation and an excessive increase in sympathetically mediated vasoconstriction in the exercising muscle . InteresThe interaction between age and sex is increasingly recognized under resting conditions. However, the translation of this to exercise remains relatively understudied. Notably, we know much more about female sex hormones and their impact on the exercise pressor reflex than we do about male sex hormones . Indeed, although studies have demonstrated a significant relationship between testosterone levels and resting BP and MSNA , surpris"} +{"text": "Massive crop failures worldwide are caused by abiotic stress. In plants, adverse environmental conditions cause extensive damage to the overall physiology and agronomic yield at various levels. Phytochromes are photosensory phosphoproteins that absorb red (R)/far red (FR) light and play critical roles in different physiological and biochemical responses to light. Considering the role of phytochrome in essential plant developmental processes, genetically manipulating its expression offers a promising approach to crop improvement. Through modulated phytochrome-mediated signalling pathways, plants can become more resistant to environmental stresses by increasing photosynthetic efficiency, antioxidant activity, and expression of genes associated with stress resistance. Plant growth and development in adverse environments can be improved by understanding the roles of phytochromes in stress tolerance characteristics. A comprehensive overview of recent findings regarding the role of phytochromes in modulating abiotic stress by discussing biochemical and molecular aspects of these mechanisms of photoreceptors is offered in this review. Despite the conserved mechanism of apoprotein binding to its associated chromophore . Due to their intricate interactions with other photoreceptors and signalling molecules, BL photoreceptors also play an essential role in low-temperature tolerance. It can be concluded from previous studies that the control of temperature responses mediated by CRYs is still uncommon. Hence, more research in this field needs to be made to establish the components that interact with CRY in response to environmental stress.The effects of temperature stress on protein stability and enzymatic processes in plants are well known. Furthermore, many of the responses to heat stress are mediated by downstream heat shock proteins (HSPs). The transcriptional profile of t stress . CRY1 al5e.g. pigments biosynthesis, expression of genes associated with the Calvin-Benson cycle, stomatal opening and chloroplast biogenesis), improved the knowledge regarding PHYs control of photosynthesis parameters under stressful conditions is equally important to improve crop in the scenario of global climate changes. Researchers should pay particular attention to the altered expression of various PHYs and associated factors that directly deteriorate the PSII machinery. It has been reported that the enhanced accumulation of Pfr form under high-light conditions influences the antioxidant system by increasing the accumulation of carotenoids and flavonoids. An intricate regulatory network involving PHYA and PHYB is responsible for targetting differential gene expression, and biochemical and metabolic changes in the face to regulate physiological processes throughout plant life under more severe abiotic stress (As sessile organisms, plants have devised innovative strategies for successfully monitory environmental pressures to enable adaptation and survival. Although the complete mechanism of perception and response from stress factors needs to be addressed before moving forward in plant improvement strategies, the role of photomorphogenic-associates proteins in the face to mitigation of abiotic stress is an important piece of knowledge necessary to provide crops and other plants with a multi-stress tolerance. Phytochromes and PIFs have been extensively studied for their critical roles in photomorphogenesis. However, their roles in various abiotic stress conditions are still poorly understood. Stress tolerance has been successfully increased by overexpression of genes associated with metabolites and hormones biosynthesis and antioxidant enzymes, yet adverse effects on plant development were detected. Therefore, it is imperative to explore upstream targets that simultaneously control a myriad of physiological and biochemical parameters at the same time to increase crop productivity and stress tolerance. PHYs play a critical role in controlling plant growth processes and agronomic properties. However, the molecular mechanisms underlying PHY-mediated stress responses in crops remain elusive. Researchers will need a comprehensive understanding of these underlying molecular mechanisms to improve resistance to adverse environmental conditions. In achieving these objectives, novel technologies, such as CRISPR/Cas9 gene editing, could prove invaluable, as they offer highly efficient and precise targeting of candidate genes. To avoid pleiotropic effects resulting from the manipulation of PHYs, new strategies have been addressed with promising results by genetic manipulation applying tissue-specific or inducible promotors. Furthermore, the close association of PHYs with plant photosynthesis (c stress : salinitc stress A, droughc stress B and temc stress C. Photo-All authors listed have significantly contributed to the development and the writing of this article.No data was used for the research described in the article.No additional information is available for this paper.The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:MAYANK ANAND GURURANI reports financial support was provided by UAE University College of Science. MAYANK ANAND GURURANI reports a relationship with United Arab Emirates University that includes: employment."} +{"text": "BMC Pregnancy and Childbirth. This commentary will discuss the scientific background and implications for future research.Bariatric surgery confers potential advantages for obese patients, but also risks for pregnancy. Perinatal outcomes may be varying between surgical procedures. This topic was recently addressed by a systematic review in Maternal obesity is a major health care issue, associated with several comorbidities in women at childbearing age, including infertility and a higher degree of insulin resistance. In pregnancy, obesity is associated with preeclampsia, pregnancy loss and the development of large for gestational age (LGA) infants. While obesity is closely related to gestational diabetes mellitus (GDM) or pregestational diabetes, there is emerging evidence that fetal overgrowth can also occur independently of maternal hyperglycaemia . ConsequBariatric surgery is an established treatment for severe obesity, especially in the presence of metabolic co-morbidities . For exaIn general, pregnancy after weight loss surgery is most probably safer than pregnancy in obese condition, however, it also poses a number of challenges and risks that need to be addressed : Previouet al., who published a systematic review of adverse perinatal outcomes after RYGB vs. sleeve gastrectomy, aiming to assess the incidence of pregnancy associated complications such as delivery of SGA or LGA infants [et al., especially the rather short surgery to conception interval of four years. This was necessary as this study primarily focused on perinatal outcomes in the few years after weight loss surgery. Timing of pregnancy is indeed an important issue and it is generally recommended to avoid pregnancy for 12 to 18 months after surgery, when weight loss and nutritional status may become more stable [et al., what may be the reason for the (unexpected) high prevalence of SGA reported in the included studies.This topic was recently addressed by Kistner infants . Thereby infants . Likewis infants . Compara infants . The obse stable . Of noteBariatric surgery and its implications for pregnancy and childbirth is gaining increasing importance in the field of obstetrics and feto-maternal medicine. However, there are still a number of open questions. Further studies are required to clarify the best surgical technique and optimal time to conception interval for younger women at reproductive age. Fetal outcomes and especially long-term implications for the offspring including metabolic and neurological development need to be addressed. In any case, bariatric surgery in women at childbearing age requires careful planning of pregnancy and management by experienced obstetricians to offer optimal preconceptional and prenatal care. Future research is required targeting specific nutritional programs for patients to optimize maternal and neonatal outcomes."} +{"text": "Sensory processing dynamics have emerged as important contributors to typical cognitive and social development alone, or by other factors contributing to increased chance of preterm birth.Subtle sensory processing changes may mediate atypical developmental trajectories even in neurodevelopmental disorders where sensory symptoms are not at the forefront, or may be indicative of neural changes related to early developmental events. Bhattacharjee et al. describe the development of a novel tactile stimulus delivery system to enable measurement of active somatosensation with the precision necessary to enable use in EEG, magnetoencephalography (MEG), and other neurophysiology studies. Tactile hypersensitivity is commonly reported in ASDs, but the neural correlates and development of the tactile system is severely understudied in ASD (Marco et al., Much work has been done in this area describing typical development in humans and animal models for visual and auditory modalities, however, gaps remain in understanding how these measures correspond across species over various developmental periods. Significant gaps also persist in describing the development of these measures in sensory modalities beyond vision and audition. In particular, the ability to deliver visual and auditory stimuli with high precision may partially account for the preponderance of neuroimaging and EEG developmental studies in the visual and auditory domains, rather than enhanced importance of these domains to developmental outcomes (Espenhahn et al., Mulligan et al., describe overlapping phenotypes in children with idiopathic sensory processing disorder, with the majority of children showing a combination of multiple sub-types, suggesting that current methodology for classifying sensory behaviors in humans requires further study to develop categories useful for assessing developmental trajectories and outcomes and for mapping to neural measures.Finally, it is important to note that studying the neural correlates of sensory systems is critically hampered by the lack of psychometrically sound measures for characterizing sensory behaviors in both humans and animal models. This is a strong limitation to what degree we can map clinical alterations in sensation to brain activity. In summary, understanding sensory system development is of critical importance for predicting functional outcomes across a variety of linked constructs in both neurodevelopmental disorders and typical development. Translational work using methodologies such as EEG can provide significant insight into neural correlates of sensory processing, and is feasible in both developmental human populations and animal models, allowing further study into circuit and molecular mechanisms for sensory system modulation. However, study in this area is limited by technological advancements in some sensory modalities more than others, and a lack of strong assessment methodology for quantifying sensory behaviors. Advancement in these areas is critically needed to incorporate already translationally sophisticated neuroimaging and neurophysiological methods into a comprehensive view of sensory system development.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "Comments on: Modified Pereira Suture as an Effective Option to Treat Postpartum Hemorrhage Due to Uterine AtonyDear Editor,The modification of the Pereira suture described by our team was performed during a cesarean section, when uterine atony was noted and was not responsive either to uterotonic drugs or to bimanual uterine massage. Given the success rates of uterine compression sutures (UCSs) described and the possibility of uterus preservation, they were the chosen method.Since hysterotomy had already been performed, the B-Lynch suture was the first technique used.The emergent need for hemorrhage control in cases of uterine atony limits the existence of quality evidence stating superiority amongst UCS techniques. Nevertheless, previous reviews report success rates\u2009>\u200975% (some of them\u2009>\u200990%), regardless of technique.The two cases reported by our team do not intend to describe a new technique, but rather to support UCSs as an adequate option to treat postpartum hemorrhage due to uterine atony, always bearing in mind the characteristics of each situation and the specificities of each suture."} +{"text": "Forest trees are the dominant species in many parts of the world and predicting how they might respond to climate change is a vital global concern. Trees are capable of long-distance gene flow, which can promote adaptive evolution in novel environments by increasing genetic variation for fitness. It is unclear, however, if this can compensate for maladaptive effects of gene flow and for the long-generation times of trees. We critically review data on the extent of long-distance gene flow and summarise theory that allows us to predict evolutionary responses of trees to climate change. Estimates of long-distance gene flow based both on direct observations and on genetic methods provide evidence that genes can move over spatial scales larger than habitat shifts predicted under climate change within one generation. Both theoretical and empirical data suggest that the positive effects of gene flow on adaptation may dominate in many instances. The balance of positive to negative consequences of gene flow may, however, differ for leading edge, core and rear sections of forest distributions. We propose future experimental and theoretical research that would better integrate dispersal biology with evolutionary quantitative genetics and improve predictions of tree responses to climate change. The overall picture is a negative correlation between \u0394 and the latitude of origin of the population as shown in panel (b) by the example in the case of Pinus contorta nditions . Reactiocontorta . FiguresTrees are characterised by their particular life history, combining long-generation time and the capacity for long dispersal distances through pollen and seeds. Given the anticipated intensity and directionality of climatic change, do trees have the adaptive capacity to respond and how will gene flow affect that response? Valuable insights into these issues are provided by the retrospective analysis of adaptation in tree populations during the climate change that occurred following the last glaciations gene flow could compensate for the long-generation time of trees, facilitating evolutionary change in a shifting climate, by reviewing both data and theory, about the extent of gene flow in forest trees and its evolutionary consequences. We first review the recent literature on LD pollen and seed dispersal in trees and show that their spatial range is frequently comparable to the predicted scale of habitat shifts within one generation. We then review the theoretical predictions and experimental evidence for the effects that such LD gene flow could have on local adaptation in trees. We conclude that the positive effects of gene flow may often dominate its negative effects, although regional variation may influence the balance of those effects. We finally elaborate on the theoretical and experimental approaches that should be implemented to improve our ability to predict the scale and distribution of gene flow effects on forest ecosystems in the context of climate change.effective propagule dispersal (Glossary) in trees depends on a variety of physical and biological processes that determine the amount and availability of pollen and seeds, their movement, their viability before and during movement, and the probability of successful pollination leading to viable seed and the seedling establishment rates. Different combinations of these components may yield effective dispersal (Glossary) distances spanning from a few centimetres to thousands of kilometres . Interactions between physical and biological processes influencing LD dispersal (LDD) and the way these will be affected in a changing climate are particularly poorly understood. The local environment around the release point of the propagule and the conditions at which the propagule was released can have strong effects of either decreasing or increasing the rate and extent of LD propagule transport between pollen release and fertilisation. Similarly, quantifying the multiple demographic and dispersal parameters affecting seed dispersal and subsequent establishment is still hard to accomplish dates along temperature gradients within the range. The simple conceptual model in genetic load (Glossary) depressing population mean fitness, and thus population growth , \u03b8 is the optimal phenotype in that location, P is the local phenotypic variance around this mean. This expression shows that the mean fitness in a variable population subject to stabilising selection is reduced in two ways: (1) Standing load (P/2Vs): caused by phenotypic variation and present even when the mean phenotype matches the optimum; (2) Evolutionary load [Evolutionary loads can be generated by selection that varies over space or time ; this part of the load increases with dispersal distance (\u03c3). The second term describes phenotypic mismatch due to the lagging response of the mean phenotype to temporal change in the local optimum (lag load). This part of the load decreases with dispersal distance because migration helps the species track its shifting optimum through space. The third term in eqn 2.2 shows that the evolutionary load declines with genetic variance G because response to selection increases. Dispersal distance also affects the evolution of genetic variance G (evolutionary load (eqn 2.2), but negative effects on the standing load P/2Vs (eqn 2.1).where adaptive divergence (Glossary) along environmental gradients (phenotypic clines (Glossary) for adaptive traits to deviate from their optima . Such migration load would be of concern if gene flow is extensive over LDs (see section \u2018How far do seeds and pollen disperse in trees?\u2019) and if phenotypic mismatch of immigrants is mostly due to long-lasting genetic effects repeatedly suggests that extensive gene flow has not prevented rapid adaptive divergence of extant populations have been replicated over a broad range of climatic conditions, provenance (Glossary) reaction norms (Glossary) allow comparison of optimal and original climate for each population: mismatches are not uncommon and often consistent with a maladaptive effect of gene flow at range margins typically above 0.4 for wood characteristics or phenological traits such as bud set date (stabilising selection (Glossary) is acting to reduce variation within populations (see genetic variance (Glossary) due to gene flow could be substantial along the typical dispersal distance is predicted to affect the spatial distribution of genetic variation and diversity of migrants by helping track the shift of the optimum phenotype through dispersal of pre-adapted genotypes found somewhere else in the range (see eqn 2.2 in response to selection (Glossary) through a general increase in genetic variation (see previous paragraph). Quite generally, dispersal should help adaptation in environments that are changing both in space and time was only moderately reduced (by 2 days) by the higher pollen and seed dispersal distances of birch along the climatic gradient.Assuming an initially locally adapted population, the new selection pressures induced by climate change will cause the optimal phenotype to deviate from the extant mean phenotype, thus creating a and time . Beyond inbreeding depression (Glossary) is widespread in largely outcrossing species such as trees and inbreeding was found more frequently in isolated marginal populations (heterosis (Glossary) is however not expected generally very strong in trees, due to the combination of large population size and extensive gene flow in trees the regional context (e.g. expanding edge or retracting part of the range) and (2) the dispersal syndrome .evolutionary load and maladaptation increases with increasing migration suffice to replenish ronments . We lackbioclimatic envelopes imply that current populations at the trailing and leading edges of the range will face different adaptive challenges. Southern margin populations will face climatic conditions not encountered anywhere in the current species range. Will these challenged populations have the evolutionary potential masking LDD, (2) dilution effect and (3) large numbers of putative sources (characterising their positions and genotypes is time- and cost-intensive). Using highly polymorphic genetic markers like microsatellites greatly overcomes the first point, and the advent of next-generation sequencing will improve power and resolution; however, it is still necessary to conceive new experimental designs dealing with points (2) and (3). We propose potential strategies here, mostly relying on a stronger interaction with mechanistic approaches.Experimental dispersal studies monitoring LD pollen and seed dispersal have often been limited in spatial scale due to (1) overlapping of the For wind-mediated gene flow, available weather data could help determine the potential range of pollen and seed dispersal within particular landscapes, regions, or continents. Such an analysis requires regional meteorological datasets, phenological observations over a wide region and sufficient understanding of the meteorological factors driving pollen and seed emission and spread. Products of regional and global weather reanalysis, such as the North American Regional Reanalysis (NARR) dataset and the European Centre for Medium Range Weather Forecast (ECMWF) data, offer useful observational and model-based information on wind, temperature, humidity, radiation and other meteorological data methods linking pollen, seeds or seedlings to candidate parental populations could be used to evaluate the effective rate and range of contemporary gene flow among discrete populations may prove efficient in detecting LD gene flow networks or placed at specific sites in a landscape. Ultimately, dispersal inferences from adequate landscape configurations could enlarge the documented range of dispersal especially for abundant species, in which dilution effects complicate the detection of LDD events in general. Note, however, that the atypical demographic conditions of isolated trees that facilitate LDD assessment may result in observed LDD patterns difficult to generalise, for which modelling approaches may be necessary.An alternative solution, not requiring trap plants but not assessing effective dispersal. The ability of mechanistic approaches to assess dispersal across multiple scales ; although this assumption is unrealistic for many systems in which the dispersal vector moves in a directional manner, such as many seasonal winds, downward flow of rivers, and oriented movement of animals. Similarly, genetic assignment methods for migration rate estimation typically incorporate neither directional nor other kinds of spatial information. Lagrangian dispersal (Glossary) simulations can account for dispersal anisotropy by incorporating turbulence patterns (connectivity maps (Glossary), depicts dispersal probabilities between sites based on large-scale datasets and/or models available for the primary dispersal vector, for example, to assess wind connectivity of plants among islands in the southern oceans , we suggest initiating experiments under controlled conditions mimicking climate change using open top chambers, where the level of CO2, temperature and rainfall can be manipulated. Ideally, such experiments should be conducted for short-generation species allowing to manipulate as well gene flow among different populations. Selection experiments on short rotation species would not only allow one to monitor genetic changes for key adaptive traits that are undergoing strong selection under climate change. They would also give access to the rate and direction of change as a function of standing variation and variation due to gene flow, under a wide range of controlled selection regimes.Finally, in addition to experiments conducted in the field among traits, which may limit or accelerate adaptation to climate change , empirical data are direly missing on patterns of genetic correlations among key ecological traits in trees and on the spatial and temporal variation of their joint selection pressures.The idea that climate change is equivalent to simple spatial shift of local climatic conditions is also a gross simplification. Rather, climatic change may result in new combinations of precipitation patterns, temperature, photoperiod and biotic conditions that occur nowhere within the current range, imposing entirely new selection pressures and favouring the assembly of novel genotypes . Adaptatnge e.g. . ModelliEfforts should be made to fill these gaps and help calibrate models with real data, to ultimately be able to merge evolutionary approaches with niche- and process-based ecological forecasting of climate-induced range shifts.Nemo, Metapop, Trait-based, mechanistic models have recently been developed enabling predictions of species ranges under current and future non-analogous climates e.g. predictsbioclimatic envelope modelling, variation of gene flow over geographical ranges and evolutionary adaptation of local populations. The basal layer, the climatic layer, defines how changes in climatic conditions over the species\u2019 geographical range modify the localisation of suitable habitats (dispersal kernels (adaptive traits by indicating how far from its local optimum a population might be. Information on gene flow from the second layer will indicate hybridisation rates and fitness effects, depending on the geographical origin of the migrants (A key aspect of the modelling approach advocated here is the overlay of predictions from different processes; ecological niche and habitats . The secmigrants . It willAlthough much emphasis has been placed on the ability of tree populations to migrate fast enough in response to climate change, we have here examined the potential consequences of LD gene flow on their adaptive response to climate change.Many tree species have evolved dispersal syndromes enabling the effective flow of genetic information across distant populations inhabiting contrasting environments. We have argued how such exchanges, although potentially maladaptive in some evolutionary and demographic scenarios, may in the case of forest trees favour adaptation to changing climatic conditions, compensating for their long-generation time. However, we are still missing adequate tools to track LD pollen and seed dispersal enabling to predict population responses to changing environments. The demographic impact of phenotypic mismatch in forest trees also remains to be quantified. Our understanding of the interaction between gene flow and local adaptation under realistic ecological, demographic and dispersal assumptions is still limited, and we have suggested potential theoretical and experimental avenues of research for the integration of dispersal biology, ecology and evolutionary quantitative genetics in a better predictive inferential framework."} +{"text": "Major investments in basic science have created an opportunity for significant progress in clinical medicine. Molecularly targeted therapies aim to interfere with molecular mechanisms, selectively involved in carcinogenesis and tumor growth in order to optimize the efficacy and minimize the side effects of anticancer treatment. Moving from concept to clinical use requires basic, translational, and regulatory science. Today, about 10% of labels for FDA-approved drugs contain pharmacogenomic information \u2014 a substantial increase since the 1990s but hardly the limit of the possibilities for this aspect of personalized medicine.There has been an explosion in the number of promising markers but significant gap exists in independent analysis of the validity of the tests used to identify them in biologic specimens. The success of personalized medicine depends on having accurate diagnostic tests that identify patients who can benefit from targeted therapies.In this presentation, case examples of how MedImmune/Astrazeneca incorporate personalized medicine/molecular diagnostic into clinical development to ensure targeted therapeutics successfully reach the right patient population will be discussed. These examples will illustrate how close cooperation among basic science, translational, clinical and regulatory departments together with partnerships with diagnostic companies are needed to reduce the dream of personalized healthcare into practice.By identifying the right patient population at the outset of the clinical development process we hope to improve the probability of success of oncology clinical trials, which is an urgent requirement across the industry, but especially for cancer patients with significant unmet need."} +{"text": "Temporal lobe epilepsy (TLE) is typically associated with long-term memory dysfunction. The frontal lobes support high-level cognition comprising executive skills and working memory that is vital for daily life functioning. Deficits in these functions have been increasingly reported in TLE. Evidence from both the neuropsychological and neuroimaging literature suggests both executive function and working memory are compromised in the presence of TLE. In relation to executive impairment, particular focus has been paid to set shifting as measured by the Wisconsin Card Sorting Task. Other discrete executive functions such as decision-making and theory of mind also appear vulnerable but have received little attention. With regard to working memory, the medial temporal lobe structures appear have a more critical role, but with emerging evidence of hippocampal dependent and independent processes. The relative role of underlying pathology and seizure spread is likely to have considerable bearing upon the cognitive phenotype and trajectory in TLE. The identification of the nature of frontal lobe dysfunction in TLE thus has important clinical implications for prognosis and surgical management. Longitudinal neuropsychological and neuroimaging studies assessing frontal lobe function in TLE patients pre- and postoperatively will improve our understanding further. Temporal lobe epilepsy (TLE) is associated with significant cognitive impairment. Difficulties in the formation and storage of long-term episodic memories (LTM) have long been recognised as a hallmark of pathological damage to medial temporal lobe structures (MTL). Frontal lobe function has been considered spared in the presence of MTL damage in TLE , althougThe frontal lobes primarily support higher-level cognitive processes, comprising executive skills and working memory . ExecutiWorking memory refers to the temporary storage and manipulation of information, and it is an early and key stage in almost all cognitive processing. Impaired function can disrupt subsequent cognition and as a consequence can have a marked impact on even basic everyday activities such as following a conversation or reading a newspaper. Much research has been undertaken on working memory and thisEvidence from psychiatric and neurodegenerative disorders support temporal lobe involvement in classically frontal lobe processes. In schizophrenia, executive dysfunction has been associated with disrupted frontotemporal connectivity , while eIn TLE, whether frontal lobe impairment is a product of critical temporal lobe involvement or is secondary to propagation of epileptic activity from the epileptogenic zone to eloquent cortex responsible for frontal lobe function is subject of current debate . IdentifThis review will examine the evidence for frontal lobe dysfunction in TLE, focussing on executive functions, working memory, and the potential mechanisms of impairment. A search of Pubmed for original and review articles of adults, in English using a combination of the keywords frontal, temporal, epilep*, working\u00a0+\u00a0memory and executive\u00a0+\u00a0function was performed. An initial total of 160 papers were identified. Animal research was discounted due to the ongoing debate surrounding the validity of the clinical translation of animal models to human frontal lobe function . Case reNeuropsychological impairment is an important comorbidity of chronic epilepsy . Focal eThe main findings from studies assessing executive function in TLE are summarized in Evidence for executive dysfunction in TLE has frequently been investigated using the Wisconsin Card Sorting Task (WCST) or its mThere is limited research using other measures of executive functions in TLE. While these studies provide evidence for executive dysfunction in TLE, there are also contrary findings. Few neuroimaging studies have examined the relationship between executive function and TLE. The main findings from studies assessing working memory in TLE are summarized in Recent models of working memory highlight the role of the \u2018episodic buffer\u2019, linking working memory to long-term memory systems LTM; . AccordiIn the only study to look specifically at material-specific lateralization of working memory in TLE, More recently, When directly assessing the role of the medial temporal lobes in working memory, there is limited evidence to suggest that temporal lobe structures are not involved. n-back\u2019 task . This places great demands on working memory, requiring the on-line monitoring, continuous updating and manipulation of remembered information. A recent meta-analysis of 24 functional MRI (fMRI) data sets for variants of the n-back paradigm found consistent activation of frontal and parietal cortical regions , intracrAxmacher and colleagues have shoA recent fMRI study examined working memory performance in 36 individuals with cryptogenic focal epilepsy; 10 temporal, 13 frontotemporal and 13 frontal foci based on EEG and seizure semiology . CompareAn optimal experimental design for studying the mechanism underlying the disruption to frontal lobe function in TLE is to assess for post-surgical change. Anterior temporal lobe resection (ATLR) is with a well-established treatment for medically intractable temporal lobe epilepsy. If medial temporal lobe structures are critical for executive functioning, then preoperative impairments would be expected and these would be maintained or exacerbated by surgery. If however the spread of epileptogenic activity to frontal regions is causing executive dysfunction, then removal of the primary epileptogenic zone should result in a gain of function. Functional neuroimaging studies have been under-utilised to date and these are likely to help in identifying the underlying neural correlates of working memory and executive functions in TLE. To date, there are no functional magnetic resonance imaging studies specifically investigating frontal lobe function in lesional TLE. The identification of these correlates will aid our understanding of the cognitive phenotypes of TLE.Evidence from both the neuropsychological and neuroimaging literature suggests both executive function and working memory can be compromised in the presence of TLE. In relation to executive impairment, particular emphasis has been paid to set shifting as measured by the WCST. Other functions such as decision-making and theory of mind appear vulnerable, but as this review demonstrates these have received little attention. Study samples are often small or suffer from heterogeneity regarding pathology for example by combing pre- and post-surgical cases.Despite a limited evidence base, the cause of executive skills weakness seems to be the propagation of seizure activity to executive skills dependant regions in the frontal lobes. With regard to working memory, the evidence more consistently supports a direct role of the temporal lobe in the encoding and maintenance of working memory but with emerging evidence of hippocampal-dependent and hippocampal independent processes. The cognitive phenotype and trajectory in TLE will likely vary depending on the underlying mechanism and this has clinical relevance and will be important to establish further.In the research reviewed little consideration has been given to the role of anti-epileptic medication and its impact on frontal lobe function. For example, there is considerable evidence that topiramate can negatively impact on working memory . This deLongitudinal neuropsychological and functional neuroimaging studies assessing executive skills and working memory pre- and post temporal lobe resections hold promise in elucidating the nature and mechanisms underlying frontal lobe dysfunction in TLE."} +{"text": "Aging is the major risk factor that contributes to the onset of cervical spondylosis. Several acute and chronic symptoms can occur that start with neck pain and may progress into cervical radiculopathy. Eventually, the degenerative cascade causes desiccation of the intervertebral disc resulting in height loss along the ventral margin of the cervical spine. This causes ventral angulation and eventual loss of lordosis, with compression of the neural and vascular structures. The altered posture of the cervical spine will progress into kyphosis and continue if the load balance and lordosis is not restored. The content of this paper will address the physiological and biomechanical pathways leading to cervical spondylosis and the biomechanical principles related to the surgical correction and treatment of kyphotic progression. Cervical spondylosis is a common progressive degenerative disorder of the human spine often caused by the natural aging process. It is defined as \u201cvertebral osteophytosis secondary to degenerative disc disease\u201d due to the osteophytic formations that occur with progressive spinal segment degeneration \u20133. EarlyOnce the disc starts to degenerate and a loss in disc height occurs, the soft tissue (ligamentous and disc) becomes lax, resulting in ventral and/or dorsal margin disc bulge and buckling of the ligaments surrounding the spinal segment, accompanied by a reduction in the structural and mechanical integrity of the supportive soft tissues across a cervical segment. As the ventral column becomes compromised, there is greater transfer of the axial loads to the uncovertebral joints and also along the dorsal column, resulting in greater loads borne by the facet joints. As axial loads are redistributed to a greater extent along the dorsal column of the cervical spine, the facet joints are excessively loaded resulting in hypertrophic facets with possible long-term ossification of the posterior longitudinal ligament . When thCervical spondylosis presents itself in three symptomatic forms as neck pain, cervical radiculopathy, and cervical myelopathy. Neck pain and cervical radiculopathy (nerve root involvement) can be acute, subacute, or chronic conditions resulting from various stages along the degenerative cascade . CervicaThe primary cause of cervical spondylosis is age-related degeneration. However, there are some exceptions where spinal injuries to the disc can augment the degenerative process in the younger patient. A secondary manifestation of spondylosis is related to the compression of the vascular and neural structures caused by a loss in the disc height and impinging osteophytes that contribute to the numbness, shock-like sensations, pain, and chronic motor and sensory affects, which if not corrected may lead to permanent disabilities.It is this physiological degenerative cascade that contributes to the biomechanical changes that can cause neural and vascular compression, pain, and loss of function. The unique properties of bone and soft tissue are the ability to regenerate and remodel the tissue along the lines of loading and stress application, thus regaining the structural integrity. However, if the load balance along the spinal column is altered and is not restored, the tissue will remodel along the altered load and stress planes, causing the tissue to remodel along new planes of loading. Since osteophyte or bone spur formation will occur in response to excessive eccentric loads, new bone will form in areas of greater stress and will be resorbed in areas of less stress.The loss in the axial load bearing capabilities of the degenerative segment leads to a disruption in the load transfer along the neutral axis of the spinal column, also known as a change in the overall load balance, thereby transferring greater loads to the uncovertebral and facet joints, further accelerating the formation of spurs and osteophytes into the surrounding foramen, with greater angulation of the cervical spinal column ventrally. The ventral angulation along the cervical spine is a continuous cascade of mechanical events. As the lordotic angle is reduced, the moment arm about the center of rotation or instantaneous axis of rotation (IAR) is increased, therefore, changing the overall sagittal angulation and reducing the spinal canal diameter , 3, 4, 9Elegant studies have been performed to characterize the histological and immunohistochemical differences between cervical disc herniation and spondylosis. Disc herniation can be an early contributor to spondylosis, as herniation creates a loss in the mechanical integrity of the intervertebral disc due to the extrusion or bulging of the nucleus pulposus through compromised annular fibers. The herniation often occurs dorsally, as the dorsal annular fibers are thinner and provide a less resistant pathway for the compromised nucleus pulposus matter. The intervertebral discs with surrounding tissues, subchondral vertebral bone, cartilaginous endplate, and posterior longitudinal ligaments were collected en bloc during decompression surgeries in 198 patients presenting with cervical intervertebral disc herniation resulting in 248 discs for evaluation. An additional 252 discs were harvested in a similar manner from 166 patients presenting with cervical spondylosis to provide a histological and immunohistochemical assessment between cervical spondylosis and disc herniation . The disKyphotic deformity with neural and vascular compression often accompanies cervical spondylotic myelopathy. Initially the loss of disc height as a consequence of disc desiccation and altered load transmission along the cervical spine can lead to postural changes . As spinHalting the progression of kyphosis related to cervical spondylosis is the main objective for surgical intervention and can be treated through ventral surgical fixation or through a combined ventral and dorsal approach of stabilizing fixation. Ventral approaches for surgical correction of this disorder provide the necessary ventral column support to resist further compression and angulation of the cervical spine and can provide improved decompression of the neural and vascular structures. Numerous in vitro and in vivo studies have confirmed that approximately 80% of the axial load is transmitted along the ventral column of the human spine with improved resistance to higher axial loads and better biomechanical stability when ventral column stabilization is employed , 4, 11. Fusion of the degenerative unstable spine is often a final alternative to alleviate a painful spinal segment. Ventral interbody fusion is incorporated in a fusion construct to maximize the axial load bearing capacity of the spine while limiting the pathologic motion across a spinal segment. In situations such as kyphotic deformity correction, multisegmental ventral interbody fusions can provide the necessary ventral column support incorporating multiple points of fixation to resist the demanding translational, rotational, and bending loads placed upon on the degenerative kyphotic cervical spine and will provide ample strength to maintain the restored lordotic posture. Ventral support using multiple interbody fusion grafts supplemented with dorsal fixation across each level will also provide similar mechanical attributes as that of ventral support, where both approaches towards kyphotic deformity will allow for better force distribution across many points of fixation, thus minimizing the risk of stress risers that can cause graft subsidence, expulsion, screw loosening, or loss of fixation. Biomechanically, these strategies will improve the restoration of the lordotic posture for long-term fixation and stability. By restoring the lordotic posture of the cervical spine, the load balance is restored, where 80% of the axial loads transmitted along the ventral column is aligned at the IAR of the spinal column, effectively, halting the progression of the kyphotic curvature. Segmental fixation results in reduced localized forces and stresses at each spinal level and across the instrumentation, with reduced stresses on each screw and across each graft site for improved long-term fixation."} +{"text": "The development of a practical, effective AIDS vaccine that can produce enduring broadly protective immunity to natural exposure by diverse strains of HIV-1 remains the ultimate goal for controlling the ongoing AIDS epidemic. The success of an effective AIDS vaccine will likely depend on designing immunogens that elicit broadly neutralizing antibodies to circulating HIV-1 strains, and it is important to thoroughly understand the mechanism of binding of HIV antigens and neutralizing antibodies. The current study was designed to determine differences in the specificity and quantitative properties of antibody binding to gp120 or gp140 envelope proteins derived from natural HIV isolates.We previously described novel assays of Env-specific serum antibodies elicited by animal lentiviral and HIV infections and immunizations that measure qualitative properties of avidity and conformational dependence in an ELISA format. However, recent data have emphasized limitations of this format. To provide a more sensitive, specific, and reproducible format for our antibody assays, we have recently developed novel procedures using SPR spectroscopy as measured in the Biacore system to characterize real time reaction kinetics (association/dissociation rates).The assays conducted under physiological conditions clearly indicate the potential of these kinetic measurements of antigen-antibody binding to provide novel data not achieved with standard assays. We have used these binding assays and a panel of well-characterized monoclonal antibodies both to linear and conformational binding domains to characterize differences in reactivity between variant gp120 and gp140 antigens as determined by kinetic rates and affinity of antibody binding. We have identified significant distinguishing differences in several binding characteristics of monoclonal antibody binding to gp120 vs gp140 antigens.These kinetic parameters offer novel insights into the fundamental interactions of reference monoclonal antibodies and variant Env proteins and have the potential to provide novel correlates of neutralization in vitro and protection in vivo."} +{"text": "Cheminformatics systems usually focus primarily on handling specific molecules and reactions. However, Markush structures are also indispensable in various areas, like combinatorial library design or chemical patent applications for the description of compound classes.The presentation will discuss how an existing molecule drawing tool (Marvin) and chemical database engine (JChem Base/Cartridge) are extended to handle generic features . Markush structures can be drawn and visualized in the Marvin sketcher and viewer, registered in JChem databases and their library space is searchable without the enumeration of library members. Different enumeration methods allow the analysis of Markush structures and their enumerated libraries. These methods include full, partial and random enumerations as well as calculation of the library size. Furthermore, unique visualization techniques will be demonstrated on real-life examples that illustrate the relationship between Markush structures and the chemical structures contained in their libraries (involving substructures and enumerated structures).Special attention will be given to file formats and how they were extended to hold generic features."} +{"text": "There are two main mechanisms by which iron overload develops in thalassemias: increased iron absorption due to ineffective erythropoiesis and blood transfusions. In nontransfused patients with severe thalassemia, abnormal dietary iron absorption increases body iron burden between 2 and 5 g per year. If regular transfusions are required, this doubles the rate of iron accumulation leading to earlier massive iron overload and iron-related damage. Iron metabolism largely differs between thalassemias and sickle cell disease, but chronic transfusion therapy partially normalize many of the disparities between the diseases, making iron overload an important issue to be considered in the management of patients with sickle cell disease too. The present review summarizes the actual knowledge on the regulatory pathways of iron homeostasis. In particular, the data presented indicate the inextricably link between erythropoiesis and iron metabolism and the key role of hepcidin in coordinating iron procurement according to erythropoietic requirement. The role of erythropoietin, hypoxia, erythroid-dependent soluble factors and iron in regulating hepcidin transcription are discussed as well as differences and similarities in iron homeostasis between thalassemia syndromes and sickle cell disease. In humans total body iron stores is maintained normally within the range of 200\u20131500 mg by adequate adjustment of intestinal iron absorption, since no excretory mechanisms existBecause there is no known regulated mechanism for iron excretion, and the amount of iron entering the body each day represents less than 0.1% of the total body iron endowment, most circulating iron must be derived from the recycling of iron already within the systemThe second pathway is the cycling of iron from hepatocytes to the blood and viceversa, according to body needs and the third is iron absorption through duodenal and upper jejunum that balances the 1\u20132 mg daily iron loss occurring through cellular exfoliation (see below: iron absorption and iron storage paragraphs).TfR1 gene causes embryonic lethality, attributable to severe anemiaTF gene demonstrate the importance of TF in animals The systemic transporter of iron in the body is transferring, an abundant, high affinity iron-binding protein. Under normal circumstances, TF carries nearly all serum iron collected from duodenal absorptive epithelium, macrophages and hepatocytes, and dampens its reactivity. Very small amounts of iron may be loosely associated with albumin or small molecules. In normal human subjects, iron occupies approximately 30% of the iron-binding sites on plasma TFIron in food is present as ferric iron or as heme. Heme is a biologically important iron containing compound and a key source of dietary iron but the mechanism by which the enterocyte takes up heme and catabolises it to utilise the iron is still poorly understood. Currently, there are two prevailing hypotheses explaining the mechanisms of this process; first, heme is taken up by receptor mediated endocytosis; secondly, the recent discovery of a heme transporter (PCFT/HCP1) that may have the capability of transferring heme from the small intestinal lumen directly into the cytoplasmb) rat and mk mouse which both exhibit a microcytic, hypochromic iron deficiency anaemia due to a G185R mutation to DMT1, resulting in a dramatic decrease in DMT1 functionMuch more knowledge has been developed on non-haem iron absorptionBesides enterocytes other cell lines, namely macrophages, hepatocytes in adults and placental cells during fetal life, have core functions within iron metabolism, that is to acquire iron from different sources (senescent erythrocytes and holotransferrin) and to deliver it to the rest of the body according to its needs . To do tFollowing phagocytosis of old and damaged erythrocytes, tissue macrophages, particularly in the spleen, lyse cells and catabolyse hemoglobin presumably by heme oxygenase, to liberate iron. Some iron remains stored in macrophages, although some is exported to plasma TF. Ferroportin is critical for macrophage iron export and can be regulated to change the ratio between stored and released ironThe liver peptide hepcidin regulates intestinal iron absorption and iron release from storage cells by binding ferroportin causing its internalization and degradation, thus exerting a general inhibitory effect on iron release in the bodyStudies on genetic disorders of iron metabolism and of corresponding animal models have identified the hemochromatosis proteins as the iron-dependent regulators of hepcidin expression. Patients affected by hemochromatosis have a defective synthesis of hepcidin that is absent in JH, reduced in type 3 HH due to TFR2 mutation or inadequate to the amount of iron overload in classical HHIn vivo studies demonstrated that the effect is predominantly due to the activation of erythropoiesis and to secondary changes in plasma and tissue ironSeveral lines of evidence indicate that iron and oxygen homeostasis are tightly connected. Anemia generates tissue hypoxia and activates the cellular mediator of biological response to hypoxia: Hypoxia inducible transcription factors: HIFs. This induce a signalling cascade involving hundreds of genes. Seminal studies established an association between oxygen and iron regulation by showing that hypoxia results in higher iron absorption in mice and rats. Accordingly, both hypoxia and anemia induce the synthesis of erythropoietin (EPO) and are the two main signals that increase iron absorption independently of iron storesHepcidin is suppressed in human cultured hepatoma cells exposed to hypoxiaPatients affected by the most severe forms of thalassemia require chronic blood transfusions to sustain life and chelation therapy to prevent iron overload. Those affected by \u03b2-thalassemia intermedia do not require chronic blood transfusions but eventually develop elevated body iron loads due to ineffective erythropoiesis and hypoxia dependent hepcidin downregulation that, in turn, induces increased gastrointestinal iron absorptionIron metabolism in SCD largely differs as compared to thalassemia. SCD is an inherited disorder of hemoglobin synthesis characterized by life-long hemolytic anemia, increased erythropoiesis and a chronic inflammatory state with endothelial activation and enhanced red cell and leukocyte adhesionThalassemia intermedia and major are the most studied human models of hepcidin modulation by ineffective erythropoiesis alone and the combined and opposite effect of both ineffective erythropoiesis and transfusion dependent iron overload, respectively. Regular transfusions, in fact, induce massive iron loading but also inhibit erythropoietic drive. Accordingly, hepcidin production is higher in thalassemia major than in thalassemia intermedia although still inappropriate to the massive transfusional iron loading that partially counteracts the erythropoietic-dependent hepcidin downregulationData on hepcidin levels in SCD are very limited and no data are presently available on GDF15 and TWSG1 expression. Kearney et al found significantly lower levels of urinary hepcidin in nine SCD patients when compared with normal controlsErythropoiesis and iron metabolism are inextricably linked. Hepcidin has a key role in coordinating iron procurement according to erythropoietic requirement. The recent tremendous advancement in the iron field have shed light on the various signals regulating hepcidin production and showed that erythroid-dependent regulation is absolutely prevailing. There are however, some issues to be clarified: a. if mediators other than GDF15 and TWSG1 exist and which are their interactions and mechanisms of hepcidin regulation; b. why, despite anemia and increased iron demand, and the evidence of reduced hepcidin synthesis, patients with haemolytic anemias do not develop the same amount of iron overload observed in the iron-loading anemias where ineffective erythropoiesis prevails on hemolysis. New links between erythropoiesis and iron metabolism have recently suggested: the link between Epo/EpoR/Jak2/Stat5 signalling and TfR1 mRNA transcription"} +{"text": "AbstractLigia italica and in prehatching embryos and premolt marsupial mancas of Porcellio scaber. Fibers expand from the tendon cells, traverse the new cuticle and ecdysal space and protrude into the distal layers of the detached cuticle. They likely serve as final anchoring sites before exuviation and may be involved in animal movements in this stage. Tendon cells in the prehatching embryo and in marsupial mancas display a substantial apicobasally oriented transcellular arrays of microtubules, evidently engaged in myotendinous junctions and in apical anchoring of the cuticular matrix. The structural framework of musculoskeletal linkage is basically established in described intramarsupial developmental stages, suggesting its involvement in animal motility within the marsupium.Specialized mechanical connection between exoskeleton and underlying muscles in arthropods is a complex network of interconnected matrix constituents, junctions and associated cytoskeletal elements, which provides prominent mechanical attachment of the epidermis to the cuticle and transmits muscle tensions to the exoskeleton. This linkage involves anchoring of the complex extracellular matrix composing the cuticle to the apical membrane of tendon cells and linking of tendon cells to muscles basally. The ultrastructural arhitecture of these attachment complexes during molting is an important issue in relation to integument integrity maintenance in the course of cuticle replacement and in relation to movement ability. The aim of this work was to determine the ultrastructural organization of exoskeleton \u2013 muscles attachment complexes in the molting terrestrial isopod crustaceans, in the stage when integumental epithelium is covered by both, the newly forming cuticle and the old detached cuticle. We show that the old exoskeleton is extensively mechanically connected to the underlying epithelium in the regions of muscle attachment sites by massive arrays of fibers in adult premolt The arthropod exoskeleton performs diverse functions, including mechanical support, sensing, prevention of desiccation and protection against pathogens and predators. Locomotion of these animals is based on extensive connections between exoskeleton and muscular system. The exoskeleton consists of a complex chitin-protein matrix, secreted by a single-layered epithelium. The chitin-protein matrix is either non-calcified or calcified, as in insects and crustaceans, respectively. Specialized epithelial cells, named tendon cells, are the sites of firm mechanical connections between exoskeleton and underlying tissues . Apical Drosophila melanogaster, with emphasis on myotendinous junction characterization by PageBreak marsupial stages of isopod crustaceans. The embryonic development of terrestrial isopod crustaceans and hatching of embryos to marsupial mancas take place inside the female brood pouch (marsupium) and were decribed in Porcellio scaber from the view of overall morphology and digestive system morphogenesis, while the issue of cuticle anchoring was not addressed were collected at the Piran Bay coast in Slovenia. Animals were inspected for ventral sternal deposits and PageBreakpremolt adult specimens were anaesthetized. The dorsal parts of pereonites were isolated, fixed in 2% paraformaldehyde and 2.5% glutaraldehyde in 0.1 M cacodylate buffer (pH 7.3) and postfixed by 1% OsO4. After washing and dehydration in a graded series of ethanol, samples were embedded in an epoxy resin mixture. Semithin sections were stained with Azure II. \u2013 Methylene blue. Ultrathin sections were either imaged non-contrasted or contrasted with uranyl acetate and lead citrate.Specimens of Porcellio scaber Latreille, 1804 (Crustacea: Isopoda) prehatching embryos and marsupial mancas were isolated from brood pouches of females maintained in laboratory culture. Determination of intramarsupial developmental stages was performed as described in 4 for 2 hours, washed again and dehydrated in a graded series of ethanol. Specimens were embedded in Agar 100 resin. Prior to embedding, mancas were perforated with a thin needle for better infiltration of resin. Semithin sections were stained with Azure II. - Methylene blue. Ultrathin sections were contrasted with uranyl acetate and lead citrate.Specimens of Light microscopy was performed by AxioImager Z.1 microscope (Zeiss) equiped with an AxioCam HRc camera and Axiovision software. Ultrastructural imaging was performed by CM 100 transmission electron microscope (Phillips) equiped with a BioScan 792 digital camera (Gatan) and Digital Micrograph software.Ligia italica. The pre-ecdysial cuticle was tightly connected to the underlying tendon cells and muscles already in the early premolt , aligned in the same direction . In longPageBreakPageBreakPageBreakarthropods, comprising a thin layer of extracellular material between cell membranes and dense cytoplasmic plaques of approximately equal densities and thicknesses below the both cell membranes (Myotendinous junctions displayed a characteristic zigzag outline, occupying the entire tendon \u2013 muscle interface . From thembranes . On the embranes .Specialized anchoring complexes between exoskeleton, tendon cells and force-generating muscle cells are essential features of the musculoskeletal system in arthropods . A complLigia italica and in premolt intramarsupial specimens of Porcellio scaber. The continuity of these fibers was clearly evidenced in both species. The fibers extending from the tendon cells deep into the cuticular matrix in non-molting specimens are known from previous studies of arthropods (Drosophila (PageBreakhe premolt Euphausia superba by Euphausia superba and in ostracods the new preecdysal cuticle in isopods is secreted while fibers maintain the connection between the old cuticle and epidermis. Our results show that the old exoskeleton is still mechanically attached to the underlying epithelium in the regions of muscle attachment sites for a certain period of the premolt phase in isopod crustaceans. We have observed massive arrays of fibers running from tendon cells through the new cuticle and ecdysal space up to the distal layers of the detached cuticle in adult premolt thropods and werethropods and in tthropods .Differenthropods , tonofibthropods , tonofilthropods , intracuthropods and intrthropods . To the thropods . In contosophila , the proosophila . The ultDrosophila tendon cells exhibit unusually large diameters of up to 30 nm, while in our study the usual microtubules of 24 nm in diameter were observed in the tendon cells of adult and intramarsupial isopods. Here we show that tendon cells in prehatching embryos and marsupial mancas of Porcellio scaber already include a substantial apicobasally oriented transcellular arrays of microtubules, evidently engaged in myotendinous junctions and in apical anchoring of the cuticular matrix. Thus we consider that in the prehatching embryos and marsupial mancas the structural framework of musculoskeletal linkage is basically established and could assist in animal motions within the marsupium. This consideration is further supported by our observation that marsupial mancas display pronouced body movements inside the marsupial fluid and is supported also by the study of Apicobasally oriented microtubule arrays are formed in several types of polarized epithelial cells. Ligia italica is a zigzag patterned junction of the tendon cell basal membrane and muscle cell sarcolemma, with an inconspicious layer of extracellular matrix inbetween. The entire basal surface and apical surface of tendon and muscle cell, respectively, contribute to this heterotypic adherens junction. Both interacting cell membranes are extensively folded, which increases the surface area of contact and contributes to enhanced mechanical resistance. The myotendinous connection in molting Ligia italica structurally resembles PageBreakthat described in non-molting specimens and in Drosophila. The myotendinous junction in Drosophila is considered to be composed of two sets of hemiadherens junctions with an intervening layer of extracellular matrix material that has a substantial thickness in certain situations (Drosophila myotendinous connection is integrin dependant and involves transmembrane integrins that connect to protein ligands in the extracellular matrix and to the cytoskeleton inside the cell (Drosophila. The molecular composition of tendon cell \u2013 muscle cell junction has not been resolved in crustaceans, but similar principles involving integrins and associated linking proteins are expected to be implied.The myotendinous junction in the dorsal parts of pereonites in molting tuations . In recethe cell . This stPorcellio scaber analysed in this study is similar to the general structural outline of adult arthropod muscle attachments. In marsupial mancas it appears to be structurally fully elaborated, while in the prehatching embryo it may not be completely formed. The cytoplasmic plaques engaged in anchoring junctions at the basal membrane of the tendon cell in the prehatching embryo are markedly electron lucent and thinner as compared to the opposing cytoplasmic plaques in the muscle cells, while in adult arthropods the myotendinous anchoring junctions comprise cytoplasmic plaques of similar thicknesses and densities in both cells. A similar situation was observed in Drosophila in vitro culture of primary embryonic cells by The ultrastructural arhitecture of myotendinous junctions in the prehatching embryos and marsupial mancas of PageBreakiated microtubules in tendon cells and myotendinous connections likely enable at least basic movements in this period. As cuticle replacement involves old cuticle detachment followed by the new chitin \u2013 protein matrix secretion at the apical membranes of epidermal cells, the rearrangement and remodeling of anchoring junctions between the tendon cells and cuticle are expected. The continuity of the fibers ranging from the tendon cells through the new cuticle and ecdysal space to the old cuticle was evident in premolt adult and intramarsupial isopods. This indicates that during premolt the reorganization of fibers and their associations with the cuticle takes place, rather then extensive formation of the new fibers. Our considerations are in agreement with previous reports on the continuity of tonofibrillae, which maintain the connection between the tendon cells and the old cuticle in molting insects (Cell to cell and cell to matrix anchoring junctions, together with their associated cytoskeletal elements, are engaged in providing tissue structural scaffold and integrity, but more than that, they are increasingly discussed from the perspective of tissue and cell dynamics . These j insects and crus insects ."} +{"text": "There are many challenges that face surgeons when attempting curative resection for gastrointestinal cancers. The ability to properly delineate tumor margins for complete resection is of utmost importance in achieving cure and giving the patient the best chance of prolonged survival. Targeted tumor imaging techniques have gained significant interest in recent years to enable better identification of tumor lesions to improve diagnosis and treatment of cancer from preoperative staging modalities to optimizing the surgeon's ability to visualize tumor margins at the initial operation. Using unique characteristics of the tumor to fluorescently label the tissue can delineate tumor margins from normal surrounding tissue, allowing improved precision of surgical resection. In this paper, different methods of fluorescently labeling native tumor are discussed as well as the development of fluorescence laparoscopy and the potential role for fluorescence-guided surgery in the treatment of gastrointestinal cancers. The primary treatment modality for most patients with solid tumors is surgery. There are a multitude of factors that can significantly alter a patient's postoperative survival, such as tumor size, histological tumor grade, and vessel invasion , 7. HoweTargeted tumor imaging techniques have gained significant interest in recent years to enable better identification of tumor lesions to improve diagnosis and treatment of cancer, from preoperative staging modalities \u201312 to opIn vivo infection of NV1066 resulted in localized expression of GFP to the tumor, which could be visualized endoscopically with the use of a laparoscope and appropriate fluorescence filters. Furthermore, the NV1066 selectively infected and replicated within the esophageal cancer cells, killing the cells in vitro and in vivo . Wit. Wit3]. The ability to visualize differently fluorescent tumors simultaneously resulted in the identification of an optimal fluorophore for fluorescence laparoscopy . The com In addition to using fluorophore-conjugated antibodies and GFP-containing viruses, there have been a variety of methods described to fluorescently label native tumor. Activatable cell penetrating peptides (ACPPs) have been used as targeting agents for cancer cells. Polycationic cell penetrating peptides (CPPs) are connected via a cleavable linker to a neutralizing polyanion whose adsorption and uptake into cells are inhibited until the linker is proteolyzed. With the upregulation of MMP-2 and MMP-9 in most solid tumors, exposure to these proteases results in cleavage and dissociation of the inhibitory peptide, allowing the CPP to bind to and enter cancer cells. Conjugating CPPs to a fluorophore then enables improved visualization of the tumor. Further conjugating dendrimers to ACPPs (ACPPDs) results in a higher absolute tumor fluorescence and tumor-to-background fluorescence contrast than free ACPPs . Our recent work with fluorophore-conjugated antibodies (FCAs) directed against the tumor antigen CEA has shown to be a method of labeling, detecting and subsequently resecting tumor to improve surgical outcomes in mouse models of pancreatic and colon cancer , 14. The The goal is to improve methods of fluorescently labeling native tumor to permit better preoperative detection of metastatic tumor and to further enhance the surgeon's ability to delineate tumor margins and allow more objective means of identifying and resecting all tumor at the initial operation."} +{"text": "An \u201centhesis\u2019 is described as a junction between tendon, ligament or joint capsule and bone. Tendinous entheses are a complex and a particularly important entity, as they are responsible for ensuring contractile force generated by muscle is transmitted to the skeleton. While complaints of pain at entheses sites are common, rupture or avulsion of tendinous tissue is not. This review aims to provide insight into what mechanisms the musculoskeletal system has developed for protecting tendinous entheses and what are the effects when these mechanisms are compromised (enthesopathy).An electronic database search was performed in October 2010. The search strategy used was enthesis* AND foot* AND (ankle* OR enthesopathy* OR enthesis organ* OR enthesitis). A secondary snowball method was conducted targeting reference lists and literature only available in hard copy.The initial electronic database search identified 526 articles. 468 were excluded based on title and abstract alone. Inclusion and exclusion criteria were applied and excluded a further 26 articles. The snow ball method retrieved a further 7 articles. 39 articles were included in the review. The literature identified comprehensive investigations on anatomical, functional and pathophysiological details of tendinous entheses at varied locations of the foot an ankle. On histological examination, there is extensive interweaving of tendinous tissue with fibrocartilage and bone to form the true enthesis. This interweaving leaves the attachment incredibly robust. Histological sections also revealed structures adjacent, and in close apposition, to entheses that would appear to reduce tensile, compressive and shear stress applied during muscular contraction. The arrangement of these structures has been termed the \"enthesis organ\". Enthesopathy was also found to be closely linked with spondyloarthropathies.Pathology of the entheses, enthesopathy, can develop for various reasons including post traumatic or rheumatological. The signs and symptoms of enthesopathy can be varied and can include formation of enthesophytes with chronic pain to changes in nail structure The review describes the associated anatomy of entheses, the process of enthesopathy and its association with spondyloarthropathies. It will introduce and consolidate podiatrists\u2019 understanding of enthesopathies and how they present in the foot and ankle."} +{"text": "Cardiovascular disease is the leading cause of death in Western countries and current research is still focusing on optimizing therapeutic approaches in the battle against this multifactorial disease. Concepts regarding the pathogenesis of many cardiovascular diseases originate from observations of human atherosclerotic tissue obtained from autopsies or during vascular surgery. These observations have helped us to disentangle the pathophysiology of atherosclerosis. However, identifying vulnerable patients, those prone to developing cardiovascular complications, remains difficult. The search for predictive cardiovascular biomarkers continues and large, well organized biobanks are needed to discover or validate novel biomarkers. Biobanks are an extremely valuable resource that enables us to study the influence of both genetic and environmental factors on the development of multifactorial diseases such as atherosclerosis. This review will focus on the advantages and pitfalls in atherosclerotic biobanking. Biobanks are organized resources of biological samples with associated clinical characteristics used for scientific investigation, they can be population or disease based . The stoFirstly, biobanks are an important resource for identifying the causes and mechanisms of many complex diseases. Biobanks enable scientists to investigate the combined influence of genetics, life style and other environmental factors in the development of multifactorial diseases. In addition, biobanks create the possibility for scientists to collect human material prior to presentation of specific diseases and provide the ability to compare different disease stages at a molecular level. Identification of pathways involved in disease initiation or progression may lead to the discovery of new therapeutic targets but also may result in the detection of biomarkers for prediction of disease progression or outcome. Furthermore, biobanks also play an important role in the process of validation of novel discovered biomarkers.Secondly, biobanks are highly relevant for scientists in case of rare disorders. In order to investigate rare disorders, researchers would have to wait for years to collect enough material to be able to reject or confirm their hypothesis. Therefore, a biobank consisting of human material of patients with rare disorders is valuable and will save years.Finally, disease based biobanks are needed to validate discoveries made in animal models. Regarding cardiovascular disease, animal studies have helped us greatly to elucidate the pathophysiology of atherosclerosis. One of the most studied animals in atherosclerotic research is the Apo E knockout mouse and major steps in the understanding of cardiovascular disease have been made by these animal studies. But although these mice do develop progressive atherosclerotic lesions, plaque rupture and its consequent cardiovascular complications do not occur. Therefore, to obtain further knowledge in the process of plaque rupture and the occurrence of cardiovascular complications novel ways to investigate this multifactorial disease are needed and human atherosclerotic biobanks can play major roles in this process.th century, Rudolph Virchow examined atherosclerotic arteries obtained from autopsies and noticed cellular inflammatory changes in the atherosclerotic vessel wall and introduced the term endarteritis deformans [in vivo experiments [Atherosclerotic tissue biobanks have led to the description of etiologic concepts that dominated basic research focused on disentangling the pathogenesis of atherosclerosis. Major steps in this process were taken by observations of large amounts of atherosclerotic specimens obtained from autopsy. In the late 18eformans . It was eriments and posteriments . Michaeleriments . He alsoeriments . Dr. Vireriments . These seriments . The vulnerable plaque, prone to rupture, is characterized by its large lipid core covered by a thin fibrous cap, large macrophage infiltration and low smooth muscle cell content. The aforementioned studies all contributed to the vulnerable atherosclerotic plaque paradigm. Overviews and histological classifications of the vulnerable plaque have been published over the years -16 and met al introduced the term \u2018vulnerable patient\u2019 in 2003 [The vulnerable plaque concept carries an important limitation which is an inherent drawback of most tissue biobank studies\u2014it is based on cross-sectional and retrospective studies on ruptured plaques. Robust prospective, longitudinal studies on vulnerable plaque characteristics and outcome are lacking. In addition, hallmarks of the vulnerable plaque, inflammation and a large lipid core, can also be observed in asymptomatic patients and can be considered as a common and locally observed phenomena of the whole vascular tree . Also, iOne of the first and famous examples of a population based biobank was the Framingham Heart Study. In 1951, 28,000 citizens from the town Framingham (US) were enrolled and periodically monitored. The occurrence of cardiovascular events was correlated with data from physical examinations, questionnaires and laboratory tests . The FraIn order to identify the vulnerable patient, several large scale population based biobanks have attempted to find novel serum biomarkers to predict cardiovascular risk more accurately than traditional risk factors. Several biomarkers have been found to be strongly associated with future cardiovascular events but on top of the traditional risk factors their extra predictive value was limited -26. Evenet al showed that plaque composition is an independent predictor of restenosis after carotid endarterectomy. They demonstrated that patients with more stable plaque phenomena had an increased risk for the development of restenosis compared with patients with unstable plaque phenomena [et al demonstrated that local plaque proteins are a source of biomarkers with strong predictive value for future cardiovascular events [Cross-sectional atherosclerotic biobanks may help us to generate hypotheses regarding the mechanisms of atherogenesis and its progression. However, for prediction studies follow up is required, therefore, atherosclerotic biobanks with a longitudinal study design might facilitate the discovery of biomarkers that are predictive for future cardiovascular events. Taking into account that atherosclerosis has been considered as a systemic disease and thathenomena . This war events . Analysir events . Thus, tWhile established circulating biomarkers are, on top of established risk factors, limited in the prediction of future cardiovascular events, the search for identification of the vulnerable patient continues. One example of a novel strategy is the Circulating Cells project. The Centre of Translational Molecular Medicine (CTMM), a consortium of 5 Dutch academic centers collaborating with industrial partners, started this multicenter study in 2009 . In thisAnother opportunity is the rapidly growing field of genomics. Sequencing of the human genome continues and large population based biobanks enable scientists to investigate the effect of the genomic variability on cardiovascular disease. A lot of attention has been received by the Genome Wide Association (GWA) studies in which allelic frequency variations in single nucleotide polymorphisms (SNP\u2019s) are compared between patients with or without cardiovascular manifestations . These GWith the increasing understanding in the pathogenesis of atherosclerosis, substantial progression has been made in the development of novel imaging techniques to detect the so called vulnerable plaque. Due to a lack of a golden standard, atherosclerotic biobanks play important roles in the validation process of these novel imaging technologies. Magnetic resonance imaging (MRI) has emerged as a promising novel technique with its superior capability to determine plaque size and composition (regarding lipid-rich necrotic core and intraplaque haemorrhage) and with a high intra-reader, inter-reader and inter-scan reproducibility . High re\u00ae) and ingenuity pathway analysis (IPA\u00ae) provide useful tools to find novel pathways and collaborate with other scientists. With the increasing number of biobanks and increasing opportunities to store different cell fractions some challenges and pitfalls merit careful consideration. While Rudolph Virchow drew conclusions from autopsy specimens obtained from a limited number of patients, research now may include thousands of patients. Enormous databases are needed to store the data obtained from long questionnaires, cytokine profiles, genomics and proteomics. Thus, presenting researchers with a challenge to work effectively and efficiently with such datasets. Fortunately, novel software and analytical programs are available. Large online databases like online mendelian inheritance in man . Cytokines reflect local or systemic inflammation and might therefore be a suitable target in the continuing quest for novel biomarkers. While enzyme linked immunoassays (ELISA) can only detect one cytokine in one sample, MIA enables detection of multiple cytokines, chemokines and other proteins in one single sample and therefore prevents spoiling large amounts of valuable and often limited human blood. et al demonstrated that the type of anticoagulant used can influence the levels of several cytokines [Recent studies raised a serious concern regarding storage of samples in biobanking. Large population biobanks, but also large conducted randomized clinical trials frequently measure proteins at different points in time using frozen samples. However, sampling, handling and storage can greatly influence the reproducibility and reliability of these immunoassays. De Jager ytokines . In addiytokines . They emBiobanks and their relevant medical ethics committees carry a serious responsibility to the patients from whom they collect their samples. Legislation of privacy issues in cardiovascular biobanking is well organized for some issues such as that patients\u2019 data must be anonymously processed. But it is also important to ask patients, before admission to the study, what to do in case of discovery of novel beneficial or adverse biomarkers. Patients should be well informed about the possibilities in case of such discoveries. Secondly, it is important to define who owns the tissue in case of long term storage. As the number of biobanks increases so does the number of private companies offering to store cells. One of the first examples of commercialised biobanking interfering with concerns about ownership and privacy issues was the Iceland Biogenetic Project. In this project the involvement of deCODE genetics, a commercial company with monopoly rights over scientific discoveries generated within the project, generated concerns about the commercialisation of the material and sensitive personal information that was being collected without the explicit informed consent of individuals . These cOpportunities in BiobankingLocal plaque proteins are a source for biomarkers with strong predictive value for future cardiovascular events.Atherosclerotic tissue banks with a longitudinal study design: Correlate cardiovascular outcome with the expression of activation markers and responsiveness of the circulating cells from patients with coronary artery atherosclerosis.The quest for novel biomarkers: Variations in single nucleotide polymorphisms (SNP\u2019s) are compared between patients with or without cardiovascular manifestations and will reveal novel causal pathways and identify potential new therapeutic targets.Genome Wide Association (GWA) studiesProgression has been made in detecting the so called vulnerable plaque.Some techniques already are at the precipice of translation to clinical practice.Novel imaging techniquesChallenges and pitfalls in BiobankingLarge online databases like OMIM\u00ae and Ingenuity\u00ae pathway analysis provide useful tools to find novel pathways.Deal with enormous datasets: Sampling, handling and storage can greatly influence the reproducibility and reliability of immunoassays. Attention towards trivial processes: Legislation concerning privacy issues and ownership: Unified worldwide legislation regarding privacy issues and ownership is needed.Registration of biobanksWorldwide obligatory registration of biobanking is necessaryThe third issue concerns registration. While it is obligatory for randomized clinical trials to register before starting, registration for biobanks is not mandatory. In 1999, the National Bioethics Advisory Commission of the US started an inventory about the amount of stored tissue in the United States, which resulted in the handbook of human tissue sources . This waIn conclusion, biobanking of human tissue and blood samples is a hot topic. Biobanks enable us to investigate the complex interplay between genetics, environmental factors and the pathophysiological features of multifactorial diseases. Important steps in the understanding of the pathophysiology of atherosclerosis have been made by observations from large cohorts of atherosclerotic specimens. Although the vulnerable plaque paradigm has some limitations, efforts have been made to develop novel imaging modalities to identify pre-cursor lesions and identify the vulnerable patient. On the other hand, the identification of the vulnerable patient continues with the assessment of multiple systemic biomarkers in the circulation in large scaled population studies. Until now, this identification process has not resulted in the golden bullet to identify the vulnerable patient. New opportunities in this field lie in the discovery of novel, more predictive biomarkers, in atherosclerotic tissue, but also in the more easy accessible circulation. Genome sequencing and genome-wide association studies will reveal more about the influence of genetics on atherosclerosis and hopefully will discover novel therapeutic targets. A lot of progress has been made in the development of novel imaging techniques to visualize unstable plaques and even some techniques are close to translation to the clinical practice. Pitfalls include trivial processes like handling and storage of patient material. Challenges lie in collaboration of biobanks and world-wide legislation and more important, registration of biobanks."} +{"text": "Environmental exposures in utero can increase risks for both childhood and adult cancers; their interactions with genetic and nutritional susceptibility factors may further increase risk. Thus, the early developmental period represents an important window for cancer prevention.Molecular Epidemiology was originally conceived as a preventive approach, providing a valuable tool for investigating risk factors for cancer in vulnerable populations. Biomarkers can be used as early indicators of risk for preventative purposes and risk assessment. The present contribution mainly refers to Thus, the early developmental period represents an important window for cancer prevention.Lorenzo Tomatis was an internationally recognized pioneer and leader in cancer prevention. The following remarks are made in honor of Lorenzo and his lifelong work. Molecular Epidemiology was conceived as a preventive approach, providing a valuable tool for investigating risk factors for cancer in vulnerable populations. Biomarkers can be used as early indicators of risk for preventative purposes and risk assessment. Humans are especially vulnerable during fetal development. Environmental exposures in utero.The fetus is generally at greater risk than the adult from toxic and carcinogenic environmental chemicals and other agents. A number of factors are involved: the high rates of absorption and retention of chemicals by the fetus, inability of the fetal liver to metabolize and detoxify toxins efficiently, the immaturity of fetal mechanisms of DNA repair and immune response, and the high rate of cell proliferation. In addition to directly damaging fetal cells and molecular/genetic targets, environmental chemicals can interfere with fetal development by disrupting the growth of the placenta and affecting the transplacental transfer of nutrients to the fetus. Thus, there is an increased likelihood that exposure to an environmental toxicant during the fetal period will result in procarcinogenic damage in the form of DNA adducts and mutation as well as epigenetic changes . Such prThe importance of the fetal period is underscored by the growing number of environmental exposures that are known or suspected of increasing risk of childhood and adult cancer when the exposure occurs during the fetal period. These include air pollutants, such as polycyclic aromatic hydrocarbons (PAHs), tobacco smoke, pesticides, solvents, and radiation -7. FetalOur studies at the Center for Children\u2019s Environmental Health (CCCEH) relating various biologic markers to air pollutant exposures have highlighted the susceptibility of the fetus. In the New York City -based \u201cMothers and Newborns Cohort Study\u201d, pregnant mothers wore personal air monitors to measure their exposure to PAHs during pregnancy . PAHs arin situ hybridization (FISH). High prenatal PAH exposure was associated with a higher frequency of stable chromosomal aberrations in cord blood . Interestingly, we also found that global DNA methylation levels in cord blood were positively correlated with levels of PAH-DNA adducts in cord blood; thus adducts do not appear to mediate or modify the inverse association between PAH exposure and DNA methylation levels. These results indicate that the fetal epigenome is vulnerable to PAH exposure and that epigenetic dysregulation in the developing fetus due to PAH exposure does not directly involve PAH-DNA adduct formation. The results are consistent with experimental evidence that PAH-DNA adducts form preferentially at methylated DNA sites and that DNA methylation may make DNA more reactive and, therefore, more vulnerable to genetic damage by PAHs and other chemicals .Regarding persistence of epigenetic changes due to prenatal exposure, comparison of methylation levels in cord blood and blood collected at age 3 from the same children showed that methylation levels did not vary significantly over time. This suggests that PAH-related epigenetic perturbations are relatively stable over this period and could contribute to a wide range of health effects throughout childhood and possibly later in life.One of the disadvantages of the studies described above is that we measured overall DNA methylation levels, not the methylation status of specific genes. We are now examining the effects of prenatal PAH exposure on DNA methylation of specific genes. In a pilot study, our colleagues at the University of Cincinnati and we identified genes with differential methylation levels in cord white blood cells between children with low prenatal PAH exposure and high prenatal PAH exposure . We are in utero exposure and biomarkers of potentially increased cancer risk, such as adducts and chromosomal aberrations. We have also found that prenatal PAH exposure affects epigenetic patterning by altering DNA methylation. Epigenetic alterations have been shown to play a role in cancer, and have also been found to be associated with a wide range of other diseases. Thus, increased fetal susceptibility to environmental contaminants can contribute to molecular alterations, quantifiable as biomarkers, which potentially increased risk of cancer and multiple diseases that may present across the life course. Measuring biomarkers associated with fetal exposure can therefore inform risk assessment and early intervention programs aimed at preventing cancer and other environmentally-related diseases.Our studies provide molecular and genetic evidence of widespread exposure to PAHs, increased fetal susceptibility, and links between The author declare no competing financial or non-financial interests."} +{"text": "To date, most studies of integrative health care (IHC) have focused on the experiences of patients and practitioners, often emphasising the tensions between CAM and biomedical cultures. Minimal research has investigated the perspectives of IHC managers. In response, this study explores the perspectives of seven IHC managers working in a diverse range of health care services in Australia, in which CAM has been incorporated as part of service delivery. The services comprised: five community-based programs including drug and alcohol rehabilitation, refugee mental health, women\u2019s health, and two hospital-based specialist services dealing with chronic conditions. The CAM practices included acupuncture, naturopathy, western herbal medicine and massage amongst others.Using in-depth interviews, this exploratory study examined the perceptions of clinical managers about the role of CAM in their services and the models and strategies employed for integrating CAM into clinical care. Key informant interviews were also conducted with a CAM academic, a CAM practitioner and a palliative care physician.Preliminary findings indicate that the managers perceive CAM as providing greater health care choice; help deliver \u2018more holistic\u2019 services; filling a therapeutic gap; enhancing quality of life; and providing clients with a \u2018point of entry\u2019 which enables them to access biomedical and psychological treatments.Preliminary findings from this qualitative study suggest a set of positive examples of integrative health care in which biomedical and CAM practitioners work collaboratively. Our findings also provide exemplars of health care contexts in which CAM and psychological therapies collaborate to provide innovative approaches for the treatment of trauma. Through the perspectives of managers in a range of different integrative clinical settings, this study is able to further our understandings about the practice of IHC."} +{"text": "Qualitative research methods are increasingly used within trials to address broader research questions than quantitative methods can address alone. Qualitative methods enable health professionals, service users and other stakeholders to contribute their views and experiences when evaluating health care treatments, interventions or policies. They can influence trial design, allowing for a fuller engagement with research questions, aims and objectives and clarify the complexities of people's social relationships, their experiences of healthcare and the context of clinical research.To develop a qualitative methods Standard Operating Procedure (SOP) which would allow the value and role of qualitative methods as part trials to be recognised, and appropriately incorporated within trials.Health researchers, including trialists, clinicians and qualitative researchers, worked collaboratively to develop a qualitative methods SOP for the West Wales Organisation for Rigorous Trials in Health (WWORTH).The Qualitative Methods SOP developed defines good practice in designing and implementing qualitative components of trials, presents the role of qualitative research while allowing flexibility in method and process. Its basic principles include: qualitative researchers should contribute from the commencement of trial with qualitative potential; the qualitative component should have clear aims and objectives; and the main study publication should report on the qualitative component alongside other aspects.We recommend that CTUs consider developing a qualitative methods SOP to enhance the conduct of qualitative trials including qualitative data collection, analysis and outputs. This could improve the value and visibility of the role of qualitative methods, in order to enhance clinical trials."} +{"text": "Application of SMS in reminders of medical appointments and delivering medical tests is not new, however its focus on clinical interventions has just begun. Usage of tailored SMS reminders to increase adherence in treatment programs among sick individuals has allowed an interventional role in self-care management of Diabetes Mellitus (DM). Respected Sir,Short Message Service (SMS) or Text messaging, is a communication feature among mobile, web or phone communication systems, allowing an exchange of short messages between mobile phones or fixed line devices. Its cost effectiveness and easy accessibility has made it one of the most widely used communication pathways in the world . The intApplication of SMS in reminders of medical appointments and delivering medical tests is not new, however its focus on clinical interventions has only recently begun . Usage oSelf-management of DM, especially type 1 Diabetes Mellitus, is important to avoid acute and long term complications .The rangMost interventions have shown positive outcomes but the evidence base of SMS based interventions is challenged by methodological limitations and is not yet conclusive. SMS education and cues to action may not be powerful enough to modify many ingrained behaviors. Future studies should use suitable sample sizes to provide greater statistical power for identifying theorized effects and should clearly report the calculations performed to estimate power . Report The authors declare they have no competing interests.TR thought of the topic. HR and SAH wrote the manuscript. DK and TR reviewed it and made edits. All authors read and approved the final manuscript."} +{"text": "Climate change is among the major challenges for health this century, and adaptation to manage adverse health outcomes will be unavoidable. The risks in Ontario \u2013 Canada\u2019s most populous province \u2013 include increasing temperatures, more frequent and intense extreme weather events, and alterations to precipitation regimes. Socio-economic-demographic patterns could magnify the implications climate change has for Ontario, including the presence of rapidly growing vulnerable populations, exacerbation of warming trends by heat-islands in large urban areas, and connectedness to global transportation networks. This study examines climate change adaptation in the public health sector in Ontario using information from interviews with government officials.Fifty-three semi-structured interviews were conducted, four with provincial and federal health officials and 49 with actors in public health and health relevant sectors at the municipal level. We identify adaptation efforts, barriers and opportunities for current and future intervention.Results indicate recognition that climate change will affect the health of Ontarians. Health officials are concerned about how a changing climate could exacerbate existing health issues or create new health burdens, specifically extreme heat (71%), severe weather (68%) and poor air-quality (57%). Adaptation is currently taking the form of mainstreaming climate change into existing public health programs. While adaptive progress has relied on local leadership, federal support, political will, and inter-agency efforts, a lack of resources constrains the sustainability of long-term adaptation programs and the acquisition of data necessary to support effective policies.This study provides a snapshot of climate change adaptation and needs in the public health sector in Ontario. Public health departments will need to capitalize on opportunities to integrate climate change into policies and programs, while higher levels of government must improve efforts to support local adaptation and provide the capacity through which local adaptation can succeed. Climate change has been identified as one of the major challenges for health this century . The ris\u00b7 Changing temperature and precipitation regimes will increase the probability and severity of extreme events including heatwaves, storms, floods, drought, and wildfires with implications for asthma, chronic respiratory disease, cardiovascular disease, and water quality and contamination -5.\u00b7 Warmer, wetter summers will affect the distribution and survival of pathogens and some disease vectors such as mosquitoes and ticks, , with imSalmonella and toxin producing organisms such as Staphylococcus aureus and Clostridium botulinum endorsement and support was important in gaining a community start [on climate change adaptation consortium], community awareness and perspective \"\"Public health programs are provincially mandated but locally designed and operated, such that climate change initiatives rely on support from senior managers and/or the Medical Officer of Health. Provincial health standards that address climate change explicitly are minimal. The shade policy in Toronto, for example, was endorsed in part because it contributed to municipal climate change mitigation and adaptation goals. Federal government agencies have provided financial and/or informational support for implementing and sustaining local adaptation projects. Examples of federal programs include piloting heat alert and response systems and the Air Quality Health Index (AQHI), vector borne disease programming (surveillance and monitoring) and tools to address climate change health risks:We were already engaged and knew we needed to do more \u2026 The funding became available to do something through Public Health Agency of Canada. [This] funding was a big impetus [for the surveillance and monitoring system]. It gave us the ability to move forward on a much larger scale - we wouldn't have had the funding to do that kind of work otherwise \"\"Adaptations in Ontario have capitalized on interdepartmental cooperation; municipal adaptation efforts include public health participation in discussions, brainstorming sessions and in developing adaptation plans. Climate change is integrated into official plans or strategies toward which public health departments provide input and implement programs that contribute to municipality wide goals. Such efforts have benefited from existing inter-departmental frameworks. Others have made use of the emergency management planning committees to mainstream climate change. Local leaders enable adaptation via organizing and chairing meetings and obtaining informational and financial support to sustain projects and create mechanisms to make the case for climate change adaptation in the community.The climate change collaborative at York University has helped us. I have been offered assistance from all the municipalities around us. It is nice to have that support, to have their knowledge, the research expertise available and to be able to connect with their resources. I also hope to work with the Alliance for Resilient Cities and the Clean Air Partnership even more. These groups and interactions provide perspective that I didn't otherwise have \"\"Expert judgment is considered important in the provision of knowledge for decision makers to prioritize adaptation activities, while conferences and workshops are helpful in identifying key concerns, sharing strategies and promoting and spreading awareness in the community.The vulnerability assessment workshops we organized [on extreme heat] were very helpful. The table top exercises were also very helpful. The continual workshops allowed issues to be raised over time. They were good venues because all stakeholders were there, and different and diverse groups were talking to one another \"\". Limited knowledge of how climate will change locally and the implications for health hinders urgency to implement plans and programs to prepare for the future. Currently, the resolution of climate change projection models is inadequate to inform adaptation at local scales. Knowledge of climate-related health outcomes, adaptation options and guidance are inadequate. Provincial health standards provide the framework for mainstreaming climate change into local programs; however, adaptation information per health vulnerability is lacking. Most notably, the \u2018creeping\u2019 nature of some climate change impacts brings uncertainty in knowing when water-borne or food borne outbreaks will occur, critical infrastructure will breakdown and/or when public health and emergency capacity will be inadequate to extreme events or disasters occurring in close succession. Health officials felt constrained by a lack of data and noted the need for more research. Furthermore, a lack of data or causal estimates of morbidity and mortality associated with environmental determinants or risks limit effective evidenced based programming. Public health officials noted inconsistencies in numbers of positive cases of West Nile Virus across communities, limiting predictability of human infection.Respondents noted that limited resources, lack of urgency and communication barriers constrained adaptation. Sustained efforts are limited by short-term funding and human resources. Long-term funding needed for hiring personnel and obtaining necessary resources for adaptation is an inherent challenge when adaptation is not mandated provincially and where urgency to adapt may not be shared from one municipal council to another. Officials noted that short political terms hinder achievement of long-term goals required for adaptation. Advocates of adaptation are concerned about competing interests and more immediate issues taking precedenceWe are supposed to anticipate health impacts from any potential health hazard and respond to it. Preparedness in terms of climate change for us means doing surveillance and putting plans in place in the event that something happens. We need to be confident with our plans. We need more environmental exposure data to guide our actions\u2026. One of our hardest challenges deals with linking environment with health outcomes. Our work needs to be evidenced based; however, it\u2019s difficult to associate respiratory outcomes with actual impact from poor air quality or linking water borne disease outbreaks with environment\u2026.. For climate change health risks that we don\u2019t have evidence for yet, the funding won\u2019t be there \"\"Effective messaging and communication of the health risks associated with climate change is a challenge. Inter-jurisdictional differences on use of triggers to inform alert and warning systems and conflicting messages to the public on extreme heat and smog days are significant issues. Difficulties exist in promoting public responses because climate change has not yet resonated in communities. Effective messaging is difficult in diverse communities and the public lacks a clear perception of personal risks and/or confuses concepts of adaptation and mitigation. Monitoring adequate responses of vulnerable groups is also challenging. Furthermore, health officials have voiced the need for standardized and evidenced based best practices for evaluating programs.There is no way of monitoring the success of our extreme weather program. We need an evaluation strategy - every year we question the validity of this. Nowadays, you have to have research-based evidence of effectiveness and climate related extreme events\"\"Table\u2009When asked to prioritize developments needed for adaptation, public health respondents indicated increased supporting roles by the provincial and federal government. Among 28 public health officials, 13 felt the Ontario public health standards were adequate in providing the framework to adapt to climate change; while 15 felt the standards could improve by including clearer guidelines for climate change adaptation. Many health officials felt they lacked information to comment on the adequacy of federal efforts to support local adaptation; while 6 (19%) believed federal efforts were adequate and 6 (19%) stated that they were not. Existing government support in the form of funding, adaptation toolkits and information on climate change planning was indicated as very helpful. Also, including \u2018climate change\u2019 in Ontario health standards has provided legitimacy to allocate funding to adaptation initiatives. Public health officials identified how higher levels of government could improve in supporting local adaptation. Of the 31 public health respondents, 14 stated the need for adaptation inventories, 10 mentioned increased funding for research and local adaptation efforts; 6 expressed the need for improved provincial environmental surveillance and monitoring systems, and improved guidance and protocols were mentioned by 4 respondents.We don\u2019t have the resources to do trial and error of what works and what doesn\u2019t. What we need is a one stop shop and easy at our fingertips best practices for making plans for these health hazard emergencies \"\"Many noted the \u201cHuman Health in a Changing Climate\u201d report produced by Health Canada as an imThe province needs a more rigorous review on what the most likely impacts of climate change are that have implications on public health in Ontario in next 50\u2009years and what needs to be done to respond to that and reduce those risks. ......I think providing evidence and best practices in the area of local climate change is certainly something we want to do here. \"\"This study provides a snapshot of climate change adaptation in the public health sector in Ontario and results will help inform future efforts to facilitate adaptation. Limitations of the study firstly include more focus on local public health authorities and less focus on officials in other sectors. Secondly, twenty-six health jurisdictions were excluded. Among the ten included, most interviewees represented central and especially southern regions; thus, experiences from northern communities are not adequately captured. Finally, the study does not address particular challenges of climate change adaptation where there are vulnerable groups. While these caveats are important, results enrich existing knowledge on climate change adaptation in the Ontario health sector and provide a basis from which to inform future action.Climate change is on the radar of health officials concerned about impacts exacerbating existing health issues and/or creating new ones. Notably, heat, extreme weather and poor-air quality are high concerns; though risk perception cannot be generalized across Ontario as most respondents represented southern Ontario jurisdictions. Health officials acknowledge their unique role in climate change adaptation; this experience will need to be drawn upon to meet the challenges posed by climate change . AdaptatCurrently, there is difficulty in operationalizing existing standards on climate change. Ontario health departments seek ways to mainstream climate change but are constrained by limited resources and guidance. Specifically, health units are required to increase public awareness on health hazards associated with climate change; but information on climate-related health burdens is limited and existing mechanisms to promote awareness may be ineffective. Promoting awareness, although critical, will be insufficient to prevent climate change risks to human health. Public health activities will contribute to reducing climate related health risks, but capacity needs to be assessed iteratively via evaluations and research as effecClimate change may be best managed in health departments via an adaptation strategy that could guide planning and implementation, streamline efforts across the health department, and inform the need for resources and staff training to prepare effectively for climate change. In Ontario health departments, climate change considerations are limited to specific health hazards per health department; there is a need for climate change to be integrated across the wider range of environmental health and chronic disease prevention areas. This is because climate change may create public health risks that health departments and partners lack experience in managing. Local stakeholders need to plan for potential impacts based on knowledge of how climate change will affect the region and design programs accordingly. Furthermore, an adaptation strategy could help to raise awareness among managers and promote the integration of a climate change perspective into risk assessments . ConsideThis study suggests that public health adaptation requires higher levels of government effort, particularly provincial public health policies on climate change adaptation and the continued support from federal departments and agencies. The province needs to undertake a comprehensive climate change vulnerability assessment in the health sector to inform research and policy gaps. Provincial public health agencies need to adopt anticipatory adaptation strategies by investing in climate change research to inform effective policies on local public health adaptation efforts and ensure that climate change is integrated into health risk management. There is a need for higher resolution climate projection models, improved and standardized surveillance, and monitoring and early warning systems to manage climate related health risks. Ontario public health departments would benefit from a research center aimed at advancing environmental health surveillance and warning systems, to support local research pilot projects, epidemiological studies and to establish long-term monitoring systems to track climate change driven health outcomes and program and policy effectiveness to reduce those risks. Health department adaptation resources will be required for enhancing programs and will need to come from higher government sources. The province already supports the development of risk management tools to manage heat related risks and works closely with public health units to raise awareness of health hazards associated with Lyme disease . FurtherSustained funding is also needed to support policies for all climate change health vulnerabilities. Federally funded and locally targeted adaptation programs should be continued as their support has greatly contributed to advancing adaptation at the local level. Federal level efforts should continue to assist in the development of surveillance and monitoring tools, adaptation best practices and downscaling climate change models in order to be used in practice at regional or municipal levels. Ontario health officials need evidence concerning whether existing efforts are effective and standardized best practices for climate change health risk prevention and responses. Ontario officials have indicated that awareness raising and education are key roles for public health departments on adapting to climate change. The call for more effective risk communication for heat warning systems to prevent heat related deaths ,42 has bNo author had any financial conflict of interest. No author was or is employed in the Ontario Public Health sector. At the time of researching, writing and submitting the manuscript, Jaclyn Paterson was employed at McGill University; at the time of publication, she was employed at Health Canada. Peter Berry was an employee at Health Canada during the full duration of the project.JP took the lead in conceptualizing and designing the study, conducted interviews, performed literature searches, and analyzed and interpreted data. JF, LB, JH, JH and AL made substantial contributions to the study design, interpreting data and critically drafting and revising the final manuscript. PB contributed substantially to the study design and in critically drafting and revising manuscript versions. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/12/452/prepubBMC Public Health Additional files- Adaptation to Climate Change in the Ontario Public Health Sector are available which summarize responsibilities pertinent to adaptation in health and health relevant sectors in Ontario. Note that electronic Additional files (word document), entitled: Click here for file Description of inclusion and exclusion criteria for selection of regional health jurisdiction.Click here for file Interview participants.Click here for file Information pertaining to regions included in interviews and the number of interviews per region.Click here for file Full survey instrument.Click here for file Codebook for identifying key themes in interview responses.Click here for file Additional representative quotes.Click here for file"} +{"text": "Dear SirEventration of diaphragm is a well known entity that may present at any age. Most of the cases are diagnosed in first decade of life. The usual clinical presentation is that of respiratory distress and recurrent respiratory tract infections; however unusual presentations have also been reported [1]. The objective of this report is to highlight a rare possibility of small bowel obstruction in settings of ineffective or incomplete separation of abdominal and thoracic cavities by diaphragm. A case of left sided eventration of diaphragm presenting with small bowel obstruction is being reported.A 6-month-old infant presented to our institution with complaints of abdominal distension, bilious vomiting, non passage of stool, and irritability for two days. The past medical history was insignificant. On general physical examination the patient was vitally stable. Abdominal examination revealed mildly distended and tender abdomen in all quadrants with absent bowel sounds. A digital rectal examination revealed only mucous in the rectum. Laboratory investigations were within normal limits. Abdominal radiographs, in supine and erect postures, delineated intestinal air shadows moving up into the left hemithorax and air fluid levels respectively . An exploratory laparotomy was performed that revealed few loops of small and large bowel adherent with each other and also with the eventration, causing small bowel obstruction at the level of distal ileum. Adhesiolysis relieved the obstruction following which plication of the diaphragm was performed. Ladd\u2019s procedure was added for the associated malrotation. Patient had an uneventful postoperative recovery. He has a follow up of 6 months and doing well.Eventration of diaphragm is an abnormal elevation of the dome of diaphragm; usually unilateral and left sided, but isolated right sided and bilateral involvements have also been reported. The lesion may be congenital or acquired as to the etiology. Embryologically, a failure of myoblastic migration to diaphragm or of its innervation, during 7th week of gestation, results in a thin and hypoplastic diaphragm on the involved side [2].During the same period of development the physiologically herniated bowel start returning to the abdominal cavity. The eventration of diaphragm impairs the process of normal rotation and fixation as happens in case of congenital diaphragmatic hernia; thus resulting in association of malrotation as found in our case. Acquired eventration always develops due to phrenic nerve palsy in conditions such as obstructed labor, surgery (iatrogenic) etc .The treatment can be delayed in asymptomatic patients. At times patients with eventration of diaphragm may present with life threatening complications necessitating urgent surgical intervention. These conditions are acute gastric volvulus, severe respiratory distress, and intestinal obstruction. The management includes plication of the eventration and the management of the complications, as done in case reported here . It is assumed that the associated malrotation and malfixation of intestine caused recurrent episodes of partial intestinal volvulus and ischemia, resulting in inflammation and adhesions between intestinal loops and the diaphragm.Few cases of intestinal obstruction after spontaneous rupture of congenital eventration of diaphragm have been reported in literature; three cases of intestinal obstruction after plication of diaphragm have also been documented .Small bowel obstruction as a sole presentation of eventration of diaphragm in pediatric patients is a very rare event. The treating physician and surgeon must keep this possibility in mind.Source of Support: NilConflict of Interest: None declared"} +{"text": "Drosophila melanogaster is the model organism of choice: it boasts a relatively small brain, its sensory systems have been anatomically well characterized and it offers an extensive genetic toolbox for visualizing and altering its neural circuits. Despite these advantages however, comprehensive models of sensory processing in Drosophila are sparse, in particular due to the lack of methods for estimating spike-processing neural circuits in higher brain centers. The majority of existing neural circuit models and methods for their identification assume rate-based systems and admit both continuous sensory signals and multidimensional spike trains as input stimuli. We thus explicitly take into account the highly nonlinear nature of spike generation that has been shown to result in significant interactions between various stimulus features , 3] and and3] an"} +{"text": "Sound localization in the barn owl relies on the early processing of two binaural cues, ITD and ILD , that takes place in two parallel pathways in the auditory brainstem. Previous modeling studies fell into one of two classes, either they used biophysically plausible neural models on simplified binaural stimuli with artificially induced ITDs, or abstract cross-correlation models on realistic acoustical inputs. Here we present a functional spiking neural model of the ITD processing pathway of the barn owl, with a realistic virtual acoustic environment.The acoustical environment was reproduced by filtering natural sounds through measured Head-Related Transfer Functions (HRTFs) in the barn owl (Tyto Alba). Basilar membrane filtering was modeled with a bank of linear gammachirp filters and compression. Monaural neurons in the Nucleus Magnucellularis (NM) receive inputs from auditory nerve fibers and project axons to binaural neurons in the Nucleus Laminaris (NL), with various conduction delays, so that best delays depend on preferred frequency in accordance with measured distributions .Empirical findings show that the best tuning of NL neurons is invariant to level and ILD changes , which iThe azimuth is estimated from the activation pattern of NL neurons. We found that the model could accurately estimate the azimuth of a large set of natural sounds with various levels, and significant background noise. Furthermore, we studied the robustness of ITD estimation in our model to reflective environments. We believe this study is a first step towards the development of neural models of sound localization in ecological environments."} +{"text": "Candida albicans is a common component of human gut and oral microbiota that can sometimes cause infections (candidiasis), particularly in immunocompromised individuals. The effects of Candida overgrowth can vary from being relatively benign, as in oral or vaginal thrush, to manifesting as potentially life-threatening systemic infections. There are considerable gaps in the current understanding of host-pathogen interactions underlying candidiasis, in part due to the lack of suitable vertebrate models for intravital imaging. To address this, Robert Wheeler and colleagues have established a new zebrafish model for mucosal candidiasis. The group report that this in vivo model recapitulates several of the canonical features of mammalian candidiasis and displays gene expression patterns that confirm recent in vitro observations. Combined with the potential for noninvasive imaging, these findings indicate that zebrafish will complement existing models and provide new leverage for studying Candida infection. 1260Page"} +{"text": "Natural peptides of great number and diversity occur in all organisms from plants to microbes to man. Examples for such rich and yet largely untapped libraries of bioactive compounds are animal venom peptides, insect peptide hormones or plant defense peptides . Our goaAs proof-of-concept we have used a genome-mining approach or mass spectrometry and peptidomics to determine the occurrence and molecular structure of naturally-occurring peptides and have investigated their pharmacological profile on human oxytocin and vasopressin receptors, representative members of the GPCR family, as well as their anti-proliferative activity on cells of the human immune system. Circular plant peptides have been identified as potent immunosuppressive agents and promise great potential as templates for pharmaceutical applications due to their enormous stability and sequence diversity . On the Unlike small molecules, peptides are just at the beginning as potential drug sources and still face a range of significant drug development challenges including efficient drug delivery, oral bioavailability and central penetration. Nevertheless, the ease of synthesis, the vast natural abundance of bioactive peptides and their immense pharmacological potential are so convincing that it is just a question of time until peptides can be utilized as orall bioavailable or even CNS-penetrating drugs together with an efficient delivery platform preserving their selectivity and interaction with extracellular targets, yet simultaneously retaining stability to enzymatic degradation."} +{"text": "Results suggest that, as the myoepithelium gains mesenchymal characteristics, a decrease in p63 and \u03b1-SMA molecule expression and increase in versican expression occurs. In addition, the direct relation between versican and invasion suggests the role of this molecule in tumor progression. In CBMT were also investigated morphological aspects and their immunophenotypical profiles, through an immunohistochemical panel based on five molecular markers . It was concluded that CBMT are predominantly characterized as low-grade malignancy neoplasms. The various immunophenotypic profiles suggest the origin of these lesions in more than one cell type . Invasive micropapillary carcinoma (IMPCa) of the mammary gland was first described by our group and should be highlighted. Despite its rare occurrence in humans and dogs, it has a distinct aggressive behaviour and poor prognosis. Were evaluated clinicopathological and immunophenotypical characteristics as well as the overall survival of canine IMPCa. Findings demonstrate that canine IMPCas are similar to human IMPCas, presenting aggressive behaviour with high rates of metastasis to regional lymph nodes and short overall survival and should be considered important lesions of the mammary gland in dogs. The distribution and intensity of lymphocytic responses in canine mammary tumors, in particular the relative abundance of the lymphocyte subpopulations which define whether the inflammatory process will act as a promoter or inhibitor of tumor development and metastasis were analyzed. Morphologic and immunohistochemical studies should be related with clinical aspects and serve as prognostics and predictive markers. Then patients suffering from mammary tumors with advanced clinical staging were studied. Analyzing the overall survival of animals treated only with surgery compared to those complementarily treated with carboplatin and Cox-2 inhibitors, the benefit of these patients from complementary therapy was verified. Carboplatin as an only drug was indicated for treating mammary tumors of female dogs in advanced clinical staging, with minimal side effects and easy administration. Limited therapeutic resources in mammary neoplasms of the female dog, the confirmed benefits of tamoxifen in human mammary tumors and insufficient data available on the canine specie justified a study that addressed additional effects of this drug in veterinary medicine. Side effects of oral administration of tamoxifen in spayed and intact female dogs were studied and were verified similar side effects to those observed in women with breast cancer treated with this medication. It was investigated the potential prognostic value of serum tumors markers and increased CA15.3 and LDH serum levels were directly related to the presence of regional lymph node and distant metastases. CEA showed no significant change among the groups . Thus, we suggest the possibility of using the criteria and the more extensive experience of human studies for the diagnosis and, in the future, treatment, of canine mammary gland tumors. On the other hand, these results reinforce the theory that spontaneous canine mammary tumors may be used as models for studies evaluating the mechanisms involved in mammary gland carcinogenesis, development of novel cancer therapeutics and may be relevant for human breast cancer studies.Mammary tumors are the most frequent neoplastic processes of the female dog and represent a problem of large impact in veterinary medicine. In this context, many efforts are being directed towards adopting criteria towards standardization of the diagnosis, understanding behavior and tumor evolution and evaluating prognostic and predictive factors such as: morphology, oncogenes expression and genetic alterations. The knowledge and adoption of these parameters are fundamentally important for choice and success of therapies that promote reduction of tumoral recurrence and increase in global survival. In addition, mammary tumors of female dog present epidemiological, clinical, biological and genetic similarities with mammary neoplasms in women and are therefore considered important models in comparative studies. The aim of our group is to evaluate clinical, morphological and molecular aspects of canine mammary tumors in order to identify comparative aspects with human breast cancer. Canine mammary tumors using TNM staging, histological grade, mitotic count and veterinary and human classifications were compared and reviewed. Results demonstrate that mammary tumor types in human and dogs are similar, although the relative frequency of each tumor type is different. Using immunohistochemical methodology, was standardized a series of specific human antigen antibodies in canine tissue. The antibodies were selected based on their ability to classify tumor types and to provide prognostic and predictive information previously described in human breast cancer studies. Results show that the expression of most markers is similar in benign and malignant mammary tumors in both species. It was also evaluated the prognostic value of mitotic index and histological malignancy grade demonstrating a sound correlation between those methods and the prognostic factors like in human breast cancer studies. Studies with found the Her-2 expression to be positively associated with nuclear pleomorphism, histological grade and mitotic count. Positive association was found between nuclear pleomorphism and MIB-1 index. These results imply that some tumor biological and morphological characteristics are associated with canine mammary gland tumors as it has been seen in human breast cancer. Studying benign non-neoplastic lesions was verified that they are pathologically and immunophenotypically similar to those in the human breast. In our diagnostic routine, mixed tumours are the most common tumour types in the female canine mammary gland. These tumours exhibit a complex histological pattern due to the presence of epithelial and mesenchymal elements and have the capacity to undergo malignant transformation, resulting in carcinomas. The origin of the several mixed tumour components is a subject of a long-standing controversy and is not yet fully understood. A suggested hypothesis states that these components originate from stem cells with a high divergence capability. This assumption is grounded on immunohistochemical studies and on the observation that the epithelial and mesenchymal components of mixed tumours are monoclonal. Carcinomas in benign mixed tumors (CBMT) are the most common malignant tumor in female dogs and may serve as a model for studies on tumor progression. Versican expression in There are no competing interests in this presentation."} +{"text": "Balanced networks of excitatory and inhibitory neurons are a popular paradigm to describe the ground state of cortical activity. Although such networks can assume a state of asynchronous and irregular activity with low firing rates and low pairwise correlations, recurrent connectivity inevitably induces correlations between spike trains . To elucIn the present study we show that this framework can be applied to approximate dynamics of networks of integrate-and-fire neurons, if the reset after each spike is formally described as self-inhibition. The reset then effectively decreases overall correlations. We study ring networks, where we are able to derive analytical expressions for the distance dependence of correlations and fluctuations in population activity. Rates and correlations in simulated networks are predicted accurately, provided that spike train correlations are reasonably small and the linear impulse response of single neurons is known."} +{"text": "In vitro and in vivo experiments including stem cells or cancer stem cells are performed at an increasing rate, producing a wealth of exciting and sometimes unexpected, even puzzling data. Intuitive speculation about underlying biological mechanisms often prevails as experimental fishing expeditions are costly and time consuming. Based on first principles of cell kinetics without assumptions about the emerging population dynamics, quantitative mathematical and computational models are emerging as invaluable tools to correlate and rank the likelihood of cell-level hypotheses with population level endpoints. To fully utilize the power of quantitative models, experimental and modeling approaches must be integrated and iteratively inform and validate each other.in vivo data thereby suggesting self-renewal as the primary mechanism behind pubertal stem cell increase. To better evaluate this mechanism, Tang et al. conducted in vitro studies on human breast cells and confirmed that cells must extensively proliferate to observe a self-renewal dependent increases in stem and progenitor cell numbers. Taken together, the iterative integration of ABM and in vitro/in vivo experiments revealed that single-cell kinetics and population level dynamics of mammary duct development render pubertal women susceptible to radiation-induced increase in mammary stem cells, which significantly increases the risk of developing aggressive breast cancer later in life (I read with great interest the article by Tang et al. and prai in life .The predictive power of quantitative models lies in the biologically informed formalization of interacting mechanisms. The rates at which these mechanisms occur, however, are encoded in model parameters, demanding a quest for parameter combinations that best match experimental data. The simple model by Tang et al. has 10 parameters. If for each parameter nine different values are considered, then the combination of all possible parameters yields one billion different versions of a stochastic model for a single experimental condition. Exploration of this parameter space is experimentally unfeasible but computationally tractable. ABMs can be subjected to brute force parameter sweeps or genetic algorithms on supercomputer clusters to identify parameters and thus mechanisms that are essential and mechanisms that are unlikely to contribute to specific observations. These invaluable insights into systems dynamics enable targeted biological experimentation and validation.in vitro and in vivo experimentation and accelerate the development toward clinical trials.While Tang et al. excellently dissect individual mechanisms that may underlie pubertal stem cell enrichment after irradiation, combinations of different mechanisms and their additive or potentially synergistic responses are neglected. The low doses of irradiation do not induce significant cell kill or cytostasis; rather they appear to initiate a milieu of activated cytokines and growth factors that prompt a transient local and systemic response permissive of stem cell activation comparable to inflammation or wound healing . While uIntegration of experimental and computational approaches is echoed in numerous integrated departments that arise throughout the academic and industry landscape, as well as federal funding programs that require the marriage of quantitative and experimental sciences to synergistically advance the life sciences. Stem cell biology, a rapidly growing field with tremendous attention and promises including novel cancer care, will greatly benefit from the inclusion of mathematics, engineering, physics, and computer science. An integrated dialog and cross-education should be encouraged if not mandated to fully unveil stem cell kinetics."} +{"text": "Very few principles have been unraveled that explain the relationship between soil properties and soil biota across large spatial scales and different land-use types. Here, we seek these general relationships using data from 52 differently managed grassland and forest soils in three study regions spanning a latitudinal gradient in Germany. We hypothesize that, after extraction of variation that is explained by location and land-use type, soil properties still explain significant proportions of variation in the abundance and diversity of soil biota. If the relationships between predictors and soil organisms were analyzed individually for each predictor group, soil properties explained the highest amount of variation in soil biota abundance and diversity, followed by land-use type and sampling location. After extraction of variation that originated from location or land-use, abiotic soil properties explained significant amounts of variation in fungal, meso- and macrofauna, but not in yeast or bacterial biomass or diversity. Nitrate or nitrogen concentration and fungal biomass were positively related, but nitrate concentration was negatively related to the abundances of Collembola and mites and to the myriapod species richness across a range of forest and grassland soils. The species richness of earthworms was positively correlated with clay content of soils independent of sample location and land-use type. Our study indicates that after accounting for heterogeneity resulting from large scale differences among sampling locations and land-use types, soil properties still explain significant proportions of variation in fungal and soil fauna abundance or diversity. However, soil biota was also related to processes that act at larger spatial scales and bacteria or soil yeasts only showed weak relationships to soil properties. We therefore argue that more general relationships between soil properties and soil biota can only be derived from future studies that consider larger spatial scales and different land-use types. Very few principles are known that explain the relationship between soil properties and soil biota across large spatial scales and land-use types, as most studies have traditionally focused on small spatial scales Soil biota play an important role in many ecosystems by ensuring a number of functions such as decomposition and nutrient mineralization Here, to contribute to such an improved understanding, we performed a comprehensive sampling campaign in differently managed forest and grassland plots in three regions that span a latitudinal gradient of more than 500 km The sampling campaign took place in the framework of the \u201cbiodiversity exploratories project\u201d and full details of the design are given in At each sample location, soil was sampled from five points in a 20\u00d720 m area to obtain a composite sample for the analysis of abiotic soil properties . After r2 area using mustard solution as expellant 2 were sampled by collecting one soil core in grasslands and two soil cores in forests at each sampling location. Soil fauna in forest plots was sampled before the organic layer was removed and all soil cores were extracted using a modified heat extraction system The data on soil biota abundances, concentrations and biomasses include microorganisms , arbuscular mycorrhizal fungi (AMF), cultivable yeast fungi and free amino acids) and soil meso- and macrofauna in grasslands The observed relationships between abundances and diversities of soil biota and sampling locations or land-use types support previous studies. However, at least three patterns could be established that describe more general relationships between soil properties and abundance or diversity of soil biota across sampling locations and land-use types:The biomass of AMF was positively related to nitrate and nitrogen content in soils. Mosse and Phillips The abundance of mesofauna and myriapod species richness were negatively related to nitrate content in forest and grassland soils. Nitrogen deposition leads to higher nitrate and ammonium content in forest The species richness of earthworms was positively correlated with clay content of soils across sampling locations and land-use types. Many earthworm species benefit from high clay contents since they can digest the carbon and nitrogen resources stored in clay-rich aggregates Our study demonstrates that abundance and diversity patterns of fungi and soil fauna relate to soil properties in a general way. However, the weak relationship between soil properties and abundance patterns in bacteria or soil yeasts and diversity of yeasts and extracellular proteins over larger spatial scales should further caution extrapolation of results from small scale studies to larger spatial scales or different land-use types. We therefore emphasise that comprehensive field studies, in which soil biota and additional important soil properties Click here for additional data file."} +{"text": "Hypacrosaurus stebingeri . This finding extends our previous report of secondary cartilage in post-hatching specimens of the same dinosaur species. It provides the first information on the ontogeny of avian and dinosaurian secondary cartilages, and further stresses their developmental similarities. Secondary cartilage was found in an embryonic dentary within a tooth socket where it is hypothesized to have arisen due to mechanical stresses generated during tooth formation. Two patterns were discerned: secondary cartilage is more restricted in location in this Hypacrosaurus embryo, than it is in Hypacrosaurus post-hatchlings; secondary cartilage occurs at far more sites in bird embryos and nestlings than in Hypacrosaurus. This suggests an increase in the number of sites of secondary cartilage during the evolution of birds. We hypothesize that secondary cartilage provided advantages in the fine manipulation of food and was selected over other types of tissues/articulations during the evolution of the highly specialized avian beak from the jaws of their dinosaurian ancestors.The skull and jaws of extant birds possess secondary cartilage, a tissue that arises after bone formation during embryonic development at articulations, ligamentous and muscular insertions. Using histological analysis, we discovered secondary cartilage in a non-avian dinosaur embryo, From our analyses we propose that different patterns of the onset of secondary chondrogenesis exist in ornithischian and saurischian (avian) embryos, that these different patterns reflect different biomechanical conditions within avian and dinosaurian embryos that may be explained by the evolution of the highly specialized avian beak from the jaws of their dinosaurian ancestors.In a previous study ebingeri , MaiasauAll necessary permits were obtained for the described field studies. Permission for the collection of MOR 1038 was granted by the Montana Department of Natural Resources . The other MOR specimens were collected with land owner permission from private land (and therefore do not recquire any specific permit).Hypacrosaurus stebingeri, Maiasaura peeblesorum (Hadrosaurinae) and a Hadrosauridae indet. The Hypacrosaurus specimens MOR 559 come from a nesting ground located on Blacktail Creek, Glacier County and differs from the surrounding flattened osteocytes in the alveolar bone . A smallH. stebingeri and is calcified in part much later (by the 15th day) Hypacrosaurus eggs, with diameters between 18 and 22 cm Hypacrosaurus than for domestic chickens. Among birds, larger eggs correlate with longer incubation periods In chick embryos, SCs arise halfway through development , possesses much larger amount of SC than birds with other lifestyles Second, the increase in the number of sites of SC in the bird lineage could be linked to the evolution of the highly specialized avian beak. A factor responsible for this increase could be mainly mechanical, i.e., intermittent pressure and shear within the beak, increasing during evolution (and possibly different from the forces acting on the dinosaurian jaws). For example it is known that the black skimmer,"} +{"text": "The dentate gyrus represents a unique system for the study of interactions between neuronal development and experience. While this hippocampal subfield has been extensively investigated in relationship to the ongoing process of adult neurogenesis, the mnemonic contributions of mature granule neurons have remained enigmatic. Much of the rationale for focusing on newly generated neurons, as opposed to mature granule cells, rests on the greater excitability of immature neurons, which positions them to make a unique contribution to memory processing. On the other hand, the assertion that mature granule cells are either inactive, or very finely tuned to specific spatial configurations, is derived from electrophysiological recording experiments and measures of immediate early gene expression conducted under conditions that are not likely to evoke significant psychological or physiological stress. In this Opinion piece, we present the argument that mature dentate granule neurons are synaptically silent under low-stress conditions, but are recruited in far greater numbers under emotionally salient conditions due to their combined input from the amygdala and entorhinal cortex. Functional activation of the far more numerous mature granule cell population could potentially serve as an emotional tag linking spatial context with stressful experiences. The underlying mechanism for emotional tagging of spatial contexts likely involves signaling cascades implicated in neuronal development, such as the reelin signaling pathway. Alterations in reelin signaling among mature granule neurons could therefore determine their ability to disambiguate stressful and non-stressful contexts.Adult born neurons account for up to 10% of the entire granule cell population , and exhibit enhanced synaptic plasticity relative to mature granule neurons and hippocampus, as seen in cooperative induction of MAPK/ERK signaling components and immediate early genes in the hippocampus and amygdala following contextual fear conditioning and retrieval Maren, . TherefoThe glycoprotein reelin has been heavily implicated in a variety of stress-related neuropsychiatric conditions and is widely expressed among interneurons in the adult vertebrate brain (P\u00e9rez-Garc\u00eda et al., Reelin facilitates adult hippocampal neurogenesis by promoting the correct migration and orientation of newly born granule cells, but may also play a role in controlling synaptic plasticity among the mature granule cell population. A number of developmentally regulated signaling molecules such as cyclin-dependent kinase 5, Notch, and WNT have been implicated in the regulation of adult dentate granule cell neurogenesis, and many of these signaling pathways overlap with reelin. The challenge in understanding how these signaling pathways influence dentate circuitry is directly related to the developmental heterogeneity of dentate gyrus granule cells; it remains uncertain whether reelin, or any other neurodevelopmental signal, impacts dentate synaptic plasticity by influencing new neurons, mature neurons, or communication between new and mature neurons, and the likely outcome is that each of these scenarios will be upheld in different contexts. The extent to which a repeated experience evokes firing among distinct or overlapping ensembles of neurons at various stages of maturation may determine the fidelity and accuracy of contextual discrimination, in part by recruiting signaling pathways associated with neural development.While the dentate circuitry is most studied with respect to adult neurogenesis, the functional role of the mature granule cell population remains mysterious. Experiments addressing the contributions of the far more numerous populations of mature granule neurons would benefit from the inclusion of high- and low-stress conditions, in order to activate amygdalar projections to the dentate gyrus. Although there has been significant speculation that mature granule neurons are essentially \u201cretired,\u201d the possibility remains that they may have simply changed \u201ccareers,\u201d by refining their responses based on emotional arousal in addition to cognitive demands."} +{"text": "Emerging persistent organic pollutants (POPs) have widely aroused public concern in recent years. Polybrominated diphenyl ethers (PBDEs) and perfluorooctane sulfonyl fluoride/perfluorooctane sulfonic acid (POSF/PFOS) had been newly listed in Stockholm Convention in 2009, and short chain chlorinated paraffins (SCCPs) and hexabromocyclododecanes (HBCDs) were listed as candidate POPs. Bohai Sea is located in the arms of numbers of industrial cities, the semienclosed location of which makes it an ideal sink of emerging pollutants. In the present paper, latest contamination status of emerging POPs in Bohai Sea was reviewed. According to the literature data, Bohai Sea areas are not heavily contaminated by emerging POPs . Therefore, humans are not likely to be under serious risk of emerging POPs exposure through consuming seafood from Bohai Sea. However, the ubiquitous occurrence of emerging POPs in Bohai Sea region might indicate that more work should be done to expand the knowledge about potential risk of emerging POPs pollution. A dozen of organic pollutants, including eight types of organochlorine pesticides (OCPs), two types of industrial chemicals (polychlorinated biphenyls (PCBs) and hexachlorobenzene (HCB)), and two types of byproducts (polychlorinated dibenzo-p-dioxins (PCDD) and polychlorinated dibenzofurans (PCDF), have been restricted as \u201clegacy persistent organic pollutants (POPs)\u201d by the Stockholm Convention in 2001. Due to POPs' physical and chemical properties, they are (1) environmental persistent; (2) widely distributed throughout the environment; (3) accumulate through food chain including humans; 4) toxic to humans and wildlife [ toxic toChina is a big country in producing and using chemicals, and the pollution problem of legacy POPs has continuously attracted public attention. Candidate POPs, also called \u201cemerging POPs,\u201d have become a hotspot in the environmental research and management.Chinese Bohai Sea is located within the arms of Liaodong and Shandong Peninsula and is cSome emerging pollutants such as PBDEs, SCCPs, and PFCs have been proved to be global pollutants. They were not only found in industrial areas but were also detected in remote areas such as Polar Regions and Tibet Plateau. This review have summarized and analyzed monitoring data available of main emerging POPs in Bohai Sea from peer-reviewed papers. Though these pollutants were analyzed by different analytical methods in various environmental media, the contamination status of emerging POPs and relative levels among legacy POPs and emerging POPs still should be clarified.n, and those with high water solubility and/or polarity such as PFCs and HBCDs were analyzed by HPLC-MS [Emerging POPs usually exist at trace or ultratrace levels in environment; thus specific pretreatment and sensitive detection instrument are indispensable. According to the currently reported analytical methods for the most frequently studied emerging POPs, mass spectrometric detector was widely applied. Generally, chemicals with high volatility and thermal stability such as PBDEs and SCCPs were usually detected by GC-MS HPLC-MS .Sediment is viewed as an important sink of all the pollutants. Sediment contamination is essential in assessing the impact of human activities on aquatic systems. Pollutants which are released into water body will reach a dynamic balance between water phase and sediment. Besides, benthonic organisms such as mollusks can accumulate toxicants and introduce them to the food web from sediment and water phase; thus sediment plays a significant role in evaluating the overall environmental quality of an aquatic system.PBDEs were additive brominated flame retardants which have been widely used around the world. Wang et al. investigPFCs, especially PFOS and perfluorooctanoic acid (PFOA), have received considerable attention due to their persistence and ubiquitous existence in environment. Up to now, the information about PFCs distribution in the sediments from Bohai Sea is still limited, but several papers reported present PFCs distribution in waters and sediments of the rivers flowing to Bohai Sea. Chen et al. investigPolychlorinated naphthalenes (PCNs) and HBCDs have been proposed as candidate compounds to the Convention recently. However, there are only a few reports about the pollution status of these emerging POPs in Bohai Sea. Pan et al. analyzedvia biomagnifications through food chains. The toxicities of emerging organic pollutants were not clear at present stage, and the levels of these pollutants in biota especially in edible organisms should be carefully concerned. Aquatic organisms such as mollusks and fishes have been proved to be good pollutants and risk indicators. They can reflect the contamination level in their surrounding environment such as water and sediment and also can evaluate the health risk on humans who intake the pollutants through seafood consumption [POPs can accumulate in the biota due to their hydrophobic and lipophilic characteristics and finally expose high health risk on higher-trophic-level organisms including humans sumption .Wang et al. measuredThe presence of PFCs was reported in biota samples from Bohai Sea, while PFOS and PFOA were major PFCs in biota. Pan et al. first reMya arenaria, Mactra veneriformis, and oyster could be selected as potential bioindicators for investigating SCCPs contamination in the coastal region.Recently, not only the PFCs and PBDEs but also several other emerging POPs in mollusk samples from Bohai Sea were investigated. It included several types of BFCs and SCCPs. Zhu et al. analyzedThe pollution status of both legacy and emerging pollutants in the Bohai Sea area has been summarized in Figures Emerging POPs have aroused wide public concern in recent years. The present study reviewed the status and congener profiles of emerging organic pollutants in the Chinese Bohai Sea, which is surrounded by several metropolises. Surprisingly, the pollution levels of some kinds of emerging organic pollutants in organisms were comparable to some legacy POPs, although the former has been paid attention to recently. Besides, the emerging pollutants also exhibited ubiquitous existence in both abiotic and biotic media. Such results suggested that the emerging organic pollutants in Bohai Sea should arouse our attention. Moreover, some of these pollutants are bioaccumulative and biomagnified through food web and finally can expose high risk to human beings. Though the data in"} +{"text": "Glaucoma is a group of heterogeneous disorders involving progressive optic neuropathy that can culminate into visual impairment and irreversible blindness. Effective therapeutic interventions must address underlying vulnerability of retinal ganglion cells (RGCs) to degeneration in conjunction with correcting other associated risk factors (such as elevated intraocular pressure). However, realization of therapeutic outcomes is heavily dependent on suitable delivery system that can overcome myriads of anatomical and physiological barriers to intraocular drug delivery. Development of clinically viable sustained release systems in glaucoma is a widely recognized unmet need. In this regard, implantable delivery systems may relieve the burden of chronic drug administration while potentially ensuring high intraocular drug bioavailability. Presently there are no FDA-approved implantable drug delivery devices for glaucoma even though there are several ongoing clinical studies. The paper critically assessed the prospects of polymeric implantable delivery systems in glaucoma while identifying factors that can dictate (a) patient tolerability and acceptance, (b) drug stability and drug release profiles, (c) therapeutic efficacy, and (d) toxicity and biocompatibility. The information gathered could be useful in future research and development efforts on implantable delivery systems in glaucoma. The public health burdens from ocular diseases/disorders are enormous. It is estimated that about 9.1 million American adults have one of the major retinal degenerations such as diabetic retinopathy, glaucoma, and macular degeneration. While the annual cost of adult vision problems in the US is approximately $51.4 billion including the direct medical cost, loss of productivity and other costs to caregivers and healthcare payers .The realization of therapeutic outcomes in ocular diseases/disorders is dependent on the ability to effectively deliver effective doses of the drugs/therapeutic agents at site of action for the intended duration of treatment. Meanwhile, the eye is a very unique vital organ that is poorly accessible to drugs/therapeutics following systemic or local administration. It is reported that only less than 5% of topically administered drug enters the eye as a result of poor permeation and extensive drug loss do occur through various mechanisms such as lacrimation, tear dilution, and tear turnover , 4. AchiIn general, conventional drug delivery systems like eye drops, suspensions, and ointments are associated with poor drug penetration and are less likely to be effective in treating the posterior segment diseases of the eye . In mostGlaucoma is the leading cause of permanent blindness and visual impairment worldwide. It is widely recognized as a multifactorial and neurodegenerative disorder characterized by the progressive degeneration of the retinal ganglion cells (RGCs) that form the optic nerve , 10. EleIt is estimated that by the year 2020, about 80 million people worldwide will be affected and close to 11 million will be bilaterally blind because of the disease . It is eThe involvement of RGCs loss and degeneration of optic nerve fibers recently gained attention in the pathophysiology of glaucoma. As such, neuroprotective therapies that delay or prevent RGC loss are considered to be beneficial to preserve vision. The broad spectrum of neuroprotective intervention could include antioxidative, anticaspase, anti-inflammatory, and antiapoptotic effects. Examples of neuroprotective agents that have been investigated to restore neuronal degeneration in glaucoma include memantine, brimonidine, and neurotrophins such as ciliary neurotropic factor and nerve growth factor \u201318. Hare\u03b12-adrenergic agonist approved for glaucoma treatment to control IOP. In addition to its IOP lowering properties, many studies on preclinical models have illustrated the neuroprotective effect of brimonidine in protecting neurons from damage [Brimonidine is a m damage , 22, 23.m damage . These rm damage , 24. Neurotrophic factors have shown promise as potential drugs for treating neurodegenerative conditions since they are responsible for the growth and maintenance of neurons. Ji et al. evaluated the neuroprotective effect of ciliary neurotropic factor (CNTF) on RGCs in a rat glaucoma model. The investigators also studied the CNTF-mediated activation of Janus Kinase (JAK)/signal transducer and activation of transcription (JAK-STAT) signaling pathway to identify the potential correlation neuroprotection of RGCs by CNTF. While it is not known how the signaling pathway mediates the protection of RGCs, it was reported that JAK-STAT signaling plays an important role in halting apoptotic neuronal death , 26. TheAnother neurotrophic factor that has been investigated in glaucoma treatment is the nerve growth factor (NGF). Topical administration of NGF in patients with severe retinal dysfunction showed promising improvement after 3 consecutive months of treatment . The stuIn general, deprivation of neurotrophins in glaucomatous optic nerve coupled with increase in vitreal glutamate concentrations have been implicated in RGCs loss. Thus, treatment paradigms that deliver neuroprotective agents to the eye will continue to hold great promise in managing glaucoma. Overall, it is not possible to draw definite conclusions on the safety and tolerability of neuroprotective agents from the studies conducted so far especially in chronic applications as required in glaucoma management. We are of the opinion that clinical viability of neuroprotective agents in glaucoma will require drug delivery systems that can achieve intraocular bioavailability while maintaining therapeutic drug levels at minimal dosing times.sustained delivery of drug (therapeutics) to the desired segment of the eye, ability to tailor drug delivery to the natural progression of the disease,achieve high ocular drug bioavailability,improve local drug activity while allaying concerns of systemic side effects or complications at the site of administration,drug administration should be noninvasive or minimally invasive without interfering with vision,drug delivery platforms should be safe and nontoxic while ensuring patient acceptance.Ideal qualities for glaucoma drug delivery systems include the following:Implantable delivery systems can potentially surmount the challenge of patient nonadherence to therapy while offering localized controlled drug delivery. There are a diverse range of biocompatible implantable devices which include nondegradable and biodegradable drug pellets, bioerodible scleral plugs, films and discs, and polymeric matrices in different shapes and sizes that aid delivery of drugs to the posterior eye segment , 29. TheThe key feature of implantable delivery systems that are fabricated from biodegradable polymers is that they do not require postapplication removal of implants after successfully delivering the loaded drugs/therapeutic agents. Also, biodegradability could connote potential biocompatibility in ocular tissues especially if the byproducts of degradation are safely eliminated. Biodegradable synthetic polymers such as polylactic acid (PLA), polyglycolic acid (PGA), and copolymer polylactic-co-glycolic acid (PLGA) are commonly studied. These polymers are well tolerated, biocompatible, and safe for clinical use with the possibility of modifying polymer degradation to occur over months to years. For instance, the degradation rate of PLGA is determined primarily by the ratio of lactide and glycolide monomers. Inclusion of high glycolide units will favor faster degradation. Other factors that will influence drug release kinetics from biodegradable implants are the molecular weight of the polymer and extent of crystallization. For instance, high crystalline nature and low degradation rates of PLGA containing high lactide units will support drug release predominantly by diffusion mechanism . There aCompared to PLA and PLGA, polyanhydrides degrade at faster rates by surface erosion. Polyanhydrides are amenable to several chemical modifications that can change the erosion properties and rate of degradation . Apart fA major challenge with most biodegradable systems is the difficulty of matching polymer mass loss to drug release. Erratic drug release and final burst release are common in cases with nonlinear erosion kinetics and usually characterized by a discontinuity of the matrix. There are reported cases that modification of the type and nature of monomeric units is effective in achieving and maintaining linear polymer erosion and drug release profiles , 48.There are a number of representative ocular biodegradable implants in the literature. For instance, Wang and coworkers studied the therapeutic efficacy of PLGA films loaded with ethacrynic acid (ECA) implanted into the sclera of rabbit eyes. The films were well tolerated in vivo, and IOP was significantly lowered and maintained for 10 days . The druFurther to the aforementioned studies on biodegradable ocular implants, there are number of clinically available ocular implants that may be adapted in developing intravitreal drug delivery platforms in glaucoma. A notable example is Ozurdex , which is a biodegradable rod-shaped dexamethasone implant approved by the FDA for intravitreal ocular implantation in the treatment of macular edema and uveitis affecting the posterior segment of the eye . A recenMany nonbiodegradable polymers have been applied in making implants that can provide long-term, controlled release of a variety of drugs/therapeutics. These include polyvinyl alcohol (PVA), ethylene vinyl acetate (EVA), and silicone \u201353. The We are of the opinion that a number of nonbiodegradable ocular devices that are approved for intravitreal drug delivery in other ocular diseases could be adapted in glaucoma management. These include (i) Vitrasert, an intravitreal implantable reservoir system by Bausch & Lomb , approved for cytomegalovirus (CMV) retinitis. The implant is composed of PVA-EVA for delivery of ganciclovir over a period of 5 to 8 months , 57; a nonbiodegradable implant has recently gained consideration for the delivery of protein therapeutics for up to a year to preserve vision cells. The implant encapsulates genetically engineered human retinal pigment epithelium (RPE) cells that secrete CNTF. The device is administered in the vitreous through a small incision in the sclera and secured at the implantation site by suturing through the titanium loop . The semNeurotech's device was initially designed for potential treatment of retinitis pigmentosa (RP) and age-related macular degeneration (AMD). A phase 1 clinical trial in ten participants with RP demonstrated that this device was safe and well tolerated during the 6 months implantation period . Also a Particulate drug delivery systems or injectable formulations such as microspheres, liposomes, and nanospheres/nanoparticles are other attractive alternatives used for extended drug release. The delivery platform involves entrapment of the drug within the nanocarrier matrix for subsequent intraocular delivery , 65. UpoAnother polymeric particulate delivery system that has currently been studied for ocular drug delivery is liposomes. Prabhu et al. developed and investigated liposomes of brimonidine tartrate for IOP lowering effects in glaucoma. The in vitro drug release showed constant delivery of therapeutics with linear release profile for extended time duration . Also thThe attraction with implantable drug delivery systems in ocular diseases/disorders could be attributed to many factors which include (1) intravitreal implantation would bypass the blood-retina barrier to enhance intraocular bioavailability; (2) sustained drug release will reduce the need for daily dosing which could improve patient adherence to treatment; (3) prolonged drug release will alleviate/minimize side effects associated with repeated intravitreal injection or systemic drug administration; and (4) effective drug delivery will avoid drug wastage while maximizing the efficacy of treatment. Despite the advantages of using implantable drug delivery system (DDS), there are a number of challenges as enumerated . Understanding the factors that influence polymer degradation and drug release will be important in achieving sustained ocular drug release. In this regard, the type of polymer (whether homopolymer or copolymer) and the molecular weight will play substantial roles in determining hydrophilicity and the rate of degradation. For example, the hydrophilic glycolide content in PLGA is a critical parameter in determining the matrix degradation kinetics and drug release rate. PLGA 50\u2009:\u200950 (PLA\u2009:\u2009PGA) exhibits a faster degradation rate compared to PLGA 75\u2009:\u200925 due to higher glycolic units. Similarly, PLGA 75\u2009:\u200925 shows faster degradation than PLGA 85\u2009:\u200915 . Hence pAnother important factor is the selection of therapeutic/drug molecule to match the type of implantable delivery systems. Studies using biodegradable polymers have shown that the chemical properties of drug can affect the rate of polymer degradation, rate of water absorption into the matrix, and drug release rate , 72. TheIn recent years, prostaglandin analogs are being considered over beta-blockers as effective topical agents for lowering IOP in glaucomatous conditions. The prostaglandin analogs are enzymatically cleaved and converted to their active form after they are delivered to the intended site . Ocular All ocular implants for sustained drug release must be free from potential health hazards. As such, sterilization is required to destroy or eliminate unwanted living microorganism contamination prior to implantation. Sterilization can be carried out by a number of methods such as aseptic method/manufacture, gamma irradiation, heating, and gassing with ethylene oxide , 74. It A major challenge in ocular drug delivery to the posterior segment is the multiple layers of protective blood-ocular barriers that limit drug access to intraocular tissues . As mostThe level of surgical procedure involved in securing the implant at the intended site will play an important role in defining the safety and acceptability of the device. Intraocular methods such as intravitreal administration involving direct injection through the pars plana is the direct delivery route to posterior eye segment because it provides high drug concentrations at the vitreous and minimizes adverse systemic effects . Due to The primary criterion of all is getting patients to tolerate the mode of administration of implantable delivery. Thus there is a growing need to investigate patient friendly delivery routes to eliminate discomfort and side effects resulting from the method of delivery to overcome the fundamental problem of patient adherence. More recently periocular pathways such as subconjunctival, peribulbar, retrobulbar, and subtenon routes are being considered for drug administration to the vitreous cavity by crossing the sclera, choroid, and RPE barriers , 78. TheThe size of the implants will play substantial roles in the feasibility of securing implants with minimal invasiveness during regular doctor's visits. Biodegradable devices with large surface areas tend to degrade faster than those with small surface areas, which may be due to the actual area of the implant in contact with ocular fluids . ReportsThe ability of implants to continuously release drug over extended period of time is crucial especially for glaucoma that requires chronic drug administration. It is highly desirable to avoid erratic drug release with potential implications in therapeutic effectiveness and toxicity. Over-all, biodegradable systems are more prone to nonlinear drug release kinetics and increased burst effects compared to nonbiodegradable systems . Also, bContinuous attempts are being made to minimize the burst effects and achieve linear drug release kinetics , 29. ForA viable approach to achieving desired drug release profiles is by modifying the polymer composition. For instance, some studies have demonstrated that combining two PLA monomers of high and low molecular weights resulted in biphasic release pattern and achieved pseudozero order kinetics comparable to nonbiodegradable systems , 48, 87.The classification of glaucoma as a neurodegenerative disease has presented the urgent need to develop strategies for drug delivery to the posterior segment. In a recent glaucoma clinical trial design and endpoints symposium, FDA emphasized the importance of structural parameters that involve optic disc and retinal nerve fiber layer (RNFL) changes in assessing clinical outcome of new glaucoma therapies . Since pConsidering that cases of glaucoma are estimated to increase in the coming years, it is important to tackle the challenges of drug delivery to the eye, as it is a complex organ that is difficult to access both topically and systemically. The fact is that most patients and clinicians will prefer less invasive methods of securing implantable delivery systems in the eye. We strongly believe that there are many factors to consider such as (i) placement of implants should be convenient and ensure less frequent drug administration; (ii) patients should be able tolerate implant placement; (iii) biomaterials used in implant preparation as well as byproducts from possible implant degradation should be safe, biocompatible, and easily eliminated; (iv) ocular drug release from implant should be predictable while avoiding the dangers of burst drug releases and dose dumping; and (v) implantable delivery systems should not compound patients medical conditions through elevation of IOP, interference with vision, and triggering inflammatory responses. We considered that a worthwhile approach of addressing these issues with predictable drug release profiles from implantable delivery systems might involve the application of stimuli-responsive (smart) strategies. Ocular implants that employ smart delivery systems can potentially offer great benefits over traditional systems since release of therapeutic agents can be controlled based on disease-specific or nondisease-specific stimuli . It is eGlaucoma is a group of multifactorial neurodegenerative diseases that collectively are the leading cause of irreversible blindness worldwide. The incidence is expected to increase remarkably in the next decade based on estimated growing aging population. Development of effective sustained intraocular drug delivery systems is a major unmet need in glaucoma management. The paper critically evaluated the rationale for implantable delivery systems as strategies of relieving the burden of protracted drug administration while maintaining high intraocular drug bioavailability. Major challenges of glaucoma-focused implantable ocular drug delivery were discussed while offering possible strategies on achieving and sustaining (i) therapeutic efficacy, (ii) desired therapeutic outcomes, and (iii) patient adherence and acceptance. It is considered that recent progress in the field of stimuli-responsive biomaterials could hold great promise in sustained drug delivery in glaucoma."} +{"text": "Dietary strategies may prevent childhood allergies and reduce the burden of disease. We undertook this systematic review to evaluate the relationship between maternal diet and childhood allergies.We included studies published up to August 2011 which compared a food-based maternal dietary intervention (intake during pregnancy &/or lactation) with another intervention or no intervention, as well as studies examining associations between maternal dietary intake during pregnancy &/or lactation and allergic outcomes in their children from the index pregnancy. Primary outcomes included child eczema, asthma, hayfever and sensitization . Studies assessing dietary supplements were not eligible for inclusion, nor were studies where dietary intakes were expressed only in terms of nutrients. Studies exclusively investigating maternal nut and peanut consumption during pregnancy &/or lactation were excluded.43 studies were included in this systematic review: 11 intervention studies, 27 prospective cohort studies, four retrospective cohort studies and one case-control study. In the RCTs no significant difference was noted overall in the prevalence of eczema and asthma in the offspring of women on diets free from common food allergens during pregnancy. One study (with multiple interventions) reported a lower rate of sensitisation in the intervention group at all ages followed up. Of the prospective cohorts only a few associations were reported between maternal dietary intake and development of allergy considering the overall number that were investigated. Of the results that were consistent, maternal dietary patterns were associated with less risk of allergic disease in offspring included \u2018Mediterranean\u2019 dietary patterns and diets rich in fruits and vegetables, fish and vitamin D containing foods. Foods associated with higher risk include vegetable oils and margarine, nuts and fast food. Studies differed in terms of the atopic potential of the participants and the final outcomes were not standardised in terms of age at follow up or diagnosis.The development of atopic disease is complex and multifactorial, depending on genetic potential along with many environmental influences. Maternal diet during pregnancy and lactation is one factor that may have the potential to influence the development of allergy in the child.None declared."} +{"text": "Suprascapular nerve and rotator cuff function are intimately connected. The incidence of suprascapular neuropathy has been increasing due to improved understanding of the disease entity and detection methods. The nerve dysfunction often results from a traction injury or compression, and a common cause is increased tension on the nerve from retracted rotator cuff tears. Suprascapular neuropathy should be considered as a diagnosis if patients exhibit posterosuperior shoulder pain, atrophy or weakness of supraspinatus and infraspinatus without rotator cuff tear, or massive rotator cuff with retraction. Magnetic resonance imaging and electromyography studies are indicated to evaluate the rotator cuff and function of the nerve. Fluoroscopically guided injections to the suprascapular notch can also be considered as a diagnostic option. Nonoperative treatment of suprascapular neuropathy can be successful, but in the recent decade there is increasing evidence espousing the success of surgical treatment, in particular arthroscopic suprascapular nerve decompression. There is often reliable improvement in shoulder pain, but muscle atrophy recovery is less predictable. More clinical data are needed to determine the role of rotator cuff repair and nerve decompression in the same setting. The suprascapular nerve provides sensory innervation to the posterosuperior aspect of the shoulder and motor innervation to supraspinatus and infraspinatus muscles. Dysfunction of the suprascapular nerve is intimately associated with rotator cuff pathology; nerve dysfunction can lead to cuff disease and vice versa. Suprascapular neuropathy is typically due to compression or traction of the nerve, and this can result in a spectrum of clinical symptoms, including pain in the posterosuperior aspects of the shoulder and weakness in forward flexion and external rotation. The various presentations of suprascapular neuropathy can make its diagnosis a challenge. Historically, suprascapular neuropathy has been viewed as a diagnosis of exclusion, but with recent advances, there is better understanding of both the etiology and treatment options, particularly relating to rotator cuff pathology.The suprascapular nerve arises from the upper trunk of the brachial plexus. It travels posterior to the clavicle and enters the suprascapular notch by passing beneath the transverse scapular ligament. The motor branches innervate the supraspinatus, and the nerve continues past the spinoglenoid notch and innervates the infraspinatus . Suprascapular neuropathy can result from traction injury or compression of the nerve at various points of its path. The most common cause of the neuropathy is due to traction injury on the nerve produced by a retracted superior or posterior rotator cuff tear. As supraspinatus and/or infraspinatus retract, there is increasing tension on the suprascapular nerve at the suprascapular notch or spinoglenoid notch . AlbrittVarious studies have shown that the tension in the rotator cuff muscle and tendon plays an important role in the health of the suprascapular nerve. Greiner et al. reported in cadavers that the maximum lateral advancement of a retracted rotator cuff tear is between 1 and 3\u2009cm; with increased advancement, the neurovascular pedicle is placed under heightened tension . Warner These are published reports that suggest suprascapular neuropathy associated with retracted rotator cuff tear may partially or completely resolve with repair of the rotator cuff. Mallon et al. reported two of four patients with suprascapular neuropathy and a massive retracted rotator cuff tear showed reinnervation potentials after partial arthroscopic rotator cuff repair . CostourBesides retracted rotator cuff tears, there can be other causes of suprascapular neuropathy. Repetitive overhead athletes have been reported to experience neuropathy secondary to traction and microtrauma \u201310. The Zehetgruber et al. published a meta-analysis reporting only 88 reports of this condition over a 42-year period . Other rPatients typically describe an insidious onset of dull, aching pain localized to posterosuperior aspect of the shoulder. Weakness and fatigue with overhead activities are common complaints. The physical finding of atrophy of the supraspinatus and/or infraspinatus fossa can be visualized on inspection. In long-standing cases, the teres minor muscle may compensate for the loss of the infraspinatus muscle and maintain nearly normal strength in external rotation . The strRadiographs are recommended to assess for fracture, callus formation around the nerve, bone tumor, and osseous dysplasia. Two additional dedicated views include the Stryker notch view which can show the suprascapular notch and the \u201csuprascapular notch view,\u201d with the beam directed 15 to 30 degrees cephalad, that allows for the evaluation of osseous variants. Magnetic resonance imaging (MRI) can evaluate the rotator cuff muscles and tendons, including fatty infiltration and atrophy Figure . It can The gold standard for diagnosis and confirmation of suprascapular nerve injury is electromyography (EMG) and nerve conduction velocity (NCV) studies. Indications for these studies should include (1) persistent posterosuperior shoulder pain without a diagnosis; (2) atrophy and/or weakness of the supraspinatus and/or infraspinatus with no evidence of a rotator cuff tear; (3) MRI demonstrating muscle edema suggestive of nerve injury; (4) massive rotator cuff tendons with retraction and traction on the nerve.Electrodiagnostic studies have normative values which have been established and published, but there is variability, and criteria for interpretation can vary between centers and practices , 33. TypFinally, a fluoroscopically guided injection of local anesthetic into the region of the suprascapular nerve may be useful to evaluate for pain relief in patients for whom the findings of these diagnostic studies are negative or equivocal and continue to have unexplained symptoms.If suprascapular neuropathy is diagnosed secondary to a labral tear with paralabral cyst or rotator cuff tear, the concomitant pathology may dictate the treatment. In the case of an isolated suprascapular neuropathy, nonoperative modalities can be attempted initially, including activity modification, nonsteroidal anti-inflammatory drugs, and physical therapy , 36. BlaIf an isolated suprascapular neuropathy (without concomitant pathology) has failed a course of conservative management, surgical intervention with suprascapular nerve decompression is offered \u201344. If tRelease of the transverse scapular ligament can be performed via either an open or arthroscopic technique. Generally, with open technique, few complications have been reported with most patients experiencing resolution of pain and improvement of muscle strength. However, reversal of muscle atrophy is not always observed. Kim et al. reported 90% of patients with profound muscle weakness showing improvement in supraspinatus muscle strength to grade 4 or better; however, improvement in infraspinatus muscle strength was less predictable. Additionally, eighty-eight percent of patients with severe pain reported improvement . AnotherThe technique of arthroscopic suprascapular nerve decompression has been described elsewhere , 48, 49.With growing body of published literature on suprascapular nerve and rotator cuff, there is better understanding of the relationship of the function and dysfunction of each. The incidence of suprascapular neuropathy may be on the rise due to improved recognition and diagnosis of this entity. In patients who exhibit vague posterosuperior shoulder pain, unexplained atrophy, and weakness of supraspinatus and infraspinatus, and in all patients with retracted rotator cuff tears, suprascapular neuropathy should be part of the differential diagnoses. MRI and EMG are indicated to evaluate the rotator cuff and the health of the nerve; fluoroscopically guided injections to the suprascapular notch can also be considered as a diagnostic option. Both open and arthroscopic suprascapular nerve decompressions have yielded good results. Additional high level studies are needed to examine the role of concomitant rotator cuff repair and nerve decompression in shoulder surgery."} +{"text": "Vancomycin-resistant enterococci (VRE) are increasing in prevalence at many institutions, especially among patients with co-morbidity conditions that associated with frequent hospitalisation. It is important to determine the risk factors for this resistance microorganism as it will guide the clinician for appropriate antimicrobial therapy and infection control measures.The descriptive, cross sectional study was carried out to determine the prevalence and risk factors for vancomycin resistant enterococci in Kuala Lumpur Hospital (HKL), Malaysia.For 12 months period, antimicrobial susceptibility testing for enterococci species were performed using disk diffusion method. E-test for vancomycin was proceed for the isolates that exhibit resistance to vancomycin by disk diffusion method. To identify the risk factors, a questionnaire was completed for all studied patients and the data were analysed using chi square and multivariate logistic regression.The prevalence of VRE among patients in Kuala Lumpur Hospital was 1%. In chi square analysis, vancomycin usage showed significance risk factor. In multivariate logistic regression analysis, prolonged hospitalization and vancomycin use were associated with potential VRE.The findings of this study will serve as an alert to the clinicians of the emergence of infections by VRE and it will encourage the implemention of appropriate infection control measures and judicious use of vancomycin in order to prevent further rise in VRE prevalence.None declared"} +{"text": "Egypt has low HIV prevalence (below 0\u221902%) among the general population, mostly attributed to the conservative culture. The 2010 second round biological/behavioral surveillance survey (Bio-BSS) conducted in some governorates revealed concentrated epidemic among male injecting drug users (IDUs).The current study aimed at exploring the perspective of IDUs regarding the HIV preventive efforts targeting them to provide relevant evidence based policy recommendations. The study included desk review, in-depth interviews with service providers and focus group discussions with IDUs of both sexes.The study described the current harm reduction interventions in Egypt and highlighted the insights of active IDUs and service providers interacting with them as regards their ability to address their needs and what they miss in these interventions and how IDUs perceive these interventions.The epidemiological reality of HIV infection in Egypt favors prioritizing efforts to the high risk groups rather than the general population. Hence, harm reduction should be at the core of interventions targeting HIV. The current study revealed that there is still a long way to go to enhance the role of these interventions in influencing a significant behavior change among target group. HIV has been documented among injecting drug users (IDUs) in at least half of the Middle East North Africa (MENA) countries and injeIDUs face the risks of HIV through sharing of contaminated needles and other drug paraphernalia, and engaging in unprotected sex sometimes occurring under the effect of or in exchange for drugs. Additionally, because of their legal status, IDUs are frequently put in prison, where clean needles are harder to find, thereby raising the threats. Several studies have documented relatively high levels of injection equipment reuse in MENA, such as the reuse of needles or syringes during last injection, last month, last six months, last year, or during lifetime. Levels of hepatitis C virus (HCV), a marker of using non sterile injecting equipment, are in the intermediate to high range, also confirming the potential for further HIV spread. FurtherHIV spread is not a question of law enforcement to prevent risky behavior; repressive measures will only complicate prevention efforts and push risky behavior further underground, making it even more difficult to reach these groups with programs. This would not change the vulnerability settings but would deprive MENA governments and their partners from the ability to prevent the epidemic and administer prevention interventions as needed. With thEgypt is a lower middle-income country situated at the heart of the Middle East and the north-east corner of Africa. Egypt has low HIV prevalence (below 0\u221902%) among the general population mostly aAccording to the United Nations Office on Drugs and Crime, drug abuse in Egypt is mainly a male problem between 20 and 30 years of age although female abusers are increasing and the main drugs of abuse in Egypt are Bango (cannabis herb) and hashish (Cannabis).Through sharing injection equipment, IDUs are also at particular risk for acquiring hepatitis C virus (HCV). In EgypThe current study aimed at exploring the perspective of IDUs regarding the HIV preventive efforts targeting them to provide relevant evidence based policy recommendations.The study included desk review of published and unpublished reports, in-depth interviews (IDIs) with key informants and focus group discussions (FGDs) with IDUs of both sexes who utilized the services of harm reduction interventions. The IDIs and FGDs were structured around the themes of current HIV interventions targeting IDUs, their ability to address their needs and what they miss in these interventions and how IDUs perceive these interventions.Key informants included 20 service providers affiliated to projects targeting IDUs and have been working in that field for at least one year at the time of the study. Five FGDs were conducted with 60 active IDUs who utilized the services of these interventions throughout the period March- May 2011 to gain their insight of these interventions. These active IDUs were approached at exit from the intervention sites where the study was explained to them and if they were interested they were asked to attend FGD meeting within one week at a non- governmental organization (NGOs) premises where discussions were conducted in a quiet confidential environment. The participants of FGDs were offered money equivalent to $5 to compensate for transportation costs. An informed oral consent was obtained from all research participants after explaining the purpose of the study, assuring voluntary participation in addition to asking permission to record the interviews. FGDs and IDIs were transcribed verbatim and transcripts were checked against the audio recordings for accuracy. Patterns in and across the discussions were coded thematically. Data saturation was reached with the data presented here. Analysis was done based on a grounded-theory. Collected data and transcripts did not have identifiers and were stored in a secure place with access only available to research team.Desk review and analysis of IDIs revealed that HIV prevention efforts in Egypt encompass public interventions for general population and recently adopted targeted interventions for high risk groups including IDUs. The public interventions mainly focused on awareness raising sessions targeting youth in schools, universities and youth centers all over Egypt, in addition to commemorating events as World AIDS Day Celebration. These public interventions are mainly implemented by governmental agency-Egypt National AIDS Program- in collaboration with international organizations and NGOs active in the field of HIV. Harm reduction interventions targeting IDUs were established in Egypt in 2008; they were funded by international organizations and implemented by NGOs with active linkages to high risk groups including IDUs, MSM and FSWs. When these interventions were conceptualized, IDUs were considered a safe entry point for the other high risk groups being the least stigmatized, former addicts were appointed as outreach workers being most familiar with congregations of IDUs and how to establish rapport with them and NGOs were selected as the implementing partner to avoid cultural sensitivities in explicit outreach efforts for stigmatized populations. The current interventions have limited outlets and are concentrated in Cairo and Alexandria mainly. The delivered services encompass outreaching IDUs by the former ones working as outreach staff, briefing them on the services delivered at the intervention sites and escorting or referring them to the service delivery sites. Harm reduction intervention model implemented in Egypt include the following services which are offered anonymously and free of charge; peer education on safe sex and safe injection, HIV voluntary counseling and testing using rapid test kits for fast delivery of results, medical services for those in need with special focus on management of sexually transmitted infections. In addition, the services include distribution of behavior change communication booklets and brochures, needles and condoms also free of charge. Active IDUs at FGDs stated that owing to Egypt conservative culture and the sensitivity of the drug use issue they feared disclosing their practice and asking for advice at the health facilities they were familiar with.\u201cWe had no place to go to and say we are addicts When we are ill, we do not tell the doctors we are addicts\u2026but I feel they know from marks on my arm and treat us with fear\u201d Male IDU.Though most supporting evidence of harm reduction interventions stem from studies in resource-rich countries or countries culturally different from Egypt conservative culture, yet harm reduction is supported by the two key tenets of Islam, Egypt prevalent religion, doing no harm to oneself or others and the worst harm is eliminated by a lesser harm.\u201cSome clients suspect the intentions of the services wondering why they would provide such services free of charge\u201d Female outreach worker.Competent outreach workers can bring prevention services to the hard-to-reach IDUs (who can serve as a safe entry point to FSWs and MSM who inject drugs)and help establish trust between them and other health and social services. Partici\u201cI felt I am at home speaking to my friends\u201d Female IDU.Low levels of needle-syringe programs (NSP) coverage may be sufficient to sustain an effective response to HIV prevention if clean injecting equipment is also available from other sources, such as pharmacies. Afforda\u201cIf I am caught with a syringe I will be imprisoned.\u201d Male IDU.Methadone is not distributed through current harm reduction interventions implemented in Egypt. IDIs with service providers revealed that opioid substitution is still an issue of debate among health professionals who believe that opioid substitution programs are not appropriate, feasible, or affordable for Egypt and can be diverted to illicit markets. Alternatively, they encourage immediate abstinence from drug use, rather than the gradual process that methadone substitution therapy entails; addicts are often given sedatives and painkillers to cope with withdrawal symptoms. However, research on the utility of drug dependence treatment as an HIV-prevention strategy has focused primarily on methadone maintenance treatment. In EgypWhen asked about what they miss in the harm reduction interventions, IDUs at FGDs stated that that the most prevalent and pressing health issue among themselves is HCV, and neither HCV diagnosis nor management is provided through current interventions.\u201cServices at the place are free and we pay a lot of money for HCV treatment\u2026can they be included?\u201d Male IDU.The similar modes of transmission of HIV and HCV present a unique opportunity to provide prevention services at a single client visit to the harm reduction service delivery points. Addressing the HCV needs of IDUs will increase their acceptability and buy in of HIV prevention services delivered at the same place and will probably improve their response to risk reduction interventions.\u201ca westernized agenda for legitimization of risky behaviors\u201d. Interviewed service providers added that when faced with such situation, they guide those who wish to quit to NA meetings. Most of the participants of FGDs are jobless and hence they recommended linking the harm reduction interventions to microfinance project or inclusion of vocational training and computer courses in the package of delivered services thus helping them to generate income and may motivate them to quit addiction. For most interviewed IDUs, poor and unemployed, getting high is their only escape from the hardships they face daily. Hence, assisting them in overcoming their daily challenge through provision of or linking harm reduction interventions to income generating activities will increase their acceptance and buy in of the delivered services.IDUs at FGDs also added that the currently delivered services do not support those who wish to quit addiction but are economically hindered. Some of them viewed this shortcoming as \u201cYouth escape to drugs because of unemployment.\u201d Female IDU.Most of the IDUs at FGDs were married mostly to addicts like themselves and have children. Some IDUs at FGDs revealed that under the effect of drugs, safe sex can never be guaranteed.Interventions to reduce the sexual risk behaviors of IDUs, including condom provision and improved access to sexual health services, have a modest impact on HIV transmission than those that reduce injecting risk behaviors. The 201\u201cWhen I am high, I do not know with whom I am sleeping so do not ask me about condom\u201d Male IDU.The epidemiological reality of HIV infection in Egypt favors prioritizing efforts to the high risk groups rather than the general population. Hence, harm reduction should be at the core of interventions targeting HIV, being the most direct and effective strategy to avert the tide of HIV through addressing the root causes of risks and vulnerabilities. However, the current study revealed that there is still a long way to go to enhance the role of these interventions in influencing a significant behavior change among target group.A structural weakness of the HIV response in MENA is the insufficient contribution of people living with HIV groups in the formulation, planning, and implementation of the response. Listening to IDUs and addressing their concerns and recommendations will scale up harm reduction interventions in Egypt and eventually enhance and sustain HIV prevention efforts. The below recommendations are meant to initiate a dialogue among stakeholders in Egypt and MENA region.\u2022 Strengthening NGOs given the epidemiological reality of HIV transmission being concentrated among largely hidden and stigmatized populations.\u2022 Expanding coverage and intensifying implementation of the harm reduction interventions.\u2022 Conducting research to assess the role of NA in empowering IDUs and enabling them to adopt safe behaviors or quit drug addiction.Bio-BSS: Biological/Behavioral surveillance survey; FGDs: Focus group discussions; HCV: Hepatitis C virus; IDIs: In-depth interviews; IDUs: Injecting drug users.The author declares that she has no competing interests."} +{"text": "Generation of action potentials (APs) is a crucial step in neuronal information processing. Existing biophysical models for AP generation almost universally assume that individual voltage-gated sodium channels operate statistically independently, and their avalanche-like opening that underlies AP generation is coordinated only through the transmembrane potential. However, biological ion channels of various types can exhibit strongly cooperative gating when clustered. Cooperative gating of sodium channels has been suggested to explain rapid onset dynamics and large threshold variability of APs in cortical neurons. It remains however unknown whether these characteristic properties of cortical APs can be reproduced if only a fraction of channels express cooperativity, and whether the presence of cooperative channels has an impact on encoding properties of neuronal populations. To address these questions we have constructed a conductance-based neuron model in which we continuously varied the size of a fraction Ion channels are integral membrane proteins which, depending on conformation, can pass ionic currents and thus induce dynamic changes in membrane potential Cooperative gating of ion channels has been proposed to represent a general capability of proteins to undergo conformational spread Prior theoretical analysis has demonstrated that the onset dynamics of AP generators critically affects coding abilities of spiking neurons Cooperative gating of It is known that inactivation of To implement this we made the kinetics of inactivation for the cooperative channel fraction dependent on the fraction of open channels. The simplest choice for this is We use this formalism to assess signatures of cooperativity in the activation of sodium channels, AP onset dynamics and encoding properties.To study the impact of channel cooperativity on AP onset dynamics, waveform shape and coding properties of neuronal populations we constructed a conductance based neuron model in which (i) a fraction Encoding properties of populations of neuron models were characterized using the established approaches of accessing frequency response function We first assume a Boltzmannian activation curve of a single channel with slope factor The steady state solution of The solutions of For stronger coupling Click here for additional data file."} +{"text": "Lipid formulations can improve the bioavailability of drugs that have low aqueous solubility. A variety of chemical compounds, including triglyceride oils (lipids), fatty acid esters and surfactants, can be included in lipid formulations. This heterogeneity makes spectroscopic study of the in ternal structure of formulation difficult. Understanding of lipid formulations at a molecular level will greatly improve our knowledge of in vivo dispersion and solubilisation patterns of lipid formulations.Molecular dynamics studies have provided useful insight into the structure and dynamics of different types of aggregates, including mixed glycerides with and without propylene glycol and bileSimulations are being performed using the molecular dynamics software suite GROMACS. Calculations are being performed on a high performance computing cluster at the Victorian Life Sciences Com putation Initiative (VLSCI). The methods highlighted in this study will prove to be an essential tool for formulators of lipid systems for oral administration."} +{"text": "Modern healthcare managers are faced with pressure to deliver effective, efficient services within the context of fixed budget constraints. Managers are required to make decisions regarding the skill mix of the workforce particularly when staffing new services. One measure used to identify numbers and mix of staff in healthcare settings is workforce ratio. The aim of this study was to identify workforce ratios in nine allied health professions and to identify whether these measures are useful for planning allied health workforce requirements.A systematic literature search using relevant MeSH headings of business, medical and allied health databases and relevant grey literature for the period 2000-2008 was undertaken.Twelve articles were identified which described the use of workforce ratios in allied health services. Only one of these was a staffing ratio linked to clinical outcomes. The most comprehensive measures were identified in rehabilitation medicine.The evidence for use of staffing ratios for allied health practitioners is scarce and lags behind the fields of nursing and medicine. Health care worldwide is a large and expensive industry for which there are high consumer expectations. As health care increasingly relies on expensive technologies and drugs, governments are under mounting pressure to find ways to contain costs. Managing staff costs has emerged as a major area of focus ,2. It haWhen introducing new services and reviewing current service delivery models, managers must make decisions on what constitutes appropriate levels of staffing. Different methods such as ratios; where staff are provided in a set ratio per measure such as bed numbers or population; and staffing according to patient acuity (for acute care services) are methods used in health care services for determining appropriate staff levels. While models of this type have been used successfully with nursing -13, and An Australian study ,16 revieThe aim of this review was to identify what workforce ratios have been used in nine allied health professions and to identify whether these measures would be useful for planning allied health workforce requirements.A systematic literature search was performed using medical, business and allied health databases to identify workplace ratios for nine identified allied health professions: audiology, dietetics and nutrition, exercise physiology, occupational therapy, podiatry, physiotherapy, psychology, social work, and speech pathology. It was anticipated few items would achieve level 1-3 evidence using recognised criteria . SimilarArticles were included if they were published between and including the years 2000-2008, were related to workplace ratios, were transferable to the Australian context (defined as being from a country meeting United Nations criteria for a developed economy ), and idhealth manpower or health care reform or health resources or health services research or government or personnel management or workload or workforce or time management or quality of health care. These were used in conjunction with the term allied health and the names of the nine target allied health professions: allied health or audiolog* or dietician or dietitian or nutritionist or exercise physiolog* or occupational therap* or podiatr* or physiotherap* or physical therap* or psychologist or social worker or speech patholog* or speech therap* or speech and language.Medical subject headings (MeSH) were identified and selected in consultation with a specialist librarian. The following search terms were used: The databases examined included: Medline, Cinahl, ABI/Inform, Apais Health, Business Source, Embase, Meditext, OT Seeker, Psychinfo, and Pedro. In addition, electronic searches were conducted of Australian Health Review, Cochrane Library Economic Evaluation Database, website of Public Health Research Unit for the United Kingdom National Health Service (NHS), and the Service Delivery and Organisation Programme of the National Institute for Health Research-a research institute associated with the NHS website for the Joanne Briggs Foundation.Requests were made to the professional bodies of the nine professional associations in Australia for any written documentation on workplace ratios and their web-sites were checked for published information. A reference group for the project included six of the nine professional groups and members were asked to search informal and grey literature (e.g. government reports and profession specific reports) relevant to their profession. Manual searching of reference lists of key articles and items recommended by informal professional contacts and peers produced three additional relevant references.The initial strategy produced 1207 titles which were screened by title and abstract for compliance with inclusion and exclusion criteria; 989 papers were excluded. Where abstracts were not available or content uncertain, the full text article was obtained. 218 abstracts or full text articles were imported into Endnote. A second more detailed review was conducted and inclusion and exclusion criteria were applied independently by the two authors (LJC and TAC) from which 30 relevant articles were extracted. Exclusions were reviewed together and disagreements resolved by discussion after viewing the full text article where necessary. A version of the CriSTAL checklist for evaluating the quality of various research designs ,20 was uPaper quality was determined by the presence or absence of study characteristics of: reliable data collection, adequate response rate, representativeness of participants, completeness of results, methodological limitations, and honest and objective conclusions.The literature review identified 12 papers where figures were given for the ratio of different AHPs to bed or patient numbers. Table Several papers demonstrated ratios by work setting rather than profession such as, adult rehabilitation -24 and eThe methods applied in developing the ratios were derived from four main approaches: consensus, experimental trial, current clinical practice and those developed using staff classifications.Consensus rather than observation or other means was used by six papers. Consensus came from working groups or committees. These papers presented standards , recommeRatios derived from experimental trial were found in one paper. A controlled trial studied Current clinical ratios were collected by survey by dieticians and psycFinally, staff classifications were used to develop a ratio system which is independent of patient characteristics . The staTable Within the Emergency Department area, for instance, it is difficult to compare the Princess Alexandra Hospital (PAH) figures with thoOf the five reports prepared by professional groups there are some similarities between the figures produced by the Allied Health in Rehabilitation group and thosThe Austin Hospital figures for physOnly one paper providedWhile one paper differenUse of staffing ratios to determine appropriate staff numbers can be a useful tool to guide service planning and delivery. This tool has been successfully used in nursing particularly in the acute care setting ,14. ThisAs the population ages and the incidence of chronic disease rises there will be increased demand for allied health services. Health managers and policy makers will need access to appropriate evidence based research to guide workforce planning to best meet community health needs. This review has found that research on staffing ratios for allied health practitioners is scarce and lags behind the fields of nursing and medicine. There is little data available on allied health requirements in general hospital settings such as orthopaedics and surgery and also in general community settings. This review highlights the need for further research on staffing ratios and their relationship to health outcomes across both hospital and community settings.The authors declare that they have no competing interests.LC conceived the research plan, undertook the systematic literature search and review and drafted the manuscript. TC conceived the research plan, undertook the systematic literature search and review and edited the final manuscript. MC, SA and LS contributed to the research plan and provided expert review and editing of the content. All authors approved the final manuscript."} +{"text": "Diabetes and osteoporosis are both frequent disorders. By chance they may thus occur together. However, evidence suggests that osteoporosis defined by bone scans (DXA) occurs more frequent than expected in type 1 diabetes (T1D) and less frequent than expected in T2D . This raWithin each of these fields, a number of questions need to be addressed. Are the measurements of biochemical markers of bone turnover reliable? One example could be if enzymatic or non-enzymatic modification of say collagen cross-links could infer with the accuracy of assays, thus measuring lower concentrations as not all of the degraded collagen is detected. Furthermore, many interactions between glucose and osteocalcin modify tThe change in biochemical markers happen rather rapidly and were in one study modified by somatostatin. The rapid changes raise novel questions as bone turnover usually is a rather slow process that takes more than hours to modify substantially. However, the interaction with somatostatin raises the possibility of an interaction from gut hormones and ghreThe field of biomechanical competence may call for novel imagining techniques and new methods to study crystal structure and biomechanical competence.The study of diabetes and bone thus not only relates to classical endocrinology and bone metabolism, but also opens new concepts of bone biomechanical competence beyond traditional DXA techniques and even beyond HrpQCT and beyond classical biochemical markers of bone turnover.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "PLoS Medicine series onMigration & Health, Brian Gushulak and Douglas MacPherson discuss thepre-departure phase of migration and the specific health risks and policy needsassociated with this phase.In the second article in a six-part The local conditions and environment at the place of origin of migrantsinfluences health during all phases of the migration process.Pre-departure health characteristics are important drivers in healthactivities directed at migrants, such as immigration medicalscreening.Some pre-departure health elements continue to affect migrant populationslong after their arrival at their destination.Improved understanding and management of pre-departure healthdeterminants will support the development and delivery ofmigrant-relevant health services.This is one article in a six-partPLoS Medicine series on Migration & Health.The flow of populations within and across international boundaries is an importantelement in today's globalized world. Recent estimates of migration patternsplace the combined numbers of international migrants and internal migrants at nearlya billion people In general, most migrants move to destination countries in the same region. A recentOrganisation for Economic Co-operation and Development (OECD) analysis involving 89reception countries The observation that one's origin, in terms of physical location and thedeterminants of health , influences one's current and future response to events is widelyappreciated across the spectrum of social and physical sciences Population mobility and migration are the result of a combination of\u201cpush\u201d and \u201cpull\u201d factors that are inter-related and oftenmutually dependent. Descriptions of these factors and examples are provided in These push and pull pressures are unequally distributed across pre-departure migrantpopulations, and together they both influence and affect migrant demography. Anillustration is provided by comparing rural to urban migration and internationalmigration from the same area. Rural to urban internal migration often represents themovement of workers, either with or without their families, from less affluent areasto metropolitan centers where jobs are perceived to be more plentiful. This broadpattern of migration has its own set of health issues and examples have beenobserved in several locations including child health in Africa, where death in thoseyounger than 5 years old was greater for children of rural\u2013urban migrantsReflecting the diversity of population mobility, not all the effects ofrural\u2013urban migration are negative. For example, some studies have notedreduced rates of cardiovascular disease in non-migrant rural populations in SouthAmerica compared to those in urban migrants in the same country Some migrants may be more vulnerable to adverse health outcomes. Refugees anddisplaced populations represent specific populations at risk Pre-departure health status affects both individual and population health outcomesHelicobacter pyloriNot all of the health concerns in migrants that are the consequences ofgeographically disparate disease epidemiology are related to infectious diseases.Health outcomes in migrants also include biological and inherited elements as wellas those associated with ethnicity and social and cultural practices, as reflectedin the selection of marriage partners Historically, there has been a tendency to consider only the adverse health risksrelated to migration, focusing on disease risks in migrant populations that weregreater than the host population. It is important to note, however, that theconsequential health outcomes for both the migrant and host population may bepositive, neutral, or negative.In several migration-receiving nations, cohorts of new arrivals often display healthcharacteristics that are better than that those of similar cohorts of the domesticpopulation. These observations are frequently related to lifestyle choices orchronic diseases but extend to other situations . Described as the \u201chealthy immigrant effect\u201d Historically, the pre-departure influences affecting the health of migrants wereapproached in terms of the potential risks migrants were believed to pose to thedomestic host population. Attempts to control the admission of epidemic diseasesgrew to include the medical screening of arriving migrants The nature, purpose, and type of migrant medical screening for exclusion varies bynation from none at all to very detailed, proscriptive programs Some nations with universal health insurance systems, such as Canada More recently, expanding the concept of immigration medical screening is beingconsidered in terms of screening not for exclusion on health grounds An additional pre-departure health element that exerts influence after amigrant's arrival is the approach to the use of health services. Models ofhealth care delivery differ across the globe. Examples include ayurvedic andtraditional Chinese medicine used by billions of individuals, which differs fromWestern allopathic medicine Migration health policies, when they exist, are frequently based on traditionalconsiderations of immigration/emigration. Those frameworks often categorize mobilepopulations of increasingly diverse origin into a limited number of administrativelydetermined immigrant categories. Health concerns in mobile populations have oftenbeen addressed in terms of traditional migrant classification . While those categories may reflect historicalmigration flows, they are often not representative of modern migrant diversity ordisparity, nor may they reflect the current reality of health differences relevantto receiving nations. An example is provided by the demographic, experiential, andpersonal differences present in current refugee populations. Depending on locationand national practice, a wealthy, educated political refugee originating in adeveloped metropolitan area who filed an asylum claim versus an economically andeducationally deprived laborer forced from his or her home into a refugee camp byconflict, could be administratively classified identically. Yet, their health statusand needs may be significantly different.Recommendations to consider health policies and programs for migrants in terms of thecountry of origin as a reference point rather than immigrant classification began inthe 1980s The repetitive, cyclic flow of migrants, such as migrant labor or migrants visitingfriends and relatives in their place of origin, can create specific healthchallenges that exceed the capacities of traditional programs developed foruni-directional migration. Nations sharing common borders frequently crossed bymigrants are developing joint projects to manage health issues in mobilepopulations. Examples include shared programs along the US\u2013Mexican border thatinvolve common health information systems and shared treatment and monitoringsystems The cumulative implications of the pre-departure health status of migrants ultimatelyextend to the delivery of patient care at the destination. Cultural competency andthe ability to deal with diversity are increasingly important aspects of health carein migrant-receiving locations The determinants of health present during the pre-departure phase of migration arecrucially important factors affecting the existing and future health outcomes ofmigrants and host populations. The effects of these factors extend throughout theremaining phases of the migratory process and apply at both the individual andpopulation level. Appreciating and dealing with these issues at operational andpolicy levels requires global focus, rapid and flexible response to change, andcurrent information on the composition and nature of the migrants themselves asopposed to traditional administrative migrant-classification- or disease-basedparadigms. Increasingly, the challenges of dealing with migrant health are beingaddressed through collaborating centers of reference and experience"} +{"text": "Sternula antillarum) (ILT) are colonial, fish-eating birds that breed within active channels of large sand bed rivers of the Great Plains and in the Lower Mississippi Valley. Multipurpose dams, irrigation structures, and engineered navigation systems have been present on these rivers for many decades. Despite severe alteration of channels and flow regimes, regulation era floods have remained effective at maintaining bare sandbar nesting habitat on many river segments and ILT populations have been stable or expanding since they were listed as endangered in 1985. We used ILT breeding colony locations from 2002 to 2012 and dispersal information to identify 16 populations and 48 subpopulations. More than 90% of ILT and >83% of river km with suitable nesting habitat occur within the two largest populations. However, replicate populations remain throughout the entire historical, geophysical, and ecological range of ILT. Rapid colonization of anthropogenic habitats in areas that were not historically occupied suggests metapopulation dynamics. The highest likelihood of demographic connectivity among ILT populations occurs across the Southern Plains and the Lower Mississippi River, which may be demographically connected with Least Tern populations on the Gulf Coast. Paired ecological and bird population models are needed to test whether previously articulated threats limit ILT population growth and to determine if management intervention is necessary and where. Given current knowledge, the largest sources of model uncertainty will be: (1) uncertainty in relationships between high flow events and subsequent sandbar characteristics and (2) uncertainty regarding the frequency of dispersal among population subunits. We recommend research strategies to reduce these uncertainties.Interior Least Terns ( Sternula antillarum) are colonial, fish-eating birds that nest on barren sandy substrates in open habitats on rivers and coasts the Johnson ,b; and or other features that provide high perches for avian predators or forest patches that may support mammalian predator communities USACE . SimilarLeast Terns also avoid portions of sandbars that are covered in low vegetation for additional analyses ESRI . FollowiWe defined ILT populations and subpopulations in ArcGIS 9.1 ESRI followinWe summarized the following characteristics for each of the populations and subpopulations identified in the analysis above: 1) the number of colony sites within each subpopulation (from a randomly chosen year among those with data available between 2002 and 2011); (2) the continuous linear extent of occupied habitat; (3) the median intercolony distance for all pairs of colonies within a subpopulation, arranged linearly along the channel; and (4) the maximum count between 2002 and 2011 as a percentage of the range-wide count of 17,571 adult ILT in 2005 Lott should be evaluated in the context of interactions between sandbar habitat dynamics and important ILT life history traits. For example, adult ILT have high annual survival rates and long reproductive lifespans , that no longer occupy large portions of their former ranges . However, the current range of ILT includes nearly all of the sand bed Rivers of the Great Plains and Lower Mississippi Valley that occurred prior to large-scale river modification. Despite range fragmentation by reservoirs, the two main habitat types that were historically present are still present and occupied by ILT. There are no historically known habitat types that may have been suitable for ILT that are not present and occupied today. Consequently, we believe that ILT populations are representative of their entire historic geographical, geophysical, and ecological range. This is in stark contrast to other endangered species, some of which have been delisted , the ability of ILT to renest up to three times in a single breeding season increases opportunities for successful reproduction after initial reproductive failure due to the challenges of creating unbiased population projection models for Least Terns (Akcakaya et al."} +{"text": "In the last few years, two paradigms underlying human evolution have crumbled. Modern humans have not totally replaced previous hominins without any admixture, and the expected signatures of adaptations to new environments are surprisingly lacking at the genomic level. Here we review current evidence about archaic admixture and lack of strong selective sweeps in humans. We underline the need to properly model differential admixture in various populations to correctly reconstruct past demography. We also stress the importance of taking into account the spatial dimension of human evolution, which proceeded by a series of range expansions that could have promoted both the introgression of archaic genes and background selection. Until recently, the out-of-Africa model of human evolution was favoured by most genetic analyses, but this model collapsed when the sequencing of the Neanderthal genome revealed that 1%\u20133% of the genome of Eurasians was of Neanderthal origin. At the same time, refined analyses of modern human genomic data In line with previous studies The finding of archaic admixture in Eurasia gives credit to previous statistical analyses, which have suggested the presence of archaic material in Eurasian and African populations OAS1. This deep lineage is found at high frequencies in Oceania (and at lower frequencies up to Pakistan). This DNA segment is more closely related (0.6 Mya divergence) to the Denisova sequence than to the Neanderthal sequence, which is itself closer to the human reference sequence. It has been speculated There is thus both direct OAS1 segment mentioned above dys44) gene, almost absent from Africa but with 9% average frequency outside Africa, has been proposed to be of Neanderthal origin Our understanding of the exact sequence and location of admixture events would highly benefit from a more precise knowledge of the nature and the distribution of Neanderthal segments in our genome. Unfortunately, current estimations of introgression levels are based on a statistic measuring a genome-wide difference in the proportion of archaic-derived alleles between two human populations It may nevertheless be valuable to identify further genomic regions of potential archaic origin. Previous candidate regions have been identified, as they showed a much larger time to the most recent common ancestor (TMRCA) in Eurasia than in Africa. This signal may, however, not be optimal, since if Neanderthals and modern humans diverged only 270\u2013440 Kya If human populations do not all have the same level of archaic introgression, the current genetic structure of human populations might be partly shaped by differential admixture. Estimates of population sizes and divergence times between human populations should thus be affected by past admixture events. The divergence time between an admixed and a non-admixed population should be overestimated if admixture is not properly modelled. Similarly, the effective size of admixed populations should be overestimated as archaic lineages inflate genetic diversity. In Most methods aiming at detecting recent episodes of selection in humans have been designed under the paradigm that adaptations were mainly driven by classical positive selection: beneficial alleles should go to fixation, strongly reducing diversity and increasing levels of linkage disequilibrium in the surrounding regions. Such selective sweeps would thus strongly affect various aspects of molecular diversity within and between populations e.g., . SeveralSTF) were not associated with large levels of linkage disequilibrium, suggesting that allele frequency shifts occurred long ago and not because of recent adaptive events Three recent observations have further shaken the paradigm of positive selection. First, it has been realized that regions showing high levels of differentiation between continents (high At a single locus, selection on standing variation A proper scenario of human evolution should explain both the current distribution of archaic introgression given the past distribution of archaic hominins and the likely migration routes of modern humans. Spatially explicit methods simultaneously modeling range expansions and interbreeding use observed levels of admixture to assess migration and demographic processes, and thus bring additional information on the biology of our species. Whereas the surfing of neutral polymorphism during range expansions has been shown to lead to molecular signatures similar to selective sweeps Scenarios of pulses of admixture do not provide any explanation for why interbreeding only occurred in some places and why archaic hominins disappeared in regions where no admixture took place. Contrastingly, scenarios of continuous admixture during range expansion explicitly posit that archaic hominins disappeared due to their interaction or competition The patterns and levels of archaic admixture in current Eurasians should be informative about modern humans' migration routes in Eurasia if they had hybridized with genetically distinct archaic populations or species. For instance, Europeans and Asians could show distinct components of Neanderthal admixture if they had admixed with European and central Asian Neanderthals Taking into account the fact that human populations went through recurrent range expansions could also help us understand the prevalence of background selection. It has indeed been shown that in addition to beneficial and neutral mutations, deleterious mutations could surf during range expansions and thus temporarily increase in frequency at the wave front As James F. Crow would have put it, in human evolution the questions have remained the same but the answers have changed. Genomics has revealed that the genome of Eurasians is partly of archaic origin, and genome-wide patterns of diversity have not revealed expected signals of adaptive selection in humans. The sequencing of additional archaic hominins should be helpful to distinguish between alternative scenarios of admixture, infer the timing and the geographic location of admixture events, and assess human migration routes over Eurasia. Archaic admixture can also seriously impact estimated human demography, which should be revisited to account for differential introgression among human populations. Scenarios of human evolution need to be geographically coherent and integrate range expansions during which deleterious mutations can readily surf and accumulate on wave fronts, giving later fuel to background selection. Whereas our view of human evolution has drastically changed over the past few years, it would be pretentious to believe we now know the true history of modern humans and that we have identified all selective forces that have shaped the diversity of our genome. However, progress in the analysis of modern and ancient genomes is likely to soon provide the data that will allow us to test complex scenarios of human evolution and contrast the role of various selective forces that are currently or were acting in our genome."} +{"text": "Rust fungi are often isolated in air samples collected from storage areas, however,their role in allergy is not investigated so far. Thus this study was designed to find out anypossible role of rust fungi in human allergy.Aspergillus sp., Rhizopus sp., Penicillium sp., Mucor sp. and along with them one variety of Rust fungi of plants was also repeatedly isolated. Formaldehyde based fungal suspensions were prepared from all the cultured fungi, workers' blood samples were collected and serums were separated. Then serum samples were teated with the formalin suspensions of the isolated fungi in the form of slide agglutination tests. Serum total IgE levels of all collected blood samples were also measured by ELISA test method.Air samples were collected during loading/unloading of stored food grains in a godown with the help of Rotorod sampler, UK on petroleum jelly coated tape at 2900 rpm for 30 minutes, the tapes were then directly inoculated on Sabouraud\u2019s dextrose media for isolation of fungi by imprint smear. Most of the collected samples yield It was found that the isolated Rust fungus of plants gave positive agglutination tests with almost all collected serum sampleswhile agglutination reactions with the other isolated fungi were much less. The reactions of the isolated Rust fungi were violent with serums showing high IgE levels. Serum IgE levels were also very high in many of the workers.This study indicates that Rust fungi of plants have got a role in human allergy and details regarding this should be explored for the benefit of the mankind."} +{"text": "This paper briefly reviews the role of central command in the neural control of the circulation during exercise. While defined as a feedfoward component of the cardiovascular control system, central command is also associated with perception of effort or effort sense. The specific factors influencing perception of effort and their effect on autonomic regulation of cardiovascular function during exercise can vary according to condition. Centrally mediated integration of multiple signals occurring during exercise certainly involves feedback mechanisms, but it is unclear whether or how these signals modify central command via their influence on perception of effort. As our understanding of central neural control systems continues to develop, it will be important to examine more closely how multiple sensory signals are prioritized and processed centrally to modulate cardiovascular responses during exercise. The purpose of this article is briefly to review the concepts underlying central command and its assessment via perception of effort, and to identify potential areas for future studies towards determining the role and relevance of central command for neural control of exercise. The neural control of the circulation during exercise has been investigated since the late 1800s . ConvincWhile defining central command is seemingly a perfunctory ritual for discussion purposes, the way in which one defines and uses the term \u2018central command\u2019 can have a primary role in determining its perceived relevance. Most would agree that the concept of central command involves descending neural signals from higher brain centres, originally defined as \u2018cortical irradiation\u2019, capable of influencing cardiovascular responses during exercise . The majDetermination of the specific sensations that drive perception of effort during exercise, as well as their potential influence(s) on central command, has proven more difficult in the interpretation of human research studies. Perception of effort has been associated with somatosenory signals can stimulate a centrally generated command signal which elicits a parallel activation of motor and cardiovascular centres. Second, an effective feedforward component should have the capacity to anticipate the effect of perturbations on the system accurately and send an appropriate signal. For example, as one approaches a hill, centrally mediated increases in heart rate, breathing and muscle activity would become evident prior to the ascent. In most situations, the cardiovascular and motor responses are closely matched to the exercise intensity , and central command certainly contributes to this response in a feedforward capacity. However, a third point regarding systems control is that even complex feedforward mechanisms cannot always provide perfect compensation. If the anticipated cardiovascular adjustments needed to ascend the hill were underestimated (and not corrected), performance could be compromised. Eventually, feedforward errors will occur and accumulate, resulting in a mismatch between cardiovascular responses and metabolic demand.To help account for potential feedforward errors, the system also integrates somatosensory signals via feedback mechanisms. As noted previously, the exercise pressor reflex serves as a primary feedback component to correct errors during exercise. Somatosensory signals from the working muscle are transmitted to areas of cardiovascular control within the medulla . Do the Control systems which incorporate both feedfoward and feedback components can significantly improve system performance over single-component systems . While aPerception can be defined as the simultaneous entry of several afferent messages, including those retrieved from memory, into consciousness . RatingsWhile an operational definition has been provided for central command, cortical modulation of the cardiovascular system can be dCentral command and muscle pain do share common neural substrate, it that both activate regions of the insular cortex and anterior cingulate cortex . It was Highly regulated neural inputs are critical to maintaining normal cardiovascular function. Operationally, central command is typically associated with perception of effort during exercise, while cortical cardiovascular modulation is more commonly associated with non-exercise conditions, such as emotion, stress and pain. The neuroanatomical infrasturcure used by central command for cardiovascular control during exercise is basically the same as that employed for central modifications of the cardiovascular system in non-exercise conditions. While the mental processes and behaviours involving sensation, perception, motivated behaviours and control of movement can be included under the umbrella of the behavioural neurosciences, they can also be studied during exercise (e.g. exercise neuroscience?). With regard to the \u2018role of the cortex in the neural control of the circulation\u2019, is this a situation where the disciplines of exercise neuroscience and behavioural neuroscience have been looking at different sides of the same coin? Some may argue the differences, yet there are certainly numerous similarities between central command and cortical cardiovascular modulation that should not be overlooked. Whether some of the more clearly defined mechanisms underlying behavioural sciences can be applied to central command during exercise remains unknown.The association between central command and perception of effort has raised questions. An individual's perceived exertion (or effort) during muscular exertion appears to integrate all afferent sensory inputs along with hedonistic sensations, which can also involve motivation . As such"} +{"text": "There is no consensus on the ideal methodology for eliciting participant-reported harms, but question methods influence the extent and nature of data detected. This gives potential for measurement error and undermines meta-analyses of adverse effects. We undertook to identify barriers to accurate and complete reporting of harms data, by qualitatively exploring participants\u2019 experiences of illness and treatment, and reporting behaviours; and compared the number and nature of data detected by three enquiry methods.Participants within antiretroviral/antimalarial interaction trials in South Africa and Tanzania were asked about medical history, treatments and/or adverse events by general enquiries followed by checklists. Those reporting differently between these two question methods were invited to an in-depth interview and focus group discussion. Health narratives were analysed to investigate accuracy and completeness of case record form data and to understand reasons for differential reporting between question methods. Outcomes were the number and nature of data by question method, themes from qualitative analyses and a theoretical interpretation of participants\u2019 experiences.We observed a cumulative increase in sensitivity of detection of all types of reports while progressing from general enquiry, through checklist, to in-depth interview. Questioning detail and terminology influenced participants\u2019 recognition of health issues and treatments. Reporting patterns and vocabulary suggest influence from the relative importance that illnesses and treatments have for participants. Perceptions were often dichotomised and this differentiation extended to ideas of relevance to report. South African participants displayed a \u2018trial citizenship\u2019, taking responsibility for the impact of their reporting on trial results, and even reaching reporting decisions by consensus. In contrast, Tanzanians perceived their role more as patients than participants; the locus of responsibility for knowing information relevant to the trial fell with trial staff as doctors rather than with themselves.Our observations of how reporting relates to participant perceptions inside and outside trials could help optimise how harms data are elicited. Questions reflecting the different ways that biomedically defined illness and treatment data are perceived by participants may help them understand relevance for reporting. We will theorise how these two disparate trial environments may have influenced how participants understood their role, as this could help researchers achieve empowered participation in similar trials."} +{"text": "Lactobacillus and Bifidobacterium strains isolated from honey. The study was not funded by ConCellae AB.\" Information is missing from the Competing Interests statement. The full statement should read: \"Alejandra Vasquez and Tobias Olofsson are the founders of and hold stocks in ConCellae AB, a biotech company that develops and markets functional food products, including honey-based products. Alejandra Vasquez and Tobias Olofsson are inventors and owners of a patent application related to the applications of"} +{"text": "The effects of hydrodynamic and thermal slip boundary conditions on the double-diffusive free convective flow of a nanofluid along a semi-infinite flat solid vertical plate are investigated numerically. It is assumed that free stream is moving. The governing boundary layer equations are non-dimensionalized and transformed into a system of nonlinear, coupled similarity equations. The effects of the controlling parameters on the dimensionless velocity, temperature, solute and nanofluid concentration as well as on the reduced Nusselt number, reduced Sherwood number and the reduced nanoparticle Sherwood number are investigated and presented graphically. To the best of our knowledge, the effects of hydrodynamic and thermal slip boundary conditions have not been investigated yet. It is found that the reduced local Nusselt, local solute and the local nanofluid Sherwood numbers increase with hydrodynamic slip and decrease with thermal slip parameters. Due to small sizes and very large specific surface area of the nanoparticles, nanofluids have better thermophysical properties such as high thermal conductivity, minimal clogging in flow passages, long term stability and homogeneity. Due to these improved thermophysical properties; nanofluids have diverse applications in many industries Most physical processes involve heat generation. Normally, fluids are used to handle and transfer this heat. However, conventional heat transfer fluids have poor heat conductivity and require high velocities or heat transfer coefficients to efficiently transfer this heat from a given surface. To overcome these problems, Choi The proposed analytical model of Buongiorno Researchers are paying their attention to investigate the double diffusive phenomena because of their many applications in chemical engineering, solid-state physics, oceanography, geophysics etc. Kuznetsov and Nield The above literature review reveals that all studies are restricted to conventional no slip boundary conditions. But the no-slip assumption is no longer applicable when fluid flows in MEMS and NEMS and the conventional no slip boundary conditions must be replaced by slip boundary conditions ngth Hak . For gas Maxwell . Some reThe present study attempts to pinpoint the effects of the momentum and thermal slips boundary conditions on the double-diffusive free convective flow of a viscous incompressible nanofluid past a semi-infinite flat heated vertical plate in the moving free stream, which up to date have not been elucidated in the literature. In an effort to achieve these goals, we used similarity transformations to transform the governing partial differential equations into the corresponding similarity equations, before solving numerically by an implicit finite difference method. The effects of governing parameters on the similarity variables are investigated and analyzed with the help of graphical representations.Consider a two dimensional steady free convective boundary layer flow of water based nanofluid along a semi-infinite flat solid stationary vertical plate in the moving free stream. The coordinate system and flow configuration is depicted in The appropriate boundary conditions are\u22121 and c is a constant with dimension We define variables as follows: It is suitable to express Our analysis reveals that Consider the following similarity transformations developed by group method . Le implies decreasing solute diffusivity which consequently reduced concentration and increases the mass transfer rate. The dimensionless solute concentration profiles are shown in The effect of momentum slip and nanoparticle Lewis number on the dimensionless nanoparticle concentration for double diffusive water-based nanofluids is displayed The impact of momentum slip, thermal slip, buoyancy and modified Dufour parameters on the dimensionless reduced local Nusselt is displayed Finally, the same behavior of the reduced nanofluid Sherwood number is shown in The effects of hydrodynamic and thermal slips boundary conditions on double-diffusive free convective boundary layer flow, heat and mass transfer of a nanofluid past a stationary vertical plate in moving free stream is investigated numerically. In the light of the present investigation, following conclusions can be drawn:The dimensionless velocity within the boundary layer increases with momentum slip but decreases with the thermal slip for both mono and double- diffusion processes in a nanofluid.The dimensionless temperature, solute and nanoparticle concentration decrease with both the momentum and the thermal slip.The dimensionless reduced local Nusselt, solute and nanofluid Sherwood numbers increase with momentum slip and decrease with thermal slip for double diffusion in nanofluids."} +{"text": "Homeostatic signaling systems are ubiquitous forms of biological regulation, having been studied for hundreds of years in the context of diverse physiological processes including body temperature and osmotic balance. However, only recently has this concept been brought to the study of excitatory and inhibitory electrical activity that the nervous system uses to establish and maintain stable communication. Synapses are a primary target of neuronal regulation with a variety of studies over the past 15 years demonstrating that these cellular junctions are under bidirectional homeostatic control. Recent work from an array of diverse systems and approaches has revealed exciting new links between homeostatic synaptic plasticity and a variety of seemingly disparate neurological and psychiatric diseases. These include autism spectrum disorders, intellectual disabilities, schizophrenia, and Fragile X Syndrome. Although the molecular mechanisms through which defective homeostatic signaling may lead to disease pathogenesis remain unclear, rapid progress is likely to be made in the coming years using a powerful combination of genetic, imaging, electrophysiological, and next generation sequencing approaches. Importantly, understanding homeostatic synaptic plasticity at a cellular and molecular level may lead to developments in new therapeutic innovations to treat these diseases. In this review we will examine recent studies that demonstrate homeostatic control of postsynaptic protein translation, retrograde signaling, and presynaptic function that may contribute to the etiology of complex neurological and psychiatric diseases. Constraining nervous system activity within stable physiological ranges is critical for robust and reliable brain function. However, this stability must also permit the flexibility necessary for learning and memory to occur during the life experiences of an organism. While various forms of Hebbian plasticity have been shown to potentiate or weaken individual synaptic strengths, these mechanisms are inherently destabilizing and would lead to unconstrained activity if left unchecked. Homeostatic processes have therefore been postulated to counteract the instability generated through Hebbian forces, adjusting synaptic strengths and intrinsic neuronal excitability to keep neural circuits functioning within stable dynamic ranges throughout developmental, experiential, and environmental challenges. While homeostatic plasticity is fundamental and conserved in the nervous systems of invertebrates, mammals, and humans, our understanding of the underlying mechanisms of these complex and robust signaling systems has been quite limited.Drosophila of postsynaptic receptor mutants at the neuromuscular junction (NMJ) also revealed robust homeostatic control of synaptic strength , a well-known regulator of mRNA translation , which encodes the Fragile X Mental Retardation Protein (FMRP), and is necessary for normal neural development have been found to disrupt homeostatic plasticity at the fly NMJ .Interestingly, mutations in the Myasthenia gravis is an autoimmune disease that causes muscle weakness and fatigue. In a majority of cases, a loss of postsynaptic acetylcholine (ACh) receptors is observed at the NMJ due to autoantibody production targeting these receptors. In recordings from muscles obtained from MG patients and also from toxin-induced animal models of the disease, miniature end-plate potentials (mEPPs) show dramatically reduced amplitudes . In addition to these findings, genetic screens in Drosophila homolog of the vertebrate gene dysbindin , composed of eight total subunits (Ghiani and Dell'Angelica, Tantalizing links have recently been uncovered that suggest synaptic processes necessary for the homeostatic control of synaptic function, when defective, may contribute to the pathogenesis of a variety of neurological and neuropsychiatric diseases. Importantly, several intriguing and novel genes and molecules have been revealed to disrupt these complex and adaptive homeostatic signaling systems Figure . The chaThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Most studies addressing the development of animal communication have focused on signal production rather than receiver decoding, and similar emphasis has been given to learning over nonlearning. But receivers are an integral part of a communication network, and nonlearned mechanisms appear to be more ubiquitous than learned ones in the communication systems of most animals. Here we review the results of recent experiments and outline future directions for integrative studies on the development of a primarily nonlearned behaviour\u2014recognition of communication signals during ontogeny in a tropical frog. The results suggest that antecedents to adult behaviours might be a common feature of developing organisms. Given the essential role that acoustic communication serves in reproduction for many organisms and that receivers can exert strong influence on the evolution of signals, understanding the evolutionary developmental basis of mate recognition will provide new insights into the evolution of communication systems. Hox gene clusters in animal evolution spurred the emergence of the evo-devo as a discipline [Seminal discoveries in the study of embryonic patterning such as the deep homology of scipline . As a fiscipline or self-scipline , there ascipline , predatoscipline , and matscipline ). In thiscipline \u201310. Althscipline , 12, we Study systems that have provided models of behavioural development share several key features , 14. FirCommunication is a particularly compelling class of behaviour for developmental studies. As a hallmark of social behaviour, one of its most important functions is to identify individuals as members of a particular group, be it family, friends, sex, or species. Studies of the development of such communication systems are numerous, owing especially to the pioneering studies of song learning in oscines by Thorpe and Marler and the legions of researchers they have spawned , 16. DueBy exploring the development of nonlearned communication behaviours, we may broaden our understanding of developmental patterns, including the role of constraints in the evolution of communication systems . And byTo overcome some of these obstacles, evolutionary studies must examine behaviour in a phylogenetically informed manner. It is not sufficient, for example, to simply compare two or more distantly related species for a character of interest and draw conclusions about the evolutionary forces (or constraints) that gave rise to differences and similarities. This matter cannot be understated and has rightly received recent attention in the context of morphological and behaIn order to draw evolutionary inferences, it is also important to have a grasp of the natural variation in a group and an understanding of the fitness consequences of such variation. Because communication systems evolve as a consequence of selection on both signalers and receivers, it is necessary to consider the implications of ecological selection on both members of a communication dyad.Behavioural evo-devo must satisfy the features essential for both traditional developmental and evolutionary studies of behaviour. This requires a uniquely integrative approach, from gene expression in the brain to ethologically relevant behaviour expressed under naturalistic conditions. For this effort to be tractable, it is essential to begin by examining the evolutionary and developmental basis of behaviours that have limited plasticity. Communication offers such an opportunity, and in fact, is one of the few historical examples of an evo-devo approach applied to behaviour.The pioneering work in evo-devo by Gilbert Gottlieb was one of the few exceptions to the focus on learned communication in vertebrates. Through a series of seminal studies, Gottlieb established that imprinting on the maternal assembly vocalization in ducklings rests on hearing their own contact vocalizations before they hatch . Gottlieper se , this is an untested assumption. Given the widespread pattern of nonlearned communication behaviour in animal taxa, it is all that more important to better grasp the development of such behaviour if we are to understand the evolutionary origins of this class of behaviour.Despite early work by Gottlieb, the task of identifying the developmental origins of acoustic communication behaviour has been undertaken largely by studies of vocal and auditory plasticity in birds and humans , 43, 44.Physalaemus pustulosus)\u2014a species that does not exhibit auditory or vocal learning.Behaviour is considered evolutionarily one of the most labile elements of a phenotype , and evoIn addition to the key features outlined above, we believe the following topics are fundamental lines of inquiry for behavioural evo-devo in the years to come: (1) when do adult behaviours emerge during ontogeny and how do these behaviours and their underlying mechanisms stay in register during development? (2) Do physiological constraints, such as the necessity of establishing, organizing, and maintaining long-distance neuroanatomical connections early in brain development, predispose organisms to express behaviours antecedent to their functional relevance? (3) Do differences in the development of species-specific predispositions provide raw material for sexual selection?Here we describe a system amenable to these questions. We illustrate the developmental trajectory of behaviour in a species that meets the prerequisites for an evo-devo approach to behaviour and then discuss future comparative studies that would provide insight into these fundamental questions.Physalaemus .As with many animals, communication subserves species recognition and mating behaviour for anuran amphibians. During the breeding season, adult males vocally advertise to reproductive females using species-typical calls\u2014the key trait which females use to localize and select amongst males. In t\u00fangara frogs, males produce two types of advertisement signals: first one is simple calls, or \u201cwhines\u201d, which are about 300\u2009ms in duration and consist of a harmonically related stack of frequency downsweeps with a dominant frequency beginning at approximately 1000\u2009Hz and terminating at about 400\u2009Hz . ComplexTwo auditory end organs in t\u00fangara frogs, the amphibian papilla and the basilar papilla, primarily process the whine and chuck components, respectively, based on the frequency tuning of the end organs . BehavioAcoustic isolation experiments using male and female t\u00fangara frogs demonstrated that males need not hear conspecific signals or interact socially during premetamorphic and postmetamorphic (juvenile) development in order to produce species-typical advertisement calls as mature adults. Likewise, females isolated acoustically from advertisement signals during development exhibit normal phonotaxis to conspecific signals as reproductive adults , 50. TheSpecies recognition and sexual behaviour in frogs can be examined by broadcasting the vocal advertisement signal from loudspeakers, thus providing control over the sensory experience and limiting it to this single modality. We performed a series of within-subject phonotaxis experiments on t\u00fangara frogs during postmetamorphic development . The resThe key feature of the behaviour that changes during development is the frequency of phonotaxis\u2014both sexes exhibit conspecific phonotaxis in a gradually increasing manner as they approach adulthood over approximately nine months of postmetamorphic development (population response frequency varies from ca. 10% after metamorphosis to ca. 70% at maturity) . While aThese results are relevant to a variety of issues in behavioural evo-devo. First, there has been a suggestion that \u201cpremature\u201d forms of species recognition occur in organisms that exhibit vocal or auditory learning of conspecific signals because such traits serve to guide the attention of young animals toward conspecifics to minimize heterospecific learning or functPhysalaemus has a number of potential advantages for use in studies of evolutionary developmental biology. First, the phylogeny in this group is well resolved [Physalaemus are presently limited to P. pustulosus, we know that the adult endpoints across the taxon differ in recognition and discrimination of acoustic advertisement signals, both behaviourally [ The genus resolved , 61 thusresolved , 62\u201364. iourally , 65 and iourally . TherefoP. petersi mating signal). The results suggest that species typical patterns of activation in the auditory midbrain are established quite early during postmetamorphic development; however, variability in expression patterns appears to be greater in juveniles compared to adults such as egr-1 represent the initial genomic response to an inducing stimulus and have been used successfully as markers of neural activation in a variety of species and systems . For exaPhysalaemus genus could yield insights into the evolutionary and developmental origins of variation in auditory species recognition. One distinct advantage of the IEG approach is that patterns of activation across most of the brain can be quantified, which enables the simultaneous inspection of low-level sensory processing as well as sensorimotor integration [The ontogeny of auditory processing is a compelling candidate for comparative studies. IEG studies across members of the egration , 72. ThiPhysalaemus pustulosus species group) holds significant promise to detail the coordinated neural and behavioural processes undergoing change during development and provide insights into how species differences might arise through differentiated development. Phonotaxis in frogs represents an ideal behavioural assay during development because no animal training is required, and unlike many other species , both sexes perform this behavioural task, thus minimizing the confounding variables of task and sex [Physalaemus species prefer these novel complex calls, providing support for the theory of sexual selection by sensory exploitation. By replicating these types of behavioural experiments and extending them with mechanistic studies in the brain during juvenile development across Physalaemus species, it might be possible to test hypotheses about how evolutionary changes in developmental programs constrain the universe of possible phenotypes in an evolving lineage.Complementing IEG studies with behavioural discrimination experiments in a comparative manner the levels of expression of large numbers of genes in a given tissue source. Transcriptional profiling can be accomplished using various approaches such as cDNA microarrays or next-generation sequencing methods, with increasing availability for nontraditional genetic model organisms. We propose comparing expression profiles of brain regions that have structural or functional differences that parallel developmental and species differences in behaviour. Focusing research on stages of development prior to and including the emergence of species differences in neural or behavioural traits would provide candidate molecular pathways that may mediate the species specificity of behaviours. Further analysis of the regulation of these molecular pathways and the differential expression throughout the developing organism using in situ hybridization would generate hypotheses about the potential constraints and pleiotropic effects that may shape the evolution of behaviour. For example, what are the developmental expression patterns for genes regulating the growth and migration of neurons in the auditory system? Do such patterns represent possible developmental constraints on the organization of neuroanatomical connections in auditory-motor pathways that regulate phonotaxis? Do we see species differences in these developmental expression patterns that nominate candidate molecular substrates for sexual selection? Do we find a consistent subset of genes in which expression patterns are more evolutionarily labile across the genus or particular stages of development in which species differences in expression are more pronounced? Given previous research exploring interspecific behavioural variability in this group, classic evo-devo approaches such as these could provide a degree of purchase in understanding the mechanistic bases underlying evolutionary patterns.P. petersi with highly differentiated male calls and female preferences [ Quantitative genetics approaches can help link molecular, neural, and behavioural differences between species throughout development to elaborate a detailed view of the evolution of behaviour in an organismal context. The IEG and transcriptional profiling experiments might identify a number of species differences in molecular or neural traits, only some of which are related to the process of species recognition and its evolution. Quantitative genetics studies that incorporate developmental and adult phenotypes at all levels can determine the degree to which different sets of phenotypes share genetic architecture. Breeding designs that shuffle genetic material from two or more clades effectively break apart suites of genes that differ among populations or species, revealing which traits cooccur in organisms and therefore might be causally related. Quantitative genetics approaches would therefore enhance our ability to integrate behavioural neural, and molecular phenotypes related to species-typical behaviour and would moreover allow us to analyze possible genetic constraints on evolution, particularly pleiotropic effects on other phenotypes. One prerequisite for the proposed studies is cross-fertility of individuals with very distinct behavior. Although limited information is available about hybrid matings across the genus, at least one interesting cross-breeding experiment is possible. F1 hybrids between two clades of ferences have beeWe can test specific hypotheses such as whether a particular gene expression difference between species in embryonic development is genetically correlated with the mate preferences of adults, thereby narrowing the list of candidate molecular pathways that contribute to particular behavioural phenotypes. Similarly, we can link molecular differences at different stages of development with specific functional neural measures later in life. We can directly assess the degree to which neural and behavioural traits correlate during development and attribute this covariation to genetic or environmental sources. Shared genetic bases for interspecific differences in species recognition behaviours and other phenotypes such as intraspecific mating preferences or body size would expand our view of the constraints and interactions that shape the effects of natural and sexual selection on behaviour.Trichopsis vittata, Wysocki and Ladich [ If we extend this inquiry concerning the origins of adult behaviours to other taxa and classes of behavior, there are a small handful of cogent examples of developmental constraints that demonstrate how underlying adult-typical physiology often precedes the onset of particular behaviours. For example, Bentley and Hoy showed td Ladich demonstrAntheraea pernyi and Hyalophora cecropia). These behaviours are typical of posteclosion adults yet are present in developing pupae and only observed if the pupal cuticle is removed. These behaviours are suppressed shortly before eclosion and then released from inhibition by the eclosion hormone at the final pupation [Antheraea polyphemus, in which pupae exhibit flight and warm-up motor patterns characteristic of adults in the week preceding pupation [Examples outside of communication behaviour include complex motor patterns such as walking and the righting response in silk moths when do adult behaviours emerge during ontogeny, and how do these behaviours and their underlying mechanisms stay in register during development? (2) Do physiological constraints, such as the necessity of establishing, organizing, and maintaining long-distance neuroanatomical connections early in brain development, predispose organisms to express behaviours antecedent to their functional relevance? (3) Do differences in the development of species-specific predispositions provide raw material for sexual selection?Physalaemus, which exhibit conspecific phonotaxis early in life. We reviewed studies demonstrating that phonotaxis, widely considered a \u201csexual\u201d behaviour in anurans, is present in young juveniles of both sexes and is increasingly expressed during growth to adulthood. We argued that whereas the developmental origin of this presumably adult behaviour occurs early, the fully formed version is not present until reproductive onset, suggesting that the principal modification during development is the motivation to respond to conspecific signals in a sexual context. Therefore an investigation of the role that sex steroids play during development (as gonads grow and differentiate) to influence the trajectory of behavioural expression is warranted. An essential area for future research is to determine how these and other aspects of developmental physiology influence the variation available for selection to act on, thus determining the evolutionary trajectory of a lineage by making some phenotypes relatively accessible and others inaccessible [To answer these questions requires a system in which developing animals naturally perform, or can be stimulated to exhibit, some form of an adult-typical behaviour. This unique prerequisite is met in cessible ."} +{"text": "L2-penalised logistic regression classifier, after univariate Anova feature selection. Figure Our semantic knowledge is essential for unimpaired cognition, language and behavior. Previously, we have used Electroencephalography (EEG) to decode the semantic categories of animals vs tools in younger adult subjects during a covert image naming task. In thisThe overall mean classification accuracy of younger and older groups increases similarly with number of channels. Further results indicate that the accuracy of the two groups varies differentially with time and spatial location. We hypothesize that differences in accuracy over time might reflect changes in neuronal and synaptic activity, while differences in accuracy with scalp location indicate that the semantic network might undergo a re-organization process with age increase. To test this hypothesis further recording and analysis are required. Data on elderly controls will serve as reference for clinical applications of EEG recordings in the diagnosis and treatment of language disorders in neurodegenerative and other diseases of the central nervous system."} +{"text": "One of the main sources of information regarding the underlying processes involved in both normal and impaired reading has been the study of reading deficits that occur as a result of brain damage. However, patterns of reading deficits found acutely after brain injury have been little explored. The observed patterns of performance in chronic stroke patients might reflect reorganization of the cognitive processes underlying reading or development of compensatory strategies that are not normally used to read. Method: 112 acute left hemisphere stroke patients were administered a task of oral reading of words and pseudowords within 1\u20132 days of hospital admission; performance was examined for error rate and type, and compared to that on tasks involving visual lexical decision, visual/auditory comprehension, and naming. Results: Several distinct patterns of performance were identified. Although similarities were found between the patterns of reading performance observed acutely and the classical acquired dyslexias generally identified more chronically, some notable differences were observed. Of interest was the finding that no patient produced any pure semantic errors in reading, despite finding such errors in comprehension and naming."} +{"text": "Interstitial cells (ICs) in the bladder have been investigated for more than a decade by many independent groups throughout the world. These efforts have provided compelling evidence that the bladder wall contains subpopulations of ICs in the mucosal and detrusor regions that are structurally associated with urothelial cells, smooth muscle cells and nerves, with some populations comprising interconnected networks.2+ signaling profiles which may be commensurate with pacemaking. However, there is currently insufficient direct evidence that ICs modulate the activity of normal detrusor smooth muscle.Physiological studies of IC subtypes in the bladder concur that these novel cells may contribute to the complex cellular signaling within the bladder wall that underpins normal bladder function. Davidson and McCloskey hypothesized that ICs may form a functional conduit for the transmission of signals from the urothelium to other cells within the bladder wall.The role of ICs in the bladder may actually be more apparent in pathophysiological conditions such as obstructed bladder, neurogenic bladder or painful bladder syndrome/interstitial cystitis, all of which are associated with detrusor overactivity. Increased numbers of ICs have been shown in samples of overactive human bladder,Observations of enhanced IC numbers in bladders from patients or animal models with an overactive phenotype raise the question of whether these 2 phenomena may be linked. It is not yet clear whether defects in IC subpopulations contribute to the cause of bladder dysfunction or whether they occur as a consequence of bladder wall remodeling, eg hypertrophy, which typically accompanies neurogenic or obstructed bladder. In vitro tension recordings from overactive human bladder tissues with enhanced numbers of ICs showed increased contractility which was more sensitive to imatinib mesylate than the activity of normal tissues.The current literature consistently indicates that changes in the numbers of IC subpopulations are associated with dysfunctional phenotypes, giving support to the notion that ICs may be responsible for bladder pathophysiology and, therefore, may present novel therapeutic targets for the treatment of dysfunctional bladder. More research is needed in this area to address the caveats associated with considering ICs as potential treatment options. Appropriately powered studies on IC expression and activity in patient tissues matched with clinical urodynamic assessment and evaluation of reported symptoms are not yet available. There are also limitations in translating basic research findings from animal models to patient symptoms. The apparent correlation between bladder dysfunction and alterations in IC numbers is unlikely to fully account for aberrant bladder activity, which has other credible explanations unrelated to ICs such as smooth muscle hypertrophy, enhanced coupling between smooth muscle cells, connective tissue remodeling, changes in afferent signaling or altered release of factors from the urothelium.2+signaling) and their interactions with other cells in the diseased bladder wall has the potential to better explain the cellular basis of the dysfunctional bladder.In summary, we currently understand ICs as modulators of smooth muscle activity in the normal bladder by integrating and communicating information from urothelial cells, smooth muscle cells, nerves and microvessels. Their role may be relatively minor, acting as passive bystanders until stimulated by changes in the bladder microenvironment to modify the activity of neighboring cells in response. The function of these intriguing cells appears to be more dynamic in bladder pathophysiology where there is convincing evidence that changes in their numbers accompany an overactive or underactive phenotype. Ongoing and future work to investigate the physiological properties of ICs (eg ion channel activity, receptor signaling, Ca"} +{"text": "Deferred consent refers to when a patient is entered into a trial without prior consent. In 2008 UK legislation was amended to enable the use of deferred consent for paediatric emergency care trials in recognition of the practical and ethical difficulties of obtaining consent in an emergency situation. However, ambiguity about how to make the process of deferred consent acceptable to parents, children and practitioners remains. In particular, little is known about practitioners\u2019 views and experiences of seeking deferred consent in this setting.This paper presents empirical data from an online survey (45 practitioners) and qualitative focus group interviews to explore the views and experiences of UK clinical trial practitioners sampled to include both those who had hands-on experience of recruiting patients within a deferred consent framework and those who had no such experience.Practitioners\u2019 views on deferred consent differed depending upon whether or not they had experience of the consent method. Practitioners who had not previously used deferred consent were negative about it; they were particularly concerned about the impact that seeking deferred consent upon the parent-practitioner relationship. In contrast, practitioners who had experience of using deferred consent described how families had been receptive to this consent method, including how deferred consent had improved recruitment, parental decision-making capacity and parent-practitioner relationships in the emergency care setting.The ethical implications of these findings will be considered. Recommendations will be offered to inform future trial design, training, research and recruitment practice."} +{"text": "Acute kidney injury has been recognized as a major contributor to end stage renal disease. Although neutrophil gelatinase-associated lipocalin has been reported as a promising biomarker for early detection of acute kidney injury, no study has yet examined its potential clinical impact in patients with normal renal function. The purpose of current study is to investigate possible difference in serum Ngal levels between dehydrated and control patients.A total of twelve patients presented with symptoms of mild dehydration defined by history of diarrheas or vomiting and orthostatic hypotension and an age and sex matched group of twelve control patients were included. The two groups of patients did not seem to differ in basic clinical and laboratory parameters. Serum Ngal was higher in dehydrated patients when compared to control group . Ngal was not correlated with age, hemoglobin, white blood cell count, red blood cell count, urea or creatinine.The presence of elevated Ngal levels in dehydrated patients may suggest its role as a very sensitive biomarker in even minimal and \"silent\" prerenal kidney dysfunction Renal impairment may be the result of a variety of renal or systemic diseases and may lead to renal failure . AlthougIn order to explore the possible role of Ngal in subclinical renal dysfunction, such as renal hypoperfusion, we prospectively evaluated twelve patients aged>18 years with medical history suggesting mild dehydration, accompanied by orthostatic hypotension. A group of twelve apparently healthy individuals with no history of dehydration and no evidence of orthostatic hypotension were treated as controls. Ethical approval was obtained by the Ethics Committee of the \"401 General Army Hospital\" in Athens, Greece and all patients gave informed consent.Dehydrated and controls were similar in age and gender and in terms of basic laboratory tests . Although no laboratory differences were detected between the two groups, serum Ngal was higher in statistically significant terms in dehydrated patients, when compared to the controls . Ngal was not significantly correlated with age, Hb, Wbc, Rbc, Ur or Cr and GFR evaluation would rule out a possible \"silent\" renal impairment.Our future research agenda points to increasing the dataset size, examining the role of urinary and serum Ngal, as well as other more elaborate indices of renal function in dehydration and evaluating their role in dehydrated patients that return to euhydrated status after proper treatment. Exploration of the underlying pathophysiological pathway of Ngal excretion in the dehydrated and hypoperfused kidney may also seem a very promising and tempting field of research.(Cr): Creatinine; : Neutrophil gelatinase-asssociated lipocalin; (Hb): Hemoglobin; (Wbc): White blood cell; (Rbc): Red blood cell; (Ur): Urea; (GFR): Glomerular filtration rate.The authors declare that they have no competing interests.CNA participated in the design of the study, performed the statistical analysis and drafted the manuscript. AK, GG, TNS and DNR participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript."} +{"text": "Most studies on plant-mediated above\u2013belowground interactions focus on soil biota with direct trophic links to plant roots such as root herbivores, pathogens, and symbionts. Detritivorous soil fauna, though ubiquitous and present in high abundances and biomasses in soil, are under-represented in those studies. Understanding of their impact on plants is mainly restricted to growth and nutrient uptake parameters. Detritivores have been shown to affect secondary metabolites and defense gene expression in aboveground parts of plants, with potential impacts on aboveground plant\u2013herbivore interactions. The proposed mechanisms range from nutrient mobilization effects and impacts on soil microorganisms to defense induction by passive or active ingestion of roots. Since their negative effects (disruption or direct feeding of roots) may be counterbalanced by their overall beneficial effects (nutrient mobilization), detritivores may not harm, but rather enable plants to respond to aboveground herbivore attacks in a more efficient way. Both more mechanistic and holistic approaches are needed to better understand the involvement of detritivores in plant-mediated above\u2013belowground interactions and their potential for sustainable agriculture. Links between the below- and the aboveground compartments of terrestrial ecosystem have been the focus of a growing number of studies in the last two decades. Integrating the two compartments is crucial for a better understanding of the ecology, function, and evolution of terrestrial ecosystems. In the first review articles on plant-mediated effects of soil biota on aboveground herbivores soil orgIn this review, I focus on plant-mediated links between detritivorous soil fauna and aboveground herbivores. With earlier reviews having focused mainly on soil biota with direct trophic links to plant roots, this review specifically deals with soil biota in indirect interaction with roots. First, I give a short summary of the reported impacts of detritivores on aboveground herbivores (see Plant-Mediated Effects of Detritivores on Aboveground Herbivores). Then I present investigated and proposed mechanisms behind the observed effects (see Mechanisms of How Detritivores Affect Plant and Aboveground Herbivore Performance), before comparing the mechanisms involved in the effects of soil biota in indirect interaction vs. direct interaction with roots (see Mechanisms Involved in the Effects of Soil Biota in Direct and Indirect Interaction with Roots). Finally, I highlight promising avenues for future research (see Research Perspectives). With this review, I hope to place detritivores \u201cin the spot light,\u201d because their rather neglected role in studies on plant-mediated interactions between soil biota and aboveground herbivores and their antagonists does not reflect their importance in below\u2013aboveground links of terrestrial ecosystems.Heteromurus nitidus and Onychiurus scotarius) and endogeic earthworms on growth of a grass (Poa annua) and a legume (Trifolium repens), and on aphid (Myzus persicae) reproduction on their leaves were investigated. Besides effects on plant growth, Collembola had strong effects on aphid reproduction that differed in direction and magnitude between the different plant species. On average, aphid reproduction was decreased by 45% on T. repens, but transiently increased ca. threefold on Poa annua in presence of Collembola. Earthworms had a strong positive, but also transient effect on aphid reproduction on both plant species. Subsequent studies investigated the impacts of earthworms (Mamestra brassicae). When considering also studies on the impact of detritivores on plant communities, two studies, as far as we are aware, investigated the effects of earthworms on herbivorous snails plants more resistant to root-feeding nematodes.It has, however, also been shown that detritivorous soil organisms can affect defense compounds in plants and the expression of defense-related genes. It has been documented that earthworms can reduce aphid reproduction and thatnceolata . Both coa leaves , aliphatpis alba . Blouin Arabidopsis thaliana . As well as enhancing nutrient availability for the plants, they also induce stress-responsive genes and systemically change the production of secondary metabolites in the plants. Since their beneficial effects (nutrient mobilization) may counterbalance their negative effects (disruption or direct feeding of roots), detritivores may not harm, but rather prepare plants to respond to aboveground herbivore attacks in a more efficient way. This issue is further developed in Section \u201cResearch Perspectives\u201d regarding future research perspectives.This duality of impact on plant growth and defense may be a characteristic feature of the impact of detritivores on plants . The relative contribution of soil biota to the indirect and the direct pathway may also change with conditions, such as the abundance and quality of roots, the microbial community and the nutrient availability in soil.The impact on shoot herbivores by soil biota with a direct trophic link to the plant can be mediated by changes in water and nutrient uptake and/or an induction of plant defense that affects the whole plant systemically in interaction with a belowground herbivorous beetle larvae and aboveground herbivores on Moricandia moricandioides (Brassicaceae) and aboveground higher trophic levels in the field. They reported effects of detritivores up to the third trophic level above the ground: parasitoid attack rate and abundance were positively affected by the presence of detritivores. This is one of the few studies natural conditions to determine their plant-mediated impacts on herbivores and their antagonists in natural and agricultural systems; on the other hand, more mechanistic studies addressing the underlying mechanisms with special emphasis on effects of detritivores on plant physiology and defense pathways. Both approaches combined will help to better understand the impact of detritivores on aboveground plant herbivore interactions and to evaluate their potential for improving crop yield and herbivore resistance in sustainable agriculture.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In the past years, we have witnessed unprecedented attention for the study of epigenetic alterations in the context of a variety of complex disorders, including autoimmune diseases . This isWe have used different methylation bead arrays to profile the DNA methylation status of CpG sites in both samples obtained from patients from different autoimmune diseases and normal individuals as well as different experimental models that allow to explore conditions where the immune tolerance is lost. Following bioinformatics analysis, we individually validate relevant genes by bisulfite pyrosequencing and check their expression levels by quantitative RT-PCR. The potential role of different chromatin factors in these changes is then explored by using experimental models where these factors can be overexpressed or knocked-down. Also, their direct association at specific genomic sites can be investigated by using chromatin immunoprecipitation assays.High-throughput and candidate sequence analysis of DNA methylation in samples from different autoimmune diseases show the existence of alterations associated with these diseases. We have also identified DNA methylation changes in association with several factors associated with autoimmune disease like infection with Epstein Barr-virus of B cells. Most of the changes observed occur in the direction towards hypomethylation associated with gene upregulation.Our findings are providing potentially relevant DNA methylation markers for the clinical managements of different autoimmune diseases and also support the notion that epigenetic alterations may be critical in the pathogenesis of autoimmune disease."} +{"text": "Pen gene. Detection method was based on isothermal DNA amplification using primers specific to target Pen genes. Detection of DNA products was based on fluorescence visualization on UV light source after competitive DNA hybridization using fluorescence beta-pyrroridinyl peptide nucleic acid probe and its corresponding quencher. This method was crustacean specific and could detect shrimp, prawn, crab and lobster residues. Its sensitivity was sufficient to detect 20 copies of specific Pen DNA to Pen gene. Presence of shrimp, prawn, crab and lobster constituents were able to detect within 2 hours at DNA level without relying on laboratory facilities. This method should provide a benefit to food manufacturers, clinical doctors and allergenic patients by providing rapid information on the presence of crustacean contamination in foods.Crustaceans is one of the most common causes of food allergies. Its persistency is life-threatening therefore, method to detect the presence of crustacean constituent in food products would be indispensable to ensure the safety. We have developed a simple and rapid method to detect the presence of crustacean residues in food products through the allergenic"} +{"text": "Analysis of various symptoms from 20000 FMF patients indicates that several issues, including the clinical manifestation in a variety of combinations and the genotype penetrance, make FMF diagnosis and management challenging. Severe phenotypes with development of serositis, ELE, splenomegaly, and vasculitis are associated with high penetrance mutations of exon 10, mainly M694V allele.Several forms of arthritis were associated with FMF and the life-threatening complications such as adhesive intestinal obstruction were present in some patients as the first and only manifestation of FMF. Family studies revealed the personalized nature of FMF symptoms and treatment based on genotype and other environmental factors. A significant number of patients have to endure pain for a long time before being properly diagnosed or treated. A major cause for such complexity could be the presence of less common FMF symptoms such as fibromyalgia or multiple sclerosis.Phenotype-genotype correlation was performed after molecular-genetic testing of FMF patients and their family members.FMF patient management may seem straightforward due to general response to colchicine therapy yet many issues including but not limited to misdiagnosis, delayed diagnosis, and renal amyloidosis could potentially complicate the patient management. We have observed a limited response to colchicine at the nephrotic stage of renal amyloidosis in FMF patients homozygous for M694V mutation. Almost all such patients have SAA1 a/a genotype suggesting that homozygous M694V patients could benefit from SAA1 genotyping for colchicine dosage adjustment and management of renal amyloidosis. FMF patients with other genotypes had a good chance to ameliorate the nephrotic syndrome and to maintain renal function. Presence of only one symptom in FMF has been a major factor for misdiagnosis and delay in treatment further emphasizing that mutations in MEFV gene could result in various forms and combinations of symptoms in different individuals. Diagnosis of member of family with FMF while his father and sister had the same genotype and no symptoms also points to a personalized development and progression of the disease. Therefore each case should be discussed in details using genotype and symptoms correlation and treated accordingly.In our experience prevention of the attacks has been a useful tool in patient management. Abrupt and extreme changes in weather patterns, strenuous activity or exercise, anxiety and stress, and even diet have triggered FMF attacks. These conditions either cause additional inflammation or lower/distort the effectiveness of Pyrin in patients with affected genotypes. Although colchicine therapy remains the dominant treatment for FMF and largely prevents the development of renal amyloidosis, its effect in some cases remains controversial. Of course for genotypes with potential for amyloidosis analysis of SAA1 gene could provide preventive values. Once the diagnosis is final immediate initiation of colchicine therapy could prevent renal complications yet emphasis on identifying environmental and/or social factors that trigger FMF attacks could reduce their frequency and facilitate patient management.None declared."} +{"text": "Unwanted effects can occur with all medical interventions and most of these are adverse but this paper concentrates on adverse effects in randomised controlled trials (RCTs) of drug treatments. The process relies on a patient or health professional noticing and recording an adverse effect. Randomisation is the main tool for inferring causality and distinguishing between adverse events and reactions . The process requires careful recording as well as appropriate analysis and reporting of potential adverse drug reactions (ADRs).Major statistical issues that arise are the recording process which should obtain unbiased data, and the problems of multiple possible ADRs. Multiplicity is a general problem in analysis of RCTs. Efficacy analyses have largely dealt with such problems by pre-specifying primary outcomes and secondary outcomes, though the use of composite outcomes and multiple \u201cprimary\u201d outcomes, together with considerable numbers of secondary ones suggests that the issues are not resolved even for efficacy.Pre-specification of adverse effects can rarely be done, at least not with any completeness. New ADRs that may be relatively rare may surprise investigators by their occurrence. Very much more statistical effort has been applied in analysis of efficacy than for analysis of harms, yet it is the absence of harm (safety) that is a primary concern of patients. Evidence both from surveys and even trials show that many patients have unrealistic expectations regarding benefits and the absence of harms .Conventional (Bonferroni) corrections for multiplicity may make the type II error for harms unacceptably high. Bayesian Hierarchical Models have the"} +{"text": "We hypothesized that, in patients with pulmonary fibrosis combined with emphysema, clinical characteristics and outcomes may differ from patients with pulmonary fibrosis without emphysema. We identified 102 patients who met established criteria for pulmonary fibrosis. The amount of emphysema and type of emphysema were characterized in each patient. Clinical characteristics, pulmonary function tests and patient survival were analysed.n = 48), trivial emphysema (n = 26) or advanced emphysema (n = 28). Patients with advanced emphysema had a significantly higher amount of smoking in pack/years than patients with no emphysema or trivial emphysema (P < 0.0001). Median survival of patients with advanced emphysema was 63 months compared to 29 months in patients without emphysema and 32 months in patients with trivial emphysema (P < 0.001). Median forced vital capacity (FVC) and total lung capacity (TLC) were higher in the advanced emphysema group compared to patients with no emphysema , whereas median DLCO did not differ among groups and was overall low. Within the advanced emphysema group (n = 28), further characterization of the type of emphysema was performed and, within these subgroups of patients, survival was 75 months for patients with centrilobular emphysema, 75 months for patients with mixed centrilobular/paraseptal emphysema, and 24 months for patients with paraseptal emphysema (P < 0.01). Patients with advanced paraseptal emphysema had similar survival times to patients without emphysema.Based on the numerical emphysema score, patients were classified into those having no emphysema (Patients with pulmonary fibrosis combined with advanced centrilobular or mixed emphysema have an improved survival compared with patients with pulmonary fibrosis without emphysema, with trivial emphysema or with advanced paraseptal emphysema. Pulmonary fibrosis is a major component of various diffuse parenchymal lung diseases, including idiopathic pulmonary fibrosis (IPF) and other forms of idiopathic interstitial pneumonia. Pulmonary fibrosis results in substantial morbidity and mortality and therapies have been uniformly poorly effective ,2.Histological changes in the lungs of patients with IPF show usual interstitial pneumonia (UIP), a pattern of fibrosis characterized by fibroblastic foci and excessive deposition of extracellular matrix. Initial hypotheses for the mechanism of IPF focused on the role of inflammation and most authorities believed that pulmonary inflammation was a prominent and necessary feature of the UIP process -5. More We specifically hypothesized that patients with combined pulmonary fibrosis and emphysema may have different clinical characteristics and outcomes than patients with pulmonary fibrosis in the absence of emphysema. In this study, we determined the presence or absence of emphysema, along with its severity and type, in a cohort of patients with pulmonary fibrosis and characterized their clinical characteristics, pulmonary physiology and overall outcomes.The study was reviewed and approved by the University of Maryland Institutional Review Board . Patients with interstitial pneumonia were identified at the University of Maryland either through direct patient care visits or through ICD-9 code review for 'interstitial lung disease'. Following our review, 102 patients were identified who met either (1) established criteria for definite or confident idiopathic pulmonary fibrosis (IPF) or (2) established clinical and pathologic criteria for idiopathic fibrotic NSIP of these three subgroups is shown in Figure We addressed the hypothesis that the prognosis of patients with pulmonary fibrosis combined with emphysema may be different from patients with pulmonary fibrosis in the absence of emphysema. We found that patients with pulmonary fibrosis and advanced emphysema (a modified NETT emphysema score > 2) survived longer than patients with fibrosis without emphysema and, furthermore, the prolonged survival benefit in patients with advanced emphysema was seen in patients with a substantial centrilobular component to their emphysema (those with centrilobular emphysema or mixed emphysema). Patients with fibrosis and trivial emphysema, as well as patients with advanced paraseptal emphysema, had survival times similar to those of patients with fibrosis and no emphysema.CO) [Other groups have previously studied patients with a combination of emphysema and fibrosis -18 and, CO) ,16. RepoCentrilobular emphysema is almost uniformly caused by cigarette smoking ,14 and, The mechanistic relationship between the development of emphysema and the development of fibrosis in patients with both processes remains unknown. It may be that this relationship is merely one of coincidence; patients with a history of smoking develop emphysema and then subsequently develop fibrosis unrelated to the presence of emphysema . AlternaCO, an indicator of abnormal gas exchange that is linked to mortality in pulmonary fibrosis, was very low in all groups [1/FVC ratio was also lower in the advanced emphysema group but the overall physiology pattern of PFTs was still consistent with a restrictive ventilatory defect, a pattern seen in pulmonary fibrosis. This restrictive PFT pattern indicates that, despite the presence of advanced emphysema in this group, the effects of the fibrotic component dominate from a physiologic standpoint.The patients in our study who had advanced emphysema did have higher lung volumes than patients without emphysema, a finding not surprising due to the presence of emphysema and a finding which had been previously reported in patients with emphysema and fibrosis . One coul groups . The FEVCO < 35% predicted had similar outcomes irrespective of their pathologic pattern [An issue which warrants discussion is our inclusion of patients with fibrotic NSIP. We believe inclusion of these patients was appropriate for several reasons which include: the occurrence in many instances of both NSIP and UIP patterns in different lobes from the same patient ; the facA limitation to our study is its observational and retrospective design. Another limitation is that we did not measure the levels of pulmonary or systemic pro- or anti-inflammatory or pro- or anti-fibrotic cytokines. This limitation will be addressed in our future studies.In summary, we have demonstrated that patients with pulmonary fibrosis and advanced emphysema (based on a modified NETT emphysema score of greater than 2) have a better prognosis than patients with pulmonary fibrosis without emphysema or with trivial amounts of emphysema. Furthermore, this improved prognosis was limited to patients with a substantial centrilobular component to their emphysema, as patients with isolated advanced paraseptal emphysema had outcomes similar to patients without emphysema. The precise mechanisms responsible for this improved survival are unknown but our data support the hypothesis that pulmonary inflammation resulting from the presence of emphysema may be partially protective against the deleterious effects of pulmonary fibrosis.We have demonstrated that patients with pulmonary fibrosis and advanced centrilobular emphysema, a well established chronic inflammatory condition of the lung, have a better prognosis than patients with pulmonary fibrosis without emphysema or those with fibrosis and trivial amounts of emphysema. Although the precise mechanisms responsible for this improved survival are not known, our data support the hypothesis that pulmonary inflammation may be partially protective against the usual deteriorating clinical course of patients with idiopathic pulmonary fibrosis.CO: diffusing capacity for carbon monoxide; ES: emphysema score; FEV: forced expiratory volume; FVC: forced vital capacity; IPF: idiopathic pulmonary fibrosis; mPAP: mean pulmonary artery pressure; NSIP: non-specific interstitial pneumonia; PFT: pulmonary function test; RHC: right heart catheterization; TLC: total lung capacity; UIP: usual interstitial pneumonia.DL The authors declare that they have no competing interests.This manuscript has been seen and approved by all authors and all authors contributed sufficiently to warrant their inclusion in the author list and to take responsibility for the content of this report. The study was designed by NWT and SPA. NWT had full access to the data and vouches for the integrity of the data analysis. Clinical data were collected and analysed by NWT, SL, JD and EJB. Pathology materials were reviewed and analysed by NWT and TJF. Radiology data was reviewed and analysed by JJ, JRG and NWT. The database was maintained by NWT and SPA, who also performed statistical analyses and prepared the manuscript."} +{"text": "In resourced settings with access to highly active antiretroviral therapy (HAART), perinatally acquired HIV-1 infection has become a chronic disease of childhood. Reduced mortality due to HAART, combined with high uptake of antenatal HIV testing and a marked reduction in rates of mother-to-child transmission has resulted in significant increases in the average age of paediatric cohorts in these regions and hence increasing numbers of children born with HIV are surviving to early adulthood and completing the process of transition from paediatric to adult services. Advances in antiretroviral therapy, reductions in pill burdens and drug side effects, new classes and new drugs within existing antiretroviral classes offer enormous benefits, although serious issues around adherence during adolescence continue. Questions persist around the optimal timing and sequencing of antiretroviral agents to maintain future treatment options, particularly with global recommendations for the earlier initiation of therapy across the paediatric age range. The longer term impact of exposure to HIV and antiretroviral therapy throughout childhood are becoming apparent, with growing concern over neurocognitive, cardiovascular, renal and bone health requiring further elucidation. Adolescents living with perinatally acquired HIV have additional psychosocial issues including the impact of HIV on other family members, roles as young carers, experience of parental and sibling bereavement, and live with a disease that is potentially transmissible to future sexual partners before they themselves have had sex. Increasing numbers of young women born themselves with HIV are becoming sexually active and having uninfected infants of their own and the long term outcomes for the next generation require monitoring. The benefits of HAART far outweigh the potential risks and the careful follow up of this early perinatal cohort as they progress through adulthood will hopefully aid the future management of the growing numbers of adolescents surviving worldwide as access to therapy improves."} +{"text": "However, GCs connectivity is not limited to local neuronal networks . These cells also receive centrifugal inputs onto their basal and proximal dendritic domains and show early synaptic responses to glutamate before the establishment of synaptic connections with mitral cells at the more distal portions of their dendritic arbors (Panzanelli et al., According to Dr. Pangloss (Voltaire, Moreno et al. have recAraC treatment impedes olfactory enrichment to improve mice discriminatory abilities. In contrast to what happens when new neurons are still present, this defect is not rescued by the stimulation of the noradrenergic system. Eventually lesioning of the noradrenergic inputs on the OB, possibly the LC, would further confirm this observation. These results strongly suggest that olfactory perceptual learning in mice is improved specifically by the noradrenergic control of newborn cell functional integration. This direct link is further supported by the observation of synaptic contacts between young GCs and noradrenergic fibers and direct GCs response to noradrenaline stimulation.They showed that blocking the noradrenergic system during olfactory enrichment abolishes its positive effects on olfactory discriminatory ability while the stimulation of the noradrenergic system alone results in better performances in the discriminatory task. To complete the picture of the involvement of the noradrenergic system, they showed that olfactory enrichment induced a higher activity in the locus coeruleus, the source of noradrenergic fibers in the brain. Previous reports revealed that perceptual learning requires the incorporation and activation of newborn GCs (Moreno et al., why individual cells are important, to how the whole brain uses them. Indeed, either stimulus novelty, arousal, or the rewarding value of olfactory cues, seem to define the functional context in which olfactory bulb neurogenesis is modulated (Figure These interesting results, combined with other studies, support the idea that the selection of functional elements in the peripheral sensory circuitry depends on the concurrence of external inputs and the consequent backward stimulation from downstream brain nuclei (Gilbert and Sigman, d Figure . In the"} +{"text": "A majority of women use complementary and alternative medicine (CAM) during pregnancy yet many are not under the care of a qualified CAM practitioner nor inform their primary healthcare clinician of their CAM use. Most conventional maternity carers do not receive training in CAM as part of their formal education and many CAM practitioners do not gain training in order to collaborate effectively with practitioners within the conventional system. Inter-professional education (IPE) is an approach which has been utilised as a tool to promote collaborative practice. However, IPE programs encompassing CAM practitioners and midwives are comparatively scarce. The aim of this study is to evaluate whether participation in an IPE program impacts upon the perceptions and practice behaviours of maternity care providers (midwives and CAM practitioners).Midwives and CAM practitioners participated in discrete workshops designed to promote a shared understanding and develop network, referral and collaboration pathways. The impact of the workshop on the perceptions and practice behaviours of the participants was evaluated using a 3 stage questionnaire: pre-workshop, post-workshop and 3 month follow-up questionnaire.Questionnaires were completed by 147 midwives and 30 CAM practitioners. Preliminary analysis identified an improvement in midwives\u2019 perceptions of self-proficiency with regard to CAM particularly with regards to perceived knowledge of CAM and ability to answer general questions about safety and effectiveness of CAM in pregnancy. Final analysis will explore changes in practice behaviours of both midwives and CAM practitioners in the 3 months after completing the IPE workshopThis study shows IPE may be an effective education tool for midwives and CAM practitioners improving participants\u2019 competence when caring for women choosing to integrate CAM and conventional maternity care during their pregnancy and birth. Further research on the issue of IPE for maternity care providers is suggested."} +{"text": "The presentation describes the novel insights on the interaction between the immune system and bone over the last 10 year, and explains molecular and cellular interactions as well as their clinical implications.Bone is subject to a continuous remodeling process which allows an ideal adaptation to the individual demands throughout life. This remodeling process is based an interplay between bone forming osteoblasts and the bone resorbing osteoclasts. Several conditions alter this balance, among them the drop of estrogens levels after menopause is the most well known factor, which leads to enhanced bone resorption and bone loss. Interestingly, all different forms of inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease also interfere with the bone remodeling process and precipitate bone loss and increased fracture risk.To study this interaction between immune activation/inflammation and the skeletal system has become a novel research discipline called osteoimmunology. This field has gained insights into the mechanism of inflammatory bone loss, in particular of how inflammatory cytokines like TNF-alpha, IL1 or IL6 foster bone resorption and inhibit bone formation, resulting in an imbalance of bone homeostasis and thereby precipitating bone loss. Therapeutic inhibition of cytokines has yields profound changes architecture in arthritis patients and protects the bone and in part also the articular cartilage. Inflammatory cytokines particularly enhance bone loss by activation of osteoclast differentiation factors such as MCSF and RANK ligand and by molecules which interfere with bone formation such as DKK1 and sclerostin.The insights into molecular regulation of bone remodelling by the immune system are thus of key interest in better understanding inflammatory diseases such as arthritis and to shape novel therapeutic concepts. Research in the field of osteoimmunology has a strong translational approach and directly affects patients suffering from inflammatory diseases, in particular arthritis, in aiming to prevent skeletal damage and loss of physical function."} +{"text": "Current pharmacotherapies and surgical intervention provide limited benefit in the treatment of neural injuries or halting disease progression. Significant advances in the area of stem cell biology in the last decade has lead to a special emphasis on the success of stem cell-based applications for the diagnosis and treatment of neurological conditions. The properties of stem cells render them appropriate for endogenous repair, disease modeling, high-throughput drug screening and development as well as neural transplantation procedures. Such applications will aide in increasing our knowledge and developing treatments for neurodegenerative disorders such as Parkinson's disease and Huntington's diseases as well as neural traumas including ischemic brain damage and traumatic brain injury. This Frontiers Research topic incorporates contributions from the general field of stem cell biology, with a particular emphasis on utilizing these cells to develop new therapies for neural repair. Related articles deal with issues including: promoting endogenous neurogenesis, breakthroughs in stem cell differentiation methodologies, using pluripotent and neural stem cells for transplantation, patient derived stem cells for disease modeling and using stem cells for drug discovery.The first 3 papers focus on understanding and subsequently exploiting, endogenous neurogenesis in order to enhance neural repair. Within the adult mammalian brain, neurogenesis is largely restricted to two sites; the dentate gyrus of the hippocampus and the subventricular zone adjacent to the lateral ventricle. In order to \u201charness\u201d these cells for repair it will be vital to understand the mechanisms regulating their proliferation, migration, differentiation and survival. Sui et al. examinesThe generation of stem cell lines provides valuable tools for disease modeling and drug development. Blastocyst screening for genetic disorders such as Huntington's disease and Down's syndrome have enabled the generation of embryonic stem cells carrying these mutations. In more recent years, inducible pluripotent stem (iPS) cell technology has allowed stem cell lines to be generated from somatic cells of patients suffering from a number of degenerative conditions including Parkinson's disease and motor neuron disease. Added to this has been the ability to generate neural stem cell lines from other sources such as olfactory ensheathing cells of patients. Combined, such cell lines provide new tools to examine the pathological events that lead to disease onset and progression as well as development and testing of novel drug targets. Here, Niclis et al. examinesin vitro and in vivo, with this knowledge having implications for improved grafting approaches for treatment of Parkinson's disease. Garcia et al. (One of the most widely anticipated applications for pluripotent stem cells is their utilization in neural transplantation procedures. This will require robust and appropriate fate restriction into more specialized lineages and their survival and appropriate functional integration into existing host circuitry after transplantation. Kirkeby et al. contribua et al. highligha et al. provide Collectively these works highlight the rapidly progressing stem cell field and draw attention to the current and on-going potential these cells have for improving our understanding of the healthy and diseased nervous system and their capacity to promote neural repair."} +{"text": "To the Editor: A recent article by Chlebicki et al (\u2013This conclusion is misleading because retinal hemorrhages alone cause scotomas. Rather, the accumulation of subretinal fluid in the macula results in metamorphopsia and blurring of vision. In previous reports of patients in whom macular changes developed from dengue fever, some were found to have macular hemorrhages (The article by Chlebicki et al. did not state whether these procedures had been performed on their patients to confirm or exclude retinal or choroidal vasculopathy in the macula. Therefore, these authors would have had difficulty concluding that retinal hemorrhages caused blurring of vision and metamorphopsia in patients with dengue maculopathy."} +{"text": "Maintenance of energy balance requires regulation of the amount and timing of food intake. Decades of experiments utilizing pharmacological and later genetic manipulations have demonstrated the importance of serotonin signaling in this regulation. Much progress has been made in recent years in understanding how central nervous system (CNS) serotonin systems acting through a diverse array of serotonin receptors impact feeding behavior and metabolism. Particular attention has been paid to mechanisms through which serotonin impacts energy balance pathways within the hypothalamus. How upstream factors relevant to energy balance regulate the release of hypothalamic serotonin is less clear, but work addressing this issue is underway. Generally, investigation into the central serotonergic regulation of energy balance has had a predominantly \u201chypothalamocentric\u201d focus, yet non-hypothalamic structures that have been implicated in energy balance regulation also receive serotonergic innervation and express multiple subtypes of serotonin receptors. Moreover, there is a growing appreciation of the diverse mechanisms through which peripheral serotonin impacts energy balance regulation. Clearly, the serotonergic regulation of energy balance is a field characterized by both rapid advances and by an extensive and diverse set of central and peripheral mechanisms yet to be delineated. The monoamine signaling molecule 5-hydroxytryptamine is utilized by diverse invertebrate and vertebrate species for the regulation of many of the behavioral and physiological processes through which energy balance is maintained agonist muscimol resulted in hyperphagia and obesity caused hypophagia . Interpretation of adult phenotypes in the genetic models is complicated by the fact that serotonin has significant roles in development . As expected, the absence of serotonin reuptake into presynaptic terminals enhanced synaptic concentrations of serotonin, and SERT null mice exhibited elevated extracellular serotonin levels , a developmental disorder resulting from loss of paternal gene expression on chromosome 15q11\u201313. The disorder is characterized by cognitive impairment, short stature, and hyperphagia often leading to morbid obesity , dorsomedial (DMH), and ventromedial (VMH) nuclei produced hyperphagia and obesity while lesions within the lateral hypothalamic area (LHA) produced hypophagia . The arcuate nucleus is located at the highly vascularized ventromedial aspect of the hypothalamus, immediately adjacent to the median eminence, allowing access to a wide range of circulating factors , an endogenous antagonist of MC3R and MC4R that compete with tryptophan for transport into the brain. High tryptophan:LNAA ratios promote central serotonin synthesis, while low tryptophan:LNAA ratios have the opposite effect. Protein-rich meals have been shown to decrease this ratio, while carbohydrate-rich meals increased it, presumably by stimulating insulin release, which in turn promoted absorption of LNAAs by peripheral tissues produced significant hyperphagia and severe obesity vs. long-term energy stores (leptin), it has been proposed that serotonin and leptin might represent independent energy-balance systems that integrate in the hypothalamus (Halford and Blundell, Htr2c null and ob/ob leptin null mutations revealed a synergistic effect on glucose regulation, indicated by a marked exacerbation of the diabetes phenotype characteristic of the ob/ob genotype (Wade et al., Some recent studies provide evidence that a complex interplay may occur between these two systems. One study examining the impact of combined Evidence for a functional interaction between serotonin and leptin arose from studies demonstrating that central or peripheral leptin administration altered serotonin levels in the brainstem and hypothalamus (Harris et al., ob/ob leptin null mice, and POMC- or SF1-specific LEPRb null mice did not display significant alterations in any of these parameters (Yadav et al., A model in which leptin actions are mediated through serotonergic circuits has recently been proposed by Yadav et al. , 2011. TThese results conflict with the prevailing notion that leptin exerts its effects on energy balance predominantly through other neuronal populations including POMC neurons of the arcuate (Balthasar et al., In response to concern that the SERT-driver mouse might have produced inactivation of LEPRb outside the serotonergic neurons of the brainstem, a follow-up study by Yadav et al. utilized a tamoxifen-inducible TPH2-driver (Yadav et al., Ghrelin is a gastric hormone that is secreted during periods of fasting, and its levels fall after food intake (Kojima et al., Evidence also exists indicating that serotonergic signaling may impact ghrelin release. Both fenfluramine and mCPP decreased plasma active ghrelin levels without altering hypothalamic ghrelin gene expression (Nonogaki et al., Insulin is secreted by the \u03b2-cells of the pancreas in response to rising blood glucose levels and it promotes glucose uptake and utilization by peripheral tissues. However insulin also acts in the brain, where it has effects on glucoregulation and energy balance (Woods et al., Several lines of evidence now indicate that serotonin and insulin are not merely parallel activators of melanocortin circuits, but that there is an interaction between the two systems. For example, systemic administration of 5HT2CR agonists decreased serum insulin at doses that did not impact food intake or body weight (Zhou et al., Orexin neurons are located in the lateral hypothalamus and project widely throughout the brain. Serotonergic neurons of the dorsal raphe nucleus express orexin receptors (Marcus et al., There is also evidence that serotonin systems can directly impact the function of orexin neurons. Orexin neurons in the lateral hypothalamus express 5HT1A receptors and serotonergic nerve terminals are in close apposition to orexin neurons (Muraki et al., In mammals, the vast majority of serotonin resides not in the brain, but in the periphery (Erspamer, Enterochromaffin cells are found in the enteric epithelium throughout the length of the digestive track (Erspamer, The primary sensory neurons of the enteric submucosa are cholinergic and their function is required for the proper peristaltic and secretory responses to food (Cooke et al., 5HT3 receptors are expressed on nerve terminals of vagal afferents located in the gastrointestinal track, where they respond to serotonin released by enterochromaffin cells (Glatzle et al., Some serotonin released by enterochromaffin cells is absorbed into the circulation by capillaries in the enteric submucosa, where it enters the blood stream (Tamir et al., Circulating serotonin has also been shown to have complex effects on peripheral glucose regulation. Peripheral serotonin seems to impact glucoregulation via at least two discrete apparently opposing mechanisms. Peripheral serotonin administration has been found in some studies to increase, and in others to decrease circulating blood glucose levels, with the discrepancy possibly depending on dose, route, or other conditions (Yamada et al., In addition, circulating serotonin influences lipid metabolism. Peripheral administration of serotonin accelerated lipid metabolism, decreasing circulating levels of triglycerides, fatty acids, and cholesterol (Watanabe et al., In conclusion, the extent to which central and peripheral serotonin signaling pervasively impact the regulation of energy balance is quite remarkable. It is challenging to identify central or peripheral neural mechanisms of energy balance regulation that are NOT sensitive to serotonergic modulation. The use of mouse genetic models with cell-type-specific patterns of gene inactivation is contributing substantially to rapid progress in this field. The most extensively characterized of the serotonergic influences on energy balance pathways relates to the modulation of arcuate nucleus POMC and NPY/AgRP neuronal populations. Clearly, this has significant functional relevance. However, the serotonergic innervation of additional hypothalamic regions and the expression of multiple 5HTR subtypes in these regions suggest that much remains to be learned regarding serotonergic regulation of hypothalamic energy balance pathways other than those originating the arcuate nucleus. Also important, but less understood, are mechanisms through which serotonin systems regulate energy balance pathways in caudal brainstem regions such as the NTS and PBN. In addition to advances in understanding how serotonergic inputs influence energy balance pathways, new light is being shed on mechanisms through which energy balance hormones influence the activity of serotonin systems. It is also becoming clear that serotonergic influences on hypothalamic energy balance pathways interact with those mediated by leptin, ghrelin, and insulin. Evidence that serotonin systems can influence circulating levels of these hormones indicates an additional level of complexity with regard to the interplay of these signaling molecules in energy balance regulation. Finally, newly uncovered roles for central and peripheral serotonin in the regulation of glucose homeostasis and lipid metabolism underscore the pervasive involvement of serotonin signaling in the interplay between central and peripheral mechanisms of energy balance regulation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Prevention of Orthopaedic Implant Infection in Patients Undergoing Dental Procedures.\u201d This evidence-based guideline ,detailed in 325 pages, has three recommendations and substitutes the previous AAOS guideline. The new published clinical guideline is a protocol to prevent patients undertaking dental procedures from orthopaedic implant infection. The guideline is developed on the basis of a collaborative systematic review to provide practical advice for training clinicians, dentists and any qualified physicians who need to consider prevention of orthopaedic implant (prosthesis) infection in their patients. This systematic review found no explicit evidence of cause-and-effect relationship between dental procedures and periprosthetic joint infection (PJI). The American Academy of Orthopaedic Surgeons (AAOS) and the American Dental Association (ADA), along with 10 other academic associations and societies recently (December 2012) published their mutual clinical practice guideline \u201cThis LTTE wishes to present a vivid summary of AAOS/ADA clinical practice guideline as a clinical update and an academic implementation to inform and assist Iranian competent clinicians and dentists in the course of their treatment decisions, to enrich the value and quality of health care on the latest international basis. Moreover, it indicates that practitioners should consider changing their customary practice of prescribing prophylactic antibiotics for dental patients inconclusive recommendation or not. The guideline emphasizes that patient preference should have a significant influencing role and practitioners should cautiously wait for future publications that elucidate the existing evidence to determine the balance between benefits and potential risk Consensus, indicating that expert opinion supports the guideline recommendation albeit the fact that no available evidence can encounter the inclusion criteria. The guideline emphasizes on the imperative role of patients\u2019 preference in decision making and also affirms the flexibility of practitioners in deciding whether to follow a recommendation rated as Consensus or not. Consensus recommendations are the weakest form of recommendation and cannot be used to ignore recommendations developed from higher levels of evidence [This recommendation was graded as evidence -3. This recommendation conveys the maintenance of good oral hygiene and apparently, it is the only consensus recommendation in the new guideline. Oral hygiene measures are available and cheap, provide possible benefit, are consistent with current clinical practice and are in concordance with good oral health .Goals and Implications for Clinical PracticeThe rate of OI infection is recorded from 0.3% to 8.3% in the available published literature. Invasion of organisms into the surgical wound during the surgery, haematogenous spread, recurrence of infection in previously involved and infected joints, or propagation from an infective local source may produce such infection .Established on the best existing evidence, the rational for this clinical practice guideline is to assist the related clinicians and dentists to choose a paramount preventing and treatment modality when it is requisite. Contemporary dental practice inevitably depends on evidence-based standards and stipulates physicians and dentists to employ the best available evidence for treatment planning in their clinical practice. That\u2019s why this guideline consists a systematic review of literature, conducted between October 2010 and July 2011 by AAOS and ADA methodologists and the doctor/dentist vocational groups and declared wherever the evidence was adequate or inadequate .They even discussed the gaps in the literature, where future researches are particularly needed [Jevsevar, an orthopaedic surgeon and chairman of the AAOS team, declared that this clinical practice guideline was not supposed to be an impartial document and he confirmed that clinicians should use it as an instructive tool in their treatment planning to improve the quality and efficacy of their health care .In summary, the guideline is deliberated to conduct clinical practice and also to provide a source of information for all qualified practitioners dealing with prevention of OI infection in dental patients. The AAOS and ADA hope that this guideline would also assist to ensure patients regarding the logics behind their treatment planning .http://www.aaos.org/research/guidelines/PUDP/PUDP_guideline.pdf and the ADA website: http://www.ada. org/sections/professionalResources/pdfs/PUDP_guideline.pdf (Therefore, The new guideline replaces the previous AAOS Information Statement and the full guideline with all succeeding credentials and workgroup declarations is available to access on the AAOS website: line.pdf ."} +{"text": "A case study of one frail elderly client with indolent arterial ulceration was conducted, with glyceryl trinitrate (GTN) patch therapy appearing to have a positive role in the healing outcome and improved vascular status as measured by photoplethysmography (PPG ) toe pressure measurements. The history and pharmacological action of this novel mode of therapy are briefly presented. The presentation of chilblains (erythema pernio) and arterial ulceration are discussed in the context of this case. Loss of sensitivity to cold perception, related to age, arterial insufficiency and other factors are considered. Current research using this medication for other applications suggests that GTN patch therapy should have a positive role in healing arterial ulceration associated with peripheral vascular disease (PVD). Positive outcomes with painful diabetic neuropathy have also been found with this therapy and its use warrants further investigation. A review of the literature on the use of GTN therapy for digits is briefly summarised. Important to clinical treatment of aged people with reduced vascular supply are decreased sensory functions of pain, protective sensation and temperature sensation. Further research on the effects of GTN therapy for wound healing should aim to control for seasonal climate and environmental temperature changes, as well as other factors that influence wound healing such as wound care, wound dressings and nutrition."} +{"text": "Over the last ten years, genome-wide association studies (GWAS) have reported over 4000 single nucleotide polymorphisms associated to more than 200 traits ,2. DespiDiseases are traditionally considered as discrete entities and classified accordingly. However, the networks of genes accountable for particular disease phenotypes most certainly overlap, with individual genes simultaneously serving the cause of multiple disorders ,7. CliniAdditional indices on where to start exploring the genome for susceptibility loci can be inferred from general principles of human diseases and clinical data. For example, a considerable fraction of diseases with onset early in life appear to result from defects in enzyme-encoding genes, whereas diseases with onset during adulthood appear to be caused by alterations in genes encoding modifiers of protein functions . Thus, cRecent years have come with major advancements in candidate gene prioritization and our understanding of the genetic architecture of human diseases is undoubtedly progressing. Here we have suggested that biological and clinical information may serve as valuable expert knowledge for genetic association studies and that disease networks may provide useful guidance prior to and during data mining."} +{"text": "The term flat epithelial atypia (FEA) was introduced in 2003 by the WHO working group on the Pathology & Genetics committee of tumours of the breast. Previously known as columnar cell change with atypia, these lesions usually present as microcalcification and although there is some evidence to suggest that FEA represents a precursor lesion in the spectrum of low-grade breast neoplasia, there are limited data concerning the ultimate clinical impact and optimum management strategy. The aim of this study was to determine the radiological characteristics of FEA and final histology following surgical excision at our centre.Retrospective review of 950 consecutive image-guided core and vacuum biopsies performed over an 8-year period revealed 162 lesions with FEA as the most prominent pathologic entity; concomitant lobular neoplasia, ADH or malignancies were excluded. The radiologic characteristics of FEA/CCC lesions were assessed with respect to size, morphology and multifocality at presentation. Biopsy technique and final histology of these lesions following surgical excision were recorded.The rate of upgrade to a more significant pathology was 10% with significant pathology being DCIS of varying grade. Microcalcification was the most common mammographic sign.Surgical excision of FEA at our centre has resulted in a low rate of upgrade to malignancy supporting current thinking that some lesions may be managed by vacuum excision, thus reducing the surgical diagnostic excision rate."} +{"text": "Infections caused by antibiotic resistant pathogens is a growing concern that complicates treatment and influences patient outcome in critical ill. The purpose of this work was to develop and test the feasibility of a system for continuous audit of resistance and compliance to antibiotic treatment guidelines for severe infections in critical care.Records from ICU patients were collected in the Swedish Intensive Care Registry (SIR). Mortality data was added weekly for each episode of care (EOC). A web service was developed for individual collection of results from microbiological cultures and analyses for each EOC. Development of the web service included a detailed and cumbersome translation of laboratory specific nomenclatures for samples, cultures, microbials and methods.Bacteriological data from clinical microbiological laboratories were merged with its respective EOC in SIR yielding data on patient-specific bacteriology and microbial susceptibility. Trends in microbial resistance among alert pathogens were examined. Data on gender, age, co-morbidity were collected from SIR and correlated to microbiological findings and 30-day mortality. Resistance patterns were analyzed to assess the appropriateness of National guidelines for the treatment of pneumonia in the ICU showing 86 % possible accuracy with suggested treatment for community acquired and 82 % for hospital acquired disease.Microbial findings matched with reason of ICU admission can be used to validate or update national guidelines for proper antibiotic treatment. This program may be developed to an early warning system for antibiotic resistance in intensive careNone declared."} +{"text": "Now that large meta-analyses of genome-wide association studies (GWAS) have been published for bipolar disorder and major depression it has become clear that main effects of common variants are difficult to identify in these disorders, suggesting that additional approaches maybe needed to understand the genetic basis of these disorders .Family, twin and epidemiologic studies all point to an important genetic contribution to the risk to develop mood and anxiety disorders. While some progress has been made in identifying relevant pathomechanisms for these disorders, candidate based strategies have often yielded controversial findings. Hopes were thus high when genome-wide genetic association studies became available and affordable and allowed a hypothesis-free approach to study genetic risk factors for these disorders. In an unprecendented scientific collaborative effort, large international consortia formed to allow the analysis of these genome-wide association datasets across thousands of cases and controls ([1] and see also Several factors need to be considered when evaluating the results of genetic association studies in mood and anxiety disorders.in vitro observations on neurons derived from inducible pluripotent stem cells from patient fibroblasts [In contrast to other medical disorders, diagnoses for psychiatric disorders are still mostly based on verbal report and observation and not biological measures. It is thus very likely that our symptom-based diagnoses include patients with different primary pathophysiological disturbances and thus likely predisposing genetic variants reducing the power of genetic association studies. In addition, our diagnostic scheme may separate individuals with common genetic risk factors into different categories. For example, it is likely that bipolar disorder patients share genetic susceptibility loci with patients with major depression as well as schizophrenia . Specifiroblasts .The published GWAS in mood disorders all highlight that a high number of common variants with small odd ratios likely cumulatively contribute to the risk to suffer from these disorders . While tIn addition, combining genome-wide protein and gene expression datasets and studies in animal models of mood and anxiety disorders with human genetic studies may also help to identify relevant candidate genes from GWAS. For example, combining GWAS and gene expression studies for bipolar disorder, association signals appear to cluster in discrete regions of the protein\u2013protein interaction network, showing replicated evidence for association for networks involving several interlinked signaling pathways, such as transmission of nerve impulse, Wnt and Notch signaling . Such anFor schizophrenia and autism but also bipolar disorder it has become increasingly clear that rare variants in addition to common variants contribute to the risk of disease . New tecFinally, the environmental risk component is strong in mood and anxiety disorders, especially major depression. A number of candidate gene studies suggest that genes might moderate the effects of environmental risk factors in the absence of main genetic effects . GWAS maIn conclusion, while the results from genetic studies in mood and anxiety disorders may seem disappointing at first sight, a panoply of new analytic strategies and molecular genetic tools is likely to yield significant discoveries in the near future that further our understanding of the pathophysiology of these disorders, some of which will be highlighted in this series."} +{"text": "Ecklonia radiata and Phyllospora comosa and neither species showed any clear patterns of genetic structuring with geographic distance within or among marine parks. In contrast, connectivity was low for the intertidal, Hormosira banksii, and there was a strong pattern of isolation by distance. Coastal topography and latitude influenced small scale patterns of genetic structure. These results suggest that some species are well served by the current system of marine reserves in place along this temperate coast but it may be warranted to revisit protection of intertidal habitats to ensure the long-term persistence of important habitat-forming macroalgae. Adaptively managing marine reserve design to maintain connectivity may ensure the long-term persistence and resilience of marine habitats and the biodiversity they support.Networks of marine reserves are increasingly being promoted as a means of conserving marine biodiversity. One consideration in designing systems of marine reserves is the maintenance of connectivity to ensure the long-term persistence and resilience of populations. Knowledge of connectivity, however, is frequently lacking during marine reserve design and establishment. We characterise patterns of genetic connectivity of 3 key species of habitat-forming macroalgae across an established network of temperate marine reserves on the east coast of Australia and the implications for adaptive management and marine reserve design. Connectivity varied greatly among species. Connectivity was high for the subtidal macroalgae Marine reserves are increasingly being promoted as a means of managing coastal resources and protecting marine biodiversity A key reason for designing networks of marine reserves is connectivity Temperate marine reserves worldwide are often dominated by macroalgae that constitutes a major biogenic habitat. Macroalgal habitats play a key role in maintaining marine biodiversity because they support a complex array of associated organisms Ecklonia radiata (C.Agardh) J.Agardh, Phyllospora comosa (Labillardi\u00e8re) C. Agardh and Hormosira banksii (Turner) Decaisne, within and among this network of temperate reserves. Given the strength of ocean currents along this coastline , we predict that connectivity will be reasonably high for all species, but variations will be correlated with differences in morphology and life history. Specifically, we predict that macroalgae possessing the ability for long-distance dispersal (e.g. gas-filled vesicles that facilitate rafting) will have greater connectivity than those that lack such structures. We discuss the implications of connectivity of these ecologically-important macroalgal habitats for marine reserve design on both local (within reserve) and regional scales (networks of reserves).A network of marine reserves has been established along \u223c800 km of the coast of New South Wales, Australia. Macroalgae constitute the dominant and most conspicuous biogenic habitats on rocky reefs within most of these reserves 2 and were different distances apart (1 to 21 km). Relevant permits for collection of algae at the 4 marine parks were obtained prior to collection.Marine reserves in New South Wales provide protection on a hierarchy of spatial scales with replicate marine \u201cparks\u201d along the coast each containing a number of fully protected \u201creserves\u201d or sanctuary zones . We chosEcklonia radiata , the endemic Phyllospora comosa and Hormosira banksii . Each species represents the dominant form of biogenic habitat on intertidal or subtidal rocky reefs in temperate Australia and supports extremely diverse faunal assemblages Phyllospora and the intertidal Hormosira are both dioecious (obligate-outcrossers) with motile sperm and either sessile (Phyllospora) or negatively buoyant (Hormosira) eggs. In contrast, the kelp, Ecklonia has an alternations of generations life history. As with other laminarian macroalgae, sperm are likely capable of dispersal on small spatial scales (e.g. cm) Phyllospora and Hormosira possess gas-filled vesicles that may facilitate rafting long-distances Ecklonia which does not possess such structures. All 3 species are considered cold temperate macroalgae and are nearing the northern limits of their distribution in northern NSW.We chose the 3 most abundant, perennial species of habitat-forming macroalgae to characterise patterns of connectivity; Phyllospora was only sampled from the southerly parks where it was most abundant (BMP and JBMP). Material was air dried, DNA was extracted and individuals were genotyped using 5 microsatellite loci for Hormosira and 7 for Ecklonia and PhyllosporaHo) and expected heterozygosities (He) and FIS (an estimate of inbreeding within populations) were estimated using GENETIX ver. 4.04 Portions of unfouled thalli of at least 32 mature individuals of each species were randomly collected from each sanctuary zone in 2009 and taken to the laboratory on ice. FST estimates FST) can reflect processes in addition to dispersal and connectivity meta-analyses have shown that such additional processes rarely overwhelm estimates of dispersal and that FST is still an informative statistic for characterising connectivity FST estimates were also estimated between parks and among sanctuary zones within parks. A sequential Bonferroni correction P<0.05 was used. Tests of isolation by distance were done via a Mantel test on pairwise FST and geographic distance matrices. This was done for all data and for each park separately using the program IBD We infer connectivity from estimates of genetic differentiation using Weir and Cockerham's Phyllospora and all loci were in Hardy-Weinberg equilibrium. There were significantly more alleles over all loci in BMP relative to JBMP . Both JBMP and BMP showed random mating with 13 out of 15 FIS estimates being non-significant was characterised by inbreeding/selfing (P>0.05). Private alleles were only found in 2 sanctuary zones within BMP.For the kelp, /selfing . There wHormosira showed no evidence of null alleles or linkage disequilibrium at any locus. Tests for Hardy-Weinberg equilibrium over all populations of Hormosira revealed that 3 loci deviated from random mating but patterns were variable among sanctuary zones . Private alleles were found in 3 sanctuary zones within BMP and 1 within SIMP.ry zones . Locus Sbreeding . The meaPhyllospora varied by orders of magnitude between parks with strong structure within JBMP and weak structure within the open coast BMP being similar to inside/outside comparisons (FST\u200a=\u200a0.229).Genetic differentiation of oast BMP . Within oast BMP . PhyllosEcklonia, there was insignificant population differentiation within most marine parks differed from all others. The only park to exhibit a positive correlation between genetic differentiation and geographic distance between sanctuary zones was PSGLMP , but not within any other park and weaker structure for Phyllospora (FST\u200a=\u200a0.14) and Ecklonia (FST\u200a=\u200a0.049). For all species, all pairs of parks were genetically different indicating that dispersal is at least somewhat restricted on these scales, however, the magnitude of these differences varied between parks and species . Patterns were more complex for Ecklonia with varying levels of differentiation among different pairs of parks but not for Ecklonia . Of these migrants, approximately half were likely sourced from a sanctuary zone within the same park (56\u201359%). Migrants with a likely source in another park were predominatly from adjacent parks.There was a significant relationship between genetic differentiation and geographic distance over all parks for Ecklonia . For HorEcklonia and PhyllosporaHormosira. These patterns were generally reflected within each park and indicate that Ecklonia and Phyllospora are well served by the current system of marine reserves in place along the NSW coast.Connectivity of habitat-forming macroalgae within and among a network of marine reserves along \u223c800 km of Australia's temperate coastline varied greatly among key habitat-forming algal species. Connectivity across the network of parks was high for the large, subtidal macroalgae Hormosira, the loss of localised populations may be particularly problematic for this species. Unlike the subtidal species, Hormosira has a more limited habitat range and is more vulnerable to direct human interactions. For example, it has been demonstrated that cover can be substantially reduced from trampling, which has flow on impacts to associated communities Hormosira to localised impacts and its highly structured populations, it may be warranted to revisit protection of intertidal habitats at Marine Park zoning plan reviews to ensure long-term persistence of this important habitat-forming species. It should be noted, however, that the Sydney region has a few intertidal protected areas and aquatic reserves in which macroalgae are protected that augment protection afforded by Marine Parks.Given the highly structured nature of populations of the intertidal Ecklonia and Phyllospora. These subtidal species broadcast spawn propagules directly into the ocean and dispersal may potentially occur over long distances. Further, fertile drift material that is torn from the substratum in storms has been found 100 s km away from its nearest source Phyllospora and EckloniaThe East Australian Current (EAC) is the strongest of Australia's continental boundary currents reaching speeds of up to 3.6 m/s and generates a characteristic cyclonic and anticyclonic eddy field EckloniaPhyllosporaThe EAC is also characterised by seasonal variation in its strength and positioning allowing inshore, north-flowing counter currents that can facilitate bi-directional dispersal Ecklonia and Phyllospora, the current system of marine reserves in place along this coastline is adequate to ensure that connectivity of these ecologically important species is maintained. Indeed, dispersal and mixing of genetic material along the NSW coastline appears to be substantial and conducive to resilience of these species to recolonise following perturbations. With predicted strengthening of the EAC with climate change over the next century Given the high connectivity and lack of isolation by distance for Ecklonia with populations within 2 sanctuary zones differing from all others. This subtropical park is near the northern limit of distribution of Ecklonia and north of the main separation point of the EAC. In this park, kelp forests are interspersed with invertebrate and coral dominated habitat and genetic differentiation may thus arise due to the more fragmented nature of Ecklonia populations relative to their southerly counterparts. Further, relative to populations at higher latitudes, populations of kelp at lower latitudes often undergo intense grazing by herbivorous tropical fish that remove the entire canopy (pers. obs) and are known to exhibit an unusual annual life history Latitude may play a role in structuring populations nearing their northern limit of distribution because of their often fragmented nature and variable population dynamics and ecology. The northern most marine park (SIMP) was the only place to exhibit significant genetic structure of Hormosira with greater allelic diversity (and expected heterozygosity) in parks at higher latitudes relative to parks at lower latitudes. Again, this pattern is perhaps not surprising given that northern NSW is the limit of distribution of this temperate alga and populations are likely to be smaller and more fragmented and experience greater population fluctuations as conditions near their physiological tolerances. Lower genetic diversity may confer a decreased ability to adapt to extreme conditions and populations at the limits of their distribution may be at greater risk of extinction under predicted scenarios of climate change. Multiple species of temperate macroalgae have already been observed to have shifted poleward on the coast of NSW Latitude also correlated with genetic diversity of Phyllospora between the 2 marine parks in which it was sampled. Populations within the large embayment of JBMP displayed reasonably high population structure and are likely isolated from the main flow of the EAC by the protruding headlands and narrow entrance of this bay. Low connectivity as seen within JBMP appears to be atypical of the NSW coastline for this Coastal topography is known to influence patterns of connectivity of marine organisms and is likely to account for the contrasting patterns of connectivity of Phyllospora and Hormosira) did not appear to greatly facilitate rafting and long-distance dispersal as evidenced by high genetic structure in Hormosira and, in some places, Phyllospora (JBMP). Hormosira has previously been shown to have the potential for long distance transport of fertile drift material that is torn from the substratum Hormosira. Nevertheless, approximately half of the Hormosira individuals sampled were classified as migrants that were predominatly from adjacent sanctuary zones in the same marine park suggesting that detached fertile individuals of this species must occasionally disperse on these spatial scales because fucoid fertilisation is generally rapid and zygotes presumably attach quickly to the substratum Hormosira may be, however, related to the intertidal habitat of this species. Intertidal fucoid algae generally have limited dispersal potential Contrary to predictions, the extent to which populations of macroalgae were connected was not related to morphology. The presence of gas-filled vesicles (e.g. Ecklonia and Phyllospora but strong correlations for Hormosira over the entire network of parks. These patterns were consistent within parks except for Hormosira where positive correlations were restricted to 1 park (PSGLMP). The spatial arrangement and distances among reserves are therefore important considerations for ensuring connectivity of Hormosira along this coastline. Clearly, dispersal and subsequent connectivity in this species is often reliant on distances between populations or availability of rocky reef. Therefore, consideration must be given to the design of networks of marine reserves to ensure adequate protection of this species, particularly in light of increasing foreshore modification and development.In designing networks of marine reserves, the relationships between spatial distances among reserves and patterns of genetic differentiation are important considerations. Such patterns may help inform planning of the arrangement and spacing of reserves on both local and regional scales. There was no pattern of isolation by distance for the highly connected Ecklonia which occurs throughout the temperate coastlines of Australia. Connectivity in this species is vastly different among Australia's eastern, southern and western coasts and differences correlate with the peak strength of continental boundary currents With networks of marine reserves being established in temperate regions worldwide there is a critical need for developing predictive models of dispersal and connectivity, particularly where little extant data exists. Generalising connectivity is problematic as spatial patterns of genetic structure can be vastly different among species and among coastlines and thus each may require specific conservation efforts. A classic example is Maintaining connectivity alone will not ensure the long-term persistence of macroalgal or other important marine habitats. With the synergistic effects of forecast climatic changes and increasing anthropogenic stressors there are likely to be large and dramatic effects on important macroalgal habitats"} +{"text": "Tumor cells can persist undetectably for an extended period of time in primary tumors and in disseminated cancer cells. Very little is known about why and how these tumors persist for extended periods of time and then evolve to malignancy. The discovery of cancer stem cells (CSCs) in human tumors challenges our current understanding of tumor recurrence, drug resistance, and metastasis, and opens up new research directions on how cancer cells are capable of switching from dormancy to malignancy. Although overlapping molecules and pathways have been reported to regulate the stem-like phenotype of CSCs and metastasis, accumulated evidence has suggested additional clonal diversity within the stem-like cancer cell subpopulation. This review will describe the current hypothesis linking CSCs and metastasis and summarize mechanisms important for metastatic CSCs to re-initiate tumors in the secondary sites. A better understanding of CSCs\u2019 contribution to clinical tumor dormancy and metastasis will provide new therapeutic revenues to eradicate metastatic tumors and significantly reduce the mortality of cancer patients. Solid tumors account for the major cancer burden, and epithelial cancers arising in breast, lung, colon, prostate, and ovary comprise approximately 80% of all cancers . HoweverMetastasis is a multi-step process. It is well recognized that cancer cells capable of metastasizing acquire epithelial\u2013mesenchymal transition (EMT)-like phenotype allowing them to disseminate from the primary tumor and intravasate into the circulation. In circulation, these disseminated cancer cells have to survive and then eventually extravasate into foreign tissues. Finally, few of these cells will adapt in the microenvironment and form macrometastases. Experimental evidence has demonstrated that early step of metastasis can be highly efficient . HoweverAccumulating evidence suggests that a subpopulation of cancer cells exhibit stem-like properties and is capable of tumor initiation, invasive growth, and disseminating to distant organs . These cIt is well recognized that some cancer cells are capable of undergoing an EMT-like transformation and develop a migratory and invasive phenotype to detach from the primary tumor . EMT is In addition to the self-renewing and EMT phenotypes, CSCs also exhibit other stem cell properties that are beneficial for them to adapt in the foreign microenvironment and eventually form clinical overt metastasis. It is apparent that several unique properties necessary for ensuring long life span of normal stem cells may contribute to protection of CSCs in the adverse microenvironment. For example, normal stem cells have increased capacity for DNA repair and express higher levels of anti-apoptotic proteins than differentiated cells . After d+ transporters that can actively efflux drugs and shield them from the adverse effects of chemotherapeutic insult . In addi+ . There i+ . For exa+ . Lower R+ . TogetheIt has been observed that a high proportion of distant metastases are differentiated and in some cases metastases can show a greater degree of cellular differentiation than the primary tumors. For example, increased E-cadherin expression in metastases compared to the primary tumors has been reported in human patient specimens . Furtherregs) when co-cultured with breast cancer cells allowing for immune subversion of breast cancer cells in the bone marrow (To complicate matters further, the metastatic niche can also supplies extrinsic factors that can further influence the proliferation and cellular states of metastatic cancer cells. Proliferation of disseminated CSCs in the targeted organs can be regulated by growth-suppressing and growth-stimulating factors secreted by or into the microenvironment. For example, a single dormant cancer cell or a dormant micrometastasis can turn into clinically detectable metastasis through an increased secretion of angiogenic factors in the metastatic niche to promote the recruitment and formation of new blood vessels (angiogenesis; e marrow . Also, ie marrow . TherefoThe presence of a distinct population with stem cell characteristics among disseminated and circulating cancer cells has an important clinical relevance in metastasis formation and recurrence, but more importantly for their role in resistance to conventional anti-cancer therapy. The stem-like properties of CSCs have been shown to be advantageous in protecting them from environmental and genotoxic stresses. The observed phenotypic plasticity of CSCs and their inherent anti-apoptotic ability can potentially render them capable of navigating through the entire metastatic cascade. It is apparent that current therapeutic strategies fail to account for potential molecular and proliferative differences between different subpopulations of tumor cells. This may explain why the majority of therapies fail in treating patients with metastatic diseases. CSC model also has significant implications for cancer progression. It has been observed in clinics that remission generally becomes more difficult to achieve with each relapse, and the diagnosis of metastatic disease significantly reduces patient survival. This suggests that the cancer cell population becomes increasingly aggressive over time, perhaps reflecting the selectively killing of the non-tumorigenic cells and enriching for the inherently therapeutic resistant CSCs in the metastatic tumor. Indeed, accumulating experimental evidence has confirmed this suspicion and demonstrated the potential benefit of selectively targeting the stem-like subpopulation in preventing cancer progression . HoweverThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The gastrointestinal tract is home to the largest accumulation of leukocytes in the body where they are constantly being exposed to a wide array of foreign antigens. Complex signalling networks between multiple cell types ensure that the appropriate balance is maintained between immune protection from infection and tolerance of harmless antigens, such as the resident bacterial flora and dietary antigens. Disturbance of this balance results in inappropriate immune activation, as observed in patients with Inflammatory Bowel Disease or food allergy. The intestine is highly adapted to facilitate immunological sampling of intestinal contents. Specialized epithelial cells, M cells, actively transport antigen to underlying lymphoid follicles for immunological processing while dendritic cells extend dendrites between epithelial cells in order to sample adherent bacterial species. We will focus on the mechanisms by which the intestinal immune system samples luminal antigen and the controlling features that determine immunological tolerance. In particular, the molecular mechanisms by which intestinal microbes induce tolerogenic responses within the gut and the relevance of intestinal T regulatory cell responses to protection from intestinal inflammation will be discussed."} +{"text": "Physicians today are increasingly faced with healthcare challenges that require an understanding of global health trends and practices, yet little is known about what constitutes appropriate global health training.A literature review was undertaken to identify competencies and educational approaches for teaching global health in medical schools.Using a pre-defined search strategy, 32 articles were identified; 11 articles describing 15 global health competencies for undergraduate medical training were found. The most frequently mentioned competencies included an understanding of: the global burden of disease, travel medicine, healthcare disparities between countries, immigrant health, primary care within diverse cultural settings and skills to better interface with different populations, cultures and healthcare systems. However, no consensus on global health competencies for medical students was apparent. Didactics and experiential learning were the most common educational methods used, mentioned in 12 and 13 articles respectively. Of the 11 articles discussing competencies, 8 linked competencies directly to educational approaches.This review highlights the imperative to document global health educational competencies and approaches used in medical schools and the need to facilitate greater consensus amongst medical educators on appropriate global health training for future physicians. Health issues are increasingly transnational and in recent years the concept of global health has emerged to address these issues. Global health is the study and practice of improving health and health equity for all people worldwide through international and interdisciplinary collaboration . FactorsIt has been argued that all medical students should have some exposure to global health issues, and groups are addressing this perceived gap in medical education by proposing global health competencies for undergraduate medical education ,5,6. In \u00ae and Web of Science. Also, previously identified articles were obtained from the McGill Global Health Programs files. The Ovid MEDLINE\u00ae search terms \"world health\" and \"international educational exchange\" were combined using the Boolean operator \"OR\" for the publication years 1996 to the 4th week of January 2009. The initial search used the terms \"global health\" and \"international health\"; however, these terms mapped to the subject heading \"world health\" in the Ovid MEDLINE\u00ae database. This procedure was repeated using the search terms \"education, medical\" and \"education, medical, undergraduate\", which was then cross-referenced with the search term \"competencies\". The resulting \"education, medical\"/\"curriculum\" set was combined with the resulting \"world health\"/\"international educational exchange\" set using the Boolean operator \"AND\". The results of the search were limited to humans and English. The Web of Science search cross-referenced the terms \"medical education\", \"curriculum\" and \"global health\" as topics for the publication years \"all years\" i.e. from 1900-1914 to January 2009. A research team comprised of all authors in this study, as well as the Liaison Librarian in the Life Sciences Library at McGill University, agreed upon these terms with the aim of avoiding researcher bias when selecting the articles. References from retrieved articles were reviewed to identify additional applicable publications.Relevant articles on global health competencies and teaching approaches were identified by applying similar search strategies to two databases, Ovid MEDLINETitles and abstracts of articles obtained from database searches were reviewed to identify those describing competencies or educational approaches currently used in global health components of medical school curricula. Articles not pertaining to contemporary global health medical educational practices or competencies were not further considered.Information relating to competencies and educational approaches was extracted from the retained articles. Information discussing the theoretical knowledge or practical skills authors believed medical students needed to obtain was categorized as a competency. Descriptions of specific programs or teaching methods were categorized as educational approaches.The results of the search strategy on global health competencies and educational approaches are summarized in Figure The percentage of articles recommending a particular competency topic, the type of competency and the suggested method of implementation are summarized in Table Global health educational approaches were described in 18 of 32 56.3%) identified articles .3% ident,26,28-33The most common recommended educational approaches for teaching global health topics were didactics and experiential learning. However, there was substantial variability across described programs in the educational approach to global health as well as the methods used to implement these approaches. No commonly applied didactic method for teaching global health to medical students was apparent from this literature review. Moreover, descriptions of educational approaches often did not provide a tangible picture of what occurred in these programs.Competencies and educational approaches were linked in 8 25.0%) articles ,26,28,29.0% articInterest in global health has grown dramatically among medical students in the past decade, and medical schools are grappling to define the skill sets and knowledge needed to ensure that graduates are appropriately prepared to work in this emerging field. Successful global health educational programs exist, and we explored the medical literature to identify competencies and educational approaches that might serve as potential resources for medical schools developing their own training programs. This literature review found no clear consensus on which global health competencies are relevant for most or all medical graduates to be able to draw on as future physicians. There also was little guidance regarding educational approaches for teaching global health competencies beyond the traditional methods of didactics and experiential learning.Fifteen competencies were mentioned in the literature. The most commonly discussed ones included an understanding of the global burden of disease; travel medicine; healthcare disparities between countries; immigrant health; primary care within diverse cultural settings; and skills to better interface with different populations, cultures and healthcare systems. Although these competencies were mentioned in more than one article, no single topic area was covered in more than 16% of identified articles, suggesting a lack of consensus on the importance assigned to any particular subject. It is not possible from this review to determine why a lack of consensus exists; one possibility may be that medical schools developed their global health curricula independent of each other. Such an approach may foster innovation, but also means that the quality of resulting programs is likely to vary widely as was found in a review of global health programs . DevelopAn alternative explanation for the lack of consensus in the retrieved articles is that published literature does not reflect common practice. Despite the tremendous growth in global health programs, only 11 articles were identified that addressed competencies. Furthermore, competencies were rarely the main focus of retrieved articles, giving little information on which to draw conclusions. A general consensus may exist among global health experts not reflected by the published literature.The most common educational approaches for teaching global health were didactics and experiential learning. However, the implementation of these approaches varied considerably in the literature. Our review was hampered by the limited descriptions of educational approaches present in identified articles that may not have provided a complete picture of these programs. More detailed documentation of global health educational approaches is needed if the literature is to serve as a resource for medical schools developing new programs.Of the 11 articles addressing competencies, 8 (72.7%) linked them to an educational approach. Conversely, educational approaches were mentioned in a majority of articles, but less than half of these linked these approaches to a competency. Competency-based descriptions of training give a more complete picture of global health education in medical curricula; schools looking to build global health educational activities should begin by defining the desired competencies, followed by enumerating the educational approaches to be used to teach them.Over one-third of retrieved articles did not provide specific details regarding global health educational approaches or competencies despite the search strategy used. These articles often focused on the creation of international institutional partnerships to improve the quality and pace of global health curriculum development. However, establishing learning objectives and corresponding educational approaches should be prerequisites for undertaking activities such as international global health partnerships. This review highlights another potential weakness in existing global health training; medical schools may be pursuing secondary activities before establishing basic program components such as competencies and educational approaches. Without well thought-out competencies and educational approaches, medical students may lack the foundation necessary to participate in international global health programs.Steps are underway to build consensus among global health experts regarding basic global health training for medical students. For example, the Global Health Education Consortium (GHEC) and the Association of Faculties of Medicine of Canada (AFMC) Resource Group on Global Health have created a joint committee to propose consensus global health core competencies for medical students . RecentlThis review highlights the imperative to document global health educational competencies and approaches used in medical schools and the need to facilitate greater consensus amongst medical educators on appropriate global health training for future physicians.There are no conflicts of interest for any of the authors of the paper, including specific financial interests and relationships and affiliations relevant to the subject of the manuscript.RB designed the study, coordinated the research team, designed the search strategy, conducted the literature search, organized and analyzed data, and was the primary author of the manuscript. RB read and approved the final manuscript. GS conducted the literature search, organized and analyzed data, and was the secondary author of the manuscript. GS read and approved the final manuscript. NC conducted the literature search, analyzed data, and edited the manuscript. NC read and approved the final manuscript. MYC conducted the literature search and analyzed data. MYC read and approved the final manuscript. JN contributed to the design of the search strategy, conducted the literature search and analyzed data. JN read and approved the final manuscript. JH conducted the literature search, analyzed data, and edited the manuscript. JH read and approved the final manuscript. AL conducted the literature search and analyzed data. AL read and approved the final manuscript. NF conducted the literature search and analyzed data. NF read and approved the final manuscript. TB conceived and designed the study, oversaw data analysis, secured funding, and edited the final manuscript. TB read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6920/10/94/prepub"} +{"text": "Given the many different proposed spiking neuron and plasticity models, it is hard to assess what functional roles their behavior may entail. One possible purpose may be to implement independent component analysis (ICA), which directly relates to sparse coding and finding relevant projections in the input space. Based on the theory of ICA , we show"} +{"text": "Using immunosuppressive drugs in younger children increases the risk of severe infections not seen in adult patients, as immunity towards several viruses is lacking.To increase the awareness of the risk of severe infections in patients without immunity towards several viruses.In a seven-year-old boy treatment with methotrexate and infliximab for bilateral panuveitis complicated by glaucoma and cataract was initiated. During treatment the uveitis went into remission and oral treatment with prednisolone could be stopped. The intraocular pressure dropped and surgical intervention for glaucoma was cancelled. The child underwent screening for tuberculosis before treatment was started. Also, as the child had not received any vaccinations in his entire life, vaccination against measles, rubella and mumps was performed before treatment.After four months of treatment the boy showed signs of chickenpox and was admitted to hospital due to viral pneumonia. The immunosuppressive drugs were withdrawn and antiviral treatment initiated immediately in high doses. He developed progressively respiratory insufficiency and required mechanical ventilation and as the condition worsened Extracorporeal Membrane Oxygenation (ECMO). He finally died from increased intracranial pressure due to encephalitis.Before initiating treatment with immunosuppressive drugs it is of severe importance to evaluate the immunity of the patient towards viruses able of causing severe infection. Vaccination prior to treatment must be considered."} +{"text": "An understanding of risks to biodiversity is needed for planning action to slow current rates of decline and secure ecosystem services for future human use. Although the IUCN Red List criteria provide an effective assessment protocol for species, a standard global assessment of risks to higher levels of biodiversity is currently limited. In 2008, IUCN initiated development of risk assessment criteria to support a global Red List of ecosystems. We present a new conceptual model for ecosystem risk assessment founded on a synthesis of relevant ecological theories. To support the model, we review key elements of ecosystem definition and introduce the concept of ecosystem collapse, an analogue of species extinction. The model identifies four distributional and functional symptoms of ecosystem risk as a basis for assessment criteria: A) rates of decline in ecosystem distribution; B) restricted distributions with continuing declines or threats; C) rates of environmental (abiotic) degradation; and D) rates of disruption to biotic processes. A fifth criterion, E) quantitative estimates of the risk of ecosystem collapse, enables integrated assessment of multiple processes and provides a conceptual anchor for the other criteria. We present the theoretical rationale for the construction and interpretation of each criterion. The assessment protocol and threat categories mirror those of the IUCN Red List of species. A trial of the protocol on terrestrial, subterranean, freshwater and marine ecosystems from around the world shows that its concepts are workable and its outcomes are robust, that required data are available, and that results are consistent with assessments carried out by local experts and authorities. The new protocol provides a consistent, practical and theoretically grounded framework for establishing a systematic Red List of the world\u2019s ecosystems. This will complement the Red List of species and strengthen global capacity to report on and monitor the status of biodiversity The world\u2019s biodiversity continues to diminish as human populations and activities expand Despite the strengths and widespread acceptance of the IUCN Red List of Threatened Species The scientific challenges in building a unified risk assessment framework for ecosystems are likely greater than those faced during development of Red List criteria for species Early development of Red List criteria for ecosystems drew from analogies with species criteria and existing protocols designed for regional applications Ideally, a Red List may be expected to identify ecosystems at risk of losing biodiversity, ecological functions and/or ecosystems services, since all three are inter-related and important objects for conservation There is growing empirical and theoretical evidence that ecosystem functions and services are linked with biodiversity Secondly, the identification and valuation of ecosystem services depend on social, cultural and economic factors, and may vary locally Thirdly, whether particular directional changes in ecosystem function or the abiotic environment are \u2018good\u2019 or \u2018bad\u2019 for conservation often involves local value judgements Our purpose here is to develop a robust and generic risk assessment method that can be applied to any internally consistent classification of ecosystems. A generic risk assessment protocol requires clearly defined assessment units, yet it also requires flexibility to assess risks across contrasting ecosystems that vary greatly in biological and environmental characteristics, as well as scales of organisation, and for which varying levels of knowledge are available. Therefore we first propose an operational definition of ecosystems to guide delineation of assessment units that will be informative about the conservation status of higher levels of biodiversity. Second, we identify the potential sensitivities of risk assessment to scale of the assessment units and suggest a suitable level of ecosystem classification for global biodiversity assessment. Finally, we outline a number of requirements for ecosystem description that are necessary to translate the operational definition into a practical assessment unit.In The unique features that define individual ecosystem types are scale-dependent. The four key elements of an ecosystem type may be organised on spatial, temporal and thematic scales The outcomes of ecosystem assessments are also likely to depend on spatial, temporal and thematic scales We do not consider ecological classifications in detail here, although we recognise that a global Red List will require a global classification of ecosystem types identity of the ecosystem type are greatly reduced in abundance and lose the ability to recruit. Chronic changes in nutrient cycling, disturbance regimes, connectivity or other ecological processes (biotic or abiotic) that sustain the characteristic biota may also signal ecosystem collapse. Novel ecosystems may retain some or many biotic and abiotic features of the pre-collapse systems from which they were derived, but their relative abundances will differ, they may be organised and interact in different ways and the composition, structure and/or function of the new system has moved outside the natural range of spatial and temporal variability of the old one. A collapsed ecosystem may have the capacity to recover given a long time scale, or with restoration, but in many systems recovery will not be possible.In the next section, we illustrate how the operational definition of ecosystem collapse can be translated into practical applications. This is most easily done for ecosystems that have already collapsed and where time series data exist for relevant variables .5. HowevTransitions to collapse may be gradual, sudden, linear, non-linear, deterministic or highly stochastic The Aral Sea (see Appendix 2.5), the world\u2019s fourth largest continental water body, is fed by two major rivers, the Syr Dar\u2019ya and Amu Dar\u2019ya, in central Asia. Its characteristic native biota includes freshwater fish (20 species), a unique invertebrate fauna (>150 species) and shoreline reedbeds, which provide habitat for waterbirds including migratory species. Hydrologically, the sea was approximately stable during 1911\u20131960, with inflows balancing net evaporation The choice of available variables for assessing the status of the ecosystem will depend on how closely they represent the ecosystem\u2019s defining features, the quantity and quality of the data, and the sensitivity of alternative variables to ecological change. Of those listed above, fish species richness and abundance may be the most proximal biotic variable to the features that define the identity of the Aral Sea ecosystem. Sea volume may be a reasonable abiotic proxy, because volume is functionally linked with salinity, which in turn mediates persistence of the characteristic freshwater/brackish aquatic fauna. Sea surface area is less directly related to these features and processes, but can be readily estimated by remote sensing and may be useful for assessment when data are unavailable for other variables.Salmo trutta aralensis), preventing reconstruction of the pre-collapse ecosystem.Collapse of the Aral Sea ecosystem may or may not be reversible. While it may be possible to restore the hydrological regime over a small part of the former sea Our risk assessment model groups sThe risk assessment protocol comprises five rule-based criteria based on thresholds for distributional and functional symptoms represented in the risk model , Table 3An ecosystem under assessment should be evaluated using all criteria for which data are available. Overall threat status is the highest level of risk returned by any of the criteria , since rThe criteria assess declines over three time frames: current, future, and historic . CurrentAssessment of future declines requires predictions about changes over the next 50 years or any 50-year period including the present and future . Past deAssessments of historical declines are essential for ecosystems containing biota with long generation lengths and slow population turnover The ordinal categories of risk are delimited by different thresholds of decline. Our rationale for setting these thresholds is partly grounded in theory and partly pragmatic, recognizing that: i) theory provides a qualitative basis for ordered thresholds for decline, but offers limited guidance for setting their absolute values; and ii) our aim is to rank ecosystems into informative ordinal categories of risk, rather than estimate precise probabilities of collapse.Species-area relationships It is noteworthy that the relationship between biodiversity and ecosystem function, when averaged over many cases, has a similar monotonic form to species-area relationships and also varies in slope Each of the five criteria implies a threshold of collapse . For criFor criteria based on functional variables (C and D), a range of values will typically define collapse for a given variable . This raThe five risk assessment criteria are summarised in Declining distribution is an almost universal element of existing ecosystem risk assessment protocols Rates of decline in ecosystem distribution will typically be estimated from time series of maps e.g. , field oCurrent reductions in distribution may be calculated directly if data are available for 50 years ago and the present, or through an annual rate as a basis for cautious extrapolation. Spatial models Many processes that threaten ecosystems are spatially autocorrelated (clustered). Examples include catastrophes or disturbance events Two metrics, Extent of Occurrence (EOO) and Area of Occupancy (AOO), represent conceptually different aspects of species range size sensu2 (1%) of cell area.Estimates of AOO are highly sensitive to both spatial and thematic grain Critically Endangered, Endangered and Vulnerable ecosystems are delineated by AOO thresholds of two, 20 and 50 grid cells, respectively . EOO thrTo be eligible for listing in a threat category under criterion B, an ecosystem must also meet at least one of three subcriteria that address various forms of decline. These subcriteria distinguish restricted ecosystems at appreciable risk of collapse from those that persist over long time scales within small stable ranges Environmental (abiotic) degradation may diminish the ability of an ecosystem to sustain its characteristic native biota by changing the variety and quality of environmental niche space available to individual species. This interpretation relies on measurement of abiotic variables and excludes biotic mechanisms of degradation. Most existing protocols conflate the assessment of biotic and abiotic declines in ecosystem function A reformulation of the species-area relationship Criterion C is strucWe suggest four requirements to assess risks posed to ecosystems by environmental degradation. First, there must be plausible evidence of a causal relationship between a process of environmental change and loss of characteristic native biota . For exaSecond, assessing abiotic degradation requires suitable spatial and scalar variables for estimating the extent and severity of degradation. The characteristics of the ecosystem, environmental dependencies of biota and agents of degradation will determine which variables are relevant. The most suitable will be those with the most proximal cause-effect relationships and the greatest sensitivity to loss of biota. Approaches that apply generic indices across functionally contrasting ecosystems are unlikely to assess degradation accurately because salient processes may differ between ecosystems. Furthermore, aggregation of multiple variables could confound different mechanisms and directions of environmental change, making the index less sensitive to degradation than individual variables. Third, assessing environmental degradation requires calculation methods to compare observed or projected changes against the criteria. Assessors may either estimate the extent of degradation (as % of ecosystem distribution) that exceeds a threshold level of severity or estimFinally, estimating, inferring or projecting the severity and extent of degradation over specific time frames may require extrapolation of trends from available time series. This requires assumptions about whether degradation is constant, accelerating, or decelerating (see criterion A), based on an understanding of the mechanism of decline and its historical and spatial context. Assessors also need to evaluate whether the available data are sufficiently representative of prevailing conditions to permit extrapolation, preferably with statistical inference . Where time series data are unavailable, it may be possible to infer changes in degradation using space-for-time substitution sampling with appropriate reference sites The persistence of biota within ecosystems depends on biotic processes and interactions , includiFeedback interactions underpin self-organisation and are crucial to ecosystem resilience, the ability to absorb environmental change while maintaining structure, characteristic biota and processes Certain types of ecosystems may be especially sensitive to disruption of biotic processes and interactions. These include systems with strong top-down trophic regulation Assessment of criterion D must address the same four requirements as criterion C: i) plausible evidence of the causes or mechanisms of functional decline; ii) selection of appropriate biotic variables for assessing declines; iii) range standardisation to estimate relative severity; and iv) calculations and justifiable assumptions to estimate declines over relevant time frames. Process models again provide a useful framework for interpretation and explicit justification of analytical choices. A broad set of variables are potentially useful for assessing biotic processes and associated functional declines . We brieSpecies loss reduces ecosystem function and resilience to ecosystem collapse and reduces the possible range of alternative ecological organizations Problems with generic measures may be mitigated by variables that are more proximal to biotic mechanisms that maintain ecosystem resilience and characteristic biota Measures of interaction diversity, such as the structure and size of interaction networks, provide another perspective on functional decline . DecouplSpatial dynamics of biotic interactions influence ecosystem resilience and function through exchanges across heterogeneous landscapes and seascapes Finally, niche diversity in some ecosystems depends on structural complexity generated by components of the biota itself . For exaA diverse range of simulation models of ecosystem dynamics allow the probability of ecosystem collapse to be estimated directly over the same 50-year future period as other criteria Twenty ecosystems were selected for assessment based on the authors\u2019 areas of expertise, spanning five continents and three ocean basins , models of environmental suitability were used to project future changes in distribution, with outputs of alternative plausible models used to estimate uncertainty in the projections.Eleven of the case studies used explicit process models to guide selection of functional variables for assessment of criteria C and D. Only one of these models was quantitative, permitting simulations to estimate risks of collapse under criterion E, although data appear sufficient to support construction of such models in at least two other case studies (1 and 8). A variety of abiotic proxy variables were used to assess environmental degradation, primarily in freshwater and marine ecosystems, including water flows and extraction rates, groundwater flows (subterranean/freshwater) nitrogen levels (both freshwater and marine ecosystems), climatic moisture, water volume, salinity, sea surface temperatures and ocean acidity. Proxy variables used to assess criterion D included the abundance of structurally important groups of species , mobile links (birds), meso-predators , sensitive species (plankton), invasive species and threatened species. In a few cases, the available data were insufficient to make an assessment, but the identification of the proxy highlighted future needs.The outcomes of assessment varied from Least Concern to Collapsed , with thA sensitivity analysis was carried out on the thresholds in all criteria using data from the 20 case studies. Thresholds were adjusted by \u00b15%, \u00b110%, \u00b115% and \u00b120% of current values i) for each individual subcriterion; ii) for all subcriteria in combination within each criterion; and iii) across all criteria in combination. This represents a plausible range of alternative thresholds, since larger adjustments would result in overlap between categories. Variation to thresholds by a given proportion across all criteria in combination resulted in a change in status for a slightly larger proportion of ecosystems . For halIndividually, criteria A, C and D displayed similar levels of sensitivity to variation in their threshold values , and this was similar to the sensitivity of the overall risk status when all five criteria were combined cf. 8a. Several aspects of the case studies show that the IUCN Red List criteria for ecosystems are workable, robust and sufficiently general for application to wide range of ecosystems types and threatening processes. Firstly, the overall status was supported by assessments of multiple subcriteria in 90% of the case studies. This high level of concordance among criteria suggests that assessments are robust because outcomes are unlikely to be very sensitive to missing data.Secondly, no one criterion had a consistently dominant or subordinate effect on overall status across the full set of case studies. This suggests strong complementarity among criteria. Collectively, they are able to detect symptoms that may signal the susceptibility of an ecosystem to any of several contrasting threatening processes.Thirdly, close correspondence between Red List status and prior assessments carried out by local experts suggest that the IUCN criteria should not produce markedly different outcomes to most listing processes that currently operate in national and regional jurisdictions.Fourthly, although poorly studied ecosystems were undersampled in our analysis, the case studies show that suitable data can be obtained from a range of sources and that defensible inferences may be drawn from appropriate use of proxies, various methods of estimation and scaling up.Several aspects of protocol performance may be attributed to their rule-based structure. This structure promotes the ensemble properties of criteria, minimises the impact of missing data and avoids assumptions that different symptoms are additive or interchangeable in their effect on overall risk of ecosystem collapse Our assessments of widely contrasting ecosystems from terrestrial, subterranean, freshwater and marine environments demonstrate the generality of the Red List criteria. A key feature of our risk assessment model and 2 isThe common set of thresholds of decline and distribution size that delimit different categories of risk promotes consistency of risk assessments across contrasting terrestrial, subterranean, freshwater and marine ecosystems. Current theory provides limited guidance for setting the precise values of these thresholds. Our choice of thresholds was aimed at promoting informative risk categories based on relatively even intervals of decline, alignment with thresholds of decline in the species Red List protocol, consistency with the monotonic relationships for species - area and biodiversity - ecosystem function, and a broad understanding of the spatial extent of threatening processes. Although these pragmatic principles could also be met by slightly different threshold values, risk assessment outcomes were shown to be only moderately sensitive to variations in decline thresholds and relatively insensitive to variations in thresholds of distribution size. In the most extreme cases, the proportional change in risk classifications was only slightly greater than the proportional adjustment of the thresholds.Although the flexibility to select appropriate variables for assessment underpins the generality of the protocol, this may have trade-offs if selections are poorly justified. These trade-offs may affect the consistency of assessments if, for example, different assessors select different proxy variables to assess the same or closely related ecosystem(s). An alternative risk assessment method could limit such inconsistency by prescribing one or a few mandatory generic variables to assess functional change , but only by sacrificing alternative variables that are more proximal to causes and/or more sensitive to functional change. Moreover, a failure to apply ecosystem-specific mechanistic interpretations to trends in generic variables runs a risk of perverse assessment outcomes.Some inconsistencies between assessments are an inevitable consequence of a risk model that seeks broad generality by incorporating flexibility to select ecosystem-specific measures of function. However, these inconsistencies can be partially offset, firstly by governance processes and standards that promote collaboration and critical evaluation of assessment outcomes (see below), and secondly by using methods to deal with uncertainties described above. Thirdly, the use of cause/effect process models to interpret salient processes and their proxies should mitigate inconsistency, especially if they are critically reviewed, either through peer-reviewed literature or though a structured elicitation process The use of standardised measures of distribution in criterion B also contributes to generality of the protocol and mitigates some of its sensitivity to spatial scale Assessments of ecosystem risk will always carry some uncertainty due to incomplete knowledge. This includes measurement uncertainty related to data availability, boundary vagueness and system variability, as well as model uncertainty due to imperfect understanding of processes. Risk assessments of ecosystems will generally be less certain than species assessments , largelyUncertainties can be incorporated into risk assessment using bounded estimates , fuzzy aUnlike species, a widely accepted global classification of ecosystems is currently lacking. Development of a global taxonomy and classification of ecosystems would strengthen the consistency and comparability of assessments between regions and terrestrial/marine realms. It would also help resolve the limits of thematic scaling discussed above. The principal difficulties in delineating units of assessment stem from conceptual uncertainties in the nature of ecosystem properties, with conflicting discrete and continuum models both having strengths and limitations In comparison, the global taxonomy for species appears well established and plays an important role in defining units for risk assessment. In recent decades, however, development of cladistic methods and advent of molecular phylogenies are driving a major reconstruction of classifications at multiple levels to resolve polyphyletic taxa. Ongoing alpha taxonomic activity continually increases the number of described taxa, often resulting in new circumscriptions of existing taxa affected by splitting or lumping. Furthermore, the current operational taxonomic units are based on different morphological, biological or evolutionary species concepts, depending on the major taxonomic groups to which they belong, partly for pragmatic reasons and partly due to historical legacies. Successive Red Data Books and Red Lists have thus developed under substantial taxonomic dynamism and inconsistency. This suggests that Red Lists can be functional and reliable conservation tools despite uncertainties in the underlying classification, even though some changes in listings occur solely as a consequence of taxonomic changes We suggest that development of a global taxonomy for ecosystems can proceed contemporaneously with risk assessment. Indeed, the shortcomings of existing regional taxonomies underscore the need to describe characteristic biota, abiotic features, distribution and an ecological process model as integral components of ecosystem risk assessment. Ideally, the taxonomic framework should be hierarchical, elucidating relationships between assessment units defined at different scales and integrating elements of existing work at global, regional and national levels across terrestrial, subterranean, freshwater and marine environments biomes www.iucn.org/about/work/programmes/species/about_ssc/specialist_groups/directory_specialist_groups/).Developing a Red List of ecosystems will involve ongoing questions about ecosystem description, variable selection, data analysis and model development. This requires a governance structure that promotes technical support and rigorous peer review. Preparation of interpretive guidelines cf. and regiwww.equator-principles.com/). The separate task of setting priorities for these actions also requires inputs on irreplaceability of biodiversity features, cultural valuations, plasticity of demand for ecosystem services and the potential for investments to reduce risks of decline The Red List criteria for ecosystems will establish a consistent, robust, practical and theoretically grounded international standard for risk assessment of biodiversity, complementing the Red List criteria for species. A global Red List can raise awareness of conservation needs in governments, industries and communities worldwide. However, guidelines are also needed to support assessment at regional and national scales, where much conservation action is planned and implemented. A Red List of ecosystems will firstly strengthen global capacity to report on and monitor the status of biodiversity under internationally agreed Aichi targets Many of the mechanisms and symptoms of species vulnerability are relevant to ecosystems, because species are integral parts of ecosystems. Yet ecosystems embody processes and higher-order components of biodiversity that are difficult or impossible to account for in species-by-species assessment. Whereas species risk assessment rests on population theory, ecosystem risk assessment must draw from a wider array of inter-related theories that deal with continua, niches, fractal geometry, succession, resilience, ecological integrity, biodiversity-ecosystem function and insurance, as well as population theory. The success of ecosystem risk assessment therefore rests on a robust synthesis of conservation planning and process ecology to translate theoretical foundations into a practical assessment protocol that can be applied to a wide variety of ecosystems by specialist assessors with differing backgrounds and limited data.Appendix S1Definitions of terms.(PDF)Click here for additional data file.Appendix S2Risk assessment case studies for example ecosystems.(PDF)Click here for additional data file."} +{"text": "Recently autophagy has attracted considerable attention because of its role in a wide variety of diseases including neurodegenerative disorders, cancer, myopathies, and lysosomal storage diseases. Autophagy is a \u201cself-eating\u201d process that brings proteins and damaged organelles enclosed in double-membrane autophagosomes to lysosomes for digestion and recycling. Functional lysosomes are essential for the completion of autophagy-initiated degradation and recycling of cellular components. In the fatal lysosomal glycogen storage disorder, Pompe disease, dysfunctional autophagy and massive accumulation of autophagic debris in myofibers greatly contribute to the cellular damage and interfere with the efficacy of enzyme replacement therapy (ERT). Analysis of single muscle fibers from patients with Pompe disease confirmed that the autophagic inclusions are prominent in humans as well. Autophagic buildup persists after years of treatment and may well be the reason for disappointing clinical response. Genetic suppression of autophagy in a mouse model of Pompe disease reduced the lysosomal glycogen load and allowed for fully effective ERT in murine Pompe disease. Our group is currently exploring a new therapeutic approach to Pompe disease; this new approach involves manipulation of transcription factor EB (TFEB), which has been shown to promote lysosomal-autophagosomal fusion and biogenesis. The appeal for Pompe disease is that unlike the current therapy, modulation of TFEB holds promise to rid muscle cells of both excessive glycogen burden and accumulation of autophagic debris."} +{"text": "The regenerative abilities and the immunosuppressive properties of mesenchymal stromal cells (MSCs) make them potentially the ideal cellular product of choice for treatment of autoimmune and other immune mediated disorders. Although the usefulness of MSCs for therapeutic applications is in early phases, their potential clinical use remains of great interest. Current clinical evidence of use of MSCs from both autologous and allogeneic sources to treat autoimmune disorders confers conflicting clinical benefit outcomes. These varied results may possibly be due to MSC use across wide range of autoimmune disorders with clinical heterogeneity or due to variability of the cellular product. In the light of recent genome wide association studies (GWAS), linking predisposition of autoimmune diseases to single nucleotide polymorphisms (SNPs) in the susceptible genetic loci, the clinical relevance of MSCs possessing SNPs in the critical effector molecules of immunosuppression is largely undiscussed. It is of further interest in the allogeneic setting, where SNPs in the target pathway of MSC's intervention may also modulate clinical outcome. In the present review, we have discussed the known critical SNPs predisposing to disease susceptibility in various autoimmune diseases and their significance in the immunomodulatory properties of MSCs. Kroner T helper cells and B cell interaction plays an important role in the breakdown of peripheral tolerance in the autoimmune disorders. The helper T cells that are not sensitive to self-tolerance mechanisms secrete proinflammatory cytokines, resulting in expansion of the autoreactive B cells which produce autoantibodies to cause the self damage . MSCs alMSCs are attractive to researchers due to their wide spectrum of immunomodulatory and regenerative properties, which collectively constitute their therapeutic activities. It is arguable that even if genetic changes such as SNPs affect one pathway, compensatory pathways may balance the functional machinery of MSCs. However, in certain situations, target pathways are crucial for the maintenance of immune tolerance, and in those conditions, MSCs could be considered as supplemental therapy along with the other immune suppressive molecules. SNPs are suggested as biomarkers for disease susceptibility in certain autoimmune disorders. Further studies are warranted in the direction of utilizing these SNPs as biomarkers for prediction of treatment responsiveness to MSC therapy."} +{"text": "Monocytes are one of the major phagocytic cells in the periphery that patrols the circulation for invading pathogens, and upon activation differentiates into dendritic cells, capable of migration to lymph nodes eliciting an adaptive immune response. Monocytes has for more than a decade been precursor cell for generation of autologous dendritic cell cancer vaccines, but clinical results have shown limiting benefits for the patients. One way of improving dendritic cell vaccines is targeting the monocytes in vivo with a suitable carrier of adjuvant together with tumor antigens, to boost monocyte differentiation towards tumor antigen presenting DCs. Here we report a novel monocyte targeting liposome technology capable of delivering TLR7 agonist to CD14 positive monocytes in fresh whole human blood. Liposomes with a positive surface charge were able to specifically target monocytes over lymphocytes and granulocytes, and showed association with 90-100 % of the monocytes. Formulation of the TLR7 agonist in monocyte targeting liposomes showed strong activation of the monocytes, with potent induction of proinflammatory cytokines, and differentiation into tissue inflammatory DCs, demonstrating that the liposomes are able to deliver compounds to the endosomes where TLR7 is present. The present monocyte targeting technology may be a promising approach for designing cancer vaccines with suitable adjuvants and cancer antigens."} +{"text": "DICER1 is an RNase endonuclease important for production of microRNAs, which regulate multiple protein-coding genes involved in growth and development. It has been linked to several tumors including pleuropulmonary blastoma (PPB), cystic nephroma, ovarian Sertoli-Leydig cell tumors and thyroid neoplasia. Most of the manifestations of DICER1 mutations occur in young children, adolescents and young adults; only thyroid neoplasia are diagnosed throughout adulthood. Although mutations in this gene behave as autosomal dominant tumor suppressor genes, the penetrance of the various tumors is highly variable, rendering screening and genetic counseling challenging.We have recently hypothesized that mutations in this gene are also responsible for the very rare but often fatal cases of infant (< 3y) Cushing Disease, which can be missed initially because of absent or only minimal signs of intracranial hypertension and hypercortisolemia in this age group. Eye signs, such as strabismus or proptosis, may be the first manifestations of these tumors. The ACTH-producing pituitary tumors seen in these infants have a histopathology and electron microscopy that has been termed pituitary blastoma. The incomplete penetrance of this and the other manifestations of the syndrome makes the involvement of additional predisposing factors highly likely, candidates of which are under investigation.This presentation will highlight the cardinal features of this new familial cancer syndrome, review the molecular biology of DICER1, consider additional polygenic influences on tumor development and discuss the current recommendations for following these families."} +{"text": "Coupled with AFM force spectroscopy experiments, the simulations reveal that the mechanisms underlying particle-particle adhesion comprise a combination of \"continuum\" capillary forces and \"discrete\" contributions arising from the structuring of physisorbed water molecules at the oxide surfaces [The interactions across interfaces between different phases govern the behavior of a wide range of systems of high technological importance, such as catalysts (gas/solid), energy storage (liquid/solid or solid/solid) or biomedicine (liquid/solid), just to cite a few examples. The simulation of such systems poses considerable challenges due to their inherent complexity, which often cannot be captured by idealized models containing only a few tens of atoms. However, large system sizes can only be modeled by means of approximate methods using force field potentials, whose predictive power and transferability can be questionable if a direct comparison of the simulation results with experimental observables is sought. Moreover, efficient sampling of the phase-space is strictly required to computationally predict measurable quantities such as adsorption free energies or adhesion forces. In this talk, I will present a strategy for the development of realistic models of oxidized metals and of force field potentials that capture the essential interactions at oxide/water interfaces, based on extensive DFT simulations. Our potentials can be seamlessly combined with widely used bimolecular force fields and predict free energy of adsorption and adhesion forces of polypeptides in quantitative agreement with experiments. This has been achieved by means of advanced molecular dynamics simulations combining Metadynamics with Replica Exchange with Solute Tempering methods, which enable converged calculations of free energies for such complex systems . Our sim"} +{"text": "The main scope of this topic is to give an update on approaches being studied and developed to improve tumor drug delivery through active targeting and other methods. Inadequate drug accumulation has emerged as one of the main problems underlying therapeutic failure and drug resistance in the treatment of solid tumors of heavily pretreated patients with metastatic melanoma and other solid tumors (Hodi et al., Enhancing penetration of immune cells into tumors may have two main therapeutic applications. The first is to improve the efficacy of immune-regulatory antibodies, such as the anti-cytotoxic Promoter drugs that improve tumor delivery of chemotherapeutics and antitumor antibodies are likely to become a clinical reality in forthcoming years. In addition, new possibilities are emerging to enhance the entrance of therapeutic agents into tumors. For example, recent results suggest that promoter drugs may be useful also for improving infiltration of immune cells into tumors. This may increase the antitumor effects of a broad range of immune-based therapeutics, including immune-regulatory antibodies, antibodies that engage cytotoxic immune cells, and cancer vaccines."} +{"text": "Tumors of the sacrum and related neurological and pelvic structures are rare pathologic conditions.Sacral tumors are a diagnostic challenge because patients often present with nonspecific complaints such as low back pain, sacrococcygeal joint pain, referred lag and buttock pain. Because of diagnostic and radiographic challenges, the detection of sacral mass can be delayed which complicates any prospect surgical intervention as tumors can be quite large at the time of treatment. Furthermore, the complex local anatomy of the sacrum and presence of numerous other structures make the resection procedure even more sophisticated and necessitate adoption of a multidisciplinary approach towards the treatment. The present study discuses the diagnosis, treatment and complication of 4 cases with large sacral mass.Resection, Sacral, Tumor"} +{"text": "The boom of next generation sequencing (NGS) technology and its applications to a wide range of biomedical fields has brought about many computational and statistical challenges. The NHGRI funded small conference \u201cStatistical Analysis for NGS\u201d was held September 26th\u201327th 2011 in Birmingham, AL, USA, to discuss these statistical challenges and strategies to tackle them. Below, we detail the major themes of the conference.Profiling the transcriptome has been a central application of NGS technologies. Since the sequencing technology generates short reads, the first step is to map the reads onto the source genome, genes, and transcripts. Despite development of many algorithms and tools for mapping reads to the reference genomes, accurately mapping RNA-seq reads remains a tough problem due to the complexity of the transcriptome. Thomas Wu from Genentech presented his recent work on mapping RNA-seq sequence reads and gene structure analysis from RNA-seq data in their Genomic Short-read Nucleotide Alignment Program (GSNAP) software package. They use probabilistic models and known splicing information to guide alignment and variant/splicing detection with consideration of all possible combinations of major and minor alleles. Wu also presented GSTRUCT, a pipeline for assembling alignment results to gene structures and predicting isoforms and gene fusion events.1.Unlike microarray data, sequencing data were originally thought to be digital and without need for intensive normalization. However, Zhijin Wu from Brown University demonstrated that gene expression data from RNA-seq could suffer from strong biases related to transcript length and GC content. She showed that the biases can be removed by a carefully formulated statistical model which combines a generalized linear model with a quantile normalization procedureMBCluster.Seq in CRAN2).The clustering of RNA-seq data often relies on heuristic methods used widely in microarray data analysis. Peng Liu from Iowa State University demonstrated that a mixture of negative binomial models for clustering the RNA-seq data together with an Expectation-Maximization (EM) algorithm to obtain the model parameters can improve the performance substantially binding changes can be inferred from profiling the dynamic changes of the epigenetic marker H3K4me2 and DNase-sensitive sites in the genome. This strategy overcomes the limitation of antibody availability for individual TFs, which has been a bottleneck for increasing throughput in ChIP-seq experiments.ChIP-PED). They first compute the correlations between the expression of a TF gene and other genes from 8000+ microarray datasets and then combine the correlations with TF binding locations to detect potential targets.Method developments for ChIP-seq data analysis have evolved from single experiment peak detection to higher dimensional data integration and pattern recognition. Several talks in the afternoon sessions focused on exploring the regulatory mechanisms of TF binding and histone modifications. Mario Medvedovic from University of Cincinnati presented a statistical framework, termed TREG, for identifying regulatory TF binding by combining ChIP-seq and gene expression data. Hongkai Ji from Johns Hopkins University discussed a method to integrate ChIP-seq data with a large collection of public expression microarray data in the search for TF target genes studies. Victor Jin from the Ohio State University Medical Center presented a multivariate hidden Markov model (HMM) to discover distinct DNA methylation patterns under different biological contexts. His results on a breast cancer dataset showed that each subtypes of cancer cell lines have a distinct methylation pattern with specific enrichments in genomic features such as genomic regions, gene expression levels, and functional annotations. Jianrong Wang from Georgia Tech presented an on-going project to cluster genomic regions based on similarities of the patterns of histone modifications. Regions that are closely clustered together are searched for common histone modification patterns. Their analysis on CD4Yingrui Li from BGI (formerly known as Beijing Genomics Institute) provided both a philosophical overview and practical solutions to the problems faced by researchers interested in using sequencing technology to understand how species, individuals, and cells/tissues differ. He described the bottlenecks in the bioinformatics pipeline as breakdowns in both data acquisition and data analysis. To address these bioinformatics challenges, the BGI bioinformatics team has developed a wide range of tools implemented in the Short Oligonucleotide Analysis Package (SOAP). Li reminded participants of the critical role of computer science in turning sophisticated statistical methods into practical bioinformatic tools accessible to biologists.A central challenge in NGS genomic data analysis is genotype calling. The low allele frequencies for rare variants can be problematic due to low coverage and non-negligible sequencing error rates. Degui Zhi from UAB presented promising strategies and tools for genotype calling for population sequencing. By modifying the HMM emission probabilities, his model can incorporate the fact that individual reads are now able to span multiple sites, particularly as technology progresses and read lengths grow. The strategy shows a substantial genotyping error reduction.While Zhi's approach is a general algorithm for whole genome variant calling, Danny Challis from Baylor College of Medicine presented an approach that is specifically tailored toward exomic regions, which have different characteristics from other genomic regions and are thought to be biomedically more important. By training a logistic regression model using exon capture data and isolating key features that affect calling errors, Challis developed a powerful predictive model that can discern between true variants and error calls in exomic regions and improve variant calling accuracy (ATLAS2 package).A common hypothesis for the missing heritability in genome-wide association studies is that rare genetic variation may account for a substantial portion of the missing heritability. Several highly inter-related difficulties exist in identifying rare genetic variants associated with disease, including the prohibitive cost of sequencing a large number of individuals and obstacles in association testing. Accordingly, several experts on rare variant analysis presented novel researches on statistical design and analysis strategies for overcoming these challenges.Standard genetic association methods are underpowered for testing individual rare variants\u2019 association. Region- or gene-based testing, wherein multiple rare variants are aggregated and their cumulative effect on a complex trait or disease evaluated, has become the standard approach for rare variant testing. A veritable plethora of region based tests have been developed under a wide range of assumptions. Suzanne Leal from Baylor College of Medicine, Joshua Sampson from National Cancer Institute, and Michael Wu from UNC Chapel Hill compared many of the commonly applied tests and established connections.Suzanne Leal systematically assessed the statistical power of many rare variant tests with some assuming that most variants are harmful and others allowing variants within a region to have bidirectional effects. Across many scenarios, the methods performed similarly with the unidirectional methods tending to be more powerful, though there were also settings in which the power was somewhat higher for methods accommodating bidirectional effects.p-value, and then correcting for multiple comparisons via permutation. The new strategy has high power across a wide range of scenarios.Joshua Sampson and Michael Wu sought to make connections among many of the existing methods. Sampson showed that the majority of statistics that are currently available for testing associations with groups of rare variants can be rewritten as a simple weighted sum of single variant statistics and their cross products. He demonstrated how to identify those statistics that perform well given a set of genetic characteristics. In a similar line of work, Wu showed that as simple weighted score statistics, many key rare variant tests reduce to special cases of Kernel Association test. Wu developed a pragmatic strategy that involves applying several candidate rare variant tests, taking the minimum Currently, even exome scale sequencing is expensive and results in limited sample sizes and hence limited power to detect rare variants with modest effects. A number of powerful design strategies can be used to ameliorate these issues. Hongyu Zhao from Yale considered the use of pooled DNA designs in which the DNA of several cases or several controls is pooled and jointly sequenced. He showed that the optimal number of individuals in a pool, with regard to detection probability is a function of minor allele frequency (MAF), read depth, and detection threshold. Interestingly, the optimal number of individuals did not differ much across MAF, but the total number of pools necessary to detect lower MAF variants was greater. An alternative cost saving strategy for population based rare variant analysis is the Exome Chip as Susanne Leal pointed out. This chip focuses mostly on the exomic regions to allow for the capture of many of the variants that are more likely to be functionally relevant. In addition to exome variants, the chip also includes SNPs for population structure, probes for HLA tags, fingerprinting SNPs, and a range of other variants of primary interest. However, Leal noted that the chips will have limited power in studies of Mendelian traits or traits with high degree of allelic heterogeneity and that it is unclear how well the chips will work for non-European populations. Nevertheless, they can provide a means for analysis of exomic regions at a fraction of the cost of exome sequencing.Cancer genome sequence data analysis post special challenges due to the massive genomic changes. Benjamin Raphael from Brown University and Stanley Pounds from St. Jude Children's Research Hospital offered some novel strategies for the analysis of tumor sequencing data. Raphael discussed a method for identifying driver somatic mutations from the background of passenger mutations in tumor progression. His strategies involve identifying subgraphs that are recurrently mutated across multiple patients using a heat diffusion strategy for defining subnetworks, which offer improvements over standard individual mutation analysis. Pounds examined the analysis of copy number variations (CNVs). The standard steps in the analysis pipeline for CNVs are often (1) mapping of reads, (2) normalization and adjustment for aneuploidy, (3) comparison of counts between tumor and normal tissues, and (4) segmentation to identify change points. Pounds re-ordered the steps, choosing to compare raw counts between tumor and normal immediately following mapping and then moving the adjustment for ploidy to the end of the analysis pipeline, after segmentation. This new order improved determination of copy number alterations due to reduced noise.After 2 days of enthusiastic discussion on the statistical challenges and opportunities associated with NGS technologies, participants left with more questions than answers. These questions will require the whole community to work tirelessly for the next several years to come up with mature statistical and computational methods for NGS data analysis."} +{"text": "During routine dissection of an approximately 50-year-old male cadaver for the undergraduate medical students at Melaka Manipal Medical College, Manipal University, Manipal, we came across a variation in branching pattern of right axillary artery. The second part of axillary artery gave rise to a common trunk which divided into the subscapular and lateral thoracic arteries. The third part of right axillary artery gave rise to anterior and posterior circumflex humeral arteries. Variations in the branching pattern of axillary artery are important for the surgeons performing interventional or diagnostic procedures in cardiovascular diseases. Axillary artery is a continuation of subclavian artery, extending from the outer border of first rib to the lower border of teres major muscle where it continues as brachial artery. The pectoralis minor muscle is related anteriorly to the axillary artery and it divides axillary artery into three parts, first part extending from outer border of first rib to the upper border of pectoralis minor muscle, second part lies behind the pectoralis minor muscle, and third part extending from lower border of pectoralis minor muscle to lower border of teres major muscle. Axillary artery normally gives off superior thoracic artery from the first part, lateral thoracic artery and thoracoacromial artery from the second part, and subscapular, anterior circumflex humeral and posterior circumflex humeral arteries from the third part . SubscapDuring routine dissection for undergraduate Medical students of Melaka Manipal Medical College, Manipal University, Manipal, we came across a variation in branching pattern of right axillary artery in a male cadaver of approximately 50 years of age. The left axillary artery was found to be normal. The first part of axillary artery gave rise to superior thoracic artery as usual, but the second part gave a common trunk which divided into the lateral thoracic and subscapular arteries. The third part of the artery gave origin to anterior and posterior circumflex humeral arteries . This isVariation of branching pattern of axillary artery is common. Samta et al. reported that 28% of cases studied have variation in branching pattern of axillary artery. Subscapular artery has been found to be arising from 2nd part of axillary artery in 4% cases and in up to 30% of it arises from a common trunk with posterior circumflex humeral artery . In anotVariations in branching pattern of axillary artery should be kept in mind while performing bypass between the axillary and subclavian artery in surgical treatment of subclavian artery occlusion . The com"} +{"text": "Chronic abdominal pain is a debilitating symptom of inflammatory bowel disease (IBD): a chronic inflammatory condition of the gastrointestinal tract, which includes Crohn's disease (CD) and ulcerative colitis (UC), and is characterized by periods of inflammation and remission. During inflammation, pain is often present due to the activation of afferent nerve endings in the gut by inflammatory mediators , which consists of connecting nerve plexuses that run between the muscular layers and the submucosa of the gut wall. The ENS controls gastrointestinal motility, secretion and absorption, which are all essential for gut function, but plays no major role in pain transmission noxious and innocuous sensations, to the spinal cord and brainstem. Brookes et al. have compiled a comprehensive review of extrinsic sensory afferent types that innervate the gut wall and capsasin (Christoph et al., Although new CNS targets for managing chronic visceral pain are emerging, the blood brain barrier represents a continual obstacle in the development of new therapeutics. The blood brain barrier presents physical, transport and metabolic barriers that can be modulated and regulated under both normal and pathological states (Abbott et al., In summary, visceral pain in chronic inflammatory diseases is poorly understood and current therapeutic strategies are limited. Further research is required to improve our knowledge of the events leading to the development chronic visceral pain. In addition, the discovery of improved CNS targets for pain management along with improved methods for drug delivery, are urgently required for the management IBD patients with chronic pain."} +{"text": "Aberrant redeployment of the \u2018transient\u2019 events responsible for bone development and postnatal longitudinal growth has been reported in some diseases in what is otherwise inherently \u2018stable\u2019 cartilage. Lessons may be learnt from the molecular mechanisms underpinning transient chondrocyte differentiation and function, and their application may better identify disease aetiology. Here, we review the current evidence supporting this possibility. We firstly outline endochondral ossification and the cellular and physiological mechanisms by which it is controlled in the postnatal growth plate. We then compare the biology of these transient cartilaginous structures to the inherently stable articular cartilage. Finally, we highlight specific scenarios in which the redeployment of these embryonic processes may contribute to disease development, with the foresight that deciphering those mechanisms regulating pathological changes and loss of cartilage stability will aid future research into effective disease-modifying therapies. The transition of cartilage to bone is the basis by which all long bones form. This transition is tightly regulated to ensure both permissive foetal development through endochondral ossification and postnatal longitudinal growth at the epiphyseal growth plate. Tighter management of these dynamic events may contribute to the inherent stability of some cartilage, such as articular cartilage, and this possibility is supported by emerging evidence reporting the aberrant redeployment of these transient events in the inherently stable cartilage in several pathological states such as osteoarthritis. It is therefore plausible that lessons can be realised from the molecular mechanisms underpinning the physiological transient chondrocyte differentiation and function. This knowledge may help to decipher those mechanisms surrounding joint pathology and ossification, and aid future research into effective disease-modifying therapies.In this review, we discuss aspects of cartilage and bone physiology, as well as the complex cellular processes involved in the cartilage to bone transition during endochondral ossification and at the postnatal growth plate. Moreover, we will compare this transient cartilage phenotype with the stable phenotype adopted by articular chondrocytes in order to ostensibly safeguard their permanence, and will discuss disease pathology in which the aberrant redeployment of the transient phenotype is observed.During mammalian embryological skeletal development, the appendicular skeleton comprising the pectoral girdle, pelvis and the limbs, arises from the lateral plate mesoderm and WNT/\u03b2-catenin -related peptide and IHH from the perichondrium true hypertrophy, indicating a proportionate increase in dry mass production and fluid uptake, responsible for approximately threefold increases in volume, ii) a fourfold enlargement solely by cell swelling and iii) a second distinct phase of true hypertrophy with proportionate dry mass and fluid volume increases. These authors show that this final stage is dependent upon insulin-like growth factor 1 (IGF1), a well-recognised regulator of longitudinal bone growth and chondrocyte hypertrophy degeneration is a major cause of back pain worldwide with complex, expensive surgery which is often prone to failure . Locatedin vitro study has sought to examine the mineralisation potential of the cells of the annulus fibrosus, and concluded that under certain conditions these cells can induce mineralisation, as indicated by their increased von Kossa staining, alkaline phosphatase, MMP13 and RUNX2 expression , MMP13 and RUNX2 is a common occurrence in muscle, tendon and ligaments following trauma by injury, disease or surgery. Initiated by cartilage formation, the endochondral ossification and ectopic bone formation in these tissues can produce severe functional impairment .Besides the trauma-induced HO described, a rare disease called fibrodysplasia ossificans progressiva (FOP) is a hereditary form of HO, presenting itself as painful and highly inflammatory soft tissue swellings which progressively ossify rendering the sufferer immobile . Like inThe aberrant redeployment of embryonic processes in diseases such as osteoarthritis and IVD degeneration is now well established. Emerging evidence has further fuelled the hypothesis that lessons for limiting disease progression can be acquired from the regulators of transient cartilage biogenesis and development. This review provides some pointers as to potential targets for future drug therapies or tissue engineering approaches which will further our understanding of the underpinning molecular mechanisms involved in these diseases, and will provide advances towards patient benefit."} +{"text": "Dear Editor,We read with great interest the study reported by Rabani . The autAlthough ureteral stents have various advantages, forgotten stents are a challenging situation even for the experienced endourologists. Forgotten stents can result in serious morbidity, mortality, and an increased financial burden for health services . ForgottGravas et al. underscoAs Rabani mentioneAlthough endourologic management of forgotten ureteral stents possible in most of the cases with success, further efforts and studies must be made for prevention strategies and possibilities for new kind or type of ureteral stents."} +{"text": "In addition to motor symptomatology, idiopathic Parkinson\u2019s disease is characterized by emotional dysfunction. Depression affects some 30 to 40 percent of Parkinson patients and other psychiatric co-morbidities include anxiety and apathy. Neuropsychological and neuroimaging studies of emotional dysfunction in Parkinson patients suggest abnormalities involving mesolimbic and mesocortical dopaminergic pathways. There is also evidence suggesting that the interaction between serotonin and dopamine systems is important in the understanding and treatment of mood disorders in Parkinson\u2019s disease. In this review we discuss the neuropsychiatric abnormalities that accompany Parkinson's disease and describe their neuropsychological, neuropharmacologic, and neuroimaging concomitants."} +{"text": "Urinary proteomics have recently identified hepcidin, a key regulator of iron homeostasis, as a potential marker of tubular stress . It appePatients meeting the inclusion criteria within 48 hours of admission had their CRP, urinary hepcidin, and serum and urinary creatinine measured. The strength of the relationship between serum creatinine or CRP and urinary hepcidin corrected for urinary creatinine was determined using Spearman's rank correlation coefficient.We enrolled 103 patients between 31 August 2010 and 17 November 2010; 22 of whom had an APACHE III diagnosis of sepsis. Serum creatinine only correlated weakly with direct and inverse urinary hepcidin measurements in septic and nonseptic patients alike. However, there was a moderately strong correlation between CRP and urinary hepcidin in septic patients, a relationship not demonstrated in the nonseptic group is preserved and filtered in lower amounts when the GFR is lost. That this relationship is not replicated in nonseptic patients with clinical evidence of SIRS suggests that the underlying pathophysiological processes are different. Further investigation of the natural history of AKI and biomarker release is warranted."} +{"text": "Biopharma process development accumulates growing collections of physicochemical product information and fermentation data, partly in response to initiatives like Process Analytical Technology (PAT) and Quality by Design (QbD) backed by regulatory authorities. The key goal of these initiatives is to ensure robust processes and consistent product quality based on a scientific and mechanistic understanding of the product compound itself and of the manufacturing process. Biopharma companies gather much high-quality data during fermentations including online measurements and omics data such as transcript and metabolite measurements. Typically, these data will be stored for documentation purposes only whereas data evaluation and interpretation lags behind and often is sporadic at best.Cellular network models can tap this underused resource for predicting fermentation outcomes and for analyzing why certain fermentations failed or succeeded based on a mechanistic representation of cell physiology. In particular, network models of cell metabolism upgrade metabolomics data by enabling predictions of cell behavior from concentration time series of extracellular and \u2013 if available \u2013 intracellular metabolites. Model simulations can be used for rapid hypothesis testing, e.g. to evaluate the impact of changes in feeding on intracellular metabolism, growth, or product formation. Identifying suitable metabolic target genes for cell line engineering represents another application area of such models. Here, we illustrate this approach using the prediction of optimal media compositions for a Chinese hamster ovary (CHO) cell line employing a genome-based CHO network model as example.in vivo reaction reversibilities can be obtained from labeling experiments combined with transient 13C-Metabolic Flux Analysis [The CHO stoichiometric metabolic network was reconstructed using information from public databases as well as from primary literature and accounts for the specific amino acid composition and glycoform structure of the product molecule. In a first step, we applied the network model to a comprehensive metabolic characterization of the existing fermentation process. Rates of cellular nutrient uptake, growth, and product formation in physiologically distinct process phases were determined from concentration time series of extracellular metabolites during a fermentation run. These cell-specific rates served to compute intracellular flux distributions using the CHO network model. Comparing flux distributions for different process phases provided insight as to when and where in intracellular metabolism significant changes occur during the fermentation. This is often not obvious from inspection of concentration time series alone. Especially for fed-batch processes, multiple feed streams and volume changes due to pH control and sampling impede interpretation of raw data. If desired, further information about the usage of alternative intracellular pathways and Analysis , which iIntracellular flux distributions also provide an ideal starting point for process optimization. Distinct optimal media compositions were computed for different fermentation phases based on the observed nutrient demand of the clone inferred from flux distributions. The chosen optimization approach combines stationary and dynamic model simulations on high-performance computing clusters. For dynamic simulations, the stoichiometric CHO network representation was transformed into a kinetic model. Model parameters were determined using evolutionary strategies and cluster computing based on the observed metabolite time series and considering thermodynamic constraints on reaction directionality. Integration of intracellular metabolite data into this workflow is easy and can further increase the predictive capabilities of the resulting model. The dynamic model also comprised a description of the fermenter including feeds and sampling. In this way, it can be predicted how changes in medium composition and feed flows impact rates of cell growth, productivity, and byproduct formation as well as intracellular metabolite profiles. Finally, media were optimized to maximize final product titer and specific productivity by varying the concentrations of glucose and individual amino acids in two continuous feed streams using evolutionary strategies on high-performance computing clusters.The resulting optimized media were tested experimentally in a fed-batch process. The improved feeding resulted in a 50% increase of final product titer and in an increased integral of viable cells already in the first iteration Figure . SimultaThe combination of metabolomics data and network models not only improves our quantitative understanding of cell physiology, but can also support and accelerate multiple steps of rational process development strategies:\u2022 Tailor media compositions to specific clones and curtail the time and experimental effort required for medium optimization compared to standard DoE techniques\u2022 Identify highly productive and robust clones for scale-up through comprehensive metabolic characterization during selection at small scales\u2022 Devise cell line engineering strategies for overcoming metabolic bottlenecks in cell growth and product formation by incorporating intracellular metabolite measurements and other omics data \u2022 Employ metabolic network models for controlling feed additions at the production scale.The above methodology enables biologics manufacturers to add value to data collected in PAT and QbD initiatives and to harness metabolomic data for quantitatively predicting and optimizing fermentation outcomes. This approach is not restricted to CHO cells, but is readily transferable to other cell lines and also to microbial production strains."} +{"text": "Dissecting ventricular septal hematoma (DVSH) rarely occurs after repair of a ventricular septal defect (VSD) but can lead to serious complications such as septal rupture, myocardial rupture, cardiogenic shock, heart block, outflow obstruction, cardiac tamponade, abscess transformation, and death. This paper describes the diagnosis and management of acute, severe, left ventricular outflow tract obstruction caused by the development of a DVSH after VSD repair. Dissecting ventricular septal hematoma (DVSH) after repair of ventricular septal defect (VSD) is a rare , potentiA 7-week-old male infant was noted to be hypoxemic prior to repair of an inguinal hernia. A postoperative echocardiogram demonstrated a large membranous VSD and a long segment coarctation of the aorta. Three months after repair of the coarctation the infant was in congestive heart failure and was brought to the operating room for VSD repair. Preoperative transesophageal echocardiography (TEE) demonstrated a large membranous VSD that extended into the inlet septum and a widely patent left ventricular outflow tract . VSD repair was performed using aortobicaval cannulation with mild hypothermia and antegrade cardioplegeic arrest. The echocardiographic findings were confirmed at surgery, and the VSD was closed in the standard manner using a Dacron patch and 5\u20130 Prolene pledgeted suture. The initial suture line was carried clockwise avoiding the crest of the ventricular septum. Near the septal leaflet of the tricuspid valve, sutures were placed superficially to avoid the conduction system. The VSD was then closed in a counterclockwise fashion staying away from the crest of the ventricular septum, across the ventricular infundibular fold avoiding the aortic annulus, and eventually transitioning to the septal leaflet of the tricuspid valve. The remainder of the VSD underneath the septal leaflet of the tricuspid valve was closed by weaving in and out of the valve leaflet and the VSD patch. The suture was then tied over an autologous pericardial patch. Postoperative TEE , performAlthough rare, DVSH has the potential to cause significant hemodynamic perturbations and may be life threatening. This process, initiated by surgical disruption of the coronary microcirculation, creates a form of myocardial rupture as blood dissects along the spiral planes of the cardiac muscle beneath the endocardium . The resDVSH after VSD repair can be readily diagnosed during intraoperative TEE, and we agree with previous recommendations that intraoperative TEE should be performed in all patients undergoing VSD repair . Both thManagement strategies of DVSH include evacuation \u20133 or obsIf the DVSH is diagnosed after the patient has left the operating room, serial echocardiograms should be performed until the size of the DVSH has stabilized and periodically thereafter until the hematoma has either resolved or is noted to be enlarging. If the hematoma enlarges, or causes any other complications, consideration should be given to surgically evacuating the hematoma."} +{"text": "Advances in sequencing technology have led to an unprecedented opportunity to characterize the genomes of human cancers. Our work has been focused on characterizing intra- and intertumoral heterogeneity in several tumor types. Work on breast cancer has revealed substantial complexity of operative cancer genes, with marked diversity between cancers revealed by exome sequencing. Further work in both renal and breast cancer has begun to define the architecture of intratumoral heterogeneity \u2013 revealing evidence for substantial branched and, in some cases, convergent evolution within the same tumors. These data and others, particularly as they relate to the challenges of translation and genomics-base medicine will be discussed."} +{"text": "Particular attention in future studies should be on shifting the experimental paradigm toward procedures that can determine the risk for developing treatment resistance in untreated depressed individuals.The search for potential biomarkers of psychiatric disorders is a central topic in biological psychiatry. This review concerns published studies on potential biomarkers of treatment-resistant depression (TRD). The search for biomarkers of TRD in the bloodstream has focused on cytokines and steroids as well as brain-derived neurotropic factor. Additional approaches to identifying biomarkers of TRD have dealt with cerebrospinal fluid analysis, magnetic resonance imaging, and positron emission tomography. Some studies have also investigated potential genetic and epigenetic factors in TRD. Most studies have, however, used a They used blood samples to compare the genotypes of subjects with well-established TRD and healthy blood donors. They found that a particular combination of 5-HT1A and BDNF genotypes was associated with TRD. Since genetic factors are viewed as stable bio-molecular items, such findings may eventually provide biomarkers for predicting the risk of someone having TRD.Anttila et al. examinedThe term \u201cepigenetics\u201d means \u201coutside conventional genetics.\u201d Epigenetics is the study of stable alterations in gene expression that take place during development by random change or under the influence of the environment ; however, also this study follows a post hoc experimental design.Monoamine oxidase (MAO) degrades biogenic amines and has been a central topic of depression research for almost 50\u2009years studies are carried out to estimate the size of brain regions. Many sMRI studies have been done in depressed subjects and healthy controls conditions, they found that functional connectivity of brain regions was generally lower in remitted subjects and in TRD patients than in healthy subjects under resting state fMRI conditions. TRD patients had decreased functional connectivity in a network consisting of the left amygdala, anterior cingulate cortex, right insula, and precuneus cortex. Li and coworkers speculated that the particular pattern of abnormal functional connectivity in depressed subjects may constitute a biomarker of TRD, but their study design precludes statements regarding the value of resting state fMRI for identifying subjects at risk.Li et al. used a ppost hoc design in their PET study of mirtazapine binding in brain regions of subjects with well-established TRD and healthy subjects. They found moderately reduced binding of radiolabeled mirtazapine in regions of the cerebral cortex and basal ganglia of TRD subjects compared with healthy subjects. Once again, the experimental design precludes statements regarding possible causal mechanisms linking reduced neuroreceptor binding and TRD.Brain imaging by positron emission tomography (PET) has often been used to study potential biomarkers of depressive disorders as well as to investigate potential beneficial effects of antidepressant drugs (Mayberg et al., Depressive disorders are complex, heterogeneous, and disabling conditions that require prompt treatment and appropriate care. Our inability to relieve the disabling symptoms of depressive disorders in many cases has stimulated research directed toward the development of more effective antidepressant treatments and improved clinical care (Rothschild, post hoc experimental design, thereby precluding statements concerning the initial level of risk of developing treatment resistance. In the author\u2019s view, our current lack of information on the initial risk of TRD stems mainly from the misguided post hoc experimental design of many studies that tried to identify biomarkers of TRD. To remedy this situation, the author proposes that a shift take place in the standard paradigm in biomarker studies of TRD toward examining depressed subjects at the time of their initial contact with treatment facilities. Systematic administration of antidepressant treatments with appropriate monitoring procedures in depressed individuals can be expected to identify biomarkers for predicting the risk level of treatment resistance. Such information is likely to disclose biological targets that can form the basis for developing more effective antidepressant treatments.An ultimate goal of biological psychiatry concerns the use of biomarkers to improve the initial diagnosis and treatment of depressive disorders (Cardoso de Almeida and Phillips, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The necessity of treating receptor flexibility in protein-ligand docking has been widely acknowledged and is the subject of extensive research in the field of drug discovery . The useFor neuraminidase and cyclin-dependent kinase II, snapshots of molecular dynamics simulation trajectories have been clustered and structurally assessed by applying a variety of methods. Extensive cross docking and virtual screening experiments show that relatively large differences in docking performance are caused by only very subtle conformational changes within the protein which cannot be captured by the currently applied characterisation methods. As an alternative, cross docking capability can be used as a reliable indicator towards the selection of suitable conformations for ensemble-based virtual screening. In combination with short minimisations of docked poses in the binding site, virtual screening performance can be further improved and ensembles of MD snapshots can be built which perform as well as the generally superior holo crystal structures."} +{"text": "Meta-analysis shows increased risk for DHPS mutations in patients exposed to sulfa prophylaxis for PCP, but clinical relevance of mutations is not known. Pneumocystis jirovecii pneumonia (PCP) patients between dihydropteroate synthase (DHPS) mutations and sulfa or sulfone (sulfa) prophylaxis and between DHPS mutations and sulfa treatment outcome. Selection criteria included study populations composed entirely of PCP patients and mutation or treatment outcome results for all patients, regardless of exposure status. Based on 13 studies, the risk of developing DHPS mutations is higher for PCP patients receiving sulfa prophylaxis than for PCP patients not receiving sulfa prophylaxis (p < 0.001). Results are too heterogeneous (p < 0.001) to warrant a single summary effect estimate. Estimated effects are weaker after 1996 and stronger in studies that included multiple isolates per patient. Five studies examined treatment outcome. The effect of DHPS mutations on treatment outcome has not been well studied, and the few studies that have been conducted are inconsistent even as to the presence or absence of an association.A systematic review was conducted to examine the associations in Pneumocystis jirovecii causes pneumonia in immunocompromised persons, especially those with AIDS, worldwide (Pneumocystis jirovecii pneumonia (PCP) has declined substantially since highly active antiretroviral therapy (HAART) was introduced in 1996 is the first-line drug choice for both prophylaxis and therapy. TMP-SMX acts in animals as sulfa monotherapy against the enzyme dihydropteroate synthase (DHPS) prophylaxis against PCP has been reported in up to one fourth of patients . ISI Web of Science was searched with the keywords \"pneumocystis pneumonia,\" \"resistance,\" and \"genes\" (last searched January 2004). The bibliographies of relevant articles were surveyed for additional studies. One author (S.R.M.) contacted 42 scientists through an informal PCP email forum to request unpublished results and conference abstracts on associations between sulfa prophylaxis and Pneumocystis mutations and Pneumocystis mutations and sulfa treatment outcome.MEDLINE was searched with the keywords \"Inclusion requirements were the following: study populations composed entirely of PCP patients; mutation results for all patients, regardless of sulfa prophylaxis exposure; and treatment outcome results for all patients, regardless of mutation status. Studies reporting the outcome (mutation status or treatment failure) only for exposed patients (on prophylaxis or with mutations) were not included because these studies would have biased the analyses by not providing information on unexposed populations for comparison. When more than one article reported on the same study population, only the more comprehensive article was included. From every eligible report, one author extracted information on publication year, study location(s), study start and end dates for calculating data collection calendar midpoint, study size, proportion of HIV-positive patients, number of isolates per patient, timing of prophylaxis in relation to PCP, treatment outcome definition, number and type of DHPS mutations in patients receiving or not receiving sulfa prophylaxis, and sulfa treatment outcome among patients with and without DHPS mutations. Multiple isolates from the same patient were included as independent counts of PCP.\u20131 was used to analyze estimates of the effect of prophylaxis on mutation occurrence and estimates of the effect of mutation on treatment outcome. Both analyses used the risk difference (RD) as the effect measure. Qualitatively similar results were obtained by using the risk ratio and incidence odds ratio . Twelve of the 13 studies reported results suggesting that prophylaxis increases the risk for DHPS mutations, and 95% CI of 10 of the 13 excluded the null value , Figure.\u2013,,,,,,,,,,,Of the examined characteristics, data collection calendar midpoint and multiple isolates both had strong associations with the study results . Higher ,,,The four studies that detailed prophylactic drug use for each specific mutation had a high homogeneity p value (p = 0.6) and a higher estimated RD .for PCP , .PCP patients receiving sulfa prophylaxis are at increased risk for DHPS mutations compared with PCP patients not receiving sulfa. The strength of the association varies greatly across studies.Not all studies adhered to a uniform definition of substantive sulfa exposure. Only some defined a minimum duration of prophylaxis use, often in conjunction with the timing of the PCP episode, for a patient to be counted as receiving prophylaxis. Some studies were more comprehensive in documenting prophylactic drug use by pulling pharmacy records to verify that prophylactic medications were dispensed or patient questionnaires to confirm that the drug was taken. Moreover, the association between prophylactic drug use and mutation was stronger for the studies that included multiple isolates than for those that did not. This difference suggests the possibility that exposure to multiple courses of sulfa prophylaxis increases the chance of developing DHPS mutations. The weakened association evident since 1996 may reflect a higher overall prevalence of mutation with a higher prevalence among those unexposed to prophylaxis, or it may reflect that fewer HIV-infected patients take prophylactic drugs because of HAART. Each of these factors may bear on the strength of the association between sulfa prophylaxis and DHPS mutations. Variations in unreported aspects of study design or patient characteristics may account for the remaining inconsistency in estimated effect size.One of the 13 studies reported an inverse association between prophylaxis and mutations (,,This systematic review was unable to resolve the conflicting results regarding the magnitude of the effect of DHPS mutations on treatment outcome. Only five studies were eligible for inclusion in this analysis. Although the small number of studies precluded a statistical investigation of possible explanations for the inconsistent findings, variation in definitions of treatment outcome may be partially responsible. The two studies with positive associations used clinical improvement after therapy to determine treatment outcome (This systematic review has both strengths and limitations. It included information on all relevant studies for which results have been reported, examined how different study characteristics influenced the magnitude of effect estimates, and provided information that may be useful when designing future studies of a similar nature. Its principal weakness was that the small number of available studies, especially for treatment outcome, made the results from stratified analysis and meta-regression less precise than would be desirable.We conclude that exposure to sulfa prophylaxis for PCP increases the risk for DHPS mutations. This finding is evident even with the heterogeneity of the individual study results. Although whether these mutations are clinically relevant is unclear, they are likely to develop in patients who have received sulfa prophylaxis for PCP for extended periods. This review did not clarify the effect of these mutations on treatment outcome. Further studies are needed to examine the association between DHPS mutations and treatment outcome in patients with PCP. Until these studies are performed, the optimal treatment for patients with PCP, who have had substantive exposure to sulfa prophylaxis and who are therefore likely to have DHPS mutations, remains speculative."} +{"text": "One task during development and control of bioprocesses used for production of recombinant proteins is to deliver fast, accurate and reliable analytical process data.Monitoring of nutrients and metabolites in animal or bacterial cell culture is essential to avoid limitations or toxic accumulation during fermentations that can effect cell growth, viability, product yield and quality. Within certain fermentation processes low levels of nutrients trigger in-process actions such as feed. Other parameters are used to track culture reproducibility and to gain process understanding for process development and validation.Typical parameters in mammalian cell culture are glucose, lactate, glutamine, glutamate, ammonia, sodium and potassium. Therefore it is common to use multi-analyzer systems based on enzymatic-dependent biosensors and ion- selective potentiometry.Furthermore the release of lactate dehydrogenase (LDH) into the fermentation media is used as an indicator of cell death during fermentation processes therefore a 96-well based photometric assay is used . The measurement of product titer like IgG is needed to track productivity or yield during fermentation and protein purification processes and is mostly done by HPLC methods.One major motivation for this new Bioprocess analyzer lies within the eminent issues of enzyme membrane based analytical technology such as: short life cycles as well as poor or changing quality of the enzyme membranes, high material costs, non-linearity of measurements and in particular insufficient sensitivity and accuracy.Additionally the laborious maintenance required to operate different analytical devices and labor intensive sample management as well as manual steps to avoid operator dependent variability needed to be reduced.Combining the knowledge of 25 years of diagnostic healthcare with expert knowledge in fermentation processes a new Bioprocess analyzer was developed. The new Cedex Bio analyzer stands out with increased sensitivity plus enlarged measurement ranges compared to currently used methods and analyzers.An automated dilution increases the measurement ranges and reduces operator variability because no manual dilution is needed before applying the sample to the Cedex Bio analyzer.The aim of this evaluation and method validation was to compare this new device to common analytical systems.Reference standards were analyzed at least once a day before and after each tray of samples to control the performance of the membrane analyzer. Day to day and side by side comparability as well as accuracy and linearity of the Cedex Bio analyzer are superior to the membrane analyzer as shown in Figure An increased sensitivity allows to operate nutrient limited fermentations and likewise to detect remote changes within the metabolite profile of the fermentation process.Monitoring of fermentations processes using a membrane analyzer required laborious maintenance, a lot of calibrations and permanent control of recovery.However correlation studies conducted with samples of a fed-batch mammalian cell fermentation show that the Cedex Bio analyzer easily replaces the membrane analyzer with comparable batch data Figure .Furthermore additional parameters like LDH or IgG can be analyzed from the same sample.\u03bf The Cedex Bio analyzer combines three devices to one with the possibility to measure up to 9 parameters in fermentation browth at once and from the same sample within a few minutes.\u03bf Automated dilution reduces operator dependent manual steps and variability.\u03bf Methods based on wet chemical photometric assays, ionselective electrodes and turbidity assays are easy to handle, reliable and robust.\u03bf The compact analyzer helps to save laboratory space and costs for different instruments.\u03bf Sensitive, precise and accurate analytical data allow a tight control of cell culture processes.\u03bf The assay portfolio will also be suitable for microbial fermentation with additional parameters like acetate or ethanol.\u03bf The Cedex Bio analyzer combines three devices to one with the possibility to measure up to 9 parameters in fermentation browth at once and from the same sample within a few minutes.* CEDEX is a trademark of Roche"} +{"text": "Heart failure is a common cardiovascular disease with high morbidity and mortality. Unlike western countries where heart failure is predominantly a disease of the elderly, in India it affects younger age group. Important risk factors include coronary artery disease, hypertension, diabetes mellitus, valvular heart disease and cardiomyopathies. Plasma brain natriuretic peptide levels are helpful in the diagnosis of heart failure. Echocardiography is the primary imaging modality of choice, through recently cardiac magnetic resonance imaging (MRI) has been found to play an increasing role. Aim of management is to improve symptoms & enhance survival. Diuretics are important in relieving symptoms. Beta-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers and adosterone antagonists improve survival in patients with impaired systolic function. Device therapy including cardiac resynchronization therapy and implantable cardiac defibrillators, though expensive are useful in selected patients. Unlike in patients with systolic heart failure where several therapies have been shown to improve survival, clinical trial results in diastolic heart failure have been disappointing and therapy in these patients is restricted to symptom improvement and risk factor control. Therapies like stem cell therapy are being evaluated in clinical trials and appear promising. Early diagnosis and appropriate therapy helps in reversing the process of remodelling and clinical improvement in most of the patients. Heart failure (HF) is a common cardiovascular condition with increasing incidence and prevalence2Heart failure is third most common cardiovascular disease in the US affecting 2 per cent of the U.S. population, or almost 5 million people2In India, we do not have data regarding the exact prevalence and incidence of heart failure. With higher propensity for cardiovascular diseases and ageing population the burden of CHF is likely to be higher in comparison to the western population. Therefore, there is an urgent need to have HF registries in the secondary, tertiary care centers and at the national level. These will help and provide us the detailed information related to heart failure incidence, prevalence, aetiology and thus guide for adopting management strategies.Heart failure may be either predominantly systolic and diastolicIt is estimated that 40 to 50 per cent of patients with heart failure have preserved systolic function or a relatively normal left ventricular ejection fraction. Although such hearts contract normally, relaxation is abnormal. Cardiac output, especially during exercise is limited by the abnormal filling characteristics of the ventricles. These abnormally high filling pressures lead to pulmonary congestion, dyspnoea and oedemaPatients with diastolic heart failure are typically elderly, often female, obese and frequently have hypertension and diabetes. Mortality among these patients may be as high as that among patients with systolic heart failure, and the rates of hospitalization in the two groups are similarThe diagnosis of heart failure is mainly clinical but various investigations help us to understand the underlying cause and assessment of severity of HF. Investigations may help in doubtful cases especially when the clinical presentation is complicated by underlying lung disease.The classical clinical symptoms of heart failure are exertional dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoea, fatigue and the signs are elevated jugular venous pressure, pulmonary rales, third heart sound and peripheral oedema. No single symptom or sign is pathognomic of heart failureSymptoms most sensitive for heart failure are exertional dyspnoea, orthopnoea, paroxysmal nocturnal dyspnoeaSigns of HF are also non-specific. These include basal crepitations, oedema, raised jugular venous pressure and hepatomegaly. These signs may be absent in patients with compensated heart failure or those on drug therapy. Features of right heart failure are not seen in 50 per cent of the patients with idiopathic dilated cardiomyopathy at initial diagnosisThe symptoms and signs bear an inconstant relationship to haemodynamic parameters including resting filling pressures, cardiac index and ventricular function in individual patients. Accurate functional classification remains problematic for individual patients. The NYHA (New York Heart Association) classification is limited by its poor reproducibility and relies exclusively on the presence and severity of symptoms rather any marker of ventricular remodelling.(i) careful history and physical examination, (ii) laboratory investigations including complete blood count, test of renal and hepatic functions, urinanalysis, electrocardiogram and chest x-ray, (iii) two dimensional and Doppler echocardiogram (iv) careful exclusion of coronary artery disease and thyroid disease in all patients, and (v) selective use of other diagnostic tests including serologic studies in selected patients based upon the clinical characteristics, risk factors, past medical and family historyThe ACC/AHA guidelines emphasize Electrocardiogram may help to indicate the underlying ventricular hypertrophy or evidence of coronary artery disease. Prolongation of QRS >120 ms occurs in approximately 30 per cent of patients with heart failure2224Cardiomegaly on skiagram has a sensitivity and specificity of 79 and 80 per cent respectivelyEchocardiogram is an important and simple tool to assess the ventricular function and underlying structural abnormality. Assessment of left ventricular systolic function in biplane Simpson\u2019s method is routinely used in clinical practice. It is a valuable tool in measuring LV volumes and assessment of regurgitation. Echocardiography plays a vital role in the diagnosis of patients with heart failure, in part because the physical examination, electrocardiogram, and chest radiograph do not provide information that distinguishes diastolic from systolic heart failure28Radionuclide cardiac imaging is an excellent modality for assessment of ventricular volumes, geometry, diastolic function and myocardial perfusion. It is commonly used for assessment of myocardial viability. It can differentiate ischaemic and non-ischaemic cardiomyopathy.CT scan is useful in the evaluation of pericardial disease. Magnetic resonance imaging (MRI) is a validated technique for quantification of volumes, regurgitation and mass of the ventricles. It is a good modality for the assessment of myocardial viability. Myocardial diseases can be diagnosed accurately with cardiac MRI. Experience with cardiac MRI in India is limited since it is not cost-effective for routine evaluation. As coronary artery disease is the leading cause of heart failure, it is preferable to perform coronary angiogram in patients with left ventricular systolic dysfunction who are more than 35 yr of age even in the absence of clinical evidence of coronary artery disease.0 In dilated cardiomyopathies endomyocardial biopsy is helpful in identification of underlying myocarditis and cardiotropic viruses. In selected cases of infiltrative diseases it can be performed to diagnose the cause when other tests fail to reveal the exact aetiology of heart failure. The current recommendation for its use is in patients with new onset heart failure of < 3 months duration, haemodynamic compromise with or without a dilated ventricle, evidence of arrhythmias and failure to respond to usual care for 1 to 2 wk durationThe precursor of brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) is a pre-prohormone BNP, a 134-amino-acid peptide that is synthesized in the myocytes and cleaved to prohormone BNP of 108 amino acids. Prohormone BNP is cleaved by a circulating endoprotease into two polypeptides: the inactive NT-pro-BNP and BNP, a bioactive peptide37Primary prevention refers to identifying the risk factors for the development of heart failure and their prevention with an aim to reduce the incidence and burden of heart failure. As mentioned earlier the most important risk factors are hypertension, coronary artery diseases, diabetes mellitus and rheumatic heart diseases. Physical activity, dietary control and lifestyle modification can drastically bring down some of these modifiable risk factors and reduce the load of HF.Heart failure can be controlled by both primary and secondary means. Screening through population- based approach and high risk approach can yield satisfactory results and greater reduction in congestive heart failure. Screening for hypertension in individuals more than 30 yr of age and at interval of every 3-5 yr. Screening for diabetic individuals >45 yr of age and persons who have other risk factors for diabetes mellitus. Cholesterol screening (lipid profile) can be performed in individuals >45 yr of age and having risk factors for coronary artery diseases. Screening school children for identification of rheumatic heart diseases, as this is the age group frequently affected. These screening tests can be incorporated into the existing cardiovascular and chronic diseases control programmes. Health education and health promotion strategies are quite important in the success of theses programmes.There are two types approaches for prevention- high risk approach and population-based approach. High risk approach produces quicker results as seen in a Chinese study in a cohort of 2700 patients (>35 yr of age) with risk factors such as hypertension, diabetes mellitus and coronary artery disease in whom after a period of 3.5 yr the cumulative incidence of stroke was significantly lower in the intervention cohort than the control cohort The management of CHF depends largely on the setting where the patient presents. Almost 75 per cent of the population of India lives in rural areas. Health care in villages are largely provided by the primary health centers from the public health systems and by local primary care physicians who practice myriad form of systems including indigenous system.In the urban areas again a large proportion of health care is provided by private practitioners and vast expenditure is out of pocket. A few secondary and tertiary centres are available both in the public and private sectors. The management largely depends on where the patient is presenting .The general principles of treatment of heart failure include improvement of symptoms and survival. Every effort has to be made to identify the treatable causes of heart failure and treat the underlying condition. Specific therapy has to be initiated for anaemia, thyroid disorders and nutritional deficiencies. Aggressive management of systemic hypertension, diabetes mellitus, underlying coronary artery disease and surgical correction of valvular heart diseases should be carried out if indicated. Avoidance of alcohol and other toxins is necessary. The detailed algorithm for the diagnosis and management of heart failure is shown in Control of heart rate, reversion to normal sinus rhythm and anticoagulation appropriately are the usual measures adopted in patients with atrial fibrillation. In patients with anaemia, characterization of the type of anaemia is important. The role of erythropoietin in patients with normocytic, normochromic anaemia in HF is being evaluated. In bed ridden patients a possibility of pulmonary embolism has to be kept if heart failure worsens in spite of adequate therapy.Other therapies that are instituted in spite of the specific therapies are similar to all forms of heart failure.Exercise training: Exercise training improves exercise capacity and quality of life in patients with mild to moderate heart failure. Early trials have shown beneficial effects of aerobic exercises. More recent trials show that an element of resistance training improves muscle strength, bulk and endurance44Diet and nutrition: Heart failure patients are at increased risk of weight loss due to loss of appetite and hypercatabolic status. Adequate calorie intake and nutrients are part of the dietary programmes in these patients. Salt restriction according to symptoms is an essential component. Fluid balance has to be maintained. A supervised nutritional intervention was shown to improve clinical status and quality of life in heart failure patientsEducation and counselling: The physician and caregivers should educate the patients regarding the nature of the disease and take steps to prevent further progression of disease. Lifestyle modification and strict compliance to medication is important. Psychological support by the treating physicians boosts the confidence of patients.These are the main stay of therapy to relieve congestive symptoms. Three classes of drugs are available: loop diuretics, thiazide group and potassium sparing diuretics.Loop diuretics: Agents belonging to this group include furosemide, torsemide and bumetinide. These are most potent diuretics that act on the ascending loop of Henle. Recent data suggest that torsemide and bumetanide are more effective than furosemide in the treatment of advanced heart failure48Thiazide diuretics: These act by inhibiting the reabsorption of sodium and chloride from distal convulted tubule. Diuresis with these agents is modest and these are ineffective at glomerular filtration rate below 40 ml/minMetalozane belongs to the quinalozone sulphonamide group. It acts by inhibition of sodium reabsorption in the cortical collecting duct and proximal convoluted tubule. Its main advantage is its efficacy in reduced renal function.The beneficial role of \u03b2-blockers in the treatment of heart failure is well established. Agents commonly used in clinical practice are sustained release metoprolol, carvedilol, bisoprolol and nebivolol. Several large randomized placebo-controlled studies in patients with class II-IV heart failure in particular the MERIT-HF, COPERNICUS, CIBIS and COMET trials showed mortality and morbidity benefit with usage of \u03b2-blockersThe drugs that produce both venous and arterial dilatation are the preferred agents in heart failure as most forms of heart failure have elevated preload and after load. The ACEI acts on both the arterial and venous capacitance vessels. They act by inhibiting the production of angiotensin II as a consequence preventing the deleterious effects of angiotensin II through its action predominantly on the type 1 receptors. The levels of bradykinin are raised which result in the production of nitric oxide and other important endogenous vasodilatorsThere is a clear-cut and compelling evidence that all patients with heart failure and asymptomatic left ventricular dysfunction should receive ACE inhibitor therapy. Multiple well designed prospective randomized placebo-controlled trials, particularly CONSENSUS I, V-HEFT II and SOLVD showed improvement in symptoms and survival in patients with mild to severe heart failureWhich first- \u03b2-blockers or ACEI?: Historically the efficacy of ACEI in setting of heart failure was demonstrated in the early 1990s, well before the utility of \u03b2-blockers was understood. Thus therapy for heart failure is usually started with an ACE inhibitors and \u03b2-blockers added later. This practice is not based on any trial evidence but rather appears to be based simply on the historical factors. In fact there is a pathophysiologic basis for the theory that it may be appropriate to start treatment with a beta-blocker. The sympathetic nervous system is activated before the renin-angiotensin-aldosterone system in heart failure, and both systems are inhibited by beta-blockers. Moreover, sudden death, the most prevalent cause of death in early heart failure, is also reduced by \u03b2-blockers. The CIBIS III trial compared bisoprolol first and enalapril first regimens. There was no significant difference in the primary endpoint between the two treatment strategiesIn the renin angiotensin aldoterone system, the action of the angiotensin converting enzyme produces angiotensin II from angiotensin I. There are other alternative pathways for the generation of angiotensisn II. They are the chymase, chymotrypsin, angiotensin generating enzyme and cathepsin D pathways. The ARBs act at the angiotensisn II receptor level blocking the downstream effects of angiotensin II. ARBs can be used in treatment of heart failure instead of ACE IIn heart failure the circulating levels of aldosterone are increased. The deleterious effects include endothelial dysfunction, increased oxidative stress, activation of matrix metalloproteinases, and activation of sympathetic nervous system. In conjunction with angiotensin II enzyme its effects are enhanced. The RALES study showed that spironolactone reduced mortality in severe heart failure patients treated with an ACE I with or without \u03b2-blockers by 30 per centDigoxin acts by inhibition of the sodium potassium adenosine triphosphatase enzyme and increases the intracellular Na. This drug is being used for more than a century in the treatment of heart failure. The randomized trials RADIANCE and the DIG trial showed significant reduction in hospitalizations for worsening heart failure but no reduction in mortality74Acute heart failure syndromes (AHFS) are often associated with reversible factors like ischaemia and the cardiac function can return to normal if these are corrected. If not appropriately treated, a vicious cycle is triggered that can lead to chronic heart failure and death. The goals of therapy thus include stabilization of the haemodynamic condition and correction of the underlying reversible factors.Based on the EFICA and OPTIMIZE HF studies the initiation of treatment in acute heart failure syndromes depend on the systolic blood pressureThese patients may need supplemental oxygen therapy to maintain oxygen saturation within normal range by increasing FiO2. In case, oxygen saturation is not maintained, non-invasive positive pressure ventilation (NIPPV) should be considered. NIPPV improves oxygen saturation, decreases the need for endotracheal intubation but does not appear to reduce mortality. Endotracheal intubation and invasive ventilation should be considered if the condition deteriorates.Some patients may also need temporary mechanical haemodynamic support with intra-aortic balloon pump or left ventricular assist device. Simultaneously, correction of the underlying cause is of primary importance.Most inotropic agents act by increasing the myocardial contractility through increase in intracellular cyclic adenylate monophosphate which ultimately leads to increased calcium in the sarcoplamic reticulum. Of these agents, the commonly used in clinical practice are dopamine, dobutamine, ephinephrine, norephinephrine, milrinone and enoximine. Of these inotropes, milrinone and enoximine are phosphodiesterase III inhibitors. Although inotropic agents temporarily stabilize the haemodynamic status, their long-term use is associated with increased mortality2Cardiac resynchronization therapy: Cardiac resynchronization therapy (CRT) is an established therapy in patients with LV systolic dysfunction and moderate to severe heart failure symptoms despite optimal medical therapy and evidence of wide QRS > 120 ms81Implantable cardiac defibrillator (ICD): Sudden cardiac death is responsible for 25 to 50 per cent of mortality in heart failure patients. The percentage of sudden deaths is higher in patients with mild to moderate heart failure as opposed to advanced forms where pump failure accounts for a larger percentage of deaths. The MADIT-II and SCD-HeFT trials confirmed the effectiveness of ICD for primary prevention in heart failure83Ventricular assist devices: Mechanical circulatory assist devices are used in both acute and chronic heart failure. They are used as a bridge to recovery, bridge to transplant or as permanent destination therapyAs coronary artery disease is one of the major causes of heart failure every effort has to be made to undertake complete revascularization after assessment of myocardial viability. In patient with valvular heart diseases repair or replacement as per recommendations and guidelines is helpful in prevention and treatment of heart failure. In patients with secondary or functional mitral regurgitation and ischaemic mitral regurgitation, valve repair surgery preserving the mitral apparatus is advocated. Other surgical modalities reshape the dilated ventricle to decrease the volume and stress on the ventricle. Partial left ventriculectomy (Batista procedure) is no longer popular due to poor long-term outcomes. Cardiac transplantation remains the gold standard therapy for end stage heart disease87Studies have demonstrated modest increase in LV ejection fraction and improvement in symptoms in patients with LV dysfunction of both ischaemic and non ischaemic aetiologyDisease management programmes (DMP) have been developed to standardize and optimize CHF treatment. These programmes focus on education of the patient and continuing support after hospital discharge. Studies have shown that these programmes have been shown to reduce mortality and hospitalization rates, improve quality of life and economically beneficial.Telemedicine is being increasely used in India in the diagnosis and management of disease to people out of reach in remote areas. Telemonitoring can also be effectively used in monitoring heart failure patients. By allowing clinical data to be collected without the need for face to face contact with the patients, telemonitoring facilitates easy access for management and therby improving the clinical outcome.There are several ways by which telemonitoring can be done. These are telephone based symptom monitoring, automated physiologic monitoring and automated monitoring of symptoms and signs. Trained nurses can collect the required information which can later be reviewed by physicians. In the automated systems the information regarding the symptoms, signs and physiological parameters are uploaded into the particular websites which are centrally located and monitored by heart failure specialists, cardiologists and or physicians.Heart failure in India has reached epidemic proportions. Early identification of the risk factors and initiation of appropriate therapy at early stages prevents development of heart failure. Clinical diagnosis and diagnostic imaging, echocardiogram in particular identifies patients with heart failure. The optimum utilization of the available drugs, general measures and surgical procedures appropriate to the condition improves the outcome of these patients."} +{"text": "Van der Woude Syndrome is the most common form of syndromic orofacial clefting, accounting for 2% of all cases, and has the phenotype that most closely resembles the more common non-syndromic forms. The syndrome has an autosomal dominant hereditary pattern with variable expressivity and a high degree of penetrance with cardinal clinical features of lip pits with a cleft lip, cleft palate, or both. This case report describes van der Woude syndrome in a 19 year old male patient with a specific reference to the various aspects of this condition, as clinical appearance, etiological factors (genetic aspects), differential diagnosis, investigative procedures and management. Key words:Cleft palate, cleft lip, lip pits, van der Woude syndrome, syndromic clefting. Orofacial clefting (OFC) is a common developmental genetic disorder that occurs with a prevalence which has been estimated at between 1 in 2500 live births depending on geographic origin, racial and ethnic variation, and socioeconomic status.Etiology of this syndrome is remarkably variable, it was initially mapped to human chromosome 1q 32 \u2013 q 41 and later demonstrated to result from mutation in gene encoding Interferon Regulatory Factor 6 [IRF 6] of 3 mm diameter with continuous secretion of saliva fig. . MaxillaWhole body physical examination was then performed to rule out other condition having similar presentation . No other abnormality was detected thus a diagnosis of VWS was made. Radiographic investigation were performed for knowing any impacted teeth, jaw pathologies and also for treatment planning. Multidisciplinary approach for correction of clefts and complete rehabilitation was planned. Patient referred to department of oral maxillofacial surgery for excision of lip pits and tracts to avoid cosmetic problems and further complications from chronic inflammatory process of these lip pits. Followed by surgery, replacement for missing teeth and further management was advised. Importance of genetic counseling which is highly recommended as it provides information on likely hood of gene transmission and possible ways of expression was explained and advised to the patient.When the labial pits occur in association with cleft lip and/or palate the condition is referred to as van der Woude Syndrome (VWS) . These cLip pits are inherited as an autosomal dominant trait, their pathogenesis is not well understood . They arvan der Woude syndrome has an autosomal dominant hereditary pattern with a variable expressivity, and its penetrance has been estimated at 80%, however later reports have shown that the penetrance is close to 100% . Eighty Management of VWS is majorly focused on surgical and cosmetic correction of clefts and lip pits, on account of secondary infection due to inflammation of pits may necessitate usage of antibiotic, analgesics and meticulous oral hygiene practices . More exvan der Woude syndrome is not frequently reported, the phenomenon of cleft lip and cleft palate combined in same pedigree makes it unique. Making a distinction between similar disease presenting cases requires thorough knowledge of various clinical features, variable manifestations and investigatory procedures. A multidisciplinary approach including genetic counseling which would give information on likelihood of gene transmission, possible ways of expression and the potential of embryoscopy to detect minor malformations such as cleft should be encouraged in early diagnosis and management."} +{"text": "Lignocellulosic hydrolysate (LCH) inhibitors are a large class of bioactive molecules that arise from pretreatment, hydrolysis, and fermentation of plant biomass. These diverse compounds reduce lignocellulosic biofuel yields by inhibiting cellular processes and diverting energy into cellular responses. LCH inhibitors present one of the most significant challenges to efficient biofuel production by microbes. Development of new strains that lessen the effects of LCH inhibitors is an economically favorable strategy relative to expensive detoxification methods that also can reduce sugar content in deconstructed biomass. Systems biology analyses and metabolic modeling combined with directed evolution and synthetic biology are successful strategies for biocatalyst development, and methods that leverage state-of-the-art tools are needed to overcome inhibitors more completely. This perspective considers the energetic costs of LCH inhibitors and technologies that can be used to overcome their drain on conversion efficiency. We suggest academic and commercial research groups could benefit by sharing data on LCH inhibitors and implementing \u201ctranslational biofuel research.\u201d Miscanthus and agricultural residues provide fermentable sugars at lower energy and fertilizer costs than grains , recent attention has been directed to overcoming the challenge of LCH inhibitors. These compounds are ubiquitous in hydrolysates, and their abundance and composition depends on pretreatment uses high-pressure/temperature ammonia to alter the cellulose matrix to allow hydrolysis by cellulases efflux transporters or net negative (by energy consumption) effect on biofuel production. Although the answer may vary by inhibitor, because some inhibitors like aldehydes are more damaging to cells than others, a general test of the positive or negative consequences of efflux pumps for biofuel yield will help advance strategies for biofuel microbe design.The cellular energy costs of maintenance and repair are more difficult to quantify but could account for significant energy loss. If cells can repair the damage caused by fermentation inhibitors quickly, then fermentation may proceed. Inhibitors can acidify cells , as well as shared computational resources like Kbase (http://www.kbase.us/) can help bridge the divide.Much like the interface between commercial and academic drug discovery communities, applying next-generation biofuel technologies will require cooperative translational research. Academic biofuel communities are developing advanced system biology techniques whereas the commercial community excels at scale-up commercialization. However, similar to drug discovery, these two groups are often isolated in their research. In both cases, public-private partnerships such as the NIH translational medicine initiatives (Zerhouni, How can researchers and funding agencies best enhance collaboration? A key advance would be greater data sharing about LCH inhibitors. Diverse hydrolysates and their respective inhibitors are major variables in the field of cellulosic biofuel production, but detailed information on specific hydrolysate compositions is not broadly available. Comprehensive efforts to identify all major LCH components and inhibitors across feedstocks and hydrolysis treatments are needed and will require a central repository of LCH data that includes data on feedstocks, pretreatment, hydrolysis, nutrients, and inhibitor. Chemical genomic profiling could be used to generate \u201cbiological fingerprints\u201d of hydrolysates to allow comparisons among hydrolysates and identify the biological effects of LCH components by standard analytical methods. A central resource would allow researchers to compare the composition and biological fingerprints of new hydrolysates with existing knowledge about tolerant microbes for further strain development. The DOE's Systems Biology Portal, KBase, offers the best outlet for community resources, and could serve as the authority of the response of biocatalysts to LCH inhibitors with open-source, community-developed analytical tools for chemical genomics datasets.LCH inhibitors are major barriers for cellulosic biofuels. The cellular energy costs of coping with these compounds are a significant drain on the already thin margins of biofuel production. However, the increasingly powerful tools of systems biology can be used to gain a detailed understanding of the cellular consequences of individual and mixtures of fermentation inhibitors, which will serve as a basis for rational engineering of customizable microbes. The biofuel research community would benefit from shared computational and database resources that can improve communication between the academic and commercial sides of biofuels.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Recent (affinity) proteomics studies have focused on the composition and dynamics of ciliary protein interaction networks. This has unveiled important knowledge about the highly ordered, interconnected but very dynamic nature of the cilium as a molecular machine in the cell. Disruption of members of functional modules of this machine leads to overlapping phenotypes. Detailed analyses of the binding repertoire, the biochemical properties and the biological functions of such modules have yielded the identification of new ciliopathy genes as well as new insights into the pathogenic mechanisms underlying ciliopathies. To gain better insights into the molecular disease mechanisms that underlie ciliopathies and to acquire knowledge about the general importance of the cilium for cellular homeostasis, we are conducting ciliary interactome studies and will combine this information with subcellular localization data, and functional data derived from gene knockdown in ciliated cells or knockout/mutant vertebrate models. This integrated dataset enables us to generate models of interacting functional modules associated with cell signalling cascades, developmental events or specific ciliary functions such as intraflagellar transport. To date, we have performed affinity proteomics for the majority of known ciliopathy-associated proteins and many other ciliary proteins. In addition, yeast two-hybrid experiments have been performed to study the physical interaction between ciliary proteins in more detail. Our current dataset shows high interconnectivity between many of the ciliopathy-associated proteins. These may be part of functional ciliary modules as many are associated with clinically overlapping phenotypes. In addition, new members of these modules are excellent novel candidate ciliopathy proteins."} +{"text": "BRAF mutation in colorectal cancer and IDH1 mutation in glioblastoma multiforme are consistent with an early role for DNA methylation alterations, providing a favorable cellular context for the subsequent somatic mutation. The analysis of whole methylomes at single-basepair resolution reveals that cancer-associated changes occur differentially across defined regions of the genome associated with the nuclear lamina. It is apparent that epigenomic analysis is essential for a full understanding of the relationship between alterations in the cancer genome and the origin and clinical diversity of individual tumors.Cancer develops not only as a result of genetic mutations and genomic rearrangements, but also as a consequence of numerous epigenetic alterations, including extensive changes in the distribution of DNA methylation throughout the genome. DNA methylation changes contribute directly to cancer by transcriptional silencing of tumor-suppressor genes through promoter CpG island hypermethylation. Broad epigenomic analysis of human tumors can reveal relationships between large numbers of epigenetic events and can provide insight into the mechanisms underlying concerted epigenetic change. Genomic loci targeted by Polycomb Group Repressors in embryonic stem cells, and involved in cellular differentiation, are predisposed to aberrant DNA methylation in cancer cells, suggesting that an epigenetic block to cellular differentiation may sometimes be an initiating event in carcinogenesis. The very strong associations between distinct epigenetic subtypes, such as CpG Island Methylator Phenotypes (CIMP) and specific somatic genetic events, such as"} +{"text": "TIA and minor stroke have a high risk of recurrent stroke. Abnormalities on CT/CTA and MRI predict recurrent events in TIA and minor stroke. However there are many other imaging abnormalities that could potentially predict outcome that have not been assessed in this population. Also the definition of recurrent events used includes deterioration due to stroke progression or recurrent stroke and whether imaging is either of these is not known.To improve upon the clinical, CT/CTA and MRI parameters that predict recurrent events after TIA and minor stroke by assessing further imaging parameters. Secondary aim was to explore predictors of stroke progression versus recurrent stroke.510 consecutive TIA and minor stroke patients had CT/CTA and most had MRI. Primary outcome was recurrent events (stroke progression or recurrent stroke) within 90 days. Further imaging parameters were assessed for prediction of recurrent events (combined outcome of stroke progression and recurrent stroke). We also explored predictors of symptom progression versus recurrence individually.36 recurrent events ) including 19 progression and 17 recurrent strokes. On CT/CTA: white matter disease, prior stroke, aortic arch focal plaque\u22654 mm, or intraluminal thrombus did not predict recurrent events (progression or recurrent stroke). On MRI: white matter disease, prior stroke, and microbleeds did not predict recurrent events. Parameters predicting the individual outcome of symptom progression included: ongoing symptoms at initial assessment, symptom fluctuation, intracranial occlusion, intracranial occlusion or stenosis, and the CT/CTA metric. No parameter was strongly predictive of a distinct recurrent stroke.There was no imaging parameter that could improve upon our original CT/CTA or MRI metrics to predict the combined outcome of stroke progression or a recurrent stroke after TIA and minor stroke. We are better at using imaging to predict stroke progression rather than recurrent stroke. Transient ischemic attacks (TIAs) and minor strokes carry a high-short term risk of recurrent stroke. Much previous work has been completed to determine the clinical and imaging factors that increase the risk of developing a disabling stroke following a TIA or minor stroke. There are several clinical and event related factors that increase the risk of stroke after TIA apriori: acute ischemia on CT, intracranial or extracranial occlusion or stenosis \u226550% (the CT/CTA positive metric), and MRI: acute lesion on diffusion weighted imaging (DWI). In the multivariable analysis, only the CT/CTA abnormalities predicted recurrent events. This main CATCH publication presented only the analysis of the simple predefined abnormalities on CT/CTA and MRI (DWI) and the literature would suggest that, particularly in the longer term, there are other imaging parameters that may add to the prediction of recurrent events. This includes white matter disease We recently showed in the CATCH study that predefined radiographic abnormalities on CT/CTA and MRI predicted recurrent events after TIA and minor stroke Additionally the definition of recurrent events in the CATCH study included the outcomes of symptom progression and a distinct recurrent stroke . These were included together in the CATCH study. Most publications have not differentiated these outcomes as they did not have the necessary imaging information and both of these outcomes are clinically relevant and impact outcome. Stroke progression and recurrence likely have different pathophysiologies and we sought to complete an exploratory analysis on clinical and imaging predictors of symptom progression versus recurrent stroke to see if we can predict one better than the other.We hypothesized that we could improve the clinical, CT/CTA and MRI parameters that predict recurrent events after TIA and minor stroke. Secondarily, we sought to complete an exploratory analysis of predictors of symptom recurrence versus progression.Consecutive patients aged at least 18 years presenting with a high risk TIA focal weakness or speech disturbance lasting at least five minutes or minor ischemic stroke (NIHSS score of 3 or less) who were referred to the stroke team at Foothills Medical Centre, were prospectively considered for enrolment. Patients were examined by a stroke neurologist and had a CT brain and CTA of the circle of Willis and neck within 24 hours of symptoms onset. The majority of patients also had a stroke MRI performed. Exclusion criteria included acute treatment with a thrombolytic drug, pre-morbid mRS of 2 or greater, and the presence of a serious co-morbid illness that would likely result in death within three months. The local ethics committee \u2013 The Calgary Health Research Ethics Board - associated with the Foothills Medical Centre and the University of Calgary approved this protocol and each patient provided written informed consent. Detailed baseline clinical and outcome data was collected for each participant. Above standard clinical data we sought to review the role of fluctuation in the prediction of recurrent events. Fluctuation was prospectively defined as having occurred if a patient deteriorated then improved on more than one occasion with symptoms referable to the same brain location. This was rated at the time of the initial physician neurological assessment and was based either on the clinical history or on clinical examination . Fluctuation later than the time of initial assessment was not recorded. Any event that occurred more than 24 hours before the initial assessment was not considered in the assessment of fluctuation. Patients received routine clinical care including antihypertensive and lipid-lowering therapy at the discretion of the treating physician. Ongoing symptoms were assessed at the time of first assessment by the stroke neurology team in the emergency department. Ongoing symptoms were defined as the patient having any deficit measureable on the standard bedside neurological examination. All individuals were trained in the neurological examination and were completed by either a stroke neurologist or stroke fellow.Detailed imaging information has been previously described apriori chose to assess the following additional imaging parameters: a) CT: remote infarcts , white matter chronic ischemia, intraluminal thrombus In this study we A recurrent event was defined as a functional deterioration in neurological status of vascular origin lasting 24 hours or longer or a new sudden focal neurological deficit of vascular origin lasting at least 24 hours 2 score Statistical analysis was completed with Stata (version 12). Imaging parameters other than those included in the original analysis Five hundred ten patients were enrolled into the study during a period of 29 months. Follow up information was available in 98% (499/510). Baseline demographics are shown in The results for the exploratory analysis of predictors of stroke progression and recurrent stroke assessed individually rather than in the combined are shown in We were not able to refine or improve upon the imaging predictors for recurrent events identified in the original CATCH paper. We did however find that the presence of symptom fluctuation was predictive of recurrent events. In the multivariable model this was additive to the CT/CTA metric in the prediction of recurrent events. In our exploratory analysis of separate predictors of symptom progression and recurrence, we found that imaging was much more predictive of progression than recurrence.Symptom progression was predicted by ongoing symptoms at initial assessment, fluctuating symptoms, and intracranial occlusion or stenosis. The relationship between symptom progression, intracranial occlusion, and fluctuation makes sense as there is the potential for ongoing cerebrovascular injury and impaired arterial blood flow in patients with intracranial occlusion. A clinical history of symptom fluctuation could be indicative of at-risk brain tissue receiving diminished perfusion near the threshold of normal functioning and may correlate with the presence of a proximal arterial occlusion or the precarious extent of active collaterals Although numbers of events are small and the precision of the estimates wide, it does appear that we are better at predicting symptom progression than recurrent stroke. It has previously been shown that a high proportion of patients with minor stroke had both clinical and radiological recurrences in the same vascular territory as their initial event There is growing evidence for patients with microbleeds being at increased risk for ischemic strokes A previous study found that CT evidence of acute and chronic ischemia identifies patients at high risk of stroke following TIA The relatively small number of recurrent events identified in our patient population is a significant limitation of our study. This is particularly true when progression and recurrent stroke events are analyzed separately and the confidence intervals are wide. This is also a single centre study with a standardized CTA and this work needs to be repeated in different populations. We also used a conservative definition of clinical deterioration and the reliability of this definition has not been tested. In terms of refining the MRI parameters that predict recurrent events, we are limited by the fact that only 82% of patients had an MRI as well as a CT/CTA.In conclusion we found that we could not improve the imaging predictors of recurrent events (combined outcome of symptom progression and recurrent stroke) by a more detailed analysis of the CT, CTA or MRI. We also found that imaging is more predictive of symptom progression rather than recurrent stroke."} +{"text": "We present a novel platform to facilitate the growth of applied quantum information processing for neural circuitry, neural stimulation, and cognitive engineering. Cognitive computation has historically been studied by rich metaphors of language constructs, computational models for information processing, and semantic interpretations. Cortical interactions at the cellular and sub cellular level have been established for various cognitive tasks by behavioral and computational neuroscientists. This has enabled us to explore cognitive circuitry given a mathematical and psychophysical basis for information processing and neural decision making.We invite original works in applied physics, computing, and information theory pertaining to neural choice specifically with the intent of developing non-linear mathematical models and theory for neural computation.Various modalities have emerged for physiological processing of neural signals with the premise of measuring electrical or magnetic activity for cortical source localization for simple cognitive tasks. Primary amongst these are EEG and MEG that measure electrical current and magnetic field strengths relative to ambient environments of signal to noise ratios.We propose to extend the physiological measurement paradigm toward creating computational and physics-based building blocks for neural information processing and cognitive function. The goals are dual, to apply our learning of neural measurements and observations toward a constructional cortical framework and improve on current neural processing model for cognitive enhancement, rehabilitation, and cognitive evolution. Efforts are orchestrated toward mathematically sound arguments and quantum information theoretic frameworks to explain neural information processing and cognitive circuitry. Theories such as the Hebbian rule for learning, \u201cCells that wire together fire together,\u201d are famous for their considerations in foundational cognitive neuroscience and address simplistic rules for cognitive behavior.We intend to create computational models for learning and neurodevelopment toward explaining complex cognitive decisions and improving cognitive function with emerging brain computing interfaces. We invite quantum simulation models for neural computing toward strides in computational neuroscience. Special preference would be given to strong foundations in mathematical neuroscience for objectifying cognitive function as relates to human brain."} +{"text": "With the recent revelations that strikingly plastic cytogenic and migratory processes take place in the adult mammalian brain, it cannot anymore be considered as an organ static or utterly unequipped against injury. The Subependymal Zone (SEZ) or otherwise called with its embryonic equivalent as the subventricular zone, is one major cytogenic area located at the lateral wall of the lateral ventricles Luskin, and is kIn contrast to the less studied SEZ-derived adult OPCs, much more is known about adult parenchymal OPCs. During perinatal development OPCs are generated in different waves are generated within the niche by stationary adult neural stem cells and TaPs. Subsequently, they migrate in chains to the OB where they disperse radially to the different neuronal layers (Lois and Alvarez-Buylla, As old age seems to be the major factor underlying the decreased efficiency of remyelination in the CNS (Sim et al.,"} +{"text": "The distribution of plants along environmental gradients is constrained by abiotic and biotic factors. Cumulative evidence attests of the impact of biotic factors on plant distributions, but only few studies discuss the role of belowground communities. Soil fungi, in particular, are thought to play an important role in how plant species assemble locally into communities. We first review existing evidence, and then test the effect of the number of soil fungal operational taxonomic units (OTUs) on plant species distributions using a recently collected dataset of plant and metagenomic information on soil fungi in the Western Swiss Alps. Using species distribution models (SDMs), we investigated whether the distribution of individual plant species is correlated to the number of OTUs of two important soil fungal classes known to interact with plants: the Glomeromycetes, that are obligatory symbionts of plants, and the Agaricomycetes, that may be facultative plant symbionts, pathogens, or wood decayers. We show that including the fungal richness information in the models of plant species distributions improves predictive accuracy. Number of fungal OTUs is especially correlated to the distribution of high elevation plant species. We suggest that high elevation soil show greater variation in fungal assemblages that may in turn impact plant turnover among communities. We finally discuss how to move beyond correlative analyses, through the design of field experiments manipulating plant and fungal communities along environmental gradients. Plant species are not randomly distributed in the landscape along environmental gradients , are obligate biotrophs that require the host plant to complete their life cycle , generated with the Glomeromycetes (AMF) specific primers pairs NS31- AM1 . We computed the R2 of the global fit, as well as, the AUC with and without the fungi biotic predictor.Using species distribution models (SDMs), we tested whether including a predictor representing the number of fungal OTUs potentially interacting with plants allowed fitting statistical models better describing the distributions of plant species. SDMs typically relate presence and absence of a given species to a set of environmental parameters and predictive power of the GLMs, when the number of OTUs was included alone in the models of plant species distributions. We found that those plant species with the strongest relationship (R2) with the number of fungal OTUs occurred at higher elevations . The relationship between fungi and plant distribution is thus independent from a potentially confounding effect of plant density. However, we did not consider plant belowground competition as such a measure is difficult to quantify in the field. As a consequence, this confounding effect cannot be fully excluded.Because mycorrhizal colonization percentage is generally positively correlated to host plant density (Genney et al., Another limitation of the analysis results from the low resolution of the OTUs assignment. The OTUs identified from the ITS reads were assigned at a coarse taxonomic level, which does not let us know to which functional group they belong. Thus, while we expect a consistent mycorrhizal function for Glomeromycetes, Agaricomycetes regroup species from distinct functional groups, including decayers, plant pathogens and mutualists. As a consequence, the richness of Agaricomycetes OTUs in soils cannot be linked directly to a function, and must be interpreted with caution. Therefore, even if we found a biological signal in our analyses, we cannot conclude on the functional link that ties fungi diversity to plant distribution. In this regard, correlative approaches provide interesting testable hypotheses, but only experimental designs can ultimately unravel the causality behind plant-fungi relationships.Our literature review highlighted our lack of knowledge about the spatial variation in interactions between plants and mycorrhizal fungi along varying ecological conditions. Most studies so far have limited their scope to a few communities under standard environmental conditions and highlighted the role of mycorrhizal fungi in affecting plant community composition. However, some evidence suggests that the role of mycorrhizal fungi may extend beyond single communities and may shift in importance along wide environmental gradients. Our results support the role of soil fungal assemblage in driving plant species distributions at the landscape scale, especially at high elevations, but also call for a more controlled approach to the problem. Manipulative field experiments will be required that consider the manipulation of both plants and mycorrhizal fungi to learn more concerning their interactions along environmental gradients. To our knowledge, no study has yet designed spatially explicit experiments that could formally demonstrate the role of fungi in driving the spatial distribution of plant species. This would require the manipulation of fungal communities in the field, either with fungal-addition treatments (Mendes et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "As a major constituent of cell membrane, cholesterol is essential for cellular homeostasis through the control of membrane fluidity and permeability. Abnormal levels of cholesterol can have important cellular consequences and may lead to diseases such as atherosclerosis and type II diabetes. Therefore, cells have developed complex mechanisms to regulate the abundance of intracellular cholesterol. Among these mechanisms, the process referred to as reverse cholesterol transport (RCT) has been shown to be critical for the removal of excess cholesterol from peripheral tissues and its transport to the liver via plasma for excretion . RCT is Since one of the major roles of lymphatic vessels is to drain macromolecules from the interstitial space back to the circulation and lymph is rich in cholesterol and HDL , the imp\u2212/\u2212) or LDL receptor which develop hypercholesterolemia. Interestingly, we showed previously that skin lymphatic vessels in these hypercholesterolemic mice exhibit structural defects which severely compromise their function [\u2212/\u2212 mice ameliorates the clearance of cholesterol from skin by supporting RCT [Accumulation of cholesterol in tissues including arteries and skin is a hallmark of atherosclerosis and xanthomas, respectively, and these features are recapitulated in mouse models lacking apoE (apoEfunction . These oting RCT . In stroting RCT . AltogetThe relevance of these findings in humans is supported by clinical studies reporting a possible interconnection between lymphatic function and lipid accumulation in tissues Figure . Patient"} +{"text": "Therapeutic hypothermia (TH) has been recently accepted as a powerful medical intervention for providing neuroprotection to patients sustaining cardiac arrest and hypoxic-ischemic encephalopathy. Further, TH has also been explored as a potential treatment strategy for patients with traumatic brain injury and ischemic or hemorrhagic stroke (for review see ). With tImportantly, the significance of nutrition therapy in critically ill patients cannot be overstated . CriticaWhether the aforementioned recommendations on artificial nutrition of the general intensive care patient population can also be applied on equal terms to patients undergoing TH is still a matter of debate. Studies addressing the various issues of nutrition therapy in TH are scarce, as evidenced by a contemporary PubMed search including bibliographies of published reviews. So far, data are available on the course of energy expenditure in patients treated with TH suffering from ischemic or hemorrhagic stroke ,16 and sIn conclusion, many questions regarding the nutrition therapy of patients treated with TH remain to be answered. Further studies that focus on the optimal amount of caloric intake, timing, preferred route of administration and monitoring of nutrition delivery during targeted temperature management are urgently needed.RB received financial support as speaker's fees from Baxter Austria and Fresenius-Kabi Austria."} +{"text": "All clinical trials that involve the prospective study of patients need some form of independent monitoring. For RCTs of therapeutic interventions, UK public funders of research \u2013 including the MRC \u2013 require an independent trial steering committee (TSC) to oversee management and finances, and a data monitoring committee (DMC) to oversee study progress and accumulating study data. This fully independent TSC/DMC model may not always be necessary for trials of tests. To address the deficit in guidance regarding oversight arrangements, a project funded by the MRC Midlands Hub for Trials Methodology Research is being undertaken to investigate how DMCs and TSCs should operate.To develop guidance on how to select between possible working models of TSCs and DMCs when organising oversight procedures for trials of tests.A review of existing guidance regarding the use of TSCs and DMCs for trials of tests, used/published by funding organisations around the world was carried out. A web\u2013based survey and structured interviews of trialists were conducted to establish the breadth of current practice for management and data monitoring during trials of tests.We will provide a characterisation of how different TSC and DMC models operate, their roles and responsibilities, why particular models are selected, how models differ according to study design, and which aspects of the chosen working models were particularly useful/disadvantageous.Analysis of the review and survey are used to develop insights into how particular models of TSC/DMC should be selected when embarking upon trials of tests."} +{"text": "Slowpoke (Slo) gene family, can contribute to action potential repolarization, regulation of firing frequency and interspike interval, repetitive firing, and burst termination [Slo genes also lead to a variety of motor disturbances [Slo current expressed in MNs can shape the timing of motor output underlying locomotion. We identify mechanisms by which the BK/Slo current changes the bursting output of MNs, and describe the different behaviors that are observed for varying membrane densities of the underlying channel. We also present preliminary data consisting of electrophysiological recordings from larval Drosophila showing that the changes in motor output predicted by the model are indeed observed when genetic manipulations of Slo channel density (RNA interference constructs) are targeted to MNs [Slo channels in MNs, but contribute more generally to the growing knowledge on the role intrinsic MN properties play in shaping rhythmic motor output.Rhythmic muscle contractions underlie a number of crucial motor behaviors, such as respiration and locomotion. The timing of contractions is determined by the intrinsic activity and synaptic interactions of neurons within what are called central pattern generating (CPG) networks ,2. In mamination . Mutatiourbances . We deved to MNs . Our res"} +{"text": "The mammalian brain is anatomically and functionally complex, and prone to diverse forms of injury and neuropathology. Scientists have long strived to develop cell replacement therapies to repair damaged and diseased nervous tissue. However, this goal has remained unrealized for various reasons, including nascent knowledge of neuronal development, the inability to track and manipulate transplanted cells within complex neuronal networks, and host graft rejection. Recent advances in embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) technology, alongside novel genetic strategies to mark and manipulate stem cell-derived neurons, now provide unprecedented opportunities to investigate complex neuronal circuits in both healthy and diseased brains. Here, we review current technologies aimed at generating and manipulating neurons derived from ESCs and iPSCs toward investigation and manipulation of complex neuronal circuits, ultimately leading to the design and development of novel cell-based therapeutic approaches. Within the mammalian nervous system, billions of neurons are intricately interconnected via trillions of synapses. From this complex network of synaptic connectivity, specialized neural circuits emerge, forming the foundation for diverse physiological processes and behaviors. Due to the sheer complexity and heterogeneity of the cell and tissue types that contribute to neural circuits, the brain is prone to an array of developmental and neurodegenerative diseases, ranging from epilepsy and induced neural stem cells (iNSCs) from affected patients' tissues . These iPSCs can be differentiated into neuronal subtypes in vitro connectivity of grafted neural cells with host tissue in neuronal subtypes allows cellular activation upon exogenous ligand administration which induces Gi-coupled silencing in the presence of the insect peptide allatostatin (Birgul et al., The desire to use cell-based therapeutic approaches toward the treatment of damaged or diseased nervous tissue is rapidly gaining popularity. However, prospects for these approaches depend both on the ability to guide selective programs of neuronal differentiation, and to engineer cells whose output can be precisely controlled. In the adult brain, it has been established that diverse forms of activity govern the integration and survival of new neurons (Nilsson et al., Chlamydomonas reinhardtii (Nagel et al., In vitro differentiated neurons harboring ChR2 and NpHR have recently revealed important information regarding the functional integration of intrastriatal grafts in a Parkinson's disease model (Tonnesen et al., Optogenetic approaches allow for fast and precise control of neuronal activity using light-activated ion channels via a spectrum of different wavelengths (Zhang et al., Additionally, genetically encoded calcium indicators such as GCaMP allow for functional readout of manipulated neurons (Pologruto et al., The emerging array of genetic tools for precise manipulation of neuronal activity gives hope to transitioning stem cell therapy from the conceptual to the clinical realm. For example, it may soon be possible to generate NSCs expressing detectable markers and/or activity-induced ion channels from patients with damaged or diseased nervous tissue and transplant these cells back into the affected patient Figure . Such gein vivo. Scientific advances are beginning to tackle these challenges. Further, transsynaptic tracing has enabled high resolution dissection of neuronal circuits, which has begun to reveal insights into the molecular mechanisms that guide synapse formation and circuit integration in the living brain. Genetic approaches to manipulate neural circuit activity have allowed for the selective \u201cactivation\u201d and \u201csilencing\u201d of discrete neuronal subtypes. This knowledge, combined with the ability to generate high numbers of neurons in vitro, promises to yield significant advances in cell therapy. In the future, it might be possible to manipulate injured and/or diseased brain circuits with artificially grafted cells, allowing for sustained symptomatic relief in a range of neurological disorder and neuronal injury models.Advances in stem cell research combined with powerful genetic technologies now allow unprecedented levels of investigation and manipulation of complex neuronal circuits. Previous efforts to implement cell-based therapies have been hindered by tumorigenesis, graft rejection, cell death, lack of circuit integration, and the inability to follow grafted cells The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The parameters of neuronal compartment models must be determined carefully in order to match experimental data. Optimization algorithms can simplify this task by automatically searching the multidimensional parameter space to identify combinations of parameters that best fit experimental data, as measured by a fitness function that represents salient differences between simulated and experimental data. The success of automated parameter fitting depends critically on many issues, including the choice of parameters selected for fitting, the parameter search method, and the design of the fitness function. Previously we developed a fitness function that explicitly quantifies the shape of action potentials and afterhyperpolarizations , and theThe present project arises from our study of neocortical pyramidal cells from young and aged rhesus monkeys in vitro . In respWe have extended our fitness function to fit firing rate time series with two single exponentials, separated by an automatically-chosen cutoff. The fitness function also includes a term to quantify action potential backpropagation, whereby voltage decays approximately exponentially with distance from the soma . The fit"} +{"text": "The aim of this study is to investigate if the use of individual, per segment reference values for cardiac strain allows for improved discrimination of pathological deformation. In a cohort of patients with a high likelihood of ischemic heart disease, preliminary results within the subgroup of patients without pathological findings on cardiac MRI suggest a spatial dependency of strain.In addition to perfusion and viability, systolic myocardial function constitutes one of the cornerstones in the evaluation of ischemic patients. Technical achievements have improved the accuracy of the quantitative assessment of myocardial function, allowing for better discrimination between healthy and diseased myocardium. These advances cannot be fully exploited without knowledge of the spatial dependency and individual variance of deformation in health and disease.In an ongoing study, a large cohort of patients with moderate chest pain and a high likelihood of coronary artery disease undergo cardiac MRI including cine loops for wall motion, perfusion at rest and during adenosine stress, acquisition of myocardial deformation with displacement encoding with stimulated echo (DENSE), and late gadolinium enhancement to demonstrate scar tissue.In this preliminary study, patient demonstrating maintained perfusion, normal wall motion, and no signs of scar at late gadolinium enhancement were selected for further evaluation.Regional deformation acquired with DENSE was evaluated in terms of radial and circumferential strains. All measurements were reported according to the seventeen segment model of the AHA. The apical cap was excluded from the quantification of regional deformation.Preliminary results for radial and circumferential strain for the 11 patients without pathological findings are presented in the Figure Preliminary results suggest a spatial dependency in deformation, larger than the fairly low standard deviation obtained using DENSE MRI. Hence, taking natural segmental variation of myocardial deformation into account might allow for better discrimination between normal and impaired myocardial deformation.County Council of \u00d6sterg\u00f6tland, Heart Foundation, Swedish Heart-Lung Foundation, and Swedish Research Council."} +{"text": "Mycobacterium marinum infection, dying infected macrophages recruit fresh ones to the site of granuloma formation. The recruited macrophages phagocytose infected cell remnants, get infected and die, thus ensuring efficient spread and multiplication of the pathogen. Maturation of granuloma, the characteristic lesions of tuberculosis, requires tumor necrosis factor (TNF) and interferon (IFN)-gamma and represents a stalemate between host and pathogen sufficient to arrest infection without eliminating the bacteria. Indeed, our macrophage / mycobacterial infection model demonstrates that virulent H37RvMycobacterium tuberculosis is more efficient in macrophage infection and killing than the attenuated Mycobacterium bovis BCG vaccine.Infection with intracellular pathogens can trigger a panel of innate immune responses including cell death. Coupled with phagocytosis this often leads to clearance of the invader. However, some pathogens use the process to disseminate and proliferate. During Today it is still unclear whether the signal promoting macrophage engagement in phagocytosis is originating from a pathogen or the infected host, and whether the effect is general or target specific. Therefore, we used a quantitative cell line based assay to study the effects of PAMPs or cellular alarm signals on the phagocytic engagement and capacity of macrophages to engulf virulent or attenuated mycobacteria and dying cells. Our results demonstrate that pretreatment of macrophage like cells with double stranded RNA, lipopolysaccharide, type I or II IFN but not with TNF, can significantly increase their capacity to phagocytose apoptotic and necrotic cells but has little effect on the phagocytosis of free mycobacteria. Although this macrophage activation process is probably an innate immune response reinforcing the capacity of the host to dispose of dying infected cells, pathogens may exploit it for their propagation."} +{"text": "ICONS is a cluster randomised controlled pilot trial designed to provide preliminary evidence of the effectiveness of a systematic voiding programme (SVP) for the management of continence after stroke. Stroke services were randomised to receive the SVP, the SVP plus supported implementation, or usual care. Process evaluations are designed to evaluate fidelity and provide explanatory evidence around trial outcomes; these need to be underpinned by a theoretical framework to explain linkages between intervention processes and outcomes.We conducted an evaluation to describe SVP implementation and assist in explaining intervention outcomes. Reflecting best practice in complex intervention research, we developed a logic model to underpin the evaluation representing practitioners' implementation activities. To increase explanatory power of the model, we synthesised principles from theoretical frameworks underpinning the study into mechanisms of action to explain conditions necessary for activities to impact on outcomes. Mechanisms were:Understanding and agreeing: conceptual work associated with the SVP, e.g. increasing awareness.\u2022 Driving and aligning: organising systems or processes to align and drive new practice.\u2022 Building and supporting: enacting the SVP.\u2022 Learning and evaluation: reflecting on performance and progress.\u2022 We will discuss the utility of the logic model in explaining conditions necessary for the intervention to work, the success of implementation strategies adopted and variations in patient outcome across trial arms. We will also consider the challenges of synthesising across multiple data sources to understand variation in intervention delivery, maintenance and outcome in cluster trials."} +{"text": "This paper demonstrates how social marketing has been used to overcome barriers to implementing screening and brief interventions across a variety of health and community settings in Wales. The Have-a-Word campaign, currently being rolled out across Wales, seeks to manage the image of screening and brief interventions and encourage those who have received training to deliver brief interventions. Evaluation of the Welsh model shows that many health and community professionals who received training continue to view a formal screening tool such as FAST as a barrier to successfully implementing the SBI model in specific settings. Social marketing has helped overcome barriers to delivery (some nurses commented that they felt part of an SBI community which empowered them). A more pragmatic approach to screening is required since the formal screening tool was dissuading some professionals from delivering brief interventions at all. Social marketing campaigns can help manage the image of brief interventions however sustaining those who have received training remains a challenge and continued support and encouragement are needed.Cardiff University, the Welsh Government and Public Health Wales are working together to implement screening and brief interventions across a variety of health and community settings through a unique collaboration; a Knowledge Transfer Partnership (KTP). Previous research has uncovered both barriers and facilitators to implementation. This KTP seeks to build upon this work and translate the research into practice. The Have-a-Word social marketing initiative, the first of its kind, was launched in 2013 in Wales and seeks to specifically address the barriers to implementing SBI. To date over 2000 health and community professionals have received training1This includes maxillofacial and trauma clinic nurses, midwives, health visitors, dieticians, custody sergeants, youth workers and practice nurses."} +{"text": "Surveillance data needs to be capable of; identifying clusters; tracking trends; assessing the effectiveness of interventions; and providing timely results. This research assesses whether this is the case for healthcare-associated infection (HCAI) and antimicrobial resistance (AMR) surveillance systems in England, and endeavours to understand why in certain areas surveillance has not been more successful.A systematic search of the literature was carried out. Original search results identified additional Government, committee and conference reports and guidelines.Surveillance of HCAIs and AMR has developed over time in response to numerous stimuli. The implementation of novel surveillance systems are often in response to issues identified through passive surveillance and research. Evidence of rising infection or resistance rates have caught the attention of the Government (and the media) occasionally leading to enhanced surveillance of specific infections to monitor progress towards targets. Several independent studies have concluded that post-discharge surveillance after surgery is required to provide more accurate surgical site infection rates. Funding for surveillance programmes has come from various sources including the pharmaceutical industry, particularly in AMR surveillance.Some surveillance schemes have been successfully implemented, partially fulfilling criteria. However, many clinical areas have yet to see advances in HCAI surveillance specific to their area and are reliant upon generic passive surveillance systems. Future development of surveillance systems to rapidly identify clusters and outbreaks, and patients at increased risk of acquiring infection will ensure that control measures are best directed to prevent further cases occurring.None declared."} +{"text": "Before liver cirrhosis and hepatocellula carcinoma can develop, the early and long lasting features of hepatitis C are host metabolism modifications with a specific and so far unique metabolic syndrome that may associate insulin resistance, liver steatosis and hypo-betalipoproteinemia. These metabolic perturbations are directly induced by heptatitis C virus (HCV) replication and regress after viral suppression. Symmetrically HCV depends on glucose and lipid metabolism for its replication.HCV induced insulin resistance is both hepatic and peripheral. The insulin receptor pathway is impacted at several steps by viral proteins with probable functional consequences. Mechanism of peripheral insulin resistance remains obscure and the viral signals send to adipose tissue or muscles have to be identified. One major IR metabolic consequence might contribute to the mobilization of free fatty acids from periphery to the liver and to the constitution of liver steatosis. Importantly, HCV modifies with genotype-specific differences, the synthesis, degradation and secretion of lipid in a coordinated fashion to promote the accumulation of neutral lipids.The lipid droplets (LD) that are the lipid storage organelles are mandatory platforms for the assembly of infectious viral particles. In particular localization of core protein and NS5A on LD and mobilization of the LD are essential steps that control viral infectivity. Interestingly, the efficiency of HCV to the LD disposal and use correlates to viral production and may influences the extent of hepatic accumulation of lipids.The most striking association of HCV with lipid metabolism resides in the coincidence of the betalipoproteins and viral particles pathways with the formation of unique hybrid viral particles. Indeed HCV depends on a functional very low density lipoproteins (VLDL) assembly and secretion process to be secreted. HCV also modifies at different degree the VLDL composition forming sub viral particles, which are minimally modified VLDL that bear the viral envelop glycoproteins, or hybrid viral particles known as lipo-viral-particles (LVP), which contain all the viral and VLDL components that are highly infectious. Functions of these hybrid particles on the disease features and progression as well as therapeutic targets remain to be fully characterized.Thus, HCV appears to have developed an original and so far unique way with major clinical consequences to modify and use the lipid metabolism to persist in the host."} +{"text": "The conversion of biomass to biofuels requires heat, pressure and acid treatments to overcome the recalcitrance of the cell wall and remove lignin that hinders access to cellulose. Economic production of biofuels from lignocellulosic biomass and efficient sugar release depends on the ability to reverse and overcome this natural recalcitrance of the plant cell wall.\"Trojan Horses\": polymer pockets of enhanced solubility within the cell wall, thus increasing cellulose accessibility to solvents and enzymes. Two different methodologies are presented. The first includes transgenic introduction of soluble polysaccharides such as hyaluronan into the cell wall during its development, leading to its intercalation with the cellulose microfibrils. Upon processing, these soluble intercalated polysaccharides are washed away, resulting in highly porous cell walls with increased accessibility to hydrolytic enzymes. The second methodology involves modification of the cellulose by expression of recombinant cellobiose dehydrogenase (CDH) in plant cell walls, leading to disruption of the cellulose microcrystalline lattice and thus increasing hydrolytic enzymes accessibility. Both methodologies result in transgenic plants that exhibit significantly enhanced cellulose hydrolysis, while maintaining their physiological and structural integrity.Most of the current ideas and methods to generate lignocellulose feedstock which is more amenable to saccharification, are limited to the modification or down-regulation of the lignin biosynthesis. This often results in dwarfing, xylem vessel collapse or reduced fitness to stress. In order to overcome these limitations, we present here a novel approach for cell wall remodeling. By introducing new trans-genes from algae, fungi and viruses we create This novel concept provides new prospects for more economical production of liquid biofuel to substitute fossil fuels."} +{"text": "The cortex is thought to process sensory stimuli from the environment by flexible routing of neuronal activity across a hierarchy of functionally specialized neuronal networks. This routing necessitates mechanisms that allow for high fidelity communication of neuronal activity between these networks . It was In our simulations, external stimulation with rhythmic pulse packets was followed by network activity oscillations, which were a consequence of mutual interactions between the excitatory and inhibitory pools. These oscillations progressively amplified in strength with each new input presentation. They synchronized excitatory activity in each FFN pool and facilitated the propagation of excitatory spike volleys along weak and sparse divergent/convergent connections. Several oscillation cycles were needed to transmit spike volleys across the entire FFN in contrast to synfire activity, in which excitation is propagated in one sweep. We also hypothesized that the precise timing inherent to coherent oscillations may induce synaptic potentiation, which would reduce the number of oscillation cycles necessary to propagate synchrony and drive the network towards synfire chain dynamics. Indeed, our simulations confirmed that an increase of synaptic weights between groups of the FFN transformed oscillation chains into classical 'synfire chains', in which synchrony was transmitted in a single wave. In summary, we propose a conceptual link between the concepts of synfire chains, coherent oscillations and synaptic plasticity. We suggest that coherent oscillatory dynamics presents an immature case of spike volley transmission across multiple neuronal networks, which may lead to secured transmission, without the need for oscillations, via the results of synaptic plasticity."} +{"text": "Various solutions have been introduced for the identification of post-translational modification (PTM) from tandem mass spectrometry (MS/MS) in proteomics field but the identification of peptide modifiers, such as Ubiquitin (Ub) and ubiquitin-like proteins (Ubls), is still a challenge. The fragmentation of peptide modifier produce complex shifted ion mass patterns in combination with other PTMs, which makes it difficult to identify and locate the PTMs on a protein sequence. Currently, most PTM identification methods do not consider the complex fragmentation of peptide modifier or deals it separately from the other PTMs.We developed an advanced PTM identification method that inspects possible ion patterns of the most known peptide modifiers as well as other known biological and chemical PTMs to make more comprehensive and accurate conclusion. The proposed method searches all detectable mass differences of measured peaks from their theoretical values and the mass differences within mass tolerance range are grouped as mass shift classes. The most possible locations of multiple PTMs including peptide modifiers can be determined by evaluating all possible scenarios generated by the combination of the qualified mass shift classes.The proposed method showed excellent performance in the test with simulated spectra having various PTMs including peptide modifiers and in the comparison with recently developed methods such as QuickMod and SUMmOn. In the analysis of HUPO Brain Proteome Project (BPP) datasets, the proposed method could find the ubiquitin modification sites that were not identified by other conventional methods.This work presents a novel method for identifying bothpeptide modifiers that generate complex fragmentation patternsand PTMs that are not fragmented during fragmentation processfrom tandem mass spectra. Identification techniques of post-translational modification (PTM) from mass spectra were developed to understand the functions of PTMs in biological pathways. Ub and Ubls play important roles in regulatory networks in most of cellular processes and the importance of identification of Ub and Ubls is increased.From tandem mass spectra, it is difficult to identify peptide with considering all possible PTMs with high performance. Standard database search algorithms and ISB by extracting spectra from spectral libraries publicly available at NIST (atlas.org). Only oDe novo peptide sequencing based upon Ub on K4 generates longer sequence tags than Ub on K15.In total, by comparison of analysis results from Mascot and the proposed method, most of mass spectra that are identified with Ub by the proposed method are also identified with Ub by Mascot with high sequence coverage, though there were mislocations of Ub by Mascot in few mass spectra. In addition, mass spectra that are analyzed as no PTM by the proposed method are also identified with no PTM or mislocation of Ub with low sequence coverage by Mascot. Standard database search algorithms can identify peptides but hard to consider various PTMs altogether especially peptide modifiers. The proposed method showed possibility of detecting peptide modifiers from tandem mass spectra dataset generated by standard database search algorithms.To attempt identification of ubiquitination from HUPO BPP datasets, the list of ubiquitin substrates with ubiquitinated site were collected from E3miner with minIdentification of peptide modifiers such as ubiquitin and ubiquitin-like proteins requires additional techniques to handle various mass shifts made by fragments of peptide modifiers. The proposed method showed the ability of identification of multiple PTMs including peptide modifiers. The proposed method can be applied on analyzing tandem mass spectra datasets built with standard database search algorithms. Though precursor ion mass can help accurate identification of PTMs, the proposed method can try to identify PTMs when there are lack of information of precursor ion mass in the mass spectra. Applied to cluster computing, our method can analyze massive mass spectra datasets from high-throughput experiments. With development of mass spectrometer in terms of accuracy and sensitivity, overall performance of our method will be dramatically increased because smaller tolerance can effectively reduce computational artifacts of mass shift classes.Though identification of peptide modifiers becomes important to understand their roles in biological pathway regulations, identification of peptide modifiers with complex peak patterns from fragment ions of peptide modifiers remains a challenge. In this paper, we introduce a method for identification of peptide modifiers from tandem mass spectra with various PTMs with considering possible clues based on unrestricted PTM identification algorithm previously developed by authors and fragmented ion patterns of peptide modifiers. The proposed method is a novel method that can identify both PTMs that are not fragmented during fragmentation process and peptide modifiers that generate complex fragmentation patterns together from tandem mass spectra. Proposed method showed excellent performance in the test with simulated spectra having various PTMs including peptide modifiers and in the comparison with methods specialized for identification of PTMs or peptide modifiers. Not only identification of mono-Ub/Ubl or mono-PTM, identification of multiple PTMs including all known peptide modifiers can be applied with the proposed method.The authors declare that they have no competing interests.CK designed and implemented the proposed method and wrote the manuscript. GSY designed and directed this study, and reviewed the manuscript. All authors worked on and approved the final manuscript."} +{"text": "Imaging modalities in the prehospital setting are helpful in the evaluation and management of time-sensitive emergency conditions. Ultrasound is the main modality that has been applied by emergency medical services (EMS) providers in the field. This paper examines the clinical applications of ultrasound in the prehospital setting. Specific focus is on applications that provide essential information to guide triage and management of critical patients. Challenges of this modality are also described in terms of cost impact on EMS agencies, provider training, and skill maintenance in addition to challenges related to the technical aspect of ultrasound. Emergency ultrasound performed by nonradiologists has been widely adopted in most emergency departments (EDs) across the United States (US) and the world with a continuously growing list of diagnostic and therapeutic applications . This teThe use of this technology in the prehospital setting is increasing with reports of physicians and nonphysicians performing diagnostic and therapeutic interventions in different emergency medical services (EMS) systems across Europe and the United States . This waLike any other intervention, the addition of ultrasound machines to the armamentarium of prehospital providers raises several questions in terms of potential clinical applications, feasibility, training requirements, cost, and more importantly its impact on the care process and on patient outcome. The type of EMS system that is in place, whether it follows the Anglo-American model or the Franco-German one, is an important factor to consider when discussing any prehospital intervention including prehospital ultrasound .This paper reviews the available literature about current applications of ultrasound use in the prehospital setting and discusses challenges, limitations, and potentials of prehospital emergency ultrasound. The evidence presented is specific to emergency ultrasound performed in the prehospital setting and does not reflect the available evidence for all the medical indications and emergency or critical medicine recommendations for ultrasound use in the ED or in-hospital. Clinically relevant applications of emergency ultrasound in the prehospital setting fall into two broad categories: diagnostic and therapeutic. Most of the published literature of ultrasound use in the prehospital setting falls into the diagnostic category. Regardless of the type of EMS systems in terms of level of available prehospital providers, diagnostic applications, which can be easily learnt, can offer crucial information needed to guide the management of severely ill trauma and medical patients in the field and to help triage these patients to appropriate hospital destinations . TherapeIn EMS systems with regionalized trauma care and field triage guidelines earlier In one prospective multicenter study of 202 trauma patients, prehospital focused abdominal sonography for trauma (PFAST) performed by emergency physicians and paramedics at the trauma scene had much higher sensitivity, specificity, and accuracy of detecting hemoperitoneum when compared to regular physical examination . The PFAST examination time had a mean of 2\u20134\u2009min SD 0\u20138) and was completed 35 (SD 13) min prior to a regular emergency department (ED) FAST. A change in prehospital management, mainly fluid resuscitation, was reported in up to 21% of patients when PFAST was used. PFAST findings also influenced the decision making process regarding the mode of transport (ground versus helicopter) and the choice of hospital destination in up to one-third of patients [ and was Prehospital ultrasound use in trauma patients with suspected pneumothorax may be useful in preventing harm from unnecessary field intervention such as needle thoracostomy. When thoracic ultrasound was used to detect lung sliding sign in the emergency department in patients after prehospital needle thoracostomy, 15 out of 57 (26%) trauma patients \u201cappeared not to have had a pneumothorax originally nor to have had one induced by the needle thoracostomy\u201d . Harm toDespite all the previous reports documenting improvement in diagnostic accuracy, a recent systematic review evaluating whether prehospital ultrasound improves treatment of trauma patients found that there is a lack of evidence regarding improved treatment . Cardiac arrest and shock or prearrest conditions are other EMS priority conditions where prehospital ultrasound adds value to patient management and outcomes. In one prospective observational study of 230 patients in peri-resuscitation state (profound hypotension and/or severe dyspnea/tachypnea) or actively undergoing cardiopulmonary resuscitation (CPR), focused echocardiographic evaluation in life support (FEEL) performed in the prehospital setting altered the diagnosis and management in a significant number of patients . The FEE Prehospital ultrasound diagnostic applications have also been reported in patients with acute undifferentiated dyspnea. Prehospital ultrasound improves the accuracy of diagnosing pulmonary edema as the cause of acute dyspnea. In a prospective cohort study of 218 patients presenting with acute dyspnea (heart failure or COPD/asthma related), ultrasound performed by prehospital physicians in less than one minute, was found to be the strongest predictor for the diagnosis of heart failure in the prehospital setting . UltrasoZechner et al. reported a similar benefit of improved accuracy in diagnosing the cause of acute dyspnea in two patients when prehospital ultrasound was used. This translated into improved clinical outcome when the treatment provided was based on the prehospital ultrasound findings .Prehospital ultrasound was also reported to be useful in patients with unexplained hemodynamic instability where it helps differentiate between cardiac and noncardiac etiologies of shock. Adding ultrasound to prehospital shock management can help rule out the presence of life-threatening conditions such as clinically significant pericardial effusion or abdominal aortic aneurysms , 21, 22.2 capnography is the gold standard method for ETT correct placement confirmation. This method has some limitations in specific situations such as cardiac arrest, low cardiac output, acute pulmonary embolism, and hypothermia [Another new diagnostic application of prehospital ultrasound consists of confirming endotracheal tube (ETT) placement through detection of the lung sliding sign . Advanceothermia , 26. Ultothermia . Most of the previously described diagnostic applications would help prehospital providers establish a more accurate diagnosis and guide patient management or triage to appropriate hospital destinations. On the other hand, therapeutic applications of ultrasound in the prehospital setting are highly dependent on the skill level and the scope of practice of the operator or prehospital provider. Applications such as ultrasound-guided pericardiocentesis have been described but mainly in systems with physicians working in the prehospital setting .Despite the wide range of applications for ultrasound in the prehospital setting, the adoption of this modality has been slow for several factors including, but not limited to, portability, cost, training and technical expertise of operators, and time limitations. Several studies with new handheld and portable models of ultrasound machines have demonstrated that ultrasound use is possible in most prehospital settings including land ambulances and helicopter EMS , 27\u201329.Time limitation is another challenge that is often cited as a reason for not using ultrasound. Lack of enough time was the main reason for not using thoracic ultrasound in one study examining the feasibility of thoracic ultrasound by HEMS . Other sTraining and technical expertise of providers are another challenge for ultrasound adoption in the prehospital setting. This limitation is pertinent only to EMS systems that use providers other than physicians to staff their ambulances. Physicians working in the prehospital setting would have to undergo the same training as other nonradiologist physicians who have ultrasound privileges and who use ultrasound in the ED or other settings . In EMS systems that use nonphysician providers such as the US and UK EMS systems, ultrasound is considered an advanced skill that is usually limited to advanced level providers such as paramedics. Ultrasound applications and more specifically therapeutic interventions are also closely tied to the scope of practice and skill levels of these nonphysician providers. Several studies have demonstrated that paramedics can easily acquire ultrasound skill with training duration varying from one hour and 15 minutes to two days depending on the type of diagnostic ultrasound application learned , 30, 32.In another study by Chin et al., twenty emergency medical technicians paramedics with no prior ultrasonography training underwent training to acquire and recognize ultrasound images for several life-threatening conditions using the Prehospital Assessment with UltraSound for Emergencies (PAUSE) protocol . The traIn a different study by Heegaard et al. paramedics underwent 6 hours of structured ultrasound training and were able to adequately obtain and interpret prehospital FAST and abdominal aortic (AA) ultrasound images with 100% interpretation agreement with physician overreader . Other pInitial ultrasound skill acquisition by paramedics is therefore possible with relatively short training courses. Ultrasound skill maintenance like any other skill requires practice and good quality management programs with physician oversight. One way to overcome the potential challenge of training prehospital providers to acquire and interpret ultrasound images is through the use of telesonography. Transmitting ultrasound images by different modalities from scene to ED is an effective tool that can be implemented in EMS systems that lack advanced level providers or in rural EMS systems for expert review of images and interpretation. Novel techniques of telesonography using cellular or satellite networks allow for the successful transmission of real-time ultrasound images from the prehospital setting to the ED without affecting the quality of the images . The cost impact on EMS agencies introducing ultrasound into the prehospital setting has not been formally assessed. The new hand held ultrasound machines cost around US$ 9000. This is a significant cost for most systems especially when considering the number of units to be deployed in order to cover a large proportion of patients with time-sensitive emergency conditions on whom ultrasound use may reduce morbidity and improve outcomes. Acute ischemic stroke is another EMS priority condition that is time sensitive and where ultrasound is showing promise. In a recent study by Schlachetzki et al. 102 patients with acute stroke symptoms underwent prehospital transcranial color-coded sonography (TCCS) assessments . PrehospPrehospital ultrasound might have limited applications in the prehospital field that constitutes only one phase of emergency care. The scope of applications of emergency ultrasound is, however, much broader for emergency cases in other settings . Added focus on three areas would increase the potential for ultrasound use in the prehospital field. First, enhancing the technology of telesonography for real-time assistance with interpretation of ultrasound images is important for EMS systems that lack advanced level providers. Second, developing effective ultrasound training programs for different level providers similar to the RUSH exam used by emergency physicians is needePrehospital emergency ultrasound has many clinical applications that would reduce morbidity and improve outcomes of patients with life-threatening emergency conditions. This imaging modality improves diagnostic accuracy and provides crucial information to prehospital providers to guide management and help triage patients to appropriate destinations. Training requirements and time limitations are the main challenges to prehospital ultrasound utilization. Structured training of nonphysician prehospital providers is needed to provide them with adequate ultrasound skill acquisition and maintenance. The potential for use of this modality in the prehospital setting is great; however outcome research is needed to provide stronger evidence on its clinical impact on patient outcome."} +{"text": "However, the influence of antihistamines on the function of eosinophils, which are the most important final effector cells in allergic diseases, is not well understood.Histamine H1 receptor antagonists on eosinophil functions was examined through the choice of levocetirizine hydrochloride (LH) in vivo.Patients with Japanese cedar pollinosis were orally treated with LH once a day at a single dose of 5 mg for two weeks during Japanese cedar pollen season (February 2012 to April 2012). Nasal secretions were obtained before and after treatment with the filter paper method. Eosinophil activation was assessed by measuring the levels of both ECP and MBP in nasal secretions by ELISA. We also examined the number of eosinophils in nasal secretions and IgE levels in peripheral blood obtained from patients before and after treatment with LH.The influence of histamine HOral administration of LH could not suppress both peripheral blood eosinophila and IgE hyper-production. On the other hand, ECP and MBP levels in nasal secretions decreased significantly after treatment with LH. LH treatment also favorably modified the clinical conditions of patients: the clinical symptom scores, such as sneezing, nasal discharge and congestion decreased significantly after treatment with LH.These results may suggest that LH exerts inhibitory effects on eosinophil activation and results in favorable modification of clinical status of pollinosis patients."} +{"text": "Unilateral visual neglect is commonly defined as impaired ability to attend to stimuli presented on the side of visual space contralateral to the brain lesion. However, behavioral analyses indicate that different neglect symptoms can dissociate. The neuroanatomy of the syndrome has been hotly debated. Some groups have argued that the syndrome is linked to posterior parietal cortex lesions, while others report damage within regions including the superior temporal gyrus, insula, and basal ganglia. Several recent neuroimaging studies provide evidence that heterogeneity in the behavioral symptoms of neglect can be matched by variations in the brain lesions, and that some of the discrepancies across earlier findings might have resulted from the use of different neuropsychological tests and/or varied measures within the same task for diagnosing neglect. In this paper, we review the evidence for dissociations between both the symptoms and the neural substrates of unilateral visual neglect, drawing on ALE (anatomic likelihood estimation) meta-analyses of lesion-symptom mapping studies. Specifically, we examine dissociations between neglect symptoms associated with impaired control of attention across space (in an egocentric frame of reference) and within objects . Results of ALE meta-analyses indicated that, while egocentric symptoms are associated with damage within perisylvian network and damage within sub-cortical structures, more posterior lesions including the angular, middle temporal, and middle occipital gyri are associated with allocentric symptoms. Furthermore, there was high concurrence in deficits associated with white matter lesions within long association and projection pathways, supporting a disconnection account of the syndrome. Using this evidence we argue that different forms of neglect link to both distinct and common patterns of gray and white matter lesions. The findings are discussed in terms of functional accounts of neglect and theoretical models based on computational studies of both normal and impaired attention functions. The complexity of the visual world requires us to have the ability to select and process behaviorally relevant stimuli while ignoring the rest of the scene. We also need to have the capacity to shift attention between different elements as we search for relevant stimuli. The cognitive processes that underlie these abilities are collectively known as visuospatial attention. These cognitive mechanisms are indispensable for numerous daily activities, as illustrated by the immense problems experienced by individuals suffering from visuospatial deficits after brain damage. The most widely studied disorder of visuospatial attention is unilateral visual neglect meta-analyses. Specifically, our analyses examined (i) the overall convergence between the results from different lesion-symptom mapping studies concerned specifically with visual neglect , (ii) the concurrence in the damage within white matter pathways associated with neglect symptoms, and (iii) the concurrence in lesion sites associated with deficits in the control of attention either across space (egocentric frame of reference) or within objects , to evaluate whether behavioral dissociations within the neglect syndrome are matched by different lesion patterns. For this last analysis we fractionated data from studies using different assessment tools to measure neglect symptoms. It should be noted that our classification of the differential assessments of neglect depends on inferences about the underlying processes. For example, we assume that tasks such as line cancelation require that multiple stimuli are coded in relation to the patient\u2019s body . In contrast, tasks such as line bisection could reflect either separate coding of the perceived ends of the lines in relation to the patient or perception of the line as a single object associated with unilateral visual neglect as well as providing evidence for disconnection accounts of the syndrome. The findings are discussed in terms of functional accounts of neglect and theoretical models based on computational modeling of both normal and impaired attention functions.For the purpose of the current study we conducted a systematic literature search to indentify relevant papers reporting the neuronal substrates of the heterogeneous symptoms associated with unilateral visual neglect. All searches were carried out using PubMedThe inclusion criteria were as follows: 1) studies published in peer-reviewed journals; (2) use of lesion-symptom mapping approaches as defined in the Introduction, i.e., either lesion subtraction methods , VBM, or VLSM/VLBM methods; (3) the studied sample consisted of mainly brain injured patients and both experimental and control patients groups were described/defined clearly; (4) the findings were reported using spatial coordinates in either Montreal Neurological Institute for each individual study entered into our ALE meta-analyses. In Table Analysis 1 included data from all relevant papers reporting the neural substrates of unilateral visual neglect considering it as a unitary syndrome, not separating out patients according to different types of symptom as well as not differentiating between gray versus white matter lesions associated with the syndrome. Specifically, in Analysis 1 we included all the data from studies examining neglect, diagnosing neglect either from one of the commonly used tests or a battery of measures without applying any prior selection criteria. Analyses 2 and Analysis 3 directly examined the link between the heterogeneity of neglect and any associated neural substrates by fractionating lesion sites associated with deficits in allocating attention either across space or within objects . The data included in Analysis 2 came from studies that defined neglect exclusively using either target cancelation tests or both target cancelation and figure copying tests, measuring the patient\u2019s ability to attend to stimuli presented on the right and left side of egocentric space followed by analysis of concurrence in lesion sites associated more specifically with deficits in the control of attention within objects after excluding reports using line bisection . As recently much attention has been given to white matter lesions and disconnection accounts of the syndrome, Analysis 6 was performed on a subset of data specifically describing the link between neglect symptoms and white matter damage based on data from identified studies diagnosing neglect based on either one of the commonly used tests or on battery of neglect diagnostic measures without applying any selection criteria. Finally, Analyses 7 and Analysis 8 examined the link between white matter lesions and the specific symptoms of neglect associated with the control of attention either in relation the patient\u2019s body or within objects .In order to examine dissociations between both the symptoms and the neural substrates of neglect, we performed several different ALE meta-analyses . The relevant papers included in these analyses are listed in Table We performed the meta-analyses using BrainMap GingerALE 2.1 softwarep\u2009<\u20090.05 FDR corrected for multiple comparisons and a minimum cluster size of 200\u2009mm3 meta-analyses using as inputs coordinates describing foci identified in functional neuroimaging studies .Table Analysis 2 we identified 15 studies and six studies . Ten of the identified studies reported neglect associated with damage within white matter (not applying any selection criteria with regards to the tests of neglect) and these data were included in Analysis 6 and four studies .For The ALE meta-analysis for the main effect, i.e., the overall concurrence in the reported neural substrates of unilateral visual neglect (not differentiating between either different symptoms or gray versus white matter lesions) revealed 15 significant clusters Table . HoweverAnalysis 2 and Analysis 3 was not as robust as in the case of the white matter analysis reported below but the findings were nevertheless striking. The two most concurrent clusters (contributed respectively by 7 and 5 out of 20 experiments) identified in Analysis 2 (egocentric neglect) were located within the right superior temporal gyrus , right insula , and sub-cortical structures including the right putamen and thalamus . The two most concurrent clusters identified in Analysis 3 were located within the right angular gyrus , right temporo-parietal junction , right middle temporal gyrus , and sub-cortically within the right SLF . Strikingly, these two analyses indicated that, while egocentric symptoms were associated with damage within perisylvian network and damage within sub-cortical structures, more posterior lesions including the angular, middle temporal, and middle occipital gyri were associated with allocentric symptoms revealed 16 significant clusters associated with egocentric symptoms and 10 clusters associated with allocentric symptoms Table A,B. The Analysis 4) and the neural substrates associated with allocentric symptoms as measured by diagnostic tests excluding line bisection . The ALE meta-analysis on biases in line bisection revealed one significant cluster , revealed six significant clusters or allocentric space revealed four significant clusters associated with egocentric symptoms and four clusters with allocentric symptoms , right superior thalamic radiation , and right ILF . The most concurrent cluster was located within the right SLF , the right IFOF, and the right posterior thalamic radiation . Strikingly, these two analyses indicated that egocentric and allocentric symptoms were associated with lesions within common long association and projection pathways, in particular the SLF and the thalamic radiation.The ALE meta-analysis examining concurrence in the reported damage within white matter pathways associated with left neglect, not differentiating between the different symptoms of neglect , the consistency across the reported findings was relatively poor, though one of the identified clusters was contributed to by approximately 50% of all experiments. This covered regions within posterior parietal cortex (IPL), the insula, and the thalamus as well as within white matter pathways. Strikingly, when the different tests were not differentiated, there was high overall concurrence in white matter lesions within the long association SLF and projection pathways. This provides strong evidence for a disconnection account of the syndrome, which can generate a common pattern of deficit across different tests. While the assessment of common cortical damage across the different tests of neglect generated moderate results, the results were stronger when we separated out tests sensitive to the positions of elements in egocentric and allocentric reference frames. Here our concurrence analyses indicated that egocentric symptoms were associated with damage within the perisylvian network along with damage within sub-cortical structures, while more posterior lesions including the angular, middle temporal, and middle occipital gyri) were associated with allocentric symptoms.Here, we examined data indicating dissociations between the heterogeneous symptoms and the neural substrates of unilateral visual neglect based on ALE meta-analyses of lesion-symptom mapping studies. There is a substantial body of evidence demonstrating that different neuropsychological tests and/or even varied measures within the same task used for diagnosing neglect can reveal different symptoms of this heterogeneous syndrome whilst also varying in their overall sensitivity for detecting mild to moderate symptoms that multiple factors arising from variability in the neglect diagnosis explain the discrepancies reported in the literature on the neuronal substrates of unilateral visual neglect. It is plausible that other modulating factors, such as for example the neuroimaging modality used , the data analysis methods and the time of assessment, i.e., acute versus chronic brain injury, may also be important. However, because of the much higher concurrence demonstrated after fractionating the symptoms of neglect, we believe that the diagnostic tools are adequate to explain the literature discrepancies.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "HowevHere, we describe MetAMOS , an openWe compared MetAMOS with other metagenomic assembly tools (Meta-IDBA and Genovo) and with genome assemblers that have previously been used with metagenomic data (CA-met and SOAPdenovo). We used both a mock/artificial dataset generated for the Human Microbiome Project (HMP) project and real metagenomic samples from the HMP and its European counterpart (MetaHIT). On the mock dataset, MetAMOS compares favorably to existing metagenomic and genomic assemblers with respect to several validation metrics that take into account contig accuracy in addition to size. On the real dataset, MetAMOS also outperforms the existing software. These improvements can largely be attributed to heavy reliance on Bambus 2 and to assembly verification techniques that help identify and remove potentially chimeric contigs while running the pipeline.In terms of biology, we were able to report several novel variant motifs that would be challenging at best to identify and extract from the output of other methods. In addition, much emphasis was placed on making MetAMOS compatible with a variety of next-generation sequencing technologies, genome assemblers and annotation methods, making the pipeline highly customizable for the beginner and advanced bioinformatics user alike."} +{"text": "Higher plants are composed of a multitude of tissues with specific functions, reflected by distinct profiles for transcripts, proteins, and metabolites. Comprehensive analysis of metabolites and proteins has advanced tremendously within recent years, and this progress has been driven by the rapid development of sophisticated mass spectrometric techniques. In most of the current \u201comics\u201d-studies, analysis is performed on whole organ or whole plant extracts, rendering to the loss of spatial information. Mass spectrometry imaging (MSI) techniques have opened a new avenue to obtain information on the spatial distribution of metabolites and of proteins. Pioneered in the field of medicine, the approaches are now applied to study the spatial profiles of molecules in plant systems. A range of different plant organs and tissues have been successfully analyzed by MSI, and patterns of various classes of metabolites from primary and secondary metabolism could be obtained. It can be envisaged that MSI approaches will substantially contribute to build spatially resolved biochemical networks. Spatially resolved analysis of metabolites and proteins has become feasible within recent years by the development of mass spectrometry imaging (MSI) strategies. Development and application of these techniques has been pioneered in medicinal and pharmacological research. MS imaging allowed the detection of novel clinical markers for better diagnosis of cancer tissues and to follow the spatial-temporal patterns of drug molecules used for pharmacological studies MS or desorption electrospray ionization (DESI) MS will be highlighted. Approaches complementary to the MSI strategies will be briefly mentioned, in particular the use of laser microdissection of defined areas of tissue sections. Finally, data evaluation and integration into modeling approaches will be addressed.Any sample preparation technique for MSI analyses aims on keeping the lateral resolution and the nature of the target molecules. According to the applied MSI technique it varies from just mounting a sample for surface analysis to delicate sectioning and matrix application procedures. Some recent publications provide detailed protocols on plant sample preparation for small molecule MSI mass resolution, (ii) spatial resolution, and (iii) MS scan speed. However, selection of one or another technique remains a compromise as none of the available mass analyzers meets perfectly all criteria, e.g., high resolution mass spectrometer typically have slower scan speed enabled the MSI of various small molecules in Arabidopsis thaliana (kaempferol derivatives) and Hypericum species (phloroglucinols and naphthodianthrones) MSI at the single cell level provided information on the spatial distribution of UV-absorbing secondary metabolites for Barley leaf tissue was subjected to MSI using direct and indirect DESI , which was derived from a conserved motif in the CLV3 sequence in Arabidopsis callus as well as commercial solutions (Kaspar et al., Analysis of multiple tissue sections at high spatial resolution necessarily generates large data sets providing challenges for the subsequent data mining. A number of imaging software packages are available, both open source (e.g., BioMap, see Spatial resolution of current instrumentation for LDI/MALDI MSI is restricted to 10\u201320\u2009\u03bcm. MSI at cellular and in particular sub-cellular resolutions requires improvements in the techniques. Recently, the Caprioli group has developed transmission geometry MALDI MS allowing submicron spatial resolution (Zavalin et al., Mass spectrometry imaging has recently been introduced into plant sciences mostly focused on the spatial distribution of low molecular weight compounds, including primary and secondary plant metabolites as well as cyclic peptides Table . These sThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Whether degenerative joint disease of the elbow may be the result of primary or posttraumatic etiologies, arthritis of the elbow commonly leads to pain, loss of motion, and functional disability. A detailed history and focused physical examination, in combination with imaging modalities, can help localize the origin of symptoms and help direct treatment. Although nonoperative treatment is the initial therapy for arthritis of the elbow, surgical interventions may provide substantial relief to the appropriately selected patient. Degenerative joint disease of the elbow may be a painful condition for a majority of patients. Although primary osteoarthritis is less common than posttraumatic arthritis of the elbow, both conditions result in symptoms which affect the quality of life. The health care provider encountering these conditions must carefully tailor treatments, both nonoperative and operative, to account for the patient's age, personal preferences, functional demands, and severity of arthritic changes. This paper will review the pathogenesis of both primary and posttraumatic arthritis of the elbow. The principles of nonoperative management will be presented as well as the indications and considerations for operative treatment.Primary osteoarthritis of the elbow is an uncommon condition which occurs predominantly within the ulnohumeral joint of the dominant extremity of patients who engage in heavy sport or labor. The intrinsic congruity of the ulnohumeral articulation preserves a majority of the articular cartilage, with degenerative changes and osteophytes initially affecting the tips of the olecranon and coronoid processes as well as their respective fossae within the distal humerus. Accordingly, the most common complaint of patients in our practice with early stages of primary osteoarthritis of the elbow is pain at terminal flexion and extension, as the osteophytes of the coronoid and olecranon engage their fossae. As the degenerative process involves more of the articular surface, pain is encountered throughout the arc of motion, and enlarging osteophytes coupled with anterior and posterior capsular contracture may provide further mechanical impediments to motion and result in measurable loss of motion in terminal flexion and extension.The majority of articular surface involvement is confined to the ulnohumeral joint. Isolated primary osteoarthritis is uncommon within the radiocapitellar articulation. Accordingly, the practitioner should carry out a detailed history and meticulous physical examination in order to localize the origin of symptoms in the patient with primary osteoarthritis of the elbow. Ulnohumeral arthrosis typically results in pain and diminished range of motion in flexion and extension, while radiocapitellar arthrosis predominantly manifests as focal lateral-sided pain over the radiocapitellar joint during forearm rotation .A variety of traumatic insults may ultimately result in specific forms of posttraumatic arthritis to the elbow joint. Radiocapitellar incongruity may result following malunion of an intraarticular radial head fracture ; patientAlthough malignments in the geometry of the articular surface alter contact pressures and expedite the development of arthritis, ligamentous instability about the elbow may also result in abnormal joint kinematics and the potential for degenerative changes. These potential injuries should be carefully evaluated, as the presence of elbow instability dramatically alters the treatment objectives in the setting of elbow arthritis, particularly when surgical intervention is considered. The most common complaints of patients with either primary or posttraumatic arthritis of the elbow are pain and/or loss of motion; it is important for the practitioner to precisely characterize the principal complaint. Complaints of pain should be localized when possible, particularly when attempting to discern between symptomatic arthrosis of the radiocapitellar or ulnohumeral joint. Pain may be associated at the extremes of motion in earlier forms of ulnohumeral arthritis but may be experienced throughout the arc of elbow flexion and extension in more advanced disease , 2. AlthFor patients who report a prior episode of significant elbow trauma, the details surrounding the initial injury as well as mechanism of trauma are important aspects of the history, as any previous treatments including operative reports from previous surgeries and therapy reports to elicit what treatments have been undertaken. Ulnar neuropathy is a frequent finding in patients presenting with degenerative joint disease of the elbow and is frequently subtle and not part of the patient's chief complaint. The examiner should specifically inquire about sensations of numbness and tingling in the ring and small finger, loss of dexterity, and soreness over the ulnar nerve in the posteromedial elbow, in order to comprehensively evaluate for cubital tunnel syndrome. Although uncommon, any suggestion or suspicion of infection in the setting of previous open trauma, surgery, or septic arthritis requires a thorough evaluation, including serologic markers and aspiration of the joint to be analyzed for synovial fluid cell count, culture, and gram stain.Finally, the demand level of the patient must be carefully considered, as certain patients may desire nearly full motion for specific lifestyle and employment demands, which would lower the threshold for motion-preserving debridement, while others may require heavy lifting which would preclude treatment with a total elbow arthroplasty. It should be noted that loss of flexion tends to be much more functionally limiting than loss of extension, as the latter can be compensated for simply by moving closer to an object to reach it. A loss of flexion, however, cannot be compensated for. A loss of pronation can be accommodated for by abducting the shoulder, whereas a loss of supination cannot be accommodated for. The willingness of the patient to comply with the required extensive programs of therapy must also be considered, as treatment outcomes depend on diligent participation in a structured rehabilitation program. Physical examination begins with inspection of the entire upper extremity, specifically evaluating for deformity, swelling, and muscle atrophy, while noting the location of any previous surgical incisions that would influence further surgical planning. Range-of-motion evaluation should include the hand, wrist, forearm, and elbow and should be compared with the contralateral, unaffected extremity. In the posttraumatic setting, loss of extension is more common than loss of flexion, whereas in osteoarthritis the loss in motion is quite variable depending on the location of impinging osteophytes.A careful neurovascular examination is important, especially during the evaluation of ulnar nerve function. Residing in the cubital tunnel and adjacent to the medial joint capsule, the ulnar nerve may become compressed either from scar tissue along the medial elbow following trauma or from thickened capsule, osteophytes, or synovitis. Traction ulnar neuritis of the elbow may manifest as medial elbow pain and patients may complain of sensory changes in an ulnar nerve distribution, particularly with elbow flexion. Patients with posttraumatic ulnar neuropathy may present simply with loss of flexion and medial elbow pain in the absence of overt symptoms of ulnar neuropathy; thus, a meticulous neurovascular evaluation, including two-point discrimination, pinch strength, and intrinsic muscle function are essential to document the preoperative function of the ulnar nerve. Electrodiagnostic testing may be considered in the setting of provocative symptoms of ulnar neuropathy.Evaluation of elbow stability is essential in order to exclude ligamentous insufficiency as a potential diagnosis. Varus and valgus stresses are applied to the affected elbow with the contralateral elbow serving as a normal comparison. Posterolateral rotatory stability is evaluated with the lateral pivot-shift maneuver; this test is performed by applying a valgus stress and axial load to the partially flexed elbow with the forearm fully supinated. Posterior subluxation of the radial head is pathogonomic for posterolateral rotatory instability; alternatively, pain without subluxation is suggestive of instability .Plain radiographs of the elbow are typically obtained and include anteroposterior, lateral, and oblique projections; diligent efforts should be made to review previous imaging for patients presenting with posttraumatic arthritis. Stress radiographs should be considered if elbow instability is suspected. Radiographs typically demonstrate preservation of joint space centrally with osteophytes along the anterior and posterior aspects of the joint which may cause impingement . RadiogrComputerized tomography (CT) is frequently useful, especially when HO or intra-articular loose bodies are suspected, or if bony deformity or malunion is suspected in the setting of previous fracture. CT reconstruction is typically helpful in further delineating bony and articular anatomy . AdvanceNonoperative management remains the mainstay of initial treatment for both primary osteoarthritis of the elbow and posttraumatic arthritis of the elbow and typically includes elbow sleeves, nonsteroidal anti-inflammatory medications, and intra-articular corticosteroid injections. For early-stage primary arthritis, symptoms are strongly associated with specific activities , and counseling patients on avoidance of aggressive terminal flexion and extension exercises can result in substantial relief of pain. A course of supervised rehabilitation by a certified therapist is reserved typically for patients presenting with an acute-on-chronic presentation of symptoms with an associated effusion and limitations in motion.Few reports have evaluated the role of hyaluronic acid as nonoperative management of elbow arthritis. A limited report on 18 patients demonstrated modest relief of pain at 3 months but no long-term benefit following the intraarticular injection of hyaluronic acid in the arthritic elbow .Surgical management is indicated for patients with elbow pain or significant loss of mobility with resultant impairment of upper extremity function and limitation with daily activities. Careful consideration of patients' primary complaints is important in selecting the appropriate surgical intervention. Patients who continue to experience stiffness rather than pain despite nonoperative management may experience improvements in upper extremity function by surgical treatment, either open or arthroscopic debridement and capsular release. Similarly, patients with pain only the extremes of terminal flexion and/or extension but not in the midarc of elbow motion may benefit most from debridement as opposed to those with pain throughout the motion arc, which suggests arthritic involvement of the entire ulnohumeral joint. From a purely mechanical standpoint, to improve elbow extension, posterior impingement must be removed between the olecranon tip and the olecranon fossa. Anteriorly, tethering soft tissues such as the anterior joint capsule and any adhesions between the brachialis and the humerus must be released. Similarly, to improve elbow flexion, the surgeon must release any posterior soft tissue structures that may be tethering the joint. They include the posterior joint capsule and the triceps muscle, which can become adherent to the humerus. The surgeon must remove any bony or soft-tissue impingement anteriorly, including any soft-tissue overgrowth in the coronoid and radial fossae. There must be a concavity above the humeral trochlea and capitellum to accept the coronoid centrally and the radial head laterally for full flexion to occur. These principles may be applied in the treatment of patients with the majority of their articular surfaces preserved but still complain of pain at the extremes of motion, as they will respond favorably to debridement of osteophytes anteriorly and/or posteriorly but with much of the articular surface well preserved.Although a flexion contracture of at least 25 to 30 degrees and/or less than 110 to 115 degrees of active flexion was historically reported as an indication for surgical contracture release, surgical management may still be offered to certain patients who may desire full or nearly full motion for specific lifestyle and employment demands. Posttraumatic patients typically must be at least 3 to 4 months removed from injury to allow them to achieve \u201ctissue equilibrium,\u201d with maximal resolution of posttraumatic swelling and inflammation. Most importantly, patients must be willing to comply with the required extensive program of postoperative therapy, as operative outcomes depend on diligent participation in a structured rehabilitation program. Advances in elbow arthroscopy have resulted in favorable outcomes. Arthroscopic debridement of the elbow, particularly in a younger patient population, has excellent results with improvements in pain and range of motion \u20139 when tOpen debridement should be considered in cases featuring severe elbow contractures with minimal joint motion, with ulnar nerve transposition surgery, and the presence of significant heterotopic bone. These patients are more reliably treated with extensive open surgery rather than arthroscopic debridement of the elbow to restore motion and protect the ulnar nerve. Open debridement, when required, is now commonly performed using medial and lateral exposures that provide adequate access for debridement and capsular release of the anterior and posterior elbow , 11. Prior surgical exposure of the radial head might result in scarring and adhesions of the radial nerve to the anterior capsule, rendering the nerve susceptible to iatrogenic injury during arthroscopy. Open debridement is also indicated in this scenario. If the ulnohumeral joint shows marked degenerative changes, a simple release of the joint may not lead to improved motion and may exacerbate pain in an arthritic joint. If advanced posttraumatic arthritis is observed in the ulnohumeral articulation, salvage-type procedures are often required such as total elbow arthroplasty or soft-tissue interposition arthroplasty if surgery is undertaken .Open ulnar nerve decompression with or without transposition should be considered along with open or arthroscopic elbow debridement if the patient has positive provocative neuropathic symptoms signs or if the patient cannot flex past 100 to 110 degrees before surgery. Increased postoperative flexion following debridement theoretically should place the nerve at elevated risk of traction neuropathy . To. To14]. For the patients with symptomatic radiocapitellar arthritis who require surgical management, favorable outcomes following both open and arthroscopic radial head resection have been reported. Lateral elbow pain localized to the radiocapitellar joint with forearm rotation helps the practitioner identify patients with symptomatic arthritis of the radiocapitellar joint, and several authors have reported favorable outcomes of radial head resection , 16. In Although radial head resection does demonstrate favorable results in the appropriately selected patient, proximal migration of the radius may occur or progressive ulnohumeral arthritis may develop at the medial joint line owing to increased valgus forces at the elbow in younger higher demand patients . Radial The evaluation of posttraumatic and primary osteoarthritis of the elbow requires a thorough, systematic approach to help accurately characterize the primary complaint and formulate a carefully considered treatment plan which accounts for the activity level and functional requirements of a given patient. Nonoperative treatment is almost always initiated although surgical treatment may be indicated in cases refractory to conservative management. Younger patients who experience pain or loss of motion in early stage ulnohumeral arthritis have experienced favorable outcomes following both arthroscopic and open elbow debridement although arthroscopic debridement should only be performed by surgeons who possess the advanced technical skills necessary for safe elbow arthroscopy. Patients with more advanced arthrosis of the elbow commonly require salvage reconstructive procedures. Although total elbow arthroplasty may be performed in the older, low-demand patient, the procedure may not be appropriate for younger, active patients who may not comply with substantial lifting restrictions required for longevity of the implants. For high-demand patients with advanced elbow arthritis, interposition arthroplasty or arthrodesis may provide acceptable functional outcomes while avoiding activity restrictions required by arthroplasty."} +{"text": "The sterile womb paradigm is an enduring premise in biology that human infants are born sterile. Recent studies suggest that infants incorporate an initial microbiome before birth and receive copious supplementation of maternal microbes through birth and breastfeeding. Moreover, evidence for microbial maternal transmission is increasingly widespread across animals. This collective knowledge compels a paradigm shift\u2014one in which maternal transmission of microbes advances from a taxonomically specialized phenomenon to a universal one in animals. It also engenders fresh views on the assembly of the microbiome, its role in animal evolution, and applications to human health and disease.While the human microbiota comprises only 1\u20133% of an individual's total body mass, this small percentage represents over 100 trillion microbial cells, outnumbering human cells 10 to 1 and adding over 8 million genes to our set of 22,000 While maternal transmission of microbes in humans has attracted considerable attention in the last few years, nearly a century's worth of research is available for vertical transmission of symbionts in invertebrates in situ hybridization (FISH) studies have confirmed the presence of microorganisms of different shapes and sizes in the oocytes of oviparous sponges Sponges are ancient metazoans that evolved over 600 million years ago as one of the first multicellular animals Deep-sea hydrothermal vent communities rely upon chemosynthetic bacteria to harness chemical energy stored in reduced sulfur compounds extruding from the vents. Metazoans that live in this extreme environment harbor chemosynthetic endosymbionts in their tissues that provide most, if not all, of the host's nutrition Wolbachia, are also widespread in insects and hijack maternal transmission routes to ensure their spread within an insect population Pea Aphid Blattabacterium-filled bacteriocyte cells migrate from the abdominal fat body to the distantly located ovarioles where they adhere to the oocyte membrane Blattabacterium cells then squeeze between the follicle cells surrounding the oocyte and are engulfed into the oocyte cytoplasm via endocytosis just prior to ovulation Just as insects are morphologically diverse, the mechanisms by which insects transport symbionts to oocytes are highly varied. In cockroaches, Whiteflies (Family Aleyrodidae)Portiera aleyrodidarum, by depositing entire bacteriocytes into its eggs. These maternal bacteriocytes remain intact yet separate from the developing embryo until the embryonic bacteriomes form, at which point the maternal bacteriocytes deteriorate The whitefly circumvents exocytosis of its intracellular nutritional symbiont, Tsetse Flies, Bat Flies, and Louse Flies (Superfamily Hippoboscoidea)Wigglesworthia glossinidia, is absent from the female germ line and surrounding reproductive tissues but is found extracellularly in the female milk glands and is first detected in tsetse offspring once milk consumption begins during the first larval stage Members of the Hippoboscoidea superfamily (Order Diptera) are obligate blood feeders that have developed a unique reproductive strategy termed adenotrophic viviparity that offers a different solution to internal maternal transfer of symbionts. Females of this superfamily develop a single fertilized embryo at a time within their uterus until it is deposited as a mature third instar larva immediately preceding pupation. During their internal development, the larvae are nourished with milk produced by modified accessory glands that empty into the uterus Stinkbugs (Superfamily Pentatomoidea)One of the most common mechanisms of external maternal transmission in insects is that of \u201cegg smearing,\u201d which occurs when a female contaminates the surface of her eggs with symbiont-laden feces during oviposition. Upon hatching, offspring probe or consume the discarded egg shells to acquire the maternal bacteria. This mode of transmission is commonly found in plant-sucking stinkbugs, including the Pentatomidae and Acanthosomatidae families Philanthus triangulum)European Beewolf (Philanthus triangulum) instead cultivates a symbiotic bacteria that protects offspring against microbial infection during development. Beewolves are solitary digger wasps that deposit their offspring in moist, underground nests, making them susceptible to fungal and bacterial infections Streptomyces philanthi bacteria in specialized glands in their antennae, which they copiously spread on the ceiling of the brood cell before oviposition Streptomyces symbiont and house them in the female-specific gland reservoirs along each antenna While nutritional symbionts appear to be the most common type of bacteria transmitted via external maternal transmission in insects, the European beewolf At the turn of the twentieth century, French pediatrician Henry Tissier asserted that human infants develop within a sterile environment and acquire their initial bacterial inoculum while traveling through the maternal birth canal Enterococcus and Escherichia, are common inhabitants of the gastrointestinal tract in utero, Jim\u00e9nez et al.Enterococcus faecium and then examined the meconium microbes of term offspring after sterile C-section. Remarkably, E. faecium with the genetic label was cultured from the meconium of pups from inoculated mothers, but not from pups of control mice fed noninoculated milk. Meconium from the treatment group also had a higher abundance of bacteria than that of the control group. Importantly, the study controlled for potential bacterial contamination from contact between skin and the meconium by sampling an internal portion of the meconium While intrauterine infection and inflammation is important in understanding the etiology of preterm birth, relatively few studies have examined the uterine microbiome of healthy, term pregnancies owing to the sterile womb paradigm. Investigations into the potential for bacterial transmission through the placental barrier have detected bacteria in umbilical cord blood Other than ascension of vaginal microbes associated with preterm births, the mechanisms by which gut bacteria gain access to the uterine environment are not well understood. One possibility is that bacteria travel to the placenta via the bloodstream after translocation of the gut epithelium. While the intestinal epithelial barrier generally prevents microbial entry into the circulatory system, dendritic cells can actively penetrate the gut epithelium, take up bacteria from the intestinal lumen, and transport the live bacteria throughout the body as they migrate to lymphoid organs in utero.Overall, the study of internal maternal transmission of microbes in mammals is in its infancy due to the enduring influence of the sterile womb paradigm and to the ethical and technical difficulties of collecting samples from healthy pregnancies before birth. Thus, we still know very little about the number and identity of innocuous microbes that traverse the placenta, whether they persist in the infant, or whether their presence has long-term health consequences for the child. Similarly, we know almost nothing about nonpathogenic viruses or archaea that may be transferred from mother to child alongside their bacterial counterparts. Fortunately, the advent of culture-independent, high-throughput sequencing will serve as a tremendous resource for this field and will hopefully lead to a characterization of the \u201cfetal microbiome\u201d Maternal provisioning of microbes to developing offspring is widespread in animals, with evidence of internal microbial transmission in animal phyla as diverse as Porifera Aside from studies in human and mouse models, very little is known about maternal transmission of microbial communities in vertebrates, especially outside Class Mammalia. Furthermore, research on vertical transmission in nonmammalians has largely focused on maternally transmitted pathogens, especially in animals of agricultural importance like chickens and fish.Salmonella infections acquired from contaminated chicken eggs is estimated to cause more than 100,000 illnesses each year in the United States Salmonella on eggs through surface contamination, direct transovarial transmission also occurs when Salmonella colonizes the reproductive tissues of hens facilities and has been observed in spores of the ovarian stroma and within developing follicle cells of spawning females, suggesting that it can be vertically transmitted, though it is primarily spread from fish to fish in contaminated water nests found several potential pathogens, including Pseudomonas aeruginosa and Serratia marcesans, in fluid from the interior of the eggs, though environmental contamination of the eggs cannot be ruled out Podocnemis expansa that collected eggs directly from the maternal cloacal opening during egg laying isolated Pseudomonas, Salmonella, Enterobacter, and Citrobacter from the eggshell, albumen, and yolk. In fact, the yolk was the egg component most heavily infected with bacteria The formation of egg components in the uterine tube and uterus of turtles takes approximately two weeks, providing ample opportunity for maternal transmission of intestinal or reproductive microbes to the egg expansa and P. uExternal maternal transmission encompasses any transfer of maternal symbionts to offspring during or after birth. In invertebrates, it is often accomplished by \u201cegg smearing,\u201d in which females coat eggs with microbes as they are deposited Lactobacillus bacterial species are enriched in the vaginal community during pregnancy and are hypothesized to be important for establishing the neonatal upper GI microbiota after vaginal delivery The higher rate of immune-mediated diseases in C-section children may indicate that maternally transferred vaginal or fecal microbes are unique in their ability to elicit immune maturation in the neonate. Development of the intestinal mucosa and secondary lymphoid tissues in the gut is contingent upon recognition of microbial components by pattern-recognition receptors on intestinal epithelial cells collected aseptically already harbors hundreds of bacterial species Overall, maternal transmission of beneficial microbes in humans has widespread relevance for human health. Evolution with these microbes has resulted in our dependence on them for the proper maturation and development of the immune system and gastrointestinal tract. Somewhat paradoxically, modern medicine designed to prevent infant mortality (such as emergency Cesarean sections and formula feeding) has likely contributed to the rise in immune-mediated diseases in developed countries due to the inherent lack of exposure to maternal microbes associated with these practices. Fortunately, biomedicine is also making strides in finding effective probiotic supplements to promote immune development and ameliorate some of the risks that C-section or formula-fed infants face as children and adults. Hopefully, as we gain understanding of the diversity and function of maternally transmitted microbes in humans, more complete and effective probiotic blends will recapitulate the microbial communities found in vaginally delivered, breast-fed infants and restore the microbe-host interactions that humans depend upon for proper development.Since the early twentieth century, the study of maternal microbial transmission has focused heavily on animal systems in which maternal transmission maintains sophisticated partnerships with one or two microbial species. However, with the development of high-throughput sequencing technologies, it is now possible to identify entire microbiomes that are transferred from mother to offspring in systems not traditionally considered to exhibit maternal transmission, such as humans. By expanding the definition of maternal transmission to include all internal and external microbial transfers from mother to offspring, we contend that maternal transmission is universal in the animal kingdom and is used to provision offspring with important microbes at birth, rather than leave their acquisition to chance.Finally, with microbes contributing 99% of all unique genetic information present in the human body, maternal microbial transmission should be viewed as an additional and important mechanism of genetic and functional change in human evolution. Similar to deleterious mutations in our genetic code, disruption of maternal microbial acquisition during infancy could \u201cmutate\u201d the composition of the microbial community, leading to improper and detrimental host-microbe interactions during development. Maternal transmission is also a key factor in shaping the structure of the microbiome in animal species over evolutionary time, since microbes that promote host fitness, especially in females, will simultaneously increase their odds of being transferred to the next generation. Thus, whether internal or external, the universality and implications of maternal microbial transmission are nothing short of a paradigm shift for the basic and biomedical life sciences."} +{"text": "The rapid demographical shift occurring in our society implies that understanding of healthy aging and age-related diseases is one of our major future challenges. Sensory impairments have an enormous impact on our lives and are closely linked to cognitive functioning. Due to the inherent complexity of sensory perceptions, we are commonly presented with a complex multisensory stimulation and the brain integrates the information from the individual sensory channels into a unique and holistic percept. The cerebral processes involved are essential for our perception of sensory stimuli and becomes especially important during the perception of emotional content. Despite ongoing deterioration of the individual sensory systems during aging, there is evidence for an increase in, or maintenance of, multisensory integration processing in aging individuals. Within this comprehensive literature review on multisensory integration we aim to highlight basic mechanisms and potential compensatory strategies the human brain utilizes to help maintain multisensory integration capabilities during healthy aging to facilitate a broader understanding of age-related pathological conditions. Further our goal was to identify where further research is needed. Each of our sensory systems provides us with a qualitatively distinct subjective complementary impression of our surrounding, which are of critical importance for perception, cognitive processing and control of action and can occur in a highly automatized manner object observation and (ii) emotional perception. For the investigation of multisensory processes during object recognition, combinations of two different modalities\u2014combined visual-auditory stimulations\u2014is the most utilized. A concurrent combination of three different and congruent sensory stimuli has yet to be applied within a neuroimaging setting. However, when analyzing areas of overlap between the three senses of touch, sound, and vision, both the STS and IPS demonstrate a considerable overlap in processing are based upon basic circuitry of the sensory systems involving several interactive neuronal loops such as prefronto-thalamo-cortical gating between the thalamus and the neocortex in order to effectively process sensory and higher-order cognitive information . Due to aging of populations in both developed and developing societies, AD affects 24.3 million people worldwide and has become one of the most severe socio-economical and medical burdens , patients demonstrate a limited ability to benefit from concurrent perceptual and linguistic cues compared to healthy aged subjects (Phillips et al., Advances are being made in disentangling the multisensory integration mechanisms in elderly, thus encouraging future larger longitudinal studies needed to understand the specific neurobiological and neuropathological basis of multisensory integration in health and disease. The current state of research on multisensory integration in healthy aging and age-related neurodegenerative disorders would greatly benefit from further studies as we aim to understand basic mechanisms and potential compensatory strategies of the human brain that help maintain multisensory integration capabilities during both healthy and pathological aging. Early identification of changes in multisensory integration will help to better inform choice of therapy and aid a personalized approach to clinical treatment. Future studies are warranted to determine the clinical translational value of multisensory integration processes in the elderly.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The twin epidemic of diabetes and obesity pose daunting challenges worldwide. The dramatic rise in obesity-associated diabetes resulted in an alarming increase in the incidence and prevalence of obesity an important complication of diabetes. Differences among individuals in their susceptibility to both these conditions probably reflect their genetic constitutions. The dramatic improvements in genomic and bioinformatic resources are accelerating the pace of gene discovery. It is tempting to speculate the key susceptible genes/proteins that bridges diabetes mellitus and obesity. In this regard, we evaluated the role of several genes/proteins that are believed to be involved in the evolution of obesity associated diabetes by employing multiple sequence alignment using ClustalW tool and constructed a phylogram tree using functional protein sequences extracted from NCBI. Phylogram was constructed using Neighbor-Joining Algorithm a bioinformatic tool. Our bioinformatic analysis reports resistin gene as ominous link with obesity associated diabetes. This bioinformatic study will be useful for future studies towards therapeutic inventions of obesity associated type 2 diabetes. Diabetes Mellitus continues to be a devastating and daunting health scourge spreading across geographical and genetic boundaries. The growing incidence of type 2 diabetes with increasing obesity reflects that obesity is an emerging risk factor for the progression of insulin resistance and subsequently to overt type 2 diabetes. Both in normoglycemic and hyperglycemic states, obese people exhibit a higher degree of hyper insulinemia that correlates with the degree of insulin resistance, in order to maintain normal glucose tolerance , 6. It hDespite multiple efforts are being made to dampen their impact on the quality of life of affected patients, there remains a lot of complexity exists in the pathogenesis of obesity mediated type 2 diabetes. By virtue of endocrinal role of adipose tissue, it is known to produce a vast array of adipocyte derived factors such as tumor necrosis factor alpha, interleukin-6, leptin, adiponectin and resistin. Since many of these adipokines profoundly influence insulin sensitivity and glucose metabolism, they form a fundamental bridge between increased adiposity and impaired insulin sensitivity . Althouget al .The present research aims at finding the proteins responsible for obesity associated diabetes in two phases. The first phase of the research attempts to identify the candidate proteins/genes which are involved in these disorders through thorough literature search. The data pertaining to these proteins is extracted from the databases that are available online for free access. The functional protein sequences of these proteins in FASTA are extracted from , (The second phase of the research analyzes the data by employing Multiple Sequence Alignment using ClustalW online tool. These alignments produce a Phylogram tree along with the alignment scores. ClustalW adds sequences one by one to the existing alignment to build a new alignment because of its progressive nature. Progressive in this context means, it starts with using pair wise method to determine the most related sequences and then progressively adding less related sequences initial alignment.From thorough literature search seventeen proteins Table were colNumerous factors in obesity such as elevated free fatty acid levels, decreased adiponectin and increased adipocytokines are majorly responsible for evolution of insulin resistance . ResistiIn animals, resistin has been shown to be secreted by adipocytes and to impair glucose tolerance and insulin action when infused into mice. A study has also reported increased resistin expression in human abdominal tissue. Several studies, however, have reported reduced resistin expression in human and rat obesity. Insulin, FFAs, and TNF-a have all been shown to inhibit resistin expression and all of these factors are elevated in obesity. Therefore, contrasting results obtained from both human and a rodent study made the role of resistin in obesity-induced diabetes is more and more controversial. The human resistin is a dimeric protein with 108 amino acids as compared to the murine resistin which comprises 114 amino acids. It raises blood glucose and insulin concentration and reduces hypoglycemic response to insulin infusion . Thus itet al (et al (Recently List Eo et al performel (et al study rel (et al . On the l (et al . Variatil (et al . TherefoAny rigid assessment of disease patterns will need support from well documented and curated databases. However, there are also severe practical and theoretical constraints known if applying bioinformatics as a tool for improved understanding and diagnostics of disease patterns Though lot of controversies exist with regard to the role of resistin in metabolic disorders such as obesity and diabetes mellitus, it\u2019s role is not completely excluded. Our Bioinormatics analysis once again heightens the possible role of Resistin gene that connects obesity and diabetes mellitus. In future studies like this may pave way for new therapeutic inventions of obesity associated diabetes."} +{"text": "More than half a century has passed since the concept of dual atrioventricular (AV) nodal pathways physiology was conceived. Dual AV nodal pathways have been shown to be responsible for many clinical arrhythmia syndromes, most notably AV nodal reentrant tachycardia. Although there has been a considerable amount of research on this topic, the subject of dual AV nodal pathways physiology remains heavily debated and discussed. Despite advances in understanding arrhythmia mechanisms and the widespread use of invasive electrophysiologic studies, there is still disagreement on the anatomy and physiology of the AV node that is the basis of discontinuous antegrade AV conduction. The purpose of this paper is to review the concept of dual AV nodal pathways physiology and its varied electrocardiographic manifestations. The term \"dual AV nodal pathways\" is loosely used by many clinicians when analyzing electrocardiograms and telemetry strips. This term, to the novice physician, might suggest two, distinct anatomic structures related to the atrioventricular (AV) node, but often the true understanding of this entity is either missing or incomplete. The purpose of this manuscript is to review the anatomy, physiology, and electrophysiologic functional characteristics of the human AV node, and demonstrate the variety of electrocardiographic manifestations of what should correctly be described as \"dual AV nodal pathways physiology\". This review may be most helpful to physicians-in-training - interns, residents, and cardiology or pulmonary fellows; practicing internists with special interest in electrocardiography may also find this of value.decremental conduction, the AV node delays the impulse arriving from the atria, thereby allowing the ventricles to stay in diastole, providing sufficient ventricular filling time. This property of decremental conduction also allows for protection of the ventricles from very rapid rates during atrial fibrillation. Though there were numerous researchers who identified the presence of an electrical connection between the atria and the ventricles, the physical existence of the AV node was definitively proven by Tawara. . Therefore, single AV nodal echo beats can mimic interpolation see .One of the rarer ECG manifestations of dual pathways physiology, a double ventricular response to a single atrial impulse is due to the anterograde conduction of the impulse in both the fast and the slow pathways see . This reThis review discusses the fundamental anatomy and physiology underlying dual AV nodal pathway function, and the resulting ECG manifestations. The astute physician will learn to recognize the myriad ECG manifestations of dual pathways physiology, and offer appropriate investigations and therapeutic decisions for optimal patient care. Recognizing dual AV nodal pathways requires a thorough understanding of AV nodal physiology."} +{"text": "In the studies of mental and behavioral disorders, comorbidity is an important issue since multiple correlated disorders are usually recorded to understand the etiology of substance dependence, which is imperative to the development of effective treatment and prevention strategies. Many studies have been reported the comorbidity between substance abuse disorders and psychiatric disorders such as anxiety and major depression. In order to investigate the association between the comorbidity of complex diseases and genetic locus, it is critical to develop a computationally efficient and powerful multiple traits association test. Recently, taking the advantage of high throughput genomic data, lots of genetic variants have been identified for individual drug addiction based on genome-wide association studies (GWAS). Despite many successes, the current GWAS may be insufficient to detect genetic variants with moderate-to-small effect since a stringent significance threshold is used to control the false discovery rate, which is a key factor to the missing heritability problem.To detect novel genetic variants, joint analyzing correlated traits are promising solutions. First, joint analyzing correlated traits may increase the power in detecting genetic variants with moderate effects across multiple traits by exploiting the correlation between traits. Second, joint analysis can alleviate multiple comparison problems which incurred in analyzing individual trait separately. Comprehensive studies have been used to demonstrate that jointly testing correlated traits is more powerful than testing a single trait at a time. Therefore, it is important to consider the comorbidity of correlated traits in order to detect novel genetic loci in GWAS. We introduce a multiple traits association test based on least square. The proposed method only needs to specify the marginal distribution of multiple traits. We systematically investigate the strengths and weaknesses of the multiple traits association test through simulation and comprehensive real data analysis. We demonstrated the advantage of multiple traits association test when multiple traits share common genetic variation. However, when multiple traits share no or weak common genetic variation, the multiple traits association test has no advantage."} +{"text": "Although pseudoaneurysms of the subclavian and axillary arteries are relatively common due to trauma and diagnostic/therapeutic interventions, true aneurysms of these arteries are rarely seen.Eight patients that were operated on between February 1998 and December 2007 due to true aneurysms of the subclavian and axillary arteries were examined retrospectively in terms of clinical and perioperative parameters.All the patients underwent selective peripheral arteriography, colored Doppler ultrasound and contrasted thoracoabdominal computed tomography (CT). All the patients were operated on under general anesthesia. Subclavicular approach was preferred except for the case operated on for pseudoaneurysm repair. In this particular case, supraclavicular approach was used for the 1st operation and supraclavicular incision plus a partial median sternotomy for the 2nd. Generally, if the calibration of the saphenous vein graft was appropriate for the arterial segment, this venous graft was used. Otherwise, an artificial graft was interposed. If acute ischemia was coexistent, brachial embolectomy was also performed.Isolated aneurysm of subclavian or axillary artery is very rarely seen among all peripheral arterial aneurysms. The true aneurysms of these particular arteries are even more seldom. One should be very careful in the diagnosis and treatment processes."} +{"text": "AbstractScaphinotus petersi are isolated in subalpine conifer forest habitats on mountain ranges or Sky Islands in southeastern Arizona. Previous work on this species has suggested these populations have been isolated since the last post-glacial maximum times as warming caused this cool adapted species to retreat to high elevations. To test this hypothesis, we inferred the phylogeny from mitochondrial DNA sequence data from several Arizona Sky Island populations of Scaphinotus petersi and estimated the divergence time of the currently isolated populations. We found two major clades of Scaphinotus petersi, an eastern clade and a western group. Our results indicated most mountain ranges form clades except the Huachucas, which are polyphyletic and the Santa Catalinas, which are paraphyletic. We estimated the Pinale\u00f1o population is much older than the last glacial maximum, but the Huachuca and Pinal populations may have been fragmented from the Santa Catalina population since the post-glacial maximum times.Populations of the ground beetle Carabidae (ground beetle family) is one of the larger families of insects with approximately 40,000 described species sequences and use these data to address questions about population structure of this species and examine the potential role of the Pleistocene climate changes in the differentiation some of the Sky Island populations of Scaphinotus petersi.The goal of this study was to infer the biogeographic history of Scaphinotus petersi in five localities in four mountain ranges was partitioned in five unlinked subsets . Maximum likelihood TEST 3.7 and likeTEST 3.7 using a Bayesian analyses were completed in MRBAYES 3.12 using foScaphinotus petersi populations using a Bayesian relaxed clock uncorrelated lognormal method in BEAST was paraphyletic with respect to a clade of Scaphinotus petersi petersi from the Pinal Mountains and Scaphinotus petersi biedermani from the Huachuca Mountains. The Scaphinotus petersi biedermani population did not appear to be monophyletic with one specimen grouping with members of Scaphinotus petersi catalinae from the Santa Catalina Mountains hypotheses of relationships based on morphological characteristics. Scaphinotus petersi grahamiPageBreak from the Pinale\u00f1o Mountains shared traits with Scaphinotus petersi kathleenae from the Santa Rita Mountains and Scaphinotus petersi corvus from the Chiricahua Mountains. Thus we would predict these three subspecies form a clade even though the Santa Rita Mountains are more geographically close to the Huachuca Mountains where Scaphinotus petersi biedermani are found. Based on morphological similarity, Scaphinotus petersi in the Rincon Mountains are closely related to those in the Huachuca Mountains, however, based on the amount of dispersal from the Santa Catalina Mountains to neighboring mountain ranges and the amount of morphological variation Scaphinotus petersi catalinae instead of other Scaphinotus petersi biedermani found in the Huachuca Mountains.In this study we sampled only four of the six subspecies of Scaphinotus petersi is structured across southeastern Arizona, indicating extrinsic barriers to gene flow are probably responsible for phylogeographic structure. It appears that a historical corridor of shared, linked habitat existed along a north \u2013 south ridge in the Western clade of Scaphinotus petersi enabling dispersal from the Santa Catalinas to the Huachuca and Pinal Mountains. This north \u2013 south ridge of connectivity pattern in biogeography has been seen in other Sky Island arthropods (Scaphinotus petersi from Eastern and Western clades as well as closely related species in Arizona and New Mexico to further investigate the role geographic barriers have played in population isolation.The distribution of genetic diversity in thropods . Future Scaphinotus petersi grahami) is considerably older than the end of the last glacial period, perhaps indicating that this population was isolated during previous interglacial events in the Pliocene and persisted during Pleistocene glaciations. The western populations of Scaphinotus petersi petersi from the Pinals and Scaphinotus petersi biedermani from the Huachucas have more recent divergence times, indicating that these areas were more recently isolated, perhaps since the end of the last glacial maximum (LGM). It is important to note that the error bars for the time estimates of nodes are large, making it difficult to pinpoint with certainty divergence dates and the impact particular changes in climate have had on population isolation. Additional loci could reduce variation in estimated time to coalescence.PageBreakThe divergence time estimates suggested the Pinale\u00f1o population (Scaphinotus petersi could have evolved within the time span of the classical Wisconsin stage and Holocene. He hypothesized that during the pluvial stages of the Pleistocene, the montane coniferous forests occurred in the lowlands, probably along watercourses, and Scaphinotus petersi dispersal took place. In subsequent pluvial stages, range expansion of populations could have led to contact between previously isolated lineages. The results from our current molecular study are in concordance with this original hypothesis. During interglacial periods, contact between neighboring lineages of Scaphinotus petersi probably occurred in low elevation populations. These same populations were also probably the first to be extirpated during elevational shifts in habitat caused by post-glacial climate warming, leaving no signature of gene flow after the loss of these contact populations. Thus lineage boundaries like those between Scaphinotus petersi grahami in the Pinale\u00f1os and Scaphinotus petersi catalinae in the Santa Catalinas were maintained during glacial age population expansion and interglacial range retraction.Several studies have focused on the biogeography of species on the Arizona Sky Island region including plants, arthropods, birds, lizards, and mammals . Most ofScaphinotus petersi. Our results suggest Scaphinotus petersi populations experienced a significant fragmentation into distinct eastern and western populations separated by the San Pedro River much earlier than the last glacial period. More recently, probably after the LGM, the western populations became more fragmented in the Pinal, Santa Catalina, and Huachuca Mountains. Future work will include more populations of Scaphinotus petersi and closely related species from additional PageBreakmountain ranges, adding missing lineages. Additional nuclear genes will be included to provide a broader picture of genetic structure and a better estimate of divergence times. These efforts will help develop a general model for understanding the phylogeographic effects of climate change in Sky Island organisms.Both recent and more ancient global climate changes could be the causal mechanisms underlying the history of habitat fragmentation in"} +{"text": "The use of ovarian stimulation for infertility treatment is associated with side effects of ovarian hyperstimulation syndrome (OHSS) and potential cancer risk. This is also true in high risk women such as those polycystic with ovary (PCO) and polycystic ovarian syndrome (PCOS). In vitro maturation (IVM) of oocytes was primarily developed to make IVF safe for women with PCO and at high risk of OHSS. The application of IVM of oocytes to assist clinical infertility treatment remains poor because of the reduced developmental competence of oocytes after IVM, despite several decades of research. Reduced meiotic maturation and fertilization rates, as well as low blastocyst production reveal short-term developmental insufficiency of oocytes when compared with in vivo-matured counterparts. In this review, the structural role of human oocytes, revealed by different technical approaches, to the success of IVM technology is highlighted. Clinical aspects of In vitro maturationIn Vitro Fertilization (IVF) baby, there have been improvements in the pregnancy and birth rates with IVF. Improvements in the birth rates have been attributed to the advances in hormonal stimulation of patients with various controlled ovarian hyperstimulation (COH) protocols and improved in vitro culture systems for gametes and embryos and potential cancer risk. This is especially true in high risk women such as those polycystic with ovary (PCO) and polycystic ovarian syndrome (PCOS) . The recTherefore, IVM is more useful for women whom respond inappropriately to FSH stimulation, particularly women with PCOS who are extremely sensitive to ovarian stimulation and have a high potential for developing of OHSS . Also, fIn addition, hCG priming promotes some GV oocytes to reach the maturity and increases the IVM outcomes . DespiteLaboratory aspects of IVMCulture conditions employed for IVM of mammalian oocytes significantly influence fertilization rates and subsequent embryonic development . The curHowever, there is a paucity of information about the effects of culture medium on maturation and developmental competence of immature oocytes. TCM-199 buffered with bicarbonate or HEPES, supplemented with various sera, gonadotrophins and steroids have been widely used in clinical IVM studies. Different energy substrates and nutrients can greatly influence oocyte meiotic and cytoplasmic maturation , 12. ChiThe core of an assisted reproduction program is oocyte quality, because one of the major problems encountered by IVF clinics is to recognize the maturation state of the oocytes obtained from follicles. The cytoplasm of the oocyte is of key interest in oocyte maturation. The best way to improve embryo development is to harvest good quality oocytes. It is known that insufficient cytoplasmic maturation of the oocytes will fail to promote male pronuclear formation, and will increase chromosomal abnormalities after fertilization . The quaGood quality oocytes are exceedingly essential for fertilization, especially for successful IVM and subsequent IVF program, which are two major assisted reproductive technology (ART) programs. Routine evaluation of oocyte morphology by phase-contrast microscopy (PCM) is an important predictive marker of oocyte quality, currently utilized for evaluation of the success of a given ART program . However, low-resolution morphological assessment is not always a sufficient measure of oocyte fertility potential and developmental competence . On the If oocytes are removed before ovulation from an antral follicle, the separation triggers a pseudo-maturation event leading in general to the completion of the first meiotic division and the second arrest at the metaphase II stage. This was described in 1939 by Pincus . This pret al has demonstrated the importance of cGMP in the control of phosphodiesterase-3 involved in the crucial decrease of intra-oocyte cAMP and meiotic resumption of GV oocytes collected from stimulated cycles , 31. Howturation . They alturation . et al reported that immature oocytes derived from normal ovaries or women with PCO/ PCOS, when using hCG priming, have a similarly high potential for maturation, fertilization, and cleavage. They also recognized that mode of anesthesia used during oocyte retrieval may affect oocyte maturation rates were approximately similar to Ubalidi et al. They also reported that other defects, such as Bull\u2019s eye, thick ZP, SER and dark ZP were not observed in human oocytes matured under in vitro condition ..et al evAn oocyte that has not completed cytoplasmic maturation is of poor quality; thus unable to successfully complete normal developmental processes. However, the cellular mechanisms that impart oocyte developmental competence are entirely unclear. Until the mechanisms involved in oocyte quality are elucidated, any effort to use ART in the treatment of infertility will be inefficient at best . OocytesUltrastructure in IVMElectron microscopy techniques are the best tools to explore the cell fine structure, but involve important limitations. They rely on expensive technology and highly trained personnel. They can be hardly used for the analysis of large numbers of samples, being the process of specimen preparation and observation lengthy and almost entirely manual. In addition, the samples are fixed for ultra-observation. Regardless, they can provide accurate and extensive information on the fine structure of the cell and its organelles . IntraceIn one recent study, the human immature oocytes were cultured for 36h and investigated by TEM . The ultTEM also distinguishes morphological differences between apoptosis and necrosis . MorpholImmunocytochemical methodsVarious immunocytochemical methods for the evaluation of DNA division or GC proliferation have been established. The first identifies the expression of proliferating cell nuclear antigen (PCNA) in GC during culture . PCNA iset al suggested that changes in chromatin configuration in human oocytes vary with size. They established three oocyte size categories , with the largest oocyte size being associated with GVBD that provide information about the chromatin condensation stage of the oocyte nuclear staining. They found that 44% of their cases were viable following H/PI florescent staining (Escrich e oocyte . For assstaining 55)..et al reThe polarization microscopy has entered the realm of clinical ARTs and has become useful in assessments of oocyte quality for human embryo production . To gainHuman immature oocytes subjected to the IVM show good general and fine structural preservation. In particular, the absence of cytoplasmic vacuolization (form of cell damage) seems the most relevant marker of quality in IVM program. Taking into account the important clinical significance, researchers need to continue pursuing their studies until morphologically competence oocytes are obtained for use in IVM. Once, success of IVM is highlighted, the availability of this treatment will probably be demanded not only by PCO patients, but also by other infertile cases."} +{"text": "Imaging can play a role at different stages of Pompe disease. In most cases the clinical presentation and high CK level are very evocative and GAA activity testing is sufficient for the diagnosis. In some cases the clinical presentation is less typical and late onset or juvenile forms cannot be differentiated from limb girdle muscular dystrophies or congenital muscular dystrophies. In such cases previous descriptions of Whole body (WB) T1 weighted MRI images have shown very evocative patterns of most often affected or spared muscles. The most typically and frequently affected are tongue, scapulae fixators and especially sub-scapularis, trunk muscles like spine erectors, abdominal belt muscles and psoas. The most frequently spared are masticators, arm and forearms, and lower legs muscles.In most cases the disease is associated with complications like respiratory involvement and disabling muscle weakness. Imaging is not taken into account when considering treatment options. On the contrary, when the diagnosis is made after family screening or in patients with minor symptoms, the distribution and severity of muscles involvement established by WB MRI could influence the decision to treat. Stability over time or degradation could also impact this decision. MR description of initial distribution and progression of muscle involvement could also yield a better knowledge of the disease.Muscle biopsies are the best indicator of treatment efficacy but patient compliance could be very low if repeated follow-up biopsies were employed. Muscle imaging and especially MRI could offer the opportunity to quantify stability or progression of muscle involvement under therapy. To achieve this goal imaging has to be quantitative and not only qualitative. Quantification techniques can be developed to assess the amount of fat into muscles (DIXON) or to detect areas of muscle remodeling activity (T2 measurement). However WB MRI is useful to determine the areas where the quantification should be performed. In totally destroyed or spared muscles quantified imaging is not very pertinent. Other imaging modalities could also be used to detect regional fat increase. DEXA scanner is not only able to detect regional bone mineral density variations but also lean mass (muscles) and fat.Muscle imaging is not always the clue for the diagnosis but it can help for recognition of atypical clinical presentations, for understanding the natural history of the disease, for the determination of patients suited for treatment as a complement of other clinical and nonclinical parameters. Medical imaging techniques of quantification could help to analyze treatment efficacy."} +{"text": "Lophosteus, Andreolepis, Psarolepis and Guiyu) retained part of the primitive gnathostome pectoral girdle condition with spines and/or other dermal components. However, very little is known about the condition of the pelvic girdle in the earliest osteichthyans. Living osteichthyans, like chondrichthyans (cartilaginous fishes), have exclusively endoskeletal pelvic girdles, while dermal pelvic girdle components (plates and/or spines) have so far been found only in some extinct placoderms and acanthodians. Consequently, whether the pectoral and pelvic girdles are primitively similar in osteichthyans cannot be adequately evaluated, and phylogeny-based inferences regarding the primitive pelvic girdle condition in osteichthyans cannot be tested against available fossil evidence.The pectoral and pelvic girdles support paired fins and limbs, and have transformed significantly in the diversification of gnathostomes or jawed vertebrates . For instance, changes in the pectoral and pelvic girdles accompanied the transition of fins to limbs as some osteichthyans (a clade that contains the vast majority of vertebrates \u2013 bony fishes and tetrapods) ventured from aquatic to terrestrial environments. The fossil record shows that the pectoral girdles of early osteichthyans Kuanti Formation, Yunnan, as well as a re-examination of the previously described holotype. We also describe disarticulated pelvic girdles of Psarolepis romeri from the Lochkovian (Early Devonian) Xitun Formation, Yunnan, which resemble the previously reported pectoral girdles in having integrated dermal and endoskeletal components with polybasal fin articulation.Here we report the first discovery of spine-bearing dermal pelvic girdles in early osteichthyans, based on a new articulated specimen of The new findings reveal hitherto unknown similarity in pectoral and pelvic girdles among early osteichthyans, and provide critical information for studying the evolution of pelvic girdles in osteichthyans and other gnathostomes. AcanthodesThe gnathostomes or jawed vertebrates comprise the extant osteichthyans (bony fishes and tetrapods) and chondrichthyans (cartilaginous fishes) along with the extinct placoderms and acanthodians Guiyu oneirosPsarolepis romeriGuiyu and Psarolepis have been placed as stem sarcopterygians in earlier studies Guiyu was first described Guiyu provided strong corroboration for the attempted restoration of Psarolepis romeriGuiyu and Psarolepis features across different groups poses special challenges to attempts at polarizing the plesiomorphic osteichthyan and gnathostome characters and reconstructing osteichthyan morphotype Psarolepis, either as a stem sarcopterygian or as a stem osteichthyan. Basden et al. Psarolepis is more likely a stem sarcopterygian based on the comparison of braincase morphology with an actinopterygian-like osteichthyan Ligulalepis. The phylogenetic analysis in Zhu et al. Guiyu in a cluster with Psarolepis and AchoaniaMeemanniaLigulalepisAndreolepisLophosteusAs the first known occurrence in any osteichthyans, here we describe pelvic girdles with substantial dermal components (plates and spines) in two early bony fishes, Guiyu and Psarolepis have advanced our understanding of early osteichthyan morphologies beyond what was previously known from Andreolepis, LophosteusLigulalepisDialipinaGuiyu oneiros was collected from the Late Ludlow (Silurian) Kuanti Formation, Yunnan, China. Observations of this new specimen, re-examination of the holotype of Guiyu oneiros, and studies of previously unidentified disarticulated specimens of Psarolepis form the basis for the finding reported below. As the first evidence for the presence of dermal pelvic girdles in osteichthyans, the pelvic girdles in Guiyu and Psarolepis reveal an unexpected morphology that stands in stark contrast to the inferences from published phylogenetic analyses , while the disarticulated specimens of Psarolepis romeri came from the muddy limestone of the Xitun Formation in Qujing, Yunnan, China The specimens are housed at the Institute of Vertebrate Paleontology and Paleoanthropology (IVPP), Chinese Academy of Sciences. The fossil blocks containing the new articulated specimen of Guiyu with PsarolepisPsarolepis (either a stem sarcopterygian or a stem osteichthyan) as our working hypotheses The phylogenetic framework for this study is based on the trees in Zhu et al. Guiyu oneiros had a polybasal pelvic fin articulation, a condition already established in the pectoral fin articulation In posterior view, the fossa from which the pelvic fin originated is dissected by a horizontal articular crest carrying at least two well defined facets of similar size art.pf, . This suGuiyu oneirosPsarolepis romeriThe pelvic girdles of The pelvic girdle finding lengthens the list of observable similarities between placoderms and osteichthyans Murrindalaspis, Guiyu and Psarolepis (when regarded as stem osteichthyans) can be reasonably explained as a retained primitive feature of gnathostome pelvic girdles (with the assumption of independent loss in chondrichthyans). Similarly, polybasal pelvic fin articulation (observable in Psarolepis) can be assumed to be a primitive gnathostome feature based on its distribution in placoderms, chondrichthyans and actinopterygians Guiyu and Psarolepis, with integrated endoskeletal and dermal components, a retention of the plesiomorphic condition for gnathostomes. For the pectoral girdle, this is the most parsimonious interpretation of the less incongruent distribution of pectoral spines and/or other dermal elements in some placoderms, acanthodians and even chondrichthyans Acanthodes (and the other acanthodids) as stem osteichthyans Guiyu and Psarolepis is an apomorphic reversal to the plesiomorphy.Among non-osteichthyan gnathostomes, dermal elements related to the pelvic girdle exist only in some acanthodians (i.e. pelvic spines) and some placoderms Guiyu and Psarolepis are stem osteichthyans. Guiyu and Psarolepis possess three of the features listed by Friedman and Brazeau Guiyu and Psarolepis described here, it is not inconceivable that Guiyu and Psarolepis will join other early osteichthyans in populating the most crownward portion of the osteichthyan stem group (position II in Friedman and Brazeau"} +{"text": "The involvement of spinal column reportedly occurs in less than 1% of all tuberculosis (TB) patients. Spinal TB is a very dangerous type of skeletal TB as it can be associated with neurologic deficit because of compression of adjacent neural structures and significant spinal deformity. Therefore, the early diagnosis and management of spinal TB has special importance to prevent these serious complications. Therefore, the present study was aimed at conducting a comprehensive narrative review and analysis of all the papers available for us published during 1990 to 2011 to extract current trends in diagnosis and medical or surgical treatment of spinal TB. Although the development of more accurate imaging modalities such as magnetic resonance imaging (MRI) and advanced surgical techniques have made the early diagnosis and management of spinal TB much easier, these are still very challenging topics. In this review we aimed to discuss diagnosis and management of spinal TB based on the studies with acceptable design, clearly explained results and justifiable conclusions.Spinal tuberculosis, Diagnosis, Treatment"} +{"text": "The current study examines the relationship between bV and body size within species with a focus on the frugivorous Varecia rubra and the folivorous Propithecus coquereli. We found no overlap in bV between the species , and least-squares regression of bV and three different measures of body mass showed no scaling relationship within each species. We believe that this lack of relationship results from the relatively narrow intraspecific body size variation and seemingly patternless individual variation in bV within species and take this study as further evidence that general scaling questions are best examined interspecifically rather than intraspecifically.In a recent study, we quantified the scaling of ingested food size ( The amount of food processed per day must meet an animal's metabolic requirements. However, while most features of the chewing system (teeth and jaw muscles) scale in proportion to body size e.g., \u20133), meta, meta3])bV; ) One implication of these results is that any broad interspecific comparison relating to the primate masticatory system should be conducted so as to maximize intraspecific sample sizes. This is extremely difficult when attempting to study rare and potentially endangered animals such as primates. However, the wide and patternless variation within a species provides a strong incentive to pool resources between investigators in order to increase total sample sizes. bV) against body mass in a taxonomically diverse sample disappear when the focus sharpens to the intraspecific, at least within these two species. The bV values between the two populations examined in this study differ greatly between species; here, there is no overlap in bV for any of the three foods examined in this study. However, no statistically significant scaling patterns exist within the species regardless of the body size measurement used. In future studies of masticatory anatomy, especially those examining bV, we recommend examination of broad interspecific samples that span wide body size ranges and that include large sample sizes for each species. Perhaps we are observing a difference in how selection acts on variation between species versus between individuals; perhaps we are observing differences between evolutionary and developmental or structural constraints on the masticatory system, and/or perhaps we are observing an effect of captivity that manifests more strongly at the intraspecific level. Much more work is needed before we can fairly evaluate these possibilities. The scaling patterns so clearly visible when regressing maximum ingested food sizes ("} +{"text": "Antiretroviral treatment (ART) has dramatically changed the lives of people living with HIV/AIDS. Until recently and despite the benefits of antiretroviral therapy, people living within HIV still expressed their fears about treatment side-effects and about possible HIV transmission.Accumulated evidence demonstrating the potent role of antiretroviral therapy in decreasing HIV transmission together with the availability of new generations of antiretroviral drugs with improved efficacy and tolerability has led to most HIV community leaders in France changing their attitudes in favor of adopting the \"test and treat\" approach. This change is also shared among leaders of HIV community-based associations in French speaking Africa. However, such an approach will not be possible without major changes in HIV policies. More than simply providing treatment availability it requiresi. a global policy against HIV discrimination and against HIV stigma in order to facilitate access to testing and treatment,ii. the involvement and empowerment of those communities most concerned by HIViii. strong political leadership to both change the representation of HIV/AIDS in the general public and to implement innovative funding mechanisms.It also implies the development of a strong international HIV policy for universal access to HIV care and prevention including respect of human rights, especially of sexual minorities, migrants and drug users. Today, the \"test and treat\" approach represents an important tool in curbing the HIV epidemic not only because it pushes political leaders to give top priority to HIV on their political agendas but also because it influences HIV policies which in turn encourage civil society to become directly involved in doing \"with people\" and not \"for people\"."} +{"text": "While integrated primary healthcare for the management of depression has been well researched, appropriate models of primary care for people with severe and persistent psychotic disorders are poorly understood. In 2010 the NSW Health Department commissioned a review of the evidence on \"shared care\" models of ambulatory mental health services. This focussed on critical factors in the implementation of these models in clinical practice, with a view to providing policy direction. The review excluded evidence about dementia, substance use and personality disorders.A rapid review involving a search for systematic reviews on The Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects (DARE). This was followed by a search for papers published since these systematic reviews on Medline and supplemented by limited iterative searching from reference lists.Shared care trials report improved mental and physical health outcomes in some clinical settings with improved social function, self management skills, service acceptability and reduced hospitalisation. Other benefits include improved access to specialist care, better engagement with and acceptability of mental health services. Limited economic evaluation shows significant set up costs, reduced patient costs and service savings often realised by other providers. Nevertheless these findings are not evident across all clinical groups. Gains require substantial cross-organisational commitment, carefully designed and consistently delivered interventions, with attention to staff selection, training and supervision. Effective models incorporated linkages across various service levels, clinical monitoring within agreed treatment protocols, improved continuity and comprehensiveness of services.\"Shared Care\" models of mental health service delivery require attention to multiple levels , and complex service re-design. Re-evaluation of the roles of specialist mental health staff is a critical requirement. As expected, no one model of \"shared\" care fits diverse clinical groups. On the basis of the available evidence, we recommended a local trial that examined the process of implementation of core principles of shared care within primary care and specialist mental health clinical services. In 2008 the New South Wales Government's Mental Health Sentinel Events Committee published its fourth report which concluded: \"a definitive set of best practice standards to guide the development and implementation of shared care for mental health consumers is lacking\" . This CoThe authors were contracted to conduct the review. This included negotiation of the research questions, presentation of preliminary scoping, draft and revised final reports. Questions and clarification were addressed via consultation involving all parties throughout the process. This form of knowledge exchange has been described as \"the problem solving, policy driven model\" but it might equally operate through a process of enlightenment by which evidence and ideas permeate the policy making system . Rapid rThere is increasing recognition that improving the detection, treatment and outcomes for mental health problems requires service models that integrate mental health care within primary health care practice . While mThe rapid review was undertaken to investigate the evidence underpinning \"shared care\" in ambulatory mental health care. The focus related mainly to adults with severe and persistent mental disorders. Evidence regarding treatment models for a broader range of conditions was outside the scope of this review.The review addressed the following questions:1. Does \"Shared Care\" improve clinical outcomes for people with mental illness?2. If so, what are the proposed ingredients of an effective \"Shared Care\" program?The latter required hypothesising a proposed set of such ingredients based on a synthesis of the literature.The research team comprised a psychiatrist with research, clinical and teaching responsibilities, a nursing academic with research and clinical experience in mental health services, a health systems researcher specialising in mental health and primary health care and an information scientist with mental health nursing experience. The group had recently completed a 12 month narrative review of effective service linkages in primary mental health care were famShared care covers a broad spectrum of collaborative treatment arrangements and there is no standard definition in the literature ,12. For A structured system for achieving integration of care across multiple autonomous providers and services [with both primary and secondary care practitioners contributing to elements of a patient's overall package of care [Shared care involves some agreement about the shared activities and levels of responsibility for each provider and appropriate communication processes to support this integration. A shared care arrangement may involve any combination of government, non-government or private sector providers.services with both of care . Shared As a rapid review, the initial step was to identify systematic reviews and examine their relevance. This was followed by a search for papers published subsequent to these systematic reviews as well as iterative searching from reference lists for any outstanding published works. The search for systematic reviews was conducted in the Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects (DARE) 2004-2010). A comprehensive search strategy was developed and applied to Medline . This stA meta-analysis of interventions targeting improved communication strategies between primary care providers and specialists (representing a model of \"shared care\" for the purposes of our review) by Foy found moTwo large US trials on collaborative care for depression (IMPACT and PRISM-E) also reported results for subgroups from ethnic minorities ,41 with There were fewer published papers about the benefits of \"shared care\" for severe and persistent mental disorders (e.g. schizophrenia) and very little work about service links outside the health sector with welfare, housing, education, or employment.Despite a high need for health and social services for people with such persistent psychotic disorders, Fuller found onStudies of Assertive Community Treatment (ACT) ,47,48, fTwo studies of supported housing and mental health follow up using ACT principles for people with persistent and severe mental illness reported improved quality of life, better physical health, higher satisfaction and improvements in housing stability and perhaps because of this, improved treatment engagement ,27We found no evidence of programs reporting adverse clinical outcomes.On the basis of the existing studies, a major focus of this review was the inductive process to propose or hypothesise a set of \"core ingredients\" that comprise effective shared care, providing a base to inform future service development projects.process of service change required to achieve these outcomes.It was evident that models of shared care varied in complexity reflecting the target population, the structure and organisation of the health services in which they were located, and other local factors . Shared In general, effective collaborations were found to use multi-component strategies that reflected the following: i) the chronic and complex nature of many mental health problems, ii) the need to improve access to and engagement in treatments , iii) the need to improve treatment adherence and continuation through care coordination, facilitation and monitoring and iv) Based on a synthesis of these findings, the following discussion proposes specific elements of effective shared care services while acknowledging this complexity and the overlap of these elements.Studies demonstrating improved outcomes for depression and anxiety using \"shared care\" in primary care have usually been well articulated clinical treatment models within an established theoretical framework such as Problem-Solving Therapy .The evidIn contrast, studies of persistent and severe mental disorders such as schizophrenia have often entailed service brokerage and linkage interventions with less emphasis on particular therapeutic strategies or clearly articulated service models. Rather, they focus on the process and organisational aspects of care and ensuring engagement and communication across service sectors, such as housing, employment, hospital and community-based care . StudiesFuller found thWhile some studies suggest outcomes are better when care coordination is provided by mental health trained practitioners others fWhile the need to increase the supply of mental health professionals is widely accepted, in some instances evidence suggests that efficient and effective use of specialists can support integrated delivery of care within primary health care sector. Improving the confidence, capacity and engagement of primary care clinicians in mental health care does however require attention to their support, training and supervision and to the attitudinal barriers to mental health service provision . JointlyButler noted thRole clarity is an important component of collaborative development and sustainability ,66. YaffShared governance arrangements between primary care and specialist services were found to support faithful application of evidence-based shared care models [Butler noted that overcoming local organisational and cultural barriers requires strong leadership to champion change .Shared ge models ,68,69. Se models ,70, and e models ,39,50,52e models ,57,71-73The ACCESS trial found that mental health and human services that received direct funding and technical support achieved better integration , while BIn most studies the research provided additional staffing and organisational infrastructure that was \"grafted\" onto existing services, with some service re-orientation. However, some small effectiveness trials did provide a more robust \"bridge\" to routine practice by utilising existing staff and resources ,53 such Physical infrastructure was also important. The provision of co-located accommodation was an enabler of collaboration, when mental health care managers were located in the primary care clinic enabling optimum team visibility and interaction , but a bthe most important factor, cited in four of the five sites, was the ability to document positive client outcomes from the research study\". Mechanisms to feedback evidence of outcomes to team staff seems to have been a key contributor to developing and sustaining service collaboration in this study, however the value of this process was not reported more widely in the other reviewed studies.In the IMPACT study ,71\"the m\"Shared Care\" between specialist and generalist services has been a major focus of mental health service reforms. The purpose of this rapid review was to examine published evidence about models of shared care in mental health with specific attention to the core ingredients and processes necessary to support effective shared care models. The available evidence suggests that models of \"shared care\" between primary health services and specialist mental health service can lead to improved clinical outcomes in some clinical groups, such as depression and anxiety disorders. There is a small amount of evidence that shared care can provide better outcomes for people with psychoses and related disorders, such as reduced relapse rates. The complexity of the systems of care necessary for people with these disorders, may explain the limited evidence for shared care in this setting.The literature to date has used inconsistent definition of shared care; hence it is not surprising that it is difficult to distil core elements of effective care from existing studies. Furthermore the majority of the evidence is drawn from studies addressing depression and anxiety. There is less evidence regarding shared care in severe and persistent mental disorders and we cannot readily assume that models developed for the former will work with the latter.On the basis of this rapid review we deduced a number of core ingredients of effective shared care models. These comprise provision of collaborative care in a coherent, evidence-based clinical management framework with:i) A systematic approach to the engagement of primary and specialist services towards the common goal of improved mental health careii) A coherent treatment model relating to the target condition/s or patient population,iii) An agreed clinical pathway and monitoring of patient outcomes with the provision of case review by specialist personnel when needediv) Attention to staffing requirements and the provision of clinical supervision to support skill development and maintenance of treatment model ,53.v) A well-established clinical governance framework.In studies of shared care for people with persistent and severe mental disorders, a common element was the provision a care coordinator acting as a link between primary care and specialist mental health services.A broader issue is the challenge of the translation of evidence into clinical practice. The gap between evidence-based care and clinical practice is widely acknowledged. While many studies demonstrate the benefits of multi-component interventions for patient outcomes, service use and cost, there is less evidence about the successful implementation of such models into routine care. Changing clinician behaviour and maintaining systems that support and promote such changes is believed to be key to the implementation of new models of care . The \"voThere are a number of important limitations to this review. A number of compromises to standard methods for systematic review were made. The shortened timescale did not permit activities to be undertaken sequentially and so activities overlapped and material was analysed as it became available. We were only able to examine a small selection of local grey literature. Particular importance was placed on published systematic reviews and the search focussed on key questions that were not addressed in those reviews, chiefly shared care for those with severe and persistent mental disorders. Despite these limitations we attempted to ensure high standards of replicability and transparency through defined inclusion and exclusion criteria as detaiIt was not possible to undertake meta-analytic evaluation of the strength of evidence as studies investigated complex interventions, with varying levels of attention to the methodological and statistical issues . Second,From many angles, it is imperative to improve the links between primary care and specialist mental health services. When joint primary and specialist level collaborative care models have been evaluated using RCT designs, a range of clinical and service benefits are reported, particularly in the primary care management of depression and anxiety disorders.The available evidence provides only limited support for shared care models for the treatment of persistent psychotic disorders. While a few robust and innovative studies have been undertaken with this population further studies are needed, including research that encompasses diverse geographic and health service contexts.Some core components of shared care warrant further targeted research . Demonstration projects with detailed and innovative evaluative designs are needed to understand better these core elements and the processes that underpin effective shared care, particularly their capacity to be translated to routine clinical practice.The strategies proposed in this review pose substantial implementation challenges for any health service, yet are critical to ensuring that shared care services are better structured to achieve sustained improvements in mental health care.The authors declare that they have no competing interests.BK led the preparation of the manuscript, participated in review of studies, collation and interpretation of findings. DP contributed to the manuscript, led the project team, and participated in review of studies, collation and interpretation of findings. JF contributed to the manuscript, participated in the review of studies, collation and interpretation of findings. SP designed the search strategy and conducted the literature searches, was responsible for data extraction and data management. She contributed to the interpretation of the findings and the drafting of the manuscript.All of the listed authors have read and approved the final manuscript.Search Strategy for Medline. Detail of comprehensive search strategy for this review.Click here for fileExclusion and Inclusion Criteria. Detail of specific criteria for papers included in this search.Click here for file"} +{"text": "The success of endodontic treatment is not only measured by the alleviation of pain and formation of healthy bone, replacing the diseased periapical tissue. Concepts for restoring pulpless teeth have been formed more from clinical observation than valid scientific investigation. Endodontically treated posterior teeth present numerous problems because of coronal destruction from dental caries, fractures, and previous restorations or endodontic techniques. The result is loss of tooth structure and a reduction in the capacity of the tooth to resist a myriad of intraoral forces. A summary of this review article suggests that coronal coverage significantly improves the clinical success rate of endodontically treated posterior teeth. Whether full cast crowns, especially in posterior teeth, are really mandatory or not after endodontic treatment has been a subject of debate for sometime now. The literature has a lot of contradictory reviews regarding this issue; while some clinicians maintain that endodontic treatment in posterior teeth should be considered complete only when the tooth is protected by full cast crown, others are convinced that all endodontically treated teeth do not require full cast crown protection, and it should be considered only in certain specific cases where the caries destruction and tooth structure loss has been extensive.Most clinicians, however, do agree that endodontically treated teeth become brittle after sometime because of the physical changes in the dentine of pulpless teeth, which reduce its toughness. More recently it has been recognized that the key change is the loss of structural tissue from tooth, which is capable of holding the tooth together under functional load. This is specially so for posterior teeth where wedging force comes into play more than in other segment of oral cavity.et al. in 1991 compared the physical and mechanical properties of dentine specimens from teeth with and without endodontic treatment at different levels of hydration. They concluded that neither dehydration nor endodontic treatment caused dehydration of the physical or mechanical properties of dentin.[Several studies have proposed that the dentin in endodontically treated teeth is substantially different than dentin in vital teeth.\u20133 It was4f dentin.These studies support the interpretation that it is the loss of structural integrity associated with the access preparation, rather than changes in the dentin, that lead to higher occurrence of fractures in endodontically treated teeth compared with vital teeth. Access p7Dentin microhardness and elasticity varies between peritubular and intertubular dentin. Hardness also changes from dentinoenamel junction to mental dentin. Products used for root canal irrigation and disinfection interact with mineral and organic contents and significantly reduce dentin modulus of elasticity,11 as welMany chemical treatments can modify biological substrates and make them vulnerable to bacterial adherence or susceptible to degradation. Microbial induced degradation or modification of collagen can cause deterioration of the mechanical properties such as strength and toughness of dentin, thus weakening the tooth structure. Keeping in view the significant contribution of collagen microstructure to the toughening mechanisms in the dentin, bacteria-induced degradation of the collagen substrate may be a significant potential secondary cause of fracture predilection in endodontically treated teeth.The major change in the tooth biomechanics is due to loss of tissue following caries lesion, fracture, or cavity preparation, including the access cavity preparation during endodontic treatment. The loss of tooth structure during conservative access cavity preparation affects tooth stiffness by only 5%, and the influence of subsequent canal instrumentation and obturation lead to reduction in the resistance to fracture. The largOne of the criteria\u2019s of success in endodontics has to be the longevity of the treated tooth in asymptomatic and functional state in the oral cavity. The retrospective study done by Sorensen and Martinoff showed that in 1273 teeth endodontic treatment was done 1\u201325 years before the study. EndodontThis same study found a et al.[Grimaldi discusseet al. indicateet al.[Mentink et al. reportedOne of the most widely quoted series of studies on endodontically treated teeth evaluated the effect of tooth location, coronal coverage, and intracoronal reinforcement on the success of 1273 root canal treated teeth over an observation period of 1\u201325 years.24 FailurAlthough the results of these studies have been questioned due to a lack of controlled clinical procedures and of generalizability,26 they h27Other forms of coronal coverage, including gold, ceramic, or resin composite onlays, and cusp-covering silver amalgam restorations may also provide root canal treated teeth with protection against fracture. Starr advocateSmales and Hawthorne, however,Steven compared the survival relationship between the root canal treated posterior teeth with and without crown placement. He concluded that coronal coverage with full cast crown reduced the risk of tooth fracture. They also reported that endodontically treated teeth with crowns had a survival rate six times greater than that of teeth without crowns.Cuspal coverage restorations appear to grant higher longevity to posterior teeth with root canal treatment; according to some recent studies, bonded restoration thought to preclude the need for cuspal coverage in such teeth might provide a short-term strengthening.33et al. evaluated endodontically treated premolars that had been restored (both with and without complete coverage) by either a post or direct composite resin restorations and reported similar success rates for both.[Conversely, Mannocci for both. A similafor both. Conversefor both.Although treatment recommendations should be made on an individual basis, the association between crowns and the survival of root canal treated teeth should be recognized during the treatment planning if long-term tooth survival is the primary criteria for success in endodontics. Root canal treated posterior teeth without crowns are lost at a much higher rate than teeth supported with full cast crowns. The risk involved in losing the endodontically treated posterior teeth to fracture if not supported by full cast crown is too high to take. To help reinforce the cusps of pulpless teeth weakened by tooth structure removal, the authors recommend the use of crown that encompasses the cusps to withstand the occlusal forces of everyday mastication.Clinically we have observed over a period of 25 years that root canal treated posterior teeth, irrespective of the amount of tooth structure lost either by caries or access cavity preparation, mostly fracture if not protected by full cast crowns. It is only a matter of time."} +{"text": "Merkel cell carcinoma (MCC) is an uncommon neuroendocrine malignancy with a propensity for the head and neck. It typically presents asymptomatically in elderly Caucasians and is characterized by early local and regional spread. There is currently limited data on the appropriate algorithm for treatment of MCC. However, multimodal therapy with wide surgical excision with or without radiation therapy has become standard of care. The location of the primary tumor and intensive adjuvant therapy is often required, provides a challenge to the reconstructive head and neck surgeon. Occasionally, free tissue transfer reconstructive techniques are employed in the reconstruction of MCC defects. This paper will discuss the role of free tissue transfer as a reconstructive option after surgery for advanced head and neck MCC. Merkel cell carcinoma, originally described by Toker in 1972 \u20135. PatieSurgery is the current standard for locoregional disease and has been shown to confer a survival benefit in MCC \u201314. Howe Frequently, adjuvant radiotherapy is employed in the management of advanced MCC. Large extensive lesions at risk for local recurrence should be considered for postoperative radiotherapy regardless of surgical margin status. There is data suggesting radiotherapy in addition to Mohs surgery results in improved locoregional control when compared to Mohs surgery alone . Primary At present, the recommendation for management of lymph node disease in MCC depends on clinical presentation. For clinically significant lymph node extension cervical lymphadenectomy or therapeutic radiation therapy is indicated after histological confirmation , 14. TheFor the majority of surgical defects in the region of the head and neck, locoregional reconstruction with skin grafting or local flaps is functionally and aesthetically adequate. A comprehensive review of factors, which influence the reconstructive approach, is beyond the scope of this paper and will be reviewed elsewhere in the special issue. The extent of disease, viability and quality of surrounding tissue, involvement of the adjacent structures, and history of prior surgery or radiation therapy can make locoregional reconstruction less appealing or impossible. Given the importance of negative surgical margins in MCC, the oncologic surgeon must consider the implications of the risk of local recurrence and consider the propensity for multiple synchronous tumors as well as immune system dysfunction in elderly patients with extensive disease. In these situations, conservative surgery may not be possible, resulting in significant ablative defects of the head and neck. In these situations, free tissue transfer can provide large volume, healthy tissue for reconstruction of the surgical defect, with favorable aesthetic and functional outcomes. The increased application of microsurgical reconstruction has resulted in several options for free tissue transfer for soft tissue defects of the head and neck. The anterolateral thigh (ALT) flap, latissimus dorsi, rectus abdominis, scapula/parascapular, and radial forearm flap (RFFF), have been employed for soft tissue reconstruction of extensive defects . A varieThe ALT flap has become a popular reconstructive option for surgical defects within the head and neck. It is easily harvested via a two-team approach, with low donor site morbidity and provides a large softtissue volume, a long and reliable vascular pedicle. The ALT offers the option for dynamic facial nerve reconstruction via motor nerve to the vastus lateralis. The pedicle length limits the necessity for venous grafting and allows microsurgical anastomosis of vessels to occur some distance from the defect , 22. TheThe latissimus dorsi flap has found use predominantly in reconstruction of scalp defects, especially those with exposed calvarium. It is harvested easily, provides a large surface area with excellent muscle volume and thickness. Donor site morbidity is well tolerated in most patients . AtrophyFor smaller defects requiring thin and pliable tissue, the radial forearm free flap is preferred. Primarily a fasciocutaneous flap is ideally suited to smaller defects with complex contours where it is desirable to avoid excessive bulk. The reliable pedicle length and predictability of harvest make the radial forearm free flap a commonly utilized reconstructive technique for cutaneous defects of the head and neck. In cases with vessel-depleted necks where veins are unavailable, a semifree radial forearm harvest has been described dissecting the cephalic vein proximally and performing a single arterial anastomosis, which is unique to this flap . Donor sThe rectus abdominis flap has been used for head and neck reconstruction for cutaneous malignancies and offers the advantage of well-vascularized muscle and large amounts of soft tissue available for reconstruction. When large amounts of muscles are harvested, donor site morbidity is increased and therefore, it is our opinion that other free tissue donor sites offer several advantages over the rectus abdominis flap in the majority of cases. Muscle sparing perforator style flaps may allow for decreased morbidity and superior control of flap thickness, and the deep inferior epigastria artery-based flaps have been shown to be a valid reliable option for head and neck reconstruction .The scapular/parascapular flap also has excellent contour and color matching with the forehead and scalp and can typically be closed primarily after harvest with very little donor site morbidity , 27. HarMerkel cell carcinoma presents frequently on the face and the propensity for vertical invasion often puts the facial nerve at risk. Therefore, there is potential for facial nerve injury secondary to extension of the primary tumor and/or surgical excision for adequate margins . Facial Reconstruction after wide excision of MCC offers several unique challenges including a propensity for elderly patients with poor tissue quality and decreased immune function, large defects and a high probability of disease recurrence, and the risks inherent to adjuvant radiotherapy. For this reason, most reconstructive surgeons favor free tissue transfer as a modality for providing healthy, uninvolved tissue with an acceptable aesthetic outcome. There is clearly a need for higher quality of data in the area, as significant questions remain for the treatment for Merkel cell cancer, as well as the reconstructive methods utilized after ablative surgery. Recently, data has been published suggesting that wide surgical margins during tumor resection may not impact overall survival in patients receiving adjuvant radiotherapy . This is"} +{"text": "Penetrating cardiac injuries pose difficult and technical challenges for both trauma surgeons and trauma centres as well as incurring high mortality.For patients arriving in cardiopulmonary arrest, emergency department thoracotomy is indicated. For those patients arriving stable enough to be transported to the operating room, median sternotomy is the incision of choice. Penetrating injuries to the heart will inevitably cause bleeding of the myocardium, mandating repair to prevent cardiac tamponade. Suture repair of a cardiac laceration is usually carried out with simple interrupted or horizontal mattress sutures but this is quite challenging in beating hearts. At times, rapid manipulation and elevation of the heart during repair results in complex dysrhythmias and even cardiac arrest.In selected cases where the cardiac injury is located in areas difficult to repair , the use of a cardiac stabilisation device with adjustable footplates such as the epRetract\u2122 II epicardial retracting stabiliser (Chase Medical, Richardson, TX, US; We recommend the selective consideration and use of this device as an adjunct for suture repair in cases where minimising cardiac manipulation is advantageous."} +{"text": "Reconstruction of intraoral soft tissue defects is important in restoring function and esthetic. In large defects, there will be demand for regional pedicle flaps or free flaps. Hard palate separates nasal and oral cavities. Due to the small surface area between flap and remaining palate after surgical resections, optimal blood supply of the flaps for hard palate reconstructions are needed. This article demonstrates immediate reconstruction of two edentulous hemimaxillectomy patients with submental artery Island flap and brief review of this flap discussed. Submental Artery Island flap is an effective and reliable method for intraoral reconstruction of large soft tissue defects of oral cavity. Donor site morbidity is low and remaining scar is inconspicuous. Head and neck surgeons familiar with facial artery and its branching pattern make this flap an appropriate choice for clinical practice. Oral soft tissue reconstruction is important in restoring function, esthetic, and elevating quality of life after surgical resections of malignant oral cavity lesions. In large defects pediculated regional flaps or free flaps are needed .Huge maxReconstruction of maxillary defects that includes alveolar processes and hard palate is difficult. Just periphery of the flap is in contact with bed, therefore, most of the blood supply depends on feeding vessels of the flap Then, and the diffusion from recipient bed has little role. Submental artery island flap is an effective way to solve this problem. Large skin paddle, its axial pattern blood supply, low morbidity of donor site, and vicinity with oral cavity are among advantages of this flap.General features of two edentulous patients with large verrucous carcinoma of palate are listed .Case1: A 72-year-old man with a large exophytic, papillary mass of the alveolar ridge referred to the Ghaem hospital or previous neck dissection.In malignant oral lesions that do not need neck dissection like verrocous carcinoma or sarcomas this flap is very useful . SupraomSince the hairy nature of this flap is troublesome in intraoral reconstructions in male patients, secondary revision after 6 weeks is required . DespiteIn Uppin research, 14 out of 20 patients were males, in Multinu article 8/12 and in Sebastian article 19/30 Submental Artery Island flaps were used in male patients for orofacial reconstruction -15. ViciThe technique is relatively simple and reproducible. Short length of hospital stay is another advantage of this flap. It has minimal donor site morbidity. Temporary or permanent palsy of marginal mandibular nerve is a possible complication of this flap.It is important to provide fixation of submental flap to the remaining palate to protect and prevent possible dehiscence of flap interface or total detachment of submental flap from reconstructed palate. This study solve this problem by securing submental flap to remaining palate by bone sutures.Submental Artery Island flap is an effective and reliable method for intraoral reconstruction of large soft tissue defects of oral cavity. Donor site morbidity is low and remaining scar is inconspicuous. Head and neck surgeons familiar with facial artery and its branching pattern make this flap an appropriate choice for clinical practice."} +{"text": "Over the last two decades, age-related anatomical and functional brain changes have been characterized by evidence acquired primarily by means of non-invasive functional neuroimaging. These functional changes are believed to favor positive reorganization driven by adaptations to system changes as compensation for cognitive decline. These functional modifications have been linked to residual brain plasticity mechanisms, suggesting that all areas of the brain remain plastic during physiological and pathological aging. A technique that can be used to investigate changes in physiological and pathological aging is non-invasive brain stimulation (NIBS). The present paper reviews studies that have applied NIBS in younger and older adults and in patients with dementia to track changes in the cerebral areas involved in a language task (naming). The results of this research suggest that the left frontal and temporal areas are crucial during naming. Moreover, it is suggested that in older adults and patients with dementia, the right prefrontal cortex is also engaged during naming tasks, and naming performance correlates with age and/or the degree of the pathological process. Potential theories underlying the bilateral involvement of the prefrontal cortex are discussed, and the relationship between the bilateral engagement of the prefrontal cortex and the age or degree of pathology is explored. Progress regarding the study of physiological and pathological brain aging achieved over the last two decades has provided strong evidence of neurophysiological correlates of cognitive and behavioral changes associated with aging.One of the primary areas of investigation in neuroscience is For example, studies at the neuronal level have demonstrated that dopaminergic decline and gray matter atrophy are both correlated with specific cognitive changes in older adults Brody, . In addiBased on evidence primarily acquired via non-invasive functional neuroimaging, four principal hypotheses have been postulated to explain the relationship between age-related neuronal activity changes and cognitive performance \u2009 =\u20098.052, p\u2009 =\u20090.0003]. Post hoc analyses (Bonferroni) were conducted. As shown in Figure p\u2009 =\u20090.000004), with a minor and insignificant decrease (p\u2009 =\u20090.08) in object naming performance compared to older adults. Finally, AD patients in the advanced stages of cognitive decline (severe) also demonstrated a drastic decrease in object naming accuracy . To investigate the possible effects of participant characteristics on naming performance, we performed a correlational analysis between age and naming abilities in all four groups, and we performed a similar analysis between mini mental state examination and naming abilities in older participants and AD patients. Significant correlations between age and both object and action naming abilities indicate a progressive decrease of naming abilities during aging. Furthermore, the significant correlations between mini mental state examination and both object and action naming accuracies indicate that a progressive decrease of naming abilities is linked to cognitive deterioration . NIBS approaches aim to induce changes in brain activity, which can lead to a wide range of behavioral alterations in naming tasks has also been evaluated. Cappa et al. reportedFunctional neuroimaging studies have revealed that older adults tend to recruit regions of the contralateral hemisphere in addition to regions of the specialized hemisphere when performing cognitive tasks in all types of individuals who experience naming difficulties.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The scientific studies of dendritic spines have experienced an overwhelming growth in the last three decades. Since the primary concept that dendritic spines are sites of excitatory synaptic contact, the most recent studies have led to theoretical proposals that relate spines' morphophysiology with the information processing that underlies cognition. Furthermore, some specific spine shapes have been related to specific components of cognitive process, such as acquisition of information (learning) or long-term information retention (memory).Dendritic spines are highly dynamic structures. In fact, their structural modifications occurring under specific conditions are strongly related to synaptic plasticity which underlies cognitive flexibility. This provides the ability to create a mnemonic trace that defines the individual experience and allows making useful decisions under different circumstances.Contributions to this special issue provide some theoretical and experimental evidence related to the dendritic spine and synapse plasticity underlying mnemonic activity, as well as modulatory mechanisms involved in it. Although the data discussed in this special issue deal mainly with the findings derived from the animal research, it is clear, however, that these experimental results can lead to the clinical approaches concerning a wide variety of neuro-psychopathological conditions in humans.The mechanisms that regulate spine and synapse morphology and function are characterized by the remarkable complexity. An example of such complex mechanism is described in the study by Chapleau and Pozzo-Miller that reveals the opposing effects of p75NTR and Trk receptors signaling in BDNF actions on spine density and morphology. The functional interplay between neuronal activity and different signaling pathways can induce new spine growth and affect spine maturation and stabilization/pruning, the processes that are essential for learning and memory. Another pathway regulating dendritic spine structural plasticity was studied by Gonz\u00e1lez-Burgos et al. They provided the evidence that estrogen receptor modulators raloxifene and tamoxifen can rapidly modify spine density and morphology and discussed the possible repercussion of these spine plastic changes on learning and memory processes. These data, obtained in experimental animals, are also of interest for the practical medicine that uses both drugs in the human treatment, and they once again highlight the importance of the fundamental knowledge for the clinical applications. Based on the fact that causal relationships between cellular changes underlying synaptic plasticity and their functional significance are difficult to establish from experimental studies in the mammalian brain, Giachello et al. review some of the actual evidence regarding the cellular and molecular mechanisms underlying synaptogenesis and synaptic plasticity in the invertebrate nervous system and their possible validation in vertebrates. According to this view, Lee et al. discuss some of the actual trends in the conceptualization of dendritic spines as discrete functional compartments regulating synaptic plasticity, as well as the spine's structural changes associated with synaptic function.In other review papers presented in this issue, the mechanisms regulating normal brain plasticity and their implications in the pathological processes are discussed. Mandela and Ma focus on Kalirin-7, a Rho guanine nucleotide exchange factor that plays important role in signaling pathways regulating formation of dendritic spines and synapses. Recent data demonstrate that Kalirin-7 not only affects spine and synapse morphology but, consequently, modulates plasticity properties of a synapse. More importantly, human analogue of this rodent protein is implicated in a wide range of human diseases related to the cognitive disability. The paper by Bitzer-Quintero and Gonzalez-Burgos reviews the role of the immune system in regulation of synaptogenesis, especially under conditions of brain injury or inflammation. Increasing data also suggest implication of the complex interactions between immune and nervous systems in the normal neuronal structural plasticity underlying learning and memory mechanisms.We hope that papers published in this special issue will serve to increase the scientific knowledge on the cellular and molecular mechanisms involved in dendritic spine's plastic changes underlying cerebral organization of learning and memory.Ignacio Gonz\u00e1lez BurgosIgnacio Gonz\u00e1lez BurgosIrina NikonenkoIrina NikonenkoVolker KorzVolker Korz"} +{"text": "Traumatic injuries may cause anatomic deficiencies in soft and hard tissues. These defects often result in the loss of attached mucosa and alveolar processes, which might reduce potential prosthesis support and require bone and skin grafting. As a result of major maxillofacial trauma, complete or partial avulsion of the palate may require extensive surgical and prosthodontic rehabilitation. The appropriate treatment for the maxillary defect demands a multidisciplinary approach by a team which consists of various fields of dentistry and medicine. The planning prostheses should replace not only missing teeth but also lost soft tissues and bone, and they should include the hard palate, residual alveolar ridges, and, in some instances, the soft palate. This paper describes the treatment procedures including plastic surgery operation procedures and prosthetic rehabilitation in a 19-year-old woman after her severe bicycle accident. Dental injuries in association with facial fractures are common in maxillofacial emergencies , 2. The Facial fractures are usually treated by reduction and immobilization or fixation of the fractured segments, followed by occlusal adjustments and restoration of missing teeth and soft tissues where necessary . HoweverThere are several treatment options available for rehabilitation in cases of partial loss of maxilla including removable partial dentures, fixed partial dentures, crown and bridges, and teeth-implant supported prostheses . The proThis clinical report describes the prosthetic rehabilitation of a patient with bilateral traumatic avulsion of the anterior maxilla treated with fixed zirconia prosthesis attached with gingival-colored porcelain. Modifications of the basic prosthodontic principles have been utilized along with conventional treatment methods and treatment is completed by depending on the patient's needs.A nineteen-year-old female patient who had severe facial trauma was referred for dental rehabilitation after a series of esthetic surgery operations. The patient's history revealed a blow to her face after falling off a cliff during mountain biking. Her initial evaluation in Emergency Service reported that her general condition was poor, and her hemoglobin value was 6\u2009mg/dL with severe maxillofacial trauma and bleeding. The patient had an emergency consultation at the Department of Plastic and Reconstructive Surgery after a rapid hemodynamic stabilization and CT scans. According to the medical records obtained from her physician, she had a severe soft tissue injury and accompanying comminuted bone fractures on bilateral maxilla, zygoma, periorbital area, mandible, and nasal bones. Bone fragments were fixed with titanium plates and screws without bone grafting. There was also a posterior vertical split fracture on the hard palate extending anteriorly to both sides creating a mobile free bone fragment on the anterior maxilla. Those fractures were also fixed after reconstruction and then soft tissue repair was done. Complications were not seen in the early postoperative period; however, followup of the patient indicated bone necrosis on the anterior maxilla including the alveolar process extending to the palate. After debridement of the necrosis process, the defect was reconstructed with mucosal flaps and bony reconstruction was postponed. The patient refused the bone graft surgery planned for the repair of the defect on the anterior maxilla and had been consulted for prosthetic treatment.Her clinical examination showed soft tissue defects on the face particularly eye area and dysmorphic appearance . The panThe patient had an Angle Class I occlusion with an acceptable vertical and horizontal overlap prior to the accident. Because of the loss of premaxillary segment, the patient experienced speech problems and had difficulty in biting and swallowing . In addiAs a treatment method, the zirconia-based crown bridge prosthesis had been planned and applied between right first molar teeth through left second premolar teeth for the replacement of the missing teeth . A new cThe advantages of combined prosthesis included esthetic and biocompatible restoration with zirconia prosthesis. A satisfactory esthetic and functional result was achieved after fixed denture adjustments . After tWide maxillofacial defects may create functional and esthetic difficulty as a result of congenital malformations, tumor resections, or trauma . The losVarious treatment approaches are often indicated in the planning and treatment of these patients who have severe maxillofacial trauma with acquired maxillary defects , 3, 5\u20138.When trauma causes significant defects in the maxillofacial region, fabrication of overdentures is preferred as both hard and soft tissue loss, and lip support can be compensated by means of acrylic resin . HoweverPatients with such defects experience functional and aesthetic problems which are caused by the edentulous area. Dealing with bone loss in the maxilla and/or mandible, bone grafting of the defect may be necessary in case of implant treatment planning. Extensive soft and hard tissue loss usually requires an implant-supported or retentive prosthesis to obtain adequate facial support and restoration of the oral functions . This trin vitro reports have demonstrated the superior flexural strength of zirconia, when being compared to other ceramic materials, such as aluminum oxide [High-strength, full-ceramic system has been recommended with increasing frequent usage for both anterior and posterior restorations. Zirconia has good chemical and physical properties such as high corrosion resistance and low thermal conductivity, high flexural strength 900\u20131200\u2009MPa), and hardness (1200 Vickers) and also excellent biocompatibility, and optimized esthetics [00\u2009MPa, aum oxide . In the um oxide . PapaspyFor appropriate treatment procedures of the patients who had wide maxillofacial defects, additional planning, modifications, and treatment considerations are required to evaluate conditions conducive to rehabilitation of both function and esthetics. This includes the establishment of soft tissue support and contour, in addition to tooth and bone health . Among tThis paper confirms that patients with traumatic injuries have specific treatment needs. Modified prosthetic rehabilitation can enhance the esthetic of the final restoration and provide support for dental rehabilitation, supplying missing teeth, and hard and soft tissue. Through the follow-up period of 6 years, the applied prosthesis was stable and there was no need for additional adjustments nor dysmorphology was observed according to panoramic and periapical radiographs. The patient adapted well to her prosthesis and was satisfied with the final esthetic and functional outcome and reported improvements in both speech and mastication as well.In the large defects of the maxilla, detailed presurgical planning and evaluation of each case individually can minimize the difficulty of the prosthetic rehabilitation. It is often necessary for many dental disciplines, including prosthodontics, oral, and maxillofacial surgery and orthodontics to interact in the planning and treatment of patients who have severe maxillofacial trauma. The treatment options should be evaluated according to the patient's need and appropriate case selection with the dental team by careful treatment planning and interdisciplinary cooperation. Prior to finalizing the esthetic design, a treatment plan should include detailed case evaluation and smile analysis as well as patient's expectations."} +{"text": "Sudden cardiac death (SCD) due ventricular tachyarrhythmias is an important cause of mortality world wide. While the majority of these deaths occur in those with structural heart disease, a small percentage (about 4%) can occur in those with structurally normal heart as well . Such prIn this issue of the journal, Madhavan SR et al present Sudden cardiac death can be an initial presentation or preceded by symptoms related to arrhythmias or hemodynamically significant cardiovascular disorders. Sometimes evaluation is called for due to family history of sudden cardiac death. In any case, the evaluation begins with a detailed history of clinical details, family history if present and a clinical evaluation to look for potential conditions which can cause SCD. This will be followed by the assessment of a baseline electrocardiogram and other investigations as deemed necessary. An echocardiogram is useful in documenting structural heart diseases prone for SCD like severe aortic stenosis and hypertrophic cardiomyopathy. Stress testing for myocardial ischemia or inducible arrhythmia; Holter monitoring, loop monitoring and implantable loop recorders for documenting siginificant arrhythmia and finally genetic testing in case of suspected inherited arrhythmias would be other important investigations to be undertaken in this setting.Prevention of SCD in heart failure and left ventricular dysfunction assumes great importance as this is one of the largest groups in the whole arena of sudden cardiac death. Rather than pump failure, sudden cardiac death is the most common mode of death in persons with left ventricular dysfunction, more so in those with mild and moderate left ventricular dysfunction. Pump failure deaths definitely increase in those with severe left ventricular failure. Implantable defibrillators have been shown to be the most important way of prevention of SCD in this subset of patients by various large clinical trials like Multicenter Automatic Defibrillator Implantation Trial (MADIT), Multicenter Unsustained Tachycardia Trial (MUSTT), and MADIT-II . OptimalAt the community level, measures to improve the coronary risk factors can bring down the incidence of coronary artery disease as it is a major contributor to SCD. Another important aspect at the community level is the implementation of emergency medical services which can provide immediate medical care at the onset of symptoms of diseases which can lead to sudden cardiac death.Even though implantation of cardioverter-defibrillator is finally the answer in prevention of SCD in most inherited arrhythmias, several other interventions have been found useful. These include beta blockers in catecholaminergic polymorphic ventricular tachycardia and many subtypes of congenital long QT syndromes, quinidine in Brugada syndrome and left"} +{"text": "Cancer is driven by mutation. Using massively parallel sequencing technology, we can now sequence the entire genome of cancer samples, allowing the generation of comprehensive catalogs of somatic mutations of all classes. Bespoke algorithms have been developed to identify somatically acquired point mutations, copy number changes and genomic rearrangements, which require extensive validation by confirmatory testing. The findings from our first handful of genomes illustrate the potential for next-generation sequencing to provide unprecedented insight into mutational processes, cellular repair pathways and gene networks associated with cancer development. I will also review the possible applications of these technologies in a diagnostic and clinical setting and the potential routes for translation."} +{"text": "Cancer pharmacogenomics have contributed a number of important discoveries to current cancer treatment, changing the paradigm of treatment decisions. Both somatic and germline mutations are utilized to better understand the underlying biology of cancer growth and treatment response. The level of evidence required to fully translate pharmacogenomic discoveries into the clinic has relied heavily on randomized control trials. In this review, the use of observational studies, as well as, the use of adaptive trials and next generation sequencing to develop the required level of evidence for clinical implementation are discussed. In the last decade, the use of genomics in oncology significantly impacted treatment decisions for many patients. Oncologists have a variety of treatment options; however one patient may experience serious adverse events whereas another patient receives no therapeutic effect. Within a population, substantial variation exists resulting in unpredictable responses. Pharmacogenomics, the study of the interaction between the genome and clinical drug response gene were associated with the development of musculoskeletal adverse events in patients receiving adjuvant aromatase inhibitors and epidermal growth factor receptor (EGFR) mutant NSCLC. Identification of this mutation not only explains some of the poor response seen in patients with CML treated with imatinib, but also provides biological insight into different strategies to overcome the resistance that are currently in preclinical testing subsequently leading to an increased risk of severe myelosuppression and mercaptopurine (6-MP). Mercaptopurine is an important component of pediatric acute lymphoblastic leukemia (ALL) treatment, and is used in the treatment of some nonmalignant diseases therefore using this large practice based cohort, investigators were able to capture enough events to evaluate the underlying genetic difference in women with and without thromboembolic events provides a wealth of information to study questions at the population level. Large patient cohorts can be quickly created for a variety of diseases and drug response phenotypes to better evaluate drug safety. With the establishment of biobanks concurrent with the adoption of EMR, studies of genomic associations of drug response may become more comprehensive. The NHGRI funded Electronic Medical Records and Genomics (eMERGE) Network is leading the way by developing best practices for EMR guided genomic studies has allowed for a more complete view of the genome. There are three types of NGS: whole exome sequencing, whole genome sequencing, and targeted gene panels (Rehm et al., With the advent of molecularly targeted therapies, prospective use of NGS is being incorporated into adaptive clinical trials, using the genomic landscape of the tumor to direct therapy as opposed to site specific treatment (MacConaill et al., Pharmacogenomics has provided significant impact in oncology treatment, but implementation differs between somatic and germline markers. Developing sufficient evidence for use of pharmacogenomic markers has been difficult, in part because RCTs cannot be performed for every marker identified. A move toward retrospective analyses, large population studies using EMRs, and the establishment of mechanism-based evidence can propel progress in the field. In addition, embracing new methods, such as NGS and adaptive clinical trials, is providing a wealth of information about tumor biology and changing the landscape of cancer treatment. To date, pharmacogenomic studies tend to focus on either somatic or germline mutations in isolation from each other, but to truly optimize clinical care both genomes need to be integrated into clinical decision making. Both well designed, forward thinking trials and population based studies are necessary to fully implement pharmacogenomics into clinical care.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Activation of the mechanistic target of rapamycin (mTOR) is a common feature in most human malignancies . Inhibitin vivo situation in a mouse model, and found that rapamycin protected the oral mucosa from radiation-induced tissue damage, similar to what we observed in human cells in culture.Although the molecular mechanism(s) underlying these paradoxical effects of mTOR are not completely understood, this concept is quite relevant in the context of the potential use of mTOR inhibitors for cancer treatment. mTOR inhibitors may prevent the growth of cancer cells that are addicted to, and hence dependent on mTOR function for their aberrant growth, while mTOR inhibition might concomitantly improve the health of normal tissues by protecting their tissue resident stem cells. mTOR drives conversion of reversible cell cycle arrest into irreversible senescence, whereas rapamycin suppresses geroconversion . As partRadiation therapy is one of the most widely used cancer treatments . In patiRapamycin and other mTOR inhibitors have been shown to prevent cellular senescence in cell culture in all cell types tested . We can Overall, we are beginning to understand how molecular circuitries are differentially wired in normal and cancer cells, and how we can perturb distinct signaling pathways to prevent tumor growth without disrupting the function of normal tissues and cells. We expect that additional molecules that play a similar paradoxical distinct role in cancer and normal cells will soon be identified, expanding the tool box of druggable targets for cancer prevention and treatment. These efforts may shed some interesting surprises, as we may be able to find feasible approaches to protect the stem cells residing in each adult tissue from the detrimental impact of environmental assaults that lead to their loss of tissue regenerative capacity and accelerated aging. Ultimately, by protecting adult stem cells from initiating premature cell senescence programs with pharmacological agents that simultaneously prevent tumor cell growth, we may be in the future in a position to delay aging without the potential increase in cancer risk."} +{"text": "Preimplantation aneuploidy screening of cleavage stage embryos using fluorescence in situ hybridization (FISH) may no longer be considered the standard of care in reproductive medicine. Over the last few years, there has been considerable development of novel technologies for comprehensive chromosome screening (CCS) of the human genome. Among the notable methodologies that have been incorporated are whole genome amplification, metaphase and array based comparative genomic hybridization, single nucleotide polymorphism microarrays, and quantitative real-time PCR. As these methods become more integral to treating patients with infertility, it is critical that clinicians and scientists obtain a better understanding of their capabilities and limitations. This article will focus on reviewing these technologies and the evidence of their validity. The concept of preimplantation genetic screening (PGS) for chromosomal abnormalities to improve clinical outcomes in patients undergoing in vitro fertilization (IVF) is based on the observation that aneuploidy represents the leading genetic cause of miscarriage and is lOne of the key limitations of FISH based preimplantation aneuploidy screening is the inability to simultaneously evaluate all 24 chromosomes found in human cells . The development of technologies for single cell whole genome amplification \u20139 has noOne important consideration is the amount of time required to complete the analysis. While rapid conventional mCGH methods have been developed \u201323, the Although aCGH and SNP array technology both involve an array of DNA based probes, these methods are not equivalent. For example, among the commonly used arrays for PGS, the BlueGnome bacterial artificial chromosome (BAC) arrays possess approximately 2,000 to 5,000 DNA probes across 24 chromosomes , the Affin silico controls) . Ra. Ra55]. n\u2009=\u2009204) displayed UPD after evaluation with SNP arrays [A second study comparing FISH and CCS analysis of the same embryos involved careful evaluation of the putative mechanisms of \u201cself correction,\u201d which reP arrays . AnotherP arrays , 56, 57.P arrays specificP arrays . While iOne of the major implications of these comparative studies is that the mitotic origin of embryonic aneuploidy may have been overestimated. Indeed, studies of products of conception have found that maternal meiosis is the predominant origin of aneuploidy , and notGiven the inconsistency and poor negative predictive value of cleavage stage FISH, new technologies such as CCS should be more carefully evaluated. Moreover, FISH based re-analysis of CCS evaluated embryos may not represent a good approach to validate new CCS methods since FISH has been shown to be an inconsistent methodology itself. Alternatively, randomized blinded analysis of single cells from cell lines with known abnormalities could be performed and used to evaluate the accuracy of aneuploidy predictions Fig.\u00a0. AnotherAs previously alluded to, accumulating evidence indicates that FISH based aneuploidy screening at the cleavage stage of embryogenesis is not only inconsistent but also poorly predictive of aneuploidy in the blastocyst. Reanalysis of blastocysts indicate that nearly 60% of embryos discarded due to an abnormal cleavage stage FISH diagnosis were in fact euploid for all 24 chromosomes in all 4 evaluated sections . A similAlthough a randomized controlled trial represents what most consider the pinnacle of clinical validation of efficacy, case\u2013control studies currently represent the primary source of evidence of clinical validity for most CCS methodologies , 64\u201368. While numerous considerations for the efficacy of using a specific stage of biopsy for PGS exist, one of the most important may be the impact that the procedure has on the reproductive potential of the embryo. Although some studies have focused on comparing outcomes in patients who had all of their oocytes/embryos biopsied to outcomes in patients who had none of their oocytes/embryos biopsied, this may not represent the best controlled study design. This is particularly true since the patients having embryos or oocytes biopsied were typically subject to PGS while the other patients were not. Instead, randomization of the 2 best oocytes/embryos so that one is biopsied (case) and the other is not (control) and subsequent paired analysis of outcomes within each 2 embryo transfer (using DNA fingerprinting) could represent a better controlled study of the impact of biopsy. Interestingly, preliminary results using this paired study design indicate that embryo biopsy at the cleavage stage, but not the blastocyst stage, significantly reduces the implantation potential of the embryo . SimilarWhile validated methods of CCS may improve clinical outcomes for patients with infertility, they may also represent an exciting tool to help identify additional markers, beyond aneuploidy screening, that provide predictive information about the long term viability of embryos and oocytes. Indeed, this objective represents one of the most important challenges in reproductive medicine . Since iDespite the failure of cleavage stage FISH based aneuploidy screening, the introduction of new CCS technologies holds great promise for achieving the expected improvements in clinical outcomes for patients suffering from infertility. A critical mass of class I evidence still needs to be generated for each CCS methodology before scientists and clinicians adopt it for routine clinical testing. Randomized controlled trials of efficacy as well as non-selection studies of the negative predictive value of embryonic reproductive potential should provide the data needed to accept or reject the validity of a given CCS methodology. While recent success of blastocyst trophectoderm CCS with qPCR and fresh embryo transfer is encouraging, results from additional ongoing randomized trials of CCS are eagerly anticipated and should help shape the future of chromosome screening in the IVF setting."} +{"text": "Neuroprosthetic approaches have tremendous potential for the treatment of injuries to the brain and spinal cord by inducing appropriate neural activity in otherwise disordered circuits. Substantial work has demonstrated that stimulation applied to both the central and peripheral nervous system leads to immediate and in some cases sustained benefits after injury. Here we focus on cervical intraspinal microstimulation (ISMS) as a promising method of activating the spinal cord distal to an injury site, either to directly produce movements or more intriguingly to improve subsequent volitional control of the paretic extremities. Incomplete injuries to the spinal cord are the most commonly observed in human patients, and these injuries spare neural tissue bypassing the lesion that could be influenced by neural devices to promote recovery of function. In fact, recent results have demonstrated that therapeutic ISMS leads to modest but sustained improvements in forelimb function after an incomplete spinal cord injury (SCI). This therapeutic spinal stimulation may promote long-term recovery of function by providing the necessary electrical activity needed for neuron survival, axon growth, and synaptic stability. Artificial stimulation via electrodes placed within the spinal cord parenchyma, termed intraspinal microstimulation (ISMS), is a promising technique for activating the spinal cord distal to an injury. ISMS may confer dual benefits of both re-animation of paralyzed limbs, as well as promoting plasticity leading to long-term recovery of function that outlasts the stimulation. Pioneering work demonstrated that intraspinal stimulation (ISMS) of the lumbar spinal cord is capable of directly evoking a range of hindlimb movements , incomplete injury to the cervical spinal cord is the most common diagnosis NSCISC, . RestoraThere is promising evidence for partial recovery following incomplete injuries that highlights the substantial capacity for plasticity of intraspinal circuits. For example, spinal interneurons sprout and form functional synaptic connections with motor neurons across a midline transection injury (Fenrich and Rose, With the substantial capacity of the spinal circuitry to remodel after incomplete injury, an underappreciated application of ISMS may be to promote or guide this plasticity by providing the necessary electrical activity needed for recovery of these orphaned spinal circuits. In the following section we review the substantial evidence demonstrating the importance of electrical activity for the recovery of neural networks after injury.Neuronal activity is an important regulator of multiple components of the nervous system, including the critical barriers to neuronal survival, differentiation, axonal growth, and synaptogenesis (For reviews see Spitzer, Numerous data suggest that activity increases neuronal survival. For example, chronic electrical stimulation leads to increased survival of spiral ganglion cells after the application of a highly excitotoxic drug (Lousteau, In vitro, acetylcholine and glutamate attract growth cones into specific directions in a calcium dependent manner (Zheng et al., Axonal growth may be critical for the formation of new circuits after SCI, and is also largely regulated by activity. Synaptogenesis and novel dendrite stabilization is necessary for functionally restorative network formation after SCI. Activity is known to strongly regulate dendrite stabilization during development. For example, developing dendrites stabilize in response to cholinergic neurotransmission and local calcium-induced calcium release in the early stages of synapse formation (Lohmann et al., Taken together, these studies strongly demonstrate that neural activity is necessary to promote long-term recovery of functional circuits after SCI. Intraspinal stimulation is one potential method for introducing this activity, either with the goal of directly re-animating the limbs, or perhaps ideally to promote sustained recovery of function.Stimulation within the spinal cord activates local spinal networks in specific patterns to evoke functional movements. Building on extensive work demonstrating the ability of ISMS within the lumbar spinal cord to evoke standing and stepping movements (Mushahwar and Horch, More recently we explored the forelimb movements evoked by cervical ISMS both before and after injury in a clinically-relevant rodent model of mid-cervical contusion injury (Sunshine et al., Electrical stimulation applied to the epidural surface of the spinal cord shows great promise for directly improving motor function after SCI. Epidural stimulation of the lumbar spinal cord can facilitate stepping movements after complete spinal transection, especially when combined with serotonin agonists and movement of a motorized treadmill underfoot (Ichiyama et al., Electrical stimulation applied to the cortex or brainstem after selective SCI promotes axon sprouting (Brus-Ramer et al., Trains of electrical stimulation delivered to peripheral nerves have been shown to substantially enhance function of both motor and sensory axons following nerve transection and subsequent surgical repair (Brushart et al., Therapeutic ISMS of the cervical spinal cord evokes complex and often highly-functional synergies, but we also have recent evidence that stimulating the spinal cord below an injury improves motor function with benefits lasting beyond the period of stimulation (Kasten et al., In a particularly interesting example, an animal in the stimulated group recovered to 75% of pre-injury reaching ability within just 4 weeks Figure . NotablyAnimals that continued to receive therapeutic ISMS for the remainder of the 12 weeks treatment period also significantly outperformed their unstimulated counterparts (Kasten et al., While the applications of ISMS to promote activity and functional recovery is very promising, several technical hurdles must be overcome prior to widespread clinical adoption. The long-term stability of stimulating electrodes within the spinal cord must be demonstrated, as negative tissue responses are common following implantation of electrodes within the central nervous system (Shain et al., To maximize the success of ISMS, the future depends upon the development of better insight in to the physiologic and molecular mechanisms of activity whereby axonal or circuit function is improved. In turn, complete restoration of neural function is likely to be achieved only by combining ISMS with complimentary therapies. Individual treatments rarely demonstrate large functional improvements, particularly in the chronic phase of SCI, and in clinically-relevant injury models. For example, combinations of intensive rehabilitation, pharmacological treatment and epidural stimulation show promise following a staggered hemisection injury (Van Den Brand et al., Cervical ISMS holds tremendous potential for both directly re-animating forelimb movements as well as promoting long-term recovery of function after SCI. Building on substantial evidence for the importance of activity in nervous system development and recovery, therapeutic ISMS may provide the otherwise absent electrical activity needed for neuron survival, axon growth, and synaptic stability. The application of therapeutic stimulation to the spinal cord distal to a lesion may therefore be critical in promoting repair of spinal circuits following injury, either alone or in combination with other rehabilitative and pharmacological interventions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Volume mesh generation is one of the vital procedures in spatial, Gillespie SSA-based , reactioSTEPS (STochastic Engine for Pathway Simulation) is a GNU-licensed simulation platform that uses an extension of Gillespie's SSA to deal Existing approaches of tetrahedral, dendritic mesh reconstruction fall into two different schemes according to their initial geometry representations. The common approach starts from a computational Constructive Solid Geometry (CSG) representation of the modeling subject, formed by Boolean operations on standard geometry primitives such as cubes, cylinders and spheres. The second approach begins with a contour tracing representation from experimental Electron Microscopic images. Meshing algorithms such as Delaunay triangulation and tetrahedralization can thenIn our investigation, we apply meshes that are generated from both approaches to STEPS simulations. Different mesh quality is achieved by varying the parameter settings of the mesh generator. Multiple instances of the simulation are executed for each mesh and the results are averaged. For simple morphologies where analytical solutions exist, we compare the simulation results with the analytical solutions, or else results of different quality meshes for the same morphology are compared. Based on these comparisons, we aim to reveal how SSA simulation is affected by mesh quality, and to draw guidelines of mesh generation for STEPS."} +{"text": "Indeed, dexamethasone-mediated immunosuppression causes broilers to develop lameness primarily associated with avascular necrosis and BCO. Prophylactic probiotic administration consistently reduces the incidence of lameness in broilers reared on wire flooring, presumably by reducing bacterial translocation from the gastrointestinal tract that likely contributes to hematogenous infection of the leg bones. The pathogenesis of BCO in broilers is directly relevant to osteomyelitis in growing children, as well as to avascular femoral head necrosis in adults. Our new model for reliably triggering spontaneous osteomyelitis in large numbers of animals represents an important opportunity to conduct translational research focused on developing effective prophylactic and therapeutic treatments.This review provides a comprehensive overview of the vascularization of the avian growth plate and its subsequent role in the pathogenesis of bacterial chondronecrosis with osteomyelitis . BCO sporadically causes high incidences of lameness in rapidly growing broiler (meat-type) chickens. BCO is believed to be initiated by micro-trauma to poorly mineralized columns of cartilage cells in the proximal growth plates of the leg bones, followed by colonization by hematogenously distributed opportunistic bacteria. Inadequate blood flow to the growth plate, vascular occlusion, and structural limitations of the microvasculature all have been implicated in the pathogenesis of BCO. Treatment strategies have been difficult to investigate because under normal conditions the incidence of BCO typically is low and sporadic. Rearing broilers on wire flooring triggers the spontaneous development of high incidences of lameness attributable to pathognomonic BCO lesions. Wire flooring imposes persistent footing instability and is thought to accelerate the development of BCO by amplifying the torque and shear stress imposed on susceptible leg joints. Wire flooring Bacterial chondronecrosis with osteomyelitis sporadically causes high incidences of lameness in meat-type chickens . BCO has been diagnosed worldwide, and is considered the most common cause of lameness in commercial broilers newborn baby would weigh 300\u2009kg (660\u2009lb) after 2\u2009months. Doubling and re-doubling of the body mass almost seven times in 8\u2009weeks cannot be sustained without equally dramatic increases in the size and structural integrity of the skeleton. Growth of the leg bones includes elongation accomplished via growth plates located at both ends of the shaft (diaphysis), as well as marked increases in the overall diameter attributable to highly dynamic remodeling of cortical bone . As demonstrated by Applegate and Lilburn a broileper se but rather by an ensuing bacterial infection the metaphysis (m) consisting of calcifying chondrocytes and the newly formed osteoid of the calcifying zone (cz), spicules of trabecular bone that provide a support scaffolding for the growth plate are terminal branches of the nutrient artery (na), which penetrates the diaphyseal cortex through the nutrient foramen (nf) located approximately at mid-shaft Figures and 2. Iin situ or spatially fixed while sequentially passing through the prehypertrophic, hypertrophic, and calcifying phenotypes during the ensuing 21\u2009h. This in situ synchronization of chondrocyte maturation creates the illusion that all zones of the growth plate are migrating together longitudinally . Environmental stressors and immunosuppression contribute to the eruption of opportunistic pathogens harbored sub-clinically in the proximal tibial joints of turkeys that develop TOC and focal ischemia induced by torque and shear stress associated with unstable footing. Inadequate blood flow and vascular occlusion contribute to delayed mineralization and focal necrosis of the growth plate, further enhancing the structural instability and susceptibility to micro-trauma. Osteochondrotic clefts and necrotic voids provide niches for bacterial colonization outside of the surveillance of circulating leukocytes. Stress-mediated immunosuppression is permissive for bacterial translocation, enhanced hematogenous distribution, and sustained infection. We have developed a wire flooring model that causes fast growing broiler chickens to spontaneously develop high incidences of lameness attributable to pathognomonic lesions of the proximal femora and tibiae. Wire flooring imposes persistent footing instability and also constitutes a significant chronic stressor that promotes bacterial proliferation attributed to stress-mediated immunosuppression. This model for reliably triggering spontaneous osteomyelitis in large numbers of animals represents an important opportunity to conduct translational research focused on understanding the structural and functional basis of susceptibility to ischemia, epiphyseal-physeal dysfunction and necrosis, and to develop effective prophylactic and therapeutic treatments.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Schizophrenia is associated with many genetic and environmental risk factors and there is growing evidence that the interactions between genetic and environmental \u201chits\u201d are critical for disease onset. Animal models of schizophrenia have traditionally used specific strain and housing conditions to test potential risk factors. As the field moves towards testing gene (G) x environment (E) interactions the impact of these choices should be considered. Given the surge of research focused on cognitive deficits, we have examined studies of cognition in rodents from the perspective of GxE interactions, in which strain or housing manipulations have been varied. Behavior is clearly altered by these factors, yet few animal models of schizophrenia have investigated cognitive deficits using different strain and housing conditions. It is important to recognise the large variation in behavior observed when using different strain and housing combinations because GxE interactions may mask or exacerbate cognitive outcomes. Further consideration will improve our understanding of GxE interactions and the underlying neurobiology of cognitive impairments in neuropsychiatric disorders. Schizophrenia is a complex group of disorders in which genetic vulnerability may lead to greater sensitivity to adverse environmental conditions and two inbred strains, Lewis and Fischer 344, which differed in stress responsivity were found to be altered by either strain or stress treatments, however changes were inconsistent across strains indicating a modulatory role of genotype. A second experiment comparing these strains using a stress protocol found that changes in Bdnf expression and associated pathways were also strain dependent (Neeley et al., With the aim of developing biologically-relevant animal models of schizophrenia, studies using a GxE approach are rapidly emerging (Millstein et al., In another recent study, rats were exposed to two commonly used risk factors, post weaning social isolation and chronic ketamine treatment, and selectively bred based on behavioral deficits relevant to schizophrenia to produce a vulnerable sub-strain (Petrovszki et al., A recent review of mouse models of GxE interactions relevant to schizophrenia has discussed a comprehensive list of weaknesses to be addressed by future studies (Kannan et al., Investigating genetic changes, such as mutant mouse models, may be easily replicated across laboratories, however environmental manipulations are more difficult to standardise. For example, wild type mice show different behavioral phenotypes when tested under similar conditions but at different laboratories (Crabbe et al., Future studies could take a number of directions, including the use of GxG and ExE studies to identify the influence of genetic and environmental factors; as well as understanding the mechanisms that lead to increased vulnerability (Giovanoli et al., There is clear evidence to show that genetic and environmental conditions alter cognitive outcomes in rodents. However, the lack of studies comparing cognitive deficits in rodent models of schizophrenia using different strain and housing conditions is surprising. Schizophrenia develops from the complex interaction of GxE and we need to incorporate this complexity into animal models to understand the etiology of schizophrenia. Although it is difficult to recapitulate complex disorders, such as schizophrenia, in a rodent model, the use of endophenotypes in carefully controlled experiments may allow us to better understand some of the mechanisms behind GxE interactions. Current animal models are falling short of replicating the complex suite of risk factors implicated in schizophrenia and using different strains or housing conditions may provide an accessible stepping stone towards understanding altered brain development. Given the infancy of GxE interaction research in animal models of schizophrenia, manipulating these factors in existing and novel animal models will be informative in terms of GxE interactions. GxE interaction models will be particularly informative for understanding the role of vulnerable and resilient phenotypes in determining the influence of secondary \u201chits\u201d on cognitive outcomes in schizophrenia.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Pain is one of the key characteristics which distress patients with chronic wounds. Chronic wound pain has a significant impact on the patient\u2019s quality of life and delays wound healing. Assessment and management of pain during wound dressing changes is well addressed, however, chronic persistent wound pain is under-assessed and under-treated resulting in patients\u2019 perception that wound pain is something they have to suffer or manage themselves. The purpose of this study was to investigate wound practitioners assessment of chronic persistent wound pain. It sought to identify what assessment tools are utilised in determining the level of pain, the frequency of assessment and how the pain is managed.A national mail survey of members of the Australian Wound Management Association was conducted. The 54% response rate included nurses, podiatrists and doctors. A cross sectional descriptive analysis will be conducted of the results.Preliminary results showed that health professionals do ask patients about wound pain mostly during wound dressing changes. Methods routinely used to assess pain were by talking to the patient or pain rating scales. Several major themes emerged linking wound pain and limitations in providing effective wound pain management.This study identified that various methods of assessment are utilized to identify pain in chronic wounds, however barriers exist that impact the implementation of effective pain management."} +{"text": "The function of neural circuits is an emergent property that arises from the coordinated activity of large numbers of neurons. To capture this, we propose launching a large-scale, international public effort, the Brain Activity Map Project, aimed at imaging the full record of neural activity across complete neural circuits. This technological challenge could prove to be an invaluable step toward understanding fundamental and pathological brain processes."} +{"text": "Over the last few years MoH and WHO have refocused their efforts on improving infection prevention and control (IPC) practice.We describe here a cross departmental approach to improving IPC capacity.Initially we focused on developing national guidelines; however, we noticed absence of policy and strategy hindered IPC activities. Consequently, while developing guidelines, we worked with partners and other departments within MoH to develop national policy and strategic plan for IPC.As a consequence of IPC policy and plan, we created a dedicated team at MoH, Provincial Health Departments (PHD), and hospitals. There are national guidelines and training curriculum. A cohort of trainers from national level and provincial hospitals is training hospital staff using the curriculum. Hospital facilities are being upgraded and supplies for infection control practice are added into essential drug list of MoH. We have piloted nosocomial infection surveillance and developing IPC model practice sites.IPC continues to suffer from poor staff capacity and commitment, limited support by decision makers and financial shortages. Its cross cutting nature means that programs assume IPC is covered by someone else. Staff behavior change is one of the biggest challenges.Having IPC policy and plan gives us a tool for fund raising and advocacy. To ensure sustainability, the program is linking IPC with quality of care, using standard assessment tools to evaluate activities which will be used to provide dedicated funding. With approval from decision makers, the IPC team of MoH has been coordinating and guiding IPC teams in most provincial hospitals and PHDs to add budget for IPC activities into their annual operational plan.We moved IPC practice from a number of disjointed vertical programs to a cohesive, comprehensive mission. Next challenge is ensuring that staff practice IPC.The evolution of IPC program in Cambodia may serve as a model for other countries that seek to initiate similar programs.None declared"} +{"text": "The fidelity of the genome is under constant threat by exogenous and endogenous reactive species, including toxic chemicals, ionizing radiation and byproducts of normal cellular metabolism. These species cause damage to DNA by modifying DNA bases, breaking DNA strands and/or altering DNA structures. When this happens, the consequences to the cell can be disastrous, ranging from single gene mutations to massive chromosomal breakdown and rearrangements. These instabilities lead to severe human diseases including cancer.Fortunately, humans and other eukaryotes have evolved multiple mechanisms to ensure genome stability. These mechanisms can be classified into two major systems, one that deals with replication fidelity and the other that takes care of various DNA lesions. The replication fidelity maintenance system involves DNA polymerases and the DNA mismatch repair pathway. First, the 3'-5' proofreading nuclease activity of replicative DNA polymerases is responsible for removing the majority of mis-incorporated nucleotides during DNA replication . HoweverThe DNA damage processing system can be divided into two steps: DNA damage response and DNA repair. Extensive studies in the past 20 years have elucidated the mechanisms of several major DNA repair pathways that remove almost all kinds of DNA lesions. These pathways include base excision repair , nucleotDNA damage response is a complex signal transduction process that has the ability to sense DNA damage and transduce the information to the cell to direct cellular responses to the damage. An arsenal of protein activities has been identified, which function to be damage sensors, mediators, transducers and effectors during DNA damage response . Unlike Cell & Bioscience presents a series of reviews attempting to define the most challenging questions in DNA damage response and repair, and to provide an overview of the latest breakthroughs and developments in the field. The article by Nan Wu and Hongtao Yu [n and (CTG)n trinucleotide repeats, whose expansions cause numerous human disorders, is extremely challenging, as is the understanding of the mechanisms that regulate the stability/instability of the repetitive sequences. In their article, Guoqi Liu and Michael Leffak [n and (CTG)n trinucleotide repeats.In this issue, ngtao Yu exploresngtao Yu describel Leffak debate hIt is our sincere hope that this special issue brings our readers enlightenment and offers sufficient introductory information to help them appreciate new breakthroughs in the field."} +{"text": "Of those patients who require extracranial shunting to manage CSF circulation disorders, some of the most challenging are those whose shunts have been placed in the subarachnoid space in infancy or childhood. While clinically well in childhood, with few if any revisions, a symptom complex may develop in mid to late childhood that is characterized by chronic, often non-specific headaches and intermittent intracranial hypertension associated with abducens palsy and/or papilloedema. Imaging shows some combination of decompressed CSF spaces, acquired hindbrain herniation or posterior fossa crowding, diploic hypertrophy, narrow spinal canal and meningeal thickening. ICP monitoring does not always provide clarification of the clinical ICP correlation.This paper describes five patients with acquired hindbrain herniation, three following subarachnoid shunting for cerebral arachnoid cyst. Various treatments, including shunt revision, shunt valve adjustments and hindbrain hernia decompression, were performed without enduring effectiveness.Based on this experience, the authors propose that the evolution of craniocerebral/cerebellar distortion due to loss of the distending forces of the subarachnoid space in early childhood results in central chronic transtentorial shifts that impact venous drainage at the level of the galenic and petrosal systems. There is a failure to shift cerebral venous return from the dural sinus system to the basilar and condylar plexuses with postural changes with or without dural sinus compression. Chronic venous insufficiency results in swelling of posterior fossa structures. Hindbrain herniation and/or crowding is the result.Prevention of this complication can be achieved by avoiding subarachnoid shunts in this age group and utilizing other options to address arachnoid cysts that are deemed to need treatment. In those patients who are symptomatic, reconstruction of the subarachnoid space by extensive supratentorial cranial expansion may be effective based on relief of transtentorial brain shifts and consequent venous congestion."} +{"text": "Despite advances in the fields of prevention, medical intervention and surgical therapy, cardiovascular disease remains a major public healthcare issue. A promising area of research is the potential application of regenerative therapies with pluripotential stem cells to reduce the burden of heart disease and its sequelae. Umbilical cord blood, a rich source of multiple populations of nonembryonic stem cells, will be a valuable resource and has the potential to advance therapeutic options for patients with acquired and congenital heart disease. Atherosclerotic heart disease and chronic heart failure remain a major worldwide health problem . Accordi Undifferentiated cells capable of self-renewal and developing into various tissues and organs are referred to as stem cells (SC) . MultiplDespite the increasing attempts to limit the use of exogenous blood and its components, allogeneic transfusion remains a necessity in a significant percentage of hospitalized patients. This is particularly true when caring for patients at the extremes of ages with cardiovascular disease. Umbilical cord blood (UCB) is rich in adult and fetal hemoglobin cells as well as platelets and other cellular constituents and offers minimal immunologic reaction . Given f Premature infants are often born with multiple major medical problems including cardiopulmonary disease requiring long-term hospitalization, interventional procedures, and blood transfusion. In the past, although the collection and preparation of placental and umbilical cord blood was technically possible, a number of questions were raised regarding its safety and utility . The proMany congenital defects requiring postnatal surgical correction are now diagnosed antenatally. A significant number of these babies will require blood transfusion. A recent study investigating the use of UCB in neonates undergoing general surgical procedures found this technique useful and noted that 64% of patients avoided allotransfusion . In addiIschemic heart disease and chronic congestive heart failure are a major worldwide healthcare problem . MyocardOn the heels of major successes in allogeneic stem cell transplantation (AlSCT) and more recently related and unrelated umbilical cord blood transplantation (UCBT) for numerous malignant and nonmalignant diseases, many researchers and clinicians see great hope for application in regenerative therapy .An animal model provided the initial evidence that cardiac structure and contractility could be improved with cell transplantation. Fetal cardiomyocytes transplanted into rat hearts following cryoinjury improved systolic function and limited scar progression . Follow-Early human studies demonstrated the feasibility of cell transplantation into patients with ischemic heart failure . OutcomeA reexamination of the animal and human data showed that only a small percentage (1%) of transplanted cells remain engrafted at the original site a few weeks following administration . Cell loHeart defects are the most common congenital affliction and occur in approximately 14 out of 1000 live births . The varChronic pressure or volume overload lesions of either the right or left side of the heart; aortic and pulmonary valve disease, coarctation of the aorta, single ventricle lesions may produce significant myocardial dysfunction resulting in chronic congestive failure. Often requiring multiple interventions, they are candidates for cell and tissue therapy to help restore contractile function.Multiple conditions may be associated with underdevelopment or absence of the semilunar valves. Currently, valve repair is attempted but often culminates in replacement of the aortic or pulmonary valves with bioprosthetic or mechanical prostheses . Although hemodynamically adequate, these valves often fail by calcification and or tissue ingrowth relatively rapidly and have no capacity for growth thus necessitating multiple reoperations, and many require systemic anticoagulation with its attendant risks. A great deal of research is now underway to develop tissue-engineered valves seeded with a patient's own cells with the potential for growth and lack of immunogenicity. Combining the techniques of cell harvesting, cell augmentation, and tissue-engineering the hope is to bank suitable stem cells and \u201cgrow\u201d them into useable valve substitutes. Scaffolds made of decellularized xenografts or tissue engineered biodegradable matrices have been designed to replace traditional valve supports . AutologPatients born with univentricular hearts (tricuspid and or pulmonary atresia as well as hypoplastic left heart syndrome) require multiple operative procedures utilizing prosthetic shunts culminating in a Fontan procedure. Often a circumferential prosthetic tube is placed to channel the deoxygenated blood from the abdomen and lower extremities directly into the lungs, thereby bypassing the missing pulmonary ventricle. Similarly, patches or baffles of artificial material are used on a daily basis in pediatric cardiac surgery to connect or reroute blood flow within the heart. These conduits and patches have no growth potential, carry a risk of thrombosis as well as infection, and may require systemic anticoagulation . Tissue-The number of adults living with congenital heart disease now outnumbers children afflicted with these conditions . Many ofUmbilical cord blood is a relatively easily obtainable source of multiple populations of pluripotent cells seemingly less hampered by mutations and immunogenicity. When harvested it provides a readily available, lifelong source of cells for therapy. It is rapidly becoming the standard of care for use in hematologic and oncologic disorders. Although the volume and numbers of particular cells may be limited in any one sample, transplantation of multiple units from different donors may be required and has been accomplished with good results \u201339, and Cardiovascular disease remains one of the world's largest and growing healthcare issues. The fields of cell transplantation, tissue engineering, and regenerative medicine are poised to impact heart disease in a similar way to that seen in oncohematologic disorders and inborn errors of metabolism. Despite the genetic, biological, and engineering complexities involved, restoration of ventricular function and the development of living and growing vascular grafts and valves is becoming a reality. Umbilical cord blood will certainly play a central role in \u201cseeding\u201d these accomplishments."} +{"text": "These tools have also been used to define mechanisms underlying development of peripheral insulin resistance in animals and humans. For example, we have recently identified perturbations of branched chain amino acid (BCAA) catabolism in multiple cohorts of insulin resistant humans compared to normally insulin sensitive controls and have translated these findings to rodent models to demonstrate a contribution of BCAA to development of insulin resistance that is independent of body weight. In collaboration with Dr. Alan Attie at the University of Wisconsin, we have integrated transcriptomic and metabolomic analysis in mouse models to identify new pathways that control hepatic gluconeogenesis and PEPCK expression. Finally, with Svati Shah and Bill Kraus at Duke, we have identified novel metabolic signatures of imminent cardiovascular events, and are integrating genomic and metabolomics analyses in large cohorts of human subjects with a high incidence of coronary artery disease to identify pathways involved in metabolic variability and risk of cardiovascular disease. These examples will serve to illustrate the potential of comprehensive metabolic profiling methods for providing insights into metabolic disease mechanisms.We seek to apply comprehensive metabolic analysis tools for understanding of mechanisms underlying chronic human diseases and conditions such as diabetes, obesity, and cardiovascular disease. Current approaches include analysis of metabolic flux by"} +{"text": "This paper presents data from the Substance Abuse and Mental Health Services Administration (SAMHSA) cross-site evaluation of the third cohort of SAMHSA grantees implementing screening, brief intervention, and referral to treatment (SBIRT) services in selected sites. Cost estimates for SBIRT service provision are needed because in the present environment, healthcare expenditures will need to be justified fiscally. The objective of the current paper is to determine the costs of delivering individual SBIRT components as well as the program as a whole.A multifaceted data collection protocol was employed to collect cost data from grantee agencies and selected sites of the third cohort of Substance Abuse and Mental Health Services Administration\u2019s (SAMHSA) SBIRT program. First, detailed labor and space utilization data were collected through direct observation of SBIRT practitioners in their duties over complete shifts. Next, administrators at both grantee and site levels were asked to complete questionnaires that collected data on wages, administrative labor, and non-labor costs. Finally, selected practitioners were asked about irregular and infrequent activities over the past month that would have been missed during direct observation.Using the detailed labor utilization data coupled with wage data collected from administrators, precise estimates of the cost to deliver each component of SBIRT will be presented. Additionally, program-level costs will be presented using data from the administrator questionnaires and practitioner past-month experiences.These results provide insight into the cost of hosting an SBIRT program in a healthcare setting. Further research is needed to compare the costs with available funding streams for SBIRT services."} +{"text": "Traits related to local adaptation by definition show high phenotypic differentiation. The underlying genetic patterns could be clines at individual loci or small effects and extensive linkage disequilibrium at the underlying loci. In any case, including many populations in an analysis provides more information, but may simultaneously induce problems due to genetic structure. Even if the neutral loci have little genetic structure, loci related to other clinally selected traits could show more structure. Here we have developed an approach to efficiently use the information along a latitudinal environmental gradient. Scots pine populations from central Europe to the species' northern range were sampled and patterns of phenotypic variation of both timing of budset and frost tolerance were measured in common garden experiments, . By hierarchical modelling of the phenotype's clinal variation and accounting for varying allele frequencies across the 10 populations, the statistical approach simultaneously exploits the genetic variation between and within populations to detect association signals. We apply shrinkage-based Bayesian variable selection to detect genetic associations between timing of bud set and ~450 SNPs in Scots pine."} +{"text": "We examined the prevalence of substance use disorders among homeless and vulnerably housed persons in three Canadian cities and its association with unmet health care needs and access to addiction treatment using baseline data from the Health and Housing in Transition Study.In 2009, 1191 homeless and vulnerably housed persons were recruited in Vancouver, Toronto, and Ottawa, Canada. Interviewer administered questionnaires collected data on socio-demographics, housing history, chronic health conditions, mental health diagnoses, problematic drug use (DAST-10\u22656), problematic alcohol use (AUDIT\u226520), unmet physical and mental health care needs, addiction treatment in the past 12 months. Three multiple logistic regression models were fit to examine the independent association of substance use with unmet physical health care need, unmet mental health care need, and addiction treatment.Substance use was highly prevalent, with over half (53%) screening positive for the DAST-10 and 38% screening positive for the AUDIT. Problematic drug use was 29%, problematic alcohol use was lower at 16% and 7% had both problematic drug and alcohol use. In multiple regression models for unmet need, we found that problematic drug use was independently associated with unmet physical and unmet mental health care needs. Problematic alcohol use was not associated with unmet health care needs. Among those with problematic substance use, problematic drug use was associated with a greater likelihood of accessing addiction treatment compared to those with problematic alcohol use alone .Problematic drug use among homeless and vulnerably housed individuals was associated with having unmet health care needs and accessing addiction treatment. Strategies to provide comprehensive health services including addiction treatment should be developed and integrated within community supported models of care. Homeless and vulnerably housed persons suffer from a high prevalence of chronic physical and mental illness, substance abuse, and mortality Substance use has been recognized as a significant barrier to exiting homelessness and further exacerbates social marginalization The types of substances people use may affect their ability to access health care and addiction treatment, particularly for those who already face significant barriers to care because of their housing circumstances We recruited participants from the Vancouver census metropolitan area (CMA), BC (population 2.33 million); Ottawa CMA, ON (population 1.22 million); and Toronto CMA, ON (population 5.62 million) (Statistics Canada 2010). On any given night, there are 2600 homeless individuals in Vancouver, over 1000 in Ottawa and as many as 5000 in Toronto The sampling strategy and recruitment of the Health and Housing in Transition Study have been previously described in detail Recruitment of homeless participants was done in shelters and meal programs. Participants who did not use shelters were recruited in meal programs proportionally to the number of homeless estimated to sleep on the street in each city. Shelters were randomly selected proportionally to the number of shelter beds at each site while meal programs were randomly selected based on their location and the number of meals served. At each shelter and meal program, the number of homeless individuals recruited ranged from 12 to 35 based on the number of recruitment sites in each city.The stock of low-cost housing includes licensed and unlicensed rooming houses in Ottawa and Toronto and single room occupancy (SRO) hotels in Vancouver. Vulnerably housed participants were randomly selected from these housing settings in the different cities according to capacity. In addition to all licensed SROs and rooming houses, unlicensed sites were identified using multiple sources. Each city aimed to recruit 20 vulnerably housed individuals from 10 SROs (Vancouver) and 10 rooming houses each in Toronto and Ottawa to obtain a sample of 200 participants in each city. Due to challenges in gaining access to residents at these sites, our sampling plan for vulnerably housed participants was modified to include recruitment at meal programs, community health centers, and drop-in centers. Agency staff initially approached potential participants who were vulnerably housed to see if they were interested and trained research interviewers then screened the potential participants. The research interviewers administered the survey on-site in a private room in the shelter, SRO, rooming house, neighbourhood coffee shop or research office. Our final sample was comprised of 595 homeless and 596 vulnerably housed adults.Trained research interviewers explained the purpose of the study to eligible individuals and asked if they were interested in participating in the study. The research interviewer answered any questions that the potential participant had and if they agreed to participate, they were given two copies of the consent form to read and sign. Individuals were provided time to review the information in the consent form and ask any questions before being asked to give consent. To ensure that consent was informed for individuals with limited literacy, the research interviewer verbally reviewed the entire consent form. The participant retained one copy and the research interviewer retained the other copy. The participants were paid an honorarium ($20 CDN) following the interview. We obtained ethics approval from the Research Ethics Board at St. Michael\u2019s Hospital (Toronto), the University of Ottawa, and the University of British Columbia (Vancouver). All potential participants who declined to participate or otherwise did not participate were eligible for any applicable treatment and services and were not disadvantaged in any other way by not participating in the study.Structured interviews lasted 60 to 90 minutes and contained validated measures as well as open-ended qualitative questions allowing participants to comment in more detail were from Vancouver, 399 (33.4%) were from Toronto and 396 (33.3%) were from Ottawa. As presented in In the two multiple logistic regression models that focused on unmet needs \u20134, we foIn the third multiple logistic regression model , which oProblematic drug use among homeless and vulnerably housed persons in our sample was associated with unmet physical and mental health care needs. Having a higher burden of chronic health conditions as well as ever being diagnosed with a mental health problem were also independently associated with unmet health care needs. Given the premature mortality among homeless and vulnerably housed persons Among those with a problematic substance use disorder, problematic drug use (DAST-10\u22656) was associated with a greater likelihood of accessing addiction treatment compared to those with problematic alcohol use (AUDIT\u226520). Furthermore, having a primary care provider was positively associated with accessing addiction treatment and highlights the importance of engagement in care. This improved access to addiction treatment is critical given that substance use among persons who are homeless and vulnerably housed can be a barrier to residential stability and engagement in mental and physical health care Our study had some limitations. Given that we do not know the characteristics or true size of the population of persons who are homeless and vulnerably housed in these three cities (or in Canada), it was not possible to construct a comprehensive sampling frame, and therefore our sample may not be representative. However, we did use sampling strategies comparable to those described in other studies of this population. Although we used the DAST-10 and the AUDIT, which are validated screening tools for problematic drug and alcohol use, including in vulnerable populations, there may have been social desirability bias in the reporting of drug and alcohol use resulting in an underestimation of prevalence levels. In addition, individuals who were under the influence of alcohol or drugs at the time of recruitment were excluded because they were unable to provide informed consent. The presence of chronic health conditions and mental health disorders was determined by self-report that may also lead to an under estimation of prevalence rates. Our measure of unmet physical health care need did not explicitly specify physical health and it is possible that some participants may have included mental health needs when responding to this question. However, this question was derived from the definition of unmet health care needs used in other population-based, national surveys In summary, we found that, among homeless and vulnerably housed individuals, problematic drug use was associated with accessing addiction treatment and having unmet health care needs. The fact that homeless and vulnerably housed individuals with problematic drug use recognize that they have unmet needs for care suggests that they will engage with services if they are provided in an appropriate context. Given the complex health and social situation of this vulnerable group, strategies to provide coordinated, comprehensive health care services that include addiction treatment should be developed and integrated within supportive and supported housing and other community support models of care. Outreach services may provide a variety of access points for these individuals with the goal of engaging this population into care. Based on the findings of this study, policymakers and planners should develop integrated services that are easily accessible and appropriate for homeless and vulnerably housed individuals to close the gap between need and treatment. Such programs would help address their physical, mental and addiction disorders while at the same time assist them to re-establish residential stability, which may decrease the possibility of relapse and improve access to other important resources"} +{"text": "The impact of excess gestational weight gain (GWG) on maternal and child health outcomes is well documented. Understanding how health care providers view and manage GWG may assist with influencing healthy gestational weight outcomes. This study aimed to assess General Practitioner's (GPs) perspectives regarding the management and assessment of GWG and to understand how GPs can be best supported to provide healthy GWG advice to pregnant women.Descriptive qualitative research methods utilising semi - structured interview questions to assess GPs perspectives and management of GWG. GPs participating in shared antenatal care in Geelong, Victoria and Sydney, New South Wales were invited to participate in semi - structured, individual interviews via telephone or in person. Interviews were digitally recorded and transcribed verbatim. Data was analysed utilising thematic analysis for common emerging themes.Twenty eight GPs participated, 14 from each state. Common themes emerged relating to awareness of the implications of excess GWG, advice regarding weight gain, regularity of gestational weighing by GPs, options for GPs to seek support to provide healthy lifestyle behaviour advice and barriers to engaging pregnant women about their weight. GPs perspectives concerning excess GWG were varied. They frequently acknowledged maternal and child health complications resulting from excess GWG yet weighing practices and GWG advice appeared to be inconsistent. The preferred support option to promote healthy weight was referral to allied health practitioners yet GPs noted that cost and limited access were barriers to achieving this.GPs were aware of the importance of healthy GWG yet routine weighing was not standard practice for diverse reasons. Management of GWG and perspectives of the issue varied widely. Time efficient and cost effective interventions may assist GPs in ensuring women are supported in achieving healthy GWG to provide optimal maternal and infant health outcomes. In the 2. Some ev2. Mean GW2,7 and th2 are commExcess weight gain during pregnancy places both mother and child at increased risk of serious health complications -12 and hEmerging evidence suggests that excess GWG is associated with increased offspring obesity. In addition to excess GWG, multiple studies have shown that maternal obesity is also a major risk factor for childhood obesity -23. IncrWhile the delivery of prenatal care will differ across countries, a number of health professionals, including physicians, midwives and obstetricians consistently deliver such services throughout pregnancy . In AustIn particular, General Practitioners (GPs) have been identified as vital contributors to the treatment of overweight and obesity in the non - pregnant population ,30 and hFew studies exist focusing on the views of antenatal healthcare professionals regarding gestational weight management and impact and, to General Practitioners in Geelong participating in shared antenatal care were identified by telephoning all medical practices from a practitioner list provided by the GP Association of Geelong. Information was obtained regarding whether or not the GP was a participant of shared antenatal care. In Sydney, two divisions of general practice were contacted from where a list of GPs participating shared antenatal care was obtained. In quantitative studies, generalizability is achieved via statistical sampling procedure, however such sampling procedures are mostly unavailable in qualitative research . In our A descriptive qualitative approach was used in this study to understand more deeply the views of GPs regarding their management of excess GWG. Methods of qualitative description as described by Sandelowski ,38 were Individual interviews were employed to enable flexibility and best opportunity to engage with the GP. Interviews were conducted face to face in the Geelong region as this was the main location of the research team and Sydney GPs were interviewed via telephone. Research comparing the reliability and validity of face-to-face and phone interviews has shown a high level of agreement . Semi - A total of 32 GPs responded to the invitation letter and two of these GPs did not schedule an interview as they were not contactable. Thirty GPs scheduled an interview however 2 GPs were not available at the time of the telephone interview and subsequently did not participate in the study. Twenty eight GPs took part in the interviews, 14 were from Geelong, and 14 from Sydney. GPs were from 22 different clinics within the Greater City of Geelong and metropolitan Sydney and the practices represented a range of socio demographic regions. No GPs withdrew from the study and data from all 28 interviews were included in the analyses. Data was collected until data saturation occurred, that is, when the number of samples have effectively addressed all aspects of the emerging themes and phenomenon with optimal data quality .The GPs' responses clustered into five broad themes: (i) GPs own awareness of the issues/identifiable problems of overweight/obesity/excess weight gain; (ii) provision of advice regarding GWG and healthy lifestyle behaviour advice; (iii) attitudes and practices around routine gestational weighing; (iv) practical barriers to management; (v) how GPs feel they could be best supported. Randomly selected quotes are presented by these themes in Table General Practitioners identified that excess GWG and gestational overweight and obesity adversely affects both the mother and child and the majority of GPs reported that gestational diabetes was one of the most important implications of excess GWG, overweight or obesity in pregnancy. General Practitioners frequently identified pre - eclampsia, hypertension and delivery complications as major implications of excess GWG and maternal overweight and obesity.Other adverse complications identified infrequently included higher rates of miscarriage, increased rates of unplanned caesarean section, general unspecified obstetric complications, maternal morbidity or mortality, conditions of fatigue, high cholesterol, decreased cardiac fitness, post natal depression and chronic diseases later in life and excessive weight in the post partum period.General Practitioners recognised varied child health outcomes associated with excess GWG and maternal overweight and obesity including macrosomia, foetal abnormalities and an inability of the practitioner to palpate and examine the baby thus placing the child at higher risk of undetected abnormalities. Few GPs identified child overweight or obesity in the long term as being amongst the most important identifiable problems.Advice regarding recommended GWG was not consistent and GPs rarely took into account BMI at the start of pregnancy when offering advice. Amount to gain in pregnancy ranged from 8 kg to 15 kg for normal weight women and a small proportion of GPs offered no weight gain advice or offered advice only when asked by the women.Other than specific nutrient advice and nutrition recommendations for pregnancy, GPs considered general healthy eating advice (in the absence of exercise advice) among the most important topics that should be covered in the initial consultation with the pregnant woman rarely. They infrequently provided exercise advice during pregnancy or mentioned that both general healthy eating advice as well as exercise advice should be given in the first consultation. GPs rarely reported that gestational weight would be among the most important issues to be discussed at the first appointment.Weighing practices differed among GPs and most GPs weighed women occasionally throughout their pregnancies. Only a small proportion of GPs weighed women at every visit and few GPs weighed at the first consultation only or never. Attitudes towards weighing varied and there was a clear division in comments provided by the GPs for and against weighing, highlighting a distinct division surrounding usefulness and appropriateness of weighing.When GPs were asked about barriers that prevent provision of support to provide healthy lifestyle advice and manage GWG, responses were mixed with approximately one third of GPs mentioning cost to the patient as a financial barrier to provision of additional support, and very few GPs reporting cost as a barrier to hire additional clinicians at the medical practice. Other barriers mentioned by few GPs included lack of space for additional practitioners at the clinic, lack of GP time and short consultation periods and lack of organisational structure within the practice including extensive patient waiting lists as well as patients for weight management being sent to the hospital diabetes clinic and therefore further GP support not being required.The majority of GPs reported being more likely to assess, advise and or refer for weight management to other health practitioners if the woman was overweight at first presentation. Many GPs reported that multidisciplinary support and input from other practitioners would help them feel best supported and most GPs reported that Dietitian support would be preferred. Some GPs suggested support from Exercise Physiologists, Diabetes Educators, Endocrinologists or Midwives would be the preferred support. General Practitioners rarely thought that Personal Trainers could offer useful support.Few GPs reported that support provided to women via the internet or written resources to reiterate their own advice would be preferred support. When asked specifically whether they thought these avenues of information would be useful in helping convey healthy eating and activity advice and to assist weight management and provide support to the practitioner and also the woman herself, most GPs thought that at least one of these forms of education would be helpful.This study aimed to examine the perspectives of GPs participating in shared antenatal care regarding GWG and to understand opportunities for primary and secondary prevention of excess GWG. To our knowledge this was the first study to investigate how GPs feel they would be best supported to provide healthy lifestyle advice to pregnant women and healthy GWG management. This study suggests that these GPs had mixed views regarding the management and prevention of excess GWG, demonstrated by their reported recommendations for weight gain in pregnancy, weighing practices and views regarding maternal and child health complications associated with excess GWG being highly varied.As revealed in this study, there is uncertainty regarding the need or even the desirability to weigh pregnant women in GP consultations. Over a third of GPs in our study either did not weigh at all or weighed only when asked to by the patient. The barriers to weighing women in pregnancy identified in this study were time restraints and uncertainty regarding what advice to give regarding weight gain. Similar findings are reported by Olander et al in a stuThe advice regarding the amount of weight to gain in pregnancy varied widely. This is perhaps not surprising as there are no formal recommendations for GWG in Australia. Women who are informed of their own target for gestational weight gain, however, have been found to be more likely to gain within recommended IOM ranges The incoIn the non - pregnant population, provision of advice from primary care practitioners incorporating weight gain targets has been found to be an effective strategy in weight management . Potter Despite inconsistencies in GWG advice, GPs in this study frequently acknowledged the impact of excess GWG, overweight and obesity on maternal and child health outcomes. Maternal conditions were more frequently reported as co morbidities of excess GWG than were implications for the child . Interestingly, long term child health conditions including offspring overweight and obesity and childhood diabetes were infrequently acknowledged as risks associated with excess GWG.Recent longitudinal studies suggest that long - term adverse effects on offspring weight and body fatness are important correlates of excess GWG. For example in a prospective study of more than 1000 mother - child pairs, Oken et al reports Antenatal care has previously been described as an opportune time for healthcare providers to assist women in altering lifestyle affecting weight, nutrition and physical activity . Given tOne alternative approach may be the provision of an Australian government subsidised (Medicare) allied health Enhance Primary Care (EPC) plan, offered to pregnant women for healthy weight and lifetyle management. In the current Australian Medicare system, EPC plans allow for a limited number of GP referred visits per year to allied health practitioners. Patients must be diagnosed with a chronic disease, such as obesity, alongside resulting co -morbidities (for example hypertension or hypercholesterolaemia), and are referred for management of these specific conditions. However pregnancy, subsequent excess weight gain and pregnancy induced co - morbidities does not qualify for management under the government subsidised EPC plan yet long term health benefits and public health savings could potentially justify this scheme for pregnant women.Limitations of the study included the structure of qualitative data collection through interviews. Assumptions might be made that individual participants have the capacity to reflect and interpret the situation and their actions. Offering the option of telephone interviews to cover accessibility issues may result in interaction not as intimate as face-to-face interviews and does not allow the researcher an opportunity to observe the informant's responses. However interviews do allow participants space to provide information, including historical information, verbally and give the researcher control over line of questioning and thisOpportunities to help address some of the existing barriers to employing additional health care providers as a referral point for GPs may lie with more cost effective and time efficient avenues of support. Perhaps GP referral to internet resources, telephone support or written education material that provides useful and reliable healthy lifestyle advice for pregnant women in the management of GWG could be beneficial.General Practitioners frequently participating in shared antenatal care identify many adverse maternal and child health outcomes associated with excess GWG, however, management of excess GWG and perspectives of the issue vary widely. From a public health perspective, health care practitioners such as GPs are vital in promoting awareness of the importance of healthy GWG. Strategies to best support GPs in their management of GWG are needed so that best outcomes are achieved for maternal and child health. Further research into how best to support GPs participating in shared antenatal care, along with women during their pregnancy, is needed to help promote healthy GWG.The authors declare that they have no competing interests.PV was responsible for co - ordination of the study, all data collection, contributed to data analyses and drafted the manuscript, KC conceived of the study contributed to its design, contributed to data analyses and helped draft the manuscript, JW contributed to the data analyses and helped draft the manuscript, JO contributed to the recruitment process of GPs in Geelong involved in the study, EDW contributed to the recruitment of GPs in Sydney and to the design of the study. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/12/124/prepub"} +{"text": "Emerging infectious diseases pose a significant threat to human and animal welfare. A high proportion of emerging and reemerging infectious diseases are zoonoses derived from wildlife Belonging to the order Chiroptera, bats represent a remarkable example of adaptive evolution. Over 1,200 species of bats exist worldwide, making them the second most species-rich mammalian order. The Chiroptera order is classified into the suborders Yinpterochiroptera and Yangchiroptera, which represent biologically and ecologically diverse species that are distributed globally In many respects, bats represent the perfect reservoir for emerging zoonotic pathogens. They often live in large colonies or roosts; they can, through flight, travel and disseminate viruses over considerable distances; and they enjoy remarkable longevity for their body size. Anthropogenic activities are increasing interactions between bats, humans, and livestock, thereby heightening the zoonotic potential conferred by those characteristics. For these reasons, bats present a significant potential source of emerging infectious diseases.The sheer number and diversity of viruses identified in bats is extraordinary and appears to be increasing almost daily. The recent identification of bat-derived viruses closely related to human pathogens, including hepaciviruses, pegiviruses The significance of bats as a source of zoonotic disease became tragically clear with the emergence of Hendra virus (HeV) in northern Australia in 1994. In two independent spillover events, this novel paramyxovirus claimed the lives of 15 horses and of two humans who had contact with infected horses RhinolophusLate 2002 saw one of the most high-profile examples of infectious disease emergence. The global epidemic of severe acute respiratory syndrome (SARS) ultimately caused the death of approximately 800 people. Initial efforts to identify the natural reservoir of the responsible SARS coronavirus (CoV) focused on palm civets, which had been sold in live animal markets in the Guangdong province in southern China. Subsequent research by two independent groups, however, demonstrated that civets were more likely an amplifying host and that the true reservoir of the SARS-like CoV were bats of the genus Rousettus aegyptiacus) that had colonised the mine. Genetic analysis demonstrated that the Marburg virus isolated from the infected mine workers was highly similar to those circulating in the R. aegyptiacus population Ebola and Marburg are among the most deadly viruses known to humankind. Despite their impact, the natural reservoir for these viruses has not been definitively identified. Viral RNA specific to both Ebola and Marburg has been identified in a number of fruit bat species from Gabon and Democratic Republic of Congo Pterpous alecto) and David's Myotis (Myotis davidii) compared to their orthologs in seven other mammalian species The strength of evidence that bats are a reservoir of zoonotic viruses is undeniable. With the exception of lyssaviruses (such as rabies), bats generally harbour viruses with no clinical signs of disease. Many species spanning the major Chiroptera suborders host zoonotic viruses, so it seems unlikely that bats' ability to asymptomatically carry viruses is a recently acquired trait. Bats and viruses have undoubtedly coevolved over millions of years. With this in mind, we would expect signatures of coevolution to be visible at the interface between bats and viruses, i.e., the innate immune system. Indeed, a number of genes involved in innate immunity were found to be under strong positive selection in the recently sequenced genomes of the Australian black flying fox and the little brown bat (Myotis lucifugus) within the NIH-funded 29 Mammals Project P. alecto) and David's Myotis (M. davidii). Pronounced genomic changes were observed in a number of immune genes in both species. For instance, all members of the PYHIN gene family, which play an important role in DNA sensing and formation of inflammasomes, appear to be lost in both bat species All things considered, bats represent an important model species for studying the evolution of antiviral immunity. Knowledge obtained from studying bats could have broad significance in human medical research. Although evolutionary signatures of coexistence between bats and viruses exist, the mechanism/s by which bats asymptomatically maintain viruses remains unknown. Comparative genomics represents one strategy for identifying such mechanisms. To date, four bat genomes have been subjected to whole genome sequencing. The first bats to be sequenced were the large flying fox (The four bat genomes now available represent vital resources to the scientific community. When combined with transcriptome and proteome datasets, these approaches provide a powerful strategy for investigating host-pathogen interactions on a global scale.The fact that bats harbour such a large number of viruses poses an important question: do these viruses provide any benefit to the host? In some instances, primary viral infections have the ability to prevent subsequent infections by homologous viruses. Continuous infection of bats with nonpathogenic antecedent adapted viruses may actually bestow a superior antiviral immune state against new invading viral pathogens. It has also been shown that persistent infection of herpesvirus can modulate the innate immune system of mice, resulting in protection against lethal infection of bacteria"} +{"text": "Future of nursing\u201d report. This paper describes specific challenges and provides strategies to improve advanced practice nursing clinical education in order to ensure that a sufficient number of APRNs are available to work in educational, practice, and research settings. Best practices are identified through a review of classic and current nursing literature. Strategies include intensive interprofessional collaborations and radical curriculum revisions such as increased use of simulation and domestic and international service work. Nurse educators must work with all stakeholders to create effective and lasting change.Nursing education programs may face significant difficulty as they struggle to prepare sufficient numbers of advanced practice registered nurses to fulfill the vision of helping to design an improved US healthcare system as described in the Institute of Medicine's \u201c National and international reports, including one published recently by the Institute of Medicine , describFuture of nursing\u201d report published in 2011 [While barriers to practice are significant, innovative approaches to clinical education and curricular transformation offer promise to nursing administrators, nursing educators, and practicing APRNs who are committed to preparing a highly qualified APRN workforce that will serve future generations of Americans. The rapid development and establishment of the practice doctorate has generated cautious enthusiasm among many nurse educators who are eager to help APRNs achieve their fullest potential in clinical practice. The purpose of this paper is to describe challenges in providing APRN clinical education and to propose achievable strategies for educating future APRNs to participate fully in transforming the United States healthcare system. We argue that the time is right to identify and implement educational practices that will lead to the optimal development of clinical skills, knowledge, and practice acumen and help meet the goals endorsed by national nursing organizations and set forth in the \u201cAdvanced practice registered nurses include nurse practitioners (NPs), certified nurse-midwives (CNMs), certified registered nurse anesthetists (CRNAs), and clinical nurse specialists (CNSs). APRNs represent an underutilized source of quality health care providers . Only 3.We define many challenges associated with providing effective APRN clinical education, particularly in clinical practice settings. Our analysis of the challenges in For the purpose of this paper, we defined internal challenges as those existing within the profession and/or within educational organizations responsible for preparing APRNs for practice. When considering these internal challenges, we discovered, not surprisingly, that the literature was dominated by information about the critical role of the growing nursing and nursing faculty shortages. Clearly, not enough qualified nursing faculty are available to meet the nation's need for increased numbers of APRNs, and the projections describing future shortfalls are bleak , 16. WhiEducational organizations find it increasingly difficult to attract qualified APRNs willing to serve in faculty roles. The demand for APRNs in both educational institutions and in a variety of practice settings has increased simultaneously, but educational institutions are disadvantaged by their inability to offer competitive compensation packages. Constrained budgets result in compressed salaries throughout higher education systems, increasing the gap between salaries available in practice and those offered for teaching positions. When APRNs do pursue education at the PhD level, they often graduate only to face the reality of the tenure process in research-driven educational institutions. Emphasis on the role of faculty in conducting research and generating research-related revenue limits the availability of PhD-prepared APRN faculty to participate in direct clinical supervision of APRN students. One result is that the primary responsibility for APRN clinical education falls to faculty not eligible for tenure and whosAs many schools of nursing transition to the Doctorate of Nursing Practice (DNP), existing advanced practitioner faculty without a doctorate may find that they are underqualified . InstituThe number of annual graduates from APRN programs has fallen from a peak in 1998 . This deSince World War II, educational programs offering Associate Degrees have proliferated and graduates of those programs have become Registered Nurses (ADNs) in increasing numbers. In turn, this internal challenge has influenced the shortage of APRNs, given that nurses prepared in ADN programs are less likely than bachelor's prepared nurses to obtain graduate degrees . If ADNsThe primary challenge facing APRN education from outside educational institutions is the limited number of available clinical sites and preceptors . To incrThe limited supply of potential preceptors and clinical sites is exacerbated by competitive forces. Medical resident preparation dominates the use of available clinical sites in hospitals. Federal funding through the Medicare program supports resident education, but not APRN preparation. In many academic medical centers, APRNs are employed for medical student and resident education, further reducing the field of potential preceptors for APRN students . NursingState regulations and specialty certification agencies place additional requirements on educational institutions that further limit the capacity to prepare APRN students. Direct supervision of students limits the number of students individual preceptors may have at any given time. The requirement for low student-faculty ratios in clinical courses makes APRN education expensive. For example, the National Task Force on Quality Nurse Practitioner Education recommends faculty-to-student ratios of 1\u2009:\u20096 in situations where there is indirect clinical supervision . RequireThe limited availability of national funding poses a significant external challenge to successful APRN education. Increasing the capacity of educational institutions to educate APRNs requires additional funding. The current prioritization for medical education and residency training through federal support makes increasing funding for nursing education difficult. Furthermore, current research funding priorities by the National Institute of Nursing Research do not support the investigation of nursing education issues, nor do they support research about the implementation of innovative practice education models at the graduate level. In many research organizations, nursing faculty pursuing academic careers and tenure are discouraged from pursuing clinical education research as a funded line of inquiry. Among potential APRN preceptors, there may be a lack of willingness to precept APRN students due to a lack of incentives beyond the ideals of serving the profession. Most educational institutions are unable to compensate preceptors financially for their teaching roles and are limited in the nonfinancial benefits they may provide preceptors such as faculty titles and access to educational resources. Potential preceptors may see the challenges to practitioner productivity or the additional time commitments of being a preceptor as disincentives to assuming the role. The lack of formal preparation and support for the teaching role may further discourage APRNs from being a preceptor. While direct or graduate entry training is increasingly used as a mechanism for increasing the supply of APRN graduates, potential preceptors may be resistant to training students with little or no health care experience.The final challenge to increasing the preparation of APRNs is closely tied to the profession's relationship with the citizens who are served. Nursing continues to be a profession dominated by Caucasian women, a limitation that affects the profession's negotiation of relationships with other more male-dominated professions. In addition to the chronic underrepresentation of men, diverse populations, and rural inhabitants in the nursing workforce, advanced practice nursing continues to contend with an identity crisis among the US population as a whole, who suffer from a knowledge deficit regarding the skills and abilities of APRNs. Historically, nurses work at the direction of physicians, and cultural and occupational patterns that reinforce this dependent relationship are slow to change. While it is not clear the American Medical Association's efforts to counter the IOM's Future of Nursing Report will be entirely successful , the lacThe IOM report presents an unparalleled challenge to nursing educators, that is, to foster the development of an \u201cimproved education system that promotes seamless academic progression\u201d [In preparing this discussion of strategies and solutions described in For the purposes of this paper, internal strategies are those that can be undertaken within nursing education programs and the universities that house them, while external are those that reflect some level of engagement with other organizations including other nursing education programs and healthcare organizations. As noted above and in the IOM report, the expansion of advanced nursing education programs is hampered by a faculty shortage that represents the convergence of multiple factors. These include supply-side problems related to the nursing shortage itself as well as to competitive factors that reflect, among other things, the relatively high cost of graduate nursing education when compared to the earning potential of nurse educators. Like prelicensure nursing education, advanced practice nursing education is resource intensive, requiring sophisticated laboratory settings, computer equipment, and high faculty-to-student ratios. One approach with potential to aid in the nursing faculty shortage and to make more clinical resources available for APRN education involves internal efforts by educational institutions to develop and strengthen collaborative partnerships. The American Association of Colleges of Nursing and the In almost every aspect, curriculum, teaching, and learning must undergo radical transformation, as Benner and her colleagues asserted in 2010 . NursingProblem-based learning can be integrated within a competency-based framework or as a stand-alone strategy to enhance the development of critical thinking and hypothesis-testing skills , 37. ProThe use of simulation in nursing education is becoming increasingly popular for its ability to enhance the critical thinking of advanced practice nursing students and because it provides a useful evaluative tool for faculty . ThroughInterprofessional education offers the potential to enhance efficiency in the provision of clinical education for all students and fostDistance education helps create opportunities for otherwise place-bound nurses to pursue graduate studies to become APRNs by extending the reach of nursing education programs beyond traditional boundaries. Improvements in online course management software and evidence-based distance teaching pedagogical approaches provide a foundation for the asynchronous delivery of high-quality and engaging course content. The use of streaming media and a wide range of unified communication technologies enhance faculty-student and student-student engagement. Despite the obvious challenges of providing adequate supervision for APRN students who may be completing coursework from remote areas and with little direct faculty contact, the rewards of accessing optimal professional education using distance education technologies can be great for place-bound students living in underserved communities. To help these programs and students to succeed, educational programs can develop innovative faculty hiring agreements, hiring APRNs who live in the students' home communities to provide supervision for didactic learning experiences as well as for clinical practice and evaluation. The education and support these faculty members may require can be provided in part by professional development or continuing education programming.Not all responsibility for enhancing advanced practice nursing lies with classroom or faculty-driven learning activities. As the number of available clinical sites and preceptors has declined, the need to consider effective alternatives for APRN clinical education has increased. Nursing education programs must \u201caggressively pursue alternative clinical learning sites and experiences\u201d if they want to assure that students participate in appropriate patient-centered learning activities .The development of partnerships with a broad range of community organizations and providers can create mutual benefits and provide additional learning opportunities for APRN students. While faculty may believe that an ideal clinical placement would pair students with preceptors in one-to-one relationships with clients arriving at set appointment times, there may be great value in developing partnerships with agencies and individuals who provide care in different models and settings . The devIn 2004, Connolly and her colleagues described the innovative creation of a collaborative approach to nursing education . AlthougAcademic health centers that integrate faculty practice opportunities with clinical education experience opportunities may well provide ideal environments for APRN education. Not all graduate nursing programs are situated on campuses that house such centers, however. Heller and Goldwater suggest that the development of innovative patient-driven programs, designed to improve access, may also offer enhanced clinical education opportunities for advanced practice students . Their eAlthough they can be costly and somewhat difficult to coordinate and offer, domestic and international healthcare missions do offer APRN students and faculty innovative opportunities to provide care to the underserved. While many available international opportunities are useful for student enrichment alone, with secure funding, careful planning, and rigorous attention to the management of learning and evaluation, successful programs can extend clinical education beyond local limits . ParticiFinally, funding must be made available to support the vision that advanced practice nurses will assume a large measure of responsibility for the success of healthcare reform in the United States. Improvement in the healthcare system requires the collaborative effort of many disciplines. At present, the current \u201csystem of medical education and graduate training\u2026 is not aligned with the delivery system reforms essential for increasing the value of health care in the United States.\u201d . It willThe Institute of Medicine Report on The Future of Nursing calls fo"} +{"text": "Hereditary gingival fibromatosis (HGF) is a rare condition which manifests itself by an enlarged gingival tissue covering teeth to various extents. The condition may occur isolated or as part of a syndrome. This paper presents a case of 9-year-old female patient suffering from HGF with chief complaint of mouth protrusion. Cephalometric findings showed severe mandibular deficiency and vertical maxillary excess. Patient exhibited perioral muscle contraction on mouth closing. After discussing the treatment possibilities with the patient and her parents, the decision was made to wait until growth potential decreases (following the adolescent growth spurt) and to correct the problem with orthognathic surgery. Hereditary gingival fibromatosis (HGF) is a rare condition with the prevalence of one per 175000 population and equal distribution in sexes . The excA 9-year-old female patient visited the department of orthodontics complaining of mouth protrusion and enlaIntraoral examination showed normal development of the dentition. Excessive overjet and protrusion of upper teeth were observed . The patPanoramic radiograph showed normal development of the dentition . PermaneSince the dentition showed normal development and the eruption of permanent teeth was not affected by the condition, repeated gingivectomies were not included in the treatment plan. Treatment options were discussed with the patient and her parents, including growth modification before adolescent growth spurt or orthognathic surgery well after patient's growth spurt at puberty. It was explained for the parents that the long face growth pattern is hard to modify and the treatment must continue over many years which needs excellent cooperation . It alsoThe mode of genetic transmission in this patient was consistent with an autosomal dominant inheritance since both sexes and successive generations were affected . As stated earlier both autosomal dominant and recessive modes of transmission of HGF have been reported \u20135. RecenDifferential diagnosis of gingival enlargements includes enlargement associated with hormonal changes (such as in pregnancy), drug-induced gingival overgrowth, or enlargements due to genetic disorders . InflammThe histological findings are nonspecific and include acanthotic and hyperkeratotic epithelium with elongated rete ridges deeply extended to a relative avascular connective tissue with densely arranged collagen bundles and numerous fibroblasts , 14. TwoAs stated earlier HGF can be an isolated or syndrome-associated condition. The association of the entity with growth hormone deficiency secondary to lack of growth hormone releasing factor secretion has also been reported . The preThe side effects of gingival enlargement in HGF include speech problems, painful mastication, spacing and diastema, malocclusion, and overretention of primary teeth . In our This paper presents diagnosis and treatment plan of a patient with HGF and severe skeletal malocclusion. Regarding the rarity of the condition only few case reports addressing the orthodontic management of the condition exist. The case presented in this paper differs from previous reports since she needed combined orthodontic and orthognathic treatment because of severe skeletal discrepancies of the jaws. After precise evaluation of risks, costs, and benefits associated with different treatment possibilities and discussing them with the patient and her parents, orthognathic surgery at appropriate time was planned."} +{"text": "When prey animals detect the odor of a predator a constellation of fear-related autonomic, endocrine, and behavioral responses rapidly occur to facilitate survival. How olfactory sensory systems process predator odor and channel that information to specific brain circuits is a fundamental issue that is not clearly understood. However, research in the last 15 years has begun to identify some of the essential features of the sensory detection systems and brain structures that underlie predator odor fear. For instance, the main (MOS) and accessory olfactory systems (AOS) detect predator odors and different types of predator odors are sensed by specific receptors located in either the MOS or AOS. However, complex predator chemosignals may be processed by both the MOS and AOS, which complicate our understanding of the specific neural circuits connected directly and indirectly from the MOS and AOS to activate the physiological and behavioral components of unconditioned and conditioned fear. Studies indicate that brain structures including the dorsal periaqueductal gray (DPAG), paraventricular nucleus (PVN) of the hypothalamus, and the medial amygdala (MeA) appear to be broadly involved in predator odor induced autonomic activity and hypothalamic-pituitary-adrenal (HPA) stress hormone secretion. The MeA also plays a key role in predator odor unconditioned fear behavior and retrieval of contextual fear memory associated with prior predator odor experiences. Other neural structures including the bed nucleus of the stria terminalis and the ventral hippocampus (VHC) appear prominently involved in predator odor fear behavior. The basolateral amygdala (BLA), medial hypothalamic nuclei, and medial prefrontal cortex (mPFC) are also activated by some but not all predator odors. Future research that characterizes how distinct predator odors are uniquely processed in olfactory systems and neural circuits will provide significant insights into the differences of how diverse predator odors activate fear. Fear and anxiety are activated by threat and the ability to regulate their responses is essential to adaptation and survival. Moreover, an extensive body of work indicates that abnormalities in the detection of threat may lead to pathological fear and anxiety that express odorant receptors (ORs) and trace amine associated receptors (TAARs) , a chemoreceptive structure situated at the base of the nasal septum, which houses the microvillar vomeronasal sensory neurons (VSNs). Pheromones are detected by three classes of VSN receptors including vomeronasal receptor type 1 (V1R) and type 2 (V2R) and formyl peptide receptors exhibit a robust increase in electrical activity in the AOB , snake (shed skin), and rat urine family Ma, . The locThe trigeminal system is essential in protecting against toxic or irritating odors by triggering reflexes such as apnea and sneezing. In mice and rats, noxious, pungent odors activate the trigeminal system via a large population of chemosensory cells that reach the surface of the nasal epithelium to form synaptic contacts with trigeminal afferent nerve fibers to rapidly trigger physiological responses that facilitate immediate survival in a dangerous situation , which was implicated a number of years ago to modulate cardiovascular functions in mice and rats plays an important integrative role in stress by sending neuronal projections to the median eminence to regulate pituitary-adrenal hormone secretion , a recipient of both direct and indirect MOS and direct AOS projections , which is widely implicated in fear conditioning using footshock as the unconditioned stimulus paired with auditory is another target of interest in predator odor studies due to the broad role of the CeA in modulating autonomic, endocrine, and anxiety and fear behavior Davis, . HoweverAnother major direct and indirect projection from olfactory systems is the BST as previously discussed. Studies revealed that inactivation of the BST, especially the ventral BST, reduces freezing when rats are exposed to TMT , hippocampal lesions exhibited deficits in freezing and crouching when exposed to cat odor is connected to a number of brain structures including the amygdala, hypothalamus, and periaqueductal gray (Gabbott et al., Recent studies implicated the mPFC, consisting of the prelimbic and infralimbic cortex, in predator odor-induced unconditioned fear but the precise role of the mPFC in modulating predator odor fear is not clear. One study reported that temporary inactivation of the prelimbic region increased freezing in rats exposed to TMT (Fitzpatrick et al., egr-1, a gene transcription factor linked to learning and memory synaptic plasticity (Alberini, egr-1 mRNA in the mPFC (Asok et al., In addition to the predator odor-induced behavioral differences involving the mPFC, studies indicate that exposure to cat odor activates c-Fos expression (Staples et al., Several distinct and overlapping brain regions have been identified that play key roles in predator odor activation of autonomic, endocrine, and fear behavior responses. For example, the MeA, which receive direct projections from MOS and AOS, appears to have a necessary role in general predator odor activation of both HPA hormone secretion and unconditioned fear behavior (see Tables A number of investigators reported that exposure to cat odor induces robust contextual (Blanchard et al., In stark contrast to the extensively studied olfactory connected neural systems in reproductive behavior or the neural systems in emotional learning and memory, based largely on work involving the application of the unconditioned footshock stimulus, knowledge on biology of predator odor fear is limited. Future predator odor research should address not only the brain circuits that modulate unconditioned and conditioned fear but also the olfactory sensory structures such as the accessory and main olfactory bulbs that are implicated in important developmental, social, and reproductive learning and memory processing (Brennan and Keverne, The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Ecklonia radiata. There was no genetic differentiation of kelp between estuaries and the open coast and the presence of estuaries did not increase genetic differentiation among open coast populations. Similarly, there were no differences in level of inbreeding or genetic diversity between estuarine and open coast populations. The presence of large estuaries along rocky coastlines does not appear to influence genetic structure of this kelp and factors other than physical heterogeneity of habitat are likely more important determinants of regional connectivity. Marine reserves are currently lacking in this bioregion and may be designated in the future. Knowledge of the factors that influence important habitat forming organisms such as kelp contribute to informed and effective marine protected area design and conservation initiatives to maintain resilience of important marine habitats.With marine protected areas being established worldwide there is a pressing need to understand how the physical setting in which these areas are placed influences patterns of dispersal and connectivity of important marine organisms. This is particularly critical for dynamic and complex nearshore marine environments where patterns of genetic structure of organisms are often chaotic and uncoupled from broad scale physical processes. This study determines the influence of habitat heterogeneity (presence of estuaries) on patterns of genetic structure and connectivity of the common kelp, Knowledge of the physical and biological factors that structure patterns of connectivity and dispersal of nearshore marine organisms is critical for effective marine conservation Marine Protected Areas (MPAs) are commonly designated in nearshore marine environments which are inherently physically dynamic and spatially complex. Further, individual MPAs are designed on local spatial scales where dispersal and connectivity of marine organisms is rarely structured by the broad scale physical processes traditionally known to impart structure along entire coastlines Nearshore marine environments are often characterised by rocky reefs that are interspersed with habitat discontinuities and potential barriers to dispersal such as sandy beaches, estuaries and bays. Such heterogeneities of habitat have the potential to restrict dispersal and gene flow of rocky reef organisms and create complex patterns of genetic structure among populations. The presence of estuaries and beaches has been shown to increase genetic differentiation among rocky coast populations of intertidal Ecklonia radiata. Ecklonia radiata (C. Agardh) J. Agardh is the dominant form of biogenic habitat on Australia's temperate reefs E. radiata mostly inhabits open coast sites and is the most abundant macroalga on temperate rocky reefs of temperate Australia. However, in estuarine habitats this species can live on the small amount of available hard substrata and in the upper reaches of estuaries where suitable rocky substrata is often lacking, it is commonly found growing on artificial structures such as pontoons, pilings and breakwalls. E. radiata has a typical Laminarian alternation of generations life history strategy with conspicuous, macroscopic sporophytes alternating with microscopic gametophytes , Broken Bay , Port Jackson and Botany Bay and positioned to the north and south of the entrance to each estuary , Table 1 estuary . All est estuary E. radiaHo) and expected heterozygosities (He) were generated using GENETIX ver. 4.04 FST and FIS estimates FST estimates were also estimated between sites. A sequential Bonferroni correction F statistics. A stepwise mutation model was not assumed and P<0.05 was used. We identified potential first generation migrants using GeneClass 2 P<0.01. Tests of isolation by distance for each estuary and surrounding open coast sites were done via Mantel tests using the program IBD Prior to conducting statistical analyses, data were checked for typographical and genotyping errors using Microchecker P>0.05, FIS estimates were mostly non-significant indicating random mating and there were no apparent patterns in the magnitude of FIS estimates between open coast and estuarine sites and among open coast sites . Similarly, comparisons of estimates of FST for each individual estuary were similar to nearby open coast sites . This result may be a reflection of low replication as graphical representation of data and south were greater than for the region in the present study (FST\u200a=\u200a0.023 for open coast sites).Estimates of mean pairwise P<0.01). These represented 9% of all individuals from estuaries and 13% of individuals from the open coast. Individuals growing in estuaries that were identified as migrants were mostly (62%) assigned to populations of origin that were open coast sites rather than estuarine sites. Conversely, individuals growing on the open coast that were identified as migrants were mostly assigned to other open coastal sites (66%).Tests for first generation migrants revealed that 11% of all individuals are likely migrants from another site and populations that would otherwise not exist. In addition, the unique environmental conditions within estuaries may extend or alter phenological factors (such as timing of reproduction) relative to open coast populations Interestingly, there was generally no genetic differentiation between open coast and estuarine populations of this species indicating that small populations of kelp within estuaries are not reproductively isolated and frequently exchange propagules with surrounding open coast populations. Indeed, large volumes of kelp from open coast habitats are often washed up inside estuaries after storms Despite weak genetic differentiation, spatial patterns of genetic structure appeared to be weakly associated with type of estuary with trends for positive relationships between genetic structure and geographic distance in wave- compared to tide-dominated estuaries. Hydrodynamics within these estuaries and water exchange between the estuaries and nearby open coast sites are vastly different between these different estuarine morphologies and may explain these differences in spatial genetic structuring. In wave dominated estuaries, waves and water motion originating from the open ocean are the dominant structuring influences and this may promote one-way, linear patterns of dispersal. In contrast, tide-dominated estuaries are structured by flushing of tidal currents as water moves back and forth and this may enhance mixing of propagules and prevent the formation of spatial patterns of genetic structure. Although this pattern was only weakly demonstrated here, consideration of the influence of estuarine morphology and associated hydrodynamics on genetic structure may be important for designing MPAs (particularly those in estuarine areas).E. radiata is cleared from small patches of established forest by storms, grazing or other anthropogenic impacts may result in genetic patchiness because migrants may only be able to colonise bare patches within existing forests or rare areas of unoccupied rocky reef Together, these results suggest that the presence of estuaries is not a barrier to dispersal in kelp, either among open coast populations or between estuarine and open coast habitats. Indeed, estuaries may enhance connectivity via provision of additional habitat. Moreover, it is likely that the strength and complex nature of prevailing currents combined with the multiple These results are particularly pertinent given that the bioregion (Hawkesbury) studied here is the only one in NSW without a marine park. It also represents the most urbanised and developed coastline in Australia and is home to Australia's largest city (Sydney). Protection of marine habitats in this region is currently achieved via numerous small, shallow Aquatic Reserves where marine macrophytes are protected. MPAs may be designated in this region in the future given the need to adequately protect biodiversity along the NSW coastline. Incorporating estuarine areas and open coast into MPA designs and considering linkages among these important habitats, as is currently done in other NSW MPAs, will be key for designing future MPAs in this bioregion. Nearshore and estuarine habitats are inherently complex with a suite of physical and biological factors determining dispersal and connectivity of marine organisms. Teasing apart the relative influence of such factors is important for effective MPA design and to ensure that species and habitats are protected into the future."} +{"text": "Hypertonia and hyperreflexia are classically described responses to upper motor neuron injury. However, acute hypotonia and areflexia with motor deficit are hallmark findings after many central nervous system insults such as acute stroke and spinal shock. Historic theories to explain these contradictory findings have implicated a number of potential mechanisms mostly relying on the loss of descending corticospinal input as the underlying etiology. Unfortunately, these simple descriptions consistently fail to adequately explain the pathophysiology and connectivity leading to acute hyporeflexia and delayed hyperreflexia that result from such insult. This article highlights the common observation of acute hyporeflexia after central nervous system insults and explores the underlying anatomy and physiology. Further, evidence for the underlying connectivity is presented and implicates the dominant role of supraspinal inhibitory influence originating in the supplementary motor area descending through the corticospinal tracts. Unlike traditional explanations, this theory more adequately explains the findings of postoperative supplementary motor area syndrome in which hyporeflexia motor deficit is observed acutely in the face of intact primary motor cortex connections to the spinal cord. Further, the proposed connectivity can be generalized to help explain other insults including stroke, atonic seizures, and spinal shock. Hyperreflexia and hypertonia are the classic upper motor neuron (UMN) signs thought to occur from the loss of corticospinal motor tract suppression of the spinal reflex arc. These \u201crelease signs\u201d were described by Hughlings Jackson in 1931 as \u201cpositive signs\u201d (Jackson et al., SMA syndrome has been described most commonly as a result of surgical resection of cortex anterior to the precentral gyrus (Laplane et al., Although the SMA has extensive projections through the motor systems, a key observation to derive an explanation for these classically LMN findings is that direct cortical stimulation of the primary motor cortex does not always cause motor movements immediately after the SMA syndrome occurs. This has been observed intra-operatively by the authors and described by others with motor evoked potentials following SMA resection (Zentner et al., In this article, we review historic explanation for the acute hyporeflexia of UMN injuries and propose a theory implicating corticospinal tracts originating outside of the primary motor cortex. We hypothesize that the SMA contributions to the motor system provide a net inhibitory influence on the spinal cord and acute compromise is a dominant effector of acute hypotonia and hyporeflexia.Spinal shock offers the classically described paradigm of acute hypotonic plegia after CNS injury. Over the last two centuries, the teaching that has persisted is that this hyporeflexia is caused by loss of excitatory background descending input to the spinal motor neurons and interneurons leading to a hyperpolarization (Ashby et al., A reflex conveys an afferent stimulus to an effector via an integration center, and a simple physiologic version is the monosynaptic arc that underlies the deep tendon reflex Figure . The resThe extensive synaptic contributions to the monosynaptic tendon reflex complex are illustrated by exploring the afferent and efferent connectivity of the alpha motor neuron Figure . SupraspAn opportunity to study the corticospinal tracts is offered by the study of discrete surgical lesions, focal stroke, cortical electrical stimulation, EEG, and functional imaging. The differences in function and response to insult between areas supplying corticospinal neurons support the concept of alternate functions and mechanisms of action beyond pure motor activation. For example, the discrete functions of the precentral and postcentral gyri are relatively easily discernible with well-established principle roles of mediating primary motor and sensory functions, respectively (Penfield and Rasmussen, Recognition of cortical inhibitory effects on motor function offers potential insights into connectivity that might participate in distal effects following injury. There is a sequential activation of \u201chigher order motor areas\u201d including the anterior cingulate, the SMA, and the inferior parietal lobe followed by activation of \u201cexecutive areas\u201d including the posterior portion of the SMA and the primary motor area (Ball et al., Brain death and some focal seizure syndromes may hint at further clinical insight into hypotonia and diminished reflexes when the primary physiology involves the CNS. While brain death can often be attributed to an isolated brain injury, the associated plegia is confidently attributed to supraspinal compromise but not to a more focal insult. Atonic seizures have been localized to negative motor areas anterior to the supplementary motor area (Luders et al., Conventional teaching holds that only one-third of the corticospinal tract arises from the primary motor cortex and one-third from the supplementary motor cortex and one-third from the primary sensory cortex (Carpenter, Extrapyramidal tracts also serve motor function and can effect reflex function but primarily act indirectly on the alpha motor neurons. Aside from the corticospinal inputs, descending tracts originate in numerous sites mostly within the brainstem and they modulate movements and participate in tone along with tracts originating in the cerebellum (Carpenter, The spinal cord serves not only as a conduit for bidirectional information flow between the brain and periphery, but also harbors circuitry that is believed to independently subserve some motor functions such as for locomotion (Iglesias et al., Even with evidence of similar projections from the varied cortical motor areas to the spinal cord (Dum and Strick, The complexity of the contribution of interneurons to the motor system for locomotion, postural maintenance, and reflex responses is evidenced throughout the literature with acknowledgment that our understanding is primarily derived from limited animal studies. Even those interneurons that participate in locomotion as \u201clast order\u201d interneurons have pyramidal and extrapyramidal descending inputs influence their actions and these inputs can be excitatory and/or inhibitory. Further, the stimuli provided by interneurons to the motor neurons can be excitatory or inhibitory, non-reciprocal or reciprocal with movements (Nielsen et al., Pyramidal tract projection to spinal interneurons has been known about for more than three decades and the ability of this architecture to manipulate reflexes is known (Rothwell, Supraspinal control of interneurons has been described in human electrophysiological study with connection likely between the corticospinal tracts and non-reciprocal, group Ib, interneurons (Marchand-Pauvert et al., This article builds upon the historical expectation of classic UMN signs, such as hypereflexia, when they are often not the acute response seen after CNS injury. Immediate hyporeflexia is a hallmark and consistent finding after many acute brain and spinal cord insults. Despite the failings of the historic explanations, extant descriptions of CNS connectivity and function support the concept of an inhibitory role for portions of the cortex, descending tracts, and spinal neurons; and a putative connectivity involving the related architecture can help explain hyporeflexia as a true acute UMN finding. The classic but tardy UMN findings that occur after CNS injury have been attributed to many mechanisms localized to the spinal cord mostly at the level of the interneurons (Ditunno et al., The theory we propose revolves around corticospinal fiber tracts originating outside of the primary motor cortex, in particular those from the SMA. This is in keeping with a central role of the SMA as an inhibitor of motor movement and consistent with the clinical and electrophysiologic responses seen after SMA resection (Schucht et al., The postulated connectivity to explain the reflex responses to CNS injury is notably consistent with that described for sympathetic activity after acute spinal transection. It has been proposed that spinal transection abolishes descending excitation of sympathetic neurons either via direct connection to the sympathetic preganglionic neurons or indirectly via interneurons; and transection also compromises descending inhibition of spinal systems with excitatory input to sympathetic preganglionic neurons Schramm, . It is tin vivo electrophysiological recording.The remarkable complexity of the pathophysiology that underlies clinical responses to insult are irresolvable with contemporary knowledge, and certainly there are often multiple pathways participating in a dynamic manner. Even in trying to strongly implicate portions of the corticospinal tract in hyporeflexia after injury, such postulations may prove inadequate given the numerous potential influences on the gain of the monosynaptic tendon reflex. While widespread projection from the SMA to the intermediate zone of the spinal cord suggests significant involvement of interneurons (Maier et al., Hurdles to understanding human reflex responses to injury include the breadth of clinical scenarios, dramatic temporal evolution of responses over time following insults, the difficulties correlating animal studies to humans, the functional heterogeneity of areas such as the SMA, the potential for individual variation in movement related cortical responses, the rarity of small focal lesions to the related areas, the limited resolution of EEG and imaging, the limited spatial resolution of cortical and subcortical stimulation, the difficulties performing the human electrophysiological studies that would be most valuable, and the remarkable complexity of the connectome (Ball et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Predicting the risk of toxic and environmental effects of chemical compounds is of great importance to all chemical industries . Expert Our knowledge discovery tool applies emerging pattern (EP) mining : a form in vitro mutagenicity.The knowledge discovery tool has been tested using a public dataset of 3489 mutagens and 2981 non-mutagens, encoded as fingerprints of approximately 2000 functional groups and ring descriptors. EPs were produced and grouped into a number of hierarchical families. Six of the EPs that represented distinct chemical classes were selected for manual inspection by a toxicology expert. Relevant literature was analysed to find a mechanistic rationale for the mined features, which resulted in four new structural alerts for"} +{"text": "The HTLV-I oncoprotein Tax is critical for T cell transformation, acting mainly through NEMO binding and subsequent NF-\u03baB activation. Tax localizes to Tax nuclear bodies and to the centrosome and is subjected to ubiquitylation and SUMOylation that are both necessary for complete transcriptional activation. By using the photoconvertible fluorophore Dendra-2 coupled with live video confocal microscopy, we show for the first time that the same Tax molecule shuttles among Tax nuclear bodies and between these nuclear bodies and the centrosome depending on its post-translational modifications. Ubiquitylation targets Tax to nuclear bodies to which NEMO is recruited and subsequently SUMOylated. We also demonstrate that Tax nuclear bodies contain the SUMOylation machinery including SUMO and the SUMO conjugating enzyme Ubc9, strongly suggesting that these nuclear bodies represent sites of active SUMOylation. Finally, both ubiquitylation and SUMOylation of Tax control NEMO targeting to the centrosome. Altogether, we are proposing a model where both ubiquitylation and SUMOylation of Tax control the shuttling of Tax and NEMO between the cytoplasmic and nuclear compartments."} +{"text": "Intraoperative acetabular fracture is a rare complication of primary total hip arthroplasty (THA), typically occurring during impaction of the cementless acetabular component. Here we report an unusual case of pelvic discontinuity caused by overreaming of the acetabulum during primary THA. Restoration of posterior columnar continuity was achieved with an autologous fibular graft and a reconstruction plate. Wall defects and cavitary defects were reconstructed with metal mesh and femoral head allograft, followed by placement and fixation of a Kerboull-type acetabular reinforcement device. Previous reports of acetabular fracture during THA have indicated that it has a relatively good prognosis without extensive treatment. However, to our knowledge, there has been no report of pelvic discontinuity necessitating acetabular reconstruction surgery as an intraoperative complication of primary THA. Intraoperative occurrence of an acetabular fracture is a rare complication of primary total hip arthroplasty (THA). Previous studies have demonstrated that underreaming of the acetabulum and insertion of an oversized acetabular component without cement may predispose to intraoperative acetabular fracture \u20133. Good The patient, a 77-year-old woman, had presented at a local hospital with severe pain and limited range of motion in her right hip. Plain radiography showed osteoarthritis in the right hip joint. Cementless total hip arthroplasty using a posterior approach was planned at that hospital. Intraoperatively, the surgeon overreamed the acetabulum because of insufficient visualization and recognized that reconstruction surgery would be required because of large acetabular defects. Bipolar hemiarthroplasty was performed with the aim of maintaining soft tissue tension, and thereafter the patient was referred to our hospital. X-ray imaging showed massive acetabular bone loss in the right hip joint . MultideRecently, cementless acetabular components have been widely used for THA. Porous coating can be used for biologically fixing the component to the host bone. It has been clearly shown that the amount of bone ingrowth that occurs into cementless implants is related to the initial stability of the component and the degree of metal apposition to cancellous bone , 9. PolyIntraoperative fracture of the acetabulum is a very rare complication of THA. Previous studies have shown that it can typically occur during insertion of an oversized cementless acetabular component , 3. HaidIn the present case, inappropriate acetabular reaming caused pelvic discontinuity with a massive bone defect. Desai and Ries reported two cases of early postoperative acetabular discontinuity after THA . HoweverIn this case, using acetabular reconstruction, we were able to treat successfully the pelvic discontinuity that had been caused by overreaming during primary THA. Although this type of situation is rather uncommon, care should be taken to avoid accidental overreaming of the acetabulum and thus creating a severe bone defect, especially in minimally invasive THA when it is difficult to totally visualize the surgical site. Acetabular bone deficiency caused by an inappropriate operative procedure is rare, but precise reconstruction is vital if ever it occurs, in order to ensure restoration of bone stock and long-term stability."} +{"text": "PRINTO asked to provide demographic and clinical characteristics of the ASPs through electronic format and to collect DNA samples of JIA familiar cases, including all first degree relatives, deriving from the different centres.Table Preliminary results confirm the findings of earlier studies showing familial aggregation of clinical features among ASPs. In our study we observed high concordance of the presence of antinuclear antibodies (ANA), providing evidence for a genetic background in this disease. The DNA samples collected will allow to develop future studies on JIA."} +{"text": "Activity-based protein profiling (ABPP) is a newly emerging technique that uses active site-directed probes to monitor the functional status of enzymes. Serine hydrolases are one of the largest families of enzymes in mammals. More than 200 serine hydrolases have been identified, but little is known about their specific roles. Serine hydrolases are involved in a variety of physiological functions, including digestion, immune response, blood coagulation, and reproduction. ABPP has been used recently to investigate host\u2013virus interactions and to understand the molecular pathogenesis of virus infections. Monitoring the altered serine hydrolases during viral infection gives insight into the catalytic activity of these enzymes that will help to identify novel targets for diagnostic and therapeutic application. This review presents the usefulness of ABPP in detecting and analyzing functional annotation of host cell serine hydrolases as a result of host\u2013virus interaction. ABPP probes consist of two key elements: (1) a reactive group/warhead for binding and covalently labeling the active sites of many members of a given enzyme class (or classes), and (2) a reporter tag for the detection, enrichment, and/or identification of labeled enzymes from proteomes. A variety of reporter tags are used in ABPP, such as fluorophores for visualization, biotin for enrichment as well as \u201cclickable\u201d handles, such as azides and acetylenes for in vivo or in situ labeling of proteins. The linker region is a flexible chain of varying length and hydrophobicity that connects and acts as a spacer between the warhead and the reporter tag.Most enzymes are tightly regulated post-translationally. Many enzymes are synthesized as zymogens, which are functionally inactive. Moreover, enzyme functions can be changed by alterations in pH and binding to inhibitors. Thus, methods that allow direct quantification of protein activities rather than simply protein abundance are required to delineate distinct protein functions in physiological and pathological events. Activity-based protein profiling (ABPP) is a chemoproteomic platform for monitoring active proteins or enzymes. ABPP utilizes chemical probes to interrogate the functional state of large numbers of enzymes in complex proteomes Drosophila proteome and aryl phosphonates, sulfonyl fluorides, and carbamates . FPs arein vivo (Microarray technologies in the field of genomics (transcriptomics), and mass spectrometry and bioinformatics technologies in proteomics, have facilitated the specific and global analyses of genes and their expression, and this has accelerated understanding the molecular basis of disease. These technologies, coupled with two-dimensional gel electrophoresis, mass spectrometry enhanced with chromatographic separations such as MudPIT , or isotin vivo . The lacA typical target discovery experiment would comparatively analyze two or more proteomes by ABPP to identify enzymes with differing levels of activity Figure . The difABPP can also be used as a competitive screen to identify both reversible and irreversible enzyme inhibitors and also to confirm target inhibition because inhibitors have the ability to block probe labeling of enzymes . CompetiQuantification of differentially expressed active proteins after virus infection is essential for better analysis of results, particularly when examining enzymes. It is difficult to compare the altered serine hydrolases between healthy and infected samples by simply visualizing gel images or merely by mass spectrometry. To address this problem an advanced quantitative mass spectrometry-based method called ABPP-SILAC (stable isotope labeling with amino acid in cell culture) has been used to identify alterations in the levels of active enzyme targets and in sUsing selective inhibitors developed through competitive ABPP efforts or RNA interference technology, the function of an enzyme of interest can be specifically blocked, and then the metabolites that the enzyme regulates can be profiled. In this manner, not only can the substrates and products of an enzyme in specific (patho)physiological contexts be examined, but also the metabolic networks that the enzyme regulates can be identified and annotated. Collectively, this platform will allow identification of novel biochemical roles of already characterized enzymes, or may allow the identification of metabolic roles of completely uncharacterized enzymes.Many enzymes and metabolites display difficult physicochemical properties that complicate their analysis in biological samples, and many metabolic pathways that enzymes regulate in a disease-specific context are not understood. These challenges can be addressed by applying innovative metabolomics and ABPP approaches to mapping biochemical pathways that support disease.Understanding the mechanisms by which viruses develop resistance is a vital component of the fight against viral diseases, and can lengthen the lifespan of existing antivirals. Potentially any antivirus molecule could be transformed into an activity-based or affinity-based probe, allowing isolation and characterization of enzymes that detoxify the antiviral drug.ABPP with live cell imaging may provide additional insight into understanding the pathogenesis due to viral infection . IdentifNatural products represent an important treasure box of biologically active molecules, from which many drug candidates have been developed . Since ain situ during viral disease progression, trying to fully understand mechanisms of resistance and developing new antiviral therapeutics and viral diagnostics will make the ABPP application more worthwhile for the field of virology.This mini review describes briefly a limited number of approaches involved in profiling serine hydrolases during viral infection and assigning catalytic functions to previously uncharacterized serine hydrolases. Visualization of the altered active serine hydrolase The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Informed consent (IC) is regarded as a cornerstone of ethical healthcare research and is a requirement for most clinical research studies . GuideliWebsites of Clinical Trial Units registered with the UK Clinical Research Collaboration were screened to identify open access PILs from ongoing or recently completed randomised controlled trials (RCTs). A total of 60 PILs were identified and 20 were purposively sampled, for analysis using the Informed Consent Evaluation instrument (ICEi). The ICEi was developed by combining informed consent guidelines and the International Patient Decision Aid Standards (IPDAS), which describe detailed recommendations about the content and delivery of information to facilitate high quality decisions for treatment or screening. Two independent raters scored PILs according to the items presented in the ICEi, any disagreement was resolved by a third rater.Variation existed amongst the PILs in terms of overall scores and scores for specific items. Some aspects were consistently poor across all PILs analysed, namely: presenting probabilities; clarifying and expressing values; and structured guidance in deliberation and communication.PILs could be improved to facilitate better quality decision making with regard to participation in an RCT. Patients need to be better supported to make more informed decisions about their clinical trial participation, which are in line with their personal values and preferences. Better informed decisions about participation may result in patients being retained throughout the duration of the trial, as their decisions will be linked to more realistic expectations and be more in line with their personal values and preferences."} +{"text": "Crotalus scutulatus scutulatus) are associated with the presence of the Mojave toxin A subunit suggesting the existence of a genetic basis for rattlesnake venom composition. In this report, we hypothesized the existence of a genetic basis for intraspecies variation in metalloproteinase-associated biochemical properties of rattlesnake venom of the Mojave rattlesnake. To address this question, we PCR-amplified and compared the genomic DNA nucleotide sequences that code for the mature metalloproteinase domain of fourteen Mojave rattlesnakes captured from different geographical locations across the southwest region of the United States. In addition, the venoms from the same rattlesnakes were tested for their ability to hydrolyze fibrinogen, fibrin, casein, and hide powder azure and for induction of hemorrhage in mice. Overall, based on genomic sequencing and biochemical data, we classified Mojave rattlesnake venom into four distinct groups of metalloproteinases. These findings indicate that differences in nucleotide sequences encoding the mature proteinase domain and noncoding regions contribute to differences in venom metalloproteinase activities among rattlesnakes of the same species.The metalloproteinase composition and biochemical profiles of rattlesnake venom can be highly variable among rattlesnakes of the same species. We have previously shown that the neurotoxic properties of the Mojave rattlesnake ( Structural domains are indicated in bold. Nucleotide differences among the genomic DNA sequences are denoted by an asterisk (\u2217).The assignment of exon and intron (underlined) regions were identified by comparing the metalloproteinase cDNA sequences from Click here for additional data file."} +{"text": "Dear Editor,Acute rejection (AR) in kidney transplant recipients is a major risk factor for chronic allograft failure and reduction in early and long term mean graft survival. New immunosuppressant agents have been developed to reduce the incidence of these episodes . ImmunobIn his trial Saghafi et al. showed aResembling data had already been shown in previous studies, Vincent et al. showed similar reduction in incidence of BPAR in low immunologic risk deceased donor kidney recipients and the same rate of bacterial infections and/or viral infections, including CMV, malignances and adverse event as placebo group . AnotherSaghafi et al. in accordance with other authors showed daclizumab as an effective induction treatment option for low immunologic risk living donor kidney recipients. However, missing data about safety drug profile such as incidence of infection, adverse events, CMV infection, and early and late cyclosporine trough levels are not reported in the text.There are several studies confirming that induction therapy with either monoclonal or polyclonal antibodies in addition to standard therapy reduces the incidence of acute rejection but none of these studies have shown statistically significant improving in long term graft survival. New trials such as ELITE-symphony study peImproving long-term outcomes in renal transplantation is still a field of challenge and numbness but the use of induction agents in adjunction with other drugs for reducing their side effects is a promising strategy for better graft and patient survival. Perhaps, most important induction therapy importance is in minimizing exposure to other immunosuppressive therapy and its side effects and this topic deserves research."} +{"text": "Despite consistently documented cultural differences in the perception of facial expressions of emotion, the role of culture in shaping cognitive mechanisms that are central to emotion perception has received relatively little attention in past research. We review recent developments in cross-cultural psychology that provide particular insights into the modulatory role of culture on cognitive mechanisms involved in interpretations of facial expressions of emotion through two distinct routes: display rules and cognitive styles. Investigations of emotion intensity perception have demonstrated that facial expressions with varying levels of intensity of positive affect are perceived and categorized differently across cultures. Specifically, recent findings indicating significant levels of differentiation between intensity levels of facial expressions among American participants, as well as deviations from clear categorization of high and low intensity expressions among Japanese and Russian participants, suggest that display rules shape mental representations of emotions, such as intensity levels of emotion prototypes. Furthermore, a series of recent studies using eye tracking as a proxy for overt attention during face perception have identified culture-specific cognitive styles, such as the propensity to attend to very specific features of the face. Together, these results suggest a cascade of cultural influences on cognitive mechanisms involved in interpretations of facial expressions of emotion, whereby cultures impart specific behavioral practices that shape the way individuals process information from the environment. These cultural influences lead to differences in cognitive styles due to culture-specific attentional biases and emotion prototypes, which partially account for the gradient of cultural agreements and disagreements obtained in past investigations of emotion perception. Faces are of central importance for social communication. They can provide a crucial window into the mental states of other people via gaze direction, which indicates focus and shifts of attention, and expression, which can reveal emotional states. The biological significance of facial cues is underlined by converging evidence from developmental and cross-cultural psychology, as well as cognitive neuroscience. As early as 9 minutes after birth, infants show attentional preferences for faces over similar objects investigations of cross-cultural differences in feature extraction during decoding of facial expressions of emotions that underline the influence of culture on cognitive styles.An important question that has emerged from decades of cross-cultural psychological research pertains to the cognitive channels through which culture shapes emotion perception in a manner consistent with previously observed patterns of cultural agreement and disagreement. While this question has received relatively little attention to date , positive and low arousal items. These simultaneously collected intensity ratings provided a finely grained glimpse into response patterns that enabled investigations of the degree of categorization of facial expressions into distinct arousal categories across culture via categorical difference scores. Furthermore, each model was shown twice, once portraying high intensity positive emotions and once, low intensity positive emotions, in order to investigate cultural differences in the perception of emotion displays of varying intensity via perceptual difference scores.The findings from Pogosyan and Engelmann revealedThese results inform underlying mechanisms through which culture-specific display rules that govern the production of emotional expressions impact emotion perception. Display rules result in sustained exposure to culture-specific intensity levels of facial expressions. This leads to culture-specific learning about facial expressions during critical developmental stages and throughout the lifespan, thereby shaping mental representations of facial expressions of affect. Mental representations can be thought of as prototype emotional expressions that are used when meaning is assigned to percepts. Given the dominance of particular display rules within a given culture (Matsumoto et al., Display rules likely influence and interact with culturally variable cognitive processing styles. For instance, Western cultures have been shown to adopt feature processing strategies, while Asian cultures demonstrate a disposition to employ holistic strategies (e.g., Nisbett and Masuda, amygdala, which is considered to be crucially involved in selective information processing of biologically significant stimuli (Pessoa, A more recent investigation replicated these findings using reverse correlation for reconstructing internal representations from average white noise templates that biased judgments (Jack et al., Pessoa, . Recent Pessoa, , 2009, uThe results reviewed above demonstrate wide-ranging influences of culture on cognitive mechanisms involved in emotion perception, including mental representations and, relatedly, emotion prototypes, as well as attentional biases. One question that arises is how these different processes interact with one another. Figure Display rules comprise one important aspect of culture-specific behavioral practices, which mediate perceptual learning about facial expressions via enhancements and reductions in exposure levels to specific emotion displays. This notion is supported by a recent computational modeling study in which the effect of display rules on learning was simulated via manipulating exposure frequency to particular emotional expressions during training of a biologically plausible neural network model (Dailey et al., The intermediate level of the cascade is represented by cognitive style, which is in part determined by attentional biases and mental representations. Cognitive style reflects how individuals habitually extract and process information from the environment. Results reviewed above have demonstrated important ways in which culture shapes cognitive style, namely by imparting attentional biases during face perception (Blais et al., It has to be noted that the proposed cascade of cultural influences reflects a simplified model that only considers two specific cognitive processes, namely attentional biases and mental representations. As demonstrated previously, the modulatory role of culture also extends to other cognitive mechanisms that include mathematical reasoning (Tang et al., We have summarized findings from past research that have made important contributions to understanding how underlying cognitive mechanisms relevant to interpretations of emotion expressions are shaped by culture. Specifically, a recent investigation has demonstrated that facial expressions of differing intensity levels are perceived and categorized differently across three cultures (Pogosyan and Engelmann, Display rules and behavioral practices also shape attentional mechanisms, such as the propensity to attend to very specific features of the face when inferring identity (Blais et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "During the last two decades, most countries including developed and developing have experienced a rapid increase in health care expenditures in general, and hospital expenditures in particular. DRG-based reimbursement systems were introduced to control healthcare and hospital expenditure, increase activity levels and standardize care. This paper reviews the theoretical and empirical evidence on whether DRGs can meet these ambitious objectives. The objective of this study is to systematically review the effect of DRG payment system on hospital efficiency and to find theoretical and empirical evidence that DRGs enhance efficiency and effectiveness in the hospital sector.This study searched the EconLit and MedLine databases for published articles in the English between 1984 and 2009. Search terms included efficiency, Hospital efficiency, and frontier analysis. These could be reduced to more relate using additional keyword such as DRG reimbursement, DRG payment system. According to review objective relevant studies have been selected.This paper reviewed 25 studies included all studies published in refereed journals or books that were either published or available in pre-print during the study period. According reviewed articles studies of the impact of DRGs on efficiency mostly focused on technical efficiency or productivity. The findings were somehow mixed, there was some evidence on improved technical efficiency but nothing significant in the US, Austria as well. The country specific points and context may explain the divergent result.DRGs contributed to enhance understanding of the relationship between resource use and the activity in acute care setting. Evidence from empirical studies of the impact of DRGs reimbursement on hospital efficiency is mixed. While some research tentatively suggests efficiency improvements, at least in the short-run, attributing these to DRGs reimbursement is complicated by confounding factors."} +{"text": "Targeted interventions for high risk groups are increasingly important. Alcohol problems are not evenly distributed. Highly differentiated patterns and prevalence have been identified among workers according to their industry and occupational groups. Young workers in the hospitality industry have been found to be among the highest consumers of alcohol and drugs yet largely overlooked for early and brief intervention. To assess the efficacy of an innovative brief intervention on risky drinking and associated psycho-social measures a trial was undertaken with a cohort of Australian first year hospitality trainees. The study comprised a block randomised controlled trial. Baseline data (T1) was collected at the commencement of hospitality training from both control and intervention groups prior to the administration of a brief intervention and 5 months later at the end of the first term of training (T2). The intervention focused on strategies to address workplace social norms and pressures, resilience and coping strategies, alternative stress management techniques, assertiveness training and social support mechanisms. The intervention was informed by a systematic review of the literature and a qualitative study involving focus groups. Measures included AUDIT, K10, quality of life measures and life satisfaction scales. The findings indicate high levels of risky alcohol consumption among this group of young workers. Significant relationships between age, gender and psycho-social measures were found for risky drinkers. The results of brief intervention indicated changes in the desired direction. Findings are presented together details of efficacy, acceptability to students, implications for wide scale implementation and the feasibility of sustained interventions of this type. This is one of few brief intervention RCTs of its type that address a high risk population using a tailored and targeted intervention and offers considerable promise."} +{"text": "Ablation of ventricular tachycardia (VT) by conventional radiofrequency ablation can be impossible if the ventricular wall at the targeted ablation site is very thick, as for example the ventricular septum. We present a case of a patient with incessant, non-sustained slow VT originating from the septal part of the lower outflow tracts. Radiofrequency catheter ablation from both ventricles as well as from the anterior cardiac vein were not successful. Both high power radiofrequency ablation and bipolar radiofrequency ablation neither were successfull. Finally, ethanol ablation of the first septal perforator successfully terminated arrhythmia. We discuss the possibilities to overcome failed conventional radiofrequency VT ablation of a septal focus. Ablation of ventricular tachycardia (VT) originating from a septal focus can be impossible with radiofrequency energy because of insufficient deep tissue heating. We describe a case with a focal septal VT where this limitation of radiofrequency ablation was successfully overcome and discuss the alternative possibilities to conventional radiofrequency ablation.A 64-years old patient with anterior myocardial infarction revascularized with CABG 16 years ago was implanted a cardioverter defibrillator (ICD) for primary prevention in 2005 because of impaired left ventricular ejection fraction (30%). In 2008 he experienced appropriate ICD interventions for VT. These VTs were successfully treated by amiodarone, which later had to be stopped because of hyperthyroidism. In the last years, he did well, was in functional class NYHA II and without ICD interventions on standard therapy including ACE inhibitor and betablocker.The patient then developed incessant, mostly non-sustained, slow ventricular tachycardia (130 bpm) below programmed ICD intervention rate, associated with worsening functional class (NYHA III). Coronary angiography revealed open coronary artery bypasses and left ventricular ejection fraction was 40%. QRS morphology of the tachycardia was compatible with an origin in the left ventricular outflow tract and ablaBecause of recurrence of VT and the presumed origin in the proximal septum it was decided to attempt transcoronary ethanol ablation.,2 The coVentricular tachycardia in patients with coronary artery disease is usually scar-related. In this case, despite reduced left ventricular ejection fraction and myocardial scar, tachycardia mechanism was probably focal as in classical forms of outflow tract VT. Both the absence of scar on electroanatomic mapping in the region of interest, as well as the repetitive, monomorphic pattern of VT point to this mechanism.Electroanatomic mapping of earliest activation on both sides of the septum as well as in the anterior cardiac vein showed activation before QRS onset for each location, but nowhere activation was convincingly early. Therefore, and as can be seen in the 3D map , the oriTo overcome this limitation of unipolar radiofrequency energy, both power and catheter irrigation can be increased in order to have more effect on deeper tissue. This was temporarily successful in the present case, but the effect lasted only during radiofrequency application. Tissue heating obviously affected the focus, but was insufficient for coagulation necrosis at the site of tachycardia origin.Another possibility to achieve deep tissue heating is bipolar radiofrequency ablation by two catheters facing each other on both sides of the tissue and connected by a custom switch box allowing bipolar ablation between the distal electrodes of both catheters (with one catheter acting as cathode and the other as anode). Bipolar radiofrequency catheter ablation has been shown to result in more transmural lesions and being less dependent on tissue contact. NevertheFinally, transcoronary ethanol ablation is another possibility to ablate deep intramyocardial foci and has been shown to be effective for septal ventricular tachycardias.,2 Alcoho"} +{"text": "In the United States, several states have made policy decisions regarding whether and how to use familial searching of the Combined DNA Index System (CODIS) database in criminal investigations. Familial searching pushes DNA typing beyond merely identifying individuals to detecting genetic relatedness, an application previously reserved for missing persons identifications and custody battles. The intentional search of CODIS for partial matches to an item of evidence offers law enforcement agencies a powerful tool for developing investigative leads, apprehending criminals, revitalizing cold cases and exonerating wrongfully convicted individuals. As familial searching involves a range of logistical, social, ethical and legal considerations, states are now grappling with policy options for implementing familial searching to balance crime fighting with its potential impact on society. When developing policies for familial searching, legislators should take into account the impact of familial searching on select populations and the need to minimize personal intrusion on relatives of individuals in the DNA database. This review describes the approaches used to narrow a suspect pool from a partial match search of CODIS and summarizes the economic, ethical, logistical and political challenges of implementing familial searching. We examine particular US state policies and the policy options adopted to address these issues. The aim of this review is to provide objective background information on the controversial approach of familial searching to inform policy decisions in this area. Herein we highlight key policy options and recommendations regarding effective utilization of familial searching that minimize harm to and afford maximum protection of US citizens. The Combined DNA Index System (CODIS) database was established by the Federal Bureau of Investigation (FBI) to aid in the exchange of DNA profiles in forensics investigations by facilitating data sharing and comparisons of short tandem repeat (STR) profiles at the local, state and national levels. The DNA Identification Act of 1994, a subtitle of the Violent Crime Control and Law Enforcement Act of 1994, authorizes the Director of the FBI to establish \"an index of DNA identification records of persons convicted of crimes, and analyses of DNA samples recovered from crime scenes and from unidentified human remains\" .CODIS was originally intended to be utilized for the investigation of violent crimes and sex offenses by using exact matches between DNA evidence and DNA database profiles to develop new investigative leads and to aid in missing persons identifications . States Recently, law enforcement agencies have successfully used existing CODIS software to detect partial matches through a low-stringency search, which allows for mismatches at some markers, in addition to absences and dropouts allowed in moderate-stringency searches. Investigators commonly use a low-stringency search of CODIS when facing an evidence sample developed from multiple sources or if the DNA evidence is of low quality . Low-strIn March 2008, the FBI determined that familial searching policies should be decided by individual states . As of JFamilial searching has immense potential to help law enforcement develop leads in investigations that would otherwise go unsolved. This novel approach presents both technical and logistical challenges for law enforcement, however, and raises distinct ethical, social and legal concerns. As policies governing familial searching develop, policymakers, law enforcement agencies and the public may consider options for improving the effectiveness and reliability of familial searches, the potential effects on society and families, the associated Fourth Amendment implications, and the costs and benefits to law enforcement. In this review, we examine the challenges presented by familial searching and the policies adopted by some states to address these challenges.For a familial search, investigators run a low-stringency search with the intention of identifying a relative of the perpetrator. Such a low-stringency search is most likely to result in parent-offspring relationships, whereas sibling and avuncular relationships are less likely to result. A familial search typically results in a list of multiple candidate partial matches whose family members may eventually be investigated further as suspects or persons of interest.A perpetrator and a profiled offender are most likely to share genetic similarities if they are close biological relatives, but partial matches might also include random unrelated individuals profiled in CODIS whose DNA profiles are by chance similar to the evidence sample profile. Consequently, when a familial search is performed, the resulting suspect pool can contain from a few up to hundreds or more suspects, depending on the search parameters used, making the initial pool of CODIS partial matches and their biological relatives too large for a manageable investigation .Additional analysis is necessary to verify relatedness between the evidence profile and the partially matched offender ,15. TakiSince the DNA Identification Act of 1994 does not explicitly authorize familial searches at the federal level, searches of the National DNA Index System (NDIS) are not currently conducted . BecauseRetesting of evidence and candidate profiles for Y-chromosome STR (YSTR) markers can greatly reduce the number of coincidental matches in the suspect pool. Because profiles in CODIS are predominantly males, paternal relatedness between two profiles may often be verified by YSTR analysis . SWGDAM Analysis of mitochondrial DNA (mtDNA) serves a similar function to YSTR analysis in reducing coincidental partial matches and narrowing the pool of true relatives by implicating maternal lineage ,20. HoweThe identity-by-state (IBS) statistical approach infers genetic similarity based on the number of matching markers between two profiles, regardless of how individual markers are inherited. When using the IBS approach, analysts rank matches based on the highest number of matched markers to the lowest number, with a full match being 26 shared alleles ,20. For In familial searching, a likelihood ratio (or kinship index) compares the probability of two profiles' being from related sources to the probability of the two profiles' being unrelated. Calculating a likelihood ratio takes into account all 13 markers typed in a CODIS profile, the allele frequencies of the 26 detected alleles and potential mutation events at each marker. The likelihood ratio can vary based on the frequency of each marker across the population, the number of loci compared in the profiles and the prior odds of the alleged relationship . The likTo improve the reliability of hits from familial searches, investigators can type markers in addition to the standard 13 STRs . AdditioTraditional police investigation of public records may support or refute suspected biological relationships in a candidate partial match list. Such public records review is costly but can reduce concerns about unwarranted investigation of families unrelated to the perpetrator of the crime . In ColoFamilial searching approaches can either positively or negatively affect individuals, families, certain racial groups and society in general, inevitably raising ethical and privacy questions. Proponents of familial searching assert that the potential to improve public safety and ensure justice outweigh any costs to individual and family privacy, especially if mechanisms are in place to minimize harm ,22,23.Between 2003 and 2010, the United Kingdom successfully used familial searching to obtain convictions in 19 cases . To addrOpponents of familial searching warn that, as a by-product of familial searches in an investigation, family members may learn information about relatives that was previously unknown to them . For exaBecause familial searching is intended to develop a suspect pool when conventional investigation of available evidence has not created leads, it by design opens the investigation of potentially innocent individuals based on their genetic material . Some arLegal scholars have taken various stances on the constitutionality of familial searches. Their opinions are based on two core questions about when a search occurs and whether a search is reasonable. The Fourth Amendment provides protections against unreasonable searches and seizures . US courSome scholars posit that, because biological materials are not collected directly from relatives under investigation during a familial search, the legal search occurs when the low-stringency DNA database search is run, such that investigators effectively include relatives of convicted offenders and arrestees in a database search. From this perspective, in a familial search, CODIS offenders' biological relatives may be considered the individuals being searched and thus are protected under the Fourth Amendment. Others argue that the legal search occurs during the creation of the profile: that is, when the sample is collected, tested or entered into the database . From this perspective, as long as law enforcement officials properly obtain a genetic sample during a search of an offender, subsequent testing and analysis of the DNA may not be protected by the Fourth Amendment .Because investigators typically use familial searching when existing leads do not point to a specific suspect, a familial search may require justification for suspicionless cause. Some scholars propose that only crimes that pose a substantial threat to public safety warrant the use of familial searching ,5. CalifWhile convicted felons may be profiled and searched nationwide, state policies differ with regard to whether arrestees and juveniles may be profiled, whether they continue to have a reduced expectation of privacy after their release from incarceration, or whether they can be profiled after their records are expunged. Some argue that arrested individuals and juveniles may reasonably expect to have decreased privacy during the time of arrest and therefore may be included in DNA databases. Others posit that arrestees' presumed innocence and juveniles' minority status might necessitate greater privacy protections than those granted to convicted felons ,36. The Because familial searching has not yet been challenged in the courts, how US courts will assess the Fourth Amendment implications of familial searching is unknown ,34,35. LFamilial searching has the potential to exacerbate the racial bias already documented in the criminal justice system ,39,40. BMaryland banned familial searching of the state-specific database as part of legislation to expand its DNA databases to include arrestees of violent crimes because of the disproportionate number of racial minorities subject to arrest . In otheState-by-state familial searching policies may also result in a disparate focus by law enforcement officials on families of low socioeconomic status. Investigations involving familial searching presently are conducted within a handful of states. Consequently, biological relatives who live outside the state in which the crime was committed will not be subject to searches of the state-specific database. Because families of low socioeconomic status tend to have decreased mobility, they are more likely to live within the same state, city and/or town as their relatives . As a reData are needed to understand the actual impact of familial searching on all facets of crime investigation. Familial searching may burden crime laboratories, crime investigators and the justice system in terms of cost and time. Because familial searching will increase the number of suspects identified on the basis of DNA forensics, law enforcement agencies may be burdened with an increased workload, particularly when they are required to investigate a broad suspect pool. Once a list of partial matches is made, law enforcement must decide whether to expend resources to retest samples for additional markers and follow up on multiple leads.Familial searching requires that evidence be retested for additional markers and to review the results of a search, thus increasing the workload of crime laboratories. Existing crime laboratory backlogs may worsen with increased searching and retesting demands. Because many crime laboratories prioritize high-profile and violent crimes, familial search requests for violent crimes may jump ahead of other backlogged DNA-based cases .The authority of the FBI to alter CODIS software is limited by the DNA Identification Act of 1994 [In implementing a familial search policy, there are several options for determining when and how the approach is used, the scope of a search and how to narrow the suspect pool to eliminate coincidental genetic matches. The six policy options outlined below might be considered in an effort to (1) maximize the efficiency of a system, (2) limit the burden on laboratories and law enforcement, (3) address some of the aforementioned impacts on society and families and (4) balance ethical implications and individual rights with the duty of law enforcement officials and agencies to carry out their responsibilities and protect the public's safety.CODIS software is not designed to perform familial searches effectively, yet a national platform is the best approach to ensure consistency across jurisdictions. Consistent application of familial searching will require standard tools to manage the pools of candidate suspects and minimize both the burden on law enforcement officials to investigate leads and the privacy intrusion on families. Software designed to conduct familial searches could incorporate both IBS and likelihood ratio analyses to maximize efficiency. FBI officials have indicated that they currently do not have the authority to make such changes .Routine analysis of YSTR markers when a CODIS profile is initially typed would improve the efficiency of familial searching by removing the need for retesting, hence eliminating one of the analytical burdens on laboratories. Individual states could develop policies for retesting stored DNA samples for YSTR markers based on their available resources and familial searching needs.Scientists and policymakers are evaluating which statistical methods and analytical tools will efficiently limit the pool of suspects without excluding the actual perpetrator. As policies and technologies develop and as the CODIS database expands, the statistical parameters for a search will need to be reviewed and adjusted. Advice from experts in relationship testing, statistics and population genetics will be crucial for consistent application of familial searching among the various population pools across the United States. An advisory consortium modeled on the DNA Advisory Board could guide the establishment and revision of the statistical criteria used to develop familial searching policies, both nationally and state-by-state. Statistical tools, including the IBS approach and likelihood ratios, can be used to rank partial matches to optimize the likelihood that a match corresponds to a true biological relationship. However, an advisory consortium may have limited authority to enforce or regulate policy.Familial searching has raised ethical concerns because of its potential to profile certain socioeconomic and minority groups disproportionately, alter family dynamics and diminish individuals' sense of liberty. The development of an ethics oversight board is one option for ensuring that the social and ethical implications of familial searching are addressed and incorporated into policy and decision-making. Federal policy-making bodies could model an ethics advisory board upon California's Familial Search Committee and the UK Ethics Group.A national advisory consortium would provide guidance on the ethical boundaries and privacy concerns of familial searching for states considering legislation and investigating ongoing cases. A national resource would provide a broad perspective on nationwide trends and emerging issues related to US Constitutional rights. Additionally, an advisory consortium might address privacy concerns by making recommendations regarding police investigation approaches. Although policy could ultimately be left to the discretion of individual law enforcement offices, a national consortium could (a) recommend safeguards for when partial match individuals' identities may be disclosed to law enforcement officials for further investigation or (b) advise law enforcement regarding the kind of information that may be disclosed to family members. An ethics advisory consortium has limited authority to enforce or regulate policy. However, a national ethics advisory consortium could provide guidance for review of familial search policies or investigations.States may individually apply the balancing test to determine whether law enforcement should use familial searching routinely or on a case-by-case basis. Policy makers may assess the circumstances for which to conduct a familial search by weighing the needs to (a) prevent crime and protect the public interest and public safety and (b) protect against the infringement of individual privacy rights, avoid social ramifications , ameliorate impacts on families and limit the potential financial and time burdens of familial searching on individual crime laboratories and police departments. Additionally, by using familial searching only for violent crimes, for example, law enforcement officials could reduce unnecessary costs and save time while aiding investigations of crimes that pose the most critical threats to public safety.In addition to deciding when a familial search is appropriate, concerns also arise over whose DNA profiles can be used for a familial search. Inclusion in a DNA database is no longer limited to individuals convicted of violent crimes. Some critics of familial searching argue that running familial searches of databases that include arrestees may by default include searches of innocent individuals whose privacy rights have not been diminished (as a convicted offenders' rights have been) ,45. IndiFamilial searching offers law enforcement a powerful tool for apprehending criminals, revitalizing cold cases and exonerating wrongfully convicted individuals. Development of familial searching policies should take into account open questions regarding the impact of familial searching policies on select populations and how to minimize personal intrusion on relatives of individuals in the DNA database. As policies develop and jurisdictions establish procedures, we will better understand the societal impact of familial searching.CODIS: Combined DNA Index System; FBI: Federal Bureau of Investigation; FSC: Familial Search Committee; IBS: identity by state; mtDNA: mitochondrial DNA; NDIS: National DNA Index System; SDIS: State DNA Index System; STR: short tandem repeat; YSTR: Y-chromosome short tandem repeat.The authors declare that they have no competing interests.JK, DM and MS each independently researched aspects of the review topic under the guidance and advisement of SHK. JK and SHK wrote the manuscript. All authors read and approved the manuscript."} +{"text": "Intraoperative evoked potential (EP) monitoring has become a routine part of operative neurosurgical procedures. The theoretical, technical, and clinical aspects of various EPs have been extensively characterized and significant clinical experience has been accumulated with this modality of neuromonitoring. Successful EP monitoring requires an adequate understanding of how anesthetic drugs and physiological variations affect EP signals and how to improve the sensitivity of neuromonitoring through appropriate drug selection and administration.Unlike intraoperative electroencephalography (EEG), EP signals are much smaller in amplitude (0.1\u201320 mcV) and indistinguishable from background noise. In order to extract the EP signal from the underlying EEG noise, multiple stimulations with summation and frequency filtering are necessary Freye, .EPs are highly sensitive to fluctuations in physiological parameters such as peripheral and core body temperature, arterial blood pressure, hematocrit etc. They are also susceptible to various general anesthetic agents and other drugs frequently given during surgery.The effects of general anesthetics on intraoperative EP depend on the mode of evoked response and the pharmacological characteristics of administered anesthetic drugs. Evoked responses that travel via polysynaptic pathways, such as visual EP are significantly more susceptible to the anesthesia and surgery when compared to EPs with fewer synapses in their pathway.In general, inhalational anesthetics are more potent suppressants of EP than intravenous agents have been successfully applied during neurosurgical interventions and neurophysiological monitoring without compromising the quality of monitoring.Balanced general anesthesia with low doses of inhalational agents combined with low-dose constant infusions of remifentanil (0.05 mcg/kg/min), propofol (50 mcg/kg/min), or dexmedetomidine (0.003\u20130.005 mcg/kg/min) may be recommended when EP monitoring is anticipated. Such an approach will provide stable anesthesia and reduce the incidence of adverse events encountered occasionally during total intravenous anesthesia such as patient movement and awareness.Sevoflurane has low solubility compared with other inhalation anesthetics and thus is eliminated rapidly, minimizing its effects during monitoring later in the case increase in latency is also a useful adjunct to general anesthesia with EP monitoring due to its ability to reduce anesthetic requirements, stabilize the cardiovascular parameters and decrease the incidence of patient movement during surgery (Sloan et al., Monitoring of motor EPs during surgery requires special caution, as they are more sensitive to anesthetics and muscle relaxants (Kunisawa et al., In addition to selection of the most suitable anesthetics, their mode of administration is also an important factor that influences the quality of EP monitoring.During procedures requiring EP monitoring, steady infusion rates and stable concentrations of inhalational agents are preferred. Administration of drugs in bolus doses and variations in anesthesia level can negatively impact the quality of signal and cause EP suppression indistinguishable from changes triggered by surgical trauma (van Dongen et al., During lengthy neurosurgical procedures, gradual attenuation of the EP signal may occur. This signal degradation is not related to the dose of anesthetics and is proportional to the length of anesthesia. This phenomenon is more frequently seen in younger patient populations and those with spinal cord pathology (Yang et al., Intraoperative monitoring of evoked responses can be successfully utilized to reduce the rate of inadvertent trauma to the nervous structures during neurosurgical procedures. Their interpretation requires profound knowledge of neurophysiology, comprehension of the surgical procedure and an understanding of the effects that general anesthesia and physiological changes may have on signal quality. Intraoperative neuromonitoring is one of the areas of medicine where team approach is a crucial prerequisite to obtain meaningful results.During neurosurgical procedures, a variety of general and local anesthetics are used, and many of them can substantially affect or even completely eliminate the EP signal. The possibility of anesthesia-related signal suppression and the influence of physiological changes on EP must be considered in order to avoid such effects. Drugs with minimal interference on neurophysiological monitoring should be used preferentially, and attempts made to keep the anesthetic concentrations, temperature, and other physiological variables constant. Maintaining steady state concentrations of an appropriately selected balanced anesthetic will reduce the incidence of false positive results and assist in the prevention of surgical trauma and ischemic damage during neurosurgical interventions. Appropriate drug selection, meticulous drug administration and minimization of physiological variation can improve patient safety by optimizing EP signal monitoring in patients undergoing neurological surgery.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Gadus morhua) is the first vertebrate reported to have lost one of these features, the antigen presenting major histocompatibility complex (MHC) II system + T cells in other vertebrates, and defects in MHC II functionality are in general considered to lead to severe immunodeficiency and death. Therefore, a functional and evolutionary understanding of this phenomenon could uncover novel immunological functionality and elucidate basic selective mechanisms affecting vertebrate immune systems.Basic features of the vertebrate adaptive immune system have been conserved since their emergence in the ancestral lineage that lead to all jawed vertebrates the metabolic cost hypothesis suggests that despite being of some adaptive value, the benefit of MHC II functionality was in some environments not sufficient to compensate for the metabolic costs of expressing this system. Thus, directional selection would favor mutations that disrupt the expression of this system, resulting in the eventual loss of genes underlying its function. Second, the functional shift hypothesis suggests that in some environments functionality of other immune system components than MHC II, either belonging to the innate or adaptive immune system, provided a more flexible alternative evolutionary immunological strategy compared to the functionality provided by the MHC II system. This strategy may then have given better adaptation to certain environmental challenges than MHC II, making the system obsolete and exposed to genetic drift. It may also be that further evolution of such alternative strategy required dismantling of the MHC II system for mechanistic reasons and thus caused a selection pressure against its presence. Below we assess the likelihood of each of these scenarios and selection hypotheses using available empirical data and elaborate on investigations aimed to separate them.The evolutionary context in which the unusual immune system of Atlantic cod evolved is unclear, though two different scenarios may explain its existence. The first scenario hypothesizes that functionality of major histocompatibility complex (MHC) II system is not crucial for the immune defense in teleosts, and that the loss in Atlantic cod has been predominantly driven by genetic drift, rather than by specific biological or environmental factors. The second scenario hypothesizes that somewhere in the evolutionary past the function of the MHC II has been lost through directional selection. An important assumption of such a directional selection scenario is that some biological or environmental factors have driven this process, in contrast to the first scenario whereby no such association is expected. Within the directional selection scenario, we here consider two alternative selection hypotheses that separately or in combination could have lead to the loss of MHC II. First, The genetic drift scenario appears implausible from a mammalian perspective. However, fundamental differences in genomic organization and functionality of the immune system have been found in teleost lineages. For example, in contrast to mammals, no conserved linkage exists in teleosts between genes for MHC I and II The metabolic cost and functional shift hypotheses regard the architecture underlying immune functionality fundamentally different. The metabolic cost hypothesis proposes that MHC II functionality can be lost independently from other changes in the immune system, whereas the functional shift hypothesis proposes that functionality of other immune components has to expand through directional selection as a prerequisite for this loss. Can we find evidence in the gene repertoire of Atlantic cod for either hypothesis? Interestingly, evidence for directional selection is found in several gene families underlying both adaptive and innate immune systems in Atlantic cod through expansions of genes for MHC I and Toll-like receptors (TLRs) While the function of these TLRs is still unknown, the increased number of TLRs in Atlantic cod highlights the possible existence of a fundamental trade-off between adaptive and innate capabilities whereby a stronger innate system may, to some extent, lead to reduced dependence on the adaptive system The indication that particular components of the Atlantic cod have experienced positive selection appears to support the functional shift hypothesis. Nevertheless, these changes may have evolved after MHC II was lost, and merely incidentally coincide with this phenomenon. They are therefore not direct evidence that rejects the metabolic cost hypothesis. Moreover, the metabolic cost and functional shift hypothesis can be difficult to distinguish retrospectively if they have affected the immune system simultaneously. If metabolic costs have been the predominant evolutionary force affecting the loss of MHC II however, then teleost lineages may exist in which MHC II functionality is absent, while no other functional changes have coincided with this loss. Following similar reasoning, if the emergence of alternate immune functionality occurred before the loss, lineages may exist that have such functionality and in addition have an MHC II system in different stages of disarray. In fact, the functional hypothesis proposes that the phenomena observed in the Atlantic cod genome are tightly coupled. The different assumptions underlying the metabolic cost and functional shift hypotheses therefore predict distinct gene repertoires underlying the architecture of immune systems among the teleost lineages.Lota lota) is a gadoid that lives in fresh water and lacks the same set of genes involved in the MHC II system in expressed transcripts Each of the directional selection scenarios assumes that definitive factors, whether biological or environmental, can be associated with this distribution. Interestingly, in the current ecological setting, no biological or environmental factors specific to the habitats of Atlantic cod are easily identifiable. Indeed, this species lives among teleosts in which genes for MHC II have been identified and which presumably rely its functionality. Moreover, the characteristics of the Atlantic cod immune system appear shared within the gadoid lineages. For example, burbot . The ice fishes may provide a particularly interesting comparison: A relatively high parasitic load has been reported in these species and Atlantic cod By characterizing the complete immune gene repertoire in a wide range of teleosts from specific environments, we can infer which of the two alternative hypotheses is more likely. These investigations will then also illuminate the strength of a potential trade-off between adaptive components like MHC II and putative functional changes in immune architecture, which may be a fundamental characteristic of vertebrate immune systems. A full comparative analysis of the immune gene repertoire of multiple species is rapidly becoming economical, considering the ongoing reduction in sequencing costs.+ T cells A central question within comparative immunology remains whether environmental factors like temperature or biological factors like host-microbial co-evolution are the most important drivers in vertebrate immune evolution. Host-commensal bacterial co-evolution recently received substantial attention, e.g. reduced commensal loads in the intestines of invertebrates could be associated with an absent adaptive immune system Here, we have discussed several scenarios and selection hypotheses for the loss of functionality of MHC II and the emergence of the unusual immune system of Atlantic cod. It remains to be determined whether a metabolic cost or functional shift hypothesis has been predominantly responsible, and which specific biological and environmental factors have driven these selection scenarios. Nevertheless, without doubt, the existence of this peculiar immune system provides a window of opportunity for studying fundamental evolutionary questions central to our understanding of vertebrate immunity."} +{"text": "Cognitive experiences during the early stages of life play an important role in shaping future behavior. Behavioral and neural long-term changes after early sensory and associative experiences have been recently reported in the honeybee. This invertebrate is an excellent model for assessing the role of precocious experiences on later behavior due to its extraordinarily tuned division of labor based on age polyethism. These studies are mainly focused on the role and importance of experiences occurred during the first days of the adult lifespan, their impact on foraging decisions, and their contribution to coordinate food gathering. Odor-rewarded experiences during the first days of honeybee adulthood alter the responsiveness to sucrose, making young hive bees more sensitive to assess gustatory features about the nectar brought back to the hive and affecting the dynamic of the food transfers and the propagation of food-related information within the colony. Early olfactory experiences lead to stable and long-term associative memories that can be successfully recalled after many days, even at foraging ages. Also they improve memorizing of new associative learning events later in life. The establishment of early memories promotes stable reorganization of the olfactory circuits inducing structural and functional changes in the antennal lobe (AL). Early rewarded experiences have relevant consequences at the social level too, biasing dance and trophallaxis partner choice and affecting recruitment. Here, we revised recent results in bees' physiology, behavior, and sociobiology to depict how the early experiences affect their cognition abilities and neural-related circuits. Apis mellifera has been considered a model within the invertebrates to study the behavioral and neural plasticity caused by early experiences presented higher responsiveness than those bees that did not extent their proboscises diluted in sucrose solution 5\u20138 days after emergence were recorded determined that those glomeruli showing structural changes after early learning were those that exhibited a significant increase in neural activity. Map of volume change in bees subjected to early learning events with 1-NON shows that the four newly recruited glomeruli were those that also exhibited the largest volume increases Figure . MoreoveThese results indicated that early olfactory learning results in long-lasting structural and functional modifications of the AL network in the form of glomerular volume variations and on the activation of new glomeruli upon olfactory stimulation with the odor that has been learned. It is then showed that early odor-rewarded experience induces a stable reorganization of olfactory circuits that accompanies the high plasticity of behavior, presumably because the olfactory system finishes its maturation at that stage to the hive. Within this complex chemical environment, middle age workers involved in food reception can learn food odors through mouth-to-mouth trophallaxis while they unload and store the scented food. One-week-old bees performing tasks such as nursing have similar opportunities when handle scented food directly from comb cells to feed the brood Winston, .Although it was suggested that young honeybees did not learn consistently under laboratory conditions until they were 6/7 days of age (Ray and Ferneyhough, At the individual and social level the presence of long-lasting odor information might have important consequences during the resource exploitation. The novice foragers might be prompted to search for sources whose scents are reminiscent of the odors learned at early ages. Furthermore, retrieval of early olfactory memories may participate in the coordination of collective tasks, leading to non-random interactions between foragers and experienced followers within the dancing context. Biases in the choice of dancing partners favor recruitment of foragers that despite na\u00efve for the advertised food source, known in advance how it smells.Floral odorant cues also alter how early and middle age bees perceive and respond to nectars of different qualities. Given the fact that the speed and extent the information propagates amongst nest mates rest on the quality and odorant cues of the food (Ram\u00edrez et al., Abundance and composition of flower species have profound ecological consequences on pollinators since both can change over their short lifespan (Kearns and Inouye, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Analysis of bone microstructure in ornithopod and theropod dinosaurs from Victoria, Australia, documents ontogenetic changes, providing insight into the dinosaurs' successful habitation of Cretaceous Antarctic environments. Woven-fibered bone tissue in the smallest specimens indicates rapid growth rates during early ontogeny. Later ontogeny is marked by parallel-fibered tissue, suggesting reduced growth rates approaching skeletal maturity. Bone microstructure similarities between the ornithopods and theropods, including the presence of LAGs in each group, suggest there is no osteohistologic evidence supporting the hypothesis that polar theropods hibernated seasonally. Results instead suggest high-latitude dinosaurs had growth trajectories similar to their lower-latitude relatives and thus, rapid early ontogenetic growth and the cyclical suspensions of growth inherent in the theropod and ornithopod lineages enabled them to successfully exploit polar regions. During the Early Cretaceous, the state of Victoria, Australia, lay within the Antarctic Circle between the paleolatitudes of 75\u00b0S and 80\u00b0S Because fossil bone histology provides insights into the growth dynamics of extinct animals Timimus based on similarities to the type femur Timimus may either be an ornithomimid Since that initial study, the number of hypsilophodontid fossils collected from Victoria has increased substantially, thus permitting a larger sample for osteohistologic examination. The current assessment includes nine femora and eight tibiae from hypsilophodontids as well as one theropod femur. Although the number of Early Cretaceous hypsilophodontid genera may be as high as six Now that more dinosaur fossils from Victoria are available, the goal of this research is to provide a more robust analysis of polar dinosaur osteohistology and to test the hypothesis that there is microstructural evidence suggesting at least some polar dinosaurs hibernated. Results of this study allow evaluation of ontogenetic changes in bone tissue, enable comparisons with the bone microstructure of lower-latitude hypsilophodontid and theropod relatives, and lead to a new hypothesis to explain the successful radiation of dinosaurs in high-latitude environments.Almost every hypsilophodontid long bone examined had cyclical growth marks in the form of lines of arrested growth (LAGs), or annuli followed by \u201cbright lines\u201d . Growth The theropod femur (NMV 186317) sectioned by Chinsamy et al. Studies performed on extant taxa imply that growth mark periodicity is annual e.g., , althougOrodromeus, Dryosaurus, and Scutellosaurus examined by Chinsamy et al. Troodon formosus had well vascularized, woven-fibered tissue throughout the cortex and lacked LAGs . Althougformosus .Despite the variability between LAGs and annuli within the hypsilophodontid samples, the microstructures and cyclical growth exhibited by both ornithopods and theropods from the high paleolatitude of southeastern Australia resemble patterns observed in dinosaurs from lower paleolatitudes, indicating similarities in growth dynamics and physiology. Although LAGs can form as a result of the slowed metabolic processes experienced during hibernation, they are not microstructural features exclusive to hibernators While it is entirely likely that polar dinosaurs had specialized behavioral and morphological adaptations to cope with their environment, only a few possibilities can be tested with fossil bone microanalyses. For instance, several microstructure studies have demonstrated that Triassic and Jurassic archosaurs (including dinosaurs) exhibited cyclical suspensions in growth as well as high growth rates early in life This research was sponsored by the 2010 East Asia and Pacific Summer Institutes program, jointly organized by the National Science Foundation and the Australian Academy of Sciences. Access to dinosaur fossil collections at Museum Victoria was provided via a letter of invitation from Dr. Thomas Rich and Museum Victoria permit number VP 2010/07.Timimus hermani, based on morphological similarities to the theropod femur (NMV 186317) sampled by Chinsamy et al. Nine femora and eight tibiae from small bodied hypsilophodontid ornithopod dinosaurs and one femur from a theropod dinosaur were selected for histological analysis from the collections of Museum Victoria, Melbourne, Victoria, Australia (NMV). Isolated limb elements were collected from either the Wonthaggi Formation (Early Aptian) of the Strzelecki Group or the Eumerella Formation (latest Aptian-Early Albian) of the Otway Group [3], [4]Samples containing the mid-diaphysis were removed from the shafts when possible and first processed using a procedure modified from Schweitzer et al."} +{"text": "EHP 120(3):332\u2013339; Snedeker and Hay]. No study has yet directly addressed that hypothesis, but this review comments on the strengths and weaknesses of studies linking environmental chemicals to obesity and diabetes and identifies gaps in the knowledge of how gut microbiota may affect the metabolism of these chemicals.The microbiota that populate human intestinal tracts vary substantially from person to person, and mounting evidence suggests these interindividual variations in gut microbiota affect how a person metabolizes chemicals they may be exposed to. A review of the literature on this topic directed attention to a new hypothesis: that interactions between gut ecology and environmental chemicals contribute to obesity and diabetes [Studies reviewed by the authors found that differences in gut microbiota affected the toxicity of certain pharmaceuticals, including acetaminophen and the chemotherapy medication CPT-11. The authors propose that the same mechanisms may be at work with environmental chemicals. Enzymes produced by different gut microbe species can render ingested chemicals either more or less bioavailable, thereby affecting their toxicity. In reviewing evidence on 3 dozen suspected obesogenic and diabetogenic chemicals, the authors found that at least three-quarters of them may be metabolized by gut microbe enzymes in a way that affects their absorption, distribution, metabolism, and excretion.Human studies have shown that obese and diabetic individuals have different gut microbiota compositions than lean and nondiabetic individuals. Likewise, bariatric surgery was associated with altered gut microbiota. The composition of a gut\u2019s microbiome may influence body weight by regulating fat storage, altering the ability of the intestines to extract energy from food, and affecting satiety by modulating the levels of hormones that regulate appetite.The reviewers also found developmental links between gut microbiota and obesity. For instance, one study connected microbiome composition of children to their mother\u2019s weight, body mass index, and degree of weight gain during pregnancy, while another linked differences in infant microbiota composition to weight gain years later. The review highlights the importance of understanding how differences in gut microbiota might affect the fate of environmental chemicals in people and influence human health outcomes."} +{"text": "The mechanisms underlying social behavior are indeed complex, yet researchers have made important contributions to our understanding of how people make judgments and behave across various social contexts. In particular, recent years has seen a proliferation of research spotlighting the guiding role of embodied and affective information in social processing. Grounded approaches to cognition offer an exciting opportunity for researchers throughout the cognitive sciences to work within a unified framework to shed light on traditionally nebulous and intractable psychological quagmires .In what follows I will describe how embodied and affective information influence some hallmark social processes and then clarify some misunderstandings about representation and processing in grounded cognitive systems. I will then argue that the term \u201cdirectionality\u201d in grounded accounts engenders misleading views about cognition and will conclude with recommendations that should improve our understanding of social behavior from the growing perspective of grounded cognition.A growing body of literature indicates that embodied and affective states influence moral judgments and prosociality. In the domain of moral judgment, research has shown that inducing physical disgust can harshen moral judgments , can seem at times like more of an exercise for the armchair than the laboratory. While classic findings from cognitive science have helped refine our understanding of representation and processing and abstract category domains. These embodied perceptual states are stored in memory and reactivated in bottom-up format during later conceptual processing. For example, many early experiences of interpersonal warmth naturally co-occur with physical warmth, such as cradling infants. Hence, perceptual experiences involved with physical and interpersonal warmth become part of the same representational and processing structure, which is one way to explain the now-popular finding that experiencing physical warmth can promote interpersonal warmth toward a stranger why such emphasis on directionality and (2) what does this mean for social behavior? First, conceptual metaphor theory was born (in part) out of research in linguistics (Lakoff and Johnson, flexible foundation that shapes people's social processing (see Lee and Schwarz, This clarification is particularly important for social behavior because conceptual knowledge has been demonstrated to be an important but In short, embodied/affective states not only help ground meaning and guide social processing but are also intricately linked to online processing and experience, upon which representational-processing states are founded. Along these lines, researchers have rightly argued that more attention should be given to cultural differences in metaphorical and embodied cognition (Meier et al., Embodied effects that were once striking, intriguing, and perhaps confounding, are now commonplace, and it is indeed time to breathe life into these effects with systematic theory-building that is predicated on a deeper analysis of the mechanisms underlying grounded theories of cognition. By nature, embodied and affective information are flexible sources of information, which is evidenced by their context dependence (Lee and Schwarz,"} +{"text": "The approach is simple and effective and can be implemented using standard bioinformatic tools.With high quantity and quality data production and low cost, next generation sequencing has the potential to provide new opportunities for plant phylogeographic studies on single and multiple species. Here we present an approach for Toona ciliata (Meliaceae), 159,514 base pairs long, was assembled from shotgun sequencing on the Illumina platform using de novo assembly of contigs. To evaluate its practicality, value and quality, we compared the short read assembly with an assembly completed using 454 data obtained after chloroplast DNA isolation. Sanger sequence verifications indicated that the Illumina dataset outperformed the longer read 454 data. Pooling of several individuals during preparation of the shotgun library enabled detection of informative chloroplast SNP markers. Following validation, we used the identified SNPs for a preliminary phylogeographic study of T. ciliata in Australia and to confirm low diversity across the distribution.The chloroplast genome of Our approach provides a simple method for construction of whole chloroplast genomes from shotgun sequencing of whole genomic DNA using short-read data and no available closely related reference genome (e.g. from the same species or genus). The high coverage of Illumina sequence data also renders this method appropriate for multiplexing and SNP discovery and therefore a useful approach for landscape level studies of evolutionary ecology. Landscape-scale studies of phylogenetic patterns and population dynamics across one or more species can reveal the genetic signatures of contrasting temporal responses to environmental change among diverse functional groups. Such information is critical for understanding how species are distributed, how communities are assembled, and in recognising different susceptibilities to threats and change .Quercus.Toona ciliata. Two SNPs in homopolymer repeat regions were excluded from the network analysis and a consistent unambiguous sequence could not be obtained for the remaining one. The combination of seven chloroplast SNPs produced six chlorotypes across five populations . All other chlorotypes were population-specific, showing geographic structure .3. Assemble contigs with reference to chloroplast genome of the closest available relative, assembling in two halves if both IR regions are required.4. Use consensus chloroplast sequence for mapping reads and detecting SNPs.The technical approach presented here provides a simple method for construction of whole chloroplast genomes from shotgun sequencing of whole genomic DNA using short-read data and no closely related reference genome. The high coverage of Illumina sequence data also renders this method appropriate for multiplexing and SNP discovery and therefore a useful approach for landscape level studies of evolutionary ecology, particularly given that Illumina sequencing is the most cost effective platform presently available .Toona ciliata. With current Illumina HiSeq output at approximately 35 Gbp per lane there is already the potential for producing up to 120 chloroplast genomes per lane by this method (depending on genome size and required sequencing coverage). The present limitation is the cost and availability of labels for multiplexing . As library costs decrease, we will see even more opportunities for discovering variable loci for large numbers of species at low cost, or for directly comparing chloroplast DNA from multiple pooled populations. We are currently exploring the latter approach to identify common phylogeographic patterns among a range of co-distributed rainforest trees.We have shown by sub-sampling dataset 1 that approximately 0.18 Gbp of shotgun Illumina data would have been sufficient for assembly of the whole chloroplast genome of The data sets supporting the results of this article are available in the GenBank repository as follows:Toona ciliata chloroplast genome have been lodged in the GenBank database at NCBI [GenBank:JX445406-JX445485].All 80 contigs generated by this study and used for assembly of the All sequences generated during chloroplast genome verification, comparison of 454 and Illumina assemblies, SNP detection and verification have been lodged in the GenBank database at NCBI [GenBank:JX445486-JX445910].The authors declare that they have no competing interests.HM participated in the design of the study, contributed molecular work for the Illumina component, participated in sequence alignment, bioinformatic analyses and drafted the manuscript; MvdM participated in the design of the study, sequence alignment, bioinformatic analyses and helped to draft the manuscript; SKD contributed molecular work for the 454 component and helped to draft the manuscript; MAE performed library preparation and sequencing for the Illumina component, provided the subsampling script, assisted with bioinformatic analyses and provided comments on the draft manuscript; RJH participated in the design of the study, and provided advice on molecular and bioinformatic components; EM participated in bioinformatic analyses and optimizing technical approach; PDR contributed molecular work for the Illumina component, participated in bioinformatic analyses and provided comments on the draft manuscript; MLM performed PCR and sequence alignment for verification and phylogeographic components, performed the phylogeographic analysis and helped to draft the manuscript; JS participated in sequence alignment and optimizing technical approach; MR conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.Toona ciliata samples used for this study.Click here for filePCR primers designed for SNP detection, assessment of differences between Illumina and 454 sequencing and verification of inverted repeat flanking regions in Toona ciliata.Click here for file"} +{"text": "The objectives of this article are to review different patterns and potential pitfalls of quantitative lung perfusion scintigraphy (LPS) in patients with congenital heart disease (CHD). The patterns of quantitative LPS in patients with CHD include normal symmetrical bilateral perfusion to both lungs, unilateral absent perfusion in one lung, unilateral decreased perfusion, and multiple segmental perfusion abnormalities that suggest pulmonary embolism. Knowledge of several potential pitfalls is very important to avoid false interpretations; common pitfalls are related to type of site of injection (upper versus lower extremities), right or left upper extremity in case of persistence of left superior vena cava and previous surgery. An important incidental finding that may prompt immediate attenuation is multiple segmental defect that suggests asymptomatic pulmonary embolism, which is relatively common in this population. In complex congenital heart disease (CHD), it is important to know the differential lung perfusion because asymmetrical lung perfusion is one of the predictors of the outcome and exercise capacity. Quantita299Tc) macroaggregated albumin (MAA) is the radiopharmaceutical used. The recommended dose of 99mTC is 37\u2013148 MBq (1\u20134 mCi). With the aid of computer software, region of interests (ROIs) are placed over the right and left lung and the geometric mean of the anterior and posterior counts in each region is calculated. Each lung can be further divided into thirds to create superior, middle and inferior ROIs. This division does not correlate with anatomic division into lobes.Quantitative LPS studies are simple to perform. No specific patient preparation is necessary. TechnetiPatients with CHD with normal pulmonary artery have normal perfusion with essentially equal perfusion to both lungs Figure and b. IUnilateral absence of lung perfusion is seen in patients with congenital absence of pulmonary artery, wherein the ipsilateral lung perfusion occurs through collaterals from bronchial arteries that cannot be assessed by lung perfusion except in patients with functioning right to left shunt. In addition, unilateral absence of pulmonary artery perfusion is seen in many CHD patients, such as patients with Tetralogy of Fallot TOF and absent right or Figure and b leUnilateral decreased relative lung perfusion is the most common perfusion abnormality seen in patients with CHD. The etiology of unilateral decreased lung perfusion can be divided into an isolated congenital branch PA stenosis and branch pulmonary artery (PA) stenosis seen in many CHD patients, such as TOF with right or left PA stenosis, transposition of the great arteries and truncus arteriosus. QuantitaWhere there is a right to left shunt, some of the MAA escape from the pulmonary circulation and lodge in the systemic capillaries. By estimThrombosis and thromoboembolism can be a significant cause of morbidity and mortality after Fontan operation . The posLPS lung scan imaging is associated with a radiation dose of about 1 mSv, equivalent to 50 frontal CXR. Repeat investigation of this exam can therefore contribute significantly to radiation burden for children and adolescents. In patients with atriopulmonary anastomoses, total or partial cavopulmonary connection (Fontan circulation), LPS does not optimally reflect the genuine perfusion ratio because the geometry of pulmonary arterial anastomoses with superior vena caval and inferior vena caval pathways leads to abnormal streaming and distribution of blood flow to branch pulmonary arteries. InjectioMagnetic resonance (MR) imaging is now increasing in the assessment of CHD in both children and adults. QuantitaThe limitations to MR are several, which include: (1) absolute contraindications as in the case of pacemaker, (2) the need for general anesthesia and (3) several potential errors, such as incorrect prescription for location or angle, incorrect technical parameters and signal dephasing owing to turbulent flow in case of discrete stenosis.It is important to measure the differential lung perfusion in patients with CHD as it predicts the outcome and exercise capacity. Quantitative LPS is simple, safe and widely available. Several patterns of LPS are seen in patients with CHD. Knowledge of different patterns, potential pitfalls and limitations are very important to avid false interpretation with subsequent patient mismanagement. PC-MR imaging may be considered as an alternative test in some patients."} +{"text": "Dear SirNeonates referred from various sources with single or more episodes of bilious vomiting undergo radiological investigation and ultrasound examination to exclude malrotation and volvulus. Although many of these will have a normal study and feed well afterwards or may have other diagnoses, nevertheless, approximately 6 to 8% will need corrective surgery for malrotation , 2. RareA study suggested that even in developed world bilious vomiting might go unrecognized by medical professionals and parents. Green colour vomiting is single most important symptom, which should lead to further investigations . It is eThe consequences of missed or delayed diagnosis can be catastrophic, leading to long-term morbidity or mortality. A typical newborn with malrotation and volvulus present with bright green vomiting Fig. . It may An unstable child with bilious vomiting and obvious abdominal signs should not undergo any further investigations as prompt surgical intervention is crucial to save ischemic bowel. There is an apparent cost of performing contrast study in majority of normal neonates but comparing it to the cost of catastrophic loss of bowel, long term requirement of parenteral nutrition, ongoing surgical care, prolonged hospital stay and loss of life is much more. Some of these late diagnosed children may even require bowel and liver transplantation.It is extremely important for all clinicians, nurses and midwives to recognize bilious vomiting and understand that green vomiting means mechanical obstruction unless proved otherwise. It is our responsibility as paediatric surgeons to spread the message to paediatricians, obstetricians, midwives and general practitioners to identify the bilious vomiting and significance of delay in diagnosing volvulus.Source of Support: NilConflict of Interest: None declared"} +{"text": "In vitro display technologies are powerful methods for the selection of such peptides from combinatorial peptide libraries. Various types of peptide binders are being selected with such technologies for use in a wide range of fields from bioscience to medicine. This mini review article focuses on the current state of in vitro display selection of synthetic peptide binders and compares the selected peptides with natural peptides/proteins to provide a better understanding of the target affinities and inhibitory activities derived from their amino acid sequences and structural frameworks. The potential of synthetic peptide binders as alternatives to antibody drugs in therapeutic applications is also reviewed.During the last decade, a variety of monoclonal antibodies have been developed and used as molecular targeting drugs in medical therapies. Although antibody drugs tend to have intense pharmacological activities and negligible side effects, several issues in their development and prescription remain to be resolved. Synthetic peptides with affinities and specificities for a desired target have received significant attention as alternatives to antibodies. This also compares the features of these synthetic peptides with those of natural peptides/proteins to provide an understanding of the relationships among amino acid sequence, structural conformation, and affinity for a desired target that allow the prediction of their potential as alternatives to antibody reagents and drugs.Since the 1990s, monoclonal antibodies have been developed as molecular targeting drugs to treat diseases such as cancers and inflammatory disorders . More thin vitro display technologies for the selection of peptide binders from combinatorial peptide libraries (CPLs). These technologies enable the creation of new peptides that can bind specifically to a wide range of target molecules was constructed through in vitro translation driven by the reconstituted system and was screened against the E6AP HECT domain . FurtherT domain . Remarkain vitro display selection of peptides from a wide variety of libraries is a powerful approach for the development of synthetic peptide binders against target molecules. Indeed, various peptide binders have been successfully selected and used in biology, biotechnology, and biomedical science. Furthermore, characterization of the selected peptides suggests that synthetic peptide binders might have in vitro molecular targeting activities comparable to those of antibodies. Based on these prospects, modified mRNA display [cDNA display \u2013cDNA\u2013mRNA complexes has been constructed \u2013cDNA\u2013mRNA complexes has been screened against mammalian cancer cells under culture conditions remain to be resolved for human administration. Therefore, establishing an innovative strategy including in vitro display selection is necessary to discover peptide binders, make chemical modifications to provide protease resistance and metabolic stability, obtain structural information to optimize target-binding modes, and perform theoretical simulation to predict dynamic actions. Such an integrated strategy would facilitate the development of next-generation peptide binders and mimics as alternatives to monoclonal antibodies and native ligands, respectively. The emergence of peptide binders that overcome the above difficulties will allow us to tailor peptide drugs for the prevention, diagnosis, and treatment of a wide variety of diseases and cancers.In conclusion, this review highlights the utility and versatility of The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Neutrophil gelatinase-associated lipocalin (NGAL) predicts the development of acute kidney injury (AKI) amongst critically ill patients . Serum aTo test these hypotheses, we studied ICU patients with SIRS and oliguria or a 25 \u03bcmol/l increase in serum creatinine. We sought to determine whether blood and urine NGAL correlated more closely with CRP or creatinine at the time of enrolment. The strength of the relationship between serum creatinine or CRP and urine and serum NGAL, as well as urinary NGAL corrected for urinary creatinine, was determined using Spearman's rank correlation coefficient.We recruited 105 patients between 31 August 2010 and 17 November 2010; 22 of these had an APACHE III diagnosis of sepsis. In nonseptic patients NGAL in blood or urine correlated only weakly with CRP, but a stronger and statistically significant relationship was observed between serum and/or urine NGAL and serum creatinine. A similar strength of relationship was observed between creatinine and NGAL and CRP and NGAL in septic patients, although it failed to reach significance. See Table In patients without a diagnosis of sepsis, NGAL is only weakly correlated with CRP and a stronger relationship is observed between NGAL and serum creatinine. This suggests that NGAL is more likely a biomarker of tubular injury or stress than systemic inflammation in these patients. Similar relationships of moderate strength are observed between NGAL in blood/urine and both serum creatinine and CRP in patients with a diagnosis of sepsis. This suggests that different pathophysiological processes may exist in the genesis of septic AKI when compared with inflammatory AKI. Further investigation regarding the natural history of AKI and the clinical and biochemical association of renal biomarkers is warranted."} +{"text": "Mechanisms of endogenous pain control are significant. Increasing studies have clearly produced evidence for the clinical usefulness of opioids in peripheral analgesia. The immune system uses mechanisms of cell migration not only to fight pathogens but also to control pain and inflammation within injured tissue. It has been demonstrated that peripheral inflammatory pain can be effectively controlled by an interaction of immune cell-derived opioid peptides with opioid receptors on peripheral sensory nerve terminals. Experimental and clinical studies have clearly shown that activation of peripheral opioid receptors with exogenous opioid agonists and endogenous opioid peptides are able to produce significant analgesic and anti-inflammatory effects, without central opioid mediated side effects . This article will focus on the role of opioids in peripheral inflammatory conditions and the clinical implications of targeting peripheral opioid receptors. Inflammation is the series of highly coordinated events that is the response of vascular tissues to detrimental stimuli which results in heat, swelling, redness, and pain . It is aAn excess of pain or long-lasting pain (not necessarily \u201cchronic\u201d) is counterproductive and so the body utilizes endogenous analgesic compounds to alleviate this sensation . EndogenOpioid-mediated analgesia is instigated in both the CNS and periphery through the release of endogenous opioid peptides. Evidence from the literature has shown that the central and peripheral mechanisms of endogenous opioid analgesia are interconnected, particularly in the early stages of inflammation . The latThere are three families of opioid peptides that have been extensively studied: the endorphins, enkephalins and dynorphins, each of which is derived from a distinct gene and the precursors, pro-opiomelanocortin (POMC), pro-enkephalin (PENK) and prodynorphin . Once reEnzymes within neurons such as phosphokinase C can phosphorylate opioid receptors, which leads to an increased affinity for arrestin molecules. Opioid-arrestin complexes have a decreased sensitivity for extracellular opioid peptides and are likely to be internalized via clathrin-dependent pathways . From heInflammation rapidly stimulates immune cell extravasation and migration into tissues . QuantitFigure 1). Upregulation of these cell adhesion molecules has been noted in many models of inflammation .Recent reports have described bidirectional communication between immune and neuronal cells as well as physical contact between these cells. Of note is the observation of peripheral nerves and opioid-containing immune cells being closely associated . In vitrG nerves whilst it nerves . The mect nerves . Inhibitt nerves , which sEndogenous opioids may enact anti-inflammatory effects as well as analgesia through their actions on neuronal cells through prevention of vesicular release of noradrenaline and substance P. The function of noradrenaline in inflammation is contested, with evidence being provided for both a positive and negative role. in vivo models of colitis. These results suggest that a variety of complex regulatory activities may be performed by opioid agonists in various tissues of the body that may be naloxone-sensitive or naloxone insensitive and these pathways may directly or indirectly inhibit the release of cytokines and mediators involved in inflammation at low doses for conditions such as rheumatoid arthritis. This may provide a much sought after alternative for the management of chronic arthritic and other inflammatory conditions whilst avoiding central opioid mediated side effects and of typical side effects produced by non-steroidal and steroidal anti-inflammatory drugs.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Ectodermal dysplasias are a heterogeneous group of inherited disorders characterized by defective formation of tissues derived from the embryonic ectoderm. Besides tissues of epidermal origin, other maxillofacial structures including hard and soft tissues can be affected. Disturbances in the early development of teeth frequently result in congenital absence or deformities of teeth. The lack of teeth leads to an impaired development of the alveolar crest, with decreased vertical and horizontal dimension. Osseointegrated dental implants in combination with hard and soft tissue augmentation techniques can be used successfully to restore the patients\u2019 masticatory function, phonetics and aesthetics."} +{"text": "In the first one, cytotrophoblasts (CTBs) fuse into a layer of syncytiotrophoblasts that covers the chorionic villi. These cells are responsible for hormone production, nutrient and gas exchanges between the mother and the developing fetus. In the second one, CTBs in the anchoring chorionic villi invade the uterus and its blood vessels establishing the maternal-fetal interface can be differentiated into trophoblast cells through bone morphogenetic proteins (BMPs) has allowed researchers to study the development and/or progression of several pathologies including neurological diseases [reviewed in Hibaoui and Feki ]. It is In conclusion, while further studies are needed to improve the efficiency of hPSC differentiation into trophoblast cells, we believe that this technology provides a promising alternative model to study trophoblast development. In fact, understanding and elucidating the mechanisms regulating human trophoblast development using hPSCs is critical not only in basic research but also in clinical medicine. It could provide novel insights into blastocyst formation, implantation and placentation processes in humans. Thus, patient-specific hPSCs will also open up new exciting avenues for the identification of genetic and biochemical markers that could be useful for the prediction and management of pregnancy complications such as pre-eclampsia, intrauterine growth restriction and aneuploidies. The coming years will tell whether these cells fulfil their promise."} +{"text": "Several natural language processing tools, both commercial and freely available, are used to extract protein interactions from publications. Methods used by these tools include pattern matching to dynamic programming with individual recall and precision rates. A methodical survey of these tools, keeping in mind the minimum interaction information a researcher would need, in comparison to manual analysis has not been carried out. We compared data generated using some of the selected NLP tools with manually curated protein interaction data (PathArt and IMaps) to comparatively determine the recall and precision rate. The rates were found to be lower than the published scores when a normalized definition for interaction is considered. Each data point captured wrongly or not picked up by the tool was analyzed. Our evaluation brings forth critical failures of NLP tools and provides pointers for the development of an ideal NLP tool."} +{"text": "The autonomic nervous system provides both cholinergic and noncholinergic neural inputs to end organs within the airways, which includes the airway and vascular smooth muscle. Heightened responsiveness of the airways to bronchoconstrictive agents is a hallmark feature of reactive airways diseases. The mechanisms underpinning airways hyperreactivity still largely remain unresolved. In this paper we summarize the substantial body of evidence that implicates dysfunction of the autonomic nerves that innervate smooth muscle in the airways and associated vasculature as a prominent cause of airways hyperresponsiveness in asthma. The symptoms of asthma\u2014wheezing, dyspnea, chest tightness, cough, reversible airways obstruction, mucus hypersecretion, and airways hyperresponsiveness\u2014all inextricably link the nervous system to this disease. It is thus remarkable that in the 440 pages of the National Heart, Lung and Blood Institute (NHLBI) guidelines on asthma, nerves are mentioned in just one sentence . Nerves Guidelines such as those produced by the NHLBI and BTS, in which immune cells including eosinophils are given a central role in asthma pathogenesis appropriately highlight the prominent feature of inflammation in the asthmatic lung. Inflammation may precipitate airways hyperresponsiveness , 5\u20138. BuGiven the strong case for neural dysfunction in asthma, it is surprising how little attention airway nerves receive in the published literature. The under emphasis on nerves in asthma and the exaggerated influence of inflammation in asthma can be illustrated by comparing the scant references to neural mechanisms in this disease with the incessant discussions of eosinophils in asthma guidelines and in all of asthma-related literature. This is especially surprising, given how strong the evidence is in favor of neural mechanisms in asthma and how comparatively weak the evidence is supporting a role for eosinophils in this disease. Even the most ardent proponents might struggle to make a strong case for a role of eosinophils in asthma. There is no increase in the risk of asthma for patients with hypereosinophilic syndrome . Nonasthin vitro, conducted using airways obtained from asthmatic and nonasthmatic lung donors, yield results that are somewhat varied [The mechanisms of airways hyperresponsiveness are poorly understood. It seems all but certain that smooth muscle is central to regulating airways reactivity. However, studies of airways smooth muscle contractility t varied \u201328. Thust varied , 30. Thecan contract human airway smooth muscle, a survey of the published literature suggests that only 3 endogenously released ligands, acetylcholine, histamine, and the cysteinyl-leukotrienes, reliably contract human airway smooth muscle to any significant extent and in physiologically relevant conditions in the airways of asthmatics. What so clearly defines the role of the nervous system in regulating the airways hyperresponsiveness in asthma is the indisputable source of the acetylcholine that regulates airway smooth muscle tone and the profound effects of anticholinergics on the airways obstruction and airways reactivity that define this disease. If, however, we accept the evidence in support of the hypothesis that airway smooth muscle accounts in large part for the most defining pathophysiological features of asthma (reversible airways obstruction and airways hyperresponsiveness) it is then critical to determine what ultimately regulates airway smooth muscle contraction. Airway smooth muscle generates little myogenic tone and so contraction depends upon the actions of contractile agonists. Despite an extensive list of autacoids and neurotransmitters that The autonomic nervous system plays a primary role in regulating airway smooth muscle tone. The highly regulated activity of these nerves allows ongoing input to the airway smooth muscle such that basal tone is regulated on a breath by breath basis. The origin of this ongoing drive depends upon centrally mediated activity established by both respiratory and reflexive inputs \u201334. In mFor years it had been widely assumed that noncholinergic neurotransmitters mediating relaxations of the airways were coreleased with acetylcholine from a single population of postganglionic parasympathetic nerves. It was further speculated that these noncholinergic cotransmitters served as a brake on the parasympathetic nervous system, preventing excessive constriction during periods of elevated autonomic tone. Our studies have revealed, however, that anatomically and physiologically distinct parasympathetic nerves mediate cholinergic contractions and noncholinergic (nitrergic) relaxations of the airways \u201338. Impo\u03b2-agonists in controlling asthmatic airway function, 2 subsequent studies reported similar findings when using the ultra-potent and long acting anticholinergic [ There is indisputable evidence supporting the hypothesis that dysregulation of airway cholinergic nerves contributes to the pathogenesis of airways obstruction and airways hyperresponsiveness. Cholinergic nerve-mediated obstruction of the airways is increased in asthma and COPD , 40. Airlinergic , 43. Thelinergic .Evidence suggesting that nitrergic parasympathetic nerves are dysfunctional in airways disease is circumstantial but compelling. In humans and in many animal species, adrenergic nerves are sparse or absent in the airways and without apparent influence over airway smooth muscle tone . Consequin vitro. Similarly, in vivo epinephrine (a nonselective adrenergic agonist that would evoke both bronchodilatation and vasoconstriction) has no effect on reactivity yet in vitro (where the vasculature is no longer intact), it is more potent and efficacious than the \u03b2-adrenergic agonist albuterol at preventing airway smooth muscle constriction [Vascular beds in the airways play an important role in basal airway obstruction through the regulation of airway wall volume . Mucosaltriction .As is the case with airway smooth muscle, vascular smooth muscle possesses a baseline level of tone that is dependent upon ongoing activity of the autonomic nervous system . HoweverWhile it is clear that the nervous system is essential to the reactivity of the airways in asthma, it is unclear precisely what drives dysfunction of airway nerves in asthma. The simplest explanation might be that inflammation alters airway autonomic function in asthma. Airways inflammation has been associated with enhanced cholinergic responses following altered prejunctional control mechanisms or by sensitizing neurotransmission through the parasympathetic autonomic ganglia (the synaptic relay between pre- and postganglionic neurons) (reviewed in ). NitrerIt seems possible that an overemphasis on the role of inflammation in models of asthma, and less attention to the central role of airways hyperresponsiveness, has contributed to the frequent failure to translate promising therapeutic strategies discovered in animals into patients with asthma , 68. Imp"} +{"text": "Sir,Mycobacterium tuberculosis) among patients with PCR positivity, compared to those with PCR negativity, thereby implying that even latent tubercular infection can give rise to positive PCR results.[We would like to thank readers for showing interest in our article and expr results.A pooled analysis of the data from 20 studies assessing the use of pleural fluid NAA tests concluded that these tests demonstrated reasonably high specificity , but generally poor and variable sensitivity .[Therefore, the disadvantages of PCR including high cost, risk of contamination and the technology involved in the procedure do not permit its routine diagnostic use at present."} +{"text": "Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and the fifth most common cause of female cancer death in the United States. Although important advances in surgical and chemotherapeutic strategies over the last three decades have significantly improved the median survival of EOC patients, the plateau of the survival curve has not changed appreciably. Given that EOC is a genetically and biologically heterogeneous disease, identification of specific molecular abnormalities that can be targeted in each individual ovarian cancer on the basis of predictive biomarkers promises to be an effective strategy to improve outcome in this disease. However, for this promise to materialize, appropriate preclinical experimental platforms that recapitulate the complexity of these neoplasms and reliably predict antitumor activity in the clinic are critically important. In this review, we will present the current status and evolution of preclinical models of EOC, including cell lines, immortalized normal cells, xenograft models, patient-derived xenografts, and animal models, and will discuss their potential for oncology drug development. Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and the fifth most common cause of female cancer death in the United States . AdvanceHigh-grade serous carcinomas (HGSCs) represent the most common type II histologic subtype and account for approximately 70% of all EOCs. These tumors exhibit histological features that are identical to those of primary peritoneal and fallopian tube serous cancers and are treated similarly to these neoplasms. A number of molecular studies and most recently The Cancer Genome Atlas (TCGA) project have shown that HGSCs are characterized by frequent genetic and epigenetic alterations in gene members of the homologous recombination (HR) DNA repair pathway, including the BRCA1 and BRCA2 genes . Furtherin vitro and to select specific histologic subtypes of EOC for further exploration of these agents. These cell lines have undergone a high degree of evolutionary selection pressure in vitro as they have been in passage for several years (or even decades in some cases). As a result, their genomic profiles have been irreversibly altered and rarely recapitulate the genetic and pathologic characteristics of the parental cells of cell lines from the Cancer Cell Line Encyclopedia (CCLE) and of tumor samples from the TCGA to evaluate the suitability of 47 EOC cell lines as of HGSCs . The invin vitro observations will be eventually translatable to the clinic.This study may provide molecular explanation for the challenges of translating preclinical observations from ovarian cancer cell lines into the clinic, a problem that is not unique to ovarian cancer but transcends multiple tumor types , 15. Howin vitro propagation and immortalization of human ovarian surface epithelial (OSE) and fallopian tube epithelial (FTE) cells which are considered the cells of origin of ovarian carcinomas. Retroviral transduction of either the human papilloma virus E6/E7 oncogenes or the simian virus 40 T-Antigen (SV40-TAg) in human OSE cells leads to increased and sustained proliferation even after multiple passages but does not induce transformation T cells into athymic mice which resulted in development of ascites and peritoneal carcinomatosis seeding of the tumor, and thereby fails to reflect the clinical course of human EOC. Conversely, IP and orthotopic implantation (OI) frequently result in peritoneal carcinomatosis and development of malignant ascites. The most commonly used xenograft model in ovarian cancer was developed by IP injection of a subpopulation of the drug resistant cell line NIH:OVCAR-3 and is generally between 2 and 4\u2009months. PDXs have been successfully established from primary or metastatic tumors (Patient-derived xenografts (PDXs) represent an evolution of the cell line xenograft model whereby fresh tumor tissue, obtained directly from patients, is implanted subcutaneously or orthotopically into immunodeficient mice , 52. Aftc tumors , 57, froc tumors , 59 therin vitro culture step grown subcutaneously in the flank of athymic nude mice . They asIn the era of personalized medicine, patient-centric PDX models for tumor growth and assessment of drug efficacy may be a valuable resource for the preclinical development of experimental anticancer agents. However, as in the case of cell lines, periodic molecular assessment of these models examining the fidelity to the patients\u2019 original tumors in terms of genetics and histology, two factors that are major determinants of their eventual predictive ability.Spontaneous EOC models including the aging hen, the cynomolgus macaque, and the rhesus macaque are rarely used in preclinical drug development due to their low incidence rates and long interval until cancer development \u201380. Howe\u2212/\u2212 mice with any combination of two or three of the c-MYC, KRAS, and AKT oncogenes, and reimplanted them in the TVA; p53\u2212/\u2212 mice resulting in rapid formation of tumors 8\u2009weeks later. The resulting tumors exhibited poorly differentiated histology with areas of papillary structures resembling HGSCs. This model was subsequently used to assess sensitivity to molecular pathway inhibitors; for example tumors with AKT and c-MYC oncogenes or AKT and KRAS were sensitive to mTOR inhibitor rapamycin while tumors with all three oncogenes were resistant to rapamycin but sensitive to a combination of mTOR inhibitor and MEK inhibitor . These experiments highlight how such models may be used to test the efficacy of molecular targeted agents in EOC. A similar experimental strategy was also employed for development of a BRCA1-associated EOC model whereby expression of c-MYC resulted in transformation of BRCA1 and p53 deficient murine OSEs . Peritoneal carcinomatosis and ascites were present in 27 and 24% of the cases respectively. Dinulescu and colleagues , and molecular fingerprints of EOC, there are several limitations of these models particularly relevant to their use for preclinical evaluation of novel anticancer agents . The mosAnother issue is that mouse models rely on specific oncogenes and tumor suppressor genes while ignoring other aspects of tumor development such as the host immune system and the tumor microenvironment. Due to the limited number of genetic alterations that induce the development of mouse tumors, mouse models are relatively homogeneous and thus may not adequately recapitulate the significant molecular heterogeneity of human tumors which is an essential element of a good preclinical model. Finally, logistical issues including cost, technical challenges in generating GEM models especially GEMs with multiple genetic alterations, long interval until development of tumors and variable penetrance are important limitations of GEM models for preclinical evaluation of novel anticancer drugs.Despite significant advances in surgical and medical management, EOC remains a highly lethal malignancy for which new therapeutic strategies are urgently needed. Appropriate experimental platforms that recapitulate the complexity of these tumors are critically important for evaluation of novel therapeutics. Table in vitro models, particularly those with well defined molecular alterations such as BRCA1/2 or PI3K mutations. Xenograft models of established EOC cell lines are still commonly used in preclinical drug development, but are increasingly giving place to PDXs which offer the important advantage of closely resembling original patients\u2019 tumors and adequately capturing the molecular and intratumoral heterogeneity of the original tumors. Finally, genetically engineered mouse models hold promise as they may mimic all major elements of human EOCs including stromal-tumor interactions without the requirement of an immunodeficient background. Clearly, there is no one best preclinical EOC model. Rather, preclinical evaluation of experimental anticancer agents should include multiple model systems in order to increase the possibility of correctly predicting their clinical activity.In conclusion, cell lines with confirmed molecular identity using targeted sequencing and copy number profiling may be extremely valuable as The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Bronchial leiomyoma is extremely rare. To date less than 60 cases have been reported in the world literature. The presented case here is a 30 year old woman who had been treated for bronchial asthma for several years. Her chest radiograph showed bulluos emphysematous changes in the right lung and computer tomography scan found the tumor in the right main bronchus near carina. Diagnosis was made by histological and immunohistochemical examination of the specimens obtained during bronchoscopy. The patient was treated by bonchoscopic resection of the 3 centimetre firm tumor and its removal through a tracheostomy incision. Primary pulmonary leiomyomas are extremely uncommon both in adults and children, constituting approximately 2% of benign lung tumors.1134Herein an additional case with endobronchial leiomyoma is reported and a simple surgical method for removing large tracheal and bronchial lesions is explained. The literature is also reviewed.A 30 year old non- smoker woman was admitted to our centre with a 10 year history of asthma like symptoms which did not respond to bronchodilators anymore.Her chest radiograph showed bullous lesions, widespread infiltrates and volume reduction in the right lung. Computed tomography of the thorax demonstrated a mass lesion in the right main bronchus extending to the trachea as well as unilateral bullous emphysema with relatively thick septa, pleural thickness and reduced volume of the right hemi thorax .Fiberoptic bronchoscopy detected a pink large mass completely obstructing the lumen of right main bronchus and extending to a point close to carina . Due to Histopathologic examination revealed that immediately beneath the intact pseudostratified ciliated columnar epithelium with some focal squamous metaplesia, the neoplasm composed of bundles and whorls of spindle shaped cells with monomorphous fusiform nuclei and acidophilic cytoplasms without cytonuclear atypia, mitotic figures or necrosis . Also, sThe patient was treated by endoscopic resection. However, the tumor was firm and large (3 centimeters in diameter) to remove through the rigid broncoscope despite great effort. In order to avoid tracheotomy and resection of a large portion of lung, a small cut was made in the neck area and the trachea was incised horizontally (tracheostomy). With cooperation of the anesthetics the tumor was brought to the incised region and removed by surgical forceps . Then thPrimary leiomyoma is one of the most rarely encountered benign tumors of lung, accounting for less than 2% of all cases.152779Symptoms depend on the location of the tumor, its size and the secondary changes of the lung distal to it. Patients with bronchial leiomyomas can have respiratory symptoms such as coughing, wheezing, dyspnea, chest pain or fever, due to partial or complete obstruction of the affected bronchus and superimposing infection resulting from atelectasis or bronchiectasis distal to obstruction).418The chest radiographic findings of endo- bronchial leiomyomas range from normal in patients with small tumor nodule to a solitary round mass or pneumonic infiltration, mediastinal shift, and collapse of lung to unilateral emphysema or hyperlucency according to obstructive sequel of bronchus due to the tumor.9101414The exact diagnosis of endobronchial leiomyoma can be made by broncoscopy in most cases because it can provide biopsy specimen for histological examination besides visualizing and localizing of the tumor.4Bronchial leiomyomas are thought to derive from smooth muscle layer of bronchi, bronchiols, or blood vessels.Pulmonary nodules with features of small muscle tumors may be in fact metastasis from extra pulmonary leiomyoma/leiomyosarcoma. Uterine is the major primary site in such cases in females and sometimes the diagnosis of secondary pulmonary leiomyomatosis is made several years after hysterectomy.2072021Differential diagnosis includes other spindle cell tumors and tumor lesions such as bronchial carcinoid of the large spindle cell variant, pleural fibrous mesothelioma, metastatic malignant melanoma, metastatic synovial sarcoma and occasionally plasma cell granuloma.8Leiomyomas of the respiratory system are essentially treated with surgical or bronchoscopic resection.153893232428Development of smooth muscle neoplasm have reported in different conditions with immune deficiency, including acquired immunodeficiency syndrome (AIDS), particularly in children,11303533In summary, endobronchial leiomyomas are among the rarest of benign tumors of the respiratory tract. These neoplasms may mimic asthma or other obstructive diseases of the lung and should be kept in mind as a rare cause of asthma like symptoms especially in an adult female who is no longer responsive to bronchodilators. Histological examination and immunohistichemistry provide the exact diagnosis which can always exclude the possibility of a metastatic leiomyoma/leiomyosarcoma. Treatment is as conservative as possible and includes bronchial resection, segmentectomy, lobectomy or pnemonectomy."} +{"text": "What has been challenging for the field is to tightly link these shifting neural processes with what is known about measureable behavioral changes and strategic processes that occur during learning. The complex nature of behavior and strategy in motor learning often result in a trade-off between experimental control and external validity. Researchers in different disciplines have employed varying approaches to understand motor learning but with relatively little crosstalk. Here, we bring together a set of papers which investigate skill learning spanning multiple domains.There are several striking and unique features about the papers assembled for this special issue. One is the broad range of investigative techniques brought to bear on the problem of understanding skill acquisition, including cutting edge analytical approaches structures in skilled learning. Using the alternating serial response task (ASRT) they report that individuals with MCI, and likely compromised hippocampal/MTL structures, demonstrate a reduced ability to reactivate/recall learned sequences in subsequent blocks of practice. Interestingly, they report that differences in learning disappeared during the second half of a practice block suggesting a differential role for hippocampus/MTL structures across practice even within a block. In a second paper, Wadden et al. evaluated individual variability in the neural networks underlying motor sequence learning in middle aged adults. Comparing initial task performance to that at a delayed retention test following 5 days of continuous tracking practice they report variability in overall measures of implicit sequence specific learning. However, when learning was decomposed into temporal and spatial elements to account for individual variation, improvement in temporal elements were associated with a network of cortical, sub-cortical and cerebellar areas tied to performance instruction stressing speed over accuracy. In a third paper, Abe and Sternad highlight time dependent changes in learning parameters across six days of a virtual ball throwing task. Analyzing both the distribution and temporal structure of variability they demonstrate and model the importance of time scales. These papers demonstrate that understanding changes across the time course of learning, consolidation and retention is crucial to evaluating the contributions of neurocognitive mechanisms and needs to be investigated despite the difficulty in undertaking such work.It is our belief that this assemblage of papers will facilitate an integrative view of motor learning, foster discussion across disciplines, and stimulate collaboration. Such a cross disciplinary focus will help to elucidate the neural and cognitive processes underlying skill learning, and may serve to further accelerate translational paradigms that are grounded in skill learning theory."} +{"text": "The human skeleton is the most common organ to be affected by metastatic cancer . The prevalence of skeletal disease is greatest in breast and prostate carcinoma. Bone metastases lesions weaken bone structure, causing a range of symptoms and complications. Sufferers of breast and prostate cancers may develop Skeletal related events (SRE). These SRE are defined as pain that require palliative radiotherapy or surgery to bone, hypercalcaemia, pathologic fractures, spinal cord compression and bone marrow failure. These complications contribute to a decline in patients' HRQOL . However, information on treatment costs of breast and prostate cancers and multidimensional assessments of QOL are limited. Thus this study aim to obtain both cost and QOL of breast and prostate cancers patients and to determine their relationship with the patients sociodemograhic profiles and disease profile .To determine the health care cost and QOL of breast and prostate cancer patients in Malaysia. The association of risk factors (sociodemographic and diseases profiles including SRE status) and cost and QOL will later be determined through statistical analysis.This will be a societal approach, cost evaluation technique through a cross sectional study for a projected period of 9 months. Both qualitative and quantitative approach to estimate the health care cost of provider and patient\u2019s cost through microcosting questionnaire method. Patient\u2019s QOL will be using the locally validated EORTC-QLC-C30 questionnaire. Selected patients from oncologic and surgical wards, outpatients specialists clinics will be taken as respondents. Outcomes of study will include cost to treat a case of SRE and projected country's burden of SRE from both cancer. Other outcomes will be compared between SRE and non-SRE through measurements of cost per QALYs; cost per life years saved (LYS) and cost per deaths averted. Associated risk factors will be measured by bivariate and multivariate analyses with power of study of 80% and p value of 0.05.The cost of treatment among prostate and breast cancer patient of lower disease compared to those of higher stages, positive bone metastasis and SRE positive. The QOL will also be expected to be higher among these groups. By similar disease stages for each cancer types, the QOL and costs are expected to be similar.This information will provide the cost burden of breast and prostate cancers for the country and will be used for strategic planning for the country. Patients with risk of lower QOL will also be identified for better risk assessment during cancer managements."} +{"text": "Reuters reported that 8400 HIV cases were detected in the voluntary screening of drug addicts in Harm Reduction Programmes, and screening in prison and Narcotics Rehabilitation Centers in 2011. However, dental treatment for HIV inmates is highly constrained by high uncertainty resulting from the changes of epidemic profile after receiving medical treatment, relative inadequacy of dental treatment and rules and regulations. Thus institutional HIV dental care cost could pose challenges to government healthcare expenditure.The marginal cost for dental treatment is estimated based on the case scenario of prison X in Malaysia. Based on literature review and economic reasoning, an integrated cost planning model is formed to address the current needs in cost planning.The marginal cost for prison dental treatment is estimated to increase by at least 3 folds for prevalence cases and by at least 7 folds for surveillance case in short run. The cost pyramid is formed with the base of cost-consequences, cost efficiency and cost effectiveness planning followed by cost benefit and financial risk planning at the second layer, and cost utility planning at the peak layer. All cost planning components are integrated vertically and horizontally.HIV dental care costs for inmates will be at the expense of government revenue if the increased marginal cost is above the average cost. Therefore, cost estimation coupled with the integrated cost planning model is essential for evaluation, monitoring and budget allocation enhancement."} +{"text": "There is the need to understand the composition of oral biofilms so that appropriate preventive and treatment regimens, including using appropriate antimicrobials, can be developed further. Additionally, when the systemic effects from specific microorganisms in oral biofilms are better understood, more targeted preventive treatment options may be recommended for persons at high risk for potential systemic diseases such as cardiovascular disease, and for aspiration pneumonia. Hence, the possible association between periodontopathic microorganisms, and also between cariogenic microorganisms in high caries risk persons, and systemic diseases requires further research involving metagenomic and large well-designed clinical studies. Effective preventive oral care is important for reducing potential systemic diseases. The significant relationship between oral and general health is increasingly recognized by both medical and dental health care personnelInvestigations of the links between oral and systemic diseases have focused largely on oral biofilm associated with chronic periodontitis, and on damage to the highly vascular periodontal tissues. There have been few investigations on the possible association of systemic diseases with other oral diseases and related biofilms such as carious tissue, mucosal and nonvital root canal biofilms. In particular, in persons at high risk for dental caries, investigation of possible links between carious tissue biofilms and systemic diseases should be pursued.The purposes of the present article are to review the association between oral biofilms and systemic disease, to review relevant information regarding carious tissue biofilms and possible systemic disease, and to emphasize the critical importance of effective preventive oral care for reducing the potential for oral and systemic diseases.Because of their deteriorating health, increasing numbers of elderly persons will reside in long-term care institutions. The presence of physical and mental disabilities, compounded by communal living, leads frequently to the neglect of oral hygiene and to major changes in diets with an increased ingestion of refined sugars. These changes, in addition to impaired saliva flow and buffering capacity arising from hyposalivation caused by many medications and dehydration, greatly increase the risk of plaque-related dental caries, periodontal disease, candidosis and associated morbidity in old ageApart from the institutionalized, other medically at risk groups of persons include those with impaired host defense systems and pre-existing respiratory conditions who are at risk for hospital-acquired and ventilator-associated pneumoniaBacterial biofilms consist of dynamic, complex three-dimensional aggregations of heterogeneous microorganisms and their sticky extracellular polysaccharide matrix, which adheres to moist mucosal and tooth surfaces and to foreign surfaces such as indwelling catheters and tubes, and dental prostheses. Biofilms are associated with, for example, brochiectasis, chronic rhinosinusitis, tonsillitis and otitis media, recurrent urinary tract infections, chronic periodontitis and dental cariesA recent review of possible systemic diseases linked to chronic periodontal disease concluded that although there were definite epidemiological associations, particularly for cardiovascular disease and poor glycemic control in diabetics, the associations for other medical conditions such as preterm births were not always strongStreptococcus sanguinis, has been reported to correlate with coronary heart disease in a Chinese populationStrep. mutans, has been detected in the heart valves and blood of persons with infective endocarditisStrep. mutans, detected the microorganism in approximately 64% of defective heart valves and atheromatous plaques, and in 95% of dental plaques obtained from patients undergoing cardiovascular surgerye of Strep. mutans from dental plaques and from defective heart valves, which contrasted with the usual serotype c found in the dental plaques of healthy individualsA microorganism found in dental plaque, Staphylococcus aureus, enteric Gram-negative bacilli and Pseudomonas aeruginosa, especially in persons with poor oral and denture hygiene and who are at high risk for aspiration pneumoniaDental plaque also has long been implicated as an important biofilm reservoir for respiratory pathogens such as The implication from these studies is that the control of pathogens in oral biofilms may prevent such microorganisms from reaching cardiovascular and pulmonary tissues, and from potentially causing or exacerbating existing diseases.The treatment needs for high caries risk adults are approximately four times that of low caries risk adults, but current methods of prevention appear unable to effect a significant caries reductionSince high caries risk persons may be linked potentially with several systemic diseases, it is important to differentiate oral biofilms formed by low caries risk persons from oral biofilms formed by high caries risk persons that may contain possible virulent pathogens. Hence, the composition of oral biofilms in the initiation and progression of caries in low and high caries risk persons requires re-evaluationThough oral biofilms are found on intact tooth surfaces, they are also implicated in the etiology of one of the most prevalent diseases, namely, dental cariesin vivo studies of artificial caries have the advantage of the actual oral environment, in vitro studies of artificial caries can be advantageous because most of the oral environmental conditions and the microbiota can be controlled and changedin vitro microbial models examined oral biofilm formed by a few known cariogenic oral microorganisms, and how they affected carbohydrate consumption and the demineralization of salivary protein-coated calcified tooth tissueIt is necessary to investigate oral biofilms more closely in an attempt to identify at different ages the pathogenic microorganisms that contribute to significant differences in caries risk (42\u2212, to measure the degree of dentin demineralization and thus show the effects of the monoculture and co-culture of oral biofilms on human tooth root surfacesActinomyces israelii [NT6-2A], as measured by mineral changes when compared with sound root surfaces, was the highest of all three biofilms tested (in vitro studies of the microflora of oral biofilms are required. Significantly, recent analysis of 1,285 bacterial 16S rDNA gene sequences from 42 persons found that almost half of the bacteria from carious lesions remain to be identifiedBacteria and yeasts from the mouths of high caries risk elderly persons have been studiedStrep. sinensis and many Prevotella species in saliva and dental plaqueThere are significant limitations when using traditional culture, direct microscopic and biochemical methods to identify oral bacteria. Not all bacteria are cultivable or have immunological characteristics that fit into the patterns of any known genus and speciesInstitutionalized persons encounter substantial barriers to dental care compared to their independent peersImmunosuppressive agents and head and neck tumor irradiation may result in severe damage to the oral mucosa and salivary glands, resulting in mucosal lesions that offer a portal for systemic infectionIn several studies, the use of antimicrobials such as chlorhexidine, and the application of high concentration fluorides in high caries risk elderly persons either failed to show their effectiveness in the prevention of cariesThere is increasing evidence of the important relationship between oral biofilms and systemic diseases such as cardiovascular, central nervous system, respiratory and skeletal infections, and to nosocomial infections that are associated with a high morbidity in institutionalized and hospitalized elderly persons in particular. Microorganisms from oral biofilms have also been identified by DNA genotyping in defective heart valves and atheromatous plaques. Persons who have many, acute carious lesions caused by virulent microorganisms may be at a greater potential risk for several systemic diseases, particularly if their general health is poor. This possible high risk association requires further metagenomic and clinical research. The physical disruption of thick oral biofilms is necessary to allow the effective action of antimicrobials."} +{"text": "Salt marshes lie between many human communities and the coast and have been presumed to protect these communities from coastal hazards by providing important ecosystem services. However, previous characterizations of these ecosystem services have typically been based on a small number of historical studies, and the consistency and extent to which marshes provide these services has not been investigated. Here, we review the current evidence for the specific processes of wave attenuation, shoreline stabilization and floodwater attenuation to determine if and under what conditions salt marshes offer these coastal protection services.We conducted a thorough search and synthesis of the literature with reference to these processes. Seventy-five publications met our selection criteria, and we conducted meta-analyses for publications with sufficient data available for quantitative analysis. We found that combined across all studies (n\u200a=\u200a7), salt marsh vegetation had a significant positive effect on wave attenuation as measured by reductions in wave height per unit distance across marsh vegetation. Salt marsh vegetation also had a significant positive effect on shoreline stabilization as measured by accretion, lateral erosion reduction, and marsh surface elevation change (n\u200a=\u200a30). Salt marsh characteristics that were positively correlated to both wave attenuation and shoreline stabilization were vegetation density, biomass production, and marsh size. Although we could not find studies quantitatively evaluating floodwater attenuation within salt marshes, there are several studies noting the negative effects of wetland alteration on water quantity regulation within coastal areas.Our results show that salt marshes have value for coastal hazard mitigation and climate change adaptation. Because we do not yet fully understand the magnitude of this value, we propose that decision makers employ natural systems to maximize the benefits and ecosystem services provided by salt marshes and exercise caution when making decisions that erode these services. Salt marshes provide humans many vital benefits known as \u2018ecosystem services\u2019 and one of the most important may be their role as buffers in protecting coastlines. Our coasts face a variety of natural hazards including storms, hurricanes, and tsunamis. These hazards are natural processes that have always affected the coastal zone, however the impacts and associated costs of these hazards to humans have increased as the amount and value of coastal infrastructure have grown and continue to grow. The effects of climate change will further amplify these impacts and costs. Sea level rise and ocean warming will increase the frequency and magnitude of many coastal hazards Historically, coastal protection plans have relied on hardened infrastructure solutions such as sea walls, jetties and groins while ignoring or even destroying coastal marshes that could provide protective benefit. However, interest in natural or ecosystem-based coastal protection strongly increased after two recent natural disasters: the Indian Ocean tsunami and hurricane Katrina. Whereas the tsunami generated a great deal of inquiry into the protective role of mangroves In the aftermath of Katrina, the issue of whether or not marshes could attenuate extreme storm surge waves quickly became a contentious issue As the implications of climate change become clearer to coastal communities, there is mounting concern over the preparation and response to those growing hazards; this response is commonly known as climate change adaptation. As with coastal hazards mitigation, the first response in seeking adaptation solutions has been in gray or built infrastructure solutions. However, there is a nascent but growing interest in identifying where ecosystem-based approaches fit into these solutions and determining when and where they can help provide protection. Ecosystem-based or green solutions are an important component of calls for strengthened collaboration between the hazard mitigation and climate change adaptation research communities wave attenuation, shoreline stabilization, and floodwater attenuation. For each service we performed an extensive search of the literature to identify primary research studies assessing the capacity for salt marshes to perform the service(s). We quantified service provision and recorded marsh vegetation characteristics and environmental factors that were associated with service provision. For services with sufficient studies (wave attenuation and shoreline stabilization), we conducted meta-analyses to assess the overall degree to which salt marshes perform each service, and where possible we did sub-analyses to examine how subgroups of studies performed differently. When meta-analysis was not possible, we quantified the frequencies of service provision across a range of salt marsh types and geographies to quantitatively summarize the evidence.In order to ascertain the utility of salt marsh ecosystem service provisioning for coastal planners and managers and to inform decision making related to ecosystem-based adaptation, we provide the most thorough synthesis of the protective benefits of salt marshes to date. We address three specific ecosystem services associated with coastal protection: We searched the literature using the Biosis Previews, Web of Science, and Aquatic Sciences and Fisheries Abstracts databases to target articles related to the coastal protection services of wave attenuation, floodwater attenuation, and shoreline stabilization, defined below.Wave attenuation is the reduction in wave energy or wave height that occurs when a wave passes through marsh vegetation. The energy of waves, tides, and currents is attenuated via frictional drag introduced by vegetation and by bottom friction in shallow water areas maintained by marshes marsh, wave, flow, attenuation and storm.Shoreline stabilization describes the processes by which salt marsh vegetation promotes sediment deposition, increases marsh elevations through below ground production, and stabilizes marsh sediments. The seaward salt marsh edge is linked to marsh elevation as a minimum elevation must be maintained to prevent marsh plant drowning and subsequent marsh edge loss. As a result, processes that maintain marsh elevation can also help maintain marsh shorelines and reduce erosion. Sediment deposition within marshes accounts for a large portion of elevation gains on the marsh surface along with small contributions from below ground processes such as root production marsh, accretion, deposition, sedimentation, and erosion.Floodwater attenuation describes the capacity of salt marshes to reduce flood peaks or durations through storage and drainage of floodwaters. It is well known that marshes have a significant influence on the hydrological cycle both in terms of water quality and water quantity. However, the majority of this understanding lies in riparian or inland systems. In 1999, Bullock and Acreman marsh, flood, coastal flooding, water storage, and flood control.We were specifically looking for studies that examined the given service in a controlled or paired experiment where the service was measured within and outside of the marsh vegetation. Where studies examined the degree to which vegetation promoted the service the studies were collected to examine correlates of service provisioning. Correlates of service provisioning were categorized as marsh vegetation characteristics or hydrodynamic and physical environmental characteristics. For each of the three ecosystem services, we used two levels of screening to identify appropriate articles. For the first level of screening, abstracts were reviewed for the following exclusions: languages other than English, publication of abstract only, and publications not chiefly evaluating one or more of the three coastal protection services in a field or laboratory setting. Model studies were not included. Full text articles were obtained for all publications that passed the first level of screening and for publications in which a decision could not be based solely on the abstract. The second level of screening excluded full text publications without original data or analysis related to 1.) provision of services in vegetated versus unvegetated areas or 2.) variation in provision of services within vegetation. For each service, we recorded the number of records identified, number of studies included and excluded, and the reasons for exclusions according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement We extracted qualitative and quantitative data from identified studies and divided them into studies that compared the service inside and outside of marsh vegetation versus those that examined the service only within vegetation. For the studies comparing vegetated and unvegetated treatments, we recorded whether each study found that marsh vegetation increased, decreased, or had no effect on the service and where possible recorded the statistical significance. When available, we also extracted mean responses for each service, sample sizes, and within system error estimates. Overall means for the vegetated and unvegetated treatments were either provided directly in the text or extracted from figures. In some cases, the presentation of raw data or means with no reported error measurements required us to calculate means and standard deviations. For example, sedimentation was sometimes measured at vegetated and unvegetated sites that we pooled to calculate means and error if a minimum of three sites was reported (n\u200a=\u200a3) per treatment. In cases where data was reported over time, we used cumulative estimates where possible, or selected the last sampling date as the point of comparison. Additional information was collected on duration of study, weather conditions, vegetation type, response metric, and geographic location. Ideally vegetated and unvegetated areas were paired within a marsh system in generally equivalent elevations. However, in some cases (mostly for the wave attenuation studies), the vegetated and unvegetated sites were located within different elevation zones.For wave attenuation, we designated percent wave height reduction per unit distance as the response variable. The typical method used to evaluate wave attenuation in the field is to measure incoming wave energy at wave recording stations along a shore normal transect that encompasses both vegetated and unvegetated areas. Laboratory based studies follow a similar approach by measuring wave energy or wave height passing through real or synthetic vegetation in a flume. We also extracted transect length and incident wave heights to evaluate the effects of these variables on attenuation.In the case of shoreline stabilization, three response variables were accepted including accretion, surface elevation change, and lateral erosion. The terms accretion, sedimentation, and deposition are frequently used interchangeably and although they generally describe sediment being deposited on the surface, they are often measured and reported differently. Sedimentation and deposition are typically measured using sediment traps, petri dishes, and filter papers to record sediment deposition over time. Accretion is usually measured by laying down a marker horizon such as feldspar or clay and then measuring the vertical thickness of sediment deposited on top of the marker layer over time. Because sedimentation, accretion, and deposition are reflective of primarily surface processes, we grouped measurements of accretion, sedimentation, and deposition into the response measure \u2018accretion\u2019. We excluded historical studies using anthropogenic radionuclide-derived chronologies to reconstruct accretion rates. While constructing salt marsh sediment chronologies using anthropogenic radionuclides is an established technique, the resulting chronologies may not be reliable indicators of contemporary processes, particularly when evaluating erosion prone areas Surface sediment level changes measured relative to a permanent or semi-permanent elevation benchmark were categorized as \u2018marsh surface elevation\u2019 measurements and were frequently measured using a Sedimentation Erosion Table. The table is used to measure changes in the sediment surface level attributable to both surface and subsurface processes Because the floodwater attenuation search yielded so few relevant studies, quantitative analysis was not possible. For each identified publication, we extracted the spatial scale, location, and conclusions to qualitatively evaluate patterns in overall findings.For wave attenuation and shoreline stabilization, each publication was further screened to identify factors, such as elevation or vegetation density, that are frequently correlated with service provision. For each publication, the factors that authors stated as being important drivers of variation in service provision were recorded. For each factor, we recorded whether or not the reported factor was shown to have a statistically significant effect and also the nature of the relationship .d. For each service, we calculated the effect of salt marsh vegetation for each study (d) by calculating the difference between the means of the vegetated and unvegetated groups divided by the pooled standard deviation and weighted by a correction factor that adjusts for small sample size bias d . We designated five studies as the minimum cutoff for performing meta-analysis. Thus, overall effect size was calculated only for wave attenuation and shoreline stabilization. For shoreline stabilization, a sufficient number of quantitative studies were available to examine the effect of vegetation on each response variable using meta-analysis. Salt marsh vegetation was considered to have a statistically significant effect on a given response variable if the 95% confidence interval (CI) did not overlap zero.Meta-analysis is a statistical technique for assessing the magnitude of a treatment effect by combining results from independent experiments. Effect size was calculated using weighted Hedges' The initial literature search identified 3285 publications for screening. Of these, 3187 abstracts were found to be largely unrelated to wave attenuation (likely a result of the wide-ranging search terms) and were rejected. Ten publications could not be retrieved prior to the retrieval cutoff. Of the remaining 88 articles, 74 did not meet our inclusion criteria which left 14 studies for analysis . Eleven Ten studies examined wave attenuation rates per unit distance in both mud flats and adjacent salt marsh vegetation, while the remaining four studies provided wave attenuation estimates only within marsh vegetation. All ten studies comparing vegetated and unvegetated areas concluded that wave attenuation is greater across marsh vegetation than intertidal mudflat. Seven of these studies had sufficient detail to include in a meta-analysis that fouFrequently identified factors that authors stated as being important determinants of wave attenuation within salt marshes were vegetation characteristics such as vegetation density, vegetation stiffness, and marsh width . Marsh wThe literature search identified 2330 citations for initial screening. 2225 publications were available for review and 2086 were rejected after reviewing the abstracts. Similar to wave attenuation, a large number of largely irrelevant studies were identified and rejected due to the breadth of our search terms. We obtained full text publications for the remaining 239 citations; only 57 publications met our criteria for inclusion . The majThirty-three studies compared vegetated and unvegetated areas, yielding 36 independent comparisons of the effect of vegetation on one of the three measures of shoreline stabilization . AccretiOf the 33 studies comparing vegetated and unvegetated areas, 18 studies and 38 independent measures of accretion, erosion, or surface elevation change had sufficient quantitative information for inclusion in a meta-analysis . Across Factors most frequently identified as being correlated with shoreline stabilization included vegetation characteristics such as species identity, vegetation density, vegetation height, and biomass production . CharactWe identified 2664 citations from the literature search and after reviewing abstracts, 2530 studies were rejected because they did not evaluate floodwater attenuation within marshes. We were unable to retrieve 13 publications prior to the retrieval cutoff which left 121 full text articles for review. Of the full text articles, none quantified floodwater storage or flood peak attenuation in a controlled or paired experiment within and outside of salt marsh vegetation. We did identify four studies evaluating the effects of marsh alteration on flooding at scales ranging from individual marsh areas to coastal watersheds , Table 3The meta-analyses and qualitative evaluations of the literature indicate that salt marsh vegetation has a significant positive effect on wave attenuation and shoreline stabilization and these results provide support for comprehensive approaches that incorporate natural features and processes into hazard mitigation and climate change adaptation. While previous individual studies have shown that marsh vegetation attenuates wave energy, the results of our meta-analysis show this to be the case across a range of geographic and hydrodynamic settings. Observation intervals for the wave attenuation studies ranged from a single wave to an extended time series of waves with wave amplitudes ranging from millimeters to just under one meter. It is important to understand how wave attenuation varies with changes in scale because salt marshes are exposed to multiple wave magnitudes and frequencies of exposure. The majority of studies evaluated small to moderate incoming waves; however these are the types of waves most frequently impacting salt marshes In addition, correlates of service provision frequently identified by authors suggest important marsh and hydrodynamic characteristics related to coastal protection and 6. VHydrodynamic and physical environmental characteristics had inconsistent correlations with wave attenuation but were less frequently evaluated than for shoreline stabilization where hydroperiod, elevation, wave energy, and sediment availability were frequently identified as having consistent positive or negative effects. Suspended sediment concentrations and proximity to sediment supplies, both reflective of sediment availability, are particularly important because sediment availability is often reduced by human modifications aimed at increasing coastal protection The effects of storms appear to be more complex. For example, increasing wind and wave energy were frequently correlated with lower wave attenuation rates and reduced shoreline stabilization. In contrast, storm activity was often identified as a likely contributor to shoreline stabilization. This non-intuitive finding is likely due to different time scales of measurement as wave attenuation rates are measured immediately while elevation or erosion changes are measured over longer time periods. For wave attenuation rates measured during extreme wave or wind events, water levels may have increased to a point beyond which significant attenuation of wave energy by vegetation is likely. Shoreline stabilization processes measured during or immediately after a storm would also likely indicate a decrease in service provision (i.e. increased erosion) within vegetation. However, once the storm has moved through the area, suspended sediment often settles back onto the marsh surface. This re-deposited sediment can cause a significant amount of accretion or elevation gain following storms (see McKee and Cherry 2009 for summary) and in some cases this deposition stimulates belowground productivity Over the past 25 years, many models have been developed to better understand the relationships between hydrodynamics, elevation, and vegetation in salt marshes There is also evidence that in addition to mitigating high frequency, low magnitude coastal hazard events, marsh processes such as wave attenuation, sediment deposition and elevation building can also contribute to the long term maintenance of the coastline. This is especially relevant for areas with significant projected increases in sea level. Sea level rise varies spatially; this is often described as relative sea level rise (RSLR). Marsh areas experiencing high levels of subsidence, such as in the northern Gulf of Mexico, experience higher levels of RSLR Our literature search revealed critical research gaps related to storm surge and coastal flooding. Most of the identified wave attenuation studies evaluated small to moderate waves (Hs<.5 m) and there was a total lack of field studies quantitatively evaluating large waves and storm surge. This gap in our understanding is of critical importance because storm surge and associated flooding cause the majority of hurricane related damage and fatalities Remarkably, what happens to storm surge water once it is pushed onshore has also not been adequately studied. As we have shown, there are a surprisingly limited number of studies that address the floodwater attenuation capacity of salt marshes and more are needed. Nonetheless, the papers we identified show a fairly clear pattern regarding the effects of marsh alteration on water quantity regulation. These studies provide evidence that natural marsh areas drain more efficiently compared to altered marsh areas and that wetland alteration increases flooding events on a regional scale. Thus it is very likely that salt marshes are providing some level of floodwater attenuation by absorbing water and moving water in a sheet flow towards the coast Although field-based studies demonstrate the effects of salt marsh vegetation on processes related to coastal protection, the extent to which each process translates into coastal protection is likely site dependent and related to interactive factors such as coastal geomorphology, marsh health and extent, and hydrologic regime. The protective value of coastal marshes may be best evaluated using innovative correlative techniques such as that employed by This review and analysis strengthens the view that management of salt marshes should be integrated into coastal zone hazard mitigation and climate change adaptation policies. Salt marsh conservation and restoration decisions can and should be framed in the larger context of sustaining our coastlines and vice versa. One version of this is already taking place in parts of the United Kingdom and the Netherlands where managed realignment is being advocated to meet biodiversity and hazard mitigation objectives. Managed realignment is the practice of moving the coastal defense line inland to allow an area of previously reclaimed land to be re-inundated and develop intertidal habitat such as salt marsh Figure S1PRISMA literature search flow diagrams.(DOC)Click here for additional data file.Figure S2publications included in review and meta-analysis.(DOC)Click here for additional data file."} +{"text": "Maxillary sinus floor elevation via a lateral approach is a predictable technique to increase bone volume of the edentulous posterior maxilla and consequently for dental implants placement. The sinus floor is elevated and it can be augmented with either autologous or xenogeneic bone grafts following an opening bone window created on the facial buccal wall. Maxillary septa are walls of cortical bone within the maxillary sinus. The septa shape has been described as an inverted gothic arch arising from the inferior or lateral walls of the sinus and may even divide the sinus into two or more cavities. Some authors have reported a higher prevalence of septa in atrophic edentulous areas than in nonatrophic ones. Radiographic identification of these structures is important in order to perform the right design of the lateral window during sinus lift. Aim of this investigation is to highlight the correct steps for doing sinus lift surgery in presence of those anatomic variations. Clinicians should always perform clinical and radiographic diagnosis in order to avoid complications related to the sinus lift surgery. The treatment of maxillary edentulous jaws with osseointegrated implants is often complex for the frequent pneumatisation of the maxillary sinus and for the remaining low-bone density and volume. The bone resorption, consequent to the loss of the dental elements, determines atrophy in height and thickness, by reducing the amount of available bone to the implant placement. In the 1970s, Tatum Jr developeAtrophy-related resorption of the alveolar process results in a vertical loss of bone volume, while progressive sinus pneumatization leads to an excavation of the alveolar process from the cranial aspect, which varies from one individual to another. Because atrophy-related resorption may occur differently in different areas of the alveolar process, bony septa can be considered residues between two such zones of resorption .Knowledge of the maxilla anatomy, and moreover, of the blood supply of the maxillary sinus is mandatory to avoid unnecessary complications. \u201313.All the surgical operations in the posterior maxillary region require detailed knowledge of maxillary sinus anatomy and possible anatomical variations. The aim of the present investigation is to underline how the presence of maxillary septa may influence the sinus floor augmentation surgical procedure. A complete knowledge of the patient's anatomical conditions is fundamental for exact planning of invasive surgery and helps to avoid complications.Several published paper underlined how dental implants positioned on posterior resorbed maxilla with extensive expanded sinus can be safely treated by a simultaneous sinus lift approach and implant insertion using the technical protocol and biomaterials studied with overall 10-years-long-term results , 15. HowThe data from epidemiological studies on sinus septa prevalence on upper maxilla is not regular or predictable cause involving several additional topics. PUBMED research by \u201cmaxillary sinus septa\u201d keywords evidences a total of sixty-one documents. However, only fifty-three manuscripts published and indexed in Medline assessing relation with \u201coral surgery diagnosis and therapy\u201d and consequently published on related dentistry journal.Fixot and Sorensons dated onA large number of studies (eighteen) involved radiological investigation on maxillary anatomy underlining how the volumetric analysis represents the more accurate way for performing sinus septa diagnosis. Nine published papers talk about sinus septa considering it on the sinus lift surgical procedure complications. Four animal studies and four cadaveric anatomy dissections and one systematic review complete the list of sinus-septa-related manuscript.Referring about the full text data, the anatomical features and the surgical technique will be exposed thorough the paper in order to give clinicians complete information before performing sinus lift surgery.In 1910, Underwood published a detailed description of maxillary sinus anatomy, evidencing antral septa of varying shape and size. Author divided sinus floor into three anatomic sections: a small anterior one over the premolar region a large median one descending between the roots of the first and second molars, and a small posterior one corresponding to the third molar region. These three sections of the floor of the sinus are usually underlined by ridges rising to distinct septa and connected to three defined periods of tooth activity, separated by intervals of growth time .For decades, these septa were considered clinically insignificant anatomical variations. However, new diagnostic methods for verification of sinus disorders, such as endoscopy, have led to a different attitude towards the maxillary sinus and its anatomical variations , 19.Krennmair et al. divided Furthermore, detailed knowledge of maxillary sinus anatomy has become increasingly important for sinus lift surgery .The sinus lift technique, or internal maxillary sinus augmentation in the sense of sinus floor elevation, allows positioning of dental implants even when the posterior maxillary region has undergone severe bone resorption \u201327. BefoIn this surgical technique, a hinged window is made in the facial antral wall and inverted to create space for the grafting material. Either an autologous or a xenogenic bone graft is then placed between the former antral floor and the elevated sinus membrane, including or not inverted bone plate . The preAlthough several modifications of this surgical technique have been proposed during the past few years, either with a supplementary or a simultaneous Le Fort I osteotomy, horseshoe osteotomy or nasal floor elevation , the oriAfter a period of 6/9 months, dental implants can be positioned in the newly formed bone Figures .The surgery procedures of the posterior maxillary region require detailed knowledge of maxillary sinus anatomy and possible anatomical variations. Detailed knowledge of the patient's morphological conditions allows exact planning of invasive surgery and helps to avoid complications. Several investigations analyzed the prevalence of sinus septa in the bone maxilla. Authors of those studies calculated the incidence number based on the number of sinus, which have septa, or on the number of subjects who have septa. The main results of those studies state how the antral septa are more commonly found in edentulous atrophic maxillae than in dentate maxillae. The septae in edentulous atrophic maxillae are usually shorter than those found in dentate maxillae. When present, maxillary sinus septae are more common anteriorly than posteriorly , 27, 30.Despite the overall progress in dental implantology, dental implants positioning in the posterior atrophic maxilla are already considered to be a challenging procedure due to great levels of reduced bone volumes in many cases . GraftinSinus lift procedure performed by using xenograft materials is today a common and predictable technique. Histological and immunohistochemical investigations of human and animal biopsies taken after implantation of those bone graft showed signs of osteoconduction as well as osteoinduction, a high biocompatibility and a angiogenic response \u201342. AutoHowever, even if the surgeon may choose several kinds of materials for doing the graft, the problems related to the septa presence should be prevented and considered before doing the surgery.Underwood observed the existence of another type of septa, indicating that it must have a different origin, as it seemed to be unrelated with teeth. Vinter et al. confirmed that resorption of maxillary alveolar process incomes irregularity in different regions, leaving bony crests on the sinus floor . ConsequUlm et al. performeAccording to several investigations, the diagnosis of the septa presence is fundamental in order to avoid surgical complications. The elevate number of false diagnosis established using panoramic investigation remarks how this kind of method cannot be suitable to entirely evaluate the sinus anatomic extensions. Otherwise, CT Scan, 3D, and Cone Beam investigation are today the better diagnostic investigation to underline the real maxillary anatomy highlighting the presence of septa.The results of this study suggest how first-level radiographic investigation like orthopantomography or X ray are not appropriate for thorough evaluation of the sinus floor and its anatomical variants. Otherwise, CT and subsequent reconstructions consent high-resolution imaging of anatomical bone structures and can be considered the method of choice for imagining and investigating sinus septa presence. Specially, the CT axial section may help clinicians on evaluationg the septa orientation. Moreover, axial section is the ideal sectional plane to examine this bony structure."} +{"text": "Subclavian and axillary arteries true aneurysms are rarely seen. The best incision for surgical approach is median sternotomy for intrathoracic right subclavian artery aneurysm, left thoracotomy for intrathoracic left subclavian artery aneurysm and supraclavicular incision for extrathoracic ones. Many surgeons approaches as subclavicular incision, subclavicular incision extending to axillary incision, anterolateral incision and posterolateral incision are also commonly used.Eight patients that were operated on between February 1998 and December 2007 due to true aneurysms of the subclavian and axillary arteries were examined. Two of these patients had subclavian and 6 of them had axillary artery aneurysms.We used subclavicular incision in one and supraclavicular incision in the other patient for operating the subclavian artery aneurysm. But median sternotomy was added to the supraclavicular incision in the second operation of the patient who developed pseudoaneurysm after the first operation with a single supraclavicular incision. In axillary artery aneurysms, however, infraclavicular, deltoidopectoral and subpectoral incisions are generally used. In our study, subclavicular approach was used.Subclavian and axillary artery aneurysms should be promptly treated surgically after diagnosis. The localization of the aneurysm is the primary determinant of the incision."} +{"text": "Plants size, shape and adaptability are determined in large by their capacity to sustain, spur, redirect or arrest localized and whole-plant growth. We show that GA signaling and metabolism determines the level and extent of shoot and root growth. Increase of GA concentrations or signaling leads to increased shoot growth but suppresses root development. These GA-related responses are underpinned by sets of highly specialized in their functions enzymes and signaling factors and cross-talk with other hormonal pathways. The differential effects of GA on root and shoot growth and development are likely associated with a regulatory mechanism responding to optimum and stress conditions. Ongoing work in the laboratory employs genomics and genetics approaches to more thoroughly understand poplar growth and development under stress conditions including nitrogen and water limitations. We use genetic networks analysis and forward genetics approaches to identify key regulators of poplar roots response to stress. Besides overall growth, trees show incredible repertoire of spatiotemporal regulation of growth in relation to control of organ size, growth periodicity and tropic responses. We have identified and characterized novel regulators of these processes in poplar."} +{"text": "Many studies in human and animal models have shown that neural plasticity compensates for the loss of motor function after stroke. However, neural plasticity concerning compensatory movement, activated ipsilateral motor projections and competitive interaction after stroke contributes to maladaptive plasticity, which negatively affects motor recovery. Compensatory movement on the less-affected side helps to perform self-sustaining activity but also creates an inappropriate movement pattern and ultimately limits the normal motor pattern. The activated ipsilateral motor projections after stroke are unable to sufficiently support the disruption of the corticospinal motor projections and induce the abnormal movement linked to poor motor ability. The competitive interaction between both hemispheres induces abnormal interhemispheric inhibition that weakens motor function in stroke patients. Moreover, widespread disinhibition increases the risk of competitive interaction between the hand and the proximal arm, which results in an incomplete motor recovery. To minimize this maladaptive plasticity, rehabilitation programs should be selected according to the motor impairment of stroke patients. Noninvasive brain stimulation might also be useful for correcting maladaptive plasticity after stroke. Here, we review the underlying mechanisms of maladaptive plasticity after stroke and propose rehabilitation approaches for appropriate cortical reorganization. For several decades, many studies in both human and animal models have demonstrated that neural plasticity can change the structure and/or the function of the central nervous system after stroke and rehabilitation \u20133. AlthoThe limbs contralateral to the side of the lesion exhibit hemiparesis after a motor stroke, and recovery of motor function after stroke is usually incomplete . HoweverThe extent of functional gains from neural plasticity on the motor recovery of normal patterns or the compensatory movements of new patterns and the effect of rehabilitation on these processes are unclear . Part ofFirst, the difference between motor recovery and compensatory movement must be clearly established. \u201cMotor recovery\u201d is defined as the reappearance of elemental motor patterns present before a stroke. In contrast, \u201ccompensatory movement\u201d is defined as the appearance of new motor patterns resulting from the adaptation of remaining motor elements or substitution, meaning that functions are taken over, replaced, or substituted by different end effectors or body segments .It is common in stroke patients with severe impairment that the compensatory or substitutive movements of the less-affected body side are encouraged to maximize functional ability \u201323. In aIn addition to a reduced range of joint motion and pain due to compensatory movement of the paretic limb, excessive use of the nonparetic limb can also induce another problem. Stroke patients often use the nonparetic limb instead of the paretic limb to perform daily activities. Dominant use of the nonparetic limb induces the phenomenon of learned nonuse of the paretic limb, which limits the capacity for subsequent gains in motor function of the paretic limb , 33. MorIn addition to enhancement of learned nonuse of the paretic limb, it has been reported that skill acquisition with the nonparetic limb may negatively impact the experience-dependent plasticity of the affected hemisphere. In rats, motor training with the nonparetic limb reduces the neuronal transcription factor, which shows experience-dependent behavioral change in the affected hemisphere after training with the paretic limb . The reaThe contribution of ipsilateral motor projections to motor function after stroke has been evaluated mainly by transcranial magnetic stimulation (TMS) studies , 38. ManFurthermore, these ipsilateral motor projections to the paretic side might be not only unhelpful but also maladaptive for motor recovery in stroke patients. Although the dominant anatomical arrangements of the ipsilateral motor projections to the proximal muscles may contribute to the relative preservation of proximal limb control , it has Despite the correlation between the expression of ipsilateral motor projections and poor motor ability after stroke described previously, the upregulation of ipsilateral motor projections may play an important role in preserving some degree of motor function, especially in children \u201351. MoreStroke alters the neuronal function of the motor cortex adjacent to or distant from the lesion through neuronal networks . TMS andIn addition to interhemispheric competitive interaction, intrahemispheric competitive interaction is thought to induce maladaptive plasticity after stroke. From the viewpoint of inhibitory function, some studies have shown how changes in neural function can affect motor patterns after stroke , 62, 63.Besides the PMC, the reduced inhibitory function of the ipsilesional M1 might induce competitive interaction between the hand and the proximal arm, because stroke patients often use the proximal arm for compensatory movement , 27. HowAs described in the previous sections, compensatory movement may introduce maladaptive plasticity and limit genuine motor recovery after stroke. In particular, compensatory use of the nonparetic limb may inhibit learning new motor skills with the paretic limb. The excessive excitability of the unaffected hemisphere, activated by the use of the nonparetic limb, inhibits the affected hemisphere through abnormal interhemispheric inhibition. Moreover, the widespread disinhibition of the affected hemisphere might induce the competitive interaction that results in incomplete motor recovery. In this section, we propose approaches to prevent maladaptive plasticity after stroke.To prevent maladaptive plasticity after stroke, we should consider the competitive interaction hypothesis. In addition to competitive interaction between the proximal and distal sides, the increased activities of proximal limb due to compensatory movement itself may be associated with poor motor function and contribute to the abnormal interjoint movement that is observed following stroke . TherefoConsidering the competitive interaction between the paretic and nonparetic sides, it is natural that the rehabilitation program should avoid nonuse of the paretic limb. In human stroke survivors, the disability of the paretic arm leads to its disuse, which limits functional improvement, a phenomenon termed \u201clearned nonuse\u201d . The facStudies on animal stroke models suggest that compensatory use of the nonparetic limb while the paretic limb is being used does not necessarily induce the maladaptive change of learned nonuse . TherefoRepetitive TMS (rTMS) and transcranial direct current stimulation (tDCS) are noninvasive brain stimulation (NIBS) techniques that can alter the excitability of the human cortex for several minutes . Many reIt has been reported that experience-dependent plasticity is impaired in the affected hemisphere , 86; howAlthough NIBS may be useful to prevent maladaptive plasticity by correcting abnormal interhemispheric inhibition and facilitation of experience-dependent plasticity in the affected hemisphere, it must be noted that the NIBS itself also induces maladaptive plasticity after stroke. A recent study has reported that the inhibitory rTMS over the unaffected hemisphere led to deterioration of the antiphase bimanual movement in stroke patients . InhibitThis paper focuses on the underlying mechanisms of maladaptive plasticity, which inhibits motor recovery after stroke, and the approaches that can be used to solve this problem. Compensatory movements may help stroke patients perform tasks in the short term but may also be associated with long-term problems such as learned nonuse, reduced range of joint motion, and pain. Moreover, compensatory movement of the nonparetic limb may induce maladaptive plasticity of the affected hemisphere and limit motor recovery after stroke. Activation of ipsilateral motor projections may be beneficial for trunk muscle movement, more severely affected patients and children. However, enhancement of ipsilateral motor projections may also be detrimental for the distal side and may induce abnormal movement patterns linked to poor motor ability. Stroke causes unbalanced excitability between both hemispheres and results in abnormal interhemispheric inhibition from the unaffected hemisphere to the affected hemisphere; this restricts motor function in stroke patients. Moreover, neural plasticity caused by localized disinhibition in the ipsilesional M1 is appropriate for motor recovery; however, widespread disinhibition increases the risk of competitive interaction between the hand and the proximal arm, which results in an incomplete recovery. To prevent this maladaptive plasticity, it is necessary to avoid learned nonuse and excessive use of compensatory movement. The NIBS technique ameliorates maladaptive plasticity by facilitating experience-dependent plasticity and correcting abnormal interhemispheric inhibition. However, it must be noted that inhibitory NIBS over the unaffected hemisphere itself might induce another maladaptive plasticity that deteriorates bimanual movement. The new method of bilateral NIBS can prevent deterioration of bimanual movement and facilitate motor function more than unilateral NIBS can because of its ability to induce disinhibition in the ipsilesional M1 and correct the imbalance between the hemispheres. Future studies should focus on better understanding the effects of rehabilitation and NIBS on maladaptive plasticity after stroke."} +{"text": "Increasing globalization may pave the way for reemergence of relapsing fever. Borrelia infections have attracted little attention in recent years; however, where endemic, these infections still result in considerable illness and death. Despite the marked antimicrobial drug susceptibility of these organisms, therapy is often delayed through lack of clinical suspicion. With increasing travel, infections may be imported, through exotic relapsing fever infection or through resurgence of infected disease vectors. Although louseborne relapsing fever is now geographically limited, it was once of global importance. The possibility for reemergence was recently highlighted by the probable reemergence of louseborne relapsing fever in homeless persons from France. Host limitations enforced through louseborne transmission are less applicable for the tickborne forms of relapsing fever. Although the latter have reduced potential for epidemic spread, they have the ability to infect diverse hosts, thus establishing reservoirs of infection and presenting greater challenges for their control.Relapsing fever Borrelia species associated with relapsing fever has doubled. This situation is in part due to improved diagnostics and molecular techniques that have enabled sequenced-based characterization of these spirochetes. Seventeen species are attributed to the relapsing fever group of spirochetes; others have been described but await further characterization and isolation before species can be designated. Infection is vectorborne, primarily by Ornithodoros ticks, which led to the descriptive name of tickborne relapsing fever. However, 1 form of the disease developed epidemic potential by adapting to louse transmission and thus became known as louseborne relapsing fever.Since the 1980s, the number of Clinically, these spirochetes all produce an undulating febrile disease in humans, with signs and symptoms often indistinguishable from those of malaria. Diagnosis in most disease-endemic areas relies on demonstrating the spirochete in Giemsa-stained blood films; however, more discriminating methods are available that can be used in suitably equipped facilities.Whether we are likely to see the reemergence of this disease is difficult to predict because we do not understand relapsing fever borreliae and their complex host interactions. Indeed, to use the words of Bryceson et al., \"Little is understood of where it lurks between epidemics and of how it suddenly springs up after silent intervals of several years\" .,,This disease still has persistent foci of infection, where control can be a major healthcare problem. Relapsing fever can be acquired by travelers and brought back to regions where the disease is not epidemic . Human ,B. turicatae and B. hermsii. Isolated reports of B. persica infection transmitted by its O. tholozani vector have also appeared in the Middle East vectors means that these ticks may play a role in transmission. Ixodid ticks have been found in association with seafaring birds and songbirds, which raises the possibility of migration-associated transmission. Furthermore, the finding of novel Borrelia spp. in Africa that strongly resemble New World relapsing fever species suggests greater globalization of these spirochetes and of East African tickborne relapsing fever (B. duttonii) may indeed be the same, or highly related clones of a common ancestor, has been raised is well established; most relapsing fevers rarely affect humans or if humans can be considered as the reservoir for infection is debatable. Recent work by Kisinza et al. in the Dodoma region of Tanzania found 5% of febrile children had positive blood slides for Borrelia spp , while others are suited to persistence in their human host (disease reservoir); additional types are associated with patients with overt clinical signs mediated through a multiplicity of host-microbe interactions. Persistence may be further facilitated through the neurotrophic tendency of these spirochetes. This hypothesis is further strengthened by observed pathologic differences associated with isogenic variants of the same isolate of B. turicatae investigated in vivo (This description does not address the question of whether spirochetes associated with clinical cases differ from those that do not appear to cause overt clinical signs. Immunity is a factor, highlighted by the high prevalence of disease in young children and pregnant women. However, for humans to serve as reservoirs for this disease, the spirochete must persist in sufficient numbers in a site where they will be acquired by new arthropod vectors. An intriguing hypothesis is that particular antigenic variants of the spirochete may be associated with life in an arthropod vector (usually ticks, except for the related spirochete, Clinical manifestations and patient management fall largely outside the scope of this review. However, clinical findings are reported elsewhere (Both innate and acquired immune responses are needed to control infection. To overcome innate immune mechanisms, these spirochetes bind the complement inhibitor factor H to their surface, thus avoiding deposition of the membrane attack complex and subsequent lysis (,Another mechanism that may enhance persistence of these spirochetes within the bloodstream is the ability of some relapsing fever spirochetes to become coated with or to rosette blood erythrocytes. This process enables prolonged persistence through a masking or steric hindrance effect, which prevents interaction with the host immune cells (GlpQ gene product was demonstrated to be a useful diagnostic aid (Traditionally, diagnosis is based on demonstration of spirochetes in blood films taken during the acute febrile period. More recently, an enzyme-linked immunosorbent assay that used the Borrelia spp. can now be facilitated through molecular approaches that allow more accurate investigation of which species are prevalent in different epidemiologic foci. Previously, such characterization relied on identification of disease vectors and compatibility with established geographic patterns. Furthermore, these techniques will enable characterization of newly discovered spirochetes (Characterization of relapsing fever Genome sequencing is under way for several relapsing fever spirochetes. This information will enable a thorough comparative analysis of these spirochetes and likely yield insights into vector competence and pathogenicity."} +{"text": "Health care sectors are facing major challenges in the form of Hospital Aquired Infections(HAI). Using six sigma we can analyze the problem, come to practical solutions and implement and sustainable improvements.rd of that rate. All the steps starting from Define to Control phase were done and we could achieve a remarkable decrease in our Infection rates. Various initiatives like Ventilator Associated pneumonia Green Star Project implementation all Intensive Care Units (ICU) Daily checks for implementation and compliance of infection control protocols,empowermentwas extensively carried out. Tools like dashboard,signages,infection control week were used to disseminate information.We introduced six sigma in our health care setup for implementation of infection control practices and studied its impact infection rates. After training the identified team in six sigma process we identified the matrices which will be included in the process. The baseline data taken was the lowest rates achieved in the previous year and the goal was to achieve 1/3We could achieve Zero SSI rates in six months, Hand Wash compliance to 69% and achieve the target in all device related infections rates. Indirect measurement of number of beds available for new patient, early discharge/shift out of patient and patient satisfaction provided the necessary data to convince all the staff the need to sustain this new initiative.This represents the first successful application of Six Sigma corporate performance-improvement method impacting purely clinical outcomes. HAI reduction was highly substantial and sustained after other traditional strategies had failed.None declared."} +{"text": "Isolated giant varicocele has been reported with portal hypertension that results in abnormal communication between portal venous system and testicular vein venous system resulting in retrograde backflow of blood into the testicular venous system which leads to varicosity of the pampiniform plexuses. 65-year-old male with no past medical or surgical history presented to us with soft inguinoscrotal swelling that disappears on lying down mimicking inguinal hernia. Clinical examination revealed soft inguionoscrotal swelling that disappears on pressure. Ultrasonography revealed varicosity of pampiniform plexus, and CT angiography to trace the extent of the varicosity revealed abnormal communication of right testicular vein with superior mesenteric vein. There was no evidence of any portal hypertension; the cause of the portosystemic shunt remains obscure, and it might be a salvage pathway for increasing portal pressure. The case is noteworthy for its rare presentation and abnormal communication with portal venous system in the absence of evidence of portal hypertension. Simple inguinal hernia presents as lump in the groin that goes away with lying down or with minimal pressure. Most cases may be painless or cause mild to moderate discomfort that increases with activity . VaricocA 65-year-old, Indian male, presented to urology outpatient with history of reducible swelling of right scrotum and groin associated with dull aching and dragging sensation that started couple of years ago. He was nonalcoholic, married, and having three children. There was no medical or surgical history of illness or trauma in the past. Examination of the genitalia revealed large painless compressible soft swelling of right inguinoscrotal region which completely disappears while lying down. Left side scrotum was absolutely normal. Ultrasound and Doppler scrotum were done as initial evaluation which reported a huge right sided varicocele. CT angiography was done which showed two communications in the venous drainage system, that is, one right testicular vein channel draining into the inferior vena cava and another large abnormal connection with superior mesenteric vein Figures and 2. TWe consulted vascular surgeon for possible embolisation of the venous communication but patient refused such intervention. He is on regular followup in our clinic with no further deterioration of his clinical condition.Isolated large varicocele may be secondary to multiple intraabdominal pathology, such as malignancy causing venous compression, portal hypertension or portal vein thrombosis, abnormal venous communications, or heart failure . The pamIn our case there was abnormal communication of right testicular vein and superior mesenteric vein in our patient without any clinical signs and symptoms or any evidence of portal hypertension; the cause of the abnormal communication still remains obscure, and it might be a salvage pathway for raising portal pressure.Our case was unique in presentation also; there was no typical finding of \u201cbag of worm\u201d in scrotum which is diagnostic in varicocele. The inguinoscrotal swelling was soft and used to disappear with pressure or lying down mimicking inguinal hernia. Treatment of such pathological condition has not been defined; some surgeon advised to avoid surgery in such situation for fearIsolated giant varicocele resulting from abnormal communication of right testicular vein and superior mesenteric vein and mimicking inguinal hernia is extremely rare condition. Surgical intervention in such situation might result in unanticipated blood loss or rupture of another portosystemic shunt. The definitive management of such condition is still to be defined."} +{"text": "Muscular dystrophy is a progressive disease of muscle weakness, muscle atrophy and cardiac dysfunction. Patients afflicted with muscular dystrophy exhibit autonomic dysfunction along with cognitive impairment, severe depression, sadness, and anxiety. Although the psychological aspects of cardiovascular disorders and stress disorders are well known, the physiological mechanism underlying this relationship is not well understood, particularly in muscular dystrophy. Therefore, the goal of this perspective is to highlight the importance of autonomic dysfunction and psychological stress disorders in the pathogenesis of muscular dystrophy. This article will for the first time\u2014(i) outline autonomic mechanisms that are common to both psychological stress and cardiovascular disorders in muscular dystrophy; (ii) propose therapies that would improve behavioral and autonomic functions in muscular dystrophy. Muscular dystrophy is a devastating neuromuscular disorder that is currently without an effective therapy. It is characterized by progressive increase in muscle weakness and muscle wasting. Myocardial disease, manifesting predominantly as dilated cardiomyopathy (DCM) and congestive heart failure or conduction system abnormalities have been observed in many muscular dystrophies. Evidence of an association between vulnerability to lethal arrhythmias and signs of either increased sympathetic or reduced parasympathetic tone as quantitative markers of autonomic activity in muscular dystrophy are becoming increasingly recognized in patients and animals Groh, .The physical and social hardships associated with the disease often lead to psychological stress disorders such as depression and anxiety, in muscular dystrophy patients. Psychological stress affects both mental and physical health. Depressed patients with or without a history of cardiovascular pathology display signs such as elevated heart rate (HR), reduced HR variability (HRV), and increased physiological reactivity to environmental stressors which may cause predisposition to cardiovascular events. Converging evidence from experimental and epidemiological studies indicate that there is a bidirectional association between psychological stress and cardiac risk, such that presence of one increases the likelihood of developing the other muscular dystrophy. HRV, as a quantitative marker of parasympathetic tone, is decreased in muscular dystrophies exhibit severe autonomic dysregulation before left ventricular (LV) dysfunction is composed of multiple proteins that form a physical linkage between the intracellular and extracellular matrix. Sarcoglycans are important component of the DGC that protects cell membrane against forces generated during muscle contraction axes Badoer, . It is nIt is important to emphasize that mechanisms of autonomic dysfunction or psychological stress in muscular dystrophy are yet to be identified. Figure 1R) and the vasodilator Ang-(1\u20137) peptide acting on Mas receptors . Angiotensin receptor blockers (ARBs) and ACEi are used clinically in muscular dystrophy and dilated cardiomyopathy has also been suggested to exert anxiolytic actions. Bild et al demonstrated that rats treated with Ang-(1\u20137) performed better in the maze test than the untreated animals is a neurotransmitter that modulates stress responses by interacting with the HPA axis and sympathetic nervous system (Chrousos, Muscular dystrophy is a catastrophic disease which is characterized by progressive muscle weakness and wasting, cardiomyopathy, and early mortality. Patients with muscular dystrophy are commonly afflicted with psychological disorders like depression, anxiety, cognitive deficits etc., which likely exacerbates disease progression and worsens the quality of life. Both muscular dystrophy and behavioral disorders are associated with autonomic dysregulation. In view of the devastating outcome of muscular dystrophy most attention has been directed toward improving muscle function and structure. However, treating both autonomic dysregulation and stress disorders is recommended for patients with muscular dystrophy. Additive and synergistic actions are likely to result in better therapeutic outcomes.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Invasive species are leading drivers of environmental change. Their impacts are often linked to their population size, but surprisingly little is known about how frequently they achieve high abundances. A nearly universal pattern in ecology is that species are rare in most locations and abundant in a few, generating right-skewed abundance distributions. Here, we use abundance data from over 24,000 populations of 17 invasive and 104 native aquatic species to test whether invasive species differ from native counterparts in statistical patterns of abundance across multiple sites. Invasive species on average reached significantly higher densities than native species and exhibited significantly higher variance. However, invasive and native species did not differ in terms of coefficient of variation, skewness, or kurtosis. Abundance distributions of all species were highly right skewed (skewness>0), meaning both invasive and native species occurred at low densities in most locations where they were present. The average abundance of invasive and native species was 6% and 2%, respectively, of the maximum abundance observed within a taxonomic group. The biological significance of the differences between invasive and native species depends on species-specific relationships between abundance and impact. Recognition of cross-site heterogeneity in population densities brings a new dimension to invasive species management, and may help to refine optimal prevention, containment, control, and eradication strategies. Invasive species are recognized as leading drivers of environmental change, and can produce significant economic and ecological impacts Invasion biology research has aimed to elucidate general patterns, sometimes at the cost of overlooking important sources of heterogeneity In contrast to the largely dichotomous paradigm of invasive species research noted above, ecologists have long documented that the abundance of many species tends to be low at most locations and high only in a few; that is, frequency distributions of abundance are right skewed Understanding invasive species abundance distributions and how they compare to those of native species is important for analysis and management of species invasions. Competing predictions are possible based on different lines of reasoning. On one hand, invasive species are often considered inherently different from native species In this analysis we compare patterns of population abundance for native and invasive aquatic species, collected simultaneously using the same methods. For each species included in our study, we obtained abundance estimates across many sites. We characterized the abundance distribution of each species in terms of its statistical moments , with the objective of determining whether abundance distributions of invasive and native species differed in terms of these statistical moments. We conclude by discussing the implications of invasive species abundance distributions for ecological theory and the management of invasive species.All data existed prior to the initiation of this study and include our own data collected for other purposes, public data collected by management agencies, and published literature sources. Data sources and sampling methods are described in detail in Supplementary Methods S1 in To examine variability in abundance across sites, we required abundance records for native and invasive species in multiple locations. We compared cross-site abundance distributions of 17 invasive and 104 native species of aquatic plants, invertebrates , and fishes from three distinct geographic regions of the abundance distribution of each species. Preliminary analysis showed that mean and variance were highly correlated; we also calculated coefficient of variation (CV) to compare variation independent of this correlation. Moments were natural log transformed and differences in moments of invasive and native species abundances were estimated using a multi-level modeling approach We generated empirical cumulative distributions (ECD's) for invasive and native species abundance overall and within each taxonomic group. For these distributions we disregarded species identity and constructed ECD's using abundances of all invasive and all native species in each taxonomic group. We then identified the median abundance (ECD\u200a=\u200a0.5) of invasive species within each group, and compared the ECD value of native species for the same abundance value. This allowed us to compare the proportion of sites containing native species at abundances equal to or above the median invasive species abundance.Abundance distributions of all species were highly right-skewed , brown trout , and signal crayfish (Pacifastacus leniusculus). Although small sample size precludes formal statistical inference, no consistent patterns in statistical moments of species in their invaded compared to native ranges were evident . Indeed, variability in distributional parameters was high, and for most taxonomic groups (4 of 7) a native species was responsible for the maximum abundance observed within the group . The sub\u22121\u22122The biological significance of differences between invasive and native species abundance distributions depend on species-specific relationships between density and ecological impact. Unfortunately, knowledge of such relationships is lacking for even the most notorious invaders The observed differences in mean abundance of invasive and native species do not necessarily reflect fundamental ecological differences between them. Widespread species tend to be on average more abundant than species restricted to small ranges, driven by higher maximum abundances Petromyzon marinus; and Eurasian water milfoil; Myriophyllum spicatum), and abundance distributions of both managed species are less right-skewed than the majority of invasive species . Thus, there is no evidence from our analysis that the propensity of invasive species to be present at low abundance arises from control measures.Every invasive species in this analysis occurred at low population densities in the majority of invaded sites , a findiAnother potential explanation for the right-skewed abundance patterns of invasive species is differences among invaded sites in time since species introduction. Temporal variation in species abundance has been shown to generate right-skewed abundance patterns similar to those observed across large spatial scales The fact that high density populations of invasive species exist in a small number of \u201chot spots\u201d has important management implications. Sophisticated modeling techniques are used in risk assessments that aim to identify which species are likely to become invasive e.g., and whicHeterogeneity in the abundance of invasive species known to cause ecological and economic impacts has received surprisingly little attention. Our finding that aquatic invasive species exist at low densities in most locations where they occur runs counter to the perception of invasive species as those that are abundant or dominant wherever they establish File S1Supplementary information, including Supplementary Methods S1 describing in detail the sampling methodology for each group; Table S1 providing examples of invasive species databases that provide presence-absence data only; Table S2 listing the invasive species included in this analysis, their impacts, and year of invasion; and Table S3 listing all species included in this analysis with their associated statistical moments.(DOCX)Click here for additional data file."} +{"text": "The present study examined yoga participation and cardiovascular exercise in relation to dietary intake and disordered eating symptomatology and the role of mindfulness. Participants were 159 female exercisers who completed a questionnaire incorporating measures of exercise behaviour, body awareness, trait mindfulness, mindful eating, and dietary intake and disordered eating symptomatology. Participation in yoga was associated with significantly lower levels of disordered eating symptomatology whereas the amount of time spent participating in cardio-based exercise was associated with greater eating disturbance. The relationship between yoga participation and eating behaviour was mediated by both trait mindfulness and body awareness; the relationship between cardio-based exercise and eating behaviour was partially mediated by trait mindfulness. The relationships between amount of exercise and actual food intake were not mediated by trait mindfulness or body awareness. The differential findings for dietary intake and disordered eating proneness indicate that mindfulness may be more beneficial for clinical populations or those at risk for eating disorders than for modifying actual dietary intake in the general population.Disordered Eating \u2013 Characteristics & Treatment stream of the 2013 ANZAED Conference.This abstract was presented in the"} +{"text": "In mixed strategy games, players make unpredictable decisions to avoid being exploited by opponents. However, human and animal subjects are often unable to make probabilistic decisions, and they cannot help but rely deterministically on past events. We studied the brain mechanisms of this fallacy in primates, and found that neural dynamics is constrained by a fundamental limitation: the integration of task events is characterized by a fixed set of timescales, and only the relative weight of different timescales can adapt to the task demands. When taking this constraint into account, the optimal strategy is to stretch memory by weighting maximally the longest timescales and counter-weighting the shorter ones. Consistently, we show that neural timescales follow the extreme-value distribution and responses display a biphasic time course. The distribution of weights predicted by the optimization process strikingly matches the experimental measurements. Our findings pose specific constraints on behavior during competitive games and highlights its underlying neural mechanisms."} +{"text": "Foot orthoses are commonly used in the management of knee osteoarthritis (OA), although the relationship between foot function and knee OA is still unclear. Therefore, the aim of this study was to compare tibial, rearfoot and forefoot motion during gait in people with and without medial compartment knee OA.Motion of the tibia, rearfoot and forefoot in 32 patients with clinically and radiographically-confirmed medial compartment knee OA and 28 age-matched controls was investigated using a three dimensional motion analysis system incorporating a multisegment foot model (the Oxford Foot Model). Multivariate analysis was used to investigate the differences between the groups for peaks and ranges of motion with gait velocity entered as a covariate.The knee OA group demonstrated greater peak rearfoot eversion , contacted the ground with a more everted rearfoot at initial contact and exhibited reduced rearfoot frontal plane range of motion and rearfoot peak inversion . The tibia was more internally rotated throughout the gait cycle with reduced range of motion and peak external rotation compared to the control group . Moreover, the tibia was tilted significantly more laterally in the knee OA group indicating a genu varum malalignment.People with medial compartment knee OA exhibit altered foot kinematics during gait that are indicative of a less mobile, flat foot deformity. Given that genu varum is a common feature in medial compartment knee OA, it is likely that the kinematic pattern observed occurs as a result of compensatory foot pronation to enable the foot to be plantigrade during gait."} +{"text": "A better understanding of the impact of global climate change requires information on the locations and characteristics of populations affected. For instance, with global sea level predicted to rise and coastal flooding set to become more frequent and intense, high-resolution spatial population datasets are increasingly being used to estimate the size of vulnerable coastal populations. Many previous studies have undertaken this by quantifying the size of populations residing in low elevation coastal zones using one of two global spatial population datasets available \u2013 LandScan and the Global Rural Urban Mapping Project (GRUMP). This has been undertaken without consideration of the effects of this choice, which are a function of the quality of input datasets and differences in methods used to construct each spatial population dataset. Here we calculate estimated low elevation coastal zone resident population sizes from LandScan and GRUMP using previously adopted approaches, and quantify the absolute and relative differences achieved through switching datasets. Our findings suggest that the choice of one particular dataset over another can translate to a difference of more than 7.5 million vulnerable people for countries with extensive coastal populations, such as Indonesia and Japan. Our findings also show variations in estimates of proportions of national populations at risk range from <0.1% to 45% differences when switching between datasets, with large differences predominantly for countries where coarse and outdated input data were used in the construction of the spatial population datasets. The results highlight the need for the construction of spatial population datasets built on accurate, contemporary and detailed census data for use in climate change impact studies and the importance of acknowledging uncertainties inherent in existing spatial population datasets when estimating the demographic impacts of climate change. The estimation of sizes of populations at risk (PAR) is increasingly being undertaken to guide strategic decision making and policy. PAR in terms of natural and manmade disasters These have included estimates of numbers impacted by flooding Approaches that are based on cartographic derivations of PAR are reliant on the accuracy of both the phenomena being mapped and the gridded population dataset. While the accuracies and uncertainties inherent in the development of climate change scenarios, and the mapping of their impacts are commonly debated and accounted for in impact studies, the accuracy of the accompanying population dataset used is rarely discussed, nor the impact on results of the choice of one dataset over another considered. Existing global population distribution datasets are built on databases of census data of varying year and resolution th century and is expected to rise up to \u223c60 cm by 2100 Global sea level has risen through the 20While such high impact climate-induced events have very low occurrence probability and SLR above 2 m by 2100 likely cannot be justified A recent study showed that elevation data from different sources introduces variations in PAR estimates The most recent (at the time of writing) population count datasets from LandScan (2008 version) The global LECZ footprint used in this study is derived from the SRTM30 Enhanced Global Map, which is based on raw SRTM data, but is enhanced with the U.S. Geological Survey's GTOPO30 and ocean bathymetry data from ETOPO2 The LECZ footprint was used to extract LECZ population data from LandScan, and GRUMP. This extraction method involved cartographic overlaying of the LECZ footprint and population grids in a Geographic Information System (GIS) resulting in raster layers for LECZ population, one each for LandScan and GRUMP. The files accompanying GRUMP and LandScan that define country cell allocations across the world were used, respectively, to summarize population data for LECZ countries, i.e. those not land-locked. Absolute differences between LandScan and GRUMP population estimates (using datasets adjusted to be comparable using the different approaches outlined above) were then calculated for the LECZ countries, and later used to calculate the differences, both at the country and continent levels, as the percentage of the total UNPD 2008 populations. The percentage differences calculated using the GRUMP and LandScan datasets adjusted in differing ways showed no overall significant differences , suggesting that projection method contributes statistically insignificant differences relative to the differences introduced through differing input datasets and modeling approaches used between GRUMP and LandScan. This is consistent with previous findings At the continental level there is little variation in PAR estimates derived from LandScan and GRUMP , howeverCensus datasets used to construct both GRUMP and LandScan for Europe are of similar, detailed resolution, meaning that the difference in modeling approach taken by GRUMP and LandScan generally have little impact on output population distributions, and thus, country-level discrepancies between PAR estimates are small . SimilarIdeally, identifying which existing population dataset produced the most accurate distributions within LECZ would provide clear guidance for future selection of datasets for PAR estimation. Determining this remains a difficult task, however, because if detailed population distribution data exists, it is often used as input data to the global population datasets themselves. Previous studies have, however, attempted to assess mapping accuracies between population datasets for individual countries, and often found large variations and inconsistent results between countries in terms of which dataset proved to be the most accurate, largely determined by the resolution and age of input census data With predicted SLR in the coming decades posing multiple threats to vulnerable coastal populations, PAR assessments are being increasingly undertaken Table S1Country-wise low elevation coastal zone (LECZ) population estimates derived from LandScan 2008 and GRUMP (projected to 2008) datasets. Relative differences in LECZ population estimates are also reported as percentage of the total population of the LECZ countries from each of these countries as estimated by the United Nations Population Division (UNPD).(XLSX)Click here for additional data file."} +{"text": "Intratumoral evolution produces extensive genetic heterogeneity in clinical cancers. This is generally attributed to an increased mutation rate that continually produces new genetically defined clonal lineages. Equally important are the interactions between the heritable traits of cancer cells and their microenvironment that produces natural selection favoring some clonal \u2018species\u2019 over others. That is, while mutations produce the heritable variation, environmental selection and cellular adaptation govern the strategies (and genotypes) that can proliferate within the tumor ecosystem. Here we ask: What are the dominant evolutionary forces in the cancer ecosystem? We propose that the tumor vascular network is a common and primary cause of intratumoral heterogeneity. Specifically, variations in blood flow result in variability in substrate, such as oxygen, and metabolites, such as acid, that serve as critical, but predictable, environmental selection forces. We examine the evolutionary and ecological consequences of variable blood flow by drawing an analogy to riparian habitats within desert landscapes. We propose that the phenotypic properties of cancer cells will exhibit predictable spatial variation within tumor phenotypes as a result of proximity to blood flow. Just as rivers in the desert create an abrupt shift from the lush, mesic riparian vegetation along the banks to sparser, xeric and dry-adapted plant species in the adjacent drylands, we expect blood vessels within tumors to promote similarly distinct communities of cancer cells that change abruptly with distance from the blood vessel. We propose vascular density and blood flow within a tumor as a primary evolutionary force governing variations in the phenotypic properties of cancer cells thus providing a unifying ecological framework for understanding intratumoral heterogeneity. The clinical importance of evolution in producing significant intratumoral cellular heterogeneity is well recognized have striking similarities to the flora and fauna of tundras . Similarly, we seek useful comparisons between tumor ecosystems and natural ones. In particular, we see an analogy between the arrangement of cancer cells around blood flow and vegetation around rivers within natural ecosystem. While other metaphors have been proposed for tumor dynamics . Beyond this point, there is an abrupt shift to much sparser vegetation that may only cover 10\u201330% of the aboveground space to support dense cellular populations within about 150 \u00b5m of the blood vessels will be densely populated by cancer cells that are highly adapted to abiotically \u2018rich\u2019 environments. Typically, cancer cells that grow in these mesic regions will be highly competitive, characterized by high substrate uptake and utilization, rapid proliferation, and less resistant to apoptosis that can tolerate environmental conditions that are lethal to mesic species. In the equivalent xeric regions of a tumor, we expect the following:Xeric populations of cancer cells should be different and distinct species from those in the riparian zones. While adjacent mesic and xeric habitats might favor a single generalist species capable of living in both habitats Brown , this isXeric species are less vulnerable to microenvironmental perturbations such as those from systemic cancer therapy. First, because they are far from the blood vessels, these tumor cells experience lower concentrations of any administered drug. The necessarily lower profusion of chemotherapy into the xeric region may facilitate the evolution of treatment resistance by the xeric cells. Second, the higher pH of the xeric regions may reduce the effectiveness and activity of weakly basic drugs such as doxorubicin and necrotic (xeric) regions of tumors. An understanding of tumor riparian ecosystems provides a framework for understanding key elements of tumor evolution and tumor responses to therapy."} +{"text": "Synthetic transvaginal mesh has been employed in the treatment of pelvic organ prolapse for more than a decade. As the use of these devices increased during this period so did adverse event reporting. In 2008, the Food and Drug Administration (FDA) Public Health Notification informed physicians and patients of rising concerns with the use of synthetic transvaginal mesh. Shortly thereafter and in parallel to marked increases in adverse event reporting within the Manufacturer and User Device Experience (MAUDE), the FDA released a Safety Communication regarding urogynecologic surgical mesh use. Following this report and in the wake of increased medical industry product withdrawal, growing medicolegal concerns, patient safety, and clinical practice controversy, many gynecologists and pelvic reconstructive surgeons are left with limited long-term data, clinical guidance, and growing uncertainty regarding the role of synthetic transvaginal mesh use in pelvic organ prolapse. This paper reviews the reported complications of synthetic transvaginal mesh with an evidence-based approach as well as providing suggested guidance for the future role of its use amidst the controversy. The Food and Drug Administration (FDA) cleared the first surgical mesh product specifically designed for the surgical treatment of pelvic organ prolapse (POP) in 2001. Surgical mesh in absorbable and permanent forms had been employed in vaginal approaches to pelvic floor surgery for several years. In fact, biologic grafts and synthetic mesh prostheses have been utilized in abdominal repairs for POP since the 1970s . DespiteUnfortunately, concomitant to the increased use of vaginal synthetic mesh was an increase in adverse event reporting, specifically medical device reports (MDRs), within the Manufacturer and User Device Experience (MAUDE) database. In October 2008, the FDA issued a Public Health Notification (PHN) to inform physicians and patients of adverse events related to vaginal reconstructive surgical use of synthetic mesh and to provide recommendations on how to mitigate risks and counsel patients appropriately .Over the next three years, the FDA observed a 5-fold increase in the number of MDRs associated with the use of synthetic vaginal mesh in POP surgery. Thus, in response to these reports and with the impetus to address growing concerns for patient safety, the FDA released a Safety Communication reflecting data from a systematic review of the literature addressing the safety, efficacy, and limitations of existing literature for urogynecologic surgical mesh .http://www.google.com/ search engine, with an alarming number of those responses referencing litigation. This in combination with challenges of patient counseling, not only for planned pelvic reconstructive surgery utilizing synthetic transvaginal mesh, but for those patients who have previously undergone POP surgery with mesh, adds to the complexity of the issue. Thus, gynecologists and pelvic reconstructive surgeons are currently without robust guidelines for the role of mesh in POP surgery and further limited by a lack of high-quality research addressing long-term patient safety and outcomes.Since this time, there has been nothing short of an explosion within the literature regarding the impact the FDA release had on patient, physician, and medical device companies, as well as the concerns for the future role of transvaginal mesh within pelvic reconstructive surgery. Currently, 547,000 web responses are noted using the terms \u201ctransvaginal mesh\u201d in the This report presents a review of the major complications of vaginal mesh use in POP surgery, addresses patient selection considerations, discusses patient counseling issues regarding the role of mesh in POP surgery, and reviews national organizational responses to the FDA Safety Communication as well as recommendations for future direction in POP mesh surgery.A wide spectrum of potential complications exist with the use of transvaginal mesh in POP surgery. Rare, but severe complications, including death, fistula formation, and mesh erosion into adjacent organs, have been reported in the MAUDE database. Three of seven deaths were related directly to mesh placement procedures and included two bowel perforations and one hemorrhage . VesicovMesh exposure/erosion and pain are the most commonly reported complications. Brill et al. recently summarized POP adverse events as reported from the MAUDE database 1, 10]., 10.1, 1P = 0.015) [Weber et al. reported a dyspareunia rate of 19 percent following traditional native tissue reconstructive vaginal surgery for prolapse . Dyspare= 0.015) . Sentilh= 0.015) . In a re= 0.015) .Another unique complication that is often associated with pelvic pain and perhaps a more morbid sequelae is mesh contraction, a shrinkage, or reduction in the size of the vaginal mesh implant that may lead to mesh prominences or strictures within the vagina . A recen The focus of transvaginal mesh implantation is often upon mesh exposures, extrusions, and related or referred pain; however, it is critical to take into account potential risks to the lower urinary tract. In 2007, a Cochrane review of the surgical management of POP included 22 randomized, controlled trials evaluating 2,368 women and noted that approximately 10 percent of women developed new urinary symptoms after surgery for POP. The meta-analysis included traditional repairs as well as abdominal and transvaginal mesh. The impact of POP surgery on lower urinary tract symptoms was limited and inconclusive . NonetheAccording to the American Urogynecological Society (AUGS) and American Congress of Obstetrics and Gynecology's (ACOG) recent joint committee opinion, vaginal mesh use in POP should be reserved for high-risk individuals in whom the benefit of mesh placement may justify the risk. These individuals were described as those with recurrent prolapse or medical comorbidities that preclude more invasive and lengthier open and endoscopic procedures .Historically, patients with bothersome symptoms related to POP including, pressure, protrusion, discomfort, and those with associated symptoms or impact on urinary, bowel, or sexual function are considered candidates for intervention . InitialAuthors from the Consensus of the 2nd International Urogynecological Association's (IUGA) Grafts Roundtable reported that the use of the term \u201cindications\u201d was too strong to employ regarding recommendations reported on the transvaginal mesh use due to the paucity of data in the literature. A summary of potential benefits of synthetic graft use is seen in Conditions that may be taken into consideration include those in which patients experience repetitive increases in intra-abdominal pressure . As noteThe authors reported that despite the possible circumstances in which mesh use may be appropriate or provide benefit to a patient with POP, they recommend that the patient be fully counseled regarding outcomes and possible complications. Furthermore, as other reviews have demonstrated that there is a timely call for more thorough investigation of surgical mesh use in POP repair, especially studies involving the use of control or native tissue repair arms as well as the inclusion of functional short- and longer-term outcomes with validated symptom and quality of life measures .There are no definitive evidence-based guidelines regarding absolute contraindications for the use of vaginal mesh in the surgical treatment of POP. Several studies have demonstrated increased risk of mesh exposure and wound infections with increasing BMI; tissue healing may also be impaired in poorly controlled diabetic patients , 30. ThuOne additional consideration that has been noted in the literature is that of hypersensitivity reactions to synthetic transvaginal mesh. A case-controlled study that included histological and immunohistochemical analysis of vaginal synthetic mesh explanations in a small population of women noted markers of humorally mediated lymphocytic reaction . Though http://www.augs.org/informedconsent/) which equips providers with a transvaginal mesh informed consent toolkit. This resource includes background information regarding the FDA releases, rationale for transvaginal mesh in surgery for POP, and overview of risks and considerations, as well as an informed consent checklist and frequently asked questions. Furthermore, physicians can direct patients to AUGS patient site (http://www.voicesforpfd.org/) to promote education and active dialogue during counseling.Patient counseling regarding the use of synthetic transvaginal mesh for the treatment of POP must be individualized. It has been recommended by several national organizations that surgeons placing vaginal mesh have a command of pelvic anatomy as well as undergoing training specific to each device as well as experience with reconstructive surgical techniques \u201337. ThusPhysicians should continually review the recommendations and publications released by our national organizations regarding transvaginal mesh and POP. Several national gynecological and urological organizations released response statements to provide further guidance amidst the transvaginal mesh controversy following FDA's 2011 release. The National Association For Continence (NAFC) called for the requirement of consistent, specialized training with credentialing by societies for all surgeons performing procedures to treat stress urinary incontinence and/or POP with or without mesh . AUGS reThe SGS reported general agreement with the recommendations made by the FDA and highlighted that discriminant use of synthetic transvaginal mesh to augment vaginal defects should be performed by trained surgeons with experience in complex reconstructive surgery and only on patients with perceived unacceptable risk of clinical failure using other nonmesh approaches. Furthermore, SGS in parallel with the FDA called for long-term clinical trials evaluating benefits and safety of vaginal mesh placement .ACOG echoed FDA's charge for rigorous comparative effectiveness research as well lending support to the formation of an advisory committee, the Obstetrics and Gynecology Devices Panel. ACOG also recommended voluntary physician reporting through the MAUDE database and noted that complications of vaginal reconstructive surgery also occur with nonmesh approaches .The Society for Female Urology and Urodynamics (SUFU) was also broadly supportive of the FDA white paper and also noted that many of the complications of vaginal mesh surgeries also occur in nonmesh procedures. It was recommended that consideration of mesh placement be conducted on a case by case basis with informed discussion. As with ACOG and AUGS, SUFU also supported a review of the FDA 501k approval process .Vaginal Placement of Synthetic Mesh for Pelvic Organ Prolapse, released in December 2011 is seen in A summary of the recommendations from AUGS and ACOG's collaborative Committee Opinion, entitled Maximizing patients' outcomes and safety while concomitantly minimizing complications is the central concern from which the transvaginal mesh controversy arises. More robust, long-term data and physician-driven event reporting promulgated by the FDA and national gynecological and urological societies will undoubtedly continue to shed light on the future role of transvaginal mesh in pelvic organ prolapse surgery. It is imperative that physicians continue to review the literature, report their own outcomes, and counsel their patients regarding new outcome data, complications, and recommendations from national organizations in women's health regarding prolapse repair. Surgeons with specialized training in native tissue and use of synthetic mesh augmented repairs and management of complications inherent in both groups should lead this charge of delivering care to women affected by POP."} +{"text": "Gap junctions are key components underpinning multicellularity. They provide cell to cell channel pathways that enable direct intercellular communication and cellular coordination in tissues and organs. The channels are constructed of a family of connexin (Cx) membrane proteins. They oligomerize inside the cell, generating hemichannels (connexons) composed of six subunits arranged around a central channel. After transfer to the plasma membrane, arrays of Cx hemichannels (CxHcs) interact and couple with partners in neighboring attached cells to generate gap junctions. Cx channels have been studied using a range of technical approaches. Short peptides corresponding to sequences in the extra- and intracellular regions of Cxs were used first to generate epitope-specific antibodies that helped studies on the organization and functions of gap junctions. Subsequently, the peptides themselves, especially Gap26 and -27, mimetic peptides derived from each of the two extracellular loops of connexin43 (Cx43), a widely distributed Cx, have been extensively applied to block Cx channels and probe the biology of cell communication. The development of a further series of short peptides mimicking sequences in the intracellular loop, especially the extremity of the intracellular carboxyl tail of Cx43, followed. The primary inhibitory action of the peptidomimetics occurs at CxHcs located at unapposed regions of the cell\u2019s plasma membrane, followed by inhibition of cell coupling occurring across gap junctions. CxHcs respond to a range of environmental conditions by increasing their open probability. Peptidomimetics provide a way to block the actions of CxHcs with some selectivity. Furthermore, they are increasingly applied to address the pathological consequences of a range of environmental stresses that are thought to influence Cx channel operation. Cx peptidomimetics show promise as candidates in developing new therapeutic approaches for containing and reversing damage inflicted on CxHcs, especially in hypoxia and ischemia in the heart and in brain functions. Gap junctions are cell\u2013cell connections that ensure harmonious integration, regulation and equalization of metabolic events and signaling in tissues and organs. Their role in the coordination of cell behavior is vividly illustrated in the heart, where gap junctions in the intercalated discs provide pathways that allow direct intercellular electrical communication essential for synchronous contraction of component myocytes and for generating waves of rhythmic contractions observed in arteries. Gap junctions are constructed of paired connexin hemichannels (CxHcs), each composed of six protein subunits arranged around a central pore, and occur at adhesive areas where plasma membranes touch. Hcs are continuously recruited from surrounding unapposed plasma membrane areas and subsequently dock head to head with partners from adjacent cells and attach to the rims of preexisting gap junction plaques. The operational area and size of gap junction plaques where intercellular communication occurs are regulated by a balanced internalization and degradation of the dodecameric Cx channel units Laird .Many approaches have been applied to study the structure and function of gap junctions and their constituent CxHcs the topographical arrangement of Cx proteins in the membrane . In contrast, CxHcs open at 500\u00a0nM examined the mechanism of action of Gap26 and -27 in HeLa cells stably transfected with Cx43 and in pig ventricular myocytes endogenously expressing Cx43 using a voltage-clamp approach. Both mimetic peptides inhibited Cx43Hc unitary currents within minutes. An important outcome of this study with cardiac translational implications was that unitary current activity was promoted by a moderate elevation of cytoplasmic Ca, an event observed in cardiac arrhythmogenesis.Gap26 and -27 have been used mainly to inhibit Cx43 channels, but actions on other Cx channels have also been studied. For example, Wright et al. carried The precise protein domains to which Gap26 and -27 mimetic peptides attach and any conformational changes induced in Cx channels remain to be determined. Fluorescently labeled Gap26 and -27 are poorly soluble; but evidence points to attachment and retention at cell exteriors, and problems of image resolution could not answer the issue of whether attachment of a mimetic peptide ligand to a \u201cchannel receptor\u201d sequence can lead to peptide internalization . Voltage-clamp approaches have been useful in deciphering the inhibitory action of these peptides on Cx channels and go a long way toward resolving questions concerning the specificity of mimetic peptide inhibitory effects. Cx mimetics have been claimed as effective inhibitors due to steric pore block and its derivatives were developed to target the Cx43CT and described as the particle\u2013receptor hypothesis that bound to the carboxyl tail of Cx43, derived from heart lysates and studied in animal and cellular models, prevented action potential block in the heart , epileptiform activity, memory consolidation and amnesia, further emphasizing the importance of Cx-mediated communication and signaling in a wide range of settings."} +{"text": "Mechanical properties of the aortic wall have been used to diagnose and characterize cardiovascular disease. Aortic stiffness correlates with aortic disease and disease progression. Mechanical regulation from strain and wall shear stress is hypothesized to influence remodeling in the cardiovascular system. Current non-invasive techniques for assessing aortic deformation are based on diameter changes, and are sensitive to through-plane motion of the aorta. Conventional methods for assessing strain, such as tagging, have limited resolution. We propose a new MRI approach that measures the regional stretch of the aortic wall itself using displacement encoding with stimulated echoes (DENSE).Six subjects were studied with standard CINE and DENSE imaging of the tubular portion of the ascending aorta. DENSE was performed at the point of max dilation according to the cine images. The aorta was segmented in the DENSE images and the stretch of the aortic wall was calculated.Two young volunteers (26 years old) had an aortic stretch of 12%, two older patients (48 years old) with cardiovascular risk factors had stretch of 5%, and two older patients (60 years old) with dilated aortas had stretch of 1%. Figure This novel application of DENSE imaging allows for direct assessment of regional stretch in the ascending aorta. Clear differences are seen between volunteers and older patients, and within patients depending on the degree of aortic dilation present. Regional differences along the aortic lumen are evident, which cannot be imaged with other techniques. Our pilot study suggests that DENSE may play central wall in better understanding how mechanical differences in the aortic wall interrelate with disease progression.VA MERIT Review, Covidien/RSNA Research Scholar Grant"} +{"text": "The incidence of colonic diverticular disease varies with national origin, cultural background and diet. The frequency of this disease increases with advancing age. Right-sided diverticular disease is uncommon and reported to occur in 1-2% of surgical specimens in European and American series. In contrast the disease is more prevalent and reported in 43-50% of specimens in Asian series. Various lines of evidence suggest this variation may represent hereditary differences. The aim of the study is to report all cases of right sided diverticular disease underwent surgical resection or identified during pathological examination of right hemicoloectomy specimensA retrospective review of all surgical specimens with right sided colonic diverticular disease selected from a larger database of all colonic diverticulosis and diverticulitis surgical specimen reported between January 1993 and December 2010 at the Pathology Department McMaster University Medical Centre Canada. The clinical and pathological features of these cases were reviewedThe review identified 15 cases of right colon diverticulosis. The clinical diagnoses of these cases were appendicitis, diverticulitis or adenocarcinoma. Eight cases of single congenital perforated diverticuli were identified and seven cases were incidental multiple acquired diverticuli found in specimen resected for right side colonic carcinomas/large adenomas. Laparotomy or laparoscopic assisted haemicolectomies were done for all cases. Pathological examination showed caecal wall thickening with inflammation associated with perforated diverticuli. Histology confirmed true solitary diverticuli that exhibited in two cases thick walled vessels in the submucosa and muscular layer indicating vascular malformation/angiodysplasia. Acquired diverticuli tend to be multiple and are mostly seen in specimens resected for neoplastic right colon diseases.Single true diverticular disease of the right colon is usually of congenital type and affects younger age group and may be associated with angiodysplasia in some cases. Multiple false diverticuli are more seen in association with caecal carcinoma or large adenomas. These are usually asymptomatic and are more seen in older patients. However this study dose not reflects the true incidence of the disease in the general population. Diverticular disease of the colon becomes more common in well-developed countries. The prevalence depends on variable factors such as national origin, cultural background and consumed diet. The occurrence of this disease appears to increases with age . DivertiCaecal diverticular disease was first described by Potier in 1912 . The incA retrospective review of McMaster Medical Center laboratory information system was conducted for all surgically resected colonic diverticular and diverticulitis cases for the period 1993-2010 to identify patients with right side diverticula. The study was approved and conducted according to Hamilton Health Science Research Ethic Board guidelines. The search revealed 465 patients underwent surgery for diverticular disease of the colon. There were 15 cases of right side colon diverticular diseases identified and selected for this study. We reviewed the patient's clinical information for age, gender, presentation, and type of surgery. The pathological specimens were retrieved and reviewed for the presence of single or multiple diverticuli, presence or absence of inflammation, perforation, angiodysplasia or malignancy. Diverticula consisting of a pouch of mucosa and muscularis mucosae projecting through and beyond muscular layer of the colon were labeled as false or pulsion diverticula and those with all layers of bowel wall were considered congenital or true diverticula.Fifteen cases of caecal diverticula were identified. The clinical and pathological summary is presented in table Pathological examination, showed single caecal diverticula with diverticulitis and perforation. There were inflammatory masses producing thickening of the caecal wall Figure . Caecal The acquired diverticula were composed of herniated mucosa and submucosa with no evidence of inflammation Figure . There wRight sided diverticular colonic disease is rather uncommon in the Western World. The frequency of this disease is reported in approximately 1-2% of surgical specimens in European and American series, but may reach as high as 43-50% in Asian series . ControvOur findings support this association in cases of true diverticula. This correlation implicates a common aetiological factor. The presence of thick abnormal vessels claimed to trigger local haemodynamic/pressure changes render the background for diverticular disease. One study claimed the morphology of myenteric plexuses, and the ganglion cells differ significantly among segments of the human large intestine. Large intestines with diverticula had significantly more plexuses but significantly fewer ganglion cells than large intestines without diverticula . The areMost patients with right sided diverticula are asymptomatic; however, patients may present with complications of diverticulosis. These include bleeding, diverticulitis, peridiverticular abscess, perforation with fistula formation . PatientCT scanning is a sensitive means by which to detect caecal diverticulitis. The radiographic appearance of the disease; however, mimics that of appendicitis, unless more specific findings such as caecal diverticula or intramural abscess with adjacent inflammation are detected. CT and barium studies are complementary methods of examination that improve our ability to diagnose caecal diverticulitis and its complications -18.MRI of right-side diverticulitis may reveal an out pouching of the right colon with associated circumferential wall thickening of the colon and surrounding inflammatory changes Some autIf technically feasible, aggressive resection with immediate right hemicolectomy should be considered in cases of extensive inflammatory changes, multiple diverticula and caecal phlegmon, or when neoplastic disease can not be excluded. This surgery can be safely performed even in the unprepared colon with few complications -23.In Western countries, diverticulosis mostly affects the left colon and the incidence of right sided diverticulitis is estimated around 2% of colonic diverticular disease. However, in Asia and countries with high Asian population, diverticular disease of the caecum and the ascending colon is more common than the left sided form of this disease. In Canada, despite the multicultural and ethnic mix, the incidence of this disease presented to surgery is rather low. Single diverticula are usually present in young patients and are prone to complication. Multiple diverticula are asymptomatic, finding in older patients mostly seen in association with carcinoma.The authors declare that they have no competing interests.JR contributed to the collection of clinical data, literature review and drafting of the manuscript. JAR and OBT contributed cases and reviewed the manuscript. All the authors gave final approval of the submitted manuscript."} +{"text": "Neurons in the primary visual cortex exhibit a baffling array of tuning properties, often unaccountable by the classical linear feedforward model. Specifically, excitatory neurons display a number of nonlinear effects collectively known as non-classical receptive field (nCRF) effects , and inhEfficient coding models of early vision have been shown to be able to explain key features of linear filtering properties and someHere we demonstrate that many of the aforementioned excitatory cell and inhibitory cell properties emerge naturally from a network that implements sparse coding. To be specific, several nCRF effects including surround suppression, contrast invariant orientation tuning, and cross orientation suppression emerge in the excitatory cell population as a result of sparse coding strategy; the excitatory to inhibitory cell ratio could be understood largely as a result of the overcompletness of representation; moreover, a subpopulation of inhibitory interneurons exhibit orientation tuning due to sparse recurrent connections with the principal cells; another subpopulation displays untuned properties due to low rank connectivity patterns. We also demonstrate that the network exhibits balanced excitation and inhibition, as a result of the receptive field structure.We simulated a population of 2048 excitatory neurons with graded response described by the dynamics of locally competitive algorithm , which"} +{"text": "To conduct a scoping review of the current evidence describing how the musculoskeletal physical examination is taught and assessed, with particular focus on the Pediatric context.We searched electronic databases for the past 15 years for relevant articles using any type of study design. Articles describing aspects of curricula focusing on musculoskeletal exam education were eligible for inclusion. Abstracts were reviewed, and full text articles were obtained for studies meeting inclusion criteria. Reference lists were examined and additional relevant articles were obtained. Full length articles were read, abstracted and then categorized based on which part of curricular design they describe, using Kern\u2019s model of curriculum development for medical education as a framework to ensure that all necessary elements are considered. The six key components for curriculum design as described by Kern are: problem identification and general needs assessment; targeted needs assessment; goals and specific measurable objectives; educational strategies; implementation; evaluation, assessment and feedback.Of 50 citations identified from the database search, 35 met inclusion criteria. An additional 33 were obtained from review of reference lists. A total of 68 papers were therefore included in this review. Using Kern\u2019s framework it was found that the general and targeted needs assessments revealed that trainees have poor musculoskeletal knowledge, and that both teachers and students have limited confidence in their musculoskeletal assessment skills. Published goals and objectives provide lengthy lists of examination skills which do not adequately describe competent performance. Educational strategies and assessment tools to improve the musculoskeletal exam rely heavily on student self-assessment, and have not shown a clear link to increased identification of abnormalities when examining real patients. Consideration of the resources and support required for curriculum implementation, and discussions of program evaluation were generally not present. The majority of studies (n=47) focused on medical student education related to adult musculoskeletal skills, with little description of curricula dealing with the Pediatric musculoskeletal examination.The current literature leaves many gaps in our understanding of the necessary knowledge, skills and attitudes required to teach the Pediatric joint exam. Methodologically rigorous educational studies focusing on the unique aspects of conducting a musculoskeletal exam in a child are required to advance our effectiveness in teaching these skills.Clare Hutchinson: UCB, Inc., 2; Marie-Paule Morin: None; Rayfel Schneider: None; Scott Reeves: None."} +{"text": "This study examines the impact of behavioural factors in the successful management of an organisation-wide Norovirus outbreak in a UK hospital.A retrospective qualitative content analysis of a Norovirus outbreak was undertaken, using critical incident analysis as the basis for conducting semi-structured interviews with 24 key clinical and managerial participants. Behavioural references were mapped to a behavioural framework that describes positive behaviours, known as \u2018mindful behaviours\u2019 and negative behaviours, known as \u2018mindless behaviours\u2019 which contribute to high and low performance respectively in the context of an unexpected event, using a qualitative software tool (NVivo). The resulting data was analysed using frequency tables.The results demonstrated a higher count of mindful behaviours than mindless behaviours in what participants perceived to be a successfully managed outbreak. Mindful behaviours included the engagement of clinical experts, daily reviews of hospital capacity and capability, prioritisation of patient safety over parochial interests, rigorous implementation of clinical reviews and effective communication with clinicians. Successful management was defined by participants as the appropriate balance between safety and performance that: minimised morbidity, ensured the hospital continued to meet its performance targets and maintained the hospital\u2019s reputation externally.This study has an in-depth focus on the behaviours that facilitate and hinder the successful management of a potentially highly disruptive Norovirus outbreak. The lessons learnt can contribute to improved management of future outbreaks and an enhanced understanding of the behavioural drivers of an effective outbreak response.None declared."} +{"text": "Understanding interactions between mobile species distributions and landcover characteristics remains an outstanding challenge in ecology. Multiple factors could explain species distributions including endogenous evolutionary traits leading to conspecific clustering and endogenous habitat features that support life history requirements. Birds are a useful taxon for examining hypotheses about the relative importance of these factors among species in a community. We developed a hierarchical Bayes approach to model the relationships between bird species occupancy and local landcover variables accounting for spatial autocorrelation, species similarities, and partial observability. We fit alternative occupancy models to detections of 90 bird species observed during repeat visits to 316 point-counts forming a 400-m grid throughout the Patuxent Wildlife Research Refuge in Maryland, USA. Models with landcover variables performed significantly better than our autologistic and null models, supporting the hypothesis that local landcover heterogeneity is important as an exogenous driver for species distributions. Conspecific clustering alone was a comparatively poor descriptor of local community composition, but there was evidence for spatial autocorrelation in all species. Considerable uncertainty remains whether landcover combined with spatial autocorrelation is most parsimonious for describing bird species distributions at a local scale. Spatial structuring may be weaker at intermediate scales within which dispersal is less frequent, information flows are localized, and landcover types become spatially diversified and therefore exhibit little aggregation. Examining such hypotheses across species assemblages contributes to our understanding of community-level associations with conspecifics and landscape composition. Understanding linkages between spatial patterns of biological communities and environmental characteristics is a central question in ecology and natural resource conservation There are at least four hypotheses that can explain the distribution patterns of species at a given resolution. First, a null hypothesis is that species are distributed randomly and are therefore equally likely to occur among patches, i.e., spatial units at the scale of an individual home range. With such a random distribution, we would predict that a species occurrence pattern corresponds with neither the condition of patches nor conspecific occupancy of adjacent patches. Although this null hypothesis contradicts much of modern ecological theory As mobile and readily observed animals, breeding birds provide an excellent opportunity for examining hypotheses about species distributions Our objectives are to 1) ascertain the relative importance of conspecific-neighborhood effects reflecting endogenous drivers vs. landcover variables reflecting exogenous drivers of bird species distributions, and 2) improve understanding about how accounting for conspecific-neighborhood effects impacts inferences about landcover drivers of bird species and community distribution within a forested landscape. We consider an avian point-count dataset from the Patuxent Research Refuge as a case study to analyze patterns in species occupancy while accounting for heterogeneity in detectability among species using a hierarchical Bayes approach. In doing so, we account for possible species-specific associations with particular landcover metrics and spatial autocorrelation. We also account for similarities among species in the community by sampling species-specific parameters from a common hyper-distribution while accounting for detectability 2 area of the refuge is primarily deciduous forest, with interspersed meadows, wetlands, and shrub-scrub areas that are managed to provide wildlife habitat. The refuge is gridded at 400-m intervals with permanent markers, and we selected a systematic sample of 316 grid points as locations for point counts . Additional details on the avian sampling methods have been published elsewhere The 1992 National Land Cover Data set (NLCD) i is present at site j and zero otherwise) for each of N species at S sites:We used a state-space approach to model species distributions, which included an occupancy process model and an observation model of detections i in site j. The observation model, which is conditional on the corresponding occupancy state, is described as follows:i in site j during k of M >1 visits across which we assume closure where j, that are occupied by species i estimated by dividing the total number of presences (in each of the r neighboring cells) of species i, denoted where For our global occupancy model, we incorporated six species-specific random effects , landcover , autologisic , and global .We used WinBUGS version 1.4.3 We evaluated model performance by computing the area under the curve of the receiver operating characteristic (AUC) th to 97.5th percentile of the posterior distribution) for one posterior excluded the BCI of the opposing posterior. When making inferences about the strength of spatial autocorrelation at the individual species level, we examined the log-odds ratio from the autologistic parameter for each species calculated as:We utilized AUC for evaluating our models in two ways. First, we calculated mean and 95% Bayesian credibility interval (BCI) AUC values reflecting goodness-of-fit for each of the four models based on the vector of AUC values across MCMC iterations for all species combined. Second, we calculated AUC values reflecting model goodness-of-fit for each species under each model rendering a mean and 95% BCI AUC value for each species-model combination Our analysis considered 90 species of breeding birds that were observed on the refuge . DetailsBased on the consolidated community-level AUC values, the landcover model and global model performed similarly and had significantly better fits than the null and autologistic models , which were themselves quite similar. We refer to the landcover model as the top model because of its parsimony . Species-specific AUC values revealed comparable patterns, with the landcover model having similar AUC values to the global model and the spatial model having similar AUC values to the null model , though With the exception of percent developed, there were few cases where the landcover model revealed a significant association and the global model did not for a given landcover type . There wAll species exhibited statistically significant positive spatial autocorrelation in both the global and spatial-only models than when accounting for landcover heterogeneity alone. This may in part be due to the fact that all of the landcover covariates were spatially correlated and thus might also explain spatial correlation in the species distributions. This notion is supported by our unpublished findings that the residuals for most species in the landcover model were not spatially autocorrelated. The landcover hypothesis therefore, was more consistent with our results than was the aggregation hypothesis for explaining local-scale individual species distributions.In our study there were numerous significant associations between specific landcover variables and patterns of individual species occupancy that were in agreement between models with and without the spatial component. We found that in both the landcover and global models, species distributions were often driven by associations with undeveloped openings . The global and landcover-only models disagreed more frequently when predicting relationships between species distribution and the amount of developed land. There was considerable uncertainty whether landscape heterogeneity alone or combined with spatial autocorrelation better reflected species distributions. Although we found consistent evidence for particular species associations with vegetated landcover between landcover models with and without spatial autocorrelation, the apparent strong and consistent evidence for conspecific aggregation across the bird community weakened for all but very few species after accounting for landcover effects . ThroughAn emphasis of our study was to better understand interactions between individual bird species distributions and various types of openings within a landscape dominated by contiguous forest. Across the bird community on the refuge, meadows and wetlands were important drivers for a number of species regardless of whether we accounted for spatial autocorrelation. Although the landcover model revealed a significant negative relationship between developed landcover and occupancy of several species, this effect dissipated when accounting for spatial autocorrelation. A possible explanation is that the sparse but highly aggregated distribution of developed lands on the refuge induces spatial autocorrelation in the associated bird species rather than endogenous factors alone. In contrast, species associations with vegetated cover types were relatively consistent whether or not spatial autocorrelation was included in the model. We hypothesize that at a local scale, intrinsic and extrinsic factors interact to generate distributions of species associated with vegetated cover types whereas aggregation of synanthropic species is largely driven by exogenous factors. Such hypotheses about interactions between spatial arrangements of habitat and mobile species, though conceptually familiar To our knowledge, few studies investigating distributions of multiple forest bird species have accounted for spatial autocorrelation 4 m) neighborhoods but less so within an intermediate (103\u2013104 m) neighborhood. This hypothesis is supported by some of our own unpublished analyses, which indicate that the strength and consistency of spatial autocorrelation across the avian community declines when considering a 103 neighborhood. We suggest that mechanisms giving rise to aggregation of conspecific mobile species at fine scales likely contrast with those at coarse scales. At a fine scale, aggregation of landcover characteristics to which species are adapted in addition to opportunities for exchange of genetic material and information about local food resources are likely powerful drivers of conspecific clustering, and certain life history strategies emerge from the particular mechanisms for this fine-scaled clustering. At coarser scales, geomorphic landforms and climatic envelopes likely drive neighborhood associations that dictate the geographic ranges of species. As highly mobile organisms, bird species may fail to exhibit spatial structuring at intermediate scales within which dispersal is less frequent, information flows are localized, and landcover types become spatially diversified and therefore exhibit little aggregation. This diminished clustering at intermediate scales has been observed in plant species Across these studies and our own, we hypothesize that bird species breeding in forested landscapes exhibit spatial aggregation within fine (100\u2013800 m) and coarse (>10Spatial resolution is a critical consideration when examining patterns of species distributions In addition to spatial resolution, we must also take into account other scopes of inference when interpreting results from our study. First, we investigated the bird community within the Patuxent Research Refuge, which should be representative of the more natural areas of the Mid Atlantic Piedmont but some care must be taken when applying these findings beyond the Refuge. Much of the original forest and wetlands in this ecoregion has been converted to agricultural and residential land uses Fourth, we examined associations between bird species occupancy and local landcover percentages but not measures of landscape configuration like edges, core areas, or patch size, which have long been recognized as important drivers of bird species distributions Finally we used AUC to evaluate and compare model fit rather than one of the information-theoretic model-selection criteria Birds are not only a useful taxon for studying species distributions, but they also present opportunities to account for imperfect detection within a community-level analysis. With regard to imperfect detection, there are at least two reasons why a bird species may be present but not detected In this paper we have addressed hypotheses about interactions between bird species distributions and landcover characteristics at a local scale while accounting for potentially confounding factors of partial observability, spatial autocorrelation, and shared traits among species in the community. We have also proposed an intermediate-spacing hypothesis by placing our findings within the context of similar investigations that spanned a broad set of spatial scales. Furthermore, we developed a modeling approach for investigating spatial autocorrelation of conspecific distribution patterns simultaneously for multiple species while accounting for partial observability and allowing for incorporation of habitat covariates. Our approach is an extension of the hierarchical Bayes multi-species occupancy modeling framework by Dorazio et al."} +{"text": "Foamy viruses (FVs) are distinct retroviruses with several features of their molecular biology and replication strategy clearly different from those of Orthoretroviruses like HIV, MLV and HTLV. One distinguishing feature of FVs is the absolute dependence of the cognate Env protein for Gag particle budding. Recent data showed that Gag has the capacity to bud from the cell, provided that a heterologous myristoylation signal is N-terminally appended. When this interaction is engineered to be reversible, even infectious particles are released. While the interaction surface of the FV-specific Env leader protein Elp required to specifically interact with Gag has been characterized to some degree, we set out to characterize the corresponding domain of Gag by separating the budding-relevant functions from those required for FV cytosolic Gag assembly.Alanine scanning and single amino acid mutagenesis of the N-terminus of feline FV (FFV) Gag domain, together with cell biology and virological methods, were used to dissect FVparticle assembly and budding.In addition to the centrally positioned arginine within the cytoplasmic targeting-retention signal (CTRS), other conserved residues upstream of the CTRS are involved in different phases of particle assembly, envelopment and budding. The different phenotypic changes of these mutants, including proteolytic Gag processing, intracellular Gag assembly into viral particles, and particle budding and infectivity, highlight their essential, distinct and only partially overlapping roles during viral assembly and budding. Importantly, there was a clear correlation between capsid formation and interaction with Elp, hinting at the requirement of higher order structures in Gag assemblies for Elp binding during budding. Finally, it appears that FV capsid assembly is a very efficient process, since monomeric Gag and lower molecular mass Gag aggregates were almost undetectable by the methods employed.The new insights into the spatial organization of the different functions within the FV Gag proteins will be presented and discussed with respect to the contribution of individual Gag residues for the different functions identified. The data implicate that FV assembly is a highly structured process and that components in this process are active only as specific molecular assemblies."} +{"text": "Adipose tissue is regarded as an endocrine organ which contributes to regulating systemic energy balance. Since adipocyte is the specialized cell that can safely store triglyceride, normal adipose tissue function in buffering excessive caloric intake is able to prevent systemic metabolic consequences related to high glucose and lipid content in nonadipose cells. Excessive caloric intake relative to energy expenditure is rapidly becoming a feature of most populations around the world, and inability of adipose tissue to fulfill its role is inevitably linked to metabolic abnormalities recognized to increase risk for cardiovascular disease (CVD) and type 2 diabetes (T2D). Several investigators currently advocate focusing on improving our knowledge of mechanisms regulating adipose tissue function independent of adipose tissue mass. Filling this gap in the literature will better enable us to identify novel approaches to treat individuals at risk or with established T2DM and CVD. This special issue is dedicated to various manifestations of adipose tissue dysfunction and, with a combination of clinical papers and reviews of the literature, it addresses various aspects of recent advances and opportunities in this field of research. The various papers discuss the existing evidence regarding the role of functional heterogeneity of various adipose tissue areas in determining risk for metabolic complications, such as insulin resistance and dyslipidemia. There is a discussion on recent evidence for adipose tissue inflammation and adipokines production as determinants of systemic metabolic abnormalities of lipid and glucose metabolism. The overall theme is completed by the topics of potential directions for future research and evaluation of the role that maternal nutrition may have in the early development of adipose tissue dysfunction. Nicola AbateNicola AbateAnne E. SumnerAnne E. SumnerManisha S. ChandaliaManisha S. Chandalia"} +{"text": "Adrian L Harris and Leo KinlenMisconceptions and ill-founded theories can arise in all areas of science. However, the apparent accessibility of many epidemiology findings and popular interest in the subject can lead to additional misunderstandings. The article below continues an occasional series of short editorials highlighting some current misinterpretations of epidemiological findings. Invited authors will be given wide scope in judging the prevalence of the misconception under discussion. We hope that this series will prove instructive to cancer researchers in other disciplines as well as to students of epidemiology. In fact, when smoking ceases, the rate stops increasing steeply and remains almost constant ("} +{"text": "The capability of performing interval timing is essential for survival, adaptation and its impairment leads to sever cognitive and/or motor dysfunctions. Although the localization of brain regions essential for interval timing is not yet clear, some progress has been made. For example, both temporal production and temporal perception are strongly connected to striatum and its afferent projections from the substantia nigra pars compacta . Since i"} +{"text": "To explain the relationship between a positive nurse practice environment (NPE) and implementation of evidence-based practices. To describe the components of NICHE programmes that contribute to a positive geriatric nursing practice environment.The NPE is a system-level intervention for promoting quality and patient safety; however, there are population-specific factors that influence the nurses\u2019 perception of their practice and its\u2019 relationship with patient outcomes. Favourable perceptions of the geriatric-specific NPE are associated with better perceptions of geriatric care quality.Discursive paper.In this selective critical analysis of the descriptive and empirical literature, we present the implementation of geriatric models in relation to the NPE and components of the NICHE programme that support hospitals\u2019 systemic capacity to effectively integrate and sustain evidence-based geriatric knowledge into practice.Although there are several geriatric models and chronic care models available, NICHE has been the most successful in recruiting hospital membership as well as contributing to the depth of geriatric hospital programming.Although all geriatric care models require significant nursing input, only NICHE focuses on the nursing staff\u2019s perception of the care environment for geriatric practice. Studies in NICHE hospitals demonstrate that quality geriatric care requires a NPE in which the structure and processes of hospital services focus on specific patient care needs.The implementation of evidence-based models addressing the unique needs of hospitalised older adults requires programmes such as NICHE that serve as technical resources centre and a catalyst for networking among facilities committed to quality geriatric care. Unprecedented international growth in the ageing population compels us to examine how to adapt the successful components of NICHE to the distinctive needs of health systems throughout the world that serve older adults. It is well established that the nurse practice environment (NPE) is essential to nurse satisfaction and subsequently to nurse-sensitive patient outcomes. Studies exploring the NPE in acute care settings serving specific patient populations such as persons receiving care in AIDS, oncology and critical care units suggest care models focused on population-specific factors have a positive impact on nurses\u2019 perceptions of their practice environments imply that that there are other dimensions that need to be specialised to the population and that influence the nurses\u2019 perception of their practice as well as its relationship with patient outcomes unit, the NICHE initiative, the Geriatric Resource Nurse (GRN) model and the HELP . In general, these models target the prevention of complications that occur more commonly in older adults and the hospital factors that contribute to complications by employing evidence-based, ageing-sensitive interventions, promoting interdisciplinary communication and emphasising discharge planning . These pNurses Improving Care for Healthsystem Elders (NICHE) provides the necessary resources and technical support to assist hospitals\u2019 systemic capacity to effectively embed evidence-based geriatric knowledge into practice. NICHE is evidence-based programme that has been evolving through research conducted over the last 20 years. The core components of a system-wide, acute care programme designed to meet the needs of older adults are grouped into eight categories , along with Evidence-Based Geriatric Nursing Protocols for Best Practice to promote a geriatric-responsive practice environment for all disciplines. This is accomplished by educating all team members through a 5-part NICHE Introduction to Gerontology learning programme that is designed to increase the hospital personnel\u2019s sensitivity to the ageing process by improving the recognition of age-related changes in older adult patients and enhancing communication skills with older patients and their families. This introductory series provides a foundation for developing geriatric sensitive care across all hospital departments provide audio and web-based examples of successful NICHE site programmes that can be adapted for use in other sites. Finally, an annual conference provides another venue for sites to describe and disseminate their innovative approaches and measurable outcomes through poster presentations and oral paper presentations. NICHE resources are developed based on successful, evidence-based examples from NICHE sites as well as in response to NICHE site requests.A key contribution to sustained NICHE site involvement is their mutual use of, and contribution to, collaborative venues facilitated by NICHE. These include discussion forums for NICHE sites whereby NICHE coordinators, site staff and administrators\u2019 dialogue about common issues they face in promoting quality geriatric care. Webinars and the NICHE Solutions series and following (n = 942) NICHE implementation (p< 0\u00b70001) and quality of geriatric care (p = 0\u00b70004) increased following NICHE implementation. These study findings indicate that organisational support for geriatric nursing exerts an important influence upon perceptions of quality of geriatric care . They aim to improve patient outcomes, specifically physical function, physical activity, self-efficacy and outcome expectations for function, while lowering the incidence of adverse events at discharge . The CAUTI intervention consists of a) electronic audit and feedback reports to hospitals on unit-specific, patient-level urinary catheter duration and CAUTI rates and b) an educational session on CAUTI prevention and evidence-based best practices for urinary catheter management dissemination of an electronic method for tracking CAUTIs and catheter duration and (2) determination of the effect of the feedback of these data on processes of care (catheter duration) and outcomes (CAUTIs) and the American Journal of Nursing, will create educational materials and toolkits to help nurses and social workers support family caregivers with a particular focus on the needs of diverse communities. These family-centred practices will be evaluated in representative NICHE hospitals prior to national dissemination.Quality geriatric care requires a NPE in which the structure and processes of hospital services focus on specific patient care needs. Although there are several geriatric models and chronic care models available, NICHE has been the most successful in recruiting hospital membership as well as contributing to the depth of geriatric hospital programming. All geriatric models of care include a high level of nursing input but only NICHE stresses nurse involvement in hospital decision-making regarding care of older adults. This professional nursing practice perspective support nurse competencies related to the complex interdisciplinary care management of older adults and the resources they need to improve the safety and outcomes of hospitalised older adults. Clearly, the ageing of our worldwide population requires a systematic incorporation of evidence-based geriatric principles in healthcare settings serving older adults.The implementation of evidence-based interventions and models addressing the unique needs of hospitalised older adults requires programmes such as NICHE that serve as technical resources centre and a catalyst for networking among facilities committed to quality geriatric care. Unprecedented growth in the ageing population worldwide compels us to examine how to adapt the successful components of NICHE to the distinctive needs of health systems beyond North America. This means much more than simply translating NICHE resources. Modifications in other parts of the world will need to take into account the financing and organisation of health care, the role of nurses and geriatric specialists (across disciplines) as well the social and economic issues that older adults face, which impacts health status."} +{"text": "Low-cost DNA sequencing has greatly democratized genomics, especially for the typically very small genomes of viruses The human microbiome project, focusing largely on single bacterial cells and metagenomic sequencing of total DNA from feces and other human sites, is unlikely to detect RNA viruses. The generally minuscule size of viral genomes relative to those of their bacterial or eukaryotic hosts also weighs against their easy detection in metagenomic approaches. Viral discovery can be greatly facilitated by simple filtration to enrich the smaller viral particles and by removal of contaminating bacterial and human nucleic acids using nuclease digestion that leave viral nucleic acids protected within their virion shells [5]. DenKnowledge of the human virome will allow the design of sensitive and specific tests to all human viruses using \u201cvirochip\u201d microarrays Despite the rapid progress being made toward deciphering the human virome, several roadblocks remain to its full characterization and utilization. Below is an abbreviated list of these problems and possible solutions.An individual's exposure to viruses is influenced by their geographic location, age, lifestyle, and even the season of the year, while their susceptibility to disease is affected by preexisting immunity and both viral and human genetics. Characterizing all human viruses will require casting a very wide nest and analyzing samples collected around the globe from a diverse collection of patients exhibiting a wide range of unexplained symptoms as well as carefully epidemiologically matched healthy subjects. Blood, respiratory secretions, feces, urine, skin swabs, and tissues may all be used for viral metagenomics . SamplesThe constituent species of the human virome will also vary over time due to ongoing zoonotic transmissions from animals whose own viromes will also be changing When will the human virome be completed? When, despite geographically diverse and intense sampling of heavily exposed and susceptible populations, the rate of \u201cnew\u201d human virus discovery falls to near zero, the human virome (at least as it exists at that time) may be considered near completion. The ongoing exchange of viruses between host species will require ongoing surveillance for zoonotic outbreaks of emerging viral pathogens.In order to acquire maximum value from the human virome, the role of newly characterized \u201corphan\u201d viruses in causing unexplained human diseases will need to be determined Anelloviridae or Picornaviridae certainly complicate studies of their pathogenicity as this may vary widely between close variants of the same species, as also seen for example between the numerous serotypes of enteroviruses or types of papillomaviruses The high prevalence in human plasma of chronic viral infections for whom there are currently no disease association such as anelloviruses and the flavivirus GBV-C, both among the earliest viruses identified by strictly molecular methods, indicates that the continued identification of human viruses causing low, rare, or no pathogenicity can be expected Identifying \u201cnew\u201d viruses through protein sequence similarities to those of already known viruses has proven its utility Several approaches may help identify such viral genomes. The repeated detection of the same unclassifiable sequence in multiple subjects with similar symptoms may indicate the presence of a novel viral family and provide genetic foothold sequences that can be extended in silico as the nucleus of larger contigs (overlapping contiguous sequences) or by laboratory means. Furthermore if viral genomes are enriched relative to contaminating host cell or bacterial DNA, randomly generated sequence reads are expected to more easily assemble into overlapping sequences and form contigs than reads from the much larger cellular genomes. Long contigs of unknown taxonomic origins derived from viral-genome-enriched nucleic acids mixture may therefore include viral segments from still uncharacterized viral families. Further improvement in the sensitivity and speed of bioinformatic methods to detect very weak viral protein motifs will also facilitate detection of highly divergent viviral sequences. Candidate viral ORFs may also be identified through in silico\u2013predicted protein folding to reveal similarities to common viral structures such as the capsid jelly-roll.Traditional approaches of virus detection such as the induction of cytopathic effects following inoculations of cell lines may also provide starting material for sequencing of viral genomes with little or no sequence similarities to the currently characterized animal virome. Expanding genome characterization of highly divergent viruses infecting diverse cellular hosts or found in environmental samples enriched for viruses such as sewage should facilitate the recognition of currently BLAST-resistant human viruses.Confirming the nature of highly divergent tentative novel viral families identified strictly by metagenomic means may involve genome copy number amplification or antigen expression following cell or animal inoculations, detection of host antibodies to putative viral antigens, and/or generation of viral-like particles by overexpression of their hypothetical capsid proteins .Finding a virus in feces or respiratory fluids does not guarantee that a virus replicates in this host's cells as it may be ingested from a dietary source or inhaled Picornavirales order (positive single-stranded picorna-like viruses), discriminant analysis was able to differentiate between viruses infecting plants, insects/nematodes, or vertebrates In silico approach to infer the phylum of the likely host of a viral genome involves the analysis of their di- and tri-nucleotides composition. After machine training with a set of distantly related viral genomes in the Reagents used for making libraries for deep sequencing may also be contaminated with reverse transcriptase sequences, and densovirus and circovirus-like sequences have been reported in nucleic acid purification columns Astroviridae, Parvoviridae, Picornaviridae, and Polyomaviridae families. As more people, from more wide spread geographic areas and exhibiting different symptoms, are sampled, the number of viral species, genera, and possibly even families shown to infect humans will continue to increase.The number of ICTV-approved viral families infecting eukaryotes is significantly greater than those infecting the more ancient and diverse prokaryotes. Approximately a third of eukaryotic viral families include species known to infect humans, also likely reflecting a sampling bias in favor of eukaryotic hosts, particularly humans A significant fraction of mild to extremely severe symptoms of likely infectious origin remains unexplained in both developed and developing countries including respiratory problems, diarrhea, and encephalitis As a result of more sensitive molecular methods, an increasing number of asymptomatic infections are also being recognized The availability of simple, open source software for effective de novo assembly and similarity searches optimized for viral discovery capable of handling an increasing data flow will greatly facilitate the entry of new groups into the field. Frequently updated and curated databases of complete and partial viral genomes that cover the full extent of known viral diversity, while minimizing redundancy of closely related variants and mislabeled sequences, will also accelerate new virus identification.Animal virus discovery is also poised for rapid advances and because disease causation can be more easily determined may rapidly lead to improved diagnostics, effective transmission control methods, and vaccinations. Characterizing more of the animal virome, whose diversity will dwarf that of human, will help identify the origins of many currently human viruses and the potential sources of future zoonoses. Given the recent expansion of arthropod-borne viruses infecting human and animals, the inoculation of mammalian cells with insect pools is likely to reveal numerous arboviruses with potential human tropism.Mining of eukaryotic genomes for viral sequences has revealed numerous viruses integrated into host chromosome germlines and the minimum age of many viral families While the human virome is a moving target due to zoonoses, the rate at which such animal viruses adapt to human\u2013human transmission is unclear"} +{"text": "Managing coral reefs for resilience to climate change is a popular concept but has been difficult to implement because the empirical scientific evidence has either not been evaluated or is sometimes unsupportive of theory, which leads to uncertainty when considering methods and identifying priority reefs. We asked experts and reviewed the scientific literature for guidance on the multiple physical and biological factors that affect the ability of coral reefs to resist and recover from climate disturbance. Eleven key factors to inform decisions based on scaling scientific evidence and the achievability of quantifying the factors were identified. Factors important to resistance and recovery, which are important components of resilience, were not strongly related, and should be assessed independently. The abundance of resistant (heat-tolerant) coral species and past temperature variability were perceived to provide the greatest resistance to climate change, while coral recruitment rates, and macroalgae abundance were most influential in the recovery process. Based on the 11 key factors, we tested an evidence-based framework for climate change resilience in an Indonesian marine protected area. The results suggest our evidence-weighted framework improved upon existing un-weighted methods in terms of characterizing resilience and distinguishing priority sites. The evaluation supports the concept that, despite high ecological complexity, relatively few strong variables can be important in influencing ecosystem dynamics. This is the first rigorous assessment of factors promoting coral reef resilience based on their perceived importance, empirical evidence, and feasibility of measurement. There were few differences between scientists' perceptions of factor importance and the scientific evidence found in journal publications but more before and after impact studies will be required to fully test the validity of all the factors. The methods here will increase the feasibility and defensibility of including key resilience metrics in evaluations of coral reefs, as well as reduce costs. Adaptation, marine protected areas, priority setting, resistance, recovery. Coral reefs are undergoing a major ecological disruption associated with climate change and human impacts that may forewarn changes among less sensitive ecosystems Ecological resilience can be defined as the capacity of an ecosystem to absorb recurrent disturbances or shocks and adapt to change while retaining essentially the same function and structure Despite gaps between resilience theory and field observations, the rapid rate of climate change disturbance has elevated demand for immediate solutions and management intervention among coral reef ecosystems By examining coral reef responses to disturbance across a range of past oceanographic and management conditions, site selection criteria for coral reef resilience can be developed that reflect how known disturbances and local environmental conditions have shaped present reef communities Here we develop empirical selection criteria for prioritizing coral reef management and conservation in the face of climate change. These criteria are intended to identify reefs with the greatest resilience to climate disturbance so that local managers can support the persistence of local coral reef ecosystems. We also identify key research priorities for coral reef resilience, based on levels of perceived importance and areas of debate within the coral reef scientific community.Among reef experts there was general agreement on combined resilience scores among factors , but theThe most important factors for recovery included high levels of coral recruitment to replenish denuded locations Identifying the top-ten ranked factors for resilience independently for perceived importance and scientific evidence, showed some overlap in factors, but produced a total list of 13 factors . From thTo calculate resilience scores for a given reef, each of the 11 key factors was given a 5-point Likert scale value to quantify its level of function and then weighted by its evidence score. These weighted factors were then averaged at each location to provide a single resilience score that could be readily compared among reefs . The fraTwo approaches have been applied to set management and conservation priorities for supporting the natural resilience of coral reefs: measure as many variables as possible and select sites with the best set of positive characteristics; or measure a feasible set of factors with scientific support for promoting resilience. While the former approach has been applied recently We compared our evidence-based rankings to rankings produced when using the 61-factor IUCN resilience assessment protocol While intuitively appealing, including large numbers of factors in a resilience assessment may be both impractical and ineffective. The inclusion of more factors in a given framework lowers the importance of each factor in the end result and serves to make surveys more resource intensive and costly, decreasing the likelihood they can or will be used in practice. Consequently, optimal resilience assessments should be tailored to a sufficient and demonstrated set of factors that will maximize the efficiency and utility of the approach. It is in this way that our evidence-based framework makes a major advance toward an optimal resilience assessment framework for coral reefs. Periodic updates that integrate new research across experts and evidence will serve to refine this approach in future. Further, once these factors are used to identify potentially resilient reefs, monitoring change over time will allow additional tests of the value of these factors in influencing reef resistance and recovery. The consensus arising from this study is that, while there are potentially many factors involved in coral reef ecosystem resilience, there are actually only a few for which there is evidence of strong effects. This builds on the developing consensus in the broader ecological literature that ecosystems are complex but frequently controlled by just a few strong variables operating at a given scale Future resilience assessments that reflect scientific understanding about coral reefs will involve new and unexplored areas of coral reef ecology. While some potentially important areas, like genetic rates of adaptation, lie beyond the immediate scientific horizon, our scoring scheme provides insight into factors that constitute current research priorities. To estimate this for resistance, recovery, and resilience, we calculated a research priority score individually for each factor. This score is based on the ratio of importance to evidence scores among the 31 baseline factors determined as important in the workshop and plotted against a scientific consensus score, based on the average coefficient of variation (CV) for perceived importance and empirical evidence from among survey respondents . This mePlotting research potential against scientific consensus revealed three key areas for future coral reef resilience research that can be partitioned into physical and biological processes . The phyEthics clearance was not necessary because only the opinions of the researchers involved in the workshop were canvassed. All researchers were aware that their responses were being used for research and individual responses were anonymized. Additional details are provided in To develop a list of factors relevant to supporting coral reef resilience, we brought together approximately 50 coral reef scientists to address 11 key questions concerning the resilience of coral reefs ; Text S1Text S1 and Results.(DOC)Click here for additional data file.Figure S1Multi-dimensional scaling of the responses to the (a) 31 and (b) top 8 factors evaluated for perceived effects of the factors on coral reef resilience.(TIF)Click here for additional data file.Figure S2Map of Karimunjawa Islands and associated coral reefs and the 43 sites studied for resilience to climate change disturbances. Sites were split evenly into three groups based on the 11 key evidence-based factors and colored green for high, yellow for medium, and red for low climate resilience. Values next to sites are the rankings based on the 11 key evidence-based factors, with the unweighted and full 61 IUCN criteria in parentheses. Closed circles are no-take areas and triangles are general use zones.(TIF)Click here for additional data file.Table S1Empirical evidence for factors relating to resistance and the evidence score (\u22125 to +5) based on evaluations from 28 coral reef experts.(DOC)Click here for additional data file.Table S2Empirical evidence for factors relating to recovery and the evidence score (\u22125 to +5) based on evaluations from 28 coral reef experts.(DOC)Click here for additional data file.Table S3Pair-wise matrix of the Pearson product correlation coefficients for comparisons of the resilience rankings produced for the study sites in Karimunjawa. Scores for individual factors were not scaled in the method highlighted in the first (our study of 31 factors) and 5th(DOC)Click here for additional data file."} +{"text": "Different elements of physical fitness in children have shown a declining trend during the past few decades. Cardiorespiratory fitness and motor skills have been associated with cognition, but the magnitude of this association remains unknown. The purpose of this review is to provide an overview of the relationship of cardiorespiratory fitness and motor skills with cognitive functions and academic performance in children up to 13 years of age. Cross-sectional studies suggest that children with higher cardiorespiratory fitness have more efficient cognitive processing at the neuroelectric level, as well as larger hippocampal and basal ganglia volumes, compared to children with lower cardiorespiratory fitness. Higher cardiorespiratory fitness has been associated with better inhibitory control in tasks requiring rigorous attention allocation. Better motor skills have been related to more efficient cognitive functions including inhibitory control and working memory. Higher cardiorespiratory fitness and better motor skills have also been associated with better academic performance. Furthermore, none of the studies on cardiorespiratory fitness have revealed independent associations with cognitive functions by controlling for motor skills. Studies concerning the relationship between motor skills and cognitive functions also did not consider cardiorespiratory fitness in the analyses. The results of this review suggest that high levels of cardiorespiratory fitness and motor skills may be beneficial for cognitive development and academic performance but the evidence relies mainly on cross-sectional studies. Fewer than 20% of children meet the recommendations for health enhancing physical activity: at least 60 minutes of moderate to vigorous intensity physical activity, preferably on every day of the week . FurtherConcerns have arisen as to whether today\u2019s lifestyle has a similarly negative effect on children\u2019s metabolic, cardiovascular, and brain health as it has on adults . PhysicaIt is hypothesised that a positive effect of physical activity on cognitive functions is partly caused by physiological changes in the body such as increased levels of brain-derived neurotrophic factor (BDNF), that facilitates learning and maintains cognitive functions by improving synaptic plasticity and acting as a neuroprotective agent, increased brain circulation and improved neuroelectric functionality . In animAs children are becoming increasingly sedentary and unfit, it is important to recognise effective interventions to improve metabolic, cardiovascular, as well as cognitive health. The purpose of the present review is to summarise the evidence of associations of cardiorespiratory fitness and motor skills with some important components of cognition and brain functioning that are linked to academic performance among children up to 13-years of age. Also relevant literature of associations of cardiorespiratory fitness and motor skills with academic performance is described. These data is accompanied by the existence of physical or motor activity studies that report measures of cardiorespiratory fitness and motor skills. In addition, factors that may confound these results are discussed.Inhibitory control is the core of the higher cognitive functions called the executive control. Inhibitory control refers to higher order mental processes that are related to the control of attention, behaviour and emotions and involves mainly the neural networks in the prefrontal and parietal cortices . InhibitThe Eriksen flanker task is one of the most used tests for inhibitory control among children in fitness studies. The flanker task requires the child to identify as quickly and accurately as possible the direction of the centrally positioned arrow in either congruent (e.g. < < < < <) or incongruent (e.g. < < > > >) conditions. The demands of inhibitory control can be further increased using incompatible conditions. That is, the child is instructed to answer the opposite direction from the direction that the centrally presented arrow is pointing.Evidence suggests that high levels of cardiorespiratory fitness is associated with a better response accuracy in the flanker task Table 1Table 1. Improved flanker task accuracy is accompanied by more efficient brain activation. Studies using event-related brain potentials (ERP) have shown that highly fit children have better inhibitory control and exhibit larger P3 amplitudes than unfit children Table 1Table 1. The ERN is an ERP component that has been related to erroneous responses in tasks that emphasise reaction time. Some evidence indicates that the ERN is related to known mistakes and is therefore a marker for error detection and compensation, that is, action monitoring . FurtherCross-sectional studies using functional magnetic resonance imaging technique (fMRI) indicate that children with high levels of fitness exhibit more efficient neural activation and cognitive adaptation during the flanker task compared with less fit children Table 1Table 1. Moreover, some evidence indicates that better response accuracy among highly fit children in comparison with unfit children is related to larger subcortical structure volumes . ChaddocAlso motor skills have been studied in relation to cognitive control. Among studies, the results are inconsistent and the magnitude of associations is dependent on the assessment of inhibitory control. Better manual dexterity has been associated with shorter reaction times in the modified day-night Stroop task whereas motor skills were not related to the reaction times during the Go/NoGo task Table 1Table 1. Working memory involves holding and manipulating the information in mind and relies on dorsolateral prefrontal cortex. Working memory involves also associative or relational memory. Relational memory involves learning about the relationship between two stimuli. In contrast, short term memory involves keeping information in mind without manipulating it, thus learning the properties of the stimulus (i.e. item memory). Short term memory does not need involvement of dorsolateral prefrontal cortex and it relies on ventrolateral prefrontal cortex . In the 2max percentile whereas the VO2max percentile among children in the control group slightly decreased. Children in the training group had a longer viewing time for displayed pictures during relational memory tasks that required the children to encode and correctly retrieve self-chosen sets of scenes and faces. In contrast, no differences in viewing time were observed during an item memory task that required retrieval of familiar faces without any need to relate them to a scene. Moreover, they found no differences in task accuracy or reaction times. Although no fitness differences were observed in response accuracy, these results indicated that increased cardiorespiratory fitness is related to more efficient hippocampal encoding. Evidence suggests that improved hippocampal encoding alone is not enough to elicit correct responses during relational memory tasks; high performance on tasks requires prefrontal cortex activation and efficient hippocampal prefrontal cortex connectivity amplitude compared with controls on post-intervention testing. The authors speculated that cardiorespiratory fitness-related increases in iCNV amplitude indicate an increased efficiency of anticipatory attention and pronounced top-down control. However, these results concerning the effect of cardiorespiratory fitness on item memory are in contrast to other studies showing no relationship between cardiorespiratory fitness and item memory. Therefore, improved item memory may be due to physical exercise per se, without a mediating effect of cardiorespiratory fitness.In addition, findings by The relationship between motor skills and memory has been investigated using mainly item memory tests. Both, a better whole body coordination and manual dexterity, have been associated with a better item memory Table 2Table 2. Academic performance refers to a child\u2032s success in school, measured by grade point averages or the child\u2019s meeting standards of various achievement tests. In addition to plain academic knowledge, grade point averages usually contain information about class attendance or classroom behaviour, whereas standardised tests rely on academic knowledge. Academic performance is affected by inhibitory control and working memory performance, as well as efficiency of other aspects of executive control .Cross-sectional studies suggest that higher cardiorespiratory fitness is related to better results and higher scores in standardised achievement tests and to hMost studies have addressed the relationship between cardiorespiratory fitness and academic performance using field-based exercise tests and cut-offs for cardiorespiratory fitness . These sIn contrast to studies concerning the relationships of cardiorespiratory fitness to academic performance that have used grade point averages and standardised achievement tests as measures of academic performance, associations of motor skills with academic performance include measures of grade point averages, estimated academic performance by a class-room teacher and reading skills. The evidence indicates that children with better overall perceptual motor abilities have better grade point averages than children with lower perceptual motor skills. Positive associations have also been found between manual coordination, static balance, asynchronous movement, and grade point averages in girls who were 10\u201311 years of age .Evidence from longitudinal studies indicates that only fine motor skills in young childhood predict improvement in reading and math skills in later years . HoweverIntervention studies aimed at improving motor skills have documented a weak positive connection between motor skill training and improved academic performance and reading skills among school-aged children , but theFurthermore, The findings presented in this review suggest that both higher levels of cardiorespiratory fitness and better motor skills are linked to a higher cognitive capacity and a better academic performance. However, cardiorespiratory fitness and motor skills may be differentially related to cognitive functions. Higher levels of cardiorespiratory fitness are mainly associated with a higher performance in tasks that require rigorous attention allocation and the use of attention resources in order to prevent undesirable results (Buck et al., 2008; Better motor skills have been related to a better performance in various cognitive tests including tasks for IQ, attention, inhibitory control, item memory and academic performance . FurtherRegardless of relatedness of cardiorespiratory fitness and motor skills, results summarised in the present review emphasise that children should engage in various physical activities including both quantitative and qualitative aspects to contribute to cognitive development. That is, physical activity should incorporate with activities improving cardiorespiratory fitness and activities that enhance motor skills. However, this conclusion is mainly drawn from cross-sectional studies and, therefore, it cannot be concluded that exercise training to increase cardiorespiratory fitness and motor skills actually contributes to enhanced cognitive performance in children. In addition, this mainly cross-sectional data may be confounded by genetic factors, maturity status and other factors.Although cardiorespiratory fitness and motor skills evidently play a role in cognition and academic performance, the extent to which these differences are mediated by genetic or biological factors is unclear. It is known that genetic factors can explain approximately 50% of cardiorespiratory fitness and moreIt is an oversimplification to suggest that only cardiorespiratory fitness or only motor skills are the important determinants of cognitive functions in children. In fact, the evidence suggests that cardiorespiratory fitness and motor skills are positively correlated, suggesting that children with high cardiorespiratory fitness also have better motor skills than those with low fitness . In thisIn the point of view of public health, the findings reviewed here are of great importance. The number of obese children continues to increase , and a gThe evidence summarised in the present review suggests that compared to less fit children, highly fit children have larger subcortical brain structures, more efficient brain activation and neuroelectric efficiency during cognitive tasks, superior inhibitory control, working memory, attention and better academic performance. Similarly, children with better motor skills show better inhibitory control, attention capacity and academic performance than children with poorer motor skills. Thus, the evidence suggests that both cardiorespiratory fitness and motor skills play an important role in cognitive development during childhood. It is strongly suggested that children are allowed to get appropriate stimulation from the environment via physical activities in order to improve the functions of their cardiovascular and neuromuscular systems. Besides the known cardiometabolic benefits, developmentally appropriate physical activity may improve brain health and function. There is a need for multidisciplinary studies that assess the interdependent relationships of cardiorespiratory fitness and motor skill with cognitive functions in cross-sectional and longitudinal settings."} +{"text": "Treatment changes are typical in epilepsy because of the chronic nature of the disease and common problems with treatment, most typically inadequate seizure control and unacceptable adverse effects. Randomised trials in epilepsy often adopt a pragmatic approach to treatment changes, in order to cater for patient needs and mirror the real-life experience of patients. Trial patients may experience multiple treatment changes taking a variety of forms, including addition of alternative treatment(s), switching to other treatment(s) and complete withdrawal from all treatment.Primary analysis of trial data is usually based on the principle of intention to treat (ITT), which ignores such treatment changes and thus avoids any selection bias that may be introduced by changes from randomised treatment. ITT however only allows estimation of the effectiveness of treatment, rather than the true efficacy of treatment, which is of particular interest to patients and clinicians alike in this setting.Methods such as per protocol or as treated analyses are commonly implemented to estimate causal effects, but are often biased because treatment changes are typically associated with prognostic factors. There exist alternative statistical methods to estimate causal effects of treatment whilst avoiding such bias, such as the rank preserving structural failure time model (RPSTFM) and inverse probability of censoring weighting (IPCW) models, but these methods are not well known and require certain assumptions. I will discuss the challenges of adjusting for treatment changes in epilepsy and demonstrate the RPSTFM and IPCW methods, discussing their advantages and disadvantages in this setting."} +{"text": "The identification of disease causing rare variants is becoming possible with the advent of next generation sequencing (Nejentsev et al., An intuitive understanding of the underlying dynamics of the evolution of rare variants can be gained by considering the coalescent trees that are likely under models of population growth. Population growth results in trees where coalescent events are rare in the recent past and tend toward a more star like topology Wakeley, , owing tThe picture with selection is less intuitive, but as population sizes increase, drift becomes less dominant and selection is more effective. Gazave et al. providesA contrasting point between these studies is the assumption of independence of the deleterious mutations in Kim and Schuster when calFinding disease causing rare variants or even risk factors in humans remains difficult, in part, owing to recent expansion. Larger sample sizes, while considering nonindependent mutations drawn from the DFE, is a promising way forward. Currently, the sample sizes required seem huge, but continued advances in sequencing technology they are increasingly feasible - indeed, we can expect to have samples sizes comparable to effective population size in the near future. However, the coalescent traditionally requires that sample size be much smaller than effective population size and extensions or behavior of the coalescent with violations would need to be considered. Wakeley and Takahashi investig"} +{"text": "The discovery of leptin has led to the elucidation of a robust physiologic system that maintains fat stores at a relatively constant level. Leptin is a peptide hormone secreted by adipose tissue in proportion to its mass. This hormone circulates in blood and acts on the hypothalamus to regulate food intake and energy expenditure. When fat mass falls, plasma leptin levels fall stimulating appetite and suppressing energy expenditure until fat mass is restored. When fat mass increases, leptin levels increase, suppressing appetite until weight is lost. By such a mechanism total energy stores are stably maintained within a relatively narrow range.Recessive mutations in the leptin gene are associated with massive obesity in mice and some humans. Treatment with recombinant leptin markedly reduces food intake and body weight. The low leptin levels in patients with leptin mutations are also associated with multiple abnormalities including infertility, diabetes and immune abnormalities all of which are corrected by leptin treatment. These findings have established important links between energy stores and many other physiologic systems and led to the use of leptin as a treatment for an increasing number of other human conditions including a subset of obesity, some forms of diabetes including lipodystrophy and hypothalamic amennorhea, the cessation of menstruation seen in extremely thin women. Identification of a physiologic system that controls energy balance establishes a biologic basis for obesity and further establishes links between leptin and numerous other physiologic responses. Recent studies have explored the relationship between leptin and the reward value of food. In addition, new methods for identifying neurons activated by leptin and other stimuli have been developed."} +{"text": "Historical proven wood species have no reported adverse health effect associated with its past use. Different historical proven species have traditionally been used to manufacture different wooden food contact items. This study uses survey questionnaires to assess suppliers\u2019, manufacturers\u2019, retailers\u2019 and consumers\u2019 (end-users\u2019) preferences for specific wood species, to examine the considerations that inform these preferences and to investigate the extent of awareness of the chemical benefits and chemical hazards associated with wooden food contact material use.Through the combined use of a cross sectional approach and a case study design, 25 suppliers, 25 manufacturers, 25 retailers and 125 consumers (end-users) of wooden food contact materials in four suburbs in Kumasi Metropolitan Area and Ashanti Akyim Agogo in the Ashanti Akyim North District of the Ashanti Region were administered with closed ended questionnaires. The questionnaires were prepared in English, but local language, Twi, was used to translate and communicate the content of the questionnaire where necessary.Suppliers\u2019, manufacturers\u2019 and retailers\u2019 preferences for specific wood species for most wooden cookware differed from that of consumers (end-users). But all respondent groups failed to indicate any awareness of chemical benefits or chemical hazards associated with either the choice of specific wood species for specific wooden cookware or with the general use of wooden food contact materials. The lack of appreciation of chemical benefits or hazards associated with active principles of wooden cookware led to heavy reliance of consumers (end-users) on the wood density, price, attractive grain pattern and colour or on the judgement of retailers in their choice of specific species for a wooden cookware.This study contributes some practical suggestions to guide national policy development on improvement in quality of available wooden food contact materials in Ghana. Wooden food contact materials serve important functions in every aspect of food preparations and, collectively, constitute the most frequently utilized cookwares in the Ghanaian home. Ghana has a rich variety of trees whose wood possess unique structural, physical and mechanical properties that allows for the manufacture of different wood based food contact materials including mortar, pestle, grinding bowl, grinding pestle, roller, chopping board, banku ladle and wooden spoon. Banku iSome wood species are valued for the curative effects of its phytoconstituents or extractives in ethnomedicinal practices. And somMost species that are new entrants into wooden cookware have scant historical records, unknown phytoconstituent bioactivity and uncertain chemical safety and their use for food contact purposes have potential implications for consumer food safety. In all cases, the reasons for manufacturers\u2019 choice of the species are yet to be clearly identified. However, there is suggestive evidence that wood species are chosen by manufacturers with little or no cognizance to the chemical benefits or to the toxicological suitability for food contact uses and that end users choice of manufactured products largely influenced by species\u2019 physical and aesthetic properties also supplants concerns over food quality and food safety. HoweverA comprehensive assessment of factors that determine wood species suitability for specific food contact uses was done using a survey research on a representative community sample of manufacturers, suppliers, retailers and consumers (end-users) of wooden food contact materials. Critical questions that the survey sought to answer included: 1. what are the perceived types of wooden food contact materials available on the Ghanaian market? 2. What are consumers\u2019 (end-users\u2019), sellers\u2019, suppliers\u2019 and manufacturers\u2019 perceptions of wood type suitability for each available food contact item? 3. To what extent do chemical benefits and/or chemical hazards of species phytoconstituents determine indigenous wood type suitability for food contact use? Answers to these questions will clarify the underlining reasons that dictate the choice of specific wood type for the manufacture, sale and utilization of specific food contact material.This study documents the type of wooden food contact materials available in Ghana, assesses consumers\u2019 (end-users\u2019), sellers\u2019, suppliers\u2019 and manufacturers\u2019 perceptions of wood type suitability for each specific food contact material, enhances understanding of the factors predictive of wood type use for food contact materials, investigates the extent to which consumers (end-users), sellers, suppliers and manufacturers are aware of the chemical benefits and chemical hazards associated with the use of these wooden cookware and contributes some practical suggestions to guide national policy development on improvement in quality of available wooden food contact materials in Ghana.The study was carried out in the Kumasi Metropolitan Area and Ashanti Akyem north District both of the Ashanti Region in Ghana, from January to May 2007. The study focused on four suburbs in Kumasi Metropolitan Area and one surburb in the Ashanti Akyim North District where most of the wooden cookware are manufactured or sold. A map of the general study area is provided by FigureCross sectional approach was adopted in conducting this research and the case study design was used because a contemporary phenomenon within real life context was being investigated. Data for the study were collected from both primary and secondary sources. Secondary data were obtained from: journals, World Wide Web, textbooks and other publications on the subject matter. Primary data were obtained from suppliers, manufacturers, retailers and consumers (end users) of different wooden cookware using closed ended questionnaires and observations.A combination of purposive and stratified sampling techniques was used for this work. Purposive sampling technique was used to select five suburbs for the study because these are the areas well noted for the sale of the wooden cook ware. The survey respondents were stratified into manufacturers, suppliers, retailers and consumers to gain an in-depth understanding of the research topic. Suppliers purchase and sell manufactured items directly to retailers for a profit. Suppliers, in this context, do not usually transact direct business with customers as retailers do.Since a list of the respondents (sample frame) from which a sample can be drawn, was not available a convenient sample size of 200 was selected: 25 suppliers, 25 manufacturers, 25 retailers and 125 consumers. Snow balling technique was used to locate the manufacture of the wooden cookware. The consumers were located at the point of sale. After pre-testing of the questionnaires, a total of 200 respondents were administered with closed ended questionnaire.The questionnaires were prepared in English, but local language, Twi was used to translate and communicate the content of the questionnaire where necessary since majority (about 80 percent) of the respondents were more comfortable with the local language. For interviews involving participants who could not read, the researcher asked questions with assistance from a translator and completed the survey questionnaire on their behalf with their proffered answers. Participants who needed no assistance completed the survey questionnaire themselves. The sex of participants was not noted. Each participant was asked by the questionnaire to provide personal information including age and area of residence. Participants were also asked to indicate whether or not they can identify wood species by visual inspection. Other survey questions included food contact items purchased, preferred wood species for purchased food contact item and the reason for choice of the species.There was a non-response rate of 11.5% each from the suppliers and manufacturers even though it was explained to them that there was no legal implication of the research. It was observed that the suppliers and manufacturers were afraid to disclose their sources of wood probably because of illegal felling of trees. Fifteen percent of the consumers did not have knowledge of the type of wood species used for the various cookwares and therefore were not included in most of the analysis.This study did not directly identify wood species. Preferred species provided by consumers (end-users), retailers, suppliers and manufacturers were reported verbatim without additional scientific identification or verification by researchers. While this approach is clearly a limitation, the study nonetheless provides a window into the diverse considerations that concerned parties make prior to wooden food contact material purchase and use. Wood type identification using current scientific technology is one of the key recommendations of this study.The nature of the research necessitated a combination of both qualitative and quantitative techniques to analyze the data. The data were analyzed using the Statistical Package for Social Science (SPSS) software and data were presented using cross tabulation, charts and graphs.The eight different wooden food contact materials identified in the market during the survey were mortar, pestle, grinding bowl, grinding pestle, roller, chopping board, banku ladle and wooden spoon Figure. As obseAs shown in TableSpecies identification is the necessary first step towards the potential use of a specific wood for food contact purposes. But species identification hinges primarily on the use of the physical senses to distinguish between species using prior knowledge of unique species features including distinctive colour, texture and smell of the wood. Therefore, manufacturers, suppliers, retailers and consumer perception of self-acquired knowledge essential for the identification of indigenous wood species were assessed. As shown, in TableThe acquisition of the appropriate indigenous knowledge necessary for the identification of wood species may be time-dependent. To examine the dependence of indigenous wood knowledge acquisition on time, the age of respondents and their self-reported ability to identify wood species were correlated. As expected, consumers (end-users)\u2019 knowledge of wood species increased with age as most respondents 31%) aged 46 and above demonstrated substantial indigenous knowledge of wood \u2019 perceptions on wood type suitability for food contact use. Manufacturers rated durability (41%) more than any of the other factors including consumers\u2019 (end-users\u2019) demand (32%), availability (9%), cost (9%), attractive grain pattern 5%) and ease of use (5%) , manufacturers (27%) and retailers 36%) rated Papao (Afzelia africana), a species that possesses low shrinkage and very good durability, as the best of the 15 wood species historically used to make mortars and Wanton (Morus mesozygia) are the two preferred species for the manufacture of pestles Table. Esia by choosing Mahogany (47%) as the best species Table. The choA grinding pestle is a short dumbbell-shaped item traditionally used together with a grinding bowl to blend pepper, tomatoes and onions sauce through the simple rhythmic movement of the wrist Figure. Due to Rollers are cylindrical shaped wood with handles at each end used primarily to blend and flatten flour dough Figure. IdeallyThe cutting or chopping boards constitute one of the most ubiquitous wooden cookware in the kitchen made from any reasonably sized piece of wood Figure. ApparenBanku ladles are large spoon-shaped wood used primarily to stir and knead cornmeal during the preparation of the local banku meal Figure. AlthougTo permit efficient turning of the banku ladle and effective kneading of the cornmeal during food preparations, lighter but firmer wood is preferred. Unanimous agreement was obtained from suppliers (50%), retailers (50%) and consumers (end-users) 43%) that Wawa (Triplochiton scleroxylon) best satisfies the additional criteria enumerated in Figure% that WaThe relatively small sizes of the ubiquitous wooden spoons suggest that they could, in principle, be crafted from any reasonably-sized piece of wood Figure. And thiIn this study, a comprehensive assessment of the factors that determine the suitability of specific indigenous wood species for specific food contact materials was conducted using a survey research on a representative community sample of manufacturers, suppliers, retailers and consumers (end-users) of wooden food contact materials. This approach was reasoned to comprehensively elucidate the underlining reasons that dictate the choice of specific wood type for the manufacture, sale and utilization of specific food contact material.The critical first step towards the potential use of a specific wood for food contact purposes is species identification. Wood species identification is important because: the intrinsic suitability of any wood for food contact purposes is species-dependent; the dose and types of beneficial or deleterious wood phytoconstituents that may augment or preclude its food contact use are species-specific; the commercial values of wooden food contact materials are species-dependent. The reason for which you need reliable identifications in order to make conclusions.The reliance of species identification on acquired indigenous wood knowledge encompassing specific colour, distinctive texture, unique grain pattern and characteristic smell of species suggest guess-work is involved in the distinction between closely related species or in the identification of different species that have similar physical features. In addiFor all types of food contact materials, species availability was found to be a key factor that determines the range of marketable products. But species availability has been adversely affected by rapid deforestation and the scarcity of some species including Odum (Chlorophora excelsa), Mahogany , and Sapele (Entandrophragma cylindricum) has placed a price premium on them and has also necessitated the use of alternatives species including Teak (Tectona grandis) and Kyere (Pterygota macrocarpa). But it Although the application of these suitability criteria, on a historical basis, by manufacturers and consumers (end-users) has successfully established distinct species of wood in current use for food contact purposes, a common observation is that none of the enumerated suitability factors included potential chemical benefits or likely chemical hazards of wood phytoconstituents. This observation emphasizes the notion that the choice of wood for the manufacture of food contact materials in Ghana is dictated primarily by reasons other than the chemical benefits or the chemical hazards presented by wood phytoconstituents. Despite increasing recognition of the possible chemical transfers from wood to food-17, respThe observation that Danta (Cistanthera papaverifera) and Mahogany are the only two species used for the manufacture of all surveyed food contact items is particularly interesting because neither the strength nor the durability of both species are exceptionally high to justify the observed multiple usage. It is reasonable to assume that the phytoconstituents of Mahogany , valued for its myriad curative properties in ethnomedicinal practices, likely accounts for its preferences for all food contact items. In fact, Mahogany -derived bioactive extracts are produced and marketed nation-wide as dietary supplements.The stem-bark extracts of Mahogany contain alkaloids, saponins, tannins, flavonoids and limoBut given the general lack of awareness of respondent groups to potential chemical benefits of species, it is also doubtful that the preferences for Mahogany for multiple items are informed by its numerous medicinal activities. This notion is perhaps supported by the additional choice of Danta (Cistanthera papaverifera), a species with no known or widespread medicinal value, for multiple uses. On an item-by-item basis, banku ladle and wooden spoons have a shared utility, namely, their use for prolonged periods at high temperatures. As a consequence, both items can potentially transfer high quantitative levels of bioactive phytochemicals to food at the earlier times of use (mostly between the first and the third time of use). Banku ladles are used mostly in aqueous environments and at temperatures high enough to facilitate the transfer of polar phytochemical functionalities to food. SimilarIt is also interesting to note that grinding pestles undergo significant attrition and wear during use and may likely leave residual ground wood in the food during contact. Wood phytoconstitutuent migrants resulting from the grinding action of the grinding pestle are probably responsible for the impartation of the unique taste to ground pepper and tomato sauce prepared from the combined use of grinding pestle and grinding bowl. Published reports on the hygienic suitability of wood as cutting/chopping board are contradictory with some studies suggesting comparatively higher bacteria accumulation and retention even after cleaning-44 and oAlthough respondent groups failed to indicate, overtly, any knowledge of possible wood phytoconstitutuent migration to food, the general practice of \u201cpriming\u201d new food contact materials seems to contradict their stated perceived lack of knowledge in this area. New food contact items are \u201cprimed\u201d prior to use by immersion in hot water and/or thorough washing with hot water followed by a purposeful disposal of the bits of food that makes first contact with the wood. People \u201cprime\u201d their utensils to reduce the amount of chemical compounds that transfers to foods at the initial stages of use. \u201cPriming\u201d is by default a practical demonstration of possible phytoconstituent migration to food. Implicit in this general practice is the recognition that some potentially toxic or unpleasant chemical substances might transfer from wood to the food at higher doses during the early stages of use of the food contact item. And that the practice of \u201cpriming\u201d reduces the concentrations of such chemical substances to low, possibly non-toxic, levels prior to regular use. This observation is demonstrated by the reduction in the initial \u201cbitter\u201d taste that wood phytoconstituents impart to the food that makes direct contact with the wooden cookware. Despite its high prevalence in Ghana, the practice, however, lacks direct report or reference in the literature.The transfers of chemicals from wood to food represents an area in which published research information is meager and thus, the nature and pattern of such chemical migration remain largely undescribed. However, mechanistic sketches of phytochemical migration from wood to food,53 can bFor a start, food contact item regulatory bodies and researchers in Ghana can initiate biochemical research that uses molecular features including cellular wood anatomy to accurately identify all species in current use for food contact purposes,64-66. TIn the long term practical sense, the dependence of wood species use on oral transmission of historical knowledge is unacceptable because cultural and economic acculturation pressures from modern society may endanger this practice. Regulatory bodies in Ghana can document and preserve this traditional historical knowledge in a curated database, cataloguing each species\u2019 distinctive features and providing a comparative perspective on differences in structural features between species, the biological and chemical differences within and between species as well as specifying the potential for chemical hazard or the likely health benefits on a species-by-species basis. The adverse effect of deforestation on species availability suggests that the use of chemically safe and beneficial alternative species from sustainably managed forest should be encouraged by regulatory bodies. To facilitate informed purchasing decision by consumers (end-users), regulatory bodies must insist that retailers label each food contact item offered for sale with both the indigenous and scientific names of species.Coupled with the comprehensive scientific analyses already suggested, this approach will provide a scientific qualitative knowledge base that will safeguard the indigenous knowledge on old and new wood species that are chemically safe and phytochemically beneficial for food contact uses and will permit the seamless translation of indigenous knowledge consistent with scientific understanding of food safety among wooden food contact items.The continued use of specific wood species for crafting unique food contact items is dictated by historical precedents, distinct species physical and aesthetic features and by species availability. The observed lack of consumer appreciation for potential chemical benefits and/or likely chemical hazards via the possible transfer of wood phytoconstituents to food offers an interesting dynamics that need to be addressed by all concerned parties.The authors declare that they have no competing interests.JKM analyzed the collated data and prepared the final manuscript. EA and DA developed and designed the study. GOA conducted field survey work and collected the data. All authors read and approved the final manuscript."} +{"text": "Several studies on pediatric and adult population proposed measurment of optic nerve sheath diameter (ONSD) as a noninvasive marker of increased intracranial pressure (ICP). Only few studies were made correlating MRI measurment of ONSD with ultrasound measurment of ONSD. Overall lower standard values of the ONSD for ultrasound measurment compared to MRI measurment were found. That might be atribbuted to variable interpretation of ultrasound anatomy \u2013 what are we really measuring?We performed a proof of concept study to evaluate the accuracy of measurments of the ONSD for contrast enhanced ultrasound (CEUS) and magnetic resonance imaging (MRI). Second generation contrast agent was used to enhance the ultrasound recognition of relevant anatomy and conduct transbulbar ONSD measurments.Nine healthy volunteers were examined with CEUS with transbulbar approach and MRI. CEUS and MRI examinations were recorded on the PACS system. Measurments of the ONSD were performed on the collected images using DICOM viewing software . Statistical analysis was performed and included the calculation of the agreement of measurment between both methods. Statistical software was used .Good correlation of measurment values was found between CEUS and MRI , MRI being regarded as a gold standard.Using CEUS significantly aids the identification and recognition of the relevant structures sorrounding the optic nerve. Measuring a small structure as ONSD with ultrasound is a demanding task. By using CEUS the exact measuring points can be quickly and easilly identified, making a measurment more exact using transbulbar sonography on living subjects. The measurment can be quickly performed, can be repeated, the introduced contrast agent is nontoxic"} +{"text": "Splitting describes fragmentation of conscious experience that may occur in various psychiatric disorders. A purpose of this study is to examine relationships between psychological process of splitting and disturbed cognitive and affective functions in schizophrenia and borderline personality disorder (BPD).In the clinical study, we have assessed 30 patients with schizophrenia and 35 patients with BPD. The symptoms of splitting were measured using self-reported Splitting Index (SI). As a measure of semantic memory disorganization we have used verbal fluency test. Other psychopathological symptoms were assessed using Health of the Nation Outcome Scale (HoNOS).Main results show that SI is significantly higher in BPD group than in schizophrenia, and on the other hand, verbal fluency is significantly lower in schizophrenia group. Psychopathological symptoms measured by HoNOS are significantly higher in the BPD group than in schizophrenia. Significant relationship was found between verbal fluency and the SI \u201cfactor of others\u201d in schizophrenia patients.Processes of splitting are different in schizophrenia and BPD. In BPD patients splitting results to mental instability, whereas in schizophrenia the mental fragmentation leads to splitting of associations observed as lower scores of verbal fluency, which in principle is in agreement with Bleuler\u2019s historical concept of splitting in schizophrenia. Splitting reflects shifts of mind related to a consciously experienced conflict of opposing mental forces. In principle it describes fragmentation of conscious experience that is typically related to long-term or acute stress that significantly disturbs self-concept, identity, memory and perception of the external world In schizophrenia the term splitting was developed by Bleuler These alterations on mental level consequently may be linked to great and abrupt changes in patterns of neural activity that may dissociate, or split off, certain external and internal stimuli and information out of awareness, which may lead to distinct states of divided consciousness With respect to recent findings a purpose of this study is to examine relationships between psychological process of splitting and disturbed cognitive and affective functions in schizophrenia and BPD.The participants were recruited from regular daily outpatients treatment programs for schizophrenic and BPD patients at the Psychotherapeutic and Psychosomatic Clinic ESET in Prague. All participants signed informed consent and the study was approved by Charles University ethical committee. In the study were included only patients who had not compromised capacity and ability to consent. This ability was confirmed by clinical data about the patients and specific written statement regarding each participant by his/her psychiatrist. Each included participant was able to consider his/her participation and no one was included in the study based on agreement of legally authorized representative consented on the behalf of a participant.The participants had diagnosis of schizophrenia or borderline personality disorder. Exclusion criteria were organic illnesses involving the central nervous system, substance, and/or alcohol abuse and mental retardation (IQ Raven lower than 90) With respect to current theoretical concepts and empirical data we have tested relationship between splitting based on Splitting Index score The symptoms of splitting were measured using self-reported Splitting index (SI) Other psychopathological manifestations in both groups of patients were measured using Health of the Nation Outcome Scales (HoNOS) As a measure of semantic memory disorganization, which is very close to Bleuler\u2019s concept of mental fragmentation, we have used verbal fluency test Statistical evaluation of the results of SI and other psychometric measures included descriptive statistics, Mann-Whitney test for independent samples and Spearman correlation coefficients. The non-parametric analyses were preferred because SI data have not normal distribution. All the methods of statistical evaluation were performed using the software package Statistica version 6. To prevent Type II error which would disable to reject null hypothesis that the measure of splitting is not linked to verbal fluency and psychopathological symptoms we performed Power Analysis and assessed the effect sizes characterizing differences between means and correlation coefficients.Results show significant differences in scores of splitting, verbal fluency and psychopathological symptoms measured by HoNOS between BPD and schizophrenia groups that were compared using Man-Whitney test . Mean scOn the other hand score of verbal fluency was significantly lower in schizophrenia group. In both assessments of HoNOS, for external evaluators and for self evaluation, the BPD group scored significantly higher in means of total scores. In the power analysis we have tested significant differences which show that all differences between means have strong effect size (r\u200a=\u200a0.5 or higher; Results also show significant Spearman correlation coefficients characterizing relationships between splitting, verbal fluency and psychopathological symptoms measured by HoNOS in both samples . Very siMain results of this study indicate significant differences in splitting, verbal fluency and psychopathological symptoms between schizophrenia and BPD patients. These findings show significantly higher level of splitting measured by SI in BPD patients compared to schizophrenia. On the other hand schizophrenia patients show significantly lower scores of verbal fluency most likely as a consequence of cognitive disorganization which in principle is in agreement with Bleuler\u2019s historical concept of splitting in schizophrenia Recent findings also show that impaired verbal fluency is associated with psychomotor slowness These typical neurophysiological changes might reflect typical differences related to splitting in schizophrenia and BPD based on psychological mechanisms of defense against unacceptable affective impulses In summary, the results show that the process of splitting has different forms in schizophrenia and BPD. In BPD patients splitting results to mental instability manifested as shifts in emotional perception of objects, other persons and the self, which are linked to increased mental tension and excessive prefrontal and amygdala activation. This specific form of splitting that occur in BPD is not typically present in schizophrenic patients, which is in agreement with the results indicating that SI score as a measure of borderline splitting is higher in BPD than in schizophrenia patients. On the other hand in schizophrenia the mental fragmentation leads to splitting of associations observed as lower scores of verbal fluency which in principle is in agreement with Bleuler\u2019s historical concept of splitting in schizophrenia"} +{"text": "We conducted a survey of 928 New York City area residents to assess knowledge and worry about AIDS and SARS. Specific sociodemographic groups of persons were more likely to be less informed and more worried about contracting the diseases. Informed behavior change may be needed to control disease transmission. Negative public reactions, such as stigmatizing persons at risk for the disease, may greatly hamper prevention and treatment efforts . AIDS may be considered the prototype of an emerging infectious disease. While AIDS has received considerable public attention since the early 1980s, the strong emotions associated with it create the possibility of nonrational information processing. The stigmatization of persons with or at risk for AIDS has persisted despite public information about the disease who lived in metropolitan New York City (NYC). The cohort was recruited through a random digit dial telephone survey conducted from March 25 to June 25, 2002. Additional details on the sampling are provided elsewhere . A strong relationship existed between being very worried about both diseases. Of the respondents who reported being very worried about AIDS, 16% reported also being very worried about SARS; 5% of the respondents who were not very worried about AIDS were very worried about SARS (p = 0.016).Finally, we examined the relationships between being informed and worried about contracting AIDS/SARS. These analyses were confined to respondents who reported having some information about AIDS/SARS; respondents who reported that they had not heard about the diseases were not asked the follow-up questions. In these respondents, no relationship between having heard and being worried about getting the diseases was shown.Given the widespread disparities in health among racial/ethnic and socioeconomic groups in the United States (The data from this study were collected in a major city of an industrialized country and should not be generalized to developing and transitional countries. Nevertheless, if obtaining and evaluating information is adversely affected by factors such as low education level, low income, and ethnic minority status, then properly informing the public may be particularly difficult in developing and transitional countries. The epidemiology of AIDS and SARS has been very different in NYC (>58,097 AIDS cases [The limitations of this study included using single items to measure knowledge and worry about AIDS and SARS and the standard limitations of telephone surveys, e.g., inability to contact households without telephones, moderate refusal rates. However, this study strongly suggests that adequate public knowledge and emotional assessment may be critical to control these diseases.Our data suggest that socioeconomic class and race/ethnicity factors may help shape public understanding of emerging infectious diseases. Targeted communication to different population subgroups may be required to achieve public understanding of an emerging infectious disease."} +{"text": "Pollutants in the ambient air result in personal exposure, target tissue exposure and health responses. Ambient air quality measurement using various indicators is important in exposure assessment. Establishment of standard air quality monitoring networks helps in scientific investigation of health effects of air pollution, national and international reporting and to enforce regulations.Particle mass concentrations alone might not be sufficient to study particle related health effects. Additional health relevant particle data including ultra fine particles and/or specific toxic constituents are also needed. Quality assurance and control by regular calibrations and parallel measurements are of crucial importance for comparability of sites and establishment of trends. The SAPALDIA cohort study relies on the air quality monitoring network established in Switzerland for ambient air quality data.Data from fixed site monitors and other sampling stations are used to create exposure models using dispersion, statistical and GIS parameters to arrive at individual exposure estimates. This air pollution exposure assessment aids epidemiological environmental health research. Evidence based on scientific research helps in the formulation of air quality regulations and standards. Good networks which provide consistent long term data from varied environments are needed with frequent collaborations among monitoring agencies and scientific disciplines."} +{"text": "Saimiri sciureus) with Nipah virus to determine the monkeys\u2019 suitability for use as primate models in preclinical testing of preventive and therapeutic treatments. Infection of squirrel monkeys through intravenous injection was followed by high death rates associated with acute neurologic and respiratory illness and viral RNA and antigen production.We infected squirrel monkeys ( Henipavirus. Reported human death rates varied from 40%\u201392% (Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus that was first identified in Malaysia and Singapore in 1999 as an experimental model of NiV infection.Several species of fruit bats of the genus We selected these New World monkeys because of their availability, reliability as a primate model with which to study infectious diseases for NiV nucleoprotein expression as described , with development in the animals of anorexia, weight loss, and depression . These clinical signs progressed for several hours and were associated with hyperthermia and an acute respiratory syndrome characterized by dyspnea and hyperventilation. During the course of the disease, the animals became more obtunded and had uncoordinated motor movements, ending, in some instances, with a loss of consciousness and coma . AlthougNiV-specific RNA was detected in various organs only in intravenously infected animals , demonstMonkeys showed mild histologic lesions, including the inflammation most obvious in the lung parenchyma , panel A3 PFU of NiV delivered intranasally was probably insufficient to induce infection in monkeys. Although NiV-specific antibodies were detected by ELISA in animals dying from the infection, sufficient titers of neutralizing antibodies did not develop in these monkeys and they were therefore not protected. These findings suggest the protective role of high neutralization titers in NiV infection. Our results agree with other studies of NiV infection that reported most human patients with fatal NiV infection had IgG and IgM in their serum and cerebrospinal fluid (NiV-specific immunoglobulin (Ig) M responses were observed starting from 8 dpi for all monkeys except in groups H and I . This fiOur results suggest some similarities of NiV pathogenesis in humans and squirrel monkeys, including development of clinical signs, progression of infection, and humoral immune response. We conclude that the squirrel monkey can be used as an animal model for experimental studies of NiV infection, and these results pave the way for further study."} +{"text": "One of the most celebrated results in neuroscience is the observation that simple cells in the visual cortex are tuned to the orientation and polarity of edges in visual stimuli . While oPerhaps the most influential functional theory of simple cell tuning is sparse coding . AccordiWe solve both of these problems, simultaneously, by proposing that simple cells provide a positive sparse coding of natural images. This is similar to 'classical' sparse coding but with positive firing rates alone. We find that positive sparse coding neurons have both orientation tuning and polarity tuning Figure , Table 1This functional theory leads naturally to a spiking neural network implementation for simple cells, because spiking network models necessarily have positive firing rates. We find that a network of tightly balanced leaky integrate-and-fire neurons can produce spike trains that optimise our positive sparse coding cost function. In this way, we can marry spiking constraints with neural function to understand the orientation and polarity tuning of simple cells."} +{"text": "Canis lupus dingo and hybrids) scats were assessed alongside additional information on predator and prey distribution, dingo control effort and predation rates to evaluate whether or not the observed frequency of threatened species in dingo scats warrants more detailed investigation of dingo predation risks to them. Three small rodents were the only threatened species detected in <8% of dingo scats from any given site, suggesting that dingoes might not threaten them. However, consideration of dingo control effort revealed that plains mice distribution has largely retracted to the area where dingoes have been most heavily subjected to lethal control. Assessing the hypothetical predation rates of dingoes on dusky hopping-mice revealed that dingo predation alone has the potential to depopulate local hopping-mice populations within a few months. It was concluded that the occurrence of a given prey species in predator scats may be indicative of what the predator ate under the prevailing conditions, but in isolation, such data can have a poor ability to inform predation risk assessments. Some populations of threatened fauna assumed to derive a benefit from the presence of dingoes may instead be susceptible to dingo-induced declines under certain conditions.The prevalence of threatened species in predator scats has often been used to gauge the risks that predators pose to threatened species, with the infrequent occurrence of a given species often considered indicative of negligible predation risks. In this study, data from 4087 dingo ( The prevalence of prey remains in predator scats (or faeces) is most often used to investigate predator diets Oryctolagus cuniculus, red foxes Vulpes vulpes and feral cats Felis catus have been particularly significant factors in the demise of many species (e.g. Canis lupus dingo and other wild-living Canis) have also been implicated in the declines of several native fauna where 14 of the 101 bettongs released were killed by undetectably low populations of dingoes within 24 hrs, the rest succumbing to predation by unidentified predators within a few months. Dingo predation has also been predicted to threaten up to 94% of listed threatened mammals, birds and reptiles in arid and semi-arid areas of these records collected prior to the turn of the century have already been summarised do present a risk to threatened species, but rather to assess the possibility that dingoes could present a risk under future conditions.This study uses dingo scat data from a large-scale manipulative experiment on dingo ecology in the arid zone of NSA The study was conducted in beef cattle production regions north of the interstate dingo barrier fence (known as \u2018the dog fence\u2019), which was erected to facilitate the eradication of dingoes in sheep production regions to the south in the early 1900s Dodonaea viscosa, buckbush Salsola kali, and a variety of grasses and burrs including kerosene grass Aristida spp. and copperburr Sclerolaena spp. Grevillea striata and spinifex Triodia spp. on the dunes, Mitchell grass Astrebla spp. on the plains, and red gum Eucalyptus camaldulensis and mineritchie Acacia cyperophylla in the drainage lines. Todmorden, Hamilton and Lambina Stations adjoin each other, and are located around the sandy Pedirka Desert in the central-north of the state, have a MAR of \u223c180 mm, and are comprised of sandy deserts dominated by mulga Acacia aneura stands, with stony plain and drainage line vegetation similar to Cordillo Downs Station. Rainfall means were derived from long-term Bureau of Meteorology (www.bom.gov.au) data collected from nearby weather stations at Birdsville (since 1892), Frome Downs Station (since 1889), Hamilton Station (since 1884), Innamincka (since 1882), Macumba Station (since 1891) and Todmorden Station (since 1949). Information on South Australian floral species was obtained from Quinyambie Station is located in the sandy Strzelecki Desert, has a mean annual rainfall (MAR) of \u223c160 mm, and is comprised of parallel sand dunes dominated by hopbush Although large, medium and small prey were present at each site, the relative abundance and availability of each species was not consistent between sites and varied throughout the study period . Most of the mammalian prey species identified in dingo scats were present at each site. However, feral pigs are found only on Cordillo Downs Dingo scats were distinguished from those of other predators based on their size, shape, smell and placement National Parks and Wildlife Act 1974 and the Australian Environment Protection and Biodiversity Conservation Act 1999. Results are expressed as the \u2018percent occurrence in scats\u2019 because our study was primarily concerned with the presence of infrequently detected prey species in dingo scats and not dingo diet per se Dingo scats collected were sterilised and washed by a professional service provider who then searched each scat for the remains of individually identifiable mammal species using established methods in this category , suggesting that the adoption of any of the published classes are sufficient to reliably categorise prey in to body weight classes. No large or medium sized threatened species were detected in dingo scats are not found in cat, fox or dingo scats from the arid zone either Click here for additional data file.Table S2The frequency distribution of reported sample sizes in 47 studies of dingo scats and stomachs from six climate types across Australia.(XLSX)Click here for additional data file."} +{"text": "Mosquito Feeding Assays are currently the only method used to assess the effectiveness of malaria transmission blocking interventions (TBIs) currently under development. Infectious gametocytes are fed to mosquitoes which are then dissected after a fixed time interval to determine how efficiently oocysts have developed on the midgut. Feeding assays include The Standard Membrane Feeding Assay (SMFA), the Direct Membrane Feeding Assay and the Direct Feeding Assay, which use different methods of parasite presentation but all assess mosquito infectivity in the same way. Operation and analysis of these assays varies between laboratories: field scientists often measure TBI efficacy as reduction in the prevalence of infected mosquitoes whilst laboratory scientists are more likely to quote efficacy as a change in the number of oocysts within the mosquito. These metrics give outputs that differ widely, resulting in need for greater understanding of how these feeding assay SMFA inform TBI assessment.Plasmodium falciparum and P. berghei, in either Anopheles gambiae or A. stephensi) is used to illustrate why generalized linear mixed models should be used to analyze mosquito feeding assays data.Data from 538 different SMFAs , with assays which have lower exposure appearing more effective. By contrast, if efficacy is estimated as a reduction in oocyst intensity, then this candidate demonstrated constant efficacy, irrespective of the exposure level.To report transmission-blockade efficacy accurately, the results of membrane feeding assays should give both the prevalence and intensity of oocysts in both the control and intervention group. Candidates should be assessed against a range of parasite exposures to allow laboratory results to be extrapolated to different field situations. Currently, many studies assessing TBIs are underpowered and uncertainties in efficacy estimates rarely reported. Statistical techniques that account for oocyst over-dispersion can reduce the number of mosquitoes that need to be dissected and allow TBI candidates from different laboratories to be accurately compared."} +{"text": "The complex neuroanatomy of pelvic organs not only makes diagnosis of pelvic pain disorders difficult but represents a challenge to development of targeted therapies. A number of potential therapeutic targets have been identified on sensory neurons supplying the FRT but our knowledge on the basic neurophysiology of these neurons is limited compared with other viscera. Until this is addressed we can only guess if the new experimental therapies proposed for somatic, gastrointestinal, or bladder pain will translate to the FRT. Once suitable therapeutic targets become clear, the next challenge is drug delivery. The FRT represents a promising system for topical drug delivery that could be tailored to act locally or systemically depending on formulation. Development of these therapies and their delivery systems will need to be done in concert with more robust Pain syndromes represent one of the major challenges of neurology. Pain has many definitions but essentially it is a concept generated across the brain in response to internal or external stimuli that the individual associates with real or perceived tissue damage or imminent threat . Pain isThe prevalence of transient pelvic pain has been placed as high as 70\u201380% of women surveyed while chronic pelvic pain was reported at >20% . Ten perChronic pelvic pain is further divided into \u201cspecific disease-associated pelvic pain\u201d and \u201cchronic pelvic pain syndrome\u201d where the underlying pathology remains obscure . Pelvic Sexual behavior and reproduction rely on the integration of nervous and hormonal signals to a widely distributed collection of structures. The external genitalia are essentially somatic structures and the distribution of sensory axons and their neurochemical coding are similar to cutaneous tissues . SensoryPain arising from the vagina, cervix, and uterus is an example of visceral nociception \u2013 or pain that comes from distension, injury, or inflammation of hollow organs . VisceraFigure 1). Limited data indicate that often pain from these structures is similar to generalized somatic pain as opposed to visceral pain and members of the glial cell line-derived neurotrophic factor family of ligands are implicated not only in survival of some sensory neurons but their receptors have been suggested as targets for alleviating neuropathic pain . Within ATP was implicated in pain signaling nearly four decades ago . The submGluR have been implicated in uterine and cervix sensory signaling where thNo studies to date have tested whether ASIC are expressed on sensory neurons innervating the FRT. However, they are expressed in vagal and coloNitric oxide generated by neuronal, inducible or endothelial nitric oxide synthase (NOS) plays many roles in the FRT. It is most notably released by autonomic vasodilator neurons to dramatically increase blood flow . HoweverThe cannabinoid signaling pathways have long been proposed as therapeutic targets . The FRTCurrently evidence based treatment for FRT pain is limited. Standard pain therapies such as paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, or neuropathic pain therapies have been used, as the type of pain is not well defined and directing treatment is difficult. Topical therapies are increasing as options for treating vulvar and vaginal pain and are recommended as first line treatment . TopicalVulvodynia and vestibulodynia treatment has been the subject of several recent reviews, which concluded there was insufficient evidence of effectiveness and safety for a range of therapies. It was determined there was evidence of a lack of efficacy for botulinum toxin injection, topical 5% xylocaine, and topical nifedipine. There was insufficient evidence to evaluate the effectiveness of steroid, local anesthetic injections, nerve blocks, intramuscular or intralesional interferon or topical capsaicin, montelukast, steroids, gabapentin, and ketoconazole . Oral trTreatment of uterine pain is limited to systemic options with little evidence. Dysmenorrhea is the best-studied uterine pain syndrome. Primary dysmenorrhea is treated with simple analgesics, usually naproxen, while secondary dysmenorrhea treatment relies on removal of the underlying cause of the pain . As otheFurther investigation is needed to determine specific targets for pharmacological management of the various FRT pain sub-types. The use of drug delivery systems may be required to effectively deliver existing or experimental compounds to the target site for improved efficacy and/or to reduce systemic adverse effects.The intravaginal route of drug administration has been studied as a suitable site for local and systemic delivery of therapeutic agents. The degree to which therapies act locally or systemically is formulation dependent. Presently intravaginal therapies are typically prescribed for vaginal infections and vaginal dryness. Systemic drug delivery includes uterine targeting or treatment of migraines . In relaThe vagina has unique features that can be exploited for optimal therapeutic responses, such as the presence of a dense network of blood vessels, large surface area, and permeability . In addiDespite its therapeutic potential, vaginal preparations show low patient acceptability due to factors including multiple daily dosing; leakage and messiness following application; and the need for night-time dosing. The effectiveness of commonly available vaginal dosage forms is often limited by their low retention to the vaginal epithelium . In ordeIntravaginal rings (IVRs) are circular drug delivery devices that are designed to provide both sustained and controlled drug release, lasting for several weeks to several months following insertion into the vagina. IVR have been shown to be effective in delivering a multitude of compounds, such as contraceptive steroids and steroids for the treatment of post-menopausal atrophy. This delivery device has been previously reviewed .BDD systems were developed to circumvent the issues associated with conventional vaginal formulations, by adhering to the vaginal mucosal tissue and prolonging the residence time of the formulation. Vaginal BDD systems have been exploited for both local as well as systemic delivery of drugs . SeveralNanocarriers have been utilized in topical drug delivery to enhance the penetration of drug compounds. For example, encapsulation of drugs within liposomes can provide characteristics such as enhanced skin or mucosal permeability, sustained release as well as controlled release . Such naPain attributed to the FRT is complex and involves several classes of nociceptive and non-nociceptive sensory neurons. The unique neural anatomy of pelvic organs provides challenges in the delivery of selective therapies. There is little evidence that current treatments are effective and new strategies need to be developed. Relative to somatic pain, or pain from the GIT, there is a lack of information on the basic neurophysiology of FRT sensory neurons. Well defined animal models of neuropathic or inflammatory pain exist for somatic structures and to some extent colitis (trinitrobenzene sulfonic acid models). At present there is no consistent approach to FRT pain. This will need to be addressed if we are to explore the many potential therapeutic targets present on FRT sensory neurons. Exciting opportunities exist for development of intravaginal drug delivery systems for either local or systemic drug delivery. Similar targeted delivery systems can be developed for the vulvodynias. Finally larger clinical trials of the few currently available promising therapies could provide useful insights in directing preclinical studies.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Aspergillus with clinical manifestations that range from colonization , to allergic bronchopulmonary aspergillosis, to disseminated forms of infection. Invasive aspergillosis (IA) has been estimated to occur in 10% of acute myeloid leukemia patients during post-induction aplasia or consolidation therapy and after 5\u201315% of allogeneic hematopoietic stem cell transplants (HSCT) Aspergillosis includes a wide spectrum of diseases caused by fungi of the genus Aspergillus. In the event these escape the ciliated epithelium, conidia will then be challenged by cells of the innate immune system, including resident alveolar macrophages and dendritic cells (DCs), as well as recruited inflammatory cells, mainly polymorphonuclear neutrophils. These cells express a vast repertoire of pattern recognition receptors (PRRs) that sense pathogen-associated molecular patterns (PAMPs) and drive the secretion of proinflammatory cytokines and chemokines that arbitrate innate and adaptive immune responses. In the case of fungi, the cell wall is the main source of PAMPs owing to its dynamic composition and structural properties according to morphotype, growth stage, and environmental conditions The physical barrier of the respiratory tract affords the first line of resistance against inhaled conidia of Aspergillus to adapt to hypoxic microenvironments has been found to involve modifications in fungal metabolism leading to the production of secondary metabolites that promote lung inflammation, exacerbate infection, and influence subsequent host immune responses Despite their undisputed relevance to pathogen resistance, innate immune mechanisms of pathogen detection may behave as double-edged swords, becoming detrimental as the result of hyperproduction of proinflammatory cytokines facilitating tissue damage or impairing protective immunity. This may explain why neutrophils, although indispensable in the implementation of the acute inflammatory response, may instead hamper resolution of infection through an excessive release of oxidants and proteases that may injure organs and promote fungal sepsis. Thus, although inflammation may serve to restrain infection, an overzealous reaction may contribute to pathogenicity and, paradoxically, favor disease progression. Along this line, genomic and transcriptomic approaches have revealed that fungal pathogenicity depends on mechanisms regulating fungal metabolism, morphogenesis, and response to stress in adaptation to the host environment. In particular, the ability of A. nidulans complex, which are weakly virulent molds that rarely cause infection in immunocompromised patients. For most individuals however, genetic propensity to aspergillosis has a polygenic source. A polygenic variant by itself has a negligible effect on phenotype; only in combination with other remarkable predisposing variants do sizeable phenotypic effects arise.The inborn deficiency of the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase leading to CGD is the best known example of primary immunodeficiency with predisposition to IA In conformity with the crucial requirement of innate immunity for effective antifungal host defense, several studies have uncovered associations between genetic variants in components of the innate immune system and risk for IA Aspergillus.Alternative strategies have been employed to uncover gene candidates for susceptibility to IA other than the \u201cobvious\u201d innate immune receptors and associated cytokines Our existing knowledge of the genetic bases of susceptibility to IA derives from studies screening single variants in candidate genes using small patient cohorts. In addition, statistical issues with multiple comparisons and the lack of validation in larger, independent cohorts or via biological studies of disease mechanisms are further limitations of candidate gene association studies. As cutting-edge \u201comics\u201d techniques are becoming affordable, multidisciplinary integrative approaches targeting variability in genome-wide association studies or expression in whole-transcriptomics studies may help to identify novel susceptibility signatures in otherwise unsuspected genes or pathways besides confirming those currently acknowledged. As \u201comics\u201d have contributed to the identification of genetic susceptibility traits in cancer research, these techniques could be ultimately extrapolated with success to the field of invasive fungal diseases. Furthermore, only now are we beginning to fully grasp the significance of the microbiota and its interactions with the mammalian immune system in defining susceptibility to infection. Indeed, the structure and composition of lung microbial communities in patients at-risk was found to diverge significantly from that of healthy individuals The identification of patient-specific prognostic signatures of susceptibility to IA in high-risk patients is currently one major priority in the fields of hematology and microbiology. Ultimately, the discovery of reliable markers of susceptibility consistently associated with risk for IA and functionally correlated with impaired antifungal mechanisms of the host may be a turning point toward innovative stratification strategies based on genetic screening or immune profiling to predict risk and severity of disease, efficacy of antifungal prophylaxis and therapy, and eventually contribute to the successful design of antifungal vaccines."} +{"text": "In previous experiments , we showTo evaluate pattern recognition performance, we ran a set of simulations using a large sample of neuronal morphologies each consisting of 128 terminal points and the same set of ion channel conductances, defined in previous models . For allThe experiments confirmed that there are different pattern recognition abilities associated with a range of different morphologies from the most symmetric to the most asymmetric ones. The initial results suggested a strong anti-correlation between pattern recognition performance and neuronal asymmetry in the presence of active conductances (see Figure Currently we are investigating the optimization of active neuronal morphologies for pattern recognition, using an evolutionary algorithm, previously presented in . In addi"} +{"text": "The therapeutic success of TNFa blockade in RA is unique and has been largely considered to result from rapid and efficient neutralization of joint inflammation based on breakdown of the inflammatory cytokine network in the affected joint, which results in an improvement of the signs and symptoms of the disease (4). It has, however, always been stunning, how fast the blockade of TNFa improves the patient condition, in particular since diseases like RA are highly chronic, building up a vast amount of inflammatory tissue and leading to irreversible damage of the cartilage and the bone. Thus, rapid resolution of this highly organized inflammatory tissue and/or tissue damage is very unlikely to explain the fast effect of TNFa blockade. There has always been a gap in understanding of how tumor necrosis factor alpha (TNFa) blockade affects the disease state of arthritis patients so rapidly, considering that diseases like rheumatoid arthritis are very chronic conditions. We thus hypothesized that blockade of TNFa acts through the central nervous system (CNS) before directly affecting joint inflammation. By use of functional magnetic resonance imaging (fMRI), we demonstrate that within 24 hours after neutralization of TNFa nociceptive CNS activity in the thalamus and somatosensoric cortex but also the activation of the limbic system is blocked. Brain areas showing blood oxygen level dependent (BOLD) signals, a validated method to assess neuronal activity elicited by pain, were significantly reduced as early as 24 hours after initiation of TNFa blockade. In contrast, clinical and laboratory markers of inflammation such as joint swelling and acute phase reactants were not affected by TNFa blockade at these early time points. Moreover, arthritic mice overexpressing human TNFa showed an altered pain behavior and a more intensive, widespread and prolonged brain activity upon nociceptive stimuli as compared to wild-type mice. Similar to humans, these changes as well as the rewiring of CNS activity resulting in tight clustering in the thalamus were rapidly reversed after neutralization of TNFa. These results suggest that neutralization of TNFa affects nociceptive brain activity in the context of arthritis, long before it achieves anti-inflammatory effects in the joints."} +{"text": "Reentry in nervous systems is the ongoing bidirectional exchange of signals along reciprocal axonal fibers linking two or more brain areas. The hypothesis that reentrant signaling serves as a general mechanism to couple the functioning of multiple areas of the cerebral cortex and thalamus was first proposed in 1977 and 1978 . A revie A large and diverse body of evidence suggests that intermittent signaling along reentrant paths is critical to a variety of neural functions in vertebrate brains, ranging from perceptual categorization to motor coordination. Reentry takes on a variety of forms enabling many different processes. These processes facilitate the coordination of neuronal firing in anatomically and functionally segregated cortical areas. By these means they bind cross-modal sensory features by synchronizing and integrating patterns of neural activity in different brain regions. By sustaining attention and short-term memory, reentry might even play a central role in generating conscious awareness. Reentrant signaling is a ubiquitous and dominant structural and functional motif of vertebrate telencephalons . Reentrya priori, but rather is acquired through experience. Reentrant neural processes involve the simultaneous exchange of signals in a coordinated manner among multiple dispersed neuronal populations.Before considering the diverse experimental observations suggesting the operation of neural reentry, clarification of nomenclature will be useful. It is important, for example, to distinguish between the terms reentry and feedback. Feedback, as originally defined and used in control system theory , refers Figure 1 illustrates reentrant connections linking neuronal populations that constitute the gray matter in dispersed cortical areas.A second definitional point is largely a matter of taste. While from its inception as a cortical process reentry An increasing number of investigators of the varied functions mediated by the cerebral cortex have invoked various roles for reentry. In this section we consider experimental findings that illustrate the multiplicity and diversity of functions in which reentrant signaling has been proposed to play a necessary role. Our aim is to marshal evidence and arguments for the widespread occurrence of reentry in vertebrate brains. We expand briefly on some of these roles and consider studies that provide strong empirical evidence for the existence of these proposed functions. The investigations we cite are representative, and they are by no means exhaustive. The majority, but not all, of these studies focus on reentrant signaling within the cerebral cortex.Figure 1). Neurons belonging to different cortical areas are also reciprocally interconnected by reentrant networks of excitatory axons methodology . BundlesIt is useful to contrast the different patterns of growth and functioning of these three fiber types. The development and functioning of transcallosal axonal links seems relatively straightforward. Axons grow in symmetrical morphogen gradients to innervate the cortical areas serving similar functions in the opposite hemisphere in a manner that acts to integrate overall organismal behavior. Perhaps the most remarkable aspect of these fibers is their dispensability: humans and other animals lacking an intact callosum, either as a result of a genetic abnormality or surgery, show a nearly normal phenotype .Intact development and functioning of corticothalamic connectivity, on the other hand, is crucial for animal survival. In addition to serving as a gate of most sensory input into the telencephalon, these pathways play critical roles in regulating arousal states and in directing and moderating attention to determine mental contents and behavioral output. It has been suggested that the conduction velocities of axons within this system adapt in a manner that allows synchrony of neuronal activity throughout the brain, even at anatomically widely separated cortical areas .The functional importance of corticocortical associational fiber tracts is well documented and appreciated. These serve the so-called \u201ctop-down\u201d and \u201cbottom-up\u201d signaling functions by which sensory input into posterior areas of the brain can be attended to, mentally manipulated, and employed to generate those motor commands that determine animal behavior. It is chiefly this network of connections that integrates memories, present input, and imagined futures in the process of creating a conscious scene . AssociaFigure 1). MRI techniques do not reveal whether axons within associational tracts project in the same or in opposing directions. In those few instances in which the issue has been experimentally investigated using retrograde tracing methods, the evidence suggests that most, but not all, of these white matter associational tracts are indeed bidirectional (Although it appears that every cortical area is connected to at least one other area in the associational network, this connectivity is very sparse. Since axons within white matter tracts imaged do not appear to branch, those within any one fiber bundle are assumed to link two separate volumes of target gray matter (ectional . ClearlyAvailable empirical evidence prompts us to speculate that the evolution and developmental functioning of the distinctive mechanisms that give rise to associational white matter tracts played a central role in the evolution of vertebrate brains. With this in mind, we propose a hypothetical developmental mechanism to account for the formation of these tracts.In this proposal, clusters of a subpopulation of neurons differentiating in deep, early-appearing cortical layers of the developing embryonic cerebrum extend axons that bundle together to form fasciculated tracts. These tracts grow beneath the developing cortical layers prior to, and thus independent of, patterned sensory input relayed by the thalamus. Since neighboring neurons would tend to project axons that bundle together, this provides a mechanism whereby topographic order can form and be maintained among axons within white matter tracts. Evidence that this occurs has been reported in studies of the growth of thalamocortical axons into early visual cortex . This meIt is proposed that tracts of pioneering corticocortical axons are guided by the local extracellular cues to grow subcortically along self-organizing networks of fiber bundles. Within the developing white matter, according to this account, they encounter, and then fasciculate with and grow upon, similar bundles of axons growing in the opposite direction. Each axon would then continue to extend along an antiparallel substrate until its growth cone reenters the developing cortical layers at the site at which its guiding substrate originated. Within this gray matter environment the axonal bundles dissociate and individual axons for the first time encounter dendritic sites that provide potential postsynaptic targets.The hypothetical process described above would repeat and continue until every cortical area projects axons in white matter that bundle together with axons that guide them to a second localized cortical area. As a consequence of this developmental process, each associational tract would be structured to send action potentials bidirectionally between two separate but reentrantly interconnected cortical areas. This network of white matter fiber bundles initially organized among axons of early forming deep-layer cortical neurons could also serve as a scaffold to guide the growth of shorter-range axons of upper-layer neurons that differentiate subsequently. This might also contribute to the reentrant white matter connections that link neuronal groups located in superficial cortical layersWhat would be the nature of the signals sent along the axons in these reentrant fiber bundles and how might they contribute to brain function? The timing and rate of action potentials sent in each direction would be determined by the pattern and level of neuronal activity in the cortical volumes that include the cell body and dendrites of the projecting neurons. Each such volume would overlap with the volume containing the terminal arbors of the reentrant axons. If the presynaptic sites within these arbors connected primarily to local inhibitory neurons, a system might arise in which the firing of neurons in one site would transiently hyperpolarize and thus inhibit the firing of neurons in the other site. Thus, this reentrant architecture could give rise to those networks of synchronously oscillating, but anatomically widely distributed cortical areas that are experimentally observed .in situ have been reported (The hypotheses put forward here regarding the functioning, development, and detailed microanatomy of long range reentrant structures in cerebral white matter make clear-cut predictions that are subject to experimental investigation. Fortunately, impressive advances in techniques that allow the imaging of genetically labeled axonal tracts reported . ApplicaA large and diverse body of experimental evidence indicates that processes of reentry play widespread and essential roles in vertebrate brain function, evolution, and development. The reciprocal exchange of signals among neural networks in distributed cortical and corticothalamic areas, when combined with appropriate mechanisms for synaptic plasticity, results in the spatiotemporal integration of patterns of neural network activity. This allows the brain to categorize sensory input, remember and manipulate mental constructs, and generate motor commands. Moreover, these reentrant processes have self-organizational properties that permit robust functioning in the face of genetic or environmentally induced malformation or injury and that allowed for the rapid evolution of the human brain. The use of new anatomical tracing methods to investigate and analyze of these processes in subcortical as well as cortical structures should contribute strongly to our understanding of higher brain function.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Yersinia species that is able to enter host cells by membrane penetration. In the cell YopM mediates down-regulation of inflammatory responses. We investigated whether YopM has the potential to act as a \"selfdelivering\" immune therapeutic agent by reducing the inflammation and joint destruction linked to RA.Osteoclasts mediate the degradation of bone during RA and are derived from macrophages. The yersinia outer protein M (YopM) is an effector protein of in vitro osteoclast formation assay. To unravel the signaling pathways of YopM, we tested for phosphorylation of MAP-kinases and activation of NF-KB signaling by Western Blot analysis. With respect to a potential in vivo application of YopM, we injected YopM intra articular and intravenous in mice and monitored the distribution by fluorescence reflection imaging (FRI). We treated hTNFtg mice, as animal model for RA, with YopM and recorded clinical parameters . Finally we analysed the destruction of bone and cartilage histologically compared to untreated hTNFtg mice and wildtype mice.Using confocal laser scanning we analysed the penetration of recombinant YopM into bone marrow macrophages (BMMs). Furthermore we studied the effects of YopM on osteoclastogenesis using As seen in confocal scanning microscopy, YopM penetrated the cell membrane of BMMs and accumulated near the nucleus. Studying the signaling pathways affected by YopM, we found that YopM reduced the TNFa induced activation of NF-kB via reducing the phosphorylation of IkBa. TNFa mediated phosphorylation of MAP kinases were not altered by YopM. Most interestingly, we found a strong reduction of osteoclast formation by YopM. Incubation of BMMs with YopM led to a 90% reduction in osteoclasts precursors and osteoclasts. YopM-Cy5 injected into the hind paws of hTNFtg mice was detectable in the joint without a systemic distribution for 48 hours and elimination mediated through renal clearance.Analysing the clinical parameters of RA in hTNFtg mice, we observed a delay of onset of paw swelling in mice treated with YopM. At histological analysis of the hind paws, we found reduced bone destruction and decreased osteoclast formation, as well as less inflammation in YopM treated hTNFtg mice in comparison to untreated hTNFtg mice.These results suggest that YopM has the potential to reduce inflammation and bone destruction in vivo. For this reason YopM may constitute a novel therapeutic agent for the treatment of RA."} +{"text": "Analyses of the macroevolutionary correlates of brain structure volumes allow pinpointing of selective pressures influencing specific structures. Here we use a multiple regression framework, including phylogenetic information, to analyze brain structure evolution in 43 Tanganyikan cichlid species. We analyzed the effect of ecological and sexually selected traits for species averages, the effect of ecological traits for each sex separately and the influence of sexual selection on structure dimorphism. Our results indicate that both ecological and sexually selected traits have influenced brain structure evolution. The patterns observed in males and females generally followed those observed at the species level. Interestingly, our results suggest that strong sexual selection is associated with reduced structure volumes, since all correlations between sexually selected traits and structure volumes were negative and the only statistically significant association between sexual selection and structure dimorphism was also negative. Finally, we previously found that monoparental female care was associated with increased brain size. However, here cerebellum and hypothalamus volumes, after controlling for brain size, associated negatively with female-only care. Thus, in accord with the mosaic model of brain evolution, brain structure volumes may not respond proportionately to changes in brain size. Indeed selection favoring larger brains can simultaneously lead to a reduction in relative structure volumes. There is compelling evidence across very diverse species that both ecological and social factors can play an important role in shaping brain evolution Although changes in whole brain size necessarily reflect selection acting on one or multiple structures within the brain, particular brain structures may not respond proportionally to changes in whole brain size Microtus pennsylvanicus) have a significantly larger hippocampus than conspecific females, whereas no sexual dimorphism is evident in closely related monogamous pine voles (M. pinetorum) Salmo trutta), where males compete intensely for females, males possess a larger telencephalon The cognitive demands associated with locating and competing for mates, as well as mate selection, could potentially lead to sexual dimorphism in brain structure Here we analyze brain structure evolution in 43 species of Tanganyikan cichlid fish. Tanganyikan cichlids are an excellent model to study brain structure evolution as they are the most diverse phenotypically, morphologically and behaviorally of the African cichlids and recent morphological analyses have demonstrated the adaptive nature of their radiation Our sample included sexually mature male and female individuals allowing us to analyze both species-specific as well as sex-specific effects. We used a multiple regression approach, controlling for phylogenetic effects The high values of the evolutionary parameter (\u03bb) in the pgls models (with the exception of optic tecta) indicate that the covariance between brain structures and their correlates evolves following Brownian motion . OlfactoThe covariance between brain structures and their correlates presented distinct evolutionary patterns between males and females, as evidenced by the differences in the values of the evolutionary parameters of the pgls models . As woulThe evolution of brain structure dimorphism showed notable departure from Brownian motion as shown by the low values of the evolutionary parameter . A signiA combination of ecological variables as well as sexually selected traits correlated significantly with structure volumes. Our results thus suggest that different selective forces influence the evolution of the distinct structures within the brain, in line with the mosaic model of brain evolution et alAgain in line with our predictions, depth was negatively correlated with optic tecta volume, which is in agreement with results from a previous study with African cichlids that also found a negative association between depth and optic tecta volume The cerebellum was the only brain structure to present significant correlations with both ecological and sexually selected traits. Cerebellum volume increased with depth and with habitat complexity, as predicted, and decreased with increasingly intense sexual selection, contrary to our prediction. These results highlight the interplay between sexual selection and environmental characteristics of a species' niche. Sexual selection is not independent of the environment. On the contrary, a species' ecological niche can influence the mating system and secondary sexual signals which may develop et al. Both the dorsal medulla and the hypothalamus presented significantly negative associations with mating competition, indicating that species with more intense precopulatory and postcopulatory mating competition have smaller dorsal medulla and hypothalamus. Pollen We had predicted a positive association between telencephalon volume and diet, based on previous results indicating that species feeding on sessile prey had larger brains than species feeding on more motile prey The results of the sex-specific analyses generally supported the findings of the species-specific analyses. However, there were also cases where the selective forces acting on male and female structures differed. For the olfactory bulbs, telencephalon and optic tecta, the correlates were the same both at the species level and between the two sexes. Habitat complexity correlated significantly with olfactory bulbs and telencephalon volumes, although the direction of the relationship was opposite for the two structures. The olfactory bulbs were previously found to be the most variable structure, in comparison with all the others, with respect to changes in total brain size Sexual dimorphism in structure volume was only apparent for the telencephalon, where mating competition was significantly negatively correlated with telencephalon dimorphism. The optic tecta showed a marginally non-significant trend in the opposite direction. This result is in line with available evidence that suggests the telencephalon is larger in monogamous than polygamous Tanganyikan cichlids Contrary to our initial predictions based on previous studies having found a positive association between strength of sexual selection and structure or brain volume e. g. , our resThere was one notable difference between the results obtained when analyzing whole brain size versus when we analyzed structure volumes. The difference lies in the association with care type: while in the whole brain size analyses we found that species in which females cared for offspring alone had larger brains Finally, the contrasting pattern observed between whole brain size, brain structure volume and care type suggest that caution must be exerted when attempting to relate the results of analyses of whole brain size to what may be occurring to brain structures Ethics statement: The study was approved by the Uppsala Animal Research Ethical Board; permit number (C264/6).We obtained volumetric measures of brain structures for 43 Tanganyikan cichlid species was obtained from dissected brains following fixation . All were done blindly since specimens were identified by number and not species name. Digital images of the dorsal, ventral, left and right sides of the brain were taken through a dissection microscope (Leica MZFLIII), using a digital camera (Leica DFC 490 and Firecam v. 3.1 software). For each image the brain was carefully placed on a Petri dish with 0.9% agar, which was solid but would yield to brains and allow for them to be placed in such a manner to ensure that the view of the brain being photographed was horizontal and both sides were symmetrical. For paired structures, both were measured and the volume was the sum of the two structures. We followed the procedure of Pollen et al. Diet and habitat were coded as continuous variables representing variation in prey motility and habitat complexity. Qualitative descriptions of both variables were transformed into quantitative continuous variables reflecting a continuum of variation. Diet reflected variation in prey motility, with sessile prey such as aufwuchs and fixed algae at one extreme and fishes at the other multiple regression models For illustration purposes we present 4 graphs showing the relationship between specific relative structure volumes and ecological characters or sexual traits. Note that the graphs represent the relationships without controlling for phylogeny and that they were created based on a least squares linear model. Plots describe the partial regression relationship between structure volume, after controlling for allometric effects with brain size, and either an ecological character or sexual traits, for which the association with brain size, if any, is controlled see . Plots wMaterial S1Brain structure volumes, ecological characters and sexually selected traits.(0.25 MB DOC)Click here for additional data file."} +{"text": "Chitin is one the most abundant polymers in nature and interacts with both carbon and nitrogen cycles. Processes controlling chitin degradation are summarized in reviews published some 20 years ago, but the recent use of culture-independent molecular methods has led to a revised understanding of the ecology and biochemistry of this process and the organisms involved. This review summarizes different mechanisms and the principal steps involved in chitin degradation at a molecular level while also discussing the coupling of community composition to measured chitin hydrolysis activities and substrate uptake. Ecological consequences are then highlighted and discussed with a focus on the cross feeding associated with the different habitats that arise because of the need for extracellular hydrolysis of the chitin polymer prior to metabolic use. Principal environmental drivers of chitin degradation are identified which are likely to influence both community composition of chitin degrading bacteria and measured chitin hydrolysis activities. The single sugar units are rotated 180\u00b0 to each other with the disaccharide N,N\u2032-diacetylchitobiose [(GlcNAc)A process is called chitinoclastic if chitin is degraded. If this degradation involves the initial hydrolysis of the 1\u21924)-\u03b2-glycoside bond, as seen for chitinase-catalyzed chitin degradation, the process is called chitinolytic. Growth on chitin is not necessarily accompanied by the direct dissolution of its polymeric structure. Alternatively, chitin can be deacetylated to chitosan or possibly even cellulose-like forms, if it is further subjected to deamination cleaving the polymer into water-soluble oligomers, (2) splitting of these oligomers into dimers, and (3) cleavage of the dimers into monomers. The first two steps are usually catalyzed by chitinases. The occurrence of chitinases in bacteria is widespread among phyla and the production of multiple chitinolytic enzymes by individual bacterial strains appear to be a common trait transporters are responsible for the main GlcNAc uptake. However, the uptake activity of other specific GlcNAc transporters as well as transporters with a broader substrate range have also been described 2 uptake being quantitatively more important Pseudoalteromonas S91 growing on chitin as a sole source of carbon and nitrogen hydrolyzed chitin (Baty et al., 2 (Keyhani and Roseman, Particles that contain chitin can act as a source of chitin degradation intermediates to the surrounding medium (Smith et al., The habitat structure in which polymer degradation takes place might have great consequences for this kind of interspecies interactions. The flux of dissolved substances as hydrolyses products is physically constrained in aerated soils. Accordingly hydrolyses products will remain in close spatial proximity to the place of enzymatic action. In terrestrial systems, interspecies metabolic interactions will therefore likely be limited to organisms growing directly adjacent to each other in biofilms. Besides commensal sharing of such hydrolysis products (Everuss et al., To the best of our knowledge, no studies exist that target species interactions during chitin degradation in soil environments specifically, nor are we aware of studies that compare the above suggested general differences in cross-feeding between aquatic and terrestrial habitats. However, a number of culture-independent studies in aquatic environments that quantify the fraction of chitin degraders vs. chitin consumers in the total bacterial community support the existence of significant cross-feeding during chitin degradation Table : chitinoActinobacteria ac1 hosts genes to take up GlcNAc while also encoding a chitinase gene (Garcia et al., The assumption that the uptake of polymer-derived metabolites in aquatic system often occurs over longer distances is supported by the observation that typically free-living bacterial groups appear to be quantitatively important receivers of this hydrolyzed material (Cho and Azam, 14C labeled chitin. This suggests that organisms with higher substrate affinity are present in the water samples compared to organisms present in the sediment. It remains to be tested whether the remaining intermediates in sediments would be metabolized over longer timescales or become resistant to further degradation by diagenetic processes. It is also unknown, whether organisms with high substrate affinity influence the efficiency of polymer degradation or if they are irrelevant for the overall ecosystem functioning.Because of the more pronounced dilution of the released hydrolyses products in aquatic systems, a successful receiving organism residing such a long distance from the polymer hydrolysis site would likely also feature high affinity uptake systems. In agreement with this idea, Boyer observedQualitative characterization of the chitinolytic community by means of culture-independent molecular methods such as PCR amplification of chitinase genes or metagenomic approaches usually results in a rather rough level of identification. This is due to the supposedly extensive lateral gene-transfer and the limited taxonomic coverage of characterized reference organisms. One consequence of this is that a large number of chitinase gene sequences cannot be clearly affiliated to specific taxa. However, at a broader phylogenetic resolution recent studies in aquatic environments indicate that group A chitinases were by far the most abundant phylogenetic subgroup of family 18 glycoside hydrolases (Beier et al., Cytophaga-Flavobacteria are known to profit from chitin addition and have been detected in dense cluster on chitinous particles where they also assimilate chitin hydrolysis products (Cottrell and Kirchman, Cytophaga-Flavobacteria in aquatic chitin degradation where they also benefit from this material as a substrate. In contrast, in soil environments bacteria affiliated with Actinomyces are often identified as being active chitin degraders, as they display enhanced growth and activity upon chitin addition. Members of this phylum are also frequently recovered in cultivation dependent studies of chitin degraders (Metcalfe et al., Proteobacteria and Firmicutes, are also commonly observed (Cottrell et al., In aquatic systems, 2 in natural ecosystems varies considerably between 30 and 93% (Table The composition of the chitin utilizing community\u2014including active degraders and organisms profiting from cross-feeding events\u2014might be decisive for the fate of chitin. It seems plausible that i.e., gram-positive chitin consumers use a higher percentage of GlcNAc in anabolic processes to synthesize the murein needed in abundance for production of their cell wall, while gram-negative bacteria might allocate more of these substrates to catabolic energy acquisition. Indeed, the fraction of hydrolyzed chitin respired to CO3% Table , it remaSince the taxonomic identity of the chitin-degrading and chitin-utilizing organisms might be decisive to ecosystem functioning, i.e., as outlined above for mineralization rates of chitin, it seems important to learn more about key players involved in different environments. One feasible strategy might be to combine designed experiments with single-cell isotope tracer methods. Another option is the direct coupling of chitin degradation traits to other metabolic features and taxonomic affiliation via single cell genome sequencing of uncultured microorganisms (Stepanauskas and Sieracki, 14C labeled chitin tracer experiments or incubation experiments with colorimetric or fluorogenic substrate analogs, have been applied to measure hydrolytic activity during chitin degradation. Due to the variety of different methods applied, measuring i.e., potential or actual rates, individual values for chitin hydrolytic activity in different studies are difficult to compare directly (Tables Chitin degradation is a regulated trait and chitin degraders will be able to also metabolize other substrates than chitin. Therefore, the coupling between the abundance and composition of the chitinolytic community and their collective hydrolytic activity might not always be strong. A number of different methods, such as weight loss, y Tables , 4. Insty Tables . Communiy Tables . Bacteriy Tables . Therefoin situ temperature (Hood and Meyers, Temperature is often considered as a critical factor controlling chitin degradation rates. There are several reports of variation in chitin degradation rates with the highest activity during periods of high There are also studies that revealed that temperature seems to play a minor role: in the York River, the correlation between chitin degradation and temperature was much less evident in the water column compared to the sediments Boyer, . Furtherper se could be decisive for measured rates.Only a few studies have directly related measured hydrolysis rates to shifts on the chitinolytic community: It has for example been shown that high chitinase activity measured after a soil was amended with sludge or chitin was accompanied by a decrease in the diversity of chitinases (Metcalfe et al., In summary, the available data suggest that temperature and chitin supply are important environmental factors controlling both chitin hydrolysis rates and the chitinolytic community structure. This further implies the existence of a link between dynamic shifts in the chitinolytic community and measured chitin hydrolysis rates across spatially or temporally connected habitats. Based on these observations, we speculate that organisms that contribute in significant ways to chitin degradation may in fact be specialized on chitin substrate use even if they likely also are able to metabolize other substrates.Environments with limited connectivity or gene flow, such as systems located in different climate zones or systems that vary in salinity, have been shown to host dramatically different chitinolytic communities (Terahara et al., In the previous sections, mechanisms and ecophysiological strategies of microbial chitin degradation and the role of parameters, such as temperature and chitin supply in determining chitin degradation rates have been discussed along with an account of compositional variation in chitinoclastic communities. The absence of long-term accumulation of chitin in natural systems implies that de novo production of chitin is the ultimate limiting factor controlling its degradation and turnover in nature. Still, the fate of this material with regards to production of new biomass or complete mineralization to inorganic constituents varies to a considerably and the underlying factors controlling this variation are only marginally understood. Besides the presence of other, more readily degraded substrates, also the composition of the bacterial community involved into chitin utilization could influence the fraction of chitin being mineralized, i.e., by the substrate affinity toward hydrolyses products. Habitat structure might determine such general characteristics of the inherent chitin utilizing community and therefore also dictate the fate of chitin in terms of its mineralization rates. This may have major implications for the cycling of carbon and nitrogen in food webs i.e., by carbon or nitrogen removal due to mineralization and volatilization. We therefore conclude that the interactive roles of habitat and the chitinolytic or chitin utilizing community and their taxonomic identification merits further investigation.The process of chitin degradation is easier to target than degradation of many other polymers such as the structurally heterogeneous lignin and humic acids or even cellulose. This is because of its simple structure and the existence of primer-systems targeting the chitin modifying enzymes. Chitin degradation could therefore be explored as a general model for understanding microbial degradation of biopolymers in the biosphere.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "While the current generation of college students has access to a multitude of health information on the Internet, access alone does not ensure that students are skilled at conducting Internet searches for health information. Ensuring that college students have the knowledge and skills necessary to conduct advanced eHealth searches is an important responsibility particularly for the medical education community. It is unclear if college students, especially those in the medical and health professions, need customized eHealth literacy training for finding, interpreting, and evaluating health- and medical-related information available on the Internet.The objective of our review was to summarize and critically evaluate the evidence from existing research on eHealth literacy levels among college students between the ages of 17 and 26 years attending various 4-year colleges and universities located around the world. We conducted a systematic literature review on numerous scholarly databases using various combinations of relevant search terms and Boolean operators. The records were screened and assessed for inclusion in the review based on preestablished criteria. Findings from each study that met inclusion criteria were synthesized and summarized into emergent themes. In the final review we analyzed 6 peer-reviewed articles and 1 doctoral dissertation that satisfied the inclusion criteria. The number of participants in each reviewed study varied widely (from 34 to 5030). The representativeness of the results from smaller studies is questionable. All studies measured knowledge and/or behaviors related to college student ability to locate, use, and evaluate eHealth information. These studies indicated that many college students lack eHealth literacy skills, suggesting that there is significant room for improvement in college students\u2019 ability to obtain and evaluate eHealth information.Although college students are highly connected to, and feel comfortable with, using the Internet to find health information, their eHealth literacy skills are generally sub par. College students, especially in the health and medical professions, would be well served to receive more customized college-level instruction that improves general eHealth literacy. Thus, wThe literature also indicated a tendency for male college students to be more likely to use the Internet to locate and acquire consumer health products and services and less likely to search for general information on illness, disease, or disease prevention using medical reference websites. Female college students, on the other hand, were generally more likely to conduct these types of general health or medical searches and were less likely to obtain health services over the Internet . In light of this interesting preliminary trend, future research would benefit from further study regarding what particular Internet search and retrieval characteristics can be attributed to male or female college students. Unique search propensities could speak to various developmental issues of marketing pressures, peer influences, and even health privacy concerns.seeking personal health information may be valued more so than the prospect of receiving individualized feedback on personal health concerns or problems via interaction with a qualified medical professional. This could be the result of contextual Web security issues affecting confidentiality. The issue of trust when using the Internet to seek and share medical information is an important one to consider, especially with the emergence of peer-to-peer or horizontal health communication among college students. More research should be done to discover what particular sources of Web-based health information college students are consulting and which cause uneasy feelings originating from potential threats to data security and privacy.While the literature supports college students wanting to use the Internet to seek out general health information, there is little evidence to suggest that students care to discuss their own health problems or obtain personalized medical advice over the Internet. College students reported reluctance to using interactive Internet applications for health communication purposes . This finding revealed itself not only in the United States, but also in 1 Finnish study that we reviewed. Among college students, the convenience of using the Internet for This systematic review had several limitations. Although we conducted a comprehensive literature search on numerous databases using a variety of pertinent search terms, certain studies may have been overlooked due to lack of indexing in searched databases. In addition, all studies were carried out in either the United States or Finland, which are both highly technologically savvy countries. Also, Finland is regarded as one of the world\u2019s most literate societies, with high levels of educational attainment . AnotherThe marketplace penetration of information technology into college students\u2019 lives and educational settings is shifting rapidly . The reviewed studies of eHealth literacy among college students did not distinguish these emerging applications among the many alternative electronic sources of information, which may not truly reflect current search tendencies of college students. These types of applications conducive to mobile health information searches have spawned the new field of mHealth, which may suggest broadening or revising the study of eHealth literacy among college students. Finally, while the mean MDSs for the studies in this systematic review were quite good, few reported sufficient validity and reliability measures for data collected with survey or testing instruments, and almost all data analyses were univariate versus multivariate.usability. Usability of an eHealth information source typically refers to the quality of a user experience when interacting with the resource, with an emphasis on behavior rather than opinion or recollection [Even where access to basic Internet infrastructure exists or is provided, optimal Internet use is often limited by other factors, such as human interface. To some extent, human interface encompasses issues commonly considered when assessing llection ,33. The llection ,35. An allection ,35 can fConsequently, collegiate degree programs for those entering the medical and allied health fields are uniquely positioned to nurture and develop eHealth competencies among future health professionals. It is important for education administrators to determine (1) what list of eHealth topics should be covered, (2) what types of courses and materials can address the needed competencies, (3) how many hours of subject matter instruction might be necessary for eHealth literacy skill development, and (4) whether eHealth warrants a specific emphasis area or track within professional preparation programs. Creating mission and policy statements that give attention to these relevant aspects of eHealth literacy instruction will help improve student outcomes.Evidence from this systematic review suggests that future health professionals need professional preparatory experiences that help build their eHealth literacy proficiencies. Enhanced skills development will likely develop as a product of practical medical Internet research opportunities that encourage critical thinking among students. As suggested by Escoffery et al , and supGiven that governmental and advisory agencies have designated eHealth literacy as paramount to improving societal health in both Canada and the"} +{"text": "Tinnitus (chronic ringing of the ears in the absence of a sound source) is a major public health challenge affecting quality of life for millions of individuals around the world. Its principal cause appears to be increasing among youthful populations owing to exposure to recreational and occupational sounds for which current protective standards may be inadequate. And at present, there are no curative treatments for tinnitus. These facts alone, and the looming public health challenge they portend, are sufficient to spark its study. But research into the neural basis of tinnitus also addresses a fundamental question in neuroscience. If we can understand how the brain generates the sound of tinnitus, we may gain insight into the question of how the brain generates the sensation of other sounds. The papers published in this special issue address topics related to the neural basis of tinnitus, their implications for hearing, and the health challenge.Brozoski et al., ). Included among the neural changes are tonotopic map reorganization in auditory cortical and thalamic structures, hyperactivity in these structures , increased burst firing in subcortical auditory nuclei, and increased synchronous neural activity particularly in tonotopic regions affected by hearing loss where tinnitus percepts also localize but not secondary (A2) auditory cortex of human tinnitus sufferers, reflecting diminished inhibition and enhanced neural synchrony in regions of A1 affected by hearing loss . Attentional effects on the auditory steady state response in tinnitus patients were deemed unlikely . Although cortical map reorganization cannot itself generate a tinnitus sound (only the activity of the affected neurons can do this), map reorganization is widely believed to play an enabling role in the generation of tinnitus. However, Langers et al. were unable to detect macroscopic map reorganization below 8\u2009kHz in functional imaging data in human tinnitus patients with normal audiometric thresholds. Whether map reorganization can be detected at higher frequencies in such patients is not known but may be the case. Map reorganization assessed by neuromagnetic imaging has been reported in tinnitus patients for whom hearing loss was present . The involvement of stress networks in tinnitus is reviewed in Vanneste and De Ridder .Deafferentation of central auditory structures by cochlear injury leads to several neural changes in auditory pathways that appear to underlie the sensation of tinnitus fills a silent gap in a background sound that would otherwise suppress an evoked startle response. Stolzberg et al. and Guitton discuss in depth how neural changes induced by salicylate in animal preparations are both congruent and in some respects different from those observed when tinnitus and hearing loss are induced by noise exposure. Middleton and Tzounopoulos call for detailed investigations of network neural activity in animal models of tinnitus, looking specifically at communication between thalamic nuclei and brain regions known to be active in tinnitus. Taking a different tack, Schaette and Kempter discuss how computational studies can reveal (or refute) whether neural network models of tinnitus are able to generate properties of tinnitus revealed in physiological and psychoacoustic studies. They emphasize that incorporating forms of neural plasticity in the models determines whether the models are able to simulate measured attributes of tinnitus.Other papers in the special issue describe animal models and computational approaches to understand mechanisms of tinnitus. Animal models are important, because such models permit measurements and interventions that cannot be performed on human tinnitus subjects. In one animal model the presence of tinnitus is signaled by making tinnitus a cue for a behaviorally relevant event. r et al. , cautionr et al. , and evaLangguth et al. give a concise description of the brain areas that distinguish between individuals with and without tinnitus. Strikingly, the affected structures are similar to brain regions that show augmented BOLD responses during performance on attention-demanding cognitive tasks in normal hearing individuals. Evidence from neurocognitive research reviewed elsewhere by Dehaene and Changeux and that communication within and among the nodes may explain documented oscillatory correlates of tinnitus in the delta, alpha, and gamma bands . Building on the network concept, Elgoyhen et al. propose that drugs that have multiple low level effects on synaptic processes in highly specialized pathways (therapeutic \u201cshotguns\u201d) may prove to be more effective at disrupting network behavior and reducing tinnitus than drugs aimed at specific triggering mechanisms. Brozoski et al. similarly suggest in this issue that drugs targeting GABAergic as well as glutaminergic function may be more effective in reducing tinnitus than pharmaceuticals that have more specific action profiles.An important fact about tinnitus revealed by functional brain imaging studies is that the brain regions affected by tinnitus extend beyond auditory structures to include brain areas that are involved in higher level cognitive processing. Changeux supportsChangeux is closeChangeux . It has One omission in the tinnitus literature (current papers not excepted) is a discussion of the possible role of the basal forebrain cholinergic system in the triggering and maintaining network behavior in chronic tinnitus. Cholinergic efferents originating from several nuclei in the basal forebrain project to all regions of the neocortical mantle in a coarse regional topography gave greater therapeutic benefit than disrupting auditory regions alone. A modest reduction of tinnitus handicap scores was found after rTMS treatment in a subset of patients, in agreement with previous studies of rTMS therapy. However, the combined protocol while trending toward greater improvement was not significantly more effective. Notably, handicap scores improved significantly between two baseline measurements that were taken before rTMS treatment had begun. This finding suggests that improvements after an intake assessment may be spuriously interpreted as treatment effects if baseline stability is not assessed . None of the studies described herein reported results from psychoacoustic measurements of tinnitus, which have been found to be more resistant to change in the treatment literature . Nine of the 13 patients (69%) reported a decrease in tinnitus when the implant was switched on, and in five of these cases tinnitus suppression was complete or near complete. Whether suppression persists after CI stimulation was not systematically assessed although one patient reported a persisting benefit 24\u2009h later. Notably, tinnitus suppression was better in this study when the implant was programmed specifically for tinnitus suppression and not for optimal speech processing.Taking a different approach, While hearing loss measured by the audiogram is present in the majority of cases of chronic tinnitus, audiometric threshold shifts are not always seen, and such shifts can occur in the absence of tinnitus (Roberts et al., Research on tinnitus has also sparked a new and important interest in understanding how long term passive exposure to background sound modifies central auditory processing in the mature brain. Contrary to the view that behavioral relevance is a prerequisite for modifying neural representations in adults (Keuroghlian and Knudsen,"} +{"text": "We discuss recently published data from microelectrode array recordings of human neocortical seizures and speculate about the possible role of field effects in neuronal synchronization. We have identified two distinct seizure territories that cannot be easily distinguished by traditional EEG analysis. The ictal core exhibits synchronized neuronal burst firing, while the surrounding ictal penumbra exhibits asynchronous and relatively sparse neuronal activity. In the ictal core large amplitude rhythmic ictal discharges produce large electric fields that correspond with highly synchronous neuronal firing. In the penumbra rhythmic ictal discharges are smaller in amplitude, but large enough to influence spike timing, yet neuronal synchrony is not observed. These If the transmembrane potential surpasses threshold it may initiate firing, or at reduced transmembrane polarization influence action potential timing (Radman et al., An electrical field effect occurs when currents associated with an extracellular field cross the cell membrane. If the current is significant the transmembrane potential (in vivo, with synaptic transmission unaffected, have confirmed that fields associated with ictal discharges depolarize the neuronal membrane and can elicit action potentials (Grenier et al., Field effects are thought to play a role in seizure initiation and propagation (Jefferys, These discharges are thought to be generated by large paroxysmal depolarizing shifts (Goldensohn and Purpura, in vitro (Anastassiou et al., in vivo (Ozen et al., The mechanism by which field effects contribute to neural synchronization has been a subject of intense study. It is estimated that DC uniform fields alter the transmembrane potential in individual neurons at the soma (Radman et al., If weak electric fields contribute to neuronal synchronization, it would be expected that neuronal synchrony would be observed during the large electric fields generated by ictal discharges in humans. Despite the importance of neural synchrony in seizures, there is a dearth of multi-electrode recordings demonstrating such synchrony over extended cortical territories. Recent recordings of partial seizures from the human cortex with the Utah microelectrode array (House et al., Schevon et al., recorded single unit activity during partial seizures with the microelectrode array implanted within the seizure onset zone. In three patients, each of the electrodes detected synchronous unit activity phase locked to the trough of the ictal discharge. However, in two other patients the microelectrode array recorded heterogeneous unit activity (Schevon et al., in vitro (Anastassiou et al., in vivo (Ozen et al., Figure in vivo did demonstrate considerable ephaptic depolarization (Grenier et al., Alternatively, neural synchrony during ictal discharges in humans may be solely due to the strong uniform synaptic depolarization and field effects may not play a role. To prove that field effects contribute to neuronal synchronization requires paired intracellular and extracellular recordings from pyramidal neurons during the ictal discharge (Weiss and Faber, Thus, neuronal synchrony during ictal discharges may be enhanced in the ictal core by field effect interactions that synergistically pace and entrain the rhythmic paroxysmal depolarizing shifts generated by glutamatergic synaptic transmission (Traub et al., Figure Besides a weaker endogenous field, another potential explanation for the heterogeneous, asynchronous firing, in the face of the observed ictal discharges in Figure The recordings from the ictal core demonstrate profound neuronal synchrony during ictal discharges. While, paired intra- and extracellular recordings are required to confirm that field effects help to generate this synchronization, the electrical field strength is likely sufficient (Ozen et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Chronic diseases are a leading contributor to work disability and job loss in Europe. Recent EU policies aim to improve job retention among chronically ill employees. Disability and occupational health researchers argue that this requires a coordinated and pro-active approach at the workplace by occupational health professionals, line managers (LMs) and human resource managers (HRM). Little is known about the perspectives of LMs an HRM on what is needed to facilitate job retention among chronically ill employees. The aim of this qualitative study was to explore and compare the perspectives of Dutch LMs and HRM on this issue.Concept mapping methodology was used to elicit and map statements (ideas) from 10 LMs and 17 HRM about what is needed to ensure continued employment for chronically ill employees. Study participants were recruited through a higher education and an occupational health services organization.Participants generated 35 statements. Each group (LMs and HRM) sorted these statements into six thematic clusters. LMs and HRM identified four similar clusters: LMs and HRM must be knowledgeable about the impact of chronic disease on the employee; employees must accept responsibility for work retention; work adaptations must be implemented; and clear company policy. Thematic clusters identified only by LMs were: good manager/employee cooperation and knowledge transfer within the company. Unique clusters identified by HRM were: company culture and organizational support.There were both similarities and differences between the views of LMs and HRM on what may facilitate job retention for chronically ill employees. LMs perceived manager/employee cooperation as the most important mechanism for enabling continued employment for these employees. HRM perceived organizational policy and culture as the most important mechanism. The findings provide information about topics that occupational health researchers and planners should address in developing job retention programs for chronically ill workers. Chronic diseases are increasingly prevalent among people of working age in Europe ,2. In thIn the Netherlands, the responsibility for the provision of work disability benefits has shifted from the state to the employer in 2002 . In respafter illness or disability has occurred and aims at reducing long-term disability . The stThis study identified both similarities and differences between the perspectives of Dutch LMs and HRM on conditions that may facilitate job retention for chronically ill employees. LMs and HRM identified four similar conditions: LMs and HRM must be knowledgeable about the impact of chronic disease on the employee; employees must accept responsibility for work retention; work adaptations must be implemented; and clear company policy. Two conditions were only identified by LMs: good manager/employee cooperation and knowledge transfer within the company. Unique conditions identified by HRM were: a company culture that facilitates trust and openness and organizational support. LMs perceived manager/employee cooperation as the most important mechanism for enabling continued employment for these employees. HRM perceived organizational policy and culture as the most important mechanism. These findings provide information about topics that occupational health researchers, planners and practitioners should take into consideration when developing job retention programs for chronically ill workers.LM: Line Manager; HRM: Human Resource Manager; HR: Human Resources; OHS: Occupational Health Services.The authors declare that they have no competing interests.JH designed and conducted the study, analyzed the data and wrote the paper. HK critically reviewed several drafts of the paper. MM helped to design and conduct the study, the interpretation of the data and she critically reviewed several drafts of the paper. FvD contributed the data analysis and interpretation and the drafting of the paper. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6963/11/104/prepubConcept maps. Figure s1 shows the cluster map indicating perspectives of line managers on what is needed to ensure continued employment for chronically ill employees. Figure s2 shows the cluster map indicating perspectives of HRM on what is needed to ensure continued employment for chronically ill employees.Click here for file"} +{"text": "Nurse involvement in research is essential to the expansion of nursing science and improved care for patients. The research participation challenges encountered by nurses providing direct care (direct care nurses) include balancing patient care demands with research, adjusting to fluctuating staff and patient volumes, working with interdisciplinary personnel, and feeling comfortable with their knowledge of the research process. The purpose of this paper is to describe efforts to engage nurses in research for the Stories and Music for Adolescent/Young Adult Resilience during Transplant (SMART) study. SMART was an NIH-funded, multisite, randomized, behavioral clinical trial of a music therapy intervention for adolescents/young adults (AYA) undergoing stem cell transplant for an oncology condition. The study was conducted at 8 sites by a large multidisciplinary team that included direct care nurses, advanced practice nurses, and nurse researchers, as well as board-certified music therapists, clinical research coordinators, and physicians. Efforts to include direct care nurses in the conduct of this study fostered mutual respect across disciplines in both academic and clinical settings. Over the years, there have been many recommendations to close the research/practice gap, including efforts to increase the availability and applicability of the evidence for practice through the involvement of direct care nurses on research teams \u20135. AcadeHaving opportunities to observe and engage in ongoing research is the key to encourage nurses' participation in research . Yet, fu Adolescents and young adults (AYA) undergoing hematopoetic stem cell transplant (HSCT) for treatment of cancer have a long, difficult journey. The typical transplant course involves (a) a pretransplant conditioning regimen with chemotherapy +/\u2212 radiation lasting 2\u201310 days; (b) the stem-cell infusion; and (c) posttransplant recovery lasting days to months. Side effects during the transplant course can be severe and include nausea/vomiting, diarrhea, mouth sores, infection, kidney/bladder problems, lung problems, fatigue, pain, and graft versus host disease. AYA experiencing this process are challenged to endure this complex treatment and find a balance between enduring the transplant and side effects and continuing the normal process development. The Stories and Music for Adolescent/Young Adult Resilience during Transplant (SMART) study was developed and implemented with the goal of identifying a way to assist AYA through the transplant process with a positive psychosocial outcome. The SMART study was a randomized Children's Oncology Group clinical trial (ANUR0631) supported by NIH-NINR and NCI designed to evaluate the efficacy of a therapeutic music (TMV) intervention compared to a low-dose audio book control intervention for AYA 11\u201324 years of age undergoing HSCT for an oncology condition. Complexities implementing this study included the following: (a) a large disciplinary team required for implementation; (b) extensive outcome measures; (c) multisession TMV intervention during the transplant course to AYA experiencing significant physical symptoms; and (d) an extensive quality assurance program to ensure consistent and accurate implementation of the study. As the SMART study was implemented, the research team held conference calls twice a month to discuss study implementation and to solve problem barriers. We recognized the need to keep all members on each HSCT unit informed and engaged with study activities. The team observed that the complex nature of the HSCT combined with the intense process of study implementation required the cooperation and participation of HSCT direct care nurses. Through our discussions, we identified key areas in which we needed the nurses collaboration. These included (a) informing study staff of patient clinical status; (b) organizing nursing care and symptom management to maximize ability of study participation to complete study activities; (c) supporting and encouraging patient participation; and (d) following quality assurance procedures to maintain evaluator blinding during the intervention. The purpose of this paper is to describe the efforts of the core research team to engage and include direct care nurses at each study site in the conduct of the study. time, which included balancing patient care demands with research needs and adjusting to fluctuating staff and patient volumes. The second key challenge was support, which included coordinating clinical and study personnel. Third, skills/knowledge included ensuring that direct care nurses had appropriate levels of knowledge and comfort with behavioral intervention research. We describe each of these challenges in detail below. Multiple challenges related to the successful inclusion of direct care nurses into the research process were encountered during study implementation. The main challenges our research team encountered were consistent with those identified in the literature , 8. The The targeted population, AYA undergoing an SCT, had high acuity and experienced multiple distressing physical symptoms including pain, mouth sores, nausea and vomiting, diarrhea, and fatigue. Sometimes, limited time and complex patient care needs made it difficult for nurses to accomplish necessary direct care while also supporting the research process. This experience is consistent with literature indicating that nurses' primary concern is delivery of timely, competent care and being an advocate for patients; hence, anything perceived as not in the patients' best interest, such as involvement in research, will likely be abandoned . To remaAlong with high patient acuity, fluctuations in nurse staffing patterns created an additional challenge for nurse involvement in the research process. Staffing patterns in clinical settings require that direct care nurses may be unpredictability assigned on a daily basis to work in different in-patient care units to accommodate changes in daily patient census patterns and acuity. For instance, nurses familiar with the study, who knew how to integrate study activities into patients' care plans, were often reassigned to work in other in-patient care units when the HCST patient census was lower. Conversely, in times of high HCST patient census patterns, direct care nurses that were not familiar with the research study may be reassigned to provide patient care to AYA in the HSCT units where the study was being conducted. The number of study-eligible patients would also fluctuate; for example, there were times when study approved clinical sites had multiple patients simultaneously enrolled in the study and other time periods in which no eligible patients could be recruited to the study. After periods of prolonged study inactivity, direct care nurses often felt less prepared to support the research protocol because they lacked recent experience integrating study procedures into routine clinical care. For example, obtaining physiological data regarding aspects of the patients' status to provide to the study interveners and coordinating patient care was less intuitive after periods of study inactivity. It became evident that fluctuations in nursing staff and study participant volumes were affecting the direct care nurses' enthusiasm and focused commitment to be actively engaged in recommended recruitment activities and that the nurses would require a booster training plan for ongoing support and education. Coordinating Interdisciplinary Clinical and Study Personnel. Coordination of clinical and study personnel was a primary challenge encountered during SMART study implementation. Study personnel included HSCT coordinators who identified study-eligible patients, project managers who obtained informed consent and scheduled study activities, clinical research coordinators who administered study measures, and board-certified music therapists who delivered the study intervention sessions. Some study team members were not familiar with HSCT patients' usual clinical pattern and the nature of their changing needs. Therefore, some of our study team members often needed to consult with the direct care nurses about the current health care status of enrolled patients and explore ways to integrate intervention sessions and measurement times into the daily flow of the patients' plans of care. Consistent and effective communication among the direct care nurses and study team members fostered successful scheduling and execution of the study sessions and activities during delivery of the enrolled patients' HSCT treatments. Ensuring Appropriate Levels of Knowledge and Comfort with Behavioral Intervention Research. Behavioral intervention studies are not commonly conducted in pediatric HSCT clinical settings. However, pediatric nurses practicing in Children's Oncology Group HSCT units often have experience in assisting physicians with the conduct of RCT studies designed to evaluate the efficacy of specific medications and treatment regimens. The role of direct care nurses in such RCT studies often involves familiar skills such as drawing blood for laboratory specimens, administering medications in a specified manner, and scheduling prescribed radiologic evaluations. Generally, direct care nurses have little or no exposure to nurse researchers who are conducting behavioral intervention studies. Thus, direct care nurses needed additional information to understand how behavioral intervention studies differ from clinical trials in terms of study design, procedures for ensuring intervention and evaluation integrity, data collection methods, and expected outcomes. In the SMART study, our team observed that when direct care nurses did not understand behavioral intervention study features, the nurses were uncertain about how to support intervention and data collection processes. For example, the study evaluators needed to be blinded (or uninformed) to which intervention arm that the enrolled participants were randomized to receive. Because the evaluators were not inadvertently unblinded, the direct care nurses had to be careful about what was discussed with evaluators while also being asked to provide evaluators with specific data about participants' symptom experiences prior to the AYA's intervention sessions. Such support and help by direct care nurses were critical to the integrity of the study. Identifying the study-related challenges that direct care nurses might experience was one key factor to successfully initiating and sustaining these nurses' ongoing commitment and engagement in the study. The second key factor, described below, was developing strategies to address and overcome the identified challenges. Throughout the study, SMART study personnel worked to address the challenges of conducting interdisciplinary, multisite behavioral intervention research within HSCT units. Some of the previously identified challenges could be anticipated and planned for, whereas others were unexpected and required quick and timely communication among the research team members. In this section, we outline some of the \u201ca priori\u201d strategies that were used for anticipated protocol challenges, as well as strategies developed in response to unexpected study challenges. Each strategy addressed the key challenges identified above. Training and ongoing research team discussions were targeted at (a) reducing protocol implementation challenges by improving study-related knowledge and skills, (b) preventing time-related challenges by integrating study procedures into the AYA's plans of care, and (c) improving study protocol adherence by generating and maintaining enthusiasm for the study. It is important to note that while each of these strategies was aimed at preventing or dealing with a specific study-related challenge, addressing one challenge inevitably addressed others. For instance, provision of education about the study protocol and ongoing relevant team communication also supported nurses' commitment to consistent protocol delivery, and strategies to support integration of study procedures into enrolled patients' plans of care also enabled the patients' assigned nurses to more easily integrate study activities into patient care. To ensure success during the start-up phase of the SMART study, a first priority was to ensure that study personnel understood and could implement the study appropriately. Prior to initiating the SMART trial, all study personnel attended team-building and educational meetings that provided extensive training on the study design and protocols, the SCT process, and the roles of all team members. These two-day meetings provided necessary foundational information and support prior to bringing the study into the clinical settings. Written manuals for each team member were developed to provide consistency and reinforce content taught during training. In addition, at each site nurses in advanced practice roles were identified and received salary support and training to assist with study coordination and integration into the clinical setting. After training, the study personnel were responsible for presenting study information to the nursing staff at their respective clinical sites. Strategies to reach other clinical personnel at each site and maintain study visibility included presentations at regularly scheduled unit-based staff meetings, informal staff meetings held on all shifts, and distribution of study information through in-service fliers, study brochures, and posters.To keep the direct care nurses informed of the SMART study progress we used several communication strategies. Updates on accrual, attrition, and timeliness of evaluation were provided to all study personnel on a regular basis, and these updates were then communicated to the nursing staff of the participating units. Project managers also communicated with direct care nurses on the HSCT units whenever enrollment of new patients into the study was anticipated. Quarterly study newsletters published to celebrate all team members' achievements included professional accomplishments such as promotions, presentations, and publications, as well as personal celebrations such as weddings and births of children and grandchildren. Each site was invited to submit personal or professional items to be showcased in the newsletters by all study personnel at each data collection site. The inclusion of pictures in the newsletters helped team members and direct care nursing staff connect names and faces of team members across participating sites. These newsletters were compiled at the lead site by the project manager and made available to all nursing staff at each site. As a whole, these strategies promoted continued interest, consistent communication, and pride in all study-related accomplishments. Communication was also fostered through the use of regularly scheduled conference calls for the study staff. The conference calls were scheduled biweekly to foster study personnel sharing of perspectives, ideas, challenges, and progress related to study activities across sites. By providing a mechanism for group participation in problem-solving, study staff members were able to use the collective wisdom of the group to prevent or address any impediments to smooth study implementation at their respective sites. The study coordinator at each site also scheduled team meetings with the HSCT personnel to provide timely study related information and suggestions for overcoming any identified obstacles related to study flow at individual sites. The site meetings provided a venue for direct care nurses to have an opportunity to share their perspectives and suggestions about strategies to be considered in order to improve implementation of the study at their respective sites, and the meetings fostered collaborative partnerships and helped to maintain study integrity. http://dx.doi.org/10.1155/2013/183984). This care plan was developed by the project manager and direct care nurses at one study site and shared with all other sites. This care plan showcased specific dates and times for scheduled study interventions and evaluations so that the direct care nurses could anticipate and plan care for their patients while simultaneously facilitating the completion of study activities. This care plan also provided a reference point that assisted the direct care nurses to remember to share key information about the health care status of enrolled patients with the clinical research coordinators. In addition to encouraging integration of study interventions into daily care, the care plan enhanced the direct care nurses' confidence in study facilitation and participation.Another important way was that commitment to the study was fostered to integrate study procedures into the patients' daily plans of care. As previously discussed, this was especially important because patients in this study were often quite sick. Academic and study nurses collaborated with the direct care nurses to develop a SMART study nursing care plan as a communication tool for study personnel AYA participants randomized to the TMV intervention created music videos and often included nursing staff in the content of their videos, (b) the last TMV intervention session included a video premiere viewing party to which nursing staff members were often invited, and (c) during the video premier, nursing staff could view the final product of the TMV intervention and witness the positive effect it had on the AYA. These activities afforded direct care nurses the opportunity to witness the important impact they were making in the lives of their patients through their participation in a behavioral intervention research study.Identifying challenges to nurse participation in a behavioral intervention study and developing strategies to address those challenges were critical to successful implementation of the SMART trial. While we did not formally evaluate our processes for including direct care nurses in the research process, a few key points emerged. Successful implementation of a research project requires a commitment to problem-solving and effective communication. The ability to foster these two tenets can lead to mutual respect and cooperation among key study personnel and nursing staff. Engaging stakeholders from both \u201csides\u201d ahead of implementation allows for troubleshooting. Open dialogue along the way keeps challenging situations from becoming more problematic. A simple, yet key strategy was ongoing and responsive communication. Building rapport with staff on both the transplant unit and individual levels at each site allowed for timely identification of challenges and enabled staff to feel comfortable reaching out when they needed help. Anecdotal interactions with the nursing staff fostered early identification of potential or actual challenges that arose periodically during study implementation; however, being able to observe how AYA during HCST were still able to complete the project and feeling that the study staff were there to support them made the direct care nurses eager to be a part of the team. Direct care nurses involved in the SMART study became more familiar with the conduct of behavioral intervention research, observed the benefits of patient and family participation, and had opportunities for career advancement through participation in professional presentations and publications, but perhaps most importantly these nurses made a significant contribution to advancing science to improve patient care. Direct care nurse participation in study implementation is essential to the success of behavioral intervention research, and their full participation will result in research products that are more readily translated into practice. Nurse researchers need to address the inclusion of direct care nurses as new research is planned and developed. Fostering a culture of respect for and accessibility to research is vital to continued efforts to advance evidence-based nursing practice , 24.The SMART Study Care Plan is a communication tool developed by academic and study nurses to provide a roadmap for staff nurses caring for patients enrolled on the SMART study. This care plan assists the nurse in integrating study activities into the daily clinical care of the patient.Click here for additional data file."} +{"text": "Food allergy often manifests on first known oral exposure. Hence, the timing of complementary food introduction is of interest. The American Academy of Pediatrics offers specific dietary guidelines that were updated in 2008.Objective: We wanted to identify the recommendations that general pediatricians and registered dietitians provide to parents and delineate any differences in counselling.A 9-item survey was distributed to pediatricians and dietitians online and by mail. Information on practitioner type, gender, length of practice and specific recommendations made regarding complementary food introduction and exposure was collected.181 surveys were returned with a 54% response rate from pediatricians. 52.5% of all respondents were pediatricians and 45.9% were dietitians. The majority of pediatricians and dietitians advise mothers that peanut abstinence during pregnancy and lactation is unnecessary. Dietitians were more likely to counsel mothers to breastfeed their infants to prevent development of atopic dermatitis than pediatricians. Hydrolyzed formulas for infants at risk of developing allergy were the top choice of formula amongst both practitioners. Pediatricians were more likely to recommend delayed introduction of peanut and egg, while most dietitians recommended no delay in allergenic food introduction to prevent development of food allergy.With the exception of whether to recommend breastfeeding to prevent development of atopic dermatitis and whether to delay allergenic food introduction, pediatricians and dietitians agreed closely in their advice and adhered to the 2008 American Academy of Pediatric guidelines. Further education using the latest recommendations should be considered."} +{"text": "Design of active ingredients is a multidimensional task. Sufficient target activity in combination with high bioavailability and no (or at least low) toxicological behaviour are prerequisites for promising candidates. In this respect, pharmaceutical and agrochemical companies need to address the same issues. Considering the target activity one can generally conclude that \"target is target\" regardless of whether the respective organism is a human or a pest. In detail however, drugs modulate activity of dysfunctional proteins or their functional counterparts aiming to reduce the pathogenic effects. In contrast to that agrochemicals modulate vitally important proteins in order to keep harmful organisms under control.Bioavailability of drugs usually addresses the human patient with regard to a preferred oral application. Agrochemicals have to be divided into herbicides, fungicides and insecticides controlling weed, harmful fungi and insect pests. For each of these harmful organisms different absorption, distribution, metabolism and excretion routes have to be considered leading to quite different physicochemical properties of lead compounds.Based on the above-mentioned similarities and differences, the presentation will give an overview on commonly applied computational approaches in pharmaceutical and agrochemical companies as well as several unique challenges relevant just for the design of potent crop protection compounds."} +{"text": "Architecture Basic Local Alignment Search Tool (ArchBLAST).The sequencing of the human genome has revealed that the vast bulk of DNA sequence is devoted to regulatory regions. This regulatory information is spread throughout the genome and is responsible for guiding the complex cellular processes producing every human cell, tissue, and organ. The key to understanding this multifaceted network of genomic interactions has been the identification of common genomic features, ie. promoters and enhancers. However, finding these locations within the genome can be a laborious and expensive undertaking requiring site specific assays. Even more difficult is identifying entirely new classes of genomic features. To facilitate identification and characterization of new classes of genomic features we have developed The ArchBLAST algorithm uses the chromatin architecture at a user defined region or regions of interest and identifies all similar regions within the genome as defined by their shared chromatin architecture. ArchBLAST differs from other methods in that it uses both the amplitude and spatial arrangement of the chromatin modifications to score similarity. Importantly, ArchBLAST allows for the identification of subtypes of known genomic features and can accurately predict previously uncharacterized locations. ArchBLAST uses an innovative weighted profile generated from only the most informative chromatin datasets and then scores the entire genome. The accuracy of ArchBLAST has been validated with well characterized genomic features from yeast and humans. In addition, we demonstrate how ArchBLAST can identify novel transcription start sites in humans and show experimental evidence for their existence. We also show how ArchBLAST can uncover novel cell-type specific enhancers using only a few characterized enhancers as a template.We have shown that chromatin architecture is sufficient to identify and characterize genomic functional elements. ArchBLAST can incorporate any genomic dataset including transcription factor ChlP-seq and automatically selects the most informative datasets for the search. Additionally, ArchBLAST provides a flexible and expandable framework for identification of similar genomic elements using any user-defined criteria."} +{"text": "To the Editor: Cutler et al. bring welcome attention to the importance of new and reemerging zoonotic diseases in the industrialized world ( In Response: Silbergeld et al. highlight pertinent points about how stochastic events can lead organisms to acquire adaptive advantages through lateral gene transfer (Staphylococcus aureus (Commonly, reemergence of infections is caused by changes in the environment or the host, genetic changes of pathogens, or alteration in the dynamic interactions that unite them. Our need for intensive protein production can have explosive consequences, as seen with the recent outbreak of Q fever among humans residing near goat farming areas in the Netherlands ("} +{"text": "Improving patient safety is one of the challenges facing our healthcare system. A report in January 2004 from the Institute of Medicine discusses key aspects of nurses' working environments, including the effect of extended hours and workload on patient safety outcomes. As caregivers, nurses play an important role in patient safety and quality of care. They represent the frontline surveillance system in many healthcare settings and can detect errors before the patient can be harmed. The risks for patient infections, occupational illnesses among nursing staff, and the possible spread of infection to nurses' family members can be avoided or reduced if working conditions are supportive. Most nursing staff are women, substantial numbers of whom appear to be leaving the field for other career opportunities. Policymakers must closely monitor emerging trends in the nursing workforce to weigh possible benefits of legislation to increase the supply of nurse workers and reduce adverse patient outcomes.The nurse shortage is a major issue affecting the healthcare system. The demand for nursing services is expected to grow 40% by 2020, while the number of nurses is projected to grow 6%. Over the past few years, health care systems have gone through numerous reengineering and redesigning processes intended to improve the efficiency of the system. These have generally resulted in heavier workloads for nurses and have, in some instances, triggered the departure of experienced nurses. In contrast to hospitals , the numbers of nursing homes and nursing home beds have substantially increased, as have the number of residents >85 years of age.Low staffing levels increase nurses' workloads and are associated with heightened risks for adverse patient events, which may generate excess costs to the healthcare system. Healthcare settings need to use errors as opportunities for improvement, while making error detection and prevention the responsibility of all involved in the interdisciplinary collaborative work of patient care.An investigation supported by the Agency for Healthcare Research and Quality is studying the effects of various working conditions in intensive care units (ICUs) on elderly patient safety outcomes, healthcare worker safety, and factors related to turnover of critical-care registered nurses (RNs). The working conditions being examined include staffing levels and organizational climate, and the outcomes for the patient include healthcare-acquired infection, length of stay, death, and disposition at discharge. Healthcare worker safety includes musculoskeletal injuries, blood and body fluid exposure, sick days, and disability days. The study involved a voluntary sample of 2,330 RNs (response rate 41%) employed across the nation in 68 different hospitals.Preliminary findings indicate that adverse organizational conditions are widespread and may be linked to patient safety outcomes. Overall, study results to date suggest that interventions and policies aimed at improving working conditions in ICUs may decrease turnover, improve patient safety, and reduce healthcare costs. Further research is needed to link these working conditions to patient and healthcare worker safety.The deepening nurse shortage internationally has a number of underlying causes, including a special convergence of demographic and financial forces in health care that can be likened to a \"perfect storm.\" Recent intense public concern about healthcare safety is an added element that has made identifying the consequences of nurse staffing levels for patients particularly urgent. A growing body of literature ties lower nurse staffing levels to higher rates of death and complications of care, including healthcare-related infections, independent of patient and hospital characteristics. Methods and problems in measuring staffing are debated in the literature. Mounting evidence demonstrates that nurse staffing is a public safety issue that will require a multifaceted policy approach."} +{"text": "Anaesthetic agents are known to affect extra-synaptic GABAergic receptors, which iThe work reveals an increase of the population gain by increasing tonic inhibition and discovers a maximum of the gain subjected to the level of inhibitory heterogeneity, cf. Fig.Summarizing, the present work has discovered an increase of the population firing threshold and a population gain modulation induced by tonic inhibition and presents a mathematical expression for the population firing rate. Since extra-synaptic receptors nduce tonic inhibition and are activated by several general anaesthetics, it is reasonable to reason that neural populations under anaesthetic action experience both effects. Consequently, we conclude that anaesthetics may both diminish the resting activity by shift of the firing threshold and disr"} +{"text": "The difficulties of conducting a randomised controlled trial (RCT) of a surgical intervention have long been recognised. Individual surgeon skill and experience introduce an additional challenge to those of conventional RCTs and as a consequence, surgeons may be reluctant to participate in orthopaedic surgery trials.The use of expertise based randomised trials has been proposed as an alternative design, where participants are randomised to surgeons with an expertise in the allocated intervention.TOPKAT, a randomised controlled trial examining the clinical and cost effectiveness of total or partial knee replacements for medial compartment osteoarthritis utilised a combined expertise/equipoise based design in order to maximise surgeon participation and recruitment to the study. The trial is on-going and has currently enrolled 460/500 (92%) participants with recruitment due to end in September, 2013. Overall, there are twenty eight participating sites, twenty one of which are equipoise and remaining seven expertise sites.Large variability in recruitment rates are seen across all sites with those participating as expertise sites demonstrating lower average monthly recruitment rates. Factors identified as additional challenges impacting recruitment rates and trial conduct to those of the equipoise sites include delays in establishing local expertise teams, patient preference for the recruiting surgeon, difficulties with patient logistics and timing of randomisation.The TOPKAT trial demonstrates that recruitment of Orthopaedic surgeons to participate in and recruit to an expertise based design is both achievable and feasible. We highlight the potential challenges and possible considerations that may facilitate the conduct of expertise based trials."} +{"text": "Guido Bastiaens and colleagues describe barriers to achieving scale-up and appropriate use of rapid diagnostic tests and artemisinin-based combination therapy for malaria in sub-Saharan Africa.Please see later in the article for the Editors' Summary Scaling up and sustaining access to malaria diagnosis and treatment in all public sector, for-profit, and informal health facilities across sub-Saharan Africa is central to current global strategies for malaria control and elimination.The use of malaria rapid diagnostic tests (RDTs) aims to eliminate reliance on signs and symptoms to diagnose and treat malaria but evidence shows health workers do not always test the right patients, nor provide treatment based on the results of the test.Expanding access to malaria RDTs on the scale needed to achieve universal coverage requires retraining of public, private, and retail sector providers as well as sustained supplies and quality assurance.Barriers to rational use of tests and drugs may be overcome through appropriate policy design for the local health service setting, which addresses health worker practice and patient perceptions.Innovative methods have been used to increase access to the most effective antimalarial drugs in the last five years, but these efforts will be incomplete and unsustainable without similar efforts to incorporate RDTs into practice.An estimated 627,000 malaria deaths occurred in 2012, mostly in African children and many of them preventable with prompt diagnosis and treatment T3: Test. Treat. TrackIn April 2012, the World Health Organization's (WHO) Global Malaria Programme launched a highly ambitious new initiative: In this Policy Forum article we examine the operational challenges to implementing the T3 strategy of scaling up and maintaining RDT coverage. We identify gaps in planning for at-scale implementation in policy design and implementation, the local health care setting, and the attitudes and demands of patients. While focussed on malaria diagnosis and treatment, the challenges illustrated here are not unique to malaria and may apply to health care provision across resource-poor settings.By 2012, 41 out of 44 endemic countries in the WHO African Region had adopted the policy of providing malaria diagnostic testing for all age groups before treatment RDTs will be introduced in health facilities and among community health workers (CHWs) who work at local levels. To translate the change in policy to a change in routine practice where tests are appropriately used by providers, unambiguous messages and guidelines that are adapted to the local context are needed Mobilising sufficient resources for the training and monitoring required to sustain the new policy is the key to success. A reliable system for RDT delivery needs to include re-training of staff and consistent quality assurance at all levels. The quality of services is likely to wane over time and can be aggravated by high staff turnover, which occurs in many health service settings. Ensuring programme quality and sustainability therefore requires constant rolling interventions and local evidence for the best models of implementation.In the local health care setting, two problems persist: firstly, parasite-based testing is generally unavailable When RDTs are introduced in presumptive treatment settings significant reductions in the overprescription of antimalarials have been seen in almost all studies published . HoweverOften, the irrational use of tests and drugs is based on perceived shortcomings of the tests. A common concern amongst health staff is that negative tests do not definitively rule out malaria Improvements in antimalarial prescription often coincide with increases in prescription of antibiotics amongst test-negative patients. All studies where antimalarial prescription rates were reduced in malaria-negative patients show an increase in antibiotic prescriptions and S2 [Identifying patients at risk of progressing to severe disease in which antibiotic treatment and/or referral would have a clinical advantage, while withholding antibiotic treatment in other patients, is a considerable challenge. Affordable rapid diagnostics for bacterial infections or markers of severe infections would support the rational prescription of both antimalarials and antibiotics.A high patient load in many clinics creates challenges in implementing new policies and motivating staff Sustaining the supply of RDTs is a substantial challenge. In rural areas, where access to services is often low but demand for services may be highest The private for-profit sector plays an important role in delivering services across most of Africa and the majority of suspected malaria episodes are initially treated by private health workers Affordable Medicines Facility - malaria provided subsidised ACT drugs in a multi-country pilot To improve access to drugs in sub-Saharan Africa, the Plasmodium falciparum prevalence were cost-effective compared to presumptive treatment, assuming that prescribers adhered fully to test results In high and very high transmission areas, presumptive treatment has cost-effectiveness advantages given the imperfect sensitivity of tests under field conditions In low-endemic settings, RDTs and microscopy remain attractive compared to presumptive treatment even when there is poor adherence to negative test results Currently available RDTs will not detect all infections with low parasite loads. These submicroscopic infections frequently occur in low-endemic areas Patients can influence the diagnostic and treatment practices of health workers Affordable Medicines Facility - malaria initiative demonstrated that large increases in access to ACTs were possible. Increasing access to RDTs is equally important. ACTs and RDTs should be seen as a package to improve management of febrile cases, and improving access to both of these in the public and private sectors has the potential to provide valuable returns.Meeting the global target of universal coverage with parasite-based diagnosis by 2015 is a huge undertaking requiring sufficient resources. The cost-effectiveness of the intervention will hinge on the accurate use of RDTs in guiding treatment. Probably the biggest challenge in RDT implementation will be to provide adequate and sustained supplies of RDTs and appropriate training to all health workers in endemic areas. With increased access to malaria diagnosis, there will also be increased use of antibiotics, and interventions to guard against even greater overuse are needed to prevent worsening antimicrobial resistance. The Table S1Patients treated with antimalarials and antibiotics in studies comparing clinical diagnosis with RDTs.(DOC)Click here for additional data file.Table S2Patients treated with antimalarials and antibiotics in studies comparing microscopy with RDTs.(DOC)Click here for additional data file."} +{"text": "By gaining a better understanding of healthy musculoskeletal aging we can provide better care and new therapies for common musculoskeletal problems.Sarcopenia is a term utilized to define the loss of muscle mass and strength and the consequent functional impairment that occurs with aging . OA is a long and slow continuum of joint changes and symptoms that has no clear-cut onset Englund, . TherefoGharbi and co-workers is another mechanism that contributes to age-related musculoskeletal deterioration. Increasing exercise capacity and physical fitness are likely to results in regeneration and remodeling within musculoskeletal tissue compartments. However, the molecular mechanisms that underscore these changes are poorly understood. Understanding age-related musculoskeletal deterioration requires co-ordinated basic, clinical, and translational studies that can generate novel and clinically testable approaches to healthier musculoskeletal aging. The elegant and original articles in this Research Topic highlight some of the major issues facing researchers in the area of musculoskeletal health and aging. We hope that this Research Topic will serve as a platform for encouraging further research into musculoskeletal aging."} +{"text": "While much of the major clinical and research interest in patellofemoral pain (PFP) has been targeted to the local knee muscles, it has long been recognized that proximal (hip and pelvis) biomechanics may be impaired in people with PFP. This clinical observation has led to recent research in pelvis and hip muscle contributions to PFP. Hip muscles are important in maintaining an optimal lower limb alignment during weight bearing activities. A growing body of contemporary evidence indicates that hip muscle function is compromised in PFP. This is highlighted by a recent systematic review, which found strong evidence for deficits in hip muscle strength in women with PFP compared to uninjured controls. We have observed a delayed onset of gluteus medius electromyographic (EMG) activity in people with PFP compared to healthy controls, confirming earlier findings. Reduced strength or neuromotor control of these hip muscles may be associated with an increase in hip internal rotation and adduction, with deleterious consequences at the knee. Notably, altered proximal biomechanics (hip and pelvis) can influence local patellar alignments and joint stress. Thus, the available evidence supports altered proximal biomechanics as an important feature of PFP, and has provided impetus for contemporary clinical management, favouring hip muscle retraining. However, there is a dearth of clinical trials investigating the clinical efficacy of hip muscle retraining in PFP. Similar to vasti muscle dysfunction, individuals with hip muscle dysfunction form a subgroup of people with PFP. Interventions designed to enhance hip muscle function are likely to benefit patients with PFP. Further scientific evidence is required to confirm the role of hip muscle dysfunction in the development and management of PFP."} +{"text": "In the light of ongoing land use changes, it is important to understand how multitrophic communities perform at different land use intensities. The paradox of enrichment predicts that fertilization leads to destabilization and extinction of predator-prey systems. We tested this prediction for a land use intensity gradient from natural to highly fertilized agricultural ecosystems. We included multiple aboveground and belowground trophic levels and land use-dependent searching efficiencies of insects. To overcome logistic constraints of field experiments, we used a successfully validated simulation model to investigate plant responses to removal of herbivores and their enemies. Consistent with our predictions, instability measured by herbivore-induced plant mortality increased with increasing land use intensity. Simultaneously, the balance between herbivores and natural enemies turned increasingly towards herbivore dominance and natural enemy failure. Under natural conditions, there were more frequently significant effects of belowground herbivores and their natural enemies on plant performance, whereas there were more aboveground effects in agroecosystems. This result was partly due to the \u201cboom-bust\u201d behavior of the shoot herbivore population. Plant responses to herbivore or natural enemy removal were much more abrupt than the imposed smooth land use intensity gradient. This may be due to the presence of multiple trophic levels aboveground and belowground. Our model suggests that destabilization and extinction are more likely to occur in agroecosystems than in natural communities, but the shape of the relationship is nonlinear under the influence of multiple trophic interactions. Land use change currently is the most important cause of terrestrial biodiversity loss Predator-prey theory predicts that stable coexistence of predators and preys is possible if their population dynamics are not too closely coupled Predator-prey theory has been tested for two trophic levels, and occasionally for tritrophic systems Disentangling the effects of aboveground and belowground control The overall aim of the present study was to investigate whether the predictions of the paradox of enrichment hold when multiple aboveground and belowground trophic levels and their searching efficiencies are included, and how the results relate to plant performance. We used herbivore-induced plant mortality as a proxy for system instability and assessed it along a land use intensity gradient from low to high fertilization levels and insect searching efficiencies. We derived three predictions from predator-prey theory and tested them using an individual-based simulation model of aboveground-belowground multitrophic interactions The individual- and rule-based ABove-BElowground interactions model ABBE was developed to investigate plant performance in a food web of plant shoots, herbivores, parasitoids and hyperparasitoids aboveground and plant roots, herbivores and their antagonists belowground Brassica nigra L. (Brassicaceae), the aboveground herbivores are represented by the specialist chewing larvae of Pieris brassicae L. (Lepidoptera: Pieridae) and the belowground herbivores are represented by the specialized root-feeding larvae of the cabbage root fly Delia radicum L. (Diptera: Anthomyiidae). Aboveground, the third and fourth trophic levels are parameterized according to the gregarious koinobiont endoparasitoid Cotesia glomerata L. (Hymenoptera: Braconidae) and its secondary hyperparasitoid, the solitary idiobiont Lysibia nana Gravenhorst (Hymenoptera: Ichneumonidae). As belowground third trophic level, we added the coleopteran egg predator Aleochara billineata Gyll. (Coleoptera: Staphylinidae) to the system of Soler et al. Aporrectodea caliginosa Savigny (Lumbricidae) and Octolasion tyrtaeum Savigny (Lumbricidae) (see The plant is simulated according to the wild cruciferous plant dae) see .The timeframe of the simulations is one growing season, the general time step is six weeks, space is not considered explicitly. The simulated processes in any one time step are nutrient pool replenishment, plant growth, earthworm action, shoot herbivore mortality, parasitoid mortality and reproduction, shoot biomass reduction by herbivores, parasitism of herbivores by parasitoids, hyperparasitoid mortality and reproduction, parasitism of parasitoids by hyperparasitoids, plant mortality due to shoot herbivory, belowground antagonist mortality and reproduction, root herbivore mortality due to antagonist attack, root herbivore natural mortality, root biomass reduction by root herbivores, plant mortality due to root herbivory, shoot and root herbivore reproduction Plant mortality and biomass was investigated along a simulated increase in land use intensity consisting of fertilization and searching efficiency parameters . These pTo investigate the direct and indirect influences of different trophic levels on plant performance along the land use intensity gradient, we designed removal scenarios. In each removal scenario, one trophic level was removed from the simulations . In total, this yielded seven removal scenarios including the standard scenario in which all levels were present. Removal can also be seen as a proxy for the application of a very effective pesticide. We performed simulated experiments with 1000 replicate runs per removal scenario and determined plant performance at the end of a growing season for each of the 40 steps along the land use intensity gradient. We measured plant performance as median shoot and root biomass of surviving plants at the end of a growing season and used plant mortality as an inverse proxy of plant performance and as a measure of instability. Plant mortality was calculated as the proportion of replicate runs in which the plant did not survive until the end of the growing season.We conducted a sensitivity analysis to identify the gradient parameters with the greatest contribution to plant performance and to assess their relative contribution to the land use intensity gradient. Plant performance was measured as shoot biomass, root biomass and \u2013 inversely \u2013 as plant mortality. We ran 1000 replicate simulations each for every possible combination of plant performance measure and gradient parameter, varying the parameters one after the other within the ranges specified for the parameters. For each combination, we separately applied a linear regression model of the form performance \u223c gradient parameter value \u00d7 removal scenario. We accounted for the removal scenario in the model formula to obtain sensitivity estimates that are independent of removal scenario. Sensitivity of the respective plant performance measure was calculated as standardized regression coefficient of the respective parameter value. Regression coefficients were standardized through division by the respective standard error.To quantify the effects of trophic level removal on plant performance along the land use intensity gradient, we compared plant performance before and after removal with Pearson\u2019s Chi-squared test statistic in the case of plant mortality and Mann-Whitney U-tests in the cases of root and shoot biomass. We used non-parametric tests and calculated the medians of root and shoot biomass, because non-normal errors and heterogeneous variance precluded calculating parametric statistics based on averages. We calculated the test statistics separately for each removal scenario and for each of the 40 steps along the land use gradient. All statistical analyses were carried out with the software package R 2.5.1 (R Development Core Team 2007).The sensitivity analysis showed that plant root and shoot biomass were by far most sensitive to the parameter nutrient supply . Plant mPlant mortality as a proxy of instability spanned the whole range from 0 to 1 . Plant mAs expected, the removal of the second trophic level significantly reduced plant mortality at most land use intensities, i.e. herbivores diminished plant performance aboveground and belowground (see points below the zero-line in The effects of the removal of trophic levels on shoot biomass generally were in line with the effects on plant mortality, only their direction was opposite . For insIn contrast to shoot biomass, root biomass was almost exclusively affected by belowground species . RemovalUsing an individual-based simulation model, we tested predictions derived from predator-prey theory Consistent with our first prediction, plant mortality as a measure of instability increased towards highly fertilized agroecosystems in the presence of all aboveground and belowground trophic levels. Hence, the paradox of enrichment is still applicable in a system with multiple trophic levels in aboveground and belowground subsystems. Our finding implies that parasitoids and antagonists were not able to offset the negative effect of herbivores on plant performance. This was not a trivial outcome, because the gradient parameters included increased efficiencies of both herbivores and their natural enemies and the removal experiments showed negative effects of herbivores on plant performance and positive effects of natural enemies. It seems that shoot herbivores alone were responsible for the 100% plant mortality plateau (sensuAboveground parasitoid removal gave more detailed insight into the efficiency of control of herbivores by their natural enemies along the land use intensity gradient: Aboveground biological control failed at high land use intensity and under natural conditions, but was successful in reducing plant mortality at intermediate land use intensities. With respect to shoot biomass loss, aboveground biological control was effective within an even smaller range located even further away from natural conditions (compare horizontal bars in sensuOur results supported the second prediction that the strength of aboveground effects on system instability should increase towards agroecosystems. Effects of belowground trophic levels on plant mortality and biomass were more important at low land use intensities whereas aboveground trophic levels had a greater impact on plant performance at intermediate to high land use intensities. This was a general trend for all components of the community (compare the location of the horizontal bars in panels a versus d, b versus e and c versus f in Removal of the fourth trophic level, the hyperparasitoids, and of the earthworms did not have marked effects on plant performance. Only earthworm removal decreased shoot biomass with increasing land use intensity, which can be explained by model architecture: Presence of earthworms increases root and shoot biomass by a certain proportion of the current biomass and current biomass increased with increasing resource supply.Our model analysis did not support our third prediction that the imposed smooth land use intensity gradient should result in smooth plant responses to trophic interactions. We observed abrupt non-linear effects of trophic level removal across all land use intensities and for all trophic levels. The most pronounced non-linearity was the rather suddenly reached 100% mortality plateau. Such enrichment-induced mortality and extinction have earlier been shown for plants in North America In conclusion, our model suggests that destabilization and extinction are more likely in fertilized agroecosystems than in natural communities, confirming the predictions of the paradox of enrichment also for communities with multiple aboveground and belowground trophic levels. Abrupt destabilization of the multitrophic system at high land use intensities implies that land use gradients as well as multiple trophic levels need to be considered to make reliable predictions on plant responses to land use change. These predictions will gain generality if more complex food webs with greater species diversities are considered in future modelling approaches. Based on our current predictions, it should be possible to tune land use in multitrophic agroecosystems such that the positive effect of natural enemies on plant performance is maximized while the risk of sudden transitions to high plant mortality is minimized."} +{"text": "The advent of affordable genome and exome sequencing provides incredible opportunities and poses significant challenges for clinical research and clinical care. For the first time, it is technically feasible to access the entire genetic architecture of a phenotype. The dissection of this genetic architecture of disease will yield unprecedented insights into molecular pathophysiology and provide numerous therapeutic targets. Soon, the primary etiology of all Mendelian traits will be elucidated and modifiers will follow. Translating this genetic architecture into diagnostics and therapeutics will be feasible and will require creative, aggressive and thoughtful approaches to numerous challenges. One of the first applications will be predictive medicine, which should initially focus on high-penetrance Mendelian phenocopies of common diseases and disorders with effective interventions. These include cancer susceptibility syndromes, cardiomyopathies and dysrhythmias, malignant hyperthermia, dyslipidemias, and a host of other disorders. These approaches will require improved abilities to predict phenotype from genotype and a clinical paradigm shift that supports a disease screening approach . As well, researcher and clinicians will need to develop creative approaches to dealing with data overload - no physician can address three million variations. Prioritizing these variants into clinically appropriate categories is urgent, as is developing an unbiased assessment of penetrance in variable expressivity. I will give examples of several of these approaches and their attendant challenges from the ClinSeq project in the intramural NIH."} +{"text": "Nearly half of the human genome consists of noncoding repetitive DNA elements, including tandem satellite repeats in large blocks at the pericentric regions of chromosomes and intergenic repetitive elements. While both repeat types were long thought to remain mostly silent, recent evidence indicates that repeats can be expressed, but the extent and regulation of their expression or their potential function(s) remain to be elucidated. Due to their critical location within regions vital for cell division, it is expected that tight regulation of pericentric satellite sequences is essential for both epigenetic and genetic stability. Our data suggests aberrant expression of pericentric satellite RNA is tightly linked to epigenetic misregulation in cancer. It is well known that epigenetic changes can be important in cancer initiation and progression, but studies have focused primarily on the inappropriate silencing and methylation of tumor suppressor genes. While pathologists have long noted the loss of heterochromatic organization in cancer nuclei, and hypomethylation of satellite DNA has been observed, the misregulation of repeat RNAs has only recently been described. Our results provide a link between overexpression of repeat RNAs and aberrant distribution of epigenetic factors in cancer. Our data suggests regulation of the repeat genome has potentially important roles in both normal and neoplastic cells in their ability to affect distribution and recruitment of epigenetic factors."} +{"text": "Surgical interventions are considered complex because they have multiple components which may act independently or interdependently to influence outcomes. These components need to be defined, described and monitored so that interventions can be accurately replicated. Process evaluations have been successfully used to inform the design and monitoring of other complex healthcare interventions and this study therefore aimed to establish the feasibility of undertaking process evaluation in the operating theatre.Case studies of surgical interventions were undertaken within an internal pilot RCT comparing the effectiveness of laparoscopic adjustable gastric banding and roux-en-Y gastric bypass for morbid obesity. Case studies involved two components: a)video recording, audiorecording and non-participant observation in theatre, and b)semi-structured interviews with surgical, anaesthetic and nursing staff to explore views of key intervention elements.Three case studies in two centres have been successfully undertaken, including interviews with seven staff. Obtaining complete datasets was challenging due to the unpredictable nature of the theatre environment and reliance on technology . Video and audiorecordings have been synchronised with observational data using Observer XT10 software. Thematic analysis of interviews is underway and triangulation of findings will help clarify the intervention and identify key components and context.Process evaluation in the operating theatre is feasible and can be used to establish how surgical interventions should be designed and monitored in main RCTs. Whether this should occur routinely is currently uncertain and requires further investigation."} +{"text": "Bronchial artery embolization (BAE) is a widely used modality of treatment for massive hemoptysis which has well known complications such as chest pain, groin hematoma and transverse myelitis but systemic embolization of the material used in the procedure is very rare and was reported only four times in the literature which were all caused by the use of microspheres. Herein we report a case of a 41-year-old caucasian male who had a history of tuberculosis 10 years ago. He had BAE with polyvinyl alcohol (PVA) for the treatment of recurrent hemoptysis. After the procedure, the patient complained of severe pain on the left upper quadrant and bilateral costovertebral regions and in abdominal CT, multiple infarcts in the subcapsular area of the spleen and kidneys were observed. This is the first reported case of inadvertent systemic embolization secondary to BAE with PVA. Although the risk of systemic embolization is greater with microspheres, still potentially serious and life threatening complications may occur with PVA.Bronchial artery emobolization; Complication; Polyvinyl alcohol Bronchial artery embolization (BAE) is a well-accepted and effective form of treatment for massive and recurrent hemoptysis but some potentially life threatening complications including organ infarcts due to inadverent systemic embolization of material used in the procedure may occur. We present a case of multiple infarcts in the spleen and kidneys secondary to bronchial artery embolization with polyvinyl alcohol (PVA).A 41-year-old caucasian male who had a history of tuberculosis 10 years ago was referred to our clinic for BAE for the treatment of recurrent hemoptysis of 30-50 cc per day for the last 3 months. Thorax and abdominal CT were performed for the suspicion of a malignancy. Abdominal CT was totally normal and thorHypertrophic common bronchial artery trunk, right bronchial artery, and fourth intercostal artery were selectively catheterized and embolized with PVA in one session without intraoperative complication. On the same day after the procedure, the patient complained of severe pain on the left upper quadrant and bilateral costovertebral regions. Physical examination revealed fever, abdominal distension, left upper quadrant and bilateral costovertebral region tenderness, defence and rebound. Complete blood count showed neutrophilic leukocytosis . C-reactive protein (CRP) was 122 mg/dL; lactate dehydrogenase (LDH) was 1193 U/L. Abdominal CT revealed multiple infarcts in the subcapsular area of the spleen and kidneys . The eleBAE has various reported complications which may be severe and life threatening such as spinal cord infarction, transverse myelitis , myocardSystemic embolization during BAE is a very rare complication and to our knowledge there are only four reported cases including infarcts in the spleen and kidneys, myocardial infarction and serebrovascular accident . EmbolizWe postulate that PVA had traversed from the bronchial circulation into the pulmonary circulation and then into small pulmonary arteriovenous malformations, and finally into the systemic circulation causing multiple infarcts in the spleen and both kidneys.Actually, the risk of systemic embolization is higher with microspheres when compared with PVA because PVA has variability in size and a tendency to aggregate. These properties limit the ability to embolize peripheral vessels and cross arteriovenous anastomoses; however, microspheres do not have these limitations .We have presented the first case of inadvertent systemic embolization secondary to BAE with PVA. Although the risk of systemic embolization is greater with microspheres, still potentially serious and life threatening complications may occur with PVA."} +{"text": "To develop a statistical map of regional wall motion in healthy and diseased populations using a standardized database of cardiovascular magnetic resonance studies.The Cardiac Atlas Project (CAP) is a NIH sponsored international collaboration to establish a web-accessible structural and functional atlas of the normal and pathological heart as a shared resource for the clinical, research and educational communities.Images, derived ventricular contours, and clinical text data have been contributed from several studies. To date, 2864 cases have been contributed from the MESA study comprisi2 test showed significant differences between the MESA cohort and subgroups of the DETERMINE cohort, stratified according to infarct location .Standardized mapping of shape and motion facilitates statistical characterization of cardiac performance, providing a powerful resource for the scientific community. Applications for use of the resource can be made from the website ("} +{"text": "Innate lymphoid cells (ILC) are immune cells that lack a specific antigen receptor, yet possess the capacity to produce an array of effector cytokines that in variety matches that of T helper cell subsets. Innate lymphoid cells function in lymphoid organogenesis, tissue remodeling anti microbial immunity and inflammation particularly at barrier surfaces. The ability of ILCs to promptly respond to insults inflicted by stress causing microbes strongly suggests that ILC are critical in first line immunological defenses. In addition ILC are involved in repair of tissue damage inflicted by pathogenic microbes. In my presentation I will present data on developmental requirements, lineage relationship and effector functions of members of two families of innate lymphoid cells: Rorgt-expressing cells involved in lymphoid tissue formation, mucosal immunity and inflammation and Type 2 innate lymphoid cells that are important for helminth immunity. In addition I present evidence for the existence of a novel ILC population that is dedicated to produce interferon gamma. I will also discuss the possible roles of ILC in pathology of immunity mediated inflammatory and infectious diseases including allergic diseases."} +{"text": "The cerebellum forms a highly ordered and indispensible component of motor function within the adult neuraxis, consisting of several distinct cellular subtypes. Cerebellar disease, through a variety of genetic and acquired causes, results in the loss of function of defined subclasses of neurons, and remains a significant and untreatable health care burden. The scarcity of therapies in this arena can partially be explained by unresolved disease mechanisms due to inaccessibility of human cerebellar neurons in a relevant experimental context where initiating disease mechanisms could be functionally elucidated, or drug screens conducted. In this review we discuss the potential promise of human induced pluripotent stem cells (hiPSCs) for regenerative neurology, with a particular emphasis on in vitro modelling of cerebellar degeneration. We discuss progress made thus far using hiPSC-based models of neurodegeneration, noting the relatively slower pace of discovery made in modelling cerebellar dysfunction. We conclude by speculating how strategies attempting cerebellar differentiation from hiPSCs can be refined to allow the generation of accurate disease models. This in turn will permit a greater understanding of cerebellar pathophysiology to inform mechanistically rationalised therapies, which are desperately needed in this field. The cerebellum, also termed \u2018little brain\u2019, is an extensively researched part of the neuraxis. Nonetheless, the molecular pathogenesis underlying cerebellar disease remains poorly understood, with the vast majority of such disorders still being immedicable to date . As one Regenerative medicine has been revolutionised by the potential of disease modelling and manipulation via hiPSC technology, a recent discovery later recognised by the Nobel Prize in Physiology or Medicine . DiffereThe advent of hiPSCs is of particular relevance to a structure like the cerebellum both from developmental and clinical neurological perspectives as most of the mysteries remain to be unravelled and no cHere we highlight the promise of iPSC technology to regenerative medicine, and especially neurology with a specific focus on the cerebellum. We first discuss the prospects and remaining challenges of iPSC technology before focussing specifically on current strategies, achievements and limitations for directed differentiation to cerebellar neurons. We conclude by summarising the advances in modelling human cerebellar degeneration using hiPSCs and speculating on future areas of interest at the experimental interface between cerebellar neurology and human stem cell-based disease modelling \u2018in-a-dish\u2019.The discovery of efficient reprogramming of adult human fibroblasts into iPSCs in 2007 has sincNeuronal cells have been amongst the earliest cell types to be generated via reproducible and efficient differentiation protocols from hESCs and hiPSAlthough this technology permits modelling of human developmental processes and diseases in an esModelling cerebellar disease with hiPSC technology has not yet become a broadly used routine approach and is reported with less frequency compared with other neurological diseases.Progress in modelling cortical, striatal, midbrain, spinal, peripheral sensory and autonomic nervous system development and disease using human pluripotent stem cells is largely attributable to the presence of established protocols for directed differentiation to region specific neurons and glia . This clAn important contribution to the lack of reliable and efficient cerebellar differentiation protocols might certainly come from the rarity of cerebellar diseases. One could argue that simply the medical and socio-economic necessity to generate hiPSC models of cerebellar disorders is lower and therefore orchestrated efforts of developmental biologists have focussed on deriving more \u2018deserving\u2019 cell types for more common disorders such as PD and Alzheimer's disease (AD). In these disciplines, significant progress in directed differentiation of disease-relevant neurons has been made . Even thAgainst this background, it seems plausible that the inherent and notorious developmental complexity of cerebellar cells [and especially Purkinje cells (PCs)] and subsequent difficulties generating them from human iPSCs have hampered significant progress in this field, despite both early and indeAt the time of writing, the authors are aware of one publication using hiPSC-derived long-term self-renewing neuroepithelial-like stem (lt-NES) cells from patients with SCA3 to study the cellular pathology of the most common autosomal-dominant degenerative cerebellar disorder . Here, tIn order to explain the lack of studies using patient-derived iPSCs to generate cerebellar cells and study their pathology we need to address the following question:Cerebellar development in humans occurs over a prolonged time span ranging from the early embryonic period to the first postnatal years. It happens in parallel to the development of the forebrain, midbrain, spinal cord and their arising substructures, but follows its own distinct stereotyped pattern. In summary, four basic processes can be delineated: Firstly, the cerebellar primordium forms at the midbrain\u2013hindbrain boundary (MHB) under close transcriptional influence of the isthmic organiser can be met, the future of modelling cerebellar diseases with iPSC technology will be bright. We are cautiously optimistic that efficient and reproducible protocols for the generation of PCs and granule cells from hiPSCs will be developed within the coming years using insights from developmental biology and also guided by recent breakthroughs . This wiIn summary, the cerebellum currently fails to obtain comparable experimental recognition as other neuraxial regions largely due to a poor translation of its underlying developmental biology into directed differentiation strategies. Noting recent breakthroughs in the directed differentiation of human pluripotent stem cells into cerebellar derivatives, we predict that this hitherto relatively understudied region of the neuraxis can now begin to receive the experimental attention it deserves. This in turn may illuminate the precise mechanisms of cerebellar development and degeneration, thus informing therapeutic strategy."} +{"text": "Depressive and eating disorder symptoms are highly comorbid. To date, however, little is known regarding the efficacy of existing programs in decreasing concurrent eating disorder and depressive symptoms.We conducted a systematic review of selective and indicated controlled prevention and early intervention programs that assessed both eating disorder and depressive symptoms.We identified a total of 26 studies. The large majority of identified interventions (92%) were successful in decreasing eating disorder symptoms. However fewer than half (42%) were successful in decreasing both eating disorder and depressive symptoms. Intervention and participant characteristics did not predict success in decreasing depressive symptoms.Indicated prevention and early intervention programs targeting eating disorder symptoms are limited in their success in decreasing concurrent depressive symptoms. Further efforts to develop more efficient interventions that are successful in decreasing both eating disorder and depressive symptoms are warranted. Eating disorders and depressive disorders have revealed strong associations, and their relationships contribute to the complexity, burden, and treatment resistance of these disorders . In viewThe lifetime comorbidity between eating disorders and major depressive disorders is high with estimates of 40% for Anorexia Nervosa and 50% for Bulimia Nervosa . ImportaSeveral types of relationships have been hypothesized and described between eating disorder and depressive symptoms, namely that 1) eating disorder and depressive symptoms may develop simultaneously; 2) eating disorder symptoms may be a risk factor for depressive symptoms; 3) depressive symptoms may be a risk factor for eating disorder symptoms. While all of these models have received empirical support -7, compeA number of theoretical models have proposed frameworks that account for these shared and specific risk factors including biological, cognitive, emotional-regulation, and feminist models. Biological models emphasize the importance of shared genetically transmitted biological factors, as described above, and in particular the importance of dysregulation of serotonergic pathways that have an impact on both mood and eating behaviors . CognitiDespite the high rates of comorbidity and the number of theoretical frameworks accounting for this co-occurrence, to date little is known regarding the common course of eating disorder and depressive symptoms within interventions for high-risk individuals or early intervention programs. Previous work exploring the effect of prevention interventions for eating disorders on negative affect revealed that programs targeting individuals at high risk of eating disorders were more successful in decreasing negative affect . FurtherThe aim of the present study was, therefore, to conduct a systematic review of interventions for high risk (indicated prevention) and symptomatic individuals (early intervention) that included both eating disorder and depression outcomes. Furthermore, consistent with previous findings , we expeThis review was conducted in accordance to the PRISMA guidelines for systematic reviews . The floThe databases PsychInfo, ScienceDirect and Scopus were searched for studies and dissertations published between January 1984 and September 2013. Two searches were conducted in each database, first a title search, second a keyword search. The searches included combinations of words describing eating concerns (eating AND disorder or disordered or disorders or pathology or disturbance or disturbed), body image concerns (body image or dissatisfaction or shape or appearance), depressive symptoms (depression or depressive or negative affect) and controlled interventions . In addition, studies included in previous reviews of the efficacy of interventions aiming to reduce eating concerns as well as the reference sections of relevant articles were scanned for additional potentially eligible studies.Peer-reviewed published work.Controlled intervention design, compared to an active or minimally active condition such as treatment as usual, or psychoeducation (randomised or not).Indicated interventions defined as interventions aimed at individuals who were identified as having minimal detectable signs or symptoms of an eating but did not meet diagnostic criteria . In our The concurrent assessment of both disordered eating and depressive symptoms at baseline and post-intervention, using psychometrically established measures for assessing both eating concerns and depressive symptoms.The resulting list of studies was inspected by one author to identify those meeting the following criteria:Data from the reviewed studies were extracted by one author (RR). The data extraction sheet listed the following categories designed to describe and compare the studies mean age, gender, country, inclusion criteria for the study, type of intervention, mode of delivery, depression and eating disorder symptom measure, effects of intervention at post-test and follow-up, baseline depression level, number of intervention sessions, and presence of content targeting negative thoughts and emotions.Depression scores were transformed into percentile ranks using norms from the general population ,27. Chi-Our review identified 26 studies corresponding to our inclusion criteria Table\u00a0. Of the Of the 27 studies, 24 (92%) revealed a statistically significant decrease in eating disorder symptoms while 12 (46%) revealed a statistically significant decrease in depressive symptoms. Eleven studies (42%) significantly decreased both depressive and eating disorder symptoms.None of our hypothesized moderators of program success on depressive symptoms were supported. Programs with content targeting negative emotions or negative cognitions were not more likely to decrease depressive symptoms. Similarly, programs implementing CBT techniques were not more likely to decrease depressive symptoms. Furthermore, initial levels of depressive or eating disorder symptoms, age, and number of sessions also revealed no association with intervention efficacy in decreasing depressive symptoms Table\u00a0.Table 2Similarly, none of the hypothesized moderators were able to distinguish between programs that successfully decreased both depressive and eating disorder symptoms, and those that were successful in decreasing only one, or none Table\u00a0. HoweverThe aim of the present study was to review the efficacy of indicated prevention and early interventions programs in decreasing concurrent depressive and eating disorder symptoms. Overall, the findings revealed that while the majority of interventions were successful in achieving decreases in eating disorder symptoms, fewer than half of the interventions identified were successful in decreasing both eating disorder and depressive symptoms. These results suggest that existing interventions may be limited in their overall impact and their long-term effects as remaining depressive symptoms could increase the likelihood of later recrudescence in eating disorder symptomatology . FurtherThe findings from our review reveal that while 92% of the interventions resulted in significant decreases in eating disorder symptoms, only 42% were successfully in decreasing concurrent depressive and eating disorder symptoms. An important consideration lies in the fact that all of the interventions identified were primarily designed to target eating disorder symptoms, thus publication bias might have affected these ratios and made it more unlikely for our review to identify interventions successful only in decreasing depressive symptoms. Nevertheless, despite the seemingly widespread recognition of the important role of depressive symptoms in eating disorder pathology, illustrated by the frequent inclusion of depressive symptoms as a secondary outcome and the consideration of the effects of eating disorder interventions on depressive symptoms or negative affect in meta-analyses of eating disorder prevention interventions , our finThe limited success of the interventions included in this review in decreasing depressive symptoms given their general success in decreasing eating disorder symptoms, suggests that, consistent with theories of comorbidity in a subset of individuals at least, depressive symptoms may not be secondary to eating disorder symptomatology . Some auOverall, our proposed moderating factors were not predictive of success in decreasing depressive symptoms. One potential explanation for this failure is that we lacked statistical power due to using dichotomous variables as outcomes and for many moderators, or that the continuous variables assessed lacked variability. However, it might also be that variables other than those assessed in these studies, predict intervention effects on depressive symptoms. Our finding did reveal a trend-level finding regarding number of sessions, with shorter interventions revealing a higher likelihood of decreasing both eating disorder and depressive symptoms. This finding is consistent with those of meta-analytic reviews of interventions targeting depressive symptoms among children and adolescents . These aOur study was limited by some aspects of the available data. We used participant recruitment criteria (self-selected versus screened) as a proxy for eating disorder severity in part due to the wide variability in eating disorder instruments used and the lack of available normative data for some of those instruments. Using a more sensitive measure of eating disorder severity might have produced different results. Furthermore, while some studies provided rates of diagnosable depression in their sample of baseline, rates of depression at post-test were not available, precluding examination of decreases in diagnosable depression.Increasing our understanding of the course of depressive symptoms in relation to eating disorder symptoms during interventions might help clarify the mechanism of change in depressive symptoms and identify individuals benefiting less from the intervention effects on depressive symptoms.Exploring participants\u2019 experience of the causes of depressive symptoms, in particular as related or unrelated to their eating disorder symptoms, would contribute to increasing our understanding of the partial success of eating disorder interventions in decreasing concurrent eating disorder and depressive symptoms.The development and evaluation of depression-specific modules in eating disorder interventions would provide evidence of increased efficacy in decreasing depressive symptoms.Including measures of eating disorder symptoms in interventions primarily targeting depressive symptoms could further inform interventions for these comorbid concerns, and contribute to greater treatment efficiency.Nevertheless, these findings reveal the gap in knowledge and practice regarding the treatment of concurrent eating disorder and depressive symptoms and suggest some directions for future work:Eating disorder and depressive symptoms are frequently comorbid and, in recognition of this, eating disorder interventions have often assessed depressive symptoms. The effect indicated prevention and early intervention programs on depressive symptoms is somewhat limited, however, and the characteristics of successful interventions are unclear. Further efforts are required to develop interventions that are successful in decreasing both eating disorder and depressive symptoms in order to increase treatment efficiency and the maintenance of therapeutic effects."} +{"text": "Significant deviations from accepted norms of eruption time are often observed. Most parents are anxious about delayed tooth eruption, as it is considered to be an important milestone during child\u2019s development. Delayed tooth eruption might be the primary or sole manifestation of local or systemic pathology[2]. The systemic conditions like malnut-rition, rickets, endocrinopathies, chemotherapy, cerebral palsy and low birth weight can lead to delayed tooth eruption. Eruption of deciduous teeth, their exfoliation followed by eruption of permanent dentition is an orderly sequential and age specific event Local factors delaying eruption may include presence of mucosal barriers, supernumerary teeth, odontogenic and non odontogenic tumors, local infections, injury and ankylosis of deciduous teeth. mixed odontogenic tumors, since they are composed of both epithelial and mesenchymal tissues. However, biologically regarded as hamartomas rather than neoplasms[3]. Most of the cases of odontomas are often undetected because they are clinically asymptomatic and nonaggressive. They are usually identified on routine radiographic examinations or during evaluation of delayed tooth eruption as in this case. A 12 year old boy referred with a complaint of missing right central incisor tooth. Examination of his upper jaw revealed that the central incisor tooth was unerupted and the deciduous counterpart was retained with mesial drifting of the lateral tooth creating an anesthetic appearance . Radiogr A thorough visual, manual and radiographic examination should be performed for all pediatric patients who present with clinical evidence of delayed eruption, missing or displaced tooth. Early identification and removal of odontomas help us to:Adopt less complex and invasive treatmentEnsure better prognosisAvoid displacement or devitalization of adjacent tooth [4]. After removal of the obstacle from the path of eruption, an impacted tooth either erupts spontaneously if it has conserved its eruptive force or orthodontic force is required to bring the tooth in normal position"} +{"text": "A general problem in biology is whether different types of cells in the same tissue are metabolically different from each other, and whether such differences are important for cellular function. Experiments that can comprehensively measure the cellular metabolome typically require millions of cultured cells and cannot be used with small numbers of rare cells freshly isolated from tissues. In particular, hematopoietic stem cells (HSCs), the blood forming stem cells of the bone marrow, have been intensively studied for decades but their metabolic composition is largely unknown.We have developed a method to measure metabolites in small numbers of HSCs. The HSC isolation and mass spectrometry methods have been optimized for maintenance of the metabolome during purification, sensitivity and robustness. About 50 metabolites can be quantified from 10,000 HSCs, covering a wide spectrum of the cellular metabolome. Several metabolic differences exist between HSCs and other bone marrow cells, including restricted progenitors. I am investigating the role of these metabolic adaptations in HSCs.The ability to profile the metabolome of rare cells isolated directly from tissues opens the possibility to metabolically compare stem cells to other purified populations of cells at different stages of differentiation, to test the metabolic consequences of physiological challenges like aging on specific populations of cells, and to test whether other rare cells, like subpopulations of cancer cells from the same tumor, are metabolically distinctive."} +{"text": "We highlight the recent findings in this field that allow the uncovering of the basic principles behind brain plasticity in light of the existing theoretical models at various scales of observation. Given the current lack of in-depth understanding of the neurobiological basis of brain structure changes we emphasize the necessity of a paradigm shift in the investigation and interpretation of use-dependent brain plasticity. Novel quantitative MRI acquisition techniques provide access to brain tissue microstructural properties in-vivo, thereby allowing unprecedented specific insights into the mechanisms underlying brain plasticity. These quantitative MRI techniques require novel methods for image processing and analysis of longitudinal data allowing for straightforward interpretation and causality inferences.In this article we provide a comprehensive literature review on the The next section outlines novel theoretical frameworks for studying brain plasticity, followed by a section on the accumulated scientific evidence on use-dependant plasticity. Recent advances in MRI acquisition techniques are presented that offer promising prospects for the exploration of the neurobiological basis of brain plasticity. Considering the most recent reviews on the topic , we aimed to infer causality using a prospective study design with multiple data acquisition time-points C isotopes generated by nuclear bomb tests during the Cold War. The main finding of this study is that neocortical neurogenesis outside the hippocampal dentate gyrus is restricted to the developmental period rather than a lifelong property of the human brain for automated data analysis in the spatial and temporal domains enabled unbiased feature reductions and statistical parametric mapping in standardized space. Despite the overwhelming variability of existing software solutions for the computation of volume, surface, and shape characteristics of the brain rely on the very same basic principles of data processing and statistical analysis. Although computational anatomy studies on use-dependant brain plasticity raised hopes to answer pertinent questions about neurobiological processes underlying the remodeling of brain anatomy, only few attempts have been made to validate measures of relative changes in gray matter volume, density and cortical thickness derived from MRI data with \u201cgold standard\u201d histology assessment.The most widespread computational anatomy technique\u2014voxel-based morphometry\u2014VBM relies on atlas information to detect the boundaries of gray matter followed by projection of the thickness values on a surface mesh to the acquired signal. Quantification of these MRI parameters, which correlate with brain tissue microstructural properties such as myelin, iron and water content allows for an unprecedented insight into the mechanisms underlying brain plasticity. This represents a paradigm shift in how we estimate and analyse brain anatomy features, which can be used to relate plasticity-associated brain tissue property alterations to changes in behavior and to estimate their specific impact on the currently used gray matter volume, density and cortical thickness. A tipping point for future advances in understanding the principles of human brain plasticity will be the creation of causal generative models based on longitudinal studies with multiple data time points acquired before, during, and after behavioral intervention. Finally, the biophysical mechanisms linking tissue microstructure and the MRI signal are still under investigation. Accurate modeling of these mechanisms will be essential to produce estimates of the microstructural properties relevant in brain plasticity studies from the quantitative MRI data. The development of biophysical models will require validation, most preferably in the form of correlation studies with \u201cgold standard\u201d histology assessment.Quantitative structural brain imaging allows differentiating between plasticity-associated tissue property changes and local brain volume/density or cortical thickness changes. Our approach includes whole-brain multi-parameter mapping at high resolution and computational anatomy studies to lend support to causality assumptions (Kanai and Rees, post mortem histological findings at higher spatial resolution. Though scientifically highly advantageous, the concept of looking for brain plasticity correlates at the microscopic level has its limitations\u2014results from animal models cannot readily be extrapolated to humans and many cognitive processes cannot be studied in animals. There are also practical limitations such as shrinking of the specimen due to fixation, artifacts of staining or difficult localization of investigation/recording sites (Sincich and Horton, Despite the steadily growing number of longitudinal computational anatomy studies reporting use-dependant brain structure changes, there has been no attempt to date to link macrostuctural morphometric findings with microstructural information (for review Fields, . We stilIn conclusion, the overwhelming number of computational anatomy studies on use-dependant brain plasticity has provided major contributions to our understanding of the characteristic spatial and temporal patterns of brain structure changes at the macroscopic scale. First animal studies applying in parallel computational anatomy methods and histological investigation provide important findings at unprecedented fine granularity. Newly emerging MRI acquisition techniques hold promising prospects that might allow the detection for the first time of the brain tissue microstructural changes associated with use-dependant plasticity beyond the vague neurobiological observation of concomitant volume or density changes. Not only will this advance our scientific understanding of brain plasticity, it will also provide an empirical basis for the creation of reliable non-invasive biomarker for the rehabilitation progress after brain function loss. A generative model capturing spatial and temporal characteristic of use-dependant changes could help in unraveling causal pathways between exercise-induced behavioral changes and remodeling of brain structure to make an important contribution to our scientific understanding of brain function and dysfunction.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Metastasis is a major cause of mortality in Breast Cancer (BC) patients in part due to lack of clinically established targeted therapies. Among the different types of BC, triple negative BC (TNBC) has been associated the most with poor prognosis and survival due to early metastasis to other organs and a lack of clinically established targeted therapies. Hence, elucidating novel mechanisms that regulate metastasis would lead to the development of targeted therapies and new treatments for TNBC and metastatic breast cancers.It is now well accepted that solid tumors, including those in the breast, have an inflammatory microenvironment. Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules which has been associated with chronic inflammation, which in turn enhances the progression of various cancers . We haveWe have shown that RAGE deficiency inhibits the growth of murine breast cancer tumor cells . RAGEdefThe link between inflammation and cancer has been postulated for a long time because of the presence of inflammatory cells in the tumor microenvironment, including myeloid cells and tumor associated macrophages (TAMs) . These cOverall, our results indicate that RAGE could be used as a novel therapeutic target and biomarker for TNBCs. Furthermore RAGE/S100A7 signaling through paracrine and endocrine mechanisms in epithelial as well as TAMs plays an important role in linking inflammation to breast cancer development and metastasis (Fig."} +{"text": "Class specific deprescribing guidelines could help clinicians taper and stop medications no longer needed or which may be causing more harm than benefit. We set out to develop methodology to create such guidelines using evidence-based methods for guideline development, evidence synthesis and recommendation rating.Using a comprehensive checklist for a successful guideline enterprise, we conducted a national modified Delphi consensus process to identify priorities for deprescribing guidelines, then conducted scoping exercises to identify feasible topics, and sequentially developed three deprescribing guidelines. We selected guideline development team members for clinical expertise; a GRADE member worked with staff to ensure guideline development processes were followed. We conducted or used systematic searches and reviews of deprescribing trials of selected drug classes, reviews or systematic reviews of drug class effectiveness, reviews of reviews of drug class harm and narrative syntheses of contextual questions to inform recommendations and guideline development. Our 8 step process for guideline development included defining scope and purpose, developing a logic model to guide the process and generate key clinical questions, setting criteria for admissible evidence and conducting systematic reviews, synthesizing evidence considering additional contextual information and performing quality estimates, formulating recommendations and providing strength estimations, adding clinical considerations, conducting clinical and stakeholder review and finally updating content pre-publication. Innovative aspects of the guideline development process included synthesizing evidence for outcomes of tapering or stopping medication, and incorporating evidence for medication harm into the recommendation strength rating. Through the development of three deprescribing guidelines and associated decision-support algorithms, we were able to gradually hone the methodology; each guideline will be published separately.Our methodology demonstrates the importance of searching for short and long-term outcomes, showing the benefits of deprescribing and studying patient preferences. This publication will support development of future deprescribing guidelines. Little deprescribing guidance is available to clinicians and the public. Current deprescribing algorithms \u20134 are noA companion paper outlines the developmental evaluation method we used to study the development and implementation of the guidelines . ResultsDeprescribing is the planned and supervised process of dose reduction or stopping of medication(s) that may be causing harm or are no longer providing benefit. The goal of deprescribing is to reduce medication burden and harm, while maintaining or improving quality of life. This is particularly important to consider as people age, given changes in pharmacokinetics, pharmacodynamics and physiological reserve . Risks oSmall studies have demonstrated successful deprescribing approaches, yet haveWe used a comprehensive checklist for a successful guideline enterprise to develop the methods for our deprescribing guidelines.We began by conducting a national modified Delphi consensus process with potential users of the guidelines to identify priorities for deprescribing guideline development . Particide novo systematic review would be required for the guideline.We conducted scoping exercises to identify three of the top five priority topics for which deprescribing guideline development would be feasible . These iWe established a Guideline Development Team (GDT), including a Methods Committee member for each of three topics\u2013proton pump inhibitors, benzodiazepine receptor agonists and antipsychotics. Each team included a guideline lead, clinical experts and a staff coordinator. For example, the BZRA guideline included a family physician (1), pharmacists (2), clinical pharmacologist (1), psychiatrists (2), psychologist (1) geriatrician (1) and GRADE methodologist (1). The names and expertise of each GDT member are described in each guideline publication. Guideline leads had clinical expertise with the topic area and experience conducting systematic reviews for guideline development. We identified clinical experts through the Cochrane network, a network of clinicians interested in the Deprescribing initiatives and through identified experts recommending other experts. Clinical and guideline method expertise contributed to the selection of additional guideline team members. We recorded team members\u2019 conflict of interest declarations .Each of the three guideline development teams followed the same process , adaptedEach GDT met either face-to-face and/or by teleconference to determine the target audience, scope and purpose of the guideline. They considered target audiences to be health care professionals involved in the prescribing or monitoring of medication effectiveness and safety within the primary care and long-term care environments. The purpose of each guideline was to provide evidence for the benefits and harms of deprescribing a drug or drug class (including feasibility and safety in terms of not worsening symptoms or causing disease recurrence), evidence of benefit and harm of continuing the drug or drug class, patient preferences and values surrounding deprescribing, resource implications of deprescribing as well as practical guidance on how to implement deprescribing .Each team identified patients for whom the guideline would and would not apply, as well as other guidelines recommending a limited duration of treatment for certain indications. While our original intention was to develop guidelines to facilitate deprescribing in the elderly, there was such a paucity of trials in this age group that we therefore expanded the inclusion criteria to include all adults (\u226518 years).Population of interest (adults >18), the Intervention (deprescribing), the Comparator (continuation of the medication) and patient-important Outcomes relevant for decision-making (both positive impact and adverse effects of deprescribing) [The Methods Committee developed a generic logic model to illustrate the possible evidence chain of each guideline . The logcribing) . Staff, Each GDT populated a standard template during their initial meeting, then revised a circulated copy of the key PICO question until consensus was reached. Each team considered and ranked the importance for patients and clinicians on the following outcomes: effect on pill burden, patient satisfaction, medication prescription numbers, cost/resource implications, adherence, health care utilization and stabilization, worsening or improvement of a symptom or disease, quality of life and changes in physical or cognitive function.Driven by their clinical experience, each GDT also identified additional contextual questions, for example: What are alternative, safer, effective pharmacological or non-pharmacological options for treatment of the symptom or condition? Are there certain populations that might be more amenable to deprescribing? What tapering strategies and monitoring approaches should be used to safely deprescribe the medication?An expert medical librarian and a systematic review methodologist with experience conducting Cochrane reviews developed the search strategies to assess benefit or harms of deprescribing the drug class of interest. The research assistants met with one investigator to reconcile the resulting list of studies and resolve any disagreements regarding selection of relevant studies.The librarian conducted a literature search to facilitate an English only review of reviews of harms using the methods outlined by Smith et al. RelevantThe librarian conducted additional literature searches to provide relevant content for considering other contextual questions . An example search strategy for values and preferences is in All evidence was synthesized into recommendations using the GRADE Evidence to Recommendations Table and their own clinical experience to provide guidance on these questions. Sample questions are outlined in A practicing family physician, nurse practitioner and pharmacist (who were not members of the Deprescribing project) provided a clinical review of each guideline using the AGREE II Global Rating Scale to guidePrior to publication, the GDT incorporated feedback from stakeholders and pilot sites, and updated guideline sections if new relevant evidence was available.deprescribing.org) to house implementation tools . Knowledge translation will be facilitated through social media and conference presentations/workshops.Dissemination of each guideline is planned via open-access publication and use of a website , using rigorous search and synthesis processes, ensuring clarity of presentation, assessing applicability (through pilot testing in both community and long-term care settings), documenting competing interests and maintaining editorial independence.Consistent with research that demonstrates guidelines are more likely to be implemented when accompanied by guideline implementation tools ,35, eachStrengths of our process included engagement of clinicians in a feedback process using AGREE II, inclusion of all GDT members with an active role in writing sections of the guideline, using the GRADE process to make judgements about directness and values transparent, honing a streamlined process for guideline development and incorporating the development of guideline implementation tools. The research team set out to develop and pilot three guidelines over 30 months. We conducted a developmental evaluation strategy of both the guideline development and implementation processes . ResultsLimitations encountered in our deprescribing guideline development process included the paucity of RCT evidence for deprescribing; this narrowed the choice of topics for guideline development using the GRADE method and highlights an important gap in research that funding agencies should note. Guideline development team members relied on observational evidence for harms data, surveys and interviews for patient preferences data, and expert clinical opinion for clinical considerations pieces when other evidence was unavailable. Our intention was to incorporate frontline patient perspective through interviews with patients in the pilot sites , however, we were unable to recruit sufficient numbers of patients to complete a valid qualitative analysis. Instead, we subsequently incorporated feedback from clinicians who had implemented the guidelines with patients, relying on their perspective to provide proxy patient input. We recognize the limitation with this approach and recommend going forward, that deprescribing guideline developers include representative patient users on guideline development panels from the outset. We recognize this approach is also fraught with challenges but feelEvidence-based deprescribing involves systematic search, evaluation and synthesis of evidence on benefits and harms to formulate recommendation on tapering or stopping medications. Decisions around deprescribing can be clinically difficult to make. We have developed methodology to create guidelines that synthesize the information needed to support deprescribing decisions. This methodology could be used as a template for future evidence based deprescribing guidelines.Our guidelines take into account evidence of benefit of the medication class, estimations of their harm and evidence of the feasibility and outcomes of deprescribing\u2013the latter two topics representing key innovations in guideline development. The GRADE approach assisted in rating the quality of evidence, particularly for the elderly population subgroup where possible, as well as taking into account patient preferences and resource implications when formulating recommendations. The process fulfills the AGREE II criteria, the current quality standard for guidelines development.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S3 Appendix(DOCX)Click here for additional data file.S4 Appendix(DOCX)Click here for additional data file."} +{"text": "Altruistic punishment, which occurs when an individual incurs a cost to punish in response to unfairness or a norm violation, may play a role in perpetuating cooperation. The neural correlates underlying costly punishment have only recently begun to be explored. Here we review the current state of research on the neural basis of altruism from the perspectives of costly punishment, emphasizing the importance of characterizing elementary neural processes underlying a decision to punish. In particular, we emphasize three cognitive processes that contribute to the decision to altruistically punish in most scenarios: inequity aversion, cost-benefit calculation, and social reference frame to distinguish self from others. Overall, we argue for the importance of understanding the neural correlates of altruistic punishment with respect to the core computations necessary to achieve a decision to punish. While m Ostrom, .Altruistic punishment occurs when an individual forgoes a personal gain to punish (Seymour et al., Altruistic punishment generates a vast array of questions about its behavioral and neural mechanisms. The evolutionary consequences for promoting prosocial behaviors, such as cooperation, remain continuously debated (Nakamaru and Iwasa, How does the brain mediate altruistic punishment? Many studies have directly explored this question Table . Blood-oFurthermore, converging evidence suggests that prefrontal regions are specialized for evaluating fairness and guiding norm compliance during punishment. In addition to the previously cited work implicating the DLFPC in administering punishment as the SP, low-frequency repetitive transmagnetic stimulation to the right DLPFC increased the acceptance rate of unfair offers in the UG (Knoch et al., However, it remains unclear what computations are primarily driving the neural signals in altruistic punishment tasks. In the following sections, we highlight three fundamental cognitive processes occurring in most altruistic punishment scenarios that might play significant roles in driving the neural activations. These processes may inform how different neural circuits are implemented in driving altruistic punishment.Altruistic punishment occurs in response to an offer perceived to be inequitable. Inequity often evokes negative affect, which may motivate the decision to altruistically punish (Montague and Lohrenz, Because inequity motivates a punishing action, neural processes associated with inequity detection and aversion could significantly guide the decision to costly punish. The aversion associated with inequity, on the other hand, may reflect how the neural signals corresponding to inequity detection are transformed and further processed by emotion-related circuitry. Converging evidence indeed indicates that task events correlated with inequity typically activate brain regions implicated in affective processing. Further research is needed to understand how these signals influence the decision to punish.In realistic settings, there are not necessarily tight temporal relations between the time of inequity detection and the punishment\u2014some punishments may occur as an immediate reaction, whereas others may occur long after the infraction, many days and even years following inequity detection. In the laboratory, most studies have had focused on relatively small time window between inequity detection and punishment for practical purposes. The role of inequity-evoked negative affect is likely to be greater when the time from the inequity detection to the punishing act is relatively short. It would be interesting to test the magnitude of affective drive in different brain regions during punishing decisions as a function of the delay between the time of inequity detection and forming the decision to punish.Cost-benefit analysis could occur when deciding to carry out altruistic punishment, requiring that the cost of punishment be weighed against the benefit of punishing (Egas and Riedl, In examining effort as a proxy for cost required for some benefit, a lesion to ACC reduced a rat's willingness to expend effort to receive a large reward, whereas control animals typically expended energy (Walton et al., Some studies have related a nonsocial reward currency with social rewards, which could be occurring in altruistic punishment when a player sacrifices money to punish another player. An exchange rate between viewing social images and receiving monetary rewards that falls along a distribution correlated with the valuation of the image is reflected in the hemodynamic activity of the posterior VMPFC (Smith et al., Regardless of whether the gains of altruistic punishment are monetary or social, cost-benefit calculations may play a key role in the neural processes leading up to a decision to punish at a predicted cost. Examining cost-benefit relations in both nonsocial rewards and social rewards and associated neural activity across different individuals during costly punishment decisions may reveal intriguing insights into the mechanisms underlying the decision to costly punish.Any behavior that involves another individual requires a set of representations across self and others. Costly punishment, in particular, may require the evaluation of others' internal states when an individual is faced with outcomes that could ultimately benefit another individual or a group. Evidence demonstrates that there are shared networks in the brain that compute information with respect to self and others (Decety and Sommerville, In addition, the TP observer likely infers the reward contingencies from the perspectives of the two players after punishing. Such multidimensional inferences across oneself and another individual must require a signal transformation across self and others Chang, Figure . InsightIn both SP and TP punishment, the punisher must be able to accurately process affective responses and reward outcomes as a result of punishment across himself and the other player or players involved. As such information is essential to behaviors directed at other individuals, it is critical to comprehend the amount and specific nature of neural activations driven by such computations in social punishment scenarios.Costly punishment poses some of the most interesting evolutionary questions for scientists. Cooperation, which rests inherently on the shared needs of individuals and groups, seems to be at complete odds with traditional evolutionary theories that pit individuals against each other in a race for survival and reproduction. Yet cooperation in animal and human behavior often determines the survival of entire populations. The neural underpinnings of altruistic punishment in humans are actively being investigated, but many questions remain unanswered. Several studies so far suggest the lateral aspect of the prefrontal cortex as a key locus in mediating altruistic punishment (Knoch et al., A paradigm with high temporal sensitivity may reveal how cognitive and affective signals in the brain converge or diverge across the entire timespan of deciding to punish at a cost. For example, future investigations combining fMRI with another method allowing for a higher temporal resolution, such as electroencephalography or functional near-infrared spectroscopy, may reveal new, crucial information on the region-to-region interactions between neural signals correlated with inequity aversion, cost-benefit calculation, and information processing across self and others. Furthermore, developing a nonhuman primate model of costly punishment may complement research in humans by providing more detailed neuronal mechanisms of the three core neural processes involved in altruistic punishment through single-unit recording and pharmacological interventions of specific populations of neurons. Another important factor to consider in any social neuroscience research is the context in which a given social behavior takes place. Understanding how social context gates the neural processes associated with inequity aversion, cost-benefit calculation, and information processing across self and others will better inform the complex contingencies behind altruistic punishment.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Tissue-derived stem cells (TDSCs) are undifferentiated cells, presented in tissues such as bone marrow, blood vessels, and adipose tissues and with the ability to repair damaged areas by generation of new cells and tissues. TDSCs have proven to be a feasible source of cells for tissue regeneration medicine in recent experimental and clinical studies. Mesenchymal stem cells revealed potential benefits in atherosclerosis and endoIn the present special issue, the significance and possible clinical applications of TDSCs were presented. Some manuscripts described important biochemical cascade underlying the processes of osteogenesis, adipogenesis, angiogenesis, and their possible applications in new therapy development. All findings and experiences of TDSCs research will open up new possibilities for the treatment of various diseases and extend the human life span.Ming LiMing LiKequan GuoKequan GuoDong Hyun KimDong Hyun KimLuca VanellaLuca Vanella"} +{"text": "Biospecimen of controlled quality thus are mandatory prerequisites for precise multiparameter diagnosis, individualized biomarker-based treatment and prognosis and therefore, are critical for the development of personalized medicine in general.This paper will address current and future challenges and projects in biobanking including biospecimen storage conditions in the light of changing technologies and future data analysis reflecting the fact that technological and medical knowledge evolve over time. The lack of standardization in clinical study reporting is another issue preventing annotation of pseudonymized individual molecular and clinical data and thus further analyses. Further, the importance of adequate funding, training and certification will be stressed, suggestions for biobank quality criteria presented and aspects such as quality management, biobank network extension and resource sharing discussed.To tackle these issues, ESBB\u2019s potential future partners and possible proposals within the new EU Program \u201cHorizon 2020\u201d will be introduced."} +{"text": "Patients admitted to the intensive care unit (ICU) with critical illness often experience significant physical impairments, which typically persist for many years following resolution of the original illness. Physical rehabilitation interventions that enhance restoration of physical function have been evaluated across the continuum of recovery following critical illness including within the ICU, following discharge to the ward, and beyond hospital discharge. Multiple systematic reviews have been published appraising the expanding evidence investigating such physical rehabilitation interventions, although there appears to be variability in review methodology and quality.To conduct an overview of existing systematic reviews of physical rehabilitation interventions for adult intensive care patients across the continuum of recovery.This protocol is registered on PROSPERO (CRD 42015001068). We will search the Cochrane Systematic Review Database, Database of Abstracts of Reviews of Effectiveness, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and CINAHL. We will include systematic reviews of randomised controlled trials of adult patients, admitted to the ICU, and who have received physical rehabilitation interventions at any timepoint during their recovery. Data extraction will include eligible systematic review aims and rationale, study types, populations, interventions, comparators, outcomes and quality appraisal method. Quality of reporting and methodological quality will be appraised using the PRISMA checklist, and the AMSTAR tool.We anticipate the findings from this novel overview of systematic reviews will contribute to the synthesis and interpretation of existing evidence regarding physical rehabilitation interventions and physical recovery in post critical illness patients across the continuum of recovery."} +{"text": "The objective of this study is to investigate effects of ionizing radiation on human hematopoietic stem cell differentiation.Despite being a strong mutagen, causing several genetic and chromosomal aberrations, ionizing radiation in the form of gamma rays and heavy ion radiation is becoming increasingly important in medical therapies and cancer. Heavy ions especially the particle beam of carbon ion are high energy radiations that is considered to be extremely hazardous during occupational radiological emergencies, manned space missions, high altitude flights, accidents casualties etc. Healthy blood cells in human body arise by the differentiation of a very small population of pluripotent hematopoietic stem cells that have the capacity of self renewal throughout their lifespan. Effects of radiation whatsoever minimum on these unique cells thus have greater impact on the human system in both long term and short term scenario which might currently lead to an idea of a new concept leading to cancer stem cells.Umbilical cord blood collected in-utero was subjected to immuno-magnetic enrichment, followed by flowcytometric estimation for stem cell content. Isolated hematopoietic stem cells were then cultured into specialized cytokine based medium and exposed to various doses of ionizing radiation for investigations on CD34+ marker based flowcytometric survival assay, differentiation & clonogenic potential by CFC assay, genotoxicity and cytotoxicity.Exposure to different doses of ionizing radiation showed a marked difference in the survival of CD34+ stem cells in both dose and time dependant manner. Differentiation of stem cells into their adult progenitor cells were also altered with varying doses of radiation treatment. Our findings show variations on response of the human CD34+ stem cells when exposed to ionizing radiation which is significantly comparable to normal blood lymphocytes and cancerous K562 cells."} +{"text": "In 2008, allowing for an increase in the number of women treated with mastectomy and immediate reconstruction, the decision at our institution was made to carry out mammography of the native and the reconstructed breast at follow-up. A literature review at that time revealed that mammography of the reconstructed breast may help diagnose recurrence before any symptom. This local practice is now audited to evaluate its impact, and whether it should continue.All women who had previously undergone mastectomy and reconstruction, and were subsequently imaged with mammography between 2008 and 2013 at Ealing Hospital were included. Subsequent findings and further investigations have been analysed.Eighty patients treated with mastectomy and reconstruction had regular screening mammograms. Ten local recurrences occurred in six patients. Four recurrences were diagnosed on imaging findings alone . Six recurrences presented with a new symptom . Routine imaging of the reconstruction generated additional imaging: seven stereobiopsies for microcalcifications (two recurrences) and two ultrasound scans (one recurrence). In the same period, 17 ultrasound scans (five recurrences) and 12 MRIs were requested for clinical concerns.Routine imaging of the reconstructed breast can diagnose local recurrence with limited harm, generating few additional investigations. However, which patients may benefit and whether this improves outcome is unclear as the number of cases in our audit is small and the event is thankfully rare."} +{"text": "Background: The roles of genetic factors in human longevity would be better understood if one can use more efficient methods in genetic analyses and investigate pleiotropic effects of genetic variants on aging and health related traits.Data and methods: We used EMMAX software with modified correction for population stratification to perform genome wide association studies (GWAS) of female lifespan from the original FHS cohort. The male data from the original FHS cohort and male and female data combined from the offspring FHS cohort were used to confirm findings. We evaluated pleiotropic effects of selected genetic variants as well as gene-smoking interactions on health and aging related traits. Then we reviewed current knowledge on functional properties of genes related to detected variants.Results: The eight SNPs with genome-wide significant variants were negatively associated with lifespan in both males and females. After additional QC, two of these variants were selected for further analyses of their associations with major diseases (cancer and CHD) and physiological aging changes. Gene-smoking interactions contributed to these effects. Genes closest to detected variants appear to be involved in similar biological processes and health disorders, as those found in other studies of aging and longevity e.g., in cancer and neurodegeneration.Conclusions: The impact of genes on longevity may involve trade-off-like effects on different health traits. Genes that influence lifespan represent various molecular functions but may be involved in similar biological processes and health disorders, which could contribute to genetic heterogeneity of longevity and the lack of replication in genetic association studies. The literature review on the genetic influence on human aging and longevity indicates limited progress in identifying genetic mechanisms regulating human aging, health, and longevity using genome wide association studies (GWAS). Most associations detected in these studies tend to be weak and have not reached the genome-wide level of statistical significance. They also suffer from the lack of replication in studies of independent populations. What factors and conditions might be responsible for such a situation? What methods and approaches have to be used to properly address these issues?The literature on genetic studies of human longevity lacks an appropriate biologically-based conceptual framework that would allow one to efficiently address questions about the dynamic roles of genes in forming aging and longevity related traits. Such a framework would help specify necessary steps for efficient comprehensive analyses of corresponding genetic mechanisms using available data. The approaches based on the systems biology of aging, health, and longevity Kriete, merged wThe literature review also revealed the underutilized research potential of available data that were used in genetic analyses of aging and longevity traits. The possibility of more efficient analyses of genetic associations with such traits was demonstrated in Yashin et al. , 2000 whIn genetic analyses performed in this paper we used a modified statistical procedure of testing genetic associations with longevity related traits. The populations whose data are used in GWAS often have genetic structures called \u201cpopulation stratification\u201d (PS). Such structures are caused by non-random mating between groups of individuals followed by different patterns of genetic drift of allele frequencies in each group. Without proper controlling for PS in the statistical procedures used in GWAS of complex traits the analyses may result in erroneous associations. To avoid such errors the genetic association studies of complex traits include control for potential PS. The method of principal components analyses (PCA) suggested in Price et al. identifip-value > 1E-7. After applying the QC procedure, the data on 1111 individuals with information about lifespan and 429,783 SNPs were available for the analysis. Life spans for 204 study subjects were censored. We used EMMAX software to perform GWAS of female lifespan data from the original FHS cohort with modified correction for population stratification. In the confirmation phase we used genetic and the life span data on males from the same FHS cohort and the life span data on males and females combined from the offspring FHS cohort. Using available data on cancer and CVD as well as longitudinal data on physiological indices we estimated age trajectories of probabilities of staying free of the corresponding diseases for carriers and non-carriers of selected genetic variants as well as associations of these variants with age trajectories of physiological indices. We also investigated how smoking modulates estimated associations. More details about methods of data analyses used in this paper are given in Section In the discovery phase of the analyses we used the life span data on genotyped females collected in the original cohort of the Framingham Heart Study (FHS) Giroux, as well p-values, genetic frequencies, and other important characteristics of these SNPs.The most significant genetic variants resulted from GWAS on human life span using female data from the original FHS cohort are shown in Table p-values, genetic frequencies, and other important characteristics of these SNPs. This table shows that the eight genetic variants that had negative associations with lifespan in females also showed statistically significant negative associations with lifespan in males.To test whether the selected genetic variants also show significant associations with lifespan in males we performed genetic analysis of the ten selected SNPs using lifespan data on 432 males from the original FHS cohort. The same (additive) genetic model and the same observed covariates were used in these analyses. The results are summarized in Table Statistical estimates in Tables S1, S2 are obtained using mixed effect regression model with imputed life span data on 204 study subjects). It is unclear whether detected associations remain statistically significant when the methods free of life span imputation are used in the association analyses. To address this issue we evaluated genetic associations of selected genetic variants with mortality risk using Cox's regression model that does not require data imputation. The results of these analyses Table showed hTo test whether detected variants are associated with life spans of the members of the offspring FHS cohort we performed genetic analyses of data for this cohort. Since the life span data for some members of this cohort are censored these analyses have been performed using the Cox's regression model using gender as an observed covariate. All selected variants showed significant associations with mortality risk using data from the offspring cohort Table .verify the research findings obtaned using regression models in GWAS by constructing and comparing empirical survival functions for carriers and non-carriers of selected variants. Note that the case-control analysis, typicaly used in genetic studies of centenarians, does not have data to make such a verification. Since associations of the variants with lifespan in our GWAS have the same direction of the effect in both genders, the Kaplan\u2013Meier estimates of conditional survival functions for the genotyped members of the original FHS cohort were evaluated for males and females combined. In such evaluation we took into account that the life span data on the members of the original FHS cohort are right censored and left truncated. Note that for genetic analyses one should use age at blood collection (not the age at baseline) as the left truncation variable. We calculated these variables using data from the DNA Draw Date file available for FHS data from the dbGaP. Then we calculated ages at death/censoring of those 1111 individuals using age at the first exam and the number of days since the first exam until the death event or censoring which are provided in the Framingham data. Using these data and the R package \u201csurvival\u201d we calculated Kaplan\u2013Meier estimates of conditional survival functions for carriers and non-carriers of selected genetic variants who survived until specific ages .An important advantage of longitudinal data for genetic analyses of lifespan is the opportunity to Figure Figures Using data on the smoking habit (ever or never) as well as life span data on genotyped members of the original FHS cohort we evaluated effects of interactions of detected genetic variants with the smoking habit on survival. The results are shown in Figure Figures Using available data on ages at disease onset, we evaluated conditional probabilities of staying free of cancer , for males and females combined who survived to 80 years of age. The results for the two SNPs, rs7894051 and rs4904670, are shown on Figure One can see from this figure that when males and females are combined, the rs7894051 does not influence cancer risk Figure , while cUsing longitudinal data on body mass index (BMI) for genotyped individuals from the original FHS cohort, we evaluated the average age trajectories of BMI for carriers and non-carriers of the minor allele for the same two SNPs, rs7894051 and rs4904670, in males and females. The results are shown in Figure One can see from Figures P-value), which could aid biological interpretation of the findings. We conducted review of current knowledge about biological and health effects of these SNPs and related genes using up-to-date publications and reliable online sources such as NCBI's PubMed, Entrez Gene, dbSNP, OMIM, Ensembl, GeneCards, GO, and MetaCore from Thomson Reuters. Genes related to SNPs identified in this study (or to SNPs that are in LD with them) are largely involved in mitochondrial oxidation, apoptosis, and protein degradation in cell. These processes are important part of cell/tissue responses to stress or damage. For example, the NRDE2 (C14orf102) gene is linked to PSMC1, a subunit of 26S proteasome involved in protein degradation, essential for cell damage response. PSMC1 may potentially interact with PSMD13, which is another subunit of the same 26S proteasome involved in protein degradation. ECHS1 is involved in mitochondrial oxidation and apoptosis, also essential for cell/tissue response to damage allele of the two selected SNPs increased cancer risk in females. For males, however, the effect of these variants on cancer was the opposite, and carrying the vulnerability allele reduced the cancer risk in males.Since most centenarians avoid cancer may sometimes do both, promote cancer and at the same time be potentially against certain phenotypes of physical senescence. This could happen because cancer and senescent phenotypes such as physical frailty, and heart failure due to muscle atrophy, have peak manifestations at different ages: cancer risk reaches its maximum typically before oldest old age (<85), while senescence-related causes become major contributors to mortality risk later (at ages 85+) in the same cohort and in the offspring generation indicates that these findings are likely to be true-positive. It also indicates that GWAS of human longevity with inappropriate controls for population stratification are likely to suffer from the low level of statistical significance and from the lack of replication.The genetic data from the original FHS cohort were one of the first prepared for genetic analyses using GWAS, and a substantial portion of genotyped cohort members died before the quality of genotyping was substantially improved. Therefore, these data have higher chances of having genotyping error than more recently produced datasets. Taking this into account we performed testing of the quality of genotyping for eight genetic variants detected in this study and CVD. One may argue that the health and longevity traits investigated in this study are too heterogeneous: individual differences in life spans may depend on susceptibility to different chronic conditions and cause specific mortality risks; cancers of distinct sites are often associated with different genetic and non-genetic factors; the term CVD includes many diseases dealing with cardio-vascular problems, each having its own sets of risk factors; etc. Although these concerns are certainly correct, one often does not have much choice: the selection of a trait for analysis is determined by the available data which has to be enough to get reliable conclusions from the analyses. Studying factors affecting aggregated traits may help us detect regularities and identify mechanisms that are common for many specific phenotypes comprising such traits. An important question is how best to analyze heterogeneous traits when you must? How can an understanding that the trait is genetically heterogeneous affect methods and results of analyses?different genetic mechanisms may be responsible for the same manifestation of a given trait. The goal of the analyses thus becomes, not just finding the one or more longevity (or vulnerability) alleles/genotypes responsible for the genetic variation of life span in all individuals, but investigating possible alternative mechanisms responsible for developing this trait. These mechanisms may involve different sets of genes in different individuals or in different groups of individuals. The genetic heterogeneity of longevity could be partly responsible for the lack of replication of respective genetic association studies.Despite the fact that the presence of such heterogeneity is recognized by many researchers in the field, there is no agreement concerning the best strategies for dealing with this issue. The recommendation that follows from our experience would be to investigate genetic heterogeneity by using different statistical models of the connections between genetic factors and phenotypic traits, to consider how the results of analyses differ for different quality control procedures, to perform careful studies of the non-replicating results, keeping in mind that Although exact replication, such as findings of identical SNPs or genes, is not common across genetic association studies of aging and longevity, biological and health effects of identified genes, especially their involvement in similar damage responses, and in similar pathology, often overlap between the different studies. In our case, the involvement of selected genes Table in canceThe results of our review of current knowledge also suggest an intriguing possibility that the vulnerability SNPs in genes involved in neurological disorders might also contribute to accelerated brain aging, and through this negatively impact longevity, which idea deserves further investigation. Connections between lifespan related genes and cancer may involve complex trade-offs. More detail on potential biological mechanisms are provided in section on Biological Meaning above.In sum, our study demonstrated genetic connections among lifespan, physiological aging changes, and complex diseases. Comparison of functional properties of genes found in this and other genetic studies of aging/longevity indicates that human lifespan may be regulated by different sets of genes; however, these genes tend to be involved in similar biological processes and complex pathology. The fact that the same biological process or health outcome may be realized through the different genes suggests that genes may potentially be interchangeable in their influence on longevity. This could contribute to both genetic heterogeneity of longevity and to a lack of replication in genetic association studies of lifespan and related phenotypes. Additional studies with a higher quality genetic data are needed to support our conclusions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Lower back pain is the leading cause of disability worldwide. Discogenic pain secondary to intervertebral disc degeneration is a significant cause of low back pain. Disc degeneration is a complex multifactorial process. Animal models are essential to furthering understanding of the degenerative process and testing potential therapies. The adult human lumbar intervertebral disc is characterized by the loss of notochordal cells, relatively large size, essentially avascular nature, and exposure to biomechanical stresses influenced by bipedalism. Animal models are compared with regard to the above characteristics. Numerous methods of inducing disc degeneration are reported. Broadly these can be considered under the categories of spontaneous degeneration, mechanical and structural models. The purpose of such animal models is to further our understanding and, ultimately, improve treatment of disc degeneration. The role of animal models of disc degeneration in translational research leading to clinical trials of novel cellular therapies is explored. Lower back pain causes more global disability than any other condition worldwide and is aThe intervertebral disc is a complex multicomponent structural tissue consisting of an outer fibrous ring, the annulus fibrosus (AF), and an inner hydrated gel-like substance, the nucleus pulposus (NP) . It is tCells of the disc NP are derived from the notochord. In man these cells are retained throughout childhood but with maturity disappear and are replaced by chondrocyte-like cells . The losHuman intervertebral disc degeneration is a complex and incompletely understood multifactorial process with contributions from genes, mechanical stresses, cellular senescence, and alterations in nutrition via the limited vascular supply . With reStudies comparing degenerate discs with nondegenerate controls have demonstrated increased evidence of senescent cells in degenerate intervertebral discs . Such ceIntervertebral discs comprise the largest essentially avascular tissue in the human body. Only the outermost layers of the AF contain blood vessels. The cells of NP are dependent on diffusion of nutrients from capillary buds in the cartilaginous endplate to meet their metabolic needs . The celUltimately there is an imbalance between the rates of production and breakdown of the matrix components leading to a cascade of events see consistiThe development of appropriate animal models of intervertebral disc disease is necessary to gain insight into the pathophysiology and to develop and test potential therapies. In vitro and in silico (computer based) systems can be helpful to investigate specific components of intervertebral disc degeneration. However, given the complexity inherent in the intervertebral disc with biochemical, biomechanical, nutritional, and metabolic factors acting simultaneously, in vivo animals are able to more faithfully replicate this environment. A range of animal models and mechanisms of replicating the process of degeneration have been investigated and utilized in efforts to develop appropriate models of intervertebral disc degeneration. However, given the extreme complexity of this system no perfect model currently exists.Initial discussion will focus on the merits and inadequacies of particular species as models for human intervertebral disc degeneration. This will be followed by a discussion of the comparative merits of the various methods of inducing disc degeneration.Animal models range from small rodents such as mice knockout models to rats The vertebral column and thus intervertebral discs of all mammals arise from aggregation of the mesenchyme around the notochord and subsequent segmentation during development . NotochoLoss of intervertebral disc notochordal cells may be observed in animal models with otherwise persistent notochordal cells following adequate stimulus , 31. ApoHowever, given the use of animal models to investigate cellular regenerative therapies for the treatment of disc degeneration the potential presence of a preexisting precursor cell population may complicate investigation of the regenerative potential of such therapies. For instance, in cell transplantation therapies, one cannot be sure that it is not the resident notochordal cells which are responsible for the regenerative effects, instead of, or in combination with, the transplanted cells.Intervertebral discs vary markedly across species and according to location within the spine. The discs of most animal models are smaller than human intervertebral discs. Disc size affects solute diffusion in the intervertebral disc. Given the largely avascular nature of the intervertebral disc and dependence on diffusion to meet nutritional requirements this is of particular significance to the clinical relevance of animal models. Given the size discrepancies between common animal models and humans investigators have analyzed disc geometry hoping to better determine the relevance of particular models to the human intervertebral disc. In a study by O'Connell et al. the geomThe vast majority of animal models of intervertebral disc disease are quadrupedal. The only bipedal models available, certain primates to varying extents and theTaking the above general considerations into account the following models are those most commonly described for use as in vivo models of intervertebral disc degeneration.Mice and rat models, despite the obvious difference in intervertebral disc size, have significant advantages with regard to ease of use and application of technology. Genetic knockout and mutation mice models have enabled the investigation of the effects of the elimination of particular proteins, for example, collagen II , on discThe mouse and rat tail provide a readily accessible model for intervertebral disc degeneration through mechanical injury, asymmetrical compression, or administration of digestive enzymes , 70.Persistent notochordal cells: limiting the potential relevance of such models to the clinical environment particularly with regard to testing potential therapeutics.Differing mechanical loading: rodent tail models: the tail may have significantly different mechanical loading to the human lumbar spine although this has been disputed by some authors.Significantly smaller disc size reducing the nutritional challenge.Ethical concerns regarding the bipedal mouse.However significant limitations exist for such models:The rabbit model of intervertebral disc degeneration has been utilized by several authors for investigation of disc degeneration and of potential therapeutic agents , 71. MajAs discussed previously CD dogs demonstrate a decrease of notochordal cells from birth onwards with complete loss by early adulthood predisposing the animal to intervertebral disc degeneration. The CD dogs, among which beagles and dachshunds number, are well-characterized models of spontaneous intervertebral disc degeneration . The larGoats have previously been used as models for intervertebral disc degeneration , 60. AdvThe sheep model has proven to have particular merit for several major reasons. Firstly, the sheep, similar to humans, suffers from a loss of notochordal cells in early adulthood, predisposing the sheep intervertebral discs to degeneration . The shePorcine models have been utilized in models of intervertebral disc degeneration and in the preclinical assessment of biological therapies such as mesenchymal stem cells , 80. MajSpontaneous disc degeneration has been demonstrated in baboon and macaque models , 25, 66.Given the complexity of human disc degeneration no animal model can perfectly mimic the entire pathophysiological process. Disc degeneration in animal models is typically initiated by various chemical or mechSpontaneous disc degeneration occurs in a limited number of species, with inconsistent onset and development over a long time frame. The most well-studied species with regard to spontaneous disc degeneration are the sand rat and the chondrodystrophoid dog species. As described above spontaneous disc degeneration has also been observed in nonhuman primates.Sand Rat. The sand rat is native to east Mediterranean deserts [ deserts and was deserts . When fe deserts . The deg deserts . In a lo deserts radiogra deserts . Additio deserts .Genetically Modified Mice. Genetically modified mice models have been developed to investigate the contribution of specific proteins to disc degeneration. Genetically modified mice with collagen IX mutations demonstrated increased cervical degeneration [neration . Similarneration .Canines. As detailed previously CD dogs demonstrate loss of notochordal cells from birth onwards and progress to demonstrate gross pathology and histopathological and glycosaminoglycan content changes similar to humans in intervertebral disc degeneration [neration . There aneration , 88. Canneration . The choPrimates. Baboons and macaques have both been demonstrated to undergo spontaneous disc degeneration [neration , 66. As Spontaneous models of disc disease can be particularly useful in providing models of disc degeneration. However, the long and at times unpredictable course of spontaneous degeneration often limits their utilization in studies of potential therapies.Mechanical models afford the advantage of initiating the degenerative cascade at a defined time point in a replicable fashion. Epidemiological studies have suggested the association between exposure of the spine to force and disc degeneration . MechaniCompression. Compression involves the application of altered mechanical stresses to the intervertebral disc through mechanism such as bending [ bending , postura bending Bending. Bending of the rat tail is one of the earliest reported methods of inducing disc degeneration [neration . In pionneration rat tailneration were abl(2) Postural Change. The bipedal rat and mouse models, as described above, are based on the hypothesis that surgically modified animals will spend more time in an erect posture thus exposing the intervertebral discs to increased mechanicals stress. Given the more recent findings indicating bipedal rats do not spend an increased time in an erect posture and, in fact, possibly less time than their quadrupedal counterparts [terparts it is in(3) Chronic and Cyclical Compression. Researchers have investigated the application of static and cyclical compression to the intervertebral disc. Iatridis et al. [s et al. describe Kroeber et al. developeCyclical compression has also been investigated. In a rat tail model Ching et al. investigInstability. Various animal models of disc disease exist in which the intervertebral disc is exposed to increased instability at the motion segment promoting intervertebral disc degeneration. Approaches to produce instability include surgical resection of posterior elements such as facet joint and spinous processes [rocesses and the rocesses . Miyamotrocesses demonstrPhillips et al. reportedInstability studies allow an inducible method of progressive disc degeneration with many of the features observed in the clinical condition. The time course of progression of these models, requiring 9\u201312 months for the establishment of severe disc degeneration, may preclude their usage in studies of regenerative therapies given cost concerns.An alternate mechanism of inducing disc degeneration is directly compromising the structural integrity of the intervertebral disc. This task can be accomplished by chemical or direct physical methods.Chemonucleolysis. Various chemical agents have been investigated as potential stimuli to induce the pathophysiological process of disc degeneration. The best described such agent, chymopapain, was first reported in clinical use in 1964 for the treatment of sciatica secondary to presumed disc protrusion [otrusion . Chymopaotrusion that prootrusion . The enzotrusion . Inadequotrusion . High dootrusion .Chondroitinase ABC is another enzyme demonstrated to produce disc degeneration in animal models . ChondroAs described above injection of enzymes leads to proteoglycan loss, an essential component of the pathophysiological process of disc degeneration observed clinically. A criticism of the chondroitinase ABC for inducing disc degeneration is that the viability of native disc cells is largely preserved, enabling regeneration of the extracellular matrix .Physical Methods. Surgical injury to the intervertebral disc is a well-established method of inducing disc degeneration. Injury can be performed to the endplate, the annulus, or the annulus and nucleus.Endplate injury has been demonstrated in a porcine model to produce changes consistent with disc degeneration. Following lumbar endplate injury with a drill bit porcine intervertebral discs were observed over a 3-month period to demonstrate annular delamination, with reduction in nucleus proteoglycan content, cellularity and loss of gel-like structure . EvidencAnnular injury models were first described in the 1930s by Keyes and Compere . Keyes aStab injuries and annulotomies have been performed in a variety of animal models including rats , rabbitsFull thickness intervertebral disc injury is demonstrated in the approach of Oehme et al. . In thisA novel full thickness intervertebral disc injury caprine model utilizing a drill bit has recently been described by Zhang et al. . The autDespite the limitations of the animal models described above such models play an integral role in increasing our knowledge and understanding of the process of disc degeneration and in the development of novel therapies for clinical application. Given the complex pathophysiological process of disc degeneration with the interplay of cellular, biomechanical, and matrix components cellular therapy is considered by many to demonstrate the greatest potential in the treatment of this condition.A recent review by Oehme et al. compreheThe EuroDISC clinical trial investigAutologous bone marrow mesenchymal stem cell administration has been investigated in two small series of patients , 107. ThThe administration of allogeneic mesenchymal precursor cells for the treatment of back pain has been investigated in a Phase II study . A signiThe discussion of clinical translation raises one of the most important considerations regarding the translation of findings from animal models of disc degeneration, that of pain. Disc degeneration causes the majority of its morbidity and disability through back pain\u2014a subjective phenomenon. Pain is a symptom experienced by patients and is multifactorial in nature. The clinical observation of significant radiological disc degeneration in the absence of significant back pain in many patients is suggestive of the notion that the two are not necessarily well correlated at all times. Thus the measures of disc degeneration employed in animal models of disc disease such as histology and radiological degeneration scores and macroscopic and biochemical analysis can serve as useful markers of underlying disc degeneration but can inform the observer to only a limited degree of the likely disability associated with such findings.The assessment of intervertebral disc degeneration related pain in animal models is still in its relative infancy. The majority of such research has been conducted in rodent models , 110. PaThe assessment of pain in small animal models is imperfect but greatly increases our power to investigate the underlying pathophysiology of intervertebral disc degeneration related pain.The complexity of the human intervertebral disc bares repetition. Given this inherent complexity no animal model will perfectly replicate the clinical condition. The best that can be hoped for is to mimic as closely as possible the clinical condition of degenerative disc disease. Important considerations in choosing an appropriate animal model are the absence of notochordal cells, animal and intervertebral disc size relative to humans, biomechanical forces acting upon the intervertebral disc, mechanistic concerns , and ethical considerations. Nonhuman primates closely match the clinical condition with regard to many of the physical and mechanistic criteria, particularly given the demonstration of spontaneous intervertebral disc degeneration in baboons and macaques. However, ethical considerations should preclude their widespread utilization.The ovine model of disc disease possesses many desirable characteristics when considering the ideal intervertebral discs model: absence of notochordal cells, similar body mass to humans, and similar biomechanical forces acting upon the intervertebral disc. A major potential criticism of this model is the quadrupedal rather than bipedal nature of sheep. As discussed previously biomechanical studies have indicated that the ovine and human lumbar spines have good comparability in many biomechanical properties in spiteCertain questions will remain unanswerable in large animal models without significant advances in technology. As such, a role for small animal models will continue, particularly in the investigation of the action of specific gene products in disc degeneration through the use of genetically modified/knockout mice.The variety of methods of inducing disc degeneration is even broader than the variation in animal models. Spontaneous models of disc degeneration, such as the chondrodystrophic dog and primate, are most likely to parallel the clinical condition in terms of underlying mechanism and time frame. However, the variability of onset and prolonged time course of the degenerative process renders such models difficult to utilize in many contexts. Investigation of regenerative therapies, for example, would be rendered exceptionally difficult if an investigator were to wait for all animals scheduled for investigation to spontaneously develop an appropriate degree of degeneration. For investigations of regenerative therapies it is thus likely that methods of inducing structural injury will be the most utilized as these enable instantaneous production of a replicable injury at a defined time point.In conclusion no animal model will mimic the clinical condition of disc degeneration with complete fidelity. This is due to the complexity of clinical intervertebral disc degeneration and the immense influence of the subjective phenomena of pain in determining patient outcomes. Animal models will continue to play an essential role in refining our understanding of the pathophysiology of disc degeneration, developing novel therapies for this condition, and ultimately translating such therapies to the clinic."} +{"text": "Diagnostic musculoskeletal ultrasound is a non-invasive, low-cost, imaging modality that may be used to characterize normal and pathological muscle tissue. Sonography has been long proposed as a method of assessing muscle damage due to neuromuscular diseases such as muscular dystrophy . Similar approaches to quantitative ultrasound have also been successfully employed to estimate body fat in adults during an imaging procedure. However, this mode of feedback alone may be insufficient to control factors related to examiner force and sound transducer orientation. The serial ultrasound image exemplar depicted in the Figure Qualitative diagnostic ultrasound is often focused on the identification and subjective description of an anatomical structure or pathological tissue anomaly. Sonographers frequently use variable levels of force and sound transducer angle to obtain images of deep structures with sufficient resolution for clinical use. In contrast, quantitative ultrasound is generally dependent on the examiner exerting minimal stress on the tissue or structure of interest, and using consistent transducer orientation to attain reliable serial or comparative measures. Therefore, the use of calibration phantoms and force-feedback-augmented ultrasound may be viable methods of providing operator training and aiding real-time ultrasound measurement consistency.The constraints associated with quantitative ultrasound tend to limit this form of assessment to superficial tissues (Pillen and van Alfen, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Despite the high prevalence of alcohol use disorders (AUDs), in a given year, only 12.1% of those meeting diagnostic criteria receive any treatment. Most individuals with AUDs are identified in primary care settings and referred to substance use disorders clinics, however only a minority attend treatment services. Developing options for treatment within primary care settings may increase receipt of services for AUDs. Safe and effective pharmacological treatments exist that could be integrated into primary care settings. This study will refine, implement and evaluate an intervention to integrate AUD treatment options, particularly pharmacological options, into primary care settings in three large Veterans Health Administration facilities.The current paper will present the implementation and evaluation strategies and the results of the developmental portion of the formative evaluation (FE). The implementation intervention targets multiple stakeholders: 1) substance use disorder and primary care mental health integration providers trained as local implementation leaders, 2) primary care providers who will have access to consultation, educational materials, a dashboard of patients with AUD on their caseload, and feedback on their prescribing practices, and 3) Veterans diagnosed with AUD who will receive educational mailings. Evaluation methods will combine FE with an interrupted time series to monitor change in facility level prescribing rate. The developmental FE consists of interviews with the local implementation leaders, primary care providers, and Veterans with AUD diagnoses. The Consolidated Framework for Implementation Research (CFIR) informed the development of the interview guides. Qualitative analysis will identify CFIR constructs that function as significant barriers and facilitators to implementation success and results will be used to refine the intervention plan. The findings will advance implementation science by demonstrating the use of theory to inform refinement of an implementation intervention and will contribute to accumulating knowledge regarding the relevance of specific CFIR constructs to implementation success."} +{"text": "The set up of large-scale, longitudinally sampled cohorts for microbiome research is logistically challenging as sample quality highly depends on the applied storage conditions. Ideally, fecal material intended for microbiome monitoring needs to be frozen immediately after sampling in order to stop the growth of residing bacteria and to conserve baseline microbial abundances. Effective fecal sampling protocols should not only combine comprehensive collection and storage instructions, but also excel in simplicity and hygiene of sample handling to avoid creating a potential population selection. To meet these criteria, the Flemish Gut Flora Project (FGFP), a large-scale (n>5000) microbiome research project based in Flanders (Belgium), developed a home sampling, aliquotting, and freezing protocol that, in combination with a cold chain collection network, would generate high-quality samples for microbiome research, while at the same time reducing logistic and post-collection analysis expenses.Here we evaluate the FGFP sampling procedure in order to share the lessons learned from this project and improve future fecal sampling methods. We investigate selection bias imposed by the recruitment and check drop out values of the different steps of the sampling procedure. Based on questionnaires and temperature-time data of a subset of the samples we evaluate the cold chain and identify pitfalls of this crucial step in fecal sample collection for microbiome research. Furthermore recommendations to improve fecal sampling user experience are deduced from the responses to a user experience questionnaire and options for better fecal sampling procedures that combine these insights with methods to reduce laboratory efforts are proposed."} +{"text": "Melitaea diamina) in its newly discovered coastal distribution region in Finland. We compared the movement parameters of the riparian population to two reference populations by using capture-recapture data and habitat-specific diffusion modelling, and analysed the role of the river and riverbank buffer zones in facilitating or hindering false heath fritillary movement with movement simulations.Species movement responses to landscape structures have been studied using a variety of methods, but movement research is still in need of simple methods that help predicting and comparing movements across structurally different landscapes. We demonstrate how habitat-specific movement models can be used to disentangle causes of differentiated movement patterns in structurally different landscapes and to predict movement patterns in altered and artificial landscapes. In our case study, we studied the role of riparian landscapes to the persistence of the endangered false heath fritillary butterfly contains supplementary material, which is available to authorized users. Studies on species movement responses to landscape structures increase our understanding on how habitat fragmentation, human-generated landscape structures or management interventions affect individual movement , landscaSpecies occurrence and movements in riverbank habitats have been studied in several taxa, including moths , spidersExperimental data on species movement responses to tested landscape structures can be analysed by straightforward statistical analyses and can give reliable estimates on the effects of such structures on species movement. In contrast, making inferences on species\u2019 movement in alternative landscapes is often not possible, since either the data lack the overall landscape context or the analysis model does not estimate the overall decision-making logic of the individuals studied. Movement researchers have expressed a need for a larger variety of methods that enable predicting species\u2019 movement patterns in structurally different landscapes based on observed data ,36 besidk times higher than the probability of it being in the other side of the edge, where the parameter k measures relative habitat preference .The data sets supporting the results of this article are available in the Dryad repository, doi:10.5061/dryad.j54vv, ["} +{"text": "Insecticide-treated nets (ITNs), which comprise conventional (cITNs) and long-lasting insecticidal nets (LLINs), are the most widely used intervention for malaria control in Africa today. At least 700 million such nets have been financed and delivered to countries since the onset of the Roll Back Malaria (RBM) partnership at the turn of the millennium, but coverage remains inadequate. Better understanding of how and why these volumes of net deliveries translate into the levels of access and use seen in households across Africa could improve the monitoring of coverage indicators, highlight opportunities for systematic efficiency gains, and allow more accurate assessment of resources needed to meet international targets.We used a simple compartmental model to represent the system linking ITN deliveries to countries, distribution to households, and resulting coverage at the national level. We assembled coverage data from 93 national surveys representing 861,000 households between 2000 and 2013 and triangulated these against yearly ITN manufacturer delivery data and national malaria control programme ITN distribution reports for 44 sub-Saharan countries. We fitted the model to these data using Bayesian inference with minimal prior assumptions.We present contemporary estimates of LLIN coverage for all endemic African countries since the year 2000. We then explore the impact of two potential inefficiencies: uneven net distribution between households and rapid rates of net loss from households. These factors substantially reduce the levels of coverage achieved relative to the volume of LLINs financed and delivered, but are not fully captured in current approaches to calculating LLIN needs. Using these inferences, we estimate the levels of coverage achievable with differing volumes of LLIN provision by 2016 under various scenarios of current or modified future levels of distributional efficiency and retention by households.Despite dramatic gains, current levels of ITN access and use remain well below international targets. Unless inefficiencies due to uneven distribution and rapid net loss can be addressed, meeting international targets will require substantially more nets than currently assumed."} +{"text": "Despite some discussion of the effect of weight stigma on psychological outcomes, little is known about specific coping factors that can reduce the impact of stigmatisation among overweight and obese persons. Furthermore, analysis of coping strategies for weight stigma within a stress-coping framework is underdeveloped. This research examined the relationship between weight stigmatising experiences, internalisation, coping strategies, and possible psychological consequences through the administration of online questionnaires with qualitative and quantitative measures to overweight and obese persons in the general population."} +{"text": "The second EurocanPlatform summer school was held in Algarve, Portugal and attracted scientists, clinicians and pathologists with a common interest in cancer research to discuss the latest developments and challenges in the field. The meeting focused on translational cancer research and also included lectures, workshops and discussions, which covered all aspects of the translational research continuum, from early detection through treatment to survivorship. The rate of new cancer cases and cancer mortality increases every year. Although the last decade witnessed enormous progress in understanding cancer biology and the development of new therapies, the efficacy of these therapies is challenged by cancer resistance. It clearly suggests that new druggable targets are required and their translation from laboratory to bedside must be faster and more efficient to improve survival rates and standards of care. The second EurocanPlatform summer school on translational cancer research was held in Portugal, and in this meeting, leading oncology scientists, basic researchers, clinicians, pathologists and patient organization representatives from Europe and the USA participated to discuss about latest developments and challenges in the field of translational cancer research.The five-day programme included lectures, workshops and discussions, which covered all aspects of the translational research continuum, from early detection through treatment to survivorship. The meeting created a unique interactive platform for young basic scientists and clinicians to connect with leading figures in cancer research and provided a forum for stimulating discussions. About 20 EurocanPlatform-OECI travel fellowships were granted to talented PhD students, early-stage postdoctoral fellows and clinicians to attend the meeting.ecancer, the German Cancer Consortium (DKFZ), the European Network for Cancer Research in Children and Adolescents (ENCCA), the European CanCer Organization (ECCO) and the Organization of European Cancer Institutes (OECI). The EurocanPlatform consortium is a European Commission-funded Network of Excellence that brings together 28 European cancer research centres and organizations to advance cancer research and treatment (www.eurocanplatform.eu).The meeting was organized by members of the EurocanPlatform consortium in collaboration with The meeting hosted several scientific sessions spanning the innovative aspects of cancer biology, research areas driving preventive and clinical research, bridging preclinical and clinical research, clinical and late translational cancer research and personalized medicine. The meeting also hosted talks given by Francesco de Lorenzo, President of the European Cancer Patient Coalition (ECPC), who presented the patients\u2019 perspective on the development of personalized cancer treatments, and by Bengt J\u00f6nsson from the Stockholm School of Economics who discussed the role of health economics in cancer research.The meeting began with invited speaker Isabelle Soerjomataram who gave an overview of the current global burden of cancer and a future prediction of 22 million new cancer cases and over 13 million deaths from cancer occurring annually by 2030, based on current trends of cancer incidence and mortality. Richard Schilsky discussed cancer evaluation and treatment in the genomic era reviewing the traditional clinical approaches and highlighting the importance of genomic information in formulating an appropriate assessment and treatment strategy for patients with cancer. Ioanna Keklikoglou presented the concept of \u2018hallmarks of cancer\u2019 [The genetic and epigenetic aspects of cancer development and progression were also highlighted during the meeting. Christopher Lord gave an insight into DNA damage and repair mechanisms and discussed targeting these mechanisms in cancer. Alvis Brazma discussed about integrative analysis of cancer genome and transcriptome, which could be helpful to explore the underlying genomic architecture of cancer and uncover unknown mutations and abnormal pathways that represent potential targets for developing new cancer therapies. Zdenko Herceg addressed epigenome deregulation in cancer and the epigenetics-based strategies for cancer treatment and prevention.The post-translational modifications (PTM) frequently altered in tumour cells were also discussed by several speakers. Pauline Rudd discussed the role of altered glycosylation pathways in promoting tumour metastasis and stressed the role of profiling glycosylation changes in cancer patients as useful clinical markers for patient stratification and determining pathways involved in the development and progression of the disease. Yifat Merbl gave insight into ubiquitin and ubiquitin-like protein modifications and presented results from work on developing new approaches for profiling PTM on a proteome-wide scale.Cancer therapy resistance, one of the main problems hampering cancer-targeted therapy, was highlighted by Sven Rottenberg who presented how molecular mechanisms underlying drug resistance can be studied in mouse models. Genetically modified mice with tissue-specific deletion of BRCA1 or BRCA2 in mammary epithelium spontaneously develop breast cancer which closely mimics the disease in humans . Loss ofAccording to cancer research carried out in United Kingdom, more than one of three people will develop cancer, but more than four of 10 cancer cases could be prevented. Pierre Hainaut discussed translation of cancer biology into preventive strategies with the main recommendations include reducing the exposure to cancer-causing agents, healthy diet, keeping active, maintaining healthy body weight and avoiding certain infections such as hepatitis B virus or human papilloma virus.in situ (DCIS). DCIS is a non-malignant lesion, and it is estimated that one in three women in their age of 40 have DCIS or closely related lesion that potentially can rapidly transform into malignant form of DCIS. In this study, gene expression signature of 31 ductal carcinomas in situ was investigated and compared against 36 invasive breast carcinomas, 42 mixed lesions (mixture of invasive carcinoma with DCIS component) and six healthy breast samples [In order to make preventive programmes effective and improve cancer treatment and monitoring, appropriate biomarkers are required. In the bridging pre-clinical and preventive/clinical research session, Anne-Lise B\u00f6rresen-Dale reported on the development of biomarkers for early detection and risk of relapse in breast cancer. Malignant transformation is a slow process and usually takes long time before single abnormal cell gives rise to palpable tumour. This creates a window of opportunity for early detection. However, appropriate markers for transformation need to be identified. The first step to know initial phase of breast carcinogenesis is to understand variability in healthy breast. Two clusters with different characteristics were identified from a study describing 9,767 genes expression profile in breast biopsies taken from 79 healthy women [ samples . ClusterSeveral speakers addressed the role of genomics and proteomics in cancer research with Ren\u00e9 Bernards discussing the role of omics technologies for the development of predictive cancer medicine and Janne Lehti\u00f6 giving an overview of recent developments in cancer proteomics and indicating a crucial role of proteomics in understanding cancer resistance to targeted therapies and identification of novel predictive markers.Radiotherapy, the standard treatment used in nearly 50% of all patients with cancer, was discussed by Michael Bauman who gave a mechanistic insight into radiotherapy-induced tumour control and highlighted the recent progress in radiotherapy technology and its impact on clinical efficacy. Cancer immunotherapy, the Science breakthrough of the year 2013 , was preCurrent challenges in paediatric oncology were highlighted by several speakers with Giuseppe Barone discussing the difficulties in paediatric drug development with emphasis on early phase clinical trials and Olaf Witt highlighting the challenges of developing targeted therapies in paediatric brain tumours. Cornelia Eckert presented how some of the challenges in paediatric oncology can be overcome by the identification of new predictive markers and molecular targets using latest technologies and gave examples of their successful integration into therapy optimization concepts.The need for multilevel partnership and infrastructure in advancing translational cancer research was also widely discussed during the meeting. Denis Lacombe discussed the current challenges in clinical research and stressed the requirement for new approaches and partnership models for biomarker-based clinical research, while Peter Riegman indicated the fundamental role of dedicated biobanking infrastructure in translational cancer research. Gunnar S\u00e4ter gave insight into the complexity of the academia\u2014pharmaceutical industry relationship and highlighted the increasing role of academia in the drug development process. Norbert Graf gave an overview of the p-medicine project that, similarly to the EurocanPlatform programme, is cooperation between 19 European and Japanese institutions whose common effort is to pave the way for more individualized therapies for patients with cancer.in vivo assessment of selected biomarkers with MI will complement laboratory diagnostic.Several speakers addressed the increasing role of imaging technologies in every facet of cancer care. Peter Dean discussed the impact of diagnostic imaging findings on the success of interdisciplinary breast cancer management. Hedvig Hricak described how advances in imaging technologies transformed cancer treatment and underlined the critical role of molecular imaging (MI) in integrated diagnostic in which rapid A final day workshop focused specifically on personalized medicine with Carlos Caldas discussing molecular stratification of breast cancer, Mathew Garnett describing how cancer cell models can be used as a therapeutic biomarker discovery platform, James Brenton presenting tumour heterogeneity as a prognostic/predictive marker, and Peter Collins discussing the merge of classical and molecular histopathology. Alberto Bardelli demonstrated the application of liquid biopsies for monitoring treatment response in colorectal cancer, while Wilbert Zwart presented the profiling of ER\u03b1 chromatin-binding sites for the identification of new biomarkers for tailoring treatment in patients with breast and endometrial tumours.In summary, the meeting highlighted the fast pace of progress in translational cancer research and stressed the need for new strategies and collaborations to surmount the increasing challenges in bringing cancer therapies from the bench to bedside. To achieve this, discussants agreed that key areas, such as prevention, early detection, treatment and research, need to be balanced and coordinated. New preventive, research and clinical strategies are required along with new forms of partnership and collaboration between academia, clinical centres and the pharmaceutical industry as well as regulatory bodies and patient organizations to facilitate faster delivery of new cancer therapies and standards of care."} +{"text": "This review aims to present advances of modern technology that can be applied to lower the radiation risk for lung cancer screening.Lung cancer remains one of the deadliest cancers with late detection and high mortality rates. Results of the NLST trial published in 2011 demonstrated a 20% decrease in lung cancer mortality in the CT arm compared to the radiography arm. One of the biggest concerns of wide implementation of lung cancer screening by CT, is radiation risk and radiation-induced cancer.We present various techniques, from tube current modulation to low dose and ultra low dose CT with adapative statistical iterative reconstruction (ASIR) and model based iterative reconstruction (MBIR), that introduce much lower radiation dose, while remain diagnostic for lung cancer screening.We will also present our model of radiation risk estimation based on lower radiation doses used in modern studies.This review will present newer currently available techniques for radiation risk reduction and our model of radiation risk estimation in comparison with available older models, based on calculations of radiation doses on population of atomic bomb survivors."} +{"text": "Drosophila is a useful organism in which to study conserved aspects of ciliogenesis. Cilia with motile characteristics in Drosophila are represented just by the sperm flagella and the sensory receivers of chordotonal neurons, which are proprioceptive and auditory sensory neurons.With only two types of ciliated cells, Drosophila to identify two new putative dynein arm assembly factors, CG11253 (ZMYND10 homologue) and CG31320 (HEATR2 homologue): impairment of function of either gene results in flies with immotile sperm and defective sensory transduction due to lack of dynein arms in the cilia. We have sought to extend these observations to other known or putative dynein assembly factor homologues to determine how much of this pathway is conserved and set up Drosophila as a model for exploring the function of these proteins in further detail. This analysis has used transcriptomic data of developing chordotonal neurons, gene regulatory analysis , genetic analysis of sensation and male fertility, and protein interaction analysis. Currently, we are also carrying out mass spectroscopy.We recently used"} +{"text": "Clonal plants spread laterally by spacers between their ramets (shoot\u2013root units); these spacers can transport and store resources. While much is known about how clonality promotes plant fitness, we know little about how different clonal plants influence ecosystem functions related to carbon, nutrient and water cycling.The response\u2013effect trait framework is used to formulate hypotheses about the impact of clonality on ecosystems. Central to this framework is the degree of correspondence between interspecific variation in clonal \u2018response traits\u2019 that promote plant fitness and interspecific variation in \u2018effect traits\u2019, which define a plant's potential effect on ecosystem functions. The main example presented to illustrate this concept concerns clonal traits of vascular plant species that determine their lateral extension patterns. In combination with the different degrees of decomposability of litter derived from their spacers, leaves, roots and stems, these clonal traits should determine associated spatial and temporal patterns in soil organic matter accumulation, nutrient availability and water retention.This review gives some concrete pointers as to how to implement this new research agenda through a combination of (1) standardized screening of predominant species in ecosystems for clonal response traits and for effect traits related to carbon, nutrient and water cycling; (2) analysing the overlap between variation in these response traits and effect traits across species; (3) linking spatial and temporal patterns of clonal species in the field to those for soil properties related to carbon, nutrient and water stocks and dynamics; and (4) studying the effects of biotic interactions and feedbacks between resource heterogeneity and clonality. Linking these to environmental changes may help us to better understand and predict the role of clonal plants in modulating impacts of climate change and human activities on ecosystem functions. Clonality is an adaptive plant strategy in which ramets (shoot\u2013root units) of the same genetic individual are spaced out and exchange resources through spacers; these spacers can be stolons, rhizomes or roots , and closensuThere is currently a large amount of interest in interspecific variation in functional traits or other monocots help to build and stabilize sand dunes organs of different species. This is an important question bearing on local-scale diversity and species composition, which are known to be a function of spatial and temporal niche diversity , and the branches, once dead, presumably turn into rather persistent litter as well, as seems to be the rule for gymnosperms , mentioned above as a key dune builder to resource stress and heterogeneity of previous clonality-related investigations with the screening for effect traits now becoming popular in ecology, we may be able to answer some of the questions emerging from this review. On the response trait side, clonal researchers have already published a lot about responses of clonal plants ecosystem effect traits among species may help us to understand soil stability and carbon, nutrient and water cycling, especially in early-successional but probably also in later-successional environments.Such insights may help us to understand spatial and temporal heterogeneity in these ecosystem functions, especially when species variation in effect traits is linked to clonal response trait variation and actual field distribution patterns of clonal plants.Spatial and temporal heterogeneity in these functions, as influenced by clonality, may in turn support the diversity of other species, another promising field of investigation.A great challenge of particular importance is to understand feedbacks between resource heterogeneity and clonality, as there is mutual causality between them.Linking all these pieces of the big puzzle to actual or predicted environmental changes and population dynamics may help us to understand the role of clonal plants, whether native or invader, in modulating impacts of global change and human activities on ecosystems.This conceptual review has highlighted the following new research agenda for linking traits of clonal plants to ecosystem functions.Supplementary data are available online at www.aob.oxfordjournals.org and consist of detailed examples of clonal bryophytes and their influence on ecosystem water regulation."} +{"text": "Literature has identified and supported links between exposure to media such as fashion magazines or television and body image concerns. With social media and networking sites becoming increasingly popular, the influence these media and sites can have on the body image of young persons deserves further investigation. Building on a recent study that revealed that young girls using Facebook had significantly more body image concerns than non-users, this study examines the influence of the use of social networking sites on the body image of 100 university students aged 18-25.A quantitative design with repeated measures where participants will complete online surveys about their use of social media over 4 months is being implemented. Use of social media, content posted on these sites, responses expected, wished for and obtained will be documented. The Objectified Body Consciousness Scale, the Sociocultural Attitudes Towards Appearance Questionnaire and the Eating Disorders Inventory 3 will be used to identify impacts of using social media and networking sites on body image.Results of this study will extend existing evidence exploring links between social media and body image concerns and contribute new information to the development of media literacy programs addressing negative body image."} +{"text": "Molecular dating of species divergences has become an important means to add a temporal dimension to the Tree of Life. Increasingly larger datasets encompassing greater taxonomic diversity are becoming available to generate molecular timetrees by using sophisticated methods that model rate variation among lineages. However, the practical applications of these methods are challenging because of the exorbitant calculation times required by current methods for contemporary data sizes, the difficulty in correctly modeling the rate heterogeneity in highly diverse taxonomic groups, and the lack of reliable clock calibrations and their uncertainty distributions for most groups of species. I will present our published RelTime method that estimates relative times of divergences for all branching points (nodes) in very large phylogenetic trees without assuming a specific model for lineage rate variation or specifying any clock calibrations. RelTime performed better than existing methods when applied to very large computer simulated datasets where evolutionary rates were varied extensively among lineages by following auto-correlated and uncorrelated rate models. I will also discuss some preliminary results aimed at assessing the prospects for building large species time trees when the gene sequence coverage is incomplete. Our results indicate that the estimates of divergence times are surprisingly good even when data from a majority of genes are missing for many species, as long as multiple genes are available from each species. The speed and accuracy of RelTime will enable molecular dating analysis of very large datasets, which will be useful for determining the relative ordering and spacing of speciation events, identifying lineages with significantly slower or faster evolutionary rates, diagnosing the effect of selected calibrations on absolute divergence times, and estimating absolute times of divergence when highly reliable calibration points are available."} +{"text": "Balance impairment is common in individuals with neurological disordersand older adults and is a major cause of falls in these populations. Evidence onthe effectiveness of conventional interventions for balance restoration islimited. We describe a novel approach to balance rehabilitation that is based onenhancing anticipatory postural adjustments. Human vertical posture is inherently unstable because of the high location ofthe center of mass, small support area, and multiple joints between the feet and thecenter of mass. When a standing person performs a quick movement and/or interactswith external objects, the mechanical coupling of body segments leads to posturalperturbations that may be destructive for fragile balance. The central nervoussystem (CNS) uses two main postural strategies to maintain and restore balance whena human body is perturbed. Anticipatory postural adjustments (APAs) control theposition of the center of mass (COM) of the body by activating the trunk and legmuscles prior to a forthcoming body perturbation, thus minimizing the danger oflosing equilibrium (reviewed in ).CompenPostural control in humans is based on the effective use of anticipatory andcompensatory postural mechanisms. In the case of an unexpected perturbation toposture (such as being hit in a crowded space), CPAs are the only mechanism used bythe CNS to restore balance. On the other hand, when the perturbation is predictable,APAs act as the first line of defense preparing the body for the upcomingdisturbance and are thereafter followed by CPAs that help in completing the processof balance restoration. As such, the utilization of APAs considerably reduces theneed for large CPAs and results in greater postural stability as demonstrated bysignificantly smaller displacements of the body\u2019s COM and center of pressure(COP) following a perturbation in healthy young adults ,6. TheseAnticipatory postural adjustments are impaired in individuals withneurological disorders such as Parkinson\u2019s Disease \u20139, strokWhile restoring APAs in people with balance deficit seems like an obvioustreatment, in clinical practice, a large percentage of individuals requiring balancerehabilitation are treated with conventional rehabilitation approaches concentratedon training compensatory recovery strategies for improving postural stability ,25.HoweIt has been widely established that for training to be effective, theprotocol needs to comply with the principle of training specificity . TherefoThe task of ball throwing involves an internal, self-initiated perturbationand ball catching produces an externally-induced perturbation. Both tasksnecessitate the generation and utilization of APAs in preparation for the upcomingdisturbance in order to maintain postural stability after thedisturbance. Moreover, perturbations induced by ball catch or throw are predictable(known) by the subjects as only predictable perturbations generate APAs ,6.AdditThe outcome of recent studies in young and older adults demonstrated that asingle training session involving a functional activity such as catching or throwinga ball improves the generation of APAs prior to a predictable external perturbation,38. MoreSubstantial evidence suggests that a decreased ability to generate andutilize anticipatory postural adjustments is linked to balance impairment and thatanticipatory postural adjustments could be enhanced with training. While additionalstudies are needed to define the specifics of the training protocols, there is nodoubt that APA-based interventions can be an effective rehabilitation approach inimproving postural control, functional balance, mobility, and quality of life inindividuals with balance deficit."} +{"text": "A major question in systems neuroscience is how a single population of neurons can interact with the rest of the brain to orchestrate complex behavioral states. The hypothalamus contains many such discrete neuronal populations that individually regulate arousal, feeding, and drinking. For example, hypothalamic neurons that express hypocretin (Hcrt) neuropeptides can sense homeostatic and metabolic factors affecting wakefulness and orchestrate organismal arousal. Neurons that express agouti-related protein (AgRP) can sense the metabolic needs of the body and orchestrate a state of hunger. The organum vasculosum of the lamina terminalis (OVLT) can detect the hypertonicity of blood and orchestrate a state of thirst. Each hypothalamic population is sufficient to generate complicated behavioral states through the combined efforts of distinct efferent projections. The principal challenge to understanding these brain systems is therefore to determine the individual roles of each downstream projection for each behavioral state. In recent years, the development and application of temporally precise, genetically encoded tools has greatly improved our understanding of the structure and function of these neural systems. This review will survey recent advances in our understanding of how these individual hypothalamic populations can orchestrate complicated behavioral states due to the combined efforts of individual downstream projections. To ensure that an animal obtains an optimal amount of sleep, food, and water, the brain must sense the internal environment and influence behavior by producing sensations we describe as \u201ctired/awake, \u201chungry/full, and \u201cthirsty/quenched.\u201d Amazingly, these complicated behavioral states are often controlled by discrete populations of neurons, some composed of only 1000\u20132000 individual cells. The hypothalamus contains many such populations including hypocretin -expressing neurons in the lateral hypothalamus that regulate wakefulness and arousal injection of Hcrt neuropeptides into the brain causes an increase in expression of Fos, an indirect marker of neural activity, widely throughout the brain neurons within the paraventricular nucleus , the lateral septum (LS), the median preoptic nucleus (MnPO), the central nucleus of the amygdala (CeA), the dorsomedial hypothalamic nucleus (DMH), the ventromedial hypothalamic nucleus (VMH), and the POMC-expressing neurons in the arcuate nucleus is selectively expressed in AgRP neurons, causing selective ablation of these neurons when mice are injected with diphtheria toxin. Ablation of AgRP neurons causes a starvation phenotype rescued feeding after AgRP ablation. Subsequent work showed that the neurons that mediated this effect are located in the external lateral region of the PBN and specifically express calcitonin gene related peptide resulted in a statistically significant increase in food intake, whereas stimulating projections in the PBN, CeA, and PAG had no significant effect , and PVT, as well as previous AgRP neuropeptide injection studies that demonstrate functional importance in the CeA and PVN, need to be reconciled. It is important to note the differences in methodology between studies: while the Palmiter group demonstrated the During a hungry behavioral state, animals tend to shut down other physiological processes such as growth, reproduction, and nociception, while increasing food exploratory activity and the HPA stress response. Consistently, previous studies demonstrate that central injection of AgRP neuropeptides inhibit puberty and sex hormones If stimulation of a neural projection does not reproduce the effects of stimulation at the cell soma, such a result does not indicate that the neural projection doesn\u2019t play a role in the overall behavior. For example, if stimulating the projections of AgRP neurons to the PAG or PBN does not produce feeding behavior (Betley et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "We conclude that oxidative stress can be in part responsible for some aspects of uremic myopathy. Further research is needed to discern clear mechanisms and to help efforts to counteract muscle weakness and exercise intolerance in uremic patients.Renal failure is accompanied by progressive muscle weakness and premature fatigue, in part linked to hypokinesis and in part to uremic toxicity. These changes are associated with various detrimental biochemical and morphological alterations. All of these pathological parameters are collectively termed uremic myopathy. Various interventions while helpful can't fully remedy the pathological phenotype. Complex mechanisms that stimulate muscle dysfunction in uremia have been proposed, and oxidative stress could be implicated. Skeletal muscles continuously produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) at rest and more so during contraction. The aim of this mini review is to provide an update on recent advances in our understanding of how ROS and RNS generation might contribute to muscle dysfunction in uremia. Thus, a systematic review was conducted searching PubMed and Scopus by using the Cochrane and PRISMA guidelines. While few studies met our criteria their findings are discussed making reference to other available literature data. Oxidative stress can direct muscle cells into a catabolic state and chronic exposure to it leads to wasting. Moreover, redox disturbances can significantly affect force production Among the clinical entities affecting thousands of patients, chronic kidney disease (CKD) is a silent epidemic expected to influence more than 50% of the Americans born today myosin II oxidation, a redistribution of existing structural states of the actin-binding cleft was implicated reduces maximum force and velocity of contraction, with the high peroxide resulting in irreversible loss of calcium regulation of force mediated by oxidation of methionines in the heavy and essential light chains oxidative stress and uremic myopathy in humans, and (ii) markers of oxidative stress in the skeletal muscle of uremic patients on HD. Eligibility of the studies based on titles, abstracts and full-text articles was determined by two reviewers. Studies were selected using inclusion and exclusion criteria. We included only those studies that met the following criteria: they assessed oxidative stress markers in the skeletal muscle of patients on HD; they used human biopsies; they addressed randomized control trials, controlled trials, or clinical trials designed to evaluate oxidative stress in skeletal muscle in uremic patients on HD therapy; they were written in English.Only three studies have examined the oxidative damage in human skeletal muscle of uremic patients on HD Table . Their fLim et al. found inThe same group also reported increased mitochondrial protein and lipid oxidative damage in skeletal muscle of uremic patients compared to age-matched controls vs type I fibers either in non-locomotory (Sakkas et al., In contrast to the findings of Lim et al. and Crowe et al. , reporteThe above discourse further highlights the difficulty faced by researchers in renal patient studies. Many confounding factors such as years in dialysis, nutrition, physical activity levels, level of treatment, and comorbidities can affect muscle status and accelerate or decelerate disease and aging effects Figure .In vitro studies however show clearly that oxidative stress does have a role whether via chronic, protein and other modifications or acute contractility effects. If anything the three studies and the peripheral literature highlight the need for a systematic study of the disease mechanisms affecting skeletal muscle performance in renal disease.CKD has a high and increasing prevalence not only in the old retirees but also in the middle-aged Europeans (Zoccali et al., As long as great unknowns remain on the mechanisms and modulation of uremic myopathy, which leads to debilitation and premature death, progress in the management of this new epidemic is the least slowed down. We suggest that more muscle research, human and animal, should be done on pro-dialysis stages including work on the role of oxidative stress. This would allow researchers to decipher early changes, and perhaps identify susceptible individuals for accelerated muscle loss, before moving into the end-stage situation which on its own has detrimental effects on muscle status.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In axonotmesis, peripheral nerve regeneration, target reinnervation and recovery of function happen remarkably well with a conservative management in most of the cases. Also, substantial axonal regrowth and nerve regeneration can occur with nerve transection injuries after primary end-to-end neurorrhaphy. Nearly similar outcomes can be obtained using a nerve autograft to repair a nerve defect between severed nerve ends. However, regardless of repair strategy, recovery of function after a more proximal neurotmesis is partial at best and catastrophe is not uncommon.Cajals\u2019 study in 1928 found that in neurotmesis the axonal sprouts emerge from the basal lamina tube and wander within a disorganized mass of perineurial and Schwann cells to form a neuroma. The neuroma is a foundation of abnormal sprouting caused by the interruption of endoneurial tubes in a traumatic nerve injury. Scadding and Thomas in 1983 and later Leis in 2003 described that the nerve sprouts might also turn back and grow in a backward direction. In addition, the nerve sprouting can extend significant distances along the parent nerve and may even backtrack to proximal branches, before innervating novel targets.In an animal study Graham et al have pointed that the antegrade, target-directed axonal regeneration can be affected by aberrant and dysfunctional regrowth due to a rich in growth-inhibiting chondroitin sulfate proteoglycan. This may contribute to misdirection of axonal regrowth and a poorer functional result bellow the initial expectation of the surgeon and patient. The idea behind this research finding is to degrade the chondroitin sulfate proteoglycan by application of chondroitinase at the site of nerve repair and in this way decrease aberrant axonal growth. The application of this principle in prepared allograft nerve can help in the target directed regrowth and probably in achieving better functional outcomes.Krekoski et al. have shown that segments of rat sciatic nerve of 1.5 cm in length were made acellular by repeated freeze thaw cycles and then bathed en bloc in a chondroitinase ABC solution for 16 hours. Then, the en bloc chondroitinase treatment of acellular nerve grafts effectively degraded CSPG (chondroitin sulfate proteoglycans) without compromising the basal lamina scaffold or dislocating its laminin content.Cho et al showed that this method is effective and favorable when compared with auto graft and nerve tubes in treating nerve gap of 5 to 50 mm in a rat study.Tang et al in an animal study demonstrated that the use of acellular nerve allograft demonstrated equal functional recovery when compared to reversed autograft and superior recovery compared to the cabled nerve autograft. Even though functional recovery after a nerve injury in humans is affected by many other factors compared with rats, the idea of using acellular allograft nerve is a resource to be considered.Finally, Neubauer et al in a rodent model found that the histological examination of acellular nerve graft revealed much better structural preservation and axonal growth throughout the ChABC (chondroitinase ABC) grafts. Numerous axons were host distal nerves and many of these regenerated axons were myelinated. In addition, the amount of aberrant retrograde axonal growth was markedly reduced by repair with ChABC grafts."} +{"text": "How can antimicrobial drugs be deployed optimally during infectious disease epidemics? Our mathematical models show it is optimal to delay treatment to maximize successful treatments. In formulating policy, however, this must be balanced against the risk of incorrectly predicting the peak of an epidemic. Background: Although the emergence and spread of antibiotic resistance have been well studied for endemic infections, comparably little is understood for epidemic infections such as influenza. The availability of antimicrobial treatments for epidemic diseases raises the urgent question of how to deploy treatments to achieve maximum benefit despite resistance evolution. Recent simulation studies have shown that the number of cases prevented by antimicrobials can be maximized by delaying the use of treatments during an epidemic. Those studies focus on indirect effects of antimicrobial use: preventing disease among untreated individuals. Here, we identify and examine direct effects of antimicrobial use: the number of successfully treated cases.Methodology: We develop mathematical models to study how the schedule of antiviral use influences the success or failure of subsequent use due to the spread of resistant strains.Results: Direct effects are maximized by postponing drug use, even with unlimited stockpiles of drugs. This occurs because the early use of antimicrobials disproportionately drives emergence and spread of antibiotic resistance, leading to subsequent treatment failure. However, for antimicrobials with low effect on transmission, the relative benefit of delaying antimicrobial deployment is greatly reduced and can only be reaped if the trajectory of the epidemic can be accurately estimated early.Conclusions and implications: Health planners face uncertainties during epidemics, including the possibility of early containment. Hence, despite the optimal deployment time near the epidemic peak, it will often be preferable to initiate widespread antimicrobial use as early as possible, particularly if the drug is ineffective in reducing transmission. Haemophilus influenzae and Streptococcus pneumoniae in the community , but planners will also want to consider the direct effects of antimicrobial use on infected patients. In particular, when antivirals have little effect on transmission, there is little indirect effect but the direct effects of treating cases successfully can be substantial. These direct effects accrue as long as resistant clades are small and available treatments are used before the epidemic ends. The direct effects count the treatment of sensitive cases regardless of whether drugs change the epidemic trajectory. In principle, a particular usage policy might result in more successful instances of treatment because it has the highly undesirable consequence of creating a larger epidemic and therefore offering more patients to treat. Thus maximizing direct effects should not be used alone as an objective in disease control planning. Instead, planners will typically want to make decisions based on a composite of both direct and indirect effects."} +{"text": "Improvement in animal productivity has been achieved over the years through careful breeding and selection programs. Today, variations in the genome are gaining increasing importance in livestock improvement strategies. Genomic information alone, however, explains only a part of the phenotypic variance in traits. It is likely that a portion of the unaccounted variance is embedded in the epigenome. The epigenome encompasses epigenetic marks such as DNA methylation, histone tail modifications, chromatin remodeling, and other molecules that can transmit epigenetic information such as non-coding RNA species. Epigenetic factors respond to external or internal environmental cues such as nutrition, pathogens, and climate, and have the ability to change gene expression leading to emergence of specific phenotypes. Accumulating evidence shows that epigenetic marks influence gene expression and phenotypic outcome in livestock species. This review examines available evidence of the influence of epigenetic marks on livestock traits and discusses the potential for consideration of epigenetic markers in livestock improvement programs. However, epigenetic research activities on farm animal species are currently limited partly due to lack of recognition, funding and a global network of researchers. Therefore, considerable less attention has been given to epigenetic research in livestock species in comparison to extensive work in humans and model organisms. Elucidating therefore the epigenetic determinants of animal diseases and complex traits may represent one of the principal challenges to use epigenetic markers for further improvement of animal productivity. The goal of animal production is to achieve increased productivity for human purposes while enhancing health and wellbeing of animals. Present gains in livestock productivity have been obtained through intensive genetic selection/breeding and management efforts in the last five decades. Recently, genetic markers associated with improved animal productivity are gaining importance in livestock selection programs. Already, numerous genetic markers, mainly in the form of singly nucleotide polymorphisms and copy-number variations, have been identified and associated with milk production, meat quality, reproduction, and growth traits. Some of these markers are already finding use in genomic selection for these phenotypes . HoweverEpigenetics and its associated terminologies have several versions of connotations and specific terms need to be defined for further discussions. Between information coded in the genotype and desired phenotypes lies a whole complex of developmental processes for which the term \u201cepigenotype\u201d has been proposed . The terIn this review, the current state of knowledge on how nutrition, pathogens and other environmental factors modify epigenetic marks leading to varying effects on reproduction, growth, and production traits in livestock species will be presented. The potential of applying epigenetic markers to improve productivity will be discussed, as well as the challenges and prospects for advancement.Epigenetic mechanisms encompass processes that alter gene expression with resultant effects on the phenotype without changes on the DNA sequence, and include DNA methylation, histone tail modifications, chromatin remodeling, and the activities of non-coding RNAs. Epigenetic mechanisms regulate gene expression at the transcriptional and post-transcriptional levels and therefore contribute to phenotypic manifestations. A plethora of information support the regulatory role of epigenetic factors in livestock phenotypes like diseases , reproduS-adenosyl-methionine as the methyl donor dinucleotides and to a lesser extent at CpA, CpT, or CpC dinucleotides . On the other hand, methylation in the body of genes can actually lead to increased transcriptional activation with yl donor . The enzleotides . DNA mettivation . TherefoDNA methylation is the most widely studied epigenetic mechanism of gene regulation. Accumulating lines of evidence indicate that DNA methylation is susceptible to nutritional and environmental influences and alterations in DNA methylation profiles can alter gene expression profiles leading to diverse phenotypes with the potential for increased/decreased productivity and disease risk .Figure 1). Heterochromatin can be in either constitutive or facultative state. Constitutive heterochromatin comprises mainly repetitive genetic elements, such as telomeres and centromeres and functions as a genome stabilizer that prevents gene rearrangements between highly similar genetic sequences, while facultative heterochromatin is often localized in promoter regions and is established either in a developmentally regulated manner or in response to environmental triggers densely packed to achieve a fold compaction necessary to fit a genome into the nucleus while also allowing enough room for proteins involved in transcription, replication, and repair to access DNA . Chromattriggers .Generally, the structure of chromatin is under strict regulation by several mechanisms that encompass chromatin remodeling, histone modification, histone variant incorporation, and histone eviction, which imposes major impediments on aspects of transcription mediated by RNA polymerase II . The N-tMultiple types of RNAs have been implicated in epigenetic inheritance across generations and include maternal stores of messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs), as well as various small RNAs [small interfering RNAs [siRNAs], piwi RNAs (piRNAs), microRNAs (miRNA)] that interfere with transcription, mRNA stability, or translation .microRNAs are a class of endogenous non-coding small RNAs of about 22 nucleotides in length with capacity to regulate post gene transcription and consequently control the activity of about 60% of all protein coding genes and participate in the regulation of almost every cellular process investigated in mammals . miRNAs Table 1.The number of miRNAs encoded by the genomes of farm animal species varies considerably from a handful to about 793 in cattle. miRNA detection in livestock species was initially slow but with advances in deep sequencing technologies and computational predictions, the number of miRNAs detected in different livestock species continues to increase. The numbers of miRNA entries in miRBase for cattle, sheep, goat and pig since 2005 are shown in http://www.lncipedia.org/). In humans, regulatory roles of lncRNA have been associated with several disease conditions including tumorigenesis, cardiac development, aging and immune system development transcription factor responds to a diversity of fatty acids to modulate expression of specific genes and PPAR-\u03b1 facilitated transcriptional activation during critical ontogenic periods may obstruct epigenetic silencing of genes involved in fatty acid metabolism . EmerginDaughters of cows fed a protein supplement during the last trimester of pregnancy conceived earlier in their first breeding season and had overall greater pregnancy rates, suggesting that changes in maternal nutrient status during late pregnancy influenced the reproductive performance of the daughters . In anotNutrients also have effects on miRNA expression in farm animals. A high/low fat diet altered the miRNA expression in subcutaneous and visceral adipose tissues of cattle . In factIt is evident that the nutritional composition of diets, how and when animals are fed impact how epigenetic marks drive gene expression and resultant phenotypes. Nutritional effects could be short or long term and more information is needed to determine when and how it can be effectively utilized in animal improvement. Harnessing the nutritional influence on epigenetic modulation of gene expression may positively impact livestock productivity. However, limited current knowledge restricts applicability thus highlighting the need to actively generate knowledge toward exploitation of the effects of nutrition on epigenetic marks toward improved livestock productivity.Diseases caused by diverse agents including bacteria, viruses, parasites, and fungi are a major threat to livestock productivity worldwide and a leading cause to production losses. Although much effort has been put into understanding the mechanisms of livestock disease pathogenesis and control, complete eradication, or treatment still present major challenges. Understanding the contribution of epigenetic marks to disease parthenogenesis may provide further avenues of control.Escherichia coli bacteria. This indicate that infection-related remethylation of this region remodeled the chromatin and spatially restricted regulatory mechanisms that protected the promoter against high levels of circulating prolactin and thus serve as an acute regulatory significance of CpG methylation ] thus suggesting an important role for the measured epigenetic enzymes in the regulation of bovine innate immune gene expression and from 3 Holstein dairy cows in mid-lactation with ConA alone or ConA plus dexamethasone and demonstrated significant effects on the expression of two cytokines, IFN-\u03b3, type 1 and IL-4, type 2, which were also consistent with DNA methylation profiles of the IFN-\u03b3 gene promoter region but not with IL-4 promoter region. Recently, In contrast to numerous reports of the involvement of epigenetic marks in the etiology of human diseases , limitedhylation . In the hylation . Recentlhylation . Exposurhylation . In anotpression . To deteStaphylococcus aureus enterotoxin B was demonstrated disease markers. From lung tissue of pigs infected with Actinobacillus pleuropneumoniae, In Pigs, Detailed knowledge on how different pathogens of importance in livestock production direct epigenetic modifications and effects on the expression of disease phenotypes may guide informed decisions on the development of strategies to effectively manage livestock diseases. This calls for coordinated efforts to make available the epigenome maps of different immune cell types in livestock species for exploitation for improved animal health.The adipose tissues and mammary glands are the main organs that produce fat, a major form of energy storage. In addition, mammary glands of ruminant animals produce milk which contributes enormously to the nutrition of humans. Milk and fat are important economic traits in livestock productivity and the proper functioning of the mammary glands and adipose tissues is vital for desired productivity. A role for epigenetic marks in the growth and differentiation of these organs including lipid metabolism and adipogenesis has been demonstrated . Furtherlongissimus dorsi muscle tissue in Korean cattle.Pioneering work on the characterization of miRNAs in bovine adipose tissues and mammary glands led to the identification of 59 distinct miRNAs and initial clues of the involvement of these molecules in mammary gland functions . RecentlAt the level of the mammary gland, differences in types and expression levels of miRNAs have been reported between lactating and non-lactating bovine mammary glands . miRNA eBased on these indications, it is obvious that epigenetic marks regulate lipid synthesis and milk production. It now remains to be determined how epigenetic factors can be managed to improve milk/meat quality like increasing the concentrations of desired fatty acids in milk and muscle tissues. This will be facilitated by a cataloging of the effects of epigenetic marks on these traits under specific conditions.in vitro embryo production and somatic cell nuclear transfer/cloning are widely applied to enhance reproductive efficiency in farm animals , the genome and the environment that ultimately work in concert to determine resultant phenotypes. Furthermore, use of genomic information in selection is finding wide application in livestock improvement schemes and obtaTo account for epigenetic contribution to an individual\u2019s true breeding value, consideration should be given to redefine the information used in calculating GEBV. Thus it is expected that, the accuracy of an individual\u2019s GEBV would increase if estimated associations would include both genomic and epigenomic information. However, such epigenetic markers need to be stable or show evidence of being transgenerationally inherited. Alternatively, understanding how certain triggers, such as diets or management strategies modulate epigenetic marks could lead to improved management practices for increased productivity.With advances in DNA sequencing technologies, the genomic portion of the variation in livestock traits is being assessed at an increasing rate in recent years. The epigenomic portion is not being given the attention that it clearly deserves. Epigenomic mutations, as is the case with DNA mutations, can have enhancing, deleterious or neutral attributes and have the potential to adapt and respond to environmental cues with great impact on heredity and breeding. Effects of epigenetic regulatory mechanisms must, however, be accurately analyzed to determine applicability. Unfortunately, epigenetic research activities on farm animal species are currently limited as compared to extensive work in humans and model organisms. This is partly due to insufficient recognition, limited tools, shortage of funding and lack of a global network of researchers.A major limitation to livestock epigenomics research is insufficient recognition of the importance of epigenomic contributions to the emergence of livestock phenotypes of economic importance and disease traits. In time past, there was uneasiness regarding the value and usefulness of mapping the epigenomes of different cell types in humans . Then, eIn humans, tools that facilitate epigenetic research have been developed enabling the elucidation of epigenetic contributions to the development of disease traits. Supported by significant funding and involvement of a large global network of research teams, human epigenome maps have been generated enablingRecently, The application of epigenomic information in livestock breeding will depend on the availability of the genome sequence of the species in question. Sequencing of the bovine, pig, sheep, and goat genomes were completed recently and avaiAdvances in next generation sequencing technologies and falling cost of sequencing have enabled advances in genomic research and in epigenomic research in humans and mice. It is expected that with the right funding, these tools could be used to generate epigenomic information in livestock species and thus identify epigenetic markers that can be included in livestock improvement programs. Epigenome wide approaches have enabled mapping of epigenomics components in many cell types with millions of putative regulatory elements identified . AdvanceFigure 2). Therefore, both genomic and epigenomic information might have been unintentionally applied in animal breed improvement all along. Given overwhelming evidence that epigenetic marks contribute to the appearance of different phenotypes in livestock species, it is probable that the primary goal over the next decade will be to accelerate epigenetic research to enable the understanding of how epigenetic marks influence livestock phenotypes under different conditions. It is only then that epigenomic information can complement genomic information and provide a better understanding of the forces that shape livestock phenotypes and directional application in breed improvement and management practices .Breed improvement progress achieved through traditional animal breeding methodologies over the years has relied on selection on the basis of the phenotype. The phenotype as it is now known results from interaction of the genotype, epigenotype, and environmental/other factors to define individual variations and phenotypic outcomes. Advances in genomics technologies have made possible inclusion of genomic information in present day breeding programs. Genomic information alone does not account for all the phenotypic variations in livestock traits. Accumulating evidence continues to associate epigenetic marks with different phenotypic outcomes in livestock species pointing to the notion that unexplained phenotypic variation in livestock traits could be due to epigenetic factors. It is expedient to accelerate research on how epigenetic marks influence livestock complex disease and production traits under different conditions and include this information to increase animal productivity and sustainability.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Over the past two centuries the surgical profession has undergone a profound evolution in terms of efficiency and outcomes. Societal concerns in relation to quality assurance, patient safety and cost reduction have highlighted the issue of training expert surgeons. The core elements of a training model build on the basic foundations of gross and fine motor skills.We provide an analysis of the ergonomic principles involved and propose relevant training techniques. We have endeavoured to provide both the trainer and trainee perspectives.This analysis is structured into four sections: 1) Pre-operative preparation issues, 2) technical skills and instrument handling, 3) low fidelity simulation models and 4) discussion of current concepts in crew resource management, deliberate practice and assessment.Rehearsal, warm-up and motivation-enhancing techniques aid concentration and focus. Appropriate posture, comprehension of ergonomic principles in relation to surgical instruments and utilisation of the non-dominant hand are essential skills to master. Low fidelity models can be used to achieve significant progress through the early stages of the learning curve. Deliberate practice and innate ability are complementary to each other and may be considered useful adjuncts to surgical skills development.Safe medical care requires that complex patient interventions be performed by highly skilled operators supported by reliable teams. Surgical ergonomics lie at the heart of any training model that aims to produce professionals able to function as leaders of a patient safety oriented culture."} +{"text": "Proximal humerus fractures are rarely associated with axillary artery injury. We present a case of a 59-year-old female who had fracture neck humerus along with absent pulsations in the left upper limb after blunt trauma. Computed tomographic angiogram revealed complete occlusion of the left axillary artery. Urgent surgical intervention was done in the form of fixation of fracture followed by exploration and repair of axillary artery. Axillary artery was contused and totally occluded by fractured edge of humerus. Repair of the axillary artery was done using basilic vein graft harvested through the same incision. Postprocedure pulsations were present in the upper limb. Injuries of the axillary artery are not common , 2 and fPenetrating trauma of the upper extremities leading to vascular injuries is more common than blunt injuries in both military and civilian population; the incidence of penetrating trauma in upper limb vascular injuries varies from 60 to 90% as reported in various studies in literature , 6. GunsRepair of axillary artery can be done either by direct repair or by using grafts like saphenous vein, prosthetic grafts, or basilic vein as was done in this case. Most of the literature on repair of upper limb vascular injuries is either on the use of saphenous vein graft or prostA 59-year-old female patient presented with fracture neck humerus along with absent pulsations in the left upper limb due to blunt trauma. Patient also had history of diabetes mellitus and hypertension. Colour Doppler study revealed monophasic flow in the upper limb arteries suggestive of proximal occlusion. Computed tomographic (CT) angiogram showed complete occlusion of the left axillary artery Figures by sharpInjuries of the axillary and subclavian artery are associated with high mortality and morbidity rates. High index of suspicion is required for early diagnosis of vascular injuries after proximal fractures of the humerus. Urgent intervention is required for axillary artery injury to prevent excessive hemorrhage or amputation. Associated injuries of the brachial plexus can also complicate the management and require due consideration; fortunately, in this patient, brachial plexus was intact. There are few reports in literature on axillary artery injuries caused bBasilic vein can be a useful graft for upper limb vascular injuries. Advantages of using basilic vein for upper limb vascular injuries are as follows. (1) can be harvested through the same incision, (2) the patient can be operated under regional anesthesia, (3) avoids extra incisions in other limbs, (4) cosmetically better for the patient, (5) easy to harvest, (6) is cost effective and has less chances of infection in comparison to prosthetic grafts. There can also be certain instances where use of basilic vein is either not possible or may not be preferred like in cases where the basilic vein itself is found injured or when there is extensive soft tissue damage or in long segment arterial repairs.Basilic vein has also been used for arterial reconstruction in the iliofemoral segment and alsoIn our experience with repair of brachial artery injuries, we have never used saphenous vein for repair but rather the basilic vein was used every time and was harvested through the same incision and allowed the procedures to be done under regional anesthesia. We are of the opinion that basilic vein is a more suitable and convenient graft for upper limb vascular injuries. Unless the basilic vein itself is damaged by the trauma, it can be conveniently used for upper limb vascular injuries involving axillary and brachial arteries.Basilic vein graft can be a suitable alternative in repair of upper limb vascular injuries. Fracture of proximal humerus neck can sometimes lead to axillary artery injury."} +{"text": "Brain proteins are detected in the cerebrospinal fluid (CSF) and blood of stroke patients and their concentration is related to the extent of brain damage. Antibodies against brain antigens develop after stroke, suggesting a humoral immune response to the brain injury. Furthermore, induced immune tolerance is beneficial in animal models of cerebral ischemia. The presence of circulating T cells sensitized against brain antigens, and antigen presenting cells (APCs) carrying brain antigens in draining lymphoid tissue of stroke patients support the notion that stroke might induce antigen-specific immune responses. After stroke, brain proteins that are normally hidden from the periphery, inflammatory mediators, and danger signals can exit the brain through several efflux routes. They can reach the blood after leaking out of the damaged blood-brain barrier (BBB) or following the drainage of interstitial fluid to the dural venous sinus, or reach the cervical lymph nodes through the nasal lymphatics following CSF drainage along the arachnoid sheaths of nerves across the nasal submucosa. The route and mode of access of brain antigens to lymphoid tissue could influence the type of response. Central and peripheral tolerance prevents autoimmunity, but the actual mechanisms of tolerance to brain antigens released into the periphery in the presence of inflammation, danger signals, and APCs, are not fully characterized. Stroke does not systematically trigger autoimmunity, but under certain circumstances, such as pronounced systemic inflammation or infection, autoreactive T cells could escape the tolerance controls. Further investigation is needed to elucidate whether antigen-specific immune events could underlie neurological complications impairing recovery from stroke. The egress of lymphocytes from lymph nodes requires lymphocytic S1P1 receptors (Matloubian et al., Besides systemic infections, factors such as severe arteriosclerosis or other systemic autoimmune diseases are also likely to promote a proinflammatory environment favoring autoimmunity in ischemic stroke. As vascular risk factors and atherosclerosis are common in stroke patients, clinical and experimental studies assessing this possibility and also the potential of commonly used drugs, such as statins, to modulate the immune reactions to stroke would be relevant. Several beneficial effects of statins may be due to immunomodulatory effects, including impaired maturation of DCs with reduced expression of molecules like MHC class II preventing antigen presentation to T cells (Kwak et al., In this review we described the current evidence suggesting the possibility that stroke can trigger antigen-specific responses. These include the finding of T-cells autoreactive to brain antigens in stroke patients, the presence of brain antigens and autoantibodies in CSF and serum, and APCs carrying brain antigens in the regional lymphoid tissue. Further support to this notion is provided by the beneficial effects of inducing immune tolerance in experimental animal models of stroke. Brain antigens are released after stroke in the presence of inflammatory mediators and danger signals. Soluble molecules can reach the periphery across the leaky BBB or across natural pathways normally allowing fluid efflux, i.e., the drainage of interstitial fluid to the CSF and from there to the blood, and the drainage of CSF through the nasal lymphatics to the cervical lymph nodes. Furthermore, antigens can be internalized locally in the brain by APCs, but whether these cells can migrate to the draining lymph nodes for efficient antigen presentation is currently unknown and deserves further investigation. Since these routes could trigger different immune responses, it is relevant to elucidate their contribution to brain antigen transfer to the lymph nodes. Mechanisms ensuring tolerance to self are tightly regulated. Peripheral tolerance relies on factors including the features of APCs and their interaction with lymphocytes, the cytokine environment, and the presence of danger signals and regulatory or suppressor cells. Although a number of studies have shown specific changes in these factors after stroke, we still lack a complete picture of how these changes are integrated in the organism over time. Furthermore, stroke co-morbidities are often associated with changes in the immune system that could play a crucial role in directing specific immune responses to stroke. Stroke does not consistently trigger autoimmunity, but several lines of evidence support that infection and inflammation could break immune tolerance controls and favor autoreactive responses to brain antigens after stroke. Infection is a frequent complication of stroke that is attributable to stroke-induced immunodepression, characterized by acute lymphopenia and monocyte deactivation. Immunodepression sets a humoral and cellular situation favorable to prevent autoreactivity, but leaves the subjects at risk of infection. In the event of infection, the risk of autoreactivity increases, suggesting a fine balance between the factors regulating tolerance and autoimmunity. Further understanding of these regulatory mechanisms is necessary to elucidate whether antigen-specific reactions could threaten the outcome of stroke patients. Some patients show partial recovery of function and respond to rehabilitation over months after stroke onset. However, certain stroke patients develop complications, as for instance cognitive decline or epilepsy, and it is often difficult to predict such effects. Whether any autoimmune reaction can underlie stroke complications deserves further investigation aiming to prevent or attenuate such adverse events.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "How an ensemble of neurons wires together to form a functional unit is a fundamental problem in neuroscience. The architecture of neuronal wiring, in fact, determines how neurons communicate and may be important for information processing performed by neuronal networks. However current knowledge is mainly limited to networks consisting of a small number of neurons, while the topological structure of biological networks remains still unknown. Primary neuronal cultures represent an ideal preparation to investigate the basic principles of network dynamics. At the mature stage, they display network-wide synchronous bursting events (SBEs) sharing similar spatio-temporal patterns of firing . InteresAltogether, the results obtained with our neural network computational model show that this model can replicate most of the salient firing properties observed experimentally in cultured neuronal networks and that it can serve for exploring the properties of signals and responses observed in neuronal networks properties."} +{"text": "We are only beginning to understand the relationship between host genetics and the gut microbiome. Two recent studies help to disentangle this interaction and show that genetic loci across the human genome shape the gut microbiome. This opens the possibility that an unexpected number of genetic factors act directly on microbial composition and function to modulate immune pathways and metabolic phenotypes in host physiology and disease. Variation in the microbiome within human populations may influence susceptibility to diseases such as obesity and inflammatory bowel disease (IBD), motivating efforts to understand the determinants of the composition of the intestinal microbiome. There is extensive literature on the effects of diet, antibiotic exposure, colonization history and other environmental factors. Whether host genetics also influences the microbiome is of growing interest; two recent studies, one by Goodrich in Cell and the Medicine , have adIt was already known that microbial composition is altered when genes that encode host mechanisms for microbial sensing and effector functions were knocked out in mouse models . Other sIn humans, it is unclear whether genetic variation in human populations contributes to the inter-individual diversity in the human intestinal microbiome. This question can been addressed by evaluating whether the composition of the microbiome is more similar between monozygotic twin pairs than between dizygotic twin pairs, an approach that controls for shared environmental factors. Two early studies using high-throughput 16S sequencing reported no difference in microbial similarity between monozygotic twins compared with dizygotic twins using a phylogenetic similarity measure . HoweverGenome Medicine, Knights et al. present a systematic analysis of the effect of 154 IBD-associated polymorphisms on microbial composition in three cohorts of patients with IBD (152 to 162 patients in each cohort) [In this issue of et al. in the November issue of Cell, which analyzed a host genomic input on fecal microbial composition, utilizing the power of twin studies [These concepts are echoed in a structurally distinct study by Goodrich et al. suggest that heritable susceptibility to diseases such as obesity may be partially attributable to genetic factors that change the microbiome, although the specific common genetic variants in the human population that influence the microbiome remain unknown. Knights et al. successfully tackled this issue by identifying 49 IBD-associated polymorphisms that were correlated with microbial composition in some of their IBD cohorts. Indeed, many of the 163 known IBD genetic risk loci are involved in host-microbe interactions [The findings of Goodrich ractions .et al., paired with validation using gene-targeted and human gnotobiotic mice. Such investigations will not only aid our understanding of human disease, but could unmask microbes such as Christensenella minuta that are relevant to human health and could be manipulated for therapeutic purposes.Existing studies of candidate IBD-associated genetic variants have identified alterations in the intestinal microbiome in individuals carrying polymorphisms in NOD2 and FUT2, an enzyme that fucosylates mucus glycoproteins ,10. The"} +{"text": "Currently, metabolic disorders are a cardinal focus of research given their impact in public health problems worldwide. The main risk factors for death in people suffering metabolic disorders are cardiovascular diseases. Metabolic changes are important settings for cardiac cells under these conditions because the cardiovascular system must maintain energy balance to preserve work output and efficiency of the heart. Cardiovascular system is regulated by hormones which control, adjust, and remodel heart metabolism.The role of hormones and growth factors in modulating cardiovascular function impacts different areas of research, especially considering that atypical plasma levels together with variable effects at cellular level are hallmarks of several medical conditions such as metabolic syndrome, obesity, diabetes, ischemic heart disease, and heart failure. Hormones and growth factors produce integrative systemic effects that involve ligand/receptor interactions, generations of second messengers, activation of intracellular signaling cascades, posttranslational modification of proteins, and gene expression. The implications of hormone and growth factor effects encompass the diagnosis, clinical evaluation, and pharmacological intervention. Several studies on metabolic effects of hormones and growth factors in the cardiovascular system are being translated into therapeutic applications.In this issue E. Ostu et al. show the heart as a neuroendocrine gland that interacts with both hormones and cytokines. The authors discuss the current evidence about the dynamic communication between the heart and other organs involved in cardiovascular homeostasis. The exploration of microvascular function is important as predictive tool and as prognosis of cardiovascular risk and progression of heart failure. This paper describes the present knowledge on whether hormones and cytokines influence microvascular function and coronary flow reserve. The work is an interesting contribution to understand the pathological mechanisms of microvascular dysfunction which could further benefit patients suffering metabolic and cardiovascular diseases.The incidence of cardiovascular mortality, including sudden death, is higher in men than in women. Obesity, metabolic syndrome, and type 2 diabetes mellitus are major risk factors for cardiovascular disease. Here, L. Skrgatic et al. review publications from the late 1980s to the present to infer whether polycystic ovary syndrome is a cardiometabolic risk factor according to its relationship to several intrinsic factors that are known to produce these metabolic disturbances. Meta-analysis and clinical evidence correlate low testosterone plasma concentrations with metabolic disorders and cardiovascular damage, but safety concerns have been raised over testosterone replacement therapy as an association between myocardial infarction and testosterone replacement therapy in men has been suggested. W. Reilly et al. carried out a large, retrospective study in a multicenter practice center for testosterone treatment. This analysis in patients treated with testosterone did not correlate with high incidence of myocardial infarction. Further studies should be conducted in this field in order to elaborate safe therapeutic replacement protocols.Adipose tissue is an endocrine gland and key controller of body metabolism that interlinks with cardiovascular system. Early, simple, and fast biomarkers determining the association between altered focal point of adipose tissue and cardiovascular risk factors are useful for handling large scale and nutritional interventions and early therapeutic. The work of G. Curic et al. shows the relationship between subcutaneous and visceral adipose tissues with incidence of coronary artery disease in cohort of patients assessed at the cardiology unit. Using low cost anthropometric measures obtained from coronary artery disease and noncoronary artery disease patients, the authors found that anthropometric measures and subcutaneous adipose tissue have nonlinear relationship with the expansion of epicardial adipose tissue which is linked to coronary artery disease. Thus epicardial adipose tissue thickness and anthropometric measures have similar coronary artery disease predictive value.Several studies have shown that consumption of energy drinks has short term impact on cardiac contractility. The cardiovascular and metabolic effects of these beverages have been associated with a high intake of caffeine, including high heart rate, palpitations, and increases in blood pressure, whereas hyperglycemic effects are associated with high sugar content. However, high concentrations of caffeine do not fully explain these effects; in this sense the paper of A. Panduric et al. explores the activation of the adrenergic system as a potential mechanism for cardiovascular and hyperglycemic effects produced by elevated energy drink intake. Through determination of heart rate, arterial blood pressure, blood glucose, adrenaline, and noradrenalin plasma levels before and after energy drink intake, the authors argue about positive cognitive functions and effect on cardiovascular and respiratory system at rest and during exercise by increasing activity of the sympathetic nervous system being due, in part, by adrenergic activation.A large number of studies have shown that altered metabolic action of hormones and growth factors correlates significantly with the incidence of cardiovascular disease. These studies suggest the molecular basis for an integrated model of energy unbalance produced in cardiovascular system and hormone action and function. Furthermore, hormone interventional studies have shown an improvement in these cardiovascular risk factors.Cristian IbarraCristian IbarraSergio LavanderoSergio LavanderoManuel EstradaManuel Estrada"} +{"text": "Accurate definition and better understanding of the mechanisms of stroke are crucial as this will guide the effective care and therapy. In this paper, we review the previous basic and clinical researches on the causes or mechanisms of ischemic cerebrovascular diseases (ICVD) and interpret the correlation between embolism and hypoperfusion based on vascular stenosis and arterial intimal lesions. It was suggested that if there is no embolus (dynamic or in situ emboli), there might be no cerebral infarction. Three kinds of different clinical outcomes of TIA were theoretically interpreted based on its mechanisms. We suppose that there is a correlation between embolism and hypoperfusion, and which mechanisms (hypoperfusion or hypoperfusion induced microemboli) playing the dominant role in each type of ICVD depends on the unique background of arterial intimal lesions (the vulnerability of vessels). That is to say, the vulnerability of vessels is involved in the role of embolism and hypoperfusion in the mechanisms of ischemic cerebrovascular diseases. This inference might enrich and provide better understandings for the underlying etiologies of ischemic cerebrovascular events. As is generally known, ischemic cerebrovascular disease (ICVD) is divided into two categories of cerebral infarction and transient ischemic attack (TIA). Based on the clinical findings and its related basic research results, the following points can be briefly summed up: firstly, the causes of cerebral infarction are due to vascular occlusion (embolus) and the role of hypoperfusion is in the second place. The role of hypoperfusion in the causes of cerebral infarction might be mediated by the microemboli. The occurrence of cerebral infarction is nothing more than the following situations: (1) extracranial to intracranial arterial thrombosis; (2) intracranial artery to its branch artery immobilization; (3) intracranial arterial thrombosis in situ; (4) atherosclerosis occlusion in the end of the intracranial artery or cardiogenic emboli; (5) other factors resulting in the formation of emboli or arterial dissection or occlusive vascular inflammatory. Therefore, we speculate that if there are no emboli (dynamic emboli or emboli in situ), there might be no cerebral infarction. Secondly, according to the condition of vascular stenosis and arterial intimal lesions, the vessel background of TIA can be divided into four categories as follows: (1) with large vessels with stenosis and arterial intimal vulnerable lesions; (2) without vascular stenosis and arterial intimal vulnerable lesions; (3) with large vessels with stenosis but without vulnerable artery intimal lesion; (4) without large vessels stenosis but with arterial intimal vulnerable lesions. Based on the different background of the vessel (the vulnerability of vessels), their cause varies from hypoperfusion to microcephalic induced by hypoperfusion. In this paper, we review the studies on the etiologies of ICVD and give some proposal and viewpoints on the correlation between embolism and hypoperfusion.The hypoperfusion has been considered as another important cause of ischemic stroke beside embolism. Since the middle of last century, most of the cerebral infarction was attributed to blood flow reduction or interruption resulting from intracranial and extracranial artery stenosis or occlusion and their arteriosclerosis. In all circumstance, there is no doubt that oxygen-glucose deprivation will lead to the brain tissue death. There is indeed no controversy for small artery occlusion and embolic material occlusion in intracranial branch resulting in cerebral infarction. However, in case of severe stenosis existing in a large vessel such as severe stenosis of the internal carotid artery or cerebral artery, is it hypoperfusion or unstable plaque which results in embolism or hypoperfusion-mediated microemboli formation based on stenosis? These problems still remain debatable up till now. It was previously known that intracranial and extracranial artery stenosis was a major risk factor of cerebral infarction, especially there is intracranial arteries stenosis found in vascular assessment: asymptomatic stenosis > 80%, symptomatic (TIA or stroke attack) stenosis > 50%, or degree of stenosis < 50%, but there is ulcerative plaque; interventional treatment is always performed to prevent possible ischemic stroke. However, it was found that a considerable part of patients with intracranial and extracranial stenosis, especially patients with extracranial stenosis, has no history of stroke in general in clinical practice. A prospective study reportedUp till now, the mechanism of watershed infarction still remains inconclusive. Hypoperfusion induced by artery stenosis is often regarded as the main mechanism of watershed infarction. Hypoperfusion and impairment in the washing capacity of emboli are usually bracketed together. A PET study on the patients with chronic internal carotid artery occlusion and without border zone infarct found that there was no difference in oxygen uptake rate between cortical and border zone tissues with contralateral and normal border zone, which prompted that internal carotid artery occlusion-mediated hypoperfusion did not make the oxygen uptake rate significantly increased in the weak blood flow border zone . It was Maybe there might exist a query. Generally speaking, patients with WCI always have large artery stenosis. However, why is hypoperfusion not the main cause of WCI? There is a relationship between microemboli formation with hypoperfusion, which should be worthy to be paid more attention to. In fact, there is an inner correlation between them. Large artery stenosis is the main factor which induced hypoperfusion and hemodynamic changes (impairment). In addition, systemic hemodynamic changes (various causes induced low blood pressure). It is vulnerable to form microemboli under the premise of hypoperfusion, hemodynamic changes, and vascular intima vulnerable lesions. Among these factors, the latter factor plays the prominent role in microemboli formation. Why does mere systemic hypotension always lead to syncope rather than cerebral infarction? Even though there is presence of systemic hypoperfusion or hemodynamic abnormalities, microemboli is not easy to form in the absence of arterial intima vulnerable lesions, which again prove that mere hypoperfusion generally does not easily lead to the cerebral infarction. This can also be interpreted as the reason why patients with severe aortic valve stenosis and internal carotid artery dissection always show TIA rather than cerebral infarction. From the perspective of treatment, antiplatelet aggregation therapy displays good effect for the WCI with vascular stenosis, which could reveal that microemboli formation might play the prominent role in the formation of WCI. Indeed, increasing blood volume and blood pressure also can improve the prognosis of WCI in the clinical practice. Improving perfusion and hemodynamics can eliminate or weakens the necessary condition for the microemboli formation, and at the same time, the washing ability of microemboli is enhanced. Previous autopsy studies indicated that visible platelet aggregation and leukocyte (white blood clots) could be found in the border zone of watershed infarction with or without large arteries stenosis . Many coInternal border zone infarction mainly results from hemodynamic impairment secondary to severe lumen stenosis, while cortical watershed infarction is due to microembolism which is secondary to inflammation or fragmentation of plaque. The results showed that there were different mechanisms between the internal and cortical border zone infarction. However, we analyze the relevant research background and then find that the core mechanism does not yet go beyond the microemboli level. The key problem lies in the different source where microemboli come from. For internal watershed infarction , microemboli originate from the supply arteries in the internal border zone; that is to say, the microemboli spontaneously form within the arteries which supply the internal border zone under the condition of hypoperfusion induced by severe vessel stenosis . For corAnother case is that multiple cortical infarctions occur under the condition of being without significant stenosis or only with artery atherosclerosis. Because there is no inducement of hypoperfusion, artery to artery embolization should be responsible for this case. If emboli go to pieces during the process of their migration, the cortical infarcts display multiple ischemic lesions in MRI imaging, which is usually lager and more scattered than that caused by hypoperfusion. If microemboli are larger and not easily smashed to pieces, the lesions are prone to aggregation and fusion , which iAnother type of infarction is symptomatic lacunar ischemic stroke which belongs to cerebral small vessel disease. Recent study reported that it resulteP < 0.05), were more frequently symptom free at discharge , and experienced a longer mean length of hospital stay than non-ISUC patients. The relevant studies suggested that ISUC was infrequent, etiologies were numerous, and hematologic disorders were the most frequent cause [Patients with ischemic stroke of unusual cause (ISUC) presented a lower in-hospital mortality rate being combined with large artery stenosis and vulnerable artery intima lesions; (2) being without any large artery stenosis and vulnerable artery intima lesions; (3) being with large artery stenosis but without vulnerable artery intima lesions; (4) being without large artery stenosis, but with vulnerable artery intima lesions. Under the different backgrounds of vessels and arterial intimal lesions, different etiologies vary from hypoperfusion and hypoperfusion induced microemboli.Firstly, for TIA patients with large artery and artery intima vulnerable lesions, especially for the patients who repeatedly experienced stereotypical attack, its cause can be regarded as hypoperfusion-mediated microemboli formation which plays the dominant role. Under the condition of hypoperfusion, microemboli are not difficult to form in the arteries with intima vulnerable plaque and the hemodynamic instability . The locIn addition, this circumstance has a relatively good outcome, even if progressing to cerebral infarction, which mostly shows watershed infarction. For experiencing TIA (ischemic preconditioning), cerebral infarction is always not serious and the prognosis is always fair in nonlacunar ischemic strokes; thus suggesting that TIA possibly displays a neuroprotective effect by inducing ischemic tolerance . It may Clinically, there is a particular type of TIA, limb shaking syndrome (LSS). It is a very effective method to explore its mechanism through this particular type of TIA . Such type of TIA is rare and more commonly observed in younger patients and rarely in elderly patients. These patients are generally combined with intracranial and extracranial artery stenosis or moyamoya disease, especially in the MCA secondly to intracranial internal carotid artery stenosis . ClinicaIn summary, this paper proposed several different opinions on the mechanisms of ICVD: first, the vulnerability of the arterial intima is the core risk factor for cerebral infarction. Embolism caused by microemboli formation induced by unstable plaque or artery stenosis induced hemodynamic compromise is the main cause of cerebral infarction. The role of stenosis factor in ischemic stroke is much smaller than the unstable plaque as well as other artery intima vulnerable lesions. Secondly, core etiology for watershed infarction and subcortical infarction is still embolization secondary to hypoperfusion induced by the large artery stenosis. Emboli formation induced by a variety of factors mainly resulted from the occlusion of responsible vessels and is the core mechanism of cerebral infarction . Thirdly"} +{"text": "In this study the influence of active ingredients of certain drugs on the activity of human diamine oxidase was quantified. DAO is the main enzyme in catabolism of biogenic amines in the intestine. Ingestion of food containing high amounts of biogenic amines in case of reduced activity of DAO leads to an accumulation of histamine which causes symptoms of histamine intolerance. Many drugs are suspected to inhibit DAO-activity, nevertheless, only few scientific data are available to support this thesis.Therefore, based on a selection of drugs / active ingredients by literature research, the interaction with purified human diamine oxidase is determined and quantified in vitro with an activity test. Various drugs at pharmacologic concentrations were incubated with human diamine oxidase. Inhibition of diamine oxidase activity was calculated as the percentage of inhibition versus control (no inhibitor). To exclude drug formulation specific influences active ingredients (AI) of drug products (D) in pure form were examined.Chloroquine and clavulanic acid showed greatest inhibition potential on diamine oxidase (> 90%). Cimetidine and verapamil showed inhibition of about 50%. Moderate influence on DAO was caused by isoniazid and metamizole, acetyl cysteine and amitriptyline (>20%). Diclofenac, metoclopramide, suxamethonium and thiamine have very low inhibition potential (<20%). Interestingly cyclophosphamide and ibuprofen displayed no effect on DAO.Since even levels of about 30% inhibition may be critical, most of the observed substances, can be designated as DAO inhibitors. Other drug components than active ingredients did not affect DAO activity or its interaction with a specific drug."} +{"text": "Over the last decade, the field of molecular diagnostics has undergone tremendous transformation, catalyzed by the clinical implementation of next generation sequencing (NGS). As technical capabilities are enhanced and current limitations are addressed, NGS is increasingly capable of detecting most variant types and will therefore continue to consolidate and simplify diagnostic testing. It is likely that genome sequencing will eventually serve as a universal first line test for disorders with a suspected genetic origin. Academic Medical Centers (AMCs), which have been at the forefront of this paradigm shift are now presented with challenges to keep up with increasing technical, bioinformatic and interpretive complexity of NGS-based tests in a highly competitive market. Additional complexity may arise from altered regulatory oversight, also triggered by the unprecedented scope of NGS-based testing, which requires new approaches. However, these challenges are balanced by unique opportunities, particularly at the interface between clinical and research operations, where AMCs can capitalize on access to cutting edge research environments and establish collaborations to facilitate rapid diagnostic innovation. This article reviews present and future challenges and opportunities for AMC associated molecular diagnostic laboratories from the perspective of the Partners HealthCare Laboratory for Molecular Medicine (LMM). Molecular diagnostic testing has undergone dramatic changes since its debut in the late twentieth century. Initially restricted to simple assays interrogating single to a few genomic sites known to harbor pathogenic variants, the adoption of Sanger sequencing enabled whole gene analysis and therefore the discovery of rare and novel disease causing variants. Over the last decade, the field has undergone another tremendous transformation, catalyzed by the clinical implementation of next generation sequencing (NGS). This disruptive technology enabled replacement of single gene tests and small gene panels with large, comprehensive gene panels and more recently whole exome and genome sequencing, reducing the need for lengthy and expensive stepwise testing algorithms and therefore eliminating many diagnostic odysseys ,2,3,4. AIn 2015, comprehensive NGS is the standard for most inherited disorders with genetic and clinical heterogeneity although limitations surrounding detection of structural and other complex variants often necessitate additional testing. This typically requires use of different technology platforms such as cytogenomic and exon arrays, which continue to be the methods of choice for detecting copy number variants (CNVs). Other variants that are non-trivial to detect by NGS include copy number neutral structural rearrangements and repeat expansions. However, it is already evident that NGS will continue to catalyze consolidation of diagnostic testing approaches. For example, NGS-based CNV detection is being implemented in diagnostic laboratories ,7,8 and The rapidly growing scope of genomic testing has implications for many small to medium sized AMC associated diagnostic laboratories, including challenges but also opportunities. Challenges: New genomic platforms require significant capital investment and typically a high test volume to be able to operate at scale and achieve competitive price points. In addition, establishing and maintaining different technology platforms is difficult. The emerging practice of offering comprehensive sequence and copy number testing illustrates this challenge. Access to genome wide cytogenomic CNV detection platforms can be an advantage until NGS is equally accurate. However, cytogenomic and molecular laboratories have historically been separately managed at AMCs, which can be an obstacle towards integrating these technology platforms to streamline comprehensive testing. Furthermore, the necessary capital to establish the infrastructure for modern genomic testing and comprehensive interpretation is often not present at AMCs, especially in the current funding climate. For example, automation is increasingly important for supporting complex genomic testing processes but requires a test volume that is often not present at AMCs. Commercial entities have an increasing presence in this space and are often better equipped to establish a cohesive suite of technology platforms to meet all testing needs and maintain a higher throughput and therefore lower price points. A second major challenge is the recruitment and retention of staff needed for high complexity genomic testing. The level and diversity of skill sets needed has grown significantly, making it difficult to recruit highly trained staff within the salary constraints present at academic institutions. This is especially problematic in two areas that have rapidly increased as large scale genomic tests become the norm: (1) The associated need for computational (bioinformatics and IT) support has proven to be extremely difficult to manage for diagnostic laboratories in several ways. First, computational/bioinformatic skills are typically present in service oriented core facilities, which serve researchers in a project oriented fashion. Diagnostic laboratories are subject to regulatory oversight and therefore the traditional computational support model does not meet all needs, which range from project-like efforts such as the development of novel genetic tests to all aspects of routine operations including quality management. As such, computational analysts and bioinformaticians need to be integrated into clinical operations and need to be trained in genetics as well as regulatory requirements, as regulators are extending oversight to computational processes; (2) Traditional (pre-Sanger) diagnostic testing required a mix of technical and interpretive work that was skewed towards technical analytic management. With the ability to interrogate large numbers of genes, this balance has been shifted significantly towards clinical interpretation of technical results, which has created a tremendous overhead associated with curating and managing genomic knowledge. The end result is an increased need for highly trained (and therefore expensive) MD or PhD level staff. While AMCs have easy access to such staff, it can be difficult to secure a sufficient level of funding to capture this resource.In addition, molecular diagnostic testing is currently under intense scrutiny as the US Food and Drug Administration (FDA) has announced its intention to begin regulating laboratory developed tests (LDTs) after decades of using \u201cenforcement discretion\u201d. This shift was in part catalyzed by the rapid adoption of NGS-based tests in clinical testing laboratories and the realization that traditional regulatory frameworks, which were largely designed for genotyping tests that interrogate known, pathogenic variants, are completely inappropriate to establish and monitor the analytic validity of assays that sequence a large number of genes in their entirety and therefore detect novel variation. In 2015, there is no clarity on how the US regulatory framework will evolve. Although any changes would affect commercial entities and AMCs alike, the latter are generally ill equipped to meet the significant financial overhead associated with traditional FDA approval processes. This has created an immense and justified fear of stifling innovation, which often originates at AMCs. Finding the right balance between regulation and flexibility to ensure quality as well as enable rapid translation of novel findings and technological advances is critical, especially in an era where we are routinely seeing the benefits of genetic and genomic testing.Opportunities: AMC associated diagnostic laboratories can often achieve a tight integration with local treating physicians, which benefits both specialties. Ideally, laboratory directors and physicians collaborate to form \u201cphysician\u2013laboratory partnerships\u201d, which are of growing importance as genomic testing is increasingly utilized as one of several modalities to establish a clinical diagnosis. Board certified PhD or MD level laboratory directors are broadly trained in clinical and technical disciplines but rarely reach the knowledge of a clinical expert. Such partnerships can therefore provide a critical foundation for maximizing the clinical utility of tests, especially in clinical areas that are new for a testing laboratory. Laboratory\u2013physician collaborations include operational activities such as selecting the most relevant genes that need to be interrogated for a particular disorder. Clinical domain knowledge is also helpful to determine whether additional, supplemental assays are required to ensure complete and clinically meaningful interrogation of a gene. In addition, laboratory directors benefit from a solid clinical knowledge base, which enhances the clinical interpretation of test results. Another opportunity involves the clinical translational research environment common to AMC associated diagnostic laboratories. Early leadership in translational programs affords AMC associated diagnostic labs an innate ability to innovate, allowing new discoveries to be rapidly translated into clinical tests and to support clinical trials where robust patient recruitment and close interaction with the clinical care environment are often necessary. This integration with clinical translational research is especially potent at those AMCs operating large consented biorepositories, which are poised to accelerate genomic discoveries with diagnostic relevance.http://personalizedmedicine.partners.org/). The LMM\u2019s mission is to bridge the gap between research and clinical medicine by accelerating the adoption of new molecular tests into clinical care. An integral component of this mission is the incorporation of advanced computational and IT support into the day to day operations of the clinical laboratory, as well as implementing innovative programs to help physicians stay current on genetic information relevant to their patients. The LMM offers disease-targeted NGS panels for a variety of disorders with genetic and clinical heterogeneity (covering ~400 genes) as well as exome and genome sequencing services with an average of ~5000 high complexity genetic and genomic tests/year. Major areas of expertise include inherited cardiomyopathies, hearing loss, respiratory disorders, connective tissue disorders, RASopathies, and multi-organ genetic syndromes. LMM\u2019s ability to innovate quickly is due to its strong academic focus , its close interaction with local physicians and its proximity and collaboration with the Center\u2019s translational genomics research core as well as its bioinformatics team. The linkage to core facilities supporting research has enabled rapid transfer of novel technologies into the clinic, most notably enabling the LMM to be an \"early adopter\" of clinical NGS [The Laboratory for Molecular Medicine (LMM) was founded 13 years ago as part of a broader program, now called Partners Healthcare Personalized Medicine that also includes translational genomics core service, bioinformatics and IT services, and a biobank certified director and a tight, \u201cmatrixed\u201d integration of its compartments and linkage with other Center cores. For example, most LMM directors have leadership roles either in other parts of the clinical operation (test development) or other parts of the Center . By linking these typically separate components through ABMGG certified individuals, many of the challenges mentioned above can be alleviated and synergy is created that benefits not only the clinical laboratory but also the other parts of the Center. Several examples illustrating the benefit of this infrastructure are described below. Clinical test development: Novel technologies typically make their debut in the research realm and are optimized over a period of time until they are mature enough for diagnostic implementation. The co-location of the LMM and the Center\u2019s translational genomics core as well as the overlap in staff enabled clinical adoption of NGS, which was clinically launched at the LMM in 2011. Prior to NGS implementation, the LMM was the first laboratory to develop clinical grade oligo-hybridization-based sequencing which supported an interim platform for disorders with genetic heterogeneity starting in late 2007 [Clinical Research: There is an increasing demand to carry out translational research studies in a CLIA environment. As this is associated with increased cost, one approach is to generate the initial data in a research environment and confirm and interpret actionable findings in the CLIA lab. This generates a revenue source for the CLIA lab and a competitive advantage for the research core. Fluid team structures. Strategic staffing approaches are of growing importance in maximizing efficiency, especially under financial constraints that are often present in AMC associated laboratories. Three examples illustrate this concept: (1) a critical activity of clinical diagnostic laboratories is quality improvement (QI), which requires expertise that is present in the clinical test development as well as operations teams. At the LMM, senior clinical operations staff participate in quality improvement projects as they operate and/or oversee the technologies on a day to day basis. Overall, QI is jointly managed by the clinical test development team in collaboration with the laboratory\u2019s operational leadership by selecting and overseeing an ad hoc team composed of development and operations staff with expertise in the specific technology underlying the QI effort; (2) Translational Core staff often participate in clinical test development as the developed clinical tests are often offered by the Core as a research grade service; (3) Most parts of the clinical lab require substantial computational and bioinformatics support. On a day to day basis this typically entails analyzing large data sets and basic programming. The LMM development team is staffed by a computational analyst with strong training in molecular genetics and genomics technologies as well as a senior bench technologist with computational and basic programming skills. These individuals participate in regular meetings of the Center\u2019s bioinformatics core, thereby embedding computational expertise directly within the clinical lab and facilitating closer collaborations when more substantial bioinformatics support is needed. This fluid interaction with the bioinformatics Core, as opposed to seeking support from a classic core facility, has proven to be crucial in efficient clinical test development.ate 2007 ,14,15. CGiven the challenge of maintaining sufficient financial resources to sustain AMC-associated diagnostic laboratories, AMCs have increasingly turned to commercial partnerships to ensure financial stability. These may take the form of acquisitions or partnerships with outside commercial entities or licensing of knowledge, software, or tests developed by an AMC-associated laboratories . These relationships present both challenges and opportunities to the laboratories. Revenues streams and financially secure business partnerships enable AMCs to sustain their innovation and ability to evolve efficiently within an increasingly competitive market; however, conflicts of interest and commercial motivations can create barriers and shifted priorities that can be at odds with advancing the academic mission of an AMC. Setting clear boundaries and expectations as well as ensuring transparency in all relationships is necessary to achieve optimal outcomes in the rapidly advancing framework of genomic medicine. Over the past 10 years, the LMM has worked closely with the Center\u2019s software development team building the GeneInsight platform . While tAs AMC-associated diagnostic laboratories look to the future, several options enable a sustained contribution to the genetic and genomic testing market. These include: (1) Partnerships with commercial entities to compete in the rapidly evolving global genetic and genomic testing market, (2) Focus on local testing needs including support for higher volume tests and/or conversion of all rare disease testing to a common genomics platform and (3) Shifting focus to support for clinical research programs and other project-oriented endeavors.The LMM has been increasingly pursuing path #3 and shifted its focus to lead or support clinical research partnerships. Examples include supporting the NIH-funded MedSeq and Baby"} +{"text": "To study the distribution pattern of lymph node metastases of stage IA to IIA cervical cancer and to clarify the individualized clinical target volume delineation of regional lymph nodes (CTVn).A total of 665 cases with International Federation Gynecology and Obstetrics stage IA to IIA cervical cancer who underwent radical hysterectomy and pelvic lymphadenectomy were retrospectively reviewed. The clinicopathological factors related to lymph node metastases were analyzed using logistic regression analysis.Pelvic lymph node metastases were found in 168 of 665 patients resulting in a metastasis rate of 25.3%. Binary logistic regression analysis showed that age, lymph vascular space involvement, and deep stromal invasion statistically influenced pelvic lymph node metastases . Pathological morphology type, lymph node metastases of the obturator, the external iliac and internal iliac, and the para-aortic had a strong influence on lymph node metastases of the common iliac . Tumor size and lymph node metastases of the common iliac were significantly related to lymph node metastases of the para-aortic . Lymph node metastases of the obturator, the external iliac and internal iliac were strongly correlated to lymph node metastases of the circumflex iliac node distal to the external iliac node .Factors related to lymph node metastases should be comprehensively considered to design and tailor CTVn for radiotherapy of cervical cancer. Selective regional irradiation including the correlated lymphatic drainage regions should be performed. Cervical cancer is the most common gynecological malignancy and the second most frequent cause of cancer death in Chinese women . RadicalAlthough the status of pelvic lymph nodes is not included in International Federation Gynecology and Obstetrics (FIGO) stage, it is one of the most important prognostic factors and also an indicator of the need for postoperative radiotherapy . The stuWe retrospectively studied 665 patients with 2009 FIGO iOur subgroup analysis suggested that endophytic tumors were associated with an increased risk of common iliac lymph node metastasis. Our results emphasized the importance of pathological morphology type in cervical cancer lymph node metastases. Although common iliac node metastases are rare in early stage carcinomas in the absence of positive pelvic nodes , they shThe survival outcome of cervical cancer patients with positive para-aortic lymph nodes is poor; a 30% 5-year survival has been demonstrated in a retrospective study of these patients . Pelvic CINDEIN, which is the most distal external iliac lymph node in the pelvic cavity, has been called the lateral deep inguinal node , suprainCTVn must be customized by experienced oncologists according to the various clinical factors that influence lymph node metastasis. Irradiation of selective regional lymph nodes and their correlated lymphatic drainage regions should be performed according to clinical and pathological factors, deep stromal invasion, and LVSI. For large and endophytic tumors, the irradiation field should be enlarged appropriately. Our results can improve the accuracy of postoperative adjuvant therapy and allow a more individualized treatment for cervical cancer patients."} +{"text": "Dietary iodine intake is required for the production of thyroid hormones. Thyroxine T4) and triiodothyronine T3) are essential for the development of the central nervous system, they regulate genes involved in myelination and neuronal/glial cell differentiation, and play an important role in axonal and dendrite growth in synaptogenesis and myelination. Deficiencies in thyroid hormones in pregnant women directly affect brain development of the fetus, resulting in neurological and neurocognitive disorders in infants with defects ranging from decrease in intelligence and lethargy to mental retardation. Thyroid deficiency at different stages of pregnancy affects different brain regions, for example, basal ganglia are affected by early thyroid hormone deficiency and cerebellar and hippocampal development is influenced by late thyroid dysfunction . Therefo are esse and trii"} +{"text": "Recently published computational work , automated 3D reconstruction from optical and electron microscopy data, fMRI, EEG, MEG, and others, are increasingly supporting a concerted effort for systematic whole-brain anatomical and functional mapping of brain connectivity (Devor et al., Computational neuroscientists are uniquely positioned to tackle the grand challenge of understanding brain evolution. Simulations can efficiently validate the functional advantages of presumed evolutionary events and the correct sequence in which these took place. The work of Moldakarimov and colleagues contributes toward solving this puzzle and motivates further research.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Medically compromised patients with disordered eating are admitted to the childrens ward of the Gold Coast University Hospital following a treatment protocol, including immediate insertion of nasogastic tube and commencement of enteral feeding, which is independent of admitting diagnosis, including anorexia nervosa, eating disorder not otherwise specified, anxiety and mood disorders.Data has been collected and analysed over a 12 month period to include the diagnosis, BMI Z-scores corresponding to severity of malnutrition on admission, weight gained over admission, length of stay and follow up plans including readmission rates.This presentation highlights the importance clear admission criteria and immediate nutritional resuscitation for the spectrum of disordered eating diagnoses and its effect on rectifying malnutrition, reducing readmission rates and improving the health outcomes for this population."} +{"text": "Primary headaches are common debilitating disorders with high prevalence and significant socioeconomic and personal impacts. Idiopathic headaches affect all aspects of the individual's life and are the result of complex interaction of biological, psychological, and environmental factors. In patients with chronic headaches the efficacy of pharmacological treatments is often not satisfactory. Pain and disability can potentially induce an escalation of analgesics/triptans intake leading to medication-overuse headache . Experie"} +{"text": "A growing body of research is highlighting the impacts root-associated microbial communities can have on plant health and development. These impacts can include changes in yield quantity and quality, timing of key developmental stages and tolerance of biotic and abiotic stresses. With such a range of effects it is clear that understanding the factors that contribute to a plant-beneficial root microbiome may prove advantageous. Increasing demands for food by a growing human population increases the importance and urgency of understanding how microbiomes may be exploited to increase crop yields and reduce losses caused by disease. In addition, climate change effects may require novel approaches to overcoming abiotic stresses such as drought and salinity as well as new emerging diseases. This review discusses current knowledge on the formation and maintenance of root-associated microbial communities and plant\u2013microbe interactions with a particular emphasis on the effect of microbe\u2013microbe interactions on the shape of microbial communities at the root surface. Further, we discuss the potential for root microbiome modification to benefit agriculture and food production. All eukaryotic organisms are influenced by complex interactions with microbial communities. The potential for gut microbiota to affect the health and nutritional status of host animals is well documented . The emergence of dominant groups in the rhizosphere from this soil biome can have major implications for resident plant species. While soil biomes are undoubtedly a key determinant of root microbiome composition, research has demonstrated that host genotype also influences the overall composition of these communities is unclear. The effect of soil and plants on the composition of rhizosphere communities has been excellently reviewed recently . Recruitment is mediated by l-malic acid, a tricarboxylic acid cycle intermediate secreted by roots in response to Pst DC3000 infection of foliage. Transcriptome analyses revealed that the interaction with B. subtilis FB17 systematically altered the expression of Arabidopsis genes involved in auxin regulation, metabolism, defence and stress responses as well as cell wall modification that can sustainably enhance crop production.Bacillus amyloliquefaciens , a type utilised by the majority of Gram negative bacterial species in QS regulation of activities such as biofilm formation, bioluminescence and secretion of virulence factors. In addition, Autoinducer-2 (AI-2), a QS pheromone regarded as conserved amongst Gram negative bacteria and a range of small peptides or post-translationally modified peptides that comprise the majority of Gram positive QS molecules and rhizobial bacteria produced greater increases in plant biomass than inoculation with AMF or rhizobia alone. These increases were also found to be higher than predicted additive effects based on the performance of AMF and rhizobia strains when applied as separate inoculants . TAD is defined as the decrease in prevalence and disease severity in wheat and other susceptible hosts due to pathogen suppression in the rhizosphere following application of inoculum comprising Azospirillum spp. and Azotobacter spp. and abiotic factors determine microbial community dynamics and composition under field conditions.The study of suppressive soils highlights the potential of customised adjustment of microbial communities to bring benefits to crop production in terms of plant growth and resistance to biotic and perhaps abiotic challenges. Utilising microbes in agricultural settings is not a new concept. Commercially available entomopathogenic z et al. , for insT. harzianum are already commercially available as fungicides and recent experiments have highlighted the benefits of T. harzianum soil enrichment. Application of T. harzianum-enriched biofertiliser to tomato plants allowed chemical fertiliser input to be reduced by 25\u00a0% with no reduction in yield with P. indica and the PGPR Pseudomonas striata found the presence of P. indica resulted in short term increases in P. striata in the rhizosphere and Meloidogyne incognita (root-knot nematode) (Akhtar and Siddiqui C. arietinum with the AMF Glomus intraradices and PGPRs Pseudomonas alcaligenes and Bacillus pumilus reduced the combined impact of M. phaseolina and M. incognita when compared to single-strain inoculants, dual-strain inoculants and controls. This synergism serves as an indication that experiments focusing on the effects of single microbial species may overlook important multipartite interactions of more naturalistic microbial communities. The study of microbe\u2013microbe synergism might provide valuable models to decipher underlying communication and validate these findings in more complex microbial communities.In addition to beneficial bacteria, the importance of fungal symbionts to many plant species is well documented. In particular AMF are recognized for their ability to increase host access to mineral nutrients, predominantly phosphate. Their presence has also been associated with reductions in bacterial foliar pathogens (for review see; Parniske Increasing demands for food by a growing human population, along with agricultural challenges posed by climate change, are risks to global food security. Microbes in the rhizosphere are involved in many processes that determine agricultural soil productivity, including preservation of soil structure, nutrient recycling, disease control and degradation of pollutants. Agricultural practices can negatively impact soil microbes by reducing organic matter content in the soil and cause contamination of groundwater. In this context, understanding the potential for manipulation of soil microbial communities to increase crop yields and reduce losses is highly relevant. Much research has focused on the potential for individual microbial strains to bring benefits to plants and has clearly demonstrated the potential benefits to agriculture of application of microbial treatments. However, it is also clear that microbes can act synergistically to impact plant health and development, and that edaphic factors also play an important role in root microbiome formation. The development of disease suppressive soils following successive seasons of crop monoculture further suggests that stable beneficial soil microbial communities can develop and be maintained without deliberate attempts at modification by humans, and are presumably induced by conditions that provide a stable environment for plant-beneficial microbial partners. The growing body of research relating to plant\u2013microbe interactions and their effects is bringing into focus the importance of these relationships to plant health and productivity. While our understanding of the importance of these interactions is increasing, there is still a requirement for research to unravel the intricacies of communication between all members of the root microbiome and their plant hosts. The multipartite interactions that lead to assembly and maintenance of the root microbiome are highly complex and not fully understood. A greater understanding of root microbiome community dynamics and communication has the potential to allow for more efficient exploitation of this largely untapped resource. Farming methods that support recruitment and maintenance of beneficial microbial communities in the rhizosphere could provide benefits to agriculture in the form of enhanced crop yields and disease suppression."} +{"text": "There are several options in the treatment of varicocele. Surgical repair either by open or microsurgical approach, laparoscopy, or through percutaneous embolization of the internal spermatic vein have been used to treat varicocele . RegardlPrasivoravong et al. report rFurther studies are necessary to determine the benefit of percutaneous embolization in men with bilateral and lower grades of varicocele. Additional comparative studies comparing the different treatment options for varicocele can help determine the best treatment option for men that present with varicocele-associated infertility."} +{"text": "Rapid advances in human genomic research are increasing the availability of genomic data for secondary analysis. Particularly in the case of vulnerable African populations, ethics and informed consent processes need to be transparent\u00bfboth to ensure participant protection, as well as to share skills and to evolve best practice for informed consent from a shared knowledge base. An open dialogue between all stakeholders can facilitate this. The health genomics revolution is well under way, thanks to the increased accessibility of rapidly advancing sequencing technologies . Africa Consent for secondary use of data and samples is sensitive within Africa, for various reasons: localised cultural sensitivities, and the vast cultural and ethnic diversity across African populations, are not always appreciated by external researchers ; many AfInstitutional and governmental ethics review boards (IRBs) are currently the gate-keepers for re-use of African genomic data and for validating informed consent processes. There are many excellent IRBs and ethicists in Africa, but they are often under-resourced . TheTo date, we have found it surprisingly difficult to access informed consent templates, standard operating procedures and `information for participants\u00bf from published African genomic studies . ReluctaIssues around data re-use and informed consent may raise concerns about secondary use of participant genomic data. Currently, a statement about ethics approval and informed consent is usually provided in publications and is often considered sufficient for secondary use access to study data obtained through correspondence with the authors. In some cases, data access committees may review proposals for secondary use of genomic data , but thThese issues raise questions around transparency and skills-sharing to develop the best practice for ethics, informed consent and participant protection particularly in Africa\u00bfalthough they are pertinent for all health genomics research.Firstly, can journals that publish genomic research involving human subjects encourage more transparency through submission of ethics-related documentation and templates when accepting manuscripts for publication? This might take the form of providing the option to submit ethics documentation templates (such as informed consent templates) for some studies or encouragement to provide such documentation as supplementary data where authors are willing to do so. Secondly, can public databases for human genome data facilitate transparency around ethics and informed consent processes? Full ethics documentation could be supplied at the time of data submission and could be provided to researchers requesting access to the data through appropriate committees. Thirdly, should the human genomic research community explore ways to share templates for informed consent and patient information in the interests of ethics skills-sharing and developing best practices for participant protection? Such resources could assist researchers in developing appropriate ethics templates for their own studies .Whilst the answers remain unclear, there is a need for open dialogue between stakeholders about maintaining and supporting sustainable ethical compliance and integrity when dealing with human genomic data. As long as economic and participant vulnerability for African populations remains, these issues are particularly pertinent when dealing with data originating from Africa.H3Africa: Human Heredity and Health in AfricaH3ABioNet: H3Africa bioinformatics networkIRB: institutional review boardNIH: National Institutes of HealthThe authors declare that they have no competing interests.The authors all planned, wrote and reviewed the manuscript. All authors read and approved the final manuscript."} +{"text": "To the Editor: Dermoscopy is a noninvasive technique that enables rapid and magnified (\u00d710) in vivo observation of the skin and detection of morphologic details often not visible to the naked eye. Videodermatoscopy, which is performed with a probe equipped with lenses providing higher magnification and connected to a personal computer, enables more detailed inspection of the skin than does manual dermoscopy and enables storage of digital images. Both techniques have been widely used for the differential diagnosis and monitoring of pigmented lesions; however, a role for these techniques in the diagnosis and follow-up of other skin disorders has recently emerged who have an itchy eruption with a likely environmental cause to 10,000 (for sophisticated systems) euros. The expense is greatly outweighed by the advantages of avoiding the high cost of managing outbreaks of epidemic parasitoses resulting from misdiagnosis, treatment failures, and incomplete posttreatment monitoring (Videodermatoscopy is a noninvasive way to diagnose some pruritic disorders while avoiding unnecessary, uncomfortable, and sometimes expensive investigations and treatments. Physicians without access to such equipment should consider promptly referring patients to the nearest available videodermatoscopy service for effective management."} +{"text": "No significant change in optical scattering orpathlength was observed. These results suggest that the measurement of chromophoreconcentration in the injured brain is not confounded by changes in optical scatteringor pathlength and that NBH induces an increase in cerebral aerobic metabolism.We report the use of a novel hybrid near-infrared spectrometer for the measurementof optical scattering, pathlength and chromophore concentration in critically illpatients with brain injury. Ten mechanically ventilated patients with acute braininjury were studied. In addition to standard neurointensive care monitoring, middlecerebral artery flow velocity, brain lactate\u2013pyruvate ratio (LPR) and brain tissueoxygen tension were monitored. The patients were subjected to graded normobarichyperoxia (NBH), with the inspired fraction of oxygen increased from baseline to 60%then 100%. NBH induced significant changes in the concentrations of oxyhaemoglobin,deoxyhaemoglobin and oxidised\u2013reduced cytochrome The concordance between the microdialysis and [oxCCO], combinedwith the absence of changes in either 2] increase, however, was smaller in our cohort than thatpreviously reported. The reasons for this are unclear, but may includepathophysiological and instrumentation factors. Interpreting the physiologicalmechanisms underlying the increase in [oxCCO] in response to NBH is challenging, butmay be enhanced by the use of a mathematical model of the cerebral circulation andmetabolism [The pattern of chromophore concentration change that we have observed during NBHis similar to that previously reported by our group using different apparatus in acohort patients who had a similar median age and admission GCS, but had a primarydiagnosis of traumatic brain injury rather than the mixed group of traumatic andvascular brain injuries reported in this study. The magnitude of[HbOtabolism . Further"} +{"text": "Information processing by cortical pyramidal neurons is shaped by the spatial distribution of synapses across the dendrites. A prominent hypothesis is that synapses with similar selectivities cluster on dendritic branches. This enables cooperative interactions between neighboring synapses through activation of voltage-dependent membrane currents, and helps establish independent integrative subunits, thereby expanding the computational power of a single neuron . Some reOne fundamental feature of the nervous system that has received little attention in this ongoing discussion is learning; specifically, how is the ability to change a neuron's selectivity affected by the spatial distribution of synapses? This is highly relevant because the selectivity of many cortical pyramidal neurons is subject to ongoing modification, not only during development, but throughout adulthood .Here, we show that the distribution of synapses across active dendrites shapes both the stimulus selectivity of the neuron, as well as the flexibility of the neuron's selectivity. Using cable theoretic analysis and numerical simulations of detailed neuron models we show that synapses that are randomly distributed across the dendrites allow for a modest stimulus selectivity that can be flexibly modified through synaptic plasticity. In contrast, a clustered distribution of synapses that encode the same stimulus allows for very strong stimulus selectivity, however, it hinders adjustment of this selectivity through synaptic plasticity, which requires slow and metabolically costly rearrangement of synaptic projections. Hence, the distribution of synapses across active dendrites creates a trade-off between selectivity and plasticity. We suggest that pyramidal neurons with different functions in the cortical information processing hierarchy exploit different ends of this spectrum."} +{"text": "Sleep is known to be important for memory consolidation , and memDuring sleep, replay events are associated with specific patterns of neuronal oscillations . Replay In the present study, we build on our previous research to develUsing hippocampal and thalamocortical models, we investigate the role of cortical inputs on ripple timing and their specific spike content. Our study illustrates the possible role of cortical Up states during slow oscillation in biasing hippocampal replay, which is a core component of the cortico-hippocampal interaction underlying memory consolidation."} +{"text": "Colonization of wood blocks by brown and white rot fungi rapidly resulted in detectable wood oxidation, as shown by a reduced phloroglucinol response, a loss of autofluorescence, and acridine orange (AO) staining. This last approach is shown to provide a novel method for identifying wood oxidation. When lignin was mildly oxidized, the association between AO and lignin was reduced such that stained wood sections emitted less green light during fluorescence microscopy. This change was detectable after less than a week, an interval that past work has shown to be too short for significant delignification of wood. Although fungal hyphae were observed in only a few wood lumina, oxidation was widespread, appearing relatively uniform over regions several hundred micrometers from the hyphae. This observation suggests that both classes of fungi release low molecular weight mild oxidants during the first few days of colonization. Determination of the spatial and temporal distribution of ligninolytic agents during fungal colonization of wood has been the focus of many studies. Schwarze comprehePhanerochaete chrysosporium .(PDF)Click here for additional data file."} +{"text": "Non-invasive assessment of the tendon properties may enhance the diagnosis of tendon injury and the characterization of recovery treatments. While ultrasonographic imaging is the most popular tool to assess the tendon's structural and indirectly, mechanical properties, ultrasonographic elastography, and ultra-high field magnetic resonance imaging (UHF MRI) have recently emerged as potentially powerful techniques to explore tendon tissues. This paper highlights some methodological cautions associated with conventional ultrasonography and perspectives for in vivo human Achilles tendon assessment using ultrasonographic elastography and UHF MRI.The mechanical properties of tendon play a fundamental role to passively transmit forces from muscle to bone, withstand sudden stretches, and act as a mechanical buffer allowing the muscle to work more efficiently. The use of non-invasive imaging methods for the assessment of human tendon's mechanical, structural, and biochemical properties This indicates that SSI can be used to compare tendon mechanical properties determined from shear modulus and then shear elastic modulus across populations and could have a clinical relevance in tendinopathy and according to age require much higher vibration frequencies for mechanical properties assessment with MRE. Current MRI scanners do not have gradient hardware that is capable of encoding wave motion at such high frequencies has the advantages of full 3D acquisition and can explore deep muscles with large spatial coverage in a well-defined and reproducible coordinate system leading to a partial or total disappearance of signal in the tendon with relatively long echo time used in conventional clinical MRI sequences in emerging 7 Tesla (7T) whole body MRI scanners\u2014SNR being proportional to the field strength\u2014provides opportunities for easier examinations of musculoskeletal structures is also used to assess musculoskeletal tissues is sensitive to changes in the microstructural architecture of biological tissues. Cell membranes and other solid structures restrict water diffusion leading to anisotropic diffusion. The integrity of tissues is then assessed by the predominant direction, intensity and isotropic characteristics of water diffusion within the biological structure. For instance, DTI is used in skeletal muscle to determine potential exercise-induced structural alterations or active stretch, multimodal MRI can accurately assess tendon structural and biochemical properties in three dimensions at rest. Further studies associating quantitative MRI and elastography are needed in order to assess non-invasively the mechanical, structural and biochemical properties of the Achilles tendon and lead to clinical applications for diagnosis, prognosis and follow-up of tendinopathies and tendon injuries.Non-invasive imaging methods for the assessment of human Achilles tendon AF has designed, written, and approved this manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "P = 0.05 or lower) between the magnitude of placebo effects and the magnitude of treatment effects. In the original review placebo effect sizes and treatment effect sizes did not differ by a statistically significant amount in the three subgroup analyses: all studies with objective outcomes (treatment effects larger), studies of anxiety treatments (treatment effects larger), and studies where all criteria for ruling out bias were met (placebo effects larger).Among studies with continuous outcomes in our systematic review comparing placebo effect sizes with treatment effect sizes we calculated mean differences between to estimate placebo effects, treatment effects, and the difference between placebo and treatment effects. In fact the standardized mean difference should have been used. There was no error in the calculations among studies with binary outcomes. We have corrected this error and revised Figs Our corrected analysis revealed no statistically significant difference between placebo effect sizes and treatment effect sizes in all but two subgroup analyses, and in both of them placebo effects were larger. These were: all studies that reported clear allocation concealment, and studies where all criteria for bias ruled out (placebo effects larger). Since placebo effects appear to be relatively greater when bias is ruled out, our corrected conclusions also reduce the possibility that placebo effects are attributable to bias.It is important to note that the placebo and treatment effects may not be independent. For example large placebo effects could be correlated with small treatment effects. Hence there is currently no perfect statistical solution to the problem of comparing effects of placebos and treatments within three-armed trials . However using the within study difference in effects (placebo effect\u2013treatment effect) and an estimate of the standard deviation of this comparison based on assuming (perhaps incorrectly) independence between effects, allows the use of the standardized mean difference to obtain a pooled estimate of the difference between these two effects.Erratum.Professor Stephen Senn assisted with the analysis that allowed us to recalculate the differences between placebo and treatment effects in this"} +{"text": "The DNA sequencing & MDx fields have seen dramatic advances since the first draft of the human genome was published, with companies reporting ever faster and cheaper methods. However, despite the race to attain the $1000 genome producing a plethora of exciting technologies, capillary electrophoresis (CE) is still being routinely used for targeted clinical sequencing and expensive real time PCR devices are still the work-horse of the MDx laboratory. QuantuMDx is developing a portable, handheld DNA sequencing device for PGx and infectious disease applications, to provide an alternative to slow and relatively expensive CE DNA sequencing & expensive slow and lab based MDx & CDx."} +{"text": "The widening gap between cancer incidence and mortality testifies to the increasing success of cancer treatment. For example, in Queensland Australia, there are now more than 7 cancer survivors for each patient newly diagnosed with cancer. These individuals represent a population at risk for recurrent malignancy for whom there is a growing demand for imaging services.Imaging for suspected recurrence may be prompted by symptoms or rising tumour markers, whilst for some tumours, imaging contributes to regular surveillance. The benefits of early detection of recurrence through imaging surveillance need to be balanced against cost, patient anxiety and radiation exposure. A recent study has estimated the absolute risk of second cancer induction resulting from use of radiological examinations in this context to be between 0.1% and 10% .Increasingly sophisticated treatments for recurrent disease present further challenges to the use of imaging in cancer survivorship. There are now more therapeutic options for patients with localised disease or recurrence to a few sites (oligometastatic disease). Although well established for hepatic metastases from colorectal cancer, surgical resection of localised recurrence is increasingly adopted for alternative sites of recurrence and for other tumour types. For tumour sites unamenable to surgery, stereotactic body radiotherapy can allow focal delivery of high-dose radiation with single or few fractions with promising local control and overall survival rates .These developments create new questions for imaging. Firstly, should imaging surveillance programmes of asymptomatic cancer survivors be developed to allow identification of the oligometastatic state prior to disseminated disease? The potential benefits of surveillance are highlighted by a study of patterns of distant failure and progression in breast cancer which found oligometastatic disease to be more common amongst asymptomatic patients . SecondlImaging protocols for cancer staging are now well established. Increasing cancer survivorship has created a need to develop equivalent protocols for the diagnosis and assessment of tumour recurrence."} +{"text": "Mathematical models can be useful tools in projects across the entire range of malaria research and intervention. The past decade has seen significant progress in malaria modeling, but challenges remain in applying, testing and refining current tools and in developing new ones."} +{"text": "To evaluate the ability of bedside lung ultrasound to diagnose and quantify pleural effusion in pediatric patients submitted to liver transplantation, in comparison with supine chest radiograph.30 pediatric patients with end stage liver failure submitted to liver transplantation from living/dead donor (split). All the patients during the first three postoperative days were submitted to supine chest radiograph and bedside lung ultrasound, during mechanical ventilation or NIV.Three measurements were made in first, second, and third postoperative day: chest x-ray was performed with a portable set; bedside lung ultrasound detected the pleural effusion at the PLAPS point. The depth of the pleural effusion was evaluated according with the quad sign: the space outlined between the pleural line and the pulmonary line .Atelectasis, lung consolidation and pleural effusion are common in pediatric patients submitted to liver transplantation during the first postoperative days: chest radiograph showed to lack sensitivity in detecting pleural effusion and in differentiating atelectasis from pleural effusion, which is easy instead with lung ultrasound.Ultrasound can detect the echogenicity of the effusion and help to assess the nature of it, measuring also its effective volume.Statistically lung ultrasound has better sensitivity (80%) and specificity (90%), compared to chest radiograph, respectively 70% and 70%.Lung ultrasound is more sensitive and even more specific in comparison to chest radiograph to detect and measure pleural effusion in children submitted to liver transplantation."} +{"text": "Intricate cognitive functions supported by the cerebral cortex endow mammals with a profound ability to adapt to a constantly changing environment. These sophisticated functions arise as a result of complex synaptic interactions between a myriad of neurons, modulating their structure and function. Decades of studies have enriched our current knowledge on the fundamental principles of neuronal and synaptic organization in the cortex expressing perisomatic targeting basket cells (BC), cholecystokinin (CCK) containing interneurons associated with the hilar commissural associational path (HICAP), and somatostatin expressing hilar perforant path associated (HIPP) interneurons. Post hoc morphological analyses of biocytin filled neurons revealed intricate patterns of local axonal and dendritic arbourization, hypothesizing plausible domains that specifically govern the spatio-temporal precision of GABAergic inhibition.In a recent article published in n et al. undertooSubsequently, the authors mapped out the local synaptic anatomy and physiology of homologous and heterologous GABAergic interneuron networks through electrophysiological and optophysiological techniques. The authors discovered that the specific combination of pre-post morphologies was critical in determining the time-course of inhibition. Among examined homologous connections, HIPP\u2013HIPP interactions occurred with the least probability, followed by a slightly higher occurrence of BC\u2013BC pairs, whereas HICAP\u2013HICAP interneuron pairs interacted most prevalently path from ipsilateral and contralateral hippocampus (for reviews see F\u00f6rster et al., Could dendritic inhibition be so positioned as to decisively alter the collective activity of local synaptic networks of GABAergic interneurons and control global information flow in the DG microcircuitry? This line of thought has been previously corroborated in the adult rodent somatosensory cortex by Ali and Thomson . Indeed,The authors have presented detailed analyses and results of their work, however, several open questions remain to be addressed. Previous work has conclusively demonstrated that GABAergic interneurons, particularly PV containing basket cells in neocortex or the hippocampal formation interact through a combination of chemical and electrical synapses (Bartos et al., in vivo from genetically defined GABAergic neurons will enable the characterization of inhibitory synaptic transmission in intact DG microcircuitry (see Pala and Petersen, Intriguingly, the authors report a striking lack of HIPP\u2013HICAP connections, although there is a likelihood of putative HIPP\u2013HICAP connections arising by virtue of axo-dendritic proximity. The authors propose a functional role for this apparent lack of HIPP\u2013HICAP connections, postulating that inhibition of proximal and distal dendritic domains are not competitive but rather complementary in a spatio-temporal fashion. Indeed, further quantitative investigations are warranted for example, to examine whether possible chemo-repellant mechanisms at play during various stages of development in the hippocampal formation cause a selective eschewal in the formation of functional synapses between specific populations of GABAergic interneurons. Groundbreaking experiments that couple single cell optogenetic interrogations with paired whole-cell recordings A receptors. The authors speculate that putative anatomical synaptic contacts in HICAP\u2013HICAP and HIPP\u2013HIPP interneuron connections are fewer than at BC\u2013BC connections. Indeed, the number of putative synaptic contacts is very likely an underestimate given that neuronal arbors are predisposed to severing attributed to slicing artifacts. In their study, the authors have not addressed connection specific binomial analyses of the voltage clamp synaptic recordings. Complementary anatomical and binomial analyses of GABAergic synaptic connections could reveal informative correlations between putative synapses and functional release sites, identifying connection specific mechanisms of unitary or multi-vesicular synaptic release as shown previously in neocortex (Gupta et al., The study in consideration endeavored to identify some of the mechanisms underlying the physiology of inhibition among identified interneurons in DG microcircuitry. Taken together, morphological and physiological analyses indicate that the number and location of inhibitory synapses, their conductance kinetics, as well as dendritic properties deliberate the efficacy and time course on somatic inhibition predominantly mediated by ionotropic GABAhI current in dendrites of neocortical pyramidal neurons controls the time course of inhibitory synaptic transmission (Williams and Stuart, It is known that a non-linear density distribution of the in vivo mapping of long-range efferents could facilitate scaffold digital reconstructions of the DG microcircuit in silico to develop a unifying picture of its anatomy and physiology in brain function and dysfunction.The authors have put together a novel data resource in characterizing the inhibitory synaptic network underlying DG microcircuitry and postulate computational roles of GABAergic interneurons in the hippocampal formation. The data set provides an overview of the organizing principles of elementary building blocks constituting the local DG microcircuit\u2014receptors, synapses, neurons, and their interactions. Further experimental work is imperative to increase our understanding of how a myriad of neuromodulators regulate these building blocks to assemble an integrated view of the function of DG microcircuitry in the emergence of different behavioral states. Such data sets complemented by The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Most of the maternal and newborn deaths occur at birth or within 24 hours of birth. Therefore, essential lifesaving interventions need to be delivered at basic or comprehensive emergency obstetric care facilities. Facilities provide complex interventions including advice on referrals, post discharge care, long-term management of chronic conditions along with staff training, managerial and administrative support to other facilities. This paper reviews the effectiveness of facility level inputs for improving maternal and newborn health outcomes. We considered all available systematic reviews published before May 2013 on the pre-defined facility level interventions and included 32 systematic reviews.Findings suggest that additional social support during pregnancy and labour significantly decreased the risk of antenatal hospital admission, intrapartum analgesia, dissatisfaction, labour duration, cesarean delivery and instrumental vaginal birth. However, it did not have any impact on pregnancy outcomes. Continued midwifery care from early pregnancy to postpartum period was associated with reduced medical procedures during labour and shorter length of stay. Facility based stress training and management interventions to maintain well performing and motivated workforce, significantly reduced job stress and improved job satisfaction while the interventions tailored to address identified barriers to change improved the desired practice. We found limited and inconclusive evidence for the impacts of physical environment, exit interviews and organizational culture modifications.At the facility level, specialized midwifery teams and social support during pregnancy and labour have demonstrated conclusive benefits in improving maternal newborn health outcomes. However, the generalizability of these findings is limited to high income countries. Future programs in resource limited settings should utilize these findings to implement relevant interventions tailored to their needs. Most of the maternal and newborn deaths occur at birth or within 24 hours of birth; therefore essential lifesaving interventions need to be delivered at basic or comprehensive emergency obstetric and newborn care (BEmONC /CEmONC) facilities -4. FacilAlongside emergency obstetric care; facilities provide complex clinical care interventions including referrals, post discharge care, long-term management of chronic conditions and managerial and administrative support to other facilities. They also serve as gateways for drugs and medical supplies, laboratory testing services, general procurement and data collection from health information systems. Facilities also disseminate technologies by training new staff and providing continuing professional education for existing staff at different facilities. In this review, we aim to systematically review and summarize the available evidence from relevant systematic reviews on the impacts of the outlined facility level inputs Table to improThe quality of health service delivery depends on the willingness and drive of health workers to perform their tasks, adequate resources, and health workers\u2019 competency . InterveInterventions to enhance interpersonal care and social support include interventions provided by professionals or non-professionals aimed at improving psychological well-being of patients as well as healthcare workers. Pregnancy, perinatal deaths, childbirth and parenting are some of the specific phenomenon that requires continuous social support. Common elements of this care include emotional support, information about labour progress and advice regarding coping techniques, comfort measures and advocacy. It is reported to contribute substantially to women\u2019s satisfaction with the childbirth experience and provides both direct and buffering effects in decreasing stress and promoting health and coping -23.Developing a culture of safety is a core element of many efforts to improve patient safety and care quality in emergency care settings. Recently, there has been a major focus on measuring and improving safety culture to enhance patient and provider safety in healthcare facilities . It invoThese are organizational interventions for staff management including skills, qualification or grade mix, maintaining staff-patient ratios, and measures for improving collaboration between two or more health and/or social care professionals. An emerging challenge in this domain is determining the most effective mix of staff and skills needed to deliver quality and cost-effective patient care in the light of rising demand for health services, cost containment, and staff shortages -31.We considered all available systematic reviews on the pre-defined facility level interventions published before May 2013 as outlined in our conceptual framework . A separWe identified 352 potentially relevant review titles and included 32 eligible reviews after further evaluation of the abstracts and full texts; 12 reviews on various aspects of well performing and motivated workforce, 5 on social support, 9 on interventions to promote safety culture and 6 reviews on staffing models and improve job satisfaction with no impact on absenteeism . Among nWe included five reviews, with a median quality score of 10 on AMSTAR criteria. Included reviews focused on various social support strategies including support during pregnancy and special circumstance like labor, perinatal death and breast feeding. All the reviews reported MNH outcomes including birth outcomes and breast feeding duration. Meta-analysis was conducted in three reviews. Generalizability of these findings is mostly limited to HIC, as there was very limited data from low- middle-income countries (LMIC). The characteristics and finding of the included reviews are presented in Table Standardized or individualized programs of additional social support throughout pregnancy were found to decrease the risk of antenatal hospital admission and cesarean birth although it did not show any impact on preterm birth, low birth weight (LBW) or perinatal mortality . SupportWe included eight reviews on interventions to promote safety culture in health facility with a median AMSTAR score of 5.5; four reviews focused on administration of preventive influenza vaccination to healthcare workers and its effectiveness and uptake -47, one Influenza vaccination among health care workers significantly reduced the mean number of working days lost and days with influenza like illness with non-significant impact on the risk of influenza like illness . Programs intended to increase influenza vaccination uptake among healthcare workers reported 5%\u201345% increase in uptake with best case cost saving of \u00a312/vaccine . AccuratWe included six reviews pertaining to staffing models and skill mix with a major focus on nurses except one review focusing on the impact of collaborative care among all healthcare professionals . The medContinuous care provided by specialized midwifery teams from early pregnancy to the postnatal period was found to reduce medical procedures in labour and resulted in a shorter length of stay without compromising maternal or perinatal safety. Under this model of care, the same midwife planned most of the care for the woman from the beginning of her pregnancy to the end of the postnatal period. However, these findings are based on a single study . The addAt the facility level, evidence suggests that social support and specialized midwifery care throughout pregnancy, labour and postnatal period have the potential to improve a range of perinatal, maternal, and labor specific indicators. However, we did not find any impact of these interventions on delivery outcomes. Among the interventions targeted at healthcare workers, stress management trainings, multidisciplinary meetings and feedback sessions can reduce work related stress and improve performance. Programs to improve influenza vaccination uptake among healthcare workers resulted in improved vaccination coverage with evidence of being cost effective as well. We found limited and inconclusive evidence on the effectiveness of exit interviews and organizational environment and cultural modifications. Most of the data from these reviews pertain to HIC hence limiting the generalizability of these findings. Notwithstanding the lack of data from LMIC, interventions like support during pregnancy and labour are expected to be effective in all settings. Moreover, such interventions would work best in resource limited settings where advanced pain relief measures are not available. Lack of evidence from LMIC may be attributable to the weak existing health system infrastructure since most of these interventions require a pre-existing healthcare infrastructure to ensure scale-up and sustainability.Facility level inputs and reported outcomes varied widely due to diverse and complex nature of interventions involved. These interventions are by and large aimed at improving general health outcomes and health workforce performance and MNH domain can also benefit from these findings. Many of these interventions including support during pregnancy and labour, staffing and skills mixing models, increasing available workforce, improving workforce performance and safety culture promotion can be tailored and directed to improve BEmONC and CEmONC facilities and their staff performances. Proven interventions to promote staff motivation can result in enhanced support and care during pregnancy and labor and consequently result in women\u2019s improved childbirth experience and confidence in the caregivers, which in itself is a determinant for positive pregnancy outcome . LikewisThere is a dearth of evidence on the facility level inputs from LMIC where most maternal and newborn mortality and morbidity is concentrated. There is also a need to describe individual components of the intervention and process measures in detail for reproducibility in resource limited settings. Policy makers in LMIC should focus on implementing these evidence based facility directed interventions to provide sufficient and skilled staff coupled with access to functioning equipment, drugs and supplies at the BEmONC/CEmONC facilities to provide timely and appropriate maternal and newborn care. This would consequently lead to reduced maternal and newborn mortality attributable to delayed treatment of obstetric complications.Future studies should evaluate the effectiveness of structural and cultural changes, educational interventions, grade mix interventions, and staffing levels on workforce performance and patient outcomes. Determinants of healthcare worker performance, sustainability and cost-effectiveness should be evaluated using rigorous study designs. Further evidences are now needed to evaluate the best possible combination of strategies tailored to the need of the area of implementation.AMSTAR: Assessment of Multiple Systematic Reviews; BEmONC: Basic Emergency Obstetric and Newborn Care; CEmONC: Comprehensive Emergency Obstetric and Newborn Care; CI: Confidence Interval; LMIC: Low- and Middle- Income Countries; MD: Mean Difference; MNH: Maternal Newborn Health; RD: Risk Difference; RR: Relative RiskWe do not have any financial or non-financial competing interests for this review.All authors contributed to the process and writing of the manuscript.Peer review reports are included in Additional file Click here for file"} +{"text": "Haemorrhage following major injury remains the most common potentially preventable cause of traumatic death with exsanguination typically occurring within three hours of injury. Key to improving outcomes is a \u201ccare bundle\u201d of measures to facilitate early diagnosis, rapid haemorrhage control, systemic and topical haemostatic support and short scene times . The lasIdentification of major haemorrhage must be performed as part of the initial on-scene assessment. Good clinical acumen and a high index of suspicion remain important diagnostic tools. Point of care measures of coagulation are of limited value in patients with major haemorrhage (low haematocrit). The utility of these handheld devices, in their current design, is confined to patients taking warfarin who have suspected traumatic brain injury and where reversal with prothrombin complex concentrate is indicated. Pre-hospital use of ultrasound, solely for diagnostic purposes, remains an area of controversy. Critiques argue it adds little additional information and may delay transfer to hospital for definitive haemorrhage control.An immediate priority is to localise any sites of external haemorrhage and provide direct control where possible with compression. Foley catheters inserted into a wound track, inflated and then retracted to the skin edge are good adjuncts for junctional injuries e.g. neck stab wound. Topical haemostatic dressings e.g. Celox impregnated gauze or granules are able to augment clot formation and can be applied into cavities where haemorrhage may be difficult to control directly. The use of limb tourniquets is now well established in combat medicine and has been shown to save lives particularly when applied before the onset of shock. Complications i.e. nerve damage are rare when tourniquets are applied correctly. The Eastern Association for the Surgery of Trauma (EAST) has recently published guidelines advocating their use in civilian patients for the management of penetrating lower extremity arterial trauma .Radical interventions for control of life-threating haemorrhage include prehospital thoracotomy (PHT) for cardiac tamponade and resuscitative endovascular balloon occlusion of the aorta (REBOA) for major torso bleeding. PHT for penetrating trauma is an established intervention in a physician-led EMS system and is associated with survival rates of 18% in selected patient groups. Relief of tamponade with control of cardiac injury is the primary objective of PHT and can be achieved with minimal equipment \u2013 scalpel, Spencer Wells forceps, heavy scissors or Gigli saw, rib retractor and sutures or skin stapler. During PHT other manoeuvres such as manual compression (or clamping) of the descending aorta to arrest abdominopelvic haemorrhage and control of lung hila to treat great vessel injuries may be of benefit but all efforts should be focused on rapid transit to hospital for definitive surgical management. REBOA describes the insertion of an endovascular balloon into the femoral artery (under ultrasonic guidance) which is advanced into the aorta and then inflated to control distal haemorrhage. It has been successfully used in the Emergency Department (ED) with and without image intensifiers depending on the aortic zone of interest . Althoughttp://cetir-tmc.org/research/proppr) is the first randomised controlled trial (RCT) to investigate blood product ratios in trauma and is due to report in early 2014. Combat pre-hospital systems utilise both RBC and thawed fresh frozen plasma (FFP) but due to the logistical challenges of carrying these blood products the vast majority of civilian EMS systems only utilise RBCs. Blood resuscitation of the exsanguinating patient may be the preferable therapeutic option compared to crystalloids but its pre-hospital use must be supported with rapid availability of plasma, platelets and fibrinogen on arrival in ED to avoid the dilutional coagulopathy associated with large volume RBC transfusion. Work is currently underway to evaluate freeze dried plasma which has the advantage of potential reconstitution at scene however the true efficacy of any plasma formulation to correct ATC remains to be seen.Direct control of haemorrhage must be accompanied with DCR - permissive hypotension, resuscitation and haemostatic support with pro-coagulant blood products. The efficacy of high dose blood component therapy and optimal plasma:red blood cell (RBC) ratio is currently unknown. However, the PROPPR trial may improve patient survival . Early ain vivo clotting processes. PHT is a life-saving and established intervention for cardiac tamponade and pre-hospital use of REBOA may provide additional treatment options to control major torso haemorrhage. Replacement of oxygen-carrying capacity with RBC, haemostatic resuscitation with fibrinogen supplementation and treatment of fibrinolysis with TXA are likely to prove important therapeutic agents in the prehospital treatment of haemorrhage.Effective treatment of haemorrhage in the pre-hospital phase of care is dependent on rapid identification of severe bleeding, direct anatomical control of vascular injury, haemostatic resuscitation and expedient transfer to hospital. Tourniquets and topical haemostats are important adjuncts for the control of junctional or extremity injuries and augmentation of"} +{"text": "Peripartum cardiomyopathy (PPCM) is a severe cardiac disease occurring in the last month of pregnancy or in the first 5 months after delivery and shows many similar clinical characteristics as dilated cardiomyopathy (DCM) such as ventricle dilation and systolic dysfunction. While PPCM was believed to be DCM triggered by pregnancy, more and more studies show important differences between these diseases. While it is likely they share part of their pathogenesis such as increased oxidative stress and an impaired microvasculature, discrepancies seen in disease progression and outcome indicate there must be differences in pathogenesis as well. In this review, we compared studies in DCM and PPCM to search for overlapping and deviating disease etiology, pathogenesis and outcome in order to understand why these cardiomyopathies share similar clinical features but have different underlying pathologies. Peripartum cardiomyopathy (PPCM) is a cardiac disease that can have many different clinical presentations but shares similar clinical symptoms with dilated cardiomyopathy (DCM) such as ventricle dilation, impaired systolic function and arrhythmias in DCM patients production differ notably between the two disease states as will be discussed below. In normal pregnancy, ROS production increases during the course of pregnancy and decreases post-partum to normal levels and are multifunctional transcription factors. In cardiomyocytes STAT3 is involved in survival, sarcomere integrity, cell growth and ROS production and thereby induce the uncoupling of nitric oxide synthase (NOS). As a result NOS no longer produces beneficial nitric oxide (NO) molecules, but itself becomes a producer of superoxide , including PPCM and DCM, and disturbs various pathways. However, the high levels of PRL during the final stages of pregnancy combined with high oxidative stress, likely make PPCM develop at such a high pace. As PRL levels are many fold lower in non-pregnant and non-nursing individuals system also leads to increased levels of ADMA cohort studies. A large, multicenter, randomized controlled clinical trial to evaluate BR treatment in 60 PPCM patients is ongoing, and the results should shed light on the effectiveness of BR treatment and outcome (US National Library of Medicine, Information about disease initiation and predispositions such as pathogenic mutations is still limited in PPCM and DCM. Therefore, more knowledge is needed on which mutations predispose people to DCM and PPCM and how these mutations exert their pathogenic effect in disease initiation and progression. Identification of these mutations would greatly enhance the ability to identify persons at risk to develop PPCM and DCM and by monitoring these patients early diagnosis and treatment could be facilitated thereby enhancing survival.As cardiac deterioration, heart transplantations and death often occur within a few months after diagnosis in PPCM, it is possible that the cardiac remodeling to cope with the new cardiac state and demands in PPCM is different than in a more slow progressive disease as DCM. For example, in heart failure it has been shown that the fetal gene program is initiated resulting in cardiac remodeling in order to compensate for decreased cardiac function, although it contributes to cardiac dysfunction at a later stage (Thum et al., Based on observations in the STAT3 mouse model, mitigation of the intracellular defense mechanism against oxidative stress in human PPCM so far mainly focused on the reduction of MnSOD levels. Indeed reduction of MnSOD levels is an important contributor to elevated ROS levels in PPCM patients. However, to further unravel the patho-mechanism of oxidative stress in PPCM, future studies should involve the potential contribution of other enzymatic and non-enzymatic ROS scavengers as well as that of potential sources of ROS. Reduced MnSOD expression and PRL cleavage as a result of concomitant oxidative stress have been identified as important regulators of PPCM. Still the complete etiology of PPCM is far from completely understood.PPCM and DCM likely share part of their pathogenesis such as predisposing mutations, increased oxidative stress, an impaired microvasculature and damaged sarcomere integrity. However, the exact underlying pathways might be differently altered in PPCM and DCM. While 16 kDa PRL is likely to be a key player in PPCM it is unlikely to play a significant role in DCM. It is this 16 kDa PRL that might explain the faster deterioration of cardiac function in PPCM by inducing an additional cascade of cardiovascular impairment. However, given the observation that pregnant DCM patients do better than PPCM patients, this difference in PRL levels between PPCM patients and non-pregnant DCM patients cannot explain all differences observed. The reports about uneventful subsequent pregnancies in PPCM patients indicate additional causative factors, such as insufficient defense mechanisms against oxidative stress or a vulnerable microvasculature. Therefore, despite their overlap in disease etiology and clinical presentation, differences in underlying pathways, disease progression and outcome argue for separation of the two disease states.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Ischemia-reperfusion (IR) injury comprises a significant portion of morbidity and mortality from heart and brain diseases worldwide. This enduring clinical problem has inspired myriad reports in the scientific literature of experimental interventions seeking to elucidate the pathology of IR injury. Elective cardiac surgery presents perhaps the most viable scenario for protecting the heart and brain from IR injury due to the opportunity to condition the organs prior to insult. The physiological parameters for the preconditioning of vital organs prior to insult through mechanical and pharmacological maneuvers have been heavily examined. These investigations have revealed new insights into how preconditioning alters cellular responses to IR injury. However, the promise of preconditioning remains unfulfilled at the clinical level, and research seeking to implicate cell signals essential to this protection continues. Recent discoveries in molecular biology have revealed that gene expression can be controlled through posttranslational modifications, without altering the chemical structure of the genetic code. In this scenario, gene expression is repressed by enzymes that cause chromatin compaction through catalytic removal of acetyl moieties from lysine residues on histones. These enzymes, called histone deacetylases (HDACs), can be inhibited pharmacologically, leading to the de-repression of protective genes. The discovery that HDACs can also alter the function of non-histone proteins through posttranslational deacetylation has expanded the potential impact of HDAC inhibitors for the treatment of human disease. HDAC inhibitors have been applied in a very small number of experimental models of IR. However, the scientific literature contains an increasing number of reports demonstrating that HDACs converge on preconditioning signals in the cell. This review will describe the influence of HDACs on major preconditioning signaling pathways in the heart and brain. Worldwide, 33 million people suffer a stroke each year . IschemiEndogenous tolerance to ischemia can be evoked in the heart and brain , 8. ClasPrevention of cell death is the primary effect of ischemic conditioning , 13. ManAcute adaptation to ischemia through conditioning stimuli is mediated by protein posttranslational modifications (PTMs) , 21. His+-dependent and will not be discussed in this review, but have been expertly reviewed elsewhere after permanent right carotid artery occlusion prevented neuronal apoptosis in a dose-dependent manner in neonatal rats . Rats trpromoter .HDAC9 gene is associated with large vessel ischemic stroke caused increased acetylation at the promoter of the FOXO3a transcription factor. This led to upregulation of FOXO3a and its targets SOD2 and catalase, free radical scavengers, which further prevented paraquat-induced renal oxidative stress in mouse kidneys (Recent work in mouse tissues demonstrated that the endogenous HDAC1 inhibitor kidneys \u2013100. Add kidneys . This wa kidneys , suggest kidneys .Histone deacetylases evidently form signaling hubs for cellular communication in cerebral and cardiac IRI. Class I HDACs appear to play mainly pathologic roles in IRI, by repressing transcription of genes required for cell survival, while Class IIa HDACs appear necessary for cell survival. The roles of the class IIb HDAC6 in preconditioning are not full understood, though HDAC6 is a major regulator of autophagic flux in neurodegenerative diseases and a coLines of evidence have begun to accumulate that support a role for communication between HDAC and kinase signaling networks in ischemia of the heart\u2013brain axis. While the mechanisms behind the protective preconditioning effect of HDAC inhibition remain to be fully elucidated, it is evident that the RISK pathway and related kinases are integral components. More research into the details of the specific interactions between HDACs and other PTMs will advance our understanding of the role of HDAC inhibition in ischemic preconditioning. Dissecting the dual roles of HDACs as transcriptional repressors and as effectors of enzymatic crosstalk is needed to dissect the chronic and acute phases of preconditioning protection. Given that several small molecule inhibitors of HDAC activity are currently used in patients or in clinical trials, HDAC inhibitors represent promising treatment modalities for patients undergoing elective brain or heart surgery, or patients at high risk of stroke or cardiac arrest.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Effective interpersonal communication depends on the ability to perceive and interpret nonverbal emotional expressions from multiple sensory modalities. Current theoretical models propose that visual and auditory emotion perception involves a network of brain regions including the primary sensory cortices, the superior temporal sulcus (STS), and orbitofrontal cortex (OFC). However, relatively little is known about how the dynamic interplay between these regions gives rise to the perception of emotions. In recent years, there has been increasing recognition of the importance of neural oscillations in mediating neural communication within and between functional neural networks. Here we review studies investigating changes in oscillatory activity during the perception of visual, auditory, and audiovisual emotional expressions, and aim to characterize the functional role of neural oscillations in nonverbal emotion perception. Findings from the reviewed literature suggest that theta band oscillations most consistently differentiate between emotional and neutral expressions. While early theta synchronization appears to reflect the initial encoding of emotionally salient sensory information, later fronto-central theta synchronization may reflect the further integration of sensory information with internal representations. Additionally, gamma synchronization reflects facilitated sensory binding of emotional expressions within regions such as the OFC, STS, and, potentially, the amygdala. However, the evidence is more ambiguous when it comes to the role of oscillations within the alpha and beta frequencies, which vary as a function of modality , presence or absence of predictive information, and attentional or task demands. Thus, the synchronization of neural oscillations within specific frequency bands mediates the rapid detection, integration, and evaluation of emotional expressions. Moreover, the functional coupling of oscillatory activity across multiples frequency bands supports a predictive coding model of multisensory emotion perception in which emotional facial and body expressions facilitate the processing of emotional vocalizations. Effective communication is crucial for the formation and maintenance of social relationships in complex societies. Emotional communication is a complex process where the expression and perception of emotional signals exchanges information about internal affective states. While some of these signals can be expressed through verbal means, much of our emotional communication occurs nonverbally through changes in facial, body, and vocal expressions. Therefore, our ability to perceive and interpret nonverbal expressions of emotion can have a profound impact on the quality of our social interactions, affecting our mental health and wellbeing. To this end, deficits in emotion perception have been observed in a number of neurological and psychiatric conditions . Evidence from neuroimaging research suggests a functional subdivision within the STS with face-sensitive regions in the posterior terminal ascending branch and voice-sensitive regions in the trunk section and magnetoencephalography (MEG) are particularly well suited for the study of emotion perception due to their millisecond temporal resolution.Results from event-related potential (ERPs) suggest differentiation between emotional and neutral facial expressions within 120 ms of stimulus onset signal as the sum of pure sinusoids, which are separated into characteristic frequency bands each associated with distinct cognitive and computational operations. Decomposing the EEG/MEG signal into its constituent sinusoids, allows for the measurement of changes in power (amplitude) and phase within and between each frequency band, at different time points and in different brain regions. While increases or decreases in power\u2014referred to as event-related synchronization (ERS) or desynchronization (ERD) respectively\u2014indicate changes in neural synchronization within a specific node or region, phase coherence across brain regions reflects synchrony between brain regions that make up a functional neural network or identity/gender (implicit) of the face. Using this type of paradigm, studies have found changes in oscillatory activity across multiple frequency bands during the perception of emotion from facial expressions.Delta oscillations have been implicated in a wide range of processes including the perception of faces and facial expressions Knyazev, . While fper se. That is, emotional expressions contain more behaviorally relevant sensory information, which reduces uncertainty, resulting in stronger neural synchronization in the theta frequency. This enhanced theta synchronization facilitates the dynamic between brain regions involved in the early detection and integration of static emotional facial expressions.Most commonly associated with memory encoding and retrieval or more subtle changes in tone of voice, or emotion prosody. While both convey important affective information, perception of emotion from these two types of vocal expressions occurs along different time scales and may rely on different patterns of neural activity and connectivity. Although very few studies have investigated the role of neural oscillations in perception of emotion from either type of vocal expression, current evidence suggests that theta synchronization may play a particularly important role in facilitating the detection of emotionally salient vocal cues.A considerable body of research suggests that theta band oscillations drive the processing of slow acoustic changes in speech perception predictions than neutral expressions and alpha oscillations over prefrontal regions, suggesting that theta synchronization mediates the integration of audiovisual emotional expressions. Previous evidence suggests that multimodal expressions generally are more easily recognizable than unimodal expressions through which the emotion is expressed as well as the emotional quality of the stimulus itself. However, emotional expressions are dynamic events that continuously evolve over time. Therefore, the neural system(s) supporting emotion perception must be able to flexibly adapt to and integrate rapidly changing sensory input from multiple modalities. Based on the reviewed evidence, we propose that neural synchronization underpins the selective attention to and the flexible binding of emotionally salient sensory input across different spatial and temporal scales. Furthermore, neural oscillations provide a mechanism through which emotional facial and body expressions can predictively modulate the processing of subsequent vocal expressions.The recognition of an expression as \u201cemotional\u201d requires the selective binding of emotionally relevant sensory information. However, individual features of an emotional expression can occur at different points in time and are processed in spatially distinct regions of the brain. Thus, the brain is challenged with the task of binding only those features belonging to the same event across both space and time. One mechanism through which this may occur is the synchronization of neural oscillations, which creates temporal windows in which information belonging to the same event can be selected and integrated or negative (unpleasant). Within the brain, some have proposed that the right hemisphere is dominant for the processing of negative emotions while the left hemisphere is dominant for positive emotions frequency bands, in basic biological, cognitive, and emotional processes highlights the need for further research into the functional role of delta oscillations in emotion perception within and between sensory modalities. Across modalities, theta synchronization most consistently differentiates between emotional and neutral expressions and may reflect the initial encoding and derivation of emotional significance. Changes in alpha power have been primarily observed in studies with a visual component, with some evidence of valence-specific lateralization over frontal regions. Based on the hypothesis that alpha synchronization reflects active inhibition of task irrelevant brain regions . All the other authors contributed equally to this work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Alcohol screening and brief intervention (SBI) programs have been shown to be effective in reducing risky alcohol consumption among primary care patients -3. AlthoThis study aims to present challenges and potential solutions to incorporating SBI as a standard of care into an existing EHR of a family medicine system.An SBI program was piloted in two underserved family medicine clinical teaching practices. Physicians, residents, nurses, medical assistants and patient service representatives (PSR's) were trained on the protocol for adopting this practice into daily clinic work. Through this implementation, an EHR template was created to complement the workflow.Utilization of the screening tool provided a mechanism to better assess risky drinking within a regular patient encounter. High rates of completion were appreciated throughout the grant period prior to leadership changes. The EHR template facilitated the intake process, the clinical encounter, and provided a mechanism for billing.The incorporation of a dedicated EHR template may mitigate providers\u2019 concerns about time constraints and establishes a more effective mechanism for billing for the service.Strong support from organizational leadership and the use of clinic champions were shown to positively contribute to the success of the SBI programs in this health system by addressing common barriers to implementation."} +{"text": "NOTCH3 gene. The neurologic manifestations of CADASIL syndrome have been well characterized; however, here we report one of the first de novo cases of CADASIL-associated coronary artery disease. A 45-year-old woman with a history of CADASIL and remote tobacco use presented with unstable angina. She was found to have diffuse and irregular narrowing of the left anterior descending artery and a drug eluting stent was deployed. Months later, she developed two subsequent episodes of unstable angina, requiring stent placement in the distal left anterior descending artery and the right coronary artery. Though the neurologic manifestations of CADASIL have been well described, these patients may also be predisposed to developing premature coronary artery disease. Patients with CADASIL and their physicians should be aware of this possible association because these patients may not be identified as high risk by traditional cardiovascular risk estimators. These patients may benefit from more aggressive interventions to reduce cardiac risk.Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common heritable form of vascular dementia and it is caused by mutations in the NOTCH3 gene [ NOTCH3 mutation analysis is now available to confirm the diagnosis [Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common heritable form of vascular dementia in adults and is caused by mutations in theCH3 gene . PatientCH3 gene . The gol NOTCH3 mutation analysis) manifested by frequent transient ischemic attacks and chronic headaches who presented to the emergency department with unstable angina and new T wave inversions in the precordial leads, consistent with Wellens' T waves risk estimator. Additionally, many recommendations that guide cardiovascular risk management, such as the 2013 American College of Cardiology/American Heart Association cholesterol guidelines, assess traditional cardiac risk factors and do not take into account the contribution of systemic vasculopathies as in our patient. Failure to recognize the possible association of CAD with CADASIL may lead caregivers to misinterpret cardiac symptoms in patients with CADASIL and undertreat CAD.The role and impact of aggressive reduction in modifiable cardiovascular risk factors such as hypertension, diabetes, obesity, and hyperlipidemia in patients with CADASIL are still unknown. However, this case report demonstrates that physicians who care for patients with CADASIL should frame common complaints of chest pain, exercise intolerance, or shortness of breath in the context of a higher pretest probability of early onset coronary artery disease. de novo CADASIL syndrome affecting the coronary vasculature and leading to multiple episodes of acute coronary syndrome. This case supports previously described pathophysiology of CADASIL-related coronary artery disease. This case report demonstrates that patients with CADASIL may have a higher probability of early onset coronary disease and may benefit from aggressive interventions to reduce risk.Although the primary clinical manifestations of CADASIL syndrome mostly involve the CNS, we report a case of"} +{"text": "Sepsis is a leading cause of morbidity and mortality worldwide and particularly in Africa where awareness is low and resources are limited. There are limited reports on the epidemiology, management and outcomes of the sepsis syndromes from Africa. However, this region is likely to account for a significant proportion of the global burden of sepsis which goes unrecognized. It is imperative to address this through research, increased awareness, capacity building and introduction of practical clinical guidelines. Infections are responsible for an estimated 300 million annual deaths worldwide, the majority from developing countries . Sepsis Firstly, health care professionals often miss the diagnosis or fail to document it in the clinical notes. Secondly, the World Health Organisation (WHO) Global Burden of Disease Report (GBDR) does not include sepsis as a cause of death. The GBDR is one of the leading information sources for healthcare decision-making worldwide. Although deaths from infections occur most commonly as a result of sepsis, the GBDR lists only the underlying infections as cause of death. It is therefore not surprising that sepsis occurs only as \u201cneonatal\u201d sepsis and is ranked 16th place, despite about 60% of deaths in children under five being due to severe infections. Thirdly, guidelines for coding of sepsis are often difficult to use especially in under resourced and busy developing world healthcare settings.Interventions to improve the management of sepsis: the last decade has seen massive campaigns to improve sepsis management via targeted initiatives predominantly in developed countries. The international Surviving Sepsis Campaign (iSSC) published international guidelines for management of severe sepsis in 2004 and this was subsequently updated and condensed into two care bundles. Following the ABC of resuscitation, the following measures are recommended to be completed within three hours of presentation: measurement of serum lactate levels; obtaining blood cultures prior to the administration of antibiotics; administration of broad-spectrum antibiotics; administration of 30 ml/kg crystalloid for hypotension or serum lactate >4 mmol/l (36 mg/dl).The iSSC guideline also has a 6 hour bundle for severe sepsis and septic shock. It consists of invasive monitoring of physiologic parameters such as central venous pressure and use of vasopressors to maintain mean arterial pressure usually in an intensive care setting. The use of such an intensive resuscitation bundle in the form of early goal directed therapy with resuscitation targeting specific physiologic goals has been shown to significantly reduce mortality in severe sepsis and septic shock when compared to standard therapy. However, recent self-reported survey data strongly suggest that these critical care measures, though beneficial, cannot be implemented in most parts of Africa due to a shortage of resources such as skilled manpower, complex equipment and drugs . A recenThe diagnosis of sepsis can be facilitated by the use of a clinical early warning score (EWS) to aid the identification of the systemic inflammatory response syndrome (SIRS). The EWS is based on the principle that physiological deterioration precedes critical illness. It assesses physiological parameters such as systolic blood pressure, pulse rate, respiratory rate, temperature and oxygen saturations. A score is allocated to each parameter as they are measured and a score is then aggregated. The total score determines the action to be taken by the assessor thus enhancing early detection of the deteriorating patient, timely clinical response and reduction in referral delays. However attempts at validating EWSs in resource limited settings have produced conflicting results.Applicability of the ISSC guidelines to the African context: this section discusses the applicability of the 3 hour iSSC bundle to the African healthcare system in greater detail.Lactate measurement: serum lactate is a marker for tissue hypoperfusion and rises in patients with severe sepsis. It is associated with disease severity and mortality. In patient with sepsis, lactate is an important component of the initial evaluation and can also be used to assess response to treatment. Point-of-care testing (POCT) of lactate is now increasingly available for use in the emergency department (ED) in resource poor settings and is low-cost. The handheld POCT device which measures fingertip and whole blood lactate has been shown to be accurate and time saving when compared with reference laboratory testing in critically ill ED patients in the USA [ the USA . ResearcBlood cultures: data from the iSSC suggests that performing blood cultures is independently associated with improved survival. An efficient blood culture system requires competent laboratory scientists and facilities for standard aerobic and anaerobic cultures. Availability, accessibility and affordability of blood cultures are a problem in many African countries. However, molecular techniques are in development and may improve ability to detect patients with bacteremia and sensitivity patterns in resource limited settings.Antibiotic administration: prompt administration of antibiotics in severe sepsis and septic shock has been shown to reduce mortality. It is advocated that empiric antibiotics be given after blood cultures have been taken. Antibiotics can subsequently be rationalized based on blood culture results. A study from Uganda showed that empiric antibacterial therapy in sepsis was rarely concordant with blood culture sensitivities [tivities . Thus, eThe aggressive use of IV fluids in sepsis can decrease duration of hypoperfusion of vital organs ultimately resulting in less end-organ damage. However despite numerous studies comparing colloids and crystalloids, research is needed to determine the ideal resuscitation fluid. Recent research suggests lower hospital mortality in patients who receive larger volumes of IV fluids within 3 hours of onset of sepsis . InteresThis bundle for sepsis management should be concatenated in user friendly guidelines that reflect actions which are feasible within the various levels of healthcare. These guidelines can then be widely disseminated with guidance notes and regular training to re-enforce the key messages and promote compliance.Quality assurance teams should be set up within healthcare facilities to improve record keeping and clinical coding.To address the challenge of sepsis in Africa, the following steps should be prioritized: awareness creation and capacity building among health workers about sepsis and its management. This should promote early sepsis recognition as the features of sepsis may be subtle; an early recognition and management bundle for sepsis should be developed to reflect primary, secondary and tertiary level of care and should include the following: use of validated EWS and SIRS criteria to identify patients with sepsis; rapid administration of oxygen, intravenous fluids, antibiotics and measurement of fluid balance; lactate measurement and blood culture collection where possible.There is an urgent requirement to explicitly recognize sepsis as a significant cause of morbidity and mortality in Africa and make greater efforts to more precisely describe the burden of disease from sepsis. Sepsis quality improvement programmes are desperately required in Africa to provide context-specific solutions to this catastrophe."} +{"text": "Two competing hypotheses about the process of de novo gene birth are discussed as well as the high death rate of de novo genes. Despite the high death rate, some de novo genes are retained and remain functional, even in distantly related species, through their integration into gene networks. Further studies combining gene expression with ribosome profiling in multiple populations across different species will be instrumental for an improved understanding of the evolutionary processes operating on de novo genes.Although considered an extremely unlikely event, many genes emerge from previously noncoding genomic regions. This review covers the entire life cycle of such For many years, it had been considered extremely unlikely, if not impossible, that genes with no detectable homology could emerge e.g., . With thIt has become common practice to identify orphan genes based on sequence similarity searches using a very relaxed significance cutoff: those genes with no hit in other species are classified as orphans sensu stricto. Mechanisms resulting in true orphans can be placed into four categories, which I outline here. (i) Origin of new genes from previously noncoding DNA \u2013 these genes have also been called de novo genes indicating that the ancestral sequence was not functional. (ii) Gene duplication and rapid divergence: either gene duplications or insertions of reverse transcribed mRNA sequences into the genome result in duplications of already existing genes. It has been proposed that duplicated copies may undergo phases of rapid evolution in a combination of neutral and adaptive changes de novo genes because it is very challenging to identify historically rapidly evolving sequences. Hence, I treat this class jointly with de novo genes. (iii) Horizontal gene transfer: integration of foreign DNA from bacteria or viruses into the host genome may result in the acquisition of hitherto absent genes. Given the vast number of viral sequences, it is very likely that the source of the acquired gene has not yet been sequenced. Although this mechanism is prevalent in prokaryotes, based on the current surveys of orphan genes in eukaryotes, very little support for horizontal gene transfer has been found de novo genes are frequently generated without frameshifts in the ancestral gene Given this imprecision, it may be more informative to focus on the biological processes generating orphan genes. When the definition of orphan genes is relaxed such that some sequence similarity of orphans with other genes is permitted, processes like exaptation of transposable elements, gene duplication, and horizontal gene transfer emerge as potential forces underlying the generation of orphan genes de novo genes. The unambiguous definition of de novo genes will be of key importance for informative meta analyses providing a general picture of the evolutionary dynamics of these genes. The importance of separating novel genes according to the underlying molecular mechanism is emphasized by their previously documented different evolutionary dynamics Given the diversity of processes underlying orphan births and the uncertainty surrounding orphan definition, I propose that future studies describing the patterns of molecular evolution focus solely on De novo genes arise from previously noncoding DNA, are short, and are expressed at low levels de novo genes. In light of these concerns, several approaches have been used to distinguish true de novo genes from random noise.de novo genes differ significantly from noncoding sequences in interspecific de novo genes are subjected to purifying selection. The codon usage of de novo genes is another feature that has been attributed to selection. Contrary to neutrally evolving sequences, several studies have demonstrated that preferred codons are enriched in de novo genes alone is not sufficient evidence for a functional gene. Therefore, many studies use mRNA expression as an indicator for functional de novo gene is functional rests on the assumption that the modulation of gene expression patterns reflects functional requirements. To this end, several studies have shown that de novo genes are not constitutively expressed, but exhibit clear patterns of regulated gene expression More strains expressed the de novo genes than expected under neutrality. (ii) Consistent with selectively favored spread of the expressed de novo genes, the amount of polymorphism around them was lower in individuals carrying the expressed variant than in those with the non-expressed copy. Importantly, because only the expression of a functional gene could confer a fitness advantage, this pattern suggests that a new mutation resulting in the expression of a pre-existing ORF leads to these de novo genes becoming functional.This model assumes that ORFs are abundant and only await the acquisition of regulatory elements that control transcription and translation. Indeed, in de novo gene birth de novo genes have only a short lifetime. Testing this prediction, however, requires a phylogenetic framework, which includes a range of species with different evolutionary distances de novo genes can be dated by applying the parsimony principle to the presence of the de novo genes in the species studied (de novo gene has been dated, its evolutionary dynamics can be studied in species that diverged subsequently (de novo genes is the greatest benefit of this analysis de novo genes than for old genes de novo genes explains why the total number of genes remains relatively constant despite the well-documented high rate of de novo gene birth de novo genes to those that acquired disabling mutations it was found that GC content, gene length, and expression level were positively correlated, and microsatellite number negatively correlated, with sequence conservation de novo genes with male-biased gene expression were less likely to acquire premature termination codons. This differential conservation may explain why previous studies identified a high number of de novo genes based on gene expression in testis de novo genes with male-biased gene expression The high rate of studied . Once thequently . Althougde novo genes. Potentially, the most rewarding approach has been the analysis of gene expression. Putative de novo genes were found to show a higher gene expression response to abiotic and biotic stressors in Arabidopsis thaliana than young genes with a different evolutionary origin de novo genes originating before the A. thaliana and A. lyrata split de novo genes in Daphnia magna are twice as likely to be differentially expressed under biotic and abiotic stress than old genes de novo genes, and their precursors were enriched for binding of transcription factors related to stress and mating de novo genes had more pronounced expression differences in a comparison of two D. melanogaster populations collected from different environments de novo genes are particularly important for population-specific responses to biotic and abiotic stresses.Several strategies have been pursued to explore the functional contribution of de novo goes beyond stress response, however, as they were also shown to serve a vital role during developmental processes Drosophila, where many de novo genes are related to male reproductive processes The function of de novo genes that were discussed above are mostly related to functions that require rapid change. Thus, the short persistence times of de novo genes nicely fits their functional role. Nevertheless, some de novo genes quickly become essential de novo genes could become essential. The prevailing hypothesis is that de novo genes become integrated into already existing networks. The first step is the integration into regulatory networks, primarily through acquisition of promoters de novo genes, a higher level of complexity is developed through the gradual acquisition of regulatory motifs de novo genes into protein\u2013protein interaction networks is significantly slower de novo genes were found to interact preferentially, but not exclusively, with genes of the same age de novo genes do not acquire catalytic functions, suggesting that they serve primarily regulatory functions in their networks The roles of de novo and may even acquire essential functions, the process of de novo gene genesis deserves more attention, as does their functional characterization.While past research has proven that genes can originate de novo genes had been mainly studied in the framework of comparative genomics. However, because the processes of de novo gene birth and death occur on the population level, population genetic approaches will be central to understanding these processes. Population genetic theory provides an analytical framework for the interpretation of the selective forces operating on nascent genes. Thus, the combined population genetic analysis of DNA sequences, gene expression, and ribosomal profiling data in multiple individuals will shed light on the selective pressures exerted on each of these levels. Extending this analysis to multiple populations from ecologically distinct habitats as well as additional closely related species holds great promise to determine the evolutionary forces determining the birth and death of de novo genes. Experimental evolution in combination with whole genome re-sequencing (evolve and re-sequence, E&R de novo genes under controlled laboratory conditions.Until recently, the evolution of"} +{"text": "Uganda Ministry of Health passed the Public Private Partnership for Health (PPPH) policy to strengthen the health system by leveraging strategic advantages of private healthcare providers . The NatThis was a plausibility design study with baseline and end-line assessments in the intervention and comparison districts. The intervention was introducing modified iCCM strategy at licensed drug shops in the rural Mbarara district. This involved training the drug shop attendants on how to manage febrile illnesses in under-fives using the standardised sick child job aid, supply of subsidized medicines and diagnostics, integration of drug shop health information system with district HMIS and routine support supervision. Qualitative interviews to explore views, attitudes and perceptions of various stakeholders and wider health systems effects of intervention are ongoing. Ethical approval was sought and granted.Baseline surveys show that drug shops provide care to over 50% of child febrile illnesses in rural Uganda. 96 drug shop attendants were trained and hence 69 drug shops in rural counties of Mbarara district are implementing the modified iCCM strategy. Continuous monitoring and support supervision has started to explore how private drug shops can be integrated into the district health system. Drug seller performance and attrition, linkages with nearest public health facility and monthly reporting on pre-determined HMIS indicators are being examined.Private drug shops provide healthcare to under-five febrile children as first point of contact in rural areas. Their recognition and integration into district health systems will increase penetration of life saving interventions especially for the most vulnerable populations."} +{"text": "Good evidence for the efficacy of alcohol brief interventions (ABIs) delivered in primary care has beenThis study aimed to ascertain how published trials of ABIs describe the training and related support provided to practitioners, what additional relevant information can be obtained from trial authors and how current frameworks or taxonomies can inform how best to analyse and describe training content and design.A systematic search identified published ABI trials involving frontline healthcare workers. Data on how training is reported in papers and supplementary materials was extracted so as to facilitate analysis of how clearly the design, duration, method and topics covered in training are described and reported. Corresponding authors were contacted to request further information on training content and design. Existing frameworks which might facilitate systematic description of ABI training will be critically appraised to assess usefulness for routine use in reporting.780 records were identified from the Cochrane Drug and Alcohol group specialised register and relevant Cochrane systematic reviews. After de-duping and screening, 221 full text articles were being assessed for eligibility and data extracted on training and support provided to practitioners in eligible reviews.Preliminary findings suggest that the quality of descriptions of training, as well as the duration and intensity of training and support provided to practitioners are highly variable and that in future standardised reporting would facilitate further analysis."} +{"text": "This review covers the structures and biological activities of peroxy natural products from a wide variety of terrestrial fungi, higher plants, and marine organisms. Syntheses that confirm or revise structures or stereochemistries have also been included, and 406 references are cited."} +{"text": "Educators and medical students assume that BST may put patients under stress and embarrass them.,,,,Obstacles that are described in the literature regarding patient behavior that could influence BST include lack of cooperation,,Students play an essential role in BST. They contribute to BST by bolstering its effectiveness through positive preparation prior to going on rounds and seeing patients. In addition to obtaining knowledge and being prepared before seeing patients, it is essential that students have strong communication skills to relate to patients and to collaborate with them.The tutor (attending physician), must have the appropriate clinical knowledge, maintain his/her information, and master the required clinical skills of a competent clinical educator.Gonzalo and colleagues proposed the following four key concepts for tutors to apply to the BST learning process in order to avoid hurdles for medical students: (1) Make BST trainee-specific: Ask trainees for their own learning goals and conduct BST on the basis of these goals. (2) Make BST disease-specific: Select the specific topic prior to BST and let both the trainer and the trainees read it thoroughly by using an updated resource. (3) Make BST patient-specific: Choose patients whose conditions have high educational value in the ward prior to BST. (4) Prepare mentally: Take steps to be mentally prepared for the many different tasks that might take place during BST.The authors thank Alzaidi Chair of Research in Rheumatic Diseases at Umm Alqura University for supporting and supervising this paper. We also thank Dr. Allison Vanderbilt for her helpful comments on the manuscript.The authors declare that they have no conflict of interest."} +{"text": "Sensory hair cells are specialized mechanotransductive receptors required for hearing and vestibular function. Loss of hair cells in humans and other mammals is permanent and causes reduced hearing and balance. In the early 1980\u2019s, it was shown that hair cells continue to be added to the inner ear sensory epithelia in cartilaginous and bony fishes. Soon thereafter, hair cell regeneration was documented in the chick cochlea following acoustic trauma. Since then, research using chick and other avian models has led to great insights into hair cell death and regeneration. However, with the rise of the zebrafish as a model organism for studying disease and developmental processes, there has been an increased interest in studying sensory hair cell death and regeneration in its lateral line and inner ears. Advances derived from studies in zebrafish and other fish species include understanding the effect of ototoxins on hair cells and finding otoprotectants to mitigate ototoxin damage, the role of cellular proliferation vs. direct transdifferentiation during hair cell regeneration, and elucidating cellular pathways involved in the regeneration process. This review will summarize research on hair cell death and regeneration using fish models, indicate the potential strengths and weaknesses of these models, and discuss several emerging areas of future studies. Hair cells are specialized mechanosensory receptors which convert external vibratory stimuli into neural signals , which has become an important vertebrate model for examining embryogenesis, organ development, disease, and genetic defects while immature hair cells at the neuromast edge expressed a large conductance Ca2 + -activated K+ current and a small IA. Further, mature zebrafish hair cells physiologically resembled those of other lower vertebrates, and to some extent, the hair cells from immature mammalian vestibular and auditory systems and with mammals have elevated hearing threshold shifts compared to wild-type controls under the control of the Morone chrysops \u00d7 striped bass, Morone saxatilis) and tilapia (Oreochromis mossambicus) exposed to pile driver noise assay shows that noise exposure and ototoxins modulate apoptosis in zebrafish lateral line and inner ear hair cells , which is strongly expressed in supporting cells, affects zebrafish hair cell proliferation and regeneration , which are small, non-coding RNAs that regulate gene expression by translation repression or mRNA destabilization (Friedman et al., One strategy for preventing damage to hair cells is to administer otoprotective drugs that counteract cellular injury from otherwise beneficial drugs (Coffin et al., Studies in zebrafish and mouse models demonstrate that they share key components of several hair cell proliferation pathways, e.g., Wnt, Notch and Rb (Hern\u00e1ndez et al., Reinnervation, the reestablishing of functional nervous system connections with target cells, is a necessary concomitant of hair cell regeneration. If neurons are unable to establish appropriate communication with new hair cells, then auditory and vestibular signaling to the brain will not occur. The neuromasts and associated neurons of the embryonic zebrafish lateral line can be stained facilitating the study of neural innervation of the neuromasts using mutant models (Raible and Kruse, Much has been learned in the last decade about hair cell death and regeneration in teleost fishes. Advances derived from studies in zebrafish and other fish species include understanding how ototoxins affect hair cells and discovering new otoprotectants that mitigate ototoxin damage, the role played by cellular proliferation and transdifferentiation during hair cell regeneration, and characterization of the cellular pathways involved in regeneration. Although the zebrafish model has the advantage of higher throughput and easier access to sensory hair cells than mammalian models, because of the different cellular and molecular characteristics of teleost and mammalian auditory cells, data obtained in zebrafish models may not apply to mammalian models. Thus, additional comparative studies involving zebrafish and mammal-based models will be needed to determine whether results obtained in teleosts can be translated into therapeutics to prevent or treat human hearing loss.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The GeneWeaver bipartite data model provides an efficient means to evaluate shared molecular components from sets derived across diverse species, disease states and biological processes. In order to adapt this model for examining related molecular components and biological networks, such as pathway or gene network data, we have developed a means to leverage the bipartite data structure to extract and analyze shared edges. Using the Pathway Commons database we demonstrate the ability to rapidly identify shared connected components among a diverse set of pathways. In addition, we illustrate how results from maximal bipartite discovery can be decomposed into hierarchical relationships, allowing shared pathway components to be mapped through various parent-child relationships to help visualization and discovery of emergent kernel driven relationships. Interrogating common relationships among biological networks and conventional GeneWeaver gene lists will increase functional specificity and reliability of the shared biological components. This approach enables self-organization of biological processes through shared biological networks. The maximal biclique algorithm is highly efficient and capable of fast enumeration of all shared network edges among a very large set of graphs. Starting with LCCs increases the efficiency of the pathway comparison analysis, but it does not necessarily ensure the best or most detailed overlap among network graphs. Performance enhancements, particularly on post-processing of sets of network edges will be required to comprehensively enumerate all shared subgraphs among sets of graphs.Understanding the conditionality of biological associations across networks and pathways provides a powerful means of interpreting broadly constructed interaction, co-expression and co-occurrence networks. The algorithms and approaches that we have devised provide a means for integrating diverse network data to identify convergent and conditional evidence for the interaction of biological entities and the mapping of those common interactions onto shared process or other contextual information. While the most immediate applications are found in functional genomics, extension is readily possible for cellular, anatomical and evolutionary biology, among other more general graph comparison problems.The authors declare that they have no competing interests."} +{"text": "Wild plant gathering becomes again a popular and fashionable activity in Europe after gathering practices have been increasingly abandoned over the last decades. Recent ethnobotanical research documented a diversity of gathering practices from people of diverse socio-economic and cultural backgrounds who gather in urban and rural areas. Few efforts were though made to study the motivations for gathering wild plants and to understand the resurgent popularity of wild plant gathering. This paper addresses the following research questions: (1) which motivations activate wild plant gatherers? (2) which motivation-types of gatherers exist in the Grosses Walsertal? (3) how do the motivations for gathering relate to the socio-demographic background of gatherers?Field research was conducted in the Grosses Walsertal, Austria in the years 2008 and 2009 in two field research periods. Thirty-six local farmers were first interviewed with semi-structured interviews. The motivations identified in these interviews were then included in a structured questionnaire, which was used to interview 353 residents of the valley. Pupils of local schools participated in the data collection as interviewers. Principal Component Analysis was used to categorize the motivations and to identify motivation-types of wild plant gatherers. Generalized Linear Models were calculated to identify relations between motivations and the socio-demographic background of gatherers.The respondents listed 13 different motivations for gathering wild plants and four motivations for not gathering. These 17 motivations were grouped in five motivation-types of wild plant gatherers, which are in decreasing importance: product quality, fun, tradition, not-gathering, income. Women, older respondents and homegardeners gather wild plants more often for fun; older respondents gather more often for maintaining traditions; non-homegardeners more frequently mention motivations for not gathering.The resurgent popularity of wild plant gathering comes along with an internalization of motivations: the main motivations for wild plant gathering changed from the external extrinsic motivation of gathering because of necessity towards the internalized extrinsic motivation of gathering for the highly esteemed product quality and the intrinsic motivation of gathering for the pleasure of the activity itself. This internalization of motivations supports the persistence of wild plant gathering, a positive self-perception of gatherers and good quality of engagement with wild plant gathering.The online version of this article (doi:10.1186/s13002-015-0032-4) contains supplementary material, which is available to authorized users. Wild plant gathering becomes again a popular and fashionable activity in Europe after gathering practices have been increasingly abandoned over the last decades. Ethnobotanical research documented a diversity of gathering practices and people of diverse socio-economic and cultural backgrounds gather in urban and rural areas , 2.Local knowledge about wild plant gathering historically was transmitted from generation to generation. Such traditional mechanisms were neglected in the last decades due to the decreasing necessity of wild plant gathering for subsistence. These days wild plant knowledge also gets transmitted via scientific and popular publications in print and online media, in books and field guides, through excursions, agrotourism, field courses, internet databases, avant-garde cuisine and food and health related associations . These rThe plants gathered in Europe belong to diverse plant families and plant species. In general most people gather occasionally and a small diversity of plant species and only few people gather frequently and a diversity of different species . Most wiTraditional and modern wild plant practices were documented and observed in many regions all over Europe. However, few efforts were made to study in detail why people gather wild plants these days, when its necessity widely faded. The motivations encountered include health-conscious nutrition, poor economy and generating income for the poor and the elderly in the case of wild food plant gathering in Hungary , supportAlthough this versatile array of motivations was indicated for wild plant gathering, few studies systematically analyzed the motivations for wild plant gathering in a given region in Europe to identify the motivations for wild plant gathering in the Grosses Walsertal Biosphere Reserve, Austria and 2) to describe the links between motivations and the socio-demographic background of gatherers.The paper addresses the following research questions: (1) which motivations activate wild plant gatherers? (2) which motivation-types of gatherers exist in the Grosses Walsertal? (3) how do the motivations for gathering relate to the socio-demographic background of gatherers?Field research was conducted in the Grosses Walsertal Biosphere Reserve, Austria in the years 2008 and 2009 in two field research periods.2. The remote location of the region supported the creation and conservation of a distinct culture including a specific dialect, the Walserdeutsch. The valley is shaped by meadows and pastures due to long-lasting livestock husbandry . Gat. Gat9]. Gathering wild plants for income might involve less sustainable harvesting practices when compared with harvesting for fun. Also conflicts between non-commercial and commercial gatherers, as well as between different social, cultural, economic groups of people, might occur due to heterogeneous gathering practices .Bergtee project for selling herbal teas and thereby promoting wild gathered plants. The project aims at conserving and valuing traditional knowledge about wild plants and is not profit-oriented, although the gatherers receive remuneration. Gatherers who work for Bergtee follow informal guidelines for gathering and processing wild plants, which are drafted by experience and enforced by mutual trust [We did not identify such dissent in the GWT, where most of the commercial gathering is done by the al trust . The embThe main motivations for not gathering wild plants in the GWT are the lack of time and knowledge.Changing lifestyles and the associated shortage of time are frequently mentioned reasons for the abandonment of traditional wild plant gathering in Europe. Furthermore, wild plant gathering can be time intensive, as shown for the harvest of wild asparagus in Spain .More than one third of the interviewees mention that not knowing plants sufficiently is a reason for not gathering wild plants. This may relate to not knowing which parts of plants can be used for what purposes or generally lacking knowledge for properly identifying wild plants.Casual but medially widely distributed reports about intoxications as a result of consumption of falsely identified wild plants might also contribute that people untrained in plant identification refrain from gathering. Besides that some intentionally gathered and consumed wild food plants may have detrimental health effects, such as those with rich amounts of bioactive compounds , toxic aThe material developed and published within the frame of the project as well as the project activities themselves intended to enhance knowledge and exchange about wild plants. This can help to increase the motivation for wild plant gathering of those people who do not gather because of a lack of knowledge. Furthermore workshops, herbal walks and ritual ceremonies about wild plants are offered in the GWT for rising awareness and increasing valuation and knowledge about wild plants .This study set out to identify the motivations for wild plant gathering, types of gatherers and variations of motivation and thereby contribute to explaining the resurgent popularity of wild plant gathering in Europe.The most pronounced motivations for wild plant gathering in the Grosses Walsertal (GWT) are to obtain high quality products and enjoying the activity of plant gathering itself. Maintaining traditions is less important, and solely a very small number of people gather for income. In the last decades, the motivation changed from an external extrinsic motivation of gathering because of necessity towards an internalized extrinsic motivation of gathering for the product quality and the intrinsic motivation of gathering for the pleasure of the activity itself. This internalization of motivations supports the persistence of wild plant gathering, a positive self-perception of gatherers and good quality of engagement with wild plant gathering .The validity of these results for other fieldsites should be tested. A generalization of findings across different user groups might result in wrong interpretation and management decisions because From our findings we hypothesize that 1) quality is an important motivation for gathering wild plants, even more in un- or less disturbed areas than in more polluted environments, like cities; 2) fun is a motivation for wild plant gathering in areas where local people detach from the necessity of wild plant gathering and find new approaches through the internalization of the motivation; 3) tradition is a motivation in areas where gathering traditions exist; 4) gathering for income and selling wild plant products is beneficial for promoting wild plant gathering; 5) gathering wild plants can be enhanced by supporting dissemination and exchange of wild plant knowledge; 6) the motivations for homegardening and wild plant gathering are by tendency similar within a region.Besides testing these hypotheses, we suggest that future research in ethnobotany should explore what plant quality means for local people and should make closer links between motivation for wild plant gathering and so far unexplored variables like gathering location, gathered plant species and gathered plant part to explore why specific plant parts are gathered but others not.Investigating the motivations for ethnobotanical activities explains why such activities are taken up, continued or abandoned and may predict future developments. It can be deducted that creating and maintaining accessible and unpolluted environments will foster wild plant gathering because the main motivations for wild plant gathering, product quality and fun, are secured. Propagating the motivations of product quality and fun in other regions might increase interest for wild plant gathering."} +{"text": "Personality is deemed to play a part in an individual\u2019s choice of work, with individuals\u2019 preferencing a profession or field of work that will satisfy their personal needs. There is limited research exploring the personality characteristics of nurses within clearly defined nursing specialty areas. Retaining nurses within specialty areas has workforce implications when vacancies are unable to be filled by appropriately experienced staff.The aim of the review was to determine the current state of knowledge regarding the personality profiles of nurses in specialty areas of nursing practice.An integrative literature review was undertaken.Five electronic databases were searched using personality and nursing based keywords. No date limit or research design restriction was applied. Rigorous screening and quality appraisal was undertaken considering the research design, methods and limitations of each manuscript.A review of the 13 included articles demonstrated some variability in the personality characteristics of the nursing specialty groups studied. A relationship was identified between personality characteristics and levels of nursing stress and burnout.There is some evidence to suggest a relationship between personality characteristics and nursing specialty choice, burnout and job satisfaction. The published literature is limited and the effect of personality on retention is not well established.The online version of this article (doi:10.1186/s12912-014-0040-z) contains supplementary material, which is available to authorized users. The nursing workforce is ageing, leading to a global shortage of experienced nurses -3. At thPersonality is believed to play a role in career choice ,12 and iPersonality testing enables the identification of an individual\u2019s personality characteristics. These characteristics can inform how an individual is likely to respond or cope when exposed to different situations . PersonaIt is well-recognised that personality has an influence on the way an individual interacts and deals with the outside world, and in turn, influences their ability to cope and deal with stressful situations . PersonaTo determine the relevance of personality testing in nursing, any link between the personality characteristics of an individual and specialty practice choice along with other factors such as stress, burnout and job satisfaction must first be established.The aim of the integrative review is to determine the current state of knowledge regarding the personality profiles of registered nurses according to clinical specialty areas of nursing practice.A scoping review was performed to determine what literature review strategy was best suited to answer the aim of the study. The quality and nature of papers found in the initial search was inappropriate for a systematic literature review method, and more suited to an integrative approach. An integrative literature review method allows for the incorporation of different types of literature and a broad range of methodologies . AdditioThe population selected for the review was qualified nurses working within a defined clinical specialty area. Studies that explored personality profiles/type or hardiness within this population group were targeted. The review process involved a search of current literature, quality evaluation of recovered data and synthesis of findings . A keywoPersonality Keywords (combined with OR)PersonalityPersonality stylePersonality traitPersonality type#Personality characteristicPersonality assessmentSearch terms for CINAHL AND emergency nurse* OR critical care nurse* OR intensive care nurse*AND career choice OR occupational choiceAND nurs*Medline, Psychinfo, Proquest 5000 and Worklit search terms AND career choice OR occupational choice AND nurs*#AND career choice OR occupational choice AND specialty # terms used in Medline only. * asterisk used on the end of search terms provides both singular and pleural forms of the word in search results.The search and screen process of retrieved literature followed the PRISMA framework summarisThe initial search identified 549 published papers. Papers were considered relevant to the review if they presented research related to the study of personality in nurses. Titles of the papers were screened and those deemed not relevant were removed (n =\u2009464). Following relevance checking, duplicates were removed (n =\u200914) resulting in 71 articles. The reference lists of these articles were hand searched, identifying a further 8 papers. The abstracts of these 79 articles were then independently peer reviewed by each author using pre-determined inclusion/exclusion criteria. Full text copies were retrieved when abstracts were not available. Papers were included in the final review if they were original research with a clear research design and explored hardiness or personality among nurses working in defined nursing specialty areas.Papers were excluded if they were not original research or failed to report separate results for qualified nurses when nursing students were included in the sample. Nursing students do not necessarily choose their area of clinical placement, therefore inclusion of their personality characteristics has the potential to skew findings within specialties. Nine PhD theses that met inclusion criteria were identified by the search, however, further database searching failed to identify any subsequent papers published by the authors. Only one thesis was available in full text and the ability to obtain other theses identified by the database search was beyond the resources of this study. Hence all theses were excluded. Differences of opinion or uncertainty between authors regarding the relevance, inclusion or exclusion of an article were resolved by discussion.Following the screening process, 29 papers were obtained in full text and reviewed independently by all three authors using a critical appraisal tool adapted from the quantitative appraisal guides of Polit and Beck . A totalThe systematic search and quality appraisal of published and unpublished literature resulted in 13 articles of sufficient quality for inclusion in the integrative literature review . Those who fall within the thinking dimension are known to take a more logical and objective approach in decision making, not allowing emotions to influence the process [Cross and Kelly compared process ,41.The results of these studies suggest that there may be differences in personality among nurses who chose to work in different specialty areas.openness and extraversion, and stress when dealing with patients and relatives, with no positive relationship identified between personality and workplace stress [The results of studies exploring the relationship between personality, and stress and burnout are difficult to interpret and compare because different personality variables have been measured with different tools ,5,25,42.e stress ,42 have commitment. One dimension of hardiness (control) yielded a positive correlation with occupational stress, that is higher scores on the control dimension were associated with higher levels of occupational stress. In contrast, Toscano and Ponterdolph [Another study exploring the effects of hardiness among critical care nurses reportedterdolph reportedSense of Coherence (SOC) is a concept that has been closely related to hardiness and has easy going and orderly that explained 3.5% of the variance and were significant predictors of job satisfaction among nurse anaesthetists. This study suggests that personality dimensions may potentially influence the level of job satisfaction among nurses.Only one paper in this review . The nursing profession and the role of nurses has evolved considerably across all nursing specialties during this time ,57. If pThere is some evidence of variance in personality characteristics between different nursing specialty areas, as well as associations between personality characteristics and stress, burnout and job satisfaction. However these variances occur largely within normal ranges. The investment required to train nurses to function as a \u201cspecialist\u201d implies a benefit exists in targeting individuals potentially suited to particular specialty nursing areas to optimise retention. More robust research using tools based on the five factor model of personality is required to generate evidence for the theory that particular individuals are suited to different nursing specialties.If employees possess the personality characteristics that are best suited to the job, this will likely result in improved workplace efficiency, job satisfaction and retention of staff. All of these factors in turn have capacity to influence the quality of care delivery. Clearly identified personality characteristics linked to stress and burnout have the potential to enable appropriate interventions and plans to be put in place to assist in improving the nurses\u2019 ability to deal with workplace stressors. This in turn would assist to reduce staff turnover in stressful work environments."} +{"text": "This paper reports the case of a 4-year-old male patient who was brought by parents requesting for replacement of multiple missing anterior teeth. The patient suffered from congenital insensitivity to pain without anhidrosis and presented with full blown sequelae of the condition in the form of oral self-mutilation leading to loss of teeth, tongue tip amputation, finger tips destruction, and lower limb wound infections. Dental and orthopaedic treatment consists of local management of oral wound and prevention from further oral and finger injuries that takes the form of dental splints and finger sleeve splints, constant feet coverage with shoes, and behavioural medical therapy. The age of the patient and parents' education present challenges in managing this condition to avoid morbidity and premature mortality. Pain is a common unpleasant experience often caused by intense or damaging stimuli. Acquired insensitivity to pain such as diabetic neuropathy is a common condition. However, congenital insensitivity to pain with or without anhidrosis \u20133 is a rThese cases are very often referred to dental clinics for emergency management of acute oral trauma resulting from their neurological condition. This case report describes a case of a four-year-old boy with congenital insensitivity to pain that was brought by his parents seeking dental help for prostheses to replace his self-extracted primary teeth at the University Dental Hospital Sharjah, United Arab Emirates.A four-year-old Arab-Egyptian boy was brought by parents to pediatric clinic seeking prosthetic replacement of multiple missing teeth. The patient was elder of two siblings from a consanguineous marriage. History revealed the patient was born at full term through normal delivery and both parents and the younger brother were healthy.Past medical history showed previous hospital admission at the age of two years and ten months for emergency intervention to treat chronic osteomyelitis and periostitis that resulted in swollen right foot above the talus. The condition at that time was diagnosed as septic arthritis and acute osteomyelitis. The condition in the right foot recovered well albeit with some scarring. At age three, patient's right little toe got hurt while playing for which he obviously never complained, which later got infected leading to necroses and ultimate amputation . At thisThe parents noticed that the patient is suffering from some chewing difficulties due to premature tooth loss but without swallowing difficulty and this was the main reason that had brought them to seek dental treatment. General examination showed a fully alert patient with hyperactive behavior and short attention span. The patient's height and weight was appropriate for his age with normal gait and posture. There was an extensive damage to index finger of the right hand due to biting and chewing Figures .Clinical oral examination demonstrated scars on tip of the tongue and around vermillion border of the lower lip suggesting self-inflicting injuries probably due to pain insensitivity. The tongue was of normal size and color but bald and depapillated. Intraoral hard-tissue examination demonstrates no carious lesion. There was an open wound in the left mandibular quadrant with exposed alveolar bone due to a very recent self-extraction of two deciduous molar teeth , according to the history. Distal to the wound, there was premature exposure of mesiobuccal cusp tips of the left mandibular first permanent molar. In addition, severely resorbed maxillary and mandibular alveolar ridges were evident clinically and radiographically. The orthopantomogram (OPG) examination of the jaw bones showed normal jaw anatomy and bone density . The croIt was noted that piercing the buccal gingiva with a sharp dental probe during oral examination did not elicit any physical reaction from the child.Based on the available pediatric, orthopedic, and neurological records, a diagnosis of oral self-mutilation secondary to congenital insensitivity to pain was established.In this case, a young child who is devoid of normal pain sensation suffers injuries in several parts of the body without showing any disability due to pain. Mardy and his colleagues reportedThe destructive behaviour of self-tooth extraction and other oral manifestations have been reported by many centers managing these special children \u20138. This The poorly healed lower left second deciduous molar extraction socket with exposed alveolar bone is likely due to continuous trauma on the painless healing granulation tissue giving rise to areas of mucosal necrosis and sequestrated superficial alveolus. Continuous traumatic contact between the upper and lower dentoalveolar region could have led to severe resorption of the maxillary and mandibular alveolar ridges which may be responsible for premature exposure of the mesiobuccal cusp tips of the left mandibular first permanent molar.These children may be shown photographs of lip injury to educate them not to bite their own lips. However, these habits may perpetuate during sleep as part of a sleep disordered syndrome in these children. In such circumstances, soft vacuum dental splints or hard acrylic splints may be used to cap either mandibular or maxillary teeth or both in an attempt to break the lip and tongue biting habit. This is only possible when the deciduous molars have erupted and able to retain the splints. Littlewood and Hutton , 11 recoThe poorly healing wound in the patient's mouth was managed by using local measures that include wound debridement and mouth rinsing with chlorhexidine 0.12% solution. In this case provision of prostheses was not possible due to deficient tooth-tissue support, from severely resorbed upper and lower dentoalveolar ridges resulting from self-extractions. In addition, implant retained prostheses were not possible due to presence of unerupted teeth contraindicating implant placement.Preventive measures such as custom fitted shoes, education regarding foot care, changing posture to relieve continuous pressure on bones and joints can prevent the need of multiple surgeries for injuries . MedicalA multidisciplinary team approach comprising the neurologist, psychologist, family physician, and pediatric dentist from whom the child needs specialized care shall collectively provide the holistic care approach. In addition, we need to educate both the child and parents to ensure that the child is always in a safe environment."} +{"text": "Hematopoietic malignancies are neoplastic tumors affecting the blood and lymphatic circulatory systems and are commonly referred to as liquid tumors. Malignancies of the blood and lymphatic systems are known to affect a whole host of cell types derived from lymphoid and myeloid progenitors including leukocytic and lymphatic cells and cells that make up the bone marrow microenvironment . Due to Hematological malignancies account for approximately 10% of all newly diagnosed neoplasms within the United States. Of the 150,000+ newly diagnosed cases of hematological neoplasms within the US, lymphomas account for 51% of the new cases followed by leukemia and myeloma . A commoScience and medicine have focused intently over the last 20\u201330 years on developing treatment regimens that efficiently and effectively target and destroy cancer cells. Although our understanding of hematological malignancies has improved exponentially, resulting in greatly increased life expectancies and improved quality of life, our ability to abrogate tumor relapse has evaded us. One shortcoming to past and current therapies are centered on the tumor's innate ability to adapt and remain one step ahead of treatment regimens. The next generation of antiproliferative drugs offers a wide spectrum of therapeutic choices. Some of the more common therapies include tyrosine kinase inhibitors like Gleevec and histone deacetylase inhibitors like vorinostat, whereas there is a wealth of new therapeutics available as immunomodulatory drugs, monoclonal antibodies, antibody conjugates, and proteasome inhibitors like Velcade. This next generation of therapies represents a new hope in controlling hematological malignancy relapse and development of refractory disease.A major underlying complication of hematological malignancies is the development of refractory disease upon patient relapse, resulting in a decreased life expectancy and quality of life , 3. More\u03b2-catenin, Notch, and Hedgehog, is showing promising preclinical and clinical results in hematological malignancies [CSCs were originally documented and described in leukemia as a rare population of cells with limitless self-renewal capabilities . Recentlgnancies . We expe BioMed Research International focuses on drug resistance in hematologic malignancies, induction mechanisms, genetics, and therapeutics. It is our goal that the reader leaves with an improved understanding of the underlying mechanisms of drug resistance in hematological malignancies and the discoveries focusing on drug responsiveness resulting in improved quality of life and increased life expectancy.Drug resistance is a universal problem with current therapies for hematologic malignancies, but very little is known about the molecular mechanisms. This special issue ofFenghuang ZhanMaurizio ZangariLugui Qiu"} +{"text": "Autism spectrum disorders (ASDs) and drug addiction do not share substantial comorbidity or obvious similarities in etiology or symptomatology. It is thus surprising that a number of recent studies implicate overlapping neural circuits and molecular signaling pathways in both disorders. The purpose of this review is to highlight this emerging intersection and consider implications for understanding the pathophysiology of these seemingly distinct disorders. One area of overlap involves neural circuits and neuromodulatory systems in the striatum and basal ganglia, which play an established role in addiction and reward but are increasingly implicated in clinical and preclinical studies of ASDs. A second area of overlap relates to molecules like Fragile X mental retardation protein (FMRP) and methyl CpG-binding protein-2 (MECP2), which are best known for their contribution to the pathogenesis of syndromic ASDs, but have recently been shown to regulate behavioral and neurobiological responses to addictive drug exposure. These shared pathways and molecules point to common dimensions of behavioral dysfunction, including the repetition of behavioral patterns and aberrant reward processing. The synthesis of knowledge gained through parallel investigations of ASDs and addiction may inspire the design of new therapeutic interventions to correct common elements of striatal dysfunction. Autism spectrum disorders (ASDs) are prevalent and devastating neuropsychiatric conditions with a pathophysiology that remains poorly understood. The high heritability of ASDs has motivated the widespread application of advanced sequencing technology to identify genetic variants associated with these disorders . The choice to spend time in the presence of these cues vs. a neutral set of cues is operationally defined as a conditioned place preference (CPP), and most drugs of abuse produce CPP of excitatory synapses onto MSNs , the gene encoding contactin-associated protein-like 4 (Cntnap4). Cntnap4 is a transmembrane protein that belongs to the neurexin superfamily of cell adhesion molecules, which interact with presynaptic proteins involved in neurotransmitter release transgenic mice Heintz, , which aNlgn3), a synaptic cell adhesion molecule that plays important roles in shaping the functional properties of synaptic transmission. Loss-of-function genetic mutations in Nlgn3 caused a specific impairment of inhibitory synaptic transmission onto nucleus accumbens D1-MSNs exhibit a diminished behavioral response to separation from their mothers, suggesting that interaction with the mother may be less rewarding encodes the metabotropic glutamate receptor mGluR4, and administration of an mGluR4 positive allosteric modulator effectively relieved many of the behavioral phenotypes exhibited by MOR knockout mice.Striatal opioid systems play an important role in the rewarding aspects of social interaction . These studies also examined psychomotor activation following acute drug administration, as well as the psychomotor sensitization that occurs following repeated drug exposure, as these behavioral processes are closely tied to striatal dopamine release and remodeling of striatal circuitry , all may be characterized by a failure to inhibit the repetition of behavioral patterns. This lack of inhibitory control over repetitive behavior may also contribute to other mental disorders, such as obsessive-compulsive disorder, which is also linked to striatal dysfunction contribute to the pathophysiology of both ASDs and addiction, while other elements within or beyond the striatum are uniquely involved in only one disorder. A growing knowledge of both common and distinct dimensions of dysfunction will help guide the development of interventions that could be broadly useful for normalizing neural circuit dysfunction that contributes to behavioral deficits in both ASDs and addiction.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The rhizosphere microbiome is pivotal for plant health and growth, providing defence against pests and diseases, facilitating nutrient acquisition and helping plants to withstand abiotic stresses. Plants can actively recruit members of the soil microbial community for positive feedbacks, but the underlying mechanisms and plant traits that drive microbiome assembly and functions are largely unknown. Domestication of plant species has substantially contributed to human civilization, but also caused a strong decrease in the genetic diversity of modern crop cultivars that may have affected the ability of plants to establish beneficial associations with rhizosphere microbes. Here, we review how plants shape the rhizosphere microbiome and how domestication may have impacted rhizosphere microbiome assembly and functions via habitat expansion and via changes in crop management practices, root exudation, root architecture, and plant litter quality. We also propose a \u201cback to the roots\u201d framework that comprises the exploration of the microbiome of indigenous plants and their native habitats for the identification of plant and microbial traits with the ultimate goal to reinstate beneficial associations that may have been undermined during plant domestication. Plants rely on their rhizosphere microbiome for functions and traits related to plant growth, development and health , Sphingobium, Pseudomonas, Acinetobacter, Stenotrophomonas, and Chryseobacterium were enriched on the low starch genotype as compared to two high starch genotypes , stimulating the colonization by B. subtilis strain FB17 and pyoluteorin (PLT) respectively, was induced or repressed by 40 different plant-derived compounds, including several plant phenolics and pectin -\u03b2-caryophyllene via the roots attracting an entomopathogenic nematode in response to insect attack; North American lines failed to release this compound probably as a consequence of the breeding process communities, the abundance and diversity of AMF was reduced compared to native grassland samples were less able to support AMF as compared with wild ancestors as revealed by significant reductions of vesicular and arbuscular colonization , broad bean (Vicia faba) and several wild legumes from the genera Vicia and Lathyrus, grown in a non-agricultural soil, it was shown that the ability to interact with symbionts was limited for pea and broad bean as compared to promiscuous wild legumes that were able to exploit the diverse rhizobial community and two domesticated maize cultivars on the rhizosphere bacterial and fungal community composition was evaluated produced a shallower root system compared with wild lettuce (Lactuca serriola). In cultivated lettuce an inadvertent selection of more laterals roots at the top of the tap root helps plants to respond to surface application of water and fertilizer in crop fields, whereas wild lettuce showed a root system able to access deeper portions of soil . Wild beet plants showed a more diverse bacterial community compared with domesticated sugar beet, as was shown by single strand conformation polymorphism (SSCP) analysis of the 16S-rRNA genes from total community DNA and 16S amplicon pyrosequencing (Zachow et al. Bacillus cereus UW85 (Smith et al. Lycopersicon cheesmanii, Smith and Goodman (B. cereus UW85 and the disease suppressive effects. However, several conceptual and experimental efforts have yet to be made in order to identify and exploit these traits in a rhizosphere-based breeding program (Bakker et al. Over the past decades, plant breeders have exploited genes from native relatives of modern crop species to improve plant growth and health. For instance, wild relatives have been used as sources of alleles to improve the ability of modern cultivars to withstand biotic and abiotic stresses in wheat (Nevo and Chen Goodman showed t"} +{"text": "Dynamic changes in the structure and composition of the membrane protrusions forming dendritic spines underlie memory and learning processes. In recent years a great effort has been made to characterize in detail the protein machinery that controls spine plasticity. However, we know much less about the involvement of lipids, despite being major membrane components and structure determinants. Moreover, protein complexes that regulate spine plasticity depend on specific interactions with membrane lipids for proper function and accurate intracellular signaling. In this review we gather information available on the lipid composition at dendritic spine membranes and on its dynamics. We pay particular attention to the influence that spine lipid dynamism has on glutamate receptors, which are key regulators of synaptic plasticity. At most excitatory synapses in the Central Nervous System, presynaptic boutons synapse onto small membrane protrusions that emerge from the dendritic shaft: the dendritic spines. Changes in dendritic spine number, size and shape contribute to determine the strength of excitatory synaptic transmission are minor components of synaptic membranes, their exceptional high rate of metabolic turnover and their compartmentalization make them key players in postsynaptic excitability triphosphate (PIP3) at the postsynaptic terminal is necessary for sustaining synaptic function in rat hippocampal neurons and PIP5K, are important for synaptic plasticity, both LTP diphosphate (PIP2) at the postsynaptic membrane, which are modulated by the activities of Phospholipase Besides PIPs themselves, PIP derived second messengers such as Diacylglycerol (DAG) and 1,4,5-triphosphate (IP3) generated by the hydrolysis of PIP2 by PLC, are also important in dendritic spine organization and function. Unlike IP3, which is released into the spine cytoplasm, DAG is embedded in the membrane and recruits and activates DAG effectors (among them PKC), which have been involved in spine maintenance is selectively expressed in the brain, where it is responsible for cholesterol oxidation and eventual excretion to the general circulation has been directly related to spine size and to postsynaptic function. NSM is the main responsible of SM degradation and conversion to ceramide at the plasma membrane Stoffel, . Its rapde novo synthesis of the lipid has been discarded. Instead, CPT1C may influence the generation of ceramide from the sphingosine pool through the salvage pathway and/or on its degradation. CPT1C deficiency increases immature filopodia and reduces mature mushroom and stubby spines, while not affecting total spine number or spine head area. These effects on spine maturation can be restored by ceramide addition , modulates ceramide levels in hippocampal neurons where it is especially enriched constitutively localizes at synapses by means of a direct interaction between its p85 subunit and the AMPARc , becomes dephosphorylated and associates with the clathrin adaptor protein complex AP-2 at postsynapses upon NMDA receptor activation , which are coupled to synaptic scaffolding proteins, tightly control synaptic DAG concentrations in AMPARc-mediated miniature excitatory postsynaptic currents has been reported in hippocampal slices. Inhibition of sphingosine kinase (SphK) impaired LTP that was fully restored by S1P addition. Consistently, mice lacking SphK show poor memory performance (Kanno et al., Different studies indicate that AMPARc trafficking depends on PIP metabolism Figure . Direct 2+ blockade of NMDA channel enhancing ion currents (Kloda et al., NMDARc are heterotetrameric ion channels directly implicated in LTP and LTD being the predominant molecular device for controlling synaptic plasticity and memory function (Bashir et al., Dysregulation of brain sphingolipid balance following inhibition of NSM alters the subunit composition of NMDARc that might account for memory impairment following long-term inhibition of NSM (Tabatadze et al., More work is needed to determine the influence of PIPs in NMDARc. The already mentioned observation that activation of these receptors recruits the PIP3 degrading enzyme, PTEN, to dendritic spines mediating NMDA dependent but not mGluR dependent LTD (Jurado et al., We are still far from having a detailed picture of how lipids participate in dendritic spine physiology. However, research in recent years has started to unveil that they are not simple structural bystanders but play relevant roles in neurotransmission, through the control of spine architecture and by modulating neurotransmitter receptor function. As key components of postsynaptic membranes, lipids affect synaptic plasticity by shaping the membrane and modulating the levels, compartmentalization, interactions, trafficking and signaling properties of many proteins that are essential for synaptic function. By these means lipids regulate glutamate receptor function and actin cytoskeleton dynamics, which are instrumental features for postsynaptic plasticity. The application to the study of synapses of new generation fluorescent probes to label lipids, modified toxins that specifically identify them, different kinds of super-resolution microscopy and more sensitive quantitative methodologies will allow us to further dissect how spine lipids precisely function. As we know more on spine lipids the traditional view of the static role for these molecules fades away and is replaced by that of a remarkable dynamism. The activity of lipid metabolic enzymes at dendritic spines guarantees this dynamism. Some of these enzymes are constitutive components of these structures that change activity or get closer to their substrates upon stimulation. Others find different ways to reach the spine membrane when required. Deep insight on the role of lipids in dendritic spines and on how lipid pathways are topologically and temporally regulated will help to understand how we learn and keep our memories. Moreover, this will unveil the reasons behind the cognitive impairment occurring during aging and in diseases like many genetic lipidosis and neurodegenerative disorders where brain lipid imbalances have been reported. These investigations could yield novel therapeutics relying on lipid based drugs that readily cross the blood-brain barrier.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "There are sensitizing haptens that are used as ingredients of both cosmetic products and foods. This provokes the question whether people with contact allergy to cosmetics could also develop dermatitis following systemic exposure to the provoking haptens present in foods - a phenomenon referred to as \"systemic reactivation of allergic contact dermatitis\" (SRACD).Ingredients declared on packages of 150 cosmetics and 150 food products available in chain superstores were analyzed. The components identified in both cosmetics and foods were further analysed for their sensitizing potential based on available epidemiological and experimental data.There were 9 haptens with known sensitizing potential occurring both in food and cosmetics - at least one of them was present in 65% food products and 87% cosmetics analyzed (Table). These sensitizers common to cosmetics and foods were predominantly present in bath lotions, shower gels, as well as filled chocolates, mayonnaise and fruit nectars.Cosmetics and food products share a range of ingredients known as causes of delayed type allergy. The possibility of systemic reactivation of allergic contact dermatitis by ingesting food products containing the same haptens as cosmetics should be considered in patients with confirmed contact allergy to cosmetic ingredients, who also demonstrate a disseminated, flexural or intertriginous pattern of eczema."} +{"text": "Hospital accreditation programs are internationally widespread and consume increasingly scarce health resources. However, we lack tools to consistently identify suitable indicators to assess and monitor accreditation outcomes. We describe the development and validation of such a tool.Staphylococcus aureus infection (SAB) rates as an outcome indicator, with the hypothesis that improved hand hygiene compliance rates and lower SAB rates would correlate with accreditation performance.Using Australian accreditation standards as our reference point we: reviewed the research evidence for potential indicators; looked for links with existing external indicators; and assessed relevant state and federal policies. We allocated provisional scores, on a five point Likert scale, to the five accountability criteria in the tool: research; accuracy; proximity; no adverse effects; and specificity. An expert panel validated the use of the purpose designed indicator assessment tool. The panel identified hand hygiene compliance rates as a suitable process indicator, and hospital acquired This new tool can be used to identify, analyse, and compare accreditation indicators. Using infection control indicators such as hand hygiene compliance and SAB rates to measure accreditation effectiveness has merit, and their efficacy can be determined by comparing accreditation scores with indicator outcomes. To verify the tool as a robust instrument, testing is needed in other health service domains, both in Australia and internationally. This tool provides health policy makers with an important means for assessing the accreditation programs which form a critical part of the national patient safety and quality framework. Scope and objectives; (2) Identify costs and benefits; (3) Quantify costs and benefits; (4) calculate Net social benefits; and (5) Sensitivity analysis.Health services accreditation programs are designed to strengthen quality and safety improvement efforts through compliance with clinical and organisational standards. Accreditation programs have been widely adopted with over 27 country specific hospital accreditation agencies active in a 2009 survey , and sevThere are a number of indicators that have been validated and accepted for measuring patient safety and quality in healthcare . HoweverStaphylococcus aureus (SAB) rates to illustrate the selection process and assess the suitability of these indicators in assessing the impact of accreditation on patient safety and quality of care.The aim of this study is to describe the development and validation of a purpose designed indicator assessment tool in identifying indicators for hospital accreditation performance. An expert panel assessed the tool using hand hygiene compliance rates and This study takes the health service accreditation standards for Australian hospitals as its reference point. We reviewed the ten National Safety and Quality Health Service (NSQHS) Standards developed by the Australian Commission on Safety and Quality in Health Care (ACSQHC) and introduced in early 2013 . In addiGovernance for safety and quality in health service organisations; Standard 2 Partnering with consumers; and Standard 3 Preventing and controlling healthcare associated infections [We focused on the first three NSQHS standards: Standard 1 fections . For eacfections , 17.Four researchers from the ACCREDIT team assessed potential indicators against the five criteria in our indicator assessment tool during a series of four evaluation meetings. The researchers were experienced in a wide range of clinical and health services research expertise including: qualitative and quantitative methods; patient safety and quality; and organisational culture. Each criterion was allocated a score ranging from low to high on a five point Likert scale Table\u00a0. For exaWe next convened an expert panel to validate the results of our prototype indicator assessment tool building on methods adopted for assessing quality indicators in primary health care . This paStaphylococcus aureus bacteraemia (SAB) incidence rates in the Australian acute care sector are routinely collected and published, and we selected these indicators to test our indicator assessment tool.We focused on Standard 3 relating to hospital acquired infection. This was partly due to the specificity of the interventions that could be mapped across the ACHS and NSQHS Standards. In addition, infection control processes have become increasingly important as infections acquired during a hospital stay are a major cause of morbidity and result in significant costs in terms of increased length of stay and additional treatment . StandarHand hygiene programs in Australian hospitals, based on World Health Organization recommendations , take a The ACSQHC has recommended that hand hygiene programs in Australia are repeatedly monitored using both process indicators (compliance rates) and outcome indicators (infection rates) . AuditorThe panel collectively reviewed the five criteria, assessed the evidence and interim evaluation provided, and awarded each a score ranging from low to high. The scores varied, with higher scores for research and proximity to lower scores for specificity. The results and rationale for the allocated scores for hand hygiene compliance rates are shown in Table\u00a0The expert panel endorsed the indicator assessment tool and its suitability for assessing process and outcome indicators for accreditation. The panel determined that hand hygiene would be suitable as a process indicator for hospital accreditation and should be assessed against accreditation outcomes. The higher scores for research and proximity were critical in this consideration and provide both face and content validity for the tool . The panOur validated indicator assessment tool can be used to systematically identify process and outcome indicators in order to assess their suitability as indicators of accreditation performance in Australian hospitals . This st"} +{"text": "In recent work, Vogels and collaborators demonstrated the ability of spike-time dependent inhibitory plasticity to stabilise recurrent spiking neural networks by balancing out the excitatory input received by neurons in the network with the required amount of inhibition . FurtherIn other research, also related to homoeostasis in neuronal networks, Butz and colleagues investigated the rewiring of deafferentated neurons driven by homoeostatic structural plasticity ,3. TheirIn our research, we measure the memory capacity of balanced spiking neural networks possessing capabilities of both fast synaptic and slow structural plasticity by calculating a signal to noise ratio . The mem"} +{"text": "Traditional medicine, both codified and noncodified, has become a global movement with rapidly growing economic importance. In many Asian countries traditional medicine is widely used, even though Western medicine is often readily available. The number of visits to providers of traditional medicine in USA now exceeds by far the number of visits to primary care physicians. Many medicinal plant species are easily available in online trade, often without correct scientific identification and with possible contamination, which creates large safety concerns. In developing countries, uncodified traditional medicine is often the only accessible and affordable treatment available.The globalization of traditional remedies, in particular from noncodified pharmacopoeia, leaves many questions unanswered: does the use of traditional medicine reflect major health issues? Some plants may have beneficial properties, while others can cause adverse reactions. Even when the herbal ingredients themselves have proven benefits and no known safety concerns, some of the administration methods may be harmful. Importantly, how can safety concerns associated with traditional medicines and practices be identified, monitored, and communicated to users and other stakeholders, and how can the safety and sustainability of the global supply of medicinals be ensured?This first special issue on traditional medicine in a global environment contains 6 manuscripts covering different aspects of traditional medicine in a global setting.Of these 6 manuscripts, two address use and conservation issues of traditional medicine in Nepal and Northern India, two address the evaluation of the biological activities of medicinal plants and their efficacy in South Africa and China, one looks at potentially problematic compounds in one of the most widely sold supplements, and finally one explores the changes of traditional medicine use in Northern Peru during more than a decade of research.We hope that this collection of papers in this special issue will give our readers valuable insights into diverse areas of the subject.Rainer W. BussmannRainer W. BussmannWendy ApplequistWendy ApplequistNarel Paniagua-ZambranaNarel Paniagua-Zambrana"} +{"text": "Hand motor impairment persists after stroke. Sensory inputs may facilitate recovery of motor function. This pilot study tested the effectiveness of tactile sensory noise in improving hand motor function in chronic stroke survivors with tactile sensory deficits, using a repeated measures design. Sensory noise in the form of subthreshold, white noise, mechanical vibration was applied to the wrist skin during motor tasks. Hand dexterity assessed by the Nine Hole Peg Test and the Box and Block Test and pinch strength significantly improved when the sensory noise was turned on compared with when it was turned off in chronic stroke survivors. The subthreshold sensory noise to the wrist appears to induce improvements in hand motor function possibly via neuronal connections in the sensoriomotor cortex. The approach of applying concomitant, unperceivable mechanical vibration to the wrist during hand motor tasks is easily adoptable for clinic use as well as unsupervised home use. This pilot study suggests a potential for a wristband-type assistive device to complement hand rehabilitation for stroke survivors with sensorimotor deficit. Many strokes survivors suffer from persistent hand impairment with tactile sensory deficits were recruited for this study. Stroke survivors with a Semmes-Weinstein monofilament score >2.83 on either the thumb tip or the index fingertip were defined as having tactile sensory deficits attached to the volar and dorsal wrist of the paretic arm using adhesive tapes Figure . White nHand dexterity and pinch grip strength constituted the main outcome measures for the hand motor function. Hand manual dexterity was assessed using the Nine Hole Peg Test (NHPT) and the Box and Block Test (BBT) Figures A,B. ThesIn addition to the hand motor function, wrist motor function was assessed using the active range of motion (ROM), in case the increased motor output with the sensory noise to the wrist extends beyond the hand. The active ROM of the wrist was measured using a digital goniometer while the subject voluntarily and maximally flexed and extended their wrist. To replicate the previous finding of finger sensory enhancement with the vibrotactile noise to the wrist significantly affected the main outcome measures \u2013 the NHPT time, BBT score, and pinch grip strength. For the secondary analysis, three additional Kruskal\u2013Wallis tests were performed to examine the effect of noise on the grip force deviation, the wrist ROM and the monofilament score, separately. In addition, responsiveness of the individual main outcome measures to the noise intervention and correlations among the noise-induced changes in the three main outcome measures were examined using the standardized response means Cohen, and Speap\u2009=\u20090.037, Figure p\u2009>\u20090.05 for all three measures).Subthreshold vibrotactile noise to the wrist significantly improved stroke survivors\u2019 hand dexterity and strength (In this pilot study, remote sensory noise enhanced the hand motor function for chronic stroke survivors with tactile sensory deficits, as seen by improved NHPT, BBT, and maximum pinch grip strength with subthreshold vibrotactile noise applied to the wrist. Moderate responsiveness was observed for all three main outcome measures. These improvements support the hypothesis that remote sensory noise facilitates hand dexterity and strength. While facilitating dexterity and maximum pinch grip strength, the remote sensory noise did not appear to affect the active ROM of the wrist, suggesting that the wrist sensory noise influenced coordination and activation of muscles located within the hand, but not those of the forearm muscles. Such specificity may suggest involvement of direct connections between the somatosensory and motor cortices (Jones et al., Contrary to the previous study (Enders et al., A number of previous studies have also shown motor improvement immediately following application of sensory noise or sensory stimulation not only in healthy adults but also in stroke survivors with motor deficits (Priplata et al., The present study applied sensory noise simultaneously with targeted motor tasks to induce improvement in hand dexterity and strength. The use of noise during targeted motor tasks for instant effects differentiates this method from others that apply sensory stimulation for up to 2\u2009h at a time to prime the sensory system prior to targeted motor tasks (Tegenthoff et al., The present method used subthreshold sensory noise to induce improvement in hand dexterity and strength. It is different from other techniques that used suprathreshold sensory stimulation, sometimes strong enough to cause paresthesia (Conforto et al., White noise was used in the present study. As opposed to constant frequency stimulation, white noise may reduce sensory adaptation and enhance the effect of sensory stimulation (McDonnell and Abbott, The last unique feature of this study is that the sensory noise was applied to the wrist, with resulting improvements in hand dexterity and strength. Spreading effects of sensory manipulation have been shown in the past. For instance, subthreshold vibrotactile noise to the wrist resulted in improved touch sensation on the fingers in stroke survivors (Enders et al., The focus of stroke rehabilitation is to regain or improve function. For stroke survivors, improving function could mean an increased ability to perform activities of daily living. Manual dexterity has been shown to be indicative of functional independence. Noise-induced improvements seen in reliable measures such as the NHPT, BBT, and hand strength in this pilot study indicate the possibility of increased functional independence.The features of our approach enable the potentially easy adoption of subthreshold sensory noise for home or clinic use. Our approach applied an unperceivable, minute level of vibration to the wrist, concomitantly during targeted motor tasks, with instant effects on hand motor function. Simple mechanical vibration can be produced with low-cost devices and fewer safety concerns, compared with deafferentation via anesthesia, constant current electrical stimulation, or transcranial magnetic stimulation, which are not readily accessible and have greater safety risks. Unperceivable, minute vibration does not cause discomfort, pain, or paresthesia, and is thus more patient-friendly. Application of noise to the wrist, as opposed to the fingers (Liu et al., The improvements reported in this pilot study may be small, although they are statistically significant. These improvements were obtained instantaneously, and repeated use with therapy may result in greater clinical impact by allowing practices in sensorimotor integration and providing intensity needed for recovery Kwakkel, . In addiUse of this approach during therapy may be designed with consideration of possible sensory adaptation. Therapy with continuous noise longer than 15\u201320\u2009min may not yield additional benefits of using the noise to improve sensory perception. Thus a few minute break may be taken before continuing another round of therapy for 15\u201320\u2009min to recover from sensory adaptation (Berglund and Berglund, In this pilot study, hand dexterity and strength improved with subthreshold vibrotactile noise at the wrist in chronic stroke survivors with tactile sensory deficits. The noise-induced improvements in hand motor function may have been mediated by cortical interneuronal connections from the wrist somatosensory area to the finger motor area. The approach of applying concomitant, unperceivable mechanical vibration to the wrist during hand motor tasks is easily adoptable for clinic use as well as unsupervised home use. This pilot study suggests the potential for developing an assistive device worn at the wrist, applying subthreshold vibrotactile noise to enhance hand motor function. Such a device would be placed remotely from the fingers and palm so as not to interfere with object manipulation or dexterous hand function and to allow the hand to receive relevant tactile stimuli. Such an assistive device or sensory orthosis may complement hand rehabilitation for patients with stroke with sensorimotor deficit, and thus, lead to increased functional independence and enhanced quality of life.There is a pending patent for a wearable device for improving tactile sensitivity, involving use of the sensory noise, similarly with the present manuscript. Na Jin Seo and Leah R. Enders are listed as inventors of this pending patent."} +{"text": "This paper maps key research questions for humanitarian health ethics: the ethical dimensions of healthcare provision and public health activities during international responses to situations of humanitarian crisis. Development of this research agenda was initiated at the Humanitarian Health Ethics Forum (HHE Forum) convened in Hamilton, Canada in November 2012. The HHE Forum identified priority avenues for advancing policy and practice for ethics in humanitarian health action. The main topic areas examined were: experiences and perceptions of humanitarian health ethics; training and professional development initiatives for humanitarian health ethics; ethics support for humanitarian health workers; impact of policies and project structures on humanitarian health ethics; and theoretical frameworks and ethics lenses. Key research questions for each topic area are presented, as well as proposed strategies for advancing this research agenda. Pursuing the research agenda will help strengthen the ethical foundations of humanitarian health action. Every year armed conflicts, natural disasters, disease outbreaks, and extreme poverty have drastic consequences for millions of individuals across the globe.,,,,,,,A wide range of ethical questions is associated with the international response to humanitarian crises In November 2012, the Humanitarian Health Ethics Forum (HHE Forum) was convened in Hamilton, Ontario, Canada. The objectives of this small expert meeting were to establish a community of practice of researchers and practitioners interested in humanitarian health ethics, and to identify priority avenues for advancing policy and practice related to ethics in humanitarian health action. The 29 participants included experienced humanitarian practitioners and coordinators from Canada and Europe, headquarters staff of international NGOs, academic researchers, two health professionals from Indonesia (with experience of the 2004 Indian Ocean tsunami), and a member of the ethics department of an inter-governmental organization. The HHE Forum was funded through a grant from the Canadian Institutes of Health Research (CIHR).,,,,,,The HHE Forum focused on ethical issues arising in the delivery of healthcare and public health interventions during humanitarian crises, and considered how these issues are shaped by organizational structures and policies. Broader topics in ethics and humanitarianism, including accountability, complicity with others\u2019 wrongdoing, the use of imagery of suffering in fundraising, and the political economy of crises, were discussed and their importance acknowledged.In accordance with the meeting\u2019s goal of identifying priority avenues for advancing humanitarian health ethics, and through a series of presentations, breakout sessions and extended discussions, participants identified key topic areas in the ethics of humanitarian healthcare and public health interventions. Small groups were assigned the task of identifying priority issues (Table 1) and generating research questions for each topic.Detailed notes were taken in each group by designated rapporteurs. Following the HHE Forum, discussion summaries were written and circulated to participants. A preliminary version of the research agenda was then developed based on the detailed notes of each working group, and subsequently refined through exchanges among the HHE Forum organizers and participants. The scope and focus of the five main topic areas were refined through this process. In this article, we present the results of this consensus building exercise and identify priority lines of inquiry related to key topic areas (compiled below in Table 2).Humanitarian health work is undertaken in diverse settings, and includes many different actors. A better understanding of the experiences and perspectives of these groups and individuals is important to better inform efforts to improve methods of providing ethics support, ethics training, and normative analyses of situations that are sources of ethical struggle or uncertainty. The HHE Forum identified two priority areas of empirical inquiry connected to experiences of humanitarian health ethics.Humanitarian workers\u2019 experiences and perceptions of humanitarian health ethicsImproved understanding of the ethical commitments, expectations and motivations of health workers will provide insight into how these actors approach humanitarian health ethics and how these orientations shape their experiences of specific situations. Investigation might also be undertaken of dual loyalty dilemmas for humanitarian workers. In addition, targeted empirical investigation of ethical issues experienced by those who participate in specific areas of humanitarian health work could lead to more detailed understanding of key ethical issues for specific groups of humanitarian health workers (such as for disaster first responders) and would be useful for developing tailored training or support mechanisms. Empirical investigation of ethical issues encountered by national health professionals and non-professionals working with international organizations would be particularly valuable and contribute to a better understanding of the experiences of a group of humanitarian workers that has received less attention to date. Key research questions related to humanitarian workers' experiences include the following:What ethical commitments, motivations and expectations inform the actions and perspectives of humanitarian health workers?How do humanitarian health workers negotiate their commitments, motivations and expectations in relation to the values and commitments of the organization with which they are working?How are ethical issues experienced by particular groups of humanitarian health workers, including national staff of international organizations?Local community members\u2019 experiences and perceptions of humanitarian health ethics,,HHE Forum participants identified a particularly strong need for empirical research exploring humanitarian health ethics issues from the perspective of local community members. There is a tendency for humanitarian healthcare ethics discussions to be centered on experiences of expatriate humanitarian workers. Forum participants agreed that defining ethical practice in humanitarian healthcare is problematic if this qualification does not take into account values and perceptions of patients, national staff, or local communities. Exploring community perceptions of humanitarian healthcare can serve to sensitize humanitarian workers, including how humanitarian workers and agencies respond to or fail to respond to local needs, deliver care, allocate limited resources, and are generally perceived. Such investigations might provide insight for humanitarian workers related to the diverse expectations, concerns, or preferences related to humanitarian efforts that might exist between but also within populations. Such research is also important as it can alert humanitarian workers to factors facilitating or impeding the optimal delivery of humanitarian healthcare in a particular context,How are humanitarian health ethics issues experienced by local communities not affiliated with humanitarian agencies, such as patients, national health workers, local organizations, and the local public more generally?How might social differences, such as class, caste, gender, religion, and other forms of social identity affect local perceptions and experiences of humanitarian healthcare?How can better understanding of the experiences and perceptions of local communities serve to inform and improve humanitarian health ethics?How should ethics guidance for humanitarian health work be responsive to and account for perceptions of humanitarian health ethics in communities where humanitarian projects are implemented?Being adequately prepared has been asserted as a duty for clinicians taking part in humanitarian relief efforts: to \u201cfirst, be prepared\u201d.,,,Questions about how best to prepare humanitarian workers are thus now being raised, alongside debates regarding the merits of increased professionalization of the humanitarian sector Pre-departure trainingAn important venue for ethics training is pre-departure courses. However, there is a paucity of evidence regarding what formats (e.g. a separate ethics module or ethics as a cross-cutting theme), teaching approaches and content are most effective. These courses are often carried out over short periods (from a few days to a few weeks) in residential settings, and they are typically replete with information on many topics. Given the scope and breadth of content to be included in such training, a deliberate strategy for incorporating ethics content is needed to optimize ethics learning. Topics covered should include a review of relevant sources of ethics guidance and of the processes of ethics deliberation. Training should also be tailored to highlight the types of ethical challenges more likely to be encountered by the participants, for example examining triage decision-making for those embarking on acute relief projects.Ethics training is also an opportunity for participants to examine their expectations and motivations for participating in humanitarian work Which curricular components should be considered essential, and which ones optional, for inclusion in ethics pre-departure training?What are the most effective formats for including ethics in pre-departure training?How best can creative or innovative pedagogical approaches and tools be incorporated into ethics pre-departure training?How can training be tailored to the needs, organizational structures and cultures of particular organizations?What is the impact of pre-departure ethics training on how humanitarian workers approach decision-making, demonstrate resiliency, and experience moral distress?Professional development and continuing educationPre-departure training is not the only opportunity for education in humanitarian health ethics. Professional development and continuing education in the humanitarian sphere, such as summer schools and humanitarian training courses, are particularly important avenues for expanding ethics knowledge and related skills for humanitarian health workers. These courses may be offered by humanitarian organizations, by independent training programs, or affiliated with academic institutions. Finally, online training focusing on or incorporating humanitarian health ethics also provides an opportunity for self-guided learning. Incorporating ethics content in professional development initiatives is associated with the following questions:What are the most pressing needs for professional development related to humanitarian health ethics?What professional development modalities and approaches are most effective for preparing practitioners for humanitarian health ethics?What are the impacts of increased professionalization for the ethics of humanitarian health work?Individuals who contribute to health-related humanitarian projects \u2013 be they national or expatriate clinicians, coordinators, logisticians, or others \u2013 are likely to encounter ethical issues as they provide assistance to individuals and communities affected by crises. In response, humanitarian agencies and local teams adopt different approaches to addressing ethical issues both during humanitarian projects and in post-mission debriefings.Ethics support within field projectsDifferent strategies have been implemented or proposed to support humanitarian workers as they respond to ethical issues in local project settings.Local project teams may also create \u201cmoral spaces\u201d What are the most effective strategies to provide ethics support during different types of field projects?How do different models of in-field support influence the process, experience and outcomes of ethical decision-making?How can international and intercultural teams best work together to provide ethics support during humanitarian health work?Ethics decision-making support toolsWhen faced with an ethical dilemma, field teams might derive benefit from ethics analysis tools that are designed to help structure deliberation and support comprehensive and rational decision-making. Current tools specific to humanitarianism include the Humanitarian Healthcare Ethics Analysis Tool (HHEAT) How effective are existing ethics tools in achieving their assigned objectives when used in humanitarian health work?How can ethics tools be validated and improved through field testing and other evaluative methods?Is there a need for additional ethics tools to be developed, and if so, what should be their focus?Guidance and support from outside local projectsIn some instances field teams identify the need for input from outside their immediate project. In such cases, local teams often seek advice from experienced colleagues at national or international headquarters. With expanded global communications, such forms of assistance may be available across large distances, including for ethically challenging situations.During the HHE Forum some experienced humanitarian practitioners questioned whether having the opportunity to consult individuals with particular expertise in ethics would be beneficial for field teams and, if so, under what conditions. It is unclear what sort of model or approach for accessing an ethics resource person would be most feasible or useful, however, which raises the following question:What are effective models of accessing and providing ethics guidance from outside local projects during humanitarian health work, including from experienced humanitarian practitioners and experts in humanitarian health ethics?Moral distressNational and expatriate humanitarian health workers frequently work in high intensity and very stressful situations.What is the relationship between moral distress and psychological stress in humanitarian health work?What is the extent and impact of moral distress in the humanitarian field?What are the sources or triggers of moral distress in humanitarian health work?How can organizations best support field workers experiencing moral distress, including through peer support or post-mission debriefing?In which ways might moral distress be positively channeled, such as through advocacy and solidarity efforts?Ethical challenges in humanitarian health work arise in the context of field projects. These challenges are shaped in turn by a range of features including social, cultural and political dimensions of the crisis situation, as well as organizational structures and policies. How organizational policies and the design and implementation of local projects function as sources of ethical challenges, or function to either alleviate or augment ethical issues, are important yet complex areas of inquiry for humanitarian health ethics. Decisions related to the selection, initiation and ending of field projects raise a particularly thorny set of ethical questions for decision-makers, those affected by the decisions, and those who implement them.Organizational policies,The policies instituted by humanitarian organizations have an important influence on the ethics of humanitarian health work. Policies may function to increase or decrease ethical uncertainty or ethical challenges. Investigation of the impact of organizational policies on humanitarian health ethics is needed to better understand these dynamics, and how they unfold in field projects. A wide range of organizational policies might function to augment or alleviate ethical issues. Three sets of policies were underlined in discussions at the HHE Forum for further examination: 1) policies related to the differential roles, responsibilities and protections for national and expatriate staff Which policies of humanitarian organizations are perceived to alleviate or exacerbate ethical issues in local field projects?What processes support the development of ethically sound policies that are responsive to the realities of field projects?How can field staff draw their organization\u2019s attention to ethical issues in the field and contribute to improving the organization\u2019s policies?Opening and closing field projectsDecisions around where to establish projects, and when and how to end them, raise a unique set of considerations related to distributive justice.Implementing a decision to end a project is especially difficult.How can humanitarian organizations develop ethically robust approaches for funding and initiating local projects?What ethical issues are associated with closing field projects, and what would constitute an ethically robust exit strategy in various contexts?How ought the obligations of organizations be conceived where withdrawal from a project is contingent upon the actions of other actors?Debate around normative and legal bases of humanitarian action has a long history.While the ethics of humanitarianism have historically been conceived in deontological terms focusing on moral duties or obligations, consequentialist approaches focusing on outcomes are an increasingly common ethical frame for humanitarian action.Clinical and public health ethics,,In current academic discourse and in health professional training in many countries, clinical ethics and public health ethics are prominent models for engaging ethical questions related to health. While clinical ethics remains dominant, public health ethics and global health ethics are expanding fields of scholarship.When and how should clinical ethics and public health ethics be utilized to help resolve ethical dilemmas in humanitarian health work, and (how) can these approaches engage with each other?How can guidance derived from clinical or public health ethics be related to models of humanitarian ethics ?Does \u2018humanitarian health ethics\u2019 need to be articulated in greater detail as a distinct approach or are existing models sufficient?Culture, asymmetries, and humanitarian health ethicsHumanitarian action is an international and trans-cultural sphere of activity. Yet organizations and individuals originating from countries in the Global North largely dominate its decision-making and agenda-setting.What are the implications of the international, cross-cultural and asymmetrical nature of humanitarian health work in terms of how ethical issues are understood and addressed?Other contributions to ethics guidanceIn light of the challenges of implementing prominent health ethics models in the context of humanitarian health work, it is possible that efforts to rearticulate or reframe ethical values or principles for the particular context of humanitarian health work would be beneficial, especially in non-ideal moral contexts that defy easy delineations of right and wrong.Other ethical theories, many of which already inform clinical and public health ethics, could also inform humanitarian health ethics.Contributions and resources from institutional ethics and health policy ethics are also relevant to issues of humanitarian organizational structures and governance.Analyses of normative foundations should also examine links between humanitarian health ethics and the legitimacy of humanitarian action, witnessing and human rights, the management of conflicts between local legal standards and ethical commitments of humanitarians, and accountability towards beneficiaries. Key questions related to these considerations are the following:What are additional ethics lenses and sources of normative guidance that can enhance and enlarge ethical analysis in humanitarian health ethics?How do the normative foundations of humanitarian health ethics relate to concepts such as legitimacy, accountability, and human rights?Questions are not lacking to animate further research on humanitarian health ethics. Researchers with diverse backgrounds and methodological expertise will be needed to develop this field of inquiry. Moving the humanitarian health ethics research agenda forward will be facilitated by interlinking research strategies and both empirical and conceptual approaches to inquiry.One strategy to advance this agenda is to build upon existing knowledge and expertise in related domains, and establish bridges between ethics inquiry in humanitarian health work to other domains of practice and research fields. A second strategy is to establish interdisciplinary and intersectoral collaborations to examine humanitarian health ethics. Ideally, these collaborative activities will include more than cooperation across academic disciplines, but also partnerships between aid agencies and academics, and between researchers and field workers from across different regions of the world. Such collaboration will enable humanitarian health ethics to draw upon diverse sets of knowledge and experience.http://disasterbioethics.eu). Humanitarian health ethics research may also be advanced alongside ongoing efforts to promote learning, innovation and knowledge generation in the humanitarian field such as ELHRA (www.elrha.org), EvidenceAid (www.evidenceaid.org) and the Humanitarian Innovation Fund (www.humanitarianinnovation.org).The HHE Forum led to an initiative that aims to advance discussion, debate and research relating to humanitarian health ethics.An example of a new initiative to advance research related to ethics and disaster response is the European COST Action on Disaster Bioethics that was launched in 2012 , was launched by participants from the HHE Forum with the goal of creating a community of practice amongst individuals interested in humanitarian health ethics. HumEthNet is an open network that invites participation from researchers, practitioners, organizational representatives, and policy-makers from around the world. It seeks to generate interdisciplinary knowledge, experience and resources to support and clarify ethical practice in humanitarian health work. One of its objectives is to promote engaged and critical analysis of humanitarian health ethics.The Humanitarian Health Ethics Network, or HumEthNet (While there has been increased discussion of humanitarian health ethics within and among humanitarian agencies, intergovernmental organizations, and the academy, participants at the HHE Forum identified five main areas of inquiry that would benefit from careful and sustained analysis. First, there has been limited investigation of experiences related to humanitarian health ethics from the perspective of various groups, including those of members of host communities. Second, there is uncertainty about the most effective means to provide ethics training and professional development for those involved in humanitarian health work. Third, strategies and resources to provide ethics support during field projects would benefit from innovation, validation and refinement. The ethical implications of project planning and the development of policies within humanitarian organizations represent a fourth area of inquiry. Finally, normative and theoretical lenses to examine humanitarian health action remain underdeveloped. A set of important research questions is associated with each of these five topic areas. Together, these research questions constitute a research agenda for humanitarian health ethics. We encourage researchers and their institutional partners to engage with these questions. Doing so is an essential step towards strengthening the ethical grounding of humanitarian health practice and policy."} +{"text": "Hepatocellular carcinoma (HCC) is a common cancer all over the world. It demonstrates a tendency for vascular invasion, producing extensive intrahepatic metastases and portal vein or inferior vena cava extension. Tumor spread of abdominal diseases via hepatic ligaments has also been reported. The author reports a rare case of HCC invading the anterior abdominal wall muscles and protruding into the subcutaneous fat. Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and the third leading cause of cancer related death , 2. Cirr32 year old gentleman was known to have Hepatitis B virus presented to our institution complaining of right upper quadrant pain, distension, jaundice and vomiting. Laboratory findings shows mildly elevated ALT/AST and highly elevated alpha fetoprotein levels reaching 1518 ng/ml.CT scan was performed and showed a large mass in the left hepatic lobe with area of central necrosis demonstrating peripheral isodensity to the liver and invading the greater momentum with mulUltrasound guided biopsy of the liver lesion was performed and the patient developed sudden drop of hemoglobin following the procedure. CT scan performed and showed interval development of intralesional hemorrhage. After discussing the plan of palliative management with the patient, he refused to start chemotherapy and decide to be discharged against medical advise.HCC is responsible for about 1 million deaths annually worldwide. The difficulty in treatment of this cancer and the reason for high mortality is the association of this cancer with cirrhosis which limits both the treatment options and increases morbidity of any modality of treatment. HCC is usually asymptomatic at early stages and has a great propensity for intravascular invasion even when the tumor is small; hence HCC is usually at an advanced stage when discovered. The most common sites of metastases of HCC include lung, peritoneum and lymph nodes. In a study by Katyal et al., tabulation of all extra hepatic metastatic sites showed the most common sites to be the lung in 81 (55%) patients, abdominal lymph nodes in 60 (41%) patients, and bone in 41 (28%) patients . Rare siHCC is a highly malignant tumor that can invade and metastasize to almost any organ in the body. Therefore unusual areas of metastases should not disclose the radiologist from calling it as metastasis. Although tissue biopsy is needed in unusual cases."} +{"text": "Stem cells, the architect of all the structural and functional units of our body, are the utmost hope for many incurable diseases like diabetes, cardiac disease, Parkinson's, Alzheimer's, and other neurodegenerative diseases and injury related trauma. These cells depending upon their nature of origin can differentiate into many or specific kind of mature cell type to rebuild the tissue. Stem cells are present at various stages of life . Adult stem cells have the most potential and are the safest for therapeutic utilization. Stem cell therapy is extensively used in clinic for curing hematological malignancies. However, for many other dreadful life threatening diseases, stem cell therapy is still in experimental phase and requires major effort to bring them into clinical practice.For any disease condition, there are two possible approaches to treatment. Treatment approaches that alleviate or suppress the disease condition are the most widespread available options for majority of diseases. This type of treatment is often applied in the form of drugs with or without surgical intervention. The second type of treatment approach reverts the pathogenic situation to normal or original state. This second option is rare, applicable to few of the diseases where drugs cannot mend the situation and are not able to restore or regenerate the normal function of the damaged tissue or organ. Regenerative remedies are commonly applied throughFor the last few months, we have been busy reviewing various articles sent by renowned scientists across the world for our special issue on \u201cApplication of Adult Stem Cells in Medicine.\u201d After stringent reviews, ten articles have been selected that cover many critical aspects of stem cell therapy. They include reviews focusing on success of stem cell therapy in various diseases and original research and articles related to improvement in various aspects of stem cell therapy. in vivo studies on adipose derived mesenchymal stem cells for the treatment of articular cartilage defect. However, C. Bauge and K. Boumediene have reviewed the current status and future developments of adult stem cell therapy towards cartilage tissue engineering. Both of these papers have elucidated the promises and limitations of stem cell transplantation for cartilage defect. Readers will be aware of the major development and the specific future focus happening in this field.Cartilage defects and/or degeneration resulting from injury, aging, and osteoarthritis are a major cause of joint pain and disability that seriously affect quality of life. Unfortunately current surgical or pharmacological treatments can only help in temporary relief and delay in disease progression. In recent years, new strategies have been devised to repair the damaged cartilage using adult stem cells. This pressing issue of regenerating cartilage using stem cells has been elaborated by two papers in this issue. F. Perdisa et al. have discussed all recentIntracerebral hemorrhage (ICH) caused by sudden increase in blood pressure is not as common as ischemic stroke but is more serious and quickly causes brain and nerve damage. Depending on the location of hemorrhage and amount of injury long term treatments including physical, speech, and occupational therapy are applied but majority survive with some kind of permanent disability. In recent years, stem cell transplantation as well as cell engineering has shown promising results for various neurological diseases and regeneration of injured nerves. Application of such therapies is rare in patients suffering from ICH. J. Zhu et al., in this issue, discussed their findings on autologous bone marrow stromal cell transplantation for treating 206 patients suffering from ICH. This clinical study assessed the safety profile, feasibility, and effectiveness of surgery combined with autologous BMSC transplantation for treating ICH. Though they were unable to assess the differentiation ability of BMSC into neuronal cells and could not pursue long term followup, their study indisputably showed encouraging clinical outcome. In another review by V. Sabapathy et al., the potential of various cell therapy strategies for treating spinal cord injury has been discussed in detail with an emphasis on source of cells and appropriate preclinical models. This review highlights the insufficient data and research involved in spinal cord injury and calls for more complete and multicentric clinical trials.Probably the most demanding area for stem cell application is the incurable neurodegenerative disorders such as Alzheimer's disease, Parkinson disease, and Huntington disease. Though etiology and symptoms of these diseases are well characterized, the underlying mechanism is yet to be understood. Therefore current treatments majorly aim towards delaying progression of the disease. Lack of appropriate animal models simulating the human pathogenesis also demands development of human disease-specific models to identify new drugs. Induced pluripotent stem cells or iPSCs have revolutionized the field of regenerative medicine and are now being utilized as models for neurodegenerative disorders to understand the biology of pathogenesis and screen novel therapeutics. Recent advancements in this newly emerging area are described in detail by W. Wan et al. in this special issue. Their manuscript presents a comprehensive review on application of iPSC in various neurodegenerative diseases narrating the promises and concerned issues. in vitro Strontium treatment of hADSCs enhances cell proliferation and osteogenic differentiation through expression of early and late osteoblastic biomarkers such as ALP and HA, respectively. Their findings clearly support the use of Strontium in in vitro induction of bone regeneration.A major thrust in stem cell research is to experiment new approaches for efficient and lineage specific differentiation of stem cells. In this special issue, three independent investigations highlight the importance of such trials for various diseases. Oliviera et al. demonstrated that priming of MSCs with endothelial growth medium improves therapeutic efficacy in the treatment of systemic arterial hypertension in a rat model. Enhanced differentiation of neuronal stem cells by Oleanolic Acid (OA) was evaluated by Y. Ning et al., who found that Nkx-2.5 transcription factor partially regulates this differentiation process. Similarly, V. Nardone et al. showed thatThe placenta, amniotic fluid, and umbilical cord are known to be rich source for neonatal MSCs. Cryopreservation of umbilical cord immediately after birth has already been commercial practice to tackle future life threatening diseases. However, such practice must be dealt with care and properly designed expreiments as discussed by O. Maslova et al. in their review.Last but not the least, S. Kumar et al. investigated an important aspect required for final acceptance of stem cells in clinic by repetitive and noninvasive tracking of ICG labeled human placental derived MSC transplanted in live mouse.Altogether, this special issue compiles a wide range of information on experimental and translational application of adult stem cell in regenerative medicine. We hope that contributions will generate new thoughts to readers of this journal."} +{"text": "Migraine headache represents a frequent reason for neurological evaluation in developmental age. Many studies in the last decades have been focused on the role of psychopathological profiles among migraineur children. On the other hand, conflicting results have been reported about the different psychopathological profiles among subjects affected by migraine.The role of psychopathological aspects on clinical findings among children may be relevant particularly for severity and frequency of attacks.A recent review showed the higher prevalence in migraine children of psychological symptoms, detected by using the Child Behavior Checklist (CBCL), than healthy controls.Moreover, clinical and population-based studies suggest that children with migraine are more likely to have internalizing symptoms , as well as psychological comorbidities.Nevertheless it is still a matter of controversy whether children with migraine have specific psychological vulnerabilities or if they only cope differently with stressful situations. In 2015 Arruda et al reported that children with migraine are more likely to present emotional symptoms, conduct problems, hyperactivity, peer problems, and total difficulties in psychosocial adjustment stressing the role of psychological adjustment styles as predisposing factors for developing psychopathological troubles among migraine children[In this perspective we could speculate that the psychopathological profile of migraine children could be influenced by environmental or familiar elements such as, by specific psychological vulnerabilities of migraine children.In this light, some studies pinpointed the role of parenting styles effects on migraine severity and frequency in children, related to parental stress levels, while a preliminary study indicated the potential value of maternal personality assessment for better comprehension and clinical management of children affected by migraine, 4.According to the analysis of specific psychopathological vulnerabilities in migraine children, a higher prevalence among migraineur children of the avoidant attachment style (type A) and the significantly lower prevalence of the secure style attachment (type B) than controls was found. Moreove"} +{"text": "Emergency departments are the leading providers of unscheduled care with over 85% of patients discharged home after their visit. Discharge communication with parents has been shown to vary across setting and illness presentation. Emergency practice environments are chaotic by nature and characterized by multiple interruptions. The primary goal of this synthesis project was to understand how and why discharge instructions worked under different conditions.We conducted a narrative review of the policy and empirical literature to examine how and why discharge instructions worked under different conditions in the context of pediatric emergency care. Three stakeholder groups were actively engaged with the research team during each step of the synthesis process. We collected data on the types of interventions and implementation strategies used in the included studies. We developed a preliminary synthesis using textual descriptions, tabulation and content analysis. We used a taxonomy of behaviour change techniques as a guiding framework to link behaviour change techniques described in the interventions with the relevant theory.Email survey of 15 Canadian tertiary care centres failed to identify any existing policies guiding discharge communication in pediatric emergency departments. Following duplicate screening of 4690 abstracts from EMBASE, PubMed and CINAHL and hand searching of 5 major journals, we included 68 studies in the final synthesis. Less than half of included studies (n=30) involved experimental or quasi experimental designs. The majority of interventions were educational strategies targeting parents of children with different illness presentations. Most studies were also carried out in larger urban paediatric emergency departments. The authors identified a range of factors influencing implementation of the interventions including duration of the educational intervention, timing of delivery in the emergency department visit, the mode of delivery, and illness acuity of the child.Improving discharge communication for parents and children in an emergency practice setting presents a significant opportunity for increasing adherence to treatment plans and improving health outcomes for children. Knowledge users agree there is an urgent need to address this important policy and practice gap. To date the majority of strategies to improve discharge communication have been educational strategies targeting parents. However, findings from this review have identified a number of barriers that would suggest the need for investigating other types of intervention strategies."} +{"text": "Parkinson\u2019s disease (PD) is a neurodegenerative disease characterized by the loss of midbrain dopamine (mDA) neurons. Clinical trials using human embryonic midbrain tissue for transplantation have provided proof of concept that cell replacement therapy (CRT) can lead to not only symptomatic relief, but also changes in the course of disease and withdrawal of medication. Human pluripotent stem cells are currently regarded as the main candidate cell type for CRT because they are readily available, expandable, and can be standardized and differentiated into mDA neurons capable of inducing functional recovery in animal models of PD. However, protocols for mDA differentiation are still far from optimal and require further improvement. We previously found that members of the Wnt family of morphogens regulate multiple aspects of mDA neuron development . Differe"} +{"text": "Thousands of pollutants enter daily into environment and exert various kinds of stress on organisms and ecosystems. Risk assessment of these pollutants to organisms and ecosystems is challenging because of diversities in chemical nature and mode of toxicity of the pollutants as well as variation in sensitivities of the organisms exposed to the pollutants. Even low, relatively innocuous concentrations of pollutants often produce deleterious effects on organisms, which are difficult to be predicted, because measurable effects are expressed only after prolonged exposure. But it may be too late to take remedial actions or steps to reduce risk when these incipient effects are expressed. Therefore, it is necessary to develop early warning signals or biomarkers that convincingly reflect adverse biological responses towards anthropogenic environmental toxins even at minute concentrations . A biomaThis special issue on biomarkers of environmental pollutants contains ten papers, which discussed some recent applications of biomarkers in terrestrial and aquatic environment. A few papers deal with a single sensitive biomarker, while others deal with combinations of selected biomarkers. The papers have been categorized under three main groups.Biomarkers of Susceptibility/Oxidative Biomarkers. Two papers have been published in this category. One paper deals with perfluorooctanoic acid (PFOA), which is widely present in the environment. Oxidative stress induced by PFOA on mice was evaluated by malondialdehyde (MDA) formation and hydrogen peroxide generation, which were considered as reliable biomarkers of anthropogenic stresses on mice. The second paper in this category also deals with MDA. Elevation in MDA associated with depletion in antioxidant enzymes activities in the tissues was measured in liver and kidney of female rats exposed to lead acetate. The authors observed that Omega-3 polyunsaturated fatty acid provided a protection against lead acetate toxicity in rats.Biomarkers of Exposure. Four papers have been published in this category. In one paper the authors established that deposition of mercury in hair served as an excellent biomarker of exposure of human population to mercury. In another paper differences in whole blood versus tibia lead concentrations over time in growing rats were evaluated prenatally and higher amount of lead found in the bone of older animals reinforced the importance of using bone lead as an exposure biomarker. In the third paper it was established that coelomic fluid instead of whole earthworm could be used to identify ecologically relevant end points. Induction of metallothionein in the coelomic fluid of earthworms served as sensitive biomarkers of heavy metal pollution in soil. The fourth paper discussed application of multiple biomarkers to assess risk of corals. Several biomarkers enzymes involved in melanin synthesis pathway (phenoloxidase (PO) and peroxidases (POD)) and free radical scavenging enzymes (super oxide dismutase (SOD), catalase (CAT)) and glutathione peroxidase (Gpx) were determined in selected scleractinian corals to evaluate stress induced by coral pathogen and to predict health and future existence of corals.Biomarkers of DNA Damage. Two papers have been published in this category. One deals with effects of contaminants on DNA damages of Zebra Mussels Dreissena polymorpha evaluated by Comet assay and micronucleus test (MNT) and another on DNA damage and telomerase activity in exfoliated urinary cells of human workers of rubber tire industry evaluated by Comet assay and quantitative telomerase repeat amplification protocol (TRAP) and fluorescence in situ hybridization (FISH) assay. MNT appeared as better tool than Comet assay in Zebra mussel while TRAP, Comet, and FISH assays worked well as early biomarkers of procarcinogenic effects on rubber factory workers.Reviews on Biomarkers. Two review papers have been published. One review paper discussed variations in the expression levels of heat shock protein (HSP) under a variety of toxic conditions. The paper discussed current knowledge on expression of HSPs and concluded that HSP was unreliable as biomarker due to synergistic effects of toxicants and other environmental factors. Another review paper deals with biomarkers of type-II synthetic pyrethroid pesticides. Applications of hematological, enzymatic, cytological, genetic, omic, and other types of biomarkers to evaluate toxicity of the major type-II pyrethroid pesticides in freshwater fish species have been documented. The papers discussed the present status of researches on type-II pyrethroids and the possible future directions.It is concluded that till today oxidative biomarkers are the most frequently used category of biomarkers to assess adverse effects of a wide variety of pollutants. In the quest to develop more specific biomarkers researchers are concentrating on emerging areas with metabolomics and proteomics forming the frontier area of biomarker research. These trends are being facilitated by the development of increasingly precise and sensitive instrumentation in recent years.Anilava\u2009\u2009KavirajErhan\u2009\u2009UnluAbhik\u2009\u2009GuptaAhmed\u2009\u2009El\u2009\u2009Nemr"} +{"text": "The need for an appropriate flap cover to protect vital structures, restore and preserve function and aesthetics of the hand following tissue loss remains a challenge to the reconstructive hand surgeon. Following the description of the angiosome concept by Taylor and Palmer and the pioneering work of authors such as Koshima & Soeda, Kroll, and Rosenfield, in the late 1980s, the perforator flap technique has moved to the centre stage in reconstructive flap surgery.A literature review of the \u2018named\u2019 perforator flaps which have been used in the hand and published in peer reviewed English literature using keywords in the title and abstract in MEDLINE served as the framework for this presentation. A further review of the references in the core articles for other perforator based flaps was also done. Clinical examples of the indications, pedicle peculiarities, ideal recipient sites and specific donor site problems of some of the workhorse perforator flaps from my personal experience are also presented.There were fifty core articles with \u2018named\u2019 perforator flaps. Despite the attempts to achieve a standardized nomenclature for these flaps , it is clear that the terminology is lacking in universal applicability or acceptance making communication and comparison of literature on \u2018perforator\u2019 flaps difficult.Pre-operative planning involves mostly a good knowledge of the anatomy and the use of the Doppler probe and occasionally imaging investigations such as duplex ultrasound, MRI and other modalities. Once the perforator is identified, the flap design and movement is based on traditional principles of plastic surgery such as rotation, transposition, V-Y flaps, pedicled, free, ad hoc or freestyle. But the conventional flap design rules of length and width ratios do not apply .The \u2018named\u2019 perforator flaps can be grouped into local (harvested from the hand itself), regional (from the upper limb excluding the hand) and distant (from the rest of the body); in other words, based on the distance of the donor site from the recipient site (the hand being the reference point). Examples (with glabrous and non glabrous subgroups) are as follows:Reverse thenar perforator, (Seyhan 2009) reverse palmar perforator flap, palmar perforator , superficial palmar branch of radial artery flap (SUPBRA) , ulnar palmar digital artery perforator , digital artery perforator flaps and palmar intermetacarpal perforator flap .Dorsal hand or metacarpal artery perforator flap (Quaba and Davison 1990), dorsal digital artery perforator flap (Kawatsu and Ishikawa 2009) and V-Y flaps based on the perforator concept (Iwuagwu and Misra 2007).Distal forearm perforator flap ; distal Ulnar artery perforator flap ; proximal ulnar artery perforator ; the dorsoradial forearm perforator flap based on perforators either from the posterior interesseous artery or interesseous recurrent artery or the common interesseous artery or the descending branch of the radial recurrent artery .Anterior trunk -- Pectoral intercostal cutaneous perforator flap , deep inferior epigastric perforator flap (DIEP), posterior trunk - circumflex scapular artery perforator flap , lattismus dorsal artery perforator flap (Lin and Chen 2014).Thighs/groin \u2013 . lateral circumflex femoral artery perforator flap (LCFA), superficial circumflex iliac artery perforator flap .Lower leg -- posterior tibial artery perforator flap (PTP) Zhao et al 2011; medial sural artery perforator flap (SAP) , soleus perforator flap and peroneal perforator flap .Foot - medialis pedis perforator , medial plantar artery perforator flaps .Donor site closure ranged from direct closure to skin grafting and occasionally closure by means of another flap.There were very contrasting views of donor site morbidity with most authors subjectively judging the morbidity of the donor site for their chosen flap to be minor or acceptable as opposed to the donor sites of other flaps.The increased appreciation of the perforator concept in reconstructive hand surgery has enabled surgeons to harvest flaps of sufficient size or \u2018tailor made size\u2019 that are much thinner and pliable than would have been feasible with reduced donor site morbidity and very importantly avoiding the sacrifice of major blood vessels. A grater precision of insetting of the flaps is possible, further reducing the need for secondary procedures.For regional and distant perforator flaps, the ability to isolate and define the \u2018final pathway\u2019 of blood supply to the skin has enabled accurate placement of expanders and recruitment of more skin safely with less donor site morbidity , safe and radical thinning of flaps making them more pliable Gao et al 1994, Oki et al 2009, Liu et al 2010), intra adipose dissection of the perforator with recruitment of greater length of pedicle and lends well to raising multiple perforator flaps or composite flaps for correction of different tissue defects in one stage (Meky and Safoury 2013).The local perforator flaps have added advantage that they provide \u2018like for like\u2019 tissue in colour, texture and resilience, one site operation, early and one site rehabilitation of the hand but suffer from limited availability.Excellent microsurgical skills are necessary for surgery of free perforator flaps especially the smaller ones utilised on the digits.As the functional donor site morbidity has been reduced by this technique, hand surgeons have to be more conscious of the aesthetic morbidity of using certain donor sites in the long term. The versatility and the gains with this concept have made perforator flaps a welcome addition to the reconstructive armory of the hand surgeon."} +{"text": "Policy measures for preventive and promotive services are increasingly reliant on contracting of NGOs. Contracting is a neo-liberal response relying on open market competition for service delivery tenders. In contracting of health services a common assumption is a monolithic NGO market. A case study of HIV control in Pakistan shows that in reality the NGO market comprises of parallel NGO networks having widely different service packages, approaches and agendas. These parallel networks had evolved over time due to vertical policy agendas. Contracting of NGOs for provision of HIV services was faced with uneven capacities and turf rivalries across both NGO networks. At the same time contracting helped NGO providers belonging to different clusters to move towards standardized service delivery for HIV prevention. Market based measures such as contracting need to be accompanied with wider policy and system measures that overcome silos in NGO working by facilitating a common construct on the health issue, cohesive priorities and integrated working. There has been an increased emphasis on contracting of Non-Governmental Organizations (NGOs) for service delivery in recent years . ContracPakistan is a country with less than 1 per cent prevalence of HIV but at high risk of spread . InfectiThere were as many as 350 local NGOs registered to be involved in HIV prevention with HIV NGOs were mostly formed during the mid-1990s and comprised of small NGOs from diverse backgrounds. In the absence of a clear ideology or strategic direction, these were best known for their identification with the HIV issue or identification with a particular high-risk group. These worked in discrete localities with an identified risk group using indigenous sources of funding. Organizationally, the majority of the HIV NGOs were under-developed; ranging from one person led outfits to small and at best medium scale organizations having a staff of 5-10 persons . Many laThe RH NGOs had evolved during the 1980s and 1990s as Reproductive Health incrementally received policy recognition and replaced older agendas of population control and primary health care (PHC) implementation. These included some of the most developed and dominant NGOs in the public health sector and drew ideological identification mainly from the ICPD 1994 with a focus on women's health and integrated service provision. RH NGOs comprised of large to medium sized organizations (some even having a countrywide infrastructure), were headed by many of the local, leading public health experts and were usually internationally funded. RH NGOs were experienced in program management, had well developed work organograms, offices and services infrastructure. Of the RH NGOs, five provided HIV prevention services through counseling and condom promotion and another two were involved in sexual health advocacy, which included HIV, amongst other issues.Both types of organizations had largely separate clientele and this shaped the type of services provided. The HIV NGOs were involved with a specialized clientele at higher risk of HIV infection that comprised of FSWs, IDUs, transvestites, distance truckers, cross-border traders and prisoners. Activities in the general population were few and targeted the youth and community stakeholders such as police personnel and religious leaders, rather than married women. Activities mainly related to awareness raising on World AIDS Day walks, awareness seminars, organization of medical camps for HIV awareness or small scaled screening projects in risk groups or provision of charitable services amongst quasi-legal groups and people living with AIDS. InvolvemThe RH NGOs, in contrast, were positioned towards married females in the general population. These NGOs faced little demand from their predominantly married female clients for sexually transmitted illnesses (STI) or HIV prevention services. HIV services provided by RH NGOs mostly consisted of awareness provision and at most stretched to screening and counseling rather than the full range of behavior change communication, STI treatment, care, support and empowerment services recommended by UN as part of HIV prevention . At leasSeparate NGO networks existed for HIV NGOs and RH NGOs. The HIV focused NGOs participated in the HIV NGO consortia initiated by UNAIDS in 1999 which served as a platform for informal interaction between NGOs and provincial AIDS Control Programs. This was a registered and active forum where HIV focused NGOs exchanged information, learnt about new programmatic initiatives and at times, formed collaborative linkages. On a parallel footing, RH NGOs participated in a number of overlapping networks including the Pakistan Reproductive Health Network, women's rights networks and the Population Association of Pakistan. These have ideologically underpinnings of women's empowerment and right to sexual health as provided for in the International Conference on Population and Development (ICPD) 1994 and the Fourth World Conference on Women (FWCW) in Beijing 1995.There were also essential differences in stakeholder interaction with government and development partners. For HIV focused NGOs, the NACP provided the major government interface while UNAIDS constituted the major international resource body. Dealings of HIV NGOs followed the vertical orientation of the NACP and had little involvement with mainstream public health infrastructure where HIV has yet to be integrated with other services. Conversely, the RH NGOs being involved with mainstream RH and PHC services liaised with a number of different entities including the Ministry of Population Welfare, Ministry of Health, WHO, UNICEF and UNFPA. They had at best occasional interaction with the separate policy network of the HIV actors.In 2003 an aggressive national HIV control response was initiated with international donor support and relied extensively on NGO involvement for HIV control. Promising local NGOs were contracted to provide HIV prevention services in high-risk groups such as IDUs, MSWs, FSWs, jail inmates, and borderline groups such as long distance truckers and youth.Nearly all NGOs active in HIV applied for contracts and included both RH and HIV NGO clusters. Contractual service packages ranged from tightly standardized packages detailing services and performance deliverables supported by World Bank and DFID to less standardized packages supported by European Commission and USAID. Under contracts, the HIV NGOs shifted from mere awareness generation activities to service delivery while RH NGOs already involved with sexual health counseling expanded into full range of HIV prevention services.Both sets of NGOs also started interacting with a common set of policy stakeholders involving the AIDS Control Program, international donors investing in HIV and International NGOs managing contracting. However, as HIV remained a vertical response, there was little interaction with other vertical programs dealing with maternal and reproductive health. HIV programs continued to be implemented through NGO outlets while reproductive health continued separately through government mainstream facilities and community health workers.Both NGO communities were under-equipped to meet the requirements of service delivery contracts for HIV. RH NGOs were able to write and negotiate sophisticated bids for HIV contracts and provided seasoned program management, monitoring and documentation but lacked links and experience with risk groups. Conversely, HIV NGOs were familiar with risk groups but lacked capacity to work at scale. Capacity building in varying measure took place alongside contracts with both sets of NGOs gaining experience in programming service delivery for risk groups. Contractual experience also encouraged NGOs to take on further HIV service delivery contracts. However, capacity building through on ground experience was a slow process and performance except for few contracts remained lower than stipulated targets (Although both NGO clusters had complimentary capacities, there were fewer than expected partnerships between HIV and RH NGOs. NGOs preferred to form partnerships with like-minded groups. Even in instances where contractual partnerships were undertaken between larger RH NGOs and smaller HIV NGOs, these did not continue over in subsequent contracts after some level of capacity was built in both NGO clusters. Both HIV and RH NGOs continued to associate in separate NGO networks. Network boundaries in fact sharpened in the wake of donor funded HIV contracts, driven by underlying suspicions of fund driven participation for HIV contracts. Some NGOs raised concern on lack of over-riding focus on service delivery and lack of effort put into developing common ideological ground and commonality of approach within respective NGO communities. There were also fears of sustainability whether NGOs would continue to be engaged with HIV prevention and control after funding for contracts ended.So far the compartmentalization debate has typically centered on government vertical programs and its In Pakistan, the HIV and RH NGO communities were historically different in terms of ideology, organizational features, programmatic goals, clientele and stakeholder linkages. These networks tended to work in parallel and derived their distinctiveness from vertically driven policy responses to HIV and RH in Pakistan. We found that both their distinctive features and lack of connects in working conditioned their response to HIV contracting.Contracting for HIV prevention was faced with uneven capacity of both sets of NGOs involving weak contract and project management skills in the HIV focused NGOs and sub-optimal contextual knowledge of risk groups amongst the larger RH NGOs. Hence none of the winning bidders was an ideal candidate for implementing HIV contracts. In the long run contracting became a means to overcome capacity gaps by providing grounded experience through contracts. Market stimulation through contracts also instigated both communities of NGOs into providing fairly uniform and standardized HIV prevention services that were underwritten by tight performance based contracts. Contracting brought NGO groups together for service delivery projects, however competition for service contracts in the absence of larger policy harmonization efforts engendered friction and rivalry, with preference for bidding partnerships with like-minded groups.Much has been written in recent years about contracting of NGOs for health service provision in developing countries. However the focus of research has been on quantitative results of contracting, mainly service coverage expansion . There sBased on the above we recommend, that market based efforts, such as contracting, need to be accompanied by wider policy and systems efforts for furthering productive interaction between parallel NGO communities. Such efforts need to be aimed across a spectrum of NGO stakeholders at developing a common construct on the issue and a cohesive common understanding of policy responses. Moreover policy measures need to operationally encourage integrated working across similar health programs such as HIV and RH . MeasureContracting for HIV control can overcome compartmentalization of NGOs by bringing providers towards more standardized service packages but is also negatively affected by market deficiencies and sharpened rivalries as a result of compartmentalization. Wider policy and systems measures are needed in addition to contracting to overcome parallel provider networks."} +{"text": "With millions of surgical procedures being performed worldwide annually, clinicians, researchers, patients, and administrators increasingly pursue understanding factors, which affect and determine perioperative outcomes. The last decades have been associated with extensive research and subsequent increased number of publications in the field of perioperative outcomes in orthopaedic surgery. The population is progressively involved in recreational and athletic activities increasing thus the prevalence of sport-related soft-tissue and bone injuries. Furthermore, the population is aging and the demand for joint replacement and spine surgery is increasing annually, raising inevitably the absolute numbers of surgery related complications such as infection, mechanical failure, and delayed union. Finally, the adoption of new technology and the introduction of minimally invasive surgical techniques still remain a controversial topic on whether evidence-based medicine has justified the risk of their use. Hence, it is important to critically evaluate the perioperative outcomes of modern orthopaedic surgery and further investigate whether a change in the perioperative management of the orthopaedic patient is warranted. Although the selected papers for this special issue are not an exhaustive representation of the area of perioperative outcomes in orthopaedic surgery, they represent an excellent panel for approaching and addressing this challenge. Without doubt they will provide significant knowledge to the readers, simulating further investigation and research and possible improvement of the current surgical technique and overall perioperative management of the orthopaedic patient.The special issue contains six papers; of these, three papers are related to spine surgery and more specifically to fusion rates of various disc substitutes and outcomes and complications of minimally invasive surgery. One paper presents short-term outcomes of surgical reconstruction of chronic functional ankle instability. Another experimental study provides data that support the combined use of flexible intramedullary nailing and Ilizarov external fixation for bone repair enhancement. Finally, the last paper covers criteria for patient risk stratification with regard to the development of surgical site infection following total hip arthroplasty.In the paper entitled \u201cPEEK Cages versus PMMA Spacers in Anterior Cervical Discectomy: Comparison of Fusion, Subsidence, Sagittal Alignment, and Clinical Outcome with a Minimum 1-Year Follow-Up,\u201d authors compared radiographic and clinical outcomes after anterior cervical discectomy in patients with cervical degenerative disc disease using PEEK cages or PMMA spacers with a minimum 1-year follow-up. They found that the substitute groups showed differing fusion rates. However, clinical outcomes appeared to be generally not correlated with fusion status or subsidence. Authors concluded that they could not specify a superior disc substitute for anterior cervical discectomy.In the paper \u201cMinimally Invasive Technique for PMMA Augmentation of Fenestrated Screws\u201d authors described the minimally invasive technique, as well as its safety and efficacy, for cement augmentation of cannulated and fenestrated screws using an injection cannula. The presented minimally invasive cement augmentation technique using an injection cannula was proven to facilitate convenient and safe cement delivery through polyaxial cannulated and fenestrated screws during minimally invasive screw-rod spondylodesis.In the paper \u201cAccidental Durotomy in Minimally Invasive Transforaminal Lumbar Interbody Fusion: Frequency, Risk Factors, and Management,\u201d authors' purpose was to assess the frequency, risk factors, and management of accidental durotomy in minimally invasive transforaminal lumbar interbody fusion. Their results showed that the frequency of accidental durotomies in MIS TLIF is low, with overweight being a risk factor. They concluded that the minimally invasive approach seems to minimize durotomy-associated complications because of the limited dead space in the soft tissue.In the paper \u201cSurgical Reconstruction with the Remnant Ligament Improves Joint Position Sense as well as Functional Ankle Instability: A 1-Year Follow-Up Study,\u201d they assessed functional improvement of chronic ankle instability after surgical reconstruction using the remnant ligament. This study showed that surgical reconstruction using the remnant ligament was effective not only for improving mechanical retensioning but also for ameliorating joint position sense and functional ankle instability.In the paper \u201cBone Healing by Using Ilizarov External Fixation Combined with Flexible Intramedullary Nailing versus Ilizarov External Fixation Alone in the Repair of Tibial Shaft Fractures: Experimental Study,\u201d authors conducted an experimental study utilizing an open tibial shaft fracture canine model aiming to study the radiographic and histological outcomes of flexible intramedullary nailing (FIN) combined with Ilizarov external fixation (IEF) versus Ilizarov external fixation alone. Authors concluded that the combination of the Ilizarov apparatus and FIN accelerates bone repair and augments stabilization of tibial shaft fractures as compared with the use of the Ilizarov fixation alone.Finally, in the paper \u201cPatient, Surgery, and Hospital Related Risk Factors for Surgical Site Infections following Total Hip Arthroplasty\u201d authors conducted an extensive review of the literature on reported patient, surgery, and hospital related risk factors for SSI after THA. This review can facilitate surgeons to identify patients at risk for infection and administrators to adopt preventive systems based strategies to reduce the overall risk and therefore the subsequent multifaceted burden of periprosthetic joint infections."} +{"text": "Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrotic interstitial lung disease of unknown origin. It has a median survival of three years but a wide range in survival rate which is difficult to predict at the time of diagnosis. Specialist guidance promotes a patient centred approach emphasising regular assessment, information giving and supportive care coordinated by a multidisciplinary team (MDT). However understanding of patient and carer experience across the disease trajectory is limited and detailed guidance for MDTs on communication, assessment, and triggers for supportive and palliative interventions is lacking. This study addresses uncertainties relating to care needs of patients and carers at different stages of the IPF disease trajectory.Following ethical approval a multi-centre mixed-methods study recruited participants with IPF at four stages of the disease trajectory. Qualitative analysis was used to analyse 48 semi-structured interviews with patients (27) and paired carers (21).Focus of clinical encountersTimely identification of changes in health status and functional activityUnderstanding of symptoms and medical interventionsCoping strategies and carer roles.Patients and carers outlined key elements of MDT activity capable of having significant impact on the care experience. These were structured around:Patients diagnosed with IPF have a clear understanding of their prognosis but little understanding of how their disease will progress and how it will be managed. In depth analysis of the experiences of patients and carers offers guidance for refining IPF clinical pathways. This will support patients and carers at key transition points in line with National Institute for Health and Care Excellence (NICE) guidance.The online version of this article (doi:10.1186/s12890-015-0145-5) contains supplementary material, which is available to authorized users. Idiopathic pulmonary fibrosis (IPF) is a progressive, life-limiting condition thought to arise from aberrant would healing following repeated alveolar microinjury, resulting in progressive lung fibrosis . EpidemiThere are few parameters that will accurately predict rate of decline at the time of diagnosis and the only therapy that improves survival is lung transplantation in eligible candidates.Patients with IPF describe reduced health status, high symptom burden and impaired quality of life , 6. TheyQualitative research provides rich data, giving insight into how people make sense of their experiences and helping elucidate complex settings and interactions. It plays an increasingly important role in health service research and is particularly helpful in understanding the supportive role of carers, whose perspective may not be appreciated in the clinical setting \u201316. A smThis study was designed to explore the perspectives of patients and their carers across the IPF spectrum to inform the development of clinical pathways and multidisciplinary service interventions as described in Table\u00a0The uncertain nature of disease progression in IPF makes a longitudinal study difficult to achieve in a set time frame. Therefore, we chose a cross-sectional, mixed method design to study patients at different stages of IPF and matched carers. Specialists with expertise in palliative care and interstitial lung disease, who were part of the research team, generated a disease typology to classify patients into four stages of IPF described in Table\u00a0An experienced qualitative researcher (CS) conducted semi-structured interviews with participants and performed an initial analysis, using Interpretative Phenomenological Analysis (IPA). Emerging results were verified by other members of the research team. In keeping with recommendations for IPA, we aimed for a sample size of 6\u201310 patients and 6\u201310 carers per group, representing a perspective rather than a population. Consolidated criteria for reporting qualitative research (COREQ) guidelines were followed .The study gained favourable opinion, 20/04/2012, from the South East Wales Research Ethics Committee, Panel B, 12/WA/0109 prior to the study commencing. The sponsor was Cardiff University (SPON 1088-12).Twenty seven patients with IPF and twenty one matched carers were recruited from two UK specialist interstitial lung disease clinics between October 2012 and August 2014. Patients were included if they met the American Thoracic Society criteria for IPF diagnosis . No patiAnonymised transcripts were analysed by the qualitative researcher (CS) to capture patients and carer themes as described in Table\u00a0Patients reported that their overall experience of living with IPF was one of coming to terms with a complex condition requiring a complicated and often protracted diagnostic work-up, with an uncertain but limited prognosis. They felt they received insufficient information on the clinical and practical management of their disease and would have welcomed more advice on pragmatic interventions at key points to help manage an unpredictable future. Although several common themes emerged for all patients, there was evidence of variation in the impact of IPF on patients from different disease trajectories.Additional file Patients and carers reported that their key needs were structured around context, timing, content and format of information. They described a need to balance honesty and hope, whilst dealing with a terminal prognosis but searched for positive ways to manage and live with an uncertain disease trajectory (Additional file The specialist IPF clinic was seen as a trustworthy source of information. However, focus of the consultation was often perceived as disconnected from participants\u2019 experience of the disease and its impact on everyday life. They felt unable to interpret the relevance of disease-focused assessments such as lung function tests to future exercise capacity or overall prognosis (Additional file The complexity of the diagnostic process often resulted in prolonged investigations and delays in referral to the appropriate specialist. Initial relief that the diagnosis was not cancer was replaced by shock at the likely prognosis. Patients and carers in the Limited Stable trajectory in particular struggled with uncertainties around the possible course of IPF. Their need to receive information at an appropriate pace triggered by changes they perceived in health status didn\u2019t always coincide with the timing of clinic appointments. Paradoxically, they recalled feeling greatest concern about attending clinics where they had observed fellow patients with more severe IPF.The specialist nurse was perceived as a key resource, enabling patients and carers to access help on practical management and triggering medical intervention when required. Despite this, patients and carers still struggled with uncertainty around key turning points if they occurred between clinic visits.Patients and carers appeared to show a good understanding of the overall prognosis for IPF but had difficulty translating this to their own particular disease progression and the management/support options available to them. They declared a need for specific information relating to oxygen therapy, nutrition, exercise, management of cough and breathlessness and disease management towards the end of life. Patients living alone were most direct in their need for information about future care planning.Written information was most often suggested as useful. The internet was sometimes cited as portraying \u2018worst case scenarios\u2019 and there were mixed responses to the utility of a peer support group.As patients and carers had difficulty interpreting objective, clinic-based disease assessments, they described how they developed their own subjective strategies for monitoring IPF. These included looking for clues to health status by observing alterations to the frequency of clinic appointments and comparison with other patients encountered in the clinic or support groups. They also associated deterioration of IPF with intercurrent illnesses such as chest infections, initiation or increased use of use of oxygen, and changes in functional activity (Additional file Sustained deterioration in health status led subjects to re-evaluate the uncertainty of their future (Additional file Deterioration in health increased risk of social isolation for patients and carers, who experienced loss in relinquishing valued activities and responsibilities. Both groups adapted to a lifestyle of gradually declining choices rather than seeking assistance to optimise their functional activities (Additional file Most patients and carers felt unable to identify potential sources of help due to their uncertainty about the IPF course. Declining health status increased the emotional and domestic burden on carers, while patients expressed fears about employment loss, finance and how their partner would cope in future.There were specific concerns, especially for carers, regarding symptom monitoring in relation to breathing, cough and use of oxygen. Differing expectations between patients and carers were particularly evident around oxygen use (Additional file Patients viewed pulmonary rehabilitation as positive intervention, enabling them to participate in the management of their own disease and improve everyday living through increased awareness of coping strategies like energy conservation and better task management. Carers felt these strategies were more readily accepted if offered by a professional rather than by themselves.Patients and carers frequently compared their situation unfavourably with cancer patients whom they considered to have \u201chelp coming from every direction\u201d. In this context, common misconceptions about palliative care emerged in relation to reasons for referral as did concerns about being referred onto \u201cthat path to death.\u201dTwo patients had received palliative care, one in a hospice out-patient programme and the other through home visits. They reported significant improvement to quality of life through peer support, and expert advice on sleep problems, palliative medication and home adaptations.This study discovered significant differences in the range of coping strategies adopted by patients and carers. Core coping strategies for patients across all four trajectories included acceptance and adapting to change (Additional file Patients with partners expressed concern about how their partner would cope as the disease progressed.Carers provided motivation and emotional support, placing the needs of the patient above their own (Additional file This is the first qualitative study to report the support needs of people suffering from IPF across defined disease trajectories, as well as providing an in-depth perspective on the needs of their carers. The results highlight specific opportunities to inform MDT assessments, case mix and resource use Fig. .A striking finding of the study is the identification of key communication strategies valued by patient and carers. Although difficulties accessing information have been previously described , 21, theThe focus of clinic consultations on disease measures such as lung function appeared disconnected from participants\u2019 lived experience of the disease and its impact on everyday life. They sought a more pragmatic needs assessment to include aspects of physical and social functioning, nutrition and symptom burden to support their self-management and guide their understanding of illness progression. This broader assessment approach has already been successfully employed in time pressured clinics in other settings including cancer .The requirement to better acknowledge the role and needs of carers within outpatient consultations is an important finding. Carers described ambiguity in how they were perceived, with negative impact on both partners\u2019 understanding of disease course and coping strategies. This implies a need for clinicians to change their perception of carers from passive observers to having active roles throughout the patient pathway. It also suggests that carers should have greater access to personal advice and support outside clinic settings, particularly at the time of diagnosis and during changes in health status.An important difference between patients and carers is the finding that, although carers maintain positivity in their supporting role, they adopt much less positivity in coping strategies for themselves. The carers we interviewed felt they required a different balance in the personal support they receive from the IPF clinic and palliative care services, with particular attention to the social isolation and restriction of lifestyle that progressive IPF brings.CaNoPy also identifies key milestones for study participants in their interpretation of disease progression. Changes in health status, even when temporary, produced significant shifts in coping. Changes in function, development of symptoms \u2013 particularly cough and breathlessness \u2013 and instigation of oxygen represented specific triggers for early and focused MDT support. Whilst Swigris and SchoThe MDT is challenged to identify systematic approaches within the care pathway which facilitate earlier recognition of change. It underscores the need for a broader needs assessment and presents opportunities to examine strategies employed elsewhere, including the roles of care trackers and emerging technologies in supporting key workers \u201326.Participants in CaNoPy who had received palliative care support identified improvements in quality of life by allowing them to achieve an adapted form of normal living. Instigation of oxygen therapy was a key turning point and an example of this type of adaptation. Whilst carers perceived this positively as an opportunity for maintenance of normal living, patients often felt it was stigmatic or an intervention to be used sparingly. Focused professional intervention at this point could maximise benefit and reinforce the legitimacy of carer strategies and patient involvement in self-management \u2013 which pulmonary rehabilitation achieved for those in receipt of it. Similarly carers appeared to take prime responsibility for management of symptoms, nutrition and exercise. It therefore seems likely that earlier access to palliative advice and interventions when symptoms first emerge may provide functional benefit and reduce carer anxiety and uncertainty.It is well known that maintaining attitudes of positivity and hope are important when communicating with people suffering from IPF , 27, 28.The clinic recruitment settings were within Wales, led by respiratory clinicians with a specialist interest in IPF: settings which may differ from other parts of the UK, including potential cultural differences and different service delivery models. Also, no patients interviewed were receiving pirfenidone, although findings should remain relevant to the majority of patients with IPF.Although a longitudinal study design might be thought preferable, the cross sectional approach was used as the uncertain nature of disease progression made a longitudinal study difficult to achieve in the set time frame.Recent guidelines have defined the need for integrated clinical pathways in managing and supporting patients with IPF. This study provides new evidence of perceived gaps in the implementation of care across the disease trajectory and highlights the needs of carers in a detail not previously described. It suggests that in the outpatient context, a more practical needs assessment based on patient and carer perceptions is required, using tools which are both relevant and applicable to the clinic settings.Greater consideration of clinic case mix and frequency of appointments is required, particularly for patients with stable disease. Clinical assessments should directly address implications for future care planning, mindful that patients and carers are likely to shift their expectations at different speeds.Finally, this study highlights the importance of timing: identifying turning points more quickly in order to trigger timely assessment and intervention to improve patient and carer outcomes. Taken together our findings have important implications for the structure and function of IPF Clinics, multidisciplinary teams and associated clinical pathways."} +{"text": "Prescribing is a complex task, requiring specific knowledge and skills, and the execution of effective, context-specific clinical reasoning. Systematic reviews indicate medical prescribing errors have a median rate of 7% IQR 2%-14%] of medication orders 4% of med. For podTo investigate the methods employed to teach and assess the principles of effective prescribing in the undergraduate podiatry program and compare and contrast these findings with four other non-medical professions who undertake prescribing after training at Queensland University of Technology.The NPS National Prescribing Competency Standards were employed as the prescribing standard. A curriculum mapping exercise was undertaken to determine whether the prescribing principles articulated in the competency standards were addressed by each profession.A range of methods are currently utilised to teach prescribing across disciplines. Application of prescribing competencies to the context of each profession appears to influence the teaching methods used. Most competencies were taught using a multimodal format, including interactive lectures, self-directed learning, tutorial sessions and clinical placement. In particular clinical training was identified as the most consistent form of educating safe prescribers across all five disciplines. Assessment of prescribing competency utilised multiple techniques including written and oral examinations and research tasks, case studies, objective structured clinical examination exercises and the assessment of clinical practice. Effective and reliable assessment of prescribing undertaken by students in diverse settings remains challenging e.g. that occurring in the clinical practice environment.Recommendations were made to refine curricula and to promote efficient cross-discipline teaching by staff from the disciplines of podiatry, pharmacy, nurse practitioner, optometry and paramedic science. Students now experience a sophisticated level of multidisciplinary learning in the clinical setting which integrates the expertise and skills of experience prescribers combined with innovative information technology platforms (CCTV and live patient assessments). Further work is required to establish a practical, effective approach to the assessment of prescribing competence especially between the university and clinical settings."} +{"text": "The validation results showed that microassay in combination with statistical experimental design can be successfully used to predict effective enzyme pretreatments that can enhance plant cell wall digestion by mixed rumen enzymes.Identification of recalcitrant factors that limit digestion of forages and the development of enzymatic approaches that improve hydrolysis could play a key role in improving the efficiency of meat and milk production in ruminants. Enzyme fingerprinting of barley silage fed to heifers and total tract indigestible fibre residue (TIFR) collected from feces was used to identify cell wall components resistant to total tract digestion. Enzyme fingerprinting results identified acetyl xylan esterases as key to the enhanced ruminal digestion. FTIR analysis also suggested cross-link cell wall polymers as principal components of indigested fiber residues in feces. Based on structural information from enzymatic fingerprinting and FTIR, enzyme pretreatment to enhance glucose yield from barley straw and alfalfa hay upon exposure to mixed rumen-enzymes was developed. Prehydrolysis effects of recombinant fungal fibrolytic hydrolases were analyzed using microassay in combination with statistical experimental design. Recombinant hemicellulases and auxiliary enzymes initiated degradation of plant structural polysaccharides upon application and improved the Rising grain prices heightened concerns over the use of food as feed for livestock production and the negative impacts of annual crops on carbon sequestration and biodiversity has prompted research into finding ways to increase the use of fibrous forage in ruminant diets. Plant cell walls can constitute a primary source of nutritional energy for ruminants. However for many types of forage, less than 50% of the cell wall fraction is digested and utilized by the ruminant host . SubstanFiber digestion in ruminants occurs primarily in the rumen and cecum. Generally, the amount of fiber digested in the lower tract is relatively small, with the rumen being the primary site of digestion. The ruminal microbial population secrets diverse hydrolases to degrade and ferment structural carbohydrates in plant cell walls. The physical and chemical nature of forages can present a barrier to their complete digestion in the rumen . Therefo in vivo numbers of fibrolytic rumen bacteria that utilize the secondary products of cellulose digestion . Cr. Cr\u22121 to pectin) , 19. Sim pectin) for barlWe hypothesize that prehydrolysis of the forage with efficient auxiliary enzymes like esterases prior to consumption may increase fiber digestibility in ruminants by reducing recalcitrant cross-linked xylan content. This would be beneficial to ruminant production in the form of increased efficiency of meat and milk production.Based on the results from the enzyme fingerprinting (experiment 1) we selected recombinant enzymes and endoglucanase EGL7A_THITE for prehydrolysis with an aim to increase the sugar yield from substrates exposed to mixed rumen enzymes. We specifically selected barley straw as the substrate in experiment 2 with the expectation that it would represent even a more recalcitrant forage source than barley silage. The model predicted a significant increase in glucose yield as result of enzymatic prehydrolysis of alfalfa hay and barley straw prior to digestion by mixed rumen enzymes . PrehydrP < 0.05) as a result of prehydrolysis digestion as compared to mixed rumen enzymes alone and ferulic acid esterase FAE 1a (50%) for barley straw and polygalacturonase PGA28A_ASPNG (50%) and arabinofuranosidase ABF54B_ASPNG (50%) for alfalfa hay confirmed that these mixtures increased the release of glucose and xylose ( Figures . Supplem Figures . A direc Figures . However Figures suggesteComprehensive digestion of cell wall requires a battery of carbohydrases. Moreover, yields of recombinant enzymes from expression systems are often low. Hence, a microassay for screening novel enzymes against diverse biomass with ability to study synergy among hydrolases at low protein load is critical for development of enzyme formulations as additives to enhance ruminal digestion. In this study we successfully developed a microassay in combination with experimental design, to screen a number of recombinant enzymes at low protein loads, to enhance ruminal digestion of barley straw and alfalfa through augmentation of natural enzymatic activity in the rumen. Development of enzyme formulations that further enhance the utilization of low quality cellulosic feedstocks will ensure the sustainability of the beef industry in an environment of increasing demand for human food.Enzyme fingerprinting was successfully used to identify principal recalcitrant constituent of barley silage. Cross-linked hemicelluloses as well as layered structure of cellulose and xylan were identified as prime recalcitrant factors to digestion. Partial digestion of hemicellulose in alfalfa hay and barley straw prior to ingestion with a cocktail of auxiliary enzymes significantly improved the hydrolysis of cellulose by mixed rumen enzymes. These results strengthen the rational of enzyme pretreatments targeting particular forage types. These same approaches could be used to improve the value of animal waste as a feedstock for biofuel production."} +{"text": "It is obvious that once blood supply to the retina, choroids, or optic nerve head is completely obstructed, severe visual functional damages occur. Even without such significant ocular blood flow insufficiency, ocular blood flow seems to influence developing or deteriorating glaucomatous damages as well as other retinal diseases. Recent advances in image analysis techniques have introduced new algorithms to study the retinal circulatory disturbances and the mechanisms underlying their pathology. Knowledge and understanding of these conditions may lead to successful therapies and provide better care to patients. For this purpose the continuing efforts to understand the role of ocular blood flow for developing retinal and optic nerve head pathology, the development of strategies to treat these conditions, and the evaluation of outcomes are important.Last year, we invited investigators to contribute original research as well as review articles that address this field. We encourage manuscripts that will describe the new developments of technologies for evaluating ocular blood flow, new insights into relationship between ocular circulatory disturbances and visual function, blood flow and structure relationship, effects of intervention for ocular blood flow on disease progression, and current concepts in ocular blood flow and its relationship to extraocular determinants influencing blood vessel itself or those of systemic factors such as aging, nocturnal hypopressure, or cardiovascular disease. Today, we are very happy to publish this special issue of this journal.In this issue, original research and review articles are accepted. The research papers focused on using color Doppler imaging techniques to understand relationship between retrobulbar hemodynamics and visual field progression in normal tension glaucoma, evaluating differences in the vascular response to a hypercapnic stimulus between normal tension glaucoma patients and normal subjects, investigating the role of systemic arterial stiffness evaluated using brachial-ankle pulse wave velocity in glaucoma patients with diabetes mellitus, and comparing the ocular pulse amplitude lowering effects of preservative-free tafluprost and dorzolamide-timolol fixed combination using dynamic contour tonometry. Besides those of analyzing glaucoma and blood flow relationship, the research papers dealing with detecting evidence for retinal damage evolving from reduced retinal blood flow in carotid artery disease, evaluating the effects of long-term tamponade with silicone oil on retinal saturation, and evaluating reproducibility of ocular circulation measurements using laser speckle flowgraphy in neonates are involved.The review described the present status of understanding relationship between ocular blood flow and glaucoma, including advancements in noninvasive imaging technologies; those have led to the characterization of magnitude and time course in retinal blood flow response to stimuli, describing systemic and ocular hemodynamic risk factors in glaucoma, and role of ocular blood flow in developing normal tension glaucoma. The papers sample the extraordinary progress that has been made in the field.Current research suggests that new developments will continue to follow. Particular importance will be given to manuscripts that address the development of techniques for evaluating systemic and ocular blood flow as well as those adopting such techniques for understanding blood flow and disease relationships. Our aim is to shed light on important knowledge gaps and to provoke thoughts for further research and the development of therapeutic strategies.Goji TomitaDavid HuangColm O'BrienKi Ho ParkToru Nakazawa"} +{"text": "No sample was positive for scrapie. Fluorescent antibody test for rabies and H&E staining on samples were carried out for differential diagnosis. These showed no pathological lesions indicative for neurological disease. While our findings do not exclude the presence of scrapie in Jos, we demonstrate that targeted sampling of small ruminants for neuroinfectious disease is feasible in developing countries, pointing to the possibility of implementing such a monitoring scheme in Nigeria to prevent economic losses in small ruminant livestock as scrapie caveats from endemic countries have shown.Scrapie, a disease of sheep and goats with a progressive course and fatal outcome, has not been identified in Nigeria. Anecdotal scrapie reports by livestock workers abound. Livestock diseases like scrapie form huddles in livestock economics of countries. For 8 months we surveyed for scrapie targeting emergency/casualty slaughter sheep and goats in Jos, Nigeria. We clinically examined 510 sheep and 608 goats of local breeds, aged from 12 months to 5 years. In total 31 (5.10%) goats and no sheep were clinically suspicious for scrapie. Caudal brainstem tissues of suspect animals collected C) mediated by the presence of the abnormal, misfolded prion protein (PrPSc). Host PrP variations are known to play a role in the susceptibility of goats and sheep to scrapie [Scrapie is a naturally occurring progressive, fatal, infectious, and neurodegenerative disease of sheep and goats that has been recognized for over 250 years. The occurrence of scrapie preceded the recognition of other prion diseases of mammals and so can be referred to as the archetype of prion disorders . It is c scrapie . It has The estimated population of sheep and goats in Nigeria is 27 million, and 40.8 million respectively . Sheep aThis study was carried out in Jos, Nigeria, which is a hub of livestock traversing the middle belt and northern parts of the country. We initially planned to sample cases of fallen stock and scrapie suspects from the field where unconfirmed reports of scrapie filter in once in a while. This proved difficult due to the uncooperative attitude of livestock owners/herds men and poor records on their animals. We noted that most diseased animals that would match the clinical picture of scrapie ended up in the abattoir for the food chain. Hence, we targeted samples of emergency or casualty slaughtered sheep and goats. We examined sheep and goats brought in for emergency or casualty slaughter at the abattoir for clinical signs of scrapie using thSampling was from January to August 2011. 510 sheep and 618 goats aged from 12 months to 5 years were clinically examined. Physical appearance and dentition were used to assess the animals age. The clinical examination included the assessment of changes in mental status, behavior and activity, pruritic activities, postural changes, gait changes, involuntary movements, weight loss, and loss of condition. Our criteria for selecting clinical scrapie suspect animals primarily focused on animals that showed pruritis, increased levels of excitement on sudden agitation coupled with ataxia or discordant movement, and signs in other categories we could examine for staining while the remaining part was left for confirmation of rapid test positive samples via immunohistochemistry (IHC) [We collected caudal brain stems from clinical suspect animals through the foramen magnum Sc. While the type of these monoclonal antibodies is subject to industrial secret, its capacity to detect classical scrapie in a range of sheep with different PrP genotypes has been shown [Sc staining method using monoclonal antibody F99 on tissue sections prepared from formalin fixed tissues [Testing for scrapie was done using the TeSeE ELISA purification kit and detection kit . This kit employs an immunoenzymatic technique (sandwich format) using two monoclonal antibodies for the detection of PrPen shown . Howeverante mortem livestock handling practices by owners/butchers prior to slaughter may have elicited increased agitation. These could have led to poor clinical examination of some sheep and goats which may have given rise to appearances of seemingly clinical suspects.By clinical examination, we did not identify any scrapie suspect sheep but idenClinical examination revealed 31 goats with neurological signs indicative for scrapie. However, this suspect could not be confirmed by laboratory testing. This underlines the limitations associated with clinical examination of livestock for prion disease , as clinThe PrP genotypes of local breeds of goats and sheep in Nigeria are yet to be determined. As the nature and proportion of PrP genotypes in the sheep and goat population in Nigeria remain unknown, it is possible that previously unnoticed PrP genotypes are present that interfere with the performance of diagnostic tests applied but this remains unknown. Additional studies are required to fill this gap of knowledge. For differential diagnosis, it may be worthwhile to mention that we did not specifically examine nor sample target animals for other diseases like listeriosis, tetanus, brain worm , caprine arthritis, and encephalities that mayDifficulties and challenges that may be faced when establishing an active surveillance in Nigeria are some we came across in this study: the nomadic nature of livestock farming, poor enlightenment, poor or inexistent records of livestock by owners, no compensatory benefit systems in place for livestock owners and inadequate veterinary services. These affect the quality of demographic data obtained and ease of diagnosis. Clinical suspect animals are not being officially reported for testing, hence an alternative means is to actively search for animals with neurological signs as we did until the challenges confronting the proper setup of a surveillance system for TSE are addressed; enlightenment programs for farmers and animal handlers, personnel training on prion diseases and proper laboratory diagnostic setups in place by government agencies concerned. ante mortem inspection of emergency and casualty slaughter animals that would have identified neurologically diseased small ruminant livestock in a relatively high proportion. We advocate the use of our findings as a platform for the setup of an active surveillance for scrapie and other animal TSEs in Nigeria so as to determine the scrapie status for economic reasons. This study lays the groundwork for an efficient and cost-effective surveillance of scrapie and other neuroinfectious diseases of livestock in resource-limited countries, such as Nigeria. This we have demonstrated by systematic"} +{"text": "The idea of two separate attention networks in the human brain for the voluntarydeployment of attention and the reorientation to unexpected events, respectively, hasinspired an enormous amount of research over the past years. In this review, we willreconcile these theoretical ideas on the dorsal and ventral attentional system with recentempirical findings from human neuroimaging experiments and studies in stroke patients. Wewill highlight how novel methods\u2014such as the analysis of effective connectivity or thecombination of neurostimulation with functional magnetic resonance imaging\u2014havecontributed to our understanding of the functionality and interaction of the two systems.We conclude that neither of the two networks controls attentional processes in isolationand that the flexible interaction between both systems enables the dynamic control ofattention in relation to top-down goals and bottom-up sensory stimulation. We discusswhich brain regions potentially govern this interaction according to current taskdemands. More than a decade ago, Corbetta and Shulman published their influential review article inwhich they introduced the concept of two anatomically and functionally distinct attentionsystems in the human brain . BroadlyThe following paragraph shall outline the critical nodes of the dorsal and ventralattention network and describe their functional and structural anatomy. The dorsal network , blueisThe ventral network comprises the temporoparietal junction (TPJ) and the ventral frontalcortex (VFC) , orange It has been proposed that the ventral system is lateralized to the right hemisphere of thebrain .WhereasFunctional MRI studies looking at spontaneous (\u201cresting-state\u201d) functional connectivitybetween brain areas have shown that the dorsal and ventral networks are clearlydistinguishable on the basis of their correlation patterns even under task-free conditionssee Fox and. This inTaken together, the dorsal and ventral networks are two anatomically segregated corticalsystems with functionally specialized nodes promoting specific processes for attentionalcontrol. It is so far unclear whether\u2014and if so to what extent\u2014functional asymmetries existbetween the dorsal and ventral areas of each hemisphere, although there is evidence for suchasymmetries in the ventral system. We will return to this issue below when we reconsidereach system in more detail and discuss how interactions between the dorsal and the ventralnetwork might be implemented in the human brain to enable a flexible deployment ofattention.It is now well recognized that the biasing of sensory areas emerges from higher-level areasin the frontoparietal cortex. Evidence for a crucial role of both IPS and FEF comes fromfunctional imaging studies looking at the effective connectivitybetween frontoparietal and sensory regions, as well as from studies combining fMRI withTMS.Effective connectivity can be studied with analysis approaches such as dynamic causalmodeling (DCM) or GrangBesides investigating connectivity patterns between brain areas, the combination of TMS andfMRI provides a valuable technique to study the causal impact of TMS applied over a targetregion exerted on other remote brain areas has provided further insights into the functionality of thedorsal system. A recent MEG study by In sum, recent research has clearly demonstrated that dorsal frontoparietal areas cancausally modulate the activity of visual areas. However, the concurrent TMS fMRI studieschallenge the view of strictly symmetrical functions of left and right IPS and FEF.Moreover, during spatial orienting of attention direction-specific responses can be found inthe dorsal attention network, but these might critically depend on the time period after theonset of the spatial cue and hence may remain undetected by methods with low temporalresolution such as fMRI. It should further be noted that dorsal frontoparietal areas arealso activated during feature-based attention , where aThe ventral attention system is typically recruited by infrequent or unexpected events thatare behaviorally relevant . Forthis reason, this network has been implicated in stimulus-driven attentional control . DuringHuman neuroimaging studies have shown that activation of TPJ can be observed across avariety of different cognitive domains such as attention, social cognition (\u201ctheory ofmind\u201d), and episodic memory. This has led to more generic interpretations of the role ofthis area in cognition. For instance, it has been proposed that TPJ might be generallyinvolved in switching between different networks . AnotherThis last section shall now focus on the interplay between the dorsal and ventral attentionsystems during attentional processing. To date, it remains to be established which areas orpathways provide the interface between both systems. The initial assumption of With regard to white matter fiber tracts, the SLF I connects dorsal frontoparietal areasand the SLF III connects ventral frontoparietal regions . The SLFHaving discussed potential hubs and pathways connecting both networks, we will proceed toreview findings that highlight the collaborative roles of both circuits.Along the same lines, it is noteworthy that activation differences between invalid andvalid trials in Posner\u2019s location-cueing task aremostly observed in both dorsal and ventral frontoparietal areas .This is not surprising because (as discussed above) there is only weak evidence thatventral areas contain spatial maps that are needed to reorient attention in space.Interestingly, whereas both networks are activated in conjunction during attentionalreorienting, the opposite effect is observed during visual search where activation of thedorsal network is accompanied by a deactivation in the ventral network see Tab. These rAs noted above, the suppression of TPJ activity during top-down guided visual search is notobserved in contextual cueing-paradigms, in which irrelevant stimuli carry predictiveinformation about the target stimulus. Further valuable insights into dorsal\u2013ventral interactions come from lesion or neuroimagingstudies in brain-damaged patients. One of the most prominent impairments of attention afterstroke is the spatial neglect syndrome, in which patients fail to orient and respond toevents occurring in contralesional space . As thisBesides a failure to orient voluntarily to contralesional space, neglect patients showpronounced difficulties in reorienting attention to invalidly cued contralesional targetswhen attention needs to be disengaged from locations on the ipsilesional side and thisreorienting deficit has originally been linked to lesions of the TPJ . HoweverAlthough both dorsal and ventral attention systems are specialized for distinct attentionalsubprocesses such as top-down controlled attentional selection and the detection ofunexpected but behaviorally relevant stimuli, respectively, it becomes obvious that flexibleattentional control can only be implemented by dynamic interactions of both systems. Recentresearch has shown that this interaction pattern is flexible and crucially depends on thecurrent task demands. Hence, activity in both systems can either be correlated oranticorrelated. There is evidence that this interplay is governed by frontal areas such asthe inferior and middle frontal gyrus. The hemispheric functional specialization of eachsystem and of their interaction needs to be addressed by future studies."} +{"text": "Skeletal muscles change length and develop force both passively and actively. Gearing allows muscle fiber length changes to be uncoupled from those of the whole muscle-tendon unit. During active contractions this process allows muscles to operate at mechanically favorable conditions for power or economical force production. Here we ask whether gearing is constant in passive muscle; determining the relationship between fascicle and muscle-tendon unit length change in the bi-articular medial gastrocnemius and investigating the influence of whether motion occurs at the knee or ankle joint. Specifically, the same muscle-tendon unit length changes were elicited by rotating either the ankle or knee joint whilst simultaneously measuring fascicle lengths in proximal and distal muscle regions using B-mode ultrasound. In both the proximal and distal muscle region, passive gearing values differed depending on whether ankle or knee motion occurred. Fascicle length changes were greater with ankle motion, likely reflecting anatomical differences in proximal and distal passive tendinous tissues, as well as shape changes of the adjacent mono-articular soleus. This suggests that there is joint-dependent dissociation between the mechanical behavior of muscle fibers and the muscle-tendon unit during passive joint motions that may be important to consider when developing accurate models of bi-articular muscles. Skeletal muscles are an organ whose primary function is to produce force and hence movement. They are a structurally organized, composite material containing multiple contractile elements, internal and external connective tissues as well as nerve and vascular tissues. They often span two or more joints and many reports have evidenced different geometric arrangements of fibers both between and within individual muscles during contraction are in part dependent upon the activation state, length, velocity, and orientation of the contracting fibers Hill, . The forVf) can be uncoupled from that of the muscle tendon unit (VMTU): a process termed MTU gearing are arranged obliquely to the mid-line of the muscle Figure . As the VMTU/Vf) is a well-documented phenomenon, and suggests the presence of underlying mechanisms that enable fibers to shorten at optimal velocities for power production across a range of MTU velocities , there are alternating phases of muscle activation and phases of quiescence. During quiescence, MTU and fiber length changes still occur as joint angles are modified by the action of antagonistic and/or synergistic muscles or external loads. Without active forces being developed within the muscle, passive MTU gearing could be influenced by the kinematics of the movement with implications for the force generating ability of the muscle during the initial period of activation .In humans the medial gastrocnemius muscle (MG) is a bi-articular plantar flexor of the foot which spans both the knee and ankle joints. It has a simple uni-pennate fascicle architecture measures of fascicle geometric properties that occurred for equivalent MTU lengths within the defined joint angle ranges of motion. The objective was to determine proximal and distal fascicle geometric property changes for the same MTU length change in both ankle and knee joint rotation conditions and hence calculate MTU gearing in each muscle region.To test whether MTU gearing in MG was joint dependent, a combination of simulation and experimental work was completed with methods selected to provide: (i) estimation of MTU lengths that occurred within a range of Declaration of Helsinki.Eight healthy volunteers gave written informed consent to take part in the study, which was approved by Manchester Metropolitan University Local Ethics Committee and complied with principles laid down by the For bi-articular muscles, the MTU length change is determined by the angle of the two joints spanned and their respective moment arms. Participant specific knee and ankle moment arm and shank length measures were therefore used to scale a kinematics model in computer simulation software , with their right leg inserted into a coil, positioned to image either the ankle or knee joint. Axial images were collected Figure . Once imThree MR images of the ankle joint were used to estimate the joint center of rotation using a geometric approach. The moment arm was calculated as the perpendicular distance from this joint center to the Achilles tendon, as described by Reuleaux and repoParticipants lay prone on an isokinetic dynamometer , with their right leg aligned to enable angular changes of either the ankle or knee joint Figure . Two lin\u22121), were completed following a short warm up period. Three trials were completed before, without moving the participant, the dynamometer was realigned to enable testing of the second joint. During ankle joint rotation the knee was fully extended along the length of the bed of the dynamometer. During knee joint rotation the ankle was fixed at 0\u00b0 using a customized boot-style brace device , while joint angle measures from the dynamometer were collected (2000 Hz) through a 16-bit data acquisition card using custom-written software . All data sources were synchronized by a common trigger signal.Ultrasound images from the proximal muscle region were analyzed using an automated Bayesian multiple hypothesis approach that provided the average shape of all MG fascicles visible in each image and all cycles of movement from each condition grouped. To provide smoothly evolving data values (and simultaneously acting to filter these data), two-harmonic Fourier series were fit to each geometric property . Predicted fascicle lengths were converted to strains (\u03b5) using a reference length, determined in each muscle region, as the mean fascicle length across all trials. MTU gearing is given as the ratio of MTU velocity to fascicle velocity (VMTU/Vf). As fascicle and LMTU changes were determined across the same time period, this MTU gearing was equivalent to the ratio of their change in lengths (\u0394LMTU/\u0394Lf) for each epoch.For each participant, based on the combination of their moment arm data and musculoskeletal simulation, a 20 mm range of MTU lengths that occurred for both ankle and knee rotations was identified. Using the identified Fourier series coefficients, muscle geometric properties were calculated for these equivalent regions . Values were interpolated to 20 equally spaced values per muscle lengthening or shortening epoch and displayed as a function of MTU length for the lengthening and shortening phase of the movement cycle. Paired T-tests were used to identify significant differences (\u03b1 = 0.05) in the slope of the best fit line between knee and ankle joint rotations within each phase. Mann Whitney U-tests were performed for nonparametric data, which were identified using Shapiro-Wilk tests.In each participant a least squares linear line of best fit was determined for the relationship between MTU length and each geometric property . The greater fascicle strains in the distal region also coincided with lower pennation and significant differences in the rate of change in pennation also occurred between conditions during both movement phases .Fascicle lengths and pennations as a function of MTU length change are shown in Figures Although not as large an effect, similar differences were also found in the proximal muscle region, with greater fascicle strains and smaller pennation occurring during ankle joint rotation. Therefore, in both proximal and distal regions knee joint rotation resulted in very small changes in fascicle length (and strain) Figure .Lf, the biggest difference in gearing values occurred in the distal muscle region with significance occurring in the statistical analysis . No significant differences in MTU gearing between rotations occurred in the proximal muscle region . In all muscle regions MTU gearing values were similar between shortening and lengthening phases of the movement cycle.MTU gearing values were typically greater than 1, with the median ranging to about 6 Figure . This reThe purpose of this study was to test whether the extent and velocity of fascicle length change, and hence MTU gearing, within proximal and distal regions of the passive MG muscle varied depending on the joint at which the motion occurred. The results revealed passive MTU gearing values greater than 1, with striking differences in the velocity of fascicle length change Figure and MTU The MTU gearing values greater than 1 Figure indicateThe gearing values greater than 1 indicates that fascicles operated at lower velocities, and hence underwent smaller length changes, than the MTU during the passive joint rotations Figures , 3. Two VMTU/Vf) is the product of two factors: (i) the ratio of muscle belly to muscle fascicle velocity (Vb/Vf) and (ii) the ratio between MTU and muscle belly velocity (VMTU/Vb) reflex activation of MG may have occurred and influenced muscle stiffness in the two conditions. A small pilot trial revealed that for both ankle and knee joint conditions such tonic activation was low (< 5% MVC). Previous reports have suggested that for any resistive torques to be considered passive muscle activation should be below 1% MVC (McNair et al., The results presented here should be considered within the context of at least one potential limitation: no measure of muscle activation was included. Given the angular velocity used within the protocol (60\u00b0 sin vitro and in vivo measures have led to questions regarding the potential of ultrasound imaging and tracking methodologies to introduce variability and bias into these measures (Finni et al., One unexpected feature of the results was the differences in fascicle lengths and pennation that are apparent between shortening and lengthening phases in both the proximal and distal muscle regions Figure . FasciclDissociation between changes in MTU and fascicle length are well documented during active contractions (Wakeling et al., EH, JW, and TD contributed to the conception and design of the work; EH and TD acquired and analyzed these data; EH, JW, and TD interpreted data for the manuscript. EH, JW, and TD drafted the work and/or provided critical revisions for important intellectual content and provided final approval of the version to be published. EH, JW, and TD agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Anorexia Nervosa is a high cost low prevalence eating disorder in children and young people presenting to tertiary child and youth mental health services across the country. The disorder creates high anxiety amongst service providers as it usually requires long term high resource service provision with limited recovery rates. Current evidence based practice identifies Family Based Treatment as the most effective treatment option with the highest rates of recovery sustained over time, however the success of the intervention has been linked with clinical practice holding model integrity. Current evidence indicates that best outcomes are achieved when delivery of treatment is provided through specialist Eating Disorders services.This presentation will share the journey of embedding a specialist multi-disciplinary eating disorder clinic utilising Family Based Treatment, within the limits of existing resources, in a large metropolitan Hospital and Health Service in Queensland. Challenges including freeing resources from other service areas, culture and practice shifts in the treatment of eating disorders, managing competing interests in the treatment of eating disorders, developing partnerships across internal and external stakeholders, and, building a sustainable workforce and service model will be discussed. Future directions including research, establishing a comprehensive evaluation strategy, accreditation of clinicians as Family Based Treatment specialists, provision of training and supervision, and seeking funding to establish an independent service will be outlined.Service Initiatives: Child and Adolescent Refeeding and FBT stream of the 2014 ANZAED Conference.This abstract was presented in the"} +{"text": "Genomic approaches are gathering momentum in biology and emerging opportunities lie in the creative use of comparative molecular methods for revealing the processes that influence diversity of wildlife. However, few comparative genomic studies are performed with explicit and specific objectives to aid conservation of wild populations. Here I provide a brief overview of comparative genomic approaches that offer specific benefits to biodiversity conservation. Because conservation examples are few, I draw on research from other areas to demonstrate how comparing genomic data across taxa may be used to inform the characterisation of conservation units and studies of hybridisation, as well as studies that provide conservation outcomes from a better understanding of the drivers of divergence. A comparative approach can also provide valuable insight into the threatening processes that impact rare species, such as emerging diseases and their management in conservation. In addition to these opportunities, I note areas where additional research is warranted. Overall, comparing and contrasting the genomic composition of threatened and other species provide several useful tools for helping to preserve the molecular biodiversity of the global ecosystem. Many genomics techniques offer opportunities for conservation and management planning in a practical and biological sense (e.g. which populations may be mixed and which show important distinctiveness that should be preserved). Although definitions vary Ailuropoda melanoleucaBrachyramphus marmoratus (a threatened seabird) Recently, researchers have begun to target adaptive molecular variation for inclusion in the assessment of conservation units. These data introduce information about evolutionary distinctiveness into the definition of protected populations In conservation, phylogenetic approaches have been used to identify the most evolutionarily distinct species, which may then be targeted for particular conservation effort . DFTD is a highly contagious and fatal transmissible cancer that has caused dramatic population declines in the species' native Tasmania, since its first observation in 1996 A particularly interesting application of genomics to the study of disease emergence in a threatened species is in the Tasmanian devil Batrachochytrium dendrobatidisXenopus and closely related species allows researchers to examine the response of the model amphibians to chytrid and other pathogens, in order to discover how diseases may affect threatened species In addition to these examples of particular disease processes, comparative genomics can be a powerful tool for the study of a species' immunome. By examining the diverse characteristics of species' immunity genes, we can learn more about how each species has evolved to respond to pathogens in its environment 2I have presented a brief overview of conservation genetics questions that can be targeted by a comparative genomic approach: including the relationships between related species or populations (delineation of conservation units and studies of hybridisation), studies of cross-species variation (examination of the genomic regions contributing to species distinctiveness and divergence) and the interactions between species and their threatening processes (whether intrinsic or extrinsic). It is clear that many aspects of preserving threatened species diversity can benefit from looking beyond the threatened species itself, and considering the differences between the rare species' genome and other genomes that share its environment, although empirical examples in this research area, utilising threatened species themselves, are scarce. A particularly exciting path of inquiry is the application of comparative genomics to the study of the ecological context of genomes, through a better understanding of interactions between species, such as hosts and parasites, in an \u201cextended phenotype\u201d, co-evolutionary framework"} +{"text": "It is a pleasant and rewarding responsibility and the editorial team of JOCGP really cherishes it.We take this opportunity to thank our contributors for sharing their ideas and experiences with the fraternity.The boom in the diagnostic technology for early detection of glaucoma has been astounding. Danekal et al threw insight on role of pattern electroretinogram (PERG) in detection of early glaucoma. They found that the P50 and N95 amplitude of patients with primary open angle glaucoma (POAG) and glaucoma suspect were significantly reduced and N95 amplitude was the better indicator for diagnosis of POAG when used individually.In another study, Asrani et al carried out noninvasive imaging of Schlemm\u2019s canal and trabecular meshwork in vivo with Fourier domain optical coherence tomography (FDOCT) to visualize ocular angular structures crucial for glaucoma management. They report that the selection of the OCT operating wavelength and exact location of the scan across different meridia minimally affects the appearance of the ocular anatomy.Health provisions vary around the globe. Some sectors do not have access to such sophisticated and objective imaging devices so clinical assessment helps to detect the disease. Bhartiya and Shaarawy evaluated the usefulness of the Van Herick technique in ruling out narrow angles in glaucoma patients in Southern Egypt. They found that even seemingly deep limbal anterior chamber could have an occludable angle on gonioscopy. They recommend that all ophthalmologists must make the final assessment with a gonioscope.Rajkumari et al bring forward the scenario of North-eastern region of India, which continues to suffer from limited resources, added upon by Mongoloid racial similarity and poor cataract surgery rate. This has significantly contributed to the increased incidence of advanced cataract like phacomorphic glaucoma. They evaluate the role of manual small incision cataract surgery in controlling the IOP and achieving good visual acuity with minimal complications.A review by Alon looks at recently published studies on the mechanisms and clinical outcome of selective laser trabeculoplasty (SLT) and attempts to address issues pertinent to SLT in the clinical practice. The key to understanding any disease entity is to understand the basic biochemical concepts. A review by Ahmed et al throws light on the new developments which form the biochemical basis of glaucomatous neural degeneration. The role of excitatory amino acids, caspases, protein kinases, oxygen free radicals, nitric oxide, TNF-alpha, neurotrophins and metalloproteins in causation of neurodegeneration has been highlighted.Faiq et al discussed the various clinical, biochemical and genetic aspects of primary congenital glaucoma. They emphasized on the fact that the etiology of this glaucoma subtype does not lie merely in a single gene or genetic factor. Gene-gene interactions, ocular embryology, ophthalmic metabolism and systemic oxidative status need to be studied to unravel the mystery surrounding this disorder.Many patients have coexisting cataract and glaucoma. IOL selection plays a vital role in optimizing visual outcomes and minimizing complications in such patients. Ichhpujani et al collated the evidence regarding the use of premium intraocular lenses in patients with glaucoma.Case reports have often been disregarded in medical literature but there is no denying the fact that they provide important information about individuals which is often not cited in larger studies. Chakraborty and Spaeth report an interesting case of overlapping syndrome with advanced pigmentary glaucoma and Marfan syndrome.As always, the editorial team looks forward to hearing from you.Best wishesShibal BhartiyaTarek ShaarawyTanuj Dada"} +{"text": "Public health interventions are needed to reduce stigma towards bulimia nervosa (BN) to enhance appropriate treatment seeking. This study aimed to evaluate persuasiveness of health messages designed to increase mental health literacy about BN. A community sample of adults (N = 2092) completed self-report measures of knowledge about BN, stigma towards BN and ratings of persuasiveness of health messages on dimensions of convincingness and likelihood of changing attitudes. Messages highlighting that BN is a serious mental illness and that BN has nothing to do with attention seeking were rated as significantly more convincing and significantly more likely to change one's and others' attitudes towards BN than messages describing treatment options for BN. Ratings of message convincingness were positively associated with knowledge about BN for males, but not for females. Knowledge was not related to likelihood of changing attitudes. Message convincingness was inversely related to dimensions of stigma, including perceived advantages of BN, and perceptions that people with BN are unreliable and personally responsible for their illness. No relationship was found between stigma and likelihood of messages changing attitudes. The findings from this study provide a clear direction for implementation in public health interventions of particular messages to reduce BN stigma.Prevention & Public Health stream of the 2014 ANZAED Conference.This abstract was presented in the"} +{"text": "Structural birth defects together of are a prominent cause of mortality and morbidity and are gaining importance with improving obstetric care and reduction in infective causes. Advances in understanding genetic (G) and environmental (E) factors and their interaction have added newer dimensions to the etiology of birth defects. Epigenetic is one such interesting field expected to provide mechanistic links between whether and how the environment interacts with maternal and fetal genomes. Some classical examples of environmental insults such as teratogens, maternal medical disorders and nutritional deficiencies as well as G-E interactions leading to birth defects will be discussed. It is important that the relevant scientific information should reach professionals and public for better awareness, appropriate policy decisions to prevent birth defects."} +{"text": "Environmental insecurity is a source and outcome of biodiversity declines and social conflict. One challenge to scaling insecurity reduction policies is that empirical evidence about local attitudes is overwhelmingly missing. We set three objectives: determine how local people rank risk associated with different sources of environmental insecurity; assess perceptions of environmental insecurity, biodiversity exploitation, myths of nature and risk management preferences; and explore relationships between perceptions and biodiversity exploitation. We conducted interviews (N = 88) with residents of Madagascar\u2019s Torotorofotsy Protected Area, 2014. Risk perceptions had a moderate effect on perceptions of environmental insecurity. We found no effects of environmental insecurity on biodiversity exploitation. Results offer one if not the first exploration of local perceptions of illegal biodiversity exploitation and environmental security. Local people\u2019s perception of risk seriousness associated with illegal biodiversity exploitation such as lemur hunting may not reflect perceptions of policy-makers (considered to be high). Discord is a key entry point for attention. The global illegal wildlife trade has dramatically accelerated in the past decade although it has long been recognized as a serious threat to biodiversity conservation and livelihood preservation. Alongside other forms of biodiversity exploitation and environmental \u201ccrimes\u201d\u2014such as illegal commercial logging and illegal unreported and unregulated fishing\u2014wildlife crime is politically destabilizing, subverts the rule of law, undermines sustainable development investments and generates monetary proceeds that fuel other organized crime and conflict ,2. In thEnvironmental insecurity is widely considered a source and outcome of biodiversity declines and social conflict ,4; the tThere are many ways to think about managing risks and negative effects of change associated with environmental insecurity and biodiversity exploitation. There are also myriad processes for translating high-level policy directives to ground-level programs. Criminologists proposed a typology of conflicts producing negative environmental consequences and insecurity. Broadly, conflict-environment relationships can be over (1) natural resources possession , (2) declining resources , (3) destroyed environments and (4) processes of natural resource extraction . ProgramSince 2013, U.S. policy on illegal biodiversity exploitation has been structured to reduce risks through improved and enhanced enforcement, reduced consumer demand and increased diplomatic cooperation and wildlife trafficking for the global pet trade . Transpaiphora)] .These trends paint a bleak picture for Madagascar\u2019s degraded environments and the fokonolona, or a group of people living within the same village or Malagasy indigenous community )any of these discussions can wholly inform assessment of the responsiveness of policy to local needs and contexts is questionable.A vibrant debate over how to attend to illegal commercial wildlife trafficking and other risks associated with global environmental conflicts is ongoing; some argue associating illegal biodiversity exploitation with environmental insecurity problematically limits response options to those within the militaristic sphere and hampers exercise of justice because borderlands become the site of security interventions . In partResults herein offer, to our knowledge, one if not the first exploration of local perceptions of illegal biodiversity exploitation and environmental insecurity. Data challenge certain assumptions and validate others. Simple regression analysis helped us consider participant perceptions about precursors to different types of illegal biodiversity exploitation. Among our study participants, if the policy objective is to reduce or mitigate charcoal production in a protected area, it is essential to focus on the psychological aspect of associated risk perception as opposed to the socio-environmental dimensions of environmental insecurity such as access to land to grow food or a reliable source of clean drinking water. It may be the case that broader, large-scale socio-environmental processes and influences were less salient in the minds of our study participants. Indeed, others have found gaps in understanding the causes and consequences of climate change from populations vulnerable to drought associated with climate change . Among oWe found myths of nature influenced environmental insecurity. Our results suggest that individuals who do not believe nature to be resilient have higher risk perceptions and perceptions of environmental insecurity. These same individuals may be less likely to accept risks and demand counteraction from managers. Interestingly, findings also point to greater perceptions of environmental insecurity and perceptions of rates of biodiversity exploitation via logging for those that believe nature to be random. Culturally-generated beliefs about nature can have important implications for preferred risk responses and overall goals of nature management and biodiversity conservation. If nature, and thus environmental change, is culturally considered to be random, environmental risks and certain exploitive activities may be more acceptable. Alternatively, if nature is considered fragile, environmental risks may undermine environmental security and tolerance for biodiversity exploitation. Although our study is limited in its ability to model all involved concepts, results suggest further exploration of the relationships between local perceptions of risk and risk response, environmental insecurity and biodiversity exploitation would be fruitful because these cognitions influence behavior. If behavior change, such as compliance, is a desired policy outcome, attitudes must be considered . ConservSome security experts recognize threats to security of the homeland and environment differ greatly by degrees of intention and levels of violence . These dA final confounding factor is the possibility that when some forms of illegal biodiversity exploitation are being perceived as threats to security in general, there is the danger that the citizens of one country will resent exploitation from other countries more so than exploitation created by their fellow citizens . This coUltimately, all of these possibilities remain empirical questions and warrant additional research from the global environmental change community, particularly from the local perspective and potentially stratified by sociodemographics . This is because changes explored at the globally and regionally averaged level can mask important local exceptions to general trends that areS1 FileFigure A. Interview instrument. Table A. New variables created for analysis.(DOCX)Click here for additional data file."} +{"text": "Inadequate retention can introduce bias and reduce the power of a trial. The aim of this qualitative study was to elicit detailed accounts from trialists regarding strategies used to enhance retention in clinical trials.A purposive sample of five trials was selected from the Health Technology Assessment Portfolio of currently funded trials. Semi-structured interviews explored methods utilised by trial teams when collecting data and retaining participants. The data was analysed thematically using techniques of constant comparison.Clear and cohesive definitions of retention were given. However, there was less agreement about the concept of \u2018withdrawal\u2019 from a trial. More experienced trialists emphasised different levels of withdrawal and were happy to negotiate with participants in order to at least collect primary outcome data. Novice trialists presumed the participants wanted to withdraw from all aspects of the trial and made no further contact with them.Research Nurses used their interpersonal skills to motivate participants to remain in their trials. This required time not routinely acknowledged within the funding of trials.Participants described proactive and reactive approaches to retention. Proactive approaches involved anticipated and considered strategies, both formal and informal, to maintain retention. Conversely, reactive approaches were typified by unanticipated and spontaneous strategies, some formalised others informal, developed in response to retention problems during the trial.The experience of trialists influences their actions during the retention of patients. Recommendations from this study highlight the need for sharing proactive approaches to retention that will benefit the trials community."} +{"text": "Cystic fibrosis (CF) is a genetic disease characterised by chronic bacterial infection of the lung and destruction of lung tissue eventually leading to respiratory failure. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. Current treatment focuses on managing the symptoms of CF including antibiotic therapy against respiratory infections and vitamin and enzyme supplements to treat pancreatic insufficiency. However, a new drug known as ivacaftor has been approved recently that treats the underlying defect and corrects the defective CFTR in carriers of the G551D mutation. Neutrophils in CF fail to eradicate pathogens causing lung infections. Reports suggesting dysregulated neutrophil activity in CF illustrated altered gene expression and increased release of proteases from primary granules. However, it remains unknown whether neutrophil dysfunction is due to chronic inflammation or the CFTR defect. Our hypothesis is that impaired neutrophil activity in CF is directly caused by a lack of CFTR protein and function. Therefore, the aim of this study was to examine CFTR expression in neutrophils by optimising the methods for optimal CFTR protein detection, by comparing the levels of expression of mature CFTR protein in healthy control and CF neutrophils to epithelial cells and by examining the function of the CFTR channel in neutrophils.Ethical approval was obtained from Beaumont Hospital institutional review board. Cell proteins were isolated from purified neutrophils from healthy controls and CF patients. The CFTR protein was investigated by Western blot analysis. Healthy control cells were loaded with the chloride sensitive dye MQAE and changes in intracellular chloride were measured following treatment with the CFTR inhibitor CFTR(inh)-172 (10 mM) to examine the function of the channel.Results clearly confirm the expression of the CFTR channel in neutrophils with levels of the mature, membrane CFTR being reduced in CF cells. Inhibition of CFTR function using the CFTR(inh)-172 resulted in accumulation of cytosolic chloride in healthy neutrophils.The results of this study strongly support a role for CFTR in neutrophil activity and dysfunctional CFTR may directly cause the impaired neutrophil killing ability which is observed in CF patients. Additionally, the presence of the CFTR protein makes it possible to treat neutrophil dysfunction directly using new drugs such as ivacaftor that correct the CFTR defect. This study was funded by the Alumni Office Claire and Nid Afdhal Award in Medicine."} +{"text": "Metastasis, the life threatening aspect of cancer, is a systemic disease process. Considerable progress has been made in recent years regarding how tumor cells circulating in the blood and lymphatic systems interact with and extravasate into secondary sites, and what determines whether these disseminated tumors cells survive, remain dormant or go on to form macrometastases. New insights into the routes that tumor cells take once leaving the primary tumor have emerged. Novel concepts regarding early seeding of metastases coupled to parallel progression, self-seeding of primary tumors by circulating tumor cells, and the induction of pre-metastatic niches in distant organs by primary tumors have come to the fore. In our presentations we will review these and other paradigm shifts that have taken place over recent years, placing a particular focus on how the use of intravital and other imaging techniques have played a major role in these developments."} +{"text": "Trauma places a massive burden on national economies, costing countries billions of dollars each year in healthcare, law enforcement and productivity. According to annual reports by police and government officials, road traffic accidents are the second most common cause of mortality after cardiovascular events among civilians in Iran . ImmediaOne of the problems with trauma care in our country is a lack of coordination among nationwide TC and trauma system organizations. Although clinical management of trauma patients has improved vastly in recent decades, however, decreasing the burden of injuries necessitates an organized approach in order to prevent and manage trauma in the context of an organized national trauma system . Trainin"} +{"text": "Bacillus thuringiensis genes reduce performance of target pests whereas upregulation of endogenous resistance traits e.g., phenolics, generates variable results. Our review identified very few studies estimating the realized benefits in tree growth of GM trees in the field. This is concerning as the realized benefit with insect resistant GM plants seems to be context-dependent and likely manifested only if herbivore pressure is sufficiently high. Future studies of secondary pest species and resistance evolution in pest to GM trees should be prioritized. But most importantly we need more long-term field tests to evaluate the benefits and risks with pest resistant GM trees.Climate change, as well as a more intensive forestry, is expected to increase the risk of damage by pests and pathogens on trees, which can already be a severe problem in tree plantations. Recent development of biotechnology theoretically allows for resistance enhancement that could help reduce these risks but we still lack a comprehensive understanding of benefits and tradeoffs with pest resistant GM trees. We synthesized the current knowledge on the effectiveness of GM forest trees with increased resistance to herbivores. There is ample evidence that induction of exogenous It has been estimated that trees can become a major source of bioenergy and help mitigate the anticipated rise in CO2 over the next 50 years and the gypsy moth (Lymantria dispar) can inflict substantial (up to 40%) stand losses . Coyle et al. technology is much more specific and is not hampered by the constraint of traditional breeding, e.g., late flowering, slow maturation, long reproductive cycles, and complex mating systems (including self-incompatibility and a high degree of heterozygosity) in trees. Difficulties in identifying the best parents (and controlling their mating), maintaining genetic gain with high heterozygosity toxins. The principal difference between these two approaches is that endogenous traits are something that herbivores have evolved mechanisms to deal with, e.g., some specialists use plant derived chemicals for their own defense such as phenolics and the second is to introduce new traits (exogenous traits) such as the production of However, even if GM trees with increased resistance to herbivores have been available for more than 25 years, we still lack knowledge on the efficiency of different modifications for resistance in reducing damage by forest pests and thereby enhancing tree growth. Lab studies evaluating resistance are relatively common but field studies are rare with increased resistance to herbivores. More specifically we ask how effective different types of enhanced resistance are at reducing damage by pests and how well this translates into increased growth and production in GM trees. In addition, based on the above synthesis we highlight areas of uncertainty and suggest future directions for resistance enhancement in GM trees.To collect the necessary literature we used the following search string in Web of Science: Tree and [ and (resistance) and (herbivores)]. Selected articles included studies on preference and performance of herbivores, and damage on plants and effects on plant performance in terms of growth and biomass production.Populus sp.Populus became the first genera to be genetically transformed and regenerated , was unaffected on Bt aspens. Furthermore, non-target herbivores belonging to different genera than the target pests seem unaffected by Bt plants as phenolic glucosides can deter herbivores are urgently needed. Still, potential drawback with the use of endogenous defenses is the intraspecific variation in insect adaptation to endogenous plant defenses foraging on Bt corn lacking the target pest species European corn borer and corn earworm (Helicoverpa zea). Similarly, Lu et al. (Helicoverpa armigera). Thus, secondary pest species could develop into a major problem in GM tree systems and strategies to counteract such development should be developed.Secondary pest species could reduce the benefits of insect resistant GM trees. Raffa suggesteu et al. found prChrysomela tremulae rapidly evolved resistance to sprays of Bt toxins in the laboratory and in the field (Augustin et al., Resistance evolution in pests is a topic of debate which may be of special concern when it comes to long lived crops such as trees. Resistance evolution in pests and weeds toward different pesticide treatments are not uncommon (Tong et al., Most studies of resistance in GM trees have been conducted on deciduous trees. However, many of the most commercially important forest trees are conifer. Furthermore, many of the pest species on conifers are not leaf-feeders but rather cambium feeders, e.g., bark beetles. It is unclear how they might respond to induction of resistance traits in growing tissue, such as leaves, because other defense mechanisms, such as resin flow, confer resistance against these types of herbivores (Boone et al., The knowledge gaps identified in this review involves the efficiency of upregulated endogenous defenses on pest species. As some specialist pest species are adapted to deal with some types of plant defenses and even use them as defenses themselves, their response to resistance enhancements might not be the expected (Pentzold et al., The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "New proteins introduced in foods through genetic engineering or processing are often evaluated for potential risks of eliciting food allergy . The primary risk is the transfer of an allergen or a protein nearly identical to an allergen and capable of causing IgE mediated cross-reactions into a new food source. The AllergenOnline.org database was developed to provide a curated set of allergenic sequences for bioinformatics comparisons to identify proteins that should be tested further (e.g. serum IgE binding). Curation is necessary as the scientific literature and general sequence databases include thousands of proteins labeled as allergens that lack proof of allergenic activity.In 2006 we developed guidelines for reviewing and classifying candidate proteins as \"allergens\", \"putative allergens\" and those with \"insufficient evidence\" of causing IgE mediated allergic reactions in humans. Airway, contact, venom, salivary and food allergens are included. Criteria were developed for judging allergic subjects; allergen sources; protein characteristics, sequences; allergenic activity and IgE binding. Candidate allergens and peer reviewed publications are identified from the NCBI Protein and PubMed databases using keywords for review by our panel. Data, evaluations and decisions are stored in an achieved data management system during an annual update process. Access and FASTA searches are free, anonymous and unrecorded.We evaluate: descriptions of allergic and control subjects ; symptom onset; route of exposure ; diagnostic methods . We consider allergen source information ; evidence the protein is present in the test material; protein characterization and source ; sequence and methods (cDNA or protein sequence); molecular mass and glycosylation status. Specific IgE measurements should include standards, controls, details of critical reagents and scoring criteria. Tests should purified proteins as well as extracts to demonstrate relevance. Four examples are presented.Data quality and evidence of the importance of individual allergens varies markedly while the rate of publication of poorly described allergens and sequences is rising rapid."} +{"text": "Intracellular renin and angiotensin disrupts chemical communication in heart.Epigenetic modification of renin angiotensin aldosterone system (RAAS) and heart disease.Intracrine renin angiotensin and metabolic cooperation.Gap junction, intracellular renin and angiotensin, cellular patterns, and heart development.The finding that intracellular renin and angiotensin II (Ang II) disrupts chemical communication and impairs metabolic cooperation between cardiomyocytes induced by aldosterone, hyperglycemia, and pathological conditions like myocardial ischemia is discussed. The hypothesis is presented that epigenetic changes of the renin angiotensin aldosterone system (RAAS) are responsible for cardiovascular abnormalities, including the expression of RAAS components inside cardiac myocytes (intracrine RAAS) with serious consequences including inhibition of electrical and chemical communication in the heart, resulting in metabolic disarrangement and cardiac arrhythmias. Moreover, the inhibition of gap junctional communication induced by intracellular Ang II or renin can contribute to the selection of cellular patterns during heart development. Cells are functional units, which play a fundamental role on tissue and organ functions. The cellular arrangement established during embryonic development is governed by several genes, which regulate the properties of surface cell membrane including the expression of receptors and ligand molecules such as glycoproteins which make possible the recognition and the interaction between cells. In this process, chemical communication between cells play an important role making possible the establishment of cellular patterns, which are essential for tissue and organ development , 2. The The gap junction permeability is modulated by different factors such as intracellular Ca concentration and cyclic AMP, which enhances the permeability of intercellular channels through the phosphorylation of the gap junction proteins (connexins) , 9. ReceThe transfer of chemical signals between cells seems to play a decisive role during tissue regeneration , and morin utero, can induce the later development of disease including the overexpression of AT1b receptors in the adrenals and hypertension axis activation during embryological development cannot be discarded because recent studies revealed that ACE2 contributes to the postnatal development of the heart, enhances coronary artery remodeling, and causes cardiac hypertrophy , 46. In Recently, Ang 1\u20137) has been found in the nuclei of NRK-52E renal epithelial cells , but the\u20137 has beFuture studies on the influence of intracellular renin and Ang II on the interchange of chemical signals between cardiac cells will provide a better knowledge of how metabolic cooperation contributes to heart physiology and disease and will help the development of novel therapeutic approaches for cardiac diseases.(1) Intracellular renin disrupts the chemical communication between heart cells with serious consequences for metabolic cooperation and electrical synchronization in the heart. The finding that there is a renin transcript overexpressed during myocardial infarction might indicate that an increase of renin inside the heart cell is an important cause of functional disarrangement; 2) gap junctions play an important role on metabolic cooperation between heart cells and are involved in the establishment of cellular patterns during heart development as well as in the adult heart; (3) the hypothesis is presented that epigenetic changes of the RAAS are responsible for hypertension and cardiovascular abnormalities including the expression of RAAS components inside cardiac myocytes (intracrine RAAS) (see Figure gap juncThe author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Congenital Heart Disease (CHD) is the most common congenital defect. Many families with left-right laterality defects and complex CHD have an unknown genetic aetiology. Many ciliopathies, including Primary Ciliary Dyskinesia (PCD), are associated with intracardiac defects. The role of primary cilia in cardiac morphogenesis remains unknown, although cardiac cilia have roles that are distinct from the definition of laterality at the embryonic node. We hypothesise that defects in genes important in the assembly and function of cilia are responsible for some inherited forms of CHD.This research project aims to recruit families with a recurrence of CHD and to perform Whole Exome Sequencing (WES) to identify putative pathogenic variants and to delineate novel genetic causes of CHD.Twelve families have now been recruited and WES has been carried out in seven of these families using paired-end sequencing. Data analysis follows a standardised pipeline to call and then filter variants in order to assess their pathogenic potential. Variants are prioritized on the basis of known or suspected function of the encoded protein, and publicly-available RNA expression data.Variant filtering has allowed the identification of a limited number of candidate variants in recruited families. Of particular interest, a likely causative homozygous variant within a PCD gene has been identified in two siblings affected with heterotaxy, thus confirming a link between ciliopathies and CHD. The function and interactions of identified genes will be assessed, using cellular techniques and animal models, to provide insights into the pathogenesis of CHD."} +{"text": "Juvenile idiopathic arthritis (JIA) is not a disease, but an exclusion diagnosis that encompasses all forms of arthritis that begin before the age of 16 years, persist for more than 6 weeks, and are of unknown origin. This heterogeneous group of chronic arthritides has been classified on clinical and laboratory grounds to try to identify homogeneous, mutually exclusives categories suitable for etiopathogenic studies. During the last years evidence has accumulated suggesting that while some JIA categories identify quite definite disease entities, others represent heterogeneous conditions and in particular that a homogeneous disease entity is included in several different JIA categories. These and other findings suggest the need to reconsider some aspects of the current International League of Associations for Rheumatology (ILAR) JIA classification and nomenclature.None declared."} +{"text": "The evolution of rodents cages marked major improvements of animal and staff protection. Aspects pertaining to animal welfare and the need for higher flexibility in space used led to the development and success of Individually Ventilated Cages (IVCs), extensively used in modern animal facilities. The concept of \"room at cage level\" along with the latest innovations in IVCs will be reviewed.The presentation will highlight how specific abilities to provide native integration among IVCs, laminar flow equipment, washing and decontamination equipment and potentially automation can lead to more efficient planning and later effective exploitation of Lab Animal facilities, as well as to significant bottom."} +{"text": "Subcutaneous allergen-specific immunotherapy (SCIT) is a valuable treatment option for patients with controlled mild to moderate allergic asthma However, SCIT is contraindicated for patients with severe persistent asthma due to a potential systemic allergic reaction. Several studies in adolescents and adults with persistent allergic rhinitis and moderate persistent allergic asthma have shown that SCIT is better tolerated when combined with. Nevertheless, no previous studies have been conducted in children and adolescents with severe asthma to assess the safety and efficacy of a combination treatment of SCIT and omalizumab.We report here the observations of six patients, aged 11 to 21 years, with severe persistent asthma controlled by omalizumab as add-on therapy who received SCIT under a cluster protocol during omalizumab treatment and then SCIT maintenance alone after discontinuation of omalizumab.Although no patients experienced severe exacerbation, one patient had to stop SCIT after one month of treatment because of uncontrolled asthma. For the five remaining patients, asthma control continued to improve during the combined treatment with SCIT and omalizumab (median time duration = 8 months) despite a decrease in maintenance treatment for all of them. SCIT was continued alone for a median time of 25.5 months and was well tolerated. For these patients, asthma was totally controlled and therapeutic levels of maintenance treatment could be further reducedPretreatment by omalizumab for patients with persistent severe allergic asthma seems to improve the safety and probably also the efficacy of SCIT. These results open up perspectives of SCIT for children suffering from severe allergic asthma. However,the primary outcomes of these observations are not included in a standardized protocol and will require further confirmation by prospective double blind studies."} +{"text": "Research during the past decade highlights the strong link between appetitive feeding behavior, reward, and motivation. Interestingly, stress levels can affect feeding behavior by manipulating hypothalamic circuits and brain dopaminergic reward pathways. Indeed, animals and people will increase or decrease their feeding responses when stressed. In many cases, acute stress leads to a decrease in food intake, yet chronic social stressors are associated to increases in caloric intake and adiposity. Interestingly, mood disorders and the treatments used to manage these disorders are also associated with changes in appetite and body weight. These data suggest a strong interaction between the systems that regulate feeding and metabolism and those that regulate stress and ultimately mood. This Research Topic compiles a number of review and research articles that focus how hormonal mechanisms regulate the nexus between feeding behavior and stress. It highlights the hormonal regulation of hypothalamic circuits and/or brain dopaminergic systems, as the potential sites controlling the converging pathways between feeding behavior and stress.The regulation of energy balance is controlled by hypothalamic nuclei that include the arcuate nucleus (ARC), a mediobasal hypothalamic region that has access to circulating peripheral signals including those that regulate metabolism and stress. Neuropeptide Y (NPY) neurons within the ARC were identified over three decades ago as potent stimulators of food intake and adiposity, and later on as important regulators of the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic activity, and anxiety related behaviors. In this issue, Sundstrom et al. use a ZeIn addition to ghrelin, other peptide hormones have been implicated in stress induced feeding and psychopathology. For instance, Merali and colleagues draw attention to the bombesin family of peptides and provide intriguing evidence that they regulate stress-induced anorexia or obesity depending on subtle differences in neural circuitry and neurochemical phenotypes (Merali et al., Collectively, the articles published in this research topic offer an in depth analysis of how neuroendocrine mechanisms connect feeding behavior and stress. All articles offer unique and novel elements on this topic and we hope you enjoy.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Nutrition is an integral component to any athletes training and performance program. In adults the balance between energy intake and energy demands is crucial in training, recovery, and performance. In young athletes the demands for training and performance remain but should be a secondary focus behind the demands associated with maintaining the proper growth and maturation. Research interventions imposing significant physiological loads and diet manipulation are limited in youth due to the ethical considerations related to potential negative impacts on the growth and maturation processes associated with younger individuals. This necessary limitation results in practitioners providing nutritional guidance to young athletes to rely on exercise nutrition recommendations intended for adults. While many of the recommendations can appropriately be repurposed for the younger athlete attention needs to be taken towards the differences in metabolic needs and physiological differences. Current estimates suggest approximately 35 million youth between the ages of 5\u201318 years participate in organized sports each year and docosahexaenoic acid [DHA]). Increased dietary intake of these essential fatty acids has been associated with decreased prevalence of cardiovascular diseases , 72, as o et al. . Howevero et al. , 77, 81,Other benefits of fish oil consumption have been noted including improved cognitive function and reduced ADHD symptoms in children . A meta- potentially have a favorable effect on anabolic effects of exercise which could be related to increased testosterone synthesis. However, given the strong relationship between growth, maturation, and anabolic hormone levels in youth, the demands for youth athletes to intentionally manipulate hormone levels are not advised.CLA is another lipid based dietary supplement that has been proposed to improve athletic performance . CLA is Human metabolism relies primarily on the oxidation of fats and carbohydrates as its fuel sources. As physiological intensity increases from rest to vigorous there is a transition from fat functioning as the primary fuel source to carbohydrate supplying a majority of the body's fuel for energy. The sources of carbohydrate for metabolism are glycogen stores in the muscle, glycogen stores in the liver, and exogenous carbohydrate entering the blood stream through the ingestion of carbohydrate. Some confusion exists in athletes understanding of the specific carbohydrate needs and it has been suggested by Burke et al. to stem from the fact that many recommendations are based on percentage of total caloric intake which adds to the difficulty in understanding the dietary needs of carbohydrate in athletes that have caloric intakes which often exceed general recommendations .General carbohydrate intake recommendations suggest adult athletes consume 5\u201312 grams of carbohydrate per kilogram per day dependent on their primary form of exercise/activity, activity intensity, sex, and environmental conditions . The greThe role of carbohydrate ingestion around active occasions is an area of intense study. Early research into carbohydrate's role in exercise performance examined the effect of blood glucose levels and physiological state following prolonged exercise , 92. AddIt is commonly suggested that normal body stores of carbohydrate can be a significant fuel source for approximately 90\u2013120 minutes of moderate to vigorous exercise. While this statement is accurate in many exercise settings where individuals are exercising at moderate-vigorous intensities typically associated with endurance exercise, more detailed investigation would demonstrate exercise intensity is a vital component in understanding glycogen depletion rates. Significant glycogen depletion can occur anywhere from ~10 minutes with supramaximal intensities to greater than 3 hours at low exercise intensities . This ovAs stated previously part of our limited understanding in the nutritional needs of young athletes is the result of proper research ethics. The research described above with adults involved muscle biopsies, exercise to failure, and exercise resulting in \u201cpoor\u201d physiological states. This type of request would be inappropriate to make to children. Therefore most of our understanding of youth athletes comes from the utilization of less invasive techniques. Young athletes have been shown to have a lower respiratory exchange ratio (RER) during exercise at similar relative submaximal intensities and the American Dietetic Association (ADA) recommend nutrients be obtained from food sources rather than supplements in healthy children . LikewisThe daily time constraints of an elite young athlete can make achieving a balanced diet difficult, thus putting these individuals at a potential increased risk for micronutrient deficiencies as well. These deficiencies are most commonly observed in girls rather than boys and in mineral intake rather than vitamin intake. Athletic youth may actually be more likely to achieve the recommended intake of vitamins than nonathletic youth due to their increased total caloric intake. Adequate intake of minerals appears to be a bigger challenge for youth, particularly girls . SpecifiIron deficiency and subsequent anemia are common in adolescents . IncreasCalcium requirements are greatest during adolescence, 1,300\u2009mg per day for both boys and girls . This hiAn additional consideration warranting attention in young athletes participating in large amounts of training and competition is the potential need to replenish sodium and potassium lost in sweat. The summation of the electrolyte loss resulting from sweat loss has been shown to be equivalent to daily intakes, even in young athletes . Much ofResearch regarding the nutritional needs of young competitive athletes is sparse and is primarily composed of investigations of youth-adult differences. In addition to the limited research, the majority of our current knowledge in the adult population is based on differences between typical adults compared to their more active counterparts. Research to date suggests similarities in the caloric and macronutrient needs of active adults and their younger counterparts; however, youth-adult differences in fuel utilization have also been clearly demonstrated. In addition to the energy needs of highly active youth, nutritional intake plays a critical role in the growth and development of young athletes and should be a principal emphasis at this stage in their lives. General guidelines for nutrition for active youth are summarized in"} +{"text": "Conservation physiology has great potential to help us understand how migratory animals interact with current and future anthropogenic threats. Migration is inherently challenging such that additional stressors derived from altered environments or interaction with human infrastructure or activities could lead to long-term changes to migratory phenotypes. Migration is a widespread phenomenon among many taxa. This complex behaviour enables animals to exploit many temporally productive and spatially discrete habitats to accrue various fitness benefits . Human activities and global environmental change represent potential threats to migrating animals , and research is underway to understand mechanisms that control migration and how migration responds to modern challenges. Focusing on behavioural and physiological aspects of migration can help to provide better understanding, management and conservation of migratory populations. Here, we highlight different physiological, behavioural and biomechanical aspects of animal migration that will help us to understand how migratory animals interact with current and future anthropogenic threats. We are in the early stages of a changing planet, and our understanding of how physiology is linked to the persistence of migratory animals is still developing; therefore, we regard the following questions as being central to the conservation physiology of animal migrations. Will climate change influence the energetic costs of migration? Will shifting temperatures change the annual clocks of migrating animals? Will anthropogenic influences have an effect on orientation during migration? Will increased anthropogenic alteration of migration stopover sites/migration corridors affect the stress physiology of migrating animals? Can physiological knowledge be used to identify strategies for facilitating the movement of animals? Our synthesis reveals that given the inherent challenges of migration, additional stressors derived from altered environments or interaction with human infrastructure or activities (e.g. fisheries) could lead to long-term changes to migratory phenotypes. However, uncertainty remains because of the complexity of biological systems, the inherently dynamic nature of the environment and the scale at which many migrations occur and associated threats operate, necessitating improved integration of physiological approaches to the conservation of migratory animals. Migration is one of nature's most captivating phenomena. Migratory movements can be as vast as the transcontinental treks of African wildebeest or as minute as diel vertical migration of zooplankton within metres of the water surface. Movement is an inextricable component of animal behaviour, but migration is distinct from dispersal or station-keeping behaviours because it is predictable, directional and persistent , owing tLife-history phenotypes such as migration are expressed through behaviours exhibited by individuals in response to internal changes to their physiology . PhysiolOver the last several decades, global changes and biodiversity losses have created a challenging landscape for conservation science. Climate change, habitat alteration, species invasions and pollution are altering landscapes and creating new challenges for animals. Migratory species represent a unique challenge because of their high mobility and their reliance on multiple habitats to complete their life history, meaning that they may be subject to multiple and varied threats in different habitats such that predicting and understanding their ability to adapt is difficult . ConservThe success of migration depends on an animal's ability to orient and navigate along migratory paths and requires physiological mechanisms for taking the best migratory route . Birds , sea turLight from the sun and other celestial bodies can be entrained by migrating animals for orientation . SpecifiOncorhynchus masou in coastal regions demonstrated a reduced ability to locate and enter natal streams use these chemical signatures to follow movements of conspecifics to feeding areas and hibernacula and to locate partners during vernal breeding migrations after even temporary exposure based on observations of high energy intake in certain hotspots of the Pacific Ocean.Behavioural strategies are combined with physiological mechanisms to limit the cost of transport and maximize distance that it is possible to travel per unit of fuel. During migration, animals exploit wind and ocean currents for conveyance along the migration path . The neeThe timing of migration exerts a considerable influence on fitness because it affects resource availability. Properly timed migration is important for avoiding unfavourable conditions and arriving at stopover sites and the ultimate destination at an appropriate time when environmental conditions are suitable. Mismatched timing may result in migrations coinciding with depleted food sources at stopover sites or reduced breeding opportunities at the destination . The timPreparation for migration begins prior to departure and ensures that energetic reserves are sufficient for the journey . ConsequAn important consequence of relying on fixed signals, such as photoperiod, is that changes to the climate result in the temporal mismatch of key life-history events of migratory animals from suitable environmental conditions . However, there is evidence of plasticity in the timing of migration because birds can adjust their migration timing, for example to compensate for poor weather . NonetheThe rate of migration and timing of arrival are controlled by multiple factors, including intraspecific differences, particularly when early arrival confers fitness benefits. The rate of movement is likely to be related to optimization of energy use e.g. . The exaSalmo salar) fisheries, release from recreational fisheries is associated with anomalous downriver movement, migratory delays and shorter migration and reduce bird strike and then training them to migrate from Wisconsin to Florida using ultralight aircraft was viable on the basis of their normal faecal corticosterone profiles during the assisted migration. Selective breeding of individuals that are adequately adapted to specific changing environmental conditions is a drastic measure that could improve stocks of migratory species via enhancement programmes. For example, there is evidence that different populations or stock complexes of salmon are better equipped for climate change as a result of aerobic acclimation to high water temperatures and phenological processes that support those events, including favourable temperatures, vegetation bloom and insect emergence. It is difficult to use physiological knowledge or tools to counteract the likely effects of mismatched timing, particularly for animals that rely on fixed cues, such as photoperiod . HoweverIn an era of substantial human-induced rapid environmental change, science is increasingly focused on generating solutions to conservation problems . There iIn the midst of unprecedented change, a comprehensive understanding of how oncoming disturbances will affect ecosystems remains elusive and requires better baseline information about animal physiology. Migratory species are an important point of conservation emphasis given their ecological and economic importance. R.J.L. and J.M.C. were supported by the Natural Science and Engineering Research Council of Canada (NSERC) Graduate Fellowships. S.J.C. was supported by NSERC and the Canada Research Chairs programme."} +{"text": "Disordered eating is common among adolescent females. Clinical eating disorders are associated with high rates of depression and anxiety in adulthood. However, the extent to which this is the case for subthreshold disordered eating remains unclear, and raises issues for early detection and intervention, prognosis and treatment planning. The current study aimed to enhance knowledge on the longitudinal course of adolescent onset disordered eating and young adult psychopathology ; and to establish whether the outcomes differed among males and females. Longitudinal data from a large community sample, the Australian Temperament Project (ATP) was utilized, with respect to disordered eating staus during adolescence and mood and anxiety symptoms in early adulthood (N = 686). Overall, adolescents meeting the criteria for subthreshold disordered eating have higher levels of anxiety in adulthood compared to the non-disordered eating group. Furthermore, males with disordered eating experienced higher levels of depression at eight-year follow up. Given the level of subsequent psychopathology associated with adolescent onset disordered eating, targeting preventative interventions at adolescents with subthreshold disordered eating may reduce the risk of developing a clinical eating disorder as well as reducing the risk of developing depression and anxiety in early adulthood.Disordered Eating and Body Image stream of the 2014 ANZAED Conference.This abstract was presented in the"} +{"text": "SVDs) of the brain are likely to become increasingly common in tandem with the rise in the aging population. In recent years, neuroimaging and pathological studies have informed on the pathogenesis of sporadic SVD and several single gene (monogenic) disorders predisposing to subcortical strokes and diffuse white matter disease. However, one of the limitations toward studying SVD lies in the lack of consistent assessment criteria and lesion burden for both clinical and pathological measures. Arteriolosclerosis and diffuse white matter changes are the hallmark features of both sporadic and hereditary SVDs. The pathogenesis of the arteriopathy is the key to understanding the differential progression of disease in various SVDs. Remarkably, quantification of microvascular abnormalities in sporadic and hereditary SVDs has shown that qualitatively the processes involved in arteriolar degeneration are largely similar in sporadic SVD compared with hereditary disorders such as cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Important significant regional differences in lesion location within the brain may enable one to distinguish SVDs, where frontal lobe involvement appears consistently with almost every SVD, but others bear specific pathologies in other lobes, such as the temporal pole in CADASIL and the pons in pontine autosomal dominant microangiopathy and leukoencephalopathy or PADMAL. Additionally, degenerative changes in the vascular smooth muscle cells, the cerebral endothelium and the basal lamina are often rapid and more aggressive in genetic disorders. Further quantification of other microvascular elements and even neuronal cells is needed to fully characterize SVD pathogenesis and to differentiate the usefulness of vascular interventions and treatments on the resulting pathology.Small vessel diseases ( Small vessel disease (SVD) of the brain is common in community\u2010dwelling elderly subjects NOTCH3 gene polymorphisms In recent years, much knowledge has come forth from the study of several monogenic disorders, which model sporadic SVD. Many of the characteristic clinical and pathological features of these and other rarer disorders bear considerable similarities to sporadic SVD Table\u2009. In partSVD remains a heterogeneous disease, and therefore, one of the greatest challenges toward studying SVD and relating this to dementia lies in the lack of consistent assessment tools for both clinical and pathological measures. For example, most clinical assessments of cognition in demented cohorts tend to concentrate on memory focused cognitive assessments used in memory clinics with a tendency to focus on AD\u2010based dementia. Ideally, there also needs to be more detailed assessment of vascular disease\u2010related clinical symptoms such as impaired gait, falls, depression and incontinence This review focuses on highlighting morphological differences in age\u2010related sporadic and various hSVDs, other than those caused by CAA, with the intent of identifying and quantifying key features that inform about the pathogenesis of the arteriopathy and the parenchymal changes. In addition, we summarize the available methods to assess microvascular pathology and discuss some advantages of gathering quantitative data for assessment of the burden of vascular pathologies that needs attention.Small vessel changes involve hyalinization of vessels, expansion of the perivascular space and pallor of adjacent perivascular myelin, with associated astrocytic gliosis Qualitatively, microvascular changes or their sequences do not appear to be necessarily different between sporadic SVD and the hSVDs. In CADASIL and CARASIL, this process is much more aggressive and intense In the early stages, small vessel changes likely lead to changes in the properties of the blood\u2013brain barrier (BBB), with chronic leakage of fluid and macromolecules resulting in tissue edema Various cells within the neurovascular unit, including astrocytes, VSMC, endothelial cells and pericytes, play a role in tissue perfusion and hemodynamic responses. Even subtle abnormalities in these cellular elements would accumulate to affect control of constriction and dilation as well as delivery of oxygen, glucose and nutrients to neuronal tissue.VSMCs within arteriolar walls and pre\u2010capillary arterioles serve as contractile elements and control blood flow responses in times of increased parenchymal demand Pericytes juxtaposed to cerebral microvessels, most prominently wrapped around capillaries have received recent attention Endothelial cell abnormalities and BBB dysfunction may further contribute to WM damage. Endothelial changes have been previously described in SVDs with particular reference to \u201cblebbing,\u201d change in volume of the cytoplasm and the presence of compact bundles of microfilaments within the cytoplasm of endothelial cells in CADASIL BBB disruption The basement membrane of cerebral vessels comprises several proteins, of which laminins, collagen (COL), nidogens and perlecans are the major constituents COL4A1 and COL4A2 are highly conserved, have gained particular importance in basement membrane changes in SVDs but also impact on large vessel disease COL4A1 and the COL4A2 genes have been linked to cerebral SVDs, which usually occur with systemic vascular abnormalities, causing a wide range of clinical phenotypes increases with age, and perivenous collagenosis (see previous discussion) increases in concert with leukoaraiosis Dilated PVSs are a frequent finding in the pathology of SVD Figure\u2009. Both neLarger areas of incomplete infarction may extend into the WM The accumulation of small, even miniscule, ischemic lesions is an important substrate of SVD Neocortical microinfarcts are increased in the presence of CAA Cerebral microbleeds are an imaging construct to represent ferromagnetic hemosiderin iron derived from extravasation of erythrocytes. Cerebral microbleeds detected by T2\u2010W* or echo gradient MRI are also associated with histopathological evidence of lipohyalinosis and CAA While there are agreed criteria for the assessment of various dementing disorders, including AD et\u2009alet\u2009alet\u2009alThe understanding of the cellular mechanisms on how cerebral arterial vessels alter with age or disease in the absence of atherosclerosis is still a matter for investigation. However, the degree of vessel wall changes is commonly reported in pathological assessments as a way of assessing extent of SVD Figure\u2009. This teet\u2009alet\u2009alAnother important obvious factor to consider is the size of the vessels. Okeda Another type of measurable cerebral change attributed to SVD is attenuation of the WM. We have previously shown that the greatest loss in myelin staining is encountered in VaD, most of which exhibited SVD The recognition of both sporadic and hereditary SVDs and their variants has enabled greater understanding of the heterogeneity of cerebrovascular disease. Recent advances in neuroimaging and quantitative vascular pathology demonstrate how SVD progresses and results in brain injury related to dementia. Quantification of degenerative changes within small cerebral vessels occurring during older age or caused by genetic defects are proposed to explain the progression of WM changes, resulting in leukoencephalopathy in both sporadic and monogenic SVDs. However, the initiating factors causing microvascular changes are the primary targets driving the progression of sporadic SVD need to be better understood."} +{"text": "Antibiotic resistance is present globally. Contributing factors in Cambodia include self-medication by the community, uncontrolled sale of antibiotics and unregulated antibiotic use in food animals.Our objective was to explore the prescribing practices of physicians in Cambodia and perceptions of antibiotic use and resistance in the country.A sample of 482 physicians from 6 national hospitals was surveyed for knowledge and prescribing practices using common disease scenarios. Focus group discussions (FGD) with physicians explored barriers to evidence-informed prescribing. Approval was given by health research ethics committee of Cambodia, UNSW Australia and ITM.Our preliminary findings from combining the survey and FDG results identified that while physicians were aware of antibiotic resistance and perceived prescribing antibiotics appropriately as difficult, they were unlikely to utilize their diagnostic microbiology service to assist their daily prescribing practice. The most common barrier to evidence-based prescribing was their habitual and routine prescribing practices and that of their peers instead of utilizing the microbiology service. Habitual prescribing practices remain unchanged despite the introduction of microbiology services. Surveyed physicians commonly reported that their patients at the time of admission had self-medicated. During discussions physicians reported that antibiotic choice was based on severity of clinical presentation: milder presentations were prescribed ampicillin and gentamicin while severe presentations or patients who had self-medicated were immediately prescribed ceftriaxone. Support from microbiology services was only accessed when patients did not respond to this prescribing regime.Antibiotic self-medication and resistance are among challenges for Cambodian physicians to prescribe antibiotics appropriately. Yet, their prescription is likely to be driven by their habit rooted from the era when there was no microbiology laboratory rather than seeking evidence from microbiology laboratory they can now access to. Training programs focusing on rational antibiotic prescribing are urgently needed.None declared."} +{"text": "Neural tube defects (NTDs) are congenital birth defects classified according to their resulting morphological characteristics in newborn patients. Current diagnosis of NTDs relies largely on the structural evaluation of fetuses using ultrasound imaging, with biochemical characterization used as secondary screening tools. The multigene etiology of NTDs has been aided by genetic studies, which have discovered panels of genes mutated in these diseases that encode receptors and cytoplasmic signaling molecules with poorly defined functions. Animal models ranging from flies to mice have been used to determine the function of these genes and identify their associated molecular cascades. More emphasis is now being placed on the identification of biochemical markers from clinical samples and model systems based on mass spectrometry, which open novel avenues in the understanding of NTDs at protein, metabolic and molecular levels. This article reviews how the use of proteomics can push forward the identification of novel biomarkers and molecular networks implicated in NTDs, an indispensable step in the improvement of patient management. Neural tube defects (NTDs) are congenital anomalies of the central nervous system and rank amongst the most common birth defects alongside congenital heart anomalies and genito-urinary defects . NTDs de\u2014The primary phase occurs in week 3\u20134 and involves the formation of the brain and neural tube from the caudal region to the upper sacral level .\u2014The secondary phase completes the distal sacral and coccygeal regions .The formation of the neural tube or neurulation, is the embryonic process that leads to the ultimate development of neural tube. This process can be broadly divided into 2 phases:Primary neurulation is associated with \u201copen\u201d NTDs and result in conditions including anencephaly, myelomeningocele (open spina bifida) and craniorachischisis. Conditions of NTDs which are associated with skin covering lesion sites of the spinal cord structure such as asymptomatic spina bifida occulta and severe spinal cord tethering are classed as \u201cclosed\u201d NTDs. These are traceable to disruption of secondary neurulation . PrimaryHistorical recordings of neural tube defects date back to the ancient Egyptian periods, which could be explained by the unmistakable clinical features observed in fetuses and infants . The cli2 or when geographical parameters may limit the use of good quality ultrasound screening at 18\u201322 weeks gestation . Ce. Ce89]. VANGL family of proteins, VANGL1 and VANGL2, due to their extreme amino identity and similarity. With the advent of the generation of monoclonal antibodies, immunopurification using antibodies specifically recognizing VANGL2 has been achieved. This provided the first detection and comprehensive biochemical characterization of the endogenous forms of these PCP proteins, demonstrating the ability of VANGL2 and VANGL1 to physically associate through their transmembrane domains to form a protein complex [The study of proteins involved in PCP has relied on the use of ectopic expression of proteins and Tag-based purification methods ,93. Endo complex . Throughatherosclerotic lesions. By analyzing the \u201csecretome\u201d of these lesions, it was noted that Hsp27 expression was correlated to the complexity of the artherosclerotic plaque [Research into cardiovascular diseases has provided some interesting insights into MS experimental strategies used to study disease characteristics of c plaque . Strategc plaque . ProteomElevated levels of the thiol-containing amino acid, homocysteine, is associated with NTDs. Computation models have been utilized to predict the reactivity of cysteine residues in proteins according to parameters such as accessibility of cysteine in a protein, pKa of free cysteines, and the dihedral strain energy (DSE) of a cysteine disulfide . Using tNeural tube defects are common congenital anomalies associated with various detrimental clinical features. Genetic studies using different animal models have been central in understanding the causative factors of the multifactorial etiology of NTDs. Clinical diagnosis of NTDs relies upon high-resolution ultrasound for detection of fetal abnormalities in the second trimester of pregnancy. However alternative methods that rely on biomarkers would be useful in reducing the costs of diagnostic techniques, providing earlier detection of NTDs and advance the development of in utero pharmacological treatments. Somewhat surprisingly, given that AFP diagnosis began in 1976 is the fact that only a small number of publications document the use of proteomics techniques for the detection of NTDs. However advances have been made in the differential analysis of proteins, discrimination of polymorphisms in populations, and identification of different protein factors and analysis of protein networks for use in neural tube defects. In the future, application of bioinformatics tools may be applied to understand the molecular mechanisms of NTDs, which may also help understand their relevance in regulating other cellular processes including cancer ,101,102."} +{"text": "Various speakers In a combined presentation and discussion session, representatives from academia and industry discuss the role of Biomarker trial design and implementation, to improve health by improving trials."} +{"text": "Recent advances in assisted reproductive technology (ART), coupled with the emerging understanding in molecular mechanisms of disorders of sex development (DSD) and that of associated genetic infertility, have given hopes for fertility in groups of patients who till recently were denied biological parenthood.Heterologous fertility potentiation, in the cytogenetic infertility by donor oocytes, has been successfully used by us and others. However, homologous fertility preservation for this group of patients is evolving. Cryopreservation of either the mature oocytes following ovarian stimulation in post -pubertal Turner Syndrome (TS) girls or that of ovarian tissue in prepubertal TS patients are to be applied before actual ovarian failure occurs. Single embryo-transfer and strict selection criteria and judicious use of this advanced technology are advocated to minimize maternal morbidity and mortality.Microdissection testicular sperm extractions (Micro-TESE) in azoospermic Klinfelter syndrome patients have resulted not only in successful retrieval of spermatozoa for intracytoplasmic sperm injection (ICSI) but also in normal fertilization and clinical pregnancies. Swyer\u2019s syndrome patients are reared as females and have female external and internal genitalia. However, with complete gonadal failure they need Oocyte donation with ICSI/IVFET for fertility. Those with partial androgen resistance (PAIS) due to genetic mutation of androgen receptor have a spectrum of abnormality like hypospadias, micropenis, undescended testes and male infertility. Though 46xy PAIS males have possibility of fatherhood complete AIS patients are female phenotype and are raised as females. This category of patients are encouraged and known to resort to fertilization of donated oocyte using husband\u2019s sperms. Resultant embryos are transferred into surrogate uterus.Advances in reproductive medicine in general and those in assisted reproductive technology in particular have revolutionized diagnosis of disorders of sex development and the management of the associated infertility. These advances have certainly provided fertility potentiation but require judicious application coupled with expert genetic counseling."} +{"text": "Captive breeding for conservation purposes presents a serious practical challenge because several conflicting genetic processes need to be managed in concert to maximize captive population persistence and reintroduction success probability. Because current genetic management is often only partly successful in achieving these goals, it has been suggested that management insights may be found in sexual selection theory . We review the theoretical and empirical literature and consider how female mate choice might influence captive breeding in the context of current genetic guidelines for different sexual selection theories . We show that while mate choice shows promise as a tool in captive breeding under certain conditions, for most species, there is currently too little theoretical and empirical evidence to provide any clear guidelines that would guarantee positive fitness outcomes and avoid conflicts with other genetic goals. The application of female mate choice to captive breeding is in its infancy and requires a goal-oriented framework based on the needs of captive species management, so researchers can make honest assessments of the costs and benefits of such an approach, using simulations, model species and captive animal data. In these programs, species may be \u2018preserved\u2019 in captivity awaiting release at an unspecified future date or captive breeding used in a supportive role to supplement dwindling wild populations . A cornerstone of this management is the equalization of founder representation in the population: this decreases selection (no variance in fitness) and slows the loss of genetic diversity. In practice, this is achieved using pedigree studbook information and \u2018match-making\u2019 sexual pairings that minimize the mean kinship between pairs. Despite the relatively beneficial population genetic outcome of such pairings, there has been little attention paid to potential genetic consequences of removing mate choice and sexual selection in captive breeding is generally smaller than the absolute population size (N), with Ne being the size of an idealized population with the same measure or rate of loss of some genetic quantity as that in the population under study can be derived from the breeder's equation , heritability (h2), the effective population size (Ne), and number of generations in captivity (t):Frankham postulatFrankham .e) and that for genetic adaptation to captivity . However, there is a direct conflict between the recommendation concerning ideal captive population size for minimizing genetic drift and inbreeding , while retaining it at the metapopulation level (managing the loss of genetic diversity). Although the idea has theoretical and some empirical support, evidence from captive populations is extremely limited \u2014that is, which animals should be released and which should remain in captivity? Earnhardt shows thCurrent captive breeding programs primarily focus on limiting the loss of genetic diversity through the careful management of sexual pairings (see above). The nonrandom access to breeding partners usually increases the among-individual variance in reproductive success with few individuals securing most of the fertilizations and therefore reducing effective population size and increasing inbreeding. For these reasons, captive breeding programs are mostly based on enforced monogamy. However, because of concerns that such management may increasingly limit population evolvability and fitness that arise through direct benefits to females , females laid more eggs when mated with preferred males (Cunningham and Russell Chlamydotis undulata), artificially inseminated females that were visually stimulated by attractive males had better hatching success and increased chick growth compared to those stimulated with less attractive males , females prefer to mate with males newly introduced or with rare phenotypes males failed to form breeding pairs with females too dissimilar at major histocompatibility complex (MHC) loci males that were genetically similar to the female achieved higher siring success than less genetically similar males compared to studies from wild populations where female choice is correlated with a limiting resource being provided by males. Third is the possibility that reproduction and survival (or current versus future reproduction) are traded-off against each other and house mice to a mutagenic treatment with ionizing radiation and then selected beetles under either enforced monogamy or sexual selection. After only two generations of sexual selection regime, the expression of male strength, a sexually selected trait, of irradiated beetles was almost twice as large as for the monogamous lines, and almost recovered the values of nonirradiated control individuals. In guppies, P\u00e9labon et\u00a0al. facing either enforced monogamy or sexual selection and looked at the extinction probability of each line. They found that 49% of the lines in the monogamy treatment went extinct versus 27% in the sexual selection group. In a similar experiment using the same species, Plesnar-Bielak et\u00a0al. , either pushed away from their adaptive peak by the income of migrant, maladapted, alleles. For each of these populations, they identified sexually successful and nonsuccessful males and used them to sire offspring. In agreement with the predictions, they found that sexually successful males sired unfit daughters in well-adapted populations, which corroborate the finding that sexual conflict produces a mismatch between sexual and nonsexual fitness in this species. However, sexually successful males sired fitter daughters in the populations where adaptation was prevented by the income of migrant alleles. This suggests that in unstable populations, the net benefit of purging deleterious alleles outweighs the cost of sexual conflicts. These results are mirrored by those reported by another recent study where the outcome of exposure to a regime of enforced monogamy versus polyandry depends on environmental quality were maintained for 39 generation either under enforced monogamy or polyandry. Beetles from these selection lines were exposed to a poor or a good environment in terms of food quality. Reproductive success of pairs formed by males from the sexual selection lines and females from the enforced monogamy was low when reared in the good environment, again suggesting that sexual conflict incurs cost. However, when sexually selected males were mated with enforced monogamous females in the poor-quality environment, their reproductive success was improved suggesting that the benefits of sexual section outweighed the cost of sexual conflicts under stressful conditions. Despite the evidence of a net benefit of female choice to population viability from many of these studies, and hence suggesting that captive population management would benefit by incorporating female choice, these \u2018benefits\u2019 have generally not been considered within the complex framework of interactions and conflicting goals for long-term population persistence . One means of preserving genetic integrity is incorporating female choice for male traits in captive breeding management. Based on current limited theoretical and empirical evidence, it appears that some mechanisms for mate choice may be safer to exploit than others. On the safer side are female preferences for compatible genes, general heterozygosity or allelic diversity at specific locus genes), and differential maternal investment based on male's attractiveness. At the riskier end of the spectrum is selection for good genes in the presence of sexual conflict, as this could favor adaptation to captivity in males while decreasing female fitness by creating unbalanced selection pressures with sexual selection on males, while natural selection is lifted on females. One possibility we have not explored in our review is sexual selection acting on females through male choice and female\u2013female competition; if and where this occurs, it could help balancing selection on both sexes and potentially obtain better results in terms of fitness for both. Another area still unexplored is the potential for integrating male\u2013male competition; however, the risks of favoring males best adapted to captivity would likely be the same as in the good genes hypothesis.To date, the main genetic focus of captive breeding programs has been on preserving genetic diversity, while genetic integrity is often neglected because of difficulty in measuring progress and conflicts with other genetic guidelines to look at specific management approaches, such has been successfully achieved in identifying ways to manage genetic adaptation to captivity through population fragmentation (Margan et\u00a0al."} +{"text": "We aimed to review existing regulations about HCWs vaccination in Romania and to identify the attitude and barriers to immunizations of HCWs through qualitative research.We collected information about HCWs vaccination policies and regulation implemented through laws and also data about specific vaccination . We conducted 5 focus groups with 39 participants , as part of the HProImmune project activities, in order to understand the risk perception behaviors towards vaccination and barriers stopping HCWs from immunization. We followed for each focus group a specific discussion guide elaborated by the HProImmune project.Each health facilities organize yearly influenza vaccination campaigns and HCWs received influenza vaccine at their work place, being covered from the Ministry of Health budget. No specific national recommendation regarding HCWs vaccination against varicella, pertussis, tetanus, diphtheria, poliomyelitis, meningoccocus exist in Romania. The main barriers included: insufficient information on benefits of vaccines, insufficient information on diseases and the risk of diseases, concerns about vaccine effectiveness and adverse events, lack of time, lack of clear national guideline concerning the HCW immunization. Dominant immunization enablers included: influence of educational programs (in school and at the workplace) and communication campaigns, importance of hospital epidemiologist, infection control personnel and occupational physicians. The majority of HCWs highlighted that the immunizations should be mandatory in health care facilities.Clear immunization policy and guidelines regarding occupational vaccination of HCWs in Romania, communication strategy and training programs are needed in order to increase confidence in vaccine and the vaccination coverage among HCWs."} +{"text": "Soft tissue artifact (STA), the deformation of skin and muscle during motion, is known to be one of the important sources of errors in human motion analysis using stereophotogrammetry. As a way to reduce the STA errors, methods estimating positions of anatomical landmarks (AL) have been proposed that keep them rigidly related to the underlying bone. The previous methods ,2 used iCurrent Controlled Trials ISCRTN73824458."} +{"text": "Repair of the injured spinal cord is a major challenge in medicine. The limited intrinsic regenerative response mounted by adult central nervous system (CNS) neurons is further hampered by astrogliosis, myelin debris and scar tissue that characterize the damaged CNS. Improved axon regeneration and recovery can be elicited by targeting extrinsic factors as well as by boosting neuron-intrinsic growth regulators. Our knowledge of the molecular basis of intrinsic and extrinsic regulators of regeneration has expanded rapidly, resulting in promising new targets to promote repair. Intriguingly certain neuron-intrinsic growth regulators are emerging as promising targets to both stimulate growth and relieve extrinsic inhibition of regeneration. This crossroads between the intrinsic and extrinsic aspects of spinal cord injury is a promising target for effective therapies for this unmet need. The adult mammalian central nervous system (CNS) has a poor ability to regenerate and restore function after injury. The pioneering work of Aguayo and colleagues showing that CNS neurons can grow into peripheral nerve grafts, but stop when they re-encounter the CNS led to the predominance of the hypothesis that the failure of axons to regenerate is attributed to the presence of inhibitory factors in the CNS microenvironment , a response that is quite limited in CNS neurons are extensively studied mediators of neurite outgrowth inhibition in the CNS. MAIs have been shown to increase the levels of active GTP-bound RhoA results in robust regeneration of retinal axons after optic nerve injury and regeneration of dorsal root ganglion neurons into the dorsal root entry zone after crush injury ecto have been shown to provide superior benefit to single interventions, supporting the idea that simultaneously stimulating neuron-intrinsic growth potential and neutralizing extrinsic inhibition can provide maximal efficacy in promoting neural repair (Wang et al., AK, SOT and AEF wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The recent revision of the legal framework for authorization of use of plant protection products and pesticides within the European Union/European Economic Area imposes a need for close collaboration across country borders within the three pesticide authorization zones in Europe. The principles of zonal evaluation and mutual recognition embedded in Regulation EC 1107/2009 concerning marketing of plant protection products are intended to reduce the approval times for pesticides. However, the three authorization zones represent a very simplified view compared to the 16 climatic zones/scenarios that have been outlined for pesticide modeling in Europe and indirect effects . As an example, Norway requires that the worst-case situation be assessed in all available modeling scenarios, assuming that none of the existing EU modeling scenarios will yield sufficiently conservative estimates for the mountainous Norwegian landscapes. Consequently, Norway is now using the WISPE model/application that is currently in use can be further developed into a northern zone PEC calculator.By comparison, better harmonization is achieved for estimation of predicted environmental concentrations (PECs) in soil. It is plausible that the Finnish PEC calculator (Targeted and country-specific pesticide monitoring programs that consider the impact of weather conditions on the risk of leaching and runoff of pesticides are a prerequisite to ensure sustainable use of pesticides (Directive 2009/128/EC). The pesticide monitoring efforts in the Nordic countries have been summarized by Fauser and Mogensen and KreuGroundwater constitutes 100\u00a0% of the drinking water supply in Denmark, and hence the pesticide leaching assessment program is essential to secure safe use of pesticides and clean groundwater free of pesticide residues. Assessment sites are located in five separate areas that have disparate geological \u201corigins\u201d and also represent the different precipitation \u201czones\u201d in Denmark. Extensive quality procedures have been established to evaluate the assessment results, because these findings are used in the approval process for pesticides in Denmark.The Swedish and Norwegian long-term pesticide monitoring programs cover selected small agricultural catchments and are mainly aimed at registering cropping practices and occurrence of pesticide residues in surface water in intensively farmed areas, because the drinking water supply in these countries is largely dependent on clean surface waters. The monitoring programs in Sweden and Norway presently comprise about 130 and 115 different substances, respectively . The flow-proportional water sampling is accurate for determining total loads, but additional sampling may be necessary to study the quality of the water in 2003\u20132008 and a broader screening (47 substances) at four locations in 2010, followed by a WFD compliance study of priority substances in 19 rivers in 2011. The overall picture indicates few detections of substances in concentrations below regulatory limits (pers. comm. K\u00fcnnis-Beres). Groundwater monitoring in the nitrate vulnerable zone during 2007\u20132011 resulted in no detections of >0.1\u00a0\u03bcg/L. Furthermore, a soil survey with sampling of 118 agricultural fields across Estonia showed in general no detections above permitted levels (pers. comm. K\u00fcnnis-Beres).In summary, the complementarity of the Nordic-Baltic monitoring systems should be exploited across borders, but there is still a need for country-specific monitoring programs to ensure that country-specific considerations and soil and weather conditions are properly addressed. Furthermore, the agricultural practices in the Nordic-Baltic countries differ markedly, being governed not only by topography and soil and weather conditions, but also by sociocultural conditions and government regulations.Pesticide fate research has shown that Nordic soil and climate conditions are challenging due to slow degradation and the risk of mobilization of sorbed pesticides in winter/spring caused by the freezing/thawing of soil extensive use; (2) frequent detections in monitoring programs; (3) toxicity to aquatic and/or terrestrial organisms; (4) measured environmental concentrations (MECs) above (no) effect concentrations (P(N)ECs); (5) cumulative risk assessment and compounds of particular concern with regard to mixture toxicity ; and (6) slow degradation in colder climates and northern soils. In addition to the traditional focus on the less sorbed and/or more mobile compounds, further attention should be given to strongly sorbed pesticides. Greater attention should also be paid to autumn-applied pesticides and pesticide metabolites in light of the challenges caused by a changing climate, such as altered precipitation patterns and rising temperatures for insecticides.In Norway, data on pesticides in groundwater are very limited. However, screening sampling has revealed occurrence of pesticides in local drinking water wells in shallow groundwater systems beneath agricultural land Roseth , with thIn Latvia, no research is currently being conducted to address leaching of pesticides from agricultural areas into waterways and soil. This situation exists despite the fact that the most intensive farming is done in areas with soils that are vulnerable to leaching, and half of the national cereal and rape seed yield is obtained in these areas .In Sweden, surface water monitoring data show that herbicides are found more frequently than fungicides and insecticides . MCPA and dichlorprop-P are the pesticides found most often in surface water monitoring, although the levels recorded have not been higher than the EQS values. However, concentrations of some low-dose sulfonylureas and some old and banned insecticides have more frequently exceeded their suggested EQS values , as well more frequent detections of these substances, especially in years with increased pressure from fungal diseases and frequent intense rainfall events during the spraying season. Potential problems connected with insecticide use are difficult to discern by monitoring, because the limits of quantification for the analytical methods applied are often 100-fold higher than the P(N)ECs in the aquatic environment. Nevertheless, some challenges have been observed to be connected with use of the insecticide imidacloprid for coating potato tubers (Stenr\u00f8d Monitoring results 1995\u20132012) from small agricultural streams in Norway show that the mobile herbicides MCPA and bentazone are the substances found most frequently, but the herbicide metribuzin is most often detected above concentrations that might have a negative effect on aquatic organisms Stenr\u00f8d . This mo Stenr\u00f8d and in g from smaIncreasing the area under low-tillage practices leads to more widespread use of the herbicide glyphosate to control weeds, but this substance is not included in all the stream water-monitoring programs in the northern zone. Monitoring results for the autumn and winter periods are especially scarce, which is particularly disturbing considering that glyphosate is applied on autumn stubble fields in cereal cropping.This brief overview shows that the northern zone collaboration will enable identification of pesticides of concern in several environmental compartments , as well as in the various agricultural practices. However, these observations also illustrate the need for increased harmonization of monitoring programs to facilitate comparison of results and also to pinpoint common pesticides of concern within the zone.The monitoring programs in the northern zone are focused predominantly on pesticides found in water samples, which by nature are hydrophilic substances, and much less interest is given to hydrophobic pesticides sorbed to soils and sediments. In Sweden , but unfortunately it also has some drawbacks. The development and coordination of pesticide risk assessment procedures for the EU and associated countries under the former EU pesticide regulations (Council Directive 91/414/EEC) resulted in a range of selected and recommended models and scenarios Fig.\u00a0 FOCUS 2, 2001. HMore work is needed to confirm the capacity of the current FOCUS scenarios for assessing pesticide fate in the northern zone countries. To accomplish this task, it will be necessary to explicitly identify the aspects that define the northern zone with respect to the environmental factors that govern the fate of pesticides in the environment , and to evaluate this definition in comparison with the currently employed EU scenarios and endpoints. Within the northern zone, there is considerable diversity in soil and weather conditions, as well as in the predominant cropping practices and environmental concerns related to agricultural activities. Previous attempts to specify Nordic reference soils Tiberg resultedThere are several collaborative activities that should be initiated to improve and harmonize fate and risk assessment of pesticides in the northern zone: (1) re-evaluate existing data from field experiments focusing on usability in a regulatory context; (2) improve existing models and increase their usability for assessments of multiple metabolites, low application rates, and the effects of winter-related processes ; (3) develop harmonized FOCUS surface runoff and groundwater leaching scenarios adapted to northern zone conditions; (4) investigate the suitability of EQS values as a measure of toxicity measures and, when possible, establish harmonized EQS values for pesticides and metabolites in the northern zone; (5) define the environmental conditions in the northern zone and analyze the representativeness of European conditions and modeling parameters.The use of available risk mitigation measures should be increased within all the northern zone countries, and this should include technical approaches such as drift-reducing and other mitigation strategies , with crop protection and pesticide use as central topics; the Norwegian forecast system for plant diseases, pests, and weeds ; the Danish decision support system for weed management ; the Finnish online information about crop protection and forecasts of the occurrence of selected pests . To establish IPM methods adapted to northern zone conditions, efforts should be made to further develop the collaboration between the countries in this zone to achieve improved pest forecasting, precision farming tools, and decision support systems for integrated pest management and sustainable pesticide use.According to monitoring results, detections of pesticide residues in the environment largely reflect use patterns, which underlines the importance of good agricultural practices . Hence, guidance tools and stewardship represent further essential approaches to increase the sustainability of pesticide use by raising awareness among farmers. Existing web-based resources designed to promote integrated pest management (IPM) and sustainable pesticide use in the northern zone include the following: the Swedish online guidance tool aimed at reducing the environmental impacts from agriculture conditions and modeling parameters.Improve existing models and increase their usability in assessing multiple metabolites, low application rates, and the effects of winter-related processes (soil freezing and thawing).Review existing data from field experiments to assess usability in a regulatory context.Develop harmonized FOCUS surface runoff and groundwater leaching scenarios adapted to northern zone conditions.Determine the suitability of EQS values as a measure of toxicity and develop harmonized EQS values for pesticides and metabolites in the northern zone.Establish a joint web information platform to facilitate dissemination and exchange of research and regulatory knowledge on pesticides and the fate of these substances in the northern zone.There is a need to improve and harmonize fate and risk assessment of pesticides in the northern zone using information derived from knowledge exchange between researchers. The Nordic-Baltic Pesticide Fate Workshop highlighted the many possibilities that are within reach. The main conclusion drawn from the workshop discussions was the need to identify the specific environmental conditions in the northern zone and to ascertain how this picture can be harmonized in (regulatory) pesticide fate modeling. Both the weather conditions and soil conditions vary markedly between different areas within the northern zone. Furthermore, the agricultural practices in the Nordic and Baltic countries differ markedly, being influenced not only by topography and soil and weather conditions, but also by sociocultural conditions and political decisions. Successful research and regulatory collaboration within the northern zone is essential to ensure that the specific conditions in this region are adequately addressed under the current European pesticide regulations. The Nordic-Baltic pesticide fate network should propose collaborative projects that entail regulatory monitoring and research to achieve the following:It is imperative to ensure a continued focus on these issues attained through the regulatory northern zone collaboration. Furthermore, the Nordic-Baltic pesticide fate network should propose a procedure outlining how pesticides of concern within the zone are to be identified and to be subjected to further actions by the northern zone regulatory work group. This procedure should include monitoring of chemical status and biodiversity (surface water) and also assessment of leaching . These tasks should be conducted on a selection of farms after approval of new pesticides and theoretical toxicity analysis, followed by more specific laboratory and field studies and risk assessment by modeling after identifying pesticides of concern. There must be agreement regarding both threshold values (surface and groundwater concentrations and toxicity assessment results) and the frequency of surpassing defined thresholds that can be accepted as qualification for more detailed studies."} +{"text": "It displays some of the well-established invasive mechanisms but there is a serious dearth of knowledge on the plant\u2013microbe\u2013soil interactions and whether the rhizobiome plays any roles in the displacement of native flora and the range expansion of BP. Several control measures, including chemical, mechanical, and biological antagonism have been used with limited success while restoration of natives in soils from which BP was removed has proved problematic partly due to a poorly understood phenomenon described as the \u201cBP legacy effect.\u201d Emerging evidence suggests that allelopathy, selective recruitment of beneficial soil microbes, disruption of microbial community structure and alteration of nutrient cycling, exhibited by many other invasive plant species may also be involved in the case of BP. This brief review discusses the well-established BP invasion mechanisms and highlights the current understanding of the molecular, below-ground processes. It also points out the gaps in studies on the potential role of microbial interactions in the success of BP invasion. These hitherto poorly studied mechanisms could further explain the aggressive spread of BP and could potentially contribute significantly to effective control measures and enable appropriate strategies for restoring native plants. The review advocates for the use of cutting-edge techniques in advancing the plant microbiome science. Ultimately, comparing metagenomic analyses of the rhizobiome of invasive plants grown in native and non-native soils could lead to a better understanding of the microbial determinants of biotic resistance, potentially empowering environmental managers with some predictive power of future trends of plant invasion.Invasive plant species constitute a major ecological and economic problem worldwide, often distorting trophic levels and ecosystem balance. Numerous studies implicate factors ranging from environmental plasticity, competition for nutrient and space, and allelopathy in the success of invasive species in general. The Brazilian Pepper tree (BP) was introduced to the United States in the 1800s and has since become a category one invasive plant in Florida. It has aggressively spread to about 3000 km Plant invasion is a global problem driven by human-mediated dispersal of plant species into new regions where they eventually acclimate, naturalize, and disturb populations of native plant species and multi-trophic ecosystems with consequent economic damage . The terFigure 1), a member of the family Anacardiaceae (cashew) began in 1898 when it was introduced to the USA from South America has become naturalized (The invasion of the Brazilian Pepper tree like other species is a multistage process including introduction (transportation), colonization, establishment, and range expansion . The fir America . Some re America as an or America . Two hap America . The col America with Flo America as seen ve flora . Successve flora , associave flora and its ve flora . There anus spp. . It is cnus spp. ; anthropcosystem . In Souturalized . BP affeuralized . More reuralized which duuralized In general, the success of plant invasion is determined by several interacting abiotic and biotic factors which define the susceptibility of the invaded habitat , and the2 plot in the Everglades National Park called the \u2018Hole in the Donut\u2019 by physically removing the plants using bulldozers, burning the plants and removal of the top soil, it was concluded that approximately US $20 million would be needed to restore 20 km2 with this method (Chondrostereum purpureum which inhibited resprouting (Neofusicum batangarum isolated from BP which was effective against seed germination and seedling growth of BP without inhibiting two other non-invasive plant species in Florida (Myrica cerifera) which is inhibitory to BP germination and seedling establishment employed by Pseudomonas spp., Xanthomonas campestris, and Colletotrichum gloeosporioides among others. Given the almost non-existent data on the rhizobiomes of the BP, extending the promise of bio-control to the BP situation would require a careful study of its interactions with, and susceptibility to highly selective agents.In Florida for example, chemical control of the BP involves the use of herbicides such as triclopyr and imazapyr which aps method ; making s method while thprouting proved m Florida . The natFigure 3) but there is a serious dearth of knowledge on the plant\u2013microbe\u2013soil interactions and whether the rhizobiome plays any direct roles in the displacement of native flora and the aggressive growth of the invading species. Moreover, it is becoming increasingly clear that the molecular basis of known plant mechanisms of invasion involve soil microorganisms and their metabolites.To bolster ongoing efforts to control the BP and improve upon restoration of natives in these disturbed niches, it is very important that the complete picture of its mechanisms of invasion be deciphered. In this review, we discuss the established or well-studied plant mechanisms of invasion in the BP and highlight key emerging mechanisms and research gaps in (a) the current understanding of the molecular, below-ground processes underlying known BP invasion processes and (b) studies on the potential role of microbial interactions in the success of BP invasion which are otherwise established for other invasive species. These hitherto poorly studied mechanisms could further explain the aggressive spread of the BP. Such knowledge would contribute significantly to development of effective and sustainable control measures and enable appropriate strategies for restoring native plants. Several studies have shown that BP displays the well-known plant mechanisms of invasion such as competitive resource use, enemy release and physical environment mechanisms by producing targeted biochemical compounds . AllelopPlatanus occidentalis) by garlic mustard (Alliaria petiolata) was influenced by the soil microbiota present; the inhibition was observed only in sterile soils, suggesting that the soil microbes may have degraded the allelochemicals produced. Allelopathy is still being debated among plant ecologists as an important invasive invasion and most recently in the case of BP, it was denounced as a plant mechanism of invasion by A. petiolata) were glucosinates which altered the composition of arbuscular mycorrhiza. This invasive plant more recently was shown to inhibit arbuscular mycorrhizal (AMF) and ectomycorrhizal (EM) mutualists needed by native plants was reported to release the allelopathic compound \u2018juglone\u2019- a plant respiratory inhibitor in the soil in large measurable quantities. This allelochemical is believed to be the cause of the absence of other species of plants normally seen in close vicinity to the tree and pigeon berry and leafy spurge (Euphorbia esula) showed an increase in AMF abundance and richness. It is still unclear, however, what specific AMF BP recruits and how these proposed mechanisms of microbial recruitment or suppression function. While it has been shown where the symbiosis with fungal mutualists exists there is paucity in research regarding the association of BP with rhizobacteria and any benefits or advantages that they may induce during plant invasion. Studies are needed to elucidate the molecular factors that regulate the complete rhizobiome community in a very complex ecological niche. This should also include a comparison of the relative abundance of fungal and bacterial micro-organisms which may denote a certain recruitment strategy at the Kingdom level exhibited by invasive and even non-invasive plants to its benefit while decreasing the prevalence of a widespread AM fungus found in the soil (Glomus mosseae) to the detriment of the native species. The exact mechanism is unknown but this phenomenon fits the degraded mutualism hypothesis where invasive plants alter the soil microbiota by reducing the AMF abundance and richness (Cladium jamaicense) in the Florida Everglades with AMF initiated the activation of a phosphate transfer gene which allowed the uptake of Pi from soil. It is quite plausible that invasive plants such as BP alter the soil microbial community much more significantly than is currently known. By recruiting or selecting for AMF and certain beneficial bacteria which facilitate nutrient cycling and pathogen protection, invasive plants gain a competitive advantage. Sulfur oxidizing, and sulfur reducing bacteria were found predominantly in the rhizosphere of two invasive species yellow starthistle and barb goatgrass while they were found in substantially less proportions in native soil rhizosphere bacteria and AMF just to richness . The symzosphere . A similzosphere and alsozosphere . The eviC. maculosa . New nanotechnologies such as microfluidics hopefully will uncover these recluse \u2018hermit-like\u2019 microbes in their natural environment. Phospholipid fatty-acid analysis (PLFA) has also been widely used to determine the structural diversity of soil microbiota . This nomaculosa and A. petiolata .The elimination/control of BP and indeed all exotic species, and the restoration of native plant communities continue to be a growing challenge and concern for ecologists. The problem will be compounded by predicted impact of climate change, underscoring the need for more research to fuel innovation in control measures. The BP plant, like other invasive species has many known advantages over native plants and possesses multiple established plant mechanisms of invasion including the traditional physical environment adaptation, high resource use efficiency and enemy release mechanisms (niche opportunity). These interconnected established mechanisms have been shown to enhance invasiveness during introduction, colonization and spread of BP. Mechanisms emerging as important employed by exotic species and possibly the BP include the use of allelochemicals to manipulate the soil community structure and the recruitment of AMF fungi for enhanced nutrient uptake, drought tolerance, pathogen resistance, and disruption of the native soil microbe community. These important emerging mechanisms shed some light into the dominance of BP during establishment of local populations. Whether soil microbes influence allelopathy, or are recruited by invasive plants during invasion, they seem to play a significant role. The soil microbial community under BP has still not been fully elucidated but new high resolution advanced molecular studies are needed to analyze in depth the bacterial and fungal soil community structural changes to determine their role in plant invasion. These advanced high throughput metagenomic studies should be integrated with metabolite/biochemical bio-assays and plant gene expression research to better understand plant mechanisms of invasion and the vulnerability of native species. This total rhizosphere community DNA can provide evidence of plant species\u2019 specific microbiomes but it\u2019sKD contributed equally to the research, drafting and editing of the manuscript. NE is the senior author who guided the research, contributing to research, drafting and editing of manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Abstracts of systematic reviews (SRs) play an important role in dissemination of results, with most evidence users consulting the abstract before reading a full article and some only ever consulting the abstract. However, abstracts of SRs are often poorly reported. The PRISMA statement for reporting SRs was extended to include guidelines for the production of abstracts to improve this.Health Technology Assessment (HTA) and Cochrane Database of Systematic Reviews (CDSR).We aimed to conduct an exploratory evaluation of the adherence to PRISMA guidelines for SR abstracts in two cohorts: HTA and CDSR between 2009-2014 were eligible for inclusion in the study. Twenty SRs from each year were randomly selected from both cohorts and their abstracts assessed against the PRISMA for abstracts checklist . Two researchers working independently extracted the data; queries were explored and resolved by the team.SRs published in Results will report adherence to guidelines in both cohorts and examine areas of weakness. Impact of PRISMA guidelines will be assessed by examining improvements in reporting standards over time, in particular by comparing publications submitted before and after 2013.The PRISMA for abstracts checklist may have limited utility for complex SRs which include multiple comparisons and economic evaluations. We will discuss possible modifications to increase its usefulness, contributing to complete reporting of complex SR abstracts."} +{"text": "We develop an analytic framework to investigate the stability of splay states in infinite networks of identical integrate-and-fire neurons coupled through synaptic pulses. More specifically we perform a linear stability analysis of the splay state probability distribution whose dynamics is governed by an appropriate Fokker Planck equation. For exponentially decaying synaptic pulses the splay state is unstable for excitation and stable for inhibition. For excitatory alpha-function pulses the splay state becomes stable for sufficiently large decay times and we find an analytic expression for the boundary of stability. This large decay time stability is analogous to the stability of synchronous states for inhibition studied by van Vreeswijk, Abbott and Ermentrout . For inh"} +{"text": "The scale and nature of cooperative efforts spanning geopolitical borders in clinical research have not been elucidated to date. In a cross-sectional study of 110,428 interventional trials registered in Clinicaltrials.gov, we characterized the evolution, trial demographics, and network properties of multinational clinical research. We reveal that the relative growth of international collaboratives has remained stagnant in the last two decades, although clinical trials have evolved to become much larger in scale. Multinational clinical trials are also characterized by higher patient enrollments, industry funding, and specific clinical disciplines including oncology and infectious disease. Network analyses demonstrate temporal shifts in collaboration patterns between countries and world regions, with developing nations now collaborating more within themselves, although Europe remains the dominant contributor to multinational clinical trials worldwide. Performances in network centrality measures also highlight the differential contribution of nations in the global research network. A city-level clinical trial network analysis further demonstrates how collaborative ties decline with physical distance. This study clarifies evolving themes and highlights potential growth mechanisms and barriers in multinational clinical trials, which may be useful in evaluating the role of national and local policies in organizing transborder efforts in clinical endeavors. Large teams involving international collaborations are a growing theme across many research disciplines and are increasingly associated with high impact science \u20134. The aPast studies characterizing authorship dynamics of research publications have revealed generic structures of collaborative networks and properties of team assembly mechanisms, though unique traits exist across subject disciplines , 12\u201314. http://www.ctti-clinicaltrials.org). We focused on clinical trials with start years from 1995 and onwards and included only interventional trials (identified through the study type field) without missing data regarding the location of clinical sites enrolling patients (hereafter referred to as an institute), yielding 110,428 studies including data for 152,611 clinical trials from the Clinical Trials Transformation Initiative portal , respiratory, and other .To categorize clinical trials by clinical specialties, we examined Medical Subject Heading (MeSH) terms, vocabulary established by the National Library of Medicine (NLM) for indexing purposes, assigned to each clinical trial based on an NLM algorithm from the facilities and location countries fields. Both nation-level and city-level networks were constructed, with either nations or cities acting as nodes and links between actors indicating a shared presence within the same clinical trial. Network analyses were performed using Visone .\u201325.22\u201325We also determined the latitudes and longitudes of each city in order to determine the great circle distance of each city-level network tie . This alThe value of collaboration in medical research is unmistakable and work stemming from multinational teams has contributed to improvements in clinical practice and patient outcomes. Multinational clinical trials may also be advantageous for established nations and institutes in order to involve the participation of additional patient demographics and to potentially improve the health outcomes of other communities. For developing countries or less experienced institutes, international collaboration may be a critical source of additional expertise or finances and engender additional network contacts. The ongoing development of many drug and vaccine candidates in the USA and UK due to the 2014 Ebola virus epidemic in West Africa further exhibits the necessity for medical researchers to maintain a broad scope, particularly when available resources worldwide should be leveraged in instances where global health is threatened but may be controlled at a discrete source .To our knowledge, this is the first study to elucidate trends in collaborations and the composition of transborder research teams pertaining to medical research involving human patients. Our results reveal a largely stagnant proportion of clinical trials involved in international collaborations spanning at least a decade, although there was also a propensity for clinical trials to involve an increasing number of nations over time. In particular, the dominating contribution of binary country relations in clinical research has waned due to the rapid emergence of larger scale collaborations. We also found that international clinical trials scaled with gross productivity in clinical research, and are associated with larger patient enrollments, industry funding, and specific medical specialties. Future studies are needed to examine whether such characteristics of international clinical trials are a prerequisite or consequence of the collaborative process. Clarifying the structure of national ties in clinical research may also pave way for future investigations on the effects of specific collaborations on trial success, clinical impact, and other possible consequences.Our analysis did not rely on authorship data and thus includes trials that have not or may never be published, possibly providing a more inclusive analysis of clinical trials. However, our dataset is limited by the fact that not all clinical trials are necessarily registered , although this is expected to be less likely for more recent years due to publication requirements in many journals and regional or institutional directives. Nevertheless, the wide scope of our study suggests that our findings are generalizable and may serve as a resource to guide research policies. For example, by illuminating patterns of international interactions in clinical trials, our study clarifies the relative isolation of geopolitical regions in research, indicating where targeted increases in the participation of investigators may lead to the inclusion of patients from underrepresented world regions within the medical community. Current such strategies likely underlie the observed flux in high betweenness countries.Our assessment of the network topology of clinical trials also reveals how established institutes may be preferentially linked to emerging clinical sites. This connotes the tremendous influence of national, city, or institutional policies of \u201chubs\u201d on the formation of new ties in international clinical trials and conceivably collaborative behaviors beyond local interactions. Thus, ambiguous or arbitrary regulations that effect the administration of clinical trials, industry relations, drug approvals, or the flow of medical information which make collaborations prohibitive, as recently exemplified in India, Russia, and other countries, may also have a delayed but rippling impact across the research network , 29. Fut"} +{"text": "The recent Ebola Virus Disease outbreak in some West African countries spanning from late 2013 and currently on as of 13th March, 2015 is the most widespread and fatal with human mortality that has surpassed all previous outbreaks. The outbreak has had its toll on conservation of endangered species. This portends danger for the wild fauna of the country if proactive measures are not taken to prepare grounds for evidence- based assertions concerning the involvement of wild species. To this end, there is an urgent need for sweeping census of reserves, national parks and wetlands. As well as the creation of a system involving reportage by sectors like the industries (extractive and construction) including persons and organisations involved with wildlife related activities. This documentation of die offs and unusual events to collaborating institutions, will help in monitoring trends which hitherto would have gone unnoticed. The importance of bats and primates in agriculture and public health via consumption of vermin insects and seed dispersal cannot be over-emphasized. There is the need for caution on the tendencies to destroy indicator species which could be silent pointers to emerging or remerging health and environmental issues. Wildlife resources are still reliably useful and caution is advised in the use of blanket destructive policies like fumigation of caves, indiscriminate culling and poisoned baits to destroy supposedly Ebola Disease Virus wildlife reservoirs. This paper highlights the immediate conservation problems and likely future implications of Ebola saga in Nigeria. It tries to identify the gaps in wildlife researches and makes recommendations for probable workable conservation strategies. The current Ebola scourge in West Africa is the most devastating and widespread of any outbreak either as Ebola or any infectious diseases in recent past. This is with attendant human mortalities of greater than 7000 as of Dec, 2014; 9000 as at February, 2015 , 4. The However the species also incriminated to be EVD reservoirs, do have their downsides namely being majorly pathogen reservoirs, damages to crop and building and nuisance accidents like plane strikes and bites/ injuries when handled inappropriately or impeded. The EDV RNA has been detected in implicated bat species namely Epauletted fruit bat (Epomophs franqueti), Little collared fruit bat (Myonycentris torquata) and Hammer headed bats (Hypsignathus monstrous) which arWe postulate that some of the likely impacts of EVD may include pressure to import food into the EVD ravaged countries leading to aggravated incursion, bush clearing and farming within protected areas with wildlife. We foresee an unusual and unexpected interplay of pathogens amongst the \u201cdrivers\u201d of disease emergence Wildlife resources are vital components of our ecology, caution is therefore advised on the use of blanket destructive policies like fumigation of caves, indiscriminate culling, use of poisoned baits to destroy supposedly wildlife reservoirs of EVD The balance in the ecosystem cannot be rocked by taking out elements of wild fauna presumed to be reservoirs of EVD. The ongoing EVD outbreak buttresses the fact that an outbreak anywhere could be a risk everywhere. Baseline data from sustained surveillance will boost our preparedness for emergencies There is an urgent need for proactive measures to generate evidence- based comments assertions concerning the involvement of wild species in Nigeria. To this end, we propose sweeping census of reserves, national parks and wetlands. We advocate for continued surveillance and periodic reviews and a regulation of hunting for bush meat. A passive surveillance system involving reportage on wildlife by sectors like mining, construction, hunting and ecotourism to designated units will suffice to fill the gaps. This will ensure documentation of die offs and unusual events which might hitherto go unreported or unnoticed to collaborating institutions. This will lead to establishment of a trend from ground zero. An adaptation of schemes like Canadian Cooperative Wildlife Health Centre may have numerous gains for epidemiological studies of diseases in wildlife. Are there benefits from harvesting sera from previously exposed non human primates? The West African outbreak underscores the need for investments by government and corporate entities into social infrastructures, development of multi disciplinary research units, holistic implementation of policies on research and infrastructural development."} +{"text": "Breast cancer is the most frequently diagnosed cancer entity and the leading cause of cancer death in females worldwide, accounting for 23% of the total new cancer cases and 14% of the total cancer deaths in 2008 [Economic burden of breast cancer management are permanently increasing negatively impacting the healthcare budgets. In the actual context of extensive debates concerning increasing costs of medical services and limited resources to cover healthcare costs, new strategies needs to be applied to more effective breast cancer management. To give an example, in the USA the costs for prescriptions against breast cancer are the second largest category of all pharmaceutical sales with enormously increasing rates. The therapy costs for each patient with metastatic breast cancer have been reported to be $128.556 over a mean follow-up time of 18 month. But also the trend towards the detection of earlier breast cancer stages is under discussion regarding treatment savings. The savings of costs for treatment and palliative care in advanced breast cancer may be counterbalanced by the high costs of more aggressive initial treatments and longer follow-up.Currently applied screening strategies lack sufficient benefits and, therefore, also become disputed. The diagnosis of breast cancer in early stages has been shown to improve the prognosis and consecutively reduce mortality of breast cancer patients. The recommended screening by clinical breast examination and mammography is able to detect breast cancer in early stages and has been shown to reduce mortality. Nevertheless, this screening procedures cause high percentages of false-negative and false-positive results that lead to both underdiagnosis and overdiagnosis respectively . FurtherBased on the enormous amount of health care costs for breast cancer screening, therapy costs as well as the economic burden of this disease, predictive medicine could be an innovative approach towards a new era in breast cancer prevention. Breast cancer risk assessment aims at detection of pre-malignant stages that will revolutionise breast cancer management in patients without family history as well as in women with hereditary disease. Innovative approaches proposed by the PPPM paradigm promote economically more attractive scenario for the investment in healthcare sector, however, should get carefully analysed through well designed pilot projects ,5."} +{"text": "Landslide hazard assessment is an important step towards landslide hazard and risk management. There are several methods of Landslide Hazard Zonation (LHZ) viz. heuristic, semi quantitative, quantitative, probabilistic and multi-criteria decision making process. However, no one method is accepted universally for effective assessment of landslide hazards. In recent years, several attempts have been made to apply different methods of LHZ and to compare results in order to find the best suited model. This paper presents the review of researches on landslide hazard mapping published in recent years. The advanced multivariate techniques are proved to be effective in spatial prediction of landslides with high degree of accuracy. Physical process based models also perform well in LHZ mapping even in the areas with poor database. Multi-criteria decision making approach also play significant role in determining relative importance of landslide causative factors in slope instability process. Remote Sensing and Geographical Information System (GIS) are powerful tools to assess landslide hazards and are being used extensively in landslide researches since last decade. Aerial photographs and high resolution satellite data are useful in detection, mapping and monitoring landslide processes. GIS based LHZ models helps not only to map and monitor landslides but also to predict future slope failures. The advancements in Geo-spatial technologies have opened the doors for detailed and accurate assessment of landslide hazards. Landslide is an important geological hazard that causes damage to natural and social environment. The concept of landslide is dealt by many authors differently. Varnes and IAEG defined Landslide causes loss of around 1000 lives and property worth $4 billion annually EM-DAT . AccordiAccording to Brabb , at leasLandslides are natural events, but may turn into hazard and cause loss of lives and damage to man-made and natural structures. The term landslide hazard is defined by many authors differently, among them definition given by Burton et al. , Rezig eThough there are numerous approaches to define landslide hazards, many of the researchers have largely adopted or modified the definition given by Varnes and IAEG .Landslide hazard zonation is an important step in landslide investigation and landslide risk management. Varnes and IAEG defines There has been significant growth both in landslide events particularly those induced by human activities and in number of landslide investigations in different parts of the world etc. Landslide data are obtained through field survey mapping, historical records, satellite images and aerial photo interpretation. Landslide distribution and density maps provide basis for other landslide susceptibility methods.Cruden defined Landslide inventory play significant role in landslide hazard assessment. The quality and completeness of landslide inventory influences reliability of landslide investigation. Galli et al. comparedGuzzetti et al. discusseColombo et al. preparedIn last few years the approach towards LHZ has been changed from heuristic (knowledge based) approach to data driven approach to minimize subjectivity in weightage assignment procedure and produce more objective and reproducible results Kanungo et al. . MethodsThe bi-variate statistical analysis for landslide hazard zonation compares each data layer of causative factor to the existing landslide distribution is a bi-variate statistical method for spatial prediction of landslides based on relationships between landslide occurrence and related parameters is dichotomous between landslide group and non-landslide group and to determine weights for these factors is of utmost importance in LHZ mapping. The Analytical Hierarchy Process (AHP) is a multi criteria decision making process of measurement through pair wise comparisons and relies on the judgements of the experts to derive priority scales Saaty . AHP opeRainfall threshold for landsliding refers to minimum intensity or duration of rainfall necessary to cause landslide model was used to predict landslides based on hydrological parameters data combined with Geographical Information System (GIS) are proved to be effective tools for generating and processing spatial information. The advancement in earth Observation (EO) techniques facilitate effective landslide detection, mapping, monitoring and hazard analysis is of immense importance in landslide hazard assessment. Several thematic data layers such as slope angle, slope aspect, curvature, lineaments, drainage, ridges etc. can be extracted from DEM with good resolution. Landslide hazard zonation studies in recent times have used DEM with high resolution to generate spatial information data layers related to landslide hazards (Gomez et al. Saraf et al. Geographical Information System is widely used in landslide hazard assessment especially for generation of thematic data layers, computation of different indices, assignment of weights, data integration and generation of LSZ maps. Several LSZ methods such as ANN, Decision Tree model, Weighted Overlay, AHP, MCDA, IVM and physically based landslide hazard models are GIS based models to predict landslide probability (Chang and Liu Landslide hazard zonation is a critical task in landslide management process. Landslides are influenced by several preparatory and triggering factors which vary significantly from region to region. It is therefore difficult to determine weights for given parameter. The assignment weights based on relative importance of landslide causative factors is determined by several LHZ methods differently. Heuristic and semi quantitative techniques involve subjectivity in assigning of weights therefore validity of these maps cannot be assessed. Quantitative methods on the other hand, provide objective methods for determining weights for a given parameter based on their relationships with landslide occurrence. Multi-criteria decision approach provides tools to determine weights based on pair wise comparison. Application of Remote Sensing and Geographical Information System is of immense importance for effective landslide hazard assessment. High resolution satellite data combined with powerful GIS techniques have improved the level of accuracy of LHZ maps in recent times."} +{"text": "In July 2012, a clinical mentoring intervention commenced in Jigawa State through collaboration between the Jigawa State Ministry of Health and the Partnership for Transforming Health Systems Phase 2 project. After 6 months, an evaluation was undertaken to assess whether clinical mentoring has benefits for the health workforce situation within the intervention health facilities as well as whether it improved maternal, newborn and child health service delivery in Jigawa State within northern Nigeria.Multiple approaches to data collection were undertaken. Pretested interviewer-administered questionnaires were used to determine if there was an increase in the clinical knowledge levels of the mentored health workers after 6 months. Operational and service statistics of the intervention facilities were examined 6 months before the commencement of the clinical mentoring intervention as well as six months thereafter. Quantitative data was analyzed with SPSS version 20. In-depth interviews were undertaken with the clinical mentors and Jigawa State government health officials. Semi-structured interviews were undertaken with the mentored health workers and health facility departmental heads for Obstetrics and Pediatrics. Qualitative data was audio-recorded, transcribed and thematically analyzed.Significant improvements in the professional capacity of mentored health workers were observed by clinical mentors, heads of departments and the mentored health workers. Across five health facilities, over 90% of the 33 mentored health workers recorded increases in their knowledge test scores after a 6 months period suggesting an improvement in their clinical knowledge and skills. Maternal and newborn deaths decreased in three out of the five clinical mentoring health facilities while normal deliveries increased in two out of the five intervention health facilities. Best practices were introduced with the support of the clinical mentors such as appropriate baseline investigations for pediatric patients, the use of magnesium sulphate and misoprostol for the management of eclampsia and post-partum hemorrhage respectively as well as the use of ambu-bags for neonatal resuscitation to reduce neonatal mortality. Government health officials indicate that clinical mentoring has led to more emphasis on the need for health workers to provide better quality health care services.The study shows that clinical mentoring is beneficial for improving the knowledge and clinical skills of mentored health workers as well as improving health service statistics. The introduction of clinical mentoring into the Jigawa State health system has improved the capacity of the mentored health care workers to deliver better quality maternal, newborn and child health services."} +{"text": "Rib stress fracture (RSF) is a relatively frequent, severe and well documented overuse injury in elite rowers. The incidence of RSF has been estimated to be approximately 9 %, but prospective studies with rigorous injury surveillance of larger groups of rowers are needed to confirm this.The burden of RSFs lies primarily in the severity as most reported cases needed 6-8 weeks of rest, rehabilitation and gradual return to rowing before a full return was possible. Anecdotal reports of non-union of RSF emphasize the necessity of \u201cplaying it safe\u201d regarding a timely, symptom dependent return to training and competition.Since no evidence based therapy is available that can decrease healing times of stress fractures, a RSF can be a season ending injury for an elite rower. Consequently, prevention of RSF is of paramount importance. Effective prevention of sports injuries requires thorough knowledge of incidence and/or prevalence, severity, risk factors and injury mechanisms. Several potential mechanisms of injury have been suggested. The relatively limited data provided in the literature (biomechanics of ergometer rowing) may at best give hints with regards to which of the suggested and rather different mechanisms of injury that are most likely to actually induce detrimental bending forces to the ribs during rowing. The aetiology of RSF has thus been described as multifactorial also referring to the plethora of potential risk factors for stress fractures.The lack of longitudinal investigations of potential risk factors for RSF in rowing necessitates looking at evidence regarding risk factors for stress fractures in general. In particular, the recent research indicating that low energy availability is of great importance to bone health of endurance athletes seems highly relevant for elite rowers \u2013 especially lightweight rowers.Future prospective studies with continuous surveillance (i.e. internet based questionnaires) of the prevalence of RSF symptoms could elucidate the true burden of RSF. If such an investigation is combined with base-line and intermittent assessment of potential risk factors for RSF stronger evidence for cause and effect relationships could be generated. This type of information could inform effective prevention strategies in the future.Based on the currently available knowledge from biomechanical studies of ergometer rowing the implementation of dynamic ergometers could be hypothesized to reduce the risk of RSF. Moreover, some of the known risk factors for stress fractures in general might be hypothesized to also contribute to increased bone health and decreased RSF risk in elite rowers."} +{"text": "Evolution creates and sustains biodiversity via adaptive changes in ecologically relevant traits. Ecologically mediated selection contributes to genetic divergence both in the presence or absence of geographic isolation between populations, and is considered an important driver of speciation. Indeed, the genetics of ecological speciation is becoming increasingly studied across a variety of taxa and environments. In this paper we review the literature of ecological speciation in the tropics. We report on low research productivity in tropical ecosystems and discuss reasons accounting for the rarity of studies. We argue for research programs that simultaneously address biogeographical and taxonomic questions in the tropics, while effectively assessing relationships between reproductive isolation and ecological divergence. To contribute toward this goal, we propose a new framework for ecological speciation that integrates information from phylogenetics, phylogeography, population genomics, and simulations in evolutionary landscape genetics (ELG). We introduce components of the framework, describe ELG simulations , and discuss design and experimental feasibility within the context of tropical research. We then use published genetic datasets from populations of five codistributed Amazonian fish species to assess the performance of the framework in studies of tropical speciation. We suggest that these approaches can assist in distinguishing the relative contribution of natural selection from biogeographic history in the origin of biodiversity, even in complex ecosystems such as Amazonia. We also discuss on how to assess ecological speciation using ELG simulations that include selection. These integrative frameworks have considerable potential to enhance conservation management in biodiversity rich ecosystems and to complement historical biogeographic and evolutionary studies of tropical biotas. Understanding how organisms adapt and diversify have been topics of fundamental importance in biology for over 150 years . It is nSpeciation \u2013 the continuous process that gives rise to biological diversity, is often intimately associated to changes in phenotypes and to adaptation to the ecological environment . NaturalThe increasing integration between molecular genetic approaches with theoretical and empirical ecological studies . For instance, 2013 has seen almost 200 publications and over 5,600 citations, compared to 60 articles and 1,600 citations in 2008. Interestingly, our evaluation shows that the majority of empirical studies (674 out of 862) used information from genetic datasets or genetic knowledge to improve pattern interpretation. Indeed, the genetics of ecological speciation is becoming increasingly studied across a variety of taxa and environments , genome scans, population genetics, phylogeography, and phylogenetics. We then use published population-level genetic datasets from five codistributed and taxonomically diverse Amazonian fish species to illusWe suggest that this framework can assist in distinguishing the relative contribution of natural selection from biogeographic history in the origin and maintenance of biodiversity, even in a complex and understudied tropical ecosystem such as Amazonia. In addition, we show that it is feasible to frame ecological speciation in a spatially explicit ELG context that includes selection. We also discuss recent developments in environmental mapping, simulations and population genomics that allow clarification of population divergence across selection gradients.Figure 1) dealt with tropical species, and only 40 of those could be classified as empirical studies. Although our searches might have missed relevant studies that did not use the words \u201ctropical\u201d or \u201ctropic(s)\u201d in the abstracts, keywords, or titles, our inspection of the literature indicates that research effort in ecological speciation is indeed largely biased toward temperate regions. This conclusion is consistent with the empirical literature reviewed in a recently published book on ecological speciation out of the 996 previously identified articles , a large proportion of studies used information from molecular phylogenetics (63%), phylogeography (50%) and morphology (42%). To our surprise, only few surveys of population genetic structure were conducted in the topics , with a handful of those also incorporating information from genome scans of selection (10%) or from landscape genetics (7.5%). As expected for any integrative field of research, ecological speciation was usually assessed by combining two or more approaches (80% of articles). Most combinations (83%) included phylogenetic or phylogeographic datasets, exemplifying the reliance of the field on molecular genealogical information.Research trends in tropical ecological speciation were collected by inspecting the 40 recovered empirical articles for key selected categories. In terms of biological realm, most publications focused on terrestrial (65%), rather than marine (20%), or freshwater (15%) organisms. Terrestrial plants and terrestrial invertebrates were the best represented taxonomic groups , followed by fishes (17%), aquatic invertebrates (15%), birds (12%), herpetofauna (10%), and mammals (3%). Comparisons involving two or more species (65%) were more common than intraspecific surveys (35%). Interestingly, 45% of studies included comparisons across habitat gradients, and 35% of the 40 articles assessed patterns of gene flow. In terms of the main approaches used to generate and analyze data are the scarcest. The latter is consistent with the positive correlation found in another review to clarify temporal and spatial patterns of diversification in tropical ecosystems. These surveys and meta-analyses have invariably compared lineages at or above the species level and framed pattern interpretation within historical biogeographic and macroevolutionary contexts. They have contributed substantially to our understanding of tropical diversity \u2013 such as improving the quality of the contentious debate about Tertiary versus Quaternary speciation timing . Although the primary impetus is to assess the role of ecology as a driver of biodiversity, this type of research also generates valuable information for several data-deficient areas in tropical research. These include improvements of biological inventory databases and taxonomy, the discovery and delineation of cryptic species, selection gradients, ecotones and regional hotspots for conservation management, and the clarification of speciation timing, patterns of connectivity and metapopulation structure.We now describe a framework to study ecological speciation in the tropics that integrates genomic (or genetic) data from populations with simulation modeling specific for ELG (summarized in Box II). Although this framework was conceived to assess ecological speciation in the tropics, it can be applied to other ecosystems and to most sexually reproducing species. This is particularly true for biotas in temperate regions for which a priori information about traits subject to divergent selection is more abundant and for which better logistics allow greater experimental tractability distributed across heterogeneous environments or ecotones while controlling for spatial genetic autocorrelation and vicariant history. In this scenario, evidence for ecological speciation is obtained if a positive correlation is found between genetic differentiation and environmental (or phenotypic) divergence, after the effects of geographic distance and histtability comparedBelow we introduce the main components of the framework and discuss design and experimental feasibility within the context of tropical research. We also provide a more detailed description of simulations and ELG and their expected contributions. This is followed by a performance assessment of the proposed research framework based on published studies of population diversification and ecological speciation of Amazonian fishes.Figure 3) is valuable for comparative surveys because the applicability of individual approaches for assessing ecological speciation scenarios is expected to vary among groups of organisms or of traits related to reproductive isolation can be fundamentally important to generate hypotheses about divergence across environmental gradients and to inform sampling strategies. In cases where a priori information is available about the distribution of phenotypically divergent ecotypes within species or between closely related lineages is required to ensure rigorous statistical analyses. Within lineages, sampling should be hierarchical to enable analyses of spatial dependence: the design should be spatially nested regarding dispersal potential to capture the degree of autocorrelated genetic data and the environmental-species relationships should contribute to improving and accelerating initiatives supporting bioinventory collections and population sampling in the tropics. Population genetic surveys should tag along to ensure that tissue samples for DNA analysis , are collected together with voucher specimens and other key associated data such as phenotypic information.The rigorous sampling regime proposed here contrasts remarkably with the sparse sampling strategies generally used in phylogeographic and phylogenetic studies of tropical biotas . AlthougLandscape (or riverscape or seascape) mapping is an important step that should be carried out in parallel with sampling design. A landscape is an area that is heterogeneous with regard to at least one variable of interest . A landsThe integration of molecular genealogical information from phylogenetic and phylogeographic analyses into the framework is a prerequisite for subsequent analyses of intraspecific gene flow. Two main reasons account for this requirement. First, these analyses enable the discovery and spatial delineation of historically isolated lineages and hidden biodiversity, such as evolutionarily significant units (ESUs) and cryptic species. Levels of species richness and morphologically cryptic biodiversity have been grossly underdocumented in assessments of tropical biodiversity e.g., because The second reason for integrating molecular genealogical studies is that they add an essential component to the understanding of patterns of population structure and levels of reproductive isolation: time. Temporal changes in the physical and biotic environment of a population lead to demographic variations that are correlated with the structure of population genealogies . PhylogeIn this step, DNA markers are used to genotype individuals across heterogeneous environments with the aim of clarifying patterns of gene flow and identifying the spatial locations of genetic discontinuities . This is a key step in the framework that should be done at the metapopulation level after historical diversification has been accounted for (as above). The expectation is that during ecological speciation, ecological or environmental distance , reduces homogenizing gene flow and correlates to genetic population differentiation. These patterns are now considered common in nature and usually referred to as isolation-by-ecology , or isolAlthough isolation-by-ecology can be detected with relatively small neutral molecular datasets such as microsatellites and AFLPs . Using aBox II). Simulations have provided many important findings in various disciplines on 1- or 2-dimensional regular lattices, or in irregular coordinate space. Specific rules in the model then define how individuals move and interact across space, for example by defining the distances they can move away from their birth location, or the distance within which they can find a mating partner. Population genetic simulations are often also spatially explicit e.g., , but whiThe ELG simulation modeling implemented in our ecological speciation framework includes an additional component: it specifically integrates landscape genetics and evolutionary genetics, focusing on how space and selection impacts on the evolution of reproductive isolation (speciation). For example, selection can be controlled via fitness landscape surfaces that detFigure 4). These included freshwater representatives of marine-derived lineages from two orders; a tetraodontiform (the puffer Colomesus asellus) and a perciform (the croaker Plagioscion squamosissimus) and ancient freshwater lineages representing three Gondwana-relict orders; a characiform , a siluriform (the catfish Centromochlus existimatus) and a gymnotiform (the electric fish Steatogenys elegans). Nuclear and mitochondrial DNA (mtDNA) sequences were used for genealogical analyses and AFLP datasets were used for analyses of gene flow and genome scans. Readers interested about species-specific datasets, analytical methods, and detailed biogeographic reconstructions should refer to our five publications . Molecular dating indicates that these lineages all diverged during middle to late Miocene . In contrast, there was no evidence for cryptic species within the marine-derived taxa or within T. albus . Despite these differences, however, several congruous patterns that may actually reflect general forces shaping freshwater biodiversity in Amazonia were detected. Below we introduce the study region and summarize key comparative findings about inferred spatial arrangements of neutral and putatively adaptive genetic diversity. These are discussed within the contexts of geomorphological history of Amazonia and divergent selection.The five species are largely codistributed, yet results indicate they have very different evolutionary histories. Phylogenetic analyses unexpectedly revealed five cryptic species within the catfish The Amazonian aquatic environment sustains dramatic hydrochemical and ecological gradients that impose physiological constraints upon its aquatic communities . These aFigure 4). The study area encompasses two putatively strong selection gradients or ecotones: where the black waters of the Negro River meets the white waters of the Amazon River, and where the clear waters of the Tapaj\u00f3s River meets the white waters of the Amazon River. Additionally, the transect allows testing for genetic structure geographically associated with river confluence. That is because two controls in which rivers of the same water color meet were included: the confluence of the black waters of the Branco and Negro Rivers and the confluence of the white waters of the Madeira and Amazon Rivers .The study system within the Amazon Basin consists of the five major rivers representing white, black and clear waters: the Amazon (white), Madeira (white), Branco , Negro (black), and Tapaj\u00f3s .Despite differences in ecology and phylogenetic history, strong evidence indicates that the biogeographic and ecological contexts of the Amazon Basin have promoted largely congruent fine-scale phylogeographic and population-level structuring. From a genealogical perspective, all species showed strong signals of demographic expansion and in every case the timing of these occurred well within the Quaternary period, with the exception of Figures 5). No significant barrier to gene flow was identified at the confluence of the Madeira and Amazon Rivers in any species. Indeed, based on both mitochondrial and nuclear datasets, population structure was strongly associated with \u2018water color\u2019 but not with river system. For instance, statistically significant differentiation was consistently found between populations from rivers of different colors, but not between those from rivers of the same color . For C. existimatus, the large number of inferred cryptic species resulted in insufficient data for intraspecific analysis. However, the C. existimatus cryptic species \u2018D\u2019 endemic to black waters of the Negro River, appeared recently derived and genetically distinct from white water lineages .From a population genetic perspective, all species and species complexes showed a predominant barrier to gene flow at the confluence of the Negro and the Amazon Rivers, and/or again at the confluence of the Tapaj\u00f3s and Amazon Rivers . These lineages likely exemplify \u201cnatural replicates of the ecological speciation in progress\u201d , irrespective of river system and tributary arrangement.Using outlier loci approaches based on genome scans, divergent selection was quantified between populations of S. elegans , selection pressures were altered due to \u2018water color\u2019 between populations by considering three spatially explicit relative fitness surface scenarios. (i) No spatial selection gradient (\u2018uniform\u2019): in this scenario, the three genotypes were being selected against, but uniformly across the \u2018water color\u2019 riverscape scenario, thus having no spatial dependency. (ii) Gentle spatial selection gradient (\u2018gentle\u2019): here, a \u2018gentle\u2019 spatial selection gradient corresponding to the three river color locations and three genotypes was used. (iii) Steep spatial selection gradient (\u2018steep\u2019): for this scenario, stronger spatial selection gradients were assigned to each genotype for black, mixed, and white waters. For further details, see Simulations were conducted in the individual-based landscape genetics program CDPOP v1.2 . IndividS. elegans replicated system, population genetic analyses and FST-based genome scans showed that recent divergence appeared linked to a major hydrochemical gradient within each cryptic species . Results from ELG simulations further corroborate these findings. These ELG simulations show that neutral data can give a low population differentiation signal . They also show that selection-driven loci can respond with high population differentiation to the water color ecotone .In the The results link selection across an ecological gradient with reproductive isolation and it was speculated that assortative mating based on chemically different water types may be driving the divergence . The ratFigure 6). Moreover, dating of speciation events within Plagioscion, S. elegans and C. existimatus are consistent with the Miocene diversification of fishes observed in the fossil record, as well as in other molecular studies . These studies also suggest that the ancestral ecotype for each species was in Andean-derived white water .The palaeogeographic and paleoenvironmental changes in South America during the Miocene are known to have profoundly affected the evolution of the Amazonian fish fauna. These changes include the uplift of the Andes and associated neotectonic events, the incursion of marine waters into previously freshwater systems and the dramatic reorientation of major river drainages , ,c,d. Ind studies . Moving te water . These ete water . This asAlthough palaeogeographic events have clearly contributed to Amazonian fish diversity, the comparative analysis indicates that the force of divergent natural selection, in this case between water colors, deserves equal consideration. One of the primary tenets of ecological speciation theory is that high ecological opportunity, such as the colonization of new environments in the absence of predation and/or competition, will promote rapid population divergence resulting in speciation . Indeed,FST-based genome scans were employed to assess the role of selection in the origin and maintenance of population divergence between water colors. However, key to ecologically based divergent natural selection is that the process should be greater between selective environments than within (Table 4).Classic signatures of vicariant biogeographic history such as genetic drift, inbreeding and migration have genome wide effects, while selection usually leaves signatures only at those loci that are adaptive or tightly linked to adaptive loci via hitchhiking . For thin within . Indeed,C. asellus, divergent selection detected between the Tapaj\u00f3s and Amazon Rivers was a powerful yet recent phenomenon, such that genetic drift had not yet accumulated in selectively neutral genomic regions . For S. elegans, both the empirical landscape genetics and simulated ELG explicitly linked selection-driven population genetic structure to the water color ecotone, validating results of FST-based genome scans. By incorporating information about population history and by independently validating outlier results with simulations, we improved our ability to exclude type 1 errors normally associated with genome scans of selection .In the context of comparative biology, the use of genome scans revealed variable, yet valuable perspectives on the process of adaptive divergence across water colors, both within and between species. Although there is no certainty that ecologically diverged lineages will eventuate as reproductively isolated species , the obsThe evidence for the role of divergent natural selection in these studies occupies a relatively recent time frame and appears associated with the formation of the modern Amazon River and its aquatic ecotones. Considering that time erases the signature of divergent selection within the genome, resulting in a more diffuse pattern of genetic divergence , ecologiClarifying the role of ecology on population adaptation and divergence is crucial for understanding the origin of species and the evolutionary potential of biodiversity to respond to ongoing global change . AlthougAs illustrated in this review, studies of ecological speciation in the tropics should merge analyses of genealogical history and gene flow with recent developments in spatial modeling and ELG simulations. This integration provides valuable biogeographic and environmental contexts to disclose associations between landscape features and evolutionary processes, including divergent natural selection. Such approaches, when combined with NGS datasets and with information about divergent phenotypes can be used to identify adaptive loci across the landscape , and to Ecological adaptation and divergence in the face of homogenizing gene flow is still a controversial topic. Many studies of ecological speciation in nature appear as correlative, are based on results from lab experiments , and shoThe time is right for implementing studies that synergistically generate and explore information from adaptive phenotypes, phylogeography, population genomics and simulations in ELG to understand ecological divergence and speciation in the tropics. Such endeavors are expected to challenge results from current surveys that assess tropical diversity based on sparse population sampling and on geographic models that do not incorporate selection. In doing so, they will complement historical biogeographic and evolutionary studies of diversification of tropical biotas. Integrative frameworks such as the one illustrated here have considerable potential to enhance conservation management in biodiversity rich ecosystems and to contribute toward a better understanding of how ecology, space and time interact with the genome.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "There is an emerging consensus that cGMP has functions in the intestinal epithelium that go beyond the regulation of secretion. Observations in mice that are deficient in cGMP signaling components have revealed an important role in epithelial homeostasis, and such animals exhibit defective barrier function and increased susceptibility to intestinal tumorigenesis. Despite recent clinical success with the GCC-agonist Linzess\u00ae (linaclotide) in treating constipation, few studies have examined the effect of these agents in colitis or colon cancer models. In addition, a paucity of work focusing on the effects of cGMP elevating agents in wild type mice have left signaling downstream of cGMP and the therapeutic mechanisms poorly understood.Our laboratory has reported that clinically relevant phosphodiesterase 5 (PDE5) inhibitors can produce sustained increases in cGMP levels in the intestinal epithelium. In support of previous work with knockout mice, we further demonstrated that PDE5 inhibitors promote the differentiation of colonic secretory cells, and alter homeostasis by suppressing both apoptosis in the luminal epithelium and proliferation in the crypts. These effects of increased cGMP in the colon mucosa led to the suppression of colitis and tumorigenesis in preclinical disease models. The cGMP-dependent signaling pathways identified as likely contributors to the therapeutic effects of PDE5 inhibitors in the gut include PKG2-dependent activation of DUSP10 and FoxO. These pathways are capable of increasing epithelial resilience to redox stress and suppressing tumor proliferation. Preliminary results indicate that these pathways might also be activated by cGMP in the human colon mucosa, which highlights the potential utility of PDE5 inhibitors for the prevention and treatment of colitis and colon cancer.Signaling through cGMP has profound physiological effects in the gut mucosa that can be exploited using GCC-agonists and PDE5 inhibitors. While our understanding of the underlying mechanisms is relatively poor, these agents have significant therapeutic potential for the treatment of gastrointestinal diseases."} +{"text": "Identifying interventions to minimise missing data was the third highest research priority in a Delphi survey of the Directors of UK Clinical Trial Units (CTUs). However, a Cochrane Methodology Review of nested randomised studies of missing data interventions shows a substantial evidence gap, with all but one of the eligible studies targeting questionnaire response rates.Research is needed to identify strategies that effectively address the broader causes of missing data, including minimising withdrawals, ensuring clinical staff capture vital outcome measurements and improving patient attendance at clinic visits.Chief Investigators of HTA funded trials and the CTUs were surveyed to identify frequently used interventions, their perceived effectiveness and any implementation problems.A subsequent two round Delphi survey was conducted with CTUs to gain consensus around which interventions should undergo further research to formally evaluate their effectiveness.We discuss the frequency and range of pragmatic interventions implemented by the 50/74 Chief Investigators and 33/46 CTUs who completed the initial surveys. Themes explored include incentives, communication strategies to patients and sites, site training and monitoring and the use of reminders.35/46 CTUs (76%) participated in the Delphi survey, leading to a ranked list of research priorities, highlighting which are likely to have the broadest impact across a variety of trial contexts.A variety of missing data interventions are used depending on trial context but with little evidence to support their use. This project will inform a roadmap for researchers to identify missing data interventions and develop an evidence base."} +{"text": "Teenage pregnant women are at risk of having low birth weight and preterm birth babies. The additional psychosocial interventions are thought to improve these outcomes for teenage pregnancy. However, the effect of additional psychosocial intervention programs on those is uncertain. The aim of this meta-analysis is to assess the effects of additional psychosocial interventions for teenage pregnancy on low birth weight and preterm birth outcomes.Search strategy: Relevant studies were identified from Medline, CINAHL, and Scopus since initiation to November 2013.Selection criteria: Randomized controlled trials investigating the effect of any psychosocial intervention on low birth weight and preterm birth were included.Data collection and analysis: Two reviewers independently assessed the quality of each study and extracted outcomes including rate of low birth weight, preterm birth rate, mean gestational age at delivery and mean birth weight. Standardized mean difference and DerSimonian-Laird method were applied for pooling continuous and dichotomous outcomes, respectively.The five studies with 712 teenage pregnant women were included. Compared with routine antenatal care, the psychosocial intervention significantly reduced risk of low birth weight by 40% . For the preterm birth, the psychosocial intervention reduced risk of preterm birth by 33% with no statistical significance . The pooled result for birth weight showed that our infants in the intervention group are slightly heavier than those of control group with statistical significance . Gestational age at delivery of intervention group was slightly increased than those of control group with no statistical significance .The additional psychosocial support to teenage pregnant women can improve pregnancy outcomes including low birth weight and birth weight. The variation in the intervention and risk of bias within included studies may limit this conclusion."} +{"text": "Systemic lupus erythematosus (SLE) is a chronic inflammatory rheumatic disease that disproportionately affects African Americans and other minorities in the USA. Public health attention to SLE has been predominantly epidemiological. To better understand the effects of this cumulative disadvantage and ultimately improve the delivery of care, specifically in the context of SLE, we propose that more research attention to the social determinants of SLE is warranted and more transdisciplinary approaches are necessary to appropriately address identified social determinants of SLE. Further, we suggest drawing from the chronic care model (CCM) for an understanding of how community-level factors may exacerbate disparities explored within social determinant frameworks or facilitate better delivery of care for SLE patients. Grounded in social determinants of health (SDH) frameworks and the CCM, this paper presents issues relative to accessibility to suggest that more transdisciplinary research focused on the role of place could improve care for SLE patients, particularly the most vulnerable patients. It is our hope that this paper will serve as a springboard for future studies to more effectively connect social determinants of health with the chronic care model and thus more comprehensively address adverse health trajectories in SLE and other chronic conditions. Systemic lupus erythematosus (SLE) is a chronic inflammatory rheumatic disease that is characterized by autoantibody production and multiple organ system involvement, including a high prevalence of polyarthritis \u20134. In thPublic health attention to SLE has been predominantly epidemiological , documenGrounded in SDH frameworks and the CCM, this paper presents issues relative to accessibility to suggest that more transdisciplinary research focused on the role of place could improve care for SLE patients, particularly the most vulnerable patients. An approach that comprehensively examines both community- and individual-level social determinants contributing to negative impacts of SLE could improve clinical knowledge and assist in improving care for those disproportionately impacted by SLE .Originally coined by Whitehead and Dahlgren , the socExpanding on Whitehead and Dahlgren's model, Robinson's SDH framework considers the importance of community and race/ethnicity to individual health outcomes . The modComplementing an SDH framework, Wagner's chronic care model , 51 CCM. The maiOne such strategy has been the implementation of self-management techniques for rheumatic, particularly SLE, patients. Over the past 25 years, research has demonstrated the effectiveness of arthritis self-management education delivered by small-group, home study, computer, and Internet modalities , 56\u201372. Drawing from the CCM for an understanding of how community-level factors may exacerbate disparities or facilitate better delivery of care for SLE patients within SDH frameworks is based on a paradigm shift from the current model of dealing with acute care issues tExaminations of health-related travel and accessibility draw our discussion of connecting SDH frameworks and the CCM together. We reviewed scientific literature that has examined travel as a potential barrier to accessing care to assess trends, discrepancies, strengths, and limitations of current attention to social determinants impacting the lives of SLE patients.Accessibility to care is an important component in understanding the influence of social determinants of health, and it has been addressed in health service policy research for several years , 94. ConWe were able to identify one study that specifically addressed health-related travel among SLE patients. Gillis and colleagues (2007) evaluated the association between Medicaid insurance and distance traveled by patients to treating physicians and health care utilization for SLE patients . Using rIn our own work, a validated psychosocial stress intervention was piloted among a cohort of African American SLE patients participating in an SLE database project at the Medical University of South Carolina (MUSC). During the course of the Balancing Lupus Experiences with Stress Strategies (BLESS) study, it became apparent that travel issues were preventing the full participation of the MUSC cohort. During followup phone calls for this project, many participants relayed that they could not participate in all aspects of the intervention because of complications related to travel. Some identified having to utilize Medicaid supported travel that required prior scheduling well in advance, but even this type of transportation was not completely reliable. Others identified having to travel long distances, which required advance planning because of reliance on family members or friends to assist with transport (unpublished observations). This information contributed to our knowledge concerning nonadherence and substantiated a need for further investigation of these issues. Specifically, this knowledge provided a foundation to investigate whether travel burden contributed to stress that may also impact the effectiveness of disease self-management programs. In that subsequent investigation, we identified four major areas of concern with respect to travel burden in accessing their rheumatologists: general travel issues; competing priorities; social/economic support challenges; and challenges surrounding general health (unpublished observations).All of these findings emphasize the importance of exploring the specific factors that limit and motivate the participation of a vulnerable disease population in critical healthcare and research activities.In conclusion, this review of SDH frameworks, the CCM, and the case of accessibility and travel issues in the context of SLE reveal that much more work can be done to improve care for SLE patients. Transdisciplinary approaches and research efforts could bring together several innovative methods for better addressing the complex issues faced by SLE patients. Further investigation of exactly how current approaches have been limited and the implications for disease manifestations and treatment are warranted to guide future SLE research. This would help to assess the appropriateness of focusing more broadly on \u201cupstream\u201d influences as a way to improve quality of life for SLE patients by exploring instances where focusing on upstream influences has improved care outcomes. Thus, we would more comprehensively elucidate the need for population health approaches rooted in the social determinants of health framework while setting the stage for connecting it to a biomedical framework that is widely accepted among physicians and medical researchers. By this, we can suggest not only continuing traditional models of biomedical research but also producing extrapolations regarding how broad social influences impact the lives of SLE patients.Our review suggests that more research is needed to expand the scope of barriers of SLE to include social determinants such as accessibility and health-related travel. GIS research methods should be used in future research to begin to fill this knowledge gap. Thus, drawing from geography research methods and theories, researchers attempting to better understand place-related disparities could benefit greatly from transdisciplinary intervention activities that include research areas that explore the impact of travel on SLE patients, especially considering the geographic coverage of clinical trials studying SLE. It is our hope that this paper will serve as a springboard for future studies to more effectively connect social determinants of health with the chronic care model and thus more comprehensively address adverse health trajectories in SLE and other chronic conditions."} +{"text": "But anyone who, casting aside and rejecting all these means, attempts to conduct research in any other way or after another fashion, and asserts that he has found out anything, is and has been victim of deception.\u2019\u2014HippocratesOne of the commonest problems of glaucoma filtration surgery is bleb scarring. The advent of antifibrotic agents, vascular endothelial growth factor (VEGF) inhibition as well as newer pharmacological compounds and materials has improved the predictability and longevity of filtration surgeries. Gaskin et al discuss and critically evaluate the application of antifibrotic agents in glaucoma filtration surgery in a comprehensive two-part review.Continuing the theme of subconjunctival scarring being an important determinant of glaucoma surgery outcomes, Howlett et al assessed bulbar conjunctival and Tenon\u2019s layer thickness using optical coherence tomography (OCT) in a pilot study designed to eventually help predict surgical success.Jung et al compare the efficacy of different surgical strategies for intraocular pressure (IOP) control in Hispanic glaucoma patients with and without visually significant cataracts and conclude that trabeculectomy and phacotrabeculectomy are both viable surgical options for managing open angle glaucoma with similar rates of success, IOP reduction, decrease in use of IOP-lowering medications and postoperative complication rates.Given that patients with glaucoma often lose vision despite adequate medical or surgical treatment, complementary and alternative medicine deserves scientific scrutiny from glaucoma surgeons. Bhartiya et al critically review the currently available evidence, most of which remains empirical and anecdotal in nature.Prado et al investigate the treatment outcomes of argon laser peripheral iridoplasty (ALPI) in angle closure mechanisms other than pupillary block concluding that it is a useful procedure, independent of the underlying mechanism, leading to angle widening and moderate IOP reduction in most cases.The demographical profile, presentation, management and outcome of traumatic glaucoma in children as well as the various factors associated with advanced glaucomatous changes are elucidated in a comprehensive review by Kaur et al.Agarwal et al evaluate the normative data of macular thickness and retinal nerve fiber layer thickness among normal subjects using spectral domain optical coherence tomography in a central Indian population, reiterating that values obtained by time domain OCT are not comparable with those of the spectral domain OCT.We hope you find this issue relevant to your day-to-day clinical practice and look forward to your feedback.Best wishesShibal BhartiyaTarek ShaarawyTanuj Dada"} +{"text": "Obesity is associated with a high prevalence of mood disorders and cognitive dysfunctions in addition to being a significant risk factor for important health complications such as cardiovascular diseases and type 2 diabetes. Identifying the pathophysiological mechanisms underlying these health issues is a major public health challenge. Based on recent findings, from studies conducted on animal models of obesity, it has been proposed that inflammatory processes may participate in both the peripheral and brain disorders associated with the obesity condition including the development of emotional and cognitive alterations. This is supported by the fact that obesity is characterized by peripheral low-grade inflammation, originating from increased adipose tissue mass and/or dysbiosis (changes in gut microbiota environment), both of which contribute to increased susceptibility to immune-mediated diseases. In this review, we provide converging evidence showing that obesity is associated with exacerbated neuroinflammation leading to dysfunction in vulnerable brain regions associated with mood regulation, learning, and memory such as the hippocampus. These findings give new insights to the pathophysiological mechanisms contributing to the development of brain disorders in the context of obesity and provide valuable data for introducing new therapeutic strategies for the treatment of neuropsychiatric complications often reported in obese patients. The prevalence of obesity has been steadily and alarmingly increasing worldwide for decades, fostering a rise in serious obesity-related outcomes, particularly cardiovascular diseases and metabolic disorders that contribute to a significant rise in mortality. In addition, obesity is also increasingly linked to a number of psychopathologies including mood disorders and cognitive dysfunctions and db/db mice], are associated with increased hippocampal cytokine expression or tail suspension test (TST), remains unchanged unless the animals are challenged with LPS formation Figure Murr et. By activice versa. Consequently, alterations of HPA axis functions and inflammatory activation are often associated in many pathological conditions, including cancers treated by immunotherapy display deficits of hippocampal-dependent memory and increased anxiety-like behavior (Stranahan et al., One of the stronger features associated with obesity is the significant increase of leptin production (Lehr et al., per se is not essential or sufficient to explain behavioral alterations occurring in obesity. For example, the increased risk of cognitive dysfunction displayed by patients with metabolic syndrome is independent from the presence of diabetes (Muller et al., db/db mice does not improve spatial cognitive impairments or anxiety-like behaviors (Stranahan et al., db/db and db/+ mice (Stranahan et al., This hormone, whose circulating levels and signaling pathway are altered in obesity, is able to interact with inflammatory processes and to act within the brain to modulate mood and cognition (Ghasemi et al., Converging evidence shows that obesity-related microbiota dysregulations, which play a critical role in induction of peripheral and brain inflammation (Bruce-Keller et al., Altogether, data presented in this review clearly show that brain inflammatory processes represent key players in the development of neuropsychiatric comorbidities in obesity. These likely rely on interactions involving multiple systems, including inflammatory processes but also neuroendocrine systems, gut microbiota and environmental influences. Indeed, neuroinflammation appears to be the cornerstone of the different factors contributing to induce neuropsychiatric symptoms in obesity. Several issues are however still unclear, in particular the identification of the specific brain pathways and/or mechanisms targeted by neuroinflammation and underlying obesity-related mood and cognitive alterations. Recent experimental results reported in this review suggest that cytokine-induced unbalanced relationship between neurogenesis and neuronal death combined with alterations in monoamine metabolism and function likely represent a major pathophysiological pathway to neuropsychiatric comorbidities in obesity Figure . Given tThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Specialist Supportive Clinical Management (SSCM) is a psychotherapy with promising potential for the treatment of anorexia nervosa. SSCM has two distinct components: clinical management, which involves alleviation of the symptoms of anorexia nervosa, particularly focusing on weight gain via resumption of eating; and a supportive psychotherapeutic approach to issues identified by the patient as important. The current study aimed to categorise, quantify and describe SSCM content across outcomes and over the course of therapy. SSCM therapy transcripts from ten participants in the original clinical trial of SSCM for anorexia nervosa were examined using thematic and content qualitative analyses. Clinical management content declined over time, whereas supportive psychotherapy content increased. Overall, there was more clinical management content for participants with a good outcome relative to participants with a poor outcome"} +{"text": "To evaluate the quality of available evidence to establish guidelines forthe use of noninvasive ventilation for the management of status asthmaticusin children unresponsive to standard treatment. Search, selection and analysis of all original articles on asthma andnoninvasive ventilation in children, published until September 1, 2014 inall languages in the electronic databases PubMed, Web of Science, CochraneLibrary, Scopus and SciELO, located using the search terms: \"asthma\",\"status asthmaticus\", \"noninvasive ventilation\", \"Bronchospasm\", \"continuouspositive airway pressure\", \"child\", \"infant\", \"pediatrics\", \"hypercapnia\",\"respiratory failure\" and the keywords \"BIPAP\", \"CPAP\", \"Bilevel\", \"acuteasthma\" and \"near fatal asthma\". The articles were assessed based on thelevels of evidence of the GRADE system. Only nine original articles were located; two (22%) articles had level ofevidence A, one (11%) had level of evidence B and six (67%) had level ofevidence C. The results suggest that noninvasive ventilation is applicable for thetreatment of status asthmaticus in most pediatric patients unresponsive tostandard treatment. However, the available evidence cannot be considered asconclusive, as further high-quality research is likely to have an impact onand change the estimate of the effect. In 1993, a searchin the PubMed database using the search term \"noninvasive ventilation\" would havelocated only 14 articles. By 2003, the number of studies retrieved with this searchterm was 88. A search conducted in 2013 resulted in the identification of 230scientific publications by the same term.Noninvasive ventilation (NIV) was first used in adults by the end of the1980s.It is characterized by diffuse lower airway obstruction caused byinflammation/edema, in addition to bronchial smooth muscle spasm and mucus plugging,being a reversible condition.Patients exhibit airflow limitation and premature airway closing, which increase thework of breathing. The expiratory phase of breathing becomes active in an attempt toempty the lungs. Increased airway resistance and hyperinflation cause overdistensionof the lung parenchyma and chest wall, rendering the next inspiration moredifficult.Hyperinflation is dynamic and results in progressively longer time constants, withconsequent increases in air trapping and intrinsic positive end-expiratory pressure(PEEP). Severe asthmaattacks are acute or subacute episodes of cough, \"shortness of breath\", \"wheezing\",\"tight chest\" or any combination of these symptoms.Acute severe asthma, also known as status asthmaticus, is essentially a fast andsevere exacerbation of asthma that might not respond to standard treatment .The rate of hospital admissions caused by asthma among children is approximately 5%;episodes of respiratory failure are uncommon in this population, being developed in8 to 24% of the asthmatic children admitted to pediatric intensive careunits.It is currently believed that in some groups of patients, such as those withexacerbation of chronic obstructive pulmonary disease (COPD), NIV reduces the needfor intubation, the mortality rate and the cost of treatment, for which reason itsuse has become increasingly more frequent. Nevertheless, the indications forNIV in acute asthma attacks still do not have solid support, and its use has beenput into question, particularlyin the case of children.As NIV seems to be efficacious and safe in COPD and the pathophysiology of acuterespiratory dysfunction in asthma is similar in many aspects to that of COPD, theuse of NIV has been investigated in cases of severe asthma attacks. The bronchodilator effect isresulted by the use of PEEP, which compensates the effects elicited by the elevationof the intrinsic PEEP. The airflow increases through collateral ventilationchannels, resulting in re-expansion of areas with atelectasis and improvement of theventilation/perfusion ratio, with a consequent reduction in the work ofbreathing. When appliedin bilevel positive airway pressure (BIPAP) mode, the inspiratory positive airwaypressure (IPAP) might help the inspiratory muscles to overcome the limitation to theairflow and chest overdistension, thus increasing the tidal volume.The mechanism of action of NIV in status asthmaticus seems to be based on itsbronchodilator effect, which induces alveolar recruitment. or nasalprongs, which means that it is without tracheal intubation, reducing thecomplications associated with invasive mechanical ventilation and becoming an optionfor patients who are poorly responsive to the standard treatments for statusasthmaticus. However, attention should be paid to the general contraindications ofNIV, such as altered state of consciousness, hemodynamic instability,gastrointestinal disorders (likely to cause nausea and vomiting), facial trauma,acute failure of more than two organs, among others.In NIV, the patient-machine interface consists of a mask, held in place with aheadgear,This ventilation support is usually provided by continuous (CPAP) or bilevel (BIPAP)positive airway pressure.The aim of the present study was to assess the quality of the available evidence toestablish guidelines for use of NIV in the management of status asthmaticus inchildren unresponsive to standard treatment.Search, selection and analysis were conducted for all original articles on asthma andNIV in children (up to 18 years old) published until September 1, 2014 in anylanguage in the electronic databases PubMed, Web of Science, Cochrane Library,Scopus and SciELO; the articles were located using the search terms \"asthma\",\"status asthmaticus\", \"noninvasive ventilation\", \"Bronchospasm\", \"continuouspositive airway pressure\", \"child\", \"infant\", \"pediatrics\", \"hypercapnia\",\"respiratory failure\" and keywords \"BIPAP\", \"CPAP\", \"Bilevel\", \"acute asthma\" and\"near fatal asthma\".The articles located by the search were initially selected based on the informationprovided in their titles and abstracts. Studies with samples containing individualswith lung disorders other than asthma were excluded. Then, the full texts of theselected articles were analyzed, and the references cited in them were surveyed insearch for additional studies that could possibly meet the inclusion criteria andhad not been located in the first search. As only a small number of articles met theinclusion criteria, all of them were included in the systematic review throughassessment of its methodology.-15The methodological quality of the articles was assessed by means of the Grading ofRecommendations Assessment, Development and Evaluation (GRADE) system for evaluationof scientific evidence. GRADE was chosen because it is a clear and explicit systemthat considers the design and execution of studies and their consistency and lineardirection in the judgment of the quality of the evidence corresponding to eachoutcome/relevant consequence.In GRADE, the quality of evidence is classified as high, moderate, low or very low. Some orJudicious evaluation of the quality of the evidence was independently performed bytwo reviewers.After the database search, only nine articles were located and included in thesystemic review . These a,18 have several limitations, such as a lack ofblinding participants and investigators and small sample sizes. In 2010, the journalPediatric Critical Care Medicine published the abstract of a paper presented at ameeting on this subject, which likely corresponds to the early stages of a studypublished in 2012. Thisprospective open-label randomized clinical trial compared NIV combined with standardtreatment and standard treatment alone for the management of severe acute asthma inchildren aged one to 18 years old.Few published studies discuss the use of NIV for the management of severe acuteasthma in children, and most of them are observational. The only two randomizedclinical trials located in the present review did not exclude the possibilityof having included participants with other lower airway obstructive diseases as afunction of difficulties in differential diagnosis. Nevertheless, it focused onasthmatic patients and even used a scale for asthma severity assessment .One of the randomized clinical trialsincluded in the present systematic review used plethysmography as an objectivemeasure for assessment of respiratory mechanics. The authors of that study concludedthat NIV is safe and effective for the management of severe acute asthma in thepediatric population.The one prospective study,20,21 andcase series/reports.,22,23The remainder of the located studies are observational, consisting ofcohorts2O over 20 minutes. This study found an increase of the vagal tone during CPAPuse, with the effect remaining after discontinuation because of activation of thenon-cholinergic parasympathetic pathway, with consequent inhibition ofbronchoconstriction caused by stimulation of the cholinergic pathway.One of the studies tested the hypothesis that use of a CPAP induces autonomicmodulations that increase parasympathetic activation, in addition to bronchodilationresulting from the mechanical effect of positive pressure. The CPAP level used was10cmH Theresults seemingly depend on countless associated factors, such as the type ofventilator, ventilation mode, type of patient-machine interface and position of theaerosol therapy connection in the circuit, among others. Nevertheless, it isbelieved that combinations of NIV and inhaled medications have beneficial effects,provided proper attention is paid to the application of this technique.The possibility that NIV improves aerosol (bronchodilator) deposition in the airwaysby inhalation therapy during asthma attacks and exacerbations of COPD was alsoconsidered. and subcutaneous emphysema, amongothers. In clinical practice, such deleterious effects might be minimized throughthe application of hydrocolloid sheets between the skin and the mask, the use of anasogastric tube attached to a collector bag, short pauses for face comfort andadjustment of the NIV pressure settings as needed.NIV might be associated with some complications, such as skin lesions (from the maskpressure), gastric distention that might cause vomiting and aspiration Some cases require some modality of sedation, which shouldbe thoroughly assessed, as it might cause respiratory depression.Another fact that should be taken into account is that some patients might feeldiscomfort caused by the air pressure and flow.2 compared to when normal oxygen therapy systems are used.The limitations exhibited by the analyzed studies might derive from the fact that theuse of a mask (or other types of interface used in NIV) will certainly be perceivedby patients and investigators. In addition, it is very difficult to deliver oxygenalone (with no pressure for a control group) through any kind of NIV interface;mainly because it might cause discomfort and thus likely fails to generate thedesired FiOThere are also ethical issues to consider. Severe acute asthma attacks might befatal; thus, treatment must be carefully chosen to resolve the attack as soon aspossible, which might make simple randomization to receive or to not receive NIVdifficult.The authors of all analyzed studies rated NIV as a safe and efficacious adjuvanttreatment for children with status asthmaticus who are unresponsive to conventionaltreatment; nevertheless, one should take the aforementioned considerations about themethodological quality of the studies into account.The results suggest that noninvasive ventilation is applicable for the treatment ofstatus asthmaticus in most pediatric patients unresponsive to standard treatment.However, the available evidence cannot be considered as conclusive, as furtherhigh-quality research is likely to have impacts on and change the estimates ofeffects."} +{"text": "Hypoxia plays an important role in tumour recurrence among head and neck cancer patients. The identification and quantification of hypoxic regions are therefore an essential aspect of disease management. Several predictive assays for tumour oxygenation status have been developed in the past with varying degrees of success. To date, functional imaging techniques employing positron emission tomography (PET) have been shown to be an important tool for both pretreatment assessment and tumour response evaluation during therapy. Hypoxia-specific PET markers have been implemented in several clinics to quantify hypoxic tumour subvolumes for dose painting and personalized treatment planning and delivery. Several new radiotracers are under investigation. PET-derived functional parameters and tracer pharmacokinetics serve as valuable input data for computational models aiming at simulating or interpreting PET acquired data, for the purposes of input into treatment planning or radio/chemotherapy response prediction programs. The present paper aims to cover the current status of hypoxia imaging in head and neck cancer together with the justification for the need and the role of computer models based on PET parameters in understanding patient-specific tumour behaviour. References are provided from groups reporting workable solutions to uncertainties arising due to the image acquisition itself; however, as the reports in cers did and cont2 to cell death probably, that is, radiosensitivity, or cell death to tumour control are nonlinear and dependent on patient specific parameters. The authors remind us that chronic hypoxia remains the focus of the discussed techniques, as opposed to acute/transient hypoxia which may alter in oxygenation faster than the time a PET scan can be acquired and analysed (or radiotherapy planned/delivered). Logistical noteworthy challenges are discussed, for example, the set-up accuracies required, volume expansion protocols for adding margins onto regions of interest nonuniform dose prescription, and how often to rescan during therapy to balance workload of scanning and replanning with the timing of substantial biological change and hence improvement in therapeutic ratio if the plan is altered.This report also discusses the issues of converting oxygenation information into radioresistance estimates and hence prescription requirements, in order to achieve increased tumour control. These are nontrivial challenges, as both functions of converting pOTumour hypoxia remains one of the major causes of treatment failure in head and neck cancer. By promoting angiogenesis as well as distant metastases, hypoxia becomes an important treatment target. In order to increase the therapeutic ratio it is crucial to identify and to quantify the hypoxic subvolumes. To date, PET-based molecular imaging is the most commonly employed technique applied for this purpose.The use of computational models for treatment assessment and prediction is fast growing. Whether simulated or actual PET data has been applied to a tumour response model, overall the current literature suggests that targeting radioresistant hypoxic tumour subvolumes using complex dose gradients or even simpler boost doses is feasible using modern radiotherapy techniques. Research has also shown that toxicity need not be compromised if careful planning is performed, with a possible solution being not to increase the integral dose but rather decrease the prescription to well oxygenated regions and increase it to chronically hypoxic areas. This is still to be confirmed in randomised clinical trials.As it stands currently, all the signs point to hypoxia dose painting as being feasible to tackle notoriously hypoxic tumours, such as head and neck carcinomas. To further improve, the field moves into requiring individual tracer pharmacokinetic information/analysis so that PET data can be accurately interpreted and then utilised appropriately to predict optimal treatment plans and overall outcome improvement.Health institutions will need to encourage and support multidisciplinary research and prioritize resources to make the use of functional PET information feasible, as assessing the dynamic changes of the tumour characteristics at a number of time points after PET injections and then at multiple intervals throughout radiotherapy will always inevitably be highly resource intensive. This will be especially true during the learning phase as this technique is translated from research into the routine clinical environment. Computational pharmacokinetics and tumour models will be vital in this translation process."} +{"text": "The terms biosurfactant and bioemulsifier have often been used interchangeably to describe surface active biomolecules. However, it is important to note that there are marked differences between them especially based on their physico-chemical properties and physiological roles. Although bioemulsifiers and biosurfactants are both amphiphilic in nature and are produced by a wide range of microorganisms, each exhibit characteristic roles in nature. These microbial surfactants have recently received increased scientific attention due to their unique characteristics relative to chemically derived surfactants. Their unique features include; non-toxicity, biodegradability, biocompatibility, efficiency at low concentrations and their synthesis from natural substrates under mild environmental conditions.The chemical composition of biosurfactants and bioemulsifiers is different and this may contribute to their specific roles in nature and biotechnological applications. Biosurfactants are generally low molecular weight microbial products composed of sugars, amino acids, fatty acids and functional groups such as carboxylic acids. The glycolipids consist of different sugars linked to \u03b2-hydroxy fatty acids while lipopeptides consist of cycloheptapeptides with amino acids linked to fatty acids of different chain lengths. These molecules are amphiphilic in nature and this property allows them to dissolve in both polar and non-polar solvents . It increases the bioavailability of poorly soluble substrates in aqueous environments for microbial access and degradation by coating the hydrophobic substrate to form a minicapsule. The producing bacterium can also have direct access to hydrophobic substrates but the emulsifying activity is exhibited by secreted emulsan. However, this emulsifier can efficiently emulsify mixtures of aliphatic and aromatic hydrocarbons in balanced proportions but cannot emulsify their pure forms. The emulsifying activities of emulsan are therefore attributed to its fatty acid components which act as multiple sites for binding different hydrophobic phases were mixed together but had no emulsifying activity when these components existed in separate forms , paraffins and crude oils. Alasan can facilitate solubilization of PAH by aggregating them into oligomer molecules and this mechanism increases their solubility by 20-fold, thereby speeding up biodegradation. The protein components in the alasan molecule have been associated with its ability to emulsify various hydrocarbons unlike emulsan. This is a 45 kDa protein with highly hydrophobic regions folded over in loops contributing to emulsification and solubilization activity of alasan while enzymatic mannoproteins have more protein moieties in their structures. These molecules are not only effective emulsifiers but have been associated with stimulation of host immunity by activating immune cells and proteins as well as triggering the production of antibodies that can efficiently emulsify hydrocarbons. This EPS is rich in uronic acids containing less carbohydrate and protein components. The uronic acid has been associated with the ability of EPS to emulsify and detoxify hydrocarbons . This outstanding contrast between biosurfactants and bioemulsifiers is especially important for accurate screening and identification procedures from microbial culture broths.24 and current research toward identification should be based on a broad spectrum of tests and not only on surface tension measurements, which are often used as primary tests. In addition, there is minimal research on the discovery and characterization of new emulsifiers from microorganisms due to the lack of a clear picture of the distinguishing features between biosurfactants and bioemulsifiers. Biosurfactants and bioemulsifiers are both unique microbial products showing advantageous features and may become future substitutes for chemically produced ones. We have noted that bioemulsifiers have often been erroneously eliminated or mis-identified in the past but, since these molecules have great potential for green technology, carefully designed screening methods will be an essential step toward the discovery of novel microbial emulsifiers.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "As part of a broader methodological programme of work around clinical trial monitoring, we plan to develop a comprehensive central monitoring strategy that is useful to staff developing clinical trial quality management and monitoring plans. In order to facilitate trial operation's staff planning a monitoring strategy where procedural and protocol compliance issues can be identified without the need to perform costly and intensive routine on-site data monitoring, we engaged in the current work that explores practical methods to achieve the aims of trial monitoring and trial conduct oversight.The current work comprises of 3 components: a literature review; informal interviews and surveys of current practice by trial teams at a large UK Clinical Research Collaboration (UKCRC) registered Clinical Trials Unit engaging in phase II and III clinical trials in cancer and HIV research; and strategy development.At the time of writing this work is still being conducted. We aim to develop our strategy from the information available from all sources with suggestions for activities centred around: preventing, identifying, monitoring and addressing patient safety and participant rights issues; ensuring, through appropriate trial design and management, the generation of unbiased, accurate and timely data; enhancing trial management processes , enhancing protocol compliance, enhancing procedural compliance; and identifying fraudulent activities ."} +{"text": "A single case of Ebola virus disease (EVD) in a physician returning from service with MSF in Liberia set off widespread public anxiety. The physician was asymptomatic on his return but became febrile several days later, tested positive for EVD, and required admission to a specialized facility. In the interim, he had traveled widely to public places in New York before his diagnosis.To describe the clinical, epidemiologic, public health and political aftermath of a single case of EVD in a physician returning from West Africa.Describe the events surrounding this physician's diagnosis, the media frenzy and political overreaction by state and local politicians including a confrontation between political leaders and public health authorities.The extensive preparedness and training activities by public health authorities and health care facilities, including establishment of designated EVD diagnostic facilities and treatment centers were inadequate to overcome the ensuing public panic about potential Ebola transmission manifested by fear about riding the subways, visiting public sites or facilities where the physician was alleged to have wandered in New York prior to his diagnosis, and fears about seeking or providing treatment at the facility where the physician was hospitalized. There was avoidance of the large African community in New York, irrespective of their country of origin. The political ramifications included orders by two local governors to involuntarily restrain and isolate any additional healthcare providers returning from Ebola endemic areas which had a chilling effect on recruitment efforts for replacement workersA single case of Ebola Virus disease in a returned healthcare worker caused widespread panic despite educational efforts by public health officials and healthcare facilities. These efforts were inadequate to overcome general distrust of the government, media frenzy, and initial misstatements by federal health officials. Considerable harm was also done by overzealous political figures anxious to use the public's concerns to advance their own political agendas.None declared."} +{"text": "Children\u2019s responses to medical treatments differ significantly from adults. Appropriately selecting and measuring child and family relevant outcomes when designing pediatric clinical trials is important for decision making with regards to the health of the child. However, outcomes used to measure an intervention\u2019s effectiveness in current pediatric clinical trials often lack child and family relevance, are heterogeneous across and within child health ages and diseases, and are not adequately measured with validated instruments. Furthermore, involvement of patients (children) and their proxies in outcomes selection is minimal. Inconsistent use of outcomes and outcomes measurement in pediatric clinical trials impairs the synthesis of evidence in systematic reviews and leads to outcome reporting bias. This high variability in outcome selection and measurement has led to a situation where child health decisions on treatment of children lack the appropriate underpinning evidence, and a subsequent inability to reach a consensus on the effectiveness and safety of a treatment. Recently, outcome selection initiatives in the general population such as OMERACT and COMET advocate homogeneity of methodology for outcome selection and measurement in trials.Toronto Outcome Research in Child Health (TORCH) is an exciting new collaborative initiative that develops and employs existing and new evidence-based methods for improving outcomes selection and measurement in cohort studies and trials in children.The TORCH platform raises awareness on the importance of meaningful outcomes selection and measurement in children; provides methodology to select measure and report truthful, discriminative and feasible outcomes in child health research; and supports engagement with research ethics boards, funders, journal editors and regulators to critically appraise outcomes selection, measurement and reporting in any child health research. The new TORCH platform will facilitate the translation of knowledge from the literature to bedside care, thereby improving child health outcomes while reducing the burden on the healthcare system."} +{"text": "Multi-centre randomised controlled trials (RCTs) in surgery are challenging. It is particularly difficult to establish standards of surgery and monitor whether interventions are delivered as intended. This can lead to uncertainties about the differences between trial group interventions and the meaning of observed treatment effects.This study developed and tested methods for intervention design and monitoring within the internal pilot phase of a surgical RCT.Two phases of work were undertaken: i) in-depth analysis of intervention reporting in published surgical RCTs to establish a typology for intervention design, ii) qualitative work in the operating theatre to identify \u2018key\u2019 components of interventions, comprising video data capture, non-participant observation of surgical interventions and interviews with surgeons.Some 80 RCTs reporting 160 interventions informed the new typology, which provides guidance for describing and monitoring surgical interventions. It prompts trialists to identify components and steps of interventions and consider whether each should be mandated, optional or prohibited within the RCT. The qualitative work identified variations in intervention delivery between surgeons and centres, established key intervention components and steps, and explored surgeons' opinions about how these should be delivered in the trial.Ensuring standards of surgery is important in surgical RCTs, even if they are considered to be pragmatic. This study has developed methods for intervention design and monitoring in RCTs. Consensus meetings have been planned with surgeons to agree the final intervention protocol for the main study. These methods are now being tested in the context of other surgical RCTs."} +{"text": "Supply chain management training remains the most critical discipline in building capacity and ensuring competitiveness and sustainability of Africa in the global context. Imperial Logistics continues to play a significant role through the development of our Fast Forward initiative. While ensuring effective operations and best practice, the company further develops sustainable platforms and solutions to expand our reach and address future skills for continued industry growth and innovation.The Imperial Logistics Academy aims to provide integrated, customised training and skills development programmes to Imperial Logistics employees. Imperial Logistics initiated an accreditation project with TETA in order to position the Imperial Logistics Academy as an Institute for Sector Occupational Excellence. With a vision to expand Fast Forward into Africa through focusing consistently on training and skills development for African countries, Imperial Logistics works through Imperial Health Sciences Supply Chain Academy as its primary implementation partner.The Fast Forward initiative contributes by providing: full learnership across occupational categories ranging from National Quality Framework education levels 1 \u2013 7, specific training aligned to standards, SOPs and business requirements, a legal framework through institutional accreditation and registration processes, a comprehensive quality assurance function and the use of its quality management system, alignment with human resources strategies, reduced duplication of efforts through the use of existing material and programmes while pooling pockets of excellence, improved skills and operational competencies, career development, personal empowerment and job satisfaction, and improved supply chain performance.Imperial Logistics remains committed to consistent investment that fast tracks capability development in the African supply chain management industry. The establishment of the Imperial Logistics Academy in combination with ISOE accreditation activities, Ikaheng acquisition, and Imperial Health Science Supply Chain Academy activities in Africa has taken the Imperial Logistics\u2019 Fast Forward initiative to a new level.Through continuous development and building further credibility as a learning organisation, Imperial Logistics further distinguishes itself as an \u201cEmployer of Choice\u201d and an industry leader in logistics and supply chain management. Utilising internal small and medium enterprises builds capacity while promoting career development and succession planning, strengthening organisational capability. In addition, the increasing duplication of the framework and utilisation of existing infrastructure improves return on investment and allows for continuous improvement."} +{"text": "Chronic obstructive pulmonary disease (COPD) is a complex and heterogeneous disease and its definition as a disease characterised by a non completely reversible airflow obstruction mainly caused by cigarette smoke does not fully describe the variability in its clinical presentation.The main complain of patients with COPD is exertional dyspnea caused by hyperinflation . TherefoYet in 2012, the Spanish guidelines of COPD (GesEPOC) identified four different phenotypes with clinical relevance and therapeutic repercussion: the non exacerbator phenotype, the exacerbator phenotype with emphysema or with chronic bronchitis and the asthma-COPD overlap syndrome (ACOS) . The exaExacerbators with emphysema should receive long acting bronchodilators (LABD) combined with inhaled corticosteroids (ICS) when LABD are not enough to control symptoms and exacerbations, and in particular if they have high concentrations of eosinophils in peripheral blood . They caThe phenotypic approach to treatment has been followed by other European guidelines such as the Czech Republic, the Finnish, the Russian or the Swedish ones . Some ofThe identification of clinical phenotypes of COPD reflects the heterogeneity of the disease and helps clinicians to select the most suitable treatment for their patients. The phenotypes proposed in recent guidelines are easy to identify in routine clinical practice."} +{"text": "Incidental pulmonary nodules in patients that are imaged for staging purposes or during follow-up may represent metastases, second primary tumours (lung cancer) or benign nodules.The probability of pulmonary metastases or primary lung cancer differs depending on the number, size, size distribution and morphology of the nodules as well as the histologic type, stage, grade and other features of the known malignancy. A large proportion of pulmonary nodules in patients with known cancer are benign. Thus, an unconfounded diagnosis of pulmonary metastases has to be avoided in order not to falsely preclude potentially curative therapy of the primary tumour.Synchronous or metachronous second primary lung cancers in a patient with a known lung cancer have to be differentiated from pulmonary satellite nodules representing either advanced tumour stages or metastatic disease as they may be amenable to curative surgery.Pulmonary consolidation or ground glass attenuation most often represents infection and other non-malignant pathology but may occasionally be due to malignant lesions.Pleural effusions and focal or diffuse pleural thickening from benign causes need to be differentiated from lesions representing pleural carcinomatosis which represents metastastic disease.During this course examples of different incidental pulmonary and pleural lesions will be demonstrated and recommendations and guidelines for the management of the findings will be presented."} +{"text": "The efficacy of Infliximab and Ciclosporin for treating moderate to severe ulcerative colitis is proven, but their relative effectiveness has not been evaluated. There is also limited understanding of patients\u2019 and professionals\u2019 views of the drugs.The COmparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis Trial (CONSTRUCT) aimed to compare the clinical and cost effectiveness of infliximab and ciclosporin in the treatment of steroid resistant acute severe ulcerative colitis, using quantitative, qualitative, and health economic data. The qualitative element explored patients\u2019 and health professionals\u2019 views of the two drugs.Within a UK multi-centre open label pragmatic randomised controlled trial, 35 interviews were conducted with 20 patients and 23 health professionals involved in the trial.There was no significant difference between the two drugs in clinical effectiveness terms, incidence of serious side effects, colectomy rates or mortality. Overall, service costs were significantly greater with infliximab, but it was viewed more positively by patients and nurses, who disliked the inconvenience of ciclosporin infusions. Healthcare professionals described the need for nurses with special knowledge of using ciclosporin for ease of drug handling.Integrated interview data with other datasets allowed us to bring additional insights about the impact of treatment and subjective benefits and disbenefits of the drugs to this trial. We could also describe context-specific preferences for the drugs from those directly responsible for patient care, offering an added dimension to clarifying decision-making in patient care, thus enabling a more holistic approach to interventional drug treatments."} +{"text": "Volar locking plates are designed to improve and maintain anatomic alignment, even in patients with dorsal comminution and poor metaphyseal bone quality. Its widespread use led to specific complications. Most part is related to tendon, nerve and complex regional pain syndrome and coulTendon and articular injury complications can be prevented by careful avoidance of dorsal cortex and intraarticular screw penetration, use of the low profile plates, and careful placement of the plate proximal to the watershed line.Most frequent tendons affected are Extensor Policis Longus (EPL) and Flexor Policis Longus (FPL). EPL tendon rupture can occur after a distal radius fractures even when not fixed by a plate .Use of standard intraoperative fluoroscopy imaging is crucial to assess dorsal cortex screw penetration. Lister tubercle can mask prominent screws tips and lateral images have limited sensibility particularly among less experienced observers and for the evaluation of the most ulnar screw positions .Irritation or rupture of flexor tendons, especially the FPL, depends on the position of the plate .Assessment of articular penetration of the screws is critical. Routine use of articular views , as wellPostoperative nerve dysfunction is one of the most common complications, especially median nerve dysfunction .K-wires used for provisional and supplementary fixation can be a source of complications. Such complication may be caused by superficial radial nerve irritation due to K-wire placement during fracture reduction.Finally, loss of reduction due to inadequate screw length or very osteoporotic bone may lead to symptomatic malunion. In extra-articular fractures, a minimum of four locked unicortical distal screws of at leOnce the fracture is healed, plates and screws are not necessary anymore and their removal can be indicated or suggested as a prophylactic measure, as this procedure is usually not associated with complications ."} +{"text": "Since its inception, the Journal for Immunotherapy of Cancer (JITC) has focused on all aspects of tumor immunology and cancer immunotherapy from bench to bedside. Clinical advances in immuno-oncology are accelerating, with an increasing number of approved drugs that specifically target the immune system to treat cancer. The success of these agents in the clinic has given rise to a rapidly expanding portfolio of trials testing cancer immunotherapies in patients with a variety of cancer types. Given the explosion of interest and clinical activity in cancer immunotherapy, we are pleased to launch a new section of JITC, the Clinical Trials Monitor, edited by Leisha A. Emens, MD PhD, of the Johns Hopkins University.The Clinical Trials Monitor section aims to publish and provide perspectives on late stage clinical trial results, highlight immuno-oncology trials in progress, and summarize important new regulatory approvals in cancer immunotherapy. The section also aims to address trial design and analysis considerations that may be unique to cancer immunotherapy, and to provide guidance for implementing and managing the use of cancer immunotherapies in the clinic. The section will disseminate clinically oriented information and perspectives in the following formats:This feature will include Phase 2 or 3 clinical trials with primary clinical endpoints, studies that define biomarkers of therapeutic response, primary resistance to immunotherapy, and immune escape, and trials that define the patient experience with cancer immunotherapies.This feature will review newly approved immunotherapies, highlighting the drug development process for the agent and indication, including any important biomarkers. It will also provide guidance about how the newly approved drug fits into the standard of care as it enters the clinic. These pieces will be written by leading immunotherapy experts in disease-specific areas, and should help inform the development of clinical practice guidelines by SITC, NCCN, and ASCO.This feature will include approval summaries from regulatory agencies around the world as new immunotherapies are approved for standard clinical use.This feature will highlight clinical trials grouped by modality, pathway, or disease subtype. These summaries will include an introduction followed by clinical trials in progress within the domain of focus. They will span early first-in-man single agent (novel immune checkpoint targets or innovative vaccine strategies) or important combination strategies (IDO inhibition with vaccines or immune checkpoint blockade), and later stage trials testing novel combinations with more established immunotherapies (radiation with immune checkpoint blockade).These pieces will succinctly highlight mechanistic principles underlying emerging immunotherapeutic strategies and technologies entering the clinic, providing a sound scientific foundation for trial design and evaluating the preclinical and clinical literature.This educational feature puts cancer immunotherapy into broad context. Subject matter may include a discussion of statistical considerations and perspectives essential for understanding results of pivotal clinical trials, clinical trial design and data analysis issues particularly relevant to cancer immunotherapy, and unresolved issues related to reduction to practice (toxicity management or issues related to access to novel immunotherapies (adoptive T cell therapy/CAR T cells).The Clinical Trials Monitor section will serve as a valuable resource for researchers and clinicians. It will report important new trial results, provide timely updates on new drug approvals and important ongoing clinical studies, and deliver key perspectives on clinical issues and advances in the field relevant to the everyday use of cancer immunotherapy in the clinic. A talented group of Editorial Board members from around the world with broad expertise in immuno-oncology will oversee the section. We expect to adapt the section to meet the changing needs of the field and the JITC readership, and we invite your feedback. These are exciting times for cancer immunotherapy, and we at JITC share your interest and enthusiasm for using cancer immunotherapy to transform cancer medicine and change the lives of cancer patients."} +{"text": "The treatment of cancer is becoming more precise, targeting specific oncogenic drivers with targeted molecular therapies. The epidermal growth factor receptor has been found to be over-expressed in a multitude of solid tumours. Immunohistochemistry is widely used in the fields of diagnostic and personalised medicine to localise and visualise disease specific proteins. To date the clinical utility of epidermal growth factor receptor immunohistochemistry in determining monoclonal antibody efficacy has remained somewhat inconclusive. The lack of an agreed reproducible scoring criteria for epidermal growth factor receptor immunohistochemistry has, in various clinical trials yielded conflicting results as to the use of epidermal growth factor receptor immunohistochemistry assay as a companion diagnostic. This has resulted in this test being removed from the licence for the drug panitumumab and not performed in clinical practice for cetuximab. In this review we explore the reasons behind this with a particular emphasis on colorectal cancer, and to suggest a way of resolving the situation through improving the precision of epidermal growth factor receptor immunohistochemistry with quantitative image analysis of digitised images complemented with companion molecular morphological techniques such as in situ hybridisation and section based gene mutation analysis. Personalised cancer medicine, depends upon and requires a detailed analysis of both immunohistochemical and molecular therapeutic targets. Over the last decade, emphasis has shifted from empirical treatment of patients to a biomarker-led, precision approach. Scientific discoveries in carcinogenesis, particularly within the field of molecular pathology, have shaped the personalised medicine paradigm \u20134. The eFollowing the application of immunohistochemistry (IHC) within the field of diagnostic histopathology in late 1970\u2019s, this method has remained popular for detecting and visualising cellular proteins in tissue samples where it can be used for both clinical diagnosis and classification of tumours , 11, incModern biomarker focused clinical trials must aim to identify reliable prognostic and/or predictive biomarkers for patient stratification , 21. How\u00ae EGFR PharmDx\u00ae kit remains the only FDA approved method for EGFR detection. Despite the pitfalls in EGFR IHC, EGFR remains one of the most commonly investigated cancer biomarkers due to its oncogenic role in various tumour types [In both the clinical and translational research setting, protein quantification and visualisation are important , 23. Theur types , 39, 40.ur types , 41\u201343.The EGFR and downstream components of the pathway have an integral role in tumorigenesis by means of regulating proliferation, angiogenesis and metastasis , 8, 39 . EGFR inThe use of cetuximab and panitumumab as both a single agent and in combination with chemotherapy has shown efficacy in several studies , 52\u201354. GCN) using fluorescence in situ hybridisation (FISH) and silver enhanced in situ hybridisation (SISH) has been shown to be extremely useful in determining efficacy of some classes of anti-EGFR therapies [CN are unlikely to respond to treatment with either cetuximab or panitumumab [CN could be used to predict the outcome after treatment with cetuximab in colorectal cancer patients and was able to predict response and overall survival independent of KRAS status [Determining EGFR gene amplification status and gene copy number of the tissue sample . The lacWhat has become apparent in precision medicine that no single field can answer the complexity of cancer. A holistic understanding of the tumour genome, phenome, immunome and a myriad of other \u201come\u201d related classifications is needed to realize the potential of precision medicine. Genomic stratification of colorectal cancers has identified at least five molecular subtypes of colorectal cancer all of which have various phenotypes and clinical outcomes , 123. IrElegant studies carried out by Prahallad et al. and CorcVisual interpretation of immunohistochemistry is a subjective measurement coupled with an arbitrary threshold to differentiate and classify patients into expression categories . In addiEGFR over-expression in colorectal cancer as determined by immunohistochemistry has led to initial clinical trials investigating patient selection for cetuximab and panitumumab therapies and shown promising results , 45. HowISH approach in HER2 [The tumour tissue investigated for EGFR expression is usually the primary tumour sample, however, this may not reflect the molecular landscape and immunohistochemical profile of the metastatic site , 144. St in HER2 . In addiDigital pathology and image analysis may indeed serve as companion prognostic and or predictive tools in personalised medicine , with soThe TCGA consortium reported the frequencies of up-regulation of other HER family members in colorectal cancer which provides scientific and clinical rationale for combination therapies to block different members , 151. FuBefore we abandon EGFR IHC as an unreliable companion diagnostic for patient selection, a detailed investigation is necessary to include quantitative image analysis of aberrant EGFR expression within the membrane and cytoplasmic compartments, combined with ligand expression, molecular analysis of genetic abnormalities such as gene copy number variation and mutational status. This will provide definitive insight into EGFR as a tissue-based biomarker in patients with colorectal cancer and other malignancies."} +{"text": "Owing to the high sensitivity, high resolution, and the wealth of contrast mechanisms, fluorescence imaging is the most versatile and widely used visualization modality to study the structure and function of biological systems and the molecular process in living organisms without perturbing them.Fluorescence molecular imaging is an evolving field of imaging sciences, which involves the development of microscopic techniques for live cell imaging at super resolution and macroscopic techniques to monitor molecular events in living organism. The breakthrough of super-resolution techniques allows researchers to obtain fluorescence images with a higher resolution than the diffraction limit. On the other hand, fluorescence imaging is also facing important challenges. Because the imaging requires exogenous probes to enhance imaging contrast or provide signal readout, the probe performance largely determines the detection limit and sensitivity. The intrinsic poor penetration of UV and visible light limits their broad applications in biology. Therefore, promising probes that exhibit high photostability, long fluorescence lifetime, strong absorption, and/or emission in the near-infrared (NIR) region are highly desirable.Nanoparticle is a collection of atoms or molecules with much higher intensity of absorbance and emissions compared to small molecular probes, which can provide strong local contrast in biological imaging. Two-photon fluorescent probe simultaneously absorbs two infrared (IR) or NIR photons. Using IR or NIR light as excitation can minimize the light scattering and suppress the background signal, which allows imaging of living tissue up to about one millimetre in depth.Applications of fluorescent probes for fluorescence molecular imaging are growing quickly for recording events from single live cells to whole animals with high sensitivity and accurate quantification. Such approaches have immense potential to track progression of metastasis, immune cell trafficking, stem cell therapy, transgenic animals, and even molecular interactions in living subjects, which represent the future and trends of optical molecular imaging technologies.This special issue compiles several selected original and overview articles that range from design of contrast agents including fluorescent molecules and nanoparticles to biomedical molecular imaging and sensing with various applications. The editors believe that the selected work presented in this issue may provide useful information and promote further investigations on the development of novel fluorescent probes to be used for diagnosis and treatment of disorders and diseases as well as understanding the biological processes."} +{"text": "Cardiovascular disease (CVD) accounts for up to 50% of all deaths in patients with Chronic Obstructive Pulmonary Disease (COPD). Increased arterial stiffness has been shown to predict cardiovascular events beyond the current traditional risk factors.We sought to assess the relationship of aortic stiffness in patients with elevated global cardiovascular risk against those with COPD and lung hyperinflation.We assessed 82 patients with elevated cardiovascular risk as estimated by the Qrisk prediction model used in the United Kingdom; 46 were in the HAPPY London study and had normal lung function, 36 had COPD and lung hyperinflation from the DEFLATA study. CMR cine SSFP cross-section images were obtained perpendicular to the ascending thoracic (TAA), descending thoracic (TDA) and abdominal aorta (AbA). Central aortic pulse pressure was measured at the time of the scan (Vicorder device). Strain was derived as relative aortic area change. Distensibility was derived by normalizing strain to central pulse pressure.The mean age in the two groups was 63 years. There was no difference in the age, sex, and global cardiovascular risk scores between the groups. There was no significant difference in the aortic strain or distensibility measures between them (see Figure Aortic distensibility and strain did not differ between high-risk CVD patients with normal lung function and COPD patients with hyperinflation despite significantly lower CVD risk factors in the COPD group, suggesting that COPD may contribute to stiffness over and above traditional risk factors. Age appears to be the strongest predictor of aortic strain and distensibility. Further studies on the physiological impact of lung hyperinflation on aortic function and the relative contribution of risk factors is warranted to best guide CVD prevention in these high-risk groups.MYK has received funding from Barts Charity and ISS has received fundings from GSK."} +{"text": "The year 2016 is a critical year for adolescent sexual and reproductive health (ASRH), when two key global health strategies \u2013 the 2030 Agenda for Sustainable DevelopmentThe Programme of Action of the International Conference on Population and Development,,This body of evidence highlights that solely tracking adolescent birth rates will provide insufficient data to inform country-specific interventions, policies and resource allocation for adolescent sexual and reproductive health. The reported decline in global adolescent birth rates is not fully explained by the decline in the adolescent pregnancy rate. By focusing only on birth rates, we are failing to address safe and unsafe abortion. Unsafe abortion is a major cause of maternal morbidity and mortality.To address the challenge of under-reporting in accurately measuring pregnancies among adolescents, we need innovative ways to generate an estimate for adolescent pregnancy rates. One approach is to use reported rates of sexual activity and contraceptive coverage from population-based surveys, in combination with adolescent birth rates. Such innovative estimation methods have been tried using data on adolescent birth rates and legal status of abortion to estimate adolescent pregnancy rates.The global decline in the adolescent birth rate should remove adolescent sexual and reproductive health needs from the global agenda. Adolescents\u2019 need for contraception and safe abortion and their right to plan pregnancies are still unfinished business for the 2030 Agenda for Sustainable Development."} +{"text": "Hypnosis is the main hallmark of the anesthesia for surgery and any other noxious procedure done in a hospital setting. The level of hypnosis is determined by the extent of noxious stimulation and the availability of supplementation with local/regional anesthesia. The level of anesthesia that prevents the patients from moving in response to the painful stimuli is universally achieved by general anesthesia.During induction of general anesthesia the patients go through 4 stages from loss of consciousness to cessation of breathing. However, with introduction of rapidly acting intravenous hypnotic agents, transition of patients through these stages is hardly noticeable. Therefore the stage of excitement and delirium is seldom detected during induction of general anesthesia. This stage is almost exclusively seen in patients who are inadvertently overdosed during moderate sedation with propofol, nowadays.With advances in safety of the anesthetic agents and evolved monitoring techniques, many more patients undergo invasive interventions who would have originally been denied of anesthesia because of their physiological limitation and severity of their illnesses. As we provide anesthetic care to patients with compromised cardiovascular reserve, a delicate balance should be maintained to preserve the myocardial contractility and systemic vascular resistance as much as possible. Most of the induction agents that are in clinical use, negatively affect cardiac inotropy and cause significant drops in the left ventricular preload and afterload.Barbiturates are the oldest class of hypnotic agents that have been used for intravenous induction of anesthesia. They share the advantage of rapid onset of action and due to their shorter distribution half-life, they do not produce noticeable prolongation of recovery from anesthesia following a single dose administration. However, repeated doses of barbiturates or continuous intravenous administration of these drugs significantly prolong the recovery due to their longer elimination and context sensitive half-lives. Hyperalgesic effects and delayed recovery have limited the use of barbiturates in moderate sedation cases. Additionally, barbiturates posses a significant negative inotropy and venodilatory effects which causes remarkable drops in arterial blood pressures in patients with hypovolemia and preexisting systolic heart failure. Because of these pharmacologic characteristics, the use of barbiturates is not favored in cardiac anesthesia.Ketamine differs from barbiturates in its ability to stimulate sympathetic activity and thereby increasing systemic vascular resistance and maintaining blood pressures during induction. It is important to note that in patients with prolonged untreated congestive heart failure where there is a depletion of the sympathetic tone, administration of ketamine may inadvertently cause myocardial suppression and lead to clinical hypotension during the induction of anesthesia. Additional lack of motivation in using ketamine in cardiac patients is due to the increases in myocardial oxygen consumption which is unmatched by limited supply in patients with ischemic heart diseases. Postoperative delirium and hallucination are also frequently reported after clinical use of ketamine that have further limited the use of this anesthetic induction agent.Propofol is the most commonly used induction agent in clinical anesthesia practice among general population. Both induction and recovery are pleasant and welcomed by the patients. Due to shorter half-life, recovery from anesthesia even in patients who have received prolonged infusion of propofol is extremely brief. Propofol infusion is also commonly used for moderate sedation in patients undergoing invasive interventions outside of the operating room settings. The major disadvantage of propofol is its strong vasodilatory effects, which may cause significant drops of the left ventricular afterload and hypotension upon induction of anesthesia.Etomidate is most commonly reserved for patients with limited cardiac function because it preserves myocardial contractility and systemic vascular resistance and therefore provide a favorable hemodynamic profile. In clinical cardiac anesthesia practice, etomidate is probably the most commonly used single induction agent. Inhibition of the hypothalamic pituitary adrenal axis by etomidate and related role in inhibiting the body homeostasis in adrenal stress response is probably the biggest shortcoming of this drug in cardiac patients.Journal of Cardiovascular and Thoracic Research, Yagan et al have randomized 90 relatively healthy patients to receive etomidate (0.3 mg/kg), propofol (2.5 mg/kg) or a combination of etomidate and propofol (propofol dose of 1.25 mg/kg + etomidate dose of 0.15 mg/kg) for the induction of anesthesia.1 Mean arterial blood pressure (MAP), heart rate and rate pressure product (HR*MAP) were measured at 10 different time points prior an after tracheal intubation. MAPs were better maintained in the combination formula compared to propofol at the same time the combination formula prevented the surges of MAP during intubation compared to etomidate. One may conclude that combining propofol with etomidate while it prevented inadvertent hypotension during induction it blocked the hemodynamic response to the tracheal stimulation.In this issue of 2 Despite these promising finding, one should remember that the pharmaceutical concerns of mixing two drugs with different physical properties (emulsion forms) need to be extensively studied and addressed before the use of combination induction formulas could be recommended.Clinical anesthesiologists have tried to achieve a better hemodynamic profile by combining various induction agents to synergistically produce hypnosis and avoid their individual side effects. Propofol has been generally used as a common ingredient of these combination therapies. This article suffers from the fact that only healthy (ASA I) patients and those with mild systemic diseases (ASA II) were included in randomization. Another recent study has enrolled 100 cardiac patients with reduced left ventricular ejection fraction. The hemodynamic profile at the time of induction with a combination of propofol with ketamine was similar to those receiving etomidate and benzodiazepines.Not applicable.Author declares no conflict of interest in this study."} +{"text": "The use of codA, DREBs, and Na+/H+ antiporters in transgenic plants has conferred stress tolerance and improved plant phenotype. However, the future deployment and commercialization of these plants depend on their safety to the environment. Addressing environmental risk assessment is challenging since mechanisms governing abiotic stress tolerance are much more complex than that of insect resistance and herbicide tolerance traits, which have been considered to date. Therefore, questions arise, whether abiotic stress tolerance genes need additional considerations and new measurements in risk assessment and, whether these genes would have effects on weediness and invasiveness potential of transgenic plants? While considering these concerns, the environmental risk assessment of abiotic stress tolerance genes would need to focus on the magnitude of stress tolerance, plant phenotype and characteristics of the potential receiving environment. In the present review, we discuss environmental concerns and likelihood of concerns associated with the use of abiotic stress tolerance genes. Based on our analysis, we conclude that the uses of these genes in domesticated crop plants are safe for the environment. Risk assessment, however, should be carefully conducted on biofeedstocks and perennial plants taking into account plant phenotype and the potential receiving environment.Transgenic plants with improved salt and drought stress tolerance have been developed with a large number of abiotic stress-related genes. Among these, the most extensively used genes are the glycine betaine biosynthetic Abiotic stresses such as salt, drought and extreme temperatures are serious threats to agriculture, and account for more than 50% of average yield losses for most of the major crop plants worldwide . AbioticWith progress in identification of genome sequence information and tools for functional genomics, several crop plants have been engineered to enhance their abiotic stress tolerance . ParticuIn addition to the efforts to improve stress tolerance, addressing environmental concerns over the use of these genes in transgenic plants remains a debatable issue for future deployment and commercialization. There is wide consensus that the current risk assessment procedures are equally applicable to more complex traits such as abiotic stress tolerance . HowevercodA gene has been reported with comparatively better results toward GB accumulation, overall protection in vegetative and reproductive parts and tolerance to multiple abiotic stresses (codA expression exhibited multiple abiotic stress tolerance (Table 1). The usefulness of codA gene is evident from the fact that its expression under constitutive promoters exerted no penalties in terms of growth retardation (codA in transgenic plants improved reproductive organs. Transgenic tomato plants with the codA gene showed chilling stress tolerance and increased fruit set by 10\u201330% (codA gene exhibited large flowers and 54% heavier fruits compared to the non-transgenic control plants.Glycine betaine (GB) is one of the most important osmoprotectants that provides protection to vital cellular organelles during plant adaptation to abiotic stress . The prostresses . Severalardation . Rather,y 10\u201330% . Furthery 10\u201330% . TransgeDREB genes encode transcription factors which act as master switches to regulate the expression of many down-stream abiotic stress tolerance-responsive genes . AtDREB1A gene to evaluate survival, recovery from stress as well as water use-efficiency under green-house conditions. Under these conditions, the transgenic lines performed well in terms of recovery from stress compared to control plants. Under field conditions, the transgenic lines did not outperform the control lines in terms of grain yield under drought stress. However, some transgenic lines which were selected for improved water use-efficiency had an acceptable yield even higher under well irrigated conditions. The authors concluded that although the transgenic lines did not show improved yield than control under stress condition, high yielding transgenic lines would be possible provided adequate transformation and screening protocols. Transgenic rice lines with sorghum DREB2 gene were evaluated under water stress condition and showed a significantly higher number of panicles as compared to wild type plants under water stress condition . Transgenic plants expressing antiporter genes have shown promising results in cotton .The t stress . In somechanisms . In addironments . HowevercodA-encoded protein on the surrounding plant vegetation and soil microbes is an important element of the risk assessment process, practiced in some regulatory regimes in the world. The codA-encoded protein and the GB have no known direct effects on the surrounding plant vegetation, diversity of soil microbes and their enzymatic activities. Crop plants may not affect or compete with surrounding plant vegetation through allelopathic activity as these plants, mainly lack allelochemicals due to the process of domestication and selection to determine if there is indeed a detectable change in water use and nutrient uptake by the codA-transgenic plant compared to that of the non-transgenic conventional counterpart.Allelopathic effect of the election . The potal state . While cTable 2). DREB transcription factors are of plant origin and may not have direct adverse effects on the surrounding vegetation, rhizosphere microbes and non-target organisms. The DREBs trigger the expression of a large number of down-stream genes, working in different stress and developmental response mechanisms in plants on transcritome profiles in drought and salt tolerant transgenic Arabidopsis . Conventional breeding approaches have utilized a natural variation at the intra-specific, inter-specific and inter-generic levels to develop salt tolerant varieties . A number of OECD consensus documents are available on the biology of crop plants . Familiarity with the conditions of agricultural fields is well established. In case of any volunteers or persistence of transgenic plants, agricultural management practices would be used in the same way as those for conventional non-transgenic crop plants. Moreover, crop plants are poor competitors in natural environments and may not compete with wild plant populations . Monsanto conducted risk assessment studies on transgenic maize with the CspB gene under drought stress engineered with the CBF transgene that confers cold/freeze tolerance is under vigorous field trials and risk assessment studies in the United States . In addition, the risk assessment studies conducted under the OGTR and Monsanto also reported limited stress tolerance in transgenic plants. The stress tolerance conferred these plants an overall growth and yield advantage that was prominent only under stress conditions. Therefore, the limited stress tolerance and fitness advantage may not have an ecological impact. Despite these few examples of risk assessment studies, the recently adopted trend of using gene stacking approach for more durable stress tolerance may result transgenic plants with fitness costs and benefits than their non-transgenic control plants are required to assess the increased fitness or related secondary effects. In regulatory decision-making on the deliberate environmental release of these genes, the final plant phenotype should be the prime target, not the transformation process and the diverse mechanisms that these genes may influence. Moreover, the use of these genes in transgenic plants and release into the environment should be considered on the risk-benefit-based analysis. In case of transgenic perennial grasses and biofeedstocks with more fitness enhancing abiotic stress tolerance genes, the environmental risk assessment would carefully consider the potential ecological impact.The environmental risk assessment process on candidate abiotic stress tolerance genes should be simple and straightforward and would take into account the long history of crop domestication, crop husbandry, agricultural management practices and natural variation of stress tolerance among crop varieties. Although a limited number of transgenic plants with abiotic stress tolerance genes have been evaluated for environmental risk assessment under field conditions, these studies have revealed no adverse effects of the transgenic plants to the environment and biodiversity. As more transgenic plants with abiotic stress tolerance genes enter field trials for agronomic performance and overall stress tolerance, more data will be generated that would help answer questions regarding uncertainties over the weediness and invasiveness issues. So far, in comparison to commercial traits such as insect resistance MSK is the main author of this manuscript. He has contributed more than 80% to the technical and management of the manuscript. MAK checked the manuscript for technical as well as grammatical errors and helped to reshape the manuscript in final shape. DA helped in finding the relevant literature and manuscript preparation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Leadership is essential for successful implementation of evidence-based practice (EBP) . Line maInterviews were carried out with a total of 28 line managers within social and older people care services in seven Swedish municipalities . A purposeful sampling was performed to ensure diversity among the municipalities in terms of size, geographical location and previous experience with EBP. The interviews were analysed with thematic analysis by two of the authors independently.Line managers perceive their role as key when implementing EBP. The extent to which they felt responsible for the implementation process did, however, differ between the social services and older people care. Line managers working within social services portrayed a more positive attitude towards and a more active role in implementing EBP compared to line managers in older people care. Overall, managers working within the social services were generally given more authority from senior management to implement changes in practice. Line managers within older people care were seldom involved in any decision-making concerning implementation of EBP and described their role as solely communicating decisions to their staff. The line managers in both care settings felt alone in the implementation of EBP, and received limited support from the other key actors in their organisation. The implementation process was usually performed ad hoc rather than systematically. Analysis of needs and goals according to the local context were rarely explored.Line managers consider themselves as central in the implementation of EBP. Variations exist concerning how line managers in the social services and older people care view and implement EBP, and thus different types of support in improving working evidence-based is required. This research contributes to understanding the perspective of line managers, who are often responsible for the translation of evidence into practice."} +{"text": "Advance preparation of oxytocin not only facilitates rapid administration after delivery to prevent postpartum hemorrhage but also could free health workers to provide immediate neonatal resuscitation to non-breathing newborns within the critical 1-minute time window. Advance preparation of oxytocin not only facilitates rapid administration after delivery to prevent postpartum hemorrhage but also could free health workers to provide immediate neonatal resuscitation to non-breathing newborns within the critical 1-minute time window. Moucheraud.See related article by Details matter. To reliably ensure good care, health workers need clearly defined processes, including provisions to ensure reliable and timely availability of all needed supplies and equipment. The paper by Moucheraud and colleagues in this issue of GHSP takes a close look at a particular service delivery setting, documenting current practices with regard to routine administration of oxytocin immediately after birth for preventing hemorrhage.According to guidelines released in 2006 by the International Confederation of Midwives (ICM) and the International Federation of Gynaecology and Obstetrics (FIGO), oxytocin is to be given within 1 minute of birth. The study by Moucheraud et al. assessed performance against this standard. The investigators found that having the injection drawn up in advance increased the proportion of cases in which oxytocin was delivered within this interval and shortened mean time to injection.Although this timing threshold is arbitrary for maternal outcomes , can ensure smooth, streamlined provision of key elements of care for both mother and newborn, even in situations where complications arise."} +{"text": "Rift Valley Fever (RVF) is weather dependent arboviral infection of livestock and humans. Population dynamics of mosquito vectors is associated with disease epidemics. In our study, we use daily temperature and rainfall as model inputs to simulate dynamics of mosquito vectors population in relation to disease epidemics.Time-varying distributed delays (TVDD) and multi-way functional response equations were implemented to simulate mosquito vectors and hosts developmental stages and to establish interactions between stages and phases of mosquito vectors in relation to vertebrate hosts for infection introduction in compartmental phases. An open-source modelling platforms, Universal Simulator and Qt integrated development environment were used to develop models in C++ programming language. Developed models include source codes for mosquito fecundity, host fecundity, water level, mosquito infection, host infection, interactions, and egg time. Extensible Markup Language (XML) files were used as recipes to integrate source codes in Qt creator with Universal Simulator plug-in. We observed that Floodwater Aedines and Culicine population continued to fluctuate with temperature and water level over simulation period while controlled by availability of host for blood feeding. Infection in the system was introduced by floodwater Aedines. Culicines pick infection from infected host once to amplify disease epidemic. Simulated mosquito population show sudden unusual increase between December 1997 and January 1998 a similar period when RVF outbreak occurred in Ngorongoro district.Findings presented here provide new opportunities for weather-driven RVF epidemic simulation modelling. This is an ideal approach for understanding disease transmission dynamics towards epidemics prediction, prevention and control. This approach can be used as an alternative source for generation of calibrated RVF epidemics data in different settings. Phlebovirus of the family Bunyaviridae. The viruses use arthropod vectors such as mosquitoes and sand flies for infection transfer to livestock and humans Rift Valley fever (RVF) is an infection caused by arbovirus belonging to genus Emergence of infected mosquito populations and amplification of the virus are determined by changes in weather conditions Mathematical models have been developed for RVFV epidemics to complement available weather only dependent prediction models Development of prediction models for RVFV epidemics faces many challenges like lack of reliable data. Absence of field-based rapid diagnostic tools results in the disease first being detected when it is actually beginning to decline from within the infected populations. RVF epidemics preparedness teams are therefore less effective for counter-measure against the impact of the disease. It is well documented that in order for disease to be controlled by vaccination, animals need to be vaccinated 4\u20136 weeks before stress and risk periods http://www.ncdc.noaa.gov/cdo-web.The Ngorongoro district in Tanzania was purposely selected as the main study scenario. The district is part of the Serengeti-Masai Mara Ecosystem, which is defined by the limits of the annual wildlife migration linking with a neighbour country, Kenya experiencing similar disease epidemics. The district represents unique interaction between livestock, wildlife and human interface with animal migrations. The area has experienced several records of RVFV outbreaks. According to 2006\u20132007 outbreaks, high animal mortality was recorded in this area The assumptions for model development include; Floodwater Aedine mosquitoes are responsible for maintenance of the virus with vertical transmission and Culicine mosquitoes play a major role in virus amplification during epidemics. Water level in potential breeding sites determines hatching of Floodwater Aedine eggs. Increased water level in breeding sites is required to allow infected eggs laid further in the soil to hatch. Mosquito developmental stages use cumulative temperature as important model input factor to determine maturation time and adults survival. Mosquito search for a blood meal is a function of availability of hosts and that the probability of a successful blood meal is a function of the availability of host. During feeding, a mosquito has the probability of transferring viral infection to a host, or becoming infected by taking a blood meal from a viremic host. Flow of infection in mosquitoes and host is governed in compartmental phases. RVFV infection is initiated in a single phase small population of Floodwater Aedine mosquitoes before reaching the amplifying Culicine mosquitoes .1-D and 2-D time-varying distributed delay (TVDD) equations were used to formulate the models During each mosquito developmental stage temperature dependence delays were used Multi-way functional response equations previously described for predator prey relations http://www.ecolmod.org). Source codes for mosquito fecundity, host fecundity, water level, mosquito infection, host infection and Aedines eggs time were prepared. Extensible Markup Language (XML) files were prepared as recipe to integrate source codes in Qt creator with Universal Simulator plug-in. Source codes incorporated control structures for hatching of infectious inactive egg laid in the soil due to water level increase in breeding sites and RVFV infection initiation from Floodwater Aedine mosquitoes to susceptible host and then to Culicine mosquitoes for virus amplification. Details of parameters used are as shown in Model algorithms were developed using an open-source Universal Simulator and Qt Integrated Development Environment in C++ programming language In order to understand the influence of many time based processes in this model, sensitivity analysis of model outputs due to variation in input parameters was assessed during simulation period. Stochastic random normal distribution was applied to quantify the sensitivity of the outputs During simulations, the following initial conditions were prescribed to run once; 50 adult Floodwater Aedine and Culicine mosquitoes that were allowed to lay eggs and initiated growth to larvae, pupae and adult mosquitoes under appropriate conditions. Similarly, initial population for host sheep was 50 lamb and 100 adults with the environmental carrying capacity of 200 sheep per square kilometer . MosquitSelected parameters were sensitive to substantial changes with vector-host population\u2019s simulation time. Low temperature thresholds had a significant impact on larvae by delaying transfer of larvae to pupae. High temperature caused high mortality in larvae and reduces adult survival days. Water level thresholds that depended on daily rainfall influenced the emergence of floodwater Aedine mosquitoes and hatching of infectious eggs laid in the soil above water level in the breeding site. At low water level thresholds, population of floodwater Aedine mosquitoes varied similar with Culicine which did not depend on water level for mosquito emergence. In this light, water level threshold for emergence of infectious floodwater is adjusted to reflect the biological role of floodwater Aedine in RVF epidemics.Mosquito attack rates for blood meal and infection introduction during vector-host interactions were sensitive to determine stage and phase flows. Vector-host interactions were influenced by infection period and RVFV incubation period in hosts. Infectious period in mosquito vectors and hosts influenced the pattern and peak size of the simulated epidemic, longer infectious period extended the duration of the epidemic. For mosquitoes, this duration was set to the lifespan of the mosquito in order to reflect the actual duration of RVF epidemic whereas in hosts ranged from three to six days. Longer disease incubation period within hosts showed a delayed increase in the number of infectious hosts and therefore a later peak in the epidemic than when the incubation period is assumed to be short. Knowing the infection and incubation period appeared to be important in predicting dynamics of a simulated epidemic.Simulation results yielded equilibrium over time with a stable and consistent number of mosquitoes, regardless of the initial starting point of the adult population following model calibration. Floodwater Aedines and Culicine vector population continued to fluctuate with temperature and water level over the entire period while controlled by availability of host for blood feeding . In ordeSheep population provided as lamb and adults were allowed to fluctuate over the whole simulation period. Sheep remained in the susceptible phase until had contact from infectious Floodwater mosquitoes . FollowiControlled simulation of mosquito population dynamics without influence of host availability for a period from 1994 to 1999 showed sudden increase after about 1450 days of simulation, a period between December 1997 and January 1998, similar to the time in which Ngorongoro district experienced a RVF disease outbreak . HoweverOur simulation modelling strategy was to produce useful tool for studying effects of daily rainfall and temperature on vector life stages in terms of stage-specific growth and death rates. Conditions that result in unusual abundance of vector mosquito species have been shown to have a positive association with RVFV epidemics Studying RVFV transmission dynamics poses a big challenge among scientists, as disease outbreaks are associated with abnormal changes in weather conditions which are essential components for prediction of disease epidemics. Choosing the right modelling procedure for this complex disease can be quite challenging. Simulation modelling of RVFV vector populations dynamic remains a useful tool in understanding these transmission dynamics. In our simulation model, we attempt to replicate the actual biological processes related to dynamics of the relevant disease vectors in a local endemic setting. This model takes advantage of previously developed mathematical equations for modelling disease vectors and hosts stages at different phases of infection but with careful selection of useful parameter in relation with the biology of RVFV The current procedures for simulations development are highly flexible to allow inclusion of factors that might accelerate the emergence and decline of Aedine population by not only considering availability of water in respective breeding sites. However, we carefully avoided including other factors such as landscape features While developing models for RVF disease prediction is highly useful, significant work is needed for further improvement in this modelling approach. We agree on simplification of some parameter estimation such as trans-ovarial transmission within Aedes mosquitoes due to the lack of more information. RVF virus vertical transmission in Aedes mosquitoes is still not known http://www.ecolmod.org/download.html.Simulation outputs from this study provide new insights for weather-driven RVFV epidemic modelling. This study shows that daily temperature and rainfall are key ecological factors to include in models that predict episodes related to RVFV outbreak Text S1File containing instructions to guide installation and use of therein attached RVF plug-in source codes.(ZIP)Click here for additional data file."} +{"text": "Not long ago, cardiac tissue regeneration was considered an impossible task. The last ten years however has seen an explosion of cell based therapeutic approaches stimulating cardiac regeneration and in the process augmenting function in the heart following injury. Encouraging preclinical results have paved the way for clinical applications of cell therapy and preliminary results obtained from various clinical trials indicate that stem cell transplantation increases cardiac function comparable to the existing interventions for treatment of heart diseases. These are promising outcomes that indicate that the cells have the ability to modulate cardiac repair programs leading to replacement of the lost tissue. Nevertheless, the search continues for the optimal cell type that can promote \u201ctrue cardiac regeneration,\u201d supplement the lost cardiomyocytes, and at the same time form the angiogenic support structure. One of the first stem cell types to be used for cardiac regeneration was derived from the mononuclear fraction of the bone marrow and the cells were designated as bone marrow mononuclear cells . Ensuingfarction . At the farction . Neverthfarction . In addifarction , corticafarction , and corDespite the excitement, significant concerns persist around the ability of adoptively transferred cells to survive in the ischemic heart and some reports suggest as low as 1% of cells make it in the heart past the first few days of transplantation. Most of the salutary effects of cell therapy have been attributed to these few surviving cells and recent efforts have focused on boosting the survival, proliferation, and cardiac commitment of the donated stem cell population. This special issue contains a cluster of articles focused on augmenting ability of adoptively transferred stem cells to repair the damaged heart. X. Xue et al. demonstrated that genetic engineering of MSCs with Bcl-xl enhances survival and engraftment after transplantation leading to reduction in scar formation and increased functional recovery. Homing and migration of the adoptively transferred stem cells are another important determinant for the success of cell therapy. An interesting approach was employed using the ultrasound microbubble technique to promote MSC migratory ability to the infarcted myocardium. Authors show that ultrasound microbubble destruction increased MSC numbers in the infarcted heart mediated via SDF-1/CXCR4 axis. In contrast, the study by J. Liu et al. utilized adipose derived stem cells to show that curcumin, a naturally occurring food chemical, can promote angiogenic and survival ability of the cells augmenting their potential for the repair of ischemia reperfusion injury to the heart. Bone marrow derived endothelial progenitor cells (EPCs) represent a widely used cell type for cardiac regenerative therapies. EPCs have been shown to increase angiogenesis and augment cardiac function animal studies and undergoing clinical trials , 8. EPCsAdditionally, controversy rages on whether the transplanted stem cells directly convert into cardiomyocytes or mediate their beneficial effects through the release of \u201cparacrine effectors.\u201d Characterization of the stem cell secretome has provided some interesting clues about how factors released by the cells modulate cellular processes in target cells. These paracrine factors include growth factors, chemokine, cytokines, various proteins, and small molecules. Recently, small microvesicles released by stem cells under different physiological conditions have been included in the definition for paracrine factors. Exosomes are tiny vesicles released by the cells, carry proteins, mRNAs, and microRNA, and have the ability to modulate cellular and molecular signaling processes . A numbeWe hope the readers will find this special issue interesting and a timely effort covering current issues and advancements in the field of stem cell based therapies for the repair of damaged heart.Sadia MohsinSadia MohsinDaniele AvitabileDaniele AvitabileMohsin KhanMohsin Khan"} +{"text": "On behalf of guest editors for this special issue, we are very pleased to publish this special interest issue. The immunological effects of various fibrous and particulate materials such as asbestos and silica as well as nanoparticles and nanotubes have received increased attention in recent years. These materials are now well known for their biological effects that include lung fibrosis and carcinogenic potential, which is the basis for the scientific interest for environmental health. Furthermore, the immunological effects of these substances are also very important issues since, from the point of initial administration of these materials, the innate immune system will recognize these materials as foreign danger signals and they may affect the systemic immune system. In this special issue, various recent investigations regarding the above-mentioned viewpoints will provide readers with recent advances in the area of environmental immunology. We hope that this special issue will contribute to the better understanding and considerations for biological effects of fibrous and particulate materials, particularly on the human immune systems.Takemi OtsukiTakemi OtsukiAndrij HolianAndrij HolianMario Di GioacchinoMario Di Gioacchino"} +{"text": "Investigators from Georg August University, Gottingen, Germany, analyzed axonal pathology in brain biopsy and autopsy samples from 19 children with early multiple sclerosis (MS). Investigators from Georg August University, Gottingen, Germany, analyzed axonal pathology in brain biopsy and autopsy samples from 19 children with early multiple sclerosis (MS). As compared to adults with MS, children present with polyfocal onset of symptoms, have a higher relapse rate during early years of the disease yet have shorter time to recovery and a higher rate of remission.Histopathologic features of CNS biopsies (and 1 autopsy specimen) from children with pediatric MS collected over 18 years (1997-2014) at two academic medical centers were assessed and compared to features of CNS tissue from adults with MS. Nineteen of 64 pediatric specimens contained sufficient tissue sample for analysis of axonal damage. Markers of axonal injury included reduction in axonal density and presence of axonal spheroids positive for amyloid precursor protein (APP).A 49% reduction in axonal density within demyelinating lesions in pediatric biopsies was calculated in comparison to periplaque white matter. Acute axonal damage was increased in early active demyelinating lesions in children as compared to adult biopsies and was negatively correlated with age of the subject at time of biopsy. An increased density of APP-positive axons in pediatric early demyelinating lesions was noted particularly in biopsies of children who were < 11 years of age in whom the counts were 50% higher than those in post-pubertal or adult biopsies. Expanded Disability Status Scale at onset of the attack correlated with the number of APP positive spheroids in the biopsy. The amount of macrophage infiltration correlated with the degree of axonal injury in both pediatric and adult biopsies. [COMMENTARY. The authors point out one of the potential limitations of their report: the selection bias relating to which clinical cases of CNS demyelinating disease were biopsied. In the cases with histology available, an atypical or unusual feature of presentation had been distinctive enough to warrant biopsy to exclude an alternative diagnosis. Clinical cases in which the clinical, imaging and diagnostic parameters all cleanly fit within an expected range of findings would be diagnosed and treated without biopsy. However, the care with which these authors staged the acuity and phase of demyelinating lesions, their comparison of the axonal density within the lesion to that in the periplaque white matter and the contrast of all of these parameters with adult biopsies from clinically similar events makes these findings independently credible and important.Other biomarkers have been noted to be different in children with pediatric MS. CSF has been noted to have more inflammatory cells such as neutrophils and lower likelihood of oligoclonal bands or elevation in IgG index in children . The autDespite the greater degrees of acute axonal damage noted in CNS demyelinating lesions in prepubertal children, their rate of clinical recovery from clinical events is greater than in adults . MR studThis article begins the important process of elucidating the differences in pathophysiology of CNS demyelinating disease in children, particularly young or prepubertal children."} +{"text": "In plants, major MAPs are identified as microtubule stabilizers (CLASP and MAP65 etc.), microtubule destabilizers , and microtubule dynamics promoters . Mutant analyses with forward and reverse genetics have shown the importance of microtubules and individual MAPs in plants. However, it is difficult to understand how each MAP regulates microtubule dynamics, such as growth and shortening, through mutant analyses. In vitro reconstitution analyses with individual purified MAPs and tubulin are powerful tools to reveal how each MAP regulates microtubule dynamics at the molecular level. In this review, I summarize the results of in vitro reconstitution analyses and introduce current models of how each MAP regulates microtubule dynamic instability.Plant microtubules, composed of tubulin GTPase, are irreplaceable cellular components that regulate the directions of cell expansion and cell division, chromosome segregation and cell plate formation. To accomplish these functions, plant cells organize microtubule structures by regulating microtubule dynamics. Each microtubule localizes to the proper position with repeated growth and shortening. Although it is possible to reconstitute microtubule dynamics with pure tubulin solution Therefore, the characterization of each MAP is important to understand microtubule dynamics in cells. Mutant analyses are powerful methods for clarifying how each MAP functions in plant cells. In plants, various mutants of MAPs have been obtained and their importance and essential roles have been described because the models of catastrophe mechanisms in pure tubulin solution remain inconsistent family, in addition to CLASP and the MAP215 family. SPR2 has one TOG domain at the N-terminus and increases the amount of microtubules in vitro reconstitution experiments with purified proteins. These results clearly reveal each MAP character. However, some MAPs do not play the expected roles in cells because many numbers and various types of MAPs regulate microtubule dynamics cooperatively or competitively in cells. Reconstitution of intracellular microtubule dynamics in vitro is one of challenges of in vitro reconstitution experiments after characterizing individual MAPs properties.In this review, I summarized the results of in vitro dynamic instability parameters close to physiological parameters in cells comparing with the presences of each MAP. Recently, synergistic effects of EB1 and MAP215 family on microtubule dynamics were well characterized (Li et al., The pioneer study is the combination of XMAP215 and kinesin-13, which mainly promote microtubule growth rate and catastrophe frequency, respectively (Kinoshita et al., In vitro reconstitution experiments with several purified MAPs will provide results like no others and help our understanding of MAPs functions along with other experiments such as mutant analyses.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "When moving beyond controlled laboratory conditions one issue encountered has been the high variability of the induced defense approach\u2014sometimes an effect is observed and sometimes it is not emission between Arabidopsis accessions has been demonstrated and this influenced the behavior of the parasitoid Diadegma semiclausum when offered headspace volatiles in two-choice experiments and this influenced the attraction of carnivorous natural enemies. They suggested that the foraging success of natural enemies of pests can be enhanced by breeding for crop varieties that release specific volatiles.Herbivore induced volatile (HIPV) emission plays an important role in indirect defense whereby natural enemies are attracted to plants after exposure to insect attack. Schuman et al. found vaes Hare, : volatiles Hare, found vaThe expression of induced plant defense responses is tightly regulated by the ecological context of the plant Ballare, . For a pPseudomonas putida BTP1 infects roots of Phaseolus vulgaris, plants become more resistant to Botrytis cinerea on leaves (Ongena et al., Trichoderma asperellum T203 root colonization of cucumber induces resistance to pathogens in above-ground parts of the plant (Shoresh et al., Sogatella furcifera, dramatically increased the resistance of plants to rice blast, Magnaporthe grisea (Kanno and Fujita, Plutella xylostella was more abundant on Pieris rapae-induced plants and preferred these plants over undamaged plants in oviposition experiments. This could perhaps be because the specialist is attracted to the HIPVs from its host plant. In contrast, the generalist Mamestra brassicae was more abundant on control plants and preferred undamaged plants for oviposition. The order of herbivore attack thus mediates the expression of plant defense phenotypes. There is negative crosstalk between plant defense pathways which means that attack by a different type of attacker could compromise responses to the defense elicitor (Bruce and Pickett, The previous history of exposure can affect plant responsiveness. When Plants are responsive to their environment and can adapt to stressful conditions. As described in the previous section, prior biotic or abiotic stress in the environment can alter how well a plant responds to subsequent treatment with a defense activator. Not only are these changes mediated by changes in metabolite levels and transcription factors but plants also have the capacity to reprogram expression levels of stress-response genes via epigenetic stress imprints (Bruce et al., Evidence is accumulating that herbivore and pathogen attack can generate defense induction phenotypes across generations (Holeski et al., Reliable and predictable treatment effects are required for practical use of plant defense activators by growers and for commercialization of such crop protection products. However, the genotype of the plant, the environmental conditions and history of stress exposure, influence the magnitude of any boost in plant defenses obtained with an activator. Walters et al. have alsDefense activators or elicitors need to be developed with the appropriate crop genotypes that can respond to the treatment. Variation between crop cultivars is a limitation if activators are developed ignoring this factor but it is also an opportunity to develop suitable packages of seeds and activator agrochemicals. Genetic variation in inducible defense traits complicates the use of plant defense activators but there is future potential to use particular plant activators in a package with selected crop cultivars that offer the best genetic potential for induced defense Bruce, .The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Epilepsy is one of the most important chronic neurological disorders worldwide affecting more than 50 million people of all ages. Among these, almost 20% of epilepsy cases are uncontrollable and have an unknown source of this abnormal electrical activity. Present techniques for the detection of epileptogenic foci include electroencephalography (EEG), positron emission tomography, and multimodal EEG/functional magnetic resonance imaging (fMRI), all with limitations in terms of spatial and temporal resolutions. In order to overcome some of those limitations a novel approach using fMRI alone was developed based on the hypotheses that the epileptogenic focus shows Blood Oxygen Level Dependent (BOLD) temporal profiles distinct from the remaining brain parenchyma during interictal activity and that the epileptogenic focus BOLD signals show lower complexity than healthy parenchyma. In this novel approach, bi-dimensional temporal clustering analysis, a data-driven technique, was used to identify brain regions with similar temporal profiles. Then, the BOLD signals of these regions were assessed regarding complexity using detrended fluctuation analysis and also using a modified multiscale entropy algorithm in order to identify which of those regions corresponded to epileptogenic tissue. In order to demonstrate the applicability of the developed method three epileptic patients were analyzed comprising two types of epilepsy: unilateral and bilateral temporal lobe epilepsies. The results showed that this method is able to detect the brain regions associated with epileptogenic tissue. The results also showed that the epileptogenic focus influences the dynamics of related brain networks. This could be a key factor in the applicability of this method to other epilepsy cases. Finally, new perspectives are envisioned concerning the use of this method in the medical care of epilepsy. In particular, by improving this method using simultaneous structural, functional, and metabolic information with hybrid MRI-PET scanners for the validation of epileptogenic focus."} +{"text": "Growth of older population in United States requires multi-generational evaluation to characterize health measures for sustaining workability. Investigation of measures that working population would need and use with their work-life in an attempt to stay healthy and fit, could potentially reveal significant association that could extend workability and enhance work productivity such as performance, presenteeism, job satisfaction. Evaluation with selective longitudinal health profiling; employment prerequisites; socio-economic and psychological scales could characterize health measures significantly associated with work sustainability. Such health measures could potentially be employed by US working population early in their life and occupation to sustain and improve workability in their later epoch. Rising health concerns and financial deficits have been adversely influencing economies of many nations and population worldwide in the last decade. Globally, countries are trying extensively to intervene with their financial crisis and there by over-burdening citizens with various economic reforms and taxations . RamificThe work-life expectancy at a certain age is the average number of years that a person in a given cohort will spend either working or actively looking for work during the remainder of one\u2019s life . Markov Continuous population growth among the older group adults, apprehensions of financial planning and independence have become emerging gerontology issues. Increasing costs of healthcare services in United States have started to raise concerns in the working class to explore new approaches in an effort to sustain and meet the goals for prolonging workability, productivity ahead of time. Older Americans, the most rapidly growing age group, are the least physically active and generate the highest health care expenditures . In nextHowever all such programs and their applicability require reliability to ascertain the extent and involvement of various measures that could relate to the needs of the elderly for maintaining their healthy status as well as financial independence. Thus characterization of work sustainability indices in US context and evaluation of health promotion practices is needed. Applicable programs need to be developed for the working population to extend, improve their work-life. Such programs and approaches also in time-course could aid in furthering the understanding of variability in the level of severity of the problem and adequately generate implementation strategies.Longitudinal investigations are needed in US to evaluate health promotion practices, which could extend, improve and sustain work-life with trans-generational appropriations and assist the working population to adhere to intelligent programs. Present health practices and planning with the anticipation of prolonging the work-life for working population with aging concerns in US is not much studied yet. Such studies could potentially provide information about the choices and availability of appropriate health promotion practices; and how various working class populations can utilize such information for sustaining workability while transitioning through the older age. Standard survey questionnaires could incorporate mental and physical assessments; and financial expectancy and independence projections congruently. Such tools could be useful to identify significant correlates of health promotion practices with indices of work-life sustainability ,17; someTargeting various age-groups with psychometric evaluation designed to explain health promotion factors for sustaining work-life expectancy in aging population could provide opportunities to evaluate multigenerational variability as well. These factors could be used as determinants for further consolidating recommendations for various growing age groups for selection of available options to sustain workability. Ultimately, health practices could be used by younger working class as a tool to enhance working abilities by improving and maintaining health condition for projected workability while transitioning through their age, securing their potential to continue with their employment by optimizing their health status. These study outcomes could help employers as well for improving responsible behavior development among employees. It could essentially serve the employees as health promotion measures tailored to their needs, structuring the health incentives and regulating the insurance and healthcare costs thereby maintaining health status of their employees targeted towards sustaining workability . Such br"} +{"text": "Although most commonly associated with the infection of domestic livestock, the replication of pestiviruses, in particular the two species of bovine viral diarrhea virus (BVDV), occurs in a wide range of free ranging cervids including white-tailed deer, mule deer, fallow deer, elk, red deer, roe deer, eland and mousedeer. While virus isolation and serologic analyses indicate that pestiviruses are circulating in these populations, little is known regarding their impact. The lack of regular surveillance programs, challenges in sampling wild populations, and scarcity of tests and vaccines compound the difficulties in detecting and controlling pestivirus infections in wild cervids. Improved detection rests upon the development and validation of tests specific for use with cervid samples and development and validation of tests that reliably detect emerging pestiviruses. Estimation of impact of pestivirus infections on herd health will require the integration of several disciplines including epidemiology, cervid natural history, veterinary medicine, pathology and microbiology. The recognized species of the Pestivirus genus include bovine viral diarrhea virus types 1 (BVDV1) and 2 (BVDV2), classical swine fever virus (CSFV), and border disease virus (BDV) , elk/wapiti (Cervus elaphus), caribou/reindeer (Rangifer tarandus), mule deer (Odocoileus hemionus), and white-tailed deer (Odocoileus virginianus) tests, end points may be determined by observation of the cell monolayer. End point determination using noncytopathic strains requires secondary detection methods such as immunofluorescence, immunohistochemistry staining or polymerase chain reaction. Use of such secondary detection methods is time and cost prohibitive for large-scale surveillance projects.Another consideration is that frequently emerging viruses, such as pronghorn virus (Vilcek et al., While there are valid reasons why serological surveys, based on VN tests, use reference strains from the four recognized species, it is highly probable that when these assays are used in such surveys they miss titers resulting from exposure to emerging viruses that are genetically distant and antigenically distinct. The greater the genetic difference between pestiviruses, the lower the cross reactivity (Ridpath et al., While commercial ELISA kits are available for detecting antibodies against the classic pestiviruses, particularly BVDV, the limited cross reactivity that exists between emerging pestiviruses and classic pestiviruses make these tests unreliable for detecting antibodies resulting from infection by emerging pestiviruses (Bauermann et al., While performing serology on a one time collection of samples from a population can give information on the occurrence and prevalence of exposure, it does not yield information on when the exposure occurred. To estimate time of exposure, multiple samples over time must be collected and archived.Ideally samples should be representative of the population under study including biological, spatial, and temporal variables (Stallknecht, If the goal is to detect a pestivirus the sample must be collected while the animal is still viremic. This not a problem with persistently infected cervids but is a problem with acutely infected cervids where the window of detectable viremia may be less than 5 days (Ridpath et al., Both passive and active surveillance systems may be used to obtain cervid samples. Passive surveillance, which relies upon the observation and subsequent testing of an animal displaying clinical signs of disease or collection of samples from animals that have died of disease, is problematic for detecting infection with viruses, such as pestiviruses, which don't cause severe clinical disease. Passive surveillance tends to under estimate the impact of diseases that have significant mortality rates let alone those that result in subclinical disease. This is illustrated by an outbreak of hemorrhagic disease in white-tailed deer that occurred in Missouri. While it was estimated that the outbreak resulted in an 8% mortality rate, not one case of mortality or morbidity was reported by the public. The occurrence and extent of the outbreak were only noted because of surveillance conducted on 100 radio-monitored deer (Beringer et al., Even though hunter harvested samples may be skewed against including PI animals, BVDV PI animals have been detected in these samples (Van Campen et al., The design of active surveillance systems requires an understanding of the social organization of the species to be studied. Unlike domestic livestock, wild deer do not confine their activities to large herd groups, cannot be rounded up without damaging ecosystems and social grouping, and are not amenable to handling. Populations are frequently divided into small breeding groups based on age and gender and contact between groups and make up within groups may change with the season. Neonates are frequently hidden rather than grazing with the herd.The ideal surveillance program would include samples collected at multiple time points allowing retrospective analysis (Stallknecht, It is easier to assess the impact of infection with high virulence pestivirus strains that result in clinically severe acute disease such as classic swine fever in swine or hemorrhagic syndrome in cattle. However, the impact of lower virulence pestiviruses is harder to assess, even in domesticated species. Previous studies using captive deer have demonstrated white-tailed deer infected by pestiviruses such as BVDV1, BVDV2, and PHV display very mild clinical signs even though they are undergoing significant immune suppression (Van Campen et al., The limited serologic surveillance that has been published focused on the levels of neutralizing antibodies against the recognized pestivirus species. Such studies may underestimate exposure to emerging pestiviruses. The value of serological studies is greatly enhanced if sequential testing of the same population over is conducted. Samples, collected from the same population, over time allows detection of changes in exposure patterns.Many studies rely on samples generated from deer harvested by hunters. However, such samples may yield skewed data as the majority of hunter-generated samples come from healthy, primarily male adults. Further, the tests available are designed for detection of recognized pestiviruses in domestic species. The reagents used may not be appropriate for wild cervids or emerging pestiviruses that are only distantly related to the recognized pestivirus species. In particular, cell cultures derived from domestic species may not work for the propagation of viruses that are adapted to cervid hosts. In summary, the full impact of pestiviruses on cervid populations may not be recognized at this time.Improved detection rests upon the development and validation of tests specific for use with cervid samples and the development and validation of tests that reliably detect emerging pestiviruses. Estimation of the impact of pestivirus infections will require the integration of several disciplines including epidemiology, cervid sociology, veterinary medicine, pathology and microbiology.JR organized and drafted article. JN reviewed and amended article. Both authors agree to be accountable for this work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Exposure to air pollution has long been known to trigger cardiovascular events, primarily through activation of local and systemic inflammatory pathways that affect the vasculature. Detrimental effects of air pollution exposure on heart failure and cardiac remodeling have also been described in human populations. Recent studies in both human subjects and animal models have provided insights into the basic physiological, cellular and molecular mechanisms that play a role in adverse cardiac remodeling. This review will give a brief overview of the relationship between air pollution and cardiovascular disease, describe the clinical effects of air pollution exposure on cardiac remodeling, describe the basic mechanisms that affect remodeling as described in human and animal systems and will discuss future areas of investigation. There was no change in basal cardiac function prior to TAC surgery. The magnitude of the effect was similar to that seen in animals exposed throughout life from conception through adulthood. Exposure during the adult period from weaning through the age of 12 weeks had no effect on susceptibility to heart failure. The hearts of animals exposed early in life showed increased heart weight to body weight ratios and interstitial fibrosis but no significant change in myocyte cross sectional area when compared to those from control mice exposed to filtered air. Interestingly, the lungs of mice exposed early in life showed differential induction of interleukin-6 expression after TAC surgery (Weldy et al., in utero exposure alone is sufficient to convey a long lasting susceptibility to myocardial fibrosis and heart failure when in utero-exposed adult mice were subjected to TAC surgery, suggesting that mediators in the maternal circulation could cross the placenta and promote long lasting susceptibility in the developing embryo hearts. Further findings include a baseline increased body weight to tibia length ratio and paradoxically lower baseline blood pressure in adult male animals. Histological examination of hearts from exposed animals showed increased interstitial fibrosis but no significant difference in myocyte cross sectional area. Examination of placental and fetal tissue from exposed dams showed a higher rate of fetal reabsorption, a lower average placental weight, increased incidence of placental hemorrhage, an increase in leukocyte infiltration and an increase in vascular oxidative stress (Weldy et al., Early life exposure to air pollution is known to cause low birth weight (Dadvand et al., As described above, particulate air pollution can cause adverse cardiac remodeling through multiple indirect mechanisms, by exacerbating processes known to promote injury to myocardium such as atherosclerosis, vasoconstriction, thrombosis and hypertension Figure . At presThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Demonstrate the importance of multidisciplinary interrelationship between the oncologist and the radiologist for correct imaging interpretation.Illustrate in a pictorial essay scenario, cases in which, considering clinical condition, laboratory values, complementary examinations and evolution of lesions on imaging exams are essential for an adequate presumptive diagnosis.The cases we will present include:Young male patient with malignant germ cell tumour, treated with bleomycin. With pulmonary small nodules in a control MDCT suspected of metastasis in the setting of negative humoral markers and surgical biopsy confirmed drug hypersensitivity.Male patient with mixed germ cell tumour in control MDCT which derived to PET CT demonstrated new hypermetabolic lymphadenopathy of mediastinum without elevated humoral markers and biopsy by mediastinoscopy confirmed sarcoidosis.Patient with colorectal adenocarcinoma with lung, liver and adrenal metastasis in the context of onset of dyspnea. According to RECIST criteria represented a pulmonary stable disease but one of the nodules produced greater extrinsic compression of the nearest main bronchus so we considered real progressive disease clarifying that we did not take into account the classical criteria.A woman with locally advanced colorectal adenocarcinoma with rapidly progressive multinodular pleuropulmonar, brain commitment and fever. We suspected infectious origin and resulted nocardia concomitant infection.We emphasise the importance of adequate clinical information and multidisciplinary interrelationship for the correct imaging interpretation in oncological patients."} +{"text": "Background: Stratified Medicine (SM) is becoming a practical reality with the targeting of medicines by using a biomarker or genetic-based diagnostic to identify the eligible patient sub-population. Like any healthcare intervention, SM interventions have costs and consequences that must be considered by reimbursement authorities with limited resources. Methodological standards and guidelines exist for economic evaluations in clinical pharmacology and are an important component for health technology assessments (HTAs) in many countries. However, these guidelines have initially been developed for traditional pharmaceuticals and not for complex interventions with multiple components. This raises the issue as to whether these guidelines are adequate to SM interventions or whether new specific guidance and methodology is needed to avoid inconsistencies and contradictory findings when assessing economic value in SM.Objective: This article describes specific methodological challenges when conducting health economic (HE) evaluations for SM interventions and outlines potential modifications necessary to existing evaluation guidelines /principles that would promote consistent economic evaluations for SM.Results/Conclusions: Specific methodological aspects for SM comprise considerations on the choice of comparator, measuring effectiveness and outcomes, appropriate modeling structure and the scope of sensitivity analyses. Although current HE methodology can be applied for SM, greater complexity requires further methodology development and modifications in the guidelines. In addition, challenges arise if the economic evaluation of SM interventions is understood as an evaluation of the benefits, harms and cost-effectiveness at the individual patient preference level; is becoming a practical reality with the targeting of medicines by using a biomarker or genetic-based diagnostic to identify the eligible patient sub-population in many countries. However, these guidelines have initially been developed for traditional pharmaceuticals and not for complex interventions with multiple components. This raises the issue as to whether these standards and guidelines are adequate to address more targeted approaches to therapy or whether new specific guidance and methodology is needed to avoid inconsistencies and contradictory findings when assessing economic value in SM.,This article addresses key methodological issues and challenges when conducting health economic evaluations for SM interventions and outlines potential modifications necessary to existing evaluation guidelines and principles that would promote consistent economic evaluations for decision making in SM. Utilizing a set of criteria represented by the guidelines for cost-effectiveness 2 approach to perceive the full health- and economic- value taking into considerations costs and long-term benefits having less adverse therapies target toward those who benefit most. However, in practice most economic analyses of SM interventions are performed from a third party perspective, since there is no longitudinal accounting in many healthcare systems in EU and the US which would enable payers to capture long-term cost savings from near-term testing. In addition, pharmaceuticals and diagnostics are considered under separate appraisal and payment processes in many healthcare systems. Only NICE (UK) has so far established a Diagnostic Assessment program (DAP) which carries out cost-effectiveness assessments of selected diagnostics , the economic analysis might be based on randomized controlled trials (RCTs), where the diagnostic test was included in the clinical studies of the drug's efficacy; i.e., sensitivity/specificity data of the test as well as efficacy data of the drug/diagnostic combination are included in the overall outcomes of the trial, which can produce direct evidence of the clinical utility of the test. For a stand-alone test, this is much harder to achieve as RCT's are often not feasible because of ethical reasons, shift to multi-therapeutic regimes, and lack of resources or small patient populations. Real-life data generation is increasingly needed in this case perhaps via prospective cohort studies, observational studies or chart review, as payers might seek additional post-market evidence for clinical utility. It is becoming increasingly apparent that new methods will have to evolve to ensure efficient evidence generation reflecting realistic expectations around evidence standards (thresholds) aligned between stakeholders given the pace of genomic discovery and the associated costs. This implies that health economists and decision makers must be prepared to accept data that have come from different settings outside RCT's. Potential alternative solutions may involve the use of novel trial designs, such as adaptive clinical trials.Furthermore it is to consider, that the overall effectiveness of the SM intervention doesn't only rely on the development of new treatment modalities, but also on providers and patients behavior when using diagnostic-based therapies. How patients are managed in practice is important and will influence the adoption of new technologies . SM underscores the need for additional information on patients and physicians response to diagnosis and will require post-approval data collection. Accounting for compliance and adherence will reduce variability of findings and should be incorporated into sensitivity analyses. The recently drafted guidelines for preparing assessment reports for the Medical Services Advisory Committee- Service Type: Investigative (version 1.3) in Australia specifically request a supplementary analysis of the non-health related impacts of diagnostic testingThe impact of an intervention on health status is the preferred outcome measure for several EU governmental advisory bodies as recommended in the health economic guidelines. However, for third party payers such standard measures may have limited applicability in assessing SM interventions rather requesting cost-offsets and budget impact information to address affordability issues in various health care systems. Methodological issues regarding the valuation of health outcomes for SM, particular the quality-adjustment of utility component in QALYs, are similar to those faced by other health care intervention. There is an ongoing discussion in academia how standard value assessment metrics can be expanded by personal utility data, as current metrics is focussed on average population based preferences rather than individual patient preference valuation. Capturing information on personal utility may be important, because additional benefits may arise from a patient's increased certainty about the likelihood of successful treatment\u2014the \u201cvalue of knowing\u201d . This might affect adherence and thereby patient outcomes. Yet, alternative metrics are underdeveloped or alternative approaches underused in policy decision making derived from resources consumed and unit cost measures based on economic to clinicians requesting the test and negotiations between suppliers and users often occur at local levels. Large variation in the unit cost of these tests can affect the findings of an economic evaluation and increase uncertainty in the estimated relative cost-effectiveness of a test. Sensitivity analysis should address robust cost estimates relevant to diagnostic testing, yet national price lists of diagnostic test costs would help avoid the currently reported variation in costs permits the analyst to assign a range and distribution to input variables and stand-alone diagnostics is occurring in a complex legal, regulatory and reimbursement environment which does not currently fit with SM approaches. New incentive structures are needed to increase the efficiency of evidence generation. Previous suggestions for economic incentives for evidence generation include value-based price flexibility, intellectual property protection from evidence generated and public investment to complement the effort of payers and manufactures will provide insight into variability of findings and should be incorporated into sensitivity analyses. Health economist may need to take new accountabilities when using observational research methods to perform additional value from utilization data to payers.Incorporating complex genetic or genomic data into cost-effectiveness analyses is a challenge that will grow as next generation sequencing technologies enter clinical practice. While there is no need to develop completely new tools, there are requirements for some refinement by including sensitivity and specificity consideration of the test as well as to address consequences of false-negative and false- positive test results on the value proposition. This may require further methodology development to address the increased complexity and the need for additional analyses associated with the testing component. Further research should also consider examining other approaches to measuring values for SM interventions. The specific aspects outlined in this article suggest there may be opportunities to improve current guidelines for economic evaluation of SM interventions.HF initiated this methodology review, addressed issues through literature review, informal interviews and discussions with international experts and prepared final manuscript. MN participated in interviewing international experts, supported the results generation and provided critical comments to the final manuscript. MP and KR provided substantial commentary for the optimization of this methodology review and critically revised it for important intellectual content.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "It is essential to conduct more studies using a larger number of patients or studies from different geographic parts and ethnicities to obtain the other important prognostic morphologic variables, other than four morphologic variables of Oxford classification.et al. studied 136 primary IgA nephropathy patients. They aimed to find the relationship of proportion of sclerotic glomeruli with proteinuria and serum creatinine and also with pathologic variables of Oxford classification. They found a significant positive association between proportion of globally sclerotic glomeruli and serum creatinine, amount of proteinuria, and also quantity of tubulointerstitial fibrosis. They also found, significant association of proportion of globally sclerotic glomeruli with M, E, S and T variables of Oxford classification have been completely observed by the author.None."} +{"text": "The ischemic penumbra refers to tissue at risk of infarction where perfusion is inadequate to support neuronal function, but just adequate to maintain cell viability . This dyThese recent studies, together with an earlier successful pilot trial of another thrombolytic agent that used MR-based selection of target penumbral patients have shoTmax, cerebral blood volume (CBV), and cerebral blood flow (CBF) maps, as well as tissue at risk (Tmax >6 \u2013 infarct volume). The presence of the additional extracranial stenosis did not affect measured infarct volume, MTT, Tmax, or tissue at risk, but had a small influence on CBV. They hypothesized that extracranial stenosis may lead to ischemic preconditioning that results in improved collateral circulation and a consequent increase in CBV in the presence of acute stroke.Kaesemann and colleagues evaluateWouters and co-workers discuss Leigh and colleagues hypothesMarsh and co-workers present Agarwal and colleagues comparedCampbell and colleagues discuss Motta et al. investigFinally, Scalzo and colleagues argue thThis Research Topic thus addresses important and timely concerns surrounding the issue of how the ischemic penumbra can best be rapidly identified on imaging in order to contribute to management of acute stroke.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Pathogenic microorganisms have evolved sophisticated mechanisms to inactivate antibiotics and rendered an urgent need for new antibiotics that would target the emerging multidrug-resistance and non-Streptomyces including rare actinomycetes Nonomuraea, Actinoalloteichus and Pseudonocardia on the basis of their 16S rDNA sequences and it was the first step toward better understanding of actinomycete community from solar saltern ponds in India. Our preliminary biological activity screening and subsequent structural characterisation experiments suggested the occurrence of antimicrobial compounds producing Streptomyces and rare actinomycetes and confirmed that hypersaline solar salterns are reservoirs of antibiotic producing actinomycetes and inland solar salterns at Sambhar Lake, Jaipur (about Latitude 26.94561 N and Longitude 75.20968 E) in India. Physicochemical characteristics from this study confirmed that this environment is a hypersaline zone. In the course of our program, diverse actinomycetes were isolated by using selective isolation methods which employed stamping, heat and dilution, and succeeded with isolation of both -In conclusion, escalating reports on discovery of diverse natural compounds from halophilic and halotolerant actinomycetes which inhabit in hypersaline environments suggested that this physiological group has enormous capacity to produce array of secondary metabolites with disparate activities. Indeed, hypersaline environments warrant significant attention as habitats of novel actinomycetes and unlock new avenues for natural products discovery.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "This commentary describes important findings of the article published by Sheroziya and Timofeev in The Journal of Neuroscience in 2015. The authors use moderate cortical temperature change, local cooling or heating of somatosensory cortex, to modulate excitable states of the brain. These changes, under physiological conditions, result from neuromodulation, as well as other network effects. They report that cooling disrupts thalamocortical slow oscillations and induces an activated cortical state, while mild heating has the opposite effect and increases slow-wave rhythmicity. We evaluate these findings regarding their utility for inducing and investigating cortical state fluctuations, compare the results to physiologically occurring state changes, and put them into perspective with other discoveries in the field.Periods of rhythmic slow-wave activity during physiological slow-wave sleep or induced by anesthesia are characterized by a waxing and waning of spontaneous neuronal firing coordinated between cortex and thalamus. This activity is generated in the cortex but influences neuronal excitability and stimulus\u2013response properties of neuronal networks throughout the brain . The corAn effect of cortical cooling on thalamocortical slow waves has previously been reported . These aAlthough the exact conditions leading to spontaneous brain state shifts remain unknown, several pathways have been described in this process, and the effects of cooling may overlap mechanistically with these pathways. In awake but restful animals, slow waves may be observed and are suppressed by the initiation of whisking or locomotion or firinHowever, the question remains whether a cooling-induced state leads to neuronal response properties comparable to those of physiological active states of the cortex. Although obtained results share characteristics of spontaneous physiological state shifts, other widespread effects due to cooling cannot be completely excluded. For example temperature change has been shown to affect brain pH , and couFinally, although therapeutic hypothermia is often used to prevent or control seizures, it is argued that moderate cortical cooling has a light epileptogenic effect . This isIn conclusion, we find that the authors provide intriguing evidence in support of temperature changes as a tool to modulate brain states. Although further studies need to evaluate whether the cooled state represents persistent population activity comparable to physiological active states of the thalamocortical network, the present study adds valuable information to current knowledge about the nature and mechanisms of cooling-induced desynchronization. Additionally it provides evidence that mild heating may be used to synchronize brain networks. The implications for these findings could be far reaching, with applications in studies of both the mechanisms of brain state shifts and the use of temperature in the treatment of diverse diseases from epilepsy to sleep disturbances."} +{"text": "Esophageal cancer, comprising squamous carcinoma and adenocarcinoma, is a leading cause of cancer-related death in the world. Notably, the incidence of esophageal adenocarcinoma has increased at an alarming rate in the Western world. Unfortunately, the standard first-line chemo-radiotherapeutic approaches are toxic and of limited efficacy in the treatment of a significant number of cancer patients. The molecular analysis of cancer cells has uncovered key genetic and epigenetic alterations underlying the development and progression of tumors. These discoveries have paved the way for the emergence of targeted therapy approaches. This review will highlight recent progress in the development of targeted therapies in esophageal cancer. This will include a review of drugs targeting receptor tyrosine kinases and other kinases in esophageal cancer. Additional studies will be required to develop a rational integration of these targeted agents with respect to histologic types of esophageal cancer and the optimal selection of cancer patients who would most likely benefit from targeted therapy. Identification of AURKA and AXL as key molecular players in esophageal tumorigenesis and drug resistance strongly justifies the evaluation of the available drugs against these targets in clinical trials. ADAM29 and FAM135B. These two genes have not been previously described in SCC. Of note, FAM135B has been characterized as a novel cancer gene that promotes malignancy of SCC cells AURKA gen stomach , have re stomach . An incr stomach , 88. Mec stomach . These rEsophageal cancer is characterized by resistance to current first-line therapies and dismal clinical outcome, underscoring the urgent need for more effective and innovative treatment strategies. Unlike other types of cancer, elucidation of the molecular mechanisms that regulate esophageal tumorigenesis of both histologic types has been incomplete. Our understanding of cancer biology coupled with the development of targeted drugs will have a positive impact in the treatment of esophageal cancer. The current ongoing clinical trials of targeted drugs in esophageal cancer patients have been mostly based on molecular targets identified in other malignancies. However, identification of AURKA and AXL as important players in esophageal tumorigenesis and drug resistance strongly justifies evaluating the available drugs targeting these molecules in clinical trials. As targeted therapy has been marred by drug resistance, it is imperative to preemptively identify the underlying molecular mechanisms and develop strategies to overcome them in a clinical setting. Notably, development of biomarkers of drug response and resistance may be useful in future clinical trials and rational management of cancer patients."} +{"text": "Reductions of both live coral cover and habitat complexity had substantial impacts on fish communities compared to relatively minor impacts after major reductions in coral cover but not habitat complexity. Where habitat complexity was substantially reduced, species abundances broadly declined and a far greater number of fish species were locally extirpated, including economically important fishes. This resulted in decreased species richness and a loss of diversity within functional groups. Our results suggest that the retention of habitat complexity following disturbances can ameliorate the impacts of coral declines on reef fishes, so preserving their capacity to perform important functional roles essential to reef resilience. These results add to a growing body of evidence about the importance of habitat complexity for reef fishes, and represent the first large-scale examination of this question on the Great Barrier Reef.High biodiversity ecosystems are commonly associated with complex habitats. Coral reefs are highly diverse ecosystems, but are under increasing pressure from numerous stressors, many of which reduce live coral cover and habitat complexity with concomitant effects on other organisms such as reef fishes. While previous studies have highlighted the importance of habitat complexity in structuring reef fish communities, they employed gradient or meta-analyses which lacked a controlled experimental design over broad spatial scales to explicitly separate the influence of live coral cover from overall habitat complexity. Here a natural experiment using a long term (20 year), spatially extensive (\u223c115,000 kms Acanthaster planci (crown-of-thorns starfish) outbreaks and coral bleaching cause coral mortality but leave skeletons intact Habitat complexity is fundamentally important for the maintenance of high biodiversity across a range of ecosystems per se have also declined in abundance following disturbances, and in these cases the role of habitat complexity has been implicated Disturbances on coral reefs can dramatically impact the diversity, abundance and community structure of reef fishes, because many fish species are closely associated with live corals and their structures 2) patch reefs surveyed over several months 2 of the Great Barrier Reef (GBR), gathered over 20 years and employ a natural experiment to formally test how the loss of live coral versus loss of habitat complexity influences reef fish community structure, the diversity of reef fish families and functional groups, and the abundance of individual species.It has previously been demonstrated through experimentation A. planci outbreaks that have occurred over the last two decades on the GBR per se was not important but rather the magnitude of changes and the proportion of the community affected.Data were gathered as part of the Long Term Monitoring Program at the Australian Institute of Marine Science (GBRMPA permit number G13/36390.1); in which fish and benthic communities have been surveyed on 47 reefs of the GBR since 1995. Large-scale disturbances, such as storms and Millepora), soft corals, coralline, turf and macro-algae, rubble, dead coral, sand, abiotic, sponges and other . Fish communities were surveyed concurrently on the same transects using underwater visual census. The abundance and number of species of fishes recorded during surveys were taken from a list of 215 mobile, diurnally active species . While parrotfishes are now considered as a tribe Scarinae within the family Labridae, we use the term \u201cScaridae\u201d to distinguish this group of fishes from other Labridae. We define \u201cspecies richness\u201d as the number of species recorded and use this term hereafter. Cryptic species such as gobies and blennies were not included. Two transect widths were used: 50\u00d71 m belts for the Pomacentridae and 50\u00d75 m belts for the remaining families o video panoramas taken at the start of each transect. This 0 to 5 scale correlates strongly with a range of other rugosity metrics and has been found to be a good predictor of reef fish diversity and abundance Three sites of five permanently marked 50 m transects were situated in comparable reef slope habitats (n\u200a=\u200a15 transects per reef) and were surveyed on SCUBA annually from 1995 until 2006 and then biennially thereafter. From 1995 until 2005, the benthic community was described using a 30-cm video swathe along the transects. Forty frames from each video transect were sampled and the benthic organisms beneath five points projected on to each frame in a quincunx pattern were identified to the finest taxonomic resolution possible, yielding 200 samples per transect. After 2006, a digital still image was taken every metre along each transect, and forty images were selected and analysed as before To provide the clearest picture of absolute changes in fish communities under varying degrees of change in habitat complexity, we compared metrics of reef fish communities at times of greatest (hereafter \u201cBefore\u201d) and least (hereafter \u201cAfter\u201d) percent coral cover (indicated by arrows in Plectropomus spp.). In order to assess the effects of loss of habitat complexity and live coral on functional roles performed by reef fishes, we examined changes to the species richness of broad functional groups including corallivorous and generalist butterflyfishes, herbivores, planktivores and predators. Models had the fixed factors of Time (Before or After) and Treatment , and random factors of reef, site and transect. Most variables were modelled against a gaussian distribution in the MCMCglmm package Changes in fish and benthic communities were further investigated using Bayesian hierarchical models b and Aa were mean values at before and after disturbance respectively. Fish species were only included in these analyses if their summed abundance was \u226510 per reef (\u200a=\u200a15 transects) in one of the two years. Changes in individual species abundance were then averaged across the four reefs within each Treatment.We assessed changes in the abundance of individual reef fish species by plotting a comparable metric to account for differences in initial coral cover Benthic and fish community structure changed from times of greatest to least coral cover, but the magnitude of change varied among habitat complexity treatments . On reefHard coral cover declined in all treatments but the decline was negligible on Control reefs. Habitat complexity only declined substantially on Major Decline reefs; reductions were minimal on reefs in the Minor Decline treatment and were similar to changes at Control reefs . ReductiChanges in the abundance of individual species varied substantially among the three habitat complexity treatments , with maThe major loss of habitat complexity also greatly reduced the capacity of reef fishes to perform their functional roles. Among the functionally important herbivorous fishes, fourteen species declined in abundance by 50% or more on reefs that underwent major declines in habitat complexity, compared to four species on reefs with a minor decline and only one species on Control reefs. Additionally, abundances of some commercially important fishery species such as coral trout, were reduced to zero on Major Decline reefs, but declined by less than 5% on Minor Decline reefs. In addition, obligate corallivores accounted for a large proportion of the species that declined in abundance in the Minor Decline treatment, but accounted for a much smaller proportion of the substantially greater number of species that declined on reefs with major declines in complexity.Using long-term data at ecologically meaningful scales on the GBR, this study has demonstrated the fundamental importance of habitat complexity for the maintenance of diverse fish communities, which is critical for maintaining healthy ecosystem function. Among reefs which underwent large declines in live coral cover, it was only on those reefs where habitat complexity also declined markedly that reef fish communities underwent wholesale reductions in diversity, species abundances and functional capacity. Previously small scale manipulative experiments While decreases in abundance of coral dependent species following loss of live coral were expected irrespective of changes in habitat complexity The extirpation of numerous species of fishes following major declines in habitat complexity contributed to a major reduction in fish diversity, with species from a range of trophic affiliations lost. High fish diversity usually equates to increased functional diversity and functional redundancy , both key components of reef resilience While the role of herbivorous fishes in reef resilience has been well established, the contributions of many other reef fishes to reef resilience and healthy ecosystem functioning is less clear. However, what is certain is that the loss of a range of coral reef species performing many functional roles will likely have unknown consequences for ecosystem functioning. For example, reductions in the diversity and abundance of corallivorous fishes (e.g. butterflyfishes) will lower coral mortality per se. Similarly, findings of diverse coral reef fish assemblages on artificial structures largely devoid of corals supports the idea that shelter provided by habitat complexity is fundamentally important to coral reef fish communities A. planci outbreaks, coral bleaching and coral disease slowly decreases habitat complexity, and may also produce lagged declines in fishes It appears that the short term loss following disturbances of adult fishes not directly dependent on live coral relates more closely to the lack of available shelter rather than to loss of living corals A. planci). Such results should be of interest to reef managers, particularly given our finding that the major fishery target species, the coral trout (Plectropomus spp.) disappeared from sites of major complexity decline, with socio-economic ramifications for fishers utilising this resource. In addition, the impact of storms on reef fish communities at sites where coral skeletons account for most of the habitat complexity will be equally devastating irrespective of any zoning to protect target species from fishing. In effect, the benefits afforded by reserve zoning can be reversed almost instantaneously. Conversely, protection of fish communities at sites where complexity of the underlying substrate is high would better preserve important functional processes performed by reef fishes, encouraging rapid recovery in the event that coral cover is removed. Given the prospect of increases in storm intensity with climate change While previous studies have identified the link between habitat complexity and reef fishes, many of these studies have focused on subsets of the fish community e.g. . We wereTable S1Model specification for hard coral cover, complexity, total species richness and the species richness of eight families of reef fishes.(DOCX)Click here for additional data file.Table S2Full names for species codes and trophic affiliations used in .(DOCX)Click here for additional data file."} +{"text": "We seek to define the gene regulatory networks that govern heart development and disease. Recently, we discovered that the hearts of neonatal mice can fully regenerate after partial surgical resection or myocardial infarction, but this capacity is lost early in life. We are currently exploring the molecular underpinnings of the neonatal regenerative response of the heart, with the long-term goal of discovering combinations of genes and drugs that promote cardiac repair and regeneration. Promotion of cardiomyocyte proliferation through activation of the Yap pathway and modulation of epicardial signaling systems have shown efficacy in enhancing these processes. We are also optimizing strategies for reprogramming of cardiac fibroblasts toward a cardiac cell fate as a means of replacing cardiomyocytes in injured hearts. We have shown that four transcription factors can cooperatively reprogram fibroblasts into cardiac-like myocytes in vitro, albeit relatively inefficiently. Forced expression of these factors in dividing non-cardiomyocytes in mice also allows reprogramming into functional cardiac-like myocytes, improves cardiac function and reduces adverse ventricular remodeling following myocardial infarction. Screens for small molecules and microRNAs that enhance cardiac reprogramming have revealed new insights into the mechanistic basis of this process and have allowed further optimization in human cells. Opportunities and obstacles in the path toward mammalian cardiac regeneration will be discussed."} +{"text": "This study aims to understand how inherent ecological network structures of nestedness and modularity vary over large geographic scales with implications for community stability. Bipartite networks from previous research from 68 locations globally were analyzed. Using a meta-analysis approach, we examine relationships between the structure of 22 trophic and 46 mutualistic bipartite networks in response to extensive gradients of temperature and precipitation. Network structures varied significantly across temperature gradients. Trophic networks showed decreasing modularity with increasing variation in temperature within years. Nestedness of mutualistic networks decreased with increasing temperature variability between years. Mean annual precipitation and variability of precipitation were not found to have significant influence on the structure of either trophic or mutualistic networks. By examining changes in ecological networks across large-scale abiotic gradients, this study identifies temperature variability as a potential environmental mediator of community stability. Understanding these relationships contributes to our ability to predict responses of biodiversity to climate change at the community level. Understanding changes in community dynamics along major environmental gradients is a major goal of community ecology. Substantial ecologically relevant gradients abound, including abiotic ones such as precipitation, temperature, or salinity gradients and consumer (j) species with the goal of assessing how network structural characteristics such as nestedness and modularity covary with community traits and stability and not to interact with organisms outside of their module. Modularity calculations were made using the Newman and Girvan algorithc) for each predictor variable, computed as the sum of Akaike weights (wi), were also calculated. Because nestedness and species richness were log-normally distributed in previous studies between years and within years (CV of monthly sums).Relationships between environmental variables and their variability and network structures were analyzed following Akaike's information criterion of temperature between years, and a model including the CV of temperature within years. However, the null model (model including only species richness as a predictor of modularity) was also included in the top models of temperature between years, the CV of temperature within years, the coefficient of variation (CV) of precipitation between years, and the CV of precipitation within years were all included in the top models. However, the null model including only species richness as a predictor of the nestedness of trophic networks was also included in the top models . If environmental properties drive network structure, understanding the timescale over which change in environment effects change in network structure and the robustness of networks to changes becomes critical. Due to the difficulty of experimental tests of changes in network structure, especially under field conditions, empirical evidence for direct causes of observed structure along large environmental gradients remains elusive. However, understanding network structure is critical as it offers potential insight into community resilience and stability, leading to better predictions of the impacts of changing environmental conditions at the global level on ecological communities and ecosystem function in this period of unprecedented change."} +{"text": "Photosensory receptors have been in the center of vision research and photobiology since the discovery of rhodopsin in 1876 by Franz Boll. However, in the last 10 years the rise of optogenetics has placed them in a broader focus. The majority of these biological light-sensors consist of a protein/pigment complex that alters the activity of a cognate biological effector upon absorption of a photon. With the nowadays available information on the corresponding genes, proteins and the vast access to (meta-) genomic data as well as sophisticated methods in molecular biology and genome engineering the photoreceptor principle of transforming light into biological information is now exploited in many different fields of research.Photosensory receptors therefore not only constitute the backbone of a major methodological breakthrough in cell and neurobiology but also offer bright perspectives for our understanding of dynamic biomolecular processes in general. The possibility to use photons as substrates enables researchers to induce and experimentally monitor biomolecular reactions with up to femtosecond resolution. Combined with techniques capable of molecular resolution such time-resolved experiments not only provide dynamic molecular information on the underlying mechanisms of photosensory and general signal transduction, but also will enable us to identify structure/function relations and design principles of biological sensor/effector complexes. Ultimately, this knowledge will allow us to rationally design novel light-responsive tools with customized properties for application in optogenetics and synthetic biology.This ebook features research articles and reviews covering the most prominent photosensory modules applied in optogenetics, as represented by flavin based photoreceptors (LOV and BLUF), phytochromes and microbial opsins. The articles of this collection showcase state-of-the-art approaches to elucidate the molecular function of such photosensory modules from the initial event of photon absorption to the activation of a downstream effector.Ritter et al. summarize recent advances in time resolved infrared absorption spectroscopy, which allows researchers to visualize structural changes involved in the activation of photosensory proteins by identifying changes in vibrational frequencies of individual chemical bonds. While infrared spectroscopic data may therefore become extremely complex in proteins, larger scale structural transformations like domain rearrangements in photosensor/effector complexes and their dynamics can be more efficiently mapped by discrete distance measurements between interacting paramagnetic centers using pulsed electron paramagnetic spectroscopy as illustrated by Nohr et al. Another elegant way of characterizing functionally relevant differences in signaling-active and inactive protein forms is presented by Lindner et al. Their review summarizes hydrogen/deuterium exchange mass spectrometry that provides information on solvent accessibility and domain flexibility, and thus important mechanistic insights on how protein dynamics determine signal transduction.Song et al.). The chromophore and its dynamic interaction with the protein environment can be studied with extremely high molecular resolution using this technique and allowed the authors to determine aggregation and hydration effects induced by sample preparation on the local structure of the chromophore. Such insights are crucial to critically evaluate experimental results and their functional implications.In their research article, Song and coworkers employ magic angle spinning solid state nuclear magnetic resonance spectroscopy to investigate the molecular and electronic structure of the protein-embedded tetrapyrrole cofactor . They identify two far-red absorbing states in the cyanobacterial phytochrome Cph1 using a combination of steady state Raman spectroscopy, ultrafast time resolved infrared spectroscopy and quantum chemical calculations.Heterogeneity in receptor conformation is a recurring topic both in photoreceptor and signal transduction research and is crucial to understand dark noise of receptor proteins. Chromophore heterogenetity and its relation to signaling is also the focus of the study of Velazquez Escobar et al. on phytochromes and to simulate molecular structural dynamics of photoreceptor proteins. Bocola et al. employ molecular dynamics simulations to investigate light-induced structural changes in dimeric LOV domains and provide a novel mechanism for the photoactivation of dimeric LOV photoreceptors. Mathes and G\u00f6tze review the currently available computational studies on the spectroscopic properties and vibrational frequencies of BLUF photoreceptors and explore an alternative mechanism of BLUF photoactivation using quantum chemical calculations.In addition to experimental methods as described in the articles above, computational methods are powerful approaches to calculate spectroscopic properties or molecular dynamics under selected conditions, which may not be accessible experimentally. In this collection computational methods are used to support experimental findings by calculating vibrational frequencies of chromophores through a VICI grant to JK.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Inflammatory bowel disease (IBD) is a chronic inflammatory disorder affecting the gastrointestinal tract and includes ulcerative colitis and Crohn\u2019s disease. During last decades, the incidence of IBD has been increased, both in children and adults \u20133. WhileGenetic factors together can only explain a small proportion of hereditability and disease susceptibility . In monoSome environmental factors play major role in the pathogenesis of IBD. There are many epidemiologic changes between populations around the world but cannot be explained by genetic variations alone. The environmental triggers, such as dietary habits, improved socioeconomic status, improved sanitation, and different microbial exposures, all increase the risk of IBD.Studies on immigrant populations can potentially help to dissect the etiologic significance of genetic and environmental factors in developing the disease. Moreover, first and second generation immigrants coming from low incidence to high incidence areas acquire levels of risk similar or higher than that of their adopted countries , 8. ThesThe molecular pathways of disease increase our knowledge in IBD to determine disease characteristics such as clinical appearance, therapeutic response and natural history. Ultimately, through the combination of genetic data and clinical with information about gene expression and environmental factors influences, like intestinal microbiota , it seemSimilar to the other complex polygenic diseases, the paradigm of personalized IBD treatment will probably only be achieved if we try to integrate the genetic and environment factors, molecular mechanisms and immunological advances with insights to the gut microbiota pattern. Multiple stimulatory and regulatory processes are also involved in maintaining the balance between host defense and pathogenic inflammation gut epithelial. To date many pathways have been known clearly. Appropriate genetic diagnostic investigations can profoundly alter the chosen approaches, from immune suppression therapy and specific drugs for biological targets to allogeneic haematopoietic transplantation of stem cells. Future cohort studies across geographic social and ethnic groups will improve our data quality in suggesting multidimensional sequential panel for analyzing the patient information to approach practically personalized IBD care."} +{"text": "The transition from fetal to neonatal life requires metabolic adaptation to ensure energy supply to vital organs and systems after separation from the placental circulation. Under normal conditions this is achieved through the mobilisation and use of alternative cerebral fuels when blood glucose concentration falls.The level of blood glucose (BG) concentration that leads to cerebral injury in newborns and adverse neurodevelopmental outcome is unknown: low BG is often observed during postnatal adaptation of healthy term infants without apparent adverse consequence, and the capacity to mobilise and use alternative cerebral fuels when BG is low varies between patient groups. Severe hypoxic-ischaemic encephalopathy (HIE) is associated with impaired metabolic adaptation, and animal and human data suggest that levels of hypoglycaemia that are tolerated under normal conditions may be harmful in association with hypoxia-ischaemia.The spectrum of cerebral injury associated with hypoglycaemia is wide and includes: white matter injury including parenchymal haemorrhage and ischaemic stroke, cortical neuronal injury, and sometimes signal change in the basal ganglia and thalami. Vulnerability of the white matter and cortex of the posterior parietal and occipital lobes has been well reported in human imaging studies, but the site of injury is more widespread in pathological and experimental studies of neonatal hypoglycaemia. In the largest series of infants with isolated neonatal hypoglycaemia and acute neurological dysfunction, there was an association with a predominantly posterior pattern of injury in one third of the cohort, and a more extensive distribution of lesions was common.Safe clinical management relies on the identification of infants at risk of neurological sequelae from hypoglycaemia, adequate energy provision after birth, monitoring of blood glucose, and prompt intervention to raise the BG at specified thresholds, with the caveat that acute neurological dysfunction in association with low BG at any level should prompt urgent investigation and treatment. The optimal target blood glucose level for ensuring adequate energy provision in health and in HIE remains unknown. However, recent data support guidance to maintain blood glucose concentration \u22652.5mmol/L in neonates with signs of acute neurological dysfunction, which includes those with HIE, and is higher than the accepted threshold of \u22652mmol/L in infants without abnormal signs or hyperinsulinism."} +{"text": "Prolonged neonatal jaundice is defined as a jaundice lasting more than 14 days of life in the full-term infants . EtiologThe differential diagnosis of cholestasis is extensive, and early recognition is essential to ensure timely treatment and optimal prognosis . DevelopIn case of neonatal cholestasis, the first step should be the assessment of coagulation and urgent parenteral vitamin K administration in case of coagulopathy and the exclusion of life-threatening conditions or disorders requiring urgent specific medical and surgery treatment. Biliary atresia is the most frequent single cause of neonatal cholestasis and affected infants appear otherwise healthy and grow normally . Early pInfants admitted in NICUs have a rate of cholestasis higher than that reported in the general population of live births; in most cases, cholestasis is associated to multiple risk factors and shows a favorable outcome .Long-term cholestasis determines malnutrition, psychomotor development delayed and immune deficiency. So that even when specific treatment is not available, infants who have cholestasis benefit from early medical management and nutritional support for malabsorption and vitamin deficiency ."} +{"text": "It has been estimated that about 20% of men and 25% of women between the ages of 65 and 74 have some degrees of chronic kidney. This complication is attributed to oxidative stress. Oxidative stress is an important factor contributing to kidney damage by increasing production of oxidants, particularly insufficiency of endogenous antioxidant defense system. Medicinal plants antioxidants are able to ameliorate oxidative induced kidney damage by reduction of lipid peroxidation and enhancement of scavenging ability of antioxidant defense system. Supplementation of medicinal plants antioxidants might be considered important remedies to abrogate pathology of oxidative stress induced kidney damage, however, single antioxidants do not act the same and might not be beneficial. Oxidative stress is an important factor contributing to kidney damage by increasing production of oxidants, particularly insufficiency of endogenous antioxidant defense system. Medicinal plants antioxidants have been shown to ameliorate oxidative induced kidney damage by reduction of lipid peroxidation and enhancement of scavenging ability of antioxidant defense system. Supplementation of medicinal plants antioxidants might be considered important remedies to abrogate pathology of oxidative stress induced kidney damage, however, single antioxidants do not act the same and might not be beneficial.More than one fifth of people over ages of 65 years have some degrees of chronic kidney disease (CKD) . This coMedicinal plants antioxidants are able to ameliorate oxidative induced kidney damage by reduction of lipid peroxidation and enhancement of scavenging ability of antioxidant defense system. Supplementation of medicinal plants antioxidants might be considered important remedies to abrogate pathology of oxidative stress induced kidney damage, however, single antioxidants do not act the same and might not be beneficial. This paper reviews the effects of antioxidants and tries to help choosing suitable antioxidant for pathologic kidney injury. It has been estimated that about 20% of men and 25% of women between the ages of 65 and 74 have some degrees of chronic kidney. CKD is more common in south Asian people especially those from Pakistan, Bangladesh, India and Sri Lanka as well as black people. The reasons for this include higher rates of high blood pressure in African people and higher diabetes in south Asia. These are two diseases attributed to oxidative stress . AlthougOxidative stress is the imbalance between the rate of production and removal of produced oxidants. In other word it is an increase in reactive oxygen species (ROS) and reactive nitrogen species (RNS) and/or decrease in endogenous/exogenous antioxidants. It is the causative factor of a wide variety of diseases such as neurodegenerative diseases, diabetes, atherosclerosis, ischemia, and kidney disease ,5.The moMedicinal plants are considered as healthy sources for the prevention of various oxidative stress-related diseases . CurrentOxidative stress induced kidney damage is associated with increased ROS/RNS production. Moreover, oxidative stress induced kidney damage is significantly reduced by antioxidants .Medicinal plants-derived antioxidants can protect renal damage through reduction of lipid peroxidation (LPO) and increase in endogenous antioxidants. Increased levels and activities of endogenous antioxidants reduce kidney damage. Tocotrienol, a member of vitamin E family, supplementation exhibited the capacity to reduce proximal tubular injury and renal LPO, and increased GSH level and catalase activity. Moreover, it is able to improve the index of NO2 -/NO3 \u2013generation. Tocotrienol can be considered a natural antioxidant supplement protecting the kidney pathology induced by potassium dichromate . LigustrOxidative stress is an important factor contributing to kidney damage by increasing production of oxidants, particularly insufficiency of endogenous antioxidant defense system. Medicinal plants antioxidants have been shown to ameliorate oxidative induced kidney damage by reduction of lipid peroxidation and enhancement of scavenging ability of antioxidant defense system. Supplementation of medicinal plants antioxidants might be considered important remedies to abrogate pathology of oxidative stress induced kidney damage, however, single antioxidants do not act the same and might not be beneficial.MRK is the single author of the manuscript.The author declared no competing interests.Ethical issues have been completely observed by the author.None."} +{"text": "Freund From a systems biology perspective, the brain and spinal cord are interwoven with the body, through afferent and efferent synaptic connections\u2014they are literally \u2018embodied\u2019 secondary processes that may be reasonable targets for interventions on their own. Moreover, standard neurological assessments often fail to distinguish between pathogenic and compensatory processes.This state of affairs calls for a better understanding of neurological disease within a formal framework that links pathology to phenomenology . We suggest that such a framework should pay special attention to the embodied nature of the nervous system and the implicit pathophysiological and compensatory processes that can be present throughout the neuroaxis. In particular, we postulate that reciprocal information flows, between the body and the nervous system, are crucial for understanding and treating neurological disorders.This framework aims to link pathology to phenomenology, while respecting the \u2018embodied\u2019 nature of the nervous system. If fully realized, the framework of embodied neurology has the potential to improve functional outcome following individualized treatment (i.e. precision neurology), promote successful translation of novel therapeutics into clinical use, and refine nosology in the context of disease heterogeneity.Our description of embodied neurology is largely theoretical and is based on a series of focused workshops. It draws on recent advances in biophysical modelling of functional structure of loops and recurrent processes that necessarily entails compensation, decompensation and the compounding of functional deficits . Each leThe embodied nature of the complex interactive sensorimotor system suggests that even successful repair of focally damaged fibre tracts through a regenerative treatment [like anti-Nogo-A antibodies in spinal cord injury pattern reflecting synchronized thalamic discharges that can occur in hypoxic and anaesthetic encephalopathy could potentially offer a wider therapeutic window, as there is often a time lag between the primary insult and secondary processes (e.g. network reorganization) that may involve a range of cellular processes. Treatments targeting secondary processes in one neurological disorder may be repurposed for another, offering novel treatment options.To achieve the objectives of embodied neurology, several challenges in functional and structural biophysical modelling, neuroimaging and clinical measures need to be met. We will consider these challenges in terms of the three tenets of embodied neurology:The central tenet of this framework relies on formulating mechanistic hypotheses about how peripheral processes translate into an embodied central response. Biophysical models of interacting central and peripheral systems can provide a mechanistic and quantitative characterization of physiology as well as pathology. Model-based indices not only furnish mechanistic insights into a distributed pathology but might also serve as more powerful clinical predictors than (level specific) local measurements causal modelling of the coupling between the central and peripheral systems and even Crucially, subject-specific structural data of this sort can be used to define anatomically informed priors, which constrain and individualize models of neuronal dynamics. For example, dynamic causal models of functional MRI were successfully informed and enhanced using diffusion-weighted imaging data describing anatomical connectivity .Preclinical studies are required to inform, constrain and validate the computational modelling in any neurological disorder. Such studies have demonstrated that features of neurodegeneration, including myelin, axonal and synaptic loss as well as functional impairments can be modulated by treatments of peripheral targets (e.g. tissues and organs outside the CNS), thereby offering new approaches to therapeutic intervention and highlighting the embodied character of the nervous system. Moreover, progress continues in the development of reparative and neuroprotective interventions to enhance recovery in many diseases.Preclinical models have proven essential for elucidating disease mechanisms and for evaluating the extent of damage and the effects of novel treatment interventions. Recent methodological advances have enabled the invasive and non-invasive detection of functional and microstructural changes at single neuron and synapse levels with a temporal resolution in the millisecond range. Many of these parameters have been identified to link structural and functional changes to outcome in motor and sensory impairment. To improve the translation of knowledge from animal models to humans, the establishment of quantifiable and specific biomarkers in animal models and humans will be essential to establish the validity of these models in the setting of disease stage and treatment interventions.Embodied neurology promises insights into the multiscale interactions across the entire neuroaxis through unified biophysical models of structure and function as well as advanced neuroimaging techniques. It may provide the basis for a better understanding of the changes in neural control and plasticity that occur across the embodied central and peripheral nervous systems under physiological and pathological conditions. Thus, embodied neurology may be well placed to finesse nosological classification, to optimize therapeutic outcome by providing specifically targeted interventions and improve clinical diagnosis in the context of heterogeneity. If fully realized, embodied neurology will enable (i) the detection of beneficial plasticity versus detrimental changes; (ii) the utilization of high-resolution imaging of the entire nervous system; (iii) more specific characterization of structural and functional changes as they relate to tissue and connectivity changes; and (iv) the identification (and simulation) of optimal treatment processes for rehabilitation."} +{"text": "Solanum tuberosum L.) is often considered as a drought sensitive crop and its sustainable production is threatened due to frequent drought episodes. There has been much research aiming to understand the physiological, biochemical, and genetic basis of drought tolerance in potato as a basis for improving production under drought conditions. The complex phenotypic response of potato plants to drought is conditioned by the interactive effects of the plant's genotypic potential, developmental stage, and environment. Effective crop improvement for drought tolerance will require the pyramiding of many disparate characters, with different combinations being appropriate for different growing environments. An understanding of the interaction between below ground water uptake by the roots and above ground water loss from the shoot system is essential. The development of high throughput precision phenotyping platforms is providing an exciting new tool for precision screening, which, with the incorporation of innovative screening strategies, can aid the selection and pyramiding of drought-related genes appropriate for specific environments. Outcomes from genomics, proteomics, metabolomics, and bioengineering advances will undoubtedly compliment conventional breeding strategies and presents an alternative route toward development of drought tolerant potatoes. This review presents an overview of past research activity, highlighting recent advances with examples from other crops and suggesting future research directions.Potato ( Solanum tuberosum L.) is of great economic value and ranks as the fourth most important food crop in the world. According to FAO .Drought already poses one of the most important constraints to plant growth and terrestrial ecosystem productivity in many regions all over the world favors oxygenation of RuBisCO which can also contribute to ROS production which largely declines in parallel with leaf water potential (\u03a81) with efficient water conservative strategy dependant on the characteristics of canopy architecture such as canopy area, open/close canopy, leaf orientation, and cuticular transpiration rates. Potatoes exhibit isohydric characteristic with soil water potential (\u03a8soil) and stomatal conductance (gs) decreasing under water stress while maintaining \u03a81 similar to values obtained from non stressed conditions shows a significant positive correlation with plant height and the dry biomass of the plant foliage in the plant dry matter compared to the ratio in the atmosphere , with lower decrease in NR associated with drought tolerance that recognizes and binds to the cap structure of RNA polymerase II transcripts in the nucleus , miR159, miR164, miR166, miR390, miR395, miR397, miR398, miR408, and miR482 improved plant tolerance to stress and it is thought that the induced upregulated expression of AtHB-7 (Arabidopsis homeobox gene), RD28 (Responsive to desiccation), ALDH (Aldehyde dehydrogenase), and ERD15 (Early response to dehydration) under drought stress conditions enhances tolerance induced water stress show that up-regulated genes were prevalently involved in carbohydrate metabolism, cellular communication, and signal transduction whereas down regulated genes mostly include ATP-dependent RNA helicase and cytochrome P450 followed by vacuolar ATP synthase and genes involved in protein synthesis in the cytosol show greater shoot extension than the WT plants due to elevated AsA (Ascorbate) leading to enhanced tolerance to drought and salt stress and biotic (herbivores and pathogens) factors either individually or in combination. Combination of stresses alter metabolism in ways that may differ from responses to different stresses applied individually , as molecular signaling pathways controlling abiotic and biotic stresses may interact or counteract one another in plant cells leading to a lowered osmotic potential, which in turn can improve cell hydration, help maintain cell turgor in leaf tissue, maintain metabolic processes and thus enhance plant growth and yield under drought stress Morgan, . StudiesF0), maximal fluorescence (Fm), variable fluorescence (Fv), and maximal quantum efficiency of PSII (Fv/Fm) is considered an important approach for the evaluation of health or integrity of the internal apparatus during photosynthetic processes within a leaf while providing a platform for rapid and precise detection and quantification of plants tolerance to drought stress and axially (within the xylem) may be great enough to increase significantly the gradient, reduce the hydraulic conductivity and increase the canopy temperature has been used as a phenotypic resource for evaluating plant stress symbiosis in developing drought tolerant maize and sweet potato cultivars respectively and for cloning and insertion of drought resistance genes applicable to diverse agrarian zones. Although genetic manipulation, using key genes identified from functional studies, offers significant opportunities for the development of drought tolerant varieties it will be necessary to ensure that any deleterious negative effects are avoided. The emergence of novel approaches involving the use of high throughput \u201comics\u201d technologies including genetic, physiological, biochemical, molecular and biotechnological techniques offer hope for exciting innovations toward maintaining food and income security, mitigation of poverty, and reduction of farmers' risk in vulnerable agricultural environments.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Juvenile Idiopathic Arthritis is a heterogeneous disease with significant variability in long-term outcome and treatment response; this occurs both between and within JIA subtypes, as defined by the current International League Against Rheumatism (ILAR) classification. There are currently no robust clinical or biological predictors of outcome or treatment response in JIA. Given that JIA is a complex genetic disorder, genetic studies provide an opportunity to address this issue, and whilst previous studies have often been limited by statistical power to identify the likely modest effect sizes, the recent establishment of a number of international consortia for JIA genetics has allowed this issue to be resolved.This presentation will summarize the current understanding of the genetic basis of JIA susceptibility, prognosis and treatment response and will describe how these genetic associations may further our understanding of the molecular mechanisms and immunological pathways involved in this disease. In addition it will provide insights into how we might utilise this data to progress towards the ultimate goals of predicting long-term disease outcomes at onset, predicting drug response, and move towards more targeted treatment options for children with JIA.None declared."} +{"text": "The ability to predict the future behavior of an individual cancer is crucial for precision cancer medicine. The discovery of extensive intratumor heterogeneity and ongoing clonal adaptation in human tumors substantiated the notion of cancer as an evolutionary process. Random events are inherent in evolution and tumor spatial structures hinder the efficacy of selection, which is the only deterministic evolutionary force. This review outlines how the interaction of these stochastic and deterministic processes, which have been extensively studied in evolutionary biology, limits cancer predictability and develops evolutionary strategies to improve predictions. Understanding and advancing the cancer predictability horizon is crucial to improve precision medicine outcomes. Large-scale genomic cancer medicine initiatives are under way in several countries across the globe.However, it remains a major challenge to use genomic information to make accurate predictions for individual cancer patients.Multiple genomic studies substantiated the notion of cancer as an evolutionary process that can readily adapt within the lifetime of a patient.Evolutionary adaptation results from the interplay of mutation generation and genetic drift, which are both stochastic processes, and clonal selection, which is deterministic in nature.The influence of stochastic factors fundamentally limits the predictability of cancer evolution.Understanding the limits of predictability and the development of more accurate prediction algorithms using evolutionary models is key to improving outcomes through genomic cancer medicine. The ability to precisely predict the future clinical course of an individual patient's cancer would be highly beneficial for oncological care. For example, patients whose cancers will never progress to the point of affecting their health may not require any treatment and those who need systemic therapy should only be treated with drugs that have a realistic chance of being effective.Genomic aberrations differ between cancers of the same histological type, to the extent that no two tumors are thought to show an identical somatic genetic aberration profile \u2018Nothing in biology makes sense except in the light of evolution\u2019 \u2013 Theodosius DobzhanskyForty years ago, Peter Nowell first formally described cancer as an evolutionary process Cancer evolution is conceptually similar to the evolution of asexual microorganisms deterministic process; see stochastic process) and spatial structures limit cancer predictability. Based on this evolutionary perspective of cancer, we subsequently assemble novel approaches such as genetic micro- and macroheterogeneity profiling and the application of empirical cancer fitness landscapes, which should expand the predictability horizon for precision cancer medicine efforts.The acquisition of heritable alterations and genetic drift are both random processes, while Darwinian selection is deterministic in nature signaling levels during cancer drug therapy Structural aberrations also result from diverse molecular mechanisms. Fusion of two chromosome ends fostering cycles of chromosome breakage and fusion during mitosis Different mutational processes can predominate at different times. Clear cell renal cell carcinomas (ccRCC) and non-small cell lung cancers (NSCLCs) both exhibited distinct mutational signatures during early carcinogenesis compared with cancer progression and between different tumor subclones Cancer originates from a single cell with a diploid genome. This encodes the blueprint for embryological development and adult homoeostasis of a complex multicellular organism and is also structurally optimized to undergo meiosis and recombination during sexual reproduction Taken together, mutations are the prerequisite for cancer evolution. Mutation rates, the genomic regions that are prone to mutagenesis, and the timing when particular mutagenic processes operate during cancer progression can vary significantly between but also within individual cancers. This influences the accessibility of novel genotypes and phenotypes and hence the opportunities for evolution, as shown for APOBEC-driven mutagenesis, which generates activating phosphoinositide (PI)3-kinase mutations in many cancers where it is active Genetic drift refers to changes of the frequency of an allele in a population due to random birth and death events: each cell in a newly generated cancer subclone has a certain probability of dying as a result of random factors and occasionally all cells of a small subclone die, even if this clone harbors a highly beneficial mutation. Drift has a bigger impact in smaller populations Drift influences cancer initiation A new mutation that increases the ability of the cell to survive and reproduce under particular environmental conditions and that has escaped drift will gradually increase in its abundance within the population. This clonal selection is arguably the only deterministic force in evolution Next-generation sequencing technologies revealed these clonal selection processes for the first time in detail and drafted the first chapters of cancer evolution rulebooks. Multiple intratumoral subclones harboring different driver mutations, displaying distinct phenotypes, and evolving with branched phylogenies were identified in many cancer types The presence of multiple subclones within a tumor can lead to clonal competition. The fitness of an individual subclone is then defined in relation to the fitness of other competing clones The identification of spatially separated subclones in many solid tumors suggests that their 3D structure hinders intermixing of subclones Resistance almost invariably develops during drug therapy in metastatic tumors and studies into the origins of acquired resistance impressively illustrated the evolutionary plasticity of cancer.EGFR T790M mutations EGFR mutations, MET proto-oncogene or erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification or non-pathway-dependent resistance through transformation into small-cell lung cancers were observed less frequently in biopsies from resistant tumors EGFR mutations are an alternative resistance mechanism to third generation EGFR inhibitors EGFR allele. As C797S mutations occur randomly on one of the two EGFR alleles, the optimal further therapy cannot be predicted until the mutational event has occurred and has been detected. This compellingly demonstrates how stochastic events can limit predictability.For example, the majority of NSCLCs treated with first generation EGFR inhibitors such as gefitinib or erlotinib acquire resistance through the evolution of RAS) or v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) genes, in individual patients with colorectal cancer (CRC) after they had developed anti-EGFR therapy resistance KRAS) resistance mutations had been present in small subclones before anti-EGFR therapy initiation Somatic mutation detection in circulating tumor DNA (ctDNA) is likely to provide a more comprehensive overview over the subclonal heterogeneity of solid tumors than single biopsies. ctDNA analysis indeed detected up to 12 distinct subclones, each harboring a different mutation in RAS-type family GTPases fusion protein, until a resistance mutation becomes detectable varies highly between patients, probably as a consequence of the stochasticity of mutation generation and drift. But once such a mutation is detectable, most cancers will progress, suggesting that these clones entered a deterministic and predictable trajectory. Distinct resistance mutations in the BCR-ABL gene have different fitness effects in the presence of imatinib and the time from detection of a resistance mutation to progression can be estimated with higher precision when the exact mutation is taken into account Chronic myeloid leukemia (CML) in the chronic phase is a cancer type in which the mutation supply is usually limited. It is genetically stable and has a small effective population size as it is maintained by a small pool of cancer stem cells All else being equal, the supply of new mutations increases with the cancer cell population size and the probability that a specific advantageous mutation will occur converges towards 100% in advanced cancers, which can harbor hundreds of billions of malignant cells . The likGenomic instability can increase the supply of beneficial mutations in small cancers to levels equal to or exceeding those of large but genomically stable tumors. A distinct difference is that multiple mutations are likely to arise and accumulate within individual cells in the former scenario. Thus, additive and epistatic effects increasingly influence overall subclonal fitness in genomically unstable tumors. Mutations can impair fitness through multiple mechanisms including loss-of-function, detrimental neo-functions, cellular stress induced by misfolded or aberrantly expressed proteins, fatal structural aberrations in the genome, or by increasing cancer immunogenicity Mathematical models POLE) indeed found a maximum of \u223c20\u00a0000 exonic mutations The irreversible accumulation of detrimental mutations in asexually reproducing organisms may eventually lead to their extinction, a phenomenon referred to as Muller's ratchet in evolutionary biology. Sequencing of ultra-hypermutator cancers in children with germline mutations in the proofreading DNA polymerase epsilon mutant clones that evade apoptosis under these hostile conditions A challenge for the quantification of the fitness of cancer subclones is that it depends on the selection pressures operating in an individual cancer. Selection can, for example, vary between tumor types as shown by the detection of star-shaped phylogenies in primary CRCs, which suggested the absence of strong selection In summary, cancer evolution is influenced by various selective pressures that can act simultaneously and vary in space and time Cancer evolution is a complex and dynamic process governed by simple principles . The spaOnce a subclone has expanded and escaped drift, its fate is increasingly determined by its fitness advantage. Methods that can identify such evolving macroscale subclones and estimate their fitness advantage may permit the accurate prediction of short-term dynamics of heterogeneous tumors. For example, detection of pre-existing drug resistant subclones before anti-EGFR therapy in NSCLCs Current genetic prediction approaches are largely based on the analysis of recurrent driver aberrations. This overlooks negative fitness effects of so-called passenger mutations, which most likely diminishes predictive accuracy. Efforts to identify non-synonymous mutations that generate neo-epitopes Mathematical models suggest that at the time of treatment, each metastatic lesion may contain several drug resistant subclones that differ in their population sizes by orders of magnitude Taken together, detecting macroscale clones that are expanding almost deterministically and precise quantification of the fitness effects of somatic mutations within such clones may significantly expand the predictability horizon. Tracking of subclonal composition through ctDNA could also inform pre-emptive therapeutic switch strategies as soon as evolving resistant subclones become detectable. By keeping the cancer cell population size small, such adaptive therapy approaches could help to restrain evolvability and the development of polyclonal resistance.Genetic analyses at the macroscale predominantly reveal mutations present in large subclones that have already been successful in evolution and provide an \u2018archaeological\u2019 record of past mutational processes. Yet, this overlooks the mutation generation ongoing at the single cell level and the heterogeneity confined to small subclones of up to a few thousand cancer cells The combined measurement of standing genetic variation and mutational processes through microscale sequencing, together with cancer cell population size estimates obtained through routine imaging, may categorize individual tumors into subgroups differing in their overall evolvability and predictability. Quantifying the size and restricting sequencing to the cancer stem cell pool will be critical in cancers maintained by stem cells to avoid population size overestimates and the erroneous interpretation of mutations confined to non-stem cells that are destined for extinction The relative fitness of genetic alterations can be illustrated as a multidimensional fitness landscape, which is a simplified graphic representation of fitness as a function of genotype The ability to observe cancer evolution repeatedly in thousands of patients with a given cancer type provides the opportunity to empirically delineate these fitness landscapes. The systematic interrogation of drug resistance genotypes already started to probe the complexity of these landscapes JAK2) and tet methylcytosine dioxygenase 2 (TET2) driver mutations were acquired in myeloproliferative neoplasms altered their biology, clinical features, and future evolutionary paths The number of patient samples that will need to be sequenced to map complex fitness landscapes in tumors with many infrequently occurring drug resistance drivers may not be achievable in practice. Large-scale mutagenesis, RNAi, and CRISPR/CAS screens of cancer cell lines Prediction approaches based on fitness landscapes could prioritize an individual cancer for pre-emptive targeting with drugs that are effective against the anticipated resistance genotypes. Similar approaches are being pursued for the prediction of antibiotics resistance and evolution in other contexts and many methods are translatable Outstanding QuestionsCan we develop realistic cancer evolution models incorporating 3D structures and empirical fitness landscapes to make predictions?What macroscale and microscale parameters need to be measured to feed these cancer evolution forecasting models?How does the strength of selection pressures influence cancer evolution trajectories?Which clinically relevant outcomes such as resistance genotype, time to resistance, probability of recurrence, or metastasis development can be forecasted most accurately?What are the most sensitive methods to detect subclones growing deterministically?How can ctDNA-based clonal dynamics analysis and rebiopsies best be combined to reconstruct empirical fitness landscapes of drug resistance evolution?How do measurement errors of the clonal composition influence predictions? Cancer is a non-linear system as a result of the ability of cancer cells to proliferate exponentially. Small measurement errors of the starting conditions may lead to major deviations in predictions from real outcomes, similar to other systems showing chaotic behavior.How can we restrain cancer evolvability to prolong time to resistance development and prevent polyclonal resistance?The development of a coherent cancer evolutionary framework that is amenable to theoretical and computational modeling is critically important to realize more accurate predictions. This model needs to incorporate the spatial constraints in solid tumors and optimal sampling approaches and parameter sets that need to be measured in a tumor to inform such predictive models need to be defined. Input parameters will most likely be tumor type-specific to take variability in growth, migration, metastasis, and driver landscapes into account. These and other questions need to be addressed to expand the predictability horizon (see Outstanding Questions). However, evolution remains centrally influenced by stochastic effects and exact measurements of the entire clonal composition of a cancer will not be possible in relevant clinical scenarios. These fundamental characteristics will continue to limit predictability in precision cancer medicine."} +{"text": "In this paper we present and discuss a novel research approach, the baseline target moderated mediation (BTMM) design, that holds substantial promise for advancing our understanding of how genetic research can inform prevention research. We first discuss how genetically informed research on developmental psychopathology can be used to identify potential intervention targets. We then describe the BTMM design, which employs moderated mediation within a longitudinal study to test whether baseline levels of intervention targets moderate the impact of the intervention on change in that target, and whether change in those targets mediates causal impact of preventive or treatment interventions on distal health outcomes. We next discuss how genetically informed BTMM designs can be applied to both microtrials and full-scale prevention trials. We use simulated data to illustrate a BTMM, and end with a discussion of some of the advantages and limitations of this approach. As advances accumulate in molecular and behavioral genetics, there is growing interest in translating those findings into practical application. Recent findings from prevention studies bolster this idea. For example, candidate gene variability moderates the impact of family-based interventions designed to reduce risk for adolescent substance use design, that holds substantial promise for advancing this agenda. In particular, we suggest that this design will be more likely to help us answer the general question of which preventive interventions work best for what groups, and why that might be so. We begin by discussing how genetically informed research on developmental psychopathology can be used to identify potential intervention targets. We then describe the BTMM design and its promise in determining whether those proximal targets mediate causal impact of preventive interventions on distal health outcomes, through combining tests of both moderation and mediation in longitudinal designs. We next discuss how genetically informed BTMM designs can be applied to both microtrials and full-scale prevention trials. We end with a discussion of some of the advantages and limitations of this approach.Prevention science has a long history of using findings from developmental psychopathology to identify proximal intervention targets. Prevention scientists focus on evidence concerning mechanisms that increase risk for future emotional or behavioral disorders, as well as mechanisms that protect people in the face of such risk. Risk and protective mechanisms must also be placed in developmental context, given evidence that risk trajectories can start early and be modulated by events occurring through childhood and adolescence. And for such mechanisms to be of use for prevention scientists, they must be malleable enough to be altered by intervention technologies allow for direct modeling of change in both targets and health outcomes, where change in the former (between baseline and post-test) precedes change in the latter (between post-test and follow-up). Perrino et al. found thAn expanded mediational design allows for statistical tests of lagged change-to-change mediation . This model increases plausibility that targeted mechanisms are having a causal impact on outcomes. Modeling the association between change in target and change in outcome is more consistent with a counterfactual account of cause involves a series of sequential mediators that transmit the effects of preventive intervention to distal health outcomes. Chaining is common in developmental theories, and is often essential to understanding the effects of early risk or protective mechanisms on later outcomes. This can be of particular importance for health conditions that emerge only at later points in development. For example, McClain et al. used lonBaseline target moderated mediation designs can be informed by genetic data in several ways. There has been a recent spate of laboratory experiments demonstrating genetic moderation of highly proximal target response to environmental manipulation. For example Lonsdorf et al. found thThe malleability and practical utility of such targets can be tested more comprehensively through microtrial methods , condition (parameter = \u22120.30), and the random effect carrying information on condition by target interaction (parameter = \u22120.30). These values were chosen to reflect the situation where control and intervention conditions showed little change in the target when baseline values were low, the control group showed almost no increase in rates of change in the target regardless of baseline levels, but the intervention group showed increasing rates of change as baseline levels increased. These effects reflect the pattern of moderated mediation predicted when an intervention successfully shapes a putative target. And finally, the baseline target was regressed on the genetic variable, with a parameter of 0.30.We used the MPLUS Monte Carlo facility to estimate and combine results from all 1000 datasets, using the model illustrated in Figure Baseline target moderated mediation designs capitalize on random assignment to prevention condition in order to buttress causal inference concerning intervention effects on both proximal targets and distal health outcomes. However, this does not extend to tests of moderation or mediation (VanderWeele, Similar issues arise concerning paths from mediators to outcomes (Imai et al., A number of years ago Sandler et al. advocateIn summary, we suggest that BTMM designs and associated statistical models hold great promise for translating studies of gene-environment dynamics into prevention science. They also provide a means of testing how and when specific proximal targets of preventive intervention will have maximal impact on distal health outcome, and as a result can guide refinement of next generation prevention trials. And, given current standards for measuring both targets and outcomes at baseline as well as at post-test and follow-up, they can be easily implemented within current prevention trial designs with little or no extra cost.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Low neighbourhood walkability has been associated with chronic conditions such as obesity and diabetes, but the relationship between neighbourhood walkability and incident childhood asthma has not been determined.We evaluated the association between neighbourhood walkability and incident childhood asthma using prospectively-collected administrative data at the Institute for Clinical Evaluative Sciences. Among the 1997-2003 birth cohorts of children living in Toronto, neighbourhood quintile of walkability was reported using a validated walkability index with 4 dimensions: population density, dwelling density, access to services and street connectivity. Incident asthma was defined by the time of entry into the Ontario Asthma Surveillance Information System (OASIS) database, requiring 2 outpatient visits for asthma within 2 consecutive years or any hospitalization for asthma. Sex and neighbourhood income quintile were obtained from the Registered Person\u2019s Database. Histories of preterm delivery, obesity and other atopic conditions were obtained from Ontario Health Insurance Plan records. We calculated the associations between incident childhood asthma and the two lowest versus the two highest neighbourhood walkability quintiles using Cox proportional and discrete-time hazard models.Twenty-one percent of the 326 383 children met the OASIS criteria for asthma. After adjusting for sex, preterm delivery, obesity, atopic conditions and neighbourhood income quintile, children with low home neighbourhood walkability at birth were at increased risk of asthma development , and the association did not change for children with healthcare visits for asthma in the past year . When walkability in each year of the child\u2019s life was considered, low neighbourhood walkability was associated with increased odds of incident childhood asthma . These associations were not substantially affected by year of birth within the cohort.Children living in neighbourhoods with low walkability are at increased risk of incident childhood asthma after adjusting for neighbourhood and individual characteristics. The association persists for children with visits for asthma within the past year. Possible mechanisms of this association include more physical activity, fewer weight problems and decreased exposure to traffic-related air pollution in more walkable neighbourhoods. Our findings suggest that promotion of neighbourhood walkability may offer a strategy for primary asthma prevention. Walkability of existing neighbourhoods may be improved by encouraging greater placement of services such as banks and grocery stores within walking distance of residential neighbourhoods and adding pedestrian paths between roads to improve street connectivity."} +{"text": "The blooming of incidence and prevalence of \u201cprosperity diseases\u201d among the broad layers of modern day populations is rather novel phenomenon in demographic history of the human race . IllnessThe ultimate demographic transition consisting of ascending portion of elderly, falling fertility rates, and bold growth of median age within contemporary nations became broadly recognized as population aging . Most ofThe increasing awareness on approaching of almost unbearable burden of NCDs led to tThe blossoming of prosperity disease did not happen suddenly. It was a consequence of long chain of evolutionary events in civil society development. We will mention only some of them such as technological revolution, improved housing conditions, sanitation and sewage disposal, public health successes in eradication of major infectious diseases, policy efforts to tackle hunger and starvation among the world\u2019s poor, and ultimately tobacco and alcoThe most challenging issue for the emerging markets\u2019 health systems appears to be universal health coverage . These sAs witnessed by current WHO estimates given in Table Catastrophic household expenditure presents particularly crucial issue throughout the countries of Sudanese Africa with very low incomes, whose medical care is dominantly supported by out-of-pocket spending . This haThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Current evidence suggests that pigs were first domesticated in Eastern Anatolia during the ninth millennium cal BC before dispersing into Europe with Early Neolithic farmers from the beginning of the seventh millennium. Recent ancient DNA (aDNA) research also indicates the incorporation of European wild boar into domestic stock during the Neolithization process. In order to establish the timing of the arrival of domestic pigs into Europe, and to test hypotheses regarding the role European wild boar played in the domestication process, we combined a geometric morphometric analysis of 449 Romanian ancient teeth with aDNA analysis. Our results firstly substantiate claims that the first domestic pigs in Romania possessed the same mtDNA signatures found in Neolithic pigs in west and central Anatolia. Second, we identified a significant proportion of individuals with large molars whose tooth shape matched that of archaeological (likely) domestic pigs. These large \u2018domestic shape\u2019 specimens were present from the outset of the Romanian Neolithic through to later prehistory, suggesting a long history of admixture between introduced domestic pigs and local wild boar. Finally, we confirmed a turnover in mitochondrial lineages found in domestic pigs, possibly coincident with human migration into Anatolia and the Levant that occurred in later prehistory. The temporal pattern of the genetic and morphometric signatures, combined with the existence of individuals possessing molars with conflicting wild and domestic identifications, suggests that the most parsimonious explanation is not independent domestication of European wild boar, but instead, reciprocal gene flow between local wild populations and introduced domestic stocks.By simultaneously investigating size, shape and mtDNA signatures in ancient pig specimens from the Mesolithic to Iron Age, our dataset has begun to reveal the shifting spatial and chronological complexity of phenotypic and genotypic signatures that resulted when non-endemic domestic pigs came into contact with the indigenous European wild boar. Subsequent analyses incorporating not just more samples, but also additional techniques including genome sequencing, will further reveal the increasingly complex narrative of domestication, human-assisted transport, gene flow and population replacement that has just begun to be deciphered."} +{"text": "Oil extraction may cause extensive environmental impact that can affect health of populations living in surrounding areas. Large populations are potentially exposed to oil extraction related contamination through residence in areas where oil extraction is conducted, especially in low and middle income countries (LMICs). Health effects among people residentially exposed to upstream oil industry contaminants have been poorly studied. Health effects of exposure to oil related contamination have been mainly studied among cleanup workers after oil spills from tankers or offshore platforms.In this paper we aim to identify the type and extension of residential exposures related to oil extraction activities and to comment on the few health studies available. We estimated that 638 million persons in LMICs inhabit rural areas close to conventional oil reservoirs. It is relevant to specifically study people residentially exposed to upstream oil industry for the following reasons: First, persons are exposed during long periods of time to oil related contamination. Second, routes of exposure differ between workers and people living close to oil fields, who can be exposed by ingestion of contaminated waters/foods and by dermal contact with contaminated water and/or land during daily activities . Third, individuals potentially more susceptible to the effect of oil related contamination and not normally occupationally exposed, such as infants, children, pregnant women, elderly or people with previous health conditions, are also exposed.There are few papers studying the potential health effects of residential exposure to oil related contamination, and most of them share important limitations. There is a need for more research through the conduct of methodologically robust studies in exposed populations worldwide. Despite the difficulties in the conduct of studies in remote areas, novel approaches, such as measurement of individual exposure using biomarkers of exposure and effect, should be used. These studies should be promoted to understand the health risks associated to residential exposure to oil related contamination, support effective control policies to avoid such contamination and to sustain public health recommendations and policies to avoid exposure in already contaminated areas. Oil extraction may cause extensive environmental contamination and this may affect the health of population living in surrounding areas . The heaOil industry includes search of oil fields and extraction of crude oil to the surface, transport and storage of crude oil or refined petroleum products and the refinery and process of crude oil. Each of these phases lead to different exposures for human populations. There are no solid data on the overall population living close to oil facilities. We estimated that 638 million persons in LMICs inhabit rural areas close to conventional oil reservoirs Fig.\u00a0. We estiThe most common acute effects reported after exposure to oil spills among cleanup workers are respiratory, eye and skin symptoms, headache, nausea, dizziness and fatigue. Chronic effects include psychological disorders, lower respiratory tract symptoms and reduction of lung function. Genotoxicity and alterations in hormonal status have also been described . High leThe health effects among people residentially exposed to oil extraction related contamination have been poorly studied. Evaluating these populations is important for several reasons: First, there are large populations living close to oil fields and persons are exposed during long periods of time. Most of the active oil fields are 50-years old, but could be active for longer . Second,There are 11 studies examining potential health effects of exposed communities. Ten of these studies have been conducted in the Ecuadorian and Peruvian Amazon \u201316 and o2), sulphur dioxide (SO2), PAHs and benzo[a]pyrene [Oil extraction related contamination leads to exposure to a mixture of contaminants. Produced waters originate in the natural oil reservoir and are separated from oil and gas in the production facility. Produced waters represent the major petroleum\u2013derived waste . They coa]pyrene .In remote areas of LMICs environmental legislation is less restrictive and control by supervisory bodies may be lacking . The actLarge populations are potentially exposed to oil extraction related contamination through residence in areas where oil extraction is conducted, especially in LMICs. Adverse health effects of exposure to oil extraction related compounds are known among oil industry workers and oil spills cleanup workers , but the"} +{"text": "Chronic kidney disease and upper tract urothelial carcinomas display a bidirectional relationship. Review of the literature indicates that early diagnosis and correct localization of upper tract urothelial carcinomas in dialysis patients and kidney transplant recipients are important but problematic. Urine cytology and cystoscopy have limited sensitivity for the diagnosis of upper tract urothelial carcinomas in dialysis patients. Enhanced computed tomography and magnetic resonance imaging could prove useful for the detection and staging of upper tract urothelial carcinomas in dialysis patients. Renal ultrasound can detect hydronephrosis caused by upper tract urothelial carcinomas in kidney transplant recipients but cannot visualize the carcinomas themselves. High detection rates for upper tract urothelial carcinomas in kidney transplant recipients have recently been demonstrated using computed tomography urography, which appears to be a promising tool. To detect carcinomas in dialysis patients and kidney transplant recipients as early as possible, regular screening in asymptomatic patients and diagnostic work-up in symptomatic patients should be performed using a combination of urological and imaging methods. Careful assessment of subsequent recurrence within the contralateral upper urinary tract and the urinary bladder is necessary for dialysis patients and kidney transplant recipients with upper tract urothelial carcinomas. HowA variety of urological and imaging methods have been employed traditionally in the diagnosis of UCs and UTUCs in KTRs, but they are all characterized by certain shortcomings , 51, 53.With advancements in imaging technology, CT urography is now a promising tool for the detection of UTUCs in KTRs. CT urography has high specificity (93\u201399%) and moderate-to-high sensitivity (67\u2013100%) in hematuria patients with sufficient renal function , 54\u201361. A pretransplantation survey of the urinary tract using cystoscopy, CT urography, renal ultrasound, and urine cytology should be conducted to exclude the presence of UC in renal transplantation candidates. The shortest interval between subsequent UC diagnosis following renal transplantation has been reported to be 2 months, suggesting that these UCs probably existed prior to renal transplantation , 37, 38.CKD and UTUC share a bidirectional association. Analgesics and aristolochic acid are common risk factors for CKD and UTUCs due to their nephrotoxic and carcinogenic effects. The ban on aristolochic acid containing medicines and foods to decrease aristolochic acid nephropathy and associated UTUCs has become an important global public health issue. Early and correct diagnosis of UTUCs in dialysis patients and KTRs is important but difficult. Urine cytology and cystoscopy have limited sensitivity for the diagnosis of UTUCs in dialysis patients. Enhanced CT and MRI could prove useful for the detection and staging of UTUCs in dialysis patients. Renal ultrasound is useful to detect hydronephrosis in KTRs with asymptomatic UTUCs; however, hydronephrosis is not specific to UTUCs. CT urography represents a promising tool to detect UTUCs in KTRs due to its high detection rate. Prior to renal transplantation, a urinary tract survey should be performed for the early detection of preexisting UTUCs. Regular screening of asymptomatic patients and diagnostic work-up for symptomatic patients using a combination of urological and imaging methods should be performed to achieve early diagnosis of UTUCs in dialysis patients and KTRs. Careful assessment of subsequent recurrence within the contralateral upper tract and the urinary bladder is essential in dialysis patients and KTRs with UTUCs."} +{"text": "TRACERx, a prospective study of patients with primary non-small cell lung cancer, aims to map the genomic landscape of lung cancer by tracking clonal heterogeneity and tumour evolution from diagnosis to relapse. The importance of intratumour genetic and functional heterogeneity is increasingly recognised as a driver of cancer progression and survival outcome. Understanding how tumour clonal heterogeneity impacts upon therapeutic outcome, however, is still an area of unmet clinical and scientific need. TRACERx , a prospective study of patients with primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through multiregion and longitudinal tumour sampling and genetic analysis. By following cancers from diagnosis to relapse, tracking the evolutionary trajectories of tumours in relation to therapeutic interventions, and determining the impact of clonal heterogeneity on clinical outcomes, TRACERx may help to identify novel therapeutic targets for NSCLC and may also serve as a model applicable to other cancer types. TRAcking non-small cell lung Cancer Evolution through therapy [Rx], ClinicalTrials.gov number, NCT01888601), is a prospective study in primary non-small cell lung cancer (NSCLC), which through multiregion and longitudinal tumour sampling and sequencing, aims to define the genomic landscape of NSCLC and to understand the impact of tumour clonal heterogeneity upon therapeutic and survival outcome.Each patient's cancer has a unique genomic landscape, often comprised of populations of genetically distinct, separated subclones with the potential to undergo dynamic evolutionary processes throughout the disease course Lung TRACERx incorporates longitudinal sample collection from diagnosis to relapse in order to investigate how each cancer responds to treatment, the potential mutational processes and mechanisms involved in drug resistance, and development of metastatic disease. Although here we discuss TRACERx in NSCLC, the proposed longitudinal sample collection and study template is also relevant to other tumour types. TRACERx, conducted across six sites in the United Kingdom , will enrol 842 patients with primary NSCLC stages I-IIIA over an accrual period of four years with a total five-year follow-up per patient. Primary surgically resected NSCLC tumours and associated lymph nodes, surplus to diagnostic requirements, will be subject to multiregion sampling and subsequent whole-exome and/or whole-genome sequencing. In patients suffering disease recurrence, consent will be obtained for a further biopsy to assess how the tumour clonal structure has changed through therapy and disease progression. The primary objectives of TRACERx are to determine the relationship between intratumour heterogeneity and clinical outcome , and to establish the impact of adjuvant platinum-containing regimens on intratumour heterogeneity in relapsed disease. The secondary objectives include developing and validating an intratumour heterogeneity index as a prognostic or predictive biomarker and identifying drivers of genomic instability, metastatic progression, and drug resistance by identifying and tracking the dynamics of somatic mutational heterogeneity. TRACERx also aims to define clonally dominant drivers of disease to address the role of clonal driver dominance in targeted therapeutic response, and to guide lung cancer treatment stratification. The sample collection per patient and overall study schema are summarised in Previous efforts to characterise the cancer genome of NSCLC have involved the analysis of copy number alterations Lung cancer is a histologically highly heterogeneous disease. Mixed lung tumours containing more than one histological type, such as adenosquamous tumours, combined small-cell tumours , or tumours with areas of histological dedifferentiation are not uncommon. Within adenocarcinomas, histological variety is the rule, with most tumours showing a mixture of patterns, the commonest being lepidic/in situ, acinar, solid, papillary, and micropapillary. Solid and micropapillary patterns are associated with worse outcome It is unclear why adjuvant chemotherapy following surgery for primary NSCLC is effective in some patients but not in others. An increasing body of evidence supports the association of patterns of intratumour heterogeneity, in multivariate analyses, with poor survival outcome in NSCLC and other solid tumours Deep sequencing analyses are revealing vast clonal heterogeneity present in solid tumours, including NSCLC, and the spatial and temporal dynamics of cancer subclones that emerge during the disease course and following acquired drug resistance Whilst evidence suggests that intratumour heterogeneity may significantly limit the antitumour activity of targeted therapeutics Primary and metastatic tumours will be genetically profiled to identify clonal and subclonal driver mutations. However, our analysis of the primary tumour is limited to tissue surplus to diagnostic requirement, albeit multiregional, and our analysis of metastatic sites is likely to be restricted to one location, emphasising the need to develop less invasive approaches to follow tumour evolution. Circulating biomarkers have the potential to monitor minimal residual disease, forecast early progression, and document subclonal evolution through therapy and acquired drug resistance There is a pressing need to define early driver events suitable for clinical drug trial stratification and to assess prospectively the role of drug target intratumour heterogeneity in the early emergence of resistance and poor DFS outcomes. Until recently, the term \u201cactionable mutation\u201d was used to define the presence of a somatic mutation or copy number event in a single tumour biopsy that might suggest a targeted therapeutic approach. However, emerging evidence for intratumour heterogeneity in breast cancer Clonal diversity between primary and metastatic tumours in the same patient has been demonstrated in different tumour types, including but not limited to, breast The importance of intratumour heterogeneity is increasingly recognised as a driver of tumour progression, drug resistance and treatment failure in solid tumours TRACERx is not without its limitations. In determining the full extent of intratumour heterogeneity, we are reliant on tissue collected surplus to diagnostic requirements, and therefore entire tumours are not sequenced. However, with deep sequencing and multiregion sampling, together with retrospective genomics analysis of residual surplus tumour tissue guided by the metastatic sample datasets, we hope to achieve significant coverage of the relevant tumour genomic landscape within each patient. Analysing circulating biomarkers, such as cfDNA and CTCs, may further complement the tumour sequencing data and identify additional genetic aberrations not detected by primary or metastatic tumour sequencing. We anticipate that a biopsy of a metastatic site may not be appropriate in all patients, but having taken into account expected rates of attrition, we will have a sufficient number of cases to meet the study outcome objectives. Finally, our ability to detect subclonal somatic events occurring at low variant allele frequencies is limited by the power of our existing methods, but as sequencing and bioinformatics methods advance, TRACERx will adapt to incorporate such improvements in technologies, including the use of deep whole-genome sequencing datasets in some cases with no clear genetic driver events. Overall, TRACERx aims to develop an understanding of the genomic landscape of NSCLC through the disease course and the biological role of underlying genetic events that might contribute to disease progression. Optimising understanding of NSCLC evolutionary processes may help to identify novel therapeutic targets to improve clinical outcomes. As the cost of sequencing decreases and informatics techniques advance, such large-scale longitudinal genomic studies may become a central component to the delivery of precision cancer medicine."} +{"text": "Information processing in the cerebral cortex requires the activation of diverse neurons across layers and columns, which are established through the coordinated production of distinct neuronal subtypes and their placement along the three-dimensional axis. Over recent years, our knowledge of the regulatory mechanisms of the specification and integration of neuronal subtypes in the cerebral cortex has progressed rapidly. In this review, we address how the unique cytoarchitecture of the neocortex is established from a limited number of progenitors featuring neuronal identity transitions during development. We further illuminate the molecular mechanisms of the subtype-specific integration of these neurons into the cerebral cortex along the radial and tangential axis, and we discuss these key features to exemplify how neocortical circuit formation accomplishes economical connectivity while maintaining plasticity and evolvability to adapt to environmental changes. Information processing in the neocortex relies on a highly ordered cytoarchitecture and its neuronal assembly to serve higher cognitive functions, such as perceptions, voluntary movements, and language. Neocortical neurons are organized into six major layers along the radial axis, which are further modified tangentially across areal and columnar subdivisions. These laminar and tangential organizations are key aspects of the cerebral cortex and are conserved among mammalian species, and they are thought to underlie the increase in neuronal numbers and expansion of the neocortex during evolution Rakic, . While tA major challenge in neocortical development is to efficiently recruit diverse cell types into its circuitry through the cost-effective production and wiring of individual neuronal elements. As dendrites and axons occupy the dominant fraction of the neocortical volume , which differ in their connectivity, dendritic morphology, and molecular character. Second, the movement of cells from their place of birth to their final destination is an essential step to recruit these diverse neurons into the circuit and accommodate massive numbers of neurons within a restricted head volume.In early development, the cerebral cortex starts from a simple neuroepithelial sheet at the anterior neural tube. This sheet gives rise to two major cell types of the neocortex, neurons and glia. The former are further classified into glutamatergic projection neurons and GABA (\u03b3-aminobutyric acid)-ergic interneurons, which participate directly in the cortical circuit through the excitation and inhibition of distal and proximal target neurons, respectively. The glia, in turn, which include astrocytes and oligodendrocytes, play pleiotropic roles in shaping the cortical circuit by modulating its activity and glutamate transporter (GLAST) in the rostral cortex. This delay results in the tangential expansion of prefrontal areas in the Fgf10 mutants cells and subplate (SP) neurons and form a transient structure called the preplate (PPL) above the VZ. CR cells were first recognized through their expression of secretory glycoprotein, Reelin (Reln) axons fail to innervate their normal targets, which are layer 4 thalamorecipient neurons in the visual cortex of newly generated layers of 6 to 2/3 neurons above their recently diverged siblings. In this view, the longitudinal radial glia serve as the warp and horizontally piled layer neurons serve as the weft to enable compacted neuronal accumulation and stratified CP. This process facilitates the efficient compression of massive number of neurons within a hard-boned skull-constrained space. RGCs, CR cells, and SP cells are also characteristic cell types of mammalian vertebrates, indicating that the appearance of these scaffolds instructed a neocortex-type laminated brain structure specifically in mammals. The numbers of CR cells and SP cells also expand during the course of mammalian evolution, suggesting that these neurons may have contributed to robust intercortical connectivity in primates showed that UL progenitors are unable to bypass DL competence for their production even at the latest period of corticogenesis identity genes play redundant roles in repressing astrocyte identity during early- to mid-stage corticogenesis, where compound knockout of Neurog1 promoter in a developmental stage-dependent manner, suppress the Neurog1 locus to restrict the neuronal competence of progenitors and promote the transition from neurogenesis to gliogenesis protein-mediated epigenetic mechanisms play key roles in this transition. PcG proteins, which repress the The latest transition from neurogenesis to gliogenesis also requires feedback mechanisms that instruct progenitors to switch competence from neurogenic to gliogenic progenitors. It has been reported that Fgf9, which is upregulated in postmitotic neurons during the later phase of the corticogenesis period, enhances the switch to gliogenic competence. In this regard, Sip1, which suppresses the expression of Fgf9 during the neurogenic period, is gradually downregulated during the progression of corticogenesis, which derepresses Fgf9 expression and facilitates the gliogenic competence transition within the SVZ exhibits the acceleration of these neurons to migrate toward the CP and ephrin A (Efna) signaling are essential for the assembly of cortical columns through the lateral dispersion of clonally related neurons are segregated in periodic arrangements across the tangential dimensions and gene duplications of FOXG1 have been associated with phenotypes including developmental epilepsy, agenesis of the corpus callosum, microcephaly, and speech impairment (O'Roak et al., TBR1 as the most connected ASD gene within the key convergence point in human midfetal layers 5/6 projection neurons (Willsey et al., de novo mutations, were assessed by introducing the corresponding TBR1 gene mutations into HEK293 and SHSY5Y cell lines (Deriziotis et al., SATB2, an evolutionary conserved chromatin remodeling gene that is activated in UL neurogenesis and required for callosal projection subtype determination (Section Deep-layer to Upper-layer Neurons and Figure SATB2 haploinsufficiency has been associated with significant speech delay and cognitive defects (FitzPatrick et al., The increased number of genes identified in their functions for the generation and integration of neocortical subtypes, has provided molecular link between neurological disorders with corresponding gene mutations and mechanisms underlying pathogenesis. Apart from the aforementioned fragile X syndrome causative gene Taken together, subtle mutations in the corresponding genes can result in profound neurodevelopmental disorders in humans; however, studies in mouse neocortex have also revealed a high compensatory feature of neurogenesis upon robust ablation of its subpopulations. Up to 84% of CR cell ablation does not demolish Reln expression in the neocortex (Tissir et al., Neocortical assembly is a highly intricate process that requires multiple layers of regulation in cell behavior at the progenitor and postmitotic cell stages. The emerging picture of neocortical assembly is that while the identities of neuronal subtypes are largely determined at birth, the mechanisms by which these neurons are navigated to their final positions involve cell type- and context-dependent combinatorial codes that enable their precise integration into the neocortical circuit. While the original finding indicated that neural stem cells undergo progressive restrictions in cell competence to sequentially produce the principal layer types (Frantz and McConnell, The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Abiotic stresses are the major causes that limit productivity of crop plants worldwide. Plants have developed intricate machinery to respond and adapt over these adverse environmental conditions both at physiological and molecular levels. Due to increasing abiotic stress constraints, plant biotechnologists and breeders need to devise and employ new approaches to improve abiotic stress tolerance in crop plants. Although the current research has divulged several key genes, gene regulatory networks and quantitative trait loci (QTLs) that mediate plant responses to various abiotic stresses, the comprehensive understanding of this complex trait is still not available. With an objective to understand the plant response/adaptation to various abiotic stresses, a special issue was planned for the journal. The current research topic \u201cAbiotic Stress: Molecular Genetics and Genomics\u201d has a combination of primary research articles, perspective, opinion and review work, written by authorities in their respective fields. These articles provide novel insights and detailed overviews on the current knowledge into different aspects of plant responses and adaptation to abiotic stresses.The perspective article by Henry presentsTwo review articles function as calcium sensors and modulate the activity of CBL-Interacting Protein Kinases (CIPKs). The CBL-CIPK network helps maintaining proper ion balances during abiotic stresses. The CBL and CIPK homologs are present in all green lineages and phylogenomic analysis suggests their expansion from a single CBL-CIPK pair present in the ancestor of modern plants and algae (Kleist et al., In summary, the articles presented here emphasize the involvement of a variety of genes/pathways and regulatory networks in abiotic stress responses. The broad-range of articles involving genomics and breeding approaches deepen our existing knowledge about this complex trait. Further, despite the existing comprehensive knowledge in this area, many questions still remain unaddressed. With the climate change threat, depletion of natural resources and ever increasing global population, sustainable and higher crop production is greatly needed. Therefore, there is an urgent need to employ various approaches and their integration to understand the molecular basis of abiotic stress response and adaptation for the development of stress-tolerant crop varieties.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "However, most thermoregulation models are validated for Tskin,mean under laboratory setting. The objective of this study is to investigate the challenges of simulating distal skin temperatures Tskin,distal during walking.Thermal sensation models require a high quality prediction of local skin temperatures (Tskin) of human subjects is measured at 15 sites , clothing models should differ between sensible and latent heat transport from the skin to the clothing and from the clothing to the environment. Furthermore, experiments are required to quantify the local evaporative resistances more accurately."} +{"text": "Climate change is profoundly affecting the evolutionary trajectory of individual species and ecological communities, in part through the creation of novel species assemblages. How climate change will influence competitive interactions has been an active area of research. Far less attention, however, has been given to altered reproductive interactions. Yet, reproductive interactions between formerly isolated species are inevitable as populations shift geographically and temporally as a result of climate change, potentially resulting in introgression, speciation, or even extinction. The susceptibility of hybridization rates to anthropogenic disturbance was first recognized in the 1930s. To date, work on anthropogenically mediated hybridization has focused primarily on either physical habitat disturbance or species invasion. Here, I review recent literature on hybridization to identify how ecological responses to climate change will increase the likelihood of hybridization via the dissolution of species barriers maintained by habitat, time, or behavior. Using this literature, I identify several cases where novel hybrid zones have recently formed, likely as a result of changing climate. Future research should focus on identifying areas and taxonomic groups where reproductive species interactions are most likely to be influenced by climate change. Furthermore, a better understanding of the evolutionary consequences of climate-mediated secondary contact is urgently needed. Paradoxically, hybridization is both a major conservation concern and an important source of novel genetic and phenotypic variation. Hybridization may therefore both contribute to increasing rates of extinction and stimulate the creation of novel phenotypes that will speed adaptation to novel climates. Predicting which result will occur following secondary contact will be an important contribution to conservation for many species. As early as the 1930s, biologists recognized that anthropogenic disturbance could result in hybridization between two previously isolated species Wiegand . In his The long-term ecological consequences of climate change are profound and range from the decoupling of species interactions formed following a 200 km northern range shift by southern flying squirrels into the range of northern flying squirrels within the last 15 years is likely the result of a range expansion by brown hares northwards into formerly allopatric mountain hare habitat taxa advances faster than the lagging edge of a retreating northern (or higher latitude) sister taxa resulting in contact at the range margins. Whether or not there is a general expectation that leading edges will expand faster than lagging edges is currently unclear. A few studies have suggested that northern edges are expanding more quickly than southern edges have retracted. For example, Parmesan et al. have fouLepus timidus) in the Smokey Mountains had previously been attributed to the end of intensive logging as the southern parental species expands its range may also be driven by climate change have increased the amount of area occupied because their total habitat breadth has increased over the last 20 years is often influenced by climate. The effect of climate change on phenology is already being observed in numerous taxa is inversely correlated with the size of the ephemeral ponds in which they breed (Pfennig and Simovich Spea multiplicata) males expressed by female Plains spadefoot toads in low water conditions Fig. and Plai Pfennig . Because Pfennig . As pond Pfennig may resu Pfennig .Lepus europaeus) and mountain hares (L. timidus) has been documented at the northern extent of the range of brown hares, and hybridization frequency is correlated with the relative abundance of each species and rock ptarmigan (L. muta) in Scandinavia . The temperatures at some nesting beaches used by several species of marine turtles are currently high enough to yield heavily female-biased clutches and a native species , temperature is shown to have an impact on locomotion, suggesting that future climate change may facilitate the spread of the hybrid swarm and cultivated (Raphanus sativus) radishes can perform better in a novel environment well outside the current invasive range.First, hybridization can exacerbate extinction risk for many species. Currently, hybridization between native and invasive species is a major conservation concern are found in more extreme environments than any parental species in environments that would otherwise be too arid for population persistence . This database could be used to identify sympatric species pairs that are becoming more similar in reproductive timing and hence overcoming temporal barriers. As above, this work would begin to identify both taxa and regions where climate-mediated hybridization is most likely to occur. Both the biogeographic models above and phenological data can also be used to establish more definitively whether hybridization will be more likely in the future.Second, the National Phenology Network is accumulating large amounts of data on reproductive timing for a wide range of taxa , males from northern allopatric populations have partially lost the ability to discriminate between conspecific and heterospecific females, suggesting that if these populations come into secondary contact as a result of climate change, hybridization will result.Third, translocation and common garden experiments will be a way of empirically testing whether species will breed and the resulting fitness of their hybrid offspring if brought into secondary contact. For example, Wellenreuther et al. found thFinally, genetic studies have already revealed a recent case of climate-mediated hybridization has recently shifted southwards with the southward range expansion of D. towndsendi, counter to climate change prediction (Krosby and Rohwer Understanding how climate change may affect hybridization is critically important in predicting community responses to climate change. Yet, this remains challenging as many studies have reported idiosyncratic responses to climate change among even closely related species (Moritz et al. Additionally, climate-mediated hybridization might allow us to observe the evolutionary dynamics of hybridization in situ. Currently, empirical studies of hybridization frequently rely on well-established hybrid zones (Rand and Harrison Recent work has estimated that a vast proportion of the Earth's biodiversity may be susceptible to hybridization, particularly as a result of human disturbance (Seehausen et al."} +{"text": "Several molecular aberrations in glioblastoma have been shown to have prognostic significance, and investigations of targeted therapies for glioma patients are ongoing. Here, Wachsberger and colleagues demonstrate that overexpression of a constitutively active form of the epidermal growth factor receptor (EGFR) found in some glioblastomas sensitizes cells to both multimodal cytotoxic therapy and cetuximab . The datDNA damage triggers a signaling cascade that affects expression, subcellular localization, and activity of mediators; the strength and nature of molecular interactions; and chromatin structure. Ongoing discovery of novel effectors has amplified understanding of the complex network that mediates the DNA damage response (DDR). Recent evidence demonstrates that genotoxic stress regulates expression of distinct microRNAs (miRNA), some of which have been shown to directly influence expression of DDR effectors including ATM, DNA-PKcs, and BRCA1. The links between miRNAs and the DDR are summarized here by Wright and colleagues, as are the implications of future investigation into this emerging field .Disparate sensitivity to the cytotoxic effects of radiation mediates selective tumor cell killing with relative preservation of normal tissues. Significant effort has been dedicated to understanding the mechanisms underlying differential radiosensitivity with the ultimate goal of enhancing the therapeutic ratio of ionizing radiation. Homologous recombinational repair is among the primary pathways utilized by cells to process otherwise lethal DNA damage, and is therefore a promising target to improve the efficacy of radiation therapy. The major pathways of double-strand break repair are summarized here by Mladenov and colleagues, as are potential targets for radiosensitizing cancer cells .Every year, more than 700 childhood cancer survivors will join the 300,000 individuals in the United States who have survived their cancer diagnoses, but will struggle with the consequences of the treatments that cured them. Twenty-five years after the first cancer diagnosis, the death rate due to subsequent malignancies exceeds that due to all other causes. Technological advances have transformed the delivery of radiation, resulting in more conformal radiation plans. We must investigate whether the benefit of decreasing acute side effects comes at a cost of lower-dose radiation distributed throughout the child\u2019s body that may increase the risk of fatal radiation-induced cancers. Braunstein and colleagues highlight such investigations into the current state of epidemiologic modeling and radiotherapy delivery data and their impacts on patient care .A comprehensive, cutting edge approach to gliomas requires first a critical understanding of the molecular underpinnings of glioma pathogenesis and response to therapy. Advances in molecular, genetic, and biochemical technologies have provided unprecedented insight into glioma biology and these are reviewed herein by Dasgupta and colleagues . TargeteRivera and colleagues explore the mechanisms underlying radiation resistance in GBM initiating cells (GICs) that are critical to enhanced therapeutic efficacy against neural progenitor cells (NPCs) The impoRecent clinical trials have demonstrated high rates of long-term local control and survival from early stage non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). Compared to conventionally fractionated radiation regimens, the success of SBRT for NSCLC suggests that hypofractionated irradiation may induce distinct molecular pathways to enhance cell killing. Using two genetically engineered mouse models of NSCLC, Perez and colleagues demonstrate superior tumor control with hypofractionated radiation. The cellular response to SBRT is incompletely understood, but the genetic reagents described here will be useful to elucidating the molecular mechanisms that underlie the SBRT DDR .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Epilepsy is one of the most common neurological disorders in humans afflicting more than 1% of the population and 65 million people worldwide and familiarity , respectively (Eichenbaum and Lipton, Understanding individual differences in morphological and connectional components of medial temporal lobe injury in TLE can lead to identification of subtypes of memory impairment, and thus help identify clinically important targets for memory augmentation. Our hypothesis is that the subtypes of memory impairment that result will preferentially respond to specific memory interventions, a notion that is also being addressed in the aphasia treatment literature (Kim et al., The application of brain stimulation in combination with specific memory rehabilitation methods (Stringer and Small, NIBS has been shown to significantly decrease seizures in individuals with treatment-resistant epilepsy (Fregni et al., While NIBS has been shown to be relatively safe, currently there is surprisingly little known about the specific mechanisms underlying the therapeutic effects (Reato et al., Future advancements in current methodologies for NIBS may provide substantial improvements during focal delivery of stimulation to the temporal lobe for memory augmentation. Also, improvements in multi-modal non-invasive techniques such as fMRI or MEG, may be able to detect neural signatures reflective of NIBS related neurophysiological changes within the hippocampus and surrounding structures that result in memory enhancement. Through the combined use of NIBS and multiunit local field potential recordings in combination with non-invasive measurements such as EEG and fMRI studies we may be able to optimize detection and determine the precise neuronal correlates of NIBS related behavioral changes. Other training techniques such as neurofeedback may also allow patients the ability to modulate electrical stimulation oscillatory activity in order to achieve improvements in memory.In summary, it will become increasingly important for future studies to build upon and elucidate the mechanism of action used in NIBS enhancement of memory. The location, parameters, and phase of delivery of NIBS may need to vary amongst individuals. Hence, systematic comparisons and consistent methodologies across studies will likely contribute to a solid understanding of NIBS and its effects on learning and memory. Resolution of these issues may be crucial as to whether NIBS based therapeutics will advance toward a useful treatment for patients with TLE related memory problems.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Pain is an outstanding problem after surgical trauma. Pain following surgery may initiate variety of mechanisms including inflammatory, visceral, or somatic in origin and may persist to be chronic pain if improperly treated. The incidence of postoperative pain has been reported to be as higher as 60%, and, despite intensive effort, it is not able to resolve completely .Most of the surgeries become less invasive and are increasingly being outpatient-based in time dependent manner. Besides technical developments on surgery, this tendency is mainly dependent on effective pain control and reduction of the side effects related to the treatments. Opioids and nonsteroidal anti-inflammatory drugs are the other main components of pain therapy which have well-known side effects that may limit their use. The modern concept of pain treatment includes multimodal approach and mainly targets to decrease opioid use in combination with other drugs or techniques in order to reduce drug related side effect profile especially to prevent postoperative respiratory depression.Until recently, there is no convincing data to demonstrate the beneficial effects of regional anesthesia on postoperative mortality, cardiovascular complications, or the incidence of thromboembolism when thromboprophylaxis is concomitantly in use, but all authors indicate that it may decrease the morbidity including postoperative pulmonary complications after major abdominal surgery and may improve the patient recovery after orthopedic surgery. It is also demonstrated that regional anesthesia reduces the incidence of postoperative pain, opioid consumption, and related side effects such as nausea and vomiting .Central neuraxial blocks alone or in combination with catheter techniques are performed in various surgical interventions in order to decrease surgically induced stress and inflammation, improve pulmonary functions, and reduce the period for ambulation with better pain control. In a meta-analysis, it has been stated that postoperative pain control with local anesthetic infusion with long term catheter placement demonstrated a decrease in the occurrence of chronic pain .Peripheral nerve blocks are the other type of regional techniques. Improvement in ultrasound technology may increase clinical applications for peripheral nerve and truncal blocks. Real time ultrasound use while performing the block may reduce the complications, performance time, and local anesthetic requirements. It also provides reappraising the older techniques with carrying potential complications. The rate of success may increase with clinical experience. Peripheral nerve blocks seem to lack systemic side effect related to sympathetic blockade and lesser incidence of minor complications including urinary retention when compared with central neuraxial blocks or catheter applications. Peripheral nerve blocks seem to be safer than either central neuraxial blocks or general anesthesia, especially in patients with severe coexisting disease .Does the addition of tramadol and ketamine to ropivacaine prolong the axillary brachial plexus block?\u201d On the same topic, the efficacy on nitroglycerine or lornoxicam combination with lidocaine for regional intravenous anesthesia was searched. Each of these drug combinations effectively increased the tolerance to the tourniquet and decreased pain during peri- and postoperative period, which is discussed in the paper entitled \u201cPeri- and postanalgesic properties of lidokain, lornoxicam, and nitroglycerine combination at intravenous regional anesthesia.\u201d Likewise, dexketoprofen or paracetamol combination with lidocaine was compared to each other for the same purpose. Addition of dexketoprofen increased the duration of motor block and decreased pain scores, and lesser analgesic consumptions were observed in groups with paracetamol or dexketoprofen when compared with the control, in the paper entitled \u201cComparison of the effect of lidocaine adding dexketoprofen and paracetamol in intravenous regional anesthesia.\u201dIn this special issue, we focused on the clinical studies and review articles related to various aspects of regional anesthesia for postoperative pain control. Some of these studies have investigated the effects of additives combined with local anesthetic mixture on postoperative analgesia in regional intravenous anesthesia. One of these reports investigated two additives, namely, ketamine or tramadol, combined with ropivacaine. While onset and duration of motor and sensorial block were shorter, the period of analgesia was longer in the tramadol group in the paper entitled \u201cThe effect of intravenous magnesium sulfate infusion on sensory spinal block and postoperative pain score in abdominal hysterectomy.\u201d In the other report, the difference of spinal block characteristics with levobupivacaine 0.5% plain solution at room and body temperature (23\u00b0C and 37\u00b0C) was observed in male patients undergoing transurethral resection of prostate operation. Authors indicated that the use of 0.5% levobupivacaine spinal anesthesia heated to the body temperature accelerated the start of sensory and motor block in the paper entitled \u201cThe effects on sensorial block, motor block, and haemodynamics of levobupivacaine at different temperatures applied in the subarachnoid space.\u201dCentral neuraxial blocks including spinal and epidural anesthesia were the subjects of the other studies. The effects of intraoperative intravenous magnesium sulfate infusion on sensorial and motor block characteristics and postoperative pain scales in female patients undergoing abdominal hysterectomy under spinal anesthesia were investigated. Authors indicated that the sensorial block period of spinal anesthesia increased, and better pain scores were observed with magnesium therapy without significant complications, in the paper entitled \u201cThe effectiveness of preemptive thoracic epidural analgesia in thoracic surgery.\u201d In a retrospective study, the difference of analgesic efficacy of epidural anesthesia was compared with total intravenous anesthesia performed with propofol and remifentanil infusion in patients who underwent abdominal aortic aneurysm repair. It was stated that the quality of analgesia improved with epidural anesthesia, and enteral nutrition was performed earlier, in the paper entitled \u201cEfficacy of continuous epidural analgesia versus total intravenous analgesia on postoperative pain control in endovascular abdominal aortic aneurysm repair: a retrospective case-control study.\u201dEpidural anesthesia was the main topic for postoperative pain control in two clinical trials. The influence of preemptive local anesthetic infusion with a thoracic epidural catheter on thoracotomy was evaluated and the effects of preemptive and postoperative infusions were compared. It was shown that preemptive administration of local anesthetic solution offered superior analgesic quality and lesser analgesic consumption, which is shown in the paper entitled \u201cThe effects of single-dose rectal midazolam application on postoperative recovery, sedation, and analgesia in children given caudal anesthesia plus bupivacaine,\u201d the effects of rectal midazolam combined with caudal anesthesia on the quality of sedation and postoperative analgesia were investigated, but no significant contribution was demonstrated.Caudal anesthesia is commonly performed in pediatric patients for surgical anesthesia and postoperative analgesia. In a clinical report entitled \u201cGabapentin in acute postoperative pain management,\u201d the influence of gabapentin treatment on postoperative pain control was documented and it was found that gabapentin was an efficacious agent for postoperative analgesia in various types of surgery.Gabapentin, a drug that is used for treatment of neuropathic pain, has also been investigated for possible effects on postoperative analgesia. In a review entitled \u201cPain is a common problem in all age groups of patients. Postoperative analgesia is a developing area and regional anesthesia is an essential part of this treatment. It is worthy of noting that future studies and technical developments about regional anesthesia will contribute vital advancements to postoperative pain control.Ahmet ErogluEngin ErturkAlparslan ApanUrs EichenbergerOzgun Cuvas Apan"} +{"text": "The protection of biodiversity is a key national and international policy objective. While protected areas provide one approach, a major challenge lies in understanding how the conservation of biodiversity can be achieved in the context of multiple land management objectives in the wider countryside. Here we analyse metrics of bird diversity in the Scottish uplands in relation to land management types and explore how bird species composition varies in relation to land managed for grazing, hunting and conservation. Birds were surveyed on the heather moorland areas of 26 different landholdings in Scotland. The results indicate that, in relation to dominant management type, the composition of bird species varies but measures of diversity and species richness do not. Intensive management for grouse shooting affects the occurrence, absolute and relative abundance of bird species. While less intensive forms of land management appear to only affect the relative abundance of species, though extensive sheep grazing appears to have little effect on avian community composition. Therefore enhanced biodiversity at the landscape level is likely to be achieved by maintaining heterogeneity in land management among land management units. This result should be taken into account when developing policies that consider how to achieve enhanced biodiversity outside protected areas, in the context of other legitimate land-uses. Halting and reversing the current and rapid loss of biodiversity is a major contemporary challenge for society ,2. BioloLagopus lagopus scotica shooting, and red deer Cervus elaphus and roe deer Capreolus capreolus stalking [Pressure on landscapes to provide multiple benefits for a range of interests mean that neighbouring land owners and managers often pursue diverse and contrasting management objectives. For example, the Scottish uplands are largely privately owned and are dominated by moorland managed for recreational shooting but are also used for sheep grazing, commercial forestry and, increasingly, conservation management \u201314. An estalking . Upland stalking .Calluna vulgaris and Erica spp) in rotation to create a mosaic of different aged stands to provide young shoots suitable as food for red grouse and older stands suitable for nesting and cover. Burning may also be employed to improve grazing for sheep. Studies have shown that rotational burning may favour some species of upland birds including curlew Numenius arquata, golden plover Pluvialis apricaria and lapwing Vanellus vanellus [Anthus pratensis, crow Corvus corone and wheatear Oenanthe oenanthe [The management of these upland areas typically differs in the extent to which four main management practices are carried out: rotational burning of heather, predator control, grazing management and conservation practices. Managing moorland for red grouse typically involves burning patches of heather , and mammalian predators is a common practice on both upland estates managed for recreational shooting and land managed by conservation organisations [The management of predators to increase survival and/or reproduction of game and conservation species is widespread \u201323. In tisations .Grazing by livestock and wild herbivores is a major driver of land-use and habitat change worldwide and can maintain or suppress vegetation diversity and associated communities depending on habitat, relative abundance of different grazers and the level of grazing \u201327. MainManagement objectives of environmental NGOs and government agencies will focus on the conservation of species, habits or landscapes. Management practices and intensity will vary depending on the organisation, but may include predator control, habitat management, population control of grazers, and rotational burning.Whilst it is straightforward to identify the activities associated with particular management objectives described above, most land owners have multiple objectives and use a variety of management practices to varying degrees depending on their main objective and geography. Therefore these broad categories can be considered as being representative of the spectrum of interventions practised by land managers in the Scottish uplands.Birds are commonly used as an indicator of biodiversity and a number of studies have looked at the effects of different moorland management objectives and practices on the occurrence and abundance of specific upland bird species. There is less information on how the different management objectives and practices affect diversity and community composition althoug2 bird survey square [Twenty six upland estates (landholdings), representing different management objectives, on mainland Scotland were surveyed for breeding birds in spring-summer 2010 . Selectery 2010) . While iry 2010) ,31. Habiry 2010) ,33. We try 2010) to estim2 areas using a modified version of the Breeding Bird Survey [For each estate, bird surveys were carried out on one to four (median = 3) 1 kmd Survey . Two parStudy sites were located on private land subject on the condition that the landowner and land holding remain anonymous. Therefore estate locations cannot be provided but, The aim of these analyses was to relate avian species diversity and community composition to the dominant management objectives and practices on heather-dominated moorland sites. Interviews indicated that the management objectives were applicable at the level of the estate not at the level of the survey square so all analyses were carried out at the estate scale. Most estates (62%) categorised themselves as having one dominant management objective, though 10 of 26 were managed for more than one dominant management objective prohibiting any direct comparison of different management objectives. All analyses were therefore carried out by comparing estates with a particular dominant management objective or activity with those estates with other objectives, for example; estates which included grouse shooting as a management objective are compared to those estates that did not include grouse shooting as a dominant management objective.Estimated percentage of heather burnt and habitat diversity were compared between estates using linear models with an identity link. To normalise model residuals we used the natural logarithm of percentage area burnt (plus one), and the natural logarithm of estate habitat diversity as the response variable. The differences in the proportion of estates carrying out different forms of predator control were compared using an Exact Binomial Test.Bird survey data were pooled for all of the survey squares on each estate. Abundance estimates were taken from the highest count of the two surveys. Abundance data were used to estimate two measures of Alpha diversity: species richness (number of species) and species diversity (Shannon-Wiener index) ,37. The Visual inspection of variograms (R-package nlme) suggeste2- tests. All analyses were carried out in R 3.2.3 [We aim to explain the effect of different land management objectives and practices on avian diversity and therefore adopt a null-hypothesis testing framework to test the significance and estimate effect sizes of explanatory variables rather t R 3.2.3 .In this study we explore relationships between community composition and particular factors (management objective) and environmental variables of interest and therefore use unconstrained ordination. We used Non-Metric Multi-Dimensional Scaling (NMDS) ,43 and pFour dominant management objectives emerged from interviews with land owners: grouse shooting; deer stalking; sheep grazing; and conservation . While tTwenty-one of the 26 estates carried out mammalian predator control and 16 carried out avian predator control; all estates that controlled avian predators also controlled mammalian predators . All estAlauda arvensis (11%). No other single species accounted for more than 5% of the observed community.In total, 58 species of bird were recorded during surveys . The uplThere was no significant effect of any management objective or practice, or percentage of burnt ground on avian species richness . EstimatDifferences in Shannon-Wiener index of species diversity, between management objective and practices were small and subject to relatively large variation and there was no significant effect of any management objective or practice on avian diversity . Avian dThere is large degree of agreement among the three ordinations used . OrdinatConservation as a dominant management objective had clear and statistically significant effects on the relative abundance of species, though the effect on absolute abundance and occurrence is less clear Tables . These eIn this study we investigated how species richness, diversity and community composition vary in relation to management objectives and practices. We found no significant effect of any management activity on overall avian diversity, however, some species and assemblages are more strongly associated with certain management types. This implies that maintaining diversity in land management at the landscape scale, at least among the management types we investigated, may help to maximise biological diversity in the wider countryside.Outside protected areas, land is managed to achieve a range of social and economic benefits and deliver food and water security, recreation opportunities and carbon storage . In ScotCircus cyaneus [Saxicola rubetra and meadow pipit are more strongly associated with landholdings not managed for red grouse.Our analysis of community composition provides insights as to how different management regimes and practices favour some species over others. Management of estates for red grouse shooting, characterised by intensive management has a strong influence on the prevalence and abundance of species found on these estates relative to estates not managed for grouse shooting. Whereas avian communities associated with estates managed for conservation and deer stalking only differed significantly in relative abundance rather than in the presence or absence of species or their absolute abundance. These results suggests that more intensive management may be beneficial for certain species, such as some wading birds, but may be less so for other species including many passerines, and that management effects the relative abundance of species rather than their occurrence per se or absolute abundance. This is further supported by the positive association of some wading birds with higher levels of prescribed burning. This confirms earlier studies that report higher abundances of some wader species on heather moorland where grouse moor management is a dominant objective ,17 where cyaneus which arGavia stellata) and riparian willow scrub in the case of willow warbler and chiffchaff (Phylloscopus collybita). This may also offer some explanation for the apparently low species richness and diversity observed on conservation landholdings where concerted management for conservation might be expected to support greater diversity. Although we selected sites on conservation focussed landholdings that were comparable with the heather moorland on the other study sites, conservation land holdings in the Scottish uplands often include areas not far from our study sites that are managed for conservation of particularly vulnerable species or groups such as woodland grouse or water birds in habitats not included in this study (e.g. native woodland regeneration). This affect may be represented in the ordination analysis which, for example, show that woodland species such as chaffinch Fringilla coelebs and willow warbler Phylloscopus trochilus tend to be associated with conservation focused landholdings.Although species richness was linked with habitat diversity in our study, it was not affected by management. The ordination results presented here also suggest that management influences abundance rather than prevalence and may indicate that species presence is more strongly influenced by factors other than those measured in this study, for example specific habitat requirements such as water bodies for red throated diver . However, 10 estates classified themselves as being managed for multiple dominant objectives, which may potentially dilute the ability of the analysis to detect the link between management objective or activity and avian diversity in this data set. The inability to disentangle possible explanatory factors is an inherent weakness of correlative studies such as ours. However it is important to investigate processes that affect biodiversity such as land management at the scale on which they act if we are to inform policies aimed at managing biodiversity in the wider countryside . Thus whEach of the management objectives and practices investigated here support different, but overlapping, avian communities suggesting that diversity in land use types and objectives within a landscape can enhance the diversity of avian species across this landscape. Land-based businesses contribute hugely to Scottish and EU economies and our results suggest that management of private land for social and economic objectives is not necessarily at odds with conservation. Although some species are currently of higher priority in policy terms, this study suggests that there are potentially significant benefits from working with land managers to ensure best practice among the diverse management types in order to deliver landscape scale biodiversity in the wider countryside ,52.S1 Fig(PDF)Click here for additional data file.S1 FileEstate and bird abundance data used in analyses.(CSV)Click here for additional data file.S1 TableAlphabetical list of all bird species recorded during surveys and indication of whether a species is included in the ordination plots Click here for additional data file."} +{"text": "The field of spondyloarthritis (SpA) has undergone substantial changes in the past decade. Increasing emphasis has been made on early diagnosis. Thus, MRI imaging has permitted new imaging modalities to detect early signs of inflammation in the axial skeleton. Additionally, much new data have emerged on the link between spinal inflammation and bone new formation, another hallmark of SpA. Classification of disease has evolved as well by focusing on the main clinical presentation and permitted to classify early forms of SpA. Early recognition facilitated early treatment regimens which showed markedly better responses in early disease and in patients with objective signs of inflammation (MRI positivity/ elevated CRP). Furthermore, there is increasing evidence that extra-articular manifestations of disease, particular gut involvement have marked impact on disease severity and long term outcome in SpA. It can be foreseen that extensive patient phenotyping will become critically important in the near future when new treatment modalities become available with differential efficacy on the various clinical features of SpA.None declared."} +{"text": "For patients who require removal of anterior teeth and their replacement various treatment modalities are available. With advancement in technology and availability of glass/polyethylene fibres, use of natural tooth as pontic with fibre reinforced composite restorations offers the promising results. The present case report describes management of periodontally compromised mandibular anterior tooth using natural tooth pontic with fibre reinforcement. A 1-year follow-up showed that the bridge was intact with good esthetics and no problem was reported. Dentists occasionally face complex situations that warrant removal of teeth from high esthetic zone. Despite wide range of treatment options that can be provided to conserve the tooth, extraction of an single anterior tooth is inevitable in case of trauma, advanced periodontal disease, root resorption, or failed endodontic therapy . FollowiConventionally, the solution to this clinical problem has been the provision of a single tooth, removable temporary acrylic prosthesis, implants, or resin bonded bridges , 4. EachA 30-year-old healthy male patient reported to the Department of Conservative Dentistry and Endodontics, MNR Dental College and Hospital, with a chief complaint of the mobility of mandibular leftcentral incisor. Upon clinical examination tooth was grade III mobile one with probing depth of 8\u2009mm. Diagnostic radiograph of the tooth revealed bone loss around the mandibular left central incisor . The diaThe tooth was extracted under local anaesthesia atraumatically Figures and 3 anThe required length of fibre strip was measured and cut. Recess grooves were prepared on the lingual surface of pontic and adjacent abutment teeth were roughened. The natural tooth pontic was stabilized with flowable composite resin on the facial surface and the wedge was placed to preserve the interdental space. Prepared surface was acid etched; bonding agent was applied and cured. A thin layer of flowable composite was placed across the grooves and abutment teeth. Precut fibre was then placed in position and pressed into the prepared grooves for its close adaptation and cured . A furthVarious treatment options were available for the replacement of edentulous space created as a result of removal of single tooth in anterior esthetic zone. Each option has its own advantages and disadvantages. Acrylic removable partial dentures which can be placed immediately after the tooth are extracted. But they may be bulky, unesthetic, uncomfortable for the patient and inadequately preserve the extraction socket which may impede healing result in loss of soft and hard tissues . The FixThe use of natural tooth as a pontic was described in literature long back. However in those earlier days these pontics were connected to the adjacent teeth with adhesive composite resins, wire, metal mesh, nylon mesh, and cast metal frameworks bonded to the adjacent teeth. The inherent problems with these materials were their inability to be chemically incorporated into the composite resin and they could not support the repeated loading stresses placed on the bridge during normal and parafunction. When the thickness of composite resin used for bonding was increased it resulted in an increase in food and plaque retention subsequently poor oral hygiene . Also duThis challenge to place a thin but strong, bondable composite resin bridge was met with introduction of fibre reinforcement by creating a chemical bond between the strengthening fibre and composite , 10. TheEverStick crown and bridge fibre consist of individual silane glass fibres. The fibres are locked to each other with linear polymers (PMMA) and cross-linking monomers (bis-GMA) to form unique and patented Interpenetrating Polymer Network or IPN structure. IPN ensures both micromechanical and chemical bonding of everStick fibres to composites, adhesives, or composite cements. The bond strength is based on the ability of the polymer matrix to partially dissolve in the resin used for bonding. The significance of this is that surfaces can be reactivated even after final polymerisation. This reactivation dissolves linear polymers and forms new chemical bonds. The resin can also penetrate deeper into the fibre matrix which improves the micromechanical retention. With these crown and bridge fibres it was possible to produce a thin but strong, composite resin bonded bridge in a single visit. This prosthesis has been referred to as Resin Bonded Fibre Reinforced Composite Fixed Partial Denture or FRC FPD. These bridges show rigidity and flexural strength 7 times that of composite resin alone .The use of fibre composite to bond natural tooth to adjacent teeth in case of isolated single tooth loss appears to be promising treatment option in immediate esthetic rehabilitation. The advantages of natural tooth pontic are its excellent shade matching, life-like translucency, and patients superior psychological acceptance."} +{"text": "Leishmania is the inadequate predictive power of the early immune responses mounted in the host against the experimental vaccines. Often immune correlates derived from in-bred animal models do not yield immune markers of protection that can be readily extrapolated to humans. The limited efficacy of vaccines based on DNA, subunit, heat killed parasites has led to the realization that acquisition of durable immunity against the protozoan parasites requires a controlled infection with a live attenuated organism. Recent success of irradiated malaria parasites as a vaccine candidate further strengthens this approach to vaccination. We developed several gene deletion mutants in Leishmania donovani as potential live attenuated vaccines and reported extensively on the immunogenicity of LdCentrin1 deleted mutant in mice, hamsters, and dogs. Additional limited studies using genetically modified live attenuated Leishmania parasites as vaccine candidates have been reported. However, for the live attenuated parasite vaccines, the primary barrier against widespread use remains the absence of clear biomarkers associated with protection and safety. Recent studies in evaluation of vaccines, e.g., influenza and yellow fever vaccines, using systems biology tools demonstrated the power of such strategies in understanding the immunological mechanisms that underpin a protective phenotype. Applying similar tools in isolated human tissues such as PBMCs from healthy individuals infected with live attenuated parasites such as LdCen\u2212/\u2212in vitro followed by human microarray hybridization experiments will enable us to understand how early vaccine-induced gene expression profiles and the associated immune responses are coordinately regulated in normal individuals. In addition, comparative analysis of biomarkers in PBMCs from asymptomatic or healed visceral leishmaniasis individuals in response to vaccine candidates including live attenuated parasites may provide clues about determinants of protective immunity and be helpful in shaping the final Leishmania vaccine formulation in the clinical trials.Despite intense efforts there is no safe and efficacious vaccine against visceral leishmaniasis, which is fatal and endemic in many tropical countries. A major shortcoming in the vaccine development against blood-borne parasitic agents such as An estimated 100,000 VL cases are reported annually in the endemic foci of northeastern India, Nepal, and Bangladesh alone and ~150 million people are at risk for infection . Vector Leishmania has gone through a long trajectory that includes phases of systematic selection of antigens, adjuvants, natural immune parameters to identify correlates of protection . SimilaSince immune cells migrate through the blood stream between lymph nodes, spleen, and peripheral tissues obtaining meaningful information of an immune response from this dynamic mix of cells remains a complex challenge. Several attempts have been made at decomposing the gene expression profile from a heterogeneous mix of cells into that of respective cell types based on unique gene expression profiles independently obtained from a pure cell population such as monocytes, lymphocytes, neutrophils, eosinophils, and basophils .With the development of genomic and proteomic tools along with advances in computational approaches, global profiling of cellular states in terms of gene and protein expression has been applied to study a broad range of immunological phenomena. These approaches have been used to study T cell activation signatures , 90, bloEven though the approaches outlined here can provide fundamental insights into the immune responses to complex pathogens, it must be noted that so far only viral vaccines were studied. In most such cases, protection is mediated by antibodies whereas clearance of parasitic pathogens needs predominantly cell-mediated immunity. The role of antibody responses in protection is at best inconclusive in human leishmaniasis . In addiLdCen\u2212/\u2212 in human PBMC in different clinical groups will provide valuable information regarding avirulence of these parasites and efficacy in terms of immune- and non-immune-related responses prior to the evaluation in human trials. Recent influenza vaccine studies substantiated that the role of non-immune parameters in protective immunity is generally under appreciated and often missed in conventional vaccine studies that measure only immunological parameters. Obtaining such information via systems biology approaches, as has been applied to study viral vaccines, will enable us to understand how vaccine-induced responses are coordinately regulated in healthy, asymptomatic infected individuals, and individuals recovered from VL. This will provide information regarding correlates of protection as well as biomarkers of safety and enable identification of immune and non-immune predictors hitherto unidentified to Leishmania antigens or live attenuated vaccine candidates in the human cells and might be useful in shaping the final vaccine formulation in the clinical trials. Studies comparing expression profiles of PBMCs from bonafide asymptomatic carriers with those that acquired protective immunity following clinical cure will likely provide biomarkers other than the IFN-\u03b3 secretion as is currently practiced. Understanding of immune modulators that confer protection in VL can lead to new targets for immune therapy.A major shortcoming in the vaccine development is the inadequate predictive power of the early immune responses mounted in the host against the vaccines. Also, for the live attenuated parasite vaccines, the primary barrier against widespread use remains safe in terms of avirulence of the parasites in host. Therefore, understanding of the pathogenesis of live attenuated parasites such as The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "For exaResearch from our laboratory has focussed on the early onset, aggressive joint destruction which occurs in the osteoarthropathy of the rare disease alkaptonuria (AKU). AKU is a single gene defect in tyrosine metabolism, which is characterised by ochronosis, the deposition of pigmented polymers in connective tissues particularly cartilage. Studying tissue samples from AKU patients and from AKU mouse models has revealed significant parallels with the pathophysiology of OA. We have discovered several previously unidentified microanatomical changes in AKU joints which were subsequently recognised in joint degeneration associated with OA and ageing. Of these the most significant are high density mineralised protrusions (HDMPs). These novel micoanatomical structures arise via the extrusion of a mineralisable matrix through cracks in the subchondral plate. Formation of HDMPS constitutes a previously unrecognised mechanism of joint destruction ."} +{"text": "A 58 year old male, known case of type 2 diabetes and hypertension, had undergone implantation of a dual chamber pacemaker(DDDR) in 2007 for complaints of recurrent syncope and trifascicular block with a normal ejection fraction andnormal coronaries. His post implantation parameters were normal at that time.He now presented to our pacemaker clinic where his ECG done showed two types o fpaced complexes. The first few complexes were consistent with atrial sensed right ventricular apical pacing with left superior axis. Later complexes showed loss of atrial sensing with pacing from right ventricular outflow tract(inferior axis) with subtle oscillation in it's axis. On application of magnet, two pacemaker spikes were visible withinterspike interval of 120 ms and paced complexes with inferior axis starting from the first spike suggesting that the atrial lead was responsible for RVOT depolarization. On interrogation of the pacemaker, atrial EGM showed sensed activity from atrium followed by large sensed ventricular complex. Fluoroscopy confirmed that the atrial lead was dislodged and was intermittently prolapsing into the RVOT. Since the patient was asymptomatic, he refused any intervention and subsequentlyhis atrial lead was switched off by telemetry. The above case signifies that asymptomatic lead dislodgement is no talways manifested as loss of capture and even subtle variation of the axis o fthe paced complexes can provide us with a clue that can be confirmed by telemetry of the pacemaker and fluoroscopy. A 58 year man presented to our pacemaker clinic for a routine follow-up visit. Previously, he had undergone implantation of a dual chamber pacemaker (DDDR) in 2007 (both leads tined) for complaints of recurrent syncope and trifascicular block on electrocardiogram. His left ventricular ejection fraction and coronary angiogram were normal. His pacing parameters after implantation, and at his last visit 4 years post-implantation, were both normal. He had been asymptomatic since then but on this visit, an interesting abnormality was recorded on the electrocardiogram (ECG) . What caThus in the initial complexes there is appropriate atrial sensed ventricular pacing proceeding from the RV apex while in the later complexes there is loss of atrial sensing with right ventricular pacing originating from the right ventricular outflow tract (RVOT) with subtle oscillations in the axis of paced QRS. On application of magnet, the following rhythm was noticed .Before application of magnet, spontaneous pacing is seen with similar QRS morphology as the latter complexes in previous figure with no atrial sensing. However a pacemaker spike is seen buried within the first two QRS complexes with interspike interval of approximately 150 ms. On application of magnet the ventricular rate accelerates to 100bpm, the QRS width varies but morphology remains same, and the interspike interval decreases to 120 ms . Thus on application of magnet, the ventricular depolarization is occurring from right ventricular outflow tract (RVOT) and presence of both the spikes with shortened interspike distance suggests that the atrial lead is responsible for this paced rhythm originating from the RVOT. As the initial complexes in On interrogation of the pacemaker, atrial lead threshold and impedance were found to be high while the ventricular lead parameters were satisfactory. The sensed and paced AV delays of the pacemaker were set at 150 and 120 ms respectively. The following electrogram (EGM) trace was obtained . The topFluoroscopy confirmed that the atrial lead was indeed dislodged and was intermittently prolapsing in the lower RVOT . A transThe ECG tracing in A delayed dislodgement of the atrial lead from the right atrial appendage was diagnosed and the patient was explained possible consequences and advised revision of atrial lead. However he refused on grounds of being asymptomatic and subsequently his atrial lead was switched off and pacemaker programmed to VVIR mode. At 3 months of telephonic follow up, patient did not report any symptoms.In the current era, the rate of lead malposition and dislodgement in a dual chamber pacemaker is around 2% . Lead diOur case was made interesting by the startling ventricular pacing complexes with alternating opposite frontal axis on ECG. Absence of AV relationship during paced complexes from RVOT with inferior axis, subtle oscillations in axis during RVOT pacing, and changing interspike distances in this case suggested a mobile right atrial lead prolapsing into RVOT. That the lead was not permanently dislodged into RV was suggested by the initial complexes in In conclusion, we report an interesting case of dislodged atrial lead with intermittent prolapse into the RVOT that presented with an uncommon ECG finding of alternate superior and inferior frontal axis of RV pacing."} +{"text": "The practice of modern anesthesiology has been developed from intraoperative period into perioperative period. Postoperative pain management is one of the most important components of adequate post-surgical patients care. This article wrote with the aim of emphasis on importance and effectiveness of post-operative pain management. Reading this article is beneficial for physicians, interventional pain managers and who care about pain medicine. Unrelieved acute pain after surgery usually elicits pathophysiologic neural alterations, including not only peripheral but also central sensitization which evolves into chronic pain syndromes. The main purpose of perioperative pain control is providing an adequate comfort level and acceptable side effects for patients. Effective postoperative analgesia improves patients\u2019 outcome as observed by early ambulation, decrease in side effects, and reduce the incidence of postoperative chronic pain -3Even though postoperative pain management and its implications have gained a significant attention in health care during last three decades, it continues to be a major challenge that still remains disregarded , 5. PostBesides, one of the most common methods for postoperative pain relief is PCA. This device is commonly assumed to imply on-demand intermittent, intravenous administration of opioids under patient control (with or without a continuous background infusion). PCA device is based on the use of a sophisticated microprocessor-controlled infusion pump that delivers a preprogrammed dosage of opioid analgesics when the patient pushes a demand button. Grass presented a more enlightened concept of PCA, noting that using any analgesic drugs under control of patient by any routes could be categorized as PCA, like patient-controlled epidural analgesia (PCEA) and patient-controlled regional analgesia (PCRA) . He propTo optimize the management of acute postoperative pain, basic mechanisms of postoperative pain must be explored and new treatments must continue to be developed. Tissue damages during surgery leads to two alterations in the responsiveness of the nociceptive system, peripheral sensitization and central sensitization. Pharmacological and non-pharmacological postoperative pain management should be started quickly to suppress the development of both peripheral and central sensitization, which involves both the primary afferent nociceptors and spinal dorsal horn neurons. Understanding the neuropharmacology of the spinal cord gives us the unbelievable opportunity to base clinical management on identified mechanisms of pain receptors, pathways, and mechanisms of action.Furthermore, evidence-based practice guidelines have the potential to provide valuable information to physicians and their patients. These guidelines not only provide guidance in routine practice, but they provide the \u201cstandard of care\u201d for the specialists. Practice guidelines for anesthesiology and pain medicine must be improved by experts in these fields using the best available data obtained from a comprehensive review of the peer-reviewed medical literature.Anesthesiology and Pain Medicine, the official journal of Iranian Society of Regional Anesthesia and Pain Medicine (ISRAPM), aims at publishing of the scientific articles submitted by all the researchers and professionals in the field of anesthesiology and pain medicine from all over the world. It would be our pleasure to take our new steps toward medical excellence."} +{"text": "Data Monitoring Committees (DMCs) are essential to the good conduct of many trials. Typically they comprise a small expert group which monitors safety, efficacy, progress and early outcome data as trials recruit. DMCs can recommend protocol revisions and early stopping of a trial. As DMC meetings usually consider unblinded interim data confidentially, they are seldom exposed to research scrutiny. An important exception was case studies presented in the DAMOCLES project.Using interviews with participants in the BRACELET Study on bereavement in neonatal intensive care trials, qualitative accounts of experiences of 18 DMC members were used to build on these earlier case studies.Interviewees considered the neonatal research populations especially vulnerable, and that outcomes that included both death and major disability were crucial for families. DMC members discussed particular difficulties of balancing the competing risks of these outcomes, especially when mortality data were available long before data on longer term disability could be collected. An additional consideration was the choice of age at which disability was assessed, as some manifestations would not become apparent in the short term. Interviewees commonly used the imagery of bravery, and described DMCs either holding or losing their nerve.DMCs for trials in other fields may also face difficult ethical trade-offs in monitoring composite outcomes. The experience from this sample of DMC members suggest that, for neonatal trials, the combination of the importance of the timing of one component of the outcome assessment, alongside the vulnerability of the population, presented particular challenges."} +{"text": "During recent years, various experimental data suggested that the functional state of the migraineur's brain fluctuates in relation with the cyclical recurrence of the migraine attack. This was historically observed with the methods of clinical neurophysiology that revealed interictal deficient habituation of any kind of sensory responses - with the notable exception of the olfaction - that was attributed to abnormal thalamo-cortical interactions and its normalization during an attack. On the other hand, studies with repetitive transcranial magnetic stimulation (rTMS), have reported interictal paradoxical cortical responses in reaction to both depressing or enhancing rTMS and their changes up to the bending point of an attack when cortical responsivity behaves differently.Such recurring changes were confirmed recently with morphological and functional neuroimaging methodologies. For instance, fMRI BOLD responses induced by painful stimuli differed between ictal and interictal scans in episodic migraine. We recently showed that cyclic changes can also be demonstrated at rest, i.e. without any sensory input, in anisotropy of thalamic microstructure, in grey matter density of temporo-parietal areas, and in interconnectivity among large scale cortical networks. The conjunction of neuroimaging and neurophysiological data can be considered as robust evidence favouring cycling morphological and functional brain alterations as prominent features of migraine pathophysiology.Both the abnormal neurophysiological information processing and morphological brain changes point to altered neural plasticity mechanisms, which prevent the immediate and longer-lasting cortical changes that allow multimodal sensory integration and reflect adaptation to headache recurrence."} +{"text": "To identify the key methodological challenges for public health economic modelling and set an agenda for future research.An iterative literature search identified papers describing methodological challenges for developing the structure of public health economic models. Additional multidisciplinary literature searches helped expand upon important ideas raised within the review.Fifteen articles were identified within the formal literature search, highlighting three key challenges: inclusion of non-healthcare costs and outcomes; inclusion of equity; and modelling complex systems and multi-component interventions. Based upon these and multidisciplinary searches about dynamic complexity, the social determinants of health, and models of human behaviour, six areas for future research were specified.Future research should focus on: the use of systems approaches within health economic modelling; approaches to assist the systematic consideration of the social determinants of health; methods for incorporating models of behaviour and social interactions; consideration of equity; and methodology to help modellers develop valid, credible and transparent public health economic model structures.The online version of this article (doi:10.1007/s00038-015-0775-7) contains supplementary material, which is available to authorized users. An increasing number of model-based assessments of the cost-effectiveness of public health interventions are being commissioned using search terms relating to economic evaluation .In order to develop an initial understanding of potential methodological issues: (1) papers relating to economic evaluation resulting from the work of the Centre for Public Health Excellence at NICE were identified by searching Medline for the names of authors identified on the NICE website; (2) the publications written by the Public Health Research Consortium, a collaboration between eleven UK institutions to strengthen the evidence base for interventions to improve health, were hand searched; and (3) a search in Medline for terms relating to problems/challenges, public health and economic modelling was undertaken. This was not limited by country. Following this initial search, key public health journals were searched , reference searching and key author searching was undertaken. The search included additional key information presented within \u201cgrey literature\u201d, including relevant working papers and presentations from workshops/conferences. The process was repeated iteratively until theoretical saturation. The search was undertaken in December 2010 and citation searching of all of the included papers was repeated in August 2013. Figure\u00a0Papers were included if they described methodological challenges associated with developing the structure of public health economic models. A relevant paper by Weatherly et al. was baseBecause of the iterative nature of the formal literature search, which used the reviewing process to enhance understanding, the reviewers\u2019 awareness of potentially relevant literature was broad in contrast to a focused Cochrane type search. Thus, during the searching and data extraction process the reviewers were aware of extensive research that had been undertaken within other disciplines that the health economics literature only briefly raised. Exploiting this broader literature offers a deeper understanding of each of these issues, which may facilitate the aim of setting an agenda for future research within the health economic context. For each such issue, either the seminal sources within that field were identified or an additional targeted search was undertaken within the relevant discipline.Fifteen articles identified from the search were considered to be relevant. The articles were divided into three categories, shown in Table\u00a0Shiell , AndersoClaxton et al. propose An opinion piece by Mooney suggestsThese papers all highlight a number of difficulties in defining relevant costs and outcomes for the evaluation. Only three of the seven studies suggest potential methods for dealing with this and all three involve presenting the model results in an alternative format, rather than how these costs and outcomes might be identified ;Valuing health inequality reduction by quantitatively weighting health outcomes according to equity considerations.The UK Government aims to increase overall health and reduce health inequities , the social determinants of health and models of human behaviour (psychology and sociology literature). This literature was explored to understand the current status of this research and to assess the research implications for public health economic modelling.A key message from the review is the methodological challenge related to public health systems being complex. Based upon seminal books about complex adaptive systems, otherwise termed dynamic complexity, and systems thinking by Miller and Page and SterA systems approach takes a holistic way of thinking about complex systems, and focuses upon the interactions amongst entities and between entities and their environment Sterman . It is rMany of the key challenges raised within the review relate to the social determinants of health and health inequities. Currently, the health economic literature gives little recognition to these relationships.Social structure is the result of individual actions (human agency) which create patterns of behaviour both individually and simultaneously to understand how society works Below is the link to the electronic supplementary material."} +{"text": "Catheter-related Bloodstream Infections (CRBSI) are most worrisome event due to the morbidity and mortality associated. Looking for elaboration of educational programs developed by nurses, revealed the following research question: \"What are the methods and teaching techniques that have proved to be effective in reducing CRBSI rates?\"To identify and to describe the methods and teaching techniques applied to training programs for healthcare workers aiming the CRBSI prevention.A Systematic Literature Review was performed following the PICO strategyTeaching Methods were assessed with their respective ability of use . Twenty-six Teaching Techniques were presented according to each category. The Verbal Technique (80%) and Dialogued Conversation (80%) showed to have higher affinity of use, respectively related to the Expository and Joint Development Methods. Ten Instructional Resources and five Analysis Methods were also assessed according to each related category and with its affinity of use.Ten studies were included among 300 gathered. Five categories of Different educational interventions found to be effective in reducing CRBSI. It was not possible to identify any one method as more effective. None of the studies included cited any specific theoretical instructional approach able to underlie their teaching technique during their training sessions. The infection preventionist needs to explore and achieve different teaching skills during educational training once the Education is one of the strategies for preventing Healthcare Associated Infections.None declared."} +{"text": "Increased abdominal imaging has led to an increase in the detection of the incidental small renal mass (SRM). With increasing recognition that the malignant potential of SRMs is heterogeneous, ranging from benign (15%-20%) to aggressive (20%), enthusiasm for more conservative management strategies in the elderly and infirmed, such as active surveillance (AS), have grown considerably. As the management of the SRM evolves to incorporate ablative techniques and AS for low risk disease, the role of renal mass biopsy (RMB) to help guide individualized therapy is evolving. Historically, the role of RMB was limited to the evaluation of suspected metastatic disease, renal abscess, or lymphoma. However, in the contemporary era, the role of biopsy has grown, most notably to identify patients who harbor benign lesions and for whom treatment, particularly the elderly or frail, may be avoided. When performing a RMB to guide initial clinical decision making for small, localized tumors, the most relevant questions are often relegated to proof of malignancy and documentation (if possible) of grade. However, significant intratumoral heterogeneity has been identified in clear cell renal cell carcinoma (ccRCC) that may lead to an underestimation of the genetic complexity of a tumor when single-biopsy procedures are used. Heterogeneous genomic landscapes and branched parallel evolution of ccRCCs with spatially separated subclones creates an illusion of clonal dominance when assessed by single biopsies and raises important questions regarding how tumors can be optimally sampled and whether future evolutionary tumor branches might be predictable and ultimately targetable. This work raises profound questions concerning the genetic landscape of cancer and how tumor heterogeneity may affect, and possibly confound, targeted diagnostic and therapeutic interventions. In this review, we discuss the current role of RMB, the implications of tumor heterogeneity on diagnostic accuracy, and highlight promising future directions. However, increasing detection of incidental SRMs, development of treatment alternatives in select patients, and the discovery of several effective biologically targeted drugs for metastatic disease have raised the awareness that pretreatment tumor histology can be useful and necessary to individualize treatment decisions,,-,,-The role of RMB has expanded to include the evaluation of complex cystic lesions, SRMs <4 cm, and determination of tumor subtype were highly inaccurate, which limited their clinical utility,-,,-,,,,,,,,,,,,RMB is a relatively safe procedure with minimal morbidity. Contemporary series reveal overall complications rates ranging from 1.4%The ultimate goal of RMB is to appropriately match tumor treatment with tumor biology, so its utility becomes dependent upon the clinical scenario encountered and the accuracy of RMB for determination of malignancy and tumor grade. The diagnostic accuracy of RMB is currently estimated at >95%,,,,,,,,,,-,,,,-Historically, many non-informative biopsies were inappropriately considered \u201cfalse-negative\u201d, representing a major criticism of RMB, in that missed malignancies would potentially remain untreated,,,,,,Inaccurate RMB, including true false-negative and false-positive results, represents the most concerning outcome for clinicians. Concern is justified, as false-negative results could lead to surveillance of a malignancy with metastatic potential. Fortunately, the rate of false-negative RMB (excluding non-informative RMB) among modern series ranges from 0% to 3.8%,,,,Concern for a coexisting malignancy in otherwise benign tumors is also a significant barrier to routine RMB, undermining the validity of RMB and likely deterring its routine use,,,,,,,,,Histological subtype and grade are known prognostic factors in renal carcinoma and potentially important in the staging and management of small renal cancers-in situ hybridization to evaluate chromosomal abnormalities increased the diagnostic accuracy of ex vivo RMB from 87% with histopathology alone to 94%Utilization of molecular characteristics and refined RMB techniques has the potential to improve the accuracy of conventional RMB. Use of larger (18 gauge) needles is safe and allows acquisition of sufficient tissue for accurate diagnosis and may increase the diagnostic accuracy of RMBet al.A potential limitation in the imagined future of oncology is its underestimation of tumor heterogeneity\u2014not just heterogeneity between tumors, which is a central feature of the new image of personalized medicine, but heterogeneity within an individual tumor and detection of many allelic imbalances at the chromosomal level, in which one allele of a gene pair is lostIncorporation of RMB results could allow clinicians to reduce the treatment burden for patients without compromising disease specific survival, and incorporation of RMB into risk stratified management algorithms has been proposed as the next refinement in RMB-Patients with bilateral synchronous (BSRT) or unilateral multifocal renal tumors pose multiple prognostic and therapeutic challenges, similar to those of patients with hereditary RCCBetween 5% and 25% of patients who undergo surgery for a presumed single renal mass are found to have multifocal diseaseIn patients presenting with a renal tumor and clinical evidence of metastatic disease, RMB of the primary tumor and/or metastatic lesion can be done to obtain a tissue diagnosis. Indications for primary tumor RMB include inability to make a tissue diagnosis from a metastatic site, atypical appearance of the primary tumor on preoperative imaging, suspicion of multiple primary neoplasms and/or the need to make a histological diagnosis to guide treatmentThe addition of molecular and genetic tests on RMB specimens has exciting potential to provide prognostic information useful for treatment decisions,,,,Cytogenetic alterations in clear cell RCC, such as loss of 9p, are known to correlate with a significantly worse 5-year cancer-specific survival,,,,,,,While the current renaissance in RMB is exciting, several notable limitations deserve mention. A definite assessment of RMB accuracy remains difficult given most series are small, single institutional, and use varying definitions for biopsy successAdvances in the understanding of the limited biological potential of many SMRs, expanding treatment and surveillance options for RCC, improved biopsy techniques, and the integration of molecular factors into prognostic and therapeutic algorithms have renewed interest in RMB. Current indications for RMB include diagnostic work-up of renal tumors that are indeterminate on imaging, assessment of the primary renal tumor prior to initiation of systemic therapy for metastatic RCC, and of incidentally detected radiologically suspicious SRMs in patients at high surgical risk to support treatment decisions and avoid unnecessary surgery. Intratumoral heterogeneity, sampling error, and inconsistent classification of RMB failures in published studies make a precise determination of RMB accuracy difficult. Uniform reporting of RMB safety and efficacy in the literature as well as further studies addressing tumor heterogeneity and sampling error are needed. Differentiation of oncocytoma from oncocytic neoplasms poses a diagnostic dilemma, but incorporation of more sophisticated molecular analyses into enhanced RMB has promising potential.Despite these limitations, RMB has a definite and expanding role in the evaluation and treatment of renal masses, but remains significantly underutilized. While the ability to differentiate between high and low grade malignancies remains the chief limitation of RMB, we anticipate the further integration of percutaneous biopsy into clinical algorithms will guide patient counseling and inform personalized decision making. Future studies will focus on the role of repeat biopsy and the use of biomarkers and molecular fingerprinting in order to facilitate a more rational approach to the management of renal masses."} +{"text": "All birds construct nests in which to lay eggs and/or raise offspring. Traditionally, it was thought that natural selection and the requirement to minimize the risk of predation determined the design of completed nests. However, it is becoming increasingly apparent that sexual selection also influences nest design. This is an important development as while species such as bowerbirds build structures that are extended phenotypic signals whose sole purpose is to attract a mate, nests contain eggs and/or offspring, thereby suggesting a direct trade-off between the conflicting requirements of natural and sexual selection. Nest design also varies adaptively in order to both minimize the detrimental effects of parasites and to create a suitable microclimate for parents and developing offspring in relation to predictable variation in environmental conditions. Our understanding of the design and function of birds' nests has increased considerably in recent years, and the evidence suggests that nests have four nonmutually exclusive functions. Consequently, we conclude that the design of birds' nests is far more sophisticated than previously realized and that nests are multifunctional structures that have important fitness consequences for the builder/s. Nest building is a taxonomically widespread activity, with birds, mammals, reptiles, fish, and insects all constructing nests of some description in which to lay eggs and/or raise offspring Hansell . There iNest design varies considerably between and even within taxa, yet all nests have the same basic, minimal, function which is to provide a receptacle in which animals can lay their eggs and/or raise their developing offspring Heenan . This raAvoiding predation is a ubiquitous challenge for most birds, and natural selection favors those individuals with effective antipredator defenses Caro . NaturalPhylloscopus fuscatus) selected safer nest sites that were farther from the ground and in more isolated bushes when predatory Siberian chipmunks (Tamias sibiricus) were abundant, despite such locations carrying costs in terms of higher exposure to cold winds (Forstmeier and Weiss Catharus fuscescens) selected nest sites with low levels of predatory white-footed mice (Peromyscus leucopus) activity showed a clear preference for inaccessible crevices on cliffs that suffered lower predation rates than more exposed cliff sites (Verlando and M\u00e1rquez Polybia rejecta) nests in close proximity to rufous-naped wren (Campylorhynchus rufinucha) nests resulted in experimental wren pairs suffering significantly lower rates of predation from white-faced monkeys (Cebus capucinus) than control pairs without wasps close by, as the monkeys actively avoided the wasps (Joyce Perisoreus infaustus) nesting areas, the jays responded by nesting in safer, but less well insulted, sites responded to novel nest predator playbacks by shifting from nesting in trees and shrubs nesting on to the ground associate with lesser kestrels and benefit through the kestrels being very vigilant for, and aggressive toward, potential nest predators. As the kestrels do not prey upon the choughs, then the association is entirely beneficial for the choughs as they suffer significantly fewer nest predation events and consequently have higher levels of breeding success when compared to conspecifics breeding without an association to the kestrels (Blanco and Tella Branta ruficollis) are generally negatively correlated with their distance to more aggressive peregrine falcon nests. However, the geese are also harassed or attacked by the falcons if they nest too close, meaning that the geese optimally nest at least 40\u201350 m away from the falcons . Mustelids favor rodent prey but shift to the contents of fieldfare nests when rodents are scarce. Consequently, mustelid predation on fieldfare nests increases as rodent density decreases, and there was a clear tendency for fieldfare colonies to form during years of low rodent abundance and for nesting to be more dispersed or noncolonial, during high rodent years. Hence, colonially nesting birds provided more effective mobbing defenses against mustelid predators, and it was suggested that the fieldfares track rodent density directly as a surrogate cue of predation risk nests on the island of Hawaii were negatively correlated with their risk of predation from introduced black rats (Rattus rattus) and the height of nests increased by more than 50% between 1996 and 2011, which led to a decline in nest predation rates nests were predated more frequently by avian predators, such as jays (Garrulus glandarius) and magpies (Pica pica), than lower nests whose nests were predated by pine martens (Martes martes) were twice as likely to nest in new locations the following year, than females whose nests were not predated found that egg patterning and color varied between, but not within, females and individual females consistently selected those laying substrates that matched the patterning and color of their eggs to make the visual detection of their eggs most challenging for predators. This suggests that the quail \u201cknew\u201d their individual egg patterning and color and actively sought out a nest site that provided the most effective camouflage found that when nests were covered with nest material, they suffered significantly lower rates of nest predation than nests which were left experimentally uncovered (Kreisinger and Albrecht Tachybaptus ruficollis) which lay their eggs on floating nests built from wet plant material and cover their eggs with surplus nesting material when no parent is incubating. When nests were experimentally left uncovered, they suffered both lower predation rates and reduced temperatures when compared to control nests that were left covered females preferred to pair with males that built nests that were well concealed by surrounding vegetation, whereas exposed nests were rarely used for nesting nests were predated significantly more often than smaller nests (Antonov Turdus merula) nests were predated more frequently than nests which remained unchanged in size and nests which were made artificially smaller constructing a 600 g nest expend 122 kJ by making an estimated 1400 trips to collect construction materials (Withers Hirundo rustica), thereby demonstrating that birds in higher body condition invested more energy in nest building.Direct evidence that nest building is a costly process comes from studies that have estimated the costs, with one study showing that cliff swallows build multiple nests within their territories, which consist of one \u201ctype 1\u201d nest that is structurally capable of holding eggs and nestlings and one or more \u201ctype 2\u201d nests that are not structurally capable of holding eggs and nestlings. When experimental males were provided with supplementary food, they built more \u201ctype 2\u201d nests within their territories than unfed control males built heavier nests than unfed control females in one study (Mainwaring and Hartley Ficedula hypoleuca) were removed, thereby forcing them to build a second nest, experimental females built smaller nests than control females , those males that constructed larger nests were more successful in acquiring a female carry about 2 kg of stones to their nest sites, and observational studies have shown that males with larger wing areas carry more stones to nesting sites than males with smaller wing areas and spotless starlings (Sturnus unicolor), males build the nest almost entirely alone, while females occasionally add feathers to nests. Both species incorporate green plant material into their nests, and the function of such material is thought to be associated either with sexual selection or with limiting the detrimental effects of ectoparasites. In spotless starlings, the majority of green plant material was carried to nests during the ten days prior to the start of egg laying, and those males that carried more green plant material to nests controlled a larger number of boxes, meaning that they had more female partners (Friedl and Klump Troglodytes troglodytes) Garson ,b. DespiMeanwhile, there is a growing appreciation that female-built nests reflect the phenotype of the building female in a similar way to male-built nests and spotless starling feathers that show higher ultraviolet and visible reflectance on their reverse side were overwhelmingly placed with this side upwards, jay feathers which have higher reflectance on the obverse side were overwhelmingly placed with this side upwards, while azure-winged magpie (Cyanopica cyana) feathers were placed randomly as both sides have similar reflectance values. This indicates that feathers were placed so that their conspicuousness was maximized and suggests that they play a role in sexual selection meanwhile, the phenotypic quality of females did not correlate with nest size or characteristics built nests with fewer feathers and had reduced fledging success when compared to older females , only males in good condition contributed to nest building, which shortened the interval between the start of nest building and the onset of laying by about 5 days. This resulted in nestlings fledging about 5 days earlier and as earlier fledged nestlings had enhanced survival prospects, then male nest-building efforts increased offspring fitness responded to greater male effort during the nest-building stage by laying larger clutches nests were found to be an honest indicator of the pair's phenotypic quality by accurately predicting their fighting ability. Black kite pairs settle to breed in territories containing suitable nesting sites, but nonbreeding birds sometimes attempt to violently take over such breeding territories. Nests containing many objects were built by pairs with high fighting capabilities and lower quality birds did not dishonestly signal their phenotypic quality. Such cheating would have easily been possible, but the honesty of this signal was maintained by the threat of individuals being severely hurt in aggressive challenges from intruding birds , both sexes collect stones in order to protect their eggs and chicks against flooding, thereby suggesting that natural selection determines the collection of stones adjusted their reproductive effort in relation to the male's nest-building efforts. When the first clutches of experimental pairs were removed, high-quality pairs that originally built large nests were more capable of building a replacement nest, and females were found to lay larger clutches in nests that were built faster, irrespective of nest size (De Neve and Soler Clamator glandarius) preferentially parasitize those magpies which have built larger nests, as nest size provides a reliable indication of parental quality . Males call to females when adding feathers to the nest, suggesting that they wish the behavior to be noticed, and when feathers were experimentally removed from nests, males responded by carrying more feathers, although the number of feathers carried to nests varied between males. The volume of feathers delivered by males was positively correlated with clutch size and female provisioning rates. While this suggests that feathers play a role in sexual selection, the feathers were usually added during the incubation and the early nestling period, when the need for insulation was greatest. Consequently, feathers probably play a role in both sexual and natural selection in house sparrows was experimentally increased in great tit nests, it was found that when compared to control pairs, experimental pairs laid their eggs later in the season, the parents deserted their clutches more frequently during the incubation period and hatched and fledged fewer nestlings in multibrooded barn swallow nests found that when compared to control pairs, experimental pairs had lower reproductive success as indicated by a reduced number of independent fledglings from first clutches and reduced clutch sizes, brood sizes, and the number of independent fledglings from second clutches nests was negatively correlated with ectoparasite abundance nests and found that the amount of cellulose acetate from the butts, which repels parasites, was negatively associated with the number of nest-dwelling parasites nests was found to provide insulation for chicks rather than to repel ectoparasites and eastern meadowlarks (Sturnella magna) breeding in grasslands built domed nests that were orientated away from prevailing winds, and the orientation of the nests shifted temporally over the course of the breeding season as the direction of the prevailing winds changed , horned larks , lark buntings , and McCown's longspurs all selected nest sites that faced away from the prevailing winds, as well as being located away from direct sunshine during the middle part of the day, which prevented the nests from overheating (With and Webb Larus fuscus) which nested adjacent to tall vegetation and were therefore sheltered from cold winds raised chicks that grew faster than chicks raised in more exposed nests which experienced cooler temperatures (Kim and Monaghan Somateria mollissima) showed that females breeding in sheltered nests experienced milder temperatures and laid larger clutches with higher hatching rates than females nesting in exposed nests at cooler temperatures. Then, when shelters were experimentally added to nests at exposed sites, experimental females had lower rates of mass loss than control females, although hatching success did not differ between the two treatments nests in an arid environment were found to be located adjacent to a bush or stone and to face north which provided shade from the midday sun breeding in a hot desert were found to select sites on gravel away from vegetation during the early part of the breeding season when temperatures were relatively cool. They then increasingly selected sites in shrubs as the season progressed and ambient temperatures increased, and while nest predation rates did not differ between the two sites, nests on the gravel experienced higher temperatures. This indicates that the exposed nest sites were preferred because the incubating adults could protect themselves from approaching predators during the early part of the breeding season, but were forced to move to more sheltered sites as the season progressed and temperatures increased preferentially laid their eggs on white pebbles that resembled the color of their eggs more closely than randomly available pebbles. Eggs that closely matched their adjacent pebbles suffered lower levels of predation, yet artificial nests constructed of randomly available pebbles warmed faster and were warmer than plover nest pebbles, with temperatures inside nests being about 2\u20136\u00b0C cooler than surrounding substrates. The nest sites rapidly lost heat when they were not incubated by an adult, which suggests that pebble selection is a trade-off between maximizing heat reflectance to improve egg microclimate and minimizing the conspicuous contrast of eggs and surrounding substrates were found to select those nesting holes that provided the most suitable microclimate for incubating parents and developing offspring. This is important for the owls as they live in northern regions of America that are characterized by inclement weather during the nesting season, and the owl pairs which chose sites out of the wind had higher reproductive success than pairs in exposed sites and yellow-throated miner (Manorina flavigula) nests were studied across three wind speeds. Nest dimensions differ between the species, despite the adults having similar body masses, although the nest conductance of both species nests is comparable. The study found that the rate of heat loss from nests increased in both species as wind speed increased and as a result of forced convection through the nest, incubating parents would be required to double their heat production to maintain a suitable microclimate within the nest (Heenan and Seymour Protonotaria citrea) pairs that nested early in the season, when ambient temperatures were low, preferentially selected those nestboxes which had the highest ambient temperatures. Pairs that nested late in the season when ambient temperatures were warm preferentially selected those nestboxes which had the lowest ambient temperatures block out 96\u201399% of air currents to which they are exposed (Kern Campylorhynchus brunneicapillus) moderate the nest environment under widely varying environmental conditions by both retaining heat during cold weather and by shading the nest contents from direct sunlight during hot weather (Ricklefs and Hainsworth Philetairus socius), where nests are huge structures that contain the individual nesting chambers of colonies of birds that sometimes compromise a hundred or more pairs. The enormous nests have been found to ameliorate the impact of low temperatures have been shown to excavate a scrape and use lining material, which reduced the rate at which the nests lost heat by 9% and 25%, respectively. Hence, lined scrapes insulate clutches much more efficiently than unlined scrapes caterpillar food supply. Despite this pattern, there was no seasonal trend in the mass of nests, but there were seasonal changes in nest composition. The mass of the nests' moss base showed no seasonal variation, but there was a seasonal decline in the mass of the cup lining material , there was a negative association between the number of feathers added to nests and the average daily ambient temperatures, which increased as spring progressed showed that the mass of feathers used as cup lining materials declined through the breeding season, but there was no seasonal decrease in nest insulation quality because of increasing ambient temperatures. Then, in an experimental study where feathers were added to experimental nests at an early stage of the lining phase of nest construction, the total mass of feathers in experimental nests was comparable to that in control nests, and there was no significant difference in the insulation quality of nests. The experimental provisioning of feathers at experimental nests meant that parents at experimental nests collected approximately 50% fewer feathers. This reduction in effort is insightful as there was no significant effect on the duration over which feathers were collected, suggesting that the seasonal decline in feather mass was due to long-tailed tits adjusting feather mass to environmental conditions. This also suggests that feathers were not a limiting resource , which are small finches in the Hawaiian honeycreeper subfamily breeding at the northerly part of their breeding range lined their nests with feathers while their more southerly breeding conspecifics did not (M\u00f8ller Dendroica petechia) breeding in northern and southern Canada showed that birds breeding further north built larger, less porous nests that retained heat better but also absorbed more water and then took longer to dry than nests from the south (Briskie Turdus migratorius), yellow warbler, and Carduelis finches nests were heavier and had thicker nest walls in northern Canada than in southern Canada nests also varied with latitude. Nests in the north were built on thinner branches, presumably to make them less accessible to squirrels. Nests in the south are better protected from the sun as they have a smaller opening and more spacious than those further north (Schaeffer An interspecific study of passerine birds in Europe demonstrated that those species which breed relatively early and hence, at lower ambient temperatures, were more likely to add feathers as nest lining material to their nests than later breeding species M\u00f8ller . Meanwhit M\u00f8ller . Other c Briskie . Also, AAmong hole nesting birds, the mass of the cup lining material and nest insulatory properties of blue tit and great tit nests decreased with increasing spring temperatures as latitude decreased in Great Britain (Mainwaring et al. In summary, these results indicate that the decrease in the mass of the nest cup lining material in birds' nests may be counteracting increasing spring temperatures to create an appropriate microclimate for both parents and offspring. There are now several studies that report the fine-scale adjustment of nest cup lining material in response to ambient temperatures in birds (e.g., McGowan et al. Our understanding of the design and function of birds' nests has increased considerably in recent years and the evidence suggests that nests have several nonmutually exclusive functions. Therefore, we conclude that far from being simple receptacles for eggs and/or offspring, the design and function of birds' nests is far more sophisticated than previously realized. Nevertheless, there are still several areas that are likely to be fruitful for future research. First, both natural and sexual selection appear to influence nest design, yet while natural selection selects for smaller nests, sexual selection selects for larger nests. One recent study (Sergio et al."} +{"text": "Critical limb ischemia (CLI) is the most severe clinical presentation of peripheral arterial disease and manifests as chronic limb pain at rest and/or tissue necrosis. Current clinical interventions are largely ineffective and therapeutic angiogenesis based trials have shown little efficacy, highlighting the dire need for new ideas and novel therapeutic approaches. Despite a decade of research related to skeletal muscle as a determinant of morbidity and mortality outcomes in CLI, very little progress has been made toward an effective therapy aimed directly at the muscle myopathies of this disease. Within the muscle cell, mitochondria are well positioned to modulate the ischemic cellular response, as they are the principal sites of cellular energy production and the major regulators of cellular redox charge and cell death. In this mini review, we update the crucial importance of skeletal muscle to CLI pathology and examine the evolving influence of muscle and endothelial cell mitochondria in the complex ischemic microenvironment. Finally, we discuss the novelty of muscle mitochondria as a therapeutic target for ischemic pathology in the context of the complex co-morbidities often associated with CLI. Peripheral artery disease (PAD) presents as either symptom-free, intermittent claudication or critical limb ischemia . CLI carries alarmingly high morbidity and mortality rates and patients have a risk of major amputation or death that approaches 40% in 1 year . Therapies aimed at the skeletal muscle represent an untapped arena with great potential to advance the field of CLI research. Table The importance of striated muscle to ischemic outcomes is readily accepted in cardiac ischemia/reperfusion, and there are numerous clinical trials involving therapeutic targeting of the cardiomyocyte that, upon re-oxygenation by surgical intervention or endogenous collateral flow with activity or mechanical loading, would be rapidly metabolized. These ischemia-reperfusion events have been well documented to produce large amounts of ROS in cardiac, brain, liver and renal tissues , produced by membrane bound enzymes may be capable of directly affecting nearby cells. It is likely that altered redox homeostasis in one cell would dramatically alter the local microenvironment through paracrine signaling. For example, skeletal muscle redox alterations have been shown to decrease endothelial cell angiogenic properties via the HIF-1\u03b1 signaling cascade and oxidants (superoxide anion and hydrogen peroxide), they serve as a metabolic rheostat controlling cellular redox homeostasis. Flux through both the reductive and oxidative arms contributes to redox signaling through redox modifications to cysteine residues that regulate the structure/function of target proteins suggested a heavy cellular reliance on glycolytic metabolism for the energy requirements of normal processes (Dobrina and Rossi, in vitro and increases markers of apoptosis under stress (serum-deprivation; Lugus et al., Mitochondria are dynamic organelles that rely on complex signals orchestrating dynamic fission and fusion events believed to be responsible for regulating mitochondrial quality control. Fission and fusion are involved in the elimination of damaged/dysfunctional mitochondria (Song et al., There are numerous risk factors linked to the CLI manifestation in PAD patients (Fowkes et al., in vitro have lower mitochondrial integrity, rapid loss of mitochondrial membrane potential, and arrest of cell cycle progression (Henderson et al., From a physiologic perspective, smoking impairs microvascular reactivity (Ijzerman et al., Type II Diabetic patients with PAD are five times more likely to present clinically with CLI accompanied by tissue loss (Jude et al., A critical barrier to developing therapeutic strategies to PAD has been a lack of understanding of the mechanisms underlying the etiology and pathology of PAD. While the cause of PAD is unquestionably occlusive arterial disease, the limited success of surgical and angiogenic treatments suggest that factors other than blood flow may significantly contribute to patient outcomes. Physiologically, angiogenesis and neovascularization are directed by the metabolic demand of the resident tissue. Simply put, the return of blood flow will have little effect if the limb tissue is beyond repair. In this review, we have highlighted recent trends in CLI research that suggest limb musculature may be a viable and potentially parallel therapeutic option for both the myopathy and vasculopathy of CLI. Furthermore, limb muscle and EC mitochondria provide attractive specific targets for novel therapeutic intervention.JM supported by NIH/NHLBI R00HL103797 and R01HL125695, and a Brody Brothers Endowment Award, DB supported by NIH/NHLBI R01 HL123647 and R15 HL122922, PN supported by NIH/NIDDK R01 DK096907.David A. Brown has served as a consultant for Stealth BioTherapeutics, which is developing novel treatments for mitochondrial diseases. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "One fundamental step in PROM development is adequacy of item generation based on the conceptual framework of the instrument. When this framework is novel and not obvious, the US Federal Drug Administration (FDA) guidance for industry recommends cognitive patient interviews be undertaken to ensure understanding and completeness of the health domains contained in the questionnaire items. Documentation of the process by which items and domains are identified (often from patient interviews) is recommended; however, transparent methods are lacking. We propose novel and transparent methods for selecting PROM domains developed in a feasibility case study.Inductive interviews were conducted with purposefully selected patients with experience of the clinical condition/intervention. An open-ended topic guide encouraged narratives of patients' experiences. Interviews were independently conducted and thematically analysed using the same electronic software package by two researchers, with an intention to code all aspects of patient experience. Codes were listed with supporting raw data (quotes), and discussed with a third independent researcher to agree an initial set of concepts . Further interviews tested the relevance and exhaustiveness of domains, with amendments noted and discussed. A final set of domains was incorporated into an initial PROM, supplemented with domains extracted from the literature and further patient interviews to establish face validity.This is a transparent process and method for documenting PROM concept and domain selection from qualitative interviews through to questionnaire items. Reporting standards for this process are needed."} +{"text": "Diseases associated with the thyroid gland are one of the most frequently seen endocrine disorders across the globe. Total thyroidectomy is currently the preferred treatment for many thyroid diseases. Controversies exist among surgeons regarding safety of total thyroidectomy due to the risk associated with it like postoperative hypoparathyroidism or recurrent laryngeal nerve damage. Since, in the recent years, the incidence of thyroidectomy is in increasing trend in south Indian population, this review aims to study the available data regarding the appropriateness and safety of total thyroidectomy and compares it with subtotal thyroidectomy and other thyroid surgeries. This is a retrospective comprehensive review of various articles and publications regarding total and partial thyroidectomy performed across the world. Many retrospective studies and few prospective studies suggest that the incidence of transient hypocalcemia is higher after total thyroidectomy than after subtotal thyroidectomy, but the incidence of other complications including recurrent laryngeal nerve palsy and postoperative hematoma is not significantly different between the two procedures. Hence in our review we found that total thyroidectomy is safe and cost effective with low complication rates and provides little significant advantage of being safer procedure compared to subtotal thyroidectomy. The incidence of thyroid disease in general population is enormous. Thyroid disorders are the most frequently encountered endocrine diseases in India . The thyTotal thyroidectomy provides the advantages of eliminating the risk of recurrence and hence an increasing number of total thyroidectomies are currently being performed for benign cases. Knowledge about the clinical profiles of thyroidectomy cases and understanding the postthyroidectomy complications are an important milestone in public health. Since, in the recent years, the incidence of thyroidectomy is in increasing trend in south Indian population, our aim was to assess the safety of total thyroidectomy. Safety of thyroidectomy procedures is a major concern for both patients and physicians. Thus, this review aims to study the available data regarding the appropriateness and safety of total thyroidectomy and compares it with subtotal thyroidectomy and other thyroid surgeries.This review was prepared by downloading various articles regarding total and partial thyroidectomy from several search engines like PubMed, Medline, Scopus, Google Scholar, and so forth. The search was limited to clinical trials, controlled clinical trials, comparative studies, and randomized controlled trials. Only articles pertaining to and relevant to the effectiveness and complications encountered during thyroidectomy were included in this review. Articles which compared total thyroidectomy with subtotal thyroidectomy and near total thyroidectomy on various outcomes were also reviewed. Primary outcomes were defined as prevalence of recurrence of thyroid diseases after thyroidectomy. Secondary outcomes were defined as incidence of complications or morbidity following thyroidectomy. Factors such as safety, outcomes of the surgery, and postoperative complications related to thyroidectomy were evaluated. A total of 41 studies were reviewed.p = 0.69; n = 1275). A review article comparing total thyroidectomy with subtotal thyroidectomy for multinodular goiter indicated that goiter recurrence was lower in the total thyroidectomy group (0.2%) compared to subtotal thyroidectomy group (8.4%) with p < 0.000 [Records identified through database searching were 187. These records were screened and 56 full-text articles were assessed for eligibility. After detailed screening 41 articles were included in this review . Most ar < 0.000 . To summDiseases of thyroid gland are of great importance because they are a challenge for medical or surgical management. Total thyroidectomy is considered as the usual surgical procedure to treat thyroid diseases. The principal diseases of the thyroid gland are goitre, hypothyroidism, hyperthyroidism, thyroiditis, and neoplasms .Reports indicate that the incidence of benign and malignant lesions in surgically treated thyroid swellings depends on the person's lifestyle and varies widely from one geographical area to another . The preThyroidectomy surgery is said to be the most common cause of bilateral vocal cord paralyses. A study suggests that thyroidectomy surgery is one of the main factors which cause bilateral vocal cord injury . There iIn a study done by Pradeep et al., incidences of complications of thyroidectomy were temporary hypocalcemia (24%), permanent hypocalcemia (3%), and permanent vocal cord palsy (1%) . When paThe prevalence of postoperative hypocalcemia following thyroidectomy which may be temporary or permanent ranges from 0% to 83%, with the highest incidence seen in patients undergoing total thyroidectomy for cancer (28%) and in those who underwent subtotal thyroidectomy for thyrotoxicosis 23%). On the contrary, the incidence of hypocalcemia is found to be lowest in patients undergoing subtotal thyroidectomy for other diseases (1.5%) and lobectomy (0%) [%. On theThe percentage of total thyroidectomies being performed for various thyroid diseases has increased significantly in recent years. Initially, the risks which were associated with major surgeries to treat thyroid disease prevented the surgeons from performing total thyroidectomies. Although the use or risks associated with total thyroidectomy remain controversial it is being performed increasingly . KaniukaNew techniques such as postoperative levothyroxine therapy seem to reduce recurrence rates in the other thyroid lobe after partial resection of the thyroid gland . But notIn the present phase, thyroid gland diseases are one of the most encountered endocrine disorders especially in south Indian population. This factor may be due to the decreased iodine intake of that region or differences in geographical distribution or any other factors. Mathew believes that there is a high burden of thyroid diseases in India but paucity of data is available on the epidemiology of thyroid diseases . He opinComplications after thyroidectomy are in a decreasing trend and most of the complications could be avoided by careful dissection and exposure of anatomical structures and proper surgical management.Based on the above evidences, we would conclude from our review that total thyroidectomy is a safe and effective procedure for most of the thyroid diseases in the hands of an expert surgeon. Subtotal thyroidectomy is similarly effective but it is associated with significant recurrence rate and may leave few traces of inadequately treated thyroid cancers. Thus total thyroidectomy provides little significant advantage of being safer procedure compared to subtotal thyroidectomy."} +{"text": "Marine organisms are exemplary bioresources that have extensive possibilities in supporting and facilitating development of human tissue substitutes. Such organisms represent a deep and diverse reserve of materials, substrates and structures that can facilitate tissue reconstruction within lab-based cultures. The reason is that they possess sophisticated structures, architectures and biomaterial designs that are still difficult to replicate using synthetic processes, so far. These products offer tantalizing pre-made options that are versatile, adaptable and have many functions for current tissue engineers seeking fresh solutions to the deficiencies in existing dental biomaterials, which lack the intrinsic elements of biofunctioning, structural and mechanical design to regenerate anatomically correct dental tissues both in the culture dish and Biomaterials are widespread in clinical and experimental medicine. Synthetic and biological origins made from polymers or ion complexes, nanoparticles, quantum dots and intricate composites have been designed and fabricated for roles in tissue replacement, biomonitoring and therapeutic delivery of drugs . The morAlmost every type of biomaterial has been used in clinical or experimental dentistry. Metals and ceramics have been predominant in fixing and replacing the major hard tissues of the tooth. Polymers have also played a major part in dental restorations and replacements . In addiIn dentistry, structural biomaterials that enable interactions between epithelial and mesenchymal stem cells have been used to facilitate tooth regeneration . These bRecently, the technical feasibility of using scaffolds to facilitate the regeneration of dental structure has been further evidenced by a study that transplanted stem cells with macroporous biphasic calcium phosphate (MBCP) into the dorsal subcutaneous pockets of 5-week-old male immunocompromised mice . The steDspp and amelogenin in adjacent layers in a relative orientation similar to that in teeth . A. A179]. Over the years, the pursuit of tooth regeneration and total tooth repair has been one of the main goals of research in regenerative and restorative dentistry. Since the turn of the last century, different biomaterials, including those from marine sources, have emerged as favorable candidates for tissue engineering and regeneration. Although we have discussed how these materials could facilitate tooth repair and regeneration in practical applications, materials and structures built from them do not meet all ideal criteria needed for proper biological application (reviewed in We have demonstrated how a small selection of structural items from the marine environment can be usefully implemented in regenerative strategies in dentistry to help address common clinical problems, particularly those regarding loss of bone and dentine. These structural products range from small microscopic skeletons to large macroscopic structures. The different applications of marine products in dental tissue engineering have been summarized in"} +{"text": "With the introduction of biologics in pediatric rheumatology the options for effective treatment have increased considerably. Consequently the majority of children with JIA reach a remission in earlier stages of their disease and the impact on joint health, ambulation and functional ability of JIA have changed accordingly. This brings new perspectives for the health professional in the field of pediatric rheumatology. \"Co-creation\", family centered care, even family integrated care models are currently explored in this field. Multi-level; composed outcome measures (PRInTO-outcomes), patient rated outcome measures are increasingly used in research and outcomes research, emphasis on family centered approaches deliver new measures such as the Family Needs Inventory What are the paradigm shifts we will face the coming decade, how does it influence our professional attitudes, skills and knowledge? What will be the added value of the healthprofessional in the coming decade?None declared."} +{"text": "After an ischemic stroke, neural precursor cells (NPCs) proliferate within major germinal niches of the brain. Endogenous NPCs subsequently migrate toward the ischemic lesion where they promote tissue remodeling and neural repair. Unfortunately, this restorative process is generally insufficient and thus unable to support a full recovery of lost neurological functions. Supported by solid experimental and preclinical data, the transplantation of exogenous NPCs has emerged as a potential tool for stroke treatment. Transplanted NPCs are thought to act mainly via trophic and immune modulatory effects, thereby complementing the restorative responses initially executed by the endogenous NPC population. Recent studies have attempted to elucidate how the therapeutic properties of transplanted NPCs vary depending on the route of transplantation. Systemic NPC delivery leads to potent immune modulatory actions, which prevent secondary neuronal degeneration, reduces glial scar formation, diminishes oxidative stress and stabilizes blood\u2013brain barrier integrity. On the contrary, local stem cell delivery allows for the accumulation of large numbers of transplanted NPCs in the brain, thus achieving high levels of locally available tissue trophic factors, which may better induce a strong endogenous NPC proliferative response. Herein we describe the diverse capabilities of exogenous NPCs in enhancing the endogenous neurogenic response after stroke, and how the route of transplantation may affect migration, survival, bystander effects and integration of the cellular graft. It is the authors\u2019 claim that understanding these aspects will be of pivotal importance in discerning how transplanted NPCs exert their therapeutic effects in stroke. Ischemic stroke represents the most common cause of serious morbidity and the second most common cause of mortality in industrialized countries . While aIn animal models, the mobilization and recruitment of NPCs from the major stem cell niches within the central nervous system are essential compensatory responses after an ischemic insult . HoweverThe observation that NPCs can be harvested from the adult brain and used therapeutically in animal models of stroke argues in favor of the potential utility of cell-based therapies in ischemic stroke. We have shown that the injection of somatic mouse NPCs ameliorates the clinicopathological features of stroke in relevant murine models by reducing secondary neurodegeneration, decreasing glial scar formation, promoting endogenous neurogenesis and stabilizing blood\u2013brain barrier (BBB) integrity . GraftedHowever, there remains an enormous need to understand how the complex interactions of stem cell grafts with the ischemic brain may be affected by the route and timing of cell delivery. In particular, we still have to define how NPCs should best be administered in order to enhance endogenous restorative responses that depend on (i) the homing, survival and integration of transplanted NPCs, (ii) the proliferation of the host\u2019s endogenous NPCs, (iii) the modification of the cerebral microenvironment, and (iv) the remodeling of ischemic tissue via actions that include the modification of glial responses and the promotion of neuronal plasticity.Herein, we summarize current knowledge with regard to how transplanted NPCs interact with host tissues, aiming to identify how exogenously delivered NPCs may eventually be used to promote neurological recovery in mouse models of ischemic stroke.The SVZ is situated within the lateral walls of the lateral ventricles and is composed of four main cell types: ciliated ependymal cells (type E), slowly proliferating stem cells (type B), transient amplifying progenitors (type C) and proliferating neuroblasts type A; . After aSignals that stimulate the stroke-induced neurogenic response have yet to be fully elucidated, but likely involve the interplay of morphogens, growth factors, and inflammatory mediators. Several groups have found that the notch pathway stimulates SVZ cell proliferation and neurogenesis after stroke . Other sFigure 1. Effects of exogenously delivered NPCs in experimental models of stroke have been summarized in Table 1.Since NPCs can secrete many of the factors that regulate neurogenesis , and areendogenous neurogenesis has been the focus of intensive research efforts. Among the different routes of NPC delivery, there are several studies suggesting that the local administration of NPCs has the most relevant effects on endogenous neurogenesis. The local route of cell delivery indeed allows for a large number of cells to be administered, which facilitates the secretion of high concentrations of growth factors that ultimately promote the endogenous neurogenic response promoted cell proliferation in the SVZ (up to 15 days post-stroke) and increased angiogenesis in peri-infarct regions . Intrapaesponses . Similarstriatum . Interesstriatum .Despite these data, which highlight the promising effects of intraparenchymal NPC delivery, comparative studies of different routes and times of transplantation (without the use of confounding immunosuppressive regimens) must be performed in order to determine the optimal spatiotemporal settings that would allow for the ideal stimulation of endogenous neurogenesis in stroke. Additionally, given that the neurogenic potential of adult NPCs declines with age , the effIn a comparative study evaluating intrastriatal, intracerebroventricular and intravenous NPC delivery (24 h after MCAO), the intrastriatal transplant of NPCs yielded the highest numbers of grafted cells within the ischemic brain . IntraceThe mechanisms that regulate the homing of transplanted cells to the ischemic lesion are extremely similar to those that regulate the migration from within the endogenous NPC compartment . Upon ispathotropism of transplanted NPCs for ischemic tissue that occurs after systemic delivery. Interestingly, intravenous transplantation of NPCs has the unique advantage of stabilizing the BBB, via mechanisms that involve a reduction of MMP9 expression and reactive oxygen species (ROS), as we recently showed after the transplantation of adult NPCs at 6 h after transient MCAO only a small minority of transplanted cells (approximately 0.3% based on systematic counts) accumulate in the brain . NotablyBeyond the proliferation of grafted NPCs, their emergence from peripheral organs (where they may have previously homed), such as the lungs, liver and spleen , may alsIt is becoming clear that the therapeutic effect of intravenous cell delivery is independent of the amount of NPCs that is achieved within the brain, while local intracerebral NPC transplantation outcomes strictly depend on the amount of NPCs that reside within the lesion site. Consequently, intracerebral transplantation of NPCs is successful only if grafted NPCs within the ischemic brain survive in adequate quantity. The major determinant of the survival of locally transplanted cells within the ischemic brain is the timing of delivery. In a recent study it has been shown that while NPC proliferation, migration, and neuronal differentiation did not differ when cells were intrastriatally transplanted in the subacute (48 h) or chronic phase (6 weeks) after stroke, NPC survival was strikingly reduced following delayed cell delivery . The reain vitro prior to transplantation -2, DCX, glial fibrillary protein (GFAP), and the oligodendroglial transcription factor (Olig)-2 . Interesin vivo -32+ medium spiny neurons were protected against delayed degeneration in the striatum, which is particularly sensitive to intraluminal MCAO , regulators of glial proliferation and reactivity and neuronal death and plasticity was observed in the brains of ischemic mice receiving intravenous transplantation of adult mouse NPCs while a single transcript was up-regulated by adult mouse NPCs, which was the spiny neuron marker DARPP-32 , it will not be possible to promote neurological recovery post-ischemia via the modulation of single targets .NPCs possess unique characteristics that differ drastically from conventional therapies . Transplanted stem cells can promote tissue regeneration by sensing diverse signals in the brain microenvironment, migrating to specific sites of damage, integrating inputs and executing complex response behaviors all aimed at the remodeling/protection of injured ischemic tissue .While the local delivery of NPCs is able to achieve high levels of protective mediators in the ischemic brain tissue, questions remain about the feasibility of such surgically invasive procedures in the clinical setting. One might therefore consider systemic NPC transplantation, which is minimally invasive. In view that systemically administered NPCs do possess potent anti-inflammatory effects, promote brain remodeling and induce functional neurological recovery in rodents, this option could be indeed of clinical value.Future studies will have to clearly define the safety and efficacy of NPC transplantation after both systemic and local delivery. Such knowledge will increase our understanding of cellular therapies and in turn guide future translational strategies that are urgently needed to promote brain remodeling and repair in stroke patients.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The blood-brain barrier (BBB) is a dynamic and highly selective permeable interface between central nervous system (CNS) and periphery that regulates the brain homeostasis. Increasing evidences of neurological disorders and restricted drug delivery process in brain make BBB as special target for further study. At present, neurovascular unit (NVU) is a great interest and highlighted topic of pharmaceutical companies for CNS drug design and delivery approaches. Some recent advancement of pharmacology and computational biology makes it convenient to develop drugs within limited time and affordable cost. In this review, we briefly introduce current understanding of the NVU, including molecular and cellular composition, physiology, and regulatory function. We also discuss the recent technology and interaction of pharmacogenomics and bioinformatics for drug design and step towards personalized medicine. Additionally, we develop gene network due to understand NVU associated transporter proteins interactions that might be effective for understanding aetiology of neurological disorders and new target base protective therapies development and delivery. The human brain is one of the most complex organs composed of around 100 billion neurons and glial cells are 10 to 50 times more than the neurons. Major role of neurons cells is to transmit information as electric impulses to other nerve, muscle, or gland cells through special junction called synapse. The brain and central nervous system (CNS) regulate sensory input and motor output as well as coordinating all other body functions. The interface between CNS and the peripheral circulatory system functions as a dynamic regulator of ion balance, a nutrient transport, and molecular trafficking is historically known as blood-brain barrier (BBB) . The NVULok et al. discusseThe CNS is the most crucial and sensitive system that needs \u201cgate keepers\u201d to be protected. The BBB is one of the main gate keepers of CNS. It is a dynamic system that plays a vital role for homeostatic aspect of the cerebral microcirculation . The braThe idea of BBB came from variance of dye absorption between periphery and brain . GoldmanHighly metabolic and dynamic activities of nervous tissue may have been regulated by blood flow in the brain through BBB, although the cellular mechanisms are not well known . DisruptThe concept of BBB gradually evolved towards \u201cextended NVU\u201d that for2+ signalling and purinergic transmission [Astrocytes are critical in the development and maintenance of BBB characteristics and act smission , 37 as wsmission . Pericytsmission . Cocultusmission . In casesmission and trausmission , pericytsmission .The extracellular matrix that serves as an anchor for the endothelium also interacts with NVU. Disruption of this matrix is compensated by increased BBB permeability . Matrix In the last decades a significant understanding of NVU associated cells and their molecular and pathophysiological signalling has been developed. This progress is very crucial for understanding neurological disorder and drug development as well as delivery to the brain for the prevention and treatment of the diverse neurological disorder. So, the integrated cellular and molecular concept of the NVU may be implemented in pharmacology and disease understanding that related to cerebral microvascular permeability.2+, cAMP, serotonin, cytokines, chemokines, and steroids may affect BBB permeability. Some endothelial transporters like P-glycoprotein and other proteins of ABC transporter family are potential target for drug design. Ablation of the gene encoding P-glycoprotein leads to defective BBB transport and increased sensitivity to various drugs [Molecular interactions and signalling usually control the major functions of NVU. Abnormalities of molecular level show physiological change and consequently neurological diseases. Proteins that associated with tight junction of endothelial cells including junctional adhesion molecule- (JAM-) 1, occludin, and claudins have significant role of maintaining permeability. Although JAM-1 is a member of IgG superfamily with large extracellular domain found inus drugs . As efflus drugs . Vasculaus drugs . ProangiWe have created a network of 13 diNVU has dynamic function to regulate BBB permeability in the brain. CNS homeostasis is maintained by complex transport mechanisms that adjust the balance between influx of nutrients and efflux of wastes, toxins, and drugs . VariousXenobiotics resistance to brain is another important function of NVU maintained by two components of endothelial cells: efflux transporters and tight junctions . P-glycoSignalling between neurons and astrocytes may influence cerebral blood flow . AstrocyAbnormal NVU selective permeability function may cause various CNS diseases . The capThere are sufficient evidences that BBB disruption is the early event in many neurological disorders; growing interest of therapeutic target on that region is not unusual , 76. AcuWhether we could stop neurodegeneration by inhabiting inflammatory cytokines is the next focus of study. Anakinra is the inhibitor of interleukin 1 (IL-1), successfully used for rheumatoid arthritis treatment . Nonster\u03b14 integrin receptor found on leukocytes that prevents adhesion of the leukocytes to brain endothelial cells [As varieties of neurological diseases are linked to NVU, continuous research efforts might lead to identifying specific biomarkers and to developing therapeutic strategies to control the abnormalities. Due to accessibility and expression in early stage, vascular compartment specific molecular biomarkers are attractive and can be detected in situ using molecular imaging or in the circulating compartment using \u201comics\u201d approaches . Angiogeal cells . Protectal cells .Combination of L-DOPA and carbidopa is the potential drug used for Parkinson's disease but bioavailability of oral dose is less than 1% due to efflux pump . RefractDexamethasone is being used for brain oedema that regulates P-gp expression and constrains TJ in brain endothelial cell . DiffereA majority of well-known drugs give only symptomatic relief for a limited period with adverse side effect and toxicity. Around 98% of small drugs and nearly 100% of large drugs molecules cannot penetrate the brain in sufficient therapeutic amount . There iProdrugs like L-DOPA could penetrate through carrier mediated transport when targeting endogenous transport protein. Molecular Trojan horses use receptor-mediated transcytosis (RMT) that could permit large molecule to the brain . InsulinOur recent understanding of cellular receptor and polymer chemistry brings a new field of drug delivery called nanotechnology. This nanoparticle could be transported in various parts of body and deliver drugs including brain . ModifieNew drugs development and increase of the existing drugs efficacy are the major challenges of pharmacology. Traditional drug designing protocol is time-consuming, risky, and indeed costly. Katara describeRecently P-gp is being used as therapeutic target for optimizing CNS drug delivery that is based on pharmacogenomics data analysis . PharmacConstant pressure of generating various drugs within limited time period with low risk has resulted in remarkable interest in bioinformatics . The majIn spite of drug target validation, bioinformatics provides different algorithms that reduce the failure of clinical trial approaches . PhysiolWe have the genomic data and we know the cellular composition of NVU as well as transporter proteins. So we could in silico validate the drug candidates regarding efficacy to brain and accessibility to BBB. TJ is the main regulator of NVU permeability and we know the structural composition of TJ associated proteins. How we could regulate and adjust the short-term opening of TJ is a burning question of drug delivery to brain. Also there is extensive study area of surrounding cell physiology and molecular function that might give us details and integrated view.Pharmaceutical companies are focused on blockbuster drugs prescribed to more than 20 million people. Recent Ebola outbreak in Africa shows us the necessary of orphan drug development. This raises an issue for developing countries and bioinformatics could be the possible hope for the orphan drug development as per need .Nowadays it is quite easy to identify drug candidate and target using online database but experimental validation is not easy. Although bioinformatics is a potential field, it did not bring any considerable change yet for drug design and delivery process. This is due to less acceptance of new technology and lack of technical expertise. Also changing the traditional drug market is a big issue for the pharmaceutical companies and investors. We can expect that in the near future the situation will change and bioinformatics based drug design and delivery through NVU will be popular and time- and cost-effective with high level of drug efficacy.We still have limited knowledge of the human brain and most of its functions that remain unknown or mysterious. This paper has described the role of NVU in CNS homeostasis and potential target for therapies. Bioinformatics and pharmacogenomics can provide huge support for pharmaceutical companies in order to design drug for neurological disorder with reasonable time and affordable cost. Drug trials might have some limitation in order to measure the functionality of therapeutics. We need to minimize the gap between cell culture and animal model study to get appropriate understanding of drug delivery. Application of molecular biology into neuroscience could help to understand genetic make-up, epigenetic variation, and near prospect of personalized medicine. Integrated system biology approaches could help to know insights into disease aetiology, progression, and target oriented cocktails drugs design. Although bioinformatics and pharmacogenomics are passing initial phase of development, they already pose enough potential for future drug industry. Brain targeted drug delivery must be safe and beneficial for patients and have to ensure minimum short- or long-term impact. Finally, it can be said that NVU would be the main target of pharmacokinetics to reduce drug abuse and to answer some unsolved questions of neuroscience."} +{"text": "In contrast to early HAT, late HAT has an insidious clinical presentation. Nevertheless, biliary and vascular reconstructions in this late setting are unlikely to improve outcome. Patent portal flow makes an important contribution to the viability of liver in case of late HAT while the allograft reconstitutes intrahepatic arterial flow through neovascularization. Concurrent HAT with PVT without immediate graft necrosis is extremely rare, and allograft and patient survival are seemingly impossible without retransplantation. In fact, hepatopetal arterial and portal venous neovascularization are known albeit obscure phenomena that can preserve posttransplanthepatic function under the extenuating circumstances of complete interruption of blood flow to the graft. We describe two such cases that developed combined HAT and PVT more than six months after OLT with perfect preservation of graft function. The survival of allografts in our cases was due to extensive hepatopetal arterial and portal venous collateralization. Simultaneous HAT and PVT after OLT are rare events and almost uniformly fatal, if they occur early. Due to paucity of such cases, however, underlying mechanisms and etiology remain elusive, and despite radiological diagnosis of these complications, there is no way to predict these events in the wake of stable graft function. The critical determinants of a successful liver transplant procedure are establishment of uncompromised inflow and adequate venous outflow. However, the postoperative course can be marred by vascular complications involving the HA and PV which are associated with high morbidity and mortality .Although HAT and PVT occur infrequently, they pose a major threat to patient and graft survival and present formidable challenges for prevention and treatment. HAT has an incidence of 4\u201315% and when present in isolation may lead to acute graft failure and biliary destruction requiring retransplantation in most cases. Mortality may be as high as 27\u201358% and may increase to 73% when retransplantation is not carried out [PVT complicates 2% of liver transplants and also can be fatal. It can present as portal hypertension, elevated transaminases, and acute graft failure . While aIn the event of hepatic artery compromise the portal vein is the main source of hepatic blood flow and the liver responds by extracting greater amount of oxygen from portal blood and inducing neovascularization while viability is maintained by portal blood flow. Isolated portal vein thrombosis has been shown to cause hepatic infarction in the absence of arterial compromise .If not recognized in timely manner, PVT leads to graft failure and retransplantation or patients death .However, the biliary ductal system is solely supplied by HA via peribiliary plexus (PBP). Recent reports have indicated important contribution by portal circulation, as ischemic type biliary lesions (ITBL) develop in patients with a patent hepatic artery and thrombosed PV, implying altered microcirculation in PBP in face of intact arterial supply. This suggests that portal blood flow, while not only supplying hepatocytes, may make an important contribution to the biliary microcirculation and that compromised portal venous blood supply alone can predispose to the development of ITBL which necessitates retransplantation in 50% of such cases . Thus, tGiven this fact it can be easily conceived that concurrent early HAT and PVT will have a devastating effect on biliary ductal system and hepatocytes necessitating transplantation. This notion is supported by few case reports in the literature showing prohibitive mortality in combined HAT and PVT . There iWith this in mind, we herein present two unique cases of concurrent late HAT and PVT in which patients survived many years after transplantation with normal graft function. The survival of the allograft in the present cases was due to extensive hepatopetal arterial and portal venous neovascularization.A 47-year-old female with a diagnosis of unresectable hilar cholangiocarcinoma had undergone biliary stents placement, neoadjuvant chemoradiation, brachytherapy, and maintenance chemotherapy according to the Mayo protocol. She subsequently underwent OLT. Concomitant pancreatoduodenectomy with native hepatectomy was performed to completely excise the distal bile duct possibly bearing malignancy and to approach the nonirradiated segment of the portal vein. The anastomosis of the portal vein was performed at the level of confluence between superior mesenteric and splenic veins in end-to-end fashion. The hepatic artery was reconstructed through an infrarenal aortic conduit using a donor iliac artery and the common hepatic artery of the recipient was ligated to avoid anastomosis to irradiated inflow vessel. After that, the continuity of pancreatobiliary and gastrointestinal tracts was restored.On the 7th postoperative day, acute PVT was diagnosed on duplex US and triple phase CT, with subsequent confirmation by mesenteric angiography. Portal vein thrombectomy and anastomotic revision were urgently performed. There was no evidence of ischemic damage to the allograft. A thorough evaluation for hypercoagulable condition did not reveal any abnormalities and empirical anticoagulation with warfarin was started.Six months after transplantation, the patient presented to the hospital with vague diffuse abdominal pain despite all normal laboratory values and therapeutic INR of 2.5 on warfarin, and surveillance DUS discovered PVT and lack of extra hepatic arterial flow. On CT, despite totally obstructive HAT and PVT, the graft liver was well enhanced without perfusion defect or infarcted area. Angiography revealed multiple arterial collaterals supplying the graft. Collaterals from right intercostal arteries, a right adrenal artery, and jejunal branches from superior mesenteric artery were confirmed with angiogram as shown in Figures A 66-year-old male underwent OLT for alcoholic cirrhosis. Operation was done in a piggy bag fashion without venovenous bypass. Bile duct continuity was restored by duct-to-duct anastomosis. Patient had an uneventful postoperative course and two years later developed cyclosporine induced kidney failure for which he received a living donor kidney transplant. The patient also had recurrent episodes of lower extremity DVT and was on warfarin therapy. Six years later he was admitted to undergo colonoscopy for bleeding per rectum and warfarin therapy was withheld in preparation for colonoscopy. Simultaneously patient developed some derangement of liver function and underwent duplex ultrasonography and MRI of liver, which revealed a homogenous hepatic lesion at the dome of liver, intrahepatic portal vein thrombosis, and patency of hepatic artery but a slurring of systolic upstroke. Tumor markers were normal . Thrombophilic workup was unrevealing. Biopsy of the liver lesion revealed normal liver architecture and no rejection. In view of extensive portal vein thrombosis as shown in Figures Complete devascularization of the native liver is difficult to achieve due to the dual blood supply and number of collaterals which develop in case of vascular interruption. Total hepatectomy at the time of transplant disrupts these collaterals; however, allograft may survive only on the portal flow while arterial collaterals develop over few weeks . When thThe foregoing data have made it clear that an effective compensatory mechanism of increased oxygen extraction from the portal venous blood is ordinarily sufficient to maintain hepatic viability. It suggested that many of the fatalities which have followed interruption of the HA are probably due to factors which either have further increased hepatic oxygen needs or have reduced the volume of portal flow like fever, atelectasis, cardiac failure, and shock.Similarly in case of interruption of portal blood flow due to PVT, which accounts for two-thirds of total liver blood flow, the liver allograft has the tendency to survive in most of the cases due to arterial buffer response and rapid development of collaterals, which become apparent in several days, reconstituting the intrahepatic blood flow .We believe that the predisposing factors for vascular thrombosis in our first patient were generalized hypercoagulable state due to previous malignancy, the presence of aortohepatic conduit, and surgical reconstruction of portal vein and portal venous thrombectomy as shown by others , 14. Of In our two cases, the concurrent HA and PVT were detected during the follow-up and the liver function was pristine. The blood flow to the liver was reconstituted by various portal and arterial collaterals. Neovascularization of the ischemic liver is an obscure phenomenon and various mechanisms have been proposed. Some ascribe a role to angiogenic properties of omentum and mesentery . Others In the present two cases we opine that neovascularization might have been triggered by the ischemic liver late in the posttransplant period as the liver got ischemic or the neovascularization might have occurred time ahead of the dual thrombosis permitting the survival of allografts. Robustness of the collateral circulation was elucidated by angiography in both of these cases. Neovascularized hepatic allografts that had suffered late HAT and PVT may survive, though there remains an increased risk of development of ischemic cholangiopathy .Concurrent HAT and PVT early in the aftermath of OLT are devastating complications leading to loss of allograft and necessitating retransplantation. However if the event occurs late, simple observation may suffice provided that the robustness of collateral circulation and reconstitution of intrahepatic blood flow are elucidated angiographically. Nonetheless, these allografts should have more rigorous surveillance due to high risk of ischemic cholangiopathy."} +{"text": "Low utilization of maternal and child care services in rural areas has constrained Pakistan from meeting targets of Millennium Development Goals (MDGs) 4 and 5. This study explores community barriers in accessing Maternal and Child Health (MCH) services in ten remote rural districts of Pakistan. It further presents how the barriers differ across a range of MCH services, and also whether the presence of Community Health Workers (CHWs) reduces client barriers. Qualitative methods were used involving altogether sixty focus group discussions with mothers, their spouses and community health workers. Low awareness, formidable distances, expense, and poorly functional services were the main barriers reported, while cultural and religious restrictions were lesser reported. For preventive services including antenatal care (ANC), facility deliveries, postnatal care (PNC), childhood immunization and family planning, the main barrier was low awareness. Conversely, formidable distances and poorly functional services were the main reported constraints in the event of maternal complications and acute child illnesses. The study also found that clients residing in areas served by CHWs had better awareness only of ANC and family planning, while other MCH services were overlooked by the health worker program. The paper highlights that traditional policy emphasis on health facility infrastructure expansion is not likely to address poor utilization rates in remote rural areas. Preventive MCH services require concerted attention to building community awareness, task shifting from facility to community for services provision, and re-energization of CHW program. For maternal and child emergencies there is strong community demand to utilize health facilities, but this will require catalytic support for transport networks and functional health care centers. Inadequate utilization of maternal and child health (MCH) services remains a major challenge across a number of low and middle income countries. Due to low utilization of MCH services, progress towards the Millennium Development Goals (MDGs) has been stalled in a subset of countries such as Pakistan . Over thWhile there are numerous studies quantitatively identifying determinants of MCH services utilization, the volume of in-depth qualitative evidence is less. Further attention is needed in the poorly performing countries to probe and address residual barriers faced by clients so as to shape relevant health system interventions. There has been a steady expansion in barrier studies in the area of maternal services, particularly over the last decade. These studies have identified the most commonly cited barriers as: traditional and familial influences on decision of place for child birth; mistreatment and misbehavior by health workers; and perceived high cost of facility based childbirth . BarrierIn order to unravel residual barriers three areas should be examined. Firstly, there has been less work undertaken on the comparative analysis across the range of MCH services to identify similar or differing barriers across services. Secondly, barrier studies currently provide the perception of mainstream clients. More contextual evidence is needed from disadvantaged population groups that fail to benefit from the service increase trends throughout the rest of the country. Thirdly, while there has been a spurt in outreach CHW programs in many countries, there is need to explore whether such programs have reduced the community perceived barriers to care seeking compared to other less well-resourced areas.We present here findings from some of the most underdeveloped rural districts of Pakistan on: i) client related barriers reported by pregnant women and their spouses in seeking MCH care; ii) how the barriers differ across emergency, routine curative and preventive care services; and iii) whether there are any differences in perceived barriers across CHWs covered and non-covered areas.Pakistan is the sixth most populous country in the world , and SinIn Pakistan, only 38.8% of births were attended by skilled providers, while figures for rural areas are 29.8% . SimilalTraditionally there has been a policy emphasis in Pakistan on expansion of health facility infrastructure through successive annual development plans. Primary healthcare services are delivered via an extensive network of 5,336 Basic Health Units (BHUs) and 560 Rural Health Centres (RHCs) . ContracAlthough Pakistan has a number of outreach programs, however these have suffered from poor governance and insufficient resource allocation . These iThis study focuses on ten of the most underdeveloped rural districts of Sindh province identified through periodic multiple cluster surveys undertaken by UN agencies, the MNCH program and Health Department of Government of Sindh. These districts were earmarked for placement of result based funding innovations through the Norwegian-Pakistan-Partnership Initiative (NPPI) to improve the MCH coverage rates across the province. The districts included Badin, Jamshoro, Tharparkar, Umerkot, Nawabshah, Larkana, Shikarpur, Kamber, Kashmore and Ghotki. The NPPI initiative in these ten districts was implemented through the MNCH program with the purpose of identifying the measures needed to improve MCH access. This study is part of the baseline studies conducted in 2008-09 for the NPPI initiative to assist in identification and design of necessary innovations. This study used qualitative exploratory design and explored behavioral dynamics, health seeking pattern and barriers for utilizing MCH services. Focus group discussions (FGDs) were conducted with purposively sampled research participants. The target population included i) mothers of children under five, ii) fathers of children under five and iii) LHWs as community level key informants. Altogether 60 FGDs were conducted, 20 with each of the target populations, involving 10 participants per FGD on average. Topic guide was developed for FGDs using literature review and modified according to the local context. It was finalized after consultation with the representatives of UN agencies, provincial government, and MNCH program. FGD guide was pre-tested in one district before initiation of data collection. The topic guide was developed around the themes of ANC, maternal complication, delivery, family planning, immunization, acute childhood illness. Box 1Utilization of servicePreference of provider for utilization and reasonsBarriers to utilization of MCH servicesTaluka (sub-district) of the selected district was defined as a cluster for this study. Two clusters from each study district were selected randomly to collect data. Hence, 20 clusters were sampled across 10 districts.The catchment of public health care facility within each Mothers and fathers of children under five were invited for voluntary and informed participation in the FGDs. One set of client FGDs was conducted in the villages close to the first level care facility (FLCF) within the distance of five kilometers (LHWs covered areas) and the other set of the FGDs was conducted in the peripheral villages of FLCF at a distance of 10-15 kilometers (LHWs un-covered areas) in each district. The villages were selected in consultation with the staff of the selected health facilities. FGDs with LHWs involved random selection of 10 LHWs from the list of LHWs available with each selected health facility. Altogether 1 FGD of LHWs, 1 of mothers and 1 of fathers was held per health facility catchment. Informed consent was taken from all study participants and confidentiality was maintained by entering data against anonymous codes.Using a semi-structured guide, a trained moderator initiated discussion among the group on utilization patterns, preferences of providers and the barriers faced by clients when accessing MCH services. The presence of a moderator ensured the free flow of discussion and facilitated the exploration of emergent topics to obtain a more detailed insight. Another trained researcher accompanied the moderator and recorded noteworthy verbal and non-verbal gestures. Debriefing occurred at the end of each FGD when the moderator summarized key points from the discussion and sought group confirmation of data accuracy. Necessary clarification was sought where disagreement arose. All FGDs were tape recorded and transcripts were prepared based on audio recordings as well as notes taken during the discussions. The data were collected in Sindhi language. It was translated and transcribed by a researcher fluent in both Sindhi and English language. The responses were coded on free nodes using NVIVO software (Version 8.0). These nodes were then organized into parent (tree), child and sibling nodes. Parent node corresponds to each type of MCH service, sibling nodes contained information on: utilization of MCH service, preference for type of healthcare provider, and broader category of barriers, while child nodes denoted issues/reasons identified under each category. In addition, transcripts were read iteratively for deeper understanding of meaning. Interpretation and assertions about findings were made by keeping in view of the local context and cultural practices.Mothers and fathers reported low utilization of MCH services particularly of facility based births, post natal care (PNC), newborn checkup, immunization and family planning. However, most clients reported using antenatal care (ANC) during pregnancy; and facility based care for maternal complications and child illnesses. Those who used services, commonly preferred private clinics over public sector facilities. Participants highlighted a number of barriers to MCH service utilization including: lack of awareness about importance of service utilization, lack of functional public sector services, transportation costs, absence of female staff in health facilities, unaffordability of medicines in private sector, and low mobility of women due to security and cultural issues. Specific barriers for each type of service are listed in Most respondents did not consider it necessary to seek routine ANC in the absence of an ailment. However, those who were interested in seeking antenatal care were not satisfied with the services provided at public sector facilities, forcing clients to seek expensive private sector services. Expense of medicines and transport, long distance from private sector facilities, and inadequate transport facility were frequently cited barriers by the majority who were interested to seek care. Law and order issues in more remotely located villages and gendered norms also restricted the mobility of women who had to wait for escort from spouses and male relatives. One of the participants narrated,\u201cWe do not consider it necessary to seek care without any ailment\u201d Another participant mentioned,\u201cPoverty is the leading barrier. Also there is neither a lady doctor nor good quality medicines available in RHC. Staff attitude is also not good with patients and that is why people do not prefer to visit the RHC\u201d .There were low levels of awareness on the importance of facility based delivery and most participants across all communities preferred home based delivery. Deliveries at the health facilities took place only in cases of complication such as obstructed labor or when traditional birth attendant (TBA) was not competent enough to handle the case.\u201cWhen I was pregnant, my husband decided for institutional delivery. But I did not agree, I had overwhelmingly shown my wish to be delivered at home. I delivered first baby at private hospital (where) I suffered a lot of pains\u2026\u2026 Later on when I delivered baby at home it was much better experience than that of the hospital\u201d .Commonly cited barriers to women seeking facility based births were long distance to facility, and difficulty in finding transport. Other barriers included the fear of Caesarian Section and vaginal examination. Shortage of female provider, blood bank and supplies at public sector facilities was a deterrent to use facility based services and most respondents were apprehensive of the expense of private sector facilities. Necessity of male consent for accessing hospital was required, particularly given the remote rural locations of villages where travel and safety of women was risky.\u201cAlmost all women deliver at home\u2026\u2026\u2026We don\u2019t have other low cost options. If Dai (TBA) feels that delivery at home is not possible then she refers the mother to deliver at a civil (Government) or private hospital\u201d .It was customary not to seek postnatal check-up unless there was a complication or threat to the mother\u2019s/baby\u2019s life. However, the importance of seeking facility based care in cases of maternal complication, such as excessive bleeding; vomiting and abnormal vaginal discharge was well recognized. In such cases, most of the mothers reported seeking treatment early from the nearest female doctor, Lady Health Visitor (LHV) or other private provider.\u201cWe get treatment in maternal complication because of fear of death or any complication or of miscarriage\u201d .The better off families sought care from private sector facilities as they perceived these to be of good quality while poorest people were unable to approach formal healthcare services due to expense of both transport and private medical care. Non-availability of round the clock services and emergency care at nearby hospitals and inadequate transport network delayed use of services.Respondents were generally lukewarm about using contraceptives, but there were few refusals to use contraceptives. Low awareness about available contraceptive services was a major factor for underlying low utilization of contraceptives. There were also complaints of side effects of contraceptive pills and injections, low effectiveness, and irregular supply by health workers.\u201cSome women of this area used injection but after getting this, they had started vaginal bleeding [due to which] we are scared of using contraceptives\u201d .The acceptance and demand for Polio vaccination at the community level was higher than the past due to ongoing polio campaigns and awareness messages through mass media. However they were not aware of other routine vaccinations. Few clients agreed to take vaccines at home but they were reluctant to approach a healthcare facility. Other reported barriers included: lack of information about the availability and schedule of immunization; and fear of side-effects.\u201cThey (Vaccinators/LHWs) come only for polio drops not for other vaccines even we don\u2019t receive any education about benefits of vaccine\u201d .There was low awareness about the importance of routine newborn care and examination. However, there was high recognition of acute child illnesses and utilization of private health sector facilities was reported by most of the respondents. The care seeking for acute child illnesses depends upon multiple factors including unaffordable transport and medicine, perceived severity of illness, and distance from the healthcare facility. The well-off families receive care from private sector irrespective to severity of the illness and distance from health care facility, while the poor and those living in peripheral areas rely on home remedies. Mostly clients reported their mistrust of public health systems for care of child illnesses due to poor quality of care, and un-availability of medicine. Others reported inadequate transport; and issues of safety and security as main barriers for care seeking. A father explains traditional healing methods:\u201cWe wrap Beatle leaves round the chest and back of the child as first line therapy. Mostly children get relieved by this therapy, which we have been practicing for generations\u201d (A father from district Khnoth Jamshoro).The study also differentiated between the type of barriers encountered by catchments covered and not covered by LHWs. Awareness of facility based deliveries, PNC, and immunization was similarly low across both LHW covered andnon-covered areas.More respondents from LHWs covered areas were aware of the importance of seeking ANC as compared to those residing in non-covered areas. However, the use of health provider for ANC visits was reported to be limited in both, the better aware LHW covered areas and the less aware non-covered areas. Expense of transport to health care facilities and recourse to purchase of medicines and diagnostics from private outlets were cited as the main hurdles. One of the LHWs stated:\u201cThose who don\u2019t get ANC\u2026. the reason is poverty! While they (women) realize that ANC visit is necessary but they (women) use to say, from where do we arrange money for transportation and medicine?\u201d .Similarly, respondents from LHW covered areas were relatively aware about use of contraceptives than those in non-covered areas but complained of the irregular supply of condoms and pills provided by LHWs. Those residing in LHW non-covered areas were less aware, however outright refusal to use contraceptives was less noticeable. Those not interested in using contraceptives either expressed the desire of having a male child or fatalistically believed that the number of children is pre-determined by God. As one of the respondents mentioned,\u201cEverything is at God\u2019s will; twins have been born even after having (contraception) pills\u201d (A Father from district Larkana).Respondents across both LHW covered and non-covered areas were less aware of the importance of delivery by skilled attendants, post natal care checkup and newborn checkups. Convenience and ease were the prime factors cited for delivering at home through the help of traditional birth attendants, hence avoiding the hassle, expense and stay over at health care facilities. Postnatal care visit by mother and newborn checkups were relatively unfamiliar concepts for respondents.There was strong buying in to access emergency care in case of maternal complications and newborn acute illness in both LHW covered and non-covered areas. However, respondents from both areas cited delayed care seeking mainly due to unavailability of functional healthcare facilities. LHW covered villages were more closely located to health facilities and respondents here complained mainly of expense of going to private sector due to poorly functional government care facilities. This often resulted in depletion of personal savings or borrowing from neighbors and relatives to seek emergency care. There was general mistrust of using government hospitals.\u201cThe people, who do not have a single rupee (penny) in hand, seek care from civil hospital \u201d .For respondents in LHW non-covered villages the long distance to health facilities was an additional deterrent. Poorly functioning peripheral government facilities made the issue worse as patients had to seek care further away in the district headquarter hospital or crossover to an adjoining district. Both mothers and their spouses from LHW covered and non-covered areas had little knowledge about the importance of routine childhood immunizations, schedule of immunization and access points. Differential barriers to MCH services utilization by outreach coverage are summarized in Qualitative studies are increasingly being recognized as helpful in the identification of barriers faced by individuals and communities in accessing healthcare services. Their value lies in their ability to provide a multi-dimensional and contextual insights not provided by quantitative studies.Pakistan is one of the countries where progress towards MDGs has fallen behind targets. This study is particularly focused on the context of remote disadvantaged districts so as to better inform the placement and utilization of health innovations. The study firstly compares barriers across a range of MCH services within the context of remote districts, and secondly explores whether the presence of community health workers helps reduce community perceived barriers.The study found that continued policy emphasis in expanding the number of government health care centers is not likely to yield results in rural disadvantaged areas of Pakistan. Low community awareness, an under-performing community health worker program, governance issues related to proper functioning of health facilities, and lack of transportation networks are key barriers to health facility utilization for MCH services. These constraints particularly impact facility based births, pregnancy care visits, well-baby checkups and childhood immunization.Community barriers differ across preventive and curative MCH services. Communities are willing to access preventive care services such as if these are provided at the villages, sidestepping the hassle of going to health care facilities, contrary to common perceptions. This is partially due to lukewarm efforts at demand generation within the community and also due to long distances to health facilities in these remote rural districts. Client refusal due to cultural and religious reasons is not a key barrier to use of preventive MCH services. In contrast, there is a strong demand for accessing health facilities in case of maternal complications and acute child illness. However, poorly functional health centers, difficult physical access, and expense of transportation fare and purchase of medicines deter families from timely access. Other qualitative studies have reported quality of care and expeThere are important lessons to be learnt particularly within the context of remote rural districts. Barriers for preventive services are clearly different from those of curative services and require a two pronged approach. In the case of preventive services, task shifting from facility to the community level is required with development of cost effective and simpler packages of care. Moreover, better governance of preventive outreach programs may be beneficial. Child illness and maternal and newborn emergency care will require different modalities. Poor governance of LHWs has been reported by independent quantitative assessments of the program with only 40% of LHWs receiving feedback from their supervisors and 59% of supervisors visiting respective catchments . StudiesWhile some of our findings confirm the existing global evidence, others are contextually different. The findings concur with maternal care studies from other settings showing clients perceiving childbirth as a natural process and skilled providers are only needed in the case of complication . HoweverThe second thrust of the study was to look at differences in community barriers between LHW covered and non-covered areas. There is surprisingly low awareness for facility based delivery, PNC, newborn checkups and childhood immunization, across both LHW covered and non-covered areas. Better awareness is only seen for ANC services and family planning services and these also are confined to the LHW covered areas. This shows that there are critical areas of preventive care- related to the period around delivery and to childhood immunizations- that go unaddressed. It calls for better preparation of outreach workers to expand from ANC and family planning counseling to childhood immunization and promotive care around birth.Our findings concur with quantitative evidence from the The strength of the study is in uncovering the perspective of disadvantaged rural communities, rather than that of the mainstream population. While most qualitative studies are confined to limited geographical areas, this study had the participation of a large number of districts. In addition, it provides a comparison of the types of barriers reported across a range of MCH services rather than solely focusing on a particular service. It also importantly highlights differences in the constraints experienced between catchments served and not served by community health workers. The limitations of this study lie in the exclusion of mother-in-laws who enjoy significant decision making power at a household level over maternity and child care. In addition, the study data collection was limited to a single method of data collection, rather than a triangulation of methods.In the context of remote rural areas, the traditional emphasis on continued investment in health facility infrastructure is not likely to address poor MCH service utilization rates. There is a community demand to utilize health facilities for preventive services, but only if services are provided in villages. Preventive MCH services require a concerted effort to build community awareness, task shifting from facility to community for provision of services, and re-energization of CHWs programs. There is strong community demand to utilize health facilities for maternal and child emergencies, but its translation into timely access requires significant support for transport networks and fewer but more functional health care centers."} +{"text": "There has been an alarming increase in the dumping of Hong Kong's municipal solid waste (MSW), predominantly food waste, in landfill [In 2013, the EPD recorded 16,199 tonnes of used waste oil exported from Hong Kong . We can The purpose of this research is to produce biodiesel from waste cooking oils in the laboratory and compare the quantity and quality of products made from domestic waste cooking oil, restaurant cooking oil and fresh cooking oil. The feedstocks used were domestic deep-frying canola oil, domestic lard, deep-frying oil obtained from a restaurant and fresh canola oil.The biodiesel was produced by alkali transesterification of the waste oils with the addition of sodium hydroxide and methanol to form methyl esters. The products were subjected to a product yield test, density test, pour point test, cloud point determination and gas chromatography.In a comparison of biodiesel yield and quality, household waste cooking oil was a better feedstock than restaurant waste cooking oil.Waste cooking oils should be used for biodiesel production to turn waste into energy. Given the required technology and the huge amount of waste cooking oil generated in Hong Kong, mass production of biodiesel is feasible. Domestic waste cooking oil produced biodiesel with a higher yield and better quality profile than biodiesel from restaurant waste cooking oil. Less downstream processing is therefore needed for the mass production of biodiesel from domestic oil and its potential for industrial biodiesel production is higher.We recommend research into the collection of waste cooking oil at the household level, such as a pilot-scaled collection and production scheme in large estates. The government should provide outlets for biodiesel in Hong Kong, for instance electricity in estates or a subsidy for drivers choosing to use environmentally friendly biodiesel as fuel."} +{"text": "Nourishing Networks (NN) is an innovative interprofessional learning program delivered in 2009 and again in 2014 for health professionals managing eating disorder clients in rural NSW. It was designed to enhance local networks and improve the knowledge, skills and attitudes of health professionals working with eating disorder clients.Impetus for re-delivering the program was high turnover of staff in rural communities and need to increase awareness of existing services. Identification of clients late in the course of illness remained a reoccurring issue.The original program consisted of a 10 week self-directed learning program with videoconferencing and a one-off workshop for health professionals. The revised program utilised a travelling roadshow to three rural locations to provide better access for outlying sites. This provided increased opportunities for networking and upskilling to a wider audience. The revised program attracted a greater range of health professionals with further involvement of general practitioners. Overall the program trained 254 participants, from nine different health professional backgrounds.Nourishing Networks has led to improvements in clinician confidence in identifying and assessing eating disorder clients, improved quality of referrals to existing clinicians, new services in some rural communities and an increase in GPs prepared to manage the clients."} +{"text": "With this characteristic of silencing, miRs act as an important component in regulation of plant responses in various stress conditions. In recent years, with drastic change in environmental and soil conditions different type of stresses have emerged as a major challenge for plants growth and productivity. The identification and profiling of miRs has itself been a challenge for research workers given their small size and large number of many probable sequences in the genome. Application of computational approaches has expedited the process of identification of miRs and their expression profiling in different conditions. The development of High-Throughput Sequencing (HTS) techniques has facilitated to gain access to the global profiles of the miRs for understanding their mode of action in plants. Introduction of various bioinformatics databases and tools have revolutionized the study of miRs and other small RNAs. This review focuses the role of bioinformatics approaches in the identification and study of the regulatory roles of plant miRs in the adaptive response to stresses. Plants are exposed to a wide array of environmental fluctuations that lead to various physiological and metabolic changes, which in turn adversely affect the growth and productivity. Abiotic stresses are the principal cause of decrement in crop production globally and are responsible for lowering the average yield of major crops by more than 50% , wind, salinity, heavy metal toxicity, nutrient deprivation in soil, and oxidative stress , hydroxyl radicals (OH), and hydrogen peroxide (H2O2) that block specific messenger RNAs (mRNAs) at the post-transcriptional levels by cleavage or translational repression represents a major sub-family of endogenously transcribed sequences, ranging in length from 21 to 24 nt and J033125N22 (AK103332), respectively in the D bodies (Dicing bodies) or SmD3-bodies includes 48,496 mature plant miRs derived from 6992 hairpin precursors reported in 73 plant species data. Each of these was followed by experimental validations by northern analysis, PCRs or microarrays.a priori knowledge of miR sequence was not required. Moreover, it provided more accuracy and efficiency by giving few false positives. Several related studies led to the establishment of different protocols for sRNA isolation and adaptor mediated synthesis of a cDNA library followed by their amplification and then cloning. The clones were screened and sequenced to identify the potential miRs . It was observed that several miRs were up-regulated or down-regulated by the abiotic stresses in several plants including Arabidopsis were predicted from in silico probes. This target-guided strategy was adopted to identify 16 families of drought stress-associated miRs from Physcomitrella patens database. These represented the true gene expression entities so they emerged as better indicators of dynamic expressions of the miR. A detailed study by identified 123 miRs from stress-induced ESTs of 60 plant species technology, which enable accessing the full complexity of sRNAs in plants. In addition, it provides quantitative information of the expression profiles, since the cloning frequency of each sRNA generally reflects its relative presence in the sample. The signature-based expression profiling method such as massively parallel signature sequencing (MPSS) has identified miRs that have thus far proven difficult to find by using traditional cloning or Figure 5). These datasets have been very successful in identification of conserved miRs where the sequence is well maintained across plant species. The targets for these miRs can also be easily predicted using Parallel Analysis of RNA End (PARE) sequencing, where miR and its target mRNA have often nearly perfect complementarily makes it easy to use for researchers, do not needs any prior knowledge of computer programming and pre-processing of NGS data. Although it is a good tool for preprocessing of NGS data but it focuses more on other genomic areas such as It uses a homology-based approach for plant miR and target identification. The tool aligns known miRs from different plant species to the EST sequences of the query plant species using blast homology search. The aligned sequences are allowed to fold in to the characteristic hairpin loop structures to identify the putative miRs. The predicted miR sequences are further used for identifying perfect or nearly perfect complimentary sites on the input transcript sequences to identify the putative targets. The tool has a unique feature of predicting the secondary structures of the miR-target duplexes. The identified targets can be annotated further by searching their functions and Gene Ontologies (GO) that consolidates extensive datasets of rice miRs from various deep sequencing datasets for examining the expression changes with respect to their targets. Development of such interactomes for different plant species shall provide a valuable tool to biologists for selecting miRs for further functional studies.miRs are an extensive class of endogenous, small regulators of gene expression in the numerous developmental and signaling pathways. There is ample evidence for the role of miRs in abiotic stress mediated genomic changes that result in attenuation of plant growth and development. The different experimental approaches have identified the intriguing expression profiles of miRs in distinctive tissues and/or stages of development. The regulation of miR expression also varies between the domesticated plant species and their wild relatives. Sequence-based profiling along with computational analysis has played a pivotal role in the identification of stress-responsive miRs, although these results require independent experimental validations. sRNA blot and RT-PCR analysis have played an equally important part in systematically confirming the profiling data. The identification of putative targets for these miRs has provided robust confirmation of their stress responsiveness. This has also enabled quantification of their effect on the genetic networks, such that many of the stress regulated miRs have emerged as potential candidates for improving plant performance under stress. However, so many efforts are still required for in-depth analysis of the miR modulation of each gene product induced by abiotic stress(es) and its interacting partners. This requires development of reliable and rigorous assays for firm characterization of the spatio-temporal regulation of these miRs under stress conditions. The potential of computational biology needs to be tapped for performing an extensive comparison of miR expression profiles among agriculturally important crops during environmental stress conditions to tap key target nodes that need to be modulated for improving crop tolerance to environmental stress. The development and integration of plant synthetic biology tools and approaches will add new functionalities and perspectives in the miR biology to make them relevant for genetic engineering programs for enhancing abiotic stress tolerance.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "P. falciparum. Most antimalarial drugs face decreased efficacy due to the spread of resistance. Most of the current compounds used for malaria treatment share related mechanisms of action so, there is an urgent need to identify new tractable targets to enable next generation of antimalarial drugs.Malaria is a global health problem that causes significant mortality and morbidity, with more than 1 million deaths per year caused by The malaria drug discovery community has embraced phenotypic screening approaches as the strategy of choice for the generation of novel chemical starting points for Lead Optimization programs. Determining the mode of action for novel whole cell hits remains a challenge, but new technologies, including genetics, chemoinformatics and proteomics are proving successful.A chemical proteomics platform aimed at identifying antimalarial targets has been established. This platform is supported by The Bill & Melinda Gates Foundation and encompasses chemical probe synthesis, biological material preparation, pull down experiments and LC-MS protein-lead family characterization for chemical families of interest. Candidate scaffolds to be investigated through this platform are selected based on their biological profile by a join Steering Committee constituted by both GSK and BMGF members."} +{"text": "Posterior Reversible Encephalopathy Syndrome (PRES) is a clinical neuroradiological condition characterized by insidious onset of neurological symptoms associated with radiological findings indicating posterior leukoencephalopathy. PRES secondary to cerebrospinal fluid (CSF) leak leading to intracranial hypotension is not well recognized etiology of this condition. Herein, we report a case of PRES that occurred in the setting of CSF leak due to inadvertent dural puncture. Patient underwent suturing of the dural defect. Subsequently, his symptoms resolved and a repeated brain MRI showed resolution of brain lesions. The pathophysiology and mechanistic model for developing PRES in the setting of intracranial hypotension were discussed. We further highlighted the importance of tight blood pressure control in patients with CSF leak and suspected intracranial hypotension because they are more vulnerable to develop PRES with normal or slightly elevated bleed pressure values. Posterior Reversible Encephalopathy Syndrome (PRES) is a clinical neuroradiological condition characterized by insidious onset of headache, altered mental status, seizures, and cortical blindness associated with findings indicating posterior leukoencephalopathy on imaging studies . AlthougA 72-year-old man with history of controlled hypertension and chronic back pain underwent spinal fusion and laminectomy surgery from the third lumber to the first sacral vertebral bodies. Surgery was complicated by CSF leak due to inadvertent puncture of the dura that presented one week postoperatively with fluid collection at the site of the surgical incision. The patient was admitted to the hospital for further evaluation and management. He developed a moderate diffuse postural headache that was thought to be related to CSF leak. He was managed conservatively with analgesia and hydration and underwent a blood patch. An external lumbar drain (ELD) was placed to reduce the leak, speed up the healing at the dural puncture site, and monitor the quantity of the leak. A total of 1150\u2009mL of fluid leak was recorded over the subsequent one week. On postoperative day fifteen, the patient developed severe occipital headache and transient vision loss for few minutes with deterioration of mental status, followed by tonic-clonic seizure. Blood pressure was elevated at the level of 170/100\u2009mmHg. Seizure was controlled by lorazepam and the patient started on levetiracetam 500\u2009mg bid. Brain computed tomography scan (CT) excluded intracranial bleeding. The patient did not regain consciousness completely after the seizure and continued to be confused for few hours. Hence, magnetic resonance imaging (MRI) was performed and showed leptomeningeal enhancement and high signal intensity lesions in the subcortical white matter involving both hemispheres consistent with PRES Figures . MagnetiThe pathophysiologic process underlying PRES is not well understood. In hypertensive emergency state, the extremely elevated mean arterial blood pressure (MAP) results in increased cerebral perfusion pressure (CPP) and brain hyperperfusion which subsequently leads to cerebral blood vessels autoregulatory failure and endothelial dysfunction , 4. The In our patient, PRES was diagnosed based on typical clinical presentation and MRI finding after excluding central nervous system infections. The magnitude of blood pressure elevation was not convincing enough to consider it as the primary precipitant of PRES in this patient and there were no other known risk factors to be blamed. Therefore, we hypothesized that the moderate elevation in blood pressure associated with the intracranial hypotension secondary to the CSF leak caused a degree of hyperperfusion that precipitated PRES and intracranial pressure (ICP). Either an increase in MAP or a decrease in ICP will result in an increase in cerebral perfusion pressure (CPP) and tacitly the brain perfusion. When the cerebral blood flow autoregulatory mechanisms are overwhelmed by the severe increase in the CPP, it results in hyperperfusion. This further leads to endothelial dysfunction at cellular level and subsequent vasogenic edema. Our patient has significant CSF leak of more than a liter over one week which resulted in decreased ICP and increased CPP.Furthermore, as the volume inside the cranium is a fixed volume composed of CSF, blood, and brain tissue, any decrease in volume of one constituent must be compensated by an increase in volume of the other constituents . In our PRES associated with CSF leak has been reported previously in the literature particularly in the setting of epidural tap see . In six In general, the prognosis of PRES is favorable if it is detected early and the precipitating factors are treated properly , 18. In"} +{"text": "Paramedics are a skilled group of clinicians with expertise in cardiac arrest. Our research group has complete a trial to comparing two supraglottic airway devices with current practice during cardiac arrest (REVIVE-Airways). This is a highly contentious topic amongst UK paramedics, The study aimed to explore the existing customs and beliefs surrounding intubation and resuscitation by UK paramedics.We used a two level qualitative approach, conducting interviews and focus groups with paramedics. Focus groups discussed the themes arising from the interview data, developing a deeper understanding and providing insight and recommendations for future research and policy development.The study took place within Great Western Ambulance Service NHS Trust (GWAS). The University of the West of England, Bristol, provided sponsorship and governance. As the trial was on NHS staff ethical committee approval was not required.Paramedics were sampled purposefully to account for differing training and subsequently customs and beliefs and participation or not in the large trial. Supplementary snowballing was used to further identify interested/eligible paramedics. There were 34 study participants, with 17 paramedic interviews; followed by 5 focus groups with a further 17 participants. Data saturation was reached.Thematic analysis was conducted. This was done in 2 stages: after interviews as a guide for focus groups, and after the focus groups. Early analysis suggests that this group of paramedics were pro-research even though some had not taken part in the earlier trial. They described four aspects of paramedic identity figure ..Specific discussion regarding intubation was focussed upon patient safety, with debate regarding the necessity of intubation in comparison to the use and success of other techniques. This stimulated concern regarding lack of training and subsequent skill fade through lack of rehearsal and competency testing. This invigorated debate about whether all paramedics should perform this task. Views differed with some vehemently protective of this skill, while others were more sanguine about this in relation to other recent skills. Frequent reference was made to the difficult situations paramedics find them selves in, specific injuries or illnesses and co-morbidities and the difficulty in retrieval of patients as a rationale for retaining the skill.Future trials in prehospital care must involve paramedics and ensure their professionalism is understood and respected."} +{"text": "The presence of pulsating varicous veins is an uncommon finding, generically attributed to right heart failure. The precise causes of this phenomenon have been poorly defined in the literature. The finding of this infrequent condition is important because it may be a sign of major diseases, often not known. Here we described a 75-year-old woman presented to the Angiology Unit for the presence of bilateral pulsatile swelling in her groin and along both lower limbs. A bedside ultrasound examination showed an arterial like pulsating flow both in the superficial and in the deep veins of the lower limbs due to a severe tricuspid regurgitation not previously known. Pulsed Doppler ultrasonographic examination of veins in proximity to the heart shows, in normal condition, a multiphasic wave with two anterograde components, one large systolic wave (S) and one smaller diastolic wave (D), as well as two retrograde waves (a and v). The S wave represents the maximum systolic velocity and is caused by the negative pressure from atrioventricular septal movement toward the cardiac apex. The v wave is produced by positive intra-atrial pressure owing to atrial filling. D wave is consequence of negative intra-atrial pressure resulting from opening of the tricuspid valve. The a wave is produced by the positive intra-atrial pressure, secondary to atrial contraction. This typical waveform is less evident in lower limb veins because the high compliance and high capacitance characteristics of lower extremity venous system dampen the pulsatility and the flow in these venous districts is typically described as spontaneous with a respiratory phasicity . In presHere we described a 75-year-old woman presented to the Angiology Unit for the presence of bilateral pulsatile swelling and pain in her groin and along both lower limbs. Her medical history included arterial hypertension and bilateral varices along both great saphenous veins. Patient was taking an ACE inhibitor.Physical examination confirmed the presence of abnormal bilateral pulsatile groin swelling and pulsating vein ectasias along the entire course of the great saphenous veins. A bedside ultrasound examination was performed. Doppler sonographic examination showed an arterial like pulsating flow in the saphenous femoral junction and alonOn the basis of clinical and sonography findings we concluded for severe tricuspid regurgitation with repercussions on the peripheral venous system.In agreement with the cardiologist diuretics and class 2 graduated compression stokings were prescribed, clinical and cardiovascular imaging follow-up were also programmed.Varicose veins in lower limbs are common. Most varicose veins are primary; only the minority are secondary to conditions such as deep vein thrombosis and occlusion, pelvic tumours, or arteriovenous fistulae.In the literature there are some case reports describing pulsating varicose veins secondary to right heart failure in some cases due to tricuspid regurgitation, but the demonstration of an arterial like pulsating flow along such veins is less frequent \u201322.The lower limb venous Doppler sonography is now widely used by different medical specialists: radiologists, vascular surgeons, internists, cardiologists, and angiologists; the careful interpretation of a simple and widely used venous Doppler ultrasound may open more complex, often not known, scenarios.In this case report we would like to strengthen the concept that, although infrequent, the presence of pulsating varicose veins and its peculiar waveform could bring out the presence of cardiac abnormalities and direct clinicians to proper course of investigation and management."} +{"text": "How the sophisticated vertebrate behavioural repertoire evolved remains a major question in biology. The behavioural repertoire encompasses the set of individual behavioural components that an organism uses when adapting and responding to changes in its external world. Although unicellular organisms, invertebrates and vertebrates share simple reflex responses, the fundamental mechanisms that resulted in the complexity and sophistication that is characteristic of vertebrate behaviours have only recently been examined. A series of behavioural genetic experiments in mice and humans support a theory that posited the importance of synapse proteome expansion in generating complexity in the behavioural repertoire. Genome duplication events, approximately 550 Ma, produced expansion in the synapse proteome that resulted in increased complexity in synapse signalling mechanisms that regulate components of the behavioural repertoire. The experiments demonstrate the importance to behaviour of the gene duplication events, the diversification of paralogues and sequence constraint. They also confirm the significance of comparative proteomic and genomic studies that identified the molecular origins of synapses in unicellular eukaryotes and the vertebrate expansion in proteome complexity. These molecular mechanisms have general importance for understanding the repertoire of behaviours in different species and for human behavioural disorders arising from synapse gene mutations. T. TDlg paenes (a) , GluN2A a) compared the results of touchscreen tests of cognitive behaviours in humans and mice carrying Dlg2 mutations. They found that both humans and mice carrying Dlg2 mutations showed impairments in the same components of the cognitive repertoire and if there was sequence variation in these genes between species, this particular behaviour could be tuned accordingly. Such mechanisms might be relevant to the differences between species such as ungulates where some species (mountain goats) dwell on precipices whereas others dwell on plains (antelopes). Hypotheses regarding the role of gene function and environmental niches could be tested by at least two approaches: the Dlg and GluN2 mutant lines of mice could be studied in more ethologically relevant environments, and genetic variants identified in other species could be engineered into the mouse genome for later behavioural testing.The synapse proteome expansion theory of vertebrate behavioural complexity has many implications for behaviour. In addition to Dlg paralogues showed specific combinations of Dlg genes were required for specific behaviours [Dlg mutations. Thus, there is not simply a redundant and promiscuous use of paralogues in the specification of components of the behavioural repertoire. Little is known about the derived restrictions and specializations that were responsible for controlling the behaviour repertoire and limiting the complexity explosion. In addition, these findings suggests a mechanism by which ancestral behaviours, regulated by an ancestral gene, can give rise to a set of related, but independently regulated, derived forms of that behaviour.The combinatorial action of duplicated genes is another mechanism that shapes the behavioural repertoire of vertebrates and has a direct link to synapse proteome complexity. An intrinsic feature of genome duplications is the multiplicative complexity that arises from the action of combinations of genes. To illustrate this, consider an ancestral receptor assembled from four subunits, each encoded by a single gene, and after 2WGDs there would be 16 genes that could be organized into a very large number of types of receptor. As the number of subunits or components in multiprotein complexes or pathways increases, the potential for vast multiplicative complexity and diversity arises from genome duplications. It is therefore important to identify the paralogue specializations that reduce this complexity. In this context, a clustering analysis of behavioural components and haviours ,25. SurpIn addition to the role of genome duplications in synapse proteome expansion, alternative splicing also generates diversity within protein isoforms. Alternative splicing is highly abundant in the central nervous system of vertebrates \u201328. InteDlg paralogues, which likely arose by gene rather than genome duplication [Drosophila is less complex than that of mouse synapses [Dlg genes in octopus encode synapse proteins and whether there are other synapse proteins that have expanded. The physiological and behavioural functions of octopus Dlg proteins remains unknown, although it is perhaps likely that the Dlg paralogues diversified the organization of the protein complexes in octopus synapses and generated multiple forms of synaptic plasticity, as observed in mice [Ciona [Dlg genes in octopus will be feasible, although the techniques for introducing materials into octopus eggs await development. It may even be possible to perform exchange of paralogue domains at the genomic level, as has been done in mice [Octopus are cephalopods with large nervous systems and among invertebrates are considered to have complex behaviours ,31. Theylication . Althougsynapses , it will in mice ,11. The in mice ,34, worm in mice and Cione [Ciona , hold ou in mice . These tDlg and GluN2 paralogues differentially distributed, but so are many of the other synaptic paralogues [Synapse proteome expansion in vertebrates also provides a perspective on anatomical complexity. The vertebrate expansion of synapse proteins was shown to result in differential distribution of synaptic proteins in different brain regions in mice and humans ,37. Imporalogues ,37. ThesDlg2 mutations result in schizophrenia and Dlg3 mutations in intellectual disability with autism features [The synapse proteome expansion and its sophisticated behavioural repertoire have come at the price of susceptibility to mental illness, because disease-causing mutations occur in many of these vertebrate paralogues. For example, features ,23,39\u201346Behavioural mouse genetics studies have largely overlooked the concept of the behavioural repertoire and have typically focused on specific component of behaviour. It is essential for scientists to develop strategies to examine the behavioural repertoire and further understand its genetic architecture. This is no less important than understanding the genetic architecture of the body plan (bauplan) or the immune response. These key areas of biology have been transformed by the understanding of homeobox genes and immunoglobulin gene structure, respectively, and both have genetic mechanisms that have been powerfully shaped and underpinned by gene and genome duplication events.Finally, we can revisit the insights of the nineteenth century pioneers who drew connections between synapse mechanisms, general features of behaviour including continuums from simple to complex behaviours, and shared mechanisms found in many life forms. A molecular understanding of the building blocks of the behavioural repertoire may lead to unifying theories of behaviour. The postsynaptic mechanisms appear to be such building blocks and with new methods of experimental genetics there is an exciting new prospect for many ethological and laboratory studies of behaviour in a wide range of species."} +{"text": "Introduction. Pelvic floor dysfunction syndromes present with voiding, sexual, and anorectal disturbances, which may be associated with one another, resulting in complex presentation. Thus, an integrated diagnosis and management approach may be required. Pelvic muscle rehabilitation (PMR) is a noninvasive modality involving cognitive reeducation, modification, and retraining of the pelvic floor and associated musculature. We describe our standardized PMR protocol for the management of pelvic floor dysfunction syndromes. Pelvic Muscle Rehabilitation Program. The diagnostic assessment includes electromyography and manometry analyzed in 4 phases: (1) initial baseline phase; (2) rapid contraction phase; (3) tonic contraction and endurance phase; and (4) late baseline phase. This evaluation is performed at the onset of every session. PMR management consists of 6 possible therapeutic modalities, employed depending on the diagnostic evaluation: (1) down-training; (2) accessory muscle isolation; (3) discrimination training; (4) muscle strengthening; (5) endurance training; and (6) electrical stimulation. Eight to ten sessions are performed at one-week intervals with integration of home exercises and lifestyle modifications. Conclusions. The PMR protocol offers a standardized approach to diagnose and manage pelvic floor dysfunction syndromes with potential advantages over traditional biofeedback, involving additional interventions and a continuous pelvic floor assessment with management modifications over the clinical course. Pelvic floor dysfunction syndromes include voiding, sexual, and anorectal disturbances characterized by urinary and fecal incontinence, pelvic pain, and/or constipation/anismus. Many patients with such syndromes present with concomitant pelvic functional disorders resulting in complex clinical picture . As suchPelvic muscle rehabilitation (PMR) is a multidisciplinary program that involves numerous rehabilitation principles such as muscle floor retraining, biofeedback, and electrical stimulation of the pelvic floor and functionally associated musculature. This program integrates the clinical presentation and assessment of the pelvic floor to identify the physiologic stressors and abnormalities from which a therapeutic program is individualized and prescribed. We initially introduced the concept into our practice in 2006 and we have since optimized the program based on clinical outcomes and reproducibility of results.We present and describe the basis of our comprehensive PMR protocol for the diagnosis and management of pelvic floor dysfunction syndromes. The protocol encompasses the concepts of muscle floor training, physiologic quieting, biofeedback, electrical stimulation, and discrimination training.Patients presenting with a prior diagnosis of pelvic floor dysfunction including urinary incontinence (UI), fecal incontinence (FI), obstructed defecation syndrome (ODS), and chronic pelvic pain (CPP) undergo a thorough evaluation, which initiates with an interview and review of symptoms. The patient interview is focused on the onset and severity of symptoms, past medical and obstetric history, medications, and history of psychological or social stressors. A systematic review of symptoms is performed to identify the presence of contributing factors such as gastrointestinal, genitourinary, endocrine, or pelvic floor disorders. Depending on the presentation, a series of pelvic health-related or bowel-focused questionnaires are completed by each patient to assess overall quality of life and severity of dysfunction.A physical exam is then performed including a thorough evaluation of the pelvic floor functional anatomy. Diagnostic evaluations and treatments are done using the Pathway CTS 2000 and are performed to assess the physiologic and functional status of the pelvic floor and accessory muscle groups. These tests include anal manometry and electromyography (EMG). Manometry is performed to quantify muscle tone and contractility of pelvic muscles using a pressure sensor inserted through the anal sphincter. On verbal command, the patient is asked to voluntarily contract and relax the anal sphincter muscles. The series of contractions and relaxations are repeated and the results are recorded over a specific time interval. Baseline manometric results can identify altered pelvic muscle function and categorize the pelvic floor syndrome into two broad categories: hypotonic and hypertonic. initial baseline phase: 60-second evaluation with the patient at rest to determine the initial resting baseline EMG; (2) rapid contraction phase: recording of electrical activity while performing five phasic rapid contractions; (3) tonic contraction and endurance phase: recording of electrical activity of pelvic floor and abdominal wall muscles following a total of 5 contractions of 10 seconds each, with a resting interval time of 10 seconds; (4) late baseline phase: 60-second evaluation with the patient at rest to determine the final resting baseline EMG activity.Electromyography is performed using an internal vaginal or rectal sensor and surface patch electrodes to evaluate accessory muscle activity. Two EMG surface electrodes are placed on the rectus abdominal muscle, two fingerbreadths apart and medial to the anterior superior iliac spine (ASIS), and one ground electrode is placed on the hipbone. With the internal sensor inserted, the patient is asked to repetitively contract and relax the pelvic floor muscles. Measurements are recorded and analyzed in 4 phases: (1)Following the diagnostic evaluation, the practitioner prescribes a therapeutic program in which one or a combination of 6 modalities is involved. The therapeutic sessions are guided by the patient clinical presentation and the results of the diagnostic EMG and/or manometry. Each session will last from 15 to 45 minutes depending on the modalities utilized and the response to the therapy. The combination of the diagnostic assessment and therapeutic intervention is what we call PMR. muscle isolation: elimination of accessory muscle substitution through identification and modulation of associated muscle groups e groups ; (2) distraction ; (3) pelruitment ; (4) endractions ; (5) dowing tone ; and (6) fatigue . Each ofAdditional adjunct therapies offered for patients with CPP, UI, and ODS associated with levator and pelvic floor spasm include physical therapy and cognitive behavioral therapy. Physical therapy encompasses the manual manipulation of the pelvic floor and includes visceral and muscular manipulation as well as bone alignment and trigger point release. Cognitive behavioral therapy consists of various psychotherapy sessions in an individual or couple setting and relies heavily on a well-developed patient-therapist relationship. This goal-oriented technique addresses dysfunctional emotions, behaviors, and cognitive processes related to the patient's pelvic disorder.We describe a standardized PMR protocol for the assessment and management of pelvic floor dysfunction syndromes. The protocol is employed not only to address a single manifestation but also to treat complex presentations and those with multiple disorders . This PMR protocol involves the principles of pelvic floor and associated muscle groups isolation, discrimination, strengthening, and conditioning. Furthermore, the concepts of biofeedback, physiological quieting, and electrical stimulation are utilized as an adjunct to achieve functional and clinical enhancement of pelvic floor dysfunction syndromes.Traditional pelvic floor treatment protocols typically involve a single modality of intervention such as biofeedback or muscle training or a combination of two modalities. Such protocols have been employed with variable rates of success. It has been shown that the addition of biofeedback to muscle exercise programs results in improved fecal incontinence outcomes compared with muscle exercises alone . For uriOur approach with a comprehensive PMR program differs from standard biofeedback in many ways. One of the unique features of the PMR protocol is that it is heavily dependent on the treating practitioner and the therapeutic interventions are both individualized and adjusted at each session based on the clinical and physiological picture. The practitioner defines and identifies the pelvic floor physiologic disturbances through diagnostic testing and then establishes the therapeutic modalities that are best employed to overcome the abnormalities in a step-wise fashion. Thus, it is critical that the rehabilitation sessions begin with a thorough discussion of the clinical symptoms combined with an assessment of the pelvic floor functional and physiological abnormalities.Another difference is that in traditional biofeedback program, the patient is prescribed a protocol and the same program is performed at given intervals to achieve pelvic retraining. The limitation of such a program is that it is a defined and fixed protocol and does not vary or take into consideration response to therapy or alterations in pelvic physiology. Furthermore, the patients are often dependent on the visual cues of the biofeedback as a crutch to achieve the functional goal of the program. Hence, the effective and successful cognitive training of the pelvic floor muscle complex is often not translated into activities of daily living in which these sensory cues are absent. In our PMR protocol, the patients are reevaluated and rediagnosed on each visit to determine the proper intervention at the given visit. As such, the therapeutic modalities employed on each visit may vary from the previous or further interventions. This approach affords continuing assessment of the functional and clinical pelvic floor dysfunction appropriately addressing their management to achieve best results.The primary single endpoint of our protocol is to improve quality of life. The protocol relies on patient satisfaction Likert scale and the goal is set for good or excellent improvement. Nonetheless, physiologic parameters are evaluated on each visit to document progress and serve also as endpoints of the protocol. We consider the clinical presentation along with interpretation of the physiologic abnormalities identified on EMG/manometry to direct the therapeutic intervention on a case by case basis . From thIn our experience, we believe there is a positive concordance rate between clinical outcomes and physiologic parameters on EMG and manometry. However, the extent and reproducibility of these correlations in regard to quality of life metrics will require further investigation.Although an economic analysis was beyond the scope of this paper, an important consideration of any protocol is the associated costs and fees. Such a cost analysis will need to include the fees associated with surgical interventions and other resources that are often avoided following completion of a pelvic muscle rehabilitation program.The PMR protocol offers a standardized and comprehensive approach to both diagnose and manage pelvic floor dysfunction syndromes. This PMR program provides potential advantages over traditional biofeedback, as it involves the employment of additional therapeutic interventions including muscle isolation, discrimination, conditioning, and strengthening, as well as physiological quieting and electrical stimulation. Moreover, the PMR program affords a continuous pelvic floor assessment with the according management modifications. Further clinical studies are warranted to evaluate the clinical results of the PMR protocol to formulate solid conclusions."} +{"text": "Temporomandibular Disorder (TMD) tends to coexist with other chronic pain conditions in affected individuals and is characterized by a report of pain greater than expected based on the results of a standard physical evaluation. The pathophysiology of this condition is largely unknown, the scientific field lacks biological markers for accurate diagnosis, and conventional therapeutics have limited effectiveness. Growing evidence suggests that chronic pain conditions are associated with both physical and psychological triggers, which initiate pain amplification and psychological distress; thus, susceptibility is dictated by complex interactions between genetic and environmental factors .The large human study named OPPERA, Orofacial Pain Prospective Evaluation and Risk Assessment Study, measures both phenotypic and genotypic markers in the TMD patients. The phenotypic markers of greatest interest include measures of pain amplification and psychological measures such as emotional distress, somatic awareness, psychosocial stress and catastrophizing. Genetic markers are also measured in a study by genotyping 2,924 single-nucleotide polymorphisms representing 358 genes known to be involved in systems relevant to pain perception .The OPPERA findings provided evidence for few single single-nucleotide polymorphisms to be associated with risk of TMD . FurtherElucidation of the biological mechanisms by which these markers contribute to the perception of pain in these patients will enable the development of novel effective drugs and methodologies that permit better diagnoses and approaches to personalized medicine.No financial relationships to disclose."} +{"text": "Involvement of lymph nodes in various pathologies of the head and neck is frequent not only in malignant diseases but also in inflammatory conditions. As size criteria are not sufficient to define a lymph node as malignant, other criteria such as shape, central necrosis and extracapsular spread are other helpful signs. However, micrometastases are still an unresolved problem although new imaging methods have already shown promising results. Typical imaging features of CT and MRI indicating extracapsular spread and carotid artery invasion will be discussed as these have therapeutic and prognostic implications.Although salivary gland pathologies are relatively rare, its large variety of differential diagnoses makes it challenging. In children and pregnant women, sonography is the first step, and CT is the method of choice in inflammatory disease. MRI is the first line examination in palpable salivary gland masses to assess the exact extent of tumours, the invasion of neighbouring structures, perineural spread and bone invasion. Differential diagnoses and imaging features of the most frequent tumour types will be discussed and an approach to differentiate between benign and malignant lesions will be provided."} +{"text": "Over recent years an increasing number of complex, high risk clients from a newly arrived refugee background have presented for podiatric intervention within Barwon Health. Whilst the clinical presentations alone have proved unusual and challenging, a range of cultural and psycho-social factors have required negotiation in order to obtain optimal patient outcomes.This presentation aims to share details relating to the experience of managing 3 particularly challenging refugee cases and the successful strategies that were employed to maximise client outcomes and demonstrates the expertise which has been developed in this niche area of podiatry service delivery.Podiatrists employed a range of culturally sensitive strategies to effectively manage clients presenting with Hansen's disease, Rickets and a Diabetes foot wound/ calcaneal fracture. These included the delivery of group education programs in languages other than english, client advocacy, working closely with family members and interpreters, negotiating health beliefs and customs, obtaining funding and problem solving around social factors that were impacting on foot health.Employing a patient centred, culturally sensitive approach was essential in obtaining the trust and engagement of clients from a refugee background. To maximise client outcomes, these strategies should become an integral component of the approach of all podiatrists who work with culturally and linguistically diverse populations."} +{"text": "Their use for imaging and intravascular intervention keeps increasing particularly in less healthy and older patients . The risiability \u20139.Thus, clinicians and radiologists, in clinical practice, ask themselves: \u201cAre iodinated radiocontrast agents nephrotoxic? If so, what are the risk factors for CIN? And what are the appropriate procedures to prevent CIN?\u201dTo answer these questions a special issue on side effects of radiographic contrast media was believed necessary, appointing expert authors to review the various aspects of contrast media nephrotoxicity. To help me in finding these expert authors, two outstanding Guest Editors were appointed: Richard Solomon and Adis Tasanarong .2+ and Na+/Ca2+ exchanger in the pathogenesis of CIN. Neither diabetes [ per se can be considered main risk factors, but the important role of associated renal insufficiency and other clinical conditions in predisposing to CIN is discussed in depth. The current evidence on ACE-I/ARB therapy for patients undergoing procedures involving use of contrast media is also reviewed. The quest to find new strategies to prevent CIN has led to a recent clinical study suggesting the use of tocopherol [For this volume we have invited authors who have been dealing with various aspects of contrast media toxicity. A wide array of topics are discussed in this special issue, including molecular mechanisms of renal cellular nephrotoxicity due to radiocontrast media; the considerable difference among iodinated contrast agents with regard to their osmolality and viscosity and the potential role of their osmolality and viscosity in the pathophysiology of CIN; the changes of renal hemodynamics as well as the renal tubular changes induced by iodinated contrast media; the crucial role of reactive oxygen species in causing CIN; and the role of intracellular Cadiabetes nor multdiabetes per se ccopherol . In this"} +{"text": "In 2012, the World Health Assembly of the World Health Organization (WHO) declared the completion of polio eradication a programmatic emergency . The GloGPEI partners, including WHO regional office teams, have assessed the risks for WPV outbreaks and cVDPV emergence in polio-free countries to support planning and prioritization of risk mitigation activities; a harmonized risk assessment approach has been used across WHO regions since 2011 . The quaCountries in the WHO AFR collect and review district-level data to make a qualitative determination of a country\u2019s risk for an outbreak after a WPV importation or emergence of cVDPV and determine subnational areas at highest risk. A similar process is conducted by countries in the WHO EMR. The analysis described in this report is restricted to the 21 countries in the \u201cWPV importation belt\u201d in the WHO AFR based on 2012 data . CountriRisk assessments have informed annual planning of activities to address the vulnerabilities of countries to improve population immunity through supplemental immunization activities (SIAs) and routine immunization, strengthen surveillance to promptly detect and investigate AFP cases, and enhance public health capacity to promptly respond after WPV importation.To prevent transmission after WPV importation or cVPDV emergence, periodic preventive SIAs are undertaken nationally and in portions of a country outbreaks have occurred in the World Health Organization (WHO) African Region (WHO AFR) since 2003, after the importation of indigenous West African WPV into 21 previously polio-free countries comprising a \u201cWPV importation belt\u201d that extends across the continent from the Sahara to the equator.What is added by this report?The Global Polio Eradication Initiative partners, including the WHO Regional Office for Africa, assess the risk for transmission of polioviruses after importation into polio-free countries and plan activities to decrease the risk for poliovirus transmission. Countries in the \u201cWPV importation belt\u201d in the WHO AFR deemed to be at high risk for outbreaks were primarily those located near countries with WPV cases in 2012 or with low population immunity indicators where routine vaccination coverage was suboptimal.What are the implications for public health practice?Suboptimal health infrastructure is a challenge in virtually all of the countries assessed as high-risk for poliovirus transmission. Insecurity and access barriers are additional challenges that will continue to threaten polio eradication efforts in the WHO AFR. All efforts to mitigate polio risks will need to continue as long as WPV transmission continues in polio-endemic countries. In addition, strengthening acute flaccid paralysis surveillance to promptly detect cases after importation will lead to quicker programmatic response and limit spread of WPV or circulating vaccine-derived polioviruses to other areas.Mitigation activities are guided by periodic risk assessments. Plans are continually adapted based on the availability of funds, variation in the vaccine production cycle, and the changing epidemiology of WPV. These variables necessitate that GPEI partners make data-driven decisions to prioritize activities.Throughout the WHO AFR, civil unrest and insecurity pose an increasing challenge for vaccination teams to access and reach children during SIAs. Insecurity has weakened routine immunization programs, hindered preventive SIAs, and limited AFP surveillance in large portions of countries, such as Mali and the Central African Republic during 2012\u20132013, and in many subnational areas throughout the region, including large parts of northern Nigeria. Partnering with relief organizations and implementing targeted SIAs as areas become accessible can assist in mitigating risks secondary to insecurity.Going forward, GPEI partners are attempting to engage all development agencies in coordinated efforts to enhance childhood immunization services to optimize population immunity . Address"} +{"text": "Staphylococcus epidermidis and Staphylococcus aureus and Gram (\u2212) Escherichia coli. When compared to the natural infusions the artificial beverages did not demonstrate any bacterostatic/cidal activity, suggesting that the antibacterial activity of rooibos is related to compounds other than the glycosylated polyphenols employed in our study. The anti-peroxyl radical quality of two aqueous rooibos infusions and solutions of their most abundant glycosylated polyphenols was evaluated using pyrogallol red and fluorescein-based oxygen radical absorbance ratios. It was observed that the artificial infusions, prepared using only the most abundant polyphenols present in rooibos and at concentrations similar to those found in the natural infusions, showed greater antioxidant quality than the latter infusions, reaching values close to those reported for tea infusions. Additionally, the antimicrobial activity of the natural and artificial infusions was assessed against three species of bacteria: Gram (+) A growth inhibition determination (GID) protocol was employed to obtain information about the antimicrobial performance of the rooibos infusions and their main constituents. The protocol was modified [5 bacteria per mL, into 96 well plates containing growth medium spiked with reconstituted or natural infusions, and allowed to grow under continuous agitation over 13 h in a Biotek\u2122 spectrophotometer set to continuously monitor OD600 levels every 15 min. Each experiment was carried out at ambient temperature and on duplicate samples with the assay repeated at least three independent times. Representative plots of the experiments done with E. coli are presented in The antimicrobial activity of rooibos infusions and their pure compounds was evaluated using the Gram-negative bacterium modified from themodified . BrieflyOur cumulative data indicate that the antioxidant activity of rooibos aqueous infusions is controlled by the presence of the two active dihydrochalcones, Asp and Not, as revealed from the ORAC ratio. We also found that only ORAC-PGR was able to measure the decrease in compound reactivity upon glycosylation as shown in the case of the quercetin glycosides, isoquercitrin and hyperoside. A synergistic effect on the antioxidant reactivity of the artificial infusions prepared using the most abundant polyphenols present in rooibos was also observed. Thus, while similar ORAC-PGR values were measured for the natural and artificial infusions, the ORAC-FL indices measured for the artificial infusions were considerable lower than for their natural counterparts. The lack of poorly reactive antioxidant molecules different from the polyphenols employed in our study is the most probable explanation for these results.The artificial infusions did not have any significant effect on bacterial growth when compared to the natural infusions. Although the glycosylated polyphenols alone might not account for earlier observed antimicrobial inhibition in the natural extract, several possibilities may explain this. Among those delineated above, the most plausible options are either antagonism of activity (Qc showed activity in single polyphenol exposures which was not enhanced in the reconstituted infusion), or simply that other, unconsidered compounds including unidentified polyphenols are responsible."} +{"text": "The diagnosis of mesothelioma is not always straightforward, despite known immunohistochemical markers and other diagnostic techniques. One reason for the difficulty is that extrapleural tumors resembling mesothelioma may have several possible etiologies, especially in cases with no meaningful history of amphibole asbestos exposure. When the diagnosis of mesothelioma is based on histologic features alone, primary mesotheliomas may resemble various primary or metastatic cancers that have directly invaded the serosal membranes. Some of these metastatic malignancies, particularly carcinomas and sarcomas of the pleura, pericardium and peritoneum, may undergo desmoplastic reaction in the pleura, thereby mimicking mesothelioma, rather than the primary tumor. Encasement of the lung by direct spread or metastasis, termed pseudomesotheliomatous spread, occurs with several other primary cancer types, including certain late-stage tumors from genetic cancer syndromes exhibiting chromosomal instability. Although immunohistochemical staining patterns differentiate most carcinomas, lymphomas, and mestastatic sarcomas from mesotheliomas, specific genetic markers in tumor or somatic tissues have been recently identified that may also distinguish these tumor types from asbestos-related mesothelioma. A registry for genetic screening of mesothelioma cases would help lead to improvements in diagnostic criteria, prognostic accuracy and treatment efficacy, as well as improved estimates of primary mesothelioma incidence and of background rates of cancers unrelated to asbestos that might be otherwise mistaken for mesothelioma. This information would also help better define the dose-response relationships for mesothelioma and asbestos exposure, as well as other risk factors for mesothelioma and other mesenchymal or advanced metastatic tumors that may be indistinguishable by histology and staining characteristics. By far, the most extensively investigated cause of mesothelioma is asbestos exposure , and negative staining for CEA, CD15, Ber-EP4 Moc-31, TTF-1, and B72.3 Ordonez, . But theTo date, searches for genetic aberrations associated with malignant mesothelioma have failed to identify a highly specific chromosomal abnormality, although several associated lesions based on newer techniques like micro-RNA expression, DNA methylation, telomere status, micronucleus formation, and gene expression profiling are under investigation are known to commonly occur in, or metastasize to, tissues along the body midline from the pineal gland to the sacrum. Due to their multi-potential nature they can exhibit features, both for histology and immunohistochemical markers, of primary pleural or peritoneal malignant mesothelioma. Mesothelioma of the tunica vaginalis is an example of this occurring within the testicle, yet little attention has been given to potential metastatic forms of this tumor and/or to extragonadal GCTs that originate from mutated embryonic cells of the urogenital ridge that may be mistakenly diagnosed as a mesothelioma of the peritoneum or pleura. The occurrence of mesothelioma in children and adolescents without significant or identifiable asbestos exposure as a result of a mutation and abnormal migration of germ cells during embryonic development such that the tumor cell histology and immunohistochemical markers of the ovarian surface epithelial cells cannot be readily distinguished from less specialized mesothelial tumors that may originate in the peritoneal lining tissue and cellular characteristics are commonly seen for both mesothelioma and PSC Fox, . Indeed,Since PSC can originate as an occult mullerian neoplasm that commonly proliferates at other peritoneal sites which encodes for a protein menin and is associated with increased risk of parathyroid, endocrine , pancreas, and pituitary neoplasia (mostly adenomas) Mayer, . MEN-1 iSimilarly, HNPCC involves germline mutations at certain loci that are associated with the formation of carcinoid tumors of the duodenum and ascending colon Mayer, . As withBased on the preceding research summary, a preliminary genetic screening matrix has been outlined in Table Diagnosing a tumor as mesothelioma based on histologic and immunohistochemical staining characteristics alone can lump together several mesenchymal tumor types of different origins that should be treated as distinct clinical entities with unique risk factors, prognosis, and best treatment modalities. Several mesenchymal tumors that are difficult to distinguish based on histology and staining characteristics are already known to be distinguished by genetic markers in somatic or tumor cells.The number of mullerian or germ cell tumors, advanced metastatic tumors, or mistaken synovial sarcomas that may have no plausible connection to asbestos exposure will remain obscure without appropriate research that supports a more definitive, evidence- based decision matrix for correct diagnosis. While the prognosis of any given individual's cancer can be difficult to predict, this research may identify genetic and/or clinical characteristics that presently, or in the future, will aid in more accurate prognostic predictions and perhaps more tumor-specific and efficacious treatments. For example, some forms of synovial sarcoma that remain circumscribed and relatively indolent are survivable without the aggressive clinical interventions typical of the treatment of malignant mesothelioma. Similarly, the confirmation of germ cell tumor origins would call for more focused clinical investigations and interventions that greatly differ from mesothelioma treatments. By adopting better diagnostic criteria for those mesenchymal tumor subtypes that may be mistaken as mesothelioma, physicians will improve epidemiologic estimates of the incidence and prevalence of the tumor types discussed above. Thus, this approach would ultimately improve dose-response relationships in the low dose region for asbestos and mesothelioma as well as that of other apparent risk factors for this deadly disease.As discussed earlier, the proportion of future mesothelioma cases that can be credibly attributed to asbestos is likely to lessen because the highly potent amphibole exposures were largely curtailed in the 1960s and the typical latency period of 20\u201340 years since first exposure has now transpired. The incidence of pleural mesotheliomas that are more specifically associated with asbestos is projected to continue declining, while peritoneal mesothelioma incidence (associated primarily with non-asbestos causes) has been essentially flat for decades (Teta et al., Physicians are urged to recognize that the proportion of mesothelioma cases unrelated to asbestos will likely increase in coming decades, and that better vigilance will be needed for proper diagnosis, treatment, and prevention. This will undoubtedly involve the development and use of more definitive diagnostic tools like genetic screening that can help differentiate asbestos-related mesothelioma from other mesenchymal tumor subtypes or advanced metastatic tumors that can mimic the histopathological presentation of mesothelioma.A national or international registry-based mesothelioma research program may be an achievable and appropriate means for augmenting the knowledge base on clinical features and genetic markers for distinguishing specific forms of mesothelioma and tumors that may mimic mesothelioma. Since the annual number of mesothelioma cases is relatively small, the scope of research each year may be reasonably defined. Incident case detection could be linked to existing state and/or national cancer registries, with the registry research program overseen by a steering committee with outside peer review resources. A working group could be tasked with developing appropriate research protocols for collection of needed clinical and family history information in addition to samples of tumor tissue and somatic cells for genetic screening. The scope of analysis and quality control procedures of the working group should be clearly defined and transparent, with assurance of evidence-based data analysis and outside peer review of findings in a manner that also assures objectivity and patient privacy.In conclusion, the identification of relatively specific clinical features and genetic markers that may avoid misdiagnosis of mesothelioma and other mesenchymal tumor subtypes or advanced metastatic tumors is an important future research need. Currently, the diagnosis of mesothelioma rests largely on histology and staining patterns that are sometimes inconclusive. It is recommended that further research be directed at identifying those genetic and clinical features unique to malignant mesothelioma and the cancers that may mimic its histopathology. This research could be fostered through a national or international mesothelioma registry with requisite medical history questionnaire and tumor/somatic tissue submission, hopefully leading to more specific diagnostic tools, better disease classification and incidence data, and a uniform and enhanced database for understanding the natural history and prognosis of various mesothelioma subtypes.The authors are research scientists employed by scientific consulting firms that are paid to conduct research for private clients relating to questions raised in regulatory and legal arenas. Each of the authors has conducted such research on behalf of clients with alleged asbestos liabilities, including expert witness activities. This work was funded solely by the authors and their institutions, without financial or technical assistance from any client. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Malaria Journal [The work of Pooda et al. published in Journal providesLLINs and IRS interventions are responsible for most of the remarkable reductions in malaria burden achieved in this century , but eveZoophagic vectors that feed predominantly on animals can sustain malaria transmission even if they only bite humans infrequently . Even wiAnopheles gambiae feeding on ivermectin-treated cattle and suggested a potential role of this strategy for integrated vector management [Anopheles culicifacies and Anopheles stephensi, the main malaria vectors of Pakistan [Anopheles arabiensis [Fortunately, by far the most common source of blood for most zoophagic malaria vectors are domesticated livestock, cattle in particular , so it inagement . These fPakistan , and morabiensis .Anopheles coluzzii, a widely distributed vector species which maintains robust malaria transmission all across west and central Africa [kdr mutation which contributes to pyrethroid resistance in many parts of Africa.This latest report by Pooda et al. now demol Africa . InteresLong-lasting injectable veterinary formulations of ivermectin already exist that can dramatically increase the effectiveness of this approach, by not only targeting a more important blood source for vector populations than humans, but also by achieving far longer duration of efficacy than is possible with the oral formulations available for human pharmaceutical delivery.A much greater diversity of different endectocides are available for cattle and other livestock, which offers an opportunity to combine drugs with different mechanisms of action, especially if ivermectin is to be used for mass drug administration to humans.Integrating an endectocide into traditional zooprophylaxis strategies removes One Health strategy by simultaneously improving livestock and human health. Nonzoonotic livestock parasites pose an important burden on human health by reducing economic output and nutrient availability. In addition to preventing malaria transmission, broadening the use of veterinary endectocides also offers an excellent opportunity to alleviate poverty and malnutrition by reducing the burden of livestock parasites on the health and economic resilience of their human owners [Endectocides can contribute to an overall n owners .Although the evidence base is growing fast, the full potential of ivermectin for malaria vector and transmission control remains to be established, but most discourse thus far has focused on medical delivery to human beings . HoweverPlasmodium falciparum and Plasmodium vivax are both strict anthroponoses, so it is understandable that ivermectin mass drug administration for malaria control and elimination is usually viewed primarily as an intervention for human populations. However, the use of veterinary antiparasitic drugs with insecticidal proprieties in domesticated livestock could perhaps achieve greater impact in many settings where persisting transmission is mediated by zoophagic vectors, and contribute to human health in previously unforeseen ways."} +{"text": "With a rapidly growing human population it is expected that plant science researchers and the agricultural community will need to increase food productivity using less arable land. This challenge is complicated by fungal pathogens and diseases, many of which can severely impact crop yield. Current measures to control fungal pathogens are either ineffective or have adverse effects on the agricultural enterprise. Thus, developing new strategies through research innovation to protect plants from pathogenic fungi is necessary to overcome these hurdles. RNA sequencing technologies are increasing our understanding of the underlying genes and gene regulatory networks mediating disease outcomes. The application of invigorating next generation sequencing strategies to study plant\u2013pathogen interactions has and will provide unprecedented insight into the complex patterns of gene activity responsible for crop protection. However, questions remain about how biological processes in both the pathogen and the host are specified in space directly at the site of infection and over the infection period. The integration of cutting edge molecular and computational tools will provide plant scientists with the arsenal required to identify genes and molecules that play a role in plant protection. Large scale RNA sequence data can then be used to protect plants by targeting genes essential for pathogen viability in the production of stably transformed lines expressing RNA interference molecules, or through foliar applications of double stranded RNA. The world\u2019s population is expected to increase to nearly 10 billion people in the next 35 years , 2015. TFigure 1).For example, global RNA profiling experiments are used to understand gene activity and can evaluate implicit changes in biological processes following the plant\u2013fungal interaction. High throughput sequencing technologies have been available to the scientific community for over a decade now , and morThus the resulting sequence reads from dual-sequencing experiments, regardless of origin, contain a snapshot of the underlying transcriptional programs from both the host and pathogen. The reads that successfully map to the respective genomes can then be used to assess gene activity in the two species. A general dual sequencing experimental outline is described by Septoria tritici, one of the most economically important wheat pathogens, was shown to alter gene activity to marginalize wheat defenses during its biotrophic phase before transitioning to a necrotic lifestyle and causing plant disease has emerged as a robust way to isolate individual cells and tissues from complex organs and tissue systems . Other tArabidopsis leaves following infection by the biotrophic powdery mildew causing Golovinomyces orontii . Likewise, smaller subsets of co-expressed gene sets can be analyzed . These modules consisting of TFs predicted to bind to these DNA motifs found within gene sets are therefore potential regulators of these processes. Of genes exclusively differentially expressed in a resistant line of canola infected with Leptosphaeria maculans, 16 WRKY homologs are predicted to control genes associated with SA biosynthesis and the hypersensitive response 6.This type of tool can be used to discover potential transcriptional regulators in large sets of genes differentially expressed in response to fungal infection. For example, in An opportunity also exists for the development of a similar prediction tool based on fungal sequencing data to better understand the regulation of processes involved in pathogenesis as well as an avenue to identify putative targets for functional applications. These bioinformatics tools can serve as a valuable resource to the scientific community through mining existing and previously published large scale genes expression data sets. Predicting transcriptional regulators in economically important crop pathogens using this targeted approach should allow researchers to identify genes essential for growth and pathogenesis quickly using functional tests.Researchers are now able to apply transcriptomic data in the development of innovative crop protection technologies. RNA interference (RNAi), promises to best the current control broad spectrum measures, eliminate negative consequences of current disease control, and combat the alarming rise of fungicide resistant phytopathogens . RNAi spFusarium oxysporum, the causative agent of Fusarium wilt. Banana plants were engineered to express intron hpRNA constructs for VELVET or FUSARIUM TRANSCRIPTION FACTOR 1 and maintained some level of resistance for at least 8 months. Despite the demonstrated success of RNAi technology against fungal pathogens, foliar applications have not yet come to fruition. However, they offer many benefits over transgenics including: the ability to explore a greater variety of novel targets compared to the production of stably transformed plants, a more rapid response to emerging pathogens and races, and wider public acceptance since host plant genomic changes have not occurred (Leptinotarsa decemlineata). The molecules were remarkably stable, showing bioactivity for over 28 days. With all the benefits and the proven viability of a topical application, future work should invest in the development of effective anti-fungal RNAi application methods.Both dsRNA and hpRNA have the potential to protect cropping systems through topical applications or using a transgenic approach. occurred . Fortunaoccurred . In partin vitro assays on various types of organisms. With meticulous molecular design, RNAi technology holds the promise to revolutionize agricultural disease management. While the cost to produce enough dsRNA molecules to protect broad acre crops is high, the expense to produce these molecules continues to decrease with the implementation of bacterial production systems (In spite of the successes, some environmentalists are concerned with RNAi technology introducing large quantities of persistent molecules into the environment. Early results show dsRNA molecules will not persist or accumulate in soil . However systems . The useThe development of innovative research technologies to protect the agricultural landscape should provide the necessary tools to sustain global food demand. Through these technologies we have developed a deep understanding of host\u2013pathogen interactions at the RNA level. However, there are still many gaps in our knowledge that surround emerging crop systems where genetic information is lacking. Fundamental details remain to be resolved on how plant defense and fungal pathogenic processes are specified at the cellular level at the site of infection and the contribution of transcriptional circuits controlling these processes. The application of RNA sequencing technologies coupled with cutting edge LMD methods should provide plant science researchers with answers to protect our food systems. While the analysis of large scale datasets still remains a challenge, new, and user friendly computational pipelines and programs will allow for broader access to and the potential for innovative product development. These strategies will also provide information essential for implementing the next generation of thorough, effective, and responsible RNAi-based fungal control measures in plant crop systems.IG, AM, TK, DF, and MB conceptualized and wrote the paper. IG and MB drafted the figures.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Bioarcheology is the study of archived human and animal remains. The term was first proposed by the British archeologist Grahame Clark to denote the investigations of animal bones from archeological sites. Since its introduction in 1972, this term has been applied to encompass additional scientific domains and has also been used for the multidisciplinary papers collected in this special issue.Agriculture's first appearance on the archeological horizon is a matter of debate. Evidence provided by multidisciplinary studies encompassing archaeobotany and zooarchaeology and the emergence of agricultural practices in the \u201cfertile crescent\u201d in Iran add to the science of ancient agriculture .Egyptian archeology has been a widely accepted aspect of bioarcheology. Here a wealth of information has been collected with the applications of new techniques to ancient tissues such as X-ray analyses applied in the field to archived human bones .Mandibles excavated from Qubbet el-Hawa cemetery in Aswan, Egypt, have yielded information on the food consumed by middle class people during several periods of ancient Egyptian history. The elemental analysis of the bones hinted at social and climatic changes affecting ancient populations and shows the effects of state socialism and agricultural conditions during the 17th Dynasty in Upper Egypt (G. D. AL-Khafif and R. El-Banna).South American frozen mummies from mountain tops of the high Andes have only recently become available for bioarcheological studies. Such studies have revealed important aspects of human sacrificial practices in pre-Hispanic times. Because of the exceptional preservation of the soft tissues of these mummies due to the intense cold and ambient dryness at altitudes at which they were found, important human pathologies accompanying life under Inca rule have become accessible to modern techniques (M. C. Ceruti).The histology of soft tissues is a well-accepted diagnostic method in modern human pathology. However, its application to ancient tissues brings challenges to the standard interpretation of histological stains because of the variable preservation of specimens depending on numerous unforeseeable factors. The postmortem interval before histological study is one crucial obstacle. The longer this time the less dependable the results. Paleopathological examinations provided guidelines to the tissues likely to be best preserved and allowed the most reliable diagnoses .Successful and cheap methods recently developed for the extraction of ancient DNA (aDNA) have led to important studies in evolution and worldwide human migrations. East Asian mitochondrial DNA (mtDNA) especially of Koreans has been used to determine single nucleotide polymorphisms in mtDNA in human bone samples from premodern Joseon tombs in Republic of Korea .Archeological materials useful for the study of bioarcheology are conserved in museums throughout the world. Curators prefer the study of their collections by noninvasive methods. The desire to maintain specimens intact is shared by bioarcheologists too. Nevertheless, invasive methods such as autopsies, endoscopies, and biopsies are sometimes unavoidable for accurate diagnosis. In this setting controversies are unavoidable but scientific criteria coupled with ethical considerations are proposed which may resolve disputes .Monastic inhabitants of ancient institutions provide fertile grounds for the investigations of diseases and social aspects of a particularly privileged population. Regional differences are not often revealed but when such studies are restricted to defined populations such as those in Bavaria, Germany, insights into paleopathology, nutrition, and lifestyles of a well-defined human group become apparent .Statistical modeling has advanced science in general and bioarcheology in particular. Growth lines in archived biological materials such as teeth and hair proved valuable in providing evidence of metabolic health, physiology, and lifestyles of long dead individuals. Thus new noninvasive methods for the analyses of curated archeological specimens could avoid ethical consideration in bioarcheological investigations .Computational methods could also predict the physical appearance, mood, and clinical diagnosis such as hirsutism (excessive hair growth) also known in some individuals as Cant\u00fa syndrome .Recent massive sequencing of ancient DNA has transformed the study of human evolution and human history. Such studies are only now beginning in bioarcheology but important insights into modern diseases are likely to be gleaned from analyses of bioarcheological specimens."} +{"text": "Iran is designing an evidence-based plan for promoting postgraduate medical education and efficient distribution of health professional human resources. An important part of this program is foresight studies for post graduate medical education considering the important trends affecting the future of health status and postgraduate medical education in Iran. In this article, we clarify such trends in Iran.For this study, we used a systematic review of current evidence about the mega trends affecting the future of medical education. Also we gathered opinions of key stakeholders in expert panels.Following trends identified as affecting the health system and post graduate medical education in Iran: demographic changes; epidemiologic transition; physician work patterns changes, female specialists number growth, changes in patients\u2019 expectations of health services; growth in information and communication technologies; new advances in diagnostic and therapeutic technologies.The present study found that trends affecting postgraduate medical education in Iran. In the near future, medical education in Iran will need to undergo major changes. When planning for these changes, decision-makers should consider the various trends that affect education."} +{"text": "The most common type of hearing loss results from damage to the cochlea including lost hair cells (HCs) and spiral ganglion neurons (SGNs). In mammals, cochlear HC loss causes irreversible hearing impairment because this type of sensory cell cannot regenerate. The protection from SGN from degeneration has implications for cochlear implant to patients with severe deafness. This review summarizes the several treatments for HC regeneration based on experiments. We discuss how transgene expression of the neurotrophic factor can protect SGN from degeneration and describe potential new therapeutic interventions to reduce hearing loss. We also summarized viral vectors and introduced the gene and drug delivery system for regeneration and protection of cochlear HCs. Finally, we introduce the novel endoscopy we developed for local injection into cochlea. Drug, gene and cell therapy are attractive to facilitate regeneration of hair cells (HCs) and spiral ganglion neurons (SGNs). For endogenous HC regeneration, it is critical to identify potential stem cells of the inner ear.Atoh 1, that can increase the regenerative properties of the sensory epithelium of the cochlea after HC loss has been shown to reduce the irreversible damage of SGNs .Neurotrophic factors and maintenance of synaptic connectivity are important to prevent neuronal degeneration . Brain-dTreatment with neurotrophic factor such as GDNF significantly enhance SGN survival compared to that in untreated deafened ears. Combining ES with GDNF overexpression treatment additionally protects against SGN degeneration . It suggThe inner ear is enclosed by a bony capsule. Such a relative anatomical isolation makes inner ear an ideal target for therapeutic local injection because spread of the injected vector, the drug, and the transgene to surrounding tissues is expected to be limited.We have several approaches into inner ear including via scala tympani, scala media, or semicircular canal. Scala media approach would be more effective with cells in organ of Corti, but more traumatic. It means via scala media approach does not preserve hearing threshold. Scala tympani approach is less traumatic and used for prevention of SGN degeneration.Gene delivery or transfer introduces exogenous genes into cells. As mentioned above, viral vectors are still the efficient vehicles for gene transfer in animal experiments about the inner ear regeneration.For inner ear gene transfer, several types of viral vectors such as ADV, herpes viral (HSV), adeno-associate viral (AAV) , Sendai in vivo in cochlea, but not systemic injections due to systemic side effects. However, pharmacokinetics of agents locally injected into inner ear is not well known. Hence, we develop the real time observation of drug delivery system in transgenic animals in vivo . We obseWe also find that RW niche obstruction such as false membrane or fibrous connective membrane blocked drug delivery into inner ear. Therefore, observing RW is very important before local injection of drug into inner ear .The RWM cannot be visualized in around 30% of all the patients with hearing loss. In those cases adhesions need to be removed first before local injection is performed. We develop a novel endoscopy to explore the RWM for the purpose of local injection . The endThe molecular signals that stimulate HCs regeneration and protection of SGNs have begun to be identified. Proliferation of HCs has been achieved in mammals by overexpressing Atoh1, and Notch inhibitor drugs. The preservation of SGNs is very important and has implications for cochlear implants. These studies will lead to therapeutic interventions for the hearing impaired.This manuscript was supported by funds from Grant in aid (OK 2012\u20132013) for exploratory research in the Ministry of Education, Culture, Sports, Science, and Technology and grant in aid from the Takeda Science Foundation.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Deciding what health services are provided is a key consideration in delivering appropriate and accessible health care for rural and remote populations. Despite residents of rural communities experiencing poorer health outcomes and exhibiting higher health need, workforce shortages and maldistribution mean that rural communities do not have access to the range of services available in metropolitan centres. Where demand exceeds available resources, decisions about resource allocation are required.A qualitative approach enabled the researchers to explore participant perspectives about decisions informing rural physiotherapy service provision. Stakeholder perspectives were obtained through surveys and in-depth interviews. A system theory-case study heuristic provided a framework for exploration across sites within the investigation area: a large area of one Australian state with a mix of rural, regional and remote communities.Thirty-nine surveys were received from participants in eleven communities. Nineteen in-depth interviews were conducted with physiotherapist and key decision-makers. Increasing demand, organisational priorities, fiscal austerity measures and workforce challenges were identified as factors influencing both decision-making and service provision. Rationing of physiotherapy services was common to all sites of this study. Rationing of services, more commonly expressed as service prioritisation, was more evident in responses of public sector physiotherapy participants compared to private physiotherapists. However, private physiotherapists in rural areas reported capacity limits, including expertise, space and affordability that constrained service provision.The imbalance between increasing service demands and limited physiotherapy capacity meant making choices was inevitable. Decreased community access to local physiotherapy services and increased workforce stress, a key determinant of retention, are two results of such choices or decisions. Decreased access was particularly evident for adults and children requiring neurological rehabilitation and for people requiring post-acute physiotherapy. It should not be presumed that rural private physiotherapy providers will cover service gaps that may emerge from changes to public sector service provision. Clinician preference combines with capacity limits and the imperative of financial viability to negate such assumptions. This study provides insight into rural physiotherapy service provision not usually evident and can be used to inform health service planning and decision-making and education of current and future rural physiotherapists. The challenge of delivering health services equitably to Australia\u2019s rural population is exacerbated by health workforce maldistribution and fewer services in rural areas. Australia\u2019s 23 million people are spread across 7.6 million square kilometres and it is widely accepted that 30% of the population live outside major metropolitan areas, in areas broadly described as rural Australia. There are many definitions and classifications used to describe or differentiate regional, rural and remote settings ,2. The AHealth workforce shortages and geographic maldistribution compound the challenge of delivering equitable health services beyond major cities. An estimated 80% of physiotherapists, for example, worked in major cities in 2012 . DThe impossibility of providing everything to everyone means making choices is inevitable. Where there is a demand-resource imbalance, decisions about resource allocation are required. Prioritisation, alternatively referred to as resource allocation or rationing, occurs at all levels of the health care system where demand exceeds available resources -13. Ratiplay a key part in the acute care and rehabilitation of their clients and the promotion of health in their communities .More physios-though very happy with my service [CN 2].Lymphoedema physios give help with Laser, massage, garments, advice etc. The physios in [this town] work very hard. Not enough of them!! [CN 4].An increase in funds available [CN 5].More related services under one roof eg massage, scanning [CN 6].Consumer responses were to the survey question about how the physiotherapy service could be improved. It was not assumed that consumers would be decision makers about service provision, but rather be drivers of service demand. Consumer responses (CN) included:In depth interviews then enabled exploration of issues identified in the surveys. Decision-making about service provision was considered within organisational levels and rationing strategies used. Responses revealed macro and meso level decision-making influences which then framed decision-making at a service or micro level. Decisions impacting the provision of physiotherapy services in the rural and regional settings fell under two broad areas: health reforms or funding decisions. These two areas provide the organisational priorities on resource allocation that inform service level decision-making (SLDM).Meso level decisions identified by participants include those made at a regional or facility level. These decisions influenced the organisation and funding of services including service directives, priorities, funding and staffing levels. Examples of meso level decisions noted by participants include centralisation of services , budget and staff cuts, local implementation of national funded programs (eg subacute care), organisational priorities and performance indicators .you spread yourself pretty thin; you do prioritise, you have to [A4]), rather than rationing, with no reference to specific methods of rationing. However, many of the strategies or processes described by participants . Similarly, decisions made at the regional or facility level, such as the reduction in funded positions or the delays in recruitment approvals, required physiotherapists to review what services could be maintained and which aspect of service provision would not be continued. These higher level decisions, often made without explicit directives about service reductions, effectively devolved the decision of rationing service provision to physiotherapists at a micro level. The consequences were expressed in terms of patients (reduced access to service and inability to provide follow up treatment) and the physiotherapists themselves (frustration and friction).Limited communication and consultation about decisions by higher level decision makers to reduce service capacity or indeed add new services without additional physiotherapy resources compounded the conflict between service, professional and personal values. Perceived lack of autonomy is a key influencing factor in the retention of health rural health professionals . FindingWhat do these findings mean physiotherapists working in regional, rural and remote areas? Firstly, the knowledge that some level of rationing was common across the cases and sites of this study may be a useful consideration when physiotherapists are required to ration services locally. The findings suggests the rationing or prioritising services forms part of rural physiotherapy practice. It is important therefore to provide education and strategies to assist physiotherapists working in regional, rural or remote practice to respond to situations where demand for services exceeds the available resources. There is an extensive literature on service planning and evaluation that provides comprehensive coverage to address issues relating to service prioritisation or rationing. The background information and findings of this study may provide some assistance in this area by posing the following recommendations for initial consideration.The effectiveness and appropriateness of current service provision and the efficiency of the current service. For example, what are the organisational priorities that must be met? Has the effectiveness of services and interventions been maximised? Are there additional efficiency strategies that could be implemented?The local community need and the relative ability to benefit. What are the expectations of the local community? Are these expectations consistent with the organisations service priorities?Firstly, assess the current service demands in terms of key drivers. Consider, for instance, macro and meso level planning and policy, community demography and available physiotherapy services within the local community. Frame questions in terms of terms of technical and distributive criteria Figure\u00a0 by consithe number of funded positions,the level of experience and skill mixthe alignment of capability to service requirementsvacancy rates, intention to stay and the odds of successful recruitmentSecondly, assess the available physiotherapy capacity and capability of the service by considering workforce issues such as:It may be possible to maintain the service scope, but manage the demand by using the rationing strategies of delay (waiting lists), dilution (decrease the frequency of treatment) or interruption (imposition of time limits).Where it is not possible to maintain the current service scope or respond to new service requests, consider firstly referral of clients to other services (deflection), then use the criteria described above to identify the recipients of care (selection) and clarify what will not be provided . The adoption of deterrence strategies such as the imposition of complex administrative requirements is a less explicit approach Figure\u00a0.Figure 3Finally, assess the match of service demands to available resources. Where demand exceeds available resources and service effectiveness, efficiency and appropriateness have been optimised, then consider which of the rationing strategies to implement Table\u00a0.It may bThis study was undertaken in one region within Australia which had a mixture of remote, rural and regional centres. Results may not be applicable to other areas with a different mixture of centres such as more remote locations and less regional centres. Although this study asked physiotherapists to identify decision-making stakeholders, not all stakeholders were involved as participants. This may have biased results, as for example state health department decision makers were not involved in this study and yet their decisions will influence the physiotherapy service provision in rural and regional areas. Also, the small number of consumer participants did not produce a detailed perspective from this key stakeholder group. Future studies could consider conducting local consumer focus groups. This study only investigated decision-making about physiotherapy services provision. The results may not be applicable to other health disciplines and there may be different factors and interactions in setting where there are interdisciplinary service delivery models. This can be seen by the differences seen in comparing public and private physiotherapy services decision-making.Deciding what health services are provided is a key consideration in delivering appropriate and accessible health care for rural populations. Participant perspectives revealed the impact of macro and meso level decisions on the capacity to provide physiotherapy services in the rural communities of this study. Increasing constraints meant that rationing of physiotherapy services, particularly within the public sector, was commonplace. The effective devolvement of rationing decisions to the micro level contributed to the stresses described by many participants working in public sector services. This study has revealed some consequences of service rationing that are relatively invisible at a system level yet so pertinent to individuals and communities. Decreased access to physiotherapy services was evident for example, for adults and children requiring neurological rehabilitation and for people requiring ongoing physiotherapy post-acute care. Responses of private physiotherapy providers indicate they are not positioned to address such service gaps, particularly when compounded by issues of affordability. Organisational and funding changes generated in recent state and national reforms have had significant, if unintended, consequences on the resources and capacity of physiotherapists in this study to deliver services in rural communities. This study provides insight into rural physiotherapy service provision not usually evident and can be used to inform health service planning and decision-making and education of current and future rural physiotherapists."} +{"text": "Clinical trials require large monetary and time commitments and should provide information on both whether and how treatments work. Treatment mechanisms can be studied using mediation analysis, allowing refinement of treatments. Mediation studies often use only single contemporaneous measures of mediator and outcome limiting the conclusions that can be drawn. Longitudinally measured mediators and outcomes, such as those in the Pacing, Graded Activity, and Cognitive Behaviour Therapy: A Randomised Evaluation trial allow for more realistic estimates of mediated effects.Autoregressive models accounting for measurement error were used to study treatment effect mediation of cognitive behaviour therapy (CBT) and graded exercise therapy (GET) in PACE. Fear avoidance and physical function were used as example mediator and outcome; these were measured at baseline and three times post-randomisation as part of the trial design. Model fit criteria, Wald tests and comparisons of parameter estimates were used.Longitudinal SEM were more flexible and gave what were likely more plausible estimates of mediated effects. Constancy of mediator - outcome effects over time and across treatment groups increased precision. For CBT and GET, 46% and 53% of the overall effect were mediated through fear avoidance.Trials should be designed to include multiple measurements of mediators and outcomes so that more realistic mediation models can be used. Longitudinal models may have more power to detect mediated effects. Approximately half of the effect of each of CBT and GET were on physical function was mediated through reducing avoidance of fearful situations."} +{"text": "Little is known about the extent of genetic diversity contained in any of them and its relation to contemporary varieties, since to date rye genetic diversity studies had a very limited scope, analyzing few loci and/ or few accessions. Development of high throughput genotyping methods for rye opened the possibility for genome wide characterizations of large accessions sets. In this study we used 1054 Diversity Array Technology (DArT) markers with defined chromosomal location to characterize genetic diversity and population structure in a collection of 379 rye accessions including wild species, landraces, cultivated materials, historical and contemporary rye varieties.Numerous rye accessions are stored in Secale germplasm. We revealed a relatively limited diversity in improved rye accessions, both historical and contemporary, as well as lack of correlation between clustering of improved accessions and geographic origin, suggesting common genetic background of rye accessions from diverse geographic regions and extensive germplasm exchange. Moreover, contemporary varieties were distinct from the remaining accessions.Average genetic similarity (GS) coefficients and average polymorphic information content (PIC) values varied among chromosomes. Comparison of chromosome specific average GS within and between germplasm sub-groups indicated regions of chromosomes 1R and 4R as being targeted by selection in current breeding programs. Bayesian clustering, principal coordinate analysis and Neighbor Joining clustering demonstrated that source and improvement status contributed significantly to the structure observed in the analyzed set of ex situ collections for broadening the genetic diversity in rye breeding programs. Obtained data show that DArT markers provide a realistic picture of the genetic diversity and population structure present in the collection of 379 rye accessions and are an effective platform for rye germplasm characterization and association mapping studies.Our results point to an influence of reproduction methods on the observed diversity patterns and indicate potential of Secale cereale L.; 2n\u2009=\u200914, RR) is an out-crossing, wind-pollinated temperate zone cereal with low water and soil fertility requirements and good tolerance for biotic and abiotic stresses. It is an important crop in several Eastern, Central and Northern European countries with cultivation area of approximately 5 Million hectares worldwide in 2011 [http://faostat.fao.org]. The primary uses of rye include bread making, alcohol production, and animal feed. Recently it is also gaining attention as a biomass crop. Rye products are a valuable diet component due to high dietary fiber content and rye bread was shown to have beneficial influence on human healthet al...et al.[cessions and in tcessions. Our resBeadChip. Apart fBeadChip. AdditioBeadChip,42.ex situ collections for broadening the genetic diversity in current rye breeding programs.We conducted the largest and most comprehensive study of genetic diversity in rye to date and revealed a relatively limited diversity in improved rye accessions, both historical and contemporary, as well as lack of correlation between clustering of improved accessions and geographic origin, suggesting common genetic background of rye accessions from diverse geographic regions that probably results from extensive germplasm exchange. Genetic distinctness of contemporary varieties from the rest of accession that was also observed indicates a great genetic potential of One of the more interesting findings of our study is the identification of accession source as a major determinant of population structure. Our result point to possible influence of reproduction methods on the observed diversity pattern. Further studies involving accessions from different genebanks would be desirable to verify our findings concerning the source of population structure in rye.We also revealed differences in distribution of genetic polymorphism among rye chromosomes that could be indicative of genome regions targeted by selection during domestication and improvement programs.Obtained data indicate that DArT markers provide a realistic picture of the genetic diversity and population structure present in the collection of 379 rye accessions and are currently a method of choice for rye germplasm characterization and association mapping studies.AK is an employee of Diversity Arrays Technology Pty. Ltd., which offers genome profiling service using the technology described in this report. This fact, however, has not interfered whatsoever with the full, objective, transparent and unbiased presentation of the research results described in the manuscript nor alters the authors\u2019 adherence to all the BMC policies on data and material release.HBB conceived and designed the experiments, wrote the manuscript. HBB, MT performed the experiments. HBB, AK, LB analyzed the data. HBB, AK, LB, MT, MRT contributed reagents/materials/analysis tools. HBB, MT, MRT contributed to the selection and preparation of germplasm. All authors read and approved the final version of the manuscript.Excel spreadsheet containing detailed information on rye used in the study and their genotypic DArT marker data.Click here for fileExcel spreadsheet containing mean PIC values for groups of accessions created according to source and type of germplasm.Click here for file(Portable Document File). Delta K values for K values (number of populations assumed) ranging from 1 to 20.Click here for file(Portable Document File). Principal coordinate analysis of 379 rye accessions based on 1054 DArT markers with defined chromosomal location. Accessions were labeled according to the geographic origin of accessions: panel a: only cultivated materials and varieties from PAS BG are shown; panel b: only landraces are shown.Click here for filePT analyses for accession source and improvement status, and for region of origin.Excel spreadsheet containing results of AMOVA and pairwise population PhClick here for file"} +{"text": "Numerous studies have focused on the optimization of ceramic architectures to fulfill a variety of scaffold functional requirements and improve biological response. Conventional fabrication techniques, however, do not allow for the production of geometrically controlled, reproducible structures and often fail to allow the independent variation of individual geometric parameters. Current developments in additive manufacturing technologies suggest that 3D printing will allow a more controlled and systematic exploration of scaffold architectures. This more direct translation of design into structure requires a pipeline for design-driven optimization. A theoretical framework for systematic design and evaluation of architectural parameters on biological response is presented. Four levels of architecture are considered, namely (1) surface topography, (2) pore size and geometry, (3) porous networks, and (4) macroscopic pore arrangement, including the potential for spatially varied architectures. Studies exploring the effect of various parameters within these levels are reviewed. This framework will hopefully allow uncovering of new relationships between architecture and biological response in a more systematic way as well as inform future refinement of fabrication techniques to fulfill architectural necessities with a consideration of biological implications. Ceramic scaffold architecture has long been explored as a factor to optimize for bone tissue engineering. While architecture has been shown to affect scaffold performance and biological response, a single optimal scaffold architecture does not exist , thus permitting them to spread and invade the material . Surface roughness was found not to have an effect on alkaline phosphatase (ALP) activity but to delay its expression. Rouahi et al. scaffolds produced by selective laser melting. All simulations were found to eventually yield spherical or cylindrical tissue fronts. The authors of the study proposed that given scaling differences in experimental versus simulation times with pore size, integrating in the model the effects of mass transport and other mechanisms necessary for biological function may improve its predictive ability.Computational models have been developed for predicting curvature-driven growth of 3-dimensional geometries and microscopic ones (such as collagen and lamellar orientation) contribute to bone anisotropy is mechanically guided (Van Oers et al., Roughness has been found to have profound effects on cell behavior, as previously mentioned, with high roughness resulting in strong cell attachments but low proliferation rates (Rouahi et al., Last, spatial control of architecture could allow controlling degradation rate and tissue formation. For example, SAV could be varied by controlling pore size and surface roughness while maintaining a mechanically appropriate local porosity. This would allow controlling degradation rates throughout the scaffold. Pore size and shape could also be tuned spatially to control locally cell type infiltration, whereas macroscopic structures and pore orientation could be used to direct the diffusion of nutrients within the structure.The advent and continual development of technologies, such as additive manufacturing that allow for a high degree of control over scaffold geometry, serve the basis for the exploration of precise geometries on cell and tissue behavior. A theoretical framework for systematic design of scaffold architecture at four different levels has been proposed. This framework will hopefully encourage the development of a suite of parameters to describe architecture that will allow a systematic design and evaluation of architectures quantitatively. Novel fabrication methods have also allowed for the development of architecturally heterogeneous materials. Evaluating the performance of architectures on these four levels in terms of outputs, such as mechanical performance, permeability, degradation behavior, cell response, and tissue microarchitecture, will assist in developing a structure\u2013function relationship toolkit that could help develop biomaterials with locally optimized architecture in a way that is patient and defect-site specific. Further, the uncovering of these relationships will allow tuning fabrication techniques to architectural necessities rather than adapting technologies developed with insufficient consideration of biological implications.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Due to the inadequacy of endogenous repair mechanisms diseases of the nervous system remain a major challenge to scientists and clinicians. Stem cell based therapy is an exciting and viable strategy that has been shown to ameliorate or even reverse symptoms of CNS dysfunction in preclinical animal models. Of particular importance has been the use of GABAergic interneuron progenitors as a therapeutic strategy. Born in the neurogenic niches of the ventral telencephalon, interneuron progenitors retain their unique capacity to disperse, integrate and induce plasticity in adult host circuitries following transplantation. Here we discuss the potential of interneuron based transplantation strategies as it relates to CNS disease therapeutics. We also discuss mechanisms underlying their therapeutic efficacy and some of the challenges that face the field. Since the turn of 20th century neural transplantation has been studied as a potential therapeutic strategy for neural reconstruction and repair . Initial2 consumption rate which may buoy their viability in new environments during the initial days after implantation . Constituting only about 20% of the adult cortical neuronal population, inhibitory neurons are potent regulators of normal brain function, sculpting the excitation-inhibition balance and entraining activity of neuron ensembles in brain circuits lesioned striatum are known to restore motor deficits . HoweverFigure 2). Intriguingly, MGE transplants made in the subthalamus fail to migrate from the injection site and instead differentiate into glial cells that show long term survival, highlighting the critical role donor-host environmental interactions may play in governing fate of transplanted progenitor cells.Neurons derived from transplants of MGE tissue in striatum of the 6-OHDA lesioned mice migrate, functionally integrate and improve motor deficits . Under dIn contrast to cortex, inhibitory interneurons form about 30\u201340% of the total neuronal population in the dorsal horn of the spinal cord. By regulating activity of primary afferents, excitatory interneurons, spinal projection neurons and descending fiber tracts, inhibitory interneurons play a crucial role in maintaining a physiological level of pain sensitivity. Disinhibition within the spinal dorsal horn has long been attributed to the symptoms of NP, e.g., GABA neurotransmission is significantly reduced following nerve injury and GABASurprisingly, transplanted MGE cells into adult spinal cord differentiate into GABA interneuron populations that integrate with the host spinal cord circuitry . ContrarFigure 2). Combined with these challenges, incomplete knowledge of the pathophysiology of vast majority of CNS diseases hinders progress to clinical translation. While excitement surrounds generation of GABAergic interneurons from human pluripotent stem cells (in vivo will also address these challenges.While pre-clinical studies have demonstrated promise for interneuron based therapy, cell based approaches have inherent limitations, including but not limited to unpredictable proliferation, differentiation, and migration, leading to pathological ectopia, including tumors. Addressing these limitations will require greater understanding of the mechanisms governing the development and function of the transplants in different brain regions and at different points in the lifespan of the host (em cells , currentThe remarkable capacities of interneuron progenitors to migrate long distances, differentiate into mature interneurons and modify diseased circuits following transplantation have made interneuron based transplantation a viable potential therapeutic approach for CNS diseases. However, further studies in the primate, a refined knowledge of interneuron ontogenesis and development of methods for reliable, high-throughput production of specific GABAergic cell types and safe cell composition of transplants need to be pursued before this approach is realized in the clinical setting. There is reason to be optimistic, given rich and growing literature on interneuron development and rapid growth of technologies that will allow the production of safe and specific transplants.MC and HM developed concepts. MC wrote and HM edited the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Tumor cells alter their metabolism to maintain unregulated cellular proliferation and survival, but this transformation leaves them reliant on constant supply of nutrients and energy. In addition to the widely studied dysregulated glucose metabolism to fuel tumor cell growth, accumulating evidences suggest that utilization of amino acids and lipids contributes significantly to cancer cell metabolism. Also recent progresses in our understanding of carcinogenesis have revealed that cancer is a complex disease and cannot be understood through simple investigation of genetic mutations of cancerous cells. Cancer cells present in complex tumor tissues communicate with the surrounding microenvironment and develop traits which promote their growth, survival, and metastasis. Decoding the full scope and targeting dysregulated metabolic pathways that support neoplastic transformations and their preservation requires both the advancement of experimental technologies for more comprehensive measurement of omics as well as the advancement of robust computational methods for accurate analysis of the generated data. Here, we review cancer-associated reprogramming of metabolism and highlight the capability of genome-scale metabolic modeling approaches in perceiving a system-level perspective of cancer metabolism and in detecting novel selective drug targets. The past decades has seen a dramatic expansion in investigations on mechanism of cancer related metabolic adaptations, and this has resulted in accumulated evidences suggesting considerable association between several pathways in human metabolism and malignant transformation are abundant amino acids in plasma from the bloodstream is the main source of satisfying lipid requirement in adult mammalian tissues. Although, fatty acids biosynthesis is limited to a subgroup of tissues, including adipose, liver and breast, reactivation of lipid synthesis is commonly observed in tumor cells with different sites of origin and the function of the many different pathways connecting these components is highly regulated. Mutations may cause dysfunction of some of these regulatory or functional pathways, and this may lead to the emergence of dysfunctional phenotypes. Uncovering how these biological systems orchestrate their activities to support specific phenotypic transformation, e.g., normal to cancer, is a major challenge in medical science, and gaining insight into the mechanisms underlying these transformation may enable improved disease diagnostic, prognostic, and treatment strategies and regulatory Boolean logic into FBA approach was used to generate an integrated model of central carbon metabolism in In vivo, nutrient availability varies for different cell types, inside and across tissues/organs. For example, the structure of liver enforces gradients of nutrients and oxygen accessibility through hepatocyte zones (Puchowicz et al., The progressive accumulation of knowledge of cancer biology has demonstrated that cancer is an extraordinarily heterogeneous and complex disease. Tumors evolve through a reiterative process of clonal extension, genetic diversification and selection within the highly dynamic and adaptive ecosystem of target tissue (Greaves and Maley, Tumor-host metabolic interactions also have strong effect on the cancer cell metabolic reprogramming. Cancer cells may attempt to induce growth favoring conditions by actively manipulating the tumor microenvironment which can directly influence tumor progression, metastasis, and redox status (Guillaumond et al., Cancer cells are shown to experience characteristic changes in their metabolic programs, including increased uptake of glucose, enhanced rates of glutaminolysis and fatty acids synthesis, suggesting that metabolic shifts supports tumor cells growth and survival. Similarity some cancer-associated metabolic alterations are similar to the metabolic response of normal cells to growth-promoting signals, and this makes it difficult to separate neoplastic alterations clearly from the ones just reflecting increased cellular proliferation. However, different metabolic components target distinct oncogenic signaling pathways, and it is therefore important to elucidate the complex interaction between cellular metabolic network and oncogenic signaling network. Obviously, transformation from oxidative phosphorylation to aerobic glycolysis cannot simply explain the complete metabolic reprogramming event of tumor cells, and fairly little is known about different metabolic activities of cancer cells with diverse genetic and mutational background. Moreover, variances in metabolic profiles of tumors with same genetic lesion but different tissues of origin, suggests an open therapeutic window through investigation of complex metabolic interplay between tumor cells and stroma. It is becoming more evident that metabolic reprogramming in cancer cells is closely connected to hypoxia and ROS metabolism. Disrupting the balance between anti-oxidant production and increased biosynthetic activities in tumor cells seems to be a therapeutic opportunity.in vitro data that were produced under experimentally controlled conditions, but utilization of richer in vivo and clinical datasets, together with integration of cellular regulatory and signaling mechanism is critical for advancement of the field. Introduction of more metabolomics, fluxomics and growth related data along with other related omics data into the reconstruction and validation process of GEMs can help in increasing the accuracy and prediction power of these models. Furthermore, more and more data points toward the important role of tumor microenvironment in promoting plasticity and supporting cancer-associated metabolic adaptations, and modeling metabolic interaction between cancer and its environment can help in developing more effective therapeutic strategies. For this it may be necessary to integrate kinetics into stoichiometric genome-scale models.Recent advances in high throughput omics technologies along with continuous progress in our understanding of cancer cell biology have portrayed a more complex and heterogeneous picture of tumor metabolism. Increased understanding of genetic and metabolic heterogeneity of cancer cells may open a new road toward development of new selective personalized diagnostic and therapeutic methods. GEMs, providing a mechanistic description of relationships between genes, metabolites and reactions within an interconnected functional metabolic network, have potential to integrate large-scale experimental datasets and extract knowledge out of their multi-dimensional complexity. Despite recent leap forward in employing GEMs to study cancer metabolism, more technical, and translational challenges are laying ahead. To date, the majority of models have been developed based on In conclusion, metabolic reprogramming is crucial to support the uncontrolled proliferation, survival and migration of cancer cells, but at the same time renders tumors more vulnerable to metabolic perturbations. Identification of these metabolic dependencies at the genome-scale may provide an opportunity for optimized therapeutic intervention.PG, AM, and JN wrote the paper and all authors were involved in editing the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "We are currently collaborating with the NIH Undiagnosed Disease Program to achieve diagnosis of problematic cases through exome analysis. In conclusion, our results clearly show the value of collecting comprehensive clinical phenotype data for translational bioinformatics and future work will focus on producing a robust solution for clinical diagnostics.Our software, Exomiser, is openly available to use at our website ["} +{"text": "Locustella warblers to test for presence of genetic introgression and its effects on tree topology and divergence estimates. Our data showed that nuDNA introgression was substantial and asymmetrical among all members of superspecies groups whereas mtDNA showed no introgression except a single species pair where the invader's mtDNA was swept by mtDNA of the local species. This introgressive sweep of mtDNA had the opposite direction of the nuDNA introgression and resulted in the paraphyly of the local species' mtDNA haplotypes with respect to those of the invader. \u0422he multilocus nuDNA species tree resolved all inter- and intraspecific relationships despite substantial introgression. However, the node ages on the species tree may be underestimated as suggested by the differences in node age estimates based on non-introgressing mtDNA and introgressing nuDNA. In turn, the introgressive sweep and strong purifying selection appear to elongate internal branches in the mtDNA gene tree.When isolated but reproductively compatible populations expand geographically and meet, simulations predict asymmetric introgression of neutral loci from a local to invading taxon. Genetic introgression may affect phylogenetic reconstruction by obscuring topology and divergence estimates. We combined phylogenetic analysis of sequences from one mtDNA and 12 nuDNA loci with analysis of gene flow among 5 species of Pacific Species' geographic ranges are dynamic and experience changes that can range from steady, slow contractions or expansions, to rapid, dramatic changes caused by crossing biogeographic barriers, geologic events, or human impact on species and their environment. For example, Plio-Pleistocene climatic oscillations and resultant periodic glacial advances had a profound impact on geographic ranges and genetic structure of arctic, boreal, and temperate organisms across the Holarctic. These climatic oscillations reduced ranges of some taxa to small refugial areas or even drove them to extinction. Ranges of other taxa experienced periodic dramatic contractions followed by rapid expansions into newly available habitats \u20134. Isolaet. al ) ochotensis) mtDNA has been swept by the mtDNA of the species it has invaded (pleskei). This introgressive sweep of mtDNA had the opposite direction of the nuDNA introgression and resulted in the paraphyly of pleskei mtDNA haplotypes with respect to ochotensis. Unlike the mtDNA gene tree, the multilocus species tree based on nuDNA data resolved all inter- and intraspecific relationships despite substantial genetic introgression of nuclear loci. However, the node ages on the multilocus species tree may be underestimated due to the effects of substantial genetic introgression [certhiola species group affected by both the introgressive sweep and strong purifying selection was 1.6 times older than the fasciolata group where mtDNA evolution is consistent with neutrality. In the multilocus species tree, the fasciolata group was almost 3 times older than the certhiola group despite the similar levels and patterns of nuDNA introgression in both species groups.The combination of phylogenetic analyses of mtDNA and multilocus nuDNA sequence data with the coalescent analyses of gene flow among closely related species allowed us to test the effect of genetic introgression and selection on tree topology and divergence date estimates. Consistent with simulations under neutrality and other empirical studies , our datgression as suggeS1 FigOnly substitutions were treated as differences, gaps were ignored.(PDF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.S2 Table(XLS)Click here for additional data file."} +{"text": "Graves' disease (GD) is an autoimmune disorder characterized by the presence of circulating autoantibodies that stimulate the thyroid hormone receptor (TSHR), resulting in hyperthyroidism and goiter. GD may affect also other organs, leading to Graves' orbitopathy, Graves' dermopathy and acropachy. It is likely that the extrathyroidal manifestations of GD are due to autoimmunity against antigens common to the thyroid and other affected organs (for example TSHR). Although its exact etiology remains to be established, GD is believed to result from a complex interaction between genetic, environmental and endogenous factors.The clinical picture of GD is highly variable. Measurements serum levels of anti-TSHR autoantibodies (TRAb) and thyroid ultrasonography represent the most important diagnostic tests for GD.Existing treatment modalities for Graves' hyperthyroidism includes antithyroid drugs (ATDs), radioactive iodine, and surgery. The use of ATDs as the initial treatment option in GD is well accepted. However, the optimal treatment duration and the predictive marker of remission after ATDs therapy are still controversial. A high relapse rate after a course of ATDs (60-70%), implies the use of ablative treatments (radioactive iodine or surgery) that remove or decrease thyroid tissue leading to lifelong hypothyroidism. There is a lack of general agreement as to which therapy for Graves\u2019 hyperthyroidism is the best as none is ideal and all may have severe side effects. Moreover, none of these treatments targets the autoimmune disease process. Therefore the treatment plan should be established individually and carefully discussed with the patient. Hopefully novel agents that might act on the autoimmune disease process will be approved for Graves' hyperthyroidism."} +{"text": "Regulated trafficking of mitochondria in neurons is essential for providing ATP at the correct spatial location to power neural function and computation, and for providing calcium buffering at sites of calcium entry or release. Indeed the regulation of mitochondrial distribution, morphology and function are proposed to play an important role in neuronal development and survival but the regulatory mechanisms remain unclear. Miro family proteins contain a transmembrane domain locating them to the outer mitochondrial membrane, along with two GTPase domains and two calcium-sensing EF-hand domains that face into the cytosol, and play a key role in regulating mitochondrial transport. Miro proteins mediate mitochondrial trafficking in neurons by linking mitochondria to kinesin and dynein motor proteins for their transport in axons and dendrites. Miro proteins are also targets for the Parkinson\u2019s Disease associated PINK1/Parkin mitophagy pathway and are therefore implicated in altered mitochondrial dynamics during mitophagy. Here I will present our recent results on the role played by Miro proteins in regulating mitochondrial trafficking and quality control. The role that Miro-mediated control of mitochondrial trafficking and turnover plays in regulating neuronal development, function and pathology will also be explored."} +{"text": "Insecure attachment styles have received theoretical attention and some initial empirical support as mediators between childhood adverse experiences and psychotic phenomena; however, further specificity needs investigating. The present interview study aimed to examine (i) whether two forms of poor childhood care, namely parental antipathy and role reversal, were associated with subclinical positive and negative symptoms and schizophrenia-spectrum personality disorder (PD) traits, and (ii) whether such associations were mediated by specific insecure attachment styles.A total of 214 nonclinical young adults were interviewed for subclinical symptoms , schizophrenia-spectrum PDs , poor childhood care (Childhood Experience of Care and Abuse Interview), and attachment style (Attachment Style Interview). Participants also completed the Beck Depression Inventory-II and all the analyses were conducted partialling out the effects of depressive symptoms.Both parental antipathy and role reversal were associated with subclinical positive symptoms and with paranoid and schizotypal PD traits. Role reversal was also associated with subclinical negative symptoms. Angry-dismissive attachment mediated associations between antipathy and subclinical positive symptoms and both angry-dismissive and enmeshed attachment mediated associations of antipathy with paranoid and schizotypal PD traits. Enmeshed attachment mediated associations of role reversal with paranoid and schizotypal PD traits.Attachment theory can inform lifespan models of how adverse developmental environments may increase the risk for psychosis. Insecure attachment provides a promising mechanism for understanding the development of schizophrenia-spectrum phenomenology and may offer a useful target for prophylactic intervention. Childhood interpersonal adversities are associated with an increased risk for psychotic disorders and subclinical psychotic phenomena \u20133. In reAttachment theory provides an integrative approach for understanding how early relational experiences become internalized and contribute to the unfolding of adaptive or maladaptive developmental pathways \u201313. AdulPrevious work examining whether insecure attachment styles mediate the adversity\u2013psychosis link has not specifically focused on adverse relational experiences with significant caregiving figures. This is a relevant domain of investigation given that attachment theory suggests that attachment styles are first formed in the context of the early caregiving environment . ResearcIn the present study we used the Childhood Experience of Care and Abuse (CECA) , an inteElucidating whether there exists specificity of type of attachment style in mediating between different childhood experiences and different phenotypic expressions of psychosis should advance theory development and may ultimately inform the design of preventative and treatment strategies. Earlier studies on the role of attachment in pathways between adversity and psychotic phenomena \u201310 have Research indicates that the psychosis phenotype exists on a broad continuum that extends from schizotypic personality variation to minimal impairment to full-blown psychotic disorder and that etiological continuity appears to exist across clinical and subclinical manifestations , 29. In The present study sought to extend previous research by examining poor childhood care, attachment style, and schizophrenia-spectrum phenomenology using interview measures in a sample of nonclinical young adults. The goals were to investigate (i) whether childhood parental antipathy and role reversal are associated with subclinical positive and negative symptoms and schizophrenia-spectrum PD traits, and (ii) whether such associations are mediated by specific insecure attachment styles.The study was approved by the Universitat Aut\u00f3noma de Barcelona (Spain) Ethics Committee and conformed to the Helsinki Declaration. The participants in this interview study were over eighteen years of age and had full capacity to consent to participation in research. All participants provided written informed consent and were compensated for their participation.The data for the present study were collected as part of an ongoing longitudinal investigation examining risk for psychosis. The participants were drawn from a sample of 589 undergraduate students from the Universitat Aut\u00f2noma de Barcelona who completed self-report questionnaires as part of mass-screening sessions. Usable screening data were obtained from 547 participants . Of these, a subset of 339 was invited to participate in an interview study with the aim of assessing 200 individuals. Those invited to take part included 189 who had elevated scores (standard scores based upon sample norms of at least 1.0) on the positive or negative schizotypy factors derived from the Wisconsin Schizotypy Scales \u201334, the Participants were administered the measures described below along with other measures not used in the present study. The interviews were conducted by psychologists and advanced graduate students in clinical psychology who were trained in the administration of the measures and were unaware of participants\u2019 scores on the screening questionnaires. Consensus meetings to discuss ratings were held regularly throughout the data collection period.Subclinical symptoms were measured with the Comprehensive Assessment of At-Risk Mental States (CAARMS) , which iThe CECA interview was used to assess antipathy and role reversal. These scales involve questioning participants about their experience with (and behavior from) parent figures or substitute parent figures prior to the age of 17. The severity of each experience is rated on a 4-point scale ranging from \u201cmarked\u201d to \u201clittle/none\u201d, based on specific rating rules and benchmarked thresholds. The ratings rely on objective aspects of experience rather than the individual\u2019s subjective attitudes or emotional responses. Overall antipathy and role reversal ratings were obtained . The analyses used the continuous severity ratings of each childhood experience.Attachment style was measured with the ASI, a semi-structured interview that assesses current attachment style based on detailed questioning of a person\u2019s behavior and attitudes in close relationships. The interview consists of two parts that together determine the individual\u2019s attachment profile: First, a rating of the ability to make and maintain relationships is made based on the overall quality of ongoing relationships with up to three supportive figures (including partner if applicable). Second, ratings are obtained on seven attitudinal attachment scales denoting avoidance and anxiety in relationships. Further details of the ASI scoring procedure can be found elsewhere , 27. TheThe Beck Depression Inventory\u2013II (BDI\u2013II) was usedp-values of less than 0.05 were considered statistically significant and the effect size of the correlations was interpreted following Cohen\u2019s [All analyses were performed using the Statistical Package for Social Sciences (SPSS), Version 19.0. Given that depressive symptoms show associations with poor childhood care, insecure attachment styles, and psychotic phenomena , 40\u201343, Cohen\u2019s guidelin Cohen\u2019s method f Cohen\u2019s . For eacThe present study showed that parental antipathy and role reversal were associated with schizophrenia-spectrum phenomenology in a nonclinical sample of young adults. Although there is robust evidence linking interpersonal childhood adversities with psychotic features, the effects of antipathy and role reversal have been scarcely investigated. Our findings point to the relevance of considering their potential etiological significance alongside other forms of maltreatment. The current study also showed that particular insecure attachment styles served as mediators of associations of antipathy and role reversal with subclinical positive symptoms and/or paranoid and schizotypal PD traits. This suggests the existence of specific indirect pathways linking each childhood experience with subclinical psychotic phenomena and, more broadly, underscores the value of examining the role of attachment styles for understanding how different kinds of relational adversities might impact upon the risk and expression of schizophrenia-spectrum phenotypes. Furthermore, by partialling out the effects of depressive symptoms in all the analyses, the study provided a conservative test of the research questions and further demonstrated the incremental value of the attachment style construct over-and-above affective disturbances.Before discussing the mediation findings it is important to highlight that the cross-sectional nature of this study limits the conclusions that can be drawn in terms of causality. The study provides useful information for the identification of potential explanatory mechanisms and we interpret the findings in accordance with the attachment literature, which has consistently identified adverse experiences with early caregiving figures as precursors to later attachment difficulties . HoOur results indicated that antipathy had an indirect effect on subclinical positive symptoms through angry-dismissive attachment and an indirect effect on paranoid and schizotypal PD traits through both angry-dismissive and enmeshed attachment. The angry-dismissive style is characterized by mistrust, self-reliance, and anger in relationships and has been associated with a coping style involving blame of others . The enmThe study also showed that role reversal had an indirect effect on paranoid and schizotypal PD traits through enmeshed attachment. Previous work has conceptualized role reversal in childhood as an experience that, among other things, inhibits the development of autonomy, interferes with the differentiation of boundaries, and increases preoccupation with relationships \u201348. IndeThe fact that fearful and withdrawn attachment did not emerge as mediators does not preclude their role in the adversity\u2013psychosis link; rather, it suggest that these styles might not be involved in pathways following from the childhood experiences measured in the current study. For example, previous self-report findings indicated that fearful attachment mediated associations between childhood trauma and psychosis-proneness . It may The strengths of the current study include the use of validated interview measures. In particular, our use of intensive interviews of childhood experience and attachment style allowed obtaining contextualized in-depth information that is not easily afforded through questionnaire approaches (and serves to minimize biases associated with subjective responding). As regards to limitations, in addition to the study\u2019s cross-sectional nature, the use of a university student sample with a predominance of female participants may limit generalizability. Data from community samples with a more representative distribution of gender and age would enhance the generalizability of the findings. Research is also required in prodromal and clinical populations in order to determine whether these mechanisms operate across the psychosis continuum.As for clinical implications, our results support previous suggestions that assessing childhood adverse experience and attachment style might inform service provision for individuals with psychosis , 15, 50."} +{"text": "While most brain tumors do not have an intact blood-brain barrier (BBB), vascular barriers in the tumor and the surrounding intact brain tissue are major challenges for the use of chemotherapy for CNS malignancies. The permeability of brain tumor vessels can be highly heterogeneous, and factors such as high interstitial pressures can prevent agents from reaching an effective concentration in all tumor regions. Furthermore, tumors such as glioma are highly infiltrative, and these infiltrating tumor cells in the brain tissue surrounding the vascular portion of the tumor are protected by the BBB.Numerous studies have demonstrated that when combined with an ultrasound contrast agent, ultrasound can temporarily disrupt the BBB and increase the delivery of agents across the \u201cblood-tumor barrier\u201d. This presentation will review data obtained in rat and mice brain tumor models that evaluated tumor growth rates and survival after ultrasound-enhanced chemotherapy delivery. These studies have evaluated a range of primary and metastatic models and drugs.These studies have all demonstrated that ultrasound-induced permeabilization of the BTB and chemotherapy can improve outcomes in rodent and human tumor models. Drugs including BCNU, doxorubicin , temozolimide, and trastuzumab have been tested. While in some cases the response has been modest, with multiple treatments dramatic improvements have been reported.These studies demonstrate the potential for this technology, either alone or in combination with focused ultrasound ablation, to provide more effective treatment options for patients with brain tumors. The next steps needed for clinical translation, including the need for tests in better tumor models, improvements to transcranial focused ultrasound systems to enable sonication of large volumes, and the development of effective methods to monitor and guide the procedure outside the MRI will be discussed."} +{"text": "Epidemic keratoconjunctivitis caused by different serotypes of human adenoviruses is an explosive and highly contagious ocular surface infection. This is the case of a young ophthalmologist who presented a filamentary keratitis complicating an adenoviral keratoconjunctivitis. Filamentary keratitis is a chronic and debilitating disorder related to dry eye syndrome. Patients with filamentary keratitis report ocular discomfort ranging from mild foreign-body sensation to severe ocular pain. Filaments are composed of mucin, and degenerating and regenerating epithelial cells of the cornea. Current management of filamentary keratitis involves treating the underlying dry eye and mechanical removal of filaments."} +{"text": "During embryogenesis, thalamocortical axons (TCAs) organize themselves in defined bundles that follow a unique pathway crossing several anatomical boundaries, which makes them easy to track during different stages of neocortical development. These features render TCAs notoriety as a model to study the extrinsic cues that regulate axon guidance and elongation in vertebrate systems. Amid neocortical development, corticothalamic axons (CTAs), project to the subpallium to target the thalamic and subcortical areas, whereas the ascending TCAs project through the ventral telencephalon toward the pallium and spread to reach diverse regions of the neocortex and meet the corticofugal axons approximately around E14. At around E16, TCAs transit via the intermediate zone (IZ) and ascend to the cortical plate in order to make appropriate networks by creating synaptic contacts to the cortical neurons play a central role in axonal progression by activating their receptors at axon growth cones, thus triggering a towing mechanism that promotes their elongation and ensures target meeting and its receptor CXCR4 on TCAs . These findings clearly stated that the IPC-mediated expression of CXCL12 drives not only proper TCA outgrowth into the neocortex, but also orchestrates a migratory route for the interneurons (Figure Cxcl12 mutants remained unexplored. It is known that the progression of CTAs and TCAs is mutually dependent during cortical development (Hevner et al., Cxcl12 mutants.The picture of INs migration linked to TCA progression remains however incomplete, as the reported migratory defect results from the analysis of the depletion of CXCL12 from IPCs at a single developmental stage. Time-lapse experiments could define the precise dynamics behind the IPC-mediated regulation of INs migration. In addition, the reciprocal effect of TCAs-CTAs in the The study by Abe et al., suggests the existence of an axis between axon development, neuronal migration and chemotaxis that is centralized in IPCs, opening a new venture in understanding how different aspects of brain development are intermingled. Their findings highlight the role of intermediate progenitors as a source of chemokines stimulating TCA outgrowth and interneuron migration in a coordinated fashion. Whether chemokines influence the precise localization of interneurons at specific cortical layers, as well as the TCA\u2013CTA crosstalk and pathfinding, remains a matter of future investigation.AL: Original concept, writing and discussion. BS: Writing, figure design, and discussion.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The positive deviance approach assumes that solutions to problems faced by a community already exist. Despite experiencing similar constraints as others, \u2018positive deviants\u2019 succeed through their deviant behaviour. Originating within international public health, positive deviance has increasingly been applied to healthcare and a four stage process has been proposed to do this. Positive deviants are firstly identified using routinely collected data then their success strategies are explored. These strategies are then tested in a more representative sample and disseminated to the community. The quality of current healthcare applications however varies and different study designs and methods are used at each stage of the process. This review aims to investigate the extent to which these stages are adopted in healthcare research.The review explored definitions of positive deviance, study designs and methods used, quality of research, level of analyses conducted and organizations or employees involvement within the research. The search strategy was applied across seven electronic databases and reference list/ citation searches were conducted for included articles. Studies were included if they used positive deviance within a healthcare organization, reported primary research and were peer reviewed. Data extraction focused on the methods used at each of the four stages of positive deviance. Quality assessment was conducted using the QATSDD and all extraction was second reviewed for accuracy and completeness. Data synthesis was conducted using the UK Economic and Social Research Council guidance on narrative synthesis.The search strategy identified 564 articles excluding duplicates. 37 articles, representing 26 individual projects met the full inclusion criteria. Positive deviance is most commonly applied to reduce healthcare associated infections and research has most frequently been conducted within North America. Research focuses on stages 1 and 2; identifying positive deviants and the strategies used to succeed. Very little research tests or disseminates these strategies. Disparate approaches, study designs and methods are used within research with little involvement from the organisation and staff.This is the first systematic review of positive deviance applications within healthcare organisations. It highlights the approaches flexibility, relevance to a range of quality improvement issues and use in identifying practical and sustainable solutions. Recommendations relate to the study designs and methods used, practicalities of conducting the approach within clinical contexts and the increased role organisations and employees could have in positive deviance research."} +{"text": "Antibiotic resistance is recognized globally as an emerging threat for public health. The recent World Health Organization report identifies an array of multidrug resistant bacterial pathogens as emerging mortality threats WHO, . AntibioMultidrug efflux systems are membrane transport proteins placed at the epicenter of intrinsic resistance and have been at the forefront of research for the last 20 years. They perform essential roles in cellular metabolism, and differ in membrane topology, energy coupling mechanisms and substrate specificities leads to increased numbers of multidrug-tolerant persisters are triggered by the host microbiota . AMPs are an integral part of the innate immune system protecting a host from invading pathogens Brogden, . Cationiin vitro resistance have been identified in successful preclinical development studies has been a rapidly expanding discipline. Conventional wisdom, the available discovery tools and the clinical necessity for alternative therapeutic strategies have pinpointed specific transporter families as targets for efflux inhibition. The most classic examples include the RNDs in Gram-negative bacteria and the prominent ABCs in pathogenic fungi and cancer cells. There is substantial progress in the identification of lead chemotypes with EPI properties, but the inherited transporter promiscuity requires an informative translational strategy to define the principles of the interaction with the host. The pivotal role of efflux systems has been shown by advances in cell physiology and host-based transporter oriented studies. Recent identification of transporters with designated novel roles directly implicated in pathogenicity and cancer is reshaping conventional views and approaches for efflux inhibition. Several promising narrow- and broad-spectrum microbial EPIs have been characterized, but they did not result in a clinically useful countermeasure have been used to profile efflux based microbial virulence as well as to develop tractable, whole-animal antimicrobial screens and MexCD-OprJ (nfxB) multidrug resistant mutants is a knowledge mining tool built on the top of a chemo-informatics database that is used to collect, select, curate, organize, analyze, and build models as well as to distribute screening results and published bioactivity data related to fungal and mammalian ABC transporters. The TLI system provides the ability to interactively query and organize the collection of substrates, inhibitors, their associated assays and chemical structural features The The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Unsafe abortion remains a public health problem in Ghana with colossal costs to families, communities and health services, evident in persistently high maternal mortality ratios. It is well known that access to and utilization of family planning, safe and legal abortion services and quality post abortion care could help curtail the ramifications of unsafe abortions. Ghana has a liberal abortion law, yet safe, legal abortion services are not easily accessible in public health facilities. The extent to which attitudes of providers are influenced by global discourse on abortion and the role of safe abortion in reducing maternal mortality rates, is not well known.Using a purposive sample of 36 providers, in-depth interviews were carried out to explore the knowledge, interpretation and application by providers of the abortion law and the MOH/GHS policy, and their attitudes and experiences vis-\u00e0-vis provision of abortion services.Many obstetricians knew the law but pharmacists and midwives were less knowledgeable of the law. The law was perceived as liberal but full of gaps and inconsistencies making its interpretation and application a problem. Obstetricians\u2019 exposure to international treaties and conventions influenced their attitudes towards provision of safe abortion services while midwives\u2019 attitudes were largely affected by their religious inclinations and social context. Lack of resources such as trained personnel who are willing to provide abortion services, unavailability of manual vacuum aspiration kits and the lack of support and cooperation of hospital administrations also influenced provider actions and hampered abortion care. Exposure of health personnel to trends in abortion care in other countries through conferences and treaties did appear to influence how they thought and acted concerning abortion care. Values clarification workshops for health providers were also cited as helping to influence their (positive) attitudes towards women with unplanned pregnancies who need abortion care.Breaking the culture of silence surrounding abortion through discussions on the topic, mobilizing health providers who are not conscientious objectors and promoting discourse from international Conferences through continuing education and in public media all hold potential for sustaining comprehensive abortion care in Ghana."} +{"text": "The goal of this Research Topic was to bring together diverse scientific perspectives on lateralized brain mechanisms underlying emotion, motivation, and memory. The Topic resulted in eight articles, three of which report original research and five of which review and synthesize past research with the aim of developing new hypotheses and theory. A range of international experts with diverse backgrounds, theoretical perspectives, and experimental methods contributed to the Topic. Contributions strongly reflect this diversity, ranging from examining pupil dilation in response to viewing Rembrandt portraits to understanding how caffeine supplementation influences levels of spatial processing. In all cases, the authors developed strong, empirically guided insights into the lateralized brain mechanisms underlying behavioral effects. Two primary themes emerge to guide and constrain continuing research.dynamic interhemispheric interactions that subserve emotion, motivational states, and memory. Elizabeth Shobe\u2019s article, Independent and Collaborative Contributions of the Cerebral Hemispheres to Emotional Processing How might other individual differences modulate lateralized and bilaterally interactive brain mechanisms involved in processing specialized information types and maintaining and updating motivational states and goals?(2)Contrasting accounts of hemispheric differences in affective and motivational processing were presented. How can we devise research paradigms to test the relative validity of these models?(3)Much of this work infers lateralized processes from behavior, but how might functional connectivity analyses advance our understanding, for instance by exploring interhemispheric communication as a result of saccadic eye movements or inconsistent handedness?(4)How might a wider range of nutritional influences, including psychostimulants and amino acids, bias attention, perception, and memory toward particular information types, motivational states, arousal, and mood states, or levels of focus?(5)How can better understanding lateralized and bilateral interactive brain processes inform applied interventions for clinical or performance-based domains, including predicting surgical outcomes, and informing targeted neuromodulation ?The diverse articles published under this Research Topic advance theoretical positions related to interactive contributions of brain hemispheres toward a broad range of cognitive functions related to emotion and memory, and highlight important characteristics of lateralized mechanisms in human and non-human primates. Relatively, integrated perspectives on brain involvement across a range of cognitive tasks provide stimulating theoretical frameworks for reconciling a range of experimental findings and motivating future research. Specific outstanding questions raised by the Research Topic include:The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Nonstationarity of neural dynamics is a ubiquitous property that is crucial to understanding many key phenomena of both healthy and diseased brain function, including circadian rhythms, dynamics of epileptic activity as well as cognitive processing. Detecting switching of brain states has recently become of growing interest in the human brain neuroimaging community. However, from the data analysis/modelling perspective the task is quite challenging, and competing approaches exist . One widWe document this danger by applying an example analysis pipeline used in to simul"} +{"text": "Meditation practices aim at modifying the emotions by reducing reactivity to both pleasant and unpleasant emotions , and showed \u201clagged coherence.\u201d All significant differences between meditation and before/after states showed lower coherence during meditation for the five meditations and eight EEG bands. This suggested that functional interdependence between brain regions was globally reduced. The reduced functional interdependence was considered to be related to minimized interaction and constraints on the self process (which includes self-awareness and embodiment), leading to non-involvement and detachment . Also, during meditation (compared to rest), in response to emotional and neutral sounds, there was increased activation in the amygdala, right temporo-parietal junction, and right posterior superior temporal sulcus. The results support the speculation that LKCM activates brain circuits related to empathy in response to emotional stimuli.Brain activity using fMRI was assessed while novice and experienced meditators practiced loving-kindness-compassion meditation . A conjunction approach was used to reveal regions common to the expert meditation state. Both FAM and LKM appeared to influence the neural responses to affective pictures.A study was designed to examine the effects of focused-attention meditation (FAM) and loving-kindness meditation (LKM) during the performance of cognitive and affective tasks (Lee et al., The difference between FAM and LKM was apparent when participants were given emotion-processing tasks, involving viewing affective pictures. When viewing sad faces the FAM practitioners showed activation in areas related to attention whereas in the LKM practitioners changes occurred in areas associated with compassion and emotional regulation.These findings showed that different meditations are associated with distinct neural activity during sustained attention and processing emotions. Hence, meditation causes changes in parts of the brain and modifies brain activity, in distinct ways based on the meditation technique.To our knowledge no study has checked whether detachment and empathy can co-exist as a result of meditation; and the pathway has not been determined. The dorsal MPFC showed increased activation associated with mental activity during introspection (Gusnard et al., The above discussion suggests that detachment and empathy can be experienced simultaneously through meditation. A study of the effects of meditation would be interesting to test whether detachment and empathy can indeed co-exist. It would also be of interest to understand whether following the necessary training empathy could lead to compassion. The present speculation suggests that through meditation an individual can reach a mental state which is disengaged and detached, but retains the choice to engage with specific situations based on empathy.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Kras allele can distinguish carriers of the human KRAS mutation in the clinical samples and, furthermore, that this signature correlates with poor patient prognosis. Finally, they demonstrate that high expression of the GEMM Kras signature predicts sensitivity to a commonly used anticancer therapy in human CRC cell lines. This study supports the use of GEMMs as powerful preclinical tools for the study of molecular heterogeneity in CRC and for testing potential therapies. 613Page The majority of cases of colorectal cancer (CRC), one of the most commonly diagnosed cancers worldwide, arise sporadically by the acquisition of tumorigenic somatic alterations. Sporadic CRC is difficult to mimic in preclinical animal models because of its heterogeneous nature, which has contributed to the current lack of effective CRC therapies. Genetically engineered mouse models (GEMMs) have been widely used to explore cancer biology and establish targeted cancer therapies. In this study, Eric Martin and colleagues at Pfizer used a unique collection of GEMMs harbouring colon-specific mutations that have been commonly observed in CRC to help resolve the genetic heterogeneity. Primary tumour material isolated from the GEMMs was used to generate gene expression signatures, which were then applied to human CRC datasets to stratify cancer subsets based on genotype. The authors show that a signature based on a mutant"} +{"text": "Thermal therapy has tremendous potential to augment the benefits of immunotherapy. The ability of heat to stimulate both general and tumor specific responses, in part through heat shock protein mediated mechanisms has been known for over two decades. Significant challenges persist however in translating these effects into predictable and meaningful clinical responses. More recently the association of radiation with immune stimulation and in some cases specific anti-tumor immune response has been defined.Coupled with the introduction of new immunotherapuetics including check point inhibitors which have demonstrated clinical survival benefit, the combination of heat, radiation, and immunotherapy to combat cancer is a timely area for investigation. The potential of focused ultrasound to augment immunotherapy including targeted heat and drug delivery will be discussed including the opportunity to enhance immune effects arising from the heated but non-ablated rim present with tumor ablation."} +{"text": "Pulmonary dysfunction is a common complication of cardiac surgery. The mechanisms involved in the development of pulmonary dysfunction are multifactorial and can be related to the activation of inflammatory and oxidative stress pathways. Clinical manifestation varies from mild atelectasis to severe respiratory failure. Managing pulmonary dysfunction postcardiac surgery is a multistep process that starts before surgery and continues during both the operative and postoperative phases. Different pulmonary protection strategies have evolved over the years; however, the wide acceptance and clinical application of such techniques remain hindered by the poor level of evidence or the sample size of the studies. A better understanding of available modalities and/or combinations can result in the development of customised strategies for the different cohorts of patients with the potential to hence maximise patients and institutes benefits. Pulmonary dysfunction is a common complication of cardiac surgery that can impact patient's outcomes and health economics. It is recognised that many patients will have altered pulmonary mechanics after surgery which may appear in a wide range of clinical presentations, from mild atelectasis to life threatening acute lung injury (ALI) or adult respiratory distress syndrome (ARDS) \u20133.Surgical incisions by abolishing the integrity of the chest wall affect respiratory mechanics leading to impaired respiratory effort. Postoperative pain has been shown to be associated with decreased lung function by precluding deep inspirations. Furthermore, patients undergoing surgical procedures associated with opening the pleura will have increased rates of atelectasis, pleural effusions, and postoperative pain especially in the early postoperative period \u20136.Cardiopulmonary bypass (CPB) can lead to the activation of different inflammatory and coagulation pathways and alters redox balance due to the passage of blood through the circuit (contact activation) and ischaemia and reperfusion injury \u201310.Vascular endothelial cells (EC) dysfunction during CPB due to changes in blood flow patterns, shear stress, ischaemia, and reperfusion and circulating cytokines will result in the activation of multiple proinflammatory and proapoptosis pathways \u201314 whileCPB is traditionally associated with inadequate lung perfusion as there is no flow to the pulmonary artery during periods of cross clamping and when the heart is not ejecting blood, and thus blood supply is limited to the bronchial arteries . PulmonaBlood and blood products usage after surgery can be associated with the production of excessive amount of ROS and systemic and pulmonary inflammation. It has been previously shown that the duration of blood storage before transfusion can influence adverse effect associated with transfusion as there are an increased risk of respiratory insufficiency and the need for prolonged ventilation in patients receiving blood stored for longer than two weeks , 31\u201334.Here we review the most commonly used strategies to minimise pulmonary dysfunction after cardiac surgery.The fact that inflammation and oxidative stress play a pivotal role in the development of pulmonary dysfunction resulted in multiple studies aimed toward modulating such events by the administration of vasodilators and antioxidant and anti-inflammatory medications in experimental animal models or patients undergoing cardiac surgery.Prostacyclins can induce vascular smooth muscle cells relaxation by the release of intracellular adenosine 3\u2032,5\u2032 cyclic monophosphate (cAMP) resulting in pulmonary and systemic vasodilation \u201338. MorePhosphodiesterase inhibitors such as pentoxifylline (PTX) which is a known nonselective phosphodiesterase (PDE) inhibitor can result in elevated levels of intracellular cAMP and vasodilatation. Although PTX has been used classically for claudication symptoms in peripheral vascular disease , it has Nitric oxide (NO) is known to play a pivotal role in vascular endothelial cells homeostasis and regulation of oxidative stress and inflammatory responses . IschaemA large number of other drugs have been used with various degrees of success. Aprotinin (serine proteases) had been shown to reduce neutrophil elastase, malondialdehyde, and proinflammatory cytokines levels in bronchoalveolar lavage fluids of patients undergoing cardiac surgery . The useDifferent strategies have been attempted over the years to minimise proinflammatory activation and oxidative stress when using CPB such as coating the circuit with biocompatible material , removal of leukocytes , ultrafiltration, and reduced haemodilution.Heparin is thought to reduce the inflammatory responses linked to platelets and leukocytes by reducing the release of IL-6, IL-8, E-selectin, lactoferrin, myeloperoxidase, integrin, selectin, and platelet thromboglobulin and decreasing the production of oxygen free radicals \u201366. It hThe use of leukocyte filtration mechanisms can modulate proinflammatory cytokines and oxidative stress \u201371. A clUnderstanding problems associated with pulmonary ischaemia and reperfusion results in attempts to provide continuous pulmonary perfusion during CPB. Experimental animal models of pulmonary perfusion demonstrated reduced inflammatory and apoptosis pathways activation with such strategy , 76, 77.The deleterious effects of surface contact activation as discussed previously have led to the development of minimised cardiopulmonary bypass circuit (mini-CPB). This is characterised by reduced surface area and thus priming volume and prevention of air-blood contact. The utilisation of mini-CPB has been shown to be associated with attenuated production of proinflammatory cytokines and complement activation and blunted leukocytes activation compared to conventional circuit. Markers of oxidative stress tend to be reduced in patients undergoing surgery using mini-CPB compared to conventional circuit , 83. AddIt has been suggested that eliminating the usual standard of no lung inflation during CPB by maintaining a degree of lung ventilation may be beneficial. The use of continuous positive airway pressure (CPAP) during CPB may result in less shunt and better gas exchange ; howeverOff pump coronary artery bypass (OPCAB) surgery seems to provide better lung protection by eliminating ischemia-reperfusion injury through maintaining lung ventilation and avoiding CPB. Many studies consistently reported better early and midterm outcomes in OPCAB when compared with conventional on-pump CABG: fewer respiratory complications, shorter intubation time and ITU stay, reduced incidence of pneumonia, and overall shorter hospital stay \u201392.Preoperative prophylactic physiotherapy with inspiratory or expiratory muscle training can be used as a preventative measure for lung protection , 94. PosThese techniques include deep breathing exercises, slow maximal inspirations with an inspiratory hold, intermittent deep breathing exercises with and without the use of incentive spirometer, and deep breathing exercises with expiratory resistance \u201398.NIV refers to the administration of ventilatory support without using an invasive artificial airway . NIV exerts its main effects on the pulmonary and on the cardiovascular systems through the application of a positive end-expiratory pressure (PEEP); with or without a pressure support during inspiration, NIV restores lung volumes by opening atelectatic areas, increases alveolar ventilation, and reduces the work of breathing \u2013101.Continuous positive airway pressure (CPAP) aims to maintain a level of positive airway pressure in a spontaneously breathing patient. It is functionally similar to positive end-expiratory pressure (PEEP), except that PEEP is an applied pressure against exhalation and CPAP is a pressure applied by a constant flow. The ventilator does not cycle during CPAP, no additional pressure above the level of CPAP is provided, and patients must initiate all of their breaths. To avoid drying of the respiratory mucosa, there has been general agreement that the application of humidified CPAP helps to recruit the lungs by increasing functional residual capacity (FRC), increase the surface area of lung, decrease intrapulmonary shunt, and improve oxygenation \u2013104.Bilevel positive airway pressure (BLPAP) is a continuous positive airway pressure with pressure support breaths. It delivers a preset inspiratory positive airway pressure (IPAP) during inspiration and expiratory positive airway pressure (EPAP). BLPAP can be described as CPAP with a time-cycled or flow-cycled change of the applied pressure level . BLPAP sPulmonary dysfunction is one of the most common and serious complications after cardiac surgery and can significantly impact on patient outcomes and health economics. The mechanisms involved in the development of pulmonary dysfunction are multifactorial and are related to the activation of different inflammatory and oxidative stress pathways. Clinical manifestation varies from mild atelectasis to severe respiratory failure. Managing pulmonary dysfunction postcardiac surgery is a multistep process that starts before surgery and continues during both the operative and postoperative phases. Pulmonary protection strategies have evolved over the years with various degrees of success. The main weakness of the majority of studies is often being observational in nature, small sample size, or being concentrated on a single intervention. Managing pulmonary dysfunction needs to be a multistep process involving more than one modality for each step of the surgical pathway. A better understanding of available modalities and/or combinations will result in the development of customised strategies for the different cohorts of patients. This in turn will help reduce pulmonary dysfunction and hence improve early outcome and costs after cardiac surgery."} +{"text": "As a term, \u201cnext generation plant breeding\u201d is increasingly becoming popular in crop breeding programmes, conferences, scientific fora and social media , the perspective of identification of DNA markers has shifted from fragment based polymorphism identification to sequence based single nucleotide polymorphism (SNP) identification to expedite the marker identification process and to increase the number of informative markers. But the WGS technologies based on Sanger sequencing are time consuming, costly and provide information only on the target individual, which have limited its use in specific gene discovery. Its direct use in large breeding populations is limited by time and cost factors. The advent of next generation sequencing (NGS) technologies and powerful computational pipelines has reduced the cost of whole genome sequencing by many folds allowing discovery, sequencing and genotyping of thousands of markers in a single step (Stapley et al., The initial steps of NGS based marker development involve library construction prior to sequencing. Several targeted marker discovery techniques have been devised using NGS platforms which involve partial representation of the genome and those can be utilized even in absence of prior knowledge on WGS Figure . Based oa priori genome sequence information. RAD-seq tagged SNPs have been used to construct a linkage map in eggplant and to identify QTLs for anthocyanin pigmentation of the fruit (Barchi et al., NGS technologies are already gaining widespread acceptability in the field of crop breeding. Many of the NGS based marker discovery techniques allow SNP discovery and genotyping simultaneously, speeding up the whole process Figure . FurtherGBS has been used in development of high density map of 20000 SNPs in wheat and 34000 SNPs in barley (Poland et al., If the reference genome sequence is available, the sequence based polymorphic marker technology is quite useful for marker discovery in targeted regions of a genome (Sahu et al., The NGS technologies are pivotal to genomic selection, where performance of a target genotype can be predicted from its genomic estimated breeding value determined through statistical models derived using rigorous genotyping and phenotyping of a standard set of breeding population (Poland et al., In spite of high potential, the achievements of NGS technologies have been limited to a few examples, most of which have been generated in by institutes with well-established genomic facilities. The technical expertise to extract usable information from huge sequence information presently is insufficient for large scale application of NGS technologies. The most important requirement for reaping benefits of NGS is to enable plant breeders to manage and extract information from huge genomic data. In addition, genomes with higher ploidy level, presence of homeologus sequences and more repetitive sequence poses problems for sequencing and assembly, but some of these problems may be addressed through upcoming technologies (Griffin et al., Cost of genotyping is another determining factor for adopting appropriate NGS technologies in plant breeding. Since crop breeding handles large population size, it is an expensive process itself. Choice between whole and partial genome sequencing would depend on the availability and judicious use of funds. The cost of WGS for a single genotype of three gigabase genome at 30X coverage is approximate $5000 Hayden, . TargeteApart from marker discovery, the NGS technologies are also being applied for targeted re-sequencing to identify domestication related genes by comparing the genome of crop species and their wild relatives Henry, , and alsThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Hepatoblastoma is a comparatively uncommon paediatric solid tumour, while hepatocellular carcinoma is very rare.The Paediatric Hepatic International Tumour Trial will be the single largest clinical trial undertaken in paediatric liver cancer patients as collaboration between the European Study Group for Paediatric Liver Tumours, Children\u2019s Oncology Group and Japanese Study Group for Pediatric Liver Tumors.In the context of the low incidence paediatric cancer, an overarching study with therapeutic questions for the separate tumour types and risk groups will be more efficient than setting up separate studies for each group. Hence, the design will incorporate randomised comparisons for five different patient groups. It is difficult to obtain feasible sample sizes based on conventional frequentist design criteria. Therefore, Bayesian methods based on probability distributions will be used with event-free survival as the primary outcome measure for each comparison summarised by hazard ratio. Posterior probability distributions, with non-informative priors, based on the number of events will be used to give probabilities of one treatment being better than another. Operating characteristics are explored through simulations of various scenarios given pre-specified decision criteria. The level of evidence needed will depend on the clinical question: for example, a stronger level of evidence is likely to be needed if treatment is being intensified than if two regimens of comparable intensity are being compared.It is important to investigate promising approaches in randomised trials. The design will enable quicker and more efficient identification of effective therapies, leading to improved outcomes for children with liver cancer."} +{"text": "Hydrothermal fields are associated with volcanic landmasses resembling Hawaii and Iceland today and could plausibly have existed on similar land masses rising out of Earth\u2019s first oceans. I will report on a field trip to the living and ancient stromatolite fossil localities of Western Australia, which provided key insights into how life may have emerged in Archaean, fluctuating fresh water hydrothermal pools, geological evidence for which has recently been discovered. Laboratory experimentation and fieldwork are providing mounting evidence that such sites have properties that are conducive to polymerization reactions and generation of membrane-bounded protocells. I will build on the previously developed coupled phases scenario, unifying the chemical and geological frameworks and proposing that a hydrogel of stable, communally supported protocells will emerge as a candidate Woese progenote, the distant common ancestor of microbial communities so abundant in the earliest fossil record.Charles Darwin\u2019s original intuition that life began in a \u201cwarm little pond\u201d has for the last three decades been eclipsed by a focus on marine hydrothermal vents as a venue for abiogenesis. However, thermodynamic barriers to polymerization of key molecular building blocks and the difficulty of forming stable membranous compartments in seawater suggest that Darwin\u2019s original insight should be reconsidered. I will introduce the A complementary approach is to visit sites that are analogs to candidate venues for biogenesis. Such fieldwork broadens our perspective by providing a more realistic assessment of the actual conditions in which physical and chemical reactions progressed toward life\u2019s beginning approximately four billion years ago. Furthermore, geologists familiar with the most ancient, Archaean fossil sites can interpret the rock record and provide knowledgeable advice about geochemical conditions to guide model building and laboratory experiments.Most workers investigating the origin of life confine their horizons to theoretical papers, computational models or laboratory simulations that use a narrow spectrum of commercial reagents reacting in buffered aqueous solutions. The results are then related to prebiotic conditions with the assumption that laboratory or In July 2015, I joined a unique scientific field trip led by Malcolm Walter and Martin Van Kranendonk of the Australian Centre for Astrobiology at the University of New South Wales. This 3000 km trek by air, The journey began with a visit to one of the best examples of living stromatolites, in Hamelin Pool at Shark Bay . These set al. \u201d ~Charles Darwin, in an 1871 letter to Joseph Hooker [h Hooker .A source of energy acts on a mixture of simple organic compounds to produce a large number of random polymers. By chance, a few rare polymers happen to form protocells defined as functional systems which are encapsulated within membranous compartments that are subject to combinatorial selection. The encapsulated polymer systems continuously cycle within a kinetic trap in which the rate of synthesis exceeds the rate of hydrolysis ,29. Over a large number of such cycles, populations of protocells emerge that are capable of growth and replication. Combinatorial selection of protocells that are better able to survive environmental stresses and more efficient in capturing energy and nutrients, drives the evolution of populations toward the first primitive forms of life.The above speculation by Charles Darwin on where and how life might have begun is prescient and deeply insightful: a warm little pond in which a useful polymer forms and evolves to ever increasing complexity of structure and function. By expanding Darwin\u2019s insight with today\u2019s knowledge of chemistry and biochemistry, it is possible to propose a novel scenario for the origin of cellular life in a small, hot, cycling pool : A sourcet al. [It is difficult to imagine how the above scenario could be applied to an origin of life at marine settings such as hydrothermal vents. First, the continuous presence of water puts thermodynamic limits on the condensation reactions that are required for polymerization of monomers. Furthermore, high concentrations of salt and divalent cations at vents or tide pools impose osmotic stresses on membranous compartments. Life today has evolved complex homeostatic mechanisms to regulate cell volume by actively pumping osmotically active ions and thereby maintain transmembrane sodium and potassium gradients as noted by Mulkidjanian et al. .These concerns led to consideration of an alternative scenario that life began in fresh water hydrothermal fields subject to cycles of dehydration and hydration as outlined by Deamer and Georgiou . To summHydrothermal pools may contain mixtures of organic solutes, some of which are potential monomers, and others capable of forming membranous vesicles. During the evaporation that drives the dehydration phase of a cycle, layers of lipid membranes form films on mineral surfaces at the pool edge as the water level fluctuates. Amphiphilic molecules assemble into multilamellar structures in which monomers are captured between the lipid bilayers . Figure Short term dehydration and rehydration of the pool through periodic fluctuations in hydrothermal water supply, rainfall events, and dew from day-night cycles or through changing humidity cause the outer layers of the dried lamellae to disperse large numbers of protocells into the bulk solution. Some of these protocells will contain random sets of polymers (coupled phases scenario proposed by Damer and Deamer [The kinetic trap provides scaffolding for the stepwise emergence of encapsulated systems of functional polymers described earlier in the d Deamer . Functiod Deamer ,40 sugged Deamer then latd Deamer some of d Deamer ,44. ThesIt is a common observation that terrestrial microbial life in the form of mats is metabolically most active in a moist, gradually dehydrating state following a short term hydration event such as rain fall . This prA gradient of selective pressures would be required to give rise to adaptations that enable the transition from a non-living gel phase to a primitive microbial population. Examples of such selective pressures are exposure to environmental gradients such as pH, temperature, nutrient and salt concentrations. Stromatolite fossils observed today were presumably produced by complex microbial communities with a number of finely tuned adaptations , right. A predecessor would therefore possess a subset of these adaptations. The microbial mats observed at Gallery Hill , center A gel phase , left caprogenote as described by Woese and Fox [collective process of evolving the relationship between genotype and phenotype. As individual protocells gradually accumulate and internalize proto-genomic functions, they will develop more autonomous phenotypic expression. A new evolutionary phase of the progenote will arise when member protocells can enzymatically replicate encapsulated genomic and functional polymers and pass them on to daughter cells without depending on dehydration synthesis. The resulting speciation and specialization of increasingly independent protocells will lead to communities becoming robust to steeper gradients of environmental pressures. Some individual protocells will eventually become advanced enough to survive and reproduce independent of their source community, passing an important milestone on the continuum to life. Wider distribution and direct competition between free-living cells will drive this early life along the long winding road to LUCA.I propose that the protocell gel phase is a candidate and Fox ,57, in wterrestrial origin of life hypothesis, offered as a model to the astrobiology community.A protocell gel progenote possesses one more property that supports its central role in the origin of life: mobility. As soon as the components cycling in a hydrothermal \u201corigin pool\u201d , upper rA kinetic trap cycling polymers through coupled phases of hydration and dehydration will produce large numbers of random molecular systems synthesized between dehydrated lipid lamellae (Combinatorial selection of encapsulated functional polymers will be observed within this kinetic trap. The initial selection criterion will be the ability of encapsulated polymers to enhance the stability of their membranous compartments, which will be tested in the hydrous phase (During dehydration, stable protocells will crowd together with concentrated solutes forming a third, gel phase , center These three phases will provide continuous resources and subject molecular systems to a variety of selective pressures, driving the system to surmount hurdles to achieve stepwise molecular evolution of new functions.Pure self assembly and random synthesis will enable the initial stages of the model, but eventually, active functions expressed through sets of robust, heritable proto-genomic instructions will enable Darwinian evolution to take hold.Degradation rates of synthesized polymers will set upper bounds on the permitted dwell time within each phase suggesting the necessity of reliable, repetitive fluid refilling typical of hydrothermal fields. Expressing a pattern emerging later as the life cycle, degraded polymers and other inert byproducts must be periodically reused or expelled and functional systems continually re-synthesized through proto-genomic blueprints drawing from solute sources (A candidate protocell gel progenote capable of growth and evolutionary adaptation will emerge and become robust to distribution to a variety of watery venues in a plausible Archaean volcanic landscape. Extensive laboratory growth, testing, and analysis of such progenotes will provide insight to possible pathways to the first microbial communities and viable free-living cells.The novel features of the model are summarized below, each carrying predictions that can be subject to testing by experimentalists:coupled phases scenario for an origin of life. A novel terrestrial origin of life hypothesis was developed through the unification of chemical and geological settings. The model is centered upon the insight into a protocell gel progenote, a candidate common ancestor of microbial communities. It seems inescapable that very soon after the first robust protocells emerged, they became communal. Primitive protocells floating free in the Archaean environment would be unlikely to survive, while selection would favor the protective, nutritional and collaborative advantages of a protocell gel progenote. This progenote is a model for an amphibious, communal aggregate of protocells that preceded LUCA, a much more highly evolved population of cells able to independently support their own metabolism and reproduction. The progenote described here represents a common pool, or roots from which the earliest inhabitants of the tree of life emerged.A field trip in Western Australia to venues ranging from living marine stromatolites to inland Archaean stromatolite fossil localities tested the"} +{"text": "New discoveries within the models contribute to reliable results with reduced variability. Despite the importance of large animal stem cell models to biomedical advances, the knowledge base surrounding them is relatively limited compared with that of human and rodents. The series of investigations presented by Niada and colleagues helps to meet this essential element of large animal models with information about et al., http://stemcellres.com/content/4/6/148See related research by Niada Stem Cell Research & Therapy provides information about in vitro behavior of adipose-derived stem cells (ASCs) from two different harvest sites in a porcine model. Effects of implant materials, titanium and silicon carbide coating, on ASC osteogenesis and porcine serum on cell proliferation are also assessed. Animal model validation that includes thorough characterization of the proposed therapy and confirms accuracy for the target clinical condition is critical to outcome information that benefits human and veterinary patients [Large animal models of human musculoskeletal and dental disorders are invaluable to preclinical safety and efficacy testing prior to advancing novel therapies to clinical trials. The article by Niada and colleagues in a recpatients . The resThe pig is an established animal model for dental, oral, and maxillofacial research and preclinical testing. In fact, it is a model of choice for novel implant design testing for a number of reasons . PorcineCharacterization of ASCs from distinct adipose tissue harvest sites is vital to clinical translation of the technology. Adipose tissue harvested during elective liposuction is a common source of ASCs for autologous administration . However+, CD271-, CD45-, and CD14-. There was no cross-reactivity of the CD73 and CD105 antibodies. Shortages of monoclonal antibodies directed against animal cell surface markers can limit the ability to determine stem cell phenotype in large animal models [A recent position statement by the International Federation for Adipose Therapeutics and Science and the International Society for Cellular Therapy provides minimal criteria to define stromal vascular fraction cells and ASCs . Basic cIn vitro knowledge of interactions between stem cells and implant materials is required to anticipate the in vivo response of exogenous and native stem cells. In vitro culture conditions that closely mimic the natural environment of the clinical target site provide valuable insight for preclinical models. Porcine ASCs cultured on titanium, silicon carbide coating, and plastic were evaluated for total protein concentration and calcium-rich deposits after 21 days of culture in osteogenic or basal medium in the study. Based on staining, there was greater deposition by ASCs on titanium discs compared with plastic when cultured in both basal and osteogenic media. Total protein levels were less supportive of differences among culture surfaces. A more in-depth evaluation of porcine ASC osteogenic differentiation on implant materials that includes protein and gene expression at several time points will provide opportunities for detailed comparisons among parallel studies with ASCs from different species as well as among investigations using porcine models [e models .ex vivo expansion of stem cells are an area of significant interest. Despite efforts to characterize FBS, there is variability among preparations, and there is always the potential for xenogeneic proteins to affect cell behavior [in vitro cell behavior observed at lower FBS levels [Alternatives to fetal bovine serum (FBS) supplementation of basal medium for behavior . QualityS levels . ContinuOptimization of preclinical animal models facilitates design and implementation of regenerative therapies, and porcine models are established for a large number of oromaxillary and dental procedures. Harvest of ASCs from the buccal fat pad for orthotopic administration is a logical extension of current surgical procedures. Information about porcine buccal fat pad ASCs is limited despite the model\u2019s importance to continued medical advances in the area. Differences among adipose tissue depots and species require individual characterization of ASCs among them. The results of the study by Niada and colleagues contribute to the current understanding of porcine buccal adipose tissue ASCs to support future investigations in this important animal model.ASC: Adipose-derived stem cell; FBS: Fetal bovine serum.The author declares that she has no competing interests."} +{"text": "Sensitisation of the trigeminal nerve (TG) has been extensively studied as a potential mechanism of migraine. Meningeal nociceptors project onto second order neurones of the trigeminocervical complex (TCC) via glutamate neurotransmission. Sensitisation of trigeminal afferents causes massive release of glutamate and central sensitisation. The TCC connects with the VII, IX and Xth cranial nerve nuclei, and participates in the trigeminocardiac reflex which is particularly important in the young .In the laboratory, application of 'inflammatory soup' causes increased trigeminal sensitisation and increased responsiveness so that dural afferents can be strongly activated by mechanical and other stimuli that initially had evoked little or no response. We wished to show that bleeding in the human dura, which produces an inflammatory response and increased mast cell numbers, may sensitise the trigeminal system.We examined our autopsy database for infants and children with chronic subdural haemorrhage who collapsed and died unexpectedly. (Ref 6321)).We identified four patients with chronic dural haemorrhage who died following following TG stimulation; one by hypertension and three by oronasal stimulation during choking. All had selective necrosis in the spinal nucleus of the TCC at autopsy.We suggest these cases represent excitotoxic damage in the presence of sensitisation by chronic dural haemorrhage. Collapse may have been mediated by the trigeminocardiac reflex resulting in bradycardia, hypotension and apnoea. Exaggeration of this protective response has been implicated in Sudden Infant Death Syndrome.No conflict of interest."} +{"text": "Specialist nurses often collaborate with researchers to facilitate recruitment of adult NHS patients, yet little is known about their experiences of inviting participation to research studies. It is well documented that clinical staff involved with recruitment often do not invite all potentially eligible patients, leading to under-recruitment and selection bias. Many barriers and facilitators perceived by clinical staff to inviting research participation have been identified, the majority of these relating to physicians or specific randomised controlled trials.This study aims to explore the barriers and facilitators perceived by specialist nurses to inviting adult patients to a variety of research studies in different NHS settings.The study employs a cross-sectional qualitative descriptive design using purposive and convenience sampling, semi-structured individual interviews and Framework thematic analysis. This study forms an MRes student dissertation and will be completed in September 2015. To date 12 specialist nurses have been recruited, representing a variety of clinical specialties and employing NHS Trusts, with experience of inviting patients to a broad variety of research studies. Data collection is ongoing and 6 interviews have been conducted thus far.Emerging preliminary themes include the perceived facilitator of rapport and clinical credibility within the nurse / patient relationship, and the perceived barrier of insufficient understanding of individual research studies by the nurse.Increased understanding of both barriers and facilitators may inform development of evidence-based interventions to optimise research recruitment involving specialist nurses and other healthcare staff."} +{"text": "Neuronal spike trains can show variability with respect to process parameters such as the rate or variability of inter spike intervals. These changes can occur on fast and slow time scales, including also simultaneous and separate changes in different process parameters.Building up on results of we preseThe separate detection of rate and variance changes requires two techniques: First, rate changes need to be detected, irrespective of potential variance changes. To this end, our approach allows the identification of rate changes in point processes with a certain variability in their lifetimes. Second, the identified rate changes need to be considered when analyzing variance changes. We investigate the empirical properties of our asymptotic MFT method in simulations and apply the MFT to spike trains recorded from auditory cortex of behaving mice, illustrating rate and variability dynamics during the task."} +{"text": "Teaching and assessment of communication skills have become essential in medical education. The Objective Structured Clinical Examination (OSCE) has been found as an appropriate means to assess communication skills within medical education. Studies have demonstrated the importance of a valid assessment of medical students\u2019 communication skills. Yet, the validity of the performance scores depends fundamentally on the quality of the rating scales used in an OSCE. Thus, this systematic review aimed at providing an overview of existing rating scales, describing their underlying definition of communication skills, determining the methodological quality of psychometric studies and the quality of psychometric properties of the identified rating scales.We conducted a systematic review to identify psychometrically tested rating scales, which have been applied in OSCE settings to assess communication skills of medical students. Our search strategy comprised three databases , reference tracking and consultation of experts. We included studies that reported psychometric properties of communication skills assessment rating scales used in OSCEs by examiners only. The methodological quality of included studies was assessed using the COnsensus based Standards for the selection of health status Measurement INstruments (COSMIN) checklist. The quality of psychometric properties was evaluated using the quality criteria of Terwee and colleagues.Data of twelve studies reporting on eight rating scales on communication skills assessment in OSCEs were included. Five of eight rating scales were explicitly developed based on a specific definition of communication skills. The methodological quality of studies was mainly poor. The psychometric quality of the eight rating scales was mainly intermediate.Our results reveal that future psychometric evaluation studies focusing on improving the methodological quality are needed in order to yield psychometrically sound results of the OSCEs assessing communication skills. This is especially important given that most OSCE rating scales are used for summative assessment, and thus have an impact on medical students\u2019 academic success. In the 21st century, teaching and assessment of communication skills in medical schools are well recognized \u20137. Over Despite increasing significance of communication skills training in a medical setting, there is a lack of a generally accepted definition of adequate physician-patient communication . Based oTo assess communication skills, most medical schools established the Objective Structured Clinical Examination (OSCE) using interactions with standardized patients (SP) . An OSCETherefore, this systematic review of rating scales on communication skills assessment in OSCEs aims at 1) identifying existing psychometrically tested rating scales on communication skills assessment in OSCEs and describing their underlying definition of communication skills, 2) determining the quality of design, methods and reporting of studies that analyze psychometric properties of rating scales, and 3) evaluating the psychometric quality of the identified rating scales.We started our systematic review by performing an electronic literature search in the data bases EMBASE, PsycINFO and PubMed. We included all articles published between January 1979, the year in which the first OSCE to assess medical students\u2019 clinical competence was developed , and JanFirst, we imported all search results into reference management software (EndNote) and removed all existing duplicates. Second, two reviewers (JZ and MC) independently performed a title and abstract screening to double-check the identified records for possible inclusion. In a next step, the remaining full texts were independently assessed for eligibility by two reviewers (EC and MC) using the inclusion and exclusion criteria. In case of disagreement regarding inclusion decisions, a third reviewer (IS) was consulted to reach consensus and to make a final decision.Final data extraction sheets were developed after pilot testing and adjustment in discussion between two reviewers (IS and MC). Data extraction sheets contained both descriptive data and data to assess the quality of the included studies. The process of assessing the quality comprised two separate steps. As a first step, the quality of design, methods and reporting of the included studies on psychometric properties was assessed by applying the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist with 4-point scale \u201326. The The COSMIN checklist was developed in a multidisciplinary, international Delphi study and serves as a standardized tool for assessing the methodological quality of studies on measurement properties ,25. The The criteria developed by Terwee et al. were useThe electronic data base search yielded 540 records. In addition, 28 records were identified through secondary search of which 25 were from reference tracking and three from consultation of experts in the field of communication in health care. In a next step, 191 duplicates were removed. We then excluded another 316 records based on title and abstract screening. The full texts of the remaining 61 records were assessed for eligibility. Of the 61 records, 49 were excluded by applying the inclusion and exclusion criteria see . As a reThe majority of the included studies were conducted in Europe. Of the twelve included studies reporting on eight rating scales, five were from UK \u201334, threThe present review included eight rating scales which have been applied in OSCE settings to assess communication skills of medical students while they interacted with SPs. From these eight rating scales, five were clearly named by the authors ,40,41. FThe assessment of the methodological quality of the included studies on measurement properties by applying the COSMIN checklist is presented in The evaluation of the psychometric properties of the identified rating scales was carried out by applying the quality criteria of Terwee et al. The corresponding results are shown in The present systematic review aimed at identifying psychometrically tested rating scales on communication skills assessment in OSCEs, describing their underlying definition of communication skills, assessing the methodological quality of the included studies and evaluating the psychometric quality of the identified rating scales. For these purposes, data were extracted from twelve studies reporting on eight rating scales.Regarding the underlying definition of communication skills of the identified rating scales, publications on three of the eight identified rating scales to be improved, future evaluation studies need clearly formulated hypotheses, larger sample sizes for multiple hypotheses and an adequate description of the comparator rating scales. Third, several psychometric properties were completely neglected in all included studies. Thus, they deserve attention in future psychometric evaluation studies.Our systematic review gives an overview of rating scales, which are applied within the medical education setting to assess students\u2019 communication skills. It can help teachers and researchers in the field of medical education to find the appropriate measure for their individual purpose. Nevertheless, we identified several research gaps regarding the methodological quality of studies reporting on psychometric properties and the quality of their results. Based on our results, the use of the eight identified rating scales to assess students\u2019 communication skills needs to be done with care, as their methodological quality is not completely satisfactory. Hence, future psychometric evaluation studies focusing on improving the methodological quality are needed in order to yield psychometrically sound results of the OSCEs assessing communication skills. This is especially important considering that most rating scales included in this review were used for summative evaluation, i.e. to make pass-fail decisions. Such decisions have a high impact on students\u2019 academic success and should be based on reliable and valid assessment.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S1 Checklist(DOC)Click here for additional data file."} +{"text": "Prolonged stay in intensive care unit (ICU) after cardiac surgery may increase the long-term risk of readmission. Preoperative risk factors, surgical complications, infections and organ failure may need specific intensive support, increasing costs of reimbursement mainly for ICU interventions. Readmission costs over months after discharge may be a dependant of the need of intensive care.We analyzed the impact of ICU interventions and patients\u00b4 conditions on readmission risk and on global costs of reimbursement from the National health service with DRG methodology and assessed the impact of ICU on global costs for complicated cardiac surgery patients.We selected 2067 patients who were admitted to ICUs after cardiac surgery in Regione Piemonte, Italy, in 2009 and analyzed all administrative data listing diagnosis and procedures according to ICD-9CM definitions. Known risk factors for complications and surgical events were selected as ICD-9CM codes. Specific ICU procedures were included if they had impact in DRG calculation. Hospital history was followed for six months after discharge and costs of new admissions were related to selected codes and conditions at the first intervention. We used hazard models and regression analysis to identify ICD9-CM codes that are predictors of readmission and their impact on reimbursement costs, with regard to ICU events.528 out of 2067 patients had in total 877 readmissions. In this population hospital length of stay, tracheostomy, heart or kidney failure, infection and the use of IABP or ECMO are strong risk factors for readmission. Tracheostomy accounts for the major increase of costs as DRG consider it an indicator for extensive use of ICU resources. Shock and prolonged mechanical ventilation are inversely related to increased risk of readmission, but they require additional significant expenditure. Some negative findings on the risk of readmission may be explained with increased mortality rate in those patients. Full results are shown in Tables The need of ICU stay and procedures after cardiac surgery may significantly increase the risk of readmission and of reimbursement fee. The ICD-9CM coding system for administrative purposes might be a reliable indicator for the actual clinical risk described in existing literature and predict an increase of expenditure. Health systems should consider ICU costs in allocating resources for cardiac surgery."} +{"text": "The Angiotensin Converting Enzyme (ACE) insertion/deletion (I/D) polymorphism has received much attention in pharmacogenetic research because observed variations in response to ACE inhibitors might be associated with this polymorphism. Pharmacogenetic testing raises the hope to individualise ACE inhibitor therapy in order to optimise its effectiveness and to reduce adverse effects for genetically different subgroups. However, the extent of its effect modification in patients treated with ACE inhibitors remains inconclusive. Therefore our objective is to quantify the effect modification of the insertion/deletion polymorphism of the angiotensin converting enzyme gene on any surrogate and clinically relevant parameters in patients with cardiovascular diseases, diabetes, renal transplantation and/or renal failure.Systematic Review. We will perform literature searches in six electronic databases to identify randomised controlled trials comparing the effectiveness and occurrence of adverse events of ACE inhibitor therapy against placebo or any active treatment stratified by the I/D gene polymorphism. In addition, authors of trials, experts in pharmacogenetics and pharmaceutical companies will be contacted for further published or unpublished data. Hand searching will be accomplished by reviewing the reference lists of all included studies. The methodological quality of included papers will be assessed. Data analyses will be performed in clinically and methodologically cogent subgroups. The results of the quantitative assessment will be pooled statistically where appropriate to produce an estimate of the differences in the effect of ACE inhibitors observed between the three ACE genotypes.This protocol describes a strategy to quantify the effect modification of the ACE polymorphism on ACE inhibitors in relevant clinical domains using meta-epidemiological research methods. The results may provide evidence for the usefulness of pharmacogenetic testing for individualised ACE inhibitor therapy. Research in genetics and genome sequencing has led to a better understanding of the molecular genetic mechanisms and to the detection of inter-individual genetic differences, so-called polymorphisms, which may have a functional consequence on the response to drugs. Pharmacogenetic tests provide information to better predict and prevent therapeutic failures and adverse drug reaction and raise the hope for an individualised pharmacotherapy -3. AlthoThe ACE polymorphism identified in 1990 by Rigat and co-workers is one oTherefore, our objective is to systematically review all randomised controlled trials that assessed to what extent the insertion/deletion polymorphism of the angiotensin converting enzyme gene influences the effect and adverse events of angiotensin converting enzyme inhibitors on any surrogate and clinically relevant parameters in patients with cardiovascular disease, diabetes, renal transplantation and/or renal failure.We will perform literature searches in (Pre-) MEDLINE , EMBASE , Biosis , the Cochrane Controlled Trials Register and the Science citation index. A preliminary literature search in Medline has been carried out to estimate the range of relevant literature. Out of the citations of the pilot searches (172 citations) we identified articles that met our inclusion criteria. Keywords of these articles were used to refine our search strategies. In collaboration with an information specialist we designed the final search strategies for the six databases avoiding any language restrictions Click here for file"} +{"text": "The success of coronary artery bypass grafting (CABG) is limited by poor long-term graft patency. Saphenous vein is used in the vast majority of CABG operations, although 15% are occluded at one year with as many as 50% occluded at 10 years due to progressive graft atherosclerosis. Intravascular ultrasound (IVUS) has greatly increased our understanding of this process. IVUS studies have shown that early wall thickening and adaptive remodeling of vein grafts occurs within the first few weeks post implantation, with these changes stabilising in angiographically normal vein grafts after six months. Early changes predispose to later atherosclerosis with occlusive plaque detectable in vein grafts within the first year. Both expansive and constrictive remodelling is present in diseased vein grafts, where the latter contributes significantly to occlusive disease. These findings correlate closely with experimental and clinicopathological studies and help define the windows for prevention, intervention or plaque stabilisation strategies. IVUS is also the natural tool for evaluating the effectiveness of pharmacological and other treatments that may prevent or slow the progression of vein graft disease in clinical trials. The success of coronary artery bypass grafting (CABG), although the gold standard for the treatment of multivessel coronary artery disease, is limited by poor long-term vein graft patency . Early vAlthough the cellular and molecular mechanisms underlying vein graft disease have been systematically investigated, the time course and development of this process in patients after coronary bypass has only recently been defined as a consequence of the increasing use of intravascular ultrasound (IVUS). Quantitative coronary angiography, traditionally the predominant imaging modality used to assess the severity of vein graft disease underestimates the severity of vein graft remodeling and athermanous plaque development by measuring the vessel lumen in only two dimensions ,14. In cGlagovian remodeling was first described as a radial enlargement of the entire cross sectional area of a vessel in response to intramural atheroma . First iIVUS changes correlate closely with the findings of experimental and clinical studies. In porcine saphenous vein bypass grafts, in the first week after grafting, adventitial medial and neointimal thickening occurs as a consequence of increased shear stress, surgical preparative injury and the subsequent activation of multiple growth factor and cytokine cascades. This is associated with the infiltration of inflammatory cells, medial smooth muscle cell proliferation and migration to form a neointima . AdventiThe early changes seen in the vessel wall of vein grafts are similar to those seen during vessel remodeling in atherosclerotic coronary artery segments . In normEarly vein graft changes can be viewed as adaptive, however they also predispose the graft to later accelerated graft atherosclerosis . SeveralRisk factors for, and the microscopic appearance of vein graft atherosclerosis are largely similar to those in coronary arteries and it is reasonable to suggest that similar pathological mechanisms are at work, however these occur over a much more rapid time course in vein grafts ,4. AtherIVUS studies have clearly shown that early 'adaptive' or pathological changes occur within weeks of grafting and that occlusive atheroma, in susceptible individuals occurs within 1 year. IVUS studies have therefore defined the window in which strategies to inhibit vein graft disease might be effective. Furthermore, in addition to its advantages over coronary angiography, IVUS in vein grafts has been shown to be both accurate ,16 and rex vivo prior to implantation using pharmacological or other methods that may inhibit subsequent disease is a feature unique to vein graft disease. There are many examples of this being successfully achieved in experimental models. Pre-treatment with rapamycin [The ability to manipulate vein grafts apamycin , paclitaapamycin , have beapamycin and endoapamycin as has tapamycin . Targeteapamycin . StabiliIVUS has significantly contributed to our understanding of vein graft failure. It also serves as the natural tool for the development of clinical strategies that may lead to significant improvements in vein graft patency and more importantly for better long-term quality of life and longevity for patients with coronary artery disease. The introduction of clinical trials to address this Achille's heel of coronary bypass surgery are long overdue.None declared.G Murphy performed the literature review and prepared the manuscript. G Angelini conceived the idea for the manuscript and prepared the manuscript."} +{"text": "This volume concludes our three\u2010part series of Genes, Brain and Behaviors special issues. The previous two volumes started with research on autism and neurodevelopmental disorders, concluding that their full understanding is impossible without understanding of innate social behaviors, and continued into research on mechanisms of such innate behaviors across several animal species.Danio rerio) in four behavioral tests: shoal preference, conspecific recognition, object recognition and open\u2010field. This characterization clustered behaviors across three principal factors: motivation, cognition and anxiety. Importantly, the social tendency module in this analysis aligned with object and social exploration, and clustered separately from object discrimination and social discrimination, which aligned together. These data provide strong support for the hypothesis that social recognition and social motivation did not evolve together as a common phenotype and instead separately co\u2010opted general cognitive and motivational mechanisms. This conclusion is further supported by analysis of single nucleotide polymorphisms (SNPs) and behavioral modules. The genetic analysis shows that SNPs in candidate genes associated with social behaviors are statistically associated with the motivational but not the cognitive module. This finding is in agreement with the recent report showing that zebrafish lacking functional oxytocin receptors are deficient in social and object recognition but have intact social motivation.In their research paper, Goncalves, Kareklas and colleagues have elegantly addressed a fundamental question on evolution: whether the motivational and the cognitive components comprising social behavior evolved independently or through selective pressure to increase sociality.Hippocampus erectus). They demonstrate that the color change (increase in brightness) occurs more frequently, especially in male fish, when they are paired with their pair mate, than when they are paired with an opposite\u2010sex stranger. In a subsequent preliminary whole brain RNA sequencing analysis authors detect a substantial overlap in pairing\u2010induced changes in gene expression between male seahorses and prairie voles. Remarkably, oxytocin receptor is among upregulated genes in paired female seahorses, in agreement with its well\u2010known importance in pair\u2010bonding in other species.Not all specific social behaviors, including social behaviors characteristic of humans, can be studied in standard laboratory species. The previous volume of the special issue highlighted the importance of choosing appropriate species for such studies by discussing the power of experiments in socially monogamous prairie voles for understanding the neurobiology of pair\u2010bonding.Animal species adopt different modes of social communication depending on evolutionary constraints. Ultrasonic vocalizations (USVs) are of great importance for social communication in rodents. Previous research demonstrated that communication via USVs depends on age, sex and can also differ between mouse strains.The behavioral repertoire of animals can not only differ between different ages, genotypes and social context, but can be even different between cagemate rodents of the same strain, sex and age. Animals living in groups usually organize themselves into social hierarchies. Behavioral repertoires, as well as general well\u2010being, are different between socially\u2010dominant and subordinate individuals within these groups.The latter observation is well in line with the next article in this special issue. The research paper by Winiarsky, Kondrakiewicz and colleagues compares effects of housing, habituation and testing conditions in males of commonly used C57BL/6J mice versus BTBR T+ Iptr3tf/J mice (BTBR) mice.The special issue is concluded with two important reviews on neurodevelopmental disorders and their animal models. The review by Benedetti and colleagues takes on one genetic mechanism with high penetrance for such disorders.While an increase in studies using relevant tests on social behaviors would benefit understanding of deficits in social behaviors associated with CNVs, the final paper in this issue questions how the animal models of neurodevelopmental disorders should be optimally utilized. Silverman and colleagues report on recommendations of the workshop held by the Autism Science Foundation with the goal of improving utilization of such models.We conclude this series of special issues on social behaviors, autism and neurodevelopmental disorders by emphasizing that this exciting research field exhibits much motivation to go beyond superficial observations of simplistic phenotypes. The front cover image of this special issue, by Dr. Yangmiao Zhang, illustrates that participants in social interactions come with different personal experiences and backgrounds. These experiences guide them to exhibit various behaviors, including social bonding. May the complexity of social behaviors serve as a common challenge to bond neuroscientists in the pursuit of intricate underlying mechanisms."} +{"text": "Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric disorder that follows exposure to a traumatic event; however, not every person who experiences trauma will develop PTSD. Women are more likely to be diagnosed with PTSD than men even when controlling for type and amount of trauma exposure. Circulating levels of gonadal hormones such as estradiol, progesterone, and testosterone may contribute to differential risk for developing PTSD. In this review, we briefly consider the influence of gonadal hormones on fear conditioning processes including fear acquisition, fear inhibition, extinction learning, and extinction recall within translational neuroscience models. We discuss findings from human studies incorporating samples from both community and traumatized clinical populations to further understand how these hormones might interact with exposure to trauma. Additionally, we propose that special attention should be paid to the specific measure used to examine fear conditioning processes as there is evidence that common psychophysiological indices such as skin conductance response and fear-potentiated startle can reveal quite different results and thus necessitate nuanced interpretations. Continued research to understand the influence of gonadal hormones in fear learning and extinction processes will provide further insight into the increased risk women have of developing PTSD and provide new targets for the treatment and prevention of this disorder. Post-traumatic stress disorder is a debilitating disorder that follows exposure to a traumatic event. Although, as much as 90% of the US population is exposed to at least one traumatic event during their lifetime , only onPTSD symptoms are characterized by exaggerated fear and anxiety behaviors triggered by learned environmental cues that serve as reminders of a prior traumatic experience . PreclinDespite the increased risk of females developing PTSD, limited studies have investigated the role of ovarian hormones using translational models of fear conditioning. Brain regions involved in fear learning and memory processes such as the amygdala, prefrontal cortex, and hippocampus show strEstrogens are the primary female sex hormones, with estradiol being the most potent in nonpregnant females. During the menstrual cycle, estradiol is lowest immediately before and during the time of menstruation and has its first peak during the late-follicular phase with a second, lower peak that roughly corresponds with the peak of progesterone during the mid-luteal phase see .There is little evidence that estradiol impacts fear acquisition in animal models, but some suggestion that there is faster extinction of contextual fear conditioning during periods of high estradiol levels and with exogenous administration of estradiol to ovariectomized animals; however, there is little evidence that estradiol impacts extinction of cued fear. In rodents, considering estrous cycle phase results in extinction recall differences in females with extinction being facilitated during days when estrogen and progesterone are higher . Also, eTwo different populations have been investigated in humans using translational models of fear conditioning to examine ovarian hormones with regard to PTSD. Community samples consist primarily of individuals who are free from major neuropsychiatric disorders, with no or limited individuals with PTSD. Clinical samples have also been investigated with individuals who are highly traumatized and who do or do not meet the criteria for a PTSD diagnosis. Community samples have primarily used skin conductance response and expectancy ratings to investigate fear acquisition, extinction, and extinction recall. Of these studies, only a few in humans have reported differential responding based on estradiol levels during fear acquisition. In one, participants with spider phobia with low estradiol levels demonstrated increased skin conductance response (SCR) to the danger signal (CS+) compared to other women during fear acquisition . FelmingWhen investigating fear extinction, Bierwirth et al. found that men displayed greater SCR during extinction than women using hormonal contraceptives (low levels of estradiol and progesterone) and naturally cycling women tested during a high estradiol portion of the menstrual cycle (Bierwirth 2021). In contThe investigation of hormonal influences on extinction recall are the most plentiful, perhaps owing to positive results found in early studies. Multiple studies have found that higher levels of estradiol are associated with enhanced extinction recall when measured by SCR while lower levels of estradiol tend toward a greater recovery of the conditioned fear ,30,32\u201334Franke et al. explored the role of estradiol on intrusions following fear acquisition that paired aversive or neutral film clips with shock . IntrusiClinical samples of individuals who either have PTSD or are highly traumatized have shown similar findings. Glover et al. examinedOne naturalistic way to examine the impact of hormones in females is to compare those who are pregnant (with higher levels of estrogen and progesterone) with those who are not pregnant. One study with a highly traumatized sample found that only women who were not pregnant displayed discrimination between the safety and danger signal via FPS measure . This laWith regard to fear extinction learning, one study compared highly traumatized women who either did or did not meet criteria for a PTSD diagnosis. Interestingly, differences in extinction learning between participants with and without PTSD were revealed only among those with low estradiol. There were no differences in extinction based on PTSD diagnosis among those with high estradiol . The afoWhen looking at extinction recall with participants divided by PTSD diagnoses, participants with PTSD in the early follicular phase (low estradiol and progesterone) displayed greater extinction recall than those in the mid luteal phase (higher hormone levels) when measured with SCR . In contThough less widely studied than estradiol, progesterone is another ovarian hormone that fluctuates with the menstrual cycle and is decreased with hormonal contraceptive usage. Most studies with community samples found no influence of progesterone on fear acquisition, extinction, or extinction recall ,33,34. OTestosterone is another gonadal hormone with possible importance for elucidating sex differences in fear conditioning and PTSD. Testosterone has anxiolytic qualities ,53,54; hThe two most common indices of threat response in human studies are an increase in skin conductance response and acoustic startle amplitude . AlthougSome studies using both SCR and FPS to examine fear conditioning have demonstrated the double dissociation between these responses ,68. SCR In conclusion, gonadal hormones have been investigated using translational models of fear conditioning with varying results. Estradiol seems to have the most apparent impact with low estradiol being associated with extinction recall deficits overall. Other effects of ovarian hormones have more sparse and less consistent results but considering levels of hormones seems to have an impact on the ability of FPS to differentiate between individuals with and without PTSD diagnoses. This underscores the importance of accounting for cycle phase or hormone levels when investigating fear conditioning processes and particularly when considering preclinical models of PTSD. In addition, we have shown that different measures, specifically SCR and FPS appear to measure different and only sometimes parallel processes during fear conditioning and studies that are investigating these processes should consider the specific measurement in both study design, conclusions, and interpretations. Further research on the influence of gonadal hormones on fear conditioning processes has the potential to illuminate potential sources of risk for and resilience to PTSD. Furthermore, a better understanding of hormonal influences on processes underlying PTSD symptomology could point to potential avenues for prevention and improved treatment to reduce the suffering experienced by those who have been exposed to traumatic events."} +{"text": "There has been a rapid growth of scientific evidence demonstrating the bidirectional role of disturbed sleep on risk and progression of neurodegenerative disease. The evidence stems from four lines of inquiry: (1) sleep disorders, particularly obstructive sleep apnea syndrome, increase risk for the development and progression of cognitive decline and dementia ; (2) sleMander and colleagues examined the relationship of topographical sleep spindle measures to cerebrospinal fluid (CSF) measures of astrocyte and microglial activation, biomarkers for Alzheimer\u2019s disease (AD), measures of synaptic and axonal integrity, and overnight memory consolidation in a sample of older cognitively healthy subjects at risk for the development of AD . The CSFThe report by Mander and colleagues has many strengths. It is methodologically rigorous, focused on CSF markers instead of peripheral blood, and has appropriate statistical adjustments for the many analyses. The multilevel approach examining age, cognition, sleep spindles, glial function, CSF AD biomarkers, and measures of synaptic and axonal integrity is quite innovative and proved to be illuminating. The authors were appropriately circumspect about the strength of their findings and acknowledged that their mediation analyses have limits for making strong causal inferences. They suggested future longitudinal studies and experimental manipulations to ultimately identify the causal drivers. Surprisingly, they did not find an effect of apnea events on tau or other CSF measures as has been demonstrated in basic model systems . AnotherThe presence of phosphorylated tau in neurons does not appear to explain why some neurons die and other don\u2019t across different neurodegenerative diseases . For exaThe lack of relationship of A\u03b2 markers with measures of tau, neuronal, and axonal integrity in this report are consistent with the emerging evidence that tau can be a primary driver of neurodegeneration even in the absence of amyloid deposition . Howeverdensity of activity [Given that sleep is increasingly understood as a causal driver of neurodegeneration, sleep-focused interventions should be considered a potential disease modifying therapy as opposed to symptom management. Further, given the heterogeneity of different neurodegenerative disorders with respect to disease onset and pattern of progression, the study of neurodegenerative disorders as models of naturalistic lesions may deepen our understanding of basic sleep mechanisms in the human brain. Lesion studies have long led major advances in understanding basic sleep\u2013wake biology . One conactivity ? It woul"} +{"text": "Variations in vascular anatomy are of great concern to surgeons, as proper identification of aberrant arteries can reduce the risk of iatrogenic injury and improve patient outcomes. Several studies have highlighted the irregular branching pattern of pelvic arteries, with a recent focus on the obturator artery (OA). The OA has an inconstant origin from the internal iliac artery, external iliac artery, or inferior epigastric artery. Within the pelvis, the OA can give off muscular branches and nutrient vessels to the ilium and pubis. Though occasionally described in text, few resources employ images of human donors that depict branches arising from the OAs. Out of the 34 hemisected pelves studied, we identified 1 individual with a substantial nutrient vessel branching unilaterally from the OA. Herein, we present the first image of this unconventional nutrient artery. This vessel should be highlighted given that its size and course make it particularly vulnerable during intrapelvic surgeries such as pelvic lymph node dissection or in procedures requiring arterial embolization of the OA."} +{"text": "The Lancet Regional Health Western Pacific on the impact on skin infections of an oral ivermectin MDA targeting scabies in Fiji. Importantly, they show in the largest before-after trial of its kind that not only did scabies and impetigo prevalence reduce, but so too did hospitalisations with severe skin and soft tissue infections and attendance at primary care with scabies and skin infections.Evaluations of Mass Drug Administrations (MDAs) targeting scabies have generally not assessed their secondary impacts on skin and soft tissue infections. These are major health burdens in the global south, with sequelae including glomerulonephritis, rheumatic fever and chronic kidney disease.Sarcoptes scabiei and is primarily transmitted by touch. It is classed by WHO as a Neglected Tropical Disease (NTD) in recognition of its high burden and the health risks associated with secondary infections of impetigo .,,Scabies is a highly irritant skin infestation with the mite Against this regional and global background Thean and colleaguesThe author declares that they have no competing interests."} +{"text": "The standard treatment of colorectal cancer (CRC) consists of a surgical resection of the colonic segment with the tumor, followed by a reconnection of the remaining bowel ends, or \"anastomosis\". The anastomosis may fail to heal in up to 20% of patients, which leads to anastomotic leak, a major complication that increases postoperative morbidity and mortality. This complication is unpredictable and its causes remain poorly understood.The objective of this study is to investigate the possible role of the gut microbiome in anastomotic healing after surgery in patients with CRC.We collected preoperative fecal samples and intraoperative mucosal samples from CRC patients undergoing surgery with anastomosis. The gut microbiota of patients with AL and of others that presented optimal healing after surgery was analyzed and compared using the Anchor 16S pipeline. To assess the role of the patients' microbiota in healing, fecal microbiota transplantation (FMT) was performed in mice using preoperative fecal samples from CRC patients with and without AL. Mice were then subjected to colonic surgery using a colonic anastomosis model. Six days after surgery, anastomotic healing was assessed macroscopically and microscopically. The gut barrier function was also assessed. The gut microbiota composition was compared between the groups colonized with samples from patients with and without AL to detect potential differences.Mice colonized by FMT with the microbiota of donors with AL displayed poor anastomotic healing macroscopically, and a weaker wound microscopically. These same mice displayed a weaker gut barrier, as objectified by higher bacterial translocation to the spleen. The anastomoses of mice receiving the microbiota of AL donors displayed lower concentrations of collagen and fibronectin and higher inflammatory cytokines and collagenolytic enzymes, indicating poor extracellular matrix formation and collagen degradation locally.The beta-diversity of the gut microbiota was significantly different between mice receiving the microbiota of donors with and without AL, and several bacterial species were differentially abundant between the two groups.The preoperative gut microbiota in CRC patients who experience anastomotic leak after surgery induces poor anastomotic healing in mice and a weaker gut barrier after colonic surgery. Several bacterial species were found to be associated with the healing process.CIHR, OtherNSERC, FRQS, New Frontiers in Research, Montreal Cancer Institute.None Declared"} +{"text": "Neuropsychiatric drugs account for 16% of drugs that can lead to hepatotoxicity and psychiatric patients can have multiple comorbidities that can increase the incidence of liver disorders such as alcoholism, drug abuse and polymedication. The continuous use of atypical antipsychotic drugs (AAD) has raised questions over their tolerability over endocrine, metabolic and cardiovascular systems. They are also associated with mild elevation of aminotransferases and occasionally cause idiosyncratic liver injury with varying phenotypes. Hepatotoxicity is defined based on biological parameters such as elevation of alkaline phosphatase enzyme, SGPT, SGOT and GGT or clinical abnormalities (jaundice and hepatitis).This work reviewed the current available evidence on the hepatic damage produced by AAD.Non-systematic review of the literature with selection of scientific articles published in the past 10 years; by searching Pubmed and Medscape databases using the combination of MeSH descriptors. The following MeSH terms were used: atypical antipsychotic drugs; hepatotoxicity; hepatic; Olanzapine; Clozapine; Risperidone; Aripiprazol; Paliperidone.Atypical Antipsychotic Drugs are generally well tolerated and hepatic alterations are in general very low or rare. The cases published were observed with Clozapine, Olanzapine and Risperidone. Atypical Antipsychotic drugs have a better profile than Chlorpromazine.In conclusion, the hepatic injury generally occurs within the first weeks of treatment and is usually reversible with drug withdrawal. Hepatic check-ups may be relevant, especially in the beginning of treatment.No significant relationships."} +{"text": "Dementia affects people with lower socioeconomic statuses disproportionately. People with undiagnosed Alzheimer\u2019s disease may or may not express dementia symptoms depending on their brain reserve, cognitive reserve, and their ability to compensate for brain pathology. Much of these depend on their childhood education, but late-life social engagement may also play a role. As lifespan increases globally, preclinical dementia care and prevention in community settings will be increasingly important. The characteristics of everyday environments that are kind to various changes amid declining cognition may enhance the quality of life of older adults with and without dementia. Such environments may be available or unavailable in diverse communities of varying socioeconomic statuses. This collaborative symposium between the ADRD and CEnR interest groups brings together multidisciplinary scholars to imagine psychosocial interventions that could mitigate place-based disparities in cognitive health. The first presentation frames the importance of relational perspectives in a biopsychosocial-ecological model of care amid cognitive decline. The second presentation shows the cognitive impact of networks among kinless older adults across Europe. The third presentation explores community perspectives on preventive brain health programs in various neighborhoods. The fourth presentation centers the voice and action of people with dementia to improve their neighborhood social environments. The final presentation identifies policy implications for community-based care and prevention from network perspectives. Discussions will distil the significance of community for persons living with and without dementia diagnosis to generate place-based interventions that may better support care and prevention in diverse settings, and identify structural barriers to these efforts."} +{"text": "Different positions within social hierarchies receive unequal access to resources, leading to health disparities in later life . Research addressing inequities must increasingly account for the many social categorizations that affect individuals\u2018 lived experiences. This symposium examines the role of intersecting social contexts on health and well-being across the life course. Surachman and colleagues use the U.S.-based National Growth and Health Study to examine the intersectionality between early life socioeconomic context and race on women\u2019s metabolic syndrome severity. Their findings have implications for societal factors leading to accelerated aging across young adulthood and early midlife. Koffer and colleagues use the U.S.-based Study of Women\u2019s Health Across the Nation to demonstrate differential midlife exposure to types and number of major life events across race/ethnicity and education. They subsequently find that major life events increase risk of cardiovascular disease events, indicating the importance of studying the life experiences of diverse women across midlife. Drewelies and colleagues use the Germany-based Berlin Aging Study II to look at the associations among multidomain identity and social background factors on physical, cognitive, and psychological aging. Implications from their work demonstrate the interplay of diversity on health and well-being in older adulthood. Conjointly, findings indicate that intersectional identities play an important role in shaping key outcomes of human functioning across adulthood and aging. Dr. Deborah Carr will critically discuss the three contributions from a life course perspective and provide considerations for future research and policy promoting equity for diverse older adults."} +{"text": "Massachusetts\u2019 27 Aging Services Access Points (ASAPs) are nonprofit organizations responsible for guiding clients and families in their geographic service areas through a maze of financial and functional eligibility criteria to receive needed home and community-based services (HCBS). These services aim to sustain function and promote engagement for older adults and persons with disabilities, and to maintain individuals in the community rather than in residential settings. Payment for HCBS flows from numerous state and Federal funding programs, including but not limited to state Medicaid waivers and Older American Act programs. We conducted semi-structured interviews with 10 ASAP directors and gathered information from documentary sources to delineate the pathways to funded HCBS that these agencies open for clients. We identified variation in the 27 ASAPs\u2019 contractual relationships with service providers. State data revealed variation in budgetary resources and area population characteristics. These nonprofit corporations appear to flexibly adapt to local conditions and needs. Understanding variation across ASAPs will support analysis of client data to examine whether ASAP processes result in different service outcomes for similar clients. Alternate payment models for health services are broadening their reach, encouraging health systems to recognize the importance of functional supports and services. Some health systems are charging their own dedicated units with assigning HCBS to enrollees, avoiding the ASAPs. Understanding and modeling the allocation of services by the ASAPs will allow investigation of trends in services for persons with varying needs under various payment methods."} +{"text": "Purpose: To report a case of central retinal artery occlusion associated with sildenafil intake and briefly discuss its causative pathogenesis.Methods: A 50-year-old man with no premorbidities presented with symptoms of sudden severe visual field constriction in the left eye (LE). Best-corrected visual acuity in the LE was 20/25. Fundus examination and fluorescein angiography of the LE were suggestive of central retinal artery occlusion (CRAO) with cilioretinal artery sparing. Further investigation revealed that 100 mg of sildenafil had been taken for the first time three hours before the onset of symptoms.Results: The patient was treated promptly with intravenous acetazolamide, sublingual isosorbide dinitrate and ocular massage, but without visual recovery. No other associated systemic or local risk factors were found, and the case was classified as a potential complication of sildenafil.Conclusion: Although no direct link could be established, the aim of this report is to highlight the incidence and to consider this issue when evaluating any case of central retinal artery occlusion. We report herein a case of central retinal artery occlusion (CRAO), which occurred a few hours after oral sildenafil intake.Sildenafil is a specific phosphodiesterase V inhibitor which is a widely used treatment for erectile dysfunction. Many reports have highlighted ischemic ocular side effects associated with sildenafil.A 50-year-old Tunisian man, otherwise healthy and unemployed, presented to the ophthalmology department with sudden severe visual field constriction in the left eye (LE) of 48 hours duration preceded by severe headaches. On ophthalmic examination, visual acuity was 20/20 in the right (RE) eye and 20/25 in the left eye (LE). LE fundus examination revealed diffuse faint retinal whitening, except for central area of normal retinal color along the distribution of a perfused cilioretinal artery (Anterior segment examination of both eyes as well as fundus examination of theRE were unremarkable. LE fluorescein angiography (FA) showed no filling of the central retinal artery, regular filling of the cilioretinal artery and late retrograde filling of the central retinal vein with cilioretinal artery sparing was diagnosed. Echocardiogram, carotid artery imaging and blood tests were unremarkable. Further investigation revealed that a 100 mg dose of sildenafil had been taken for the first time three hours before the onset of symptoms.Ocular massage was performed as well as sublingual isosorbide dinitrate and intravenous acetazolamide were administered. Two weeks later, reduction in retinal oedema was evident on left eye fundus examination, although there was no improvement in either visual acuity or visual field. acute macular neuroretinopathy, anterior ischemic optic neuropathy,, central retinal vein occlusion and cilioretinal artery occlusion.Various ischemic ocular events related to sildenafil have been reported. The most notable are branch retinal artery occlusion,,Only two cases of CRAO with sildenafil have been reported in the literature.The patient presented here reported taking sildenafil (100 mg) a few hours before the onset of ocular symptoms and headaches. In fact, ocular side effects are directly proportional to the blood concentration of the drug, which usually appears between 15 and 30 minutes after administration, reaches a peak one to two hours later and clears halfway in 3 to 5 hours. it may decrease cerebral blood flow leading to severe headaches as experienced by our patient. Similarly, numerous clinical studies have demonstrated that sildenafil induces retinal veinous vasodilatationin vivo.As sildenafil has a high systemic vasodilator effect that reduces systemic blood pressure,Both the absence of risk factors for retinal vascular occlusion and the timeline of events indicates that oral sildenafil was probably a contributing factor in the development of CRAO, but its pathogenesis remains speculative. We suggest that central retinal artery occlusion occurs in the region of the lamina cribrosa where the central retinal vein and artery share a common adventitia. We speculate that sildenafil-related vasodilation of the central retinal vein causes central retinal artery compression, resulting in secondary changes, including blood flow changes, endothelial damage and platelet thrombi, leading to CRAO. This case underlines the importance of a careful drug intake investigation in cases of CRAO without obvious cause. This incident should not be overlooked by physicians and must be seriously discussed with patients requiring sildenafil, especially since most of them are at risk for ocular ischemic events. Nevertheless, this association remains poorly explained and requires further documented cases.In summary, CRAO secondary to sildenafil is extremely rare and has only been reported in the literature twice previously. Clinicians should be aware of this risk and should avoid prescribing sildenafil in patients with a history of ischemic ocular events.All data underlying the results are available as part of the article and no additional source data are required.Written informed consent for publication of their clinical details and clinical images was obtained from the patient. The author reported an original case of a young adult patient with no personal history who presented with a central retinal artery occlusion following the intake of Sildenafil. The retinal imaging is interesting, moreover, it would be necessary to add the early times of the retinal angiography and a B mode OCT,\u00a0 as well as it should be specified that the imaging was not done at an acute stage of the arterial occlusion seen the blood flow recovery exceeding the cilioretinal artery area. It may be relevant to detail the biological radiological and clinical explorations done to rule out other etiologies of retinal arterial occlusion like cardiovascular pathologies, dysimmune diseases with vasculitis, and hematological disordersAre enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?YesIs the case presented with sufficient detail to be useful for other practitioners?YesIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?YesIs the background of the case\u2019s history and progression described in sufficient detail?YesReviewer Expertise:Ophtalmology Ocular Surface Disease , glaucoma, retinal diseases, anterior segment surgery, contactologyI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The authors report a case of central retinal artery occlusion as a potential complication of Sildenafil. they conclude that Clinicians should take into account this complication while prescribing this treatment.\u00a0 In this case, multimodal imaging was well detailed with high quality images. It would be also interesting if the authors could add structural OCT imaging of the posterior pole. On LE fluorescein angiography, are there more earlier phases that could better describe the retrograde filling of the posterior pole vessels? Did the general examination of the patient reveal some characteristics that could be possible markers predicting this potential complication when prescribing this treatment Are enough details provided of any physical examination and diagnostic tests, treatment given and outcomes?YesIs the case presented with sufficient detail to be useful for other practitioners?YesIs sufficient discussion included of the importance of the findings and their relevance to future understanding of disease processes, diagnosis or treatment?YesIs the background of the case\u2019s history and progression described in sufficient detail?YesReviewer Expertise:retinal imaging, peridatric ophthalmology, cataract surgery, oculogeneticsI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard."} +{"text": "Dr. Bhatt will discuss the differences in types of cognitive motor interference patterns experienced for different tasks in cognitively intact versus people with mild cognitive impairment. She will discuss the effectiveness of dual-task training and exergaming on gait, volitional and reactive balance control in older adults with mild cognitive impairment. After 4 weeks of such training, the results showed beneficial effects on improving volitional based performance when performed with a cognitive task and had significant improvement in NIH toolbox . However, its positive effects on dual task reactive balance control were limited. Additionally, the speaker will go on to discuss the associations of balance control deficits in mild cognitive impairment with neural correlates to understand the attributing factors to increased fall risk in people with mild cognitive impairment."} +{"text": "In this article, the authors assess the clinical presentation of patients with urethral cuff erosion after the implant of an Artificial Urinary Sphincter (AUS) and also attempt to establish risk factors in this patient population . As wel"} +{"text": "Psychiatric comorbidities, including depressive and anxiety disorders, are common in individuals with autism spectrum disorder (ASD). Use of conventional therapies for treating depression and anxiety are of limited efficacy in individuals with ASD making treatment a challenging field. Repetitive Transcranial Magnetic Stimulation (rTMS) is a safe and efficacious technique in major depressive disorder, and a similar approach could yield therapeutic benefits in ASD.The aim of this case study is to present the effectiveness of rTMS in a 17 year old patient diagnosed with ASD and comorbid major depression disorder with anxiety symptoms.This is a case study of a male adolescent aged 17, diagnosed with ASD and comorbid major depression disorder with anxiety symptoms, suicidal ideation and aggressive behavior. The protocol applied was 4 weeks of daily rTMS sessions. This involved rTMS to the left dorsomedial prefrontal cortex to treat depressive symptoms and to the right to treat anxiety symptoms. Assessments were conducted using the BDI, PHQ-9 and GAD-7 scales at baseline and one month follow up. Suicidal ideation and aggressive behavior were assessed by a clinician at same intervals.Patient showed overall improvement in scores both in depression and anxiety scales. Suicidal Ideation and aggressive behavior showed significant reduction. No side effects were recorded during therapy.Our findings suggest that the use of rTMS therapy in adolescents in the autistic spectrum and comorbid major depression disorder and anxiety symptoms is an efficacious and safe therapeutic treatment option."} +{"text": "Recent warm temperatures driven by climate change have caused mass coral bleaching and mortality across the world, prompting managers, policymakers, and conservation practitioners to embrace restoration as a strategy to sustain coral reefs. Despite a proliferation of new coral reef restoration efforts globally and increasing scientific recognition and research on interventions aimed at supporting reef resilience to climate impacts, few restoration programs are currently incorporating climate change and resilience in project design. As climate change will continue to degrade coral reefs for decades to come, guidance is needed to support managers and restoration practitioners to conduct restoration that promotes resilience through enhanced coral reef recovery, resistance, and adaptation. Here, we address this critical implementation gap by providing recommendations that integrate resilience principles into restoration design and practice, including for project planning and design, coral selection, site selection, and broader ecosystem context. We also discuss future opportunities to improve restoration methods to support enhanced outcomes for coral reefs in response to climate change. As coral reefs are one of the most vulnerable ecosystems to climate change, interventions that enhance reef resilience will help to ensure restoration efforts have a greater chance of success in a warming world. They are also more likely to provide essential contributions to global targets to protect natural biodiversity and the human communities that rely on reefs. Coral reefs are one of the most vulnerable ecosystems to climate change, and scientists have increasingly called for restoration interventions to be used to increase coral reef resilience to climate change. However, recent global reviews highlight a critical gap in implementation in the design and practice of restoration programs. We review the current literature and provide recommendations that integrate resilience principles into restoration design and practice for project planning and design, coral selection, site selection, and broader ecosystem context. We also discuss future opportunities to improve restoration methods to support enhanced outcomes for coral reefs in response to climate change. A new pPartnerships between local communities, Indigenous groups, management agencies, and scientists enable the integration of traditional and local ecological knowledge with climate projection data for project planning such as the selection of restoration sites and methods to support reef resilience will be critical to informing these efforts.2.2Acropora cervicornis , in general scientists are raising the alarm that coral reef restoration practices must move from a focus on single species and coral outplanting to ecosystem\u2010wide approaches to ensure reef survival to climate change . To integrate diversity at the genetic level into restoration projects, corals should be sourced from a variety of habitats with diverse environmental conditions within species boundaries in the restoration region Table\u00a0. In lessCorals with various morphologies fulfill a variety of functional roles within the reef habitat Veron,\u00a0 and tendThermally\u2010resistant coral species should be included in restoration projects, such as those that have a history of surviving stress or are naturally acclimated to environmental extremes, to promote the mixing of heat tolerance genes within future generations and growth in corals . One potential low\u2010cost approach to identifying resilient reef sites includes rapid and standardized testing of coral thermal tolerance using portable devices to control invasive macroalgae and rehabilitate reefs could be an important research frontier to enhance coral population recovery after disturbance. Examples include innovations in new materials to protect corals in vulnerable early life stages and increase survivorship of coral recruits provide diverse species for restoration practitioners that are acclimated for distinct microhabitats. For example, a regional coral nursery might stock coral fragments of different growth forms and genotypes suited to different environmental conditions for a range of restoration projects in the area. Such facilities have already been constructed in some reef environments such as hatcheries for giant clams, turbo snails, or other species begins and nations seek to meet ambitious conservation and biodiversity targets, it is necessary to conduct restoration as part of broader resilience\u2010based management of coral reefs and incorporate resilience principles and climate change adaptation into restoration practice. The recommendations presented here provide guidance to help the coral reef restoration community enhance reef resilience to climate change and other reef threats , which are increasingly recognizing the use of restoration for achieving social and ecological outcomes. Key to supporting these global efforts is the demonstration of how countries can meet their biodiversity and climate adaptation goals through targeted coral reef restoration. Global conservation and climate change commitments are transformational opportunities to use restoration to stimulate social\u2013ecological recovery, and the strategic integration of resilience and climate change adaptation into restoration practices in the coming decade is likely to be crucial to this effort. This work provides a first opportunity to address the gap in implementation of restoration to promote reef resilience and climate adaptation and seeks to assist coral reef managers and restoration practitioners to deliver on local and global commitments to sustain coral reefs in the coming decades. While the future of coral reefs is critically dependent on the strongest possible global reductions in greenhouse gas emissions and climate change mitigation, resilience\u2010based coral reef restoration plays an essential role in maintaining these valuable ecosystems while global climate action is achieved."} +{"text": "The full range of cell functions is under-determined in most human diseases. The evidence that somatic cell competition and clonal imbalance play a role in non-neoplastic chronic disease reveal a need for a dedicated effort to explore single cell function if we are to understand the mechanisms by which cell population behaviors influence disease. It will be vital to document not only the prevalent pathologic behaviors but also those beneficial functions eliminated or suppressed by competition. An improved mechanistic understanding of the role of somatic cell biology will help to stratify chronic disease, define more precisely at an individual level the role of environmental factors and establish principles for prevention and potential intervention throughout the life course and across the trajectory from wellness to disease. Infectious disease is perhaps the most obvious and acute form of cell \u201ccompetition\u201d in human experience, with innate and adaptive immune responses collaborating to eliminate exogenous cells which themselves are participants in the competition. Related biology also drives the clearance of aberrant native cells, such as damaged or neoplastic cells. These processes require activation and consumption of the immune system, generally described as the inflammatory response . A substAccumulating evidence shows that individual variation in inflammatory responses may also be influenced by lifelong competition between different somatic cell populations, some of which arise as they acquire cell behaviors with differential advantages in various tissues. Such competitions among somatic cell populations represent potentially modifiable components of many chronic diseases . In thisThe preponderance of genetic selection in evolution antedates multicellularity, so that cell competition is a useful framework for understanding emerging mechanisms of somatic selection and for understanding the net outputs of competing cell behaviors . In thisThe specification of cell behaviors during development, the general patterning of the body plan, tissue architecture, and even long-term features of cell states, are dependent on stereotypic cellular events prespecified by transcriptional programs and interactive cues from neighboring or remote cells . These cMyc and Tp53 , and a wide range of other chronic disease outcomes including heart failure, atrial fibrillation, chronic obstructive lung disease, osteoporosis, transplant outcomes, and severe COVID-19 on incident coronary events and on incident lung cancer in the rigorous CANTOS trial . This reAs sequencing depth increases, evidence is accumulating from genotyping of peripheral blood and tissue samples from broader populations that somatic variation is a universal phenomenon. The initial identification of CHiP mainly focused on genes that have been previously implicated in causing hematologic malignancy. It has become clear that those genes may only underlie a limited portion of clonal selection . ExampleUnassayed somatic variation and underlying clonal competition must be considered as potential contributors in all genotype-phenotype associations . It willThe existence of cellular competition between clones with a definable genomic basis for winning or losing, also implies a need for single cell genomic and functional analyses to understand those clonal attributes selected or lost in the competition. In addition genomics (even single cell genomics) may offer insufficient resolution to detect cell population shifts in the setting of epigenetic differences due to prior exposures or in the context of small or isogenic clones. There is now emerging definitive evidence of the existence of active cellular competition and selection based on functional attributes resulting not from genetic variation between clones, but rather from acquired \u2018fitness\u2019 under specific environmental constraints. In the absence of genetic mechanisms and consequent effects on allelic distributions, such selection may only be detected using single cell analyses. Together these observations suggest that single cell genotypic and phenotypic characterization of somatic cellular populations will be an important step in improving our understanding of the relationship between genotype and phenotype as well as the discrete and dynamic contributions of cell competition to the trajectories of common diseases.2) may result in an erythrocyte cohort with dysregulated expression of erythropoietin (EPO) and hypoxia inducible factors (HIFs), with potential consequences for numerous disease states through the life cycle of these specific erythrocytes. Systematically classifying, across multiple phenotypic dimensions, single cell responses to disease, drug and other \u201cenvironmental\u201d exposures will enable the development of mechanistic insights into clonal and non-clonal behaviors underpinning individual variation in disease biology.Functional selection may operate through multiple mechanisms and is also likely to be more readily modifiable than intrinsic genotype-based clonal imbalance. All the factors that influence clonal behaviors can bias cellular, tissue or organ physiology in the absence of any changes in the genotypes, numbers, or capabilities of the underlying cell populations. For example, a period of exposure to low oxygen tension . GeneticTET2, DNMT3A, ASXL1, and PPM1D , fibrinogen, and leukocyte count, due to its direct effects on macrophage, neutrophil, and dendritic cell activity, as well as activation of subsequential immune responses due to epithelial and endothelial cell damage caused by reactive oxygen species. Analyses of human whole genome and whole exome sequencing data established a strong association between smoking and the occurrence of clonal hematopoiesis. The proinflammatory environment caused by smoking promotes the outgrowth of ASXL1-mutant hematopoietic stem cell clones . Moreovend PPM1D , suggestMechanical cues from the local environment or neighboring cells regulate cell behaviors and competitive interactions. Ion channels in the cell membrane, including the mechanosensory ion channel Piezo1, transduce mechanical cues into rapid electrical signals that control and amplify many downstream cellular functions. While the roles of ion channels are well-defined in excitable cell types, such as cardiomyocytes and neurons, their functions in non-excitable cells remain poorly understood. Recent studies reveal that ion channels are expressed abundantly on the cell membranes of peripheral blood cells and regulate processes including adaptive and innate immune responses, platelet activation, and red blood cell homeostasis . Besidesex vivo HSC differentiation and in vivo zebrafish whole kidney marrow transplantation, there was evidence that exposure to an elevated glucose concentration enriched high-PIEZO1-expressing HSCs and enhanced HSC differentiation towards pro-inflammatory monocytes and dendritic cells. The net effects of this modulation of mechanosensory channel expression and function in T2DM were a distinctive prothrombotic state which could be suppressed by specific inhibition of the Piezo1 channel. Subsequent studies in human samples confirmed a Piezo1-dependent prothrombotic state in a significant proportion of patients with T2DM. Findings from this study implicate the hyperglycemic environment in HSC clonal expansion and differentiation based on underlying variation in mechanosensitivity, which substantially contributes to elevated thrombotic risk that is triggered by disordered blood flow . Piezo1 tic risk . This moTogether these examples suggest that general environmental exposures or acquired microenvironmental features of chronic diseases exert selection pressure during hematopoiesis and lead to distinctive pathophysiologic courses. The detection and modulation of such effects in chronic diseases may open new therapeutic strategies, while the exploration of such single cell biology in simple blood samples highlights the possibility for scalable translational studies to define the dynamic effects of acquired factors on cellular physiology .Cell biology offers critical insights into the dynamic interactions between genes and environment but has long been relatively inaccessible in clinical and translational investigation. Human cell biology has been studied in only a few clinical settings; excised neoplastic tissue, liquid tumors and immunophenotyping, all typically at modest scale. Even in these contexts, the collection of single cell functional data is limited, though interest in circulating tumor cells and the falling costs of flow cytometry are slowly impacting the field. Unbiased approaches to even simple cellular data can predict clinically useful disease outcomes , and theHow can cell biology be implemented at a scale similar to that of population genomics? The use of simple accessible technologies in large clinical populations would enable efficient expansion of the collection of clinically annotated cell biological data. An initial focus on widely available tools including morphometry, microscopy and vital dyes could identify disease areas where deeper exploration of cell function might be of utility. Using cellular data, computational approaches, including deep learning, can facilitate the extraction of relevant functional response signatures and identify discrete and previously unobserved cell populations or behaviors. Microfluidic systems, single cell capture methodologies and a range of cellular resolution phenotypes will enable much more granular exploration of the basic functional abnormalities in disease states. Expanding the capabilities of such tools to include exosomes and other circulating cell-derived particles with their contents will open a window into non-circulating cells in health and disease. Combining these assays to discern the features associating with specific cellular states will offer novel insights into the inflammation and other chronic disease mechanisms.Ultimately, it will be important to characterize the full range of cell states and behaviors in health and disease. Exploring cell biology and its effects on cell population dynamics will likely offer mechanistic insights which are pertinent far beyond the specific cell types that are assayed. For instance, a combination of single cell transcriptional profiling, spatial, and temporal tracking has been applied to reveal dynamic and complex immune cell populational behaviors at the site of inflammation. There are now numerous examples of peripheral cellular phenotypes revealing biology of impact in remote and inaccessible cell types such as podocytes, adipocytes or even cardiomyocytes . ScalablThe full range of cell functions is one of the most underdetermined aspects of disease biology. The evidence that somatic clonal imbalance and cell competition play a role in non-neoplastic chronic disease reveals the need for a dedicated effort to explore single cell function to understand disease mechanisms. It will be vital to document not only the prevalent pathologic behaviors but also those beneficial functions eliminated or suppressed by competition. Phenotype expansion in this way to define the roles of somatic cell biology will help to stratify chronic disease, annotate the human genome in regular clinical encounters, and define quantitative contributions from genes and environment across the lifecourse."} +{"text": "High median nerve (HMN) injuries are unusual clinical conditions, but they generate significant disability of the affected extremities to perform even basic activities of daily living. Even though they can display different degrees of dysfunction due to overlapping innervation and musculature compensation, an early assessment of the existing functional deficits and a timely surgical approach can optimize the long-term outcome. The use of distal nerve transfer procedures has gained popularity since they reduce the distance between the injured zone and the disrupted targets, accelerate the nerve regeneration and subsequently optimize the postoperative motor and sensory recovery.This report describes a patient with a significant segmental loss of the median nerve at the upper third of the left arm after a motor vehicle accident that caused multiple other injuries. The motor deficit of this injury was managed soon after the admission with extensor carpi radialis brevis (ECRB) nerve transfer to the anterior interosseous nerve (AIN). Subsequently, double side-to-side cross-palm nerve allografts between the ulnar and median nerves were utilized to restore the sensory deficit of the HMN lesion.An important functional improvement was obtained with these nerve transfer procedures, and the patient successfully returned to the workforce without limitations. Other surgical options for motor and sensory reconstruction are briefly reviewed. High median nerve (HMN) injuries are defined by their location above the origin of the anterior interosseous nerve (AIN). These lesions can produce a significant impact on the affected extremities and deteriorate the patients\u2019 capacity to work and even perform basic activities of daily living. Even though different degrees of clinical findings may occur due to overlapping innervation and musculature compensation, the traditional description of these injuries includes lack of forearm pronation, weakness of wrist flexion, loss of index and long fingers\u2019 flexion, absence of sensation of radial half of the palm and ring finger as well as volar aspect of the thumb, index and middle fingers .The timing for nerve repair and the distance between the injured level and the targeted structures are crucial for a meaningful functional outcome. In this regard, distal nerve transfer procedures shorten the reinnervation process, and therefore optimize the postoperative motor and sensory recovery . Thus, nAn 18-year-old male unrestrained driver was involved in a motor vehicle rollover. The accident caused multiple injuries including moderate left pneumothorax, comminuted fracture in the left distal ulnar diaphysis, fracture of greater trochanter of the left femur, and comminuted open fracture of the proximal left humerus associated with a complete transection of the brachial artery.\u00a0The injuries of the left upper extremity required an urgent bony stabilization with a proximal humerus locking plate and arterial repair with a reversed great saphenous vein graft , he has been working as a truck driver without problems and restrictions. He exhibited no evidence of hypertrophic scars or soft tissue edema (Figure On examination, the patient presented no local pain and significant improvement of range of motion and strength Figure\u00a0, panel FThe HMN injuries\u00a0are unusual lesions of the upper extremities that exhibit, contrary to the classic description, significant variability of clinical deficits . In geneIn summary, the reported patient underwent two distal nerve transfer procedures to restore motor and sensory functions after a high median nerve injury with extensive structural gap. After 24 and 20 months since these surgical interventions, the patient has recovered enough motor and sensory functions that allow him to have a highly demanding occupation without restrictions. Interestingly, however, it is difficult to estimate the definite contribution of nerve transfer techniques in the motor and sensory recovery of HMN injuries due to the presence of overlapping innervation that usually occurs below the elbow level . Thus, tDistal nerve transfers are effective surgical procedures for HMN injuries that help optimize motor and sensory recovery that otherwise are not possible with the repair at the injured level. To get their maximum benefits, they should be done within 10 months post-injury. The surgical plans should be specific to the functional deficits and the patients\u2019 expectations, and therefore they may consist of one or more procedures."} +{"text": "Machine learning has immense novel but also disruptive potential for medicine. Numerous applications have already been suggested and evaluated concerning cardiovascular diseases. One important aspect is the detection and management of potentially thrombogenic arrhythmias such as atrial fibrillation. While atrial fibrillation is the most common arrhythmia with a lifetime risk of one in three persons and an increased risk of thromboembolic complications such as stroke, many atrial fibrillation episodes are asymptomatic and a first diagnosis is oftentimes only reached after an embolic event. Therefore, screening for atrial fibrillation represents an important part of clinical practice. Novel technologies such as machine learning have the potential to substantially improve patient care and clinical outcomes. Additionally, machine learning applications may aid cardiologists in the management of patients with already diagnosed atrial fibrillation, for example, by identifying patients at a high risk of recurrence after catheter ablation. We summarize the current state of evidence concerning machine learning and, in particular, artificial neural networks in the detection and management of atrial fibrillation and describe possible future areas of development as well as pitfalls.Typical data flow in machine learning applications for atrial fibrillation detection. Machine learning (ML) constitutes a subdiscipline of artificial intelligence (AI) and is characterized by the automated detection of patterns from data. Its use is particularly advantageous in the detection of non-linear associations and modern computational power allows for the analysis of large datasets. The use of artificial neural networks has already led to transformation of scientific studies and understanding of vastly different areas such as language processing, object recognition, and predictive analysis. One important aspect is the increasing availability of large standardized digitized datasets, for example, electronic health records or imaging and ECG databases.Atrial fibrillation (AF) is the most common sustained arrhythmia in adults and characterized by unorganized electrical activation leading to ineffective mechanical contraction of the atria . While aArtificial intelligence describes the ability of technical constructs such as computers to independently process data and reach conclusions which typically require human cognitive function . To thisAs a powerful technology, deep learning utilizes artificial neural networks to independently identify features in the input data and therefore to detect previously unknown patterns too. Artificial neural networks are computational structures modeled after biological neural systems such as the human brain . In its In supervised machine learning, data are commonly split into separate training and test sets. The learning algorithm is first trained using the training dataset including varied data with appropriate labels for its planned purpose. In addition to both sets, training of neural networks is usually monitored by a third set, the validation set. This is used to detect shortcomings of the algorithm before the final evaluation of the neural network is conducted by assessing its predictive accuracy in an analysis of the test set. Further literature details computational foundations outside the scope of this review as well as limitations in the implementation of individual machine learning methods \u201313.In recent years, medical research has been transformed using machine learning approaches. The applications can be divided into strategies for the detection of AF and approaches improving the care of patients with known AF.Atrial fibrillation detection plays an important role in the avoidance of mortality and morbidity associated with AF. To this end, traditional machine learning methods have been used in clinical practice for decades and include, for example, automated ECG machine diagnoses. Novel approaches have included transferring this well-known technology to mobile devices such as smartphones and wearable technology. While smartphone-based ECG devices have been developed by multiple companies , the AliVarious studies have evaluated the utility of deep neural networks in AF screening. At least two working groups independently evaluated a DNN in the interpretation of smartwatch plethysmographic data und were able to document a significantly increased sensitivity and specificity compared to previously presented studies utilizing traditional machine learning methodology , 27. ConConcerning the management of patients with known AF, multiple studies have evaluated the utility of both traditional machine learning algorithms and neural networks for the improvement of patient care. Handheld cardiac devices were shown to have a comparable diagnostic accuracy to traditional Holter monitors in the detection of AF recurrences after catheter ablation and a deMobile health devices and wearable technology including traditional machine learning algorithms are currently being integrated into clinical practice across different health systems throughout the world. In contrast, multiple issues impede the widespread implementation of deep neural networks into routine clinical care.Since most algorithms developed for the detection of AF rely on the recognition of absolutely irregular R-R intervals, these have a high likelihood of missing cases of atrial flutter. In contrast to AF, atrial flutter is commonly symptomatic because of a rapid ventricular response and is therefore more likely diagnosed through conventional clinical pathways. Nonetheless, both arrhythmias confer a similar risk of thromboembolism and their possible underdiagnosis by automated algorithms may undermine confidence in their reliability. To this end, a recent publication was able to train a DNN to correctly identify both AF and cavotricuspid isthmus-dependent atrial flutter .Additionally, major concerns persist about the intransparency of DNN models in clinical practice, which may provide physicians with highly relevant information but little to no explanation about how a conclusion was reached. Different working groups have attempted to ameliorate this problem. For example, Tison et al. combined different machine learning methods to create a personalized ECG vector profile able to estimate values such as LV mass and e\u2019 velocity while simultaneously annotating the ECG sections most important for the individual value, therefore enabling clinicians to check the results for plausibility . SimilarConcerning algorithm-based screening for AF, doubts persist about the transferal of previous findings of thromboembolic risk onto these patients with often short-lasting, asymptomatic episodes. Importantly, a recent large study evaluating loop-recorder based AF screening in patients with risk factors for stroke was unable to find an improvement in the prevention of thromboembolic events even though patients with a loop-recorder were three times as likely as a control group to be diagnosed with AF . SimilarWhile diverse applications for machine learning and artificial neural networks have been described, no large prospective studies have evaluated an impact of these technologies on hard clinical endpoints such as thromboembolic events or mortality. Although the question of direct clinical impact, especially concerning anticoagulation in newly diagnosed AF patients, should warrant further investigation, no prospective study on this subject has been registered at clinicaltrials.gov as of January 4, 2022. However, both artificial neural networks and mobile health applications have the potential to change clinical practice in the near future and a recent position paper by EHRA and ESC working groups was the first to specifically comment on these novel technologies . One furA perspective on the future of artificial intelligence in the diagnosis and treatment of atrial fibrillation may be obtained by looking at recent advances in cardiac imaging. While echocardiography and magnetic resonance images have traditionally been manually acquired and interpreted, studies have recently been able to show the feasibility of AI-guided image acquisition and autoMachine learning has the potential to transform medical practice in general and the screening for and management of patients with AF in particular in the near future. In this regard, novel technologies such as mobile, automated screening for AF and the utilization of artificial neural networks allow for approaches to AF care not possible with traditional technologies. Obstacles in the application of machine learning into routine clinical practice which should be addressed by future studies include the intransparency of neural networks and the lack of evidence showing an improvement in clinical outcomes."} +{"text": "Morbidly adherent placenta is a spectrum of obstetric complication which is life threatening to both mother and fetus. Congenital uterine malformation is a rare cause of such a condition. Here we present a case report of placenta increta in bicornute, unscarred uterus. An 18 year old para1+1 presented in emergency with history of vaginal delivery of still birth baby followed by vaginal bleeding with retained placenta. Her Examination under anaesthesia and failed attempt of manual removal of the placenta performed in emergency followed by Doppler ultrasound showed a bicornuate uterus with possibility of placenta increta, later this diagnosis was confirmed on magnetic resonance imaging (MRI). Patient managed with injection methotrexate along with folinic acid followed by removal of placenta under general anesthesia, hence we preserved her fertility. The aim of this report is to emphasize the importance of this rare but a possible association of nonscar and malformed uterus with spectrum of abnormal placentation. Obstetrician should run a full set of investigations in such cases to prevent maternal and fetal mortality and morbidity. Morbidly adherent placenta is a condition of abnormal placentation in which trophoblastic cell invades into myometrium rendering the placenta unable to detach from the uterine wall causing massive antepartum or postpartum hemorrhage and significant maternal and fetal mortality. Depending on the degree of invasion, this condition can be presented in any of these three conditions.2When the placental chorionic villi is attached directly with the myometrium.When placental chorionic villi invades into the myometrium.When placental chorionic villi invades through the uterine wall, in some condition may permeate to close by organs like bladder or bowel.The risk factors of morbidly adherent placenta include previous caesarean sections, previous myomectomy, previous uterine evacuation and uterine anaomolies.An 18 year old patient, para 1+1, was brought to emergency of our hospital with the history of delivery of still birth baby three hours ago at home by traditional birth attendant (Dai) at 30 weeks of gestation followed by vaginal bleeding and retained placenta. Her previous pregnancy was ended spontaneously in first trimester miscarriage followed by instrumentation by traditional birth attendant that was uneventful. In index pregnancy her antenatal period was not followed except for a dating scan that was done at nine weeks of gestation. She went into preterm labor at 30 week of gestation and was attended by traditional birth attendant at home, which ended up in vaginal birth of still born baby boy and retained placenta. After one hour she was referred to tertiary care hospital.In Emergency patient was received in hemodynamically stable state with GCS of 15/15, blood pressure of 110/70mmHg, Pulse rate of 100 beats/mins. After initial stabilization she was shifted to operation theater for manual removal of placenta (MRP). We were unable to remove the placenta as cleavage plane was not found, she remained hemodynamically stable throughout, therefore procedure was abandoned. Doppler ultrasound showed bThe incidence of morbidly adherent placenta is reported as 2-90/10000 live births and according to a study the incidence rate was 0.017%.1As already discussed there are many risk factor for abnormally adherent placenta among which previous caesarean section is the most common cause, other causes are previous myomectomy, multiparity, previous manually removed placenta, placenta previa , septic endometritis , any uterine malformation.8Antenatal diagnosis and anticipation of risk factor is a crucial step in managing such obstetrics complications as undiagnosed case leads to complications like retained placenta, exsanguinating postpartum hemorrhage, sepsis, maternal and fetal mortality.9Screening with Doppler ultrasonography and magnetic resonance imaging is very helpful in the early diagnosis of morbidly adherent placenta but the final diagnosis is based on histological examination.10The role of methotrexate in treating morbidly adherent placenta remains controversial because of its uncertain function and risk of adverse side effects like, pancytopenia, nephrotoxicity, hepatotoxicity, immunosuppression and gastrointestinal upsets. It is hypothesized that methotrexate acts by inducing placental necrosis causing rapid involution of placenta though there is a lack of consensus for the optimum dose, frequency and timing of administration of methotrexate.However, many small studies have shown promising results of methotrexate in the management of morbidly adherent placenta. This method was chosen for the patient due to strong desire of preservation of fertility by patient and her family. Though the treatment was successful without any complication, there is a need to have studies with adequate sample size before referring this management as preferred choice for morbidly adherent of placenta.In this case report patient has presented with rare risk factors of this condition like having of history of previous single uterine evacuation and undiagnosed uterine malformation. Case handling by traditional birth attendant and lack of antenatal care seems to be the primary reason for complications. As most of such patients need hysterectomy but fortunately in this case conservative management succeeded by methotrexate chemotherapy along with injection folinic acid and her fertility was preserved. Doppler ultrasonography can be considered for screening abnormal placentation in pregnant women having congenital uterine malformation or past history of surgical intervention for optimal maternal and fetal outcome.Abnormally invasive placenta is a life threatening condition to both mother and fetus. Increasing incidence makes screening of all the potential high risk pregnancies necessary for their appropriate management. Awareness regarding the common and rare risk factor is very crucial in early detection and prevention of morbidity and mortality associated with this condition.NN, DK: Selection of case, Designed, writing, Editing of manuscript.FDN, RJ: Supervision of Management Plan, Final review and approval of case report."} +{"text": "Precision medicine programs to identify clinically relevant genetic variation have been revolutionized by access to increasingly affordable high-throughput sequencing technologies. A decade of continual drops in per-base sequencing costs means it is now feasible to sequence an individual patient genome and interrogate all classes of genetic variation for < $1,000 USD. However, while advances in these technologies have greatly simplified the ability to obtain patient sequence information, the timely analysis and interpretation of variant information remains a challenge for the rollout of large-scale precision medicine programs. This review will examine the challenges and potential solutions that exist in identifying predictive genetic biomarkers and pharmacogenetic variants in a patient and discuss the larger bioinformatic challenges likely to emerge in the future. It will examine how both software and hardware development are aiming to overcome issues in short read mapping, variant detection and variant interpretation. It will discuss the current state of the art for genetic disease and the remaining challenges to overcome for complex disease. Success across all types of disease will require novel statistical models and software in order to ensure precision medicine programs realize their full potential now and into the future. Precision medicine programs are increasingly being implemented worldwide with a goal of improving patient care for an individual . LargelyCTFR gene however their impact is often heterogenous amongst individuals is caused by up to ~300 pathogenic variants in the ividuals . Functioividuals . Overallde novo mutations for trios with an affected child and unaffected parents and small insertion/deletions (indels) particularly with short read sequencing technologies . Even foInherent to any successful precision medicine program is the timely and accurate detection of genetic variation and the prioritization of the variants most likely to be relevant to the patient's condition. Advances in software and hardware are playing an increasingly innovative role in delivering on these goals particularly for accurate variant detection and prioritization. Software-based approaches are varied and include developing new algorithms, increasing efficiencies of existing algorithms, increasing parallelization and improved standardization of common file formats . HardwarPharmacogenetic variants are also important in precision medicine with individual variability in drug response increasingly being attributed to genetic variation. An average individual is estimated to carry three clinically actionable pharmacogenetic variants with 97% of individuals carrying at least one such variant . IncreasLarge-scale translation of research results into the clinic remain a significant bottleneck for the wide-spread implementation of precision medicine programs. While increasingly detailed annotation and prioritization workflows are being described and shared , most stDespite substantial progress, reliably detecting genetic variants within precision medicine programs has many challenges remaining. While solutions are actively being developed it is clear more improvements are needed if we are to realize the full potential of population-wide precision medicine programs. In this review, I will describe the current and future challenges for identifying clinically relevant genetic variants in precision medicine programs with resources summarized in A wide variety of strategies are being employed to detect clinically relevant genetic variation at scale. These approaches can be broadly classified as software-based or hardware-based .via a variety of mechanisms including the development of new algorithms, optimization of existing algorithms, increasing parallelization via job partitioning, and standardized file formats . For example, read alignment generates an extremely large SAM file containing one row per read pair. Given whole genome datasets routinely contain >1 billion read pairs SAM files quickly become large and unmanageable for manipulation. To address this, a lossless binary version of the SAM file was created that reduces the file size by up to 75%. The resultant BAM file is significantly smaller and can be effortlessly queried and manipulated via bioinformatic packages such as SAMTools files. Standardizing file types can reduce ongoing storage requirements SAMTools . DespiteSAMTools . While pvia increasingly large and accessible compute infrastructure and hardware accelerated solutions designed to address software bottlenecks. The increase in available computational resources is primarily driven by increasingly large and accessible cluster and cloud compute resources while the hardware accelerated solutions consist largely of new FPGA devices and GPU-enabled algorithms. Collectively the increasing uptake of these hardware-based solutions is easing existing computational bottlenecks within precision medicine programs was available for benchmarking which was limited by ~30% of the reported variants being classified as low confidence due to either low coverage, local alignment problems, or systematic sequencing errors . The widin silico data. It should be noted that despite the highly precision and recall reporting for SNV calling, studies have shown that recurrent false positive variants are routinely called and exist within variant repositories to run. While for many analysis steps a single algorithm is determined to perform sufficiently, for many variant detection applications leading algorithms generate highly discordant results with no single algorithm performing optimally under all conditions . To addrWhole genome sequencing (WGS) generates millions of raw variant calls, the large majority of which are not relevant to disease. While targeted sequencing experiments such as exome or gene panel sequencing reduce the number of raw variant calls, the challenge of variant filtering and interpretation to identify clinically relevant variants remains. Beginning with raw variant calls, the most common filtering strategy is to apply a series of successive annotation and prioritization steps in order to reduce the genomic search space for clinically relevant variants. Such strategies include stratifying variants by impact on genes, running functional inference prediction software for missense mutations, overlapping to both ethnically matched population-level and disease-specific variant repositories, and sequencing pedigrees for germline disease and paired tumor/normal samples for cancer . OverallOften the first annotation step is to stratify variants based on their impact on genes. For example, SNVs causing non-synonomous/nonsense mutations or small indels situated within exons causing a frameshift are prioritized. Determining this impact can be challenging however due to factors such as differences in gene models or multiple isoforms reported within a single gene model. For example, a recent study aligned RNA-Seq data to three popular gene models and found 95% of non-junction read alignments were identical across the three gene sets however only 53% of junction spanning read alignments were identical . Such stde novo mutations and validation studies have reported consistently high false positive rates for both candidate disease-causing increasingly other patient sequence data is being generated including transcriptome, long read, microbiome and single cell sequencing. For example, sequencing the transcriptome from a patient can be used to identify transcriptional changes likely caused by genetic mutations. A recent study used this strategy to improve diagnosis rates by 35% over genome sequencing alone by identifying deep intronic variants which altered splicing . Long reThe ongoing success of precision medicine programs for genetic disease has led to increasingly large and diverse sequence information being generated per patient. Programs are expanding in terms of number of patients sequenced, the sequencing technology employed and the type of diseases being examined. Scaling up and standardizing existing programs to population level numbers requires significant improvements in the throughput and interoperability of the systems. The other significant challenge will be the incorporation of information from additional sequencing applications including transcriptome, long read, microbiome, and single cell sequencing. The next generation of supporting software and hardware needs to be flexible and robust to manage the coming deluge of data.Identifying clinically relevant genetic variation is one of the hallmarks of successful precision medicine programs. This review discusses the wide variety of strategies being employed to both speed up and improve the detection of clinically relevant variants. While challenging today, increasingly complex patient data sets will be generated in the near future which will require sophisticated hardware and software solutions. To support this, substantial new methodologies able to synthesize large volumes of disparate data types will be needed. These new tools will allow precision medicine programs to realize their full potential both now and into the future.The author confirms being the sole contributor of this work and conceived and wrote the manuscript. The author approved it for publication.MF is funded by NHMRC APP5121190.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Contextual factors, including social determinants of health, have gained recognition for greatly influencing aging trajectories and chronic disease progression. Although traditional qualitative research gives a rich understanding of the internal psychological experience, it is unable to assess socio-cultural and built environment aspects of life apart from the verbal descriptions from participants. This symposium examines the use of Photovoice as a tool to assess the socio-cultural and structural context surrounding the participant. This symposium will present a narrative review on the use of current Photovoice methodologies in dementia care; results from three studies using photovoice, one with participants with mild cognitive impairment and their caregivers to explore their perceptions of aging in their home, the second exploring the lived experience and structural barriers among older adults with pre-frailty or frailty awaiting kidney transplant, and the third exploring the older adult peer mentors\u2019 experience providing community-delivered hearing care. The talks will also address practical aspects of using photovoice such as institutional review board tips, logistical challenges, interview preparation and coding approaches. The fifth talk will describe Photovoice result dissemination strategies, including photo exhibits and stakeholder meetings, used to engage the community and advance policy to improve disparities. Photovoice as a research tool originally aimed to reinforce empowerment for those marginalized in society to describe their lived environment. This important aim is augmented in this symposium by improving researchers\u2019 understanding of context to design more impactful research."} +{"text": "This talk will focus on leveraging the strengths of small rural communities to improve transitions of care post ED discharge. We moved beyond post discharge telephone calls, and partnered with already existing community based organizations. These collaborative partnerships enabled the use of standardized bundles of interventions targeting specific risks such as falls, depression, polypharmacy and the lack of documentation around goals of care."} +{"text": "Previous literature has examined the consequences of loneliness coping methods; however, scarce research has examined racial/ethnic disparities and the differential association between coping activities and psychological outcomes. This study aimed to fill this gap in the literature by examining racial/ethnic differences in loneliness coping strategies and their impact on anxiety and depression among middle-aged and older adults. Data were from the 2018 Loneliness and Social Connections survey conducted by AARP. Findings revealed minorities reported higher levels of loneliness and coped with loneliness by socializing with friends in person, socializing with friends using technology, and individualized activity significantly more compared to white counterparts. Logistic regressions revealed that minorities who engage in risky behaviors are 1.66 times more likely to be depressed and 1.98 times more likely to be anxious . Moreover, the odds of being anxious increased by 58% if minorities coped with loneliness by socializing with friends via technology . However, minorities who socialize with friends in person are 48% less likely to be anxious . In general, socializing methods have more implications for mental health among minorities. Findings suggest that differential coping strategies may have differential outcomes for minorities. The results of this study point to the need for further longitudinal research examining factors contributing to coping strategies and the direction of causality between coping strategies and psychological outcomes."} +{"text": "Cancer is responsible globally for more than one in five of all deaths from non-communicable diseases. Cancer of the lung and stomach are among the top 10 causes of death in upper-middle-income countries, from where the bulk of international travellers originate.Impressive advances in cancer care have greatly improved clinical outcomes with a strong focus on cancer survivorship and the enhancement of patients\u2019 quality of life in partnership with multidisciplinary healthcare teams. As society emerges from the most devastating effects of the COVID-19 pandemic, which exacted a heavy toll on immunosuppressed cancer patients, we anticipate that levels of confidence towards international travel will gradually increase in the cancer survivor community. A recent study of websites aimed at patients living with a variety of chronic illnesses, including cancer, exposed significant deficiencies in the quality of travel health information they provide.The therapeutic effect of travel is an undeveloped concept in travel medicine journals and the few reports on the health benefits of international leisure travel have emerged from tourism studies research. Two decades have passed since a qualitative study was published on the perceived role of holiday-taking in the post-cancer rehabilitation and recovery of cancer patients. Patients, their families and carers identified multiple positive effects of leisure travel, including enhanced mood, a feeling of wellbeing from sunnier climates, improved mobility, increased energy levels, diminished social isolation, recovery of lost self-esteem, a more positive self-image, greater independence and an opportunity to escape from a burdensome sick role.We have an incomplete understanding of the international travel patterns, travel behaviour and clinical outcomes of patients travelling with cancer. The travel health challenges faced by people with cancer usually focus on whether it is safe to administer live-attenuated vaccines such as yellow fever vaccine and infectious disease risks, including travellers\u2019 diarrhoea and malaria, arising from the immunocompromising effects of malignancy and its treatment, including chemotherapy, biologic agents, radiotherapy and surgical splenectomy. A retrospective cohort study of 149 patients with diagnosed cancer presenting for pre-travel health advice found that 47% were immunocompromised at the time of travel with similar exposures and travel itineraries to patients whose cancer was cured or in remission. Most reported travel-related illnesses in that cohort were classified as minor.The non-infectious risks of travel faced by cancer patients have received less attention in the literature and there is little evidence-based information to guide practitioners\u2019 advice, which is still primarily based on expert opinion. Based on the authors\u2019 combined clinical experience in medical oncology, patients often seek guidance on these issues when discussing international travel plans. Healthy behaviour during times of peak ultraviolet (UV) radiation exposure and skin protection with high sun protection factor cream are essential for cancer patients who have received chemotherapy. Depending on the phase of their cancer treatment, fatigue can be a significant barrier to normal daily activities and travel itineraries and modes of transportation may need to be adapted to the patient\u2019s energy levels. The disfiguring cosmetic effects of cancer treatment, including surgical scars, hair loss, skin grafts and stomas can be a source of anxiety for travellers, especially if they are at an early stage of their cancer experience. The care of central venous catheters, percutaneous endoscopic gastrostomy (PEG) tubes and portacath lines in patients undergoing active cancer treatment will require specific advice from the patient\u2019s oncologist or specialist cancer nurse. Travellers to high altitude who have received radiotherapy for head and neck cancer should be warned about their increased risk of acute mountain sickness arising from damage to the carotid bodies.Depression is common among active cancer patients and cancer survivors and travelling with at least one supportive companion should be encouraged. Sleep may be disturbed and cancer patients may request sedative-hypnotic agents from their travel medicine provider. Melatonin may be an effective treatment for jet lag; it is a safe option in cancer patients and may even help to alleviate some chemotherapy side effects.Communication between the traveller\u2019s clinical oncology team and travel medicine clinician will facilitate informed decisions around patients\u2019 fitness to travel. Cancer patients are likely to delay travel until cycles of chemotherapy and radiotherapy have been completed and bone marrow suppression has subsided, but occasionally travel may be prioritized for important family events or in situations where people have been displaced from their homeland by conflict or natural disasters. Under normal circumstances, travel insurance companies are unlikely to provide specialized cover for a traveller with cancer without a medical clearance certificate from the patient\u2019s physician. Most routine travel insurance policies exclude pre-existing diseases, including cancer, so travellers may be required to purchase special cover for an extra premium and undergo medical screening.Previous tracheostomy or laryngectomy should not be a barrier to air travel and patients may benefit from precautionary measures including keeping the breathing stoma moist, arranging for supplemental oxygen and carrying a portable nebuliser. Prevention of deep venous thrombosis will necessitate the use of graduated compression stockings and possibly use of low molecular weight heparin under specialist supervision. Bleeding risk in cancer patients with bone marrow suppression causing thrombocytopenia should be considered before prescribing antiplatelet or anticoagulant agents. Gas expansion at aircraft cruising altitude may increase the risk of wound dehiscence so minimum safe intervals following cancer surgery or laparoscopic procedures should be respected. This is a major consideration in cancer patients who have undergone neurosurgery because of the risk of expansion of gas in the skull. Changes in air pressure may result in increased gas in stoma bags, which may benefit from a flatus filter. Adhering to a healthy diet is essential to avoid increased intestinal output.The incidence of lymphoedema exacerbation in cancer patients who have undergone surgical lymph node clearance is lower than previously suggested and this should not generally represent a barrier to air travel.Medical and surgical tourism is not uncommon among cancer patients, especially those living in smaller high-gross domestic product (GDP) countries in the Middle East such as Bahrain and the United Arab Emirates. In addition, cancer patients may travel overseas to enrol in a clinical trial or receive complementary and alternative medicine as part of a holistic programme of cancer survivor health care. A comprehensive review of the infectious risks of medical tourism has been recently published in this journal.For all travellers with cancer, their resuscitation wishes and advance directives should be made known to their travelling companions and clinicians who care for them abroad. Travellers should be aware that commercial airline flight attendants are unlikely to withhold basic life support in the event of a cardiorespiratory arrest occurring during flight in a passenger whose intentions not to be resuscitated have been communicated by their family members. This may cause considerable distress to the family of the traveller with cancer. For travellers with advanced cancer or receiving palliative care for a terminal diagnosis, education of accompanying persons about repatriation procedures in the event of a death occurring overseas is distressing but necessary.A more holistic approach to advising the traveller with cancer reflects the increased survivorship and expectations for a normal quality of life in this community. Although the infectious disease risks associated with immunosuppressive therapy are central to their preparation, we advocate a broader consideration of non-communicable disease risks and a discussion of the health benefits of international travel. Future qualitative research should elucidate the lived travel health experiences of this vulnerable group of travellers.This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.The authors have no conflicts of interest to declare."} +{"text": "This study identifies typologies of caregiving networks of older adults and their effects on older adults\u2019 well-being and unmet needs in late life using the National Health and Aging Trends Study (NHATS). NHATS identifies the entire care network of older adults, cataloguing all activities each respondent assists with and the amount of time they spend helping, providing a unique opportunity to evaluate caregiving networks. Using network analysis and cluster analysis, we find that older adults have different types of caregiving networks including large and small networks with a primary caregiver and networks where caregivers share caregiving responsibilities more evenly. Size and structure of the networks are significantly associated with older adults\u2019 well-being and unmet needs. These findings highlight the importance of considering the full care network in developing policies and programs to support family caregivers."} +{"text": "Humanities scholarship on dementia has long focused on the depiction of dementia in literature, film, and other genres. Recent research on neurodiversity includes humanistic scholarship on creativity within dementia. It is time for interdisciplinary humanities scholarship to focus on narratives of dementia that circulate within aging societies, are embedded in policy, and shape experiences of typical people living with dementia or providing dementia care. This paper argues for the normative importance of studying values-laden cultural narratives, recognizing competing or evolving narratives within a society, and demonstrating how to reframe flawed narratives beyond necessary attention to ageist and ableist language. It presents examples of approaches to social narrative analysis; describes tools and training that could be integrated into humanities scholarship on dementia and aging, and considers the potential role of social narrative analysis in articulating and launching policy ideas for aging societies."} +{"text": "Moving beyond technocratic approaches to climate action, climate justice articulates a paradigm shift in how organizations think about their response to the climate crisis. This paper makes a conceptual contribution by exploring the potential of this paradigm shift in higher education. Through a commitment to advancing transformative climate justice, colleges and universities around the world could realign and redefine their priorities in teaching, research, and community engagement to shape a more just, stable, and healthy future. As inequitable climate vulnerabilities increase, higher education has multiple emerging opportunities to resist, reverse, and repair climate injustices and related socioeconomic and health disparities. Rather than continuing to perpetuate the concentration of wealth and power by promoting climate isolationism\u2019s narrow focus on technological innovation and by prioritizing the financial success of alumni and the institution, colleges and universities have an opportunity to leverage their unique role as powerful anchor institutions to demonstrate climate justice innovations and catalyze social change toward a more equitable, renewable-based future. This paper explores how higher education can advance societal transformation toward climate justice, by teaching climate engagement, supporting impactful justice-centered research, embracing non-extractive hiring and purchasing practices, and integrating community-engaged climate justice innovations across campus operations. Two climate justice frameworks, Green New Deal-type policies and energy democracy, provide structure for reviewing a breadth of proposed transformational climate justice initiatives in higher education. Higher education leaders often claim that their institutions, through research and teaching, contribute to addressing humanities biggest challenges Gamoran . In pracThe urgent need for societal transformation to simultaneously address worsening economic and health inequities and growing climate vulnerabilities has become more obvious since the wealthiest billionaires in the world more than doubled their wealth since the beginning of the pandemic a synthesis of our collective empirical knowledge and experiences engaging with and reviewing climate action planning processes at multiple colleges and universities, and (2) application of two climate justice frameworks, the Green New Deal and energy democracy, to explore how higher education can advance and accelerate a transformative climate justice response to humanity\u2019s intersecting crises. This paper is primarily a conceptual contribution because despite our engaged analysis of university sustainability initiatives and despite focused efforts to systematically review current university climate commitments, we have not been able to identify empirical examples to demonstrate the novel paradigm shift that we are proposing. To complement our conceptual proposal, we have reviewed and synthesized a breadth of specific actionable initiatives aligned with this paradigm shift that we present within two compatible climate justice frameworks.This paper first reviews climate justice literature to explain how a commitment to climate justice is a paradigm shift in higher education. Then, to explore the transformative potential of specific higher education climate justice initiatives, we apply two climate justice frameworks to our empirical assessment of innovative opportunities in higher education. We end with conclusions and recommendations.More frequent and extreme disruptive climatic events are adversely impacting water access, food production, physical and mental health, and physical and economic infrastructure\u2014particularly for vulnerable communities around the world IPCC . In thisDisparities in current and predicted climate impacts exist at multiple levels, including global inequities, within-country inequalities, and regional inequities, particularly across differences in race, class, gender, and disability . To advance a just societal transition away from worsening climate suffering, the dominant knowledge paradigms on which current societal systems were built must be challenged and GND-type policies and energy democracy Fig.\u00a0. GND-typThe GND policy framework has inspired climate justice policies at all levels of governance\u2014Indigenous, municipal, state, national, and regional\u2014in many parts of the world, including in Europe, Canada, and South Korea (Boyle et al. Energy democracy embraces the idea that transformation away from centralized fossil fuel-based energy systems to a distributed renewable-based future can also redistribute power\u2014political and economic power as well as electric power Burke . Three kThe climate justice policy frameworks of both the GND and energy democracy provide a valuable structure for considering the broad range of institutional initiatives that could advance climate justice in higher education.This section reviews a broad range of proposed university initiatives that would align with an institutional commitment to advancing climate justice. These proposed initiatives are based on a review of the literature on connections between the core elements of each climate justice policy framework and institutions of higher education. We detail specific potential climate justice initiatives first within the GND policy framework Table and thenIn Table While the GND framework provides a structure to consider the potential of climate justice initiatives by linking climate and energy with jobs, health, infrastructure and equity, the energy democracy framework provides a conceptual structure to consider how climate justice initiatives challenge existing power dynamics Fig.\u00a0, Table 4Resisting fossil fuel interests in higher education is a critically important part of a commitment to climate justice (UnKoch My Campus Resisting the influence of fossil fuel investments in research and teaching in higher education is connected to transformative climate justice in many ways including prioritizing the fundamental knowledge creation and knowledge dissemination roles of higher education. With expanding research highlighting how strategic research funding by fossil fuel interests has been promoting misinformation and public ignorance rather than knowledge\u00a0dissemination (Supran et al. Another challenge is the lack of transparency and community-driven governance in most higher education institutions. The power and influence of faculty governance in higher education has been in decline, as senior administrators increasingly make strategic decisions without the input of faculty or students (Fitzpatrick In addition to resisting corporate interests including fossil fuels and reclaiming decision-making, a restructuring of higher education incentives, financing, and purpose is needed to reorient the mission toward the public good and climate justice. Restructuring the way research projects and campus energy infrastructure projects are designed and conducted, to include co-design and co-development with non-academic communities, creates opportunities for building local relationships and prosperity. For example, universities as anchor institutions can link more closely their intellectual and practical innovations with external communities and partners (Brown and Bozuwa Restructuring higher education toward advancing societal goals of transformative climate justice clearly requires change and innovation at multiple levels including changes beyond what can be achieved at any individual college or university. Broader innovations in educational policy and public funding for higher education are essential for the paradigm shift that we are exploring here. There is a growing movement calling for a new scale of transformative public investment for higher education, i.e., Scholars for New Deal for Higher Education SFNDHE .As the climate crisis continues to exacerbate vulnerabilities around the world, a paradigm shift in how higher education engages with transformative social change could alter policy options for a more just and climate stable future. Higher education is a critical sector of society that is so-far under-leveraged in terms of preparing for the future.This conceptual contribution suggests that unless and until climate justice is prioritized and embraced within higher education, colleges and universities are not only sustaining the status quo, but are further reinforcing climate vulnerabilities and exacerbating and perpetuating climate injustices.Universities are critically important places of knowledge production, knowledge perpetuation, and knowledge dissemination, so during this era of climate disruption and instability they can apply this knowledge capacity to advance systemic social change (Stephens et al. A commitment to climate justice provides an intersectoral and interdisciplinary approach to identifying research priorities, training students, interacting with local governments and communities, and supporting employees. Campus operations including renewable energy generation and procuring equipment and food provide other opportunities for demonstrating innovations. This opportunity for leadership in reprioritizing educational and research goals toward transformative structural change for climate justice is amplified among institutions with large endowments who have more financial flexibility in demonstrating and catalyzing change.To achieve their missions of advancing the common good through learning and innovation, colleges and universities can leverage their resources and reprioritize and reorient their educational and research initiatives toward building transformational climate justice in society. New kinds of strategic collaborative relationships and partnerships with non-academic partners at multiple scales are critical to expanding beyond traditional siloed academic work. New kinds of collaborations may include co-producing climate justice knowledge with community partnerships, expanding international, global research partnerships particularly among interdisciplinary teams in the global north and global south, and growing intergenerational research such as early career and graduate training opportunities, and cross-cutting curricula linking climate justice across disciplines, programs, departments, and schools.Prioritizing climate justice is an opportunity for colleges and universities to commit to leading the way in ending fossil fuel reliance including shifting how they invest endowments and eliminating unethical petrochemical funding sources. To realize this potential, higher education institutions need to resist corporate influence and recommit to advancing the cutting edge of research and practice for the public good.Many universities\u2014even those that have made ambitious climate commitments\u2014have not yet leveraged the opportunity to lead the transformation toward a climate just society. Courage and a commitment to advancing social justice are necessary for universities to overcome the many challenges of innovating for climate justice Bartlett . Climate"} +{"text": "Heat stress during the flowering stage induces declining spikelet fertility in rice plants, which is primarily attributed to poor pollination manifesting as insufficient pollen deposited on the stigma. Plant pollination is associated with anther dehiscence, pollen dispersal characteristics, and stigma morphology. The mechanisms underlying the responses of spikelet fertility to heat stress have been clarified in depth in terms of the morphological and behavioral characteristics of the male reproductive organs in rice. However, the roles of female reproductive organs, especially the stigma, on spikelet fertility under heat conditions are unclear. The present study reviews the superiority of stigma exsertion on pollen receptivity under heat during the flowering stage and discusses the variations in the effects of exserted stigma on alleviating injury under asymmetric heat (high daytime and high nighttime temperatures). The pollination advantages of exserted stigmas seem to be realized more under high nighttime temperatures than under high daytime temperatures. It is speculated that high stigma exsertion is beneficial to spikelet fertility under high nighttime temperatures but detrimental under high daytime temperatures. To cope with global warming, more attention should be given to rice stigma exsertion, which can be manipulated through QTL pyramiding and exogenous hormone application and has application potential to develop heat-tolerant rice varieties or innovate rice heat-resistant cultivation techniques, especially under high nighttime temperatures. Global warming has caused rising surface temperatures and frequent extreme heat events. In the past 50 years, six large-scale extreme heat events have occurred in the middle and lower Yangtze River region (the main rice production area in China) during the midsummer season . Taking Previously, the effects of high temperatures on rice have mainly focused on high daytime temperatures during the reproductive stage . Unless Stigma exsertion, which is a key determinant of the rice mating system among the stigma morphological indices, greatly contributes to pollination and has been widely utilized in hybrid rice seed production due to its pollination advantages . HoweverIn the present review, the benefits of exserted stigma on pollen receptivity under heat stress during the flowering stage are analyzed, the different effects of exserted stigma on the alleviation of heat injury under asymmetric heat are discussed, and the possible underpinning mechanisms are also explored. Based on previous findings, some further thoughts on the future direction of rice cultivation and breeding for heat resistance/tolerance in terms of stigma exsertion are proposed, which will help provide new clues for overcoming pollination barriers and exploring the mechanisms of reduced spikelet fertility induced by asymmetric heat during the flowering stage in rice.Spikelet fertility of rice is associated with pollination and fertilization, which include four main stages: (i) anther dehiscence, which proceeds through the sequential processes of thickening of the inner wall of the locule, swelling of pollen grains by water absorption, rupturing of the septum, and dehydration and cracking of the stomium ; (ii) poTo varying degrees, heat stress during the flowering stage inhibits anther dehiscence, hinders the timely dispersal of pollen grains, decreases the number of pollen grains deposited on stigmas, inhibits pollen germination , impedesAs the initial step of pollination, anther dehiscence is highly susceptible to heat stress and thus was suggested to be a selective marker for screening heat tolerance . The welTo summarize, the pollination barrier due to insufficient pollen shedding onto the stigma is the key issue underlying low spikelet fertility under heat stress during the flowering stage. Previously, the causes of heat effects on pollination and spikelet fertility in rice and the underlying mechanisms have been explored in depth in terms of anther dehiscence, based on which countermeasures have been proposed. However, given that the stigma serves as the receiver of pollen and the site of pollen germination, the effect of the morphological characteristics of the stigma on pollination and spikelet fertility under heat stress during the flowering stage is less considered.Among the morphological and physiological characteristics of the stigma, stigma exsertion and stigma receptivity play the most important roles in rice pollination and fertilization . Stigma The pollination advantages of the exserted stigmas are manifested as follows. (i) Stigma exsertion enlarges the spatial basis of pollination. The exserted stigmas show a high degree of expansion and a lajaponica or indica rice.Stigma receptivity influences the success of pollination in rice under heat conditions. The duration of stigma receptivity can last for 4\u20137 days in rice; the vitality of the exserted stigma remains normal during the 1\u20132 days after flowering, and the receptivity begins to decline on the third day and is completely lost on the seventh day after flowering . In riceHigh daytime temperature during the flowering stage delayed the dehiscence of anthers; thus, asynchronous anther dehiscence misses the flowering time, resulting in insufficient pollen grains deposited on the stigma. However, we observed that the uncracked anthers induced by heat treatment at flowering time could eventually dehisce and release pollen grains over time. After the lemma and palea have closed, the anthers usually remain outside the lemma and palea, while the stigmas are either exserted outside of or enclosed within the lemma and palea , 2. UndeHowever, the exserted stigmas are not restricted to being pollinated by flowering time and can receive pollen grains at any time after flowering , and theindica rice (20%) is higher than that of japonica rice (5.9%), and indica rice varieties are generally more heat-tolerant than japonica rice varieties , high nighttime temperature treatment negligibly impacted stigma receptivity (3 application augments spikelet fertility, and depressing stigma exsertion by paclobutrazol application reduces spikelet fertility, irrespective of the tolerance to heat of rice genotypes (The temperature during the daytime is the normal control under a high nighttime temperature treatment , during eptivity . Therefoenotypes . These oAn insufficient pollen count on the stigma is the primary factor underlying reduced spikelet fertility caused by heat stress during the flowering stage. Exserted stigmas have certain pollination advantages and can continuously receive pollen released by delayed dehiscent anthers caused by heat stress, thus having the potential to mitigate the injurious effect of heat stress on spikelet fertility. However, the roles of the exserted stigma on spikelet fertility are quite different under asymmetric heat. High stigma exsertion may be positive for obtaining higher spikelet fertility under high nighttime temperatures but may be negative for spikelet fertility under high daytime temperatures. Under heat conditions, particularly high nighttime temperatures, it is more feasible to develop heat-tolerant rice varieties or innovate rice heat-resistant cultivation techniques by modifying stigma exsertion than by restoring anther dehiscence. The great application potential of stigma exsertion is thus emphasized and deserves more attention during the course of combating heat stress under global warming.OsPID can lead to the formation of extra stigmas in rice (OsPID. In addition, phytohormones significantly regulate stigma exsertion. It has been reported that OsPID regulates stigma exsertion through auxin signaling in rice plants (3 and jasmonate application and decreased by paclobutrazol application in rice and tomato plants (Floral organ development can be manipulated by genetic modification . Stigma in rice , and thee plants . Gibberee plants . It is ce plants . Under ho plants .Thus, stigma exsertion can be manipulated through molecular engineering approaches and/or the application of exogenous hormones, which have great potential to create heat-tolerant rice varieties. However, the degree of stigma exsertion should be manipulated appropriately to obtain full potential of spikelet fertility under the situation of high temperatures during the whole day because trade-off effects should be considered between high daytime temperature and high nighttime temperature in terms of the pollination advantage of exserted stigmas in rice.CW performed the experiments. BQ analyzed the data and compiled the figures. BQ and CW wrote the manuscript. CW edited the final manuscript. Both authors contributed to the article and approved the submitted version."} +{"text": "Hair loss resulting from childhood irradiation for tinea capitis has been linked to mental health effects in women. However, the association of hair loss severity with mental health in this population is unknown.The aim of this study is to examine the association between hair loss severity and mental health outcomes in women irradiated for tinea capitis in childhood and to identify contributing factors to these outcomes.Medical records, held at the archives of Israel National Center for Compensation of Scalp Ringworm Victims, were retrospectively reviewed for 2509 women who received compensation for full or partial alopecia resulting from irradiation in childhood for tinea capitis. Mental health outcomes were determined by the number of mental health conditions reported.Among women with high hair loss levels, risk was increased for a range of mental health problems, including depression symptoms, emotional distress, social anxiety, low self-esteem, and suicidal ideation. Hair loss severity emerged as a significant predictor of mental health, adding to the effects of other predictors such as family, and social and physical health problems. Effects of hair loss severity on mental health outcomes were mediated by women\u2019s negative social experiences.Hair loss severity is a significant risk factor for mental health problems in women irradiated for tinea capitis in childhood. Further research is needed to assess mental health risks among women with severe hair loss associated with additional diseases.No significant relationships."} +{"text": "Depression is a heterogeneous syndrome linked to significant structural brain abnormalities, such as volumetric reductions in the hippocampus, anterior cingulate cortex and prefrontal cortex, as well as compromised white matter integrity. Recent growing evidence suggests that exercise is a promising and compelling treatment for depression in adults, showing effects that are comparable to other first-line treatments for depression.This review aims to improve our understanding of the biological pathways involved in both the pathophysiology of depression and the antidepressant effects of exercise.This literature review considers the latest available scientific research addressing a comprehensive analysis of the antidepressant effect of physical exercise and the biological pathways involved.Physical activity has been shown to have a multimodal effect that stimulates biochemical pathways and restores neuronal structures disturbed in depression. Experimental evidence supports exercise-induced increases in hippocampal, anterior cingulate cortex and prefrontal cortex volume, suggesting that exercise and antidepressant medication may alleviate depression through common neuromolecular mechanisms. However, the benefits of exercise may also persist beyond the end of treatment, unlike antidepressant medication.Given the undeniable scientific evidence favoring physical exercise in alleviating depression, it is of crucial importance to recommend this treatment in adjunct to psychotherapy and medication. Individuals at risk for depression also greatly benefit from it\u2019s neuroprotective effects and should prioritize lifestyle changes. In older adults, there is a greater need for non-pharmaceutical treatments for depression due to limited efficacy of pharmaceutical treatments in this population."} +{"text": "Repairing injured tendon or ligament attachments to bones (enthesis) remains costly and challenging. Despite superb surgical management, the disorganized enthesis newly formed after surgery accounts for high recurrence rates after operations. Tissue engineering offers efficient alternatives to promote healing and regeneration of the specialized enthesis tissue. Load-transmitting functions thus can be restored with appropriate biomaterials and engineering strategies. Interestingly, recent studies have focused more on microstructure especially the arrangement of fibers since Rossetti successfully demonstrated the variability of fiber underspecific external force. In this review, we provide an important update on the current strategies for scaffold-based tissue engineering of enthesis when natural structure and properties are equally emphasized. We firstly described compositions, structures and features of natural enthesis with their special mechanical properties highlighted. Stimuli for growth, development and healing of enthesis widely used in popular strategies are systematically summarized. We discuss the fabrication of engineering scaffolds from the aspects of biomaterials, techniques and design strategies and comprehensively evaluate the advantages and disadvantages of each strategy. At last, this review pinpoints the remaining challenges and research directions to make breakthroughs in further studies. Movements, as the synergistic effect of the muscle\u2013bone\u2013joint system, partly depend on interfaces at one end of specific connections such as ligaments and tendons to obtain flexibility and stability. The soft\u2013hard interface (enthesis) is a highly specialized site where tendon, ligament or joint capsule inserts into the bone and transmits tensile load from soft tissues to the hard tissue . Therefoin situ is modified and fixed directly on the bone through the combination of anchors, sutures and bone tunnels, or the injury site is implanted with autologous or allogeneic tissue patches. However, movements are highly limited during recovery and the highly disorganized scar tissues located at the interface vary dramatically in mechanical properties, which may account for 20\u201395% recurrence rates after surgical repair ) AND (enthesis)], 94 papers on [(\u2018Achilles Tendon\u2019 [Mesh]) AND (enthesis)] and 34 papers on [(\u2018Anterior Cruciate Ligament\u2019[Mesh]) AND (enthesis)] are included in the NCBI database. Apparently, studies of the enthesis at the end of tendons superfluous ligamentous enthesis. Partly because tendon-bone enthesis tend to experience greater stress and rupture by overstretching, while ligaments maintain stability. The shearing between fibers components and the expansion of fibers are main mechanical effects when tendon stretching . Executescaffold , 121.We summarize the latest research or applications in each position . A recenet al. [Despite the spring up of scaffold-based enthesis regeneration strategies, some challenges are still here to be overcome . Firstlyet al. found thMoreover, a deeper and more accurate understanding of the composition, structure and function of the enthesis at different scales as well as the relevant mechanism is helpful to further elucidate how biomechanical properties in compliant region form, while optimism of engineering enthesis scaffolds techniques and stimulation strategies are vital to restoring certain mechanical properties. Practically, the focus of researchers in this field has also gone through several different stages as factors affecting mechanical properties are constantly being re-understood. At present, people seem to pay more attention to the improvement of mechanical properties by designing fibers\u2019 arrangement, distribution and microstructure. However, how the randomness of fibers affects mechanical properties requires more detailed molecular studies and rich mechanical knowledge to elucidate. Furthermore, the smooth stress distribution is only an unclear understanding of the enthesis\u2019s function, while dynamic changes in structure and transfer of substance under specific stress are likely to be more related to the mechanical properties. More efforts are needed to figure out mechanical properties of the enthesis and to reconstruct mechanical properties of them.in vivo should be paid special attention, because they are related to the living of cells, the efficiency of factors delivery and the maintenance of mechanical properties and the Department of Science and Technology of Sichuan Province (Grant/Award Number: 2021YFH0139).Conflicts of interest statement. None declared.This article does not contain any studies with human or animal subjects performed by any of the authors."} +{"text": "Stimulus delivery is a major challenge in the investigation of sensory physiology and physiopathology, with translational implications while targeting bionic substitution of impaired sensorimotor functions by means of neuroprostheses. The complexity represented by stimulus administration is generally valid for all senses, and particularly for touch among physical senses because of the distributed positioning of receptors throughout the large area of the whole skin and the intrinsically interactive characteristics of somatosensation.In touch studies, the experimental protocols typically involve the delivery of mechanothermal or electrical stimuli and the collection and analysis of stimulus\u2010induced responses, either at perceptual level by means of psychophysical methods or by investigating peripheral or central bioelectronic activity in humans or animals via techniques such as microneurography and microstimulation, patch clamp, electrode arrays, functional magnetic resonance imaging, or electroencephalography.When the stimulus is delivered mechanically directly to the epidermis of intact subjects, such as with vibrotactile probes, extended textures or shapes, the spatiotemporal interaction with the skin should be carefully controlled over multiple sessions, for example by using custom biorobotic tools. Such automatic mechatronic platforms should be developed to allow gathering of repeatable responses of the somatosensory pathways in order to enable modelling attempts based on brain imaging or electrophysiological recordings at higher stages with respect to the cutaneous haptic stimulation site.et\u00a0al. Another suitable approach involves accessing directly the nervous system in order to release electrical pulses to the afferent pathways. The electrical delivery of the stimuli is extremely challenging because of the complexity of guaranteeing mechanical, electrical and biological stability of the electrode\u2010nerve interface, the high number of stimulation sites, and selectivity, both spatially and temporally. Among the possible methods for releasing electrical patterns to the nervous system, microstimulation with needle electrodes is a technique used by trained neurophysiologists for eliciting action potentials with excellent axonal selectivity within a microneurographic session Vallbo, . While bJournal of Physiology, builds on these recent technological and medical advancements and by the European Commission through the NEuro\u2010controlled BIdirectional Artificial upper limb and hand prosthesiS project .Peer Review HistoryClick here for additional data file."} +{"text": "Population variability was introduced to the routine musculoskeletal modeling framework by perturbing input parameters of the lower limb muscles around their baseline values. Using ground reaction force and skin marker trajectory data collected from six subjects performing body-weight squat, the knee contact force was calculated for the perturbed models. The combined impact of input uncertainties resulted in a considerable variation in the knee contact force estimates (up to 2.1 BW change in the predicted force), especially at larger knee flexion angles, hence explaining up to 70% of the simulation error. Although individual muscle groups exhibited different contributions to the overall error, variation in the maximum isometric force and pathway of the muscles showed the highest impacts on the model outcomes. Importantly, this study highlights parameters that should be personalized in order to achieve the best possible predictions when using generic musculoskeletal models for activities involving deep knee flexion.Understanding the sources of error is critical before models of the musculoskeletal system can be usefully translated. Using To reprin vivo data for validation. As a result, to date, there is no comprehensive probabilistic analysis that provides a reference for guiding the selection of influential model parameters that need to be personalized, especially for activities involving deep knee flexion.A probabilistic analysis can provide important insights into the relative impact of different sources of uncertainty on the muscle and joint reaction force estimates of generic musculoskeletal models . Using ein vivo measured tibiofemoral joint contact forces reported within the CAMS-Knee data sets , and ata sets to perfoin vivo KCF data, measured in six subjects with an instrumented knee implant were obtained from the CAMS-Knee data sets with MIThe muscle\u2013tendon model parameters were probabilistically represented as Gaussian distributions based on the inter-individual variability reported in the literature , SupplemTo assess the overall impact of uncertainty in muscle model parameters on predicted muscle and knee contact forces, we performed one general MC simulation with 2000 iterations for each subject and muscle group, where all the five input parameters of the included muscles were perturbed. In addition, to assess the isolated effect of each source of uncertainty, five individual MC simulations each with 500 iterations were performed where only a single muscle parameter was perturbed at a time. The number of iterations was chosen based on convergence at approximately 1,600 and 350 simulations during early model testing. Here, similar to previous probabilistic musculoskeletal modeling studies , convergFor each subject, skin marker trajectory and GRF data of a single representative squat trial were input to the standard OpenSim tools. Inverse kinematics (IK), static optimization (SO), and joint reaction force (JRF) analysis tools were used to calculate muscle activation and total KCFs in the baseline as well as in the perturbed models by minimizing the sum of the squared muscle activations. To assess the influence of using more simplified muscle models, baseline model simulations were repeated without muscle\u2013tendon force\u2013length characteristics in the static optimization tool.The measured EMG signals were processed within MATLAB where the raw signal was bandpass filtered , offset corrected, rectified, and finally lowpass filtered using a moving average filter. The maximum activation value recorded across all trials of all activities performed for each subject was used to normalize the processed EMG signals. Regarding measurement errors/artefacts and uncertainty introduced by normalization technique, EMG signals were only used for qualitative validation of the muscle activation patterns estimated by the baseline models. In addition, the 5th\u201395th percentile range of the muscle activation outputs was used to understand how model parameter uncertainty influenced muscle redundancy solutions. The calculated 5th\u201395th percentile range of the KCF error distributions obtained from general MC was compared between different muscle groups to identify the muscle group with the highest contribution toward the overall KCF uncertainty. In addition, for each muscle group, the ratio between 5th\u201395th percentile range of individual and general MC outputs was calculated to assess the relative contribution of each muscle parameter to the overall uncertainty observed in the KCFs. Finally, perturbed models with the least root mean squared error (RMSE) between predicted and measured KCFs were selected to understand whether subject-specific measurement of all muscle parameters can guarantee fully accurate KCF estimates when squat activity is simulated using generic models.Activation patterns of the knee extensor muscles predicted by the baseline models displayed similar trends to the measured EMG signals, especially during the descending phase of the squat . The fleSimultaneous perturbation of the MIF, PEN, TSL, OIP, and VIA parameters of the lower limb muscles resulted in variations of up to 80% in the activation levels of the rectus femoris, vastus medialis, and biceps femoris long head, as well as up to 50% variation in activation of the vastus lateralis and semimembranosus . These vAs required to balance the external knee moment, predicted muscle forces from the baseline models generally showed the greatest forces in the knee extensor muscles . For exaSimultaneous perturbation of the input parameters of all lower limb muscles resulted in considerable variations in the estimated muscle forces . These vin vivo measured forces . Similarly, the KCF simulation error was greatly influenced by the input uncertainty and showed large variation at deep knee flexion that could explain up to 70% of the simulation error . Here, tAmong the studied parameters, MIF and PEN were the most and least influential factors, explaining around 70% and 10% of the overall uncertainty ; Table 2Perturbed models with the lowest RMSE of the simulation results showed the greatest improvements in the KCF predictions . In an at 2,392) , when KCpetition , errors petition ).We found varying contributions between the studied muscle groups toward the overall uncertainty in KCF estimates. Here, the knee flexor muscles played a greater role at lower flexion angles, while knee extensors became considerably more influential at larger flexion angles . We alsoMIF was found to be the most influential parameter on the resultant KCF throughout the entire range of knee flexion , which cAfter MIF, VIA showed the largest impact on KCF predictions . VariatiOur data suggest that parameters with low impacts can be directly taken from the generic model . The pennation angle of the muscle fibers (PEN) is a clear example of such a parameter, considering its relatively small impact on the KCF estimates . For theOur results indicate that uncertainty in muscle parameters cannot completely explain KCF errors when generic models are used to simulate activities involving high knee joint flexion . As a reSeveral limitations need to be considered when interpreting the results of this study. First, we chose the generic model developed by Personalization of musculoskeletal models remains technically and financially challenging. This study provides a more complete understanding of the impact of uncertainty in the input parameters on the estimated KCFs and can help to identify the most influential parameters that need to be accurately measured and implemented. The results suggest that attention should be paid to the subject-specific measurement of MIF and VIA in order to ensure errors in musculoskeletal modeling remain minimal. In addition, adaptive muscle optimization techniques that enable accurate prediction of the muscle co-contractions at the beginning and end of the squat cycle might well present improvements in KCF prediction deficits revealed in this study."} +{"text": "AARP has a long history of being an advocate for marginalized and vulnerable adults. AARP staff will discuss policy needs and what the post pandemic workplaces needs to ensure that older LGBTQ people can thrive in the workplace with dignity and respect. The 2021 AARP\u2019s Vital Voices research will be used to showcase the economic impact the pandemic has had on older adults, African American communities, Hispanic/Latino communities, Asian Pacific Islander communities and LGBTQ communities. AARP staff will discuss strategies and tactics needed to ensure that opportunities for economic recovery for older adults. The survey gathers information to gauge opinions on a range of topics as well as breaking and current issues. Among other issues, it explores concerns about racism and experience with age discrimination and employment experience among older adults."} +{"text": "This poster describes a partnership during Fall 2021 between the Wayne State School of Social Work and the Federal Emergency Management Agency (FEMA) to assist older adults whose homes sustained damage during flooding in June 2021. This short-term project helped people access resources to repair and restore damaged homes, repair, or replace mechanical and electrical systems, deal with mold and other health hazards, and replace their personal belongings. Social work students trained by FEMA made over 700 outreach calls to homeowners whose applications for relief were rejected. The students worked with the homeowners to facilitate access to help that either resulted in the approval of their FEMA application or connected them with alternative sources of help and support. A focus group with students provided insights on their motivations, training experiences, issues affecting the applicants, and skills developed. While FEMA-required training offered little relevant assistance, SSW staff and faculty overseeing the program provided ongoing support that students considered vital as they worked to assist applicants. Some homes were extensively damaged and resources available from FEMA were insufficient. Some homeowners suspected the students were scammers; students also learned of exploitation by contractors. Students honed empathy, reflection, and supportive listening skills as they heard stressors associated with maintaining their homes amidst losses due to covid and their knowledge of community resources expanded. Lessons learned to aid in future efforts to assist in disaster relief are described."} +{"text": "Popsy@Work) aims at addressing this global challenge by: i) digitally collecting psychosocial data on the PWP; ii) implementing and strengthening of a psychosocial occupational health surveillance digital system; iii) providing reference values for the PWP concerning Psychosocial Health; iv) Transferring to society knowledge and best practices; v) Raising awareness on the importance of psychosocial management in occupational settings based on science. Popsy@work is a digital platform that collects and aggregates psychosocial data analytically and creates a visualization hub adding value to data on the PWP and giving science back to society in a usable way, empowering workers, strengthening organizations and grounding public policies. Pospy@Work considers the development of strategic intelligence on levels and inequalities of psychosocial health and well-being in occupational settings by robust metrics and reference data. Creating opportunities for national policy dialogue on inequalities, including the psychosocial health of the PWP through collaboration with diverse sectors identifying and mapping subgroups of populations whose unmet needs require specific outreach measures.To achieve the goal of sustainable employment, considering the profile of the Portuguese working population (PWP), is needed a range of strategies to ensure long, productive, and sustainable careers allied with a better quality of working life, health, and wellbeing, but also with public health policies grounded on scientifically validated and reliable data. This is possible through a comprehensive working system approach that ensures workers will be mentally and physically able to remain at work by the balance between work demands and individual resources allied with public health policies transfer into the workplaces by organizations\u2019 leadership and policy makers. The Portuguese Observatory on Occupational Factors (Popsy@work allows psychosocial health monitoring, reporting and foresight, promoting the provision of robust metrics and reference values for the Portuguese working population.Popsy@work allows psychosocial health on occupational settings to be digitally monitored in a continuous way and sustain public health policies."} +{"text": "Dr Hargreaves will discuss the current guidance for EU/EEA countries on public health considerations for newly arrived migrants, with a specific focus on catch-up vaccination delivery across the life course in mobile populations. She will explore current initiatives and best practices to ensure child, adolescent and adult refugees and migrants are included in catch-up planning and delivery for missed vaccines and missed doses and to align them with the host country vaccine schedule."} +{"text": "This study considers some of the effective governance tools that have been utilised to mobilise, redeploy and repurpose the health workforce during the COVID-19 pandemic to create surge capacity, protect workforce health and wellbeing and ensure effective implementation of vaccination programmes.Data were systematically extracted from the Observatory/WHO Europe/European Commission Health System and Response Monitor, covering the period from March 2020 to May 2021 with a focus on four dimensions of health workforce governance: national/regional government policies; legislation; regulation; the role and remit of employers and management.A wide-range of governance actions across all levels were required to ensure the health workforce could provide effective pandemic responses. Creating surge capacity, for example, often required adoption of emergency legislation to facilitate exceptional hiring procedures and the changing of (re-)registration requirements, as well as additional training and development of new competencies among other actions. Putting in place physical and mental health support meanwhile required defining infection control policies, monitoring PPE supply and distribution, ensuring access to free mental health support, and implementation of breaks. Some countries also allowed \u201cnew\u201d types of workers to vaccinate; online or in person training; adjustments to payment mechanisms; and creating new supervision requirements.Pandemic responses have broken up sclerotic governance structures which have hampered past health workforce development and reform, new training programmes have been rapidly developed, leadership roles have been delegated to a wider-range of health professionals than before and monitoring systems that provide more rapid data on staffing levels have been put into place. Learning from and evaluating these changes will be important to help inform future pandemic responses."} +{"text": "A training protocol applied elastic band to hamstring curl exercise for young basketball players (Kamandulis et al., The existing studies usually adopted 8 weeks of elastic band training (Jensen et al., The current study proposed an opinion on the promising effects of integrating elastic band training into physical education classes to promote muscular strength for students. This opinion is justified by the following reasons. First, the neurodevelopmental perspective emphasizes on the importance of developing muscular strength during the critical periods of preadolescence and early adolescence. Second, an overview on the existing literature suggests that elastic band offers integrative training modes including variable resistance training, eccentric training, plyometric training, and flexibility training. Third, research on adolescent athletes provided information as to the frequency, load, and duration of the elastic band training program. In conclusion, elastic band training can be a feasible addition to physical education classes for muscular strength development.QF and XZ prepared the draft. YX and FH worked on revision and approved the submitted version. All authors collaborated in preparing the manuscript. All authors contributed to the article and approved the submitted version."} +{"text": "Networking is the action or process of interacting with others to exchange information and develop professional or social contacts. The newly piloted GSA student chapters are encouraged to build relationships that can lead to networking and collaboration. While it is important to maintain a unique Sigma Phi Omega institutional chapter identity, the GSA student chapters also focus on the field of aging within a Higher Education Institution. Sigma Phi Omega collaborating with GSA Student Chapters is mutually beneficial in expanding learning, exploring new ideas, building professional connections, creating innovative projects, and gaining insights to other opportunities for professional and personal growth. This session will provide guidance on how to foster collaboration and growth for each of these chapters while honoring respective chapter missions, requirements, and educational experiences."} +{"text": "Isolated tricuspid valve endocarditis accounts for only 5 to 10 percent of infective endocarditis cases globally. Numerous surgical procedures ranging from simple vegetectomy, creation of neoleaflets or complete replacement by a prosthetic valve have been described. We aimed to evaluate our experience in surgical management of this entity and to formulate an approach for timing, appropriateness and extent of surgery. Patients operated on semi elective/emergency basis had adverse outcome with residual regurgitation and had longer ICU stay. Also, patients who required excision of leaflet and creation of neoleaflets had a higher incidence of regurgitation. This suggests that maximal preservation of native valve lessens the incidence of residual regurgitation. Simple vegetectomy and patch repair of the residual defect offers the best outcome. Numerous surgical procedures ranging from simple vegetectomy, creation of neoleaflets following excision of affected leaflet to complete excision of the native valve and replacement by a prosthetic valve have been described.3 The purpose of our study was to evaluate our centers` experience in the surgical management of this entity and to formulate an approach for timing, appropriateness and extent of surgery for this rare disease. Isolated tricuspid valve (TV) endocarditis accounts for only 5 to 10 percent of infective endocarditis cases globally. This is a retrospective study carried out at ABVIMS and Dr RML hospital, a tertiary care centre in New Delhi, India. A total of 6 patients were operated for this disease from April 2019 to April 2021. Detailed preoperative history taking and evaluation was done in all cases to evaluate any intracardiac shunt, peripheral abscesses, osteomyelitis, and any IV drug abuse to assess risk factors for TV endocarditis. Out of the six patients operated, four patients were electively operated after adequate and appropriate antibiotic therapy once they were culture negative and afebrile. Indication for surgery in these patients was clinical evidence of right heart dysfunction and Echocardiographic finding of severe Tricuspid valve regurgitation (TR) along with vegetation. Two patients were operated on a semi elective basis due to large size of the vegetation, progressive heart failure despite medical management and recurrent lung embolization from the vegetation. All patients were kept on serial clinical and echocardiography (ECHO) follow-up \u2013 weekly for one month and three monthly thereafter. Vegetectomy was carried out in all cases with adequate margin to ensure removal of all infective foci. The valve was reevaluated after vegetectomy and appropriate reconstructive technique was planned. Small residual defects in the leaflets were closed with autologous untreated pericardial patch using 5 0 polypropylene sutures. In patients where the whole leaflet was excised, neoleaflet was constructed using autologous pericardium. Residual tricuspid regurgitation was evaluated by saline insufflations during cardioplegic arrest and by transesophageal echocardiography after removal of cross clamp. Residual tricuspid regurgitation was managed by limited annuloplasty using autologous pericardium. Once satisfactory leaflet coaptation and tricuspid repair was achieved, right atrium was closed in a single layer and patient was weaned of cardiopulmonary bypass Vegetations were multiple in most cases and vari All patients were evaluated by transesophageal (TEE) echo intraoperatively for adequacy of repair and degree of residual TR if any and followed up by serial transthoracic (TTE) echocardiography in the post op period for residual disease or progression of disease. While four patients on TEE intraoperatively had mild TR, two patients had moderate TR with central jet which was acceptable without any evidence of right ventricular dysfunction and acceptable hemodynamics. Both these patients belonged to surgical group which were taken on semi urgent basis for surgical repair. They also required inotropic support along with decongestive measures in the postoperative period. These patients were taken up for surgery with elevated inflammatory markers in view of their symptomatic status despite optimal medical therapy. Subsequently, one other patient had progression of severity of TR from mild to moderate in intensity after one month follow up in post operative period. The symptoms were successfully managed by diuretics and fluid restriction and needed no further surgical intervention. This patient had severe TR preoperatively and had to undergo leaflet reconstruction of all three leaflets following wide excision of the vegetation. None of the patients in our study had any conduction block requiring pacemaker insertion and there was no mortality amongst the operated patients. No patient underwent prosthetic valve implantation in our series.4 Surgical intervention in tricuspid endocarditis remains an enigma for surgeons regarding the timing and type of intervention. Medical management with appropriate antibiotics and decongestive therapy remain the cornerstone of therapy for this disease entity. Isolated tricuspid endocarditis follows a more benign course as compared to left sided endocarditis involving the aortic and mitral valve.5 While initial consensus was that tricuspid valve endocarditis responds well to conventional antibiotic therapy, long term follow up suggested that progression to heart failure was high with mortality rate ranging from 50 to 90 percent in such cases.5 This paved way for simple vegetectomy as a viable surgical option in complete treatment of this entity. In his pioneer work Hughes et al suggested that, where indicated, early operation and vegetectomy may have even greater benefits than have been previously appreciated, including preservation of the normal, native valve, preservation of normal hemodynamic function, abolition of the risks of anticoagulative medication, and abolition of the risks of prosthetic endocarditis.6However, residual regurgitation of the tricuspid valve is well tolerated and easily managed medically.6 Historically, Arbulu et al proposed tricuspid valve excision without replacement as adequate treatment, highlighting that tricuspid valve regurgitation is well tolerated.7 Complete excision of all infected tissue and restoration of valvular competence is the cornerstone of surgical management. Preservation of native tissue and valve reconstructive procedures such as leaflet enhancement using autologous pericardium and limited annuloplasty assist in achieving this aim.8 However, there is some risk of recurrence of infection and progressive valvular dysfunction with this approach.9 Replacing the tricuspid valve with a prosthetic valve is an option for severely diseased valves where preservation of native tissue is not possible.10 However, they have their own inherent disadvantages \u2013 anticoagulation in mechanical prosthesis and degeneration in bioprosthetic valves.11 There are limited surgical options due to the inherent complexity of the mechanics of the tricuspid valve and persistence of mild to moderate regurgitation after repair.12 This reiterates that adequate clearance of infection by optimal antibiotic therapy should always be the cornerstone of therapy12. Also, patients who required excision of leaflet and creation of neoleaflets had a higher incidence of regurgitation. This suggests that maximal preservation of native valve lessens the incidence of residual regurgitation. Simple vegetectomy and patch repair of the residual defect offers the best outcome. However, this technique also requires meticulous excision of all infected tissue and a certain amount of surgical skill. In our series, two patients were taken up for surgical correction on a semi elective basis and had elevated inflammatory markers. These patients had residual regurgitation and had longer ICU stay. The limitation of our series was the small number of patients and no long term follow-up. To conclude, optimum medical management with appropriate antibiotics forms the first line of management of isolated tricuspid valve endocarditis before consideration of surgical intervention. Simple vegetectomy and patch repair of the residual defect offers simple and effective outcome in patients who are optimized medically. Asymptomatic mild to moderate tricuspid regurgitation in patients who had severe regurgitation preoperatively was well tolerated. However, this group of patients requires longer follow up to assess further progression of disease. The authors would like to thank the co-authors, teachers and colleagues who have contributed at various stages through the development of this publication. The project did not receive any funding. The study was approved by the ethical committee of ABVIMS and Dr RML Hospital, New Delhi (code: 550(86/2021)/IEC/ABVIMS/RMLH/698). The authors declare that there are no conflicts of interest."} +{"text": "Teeth were some of the first organs whose function was effectively restored by inert refilling materials that have become widely known to the general public; amalgams, polymeric resin composites, and gutta-percha are some such examples. These materials have brought incredible benefits to the health of millions of patients worldwide. In recent decades, there has been overwhelming progress in the dental material field. Even though dental diseases like caries and periodontitis are still extremely common in humans of all ages , many ofhttps://www.mdpi.com/journal/bioengineering/special_issues/dental_material; accessed on 5 December 2022), some interesting papers were published regarding the upgrading and functionalization of dental resin composites and pulp refilling materials with the incorporation of antibacterial compounds which would prevent secondary caries and root canal re-infections. Secondary caries is an overwhelming health problem that is responsible for the vast majority of failed tooth restorations [In a previous Special Issue of Bioengineering, edited by Prof. Roy George are currently the treatment of choice against irreversible dental pulpitis. The main problem associated with modern endodontics is that the tooth pulp is completely removed and deprived of its endogenous maintenance and mineralization capacity. In the absence of a functional dental pulp containing dentin-producing odontoblasts, the tooth is left with a much higher propensity to undergo fracture and secondary complications . The issPerhaps one of the most difficult remaining challenges in modern dentistry is the regeneration of a functional periodontal ligament (PDL) after the placement of a prosthetic dental implant. The PDL is a narrow strip of fibrous collagen-rich and highly vascularized connective tissue that connects the dental root with the surrounding alveolar bone, substantially cushioning mastication impacts. After a complete dental extraction, the empty alveolus is naturally refilled with compact bone, which is eventually used to screw the implant root pillar onto. However, because the implant stays bound in direct contact with the alveolar bone, the latter is inevitably subjected to a much higher mechanical load than it would be in normal teeth, usually causing marginal bone loss and risk of peri-implantitis in the long term . The accWe are witnessing ever-growing research activity in the fields of tissue engineering and bioactive materials for dentistry applications. Contrary to last-generation dental materials, which were largely chosen because of their inert nature and lack of adverse reactions, next-generation dental materials will be expected to exert true biological effects in the surrounding oral and dental tissues to promote better and more functional integration."} +{"text": "Social cognition refers to a complex set of mental abilities that support the construction of adequate social competence and adaptation. Impairments in social cognition can be found in several psychiatric disorders, particularly in psychoses. Polygenic Risk Scores (PRSs) represent single metrics of molecular genetic risk and are a predictor of the genetic susceptibility to diseases, although they explain only a small part of the risk.To explore the association between PRS for psychiatric disorders and social cognition.We conducted a systematic search in PubMed and Scopus according to the PRISMA guidelines up to August 2021. We included papers evaluating PRS and social cognition with psychometric scales. Articles concerning single-nucleotide polymorphisms and biological measures of social cognition were excluded.We initially retrieved 150 articles. After removing duplicates, we screened 133 titles and abstracts and preliminary selected 19 papers. Participants recruited in the papers of interest were either people with schizophrenia, ASD or ADHD, their family members or healthy subjects. Articles evaluated the association between different psychometrical measures of social cognition and PRS for schizophrenia, Autism Spectrum Disorder and ADHD.Literature regarding the association between PRS for psychiatric disorders and social cognition is heterogeneous in terms of populations, genetic risk evaluation, and outcome tools. Given the critical role played by social cognition in the onset and progression of mental disorders and its association with real-world functioning, future research should try to disentangle the complex genetic basis of this domain.No significant relationships."} +{"text": "Evidence has been steadily increasing about the benefit of social connectedness for healthy aging. Yet, thanks to the complexity of human social interactions, it remains difficult to pinpoint specific benefits and mechanisms by which such benefits emerge. We offer this symposium to address this issue by presenting new findings from ongoing work at Indiana University in collaboration with the Indiana Alzheimer\u2019s Disease Research Center. First, an overview of recent literature will be presented alongside a brief introduction to egocentric network analysis and its utility in probing social determinants of health. Next, we turn our attention to characteristics of social networks and their importance for cognitive health in later life. Different types of social enrichment will be evaluated in terms of their respective influence on cognitive reserve . Additional attention will be paid to the comparison of emotionally supportive and more informationally supportive ties as promoters of brain health. Then, the final talks will describe potential avenues for increasing social connectedness in older adulthood. Individual differences in social cognitive function, namely Theory of Mind , has been implicated as mechanism by which older adults can maintain larger networks with more weak ties, in turn, promoting cognitive function. Separately, the presence of ambivalent ties may serve as a window of opportunity whereby older adults can leverage strengths in emotion regulation to maintain these ties without negative health consequences."} +{"text": "Psychopathological symptoms and cognitive impairment are core features of patients with psychotic disorders. Executive dysfunctions are within the most commonly observed deficits and the Wisconsin Card Sorting Test (WCST) is the test most extensively used for their assessment. Yet, the structure of executive deficits remains unclear, as there may be different underlying processes.The study\u2019s aims were to explore and compare the network structure of the WCST measures in psychosis and their unaffected siblings.Subjects were 298 patients with a DSM 5 diagnosis of psychotic disorder and 89 of their healthy siblings. The dimensionality and network structure of the 13 WCST measures were examined by means of the Exploratory Graph Analysis (EGA) and centrality parameters.The WCST network structure comprised 4 dimensions: Perseveration (PER), Inefficient sorting (IS), Failure to maintain set (FMS) and Learning (LNG). Patient and sibling groups showed a similar network structure and in both cases the network structure was reliably estimated.Perseveration measures reflect the inability to switch sorting rules when necessary. Scores for the IS dimension can occur when the subject ineffectively tries to test different sorting hypotheses, changing at random the response. FMS reflects the subject\u2019s strategy when he/she is able to find out the sorting rule, but is unable to keep applying that rule long enough. LNG comprised conceptual ability and learning items. The lack of significant difference between network structures is in keeping with results from exploratory and confirmatory studies demonstrating an invariant cognitive factor structure between schizophrenia patients and their unaffected siblings."} +{"text": "Secure forensic mental health services have a dual role, to treat mental illness and reduce violent recidivism. Those admitted to secure forensic services have a significant history of violence and treatment needs in multiple domains including psychiatric illness, violence and other areas such as substance misuse and physical health.The aim of this study was to ascertain if the units in a medium secure forensic hospital are stratified according to individual risks and needs. We also aimed to clarify if there were differences in the symptom level, risks and needs of those with and without community leave and to clarify the risks and needs of the female patients and ID patients.This is a cross sectional study a cohort of patients (n=138) in a secure forensic hospital.There was a total of 138 patients, the majority of whom were male . The most common diagnosis was schizophrenia . Placements in the care pathway of the medium secure forensic hospital were associated with level of symptomatology (PANSS positive), dynamic violence risk , DUNDRUM-3 therapeutic programme completion , and DUNDRUM 4 recovery . Patients with community leave had better scores than those without leave on violence risk , therapeutic programme completion and recovery .Stratifying secure forensic psychiatric hospitals according to individual risks and needs provides in-patient care in the least restrictive setting appropriate for individuals, however niche groups such as female forensic patients and ID patients may need special consideration."} +{"text": "Partnerships between food prescription programs and food banks can address food insecurity and support health; however, few studies have examined the experience and perceptions of health care partners about these programs. Our objective was to analyze secondary qualitative data from clinicians and clinic staff involved in implementing a food prescription program in Houston, Texas. We collected data from 17 health care clinics from May 2018 through March 2021 to learn how implementation of the food prescription program was perceived, and we received 252 responses. Principal themes were the importance of a value-based care strategy, patient and food pantry barriers to success, the importance of interorganizational care coordination, and the need to integrate food prescriptions into clinic workflow. Insights of clinicians and clinic staff on implementation of food prescription programs can inform program development and dissemination. Food prescription programs are increasing rapidly nationwide through health care clinic\u2013community partnerships to reduce household food insecurity and improve health outcomes.We surveyed clinicians and clinic staff in several diverse health care clinics about their experience with a food prescription program that involved collaboration between clinics and food banks. Careful planning of collaboration among clinics, food banks, and food prescription programs could promote patient participation to improve health outcomes and reduce food insecurity. Collaboration will require thoughtful care coordination, communication, data sharing, and education.Food insecurity affects approximately 10.5% of households in the US, 13.1% in Texas, and 16.3% in the Greater Houston area and is sWe conducted a retrospective secondary analysis of the data HFB collected from May 2018 through March 2021. Electronic surveys were sent by HFB to all clinic staff in 21 participating clinics involved in implementing HFB\u2019s food prescription program, HFB Food Rx; 17 responded (81% response rate at the clinic level) . A conveThis study was part of a parent study to assess the clinical impact of the HFB food prescription program. The study was approved by The University of Texas Health Committee for Protection of Human Subjects.We identified 4 broad areas of experience and perception among survey respondents . The firThe perspectives of clinicians and clinic staff in collaborative food prescription programs are critical to understanding program shortcomings and guiding implementation and dissemination design to improve participation and drive overall program success. A consistent theme that emerged from our survey was the perception that a food prescription program is an effective value-based care strategy to address social determinants of health, indicating a positive shift of clinicians\u2019 thinking toward offering such programs as part of the standard of care for patients who are food insecure and struggling with diet-related diseases. A recent systematic review and meta-analysis demonstrChallenges identified by participating clinic staff for program success included the variability of fresh food availability at the food pantry. Although food quality is important to food banks, a recent qualitative study of food bank leadership found that maintaining sufficient stocks of a variety of fresh produce and refrigerated items poses a challenge for food pantries that historically provided only shelf-stable foods . This chAdditionally, respondents emphasized the importance of interorganizational care coordination, which was reported in prior qualitative research on clinician perspectives on food bank\u2013food prescription partnerships . CurrentFinally, we identified clinic workflow integration and use of quality metrics around food prescription programs as important predictors of implementation success. These 2 processes involve developing and training clinic staff in detailed clinic workflow on who will be screened for food insecurity and how, what the clinic response will be to a positive screen , and potentially integrating food prescriptions into regular patient care for food-insecure patients. Other studies have reported barriers to program implementation resulting from poor workflow integration, including lack of consistent screening for food insecurity resulting from time constraints and inadequate training of clinic staff ,13. FurtClinicians noted the importance of maintaining communication with patients during the COVID-19 pandemic. In the initial phase of the pandemic, issues related to the food supply chain and unemployment increased rates of food insecurity , and locOur study had limitations related to the evaluation of clinician feedback. We used a convenience sample rather than a random sample, which may have resulted in selection bias. The time point of survey administration varied across different clinics, and our evaluation approach was not guided by a validated framework, which could strengthen future studies. However, our scaled evaluation across 21 health care organizations of various types, and a high response rate at the clinic level with a wide range of clinic respondents, provided important feedback related to produce prescription implementation with strong external validity.In conclusion, our study reports perspectives of clinicians and clinic staff in diverse health care settings on the benefits of food prescription programs for patients, as well as challenges and facilitators to program implementation. Food prescription programs are gaining popularity nationwide, and our study provides insight into successful implementation of such programs. Future studies should incorporate a mixed-methods approach guided by a validated framework to obtain regular input from implementation partners."} +{"text": "Following the publication of the original article , the autThe correct title should read: \"Adverse childhood experiences among adults with eating disorders: comparison to a nationally representative sample and identification of trauma profiles\".The correct title has been captured both in this Correction and the original article, which has now been revised."} +{"text": "There is some evidence that intrauterine manipulation may result in retrograde seeding of the peritoneal cavity with cancer cells,3 and a recently published retrospective trial analyzing 2661 patients showed an association of the use of intrauterine manipulators with higher recurrence rates and worse survival in endometrial cancer.4 This study aimed to analyze the association of intrauterine manipulation, peritoneal cytology, and oncologic outcomes for endometrial cancer patients.Endometrial cancer, the most common gynecologic tumor in developed countries, has a generally favorable prognosis, with an overall 5-year survival rate of 80%. Its primary treatment consists of surgery including total hysterectomy and bilateral salpingo-oophorectomy as well as nodal staging if indicated.5 Three different sets of peritoneal washings were obtained: at the beginning of the surgical procedure, after insertion of the intrauterine manipulator, and after closure of the vaginal vault. Peritoneal cytology was negative for 98 patients and positive at the beginning of the surgery for 16 patients. During the procedure, 10 patients had a positive cytology conversion. The results showed a strong correlation of recurrence rate with peritoneal cytology, and the patients with converted peritoneal cytology presented with the worst oncologic outcomes. The findings suggest that the use of intrauterine manipulators may lead to a positive peritoneal cytology conversion, which in turn would enhance the recurrence rate. This study supplies crucial knowledge for understanding the impact of the use of intrauterine manipulators on oncologic outcomes for endometrial cancer patients and provides further evidence to fill the remaining gaps between uterine manipulation, peritoneal cytology, and recurrence in endometrial cancer.This multicenter prospective trial included 124 endometrial cancer patients undergoing laparoscopic staging surgery with the use of an intrauterine manipulator.2 However, these trials did not report on the use of uterine manipulators. Because no data exist to prove that the use of uterine devices reduces surgical complications, and because current evidence shows a safe possibility of performing hysterectomy without the use of intrauterine manipulators, clinicians should consider abandoning intrauterine manipulators in surgery for endometrial cancer. However, larger prospective clinical trials including a control group that has surgery without an intrauterine manipulator are needed to confirm the results of this study.Minimally invasive surgery certainly remains the standard of care in endometrial cancer treatment after the results of prospective randomized trials proving its oncologic safety."} +{"text": "The impact of living with palliative care needs arising from COPD disrupts an individual\u2019s existential situation. However, no comprehensive synthesis of existing research has been published to determine the presentation and impact of existential suffering.To provide a synthesis of existing evidence on existential suffering for those living with palliative care needs arising from COPD.This is an integrative review paper, undertaken using the methodological approach developed by Soares and reported in accordance with PRISMA guidelines. Data analysis was undertaking using an integrated convergent synthesis approach.Nine electronic databases were searched from April 2019 to December 2019. A second search was undertaken in January 2021 to identify recently published papers meeting the inclusion and exclusion criteria. No date restrictions were imposed. Only papers published in the English Language were considered for inclusion. Empirical research papers employing qualitative and/or quantitative methodologies and systematic literature reviews were included. Articles were accepted for inclusion if they discussed any component of existential suffering when living with COPD and palliative care needs.Thirty-five papers were included within this review comprising of seven systematic reviews, 10 quantitative studies and 18 qualitative studies. The following themes relating to existential suffering were found: Liminality, Lamented Life, Loss of Personal Liberty, Life meaning and Existential isolation. The absence of life meaning, and purpose was of most importance to participants.This review suggests existential suffering is present and of significant impact within the daily lives of those living with palliative care needs arising from COPD. The absence of life meaning has the most significant impact. Further research is required to understand the essential components of an intervention to address existential suffering for this patient group, to ensure holistic palliative care delivery. What is already known about the topic?When living with palliative care needs arising from COPD, an individual\u2019s existential situation is disrupted, often resulting in existential suffering.Much of global COPD palliative care policy is based upon the management of physical symptoms and not on existential problems, despite the negative impact existential suffering has upon quality of life.What this paper adds?Patients living with palliative care needs arising from COPD experience existential suffering across many elements of their daily lives.Existential suffering is manifest in feelings of living in liminal space, a loss of personal liberty, isolation from social and family relationships alongside beliefs of life ceasing to exist.Identification of the limited literature available about the presence and absence of life meaning when living with palliative care needs arising from COPD and how these impact upon daily life.Implications for practice, theory or policy:The need for a conceptual framework to guide patient care in COPD and address existential well being has been identified.This review highlights potential areas of concern in the daily lives of those living with palliative care needs arising from COPD, giving clinicians the knowledge to explore these when undertaking patient assessment.2 with predictions of it becoming the third biggest cause of death worldwide by 2030. Over 90% of COPD related deaths occur in low to middle income countries, with the condition receiving little interest and financial support when compared to other causes of international morbidity and mortality. This results in increasing challenges to the delivery of holistic and patient-centred palliative care.There are an estimated 328\u2009million people living with COPD globally,57 Timely and consistent transitions to palliative care remain absent, and although models of palliative care for patients with COPD are well-evidenced, they are largely focussed upon the relief of physical symptoms.911Whilst the physical symptoms of COPD can be severely debilitating, the impact of COPD extends beyond physical symptoms, disrupting an individual\u2019s existential situation. The aim of this integrative review is to provide a synthesis of existing evidence on existential suffering for those living with palliative care needs arising from COPD, and explore its significance within, and impact upon, day to day life. results in a reactive approach to COPD exacerbation management,16 rather than the delivery of active treatment and palliative care concurrently.The unpredictable disease trajectory of COPD causes delays in commencing palliative care. Limited understanding of the COPD disease trajectory among healthcare professionals, Existential disruption occurs when the importance and purpose within life becomes unidentifiable, resulting in existential suffering. In the context of its emotional effects, existential suffering leads to feelings of fear, guilt and a lack of self-worth,1719 exacerbated by the associated meanings attached to these symptoms. If unaddressed, disruption to an individual\u2019s existential situation results in them feeling incomplete and lacking a sense of peace.20 Existential suffering often remains undisclosed by individuals, in an attempt to maintain personal integrity and some state of normality,21 yet the deep-rooted effect of this experience manifests as an inability to live a fulfilling life. Existing literature demonstrates that existential suffering is one reason why patients may wish to end their lives.23 Understandings of individuals\u2019 existential situations within COPD are limited in the research literature and are rarely addressed within clinical practice, yet existential suffering has been linked to poor health-related quality of life for those living with other chronic conditions.26Conceptually, existentialism explores the human existence, and focuses upon lived experiences through thoughts, feelings and actions. Existentialism describes how our existence constructs meaning about what is important and has purpose within our daily lives. Some individuals, despite the daily overwhelming symptom burden, remain unwilling to discuss death and dying and redirect their hopes and desires elsewhere in search of stability and normality.2730 This coping mechanism, often grown from feelings of guilt and shame, inhibits future care planning.When those living with COPD are nearing the end of life, associated physical and mental symptoms preoccupy them.32The need for interventions designed to address elements of existential suffering in COPD is evident. People with other chronic illnesses with similar symptoms to COPD have also been found to experience existential suffering. Interventions focussed upon alleviating elements of existential suffering have been reported as effective in patients living with cancer, heart failure and chronic kidney disease, with participants reporting a greater sense of well-being and inner peace. and inconsistent definitions as well as limitations of the evidence base present difficulties for healthcare providers in responding to this patient need.23Within the wider palliative care literature, existential suffering remains under researched with an absence of evidence-based tools and interventions to assess, plan care and facilitate the alleviation of symptoms. Existential suffering is a complex and individualised conceptDespite the exploration of elements contributing to, and impact of existential suffering in day-to-day life in COPD, no synthesis of the literature exists. Understanding the degree of impact of existential suffering for those living with palliative care needs arising from COPD will allow healthcare professionals to explore the necessary components of assessment, care planning and intervention content to enhance palliative care delivery. The aim of this integrative review is to provide a synthesis of existing evidence on existential suffering for those living with palliative care needs arising from COPD, and explore its significance within, and impact upon, day to day life. to allow for the merging of findings from differing data types, to develop an inclusive understanding of a particular topic. Using this interpretivist approach allowed the development of an understanding of how the phenomenon of existential suffering is present within the daily lives of those living with COPD. Insights into the deep meanings of individuals experiences were able, with consideration given to differing cultures, circumstances and social realities. The review was reported in accordance with PRISMA guidelines.This is an integrative review paper, following methodological approaches developed by Soares et al.,A pre-defined keyword search of the following nine electronic databases was performed in March to December 2019: Web of Science Core Collection, CINAHL, Cochrane Systematic Review Database, EThos \u2013 Thesis database, PsychINFO, SCOPUS, PROSPERO, ASSIA and Google Scholar. A second search was undertaking in January 2021 to identify any further published papers meeting the study inclusion criteria. No new papers were identified. The search terms used are displayed within The COPD and existential suffering search terms were searched initially as individual lists using the \u2018OR\u2019 function to focus the search by connecting similar concepts, as demonstrated in A total of 68,427 citations were identified for title and abstract screening. The large number of initial search results came due to the use of broad terms such as \u2018respiratory disease\u2019, \u2018pulmonary disease\u2019 and \u2018respiratory conditions\u2019 which identified papers not related to COPD but other respiratory conditions. These terms were necessary for inclusion as they did produce some relevant results that would have otherwise been missed. Weekly database searches were undertaken until December 2019 and a final search in January 2021. No date restrictions were placed upon the searches.The study inclusion and exclusion criteria are provided in The study selection process is displayed within Data from each study were extracted to identify study characteristics and establish study quality. A data extraction tool, developed for this review, allowed organisation of study information including study aims, study design, sample selection, data collection, data analysis and findings. The qualitative data analysis software QUIRKOS was used to store and organise the data into themes. The initial analysis was completed by the lead author. The second and third authors reviewed the themes for accuracy and representation of the initial data prior to confirmation.Data analysis was undertaken using integrated convergent synthesis to develop themes relevant to the review aims. This involved the identification of themes from the data presented in qualitative and quantitative studies separately, followed by identification of meta-themes across all study types. The approach allowed for little consideration to be given to the methodological approaches of each included paper, allowing for integration and synthesis of study findings based upon their focus all being upon the same concept.38 Therefore, quality assessment tools specific to each study type were adopted, to evaluate the specific methodological features of each included study,37 The following quality assessment tools were used; Critical Skills Appraisal Programme Checklist for Qualitative Research, Checklist for Quasi-Experimental Studies (The Joanna Briggs Institute) and for mixed method-studies both tools were used for relevant study components. The quality assessment determined the methodological rigour of each included study alongside the risk of bias. Studies of poor methodological rigour carried less weight within the review analysis but were not excluded.Data evaluation and quality assessment within an integrative review is a complex process lacking clear guidance.4146 10 quantitative studies4756 and 18 qualitative studies285770 were included. Study characteristics and a summary are provided in A total of 35 papers comprising seven systematic reviews,The studies explored a range of issues relating to COPD, all directly or indirectly related to existential suffering. Five themes were identified : A systematic integrative literature review by Louise Elizabeth Bolton, Jane Seymour and Clare Gardiner in Palliative Medicine"} +{"text": "Reproductive physiology and breeding have fascinated scientist since ancient times, and it is not surprising that explorations in these fields are included among the oldest and most well-documented branches of veterinary medicine . Crop prKoz\u0142owska and collaborators provided a new ultrasonography-based method to monitor the semen quality of rams and thus maximize fertility by comparing the parameters of basic and advanced semen evaluation tests and testicular blood flow dynamics [Papers accepted for this Special Issue cover distinct aspects of the reproductive sphere. Considering food-producing species, dynamics . Wojtysiak and collaborators provided insights into post-breeding-induced endometritis in the mare, by determining the secretion of anti-inflammatory cytokines and acute-phase proteins in the uterus before and after artificial insemination [In the context of new diagnostic supports, serum amyloid A is an acute phase protein that recently gained visibility also in reproduction medicine and two manuscripts of this Special Issue cover the subject. mination . As acadmination . This prHinderer and collaborators investigated canine progesterone concentrations during pregnancy and challenged widespread beliefs in the context of hypoluteoidism and progesterone supplementation [Rodrigues da Rosa Filho and collaborators analyzed the effects of two different medical interventions based on aglepristone alone or in combination with prostaglandin in the course of canine pyometra on clinical, laboratory and uterine hemodynamic features [Dziecio\u0142 and collaborators presented an observational study on the influence of NSAID drugs on female fertility, monitoring corpora lutea function during the periovulatory phase in the domestic dog [The remaining papers cover aspects of canine reproductive medicine. Sub-optimal serum progesterone levels have frequently been linked to pregnancy loss or early parturition, without any scientific evidence to support those claims. In their paper, entation . Pyometrfeatures . Finallystic dog .In this Special Issue, we collected contributions by researchers from different countries that provide novel insights about diagnostic approaches for different reproductive disease in domestic species. We are sincerely grateful to all the reviewers who took time to carefully read the submitted manuscripts and provide critical comments which helped to maintain the quality of this issue."} +{"text": "With the proven relationship between oral and general health and the growing aging population, it is pivotal to provide accessible therapeutic approaches to regenerate oral tissues and restore clinical function. However, despite sharing many core concepts with medicine, dentistry has fallen behind the progress in precision medicine and regenerative treatments. Stem cell therapies are a promising avenue for tissue regeneration, however, ethical, safety and cost issues may limit their clinical use. With the significance of paracrine signalling in stem cell and tissue regeneration, extracellular space comprising of the cell secretome, and the extracellular matrix can serve as a potent source for tissue regeneration. Extravesicles are secreted and naturally occurring vesicles with biologically active cargo that can be harvested from the extracellular space. These vesicles have shown great potential as disease biomarkers and can be used in regenerative medicine. As a cell free therapy, secretome and extracellular vesicles can be stored and transferred easily and pose less ethical and safety risks in clinical application. Since there are currently many reviews on the secretome and the biogenesis, characterization and function of extracellular vesicles, here we look at the therapeutic potential of extracellular space to drive oral tissue regeneration and the current state of the field in comparison to regenerative medicine. Medicine is rapidly advancing towards precision therapy, using the latest advancements in biotechnology to provide patient-tailored treatments. In dentistry the emphasis has been placed more on enhancing the quality and aesthetics of dental fillings or impression materials and use of digital technology for diagnosis and rapid chair side treatments. With the growing aging population and the predicted increased number of people aged 65 and over by 2050, the need for a more accessible, efficient and targeted dental treatment is more palpable to regenerate dental tissues and restore clinical function .Functional tooth is comprised of innervated and vascularized dental pulp encased by dentin, cementum, and the harder enamel as the external protective layer. Periodontal or tooth supporting tissue consists of periodontal ligament, gingiva and alveolar bone. Dental caries and trauma often require restoration of the tooth by placement of filling material in the crown or endodontic therapy, to remove and replace dental pulp. Inflammation of tooth supporting tissue results in periodontitis, loss of alveolar bone, tooth mobility and ultimately tooth loss. Conventional treatment replaces the missing tooth with removable dentures, fixed restoration such as crown, bridges, or placement of an implant. All of which aim to replace a biological tissue with metal prosthesis.Regenerative dentistry aims to replace conventional dental treatments with biologically driven approaches to induce repair of the diseased tissue, reduce inflammation and eliminate scarring. These therapies aim to be minimally invasive and can involve local delivery of active molecules into the region of interest to stimulate tissue regeneration. Regenerative approaches may be relatively easy for some dental tissues such as dental pulp since dental pulp cells can be grown and maintained in culture and subsequently applied in regenerative endodontics . Similarin vivo . These cells have the advantage of enhanced regenerative ability and good accessibility. DMSC can be harvested from multiple sites in the oral cavity such as Dental pulp stem cells, exfoliated deciduous tooth stem cells, apical dental papilla stem cells, periodontal ligament stem cells, dental follicle stem cells, gingiva derived mesenchymal stem cells and tooth germ progenitor cells . SimilarThe promising results of EVs and their benefit over cell-based therapeutic approaches has resulted in them being tested in clinical settings and their clinical safety being approved . As a ceDespite these advantages, the role of EVs as sole therapy still requires further investigation. Identification of the active molecule that exerts the biological function in EVs is extremely challenging. Sensitivity of mass spectrometers should be able to cover the range of low abundance proteins over highly abundant proteins in the secretome and EVs to better characterize them . The purTo bypass some of the limitations of natural occurring EVs and avoid some of the mentioned inconsistencies, EVs can be bioengineered and enriched with favourable factors resulting in enhanced yield and better isolation but the full impact of these modifications on target cells needs to be investigated in detail . In clinMajority of currently running EV clinical trials are aimed to monitor circulating EV as biomarkers, disease progression and cancer diagnosis and very few are addressing tissue repair and regeneration. With the proven link between the oral and general health, designing preclinical studies and clinical trials that aim to improve oral health using regenerative approaches is important. The great advantage of cell free approaches over cell-based therapies, makes secretome and EV a very attractive tool for regenerative treatment. Much work must be done to uncover the full potential of secretomics in oral health and to then develop standards for reproducibility, clinical transition and accessibility for public."} +{"text": "The field of animal welfare science studies the well-being of animals, including an animal\u2019s physical and emotional state. Previous studies have investigated veterinary students\u2019 perceptions of animal welfare, although few studies have focused on animal science students\u2019 perceptions of the topic. The aim of this study was to determine if animal science students\u2019 perceptions of animal welfare differed across a multitude of animal categories, including agricultural animals, cats and dogs, horses and other equids, research animals, and wildlife. Results indicate that most survey respondents agreed that animal welfare was important for all animal categories. In qualitative analyses of the open-ended survey questions, basic needs and human interaction were identified by respondents as key welfare components for all animal categories; however, the frequency with which identified welfare themes was mentioned differed by category. Results also highlighted perception differences within different agricultural animal species; fewer respondents agreed that poultry and swine are raised with an appropriate level of welfare compared to dairy and beef cattle. Understanding animal science students\u2019 perceptions of animal welfare may lead to a greater understanding of how they will assess and manage animal welfare issues as part of their future careers in the agricultural and animal-related sectors.p < 0.0001), e.g., fewer respondents indicated having positive interactions with humans was important for agricultural animals. In a subset of questions about agricultural animals, fewer respondents agreed that swine and poultry are raised with an appropriate level of welfare compared to dairy and beef cattle . Four free-response questions asked respondents to report their general perceptions of welfare. Thematic analysis identified multiple themes, such as basic needs and human interaction, with most responses (75%) including two or more themes.Animal welfare is an increasingly important topic across multiple academic disciplines; however, few studies have investigated student perceptions of animal welfare outside of veterinary medicine. The objective of the study was to evaluate animal science students\u2019 perceptions of animal welfare to determine if perceptions differ across animal categories. An online survey was distributed to animal science programs at institutions across the United States. Quantitative and qualitative analyses were performed on 624 responses. Almost all respondents agreed welfare was important for all animal categories (\u226597%). The survey asked respondents to rate the level of importance of 12 welfare parameters and there was evidence that the level of importance differed by animal category ( Blackfish provide an appropriate level of animal welfare.\u201d These findings align with several survey studies that have found overall perceptions of food and/or fiber animal welfare are generally positive, particularly regarding standard production practices for beef and dairy animals (veterinary faculty, ; animal While animal welfare is an important topic that has widespread impacts, including influencing animal usage laws and impacting consumers\u2019 purchasing decisions, public perceptions of animal welfare are complex and understudied. Perceptions of animal welfare have been shown to vary between species and between production system types, congruent with the findings in the current study. Understanding animal science students\u2019 perceptions of animal welfare is particularly important, both because many animal science programs lack formal animal welfare education components and because animal science students will potentially work in the agricultural and animal sectors, managing animal welfare issues as part of their careers. In general, the results of this survey suggest most respondents agree that animal welfare is important for all species, but clear perception differences emerged between animal categories when asked about specific welfare needs. The provision of basic needs and human interaction was recognized as a necessity of welfare across animal categories, although the frequency of and nature of mention was less frequent in agricultural animals. Future research should explore how these differences in perception of welfare across animal categories impact welfare assessments and the adoption of new management practices and interventions."} +{"text": "The role of diet in cancer management is gaining more attention and multiple studies suggest nutritional interventions to augment conventional anticancer therapies. Mediterranean diet is one of the healthful dietary patterns. It is composed of many types of foods and drinks rich in antioxidant and biologically active ingredients. This special issue provides new details for researchers, patients, nutritional specialists, and oncologists about the possible role of Mediterranean diet in cancer management.Azzeh et al.(a). In this case-control study, researchers concluded that consumption of a diet rich in fruits and vegetables, fish, legumes, black tea, coffee, and low dairy products can significantly reduce the risk of breast cancer [Azzeh et al.(b)]. Spices used in Mediterranean diet were reviewed by Talib et al.. The study showed that black pepper (Piper nigrum L.) is the most common spice used in Mediterranean diet. Giger and black cumin were the most active against cancer and apoptosis induction is the most common anticancer mechanism activated by Mediterranean diet spices . The chemoprevention effect of the Mediterranean diet on colorectal cancer was also investigated by Mahmod et al.. Researchers concluded that components in the Mediterranean diet can reduce the risk of colorectal cancer by reducing inflammation and inhibiting the attachment of pathogenic microbes .Consumption of Mediterranean diet is associated with low incidence of breast cancer as shown by Al-Ataby and Talib showed that daily consumption of lemon and ginger herbal infusion inhibited breast cancer in mice. Phytochemicals in this herbal infusion exhibited high capacity to induce apoptosis, inhibit angiogenesis, and stimulate the immune system . Barley bran grown in Jordan was evaluated by Abuarab and Talib. Results showed anticancer and immunomodulatory effects of barley bran and supported its use as prophylactic agent against cancer . Aqueous extract of Elaeagnus angustifolia flowers inhibited triple-negative breast cancer cells by apoptosis induction as indicted by Fouzat et al.. The anticancer activity of this plant involved activation of P53 and signal transducer and activator of transcription 3 signaling pathways .The use of alternative and herbal medicine is increasing among cancer patients. Patients depend on consuming selected herbal infusions or foods containing plant extracts to fight cancer . Al-AtabGamal-Eldeen et al. showed that the polysaccharide extract of Sargassum dentifolium reduce drug resistance in tongue squamous cell carcinoma by reducing hypoxia.Quercus brantii leaves .Gaz-alafi is a local sweet produced mainly in the north of Iraq and west of Iran. Its composition includes secretions from insects and plant products produced from the infected i leaves . Al SafiJawarneh and Talib concluded that a combination of Ashwagandha (Withania somnifera) root extract and intermittent fasting acts synergistically to overcome cisplatin drug resistance in breast cancer.The special issue also discussed the role of intermittent fasting combined with plant extracts to overcome drug resistance. Intermittent fasting is a type of a calorie restriction and involves fasting for 16\u201348 h. Such fasting stimulates multiple anticancer mechanisms and cause cancer regression . JawarneOverall, articles included in this issue present a comprehensive scientific contribution to support the use of components in the Mediterranean diet as anticancer nutritional interventions. The special issue also presents the successful use of Mediterranean diet in different combinations to inhibit cancer and reduce drug resistance.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Cluster B personality disorders are characterized by a higher prevalence of suicidal ideation and behavior than others, and Narcissistic Personality Disorder is no different. Very intense feelings of shame, intolerable for the individual, are often found in patients with Narcissistic Personality Disorder and may have a role in suicidal behavior.To offer preliminary empirical evidences concerning the relationship between narcissism, shame and suicide ideation.We administered Pathological Narcissism Inventory (PNI), Test of Self Conscious Affects (TOSCA) and Beck Scale for Suicidal Ideation (BSI) to a sample of individuals with Suicide ideation (n= 65) and a sample of community participants (n=65).Controlling for age and gender, in the merged sample we found that BSI scores correlated significantly with the vulnerable dimension of narcissism and with TOSCA Interpersonal Shame subscale. In the clinical sample, Interpersonal shame partially mediates the relationship between vulnerable narcissism and suicidal ideation.Shame seems to play a key role in the relationship between the vulnerable facet of narcissism and suicidal ideation, although the profound mechanism by which it works remains to be understood. Future directions and clinical implications are discussed."} +{"text": "COVID-19 caused an ongoing health emergency that rapidly spread worldwide, so all countries adopted exceptional health measures to reduce disease\u2019s transmission. The stress caused by pandemic presents increasing risks for family violence and for child abuses. Interinstitutional Equips of Abusive and Maltreatment (IEAM) deals with the management of abusive families in Palermo\u2019s territory. IEAM starts evaluations after the interventions of the court solicited by a complaint filed by teachers, law enforcements or members of the family. IEAM is formed by consultations in maternity ward, child welfare service and school educational psychologists.The purpose of this research was to evaluate the variations of child abuse and maltreatment reported during local and National lockdown due to pandemic. Reported cases were compared with the previous year.The authors collected data of IEAM\u2019s advisory from January 2019 until August 2021. The number of cases was evaluated monthly.We observed 124 cases in 2019, 145 in 2020 and 94 until August 2021. Advisory reductions coincided with the service activity reduction in August of every year and in March 2020 when Italy declared national lockdown. Social isolation represents a risk factor for child abuse. Although the increase of cases was quite stable, there are reasons to speculate that the reporting of child abuse and maltreatment decreased since home isolation hampered the access to responsible services.School closure together with the strong reduction of social care and monitoring during and after lockdown might have increased the domestic violence. Lastly, the child abuse may be underreported despite the effective increase.No significant relationships."} +{"text": "The COVID-19 pandemic has disproportionately affected nursing home residents and staff, including the nursing assistants who provide critical supports for older adults and people with disabilities. The pandemic has added significant strain to an already vulnerable nursing home workforce, which has historically experienced high levels of turnover, chronic staffing shortages, and high burnout. At the same time, it has generated awareness of the value of the direct care workforce to provide care in places for those most at risk from the disease. Job satisfaction of nursing assistants is as major driver of turnover and intent to leave the job. Research has demonstrated organizational supports and job stresses that are associated with job satisfaction and turnover. However, limited research has investigated the factors associated with job satisfaction in nursing homes during the COVID-19 pandemic. Using data from an employee engagement and management system, we examined organizational supports and work-related stresses associated with job satisfaction among nursing assistants in nursing homes (n=402). Higher quality of supervision, feeling appreciated for the job, and feeling safe and comfortable at work were associated with higher levels of job satisfaction. Work-related job stressors \u2013increased workload demands and understaffing \u2013 were associated with lower job satisfaction. Our findings provide insights into the importance of employer supports and reducing work-related stressors in nursing assistants\u2019 job satisfaction and practical implications for nursing home leadership regarding how to support workers"} +{"text": "Heavy metals pollution causes a threat to the aquatic environment and to its inhabitants when their concentrations exceed safe limits. Heavy metals cause toxicity in fish due to their non-biodegradable properties and their long persistence in the environment. This review investigated the effects of heavy metals on early development, growth and reproduction of fish. Fish embryos/larvae and each developmental stage of embryo respond differently to the intoxication and vary from species to species, types of metals and their mode of actions, concentration of heavy metals and their exposure time. Many of the heavy metals are considered as essential nutrient elements that positively improve the growth and feed utilization of fishes but upon crossing the maximum tolerable limit these metals cause not only a hazard to fish health but also to human consumers and the disruption of ecological systems. Reduced gonadosomatic index (GSI), fecundity, hatching rate, fertilization success, abnormal shape of reproductive organs, and finally failure of reproduction in fish have been attributed to heavy metal toxicity. In summary, this review sheds light on the manipulation of fish physiology by heavy metals and seeks to raise sensitivity to the prevention and control of aquatic environmental contamination, particularly from heavy metals. \u2022Heavy metals in water exceed the safe limits, causes toxicity in fish is a global concern.\u2022Describes the occurrences of heavy metals in water.\u2022Provides a general view on the effects of heavy metals on fish. Another study reported that embryo and larvae survival, hatching of Ide (Leuciscus idus) were significantly affected by Cd exposure and non-essential heavy metals Gambusia affinis) than Cd or temperature alone Toxicity levels of heavy metals in embryos and larvae of freshwater fish are different from marine fish because of salinity differences. At higher salinity levels, the bioavailability of the toxic forms of heavy metals in water decreases. Information is limited about the toxic effects of heavy metals on marine fish embryos and larvae. Low hatchability, high mortality, morphological abnormalities etc. are reported in embryos and larvae of marine fish exposed to different heavy metals Carassius auratus), these enzymatic activities were significantly inhibited due after exposure of high Cu concentration (1.0\u00a0mg/L), causing oxidative stress responsible for lipid peroxidation Oryzias latipes) induced significant DNA damage The mode of action of each heavy metal exposure in embryo and larvae are at early stage of investigation and gaining importance among the researchers investigating molecular mechanisms of their effects in fish. Superoxide dismutase (SOD) and catalase (CAT) enzymes are known to convert reactive oxygen species to non-toxic oxygen in the liver. It has been found that in embryos and larvae of goldfish , it is important to evaluate the combined effects of those heavy metals on embryonic and larval development. The combined effect of Cu-Zn and Cd-Zn has been investigated in Rainbow trout Cyprinus carpio) exposed to mixture of Zn and Cd increased the ontogenic development and quality and quantity of the larvae through the improvement of immune system Rhamdia quelenSupplementation of vitamin C with the dry feed to the embryo and larvae of common carp upto 4\u00a0mg/kg but greater concentrations resulted in lower growth with higher micronucleus frequencies (Nutritional adequacy is prerequisite sustainable aquaculture. The overall growth, health status and reproductive performances of various aquaculture species especially fish are dependant on appropriate nutrition quencies [10]. On4Carassius gibelioOdontesthes bonariensisOryzias melastigmaClarias magurReproduction is essential to all animals and successful reproductive performance among the most important determinants of survival at the species level 5Heavy metals contamination is a serious threat to entire aquatic ecosystems including associated flora and fauna. The devastating impacts of heavy metals on aquatic organisms specifically fish result an irreparable loss in aquaculture industry. In this review, destructive effects of heavy metals on fish focusing the embryonic and larval development, growth and reproduction of commercially important species are discussed very concisely with a view to using it as a tool for further genotoxicity related experiments by the researchers of the associated areas. Heavy metals resulted in severe deformities in several aquatic organisms that will ultimately pose a substantial threat to associated consumers. To enlarge the sustainability of the aquaculture sector and to produce safe fish for human consumption, regular monitoring of the fish and associated environment should be done by the appropriate authorities at the local government, state, and national levels. A well-established framework should be developed as soon as possible to mitigate this great problem.Khanam Taslima: preparation of the first draft of the manuscript. Md Al-Emran, Mohammad Shadiqur Rahman, Jabed Hasan, Zannatul Ferdous and Md Fazle Rohani: data collection and preparation of the Tables. Md Shahjahan: conceptualization, edited the manuscript and final approval. All authors have read the final version and approved the manuscript.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper."} +{"text": "Maintaining sexuality is important to the well-being of women, particularly after menopause and benefits of sexual satisfaction in terms of emotional well-being and quality of life have been well demonstrated.This study aims to assess the sexual health behaviors in Tunisian women during and after menopause and the awareness of Tunisian partners about the role of the quality of their sexuality regarding their physical and psychological wellbeing.We comprehensively review the scientific literature using Pubmed database to state Tunisian literature regarding sexual behaviors and function in women during and after menopause. Interviews with twenty Tunisian women after menopause about sexual health have been conducted.Our bibliographic research revealed a poor literature with only two papers responding to our inquiry but among a specific female population investigated after experiencing breast cancer \u201cFemale sexuality in premenopausal patients with breast cancer on endocrine therapy and sexuality after breast cancer: cultural specificities of Tunisian population\u201d. Interrogated women reported a poor sexual satisfaction as well as sexual difficulties in the partner or with him. In fact, there is an important wrong understanding of the female anatomy and physiology by both partners, for the female sexual satisfaction. There is also many wrong cultural ideas about menopause and sexuality.Currently, sexuality in Tunisian women during and after menopause is influenced by ageing, by previous sexual function and experiences, the male domination in partner\u2019s sexual practices and the sexual functioning in the partner. In general, there is an unfavorable body image and disturbed sexual health.No significant relationships."} +{"text": "Tendency to experience inaccurate beliefs alongside perceptual anomalies constitutes positive schizotypal traits in the general population and shows continuity with the positive symptoms of schizophrenia. It has been hypothesized that the positive symptomatology of schizophrenia, and by extension, positive schizotypy, are associated with specific alterations in memory functions. Imbalance between memory generalization and episodic memory specificity has been proposed on several counts; however, the direction of the imbalance is currently unclear.We aimed to contrast two competing hypotheses regarding the association between positive schizotypy, and memory alterations in a general population sample (N=71) enriched for positive schizotypy from a larger pool of individuals (N=614).Positive schizotypy was measured with the short-version of the O-LIFE questionnaire, and memory specificity and generalization was captured by the well-established Mnemonic Similarity Task.Distortions in the behavioural memory performance indices were found to correlate with positive schizotypy: individuals prone to unusual experiences demonstrated increased discrimination and reduced generalization . Associations were robust when controlled for the disorganized, negative and impulsive-asocial dimensions of schizotypy and associated psychopathology.Our findings show that people who are prone to irrational beliefs and unusual experiences also show measurable alterations in memory and likely have difficulty grasping the global picture and rather be overpowered by fragments of information.No significant relationships."} +{"text": "Occurrences of liver failure following jejunoileal bypass were extensively reported in the past and were one of the main factors that led to abandonment of this procedure. The newer predominantly malabsorptive procedures called biliopancreatic diversions (BPDs) have also been implicated in several cases of acute and subacute liver failure. The aim here was to review the current available evidence on occurrences of liver failure following BPDs. Narrative review; bariatric surgery service of a public university hospital. A review of the literature was conducted through an online search of medical databases. Associations between BPDs and liver failure have only infrequently been reported in the literature. However, they appear to be more than merely anecdotal. The pathophysiological mechanisms remain obscure, but they seem to be related to rapid weight loss, protein malnutrition, deficits of hepatotrophic factors, high circulating levels of free fatty acids and bacterial overgrowth in the bypassed bowel segments. Reversal of the BPD may ameliorate the liver impairment. Although infrequent, liver failure remains a concern following BPDs. Careful follow-up is required in individuals who undergo any BPD. Obesity has become a worldwide public health concern over recent decades. In 2014, according to the World Health Organization (WHO), more than 1.9 billion adults were at least overweight; of these, over 600 million were obese.The first bariatric procedures, which were described as early as in the 1950s, were jejunocolic and jejunoileal bypasses. Jejunoileal bypass was characterized as a bypass from the proximal jejunum to the distal ileum, with exclusion of the majority of the small bowel of the digestive tract. Despite its popularity from the 1950s to the 1970s, it was abandoned especially because of high rates of severe protein-calorie malnutrition and acute and subacute liver failure related to the procedure. However, the newer predominantly malabsorptive procedures called biliopancreatic diversions (BPDs) have also been implicated in several cases of acute and subacute liver failure.BPD mainly encompasses two different bariatric procedures: the Scopinaro operation and the duodenal switch procedure. The Scopinaro operation basically involves distal gastrectomy with a bypass from the remnant stomach to the distal ileum. The duodenal switch consists of resection of the gastric greater curvature and distal bypass from the duodenum to the ileum. The duodenal switch procedure is a modification of the original BPD and uses a longer common channel than the classic BPD. It was designed to improve gastric emptying and to decrease postoperative diarrhea and anastomotic ulceration. Both procedures are associated with high rates of resolution of type 2 diabetes. However, they are also associated with occurrences of protein-calorie malnutrition. Hence, although they are still performed today, they are not routinely the operations of choice in most centers.Regarding liver disease, BPDs are usually linked to major improvements in metabolic abnormalities relating to nonalcoholic fatty liver disease (NAFLD), especially insulin resistance, but at the same time, there has been a steady rate of occurrence of reports of acute and subacute liver failure following BPDs over the years.This study aimed to review the current available evidence on occurrences of liver failure following biliopancreatic diversions.A review of the literature was conducted through an online search for the MeSH terms \"liver failure\", \"biliopancreatic diversion\" and \"bariatric surgery\" in Medline (via PubMed); and the MeSH/DeCS terms \"liver failure\", \"biliopancreatic diversion\" and \"bariatric surgery\" in Lilacs (via Bireme) .After extensive online research, we identified three case reports and two case series on liver failure subsequent to the classical Scopinaro operation; and one case report and one case series of liver failure subsequent to the duodenal switch procedure. Additionally, we also researched population studies that addressed the evolution of liver disease after biliopancreatic diversions and identified two large cohort studies (one retrospective and other prospective) on liver impairment subsequent to the classical Scopinaro operation; and two retrospective cohorts on liver impairment subsequent to duodenal switch. We also excluded two case reports on liver failure after jejunoileal bypass: one case report on liver failure after biliointestinal bypass and one case series on liver failure after conversion of classical gastric bypass to distal bypass.The reports on liver failure requiring liver transplantation or leading to death following the Scopinaro operation are more than anecdotal. Although the rate of occurrence of liver failure appears to be non-significant in large cohort studies, there is enough evidence to consider that these occurrences in individuals who underwent this procedure are more than mere coincidence.,,Grimm et al.Despite the reports of liver failure, large population studies have not identified a significant frequency of occurrence of this complication. Scopinaro et al. conducted a classical retrospective analysis on 2,241 individuals who underwent their procedure and did not identify a single case of liver failure.Although the duodenal switch procedure has been more frequently performed than the Scopinaro operation, at least since the 2000s,The exact mechanisms that lead to liver failure following BPD and its current prevalence remain uncertain. Baltasar et al.,,The pathophysiological pathways potentially enrolled in development of liver failure following BPD appear to consist of early rapid weight loss, a degree of protein malnutrition, lack of hepatotrophic factors and the effect of high levels of mobilized circulating free fatty acids.,Even in individuals who do not develop liver failure, BPDs seem to promote a bimodal effect in liver function tests, with early worsening of liver injury, followed by normalization and improvement.Although very rare, liver failure remains a concern following BPDs. However, since the vast majority of the evidence available is from case reports, there is no evidence level sufficient to provide definite conclusions. Randomized trials comparing the different available bariatric techniques are needed in order to provide data of better quality. Nonetheless, despite the low frequency of occurrences of liver failure, such events are reported nowhere near as often following other, more frequently performed bariatric techniques. The exact mechanism that leads to this ominous complication remains to be determined, but it seems to be characterized by an acute-on-chronic failure that occurs in predisposed individuals who present previous liver impairment. Careful follow-up is required among individuals who undergo any BPD. Reversal of the procedure is warranted when early clinical or laboratory signs of liver failure appear. Despite the lack of specific evidence, it is reasonable to avoid this surgical technique among subjects who present to bariatric surgeons with any degree of significant liver function impairment."} +{"text": "Sexual minority individuals consistently report higher rates of mental disorders and suicidal behavior than heterosexuals. However, much of this research is limited to Anglo-Saxon studies and no information on Portuguese reality is available.The purpose of this study is to compare levels of mental functioning and suicidal behavior among heterosexual, bisexual, and homosexual individuals in Portugal.Using online surveys, 1140 individuals completed the BSI subscales for depression and anxiety symptoms, as well as the Suicide Behaviors Questionnaire-Revised.Self-identified bisexual participants presented higher levels of depressive and anxiety symptoms and higher levels of suicidal ideation and likelihood of suicidal behavior than homosexual and heterosexual participants (who scored the lowest); yet, homosexual participants showed higher levels of suicide attempts. Also, depression and anxiety symptoms were strongly and positively correlated with all dimensions of suicidal behavior. Finally, hierarchical multiple regression analysis showed that higher levels of depression and non-heterosexual sexual orientations were significant predictors of suicidal ideation and the likelihood of suicidal behavior.The present study adds to the evidence that sexual minority individuals are at risk of increased mental health problems and suicidal behavior, compared to heterosexuals, and reiterates the need for local political and legislative efforts to normalize LGB identities, fighting continued institutional heterosexism, interpersonal intolerance. Mental health providers and mental health policymakers need to consider these results if they want to address inequalities in mental health and in suicidality among these minority groups."} +{"text": "We analyzed the contribution of genetic factors on the association between puberty timing and body mass index (BMI) using longitudinal data and two approaches: (i) genetic twin design and (ii) polygenic scores (PGS) of obesity indices. Our data were derived from Finnish cohorts: 9080 twins had information on puberty timing and BMI and 2468 twins also had genetic data. Early puberty timing was moderately associated with higher BMI in childhood in both boys and girls; in adulthood these correlations were weaker and largely disappeared after adjusting for childhood BMI. The largest proportion of these correlations was attributable to genetic factors. The higher PGSs of BMI and waist circumference were associated with earlier timing of puberty in girls, whereas weaker associations were found in boys. Early puberty is not an independent risk factor for adult obesity but rather reflects the association between puberty timing and childhood BMI contributed by genetic predisposition.The online version contains supplementary material available at 10.1007/s10519-022-10100-3. The timing of puberty is influenced by both genetic and environmental factors. Previous twin studies have shown that from 50% to more than 90% of individual variation of puberty timing is accounted for by inter-individual genetic differences using menarche age in girls to estimate the genetic correlations between puberty indices and BMI measured in adolescence and adulthood using a classical genetic twin design, (ii) to analyze whether the timing of puberty is associated with adult BMI when adjusted for BMI in adolescence, and (iii) to analyze how the genetic liability to obesity measured as polygenic scores (PGS) is associated with the timing of puberty in adolescence. The strength of the data is that the two analytical approaches\u2014the classical twin design utilizing the genetic similarity of twins and the PGS design utilizing measured information on genetic polymorphisms through the whole genome\u2014make different theoretical assumptions thus complementing each other. Briefly, the classical twin design is based on the different genetic relatedness of monozygotic (MZ) and dizygotic (DZ) twins, whereas the PGS design is based on observed associations between genetic polymorphisms and the trait under study was calculated from self-reported values, which showed high reliability in these cohorts in each bivariate model varied between 822 and 1475 for PDS (FinnTwin12 study) and between 930 and 978 for PA (FinnTwin16 study) (Supplementary Table 1). We then analyzed the associations of PDS and PA with BMI in adulthood after adjusting for the baseline BMI using the linear regression model. If independent associations between the puberty indices and post-puberty BMI existed, we decomposed the regression residuals to additive genetic and unique environmental components.The heritability estimates of puberty indices and BMI have previously been reported in these study cohorts, suggesting the presence of dominance genetic factors for PA of PDS or PA per the change of 1 SD of each PGS of obesity indices. The PGS analyses, as well as all statistical testing in the descriptive analyses, were performed using linear regression models by the Stata/SE 16.1 for Windows statistical software . The cluster option was used to correct the standard errors and confidence intervals (CI) for the lack of statistical independence of twins sampled as twin pairs Williams .2 higher BMI than women.Table We started the analyses by studying the contributions of genetic and environmental factors on the correlations between PDS, PA and BMI at different ages Table . SeparatNext, we analyzed how the puberty indices were associated with post-pubertal BMI after adjusting the results for baseline BMI Table . HoweverFinally we analyzed how the PGSs of different obesity indices were associated with puberty timing Table . In girlIn our study based on two independent longitudinal cohorts of twins, we found clear evidence that there is shared genetic overlap between the timing of puberty and BMI being the strongest in childhood but still existing in adulthood. When using classical twin modeling, the results were very systematic for males and females: the genetic correlations were moderate between puberty timing and childhood BMI and decreased when studying BMI in adulthood. When studying the associations between the PGSs of adiposity indices and puberty timing, the associations were stronger in females than in males. However, the confidence intervals were also wide and the results were not statistically significant for males. Thus, larger data sets are needed to analyze the question of sex differences in detail. However, in general, our results correspond well with previous twin studies Hur and GWA When studying the longitudinal associations, we found only a little evidence that the timing of puberty is associated with adult BMI independently of pre-pubertal BMI. We found that the early timing of puberty was associated in males and females with higher adult BMI, but the correlations were weaker than with childhood BMI and largely disappeared when adjusted for childhood BMI. These results are largely similar to those found previously in population-level studies, but it is noteworthy that only a few studies so far have studied these association in males Below is the link to the electronic supplementary material."} +{"text": "There are an estimated 25.9 million refugees worldwide, who require health serviceswhile living in host countries. To effectively treat refugee patients, nurses mustdocument their history which requires hearing about their traumatic journeys. Listeningto trauma has been shown to cause vicarious traumatisation.To identify the risk and protective factors involved in the development of vicarioustraumatisation.After searching four databases, nine studies were selected for review. Key words\u2018vicarious trauma\u2019, \u2018refugee\u2019 and \u2018nurse\u2019 formed the search. Articles were appraisedusing the Critical Appraisal Skills Program and Mixed Methods Appraisal Tool.Vicarious traumatisation is common amongst nurses working with refugees. Aspects ofculture formed the principal risk and protective factors. Differences between culturesmade for strained communication while similarities created better understanding. Somecultures provided more resilience than others. Vicarious resilience, a feeling ofpersonal growth resulting from hearing about and helping patients overcome trauma, wasalso highlighted. The development of vicarious resilience was a protective factor.Further investigation into how to minimise risk and establish protective factors isrequired. Some coping recommendations include personal reflection, comprehensivetraining and better access to counselling. Following the Vietnam War, there was an emergence of trauma literature studying the impactof traumatic events on individuals . In 1980Instances of compassion fatigue amongst nurses are well documented, particularly inemergency departments, intensive care units and oncology centres . These fThere are currently an estimated 25.9 million refugees worldwide , in 2018The worldwide nature, and number, of refugees means they encompass people from manydistinct cultures, beliefs, religions and with varying health states. It has been noted thatmany refugees arrive in host countries with undiagnosed or untreated health problemsincluding lack of vaccination, nutritional deficiencies and infectious diseases, whichcreates a disparity between the physical and mental health of refugees and the hostpopulation and which is exacerbated by language, cultural barriers and inadequate healthliteracy . A succeWithin this paper there will be a focus on refugees and not asylum seekers. As defined bythe It has been noted that terms such as compassion fatigue, burnout, vicarious traumatisationand secondary traumatic stress have been used synonymously by some academics while othershave chosen to define them individually . BurnoutA literature search was carried out from September to November 2019. Four databases wereused: Medline, Web of Science, PsychINFO and the Cumulative Index of Nursing and AlliedHealth Literature (CINAHL). All four databases were chosen because they are specific tohealthcare. The PICo acronym was used to determine thekey words needed to ensure the most effective literature search . These wInclusion and exclusion criteria were set to provide focus to the search and ensure themost relevant material was uncovered. Both were devised from a review of the question asadvised by The selected papers were apprised using the Critical Appraisal Skills Program (CASP) tooland Mixed Methods Appraisal Tool (MMAT) to ensure validity to the study and consistency inappraisal of articles. The CASP specialises in healthcare research and focuses on evaluatingqualitative research which is included in all but one of the chosen articles . The MMAThe search terms were input to the databases resulting in 46 articles being found. Onceduplicates were removed there were 39 sources to review. An analysis of their titles andabstracts using the inclusion and exclusion criteria eliminated 35 articles leaving justfour. The remaining articles were read in full to ascertain usefulness before a citationsearch of their bibliographies was undertaken. Twenty-two more articles were identified andhad their abstracts screened, five were found to be relevant to this study. This left atotal of nine papers to be used in the literature review. Vicarious traumatisation has been shown to be present to some extent in every researchstudy analysed in this review. The evidence suggests vicarious traumatisation hassignificant clinical implications for the individual and wider health systems. As a result,it is beneficial to consider the risk and protective factors associated with itsdevelopment. Other themes were identified during the literature review however the scope ofthis paper did not allow for them to be discussed in further detail.Several studies within tIn the study conducted by Ethnocultural variations exist in presentations of PTSD . MarsellIt has been identified that caregivers who themselves have a migrant past, eitherdirectly or as a recent descendant, are better equipped to assist refugees . TheyhaThe term vicarious resilience encompasses the positive outcomes of working with traumasurvivors . It emerVicarious traumatisation causes stress, among other symptoms. Cultural resilience hasbeen identified as an effective stress management technique . This isAccording to Only four databases were used to conduct the literature search, allowing for potentialresearch papers to be missed if they were not on the selected databases. Additionally, thereview was only conducted by one researcher, as an undergraduate nursing dissertation,which leaves room for unintentional bias and a lack of alternative perspectives.The aim of this review was to determine the risk and protective factors surrounding thedevelopment of vicarious traumatisation amongst those working with refugees. Culture hasemerged as the key element in both features. Although culture has been shown throughnumerous studies to be a risk factor for vicarious traumatisation, its crucial role inencouraging vicarious resilience helps to counteract the fact it can expose people to moretrauma.As mentioned, this study has its limitations however it creates an overview of currentliterature in the area which can be used as a base for further study into the subject withthe aim of finding a solution to minimising vicarious traumatisation.As stated by Many of the risk and protective factors uncovered from the literature review arenon-changeable as they are engrained in culture and history. Since recruitment based uponcultural identity is unethical, alternative risk and protective factors need to beexplored.\u2022 Greater availability of counselling for nurses working with refugees. This wouldfacilitate discussion around the subject of trauma to relieve feelings of isolationand to provide helpful coping mechanisms.\u2022 Facilitation of time for reflection that can enhance the instances of meaningmaking which has been shown to encourage post-traumatic growth as part of vicariousresilience to overcome the effects of vicarious traumatisation.\u2022 Provide comprehensive training to nurses prior to entering a position which willrequire interaction with refugee patients. If they are made aware of the signs fordeveloping vicarious traumatisation they can take responsibility for their ownmental health and seek help when necessary.\u2022 Ongoing monitoring of all nursing staff working with refugees using a combinationof the questionnaires such as the ProQOL to determine those at ahigher risk of, or those who have already developed, vicarious traumatisation.The following changes to practice are recommended to reduce the instances of vicarioustrauma amongst nurses working with refugees:\u2022 Further research into changeable risk factors to discover how to reduce thedevelopment of vicarious traumatisation. This includes risk and protective factorsout with culture that can be applied to the whole workforce.The following areas require investigation to learn how to reduce the instances ofvicarious traumatisation amongst nurses working with refugees:Vicarious traumatisation affects almost every healthcare professional whointeracts extensively with refugees and consequently requires investigation tominimise the impact on caregivers and their patients.Culture is both a risk and protective factor for vicarious traumatisation andcan therefore potentially be manipulated into promoting resilience overtraumatisation with further research.Vicarious resilience has been shown to have a positive impact for almosteveryone and so ongoing investigations into combating vicarious traumatisationshould focus around encouraging quicker and more sustainable development ofvicarious resilience.More training on the subject to provide awareness and enable caregivers torecognise its development in themselves is an important next step in itstreatment."} +{"text": "The management of multiple chronic health conditions often requires patients to be exposed to polypharmacy to improve their health and enhance their quality of life. However, exposure to polypharmacy has been associated with an increased risk for adverse effects, drug-drug interactions, inappropriate prescribing, medication nonadherence, increased healthcare utilization such as emergency department visits and hospitalizations, and costs. Medication-based risk scores have been utilized to identify patients who may benefit from deprescribing interventions and reduce rates of inappropriate prescribing. These risk scores may also be utilized to prompt targeted discussions between patients and providers regarding medications or medication classes contributing to an individual\u2019s risk for harm, eventually leading to the deprescribing of the offending medication(s). This opinion will describe existing medication-based risk scores in the literature, their utility in identifying patients at risk for specific adverse events, and how they may be incorporated in healthcare settings to reduce rates of potentially inappropriate polypharmacy and avoidable healthcare utilization and costs. Patients with multiple chronic conditions may be exposed to several medications to improve health, enhance quality of life, and reduce healthcare utilization. The chronic exposure of multiple medications has been termed polypharmacy . While tMedication-based risk scores can be utilized by healthcare providers to identify patients who would benefit from deprescribing interventions to reduce rates of potentially inappropriate polypharmacy, adverse health outcomes, and avoidable healthcare utilization. The utilization of these tools is especially important due to the increasing proportions of adults with multiple chronic conditions, resulting in higher prevalence of polypharmacy . The higThe MRCI is a risk assessment tool that quantifies the complexity of an individual\u2019s medication regimen by taking into consideration the medication dosage form and route, dosing frequency, and unique directions provided to take certain medications . This toThe development of the MRCI allowed clinicians and researchers to quantify the complexity of an individual\u2019s medication regimen. However, since part of the score requires the use of unique prescribing details , the scoJust under 1,000,000 patients fall within healthcare facilities each year in the United States (US) . ReducinAnother tool used to measure fall risk is the MedIP. This tool was developed to overcome biases from tools that focus on specific medication classes . The MedThe use of medications with sedative and anticholinergic properties has been associated with adverse events among older adults including cognitive impairment and falls . The DBIWhile the findings of studies assessing the relationship between DBI and healthcare utilizations and outcomes such as falls have varied, higher DBI has been consistently shown to be associated with frailty, poorer quality of life, and physical impairment . HoweverMedications contributing to anticholinergic burden is a field of significant interest due to widely used drug classes with anticholinergic properties being associated with significant healthcare utilization and poor health outcomes. This has led to the publication of numerous scales, lists, and risk scores that quantify an individual\u2019s anticholinergic burden to estimate their risk of adverse outcomes. Furthermore, given the substantial interest and breadth of research examining anticholinergic burden, several systematic reviews have been published examining the utility of these scales to predict poor health outcomes such as adverse events, falls, mortality, delirium, and poor quality of life ,22,23,24Scores, scales, and lists available to measure anticholinergic burden or identify exposure to anticholinergic medications include the anticholinergic drug scale (ADS), aThese tools provide prescribers with an understanding of a patient\u2019s risks for specific adverse outcomes based on their cumulative exposure to medications with anticholinergic activity. However, despite the large number of tools available to highlight anticholinergic burden, there are several details to consider. Significant variability exists between tools, with some taking into consideration the dose of medications, and several tools identifying <30 medications and others considering >500 medications with expected anticholinergic activity . FurtherThe SLM was designed to characterize an individual\u2019s exposure to medications with sedative properties and to quantify their risk of impaired mobility ,48. ThisSloan et al., modified the SLM to construct a sedative load risk score that incorporated the dose of a medication as well . This riAnother measure that was developed to quantify an individual\u2019s medication related risk for falls included the CNS medication burden . This riA challenge in deprescribing medications is the identification of prescriptions that are appropriate and inappropriate. While the previously noted risk scores identified medications or medication classes that were potentially inappropriate for an individual, the MAI is a scoring system that determines if a medication is inappropriate and should be targeted for modification or deprescribing. The original tool utilizes 10 questions where a clinician assesses if a drug is indicated, effective, appropriately dosed, given with appropriate instructions, practical to use, prescribed with appropriate length of therapy, relatively affordable compared to similar drugs, and does not have any clinically significant drug-drug or drug-disease interactions . A cliniDespite the advantages of utilizing an individual clinician\u2019s knowledge to determine the inappropriateness of a medication or medication regimen, there are important limitations of MAI. Agreement between clinicians on the determination of the inappropriateness of a medication may improve after discussion, suggesting that interpretation of inappropriateness based on patient specific factors and identification of clinically relevant drug-drug or drug-disease interactions can differ based on a provider\u2019s experience and background . FurtherPrevious medication-based risk scores may be limited in their utility given that they are used to track one or two specific risk factors in a patient\u2019s medication regimen, such as fall risk, anticholinergic burden, sedative load, complexity, or appropriateness. In contrast, the MedWise Risk Score measures an individual\u2019s risk for adverse events based on specific risk factors including sedative load, anticholinergic burden, competitive CYP450 drug interaction burden, risk of QT prolongation, and risk for adverse events utilizing the FDA Adverse Event Reporting System . This scAn important goal of care among patients with asthma is to improve quality of life and reduce healthcare utilization such as emergency room visits and hospitalizations. In 2013, asthma was associated with approximately $50 billion in medical costs in the United States . The MISMedication-based risk scores are a set of tools that can be utilized at the healthcare system level and the individual prescriber level to identify patients at significant risk for experiencing specific adverse events or potentially avoidable healthcare utilization. While risk scores have been traditionally utilized as tools for risk adjustment and prediction of healthcare utilization , medicatThe use of medication-based risk scores should be used with resources that facilitate deprescribing interventions. While most medication-based risk scores are validated to detect an increased risk of specific adverse events or healthcare utilization, they have not been studied extensively in their efficiency in identifying medications that should be deprescribed nor have they been compared to each other in this respect. It is important to note that medication-based risk scores should not solely be used to determine the appropriateness or inappropriateness of a medication. They should be used to complement a comprehensive evaluation of an individual\u2019s medications. These tools are used to identify potential targets for deprescribing and enhance the quality of information contributing to the risk-benefit assessment of an individual\u2019s prescriptions. Within primary care and outpatient settings, these risk scores can be used to identify patients who may benefit from deprescribing before a potentially avoidable event occurs, while hospital or emergency room settings can utilize these risk scores to compliment the identification of adverse events related to medication use. Hospital settings may benefit more from using risk scores that incorporate physiological data to identify emergent events that require prompt intervention.Providers need to evaluate which risk scores are most useful in identifying patients at greatest risk for specific harms or healthcare utilization within their specific healthcare settings. Presently, each risk score describes the risk for exposure to certain medications and medication classes in relation to specific adverse outcomes. It is also important to realize that risk scores alone do not overcome barriers to deprescribing such as managing interprofessional relationships, increasing provider workload, the reluctance to discontinue chronic medications, or differences in knowledge between providers . Some ofPrimary care and outpatient healthcare settings may want to utilize medication management programs or pharmacovigilance services to monitor the use and prescribing of medications without additional work and burden for prescribers. Alternatively, insurance plan providers can utilize prescription claims data to identify patients at greater risk of adverse events based on their prescribing data. Medication management programs can be utilized to communicate with the providers of these patients to prompt review of their medications to consider deprescribing interventions. The implementation of medication reviews at the insurance claims level can overcome challenges associated with patient fragmentation of data across various healthcare and dispensing settings. Additionally, having personnel specialized in the deprescribing of medications can ensure that medication-based risk scores and deprescribing tools are used optimally and efficiently among patient populations. Patients with higher risk for medication related adverse events may benefit from periodic medication reviews where medications with the lowest benefit to harm ratio are targeted for deprescribing .Medication-based risk scores are useful in identifying patients potentially at risk for suboptimal health outcomes and avoidable healthcare utilization and adverse events. To ensure that healthcare settings are able to efficiently reduce harms associated with exposure to the medications, combining these tools with deprescribing algorithms and guidelines may facilitate the discontinuation of medications that provide the least benefit and most harm to patients. The utilization of pharmacovigilance and medication management programs may be implemented within healthcare settings to identify opportunities for deprescribing and reduce potentially avoidable healthcare utilization."} +{"text": "The underlying cause of the inflammation is multifactorial, with both genetic and environmental contributionshich patients with rhinosinusitis are the best candidates for topical approaches? Desired properties of all topical therapies include complete sinus distribution, high local drug absorption, low systemic absorption, and minimal toxicity to the cilia and sinonasal mucosa. Understandably, the benefits of saline irrigation and topical therapies are greatest in patients who have had prior functional endoscopic sinus surgery (FESS)Nasal Irrigation has also been recognized as a potential route for topical drug administration into paranasal sinuses due to ease of use and direct drug effects on the sinonasal mucosa. Topical drugs being investigated for use in CRS include antimicrobial, anti-inflammatory and immunomodulatory agents. One difficult question for rhinologists to answer is wPseudomonas sinusitis, and found that topical tobramycin resulted in the eradication of viable bacteria within the lumen of the sinus. However, even at high concentrations, topical tobramycin could not eradicate Pseudomonas attached to the mucosa in biofilmsOral and intravenous antimicrobial therapies have traditionally been prescribed to manage infectious exacerbations of CRS. However, these agents are not without significant side effects, especially for patients requiring prolonged courses. Topically applied antibiotics in irrigation have a theoretical advantage to localize high doses of antibiotics to the sinonasal mucosa while minimizing systemic side effects. The majority of clinical data for topical antibiotics has investigated and provided support for the use of mupirocin sinus irrigation for patients with MRSA infectionsIn vitro studies by Desrosiers et al. and Ha et al. were able to eliminate S. aureus biofilms with antibiotics in concentrations easily obtainable in topical solutionsBiofilms have been identified as a potential risk factor for worse outcomes after endoscopic sinus surgery, persistent sinonasal inflammation, and a cause of recalcitrant infectionsSurfactants in nasal irrigation have been shown to be effective for some patients with CRS. Surfactants are thought to improve mucocilliary clearance by reducing the adherence of sputum to the epithelial layer which increases efficiency of energy transfer from the cilia to the mucus layer. We previously reported on the use of commercially available dilute baby shampoo irrigation in 18 patients with recalcitrant CRS. Almost half of patients in this study experiencing an overall improvement in their subjective symptoms, and 60% noting reductions in postnasal drainage and thick mucusTopical and oral steroids are commonly used to reduce sinonasal mucosal inflammation and to treat nasal polyps. Use of steroid irrigation has become more common to spare patients from the side effects and toxicities of systemic steroids, while providing higher concentrations of steroid directly to the sinus mucosa than what is possible with topical nasal sprays. Various off-label mixtures have been described for irrigation, including mixtures of budesonide with saline at various concentrationsDespite increasing use of topical therapies for CRS, many questions remain regarding the optimal length of treatment, optimal delivery mechanism, and long-term effects of the treatments on the sinonasal mucosa and cilia. In addition, treatments with topical antibiotics, corticosteroids, and surfactants in combination could show synergistic benefits depending on the specific clinical presentation. Future studies will undoubtedly shed light on these questions, and provide more evidence of the efficacy of topical therapies for CRS."} +{"text": "The adaptive immune system relies on formation of the memory of past microbial challenges to accelerate protective immune responses in the event of reinfection. This memory is accomplished in part by the retention of antigen-specific B and T cells within barrier tissues. As the healthy central nervous system parenchyma is virtually devoid of adaptive immune cells, the meningeal spaces carry out the vital function of coping with environmental threats during aging. We conducted an extensive molecular and functional analysis of meningeal T cells to test the hypothesis that the meninges in the brain sense and respond to internal and external cues throughout life, and that alterations in the meningeal T cell repertoire alter brain function. We found presumably self-reactive tissue-resident T cells in the meninges of naive mice. Using models of pathogen exposure, we describe a neuroimmune axis in which antigen experienced resident Tcell subsets dynamically record immune perturbations, which resulted in behavioral abnormalities that were exacerbated with aging. Our findings elucidate molecular properties of T cells that survey the brain borders under both homeostatic and pathological conditions and provide insights linking CNS immune privilege with memory."} +{"text": "Patients living with Inflammatory Bowel Disease (IBD) commonly experience a number of mental health-related challenges, specifically anxiety and mood disorders (AMDs). Although there has been an awareness of the relationship between IBD and AMD within the GI research and clinical space; detection, treatment, and management amongst care providers is limited. Therefore, we are seeking to explore the overall experiences of patients living with Inflammatory Bowel Disease to identify and evaluate their experiences in interactions with GI clinicians around mental health in diverse care settings in order to determine how to best support mental health care amongst IBD patients.We aimed to explore perspectives, experiences and barriers to engaging with mental health-related challenges amongst IBD patients when interacting with gastroenterologists over the course of their health journey.Zoom which spanned for a total of 2.5 hours each. Participants were recruited through social media channels, GI clinics, the IMAGINE-SPOR unit, and Crohn\u2019s and Colitis Canada. A semi-structured interview guide was developed for patient researchers to follow during the focus groups which provided guided questions that would allow patient participants to explore and reflect on: their experiences living with IBD, their expectations around mental health support, their perception of the engagement of GIs in mental health discussions, and their expectations for mental health support and services moving forward. Audio recordings from the semi-structured focus groups were then transcribed and thematic analysis was used to identify emerging themes and patient expectations.We conducted 5 semi-structured online focus groups co-facilitated by patient researchers in early 2020 through We identified the following key themes: 1) experiences with IBD: difficulties related to reintegrating into social settings, feelings of loneliness; 2) expectations around mental health support: the need to develop their own resiliency strategies due to the lack of structural resources regarding mental health and IBD in the clinical space; 3) GI engagement: HCPs were dismissive of mental health symptoms, often gaslighting patients when mentioning mental health concerns during clinical encounters; and 4) expectations: a need to standardize mental health care across IBD care practice with a focus on potentially integrating healthcare providers of diverse care settings to help address the need for mental health support in such a vast patient population.Our study suggests that effective detection, management and awareness, along with the integration of feedback from patient lived experiences can help inform the development of mental health support and services which cater to the needs of people living with IBD. Results from this study will be interpreted in line with insight gathered from upcoming interviews of gastroenterologists and HCPs.CIHR, OtherIMAGINE SPOR INCUBATOR GrantNone Declared"} +{"text": "Adipose tissue is a highly adaptive and critically important metabolic tissue, with intrinsic roles in both health and disease. It is now well established that adipose tissue plays a significant role in a diverse range of physiological processes, including metabolic homeostasis and disease progression. Obesity, a chronic condition defined by excessive adipose tissue expansion, has now become one of the greatest medical challenges of the modern world. Consequently, understanding the mechanisms that underpin adipose tissue in obesity and disease progression is becoming increasingly important, such that novel targets for the treatment of obesity and its complications may be identified. The aim of this Research Topic is to provide an overview of the important physiological roles that adipose tissue plays in both health and disease, by summarising current knowledge and providing novel insights into adipose tissue biology.Nunn et al. where they describe the functional differences that occur in hypertrophic adipocytes and how this can contribute to metabolic complications. The authors detail how initiating adipogenesis (hyperplasia) as opposed to hypertrophy is metabolically beneficial and could be targeted therapeutically to treat metabolic disease. The review then evaluates known adipogenic regulators that could potentially be manipulated to induce adipogenesis. The concept of adipose tissue expansion is extended upon in a detailed review by Hilgendorf, which analyses the current literature regarding adipocyte primary cilia and their role in adipose tissue expansion and metabolic disease. The primary cilium is a cellular protrusion found on most mammalian cell types, including adipocytes, where it can regulate pro- and anti-adipogenic signalling pathways. Hilgendorf concludes by postulating that adipocyte primary cilium may function as a signalling hub through ciliary remodelling, enabling the primary cilium to sense and respond to extracellular signals, which can initiate adipogenesis. Garritson and Boudina further elucidate on mechanisms of adipose tissue expansion in a review that describes the effect of exercise on adipose tissue plasticity. It is well known that lifestyle interventions such as diet and exercise can reduce the risk for developing cardiometabolic disorders, but many of the underlying mechanisms remain unknown. Garritson and Boudina summarise the positive metabolic benefits of exercise on adipose tissue and highlight important questions that remain to be addressed.Excessive adipose tissue expansion is associated with declines in health and quality of life, however, the type of expansion (hyperplasia or hypertrophy) and the anatomical location of the adipose depot, are now known to be key factors that affect metabolic health. This is nicely summarised in the review by Wade et al. provide a detailed update on the previously underappreciated role of lipid uptake into activated brown fat. Here, the authors highlight the importance of peripheral lipid storage for non-shivering thermogenesis and present an update on known mechanisms of lipid transport and uptake into brown fat. Researchers have long been looking for ways to artificially stimulate brown fat, such as the identification of novel browning mechanisms, to harness the positive metabolic effects of activated brown fat. Wang et al. original research article demonstrates a previously unknown CLK1-THRAP3-PPAR\u03b3 axis that plays a role in adipose tissue browning and insulin sensitivity. The authors observe that CLK1 KO mice are resistant to high fat diet with preserved glucose tolerance and insulin sensitivity. They further demonstrate that CLK1 phosphorylates THRAP3 which promotes docking of PPAR\u03b3 to inhibit PPAR\u03b3 activity. Moreover, the original research article by Xiong et al. examines the role of the transcription factor E2F1 on mouse white adipose tissue browning and autophagy. In this article the authors demonstrate that global deletion of E2F1 leads to smaller adipocyte cell size and increased mitochondrial content which are associated with reduced expression of genes and proteins related to autophagy. Although activation of brown fat has been shown to be beneficial to metabolic health, the ability to therapeutically target brown adipose tissue has not yet translated to the clinic. Potentially the activation of brown fat in the setting of obesity provides many therapeutic challenges, including a reduction of brown fat in obesity and the difficulty in specifically targeting brown adipose tissue. Bond et al. review on adipose extracellular vesicles summarises the literature regarding the role of adipocyte extracellular vesicles in health and disease, where the authors postulate that extracellular vesicles secreted from activated brown fat may provide a new therapeutic avenue to mimic the metabolic benefits of brown fat activation.There are three distinct forms of adipocytes; white (the body\u2019s main depot for storing energy), brown (accrue and burn lipid for energy) and beige (ability to switch between white and brown adipocyte roles). Since the discovery of brown fat in both humans and rodents, there has been significant advances in our understanding of its role in metabolic homeostasis, however, there are still existing knowledge gaps regarding brown fat biology. Although previous research has focused on glucose uptake into brown fat, Van Meijel et al. investigates proteomic profile alterations in the abdominal subcutaneous adipose tissue from overweight/obese and insulin resistant male subjects caused by mild intermittent hypoxia. Using untargeted liquid chromatography-mass spectrometry the authors identify 123 proteins that are differentially expressed due to mild intermittent hypoxia exposure and find a correlation between adipose tissue insulin sensitivity and changes in TMOD3 expression. Approved treatments to improve insulin sensitivity include the thiazolidinedione class of drugs, which have had mixed success largely due to off target effects, where many of the beneficial and detrimental mechanism remain poorly understood. Original research by Palavicini et al. contributes additional knowledge on how the insulin-sensitiser pioglitazone exerts its cardiometabolic benefits in the setting of type 2 diabetes. Using shotgun lipidomics to measure changes in lipid species from human subcutaneous abdominal adipose tissue and vastus lateralis muscle from obese patients with type 2 diabetes following a chronic 6-month treatment with pioglitazone, the authors determine that the majority of the lipid composition changes occur in the glycerophospholipid pool. Glycerophospholipids enriched for the inflammatory pathway modulator arachidonic acid and its precursor linoleic acid were reduced by pioglitazone highlighting the importance of adipocyte membrane function in immunometabolic health. Adipose lipid metabolism, in particular ether lipids in obesity, is discussed further in a review by Schooneveldt et al., in which they delineate the functional and protective roles of ether lipids in the setting of obesity. The authors discuss how ether lipids have been linked to lipid droplet formation, regulating thermogenesis and mediating browning of white adipose tissue, as well as the therapeutic potential of ether lipid supplementation to alleviate obesity and its associated complications.Declines in insulin sensitivity are strongly correlated with obesity and dysfunctional adipose tissue. Original research by Keating et al. Here the authors evaluate oligonucleotide-based therapies in the setting of obesity and fatty liver disease, as well as discussing the current limitations and challenges of oligonucleotide-based technologies in pre-clinical studies and their use as therapeutics.The overarching theme of this Research Topic is to better understand adipose tissue biology to uncover new therapeutic targets to treat obesity and metabolic disease. The potential of synthetic oligonucleotide technologies, as a means to target specific genes or proteins, to treat metabolic disease is explored in a review by In conclusion, this Research Topic on adipose tissue incorporates a Research Topic of reviews and novel data summarising our current understanding of adipose tissue biology and its role in maintaining metabolic homeostasis. Elucidating the physiological mechanisms of adipose tissue function, in both health and disease, could help to uncover novel therapeutic targets to treat obesity and metabolic disease."} +{"text": "Scavenging plays a vital role in maintaining ecosystem health and contributing to ecological functions; however, research in this sub\u2010discipline of ecology is underutilized in developing and implementing wildlife conservation and management strategies. We provide an examination of the literature and recommend priorities for research where improved understanding of scavenging dynamics can facilitate the development and refinement of applied wildlife conservation and management strategies. Due to the application of scavenging research broadly within ecology, scavenging studies should be implemented for informing management decisions. In particular, a more direct link should be established between scavenging dynamics and applied management programs related to informing pharmaceutical delivery and population control through bait uptake for scavenging species, prevention of unintentional poisoning of nontarget scavenging species, the epidemiological role that scavenging species play in disease dynamics, estimating wildlife mortalities, nutrient transfer facilitated by scavenging activity, and conservation of imperiled facultative scavenging species. This commentary is intended to provide information on the paucity of data in scavenging research and present recommendations for further studies that can inform decisions in wildlife conservation and management. Additionally, we provide a framework for decision\u2010making when determining how to apply scavenging ecology research for management practices and policies. Due to the implications that scavenging species have on ecosystem health, and their overall global decline as a result of anthropic activities, it is imperative to advance studies in the field of scavenging ecology that can inform applied conservation and management programs. Scavenging plays a vital role in maintaining ecosystem health and contributing to ecological functions; however, research in this sub\u2010discipline of ecology is underutilized in developing and implementing wildlife conservation and management strategies. We provide an examination of the literature and recommend priorities for research where improved understanding of scavenging dynamics can facilitate the development and refinement of applied wildlife conservation and management strategies. For example, feral cats are eliminating native species on Little Cayman Island in the Caribbean. The Department of Environment and Department of Agriculture intend to trap and humanely euthanize all feral cats and common buzzard (Buteo buteo), both protected species in Europe, may be declining in numbers due to rodenticides after consuming poisoned rodent carrion. These and other studies evaluating effects of poison bait uptake on nontarget species are often undertaken after eradication plans have been implemented eradication study was conducted in Australia using non\u2010toxic baits to assess uptake by nontarget species before deploying toxic baits are used globally in poison baits for rodent population control, and although some risk mitigation measures have been instituted, such as safe disposal of poisoned rodents and tamper\u2010resistant bait boxes vultures through ingestion of nonsteroidal anti\u2010inflammatory drugs administered to livestock, particularly diclofenac\u2010sodium, reduced the vulture numbers by over 95% , and Old World vultures , as well as mammals , and human provisions due to their unpredictable nature, specifically how they affect scavenging communities, disease spread, and ecosystem health , a common facultative scavenger, are able to pass infectious prions in their feces after consuming prion\u2010positive tissues, such as those from transmissible spongiform encephalopathy (TSE) diseases including chronic wasting disease, scrapie, and bovine spongiform encephalopathy. Alternatively, it was previously speculated that scavenging species played a critical role in the spread of anthrax by scavenging infected carcasses, but now it is understood they do not increase transmission were the primary scavenger consuming bats, but raccoons, gray foxes (Urocyon cinereoargenteus), and domestic cats also consumed bat carcasses, acting as potential vectors for the rabies virus. Although recent studies have elucidated the complexities associated with the landscapes of fear and disgust and scavenging of conspecifics, there are still areas to investigate such as animal responses to signals associated with parasite risk is an obligate scavenger that requires larger vertebrate carcasses than are used by congeners for feeding and reproductive purposes, resulting in increased competition with vertebrate scavengers in addition to other invertebrates such as flies and ants have been implemented globally and contributed to conservation strategies for many scavenging species. Vultures have benefitted from SFS and studies have documented increasing population numbers worldwide at these sites , African lion (P. leo), and red wolf (Canis rufus). Despite the extensive efforts made to protect endangered and threatened animals globally, little research has been conducted to understand how carrion provisioning can play a role in facultative scavenger conservation, particularly for mammalian predators. Most predators are facultative scavengers, consuming carrion if and when it is available ; investigation ; methodology ; writing \u2013 original draft (lead). Travis DeVault: Conceptualization ; writing \u2013 review and editing . James Beasley: Conceptualization ; writing \u2013 review and editing .The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript."} +{"text": "Threatened preterm labor (TPL) is a traumatic event during pregnancy that involves a threat to the physical integrity of the upcoming baby. Despite biomarkers would be the strongest delivery date predictors, an assessment of chronic and acute stress response to TPL diagnosis may improve this prediction.The objective is to predict delivery date in women with TPL based on their response to this diagnosis and chronic stressors, along with relevant obstetric variables.A prospective cohort study was conducted with a sample was formed by 157 pregnant women with TPL diagnosis between 24 and 31 weeks. Determination of salivary cortisol, \u03b1-amylase levels, along with anxiety and depression symptoms were measured to estimate stress response to TPL. Cumulative life stressors as traumas, social and familiar functioning were also registered. To examine the effect of the possible predictor variables of delivery date, linear regression models were used.A correlation was found between the variables of response to chronic stress and between the variables of psychological response to stress. The main predictors of preterm delivery were low family adaptation, higher BMI, higher cortisol levels, and the week of diagnosis of TPL (<29 weeks of gestation).The best predictor of delivery date was the combination of the stress response to the diagnosis of TPL measured by cortisol in saliva, cumulative life stressors (mainly family adaptation) and obstetric factors (week TPL and BMI). Through psychosocial therapeutic intervention programs, it is possible to influence this modifiable predictive factors of preterm birth in symptomatic women."} +{"text": "AAAs have always been deeply engaged in addressing the health-related social needs of older adults from historically marginalized and underserved communities. As a confluence of COVID and social injustices moved issues of racial equity and inclusion to the forefront of national conversation, AAAs refocused their efforts to identify and address health inequities related to the social determinants of health (SDOH). One result of the COVID-19 pandemic and the urgency to reach and vaccinate older adults was that AAAs quickly formed new partnerships with culturally specific organizations. These relationships have developed and resulted in expanding culturally responsive service delivery. Presenters will describe this and other findings from a mixed methods study about AAA initiatives that seek to improve access and equity, such as inclusive community needs assessments, equity analyses that leverage census data to identify areas of greatest SDOH disparities, and dashboards to compare service recipients with community demographics."} +{"text": "Land reclamation and ecological restoration are required to mitigate land surface disturbances associated with natural gas extraction in the western United States. Traditional focus on these lands has been to stabilize soil to prevent erosion, though more recently, there has been an emphasis on restoring ecosystem services. Insects provide numerous ecosystem services and can be considered indicators of success for ecological restoration projects. It has been suggested that creating spatial and temporal mosaics of flowering plants will be necessary for pollinator conservation. In this study, we found insect abundance to be significantly higher on sites undergoing restoration than in adjacent reference areas during early and late growing season within the Jonah Infill natural gas field in Sublette County, Wyoming, USA. Family richness was significantly higher on well pads in the late season compared to reference sites. While our study only looked at sites within the Jonah Infill and had limited scope in terms of seed mixes, our results are promising and suggest that further work be done to investigate the efficacy of flowering plants on increasing insect abundance and richness in future restoration projects associated with oil and natural gas development. Insects are critical components of terrestrial ecosystems and are often considered ecosystem engineers. Due to the vast amount of ecosystem services they provide, because statistically valid samples can be captured in short durations, and because they respond rapidly to environmental change, insects have been used as indicators of restoration success and ecosystem functionality. In Wyoming (USA), ecological restoration required on thousands of acres of land surface have been disturbed to extract natural gas. In this study, we compared early seral reclamation sites to reference areas at two points within a growing season. We compared insect abundance and family richness on 6 natural gas well pads with early season perennial forbs and 6 well pads with the late season to insect communities on adjacent reference areas. A total of 237 individual insects were found on early season reclaimed sites compared to 84 on reference sites, while 858 insects were found on late season reclaimed sites compared to 38 on reference sites. Insect abundance was significantly higher on reclaimed well pads compared to reference areas at both points in the growing season, while reclaimed sites had significantly higher Shannon Diversity Index in early season and significantly higher family richness in late season compared to their paired reference sites. We also found interesting differences in abundance at family levels. Insects, the most abundant and diverse group of animals in the world, provide numerous ecosystem services ,2. InsecIn the western United States, extraction activities related to energy development have resulted in hundreds of thousands of acres of land surface disturbance. In Wyoming, oil and gas operating companies are required to reclaim surface disturbances after extraction activities take place while complying with multiple regulatory criteria ,16. ThesCleome serrulata; hereafter RMBP) at one point in the growing season. This issue is found among studies which have tested the mass flowering hypothesis in agricultural systems. Research suggests having a diverse spatial and temporal mosaic of flowering plants which bloom at different periods throughout the growing season is an effective strategy for insect and pollinator conservation e.g., . This is the first study to compare insects at more than one point in a growing season on well pads undergoing restoration activities while flowering events are occurring with distinctly different vegetation species. While a total of nine out of 24 insect families found across the two sampling periods were common to both collections, we were unable to determine if insects from early sites traveled to later sites or if unique insects at each time period were found due to specific life history characteristics of those families. As insect dispersal studies are becoming more common and affordable , future Although this study was limited to one year, the results were highly significant and will help direct future research related to insect response to reclamation and restoration activities related to oil and gas development. Additionally, the study is limited in that insects were identified to family, rather than species-level. While insect richness at the family-level is closely linked to insect richness and the species-level ,35, futuNatural resource extraction is expected to continue into the foreseeable future with growing populations. Reclamation and restoration of areas disturbed for energy extraction will become increasingly critical to restore habitat for wildlife species including insects, and therefore is important to overall insect conservation. This study suggests that adding native, flowering plants to reclamation efforts within a sagebrush-steppe ecosystem results in increases in insect abundance and family richness compared to reference areas when the reference areas are devoid of flowering plants. Continued use of native forb species in reclamation and restoration efforts will be important for insect and pollinator conservation in the western United States and other areas where anthropogenic activities result in land surface disturbance."} +{"text": "Solanum lycopersicum) which is a globally important crop species. Here we outline the unique combination of attributes that make tomato a powerful model system for meiosis research. These include the well-characterized behavior of chromosomes during tomato meiosis, readily available genomics resources, capacity for genome editing, clonal propagation techniques, lack of recent polyploidy and the possibility to generate hybrids with twelve related wild species. We propose that further exploitation of genome bioinformatics, genome editing and artificial intelligence in tomato will help advance the field of plant meiosis research. Ultimately this will help address emerging themes including the evolution of meiosis, how recombination landscapes are determined, and the effect of temperature on meiosis.Meiosis is a specialized cell division during reproduction where one round of chromosomal replication is followed by genetic recombination and two rounds of segregation to generate recombined, ploidy-reduced spores. Meiosis is crucial to the generation of new allelic combinations in natural populations and artificial breeding programs. Several plant species are used in meiosis research including the cultivated tomato ( Meiosis is a cell division that takes place during reproduction and leads to the generation of recombined, ploidy-reduced spores in most sexual eukaryotic organisms and related wild species are highly suitable model systems for plant meiosis research and rice (~\u2009410\u00a0Mbp) and even for medium-size plant genomes like tomato (~\u2009900\u00a0Mbp) mixed background and an interspecific (S. lycopersicum x S. pimpinellifolium) hybrid leads to increased meiotic CO DNA repair complex mutants in Arabidopsis and tomato has revealed different phenotypes in the two species and represents an important example of the power of comparative genetic studies. The RTR complex, conserved in eukaryotes, is involved in the dissolution of Holliday junction-like recombination intermediates and favors NCO DNA repair pathways in both somatic and meiotic contexts (Hatkevich and Sekelsky self-pruning (sp) mutation centromeres, genetic polymorphism and temperature are now ripe to be addressed in tomato and wild relatives.cis and trans factors that contribute to low recombination in plant (peri)centromeres could be readily carried out in tomato. Roughly 65% of the physical length of tomato chromosomes do not recombine during meiosis (Demirci et al. The identification of Another relevant topic to explore in tomato is the role of genetic polymorphism in determining chromosomal landscapes of meiotic recombination. A recent study indicates that genetic polymorphism may not be the key driver of broad recombination patterns in intraspecific Arabidopsis hybrids (Lian et al. Meiosis and meiotic CO rate are sensitive to temperature in a series of plant species, including Arabidopsis and barley (Higgins et al. Here, we outlined several resources and modern approaches that can be used in the future study of meiosis in tomato and wild relatives. More than being an important fruit crop, the wide diversity of natural and artificial tomato genetic resources together with the burgeoning possibilities brought about by genome editing and third generation sequencing suggest that the tomato model can play an important role in the fertile field of plant meiosis research. We conclude that tomato represents a suitable model system to address outstanding problems on recombination suppression, the impact of genetic heterozygosity on CO landscapes and the sensitivity of meiosis to abiotic stress."} +{"text": "Recent studies have mapped key genetic changes in colorectal cancer (CRC) that impact important pathways contributing to the multistep models for CRC initiation and development. In parallel with genetic changes, normal and cancer tissues harbor epigenetic alterations impacting regulation of critical genes that have been shown to play profound roles in the tumor initiation. Cumulatively, these molecular changes are only loosely associated with heterogenous transcriptional programs, reflecting the heterogeneity in the various CRC molecular subtypes and the paths to CRC development. Studies from mapping molecular alterations in early CRC lesions and use of experimental models suggest that the intricate dependencies of various genetic and epigenetic hits shape the early development of CRC via different pathways and its manifestation into various CRC subtypes. We highlight the dependency of epigenetic and genetic changes in driving CRC development and discuss factors affecting epigenetic alterations over time and, by extension, risk for cancer. Colorectal cancer (CRC), which involves cancers occurring in the colon and rectum, is the third most prevalent cancer by incidence and mortality worldwide. In fact, it is estimated that by 2030 there will be globally >2.2 million new cases and 1.1 million deaths due to CRC . This reCRC carcinogenesis occurs due to the progressive accumulation of different combinations of molecular changes in the form of genetic and epigenetic insults during aging that inactivate tumor suppressor genes and activate proto-oncogenes , 8. ClasCRC is primarily classified based on the following genetic and epigenetic molecular features, which are important determinants of the alternate routes of genomic instability in CRC development.APC, which occurs by sporadic mutation in one allele of APC followed by loss of the other APC allele due to flaws in chromosome segregation ."} +{"text": "Loneliness is highly prevalent among older adults and can negatively influence their mental health. However, less is known about the factors that might mitigate the effects of loneliness on mental health outcomes such as depression. We propose that resilience resources may serve as potential protective factors that buffer the impact of loneliness on depressive symptoms. This study aimed to (a) test the effects of loneliness, as well as resilience factors of perceived family support and optimism, on depressive symptoms, and (b) examine resilience factors as moderators of the relationship between loneliness and depressive symptoms. Participants derived from the Health and Retirement Study (HRS), a nationally representative sample of the population aged 50 years and older. The analytic sample was selected with baseline measurements in either 2006 or 2008 and two follow-ups across four-year intervals . Structural equation modeling with latent variables and interaction terms was used to investigate study aims. Results revealed that (a) loneliness was significantly related to an increase in depressive symptoms; both perceived family support and optimism significantly reduced depressive symptoms, and (b) the link between loneliness and depressive symptoms was weaker when older adults reported higher levels of perceived family support and greater optimism. This study highlights the important protective roles played by perceived family support and optimism in reducing the adverse impact of loneliness on depression. Results suggest that strengthening family support and fostering optimism might be promising avenues for improving mental health in older adults particularly among those experiencing loneliness."} +{"text": "This paper examines the relationships between Direct Care Workers (DCW) and other nursing home (NH) staff. Specifically, we examine how trust, and the context in which trust exists, influences care practices and implementation of innovations in NHs. This secondary analysis of interviews and field observations from three separate NHs in different Canadian provinces shows differing levels of trust that between HCAs and other staff. We also analyze the organizational context can mediate trust in these relationships. Specifically, we analyzed trust DCWs have at the interpersonal, institutional, organizational levels and what ways they act as facilitators of programs aimed at improving care practices health outcomes of residents in NHs. Using the Alberta Context Tool\u2019s dimensions of organizational context as a framework, this research shows how trust in the relationships between DCWs and other LTC staff influences caregiving practices and the uptake of new innovations."} +{"text": "Recently, clinical models based on neuroscientific evidence have highlighted the detrimental role of executive functions impairments in negatively contributing to the functional decline of patients with Substance Use Disorder (SUD). Yet, despite these potential implications, the screening tools that are typically used to assess such impairments are not specific for patients presenting addiction and are not able to properly sketch their dysfunctional executive control profile.This study aimed at testing the clinical potential of a novel screening battery for neurocognitive disorders in addiction.The screening battery was tested on 151 patients with SUD and 55 control subjects. The battery consisted of five neuropsychological tests tapping on verbal and working memory, focused attention, and cognitive flexibility and two computerized neurocognitive tasks .Statistical analyzes showed worse cognitive performance in patients with SUD compared to controls, both at neuropsychological tests of cognitive flexibility, focused attention and verbal memory and at neurocognitive tasks, suggesting the presence of deficit of regulatory mechanisms involved in inhibition and orientation of attention/cognitive resources. These results were also confirmed by second-level analyses where the role of age and education as potential moderators was checked, suggesting the robustness of the tested measures.The results further stress the link between specific executive impairments and SUD and suggest the potential of the battery as a quick yet valid neurocognitive screening tool."} +{"text": "Oral diseases are increasingly recognized as one of the most prevalent conditions in Europe, affecting nearly half of the European population. They are the third most expensive diseases to treat in the EU and dental expenditures are set to rise substantially. Within EU countries, oral health policy and financing are most often separated from the general health system and vary considerably between countries with different public and private organisation structures providing oral health services, different levels of out-of-pocket payments for patients and a variety of financing models. Oral diseases are a main driver of unmet need and financial hardship in the EU and particularly affect poorer and marginalized groups. However, current provider payment systems prioritize expensive invasive and technology-based methods which drives public expenditure while disserving the healthcare system's central objective of better health outcomes and reducing waste. Moreover, broad and effective oral health promotion policy that spans various care settings and areas of life is not sufficiently implemented. Oral health care systems thus face complex challenges regarding efficiency, quality and integration of care which requires good evidence to steer oral health policy. However, current health information systems only collect few indicators on oral health and oral health care. There is thus need for an improved evidence base for more meaningful assessments and comparisons of oral health systems performance which would allow better informed policy decisions and enable more targeted and effective oral health interventions. In May 2021 the World Health Assembly approved an historic resolution on oral health which urges Member States to include oral health in universal health coverage (UHC) benefit packages and to shift from the traditional curative approach towards a preventive approach. Oral health and the urgent needs for improving the financing of oral health systems have thereby received increased policy attention also in Europe. In this workshop evidence from a cross-country comparison of oral health financing, access and provision in Europe will be presented and the lack of supportive information systems for oral health system performance assessment will be highlighted. Recent research activities will be discussed such as the Horizon Europe project DELIVER which aims to create a synergistic problem-solving ecosystem to improve oral health systems. Debates in oral health research and policy in Europe are influenced by global developments such as the WHO resolution. To this end, the recent call for urgent system reform and policy action to address the burden of oral diseases will be set in context and discussed.\u2022\u2002Oral care systems are still dominated by a traditional curative and technology-driven approach which fail to sufficiently encourage prevention and support holistic and integrated oral health care.\u2022\u2002Lack of harmonized data reporting on oral health and oral health system indicators impedes oral care systems performance monitoring and evidence-informed policy-making."} +{"text": "The relationship between individuals living with dementia and their caregivers is important and can impact their dementia journey. However, limited national longitudinal data exists about the caregiver-person living with dementia dyad. Availability of such data would provide important information about joint trajectories and help to better identify the needs of caregivers and persons living with dementia across the dementia journey. The objective of this study was to develop a linked national longitudinal database of persons living with dementia and their caregivers. The Canadian Primary Care Sentinel Surveillance Network (CPCSSN) extracts and de-identifies clinical data from electronic medical records (EMR) from approximately 2 million patients across Canada. CPCSSN data is used to identify persons living with dementia and caregivers willing to participate in the study. CPCSSN data from participating dyads are linked and additional information about the experiences of persons living with dementia and their caregivers are collected yearly using surveys. The growing database contains linked, de-identified, comprehensive information about persons living with dementia and their caregivers that will become a rich source of data for researchers, clinicians, and policymakers. Specifics around how the database was developed, and lessons learned will be discussed as these findings can be used as a template to develop similar linked health surveillance databases."} +{"text": "In the last decade, migration has increased due to climatic, economic, and social factors. Oral health is an integral part of overall health, but primary health packets for migrants/refugees often neglect oral health education and care in the care delivery system. The present article aims to present a realistic approach to integrating oral health into existing structures for young migrant/refugee mothers on a community level in Switzerland.As a young child's oral health is closely related to mother's oral health status and oral health knowledge level, it would be critical that migrant/refugee mothers have access to timely oral health education and care through the primary health care system.We propose an integrated oral health care model for migrant/refugee mothers that maximizes the existing primary health care system. Using existing maternal oral health resources, a training module is developed for the primary care care workforce that serve migrant/refugee mothers. This training module includes oral health needs and status assessment and delivering preventive oral health services in primary care settings. The module includes drawings and images to describe the dangers of poor oral hygiene during pregnancy related to the health of mothers and babies and how to keep the mouth healthy with low-cariogenic diet practice and home oral hygiene care. Primary health care workforce in selected migrant health centers, like nurses, medical aides, and community health care workers, is trained by this module and evaluated by a set of self-assessed questionnaires before and after the training for knowledge improvement, attainment, and clinical practice changes. Migrant mothers participate in questionnaires on oral health hygiene practice and access to dental care during pregnancy and for their young children. The questionnaires are validated by the affiliated university-hospital clinical research center."} +{"text": "The primary healthcare sector comprises various health services, including disease prevention at local level. Research shows that targeted primary healthcare services can prevent the development of acute complications and reduce the risk of hospitalisations. While interdisciplinary collaboration has been suggested as a means to improve the quality and responsiveness of personal care needs in preventive services, effective implementation remains a challenge. The aim was to investigate perceptions of preventive care among primary healthcare providers by examining their views on what constitutes a need for hospitalisation, and which strategies are found useful to prevent hospitalisation. Further, to explain how interdisciplinary collaboration can be supported with a view to providing person-centred care.Five focus group interviews were conducted with 27 primary healthcare providers. Interviews were transcribed, and analysed with qualitative content analysis.Three categories emerged: 1) Mental and social conditions influence physical functioning and hospitalisation need, 2) Well-established primary healthcare services are important to provide person-centred care through interdisciplinary collaboration and 3) Interdisciplinary collaboration in primary healthcare services is predominantly focussed on handling acute physical conditions.By focusing on the whole person, it could be possible to provide more person-centred care through interdisciplinary collaboration and ultimately prevent some hospitalisations. The findings have clear implications for person-centred care and health system quality, and they highlight the need for involving stakeholders at all levels and for informing about the relevance of social and mental conditions, as they may influence the general health state and the risk of hospitalisation. The study supplements existing knowledge by providing valuable insight into the views of key primary healthcare providers.\u2022\u2002Healthcare providers are attentive towards the influence of mental, social and physical conditions on the risk of hospitalisation highlighting the importance of care that considers the whole person.\u2022\u2002The development and sustainable implementation of person-centred care in local primary care settings may be supported by evidence-based practices and co-production trajectories."} +{"text": "Frontiers in Physiology that focused on integrative physiology of common chronic MSK disorders. We received 13 submissions for this special topic issue, of which seven were judged by us (the editors) and the peer-reviewers as meritorious for inclusion. These are briefly summarized here.Musculoskeletal (MSK) disorders are most one of the most commonly reported medical conditions , and areBird et al.) identified movement strategies associated with the development of MSK injuries in military personnel, and observed that lower braking rate, braking impulse, and propulsive impulse during a countermovement jump were associated with increased MSK injury risk. Additionally, higher degrees of flexion and longer countermovement jump phase durations were linked to increased MSK injury risk. Interesting, males were distributed equally across injury clusters while females were primarily distributed in the high-risk cluster. Their findings hold strong clinical relevance to numerous fields as they provide actionable thresholds that can be applied to screening measures to identify individuals at increased MSK injury risk.Bird and others examined whether baseline measures of bone density, geometry, and estimated bone strength are predictive of tibial bone stress injuries in military personnel. Their findings indicated that narrower bones, with reduced circumference, lower total area, and lower estimated bending strength were associated with increased risk for tibial bone stress injury during military training. These findings highlight the importance of assessing factors beyond bone mineral density to understand fracture risk.Davi et al.) leveraged a non-invasive anterior cruciate ligament (ACL) injury rodent model to explore the effect of an isolated ACL injury on mitochondrial function, atrophy, and muscle phenotypic transitions. They observed that mitochondria-derived reactive oxygen species increased following ACL injury concomitant with a two-fold reduction in the mitochondrial respiratory control ratio. Male rats displayed myofiber atrophy and fiber type shifts while female rats displayed no such changes. A positive relationship was observed between mitochondrial respiration and myofiber size. Thus, they concluded that long-lasting impairments in mitochondrial health are present after ACL injury and play a key role in the dysregulation of quadriceps muscle size and composition.Davi and others used a rat model to examine whether muscle unloading imposed during juvenile development would elicit more severe disruption in neuromuscular function than when imposed on mature neuromuscular systems. Juvenile and mature rats were divided into a 2-weeks hindlimb unloading group or a control group. The unloading protocol resulted in similar degrees of atrophy in juvenile and mature muscles. Interestingly, though, the juvenile muscle displayed significantly more loss of specific tension as well as more degradation in the function of the neuromuscular junction. These results indicate that juvenile neuromuscular systems are more sensitive to the effects of unloading than mature ones and suggest the primary locus of this developmental related difference is the neuromuscular junction.Deschenes and others used wild-type and several dystrophic mouse models to determine if maintenance of plasmalemmal excitability during and after a bout of eccentric contractions is dependent on the dystrophin glycoprotein complexes rather than, solely, dystrophin expression. The contractions caused all mouse lines to lose torque with the deficits being greatest in the dystrophic mice. Notably, loss of torque did not correspond to a reduction in plasmalemmal excitability in wild type mice, but a more than 50% reduction in plasmalemmal excitability was observed in the dystrophic mice. An large amount of the variability (98%) of the torque loss was explained by reduction in plasmalemmal excitability in the dystrophic mice. Thus, by comparing mouse lines that had varying amounts and functionality of dystrophin and other dystrophin glycoprotein complexes they demonstrate the significant role the dystrophin glycoprotein complexes play in maintaining plasmalemmal excitability.Baumann and others probed the skeletal muscle proteome of cancer patients who were in a randomized trial investigating the effect of adjunct testosterone on body composition in late stage or recurrent head and neck or cervical cancer. Muscle biopsies were obtained before and after 7-weeks of treatment. Proteoforms showing significant changes were identified by mass spectroscopy, and lists of altered proteins were subjected to Gene Set Enrichment Analysis to identify affected pathways. Their findings indicated that cancer and standard of care treatment significantly altered the skeletal muscle proteome in a manner suggestive of loss of structural integrity, reduced contractile function, and disrupted metabolism. Proteomic analysis suggests that the addition of adjunct testosterone minimized the structural and contractile influence of cancer and its associated therapies.Dillon and others describe and discuss the MSK effects of altered growth hormone action. Growth hormone, a peptide hormone that can signal directly through its receptor or indirectly through insulin-like growth factor 1, draws its name from its anabolic effects on muscle and bone but also has distinct metabolic effects in multiple tissues. In addition to its metabolic and MSK effects, growth hormone is closely associated with aging, with levels declining as individuals age. However, growth hormone action has been negatively correlated with lifespan. This review article provides an overview of the MSK effects of growth hormone using data from both clinical and animal models.Lastly, Young and others as well as muscle wasting and weakness disorders. Overall, they represent basic and applied physiology work with relevance to these highly prevalent and burdensome conditions."} +{"text": "In this theme issue, our multidisciplinary contributors highlight the cognitive adaptations of marine mammals. The cognitive processes of this group are highly informative regarding how animals cope with specifics of and changes in the environment, because, not only did modern marine mammals evolve from numerous, non-related terrestrial animals to adapt to an aquatic lifestyle, but some of these species regularly move between two worlds, land and sea. Here, we bring together scientists from different fields and take the reader on a journey that begins with the ways in which modern marine mammals utilize their perceptual systems, next moves into studies of the constraints and power of individuals\u2019 cognitive flexibility, and finally showcases how those systems are deployed in social and communicative contexts. Considering the cognitive processes of the different marine mammals in one issue from varying perspectives will help us understand the strength of cognitive flexibility in changing environments\u2014in marine mammals and beyond. Tursiops truncatus) in human care has revealed astonishing cognitive capabilities, sometimes even rarely observed in other non-human animals . Particularly, research with bottlenose dolphins in which they frame new developments in the field, review past research, or highlight ideas as well as novel experimental approaches for future research.Megaptera novaeangliae) produce remarkable vocalizations heard over many kilometers .While most research on perception deals with sensory modalities in isolation, marine mammals often rely on input from numerous modalities at once. Hence, it is important to assess how sensory systems work together and how sensory information is integrated an \u201cinnovate cue\u201d to which the whales either presented entirely novel behaviors or displayed a behavior not shown in the session before. Behavioral flexibility was also approached in two reversal learning experiments including harbor seals (Phoca vitulina) brain and the size and connectivity of its caudate nucleus as putative neural substrate for three dimensional sensorimotor transformations. The sea lion\u2019s caudate nucleus is large relative to brain volume, whereas the putamen is surprisingly small, and shows strong connections to other brain regions, unusually so when compared to other species. This study advances our understanding of the pinniped brain which has received relatively little scientific attention heretofore and raises a number of aspects such as the function of the caudate nucleus in respect to the three-dimensionality of the environment, to hunting behavior and even to cognitive flexibility, also discussed in three manuscripts in this special issue (Erdsack et al. The specific conditions encountered underwater might have also affected neural adaptations. One of the most prominent differences between aerial and underwater habitats is the three-dimensionality of the underwater environment which allows for a high degree of freedom of movements, perhaps even more so than flying animals experience given how many marine mammals periodically swim upside down and rotate quickly around all body axes. Cook and Berns focus onOur final section takes perceptual and cognitive processes into the social domain. Acquiring insight into mechanisms of conspecific interactions is critical to understanding marine mammals as many species are social, and all species interact for breeding purposes. In this special issue, entries on communication and social cognition move from a demonstration of conspecific gaze following in bottlenose dolphins (Johnson et al. Overall, this issue brings together complementary aspects of work with marine mammals under human care and in the field, providing insight into the neural, perceptual, and cognitive structures of marine mammals as we understand them today. The contributions highlight that adaptation to the underwater realm has shaped cognition and that marine mammals possess cognitive flexibility on numerous levels\u2014two avenues of marine mammal cognitive research worth pursuing further in future studies. From the contributions, we additionally learn that we should look for and expect species-specific cognitive adaptations and should document individual approaches to, or performances in, cognitive tasks (as reported in Erdsack et al. This special issue also helps to assess and stress the role of cognitive processes with respect to environmental changes. Numerous authors mention the need to include cognition in conservation plans or to consider cognitive abilities when assessing the impact of anthropogenic activities in the ocean, the habitat of the marine mammals. Gulland et al. note aspIn conclusion, this special issue on marine mammal cognition presents variety within a shared focus and functions as a comprehensive source of literature as well as inspiration for experts both within and outside the field. We hope that your reading will offer many enjoyable moments of discovery."} +{"text": "While extensive recent data details risk factors for psychoses in urban milieu, insights regarding recovery processes in cities are scarce. This hampers the translation of promising epidemiological and neuroimagery findings into effective therapeutic strategies. Given the twofold higher incidence of psychoses in cities and the fact that 68% of world population will be urban by 2050, it becomes an urgent matter of psychiatric care.This presentation details specific targets for therapeutic interventions in city context to further discuss a pioneering participatory project with the aim to conceive a novel city specific recovery-oriented program.Based on most recent research data, some of which our own, a comprehensive survey of urbanicity studies and an overview of main avenues for developments will be presented.Urban milieu is a complex dwelling space made of protective and disruptive features. During each life course they may form unique combinations hampering or enhancing psychological well-being. Urban living is not only correlated with higher prevalence of psychoses, but also with better access to health care and lower rates of treatment resistant schizophrenia, pointing to some beneficial aspects of city living on recovery processes. The interplay between personal characteristics, urban resources and supportive social environments seems pivotal to recovery calling for multilevel interventions and integration of different stakeholders .Participatory approach represents an important means of innovation and ensures the best match between patients needs and therapeutic propositions."} +{"text": "Neurosurgery Focus: Video provides 11 videos that illustrate a variety of spinal deformity treatment techniques and revision strategies.Spinal deformity includes a broad range of pathologies and has an impact across the continuum of life, from early-onset scoliosis (EOS) in a young child to degenerative scoliosis with sagittal malalignment in the elderly. How these patients are managed clinically and surgically has advanced remarkably over recent decades, but the field remains in evolution. Surgical treatments are often complex, include techniques that are challenging, and continue to have relatively high complication rates. This issue of Three-column osteotomies are among the most complex procedures for spinal deformity correction. Two videos focus on these osteotomies, including the use of vertebral column resection (VCR) for severe kyphosis correction by Gupta and the use of a special hinged table for closure of pedicle subtraction osteotomies (PSOs) by Chang and colleagues. Two additional videos describe approaches to help avoid the need for these major osteotomies, including the application of hyperlordotic anterior lumbar interbody fusion (ALIF) cages by Marino and colleagues and the performance of minimally invasive lateral anterior column release (ACR) by Ohiorhenuan and colleagues.Two videos describe the relatively new technique of oblique interbody fusion, one demonstrating its application to iatrogenic deformity and the other incorporating the use of navigation . Two additional videos focus on revision techniques, one addressing the challenging problem of proximal junctional kyphosis (PJK) and the other demonstrating the revision of surgically treated adolescent idiopathic scoliosis (AIS) in a patient who developed symptomatic degenerative changes later in life . High cervical pathologies are discussed in two videos that address posterior treatment for os odontoideum and techniques for vertebral artery mobilization at the atlantoaxial level . Navarro-Ramirez and colleagues show a novel growing rod technique to treat EOS.Collectively, the videos in this issue illustrate techniques and strategies to address a broad range of deformities, from EOS in infants and children to fixed sagittal plane deformities in adults. Modern surgical treatments for spinal deformity continue to evolve, and it is in large part by sharing these skills and advancements through the literature and video media that this knowledge is disseminated. We offer our sincere appreciation to those who submitted works for this special issue and hope that the audience finds these videos useful as they endeavor to care for their spinal deformity patients."} +{"text": "The current study aimed to examine the associations between drinking water quality and cognitive function and to identify the direct and indirect effects of drinking water quality and dyslipidemia on cognitive function among older adults in China. Data for the study were selected from China Health and Retirement Longitudinal Study and 4,951 respondents aged 60 and above were included. Dyslipidemia was measured by self-reported dyslipidemia diagnosis and lipid panel. Three composite measures of cognitive function included mental status, episodic memory, and global cognition. Mixed effects models were conducted to assess the associations between drinking water quality or dyslipidemia and cognitive function. The mediation effects of dyslipidemia were examined by path analyses. Results showed that exposure to high quality drinking water was significantly associated with higher scores in mental status, episodic memory, and global cognition . Elevated blood triglycerides was associated with higher scores in mental status and global cognition . Self-reported dyslipidemia diagnosis was a suppressor, which increased the magnitude of the direct effect of drinking water quality on mental status and global cognition. Findings of the study suggest that improving drinking water quality could be a potential public health effort to delay the onset of cognitive impairment and prevent the dementia pandemic in older people."} +{"text": "Estimating the effects of variants found in disease driver genes opens the door to personalized therapeutic opportunities. Clinical associations and laboratory experiments can only characterize a tiny fraction of all the available variants, leaving the majority as variants of unknown significance (VUS). In silico methods bridge this gap by providing instant estimates on a large scale, most often based on the numerous genetic differences between species. Despite concerns that these methods may lack reliability in individual subjects, their numerous practical applications over cohorts suggest they are already helpful and have a role to play in genome interpretation when used at the proper scale and context. In this review, we aim to gain insights into the training and validation of these variant effect predicting methods and illustrate representative types of experimental and clinical applications. Objective performance assessments using various datasets that are not yet published indicate the strengths and limitations of each method. These show that cautious use of in silico variant impact predictors is essential for addressing genome interpretation challenges. The drastic reduction in the cost of genome sequencing over the last decade to achieve their goal, which may either be narrow sets of orthologous sequences or larger sets that include distant homologs and paralogs. The choice of MSA affects the performance of the prediction methods and using the MSA provided by each method does not guarantee optimal performance the repression activity of 4041 lac repressor mutations in E. coli compared to unaffected individuals (controls). These selection patterns arise because trait driver genes harbor several pathogenic variants in cases, in addition to non-pathogenic variants that may appear in either the cases or the controls. Current gene discovery methods may quantify patterns such as whether the gene has more mutations compared to the expected number (Lawrence et al. Many cancer studies use variant impact prediction methods either as supporting evidence for the pathogenicity of gene variants (Bailey et al. Variant impact prediction methods are commonly used in prioritizing the functional effects of de novo variants (Hu et al. Case\u2013control studies are routinely designed for the discovery of genes associated with a particular trait. For Mendelian traits, these associations are straightforward, and methods predicting protein function effects can help (Carter et al. This review of current computational estimates of protein function effects due to variants illustrates several practical applications. They routinely guide experimental studies of protein structure and function and clinical studies of variants of unknown significance that are candidate disease drivers. Most recently, they played a major role in identifying new genes associated with traits, for either somatic, de novo, or inherited variants. This ability to translate genomic data into quantitative traits raises hope for improved diagnostic tests with polygenic risk scores that account for functional effects rather than relying only on observational statistics.\u00a0A caveat is that the basis for most methods remains rooted in homology information. The scores will thus tend to assess long-term \"evolutionary\" effects. Generally, and depending on the prediction method and the test data, these effects will tend to align with clinical or experimental impact as shown by strong correlations through extensive validation studies and objective assessments. In other words, the fitness landscape may appear similar at different scales.evolutionary sense,\" which at best matches the human population at large rather than addressing the context-dependent effects of the variants (DiGiammarino et al. average context\u201d of the computation and its potential biases and errors will affect the accuracy of the predictions (Hicks et al. In the past, variant impact prediction methods sustained pointed criticism (Flanagan et al. Whole genome sequencing shows that non-synonymous variants are less than 0.3% of the total calls (Shen et al. Genome interpretation relies on the classification of genetic variants as pathogenic or benign, which necessitates the estimation of impact for all single variants. Clinical associations and experimental data are too limited for characterizing all variants, since more than 98% of the variants in human exomes have frequency of less than 1% (Karczewski et al."} +{"text": "There is growing recognition that the mental health and wellbeing of the LTCF workforce have been disproportionately impacted by COVID-19. Therefore, we sought to describe the experiences and challenges LTCF employees faced during COVID-19 in rural and northern communities and highlight factors affecting their ability to be resilient and provide high quality care. We conducted 53 qualitative interviews using zoom with LTCF care providers , staff , and management between November 2021 and February 2021. Data was transcribed and thematic analysis undertaken. We will describe participants experiences stratified by LTCF employee type and highlight similarities and differences in participants experiences across geography and facility type and describe factors affecting well-being, job satisfaction, and retention. We will share an inventory of programs and strategies participants found useful to mitigate negative effects on their mental health and well-being."} +{"text": "Population aging in wealthy western nations has raised concerns about who will provide care to older adults. At the same time, the rise of single parenthood and dual-career families has heightened the need for childcare. As governments and families face challenges in meeting these dual needs, this study compares responses to the question of \u201cwho should primarily provide\u201d eldercare and childcare across three countries: the US, Germany and Israel. Analysis of 2012 International Social Survey Programme data reveals that while persons in the US endorse family as care providers to both older adults and children, Israelis endorse government as eldercare providers yet family as the source of childcare provision. German respondents prefer both government and family as childcare providers, yet believe the government should provide eldercare. The paper discusses how cross-national differences in attitudes toward care are associated with cultural and socio-economic characteristics, and highlights implications for policy and practice."} +{"text": "Knowledge about diurnal, seasonal, and annual fluctuations in airborne pollen and fungal spores in any geographical area is essential for effective diagnosis and treatment of allergies. Aerobiological analysis enables the detection of airborne pollen and spores, thus providing information on plant phenology, plant distribution, related diseases, and the risks for some species in terms of allergies. Although pollen and fungal spores have been widely studied as aeroallergens throughout the world, not much is known about the biological aerosols in countries with a desert environment; and these could be present in much higher concentrations than expected. Arid desert regions (including the region surrounding the Arab Gulf), characterized by hot weather, poor soils, and low biological productivity, have typically been neglected when building ambitious biomonitoring networks for the large-scale monitoring of biological particles; however, few studies in Kuwait, Saudi Arabia, and recently Qatar have aimed to delineate the various botanical families that contribute to inhalant allergens in this region.Understanding the aerobiological features of countries with hot and desert climates may better prepare healthcare providers to assist patients with allergic rhinitis. It may be argued that one of the reasons why aerobiologists have only recently turned their attention to the state of Qatar investigating how pollen and fungal spore records could contribute to evaluating the correlation between different pollen conditions and allergy symptoms.The first aerobiological network of Qatar was monitoring (2017\u20132020) the atmospheric pollen concentrations of Doha and Al Khor to determine the association between the possible risk of respiratory allergies and the distribution of certain species throughout the region. In the Qatari database, more than 25 native taxa have been recorded, up to 50% of which can be considered allergenic. This includes Amaranthaceae and Poaceae pollen among the major aeroallergens causing allergy symptoms in Qatar. Our study has confirmed a statistically significant association between Amaranthaceae and asthma and allergic rhinitis. To summarize, it is worth considering aerobiological monitoring in desert climate regions when assessing the effectiveness of pollen allergy therapy and planning prevention methods for patients."} +{"text": "Neurocognitive disorders are among the most stigmatized medical conditions in the USA and across the globe. Cultural beliefs about cognitive aging also impact how individuals, families and healthcare teams respond to concerns about cognitive impairment. GSA\u2019s revised KAER Toolkit for Primary Care Teams provides useful information for the early stages of this process, including kickstarting the conversation about brain health concerns and conducting screenings. This presentation outlines additional competencies for behavioral health clinicians involved in patient, family, and health care team discussions regarding cognitive health concerns. Culturally responsive strategies and resources are suggested to help clinicians explore the decision for a formal evaluation and shape the nature of the referral question(s)."} +{"text": "Integrating electronic health records (EHR) with health administrative data offer opportunities for enhanced decision support, health systems evaluations and research for improved patient care. We describe the process of integrating EHR data from 12 hospitals in Southwestern Ontario, Canada and present a health systems evaluation enabled by this linkage.With support and buy-in from the hospital Chief Executive Officers, a data sharing agreement (DSA) with ICES was executed, outlining the process to approve data transfer requests. Due to the complexity and volume of the EHR, complete data were not immediately transferred to ICES; instead, a project subcommittee comprising of physician leadership, local and regional privacy and risk officers, and ICES staff was assembled to review and approve project-specific data integration requests. An evaluation of the adoption of an electronic medication reconciliation system within the EHR on potentially inappropriate prescribing after hospital discharge was conducted using interrupted time-series analyses.The data integration request process begins with confirmation of data availability and accuracy within the EHR, enabled by a dedicated health information analyst and institutional decision support teams. Once data feasibility is confirmed, project rationale is submitted to the project subcommittee approval. Following approval, the request undergoes privacy and legal assessment as per the DSA and a project-ready dataset is submitted for linkage.An evaluation of the adoption of an electronic medication reconciliation system demonstrated an immediate and dramatic reduction in inappropriate medication prescribing and associated adverse events such as a fall or fracture among elderly patients discharged following acute inpatient stays.Administrative data are valuable at assessing population-based health, but often lack key clinical information present in EHRs. Integrating both data sources offers a more comprehensive picture of patient care and allows for robust analyses. Rigorous investigations generate trusted evidence for decision makers to inform policy and quality improvements within the healthcare system."} +{"text": "The association of ADHD with mental health and medical conditions is commonly encountered in clinical practice. Interestingly there are patients with congenital conditions who present with features of ADHD and little is known about their association and neurological basis. There is no strong literature but anecdotal reports that indicate children with congenital heart disease are more likely to suffer from mental health conditions including ADHD. The clinic however is unable to analyze such hypothesis and instead decided to evaluate cases related to Neurofibromatosis (NF1), Arnold Chiari Malformation, Transposition of great arteries, Di George syndrome to understand the longitudinal history, symptom persistence and functional impact of ADHD.Index patient aged 45 years referred for possible association of ADHD and Neurofibromatosis with issues related to long-standing trouble with sleep and movement disorder.Index patient aged 41 years received a surgical repair for a Chiari malformation hoping it would improve the cognitive functioning but still suffers lot of symptoms that are consistent with clinical picture of ADHD.Index patient aged 19 years referred for ADHD assessment reported history of transposition of great arteries and VSD that warranted emergency operative procedure before age 3. The behavioural symptoms that were suspected as related to physical illness and frequent attendance to hospital however did not resolve and were noted to be in line with possible ADHD.Index patient aged 40 years admitted to general psychiatry following episode of psychosis and during examination presented history of Di George syndrome with brief input from Cardiology. It was apparent that patient struggled with poor understanding, lack of consistency, disorganization, distractibility, learning difficulties and the features suggested a pattern of Attention deficit disorder.The qualitative analysis of developmental history, childhood rating scale, symptom comorbidity and functional impairment of such cases.It studied the family history of physical and mental illness including predisposition to ADHD or neurodevelopmental conditions.It also evaluated the treatment response to stimulant/non-stimulant therapy.Focused onClinically there was no typical co-relation of increased mental illness or genetic predisposition for ADHD in the family history and qualitatively the presentation did not differ from other ADHD patients and the treatment response was not variable, however it still draws attention towards the need for regular screening of all nervous and cardiac origin congenital conditions for an early intervention."} +{"text": "In Europe, maternal and child mortality and morbidity during pregnancy and childbirth have declined markedly since the turn of the 20th century, but recent data suggest this trend may be slowing or reversing. Improvements in perinatal health were due primarily to increases in overall standards of living and clinical advances in obstetrics and neonatology which successfully increased maternal and newborn survival when pregnancy complications arose. However, fewer gains have been made in prevention and, in many countries, preterm birth and low birthweight rates have increased. To further improve perinatal health, a population-level approach focusing on prevention and appropriate use of clinical interventions is required. Prevention strategies include reducing risk factors and ensuring universal access to high-quality health care due to the key roles played by early antenatal care, regular antenatal appointments and referral pathways in the timely identification and management of pregnancy complications. A population approach is particularly essential because both the burden of disease and the dangers of poor care organization fall disproportionately on socially disadvantaged women and babies, contributing to lifelong health inequalities. A final challenge is to avoid over-medicalising pregnancy and childbirth for the large majority of women with uncomplicated pregnancies. Medical technology has contributed greatly to the decline in maternal and infant mortality and morbidity, but clinical intervention can carry risks and must be used appropriately to optimise health outcomes. Despite commonalties such as universal access to health care and access to scientific knowledge, perinatal health outcomes and approaches to maternity care differ greatly between European countries. In this context, comparisons between different European models can be powerful tools for identifying population risk factors, assessing care practices, setting targets for population policies and for understanding their strengths and weaknesses to provide insight into the efficacy of health and medical policies. Currently, European comparisons are limited by the availability, timeliness and quality of population data on maternal and newborn health. This workshop reports on a new protocol implemented by the Euro-Peristat network to provide comparable perinatal indicators from countries across Europe. Based on select core indicators collected using a common protocol, we provide a proof of concept study for a future health information system and report up-to-date data on perinatal outcomes. The four presentations in this workshop present this protocol, describe most recent trends and disparities between countries, explore social inequalities in perinatal outcomes across Europe and raise questions about approaches which can achieve low mortality and morbidity while keeping intervention rates low.\u2022\u2002A federated analytical approach is an efficient and feasible way to collect timely, high-quality and comparable population data on perinatal health in Europe.\u2022\u2002Marked disparities in perinatal health remain between and within European countries. Our results demonstrate a need for targeted policies in many countries and offer data to inform these initiatives."} +{"text": "The literature shows a high prevalence of psychopathological problems, anxiety and depression among university students because of academic expectations, uncertain future plans, staying away from their family, economic issues and peer relationships. Although these problems show high prevalence among university students, providing them a professional care is limited so most of problems remain untreated. Nowadays the students use digital technologies commonly therefore web based and computer delivered interventions may be useful for them to improve resilience and coping strategies.The intent of the study was to review systematically the impacts of web based and computer delivered interventions regarding stress management among university students.Several databases were searched with using key words such as university students, online interventions, web based interventions and stress management. Randomised controlled studies were reviewed.We found 284 article with the key words. Only four of them met the including criterias. All results of reviewed articles show that web based online interventions have an impact to reduce depression, stress and anxiety level among students. According to the results students improved coping skills against stress after web based online sessions.The findings show that web based and computed delivered interventions can be effective to improve resilience and reduce students` depression, anxiety and stress symptoms when compared non-interactive and inactive controls. In addition online interventions regarding stress management may provide us to reach out large group of university students.No significant relationships."} +{"text": "Evidence suggests that individuals with serious mental illness (SMI) die up to twenty years prematurely compared to the average population without SMI with the main causes of death linked to preventable cardiovascular disease, respiratory failure, and endocrine disorders. This early mortality remains despite national efforts to recognise the issue and promote development of processes to enhance quality of physical health care in patients with SMI. The National Institute for Health and Care Excellence (NICE) clinical guidelines (CG178) recommendation 1.5.3.5 states that healthcare professionals in secondary care should ensure individuals with SMI receive physical health checks from primary care. This idea may be suitable for patients in the community setting or those who undergo shorter hospital admissions, however the process of psychiatric rehabilitation in secure mental health hospitals is challenged by long average stays resulting in no access to routine primary care facilities. The aim of the project is to introduce tailored measures that would aid in delivering high quality physical health care to patients within secure mental health hospitals.Ravenswood House Medium Secure Hospital supported a project to improve the physical health of individuals with SMI. An audit was completed to evaluate the assessment and management of baseline physical health measures that would have usually been completed in primary care as per the standards set out in NICE guidelines. The results showed that not all measures were being met and there was room for improvement.Based on these NICE recommendations, an annual health check template and a centralised documentation toolkit were implemented and integrated within a new Physical Health Care Pathway in collaboration with General Practitioners, Dentists, Physiotherapists and other Allied Healthcare professionals.Following implementation of the Physical Health Care Pathway, the number and quality of annual physical health checks in Ravenswood House Medium Secure Hospital increased resulting in significantly better-quality outcomes for patients by completing appropriate referrals and follow-up care.This collaborative approach of providing a high-quality physical health care was delivered in-house by arrangement with external healthcare practitioners. This pathway of providing care assisted us in overcoming several challenges faced within secure hospitals due to legal sanctions and related security protocols involving the patient group."} +{"text": "Lung physiology research advanced significantly over the last 100\u00a0years. Respiratory mechanics applied to animal models of lung disease extended the knowledge of the workings of respiratory system. In human research, a better understanding of respiratory mechanics has contributed to development of mechanical ventilators. In this review, we explore the use of respiratory mechanics in basic science to investigate asthma and chronic obstructive pulmonary disease (COPD). We also discuss the use of lung mechanics in clinical care and its role on the development of modern mechanical ventilators. Additionally, we analyse some bench-developed technologies that are not in widespread use in the present but can become part of the clinical arsenal in the future. Finally, we explore some of the difficult questions that intensive care doctors still face when managing respiratory failure. Bringing back these questions to bench can help to solve them. Interaction between basic and translational science and human subject investigation can be very rewarding, as in the conceptualization of \u201cLung Protective Ventilation\u201d principles. We expect this interaction to expand further generating new treatments and managing strategies for patients with respiratory disease. Respiratory mechanics has been extensively studied during the last century with resOver the years, accumulated knowledge in respiratory mechanics has been incorporated into mechanical ventilators and respiratory functional assessment of patients . RespiraIn this review, we describe some of the mathematical approaches used in respiratory mechanics in animal models and in patients and their application in the development of mechanical ventilation. Finally, we will discuss how respiratory mechanics is still important for both research and clinical care and how it can provide insightful information moving respiratory science forward.Animal models have been extensively used to elucidate different physiological mechanisms leading to respiratory disease development, such as asthma and chronic obstructive pulmonary disease (COPD).Generally, the assessment of respiratory mechanics in animal models is based on the acquisition of pressure and volume/flow data. From these data, mathematical models whose parameters have physiological significance are applied .The most used model for evaluating respiratory mechanics is known as the \u201cequation of motion.\u201d It is a linear one-compartment model that assumes the respiratory system is excited at a single frequency, usually very close to the respiratory rate Bates, . The parThe equation of motion does not contemplate viscoelastic phenomenon. Viscoelasticity is the property to accommodate stress following changes in volume (stress relaxation) . It can The respiratory system has a high frequency dependence. This led to the use of excitations with more than one frequency in order to calculate the respiratory impedance that basically characterizes the biomechanical behaviour of the respiratory system in the frequencies contained in the excitation Hantos .For a better physiological understanding of respiratory impedance, models are used whose parameters are correlated with dissipative (airway resistance and tissue viscosity) and conservative (elastance or tissue compliance) components. The most used model for understanding respiratory impedance in small rodents is the constant-phase model . This moRespiratory mechanics have been studied in several animal models of respiratory diseases. In experimental emphysema, researchers observed a decrease in tissue elastance and viscosity related to alveolar destruction and loss of viscoelastic properties , 2019b. Airway resistance increase is usually detected in experimental models of asthma where structural changes in airways are the major histological finding . Edema iin vitro. Using this technique, it is possible to calculate resistance and elastance of lung tissue strips and metal clips are glued to either end of the tissue strips with cyanoacrylate. Steel wires are attached to the clips; one side is connected to a force transducer and the other side is connected to a servo-controlled lever arm. The lever arm is capable of peak-to-peak length excursions. It is connected to a function generator, which controlled the frequency, amplitude, and waveform of the device oscillation (A0) of the strip was obtained from the formula:Oscillatory mechanics and the constant phase model described above allowed a more complex and accurate description of lung function . In the Besides allowing mechanistic investigation on several lung diseases, respiratory physiology largely contributed to evolution of mechanical ventilation. In the past century, mechanical ventilation evolved from bulky and cumbersome negative pressure chambers (iron lungs) to modern positive pressure ventilators . Over deIncorporation of positive end expiratory pressure (PEEP) to mechanical ventilators became widespread after the description of Acute Respiratory Distress Syndrome (ARDS) in 1967 and obseSome ventilatory modes added in time to ventilators were largely based on lung physiology. In Proportional Assist Ventilation (PAV), lung compliance and resistance are used to determine the amount of airway pressure delivered by the ventilator . In NeurAssessment of lung mechanics is used in daily clinical care. In patients receiving invasive mechanical ventilation, the equation of motion is used to describe lung mechanics and to assist in the characterization of respiratory failure . PhysiciIn ARDS, measurements of lung compliance inform t2-based table to guide PEEP setting. This method can be suitable in the busy ICU environment but did not reduce ARDS mortality generated by reduction tidal volume were initially regarded as benign. Later, some authors recognized hypercapnia was associated to impaired immunologic response and vascular tonus dysfunction. Hypercapnia increases pulmonary resistance and can contribute to acute cor pulmonale or mechanical ventilator (after intubation) . Even whGuidelines for properly managing those patients are still missing. We will need further cooperation between basic and clinical science to understand the limits of lung protective ventilation. We need to understand when this strategy is absolutely required warranting muscle paralysis; and when we can be more flexible on these rules. We also need to understand what other lung disorders require limiting tidal volume.Patients with respiratory failure secondary to obstructive lung disease can require mechanical ventilation. Ventilatory strategies for these patients are designed to avoid air trapping and intrinsic PEEP (PEEPi) generation . PEEPi iIn obstructive patients, equation of motion can be used to measure lung resistance and monitor the response to treatments: bronchodilators, antibiotics and management of airway secretion. PEEPi can be measured with expiratory pause, informing bedside decisions on setting ventilator parameters.However, there are limitations for the use of lung mechanics in those patients. Equation of motion is usually applied only to inspiratory phase, where airway pressure variation is significant. Measurement of airway resistance during expiration is often neglected despite its importance in generating PEEPi. Some patients in respiratory failure reach a condition of expiratory flow limitation, where airways collapse at the mid-end expiration . In thisAdditionally, patients on mechanical ventilators are often awake and have spontaneous breathing. In this setting, if pressure generated by respiratory muscles is not measured , lung meIn the future, widespread use of esophageal pressure catheters can allow monitoring of respiratory effort and assessment of lung mechanics in patients with spontaneous breathing . PEEPi cFor different reasons, several physiological approaches developed in the lab did not reach bedside yet and will be discussed in the paragraphs below. Some of these techniques are laborious or provide data clinicians are not ready to use. Some techniques, on the other hand, did become commercially available but are still seldom employed.Multiple inert gas elimination technique (MIGET) was designed for determining ventilation/perfusion distribution throughout the lungs using several gases with different solubility on blood. MIGET advanced knowledge of respiratory physiology in different species and elucidated mechanisms of hypoxia in different disorders . The tecElectrical Impedance Tomography (EIT) evolved from very simple and inaccurate devices to monitor respiratory rate into complex continuous monitors of lung ventilation. Recent advances in the technique also included perfusion and V/Q distribution measurement using electrocardiography-gated impedance signals or following hypertonic saline infusion . There sAlthough not used in many ICUs, EIT became commercially available and can provide useful information on ventilation during patient care. It can be used to improve PEEP titration since it displays both overdistention and lung collapse. It also provides a visual and numerical analysis of ventilation homogeneity, can detect pneumothorax in real time and displays patterns of ventilation during spontaneous efforts . In the 2 concentrations and nitrogen dilution to estimate lung volumes has brough additional complexity to the field. Once limited to operating rooms, ECMO use in ICU became more popular after influenza (H1N1 in 2009) and COVID (2020) pandemics . AlthougThe study of lung mechanics has substantially contributed to development of knowledge of respiratory diseases. It was also a cornerstone in the creation and evolution of mechanical ventilation. The combination of basic, translational and applied sciences has proved very useful in respiratory physiology leading not only to better understanding physiopathology but also to designing supportive treatment. In the years to come, we expect this partnership to continue as we face new challenges in managing patients with respiratory failure."} +{"text": "Antimicrobial resistance (AMR) is a quickly advancing threat for human health worldwide and almost 5 million deaths are already attributable to this phenomenon every year. Since antibiotics are failing to treat AMR-bacteria, new tools are needed, and human monoclonal antibodies (mAbs) can fill this role. In almost 50 years since the introduction of the first technology that led to mAb discovery, enormous leaps forward have been made to identify and develop extremely potent human mAbs. While their usefulness has been extensively proved against viral pathogens, human mAbs have yet to find their space in treating and preventing infections from AMR-bacteria and fully conquer the field of infectious diseases. The novel and most innovative technologies herein reviewed can support this goal and add powerful tools in the arsenal of weapons against AMR. The phenomenon called antimicrobial resistance (AMR), emerged as one of the leading public health threats of the 21st century. The review on antimicrobial resistance, commissioned in 2014 by the UK Government, estimated that AMR could kill 10 million people per year by 2050 that targeted the RSV fusion (F) protein : Multimerized antibodies that include several antigen binding sites are a potent tool of considerable interest in the field of therapeutic mAbs. In a recent study, Divine and colleagues established a new method, applicable to IgG antibodies, to increase antibodies valency through antibodies protein nanoparticles Fc receptor, an intracellular detection system for opsonized pathogens that have evaded lysosomal degradation while promoting their pairwise hetero-oligomerization after binding co-expressed antigens on the surface of the targeted cells (Oostindie et al., The technological and methodological advancements of the last 50 years brought the field of mAb discovery and engineering at their peaks. Despite that, only 26 mAbs against bacterial pathogens have so far reached clinical phases for efficacy evaluation and only five were approved by the FDA. Therefore, a further step forward needs to be made. The new technologies herein described can contribute to this effort and finally allow monoclonal antibodies to find their place in the fight against AMR.All authors contributed to the conceptualization, writing, and final revision of this manuscript."} +{"text": "While current consensus-driven sarcopenia staging algorithms relate loss of muscle strength, muscle mass, and diminished physical functioning, there is a need to incorporate muscle quality and metabolic health into the larger concept of age-related Skeletal Muscle Function Deficit (SMFD). Factors underpinning muscle quality play a critical role in decreased muscle function, impaired mobility, and metabolic dysfunction in older adults. Changes in muscle quality develop faster and appear earlier compared to changes in muscle mass. Recent attention has focused on changes in muscle composition based on myosteatosis (inter and intramuscular adipose tissue and intramyocellular lipids), which are known to adversely affect metabolism and peak muscle force generation and lead to a multitude of negative outcomes. The age-associated decline in lean body mass and the increase in myosteatosis are part of the development of several comorbid conditions in older adults that can result in physical impairment, frailty, and disability. .Standardized approaches to assess the various aspects of muscle quality that influence major muscle functions and contribute to SMFD are needed. A rapid assessment of muscle composition across multiple clinical settings with minimal patient burden is highly desirable, but garnering consensus on the major domains of muscle quality and on measurement methods suitable for a variety of such settings are pending. This will help advance knowledge of SMFD and identify individuals who would benefit from interventions directed at improving muscle quality. .This Research Topic holds manuscripts primarily using original studies including experimental research, with a focus on the biology, epidemiology, clinical or interventional research that document advances in knowledge of the role of muscle quality in aging related SMFD.Eshima discusses the impact of metabolic disorders, such as obesity and type 2 diabetes, on the regulation of (Ca2+)i in skeletal muscle. The author suggests that impairment of the (Ca2+)i flux in obesity and type 2 diabetes may contribute to skeletal muscle contractile dysfunction, which represents a reduction in muscle quality, and may be a promising target for a therapeutic approach for obesity- and type 2 diabetes-induced myopathy.The mini review by Poggiogalle et al.investigated the impact of protein intake in the context of an obesogenic diet on skeletal muscle function and intramuscular lipid infiltration. Adult and old male Wistar rats were randomly assigned to isocaloric standard or high protein diet and hypercaloric high fat with normal or high protein diet. The authors suggest that the effect of high-fat diet with enhanced protein intake (25%) may be linked to the reduced intramuscular fat seen in adult rats; this may have contributed to at least some preservation of skeletal muscle contractile properties. Although further investigation is needed on the high-protein diet\u2019s potential role in preventing ectopic lipid deposition, high-protein intake seemed to mitigate the negative effects of a high-fat diet on skeletal muscle performance in adult rats but not in old rats. The authors relate these findings to lifespan changes in adult rats and their old counterparts in response to nutritional modulation of body composition and physical function.Brown et al.evaluated muscle quality in the diaphragm muscle (DIAm) of rats. Muscle quality is distressed with age, exclusively in type IIx/IIb fibers. Aging does not seem to impact mitochondrial structure and function in type I and IIa DIAm fibers, as these continue to sustain breathing throughout life. In such fibers, mitochondria are abundant and more filamentous. In type IIx/IIb DIAm fibers, mitochondria are less abundant, more fragmented, and less functional. The authors suggest that mitochondrial fragmentation is likely a prime determinant of muscle fiber quality, and that interventions aimed to improving mitochondrial deficits in vulnerable fibers could prevent the age-associated decline in skeletal muscle quality.Marron et al. document the need for separate examination of specific muscle groups when investigating fat infiltration. Data from the Multi-Ethnic Study of Atherosclerosis showed that associations differed between lipoproteins and intermuscular adipose tissue (IMAT) in the abdominal musculature, with the strongest relationships observed in the oblique muscles. Higher very low-density lipoprotein (VLDL) and lower high-density lipoprotein (HDL) were linked with higher muscle area, higher IMAT area, and lower IMAT density. The authors believe that such results are relevant to support additional studies seeking to establish whether the observed associations indicate a lipoprotein profile contributing to a decline in skeletal muscle quality and increased fatty infiltration with aging.Rossi et al. opens a new area of research by investigating IMAT as a risk factor for mortality and muscle injury in critically ill COVID-19 patients. Cross sectional data suggest that higher levels of IMAT/muscle and low muscle density are associated with higher risk of intensive care unit (ICU) mortality and muscle injury. Muscle quality measurements from thoracic imaging performed during hospital stay could provide valuable information on health outcomes . It was hypothesized that different factors, related to both intermuscular and intramyocellular adipose tissue deposition, can interfere with satellite cell activation and myoblast proliferation and differentiation, which are necessary steps to muscle repair after COVID-19 induced muscle injury. Intense inflammatory response in these patients leads to muscle strength deficit (upper and lower limbs), a phenomenon particularly relevant in obesity due to poorer clinical outcomes, higher mortality, and longer hospitalization. Additional longitudinal imaging and/or histological studies are critical to clarify the impact of COVID-19 induced inflammation on muscle damage in hospitalized subjects and the possible role of different muscle fat depots.Clark et al. provide new insights into prior and current evidence on the potential use of electrical impedance myography (EIM) as a measure of muscle health in aging and geriatric medicine. EIM has been shown to reflect muscle health status in a variety of conditions and neuromuscular diseases . EIM is mainly limited by the impact of the subcutaneous fat layer, but it is a simple, broadly available and not invasive method that reflects information on muscle quality. The authors suggest that EIM measurements combined with machine learning approaches could support the development of prediction equations for common key outcome variables indicative of muscle health. They find EIM a promising technique to be used clinically alongside the most common assessment methods for muscle strength and mass as an indicator of muscle quality.\u2713 Bridging molecular, pathologic, and population studies to identify what is being examined in the tissue and promote a better understanding of risk factors and mechanisms for myosteatosis, and whether the condition is reversible and to what extent.\u2713 Generating new evidence on other biologic causative factors including reactive oxygen species (ROS) known to closely relate to aging muscle and to negatively impact muscle quality.\u2713 Determining features of skeletal muscle characteristics that aid the sarcopenia and SMFD diagnosis including discriminating between patient groups and predicting incidence of metabolic disorders or disablement.\u2713 Identifying best practices for the method(s) of acquisition for cross-sectional and longitudinal studies, data acquisition and analysis using the same cutpoints nomenclature, followed by crosstalk between imaging modalities to ensure what is being assessed.\u2713 Identifying clinically feasible standardized imaging assessment tools to reliably evaluate muscle quality across a variety of settings. New validation studies remain essential to move toward a wider adoption of alternate imaging methods.\u2713 Conducting longer longitudinal cohort studies to examine a variety of muscles across sex/gender and racial/ethnic groups, and disease populations. The identification of which muscles should be examined and measured (how), as well as the establishment of widely accepted cutpoints will likely enhance clinical practice .\u2713 Determining the magnitude and significance of the associations between lifestyle risk factors such as objective measures of physical activity and sedentary behavior with muscle quality, particularly among older adults.\u2713 As therapies for preserving muscle mass, such as myostatin inhibitors and irisin-activating compounds, are already in development studies focusing on the biological determinants of myosteatosis and other components of muscle quality may have potential therapeutic implications.\u2713 Establishing multidisciplinary collaborations to examine combination treatments essential to manage individuals at risk. Combined examination of interventions will likely result in more useful information and provide new treatment options.The field of muscle quality and its impact on aging related SMFD is still in its infancy. Although muscle quality has been included in the definition of sarcopenia , no cons"} +{"text": "Neighborhood environments are increasingly recognized as an important determinant of health and function in older adults. Environmental supports such as density of intersections and available community resources can promote activity and participation which in turn promotes physiological health. In contrast, barriers such as disorder and high traffic can limit activity and participation, particularly for those at high risk for mobility limitations and falls. Here, we present five papers exploring these relations. First, Kate Duchowny presents work assessing relations of the built and social environment with muscle strength in the Health and Retirement Study. Two papers utilizing walkability assessments using Google Street View in a physical activity intervention trial are presented; Kyle Moored demonstrates relations of neighborhood walkability with Global Positioning System (GPS)-derived time out of home and Anisha Suri assesses how the relation between actigraphy-derived gait quality and daily step counts differs by walkability. Next, Philippa Clarke presents data on the association of neighborhood environment with diabetes risk in those with low visual function in an administrative claims database. Finally, Pam Dunlap describes results of a systematic review of outdoor environmental risk factors for falls and fear of falling. Together, these papers will demonstrate the breadth of ways in which neighborhood environments and function relate to determine health outcomes for older adults."} +{"text": "The platform also allows users to create customized charts and graphs to visualize caesarean section data quickly and effortlessly at specific time points, or over time for the whole obstetric population or per individual Robson groups . This feIn the Robson platform, users can view caesarean section rates for each health facility according to specific criteria of interest . Users will also be able to share data on clinical processes that will enable a deeper understanding of differences in caesarean sections and perinatal outcomes across maternity units. The platform is dynamic and will undergo continuous improvement, with additional features added according to user needs and feedback.When assessing and interpreting caesarean section rates and perinatal outcomes using the Robson classification, users are encouraged to consider other factors that are not provided in the platform but can have a significant impact on results. Health-system factors and clinical processes that vary between maternity units may impact caesarean section rates and outcomes.The platform can help to standardize routine audit of caesarean section rates and outcomes, simplify comparisons and quickly identify obstetric subgroups driving caesarean section rates. Enhanced understanding of the drivers of caesarean section trends can help users to develop more tailored and effective interventions for their setting. Embedding the Robson classification system into routine maternity data collection can motivate facilities to improve the quality of their obstetric data.Caesarean section use is increasing worldwide; its use is unequal in low- and middle-income countries, and its underuse and overuse is associated with adverse outcomes. Therefore, using tools such as the Robson classification system is a priority for the health community. We hope that the platform will help build evidence to inform tailored, data-driven policies and actions to optimize caesarean use."} +{"text": "Treatment of oncological pain is complex and requires a multidisciplinary management approach between oncology services and pain units. Although significant improvements have been achieved in the treatment and overall survival of cancer patients, the management of oncological pain has not followed the same directions. Many patients are not referred to pain units even though they could benefit from it. The purpose of this Delphi survey was to map the current situation in the management of cancer pain, identify barriers and propose recommendations to improve its management by emphasizing the importance of collaboration and coordination between oncology services and pain units. A survey among members with recognized experience in the management of oncology patients and oncological pain was held based on the Delphi method principles. The experts were asked to vote preselected statements on cancer pain management in two rounds and conclusions and recommendations were formulated based on the consensus reached for each statement. Barriers and areas for improvement were identified: need of multidisciplinary management approach, effective communication between oncology services and pain units, timely referral of cancer patients to pain units, training of health care professionals dealing with cancer aspects and identification of those patients that could benefit from a multidisciplinary management of their oncological disease. The experts issued recommendations targeting the identified barriers and areas for improvement by defining the service requirements of hospital and units treating cancer pain patients, establishing referral pathways necessities and adopted measures to improve the care of cancer patients. Cancer diagnosis is almost always synonymous with pain, which affects life quality of patients, their family and caregivers2. Pain can be present even in early disease stages and its frequency and intensity increase progressively affecting almost 90% of patients during its late stages4. Effective pain treatment is essential in the overall management of cancer patients and the importance of controlling cancer pain effectively cannot be overemphasized5. Aggressive and meticulous pain control prolongs cancer patients\u2019 survival6.Cancer is a devastating diagnosis equally for patients and their families7. Interestingly, this lack of adequate pain control either due to cancer or its complications or its association with surgical procedures did not improve significantly over the years8. Ineffective cancer pain control is a multifaceted issue and its adequate evaluation depends on a collaborative interaction between patients and healthcare professionals.Many patients still suffer from significant amount of pain, as analgesic treatments might be inadequate9. Also health care professionals have often limited knowledge and skills when using opioids, a cornerstone in the pharmacotherapy of cancer pain, which together with local opioid accessibility problems, contributes importantly to the under management of the symptoms.Pain is subjective and, often, patients do not emphasize it adequately believing that their doctors will divert their attention to the symptom rather than focusing on main disease treatments10. A review published by Kwon regarding barriers in cancer pain management highlighted important topics like opioid rotation and appropriate breakthrough pain handling as suitable educational targets to improve outcomes4.Recent surveys have identified a need for education regarding pain practices amongst the various professionals involved in cancer pain treatments11. An extensive collaboration and coordination amongst providers and optimal use of available therapeutic options are necessary, together with accurate technical information exchange and frequent communication flow amongst not only the health care professionals involved in the management of cancer pain but the patients as well12.Cancer pain management can be quite complex because pain is often accompanied by emotional problems and a variety of other symptoms. Therefore, a multidisciplinary approach is required to assess and manage patients suffering from itIdentifying the necessary resources that an institution or clinical service should be equipped with to effectively manage cancer pain patients.Proposing referral pathways and coordination/communication processes between the country's pain units and oncology services for an effective treatment and follow up of cancer pain patients.Introducing training opportunities for the health care professionals handling cancer pain cases to improve therapeutic outcomes and consequently life quality of affected patients.Our aim was to outline current trends in oncological pain management, recognize barriers and recommend measures to improve the situation by:The Spanish Medical Oncology Society (SEOM) and the Spanish Society of Pain (SED) promoted the initiative and designated 3 representatives from each one to appoint a lead scientific committee. This committee was composed of experts with recognized experience in clinical oncology and oncological pain management.The scientific committee generated statements/items, focusing on patients, healthcare providers and healthcare system perspectives, addressing current issues and identifying barriers in the various management stages of cancer pain. These statements were sent for assessment to an expert panel consisting of 35 members, who were selected by the scientific committee and all were SEOM and SED members. They were chosen taking into account their recognized experience, professional prestige and publications in their reference field respectively.13. After an exhaustive literature review and discussion, the scientific committee generated 79 debatable items distributed in three content blocks: general considerations on the cancer pain management, referral criteria to a pain unit, and barriers and opportunities for the improvement for cancer pain management improvement.A Delphi method was used, whose aim is to transform individual opinions into an expert group consensus13.The items were sent to the panelists for an online evaluation and validation by voting in two rounds. Panelists assessed the items using a single 9-point Likert-type ordinal scale, according to the model developed by the UCLA-RAND Corporation for the comparative assessment and prioritization between different health options To analyze the group\u2019s opinion and the consensus degree reached on each question, the median and the interquartile range of the scores obtained for each item were used.Those items that did not reach consensus (in favor or against) in the first round were reformulated and included again in the second round questionnaire. In this second round the panelists received the first survey results so that they could contrast their personal opinions with those of their fellow panelists and, if necessary, reconsider their initial opinion.Results are shown in tables as median and IQR of the panelists\u2019 responses and degree of agreement. Taking into account the consensus statements, the scientific committee developed a table of conclusions and recommendations on the management of cancer pain patients.The questionnaire consisted of 79 items addressing the current coordination status between pain units and medical oncology services in Spain regarding cancer pain patients treatments, and proposed measures to improve patient flow and collaboration between pain units and medical oncology services for better therapeutic outcomes and life quality of the affected patients Tables , 2, 3.TaThe questionnaire was submitted to the experts\u2019 panel. Of the 35 panelists to which the items were sent, 30 responded to both evaluation rounds. Consensus was reached on 46 out of the 79 items evaluated in the first round. Additional 5 items reached consensus after the second evaluation round making a total of 51 out of the 79 proposed items (64.6%). Of them, 55 reached consensus on agreement and 6 on disagreement. The results of the items that reached maximal consensus are shown in Table Table Regarding cancer pain management Table the paneMedical oncologist should be familiar with the services available in the referral pain units and both should organize training courses for their healthcare professional and trainees and issue regular updates regarding advances in their fields of practice aiming to keep healthcare professionals well informed and familiar with oncological and cancer pain treatments.Regarding the referral criteria Table , it appeThe panelists identified various barriers to an adequate management of cancer pain patients and also indicated improvement opportunities Table . Lack ofIn order to improve cancer pain care, they prioritized communication and coordination between oncology services and pain units, consultation waiting times reduction, infrastructure improvements and staff expansion of the pain units and interdisciplinary committees creation together with establishment of care quality evaluation systems for cancer pain Table .15. Epidemiological studies in Spain have also indicated that almost 55% of cancer patients experience pain16, frequently neuropathic in origin (20\u201333%)17 and 41% of cancer pain sufferers experience breakthrough pain18.Approximately 10 million individuals are diagnosed with cancer yearly. Almost 70% of them will succumb to their disease or its complications and 60% will suffer from severe pain19. Remarkable efforts to improve pain management quality have been made; however, many cancer patients worldwide have their cancer-related pain inadequately managed20, causing poor life quality, anxiety and distress, depression and poor functional status21.Since the introduction of the WHO\u00b4s analgesic ladder together with the American Pain Society recommendations on the assessment and quality indicators development for effective cancer pain management, an immense progress in oncological pain control has been achieved22, preferably in specially created facilities, which allow for flexible collaborative pathways and movements among health care professionals. The International Association for the Study of Pain (IASP) proposed a four types (I-IV) classification of pain units depending on characteristics such as healthcare professionals participation, treatment options available, focus on pain types and education and research provisions23 The panelists agreed , which besides a shared philosophy, mission and objectives, is characterized by several other aspects: interdependence among team members, mutual respect, open communications, cooperation and diverse viewpoints being some of the most important ones25. Constant communication, not only among the team members but also with the patients and their families by encouraging active participation, is a central element for coordinated care and clinical and mental status improvement of the patient by focusing on specific issues furthering common aims and managing pain and possible side effects in a holistic and multidisciplinary way.Both patient-centered care and continuity of care are fundamental for coherent and consistent interventions directed to cancer patients\u00b4 medical and personal needs22. Shared clinical sessions for cancer pain cases discussion, shared cancer pain management protocols, common referral pathways arrangements and extensive and constant contact possibilities via telecommunication facilities for case consultation are essential requirements for a high quality care of cancer pain patients and they have been strongly recommended by the panelists , psychological support, pain topics such as controlled analgesia methods, pain evaluation scales, questionnaires for practicing physicians, trainees of medical oncology units and similarly cancer therapeutic modalities and communication skills with cancer patients and their families for the pain services providers, multidisciplinary cancer and cancer pain rounds where cases can be discussed and most importantly familiarity of the involved parties with portfolios of the available services.Another area of attention highlighted by our experts was training and education of oncologist and pain healthcare professionals and research Table . Lack of26. The complexity of this process is also displayed in our panelists\u2019 answers, where 41% of the items regarding referral criteria to pain units did not reach consensus.Deciding who, how and when to refer cancer pain patients to pain units can be quite complex and factors such as resources availability, involved teams capacities, disease characteristics, levels of care provided and health care policies may play an important role27. Often this referral pattern leads to treatment delays.Referrals to pain units can be either oncologist-driven or automatic. Oncologist-driven referrals require identification of patients with specific symptomatology and care necessities, and are subject to varying thresholds the referring physicians might have depending on their knowledge, experience and skills28. The items that reached consensus could be used as the triggering criteria to structure this referral pattern.In the automatic referral process pre-established criteria act as consultations triggers with pain units depending on patients clinical needs. It appears that this referral pattern has the potential to streamline cancer pain management and, in general, palliative care2. Recent studies have identified various barriers to their adequate treatment, such as insufficient understanding and experience with the available therapeutic options and approaches to the evaluation and management of cancer pain, lack of coordination and cooperation amongst the various disciplines involved in the management of these patients, often inadequate pain management resources in cancer units, inefficient communication flows and referral patterns between oncology and pain control units, anxiety for opioid use side effects and patients misconceptions regarding analgesic usage29.As it has been mentioned already, 33% of cancer pain patients are not controlled effectively30. Clinicians are often reluctant to start opioid treatments and tend to use them only in terminal cancer or intractable pain cases10. Finally, lack of specific knowledge concerning medications for chronic cancer pain, pain pathogenesis, dose titration, breakthrough pain, addiction and tolerance appears to be another barrier in the effective treatment of these patients31.Furthermore, barriers in cancer pain management may be related to healthcare professionals, patients themselves or the existing healthcare system . The most frequently mentioned barrier related to the clinicians is inadequate pain evaluation. Pain assessment can be very subjective and only a small percentage of physicians use the available pain assessment tools routinely for an accurate evaluation32. Depression, stress and anxiety are affective barriers that alter pain perception and predict treatment responses33. Finally, adherence to pain medication is positively related with better pain control34.Patients\u00b4 perspective barriers can be of cognitive or affective nature or related to non-adherence to analgesics. Under cognitive barriers we see situations where painkillers concern and misconceptions lead to pain underreporting, inadequate communication with clinicians and side effects fear, addiction and tolerance4. Our experts have also highlighted the importance of the above interventions during their assessment in order to improve the management of cancer pain and consequently the patients\u2019 wellbeing (Table A series of interventions have been proposed to overcome all these barriers between oncology and pain management units with the aim to facilitate patient flow, minimize waiting times and achieve adequate cancer pain control: effective pain assessment by using appropriate validating tools and multidimensional evaluations; pain management according to the published guidelines, by using the indicated medications, monitoring outcomes and side effects in a multidisciplinary approach; educating health care professionals and trainees through continuing medical education, lectures and interdisciplinary pain management rounds; educating patients and their families by informing them regarding their disease and appropriate medication use and providing psychosocial support and finally, healthcare system-based issues can be better controlled by increasing pain and palliative servicesng Table .There are some limitations of our work that ought to be mentioned. The consensus methodology prevents in depth discussions and some matters may be overlooked. In addition, subjectivity linked to personal evaluations may be a problem, and there is a potential bias in the selection of the expert panel. However, panelists were selected taking into account their contrasted clinical experience and expertise in cancer field, and in our opinion their point of view could be helpful for the rest of the health providers. Further studies may be carried out to identify impediments and approaches to overcome these barriers from the point of view of other healthcare professionals such as nurses specialized in cancer or primary care physicians.In summary, the results of this survey identified patterns of effective collaboration between oncology and pain units, referral criteria regulating cancer pain flow among the involved services in a multidisciplinary way, and the main barriers to optimal cancer pain management. Also practical recommendations to overcome these barriers were proposed. This consensus may be useful for clinicians and health managers to implement measures aimed to improve cancer patients\u2019 pain management."} +{"text": "Gender representation matters to our learners9WestJEM, Gibney et al. report EM residency gender composition along purely binary lines. However, the composition of EM residents includes physicians who are outside of traditional binary definitions of sex and gender. A lack of acknowledgement of our colleagues from these backgrounds has important ramifications for them and our patients.In the current issue of In a 2010 survey of SGM patients, most believed that providers were not adequately prepared to care for their needs.One potential solution to SGM patients\u2019 significant discomfort in seeking emergency care would be diversifying the composition of emergency physicians to reflect the general population more closely. As racial diversity in medicine has increased, studies have shown that racial concordance between patient and provider can improve both patient satisfaction and participation in health care decisions.Gibney et al., explored the potential effect of having more women in positions of leadership in emergency medicine departments on the make-up of their residency classes. In their study, the authors used photographs to assign gender to residents and faculty members. We believe this approach provides an opportunity for reflection on how current research practices and normative behaviors in emergency medicine have unintended negative consequences. What is often lost in the methods employed by researchers when studying issues of representation Utilizing a binary lens can also be a consequence of studies designed toward advocating for equal representation and treatment of cis women where they are underrepresented. Dayal et al found that, despite being evaluated similarly as interns, over the course of residency, female emergency medicine residents were consistently evaluated lower than their male colleague across all subcompetencies.While the focus has long been on achieving gender parity between cisgender women and cisgender men in medicine, this is insufficient to support everyone. The consistent use of binary language and the exclusion of gender-diverse identities create gaps in our understanding of the treatment of gender-diverse individuals in our field. When reading the Gibney paper, we hope the reader considers how and by whom gender was assigned and how similar approaches in related research in education and workforce development can be reductive. An important consideration should be how, when trying to advocate for increased equity for one group, we may inadvertently create exclusionary language for others. In any case, repeatedly representing gender in binary terms has consequences for our understanding of the true make up of our emergency physician workforce, and how that representation may impact patient care. Continuing to focus on binary sex and binary gender will hamper efforts to create true equity for physicians of all identities in emergency medicine. In our efforts to address structural barriers for some historically underrepresented groups, such as cisgender women, we must not further discourage other underrepresented groups from considering emergency medicine."} +{"text": "Older adults with cognitive impairment are at risk of higher loneliness due to increasing challenges to retain essential social skills and decreasing social networks. This study explores ways to reduce the relationship between cognitive function and loneliness. Drawing on the cognitive discrepancy theory of loneliness, we hypothesized loneliness may be reduced by improving an individual\u2019s actual level of social interaction, creating opportunities for social relationships. This study examined complex relationships among informal and formal support , and loneliness, among older adults with different levels of cognitive impairment. Data came from the Health and Retirement Study (2012) (N=651) with the sample included respondents 51+ years who completed a modified Telephone Interview for Cognitive Status. Results from hierarchical regression showed older people with a lower level of cognitive function were less likely to experience loneliness . Although frequent social contact with family and friends reduces loneliness , it did not moderate the relationship between cognitive function and loneliness. Interestingly, the use of HSBC also turned out to be not a significant protective factor. Our findings suggest merely increasing social interaction levels with family and friends may not necessarily curb loneliness for older adults with cognitive impairment. Given the current characteristics and nature of HCBS primarily focus on providing basic physical needs of older adults, prioritizing the development of emotional comfort and recreational activities that alleviate their psychological loneliness is essential, especially amidst the pandemic."} +{"text": "There is an ongoing need for novel biomarkers in clinical neuroscience, as diagnosis of neurological and psychiatric disorders is hampered by the pronounced overlap of behavioral symptoms and other pathophysiological characteristics. The question that this Focus Feature puts center stage is whether network-based biomarkers may provide a viable tool for distinguishing between disordered populations or whether they may yield only limited differentiating power because of largely shared network characteristics across conditions. Multiple approaches exist to address the question of whether network-based biomarkers may have clinical utility; we explore many of these in this Focus Feature. Blomsma and colleagues focus onThe work by Rodriguez-Cruces and colleagues uses a dThis Focus Feature also provides and evaluates new network-based biomarkers. Kulik and colleagues explore Iraji and colleagues use the Finally, Scheijbeler and colleagues introducThere is promise for network-based biomarkers in clinical neuroscience. An important step towards adequate investigation of brain network measures as biomarkers is to consistently report reliability, reproducibility, sensitivity, and specificity of such measures. The increasing availability of large databases with multimodal data in order to crosslink different approaches will aid development of biomarkers suitable for differential diagnosis and prognosis. We hope that the work included in this Focus Feature may inform future studies into this important topic."} +{"text": "Artificial intelligence (AI) solutions use deep neural networks that imitate human brain neural interconnections. By doing so AI solutions can analyze endoscopy videos or images during or after an endoscopy . This alAI is expected to create many disruptive technologies in endoscopy with far-reaching and significant impact on quality and practice in general. Since endoscopy relies heavily on pattern recognition within video or image frames, AI seems an ideal technology to assist endoscopists in reaching quality benchmarks by providing live feedback. Colonoscopy quality metrics such as adenoma detection rate (ADR), withdrawal time of the colonoscope, cecal intubation rate and bowel cleanliness score are all ideal targets for automatic assessment and documentation using adapted AI solutions ,2. SinceThe first wave of AI applications that has been implemented in endoscopy units includes automated and integrated AI solutions to assist endoscopists in the detection and classification of colorectal polyps. Many image-based modalities have been developed to increase ADR, since an increase in ADR is closely linked to the prevention of interval colorectal cancers (CRC) . AlthougAI can characterize polyps and predict histology with high accuracy. While experienced endoscopists are usually able to predict pathology without needing AI, AI solutions can increase diagnostic accuracy for less experienced endoscopists . StudiesOther AI solutions improve quality monitoring with automated assessment of quality metrics . For upper endoscopy, AI can assist in the assessment of the extent of Barrett\u2019s esophagus, and in identifying areas with high-grade dysplasia or cancer . To imprTo further develop and promote AI technology, we have formed a special interest group (SIG) in AI at the Canadian Association of Gastroenterology (CAG. This CAG AI SIG core group is currently comprised of six gastroenterologists (the authors of this opinion piced) from five Canadian institutions across three provinces. We have started evaluating AI technologies using cohort studies and randomized controlled trials, and are in the process of establishing video and data biobanks to accrue raw data from which additional novel AI solutions can be created. Our research activities to date have been supported through seed funding from CAG, and we have organized and hosted webinars and sessions at Canadian Digestive Diseases Week (CDDW), inviting international experts on selected pertinent topics. Further activities of group members include the development and implementation of AI curricula since the next generation of gastroenterologists needs to be trained to develop and implement AI solutions at institutions across Canada. The CAG AI SIG has an open model inviting new members, industry and AI researchers to maximize the potential that this novel technology offers in improving endoscopy quality and patient outcomes."} +{"text": "Participating in social activities through formal and informal avenues is known to positively contribute to mental wellbeing. Family caregivers are at risk for limited social participation and increased depressive symptoms. However, little is known about which social activities are associated with depressive symptoms among spousal and adult child caregivers. The purpose of this study was to examine the effects of participating in various social activities on depressive symptoms among spousal (n=422) and adult child caregivers using data from the 2017 wave of the National Study of Caregiving. Caregivers reported on participating in six social activities in the past month and completed the 2-item Patient Health Questionnaire to assess depressive symptoms. Data were analyzed using multiple linear regression, with separated models for spousal and adult child caregivers. Sociodemographic characteristics, self-rated health, and dementia caregiving status were included as covariates. For spousal caregivers, visiting friends or family and attending religious services were associated with lower depressive symptoms . For adult child caregivers, going out for enjoyment was associated with lower depressive symptoms . Findings suggest that spousal and adult child caregivers may benefit from participating in different types of social activities. Interventions targeting social participation to reduce depressive symptoms need to be tailored to the needs and preferences of spousal and adult child caregivers to be most effective."} +{"text": "Cataract surgery is one of the most frequently performed surgical procedures in many countries. The procedure itself is considered safe and efficient with good visual outcomes, and the development of modern surgical techniques and technologies has considerably reduced the frequency of complications. With increased life expectancy, cataract surgery is becoming more common, even among very old patients. As shown in the article by Nussinovitch et al., cataract surgery in very old patients may demand more experienced surgeons due to higher nuclear density and the rates of intraoperative floppy iris syndrome . This isCurrently, the refractive outcomes of cataract surgery have enabled the use of the procedure for refractive lens exchange. The standard deviation of the new-generation intraocular lens (IOL) calculation formulas in patients undergoing cataract surgery is less than 0.4 D , which tComplications are still a substantial burden because of the sheer number of cataract surgeries performed worldwide each year. Pseudophakic cystoid macular edema is one of the most common causes of visual impairment after cataract surgery. PCME may occur even in the absence of complications and risk factors. Intraoperative complications, including capsule rupture, vitreous loss, and iris trauma are associated with a higher risk for PCME . Other rOutcomes of phacoemulsification cataract surgery depend largely on surgeon skills, as well as adherence to a complicated multidrug regimen of anti-inflammatory and antimicrobial therapy . The sucAnother significant late complication of cataract surgery is posterior capsular opacification (PCO), which is associated with the proliferation and migration of lens epithelial cells . The ris"} +{"text": "Black swan events such as the coronavirus (COVID-19) outbreak cause substantial supply chain disruption risks to modern companies. In today\u2019s turbulent and complex business environment, supply chain resilience and robustness as two critical capabilities for firms to cope with disruptions have won substantial attention from both the academia and industry. Accordingly, this study intends to explore how digitalization helps build supply chain resilience and robustness. Adopting organizational information processing theory, it proposes the mediating effect of supply chain collaboration and the moderating effect of formal contracts. Using survey data of Chinese manufacturing firms, the study applied structural equation modelling to test the research model. Results show that digitalization has a direct effect on supply chain resilience, and supply chain collaboration can directly facilitate both resilience and robustness. Our study also indicates a complementary mediating effect of supply chain collaboration on the relationship between digitalization and supply chain resilience and an indirect-only mediation effect on the relationship between digitalization and supply chain robustness. Findings reveal the differential roles of digitalization as a technical factor and supply chain collaboration as an organizational factor in managing supply chain disruptions. Paradoxically, formal contracts enhance the relationship between digitalization and supply chain resilience but weaken the relationship between supply chain collaboration and supply chain resilience. The validation of moderating effects determines the boundary conditions of digitalization and supply chain collaboration and provides insights into governing supply chain partners\u2019 behavior. Overall, this study enhances the understanding on how to build a resilient and robust supply chain."} +{"text": "Clinical staging is now recognized as a key tool for facilitating innovation in personalized and preventative mental health care. It places a strong emphasis on the salience of indicated prevention, early intervention, and secondary prevention of major mental disorders. By contrast to established models for major mood and psychotic syndromes that emerge after puberty, developments in clinical staging for childhood-onset disorders lags significantly behind. In this article, criteria for a transdiagnostic staging model for those internalizing and externalizing disorders that emerge in childhood is presented. This sits alongside three putative pathophysiological profiles that may underpin these common illness trajectories. Given available evidence, we argue that it is now timely to develop a transdiagnostic staging model for childhood-onset syndromes. It is further argued that a transdiagnostic staging model has the potential to capture more precisely the dimensional, fluctuating developmental patterns of illness progression of childhood psychopathology. Given potential improvements in modelling etiological processes, and delivering more personalized interventions, transdiagnostic clinical staging for childhood holds much promise for assisting to improve outcomes. We finish by presenting an agenda for research in developments of transdiagnostic clinical staging for childhood mental health. Enhanced prevention, earlier intervention and delivery of more effective treatments for childhood-onset mental health problems represent an important agenda for tackling the \u201cgrand challenges\u201d in mental health is crucial to determining treatment needs in childhood. Early neurodevelopmental syndromes are often lifelong, associated with atypical cognitive, social and emotional development from the first years of life follows the anxious phenotype and hyperarousal pathophysiology in illness trajectories to affective syndromes. For our model, this relates to fear-related and distress-related internalizing problems in childhood and third \u2019 illness subtypes that are presented are aligned, in part, to the circadian profile. The irritability subtype is based on evidence that trait irritability is a transdiagnostic risk factor for externalizing problems, depression/anhedonia, and mood lability in bipolar depression may then augment clinical staging and enhance assessment of types and extent of disease progression in internalizing, externalizing, and comorbid trajectories for childhood mental health problems are tied to single clinical diagnosis, while treatments for children in earlier clinical stages and/or presenting with nonspecific symptoms are less established (Shah et al., Following our model, we recommended building an evidence base of interventions stratified by clinical stage and illness subtype, and taking into account individual clinical and biological characteristics underlying disease progression (Manchia et al., Staged care needs to be formally evaluated for its comparative effectiveness compared to treatment as usual. At the individual level, attention should be given to evaluating whether stratifying treatment selection based on stage and illness type results in better clinical outcomes compared to those based on a conventional diagnosis. Outcomes should include assessment of changes in symptoms and distress, as well as the ability of stage-based interventions to prevent illness progression to advanced stages (McGorry et al., The final suggestion circles back to the initial premise of this article: sustainable development in mental health (Patel et al., Further consideration of how clinical staging may operate across the life course warrants specific attention. Life course approaches to mental disorders is one of the main principles of global sustainability in mental health by emphasising the interplay of social and biological risk factors during key developmental stages over the life span (World Health Organization, Childhood is a developmentally sensitive period where vulnerability for the onset of lifetime mental health difficulties is significant (Kessler et al., Given potential improvements in modelling etiological processes, transdiagnostic clinical staging for childhood holds much promise in optimizing the effectiveness of treatment and prevention for children. Staging risk and prodromal features of childhood psychopathology in earlier clinical stages helps to identify those children that require earliest provision treatment to prevent the onset of clinical impairment (Colizzi et al.,"} +{"text": "When dealing with patients who talk about their illnesses, medical doctors need to interpret the stories they hear. Also, they need to make sense of their own experiences regarding their medical encounters. Narrative and its analysis plays a central role in such processes that require empathy and self-reflection. The interdisciplinary practice of teaching medical students concepts and theories from literary studies as well as discussing literary texts with them can expand their scientific medical understanding. This paper explores the concept of narrative in the context of geriatric medical humanities and narrative medicine, looking at how narrative competence translates into medical practice. Presenting findings from a seminar on Narrative medicine at the Medical University of Graz, Austria, it also addresses some methodological and didactic challenges of this interdisciplinary approach."} +{"text": "Routine utilization of evidence-based clinical practice guidelines (CPGs) is an effective strategy to optimize patient care and reduce practice variation. Healthcare professionals\u2019 failure to adhere to CPGs introduces risks to both patients and the sustainability of healthcare systems. The integration of theory to investigate adherence provides greater insight into the often complex reasons for suboptimal behaviors.To determine the coverage of literature surrounding the use of theory in studies of CPG adherence, report the key findings and identify the knowledge gaps.In April 2021, three bibliographic databases were searched for studies published since January 2010, adopting theory to investigate health professionals\u2019 adherence to CPGs. Two reviewers independently screened the articles for eligibility and charted the data. A narrative approach to synthesis was employed.The review includes 12 articles. Studies were limited to primarily investigations of physicians, quantitative designs, single disease states and few countries. The use of behavioral theories facilitated pooling of data of barriers and facilitators of adherence. The domains and constructs of a number of the reported theories are captured within the Theoretical Domains Framework (TDF); the most common barriers aligned with the TDF domain of environmental context and resources, fewer studies reported facilitators.There is emerging use of behavioral theories investigating physicians\u2019 adherence to CPGs. Although limited in number, these studies present specific insight into common barriers and facilitators, thus providing valuable evidence for refining existing and future implementation strategies. Similar investigations of other health professionals are warranted.The online version contains supplementary material available at 10.1007/s11096-022-01490-9. Investigations underpinned with behavioural theory provide more robust and generalizable evidence of healthcare professionals\u2019 failure to adhere to Clinical Practice Guidelines, such data is essential to inform the refinement of existing and future implementation strategies.The domains and constructs of a number of the reported theories are captured within the Theoretical Domains Framework, thus demonstrating its versatility and advantage for such studies.Further investigations of physicians in alternative settings and of other health professionals are warranted to confirm the generalizability and the association of the existing literature.Healthcare systems continuously seek strategies to enhance the quality of service delivery through promoting evidence-based practice and addressing inefficiencies. The implementation and routine utilization of clinical practice guidelines (CPGs) has long since been proposed to be an effective strategy to optimize patient care and reduce practice variation . EquallyFor example, implementation investigations, which refers to the extent to which efficacious health interventions, such as CPGs, are effectively integrated into real-world clinical service systems ; have reThe definition of CPGs most frequently cited is that of Field and Lohr, \u201csystematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances\u201d . Since tHowever, the development of CPGs is complex and not without its challenges. Panel composition influencing recommendations; multiple scoring systems for the quality of evidence and \u2018grades of recommendations\u2019 and the limitations thereof; and timely guideline updating are but a few of the issues that warrant significant consideration in order to develop credible CPGs and necessitate appropriate critical appraisal skills of clinicians in order to advantage from them . FurtherEccles et al. propose that adopting theory in such investigations provides further valuable insight on how determinants (e.g. physician attitude) influence the association between processes and outcomes, and facilitates more detailed understanding of strategies that may mitigate against determinants to support processes associated with desirable outcomes . One subSimilarly a systematic review by Davies et al. on studies evaluating guideline dissemination or implementation strategy targeting physicians concluded greater use of explicit theory, specifically behavioral change theories, is required to understand barriers, design interventions, and explore mediating pathways and moderators . These tSuch recommendations are closely aligned to those of the United Kingdom (UK) Medical Research Council (MRC) guidance on \u2018Developing and implementing complex interventions\u2019, which attributes theory a central role within the process .While reviews have focused on the stage of implementation of CPGs and the use of theory, none have reported the key process of adherence.The aims of this scoping review were to determine the coverage of literature surrounding the use of theory in studies of CPG adherence, report the key findings and identify the knowledge gaps.The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist guided the conduct and reporting of this review , 40.Studies reporting any health professional practicing in any setting which applied any theory or theoretical framework to study adherence to clinical guidelines were included in the review; this included both interventional and non-interventional studies. Studies which focused on implementation were excluded. The search included peer-reviewed studies published in English from January 2010 until April 2021 were included; editorials, commentaries, abstracts and letters were excluded.The search was conducted in PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Scopus. References lists of included articles were reviewed for inclusion. The following Medical Subject Headings [MeSH] and keywords were adapted to each database using \u2018OR\u2019: \"theor*\", \"framework(s)\". These were combined with \"guideline(s) using \u2018AND\u2019. The results from this search were combined with the following using \u2018AND\u2019: \"health personnel\", \"clinician(s)\", \u201cdelivery of health care\", \"practitioner(s)\".All articles were exported to the support platform for the development of systematic reviews Rayyan QCRI\u00ae , and dupData were independently extracted by two reviewers using a standardized pilot data collection tool. The following data were extracted: study aim; setting, study design; simple size; health professionals studied; and the theory or theoretical framework used.A narrative approach to data synthesis was employed to pool the evidence on how the theories and theoretical frameworks were used, and the main findings in relation to the aim around clinical guideline adherence. These findings were mapped to key behavioural determinants of adherence.n\u2009=\u200938) are captured within TDF. Almost all studies reported barriers to adherence, the most common aligning with the TDF domain of environmental context and resources. Participants reported several related factors limiting adherence, including busy schedules , 52, 53,Fewer studies reported facilitators to guideline adherence. These included belief of consequences of the clinical gain to be achieved and costThe key finding of this scoping review is that a limited number of studies have applied any theory to explore health professionals\u2019 adherence to CPGs. Use of TDF identified barriers to adherence relating to the environmental context and resources, beliefs of consequences, beliefs of capabilities and aspects of knowledge. Few studies reported any facilitators to adherence.adoption and implementation are reported on in the literature without clear distinction; further complexity may be added by the variation in terminology and classification of terms across countries. Indeed, a review of research funding agencies in nine countries revealed 29 distinct terms referring to aspects of dissemination and implementation research [This scoping review was conducted according to best practice through the application of rigorous and transparent processes , 40. Munresearch .This scoping review has identified a paucity of theory informed studies, with only 12 identified from seven countries, which contrasts with the vast number of systematic and scoping reviews on the wider literature of health professionals\u2019 adherence to CPGs. There is therefore a clear gap in the literature in terms of the number and coverage of studies. This gap is reinforced given that most studies were cross-sectional surveys with less qualitative studies and no mixed methods studies. The lack of studies must be borne in mind when interpreting the findings.Theories were largely used to develop data collection tools and analytical frameworks, with the most common being the Cabana Framework and TDF. TDF is an integrative framework of 33 behaviour change theories and 128 theoretical constructs, described in 14 overarching domains , 57. Of There are a number of benefits to applying theory, including enhancing the robustness and rigour, and the relevance and impact of research findings. Theories provide comprehensive explanations, e.g., the 14 domains TDF represent the determinants of (influences on) any behaviour which may be facilitators, barriers, or have no or little influence. Using theory enables researchers to connect pieces of research data to generate findings which fit into a collation of other studies . The robKey barriers to adherence were TDF domains of environmental context and resources , belief of consequences , belief of capabilities and knowledge . Those studies which used the Cabana Framework identified similar issues. These barriers can act as behaviour change intervention (BCI) targets, defined as `coordinated sets of activities designed to change specified behaviour patterns'. BCIs consist of interacting components known as `behaviour change techniques' (BCTs) which are `observable and replicable components designed to change behaviour' , 62. Evienvironmental context and resources TDF domain, and less frequently the facilitators of physicians\u2019 adherence to CPGs. This data provide valuable evidence for refining existing and the development of future implementation strategies. Similar investigations of physicians in alternative settings and of other health professionals are warranted to confirm the generalizability and the association of these findings.There is emerging use of behavioural theories investigating physicians\u2019 adherence to CPGs; notably the domains and constructs of a number of the reported theories are captured within the TDF. Although limited in number, these studies present specific insight into the barriers, which align to the Supplementary file1 (PDF 39 kb)Below is the link to the electronic supplementary material."} +{"text": "There is a long-standing literature that has documented how one\u2019s neighborhood context has the potential to shape mental and physical health across the adult lifespan. An abundance of research documents how various components of the neighborhood, such as disorder, cohesion, in addition to pollution and sidewalk quality are linked to short- and long-term mental and physical health outcomes across adulthood. One key component that has been less studied within this literature is the extent to which objective or subjective neighborhood indicators exert a more potent impact on mental and physical health. Up to this point, much of the research has focused on subjective indicators of neighborhood context. This study explores whether and to what extent objective neighborhood factors of income inequality, residential stability, and greenness and subjective neighborhood factors of social ties, collective efficacy, and neighborhood disorder are predictive of mental and physical health in midlife. We use data from a sample of participants in midlife to analyze our research questions. Structural equation models found that both subjective and objective indicators of neighborhood were related to health and well-being when considered separately. When considered simultaneously, subjective neighborhood indicators (sense of community) mediated the association between objective constructs and health. Our findings demonstrate the independent associations between objective and subjective neighborhood context and highlight the particularly strong association between subjective context and health and well-being. Our discussion elaborates on how our findings can inform interventions and sparks future research aimed at exploring potential mechanisms underlying the associations found."} +{"text": "The effective exploitation of what are often called big data is increasingly important. They provide the evidence in evidence-based health care and underpin scientific progress in many domains including social/economic policy. Typically, an optimal analysis involves working directly with microdata; i.e. the detailed data relating to each individual in the dataset. But there are many ethico-legal and other governance restrictions on physically sharing microdata. Furthermore, researchers or institutions may have an extensive intellectual property investment in complex microdata and although keen for other researchers to analyse their data they may not wish to give them a physical copy. These restrictions can discourage the use of optimum approaches to analysing pivotal data and slow scientific progress. Data science groups across the world are exploring privacy-protected approaches to analysing microdata without having to physically share the data.A two day international workshop was arranged focussing on privacy protected approaches to data analysis - particularly federated analysis where raw data remain at their original site of collection. The workshop considered the range of approaches that exist, and those that are currently being developed. It explored the strengths, weaknesses, opportunities and challenges associated with these methods and identified situations where specific approaches have a particularly important role. The workshop included a number of practical sessions where potential users could watch demonstrations of the various approaches in action and run analyses themselves.The Data Analysis with Privacy Protection for Epidemiological Research (DAPPER) workshop was held 22-23rd August 2016, Bristol. We report back to the broader community on the outcomes of this workshop that focussed on exploring current approaches, tools and technical solutions that facilitate sensitive data to be shared and analysed.The workshop has helped map out key opportunities and challenges and assisted potential users, developers and other stakeholders to recognise the strengths and weaknesses of different privacy protected analytic approaches. The workshop will encourage further methodological work in this field and better informed application of existing methods."} +{"text": "Woody plant species represent an invaluable reserve of biochemical diversity to which metabolic engineering can be applied to satisfy the need for commodity and specialty chemicals, pharmaceuticals, and renewable energy. Woody plants are particularly promising for this application due to their low input needs, high biomass, and immeasurable ecosystem services. However, existing challenges have hindered their widespread adoption in metabolic engineering efforts, such as long generation times, large and highly heterozygous genomes, and difficulties in transformation and regeneration. Recent advances in omics approaches, systems biology modeling, and plant transformation and regeneration methods provide effective approaches in overcoming these outstanding challenges. Promises brought by developments in this space are steadily opening the door to widespread metabolic engineering of woody plants to meet the global need for a wide range of sustainably sourced chemicals and materials. Woody plants are resilient perennials defined by their characteristic woody stems and large root systems. Woody plants are a highly diverse group that is polyphyletic in origin and have both flowering and non-flowering members. Many species of woody plants have evolved since their origins around 380 million years ago, and they have since come to dominate various landscapes around the globe in two studies despite piceid not occurring naturally in apple in apple resulted in the accumulation of piceid in transgenic apple fruits terpenoids, alkaloids, simple phenolics, coumarins, tannins, and lignins. There have been several examples of successful metabolic engineering efforts centered on the accumulation of such compounds in woody plants Table . ProanthCitrus sinensis) was engineered to produce less limonene (major VOC in oil glands of mature orange fruit) and instead accumulate increased monoterpene alcohols that share the common biosynthetic precursor geranyl pyrophosphate with limonene, increasing resistance to fungal pathogens that would otherwise lower yields and shelf life is similarly applied to the protection of woody plants from pests and pathogens by disrupting their interactions with the host plant in transient transgenic apple calli overexpression cassette to considerably shorten the seed-to-seed time in the resulting lines and the vaccine adjuvant QS-21 from Quillaja saponaria. Some chemical classes represented in woody plants used in herbalism are quinoline alkaloids {Dey, Berberis species), purine alkaloids , benzophenones (the major bioactive compounds in mango leaves which are used to treat diabetes), and flavonoids expressing an RNAi construct suppressing 7-N-methylxanthine methyltransferase showed up to a 50% reduction in caffeine content in embryonic tissues and plantlets\u2014opening the door to naturally decaffeinated coffee and willow grow quickly and tolerate coppicing well, making them good targets of metabolic engineering for biofuel production. As high lignin content constrains the effectiveness of chemical pulping and of lignocellulosic ethanol production, ideal woody feedstocks for this process would also have optimal cellulose and lignin compositions and benefit from the redirection of metabolites away from lignin biosynthesis and Jatropha curcas are promising sources of biodiesel catabolism was suppressed by downregulating a lipase via RNAi, resulting in higher storage lipid accumulation in seeds and can be extended to metabolic phenotypes that are potential targets of metabolic engineering not only in walnut, but also in other highly heterozygous woody plant species for which a reference genome exists , mandarin orange (Citrus reticulata), apple, pear (Pyrus communis), and grape endonuclease systems have been used in woody plants such as poplar , transformation efficiencies using hairy root culture far exceeded aerial tissues, showing efficiencies over 80% alongside of higher regeneration rates , GRF-INTERACTING FACTOR 1 (GIF1), LEAFY COTYLEDON 1 (LEC1), WUSCHEL, and BABY BOOM (BBM) successfully improved the regeneration of Arabidopsis shortened the generation time to one year in sweet orange and citrange . In the case of citrange, the transgenic plants were used in re-transformation to test gene stacking; the reporter genes were stably expressed in the re-transformant and were evaluated as early as one year and passion fruit (Passiflora edulis) , metabolic flux was redirected from carotenoid to taxadiene biosynthesis and resulted in high amounts of taxadiene in leaves and fruits of the transgenic plants was boosted in multiple complementary plant systems that produce carotenoids such as tomato . To this end, biosynthetic precursors and their derivatives can be fed to the complementary systems to produce downstream products uses multiple unidirectional site-specific recombinases to stack multiple genes in vivo. The GAANTRY ArPORT1 strain of A. rhizogenes was demonstrated to be effective at stacking up to ten genes in rice are stable in plant cells and multiple genes on artificial chromosomes can be stably expressed. PACs have been the subject of research in non-woody plants such as barley, maize, and Arabidopsis, and promise remains for implementing PACs into woody plant species with established transformation and regeneration methods (Yu et al. Pivotal discoveries in herbaceous model systems such as Though gene regulatory networks have been extensively explored in herbaceous plants, considerable work remains to gain a more complete understanding of such regulatory networks in woody plants. The task of unraveling these networks in woody plant species is complicated by the diversity of tissue types present as well as the maturation time needed for such gene networks to emerge and be adequately explored. Poplar serves as a suitable woody model plant from which findings can be translated. Methods and knowledge developed in poplar can prove instrumental in exploring other woody plant systems to bolster our knowledge of their metabolic networks and to translate suitable approaches for metabolic engineering. Conquering the bottlenecks of transformation and regeneration in non-model woody plants will shorten the design-build-test-learn cycles in gene editing and transgene insertion to streamline their usage in metabolic engineering as well. Finally, a large amount of untapped diversity exists in domesticated cultivars across broad geographic ranges and non-domesticated genotypes. Comparative genomics can take advantage of the highly diverse genomes of woody species around the globe not only for breeding, but also to study the evolution of genes and gene families to facilitate gene mining for metabolic engineering (Tuskan et al. As woody plants are understudied, there is room to integrate current genetic and metabolic engineering strategies developed in other plant and microbial systems. Implementation of these strategies is finding increasing success in more studied woody plant systems such as poplar and citrus. Translating these tools into more woody plant systems not only leverages different native metabolic networks, but also expands the collection of ecosystem services available to the site of interest due to the broader species selection. These ecosystem services brought by woody plants are unique among plant chemical factories and include habitat, carbon sequestration, erosion reduction, and water retention. These ecosystem services can be viewed as the key benefits of a sustainable bioeconomy anchored in the used of long-lived woody plants. Low resource and labor demand further complement the vast ecosystem services of woody plant platforms. Metabolic engineering expedites our capability to simultaneously capitalize on the rich biochemical diversity of woody plants in tandem with the suite of environmental benefits associated with their usage. The transition from an oil-based economy to a sustainable bio-based economy will be facilitated by advances in this space."} +{"text": "Older adults who do not qualify for government entitlement programs but lack sufficient financial or other personal resources help them to age in place rely on community organizations to assist them with social determinants of health. However, these organizations struggle with high rates of volunteer caregiver turnover, a looming crisis spotlighted during the COVID-19 pandemic. At least one group of volunteer caregivers continued to serve during this period. This phenomenological study investigated the experiences of eight volunteer caregivers who served older adults through a Faith in Action model volunteer driver program during the first year of the pandemic. Findings indicate that a volunteer\u2019s commitment to older adults, awareness of the needs of older adults, and established relationships with older adults were more important than concerns about COVID-19. Study participants were alert to the needs of older adults during and between service activities, making personal sacrifices of time, money, and physical exertion to accommodate needs. Participants approached service caring for the older adult and expected reciprocal care in the form of appreciation and respect. They considered discontinuing service if efforts weren\u2019t appreciated or if deeply held values were violated. The volunteer service organization was key in mitigating conflict within the relationship of the volunteer and older adult, thereby increasing the likelihood that the volunteer would continue serving. Implications include training older adult clients to meet expectations of care and appreciation for volunteers, managing volunteers whose personal sacrifices exceed the scope of volunteer service, and supporting volunteers whose values have been violated."} +{"text": "In the last decade several neuroprostheses have reached technical maturity and are now used in patients\u2019 daily activities in their homes, including, for example, osseointegration with peripheral nerve interfaces (PNI) to control a robotic prosthesis for patients with amputation . As neurA key theme presented throughout this Research Topic has been multidisciplinary collaboration, a theme strongly supported by the editors . As techJones et al.) provides a framework for collaboratively establishing needs-based assessments to facilitate relevant in-home research. Through the engagement of multiple stakeholders, the challenges and opportunities of clinical research in private homes were weighed against the potential to address users\u2019 real-world needs. Clinical research in private homes present many challenges in particular from data privacy, and policy perspectives. It, is also, of great importance to clinicians for improving the functionality and, ultimately user satisfaction since the usage of neuroprostheses at home often identifies new challenges compared to a clinical setting.Patients living with neurological deficiencies represent key stakeholders of neuroprosthetic technologies, and therefore serve as invaluable members of many clinical research teams. Much of what we know about prosthetic usage comes from acute evaluations in rehabilitation clinics or heavily controlled laboratory settings. Given the increasing maturity of these technologies, research is now expanding to include long-term studies in users\u2019 homes to study realistic their daily needs. Towards user-centered prosthetics research beyond the laboratory utilizes Statistical Process Control frameworks to identify corrupt neural recording channels in a neural network decoder. Corrupted channels are adjusted without requiring user input. The ability to compensate for corrupted BCI data has the potential to reduce computational and user burden while also improving the robustness and longevity of the BCI required for chronic uses in everyday living.Neuroprostheteses replacing daily functions need to last decades without creating cognitive or computational burdens for the user. Increasing robustness of brain-computer interfaces through automatic detection and removal of corrupted input signals provides an overview of the present capacity and future potential for clinical application of BCIs to treat a range of neurological deficiencies. Limitations in learning exist for patients and BCI devices. Clarification of neural mechanisms relative to motor neurorehabilitation was identified as a key component for improving clinical applications of BCI, including exploration of the interplay between cognitive and motor domains relative to the quality of life. Continued multidisciplinary collaboration between fundamental and clinical research is required to drive mechanism-based application alongside standardization of guidelines and protocols to facilitate improved clinical outcomes.Standardization is another fundamental step when considering very long-term protocols. Challenges and opportunities for the future of brain computer interface in neuromodulation . Clinical basis for creating an osseointegrated neural interface utilizes anatomical dissection and virtual implantation to demonstrate the clinically relevant framework to create an osseointegrated neural interface (ONI) for prosthetic control. The ONI represents a modular surgical strategy for neural interfacing, combining clinical treatment for post-amputation pain with osseointegration, and capable of utilizing a range of neural interfaces based on the site of amputation and patients\u2019 needs. Implementation of novel osseointegrated implants was used to demonstrate the need to remove less bone and increase intramedullary free space for the housing of the neural interface components. While this technique and technology remain experimental, the use of clinically relevant techniques applied to human anatomy address key technical aspects required for clinical and regulatory acceptance towards clinical trials and translation.Most of neuroprosthetic development is performed in rodents, often serving as of proof of concept . NeuroprLoeb and Richmond) provides a comprehensive account of the paths and processes required to take technologically complex and invasive BCIs to the market. This includes regulatory requirements of the North American Food and Drug Administration (FDA) and European health, safety and environmental protection standards (CE). Furthermore, considerations for intellectual property, risk management and potential for medical reimbursement must be made. The presented roadmap highlights the importance of collaborations between academia, industry and the government in delivering improved quality of life to patients living with neurological deficiencies.Finally, Turning neural prosthetics into viable products ("} +{"text": "Over the course or early decades of twenty-first century, global economic growth has been driven largely by developing world economies . Those cThe Topic was initiated in order to address the core challenges of medical care financing and its affordability across the emerging global markets. Submitted manuscripts were mostly focused on health care economics and policy in recognized global emerging markets. Outside the aforementioned key markets , submissions referring to several of the dynamically developing Asian, Latin America, Eastern Europe, or MENA countries were presented .The Emerging BRICS markets remain the cradle of real economic growth worldwide. Such countries have profound impact on the global demand for medical goods and services. Corona pandemics caused lock-downs largely interrupted traditional supply chains and world trade routes. Such evolving dynamics impedes prospects for market recovery. The Global South nations largely described by published contributions in this topic, expose heterogeneity in historical legacy of their medical care financing and provision patterns. Burden of premature mortality and absenteeism are multiplied by prevalence and incidence of NCDs . LMICs cSui et al.).The first contribution entitled: \u201cHousehold Socioeconomic Status and Antenatal Care Utilization Among Women in the Reproductive-Age\u201d explored a large sample size of 819 Nigerian women of reproductive age and their socio-demographic characteristics on antenatal care (ANC) utilization. The findings of this study revealed that maternal education, media exposure, time involved in walking to the nearest healthcare centers, costs as barriers to maternal care, health insurance and free maternal care, and household wealth were the significant predictors of ANC utilization among these women mostly living in poor rural households. A set of health policy and educational opportunities have been recommended closely tailored to Nigerian health system .Zhu et al. attempted to test the hypothesis that higher salary levels of the medical staff are associated with lower medical service utilization and expenditure. Their findings indicated that indeed their anticipated causal relationship was true. Further studies appear to be necessary to explore whether higher medical staff's salaries will attenuate over-treatment and that savings from reduced prescriptions and service charges will offset the increased salaries of medical staff .The third valuable contribution focused on Foundational Capabilities of the public health (PH) infrastructure areas which remain essential to support a \u201cminimum package\u201d of programs and services that promote population health. This study should help guide effective local health departments resource allocation .Zhang elaborate that Chinese aging population highlights the significance of long-term care insurance (LTCI). Their study has developed policy suggestions how to establish a sustainable LTCI financing mechanism by predicting the trend of funds balance and screening the appropriate financing scheme .Piece of Iranian original research study deals with the health economic consequences mushroom poisoning patterns in certain Persian regions and their hidden underlying patterns. The total cost of poisoning with cyclopeptide-containing mushrooms in Kermanshah province were estimated at $1,259,349.26. This study has revealed that there is a significant financial burden due to cyclopeptide-containing mushrooms on patients, the health system, and society as a whole .Last but not least Alatawi et al. have conducted a thorough exploration of underlying drivers of efficiency of hospital sector in Saudi Arabia as the wealthiest and most influential Gulf health system. The authors claim that inefficiencies in health services remain a critical challenge in their public hospitals system. Authors also propose large scale awareness-raising and training on efficient resource utilization as an imperative to improving hospital performance (Editors believe these valuable and diverse Topic contributions might open new horizon of knowledge. Last but not least this is a unique opportunity to open the floor for a public debate on the Global South and LMICs challenges from the lens of health economics , 12. TheMJ has prepared the manuscript draft. WG and KS have revised it for important intellectual content. All authors fulfill ICMJE conditions for full authorship. All authors contributed to the article and approved the submitted version.Serbian part of this contribution has been co-funded through the Grant OI 175 014 of the Ministry of Education Science and Technological Development of the Republic of Serbia.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Oligodendrocyte progenitor cells (OPCs) are a subtype of glia giving rise to the myelin producing cells in the central nervous system. OPCs are not passive actors unavoidably committed to become oligodendrocytes (OLs) through a precise intrinsic program. As highlighted in this Research Topic, OPCs are extremely plastic and functionally heterogeneous and adapt their program in response to a multitude of signals both in physiological and pathological conditions has a plethora of effects that regulate both OPC proliferation and differentiation , a negative regulator of OPC maturation acting at the TLR-4 receptor. They investigated how ENV could be neutralized to improve remyelination and identified pharmacological agents acting at TLR-4 that restore oligodendroglial differentiation and fully rescue myelination deficits by counteracting ENV-dependent changes in mitochondrial integrity.Successful differentiation of resident OPCs is a key event to restore damaged circuitry and myelin loss that takes place during chronic inflammation. However, a non-permissive environment negatively affects OPC maturation capabilities . Network analysis on the aging myelinating OL transcriptome revealed core genes belonging to the EGF signaling commonly dysregulated in Alzheimer's disease and multiple sclerosis. The identification of drugs that target this signaling pathway could positively influence rejuvenation and myelin regeneration.Considerable myelin loss and consequent progressive cognitive deficit were also found in aging brain (Rivera et al., The cellular and molecular context makes OPCs highly heterogeneous and plastic both in time and space with mechanisms largely unknown. The articles in this Research Topic contributed to gain insights in the multitude of signals received by OPCs and how these signals are processed to determine OPC behavior. Many, if not all, neurodegenerative diseases are likely to share common pathogenetic mechanisms; deciphering how OPCs rewire their program in response to injury signals may open new therapeutic chances to facilitate CNS homeostasis in disease.DL wrote the manuscript. AB and WB revised the manuscript. All authors have read, revised, and approved the submitted version."} +{"text": "Social attachments, the enduring bonds between individuals and groups, are essential to health and well-being. The appropriate formation and maintenance of social relationships depend upon a number of affective processes, including stress regulation, motivation, reward, as well as reciprocal interactions necessary for evaluating the affective state of others. A genetic, molecular, and neural circuit level understanding of social attachments therefore provides a powerful substrate for probing the affective processes associated with social behaviors. Socially monogamous species form long-term pair bonds, allowing us to investigate the mechanisms underlying attachment. Now, molecular genetic tools permit manipulations in monogamous species. Studies using these tools reveal new insights into the genetic and neuroendocrine factors that design and control the neural architecture underlying attachment behavior. We focus this discussion on the prairie vole and oxytocinergic signaling in this and related species as a model of attachment behavior that has been studied in the context of genetic and pharmacological manipulations. We consider developmental processes that impact the demonstration of bonding behavior across genetic backgrounds, the modularity of mechanisms underlying bonding behaviors, and the distributed circuitry supporting these behaviors. Incorporating such theoretical considerations when interpreting reverse genetic studies in the context of the rich ethological and pharmacological data collected in monogamous species provides an important framework for studies of attachment behavior in both animal models and studies of human relationships. Social attachments, or selective affiliations between individuals, play a central role at all levels of human relationships and represent a key determinant of psychological and physical health , a socially monogamous rodent species, have been foundational in our understanding of the biology of attachment. Prairie voles were first identified as living in burrows in extended families, and consistent male-female pairs are trapped together in the field and arginine vasopressin (AVP), and their homologues, despite arising in the context of diverse ecological pressures and social constraints of these genes throughout development reveals developmental compensation, as no obvious phenotype is observed , also reveal distinct compensatory responses. Mice-bearing null mutations for these genes lack the phenotypic effects seen in the context of knockdown of gene expression, in otherwise wild-type animals (Daude et al., Diverse species exhibit evidence for developmental compensation with genetic manipulation. In zebrafish, knockdown of genes associated with vascular function, for example The abundance and dynamic nature of oxytocin peptide and receptor expression during early development suggests a possible role in organizing the neural circuits for certain behaviors Hammock, . ExpressWhile it is unknown what specific molecular and neural mechanisms facilitate attachment in the absence of Oxtr, the vasopressin neuropeptide system is an obvious candidate as an alternative and potentially compensatory mechanism of regulation on pair bonding behavior (Bosch & Neumann, modularity can be defined as the division of a biological process into distinct units, each of which can develop or be regulated largely independent of other units (Hoke et al., The selective nature of behavioral deficits with genetic loss of Oxtr suggests modularity in the genetic and neural encoding of pair bonding behaviors. In developmental terms, Astyanax, examined schooling, a group behavior in which fish swim in a synchronized and polarized manner. Deconstruction of this dynamic social behavior identified separable genetic signatures that underly distinct components or modules of schooling behavior, such as tendency to school and body position (Greenwood et al., Some of the most striking evidence for modularity in behavior has come from studies of circadian behaviors as well as sexual behavior and associated sexually dimorphic regions within the brain (Anderson, Studies in Oxtr knockout animals, including voles, mice, and rats, have demonstrated selective and species-specific deficits in behavioral and affective phenotypes suggesting modularity in the genetic and neural structures underlying attachment behaviors. Prairie voles bearing mutations in Oxtr demonstrated decreased affinity for social novelty in a three-chamber sociability test, without more general effects on sociality or anxiety-like behavior (Horie et al., While further experiments are necessary to delineate the behavioral domains affected by loss of Oxtr and the genetic and neural substrates affected, examining social behaviors in the absence of Oxtr begins to reveal the modular structure and component behaviors that comprise attachment. The species-specific sensitivity of particular behaviors to loss of Oxtr signaling, and the potential selectivity of the brain regions involved provide further clues regarding the structural and functional building blocks of the systems supporting attachment behaviors. We can now combine molecular genetic techniques with, for example, transcriptomic and chromatin-profiling approaches and in vivo Ca2+ imaging to analyze gene expression and regulatory signatures, as well as patterns of neural activity across behavioral conditions and between species. These approaches will allow us to differentiate the genetically delineated components underlying pair bonding and their developmental origins (Gegenhuber et al., distributed encoding is observed in numerous neural systems underlying behavior across species, including olfactory processing, associative learning and motivated behavior, motor function, as well as mating and aggression and social behaviors more broadly (Anderson, The striking observation that pair bonding occurs in the absence of Oxtr function may suggest that, like other neuromodulators, Oxt and Oxtr modulate specific behaviors not through binary, all-or-nothing action on isolated brain regions, but rather via coordinated, selective control of activity across a network comprised of multiple circuits. Such Drosophila, dopaminergic signaling in the mushroom body, a structure in the insect brain important for olfactory learning and memory, influences the flow of sensory information to direct specific circuit states that result in the appropriate enactment of innate and learned behaviors in response to olfactory cues (Aso et al., Circuit organization characterized by parallel processing and functional \u201cswitches\u201d between parallel streams allows for a distributed but interconnected circuit structure. Such a structure permits variability in specific components that comprise larger behavioral routines in response to genetic or environmental factors, and has been suggested as a mechanism by which the nervous system achieves behavioral flexibility (Bargmann, C. elegans (Garrison et al., Studies across species suggest that oxytocin also functions as a neuromodulator across circuits recruited under specific ethological contexts. The invertebrate homologue of oxytocin, nematocin, coordinates circuit states in the context of mating behavior in the invertebrate species Oxytocinergic signaling may act during pair bonding in prairie voles to coordinate the function of parallel and distributed circuits mediating bonding. Changes to activity across neurons projecting from the medial prefrontal cortex to the NAc within the context of pair bonding causally accelerates female affiliation towards na\u00efve, opposite sex voles (Amadei et al., . Local Oxtr signaling may modulate the behavioral expression of these modules only in the context of regional circuit activity that occurs during specific social behaviors (D\u00f6len et al., The nervous system thus balances developmental stability and flexibility to environmental stimuli using redundant or distributed processes comprised of genetically defined functional modules expressed in specific contexts (Cohn et al., Numerous reviews and studies over the last decade have expressed caution in attributing widespread, functional necessity to oxytocinergic signaling in social behavior (Fink et al., The genetic and developmental perspectives offered here have implications for the intensive interest in and efforts to use oxytocin as a therapeutic agent for a host of clinical disorders in humans. Based on observations in prairie voles and other mammals including humans, clinical trials have sought to use exogenous Oxt and AVP or small molecule ligands to their receptors to ameliorate the deficits in social attachment and cognition experienced by patients with diverse neuropsychiatric conditions, yielding mixed results (Di Simplicio & Harmer, The approaches to understanding neural mechanisms in behavior outlined here may also influence our understanding of affective processes that support attachment behaviors across species. Modularity in affective-related constructs like valence processing, reward, fear or stress response, and motivation, as well as a distributed circuitry across brain regions for encoding these affective states, is reflected in behavioral domains as well as endophenotypes within clinical syndromes (Anderson & Adolphs,"} +{"text": "Different proxies for changes in structure and/or function of microbiomes have been developed, allowing assessing microbiome dynamics at multiple levels. However, the lack and differences in understanding the microbiome dynamics are due to the differences in the choice of proxies in different studies and the limitations of proxies themselves. Here, using both amplicon and metatranscriptomic sequencings, we compared four different proxies to reveal the impact of a severe summer drought in 2018 on prokaryotic and eukaryotic microbiome structures and functions in two rewetted fen peatlands in northern Germany. We found that both prokaryotic and eukaryotic microbiome compositions were significantly different between dry and wet months. Interestingly, mRNA proxies showed stronger and more significant impacts of drought for prokaryotes, while 18S rRNA transcript and mRNA taxonomy showed stronger drought impacts for eukaryotes. Accordingly, by comparing the accuracy of microbiome changes in predicting dry and wet months under different proxies, we found that mRNA proxies performed better for prokaryotes, while 18S rRNA transcript and mRNA taxonomy performed better for eukaryotes. In both cases, rRNA gene proxies showed much lower to the lowest accuracy, suggesting the drawback of DNA based approaches. To our knowledge, this is the first study comparing all these proxies to reveal the dynamics of both prokaryotic and eukaryotic microbiomes in soils. This study shows that microbiomes are sensitive to (extreme) weather changes in rewetted fens, and the associated microbial changes might contribute to ecological consequences. Soil microbiomes are complex assemblages, consisting of both prokaryotic (bacteria and archaea) as well as eukaryotic organisms that intUnderstanding the temporal dynamics of microbiomes in the course of drought in wetland ecosystems is important as such extreme weather now occurs more often due to climate change. However, there are still the lack and debates in understanding the temporal dynamics of microbiomes due to the differences in the choice of proxies in different studies and the limitations of proxies themselves. Rewetted fen peatlands are locally novel ecosystems , and micHere, we delineated the impact of summer drought on the microbiome structure and function in two rewetted fen peatlands in northern Germany, namely coastal fen and percolation fen , with thTo assess the drought impact, 18-Apr and 19-Feb were considered as wet months change based on corresponding proxies Fig.\u00a0. These cOur study compared four different proxies for microbiome structure and function, suggesting that the choice of proxy matters in revealing microbiome dynamics. With corresponding proxies, we found that both prokaryotic and eukaryotic microbiomes showed a strong response to summer drought in two rewetted fens. Future microbiome analyses are needed with integrated process data to understand the related ecological consequences.Supporting Information"} +{"text": "Older immigrants are at increased risk for social isolation and loneliness due to cultural and linguistic barrier to forming social networks. The vulnerability to social isolation could be exacerbated by the gaps between older immigrants\u2019 cultural expectations on social relations and actual social connectivity. Guided by the cognitive discrepancy model of loneliness, this study examined how social isolation influences loneliness among low-income older residents living in subsidized senior housing and if the relation varies by immigration status. Survey data were collected in 2019 and 2020 from 231 residents in subsidized senior housing communities located in St. Louis and Chicago. Social isolation was measured by frequency of social contacts, accounting for the types of relationships (family vs. friends) and the modes of contacts (in-person vs. remote). Loneliness was measured by the Revised University of California Los Angeles loneliness scale. Perceived quality of friendship was also included in the analytic models. The results of multiple linear regression showed that having positive friendship and more frequent in-person contacts with friends were negatively associated with loneliness, respectively. A significant moderating effect was found that older immigrants felt less lonely than non-immigrant counterparts when they had more in-person family contacts . The results suggest that the impacts of social isolation on loneliness among senior housing residents could differ depending on immigration status. The findings of this study could contribute to developing culturally sensitive interventions to enhance social connectedness and reduce loneliness among older immigrants in subsidized senior housing."} +{"text": "Occupational burnout has become a pervasive problem in human services. Medical professionals are particularly vulnerable to burnout, which may lead to reduced motivation, medical errors, and voluntary absenteeism. To ensure effect functioning of medical systems, better understanding of burnout among medical professionals is warranted.We aimed to investigate the structural brain correlates of burnout severity among medical professionals.Nurses in active service underwent structural magnetic resonance imaging. We assessed their burnout severity using self-reported psychological questionnaires. This study was approved by the Committee on Medical Ethics of Kyoto University and was conducted in accordance with the Code of Ethics of the World Medical Association.The results reflected considerable individual differences in burnout severity in our sample. Our findngs revealed that the levels of burnout severity were associated with the regional gray matter volumes in brain areas such as ventromedial prefrontal cortex and insula.Since the outbreak of the COVID-19 pandemic, medical professionals have faced even greater stress. We hope that our findings will contribute to a better understanding of the mechanisms of burnout and offer useful insights for developing effective interventions to manage stress and burnout.No significant relationships."} +{"text": "AORTA is proud to publish the abstracts from the 2022 joint IMAD and ESCVS (European Society for Cardiovascular Surgery) meeting in Liege, Belgium.To assure availability for the meeting, these abstracts are being published in original form, without proof reading or copy editing.IMPORTANT NOTE:AORTA is pleased to receive full manuscripts corresponding to these abstracts for expedited review and publication."} +{"text": "The voices of lesbian, gay, bisexual, transgender, and queer (LGBTQ+) older adults are very often overlooked in research contexts. Creative qualitative methods have been utilized to study populations who have been neglected, empowering marginalized communities, and fostering equitable research processes and outcomes . This innovative symposium explores creative qualitative methods of data collection and analysis, such as creative writing and poetry, which have been employed in research about LGBTQ+ aging and also describes how each method may provide a unique contribution to the research process and literature. The first presentation describes the process of facilitating a weekly creative writing group with LGBTQ+ older adults and how creative writing can facilitate the retelling of life events and reimaging of new futures. The second presentation describes the process of analyzing pieces of creative writing in order to elucidate the potential and possibility of queer futurities and their implications for research on aging trajectories and imaginings. The third presentation details how found poetry created from dyadic semi-structured interviews sheds new light on the relationships of LGBTQ+ couples facing cancer. Through these three presentations, we will illustrate how creative methods contribute strengths of generating evocative and poignant narratives, illuminating not-yet-possible futures, and inspiring equally creative interventions. The overall objective of this symposium is to explore creative qualitative research methods for their utility in research with LGBTQ+ older adults, ultimately fostering more inclusive and nuanced research processes and products."} +{"text": "Previous studies report that poor oral health reduces the opportunity for social interaction and increases the risk of psychological distress and that eating alone affects depressive symptoms and its connection differs by living arrangements. The present study aims to investigate the moderating effects of eating alone and living arrangements on the relationship between difficulty eating food due to poor oral health and depressive symptoms among Korean older adults.Data were drawn from the 2020 Survey of Living Conditions and Welfare Needs of Korean Older Persons, a nationally representative survey. A total of 9,920 participants aged 65 years and older were included in analyses.Results from hierarchical regression analyses showed that difficulty eating food was positively correlated with depressive symptoms and eating alone did not moderate the relationship between difficulty eating food and depressive symptoms . However, the effects of eating alone significantly differed by living arrangements . In the case of older adults who live alone, eating alone significantly moderated the relationship between difficulty eating food and depressive symptoms, whereas for those living with others, eating alone did not moderate the relationship. Discussion: Social isolation can be a risk factor that worsens the mental health of older adults who have difficulty eating due to poor oral health. Practical implications for ways to reduce loneliness are discussed."} +{"text": "Given the current threats to health for older Indigenous people, it is important to understand the health needs and perceptions of older Indigenous people who play a pivotal role in the health and wellbeing of their communities. The underrepresentation of Indigenous voices has led to research, health promotion efforts, and community engagement that has largely been unsuccessful in facilitating culturally grounded and effective health promotion. Engaging Indigenous Elders in research has often been a challenge for researchers \u2013 Indigenous and non-Indigenous. Reaching Indigenous Elders within the urban environment can even be more challenging at times based on dispersed communities due to challenging historical contexts, experiences of racism, and mistrust. This presentation is based on the employed engagement strategies of urban-based Alaska Native Elders. Developing policies and programs to promote healthy aging in Indigenous communities requires the voices of those living within their communities."} +{"text": "The ability to drive a vehicle is an everyday function that helps older adults maintain independence. Few observational studies have examined the relationship between cognitive decline and driving mobility and in context of racial differences and social determinants of health (SDOH). To address this empirical gap, this study aimed to characterize how cognitive functioning is longitudinally associated with driving mobility in older age, and how it may vary by race and SDOH. Using the control arm of the Advanced Cognitive Training in Vital Elderly study , multilevel models examined longitudinal associations between processing speed, visual attention, memory, and reasoning with driving mobility outcomes. Race and SDOH moderations were explored. Only declines in reasoning and processing speed related to driving mobility, moderated by race and SDOH. Reasoning decline related to increased driving space in White but not Black older adults (p=.286). Processing speed decline related to greater driving exposure in Black older adults but less driving exposure in White older adults . Processing speed decline related to reduced driving exposure and increased driving difficulty , but only in people living in poorer neighborhood and built environment and poorer social community contexts, respectively. Overall, findings emphasize that relationships between cognitive decline and driving mobility are dependent on race and SDOH. Consideration of such factors may help target those in greatest need to sustain safe driving mobility and functional independence."} +{"text": "Sigma Phi Omega, The International Academic Honor and Professional Society in Gerontology (aka Sigma Phi Omega), was established in 1980 to recognize excellence of those who study gerontology and aging, and the outstanding service of professionals who work with or on behalf of older persons. The formation of this society provided a much-needed link between educators, practitioners, and administrators in various settings where older persons are served. Through the efforts of the international office and executive board officers, Sigma Phi Omega builds avenues to further their members\u2019 academic and professional gerontological excellence. The goals of Sigma Phi Omega are achieved primarily through activities of local chapters at higher education institutions worldwide. Sigma Phi Omega chapters serve as links within their respective communities to promote interaction between gerontology educators, students, alumni, and local professionals. This international organization has a laser focus on excellence within gerontology and health professions education. In this session, the first presentation will provide the history of Sigma Phi Omega and its outreach efforts; the second presentation will focus on the future goals of Sigma Phi Omega to expand its role as an international honor society in preparing gerontologists, service providers and health professionals working with or on behalf of older adults; and the third presentation will focus on the SPO Chapters and their relationship with the piloted Gerontological Society of America Student Chapters."} +{"text": "Mentors have the responsibility to guide their mentees through academic and scientific challenges that they might encounter during their educational and professional development. In embodying the role of mentors, senior academics are also expected to transmit knowledge and competencies on the topic of research integrity to their junior colleagues. However, senior academics do not always succeed in transmitting responsible research practices and enhancing the research integrity climate. The implementation of the concept of reverse mentoring can be an option to overcome this issue. Different from traditional mentoring, the flow of information is reversed, going from juniors to seniors. Reverse mentoring, as a developmental partnership between mentees and mentors, has been already used successfully within the private sector and in medical education. In times in which most universities invest resources in organizing dedicated research integrity trainings for PhD candidates and junior researchers, it would be valuable to consider reverse mentoring for fostering responsible research practices and enhancing the research integrity climate. PhD candidates and junior researchers can join and fully contribute to the endeavor of enhancing the research integrity climate by co-creating, together with their senior colleagues a new-shared learning environment. Universities and research institutions rely heavily on senior academics. Besides having the central role of facilitating the development of research skills and competencies, senior academics have the role of transmitting professional values and, promoting high research integrity standards at the individual and the collective level. Research integrity is defined as performing research according to responsible research practices, in line with high professional, methodological and ethical standards . UniversAlthough senior academics are expected to be in charge of the process of socialization, they do not always succeed in the task, falling short in creating, fostering, and maintaining a healthy research integrity environment . In othehttps://www.nhs.uk/), focusing on exploring equality, diversity, and inclusion by pairing senior white leaders (considered as mentees in the program) with black and minority staff (considered as mentors in the program) [The concept of reverse mentoring has been successfully implemented within different corporations and private settings since it was first formally introduced at General Electric in 1999 . At firsprogram) .However, reverse mentoring has also disadvantages that lie in its structure. These disadvantages may be related to the level of confidence of junior colleagues when acting as mentors, the willingness of seniors to accept and be responsive to what they are learning when acting as mentees, and issues concerning cross-generational differences , 17, 18.Without being limited to the experiences in the private sector and in the NHS, it is fair to explore whether reverse mentoring might benefit the academic environment . In the Besides being possibly beneficial to the research environment in its entirety, reverse mentoring might be useful to foster responsible research practices and enhance the research integrity climate in particular. Although senior academics can contribute to creating a responsible research environment by fostering research integrity awareness and practices, it might be the right time to let junior researchers join this endeavor. Universities are already investing resources in their PhD candidates and undergraduates by providing dedicated training sessions on research integrity that rarely target senior academics \u201323. AlonAccording to the reverse mentoring model, doctoral candidates and junior researchers (acting temporarily as mentors) can provide seniors (acting temporarily as mentees) with a new impulse in terms of awareness and more up-to-date knowledge on the topic of research integrity and open science. Junior researchers can start collaborating with senior colleagues in giving new momentum to research integrity and a start to the discussion surrounding open science practices within the research environment. This collaboration can only be extremely beneficial to enhancing the research integrity climate Fig.\u00a0.Fig. 1JuPhD candidates and junior researchers can assist senior academics in fostering research integrity in different possible ways. First, junior researchers can collaborate with senior colleagues in discussing and promoting activities in relation to research integrity. Second, junior researchers can provide monthly seminars on general or more discipline-specific research integrity issues within their research teams. Third, junior researchers can update new colleagues (junior and senior) on what is expected from them in terms of research integrity, responsible research practices and open science. Forth, junior researchers with specific expertise on the topic of research integrity and open science can facilitate workshops involving senior colleagues. Finally, junior researchers can be involved in the definition of some recommendations to regulate the supervisor\u2013supervisee relationship. Besides having possible direct benefits in fostering responsible research practices and in promoting open science practices, reverse mentoring might have an impact on issues not strictly related to research integrity or open science, but still influencing the research integrity climate. Reverse mentoring might be valuable for senior academics for improving their mentorship and inter-relational skills and for junior researchers to improve their leadership and managerial skills \u201314. SuppOvercoming the issue of senior academics\u2019 occasional inability to foster responsible research practices and to enhance the research integrity climate has to be taken seriously. Universities should start recognizing and supporting the role that PhD candidates and junior researchers play in fostering research integrity. Universities should start involving PhD candidates and junior researchers in the organization of and in facilitating training sessions on research integrity and open science. Involving juniors in the discussion surrounding responsible conduct of research and practices could provide some much-needed momentum to the topic of research integrity. Junior researchers and doctoral students should start joining senior colleagues in enhancing the research integrity climate by creating a shared learning environment."} +{"text": "Longevity and quality of life are core interests in gerontology, but debate has ensued as scholars have sought to integrate the two. I propose the concept of dual functionality to examine how humans reach advanced ages while maintaining both physical and cognitive function. Using a large national sample, my colleagues and I operationalize dual functionality and identify life course factors that predict it. Analyses of 33,310 respondents 50 years or older from the Health and Retirement Study show an estimated median age of 74 for loss of dual functionality. Lifetime stress exposure leads to earlier loss of dual functionality, even after adjustment for socioeconomic status and lifestyle factors. Estimates of dual-function life expectancy, moreover, reveal greater racial-ethnic disparities than those for life expectancy per se. Dual functionality may be useful for assessing the quality of longevity across societies and social categories and for identifying exceptional longevity."} +{"text": "From May 2018 to September 2022, the Democratic Republic of Congo (DRC) experienced seven Ebola virus disease (EVD) outbreaks within its borders. During the 10th EVD outbreak (2018\u20132020), the largest experienced in the DRC and the second largest and most prolonged EVD outbreak recorded globally, a WHO risk assessment identified nine countries bordering the DRC as moderate to high risk from cross border importation. These countries implemented varying levels of Ebola virus disease preparedness interventions. This case study highlights the gains and shortfalls with the Ebola virus disease preparedness interventions within the various contexts of these countries against the background of a renewed and growing commitment for global epidemic preparedness highlighted during recent World Health Assembly events.Several positive impacts from preparedness support to countries bordering the affected provinces in the DRC were identified, including development of sustained capacities which were leveraged upon to respond to the subsequent coronavirus disease 2019 (COVID-19) pandemic. Shortfalls such as lost opportunities for operationalizing cross-border regional preparedness collaboration and better integration of multidisciplinary perspectives, vertical approaches to response pillars such as surveillance, over dependence on external support and duplication of efforts especially in areas of capacity building were also identified. A recurrent theme that emerged from this case study is the propensity towards implementing short-term interventions during active\u00a0Ebola virus disease outbreaks for preparedness rather than sustainable investment into strengthening systems for improved health security in alignment with IHR obligations, the Sustainable Development Goals and advocating global policy for addressing the larger structural determinants underscoring these outbreaks.Despite several international frameworks established at the global level for emergency preparedness, a shortfall exists between global policy and practice in countries at high risk of cross border transmission from persistent Ebola virus disease outbreaks in the Democratic Republic of Congo. With renewed global health commitment for country emergency preparedness resulting from the COVID-19 pandemic and cumulating in a resolution for a pandemic preparedness treaty, the time to review and address these gaps and provide recommendations for more sustainable and integrative approaches to emergency preparedness towards achieving global health security is now. However, developing the legal and regulatory mechanisms, physical infrastructure, human resources, tools and processes to meet IHR 2005 compliance assumes a foundation of a functional health system [From May 2018 to September 2022, the Democratic Republic of Congo (DRC) experienced seven Ebola virus disease (EVD) outbreaks within its borders \u20135. The rh system . This ish system . In viewrd, 74th and 75th World Health Assembly (WHA) events [This case study thus highlights some of the gains and shortfalls with the EVD preparedness interventions against the background of the renewed and growing commitment for global epidemic preparedness highlighted during the 73) events and esta) events . Focusin) events , simulat) events \u201321 and fThe most recent outbreak of EVD in the DRC declared on August 21, 2022 is the fifteenth outbreak since the first EVD outbreak was reported in the country and globally in 1976 . Among tThe eleventh EVD outbreak was declared following laboratory confirmation of samples taken during investigation of a suspected cluster of deaths in Equateur Province on June 1, 2020 and prior to the ending of the tenth outbreak . The natBased on a World Health Organization risk assessment, nine countries sharing borders with the DRC during the tenth EVD outbreak were considered as moderate to high-risk and referred to as \u201cpriority countries\u201d. The priority countries were further classified into priority one and two depending on their geographic proximity to the epi-center of the outbreak, volume of cross border movement and shared transport routes. As a result, Burundi, Rwanda, South Sudan and Uganda were identified as priority one countries and Angola, Central African Republic (CAR), Congo, Tanzania and Zambia as priority two.Further consideration was given to the priority one countries based on their geographic, infrastructural, political and socio-economic contexts as determinants of their respective population vulnerabilities and health system capacities. Uganda had experienced six EVD outbreaks between 2000 and 2019 and demonstrated progressive capacity for detection and containment since the first and largest outbreak occurred in Northern Uganda in 2000 resulting in 224 deaths , 28. ThiBetween October 2018 and December 2019, over 70 million USD was provided by the international donor community to the priority one countries for EVD preparedness . EffortsUsing the same risk assessment criteria for allocating countries into priority one and two categories for EVD preparedness during the tenth EVD outbreak, the Republic of Congo and CAR were classified as priority one countries during DRC\u2019s eleventh EVD outbreak. Despite their high-risk status and weak preparedness capacities, external funding to support either of these countries for EVD preparedness during the eleventh and fourteenth EVD outbreaks was negligible.The lessons learnt from the outbreaks captured the benefits of EVD preparedness in the countries bordering the DRC that were at high-risk of cross border transmission during the DRC\u2019s tenth, eleventh and subsequent EVD outbreaks. The reports and experiences also captured several shortfalls in implementation processes. The gaps between building detection and response capacities in a sustainable manner in alignment with global policy frameworks as stipulated under Article 44 of the IHR 2005 and other international frameworks are highlighted and discussed.Experiences from the priority countries showed how national capacities built under several pillar areas were leveraged upon to respond to the COVID-19 response. Capacities in national and sub-national multi-sectoral coordination were strengthened, the need for institutionalization of infection prevention and control was realized and a heightened appreciation for the role of risk communication and community engagement in public health was acknowledged , 33, 34.However, in some cases during these EVD outbreaks, some countries continue to depend on external intervention and a significant proportion of donor funding to conduct a response. For example, following emergence of the DRC\u2019s eleventh EVD outbreak on June 1, 2020 in Equateur Province, little evidence of local capacity developed during the ninth outbreak, occurring in the same location less than two years earlier, was evident. Most of the response pillar areas had to be re-established and re-operationalized by external partners resulting in a delayed response. A similar situation was observed during the EVD outbreak in Guinea in 2021 and to a less extent in Beni in 2020 and 2021. One pillar area where the gap in national capacity is most evident is in critical care specific to managing EVD patients. In the majority of EVD outbreaks critical patient management was conducted by external partner organizations due to inadequately trained healthcare workers in critical care capacities within the health sector of sub-Saharan African countries .Building local capacity from the existing pool of experienced human resources in countries and communities or shariDuring EVD preparedness\u00a0interventions in the priority countries, the role of the local community was mostly limited to rumour tracking, community volunteer roles such as social mobilization activities, health promotion and community surveillance. There were lost opportunities to capture gender disaggregated data, community perspectives and suggestions on how existing local capacities and knowledge could be identified, leveraged\u00a0upon and actively engaged in broader\u00a0roles in preparedness and response operations. For example, communities in the DRC and some of the priority countries argued that large deployments of international personnel during EVD outbreaks undermined local expertise and little opportunity remained for integration and sustaining the skills developed during preparedness and response after these personnel left .EVD preparedness interventions during the tenth outbreak benefitted from increasing integration between epidemiology, public health and clinical medicine with the social sciences to understanding the social, cultural and political pathways of Ebola emergence and the perceptions of the community and individuals to the disease and their acceptance of the associated\u00a0public health interventions. An increase in activities supporting and implementing participatory and evidence-based field work was observed in the neighbouring countries during the tenth EVD outbreak providing more nuanced understandings to inform more effective interventions , 41. WhiEVD outbreaks are usually accompanied by rapid investment into the response phase allowing little time for formal planning of good quality training programmes. During the preparedness and response phase of these outbreaks, national staff and community volunteers were provided with basic trainings to implement field level activities under several pillar areas. Trainings were largely undertaken by an array of partner agencies in an ad hoc manner using multiple methods such as sensitizations, briefings, orientations, theoretical and practical workshops , 33. An There were few examples demonstrating effective coordination of EVD preparedness trainings or establishment of formal procedures for reviewing the structure, mode of delivery and quality of the training content, assessing the capacity of the trainers or selection process of the participants. The collaboration between the academic and public health sectors for EVD preparedness capacity in the priority countries during the tenth EVD outbreak was a new development and represented an opportunity for countries to encourage inter-regional partnerships between higher level institutions to ensure institutionalization of training programmes for EVD outbreak preparedness and response.The importance of research and development in EVD outbreaks cannot be overemphasized, particularly the development of vaccines and therapies for high impact pathogens including EVD . The lowObservations show that countries seeking vaccination of high-risk health workers in districts bordering the eleventh, twelfth and thirteenth outbreaks failed to access adequate quantities of the licensed vaccine. Furthermore, little attention was targeted towards local clinical research into homegrown interventions which could reduce mortality in low resource settings. For example, allocation of research funding to explore the contribution of supportive care interventions such as blood volume enhancers including intravenous fluids, colloid and crystalloid solutions, blood transfusion and parenteral nutrition as life-saving interventions in patient management during EVD preparedness was lacking in the DRC and other at-risk countries during the EVD outbreaks.EVD outbreaks were frequently accompanied by a cascade of medico-technical innovations such as the use of robots to monitor patient body temperatures at airports in some African countries and piloting drones to transport EVD alert samples across the equatorial forests of Equateur Province raising serious safety concerns are some examples. Whilst technological interventions can address gaps in response operations and reduce costs, such innovations need to be informed by public health principles.When the eleventh EVD outbreak emerged in Equateur Province at the end of May 2020, temporary facilities constructed during the ninth outbreak to isolate and treat patients either no longer existed or were unfit for purpose. This demanded rapid construction of inferior quality structures that were poorly managed in the initial phase of the response due to weak partner co-ordination. In some communities, in addition to fear and stigma, reports of poor patient care of those admitted at the treatment centers translated into additional fear, avoidance to report alerts and resistance to allow access to safe and dignified burial teams to respond to community deaths. Reversing mistrust required considerable time and investment, not only by improving the physical infrastructure and system of care but through intensive community engagement. In the 2021 EVD outbreak in Guinea mistrust remained among communities from bad experiences associated with Ebola Treatment Centers (ETCs) during the West African outbreak (2014\u20132016) .The design and materials used to construct ETCs have witnessed several innovative improvements in the past decade. These innovations materialized in response to the need for improved health worker and patient safety, improved comfort and visibility for the patient of their surroundings and for family members, reduced time constraints to monitor and treat patients and a reduction in personal protective equipment (PPE) use and waste management costs without compromising infection prevention. The concept of transit centers introduced in North Kivu during the tenth EVD outbreak using semi-permanent materials as extensions to existing permanent structures helped to buffer community fear.Building permanent or semi-permanent structures for isolating and treating patients versus temporary structures became an area of considerable debate between donors and countries throughout EVD preparedness efforts in the at-risk countries. The argument for not investing in infrastructural projects lies in the assumption that such projects are highly costly, take time to complete and funds might be misused or diluted into a larger funding pool resulting in a poor-quality product that does not serve the intended purpose. Another argument against permanent structures is that the location of an EVD outbreak cannot be known in advance, therefore constructing permanent buildings in several locations in expectation of a confirmed case is not feasible. Temporary structures are considered suitable to serve the purpose for the duration of the project and pose a lower risk for the investment. However, in practice it has been shown that the cost of constructing and maintaining a temporary ETC is equivalent and (in some cases) more costly to construct and maintain than semi-permanent/permanent structures. Temporary structures inevitably decompose over time due to exposure to weather and represent poor value for money. Many of the at-risk countries expressed preference for semi-permanent/permanent structures or renovation of existing buildings as a more sustainable and cost-effective solution that can be repurposed to general isolation facilities for other infectious diseases following EVD outbreaks. In South Sudan, the semi-permanent structure built during EVD preparedness in 2019 was sustained and continued to be used throughout the COVID-19 response ; this deHowever, despite attempts to humanize ETC design in recent years, all EVD outbreaks in the DRC between 2018 and 2022 continue to see patients treated in temporary structures. The consensus that emerged is that there is \u201cno one size fits all solution\u201d. Each outbreak evolves and behaves differently and can emerge in a variety of contexts warranting different design options. Decision making processes at country level requires further dialogue and review of case studies from EVD preparedness inclusive of community perspectives.The large influx of funding and resources associated with epidemics has in the past resulted in the duplication of efforts and implementation of short-term interventions that fail to strengthen country capacity in the longer term often representing missed opportunities. A key lesson from the EVD preparedness in the priority countries was the need to leverage existing health programmes and identify existing systems and use them as entry points for integrating EVD preparedness. This is more pertinent in view of the\u00a0more recent discovery that latent EVD infections lasting for several years could trigger outbreaks as was seen in the case of the 2020\u20132021 outbreaks in Guinea , 51. ThiAnother example was the need for enhanced integration of EVD surveillance into the Integrated Disease Surveillance and Response (IDSR) system, the primary disease surveillance system for the general population, used in the priority countries. In South Sudan for example, a project approach under EVD preparedness resulted in an EVD alert management system limited to high-risk districts for EVD that ran parallel to the existing IDSR system . This waA similar observation was noted for enhancing community surveillance which gained a lot of traction during EVD preparedness, but its momentum waned following withdrawal of Ebola specific funding . This isSouth Sudan and CAR are both conflict-affected countries experiencing protracted and complex humanitarian crises, internally displaced populations and highly fragile health systems. Uganda,\u00a0Rwanda\u00a0and Burundi host large numbers of refugees. This presence of internally displaced persons and refugees in the countries undergoing preparedness presented special challenges . First, Cross border collaboration and regional coordination of preparedness and response efforts for EVD outbreaks is a critical factor in containing cross border transmission of outbreaks. Observations showed that\u00a0progress\u00a0in this preparedness area varied across\u00a0the neighbouring countries during the tenth and eleventh EVD outbreaks in the\u00a0DRC. In Uganda and Rwanda, the Ministries of Health successfully organized cross border meetings and signed Memoranda of Understanding for cross border collaboration with their counterparts in the\u00a0DRC which faAlthough several regional coordination meetings involving the\u00a0DRC and the priority countries were held , these wA recurrent theme that emerged in the lessons learnt from EVD\u00a0preparedness in countries bordering the DRC\u00a0EVD outbreaks is a propensity towards implementing short-term vertical interventions during EVD outbreak preparedness and response rather than sustainable investment into strengthening systems for health security in alignment with IHR 2005 obligations, Universal Health Coverage\u00a0and the Sustainable Development Goals (SDGs).Since the first recorded EVD outbreaks in 1976, response interventions have been mostly reliant on international emergency funding and expertise. As a result, resources are limited to the timeframe of the outbreak period and withdrawn once the outbreak is declared over. In contexts such as the DRC and its neighbouring countries known to frequently experience or be at high-risk of EVD outbreaks, negligible national investments have been made to establish foundational preparedness elements on which emergency responses can rapidly become operational prior to arrival of external support. Unfortunately, the current approach for supporting EVD preparedness, follow a declared outbreak and is an extension of the response. Also, limiting EVD preparedness support to \u201coperational readiness\u201d after emergence of a nearby outbreak risks undermining the importance and volume of work required to build the foundation of preparedness in countries, particularly in contexts where weak health systems exist. Even more concerning than limiting EVD preparedness support is absence of support for preparedness in high-risk areas bordering outbreaks as observed in relation to the\u00a0majority of DRC outbreaks following the tenth EVD outbreak. This is particularly concerning for CAR and Congo bordering Equatorial Province in western DRC, where no significant investment towards implementing EVD preparedness has occurred despite\u00a0experiencing three outbreaks since 2018 across a shared landscape.While extending EVD response capacities to support preparedness appears to make sense at several levels it has several limitations. In support of the argument, preparedness benefits from being an extension of a response in that having expertise, experience and capacities available during the response can inform and guide inputs and activities required for coordinating preparedness activities simultaneously. Also, the proximity of a response influences increased alert reporting in neighbouring areas due to enhanced awareness and surveillance activities. This also increases willingness of neighbouring countries to engage in preparedness activities and cross-border collaboration and finally it highlights gaps and funding needs. However, when EVD preparedness is limited to being an extension of the response, it falls within the timeline allocated for supporting the response. This does not allow sufficient time to develop national capacities and skills for countries to affect an independent response or generate a baseline of resilience to mitigate future events. Once the outbreak is declared over, support for the response and preparedness efforts initiated in bordering countries is withdrawn leaving these health systems in much the same state as prior to the outbreak. As the DRC\u2019s tenth EVD outbreak phased down in the latter part of 2019, funding for additional EVD contingency plans waned, yet several gaps remained for the priority countries to reach a minimum level of capacity. Another limitation is that when preparedness support is an extension of a response it can become defined by the response, resulting in carbon copied approaches and activities, some of which tend to be reactive in nature allowing little scope to conceptualize more sustainable or context appropriate methods.Constructing temporary ETCs versus permanent structures in EVD prone contexts is one example highlighted above. If issues such as ETC design, incentive payments to responders, mapping and co-ordination of local capacities, capturing community insight on their understanding and application of EVD preparedness measures and vaccination strategies were explored and resolved at country level outside the urgency of a response environment, analysis of previous case studies and lessons learnt could be more effectively reviewed to inform decision-making\u00a0and planning processes for future responses.In the event of public health threats with capacity to cross borders, building core capacities to prevent, detect and implement a public health response is a mandatory requirement of Member States under the revised IHR. However, the renewed commitment for post COVID-19 pandemic preparedness needs to look beyond the confines of a global health security agenda. Other factors such as the social determinants of health, local culture and human behavior are also critical in this regard. Poverty and its associated challenges of poor living conditions, inadequate access to water and sanitation, illiteracy, engagement in alternative means of sourcing food and livelihood such as forest activities and inaccessibility to conventional health services is one example why the poor are increasingly vulnerable to increasing EVD incidence in endemic areas. The global community including governments, regional blocks and development agencies thus need to look beyond the health aspects of EVD outbreaks and focus on the linkages between the social and political determinants of high impact disease emergence.Some recommendations to inform more sustainable preparedness approaches for future EVD preparedness investments into EVD and other viral hemorrhagic fever (VHF)\u00a0disease prone contexts have emerged from this case study are outline in Box Global health security and health system strengthening are two sides of the same coin. Unfortunately, the lessons learnt from this case study demonstrate that rapid and temporary preparedness and mitigation measures in reaction to EVD outbreaks threatening international borders and regional health security on the Africa continent continue to be the preferred approach to EVD preparedness in high-risk contexts. Hard lessons learnt including those highlighted in this paper should drive advocacy for a shift from reactionary and short-lived interventions towards more sustainable long-term approaches to EVD and emergency preparedness which would build health system resilience in general. A starting point would be for countries\u00a0including representatives from previously affected\u00a0communities and global actors to create a space where the much-needed open dialogue can occur to review these and other best practices and lessons learnt around EVD preparedness long before outbreaks occur. From here resolutions, contextual view-points and recommendations can evolve to disentangle recurrent bottlenecks that emerge time and again during EVD response and preparedness. The time for this open dialogue, engagement and inclusive collaboration is now."} +{"text": "COVID-19 pandemic had an important impact in mental health across all countries and populations. However, health care professionals, particularly those in the front line have been subjected to increased levels of stress, workload, deterioration of work environment and working conditions while potentially being afraid of contracting the infection themselves or infecting love ones due to the higher risk of contagion when dealing with infected patients. Some studies have stressed out this impact showing increased levels of burnout, depression, hopelessness, stress and post-traumatic stress in all physicians however, the impact of the pandemic may have been different depending on the specialty. We intended to study the impact of COVID-19 pandemic for doctors working at general hospitals and liaison psychiatrists dealing with COVID-19 patients in Europe. We developed and applied online questionnaires to physicians working at general hospitals and psychiatrists working at liaison services, in different European countries , in order to determine what were their working conditions and it they reported mental health symptoms during the pandemic. This questionnaire included demographic data, questions about working conditions when dealing with general and COVID patients and the Hospital Anxiety and Depression scale (HADS). It was distributed thought email and social media platforms used by doctors. This work has been approved by each local Ethics committee and all participants signed an informed consent.No significant relationships."} +{"text": "Dementia caregiving is a family affair, yet prior research suggests that families often disagree about care provision. We explore correlates of such disagreements and how disagreements relate to stress process outcomes of care. The current study examines 552 family caregivers for Medicare-eligible older adults with dementia from the 2017 National Study of Caregiving. We consider demographic and care characteristics as predictors of family disagreement in a multinomial logistic model, and family disagreement as the key predictor of caregiving overload, emotional difficulty, and gains in linear regressions. Females had greater odds of disagreement, while those with friends and family to talk to and providing assistance with household care activities had lower odds of disagreement. Family disagreement was significantly associated with overload and emotional difficulty , but not gains. Interventions to help families manage care disagreements and coordinate care may have great impact on caregiver well-being."} +{"text": "The Afromontane mountains are a complex series of highlands that have intermittently been connected by habitat corridors during climatic cycles, resulting in a mosaic of range disjunctions and allospecies complexes in the present day. Patterns of community relatedness between geographic regions are often determined through single-species analyses or spatial analyses of diversity and nestedness at the species level. To understand patterns of Afromontane community evolution and to assess the effects of taxonomy on our understanding of biogeographic patterns, I concatenated three lists of Afromontane bird taxa divided into five taxonomic hierarchies. These lists were converted into a presence-absence matrix across 42 montane regions and analyzed using a variety of clustering techniques based on a replicable coding pipeline. I used these lists and methods to determine patterns of relatedness between montane blocks, to assess the consistency with which biogeographic regions were recovered, and to shed light on the patterns of connectivity within the Afromontane region. My results reaffirm the distinctiveness of many biogeographic regions while also clarifying regional relationships and the presence of \u2018transition zones\u2019 between regions. Differences between lists illustrated how our understanding of taxonomy and distribution in the Afromontane highlands can also change our understanding of Afromontane biogeography. Most notably, I found evidence for an Expanded Eastern Arc that included the Eastern Arc Mountains and highlands in Malawi, Mozambique, and Zimbabwe. This study presents a rigorous yet easily adjustable pipeline for studying regional biogeography from multiple taxonomic perspectives using both traditional and novel approaches. This relict genus has persisted in the Eastern Arc Mountains of Tanzania, where the complex regional geography and climatic cycling has promoted the differentiation of two geographically proximate taxa that are often regarded as separate species [formerly placed in Kupeornis (Serle 1949)]) while others show no obvious differentiation across widely separated populations and on the distribution of \u2018superspecies\u2019 that consist of multiple allopatric taxa that are or appear to be closely related , species that are found in lower-lying montane regions that are more xeric , species that are geographically restricted around montane regions , and species that are elevational migrants within specific montane regions . Hereafter, this list will be referred to as the \u20182021 list\u2019 , taxa that migrate between montane regions latitudinally , and taxa that are locally montane but occur broadly in lower elevations within the tropical latitudes were excluded from all iterations of the analyses possesses two phenotypically differentiable Groups, tullbergi and taniolaema/hausburgi, which have been considered as a monotypic C. tullbergi and polytypic C. taniolaema by some authors : Genus, Superspecies, Species, Group, and Subspecies. Taxonomic hierarchies and taxonomy implemented can affect the patterns recovered by scientists, and understanding the bias introduced by human classification is an important facet of biogeographical research . I deriv authors . Supersp authors . I incluS) to estimate the similarity in taxonomic composition among montane regions using the 2021 species list. The Jaccard index has a range from 0 to 1 (wholly different communities). I used the function \u2018vegdist\u2019 in the R package vegan to calculate the Jaccard index to study the geographic structuring of communities. Unlike other methods employed herein, ecostructure also allows for viewing the \u2018admixture\u2019 between community motifs, allowing for clearer interpretation of connectivity between montane regions in a format that is not limited by group assignment or dendrogram formation. I performed iterations of ecostructure for K of 2\u201314 for each taxonomic hierarchy in the 2021 list, with particular attention paid to the number of groups determined from k-means clustering. This pipeline uses the grid function in the R stats library and functions in the R package gridExtra , ImageMagick . Compositional similarity declined with increasing geographic separation, although the magnitude and rate at which differences accumulated depended on taxonomic scale, with finer scales accumulated differences faster than coarser scales and subspecies levels . The largest number of clusters (k = 20) were estimated at the Superspecies level using the k = 3) were estimated at the Group level using the The optimal number of clusters for subdividing the Afromontane highlands varied by source list and by taxonomic level, with an average of 9 clusters for the Through all methods, several biogeographic regions were recovered that largely corresponded to those noted in the literature. The consensus dendrogram for all lists contained polytomies a polytomy of the northern Eastern Arc Mountains from Taita Hills, Kenya to Rubeho and Ukaguru Mountains, Tanzania; B) the Udzungwa and Uluguru Mountains, Tanzania; C) Southern Highlands, Tanzania and Nyika, Malawi; D) Central Malawi south through Mozambique and Zimbabwe (with a southern terminus of the Chimanimani Mountains). Consensus trees for Within-region relationships were largely conserved through all sources, though the topology of the higher-order relationships within the dendrograms varied. The major subsets of the Kenya-Tanzania highlands, the Northern (Volcanic) Tanzania and Kenya-Uganda Highlands, however, are sister clusters within the k-means analyses), but had little effect on the overall topology of dendrograms within specific biogeographic regions. Transitional regions that possessed sufficient species richness to maintain their inclusion in these analyses became more \u2018fluid\u2019 in their position after the removal of other, minor satellite regions. Namely, the Imatong Mountains and the Southern Ethiopia/Northern Kenya Transitional Highlands were often placed sister to each other and were not always linked to the nearby Kenya-Tanzania Highlands. Likewise, Angola fluctuated between different positions, reflecting its complicated biogeographic history with clear connections to multiple different montane regions. Many of these polytomies and the changing placement of specific montane regions within the dendrograms reflect patterns of historical connectivity and colonization between multiple Afromontane regions in the formation of communities. Transitional regions and regions that have been built by repeated colonization events from multiple montane blocks therefore \u2018jump\u2019 between biogeographic clusters depending on the taxonomic level and species list being used.The removal of satellite regions with low species richness affected the number of clusters being recovered species inherently shared many absences, leading to their aggregation.The addition or subtraction of species from the presence-absence matrix had less of an effect on the topology of the dendrograms and regional Gypeatus barbatus [Linnaeus 1758] and the genus Heteromirafra [Grant 1913]). The ecostructure analysis more clearly illustrated these patterns of connectivity, with many intermediary regions showing admixture from multiple biogeographic motifs that provides a novel perspective into the motifs contributing to transitional montane bird communities levels of diversity varies, it serves as a proxy for varying amounts of accrued diversity through time. Assessing the Genus and Superspecies levels allows historical relationships to provide more weight for clustering models, whereas analyses of Group and Subspecies levels divided populations as finely as possible between individual montane regions to further elucidate recent relationships. The most consistent group numbers between authors is subject to vary with inclusion of satellite regions, but often includes the most intermediary hierarchy used, Species. The ecostructure method are particularly illuminating for relationships between major biogeographic regions, especially for transitional and some satellite regions . Regions such as the Taita Hills, located near the often difficult-to-classify Usambara Mountains , which demonstrates connectivity between parts of the southern Malawi-Mozambique highlands and the Eastern Arc Mountains of Tanzania are also largely recovered across source lists. Polytomies exist in every dataset and may never be fully resolved given the complex nature of colonization and connectivity between montane regions.Zosterops; Linneaus 1766, Sheppardia gunningi alticola; Nesocharis ansorgei (Hartert 1899) are discovered in regions where they were previously overlooked of all Afromontane bird taxa used in this study, with annotations for source (e.g., TableS2Table S2. Discrepancies between Afromontane bird taxa source lists used in this study.TableS3Table S3. Afromontane bird species excluded from these analyses, with reason for exclusion."} +{"text": "Combining clinical and academic roles during psychiatric training can be challenging but equally enriching. However, the Covid-19 pandemic has complicated many aspects of psychiatric training, including changes of service provision, clinical duties, training activities and academic opportunities. In this interactive Workshop session, tips and strategies for balancing academic and clinical responsibilities during psychiatric training will be discussed based on real-life experiences and literature recommendations. The impact of the pandemic and what skills could be useful to flexibly tackle the challenges that come with an ongoing public health crisis while working to satisfy academic and clinical requirements in a set period of time will also be considered. The speaker will also include additional resources to improve such soft skills for participants.No significant relationships."} +{"text": "Nursing facilities (NFs) have historically struggled to maintain adequate nurse staffing. We used PBJ data linked with other publicly available sources and conducted stakeholder interviews to understand nurse staffing between 2019 and 2020. We found large declines in the population of NF residents and in staffing hours. Measured in hours per resident day (HPRD) to account for the size of the NF resident population, there were slight increases in staffing. Staffing was nonetheless a major challenge for NFs because they required increased staffing due to the impact of the pandemic. NFs in higher quartiles of percentage of minority residents lost nurse staffing HPRD relative to NFs in the lowest quartile of minority residents. Stakeholders explained that NFs with more minority residents were likely to employ staff who live in more vulnerable communities with a greater concentration of minorities, who were more impacted by COVID."} +{"text": "Suicidal behaviour is the result of several risk factors, such as acute stress, severe depression, violence, sexual abuse, etc. A mental public health approach to suicide prevention needs to look beyond the demographic characteristics of deaths by suicide and to take into account specific country determinants. Available clinical information can help identify and quantify risk, analyse patterns of behaviour, explore links between risk and behaviour and generate possible suicide prevention pathways.162 deaths by suicide for the period January 2015 - June 2021 in Malta are analysed against available clinical information. Major sources of detailed clinical information include obligatory notifications to the Commissioner for Mental Health of all cases of persons involuntarily admitted to acute psychiatric services and other medical records held within the Maltese public mental health system.81% of 162 deaths by suicide for the period under study were males, two-thirds of them between 25 and 54 years. The preliminary findings have confirmed that less than 50% of these deaths had previous contact with the public health system. The two main diagnostic criteria among deaths with recent psychiatric admission/s were acute stress reaction to personal life events and very severe mood disturbances, particularly depression. There seems to be increased risk among migrants and foreign workers residing and working in Malta. The frequency of prior admissions, age-related issues, the time-event relationships, and relevance of elicited clinical findings are still being evaluated and will be presented in more detail in the workshop.Exploring risk factors within the history of cases of suicide through available clinical information can contribute to the development of suicide prevention pathways, relevant to the specific context of local communities."} +{"text": "The Mechanistic Target of Rapamycin (mTOR) pathway integrates a variety of intracellular and extracellular signaling and coordinates many essential cellular processes, including protein synthesis and autophagy. During the neurodevelopment, mTOR acts as one of the main directors controlling the differentiation and proliferation of neural progenitor cells, neuronal morphology and migration, and synaptic plasticity model induced by homozygous Tsc2 mutant. These results demonstrate that Tsc2 has a critical role in regulating neural development and shapes inhibitory granule cells molecular and morphological characteristics. In addition, they performed a transcriptome profiling revealing a significantly different expression in the gene networks regulating neural circuitry following the loss of Tsc2 gene. Ouyang et al. assessed GWAS data of epilepsy from the International League Against Epilepsy and gut microbiota from MiBioGen, and applied Mendelian Randomization analysis to explore the potential causal relationship among the gut microbiota, metabolites, and epilepsy. The study allows to explore the etiology of epilepsy from a new dimension. In the review articles, Girodengo et al. summarized the accumulating evidence from single-cell transcriptomics and cerebral organoid-based studies to improve our understanding of the crucial role of mTOR pathway in brain development and neurological disorders. Furthermore, they highlighted new ultra-sensitive techniques for the identification of somatic mTOR pathway mutations shedding light on the neurodevelopmental origin and phenotypic heterogeneity in mTORopathy patients. Wang et al. reviewed the current advances in imaging genetics in brain microcircuits and epileptic networks during brain development. The imaging genetics analysis accurately and efficiently integrates multidimensional datasets within a unified framework, providing a unique opportunity to generate a global vision for epilepsy to promote the molecular mechanism exploration and develop targeted treatment strategies.In this Research Topic, a diverse insight into the different areas of research aimed at better understanding of neurological disorders caused by mTOR dysregulation. The original research by In summary, the present Research Topic comprises original research and comprehensive reviews highlighting the role of mTOR signaling in neurodevelopment disorders. We hope that this topic will inspire further mechanism exploration of mTOR with the aim of fully restoring function to those neurological disorders.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "Loneliness is a serious public health problem that affects over 25% of older adults and is associated with an increased risk of depression, cognitive decline, and premature death. Previous research on social support mechanisms that contribute to loneliness has consistently illustrated the role of emotional support in reducing loneliness. However, the importance of compassionate love in reducing loneliness and, as a consequence, improving psychological well-being in later life has received little attention. Neurobiology indicates that the brain regions associated with loneliness and compassion overlap, suggesting that increasing compassion-related emotions may help alleviate loneliness. Using data from a nationwide web-based survey , we examined the influence of compassionate love on loneliness and assessed whether loneliness mediates the relationship between compassionate love and mental health outcomes. Even after controlling for emotional support, estimates from an ordinary least squares regression (OLS) model suggest that older adults who felt loved had significantly lower levels of loneliness . Feeling of love also contributed to significantly fewer depressive symptoms and anxiety . Loneliness completely mediated the effect of compassionate love on anxiety and significantly mediated its influence on depressive symptoms . Our findings underscore the need to design interventions that increase compassionate love to reduce loneliness and improve psychological wellbeing among older adults."} +{"text": "It is well documented that ageism negatively affects older people's opportunities for productive aging, and access to the workplace and healthcare. Ageism as it manifests within families, however, has not yet been well studied despite significant implications for the wellbeing of older adults and families. This study presents the problem of ageism in the family through the lens of larger social structural factors shaping meso- and micro-level behaviors. Negative implicit ageism and stereotype embodiment theory underscore the unconscious perpetuation of negative age stereotypes and attitudes in families. To illustrate this concept, we describe three evidence-based case examples involving interactions among family members observed by a geriatric care manager. The first describes how ageism expressed by an adult child undermines choice, opportunity, and power of the parent when an older adult enlists the help of her adult children in downsizing from the family home to a smaller apartment. The second explores ageism when adult children attempt to persuade their older father to leave his home, pointing out dangers living alone at his age. The third describes a relatively healthy newly widowed woman who is coerced by her adult children to move to an assisted living facility by threatening social and emotional abandonment. These examples demonstrate how macro and meso-level factors combine with the implicit ageism of both adult children and older adults converge, influencing pathways to create healthy, tolerable and toxic living conditions within the family."} +{"text": "Dementia care research typically focuses on primary family caregivers with limited consideration of their engagement with a broader care network and the geographic area in which they reside. Using a mixed-methods approach, we analyzed care networks of 163 primary caregivers and their relative living with dementia in rural Virginia. Six distinct care network types emerged based on the primary caregiver's gender, relationship to the person living with dementia, and presence of other informal caregivers. Networks differed by the caregiver\u2019s emotional connectivity with family/friends and feelings of caregiver strain, role overload, and loneliness. Caregivers\u2019 service use attitudes and support service utilization varied across network types and across divergent economic resources of the rural counties in which families resided. Findings establish a framework for understanding the types and influences of care networks and tailoring services to support dementia family caregivers in diverse rural areas."} +{"text": "Background: Although social determinants of health (SDOH) are to some extent incorporated within preclinical medical education, little validated educational methodology exists to provide guidance on how to integrate teaching about SDOH within the competency-based training of medical students\u2019 clinical years. This is potentially important. The COVID-19 pandemic has highlighted the importance of SDOH, and social determinants have become topical, with increasing discussion in journals about equity, inequality, and sustainability. Sir Michael Marmot's 2020 review has highlighted these issues. Consequently, the evaluation of medical students\u2019 experience of prison placements is an interesting area to investigate. This will help us to explore their understanding of SDOH, and implications of gained knowledge for their future practice. Aims: This study explores changes in year four psychological medicine students\u2019 knowledge and attitude towards SDOH during prison placements.A mixed-methods study between Sep 2021 to Apr 2022 recruiting all year four medical students on their psychiatry placement in North Wales. Data collection involves baseline and mid-placement questionnaires and end-of-placement individual interviews to explore their understanding of SDOH.Thematic analysis will be used to describe students\u2019 reflection on placement satisfaction; explore impacts on trainee doctors and supporting staff; make suggestions to improve placement structure in the future; and evaluate the utility of placements in prison.Data collection is in progress. However, early indications suggest that students view these placements favourably and find them a helpful learning experience. Preliminary results will be reported at the conference.We are hopeful that this evaluation will suggest a way forward to raise awareness about SDOH during clinical placements and will give these students confidence in working with socially excluded populations in the future.Findings of this study may provide exploration of means of capacity building and training with improved knowledge of the SDOH in partnership between the medical school, the local health board and the prison.We have developed systems and processes to raise awareness of social factors to be considered by medical students in their future practice. These can guide further development of such placements at HMP Berwyn and in other prisons.This research was funded by Betsi Cadwaladr University Health Board and sponsored by Bangor University in North Wales, UK."} +{"text": "Suicide attempts and suicidal ideation are peculiar aspects of several cluster b disorders, including Narcissistic Personality Disorder. Similarly, difficulty in regulating negative affects can play a role in the relationship between narcissist features and suicidal ideation. To date, it is still unclear which facet of narcissism is more related to the desire to die and which other factors are involved in this relationship.To offer preliminary empirical evidences concerning the relationship between narcissism, emotion regulation and suicide ideation.We administered Pathological Narcissism Inventory (PNI), Difficulties in Emotion Regulation Scale (DERS) and Beck Scale for Suicidal Ideation (BSI) to a sample of individuals with Suicide ideation (n= 68) and a sample of community participants (n=140).Controlling for age and gender, we found that BSI scores correlated significantly with the vulnerable dimension of narcissism, but not with the grandiose one, and with all DERS dimensions. Nevertheless, emotion dysregulation moderates the relationship between vulnerable narcissism and suicidal ideation.Suicide ideation seems to be deeply connected with the vulnerable dimension of pathological narcissism and the relationship between the constructs is partially mediated by emotion dysregulation. Future directions and clinical implications are discussed."} +{"text": "Early hospital presentation and completion of treatment is crucial for better treatment outcomes in children with cancer. There are thousands of children who die of cancer each year without ever being diagnosed in Tanzania. To address this gap and inform childhood cancer awareness campaigns, it is important to understand the inherent cultural values and beliefs that influence health care seeking behavior among the Tanzanian community.This was a descriptive qualitative study conducted in Mwanza, Kilimanjaro and Dar- es Salaam regions. Community members aged \u2265 18 years from three rural and three urban communities were purposively selected to participate in seven focus group discussions (each with 8-12 respondents) between March and June 2021. Data were transcribed, coded and analyzed by thematic content-analysis with the support of NVIVO software.A total of 72 participants were interviewed. Many had heard of breast or cervical cancer however, awareness of pediatric cancer was low. The belief that cancer in children is caused by witch craft led to initial evaluation by traditional healers leading to delayed presentation to the hospital. Additional community concerns included the cost of transportation and investigations, duration of treatment and community influence on families to abandon hospital treatment for spiritual or traditional treatment.Low community awareness about pediatric cancer, late hospital presentation and treatment abandonment remains a challenge in most parts of Tanzania. The common belief that childhood cancer is a result of witchcraft and superstition contributes to limited health seeking behavior, especially in the rural areas. Cultural and contextually relevant awareness interventions are needed to increase cancer knowledge and cancer health-seeking behavior in Tanzanian communities."} +{"text": "The adverse impact of the outbreak of COVID-19 has reduced ports\u2019 operational efficiency. In addition, ports and inland logistics providers are generally independent of each other and difficult to work together, which leads to time loss. Thus, as the core player, ports can integrate with inland logistics providers to improve the efficiency and resilience of maritime supply chains. This study examines the strategic options of two competing maritime supply chains consisting of ports and inland logistics providers. We investigate the impact of cooperation between ports and inland logistics providers and government regulation on the maritime supply chain by comparing members\u2019 optimal pricing and overall social welfare under centralized, decentralized, and hybrid scenarios. Results indicate that the hybrid scenario is an equilibrium strategy for maritime supply chain, although this strategy is not optimal for governments seeking to improve supply chain resilience and maximize social welfare. Furthermore, observations show that through government economic intervention, both seaborne supplies can be incentivized to adopt an integrated strategy, and business and society can achieve a win\u2013win situation."} +{"text": "Loneliness is a serious public health problem that affects over 25% of older adults and is associated with an increased risk of depression, cognitive decline, and premature death. Previous research on social support mechanisms that contribute to loneliness has consistently illustrated the role of emotional support in reducing loneliness. However, the importance of compassionate love in reducing loneliness and, as a consequence, improving psychological well-being in later life has received little attention. Neurobiology indicates that the brain regions associated with loneliness and compassion overlap, suggesting that increasing compassion-related emotions may help alleviate loneliness. Using data from a nationwide web-based survey , we examined the influence of compassionate love on loneliness and assessed whether loneliness mediates the relationship between compassionate love and mental health outcomes. Even after controlling for emotional support, estimates from an ordinary least squares regression (OLS) model suggest that older adults who felt loved had significantly lower levels of loneliness . Feeling of love also contributed to significantly fewer depressive symptoms and anxiety . Loneliness completely mediated the effect of compassionate love on anxiety and significantly mediated its influence on depressive symptoms . Our findings underscore the need to design interventions that increase compassionate love to reduce loneliness and improve psychological wellbeing among older adults."} +{"text": "It\u2019s established that aesthetic dysfunctions can be associated with psychiatric conditions. In present times, considering the exponential growth of minimally invasive and accessible techniques, alongside with ideals of beauty present in everyday life through exposure in social media, the importance of early detection of mental illness and its impact on the respective outcome should be emphasized.To review evidence regarding psychiatric disorders in people searching for aesthetic treatments and their impact on the outcome.Literature review using Medline database.Around 50% of individuals seeking aesthetic procedures fulfill the diagnostic criteria for psychiatric disorders. The prevalence of Body Dysmorphic Disorder (BDD) can vary from 5-15%, with some studies showing a prevalence of more than 50%. Patients with heightened BDD symptoms are less satisfied with the outcomes of aesthetic procedures which could result in exacerbation of said symptoms. With regards to eating disorders, evidence suggests the initial satisfaction following aesthetic procedures, when observed, is usually transitory, not leading to long-term changes in self-perception relating to body image, nor improving prognosis or quality of life. There\u2019s also some evidence suggesting that personality disorders may be a predictor of poor satisfaction with the results of aesthetic treatments.Awareness should be raised in this matter, since psychiatric conditions are more common in patients seeking aesthetic treatments and early identification can lead to a better prognosis by providing patients with the mental health treatment they need; this could also reduce the probability of dissatisfaction and subsequent aggravation of psychiatric symptoms following aesthetic interventions."} +{"text": "Plasmodium that cause malaria survive within humans by invasion of, and proliferation within, the most abundant cell type in the body, the red blood cell. As obligate, intracellular parasites, interactions between parasite and host red blood cell components are crucial to multiple aspects of the blood stage malaria parasite lifecycle. The requirement for, and involvement of, an array of red blood cell proteins in parasite invasion and intracellular development is well established. Nevertheless, detailed mechanistic understanding of host cell protein contributions to these processes are hampered by the genetic intractability of the anucleate red blood cell. The advent of stem cell technology and more specifically development of methods that recapitulate in vitro the process of red blood cell development known as erythropoiesis has enabled the generation of erythroid cell stages previously inaccessible in large numbers for malaria studies. What is more, the capacity for genetic manipulation of nucleated erythroid precursors that can be differentiated to generate modified red blood cells has opened new horizons for malaria research. This review summarises current methodologies that harness in vitro erythroid differentiation of stem cells for generation of cells that are susceptible to malaria parasite invasion; discusses existing and emerging approaches to generate novel red blood cell phenotypes and explores the exciting potential of in vitro derived red blood cells for improved understanding the broad role of host red blood cell proteins in malaria pathogenesis.Parasites of the genus Plasmodium that cause malaria results in approximately 240 million clinical cases and 627,000 deaths per year according to recent statistics to pluripotency was a landmark in stem cell biology . The iniod cells . Effortsod cells , howeverod cells .Generation of immortalised erythroblast cell lines, capable of infinite proliferation whilst retaining the capacity to undergo terminal erythroid differentiation and enucleation has presented a holy grail within the erythroid biology research community. Such lines could provide a sustainable source of isogenic erythroid precursors, be readily genetically manipulated, selected or clonally screened for the derivation of modified sublines and cryopreserved for long term and repeated experimentation. Immortalisation at a committed stage of erythropoiesis also reduces the culture time required to obtain reticulocytes, which for culture from HSCs takes approximately 18-21 days.P. falciparum and resP. vivax ) reticulP. vivax . Only moIn vitro culture of erythroid cells has allowed for the generation of proerythroblasts and subsequent intermediately differentiated erythroblasts that can be exposed to malaria parasites for tracking of both host and parasite cellular development. In 2009 Tamez and colleagues used in vitro derived erythroid cells to assess stage specific susceptibility of human erythroblasts to P. falciparum infection, reporting efficient invasion and intracellular development of parasites within orthochromatic erythroblasts and retain expression of the transferrin receptor CD71 (at varying levels) that is lost progressively during maturation , they provide an extremely valuable model to generate insight into surface receptor independent, or downstream aspects of malaria parasite invasion and host protein co-option that may be conserved across species.Reticulocytes can be successfully invaded by a broad range of malaria parasites including nd vivax . P. falculocytes , this maP. vivax invasion, access to reticulocytes in sufficient quantity and of sufficient levels of purity to be useful for invasion studies has proved a major obstacle for many years. The capacity for in vitro stem cell differentiation to derive relatively large, pure populations of these cells from a single donor without the need to pool samples (e.g. from multiple cord blood units) has already recently yielded insight into variation in receptor reliance that exists between strains that are susceptible, at least to invasion, by P. vivax, stem cell biology has an important role to play whether directly or indirectly in any future development of such a system . Succesa system Figure\u00a02Historically, studies of malaria parasite invasion of the red blood cell have focused predominantly upon identification of the proteins on the surface of the host red blood cell and morein vitro culture and differentiation of haematopoietic stem cells that are susceptible to invasion by malaria parasites through em cells unlocks Ex vivo access to nucleated erythroid progenitor cells (from various sources as outlined in this review) allows for the genetic manipulation of cells, inducing alterations to protein expression that can be retained during subsequent terminal erythroid differentiation to produce enucleated red blood cells with novel phenotypes. As improvements in erythroid culture methodology and advances in genetic manipulation and gene editing approaches have boomed over the last decade, so the level of sophistication of this approach has, and continues to increase.P. falciparum, confirming the important role played by this protein and validating the approach for host focused studies of invasion receptor requirements. The same approach was used as part of the seminal identification of basigin as the essential PfRh5 binding receptor necessary for successful P. falciparum invasion were found to support invasion by both P. falciparum and P. vivax, albeit less permissively than primary erythrocytes and reticulocytes respectively . DARC (Duffy) knockout and re-expression abrogated and rescued invasion by P. vivax respectively and to knock out candidate receptors should increase our understanding of the repertoire of host cell proteins that may be involved in invasion by this species.To date, most insight derived through genetic manipulation of by shRNA and moreby shRNA . In faciPlasmodium invasion and development.As technology and methodologies advance however, so too do the possibilities for further insight using stem cell derived red blood cells. By complementing a BSG knockout (KO) line with a wild type and truncated BSG open reading frame Satchwell and colleagues were able to expand upon the use of KOs alone to interrogate the requirement for a specific intracellular receptor domain for the first time . ExpansiSite specific requirements of host cell proteins in malaria parasite invasion, development and host remodelling have been widely documented and postulated, with many as yet unidentified contributions undoubtedly still to be uncovered. These range from single nucleotide polymorphisms, sites of glycosylation and palmin vitro derived red blood cells present for malaria research, their application to such studies is not without its practical challenges. Manipulating erythroblasts with a view to generation of enucleated red blood cells must consider the need to ensure that the programme of differentiation and enucleation is not compromised, and pleiotropic effects of alterations carefully assessed and considered.For all the exciting opportunities for novel insight use of in vitro derived red blood cells, particularly those that have undergone genetic manipulation represents a considerable investment of labour and resource. It is not always possible to replicate assays that may be considered routine using donor red blood cells. Where flow cytometry assays of parasitemia using nucleic acid staining dyes is routine for donor erythrocytes, the confounding nuclear signal where orthochromatic erythroblasts are studied prohibits this means of assessment and in the ideal situation where purified reticulocytes are studied residual RNA in reticulocytes necessitates careful controls (in vitro red blood cell use however efforts to adapt and improve flow cytometry based assessment through robust, nucleic acid labelling, use of fluorescent parasite lines (via advanced technologies such as Imaging Flow Cytometry (in vitro erythroid culture enucleation rates, scalability and purification methods are of continued importance to improve accessibility (Where donor red blood cells are plentiful and easily accessible, derivation of controls . Miniatucontrols have beete lines , label fte lines or via aytometry represensibility .Malaria is a complex and multi-faceted disease, caused as it is, by a parasite that transitions between multiple forms, residing in multiple host cells throughout its lifecycle, each presenting their own unique difficulties for study. In the case of the red blood cell host, genetic intractability of the mature cell and inaccessibility of its increasingly interesting precursors have presented major historical obstacles to detailed understanding of the ways in which host proteins resist, contribute or are co-opted during malaria invasion and pathogenesis. Stem cell biology and the more recent use of immortalised erythroid cells has already demonstrated its value to malaria research, identifying new and overlooked host protein requirements for invasion and opening up new areas for investigation. We look forward to the exciting new avenues, insights and opportunities for interventions that it may uncover in the coming years.This study did not involve any underlying data.TJS conceptualised and wrote the review. The author confirms being the sole contributor of this work and has approved it for publication.TJS was supported by the UK Medical Research Council Grant ID. MR/V010506/1.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Chronic inhalation of titanium dioxide or carbon black by rats at concentrations which overload lung particle clearance can result in lung cancer. Based on this rat lung response, IARC, NIOSH, and ECHA classified titanium dioxide, and IARC classified carbon black, as potential human carcinogens. These classifications have been questioned based on an extensive data base demonstrating: the rat lung cancer occurred only under conditions of extreme lung particle overload; the lung cancer response in rats has not been seen in other animal species; and studies in titanium dioxide and carbon black exposed human populations have not shown an increased incidence of cancer. In 2019 an international panel of science and regulatory experts was convened to document the state of the science on lung particle overload and rat lung cancer after exposure to poorly soluble low toxicity particles. Regarding hazard identification, the expert panel concluded, in the absence of supporting data from other species, lung particle overload-associated rat lung cancer does not imply a cancer hazard for humans. Regarding high to low dose extrapolation, the expert panel concluded rat lung tumors occurring only under conditions of lung particle overload are not relevant to humans exposed under non-overloading conditions. The conclusions of the Edinburgh Expert Panel directly conflict with IARC, ECHA and NIOSH's extrapolation of lung particle overload associated rat lung cancer to hazard for humans. The hazard classifications for titanium dioxide and carbon black inhalation should be assessed considering the state-of-the-science on lung particle overload and rat lung cancer. The term \u201clung particle overload\u201d refers to impairment of particle clearance from the deep lung after inhalation of high concentrations of poorly solubility, low toxicity materials exemplified by titanium dioxide and carbon black. The impairment of particle clearance under these circumstances was proposed by Morrow to be du3 of respirable particles with lung cancer observed only for the 250 mg/m3 exposed rats. Following the Lee et al. after chronic inhalation exposure to the materials in Epidemiology studies have not demonstrated a significant increase in lung cancer after exposure to the materials in Several organizations have characterized the health hazards associated with titanium dioxide and carbon black inhalation, including IARC, ECHA, and NIOSH. The outcomes of these evaluations are summarized below.IARC classified titanium dioxide and carbon black as \u201cpossibly carcinogenic to humans\u201d based on lung cancer occurring in rats . The IARinduced lung tumours in rats under conditions of marked particle loading in the lung.\u201d RAC concluded human data do not support an association between occupational exposure to titanium dioxide and risk of lung cancer. ECHA subsequently adopted the RAC recommendation on titanium dioxide hazard. Observations from the RAC documentation on titanium dioxide include:ECHA's Committee for Risk Assessment (RAC) recommended titanium dioxide be classified as suspected of causing lung cancer through the inhalation route . This asthese exposure conditions represent excessive exposure which invalidates the results of the Lee et al. study on their own for classification purposes.\u201d RAC noted such a marked condition of overload should not be a determining factor on classification of titanium dioxide.RAC did not use the Lee et al. study toselected carcinogenicity data for poorly soluble low toxicity particles as supporting evidence.\u201d RAC did not provide a definition of poorly soluble low toxicity particles, although carbon black was discussed in this context.RAC's classification of titanium dioxide relied on \u201cIn selecting relevant studies for classification RAC chose not to follow OECD Guidance Document 116 which reRAC discussed coal dust as an example of human exposure to a poorly soluble low toxicity material which supports the potential human relevance of rat lung overload associated cancer .3) and fine size titanium dioxide (2.4 mg/m3). The RELS were based on an extrapolation of the rat inhalation data to humans using particle surface area as the dose metric which several studies have suggested is a more relevant dose metric for the cancer response in the rat studies .The Edinburgh Expert Panel's conclusions on the state of the science regarding extrapolating hazards of poorly soluble low toxicity materials have implications for the cancer hazard classifications developed previously for titanium dioxide and for carbon black (by IARC).In their reviews of the titanium dioxide data base IARC, ECHA and NIOSH made several general observations which can be summarized as follows: lung cancer in rats was associated with the overload of lung particle clearance; lung cancer was not observed in other animal species exposed chronically by inhalation; and there was no convincing evidence of lung cancer in humans. In the end, IARC, ECHA, and NIOSH rendered classifications of titanium dioxide based solely on studies in rats in which lung cancer occurred under conditions of lung particle overload. IARC based its concern classification of titanium dioxide solely on studies in rats in which cancer only occurred under lung particle overload , 5. Simi4, carbon black, toner as a group they consider to be poorly soluble and low toxicity. A scientific issue regarding use of coal dust lung burden data to support the human relevance of the rat cancer after titanium dioxide, is coal is quite different toxicologically. Briefly, coal dust can contain significant amounts of quartz; trace metals such as boron, cadmium, copper, nickel, iron, and zinc; as well as in organic minerals (In their classification of titanium dioxide, both ECHA and NIOSH reference coal-dust exposed workers to support the human relevance of the lung burdens in rats causing lung cancer. First, it should be noted that a preponderance of the epidemiology data does not support an association between coal dust exposure and lung cancer or lung clearance impairment , 27. Regminerals \u201330. Moreminerals . As concThe expert panel agreed that lung particle overload has been demonstrated in all laboratory animal species evaluated. As such, there was agreement lung particle overload could occur in humans, however, there was not agreement on whether this has been proven . In thisThe finding that chronic inhalation of titanium dioxide or carbon black results in lung cancer in rats but not in other species and that the rat lung cancer occurs only under conditions of extreme lung particle overload has raised questions on the relevance of overload-associated rat lung cancer to human hazard , 34, 35.In 2019, a panel of scientists and regulators expert in inhalation toxicology and risk assessment was convened at the University of Edinburgh to document the state-of-the-science on rat lung cancer and lung particle overload. Regarding hazard identification, the expert panel concluded that in the absence of supporting data from other species, lung particle overload-associated rat lung cancer does not imply a cancer hazard for humans. In the context of high to low dose extrapolation, the expert panel concluded rat lung tumors occurring only under conditions of lung particle overload are not relevant to humans under non-overloading exposures to poorly soluble low toxicity materials. Hazard identification represents an important activity to ensure public health; however, such identification needs to take full account of the state-of-the-science and be updated as scientific understanding advances. In this respect, the conclusions of the Edinburgh expert panel call for a reassessment of the cancer hazard classifications on titanium dioxide and carbon black taking into full account the current scientific understanding of lung particle overload, rat lung cancer and species differences in lung cancer response to poorly soluble, low toxicity materials.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "The findings of the last South African National Children Oral Health Survey conducted between 1999 and 2002 indicated a national prevalence of dental caries at 60% among 6-year-olds, with over 80% of untreated caries. Various studies have shown that one of the successful strategies in preventing dental caries is intervention during pregnancy by providing prenatal oral health education.To successfully mitigate the challenge of ECC, South Africa needs a holistic approach strategy that will integrate oral health services into existing general health programmes, especially into antenatal care (ANC). South Africa National Oral Health Policy and Strategy states that \u201cIntegrate oral health strategy elements and strategies into programmes and policies of all sectors that impact community health like maternal and women's health.\u201d All government health care facilities offer free essential ANC services, identifying risk factors relating to poor maternal and birth outcomes. This existing infrastructure can be utilized to deliver oral health education and care for expecting mothers as essential ANC services.The Public Oral Health Forum, a non-profit organization in South Africa, seeks to develop maternal and oral health policies that can be aligned with its research and policy development strategy. It proposes maternal oral health policy and strategies, which could be applicable in the South African context: Education of pregnant women, prenatal providers, and dental and medical students about perinatal and infant oral health, integration of oral health in primary health care services, interprofessional workforce development and research to improve oral health and access to dental care among pregnant women and new mothers. This presentation will demonstrate how such maternal oral health policy and strategy are developed, aligning with existing policy and infrastructure in South Africa."} +{"text": "Achieving and maintaining good oral health is essential for both the oral and overall health of expecting mothers and the oral health of their young children. Dental caries can negatively affect daily activities, including eating, speaking, and social interaction. When expecting mothers have active dental caries, the risk for dental caries in these children becomes higher. Another common oral disease, periodontitis, was associated with systemic conditions, including cardiovascular disease, respiratory disease, diabetes, and potentially adverse birth outcomes. Some studies also showed the systemic impact of periodontal disease and the related pathogens that can lead to systemic inflammation and adverse birth outcomes, even though periodontal treatment has not been shown to improve birth outcomes. A mother's oral health status, her oral health knowledge, and beliefs also have been shown to significantly affect diet and home oral hygiene practice for young children. All the evidence suggests that pregnancy should be considered a critical period in which oral health education and dental care should be provided to improve the oral health of mothers and their young children. Despite the importance of a mother's oral health and their oral health knowledge in preventing dental caries in young children, maternal oral health is much neglected in primary and prenatal health discussions. This is even more significant in developing countries with inadequate oral health care infrastructure and workforce. In addition, with increased sugar consumption worldwide, oral disease prevention and oral health promotion are the keys to achieving oral health parity among the maternal and child population. This workshop aims to position maternal oral health as essential primary and perinatal health care and discuss the care models and initiatives in various contexts and geographical locations. At the care delivery and community-based interventions, Dr. Sophia will discuss her oral health education and tobacco cessation initiative for pregnant women in India. Dr. Irene will demonstrate her integrated oral health training model for midwives and dental providers in Indonesia. She will describe how her collaboration with the local government achieves collaborative training and care delivery to improve mothers and their spouses\u2019 oral health and oral health knowledge in rural Indonesia. Dr. Jane will showcase her material oral health model for refugee and immigrant mothers in Switzerland. Lastly, Dr. Khabiso from South Africa will present how maternal oral health can be integrated at the national policy level through the collective efforts of public health organizations. Dr. Lee, the chair of this workshop, will provide a literature review on maternal oral health studies and how maternal oral health can be an essential part of primary and perinatal care and the WHO oral health initiative set for 2030.\u2022\u2002Maternal oral health is essential in primary and perinatal health care discussion and a critical optic for global and public health agendas.\u2022\u2002There are various maternal oral health programs and initiatives around the globe at care delivery level, community level, and policy level."} +{"text": "Social capabilities are the opportunities to realize people\u2019s potential. Despite an established positive link between health status and social capabilities among older adults, the relationship mechanisms are understudied.Using the China Longitudinal Aging Social Survey data 2014\u20132018, this paper examined the possible mediating role of community participation through which older adults (aged 60 and above) in China with functional limitations improved or maintained their social capabilities. By conducting the 12 in-depth interviews, this study explores how community participation altered the negative associations between functional limitations and social capabilities among Chinese older adults.Findings from the quantitative study show that both physical and cognitive functional limitations showed consistent and negative effects on the social capabilities of older adults, and the effects varied between males and females. The mediation analysis results show that community participation accounted for a substantial proportion of the impact of functional limitations (36.33%) on social capabilities. However, functional limitations still had strong, negative direct effects of their own. Findings from the qualitative narrative synthesis show that peer companionship, regular physical activities, and reduced digital obstacles to accessing online social media during social participation are the self-perceived driving force in enhancing their sense of security, freedom of expression, and sense of social cohesion. Discussion: Findings from this study highlight the need for more social policies and services to encourage community participation among older adults."} +{"text": "Mental health care remains a pillar of suicide prevention also in late, but the range of interventions should include attention to the many socio-environmental conditions that are relevant to this stage of life. Community programs that promote a sense of worthiness and belonging should be strongly encouraged in order to preserve personal identity and social integration. Loneliness has to be counteracted in its many facets and with vigour, given its multiple negative impacts. The fight against stigma and ageistic views - still deeply rooted even among health workers \u2013 should be carried out with determination. Active promotion of a culture of resilience and adaptation to different phases of life and the changes imposed by them should constitute the founding bases of all efforts aimed at promoting a successful aging process. Combating discrimination against older people, as well as promoting basic social determinants of health, would help prevent suicide. However, these issues are still very underrepresented in the global agenda of health care. While having an effective impact on the numerous forms of discrimination would require legal interventions by governments, fighting stigma would primarily involve education aimed at changing beliefs and attitudes. Promotion of human rights, with particular regard to protection against abandonment, abuse and violence - particularly deleterious aspects in old age \u2013 appears as essential for personal empowerment of older individuals. Once become more powerful, older people may become more capable of defending their interests in terms of quality of life and protection against risk factors for suicide.No significant relationships."} +{"text": "Research suggests social connectedness reduces dementia risk and helps older adults with neuropathology maintain cognitive functionality and quality of life. However, little is known about the specific underlying social and biological mechanisms. This presentation provides an overview of three promising pathways through social bridging , social bonding , and social stress . It discusses how personal social network methodology combined with tests of general and social cognitive function and/or biomarkers can identify specific etiological mechanisms. These insights can be leveraged to develop policies and programs that support brain health and cognitive function in older adults. This presentation sets the stage for the remainder of the symposium, which presents empirical findings examining these mechanisms from a social network perspective."} +{"text": "Some studies have documented cognitive health among older immigrants in the United States; however, little is known about how the life-course immigration experiences were associated with cognitive trajectories among older Chinese immigrants. This study filled the research gap by identifying the patterns of cognitive change trajectory among older Chinese immigrants and examining the associations of immigration experiences with cognitive trajectories. The sample comprised 2,075 participants from the Population Study of Chinese Elderly (PINE), who completed a battery of cognitive tests at four time points (2011-2019). Latent class growth analysis and multinomial logistic regression were utilized. Three latent classes of cognitive trajectories were identified: the low functioning with the fastest decline , the moderate functioning with a medium decline rate , and the high functioning with the slowest decline . Perceiving more discrimination reduced, while speaking Taishanese increased the odds of being in the LCF and MCF. High acculturation only distinguished MCF from HCF after controlling for the known factors of cognition such as age, education, and social engagement. This study identifies a group of older Chinese immigrants who are especially vulnerable to cognitive impairment, and indicates that the immigration-related risks for cognitive decline, such as late-life migration and lower acculturation, could be buffered by education in early life and social engagement post immigration. Practice and policy efforts are needed to increase socioeconomic and cultural opportunities for social integration among older immigrants."} +{"text": "Salmonella gallinarum phage to protect chickens during a fowl typhoid outbreak in 1919 and products for decontaminating surfaces and foods are also being marketed for over a decade began selling customized bacteriophage mixtures for use against plant pathogens. Initially the target diseases were tomato and pepper bacterial spot diseases caused by Xanthomonas and Pseudomonas species but they now provide phages against the pathogens causing tomato bacterial canker (Clavibacter michiganensis); apple and pear fire blight (Erwinia amylovora); and citrus canker (Xanthomonas citri). Much of this product development built, of course, on experimental work published previously sells a product against Pectobacterium soft rot of potato.Early work on phage therapy of plant diseases also began in the 1920s. Moore reported in 1926 on the detection and testing of an \u201cinvisible agent\u201d to treat Wildfire disease of tobacco, citing d'Herelle's work as a basis of the study Moore, . These fPhytophthora infestans, have not proved suitable for biocontrol applications and may actually increase oomycete fitness but, to date, has not been implemented in any significant trials (Barrow et al., In summary, while most discussions of viruses as biocontrol agents focus on phage therapy of human diseases, there are a great many other applications of this approach. Some, like the Agriphage products for plant diseases and the hypovirulent mycoviruses of chestnut blight fungus, are already in widespread use. Thus, the future seems bright for these broader applications beyond human disease.PH and EV prepared the editorial. HA edited the editorial. All authors contributed to the article and approved the submitted version."} +{"text": "The Royal College of Psychiatrists\u2019 Fair Deal (RCPsych 2008) highlighted the far-reaching impact of stigma and discrimination on the lives of people with mental illness. The pervading nature of stigma has been acknowledged in recent national and international mental health policies (WHO). The World Health Organisation reiterates people affected by mental illness should not suffer social exclusion and marginalisation due to stigma.A sixty-year-old gentleman presented to the Emergency Department following self-inflicted stabbing to the neck resulting in pharyngeal tear and surgical repair. Previous psychiatric history included inpatient admission on Section 2 following a major depressive episode. On this admission, inpatient psychiatric review elicited three months of psychotropic medication non-adherence due to difficulties the patient had encountered in acquiring repeat medications from his GP. He had relapsed into alcohol misuse as a coping mechanism culminating in a suicide attempt at home with a knife. Upon recommencing of sertraline and risperidone during admission, he was assessed as euthymic with low risk to self. The patient had been previously abstinent from alcohol and described religion as a protective factor. Prior to discharge, the patient's GP stated he must present to the surgery in person with a form of identification. This is despite CQC guidance stipulating practices should not refuse patients registration if proof of identity cannot be produced.This case illustrates the socioeconomic factors increasing likelihood of suicide including forensic history, low financial status, unstable housing and lack of social support. Substance dependence is a risk factor that can be reduced by supporting patients in accessing specialist misuse input from inpatient and community teams. The patient reported fear of stigmatisation and criminalisation which led to the avoidance of seeking treatment, deterioration in mental health and severe clinical consequences. It is imperative marginalised patients with mental illness can access quality health care and this starts with GP registration.Forensic mental health patients experience multiple stigmas impacting on well-being including social, institutional and media stigmatisation and high levels of internalised stigma. The Time to Change campaign focused on changing attitudes and behaviour however evaluation illustrated difficulties in tackling this issue. Healthcare professionals should be mindful to avoid stigmatising language and actions to ensure fairness in care. There is a need for the medical profession to continue striving for a tangible shift in attitudes. Advocating for those with mental illness can enhance quality of life for vulnerable patient groups."} +{"text": "Oligodendrocytes form multiple myelin sheaths in the central nervous system (CNS), which increase nerve conduction velocity and are necessary for basic and higher brain functions such as sensory function, motor control, and learning. Structures of the myelin sheath such as myelin internodal length and myelin thickness regulate nerve conduction. Various parts of the central nervous system exhibit different myelin structures and oligodendrocyte morphologies. Recent studies supported that oligodendrocytes are a heterogenous population of cells and myelin sheaths formed by some oligodendrocytes can be biased to particular groups of axons, and myelin structures are dynamically modulated in certain classes of neurons by specific experiences. Structures of oligodendrocyte/myelin are also affected in pathological conditions such as demyelinating and neuropsychiatric disorders. This review summarizes our understanding of heterogeneity and regulation of oligodendrocyte morphology concerning central nervous system regions, neuronal classes, experiences, diseases, and how oligodendrocytes are optimized to execute central nervous system functions. Understanding the information processing in the central nervous system (CNS) by exploring brain structures has been a challenge in life science. Evidence demonstrates that the regulation of nerve conduction by myelin ensheathment plays a critical role in the development, physiology, and diseases of CNS. The term myelin was coined by Rudolf Ludwig Virchow (1821\u20131902), but at that time, myelin was thought to be produced by neurons . Pio delOligodendrocytes form multiple myelin sheathes on neuronal axons in the CNS, in contrast to Schwann cells in the peripheral nervous system, where a single Schwann cell forms myelin sheath on a single axon. This unique characteristic of oligodendrocytes raises the question of which axons are myelinated by individual oligodendrocytes. Recent tools such as transgenic mice, viral vectors, two-photon microscopy, and three-dimensional analyses with electron microscopy (3D-EM) have enabled us to observe dynamic and complex interactions between oligodendrocytes and other cells and reveal patterns of myelination in a particular class of neuronal axons. Studies revealed that the oligodendrocytes dynamically change their morphology depending on experience or diseases, and the regulation of myelination can be biased toward a particular set of axons. Recent studies revealed that oligodendrocytes have heterogeneous morphology and gene expression patterns in different CNS regions, suggesting that the morphology of oligodendrocytes is optimized to execute the function of each CNS region. In this review, we summarized oligodendrocyte/myelin morphological changes depending on neuronal classes, experience, and diseases and discussed their connection to brain functions.The characteristic morphology of individual oligodendrocytes is established through sequential events of migration and differentiation of oligodendrocytes characterized by the expression of specific markers. The oligodendrocyte progenitor cells (OPC) positive for NG2 and PDGFRa originate from specialized areas of the subventricular zones and migrate with bipolar morphology to distribute throughout the CNS regions . The OPCThe mature oligodendrocytes are frequently shown as cells with small cell bodies and myelin sheathes at the tips of processes. However, the morphology of individual oligodendrocytes and their myelin could be variable in different brain regions depending on the structures of ensheathed axons. When oligodendrocytes were first discovered, they were classified into four types . Type I + channels at the nodes mediates local depolarization vectors are widely used to label neurons, it is difficult to observe oligodendrocyte morphology using AAV vectors e matter . The adve matter .The development of electron microscopy in the mid-20th century unequivocally identified the myelin formation around the axons by oligodendrocytes. It revealed the ultrastructure of nerve fibers with myelin ensheathment . ObservaUsing these approaches for observing individual oligodendrocytes, whose advantages and disadvantages are summarized in in vitro, indicating that OPCs in the cerebral cortex and spinal cord intrinsically form different myelin sheathes following differentiation of oligodendrocytes in multiple CNS regions revealed that the ratio of oligodendrocyte subtypes varies within CNS regions . ReportsRecent studies have revealed the interaction between neuronal activity, myelination, and oligodendrocyte morphology . IncreasNeuronal activity\u2019s effects on myelination seem to differ between CNS regions. Increased activity of callosal projecting neurons increased the number of mature oligodendrocytes and increased myelin thickness in the mouse corpus callosum . In contIt was revealed in previous studies that new oligodendrocytes are generated in response to the experience and that oligodendrocyte generation is required for motor learning and remote memory . HoweverSocial isolation results in behavioral dysfunction with abnormal oligodendrocyte/myelin morphology in the prefrontal cortex (PFC) . In a seIn addition to neuronal activity, microglia and astrocyte have been implicated as environmental factors regulating oligodendrocyte morphology. Microglia regulate oligodendrocyte number and morphology through myelin pruning and phagocytosis of OPC . AstrocyRecent studies have also revealed the intrinsic molecular mechanism modulating oligodendrocyte morphology. Tubulin polymerization promoting protein (TPPP) that regulates myelin sheath number, myelin thickness, and myelin internodal length formed by oligodendrocytes , and hypCollectively, oligodendrocyte number and morphology are regulated by intrinsic and extrinsic factors, while the impact of that varies with population of activity-modulated neuronal axons, developmental timing, and CNS regions. On the other hand, their morphology is substantially changed under pathological conditions, and such changes are implicated in the pathophysiology of neurological diseases.Morphological abnormalities in oligodendrocytes are likely involved in various pathological conditions, given that such morphogenesis is important during myelination and remyelination. Multiple sclerosis (MS) is a major demyelinating disease and causes sensory and motor paralysis . White mOn the other hand, the current basic research visualizes the morphology of oligodendrocytes in conditions of demyelination and remyelination and has provided some interesting findings in demyelinating disease models. The generation of new oligodendrocytes and remyelination of previously myelinated axons can be reliably established following focal loss of myelin using temporally and spatially controlled demyelination . In contIt has been reported that the cell density, the volume of the nucleus, and the volume density of mitochondria in oligodendrocytes decreased in patients with schizophrenia and mood disorders . DownregThus, it is inferred that the morphology of oligodendrocytes is involved in the pathogenesis of neurological diseases. Further morphological analysis of oligodendrocytes specific to each pathological condition is expected to lead to a deeper understanding of the pathophysiology.Myelination of oligodendrocytes is critical for basic and higher brain functions, including sensory and motor systems, learning/memory, and social behavior. However, the mechanisms of how oligodendrocytes are engaged in the diverse CNS functions are still poorly understood. Recent advancements in imaging technologies led us to a deeper understanding of the dynamic changes and heterogeneity of oligodendrocyte/myelin morphology. Some studies utilizing those approaches supported the concept that some classes of the oligodendrocyte population can selectively myelinate a certain group of axons and alter their myelin structures, thereby modulating specific neuronal circuits and brain functions. Various intrinsic and environmental factors have been proposed to regulate the oligodendrocytes\u2019 heterogenous morphology and functions. However, it remains unclear whether morphological changes in oligodendrocytes are necessary for memory consolidation in spatial learning or visual deficits in monocularly deprived animals. In future studies, it is essential to develop approaches precisely manipulating oligodendrocyte morphology and investigate whether the prevention of morphological changes in oligodendrocytes impairs experience dependent modulation of brain functions. Structural adaptation and impairment of oligodendrocytes and myelin have been studied in animal models and human tissues with neurological disorders, where abnormal neural functions and impaired myelin regeneration are implicated. In this regard, elucidating the subtypes of oligodendrocytes vulnerable to demyelinating diseases may facilitate the development of new therapies. Further efforts to understand the structural remodeling of oligodendrocytes and their myelin in response to environmental and behavioral changes and identification of specific neural circuits myelinated by different subtypes of preexisting and newly generated oligodendrocytes would contribute to a deeper understanding of CNS functions and development of novel therapies in neurological disorders."} +{"text": "Indigenous peoples worldwide face unique challenges growing old. Many of these challenges are founded in historical colonization practices, present oppressive systems, racism, and underrepresentation in research, service provision, health education, and successful aging theories. The focus of this symposium is to discuss specific barriers and challenges related to Indigenous aging in rural and urban communities, as well as community strategies supporting aging well. The first presentation by Zayla Asquith-Heinz and colleagues will share the results of what successful aging or \u201cEldership\u201d means in the Norton Sound southern subregion of Alaska. Results indicate that family plays a central role within the Norton Sound model of successful aging. The second presenter, Steffi Kim and Jordan Lewis, are discussing the role of cultural influences and Elder identity on successful aging in the context of Alaska Native Elders migrating from rural traditional communities to a western urban community. The third and fourth presentations by Sarah Russell and Rachel Quigley will share the results on what aging well means within Torres Strait Islander people. The results suggest that the availability and accessibility to traditional practices, language and foods can facilitate aging well within these communities. They will also describe the development and implementation of a toolbox of culturally appropriate screening tools and interventions. Lastly, Jordan Lewis will explore the Indigenous concept of \u201cdoing\u201d successful aging rather than having good health. He will outline differences and similarities with BIPOC studies on successful aging."} +{"text": "New and emerging technologies offer opportunities for the delivery of wide-ranging, adaptable interventions to improve quality of life of older adults. Novel technologies can also improve the quality of measurement methods used in aging research. In this symposium five presentations will describe advanced technologies to promote health and function in older adults. The first will discuss the Urban Aging Residents Coalition (UARC), an organization founded in partnership with an African American older adult community leader to address engaging urban older adults with technology. A primary goal of UARC is to prevent social isolation and promote mental wellness through education and computer literacy. The second presentation will describe a project testing socially assistive robots (SARs) to complement personnel resources in older adults with cognitive impairment in long term care facilities. Study participants were successfully engaged in a participatory design involving repeated sessions with SARs that resulted in prototype refinement. The third presentation will describe current applications of patient communication technologies in acute-critical care settings with a focus on the user experience among older adult patients. The fourth will report on the implementation of an ongoing, in-home Smarthealth technology intervention for two older adult family caregivers of persons with dementia. Study findings showed the intervention improved self-awareness of emotional care and reactions to care recipients. The final presentation will explain an advanced wound measurement system using artificial intelligence to track healing progress in clinical research. The presentations will highlight technologies to support healthy aging and discuss implication for practice, policy, and research."} +{"text": "Research in various medical specialties has created excitement around the potential for artificial intelligence (AI) to transform clinical practice by improving the accuracy and efficiency of diagnosis and prognosis. Travel medicine is uniquely positioned to embrace its benefits. Education and training should reflect this and will require greater cooperation with data scientists.The global public health response to the coronavirus disease 2019 (COVID-19) pandemic has accelerated the adoption of novel digital technologies in everyday life and in the workplace, particularly in the healthcare and education sectors.Within the technology sector, AI has enabled the development of innovative systems that have been integrated into our everyday lives. These include intelligent web search algorithms, targeted advertising, entertainment content recommendations, product recommendations, smart watches that process inputs from accelerometer/biometrics sensors, and autonomous vehicles. AI has already found multiple applications in the travel industry but preventive travel medicine has been slow to embrace its potential. This editorial considers the current and future status of AI in travel and reflects on how travel medicine may benefit from its wider application in clinical practice and research.The travel industry has been an early adopter of AI technology. Personalized travel recommendations based on travel patterns and preferences are a well-established feature of online trip searches. Flight price forecasting applications already alert travellers about favourable deals and the optimum time to make their travel bookings. Some providers employ chatbots to engage with the traveller. Social media sentiment analysis has multiple travel-related applications and may help the industry to improve health and safety aspects of their travel experiences. It is likely that personalized end-to-end travel planning will become the norm for travellers, with personalized recommendations based on the traveller\u2019s health data. For example, package holidays may be customized to suit the traveller\u2019s fitness levels and travellers with chronic medical conditions may be advised to travel to specific destinations with a high-quality medical infrastructure, linked with their travel insurance policies.Facial recognition technology developed further during the COVID-19 pandemic and has already been deployed at major international airports. It is expected to gain greater acceptance among the traveling public as a touchless method of flight and hotel check-in, but its potential applications extend beyond this to user authentication when using unfamiliar computers overseas and as a means of ensuring traveler safety. Imagine a scenario where facial recognition of a traveler walking towards a terrorist attack, public demonstration or other disturbance triggers a smartphone notification with real-time safety advice. Opponents of such technology may not welcome such surveillance but, with proper safeguarding of personal data and civil liberties, the outcomes in terms of enhanced traveler safety and security may be significant. AI-assisted smart baggage handling may help to reduce the burden of lost or diverted passenger baggage. Robots are being used as disinfection devices at airports and as hotel concierges. A robot which transports vaccines from the refrigerator to the clinic room is already in use at the Travel Health Clinic at Mahidol Hospital for Tropical Diseases. Will robots eventually assist in the preparation and administration of vaccines? Robotic surgery is widely accepted now, particularly in the field of urology, so robotic travel health assistants may not stretch the imagination much further.The volume of publications on AI in medicine has increased exponentially in recent years, especially in fields that rely on image-based or data-driven patient diagnosis, or where big data help to inform patient management or prognosis. Thus, AI research has featured prominently in highly visual specialties such as histopathology, haematology, radiology and dermatology with performance comparable to or better than human experts reported from studies of image analysis algorithms. Beyond the visual recognition domain, AI diagnostic skills are becoming more intelligent; witness IBM\u2019s Watson diagnostic tools or Babylon Health, a chatbot offered by the UK\u2019s National Health Service (NHS). AI has also found application in the analysis of genomic data in precision medicine and in novel drug discovery. It has been applied to infectious disease outbreak surveillance activities and to public health contact tracing during the COVID-19 pandemic.A systematic review of patient and general public attitudes towards AI revealed that patients welcome the potential of AI to yield more accurate diagnoses, to support the training of physicians, to improve health access, to reduce healthcare costs by improving clinical workflow and to activate patients by encouraging them to seek health information or healthcare.As travel medicine practitioners, many of us are older than our specialty. We can anticipate exciting developments in our capacity for risk assessing and protecting travellers in the near future. It is therefore intriguing to reflect on the potential of AI for disruptive innovation in this field. AI is being used by our journals to capture insightful data by analyzing the public attention given to published articles. This journal was among the first to compare these altmetrics with conventional citation data.There may be a role for virtual reality to assist in the preparation of anxious travelers or those embarking on emotionally or physically demanding trips abroad; indeed, the future carbon-conscious traveler may use immersive virtual reality platforms as a substitute for physical travel.AI could have an important role in supporting travel-related disease surveillance activities and could become a useful tool for deriving insights from big data collected by the ISTM GeoSentinel\u00ae Network. AI models have already been used at one of the authors\u2019 institutions to improve the accuracy of dengue diagnosisData relating to travelers who travel abroad for planned healthcare remain sparse, rendering the counseling of medical tourists quite limited. Here again, AI may serve a useful role if it is embraced by medical tourism healthcare providers returning data to a central registry. Finally, future travelers and especially those with pre-existing conditions will benefit from real-time feedback from wearable or implanted biosensors or even nanotechnology tattoos which will provide timely reminders of important health interventions and alert them to detected deteriorations in their underlying illnesses. This could be useful for predicting hypoglycemic episodes in diabetic travelers or exacerbations of asthma during travel to polluted cities, for example.Much of the excitement surrounding the transformative potential of AI resides in the medical research domain but applications are gradually being integrated into clinical practice. It is likely that we will witness extraordinary developments in this arena in the next decade. Travel medicine should position itself to become an early adopter of AI technology. We expect that AI will soon become a core component of undergraduate medical curricula. The ISTM and regional travel medicine societies and faculties play a key role in postgraduate travel health education. We should collaborate with data scientists and invite them to speak at our conferences and webinars. The ISTM body of knowledge should be updated to include AI and other technological advances in the field. Research grant funding calls should be issued to encourage interdisciplinary cooperation between AI experts and travel medicine researchers. Concerns about erosion of the clinician\u2013patient relationship, loss of essential clinical skills, data privacy and the risks associated with biased data should be openly discussed.This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.The authors have no conflicts of interest to declare."} +{"text": "The overall aim of the Bloom Trial is to develop and test a program promoting healthy weight development during infancy within the community health nurse setting in Denmark. Many interventions are poorly implemented, and to ensure adequate implementation support, previous studies have suggested to assess barriers and organizational readiness before intervention start. The aim of the present study is to assess barriers for implementing and sustaining the Bloom Trial among program adopters and implementers.Telephone interviews with managing health nurses (adopters) and health nurses (implementors) from twenty Danish municipalities were carried out (n = 22) in 2017. Moreover, two workshops with health nurses, and continuously meetings with implementation science experts were conducted in 2021-2022.Barriers were identified on different levels. Organizational barriers within the work of health nurses included lack of time, economic resources, project fatigue, and political priority. Furthermore, health nurses lacked relevant tools to guide parents about promoting healthy weight development. Interpersonal barriers between health nurses and parents were identified as the difficulties of having conversations about healthy weight development, especially if the parents or health nurses were overweight themselves. Cultural differences including language barriers and different perceptions of for example healthy food choices were also found.The findings are central for ensuring that the Bloom Trial is relevant and applicable to the setting of health nurses in Danish municipalities. This is crucial for ensuring successful adoption, implementation, and prolonged sustainability.\u2022\u2002The study pinpoints key barriers of implementing an intervention promoting healthy weight in the community health nurse setting in Denmark.\u2022\u2002Involving community health nurses\u2019 perceptions aim at increasing the chances of producing a relevant and successful implementation strategy."} +{"text": "This study explored the role of caregiver background, stressors, and resources for Mexican American caregiver turnover and depressive symptoms. Using two waves of the Hispanic Established Epidemiologic Study of the Elderly Caregiver Supplement and informed by the sociocultural caregiver stress process model, we estimate logistic and OLS regressions of change in dementia and change in caregiver over five years. Neuropsychiatric expressions were significantly associated with caregiver turnover. Adult children and grandchildren caregivers were more likely to experience caregiver turnover than spouses. While depressive symptoms were relatively low at both waves, there was a greater increase in depressive symptoms occurred for caregivers who completed the interview in Spanish rather than English, which was partially explained by greater perceived stress at baseline. Findings demonstrate the need to provide dementia care supports for Mexican American caregivers, reduce stress for Spanish-speaking caregivers, and support Mexican American grandchildren who unexpectedly become caregivers."} +{"text": "The term \u201cstress\u201d is often regarded in the negative context, such as causing damaging effects on animal health and welfare. However, the underlying neuroendocrinological mechanisms of stress responses in animals are context-dependent and are mostly adaptive to change. The current fragile atmosphere of shifting perspectives in the animal production sector and societal awareness has placed increasing pressure on finding this balance between management practices that can reduce stress and, equally, improve farm animal productivity.In this section edition, we focussed on discussing this balance between welfare and animal productivity. Getting the appropriate balance will be challenging, however it is possible. This requires a detailed understanding of the neuroendocrinological mechanisms of stress responsiveness in animals across crucial life-history stages and contexts. It also requires detailed studies applying novel physiological biomarkers to quantify the stress responses arising from the higher brain centers using techniques that can be readily adopted in the field.We received 5 papers from animal welfare experts, veterinarians, animal physiologists and animal managers to generate a healthy discussion and showcase latest studies working toward finding the harmony between animal welfare and productivity. This is a volume III of the original special issue \u201cAnimal welfare assessment.\u201dIn 2022 Edition of this Research Topic, we show a collection of 5 peer reviewed articles which highlight the different advancements in the fields of animal welfare and behavior.Ma et al. demonstrated a simple, objective, and reliable welfare assessment tool, coined the Animal Welfare Assessment Grid (AWAG) for application in South Korea Zoos. The AWAG has for components including physical, psychological, environmental and procedural, and they incorporate animal welfare factors such as behavior, housing, restraint etc. Animals are given a 6-point Likert scale score and averaged data is used as an AWAG score for each zoo. The study included participation by 16 zoos selected for holding large cohort of animals, and the AWAG data showed large differences between zoos especially showing inadequate welfare. The AWAG tool could be crucial for improving animal welfare standards in South Korea Zoos.The first manuscript by Chang et al. conducted an analysis on the debatable Research Topic of Greyhound racing in Australia by reviewing 6 years of Greyhound management data available on public domain. The researchers wanted to determine if/how Greyhound mortality and morbidity events could be benched marked. Data across three states of New South Wales, Victoria and Queensland were analyzed. Results showed inconsistency in report availability in some state(s). The researchers raised alarm of this lack of consistency in data reporting which will be necessary for accurate evaluation of whether animal welfare standards are being met in Australian greyhound racing industry. The researchers also recommended the development of a publicly available whole-of-life tracking for individual racing greyhounds.In the second research, Malkani et al. was based on the welfare of dogs which the researchers evaluated using the Animal Welfare Assessment Grid (AWAG). Veterinary professionals were consulted to refine and improve the AWAG. Subject matter experts rated the validity of the factors for assessing dog welfare. Results showed the potential for AWAG to differentiate between healthy and sick dogs, and healthy and healthy dogs post elective surgery.The third paper by Mayes et al. who tested the welfare implications for sheep during live export by simulating stocking density and trough space. Merino weathers were housed under high or low stock density and monitored for 18 days. Results showed that higher stocking density ewes spent less time lying and increased agonistic social interactions. Live weights showed minor reduction at the end of trial however physiological parameters were unaffected. In their corrigendum Mayes et al. provided correction to the y-axis of their figure showing the proportion of animals lying with head down across days.The fourth and final papers were from the researchers Overall, this Research Topic highlights some of the recent developments in the broad field of animal welfare assessment.EN conceptualized this special topic and edited the manuscripts."} +{"text": "The COVID-19 pandemic has impacted medical students in many ways. They are not exempt from personal struggles caused by the health crisis, and many have faced similar challenges adapting to a new learning experience. The University of East Anglia (UEA) has initiatives in place to support medical students including the society Headucate UEA and the Wellbeing Champions scheme established by Norwich Medical School (NMS).Headucate aims to improve mental wellbeing by educational online webinars and social events aimed at university students. NMS Wellbeing Champions offer support and signpost students to resources and the wider student support system at the UEA.Headucate was established in 2012 by NMS students that began running workshops at local secondary schools. Their work has expanded to include wellbeing workshops, social events for students and mental health first aid training, so members can provide peer support. Wellbeing Champions are medical student representatives responsible for completing mental health first aid training, communication between students and faculty, providing resources and signposting, creating mental health bulletin newsletters, and running socials exclusively for medical students.100% of Headucate workshop attendees who completed anonymous feedback agreed that they enjoyed it and that it was useful. No feedback has been collected regarding the success of the Wellbeing Champions. This should be carried out to assess and enhance the project further.More data is needed to establish the success of the initiatives at NMS and their impact on medical student\u2019s wellbeing.No significant relationships."} +{"text": "Parasitism is an energetically costly event for host species. Dynamic energy budget (DEB) theory describes the metabolic dynamics of an individual organism through its lifetime. Models derived from DEB theory specify how an organism converts food to reserves (maintenance-free energy available for metabolism) and allocates mobilized reserves to maintenance, growth and maturation or reproduction. DEB models thus provide a useful approach to describe the consequences of parasitism for host species. We developed a DEB model for siscowet lake trout and modeled the impact of sea lamprey parasitism on growth and reproduction using data collected from studies documenting the long-term effects following a non-lethal sea lamprey attack. The model was parameterized to reflect the changes in allocation of energy towards growth and reproduction observed in lake trout following sea lamprey parasitism and includes an estradiol module that describes the conversion of reproductive reserves to ovarian mass based on estradiol concentration. In our DEB model, parasitism increased somatic and maturity maintenance costs, reduced estradiol and decreased the estradiol-mediated conversion efficiency of reproductive reserves to ovarian mass. Muscle lipid composition of lake trout influenced energy mobilization from the reserve and reproductive efficiency. These model changes accurately reflect observed empirical changes to ovarian mass and growth. This model provides a plausible explanation of the energetic mechanisms that lead to skipped spawning following sea lamprey parasitism and could be used in population models to explore sublethal impacts of sea lamprey parasitism and other stressors on population dynamics. Salvelinus namaycush) in the Laurentian Great Lakes is parasitism from non-native sea lamprey (Petromyzon marinus). Sea lamprey are large ectoparasites that feed by attaching to host fish with a suction-cup-like mouth, mechanically removing scales and tissue with a rasping tongue and consuming blood and tissue theory . BecauseWe parameterized a DEB model for female siscowet lake trout using available life history data from the literature and used the resulting model to explore the effects of sea lamprey parasitism on reproduction, growth and other life history characteristics. Lake trout display tremendous variation throughout their range; four currently recognized lake trout ecomorphs are present in Lake Superior alone, differing in morphology, habitat preference, metabolism and life history characteristics , but becIn prior studies, we empirically measured the influences of sea lamprey parasitism on siscowet lake trout growth, reproduction, energy storage and gene expression DEB model is the simplest model in the family of DEB models which can be adapted to model most species . Briefly, parameter estimates are derived through simultaneously minimizing the weighted sum of squared deviations between provided data and model estimates. Model goodness of fit was evaluated with the mean relative error (MRE) and symmetric mean squared error (SMSE) . When estradiol is used for immune-related functions, more estradiol is required to produce the same ovarian mass as an individual not facing an immune challenge. We account for the likely reduction in estradiol availability due to an increased immune response by assuming a reduced fraction of estradiol is available for egg development following parasitism, i.e. by reducing the rate of reproductive reserve ripeness In addition to muscle lipid concentrations, reproductive hormone dynamics also play a critical role in reproduction. Plasma estradiol concentration is an important predictor of the likelihood of skipping spawning for siscowet lake trout . It is lLipid storage also plays a key role in reproduction for siscowet lake trout. Surveys of wild lake trout found that siscowet lake trout that skipped spawning had significantly lower energy reserves than those that did not skip resulted in an ovarian weight of 222\u00a0g at spawning (day 365). A 10% reduction in muscle lipid resulted in a reduction of ovarian mass to 137\u00a0g, while a 10% increase in muscle lipid increased ovarian mass to 229\u00a0g . Adding Differences in ovarian mass driven by parasitism and muscle lipid are observable in the wet weight of the reproductive buffer . In scenian mass result iSomatic growth was also influenced by both parasitism and muscle lipid concentration in our tested scenarios, albeit subtly. Growth was slightly lower in parasitized scenarios than in unparasitized scenarios with the same muscle lipid concentration . At a 55Parasitism is a complex stressor for host species and influences multiple physiological processes simultaneously. Capturing the full extent of these effects, and their implications for the whole organism, is challenging using empirical measurements alone. DEB theory allows us to cumulatively incorporate empirical measurements of the effects of parasitism into one coherent framework that allows the consequences for many different processes to be evaluated simultaneously. In this study, we developed and parameterized a DEB model that captures the energy dynamics of siscowet lake trout. The model reproduced key life history features specific to the siscowet lake trout ecomorph and produced model estimates that adequately matched field and laboratory collected data. We also developed modifications to key DEB parameters to capture the effects of sea lamprey parasitism on reproduction and growth and account for the influence of individual variation in muscle lipid concentration and estradiol profiles observed in laboratory studies. Using these modifications, we explored several scenarios and evaluated their influence on ovarian mass and growth. We found that implementing stress from sea lamprey parasitism via increases to somatic and maturity maintenance and a reduction to estradiol concentration in our model resulted in a good approximation of observed empirical results for reproduction and growth. Altering energy conductance and reproductive efficiency with muscle lipid concentrations also represented the natural variation observed in siscowet lake trout populations well and provided insight into the modulating role muscle lipid concentrations can have in the response to sea lamprey parasitism. These findings point to the plausible physiological mechanisms at play during sea lamprey parasitism and can guide future empirical studies. Because our model can estimate reproduction and growth outcomes with and without sea lamprey parasitism and account for natural variation in lipid levels, it can help inform existing models that attempt to estimate lake trout populations under various sea lamprey control scenarios. Additionally, this work provides the foundation for future DEB models that wish to assess the effects of parasitism on other species.Studies of wild and laboratory-raised siscowet lake trout indicate unparasitized individuals skip spawning at some baseline rate as a part of their life history, and that skipping is at least partially dependent on muscle lipid concentration . The thrAs expected, parasitism reduced ovarian mass at all muscle lipid concentrations in our modeled scenarios . Even atThe alterations to DEB parameters we implemented are not necessarily an accurate representation of how sea lamprey parasitism influences the energy budget of a siscowet lake trout. Because the metabolic parameters in DEB models are abstract and include many processes that cannot be directly measured, the process for implementing stress is inherently arbitrary . RegardlOther DEB models have similarly captured the influence of parasitism on host reproduction. Other approaches using DEB models to represent parasite\u2013host dynamics have highlighted the importance of factors other than parasitism for understanding the full scope of parasitism-driven changes to reproduction. For example, variation in host food consumption can drastically change parasite virulence, host survival and reproduction (It is important to highlight the limitations of this model and resulting simulations. First, the alterations to the DEB model implemented to represent parasitism are not directly measured. Because each DEB model parameter represents an abstracted process within the organism, changes to observed empirical endpoints often involve many DEB parameters. Thus, we were required to rely on our best judgement and implement changes to DEB parameters that matched our knowledge of the physiological modes of action caused by parasitism and that resulted in changes to endpoints we were able to empirically observe. The changes we implemented to DEB parameters are therefore presumptive and other processes that we did not consider could be important. For example, sea lamprey parasitism could potentially influence host feeding behavior, but we did not alter lake trout food intake in our model due to a lack of empirical evidence. If food intake is substantially reduced, it could further influence predicted reproductive and growth outcomes. Our model therefore only serves as a reasonable hypothesis for how parasitism, muscle lipid and estradiol concentration influence lake trout energy budgets. Likewise, our simulation results reflect the decisions we made when developing the relationships between parasitism, muscle lipid, estradiol and respective DEB parameters. Despite these limitations, our model and simulation results provide testable hypotheses that can drive empirical research going forward. For example, future work looking to identify the physiological mechanisms leading to skipped spawning in lake trout should consider mechanisms related to energy mobilization and the efficiency of processes related to egg maturation as our model hypothesizes these factors to be critical components of reduced ovarian mass. Our model also hypothesizes that sea lamprey parasitism influences hosts by increasing energetic costs associated with healing a large wound, replacing lost blood cells and mounting an immune response, but not by causing the host to reallocate energy directly away from reproduction. A study could evaluate this hypothesis by simulating the tissue damage and blood loss of sea lamprey parasitism on unwounded lake trout and observing if the changes to reproduction and growth match observations under sea lamprey parasitism.Modeling the effects of sea lamprey parasitism on lake trout in the context of DEB models is a powerful approach that accounts for the entire energy budget of the organism. Parasitism is a complex stressor that influences many different physiological functions and interacts with the life history of the host, which makes the understanding of the cumulative effects on growth and reproduction challenging. The presented DEB model for siscowet lake trout allows us to explore these cumulative effects and interactions of sea lamprey parasitism and is a step towards accounting for the sublethal effects of sea lamprey parasitism in lake trout population models.The DEB model presented in this paper can be useful for improving existing efforts to monitor lake trout populations and direct resources for sea lamprey control in the Laurentian Great Lakes. If integrated into an individual-based model, this DEB model could allow lake trout populations to be estimated while accounting for the population-level influences of sea lamprey parasitism and individual variation both among and between lake trout ecomorphs. Additionally, simulations evaluating the effects on reproduction and growth can be developed to adjust stock-recruitment model parameters in existing models such as spawning stock biomass, or spawners per recruit. Accounting for changes in spawning stock biomass or spawners per recruit with DEB model outputs is a promising approach for incorporating the sublethal effects of parasitism and other stressors into population models going forward. Additionally, these efforts help identify knowledge gaps in our mechanistic understanding of sea lamprey parasitism and can provide us with testable hypotheses that can inform future empirical studies.This work was supported by a grant awarded to CM from the Great Lakes Fishery Commission. CM was also partially supported through the Michigan State University AgBioResearch through USDA National Institute of Food and Agriculture, Hatch project 1014468. TF was additionally supported by the Howard A. Tanner Fellowship.The authors have no conflicts to declare.The data underlying this article are available in the article and in its online supplementary material.TF analysed and prepared data, developed the base model and parasitism model, wrote the manuscript, prepared figures and provided editorial feedback. KL developed the base model and parasitism model, developed the egg module, wrote the manuscript, prepared figures and provided editorial feedback. ND analysed and prepared data and assisted with development of the base model. CM conceived the project concept, procured funding, assisted in writing the manuscript and provided editorial feedback. All authors approved the final manuscript.Web_Material_coad006Click here for additional data file."} +{"text": "Rural communities are often characterized by sparse service environments offering limited care, services, and conveniences that help with daily activities. In lieu of community services that target older adults to assist with aging-in-place, alternative supportive features, including environmental modification and informal social networks may be especially important in rural settings to preserve functional independence. The purpose of this study was to assess the role of alternative support resources as potential mediators between service environments and Activities of Daily Living (ADL) functioning of older adults living in rural settings. Data from the National Health and Aging Trends Study (NHATS) were analyzed. Guided by the International Classification of Functioning, Disability and Health, regression models included covariates for sociodemographics, chronic conditions, mobility functioning, and participation. Service environments were quantified using a measure of the number of services available in communities. Two potentially important support features were tested as mediators. Environmental modification was operationalized using indicators of whether homes had been modified . Size and quality of individuals\u2019 social networks were calculated using indicators of whom participants spoke to about important things in their life. Measures of ADLs served as key dependent variables. Results suggest a negative statistical relationship between service environments and disability that is explained in part by the availability of alternative support resources. Implications are that older adults who live in rural communities may often benefit by employing home modifications and relying on informal care options to meet their needs."} +{"text": "The Disability Adjusted Life Year (DALY) is a frequently used metric to assess burden of disease (BoD). Many independent BoD studies have been performed across Europe, showing wide variations and inconsistencies in the application and reporting of DALY specific methods. The European Burden of Disease Network (burden-eu) aims to develop guidelines for reporting DALY calculation studies which may enhance transparency and comparability of BoD estimates across Europe and beyond.A burden-eu working group of experts generated a list of potential reporting items based on existing literature, guidance for developing guidelines and consultations with BoD experts. To pilot the drafted product, we asked BoD experts and non-experts to apply it to existing BoD studies. We received feedback and we revised the guidelines accordingly.The guide for DALY calculation studies comprises about 25 items that should be reported in BoD studies. We included information about the study setting, data input sources including methods for data corrections, DALY-specific methods , data analyses, and data limitations. We also included information on how users can compare their new estimates with previously available BoD estimates.We introduced a reporting instrument for DALY calculations that can be used to document input data and methodological design choices in BoD studies. The application of such guidelines will enhance usability of BoD estimates for decision-makers as well as global, regional, and national health experts.Application of reporting guidelines will increase consistency and transparency in reporting of BoD studies, thus enhancing usability of BoD estimates.Reporting guidelines for BoD studies will serve as an educational tool for better understanding the complexity of DALY methodological design approaches."} +{"text": "The deep subsurface hosts one of the largest, yet least explored ecosystems on Earth. Exploration of the deep biosphere has implications for our understanding of the sustainability of our planet, particularly in ecosystems where life faces the extreme deprivation of energy and nutrients as well as 15 metagenomes and 10 metatranscriptomes. Their results show that presence of prophage sequences and accessory functions such nitrogen fixation and the CRISPR/Cas immune response does not confer selective advantages. In addition, the accumulation rate of single nucleotide variants was high in Methanothermococcus genomes, suggesting that Methanothermococcus lineages are maintained in high abundances at the vent sites. This work highlights the power of combining single-cell, metagenomic, and metatranscriptomic datasets to determine how evolution shapes microbial abundance and diversity in hydrothermal vent ecosystems.Chemoautotrophic archaea are globally distributed in deep-sea hydrothermal vent and sub-vent ecosystems. At the Mid-Cayman Rise, hydrogenotrophic methanogens from the genus \u22121) crustal fluid from borehole observatories installed at the North Pond study site on the western flank of the Mid-Atlantic Ridge, D'Angelo et al. applied redox-sensitive fluorescent molecules to flow cytometric sorting of cells for subsequent single cell genomic sequencing. Comparison of data from single cell genomics with previously profiled metagenomic and metatranscriptomic data shows that even with low coverage genome sequencing, sorting cells from < 1 ml of crustal fluid results in similar taxonomic and metabolic profiles as conventional omics approaches that require orders of magnitude higher fluid volumes. Their results reconfirmed that the diverse community dominated by Gammaproteobacteria, Bacteroidetes, Desulfobacterota, Alphaproteobacteria, and Zetaproteobacteria. Gammaproteobacterial members had genes for the fixation of carbon and nitrogen, whereas those of Bacteroidetes were annotated as putative heterotrophs. These results strengthen the technical advantage of fluorescence activated cell sorting as an alternate molecular tool for low biomass ecosystems ubiquitously encountered in the rocky biosphere.Fluid circulation through oceanic crust plays important roles in sustaining microbial habitats and global biogeochemical cycling. However, studying rocky habitats is challenged by sampling logistics and low biomass. By using small volumes of low biomass from communities involved in the biofilm formation. The MAGs also suggest ubiquitous organic carbon oxidation and capacity for arsenate and selenate reduction. The authors propose that the observed interaction between the deep subsurface microbial communities and the rock surfaces might be crucial for sustaining life under oligotrophic conditions in the deep subsurface environment of crystalline bedrock.In the deep terrestrial biosphere, Takamiya et al. provide a mini-review describing the current understanding of the rocky biosphere based on inorganic and organic energy sources independently from photosynthesis. Such energy sources are supplied in the deep subsurface where water radiolysis occurs at uranium ore deposits, while serpentinization produces H2 and hydrocarbons. Advances in omics-based approaches and nanosolid characterizations have unveiled taxonomic and metabolic features of microbiomes deeply hosted in the oceanic and continental crusts in association with mineral assemblages prevalent on early Earth and other planetary bodies potentially harboring extant life.The deep subsurface hosts the significant portion of prokaryotic biomass on modern Earth, which might be analogous on early Earth and modern Mars where the surface environment is harsh even for microbial life. The rocky biosphere is not sustained by photosynthetic energy sources but by those derived from rock-water interactions. via serpentinization reactions. Smith et al. provide the metagenome assembled genome (MAG) of a novel acetogen, Candidatus Acetocimmeria pyornia, from an olivine biofilm in the basaltic crust of the Juan de Fuca Ridge (JdFR). The samples were retrieved from 4-year incubations of rocky substrates within the crustal fluids of the JdFR borehole observatory. This MAG may represent a new lineage of acetogens within the class Clostridia. The MAG encodes the complete Wood-Ljungdahl pathway, a metabolically flexible and potentially ancient carbon metabolism, as well as genes for use of molecular hydrogen and import of metallic cations that could further support an organism adapted to life in basalt crust biofilms. This study furthers our knowledge of deep subsurface microbial communities that shape ocean geochemistry.Olivine is widely available in ocean crust on Earth, as well as other astrobiology targets, and can provide an energy source for chemolithoautotrophs Casar et al. have addressed this issue by interrogating the relationship between biofilm biomass and host rock minerology via in situ cultivation of biofilms on native rocks with coupled microanalysis techniques. Their results from the Deep Mine Microbial Observatory in South Dakota suggest mineral selectivity plays a role in biofilm formation, which is a key constraint on subsurface systems considering biofilms are estimated to account for most of the biomass in the subsurface. The observed mineral preferences have additional implications for understanding bulk cycles of iron and sulfur bearing minerals in deep continental settings.While the deep subsurface is known to contain a vast reservoir of microbial life, the spatial heterogeneity of microbes and their potential mineral substrates complicate our ability to constrain bulk estimates of abundance and activity. Sheik et al. interrogated how potential nutrient limitation(s) in such sequestered fluids might structure microbial communities in subsurface brines from the Soudan Underground Mine in Minnesota. From metagenome assembled genomes (MAGs) they recovered evidence for carbon, nitrogen, sulfur, and hydrogen elemental cycling and provide further examples of potential deeply branching lineages from subsurface systems. They also provide additional evidence that the byproducts of the osmolyte glycine-betaine may fuel methylotrophy in subsurface systems as no other forms of methanogenesis were recovered from MAG analyses. Overall, these findings support theories that metabolically versatility may be a key trait for subsurface survival.Microbial communities sequestered in subsurface fluids can be separated from surface interactions for hundreds to millions of years. The rocky-biosphere is one of the least understood biospheres. With this Research Topic, we have gathered a collection of timely additions to take the knowledge of this realm further, both in the oceanic and continental deep biospheres. The interpretations presented in this Research Topic are dominantly based on metagenome assembled genomes, metatranscriptomes and amplicon sequencing of indigenous communities from oligotrophic environment, as well as from long-term incubations of these type of communities. The results of the studies presented here increase our knowledge of deep subsurface microbial communities, including their community structure, biofilm formation and metabolic versatility.The oceanic and continental rocky subsurface biosphere is one of the least understood microbial ecosystems. The studies of this Research Topic expand our knowledge of community structure, biofilm formation and metabolic versatility of this realm, drawing on MAGs, metatranscriptomes and amplicon sequencing of indigenous communities from oligotrophic environments, as well as long-term incubations of these communities. Our future efforts need to be directed to understand the correlation between environmental variables and phylogenomic properties of microbial communities and to constrain the limit of the deep rocky biosphere with respect to temperature, depth, and nutrient availability.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "Financial hardships during COVID (FHDC) are a particularly salient stressor that older people faced during the pandemic. Financial stress is associated with increased depressive symptoms and may be especially consequential to mental health among older people who have fewer resources . Recent evidence shows that psychological resilience has important protective effects for mental health among older adults who experience major stressors. This study, based on the recently released full 2020 core wave of the Health and Retirement Study, examines the association between having experienced one or more major financial setbacks following the start of the pandemic and depressive symptoms. We evaluate the consequences of FHDC for mental health, how FHDC are associated with previous financial vulnerability, and the role of psychological resilience in shaping the effects of FHDC. Results show that having experienced FHDC is associated with an increase in depressive symptoms. In addition, reporting financial vulnerabilities four years prior to the pandemic was also associated with increased depressive symptoms. Finally, psychological resilience was associated with a significant, protective effect on depressive symptoms, and moderated the consequences of FHDC. Specifically, we find that those who had FHDC and had average or below average resilience experienced significant increases in depressive symptoms, but those with above average resilience did not experience increases in depressive symptoms despite having FHDC, accounting for the consequences of previous financial vulnerabilities. These results suggest that psychological resilience has potential to be a protective resource for mental health consequences of financial stress among older adults."} +{"text": "Major depressive disorder (MDD) often involves immune dysregulation with high peripheral levels of pro-inflammatory cytokines that might have an impact on the clinical course and treatment response. Moreover, MDD patients show brain volume changes and white matter (WM) alterations that are already existing in the early stage of illness.The aim of the present review is to elucidate the association between inflammation and WM integrity and its impact on the pathophysiology and progression of MDD as well as the role of possible novel biomarkers of treatment response to improve MDD prevention and treatment strategies.We conducted an electronic literature search of PubMed on studies that examined the role of inflammation in depression and that focused on WM integrity and pro-inflammatory cytokines as predictors of antidepressant response.There is evidence for central effects of peripheral inflammation which could activate microglia which, in turn, might trigger a cascade of inflammatory processes leading to neurotransmitter imbalances. Numerous studies indicated that both altered levels of peripheral inflammatory markers, particularly TNF-\u03b1, IL-6, and CRP as well as WM integrity might predict antidepressant treatment outcome.Despite mounting evidence on the impact of the immune system on WM microstructure, no study has yet addressed the interaction between the two factors in influencing antidepressant response. There is a lack of reproducible biomarkers predicting treatment response on an individual basis. The availability of such biomarkers would enable more efficient and personalized treatments with a faster treatment response and better prevention of treatment resistance.No significant relationships."} +{"text": "The subspecialty of Clinical Neurophysiology involves the assessment of function of the central, peripheral, and autonomic nervous systems as well as skeletal muscle using both clinical evaluation and electrophysiologic testing. The latter includes electroencephalography (EEG), magnetoencephalography (MEG), electromyography (EMG), nerve conduction studies (NCS), polysomnography (PSG), evoked potentials, and autonomic testing. Practicing in clinical neurophysiology requires a sound understanding of clinical neurology, normal neurophysiology, and the wide array of abnormal neurophysiologic findings that may be associated with different neurologic disorders.Arquivos de Neuro-Psiquiatria recognizes the need for a new journal subsection exclusively focused on the field of clinical neurophysiology. We hope this subsection will expand trainees\u2019 learning experience and ultimately improve patient care as well as potentially encourage some trainees to pursue further training in neurophysiology.It is often challenging for neurology trainees to acquire optimal knowledge in neurophysiology during residency given its high clinical demand coupled with the multitude of subspecialties within neurology. Similarly, trainees may not have the opportunity to be exposed to all facets of clinical neurophysiology thereby narrowing their experience as budding neurologists. In light of these system-based constraints, the Images in Clinical Neurophysiology welcomes manuscripts with highly educational value related to the subspecialty of neurophysiology. Neurophysiologic content should be previously unpublished, interesting material highlighting clear examples of established observations curated for a trainee readership. Authors should also submit three multiple-choice questions along with answers related to the respective manuscript.Authors may consider selecting cases of uncommon presentations of common neurophysiologic disorders or common presentations of uncommon neurophysiologic disorders. Additionally, describing artifacts that may be mistakenly interpreted as abnormal also has great educational value. Within the realm of EEG and epilepsy, authors may consider the following examples as reference:A case of typical notched delta pattern on EEG in a patient with Angelman syndromeA report of the \u201ctexting rhythm\u201d on EEG associated with cortical processing related to the use of personal electronic devicesA description of snoring-related artifact, which was previously thought to arise from the cortex overlying the amygdala (\u201climbic spindles\u201d)Within the realm of electrodiagnostic testing in neuromuscular medicine, the following examples may serve as excellent teaching tools in highlighting the technical aspects of testing as well as the importance of a keen clinical correlation:The presence of \u2018pseudo-conduction block\u2019 without other demyelinating features in vasculitic mononeuritis multiplex, where a conduction block is manifested by focal infarction and axonal loss rather than the typical demyelinating mechanismThe lack of temporal dispersion and conduction block with a predominance of prolonged distal latencies in anti-MAG demyelinating neuropathy, which provides a distinguishing feature from CIDP (chronic inflammatory demyelinating polyradiculopathy)The evaluation of anatomical variants, such an accessory deep peroneal nerve, in case of peroneal neuropathy resulting in foot drop with preservation of toe extensionArquivos de Neuro-Psiquiatria for creating this new subsection in the journal. We hope Images in Clinical Neurophysiology will become a unique educational resource and serve to (i) supplement neurophysiology education on an international level and (ii) inspire neurology trainees to embrace the fascinating field of neurophysiology.We hope to attract outstanding and highly educational neurophysiology manuscripts ideally led by trainees from across the globe. We are truly grateful to the"} +{"text": "The hypothalamic neuropeptide, oxytocin (Oxt), has been the focus of research for decades due to its effects on body physiology, neural circuits, and various behaviors. Oxt elicits a multitude of actions mainly through its receptor, the Oxt receptor (OxtR). Despite past research to understand the central projections of Oxt neurons and OxtR- coupled signaling pathways in different brain areas, it remains unclear how this nonapeptide exhibits such pleiotropic effects while integrating external and internal information. Most reviews in the field either focus on neuroanatomy of the Oxt-OxtR system, or on the functional effects of Oxt in specific brain areas. Here, we provide a review by integrating brain wide connectivity of Oxt neurons and their downstream circuits with OxtR expression in mice. We categorize Oxt connected brain regions into three functional modules that regulate the internal state, somatic visceral, and cognitive response. Each module contains three neural circuits that process distinct behavioral effects. Broad innervations on functional circuits enable Oxt signaling to exert coordinated modulation in functionally inter-connected circuits. Moreover, Oxt acts as a neuromodulator of neuromodulations to broadly control the overall state of the brain. Lastly, we discuss the mismatch between Oxt projections and OxtR expression across various regions of the mouse brain. In summary, this review brings forth functional circuit-based analysis of Oxt connectivity across the whole brain in light of Oxt release and OxtR expression and provides a perspective guide to future studies. Oxytocin (Oxt) was originally identified in 1906 as the primary molecule involved in parturition and lactation . FurtherSir Henry H Dale, a British physiologist, initially discovered that extracts from pituitary glands (from oxen) when administered intravenously facilitated contractions of the uterus . In 1909Oxt is synthesized mainly in the paraventricular hypothalamus (PVH) and the supra optic nucleus (SO) along with a smaller number of neurons in the accessory nuclei of the hypothalamus and extended amygdala . In addird ventricle . This hyesponses . Site spesponses . It is aesponses . All theinternal state control, somatic visceral control and cognitive control , substantia innominata (SI), magnocellular nucleus (MA) and medial septal nucleus (MS) release acetylcholine upon receiving an attention relevant cue in the rat brain . AlthougThe LC sends adrenergic projections to the medial prefrontal cortex (mPFC), thalamus (TH), BF and many other brain areas . Oxt is There are several other brain areas along with the BF and LC, that are relevant in the attention circuit. For example, the claustrum (CLA) in primates is an area relevant for top-down control of attention with its extensive connections to the neocortex . The mouFear is a combined response constituting physiological and behavioral counterparts experienced due to an exposure to possible threats that can affect one\u2019s survival . The braOxt neurons send projections to all these areas, controlling many aspects of fear response. For example, Oxt released from the PVH to the extended amygdala (the CEA and the BST), is critical for regulating fear/threat responses . Oxt in Sleep can be defined as a fast reversible state of immobility accompanied by reduced neurophysiological and behavioral responses to environmental stimuli . Sleep iOne of the earliest identified sleep promoting areas is the preoptic area . The NREWhile Oxt has been implicated in this system, Oxt\u2019s role in sleep regulation remains relatively understudied. Oxt neurons project to all the previously mentioned major nodes that control REM, NREM and circadian aspects of sleep. Despite the lack of evidence for the exact mechanism of sleep regulation by Oxt, there are several clinical studies implicating better quality sleep with increased Oxt levels in humans. For instance, increased endogenous Oxt in postpartum women facilitates sleep . Oxt admOxt in the somatic/visceral control module share abilities that regulate a host of homeostatic activities and can be further subdivided into three groups: pain controlling areas, areas involved in sensory motor regulation and areas regulating body physiology and metabolism .Pain is a distressing sensation and an emotional experience often associated with either actual or potential tissue damage, with the major intention of starting the body\u2019s defense mechanisms to react toward the causal stimuli and thus prevent further tissue damage. The ascending pathway carries pain information from the peripheral to the central nervous system while the descending pain pathway brings responses from CNS to the peripheral reflex organs .Ascending pain pathways include spinothalamic pathways that relay pain information from the spinal cord to different thalamic areas followed by thalamocortical pathways which relay information from thalamus to the cortical centers that process different aspects of pain perception. The medial thalamus sends the emotional and motor related information to the mPFC . The lateral thalamus conveys sensory pain information to the somatosensory cortex (SS), and the posterior thalamus relays pain perception and intensity information to the posterior insular cortex . AnotherOxt exerts its effects on both ascending and descending brain regions that modulate pain. Oxt neurons send projections to multiple thalamic areas to regulate the ascending pain pathway. Oxt neurons also send projections to the PB and various amygdalar nuclei to modulate the pain inputs. In the descending pathway, Oxt neurons project to the nucleus raphe magnus (RM) to further modulate pain responses . Even thOxt is known to have analgesic effects, both from preclinical and clinical studies. In rats, partial sciatic nerve ligation induced pain results in increased Oxt synthesis . MoreoveSensorimotor integration is defined as the ability to integrate different sources of sensory stimuli in the central nervous system and transform this into goal directed motor functions . The motThe visual inputs from the retina reach the lateral geniculate nucleus (LG) in the thalamus from which the information is sent to the visual cortex (VIS). Visual information is passed on to the suprachiamatic nucleus (SCH) of the hypothalamus from the retina to direct attention to the visual stimuli . The preAuditory inputs received via the cochlea are sent to the superior olivary nucleus (SOC) followed by the inferior colliculus (IC). The IC is the relay station where ascending and descending auditory pathways converge. From the IC, auditory signals are passed to the AUD through the medial geniculate nucleus (MG) . The posOlfactory inputs arise from the olfactory epithelia and reach the main MOB. From the MOB, it projects to the taenia tecta (TT), anterior olfactory nucleus (AON), PIR, olfactory tubercle (OT) and entorhinal cortex (ENT). Vomeronasal inputs that carry pheromone information also start from the olfactory epithelium, but flow to the accessory olfactory bulb (AOB) and further to the bed nucleus of stria terminalis (BST), nucleus of the lateral olfactory tract (NLOT) and various amygdaloid nuclei. Processed olfactory information is passed to multiple brain regions depending on the action to be performed . DespiteTaste inputs received through the taste receptors reach the brain through the nucleus of the solitary tract (NTS). From the NTS, there are three distinct pathways that relay taste information: the reflex pathway for either enhancing or reducing ingestion, the lemniscal pathway for taste perception and discrimination, and the visceral-limbic pathway mostly for regulating homeostatic and motivational states. The reflex pathway involves NTS signals conveyed to medullary and reticular formations that further innervate the cranial motor nuclei . The lemThe cutaneous afferents from both the forelimbs and the hindlimbs reach the thalamus either through direct spinothalamic pathways or from the spinal cord via the cuneate nucleus (CU). Tactile information is processed in different areas of the ventral posterior complex of the thalamus: the ventral posterolateral nucleus of the thalamus (VPL) \u2013from the foot and hand and the ventral posteromedial thalamus (VPM) -from the face . From the thalamus this information is passed to the somatosensory cortex that then delivers the processed information to the motor cortex . Oxt proThe integration of visual, auditory and somatosensory inputs occurs in the multisensory midbrain, the superior colliculus (SC), which also receives direct projections from Oxt neurons. The heavy inputs from the SC to Oxt neurons transmit visual information required for learning of pup retrieval in virgin female mice, a process that requires integration of multiple inputs . AlthougMotor control is a well-studied area which mainly involves the basal ganglia circuit. The dorsal striatum , the globus pallidus (GP), and the subthalamic nuclei (STN) as major stations of the basal ganglia receive motor inputs from cortical and sub cortical areas. There are three main pathways that control different aspects of locomotion. The direct pathway relays signal from the motor cortex that results in active motor responses. The motor cortex sends excitatory inputs to the CP, which in turn results in inhibition of the globus pallidus internus (GPi) and substantia nigra pars reticulata (SNr), activating the thalamus and resulting in motor activity. The indirect pathway mediates inhibitory outflow and thus reduces the motor activity. Inputs from the motor cortex reach the globus pallidus externa (GPe) that inhibits the STN, resulting in the activation of the GPi and SNr, causing inhibition of motor activity. The hyperdirect pathway is a direct relay signal from the motor cortex to STN inhibiting ongoing motor activity . Oxt proBody physiology is the branch of biology that deals with regulating the normal function of organs. Metabolism can be defined as the sum total of all reactions within the body that converts food to energy . Major bBody physiology and metabolism is not only regulated by nutrient/glucose uptake, but also by fluid intake and homeostasis. Fluid intake and regulation is maintained mainly through the projections from NTS to PB and downstream areas- the CEA, MEPO, vascular organ of lamina terminalis (OV) and anteroventral periventricular nucleus (AVPV) . Fluid iRyan, 2018Cardiovascular activity is also regulated by Oxt that is released from the brain . The NTSCognitive control refers to the selection of emotions, behaviors and thoughts based on social context and current requirements along with avoiding inappropriate actions . The cogMemory is defined as the process of encoding, storing and retrieving information . Memory Explicit memories include events that happened in the past (episodic) as well as general information and facts (semantic). Episodic memory mainly functions through neocortex -entorhinal area (ENT) -hippocampal circuits . The hipMemory modulation by Oxt is studied specifically in the context of social memory . OxtRs aReward is an act of pleasant or positive affective experience . The maiSocial reward is mainly regulated by Oxt\u2019s effect on reward circuitry. Oxt released in the VTA promotes prosocial behaviors. Optogenetic activation of Oxt-PVH neurons resulted in activation of reward specific VTA dopamine neurons that project to the ACB. This circuit is necessary to elicit social reward . DR seroReproduction is a basic instinct crucial for survival of a species that can be defined as the process by which genetic material is transmitted from one generation to the next . ReproduOxt acts at multiple brain areas to regulate different aspects of reproduction. During pregnancy and parturition, the role of hypothalamic release of Oxt is well discussed . HypothaIn mice, Oxt from the PVH to VTA induces erection . During In this review, we addressed functional circuits in the brain and explained the specific areas at which Oxt can exert its effect to modulate particular behaviors. We explained the neural circuits responsible for nine different functions and at what levels Oxt can act within each circuit. Oxt neuronal fibers reach all the major brain areas involved in most of the functional circuits. An exception to this is the thalamic regions , the major relay station for sensory circuits and pain circuits to the cortex, that neither receive projection fibers, nor have OxtRs. We were also able to identify cross talk between multiple functional circuits and illustrate how Oxt can modulate different behaviors by acting at one brain area. For example, the PAG mediates fight and attack responses as well as receiving pain information. Another region that receives both pain and visual inputs is the PB. Social reward and memory areas in the brain are also heavily interconnected with each other and Oxt exerts effects on most areas within these two circuits to impact social memory . Thus, OSM and YK conceptualized the manuscript. SM wrote the initial manuscript and figures and further developed the manuscript with RB. YK handled the funding and critically revised the manuscript. All authors contributed to the article and approved the submitted version."} +{"text": "Community health workers can play an important role in health education and ante-natal care that will help reduce the number of preterm births. As members of their communities, they are best placed to advise and support parents and extended families in reducing the risk of ROP and visual loss.Preterm births are an important public health concern worldwide due to the resultant morbidities. Survival of premature babies has improved largely due to improved neonatal care services. However premature infants are at greater risk of cerebral palsy, developmental delays, hearing and vision related issues.Retinopathy of prematurity (ROP) remains one of the leading causes of childhood blindness worldwide. Recent estimates show that worldwide 32,000 infants become blind or visually impaired due to ROP. Most of the ROP blind infants are born in countries in Asia.Community health workers are members of communities where they provide preventive, promotional and rehabilitation care to other members. The community health workers in India areAuxiliary nurse midwife (ANM)Anganwadi worker (AWW) andAccredited social health activist (ASHA worker).They play a crucial role in the health care system especially in maternal and child health care and thus can help in prevention of blindness due to ROP.Commonly known as ANM, they are a village level female health worker who is the first contact person between community and health services. ANMs are regarded as the grassroots workers in health organisation pyramid.Anganwadi centers are government run mother and child care center in villages in India. The anganwadi workers ensure antenatal and postnatal care for pregnant women, nursing mothers and immediate diagnosis and care for new born children. Monitoring regular health and medical check-ups for women and children is one of their key responsibilities.ASHA workers are local women trained to act as health educators and promoters in their communities. Their tasks include motivating women to give birth in hospitals, bringing children to immunisation clinics, encouraging family planning, treating basic illness and injury with first aid, keeping demographic records and improving sanitation.Community health workers serve as a key communication pathway between the healthcare system and the rural population, especially in reducing preterm deliveries and in prevention of ROP in babies born too soon. Preterm deliveries can be reduced by working on modifiable risk factors such as maternal nutrition, pregnancy planning, birth spacing etc. ROP blindness can be reduced by expanding and improving screening and treatment services at medical colleges and district hospital sick newborn care units (SNCUs) and neonatal intensive care units (NICUs). The community health workers play a key role in preventing ROP blindness in three different stages:Reducing preterm deliveriesPrevention of ROP in preterm babiesScreening and treatment services for ROPChild marriage has lasting consequences on girls, from their health, education and social development perspectives which often last well beyond adolescence. It has been found that teenage mothers are three times more likely to deliver preterm babies and twice as likely to deliver low birth weight (LBW) babies compared to older mothers (21 Yrs to 34 Yrs).It is likely that when the space between births is short, there will be depleted nutrition in new mothers, as these women do not get enough time to recover before getting pregnant again. Therefore, after a birth, the interval before attempting a new pregnancy should be at least 24 months to reduce the risk of adverse maternal and infant outcomes.Maternal undernutrition is still a major problem in India. In populations with food insecurity and high rates of maternal undernutrition, balanced protein energy supplementation may improve foetal growth and reduce the risk of foetal and neonatal death.Prenatal maternal stress, depression and anxiety are found to be related to preterm labour.ASHA workers can help in educating pregnant women about regular antenatal check-ups and the importance of periodic follow-up. This aids in monitoring for hypertension, diabetes, infections etc, which if properly managed may reduce preterm deliveries. The community health workers play a role in birth preparedness which consists of preparing the mother, family and community for delivery and potential complications. They should encourage and increase the percentage of hospital deliveries which are safe for the mother and child.With a preterm birth, the focus shifts to prevention of ROP and other morbidities. A well- trained health worker anticipates and prepares to minimise the morbidities that may ensue. Risk factors like poor weight gain, infection etc if tackled properly can prevent ROP related childhood blindness.A significant reduction in the risks of mortality, respiratory distress syndrome and intraventricular haemorrhage have been confirmed after administering antenatal steroids in babies delivered before before 34 weeks gestation.It has been found that exclusive breastfeeding for six months starting within an hour after birth may prevent ROP. Health workers can help in explaining to mothers the importance and advantages of exclusive breast feeding. There are several significant short term and long term benefits of breastfeeding preterm infants. Neurodevelopmental outcomes are also proven to improve with early and exclusive breastfeeding.As sepsis in preterm infants leads to increased risk of ROP, infection control procedures like personal hygiene can be clearly explained to mothers. Small yet significant measures such as bathing regularly and washing all clothes used for the baby can be easily explained to the mothers in the local language. Educating family members along with the mother on washing hands thoroughly before touching the baby and keeping surroundings clean help in keeping infections under control.Hypothermia is another concern in the management of pre-term infants. Kangaroo mother care (KMC) involves direct and continuous skin to skin contact between infant and mother. It helps in preventing hypothermia, improving weight gain and reducing incidence of infection. The procedure and benefits of KMC when explained clearly to the mothers, help in improving survival and decrease ROP. Along with KMC, the ASHA workers can also show proper swaddling of babies and keeping babies warm.Community health workers should be made aware that all the babies born too soon (<34 weeks) and small (<2000grams) who have been admitted to SNCU/NICU should undergo first eye screening for ROP before 30 days of birth. They are best placed to motivate parents to take their preterm infant for ROP eye screening to a trained ophthalmologist nearest to them. Educating parents about the disease with the help of visual aids like flash cards or posters of the disease and how it leads to blindness helps in reaching out to illiterate population in a better way. Health workers can also encourage parents to take the baby for ROP screening before they are 30 days old.Community health workers can help parents understand that ROP is a disease with a narrow time period between detection and treatment and that treatment cannot be delayed. Counselling parents and their families about laser photocoagulation can also be done by a community health worker.The most common challenge faced in management of ROP is lack of compliance and follow-up. Though the initial screening is done when the baby is in NICU, parents especially in rural areas do not come back for follow-up. As ROP is a disease which requires multiple visits the ASHA workers can help in tracking pre-term infants in their communities and motivating parents to go for follow up visits. Educating parents about long term effects a pre-term birth can have on the eyes is also important, to encourage them to attend for follow up. Simple language must be used in training the ASHA workers so they can effectively counsel parents.Community health workers can play an important role in health education and ante-natal care that will reduce the number of premature babies born. They also have an important role in advising and supporting the mothers of preterm babies in order to reduce the risk of ROP and visual loss."} +{"text": "Genomic sequence data from worldwide human populations have provided a range of novel insights into our shared ancestry and the historical migrations that have shaped our global genetic diversity. However, a comprehensive understanding of these fundamental questions has been impeded by the lack of inclusion of many Indigenous populations in genomic surveys, including those from the Wallacean archipelago and the former continent of Sahul . Notably, these regions have been important areas of human evolution throughout the Late Pleistocene, as documented by diverse fossil and archaeological records which attest to the regional presence of multiple hominin species prior to the arrival of anatomically modern human (AMH) migrants. In this review, we collate and discuss key findings from the past decade of population genetic and phylogeographic literature focussed on the hominin history in Wallacea and Sahul. Specifically, we examine the evidence for the timing and direction of the ancient AMH migratory movements and subsequent hominin mixing events, emphasising several novel but consistent results that have important implications for addressing these questions. Finally, we suggest potentially lucrative directions for future genetic research in this key region of human evolution. Homo erectus in the island of Java [H. erectus likely reached Java while it was still contiguous with mainland Asia due to lower sea levels during the mid-Pleistocene, further east lies the maritime barrier known as Wallace\u2019s Line, which has separated mainland Asia from the Wallacean and Philippine archipelagos and Sahul throughout hominin evolutionary history. This persistent barrier was responsible for the diversification of marsupial and placental mammals around 50 Mya, though notably, it did not prevent multiple hominin groups from venturing further east , including the oldest known hominin remains outside of Eurasia; i.e., of Java . While Hher east . Indeed,f Flores ,4,5, whihipelago . The thrhipelago and northipelago ,10,11,12Crucially, efforts to obtain robust estimates of the timing and direction of the historical migratory movements that eventually brought AMH and other hominin groups into Sahul have been complicated by the sparse archaeological record in Wallacea. Indeed, the current oldest evidence for AMH occupation in Wallacea recorded in Timor ,13 and SWith the current limited availability of archaeological sites across much of Wallacea, researchers have recently turned to genetic sequence data from local modern populations and ancient remains as an alternative empirical tool to help resolve fundamental questions around AMH arrival and hominin mixing events in the region. In the following sections, we review key findings from the small but growing number of population genetic and phylogeographic studies examining the human history in Wallacea and Sahul, with a particular focus on studies of Wallacean populations from the past decade. These studies have begun to illuminate a complex population history marked by multiple migrations and population mixing events, which may have erased much of the ancestry descending from the original AMH founders. We discuss the implications of these findings for our understanding of the broader human and hominin regional history and conclude by highlighting potentially fruitful areas of future research.While human genetic research has accumulated steadily for populations in most parts of the world, comparatively few population genomic and phylogeographic studies leveraging complete mitogenome sequences or Y-chromosomes currently exist for present-day Indigenous peoples from the former continent of Sahul ,25,26,27These genomic results are consistent with phylogeographic studies of mitogenomes and Y chromosomes ,36,37,38To further investigate AMH migratory pathways into Sahul, Brucato and colleagues comparedThe findings from these recent phylogeographical studies strongly suggest that the movement of Papuan lineages may have reconfigured the genetic profile of AMH populations in Wallacea, with impacts likely extending into surrounding regions . ImportaThe handful of prior population genomic studies that have investigated historical Wallacean demography have revealed a highly dynamic history, with multiple genetic ancestries being introduced into the region around the arrival of Austronesian-speaking seafarers during the late Holocene. One of the first genomic studies attempting to reconstruct the history of ISEA by Lipson and colleagues used a vHighly consistent genetic patterns were also reported in a more recent study by Hudjashov and colleagues which utThese studies indicate that the genetic profile of modern Wallacea was largely determined by movements and mixing events in the late Holocene, possibly through the arrival of admixed Austronesian-speaking seafarers that carried multiple ancestry sources. Crucially, these interpretations implicitly assume that the Papuan-related ancestry observed in Wallaceans most likely reflects the AMH founder ancestry endemic to each island. However, the strict partitioning of Negrito and Papuan-related genomic ancestries reported for populations situated either west or east of Wallace\u2019s Line, respectively, may instead signal the effective replacement of an ancient AMH genetic profile across Wallacea by incoming migrants bearing Papuan and potentially additional \u2018Asian\u2019 related ancestries. Indeed, it remains possible that the underlying mixing events may not have been local to each Wallacean island and could even have occurred outside of Wallacea. The extent to which these mixing events have decoupled Wallacean genetic profiles from their original island context remains an outstanding empirical question, and its resolution will be crucial for future genetic reconstructions of the deep human history of the region.The complex population history of Wallacea evident in genetic studies suggests that ancient DNA (aDNA) research may provide the key to recovering key historical details. By situating genetic sequences within specific historical, geographical, and archaeological contexts, aDNA can illuminate aspects of human population history that may no longer be evident in modern genetic data. The field of ancient aDNA has developed rapidly since researchers first retrieved fragments of DNA from the desiccated muscle of an extinct subspecies of an Equus quagga museum specimen in 1984 . In the f-statistic analyses showed that the Leang Panninge specimen has two distinct genetic ancestries, with one component that is genetically equidistant to both modern Indigenous Australians and Papuans, and another that is genetically closer to ancient East Asian and modern Andamanese (Onge) populations. Admixture graph models suggest that the Australo-Papuan-like component may reflect the genetic profile of the initial AMH migrants to ISEA, with subsequent mixing with an unknown Asian lineage resulting in the Leang Panninge specimen\u2019s distinctive dual ancestry [In 2021, the first Wallacean paleogenome was published from an ~8000-year-old female from Leang Panninge in southern Sulawesi , which nancestry . InteresA more recent study of 16 paleogenomes from multiple sites in Sulawesi, Moluccas, and Lesser Sundas, which range from several hundred to ~2300 years old, also found no evidence for genetic continuity between these 16 individuals and the Leang Panninge specimen , indicatThese paleogenomic studies provide the first direct support for the erosion of genetic profiles associated with founder AMH migrants across Wallacea through the introduction of external genetic ancestries. While the timing and ordering of the underlying mixing events appear to have varied across Wallacea, estimates of admixture times from ancient and modern genomes consistently point to initial mixing events occurring around 1\u20132.5 kya ,45, withThe landmark sequencing of hominin genomes from two distant AMH relatives, namely Neanderthals and Denisovans, led to the momentous finding that these now-extinct hominin species had interbred with AMH as they dispersed from Africa across the rest of the planet ,34,55,56Ongoing investigations of the geographic patterning of hominin admixture in populations from ISEA and Sahul attest to a particularly complex set of historical interactions in this region, suggestive of multiple distinct mixing events occurring in situ across different islands ,61,62,63H. erectus, H. floresiensis, and H. luzonensis\u2014were present in the region prior to the arrival of AMH in the region by 50\u201370 kya [The high levels of Denisovan-related ancestry found across ISEA and Sahul is particularly surprising given that all currently identified Denisovan fossils come from mainland Asia . However0\u201370 kya ,4,5,6,650\u201370 kya . To addrWallacea and Sahul are key regions of hominin evolution whose history remains only partially explored, partly due to conditions that have made fossils and archaeological records challenging to retrieve and preserve. In the past two decades, a small but growing number of genetic and phylogeographic studies from Wallacea and Sahul\u2019s populations have started to explore the deep human history of this region, attempting to unravel the timing and location of the original human migrations and mixing events with now-extinct hominins. Notably, these studies have revealed a complex demographic history marked by multiple migrations that appear to have largely erased the deep genetic signals needed to properly resolve these fundamental questions. Moving forward, further genomic studies are sorely needed to determine the timing and origin of the migrations that brought Papuan-related ancestry into Wallacea and beyond, and to ascertain the extent to which modern Wallacean populations retain genetic information from the original AMH migrants. Notably, even if this genetic information has been retained, the complexity and extent of historical migrations impacting Wallacea may have sufficiently decoupled these genetic signals from their initial geographical context, to make the resolution of the migration routes impossible from modern genomes alone. Accordingly, the path ahead may ultimately require the generation of paleogenomes from AMH specimens across Wallacea and ISEA in the period preceding these mixing events. Similarly, determining the identity of hominin ancestry in modern populations east of Wallace\u2019s Line may require ancient DNA or proteomic data from regional hominin fossils. Encouragingly, aDNA recovery from tropical regions has improved rapidly in recent times, suggesting that at least some of the paleogenomic data necessary to address these important questions may yet emerge in the foreseeable future."} +{"text": "To assess a range of tools and methods to support Trusted Research Environments (TREs) to assess output from AI methods for potentially identifiable information, investigate the legal and ethical implications and controls, and produce a set of guidelines and recommendations to support all TREs with export controls of AI algorithms.TREs provide secure facilities to analyse confidential personal data, with staff checking outputs for disclosure risk before publication. Artificial intelligence (AI) has high potential to improve the linking and analysis of population data, and TREs are well suited to supporting AI modelling. However, TRE governance focuses on classical statistical data analysis. The size and complexity of AI models presents significant challenges for the disclosure-checking process. Models may be susceptible to external hacking: complicated methods to reverse engineer the learning process to find out about the data used for training, with more potential to lead to re-identification than conventional statistical methods.GRAIMatter is:Evaluating a range of tools to determine effectiveness for disclosure controlAssessing the legal and ethical implications of TREs supporting AI development and identifying aspects of existing legal and regulatory frameworks requiring reform.Running 4 PPIE workshops to understand their priorities and beliefs around safeguarding and securing dataDeveloping a set of recommendations includingsuggested open-source toolsets for TREs to use to measure and reduce disclosure riskdescriptions of the technical and legal controls and policies TREs should implement across the 5 Safes to support AI algorithm disclosure controltraining implications for both TRE staff and how they validate researchersRecords can be linked successfully, but estimated performance of record linkage depends on the validation set used. Manually reviewed data contain noise and may underestimate performance, while national ID numbers may overestimate performance due to non-random patterns of missingness."} +{"text": "Colorectal cancer (CRC) recurrence is a leading cause of mortality worldwide. It has been suggested that poor anastomotic healing and leakage (AL) after surgery allows cancer cells to implant at the anastomotic site thereby increasing the risk of local cancer recurrence and metastatic spread in the peritoneum and to extraintestinal organs. We have previously showed that inulin, a well-known prebiotic, improves anastomotic healing and strengthens the gut barrier.The objective of the this study was to investigate the relationship between the promotion of postoperative intestinal healing using inulin and local and distant cancer recurrence.A 10-years' retrospective review of AL and non-AL cases after CRC surgery was performed in our institution. The effect of dietary supplementation with inulin on the occurrence of local anastomotic tumors was assessed in a mouse model inoculated with tumor cells directly in the gut lumen after colonic surgery. We also investigated in mice whether inulin may prevent metastatic spread and growth of tumor cells in the liver by transplanting CRC cells surgically into the spleen.Patients experiencing AL displayed significantly lower overall survival and more cancer recurrence and progression compared to non-AL patients. Poor anastomotic healing in mice led to larger anastomotic tumors and peritoneal cancer dissemination. Inulin supplementation significantly inhibited local tumor implantation at the anastomotic site, and metastatic spread to the peritoneum and liver. Inulin increased the production of beneficial short-chain fatty acids, reinforced the gut barrier function and alleviated systemic inflammation in mice.Anastomotic leak was associated with worse oncological outcomes in patients and mice. Inulin was shown to reinforce the gut barrier, decrease the implantation of cancer cells at the anastomosis, and to prevent tumor dissemination and progression of liver metastasis. This paves the way toward future clinical trials in which such supplementation may be used to promote better oncological outcomes.CIHR, OtherCRS, FRQSNone Declared"} +{"text": "Psychosocial working conditions have been associated with cognitive and physical impairment among older adults. However, less is known on whether psychosocial working conditions are associated with a combination of cognitive and physical impairments. The aim of this study was to investigate the associations between midlife psychosocial working conditions and physical and cognitive impairment among older adults, and to assess whether there are sex differences in these associations.The data were derived from two Swedish nationally representative surveys (n=839) with a follow-up time of 20-24 years. Multinomial and binary logistic regressions were used to assess the associations between work stressors according to the job demand-control model, and a combination of cognitive and physical impairment.Low control jobs were significantly associated with higher odds of both cognitive and physical impairment as well as a combination of cognitive and physical impairment. Passive jobs were associated with higher odds of cognitive impairment, and cognitive and physical impairment in combination. Active jobs were associated with lower odds of cognitive impairment. Sex-stratified analyses showed stronger associations among men than among women. Among men passive jobs were significantly associated with both cognitive and physical impairment. Low strain jobs were significantly associated with less physical impairment.These results highlight the importance of midlife psychosocial working conditions for late-life physical and cognitive impairment, and especially among men. Jobs characterised by higher control, lower strain and active jobs may promote resilience and cognitive reserve among older populations."} +{"text": "Global health challenges require systematic approaches that bring together a wide range of stakeholders and experts unevenly distributed worldwide. We saw an even greater need to find novel ways to collaborate during the pandemic due to limited in-person meetings and travel restrictions. The purpose of this project is to accelerate collaborations in learning health systems with online technologies to improve communication, education, and knowledge management.We developed Alicanto Cloud, an online collaboration platform for healthcare professionals to support learning health systems. Alicanto aims to help groups communicate, share educational resources, discuss complex clinical cases across institutions and countries. Alicanto provides multiple ways for users to create synchronous and asynchronous discussions. Alicanto was developed by the BIDMC Division of Clinical Informatics in collaboration with local and international colleagues with a specific focus on global health and capacity building.Alicanto is being used worldwide for cancer, pediatrics, and diabetes collaborations. Online communities use Alicanto to standardize care guidelines, disseminate clinical care best practices, provide online training, conduct virtual tumor boards, and improve knowledge management. Beth Israel Deaconess Medical Center has used Alicanto to connect 13 hospitals and has completed over 600 virtual tumor board case discussions. Dana-Farber Cancer Institute uses Alicanto as an online cancer training network for sub-Saharan Africa. Doctors from Joslin Clinic have used Alicanto to create a global diabetes education network. We will discuss lessons learned in implementing these networks and best practices for accelerating the process of evidence synthesis to dissemination and capacity building.Communities of practice can accelerate their communications and collaborations with the appropriate tools and platforms tailored to their network needs. Further research is needed to understand the optimal ways to create sustained growth and support of communities of practice in learning health systems."} +{"text": "This study aimed to estimate the level of underestimation of National Dose Registry (NDR) doses based on the workers\u2019 dosimeter wearing compliance. In 2021, a nationwide survey of Korean medical radiation workers was conducted. A total of 989 medical workers who performed fluoroscopically-guided interventional procedures participated, and their NDR was compared with the adjusted doses by multiplying the correction factors based on the individual level of dosimeter compliance from the questionnaire. Ordinal logistic regression analysis was performed to identify the factors for low dosimeter wearing. Based on the data from the NDR, the average annual effective radiation dose was 0.95 mSv, while the compliance-adjusted dose was 1.79 mSv, yielding an 89% increase. The risks for low compliance with wearing a badge were significantly higher among doctors, professionals other than radiologists or cardiologists, workers not frequently involved in performing fluoroscopically-guided interventional procedures, and workers who did not frequently wear protective devices. This study provided quantitative information demonstrating that the NDR data may have underestimated the actual occupational radiation exposure. The underestimation of NDR doses may lead to biased risk estimates in epidemiological studies for radiation workers, and considerable attention on dosimetry wearing compliance is required to interpret and utilize NDR data. Data on the level of occupational radiation exposure in workers is periodically obtained from individual dosimeters worldwide and stored in the National Dose Registry (NDR). Such registries are important parts of national occupational radiation protection programs in many countries. The NDR data are essential to protect radiation workers from radiation exposures and facilitate the conduct of epidemiological studies that estimate the effects of low dose and low dose rate ionizing radiation ,2. ThereHowever, some radiation workers do not always wear dosimeters due to various reasons, such as reduction in their work performance and discomfort while working, and problems with regulatory authorities for exceeding the dose limits ,4,5. LowAmong radiation workers, the medical workers who perform fluoroscopically-guided interventional procedures are exposed to a substantially higher dose compared with that of other medical radiation workers performing conventional radiography . Hence, This study aimed to investigate the level of potential underestimation of occupational radiation doses among medical workers who perform fluoroscopically-guided interventional procedures. Identifying the level of NDR underestimation and related factors may serve as a fundamental step in developing strategies to protect radiation workers against occupational radiation exposure and in applying the NDR badge doses in radiation epidemiology studies.A web-based nationwide survey was conducted from June 2021 to August 2021. The target population included all diagnostic medical radiation workers who performed or assisted in interventional fluoroscopy procedures and were registered at an NDR in the Korea Disease Control and Prevention Agency (KDCA), which operates a lifetime management system for occupational radiation doses. The registry includes physicians, dentists, dental hygienists, radiologic technologists, nurses, and medical assistants. The participants were invited through the nationwide branches of 15 professional societies that specialize in interventional radiology such as the Korean Society of Interventional Radiology, the Korean Society of Interventional Cardiology, the Korean Pain Interventional Society, the Korean Orthopedic Association, the Korean Society of Interventional Neuroradiology, and the Korean Pancreatobiliary Association. A total of 989 medical workers who reported wearing a TLD (thermoluminescent dosimeter) badge beneath their apron on the left side of the chest (standard protocol in South Korea) participated in this study. Written informed consent, with permission to use the radiation dosimeters, was voluntarily provided by all study participants prior to the study enrollment. This study was reviewed and approved by the Institutional Review Board of Korea University (KUIRB-2021-0181-01).http://www.rhs.kr/intervention, accessed on 20 June 2022) for interventional medical radiation workers was developed based on our previous study . An ordinal logistic regression analysis was used to examine the association between the compliance of dosimeter wearing and occupational characteristics after adjusting for age and sex. In this analysis, workers were categorized as four compliance groups of dosimeter wearing as the outcome variable. All statistical analyses were performed using the R software, version 4.1.1 .Demographic and occupational characteristics of the study participants according to compliance of badge wearing are presented in The average annual occupational radiation doses before and after adjustment by level of badge wearing compliance are summarized in The results of ordinal logistic regression analyses with low badge wearing compliance after adjustment for age and sex by occupational characteristics are presented in This study indicated that the NDR data could underestimate the actual occupational radiation exposure level among medical workers who perform fluoroscopically-guided interventional procedures by approximately 90%, and a few subgroups had low dosimeter badge wearing compliance. These findings suggest that it is necessary to monitor the dose uncertainty when using the NDR dose in the epidemiologic studies to obtain more reliable estimates of the level of radiation exposure by conducting a sensitivity analysis excluding workers who had low reliable NDR doses. Therefore, it is important to increase the badge wearing compliance that can reflect the actual radiation exposure level and collect the data on the badge compliance proportion to validate the reported dose data. This study could add quantitative evidence for emphasizing the appropriate use of the NDR dose in epidemiologic studies and help develop workplace policies by increasing the dosimeter wearing compliance.Our findings indicated that the actual occupational radiation doses could be higher among low compliance dosimeter wearers than among always wearers, although the official NDR data reported the highest values among always wearers as compared to other groups of dosimeter wearers . The difference in the estimated actual doses among study participants was increased with decreasing the compliance level of dosimeter wearing. Therefore, the risk reported in epidemiologic studies would be biased when the doses are only assessed based on the reported NDR doses, especially among irregular badge wearers. The underestimated doses caused by censoring of minimum detection limit doses resulted in the overestimation of the radiation exposure risk in the Canadian occupational radiation workers , while tThe level of underestimation reported in the present study (approximately 90%) may be comparable to that among Korean interventional radiologists . In addiOur findings on a few subgroups who had significantly higher risks of wearing a badge irregularly may be attributable to their occupational characteristics. Doctors may feel uncomfortable wearing the badge while working and are more sensitive when prohibited from being exposed to radiation that exceed the dose limits compared with the radiologic technologists and nurses, thus increasing the tendency to be less compliant in wearing a badge. Workers who specialize in radiology and cardiology may have more radiation safety education than in other specialties because they are more frequently involved in the performance of fluoroscopically-guided interventional procedures. Radiologists have received more training and more knowledge on radiation exposure compared with doctors of other medical specialties in Spain and the In addition, workers who less frequently perform fluoroscopically-guided interventional procedures are not informed about the need to wear a badge since their job does not always involve exposure to radiation. It is also possible that workers who wear dosimeters are more cautious about performing fluoroscopy , and thiHowever, the validity of NDR data could vary depending on the characteristics of the study participants. For example, no difference was found in the compliance level between sexes, positions, and hospital types and sizes among radiologists in Jordan . TherefoThe proportion of regular dosimeter wearers in our study (53%) was generally comparable with that in previous studies conducted in South Korean radiologic technologists (66%) , US cardOur study has some limitations. The questionnaire related to dosimeter wearing compliance represents the overall compliance level of radiation workers and may not capture detailed information about the frequency of wearing a badge by time period and specific work procedures. In addition, the correction factor used in this study was based on a self-assessment in the questionnaire. However, the compliance level may be non-differentially misclassified among the participants, and information on self-reported working practices that involve radiation exposure has been generally reported as reliable among South Korean radiologic technologists . FurtherIn summary, we provided quantitative information demonstrating that the NDR data may have underestimated the actual occupational radiation exposure level among medical radiation workers who perform fluoroscopically-guided interventional procedures in South Korea. Such an underestimation of occupational radiation doses may lead to biased risk estimates in epidemiological studies of radiation workers. Thus, considerable attention is required when interpreting and utilizing the NDR data, such as conducting a sensitivity analysis excluding workers who had low reliable NDR doses. Further studies are needed to evaluate the influence of the dose uncertainty induced by the underestimation of the true doses due to the low dosimeter wearing compliance."} +{"text": "Newcomer mothers of African descent are at risk for maternal mentalstress because of inadequate social support, newcomer status,and stress of motherhood. Limited participation of newcomerAfrican mothers in mental health research contributes to aknowledge gap in this area further impacting culturallycompetent health services. This article reports recruitmentstrategies to better engage African newcomer women in maternalmental health research.In-depth discussion of recruitment strategies, used in aqualitative descriptive study conducted with Black Africannewcomer mothers in Canada.Ten African newcomer mothers were successfully recruited usingrecruitment strategies such as engagement with religiousorganizations, snowballing, and the use of social media.Cultural beliefs on motherhood, resilience, and mental illness mayaccount for hesitancy to engage in maternal mental healthresearch. Recruitment strategies could help overcome thechallenges and potentially diversify maternal mental healthresearch in Canada through the engagement of African newcomermothers. Approximately 23% of new mothers in Canada experience symptoms of mentalunwellness after birth . SeveralResearch that includes societal and ethnic diversity is essential to gain afull understanding of individuals\u2019 experience of mental health issues and toinform health services and mental health programs . Canada\u2019Mental illness stigma is a significant factor associated with theunderutilization of mental health services among populations of Africandescent . InadequF\u00eate et al. (2019) suggest immigrants, being a vulnerable and hard-to-reachgroup, are under-represented in research. Inadequate representation ofethnic and visible minorities in health research impacts The purpose of this paper is to provide an in-depth discussion of recruitmentstrategies for engaging African newcomer women in maternal mental healthresearch in Canada. First, an overview of African newcomer mothers\u2019hesitancy to participate in maternal mental health research is presented. Aswell, a discussion on how mental illness stigma, intersectionality, and theresilience of African newcomer mothers influence their participation isdiscussed. Finally, recommendations for recruitment strategies to encourageand engage newcomer mothers of African descent in maternal mental healthresearch are outlined. The exposition from this paper seeks to informmaternal mental health researchers on engaging newcomer mothers of Africandescent in Canada in future research activities.The discussion stems from results of a qualitative descriptive study to explorethe sociocultural determinants of the perception of mental health and mentalhealth services utilization among 10 Black African newcomer women in Canadawho had given birth within the past year .NewcomeResilience, among African mothers in Rwanda, promotes maternal mentalwell-being and is fostered by the community because of the collectivistculture . Thus, tThere is an urgent demand for culturally competent health care professionalsand increased public awareness of maternal mental health throughout theperinatal period among this group . The recAfrican immigrant women are less likely to utilize mental health servicesdue to their cultural beliefs that mental stress during motherhood isa sign of weakness . In CanaThere are several challenges to successful recruitment and participationof Black African women in conducting mental health research. Findingsof systematic literature review revealedRevealing barriers and facilitators of mental health and serviceutilization by African newcomer women are important to improveinteractions with African newcomer mothers in maternal mental healthresearch. Stigma and cultural beliefs on mental illness during thematernal period are barriers to mental health utilization among thewomen while, awareness, partner support, spirituality, healtheducation, and anonymized services act as facilitators . UnderstAccording to In the recruitment and engagement of Black African newcomer women inmaternal mental health research, researchers need to draw on thecommonalities they share as well as acknowledge and be thoughtful oftheir diverse backgrounds/experiences and worldviews to create arespectful and culturally safe space for trust building and meaningfulresearch. Several strategies were used to invite women to participate in theabovementioned qualitative study. Posters with details about the studyand contact information for interested women were displayed on thebulletin boards of churches of primarily congregants of Africandescent. Similarly, The first author attends a Black church and was a student member of anorganization that offers support and provides access to resourcesappropriate for African immigrants in the local community. As a memberof an African immigrant organization, she consulted the executives ofthe organization as part of the recruitment strategy. She builtrapport by sending e-mails, making phone calls and/or scheduling inperson meetings with potential gatekeepers in churches who also spokewith other gatekeepers in various cities in Southern Ontario .Posters advertising the study were also displayed in hair salons offeringhair services to Black clientele. The digital poster was circulated onWhatsApp group pages whose membership included recent immigrant women.Administrators of social media pages were contacted for their consentto share the posters on their social media group pages. Similarly,Snowballing was another effective recruitment strategy, whereparticipants engaged with other newcomer women in their social networkby informing them about the study and advertising the research to gaincommunity support. The researchers verbally communicated details onthe study to these potential participants if contacted. Many of thewomen were recruited through casual conversations about the studyamong newcomer mothers. The use of casual conversations as arecruitment and engagement strategy when conducting sensitive researchwith populations of African descent has been successful in the UnitedStates . Inthe Unexpected challenges occurred during the initial stages of recruitmentwomen to our study. Cultural nuances in language and negativeinterpretation and stigma linked to the word \u201cmental health/illness\u201dcreated a barrier to recruitment. We amended the language used inadvertising the study and in our conversations with Black Africannewcomer women. We substituted \u201cmental illness\u201d with \u201cmental stress,stress, and emotional stress.\u201d In addition, emotional well-being andfeelings after childbirth were used, as the women did not equatemental illness as something new mothers would experience. Thisamendment improved participation in the study and confirms findingsfrom Our study suggests that intersectionality of gender, race/ethnicity,culture, stigmatization of mental illness, and mental strengthcontributed to the Black African newcomer mother\u2019s hesitancy toparticipate in maternal mental health research. Intersectionality,first devised by Kimberle Crenshaw, originates from Black feminism andacknowledges the impact of multiple social identities on healthinequities . For insThe SBW schema is a phenomenon to describe Black women\u2019s reliance onmental strength and their censoring of symptoms of mental illness tosatisfy cultural and societal beliefs of motherhood and overcomingstress, thus affecting their willingness to use maternal mental healthservices . TheSBWImmigrant mothers of African descent in the United Kingdom believedmaternal mental stress can be treated by spirituality, social support,and bonding with baby, and downplayed symptoms of postpartum mentalunwellness because of associated stigma . ThewomIntersectionality and health-related stigma affect populations uniquelybased on their marginalized social identities .AccordiThere are several hurdles to the recruitment and engagement of newcomer mothersof African descent in maternal mental health research. Influential factorssuch as the intersection of gender, race/ethnicity and culture, resilience,and mental health stigma may add to the hesitancy of African newcomer womento participate in maternal mental health research. Recruitment strategiessuch as engaging Black churches and hair salons, using snowballing andinformal conversations, and the considerations of the cultural nuances oflanguage are effective in improving research participation by thispopulation. An increase in participation of African newcomer women inmaternal mental health research would lead to more representation and thediversification of literature. Such research would in turn translate toinforming equitable health policies and programs, and the provision ofculturally safe health care."} +{"text": "Recent advances in our understanding of cancer, driven mainly by the emergence of new technologies have highlighted that heterogeneity shapes not only the genetic profile of tumors but also their epigenetic and gene expression profile. Moreover, the emerging picture supports a view of cancer which goes beyond the genome of tumor cells and emphasizes the level of cell-tissue interface. In this framework, communication between different tumor subclones as well as between tumor subclones and stroma cells plays a crucial role in tumor evolution. Deregulated epigenome and altered gene expression in tumor subclones generate different cellular states and increase the phenotypic plasticity of cancer cells. During tumor evolution, this plasticity promotes adaptation to selection pressures driven by different factors such as the immune system, mechanical stress, metabolic and oxygen supply stress, and drug treatment . In thisVariability in the genetic context of tumor cells is a major mechanism of resistance to therapy and cancer recurrence. Siraj and colleagues profiled approximately 200 colorectal tumors by whole exome sequencing, that were either therapy-naive primary, treated primary or metastases. This approach revealed how genetic diversity affected therapy outcome, and conversely how therapy affected genetic diversity in the primary tumors and metastases. Among other findings, they identified actionable mutations in primary tumors and metastases that could improve clinical outcome . Kanaki Heterogeneity in gene expression can influence the extracellular environment and alter metastatic potential. Gant and colleagues used Second Harmonic Generation (SHG) microscopy, machine learning and mass spectrometry to examine collagen architecture in high grade serous ovarian cancer (HGSOC). Their methodology uncovered differential collagen isoform expression during disease progression that is associated with changes in the collagen fiber and extracellular matrix (ECM) morphology . In breaCancer cells can adapt their metabolism to stress based on their genetic background. This type of metabolic plasticity is associated with heterogeneity and resistance to treatment. Interestingly, Mostazo and colleagues identified a link between metabolic plasticity and resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) . TKI-resThe TME is rich in various types of immune and stroma cells that interact with the tumor and influence its progression and response. The advancements in cancer immunotherapy have underscored the importance of innate immunity for therapy. HNSCC tumors are characterized by inflammation and immune cell infiltration. Economopoulou and colleagues review how HNSCC tumor cells interact with other TME cell populations to escape the immune system, as well as the ongoing efforts to improve response to therapy by stimulation of immune cells through immunotherapy and antiangiogenics .Signals from the TME influence cancer cell biology in a localized manner and thus promote tumor heterogeneity. Brunn and colleagues found a novel link between the interferon inducible gene IRF9 and increased tumor growth and metastasis in lung adenocarcinoma cell lines through transcriptional regulation of the ECM protein versican (VCAN) . Novotn\u00fdBiomarkers provide valuable prognostic information and can guide clinical course of action. Moreover, the identification and characterization of biomarkers can improve our appreciation of tumor heterogeneity and guide therapy. In this issue, several novel types of biomarkers were reported. Zavridou and colleagues profiled circulating tumor cells (CTCs) and exosomes in metastatic castration resistant pancreatic cancer (mCRPC) patients for biomarkers that can inform clinical management . They identified significant associations of worse overall survival with gene expression in CTCs and with DNA methylation in exosomes . Recent Heterogeneity presents a major obstacle for the treatment of most types of cancer. Shlyakhtina and colleagues reviewed current literature on models of clonal evolution during cancer development . Their wIn conclusion, this special issue includes a wide collection of publications that present novel methodologies, findings and perspectives that contribute to our understanding of tumor heterogeneity. Highlights include development of new models and tools for tumor studies, discovery of genetic interactions and biomarkers and thought-provoking insights on future therapeutic avenues."} +{"text": "Research on intergenerational connections is wide ranging, highlighting the various ways that people from across the life course interact for mutual and community benefit. Intergenerational connections occur through both formal and informal means. Studies have shown that intergenerational connections can lead to an assortment of physical, social, psychological, and interpersonal health and well-being outcomes for younger and older people alike. This symposium will highlight the breadth of research on intergenerational connections, bringing together scholars who have used primary and secondary data to better measure, understand, and support them. The first presentation will report the results of a randomized controlled trial in Tarrant County, Texas that trained college students to connect with older adults experiencing cognitive impairment through reminiscence and digital storytelling. The second presentation will describe how intergenerational transfers of emotional and instrumental support relate to self-rated health among older Chinese adults living in Honolulu while considering the roles of gender and resilience. The third presentation will address an important question within intergenerational scholarship\u2014how to measure intergenerational connections\u2014by reporting the results of the newly developed and validated Intergenerational Contact survey among an online sample of younger and older adults. The fourth presentation will describe the pilot-year evaluation of the Gen2Gen Innovation Fellowship, a cohort model that supports and connects leaders of intergenerational initiatives throughout the U.S. To conclude, our discussant will place these diverse studies into context and note places for continued innovation in intergenerational scholarship to better inform the field."} +{"text": "Hepatitis B infection is an important problem in immune suppressed patients. Anti HbcAb is an important marker that shows past exposure to virus. In this study, we retrospectively searched HBV serology among the patients who had Bone Marrow Transplantation (BMT) or chemotherapies (CT) at Medicalpark Izmir Hospital Bone Marrow Transplantation Unit; changes in viral parameters throughout therapy; and tried to find the efficiency of antiviral prophylaxis.We retrospectively evaluated the viral parameters; HbsAg, Anti HbsAb, Anti Hbc IgG, HbeAg, Anti Hbe Ab, HBV DNA, HCV RNA which were carried out before BMT and CT. We grouped the patients as latent HBV infection and inactive carriers. Started antiviral treatment as prophylaxis, monitored the changes in serological parameters and defined HBV related situations.A total of 584 patients were evaluated retrospectively. Twenty patients were having latent HBV infection. Ten patients were inactive carriers of HBV. In post-transplant period, the patients were screened for 11 months (1\u201338 months). None of the patients experienced HBV activation during follow period.The best approach in HbcAb positive patients with planned immunosuppressive treatment is the use of anti-viral agents before immune suppression and close monitoring of the patients HBV-related markers. Hbv infection is one of the most widely seen viral infections. About 350 million of people worldwide have the diagnosis of chronic hepatitis BBone marrow transplantation (BMT) has become an important and curative therapy for hematological disorders but also creates a high risk of morbidity and mortality by causing viral reactivation in patients who had met the virus before immune suppressive treatments. The same risk continues with the use of donors who are Anti-Hbc positive. Studies about the mechanism of HBV reactivation after immune suppression points a rebound increase in number of lymphocytes after stopping immune suppression which results in destruction of infected hepatocytes causing hepatitis. Cytokine analysis showed a decrease in CD4-CD25 T-regulatory cell numbers and an increase in antigen specific cytotoxic T-lymphocytes responsible for liver injuryReactivation of HBV can initiate a cascade of events from hepatitis to acute liver failure and death. HBV reactivation may also result in discontinuation of hematological treatment. Proper treatment of HBV infection should be given as early as possible, but there may be problems about the recognition of reactivation since these patients are prone to drug induceliver diseases and other forms of viral hepatitis which can cause delay in diagnosis. The ability of HBV to persist in latent replicative form despite the signs of viral clearance may also cause confusion7In this study, our aim was to evaluate the seroprevalence of HBV among hematology patients, the changes in viral parameters after chemotherapies and bone marrow transplantation and find the efficiency of antiviral prophylaxis given according to the serological parameters.In this study, we retrospectively searched HBV serology among the patients who had BMT or CT between the years 2012 and 2016, at Izmir University of Economics, Medical park Izmir Hospital Bone Marrow Transplantation Unit, changes in viral parameters throughout therapy; and try to find the efficiency of antiviral prophylaxis given according to the serological parameters. We evaluated the viral parameters; HbsAg, Anti HbsAb, Anti Hbc Ab, HbeAg, Anti Hbe Ab and HBV DNA; which are the assays routinely carried out before BMT and CT. These assays take part in pretreatment protocol and are not specific for this study. Among patients with a positive serology for HBV; the ones with the diagnosis of chronic HBV infection who were on antiviral treatment were not included. We grouped the patients as latent HBV infection and inactive carriers and monitored the efficiency of antiviral prophylaxis in these groups. In this study, we also documented changes in liver function tests and searched the signs of HBV activation.Among 584 patients, we observed changes of viral parameters only in 3 patients mentioned above. No viral parameter change has been detected at the remaining.Hepatitis B is a global health problem, affecting 6% of the whole world population with a large regional variation of prevalenceCakar et al reported 5 patients with HBV reactivation and 2 patients with acute hepatitis B among 197 patients who underwent hematopoietic stem cell transplantation. They did not give prophylaxis in patients with anti -Hbc positive and Hbs ag negative patients and observed no HBV reactivation in this groupMikulska et al reported HBV reactivation ratio of 10% in patients who were HbsAg negative but HbcAb positive before allogenic hematopoietic stem cell transplantationIn our study, we continued antiviral prophylaxis up to one year after cessation of immune suppression, and it was effective since we did not observe any patients with HBV reactivation. There are different proposals like the use of antiviral prophylaxis more than 24 monthsIn 3 of our patients, that were HbsAg and anti-hbc negative before BMT, we detected increase in serum ALT levels by routine controls after transplantation. These patients were having acute HBV infection, with Hbsag and anti-HbcIgM positivity. Rapid and effective antiviral treatment enabled us to control the infection. Close monitoring of the patients through elevated ALT levels, which was the warning sign, made us be aware of the problem.Since the serological tests of these 3 patients were negative for HBV before BMT, the only explanation of the situation could be seronegative occult HBV infection either in the donor or in the recipient. Occult HBV (OBI) infection can be defined as the persistence of HBVgenomes in the liver in individuals testing as negative HBsAg and positive / negative anti-HbcIgG.Vaccination of both HBV naive donor and recipient before BMT may decrease the risk of acute HBV infection especially in intermediate and highly endemic regionsAs a conclusion, patients undergoing BMT or CT should be checked for viral serological markers before hematological treatments. It is important to be aware of the complications of HBV in these immune suppressed patients. In our opinion, the best approach in inactive HBV carriers and HbsAg negative, HbcAb positive patients with planned immune suppressive treatment is the use of anti-viral agents before immune suppression. Antiviral treatment is safe and effective in preventing HBV related complications. Our study also showed that serological markers such as HbsAg, Anti Hbs and HbcAb may not be adequate for detection of occult HBV infection. Close monitoring of the patients both by clinical and laboratory parameters is the key point for being aware of complications of HBV."} +{"text": "Hearing loss is a global public health issue with disproportionate negative impacts on those who live in rural regions, such as Appalachia. This commentary provides an overview of hearing health and healthcare disparities in rural regions along with discussion of the significance of recent research findings which highlight the incidence of hearing loss and the shortage of hearing specialists in Appalachia. Journal of Appalachian Health by Pudrith et al.Hearing loss is a major global public health problem. According to the 2021 World Report on Hearing, approximately 1.5 billion people, including adults and children, worldwide have hearing loss.Hearing loss is medical condition that involves multi-specialty hearing healthcare specialists such as otolaryngologists and audiologists and may be managed with a variety of medical, surgical, and technological treatments. The lack of hearing healthcare access, utilization, and affordability continues to play a major role in preventing timely diagnosis and treatment of hearing loss. The inaccessibility and under-utilization of hearing healthcare is amplified in vulnerable populations, such as rural adults. Approximately 20% of the US population reside in rural areas and rural Americans tend to be poorer, less educated, suffer higher rates of disease and disability, and are more likely to be uninsured than their urban counterparts.19Against this backdrop of hearing loss significance and long-standing rural hearing healthcare disparities, this manuscript presents novel findings regarding hearing loss prevalence and audiological disparities in Appalachia. Much of what we know about rural hearing loss prevalence and accessibility to hearing healthcare specialists in rural regions is based on work outside the Unites States or in non-Appalachian regions of the U.S. This manuscript utilizes a combination of population databases to conduct their univariate and multivariate analysis comparing Appalachian regions with non-Appalachian regions. The authors have quantified the higher incidence of subjective hearing loss among Appalachian residents and through their multiple linear regression analyses have presented data that demonstrates that Appalachian residence, apart from rural residence, is independently associated with a higher incidence of hearing loss. Furthermore, their pairwise linear regression data provides us with a deeper understanding of the disparity at hand by quantifing that relationship between rurality, prevalence of hearing loss, and the shortage of audiologists. While we neither understand the causes underlying this health disparity nor the solution to this problem, this study gives us clearly articulated evidence that helps us understand this disparity better. This data pushes us to consider how specialty care can be delivered to vulnerable populations in remote locations. Considerable innovation is needed to address rural and Appalachian hearing health and healthcare disparities. New models and methods for care delivery are needed to explore how to deliver specialty healthcare when there are no or very few specialists nearby. Research related to hearing loss may be less familiar for the readers of this journal; however, I encourage readers to consider the importance of work such as this to define and describe a complex health disparity issue within a resource-limited region such as Appalachia."} +{"text": "Considerable research has examined communication dynamics among family members and staff in nursing homes (NHs) and has demonstrated that better communication is associated with more optimal psychosocial outcomes in both family caregivers and formal care providers. However, the literature on how communication dynamics influence resident functioning is limited, and it has yet to be determined how communication impacts residents across other care contexts, such as Assisted Living Facilities (ALFs). Thus, using data from the National Health and Aging Trends Study and the National Study on Caregiving, the purpose of this study was to examine family perceptions of communication with formal care providers and its influence on resident outcomes in two samples of long-term care residents and their family caregivers, and to compare how results differ across care setting. When examining the full sample of long-term care residents, findings showed that better communication was associated with lower depressive symptoms and negative affect. When investigating differences across care settings, we found that those residing in NHs exhibited higher levels of depressive and anxiety symptoms compared to ALF residents. Further, better communication was associated with lower levels of depressive symptoms only among ALF residents. Our findings provide insights into how interpersonal dynamics between family and formal care providers influence resident functioning and underscores the importance of enhanced communication among all members of the primary care team \u2013 that is, healthcare providers, residents, and their family members."} +{"text": "Total annual costs of crime in England and Wales is estimated at \u00a350bn.The age-crime curve indicates that criminal behavioural peaks in adolescence and decreases in adulthood. Life-course persistent offenders begin to behave antisocially early in childhood and continue this behaviour into adulthood. By contrast, adolescent-limited offenders exhibit most of their antisocial behaviour during adolescence, with a minority continuing to offend into adulthood. However, evidence suggests that this curve conceals distinct developmental trajectories. Prospective cohort study data has highlighted distinct risk factors for these offending trajectories, but this research is limited because of small sample sizes for disadvantaged groups, selection bias and infrequency of data collection.The current study began in February 2022 and is one of the first to use UK linked national crime and education records. The aim is to: (1) establish the offending trajectories of individuals between the ages of 10 and 32 years following their first recorded conviction or caution using national crime records; and (2) develop prediction models of these offending trajectories using administrative education and social care data.In my talk, I will share findings on the offending trajectories identified and present some early results on the key education and social care drivers of the offending trajectories.Findings from the project have the potential to identify previously unknown, or confirm lesser known, offending trajectories using real world data based on the UK population. It may also lead to the detection of previously unknown risk or protective factors for offending, which has implications for early intervention and could help inform criminal justice system responses to early antisocial behaviour."} +{"text": "Drawing from the Conservation of Resources Theory, we aim to understand the implications of loneliness on psychological resources and cognitive health in later life. This study utilizes data (2006-2018) from the Health and Retirement Study to examine pathways, both direct and indirect through psychological resilience and purpose in life, from loneliness to cognitive trajectories over time. Respondents reporting higher levels of loneliness had worse initial cognitive function and accelerated cognitive decline . Feeling lonely is associated with reduced resilience and purposed in life which, in turn, are associated with worse cognitive health. Finally, pathway analyses confirm that loneliness is indirectly associated with initial cognitive health and accelerated cognitive decline through deteriorating phycological resources. Positive psychological interventions can be beneficial by promoting resilience and purpose in life and subsequently improve cognitive health."} +{"text": "The development and translation of regenerative medicine approaches for the treatment of hypoplastic left heart syndrome (HLHS) provides a promising alternative to the current standard of care. We review the strategies that have been pursued to date and those that hold the greatest promise in moving forward. Significant challenges remain. Continued scientific advances and technological breakthroughs will be required if we are to translate this technology to the clinic and move from palliative to curative treatment. Hypoplastic Left Heart Syndrome (HLHS) is a critical congenital cardiac anomaly defined by a hypoplastic left ventricle, mitral and aortic valve stenosis/atresia, and a diminutive ascending aorta . It is gRegenerative medicine is a multidisciplinary endeavor that attempts to leverage our cells\u2019 innate capacity to multiply and self-organize into functional units or neotissues. The resulting neotissues can be used to surgically repair or replace tissues that are either diseased, damaged, or congenitally absent. Since its inception, regenerative medicine has held promise for advancing the field of congenital heart surgery under the premise that regenerative medicine techniques could be used to create autologous cardiovascular neotissues, which, in turn, could be used to repair or replace malformed or congenitally absent tissues such as those associated with HLHS . While some promising early preclinical studies highlighted the potential to use tissue-engineering methods to create cardiovascular patches, vascular conduits, and replacement heart valves, the development and translation of this technology to the clinic have been slow . The firMore recently, results of clinical trials evaluating the use of autologous tissue-engineered constructs developed using either cell-seeded or unseeded scaffolds, which provide sites for cell attachment and space for neotissue formation while also serving as a template to direct neotissue formation, have moved beyond being the first in human studies, and into late-stage clinical trials in Europe and the United States ,10. FurtFinally, the creation of living neotissues with growth capacity enables the avoidance of somatic overgrowth, a significant concern in all major congenital heart operations, especially in those performed in the newborn period . Recent In vivo cell-based therapies to regenerate damaged myocardial tissue in response to myocardial ischemia have generated significant interest in preclinical and clinical studies . VariablThe general treatment paradigm promotes favorable right ventricular remodeling, which structurally and functionally did not evolve to support the systemic circulation and must function within the foreign hemodynamic environment of Fontan palliation and multiple prior exposures cardiopulmonary bypass and cardioplegia through staged surgical palliation. Similar to the adult experience, only modest improvements in ventricular function and size have been demonstrated ,20. FutuOne potential method for the treatment and prevention of HLHS includes transcatheter fetal intervention with the delivery of current scaffold-based tissue-engineering techniques described above to leverage the unique features of the fetal environment. Early clinical fetal valvuloplasty studies demonstrated that approximately one-third of patients with severe midgestational aortic stenosis that are at risk for progression to hypoplastic left heart syndrome (HLHS) could be converted to biventricular anatomy by performing fetal aortic valvuloplasty, thus restoring flow through the left ventricle and preventing the left ventricular hypoplasia . BuildinThe holy grail of regenerative medicine strategies applied to patients born with HLHS or patients with HLHS and Fontan failure includes the creation of autologous pulsatile cardiac tissue to supplement the diminutive left ventricle and autologous replacement donor hearts.Early preclinical studies using decellularization-recellularization tissue-engineering methods demonstrated the concept of using regenerative medicine techniques to create whole organs, including the heart . When coWhile the promise of iPSC methods for creating autologous cells for regenerative medicine applications is great, so too are its complexities. Fundamental biological questions such as which cell types are required to make functional pulsatile cardiac tissues of adequate purity that will stably integrate into the host remain to be answered . SuccessDeveloping strategies to directly connect or enable inosculation into the host vasculature are also areas of focus and advancement. The application of bioprinting coupled with advancements in bioreactors have demonstrated promise in early preclinical studies for assembling, maturing, and preserving these tissue-engineered constructs before implantation but is at an early stage of development ,30. SignContinued scientific advances and technological breakthroughs will be required if we are to move beyond the palliative and towards curative treatments for critical cardiac anomalies. The development and translation of regenerative medicine approaches for the treatment of HLHS provides a promising potential approach towards achieving this goal, but significant challenges and enormous amounts of research will be required if we pursue this approach. We recently celebrated the 50th anniversary of the first successful heart transplant, an amazing feat built upon a half-century of research . Where w"} +{"text": "Exercise priming is a novel concept that utilizes the neural stimulating effects of physical exercise to assist with learning, memory, and skill retention of a task. In clinical practice, a bout of exercise performed in close proximity (either before or after) to behavioral treatment may improve an individual's ability to retain the information learned in therapy. For example, the partnership of exercise with treatment for depression and anxiety has been shown to be more effective at improving symptoms than treatment alone and vascular endothelial growth factor (VEGF). In addition, neuroendocrine responses to exercise may help to explain the exercise priming effect. Specifically, catecholamines released during short duration bouts of exercise have been shown to promote arousal and attention. Evidence also suggests that exercise-induced release of cortisol via activation of the hypothalamic-pituitary-adrenal (HPA) axis improves learning and memory. In this Research Topic, we invited scientists to further explain and comment on the mechanisms of exercise priming along with analyzing the potential benefits of exercise priming in learning scenarios. We have summarized and discussed the major findings and application aspect of each article below.Wunder and Staines used event-related potentials (ERPs) extracted from electroencephalography to compare cortical activity associated with \u201cresponse conflict\u201d in individuals reporting high and low levels of physical activity. ERPs linked to conflict monitoring, error processing, and attentional resource allocation were examined during performance of a modified flanker task with varying degrees of response conflict. Notably, highly active participants demonstrated modulation of performance and ERPs corresponding to the degree of conflict provided in flanker task trials. Similar modulations based on the degree of response conflict were not observed in participants reporting low physical activity levels. The authors suggest that highly active individuals may demonstrate greater adaptability of cognitive control compared to those performing low levels of physical activity. Future work may consider whether and how habitual physical activity affects cortical activity that supports cognitive function.Cognitive control includes the ability to monitor actions and suppress those that may be undesirable. Moriarty et al. investigated the effect of either acute moderate or high intensity aerobic exercise on piano performance among university music majors; and, further aimed to determine if performance was linked to exercise-induced activation changes within the primary motor cortex (M1) using functional near infrared spectroscopy (fNIRS) techniques. Piano performance scores were higher after 15 min of moderate intensity cycling exercise compared to a sedentary control trial, but not after 15 min of intense exercise. They further reported a significant linear relationship between post-exercise M1 activation and piano performance, which highlights neural activation as a possible mechanism explaining the exercise priming effect. The authors note that moderate intensity may be a more effective approach if the goal of exercise priming is to improve performance of a motor skill activity. This was further demonstrated by the report of a negative relationship between exercise heart rate during intense exercise and piano performance outcomes. The creative work of Moriarty et al. demonstrates that brief moderate intensity exercise may be more suitable for improving motor skill tasks. Limitations include a small sample size and not controlling for exercise workloads between exercise trials. This work is a small step forward in understanding the influence of exercise on cognitive demanding tasks, and future work should continue to explore the utility of various exercise modalities and intensities on various types of cognitive tasks.As previously discussed, exercise priming is the partnership between exercise and performance on a cognitive demanding task. Hendy et al. extend prior research to the sedentary population. Using a randomized cross-over study design, transcranial magnetic stimulation was delivered and venous blood samples collected from sedentary young adults before and after a 20 min bout of high-intensity interval training (HIIT) on a stationary leg cycle or a period of rest. HIIT increased corticospinal excitability and decreased motor cortical inhibition, similar to past reports, but did not change systemic concentration of neurotrophic factors. The authors speculate that the cortical changes may support motor outcomes if HIIT were paired with motor practice. A priority for future research will be to translate such work into real-world motor learning applications.Past work indicates that high-intensity interval leg cycling increases facilitation and reduces inhibition in motor cortex circuits projecting to non-exercised muscles of the hand (Singh et al., Pickersgill et al. reviewed the intersections of exercise, diet, and sleep patterns on neuroplasticity. They discuss the neurophysiological mechanisms underlying exercise priming and suggest that a combination of aerobic and resistance exercise may be superior to either form of exercise alone for upregulating biomarkers of neuroplasticity (Marinus et al., Manuscript conceptualization, original draft preparations, and revisions were completed by AS, MZ, and CM. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Resilience is the adaptation of bouncing back from adverse life events. Older adults provide rich and varied resilience narratives of personal growth across the life course, especially related to others. Many people describe resilience as part of their identity, formed in childhood and maintained throughout adulthood. As adults age, they continually integrate new information into their identity, and aging presents long-term adversity and new life course challenges that older people must navigate. This qualitative study explored how older adults describe their sense of resilient identity compared to their younger selves and other older adults in their lives. Our narrative findings indicate resilience narratives often include comparative appraisals to the strengths and weaknesses of younger selves . Additionally, our findings show older adults comparing their resilience to others in a similar age category . Comparisons to other older adults fit two themes: empathic and connected and judgmental and distanced. We conclude the participants who view other older adults in an empathic and connected way maintained solid social connections and a general sense of interconnectedness, while those in the judgmental and distanced category might be reacting to internalized ageism. The social implications of these findings will be discussed in detail. In addition to specific examples, our study also provides limitations and future directions in resilient identity and resilience appraisals."} +{"text": "Background: The obturator artery (OA) often presents multiple anatomical variations. These can be an atypical origin, variable anastomosis, or abnormal course within the pelvis. Methods: This study aimed to report a rare arterial variation in a Puerto Rican female cadaver that showed two abnormal obturator arteries with multiple pelvic branches. The OA emerged from the anterior branch of the internal iliac artery, which typically runs anteroinferior along the lateral wall of the pelvis to the upper part of the obturator foramen. Results: The atypical OA described in this report provided two variant branches. Abnormal obturator artery I (AOAI) emerged first and gave rise to three additional branches, while abnormal obturator artery II (AOAII) emerged second and gave rise to two other branches. Conclusions: Identifying these accessory arteries is essential for surgical interventions, particularly within the field of gynecology and urogynecology. Knowledge regarding anatomical variations within this region must be assessed preoperatively to decrease the risk of iatrogenic injury. The vascular distribution of the obturator artery (OA) is crucial during surgical interventions within the pelvis, such as those involving femoral hernias . The latThe OA is a parietal pelvic branch of the anterior division that runs anterior-inferiorly on the lateral pelvic wall . Before Variations regarding the OA are of clinical importance and of consideration for gynecological and urological procedures. Unawareness of such variation could lead to iatrogenic injuries during surgical procedures. For instance, one of the most important causes to consider is major obstetric hemorrhages as one of the main causes of maternal mortality . Major hEmbryologically, variations of the OA have been hypothesized to be due to an unusual selection of channels from a primary capillary plexus that establishes the final arterial pattern ,10. AwarDuring a gross cadaveric dissection session, an anatomical variation was found in an elderly adult female cadaver with proliferous pelvic branching prior to exiting the pelvic cavity through the obturator foramen . The cliFemale pelvic cavity dissection was performed following Grant\u2019s Dissector. After complete visualization of the pelvic viscera and adnexa, they were removed. The pelvis was sectioned in the midline to proceed with the study of the hemipelves. Upon visualization of the common iliac artery (CIA), pelvic vascular components were evaluated. Examination of the right hemipelvis showed an external (EIA) and internal iliac artery (IIA) following their respective courses. After coursing over the pelvic brim, the IIA was divided into an anterior and posterior division , with thThe OA has been well documented to present significant anatomical variability. The atypical origins of OA variations have been extensively described and correlated to hemorrhagic risks in surgeries involving the pelvis ,21,22,23The embryological basis for abnormalities in the arterial patterns of IIA vessels is theorized to be the result of an unusual selection of channels from a primary capillary plexus ,9,10. ThWhile the embryological basis for OA anatomical variations of origin and anastomoses can explain the patterns observed, we propose that AOAI and AOAII could be the result of the development of collateral branches to fulfill the demand of pelvic structures, insufficiently supplied by other vessels. These inadequate IIA system vessels may have underlying vascular pathologies associated with aging.Anatomical variations in the pelvic blood supply are common ,18,19,20The dissection of the vesicovaginal space exposes the cranial and caudal portion of the vesico-uterine ligament, allowing the exposure of vessels and nerves, described by Fujii . Based oAnatomically variant branches can also be at risk during other urogynecological procedures for vaginal wall descent, uterovaginal prolapse, and neovaginal reconstruction . TensionThese variants could be also at risk during gynecologic oncology procedures, such as lymphadenectomy in the obturator and external iliac region. Identification of obturator artery vascular variations in the pelvic region has multiple surgical applications in gynecology and should be considered during the preoperative course. Proper identification of these vascular abnormalities can decrease the risk of intraoperative complications such as hemorrhage. Bilateral internal iliac artery (IIA) ligation is a life-saving procedure which significantly reduces the pulse pressure and rate of blow flow caused by a hemorrhage, subsequently allowing effective thrombosis within small bleeding vessels, such as the OA . After lPelvic surgeons should be aware of the anatomical variations regarding the IIA branching pattern while performing procedures such as the ones discussed in the reported study. This will potentially reduce the risk of iatrogenic injuries and subsequent long-term complications. Tracing along the neurovascular bundle within the obturator foramen is an anatomic landmark that indicates an adequate inferior dissection and the course of the neurovascular bundle in the preperitoneal space.Among the limitations of the presented case was the unavailability of clinical and family history, as well as the cause of death.We report for the first time an abnormal OA with proliferous pelvic branching before exiting the pelvic cavity through the obturator foramen. Halfway through its course, within the lateral pelvic wall, two abnormal branches were identified, AOAI and AOAII. AOAI was further subdivided into three small branches, while AOAII was subdivided into two small branches. Based on the anatomical position of these lateral branches, we suggest they might be anastomosing with external iliac arteries, thereby providing collateral circulation.Currently, no extensive reports have focused on the obturator vasculature variants in the elderly female population. Advancing age and predisposing vascular pathologies may be responsible for the development of collateral vessels, such as the ones previously reported, contributing to the OA findings in this population.Furthermore, clinical anatomy studies of pelvic vasculature among this population are strongly encouraged to advance pubic surgical procedures, such as internal fixation of pubic fracture, an inguinal hernia repair, or other gynecologic interventions discussed in the reported study, in order to prevent adverse surgical outcomes among patients."} +{"text": "Care partners play a critical role in caring for an increasingly complex, aging population in the United States after hospital discharge. However, care partners\u2019 preferences and needs are often not formally assessed during their loved one\u2019s hospitalization. The Care Partner Hospital Assessment Tool (CHAT) is a standardized decision-support tool that facilitates the inclusion and training of care partners during hospital care. The purpose of this exploratory descriptive study was to understand the preferences and needs of 12 care partners of older adult patients admitted to a large academic hospital utilizing the CHAT. The majority (8 of 12) of care partners surveyed were spouses while the remainder were adult children of the patients. All care partners provided comparable support including physical and social support as well as healthcare management. Despite providing similar support, there were differences in the care preferences and needs of spouses compared to adult children. A greater proportion of spouses preferred to be present for care in the hospital and requested information on adaptive equipment and community services. All adult children desired access to the electronic medical record while there was a mixed response among spouses. The most common needs across care partners included training on mobility assistance and medical devices. Findings from this study demonstrate that care partners have varying preferences and training needs during hospital care and suggest differences across care partner relationships. Further investigation is necessary to better understand these patterns and improve hospital care for patients and their care partners."} +{"text": "Wound healing and prevention of chronic wounds are challenging issues in public health. Chronic wounds often result from pressure ulcers/injuries, diabetic foot ulcers, and skin breakdown of the residual limb in the case of limb deficiency. Pressure ulcers occur in people with limited mobility and impaired sensation, such as people with spinal cord injury, Alzheimer disease, and Parkinson disease . DiabetiWounds are thought to result from prolonged, repetitive mechanical loads which may be either compressive or shear forces. The current clinical practice emphasizes the decrease of mechanical loads by providing support surfaces to relieve points of high interface pressure between the device and the soft tissues of the individual. However, interface pressure alone does not fully describe the risk of wound development and thus preventive and treatment interventions based on this principle may not be fully effective . In addiRankin et al. used a high-velocity environmental debris in an animal cadaveric model to study mechanisms of traumatic amputation due to blast injury. The authors showed that high velocity sand blast is an independent mechanism of injury causing traumatic amputation. Kelly et al. explored the use of forefoot computational models from people with rheumatic arthritis (RA) to predict patient outcomes. Their magnetic resonance based models showed promise on predicting real life events in people with RA. Wang et al. performed a thermal analysis to predict blood flow of a foot using a vessel-porous media model and demonstrated exciting findings using thermal analysis to predict blood flow in 31 diabetic patients. These models allow for better understanding of the mechanisms of wound development and personalized prediction of outcomes.Computational and theoretical models can provide new insights on the development of wounds as well as optimization of the current clinical interventions. Roberts et al. showed a novel application of using low intensity vibration to improve angiogenesis and wound healing in diabetic mice. Ren et al. explored whether weight-bearing exercise increases risk for diabetic foot ulcers. The authors compared plantar microvascular function and tissue hardness in 80 participants with different volumes of weight bearing exercise. Their study demonstrated that higher volumes of exercise are associated with better microvascular function and lower plantar tissue hardness in people with type 2 diabetes. Duan et al. investigated the relationship between plantar tissue hardness and peak plantar pressure and pressure-time integral in people with and without Diabetic Peripheral Neuropathy. They provide evidence of the effect of soft tissue hardness on plantar pressure patterns.Theoretically, a single mechanical overload can cause soft tissue damage, while repetitive sub-maximal mechanical loads can trigger adaptation . The adaSonenblum et al. explored the relationship between adipose characteristics and pressure injury history in 43 wheelchair users. The adipose characteristics were obtained from MRI in a seated posture. The authors demonstrated that wheelchair users with a history of pressure injury had different subcutaneous fat characteristics than wheelchair users without a history of pressure injury. Similar to the findings of Duan et al., tissue properties, specifically intramuscular adipose, varied with years since injury or long term exposure to load. Qian et al. investigated the role of morphology and mechanical properties of plantar fascia in flexible flatfoot and plantar injury using B-mode and elastographic ultrasound. Another study conducted by Choi et al. used an optical coherence tomography-based air-jet indentation system to investigate the correlation between the indentation stiffness and type I collagen abundance, and organization of a wound in diabetic rats. Their study showed evidence of the relationship between indentation stiffness and collagen content of a diabetic wound.Different patient populations and different sites of soft tissues can demonstrate very different structures, properties, and hence stress-strain relationships that respond differently to mechanical loads. Furthermore, the current understanding of soft tissue biomechanics is based primarily on the behavior of ligaments, tendons, and muscles under tension rather than on the mechanics of bulk soft tissue under compression. Balasubramanian et al. reviewed skin blood flow in response to occlusion, pressure and temperature with the intention to establish the link between impaired skin perfusion and the development process of diabetic foot ulcers. Yeh et al. explored the use of cross-correlation and chaotic analyses of blood pressure and blood flow velocity to predict cardiovascular dysfunction and stroke. Their results show promise of using cardiovascular dynamics for early detection of cardiovascular related diseases.Assessing microvascular networks embedded in the soft tissues can be used to evaluate risk for ischemic injury and wounds . BalasubIt is evident from the articles in this research topic that biomechanical properties of soft tissues, including microvasculature embedded in soft tissues, affect the risk of developing pressure injury as well as wound healing. It is imperative to assess the changes of soft tissue in various pathological conditions as well as microvasculature in addition to traditional risk assessments, such as interface pressure. Mechanical stimulations show promise on promoting wound healing and decreasing plantar tissue stiffness associated with diabetes. More studies will be needed in order to translate these findings into clinical practice."} +{"text": "Motor vehicle crashes are a leading cause of injury and death for older adults in the United States. Braking reaction time (BRT), how quickly a driver responds to the situational demands of driving, is a known predictor of driver fitness and hypothesized as sensitive to difficulties with executive functioning. Unclear is how BRT may vary across different levels of executive functioning, including objective test performance and perceived executive dysfunction, and if awareness of executive dysfunction in the presence of objective difficulties jointly predicts BRT. Using data from a simulated driving study, 50 adults aged 65-94 years old completed computerized EF tests , the Behavior Rating Inventory of Executive Function, the Big Five Inventory, and a simulated drive. Multilevel modeling analyses controlling for covariates of empirical and design relevance were performed. Our results show a significant interaction between perceived executive dysfunction and objective test performance on BRT. Specifically, associations with BRT were stronger for individuals who perceived more executive dysfunction in the presence of worse inhibition and worse working memory . Findings provide further justification for the role of executive functioning in monitoring driver fitness in older age. Future directions and implications are discussed."} +{"text": "Crucial to understanding the aging process is to identify modifiable characteristics that can be targeted in hope of optimizing health across adulthood. This symposium brings together a diverse set of talks about the biopsychosocial and behavioral processes that influence aging outcomes. Turiano used a national sample to demonstrate that individuals with higher levels of neuroticism often use food to cope with stressors which ultimately results in a greater central adiposity and elevated glycated hemoglobin. Zavala used an epidemiological sample of long-banked frozen blood samples to successfully extract DNA and methylation biomarkers from 140 adults and found that stress measures are associated with accelerated biological aging. Luo used coordinated analysis to explore how correlations between personality traits and four health outcomes fluctuate over time, and found the associations between personality (level/change) and health increased in strength through middle adulthood and early stage of late adulthood but weakened in very old age. Jackson found that individuals who experienced high and increasing loneliness in older adulthood had worse cognitive function and steeper cognitive decline than expected given their observed post-mortem neuropathology . Lastly, Pfund investigated how personality and social support change together and found within and between person associations between personality and social support, and evidence that retirement was associated with an increase in social support. In sum, this symposium presents novel evidence for the associations among personality, stress, social support, and lonliness are associated with physical and cognitive health in old age."} +{"text": "Facing the COVID-19 pandemic, individuals are experiencing severe mental distress. Following social distancing and economic insecurity, significant increases in mental health concerns have developed.The aims of this study was to report the levels of depressive and anxiety within active population in Romania, and to identify possible risk and protective factors for mental health.Data collection occurred between February-March 2021. The online survey included questions regarding socio-demographic characteristics and Hospital Anxiety and Depression Scale (HADS). 620 responses were validated (331 students and 289 workers).Among active population, risk of anxiety symptoms is lower in those who already were infected with SARS-Cov2 , while positive screening for anxiety or depression in this study was statistically significant associated with younger age and female gender . Even though anxiety and depression scores are similar among students and employees, there are different aspects regarding symptomatology between these two groups. Students have experienced more frequently tendency to worry and sudden feelings of panic . Also, their ability to laugh and see the funny side of things is affected and they feel less enthusiasm about future . Participants living with someone else scored lower on anxiety and depression subscales and those are not influenced by the person with whom they are cohabitating or residing .Findings from the current study offer initial insights into the rates of anxiety and depression within active population in Romania, one year after the onset of the COVID-19 pandemic.No significant relationships."} +{"text": "The spectrum of suicidal behavior is a core factor of the prognosis and care of Borderline Personality Disorder (BPD).Identify possible BPD specific personality traits that could act as protective factors of nonsuicidal self-injuries (NSSI).We performed a cross-sectional, observational and retrospective study of a sample of 134 BPD patients aged from 18 to 56. We assessed the presence or absence of suicidal behavior and NSSI as well as different sociodemographic variables. Millon, Zuckerman-Kuhlman and Structured Clinical Interview for DSM personality questionnaires were also applied. The analysis of the association between variables was carried out with a multivariate negative binomial logistic regression model.A statistically significant association between NSSI and suicidal behavior was found. Elseways, statistically significant differences were also found in the association between NSSI and the SCID variables for Narcissistic Disorder, which appears as protective variables. These results provide an idea of the dynamic relationship between NSSI and suicidal behavior in a BPD population with particularly severe characteristics.The role of narcissistic personality traits appears to be important in identifying protective factors for NSSI and suicidal behavior in BPD patients and could be the subject of further research projects.No significant relationships."} +{"text": "Chronic infections are prolonged infections not cleared by treatment and become persistent and latent, causing mobility issues and mortality in patients. To date, there is still no drug to tackle chronic infections efficiently in clinical settings. This Research Topic aims to better understand the molecular basis of chronic infections in both host and pathogen, which will facilitate early intervention and targeted therapeutic strategies.With advanced technologies, microbiome studies have moved from 16S rRNA gene studies to complete genome (metagenomics), transcriptome sequencing (meta-transcriptomics), and metabolome and resistome characterization. This Research Topic collects new insights, the latest discoveries to understand the molecular insight and pathogenesis of chronic infections, and advanced methods to better predict and study chronic infections. We have received 10 submissions, six of which were published in this Research Topic, including two original research papers on chronic obstructive pulmonary disease (COPD), one original research paper on chronic periodontitis, one review paper on the pathogenesis of inflammatory bowel syndrome (IBD), and two papers using advanced bioinformatics methods in predicting IBD and protein-protein interactions (PPIs) in chronic infections, respectively.Yang et al. explored the changes in the abundance of microorganisms and the different expression levels of host genes between acute exacerbation COPD (AECOPD) and stable COPD using metagenomic and meta-transcriptomic approaches. This study found that there was no significant difference in sputum transcriptionally active microbiome at every level between AECOPD and stable COPD, but the expression levels of five host genes significantly increased in stable COPD. The five differentially expressed host genes play a part in immune response and inflammatory pathways and may provide a clue to investigate the mechanism of COPD and potential biomarkers in the clinical diagnosis and treatment of COPD.COPD is the third-leading cause of death worldwide, causing 3.23 million deaths in 2019 , bacterial composition, and antibiotic treatment patterns in patients with COPD and Clostridioides difficile infections who had chronic or acute intermittent use of antibiotics and compared them with healthy individuals. This study demonstrated the enrichment of ARGs in antibiotic-affected gut microbiomes and correlated the abundance of resistomes with antibiotic use and gut bacterial diversity.Antibiotics alter the gut microbiome and cause dysbiosis, which leads to antibiotic-resistant organisms. Wei et al. investigated the salivary microbial community and metabolic characteristics in patients with generalized periodontitis and revealed the distinct differences in the salivary microbiome and metabolomics between periodontitis and healthy controls. Striking differences were observed in the composition of salivary metabolites between the aggressive periodontitis and chronic periodontitis groups. It is possible to understand the potential process underlying periodontitis by the integration of microbial and metabolomic data, which may also provide useful biomarkers to monitor the incidence and progress of periodontitis.Periodontitis is the inflammation of periodontal tissue that results from the host's immune response to bacterial infection and can cause alveolar bone resorption from fecal samples using a publicly available database and machine learning models. The predictive capacity was validated in two independent external cohorts containing CD and UC, respectively. Their results demonstrated the strong relationship between the intestinal microbiome and IBD. They also showed that these two subtypes have similar microbial patterns and found genera that play an important and common role in their development.Hu et al. established an efficient Network-based Graphical Probabilistic Model (NGPM) for PPI prediction by integrating Gene Ontology (GO) information about proteins, thus alleviating the negative influence of noise data. They proposed a novel scoring function by combining the membership distributions of proteins with network paths. Experimental results show that NGPM has a promising performance and reveal that the consideration of modularity in PPI networks provides a more flexible way to accurately predict PPIs.Prediction of protein-protein interactions (PPIs) is crucial for understanding the molecular basis of biological processes, such as chronic infections. Finally, we thank all the authors who contributed their original work to our Research Topic and the reviewers for their valuable comments. We would like to express our sincere gratitude to the editorial office of Frontiers in Microbiology, for their excellent support and for providing us with this opportunity to hold this Research Topic successfully.HH and QZ drafted the manuscript. LW revised it. All authors made a direct and intellectual contribution to the work and approved the final version for publication."} +{"text": "Recent literature has addressed the perceptions of individuals with dementia to understand how they experience their illness, with evidence suggesting these perceptions are impactful. Few studies, however, have used a conceptual model to explore different aspects of the illness. One aspect to consider is dyadic relationship strain, or feelings of tension, manipulation, and stress between the individual and caregiver. Little work has addressed this strain from the perspective of the individual with dementia who may have different feelings about the quality of the relationship. Cognition and function are two hallmark symptoms in dementia, however little work has addressed how the perception of these two areas impacts the illness experience. Perceptions of difficulties in these two areas may impact dyadic relationship strain as they necessitate increased care and changes in the relationship. Guided by the Stress Process Model for Individuals with Dementia, this study assessed potential predictors of dyadic relationship strain, finding personal activities of daily living (PADLs) to be impactful. In a multiple regression, PADLS predicted strain above and beyond two measures of cognition: objective cognitive impairment and perceived memory difficulty suggesting that perceived function is impactful for dyadic relationship strain. Because PADLS include more hands-on assistance, the perception of difficulty may create more feelings of embarrassment or stress and impact the perception of relationship strain. Future intervention work may target perceptions of function to improve the dyadic relationship by using techniques such as open communication about difficulties."} +{"text": "The aesthetic indications for this procedure are specifically in the full face patient, providing for a reduction in submalar volume, producing a more tapered angular facial shape following fat removal. This invited video commentary discusses both the indications and limitations of buccal fat removal (Video). Caution of the overuse of buccal fat removal in the older patient is discussed, where buccal fat may accentuate submalar deflation, which is common in this age group. The limitations of buccal fat removal in improving the appearance of the lower cheek and jowl are emphasized.This article"} +{"text": "Impressive advances have been made in new cholera vaccine development and vaccination control strategies. Possible future goals in this field could extend these advances by developing vaccines with higher efficacy and longer duration of protection, particularly in young children and individuals from non-endemic areas. The identification of more vibrio antigens may lead to confirmation of protective immune responses as surrogates of protection, a need arising from evidence that the traditionally monitored vibriocidal response, while paralleling evidence of protection, is not the protective mechanism. Such further developments could overcome current limitations, including the occurrence of cholera outbreaks in war-torn areas in which short-term vaccination programs often prove impracticable.The advances in understanding of cholera immunology, bioecology, vaccine innovation and therapy presented in this series of articles have led to ambitious goals for controlling the incidence and the mortality of cholera, which persists in affected areas. The discussion would not be complete without noting areas not included or given priority in the current goals, but which may prove to be of value for achieving them. First, there is too much talk and too little pressure brought to bear on the need for action to provide safe chlorinated drinking water and sanitary waste disposal to unserved areas. More effort is required to reframe national priorities so that adequate funds for these essential elements of modern public health are provided in both urban and rural environments, along with the educational and motivational components to ensure their effective usage. International standards and regulations governing urban development in the age of global urbanization are esseV. cholerae fail to cause disease in normochlorhydric subjects, it is likely that elimination of tropical hypochlorhydria would greatly reduce cholera incidence in affected areas and potentially make vaccines significantly more protective.Second, insufficient attention has been given to the etiologies and prevention, nutritional and otherwise, of tropical hypochlorhydria , which iThird, far too little research funding has been directed at discovering safe and effective anti-cholera medicines capable of quickly stopping cholera diarrhea. No mass screening of compounds likely to have such efficacy has been undertaken despite an abundance of potential candidates. Recent advances in cholera pathophysiology, such as confirmation of the role of VIP in human cholera , suggestFinally, the continued high cholera case-fatality rates despite established highly effective and widely available treatment modalities demand renewed focus on the gaps preventing therapy from reaching patients."} +{"text": "Arthropod pests are remarkably capable of rapidly adapting to novel forms of environmental stress, including insecticides and climate change. The dynamic interplay between epigenetics and genetics explains the largely unexplored reality underlying rapid climatic adaptation and the development of insecticide resistance in insects. Epigenetic regulation modulates gene expression by methylating DNA and acetylating histones that play an essential role in governing insecticide resistance and adaptation to climate change. This review summarises and discusses the significance of recent advances in epigenetic regulation that facilitate phenotypic plasticity in insects and their symbiotic microbes to cope with selection pressure implied by extensive insecticide applications and climate change. We also discuss how epigenetic changes are passed on to multiple generations through sexual recombination, which remains enigmatic. Finally, we explain how these epigenetic signatures can be utilized to manage insecticide resistance and pest resilience to climate change in Anthropocene. DarwiniIt is not unexpected that climatic changes are altering the physiology, behaviour, abundance, and distribution of many species, given that global temperatures and precipitation patterns are changing quickly and profoundly impact living forms . The genThe ability of arthropod pests to develop resistance to insecticides and manage insect infestations is crucial nowadays, and insecticide expenditures in the world are approximately $40 billion each year . InsectiResistance development is influenced by genetic, ecological, and operational factors, and the pace of insecticide resistance evolution varies significantly between species, yet the literature lacks systematic comparisons across geography and insecticide chemistries between species . AlthougInsecticides and climate change alter insect development, physiology, and inheritance, and recent studies have focused on a link between insecticide and climate change effects on insects and their epigenetic regulations at the molecular level. Epigenetic mechanisms control gene expression without modifying genetic sequences against different stresses and compensatory mechanisms. This review summarises epigenetic changes from insecticide exposure and climate change on arthropod pests.The central idea of modern biology is Charles Darwin\u2019s theory of evolution by natural selection, yet Darwin was unaware of the molecular mechanisms behind this process . A robusNasonia vitripennis, Bombyx mori, and Apis mellifera , and intriguingly, injection of HDAC inhibitors (sodium butyrate) delayed pupation. In addition, in the honeybee A. mellifera, sodium butyrate improved insecticide resistance (imidacloprid and microsporidian) by stimulating the production of immune and detoxification genes , and another miRNA from the fat body was also discovered to influence immunity-related gene translation are non-protein-coding short RNAs (18\u201325\u00a0bp) that can epigenetically upregulate or silence their target genes at the post-transcriptional level through either degradation of the target mRNA or translation inhibition . They prnslation . Bacterinslation . Wolbachlifetime . In addiar miRNA .DNA methylation is one example of an epigenetic process that can be imprinted and passed down to generations . It has https://irac-online.org/) was established to offer the crop protection sector a coordinated response to the problem of insecticide resistance and develop a few agrochemical businesses in Europe and the United States into a much bigger group of companies with global representation and an active presence encompassing corporations from more than 20 countries. IRAC also proactively addressed insecticide resistance management (IRM) by making various informational and educational tools on insect pests, bioassay methods, modes of insecticide action, and resistance management. The Insecticide Mode of Action (MoA) Classification Scheme, established by IRAC, has evolved from a relatively simple acaricide classification begun in 1998 to a significantly broader scheme that currently covers biologics as well as insecticides and acaricides. Since the discovery of insect resistance to insecticides, a growing number of insects have developed resistance to at least one or more of the insecticides available on the market . This is supported by comparisons of genetic studies of host plant adaptation and insecticide resistance and Colorado potato beetle, L. decemlineata, and discovered that CncC regulates genes coding proteins involved in insecticide detoxification and chemical insecticides (Fenitrothion) could be caused via symbiont-mediated processes (Designing novel chemical tools for insecticide resistance management in pest control requires a thorough understanding of the potential epigenetic mechanisms underlying insecticide resistance. Alternatively, the epigenetic system can most likely be used by insect molecular biologists and biochemists as targets for creating new insecticidal compounds . Numerourocesses . HoweverDue to the widespread use of insecticides for insect pest management and unanticipated climate change, ecosystems can serve as excellent research subjects for studying epigenetic regulators of evolutionary and eco-evolutionary studies. However, the development of resistance also brought about conditions that were challenging to manage. More research on the epigenetic regulation underlying climate change and insecticide resistance evolution is needed to corroborate this pattern. Understanding the ecological and evolutionary consequences of insecticide resistance and climate change in arthropods and their symbiotic microbiomes will shed light on the potential effects of insecticides on multitrophic interactions and ecosystem functioning, which could aid in the development of more sustainable pest management methods ; Table 1"} +{"text": "Mining is the upstream activity to the mineral processing, energy exploitation, and metallurgical extraction of desired metals for the production of materials and energy, which is essential for human beings and drilling muds (20%) using the bioaugmentation and phytoremediation techniques. They concluded that greenhouse incubated WDCs (over 120 days) with and without black locust plant (Robinia pseudoacacia) bacterial and fungal consortia in a combination mode could enhance the contaminant removal efficiency compared to natural attenuations.Cockell et al. investigated the possibility of accomplishment of biological mining under extra-terrestrial gravitational conditions in ESA BioRock experiments. They demonstrated the potential use of microorganisms for mining activities and bio-industrial practices, in space locations, with non\u22121\u00d7g gravity. They have stated that same fundamentals are applicable to extra-terrestrial bioremediations and elemental recycling beyond the Earth.Di et al.. The authors screened out a cadmium and antimony tolerant fungus namely, Curvularia coatesiae XK8 from a metallurgical waste (slag) that showed good potential as a biosorbent material to remediate the soil with a removal rate of 67.5%.The heavy metals polluted soil that particularly contains the highly toxic antimony and cadmium has been treated by Hu et al. isolated Pseudomonas mosselii K17 from elution-deposited resources of rare earths located in Longnan county site of China. The strain, with an efficacy of about 95%, was capable to treat residual ammoniacal solution after leaching of rare earths.Ammoniacal-nitrogen contamination is an obstacle for sustainable development of rare earths industries. Chang et al. observed the difference in key microbial clusters, their molecular ecological network, and their interactions under various vegetation restoration models and demonstrated the correlation of diverse vegetation restorations with microbial community diversities. Current work helps to effectively understand about natural restoration of ecosystems for ecologically damaged mining sites.Revegetation is an imperative indicator for restoration of ecosystems of mining area. In this context, We hope that current collection of Research Topic on microbial remediation of the mining legacy will be useful for researchers of relevant domain.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "What life lessons emerge from a group of older Puerto Ricans concerning their experiences with COVID-19. We will review study participants\u2019 reports of how they spent their time during the pandemic, what they found most difficult to cope with, and life lessons they learned as a result. We will use Erickson\u2019s life course theory of psychosocial development to frame their responses to these questions, including the crises (and strengths) of generativity versus stagnation (care) and ego integrity versus despair (wisdom). We will report evidence of care and wisdom as core ego strengths resulting from their lived experience. We will also review how isolation, sense of community, and key mental and physical health factors seemed to influence how their responses suggest coping strengths. We will discuss our findings in the context of social and cultural norms of current cohorts of older Puerto Ricans, highlighting the salience of community and family relations. (150 words)"} +{"text": "Refugees and asylum seekers are exposed to a unique set of circumstances and experiences that are associated with an increased suicide risk. Suicide prevention training has been recognised as a central component supporting a comprehensive approach to suicide prevention. Limited literature exists exploring the role of suicide prevention training for health and support staff working with refugee and asylum seeker consumers.To determine the impact suicide prevention training for health staff may have in supporting refugee and asylum seeker suicide prevention, researchers undertook a rapid literature review exploring what elements should be considered when developing suicide prevention training for health and support staff working with refugee and asylum seeker consumers.Results of academic and grey literature screening identified 14 studies exploring suicide prevention training for health and support staff working with refugee and asylum seeker consumers. Findings of the literature review suggest suicide prevention training for health and support staff working with refugee and asylum seekers should consider the inclusion of content which increases participant competence and confidence to identify and respond to suicide risk; provide staff with an understanding of cultural differences and its impact on refugees and asylum seekers recognition of mental health and suicide as a health matter; highlight the importance trauma informed practices in care and consider the lived experience of refugees and asylum seekers.Inclusion of specific content in refugee and asylum seeker suicide prevention training may provide health and support staff increased competence and confidence to identify and respond to suicide risk in refugees and asylum seekers. The United Nations High Commissioner for Refugees estimates approximately 79.5 million people are forcibly displaced worldwide . RefugeeSuicide is the act of deliberately ending one's life, although it can be difficult to determine if a person intended their actions to result in death. Suicidal ideation refers to a person having thoughts of ending their own life. These thoughts may vary in intensity and duration from fleeting thoughts to a complete preoccupation with wanting to die. Although not all suicidal thoughts lead a person to suicide or attempt suicide, suicidal ideation should always be taken seriously , 5. SuicResearch in the field of suicidality suggests that suicide is a largely unpredictable outcome that arises from a complex interaction between many vulnerabilities and risk factors in a person\u2019s life . RefugeeRefugees and asylum seekers experience long periods of displacement and insecurity due to the often-lengthy visa process. Nickerson et al. found thExposure to trauma is a known factor linked to suicidality . A studyAsylum seekers held in detention settings are placed at an increased risk of psychological distress and suicide , 12. ConRefugees and asylum seekers are placed at an increased risk of experiencing feelings of isolation if they are separated from their families, culture and spirituality , 15]. LoRefugees and asylum seekers may be vulnerable to poor physical and mental health due to the inequalities stemming from the social determinants of health . On arriPoor financial situations coupled with visa restrictions limiting access to\u00a0services, welfare and health care in the country of resettlement place refugees and asylum seekers in a vulnerable position impacting both mental and physical health . Visa reExisting evidence suggests mental illness and suicide in refugees and asylum seekers may be prevented through early intervention practices , 19. SuiHealth workers and support staff who work with refugees and asylum seekers are in a unique position to identify signs of mental illness and suicidality among refuges and asylum seekers because of the close proximity of which they work. The development of refugee specific suicide prevention training that is delivered to health and support staff working with refugee and asylum seeker consumers may support an early intervention strategy to suicide prevention. Limited research exists about the effectiveness of suicide prevention training to improve ability for health and support staff working with refugees and asylum seekers to effectively identity and manage suicide risk in refugee and asylum seeker clients.Given the increased risk of suicide for refugees and asylum seekers, and the limited research exploring the role of suicide prevention training to support an early intervention approach to suicide prevention in refugees and asylum seekers, this rapid literature review aims to explore existing suicide prevention training content for health and support staff working with refugees and asylum seekers.To be eligible for inclusion in the rapid literature review, publications were limited to full text articles in English only, were published between January 2000 and January 2022, were journal articles, books, reports, reviews, or official publications, and the sources of literature for inclusion were from academic journals, government and official publications, reports, grey literature. The date of the literature search was February 2022.I.Literature that was not in English, full text was not accessibleII.Literature that was not published between January 2000 and January 2022III.Literature that was not classified as a journal article, book, report, review, official publication, or literature reviewIV.Literature that did not focus on mental health or suicide prevention training or refugee health practices in the context of health and support staff working with refugees and asylum seekers.Due to limited existing research in suicide prevention training for support staff working with refugees, search terms remained broad to ensure that all relevant publications were captured in the search. The search terms included key words for suicide prevention and mental health, asylum seeker, and refugee, which were combined using the Boolean Operator \u201cAND\u201d with search terms suicide, prevention, training, health, staff, worker, employee, refugee, and asylum. An example search strategy and search terms are referenced in Appendix 2 and 3.A literature search specialist from Hunter New England Health Libraries was consulted to identify key databases suitable for the literature search. The following databases were searched to increase the likelihood of capturing relevant publications given the recognition of limited research in the space of refugee and asylum seeker health. Databases included BioMed Central (Part of Springer Nature), EBSCOhost Academic Search Ultimate, EBSCOhost- Sociology Source Ultimate, ELSEVIER Clinical Key, ELSEVIER Science Direct, Informit Health Collection, ProQuest, PubMed Central, SAGE journals, Taylor & Francis Online, and Wiley Online Library were selected for the literature search.To increase identification of relevant published and grey literature, authors also searched publication lists of known prominent researchers working in the refugee and asylum seeker suicide prevention field.Grey literature search focused on data and statistics published by Australian government departments and leading refugee and asylum seeker organisations in Australia and internationally.Search results were exported into Endnote X6. Duplications were removed from the search results. Two authors identified and screened literature results for eligibility for inclusion in the review according to eligibility criteria, with literature selection undertaken by reading the title and abstract of each literature source. Any discrepancies regarding suitability for inclusion in the rapid literature review that arose between the two authors were reviewed and resolved by the third author.The literature results remaining after screening procedures and inclusion criteria were applied were read in full by two authors to identify key themes, information and content that relate to the aim of the rapid literature review.To narrow the results of the database and grey literature search, all publications were screened against title and abstract in reference to inclusion and exclusion criteria and the focus questions of the rapid literature review. Further full text reading was undertaken for papers thought suitable from the title and abstract screening stage. Eligible papers were saved within EndNoteX6 software.A total of 14 publications were deemed eligible (n= 378 excluded), of which are referenced in this rapid literature review.Study characteristics presents the final literature accepted for the reviewOf the final 14 results of the literature search, one author read through the full text papers and identified content relating specifically to (i) elements of suicide prevention training including content and format, (ii) type of staff undertaking the training, and iii) cultural sensitivities relating to suicide prevention training. Extracted data was categorised under key themes and topic areas. These topic areas were distinguished during the analysis of full text literature included in this review. To inform the results, two authors identified and developed key subheadings that would be best suited to logically present the findings of the rapid literature review for each topic area. Table Of the academic databases searched, 447 search results were returned. Of the grey literature searched, The Australian Bureau of Statistics, Australian Human Rights Commission, New South Wales Government and The United Nations High Commissioner for Refugees (UNHCR) contained data and information regarding refugee and asylum seeker suicide that supported understanding of suicide and suicide prevention in both international Australian contexts, however was not training focused and excluded from this rapid literature review.Of the search results, the content within the literature relating to a) refugee and asylum seeker specific suicide prevention training, and b) the effectiveness of refugee and asylum seeker suicide prevention training for health and support staff was limited. The researchers however identified a small number of publications that outlined the type of information and content for consideration in the development of refugee specific suicide prevention training.The literature results showed potential benefit of a specific refugee and asylum seeker suicide prevention training if the training content included expert knowledge, clinical skills including screening practices, and perspectives of the lived experience of refugee and asylum seekers.The inclusion of expert knowledge may support the usefulness of refugee and asylum seeker suicide prevention training. A training program for support staff working with refugees and asylum seekers in the community led by researchers from The University of South Australia\u2019s Mental Health and Suicide Prevention Research Group suggest that the effectiveness of the suicide prevention training program was due to the inclusion of expert knowledge, evidence and lived experience of refugee and asylum seeker suicidality in its development .In addition to expert knowledge, the inclusion of clinical elements in suicide prevention training for health and support staff may increase staff ability to identify suicide risk in refugee and asylum seekers clients through knowledge of screening practices. Research from the New South Wales Service for the Treatment and Rehabilitation of Torture and Trauma Survivors (STARTTS) surrounding mental health and suicide prevention training for school staff found the inclusion of clinical content in suicide prevention training can help to increase suicide prevention screening in support staff working with refugee and asylum seeker populations .Although clinical knowledge is not a prerequisite of many support roles, a level of knowledge in clinical practices for mental health and suicide may increase the confidence of the support workers in their ability to screen for and address mental illness and suicidality in their refugee and asylum seeker clients .Suicide prevention training that includes information about mental health screening practices and techniques can improve screening rates and identification of suicidal risk. A 2015 US study exploring mental health screening feasibility and training of refugee health coordinators found staff who had received higher levels of mental health training were more likely to screen for war trauma, torture and other mental health symptoms . The stuInclusion of examples of screening techniques and practices may be a beneficial inclusion in suicide prevention training for health and support staff working with refugees and asylum seekers. A 2018 Delphi study by Colucci et al. , investiThe use of case studies and role play within suicide prevention training for health staff working with refugees and asylum seekers may improve health staff confidence and ability to respond to suicidal distress. A 2021 study by Procter et al. saw improved participant competence and confidence after completing a specialised training course may be due to the use of case studies and examples to help participants understanding of suicidal psychology and behaviour .The benefit of role play in training was also identified by L\u00f6fving Gupta et al. amongst Refugee and asylum seeker suicide prevention training should consider the inclusion of content that provides health and support staff with the skills to communicate in a culturally responsive way. Existing literature highlights the differences in mental health and suicide literacy between different cultural groups. Colucci et al. exploredSuicide prevention training that teaches health and support staff the skills to communicate in a culturally appropriate way, that also meet the literacy needs and understanding of mental health of refugee and asylum seeker clients is paramount. Ferguson et al. highlighThe value of co-designing suicide prevention training with refugee and asylum seekers has been recognised by Procter et al. 2021. The research paper highlights the collaboration with asylum seekers with lived experience of attempted suicide and/or witnessing suicidal behaviour in held detention and/or in the community to develop a suicide prevention training package that is culturally responsive and reflects the experiences of refugees and asylum seekers .Existing literature in the space of refugee and asylum seeker mental health and suicide primarily focuses on psychosocial, economic, cultural and individual factors that impact on mental health and suicidality, with few publications examining what mental health and suicide prevention interventions work best in preventing suicidal distress in refugees and asylum seekers. Of the literature focusing on training as an intervention, there are limited publications demonstrating the effectiveness of suicide prevention training for health and support staff working with refugees and asylum seekers.Of the identified literature in this review, there was some evidence to support the effectiveness of training to improve health and support staff knowledge, competence and ability to identify and respond to suicide which in turn may prevent suicide deaths. The University of South Australia\u2019s Mental Health and Suicide Prevention Research Group designed and delivered a targeted two-day suicide prevention education program to government and non-government staff working with refugees and asylum seekers in the fields of nursing, social work, case work and volunteering. Findings from the study suggested the training led to significant improvement in refugee support workers\u2019 confidence, attitude and competence to identify, manage and reduce suicide .Continuing to explore the effectiveness of suicide prevention training on health and support staff working with refugees and asylum seekers, Procter et al. (2021) evaluated the outcomes of a specially designed suicide prevention training program specifically designed for and delivered to 400 staff members, volunteers and students from Australian non-government organisations who provide mental health support and case management to refugee and asylum seekers. The research study found an increase in competence and confidence, and change in attitude, of participants following undertaking a two-day specialised training program .Screening practices are a critical component in identifying suicide risk and should be considered as the primary step in identifying suicide risk in refugees and asylum seekers. Shannon et al. found thProcter et al. 2018 identifies the risk of not using trauma informed approaches when working with and screening refugee and asylum seeker consumers. Health staff and support workers must consider the risk and benefit of asking refugee and asylum seeker consumers to recall on past traumtic events to prevent further stress. In favour, Procter et al. 2018 encourages health and support staff to include screening practices that gain an understanding of \u2018what has happened to this person\u2019 as opposed to \u2018what is wrong with this person\u2019 . With the above mentioned studies, development of suicide prevention training should consider the inclusion of content that not only improves the knowledge and competence of support staff to identify and respond to suicide risk, but should also provide guidance in screening practices and trauma informed care.Even with strong screening practices, the ability of refugees and asylum seekers to communicate traumatic experiences and their emotional state may be either supported or hindered by the use of an interpreting service and individual understanding of mental illness and suicide . For somSuicidality in refugees and asylum seekers is influenced by a range of complex personal, social and economic factors and experiences. The ability of health and support staff working with refugees and asylum seekers to identify and support suicidality may support an early intervention approach to suicide prevention. Due to the increased risk of mental illness and suicide in refugees and asylum seekers, it is important that health and support staff engaging with refugees and asylum seekers have the competence and confidence to identify and manage suicide risk.The literature results included in the review highlight the potential for suicide prevention training to increase the knowledge, skills and confidence of health and support staff to identify and respond to suicide risk in refugees and asylum seekers, providing the training includes core components that reflect the existing evidence. Evaluation of the training model explored in Procter et al. 2021, suggests the inclusion of role plays, or ability to observe others respond to suicidal distress, the inclusion of practical skills and tools such as safety planning, and the varying states of distress that a refugee or asylum seeker experiencing suicidal distress may encounter were training components that provided most benefit to the training participants .i.increases the knowledge and confidence of training participants to assist refugees and asylum seekers experiencing psychological distress .ii.develops the competency of participants to respond to and manage suicide risk in refugees and asylum seekers , 30.iii.addresses the importance of trauma informed and culturally appropriate approaches when working with refugees and asylum seekers , 31, 34.iv.is informed by the lived experience of refugees and asylum seekers .Specific suicide prevention training for health and support staff working with refugees and asylum seekers can provide the specific skills required to support refugees and asylum seekers experiencing suicidality or psychological distress . With reImproving the knowledge and confidence of health and support staff working with refugee and asylum seekers through suicide prevention training may improve screening practices to support an increase in early identification of mental illness and suicidality. Increase in staff knowledge, confidence and competence as the result of suicide prevention training may lead to increased referrals to appropriate services, again supporting an early intervention approach to refugee and asylum seeker suicide prevention.This rapid literature review identified a small number of published research items. Expanding the literature search to include research relating to mental health, mental illness, and distress may capture other published literature. Similarly, extending the search terms to include medical staff or staff and support workers from other disciplines again may return a higher number of literature results with valuable information. The method used to screen articles using title and abstract to determine potential inclusion of literature instead of reading full text may have also captured other information not included in this review. Finally, the inclusion of English only publications may have also impacted literature results.Given the increased risk of suicide for refugees and asylum seekers, further research exploring what factors are the biggest contributors to suicidality for refugees and asylum seekers would strengthen academic knowledge in best practice suicide prevention, and provide a foundation to inform key components for inclusion in refugee and asylum seeker specific suicide prevention training. In addition, further research to determine the efficacy of refugee and asylum seeker specific suicide prevention training to support an early intervention approach to suicide prevention would contribute valuable knowledge to this emerging field of research. Expanding literature search to include literature relating to suicide prevention and cultural considerations for different cultural groups may also inform content for inclusion in refugee and asylum seeker suicide prevention training.There are a number of social, economic and individual factors contributing to increased suicide risk in refugees and asylum seekers. Health and support staff working with refugee and asylum seeker consumers are well positioned to identify mental illness and suicidality in refugee clients. Specially designed refugee and asylum seeker specific suicide prevention training for health and support staff working with refugees and asylum seekers has the potential to improve the competence and confidence of health and support staff to effectively identify and respond to suicide risk in refugee and asylum seekers."} +{"text": "Humanist values of aging are relevant for understanding diversity in gerontological education because they are manifested across all cultures and ages. This paper proposes attention to four humanist values of aging: Love, Hope, Peace, Stewardship. This paper seeks opportunities for students to understand aging diversity in half century context: from traditional frames of race and sexuality to global conversations on language and geography. Drawing from stories about older adults this paper gathers diverse opportunities for understanding of humanist values of aging. Selections strive toward expanding representation of aging diversity and accessibility for students. Teaching with stories of love, hope, peace, and stewardship as humanist values of aging matches AGHE initiatives for incorporating humanities into gerontological education and opens opportunities for recognizing diversity representation in our society for all ages. Understanding aging diversity through stories of older adults engaged with humanist values of aging promises enriching educational experiences for lifelong learning."} +{"text": "Mental health care is considered to be one of the main sources of mental illness stigmatization. Detailed information about these stigmatization experiences is needed to reduce stigma in mental health practices.The study aimed i) to identify the most relevant stigmatizing situations in mental health care encountered by users and families, ii) to characterize the relative importance of these situations in terms of frequency, experienced stigmatization and suffering, and iii) to identify individual and contextual factors associated with these experiences.In a focus group, users were asked to select the 15 most relevant stigmatization situations among those they elicited and those that were taken from the literature. An online survey was then conducted among users and family members to characterize these situations and identify predictors.A total of 235 participants were included: 59 participants with schizophrenia diagnosis, 96 with other psychiatric diagnoses and 80 family members. The results revealed 15 situations with different levels of frequency, stigmatization and suffering. Participants with a diagnosis of schizophrenia experienced more situations of stigmatization and with a higher frequency. Moreover, factors such as recovery-oriented practices and measures without consent were the best predictors of experienced stigmatization.These original stigmatization situations could be targeted to reduce stigmatization and associated suffering in mental health practices. Results strongly suggest that recovery-oriented practice should be fostered to fight stigma in mental health care.No significant relationships."} +{"text": "The medial septum (MS) has long been studied for its role in the generation of hippocampal theta oscillation, the dominant rhythm of the limbic system during information collecting behaviors and REM sleep Buzs\u00e1ki, . Early lMocellin and Mikulovic attempts to redirect attention back to coordination of affective states and accompanying motor actions by the medial septum. They provide an integrated view of how the medial septal circuit in concert with connected regions supports the correlated functions of theta genesis and modulation of movement during motivated behaviors.Exploration of medial septum's involvement in motivated behaviors predates the discovery of its role in hippocampal oscillogenesis. However, following the report of rhythmic bursting medial septal neurons coupled to theta activity in the hippocampus, the main focus shifted to studying how medial septum controls memory-related physiological phenomena. The review by Kopsick et al. show by using fiber photometry that MS cholinergic neurons' activity correlates with the logarithm of movement speed, with fast enough dynamics to serve as a speed signal for the hippocampus. Importantly, this cholinergic speed signal was independent of visual inputs and also reflected the speed of neck movements when mice were stationary.Glutamatergic MS neurons were shown to potently control locomotive behavior in mice; however, MS cholinergic and GABAergic neurons also show correlations with locomotion, indicating complex MS functions related to animal speed. In an original research article, Tsanov provides a systems model for the MS in memory processing that reflects these recent findings and discusses how this updated model may influence treatment strategies of neurodegenerative disorders. These potential interventions include targeting the dopaminergic system, deep brain stimulation in cholinergic areas, vagus nerve stimulation, as well as exercise-based and cognitive enhancement strategies.MS neurons process motion, reinforcement, memory and attentional information, prompting an update on how the MS participates in mnemonic processing. Takeuchi et al. review MS stimulation strategies that may alleviate the negative consequences of such \u201coscillopathies,\u201d stressing the importance of stimulation timing at varying timescales as a key determinant of therapeutical success. Such strategies may eventually prove successful in a broad range of conditions from Alzheimer's disease to schizophrenia to anxiety to pain.As noted, the MS orchestrates hippocampal theta oscillations related to learning, memory, and spatial navigation, but also to anxiety and fear in the ventral hippocampus. Additionally, oscillatory control by the MS may go beyond the theta frequency band, and physiological rhythms affected by the MS are often disrupted in pathological conditions. Ibrahim et al. investigated how intraseptal components of glutamatergic signaling modulates spontaneous and sensory-evoked theta oscillation. They reported a surprising decoupling of theta genesis and motor control in response to NMDA-receptor blockade. Further findings uncovered the antinociceptive effect of AMPA-receptor antagonism that links their paper to the growing number studies exploring the therapeutic potential of medial septum manipulation.Network mechanisms whereby sensory inputs are transformed into the rhythmic output of the medial septum are still largely unknown. The original research by Leung and Ma's review places the medial septum in the intersection of gamma oscillations and consciousness. Information about medial septum's role in extra-theta rhythms is relatively scarce compared to the huge body of theta literature. Likewise, the medial septal control of conscious states, especially in the context of pathological alterations or artificially induced but clinically relevant brain states, is also an understudied field. This review gives a comprehensive survey of studies focusing on the correlated alteration of gamma oscillation and conscious states following seizures or anesthesia. The many cited reports are thought-provoking and by shedding light on our gaps of knowledge may motivate further translatable research of medial septal function.Griguoli and Pimpinella's review. Many psychopathologies are accompanied by the severe disruption of social life. As thoroughly reviewed in this paper, the medial septum is a key hub not only for episodic but also for social memory formation, that may render it a potential therapeutic target for treating debilitating social psychological impairments.Recent landmark discoveries unraveled fundamental mechanisms of social memory formation. The medial septum is thought to be a key coordinator of the episodic memory circuit; thus, linking its already known functions with new findings about social learning is the key objective of We live in exciting times. The methodological revolution of neuroscience research has uncovered countless novel findings and put old discoveries into new light. The medial septum has long been known as a key center for rhythm genesis. Despite decades of research, it remained an enigmatic region holding its secrets tight to its chest. Nonetheless, novel methods enabled cracking many unknown aspects of medial septal functions. Authors of this collection of papers highlighted many new discoveries and placed them into the context of what we already know about the medial septum. Furthermore, connecting basic discoveries with clinical findings raised the intriguing possibility that this region, through its many connections, is in an ideal position whereby lost coordination of activity can be restored. Thus, many new directions of medial septum research may emanate from both long-known facts and new findings, a large part described in this article collection.BH and VV wrote the editorial. All authors contributed to the article and approved the submitted version."} +{"text": "This presentation will describe a series of research projects using Social Network Analysis (SNA) to measure the personal social networks of community-dwelling older adults at-risk for or currently experiencing dementia. The first part of the presentation will provide a brief overview of SNA methods, including advantages of SNA compared to more traditional social activity scales. The second part of the presentation will present evidence from multiple studies to identify distinct pathways linking upstream social network characteristics to downstream pathophysiological processes in the aging brain. In particular, we will distinguish between cognitive stimulation experienced in expansive social networks and neuroendocrine benefits derived from cohesive social networks. The third part of the presentation will present implications for psychosocial interventions to reduce health disparities in dementia care and prevention. We recommend leveraging the multidimensional functionality of social networks across the lifecourse to influence multiple cognitive health pathways simultaneously."} +{"text": "Achieving and maintaining good oral health during pregnancy is essential for both the oral and overall health of expecting mothers and their young children. Dental caries can negatively affect daily activities including eating, speaking, and social interaction, and when expecting mothers have active dental caries, the risk for dental caries in these children becomes higher. Another common oral disease, periodontitis, was found to be associated with systemic conditions, including cardiovascular disease, respiratory disease, diabetes, and potentially adverse birth outcomes.Some studies also showed the systemic impact of periodontal disease and the related pathogens that can lead to systemic inflammation and adverse birth outcomes. A mother's oral health status, her oral health knowledge, and beliefs also have been shown to significantly affect diet and home oral hygiene practice among her children.Despite the importance of mother's oral health and oral health knowledge to prevent dental caries in young children, maternal oral health is much neglected in primary and prenatal health discussion. This is even more significant in developing countries where oral health care infrastructure and workforce are inadequate. With increase in sugar consumption growing worldwide with this lack of oral health care infrastructure, oral diseases prevention and oral health promotion are the key to achieve oral health parity among the maternal and child population.In this presentation, the author will discuss literature on maternal oral health and how to position oral health as an essential part of perinatal care along with WHO oral health initiative set for 2030. This is an introduction presentation for this workshop to set a stage and make a case why maternal oral health is a critical topic to discuss in global health and public health perspectives."} +{"text": "With interest we read the article by Takuya Taira and coauthors on blood glucose levels and outcome in patients undergoing extracorporeal resuscitation (ECPR) . The autBut association does not prove causality. A plausible hypothesis on the pathophysiological bases of the observed correlation is important before conclusion can be drawn. The human brain almost exclusively relies on aerobic glycolysis for homeostasis and seveWe, therefore, feel that neglecting hypoglycemia in the present research significantly limits the conclusions that can be drawn from the presented dataset . Clinici"} +{"text": "Monozygotic human twins will age at different rates. The same is true for isogenic laboratory animals. Some of these differences in the rates of aging are caused by differences in the expression of genes. And, some of the differences in gene expression between isogenic individuals are caused by seemingly non-heritable, stochastic epigenetic differences. Here we discuss how differences in chaperone expression can influence aging and a model of Ras-driven neoplasia risk and survival in the model nematode Caenorhabditis elegans. We review evidence suggesting differences in epigenetic silencing machinery contribute to differences in chaperone gene expression. We suggest models for germline and somatic epigenetic regulation of chaperones. We discuss potential means of targeted epigenome modification, and potential implications for human health during aging."} +{"text": "Cancer is a very heterogeneous disease, and uncontrolled cell division is the main characteristic of cancer. Cancerous cells need a high nutrition intake to enable aberrant growth and survival. To do so, cancer cells modify metabolic pathways to produce energy and anabolic precursors and preserve redox balance. Due to the importance of metabolic pathways in tumor growth and malignant transformation, metabolic pathways have also been given promising perspectives for cancer treatment, providing more effective treatment strategies, and target-specific with minimum side effects. Metabolism-based therapeutic nanomaterials for targeted cancer treatment are a promising option. Numerous types of nanoparticles (NPs) are employed in the research and analysis of various cancer therapies. The current review focuses on cutting-edge strategies and current cancer therapy methods based on nanomaterials that target various cancer metabolisms. Additionally, it highlighted the primacy of NPs-based cancer therapies over traditional ones, the challenges, and the future potential. Targeted drug delivery in cancer has been the subject of extensive research and advancement. Either active targeting or passive targeting is used to achieve it has great promise for bioimaging and anticancer therapy because of its high photoluminescence and photodynamic properties is overexpressed in various tumors and has been associated with poor clinical outcomes. In addition, PLK1 overexpression has been associated with chemotherapy resistance, and PLK1 inhibition can increase the cancer cell sensitivity to chemotherapy and radiation . Metabolic dysfunction and estrogen imbalance play key roles in its pathogenesis. The global prevalence and mortality of EC patients have increased in recent years, paralleling the rising prevalence of metabolic disorders and the surrounding microenvironment . Knowing the proportional impact of these factors on the tumor is essential for understanding the emergence and development of metabolic abnormalities and glycolysis. Cancer cells get ATP mostly by glycolysis instead of OXPHOS despite having sufficient oxygen , regulates and controls the growth and proliferation of cells. Various cancers have been found to have mutated mTOR overexpression and some mTOR kinase signaling targets signaling has been shown to play a crucial role in human cancer. Currently, smoothened (SMO) inhibitors have been the primary drug targets for studying Hh signaling. Patients with basal cell carcinoma have unfortunately already shown resistance to the currently employed SMO inhibitors , reactive nitrogen species (RNS), free radicals, and reactive lipid species) in relation to antioxidant capacity are referred to as \u2018oxidative stress.\u2019 Sies, . ElevateIt has long been believed that suppressing oxidative stress in cancer cells is a promising therapeutic strategy, and the antioxidant\u2019s role in supporting the immune function of the cell cannot be overstated. The safety of antioxidants used as adjuvant therapy in cancer treatment protocols is still under debate because ROS are involved in the mechanism of action of common cytotoxic drugs , potentially leading to oxidative injury of unsaturated fatty acids, decreased membrane fluidity, and which ultimately induced cell death to ROS and catalysts to generate cytotoxic hydroxyl radical (\u2022OH) that are successfully turning the lives of cancer patients back to life. Still, much work has to be done to make NP-based cancer therapies efficient in clinical use. Most of the studies are being conducted and successful in animal models like mice. The promising results motivate cancer researchers to further explore different types of NPs, their cancer therapeutic potential in targeting cancer metabolism, challenges, and ways to overcome them.This does not involve any animals or humans.All authors approved the final version of the manuscript."} +{"text": "Anticholinergic drugs block muscarinic receptors in the body. They are commonly prescribed for a variety of indications and their use has previously been associated with dementia and cognitive declineIn UK Biobank participants with linked health-care records , we calculated total anticholinergic drug burden according to 15 different anticholinergic scales and due to different classes of drugs. We then used linear regression to explore the associations between anticholinergic burden and various measures of cognition and structural MRI, including general intelligence, 9 separate cognitive domains, total brain volume, volumes of 68 cortical and 16 subcortical areas, and fractional anisotropy and median diffusivity of 25 white-matter tracts.Anticholinergic burden was modestly associated with poorer cognition across most anticholinergic scales and cognitive tests . The association was mostly driven by antibiotics and drugs to treat disorders of the nervous system . Anticholinergic burden due to the pharmacological subclass of glucose-lowering drugs and the anatomical class of respiratory drugs was associated with total brain volume. However, anticholinergic burden was not associated with any other measure of brain macro- or microstructure (p>0.07).Anticholinergic burden is mildly associated with poorer cognition, but there is little evidence for an effect for measures of brain structure. Future studies might focus more broadly on polypharmacy or more narrowly on distinct drug classes, instead of using purported anticholinergic action to study the effects of drugs on cognitive ability."} +{"text": "Intergenerational contact is beneficial for improving attitudes toward older people, including age stereotypes (AS). To date, however, research on the topic has focused on younger adults , overlooking the possible perks for older adults themselves (contact with same-age peers). The current study investigated the association between contact with older adults and views of the self in old age (VSOA) among younger and older adults in a domain-specific way. The sample comprised younger and older adults from the Ageing as Future international study. Findings indicated that contact with older adults was related to more positive VSOA and this was partly mediated by AS. These relations were stronger for older adults, indicating that interactions with other older adults may help favorably shape how older adults view their ingroup and aging. Beneficial effects emerged mostly in the friends and leisure domains."} +{"text": "Health policy and research communities have taken new approaches to addressing health equity, going beyond traditional methods that often excluded the contributions of health care consumers and persons with lived experience. This reevaluation has the potential to drive critical improvements in how we conduct research and innovate policy toward reducing health and health care disparities in the United States. Such considerations have led Fountain House, the founder of the Clubhouse model for peer-based psychosocial rehabilitation for persons with histories of serious mental illness, to incorporate community-based participatory action research (CBPAR) protocols within their research and service programs. The combination of CBPAR research methods within novel participatory care settings like Clubhouse programs presents unique and informative opportunities for the advancement of innovative health equity approaches to consumer empowerment in health care.In this piece, the authors (two staff researchers and one member researcher) propose how CBPAR research methods conducted in Clubhouses can uniquely advance equity-focused research methods, and how the benefit and enhancements from equity-focused research are continuously applied, practiced, and accountable to the communities within which the research is conducted. Embedding CBPAR practices within participatory care settings like Clubhouses, creates novel opportunities for research work to not only become more equitable but also become a part of the rehabilitative process, empowering the main beneficiaries of the research with the means to sustain and achieve further improvements for themselves. Such experiences are particularly important within rehabilitation settings, where there is a process of reclaiming empowerment and self-efficacy over a disability or illness and the social circumstances surrounding those conditions.Different stakeholders can all play important roles in advancing health equity\u2013oriented research agendas by leveraging CBPAR principles. Academics and others in the research community can more comprehensively embed CBPAR methods into the design of their research studies. A critical link exists among how researchers conduct their studies, how providers organize care delivery and support, and how health plans pay for and evaluate care. CBPAR-generated research needs to fully engage clinical teams to ensure that ongoing community-involved care settings have direct applications to real-world care delivery. It is equally important that providers fully engage with their communities as they adjust their approaches to supporting the populations they serve. In recent years, health policy and research communities have adapted and rethought traditional approaches to health equity that often excluded the contributions of health care consumers and persons with lived experience. This reevaluation has the potential to drive critical improvements in how we conduct research and innovate policy toward reducing health and health care disparities in the United States, consistent with the recent 2021 call to action by the Robert Wood Johnson Foundation (RWJF) \u201cfor its health equity agenda, the Biden administration needs research that focuses on impacted communities\u201d begins with a research topic of importance to the community...[combining] knowledge and action for social change to improve communities and eliminate disparities\u201d .Going beyond aligning research with community priorities and experiences, CBPAR methods also prioritize the training of community participants in scientific design and procedures so that the community can collaborate in research decision-making from a shared knowledge position. This level of participation and training empowers the community to leverage skills for continued assessment and advancement of the community\u2019s interests beyond the scope and limitations of a given research study . This isCBPAR methods have particular importance for communities of interest that have historically been marginalized from participating in larger social systems that impact their daily lives. Some prominent CBPAR practice examples have occurred within indigenous communities managing diabetes prevention resources , migrantHealth equity has been defined in multiple ways. Borrowing from RWJF, \u201chealth equity means that everyone has a fair and just opportunity to be as healthy as possible.\u201d The RWJF definition further elaborates that health equity \u201crequires removing obstacles to health such as poverty, discrimination, and their consequences, including powerlessness and lack of access to good jobs with fair pay, quality education and housing, safe environments, and health care.\u201d Powerlessness and access barriers, in particular, have been parallel obstacles to equity in both health and health research .In alignment with health equity goals, CBPAR methods offer unique research strategies to help address larger systemic issues related to health care accessibility, health literacy, and poor patient experiences . HoweverGiven such circumstances, while CBPAR methods can be readily used in traditional health settings, the persistent empowerment of patient communities to participate in the continuous change-oriented enhancements, delivery, and assessments of their own ongoing care is often limited . To overAlthough minimal in their overall presence in health care, there are some rehabilitation settings that operate unique care models focused on uplifting consumers into roles of treatment decision-making and peer-support delivery. A historical leader in such approaches is the Clubhouse model, a community-based psychosocial rehabilitation program for persons with histories of SMI. Founded in 1948 by persons with an SMI, the New York City\u2013based Fountain House launched the Clubhouse movement with the purpose of creating communities of lived experience, where persons with histories of SMI could support and care for one another in their recovery journey.Clubhouse programs offer strength-based peer interventions to help persons with SMI socially reintegrate and achieve agency in their health, quality of life, and care. This is achieved through the creation of an intentional peer community, where members are invited to (co)operate and administer Clubhouse operations, working side by side with Clubhouse professional staff to either receive or provide a range of social support services . Member Recognizing the participatory congruence between Clubhouse model and CBPAR research methods, Fountain House has sustained a legacy of incorporating CBPAR practices in its research initiatives. Programmatically, this has taken the form of Fountain House maintaining a longstanding Research Unit as one of its program service areas, where members learn and direct the community\u2019s research interests and priorities. Members and staff have also created a Research Committee to manage high-level administrative decisions in developing research collaborations across the national Clubhouse network and public health policy agenda. These continuous peer-led research forums empower members to develop research skills, translate their research priorities, and self-administer the change-oriented outcomes of their research toward positive program enhancements in their own care settings. The opportunities, insights, and skills developed through CBPAR within peer-driven programs like Clubhouse allows not just for health equity research advancements to be discovered but for them to also be accountably enacted and implemented by the very people whom they are intended to benefit within the settings they help operate.One example of this unique CBPAR health equity dynamic within Clubhouse care settings occurred in a collaboration between Fountain House and Yale University, where Clubhouse members were trained in qualitative research to conduct an analysis of member care experiences, trajectories, and differing needs within the community. The results of this study, conducted from start to finish by members, informed programming decisions around new member orientation and needs assessment procedures that seek to engage members during \u201ccritical periods\u201d of early membership, identifying a spectrum of member experiences interacting with the Clubhouse as either a supportive stepping stone or a long-term community destination. The members who administered the study were able to inform new program practices and further apply their research training toward training other members and even work as paid research consultants and coders in future research collaborations. This has been the case with a current CBPAR project with Harvard Medical School to co-design a virtual healthy lifestyle intervention that seeks to involve members not only in the development and implementation of the research study but also in administering components of the intervention themselves, after the study\u2019s completion. What we have seen from this approach with Harvard, in addition to other CBPAR projects, is that members of different racial, social, and health backgrounds actively engage and adjust interventions and research protocols that address their collective needs, thus driving more equitable care support approaches that they can supervise and perform continuously.By embedding CBPAR practices within participatory care settings like Clubhouses, the research work not only becomes more equitable but also restorative, empowering the individuals who are meant to benefit from the research with the means to achieve that improvement for themselves. This is especially important within rehabilitation settings, whereby in virtue of being in need of rehabilitation, there is a drive to reclaim empowerment and self-efficacy not only over a disability or illness but also the social circumstances surrounding those conditions. This has been the experience of one of the authors, who took an academic leave for mental health reasons, engaged with the CBPAR program at Fountain House, and is now undertaking academic pursuits toward developing strategies for consumer-informed solutions within the mental health industry.Different stakeholders can all play important roles in advancing health equity\u2013oriented research agendas by leveraging CBPAR principles. Academics and others in the research community can more comprehensively embed CBPAR methods into the design of their research studies. Although the National Institutes of Health has a CBPAR program in its National Institute on Minority Health and Health Disparities, it has not built CBPAR requirements into its standard grantmaking process. National Institutes of Health and other federal agencies can create more robust expectations for applying researchers and support the promotion of community health settings, where CBPAR practices can be fully enacted for the continued benefit and empowerment of patient communities and their role in care design and delivery.How researchers conduct their studies will benefit from greater coordination with and application within participatory care settings. To further enhance health equity\u2013focused research approaches, CBPAR-generated research needs to fully engage clinical teams and consumer communities to ensure that ongoing community-involved care settings have direct applications to real-world care delivery. This is particularly important for exploring and promoting innovations in how health plans pay for certain types of care. Indeed, providers are unlikely to shift their models unless health plans and other payers embed community-based participation and human-centered design into their payment models. The final piece of this effort relates to the role that state and federal policy making has on this intersection between health equity and community-oriented research models. Policy makers\u2014those involved in both legislative and regulatory aspects\u2014need to fully embrace CBPAR as one of several vehicles for advancing a national agenda to promote health equity, which includes the investment and promotion of participatory and peer-driven treatment settings where CBPAR methods can be implemented. Ultimately, how we measure and improve health equity will be dramatically influenced by the research questions we ask and the way we conduct that research. The communities we want to support must be integrally involved."} +{"text": "The COVID-19 pandemic represents a complex stressor that is experienced differently across individuals and age strata. The present study explored perceptions and experiences of older adults within the domains of health, social interactions, finances and care of existing chronic medical conditions; and strategies used to cope with these stressors. We recruited 30 people (mean age 81.4 years) stratified by frailty status to complete semi-structured interviews about what changes to the above domains had occurred and what coping strategies were utilized. Using inductive and deductive coding techniques, thematic analysis revealed three overarching themes. The first was Pandemic Experience, which was perceived as stressful, especially in the domains of social isolation from friends and family and concern for others\u2019 well-being. The second domain was Resilience where participants reported highly adaptable and creative ways to connect with others and viewed the pandemic from a lens of lifetime experience, which acted as a stress buffer. The third theme was Silver Linings where participants reported unexpected renewal like reconnecting with family and friends in more meaningful ways and reconnecting with nature. We found no meaningful distinction in experience by frailty status and explore reasons for this. Policy implications including internet access and training and societal aging biases are discussed in the context of aging and coping theories."} +{"text": "After the successful publication of three Special Issues devoted to highlighting novel scientific research results in the field of bladder cancer and their clinical implications, we are now directing our efforts towards a fourth edition which will aim at compiling innovative research strategies that will ultimately guide and support clinicians in the decision-making process for targeted bladder cancer therapies.Urothelial carcinoma is a fascinating tumor type characterized by marked tumor heterogeneity. This heterogeneity poses particular challenges for routine clinical practice and research. Research on urothelial carcinoma is currently speeding up\u2014much more than in the years before. Methodological developments achieved in recent years, particularly in the area of high-throughput analyses, have contributed to a better understanding of the biology and heterogeneity of urothelial carcinoma, which has led to the development of new biomarkers and approaches for targeted therapy. Accordingly, this fourth edition includes many new chapters on molecular characterization, urothelial carcinogenesis and potential clinical applications.Cystoscopy and imaging systems are still considered the gold standard for the detection and monitoring of bladder cancer as they have shown unequal combined overall sensitivity and specificity. However, they still have a limited sensitivity in detecting small lesions of the urinary tract. For this reason, urine cytology is still the most widely used complementary non-invasive test for the detection and surveillance of bladder cancer. Despite its high specificity of around 86%, the limitation of this method lies in its low sensitivity of approximately 50% , especiaIn contrast to other urine markers, cytology is still recommended in bladder cancer diagnosis and surveillance for recurrence . HoweverNovel markers or combinations of existing tumor markers could significantly contribute to more precise diagnosis and tumor subclassifications as well as facilitating therapeutic decision making. The classification of bladder tumors based on grade and stage alone is suboptimal in predicting the biological behavior and in guiding the choice of treatment, especially in high-risk cases ,11,12.The molecular subtyping of bladder cancer based on its transcriptional features has been well characterized after its initial introduction in 2014 ,14,15. IThe Lund study included both NMIBC and MIBC and described five expression subclasses with some presenting features that overlapped with luminal and basal subtypes of MIBC . The UROIn addition to transcriptional molecular subtypes, DNA methylation profiles and copy number alterations have defined bladder cancer subtypes that may have some relevant prognostic implications. It is therefore expected that a multi-omics integrated approach could refine the molecular subtyping of bladder cancer, eventually providing the best clinical relevance . InnovatIn conclusion, there is an urgent and tremendous need for clinical markers that can reliably predict the recurrence and progression of bladder cancer; these markers will likely contribute to establishing better personalized treatments. Molecular staging of urological tumors will allow selecting cases that will require systemic and/or target treatments ,23.The editors thank all submitting authors for their efforts and time spent on each manuscript. The lead editor would like to thank all editors for the time spent in reviewing, assigning reviews and commenting on the submitted manuscripts. As the editorial team, we hope that this Special Issue will prove useful in planning future bladder cancer research studies."} +{"text": "Our populations are not only becoming older, but also becoming more diverse on several fronts. Our new social structures call for new strategies for embracing our diversity in how we design and deliver education about aging in and beyond the classroom. In this AGHE Presidential Symposium, educators will discuss innovative and needed ways we can integrate diversity in gerontological pedagogical practices. To begin, Rona Karasik (St. Cloud State University) will discuss the call for integrating anti-racist strategies in classroom practices, and offer examples of several such strategies. Next, Brian Carpenter (Washington University in St. Louis) will discuss shrinking geropsychology pipelines, especially for students from racial and ethnic groups, and will share recommendations for expanding these pipelines. Aaron Guest (Arizona State University) will then discuss the need to extend diversity and education efforts to include LGBTQ individuals and issues. Karen Lincoln will discuss the need to move educational efforts beyond our classrooms to diverse learners in our communities. To this end, she will describe a dynamic academic\u2212community partnership that provides aging-focused education to African-American older adults. Dana Burr-Bradley will give the final presentation with a discussion about the need for an international lens that appreciates the global diversity of the aging experience. Tamara Baker will serve as the discussant and offer her perspective on how the need to embrace our diversity in gerontology education cuts across all GSA units and connects them with AGHE\u2019s educational mission."} +{"text": "Numerous challenges remain in research to generate RWE for FDA approvals and other health care decision-makers or stakeholders. This is particularly true for research to evaluate the effectiveness of pharmaceutical care and patient outcomes in older populations. For example, data sources available for RWE in the older populations are limited and data access can be daunting; identifying appropriate data sources for FDAapprovals remain challenging. Most of the FDA approvals are based on RWE rely on multiple data sources instead of a single database. In addition, pharmacoepidemiologic studies in older adults using RWD are often limited in capturing important clinical information and prognostic factors that are useful for decision-makers. Polypharmacy, frailty, and patient outcomes measures are often inconsistent depending on specific databases and thus produce controversial results. We will discuss different data sources appropriate for pharmacoepidemiology research and make comparisons and contrasts of different research approaches using different databases."} +{"text": "Engaging diverse groups of older adults is essential to addressing health disparities. In this presentation, we will describe how we used our research team\u2019s networks and knowledge of the target population to engage key stakeholders in our KAP project. We will address our partnerships with clergy, NGO staff and administrators, housing authorities, colleagues at Puerto Rican universities, and older adults who serve as informal community and institutional gatekeepers. We will discuss how these partnerships facilitated our ability to identify and access study sites and participants; conduct telephone and in-person interviews; ensure data quality through training and monitoring; and, assure safety through adherence to COVID-19 protocols. Finally, we will describe key cultural and ethical issues of conducting research with older adults through community partnerships during a pandemic. The presentation has implications for developing beneficial partnerships with local community leaders and enhancing the representation of diverse groups of older adults in research."} +{"text": "This article has been corrected at the request of the authors to add author Charlene Chin See, who was erroneously omitted from the original submitted and published article. The updated author list is as follows:Priyan MaganCharlene Chin SeeDaine ClarkeFerin PatelDhanuja SennAdditionally, author Daine Clarke\u2019s affiliation has been corrected from Orthopaedic Surgery, Royal Derby Hospital to Trauma and Orthopaedics, Faculty of Medical Sciences, The University of the West Indies.The authors deeply regret that these errors were not identified and addressed prior to publication."} +{"text": "Dolichoarterial disease of the carotid arteries refers to elongated arteries with tortuous, coiling, and kinking anatomy. This morphology is usually met in the elderly and not associated with atherosclerotic risk factors. Current practice reserves surgical correction only in symptomatic patients. Significant tortuosity index may be associated with stroke and poses extra difficulties to the endovascular passage of guidewires and catheters for the treatment of extra- and intracranial vascular lesions. This article presents a typical case of bilateral dolichoarteriopathy of the common carotid artery and stresses the need for further categorization of the particular morphology based on modern angiography techniques and three-dimensional reconstruction software. Dolichoarterial disease (DAD) refers to elongated arteries with tortuous, coiling, and kinking anatomy.Current guidelines of the European Society for Vascular Surgery suggest surgical correction only in symptomatic patients with isolated coils/kinks, provided that all other causes for transient ischemic attack or stroke have been excluded by multidisciplinary team review.Bilateral dolichoarteriopathy of the"} +{"text": "Older adults have been neglected in biobehavioral oxytocin research. Emerging research indicates that oxytocin signaling activity fluctuates over the lifespan, which suggests that results from studies investigating youth and young adults cannot be easily generalized to older adults. The recruitment of a wider age range of research participants using a variety of research tools is required to uncover the role of the oxytocin signaling system over the lifespan and may reveal novel treatment target candidates in older adults, beyond social cognition and behavior. Oxytocin is a neuropeptide primarily synthesized in the hypothalamus that helps coordinate a broad range of somatic processes Human oxytocin research in the biobehavioral sciences has primarily recruited youth and young adult samples, with only a small number of studies investigating health and cognition in older populations e.g., . This isTo help remedy this situation, a recent study by Valdes-Hernandez and colleagues does modulate functional connectivity of brain regions involved in social perception in older adults. These observations are consistent with neuroplastic modification by chronic oxytocin administration, which adds to our understanding of oxytocin's effects on brain function and the therapeutic potential of chronic administration. But perhaps more importantly, this study also provides a greater insight into the role of the oxytocin system in older adults.Using fMRI, Valdes-Hernandez and colleagues OXTR) single nucleotide polymorphisms (SNPs) influence cognition and behavior over the lifespan. An alternative to the SNP approach is to evaluate how OXTR expression levels shift over the lifespan, which reflects changes in the distribution and activity of oxytocin binding OXTR expression levels in the brain influence behavior OXTR expression dynamics in the brain across the lifespan and genes with similar spatiotemporal expression profiles can help identify critical lifespan periods for oxytocin signaling and the functional relevance of these fluctuations for both somatic and cognitive processes.We currently lack a comprehensive understanding of how oxytocin signaling changes throughout the human lifespan, from the prenatal phase throughout late adulthood, and how these dynamics impact health, cognition, and behavior. As noted by Valdes-Hernandez and colleagues OXTR expression pattern across the lifespan OXTR expression was shown to first peak during childhood, which is a critical period for social learning. Following this lifespan period, OXTR expression across the brain reduced during early adulthood, then peaked again in late adulthood , bone regeneration (DIRAS3), and energy homeostasis (INHBB), which points to a strong interplay between these genes and OXTR. Intriguingly, research has found that oxytocin administration in animals can reverse bone deterioration Recent cross-sectional research using human brain samples from 57 donors revealed a distinct dulthood . IncreasOXTR expression fluctuations across the human lifespan. With the average age of industrialized populations on the rise, research on the needs and interests of older individuals is required where the focus should not only be on living longer, but also living better. Given the emerging research indicating the fluctuating role of the oxytocin system across the lifespan in both cognitive and somatic processes, treatments targeting the oxytocin system are a promising avenue to help address the health needs of aging populations. The neglect of oxytocin research in older populations also represents a missed opportunity, as evaluating the neurobiological mechanisms underpinning the decline of social cognition in healthy aging may help researchers better understand oxytocin\u2019s role in social cognition difficulties in younger people with neurodevelopmental disorders. Integrating studies investigating exogenous effects of administered oxytocin and endogenous levels of oxytocin across age groups can help us better understand oxytocin\u2019s dynamic and allostatic role across somatic and psychological processes throughout the lifespan.Despite early promising results for oxytocin\u2019s effects on social cognition and behavior, more recent evidence has been mixed We are certainly not the first to state the necessity of expanding the age diversity of samples used in oxytocin research e.g., . HoweverKristin Audunsdottir: Conceptualization, Writing \u2013 original draft. Daniel S. Quintana: Conceptualization, Funding acquisition, Writing \u2013 review & editing."} +{"text": "Food environment factors were assessed using questionnaires measuring perceived food accessibility and affordability. The negative perceptions of food environment were related to lower vegetable and fruit acquisitions and poor healthy eating behaviors. The higher risks of low vegetable and fruit acquisitions in older rural adults were related to a negative perception of food accessibility only . For older urban adults, negative perceptions of both food accessibility and food affordability were related to the increased risk of low vegetable acquisition . In terms of healthy eating behaviors, for those who perceived that either food accessibility or affordability was poor, older urban adults were less likely to have various and healthy food eating behaviors when they had a negative perception of affordability ; however, older rural adults were less likely to have the behaviors when they had a negative perception of accessibility . In conclusion, the negative perceptions of food accessibility and affordability were related to low vegetable acquisition and poor healthy eating behaviors. The effects of food accessibility and affordability on vegetable and fruit acquisitions and healthy eating behaviors were different between urban and rural areas.The food environment has been determined to affect a range of healthy eating and health indicators, but the study on the regional difference of food environment effects on these outcomes is limited. This study aimed to examine whether food environment factors influence vegetable and fruit acquisition and healthy eating behaviors in urban and rural areas using a nationwide dataset. The study participants were community-dwelling older adults aged 65 years and older ( In 2021, the Korean older adult population was 16.5% of the total population, and it continues to increase, predicted to reach 20.3% in 2025 and 25.1% vs. 15% for food affordability [p = 0.011]). Older adults with positive perceptions of both accessibility and affordability had a higher proportion of acquiring vegetables more frequently than those with negative perceptions of both of them (86.3% vs. 68% for once a week or more times [p = 0.001]).The relationship of food environment with vegetable and fruit acquisition by region is shown in p = 0.014). For older rural adults with a negative perception of food accessibility, the proportion of vegetable acquisition less than once a week was 34.9%, whereas it was 18% in those with a positive perception of accessibility (p = 0.014). Regarding fruit acquisition, older rural adults with a negative perception of food accessibility had a marginally significantly higher proportion of acquiring fruits less frequently than those with a positive perception of accessibility .The difference in food acquisition frequency by food environment was affected by region. The frequency of vegetable acquisition was more influenced by food affordability in urban areas and influenced by food accessibility in rural areas. The proportion of vegetable acquisition less than once a week was 21.3% in older urban adults with a negative perception of food affordability, whereas it was 10.8% in those with a positive perception of food affordability (p < 0.001). In older urban adults, all proportions of healthy eating behaviors were higher in those with positive perceptions of both food accessibility and affordability than in those with negative perceptions. However, in older rural adults, the proportion of variety of food intakes and eating healthy foods was not different by perceived food affordability. The relationship between food store accessibility and healthy eating behaviors by region is presented in The effect of the perceived food environment on food acquisition by region is presented in The effect of the perceived food environment on healthy eating behaviors by region is shown in Older adults with negative perceptions of both food accessibility and affordability were less likely to have healthy eating behaviors than those with positive perceptions of both food accessibility and affordability. For those with a negative perception of either of them, the risk of each healthy eating behavior was different by region. Older uban adults were less likely to have various and healthy food eating when they had a negative perception of food affordability and a positive perception of food accessibility than vice versa ; however, older rural adults were less likely to have the behaviors when they had a negative perception of food accessibility and a positive perception of food affordability than vice versa .The nutritional disparity between urban and rural older adult populations has been underscored in Korea ,27. The Understanding context-specific factors to enable the older adult population to acquire their food is crucial to develop and implement effective interventions. The effect of the local food environments on food intakes could depend on distinct characters in urban and rural ecological contexts. Several previous studies on the association of the food environment with healthy diets found that the effect of food environment on healthy diets was stronger in rural areas than that in urban areas owing to poorer spatial accessibility of food stores and inadequate household food resources in rural areas ,30. SimiConversely, some studies have reported that spatial accessibility of grocery stores was not related to healthy diets ,17,33,34This study found that the food environment affected healthy eating behaviors focusing on moderation, variety, and eating healthy foods, showing that a supportive food environment with easily accessible healthy foods may provide an opportunity to change to healthy dietary behaviors. A different effect of each food accessibility and affordability on the behaviors by regions was noted, which was consistent with their effect on healthy food acquisition. Although the effect of the food environment on eating behaviors could be mediated by that of healthy food acquisition, further study of mediation analysis focusing on identifying the mechanisms through which interventions have an effect may help design more efficient and effective interventions in various regional contexts.This study had some limitations. First, the causal direction of the relationships of food environment with healthy food acquisition and healthy eating behaviors were unknown owing to the cross-sectional design. Second, the methodological weaknesses of this study stemmed from the subjective two-item measures of the food environment, which was not validated. In the future, the effect of the regional food environment on dietary quality with extra dimensions of food environmental variables related to the characteristics of the community should be studied. Finally, other plausible factors related to food acquisition or eating behaviors, including social network or psychological factors, could not be considered for the analysis due to unavailable information. Despite several limitations, this study emphasized the significance of the food environments in the design of interventions across urban and rural food environments using nationwide representative data. Food choice or eating behavior is a behavior that occurs within an ecological context consisting of distinct characters in urban and rural food environments. Therefore, the intervention should account for the difference in the context of the regional food environment.Our findings showed that negative perceptions of food accessibility and affordability were related to lower vegetable acquisition and poor healthy eating behaviors. The effects of two food environment dimensions on vegetable and fruit acquisitions and healthy eating behaviors were different between urban and rural areas. For older rural adults, low vegetable and fruit acquisitions and poor healthy eating behaviors were significantly related to a negative perception of food accessibility, whereas for older urban adults, the low vegetable acquisition and poor healthy eating behaviors were significantly related to a negative perception of food affordability. These findings would be meaningful in developing a policy intervention strategy from a macro perspective, making food environments more conducive to healthy choices."} +{"text": "Calcium homeostasis exerts a profound role in determining the quality of gametogenesis, the resultant efficacy of fertilisation and ultimately the competency of embryogenesis. Perhaps no other single ion plays such a profound and determinative role in reproductive success as calcium, since it is critical for germinal vesicle breakdown, sperm capacitation and hyperactivation, oocyte activation, maintenance of zygote calcium homeostasis and embryogenic developmental gradients.This Research Topic aimed to collect, collate, and summarize the most recent and cutting-edge advances and propositions studying the molecular determinants and effectors of calcium signalling and homeostasis throughout the early events of fertilisation and preimplantation embryogenesis, with a specific view to examine how calcium can affect the efficacy of such important phenomena.Shum et al. summarise the mechanisms that regulate calcium homeostasis in the epididymis, an essential organ for sperm maturation, wherein sperm cells are protected and acquire mobility and the ability to fertilize. More specifically, this review focusses on the potential role of vitamin interactions on epididymal calcium, especially the role of calcium in the epididymal lumen as a cofactor for the matrix Gla protein (MGP), which plays an essential role in promoting calcium-dependent protein aggregation. Alhajeri et al. examine the potential connection between neuronal signaling and physiological changes during oocyte maturation and fertilization, providing an overview of reported neurotransmitters and neuropeptides that participate in early embryogenesis in relation to calcium signaling. Shafqat et al., in their novel perspective article, examine the potential links between alterations in cytosolic calcium within the fertilising zygote in the context of the dynamics of DNA methylation during this process. The authors draw upon cancer research that has examined such links in more detail compared to reproduction.This Research Topic includes two novel reviews and a perspective. Savy et al. examine oocyte calcium in the context of superovulation, a common approach utilising extra-physiological levels of gonadotropins to promote continued ovarian follicle maturation that otherwise would undergo atresia, to ultimately maximize the number of oocytes available for either clinical assisted reproductive technologies or experimental animal studies. As evidence suggested a detrimental effect of superovulation upon the quality of oocytes/embryos, the authors examined the hypothesis that this procedure resulted in a diminished capacity for calcium release at fertilisation. The authors find that despite subtle differences in calcium patterns, superovulation did not disrupt physiological calcium signalling at fertilization, and supported the continued use of this method for both clinical and experimental purposes.Three additional original articles complete this edition. In their brief research report, Meng et al. examine the potential role of calcium within in vitro maturation (IVM) and oocyte reprogramming in low calcium culture conditions. The authors observed a delayed rate of first polar body extrusion, and a delayed mitochondrial and endoplasmic reticulum organisation, suggesting important roles for calcium within oocyte maturation. Indeed, this low-calcium derived defective maturation seemed to also underlie poor developmental profiles of somatic cell nuclear transfer (SCNT) embryos. It is also proposed that low calcium may promote oxidative stress and apoptosis at both maturation and early embryogenesis.Chen et al. examine the role of the SEPTIN12 gene in the context of male infertility, identifying a novel heterozygous mutation within the SEPTIN12 gene of the male partner in an infertile couple with a history of fertilisation failure . Indeed, this couple was able to achieve successful fertilisation and pregnancy following intracytoplasmic sperm injection (ICSI) with artificial oocyte activation . The authors also generated a Septin12 knockout (KO) mouse model finding that only homozygous KO mice were infertile, exhibiting diminished sperm counts and abnormal sperm morphology. Rather intriguingly, not only did AOA rescue the failed fertilisation phenotype of homozygous KO mice, but also enhanced the rate of embryogenesis progression to the 2-cell stage, suggesting an improvement in embryogenesis quality. The authors demonstrated a reduced level of phospholipase C zeta within Septin12 homozygous KO sperm, linking Septin12 to PLC\u03b6 and oocyte activation probably via mediation of sperm quality.Collectively, we hope that this article collection further enhances our understanding of the demonstrated and theorised roles played by calcium in almost all aspects of reproduction, all the way from gametogenesis to fertilisation and finally embryogenesis. We anticipate that these articles will be of significant value to the community of reproductive medicine and biology, and help pave the way for further understanding the complexity and enormity of calcium signalling in mammalian reproduction."} +{"text": "Brain hypoxia and ischemia: New insights into neurodegeneration and neuroprotection\u201d was released, numerous studies have expanded our understanding of the molecular mechanisms by which hypoxia can exert its destructive or protective actions. Normal brain development and function depend immensely on oxygen supply and its insufficiency, either due to reduced oxygen levels in the environment (hypoxia) or reduced blood flow (ischemia), can lead to neuronal cell death and subsequent neurodegeneration. Oxygen deficiency affects significantly various cellular functions starting with an immediate response on the composition of membrane lipids, changes in enzyme activity, mitochondrial remodeling, and subsequently resulting in changes in gene expression and translation. Impaired vascular health and reduced oxygen supply to the brain are linked to the pathogenesis of many neurodegenerative disorders including vascular dementia and Alzheimer's disease. Moreover, maternal hypoxia during pregnancy or fetal hypoxia/ischaemia in labor significantly affect new-born brain development and functions, thereby increasing the risk of developing various neurological pathologies in later life. Intensive research during the last decade has suggested various therapeutic avenues for developing treatments and preventive approaches against the pathological effects of hypoxic and ischemic insults which include hypoxic pre- and post-conditioning aimed at increasing brain hypoxic\u2013ischaemic tolerance. In the recent years following the COVID-19 pandemic it became evident that hypoxia is one of the major factors which accompanies this systemic disease, leading to long-lasting neurological manifestations in patients not only with severe hypoxic conditions but also with milder symptoms. We were pleased with the number of papers submitted to the second issue of this Research Topic demonstrating the great interest of the research community in studying the effects of hypoxia on the brain starting from prenatal development up to the aging population and also reviewing various therapeutic avenues.Since the first issue of the Research Topic \u201cAmakhin et al. have demonstrated that hypoxia on the 14th day of embryogenesis mainly affected the progenitors of cortical glutamatergic neurons but not GABAergic interneurons or hippocampal neurons resulting in a reduced number of NeuN-positive neurons in the entorhinal cortex (EC) but not in the CA1 field of the hippocampus. However, the principal neuronal electrophysiological characteristics were altered both in the EC and hippocampus of animals exposed to hypoxia. Using the dosed electroshock paradigm, they found that seizure thresholds were lower in the hypoxic group making them more prone to developing seizures which suggests that prenatal hypoxia might be among the factors predisposing to epilepsy.Using a model of acute prenatal hypoxia in rats in the period of embryogenesis when generation of the pyramidal cortical neurons takes place Zhang et al. using magnetic resonance imaging have demonstrated that in a human population residing in chronic hypoxic environment at high altitude there are significant changes in structural and physiological characteristics of the brain including decreased gray matter volume, damaged nerve fibers, and unbalanced intensity of neuronal activity in different brain regions compared to residents of lower altitude. These alterations may underlie the structural and functional basis of lower scoring in cognitive tests observed in the high-altitude population due to chronic hypoxia. In line with these observations, the work by Ponirakis et al. reports the role of cerebral ischemia in development of mild cognitive impairment and dementia. It demonstrates that patients with subcortical and cortical ischemia had decreased hippocampal volume, corneal nerve fiber length and larger ventricular volume which correlated with cognitive impairment.On the other hand Tang et al. have analyzed a possible role of the silent information regulator 1 (SIRT1) and its involvement in regulation of autophagy and attenuation of the cerebral ischemia-reperfusion outcome. The authors have discussed the molecular mechanisms by which both SIRT1 and autophagy exert their neuroprotective effects and their interaction, which provide a platform for developing drugs targeting SIRT1 levels in the brain. Another possible approach for treatment of patients with ischemic stroke (IS) is utilization of exosomes derived from mesenchymal stem cells as critically reviewed by Xiong et al. Due to the nano-scale of exosomes, their ability to cross the blood\u2013brain barrier and low immunogenicity, they can be used as carriers of regulatory molecules (including microRNAs) aiming to improve the microenvironment of the ischemic tissue and regulation of neuronal activity. Although only applied in animal models, the method of transcranial direct current stimulation (tDCS) might also represent a neuroprotective approach in treatment of IS consequences as reviewed by Huang et al. Such treatments might have some beneficial effects reducing infarct size and improving neurological deficits, although the optimal application of tDCS and their full therapeutic potential require further investigation.Several review artices in this Research Topic have critically assessed therapeutic strategies for treatments of the consequences of brain hypoxia and ischemia developed in recent years. In this regard Gulyaeva et al. both clinical data and the results from rodent ischemia models show that glucocorticoids are involved in IS-induced brain dysfunction, in particular via glucocorticoid-dependent distant hippocampal damage. Designing valid models that reproduce the state of the HPA axis in clinical cases of IS will help both to plan better pre-clinical research and reinforce the diagnostic and prognostic potential of cortisol and other HPA axis hormones.One of the important aspects in designing effective therapy for patients with brain IS is understanding their responsiveness to treatment which to a great extent depends on their hormonal status regulated by the hypothalamic-pituitary-adrenocortical (HPA) axis. As very convincingly presented by Rybnikova et al. This review highlights the importance of studying molecular mechanisms by which intermittent hypoxic training mediates its neuroprotective effects at the tissue and molecular levels and emphasizes its high preventive potential against neurodegeneration and age-related cognitive decline.To stimulate brain tolerance to IS and also to enhance endurance and working capacity of the whole organism, various modes of hypoxic training have been developed over the years which are critically reviewed by All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "As part of the effort to support core psychiatry trainees in North Wales to prepare for their CASC exam, the North Wales SPiCE Project has been initiated. This article aims to evaluate the SPiCE based on medical educational principles.TM. The specialist registrars\u2019 performances in feedback provision were assessed for their teaching using the AOT (Assessment of Teaching) form by the consultants. For core trainees who had played the part of organising committee members and role players, their volunteerism and educational management experience were assessed using the DONCS form by specialist trainees.A total of five candidates preparing for the CASC exam expressed interest and an organising committee was set up. Examiners consisted of a consultant and four specialist registrars while role players were recruited from non-exam sitting junior trainees. Five mock CASC stations were written and role-players were calibrated accordingly. The stations included: History taking for a patient with FTD , MSE of a patient with mania and psychosis, explanation of CBT , breaking bad news of NMS , and explanation of ECT (electroconvulsive therapy). The mock exam was conducted virtually using Microsoft TeamsAll five candidates passed all the stations in the mock exam with 25% improvements in confidence level were seen among candidates in four stations, i.e. ECT explanation, breaking bad news of NMS, CBT explanation, and MSE of a patient with mania and psychosis. All candidates feel the SPiCE programme was useful in helping their final preparation and they would recommend it to other candidates. Four of the candidates sat for the immediate CASC diet after the SPiCE received a pass result. All specialist registrars received positive AOT feedback for their teaching and all non-exam sitting junior trainees received positive DONCS feedback for their spirit of volunteerism and collaborative teamwork.The main strength of the SPiCE project is it utilises existing resources and volunteerism of the organising committee while its main limitation is it has only five stations rather than 16 stations in the real exam. Although the mock exam has improved the confidence of candidates and the majority of candidates pass the exam immediately after that, the causal link between the SPiCE and candidates\u2019 results cannot be conclusively established given all candidates have a good baseline."} +{"text": "Social isolation is a public health issue that is linked to poor health outcomes. However, the mechanisms underlying this association remain unclear. The main objective of this study was to explore whether changes in frailty moderated the relationship between changes in social isolation and changes in health outcomes over two years. We examined the mediating role of changes in frailty when the moderation hypothesis was not supported. A series of latent growth models (LGMs) were used to test our objectives using data from three waves of the FR\u00e9LE study among 1643 Canadian community-dwelling older adults aged 65 years and over. Missing data were handled by pattern mixture models with the assumption of missing not at random. We measured social isolation through social participation, social networks, and social support from different sources of social ties. We assessed frailty using the Fried frailty phenotype. Our moderation results revealed that high levels of changes in social participation, support from friends, nuclear, and extended family members, and social contacts with friends were associated with greater changes in cognitive and mental health among frail older adults with diminished physiological reserves compared to robust older adults. Additionally, changes in frailty mediated the effects of changes in social participation and social contacts and support from friends on changes in chronic conditions. This longitudinal study suggests that frailty moderated the relationships between social isolation and mental and cognitive health but not physical health. Overall, social support and strong friendship ties are key determinants of frail older adults\u2019 health."} +{"text": "The social and economic impacts that have occurred during the pandemic can disproportionally affect those already experiencing poverty. The social determinants of health aggravate inequalities and can adversely affect wellbeing. This study aims to gain rich insight into Australian adults\u2019 experiences of the social determinants of health and the impact on their wellbeing during the COVID-19 pandemic.A descriptive qualitative study using purposive sampling to recruit participants for semi-structured interviews, conducted via videoconferencing between March-August 2021. Thematic analysis was performed with the support of NVivo 12.Participants included 20 Australian adults from various socioeconomic areas ranging in age from 21 to 65 years. Three main themes emerged from the analysis of the data: Food-related concerns; Housing outcomes; and Psychological and emotional impact. Accessing food, during the COVID-19 pandemic, for most participants who resided in low socioeconomic areas, was described as stressful and challenging. Along with the burden of food security, many participants from low socioeconomic areas expressed emotional distress in relation to securing and maintaining adequate housing.The pandemic has amplified existing social determinants of health experienced by those within low socioeconomic areas, particularly those who are female and from migrant communities. The wellbeing of participants from low socioeconomic areas decreased in response to their experiences and challenges with food insecurity and housing instability, highlighting the need for housing affordability strategies and funding of emergency food relief initiatives. Food access for those in areas with high socioeconomic disadvantage, can be improved to address some of the barriers associated with food security by providing supermarket meal vouchers, access to community gardens, and school food programs.\u2022\u2002The housing and food insecurity experienced by participants in this study during the pandemic has influenced their overall wellbeing.\u2022\u2002The pandemic has amplified existing social determinants of health experienced by those in low socioeconomic areas."} +{"text": "The gender diverse and transgender community is a minor patient group that is encountered with increasing frequency in the clinical setting, attributed to the improved awareness and access to medical facilities. Partial impairment to permanent elimination of fertility potential and outcomes depending on the treatment modality usually is a result of gender-affirming therapy, which includes both hormone therapy and surgical intervention. Although seldom conducted in the clinical field, transgender patients should be counseled on their fertility preservation options prior to medical and surgical gender transition. There is relatively limited data and clinical information regarding fertility preservation for transgender individuals. Current treatment regimens are based on protocols from fertility preservation after oncological treatments. Major barriers for the transgender population exist due to the lack of information provided and clinical narrative that is not familiar to the physician or health care provider, although there are various options for fertility preservation. A deeper understanding of this clinical agenda and the mandatory processes will ultimately result in a much more comprehensive and specific care for transgender individuals who are in great need for fertility counseling or treatment options that concern fertility preservation. In this review, current clinical approaches will be summarized and fertility preservation options along with ongoing and future clinical trials in fertility preservation for transgender individuals will be thoroughly reviewed. The transgender community represents a minor but growing patient population in the field of fertility and reproductive medicine. Transgender and nonbinary individuals comprise approximately 2% of the total population, with an estimated total number of 1.4 million transgender and nonbinary people residing in the United States, alone according to a 2016 survey . DefinitAccess to medical treatment and hormonal interventions has become less challenging to this minority population with an increased cognizance of gender variance and social acceptance to transgender and nonbinary people. Gender-affirming hormonal therapies include puberty-suppressing gonadotropin-releasing hormone agonists (GnRH) and sex hormone treatments, such as estrogen administration for those desiring feminine secondary sex characteristics and testosterone hormone therapy for male secondary sex characteristics. Surgical interventions of gender-affirming therapy consist of breast augmentation or mastectomy and gonadectomy. Although treatment modalities are potentially available to all gender fluid and transgender individuals, the patient may undergo some or all of these aforementioned treatment modalities, depending on their specific needs .With the increase in gender-affirming therapy, counseling transgender patients about fertility and fertility preservation has become an area of increasing concern. One of the main adverse effects in the long-term use of gender-affirming hormone therapy is infertility, although further clinical studies are required to elucidate the exact duration of hormonal treatment that causes irreversible effects ,7. RecenFor this specific patient population, physicians and medical providers may be less accustomed to the treatment modalities that are available. Results from a 2019 survey led by Tishelman et al. showed that medical providers from different nationalities acknowledged the need for further data and research based on the available options for transgender fertility preservation . There iIn this review, current clinical approaches and options on fertility preservation for the transgender population will be reviewed and provide insight along with an in-depth discussion on ongoing trials and future studies on fertility preservation for transgender individuals.The spectrum of an individual\u2019s specific gender identity varies considerably in the transgender population. Often described as nonbinary, the gender of the transgender population falls outside the traditional binary system of man/woman. Commonly used terms to define an individual who does not fit the gender binary classification include gender fluid, gender neutral, and gender diverse. Gender identity is a person\u2019s initial experience of gender or the internal being of self from a gender perspective ,16. GendMany patients have shown their interest in having biological children, contrary to the prevalent assumption that transgender people are not interested in parenthood. In some studies, more than half of the patients showed a strong desire to become parents; one study showed that 54% of transmen desired to have children of their own , whereasTestosterone is the treatment of choice for transmen and nonbinary persons undergoing masculinizing therapy. Testosterone is administered to transmen who are receiving masculinizing gender-affirming medical treatment via intramuscular/subcutaneous injection or through a transdermal route. Testosterone administration causes amenorrhea in the majority of the patients, as shown in one study where 82% of the patients became amenorrheic within 3 months . HoweverHistopathologically, testosterone administration affects folliculogenesis and the ovaries. Grimstad and colleagues showed that testosterone therapy for a mean exposure time of 36 months resulted in persistent ovarian function with follicular cysts in approximately half of the study population (49%), polycystic ovaries in 6%, and ovarian atrophy in 4% of the cohort, whereas 39% of the patients had normal ovarian histology. Patients with prolonged testosterone treatment showed an overall decrease in ovarian volume, although the mean volume of the ovaries in the study population remained within the normal range . In a reFertility preservation options for transgender men are oocyte cryopreservation, embryo cryopreservation, and ovarian tissue cryopreservation with in vitro maturation (IVM) . Oocyte There are few studies and limited data concerning COS while on gender-affirming hormonal treatment. Theoretically, a prolonged testosterone discontinuation may result in the reoccurrence of intrinsic ovarian stimulation and a healthier resting follicular pool compared to those on hormone therapy. However, the majority of the transmen community is reluctant to the discontinuation of hormonal treatment, resulting in a lower participation rate in fertility preservation. One study confirmed that a patient with a 1-week cessation of testosterone treatment was able to undergo ovarian stimulation and ended up with successful cryopreservation of 11 mature oocytes , whereasAs an alternative fertility preservation method, transmen patients have the option of embryo cryopreservation. Patients may use cryopreserved oocytes with sperm from either a partner or a donor for embryo fertilization. One of the advantages of cryopreserved embryos when compared to oocyte cryopreservation is the confirmation of higher quality blastocysts developed from the retrieved oocytes. Furthermore, several studies have reported a higher survival rate of the embryos (95\u201398%) in comparison to the 80% survival rate for oocytes ,35. EmbrIn 2019, the ASRM practice committee announced that ovarian tissue cryopreservation with IVM is no longer considered experimental . This feHaving female secondary sex characteristics and serum hormonal levels of estrogen and testosterone similar to cisgender women is the main objective of gender-affirming hormonal treatment in transwomen. Feminizing hormone therapy for transwomen usually involves a combination of androgen-lowering medications, which include GnRH agonists, spironolactone, or cyproterone acetate along with estradiol . Feminizp < 0.01). The authors of this study concluded that feminizing hormone effects on spermatogenesis may not necessarily be irreversible [Semen cryopreservation or testicular tissue cryopreservation is one of the fertility preservation options for transwomen . Sperm cversible . A recenversible . Anotherversible . The decMany transwomen patients find masturbation or ejaculation distressing, resulting in worsening of gender dysphoria, although it may seem relatively less invasive compared to transmen who have to undergo ovarian stimulation and oocyte retrieval. Some patients may have erectile and/or ejaculatory dysfunctions due to hypoandrogenism and electroejaculation, and penile vibratory stimulation may be helpful in such cases ,56,57. TTranswomen who have completed gender-affirming reconstruction are irreversibly sterile, and there are no fertility preservation methods available at this final stage of gender-affirming treatment. Alternative options such as surrogacy or uterine transplantation can be considered for this group of patients. Due to the diverse nature of elected partners in the transgender and gender fluid population, it is necessary to consider the fact that a gestational carrier may be required for a transgender couple to build a family . UterineThe Micro RNA Profile in the Ovarian Follicle Fluid of Transgender Men Treated with Testosterone and the Association with Fertility Potential (NCT03725280) is a proA Belgian observation retrospective study entitled \u201cFertility preservation in Transgender Persons: A Retrospective Look at the Decision and a Survey of the Desire for Children\u201d (NCT05120245) is curre\u201dFertility preservation and Reproductive Needs of Transgender People: Desires, Attitude, and Knowledge of Subjects with Gender Dysphoria\u201d (PaFer) (NCT03836027) is a prospective cohort observational study that has completed recruitment . The aimThe recently completed Fertility Decision Making in Youth and Young Adults (AFFRMED) (NCT05175170) is a sinAlthough there is a strong desire for parenting among transgender individuals, various studies have reported the low usage of available reproductive and fertility services. Riggs et al. conducted a survey with a study population of 409 transgender and nonbinary individuals and results showed that of the people who were not parenting, 33% of the cohort had a strong desire to be parents . MoreoveThere is still an inconsistent and a small percentage of patients utilizing fertility preservation counseling and procedures, despite recommendations for fertility preservation counseling prior to gender-affirming medical treatments. Chen and colleagues showed that with transgender adolescents initiating gender-affirming hormone therapy and were referred for fertility preservation counseling, approximately 12% had preservation counseling, and only 5% of the study group underwent gamete cryopreservation . Only 45The transgender community experiences various limitations to achieving parenthood such as cost of treatment or lack of insurance coverage, gender dysphoria, and the invasive nature of gender-assigning procedures, although there are established recommendations for fertility counseling prior to gender-assigning therapies . A KoreaThe invasive nature of fertility preservation procedures is another barrier that causes reluctance for transgender patients to continue treatment, in addition to the high medical costs. Ovarian stimulation may take several weeks with multiple injections of gonadotropins, which results in the increase of serum estradiol levels, and the transgender patient is exposed to multiple transvaginal ultrasounds which may trigger gender dysphoria . The amoThere are currently no guidelines regarding fertility preservation for transgender individuals. As the parenting desire and demand of fertility counseling of transgender people is increasing, counseling and medical services should be readily available . Since tResults from various studies and clinical trials based on gender-affirming therapy have shown a detrimental impact on the potential for future fertility. Transgender patients undergoing gender-affirming treatment are at a risk for decreased reproductive capacity, and there is a growing awareness in the medical community focusing on the need for fertility preservation counseling prior to initiation of gender-affirming care. However, numerous studies have reported a limited standard of care with many transgender patients who are experiencing inadequate fertility counseling. Further prospective multicenter studies are needed to address the aforementioned shortcomings and advocate for better quality fertility services and parenting options for transgender and nonbinary individuals."} +{"text": "Cognitive impairment is a core feature of schizophrenia and other psychotic disorders and executive deficits are within the most impaired cognitive functions The Wisconsin Card Sorting test (WCST) has been extensively used in literature on schizophrenia and psychosis. The underlying structure of executive impairment may have important implications for our understanding of the complex connections between executive dysfunction and the psychopathology and neurofunctional basis of psychosis.The objective was to empirically validate the dimensions of the WCST network structure of patients regarding antecedent, concurrent and outcome variables.Subjects were 298 patients with a DSM 5 diagnosis of psychotic disorder. To assess the empirical validation of network structure of the WCST antecedent, concurrent and outcome variables were selected from the CASH interview and other scales of patients.Pearson coefficient correlations between the 4 network loadings (NL) of WCST, namely perseveration, inefficient sorting, failure to maintain the set and learning, and antecedent, concurrent and outcome validators are shown in the table. PER and IS showed common and strong associations with antecedent, concurrent and outcome validators. LNG dimension was also moderately associated and FMS did not show significant associations.\u2018Perseveration\u2019 and \u2018Inefficient sorting\u2019 dimensions achieve and share common antecedent, concurrent and outcome validators. While \u2018Learning\u2019 dimension achieves partial validation in terms of antecedent and outcome validators and \u2018Failure to maintain the set\u2019 dimension was not associated with external validators. These four underlying dysfunctions might help to disentangle the neurofunctional basis of executive deficits in psychosis."} +{"text": "In ruminants, prolonged exposure to high ambient temperatures negatively affects placental development and function. The pursuing limitations in placental oxygen and nutrient supply between the mother and fetus slow fetal growth lowering birth weights and postnatal performance. The pregnant ewe is a long-standing animal model for the study of maternal- fetal interactions and is susceptible to naturally occurring heat stress, which causes fetal growth restriction. In the pregnant ewe, studies show that the fetus adapts to hyperthermia-induced placental insufficiency to preserve placental transport capacity of oxygen and nutrients. These adaptive responses are at the expense of normal fetal development and growth. Enlarged transplacental gradient for oxygen and glucose facilitates diffusion across the placenta, but develops by lowering fetal blood oxygen and glucose concentrations. Fetal hypoxemia and hypoglycemia slow growth and alter their metabolic and endocrine profiles. Deficits in amino acids transport across the placenta are present but are overcome by reduced fetal clearance rates, likely due to fetal hypoxemia or endocrine responses to hypoxic stress. Here, we provide an overview of the performance limitations observed in ruminants exposed to heat stress during pregnancy, but we focus our presentation on the sheep fetus in pregnancies complicated by hyperthermia-induced placental insufficiency. We define the characteristics of placental dysfunction observed in the fetus of heat stressed ewes during pregnancy and present developmental adaptations in organogenesis, metabolism, and endocrinology that are proposed to establish maladaptive situations reaching far beyond the perinatal period. Environmental heat stress diminishes revenue for livestock producers by negatively impacting nutrient utilization, growth, and reproductive performance. Consequences of heat stress on early embryonic survival have been well documented, both scientifically and economically . AlthougBecause offspring from a heat stressed dam are growth restricted during gestation, we begin with a closer look at the characteristics of placental dysfunction that restrict fetal growth and cause metabolic adaptations. We provide an overview of the performance limitations observed with maternal heat stress in ruminants, but focus our presentation on work conducted in sheep that are experimentally heat stressed during mid gestation, a time when the placenta is established and placental growth is at maximum . After 130 days of gestation, both fetal and placental weights were significantly less in heat stressed ewes compared to controls (49% for fetus and 56% for placenta). These data indicate that the majority of fetal growth restriction occurs during the final stages of gestation after placental growth restriction and D. TEnvironmental heat stress imposes significant limitations on fetal growth and milk production in several species of ruminants, but some species, usually those with higher production rates, are more susceptible to heat stress. For this reason, lactating dairy cows have a low tolerance to heat stress because as milk production per cow is increased there is a concurrent increase in metabolic heat production that spares brain and heart growth relative to overall body weight . In heatThe fetus uses the umbilical uptake of nutrients to fulfill two major requirements: oxidation to fuel energy metabolism and accretion for growth and storage of substrates. Energy metabolism can be estimated from rates of oxygen consumption, which based on net umbilical oxygen uptake per fetal mass was only marginally less in IUGR fetuses compared to control fetuses . For metAlthough net umbilical glucose uptakes were not significantly lower for all reports individually, the meta-analysis performed herein for ten reports that measured umbilical glucose uptake show that glucose uptake was lower in IUGR fetuses . ExperimFor glucose metabolism, three adaptations are apparent in IUGR fetuses with placental insufficiency. First, there is greater avidity for glucose uptake and utilization by fetal tissues in the presence of low glucose and insulin concentrations, indicating that there is greater insulin sensitivity in the IUGR fetus. Explanations for the greater glucose uptake capacity include a larger proportion of neuronal tissue to body weight and is sWe have followed IUGR lambs from heat stressed ewes and identified persistent augmentations in insulin sensitivity at least until two weeks of age , more than 1000 genes were differentially expressed and explained decreased cell proliferation is increased preferentially in response to acute bouts of hypoxia. As a result, blood flow decreases to the gastrointestinal, renal, and peripheral vasculature. This pattern for redistribution of cardiac output is also maintained during chronic periods of hypoxia such as those found in hyperthermia-induced placental insufficiency, which may result in the asymmetric fetal growth .IUGR fetal myocardium responds through unique metabolic and cardiovascular adaptations that support myocardial growth and function. The reduced circulating anabolic factors present Fetal cardiac function appears to be relatively unaffected by placental insufficiency because heart rates are similar between IUGR and control fetuses (We have presented evidence for prolonged exposure to heat stress causing placental insufficiency in ruminants. Maladaptive responses during development, which include fetal growth restriction, persist as lifelong deficiencies lowering the performance and health of the animal. We discuss how the enlarged transplacental gradient for oxygen and glucose facilitates umbilical uptakes but results in low blood oxygen and plasma glucose concentration in the fetus. These conditions slow growth by altering glucose metabolism, decreasing amino acid clearance, and decreasing anabolic hormones while increasing catabolic hormones."} +{"text": "The prevalence of inflammatory bowel disease (IBD) in Canada is among the highest in the world and is estimated to affect 1 in 100 Canadians by 2030. Ulcerative colitis (UC) is a type of IBD characterized by mucosal inflammation of the large intestine. UC is believed to arise through a complex interplay of the host immune responses and changes in the gut microbiota in a genetically susceptible individual. Therapies targeting the gut microbiota, such as antibiotics and fecal microbiota transplantation (FMT), have been effective in treating UC, suggesting infectious triggers should be explored.Enterobacteriaceae, which can carry virulence genes important for colonizing the gut (e.g. fimH) and disrupting the intestinal epithelium (e.g. hylA). However, many studies have focused on a single species (e.g. Escherichia coli) and thereby underestimate the importance of these virulence genes that are shared across the Enterobacteriaceae family. Enterobacteriaceae species.I aim to investigate whether specific virulence genes contribute to disease activity in some patients with UC and to show that these virulence genes are carried by strains of many Some data suggests the development of UC can be driven by pathogenic bacteria of the family Enterobacteriaceae. Samples from before and after treatment were sent for targetted cultured-enriched metagenomic sequencing and strains were isolated from baseline samples only for whole genome sequencing. The taxonomy of each genome and taxonomic composition of each metagenome were annotated along with virulence genes and antimicrobial resistance genes. Phenotypic assays of cultured isolates were used to capture diversity and virulence activity.UC patient stool samples were collected throughout enrolment in randomized control trials of FMT for adult UC and microbiome studies in early-onset pediatric UC. The stool samples were cultured on MacConkey agar to enrich for Enterobacteriaceae strain collection. Across all patient samples, we detected 19 different species of the Enterobacteriaceae family across six genera from the genomic and metagenomic data. We identified virulence genes found across multiple species from the Enterobacteriaceae family within genomes and metagenomes, and by performing phenotypic assays of the cultured isolates.Approximately 7500 colonies from UC patient stool samples were isolated and phenotyped. Based on the initial screens, 130 isolates were selected to comprise our Further exploration of the distribution of these virulence genes in UC patients during active disease or remission and healthy controls can provide insight into the pathogenesis of UC. Identifying infectious agents in even a subset of UC patients will allow for more targeted diagnosis and treatment approaches.None Declared"} +{"text": "Focusing on Covid-19 recovery, this symposium will feature a selection research studies that highlight lessons learned that are applicable across the continuum of care for older adults, their families and care partners. The collection of presentations bring perspectives from local to global. Each of the presenters will highlight implications for health and aging policy."} +{"text": "With a growing interest in intersectionality, critical qualitative researchers acknowledge the benefit from incorporating an intersectional lens. Incorporated intersectionality can be beneficial since it allows researchers from different disciplines to consider and account for the participant identities as multidimensional, fluid and, interdependent at each stage of the research process. In this presentation we will offer insights how qualitative research can be enhanced by incorporating an intersectional lens when analyzing the interconnectedness of numerous socially constructed identities . Furthermore, we will address challenges how to conduct intersectional qualitative research and analysis . This approach challenges on many levels, but since qualitative and interdisciplinary research is about utilizing meaning of phenomena, incorporating an intersectional lens will not only expand the methodological horizon of researchers but also stimulate ethical and critical inquiry throughout the research process."} +{"text": "Moreover, SPNs are the earliest substrates to receive early sensory-driven activity from the periphery and are involved in its modulation, amplification, and transmission before the maturation of the direct adult-like thalamocortical connectivity. Consequently, SPNs are vulnerable to sensory manipulations in the periphery. A broad range of early sensory deprivations alters SPN circuit organization and functions that might be associated with long term neurodevelopmental and psychiatric disorders. Here we provide a comprehensive overview of SPN function in activity-dependent development during early life and integrate recent findings on the impact of early sensory deprivation on SPNs that could eventually lead to neurodevelopmental disorders.Early neural activity in the developing sensory system comprises spontaneous bursts of patterned activity, which is fundamental for sculpting and refinement of immature cortical connections. The crude early connections that are initially refined by spontaneous activity, are further elaborated by sensory-driven activity from the periphery such that orderly and mature connections are established for the proper functioning of the cortices. Subplate neurons (SPNs) are one of the first-born mature neurons that are transiently present during early development, the period of heightened activity-dependent plasticity. SPNs are well integrated within the developing sensory cortices. Their structural and functional properties such as relative mature intrinsic membrane properties, heightened connectivity The efficiency of information processing in the sensory cortices relies on precise wiring and organization of underlying circuits that include billions of neurons and hundreds of thousands of synapses. Unfolding of genetic programs instruct a significant proportion of events in circuit development by establishing the first rough arrangement of connections which includes neural differentiation, migration, axon guidance, dendritic extension etc. Polleux, . HoweverA signature feature of neural activity during early development includes periodic \u201cspontaneous\u201d bursts of patterned activity within neural networks that are correlated among neighboring cells and are independent of external sensory stimulation . SPNs are one of the first born mature neurons in the sensory cortices that are transiently present during early corticogenesis and additionally that these markers can vary across cortical areas.A hallmark of SPNs is their relatively mature structural and functional properties. Due to their earlier generation and mature developmental stage, SPNs possess extensive axonal and dendritic extension and arborization in the mouse somatosensory cortex during the first postnatal week after electrical and optogenetic activation of thalamic afferents in thalamocortical slices and some additional markers have been identified in subpopulations of SPNs in sauropsids and mammals , spinal cord, cerebellum, hippocampus, and neocortex in a variety of species . BDNF is an indispensable mediator of activity-dependent plasticity in awake animals ] never develop mechano-transduction in the cochlea and are born deaf in the ribbon synapses of inner hair cells in the cochlea . Importantly, animal research and clinical studies strongly indicate that early pathophysiological disturbances to SPNs are associated with several long term neurodevelopmental and psychiatric disorders . As a result, those techniques lacked cell-type specificity. Thus, it is time we revisit those experiments using modern and more selective techniques. For further understanding the function of SPNs we propose the following future directions:Unambiguously mapping and characterizing SPN inputs and outputs to key targets using more selective approaches such as optogenetics.Validating results from the older SPN lesioning experiments by using selective ablation or targeted silencing methodologies. Newer techniques have the potential to reveal a more nuanced picture and uncover new findings that the older and less sensitive technologies failed to do.Determining if SPNs perform similar roles in different species.Directly identifying the functional coupling between thalamus, SPNs and cortical plate neurons across sensory systems to confirm the assertion that SPNs process early sensory stimuli in all sensory systems.Directly testing the assertions that SPNs amplify thalamic activity by using experimental systems studies or computational models. What would be the characteristics of such amplifier systems?Developing sensory cortices receive crossmodal multisensory input from other sensory pathways . As much as we need to apply high-end techniques to go beyond the circumstantial/ indirect evidence to understand SPN functions, it is also high time we focus on optimizing tools and techniques to overcome the technical challenges to study early development.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.Both authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication."} +{"text": "Communities may lack the infrastructure and required resources to support healthy aging and aging in place. Advancements in technology development such as socially assistive robots and artificial intelligence present new opportunities to support and meet the needs of older adults. For example, Misty is a socially assistive robot designed to allow customizability and adaptability to support and meet diverse user needs pertaining to tasks and activities. Our research aim is to understand if Misty can facilitate social interactions with older adults, control the home environment, and provide reminders. We are exploring older adults\u2019 attitudes towards Misty through demonstrations of these activities. Through this research we provide insights pertaining to the facilitators and barriers in the acceptance and use of a socially assistive robot like Misty, to support healthy aging. Furthermore, our findings will provide guidance for design and implementation of artificial intelligence through socially assistive robots in a home environment."} +{"text": "Emotional and instrumental supports from adult children have been shown to increase positive outcomes among older adults. In this study, we examined the association between intergenerational transfer and self-rated health as well as the mediating and moderating roles of resilience and gender, respectively, using data from Chinese older adults in Honolulu (N=400). We found that the impact of emotional and instrumental support varied by gender. Further, we found that resilience significantly mediated the positive effect of provided economic support on health of older men as well as the positive effect of received emotional support on health of older women . Our study highlights the importance of considering resilience and gender differences when examining intergenerational transfers and health among Chinese older adults. The design of a culturally tailored policy would help promote the health of Chinese older adults."} +{"text": "Nonhuman primates (NHPs) are critical for translational research due to their close genetic, physiological, and behavioral similarity to humans. In particular, higher brain functions depend on brain regions and neural circuits that evolved differently between primates and rodents. Thus, NHPs are a strong translational model system to investigate the pathophysiology and relevant biological correlates of mental disorders. This talk will focus on translational approaches leveraging NHP models to advance our understanding of environmentally induced epigenetic changes in post-traumatic stress disorder (PTSD). Environmental factors including early life stress significantly contribute to risk and resilience for psychiatric disorders including PTSD. However, human studies are often confounded, and it remains challenging to identify robust epigenetic signals in clinical populations even in large studies. We investigate the natural spectrum of behavioral phenotypes in rhesus macaques to complement human studies with a focus on stress and fear. This talk will present data on epigenetic signatures of fear and the effects of early life stress in rhesus monkeys and their relationship to human studies.No significant relationships."} +{"text": "Diabetes is a major risk factor for a variety of cardiovascular complications, while diabetic cardiomyopathy, a disease specific to the myocardium independent of vascular lesions, is an important causative factor for increased risk of heart failure and mortality in diabetic populations. Lysosomes have long been recognized as intracellular trash bags and recycling facilities. However, recent studies have revealed that lysosomes are sophisticated signaling hubs that play remarkably diverse roles in adapting cell metabolism to an ever-changing environment. Despite advances in our understanding of the physiological roles of lysosomes, the events leading to lysosomal dysfunction and how they relate to the overall pathophysiology of the diabetic heart remain unclear and are under intense investigation. In this review, we summarize recent advances regarding lysosomal injury and its roles in diabetic cardiomyopathy. Diabetes is a major risk factor for the development of various cardiovascular complications, which constitute the leading causes of mortality in both type 1 and type 2 diabetic populations. Moreover, diabetic patients have an especially poor prognosis following myocardial infarction . In addiOxidative stress has been thought to be the major mechanism that mediates diabetic cardiomyopathy , which iper se, but also repair or remove injured intracellular contents resulting from the stressors , and a calcium channel TRPML1 embedded in the membrane , to maximize the efficiency of digestive enzymes. The acidic pH of the lysosomal lumen is maintained by multiple ion pumps and channels such as a proton pump Vacuolar Hmembrane . In the membrane . Insteadmembrane .via Ragulator. mTORC1 phosphorylates the serine 211 residues to promote TFEB degradation and inhibit nuclear translocation pathway mechanism plays a key role in closing holes in the lysosomal membrane; the ESCRT complex forms spiral filaments at the fray of membrane that require suturing, to catalyze membrane remodeling, guided by ALG2-interacting protein X (ALIX)-ESCRT complex. A lysosomal membrane tension reduction and calcium ion leakage have been proposed as the cues triggering ESCRT assembly at the site of lysosomal injury. The ESCRT complex appears to be recruited to the site of injury upon detection of endo-lysosomal tension . Calciumt manner . Another pathway . These lWhen the damage to the membrane becomes more severe, to the extent that proteases and other macromolecules leak out, the glycan-binding protein galectins bind to the sugar chains (glucagon) in the lysosome and navigate ALIX complex to repair the membrane by the ESCRT system . At the Due to the pleiotropic effects of the lysosome on cell death and survival, lysosomal dysfunction can cause various diseases through either decreased or excessive activity. Lysosomal storage diseases (LSDs) are often caused by the accumulation of substrates that have been incorporated into lysosomes and are not fully processed by the hydrolytic enzymes. Mutations or abnormalities in any one of the lysosomal enzymes can result in inadequate degradation or inability to process the accumulated substrates at the required pace. In Fabry disease and Krabbe disease, mutations in the degrading enzymes alpha-galactosidase (GLA) and galactocerebrosidase (GALC) both lead to cardiomyopathy . LSDs thAccumulating evidence suggests that altered autophagy is often associated with lysosomal dysfunction . The conIn cardiomyocytes, the transcription factor EB (TFEB) plays a role in promoting autophagosome formation and lysosome biogenesis. There is evidence that TFEB is inactivated by phosphorylation in mice fed a high-fat, high-glucose diet, inhibiting its translocation to the nucleus, which leads to an inhibition of autophagosome formation, autophagosome-lysosome fusion, and lysosome biogenesis . Indeed,The autophagy-lysosomal degradation pathway is critical for maintaining cardiac homeostasis under both normal and pathologic conditions . In fact2+. Disruptions of lysosomal acidification and the release of iron caused by LMP can lead to the lipid peroxidation of lysosomal membranes and the release of CTSB, promoting cell death and the ensuing cathepsins release are responsible for diabetic cardiac injury. An emerging hypothesis postulates that the increased LMP and the ensuing cathepsins leakage and aberrant accumulation are an important mechanism that mediates diabetic cardiomyopathy and heart failure; thus, enhancing lysosomal quality control and minimizing the ectopic effects of cathepsins would be expected to protect the diabetic heart. To test this hypothesis, one needs to address a number of different questions, including: What causes LMP in diabetic myocardium? What is the extent of lysosomal damage caused by diabetic stress? Are there biomarkers to assess such damage? How do cardiomyocytes repair lysosomal membrane damage caused by diabetes? Which and how cathepsins affect cardiomyocyte death and survival? Further investigation is warranted to determine the exact functional roles of these cathepsins in the diabetic heart by using pharmacological agents and/or genetic animal models with increased or decreased activities of each of the cathepsins. Moreover, future studies should also determine whether ectopic localization of these potential targets occurs in the diabetic heart and how the LMP repairing mechanisms and lysophagy respond to these changes. Addressing all the above issues will help elucidate the mechanisms underlying diabetic cardiomyopathy and suggest novel strategies for restoring lysosomal function and reducing diabetic cardiac injury."} +{"text": "The growing racial and ethnic diversity of the older adult population, along with continued inequities in brain health outcomes highlight the need to examine risk-factors for reduced cognitive health in racial-ethnic minoritized adults. Stress is an important risk factor for reduced cognitive health, but the conditions under which stress operates among minoritized older adults is poorly understood. This presentation will discuss how studying sources of stress across multiple levels of analyses, including neighborhoods and interpersonal interactions, and the timing and duration of these experiences is needed. Further, addressing within group heterogeneity and shifting from between group comparison will enrich our understanding of risk-factors. Theoretical and empirical support for these propositions will be discussed, particularly as they relate to how neighborhood contexts and experiences with discrimination are associated with reduced cognitive health across multiple timescales."} +{"text": "Danio rerio) model to study adult neurogenesis and neuroregeneration in the central nervous system (CNS), it has become evident that aNSPC proliferation is regulated by a wealth of stimuli that may be coupled with biological function. Growing evidence suggests that aNSPCs are sensitive to environmental cues, social interactions, nutrient availability, and neurotrauma for example, and that distinct stem and progenitor cell populations alter their cell cycle activity accordingly. Such stimuli appear to act as triggers to either turn on normally dormant aNSPCs or modulate constitutive rates of niche-specific cell cycle behaviour. Defining the various forms of stimuli that influence RGC and NEC proliferation, and identifying the molecular regulators responsible, will strengthen our understanding of the connection between aNSPC activity and their biological significance. In this review, we aim to bring together the current state of knowledge on aNSPCs from studies investigating the zebrafish CNS, while highlighting emerging cell cycle regulators and outstanding questions that will help to advance this fascinating field of stem cell biology.Adult neural stem and progenitor cells (aNSPCs) persist lifelong in teleost models in diverse stem cell niches of the brain and spinal cord. Fish maintain developmental stem cell populations throughout life, including both neuro-epithelial cells (NECs) and radial-glial cells (RGCs). Within stem cell domains of the brain, RGCs persist in a cycling or quiescent state, whereas NECs continuously divide. Heterogeneous populations of RGCs also sit adjacent the central canal of the spinal cord, showing infrequent proliferative activity under homeostasis. With the rise of the zebrafish ( Teleost fishes serve as exceptional models to study the cell cycle dynamics and function of adult neural stem and progenitor cells (aNSPCs) throughout the central nervous system (CNS). The lifelong presence of proliferating aNSPCs across diverse stem cell niches of the brain , along wDanio rerio) has become one of the most popular laboratory models to study these factors in the brain and spinal cord. The social nature and complex behaviours displayed by this species , as well as lateral line input . A unique feature of zebrafish is that aNSPCs exist in neurogenic niches within primary processing sensory structures of the mature brain, including the forebrain olfactory bulbs (smell), midbrain optic tectum (vision), and hindbrain vagal/facial lobes taste; . These sStudies applying forms of environmental enrichment or selective visual cues have shown a strong link between sensory input and aNSPC activity. A pointed example of how the mere opportunity for visual stimuli can induce changes in long-term aNSPC activity comes from recent work by Dunlap et al. (2021). Here, socially acclimated zebrafish that were first isolated, before being exposed to conspecifics in an adjacent tank chamber, was sufficient alone to enhance forebrain aNSPC activity. The above finding is supported by an early study exposing zebrafish to an enriched environment adorned with aquatic plants and gravel, or devoid of such items, showing a general increase in proliferation of forebrain aNSPCs with enrichment . An outsVisual and chemosensory assays have also been employed to more directly test the effect of modality-specific sensory input on the activity of aNSPCs in corresponding sensory niches. Exposing zebrafish to monochromatic light has been demonstrated to decrease the proportion of cycling aNSPCs in the tectal sensory niche . ExperimTaking advantage of sensory niches in the adult zebrafish brain further offers the chance to study the functional significance of aNSPCs for learning. Using sensory paradigms to explore the impact of task complexity on endogenous neurogenesis arising from sensory zones would provide new insight not possible in mammals. For instance, building on previous olfactory learning paradigms , researcModulation of spinal cord RGCs for the most part has not been explored as this population resides mainly in a quiescent state. Recently, one of the first studies of its kind has shown that zebrafish subjected to increased swimming using a swim tunnel was sufficient to enhance cell cycle proliferation of normally dormant spinal cord ependymoglia, and the generation of newborn motor neurons . ApplyinMuch effort has been placed on understanding the behaviour of RGCs and NECs following CNS damage compared to homeostatic modulation. More recently, this has also included examination of aNSPCs in a neurodegenerative context. Common to brain and spinal cord injury is the involvement of quiescent RGCs that are awakened following insult to re-enter the cell cycle and repopulate lost neuronal subtypes. In some instances, constitutively active NECs have been shown to additionally contribute to repair. Growing evidence suggests that aNSPCs retain diverse regenerative capacities that differ by stem cell niche in the adult CNS , but thecxcr5 and Gata3 during neurorepair , that serve to replenish lost neurons and oligodendrocytes, respectively . Most rerorepair ; 2012b. haustion . This fihaustion . In the haustion . In bothhaustion . Additiohaustion and larvhaustion confirm haustion . Such stA small number of studies have also underscored the contribution of constitutively cycling NECs following brain injury. In the optic tectum, quiescent RGCs reside along the roof of the tectal ventricle whereas a pool of NECs sit at the midline tectal marginal zone, continuously furnishing the optic tectum with a small number of newborn neurons . FollowiModels of Alzheimer\u2019s and Parkinson\u2019s disease have also been established in the zebrafish, permitting studies of aNSPC activity during the process of neurodegeneration. Alzheimer\u2019s models along with single-cell transcriptomics have illustrated neurodegenerative specific regulation of aNSPCs. These studies show that induced inflammation leads to a cascade of events, initiated by the activation of the IL4/STAT6 pathway. Subsequent downregulation of serotonin metabolism and promotion of BDNF in turn increase aNSPCs proliferation in a subtype and niche-specific manner . ParalleThe zebrafish is a tractable model to probe the mechanisms regulating aNSPC function. Still many outstanding questions persist. First, many niches of the brain are composed of populations of both quiescent and actively cycling RGCs. Adult neurogenesis by definition focuses on constitutively proliferating cells, whereas CNS regenerative studies concentrate primarily on the reactivation of quiescent aNSPCs. Whether certain forms of stimuli under homeostasis are sufficient to push quiescent RGCs into a cycling state, or a subpopulation of normally dividing RGCs of the forebrain might contribute to regeneration, is unclear. Equally unknown is whether RGCs or NECs can undergo shifts in their multipotency to generate specific neuronal lineages under different contexts, and if so, what are the intrinsic programs or changes in the microenvironment responsible for this cellular plasticity? Second, without knowledge of the molecular signature of similar aNSPCs found in different adult niches, it is unclear whether their gene expression profiles align with their varied response to environmental or injury-induced cues. Many cell autonomous features also remain to be understood, including cell metabolism , senescein vivo studies, 3-dimensional imaging of the CNS (Methods to study the activity of zebrafish aNSPCs are extensive. These include the use of thymidine analogues such as BrdU and EdU, that label cells undergoing DNA synthesis , as well the CNS , and adv the CNS , the nex"} +{"text": "Unfilled resins based on bisphenol A-glycidyl methacrylate (Bis-GMA) seem to be the best choice for the lubricant, as bonding agents containing hydrophilic molecules and alcohols carry a bigger risk of altering the composite properties. Further research is necessary to evaluate lubricants' influence in clinical practice conditions.Resin composites are one of the most commonly used materials in restorative dentistry. To improve their handling and facilitate restoration sculpting, clinicians began to lubricate modeling instruments with various substances like alcohol, unfilled resins, or even bonding agents. Although the technique is commonly present in daily clinical practice, it has not been precisely described in the literature and both application methods and lubricating materials vary across the available studies. This study aims to summarize the currently available knowledge about influence of instrument lubrication on properties of dental composites. Literature selection was conducted within MEDLINE, SCOPUS, and EBSCO databases. Instrument lubrication seems not to be indifferent for composite mechanical and optical properties. Moreover, various lubricants can differently affect the composite material, so the choice of lubricating agent should be deliberate and cautious. Available Composite resins are fundaments of contemporary restorative dentistry.Composite resins present viscous consistency which can impede proper anatomical contour modeling or adaptation of the material to cavity walls.in vitrostudies, authors investigated multiple materials and methods of their application on mechanical and optical properties of restorative materials.Instrument lubrication technique has not been officially described in the scientific literature, thus lack of standardized research methods to analyze this topic can be observed. Within availableThe study aims to summarize the currently available knowledge about influence of instrument lubrication on properties of dental composites. Literature selection was conducted within MEDLINE, SCOPUS, and EBSCO databases. Studies describing usage of resins as a surface glaze after the finished composite polymerization were excluded.Widely used group of lubricants meant to facilitate material modeling include resins existing either in clear form, as the so called unfilled resins, or being part of the adhesive systems. They are composed of various methacrylate derivatives present also in organic matrix of dental composites, that is, bisphenol A-glycidyl methacrylate (Bis-GMA), urethane dimethacrylate (UDEMA), triethylene glycol dimethacrylate (TEGDMA), and photoinitiators that allow light curing and in the case of the bonding agent, also additional ingredients facilitating efficient application and adhesion to tooth structure. Hydrophilic molecules present in adhesive systems, such as water, ethanol, or acetone, might affect elements of the composite matrix.Most of contemporarily used composite materials are based on Bis-GMA monomers and comonomers present relatively lower viscosity and molecular weight.Materials used for replacing dental tissues must be characterized by high and universal resistance to withstand constant occlusal forces.Dunn and Strong have not shown any significant differences in flexural strength between composite samples layered with or without the use of modeling resin.Negative outcome of instrument lubrication on composite resistance was observed by Patel et al. Authors described higher diametral tensile strength (DTS) in control group than in groups where IV-, V-, and VII-generation bonding agents were used as lubricants.Majority of clinical situations require composite layering because of limited depth of curing light penetration through the material and need of polymerization shrinkage reduction, as well as from esthetic reasons, to compose a restoration from materials with different optical properties.Tjan and Glancy observed reduced resistance of Heliomolar material lubricated with currently unused bonding system based on polyurethane, Dentine Adhesit .Barcellos et al study has shown reduction of tensile strength between composite layers caused by instrument lubrication with all tested self-etch adhesive systems except for Adper SE Plus Adhesive , adhesive resin from VI-generation system. According to the authors, this is due to fact that ionization of acidic phosphate monomer (MHP) present in Adper SE Plus occurs only in presence of hydrophilic radicals contained in the primer of this system.In earlier studies, the same authors proved that only one out of three tested total-etch adhesive systems, ScotchBond MultiPurpose used during composite modeling caused the increase of cohesive strength of layers in comparison to the control group. ASB, Prime & Bond NT and modeling resins did not influence this parameter. This relation has been explained by chemical similarity of SBMP and compounds of tested composites, as well as by its lack of hydrophilic solvents.Positive effect of instrument lubrication with SBMP on composite tensile strength was not confirmed during microtensile bond strength (\u00b5TBS) test, performed after 24\u2009hours of water storage. Similarly, as in case of flexural strength tests, lubrication with ASB and SBMP decreased tensile strength loss after 6 months of water storage compared with control group.Surface quality and smoothness are some of the conditions providing clinical success and durability of created restoration. High gloss of composite surface apart from obvious patient's esthetical satisfaction guarantees also higher staining resistance of the resin.No effect of instrument lubrication with universal bonding agents and modeling resin on nanohybrid composite microhardness was observed by Kutuk et al. Microhardness reduction was only obtained during lubrication with self-etch system primer. Both tested adhesive systems and modeling resin had no effect on surface roughness of the composite.In the study, investigating instrument lubrication with modeling resin, Tuncer et al proved reduction in composite surface microhardness in a group where superficial layer was not mechanically finished. Samples modeled with lubricated instrument but thereafter grinded with aluminum oxide discs have not shown statistically significant difference in surface roughness compared with control for five out of seven examined composites. The results observed were related to removal of resin-rich superficial layer during finishing. Samples modeled with lubricant and polymerized under polyester strip exhibited the lowest surface roughness. Among groups polished after polymerization, instrument lubrication positively affected surface smoothness of Grandioso composite but negatively influenced Filtek Silorane and Aelite All Purpose Body composites. The remaining restorative materials showed no difference compared with the control group.In the research by Bayraktar et al, evaluating the effect of three different modeling resins, composite microhardness reduction was observed for all of the tested composite materials.The achievement of desired performance by dental composite materials depends highly on their correct polymerization.In the study conducted by Melo et al, instrument lubrication with SBMP caused reduction in the degree of conversion of all examined composites. Usage of ASB as a lubricant also decreased the degree of conversion for Empress Direct A2 and Bleach shades however increased it for Esthet X HD A2 shade.The amount of available studies verifying effect of instrument lubrication on polymerization quality is limited. Results suggest possible incorporation of lubricant particles into composite matrix and alterations in the polymerization reaction kinetics.During cross-section surface analysis of freshly placed composite samples using SEM, no changes in the micromorphology of interlayer interface have been observed.Superficial composite layer examination after wine storage showed lower surface degradation in the group modeled with adhesive system as a lubricant compared with the control group. Authors connect that surface degradation with influence of the alcohol contained in wine.Composite restorations in the in vivo conditions are permanently interacting with surrounding water solution: composite absorbs little amounts of water and also its small particles get dissolved during the hydrolytic reaction.The use of SBMP and ASB as instrument lubricants reduced composite solubility compared with control group. Water sorption was reduced only with the use of SBMP.Different outcome was obtained during measurements of water sorption, it has increased in all tested groups. Additionally, the study has shown no linear relation between number of layers modeled with lubricant and water sorption.Composite modeling with lubricated instruments or brushes is especially helpful during work in the esthetic region. Replication of correct anatomical form and proper surface texture already at the application stage allows clinician to save time needed for contouring and finishing of the restoration. Qualitative and quantitative compositions of organic matrix affect color, translucency, light refraction index of dental resins, and also their staining susceptibility.Studies examining influence of instrument lubrication with modeling resins and adhesive systems on composite optical properties are listed inIncreased translucency of Filtek XT Z350 and Filtek Z250 was described in the literature while using the instrument lubrication technique with bonding agents from the same manufacturer, ScotchBond MultiPurpose and ASB.Color stability is one of the requirements for restorative materials. Pigments contained in daily diet can cause external and internal discoloration both within the dental tissue and in the composite.Tuncer et al examined effect of instrument lubrication with Modeling Resin on color change of composites. Higher color change range was observed after thermocycling Filtek Ultimate and Filtek Silorane samples; however, only for the latter change was greater than estimated acceptation threshold.Instrument lubrication with SBMP, ASB and Adper Universal resulted in lower composite color change after storage in strongly staining solutions.Usage of alcohol as a substance preventing sticking of the chemically cured composite to plastic modeling instruments was for the first time described already over 40 years ago. Instruments moistened in alcohol did not affect material adaptation to cavity walls and composite resistance.Tjan and Glancy have shown negative influence of instrument lubrication with alcohol during layering of UDEMA-based composite on tensile strength. Such relation was not observed for composite based on Bis-GMA, where samples during the tests sustained mostly cohesive fractures. Different behavior of those two materials can be explained by different vulnerability to degradation by hydroxyl ions contained in alcohol.Negative influence of instrument lubrication with alcohols on physical properties of layered composite was described by other researchers. Patel et al demonstrated composite resistance decrease in diametral tensile strength test for samples applicable with the use of 70% ethanol and also their increased water sorption compared with control group.Research results differ according to the application method used and composite type. The amount of alcohol present on the instrument during the modeling can be significantly different in mentioned studies. Furthermore negative effect of instrument lubrication with alcohol seems connected with its quantity introduced into composite portion, what is consistent with the observations of Sneed and Draughn.The quoted results present current knowledge about influence of instrument lubrication with resins, bonding agents, and alcohol on properties of dental composites.From all tested lubricants the least negative effects on mechanical properties of composites could be observed for resin with composition similar to composite organic matrix, as well as in case of alcohols, presence of hydrophilic particles in adhesive systems can more affect the composite properties compared with bonding agents with more hydrophobic composition and unfilled resins.Changes in conversion degrees and microhardness values of superficial composite layers indicate incorporation of lubricant particles into the composite structure and consequently creation of external resin-rich layer.Most often examined resin was ScotchBond MultiPurpose adhesive, consisting mostly of Bis-GMA and hydroxyethyl methacrylate (HEMA). Viscosity of monomer mixture has a direct effect on degree of conversion and polymerization shrinkage of composites.Instrument lubrication does not seem to have a noticeable effect on base color of methacrylate composites when both the material and the lubricant present similar monomer composition. The increase in staining resistance of composites after modeling with resin lubricated instrument is an interesting relationship. This positive outcome might be mainly connected to improved composite adaptation and reduction of surface microdefects. As a result, a material sealing effect is obtained, similarly to surface glaze application on already cured composite.The use of ethanol and isopropanol carries high risk of damaging composite resin matrix elements which can cause decrease in tensile strength between the layers and surface degradation. Observed lack of effect of ethanol on composite properties might be a consequence of a full evaporation of that substance from the modeling instrument. As a result, it cannot be equated to instrument lubrication but rather just instrument cleaning and degreasing.The topic of instrument lubrication during composite sculpting has been discussed from several dozen years. Usage of that technique in everyday clinical practice is a fact, despite the doubts around its safety and influence on applied material. Methodological differences present in particular studies involved in this analysis increase the number of variable parameters, in example type of the instrument used to smoothen the composite surface which additionally impede direct results comparison. According to current research, the following inferences can be drawn:The composition of the lubricant can influence properties of applied composite.Usage of alcohol as an instrument lubricant carries a risk of damaging the resin matrix and consequently decreases the mechanical performance of the material.Among analyzed bonding agents, the least negative effects were observed after use of adhesive resins, which are free from hydrophilic particles, results were close to those obtained with the use of dedicated modeling resins.Methacrylate based lubricants do not seem to negatively influence the optical properties of the most of composite materials; however, they are not recommended for work with silorane matrix based composites.Instrument lubrication technique allows to obtain more regular surface, with less microporosities and imperfections what positively affects composite staining resistance and stability in water environment.An important issue that has not been yet answered is the real amount of lubricant incorporated into the composite structure and consequent potential modification of its chemical composition taking into consideration an accurate representation of clinical conditions."} +{"text": "Introduction: Precision medicine is focused on serving the unique needs of individuals. Oral and oropharyngeal cancer risk assessment identifies individual risk factors while providing support to reduce risk. The objective is to examine potential current and future strategies to broadly implement evidence-based oral and oropharyngeal cancer risk assessment and screening in dental practices throughout the United States. Methods: Feasible and effective oral cancer risk assessment and risk reduction strategies, ripe for implementation in dental practice, were identified in the published literature. Results: The Screening, Brief Intervention, Referral for Treatment (SBIRT) model is a feasible approach to assessing individual oral cancer risk and providing risk reducing interventions in the dental setting. HPV is a more recently identified risk factor that dentistry is well positioned to address. Evidence supporting the utilization of specific risk assessment tools and risk reduction strategies is summarized and future opportunities discussed. Discussion: Current knowledge of risk factors for oral and oropharyngeal cancers support the recommendation for dental providers to routinely assess all patients for risk factors, educate them about their personal level of cancer risk, and recommend actions to reduce relevant risk factors. Individuals ages 9\u201326 should be asked about their HPV vaccination status, educated about HPV and oropharyngeal cancer and receive a recommendation to get the HPV vaccination. According to the National Institute of Health\u2019s All of Us Research Program , precisiEach year, an estimated 53,000 US adults are newly diagnosed with oral or oropharyngeal cancer . Visual A more upstream approach that identifies and addresses known risk factors offers the potential to reduce oral and oropharyngeal cancer . This prOral cancer risk assessment tools are currently available with electronic versions available in dental schools . The utiIncorporating strategies for addressing smoking-cessation with their patients into the curriculum for dental providers is expected to facilitate uptake of smoking cessation counseling into routine dental practice because dental providers initially model their care practices on what they were taught in school ,19,20. HPrevention is defined as the protection of health . PreventThis objective is achieved by examining the current peer-reviewed literature to determine what approaches are feasible in the clinical setting and the current evidence on the efficacy of various prevention strategies to address the currently known risk factors. Future opportunities to improve both the accuracy and implementation of risk assessment are also examined in the context of addressing known barriers. These barriers are explored from the perspective of the division of medicine and dentistry and the changing trends in dental practice. These trends include the integration of dental care delivery into health care systems such as Federally Qualified Health Centers, HealthPartners in Minnesota, Kaiser Permanente in Oregon, and the Marshfield Clinic in Wisconsin. Dental practice models are also changing with an increase in large dental service organizations with more collective resources to support a more robust oral cancer risk assessment program. The two authors conducted the literature searches identifying current evidence and the research gaps.Screening, brief intervention and referral to treatment (SBIRT) is an evidenced-based practice that that encourages healthy behaviors, identifies problematic drug and alcohol use early, reduces substance misuse, and refers individuals to treatment if they need it. It involves a process of steps that a healthcare professional including dental clinicians can take to assess alcohol and drug use behaviors in their patients to reduce oral cancer risk along with other risks to their health . This apCurrent use of SBIRT in dental settings is limited ,30. A 20Research on barriers to dental providers addressing substance use is limited. However, over a decade ago Neff and colleagues examined factors affecting readiness to screen or provide brief intervention for substance use in dental practice . PerceivPersistent HPV infection is a well-established risk factor for developing oropharyngeal cancer . Most deUptake of the HPV vaccine remains modest, despite evidence that vaccine-type HPV prevalence is decreasing as a result of HPV vaccination . Dental Opportunities for collaborative practice between dentists and physicians can occur in health care systems with a dental component. The full integration of dentistry in health care teams remains unrealized leaving dentistry on the margins of new innovative new models of care delivery . The neeSystems of care in which teams are currently practicing integrated oral health care delivery with an integrated EHR include Permanente Dental Associates and HealthPartners . These oWe are seeing some progress in EHR software companies such as Epic integratElectronic health record-based clinical decision support (CDS) \u201cprovides clinicians, staff, patients, or other individuals with knowledge and person-specific information, intelligently filtered or presented at appropriate times, to enhance health and health care\u201d . CDS canA tobacco CDS tool increased dental practitioners\u2019 advice to quit smoking and referral to a quitline during a group randomized trial. After completion of the trial, the CDS was implemented in all the dental clinics within HealthPartners. Sustained use was examined, and the results showed that the dental practitioners persisted in using the CDS tool to refer smokers to a quitline . This onIn summary, an integrated EHR enhances the information needed to make better diagnoses and treatment decisions. These benefits need to be balanced with extra time spent in front of a computer searching for relevant information and entering information about the visit . CDS canThe dental profession is experiencing disruptions in technology, communications, workforce, payment, and management, all driven by creative innovators sponsored by venture capital, nonprofits, and governments . Two disn = 71). Development of these measures often lacked involvement of patients and dental professionals. Few projects reported on the validity (n = 2) and reliability (n = 3) of the measures, and few (n = 3) piloted the measures in practice [Quality measures are not well developed in dentistry. A recent systematic review examined existing quality measures in the field of oral health care. This review identified measures of quality pertaining to treatment and preventive services refers to the ability of machines to perform tasks normally performed by humans. The potential for Artificial Intelligence (AI) to transform healthcare delivery is tremendous . The maiTo date, AI in health care has had the greatest utility in the area of aiding diagnostic imaging but has seen little uptake to date due to lack of data which is due to privacy concerns and logistical issues in accessing the data. Several issues have prevented AI from enjoying widespread adoption, despite its promise. Lack of a financial reimbursement model for AI diagnosis is one obvious barrier discussed in detail elsewhere . AnotherConsidering that NIH is making investments to pave the way for AI in health research , and thaCurrent knowledge of risk factors for oral and oropharyngeal cancers support the need to routinely assess all patients for risk factors, educating patients about cancer risk and recommending actions to reduce the relevant risk factors. Implementing SBIRT into all dental practice settings is a feasible and effective approach to address substance use with patients while addressing perceived and real barriers. Individuals ages 9\u201326 should be asked about their HPV vaccination status. Dental providers should educate patients and parents of age-eligible children about the link between HPV and oropharyngeal cancers which are impacting younger adults and recommend HPV vaccination as cancer prevention.For patients using tobacco products, unsafe alcohol use, and other high-risk substances the dental provider should educate the patient about the cancer risks, provide a brief intervention supporting the patient on quitting and provide a referral to a tobacco quit line or a substance use specialist for further assessment and support. In healthcare systems that include dental utilizing an integrated EHR these activities can be further supported by utilizing CDS tools that systematically support the dental provider in collecting the risk information, prompting further assessment questions and providing recommended scripts based on motivational interviewing. For dental providers embedded within health care systems this can be further augmented by facilitating the referral of the patient to other medical services addressing substance use or initiating the vaccine series.The American Dental Association has taken leadership in developing quality measures for dentistry. The Dental Quality Alliance has published measures that will be used by Medicaid and dental plans to measure quality . In addiValue-based payment (VBP) arrangements are growing in health care but just emerging in oral health care. Embarking on a new payment arrangement presents new challenges. Probably the biggest challenge is related to the electronic data currently available at the practice level. Significant gaps exist in coding, data collection, exchange, and analysis . VBP canWhen AI makes inroads into dentistry, we see opportunities to incorporate AI findings into the CDS platform. The future advances will happen when we have better EHR data and systems that can integrate CDS. The time is not now but we need to start planning for that future by thinking about what can be done now to prepare. In addition, research is examining the relationship of the oral microbiome and various cancers including oral cancer . If new Advancing the implementation oral and oropharyngeal cancer risk assessment in dentistry will start with larger group practices who have invested in better EHR systems and are linked with academics and researchers with a care agenda prioritizing risk assessment and risk reduction. These leaders will also see the value in better data, quality measures, and value-based care. These early adopters will need to demonstrate better health outcomes, reducing costs, and improving the patient experience which aligns with the triple aim as defined by the Institute for Healthcare Improvement . Once th"} +{"text": "With higher life expectancy of the aging population, retirees nowadays will spend a prolonged period of time after retirement. Yet, past studies have consistently revealed a lack of retirement savings among working adults, implying an inadequacy to maintain the quality of life in late adulthood. This study therefore aims to identify the factors influencing the working adults\u2019 intention to purchase financial products for retirement (such as deferred annuity and voluntary contribution to retirement fund) and develop an integrated model of financial planning for retirement. A total of 598 Hong Kong Chinese working adults from diverse age and income groups completed an online survey on intentions to save and purchase specific financial products for retirement. The results of MANCOVA reveal that compared to older workers, younger workers had lower intentions to save and purchase financial products for their retirement even after controlling for their monthly income . An integrated model of financial planning for retirement is proposed by incorporating the concepts of the interdisciplinary psycho-motivation model and Theory of Reasoned Actions . In particular, the positive effects of financial literacy, subjective norms, social support, and future time perspective on intention to save and purchase financial products for retirement have been found to be mediated by retirement goal clarity but not attitudes towards retirement. Future direction on promoting younger and older workers\u2019 retirement planning especially in the financial domain will also be discussed in the presentation."} +{"text": "The efficacy of diet and its influence on gut microbiome composition has been largely demonstrated in inflammatory bowel disease (IBD). Little is known about its potential in the management of extraintestinal manifestations. We report a successful application of Crohn disease exclusion diet (CDED) in association with infliximab and methotrexate, as salvage therapy in a child affected by chronic recurrent multifocal osteomyelitis (CRMO) and Crohn disease (CD) resistant to optimized therapy. Both intestinal and bone symptoms remitted after the application of CDED. Diet may have acted on common microbic inciting agents that trigger both intestinal and bone inflammation, supporting the role of microbiota in the pathogenesis of IBD-associated extraintestinal manifestations. Our experience suggests the potential benefit of CDED in association with combined therapy in resistant patients affected by CD and extraintestinal manifestations. We read with interest the publication by Starz and colleagues regardinThis is the first reported case of CRMO associated with CD in which CDED has been attempted. Both intestinal and bone symptoms were resistant to biologics associated with immunomodulator, even after optimization. Remission was achieved after application of CDED. In recent years, the efficacy of exclusion diet plus PEN in inducing sustained remission in CD pediatric patients has been demonstrated, even in subjects resistant to biologics ,5. SimilIn conclusion, our experience suggests the potential benefit of CDED in association with combined therapy in resistant patients affected by CD and extra-intestinal diseases such as CRMO. Further studies are needed to better understand the role of nutritional strategies in these conditions."} +{"text": "Since 2000, the National Cancer Institute\u2019s Cancer Intervention and Surveillance Modeling Network (CISNET) modeling teams have developed and applied microsimulation and statistical models of breast cancer. Here, we illustrate the use of collaborative breast cancer multilevel systems modeling in CISNET to demonstrate the flexibility of systems modeling to address important clinical and policy-relevant questions. Challenges and opportunities of future systems modeling are also summarized. The 6 CISNET breast cancer models embody the key features of systems modeling by incorporating numerous data sources and reflecting tumor, person, and health system factors that change over time and interact to affect the burden of breast cancer. Multidisciplinary modeling teams have explored alternative representations of breast cancer to reveal insights into breast cancer natural history, including the role of overdiagnosis and race differences in tumor characteristics. The models have been used to compare strategies for improving the balance of benefits and harms of breast cancer screening based on personal risk factors, including age, breast density, polygenic risk, and history of Down syndrome or a history of childhood cancer. The models have also provided evidence to support the delivery of care by simulating outcomes following clinical decisions about breast cancer treatment and estimating the relative impact of screening and treatment on the United States population. The insights provided by the CISNET breast cancer multilevel modeling efforts have informed policy and clinical guidelines. The 20 years of CISNET modeling experience has highlighted opportunities and challenges to expanding the impact of systems modeling. Moving forward, CISNET research will continue to use systems modeling to address cancer control issues, including modeling structural inequities affecting racial disparities in the burden of breast cancer. Future work will also leverage the lessons from team science, expand resource sharing, and foster the careers of early stage modeling scientists to ensure the sustainability of these efforts. Since 2000, our research teams have used computer models of breast cancer to address important clinical and policy-relevant questions as part of the National Cancer Institute\u2019s Cancer Intervention and Surveillance Modeling Network (CISNET). Our 6 CISNET breast cancer models embody the key features of systems modeling by incorporating numerous data sources and reflecting tumor, person, and health system factors that change over time and interact to represent the burden of breast cancer. We have used our models to investigate questions related to breast cancer biology, compare strategies to improve the balance of benefits and harms of screening mammography, and support insights into the delivery of care by modeling outcomes following clinical decisions about breast cancer treatment. Moving forward, our research will continue to use systems modeling to address issues related to reducing the burden of breast cancer including modeling structural inequities affecting racial disparities. Our future work will also leverage lessons from engaging multidisciplinary scientific teams, expand efforts to share modeling resources with other researchers, and foster the careers of early stage modeling scientists to ensure the sustainability of these efforts. The purpose of systems epidemiology is to draw on expertise from different disciplines to enhance understanding of factors influencing health and disease and to use that knowledge to evaluate interventions for improving health outcomes \u20133. SysteSystems modeling provides a flexible epidemiologic method to address a variety of policy and clinically relevant questions in cancer control. Since 2000, the National Cancer Institute\u2019s Cancer Intervention and Surveillance Modeling Network (CISNET) modeling teams have developed and applied microsimulation and statistical models of several types of cancer, including breast cancer . CISNET Here, we illustrate the use of collaborative breast cancer modeling in CISNET as a systems epidemiology method. Examples are provided that demonstrate the key features of systems modeling. We also provide recommendations for future team science efforts to develop and apply systems modeling to address policy-relevant cancer prevention and control questions. This article is intended to illustrate the potential of systems modeling and highlight challenges and opportunities for systems modeling to contribute to meeting national cancer goals.No personally identifiable information was used in this study or the modeling research summarized herein. The University of Wisconsin Health Sciences Institutional Review Board determined that this study was not human subjects research (Protocol #2020\u20130620).The CISNET Breast Working Group includes 6 multilevel microsimulation or analytic models: Model D (Dana Farber Cancer Institute) , Model EThe tumor, individual person (woman), and health system levels in the models interact to provide insight into the factors affecting breast cancer incidence, mortality, and other health outcomes. The models incorporate estimates of age-specific breast cancer incidence and estrogen receptor (ER)/human epidermal growth factor receptor 2 (HER2) subtype-specific survival trends in the absence of screening or treatment and then incorporate information on how screening and molecular subtype-specific treatment patterns affect the underlying trends. Based on age-specific performance characteristics, screen detection during the preclinical screen-detectable period can result in diagnosis of earlier-stage or smaller tumors than diagnosed via symptomatic detection. Regardless of method of tumor detection, women diagnosed with breast cancer receive treatment specific to the molecular subtype of their tumors and their age at diagnosis .Table 1 with additional details available in prior publications at age 40 . Women aAlthough women are assigned receipt of screening or therapy at the individual person level in the models, these interventions are delivered via the health system. Hence, healthcare policies at the health system level heavily influence breast cancer screening and treatment that women receive. Women are assigned an age at first mammogram and screening frequency based on the distribution observed for their birth cohort using data from the BCSC, the National Health Interview Survey, and the US Food and Drug Administration\u2019s Mammography Quality Standards Act and Program . Model iAll women diagnosed with breast cancer are assumed to receive initial therapy with mastectomy or lumpectomy with radiation, but local therapy is not explicitly modeled. Subtype-specific adjuvant treatment is assigned according to a dissemination model based on SEER patterns of care special studies 1980 to 1996) and the National Comprehensive Cancer Network Outcomes Database (1997 to 2012) . Breast 0 to 1996Table 2).The population of US women is modeled starting in the year 1975 until the most recent year of data available in the SEER Program. Either the entire population can be modeled or a single recent birth cohort can be selected to simulate expected outcomes of a contemporary cohort of women receiving the current standard of care for breast cancer screening and treatment. The models generate a wide range of benefit and harm outcomes .As an exercise to validate models against data that were not used in their construction and calibration, we have replicated results of the United Kingdom Age Trial of mammography screening for women in their 40s. The results demonstrated that the models closely reproduced the effect of annual mammography screening on breast cancer incidence and long-term mortality . To captPrevious studies have demonstrated the flexibility of the CISNET breast cancer models to incorporate the complex interplay between the multiple factors on breast cancer as reflected by tumor, person, and health system levels. Here, we summarize exemplar findings by the CISNET breast cancer researchers that demonstrate these interactions.Fig 1). For example, for ER-negative/HER2-negative cases, the relative contributions by treatment were always lower than those by screening reflecting the lack of effective treatments for this subtype.The number of treatment options for women diagnosed with breast cancer has increased dramatically over the past 2 decades. The CISNET breast cancer modelers have quantified the associations of screening and treatment with reductions in US breast cancer mortality rates. Recent work extended a previous analysis by updatCISNET modeling teams have also examined linkages between the tumor and health system level interactions related to the impact of radiotherapy by simulating a clinical trial. This research conducted by Models GE and M illustrated that simulation modeling can prove useful in the modification or redesign of clinical trials. This analysis found that omission of radiotherapy in hormone-sensitive patients with low recurrence risk may lead to a modest increase in locoregional recurrence event rates, but did not appear to increase the rate of distant recurrence or death ,38. ModeAs another example of the interaction between the natural history of breast cancer represented by tumor growth and the health system in the CISNET models, we have investigated several issues focused on ductal carcinoma in situ (DCIS). Following the widespread dissemination of mammography screening for breast cancer, DCIS incidence increased sharply . While oTwo CISNET models (Models D and E) investigated the natural history of DCIS and selected 6 plausible parameterizations that could explain DCIS and invasive breast cancer incidence in the US. Using the models, they estimated mean sojourn time in the preclinical screen-detectable DCIS state, overdiagnosis of DCIS, and progression to invasive breast cancer in the absence of biopsy or complete excision . OverdiaThe modeling work on DCIS shows the challenges to deciding between alternative representations of DCIS natural history and the complexity of healthcare decisions for DCIS. Main findings from Models D and E indicate that the majority of screen-detectable but unbiopsied preclinical DCIS lesions progress to invasive breast cancer and that the mean sojourn time in preclinical DCIS is relatively short. Given the heterogeneous nature of DCIS, the progression of DCIS needs to be further modeled by grade and molecular subtype to more completely reflect the key features of DCIS biology. Overall, this body of work illustrates that screening approaches for breast cancer selectively detect different tumor characteristics, and CISNET models are well suited for representing the interplay between tumor and detection features in healthcare delivery.Table 3). Overall, we found that using the person-level factors breast cancer family history and polygenic risk to tailor (system level) screening strategies, more breast cancer deaths can be prevented and lives extended [In CISNET, we have examined several instances where person-level factors interact with health system level factors to influence breast cancer outcomes. In a first example of person and health system level interactions, we used 2 CISNET models (Models E and GE) to evaluate the benefits and harms of mammography screening based on polygenic risk and famextended . In geneTable 4). Person-level differences in terms of risk of breast cancer and life expectancy between women with and without Down syndrome implied that health system level policies for starting and ending ages of mammography screening may need to be set differently for these women.In another example of person and health system level interactions, we used two of the CISNET models (Models E and WH) to evaluate the benefits and harms of mammography screening for women with Down syndrome, who have unique personal characteristics related to breast cancer outcomes . Women wBRCA1 mutation carriers [Similarly, we used 2 CISNET models (Models GE and WH) to evaluate the clinical benefits and harms associated with screening guidelines for a group with unique personal characteristics . Survivocarriers . These wcarriers This comcarriers , adherenFig 2). Importantly, we found that MRI accounted for the majority of the screening benefit. Our findings highlight the importance of reducing barriers to MRI screening for these high-risk women and underscore the need to identify other options for breast cancer prevention as some survivors may prefer mammography and/or seek to reduce their risk even further. In future modeling research, we will be extending this work to evaluate the impact of healthcare system level factors such as physician recommendations for primary prevention with hormonal therapy on screening strategies and outcomes.To estimate the clinical outcomes associated with screening among these women, we adapted the models using data from the Childhood Cancer Survivor Study to refleTable 1). In certain focused analyses, risk of breast cancer incidence, and thus tumor inception for models with natural history components, depends on breast density. In these analyses, sensitivity and specificity of screening mammography also vary by breast density in addition to age, screening round (first versus subsequent), and screening frequency. For example, in an analysis parallel with modeling conducted for the USPSTF [Fig 3) [Modeling of 2 factors\u2014age and breast density\u2014are an example of modeling that incorporates interactions across all 3 levels of factors that affect breast cancer outcomes. Breast density in the CISNET models is assigned to each woman at the time she begins receiving mammography screening. As described above, density is assigned to women in 4 values (reflecting lower to higher density) and 3 age groups .Findings demonstrated how, for average-risk women, moving from screening mammography every 3 years to every 2 years increases the harm/benefit ratio\u2014as measured by false-positive mammograms per death averted\u2014less than moving from biennial to annual screening. This harm/benefit ratio is higher for women with scattered fibroglandular and heterogeneously dense breasts than for women with almost entirely fatty or extremely dense breasts. For older women, this harm/benefit ratio is essentially equivalent for biennial and triennial screening. As screening performance improves with technological advances, such as digital breast tomosynthesis , the CISThe CISNET Breast Working Group has used multilevel systems modeling over the past 20 years to provide evidence to guide high priority public health, clinical, and individual decisions to reduce the burden of cancer. Models incorporate key features of tumors to address questions related to the biology of breast cancer and its relation to the different approaches for early detection. Person-level characteristics such as age, family history of breast cancer, polygenic risk, and breast density have also been evaluated to elucidate screening strategies that improve the balance of benefits, harms, and costs of screening. As an extension of our work focused on women of average risk, we have also examined screening and treatment approaches for special populations including survivors of childhood cancer and women with Down syndrome.The models include the interactions between breast cancer epidemiology trends, evolution in screening technology, advances in breast cancer therapy, and new insights into the heterogeneous biology of each molecular subtype of breast cancer. The models incorporate various data types, structures and sources to reflect the tumor, person, and health system levels of data needed to portray the complexity of this common disease. As the CISNET Consortium continues its efforts to interrogate the pressing issues related to breast cancer incidence, detection, treatment and survival, additional challenges and opportunities remain to increase the impact of the consortium.Racial disparities in breast cancer outcomes have persisted for decades. These disparities are substantial, including the 40% greater breast cancer mortality experienced by Black compared with White women . SimulatCISNET models have been used to quantify the impact of breast cancer natural history, screening, and adjuvant treatment on mortality disparities . This woRecent CISNET work has begun to develop updated race-specific subtype-specific parameters and incorporate modern data on treatment disparities, enhancing the ability of CISNET models to account for present-day disparities. Future refinement of CISNET models will permit more precise attribution of mediating factors, including disparities in stage at diagnosis, screening receipt, and treatment receipt and timeliness. Enhanced modeling of mediators will, in turn, help identify the highest yield solutions for reducing disparities. Indeed, recent model updates have permitted identification of equitable screening strategies for Black women. The results of a recent CISNET study using updated model inputs demonstrated that screening may need to be initiated for Black women 5 to 10 years earlier than for White women (age 40 or 45 versus 50) to derive similar health benefits . This stPrimary breast cancer prevention interventions have been underutilized \u201362, and Screening is designed to detect breast cancers earlier than would have occurred in the absence of screening so that treatment confers a benefit when applied sooner, whereas breast cancer prevention strategies can be used to avoid disease and its therapies. While lifestyle changes such as avoiding obesity or reducing alcohol intake could potentially reduce risk of developing breast cancer \u201369, hormAs noted earlier, the CISNET models can also be useful to assess the potential impact of hormonal therapy for primary prevention in women who have survived childhood cancer and are at high risk for developing a subsequent breast cancer. This includes female survivors who received chest radiation and poteThe CISNET Consortium embodies the key features of team science. Team science is an emerging interdisciplinary field that empirically examines scientific collaboration described as the processes by which members of research teams organize, communicate, and conduct research in an interdependent fashion . TransdiSome challenges typically inherent in team science have been effectively managed in CISNET, including high disciplinary diversity of membership, knowledge integration, relatively large size , goal alignment, geographic dispersion, and high task interdependence. Factors contributing to effective management of common challenges have included strong commitment by team members to the mission of the consortium, collegial respect, and consistent support by champions at grant funding agencies. Furthermore, reports including multiple disease models demonstrate how scientific impact is increased by transdisciplinary collaborations that reach across single organ and disease types ,80,81.However, other areas present opportunities for greater emphasis in future endeavors. First, \u201cpermeable boundaries\u201d across mSecond, traditional academic laboratory structure, including the demands of tenure and promotion considerations, create challenges for the support of junior modelers and early career researchers. Programmers for each modeling team usually require over a year of training prior to gaining independence for modifying software code and executing modeling scenarios within the timeline constraints of multiple ongoing projects. To address these challenges, the CISNET Consortium has increasingly added training and mentoring opportunities for junior modelers to expand the pipeline and ensure the ongoing impact of CISNET after each grant cycle ends.Making the CISNET breast cancer control models accessible to the broader research community poses opportunities and challenges. Due to the complexity of the models and increasing use of the models by policy makers, it is important to increase the transparency of the models. To this end, we recently published a special issue of a journal dedicated to CISNET breast cancer models in which we described all main inputs and each individual model in great detail . The modWhile past collaborations with policy-making bodies such as the CDC or the USPSTF have been fruitful ,88,89, oIn conclusion, over 2 decades, the 6 modeling teams in the CISNET Breast Working Group and their consultants and collaborators have produced numerous examples of impactful systems modeling. Ongoing work is highly likely to provide new insight into avenues for reducing the burden of breast cancer. Collateral benefits of the CISNET Consortium have included advances in modeling and simulation techniques, support of the careers of junior scientists, and the provision of research tools for the broader scientific community. CISNET researchers are committed to increasing their focus on leveraging their powerful modeling resources to reduce the long-standing racial disparities in breast cancer outcomes, and we encourage other scientists to draw on team science approaches to also use modeling for this purpose."} +{"text": "Although striking racial and ethnic disparities in health are manifest during later life, they may be rooted in early-life exposures. Drawing from cumulative inequality theory, we investigate whether experiencing life course stressors increases the risk of later-life functional limitations and whether this relationship differs by race and ethnicity. This study utilizes longitudinal data from the Health and Retirement Study to test whether six indicators of child stressors and eleven indicators of adult stressors predict trajectories of the onset and severity of functional limitations in later life among a diverse sample of adults. We find that child and adult stressors are associated with earlier onset and greater severity of functional limitations during later life. Mediation analyses reveal the indirect influence of child stressors via adult stressors on onset and severity of functional limitations; however, the indirect effects are slightly stronger for Black and Hispanic adults than their White counterparts . In sum, child stressors, in and of themselves, do not increase functional limitations among Black and Hispanic people but are associated with greater adult stress exposure, leading to more functional limitations in later life. Disparities in functional limitations are also partly due to lower education and less wealth among Black and Hispanic adults."} +{"text": "Infection prevention and control (IPC) measures remain crucial to breaking transmission of the virus in the wake of inconclusive efforts underway to find an effective vaccine and treatment. While acknowledging that many lessons evolve as the pandemic unfolds, an initial understanding and recognition of the complexities that surround IPC policy implementation and adherence is vital for effective control of on-going pandemic in particular and to inform national IPC policies beyond the epi-curve. This short communication therefore seeks to unravel initial thoughts, themes and concepts that have unfolded in the implementation of IPC policies and guidelines in the context of the ongoing outbreak response in Ghana. A rapid desk review was done. Reflexive journals, field notes, observations and workshop experiences were compiled and overlapped with authors\u2019 experience as a member of the COVID-19 national response team for Infection Prevention and Control (IPC). Thematic content analysis was then used to categorize the lessons into common themes. While aligning with global strategies, the concept of \u2018looking within\u2019 for initial solutions and strengths have proven useful for a public health emergency response in Ghana. Future IPC policies must inculcate perspectives from the politics and economics of IPC practices and employ varieties of multidisciplinary approaches required to broaden the scope of IPC practice. It has ber 2020 . The oveber 2020 . Approprber 2020 . Similarber 2020 . An initA rapid desk review was done. Reflexive journals, field notes, observations and workshop experiences were compiled and overlapped with author\u00b4s experience as a member of the COVID-19 national response team for infection prevention and control. Thematic content analysis was then used to categorize the findings into common emerging themes.Initial lessons learned have emerged around four main themes namely; (1) human resources development, (2) governance and scope, (3) information management and research and (4) the politics, economics and ethics of preventive and control measures. While it is important to ensure that country mechanisms are evidence based and aligned with international mechanisms, the concept of 'looking within' has emerged strongly as a key lesson learned across all thematic areas for implementing preventive and control measures in Ghana. The concept of 'looking within' is generally understood in Ghana's context as harnessing and mobilizing material, monetary and man-power resources within country's existing public health and administrative systems and structures as initial and continuing contextual evidence-based interventions without over-relying on external strategies, solutions, standards and aid. Ghana has demonstrated this across the four themes by mobilizing its existing public health workforce and its experience with the support rendered during the Ebola virus response to affected peers, activating and enhancing existing public health surveillance, response structures and systems, enhancing existing reporting and command systems and promoting self-reliance through the empowerment of local standardization and production of IPC logistics such as hand sanitizers and PPEs.Human resources development for IPC: a quick human resource needs assessment and existing capacity has been useful in Ghana. A key lesson learned is that knowledge and practice of IPC are required across all specialties of the public health workforce and not only the clinical professionals. The ability to acquire such technical capacity can be constrained by healthcare professionals' degree of education. It has therefore proven useful to design separate modules for clinical and non-clinical staff as well as translate teaching content to local languages that are understood by cadres who have lower educational levels where need be, such as mortuary workers. Additionally, inadequate IPC preparedness increased health worker anxiety about their safety and diminishes their confidence to provide safe care. Regular risk assessment of healthcare workers therefore helped to institute the appropriate strategies for health worker safety particularly in reducing infections among them. Also, remote learning and guidelines dissemination using webinars, communities of practice presented new opportunities for IPC capacity building however, health workers found remote learning and training activities more useful where these were accompanied with appropriate supportive supervisory strategies to support their continual learning and performance.Infection prevention and control governance and scope: evidence-based strategies, guidelines, clear policies and communication structures are important for IPC practice decision making. A quick review to identify strengths and gaps in existing IPC policies and guidelines have been useful. It has become more emphasized that decision making around IPC implementation requires strong leadership and political commitment at all levels. Such leadership support may include resource mobilization and allocation for program funding, capacity building activities, provision of hand hygiene logistics and personal protective equipment, discussion of IPC issues at high-level meeting and review meetings, invitation of IPC stakeholders to meetings and strong monitoring and evaluation systems for IPC programs. Integrating IPC guidelines into existing programs while standardizing IPC tools and adapting these guidelines to local context have been helpful. Rapid but effective local accreditation and regulatory mechanisms to assure safe production of IPC logistics including PPEs and hand hygiene products were key strategies to meet country's demand. Recognizing power relationships in the IPC decision process enabled appropriate negotiations among stakeholders. Additionally, the scope of IPC preparedness must be broadened to include communities such as prisons, work places and corporate settings, schools, markets and refugee camps early enough in the response strategies. Finally, IPC governance in Ghana requires strong partnerships with diverse stakeholders for effective implementation.Infection prevention and control information management and research: the COVID-19 response in Ghana has highlighted the need to look within health systems for influential local leaders who are able to build trust and social capital with communities for effective communication and collective IPC compliance. Such communication must be timely, audience and context appropriate and sustained through out the response. Similarly, while Ghana drew content from global health authorities, policy makers also looked within to generate local evidence from Ghanaian researchers to inform key policies.The politics, economics and ethics of preventive and control measures: health economists generally argue that health as a public good does not obey open market principles, the pandemic has however highlighted the huge economics of demand and supply forces that lace the supply chain of IPC logistics, how these influence IPC policy formulation and implementation, and ethical issues that arise therein. Governments can mitigate these open market forces by public-private partnerships to keep the cost of these logistics in acceptable limits within which they remain safe, affordable and available to healthcare workers and the general population. Similarly, non-direct IPC logistics such as testing systems are prone to subtle open market forces thus availability of such logistics may also drive IPC policy formulation and implementation. For instance, this has been seen in the advocacy for IPC logistics such as mask to be reserved for the use of health workers at the early stage of the response since they were at higher risk of exposure to the virus. Ethical issues thus arise under such conditions when masks should have otherwise been used, as well as when health workers need to attend to confirmed infectious cases without adequate PPEs. Ghana controlled these open market forces through an intentional self-reliance strategy by looking within for local production of IPC logistics.The 'looking within' approach has proven useful in IPC governance, human resource capacity building, logistics supply and IPC education in Ghana's COVID-19 response. A variety of multidisciplinary approaches are required with a focus across clinical, public health and administrative domains. Local infrastructure and systems for IPC have proven useful in responding to a pandemic such as the on-going COVID-19. Additional lessons learned need to be institutionalized into existing IPC policy formation and implementation for sustainability and continuous IPC learning for routine IPC practice and future outbreak responses. Future IPC policies must inculcate perspectives from the politics and economics of IPC practices and employ a variety of multidisciplinary approaches required to broaden the scope of IPC programs.The corona virus disease 2019 (COVID-19) is now a pandemic and has been devastating to the world;Infection prevention and control measures remain crucial to breaking transmission of SAR-COV-2 in the wake of inconclusive therapeutic interventions.While aligning with global policy is important, 'looking within' country's existing public health systems as initial and continuing contextual evidence-based interventions without over-relying on external strategies and solutions presents a useful approach in a public health emergency;The pandemic highlights open market forces that lace the supply chain of IPC logistics and how these influence IPC policy formulation and implementation."} +{"text": "Players are Rugby's key asset, what recent research has been conducted into the Mental Health of rugby players/former players?Initially a Literature Search using HDAS, Ebsco, Researchgate and Googlescholar followed by a Literature Review of relevant articles.A significantly higher prevalence of anxiety and depressive symptoms in Professional rugby players is something that authors agree on. This review considers some of the rugby specific variables not limited to injuries (including concussion), retirement from the sport and finally alcohol abuse.In 2014, Sullivan looked at the role of potential mediators between concussion and later life depression. Sullivan suggested that the effects of concussion on later life depression may be directly neurological.Chronic Traumatic Encephalopathy (CTE) is a neurodegeneration which is only definitively diagnosed by post-mortem examination of brain tissue at this time. Today, Chronic Traumatic Encephalopathy is a very controversial subject, for every piece of research which claims to prove CTE, there is another piece of research apparently disproving it.Alcohol Misuse - Whilst it is well known in general adult psychiatry that alcohol has a significant negative impact on depression and anxiety in the general population, this review summarises findings from research into alcohol misuse in elite rugby players.In addition to personal variables there are rugby specific variables which are not limited to injuries, retirement from the sport and finally alcohol abuse.As mentioned in the paragraph on depression and anxiety, numerous recently published authors agree that a significantly higher prevalence of anxiety and depressive symptoms are seen in Professional rugby players .As alcohol misuse has already been researched, there would seem to be an opportunity for future research into the extent of illicit drug use by elite rugby players and potentially the effect of illicit drug use on depressive symptoms and anxiety. As mentioned in the paragraph on depression and anxiety, numerous recently published authors agree that a significantly higher prevalence of anxiety and depressive symptoms are seen in Professional rugby players .Finally, given the limited recent published literature on suicide in elite rugby players and former elite rugby players, a significant research gap exists in this particular field."} +{"text": "Fibroblasts are an integral part of connective tissue and play a crucial role in developing and modulating the structural framework of tissues by acting as the primary source of extracellular matrix (ECM). A precise definition of the fibroblast remains elusive. Lung fibroblasts orchestrate the assembly and turnover of ECM to facilitate gas exchange alongside performing immune functions including the secretion of bioactive molecules and antigen presentation. DNA methylation is the covalent attachment of a methyl group to primarily cytosines within DNA. DNA methylation contributes to diverse cellular phenotypes from the same underlying genetic sequence, with DNA methylation profiles providing a memory of cellular origin. The lung fibroblast population is increasingly viewed as heterogeneous with between 6 and 11 mesenchymal populations identified across health and lung disease to date. DNA methylation has been associated with different lung fibroblast populations in health and with alterations in lung disease, but to varying extents. In this review, we will discuss lung fibroblast heterogeneity and the evidence for a contribution from DNA methylation to defining cell populations and alterations in disease. Fibroblasts synthesize and integrate structural proteins including collagen and elastin into the extracellular matrix (ECM) of mesenchymal tissues . They arThe role of fibroblasts in human lung is multifaceted. Lung fibroblasts orchestrate the assembly and turnover of ECM to facilitate gas exchange alongside performing immune functions such as secretion of bioactive molecules and antigen presentation. Lung fibroblast heterogeneity is at the beginning of its investigation. However, studies comparing fibroblasts isolated from the airway and the parenchyma, and more recently single cell gene expression studies in whole lung sections have identified clear heterogeneity. Early studies clearly show fibroblasts isolated from the airways are different to parenchymal fibroblasts from distal parts of the lung. Airway fibroblasts (AFs) are larger with more cytoplasmic projections as opposed to the spindle shaped morphology of parenchymal fibroblasts (PFs). While AFs produce more collagen, eotaxin-1, CXCL8 and GRO-\u03b1 at baseline , PFs expMore recently, single cell RNA sequencing technology has facilitated discovery of new cellular phenotypes using cell type specific transcriptome signatures in tissues with heterogenous cell populations ,15,16,17Transcriptional profiling has extended our knowledge of fibroblast heterogeneity and phenotypes dramatically. It is likely that further studies that integrate other \u2018omic approaches will provide further dimensionality to the understanding of cell lineage and specific fibroblast roles in human development and disease . In thisDNA methylation refers to the covalent attachment of a methyl group to DNA bases. DNA methylation on the fifth position of cytosine (5mC), is mainly restricted to CpG sites in vertebrates, with 60\u201380% of the ~29 million CpG sites in the human genome methylated ,21. The Techniques to measure DNA methylation levels have evolved extensively over the past two decades. Global DNA methylation profiling can be achieved by methylated DNA immunoprecipitation using a methyl cytosine antibody . Genome DNA methylation contributes to diverse cellular phenotypes from the same underlying genetic sequence with DNADNA methylation profiling of different fibroblast populations is limited compared to transcriptional profiling; however, these studies do show large variation in DNA methylation profiles between fibroblasts from distinct locations, suggesting a high-level contribution from DNA methylation to different fibroblast phenotypes. DNA methylation profiles of fibroblasts cultured from the scalp versus the dura (layer of connective tissue that surrounds the brain), which are morphologically identical, showed 22% of CpGs profiled (Illumina HumanMethylation450K array) were differentially methylated between the fibroblast types, with >50% of effect sizes greater than a 10% difference in DNA methylation . FibroblSpecifically, to the lung we have shown that fibroblasts isolated from the airway and parenchyma, display very distinct DNA methylation profiles . While oFibrosis encompasses a cascade of molecular processes including inflammation, abnormal accumulation of interstitial ECM proteins, increased proliferation of fibroblasts and subsequent imbalance between ECM formation and degradation. It is a progressive pathological event that results in increasing margins of fibrotic mass causing dysfunction of tissue and organs. Fibrosis in the lung is a complex event involving cascades of paracrine signaling between fibroblasts, lung airway and parenchymal cells and inflammatory cells. It follows the mechanism of fibroblast mediated wound healing, but without complete resolution of injury. A site of lung injury often begins with damaged epithelium and basement membrane which triggers inflammation mediated activation of fibroblasts, secretion of proteases and matrix proteins and remodeled ECM ,49. FibrIdiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease, characterized by excessive extracellular matrix deposition in the lung interstitium, destruction of the normal parenchymal structure and progressive loss of pulmonary function ,51. The As with the healthy lung, transcriptional profiling is more advanced than DNA methylation profiling, however, DNA methylation is altered in parenchymal lung tissue from individuals with IPF compared to controls. First shown in 2012, of >14,000 genes represented by on the Illumina HumanMethylation27 BeadChip, 870 genes were differentially methylated in IPF lung tissue compared to controls, 35 of which linked to differential expression of the annotated gene includinAsthma is an inflammatory disease of the airway that manifests as bronchoconstriction, wheezing and shortness of breath. Structural changes within the asthmatic lung are driven by multiple cellular processes including epithelial cell damage and apoptosis, increased airway smooth muscle cell mass, aberrant and prolonged immune responses and fibroblast activation . GeneticFunctional alterations to sub-populations of fibroblasts in asthma have not been well investigated. Single cells expression studies have primarily focused on epithelial cell subpopulations and further focus on fibroblast populations has potential to vastly increase our understanding of fibrotic mechanisms in asthma. Genome wide gene expression comparison of airway versus parenchymal fibroblasts in asthma did not identify any differences between asthmatic and non-asthmatic donors in either fibroblast population however this was in relatively small donor numbers . In contChronic Obstructive Pulmonary Disease (COPD) is a heterogenous disease of the lung, clinically defined by airflow obstruction that is not reversible and caused by inhalation of noxious particles or gases primarily from cigarette smoke. COPD involves two seemingly opposing components; parenchymal lung destruction (emphysema) with a loss of ECM deposition and small airways disease with increased ECM deposition in small airway fibrosis . EmphyseThere is evidence for a link between DNA methylation and COPD pathogenesis ,82,83,84Respiratory infections that cause an acute inflammatory response in lungs known as acute respiratory distress syndrome (ARDS) predominantly present with pulmonary hypoxia, excessive infiltration of immune cells, oedema and result in mild to severe respiratory failure ,88. InfiCystic fibrosis is a multi-organ associated, genetic mutation-based disorder. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation is the cause for this life shortening disease that results in progressive airway destruction through chronic.Inflammation along with pancreatic insufficiency, ion and water transport imbalance in organs and male infertility. Although it affects multiple organs, the main cause of mortality/morbidity in cystic fibrosis is poor prognosis of lung dysfunction ,96. PersIn this review we have highlighted and summarized the current evidence for the contribution of DNA methylation to the complex fibroblast heterogeneity in the healthy lung and in fibrosis associated with multiple lung diseases .The development of single cell expression technology has seen an explosion of transcriptional profiling data of the lung in health and in disease, with DNA methylation profiling taking a back seat due to the increased complexity of profiling DNA methylation at the single cell level. DNA methylation profiling by next generation sequencing requires bisulphite conversion to convert cytosine methylation information into sequence-based information. The increased physical manipulation generates issues with levels of DNA remaining for sequencing, while the conversion of unmethylated cytosine to uracils makes alignment of sequencing data more difficult than for expression profiling. However, there is strong evidence that DNA methylation is involved in determining cell phenotype and work from ourselves and others has shown that DNA methylation profiles are associated fibroblast population in both health and lung disease. Increased optimization of single cell technologies to profile DNA methylation has large potential to inform our understanding of fibroblast phenotype, function and alteration in disease. Even though, it is important to consider that even with the wealth of information coming from single cell profiling, it now needs to be integrated with positional techniques so that we can determine exactly where within the lung cells are positioned and modifications in disease are occurring.However, even upon profiling and definition of these cell types, challenges still remain. Even though it may be possible to isolate these subpopulations, they may not maintain their phenotype in culture . OutgrowThe association between DNA methylation and gene expression is complex. While gene expression provides a snapshot of the functional transcriptome at the time, DNA methylation can represent a cellular memory that does not link directly to simultaneous gene expression levels. Furthermore, methylation of CpG sites can trans-regulate expression of genes distant from the CpG. Using targeted DNA methylation editing, such as dCas9-Dnmt3a/Tet1 to understand the role of site-specific DNA methylation in gene expression and cell fate determination will be important . In vitrThe bulk of lung fibroblast transcriptional profiling has been undertaken in IPF resulting in a focus on parenchymal fibroblasts. However, our work has highlighted DNA methylation differences between airway and parenchymal fibroblasts in both health and asthma/COPD. Asthma is primarily considered an airways disease so identifying modification to parenchymal populations indicates the potential for modifications outside of our historically standard lung regions and moving forwards, as techniques improve and become more mainstream, it will be beneficial for studies to consider sampling different areas of the lung in both health and diverse lung diseases.In conclusion, our understanding of lung fibroblast heterogeneity has increased dramatically over the last 5 years. This is particularly true of transcriptional profiling, but also for DNA methylation although on a more granular level. Improvements in technology over the next few years will allow us to integrate DNA methylation and other \u2018omics data to further understand cellular phenotypes and their molecular definition."} +{"text": "Scholars and practitioners recognize the importance of family caregivers for persons with dementia (PwD) persevering through difficulties and remaining committed to providing care . Based on Pearlin\u2019s stress process model, we examined how grit is associated with stressors and strains that interfere with caregiver well-being and jeopardize continued caregiving. The sample included 158 family caregivers of PwD from rural Appalachia. SEM analysis revealed that grit and family and friend affectual solidarity contributed significantly to mastery. Grit and family solidarity were associated indirectly with role overload through their effect on mastery. Results demonstrate the value of acknowledging the role of grit in enhancing caregivers\u2019 confidence about managing difficulties they face and reducing their sense of being overwhelmed by caregiving responsibilities. Thus, strengthening dementia caregivers\u2019 commitment to and perseverance in their role is crucial for sustaining their motivation to provide care, despite the challenges they face."} +{"text": "Research suggests that minority stress can influence the healthcare utilization of aging LGBT adults, and that social resources can buffer the effect of stress on healthcare utilization. Using data from Aging with Pride: National Health, Aging, and Sexuality/Gender Study , multiple logistic regression assessed the associations between minority stress and healthcare utilization . We also examined the moderating effect of social resources, including social network size, social support, and LGBT community belonging, in these associations. Internalized stigma was negatively associated with having a routine checkup in the previous year . Disclosure was positively associated with having a health screening within the past 3 years and having a regular provider . Further, we found that social support moderated the association between disclosure and health screenings ; thus, having higher levels of social support and disclosure in tandem increased the likelihood of getting a health screening in the last three years. Health and human service professionals should provide information about internalized stigma and LGBT identity disclosure to educate their clients about the ways in which these minority stressors can impact their healthcare experiences. Providers should assess the social support of their aging LGBT clients and inform them about the added benefit that social support can have in their healthcare experiences."} +{"text": "Ageism is stereotyping and discrimination against individuals or groups based on their age. Ageism toward older adults is ubiquitous in American society and takes many forms including prejudicial practices and institutional policies that lead to unfair treatment of older adults. Ageism negatively impacts older adults in numerous domains such as health care and the workplace. Older adults themselves often internalize ageist views with detrimental effects on physical and mental health including increased risk for suicidal ideation and worse memory performance. This symposium addresses ageism from multiple perspectives and describes strategies for detecting and combatting ageism. The first speaker is Patricia D\u2019Antonio, Vice President of Policy and Professional Affairs of The Gerontological Society of America (GSA). Ms. D\u2019Antonio will describe GSA\u2019s Reframing Aging Initiative which aims to improve the public\u2019s understanding of the meaning of aging in order to counter ageism and support policies and programs that benefit older adults. The second speaker, Dr. Fredriksen Goldsen will use an Age Equity Framework to present her research on the relationship between ageism and mental and physical health and quality of life in LGBTQ older adults. The third speaker, Dr. Gendron will describe a content analysis of an anti-ageism resource that evaluates ageism interventions using an ecological framework. The fourth speaker, Dr. Hinrichsen will discuss ways psychotherapists can help older adults identify and move beyond internalized ageist beliefs. Finally, Dr. Levy, an internationally recognized expert in ageism will discuss themes across speakers and comment on the future of work in this area."} +{"text": "Social isolation affects one in five older adults, significantly increases the risk of premature death from all causes and is associated with higher rates of depression, anxiety and suicide. Covid-19 has exacerbated social isolation, including among older adults that reside in senior apartments. In response, a Friendly Caller Program was developed to foster intergenerational social connections among university students and residents in a large housing community that serves older adults aged 62 and older who have limited income and have mobility impairments. This study aimed to evaluate the Friendly Caller Program from the perspective of the older adult. An online survey includes questions about the participants\u2019 demographic characteristics, physical and mental health self-assessment, social support, and ways in which the Friendly Caller Program has affected these areas of their life. An open-ended question assesses older adult participant expectations of the Friendly Caller Program. Results describe the population currently being served by this program and indicate that the program has a positive influence on participants\u2019 feelings of safety, support and ability to function. Suggestions for future research include assessing university student perceptions about the benefits of participation as callers in the program and creating a toolkit that can guide other universities to create similar programs in partnership with housing communities that serve older adults."} +{"text": "Thank you to authors of the article \u2018Development of virtual ophthalmic surgical skills training\u2019 for an interesting perspective on how ophthalmic surgical skills can be taught successfully online to a diverse student cohort . The autAs a second year Ophthalmology Speciality Trainee, I can appreciate the immense adverse impact COVID-19 has had, particularly on surgical training where the majority of elective surgery was postponed during the initial acute phase of the pandemic. A recent Royal College of Ophthalmologists (RCOphth) trainee survey found over half (55%) lacked surgical opportunities to achieve objectives of their placement .Simulation has already proved extremely effective in ophthalmology training with evidence showing that trainees who have spent time using the EyeSi have reduced complication rates and a shorter learning curve when they transfer to live cataract surgery .Given access to EyeSi simulators is variable across different deaneries, virtual surgical skills training provides an ideal cost-effective, safe solution for developing surgical skills amongst trainees. Virtual training can speed up the learning curve through improving manual dexterity, the basics of instrument handling and suturing skills.Limited information is provided in the article on the training received prior to the course for the trainers, this is essential for success. Furthermore, it is crucial trainers and consultants have dedicated time and renumeration to support these virtual simulation sessions.This method of training also requires adequate digital literacy for both trainees and trainers. This is defined as the ability to use digital technology, communication tools or networks to locate, evaluate, use and create information . TrainerTo conclude virtual ophthalmic surgical skills is an efficient and convenient way of learning. It can be harnessed in ophthalmology training as an additional method of teaching in overcoming limited surgical opportunities due to COVID-19 and assist trainees in becoming more confident surgeons."} +{"text": "Assumptions about gliomas and their classification, including their most aggressive subtype, the glioblastoma (GBM), changed dramatically by the revised version of the WHO Classification of Tumors of the Central Nervous System in 2016 [Besides the clinical examination, magnetic resonance imaging (MRI) remains the gold standard for the diagnostic evaluation of affected patients and their response to treatment using the Response Assessment in Neuroradiology (RANO) criteria . NeverthBasically, there are two scientific areas that hold promise for advancing the diagnostic characterization of GBM heterogeneity. One is the use and development of artificial intelligence (AI)\u2013based image postprocessing algorithms including radiomics analysis, which may have the potential to significantly improve noninvasive diagnosis and subsequent management. The other are novel and advanced MRI techniques, which can be the ground truth for upcoming AI image postprocessing solutions and with doing so also multiplying their potential.Furthermore, a multiparametric imaging approach may provide the desired prognostic tool that is both sufficiently accurate and easy to use in clinical practice. Therefore, several qualitative and quantitative MR techniques including diffusion-weighted imaging with apparent diffusion coefficient mapping (DWI/ADC), perfusion-weighted MRI, and volumetric approaches based on segmentation of different tumor subsections have been evaluated , 6. An eAnother promising candidate is electrical property tomography (EPT), which allows determination of tissue conductivity and can be quantified by means of a mapping-based analysis . With EPAn interesting review by Suh et al (2018) analyzed the value of multiparametric MRI for determining the treatment response in patients with GBM focusing on the discrimination of pseudoprogression from true progression. They concluded multiparametric MRI to be a promising tool for overcoming this pitfall, which is why the community is so excited about multiparametric approaches including EPT . In thisIn conclusion, multiparametric MRI, including promising newer techniques like EPT and mapping, may have the potential to provide enough information for intelligent imaging postprocessing algorithms that may allow us to noninvasively decode GBM heterogeneity. If this can be accomplished, the next challenge will be to establish a protocol including techniques and software solutions smart and easy enough to implement in daily clinical routine."} +{"text": "The unprecedented nature of the coronavirus pandemic created significant socioenvironmental changes for working caregivers who found themselves juggling a new landscape of working and caring. Changes in workplace policy were often intended to accommodate those with caring responsibilities, however, there is little information available on how working female informal caregivers of older adults received, interpreted, and experienced those policy changes. Given this, it is necessary to gather a complete picture of workplace policy in the daily lives of working female caregivers during the pandemic. This qualitative study involved interviews held between February and April 2021 via video conferencing technology with 29 working female caregivers, ranging in age from 27 to 75 years old. Using a Role Conflict framework and descriptive, structural, and emotion coding strategies, analysis of written transcripts revealed that, while many caregivers were grateful that their workplaces had become more accommodative during the pandemic, apprehension and uncertainty about the future, both with caregiving and with work, also weighed heavily on many of them. The most positively endorsed workplace policy changes were flexibility in work schedules and the ability to work remotely during the pandemic. This research elucidates policy implications for working female caregivers outside of the pandemic context, as many of these policies enabled caregivers to provide care while working with greater ease."} +{"text": "Assessment is an important component of advancing age inclusivity on your campus, and the AFU Principles are a useful guiding framework. Assessment helps move the campus from making a commitment to endorse the principles to actually taking stock of current campus practices and movement toward achieving the vision of an age-friendly institution of higher education. To establish a baseline of campus practices, assessment can be done before or after an institution joins the AFU Global Network. Evaluation also follows periodically to assess how well a campus is adhering to the AFU Principles once measurable goals are established and priorities are integrated within an institution\u2019s strategic plan. The toolkit contains examples from multiple campuses of mapping the principles, conducting an audit, doing a photovoice evaluation, holding listening tours, and using the newly developed AFU Inventory and Campus Climate Survey (ICCS)."} +{"text": "Research cooperative groups aim to facilitate collaborative and rigorous palliative care research. The purpose of this article is to (1) demonstrate how cooperative groups are taking formal and sustainable steps with commitment to pediatric palliative care research programs and (2) provide an example of how one cooperative group is implementing these innovative efforts to partner with programs to integrate pediatrics on an expanding scale. Details are described for how pediatric studies can benefit from cooperative group infrastructure and expertise. In turn, we describe how cooperative groups can benefit from collaborating on pediatric studies through broadening of data dictionaries, data repositories, and reach in palliative care research communities. Substantial progress has been made for the past 20 years in the care of children with serious illnesses. However, crucial gaps still exist in the evidence to inform our understanding of the struggles families face and how to address the needs of pediatric palliative care patients and their families. A potential limitation of current pediatric palliative care research is that a lack of research infrastructure may contribute to studies being conducted that are not well suited to answer the research questions they seek to address. One strategy to improve pediatric palliative care research infrastructure is through use of cooperative organized structures, such as the Pediatric Palliative Care Research Network (PPCRN)Two examples of well-established research cooperative groups are the PPCRN and PCRC. The PPCRN was established in 2006, is focused on fostering a community of pediatric palliative care investigators and strengthening the pipeline of young and early career investigators, and currently includes 118 members.Cooperative groups can play a significant role in supporting pediatric palliative care research. For example, the PCRC resources include data harmonization, participant registry, quality assurance, caregiver research expertise, measurement expertise, and study closeout support. Each of these domains of PCRC support and potential benefits to researchers will be described with specific examples from our study in The PCRC uses common data elements, measurement instruments, and data dictionaries to standardize datasets to support data harmonization across studies and increase efficiency. The PCRC also houses a de-identified data repository and solicits investigators to deposit their data for other researchers to ask important research questions and conduct secondary data analyses.The PCRC study participant registry documents all participants enrolled in PCRC studies, providing an accounting of overall PCRC enrollment and activity. The PCRC developed and maintains this trans-PCRC participant registry.PCRC statisticians conduct annual quality assurance reviews of study databases to ensure compliance with PCRC standards. Quality assurance includes assessment to ensure that PCRC data standards are followed . Reviews also provide study closeout information for researchers to plan ahead for materials required to be submitted at study end.The PCRC Caregiver Research Core ensures that studies align with state-of-the-art caregiver research methods.The PCRC Measurement Core assists researchers to ensure that instruments align with PCRC standards.At study end, the PCRC lead statistician and informatics team worked with researchers to close out the study database and prepare it to meet the PCRC data sharing requirements. This allows for the PCRC to coordinate any future data sharing requests from other researchers and increases availability of our dataset to inform future studies.These cooperative group domains can provide support and quality control and assist with successful completion and increased rigor of pediatric palliative care research. While accomplishing their mission, research cooperative groups can support researchers in successfully addressing the aims of research studies and expanding the knowledge base in pediatric palliative care.The contribution of pediatric palliative care researchers can substantially expand and pragmatically benefit research cooperative group paradigms. Pediatric-specific contributions in areas of data harmonization, measures, data sharing, and visibility within cooperative groups and beyond can be added as a result of pediatric palliative care research. These contribution domains are described hereunder and summarized with specific examples from our study in Studies can contribute data elements specific to pediatric parent-proxy report and pediatric palliative care to cooperative groups. Researchers can work with collaborative groups to ensure that these important categories of data are part of the collaborative information ecosystem.Pediatric-specific measures can be added to cooperative group resources, specifically for child self-report and parent caregivers of pediatric patients, as the majority of current family caregiver measures are adult based. In this way, researchers can both draw from and contribute to the palliative care community.In addition to data availability in accordance with National Institutes of Health (NIH) requirements, research databases and data dictionaries can be invested into cooperative group repositories of shared data to support subsequent secondary analyses, pilot research projects, and aggregated analyses.Pediatric palliative care research studies can contribute to increased visibility of pediatric expertise of research cooperative groups and their members. Study dissemination of results to peer-reviewed journals and national conferences include acknowledgement of collaborating cooperative groups, increasing their visibility and exposing the benefits of cooperative groups to pediatric palliative care research across the nation. Collaboration between research and cooperative groups can also provide leadership opportunities for pediatric researchers within the cooperative group community. Such increased research visibility can help grow the network of pediatric palliative care researchers by encouraging new members across disciplines and levels to join cooperative groups, thus helping to support established pediatric palliative care researchers and grow the pipeline of junior investigators in palliative care.Examples from our project demonstrate how cooperative groups can offer bidirectional benefits from recruitment through dissemination and demonstrate that their commitment to pediatric palliative care research is wide, far-reaching, and growing. With a variety of interacting resources, benefits of cooperative groups include assistance for both novice and expert researchers. Research design recommendations and pediatric measures stored in instrument libraries can be used by pediatric palliative care researchers with confidence, knowing they have been endorsed through published systematic reviews. Implications for additional expansion of use of the assistance offered by existing palliative care cooperative groups could include (1) increase in pediatric palliative care researcher involvement and (2) replication of collaborative models for use in other settings and conditions . Each of these opportunities is described further as follows.An important implication for future study is the addition of more pediatric palliative care researchers to be actively involved in existing palliative care collaborative groups. Based in children's hospitals and communities across the country, researchers who concentrate on building the knowledge base and evidence-based practice with children and families can benefit from scientific collaboration and advanced knowledge. This may be accomplished most efficaciously through membership in research group cooperatives where resources and expertise are shared. The addition of pediatric expertise is one of the goals of the PCRC's U2C, and as such, the PCRC added leading pediatric palliative care researchers to the Steering Committee and Scientific Review Committee and have regular meetings with pediatric palliative care research leaders. Thus, both the PPCRN and PCRC are strongly committed to continuing and further expanding their support for pediatric palliative care research.The collaborative model of palliative care cooperative groups is one worthy of replication and expansion. For example, similar models could be used at the university level to facilitate research collaboration within institutions. Other researchers could use components of palliative care cooperative group models to develop national cooperative research groups for nonpalliative care research areas of interest. Internationally, these models could be used to engage more global pediatric palliative care researchers into our existing palliative care groups to better address the needs of researchers working to enhance the quality of lives of some of the 21.5 million children in other countries and settings. With an emphasis on scientifically based methods, results provide meaningful evidence that may be useful across settings, borders, and languages.pediatric palliative care research. Palliative care researchers can greatly benefit from the value of a collaborative group, including enhanced family caregiver research, measurement and study design, and data harmonization. In addition, studies can contribute back to a cooperative group's mission through the development of new resources related to a specific population , including measures, methods, and standards for palliative care research. Although the PPCRN is pediatric-specific and similar in its mission of fostering multicentered collaborative interdisciplinary research, our study was one of the first to demonstrate the value of the PCRC related to pediatrics and supports long-term sustainability. Pediatric palliative care researchers can benefit from joining a collaborative research group to further strengthen our pediatric community.Our study was pioneering in its use of formalized collaborative resources and infrastructure for"} +{"text": "A young female with old traumatic third nerve palsy presented with characteristic lid signs of aberrant regeneration of third nerve. There was noticeable disparity in the lid aperture and surgery on the normal fellow eye was undertaken to offer the patient a satisfactory aesthetic appearance. Full blown features of the syndrome might not be present in each case but the lid signs are characteristic and important clues for diagnosis [2]. The most common lid signs include horizontal gaze-eyelid synkinesis, pseudo Graefe (Fuch\u2019s) sign, adduction of eye on attempted vertical movement with retraction of globe on attempted vertical movement and Pseudo Argyll-Robertson pupil. In our case, noticeable changes were observed in eye aperture; large amount of EOM surgery may possibly have worsened the lid aperture disparity; surgery on the fellow eye was undertaken for better aesthetic appearance.Aberrant regeneration of third nerve is known to occur most frequently following traumatic head injury and aneurysm of posterior carotid artery . The phenomenon of aberrant regeneration of third nerve being caused by misdirected regenerating third nerve fibers is uncommon but has been well described in literature and documented by ocular electromyography. Chua HC et al. reported three patients with aberrant regeneration of third nerve following traumatic brain injury and concluded that full blown features may or may not be present; the misdirection incidence in their series was 15% [4]. They also found a slightly higher success rate with adjustable versus nonadjustable sutures. However, while pre-operatively assessing this case, it was realized that the difference in lid aperture in primary gaze was an important concern. Moreover, synkinesis in adduction could not have been well treated, but the young female was concerned for her cosmetic appearance in the primary gaze. Performing any large EOM surgery in the palsied eye might have worsened the lid aperture disparity in the primary gaze. A surgery in the fellow eye was thus undertaken in the form of large recession and resection resulting in satisfactory aesthetic appearance in the primary gaze. Also, the adjustable technique was not used since visual acuity was already much compromised and a more than full correction was required.In a retrospective series of 46 operated patients for third nerve palsy, the authors observed that the success rate was unaffected by the presence of aberrant regeneration [5]. Various methods have been described; large recess resection procedures have been time tested; newer globe fixation techniques in the form of periosteal fixation and medial transposition of split lateral rectus muscle [6] have also been successfully done in third nerve palsy patients. While functional results were not very good, in most cases, the aim was to provide acceptable aesthetic appearance. In 2003, Parulekar MV introduced for the first time the concept of operating the fellow eye to restore ocular alignment [7]. Our results further strengthen the idea of making use of the non-paretic eye for managing the lid aperture disparity. However, at present, a further modification in the form of adjustable suture would be a better procedure. But this was not required in our case.Surgical management of acquired third nerve palsy depends on the number and extent of involvement of extra ocular muscles as well as the presence or absence of signs of aberrant regeneration [In cases of acquired third nerve palsy, it becomes important to recognize clinical signs of aberrant regeneration and decide the surgical procedure accordingly. Disparity in lid aperture could be a concern in some patients, whose condition might worsen by performing EOM surgery on that eye. Yet, the surgery of the fellow eye was a viable option.Conflict of Interest statementThe authors state no conflict of interest.Informed Consent and Human and Animal Rights statementInformed consent has been obtained from all individuals included in this study.Authorization for the use of human subjectsEthical approval: The research related to human use complies with all the relevant national regulations, institutional policies, is in accordance with the tenets of the Helsinki Declaration, and has been approved by the review board of Pediatric Ophthalmology and Strabismus Services, BPS GMC for Women, Khanpur, Sonepat, Haryana, India.AcknowledgementsNone.Sources of FundingNone.DisclosuresNone."} +{"text": "Chronic Kidney Disease (CKD) is characterized by organ remodeling and fibrosis due to failed wound repair after on-going or severe injury. Key to this process is the continued activation and presence of matrix-producing renal fibroblasts. In cancer, metabolic alterations help cells to acquire and maintain a malignant phenotype. More recent evidence suggests that something similar occurs in the fibroblast during activation. To support these functions, pro-fibrotic signals released in response to injury induce metabolic reprograming to meet the high bioenergetic and biosynthetic demands of the (myo)fibroblastic phenotype. Fibrogenic signals such as TGF-\u03b21 trigger a rewiring of cellular metabolism with a shift toward glycolysis, uncoupling from mitochondrial oxidative phosphorylation, and enhanced glutamine metabolism. These adaptations may also have more widespread implications with redirection of acetyl-CoA directly linking changes in cellular metabolism and regulatory protein acetylation. Evidence also suggests that injury primes cells to these metabolic responses. In this review we discuss the key metabolic events that have led to a reappraisal of the regulation of fibroblast differentiation and function in CKD. While the kidney can recover from acute injury, persistent and/or severe injury results in the chronic accumulation of scar tissue (fibrosis) and progressive renal failure. Understanding the mechanisms that regulate the transition from acute kidney injury to chronic kidney disease (CKD) is important, because once fibrosis is initiated it can be extremely difficult to switch off or reverse , a protein normally associated with smooth muscle cells , and uncoupling from oxidative phosphorylation in the mitochondria Ding et. This mein vitro than oxidative phosphorylation coupled with the electron transport chain, glycolysis produces ATP faster is an important metabolic switch in maintaining a chronically activated fibrogenic state , where it is converted into glutamate by glutaminase (Gls 1 or Gls 2 depending on the tissue). Augmented glutamine consumption in lung myofibroblasts appears largely driven by elevated levels of Gls1 fibroblast activation and fibrogenesis . DespiteTH and ES jointly wrote and edited the manuscript. Both authors approved the manuscript for submission and agree to be accountable for its contents.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Myocardial recovery associated with durable mechanical circulatory support represents an important potential treatment paradigm but is poorly understood.182.See Article page Durable left ventricular assist device (LVAD) therapy provides lifesaving benefit and improvement in quality of life for patients with advanced heart failure refractory to guideline-directed medical care. Although originally intended for bridge-to-transplant and later as permanent therapy , mechanical unloading with durable LVADs has been associated with improvement in myocardial function that has permitted device explant with long-term freedom from heart failure in a small cohort of patients; that is, a bridge to recovery. This observation has raised the possibility that mechanical unloading with durable LVADs can facilitate myocardial recovery and alter the clinical phenotype of advanced heart failure.heart failure remission rather than recovery reflects our uncertainty and the lack of a basic understanding of the recovery phenomenon. Second, the prevalence of myocardial recovery during support is generally believed to be low, but some important clinical characteristics such as young age, short duration of heart failure, nonischemic etiology of the heart failure, and smaller left ventricular volumes predict a higher prevalence of myocardial recovery. Aside from these factors, the ability to accurately predict with high probability those patients who might respond to mechanical unloading is lacking. Third, concomitant treatment with optimal medical therapy and use of guideline-directed heart failure therapies in addition to mechanical unloading is likely essential to the recovery paradigm. Fourth, we lack an understanding of how LVADs should be managed to promote myocardial recovery. Current LVADs are operated in a fix speed mode and unload the left ventricle during all phases of the cardiac cycle, conditions that may not optimize myocardial recovery. Further, the functional assessment of myocardial recovery and selection of patients for device explantation remains arbitrary, although some clinical weaning characteristics or criteria appear relevant to patient selection. Last, current device technology presents a formidable challenge to device removal in the setting of myocardial recovery. The complexity of device removal has some surgeons advocating for device decommissioning rather than device explantation. Whether device decommissioning and retention of the device in a young patient (most commonly the cohort likely to experience recovery), is safe over the long-term is not known.Faerber and colleaguesFaerber and colleagues provide a succinct summary of the state of using durable LVADs to promote myocardial recovery. This is an important area that needs continued investigation to bring to reality a potentially important treatment paradigm and option for patients with advanced heart failure."} +{"text": "Canis lupus baileyi) in Arizona and New Mexico, USA, responded to changes in policy that reduced protections to allow more wolf-killing. We employ advanced biostatistical survival and competing risk methods to data on individual resightings, mortality and disappearances of collared Mexican wolves, supplemented with Bayes factors to assess the strength of evidence. We find inconclusive evidence for any decreases in reported poaching. We also find strong evidence that Mexican wolves were 121% more likely to disappear during periods of reduced protections than during periods of stricter protections, with only slight changes in legal removals by the agency. Therefore, we find strong support for the \u2018facilitated illegal killing\u2019 hypothesis and none for the \u2018killing for tolerance\u2019 hypothesis. We provide recommendations for improving the effectiveness of US policy on environmental crimes, endangered species and protections for wild animals. Our results have implications beyond the USA or wolves because the results suggest transformations of decades-old management interventions against human-caused mortality among wild animals subject to high rates of poaching.Despite illegal killing (poaching) being the major cause of death among large carnivores globally, little is known about the effect of implementing lethal management policies on poaching. Two opposing hypotheses have been proposed in the literature: implementing lethal management may decrease poaching incidence (killing for tolerance) or increase it . Here, we report a test of the two opposed hypotheses that poaching (reported and unreported) of Mexican grey wolves ( HoweWe suspect wolves are not exceptional among large carnivores regarding the effect of relaxing or fortifying legal protections, because the same justifications for liberalizing killing of brown bears and lions have been used whenever prohibitions on hunting or other lethal management are proposed ,68\u201370. WClick here for additional data file."} +{"text": "In 2019, Barstow proposed a deep physiological explanation of the NIRS technique, and described its strengths, limitations and a few applications to skeletal muscle research during common exercise modalities . The NIRS technique is based on the light absorption of oxygenated and deoxygenated hemoglobin (Hb) and myoglobin (Mb) in the near infrared tissue, using the interaction of light at different wavelengths. It allows to measure the changes in oxyhemoglobin (O2Hb), deoxyhemoglobin (HHb), total hemoglobin, and tissue saturation index (StO2) in skeletal muscle during exercise. These last years, small wireless and portable NIRS devices have been built for sports applications.Our understanding of the human physiology during exercise lags behind our understanding of human behavior for decades. However, the number of available technologies for monitoring physiological functions \u201cin the wild\u201d and for assessing various training related-parameters has increased dramatically in recent years. In order to maximize exercise performance, mitigate fatigability as well as minimize the risk of injury, coaches and practitioners need a tough understanding of the relationship(s) between the external work outputs and its physiological impacts among other performance determinants growing in availability, offer promising approaches but formal longitudinal and cohort studies are still needed to assess their use-case for sports ? What are the current challenges?biceps brachii, latissimus dorsi and vastus lateralis muscles was shown to be more relevant than VO2max in predicting canoe-kayak performance status. These last two decades, much attention has been devoted primarily to muscle oxygenation time course analysis during incremental exercise tests , allows for predicting time to exhaustion during continuous and intermittent exercise to achieve adaptations. As a consequence, accurate assessment and monitoring of training load is of paramount importance. To quantify the training load, both external and internal indicators can be used , appear stronger predictors of kayak performance compared to VO2max in both short and long events and methods for diagnosing muscle oxygenation in a personalized manner and identifying responders/non-responders to exercise bouts. Modeling the inter-individual differences of muscle oxygenation and the intra-individual responses according to the muscle groups in responses to exercise would lead to propose more accurate exercise prescription. Machine learning and data-driven artificial intelligence approaches can help to achieve this goal. Last potential limitation to consider may be for most practitioners and club the relatively substantial cost of current NIRS devices although their costs have dramatically decreased during recent years, as compared to HR monitors.To date, there are still obstacles plaguing the widespread use of portable NIRS sensors in sports settings. The development of NIRS applications during exercise faces some challenges including methodological considerations and the knowledge of the collected metrics on what constitute a good interpretation. The first main limitation to all NIRS devices is the reduced sensitivity (due to scattering attenuation) to muscles in the presence of subcutaneous adipose tissue where thin adipose layers provide larger changes in StO2 values for the athlete suggest that it may be very useful for measuring changes in local microvascular oxygenation in diverse sports settings. Portable NIRS devices provide vital insights into how muscles are exerting during training that are not provided by other systemic metrics. In addition, it can be used to compliment other external load metrics to give a clearer picture during training. NIRS devices could provide a collection of athlete internal load data, whereby coaches and practitioners can use various derived oxygenation metrics to monitor, evaluate, and prescribe training (and competition) characteristics. It is now time to integrate muscle oxygenation metrics beside the most common methods for quantifying internal training loads.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Over the past decade, repeated studies demonstrated that the vertebrate brain had a specialized lymphatic transport pathway, which overturned the traditional concept of central nervous system (CNS) immune privilege. Despite the lack of lymphatic vessels, the glymphatic system and the meningeal lymphatic vessels provide a unique pathway for solutes transport and metabolites clearance in the brain. Sleep, circadian rhythm, arterial pulsation, and other physiological factors modulate this specialized lymphatic drainage pathway. It has also changed significantly under pathological conditions. These modulatory mechanisms may arise critical targets for the therapeutic of CNS disorders. This review highlights the latest research progress on the modulation of lymphatic transport in the CNS under physiological and pathological conditions. Furthermore, we examined the possible upstream and downstream relation networks between these regulatory mechanisms. The lymphatic transport system in vertebrates maintains body fluid homeostasis, immune surveillance, and lipid reabsorption in the peripheral organs; it also plays an essential role in the pathological process underlying inflammation, cardiovascular disease, tumor metastasis, and in the onset of other diseases For a long time, researchers have suggested that cerebrospinal fluid (CSF) may be the \"sink\" through which brain metabolites is cleared Numerous studies have focused on this specialized lymphatic transport system's physiological modulation and pathological changes Sleep is a naturally occurring physiological state of decreasing arousal. During non-rapid eye movement (NREM) sleep, more CSF flows into ISS, and the brain's metabolites clearance is significantly more efficient than that in awake NREM sleep electroencephalography (EEG) slow-wave activity represents the principal marker of the process S during sleep Still, there are some unclear and even confusing issues. As a marker of neurons' spontaneous and rhythmic electrical activities, EEG has been a leading tool to study brain function in health and disease. However, much less is known about its content, given the complex relationship between EEG features and microcircuit structure Besides, some studies found that the glymphatic inflow decreased following sleep deprivation 217O to capture both paracellular flow and diffusive transcellular exchange of water showed a faster and more active glymphatic transport 217O tracer freely travels through the intracellular and extracellular pathways, extracellular volume fraction will also have a minor impact on the water transport of CSF Furthermore, current researches on glymphatic transport rely on tracers of larger molecular solutes to simulate CSF transport, which may underestimate the flow of CSF water into brain parenchyma. The classical tracer study measured AQP4-dependent paracellular flow of the liquid exchange of ISS confirmed that tracers inflow were related to molecular solute size During NREM sleep, the inhibition of the adrenergic system increases the area of the ISS; consequently, it reduces the fluid resistance and increases the solute transport efficiency -2 adrenergic receptors; this effect is consistent with the inhibition of norepinephrine release during natural sleep The sympathetic tone is reduced during natural sleep, whereas the parasympathetic tone is increased Summarizing these results, we speculate that the autonomic nervous system (ANS) has a wide range of modulatory effects on the glymphatic inflow. The ANS also regulates physiological parameters such as respiration, heart rate, and vascular pulsation. Some studies examined the impact of physiological parameters on GS, which were reviewed later in this paper.Endogenous sleep factors (ESF) such as adenosine, nitric oxide, and prostaglandin D2 have significant efficiency in regulating NREM sleep homeostasis (process S) The circadian rhythm controlled by the suprachiasmatic nucleus of the hypothalamus plays the role of a pacemaker in the two-process model of sleep regulation Many physiological factors, including intracranial pressure (ICP), blood pressure, heart rate, and respiratory, regulate the fluid transport of the cerebrovascular system and PVS in vivo two-photon imaging have demonstrated that aPVS was a flat, double tubular eccentric structure, 1.4 times (whereas fixation reduced this ratio to 0.14) the cross-sectional area of the adjacent artery with low fluid resistance 217O, a recent study revealed that the glymphatic transport was dramatically faster and more extensive than previously thought It is still controversial about the fluid transport mode in the ISS: convection or diffusion. Some modeling studies showed that arterial pulsation alone could not provide sufficient driving force to account for convective transport due to the narrow aPVS The flow of CSF in the ventricular system and subarachnoid spaces (SAS) is mainly regulated by respiration, while the contribution of cardiac pulsations on this process is low Decompressive craniectomy reduces ICP and impairs the glymphatic inflow, which cranioplasty reversed in mice Some researchers believe that the efficiency provided by arterial pulsation should not exceed 15-25%, and vasomotion is a more efficient driving force Mammalian aquaporins, transmembrane proteins that promote the bidirectional transport of water across the cell membrane, are the primary water homeostasis regulators and participate in molecular transport and membrane protein expression, cell adhesion, and cell volume regulation AQP4 also plays a vital role during brain edema. CNS edema is associated with increases in total AQP4 expression and AQP4 subcellular translocation after TBI, spinal cord injury (SCI), and stroke Is there any intrinsic relationship between brain edema and GS transport? The source of water for brain edema is also a controversial issue. A recent study showed that CSF flowed into the ischemic area through PVS (the same inflow pathway as the GS), driving acute tissue swelling Figure D 76. DoeAQP4 inhibitors may benefit from the reversible blockade of AQP4 within one week after brain injury CSF is mainly produced by the choroid plexus of the ventricular system and other tissues (such as the BBB) The direct measurement of CSF production in mice by blocking the aqueduct of Sylvius indicated that isoflurane caused a higher rate of CSF production than that of the K/X cocktail In contrast, although there is no direct research evidence, other studies have demonstrated that the increased CSF production was consistent with the increased glymphatic influx. The production of CSF increases during the mid-rest phase and the treatment with non-selective \u03b2-adrenergic receptor antagonists in mice We speculate that the regulation of CSF production under physiological conditions may be intrinsically related to the modulation of sleep, ANS, physiological parameters, and cerebrovascular, all of which ensure a stable and adequate brain clearance. Changes in CSF production during pathological conditions may be related to brain clearance disorder's compensatory or decompensated mechanism.CSF in the ventricles converges into the fourth ventricle through the interventricular foramen, the third ventricle, the midbrain aqueduct, and eventually flows into the cisterna magna circulate in SAS. CSF in the fourth ventricle can also flow into the central canal of the spinal cord. The drainage of CSF into the spinal cord is far less than that into the cranial cavity under physiological conditions The novel pathway, GS, elaborates that some CSF flow into the brain parenchyma before efflux out of the skull cavity In addition, these traditional and novel drainage pathways also have some outstanding open scientific issues that need to be further characterized. For example, is there an essential connection between the conventional drainage path of the perineural space and the MLVs located around these nerves? The exact contribution of these outflow pathways to CSF drainage remains clarified. What anatomical pathway does the ISF pass into the dorsal and base MLVs?Although the mechanism of how CSF is transported to MLVs is unclear, many studies showed that CSF primary outflowed cranial cavity through MLVs The degeneration of MLVs in aging mice and the blockade of the CSF outflow pathway does not increase brain water content and ISF pressure Moreover, the proliferation and remodeling of MLVs have both sides in CNS disorders. Structural and functional disorders of MLVs will impair the brain clearance system and reduce the immune-inflammatory response, which may be a potential therapeutic target for CNS autoimmune response such as multiple sclerosis 2 partial pressure; after that, through internal chemical regulation mechanisms, the cerebrovascular dilation and vascular compliance increases, along with the lowering of heart rate, which eventually increases the arterial pulsation amplitude In this review, we systematically review the physiological regulatory mechanisms of the lymphatic transport in the CNS based on the two-process model of sleep regulation. It is now clear that no single pathological feature can explain this complex modulatory process in isolation. These mechanisms are related and interact upstream and downstream Figure . Sleep iUnlike physiological regulation, pathological changes are often compensatory or decompensated physiological reactions occurring after disease onset. Like inflammation, which has both protective and adverse effects, we need to investigate the comprehensive impact of these physiological regulations on different diseases and stages after pathological CNS disorders and further identify the regulatory strategies that can be the most beneficial. These physiological parameters will also change during pathological stress after brain injury in different periods throughout the disease course. Many clinicians have been developing individualized and accurate therapeutic schemes by adjusting these physiological parameters to reduce secondary brain injury, and these therapeutics are also controversial. For example, which is a better therapy after severe TBI, the Lund concept, or the Brain Trauma Foundation guidelines Under physiological conditions, the rapid outflow of CSF reduces the glymphatic influx. Pathologically blocking MLVs does not increase cerebral water content and glymphatic influx. We speculate that the outflow pathway of CSF in the SAS may differ from that in the brain; other complementary routes may be hidden. Further studies that characterize the exact anatomical structure of these outflow pathways will help us find new therapeutic strategies that effectively regulate these pathways to counteract the brain damage caused by the changes of outflow pathways in pathological conditions.The lymphatic transport may be involved in most pathophysiological processes in the CNS, so these directions are far from enough. We can restudy any CNS disease by targeting the specialized lymphatic transport system with new information and insight."} +{"text": "Caregivers of individuals with dementia have increased levels of burden because of their caregiving duties which in turn results in negative effects on their physical, emotional, and mental wellbeing. Few studies have examined individual difference-based constructs such as positive and negative affect in relation to caregiver burden. Positive affect is characterized by pleasant emotions and expressions and higher levels of overall life satisfaction whereas negative affect is characterized by more pessimistic emotions and expressions and lower overall life satisfaction. Analyses were performed on dementia caregivers (n=102) using the online data collection tool MTurk Prime. The average caregiver provided 21 or more hours of care with 76.9% of caregivers living with their loved one with dementia. Significant correlations were found between caregiving burden and positive affect and negative affect , with higher positive affect related to lower burden and higher negative affect related to greater burden. Results of multiple regression models showed that positive affect and negative affect were significant predictors of burden even while controlling for other constructs including types of coping, compassion towards other, and assessment of family dynamics. Understanding the relationship between these constructs will allow for more individualized interventions to be created to help reduce the level of burden that dementia caregivers experience."} +{"text": "Learning is fundamental to rehabilitation and practice-independent processes. Skill acquisition during initial practice is typically exhibited by fast improvements in performance is sufficient for implicit aspects of memory, a period of sleep is necessary for slow consolidation of explicit aspects of memory a memory that has been consolidated through slow consolidation, online and offline processes can occur again to further fine tune recall (or performance) of the memory, known as reconsolidation more easily, whereas a stable memory is harder to modulate. There are two primary factors that have been found to enable memories to stabilize. The first factor is the amount/duration of practice. Increasing the number of repetitions of task A helps to stabilize a memory trace, thereby reducing retroactive interference. However, increased repetitions of Task A can also transiently increase proactive interference to a subsequently learned task as Task A is being consolidated (Krakauer et al., Second, the duration between sessions of learning helps to stabilize memories via consolidation. Allowing for several hours between task practice has been shown to decrease both retroactive and proactive interference compared to a period of several minutes between tasks (Walker et al., While consolidation and reconsolidation are relevant to psychotherapy treatments such as the extinction of fear memories (Monfils et al., We propose that future research investigate consolidation and reconsolidation between rehabilitation sessions. Given the overwhelming evidence for the process of memory reconsolidation in declarative and procedural memories, it might be expected that individuals undergoing rehabilitation would also experience reconsolidation between sessions of therapy. For example, regaining independence in performing activities of daily living involves learning processes (Bayona et al., Recipients of rehabilitation would also benefit from the continued development of clinical protocols using non-invasive brain stimulation as an adjunct to enhance therapy-related memory consolidation and reconsolidation. Indeed, several studies regarding stroke rehabilitation have found benefits of pairing non-invasive brain stimulation with participation in rehabilitation (Khedr et al., In addition to task-specific memory modulation, future research should also focus on how to best induce generalization of skill between therapies in relation to the degree of memory stability and task similarity. For example, Mosha and Robertson had partRehabilitation often involves learning. We first describe why clinicians should consider memory consolidation and reconsolidation. Secondly, we encourage future research to investigate how consolidation and reconsolidation relate to rehabilitation and translate previous work to decrease interference effects and enhance memory consolidation between rehabilitation sessions. Doing so may aid in the development of efficient and long-lasting interventions that are generalizable to clinically meaningful activities.BJ: conceptualization, literature review, and manuscript writing. LC and KW: conceptualization and manuscript writing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Although research on the health benefits of volunteering has proliferated in recent decades, most studies have focused on whether or not a person volunteers or the monthly frequency of volunteering. This study examines whether sustained volunteering has health benefits above and beyond occasional or short-lived volunteering. To investigate the salubrious effects of volunteering, the present study considers sustained volunteering engagement in terms of both formal and informal volunteering. Using four waves of data from the Health and Retirement Study, we assess the influence of sustained volunteering on chronic inflammation, measured by C-reactive protein (CRP). Results reveal that sustained engagement in formal and informal volunteering is related to lower CRP concentration, but this association is partly mediated by adult health and socioeconomic factors. Although sustained volunteering is associated with lower levels of chronic inflammation, older adults who maintain their volunteering over time are a select category of adults, characterized by higher education and wealth and better health."} +{"text": "The increased morbidity and mortality relating to the poor physical health of patients with severe mental illness has repeatedly been an area identified as requiring improvement. Despite this, no national minimum standard has been published around the minimum level of physical health equipment that should be available within an inpatient psychiatric setting.The aim of this project was to improve and standardise availability of physical health equipment across the five clinical areas within a medium secure inpatient forensic setting, thus enabling optimal and timely medical care and physical examination of patients to occur.This project used a combination of audit and quality improvement practices. An audit standard was created and current practice was established within the 5 clinical areas of a Medium Secure Forensic Unit. Improvements were made in a systematic and measured way and two audit cycles were completed.At baseline, the attainment of audit standard ranged from 14-76%. Clinical areas were sharing equipment and there was an inconsistency as to where and how equipment was being stored. Changes implemented included redistribution and reorganisation of equipment which increased attainment to between 48% - 86%. Following this further equipment was ordered and the equipment was separated into that which was required on a daily basis to conduct physical observations and more specialist specific examination equipment. Re-audit found attainment across the five clinical areas being between 90-100%.Monitoring of physical health within psychiatric inpatient settings is a key area of patient care, and is frequently identified as requiring improvement. Without access to equipment to monitor and assess physical health, this becomes challenging and potentially poorly completed. By standardizing available equipment and furthermore through practical steps such as separating the equipment required on a daily basis and that used less frequently the retention of equipment improved. This enables delivery of high quality, timely and thorough monitoring and assessment of physical health to be achievable."} +{"text": "Cancer disproportionately affects Black Americans and consequently, their families. In addition, cancer is often just one of the significant health concerns facing Black families at any one time. Research on family support after an adult cancer diagnosis overwhelmingly focuses on a single caregiver and spousal family caregivers, limiting understanding of the complexity of caregiving within family systems facing multiple health challenges. This presentation presents a framework for a broader focus on the role of family systems in providing cancer care, highlighting both the unique strengths and challenges facing Black families who provide care. A family comorbidity lens is used to underscore the need to better understand the nature and impact of concurrent health challenges within families. Ultimately, this perspective reflects the lived experiences of older Black adults and their families after a cancer diagnosis and has implications for future research and interventions to address health issues interdependently."} +{"text": "Dementia is a global public health priority which cost global societies $818 billion in 2015 and is disproportionately impacting low and middle-income countries (LMICs). With limited availability of disease modifying drugs to treat Alzheimer's disease (AD), researchers have increasingly focused on preventative strategies which may promote healthy cognitive aging and mitigate the risk of cognitive impairment in aging. Lifelong bilingualism has been presented as both a highly debated and promising cognitive reserve factor which has been associated with better cognitive outcomes in aging. A recent metanalysis has suggested that bilingual individuals present on average 4.05 years later with the clinical features of AD than monolinguals. Bilinguals are also diagnosed with AD ~2.0 years later than monolingual counterparts. In this perspective piece we critically evaluate the findings of this metanalysis and consider the specific implications of these findings to LMICs. Furthermore, we appraise the major epidemiological studies conducted globally on bilingualism and the onset of dementia. We consider how both impactful and robust studies of bilingualism and cognition in older age may be conducted in LMICs. Given the limited expenditure and resources available in LMICs and minimal successes of clinical trials of disease modifying drugs we propose that bilingualism should be positioned as an important and specific public health strategy for maintaining healthy cognitive aging in LMICs. Finally, we reflect upon the scope of implementing bilingualism within the education systems of LMICs and the promotion of bilingualism as a healthy cognitive aging initiative within government policy. Twenty first century societies are rapidly transitioning to aging populations which are often characterized by a burden of age related conditions such as dementia . There aWhilst there have been limited successes of clinical trials and disease modifying drugs , researcCognitive reserve is a hypothetical construct which posits that enriching lifetime experiences and activities support the brain in mitigating the impact of pathological damage over time \u201315. ThisA recent metanalysis by Paulavicius et al. revealedWe propose that incorporating bilingualism into dementia public health policy to delay the onset of dementia is an important and specific strategy in maintaining healthy cognitive aging in LMICs. We reflect how bilingualism can be incorporated into governmental and educational policy and overall health strategy in LMICs settings and the challenges associated with this.Bilingualism can be classified as individuals' ability to communicate using two languages either actively using speech or listening, or passively using writing, reading, or listening. The bilingual experience is a dynamic process and proficiency may differ according to the level of exposure to other users of each language and level of opportunity to use each language . BilinguLifelong bilingualism has been positioned as a cognitive reserve factor and promBilinguals simultaneously attend to two competing languages for selection which may induce neuroplasticity and leadThe bilingual experience may promote more widely distributed neural activity , recruitThe positive findings which are reflected in the neuroimaging studies of bilinguals are also depicted in multiple neuropsychological and epidemiological studies of bilingual adults. Bilinguals have been shown to outperform monolinguals in tests of executive function, such as cognitive control , workingA 12 year longitudinal Israel based study of 814 elderly Jewish people revealed trilinguals performed better on cognitive tasks than monolinguals and bilinguals . These fHaving explored the contextual evidence supporting bilingualism as a cognitive reserve factor, we now evaluate the systematic review from Paulavicius et al. explorinThis systematic review reported findings from eight studies which examined the relationship between bilingualism and the age of onset of dementia. Metanalysis from these studies determined that bilinguals with AD F = 4.89, p = 0.027] after adjustment for immigration, socioeconomic status, illiteracy, education, and residence in rural and urban areas, number of languages spoken and occupational status and the Finally, we address how future studies of bilingualism and cognitive reserve could be conducted to help us understand the potential benefits of bilingualism in a globalized context. We propose that studies of bilingualism could be performed in high risk and vulnerable populations, such as individuals with mild cognitive impairment (MCI), those with a strong family history of cognitive impairment or genetically susceptible populations. Furthermore, we suggest that prospective studies could be explored in bilingual and monolingual cohorts with a strong vascular history , culturaWith the advent of neuroimaging modalities and possible increased availability of investigations in LMICs it may be possible to examine how bilingualism may be linked with specific structural neuroimaging findings such as volumetric temporal lobe changes. More relevant information may also be gained from functional magnetic resonance imaging and diffusion tensor imaging. The use of specific neuroimaging techniques, such as fluorodeoxyglucose positron emission tomography (FDG-PET) may be helpful , as is tWe emphasize that taking a detailed linguistic history is particularly salient in establishing bilingual proficiency in studies of bilingualism and cognitive reserve. Practical considerations include structured documentation of the level of frequency of language use, subjective linguistic competency, age of acquisition of languages, context of use, formal competency assessment of verbal fluency of languages, formal qualifications in each language and degree of language switching. These factors could be compiled in a structured linguistic competency questionnaire. We assert that by employing a more global and structured approach to linguistic competency we may be able to devise a rating scale which may provide an objective measure of linguistic proficiency.We now propose bilingualism as a significant public health initiative for healthy cognitive aging in LMICs and consider how this could be incorporated into policy. The G8 and WHO have highlighted that upscaling public health indicatives should be a focus on dementia management in LMICs . We encoThere is an intrinsic value of delaying the onset of dementia . A delayWe discuss how bilingualism-based measures could be practically adopted within public health strategies in LMICs. One approach would be to promote bilingualism from childhood. Benson explored how bilingual language programs can be incorporated into school curriculum in LMICs using examples from Guinea-Bissau, Niger, Mozambique, and Bolivia . Benson Whilst we have demonstrated the contribution of bilingualism toward cognitive reserve, we consider whether language learning in older age could be a feasible public health strategy to delay the onset of dementia in LMICs. Prior research has suggested that brain training may foster positive brain changes in healthy adults and oldeA study which examined the benefits of one week of intensive Scottish Gaelic language training in older monolinguals revealed that these participants had improved in task switching cognitive tests . ImproveBak and colleagues suggest This perspective has examined the role of bilingualism as a cognitive reserve factor from a wide range of evidential sources. We have explored studies of bilingualism conducted in both HICs and LMICs and reflected upon an important metanalysis that demonstrated that bilingualism is associated with a significant delay of onset of dementia. We determine that many key studies of bilingualism are limited by inconsistent working definitions of bilingualism and few have utilized objective measures of bilingual fluency. Furthermore, while several retrospective bilingualism studies have identified a significant delay in dementia onset this finding has not been replicated in prospective studies. We suggest that future research should explore the reasoning behind this discrepancy. Contextual challenges in LMICs including the high prevalence of illiteracy, HIV, socio-cultural and environmental disparities, and differing risk factors may complicate the overall picture.Whilst finding a definitive treatment is the gold standard in dementia research, we suggest that public health measures that may promote the delay of clinical features of dementia, such as language lessons for the elderly or augmenting pre-existing bilingual proficiency in older age is important. This may be particularly salient in LMICs where cheap, pragmatic, and easily accessible approaches are warranted. If we are to harness the key benefits that bilingualism may provide, we encourage major stakeholders including governmental and health system providers to develop social programs and interventions to support the preservation of a second language.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.SM was the principle author for this paper and derived the key topics for discussion in this paper. NT and VR provided general feedback and editorial comments. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The interview participants were purposively sampled to recruit clinical or academic staff involved in education of students on undergraduate HCP programmes and public health programmes in an Irish university. Participants were asked to outline their views on current teaching and assessment methods, use of AMS competency frameworks and potential areas for improvement. Interview recordings were conducted online, the recordings were transcribed verbatim, and transcripts analysed by thematic analysis. Ethical approval was obtained, and all participants provided written informed consent.2 with most participants believing that this would improve the structure of AMS education, ensuring that key learning outcomes would be addressed in the curriculum. The importance of preparing students for interprofessional practice in AMS in the future was identified as a key theme, with participants highlighting the importance of interprofessional education opportunities to foster communication and teamwork skills in AMS at an early stage.Interviews were conducted with 15 participants . A range of disciplines were represented as outlined in the methods. The main interview themes included the challenge of balancing curriculum priorities and capacity in HCP programmes, the importance of ensuring student understanding of AMS/AMR principles, and patient centred application of knowledge. Current teaching and assessment methods were found to vary between the HCP programmes with a mix of didactic lectures and workshops, and assessment ranging from written exams and multiple choice questions to observed structured clinical exams. Very few participants reported educating different HCP students together. Participants were asked to review an antimicrobial education competency framework,The importance of AMS and AMR education in HCP programmes was reported in this study, however the main challenge is limited curricular space in busy HCP programmes. Education may be improved by aligning AMS education with an appropriate competency framework. Enhancement of undergraduate interprofessional education opportunities, to prepare students for interprofessional AMS in future practice, is recommended."} +{"text": "Romantic jealousy, especially in its pathological form, is a significant contributor to both domestic abuse, including partner sexual coercion and even murder, although relatively little research has been conducted on it. Both obsessive and delusional forms have been identified although only the latter is currently recognized as a pathological disorder. Studies in both clinical and healthy populations have identified altered fronto-striatal responsivity as being associated primarily with romantic jealousy and to date drug based treatments have targeted both dopaminergic and serotonergic systems. However, there is increasing interest in a potential role for the neuropeptide oxytocin, which can also modulate dopaminergic and serotonin systems in the brain and has been shown to altered in other psychotic conditions, such as schizophrenia and obsessive compulsive disorder. Recent studies in healthy populations have reported that when oxytocin is administered intranasally it can influence the brain to promote strengthening of romantic bonds and reduce romantic jealousy in both men and women evoked in either imagined or real contexts. These findings indicate a possible therapeutic use of intranasal oxytocin administration in pathological jealousy. Jealousy has been defined as \u201ca perception of threat of loss of a valued relationship to a real or imagined rival which includes affective, cognitive and behavioral components\u201d . As suchBoth obsessive and delusional forms of pathological romantic jealousy are associated with self-harm and predominately male-to-female violence such as domestic abuse and even murder . A commuWhile the major focus has been on pathological forms or romantic jealousy, like other disorders, it is reasonable to consider it in a dimensional manner in the same way as other disorders, with jealousy traits being present in everyone and normality compared to pathology only differing in terms of the intensity and irrationality of the feelings experienced. Multidimensional scale questionnaires, such as the Multidimensional Jealousy Scale , have thA small number of neuroimaging and neuropathology studies in humans, have demonstrated that pathological jealousy is particularly associated with altered fronto-striatal circuitry, the ventral medial prefrontal cortex (vmPFC), thalamus, insula and amygdala. These circuits are involved in the control of a range of behaviors including reward and emotion processing, impulsivity, mentalizing/self-related processing and interoception/salience processing and, most notably, dopaminergic and serotoninergic signaling see . In addiA number of case reports have suggested that damage to the right or left frontal lobe is associated with delusional jealousy see and one A few neuroimaging studies have investigated the neural basis of jealousy in healthy populations either using exposure to jealousy-evoking contexts or as a function of trait jealousy scores. In male monkeys confronted with threats to their exclusive sexual access to a female partner were associated with increased activity in the amygdala, striatum and superior temporal sulcus, the temporal pole in right hemisphere and bilateral insula . In healAn important issue in determining neural substrates associated with romantic jealousy is that most studies have not controlled for contributions from trait aggression. In a recent study using a dimensional approach with healthy subjects we therefore established associations between neural substrates responding to threatening (angry) faces and trait romantic jealousy while controlling for trait aggression and gender. Our findings revealed that individuals with higher trait romantic jealousy exhibited greater activation in response to angry, but not other emotional faces, the frontal cortex and dorsal striatum as well as the insula, hippocampus, thalamus, fusiform gyrus, superior parietal lobule and bilateral cerebellum. Functional connectivity between the frontal cortex and dorsal striatum was also stronger in more jealous individuals during processing of angry faces . This paIn line with evidence from neural studies of romantic jealousy indicating involvement of fronto-striatal and limbic dopaminergic and serotonergic systems drugs taOver the last few decades there has been increasing interest in the use of intranasal administration of neuroactive peptides and drugs which do not readily cross the blood-brain barrier to deliver them into the brain and thereby influence both brain and behavior see . One neuWhile the mechanism(s) whereby oxytocin may stimulate its receptors in the brain following intranasal administration has been the subject of some controversy there isIn terms of the effects of intranasal administration of oxytocin which are of relevance to a potential role in modulating romantic jealousy several studies have reported that it can act to strengthen romantic bonds in humans. In both men and women in established relationships intranasal oxytocin can enhance the perceived attractiveness of the face of an existing partner, but not of others, and this is associated with enhanced activation in the striatum and ventral tegmentum regions of the reward system ; 2016. IWhile some studies have reported that intranasal oxytocin can increase envy in non-romantic contexts and reduFinally, given that a number of studies have associated romantic jealousy with an anxious-ambivalent attachment pattern , it is iOxytocin has also been shown to be potent modulator in both dopaminergic and serotonergic systems . In animWhile no studies have directly investigated possible associations between pathological jealousy and oxytocin, methylation of the oxytocin receptor is reported to be reduced in schizophrenia and other psychotic disorders and obseWhile we are gaining a better understanding of the behavioral, neural and neurochemical systems involved in trait and pathological romantic jealousy there is clearly an urgent need for more research in this field. Current drug treatments targeting either dopaminergic or serotonin systems have produced some success in controlling jealousy behaviors targeting other interacting systems such as the neuropeptide oxytocin may offer a different strategy to strengthen romantic bonds between partners and promote greater tolerance of either real or imagined infidelities. Intranasal administration of oxytocin provides a safe and effective way to target its receptors in the brain and there is increasing evidence that this facilitates reductions in jealousy and can help to strengthen and maintenance of romantic bonds. As yet however, no trials have investigated the potential therapeutic efficacy of oxytocin administration on pathological jealousy, although importantly not only can it reduce trait romantic jealousy but also modulates both dopaminergic and serotonergic systems which are the current main therapeutic drug targets for this disorder."} +{"text": "This PRISMA informed scoping review sought to understand the longitudinal association between workplace demands with cognitive health; and to review how race and ethnicity are investigated in this area of research and evidence of moderating effects. Peer-reviewed articles were drawn from five databases. Inclusion criteria were populations aged 18+, broad conceptualization of workplace demands , and cognitive health outcomes . The majority of studies drew from theories that did not interrogate heterogeneity and diverse aging experiences. Consequently, the majority of studies (85%) did not investigate inequities by race and ethnicity although variables and methods are available. Cognitive health inequities are evidenced but findings are mixed and more rigorous causal research is needed. We discuss integrating emerging critical theories to sharpen the focus on racial health inequities in an emerging area of prevention research."} +{"text": "To assess existing knowledge related to methodological considerations for linking population-based surveys and health facility data to generate effective coverage estimates. Effective coverage estimates the proportion of individuals in need of an intervention who receive it with sufficient quality to achieve health benefit.Systematic review of available literature.Medline, Carolina Population Health Center and Demographic and Health Survey publications and handsearch of related or referenced works of all articles included in full text review. The search included publications from 1 January 2000 to 29 March 2021.Publications explicitly evaluating (1) the suitability of data, (2) the implications of the design of existing data sources and (3) the impact of choice of method for combining datasets to obtain linked coverage estimates.Of 3805 papers reviewed, 70 publications addressed relevant issues. Limited data suggest household surveys can be used to identify sources of care, but their validity in estimating intervention need was variable. Methods for collecting provider data and constructing quality indices were diverse and presented limitations. There was little empirical data supporting an association between structural, process and outcome quality. Few studies addressed the influence of the design of common data sources on linking analyses, including imprecise household geographical information system data, provider sampling design and estimate stability. The most consistent evidence suggested under certain conditions, combining data based on geographical proximity or administrative catchment produced similar estimates to linking based on the specific provider utilised (exact match linking).Linking household and healthcare provider data can leverage existing data sources to generate more informative estimates of intervention coverage and care. However, existing evidence on methods for linking data for effective coverage estimation are variable and numerous methodological questions remain. There is need for additional research to develop evidence-based, standardised best practices for these analyses. We systematically reviewed a wide range of methodological issues pertaining to linking population-based and health provider data for effective coverage estimation.The review was limited by the diversity of terminology and fields related to the linking methodology.Multiple search strategies were used to minimise the likelihood of overlooking relevant publications.Results of the review are summarised and related to actionable items and needs for future research.There is growing demand for tracking progress towards the sustainable development goals through effective coverage estimates.Linking household and health provider data is a promising means of generating effective coverage estimates that provide population-based estimates and incorporate data on service quality from health facilities. Data from household surveys can provide a population-based estimate of intervention need and care-seeking for services, such as the proportion of women with a recent live birth who delivered in a health facility. However, a number of maternal, newborn and child health interventionsThere are many approaches for combining household and provider datasets.We searched for papers addressing methods or assumptions regarding: (1) the suitability of household and provider data used in linking analyses, (2) the implications of the design of existing household and Multiple Indicator Cluster Survey (MICS)) and provider (Service Provision Assessment (SPA) and Service Availability and Readiness Assessment (SARA)) data sources commonly used in linking analyses and (3) the impact of choice of method for combining datasets to obtain linked coverage estimates.et al,et al on linking household and facility data to estimate coverage of reproductive, maternal, newborn and child health (RMNCH) services,et al of effective coverage analyses.Our primary search was conducted in Medline. The search was limited to papers published between 1 January 2000 and 29 March 2021 that included terms related to (1) effective coverage, benchmarking, system dynamics or universal health coverage (UHC) metrics, or (2) structural, process and/or health outcome quality, 3) linking analyses using terms adapted from Do linking 10.1136/bmjopen-2020-045704.supp1Supplementary dataPublications were reviewed for relevant analyses or commentary related to linking methodologies. Articles were included if they explicitly evaluated or compared assumptions used in linking approaches for at least one of the areas defined above. The review focused on low-income and middle-income countries (LMICs) and data sources common in these settings, however, publications from high-income settings were retained if the relevant evidence could translate to LMICs location in estimates of distance, validity of provider quality measures). No formal quality assessment was conducted due to the diversity of study designs and research objectives of the papers relevant to the review. Title and abstract review were conducted simultaneously by the first author (EC). Data extraction included the title, author, year of publication, country or countries included in analysis, data source and specific analyses or findings relevant to linking loosely categorised by topic areas. Topical area groupings emerged from the review and were used to structure the findings.As a systematic review, neither patients nor the public were involved in the design, conduct, reporting, or dissemination plans of our research.et al and 49 papers included in the review by Do et al meeting the publication date restrictions. After removing duplicates, 3805 publications were included in the title and abstract review and 236 were included in the full text review. Of those papers included in the full text review, 56 publications addressed a methodological concern related to linking household and provider data and were included in the final review. Fourteen additional publications were identified through the snowball review of references and related works and care-seeking (n=5) that should guide selection of indicators for linking.et al demonstrated the effect of the divergence of true from perceived intervention need on effective coverage estimates. The authors propose estimating the posterior probability of disease based on responses to symptomatic questions using a Bayesian model to measure disease presence on a probabilistic scale.Estimation of intervention need may require solely population demographics such as age or may require defining specific illnesses or conditions. The latter is more subject to reporting bias.et al note that provider categories are not standardised between population surveys and health system assessments, with population surveys often including vague or overly broad categories that do not directly match SPA/SARA categories and require harmonisation.19Four studies addressed the accuracy of respondent report of seeking care. Mothers in Zambia and Mozambique were able to accurately report on the type of health provider where they sought sick childet al.Provider assessments present data on service content and quality for effective coverage linking analyses. However, the measurement, construction and interpretation of provider quality measures are highly variable and may significantly alter effective coverage estimates. This paper does not present an exhaustive review of healthcare quality measures or the association between levels of quality. A comprehensive summary of quality of care concepts and measurement approaches, along with their relative strengths and limitations, was presented by Hanefeld et al found significant variability in the data collected and methods used in health facility assessment tools in LMICs.23A review by Nickerson et al found few studies to support use of patient report, provider self-report or record review as proxy measures of clinical care quality.Nine publications assessed alternatives to direct observation of clinical care for collecting process quality data. Two studies found no association between process quality and maternal perceptions of the quality of care receivedMost linking papers estimating effective coverage included in this review (n=15) characterised provider quality using structural measures of quality, with or without measures of process quality. Various approaches were used to select items for inclusion in these measures. Measures of structural and process quality were derived from either national or international guidance on minimum service availability and required commodities, equipment, infrastructure, training or actions. Measures used by effective coverage analyses included SPA or SARA structural indicators46 47In addition to the range of variables used in provider measures, there was no consensus on the approach to use to select and combine variables to generate quality indices. The reviewed publications used a variety of approaches to construct indices including weighted indices,45 51Despite the common usage of SPA and SARA data-derived structural and process quality measures, the review found limited data explicitly assessing the association of these measures with each other and health outcomes (n=7). Three studies, two incorporating data from multiple countries, found little association between structural quality and process quality.59The way in which common household surveys, particularly the DHS and MICS, collect and process location data may also impact the validity of some linked estimates. In many household datasets used for linked analyses, the precise location of individual households is often unknown. The DHS collects central point locations for clusters, rather than household locations, and displaces these points in publicly released datasets.The effect of using cluster central point locations rather than individual household locations in linking analyses was not addressed by any publication identified in this review. However, four studies looked at the effect of using centroids of varying areal units versus household locations in distance analyses. Two studies found using US census tract65Displacement of cluster central points might induce additional error in analyses based on geographical proximity. A DHS analytical report found that ignoring DHS displacement in analyses that used distance to a resource as a covariate resulted in increased bias and mean squared error. However, this will not affect linking by administrative unit because DHS has restricted displacement to within the representative sample administrative unit since 2009.66Typical sampling designs for healthcare provider data also present issues for linking analyses. Both SPAs and SARAs are sampled independently of household surveys, thus, there may be no sampled facilities near household survey clusters.Two papers assessed the impact of excluding non-facility providers on linked effective coverage estimates. In Zambia and Cote d\u2019Ivoire, CHWs offered a level of care for sick children similar to first-level public facilities. Excluding these providers reduced estimates of effective coverage in Zambia where CHWs were a significant source of skilled care in rural areas,33 40et al\u2019s analysis demonstrated that sampling facilities, rather than using a census, led to an underestimation of the adequacy of the health service environment and substantial misclassification error in relative service environment for individual clusters.Two publications addressed the impact of facility survey sampling designs. At the facility level, Skiles A Measure Evaluation manual emphasised that data on provision of services (collected through observation of client\u2013staff interactions), experience of care (collected through client exit interviews) and staff characteristics are sampled independently and collected among health workers and care interactions available on the day of the survey. These data are a subsample of the overall survey and representative at the level the survey is sampled to be representative\u2014not at the facility level.Both care-seeking behaviour and provider quality are likely to vary over time, and both household and provider surveys are conducted infrequently in LMICs (~3\u20135 years). Linked coverage estimates for RMNCH may cover a long time frame as the reference period for care-seeking in household surveys varies from 2 weeks (sick child care) to 2\u20135 years (peripartum care). Population movement and quality improvement efforts at facilities further complicate associations with increasing time lags. The implications of linking household and provider indicators of different temporal periods is unclear.No paper in this review specifically addressed the effect of provider indicator stability on linked effective coverage estimates. However, three linking papers presented data on the stability of some health facility indicators over time. Expanded Quality Management Using Information Power (EQUIP) studies in Uganda and Tanzania found moderate variability in the availability of some maternal and newborn health commodities and services over a period of 2\u20133\u2009years.44 68 69Care-seeking behaviour, including overall rates of care and utilisation of different sources of care, may also change over time. Analysis of care-seeking for child illnessThe approach for combining household and provider data can potentially have a significant impact on linked coverage estimates. Methods used to link data, including exact match and various types of ecological linking, are defined in Three publications explicitly compared effective coverage estimates generated using exact match and ecological linking methods .33 40 44Eight studies assessed the performance of geographical measures for assigning households or individuals to their reported source of healthcare. Four studies in sub-Saharan Africa compared the predicted source of care based on geographical proximity against the true source of care. They found straight-line and road distance performed similarly,77Most linking analyses that have generated effective coverage estimates by assigning individuals the quality score of the reported or linked source of care have derived estimates of uncertainty based on household sampling error and ignored any sampling error around provider data. However, two analyses used the Delta method79This review found a variable number of publications that addressed the diverse methodological issues related to linking household and provider datasets. A summary of key findings and needs for further research is presented in We identified a number of papers that critically assessed household and provider data needed for linking analyses. The limited existing data on respondent-reported care-seeking suggest respondents can identify sources of care if not individual healthcare worker cadre, but additional validation in various settings and service areas, such as postnatal care, would be informative. Further, it is essential to ensure that categorisation of sources of care in household surveys align with the categories used in provider assessments to facilitate linking datasets. The validity of household survey data for estimating populations in need was more variable. While some populations in need can be clearly defined, others, particularly those requiring symptom-derived diagnoses based on respondent report, have demonstrated potential for bias. Additional work is needed to explore alternative methods for identifying populations in need of interventions within population-based data sources.et al, there is need to consider quality indicators\u2019 \u2018intrinsic value as levers for management action\u2019 and application to policy decision making in addition to their ability to capture or predict associated health gain.The content and construction of provider quality indices was highly variable across publications, but largely derived from facility surveys and informed by international guidelines or recommendations. Methods for collecting provider quality have a number of limitations, and no single method perfectly encompasses all aspects of care.Few studies addressed the influence of the design of common data sources on linking analyses, including the impact of imprecise household GIS data, provider sampling frame and sampling design and estimate stability. However, there was a lack of concrete evidence around the impact of these factors on linked effective coverage estimates. Explicitly evaluating the impact of imprecise household location, sampling design and temporal gaps between measures within the context of effective coverage estimation would be informative. Mixed results on the inclusion of non-facility providers in provider assessments for effective coverage estimation emphasise the need to empirically assess the utilisation and service quality of non-facility providers in a given setting prior to conducting a linking analysis, as the quality and use of these providers varies by health area and setting.The most consistent evidence found through the review was around methods for combining data sets. Three papers compared ecological and exact match linking and reported that ecological linking (when accounting for frequency of provider utilisation by type) produced similar estimates to exact match linking. The agreement between the three publications that compared exact match and ecological linking is promising. Exact match linking is considered the most precise method for generating linked estimates; however, ecological linking is often more feasible because it does not require information on exact source of care or data on all providers. The papers further point to the need to maintain data on type of provider from which care was sought or the relative volume of patients seen by providers in order to generate valid estimates of effective coverage. All three studies were conducted in rural sub-Saharan Africa in settings with high utilisation of public sector health facilities; additional studies evaluating the performance of these methods in settings with a more diverse healthcare landscape would be informative. Other papers evaluated ecological linking approaches and found similar estimates of access to care or effective coverage using different approaches for assessing geographical proximity, although the ability of methods to capture true source of care was more variable. External to this review, additional data suggest that individuals may not always use the closest source of care and may bypass providers in favour of providers offering better care.Evidence across the review demonstrates the need for careful choice of methods, data sources and indicators when conducting studies or analyses to link household and provider data for effective coverage estimation. An exploration of the precise effect of setting characteristics, such as variation in provider quality, on effective coverage estimates is needed to guide decision making in the selection of linking methods. Once more of these issues have been evaluated, additional tools and guidance to facilitate use of these methods will be needed.The review was limited by the diversity of terminology and fields related to the linking methodology. However, the use of multiple search strategies minimised the likelihood of overlooking relevant publications. No formal grading of publication quality was included in the assessment, but the choice to conduct the search through Medline was intended to ensure a basic level of quality across the diverse study designs included in the review. Additionally, the diversity of fields, approaches and questions made it difficult to summarise the findings neatly, emphasising the need for communication between researchers, more standard terminology, and, ideally, a cohesive research strategy going forward. Recent efforts have aimed to align definitions of effective coverage.Linking household and healthcare provider data is a promising approach that leverages existing data sources to generate more informative estimates of intervention coverage and care. These methods can potentially address limitations of both household and provider surveys to generate population-based estimates that reflect not only use of services, but also the content and quality of care received and the potential for health benefit. However, there is need for additional research to develop evidence based, standardised best practices for these analyses. The most pressing priorities identified in this review are: (1) for those collecting data from health systems to explore methods to strengthen existing provider data collection mechanisms and promote temporal and geographical alignment with population-based measures, (2) for those collecting population-based data to address validity of self-reported intervention need and ensure indicators of access and utilisation of care are measured to facilitate linking analyses and (3) for those conducting linked analyses to standardise approaches for generating and interpreting effective coverage indicators, including sources of uncertainty, to ensure we are producing evidence that is harmonised, informative and actionable for governments and valid for monitoring population health globally."} +{"text": "Evidence suggests that having a sense of life meaning and purpose is related to physical health. However, the association between life meaning and purpose and physical and mental health among family caregivers remains unclear. This study aimed to examine whether family caregivers\u2019 perceived life meaning and purpose was associated with their physical and mental health (depression and anxiety). The National Study of Caregiving (NSOC) III cross-sectional survey was utilized. One item was used to measure family caregivers\u2019 perceived life meaning and purpose and two composite variables were generated to measure depression and anxiety. Physical health was assessed by questions including pain, breathing problems, limited arm/leg strength, low energy, and sleep problems. Weighted logistic regression analyses with covariate adjustments were conducted to examine the association among family caregivers\u2019 perceived life meaning and purpose, mental and physical health. Results indicated that family caregivers\u2019 perceived life meaning and purpose was associated with a lower probability of having depressive symptoms and anxiety . Furthermore, perceived life meaning and purpose was associated with a lower probability of having breathing problems . Findings suggest that having a strong sense of life meaning and purpose is linked to better mental health and physical symptoms. Further research is needed to determine the mechanism regarding how life meaning and purpose may improve mental and physical health among family caregivers."} +{"text": "The swift endorsement of the robotic surgical platform indicates that it might prevail as the preferred technique for many complex abdominal and pelvic operations. Nonetheless, use of the surgical robotic system introduces further layers of complexity into the operating theatre necessitating new training models. Instructive videos with relevant exposition could be optimal for early training in robotic surgery and the aim of this study was to develop consensus guidelines on how to report a robotic surgery video for educational purposes to achieve high quality educational video outputs that could enhance surgical training. A steering group prepared a Delphi survey of 46 statements, which was distributed and voted on utilising an electronic survey tool. The selection of committee members was designed to include representative surgical trainers worldwide across different specialties, including lower and upper gastrointestinal surgery, general surgery, gynaecology and urology. 36 consensus statements were approved and classified in seven categories: author\u2019s information and video introduction, case presentation, demonstration of the surgical procedure, outcomes of the procedure, associated educational content, review of surgical videos quality and use of surgical videos in educational curricula. Consensus guidelines on how to report robotic surgery videos for educational purposes have been elaborated utilising Delphi methodology. We recommend that adherence to the guidelines presented could support advancing the educational quality of video outputs when designed for training. Robotic assisted surgery has the potential to surmount some of the restraints of laparoscopy, presenting an immersive 3-dimensional depth of field, articulating instruments and a stable camera platform . The swiEach robotic system is costly and is likely to be highly demanded for clinical use; as a consequence simulation training exercises may need to happen outside of clinical work time to access this resource, which can inhibit its use. Further challenges, especially for trainees, comprehend the competition for trainee time for other highly set educational activities, clinical commitments and working hours restrictions .\u00a0ObserviOn the basis of these premises, the aim of this study was to develop consensus guidelines on how to report a robotic surgery video for educational purposes to achieve high quality educational video outputs that could enhance surgical training.https://www.agreetrust.org/agree-ii). A steering committee was selected to incorporate surgical trainers as contributors across several specialties such as general surgery, gynaecology, urology and lower and upper gastrointestinal surgery. Committee members were selected on the basis of previously published experience in guidelines development [The guidelines were established according to The Appraisal of Guidelines Research and Evaluation Instrument II was used for the voting round of the Delphi survey items after 46 statements were prepared by the consensus committee.A steering subcommittee comprising 10 members from 5 countries and 4 surgical specialties defined the consensus report. The steering committee was accountable for the selection of the survey items and statements were agreed upon following teleconferences, e-mails and face-to-face meetings. An electronic survey tool (Enalyzer, Denmark, The Delphi methodology is a generally adopted procedure with a systematic progression of repeated rounds of voting for attaining agreement among a board of experts . The expAll 18 representatives of the consensus committee answered both the first and the second round of the Delphi survey. The first Delphi analysis comprised 46 items. The statements not achieving the minimum required 80% agreement at the first round were reviewed and circulated for a second vote. 36 consensus statements were finally agreed and are summarised in seven categories with the rate of agreement shown in Table Before undertaking robotic surgery clinical training operating on real patients with expert supervision, novice surgeons must first become familiar with the robotic interface by attenOne of the main strengths of our research is that we have collated the expertise of several international committee members across different surgical specialties to establish consensus agreement on how to present a robotic surgery video developed for the scope of surgical education, with the main aim to enhance the educational content of videos by introducing a reference standard to reduce the variability in the quality, trustworthiness and educational accuracy of online robotic surgery videos, as we previously published in laparoscopic surgery . ConsensProcedural competency can depend on the number of cases performed under supervision , which iThe proficiency curve in robotic surgery concerns the whole team , not jusThere is currently no standard accreditation or regulation for medical videos as training tools . The HONConsensus guidelines on how to report robotic surgery videos for educational purposes have been developed utilising Delphi methodology. Adherence to the presented guidelines could help enhance the educational value of video outputs when used for the scope of surgical training."} +{"text": "Plasmodium, the etiological agent of malaria, are transmitted through the bite of anopheline mosquitoes, which deposit sporozoites into the host skin. Sporozoites migrate through the dermis, enter the bloodstream, and rapidly traffic to the liver. They cross the liver sinusoidal barrier and traverse several hepatocytes before switching to productive invasion of a final one for replication inside a parasitophorous vacuole. Cell traversal and productive invasion are functionally independent processes that require proteins secreted from specialized secretory organelles known as micronemes. In this review, we summarize the current understanding of how sporozoites traverse through cells and productively invade hepatocytes, and discuss the role of environmental sensing in switching from a migratory to an invasive state. We propose that timely controlled secretion of distinct microneme subsets could play a key role in successful migration and infection of hepatocytes. A better understanding of these essential biological features of the Plasmodium sporozoite may contribute to the development of new strategies to fight against the very first and asymptomatic stage of malaria.Parasites of the genus Plasmodium sporozoites, the mosquito\u2010transmitted forms of the malaria parasite, traverse multiple cells during their migration from the skin to the liver, before switching to productive invasion of a suitable hepatocyte for replication. Cell traversal and productive invasion are functionally independent processes that require proteins secreted from specialized secretory organelles known as micronemes. This review summarizes what is currently known of the sporozoite invasion modes, and discusses the role of microneme heterogeneity and environmental sensing in switching from a migratory to an invasive state. Infection begins with the inoculation of motile sporozoites into the host dermis by infected mosquitoes. Some of these sporozoites enter the bloodstream and traffic to the liver, where they actively invade hepatocytes to differentiate into thousands of merozoites or transient nonreplicative vacuoles (TVs) illustrates the difficulty in disentangling both invasion modes to infect cells domain protein family proteins, including RON2, RON4, and RON5, into the host cell. RON2 is inserted into the host cell membrane and acts as a receptor for the protein Apical Membrane Antigen 1 (AMA1), which is secreted from the micronemes onto the parasite surface concentration, mimicking the intracellular environment, was shown to decrease CT activity and enhance productive invasion , independently of cell traversal activity onto the parasite surface and/or into the extracellular milieu, sometimes after proteolytic cleavage. SpMICs form a diverse group of proteins with various functions in sporozoite motility , traversal , or productive invasion . How different SpMICs fulfill specific functions at distinct locations and times is currently enigmatic. One possibility is that the activity of secreted SpMICs varies depending on the cellular context and/or environmental cues, such as the pH, which regulates PLP\u20101 function play a central role in these processes. Ca2+\u2010mediated regulation is known to play a prominent role in sporozoite gliding and invasion activates protein kinase G (PKG), resulting in the release of intracellular Ca2+ . CDPK4 conditional knockout mutants display a twofold decrease in productive invasion of HepG2 cells, and CDPK4 chemical inhibition leads to reduced sporozoite motility in P. berghei or PKA inhibit TRAP secretion, sporozoite motility and host cell invasion in P. berghei and P. yoelii and protein kinase A (PKA) is essential for merozoite invasion in T. gondii, microneme secretion plays a key role in parasite egress after intracellular replication. Tachyzoite egress is followed by reinvasion of a host cell, which is associated with a new burst of microneme secretion associated with rhoptry discharge for the formation of the MJ (Bullen et al., Plasmodium sporozoites during their journey from the skin to the liver. It is thus plausible that sequential exocytosis of discrete microneme populations during sporozoite migration or upon productive invasion may rely on successive waves of Ca2+ release, possibly from distinct stores. Distinct extrinsic stimuli may initiate successive cGMP and/or cAMP signals. Alternatively, distinct downstream effectors, including Ca2+\u2010dependent enzymes or proteins that target micronemes to the plasma membrane for exocytosis (Bullen et al., In most of the aforementioned studies, interfering with signal transduction pathways involved in microneme secretion had major impacts on sporozoite gliding motility, which is necessary for CT and productive invasion. How signaling cascades integrate to control sporozoite microneme secretion in a timely and spatially controlled manner to induce a switch from traversal to productive invasion is, therefore, difficult to disentangle. In 7Plasmodium sporozoite stage has been a leading target for the development of malaria prophylactic strategies. Our understanding of how sporozoites achieve their complex journey from the skin to the liver, to ultimately invade and replicate inside hepatocytes, has greatly improved, but major questions still remain unanswered. Questions pertaining to the molecular mechanisms of productive invasion, or how distinct micronemal effectors fulfill distinct functions at different places and times still remain open. Moreover, questions concerning the existence of specialized micronemal subsets and the regulation of their secretion or the signaling cascades controlling the switch from a migratory to an invasive state and if all these mechanisms are conserved across all Plasmodium species are yet unresolved.The Although recent technological advances in gene targeting strategies will definitely help to address some of these questions, novel robust methods to distinguish CT from productive invasion events are also needed to capture the elusive sporozoite junction and dissect the mechanisms underlying the formation of the PV. Malaria sporozoites have evolved highly efficient mechanisms relying on coordinated secretion of apical organelles to safely travel from the inoculation site in the skin to their final niche in the liver. A better understanding of these mechanisms may contribute to the identification of potential targets for novel antimalarial intervention strategies."} +{"text": "Journal of Kidney Cancer and VHL, a systematic literature review of clinical trials of metastatic renal cell carcinoma (mRCC) patients evaluates the incidence of osseous, lymph node, and lung metastases imaging, bone imaging and brain magnetic resonance imaging (MRI) should be obtained when clinically indicated. In this issue of the tastases . In partThe cause of an increased incidence of osseous metastases overtime may be multifactorial. For example, an increased incidence of kidney cancer has been appreciated for some time and is partly because of advances in and increased use of imaging . This maHowever, just as the increased incidence of kidney cancer likely cannot be explained by increased use of imaging alone, similarly, the natural history of kidney cancer must be considered when examining this increased incidence of bone metastases. In particular, the evolving treatment paradigms of mRCC have led to dramatic extensions in survival. For example, consider that the SWOG-8949 trial of patients treated with interferon alfa-2b and cytoreductive nephrectomy demonstrated a median overall survival (OS) of 11.1 months . In contAnother limitation of the literature review is that the outcomes were not evaluated concerning osseous metastases. Some studies have suggested that patients with bone metastases have worse results. An analysis of the International Metastatic Renal Cell Carcinoma Database Consortium during the era of vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) therapy demonstrated a median survival of 14.9 months for patients with bone metastases, compared with 25.1 months for those without bone metastases (Demonstration of an increased incidence of bone metastases over time is not independently a justification for the adoption of routine bone imaging in all patients with mRCC. When determining whether a test should be routinely and uniformly utilized, the application of its results must also be considered. In the case of osseous metastases, one must consider the benefits of early intervention in asymptomatic patients or if therapies are specifically beneficial to patients with osseous metastases. Bone-targeted therapies like zoledronic acid and denosumab have shown demonstrated benefits in delaying skeletal-related events in mRCC patients in small studies or subset analyses. Their gain has not been significant in the current era since the use of VEGF-TKIs . Though Whether mRCC patients with osseous metastases may benefit from specific therapies remains an area of interest. Cabozantinib could potentially alter the bone microenvironment, and as a result, been studied in patients with mRCC who have osseous metastases. The Phase III METEOR study evaluated and demonstrated a clinical benefit of cabozantinib compared with everolimus in patients with refractory mRCC , 8. The While it may be premature to incorporate routine bone imaging in the treatment of mRCC patients based on the results of this systematic literature review, including routine bone imaging in clinical trials may become increasingly important for enhanced determination of sequencing or choice of therapies. Studies designed to evaluate patients with bone metastases specifically may allow for data that may justify the use of routine bone imaging in the future."} +{"text": "Hybrid and parallel extracorporeal membrane oxygenation circuits offer important options in clinical scenarios of inadequate perfusion or oxygenation.77.See Article page JTCVS Techniques, Shah and colleaguesThe application of extracorporeal membrane oxygenation (ECMO) for treatment of respiratory and/or cardiac failure has increased over the past decade.Importantly, the authors emphasize 2 principals: that clinical situations necessitating hybrid or parallel circuits are infrequent and that optimal patient management and technical application of conventional ECMO circuits is paramount before considering hybrid or parallel ECMO circuits. Appropriate cannula positioning, optimal hemodynamic and respiratory management, appropriate left ventricular venting, and potential conversion to central cannulation are important key tenets determining successful support with conventional ECMO circuits.Shah and colleagues describe several specific hybrid circuits and the clinical scenarios in which hybrid circuits are useful. With respect to patients supported with VA ECMO who experience upper body hypoxia due to concomitant respiratory failure and competition of ECMO flow with native cardiac output , the authors describe the value of the venoarteriovenous ECMO circuit. In this scenario, an additional venous cannula positioned in the right side of the circulatory system returns oxygenated blood from the ECMO circuit to the heart to reduce the proportion of deoxygenated blood being ejected by the native heart to resolve the upper body hypoxia. Importantly, the authors review strategies to assess and manage arterial flow diversion in this hybrid circuit, specifically applying resistance to the arterial outflow to the venous system to prevent overflow. For patients initially supported for respiratory failure with VV ECMO, progressive hypoxia or cardiac failure may lead to the addition of an arterial cannula to establish a VVA ECMO circuit, where both cannulas now in the right side function as venous return to the ECMO circuit.In addition to the hybrid circuits, the authors also discuss the use of parallel circuits. For patients with high cardiac output and ongoing hypoxia or with evidence of inadequate perfusion a second or parallel ECMO circuit could provide additional capacity for oxygenation and flow. The use of parallel circuits can be applied in the scenarios of both VV ECMO and VA ECMO support. The authors raise appropriate concerns for recirculation in the setting of parallel VV ECMO circuits. In the setting of parallel VA ECMO circuits, capture of too much of the native flow through the heart and lungs could increase the risk of thrombosis.Shah and colleagues have provided readers with a valuable review of hybrid and parallel ECMO circuits, including an excellent diagrammatic presentation and summary of clinical outcomes. Application of these techniques, although infrequently needed, is an essential and required skill set for centers managing patients supported with ECMO."} +{"text": "We investigated how changes in erectile function and sexual satisfaction relate to cognitive decline in men from midlife into early old age. This is a major transitional period for increased incidence of erectile function and for cognitive decline. We examined 833 men from the Vietnam Era Twin Study of Aging whose mean ages were 56, 61, and 68 at the time of assessment. Erectile function and sexual satisfaction were measured using scores from the International Index of Erectile Function. Individuals with erectile dysfunction at baseline were excluded. Cognitive performance was measured using factor scores for separate domains of episodic memory, executive function, and processing speed. We tested linear mixed models hierarchically adjusted for demographics, sexual activity, as well as physical and mental health confounders to examine how changes in erectile function and sexual satisfaction related to changes in cognitive function. Declines in erectile function were associated with declines in episodic memory , while declines in sexual satisfaction were associated with declines in processing speed . Decreasing erectile function and sexual satisfaction may be indicative of individuals also likely to be facing cognitive decline. Possible mechanisms accounting for these changes may include white matter microvascular disease and/or various lifestyle influences. Discussing and tracking sexual health with middle aged men may be a crucial step in identifying those likely to face cognitive decline."} +{"text": "The living arrangement of older adults plays a key role in their health status and psychological well-being. Yet the relationship between living arrangement and activity engagement remains unclear. Using data from three waves of the nationally representative China Health and Retirement Longitudinal Study (CHARLS) with a study sample of 7,479 respondents aged 60 or older, this study examined the effect of living alone on the frequency of activity engagement among Chinese older adults. Two types of activity engagement were examined in this study, including social interaction with friends and leisure activity . The multinomial logistic regression analyses were performed using generalized structural equation modeling (GSEM). Compared with those living with others, older adults living alone were older, more likely to be female and living in urban areas, and with fewer years of education and more functional limitations. The results also indicated that after controlling for a set of covariates, living alone status was significantly associated with the increased likelihood of high and medium frequency of both social interaction and leisure activity in reference to no engagement. This study not only improves the understanding of activity engagement preference of Chinese older adults who are living alone but also indicates the importance of improving community facilities and outdoor spaces to promote activity engagement among older adults."} +{"text": "Background: Health-justice partnerships (HJPs) are collaborations between healthcare and legal services which support patients with social welfare issues such as welfare benefits, debt, housing, education and employment. HJPs exist across the world in a variety of forms and with diverse objectives. This review synthesizes the international evidence on the impacts of HJPs.Methods: A systematic scoping review of international literature was undertaken. A wide-ranging search was conducted across academic databases and grey literature sources, covering OECD countries from January 1995 to December 2018. Data from included publications were extracted and research quality was assessed. A narrative synthesis approach was used to analyze and present the results.Results: Reported objectives of HJPs related to: prevention of health and legal problems; access to legal assistance; health improvement; resolution of legal problems; improvement of patient care; support for healthcare services; addressing inequalities; and catalyzing systemic change. There is strong evidence that HJPs: improve access to legal assistance for people at risk of social and health disadvantage; positively influence material and social circumstances through resolution of legal problems; and improve mental wellbeing. A wide range of other positive impacts were identified for individuals, services and communities; the strength of evidence for each is summarized and discussed.Conclusion: HJPs are effective in tackling social welfare issues that affect the health of disadvantaged groups in society and can therefore form a key part of public health strategies to address inequalities. Social welfare is a diverse area of civil law that includes issues such as welfare benefits, debt, housing, education and employment, among others. Social welfare legal problems are known to be harmful to health: population surveys of legal need have shown direct impacts such a stress-related illnesses and physical ill health , 2. IndiPartnerships between healthcare and legal services have emerged across the world in response to the close relationship between health and social welfare issues \u20137. A widHealth-justice partnerships (HJPs) have potential to generate outcomes that are important policy objectives for both health and legal sectors. In the health field, forming integrated service partnerships is promoted as a means to address social determinants of health and improve the wellbeing of populations . In the i.What are the key objectives of HJPs?ii.What is the range and strength of evidence to demonstrate outcomes against each of these key objectives?Understanding the impacts of HJPs is important given the many potential benefits of these service models. International evidence on the impacts of HJPs has not been systematically reviewed. Previous reviews have focused on specific regions and service models , 18, or Scoping reviews involve undertaking broad assessments of available evidence in areas where the literature has not previously been characterized . The metAll literature sources are detailed in The following key concepts were used to develop search terms: \u201csocial welfare legal advice\u201d AND \u201chealthcare\u201d OR \u201chealth-justice partnership\u201d. For full search terms see Records retrieved from the academic databases were exported to Endnote software and duplicates removed. Records were selected based on the relevance of the title, followed by the abstract and full text. Inclusion and exclusion criteria are specified in Key information relevant to the review questions was extracted from the publications and entered into a spreadsheet for analysis. This included publication characteristics, details of service design and delivery, study research methods and reported results. A quality assessment tool was developed using items drawn from existing checklists . ExistinA narrative synthesis was used to characterize the literature and summarize key findings, integrating both qualitative and quantitative data . FindingSearches of academic databases, gray literature and other sources returned 3,687 records, of which the full text of 469 articles were screened against inclusion and exclusion criteria. The selection process led to a final sample of 118 publications included .Reports that mapped characteristics of HJPs in various countries demonstrated their broad diversity , 8, 25. Approaches to linking delivery of healthcare and legal services varied: co-location and referral pathways were common in all geographical regions; other approaches included incorporating legal advisors into multi-disciplinary teams , 27, intObjectives of HJPs reported in the literature fell into a number of broad themes . These w77 publications reported results of primary research assessing outcomes of HJPs; these are considered in the following narrative synthesis. Broad characteristics of the 77 studies are presented in Several high quality qualitative studies conducted in the United Kingdom primary care context have found that additional income gained as a result of welfare rights interventions was commonly spent on settling bills such as fuel payments, and affording more or better quality food , 33\u201337. High-quality studies conducted in United Kingdom primary care found that people referred to advice by healthcare professionals would not otherwise have sought assistance , 38, 45.Experimental studies of health outcomes had only been conducted in the United Kingdom primary care setting: two papers reported pilot randomized controlled trials, of which one was insufficiently powered for statistical analysis . The othUncontrolled prospective studies have been conducted in a variety of settings. In United Kingdom primary care, improvements in mental health and emotional role functioning were found where income had increased as a result of financial interventions , 34. A sQualitative studies conducted with patients receiving legal assistance in a variety of healthcare settings internationally have reported reduced feelings of stress and anxiety , 42, 51,Two studies have assessed legal outcomes against a comparison group, both focusing on welfare rights interventions in the United Kingdom primary care setting; they found significantly greater improvements in financial strain and finaFeedback gathered from project staff in a variety of international settings suggests that HJPs provide a more rounded service for patients, addressing interconnected health and welfare issues in a comprehensive way , 16, 74.Studies had investigated whether HJPs could reduce pressure on health services by reducing care utilization. The only experimental study investigating this outcome did not have sufficient statistical power to show significant changes . A quasiIn the United States where access to health insurance is not universal, legal services had obtained insurance cover for patients and intervened against complex insurance denials, thereby facilitating access to needed healthcare , 70. HJPHigh quality studies exploring perspectives of healthcare professionals in the United Kingdom and Canada report that partnerships with legal services can be a beneficial resource to support them in their work: clinicians reported that these partnerships provide an opportunity to address patients\u2019 non-medical issues outside their expertize , 33, 49 Studies had not specifically investigated whether HJPs were effective in reducing health or social inequalities. One study investigated differential mental health outcomes across gender, ethnicity and health status; it found that women and participants of a Black/Black British ethnicity were particularly likely to benefit in terms of common mental disorders as a result of a welfare rights intervention in United Kingdom primary care . TargetiHJPs occupy a unique position at the intersection of health and rights , which eThis systematic scoping review identified the stated objectives of Health Justice Partnerships (HJPs), and mapped the international evidence on impact against each key theme. There was strong evidence for their effectiveness in resolving legal problems and thereby improving the socioeconomic circumstances of individuals, outcomes that were reported from all regions and service types. This demonstrates the important role of HJPs in addressing social determinants of health, a cornerstone of public health policy in health systems across the world . There w. The reviewed publications had examined different health outcomes (mostly self-reported), among different patient groups, for different legal interventions and over different time periods. Broad generalization is therefore not possible from the current evidence. Health impacts are likely to depend on the patient population and legal issues addressed. However, overall there was strong evidence among the studies for improvements in mental health, particularly stress, depression, anxiety and wellbeing, and that these improvements occurred as a direct result of the legal interventions [The impacts of HJPs on individual health has been the subject of debate . The revventions \u201338, 40. ventions , 40, 55.ventions found noventions found siThere were some areas where the evidence was of lower quantity and quality. For example, no studies had assessed prevention directly, although many provided evidence of wider social benefits which could prevent ill health in the long term . Few studies had measured direct effects on inequalities; however, the benefits of HJPs as a whole are likely to accrue to those of lower socioeconomic status given the nature of the social welfare issues they address and their focus on low income and disadvantaged groups. Studies reporting impacts on health service utilization showed inconsistent patterns and mostly lacked appropriate comparative evidence. This outcome is likely to depend on the characteristics of local services and further research would be needed to investigate how health service utilization outcomes may be influenced by the service context. The opposite goal is relevant in situations where patients may face legal or social barriers to access, and the studies highlighted a role for HJPs in facilitating engagement with needed healthcare. Other impacts for health services and patient care had been explored to a lesser extent and were not the focus of much high quality research; benefits identified qualitatively included supporting healthcare professionals to manage patients\u2019 non-medical needs and improving both practitioner and patient experience. Catalyzing systemic change through legal and policy action was more rarely reported in the literature, however case studies demonstrated the wide-reaching effects of these activities in protecting the health of populations.This paper presents the first systematically conducted review to include publications from across international regions and to consider a range of service models and settings. The review drew on a wide-ranging systematic search that included both academic and grey literature, ensuring evidence from practice was included alongside academic research. This broad scope means that service objectives and impacts are reported comprehensively and the full range of diverse HJPs are represented. The study selection process was verified by a second reviewer to ensure the inclusion and exclusion criteria were applied accurately. However, it is unlikely that every paper on the topic was uncovered, particularly in the grey literature where relevant international sources may have been unknown to the authors. The quality assessment checklist was developed by the lead author and has not been validated formally as a tool. It enabled a consistent approach for quality assessment across all the papers, but offers a general rather than specific estimate of quality given the range of disciplines, study types and outcomes it was designed for.This review demonstrates the potential of HJPs in addressing interconnected health and welfare issues at the level of individuals, services and communities. With the current Covid-19 pandemic following a decade of global austerity, social welfare legal need in the population is likely to rise. Worsening economic and social conditions may lead to and exacerbate long term health consequences and widening inequalities . As withThis review summarizes the objectives of HJPs and assesses the strength of international research evidence on service impacts. There is strong evidence that HJPs are effective in reaching people at risk of social and health disadvantage, positively influencing social determinants of health through the resolution of legal problems, and improving mental wellbeing. A wide range of other benefits for individuals, services and communities are identified and discussed. HJPs have an important role to play in tackling the social determinants of health and should be considered in public health strategies addressing health and social inequalities.The review also highlights areas that future research could build on. Use of robust study designs with comparator groups would strengthen current evidence of effectiveness. Randomized controlled trials have been hampered by design issues when used to investigate these complex interventions, but alternatives such as natural experiments and use of routine data sources offer an alternative approach for robust evaluation. Outcomes such as health improvement and healthcare utilization are likely to depend on population groups and local service models; comparative studies would help identify how outcomes may vary by context. Impacts that could benefit from further investigation include the role of HJPs in prevention and early access to services , their contribution to patient care (such as engagement and longer-term trajectories), health inequalities and their role in health service functioning ."} +{"text": "Glioma is the most common intracranial tumor, representing about 60% of all brain tumors, and show varying degrees of malignancy . GliomasLiquid biopsies from cancer patients can enhance prognosis prediction and treatment accuracy. Many risk factors have been examined as potential contributors to glioma risk, and these studies offer new insights into the diagnostic and therapeutic strategies to suppress cancer metastasis. Analysis of circulating tumor cells (CTCs), which are highly efficient metastatic precursors, is reported to be a promising method to study the mechanisms of tumor cell dissemination and metastasis formation , 4. CTCsThe paper presented by Zhang et al. providesUnderstanding mechanisms of metastasis not only involves CTCs but also their interactions with circulating immune cells. Another recent study used single-cell RNAseq to find that cooperation between neutrophils in the immune system and CTCs in the blood of patients with breast cancer can promote CTC proliferation and metastasis . AccordiWhile these studies have established the high diagnostic value of glioma CTCs, the precise detection of glioma CTCs is challenging because of physiological features such as circulation dynamics and the lack of consistently expressed tumor markers . Besides"} +{"text": "Although the demand for hospice care increases as our society ages, the awareness of hospice care among adults in the southern rural region of the US has not been documented. This study aims to assess the rate of hospice care awareness among rural residents living in the Black Belt Region and examine social determinants of health (SDH) associated with the awareness. A cross-sectional survey was conducted among a convenient sample living in rural Alabama . Participants\u2019 awareness of hospice care, demographic characteristics , and SDH were assessed. Lastly, a binary logistic regression was used to examine the association between SDH and awareness of hospice care among participants while controlling for demographic characteristics. The majority of participants had heard of hospice care (82.4%), and older participants (over 50 years old) were more likely to report having heard of hospice care . Participants reporting worries about stable housing and higher social isolation were less likely to have heard of hospice care , while participants with higher health literacy had a higher likelihood to have heard of it . Our study is the first study assessing the status of hospice care awareness among residents living in the Black Belt Region. This study highlighted that factors including age and certain SDH might be considered in the intervention to improve hospice care awareness."} +{"text": "Using three types of cherries, another study reported that different dose ranges of cherry juices induce an overall beneficial modulation of the murine gut microbiota and suggest that amounts of cherries consumed should be carefully chosen in the health and nutritional feeding studies. In addition, anti-tumorigenesis of berry polyphenols, health-promoting effects of Myrtle berries, berries\u2019 effects on Helicobacter pylori and gastric cancer, and berry compounds for the development of therapeutics are discussed. It is encouraging that overall findings support the beneficial claims of berries on health from both the preventive and therapeutic points of view.Berries are widely appreciated for their abundant phytochemicals and bioactive compounds. As such, consumption of berry fruits has been proven to have a profound beneficial impact on human health and diseases. This special issue collected articles that reported recent advances in berry research. For example, one study reported that the fecal material from mice fed black raspberries increase natural killer cells and CD8"} +{"text": "PLOS Genetics publications that exemplify recent progress in domestic animal genetics. Rather than grouping by species, we assigned the publications to 5 thematically related topics, which we will briefly introduce in the following sections.Domestication of wild animal and plant species may be considered the largest genetic experiment in human history. Human selection for specific traits and targeted breeding over hundreds or thousands of generations has shaped very special populations that provide unique opportunities for research. Domestic animal genetics contributes to technological advances facilitating a more sustainable, environment and climate friendly food production that respects changing societal expectations related to ethical and animal welfare issues. Domestic animal genetics also enables fundamental insights into gene functions and provides animal models for biomedical research. Under this theme, we present a selection of The 7 articles in this group provide either new methods or resources for research in domestic animal genetics. This ranges from an improved cat reference genome assembly over the generation of a comprehensive gene expression atlas in sheep to the presentation of a comprehensive database on breed-specific disease allele frequencies in dogs.The genetic changes associated with domestication show many parallels across different animal species, such as specific changes in behavior or the loss of seasonality of reproduction. In our collection, we present 8 articles that investigate specific genetic changes that are the consequence of breeding in closed populations or that investigate admixture and subsequent selection mechanisms in domestic animals.Nine articles in this section nicely reflect different levels of genetic complexity. They range from oligogenic traits to very complex traits such as the influence of the host genome on rumen microbiome diversity. In many livestock populations, a wealth of environmental and phenotypic data is recorded. This enables powerful studies with respect to many complex traits and genotype x environment interactions. With the intensive use of artificial insemination, elite livestock sires can have many thousands of offspring, which is a unique situation in mammalian species and predestines livestock populations for genetic research. When it comes to disease genetics, dogs with their many breed-specific predispositions for specific diseases provide excellent opportunities to identify genetic risk factors for complex diseases.With 23 articles, this is by far the largest group in our collection. The special population structure of domestic animals greatly facilitates the identification of the causative genetic variants for hereditary traits. At the same time, sophisticated veterinary diagnostics approaching the standards in human medicine is widely available for cats, dogs, and also other domestic animals. Purebred animals are maintained in strictly closed populations with a substantial amount of inbreeding, which favors the emergence of new recessive traits and diseases. The elucidation of the causative genetic variants in spontaneous domestic animal mutants may assign physiological functions to uncharacterized genes, provides candidate genes for human medical genetics, and helps to obtain more comprehensive genotype\u2013phenotype correlations.Dogs and also cats may develop very similar tumors as humans. The shorter life span and striking breed predispositions for certain cancer types facilitate the identification of genetic risk factors. With 5 articles, this is the smallest group in our collection. However, the potential of domestic animals and especially dogs for cancer research in general and cancer genetics in particular has by far not yet been fully utilized.PLOS Genetics continues to publish articles with some of the best research in domestic animal genetics. This is a field with many facets enabling fascinating new fundamental insights as well as laying the basis for applications in animal breeding that are absolutely vital for a sustainable future of mankind."} +{"text": "Testing the compliance and completion rate of a transfer checklist (proforma) created in accordance with local hospital policies.The proforma was developed following serious incidents where medically unstable patients were inappropriately discharged to mental health hospitals, requiring readmission to acute medical hospitals. Frequently these events reported an inadequate handover from medical to mental health teams and patients were often prematurely deemed medically fit with evidence to the contrary.Although parity of esteem between mental and physical health has been a high profile political issue in the UK since 2011, evidence indicates that parity is far from being achieved. This first ever checklist was designed to improve safety of patient transfer from acute physical health hospitals to mental health hospitals by ensuring patients are medically fit and better communication between the two trusts.Data were collected retrospectively over a six-month period between August 2018 and January 2019 and retrieved from patient notes available at relevant trusts. Electronic notes were obtained from medical wards, accident and emergency and Mersey Care electronic systems. Notes were specifically scrutinised for presence of the proforma, quality of completion and, number and reasons for readmission from mental health hospitals to acute physical health hospitals following their medical optimization. Readmissions were considered as admissions to physical health hospitals up to one month following discharge with evidence of ongoing concerns.6597 referrals were made to liaison services from Liverpool University Hospitals, of which 5\u20136 % were admitted to inpatient mental health units. 31% of admissions from Liverpool University Hospitals were readmitted to a physical health hospital within one month of discharge indicating inappropriate and unsafe discharges. Of all those readmitted, 10% had ongoing acute medical concerns prior to admission to a mental health hospital. The proforma was filled in 13% of admissions from Liverpool University Hospitals. None of the forms were fully complete.10% of patient admissions to mental health hospitals were identified as inappropriate due to ongoing acute medical concerns. The proforma served as structured guidance and evidence of medical fitness at time of transfer. However poor compliance was observed, which could be secondary to lack of awareness of the proforma and inadequate dissemination of the policy. Findings were shared and discussed with the appropriate teams both in acute physical health and mental health hospitals and steps will be taken to raise awareness of the proforma before completing a second audit."} +{"text": "Sural nerve biopsy has long been a valuable diagnostic tool for the study of peripheral neuropathies, although the recent introduction of non-invasive techniques and advanced genetic and immunological testing has changed the diagnostic workup of peripheral nervous system diseases. Besides its diagnostic role, sural nerve biopsy has helped one understand the pathogenesis of several neuropathies, and, in selected cases with difficult clinical diagnosis, it continues to represent a useful and irreplaceable tool.In chronic inflammatory demyelinating polyneuropathy, nerve biopsy shows a great pathological heterogeneity that may be strictly dependent on the disease phase or on the multifocality of inflammatory process, but it could also reflect different mechanisms of immune responses involved .In hereditary transthyretin amyloidosis, sural nerve biopsy may occasionally show not only an axonal loss but also myelin alterations, suggesting a Schwann cell damage caused by toxic effect or by mechanical stress from the formation of amyloid fibrils .In hematological diseases, sural nerve biopsy remains the gold standard for the diagnosis of vasculitis, neurolymphomatosis, and light chain amyloidosis .Nerve biopsy is not only useful in the diagnosis of neuropathies: many investigations rely on nerve pathology to confirm their hypothesis about pathogenetic aspects of diseases or even Eventually, nerve biopsy will not be the only technique available to study nerve morphology: there is an increasing interest in literature about ultrasounds, used not only as a diagnostic tool, but also to treat many mononeuropathies ; and aboThe purpose of this Special Issue is to publish original research regarding pathological findings in different types of peripheral neuropathies which can contribute to help clinicians in final diagnosis."} +{"text": "While hearing loss is highly prevalent among patients with dementia, it frequently goes unidentified and unmanaged. It has been a commonly-held belief that older adults with dementia are unable to benefit from hearing rehabilitation, but recent evidence shows that many individuals with dementia can successfully use amplification, helping to improve communication, social interaction and quality of life for these individuals and their caregivers. This presentation will describe how modifications to practice led to successful outcomes for the majority of patients of a geriatric audiology clinic with co-morbid hearing loss and cognitive impairment. In a study of hearing aid use in 67 patients with these comorbidities, over 90% used hearing aids successfully with measurable benefit for both patients and caregivers. Furthermore, we will discuss approaches to improving communication for LTC residents with dementia and hearing loss through the support of audiologists during remote visits with physicians and families during the pandemic."} +{"text": "An Ohio Executive Order forced adult day service providers across the state to close from March 24, 2020 until September 21, 2020 due to COVID, resulting in significant hardship for providers and families. In fact, 65% of programs reported laying off or reducing staff and 83% of directors reported participants had to move to higher and more expensive levels of care such as nursing homes and assisted living. Programs reported that 74% of caregivers had to choose between working and taking care of their family members. Ninety-one percent of ADS program directors in Ohio reported their caregivers were experiencing an increase in stress and anxiety. This paper explores the experiences of Ohio adult day providers during the COVID epidemic, and identifies the challenges and opportunities to coalition building to educate policy makers about day services and the crucial care centers provide."} +{"text": "ABSTRACT IMPACT: The development of marketing materials such as flyers and brochures will ultimately be used to promote integration of special populations who are traditionally underrepresented into research by informing and attracting scholars and investigators of available consultative and analytic services that are provided by the ISP Core staff. OBJECTIVES/GOALS: The development of informative and memorable marketing materials is to increase awareness of the ISP Core and its service functions to help with the integration of special populations, as well as promoting scholar and investigator use of these services. METHODS/STUDY POPULATION: After assessing how many CTSA hubs market their ISP services, a flyer and brochure were developed using Adobe InDesign to include information commonly found on CTSA hubs. Flyers and brochures were chosen because they make information physically available outside of a website and be sent to email listservs, making it possible to reach more scholars and investigators. The marketing materials will contain sections to explain the purpose of NJACTS and the ISP Core, list related special populations and available service functions, introduce the ISP Core leadership team, provide examples of past consulting work and contact information for investigators to request service consultations. Flyers will be emailed digitally to listservs and distributed physically along with printed tri-fold brochures to investigators. RESULTS/ANTICIPATED RESULTS: The primary anticipated result from the development of marketing materials include an increased awareness and utilization of ISP Core services and an increased inclusion of special populations in research with NJACTS. The impact of these marketing materials maybe assessed by providing investigators with a short survey when ISP services are requested, which will ask how investigators learned about ISP and its services. DISCUSSION/SIGNIFICANCE OF FINDINGS: Through the work of creating physical marketing materials, the ISP Core will have a method to effectively distribute information about its services, ultimately promoting investigators at all stages to integrate special populations into their research."} +{"text": "The UN Decade of Ecosystem Restoration is poised to trigger the recovery of ecosystem services and transform structural injustices across the world in a way unparalleled in human history. The inclusion of diverse Indigenous and local communities to co-create robust native seed supply systems is the backbone to achieve the goals for the Decade. Here we show how community-based organizations have co-developed native seed supply strategies for landscape restoration from the bottom-up. We draw on the interconnections over two decades of seed networks in Brazil and the emerging Indigenous participation in native seed production in Australia. From an environmental justice perspective, we provide a participatory seed supply approach for local engagement, noting local geographical, social and cultural contexts. Meeting large-scale restoration goals requires the connection between local seed production and collaborative platforms to negotiate roles, rights and responsibilities between stakeholders. An enduring native seed supply must include a diversity of voices and autonomy of community groups that builds equitable participation in social, economic, and environmental benefits. Global policies and commitments are driving multiple incentives to restore hundreds of millions of hectares of degraded lands by 2030 . Implementing this national restoration goal would require an unprecedented effort to structure a restoration production network to quantify seed production costs that ensure the long term viability of the commercial arrangements providing useful technical feedback to continually improve practices and efficiencies and (ii) increase motivation, engagement and commitment of the local community through positive feedback that locally sourced seed is \u2018making a difference\u2019. For example, if the seed success rate on a restoration site is low, but seed quality information is known, then other causes of failure can be investigated and resolved, such as timing of seeding, seeding depth, seeding density, site preparation, seeding time (Shaw et al. Community participation in the restoration economy is required beyond native seed supply systems. Native seed production areas and plant nurseries, for example, offer abundant opportunities to increase the availability of high-quality plants for restoration, while strengthening economic returns (Nevill et al. Community restoration networks focused on efficiency and revenue alone will not guarantee the long-term sustainable success of local seed production. We suggest that participation in seed supply requires full recognition of geographical, cultural, and social dynamics that transform structural power asymmetries into effective justice procedures for scaling up equitable restoration interventions. It is central to enshrining participation that builds visibility and recognises diverse groups within local communities (Schlosberg Seed programs are just the beginning of the shared journey towards community engagement linked to nature and natural environments. A transformative restoration economy to overcome structural inequalities during The Decade on Ecosystem Restoration must recognize that degraded lands and environmental impacts are often the result of historical socio-spatial asymmetries. Policies, funding support, and business investment for landscape restoration designed within national or international frameworks may not reflect the intentions and aspirations of local communities (H\u00f6hl et al."} +{"text": "Acrocephalus arundinaceus) nest, an extreme form of multiple brood parasitism.Multiple parasitism in obligate avian brood parasites occurs when several brood parasitic females lay their eggs in the nest of the same host. While multiple parasitism is common in the highly social, nonevicting cowbird species (Molothrus sp.), in which multiple parasitic nestlings can be raised simultaneously by the same hosts, it is less common in the case of cuckoo species (Cuculus sp.). The first cuckoo nestling to hatch from the egg evicts all nestmates; therefore, it is costly for cuckoo females to lay eggs in already parasitized nests. However, this can occur in sites with very high parasitism rates, and it can even increase the breeding success of the brood parasites, as the presence of multiple parasitic eggs in the nest of the host decreases rejection rates. Here, we present a case of a quintuple brood parasitism of a great reed warbler ( Cuculus canorus), an obligate brood parasite. However, this can occur in sites with very high parasitism rates, and it can even increase the breeding success of the brood parasites, as the presence of multiple parasitic eggs in the nest of the host decreases rejection rates. Here, we present a case of a quintuple brood parasitism of a great reed warbler nest, an extreme form of multiple brood parasitism.Multiple parasitism of a host nest by several females is rare in the case of the common cuckoo ( These 1Molothrus ater) and common cuckoos (Cuculus canorus), the two most widely studied brood parasites, are unable to differentiate between their hosts\u2019 eggs and the eggs previously laid by another brood parasitic female hosts breed in narrow reed beds along irrigation channels and face a parasitism rate of 50%\u201360% and a multiple parasitism rate of 10%\u201325% , we found a nest containing three great reed warbler eggs and five common cuckoo eggs, with one of the cuckoo eggs being buried in the bottom of the nest in nature might be biased because, due to logistic reasons, the relationship between these brood parasites and their hosts is generally studied at sites with high parasitism rates ; project administration (lead); visualization (lead); writing\u2013original draft (lead); writing\u2013review and editing (lead)."} +{"text": "Autophagy function has been closely linked with the loss of proteostasis that characterizes most old organisms and tissues. However, the cellular functions of selective types of autophagy such as chaperone-mediated autophagy (CMA) go beyond cellular quality control. CMA can degrade fully functional proteins to terminate their function and thus contribute to regulation of multiple cellular processes. To fully understand the consequences of loss of CMA function with age, we have developed genetic and pharmacological ways to modulate this pathway in old mice. Our data supports involvement of CMA in other hallmarks of aging such as metabolism, senescence, cellular response to stress, epigenetics and cellular stemness. This interconnection among the cellular processes that drive aging highlights the potential of acting on only some of them with geroprotective effects."} +{"text": "Planning and designing thermally comfortable outdoor spaces is increasingly important in the context of climate change, particularly as children are more vulnerable than adults to environmental extremes. However, existing playground standards focus on equipment and surfacing to reduce acute injuries, with no mention of potential negative health consequences related to heat illness, sun exposure, and other thermal extremes. The goal of this project was to develop proposed guidelines for designing thermally comfortable playgrounds in Canada for inclusion within the CAN/CSA-Z614 Children\u2019s playground equipment and surfacing standard.The project to develop guidance for thermally comfortable playgrounds was initiated with a municipal project in Windsor, Ontario, to increase shade, vegetation, and water features at parks and playgrounds to provide more comfortable experiences amid the increased frequency of hot days (\u226530\u00b0C). The lack of available information to best manage environmental conditions led to a collaborative effort to build resources and raise awareness of best practices in the design of thermally comfortable playgrounds.A group of multidisciplinary experts developed technical guidance for improving thermal comfort at playgrounds, including a six-page thermal comfort annex adopted within a national playground and equipment standard. The annex has been used by Canadian schools in a competition to design and implement green playgrounds.Both the technical report and the thermal comfort annex provide increased awareness and needed guidance for managing environmental conditions at playgrounds. Thermally safe and comfortable play spaces will help ensure that Canada\u2019s playgrounds are designed to minimize environmental health risks for children. Playgrounds are found in communities across Canada and provide children with healthy spaces to play. Playing in outdoor spaces, especially in nature, can increase children\u2019s physical activity levels is expected to become more common because of climate change, with negative impacts to human health to help increase visitor comfort, satisfaction, and utilization of these spaces of the invited participants, with 91% of respondents (50) having professional expertise in the Canadian context, covering all geoclimates of Canada.The focus of the survey was to collect information on thermal comfort and playgrounds. The survey gathered participant perspectives on: environmental factors which influence design priorities and safety elements, perceptions and contributions of thermal comfort, and mitigation strategies associated with thermal comfort management. The survey found that thermal comfort was universally recognized as an important element in children\u2019s playgrounds (97%), yet there was a strong consensus that these environmental factors have not been integrated into playground designs, as compared with playground safety factors addressed within the previous version of the standard . Additionally, the survey found that topics addressed within the standard as informative annexes were much more likely to receive design priority than shade, water features, or other issues related to thermal comfort.This project has resulted in three important outcomes that help promote the design of playgrounds where children can enjoy safe and active play in all environmental conditions.The NPPS developed a detailed report to provide contextual knowledge of the impacts of environmental conditions on children\u2019s usage of play spaces and recommendations for integrating thermal comfort into the CAN/CSA-Z614 standard , as well as maintenance, accessibility, and design for supervision. The topic of thermal comfort at playgrounds is much less widely understood. For example, out of the 141 applications received in Tree Canada\u2019s 2019 The technical report identified the need for comprehensive research to assess the health impacts of children\u2019s exposures to extreme temperatures, solar radiation, and air pollution within playground environments. Future research could evaluate how the Thermal Comfort Annex has been used by playground designers and assess whether the standards help improve the health and safety of children in hot summer months. Quantification of various factors\u2014such as monitoring surface temperature reductions, activity level increases, or frequency and duration of use changes\u2014would expand knowledge of practices that moderate environmental exposure, and help identify which are most impactful by season and climate type, and how these factors affect duration and frequency of playground use.Communication materials and activities could help to raise awareness of thermal comfort strategies and increase practical uptake. Materials could highlight the co-benefits of thermal comfort strategies, for example, by sharing how trees not only improve thermal comfort but can also help adapt to climate change, increase biodiversity, and reduce storm water overflows. Future work could adapt standards and guidelines for use in visual communication tools such as infographics to help reach a variety of audiences, including those of different ages, cultures, professions, and languages.Pilot projects help raise awareness and build expertise, while providing valuable opportunities for policy makers in higher levels of government to better understand the issues. The City of Windsor\u2019s practical measures to address thermal comfort within their playgrounds helped increase physical activity levels and protect the health of children. The project also provided contextual insight to federal government employees who worked to integrate what they learned into a national standard that could be used by communities across Canada.The involvement of subject matter experts in collaboration with existing technical committees results in stronger and more holistic recommendations. The CSA Group Technical Committee is comprised of people with diverse professional backgrounds. The desire to expand the standard beyond traditional issues required the insight of external playground safety experts, atmospheric scientists, biometeorologists, child health experts, and others. The diversity of professionals involved in this project helped reveal important considerations and contextual knowledge from various practical disciplines to aid in the development of more complete guidance.Standards and guidance are essential to maintain uniform compliance and raise awareness. While environmental safety considerations have seen increased attention due to the growing concerns of climate change, addressing these issues is challenging because of a lack of available guidance. Low levels of awareness of thermal comfort concepts limit uptake by playground designers relative to traditional injury prevention and safety issues. In addition to the thermal comfort annex within the standard, the technical report is freely available to raise awareness of these issues.The establishment of design guidance for addressing environmental hazards such as extreme heat is needed to help communities across Canada prepare for climate change. Many communities across Canada are projected to experience an increasing number of hot days throughout the summer. Building awareness of summertime environmental considerations\u2014such as sun protection, shade, water access, and ventilation\u2014for creating thermally safe and comfortable spaces will result in playgrounds and outdoor spaces that children and visitors can use safely into the future under different climate scenarios.This project underscores the importance of standards and guidelines to promote awareness and provide practical design advice that can help communities prepare for increasing temperatures expected in many parts of Canada due to urban growth and climate change. The following key lessons learned emerged through the process of developing the guidelines:Children are physiologically vulnerable to environmental extremes. Given the hotter summers in many parts of Canada from climate change, it is increasingly important to plan and design thermally comfortable outdoor spaces. While this project focused on developing guidance for designing thermally safe playgrounds in the Canadian context, many of the principles universally apply to playgrounds in other parts of the world for all seasons. It is hoped that this Canadian example could help spur additional research and action to improve thermal comfort in playgrounds as well as inspire the production of similar and expanded guidelines and standards in other countries.This project developed innovative ideas for integrating microclimate concepts into playground designs.Existing Canadian and international standards for children\u2019s playground equipment and surfacing focus exclusively on reducing acute injuries.With climate change, many parts of Canada could experience more frequent hot days (>30\u00b0C), which could increase heat stress in children during play.A Canadian playground safety standard was updated to include guidance on how to design for thermal comfort by increasing shade, vegetation, and water features.What are the innovations in this policy or program?Many of the health benefits expected from the development of thermally comfortable playgrounds are long-term in nature; therefore, it is imperative to develop new ways to assess the effectiveness of these practices in order to promote adoption.It is important to develop communication materials tailored to different users to raise awareness of strategies included in the thermally safe playground guidelines and increase their practical uptake.Further research is needed to evaluate which playground design factors maximize children\u2019s physical activity levels and improve the health of children under a range of weather conditions.What are the burning research questions for this innovation?"} +{"text": "Epilepsy is a prevalent condition that affects 1\u20133% of the population or about 50\u201365 million people worldwide (WHO estimates) and about 3.5 million people in the USA alone (CDC estimates). Refractory epilepsy refers to patients that respond inadequately to medical management alone (at least two anti-seizure medications at appropriate doses) and are appropriate candidates for other interventions such as brain surgery or the use of neurostimulators for their epilepsy. Minimally invasive techniques like stereotactic EEG electrodes offer excellent investigational abilities to study the diagnostic attributes of the seizure networks, while therapies like laser ablations and neurostimulators permit intervention and modulation of these networks to offer seizure control with minimal cognitive compromise and surgical morbidity. The accuracy of these techniques is highly contingent on precise anatomical correlation between the location of the electrodes and their proximity to relevant structures of the brain. Ensuring good anatomical correlation using 3-dimensional (3D) reconstructions would permit precise localization and accurate understanding of the seizure networks. Accurate localization of stereotactic electrodes would enable precise understanding of the electrical networks and identify vital nodes in the seizure network. These reconstructions would also permit better understanding of the proximity of these electrodes to each other and help confirm arrangement of neurostimulators to maximize modulatory effects on the networks. Such reconstructions would enable better understanding of neuroanatomy and connectivity to improve knowledge of brain structures and relations in neurological conditions. These methods would enable medical students and doctors-in-training to better their understanding of neurological disease and the necessary interventions. Epilepsy affects about 1\u20133% of the population or about 50\u201365 million people worldwide . SeventyReconstruction involves the use of presurgical and postsurgical scans. The presurgical MRI scans of the brain act as a template on which postsurgical CT scans with intracranial electrodes are superimposed to achieve accurate localization of electrode contacts vis-\u00e0-vis anatomical structures in the brain. Coregistration and reconstruction of brain structures is performed using software like Freesurfer or 3-dimensional (3D) Slicer to accurately reproduce neuroanatomy and enable surgical planning. Such digital reconstruction helps achieve precise spatial correlation between electrode locations and cerebral structures. Newer software upgrades also permit superimposition of brain mapping data from imaging studies or cortical stimulation procedures to achieve excellent anatomical, electrical, and clinical correlation in these patients. Such multimodal reconstructions and superimpositions generate a 3D topographic map that enables easy recognition of the seizure onset zone and overlap and margins between the seizure networks and eloquent cortical regions. Reconstruction is used by many centers for surgical planning and many different techniques are used across centers, albeit there is no single standardized protocol. Reconstruction can be used with all the commonly available surgical planning software, a feature that should exponentially increase its use across centers.These digital and physical representations can be used in teaching anatomical and surgical techniques in addition to teaching cerebral anatomy and network characteristics of neurological disorders. In this article, we briefly elucidate some of these applications of 3D reconstruction to the field of epilepsy surgery and its use in surgical planning and medical education as well.Resective surgery, while effective in many cases, produces cognitive deficits, which necessitate the need to estimate risks and benefits accurately prior to proceeding with it. Minimally invasive surgical options permit good outcomes comparable to the more invasive ones, while permitting much better preservation of cognition in most cases. There is a growing tendency to use minimally invasive options for surgery whenever necessary, and only use the more aggressive options as a last resort.Both types of procedures include diagnostic and therapeutic options. Minimally invasive diagnostic procedures include stereotactic EEG and the diagnostic aspects of neuromodulation, especially with the use of responsive neurostimulation systems. Therapeutic procedures include laser and ultrasound ablations, responsive neurostimulators, deep brain stimulators and disconnection procedures.Highly invasive procedures include subdural grids and strips for EEG as diagnostic modalities, while resections or lobectomies and invasive surgeries like corpus callosotomies represent the therapeutic options.Accurate anatomical correlation and structural analysis is essential for efficacious outcomes from all of these procedures, minimally invasive or otherwise. Coregistration of pre and post-surgical images using a variety of techniques to study the efficacy of surgery and plan surgeries accurately has been a consistent desire of physicians and surgeons for many years. Various techniques have been implemented and continue to be experimented upon to produce accurate imaging correlation permitting the highest degree of surgical accuracy and best estimates of surgical efficacy from such procedures.Temporal lobectomies were among the earliest performed procedures and remain efficacious to this day with excellent surgical outcomes seen in appropriately selected patients. Modern techniques to improve on such surgeries have focused on accurate reconstruction and imaging correlation to permit good surgical outcomes. The use of such correlation techniques permits accurate localization of anatomical landmarks like Brodman's areas and resultant surgical planning to minimize volume of resected tissue . BleedinCognitive deficits from surgery often result due to loss of cortical gray matter and damage to subcortical white matter tracts as well. Diffusion Tractography Imaging (DTI) studies the locations of these white matter tracts and permits accurate estimations of their locations for surgical planning. Three-dimensional reconstructions of these images permit accurate surgical planning and minimize structural damage to white matter tracts and improves cognitive outcomes. DTI based reconstructions also permit identification and targeting of cerebral connections that are part of the seizure network but may not be obviously apparent on regular imaging. Targeting such structures would result in better surgical outcomes and minimize morbidity. The use of DTI to avoid Meyer's loop of the optic radiation to preserve visual fields in temporal lobe epilepsy surgery would be a classic example of such an application . AnecdotEpilepsy surgery often relies on the use of an accurate estimation of a patient's seizure network to choose the most appropriate intervention for them. Localization of the seizure network often relies on multimodal presurgical investigations including MRI, PET, and other kinds of tests. The gold standard to localize the seizure network is however, intracranial EEG. Subdural grids and strips are the older method while stereotactic EEG is a relatively newer technique . StereotPre-surgical and post-surgical imaging and correlation are necessary to ensure prevention of electrode shift during EEG recording and functional mapping to preserve integrity of the data. Performing these reconstructions enables us to ensure that electrodes have not moved, or if they have moved, to account for these shifts and calibrate our imaging to plan our surgeries accurately . ExcludiThe use of robotic surgical assistants (ROSA) in implanting these electrodes accurately with minimal error has greatly contributed to the efficacy and accuracy of this technique and revolutionized diagnostic approaches in epilepsy surgical evaluations . The marPrecise coregistration and reconstruction would greatly enhance ability to localize seizure onset and spread, especially in conditions like bottom-of-sulcus dysplasias, which are highly amenable to focused intervention resulting in excellent surgical outcomes. Three-dimensional reconstructions would help define the seizure network better and enable placement of more intracranial EEG electrodes for better definition of the seizure network, if needed, resulting in narrowing down the seizure onset zone, thus offering amore limited field of surgery and a higher probability of precise targeting of the seizure network. Neuromodulation would also achieve better seizure control if the electrical stimulation fields were targeted better with accurate directional juxtaposition as well. While all these methods of improved diagnosis and therapy are expected to improve with the use of reconstruction, well-designed studies proving these findings are absent and need to be performed to offer clinically reproducible and valid evidence.Stereotactic laser ablation represents a relatively newer innovation in the field on minimally invasive epilepsy surgery that involves ablating tissue in the seizure onset zone or network using thermal effects of laser to cauterize said tissue. The best evidence supporting the efficacy of laser ablation to treat patients with epilepsy with curative intent comes from the ablation of structurally well-defined targets . It is aResponsive neurostimulator and deep brain stimulation systems represent a newer approach to the field of surgical epilepsy and involve implanting a generator battery attached to intracranial electrodes. These electrodes are able to identify and store seizures and enable electrical stimulation for treatment. Patient responses to the use of such responsive neurostimulators have been very good with excellent outcomes being reported in most cases . AccuracTeaching complex concepts of neurophysiology to trainees and practicing physicians requires a deeper understanding of structural connectivity in three-dimensional space. The use of interactive reconstruction would greatly improve understanding of such concepts relevant to surgical epilepsy. It would promote individualized approaches to surgeries, especially in patients with variant anatomy or prior surgical intervention. The use of reconstructions permits us to guide and instruct trainees or physicians to improve their planning and surgical skills. Similar approaches are already underway concerning teaching and performing surgeries like disconnections or resections . ImproveReconstruction has produced change in our understanding and approach to the evaluation of epilepsy patients and syndromes as a whole. Diagnostic approaches are determined by the nature of imaging and quality of available EEG data to understand the seizure network and design an appropriate treatment paradigm for individual patients as well.Reconstruction has necessitated the need for higher definition in medical imaging resulting in improved detection rates of brain anomalies and increased abilities to target these regions of the brain and confirm their involvement in seizure networks. There has been an increase in publications showing the efficacy of higher definition imaging and reconstruction in identifying brain abnormalities, higher rates of intervention and modification in surgical planning, better targeting with stereotactic EEG and resultant improvement in surgical outcomes and seizure reduction , 19. PreStereotactic EEG studies are able to localize and identify nodes in a seizure network with increasing accuracy enabling precise targeting for resection or laser ablation. Focal epilepsies arising from or adjacent to eloquent cortex can be intervened upon with great precision using reconstruction. This is especially useful when these reconstructions are combined with electrographic data from brain mapping to delineate margins of resection or identify regions of overlap between epileptogenic cortex and eloquent cortex. Physicians are able to use this data to determine amount of tissue to be resected and targets for neurostimulation using responsive neurostimulators for treatment. We have expanded the number of patients that can be intervened upon and improve seizure reduction, tremendously changing the landscape of epilepsy surgery.Bitemporal epilepsy has had significant changes in management resulting from reconstruction and neurostimulation. Current practices include presurgical testing followed by responsive neurostimulation over both temporal lobes to capture chronic electrocorticography from both sides to make an informed decision about the need for a unilateral temporal lobectomy or laser ablation . ReconstMultifocal epilepsies remain a challenging group of conditions to define and treat, but reconstructive approaches have improved our diagnostic efficiency and expand our therapeutic surgical options. Combined use of ablations or resections with neurostimulation to target the most active nodes in the seizure network is expected to improve seizure reduction rates in such syndromes, although scientific studies on these are yet to be published. Some studies showing targeted intervention at nodules in tuberous sclerosis with resultant improvement have been published \u201323, and Generalized epilepsies remain a challenging group of syndromes to treat due to their diverse network properties and refractoriness to anti-seizure medications. The use of deep brain stimulation for movement disorders like essential tremor or Parkinson's disease is well-known and these concepts were extrapolated to the management of epilepsy as well. The US FDA approved deep brain stimulation of the anterior nucleus of thalamus for the treatment of refractory epilepsy following results from the SANTE trial . ResponsReconstruction involves using preoperative MRI scans of the brain and postoperative CT scans to precisely identify structures and recognize their relative position with respect to EEG electrodes with supporting roles played by reconstruction software. While the precise details are beyond the scope of this review, basic principles are outlined in Diagnostic and therapeutic approaches are constantly being redefined to meet ever-increasing standards of efficacy and cognitive preservation to permit the best possible quality of life for patients. Three-dimensional reconstructions permit accurate anatomical and electrographic correlation enabling precise localization of seizure networks and functional mapping resulting in tailored and accurate intervention to maximize surgical outcomes and seizure control in patients with the least amount of cognitive compromise. The use of such techniques for teaching trainees is paramount and beneficial to the field of epilepsy surgery as a whole. Improved quality and innovations in such techniques are expected to advance the field and are a continuous source of interest to clinicians and academics alike.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "The lack of tracer affinity to specific biological processes and high background uptake from urinary excretion have added many difficulties to precision renal diagnosis. In this issue of Theranostics, Jin and colleagues innovatively devised a recombinant probe for preferential kidney imaging through targeting of tubular neonatal Fc receptor and proximal tubular basement membrane for sustained tubular reabsorption and accumulation. This work has broad implications regarding how an in depth understanding of physiology and pathology may be of service for tracer development, renal diagnosis, and disease theranostics.Ideal nuclear imaging tracers should exhibit high target uptake and low background signal. Traditional renal scintigraphy and SPECT scans examine kidney function Low molecular weight antibody fragments in the forms of Fab, single-chain Fv fragment (scFv), diabody, and nanobody, have all been found to excrete from the kidneys 68Ga]Ga-NOTA-Nb1053 Additionally, passive tracer excretion Imaging comprehensive renal function while avoiding non-specific urinary excretion has been a real challenge. The desired tracer should have a positive and stable kidney accumulation regulated by a known biological process. In cases of kidney injury, acute or chronic, the tracer needs to faithfully reflect biological changes of the kidney in the living organism.Theranostics, Jin and colleagues purposely combined the IgG fragment crystallizable (Fc) domain with the VEGFA extracellular matrix (ECM) binding domain to construct a chimeric fusion protein In this issue of While most nuclear imaging tracers are developed to probe a known target in diseased sites such as cancer This study is also an excellent example of the development of hybrid nuclear imaging tracers. The direct fusion of two targeting domains perfectly delineated kidney parenchyma for imaging of multiple renal diseases. Currently, nuclear imaging probes based on bispecific peptides or antibodies have piqued great interest for cancer diagnosis. Combining two tumor-targeting peptides may expand the diagnostic scope of nuclear imaging tracers Theranostics showed the authors' clear understanding of kidney excretion and excellent execution of tracer development, which is highly desired in the pursuit of ideal theranostics for disease imaging and treatment. The employed methods may also have broad implications for the development of recombinant proteins specific for multiple targets to elicit integrated effects for nuclear imaging.The work presented by Jin and colleagues in this issue of"} +{"text": "These d) by AAs . In addi) by AAs , matrix ) by AAs and alte) by AAs , among oIn recent years, the ubiquitous methoxyindole melatonin, has received increased attention as an adjuvant supportive treatment in patients of several cancers types . MelatonThere is strong clinical evidence that germ cells are especially sensitive after administration of AAs, which leading to DNA damage and consequent induction of cell death . In thisNutritional interventions may play an important role both in the growth and development of tumor cells and in the treatments with established chemotherapy regimens to maximize the drug efficacy and tolerability. Thus, it has recently been reported that metabolic changes associated with fasting has led to a reduction the toxic effects of chemotherapy while enhancing therapeutic efficacy . The invImportant questions still need to be addressed regarding the combined use of chemotherapies and melatonin. When would it be reasonable to use melatonin as a supplement with a chemotherapy? Melatonin production declines with age in humans which may is thought to contribute to numerous dysfunctions and make organs more vulnerable to the development of pathologies, including cancer . Among oProtecting normal cells from the side effects of chemotherapy has gained significant interest. In this regard, we recently proposed a strategy based on a combined treatment of chemotherapeutic drugs plus melatonin . In thisChemoresistance and tumor relapse represent two important challenges for increasing the quality and life expectancy of cancer patients. Tumor cells often develop resistance to several chemotherapeutic drugs through various mechanisms such as dampened apoptosis, drug efflux through ATP-binding cassette (ABC) transporters, alterations in pro-survival signaling pathways or improved DNA repair mechanism . Thus, fA current focus of our group is to develop high dose melatonin formulations that will be beneficial for its use in cancer patients by mitigating its side-effects on normal cells and enabling a higher dosing of the chemotherapy. We are currently working on the pharmacokinetics characteristics, that should help us direct the adjuvant use of orally and/or parenterally administered melatonin in cancer patients undertreatment with AAs. Ultimately, our purpose is to help deciphering the potential of melatonin to maximize the drug efficacies while mitigating chemotherapeutic drug-induced toxicity and side effects in cancer patients."} +{"text": "Anomalies of the portal venous system can be congenital or acquired, the latter being related to spontaneous thrombosis or iatrogenic alterations such as complications of perinatal catheterization of the umbilical vein. These conditions can be clinically silent for years and then manifest abruptly causing severe clinical emergencies.This case report describes the diagnosis and interventional management of a singular abnormality in the portal venous system of an 8-year-old female that led to severe portal hypertension and acute variceal bleeding. Peculiar imaging findings were not pathognomonic for any of the known congenital and acquired portal vein anomalies: absence of a normal extrahepatic portal vein; splenic and mesenteric veins merging into a dilated left gastric vein; presence of an aberrant mesenteric venous collateral with a stenotic connection with the intrahepatic right portal branch; and absence of porto-systemic shunt. The case was successfully managed with percutaneous transhepatic portography and angioplasty.Prompt non-invasive imaging characterization allowed to understand the singular vascular abnormality and mini-invasive interventional radiology management resolved portal hypertension and variceal bleeding. Anomalies of the portal venous system can be congenital or acquired, the latter being related to spontaneous thrombosis or iatrogenic alterations such as complications of perinatal catheterization of the umbilical vein . Blood tests, including platelet and white blood cells count, liver function and coagulation, were within normal limits both at the admission and discharge.Based on these findings and no liver disease history, abdominal Computed Tomography Angiography (CTA) and Doppler Ultrasound were performed to assess the liver parenchyma and vascularization. CTA showed normal liver morphology, volume and density; absence of splenomegaly and ascites. The extrahepatic portal vein was not detected at the expected site, and a single large mesenteric retroduodenal venous collateral Fig.\u00a0a connectDevelopmental anomalies and acquired alterations of the portal venous system lead to a wide spectrum of uncommon clinical conditions. Herein, we describe a unique and singular case which has some clinical features common to PVT. Interestingly, in this case portal hypertension was not associated with ascites, hypersplenism or altered liver morphology: we hypothesize this was due to absence of liver disease and to the peculiar vascular anatomy, with spontaneous portal system decompression through an enlarged left gastric vein; although reduced by the stenosis, liver flow was probably enough. The case presents peculiar aspects suggesting a possible developmental anomaly: we hypothesize the persistence of the caudal ventral anastomosis of the right vitelline vein that may have compensated a portal vein agenesis or embryonic thrombosis. To our knowledge this vascular abnormality has been never reported with this clinical presentation.Percutaneous transhepatic angioplasty led to the resolution of portal hypertension with no further risk of bleeding."} +{"text": "To assess the impact of common mental health disorders (CMHDs) on university students\u2019 function and wellbeing. To understand the barriers to receiving adequate support for CMHDs during both adolescence and at university. To provide feedback to healthcare professionals about how young people perceive the support provided when initially seeking help for psychological distress. To explore which forms of support students find the most useful.A literature review was initially undertaken, identifying the lack of prior research in this area. The current study addressed the gap by considering the needs of students with CMHDs in the context of primary care services, with a retrospective exploration of their views about support received during adolescence. 15 semi-structured qualitative interviews were conducted with both current university students and recent graduates from across the UK, transcribed verbatim and subjected to thematic analysis. The study population included 7 men and 8 women, between the ages of 18\u201325 years.Five main themes emerged from the data:The Journey to Disorder \u2013 Explored the difficulties faced by adolescents, and how these might contribute to their experience of CMHDs and their management.Attitudes Towards Help-Seeking \u2013 Many participants had little trust in healthcare professionals as adolescents. This contributed to limited trust in university support systems as young adults.Primary Care Support - Perceived effectiveness of General Practitioner (GP) support during adolescence in this cohort was highly variable. Although some participants described good experiences, others felt their views were ignored, with responsibility diverted to their caregivers. A lack of understanding from GPs about CMHDs in adolescents resulted in trust issues for them as young adults.Recommendations for Change - Participants reflected on their previous and current experiences to inform suggestions for changes to tackle issue of psychological distress in adolescents.Previous experiences of the care they had received when presenting with CMHDs during adolescence potentially affected the long-term wellbeing of university students and graduates; the initial support received was inconsistent with the needs of this age group. Recommendations for change included a greater emphasis on the importance of adolescent mental health education, tailoring interventions to personal growth and maturity, and ensuring primary healthcare providers are equipped with the skills required to manage psychological distress in young people."} +{"text": "Explanation of the Correction provided by the authors:The authors were recently brought to attention about inconsistencies in the color-coding of helminth positive vs. helminth negative individuals between panels in Figs Since these corrections constitute an important component of the study, we wish to address several conclusions that have been discussed in the original publication. First, the gut microbiota of helminth positive individuals in this study have higher species richness (measured using Phylogenetic Distance), but there appears to be no differences in the number of distinct OTUs or species evenness (measured using Shannon index). While these inconsistencies between alpha diversity metrics could simply be due to the small sample size, it could reflect the underlying biology of intestinal helminth colonization and gut microbiota, or sensitivity of the Kato-Katz technique to differentiate positive and negative individuals. In a follow up study, we demonstrated a significant reduction in Observed OTUs among individuals treated with deworming medication . DewormiS1 FileValues for each alpha diversity metric, along with the associated helminth status.(TXT)Click here for additional data file."} +{"text": "As the Hmong community continues to grow and age in the United States (US), mainstream healthcare providers may encounter Hmong older adults who prefer their cultural end-of-life (EOL) care. The challenge for these providers is to offer culturally sensitive EOL care to Hmong older adults within the realm of the Western healthcare system. One factor contributing to this challenge may be the lack of knowledge regarding Hmong older adults\u2019 EOL care preferences. Another is Hmong EOL care is interwoven with care from domains such as culture, religion, and spirituality. The purpose of this study is to garner an understanding of the care preferences of Hmong older adults during the dying process. A qualitative study using inductive content analysis was conducted. Thirty Hmong older adults who reside in Wisconsin participated in semi-structured interviews that were audio recorded and transcribed. Data was analyzed using inductive content analysis by Elo & Kyng\u00e4s (2008). The findings revealed that participants preferred care at EOL in the domains: physical, psychosocial, cultural, religious, and spiritual. Physical care included ADL\u2019s while psychosocial care related to communication and companionship. Cultural care included children as caregivers and decision-makers. Religious and spiritual care surrounded Animism and Christian beliefs such as soul calling and prayers. Findings also suggest Hmong older adults\u2019 care preferences as heterogenous and holistic. The findings have implications for the Hmong community and formal care services to collaborate on how culturally sensitive care can be provided to Hmong older adults at end of life."} +{"text": "Neuroradiological methods play important roles in neurology, especially in cerebrovascular diseases. Fluid-attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH) is frequently encountered in patients with acute ischemic stroke and significant intracranial arterial stenosis or occlusion. The mechanisms underlying this phenomenon and the clinical implications of FVH have been a matter of debate. FVH is associated with large-vessel occlusion or severe stenosis, as well as impaired hemodynamics. Possible explanations suggested for its appearance include stationary blood and slow antegrade or retrograde filling of the leptomeningeal collateral circulation. However, the prognostic value of the presence of FVH has been controversial. FVH can also be observed in patients with transient ischemic attack (TIA), which may have different pathomechanisms. Its presence can help clinicians to identify patients who have a higher risk of stroke after TIA. In this review article, we aim to describe the mechanism and influencing factors of FVH, as well as its clinical significance in patients with cerebrovascular disease. Cerebrovascular diseases are harmful to human life because they have high mortality and disability rates. Fluid-attenuated inversion recovery (FLAIR) is widely used for the diagnosis of various intracranial diseases and is now recommended as a part of the routine protocol for magnetic resonance imaging (MRI) of stroke. FLAIR vascular hyperintensity (FVH) was first described in 1999 in a series of patients with acute stroke and subacute stroke . This fiFLAIR vascular hyperintensity is most likely to represent slow arterial blood flow, which is frequently encountered in patients with acute ischemic stroke. Slow blood flow is interpreted as slow retrograde flow in leptomeningeal collaterals or antegrade flow that corresponds to impaired hemodynamics . FVH mayThe exact pathophysiology of FVH has not yet been clearly defined, but its associations with acute large-artery occlusion and chronic arterial stenosis have been widely accepted. FVHs are classified into distal and proximal FVHs according to their extent and location , which hPrevious studies have attributed the presence of FVH to large-artery disease, leptomeningeal collateral flow, and local alterations in hemodynamics . This hyFLAIR vascular hyperintensity has frequently been encountered in patients with acute ischemic stroke and significant intracranial arterial stenosis or occlusion, and it has also been observed in patients with chronic intracerebral arterial stenoocclusive disease. The frequency of FVHs has varied immensely between different studies. FVH signs on FLAIR have been reported to be observed in 45\u2013100% of patients with acute ischemic stroke, primarily in strokes involving the MCA territory. Many factors may influence the presence and extent of FVHs, of which the blood flow velocity is regarded as the most important. A quantitative MRI study of a phaThe average time interval between symptom onset and imaging might be another important factor that influences the presence of FVH. Many studies have examined the time course of FVH in acute and subacute cerebral infarctions of the MCA territory, and the results showed that the frequency of FVH declined over time . Maeda eSeveral approaches have been proposed for investigating the extent of FVHs. The Alberta stroke program early computerized tomography score (ASPECTS) was a widely used method for assessing computerized tomography scans in patients with acute ischemic stroke . The scoFLAIR vascular hyperintensities are most frequently identified in patients with persistent large-vessel stenosis or occlusion and acute ischemic stroke. FVH has demonstrated excellent diagnostic performance for the identification of large-vessel occlusion, especially in MCA and ICA. Many studies have assessed the accuracy of FVH for the confirmation and location of a large-vessel occlusion. They reported that FVH had excellent sensitivity (76\u201398%) and specificity (69.8\u201386%) for the identification of a large-vessel occlusion . In someFLAIR vascular hyperintensities frequently appear in patients with acute ischemic stroke and can, in fact, also be seen in TIA patients. The collateral vessels can maximize the odds of survival of a high volume of brain tissue by sustaining the ischemic penumbra. Most patients with acute stroke who have robust collaterals usually have better clinical outcomes. FVH in collaterals could serve as good evidence of hemodynamic impairment in patients with cerebral infarction and TIA. FLAIR vascular hyperintensities are common in patients with acute ischemic stroke and represent marked hemodynamic impairment and slow retrograde flow in the ischemic territory due to intracranial stenoocclusive disease. The presence of FVH in acute ischemic stroke may indicate cerebral hypoperfusion. The FVH sign is associated with larger lesion volumes on perfusion-weighted imaging (PWI) and mismatches between PWI and DWI volumes in acute stroke. Prominent or extended FVHs indicate large areas of salvageable tissue and greater potential benefits from recanalization. Patients in an FVH-positive group exhibited more severe hemodynamic impairment than those in an FVH-negative group . A quantThe FVH score has been strongly associated with the area of hypoperfusion and the extent of prolongation of mean transit time, which suggests that the presence of FVH is representative of impaired cerebrovascular autoregulation. FVH can even sometimes be observed during the hyperacute phase of ischemic stroke. A previous study showed that patients with lower FVH scores were more likely to have smaller penumbras on computed tomography perfusion imaging and larger infarct volumes. The presence of FVH may be especially important in instances where MRA or perfusion imaging is not available or images are degraded by artifacts.An FVH\u2013DWI mismatch is considered to be present when FVH extends beyond the boundaries of the DWI cortical lesion . LegrandWhether an FVH\u2013DWI mismatch is a primary indicator of clinical outcomes in acute ischemic stroke is controversial. FLAIR vascular hyperintensity located beyond the boundaries of the DWI lesion reflects impaired yet viable tissue. This tissue recovers its function when recanalization is achieved, which explains why patients with an FVH\u2013DWI mismatch are more likely to have favorable outcomes. PWI\u2013DWI mismatch has been proposed for use in selecting patients with acute stroke for recanalization therapy. FVH\u2013DWI mismatch provides an alternative to PWI\u2013DWI mismatch for selecting patients as candidates for thrombectomy. FVH\u2013DWI mismatch may rapidly identify patients with proximal occlusion who are most likely to benefit from recanalization . It may Transient ischemic attack is characterized by sudden focal brain dysfunction lasting less than 24 h, which is linked to cerebral or optic ischemia. Patients presenting with transient neurological symptoms have an increased risk of a subsequent stroke. Therefore, the clinical importance of early diagnosis and treatment of TIA should be emphasized to prevent the development of stroke. According to previous studies, the incidence of FVHs in TIA patients was markedly lower than in acute ischemic stroke and varied remarkably from 16 to 39.6% . BecauseFLAIR vascular hyperintensity has not been fully evaluated in patients with TIA in contrast to ischemic stroke. Two factors \u2013 arterial occlusion or stenosis and atrial fibrillation \u2013 have been reported to have significant and independent associations with FVH . It has FLAIR vascular hyperintensity can predict an oncoming acute ischemic stroke in the 30 days following a TIA . The occMany studies have focused on the association between FVHs and clinical outcomes in patients with ischemic stroke. However, the prognostic value of FVH findings is unclear. Some studies demonstrated that the presence of FVHs was associated with severe clinical impairments and poor functional outcomes, whereas FLAIR vascular hyperintensity has been recognized as a marker of collateral flow in ischemic stroke, but its relationship with outcomes is still controversial. There is little consensus on the interpretation of prognostic information from FVH studies, which should adopt an accepted standard as a prognostic assessment tool. In previous studies, the populations with stroke that were included were heterogeneous, especially in terms of the time to the initial MRI scan from symptom onset, and patients with proximal and distal FVHs were considered together, which potentially confounded tests for significance. Furthermore, studies used different prognostic assessment criteria, including the NIHSS score, Modified Rankin Scale score, and infarct volume on DWI.The association between FVH and functional outcomes varies with time. Although the mechanism underlying FVH remains to be established, this phenomenon is associated with retrograde collateral blood flow and impaired hemodynamics in the ischemic territory due to intracranial stenoocclusive disease. FVH can be detected in acute infarction and chronic large-vessel occlusion. It is worth noting that FVH occurs in patients with TIA and might be correlated with clinical conditions such as atrial fibrillation and not only with large-vessel occlusion. However, it is still controversial whether FVH may serve as an imaging marker of hemodynamic impairment or good collateral status and may predict patients\u2019 prognosis. Many factors should be considered when assessing the prognostic value of FVH, especially for symptom-to-imaging time and differences between before and after treatment. FVH may be an important neuroimaging marker, and radiologists and clinicians should be trained to look for its presence.LZ and JC: conceptualization. LZ and HL: methodology and writing \u2013 original draft preparation. QW and MX: formal analysis and investigation. LZ and WW: writing \u2013 reviewing and editing. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Modern perioperative medicine has dramatically altered the care for patients undergoing major surgery. Anaesthetic and surgical practice has been directed at mitigating the surgical stress response and reducing physiological insult. The development of standardised enhanced recovery programmes combined with minimally invasive surgical techniques has lead to reduction in length of stay, morbidity, costs, and improved outcomes. The enhanced recovery after surgery (ERAS) society and its national chapters provide a means for sharing best practice in this field and developing evidence based guidelines. Research has highlighted persisting challenges with compliance as well as ensuring the effectiveness and sustainability of ERAS. There is also a growing need for increasingly personalised care programmes as well as complex geriatric assessment of frailer patients. Continuous collection of outcome and process data combined with machine learning, offers a potentially powerful solution to delivering bespoke care pathways and optimising individual management. Long-term data from ERAS programmes remain scarce and further evaluation of functional recovery and quality of life is required. The field of perioperative medicine has undergone radical change in the last 30 years witnessing major advances in anaesthetic and surgical technique. Along with this, traditional models of care have been disbanded in favour of enhanced recovery programmes in almost every surgical specialty. In this review, we have presented the evolution of modern perioperative care; we have discussed current practice, areas of contention, and future directions for advancing the field.Historically, patients knew very little of what to expect following a major surgery. Perioperative care was often characterised by prolonged fasting, aggressive bowel preparation, nasogastric decompression, bed-rest, and prolonged convalescence. A paradigm shift came during the 1990s with the work of Henrik Kehlet on the physiological stress response and organ dysfunction following surgery. He hypothesised this was a key factor in postoperative morbidity and that combined approaches to inhibit this response would improve clinical outcomes .Kehlet and others pioneered modern recovery \u2013 advocating multimodal analgesia and regional anaesthetic techniques combined\u00ae) study group. The group sought to address the variability . H. H51]. HOther areas of controversy include intraoperative fluid therapy, which has been an important component of ERAS from its inception. Balancing fluid therapy to achieve adequate splanchnic perfusion whilst avoiding oedema, paralytic ileus, and fluid overload remains challenging. This is particularly true amongst high-risk patients such as those with limited physiologic reserve, severe cardiopulmonary disease, renal impairment, or patients undergoing extensive surgery . Early tERAS challenged all the dogmas of conventional perioperative care, but it needs to continue to evolve, or else risk becoming dogmatic itself. ERAS must be responsive to the latest research evidence as well as novel surgical approaches and technologies. Enhanced recovery programmes have already begun to influence the care of emergency general surgery , 61] an an61] anResearch within ERAS is also evolving with on-going work to investigate ways of enhancing the success of ERAS. Studies to predict which patients are likely to deviate from the expected perioperative course has been of interest as it may allow remedial action to be taken to avert this . Recent Deconstructing ERAS protocols by analysing the effectiveness of specific items may seem counterintuitive given the evidence base is required to justify each component. Efforts to simplify and streamline protocols are primarily borne from a desire to improve compliance, but may also represent a response to criticism that ERAS has become overcomplicated and unwieldy . Debate What is increasingly clear in perioperative medicine is that one size does not fit all. The individual stress response to surgery remains highly variable without a means to measure or predict this currently. The increasing complexity of patients\u2019 medical needs combined with heterogeneity in service infrastructure, operative, and patient factors are driving a need for more personalised care programs. This is particularly true in the context of an aging global population and the rising number of elderly and comorbid patients undergoing surgery. The increasing prevalence of frailty and geriatric syndromes amongst this patient group places them at increased risk of adverse outcome following surgery including medical complications, prolonged hospitalisation, institutionalisation, and readmission as well as short and long-term mortality .Although series have demonstrated that ERAS is safe and beneficial in caring for elderly surgical patients , a numbeThe growing complexity of perioperative care and the need for increasingly personalised and bespoke pathways has stimulated interest in digital technological solutions and automated care processes. Digital technology is likely to have a major role in shaping the future of perioperative care and a number of advances relevant to enhanced recovery programmes have been investigated. These include apps directed at lifestyle modification and preoperative optimisation, objective nociceptive measurements, portable non-invasive sensors calibrated to recognise postoperative cardiopulmonary complications, and activity trackers to monitor postoperative ambulatory recovery .An exciting frontier in medical technology is in combining big data analytics with artificial intelligence in order to guide patient management. Artificial neural networks and machine learning programmes have exhibited superior performance to conventional prediction models in diagnosing acute appendicitis , selectiThis may well revolutionise care of the surgical patient within the next 20 years. We envisage a system whereby data from electronic health records combined with metrics prospectively measured throughout the perioperative period are harvested by machine-learning programmes. This continuously updates the optimum care pathway with targeted adaptations or adjustments for an individual patient as well as the local population in an automated fashion .There is cause for great optimism about the future of perioperative medicine. There has been greater consensus and collaboration on issues such as nutrition , anaemiaStudies examining patient satisfaction and health related quality of life with ERAS have so far found no significant difference when compared to conventional care. Some evidence supports a reduction in postoperative fatigue and earlA limited number of reports have now been published examining medium to long-term survival, which reveals both an overall and cancer-specific survival advantage with ERAS , 96], , . It is lCrucially these studies have reasserted the importance of adherence to ERAS protocols which was strongly associated with survival independent of cancer stage and postoperative complications , 96], , .From a global perspective there is still considerable progress required in perioperative care. In 2015 the Lancet commission on global surgery highlighted the alarming deficit in essential, life-saving surgical and anaesthesia care in low and middle income countries . The repClick here for additional data file."} +{"text": "To critically appraise the literature regarding the effect of Drug Consumption Facilities in reducing overdose mortalityDrug consumption facilities (DCF) are places where people can use illicit drugs in the presence of medically trained staff, they aim to reduce fatal overdose risk, reduce risky injecting practices, and to serve as a bridge for users into mainstream treatment, healthcare and social services. Increasing numbers of fatal overdoses due to illicit drug use are a significant public health concern. The UK's statutory independent advisory body (the Advisory Council on the Misuse of Drugs) has recommended DCFs as a mechanism to reduce fatal overdoses due to illicit drugs. However, current UK legislation prohibits their provision.Systematic extraction of relevant literature from PubMed, using a search string with a focus on observational cohort studies with fatal overdose as the outcome. Appraisal of identified papers using the CASP tool184 papers were identified, two of these met the inclusion criteria. Quality was fair/good. Neither demonstrated a clear effect of DCFs in reducing overdose mortalityIt is difficult to draw firm conclusions due to design weaknesses and potential confounding variables. Robust design is difficult in this research area, due to lack of suitability for RCTs. Despite the lack of a clear effect on overdose mortality, DCFs may exert other positive effects and are a pragmatic and humane response to reducing risk in this target population"} +{"text": "Posterior circulation ischemic stroke comprises an estimated 15\u201320% of all ischemic strokes and differs from anterior circulation stroke in many ways. An acute occlusion of the basilar artery can trigger one of the most devastating ischemic stroke syndromes with reduced level of consciousness, loss of brainstem reflexes and tetraplegia. However, posterior circulation stroke is frequently difficult to diagnose clinically due to varying symptoms and signs like isolated vertigo and dizziness. Knowledge about specific brainstem symptoms and syndromes can aid early clinical recognition and thus, rapid initiation of appropriate diagnostic and therapeutic approaches . While mIn the context of this clinical and scientific background, this Research Topic covers relevant aspects of posterior circulation ischemic stroke. Three main aspects are discussed.Hoyer and Szabo summarizes important pitfalls in its diagnosis in the prehospital and emergency department setting, and provides strategies and approaches to improve speed and accuracy of its recognition and early management. Data on anatomical variants, i.e., bilateral vertebral hypoplasia as a potential risk factor for ischemic stroke, posterior fossa venous drainage and mechanisms of posterior circulation blood flow regulation and its implications for posterior circulation stroke are detailed in the articles by Hsu et al., De Miquel, and Tamayo and Siepmann, respectively.First, the clinical diagnosis of posterior circulation ischemic stroke is frequently difficult due to varying and non-specific symptoms. The narrative review by Macha et al. Their findings may inform clinicians in the usage of alteplase beyond 4.5 h from symptom onset in selected patients with posterior circulation ischemic stroke. Scientifically, however, more data on this topic is needed until a general recommendation can be made.Second, several articles of the collection cover novel aspects of acute treatment in patients with posterior circulation ischemic stroke and particularly basilar artery occlusion. Known data for IVT in late or unknown time window mostly focus on patients with anterior circulation ischemic stroke. It is therefore reassuring that the safety and efficacy of IVT in this scenario seem similar in patients with posterior circulation ischemic stroke, as addressed in the article by Mbroh et al. suggests that EVT in posterior circulation large vessel occlusion (pcLVO) may be comparably sufficient in obtaining favorable functional outcome compared with acLVO. These findings parallel results of the recently published BASILAR registry, where patients who received EVT within 24 h after the estimated time of basilar artery occlusion had an improved chance to achieve a favorable functional outcome compared to patients who received best medical management only of these patients can still achieve a favorable functional outcome. Moreover, recanalization and a lesser extent of early ischemic changes on neuroimaging were associated with favorable outcome in this study. These results confirm findings from a previous analysis of the BASICS registry data and underline the prognostic importance of imaging in patients with basilar artery occlusion is associated with a higher chance for successful first pass reperfusion in patients with acute basilar artery occlusion which confirms previous findings in patients with acLVO occlusions. Whether EVT is safe and effective in patients with posterior cerebral artery (PCA) occlusion has been analyzed in the article by g stroke . Lastly,th acLVO .Hou et al. demonstrated that intraplaque enhancement and vertebral artery involvement were associated with artery-to-artery embolism. Questions arise whether these patients may benefit from more aggressive antiplatelet regimens.Third, as outlined above, the stroke etiology in patients with basilar artery occlusion seems more heterogenous compared to acLVO. Artery-to-artery embolism and intracranial atherosclerotic disease play an important role. Characterization of such stenoses is important for acute treatment decision making and to tailor therapy in secondary stroke prevention. By using 3T high-resolution magnetic resonance imaging in patients with recent posterior circulation stroke due to intracranial vertebrobasilar atherosclerotic disease with 70\u201399% stenosis, Frontiers in Neurology provides an integrated overview of the hot topics in the field of posterior circulation ischemic stroke. Emerging from the article collection is a complex picture with focus on the anatomical, clinical and pathophysiological correlates of posterior circulation stroke, acute treatment including intravenous and endovascular therapies. The studies published in this issue emphasize the need for further research to better delineate pathophysiological aspects, clinical recognition and treatment decision making in these patients, in the wake of the BASICS and BEST basilar artery occlusion trials (In conclusion, this issue of n trials , 5, 21. VP drafted the manuscript. DS, TN, and SN revised the manuscript for intellectual content. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Over the last year, mental health services offered virtually have increased significantly in response to COVID-19. The rapid adoption of telehealth practices has raised many questions about how to develop and deliver effective interventions for older adults targeting their mental and cognitive health. In this symposium, we present on the feasibility of mental and cognitive health interventions for older adults using telehealth methods with particular focus on how adoption of these telehealth tools have been impacted by the current pandemic. Dr. Touchett and colleagues will present data on the telehealth utilization disparities among older veterans with comorbid disabilities and discuss ethical considerations when providing care for older adults. Dr. Kornblith and colleagues will present pilot data on the feasibility of GOALS, a video telehealth cognitive remediation group intervention for older adults with cognitive and emotional dysfunction related to traumatic brain injuries. Dr. Gould and colleagues will present pilot data on the feasibility and preliminary efficacy of a brief video-delivered self-management intervention BREATHE for older veterans with anxiety disorders. Dr. Weiskittle and colleagues will present their work on the development and dissemination of a brief 8-week telephone group intervention for homebound older adults targeting social isolation. Dr. Jacobs and colleagues will share their findings of a telephone delivered mindfulness intervention for caregivers and persons with dementia. Finally, the discussant, Lauren Moo, MD, an expert in assessing the efficacy of telehealth interventions will tie findings together and provide directions for future research and innovation."} +{"text": "Black adults have a higher likelihood of experiencing bereavement and increased negative implications of systemic racism compared to other groups. The effects of racism have also been suggested to have an impact on how bereaved Black individuals conceptualize their loss and the deceased. However, there is limited literature on how direct and indirect childhood experiences with racial violence and viewing racially violent deaths impact bereaved Black adults later in the lifespan. The current study seeks to explore the impacts childhood engagement with racial violence might have on bereaved middle to older Black adults. 103 middle to older aged Black adults from a larger online grief study were probed about factors including somatization, depression, affect, grief, and the prevalence and intensity of exposure to race-based violence during their childhoods. Linear regressions and bivariate correlations were used for data analysis. Childhood racial violence significantly predicted grief . Additionally, experiencing childhood racial violence was significantly associated with somatization , depression , and negative affect . Endorsed intensity of racial violence was significantly associated with depression and negative affect . Bereaved Black middle to older adults seem greatly impacted by childhood experiences of racial violence. It is important to consider the role outside cultural influences such as racial trauma might have on other deleterious mental health experiences such as bereavement. Furthermore, in the assessment of ACEs among Black and other people of color, it could be important to include childhood racial violence."} +{"text": "Suicide has emerged as a serious concern for public health; however, only few studies have revealed the differences between major psychiatric disorders and suicide. Recent studies have attempted to quantify research domain criteria (RDoC) into numeric scores to systematically use them in computerized methods. The RDoC scores were used to reveal the characteristics of suicide and its association with major psychiatric disorders.We intended to investigate the differences in the dimensional psychopathology among hospitalized suicidal patients and the association between the dimensional psychopathology of psychiatric disorders and length of hospital stay.t test. A linear regression model was used to analyze the association between the RDoC scores and sociodemographic features and comorbidity index. To estimate the association between the RDoC scores and length of hospital stay, multiple logistic regression models were applied to each psychiatric disorder group.This retrospective study enrolled hospitalized suicidal patients diagnosed with major psychiatric disorders between January 2010 and December 2020 at a tertiary hospital in South Korea. The RDoC scores were calculated using the patients\u2019 admission notes. To measure the differences between psychiatric disorder cohorts, analysis of variance and the Cochran Q test were conducted and post hoc analysis for RDoC domains was performed with the independent two-sample We retrieved 732 admissions for 571 patients . We found significant differences in the dimensional psychopathology according to the psychiatric disorders. The patient group with depression showed the highest negative RDoC domain scores. In the cognitive and social RDoC domains, the groups with schizophrenia and bipolar disorder scored higher than the group with depression. In the arousal RDoC domain, the depression and bipolar disorder groups scored higher than the group with schizophrenia. We identified significant associations between the RDoC scores and length of stay for the depression and bipolar disorder groups. The odds ratios (ORs) of the length of stay were increased because of the higher negative RDoC domain scores in the group with depression and decreased by higher arousal RDoC domain scores in the group with bipolar disorder .This study showed the association between the dimensional psychopathology of major psychiatric disorders related to suicide and the length of hospital stay and identified differences in the dimensional psychopathology of major psychiatric disorders. This may provide new perspectives for understanding suicidal patients. The World Health Organization states that nearly 800,000 people die each year from suicide, one every 40 seconds . Most paSuicide attempts vary depending on the method, intent, and medical severity of the aftereffects . The lenMeanwhile, the diagnosis of psychiatric patients so far has relied on categorical diagnostic systems. As the limitations of categorical diagnostic systems became increasingly apparent, the research domain criteria (RDoC) was introduced as an alternate nosology by the National Institute of Mental Health (NIMH) . NaturalIn this study, we aimed to explore the differences in the RDoC domains extracted by NLP among patients with depression, schizophrenia, and bipolar disorder who were hospitalized for suicide attempts. We sought to determine whether narrative clinical notes could identify suicide-related features of each disorder. We also investigated how these domains were associated with the length of hospital stay and compared them for each disorder.Clinical and sociodemographic data were extracted from the electronic health records of patients in the psychiatry inpatient unit at Ajou University Hospital in South Korea between 2010 and 2020. All patients received a Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV-TR or DSM-5 diagnosis from a trained psychiatrist ,13. ClinMcCoy et al previoust tests. Linear regression modeling with adjustments for the sex, age, and CCI was used to analyze five domains of the RDoC in different sociodemographic profiles. For each psychiatric disorder, a multiple logistic regression model analyzing the sociodemographic variables and RDoC domains was used to identify the factors associated with the length of hospital stay. For a secondary analysis, a Cox regression model with adjustments for demographics and categorical diagnosis was used to identify each domain associated with the length of hospital stay without controlling the other four domains. As the Mental Health Promotion and Welfare Act in South Korea defines involuntary psychiatric admission within 3 days [We conducted a retrospective cohort study to explore the differences in the RDoC domains extracted by NLP among patients with depression, schizophrenia, and bipolar disorder who were hospitalized for suicide attempts. We also investigated how these domains were associated with the length of hospital stay and compared them for each disorder. Baseline demographic and clinical data are expressed as numbers (%) for categorical variables and means (SDs) for continuous variables. Differences between psychiatric disorders were compared using analysis of variance (ANOVA) for continuous variables and Cochran Q tests for categorical variables. Post hoc analysis of the RDoC domains was conducted using independent two-sample n 3 days , hospitaP<.001), whereas cognitive systems were significantly higher in the schizophrenia group than in the depression group (P=.004) and in the bipolar disorder group than in the depression group (P<.001). Like cognitive systems, systems for social processes were significantly higher in the schizophrenia group and the bipolar disorder group than in the depression group (P<.001). Arousal/regulatory systems were significantly higher in the depression (P=.004) and bipolar disorder (P=.04) groups than in the schizophrenia group. Furthermore, the RDoC domains differed in their associations with sociodemographic variables given in The demographic and clinical characteristics of 732 admissions for 571 participants are shown in Next, we examined the association between the RDoC domains extracted from the admission notes and length of hospital stay. In the secondary analysis, compared to the primary analysis, which considered 3-day hiccups and other domains, the depression group similarly showed significant association with negative valence . The association found between negative valence and depression as well as suicide is consistent with previous findings ,25. In tOur findings show significant associations between the RDoC domains and length of hospital stay for depression and bipolar disorder. This result is consistent with those in existing literature reporting that the estimated RDoC domain scores were associated with the length of stay . MoreoveOur study has a few limitations. First, even though we extracted database records of suicidal patients from 2010 to 2020, we could identify only 732 psychiatric admissions in 571 patients. To validate our findings more accurately, a large data set is required. Second, our study has analyzed the conditions most highly related to suicide, but other suicide-related conditions, such as substance use disorders and personality disorders, have not been considered. Because substance use disorders and personality disorders frequently coexist with depression, schizophrenia, and bipolar disorder , it was Our study showed that the estimates of dimensional psychopathology derived from NLP are associated with the length of hospital stay in suicidal patients with depression or bipolar disorder and vary significantly among suicidal patients with depression, schizophrenia, and bipolar disorder. Therefore, our findings suggest that more attention might be paid to negative valence for depression and arousal/regulatory systems for bipolar disorder in relation to suicide. Additionally, our results may increase the understanding of the differences in dimensional psychopathology among suicidal patients with depression, schizophrenia, and bipolar disorder. We hope that further investigations will clarify the differences in the RDoC scores of suicidal patients and associations between the RDoC scores of suicidal patients and clinical outcomes."} +{"text": "As the primary cause of cancer-induced fatality and morbidity, cancer metastasis has been a hard nut to crack. Existing studies indicate that lipid metabolism reprogramming occurring in cancer cells and surrounding cells in TME also endows the aggressive and spreading properties with malignant cells. In this review we describe the lipid metabolic reprogramming of cancer cells at different steps along the metastatic process, we also summarize the altered lipid metabolism of non-cancer cells in TME during tumor metastasis. Additionally, we reveal both intrinsic and extrinsic factors which influence the cellular lipid metabolism reprogramming. As the primary cause of cancer-induced fatality and morbidity, cancer metastasis has been a hard nut to crack Reprogramming of cellular metabolism has been considered as a major hallmark of cancer, it fuels fast cell growth as well as provides tumor cells with several benefits, including macromolecule biosynthesis, adaptation to the microenvironment, and an ability to cope with oxidative stress Lipids, also known as fats, contain thousands of different types of molecules, including phospholipids, fatty acids (FAs), triglycerides, sphingolipids, cholesterol and cholesteryl easters (CE) It is also worth noting that in addition to cancer cells, the surrounding cells in tumor microenvironment (TME) such as fibroblasts, immune cells and adipocytes may undergo lipid metabolism reprogramming as well The association between lipid metabolism reprogramming and cancer development has been well established, but the global lipid metabolism reprogramming in cancer metastasis still remains elusive. Therefore, in this review we describe the altered lipid metabolism of cancer cells occurring in cancer metastasis and unravel the underlying mechanisms. We also summarize the altered lipid metabolism occurring in TME which may cooperate with cancer cells to induce progression of cancer. In addition, the possible regulations of both extrinsic and intrinsic factors on lipid metabolism remodeling in cancer cells are also discussed in this paper. We believe that revealing lipid metabolism reprogramming in cancer cells and TME will provide more opportunities for clinically directing against cancer metastasis.de novo lipogenesis include fatty acid synthase (FASN), ATP citrate lyase (ACLY) and Acetyl-CoA Carboxylase (ACC), and studies have shown that the altered expression levels of these enzymes are closely related to increased migration and invasion of cancer cells in various cancers, such as pancreatic cancer, breast cancer (BC), HCC and so on The altered lipid metabolism in cancer cells involves a series of altered enzyme activities and were considered to be associated with the metastasis of various cancers to a certain extent de novo lipogenesis plays a crucial role in rendering the capabilities of adhesion, migration and invasion to CRC cells via upregulation of sphingolipid metabolism Known as the first step of metastasis, epithelial-to-mesenchymal transition (EMT) which is characterized by losing epithelial markers together with enhanced mesenchymal markers confers to cancer cells increased survival, stemness and metastasis-initiation ability in vivoin vivo, which provides a potential target for cancer metastatic treatment Conceivably, after acquiring the capability of migration, metastasizing cancer cells must constantly adapt their metabolism to the distinct environment of the blood or lymph based on the nutrients available in corresponding microenvironment as long as they leave the primary tumor site + cells have the function of lipid uptake, a recent study has shown that their potential for initiating cancer metastasis requires the involvement of CD36-induced FAO activation Finally, these metastasizing cancer cells extravasate and colonize into a new organ to complete the metastasis Currently, TME become to be believed as an arena where tumor cells constantly interact with various microenvironmental components, giving rise to a protean landscape in which the tumor cells, the host cells and other tumor-associated cells acquire phenotypic alterations It has become clear that various kinds of immune cells accelerate metastasis, partially due to their involvement of the establishment of an immunosuppressive microenvironment within primary lesions in vitro and decreases tumor growth and intraperitoneal dissemination in vivoAs a kind of specialized fibroblasts, CAFs are considered to be the principal non-cancerous cell type within TME, which actively promotes tumor cell differentiation and support metastasis by promoting matrix remodeling and EMT Furthermore, it has been confirmed that adipocytes in TME affected by tumor-secreted factors leading to activated phenotypes are called cancer-associated adipocytes (CAAs) It has been known that cancer cells are able to alter their metabolic state due to various intrinsic or extrinsic factors. Lipid metabolism reprogramming may occur in cancer cells as a result of intrinsic alterations like oncogenic mutations stimulate signal transduction components that either directly increases metabolic enzyme activity or transcription factors, thereby increasing expression of metabolic regulators Increased biosynthesis and uptake of lipids are supported by enhanced expression of the enzymes belonging to these pathways, which are regulated by a subclass of transcription factors called sterol regulatory-element binding proteins (SREBPs) In fact, the physical and chemical nature of the TME may alter cellular lipid metabolism as a kind of extrinsic factor. Recently a study has reported that chronic acidosis in TME induces LDs formation in cancer cells and leads to more metastasis, with CD36 and diacylglycerol acyltransferase (DGAT) as key players to mediate LD biogenesis via the uptake of exogeneous FAs and triglyceride synthesis in a TGF\u03b22-dependent way Growing evidence suggests that systemic factors and their intracellular pathways may activate oncogenic signals to reshape the metabolism in cancer cells de novo hepatic lipogenesis, indicating an unneglectable role of gut microbiota in altering metabolic response Actually, it has been supposed that obesity and other metabolic diseases are associated closely with the gut microbiota which has been has considered as \u201cmetabolic organ\u201d, plays a pivotal role in maintaining homeostasis of host lipid metabolism in vivo. And the effect of LPS on lipid metabolism was then demonstrated to be resulted from LPS stimulation induced overexpressed TNF-\u03b1 in macrophages as TNF-\u03b1 was able to activate caspase-3 which downregulates the expression levels of CD36 and FATP4 de novo synthesis from cholesterol On the one hand, the human gut is regarded as reservoir of lipopolysaccharide (LPS) which consists mainly of outer membrane of gram-negative bacteria, and it has been reported that the enhanced LPS levels is related to increased adipose macrophage infiltration and IR Specific molecular features of cancers that distinguish from the normal ones were called \u201challmarks of cancer\u201d and it is supposed that metabolism reprogramming has been considered one of the hallmarks of cancer SREBP2 and its downstream target gene HMGCS and HMGCR, and knocking down SREBP2 significantly inhibited cancer liver metastasis The so-called lipid metabolism remodeling in cells actually involves a series of altered enzyme activities which are likely to be associated with metastasis of various cancers In recent years, the inhibitors targeting major participants in lipid metabolism such as fatty acids synthesis, FAO, and cholesterol metabolism have been broadly tested in cancer treatment Furthermore, exploring the factors influencing lipid metabolism remodeling may help find out new auxiliary therapeutic targets for cancer. On the one hand, it is thought that the metabolic demands of tumor cells were enhanced due to the mutational alterations in oncogenes and functional loss of onco-suppressors To sum up, we review aberrant lipid metabolism occurring in cancer cells which plays a role in cancer metastasis. We also describe lipid metabolism alterations of surrounding cells in TME, which further contribute to cancer cell EMT, migration invasion and metastasis. This review can shed some light on the mechanisms underlying lipid metabolic reprogramming during tumor metastasis and reveal the intrinsic and extrinsic factors influencing the lipid metabolism reprogramming, and ultimately result in the identification of new therapeutic targets for cancer metastasis and improvement of patients' prognosis."} +{"text": "Ischemic heart disease is the leading cause of death around the world, and though the advent of coronary revascularization has revolutionized its treatment, many patients who sustain ischemic injury to the heart will go on to develop heart failure. Biofabrication of ventricular myocardium for replacement of irreversibly damaged ischemic myocardium is sought after as a potential therapy for ischemic heart failure, though challenges in reliably producing this biomaterial have limited its clinical application. One method that shows promise for generation of functional myocardium is the use of tissue decellularization to serve as a scaffold for biofabrication. This review outlines the methods, materials, challenges, and prospects of tissue decellularization techniques for ventricular myocardium biofabrication. Decellularization aims to preserve the architecture and composition of the extracellular matrix of the tissue it is applied to, allowing for the subsequent implantation of stem cells of the desired cell type. Decellularization can be achieved with multiple reagents, most of which have detergent properties. A variety of cell types can be implanted in the resulting scaffold, including cardiac progenitor cells, and embryonic or induced pluripotent stem cells to generate a range of tissue, from patches to beating myocardium. The future of this biofabrication method will likely emphasize patient specific tissue engineering to generate complex 3-dimensional constructs that can replace dysfunctional cardiac structures. Ischemic heart disease remains the number one cause of mortality around the world . Though While orthotopic heart transplantation is the gold standard treatment for end-stage heart failure, it is challenged by limited donor supply, the lifelong need for immunosuppression, and the need to monitor for rejection . Though The two prevailing approaches to generating bioscaffolds for myocardial repair or replacement are \u201cbottom-up\u201d and \u201ctop-down\u201d engineering . The \u201cboHerein, we will briefly review the history and prevalent methods of decellularization as a method of biofabrication of myocardial tissue, and then focus on its application to replacing ventricular myocardium.Tissue decellularization is the process by which chemical, enzymatic, or mechanical stimuli are used to produce an acellular bioscaffold from previously cellularized tissue or whole organs . Prior tConventional approaches to decellularization of tissue include bathing the tissue in a decellularization agent or, in tEnzymatic decellularization involves the use of nucleases such as Dornase or trypsin meant to cleave RNA and DNA or attachments from cells to the ECM, to achieve the standard thresholds of decellularization . This meDecellularization can be achieved using physical agitation or alternating cycles of freezing and cooling, or pressurization with supercritical carbon dioxide that lyse the cells . Each ofDecellularized tissues can subsequently be seeded with stem cells via a process called recellularization. The decellularized tissue can be stereotropically repopulated with vascular tissue, muscle, and other functional components of organized myocardium . RecelluInduced pluripotent stem cells (iPSCs) and mesenchymal stem cells (MSCs) are the most commonly used recellularization agents, and differentiate into the appropriate functional unit of the area into which they are seeded due to biomechanical cues from the extracellular matrix (ECM) . PerfusiAdvances in recellularization have centered on improvements in engraftment as well as specific programming of iPSCs into complex cell lines that form the components of functional myocardium . A majorTissue decellularization, with or without recellularization, can be applied to augment or fabricate ventricular myocardium . When apEven in the absence of recellularization, purely decellularized ECM can support ventricular myocardium. Wang et al. minced and decellularized neonatal and adult mice hearts using combination of chemical (antibiotic/antimycotic/gentamycin solution), followed by physical (freezing), and finally enzymatic (deoxyribonuclease and ribonuclease) decellularization, producing an ECM powder that was resuspended into a hydrogel . They deDecellularized non-cardiac ECM can be applied in a similar manner to infarcted or damaged ventricular myocardium. Francisco et al. demonstrated that human amniotic membrane could be decellularized via chemical decellularization to produce an ECM bioscaffold patch, impregnated with an anti-inflammatory nanoparticle, and then implanted on the surface of infarcted rat hearts . Hearts A limitation to clinical translation of conventional decellularized ECM patches or hydrogels is their physical weakness, ultimately leading to poor long-term engraftment and inability to reliably maintain geometric configurations . Gul KimBioscaffolds generated from decellularized ECM and then subsequently recellularized stand to provide the benefits of decellularized ECM patches, namely scar limitation, improved left ventricular remodeling and preservation of ejection fraction, with the added potential of repopulating cardiomyocytes. Kajbafzadeh et al. demonstrate this by decellularizing rabbit pericardium and then recellularizing with autologous adipose-derived mesenchymal stem cells (ADMSCs) . Within Tan et al. demonstrated the added benefit of seeding decellularized tissue with stem cells by showing that decellularized small intestinal submucosa patched onto infarcted rabbit ventricular myocardium in itself could preserve ejection fraction and mitigate adverse remodeling, but patches seeded with mesenchymal stem cells grossly improved capillary formation within the infarcted territory of the rabbit ventricular myocardium . DemonstBiofabrication of pure ventricular cardiomyocytes for direct engraftment onto damaged ventricular myocardium has been largely limited by challenges in reliably inducing iPSCs to differentiate into ventricular myocardium when delivered via a decellularized patch. Li et al. addressed this challenge by decellularizing adult rat hearts to produce dECM patches, and subsequently recellularizing them with iPSCs genomically engineered through transcription activator-like effector nucleases (TALEN) to select for cues to differentiate into ventricular cardiomyocytes . The resEven without directly fabricating ventricular myocardium, decellularization and recellularization can improve currently existing therapies for ventricular disease. For example, congenital defects that result in single ventricle physiology can be treated using surgical techniques such as the Fontan procedure. This procedure utilizes a vascular conduit to redirect central venous blood flow directly into the pulmonary artery in situations where the right ventricle is physiologically or physically absent. A struggle of the procedure is reliably generating forward flow into the pulmonary arterial circuit. Park et al. demonstrate a novel technique to generate a pulsatile vascular conduit that can act like the right ventricle to generate stroke work to push blood flow into the pulmonary artery circuit . The appVentricular biofabrication represents an area of application of decellularization/recellularization that has not been meaningfully translated into clinical practice, unlike other applications such as bovine pericardial patches or certain decellularized heartvalves . Though Preserving the ECM microarchitecture contributes significantly to the major limitation of recellularization: generating enough viable cardiomyocytes from stem cells. Several billion, organized and functioning cardiomyocytes are needed to repopulate a whole decellularized human heart . While pThe clinical utilization of these fabricated sections of ventricular myocardium will likely be incumbent on the reliable generation of microvasculature and generation of a reliable conduction system as well.Biofabrication of ventricular myocardium has been propelled forward, especially in the past 6\u00a0years, through the advent of decellularization and recellularization techniques. Though there are competing methodologies to produce functional myocardium or augment dysfunctional myocardium, decellularization based methods uniquely provide organized, three-dimensional structural support, while preserving biophysical cues to instruct native or seeded stem cells to promote angiogenesis and differentiation into fully functional cardiomyocytes. The therapeutic potential of biofabricated myocardium stands to revolutionize the treatment of ischemic cardiomyopathy, and the last decade has introduced unique advancements in these methodologies, bringing the field closer to meaningful clinical translation."} +{"text": "Older adults face a unique challenge in maintaining their oral health due to an increased disease burden, polypharmacy, functional impairment and other reasons. The five papers in this symposium describe the oral health issues in various groups of older adults and discuss different approaches to improve oral health for older adults. Using data from the Population Study of Chinese Elderly in Chicago, the first paper examined the relationship between self-reported discrimination and oral health related quality of life and investigated how resilience mediated such a relationship among foreign-born older Chinese Americans. The second paper described the oral health concerns and related treatment needs in older adults receiving palliative care using a mixed method design. The third paper demonstrated how to use behavior change techniques to improve oral self-care skills of individuals with mild dementia and support their family caregivers. The fourth paper described a project that integrates the age-friendly health system's principles into specialty dental care to address healthy aging and oral health. This initiative helped prevent and change the false belief that aging inevitably involves deterioration in oral health. The fifth paper described the impact of COVID-19 on the management of oral health problems and access to dental care in older adults. Transformative changes in care delivery and the impact of vaccination on access to care was also explored. This symposium helps better understand the oral health needs in older adults and provides new evidence to improve oral health for these individuals."} +{"text": "Caring for a family member with dementia is particularly challenging. Unpaid family caregivers provide a significant amount of the care for aging relatives, and they provide the vast majority of long-term care. Family caregiving often results in negative effects, which compromises the caregiver\u2019s physical and psychosocial health. Social media support groups are an increasingly common venue for family caregivers supporting patients with dementia to exchange emotional, informational, and instrumental support. This study examined the utilization of social media support groups among family caregivers of patients with dementia during the pandemic. Using deductive thematic analysis, the use of social media support groups of family caregivers provide link to social interaction as a means when social distancing is enforced due to the pandemic. Family caregivers use social media support groups to share their personal experience, express their mood and feelings, offer prayers and positive quotes, keep up with the current events, gather information, and share feedback about dementia care services. Awareness of the potential advantages that social media support groups offer, healthcare providers can encourage family caregivers to use social media support groups as an empowering and practical platform. Further research is required about the long term benefit from social media support groups and the reliability and validity of the information that the family caregivers can get from the group."} +{"text": "Orbital compartment syndrome (OCS) is a rare ophthalmic surgical emergency in the setting of increased intraocular pressure (IOP) Irreversible vision loss can occur without immediate surgical treatment consisting of lateral cantholysis. We present a case of acute OCS discovered after cardiopulmonary resuscitation (CPR) with subsequent immediate lateral canthotomy and notable decrease in IOP. This in part demonstrates the importance of recognizing the clinical signs of OCS with or without trauma in the emergency department in addition with preparedness to perform a vision-saving procedure. Diagnosis is clinical and early recognition is essential. Index of suspicion for OCS in cardiac arrest without signs or history of trauma would typically be low, however, given the case presented, it was important for it to be excluded once the return of spontaneous circulation (ROSC) was achieved. The orbit typically holds a volume of 30 mL containing globe, fat, extraocular muscles, vessels, nerves, lacrimal gland, and lacrimal sac held within fascial compartments -3. The vA 57-year-old African-American male presented to the emergency department via emergency medicine service (EMS) with witnessed cardiac arrest. Patient reportedly was at work talking to a coworker when he collapsed and received immediate cardiopulmonary resuscitation (CPR) on scene. Patient was found in ventricular tachycardia arrest by EMS and received advanced cardiac life support (ACLS) protocol treatment with ROSC en route to the emergency department. Upon department arrival, the patient arrived with supraglottic device in place and remained unresponsive. No obvious signs of trauma were noted; however, the patient was noted to have leftward gaze with bilateral pupils responsive to light. The patient then went into ventricular tachycardia arrest upon being placed on department bed. CPR and ACLS protocol were initiated and continued for approximately three rounds when ROSC was achieved. Epinephrine drip was started and definitive airway was established. Soon after, the patient was noted to have spontaneous movements with opening eyes and was placed on Diprivan drip for sedation. While preparing for central line placement to the right internal jugular, it was noted that the patient\u2019s left eye became significantly proptotic and chemotic appearing without pupil reactivity to light. IOPs were then immediately measured with tonometer device demonstrating pressure of 35 mmHg to the left eye and approximate pressure of 8 mmHg on the right. Decision to perform cantholysis was made given these findings. There was concern of retrobulbar hematoma likely in setting eye trauma upon patient collapsing prior to cardiac arrest. Using materials from laceration kit commonly found in the emergency department, hemostat pressure was applied to lateral canthus using Kelly clamp and then careful dissection of lateral canthus was made using tissue scissor. Upper and lower eyelids were retracted for better visibility of the superior and inferior crux, which were both cut given the extent of proptosis and chemosis Figure . Post caIn this case, the patient presented in cardiac arrest without signs of trauma. On initial evaluation, the physical exam showed an unresponsive patient, supraglottic airway in place, and PERRLA bilaterally and leftward gaze. There were no findings or portion of the history of present illness that would have led us to include OCS within the differentials. Incidence of OCS is 0.88% for the average patient population . It is nPrompt action regardless of the mechanism was taken based on our physical exam findings. If globe rupture is unlikely, it is reasonable to delay imaging and opt to perform the procedure and preserve vision . This caThis case presentation demonstrates the importance of prompt recognition of OCS and preparedness to perform lateral canthotomy in the emergency department.\u00a0Although OCS may be extremely rare post-cardiac arrest and ROSC, routine repeat thorough physical exams are crucial in identifying OCS and performing lateral canthotomy in a timely fashion."} +{"text": "The COVID-19 pandemic has caused a health crisis for vulnerable older adults, physically and psychologically. Despite the urgent demand for clinical research for people with dementia, research activities are restricted due to the pandemic. This symposium will share the experiences of researchers conducting studies with older persons with dementia during the COVID-19 pandemic. The presenters share their strategies to overcome challenges at different stages of the study process during the pandemic. The research projects include work conducted in acute care, assisted living, nursing homes, and the community. The presentations include perspectives from different geographic areas and across countries in North America. The first presenter reports the challenges in continuing an ongoing research project, and shares strategies to engage stakeholders and plan a new protocol for recruitment and in-person data collection with residents with dementia in nursing homes. The second presenter reports on the barriers and facilitators of conducting an ongoing clinical trial with older adults with dementia across hospital and community settings and discusses strategies to meet project goals which include modifications to the protocol and analytic plan. The third presenter describes adaptations made to a study intervention designed to promote quality resident-staff interactions in assisted living and alterations to stakeholder engagement. The fourth presenter describes challenges and strategies to engage older adults with dementia via technology. The discussant will synthesize the findings across studies and highlight policy and research implications for the COVID-19 pandemic as well as other emergency situations."} +{"text": "We investigated how changes in erectile function and sexual satisfaction relate to cognitive decline in men from midlife into early old age. This is a major transitional period for increased incidence of erectile function and for cognitive decline. We examined 833 men from the Vietnam Era Twin Study of Aging whose mean ages were 56, 61, and 68 at the time of assessment. Erectile function and sexual satisfaction were measured using scores from the International Index of Erectile Function. Individuals with erectile dysfunction at baseline were excluded. Cognitive performance was measured using factor scores for separate domains of episodic memory, executive function, and processing speed. We tested linear mixed models hierarchically adjusted for demographics, sexual activity, as well as physical and mental health confounders to examine how changes in erectile function and sexual satisfaction related to changes in cognitive function. Declines in erectile function were associated with declines in episodic memory , while declines in sexual satisfaction were associated with declines in processing speed . Decreasing erectile function and sexual satisfaction may be indicative of individuals also likely to be facing cognitive decline. Possible mechanisms accounting for these changes may include white matter microvascular disease and/or various lifestyle influences. Discussing and tracking sexual health with middle aged men may be a crucial step in identifying those likely to face cognitive decline."} +{"text": "Older adults\u2019 civic participation has received considerable attention, but most scholarship has focused on formal volunteerism and voting. The literature shows that rates of voting and volunteering have been consistently lower among African Americans and Latinx older adults compared to their White counterparts. However, little research has explored civic participation in the context of historical structures of inequality that exclude these populations from participating in formal civic activities and continue to do so today. In addition, other civic activities are going unrecognized. To understand civic participation through the lens of Latinx and African American older adults I draw from intersectional life course perspective to contextualize participants\u2019 lived experiences across the life course and within historical and current socio-political space in which they live and participate. Study\u2019s findings could improve conceptualizations and measurements of civic participation for future studies, and inform efforts to support civic participation among these populations."} +{"text": "Dipender Gill and Stephen Burgess discuss the accompanying study by James Yarmolinsky and colleagues investigating the associations between genetically-proxied inhibition of antihypertensive drug targets and risk of common cancer subtypes using Mendelian randomization. PLOS Medicine by Yarmolinsky and colleagues [Proteins represent the majority of drug targets; therefore, genetic variants affecting the function or expression of genes encoding these proteins can be used as proxies for investigating the effect of pharmacologically perturbing the corresponding protein drug target . Random lleagues , geneticACE gene, the authors found genetic evidence supporting an effect of angiotensin converting enzyme (ACE) inhibition on increased risk of colorectal cancer in UK Biobank participants of European genetic ancestry. Through colocalization analyses, the authors went on to show that a shared variant within the ACE locus was likely to be related to both circulating ACE protein levels and colorectal cancer risk. This is a critical experiment for corroborating the findings of mendelian randomization analyses performed to investigate the effect of drug target perturbation because it provides evidence to support that any identified association is not attributable to genetic confounding through a variant in linkage disequilibrium [Using genetic variants related to blood pressure at the ilibrium . While tACE gene that associated with lower circulating ACE protein levels and lower blood pressure) was shown to be associated with increased ACE gene expression in the colon [While the observed association between genetically proxied ACE inhibition and increased colorectal cancer risk warrants further investigation , there ahe colon . Indeed,he colon . It is fhe colon . FinallyTaken together, these findings generated by Yarmolinsky and colleagues offer a number of potential insights and areas for future study. First, they raise the possibility that ACE inhibition may increase the risk of colorectal cancer, in turn highlighting the need for pharmacovigilance toward this association. Second, they offer possible mechanistic insight into the development of colorectal cancer, which may, in turn, reveal therapeutic opportunities. Third, the discrepancy in findings between individuals of European and East Asian genetic ancestry may suggest effects that are confined to specific ethnic groups, thus having implications for prescribing strategies.The work also demonstrates some of the progress that has been made over the last decade in genetic analyses investigating drug effects. The complementary application of drug target mendelian randomization and colocalization analyses by Yarmolinsky and colleagues was able to strengthen the genetic evidence for causality through investigating whether it is the same genetic variant that underlies the observed associations with the exposure and the outcome. Other methodological developments have further allowed for mendelian randomization studies to provide insight into interactions between drug effects , as well"} +{"text": "Porphyromonas gingivalis was confirmed as the etiological agent via biopsy. Subsequently, the family members reported that the patient had undergone a dental procedure 1 month before symptom onset. Because of a delayed surgical approach, the lesions progressed and the patient developed an ischemic vascular insult in the territory of the middle cerebral arteries , systemic hematogenous bacteremia , and direct venous drainage--Intracranial abscesses are treated by surgical drainage combined with antibiotic therapy (ceftriaxone and metronidazole)Dental foci should always be considered in the evaluation and treatment of intracranial abscesses of unknown origin."} +{"text": "Individuality is increasingly recognized as important and has become a focus of exploration in many fields that study behavior and other responses. Specifically in Animal Welfare where a variety of responses must be amalgamated comprehensively as animals adapt to stressors, animal individuality should be considered essential. The shift toward a focus on individuals (from group-level observations) has largely been driven by a growing awareness that differences between individuals can be consistent over time and across varied settings \u20134. With Campbell et al. looked at the impacts of different types of rearing enrichments on subsequent ranging behavior in free-range hens. Radio-frequency identification technology was used to track individuals across a flock cycle to show that the type of environment they were reared in, affected how much they utilized the range area as adults with rearing perching structures increasing range usage.Measuring the behavior of individuals in their current housing environments should consider long-lasting impacts of previous environments. Bari et al.. Regular external measures of bird welfare such as body weight, plumage coverage, and comb wounds showed that hen welfare was affected by their rearing environment with control-reared hens showing worse feather coverage with age. There was also a relationship with range use where hens that spent more time outside had better feather coverage.The impacts of rearing environments as well as subsequent individual variation in ranging behavior on hen welfare was further explored by Peixoto et al. assessed offspring of stressed hens for anxiety-like and fear responses. The behavioral tests demonstrated limited impacts of maternal stressors and impacts did not appear to be caused by corticosterone depositions. The greatest differences were found among varying genotypes demonstrating the importance of considering the overarching influence of animal strains on individual variation in behavior when drawing general conclusions based on a specific breed.Developmental impacts on behavior can even precede the rearing environment, occurring via maternal stress and hormone deposition in chicken eggs. Keshavarzi et al. analyzed GPS data to demonstrate that na\u00efve cattle in paddocks with a virtual fence were facilitated by their herd mates when learning the correct responses to this new technology that signals the presence of an invisible fence line via audio and electrical cues.While a focus on the individual is critical for direct understanding of behavior and welfare impacts, livestock animals are typically housed in groups and will thus be affected by those individuals surrounding them. McVey et al. examined the sequential order of dairy cows entering the milking parlor over a 6-month period using entropy as a tool to assess variance and the relationship to social and temporal correlates. Interestingly, cows at the front and rear of the queue proved to be most consistent, a feature reminiscent of classical concepts of dominance hierarchies. Further analysis using machine learning proved effective in relating the variables with productivity, health status, and behavior within the home pen.Advances in sensor technology and computational abilities often require novel statistical methods to ensure generated data is used most effectively. In an example of how large complex datasets can be analyzed using these novel methods, Chopra et al. examined the structural consistency of a commercial dairy herd using remote identification of pairs of cows within 3 meters of each other for more than 60 s. Proximity networks were then related to feeding-specific areas and the entire barn, as well as health status and productivity factors. The study employed applied network visualization and social network analysis to determine that associations of dyads were non-normal but rather related temporally and to specific barn areas.Similarly, Baur et al. described the development of a radiography protocol for assessing keel bone health in conscious laying hens. The radiographs distinguished between different types of fracture. They demonstrated that keel bone fractures are likely more common than was previously recognized, with 97% of the 150 birds studied having at least one fracture, showing that this method, which is easier to use on farm than other scanning technology, provides more detail and likely greater sensitivity than the common approach of physical palpation.Rokavec and \u0160emrov thus hypothesized that low body weight and high fear or stress would associate with bone condition. Although they did not find that low body weight or indicators of fearfulness and corticosterone levels in the feathers of younger birds predisposed them to bone deviations or fractures, such bone damage during lay was associated with lower concurrent open field activity and higher later sociality, posing questions about the causal relationships between putative indicators of fear, stress, social behavior and physical health in this species.Bone health in poultry is an example of how health outcomes can be linked with individual developmental and psychosocial factors. van der Zande et al. meanwhile, tested new behavioral analyses to quantify what they considered Dynamic Indicators of Resilience in pigs: measures of consistency in physical activity levels, automatically detected by ear tag accelerometers on piglets injected with Porcine Reproductive and Respiratory Syndrome Virus (PRRSV). They found that changes in skewness from pre-to post-injection predicted mortality risk, and that statistical tendencies suggested possible relationships between high variation in activity, as measured by the Root Mean Square Error (RMSE) in the days after the injection and its increase from pre-exposure levels, and clinical illness symptoms. This novel use of accelerometer data thus holds some promise for quantifying individuals' resilience to health challenges.Armstrong et al. who tracked over 400 hens using RFID technology and correlated this with responses to standardized behavioral tests and brain samples from a subset of the hens. The results showed that increased ranging behavior may stimulate cell proliferation, a measure of plasticity, in the rostral hippocampus, thus contributing to the cognitive benefits of outdoor access, and that overall proliferation correlated with a personality indicator, tonic immobility as a fear response.Finally, individual monitoring of behavior can provide insight into changes in the brain, as demonstrated by Overall, this body of research highlights the use of technology for precise data collection at the level of the individual and novel analysis methods to better understand factors that affect animal behavior and welfare as well as how these individuals are influenced by the groups they are housed within.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Efforts targeting biological aging pathways are advancing interventions which could extend healthy lifespan. Design of clinical trials to test such interventions necessitates an operational definition of healthspan, such as slowed accumulation or progression of multiple chronic diseases, functional decline, and disability. In this talk we explore these composite measures of healthspan proposed as outcomes for clinical trials in aging. This will be examined in example cases including multimorbidity and deficit accumulation frailty indices in an 8\u2010Year intensive lifestyle intervention trial, and an update on multimordbity, functional, and biomarker endpoints in the trial Targeting Aging with MEtformin (TAME). Through these examples we will explore issues related to effect sizes and statistical challenges related to composite endpoints. Finally, we will discuss the role existing and emerging biomarkers of aging in clinical trials in geroscience and summarize evidence linking biomarkers to clinically meaningful outcomes."} +{"text": "Studies of living children demonstrate that early life stress impacts linear growth outcomes. Stresses affecting linear growth may also impact later life health outcomes, including increased cardiometabolic disease risk. Palaeopathologists also assess the growth of children recovered from bioarchaeological contexts. Early life stresses are inferred to affect linear growth outcomes, and measurements of skeletal linear dimensions alongside other bioarchaeological information may indicate the types of challenges faced by past groups. In clinical settings, the impacts of stress on growing children are typically measured by examining height. Palaeopathologists are limited to examining bone dimensions directly and must grapple with incomplete pictures of childhood experiences that may affect growth. Palaeopathologists may use clinical growth studies to inform observations among past children; however, there may be issues with this approach. Here, we review the relationship between contemporary and palaeopathological studies of child and adolescent growth. We identify approaches to help bridge the gap between palaeopathological and biomedical growth studies. We advocate for: the creation of bone-specific growth reference information using medical imaging and greater examination of limb proportions; the inclusion of children from different global regions and life circumstances in contemporary bone growth studies; and greater collaboration and dialogue between palaeopathologists and clinicians as new studies are designed to assess linear growth past and present. We advocate for building stronger bridges between these fields to improve interpretations of growth patterns across human history and to potentially improve interventions for children living and growing today. Studies of living children demonstrate that early life stress impacts linear growth. Stresses affecting linear growth may also impact later life health, including cardiometabolic disease risk. Palaeopathologists also investigate if children and adolescents recovered from bioarchaeological contexts experienced growth disruptions due to early life challenges. In clinical settings, the impacts of stress on growing children are typically measured by examining height. Palaeopathologists are limited to examining bone dimensions directly and must grapple with incomplete pictures of childhood experiences that may affect growth. Here, we review the relationship between contemporary and palaeopathological studies of child and adolescent growth. We advocate for: the creation of bone-specific growth reference information using medical imaging and greater examination of limb proportions; the inclusion of children from different global regions and life circumstances in contemporary bone growth studies; and greater collaboration and dialogue between palaeopathologists and clinicians as new studies are designed to assess linear growth past and present. These steps may improve interpretations of growth patterns across human history and interventions for children living and growing today. Growth among infants, children and adolescents is an important component of ontogeny. Growth refers to changes in size, which are variable in absolute magnitude (distance) and rate of change (velocity), and result in variation in adult size . A full In this article, we focus on linear growth among children and adolescents across development. Intrauterine and infant growth are also impacted by genetic, endocrine and metabolic factors, potentially resulting in intrauterine growth restriction (IUGR) and compromises in postnatal growth and development , 22. HowInvestigating what constitutes a \u2018healthy\u2019 growth pattern and the factors that cause individuals to deviate from this pattern is essential for child and population health. Healthy growth and development may be defined as the interaction of physical, mental, emotional and social well-being during ontogeny ; howeverGrowth patterns may be altered through developmental plasticity and the canalization of essential organs . DevelopPalaeopathologists may assess growth among children and adolescents as well as adult body size and shape phenotypes as indicators of past stresses experienced during ontogeny . For exaPalaeopathological researchers may use archaeological or historical information to infer potential stresses, and examine skeletal remains to assess how people responded to diverse challenges, including socioeconomic changes , environClinicians will track whether an individual is following a normal linear growth trajectory and use this information to plan interventions and improve linear growth outcomes if faltering is observed . AdditioIn this article, we seek to further bridge the gap between linear growth studies of living children and those of children recovered from bioarchaeological contexts. Until the 1990s, bioarchaeological research had largely excluded children , meaningHere, we: review the methods currently used in both palaeopathological and biomedical research to evaluate linear growth trajectories among children and adolescents; identify new approaches that may harmonize methods across these fields; and identify future directions for research in both fields that may clarify how linear growth varies under diverse life circumstances.Human growth assessment allows clinicians to examine how environmental and genetic influences affect human body shape and size and represents a proxy for examining basic biological processes . Many eaThe predictability of linear child growth has allowed researchers to create normalized growth standards or growth reference data for clinical evaluations of child health. These standards are typically developed from longitudinal studies that track child growth across development. In the past, growth standards for different countries were produced in the form of centile charts . A centiA range of measurements can be collected from children to quantify linear growth. Height (or stature) is measured to create an estimate of growth velocity, with the understanding that a normal growth trajectory in height typically indicates good general health . Linear Measuring growth can be divided into three contexts: screening, surveillance or monitoring . In screComparisons of groups experiencing stress to growth standards or intra-population comparisons incorporating lifestyle information illustrate how growth may be compromised in different contexts. For example, height may vary in response to immune function , psychosPalaeopathologists use a range of techniques to assess linear child growth and factors that may have altered growth among past populations. When analyses are centred on adult human skeletal remains, standard osteometric methods are typically used to measure long bones directly . PalaeopPalaeopathological assessments are unable to track linear growth across an individual\u2019s childhood in a longitudinal fashion, as skeletal remains represent a \u2018snapshot\u2019 of a child\u2019s status at their time of death. This makes it difficult to calculate growth velocity or create true growth curves . Palaeopet al. [Studies may combine osteometric information, indicators of physiological stress, and archaeological information to see if childhood skeletal dimensions were affected by external factors. Researchers may compare children with and without skeletal markers of specific diseases or indicators of physiological stress to see if linear growth varies between these groups . Temporaet al. comparedet al. , 91. Skeet al. . Additioet al. .Cross-sectional linear growth information from bioarchaeological contexts may be compared to contemporary longitudinal datasets based on the principle that modern children likely experienced normal growth trajectories and represent a proxy against which past children may be measured. As most growth standards, such as the WHO growth standards , are derThe limitation of comparing measurements of skeletal elements to living height measurements may be reduced using modern studies where skeletal measurements of long bones with fused and unfused epiphyses across the entire ontogenetic series are available , 95. TheAs the Maresh dataset includes measurements of long bones with both fused and unfused epiphyses across a large developmental window, it has been extensively used as a comparator in bioarchaeology. Johnston was one However, there are issues with the use of the Maresh dataset in palaeopathology. The Maresh dataset is focused on Euro-American children from middle to upper-middle class backgrounds, which may not be wholly representative of the growth patterns expected among past or contemporary populations , 104. FoPalaeopathological studies of growth often include cautions around interpretation. There are persistent questions about whether comparing those who did not survive the stresses of childhood and those who did presents an interpretive challenge , 109. FoBiocultural information is limited in palaeopathology, but we can continue to focus on groups with clearer contextual narratives based on archaeological or historical data. An example of a recent study with a clear narrative is DeWitte\u2019s work on The above study reveals the nuance that can be achieved in palaeopathology by focusing on specific episodes in the past. This type of work could be readily compared to contemporary research with clinicians further exploring the relationship between menarcheal timing and bone growth longitudinally, allowing for an understanding of pubertal timing and linear growth that translates across centuries. Some palaeopathologists are advocating for stronger connections to clinical research to identify the factors that are most likely to impact skeletal growth to improve interpretations of past growth variability , 113. ItComparing the linear growth of living children to those from bioarchaeological contexts is challenging due to differences in sample composition, measurement techniques, biocultural detail, and issues with interpretations. However, such comparisons identify key factors affecting growth and development, refine interpretations regarding past groups, and may improve interventions for contemporary children. Here, we outline several approaches that may help bridge the gap between clinical and bioarchaeological skeletal growth research. Bioarchaeological contexts inherently limit the measurements that can be used to compare past and present children. However, contemporary medical imaging allows us to closely track skeletal growth among modern children in ways that complement bioarchaeological methods. We can address issues with the representativeness of current growth reference datasets by including a more diverse range of children in future studies. Palaeopathologists can collaborate with clinicians to develop datasets that incorporate survey questions designed to match the kinds of information available for past groups.Researchers are increasingly repurposing medical imaging technologies, such as dual-energy X-ray absorptiometry (DXA), magnetic resonance imaging (MRI) and computed tomography (CT), to track skeletal growth. DXA is primarily a means of measuring bone mineral density via low-level X-ray beams, but can also be used to assess body composition or monitor chronic medical conditions like anorexia nervosa . As the DXA has been used to update growth standards and investigate the impact of different diseases on child growth (see DXA may be used to create new bone-specific growth reference information to identify normal patterns of growth in contemporary children and explore different types of morphological assessments, such as intralimb proportions. Intralimb and interlimb proportions, which may be more nuanced indicators of early life linear growth restrictions , can be Traditional growth standards, like the Maresh dataset, contained limited diversity. Contemporary height growth standards incorporate children from a greater range of geographic and socioeconomic contexts to encompass a wider range of ontogenetic variation . HoweverWhilst researchers often seek to limit the variability within a study group to ascertain normal growth circumstances, we advocate for embracing the diversity of childhood experiences and contextualizing variability with a greater amount of biocultural information collected via survey or interview. By incorporating comprehensive lifestyle information into study surveys and moving beyond the creation of growth reference data based on healthy, wealthy children, clinical researchers can better understand how stressors such as malnutrition, psychosocial stress, socioeconomic status affect linear skeletal growth and body proportions. The creation of both population-specific bone growth standards for non-Western contexts and quantification of the range of variation that may arise under challenging childhood circumstances would greatly help palaeopathological researchers identify the most appropriate contemporary comparative group and see if growth variability observed in the past overlaps with the variability observed under present stressful conditions. Differences between children from different geographic regions or socioeconomic contexts may or may not be evident upon further investigation , 147; hoAs we increasingly acknowledge that \u2018normal\u2019 patterns may incorporate biases , clinicaGrowth studies among living children and children recovered from bioarchaeological contexts have provided a wealth of information. These studies identified normal growth trajectories and the environmental factors that cause deviations from normal patterns. However, clinicians and palaeopathologists would both benefit from the creation of new bone-specific growth reference data. Tools such as DXA could be used to assess multiple aspects of skeletal growth longitudinally with a low risk posed to children or adolescents. Incorporating a greater amount of lifestyle information and a greater diversity of children in new studies allows for clarification of the factors that shape bone growth and expand the observed range of variation in growth patterns among living children. These approaches would allow researchers to better characterize growth and when it falters in modern children and may provide more applicable reference datasets for palaeopathologists. Palaeopathologists can use this information to focus on archaeological contexts where factors that affect skeletal growth in contemporary studies are known to vary between subpopulations to clarify interpretations.We advocate for greater communication between those researching growth past and present. Palaeopathology and clinical research have the capacity to improve each other in meaningful ways and moving from siloed investigations of human biology is crucial to understanding the growing human body as an integrated whole. Projects that feature collaborations between these fields can improve investigations of how stressors moderate growth today; interpretations of how children may have negotiated stressors in the past; and outcomes for children growing in the future. We propose harmonizing methods of assessing skeletal linear growth across clinical practice and palaeopathology, allowing both specialties to expand and make more direct comparisons across human history and into the present."} +{"text": "Integration of ecological and evolutionary features has begun to understand the interplay of tumor heterogeneity, microenvironment, and metastatic potential. Developing a theoretical framework is intrinsic to deciphering tumors\u2019 tremendous spatial and longitudinal genetic variation patterns in patients. Here, we propose that tumors can be considered evolutionary island-like ecosystems, that is, isolated systems that undergo evolutionary and spatiotemporal dynamic processes that shape tumor microenvironments and drive the migration of cancer cells. We examine attributes of insular systems and causes of insularity, such as physical distance and connectivity. These properties modulate migration rates of cancer cells through processes causing spatial and temporal isolation of the organs and tissues functioning as a supply of cancer cells for new colonizations. We discuss hypotheses, predictions, and limitations of tumors as islands analogy. We present emerging evidence of tumor insularity in different cancer types and discuss their relevance to the islands model. We suggest that the engagement of tumor insularity into conceptual and mathematical models holds promise to illuminate cancer evolution, tumor heterogeneity, and metastatic potential of cells. SignificanceThe integration of ecological and evolutionary aspects holds promise for understanding cancer evolution and metastatic potential. Here, we suggest that tumors are evolutionary island-like ecosystems, that is, isolated evolutionary ecosystems with their heterogeneity shaped by features such as physical distance and connectivity between anatomical sites. We suggest that these features dictate the evolutionary and spatiotemporal dynamic processes in tumors and drive the migration of cancer cells. The analogy of tumors as insular evolutionary systems is a conceptual framework that can leverage extensive genetic and epigenetic aberrations observed in the genomes of cancer cells. The tumor island framework will enable us to explore the relationship between tumor heterogeneity and microenvironment and illuminate the metastatic potential of cells.\u2003\u2003\u201cIslands are reminders of arrivals and departures.\u201d\u2003\u2003\u2003\u2003\u2003\u2003\u2003\u2003\u2003\u2003 Ehrlich (1992)Cancer cells can move, spread, and form metastases at proximate and distant locales in the body . The forWe suggest that tumors are evolutionary island-like ecosystems (islands hereafter) that experience insularity and evolution like true islands inhabited by biological organisms. In this framework, molecular, histological, and morphological heterogeneity within and among tumors is a response to distinct features of insularity, such as physical distance, connectivity, and species\u2013area relationships. These features are fundamental properties that shape the diversity of islands experiencing founder effects, waves of migrations, and organismal evolution. We propose that similar features dictate tumor heterogeneity, drive migration of cancer cells, and lead to metastases. This is because there is emerging evidence that new tumors are seeded by one or more The analogy of tumors as evolutionary insular systems is a unique, conceptual approach that needs to be explored and integrated into mathematical and computational models being developed to study tumor evolution. Our proposed conceptualization follows the recent application of organismal biogeographic approaches into the investigation of cancer cells movements in a patient , 2021. Wcancer makes sense except in the light of evolution\u201d and the recipient area (island). Islands closer to the mainland harbor higher diversity than islands at a greater distance from the mainland. This is because new species are introduced to the adjacent island constantly , keeping a high dispersal rate between the mainland\u2013island ecosystems. This prompts the second hypothesis about the possible effect of physical distance between the primary tumor and subsequent metastases and its impact on tumor genetic divergence . Under tThe second hypothesis can be tested through the presence of isolation by distance (IBD) and of pOn the other hand, a low genetic distance between distant tumor samples will show the absence of IBD and no effect of physical distance on tumor heterogeneity. We also expect low or high tumor heterogeneity to be the result of the number of clones (single or multiple) and the presence of reseedings involved in the formation of tumors, because this type of migrations would contribute to tumors net genetic diversity. Considering the type and number of seedings between tumors will be critical when interpreting inferences related to the effect of physical distance on the overall tumor heterogeneity. Findings related to the presence or absence of IBD in tumors will be exciting as they would provide insight into the relevance of tumor heterogeneity to the specific tissues and organs where tumors manifest and indicate molecules or mechanisms specifically found there that might be contributing to tumor heterogeneity and driving cancer cell migrations.In addition, we expect intertumor heterogeneity to be primarily a function of past evolutionary events because clones that seeded a metastasis, and further diversified within tumors, will always have a much larger intertumor difference than clones that have evolved within tumors. This is similar to the expectation for natural populations in which divergence and diversity are thought to be primarily a result of past spatial isolation caused by physical distance and connectivity . This tyOf course, molecular evolution is driven by random mutations and genetic drift. By random chance, genetic differences will accumulate across the genomes of cancer cells in every tumor of the patient\u2019s ecosystem, causing genomic divergence and tumor heterogeneity. This leads to our third hypothesis that the observed tumor heterogeneity and divergence is primarily due to stochastic processes operating within tumors on existing and newly generated genetic variation. That is, the tumor area relationship, distance, and connectivity should have less influence on shaping tumor heterogeneity than random genetic drift and selection within tumors . In thisTesting these above hypotheses about tumor insularity will ideally require spatial (multiple regions and tumors) and longitudinal (over the course of the disease) sequencing data, along with information about the size and distances between tumor sites. Tumor data manipulation and interpretation will also require much attention because tumor data often suffer from incomplete sampling of clones per tumor region and anatomical location . This caFurther limitations might also arise due to a low number of sampled genetic variants or errors in tumor sequencing data , becauseWe anticipate that exploring and validating the three hypotheses proposed here will enable us to leverage unique features of tumors to interrogate patterns of tumor heterogeneity among patients and across cancer types. Moreover, validation of the first hypothesis will not necessarily reject the second hypothesis. This is because variation on tumor heterogeneity patterns could arise due to the size and carrying capacity of the tumor and the distance and connectivity between tumors. However, rejection of both these hypotheses could lead to validation of the third hypothesis and the detrimental effect of stochastic processes on tumor heterogeneity. Ultimately, modeling and predicting tumor insularity will enable finding cohesion and establishing shared and unique features among tumors and their heterogeneity, accommodating the spatial and environmental dimensions of tumors that are being ignored or not so well understood.Several methods and frameworks in organismal biogeography explore the physical distance and species\u2013area relationship while inferring origin and migration routes. These approaches leverage phylogenetic and evolutionary information and the location and sampling time information of the sampled sequences. Popular biogeographic methods include Bayesian Binary MCMC (BBM), BayArea, Dispersal Extinction Cladogenesis (DEC), and Dispersal-Vicariance Analysis (DIVA) table 1table 1.Recent studies showcase the usefulness of applying biogeographic approaches to exploring cancer cells\u2019 origin and evolutionary trajectories , 2021. MAnother interesting aspect of the application of biogeographic methods and frameworks in cancer is that these enable conceptualizing and modeling processes that are critical to consider while inferring the origin and trajectory of migrations: duplication (genetic divergence within an area), extinction, founder events, and migration . These pWe next discuss recent studies that reveal a spatial and temporal separation between tumors within a patient and how such evidence might indicate insularity in tumors. Recent data analyses of large cancer patient cohorts have reported extensive tumor genomic, histological, and phenotypic heterogeneity in different cancer types. Their review for their relevance to evidence of tumor insularity prompted us to categorize tumor ecosystems into islets, islands, and Archipelagos (box 1). Because cancer progresses over time and tumors are formed and cured in a patient, we anticipate that the tumor ecosystem may transform from one type into another. For example, cancer disease may begin in a patient as a tumor islet that becomes islands and forms an archipelago of tumors.Many cancer patients present with solitary primary tumors. We refer to these cases of tumor ecosystem as tumor islets because of the absence of recipient areas. Such cases have been reported in breast cancer , BarrettPrimary tumors and at least one surrounding or distant metastases are often identified in patients at the time of the first diagnosis. These patient cases will appear with slightly more complex tumor ecosystems with one or more recipient areas with limited connectivity between anatomical sites, which we call tumor islands. In these patient cases, we anticipate that tumor heterogeneity will be affected by the distance and degree of connectivity between anatomical sites. Indeed, studies show tumor heterogeneity to be the outcome of spatial and temporal separation between tumors in lung cancer , prostatSimilarly, studies on nonsmall cell lung cancer (NSCLC) show tumors exhibiting spatial and temporal heterogeneity and extensive isolation . In thesCancer patients frequently manifest multiple tumors at proximate and distant anatomical sites. The degree of connectivity between these anatomical sites, for example, via lymph nodes, may facilitate the migration of cancer cells and contribute to tumor heterogeneity. In these instances, tumors with both source and recipient areas (primary and at least two metastatic tumors) with an extensive degree of connectivity are present in the form of back-and-forth clone migrations. So, we expect a higher degree of complexity in tumor ecosystems that would lead to the formation of tumor Archipelagos.Indeed, there has been an ongoing discussion about the role of lymph nodes in formulating new metastases as in the metastatic progression in some cancer types. For example, a study on lung cancer showed evidence of correlation of lymph nodes to tumor relapse in specific histological subtypes and temporal isolation between primary and recurrent tumors during the progression of the disease . Two recThere is a growing body of evidence supporting the presence of high tumor heterogeneity within and among patients in all cancer types . At the"} +{"text": "Disaster preparedness among assisted living communities (ALCs) has not been widely researched, despite the growth of ALCs and evidence of disability in this population. An additional issue of concern is the way in which ALCs vary, including variation by size. The purpose of this paper was to explore the experiences of ALCs in Florida that experienced Hurricane Irma in 2017 and how experiences varied by ALC size. Qualitative interviews and focus groups were conducted with representatives of small ALCs and large ALCs . Transcripts were analyzed using Atlas.ti version 8, and research team members collaborated to reach consensus on codes and further analyze differences based on ALC size. Results suggest there are differences among ALCs in their disaster preparedness and response, and these differences are related to size . Implications for ALC resident wellbeing and future disaster planning will be discussed."} +{"text": "Postpartum weight retention (PPWR) is a strong predictor of obesity in later life with long term health consequences in women. Suboptimal lifestyle behaviours contribute to PPWR. Postpartum lifestyle interventions are known to be efficacious in reducing PPWR; however, there are challenges to their successful implementation. To inform implementation, this narrative review provides an overview of the factors that contribute to PPWR, the efficacy of existing postpartum lifestyle interventions and key determinants of effective implementation using the Consolidated Framework for Implementation Research (CFIR) across intervention characteristics, implementation process, individual characteristics and outer and inner setting. We then suggest strategies to improve the translation of evidence into large-scale interventions that deliver on health impact in postpartum women. We have identified gaps that need to be addressed to advance postpartum lifestyle research, including the involvement of postpartum women and community members as key stakeholders for optimal reach and engagement, more complete reporting of intervention characteristics to optimize translation of evidence into practice, capacity building of health professionals and guidelines for postpartum lifestyle management. The prevalence of overweight and obesity is on the rise globally, presenting a challenge to public health . In 2016A range of factors contribute to PPWR including lifestyle behaviours, sociodemographic and psychosocial factors. An understanding of these could help inform intervention development to address PPWR. Postpartum lifestyle interventions to date targeted mainly lifestyle behaviours without addressing other contributing factors. Despite these limitations, these postpartum lifestyle interventions have demonstrated efficacy in weight and lifestyle management as shown in previous meta-analyses ,17. HoweThis narrative review aims to inform implementation of postpartum lifestyle interventions in clinical practice. First, we provide an overview of the factors that contribute to PPWR and the efficacy of existing postpartum lifestyle interventions. Then, using the Consolidated Framework for Implementation Research (CFIR), we summarize the key determinants of effective implementation of postpartum lifestyle interventions across intervention characteristics, implementation process, individual characteristics and outer and inner setting. The CFIR is a comprehensive implementation science framework that guides the identification of factors that may influence implementation outcomes ,21. It iThe literature search was conducted in November 2020 using PubMED and Google Scholar databases. Key search terms were \u201cpostpartum AND postpartum weight retention AND \u201d. We included only systematic reviews of primary studies that examined the predictors of or factors associated with postpartum weight retention and postpartum lifestyle interventions with weight-related outcomes. To be included, interventions had to have occurred in the postpartum period, including those commencing during pregnancy. Only reviews published in English were included without limitation to the year of publication. The quality of the included studies was assessed using AMSTAR 2, a measurement tool to assess systematic reviews .Lifestyle behaviours, sociodemographic and psychosocial factors may contribute to PPWR . SociodeThere is generally a decline in healthy dietary behaviours from pregnancy through to postpartum ,30,31 T. Diet quIrregular sleep and meal times during the postpartum period could also interfere with body weight. Emerging evidence suggests that the misalignment of eating and fasting patterns with the circadian rhythm of the body could impact on metabolic function and consequently body weight . A recenPhysical activity levels are generally inadequate in postpartum women . The decSedentary behaviours may also be associated with PPWR. Oken et al. reported that women who watched fewer than two hours of television daily were less likely to retain \u22655 kg postpartum at 1 year postpartum . HoweverPsychosocial factors such as depression and anxiety are also predictors of PPWR . PreviouBox 1There is a decline in healthy dietary behaviours in the postpartum periodThere is a maintenance of light physical activity such as walking and a decline in moderate to vigorous physical activity in the postpartum periodDepression is positively associated with postpartum weight retention but not anxiety and stressShort sleep duration is positively associated with postpartum weight retentionThere is inconsistency in literature on the association of breastfeeding with postpartum weight retentionThere is inconsistency in the literature on the effect of breastfeeding on postpartum weight with systematic reviews reporting beneficial , negativBox 2Lifestyle interventions combining diet and physical activity components are efficacious for postpartum weight lossDiet-only interventions are efficacious for postpartum weight lossPhysical activity only interventions are inefficacious for postpartum weight lossDiet and physical activity behaviours are modifiable lifestyle behaviours that can be targeted for postpartum weight loss. Several systematic reviews have explored the efficacy of lifestyle interventions for postpartum weight loss ,80,81,82Implementation is critical to the effective translation of existing evidence on the efficacy of postpartum lifestyle interventions into practice and to allow delivery of sustainable health impact on a large scale. Identification of both the core and adaptable components for intervention effectiveness as described in the CFIR is an important step in the implementation of postpartum lifestyle interventions . The CFIBox 3Efficacious postpartum interventions should include dietary and physical activity components and be delivered by health professionalsNon-core intervention components that could be left to contextual needs of the target population include intervention intensity, duration, length, delivery mode and settingMore research is required to determine the optimal timing for the initiation of postpartum lifestyle interventionsThe total number of BCTs included and including the BCTs \u2018goal setting\u2019 and \u2018self-monitoring of behaviour\u2019 are associated with greater reduction in energy intake and improvement of physical activityIntervention characteristics refer to what the content of interventions are, why they are effective, how they are delivered, by whom, at what frequency, for what duration, in what setting and how well they are delivered to be most effective. The intervention characteristics associated with weight loss in postpartum women have previously been identified using the Template for Intervention Description and Replication (TiDieR) framework Table 2Table 2. There is no consensus on the optimal timing for the initiation of lifestyle interventions in postpartum women with timing ranging widely across studies from immediately post-birth to 18 months postpartum ,80,82. PPrevious interventions successful in promoting weight loss, dietary and physical activity behaviours have used a range of settings, including home-based and/or hospital clinic based ,93. The Behaviour change techniques (BCTs) are the active ingredients of interventions aimed at behaviour change which can impact on the effectiveness of the intervention ,105. IdeBox 4Penetration and participation are rarely reported in randomized controlled trials and needs to be the focus of future researchStudies with good penetration and participation rates were conducted within existing health services for postpartum women or involved recruitment during pregnancyAlthough the efficacy of lifestyle interventions in postpartum women has been established, their impact at the population level is determined by the program reach (penetration) and engagement (participation) ,107. TheBox 5Postpartum women face barriers unique to this life-stage relating to capability (e.g. tiredness and fatigue), opportunity and motivation (lack of confidence in their ability and lack of enjoyment of exercise)These barriers may result in low levels of engagement in lifestyle interventionsApart from including the core components identified in the previous section, it is important that interventions for postpartum women address the specific barriers to lifestyle management in this group. These barriers could hinder participation in lifestyle interventions and contribute to high attrition rates of up to 42% as reported in previous systematic reviews ,90,109. Determinants that influence engagement with lifestyle interventions beyond the individual woman include family and friends, cultural influence, health professionals, the built environment and socio-economic impact . The infSupport from health professionals play a key role in facilitating behaviour change in postpartum women. During pregnancy, women have regular contact with health professionals about both their health and the health of their foetus. However, health professional support in postpartum care is less regular and usually focused on breastfeeding and care of the child rather than on maternal health ,35,115. Box 6Health professionals play a significant role in providing lifestyle behaviour counselling and support for postpartum womenHealth professionals face barriers of limited time and skills to provide support to postpartum womenCapacity building of health professionals is required to ensure they are equipped to provide lifestyle support for postpartum womenClinical guidelines for postpartum care do not include lifestyle or behavioural counsellingThere is need for more research into the timing and frequency of postpartum visitsComprehensive clinical guidelines for routine postpartum care are limited and do not include recommendations for lifestyle or behavioural counselling ,117. GuiThe core components associated with efficacy of postpartum lifestyle interventions are: inclusion of both diet and physical activity components, delivery by healthcare professionals, use of electronic health technology, including more BCTs and embedding interventions in existing services. It is also important to train health professionals in time management and counselling skills to equip them to adequately support postpartum women. Including these components in the design while tailoring interventions to postpartum women\u2019s specific needs and addressing barriers may be effective strategies to improve penetration and participation and reduce attrition rate ,94. ConsConsidering the high prevalence of postpartum weight retention and the lack of translation of research evidence to practice on this topic, this review is an imperative for action to address implementation challenges through pragmatic, real-world trials for the effective translation of evidence into clinical practice to reduce postpartum weight retention. Future research should address knowledge gaps in terms of identifying the optimal timing for the initiation of lifestyle interventions. Randomized controlled trials of lifestyle interventions need to adequately report penetration, participation and other intervention characteristics to enable translation and replication of trials into practice. There is need for more research into the capacity building of health professionals to provide support and for a review of clinical practice guidelines for postpartum care to include lifestyle counselling."} +{"text": "The Research Topic on Myelin Plasticity in the Non Neuronal Cells Section of the Frontiers in Cellular Neuroscience aims to provide an overview and new perspectives on the myelin formation and repair mechanisms. New insights into the cellular process and advances in technological tools in this field could reveal novel therapeutic strategies that may lead to the development of new treatments for central (CNS) and peripheral (PNS) nervous system de-/dys-myelinating pathologies. This is timely work given the high impact of CNS and PNS demyelinating disorders and is expected to contribute to the prevention of severe disabilities that have a serious impact on a patient's everyday life as well as on the society. Myelin plasticity is also a key mechanism that is involved in repair processes, a major challenge in human disorders.The majority of myelin is formed postnatally in the rodents and by adulthood in humans. Although myelin plasticity in response to neuronal activity is an old observation, its extent has been appreciated relatively recently. It is now accepted that myelin can be shaped by environmental stimuli and undergo significant structural changes throughout life. This fine-tuning mechanism enhances neuronal function by orchestrating adjustments in myelin structure and axo-glial interactions. The potential link between this adaptive myelination and neuropsychiatric conditions is an active area of research.Ronzano et al. summarizes how neuronal activity shapes the myelination profile during life emphasizing key parameters of the myelination process such as oligodendrocyte progenitor (OPC) proliferation, maintenance and differentiation, axon selection and myelination pattern. The authors examine myelination in adulthood as an adaptive mechanism and lastly but importantly, discuss how myelination and repair are also modulated by other glial cells such as astrocytes and microglia.In the special Research Topic, the review by Bonetto et al. focuses on myelin plasticity during adult life and described new insights into the link between this plasticity, learning and behavior, as well as mechanistic aspects of myelin formation that may underlie myelin plasticity, highlighting OPC diversity in the CNS.The review presented by Murphy et al. analyzes experience-dependent changes in myelin content in the adult visual and somatosensory cortex. Using models and conditions that drive adult plasticity and myelin basic protein (MBP) expression modulation, the authors demonstrated that induced plasticity can directly control visual activity in visual cortex. Using a deprivation visual paradigm, they showed that MBP content increased in the non-deprived hemisphere, while it decreased in the deprived hemisphere suggesting that modulation of myelin expression in adult visual cortex may reflect the levels of visually driven activity.Traiffort et al. focuses on the important contribution of astrocytes and microglia in the myelination process in normal and pathological conditions. The authors discuss the mechanisms by which astrocytes and microglia influence developmental myelination and their interplay with oligodendrocytes. They then proceed in discussing both beneficial and detrimental roles of these two glial cell types in de- and remyelination.The review by Petratos et al. analyze one of the key mechanisms at play during neuronal injury, namely the Nogo receptor A (NgR1)-mediated signaling cascade during myelination. Nogo is recognized as one of the major myelin-associated inhibitors but its role in maintaining axo-myelin stability and receptor binding is not completely elucidated. The authors provide recent insights as to how neuronal NgR1 regulates myelin thickness under normal and pathological conditions with particular emphasis on the regulation of perinodal domains. They further discuss how NgR1 signaling can be targeted in animal models as a future potential therapeutic strategy.Deboux et al. have investigated the role of Slit1, a secreted axon guidance molecule also involved in adult neurogenesis, during myelin formation and in pathological condition. Using Slit1 deficient mouse, the authors showed that while Slit1 does not affect the normal developmental process of oligodendrogenesis and myelination, it regulates adult progenitor mobilization during remyelination by controlling cell migration and renewal within lesions.El Waly et al. describe an innovative method to characterize the cascade of cellular events involved in lysolecithin (LPC)-induced demyelination by combining intravital coherent antistoke Raman scattering microscopy with intravital two-photon fluorescence microscopy in multicolor transgenic reporter mice. Taking advantage of spinal glass window implantation, a longitudinal description of cell dynamics during focal and reversible demyelination in the same volume of interest over weeks could be obtained. The authors detected early oligodendrocyte injury followed by axon degeneration within 2 days after LPC incubation, amplified by the recruitment of peripheral proinflammatory cells at day 4. Recovery took weeks and involved a new wave of anti-inflammatory innate immune cells at day 14. Overall, the use of recurrent imaging provided new insights into the role of peripheral immune cells in regulating both the axonal and oligodendroglial fates during de- and remyelination.Finally, In conclusion, this special issue hosted manuscripts that highlighted several aspects of myelin plasticity both as reviews of current literature but also as original research contributions. They all provide insights into how myelin can be shaped throughout life under physiological or pathological conditions. We hope this collection of articles would be a useful contribution to the myelin field.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Neighborhood environment has been playing an important role in late-life health; yet, the social aspect of neighborhood environment and its impact on mobility limitations have been rarely examined. This study examines the relationship between neighborhood social cohesion and mobility limitations and the potential mediators of this relationship. A total of 8,317 Americans aged 65 and older were selected from the Health and Retirement Study. Using ordinary least squares (OLS) regressions, this study shows that neighborhood social cohesion is negatively associated with mobility limitations, and this association is mediated by depressive symptoms and mastery respectively. Specifically, neighborhood social cohesion can reduce mobility limitations through mitigating depressive symptoms and increasing mastery. The findings have implications for developing community measures to promote neighborhood social cohesion and applying psychosocial interventions to reduce depressive symptoms and improve mastery among older adults."} +{"text": "To review literature on the importance of caffeine intake with regard to psychosis. The need for intervention with regard to caffeine intake hinges on effectively recognizing potential risks.Caffeine is the most widely consumed psychoactive substance worldwide and as such is generally considered acceptable but as a competitive adenosine antagonist, it affects dopamine transmission. Patients with serious mental illness are known to have higher caffeine intakes than the general population. The hierarchy of needs for this patient population is complex, frequently leaving the intake of caffeine under the radar of clinical priorities.PubMed and Google Scholar search for caffeine/coffee and psychosis/schizophreniaOf the 43 articles that were considered relevant for clinical practice, caffeine consumption was associated with 1) appearance of psychotic symptoms and episodes (caffeine-induced psychosis) and chronic psychosis in high intake 2) exacerbation of psychosis in schizophrenic patients even in lower intakes, 3) treatment resistance possibly due to interference with antipsychotics (ex. clozapine), 4) abuse and addiction, 5) comorbidity with tobacco smoking and other addictions. Caffeine in low doses was associated with ameliorating cognitive and extrapyramidal side-effects of medication and as a potential treatment strategy for treatment-resistant schizophrenia.Caffeine consumption may have a greater impact on psychotic symptoms and episodes than is recognized with negative effects outweighing any potential benefits. Greater awareness of the necessity to quantify caffeine intake and implementation of interventions to curb intake may contribute to better quality of care of serious mental illness. Further research is warranted."} +{"text": "Xenopus laevis tadpoles. This intervention causes severe scoliotic deformations that remain permanent and extend into adulthood. Accordingly, the functional influence of weight-bearing otoconia, likely on utricular hair cells and resultant afferent discharge, represents a mechanism to ensure a symmetric muscle tonus essential for establishing a normal body shape. Such an impact is presumably occurring within a critical period that is curtailed by the functional completion of central vestibulo-motor circuits and by the modifiability of skeletal elements before ossification of the bones. Thus, bilateral otolith organs and their associated sensitivity to head orientation and linear accelerations are not only indispensable for real time postural stabilization during motion in space but also serve as a guidance for the ontogenetic establishment of a symmetric body.Vestibular endorgans in the vertebrate inner ear form the principal sensors for head orientation and motion in space. Following the evolutionary appearance of these organs in pre-vertebrate ancestors, specific sensory epithelial patches, such as the utricle, which is sensitive to linear acceleration and orientation of the head with respect to earth\u2019s gravity, have become particularly important for constant postural stabilization. This influence operates through descending neuronal populations with evolutionarily conserved hindbrain origins that directly and indirectly control spinal motoneurons of axial and limb muscles. During embryogenesis and early post-embryonic periods, bilateral otolith signals contribute to the formation of symmetric skeletal elements through a balanced activation of axial muscles. This role has been validated by removal of otolith signals on one side during a specific developmental period in The vertebrate vestibular system was implemented in pre-vertebrate ancestors as the principal sensor to detect self and passive body motion . MorpholThis lifestyle transition was made possible by the benefits arising from detection of changes in body orientation coupled with immediate transformations into motor commands that assist the retention of a stable posture within the environment. Vestibular signals optimally produce such reactions by driving posture-stabilizing reflexes . Early vXenopus laevis in the roll axis (Tonic otolith signals play a prominent role in the control of axial musculature. Though species-specific differences in individual endorgans do exist, e.g., saccular contributions to vestibulo-spinal pathways in cats and audioll axis . The loroll axis . Reductioll axis . Likely,oll axis . Though oll axis . Such a oll axis . Irrespeoll axis .Toadfish in microgravitational environments demonstrate an increased sensitivity of utricular afferents, a plasticity mechanism that potentially offsets a reduced otoconial impact on hair cell cilia and thus a decreased synaptic activity . The appXenopus remains unexplored, the conceptual consistency of normal gravity magnitudes as a relevant stimulus for bilateral utricular sensation and for proprioception is undoubtedly a key element for the establishment of a symmetric body shape. However, the emergence of a left-right asymmetry during development through an imbalanced activity of bilateral utriculo-spinal pathways or other major descending projections (Xenopus, is marked by skeletal elements that are sufficiently deformable by a constant asymmetric muscular pull and manifestation thereafter through ossification. This critical window probably varies between different vertebrate species, although functionally established vestibular circuits are likely a common prerequisite for inducing an asymmetry in body shape.Related plasticity mechanisms have been explored in models where asymmetry was engineered to arise concomitantly with the development of vestibular circuits and the inner ear. Embryonic rotation of the chick otocyst, which results in truncated utricular maculae, produce hatchlings with chronic head tilts and impaired walking . Despitejections obviousljections . The earThe vertebrate vestibular system detects motion and head orientation in space. Beyond its traditional role in driving stabilizing reflexes, continual signaling from endorgans about head orientation contributes significantly toward the developmental establishment of the body shape. Uncompensated signaling asymmetries from the periphery, particularly those mediated by otolith endorgans often initiate impairments in postural maintenance. The severity and permanency of such postural instabilities appear to have an effect on the developing skeletal geometry and likely contribute to deviations in the formation of a symmetric body axis. The time of appearance of such asymmetric signals during ontogeny guides this influence, with asymmetries early during a critical period in neurodevelopment driving long lasting geometric skeletal malformations. Contributions by otolith endorgans are potentially a primary force behind these developmental influences, largely evidenced by experimentally directed loss of function studies. Collectively, vestibular signaling therefore acts as guidance for the structural development of body shapes in vertebrates. Future insights will continue to benefit from multiple biological fields, ranging from preventative and restorative medicine to biomedical considerations of space flight/travel, where exposure to microgravity is at the moment inevitable. Determining the precise developmental periods where gravitational influences are prevalent is a necessary step along with a disclosure of the physiological mechanisms of their activation. Modern genetic and molecular techniques with expansion into targeted application to different otolith endorgans will undoubtedly help expand these considerations into the next decades.CG and HS wrote the manuscript and compiled the figures. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Gainful livestock farming requires selective breeding of animals with certain heritable desirable traits which gives profitability in terms of farm produce. Modern dairy animals are selected for traits which directly or indirectly contribute to high milk production. The concept of \u201cfeed conversion efficiency\u201d in terms of milk production is now vigorously taken up by researchers and farm managers for recognizing and breeding efficient milk-producing animals. The whole concept of economic farming thus requires identification of \u201celite\u201d animals, meeting above criteria as base population for the farm enterprise. Farmers and animal traders have been selecting best animals based on certain physical characters, which were also accepted by the breeding scientists as phenotypes. Data mining allows uncovering of hidden patterns in the data for better understanding of data relationship for developing suitable models for further improvements. Along with artificial intelligence techniques, data mining has opened new avenues for achieving high resource utilization efficiency and sustainable profitability in livestock production systems. The present review discusses and summarizes various data mining techniques and decision support systems for scientific dairy farming. The animal rearing has become highly competitive with narrow profit margins and therefore, there is increased focus on research for improving the efficiency of animal production. Proper selection of animals is the first and the most important step in dairy farming. Animal records, which can be utilized in data mining-based animal evaluation, form the basis of selection for breeding programs and/or a new dairy herd. For this, farmers need to be well informed about best practices in the selection of elite animals. It is not uncommon for the animal breeders to ask: Which is the best dairy animal? When an owner offers an animal for sale, he must be putting on animals that are being culled from the herd for undesirable traits. Therefore, the purchaser has to be well aware of the characters of a good animal.For any dairy setup, most common criteria for the selection of dairy animals for breeding, production and sale/purchase include \u2013Milk production potential \u2013 High milk yield is preferred because of higher economic returns it givesMilk composition \u2013 In India, fat content is a key factor in determining price of milk. However, in western countries, fat, protein, and solid not fat are considered. Buffaloes with high milk fat and protein content are preferred for Mozzarella cheese productionFertility \u2013 Animals with a pedigree history of regular breeding are desiredSex of the offspring \u2013 Female offspring is preferred for dairying while male is preferred for raising bulls for natural service or semen productionPerformance of the breed in the local environment \u2013 Better climate resilient breeds are preferredResistance against prevalent diseases \u2013 Disease resistant animals incur lesser expenses on healthcare and hence preferred over vulnerable animalsAge of the animal \u2013 Age of the animal determines the longevity of the animal in farm and hence its production life. Therefore, younger animals are preferredFeed conversion efficiency \u2013 It is an indicator of how efficiently the animal utilizes feed offered for conversion into animal produce . Thus, animals with higher efficiency will produce more with same amount of feed offered and hence selectedTrue to breed characters \u2013 These are indicative of good production potential and high resale valueDisposal of spent/unproductive animals \u2013 Cow slaughtering is not allowed in India but buffalo slaughtering is permissible, so spent/unproductive buffaloes realize higher price and therefore preferred by many farmers for dairy.A good farm animal is not universal and much depends on what you want and where you are. Researchers have used data mining tools on recorded data for the development of intelligent decision support systems. The present review provides an insight into the progress made with regard to finding smart computer-based solutions to various problems related to commercial animal farming.As elaborately above, for success of any dairying program, identification of the best animals is a prerequisite. Conventionally, farmers have developed certain assumptions with respect to good dairy characters and this indigenous technical knowledge has been passed on from generation to generation. Animal breeders and dairy managers have added a lot of information on scientific assessment of the animal for their selection. It has now been widely accepted that there is high level of correlation between physical characters (\u201cphenotypes\u201d) and the production potential of the animal. Farmers, animal lovers, researchers, and breeders have been following \u201cScore Card\u201d methods for various type of animals\u2019 selection during judging in animal championships. Scientifically, animals are evaluated in terms of heritability of characters and genetic gain in subsequent generations . GloballStatistical analysis of the historical animal production data and subsequently its data mining applications gave impetus to for developing smart dairying solutions including automation of operations. ANN and fuzzy logic are most important arithmetic tools that have been widely used in developing artificial intelligence (AI) for decision making machines. Introduced by Lotfi Asker Zadeh in 1965, fuzzy logic (or fuzzy rule) models are based on the principal of logic, which is similar to the human reasoning ability . The earMany studies have indicated higher accuracy of ANN and fuzzy system models for calculating breeding estimates: (1) First lactation 305-day milk yield -6, (2) fAutomation in milking at large-sized dairy farms facilitated accumulation of large volumes of accurate data and development of expert systems for its earliest detection of mastitis. Mastitis, affecting dairy production globally, is one of the most extensively studied dairy animal diseases. Early detection of mastitis helps in checking its further spread and minimizing chances of permanent udder losses. A fuzzy logic model for classification and control of mastitis was developed using a data set of 403,537 milking\u2019s from 478 cows . MastitiData science is of enormous importance in poultry production. A neuro-fuzzy algorithm \u2013 combination of ANN and fuzzy logic, for poultry feed formulation is a useful tool wisely used in African poultry industry . The algThe decision support systems help a setup in decision making processes by the use of computer-based models to identify and solve problems . DSS essDuring the last decade of twentieth century, a very basic DSS was developed for pasture-based livestock production . This moWith accumulation of scientific data over the years, better understanding of animal biology and recent developments in data mining applications, DSS for specific purposes are now in use in livestock production. Most DSS have been developed from simulation models using multiple computational methods.Nevertheless, these systems offer great benefit to the dairy enterprises by assisting decision-making process in the management programs. Efforts to develop an expert system for replacing human expert in dairy cattle judging by linear approach using data mining applications has been tried in Iran . JudgingComputational intelligence techniques have also been used for development of a decision support system in dairy cattle health management . Here, ASustainable dairy farming requires comprehensive decisions in husbandry practices for efficient utilization of resources, better health, and productivity. The software programming should enable us to manage a database consisting of every animal on the farm and utilize the database using data mining techniques and decision support systems. Advances in arithmetical systems have given rise to modeling farm situations close to real and therefore provide highly efficient DSS framework to the stakeholders. The tech-savvy dairy farmers are investing in computer-based tools and software products to improve farm economics through monitoring farm products quality and quantity, breeding management, feed \u2013 fodder and pasture availability, disease control, and prevention and environmental parameters in their surroundings. AI acquired through data mining techniques, decision support systems and algorithms are bound to make smart decisions for efficient and sustainable dairy production systems.SB: Did all the literature search and manuscript writing. RPS and APR: Read the manuscript and made corrections. All authors read and approved the final manuscript."} +{"text": "Long term care facilities (LTC) provide ongoing care for seniors and chronically ill. To maximize the quality of the care, LTC staff must be properly trained to respond to patient care crises and communicate across departments. Although researchers have studied the leadership styles, strategies and interactions of facility administrators and nursing directors there is a substantial gap in the literature on the leadership styles and strategies employed by Directors of Social Work (DSW). The aim of this phenomenological study was to address this gap in research by exploring how DSW influenced leadership policies, prepared subordinates for crisis intervention and management, perceived that social workers influence decision making in patient care, and believed that communication amongst LTC staff about patient care could be improved."} +{"text": "The current audit aims to assess the compliance with Prescribing Observatory for Mental Health (POMH-UK) guidance on monitoring of metabolic side effects of patients prescribed antipsychotics. Compliance was monitored to ensure that all patients prescribed continuing antipsychotics have their body mass index (BMI), blood pressure, blood glucose and lipids checked within the expected time limits of minimum once per year.Patients diagnosed with Schizophrenia rank amongst the worst of chronic medical illnesses in terms of quality of life. This may in part be due to the use of long term antipsychotic medications, in particular the use of atypical antipsychotics which have been increasingly associated with metabolic side effects including hypertension, weight gain, glucose intolerance and dyslipidaemia. These side effects are related to the development of both diabetes mellitus and cardiovascular disease and can lead to increased mortality and morbidity, affecting compliance and engagement to healthcare services. Despite the availability of clinical guidelines, monitoring and screening of metabolic side effects in patients prescribed antipsychotics continues to be suboptimal.The audit involved a review of electronic records relating to physical health monitoring of patients at two acute inpatient units from January-March 2019. Demographic and clinical variables were collected which included ethnicity, diagnostic grouping as well as current medications. Data were collected on evidence of screening for hypertension, BMI, blood glucose and lipids. Descriptive statistics were applied to study the clinical features of the sample and examine whether performance met clinical practice standard.The audit overall demonstrated partial compliance with POMH-UK guidelines with a total of 31 patients admitted on long term antipsychotics. Of these patients, 86% were prescribed atypical antipsychotics with 14% prescribed typical antipsychotics. Screening only occurred in 68% of patients for lipid profile with only 71% for BMI and 74% for blood glucose. Blood pressure had the highest compliance rate of 87% of patients being screened.Early identification and monitoring of complications from metabolic syndrome may decrease the risk of more serious health outcomes and improve patients\u2019 quality of life. However in clinical practice, standards are not always met in accordance with best practice recommendations. Requirement of a tailored guideline for physical health monitoring with weekly planned interventions as well as adequate training and awareness of healthcare staff is imperative to drive improvement and increase adherence rates."} +{"text": "Emerging evidence suggests a significant functional role of adipose tissue in maintaining whole-body metabolic health. It is well established that obesity leads to compositional and morphological changes in adipose tissue that can contribute to the development of cardiometabolic disorders. Thus, the function and size of adipocytes as well as perfusion and inflammation can significantly impact health outcomes independent of body mass index. Lifestyle interventions such as exercise can improve metabolic homeostasis and reduce the risk for developing cardiometabolic disorders. Adipose tissue displays remarkable plasticity in response to external stimuli such as dietary intervention and exercise. Here we review systemic and local effects of exercise that modulate white and brown adipose tissue cellularity, metabolic function and remodeling in humans and animals. Moreover, smaller adipocytes have been shown to be protective against metabolic decline is associated with increased rates of development and mortality from cardiovascular disease and various cancers . While t decline and adip decline . AdiposeAdipose tissue is a complex organ composed of different cells and niches that control key processes including adipogenesis, adipokine secretion and inflammatory responses. While mature adipocytes are the main functional cells regulating lipid uptake and release, they only constitute a fraction (about 20% in humans) of the cells contained in this tissue . Other cEffects of exercise on adipose tissue cellularity in rats have been observed as early as the 1970\u2019s. This early work highlights the potential of exercise to favorably modulate adipose tissue cellularity, with exercising groups consistently presenting with smaller adipocytes in white adipose tissue . These eIn comparison to the work in animal models described above, evidence for an effect of exercise on adipose tissue cellularity in humans is lacking. This is likely due to limitations in obtaining adipose tissue biopsies, especially in VIS fat pads. Additionally, investigators are finding that the physiology of adipose depots in mice may not directly translate to human adipose tissue . In compde novo recruitment and differentiation (adipogenesis) of APCs. Recruitment and differentiation of preadipocytes is believed to be protective against metabolic decline by limiting cell hypertrophy, hypoxia, and adverse tissue remodeling. It has recently been demonstrated that functionally distinct populations of APCs exist in adipose tissue of mice and humans , treadmill exercise in high fat diet (HFD) mice resulted in an increase in preadipocytes in brown adipose tissue (BAT), with increased adipogenic capacity of UCP1 . Further of UCP1 . The autThere are three primary types of adipose tissue that have been very well characterized: white adipose tissue (WAT), brown adipose tissue (BAT) and beige adipose tissue. WAT has long been thought of as an energy storage depot with the primary function of storing excess lipids. It is now well established that WAT functions as an endocrine organ, secreting various adipokines that affect whole body metabolic homeostasis and normal adipose tissue function is disrupted with obesity . BAT is It has been consistently reported that diet-induced obesity results in a significant decrease in angiogenesis and capillary density in white adipose tissue . This anMdm2 expression increases in both SUB and VIS fat in trained mice and knockdown of Mdm2 in vitro resulted in a decrease in capillary growth following adrenergic stimulation (In animal models, one study found that exercise training in obese rats resulted in improved vessel density in both SUB and VIS fat when compared to sedentary obese animals . Interesmulation . In compmulation . In contmulation . While iObesity is known to cause increased fibrosis in adipose tissue which has been linked to metabolic dysfunction by limiting the healthy expansion of adipose tissue . Minimal+ T cell in adipose tissue with obesity (Infiltration of inflammatory immune cells in adipose tissue has be extensively studied and is known to contribute to obesity-related inflammation and insulin resistance . Exercis obesity . While w obesity . MechaniImmune infiltrates in response to exercise have not been extensively studied in BAT when compared to WAT, however, one study found that exercise training in mice resulted in increased BAT mass and anti-inflammatory gene expression , suggestThere are well documented effects of exercise on mitochondrial activity ,b, gene The effects of exercise on BAT are less clear in comparison to WAT adaptations. Considering that both exercise and BAT increase thermogenesis and energy expenditure, some have hypothesized that exercise may downregulate BAT to maintain body temperature . One stuExercise improves adipose tissue cellularity, stimulates angiogenesis, and improves metabolic function of WAT . Also, eJG wrote the manuscript. SB critically revised the manuscript. Both authors approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Housing insecurity, or limited/unreliable access to quality housing, is a powerful chronic stressor that can negatively affect individual health and well-being. This study extends prior research by examining the effect of multiple forms of housing insecurity on both the mental and physical health of aging adults using the Midlife in the United States study . Participants reported on experiences of anxiety/depression in the past year, number of chronic health conditions experienced in the last year, and experiences of housing insecurity since the 2008 recession . 14% of participants reported experiencing one or more housing insecurity events in the aftermath of the recession. Higher levels of housing insecurity were experienced by midlife participants (ages 46-65) and black participants. Regression results showed that, even when controlling for prior health, housing insecurity was significantly associated with higher odds of experiencing anxiety/depression and additional chronic health conditions. These results suggest that housing insecurity experiences are fairly prevalent among midlife and aging adults, and that housing insecurity experiences leave these adults susceptible to compromised mental and physical health. This work has various implications for policy around addressing housing access and affordability issues for aging adults as a public health concern. Subsequent analyses will examine age, gender, and race/ethnic differences in these associations between housing insecurity and health outcomes."} +{"text": "Mexican Americans live longer on average than other ethnic groups, but often with protracted cognitive and physical disability. Little is known, however, about the role of cognitive decline for transitions in IADL disability and tertiary outcomes of the IADL disablement for the oldest old. We employ the Hispanic Established Populations for the Epidemiologic Study of the Elderly to investigate the longitudinal patterns of IADL decline using Latent Transition Analysis. Three IADL groups were identified: independent (developing mobility limitations), emerging dependence (limited mobility and community activities), and dependent (limited mobility and household and community activities). Declines in cognitive function were a consistent predictor of greater IADL disablement, and loneliness was a particularly salient distal outcome for emerging dependence. These results highlight the social consequences of cognitive decline and dependency as well as underscore important areas of intervention at each stage of the disablement process."} +{"text": "There is a paucity of research that seeks to understand why race disparities in health across the life course remain elusive. Two such explanations that have been garnering attention is stress and discrimination. This symposium contains papers seeking to address the impact of discrimination or stress on African American health or health disparities across the life course. Brown and colleagues examine the differential effects of chronic stress exposure by means of latent class analysis on mental and physical health in the HRS. Analysis revealed four subgroups, each demonstrated a typological response pattern with the most pronounced health consequences for high stress exposure, appraisal and few or no coping mechanisms. This suggests an alternative approach to examining the stress-health link by using a combined person- and variable-centered approach. Thomas Tobin and colleagues evaluate the life course processes through which early life racial discrimination (ELRD) and racial centrality shape adult allostatic load (AL) among older Blacks in the Nashville Stress and Health Study. Findings indicate that racial centrality is protective against adult high AL for those who experienced racial discrimination as children or adolescents. Cobb and colleagues examine how multiple attributed reasons for everyday discrimination relates to all-cause mortality risk among older Blacks in HRS. The authors report the 3 or more attributed reasons for everyday discrimination is a particularly salient risk factor for mortality in later life. This collection of papers provides insights into how discrimination or stress impacts African American health or health disparities in middle to late life."} +{"text": "Shared decision making (SDM) has been acknowledged in the last decade. Literature has shown that when physicians are engaged in SDM and form a relationship with their patients, there is higher patient satisfaction of care. Moreover, SDM has been reported to improve patient outcomes and clinical measures. Despite this clear benefit of implementing SDM into clinical practice, there is little evidence for including SDM learning into preclinical medical education. We integrated an exercise for second year medical students to practice the steps of shared decision making. In this paper, the quantitative and qualitative results from a survey of medical students following the SDM learning exercise will be discussed. Students were more educated regarding SDM after this exercise and were motivated to use it in their future clinical careers. They also expressed overall positive attitudes towards SDM tools such as decision aids. Feedback to improve this SDM learning experience included the use of standardized patients, and to expand such education to the clinical environment training. This research provides a model of SDM practice integration into medical education. Similar programs can be beneficial for the development of SDM and other interpersonal skills. The patient-physician relationship has evolved from a paternal model into a collaborative shared decision-making (SDM) relationship. Shared decision making (SDM) is an approach where clinicians and patients make decisions together based on patients\u2019 preferences and values while utilizing the best available evidence. SDM has been associated with higher patient satisfaction of care and enhanced performance on clinical measures ,2. SeverIntegration of SDM courses into undergraduate medical education has been effective in improving medical students\u2019 skills, confidence, and attitudes regarding SDM . Most ofWe describe our approach to integrate SDM introduction, training, and assessment in to second year medical students\u2019 education.Our SDM session included an introductory didactic teaching followed by a role-play exercise and survey questionnaire. The didactic segment focused on AHRQ\u2019s SHARE approach and included the slides and videos from the training module 1 .AdaptedSubsequently, medical students performed role-play exercises in the clinical skills area of the medical school Simulation Center. The role play was conducted amongst the students within their established case-based learning small groups. Patient, physician and observer triads of students participated in the exercise with different clinical scenario scripts see and prac96% of the students answered the SDM knowledge questions correctly. 81% agreed or strongly agreed that the session was helpful in adding to their knowledge and practice of shared decision making. Student feedback included consideration of Standardized Patients in future. 96% of the students agreed that performing shared decision making is realistic regardless of time constraints and 84% felt that SDM can be done with patients regardless of their level of education and comfort in discussing medical treatment options. 100% of our student participants agreed that having resources which summarize the risks and benefits of treatment options such as decision aids will be helpful in successful implementation of SDM.In summary, following SDM training and exercise, our students felt more knowledgeable with increased comfort regarding the practice of SDM and were motivated to use it in their future career. The patient\u2019s education level and time constraints were not of great concern to the students. Feedback to improve this SDM learning experience included the use of Standardized Patients, and to expand such education in the clinical environment. Our students favored a combination of didactics and practical exercise for their SDM education. These findings can inform both undergraduate and graduate medical education curricula as we strive to enhance teaching and experience of our learners in incorporating patient engagement into clinical decision making. As the patient population in the USA becomes increasingly diverse, performing SDM with all patients regardless of their education level or understanding while keeping their preferences and values in mind has the potential to enhance patients\u2019 trust in the health care system, increase uptake of care recommendations and improve clinical outcomes.This project has several limitations. Didactic component of our training was brief with selective discussion of one of AHRQ\u2019s SDM modules. We did not use a comparison group or pre and post analysis and we did not replicate similar training during clinical years or assess the retention of SDM knowledge and skills.Future direction of our project includes expansion of similar exercise into clerkship curricula to reinforce the skills and practice. Familiarity and comfort with utilization of decision aids are also of paramount importance. Clinical decision aids have been shown not only to increase patient knowledge, but also to increase the level of shared decision making without lengthening the duration of the encounter . Thus, sIn conclusion, a structured approach to enhance medical students\u2019 ability, interest, practice and comfort in taking patients\u2019 perspective by incorporating SDM training and assessment in the medical education curriculum has the promise of promoting patient engagement in health care decisions and quality of care delivered."} +{"text": "Microcirculation is the system that brings oxygen and nutrients to local cells and removes metabolic wastes. The study of the structure, function, and adaptation of the microvascular system plays an essential role in understanding cardiovascular diseases . ResearcUnder pathophysiological conditions , structural and functional adaptations of microvascular networks and erythrocytes can be quantified using novel imaging technologies and advanced quantification metrics, such as multispectral and hyperspectral imaging and optical coherence tomography. Asaro and Cabrales propose Macular degeneration is one of the most popular applications of microvascular research. Shu et al. investigSkin is the most accessible organ . ResearcThe microvascular dynamics assessed by LDF provides a novel way to diagnose the underlying mechanisms of microvascular dysfunction caused by the endothelial, neurogenic, and myogenic controls . Bau et Finally, Nikolov and Popovski review tThis Special Issue elucidates some new aspects of microvascular dysfunction as well as novel applications using microvascular dysfunction as the disease state. These new studies provide new insights into microvascular dysfunction as well as its potential role in diagnosing various diseases."} +{"text": "The aim of this review is to systematically investigate simulation in psychiatry to enable the evidence based introduction of psychiatry simulation into the undergraduate curriculum at the University of Liverpool.Transformations in the structure of psychiatric delivery and reductions in funding to mental health care have limited the availability of direct patient clinical experiences for medical students. Experiential learning through simulation can be utilised as a powerful pedagogical tool and provide exposure to a broad range of psychopathology.Although psychiatric skills and knowledge are gained from the current University of Liverpool undergraduate curriculum, there is no specific well-designed psychiatry simulation.The author searched MEDLINE, EMBASE and PsycINFO databases for studies that met the inclusion criteria. Search terms included \u2018simulation . Studies were also searched using snowballing via citation tracking within the databases.Inclusion criteria comprised studies of an educational intervention that involved simulation. The intervention had to be utilised within the field of psychiatric teaching.The literature review illustrated the dearth of studies analysing role-playing (RP) and/or simulated patients (SP) in psychiatry with it typically encountered as part of the more general communication skills curriculum. Studies analysing SP and RPs demonstrate how they build on the social context of learning alongside drawing on a range of educational theories, including experiential learning. However, studies show that well-designed simulation training should encompass more facets of learning to be transformative, specifically reflecting upon ones experiences alongside understanding and interpreting this new knowledge, allowing it to guide future actions and change practice.Studies analysing virtual-reality in psychiatry are limited but demonstrate significant improvements in students\u2019 acquisition of key psychiatric skills and exposure to psychopathology. More studies are needed to evaluate the efficiency and cost-effectiveness of virtual-reality over more traditional methods.Despite the increase in simulation teaching within psychiatry, and the expansion of innovative simulation approaches in other specialties, there was limited use of novel approaches found within the studies analysing psychiatric simulation. There were studies evaluating novel approaches to psychiatry simulation outside of the undergraduate curriculum.Whilst there are barriers to overcome in simulation training, these are primarily logistical and are clearly outweighed by the educational gain demonstrated throughout this review. Simulation training in psychiatry has often remained limited to traditional communication-oriented scenarios using RP or SP. A greater emphasis on furthering the advancement and integration of more innovative approaches into psychiatric undergraduate teaching is needed."} +{"text": "Our study indicates a strong backscattering increase in the upper part of the cervical epithelium caused by dysplastic microstructural changes. Quantization of relative depth-dependent backscattering is confirmed as a potentially useful diagnostic feature for detection of precancerous lesions in cervical squamous epithelium.A fiber optic imaging approach is presented using structured illumination for quantification of almost pure epithelial backscattering. We employ multiple spatially modulated projection patterns and camera-based reflectance capture to image depth-dependent epithelial scattering. The potential diagnostic value of our approach is investigated on cervical Nevertheless, current endomicroscopy systems are capable of resolving the morphology of single nuclei and cells with decent image quality.\u2013in vivo microscopy devices is, however, suited only for small-area inspection. Furthermore, image interpretation by an experienced clinician during or after image capture is necessary.The \u2013\u2013An alternative yet more indirect way of measuring tissue microstructure is to study the tissue\u2019s light-scattering properties. Several theoretical and experimental studies suggest that the microscopic and submicroscopic refractive index variations within the cell are the dominant sources of cellular scattering, rather than the shape of the cell and that of its organelles.\u2013Several experimental tissue studies report significant cancer-induced changes in the reduced scattering coefficient \u2013\u2013Most cancers originate from epithelium, and, therefore, early detection of cancer by optical means must focus on the optical properties of superficial tissue layers.,,The above-mentioned diffuse optical imaging modalities are mostly designed as point probes and often have limited control over the actual penetration depth related to their signals. Especially for layered tissue with a mostly complicated tissue structure, this undermines the quantification and analysis of isolated epithelial scattering. In spite of reportedly high sensitivity and specificity values for detection of precancer,In this study, we report a new endoscopic imaging modality for detection of surface scattering, which allows for imaging of almost pure epithelial scattering contrast through the use of structured illumination. Similar to spatial frequency domain imaging (SFDI)2SFDI and SIM both employ projections of laterally structured illumination patterns and thereby achieve imaging depth control. The two approaches operate in different projection frequency regimes. SFDI typically uses frequencies in vivo detection of precancerous conditions.Our approach aims at the intermediate frequency regime of about in vivo imaging techniques require ease and flexibility of use and need to address specular surface reflections, which frequently impair quantitative imaging. Our system design is an adaption to these needs and utilizes a flexible image guide for projection and detection of light. Apart from high optical sensitivity, Monochromatic two-dimensional light patterns (256 gray levels) with sinusoidal modulation along one axis and iso-intensity along the other axis are produced by a digital light projector at a wavelength of The incident light pattern interacts with the microscopic tissue structure and is in part diffusely backscattered into the image guide. The fiber projection and detection numerical aperture in air has been measured to be Both projector and CCD camera are computer controlled via USB using a custom-built software, and image capture is projection-synchronized by a trigger connection. This allows for an imaging and projection frame rate of about 15 images per second.3The benefit of structured illumination lies in the possibility to subtract the diffuse imaging background caused by deeply penetrating light. Propagation depths of diffuse light in tissue for near-infrared light typically range a few millimeters.,We demonstrate the subtraction of background scattering with the help of mage see quantifyIn order to increase the dynamic range of reflectance images, we perform The small imaging field of view as constrained by the dimensions of the image guide gives rise to considerable boundary effects.To allow for absolute comparison and quantification of reflectance intensities, every tissue measurement is accompanied by a measurement of a freshly diluted emulsion of Intralipid .In order to select spatial frequencies with penetration depths corresponding to that of cervical squamous epithelium, we performed numerous Monte Carlo simulations. Spatial frequency domain reflectance can be most efficiently modeled by Monte Carlo simulations using a point source along with one-dimensionally binned photon detection. We sketch such a simulation geometry in As indicated in For Monte Carlo simulations in the studied frequency regime, an optimization that aborts photon migration beyond a certain depth was used to enhance the signal-to-noise ratio of the simulation result. At the same time, we used such an optimization to study the signal penetration depth by monitoring the change in reflectance with different depth constraints.The penetration depth, especially for the lower spatial frequencies, is observed to depend on the assumed scattering phase function Photon paths in As can be anticipated from the studied photon paths, there are two major influences on epithelial backscattering. The probability for high-angle backscattering as quantified by the scattering phase functions of epithelial scattering particles is one of these major influences. The second major influence is the number of epithelial scattering interactions corresponding to the quantity and cross-section of scattering particles. This second influence is quantified by the scattering coefficient In It is also possible to expand the employed frequency regime to lower frequencies for solving the inverse problem. However, unknown layering properties of the epithelium and the underlying stroma accompanied by strong heterogeneity of tissue render this approach infeasible. Nevertheless, we employed this strategy for measurement of polystyrene particle suspensions and for Intralipid emulsions and achieved separation of scattering intensity It might occur to the reader that there is the possibility of measuring a phase shift between the projected and reflected sinusoidal light pattern due to the oblique projection in connection with the obliquely polished fiber end. Contrary to intuition, the image guide is almost insensitive to any phase shifts, as the axes of projection and detection coincide and as the detection aperture is small. Therefore, light featuring a single or few scattering interactions can hardly induce phase shifts, as it has to exit the medium in a direction almost parallel to the fiber axes to allow for detection following colposcopic examination and a preceding abnormal Pap smear result. Patients were in the age range of 25 to 60 years and had consented to the use of their tissue for biophotonic imaging prior to histopathology processing. The diameter of tissue samples was ,We performed During a time interval of Subsequent to imaging and before immersing the sample in formalin, LEEP samples were marked with a line of ink to later facilitate co-registration of histology and DOM.Histopathologic analysis was performed by a board certified pathologist following tissue sectioning and slicing according to a specified radial sectioning protocol. Based on the pathology report and histologic images, diagnostic maps could be created for each LEEP specimen. However, the lateral localization uncertainty of every point measurement of in situ (AIS), and cervical intraepithelial neoplasia of different grade . AIS relates to the dysplastic or precancerous state of columnar epithelium. In its benign state, columnar epithelium is formed by a single layer of cells. Columnar epithelium mostly lines the endocervix, which is characterized by glandular surface structures and subsurface ducts or cysts. Parts of columnar epithelium are often hidden from the surface due to the undulating tissue structure, and potential lesions may thus be occluded by the overall tissue irregularity.The six diagnostic categories are benign columnar (BC) epithelium, benign squamous (BS) epithelium, adenocarcinoma CIN 1 to 3 are lesions associated with squamous epithelium, which are diagnostically grouped into low-grade squamous intraepithelial lesions may qualify the imaging modality also for developing countries with the highest incidence of cervical cancer and high associated mortality.The heterogeneity of cervical epithelium including metaplastic and glandular tissue structures states a major difficulty for the interpretation of imaging data. Larger imaging fields of views enabled by a wider image guide or a potential noncontact colposcopic or endoscopic implementation may help with the overall differentiability. DOM allows for fast and near-real-time imaging and our setup achieved an AC image frame rate of five images per second. However, lateral scanning during capture of successive phase images produces considerable artifacts in derived AC images. Faster imaging and fewer required phase projections may help in reducing these artifacts, thus allowing for rapid inspection of large tissue areas. Further image quality improvement is possible by enhanced suppression of internal specular reflections within the optical setup by using a microscope objective designed for epi-illumination and a camera with higher dynamic range.We hope that our imaging modality will find use in further tissue studies, potentially confirming the sensitivity to high nuclear density in cancer and in other epithelial dysplasia."} +{"text": "Self-sovereign identity (SSI), an identity management system where individuals own and manage their digital identity, can improve access and management of one\u2019s personal data. SSI is becoming feasible for the general public to use for their health and other personal data. Like any data system, when persons living with dementia no longer have capacity to provide informed consent, guardianship over their data is required. The purpose of this study was to examine the concept of guardianship within the context of SSI, specifically its application to persons living with dementia. This study followed a qualitative description approach. Seventeen semi-structured virtual interviews were conducted with persons living with dementia and care partners to elicit their perspectives on existing guardianship practices and guardianship within the context of SSI. Interviews were digitally recorded and transcribed verbatim. Conventional content analysis guided the analytic process. Participants had mixed impressions of existing guardianship practices. While some were positive, others thought existing practices failed to consider the complexity of caring for someone with dementia . Participants suggested that SSI has the potential to improve the security and safety of persons living with dementia who have had guardianship enacted Recommendations included ensuring that SSI guardianship processes are simple and flexible, building a user-friendly system that also considers the heterogeneity of persons living with dementia and their care partners. Overall, guardianship within the context of SSI was well received. Findings will be used to further inform the SSI guardianship processes."} +{"text": "Soil-transmitted helminth infections (STH) remain among the most common pathogens infecting humans globally However, because these programs are designed to target only populations at high risk of morbidity, a large reservoir of infection persists in untreated adults and non-school going children. There are important implications that result from these persistent reservoirs of infection. In many settings, STH control programs will need to be maintained indefinitely, or at least until substantial reductions in poverty and improvements in infrastructure are achieved. In addition, microscopy-based diagnostics currently utilized by STH programs are highly insensitive, particularly for the detection of low-intensity STH infections. The combination of continued transmission of infection within communities, sustained drug pressure from repeated mass drug administration and a failure of current diagnostics to accurately identify infection poses substantial risks to population health.The Lancet Region Health \u2013 Western Pacific, Colella and colleagues describe the results of a survey conducted across ten villages in Cambodia in which samples were collected to ascertain hookworm infection prevalence In a recent issue of These results demonstrate that cure rates are dramatically overestimated when relying on microscopy-based diagnostics. Other studies have also determined that the risk of misclassification due to poor diagnostic performance of microscopy-based diagnostics is greatest for hookworm spp Finally, the failure to correctly identify infection in treated populations may have important consequences for decisions related to stopping STH treatment programs. Increasingly, there is interest in identifying strategies to interrupt transmission using alternative anthelmintic treatment strategies. Mathematic models suggest that transmission interruption may be possible in some geographic settings by treating entire communities with multiple rounds of anthelmintic drugs at high coverage and compliance JLW conceived of and wrote all content included in this commentary.I have received grant funding from the Bill & Melinda Gates Foundation for work related to STH transmission interruption and to the development of qPCR based methods for STH identification.The authors declare no conflict of interest."} +{"text": "The World Health Organization working group focused on nutrition as a key component of disease prevention, indicating that \u201co years\u201d . In theio years\u201d , was devo years\u201d .However, a greater controversy exists in the scientific community regarding the role of nutrition on the onset and progression of mental diseases and behavioral problems, and it is unclear how diet may contribute to therapeutic efficiency regarding patients with diverse psychopathological states. Unfortunately, strategies based on making diet changes and sticking with them are often overlooked in treatments for mental health conditions.In the following sections, we review current studies that analyze the role of specific diet components in the interventions addressed for common mental disorders in developed countries among children and adolescents. Since the psychopathologies considered in this review have elevated risk of comorbid health hazards, the evidence-based interventions for psychiatric patients covering proper nutrition could promote large-scale physical and mental wellbeing. Furthermore, the results of these intervention programs could provide the basis for developing targeted disease prevention programs aimed to reduce modifiable risk factors.Attention-deficit/hyperactivity disorder (ADHD) is a chronic neurodevelopmental disorder whose etiology is the result of complex interactions between multiple factors, including genetic, biological and environmental influences. The disorder is usually diagnosed when a child is of school age, with a worldwide prevalence estimate of 6% during childhood , and perThe standard intervention for ADHD combines pharmacological treatment (largely psychostimulants) with psychological therapy. The beneficial short-term efficacy of such treatments in reducing acute core symptoms is largely verified, but the long-term effects are not clearly evidenced: most patients may still show ADHD symptoms and may not attain normalized behavior even with combined medication and behavioral therapy, which results in frequent medication nonadherence (around 50% within months 12 to 36 of the follow-up). Current studies on alternative interventions for ADHD aim at the prevention of ADHD progression and targeting the underlying triggers . On the basis that making adequate lifestyle changes to minimize these triggers could contribute to better control of ADHD symptoms, studies addressing the efficacy of nutrition on the developmental course of ADHD have observed that deficiencies in certain types of foods can worsen the symptoms of attention deficit, hyperactivity and impulsivity, while adequate dietary plans could optimize brain functions. Most of these treatment studies are focused on exploring the role of vitamins, minerals and polyunsaturated fatty acids , with coResults obtained by a current systematic review reinforce the effectiveness of ADHD treatments with complementary diet interventions, although the benefits could be different for subgroups of patients with different profiles. Concretely, the study of Granero and colleagues focused The systematic review of H\u00e4ndel et al. was centered around assessing the contribution of using polyunsaturated fatty acids in the treatment plans of ADHD children and adolescents, obtained from randomized clinical trials . Based oAn open trial conducted by Yorgidis and colleagues explored the role of oligoantigenic diet (OD) as a therapeutic tool within ADHD children and obseOn the other hand, some studies have also assessed the role of caffeine exposure within the ADHD profile and as a therapeutic tool. Since it was observed that both chronic and acute exposure to caffeine impacts the central nervous system modulating neuronal pathways, the possible existence of a link between the modulation of these neurotransmitters and the development/attenuation of neuropsychiatric outcomes is supposed. Animal research has observed that non-toxic doses of caffeine elicit neuro-pharmacological actions by blocking adenosine A receptors in the brain, which leads to the blockade of adenosine kinase and a decrease in the release of adenosine . Since aStudies have identified a strong link between persistent stress and several adverse effects on the body\u2019s immune, neuroendocrine, cardiovascular and central nervous systems . UntreatMedical intervention (benzodiazepines and antidepressants) plus cognitive behavioral therapy is considered the gold standard intervention for depression and anxiety states. However, in some cases, these treatments are not effective, induce severe side effects (mostly medications) or are not recommended due to the patients\u2019 characteristics . This scenario guided the search for new interventions for assisting in the prevention and management of anxiety-depressive illnesses, with less risk of side effects. Since the prerequisite to developing adequate evidence-based clinical guidelines is to assimilate dietary patterns and identify the biological mechanisms of action of critical nutrients , studiesDietary changes and nutritional supplementation may also be beneficial in improving treatment response and quality of life among patients with depression and anxiety. The comprehensive scoping review conducted by Aucoin and colleagues , with a The meta-analysis of Berthelot and colleagues selecting randomized controlled trials concluded that fasting interventions, compared to control groups, achieved lower anxiety and depression levels, and it was also useful to decrease body mass index levels . The benThis set of results are consistent with established evidence regarding healthy eating patterns and improvements in anxiety and depression states and the benefit of complementing the classic treatments with dietary interventions according to the specific needs of each patient. The low cost and the high effectiveness of these complementary plans may also confer additional benefits to physical aspects of health . It is known that some mental health conditions, such as those included within the autism spectrum, could severely impact the appetite and food choices . Autism A current empirical study aimed to explore the dietary patterns and nutrient intakes of ASD children compared to a healthy control group observedHowever, most interventions used to treat dysfunctional eating behaviors within the ASD spectrum are aimed to increase the volume of food consumed, and few consider increasing the variety of foods and addressing protein\u2013energy\u2013micronutrient deficiencies ,37. OtheProblems related to nutrition are often overlooked in patients with common mental health disorders towards interventions focused on medication complemented by behavior/psychotherapy treatments. Current research within the nutritional psychiatry area provides evidence regarding the role of nutrition and diet on these psychiatric conditions and offers a basis for developing new evidence-based intervention plans from a multidisciplinary perspective. Given the multifaceted and complex nature of mental and neurodevelopmental problems, the onset at early ages of the child (particularly for ADHD and ASD) and its persistent presentation across development stages (from early childhood to older age), the findings of these works could also contribute to the elaboration of guidelines/recommendations for improving the caring capacity of healthcare practitioners and family caregivers. In the end, improving the nutritional status of the patient will contribute to the individuals\u2019 wellbeing and facilitate better progression of medical conditions. However, the design of effective dietary plans is based on the existence of reliable and valid assessment tools. Unfortunately, the current evidence does not propose nutritional assessment instruments specifically developed for individuals with different mental disorders . Nutritional psychiatric research warrants additional attention and effort, combining varied methodologies and analyzing larger groups . Therefore, based on the existing research, dietary markers , biochemical indexes and anthropometric evaluation should be key components of these measurement tools.As a final thought, the study of how nutrition and mental health are linked is a growing research area, and the results obtained so far are highly promising. The ultimate objective is to facilitate new strategies for improving the quality of life and health of people with mental illness and to prevent the onset, aggravation and negative impacts of diseases."} +{"text": "Geriatrics Workforce Enhancement Programs (GWEPs), funded by the Health Resources and Services Administration have a strong focus on age friendly care and community engagement. With a wide range of populations, locales, and health systems served, GWEPs have significant experience working with a wide variety of communities to implement age friendly care. In this symposium, we present successes and lessons learned from GWEP projects representing diverse populations and approaches to achieving age friendly communities. For instance, one GWEP is utilizing Patient Priorities Care to lay the framework for What Matters in clinical decision-making. Another GWEP is focusing on What Matters by uniquely embedding Area Agencies on Aging care coordinators within primary care settings to invite the participation of aging patients in advance care planning, among other health interventions. A third GWEP is using the 4Ms to educate patients and caregivers in geriatric psychiatry clinics in a population of veterans. Another GWEP is pairing Age Friendly Health System efforts within a health system with community-based efforts to become an age friendly and dementia friendly city. A final GWEP is using multiple educational modalities to create Age-Friendly Communities and assure that health systems, community-based organizations, and older adults and families are educated about the 4Ms. By exploring successes and lessons learned in making communities age friendly, we can improve existing and future programs centered on age friendly care for older adults."} +{"text": "With the increasing growth rate of older persons and a rise in related illnesses in Ghana, it is vital that health practitioners are equipped with geriatric-oriented knowledge and expertise to provide the needed services to geriatric patients. The purpose of this study was to examine (i) the differences in the level of geriatric-focused educational preparation between graduating medical and nursing students in a Ghanaian public institution, and (ii) the association between educational preparation and students\u2019 beliefs about providing care to geriatric patients. The study hypothesized that students with more positive beliefs will be linked to higher educational preparation. Descriptive and inferential statistics were conducted (n=136 students). Findings show significant differences in the educational preparation of medical and nursing students . Graduating nursing students, comparatively, had higher educational preparation than medical students . However, there was no significant association between students\u2019 educational preparation and their beliefs about geriatric care. The findings underscore the need for extensive or more focused training. Further, the association between beliefs and educational preparation warrants further exploration. The need to examine the social cultural environment within which the research participants reside are discussed."} +{"text": "CO2 can be sequestered by engineered photosynthetic microorganisms and used for chemical production, representing a renewable production method for valuable chemical commodities such as biofuels, plastics, and food additives. The main challenges in using photosynthetic microorganisms for chemical production stem from the seemingly inherent limitations of carbon fixation and photosynthesis resulting in slower growth and lower average product titers compared to heterotrophic organisms. Recently, there has been an increase in research around improving photosynthetic microorganisms as renewable chemical production hosts. This review will discuss the various efforts to overcome the intrinsic inefficiencies of carbon fixation and photosynthesis, including rewiring carbon fixation and photosynthesis, investigating alternative carbon fixation pathways, installing sugar catabolism to supplement carbon fixation, investigating newly discovered fast growing photosynthetic species, and using new synthetic biology tools such as CRISPR to radically alter metabolism.Biological chemical production has gained traction in recent years as a promising renewable alternative to traditional petrochemical based synthesis. Of particular interest in the field of metabolic engineering are photosynthetic microorganisms capable of sequestering atmospheric carbon dioxide. CO One strategy used to harness the excess energy being lost by the PETC in cyanobacteria involved overexpressing the protein OmcS . This ston 2973) .2 in the process. As much as 30% of energy produced by photosynthesis has been observed to be lost through photorespiration in plants cycle and the tartronyl-CoA (TaCo) pathways natively possesses photomixotrophic machinery to assimilate glucose. A recent study was able to improve these photomixotrophic conditions through the installation of the NOG pathway along with targeted gene knockouts to increase the intracellular concentration of acetyl-CoA, thereby improving the growth phenotype of 6803 have risen in popularity as they are faster growing than the traditional S. elongatus PCC 7942 (hereon 7942) and have been shown to produce higher titers of target chemical products under certain circumstances by using dead Cas9 (dCas9) . While tE. coli . While tWhile many challenges remain and must be overcome to enable widespread adoption of photosynthetic chemical production hosts, the above studies suggest that there are myriad avenues of research that can get closer to this goal. The renewed interest in the field due to the ongoing climate crisis has spurred efforts to improve and adopt these microorganisms as a sustainable alternative for traditional petroleum-based synthesis. Many of the challenges in this field revolve around the intrinsic inefficiencies of carbon fixation and photosynthesis. While engineering RuBisCO remains an interesting target for improving carbon fixation, it has proven to be highly resistant to traditional engineering and decades of research would suggest that it is next to impossible to improve. Focusing on engineered carbon fixation pathways is a more promising route towards improving the carbon sequestration ability of cyanobacteria. Other research into improving the efficiency of photosynthesis by introducing alternative pathways downstream of the PETC for the production of chemical products is a prime example of how we can engineer these microbes to make full use of excess reducing potential from the PETC. The aforementioned approaches aim to enhance our understanding of the inefficiencies related to carbon fixation and photosynthesis while also representing some of the more novel approaches being undertaken by the field of synthetic biology. The discovery of new synthetic biology tools and investigation into faster growing cyanobacteria is also expanding the field of photosynthetic microbial research to make photosynthetic microorganisms a more viable alternative to petroleum based chemical production.de novo carbon fixation pathways capable of operating in parallel to the Calvin-Benson cycle and RuBisCO holds great promise for circumventing the inefficiencies of carbon fixation in cyanobacteria. Multiple carbon fixation pathways operating in tandem could exponentially increase the amount of CO2 sequestered by cyanobacteria and greatly enhance growth and product formation. The process of carbon fixation is a highly regulated process, and this strategy will likely face further challenges before successful implementation. Overall, it is highly likely that the optimal route for improving the conversion of CO2 into valuable chemical commodities in cyanobacteria lies in exploiting multiple of the aforementioned strategies contained within this review (Of the discussed challenges for synthetic biology in cyanobacteria, improving the rate and efficiency of carbon fixation seems to be the most difficult, however, this task also holds the most promise. While RuBisCO is resistant to direct engineering strategies, adding additional carbon fixation modules can enhance the viability of cyanobacteria as a chemical production chassis. Further research into s review .As new synthetic biology tools become available for cyanobacteria, high throughput screening will allow for rapid progress to be made within this field. The advent of CRISPR technology has had profound effects on research in a wide variety of fields but is relatively new to cyanobacteria. Additionally, faster growing species of cyanobacteria are rising in popularity and more have yet to be discovered. While these newly discovered cyanobacteria are efficient production hosts in their own right, they also inform the field on future targets for modification. Understanding the inherent differences among these organisms is vital to improving our understanding of carbon fixation and photosynthesis. It stands to reason that research into discovering more of these faster growing species, as well as studying the known cyanobacterial variants will provide insight and guidance for future work in this field. While improving photosynthetic production hosts has been historically difficult, the studies described in this work point to a promising future."} +{"text": "This symposium will showcase life course and aging research that is possible using freely available integrated census and survey data available via IPUMS. This session is organized by the Network for Data-Intensive Research on Aging (NDIRA) initiative at the University of Minnesota\u2019s Life Course Center. NDIRA seeks to build and support an interdisciplinary community of scientists leveraging powerful data resources in innovative ways to understand health outcomes at older ages, as well as the demography and economics of aging. The session features papers that illustrate how to examine aging-related topics including health at older ages, work and socioeconomic conditions, and living conditions with a common thread of examining heterogeneity within groups. These papers all leverage freely available census and nationally-representative survey data, highlighting the potential value of these data for studying aging and the life course. By combining papers on an array of topics from a variety of data sources, this symposium highlights exemplar papers that demonstrate the types of novel research possible using public use census and survey data that NDIRA seeks to foster."} +{"text": "All authors declare that they have no conflict of interest.SM and NS\u2010C designed and wrote the manuscript.To the editor,The metabolic health of adipose tissue and skeletal muscle is critically intertwined with the overall health of the human body. Muscle and adipose tissues\u2019 functional decline will bring a series of metabolic and health problems with aging, including adipose and muscle inflammatory infiltration and insulin resistance (IR), ultimately leading to the metabolic syndrome (MetS). Accumulating evidence suggests that the balance of adipose tissue and muscle metabolism is essential for health.Adipose tissue redistribution and ectopic fat deposition, which involves subcutaneous adipose tissue degenerative atrophy and inflammation, visceral adipose tissue (VAT) expansion and exhaustion and lipid infiltration into visceral organs and muscles , occur during the course of obesity.Excessive hyperlipidemia will upregulate fatty acid oxidation (FAO) in myocytes and fibro\u2013adipogenic progenitor (FAP) cells, the intermediates and side products of which can regulate cell fate by regulating epigenetic modifications,At the physiological level, obesity and sarcopenia often coincide during aging,Aging is the net result of a functional decline in various organs and tissues, and systemic IR/inflammation\u2010induced senescence is an important factor that triggers this deterioration. Once the vicious cycle of Metabaging occurs, it will become increasingly difficult to reverse, because the interactions between multiple organs and tissue systems make the systemic IR/inflammation situation increasingly more complicated and interlinked. Regular exercise could help stimulate and maintain mitochondrial homeostasis through mitohormesis, so that myocytes which make up ~40% of our body mass can counter and resist the lipotoxicity more avidly, and also increase their secretion of beneficial myokines,"} +{"text": "Informal caregivers provide substantial practical and emotional support for individuals with chronic and acute conditions. Consequently, many experience caregiver burden and are at high-risk for psychological morbidity and associated breakdown in the provision of care for care recipients. Many psychosocial interventions have been designed to help caregivers. However, more work is needed to identify which, or what kind of, interventions are optimal for identifying suitable strategies and care management. The main objectives of this symposium are to (1) address psychosocial and demographic factors contributing to caregiver resilience, (2) understand the role of cognitive and behavioral factors that have implications for caregivers\u2019 psychological well-being, and (3) specify different caregiving styles and adaptive outcomes. This symposium assembles a panel of experts and brings together empirical research on various challenges that need to be addressed and potential opportunities for creating effective psychosocial intervention targets for caregivers. The first session will discuss several psychosocial and demographic factors associated with resilience among caregivers. The second session will share how caregiving appraisals are closely related to positive and negative affect and whether the level and changes in caregivers\u2019 activity participation moderate this linkage. The third session will identify caregiving styles and strategies utilizing k-modes machine learning analysis and share how caregivers adapt to care situations. The final session will present caregivers\u2019 stress experiences related to dementia patients\u2019 behavior and psychosocial symptoms in dementia during the day. The session will conclude with Dr. Zarit, who will integrate the four papers and offer insight on implications across studies."} +{"text": "Housing insecurity, or limited/unreliable access to quality housing, is a powerful chronic stressor that can negatively affect individual health and well-being. This study extends prior research by examining the effect of multiple forms of housing insecurity on both the mental and physical health of aging adults using the Midlife in the United States study . Participants reported on experiences of anxiety/depression in the past year, number of chronic health conditions experienced in the last year, and experiences of housing insecurity since the 2008 recession . 14% of participants reported experiencing one or more housing insecurity events in the aftermath of the recession. Higher levels of housing insecurity were experienced by midlife participants (ages 46-65) and black participants. Regression results showed that, even when controlling for prior health, housing insecurity was significantly associated with higher odds of experiencing anxiety/depression and additional chronic health conditions. These results suggest that housing insecurity experiences are fairly prevalent among midlife and aging adults, and that housing insecurity experiences leave these adults susceptible to compromised mental and physical health. This work has various implications for policy around addressing housing access and affordability issues for aging adults as a public health concern. Subsequent analyses will examine age, gender, and race/ethnic differences in these associations between housing insecurity and health outcomes."} +{"text": "While epithelial-fibroblast interactions are viewed as the primary drivers of Idiopathic Pulmonary Fibrosis (IPF), evidence gleaned from animal modeling and human studies implicates innate immunity as well. To provide perspective on this topic, this review synthesizes the available data regarding the complex role of innate immunity in IPF. The role of substances present in the fibrotic microenvironment including pathogen associated molecular patterns (PAMPs) derived from invading or commensal microbes, and danger associated molecular patterns (DAMPs) derived from injured cells and tissues will be discussed along with the proposed contribution of innate immune populations such as macrophages, neutrophils, fibrocytes, myeloid suppressor cells, and innate lymphoid cells. Each component will be considered in the context of its relationship to environmental and genetic factors, disease outcomes, and potential therapies. We conclude with discussion of unanswered questions and opportunities for future study in this area. Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable condition defined by the radiographic and histopathologic pattern of usual interstitial pneumonia (UIP) in the absence of an identifiable cause or exposure . With a Parenchymal fibrosis is proposed to originate from prolonged or perpetuated alveolar epithelial injury . This evThe clinical features of IPF provide very limited insight into associated immune factors. Diagnostic criteria for IPF are essentially the presence of a pattern consistent with Usual Interstitial Pneumonia on chest imaging or lung biopsy in the absence of an identifiable cause. Compared to other ILDs, IPF lungs contains fewer inflammatory cells and chest imaging contains very little of the ground glass opacities that are typically reflective of inflammation . FeatureImmune responses are dichotomized into innate and adaptive processes. The former component, which is the focus of this review, is currently understood as a rapid and programmed response to chemical or physical stimuli and the latter being a specific response to a particular antigen. While abnormalities in both components have been described in IPF, the available evidence suggests a pathogenic contribution of innate immunity whereas the role of adaptive immunity is less clear. Thus, this review will focus on the innate immune processes that could contribute to IPF.Fibrotic immunopathology has been reported in the context of pattern recognition receptor (PRR) activation. PRRs respond to the physical or chemical structure of their respective ligands to initiate and in some cases perpetuate host defense. PRR-activating structures derived from microorganisms are termed \u201cpathogen associated molecular patterns,\u201d or \u201cPAMPs\u201d and substances generated by tissue injury are called \u201cdanger associated molecular patterns,\u201d or \u201cDAMPs\u201d . AnotherPathogen associated molecular patterns. While not viewed as an infectious process, several lines of evidence derived from animal and human studies support a connection between IPF and microbes. The contribution of viral and bacterial PAMPs has been explored as follows fluid and lung tissues inflammasome activation in IL-1\u03b2 associated fibrosis in the bleomycin mouse model . Recent 9 (TLR9) which al9 (TLR9) . In fact9 (TLR9) and exce9 (TLR9) . The inf9 (TLR9) , heighte9 (TLR9) and it iAs the first line of defense against invading pathogens, cells of the innate immune system have important roles in host defense and tissue homeostasis. The best studied cells in the context of IPF are macrophages and neutrophils, though more recently described populations such as fibrocytes, myeloid-derived suppressor cells (MDSCs), and innate lymphoid cells (ILCs), may also be involved. It is worth noting that stromal populations such as fibroblasts and epithelium also demonstrate innate immune functions but becaMacrophages are both the major antimicrobial phagocytes in the lungs and central mediators of fibrotic lung disease , is increased in IPF BAL . The invFinally, an additional fibrogenic neutrophil function is the formation of extracellular neutrophil traps. These highly inflammatory aggregates of chromatin and neutrophils regulate activation of immune cells and fibrTo summarize, neutrophils could participate in IPF through their production of soluble mediators, regulation of epithelial injury, control of ECM turnover, and formation of NETs. . HoweverFibrocytes are bone marrow-derived cells displaying characteristics of leukocytes, hematopoietic progenitor cells, and fibroblasts. Viewed as originating from monocytes, they are found in the systemic circulation from which they migrate to areas of tissue injury and participate in wound repair are a heterogenous population of myeloid origin first observed in cancer patients. Despite their reported heterogeneity, MDSCs share the common function of contributing to regulatory T cell (Treg) expansion and, subsequently, suppressing T cell activation and proliferation. Pathologically, there is an increasing evidence of MDSCs being involved in non-malignant inflammatory diseases including fibrotic disorders (isorders . Specifiisorders . Along tisorders . The vasisorders . The recisorders .Innate Lymphoid Cells are recently identified lymphoid cell populations distinguished by their lack of recombination activating gene (RAG) and classical T or B cell receptors (eceptors . The laceceptors ; ILC2, ieceptors . ILCs ineceptors . In the eceptors . While Ieceptors , their dBox 1Is innate immunity protective or pathogenic in IPF?Are PRRs that recognize DAMPs or PAMPs protective or pathogenic in the setting of pulmonary fibrosis?Does the altered microbiome cause PAMP driven innate immune activation in IPF?Does perpetuated microinjury cause DAMP driven innate immune activation in IPF and are therapies targeting DAMPs and their receptors efficacious in IPF?Can immune events detected in the circulation be used to guide personalized therapies in IPF?via the regulation of epithelial cell activation?Do macrophages participate in pulmonary fibrosis Does production of lipid mediators in macrophages contribute to pulmonary fibrosis?Can therapies targeting macrophage activation stabilize or restore lung function in patients with IPF?Are NETS an important part of IPF pathogenesis?Can fibrocytes be a therapeutic target or biomarker in IPF?Do myeloid-derived suppressor cells or ILCs participate in IPF?in situ?How do circulating myeloid cells, other than monocytes, contribute to the increased pool in the lung? Do they invade the lung and provide \u201ctransitory or permanent\u201d populations The connection between innate immunity and IPF continues to evolve and now encompasses a contribution from numerous processes and cell populations enacting competing and overlapping functions. The presence of these processes in fibrotic conditions affecting numerous organs frames innate immune dysfunction as a convergent molecular feature of divergent clinical states. The detection of these mediators in both diseased organs and the systemic circulation could represent a more significant hematologic contribution than previously believed. Conversely, it could represent the nonspecific and intrinsic nature of the response. When compared with epithelial cells and fibroblasts, whose proposed role in fibrosis is relatively well defined, the more heterogeneous contribution of innate immunity is nuanced and unlikely to respond to a single intervention which may make it challenging to target. Additional challenges include critical aspects of host defense and tissue homeostasis both in the lung and in distant organs. Because some of these limitations may be overcome by the relative ease of isolating immune cells and mediators from bronchoalveolar lavage and blood, innate immunity is an attractive area for the development of personalized therapies based on easily accessible biomarkers. Areas of particular interest and important questions in this context that would benefit from concerted efforts performed in large scale multicenter recruitment efforts, leveraging of existing datasets and registries, and the generation of improved modeling systems that more faithfully recapitulate the complex microenvironment of the fibrotic human lung and improve the understanding and treatment of IPF on a global scale are shown in"} +{"text": "Many older adults experience challenging financial circumstances and do not have sufficient income to afford a basic budget in their home communities. Far higher proportions of racial and ethnic minority older adults live on incomes that fall short of what is needed to make ends meet relative to their White counterparts. We describe racial/ethnic disparities in late-life economic insecurity, which occurs when an older person lacks sufficient financial resources to cover necessary expenses in their home community. Although nationwide half of older singles are economically insecure, Massachusetts (62%), New York (65%), Vermont (57%), and Mississippi (57%) have the highest shares of older adults who experience economic insecurity. Compared to Whites, minority older adults have higher rates of economic insecurity in nearly every state, but racial/ethnic disparities are higher in some locations and lower in others . Disparities in economic insecurity reflect the precarious financial situations experienced by many older adults, rooted not only in risks and disadvantages accumulated over time, but also in the variable and uncertain social and economic contexts that accompany the aging experience. By situating older adults in their places of residence, we observe that the cost of remaining in community intersect with life-course experiences associated with social identities to produce disparities in economic security at older ages. The geographic variation in cost of living calls for context-specific assessment of economic security to evaluate the adequacy of economic resources and the associated risk of hardship."} +{"text": "This review summarizes advances in methodology and technology for spatially targeted mass spectrometry analysis of kidney tissue. Profiling technologies such as laser capture microdissection (LCM) coupled to liquid chromatography tandem mass spectrometry provide deep molecular coverage of specific tissue regions, while imaging technologies such as matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) molecularly profile regularly spaced tissue regions with greater spatial resolution. These technologies individually have furthered our understanding of heterogeneity in nephron regions such as glomeruli and proximal tubules, and their combination is expected to profoundly expand our knowledge of the kidney in health and disease.The kidney functions through the coordination of approximately one million multifunctional nephrons in 3-dimensional space. Molecular understanding of the kidney has relied on transcriptomic, proteomic, and metabolomic analyses of kidney homogenate, but these approaches do not resolve cellular identity and spatial context. Mass spectrometry analysis of isolated cells retains cellular identity but not information regarding its cellular neighborhood and extracellular matrix. Spatially targeted mass spectrometry is uniquely suited to molecularly characterize kidney tissue while retaining The kidney is a complex and vital organ that filters waste products from the blood, stabilizes electrolyte and water content, and secretes essential hormones . It funcin situ to visualize molecular distributions in situ . Micro-lin situ . Peptidein situ . Althougin situ . Each rein situ .Imaging mass spectrometry (IMS) is a powerful technology to construct spatial maps of analytes without labeling and in an untargeted manner . The mosEach of these strategies requires a trade-off between spatial resolution and sensitivity, where methods approaching cellular or subcellular resolution often detect fewer analytes. Sample preparation and ionization methods also impact the molecular class that can be analyzed. This continuum is especially notable in spatially targeted MS, and researchers must use their judgment to select the technology most suited to their experimental goals .a priori knowledge of antibody targets. It also retains information about truncated and post-translationally modified proteoforms that can be impacted by renal disease and co-detection by indexing (CODEX) to molecularly characterize and discover markers for kidney FTUs and cell types ,b. To enIn summary, spatially targeted MS is a powerful set of technologies for the discovery of molecular profiles of critical FTUs and cell types in the kidney. As the field matures, multimodal data integration will certainly become more common requiring interdisciplinary, and often multi-institutional collaborations bringing together researchers with a wide array of expertise including cell biologists, pathologists, analytical chemists, computer scientists, and mathematical engineers. The application of this diverse set of expertise and technological capabilities is expected to dramatically enhance our understanding of the cellular and molecular makeup of the kidney to personalize medical care and improve health outcomes.AK and JS completed the original manuscript draft and contributed to critical review and editing of the manuscript. Both authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "By definition, older adults living in rural communities have fewer formal resources available to address aging-related functional needs. Supportive environments are frequently relied on in rural settings to help address this discrepancy. The purpose of this study was to assess the role of supportive housing features and home modifications in mediating the association between rurality and disability. We hypothesized that environmental supports would be more crucial in rural settings than non-rural settings. We analyzed data from the National Health and Aging Trends Study (NHATS). Variable selection was guided by the International Classification of Functioning, Disability and Health (ICF), including covariates for sociodemographics, chronic conditions, mobility functioning, and participation. A series of regression models tested mediation by environmental variables of the association between rurality (as determined by the metro/nonmetro file indicator) and ADL/IADL disability. Supportive home environments were operationalized using indicators of whether participants had access to homes from the outside without having to use stairs; presence of a bedroom, kitchen, and full bathroom with a shower or tub on the same floor; and whether bathroom fixtures had been modified with features such as grab bars. Results suggest a statistical relationship between rurality and disability that is explained in part by the presence or lack of supportive home features, and these effects were greater in rural settings. Implications are that older adults who live in rural settings can benefit greatly by supportive environments and modifications in areas of the home that are known to cause difficulty."} +{"text": "Food insecurity is a public health concern that is associated with poor diet and obesity. Poor food environments with low access to healthy, affordable food may amplify the negative impact of food insecurity on diet and obesity. This study aims to investigate whether food insecurity and food environments are jointly associated with an increased risk of poor diet quality and obesity. We used data from a nationally representative sample of 6,395 older adults in the Health and Retirement Study Health Care and Nutrition Survey and the National Neighborhood Data Archive. Weighted regression models were estimated to examine the relationship between food insecurity and food environments with diet quality and obesity. Both food insecurity and poor food environment were associated with lower healthy eating index scores, indicating poorer quality diet. Food insecure older adults were more likely to be obese than food secure older adults and poor food environments exacerbate the negative impact of food insecurity on obesity risk. However, there was no statistical difference in obesity risk by food environment among food secure respondents. Findings from this study highlight the negative impact of limited access to healthy food due to financial difficulties and/or poor food environments on diet quality and obesity risk. Providing financial or nutritional supports along with efforts to promote healthy food environment may reduce disparities in diet quality and obesity. Special support should be provided to food insecure older adults with poor food environment, those at the greatest risk of poor diet quality and obesity."} +{"text": "Due to the COVID-19 pandemic, it is common to hear news of older adults being socially isolated due to difficulties in purchasing or accessing online services and in interacting with family or friends through video calling apps. Despite an increasing ease of access to digital devices, such access far from universal. Thus, digital inequality has become a serious problem for older adults. To understand why digital inequality issues are so relevant for older adults, we must understand older adults' entire life contexts and the potential of digital technologies in their lives. With these understandings, the purpose of this study was to explore the technology acceptance process and identify key precursors to acceptance of digital technology using the Technology Acceptance Model (TAM) 3 as a framework. This study used data from the 2018 Digital Divide Survey of the Ministry of Science and ICT. A total of 1,662 older adults (aged 55+) were analyzed using structural equation modeling with bootstrap sampling. Model fit indices suggested an acceptable fit. Results indicated that two environmental dimensions, personal environment and social environment , had a significant impact on the intention to use technology both directly and indirectly. Furthermore, perceived usefulness and perceived ease of use mediated between environmental domains and the intention. This study indicates that providing appropriate digital support for older adults is important to achieve greater digital inclusion."} +{"text": "As the aging population in the United States continues to grow, so does the need for advancement and critical research to better understand later life experiences. The presence of cumulative disadvantages among racial minorities can often lead to later life health disparities. The goal of this study is to assess the role that social networks and community support play in later life health for marginalized communities. Data from the National Health and Aging Trends Study were analyzed using general linear regression techniques. This allowed for better understanding into the relationships between community support, social networks, race/ethnicity and self-reported health. The final sample included 3,857 participants aged 65 and older. After controlling for other variables, community support and social networks had statistically significant positive relationship with later life health. Race/ethnicity was the strongest predictor of worse later life health. The results of this study show the importance of later life social support for predicting health scores. White participants not only maintained higher health scores as compared to Black and Hispanic participants, but they also reported higher levels of social networks and community support. Findings from this study help build upon the literature regarding community support and social networks in later life."} +{"text": "Classic implementation of calorie restriction (CR) in laboratory animals increases health and longevity in most model organisms. Traditionally, chronic CR is the reduction of daily energy intake without malnutrition. Recently, paradigms have emerged that recapitulate some of the beneficial aspects of this intervention, avoiding some of its challenges. The length of daily fasting length and periodicity have emerged as potential drivers behind CR\u2019s beneficial health effects. Numerous strategies and eating patterns, including prolonged periods of fasting, have been successfully developed to mimic many of CR\u2019s benefits without its austerity. These new feeding protocols range from short mealtimes designed to interact with our circadian system (daily time-restricted feeding) to more extended fasting regimens known as intermittent fasting. We will discuss the current status of knowledge on different strategies to reap the benefits of CR on metabolic health in rodent models and humans without the rigor of chronic reductions in caloric intake."} +{"text": "Access to appropriate healthcare for children remains a challenge in Botswana, as evidenced by the under five mortality rate and integrated management of childhood illness indicators. Successful implementation of the integrated management of childhood illnesses strategy can drastically reduce child mortality through innovation, national health care worker training coverage, enhanced supervision and use of guidelines. Child health is a significant aspect of life that cannot be over-emphasized. An unwell child has poor growth, community integration, poor cognitive development and ultimately poor economic participation in adulthood ,2. It isDespite the training achievements and presence of regional coordinators, the impact is somewhat lacking. This is evidenced by the poor performance of indicators reflected in the IMCI health facility 2017 survey. This survey showed that diarrhea and pneumonia were the leading causes of mortality and were poorly managed. Only 3% of children with diarrhea were correctly managed while 43% of children with pneumonia were correctly treated. Furthermore, only 17% of children were assessed for danger signs . The aboStrategic planning: the IMCI program should develop a national strategic document and an operational plan document. This would allow for a comprehensive and easy review and monitoring of the program achievements and challenges.Training: all health care workers who provide service to children should be trained in IMCI. Therefore, trainings should continue, to achieve full coverage of all healthcare workers especially for those in primary care. This will also address issues of distributive equity of trained HCW.Supervision: since training alone does not guarantee implementation of guidelines, other measures to enforce implementation should be put in place. It is evident that the supervision capacity or strategy of the regional coordinators is not achieving the desired effect as even the trained HCW are not utilizing the IMCI guidelines [idelines . An IMCIComprehensive child welfare clinics: the already existing child welfare clinics (CWC) can be well-rounded with addition of child consultation by IMCI trained nurses and doctors. Currently CWC focuses on nutrition monitoring only but a comprehensive child welfare clinic would better improve the health of our children through integration.Community education: intensive and focused health education of caregivers on what to expect when their child is consulted appropriately via IMCI should be done. An educated client, who knows what service to expect, will hopefully force the health care worker to render the appropriate service to children. Successful implementation of the IMCI strategy across the country can drastically reduce child mortality. Botswana will be well on its way to achieve the sustainable development goal 3 once the challenges are addressed effectively and in a timely manner. National HCW training coverage, supervision and ensuring use of guidelines as well as comprehensive childcare clinics are key to efficacious IMCI implementation."} +{"text": "Symptoms of dryness discomfort in soft contact lens wearers frequently lead to discontinuation from wear. The negative influence of pre-fitting tear dysfunctions appears likely to be exacerbated by the challenges to tear homeostasis caused by contact lenses. The corneal mechanisms for symptoms in contact lens wearers are different to those for dry eye disease because the cornea is insulated by the lens from ambient conditions as well as from lid wiper friction during blinking. Symptoms of dryness discomfort might be the consequence of increased lid wiper friction during blinking when the lens front surface becomes soiled and dry and exhibits very rapid tear break up. It is possible that some cases of contact lens intolerance and discontinuation could be a function of lid wiper neuropathy. In relation to the possibility of corneal neuropathy, a stagnant post-lens tear pool with the possibility of increased concentrations of metabolic by-products, cellular debris, and bacterial exotoxins, might have the potential to disturb the corneal epithelial and sub-basal nerves. Contributions by contact lens-induced inflammation to any neuropathic changes may partly depend on the degree to which inflammatory mediators are concentrated in a stagnant post-lens tear pool. It does not appear to be known if corneal neuropathic changes could develop under these conditions. The chances of neuropathic involvement may be greater if discomfort develops after a significant period of successful wear and there is a history of comorbid pain conditions. Esthesiometry and in vivo confocal microscopy in discontinued contact lens wearers may support a diagnosis of contact lens-related corneal neuralgia. Findings of a poor correlation between symptoms and signs of dry eye disease and/or lack of satisfactory responses to treatment for tear dysfunction , warrantCorneal neuropathic pain, which is also termed corneal neuralgia and corneal allodynia, remains an ill-defined entity . The diaContact lens care system-related discomfort symptoms can usually be avoided by changing to a different system of care or to daDryness is the most common symptom of discomfort in contact lens wearers, with related symptoms of grittiness, scratchiness and foreign body sensations also being very frequently reported . These sAll soft contact lens materials examined have been found to adversely affect tear physiology with theA growing body of literature suggests that symptoms of dry eye disease may sometimes be better characterized as neuropathic ocular pain rather than dry eye . For insEsthesiometry might detect abnormally sensitive corneal nociceptor thresholds and in vivo confocal microscopy might detect corneal sub-basal plexus corneal nerve fibre damage or evidence of repair in the form of abnormal fibre length and the presence of beading and neuromas for instance . DastijeMany medically unexplained disorders are understood to involve an interplay between peripheral and central neuropathological mechanisms . CentralThe corneal epithelium produces and releases neurotrophic factors to support nerve trophism and healing, and corneal nerves produce trophic neuromediators for the survival, trophism and healing of the corneal epithelium . Could cThat soft lens movement can vary over time is indicated by the finding that during the first 25\u2009min after insertion, a significant reduction in soft lens movement was observed but after 8\u2009h, a significant increase in movement could be detected . IncreasThe post-lens tear pool in soft lens wear is relatively stagnant and less well understood due to difficulties in evaluation . LimitedContact lens-induced inflammation can be apparent by slit lamp examination, especially toward the end of the day in association with discomfort . Markoul4 was the only inflammatory mediator showing an increased concentration in the evening with contact lens wear and suggested the possibility that leukotriene B4 concentration could be associated with discomfort during contact lens wear [Both immune and mechanical processes are associated with increased concentrations of a wide variety of inflammatory mediators in the tears of soft contact lens wearers . Eveningens wear . The extens wear . Nomura ens wear .In non-contact lens wearers, the nociceptors under normal conditions are protected from the ambient environment by the glycocalyx, mucin layer and tear film . In dry Corneal sub-basal nerve fibres are located in the deep subnuclear region of the basal epithelial cell layer, either between the basal epithelial cells and their basal lamina or within cytoplasmic infoldings of basal epithelial cell membranes . Using tBinotti and co-authors reported that corneal nerve sub-plexus alterations can be evaluated according to total, trunk and branch nerve density and length, tortuosity, beading, nerve reflectivity, thickness and microneuromas . Moein aContact lens discomfort may depend on more appropriate choices of lens type fit and care system. Daily disposable lenses may be the most suitable. To the extent that discomfort has a neuropathic basis, treatment for tear deficiencies may support peripheral neurotrophic functions . For exaThat factors such as genetic susceptibility variations are believed to play pivotal roles in dictating phenotypic manifestation of ocular pain may helpIt is not clear as to whether the potential benefit from physical insulation of the cornea from the ambient environment by the bandage function of a soft contact lens can be undermined by any adverse influences which are associated with stagnant post-lens tears. Chronic wound healing responses in soft contact lens wear, perhaps related to limbal conjunctival trauma, stem cell deficiency and persistent epitheliopathy, as well as one or more immune responses, may contribute directly or indirectly to inflammation and an amplifying evaporative dryness symptom cascade . Symptom"} +{"text": "Partnerships between charitable food systems and healthcare systems have been forming across the country to support individuals and families experiencing food insecurity, yet little research has focused on these partnerships, particularly from a food bank perspective. The objective of this exploratory pilot study was to identify implementation challenges and facilitators of charitable food system and healthcare partnerships from the food bank perspective.n\u2009=\u20094) and charitable food system experts (n\u2009=\u20092) about their experiences of working with food bank/healthcare partnerships. All interviews were completed via Zoom and took between 30 and 60\u2009min to completed. Detailed notes were taking during each interview, and immediately discussed with the complete research time to formulate broad implementation themes.Texas food banks with existing food bank/healthcare partnerships were identify through website review and support from Feeding Texas. Interview questions were tailored to each interview, but all focused on identify program components of the food bank/healthcare partnership and implementation barriers/facilitators of the partnership. In total, six interviews were conducted with food bank/healthcare partnership leaders (Interviews suggest unique implementation challenges exist at all levels of food bank/healthcare partnerships including the partnership, program, and system levels. Partnership-level implementation challenges focused on issues of partnership scale and data collection, sharing, and analysis. Program-level implementation challenges focused on food and produce expectations. Structural-level implementation challenges included issues of food safety, subsidized food regulations, and patient privacy. Implementation facilitators included leadership support, mission compatibility/organizational readiness, food insecurity training, and identify of partnership champions.This study adds to the growing interest in food bank/healthcare partnership as it highlights unique implementation challenges and facilitators for cross-sector partnerships between healthcare systems and community-based charitable food systems. Ultimately, we believe that collaborative discussion among leaders of charitable food systems and healthcare systems is needed to overcome outlined implementation challenges to better facilitate sustainable, equitable implementation of food bank/healthcare partnerships. The COVID-19 pandemic has exposed the vulnerability of many Americans to food insecurity, meaning that at times they were unable to acquire adequate, nutritious food for the household . This isThe recognition of food security as a critical social determinant of health has led to resolutions from leading health professional organizations including the American Academy of Pediatrics and the Research on food bank/healthcare partnerships has begun to provide insights into the clinic experience and context of these partnerships. For example, four models of partnership have been identified in the literature including partnerships focused on food insecurity screening within the healthcare setting followed by referrals to local food banks and pantries \u201313, in aThe purpose of this pilot study was to explore the challenges and facilitators to implementing partnerships between food banks and healthcare, specifically from the perspective of food banks. This study uses qualitative interviews with charitable food system representatives to outline implementation challenges and facilitators needed to successfully implement and sustain food bank/healthcare partnerships.Food banks with healthcare partnerships were identified through a review of food bank websites in Texas and documentation on Food Bank/Healthcare Partnerships from Feeding Texas, the state-wide organization that supports collaboration across food banks . Of the Questions for each interview focused on identification of food bank/healthcare partnership programs, implementation challenges and facilitators for these partnerships, and sustainability challenges for food bank/healthcare partnerships. Interviews were completed on Zoom by trained research staff and took between 30\u2009min to an hour to complete. Detailed notes were taken during each interview, and immediately reviewed and discussed by the complete research team. Structured interview questions were not asked of each participant nor was the interview recorded to allow for interviews to be based on participants experience and expertise, while simultaneously protecting participants privacy.Generation of themes was derived through inductive analysis of interview notes and iterative discussion with the complete research team until consensus was reached. All team members have graduate-level education and experience in qualitative methods and analysis. Individual participants are not attributed to thematic content, as the focus of the interview was on organizational implementation. All interviews were completed in June 2020.Data pertaining to the food bank/healthcare partnership was the only data collected during interviews. After reviewing the Health and Human Services (HHS) guidelines on human subject research, this study was determined to be nonhuman subjects research according to HHS guidelines ; therefon\u2009=\u20094). Charitable food system experts included individuals with extensive knowledge of food bank networks (n\u2009=\u20091) and management of charitable food organizations (n\u2009=\u20091). See the Table\u00a0Overall, eight food banks and two charitable food system experts were contacted to participate in the interviews. A total of six interviews were completed. Four of the food banks contacted did not respond to the participation request. Each food bank participant directly worked within the food bank/healthcare partnership . These highly perishable foods can be distributed to any clinic visitor, regardless of income, to ensure that the produce was distributed quickly.Given the nature of any healthcare partnership, issues of patient privacy were discussed by participants as a barrier that must be overcome or addressed before entering a partnership. Participants indicated that food bank/healthcare partnerships would likely involve data sharing of sensitive medica data, and therefore, food bank staff should receive training on patient privacy and the Health Insurance Portability and Accountability Act (HIPAA), something that is currently uncommon in food bank staff trainings. Participants also discussed that healthcare partners need to have a similar understanding of protected patient data. Specifically, results highlighted that some healthcare systems see sharing food insecurity screening results with the food banks as a violation of HIPAA, yet other healthcare partners willingly share this information with the food bank. This discrepancy should be addressed in early discussions of data sharing between the food bank and healthcare system.Across interviews with food banks and charitable food system experts, four facilitators needed for developing and sustaining food bank/healthcare partnerships were 1.) leadership support for addressing social determinants of health, 2.) mission compatibility/organizational readiness, 3.) food insecurity training, and 4.) identification of program/partnership champions.All participants emphasized that need for leadership and staff at both the food bank and healthcare partner to have a strong desire to support all social determinants of health. Specifically, food bank leadership should have an interest in addressing other social determinants of health in addition to food access, and clinical partners should understand the interconnectedness of food insecurity with other social determinants of health. To address a variety of social determinants of health among food bank clients, participants suggested that food banks should participate in local health coalitions to collaborate with partner agencies and facilitate development of referral strategies.The importance of mission compatibility and organizational readiness across both food banks and healthcare partners was also highlighted across all participants. Food banks must ensure that a food bank/healthcare partnership would further the food bank\u2019s mission priorities, as it is possible that this kind of partnership may not be of interest or within scope for all food banks. Participants also reiterated that healthcare partners must have the willingness to treat food insecurity as an essential part of health and be willing to devote time and resources toward the partnership.Food insecurity training was also discussed as a critical facilitators of food bank/healthcare partnerships. Participants felt it was essential for healthcare partners to receive training on the significance of food insecurity and how to successfully identify food insecure patients using the Hunger Vital Signs, a validated two-item food insecurity screening questionnaire based on the U.S. Household Food Security Survey Module to identify households at risk of food insecurity . To suppProgram champions on both sides of a partnership was also discussed as a program facilitator. Within the food bank, there should be a partnership/program leader, as this person will be the point person for healthcare partnerships, decision making, and partnership outreach. Similarly, there is a necessity for a healthcare champion with dedicated time for the partnership that also holds leadership responsibility within the clinic, as this person will help facilitate partnership programs and ensure that the clinic upholds its responsibility.Partnerships between charitable food systems and healthcare systems have the potential to provide support for at-risk communities through strategic support for both healthcare and emergency food relief. Study results outline unique implementation challenges for food bank/healthcare partnerships from the perspective of the charitable food system that are often not included in the literature discussing these food bank/healthcare partnerships. Results also outline implementation facilitators among food banks with existing food bank/healthcare partnerships.Implementation challenges identified in this study can be organized into categories including partnership, program, and structural-level challenges. Partnership challenges are those that need to be discussed during formation of the partnership, as they hinge on the ability for both partners to work together efficiently and equitably. The most mentioned partnership-level implementation challenge was partnership/program scale. Scale was discussed in a few capacities including the number of participants that could be served, as well as the industrial-level scale that food banks operate most efficiently. This finding mirrors a recent review that suggested successful implementation of programs and partnership by food banks hinges on the ability to keep costs low , such thThe importance of data collection and evaluation were highlighted among implementation challenges. Results suggest that food banks and healthcare partners should invest time and energy into reaching an agreement on measurable outcomes that show meaningful success for both partners. This means that both food banks and healthcare must rethink traditional measures of success such as pounds of food distributed or clinical biometric health markers such as body mass index or hemoglobin A1c, a measure of long-term blood sugar control, as there are many other aspects of health. For example, it is reasonable to believe that food banks and healthcare partners would both value an outcome of increased healthcare provider self-efficacy for screening and referring patients with food insecurity to the local food bank, as this would allow providers to better serve their patients and food banks to serve additional clients. Differing measured outcomes across food bank/healthcare partnerships models also makes it challenging for evaluations across partnership types. A recent review found 23 published studies addressing food insecurity within the healthcare setting, yet few studies used the same methods or outcomes , making Another challenge in food bank/healthcare partnerships are expectations around food consistency and variety. This discrepancy centers on the inability of food banks to ensure consistent food products or produce at any given time of the year. While food banks have high purchasing power, their ability to purchase foods largely depends on funding and the ability to safely pack, transport, and store foods . As noteIn addition to partnership and program implementation obstacles, there will also likely be structural challenges such as food safety, federal regulations among food programs, and patient privacy. Food safety should be at the heart of any partnership that is planning for onsite food distribution, as there must be adequate dry and cold food storage in areas that meet food safety standards. The need for food safety and appropriate storage is echoed in a recent publication outlining the feasibility of healthy food pantries . This stFacilitators of food bank/healthcare partnerships documented in this study including leadership support, food insecurity training, and program champions are comparable to previous research findings among healthy food pantries . With a Another study finding worth highlighting was focus on social determinants of health among food banks. Focusing on social determinants of health among food banks has increased in the past few decades given the vast research base linking food insecurity and other social determinants of health . While tWhile this study provides a unique perspective on partnerships between charitable food systems and healthcare, study limitations exist. This study was competed with a limited sample that largely represented a single state, yet many implementation barriers and facilitators should be similar regardless of where this partnership is taking place. This study was also completed as a pilot study with interview goals of exploring implementation barriers and facilitators, so structured questions were not asked of each participant nor were interviews recorded. Instead, interviews differed based on the participants experience and expertise and notes were taken. This method was chosen to provide the most comfort and privacy of participants while discussing barriers and allowing interviewer flexibility to explore new ideas, implementation barriers, and facilitators discussed by participants. To provide a more comprehensive understanding of food bank/healthcare partnerships, future research should consider a more systematic approach to understanding food bank/healthcare partnership models, logistics, and goals, as well as include perspectives from both food banks and healthcare partners.Ultimately, interviews with food bank experts suggest careful planning and implementation of food bank/healthcare partnerships can be formed to support the physical and social needs of individuals and families experiencing food insecurity. Attention should be given to implementation challenges both within the partnership and program, as well as structural challenges working across systems. To continue moving this work forward, a convening of leaders within charitable food systems and healthcare systems is needed to provide direction for partnerships, improve future collaborations, and create a more equitable implementation framework."} +{"text": "Clinical trials for dementia caregivers have suffered from small sample sizes that lack adequate power to detect treatment benefits. Addressing these methodological shortcomings is contingent upon successful recruitment and enrollment of caregiver participants, but major barriers impede their participation in research. This presentation describes the lessons learned from recruiting and enrolling dementia caregivers into a pilot randomized controlled trial designed to help caregivers recognize and communicate about pain in dementia care recipients. Using Bronfenbrenner\u2019s ecological model, we organize our discussion of challenges and opportunities into three levels: community (ecosystem), institution (microsystem), and individual. A key challenge at the community level was gatekeeping by organization leaders, including those from support groups, senior centers, and congregate living facilities. At the institutional-level, challenges included an absence of administrative mechanisms for identifying caregivers and a lack of caregiver research expertise on the Institutional Review Board. At the individual-level, challenges included time constraints and varying motivations for participating in research. Strategies for overcoming these challenges spanned the three levels and included establishing trust and rapport with various constituencies; adapting our recruitment approaches to meet the specific motivations of prospective participants; and refining recruitment scripts to allow for greater personalization. Employing these strategies, which can be generalized to recruit other hard-to-reach populations, helped to overcome recruitment challenges and expedite enrollment of caregivers from a diverse range of sociodemographic backgrounds. Further improvement will require coordinated changes at the institutional and community levels, including the development of central research registries and administrative mechanisms for identifying caregivers."} +{"text": "Using longitudinal data from the 2006 to 2018 Korean Longitudinal Study of Aging, this study explores depression trajectories among individuals who are 60 or older with at least one living adult child at baseline. We estimated linear growth curve models of depression trajectories separately for married, unmarried and widowed using the Center for Epidemiologic Studies Depression Scale (CES-D). Results indicate that declining health and recent widowhood are positively related to depressive symptoms. Satisfactory intergenerational relationships and social support in the form of caregiving decrease depressive symptoms of older parents, especially among the widowed. Having at least one son and a first-born daughter positively impact psychological well-being of older parents. A son was particularly important for those who are widowed. We conclude that the psychological benefits of intergenerational relationships and social support are contingent upon the vulnerability of Korean older adults and discuss the implications for public policy."} +{"text": "The pandemic has revealed a multitude of challenges disproportionately impacting older adults, including older adult learners. Institutions of higher education are uniquely positioned to respond to various challenges using the guiding framework of the Age-Friendly University global initiative. This presentation highlights how preexisting university student support practices and services were adapted to provide older adult learners with guidance for navigating their educational needs during the pandemic. Specifically, it expands on strategies utilized by Adult Learner Programs and Services to effectively pivot to virtual services to support the advising and programming needs of older adult learners. Survey data identifying areas of interest for virtual programming for older adult students will be explored. Recommendations will be discussed for promoting effective transitioning to virtual support systems, preserving student engagement and intergenerational learning, and advocating for aging to remain central to university diversity and inclusion initiatives."} +{"text": "A vertical annular configuration with differently heated cylindrical surfaces and horizontal adiabatic boundaries is systematically studied in view to their industrial applications. In this paper, we investigate the effects of conjugate buoyant heat transport in water based nanofluids with different nanoparticles such as alumina, titania or copper, and is filled in the enclosed annular gap. The annulus space is formed by a thick inner cylinder having a uniform high temperature, an exterior cylindrical tube with a constant lower temperature, and thermally insulated upper and lower surfaces. By investigating heat transport for broad spectrum of Rayleigh number, solid wall thickness, thermal conductivity ratio and nanoparticle volume fraction, we found that the influence of wall thickness on thermal dissipation rate along wall and interface greatly depends on conductivity ratio and vice-versa. In particular, we uncover that the choice of nanoparticle in a nanofluid and its concentration are key factors in enhancing the thermal transport along the interface. Specially, copper based nanofluids produces higher heat transport among other nanoparticles, and for the range of nanoparticle concentration chosen in this analysis, enhanced thermal dissipation along the interface has been detected as nanoparticle volume fraction is increased. Our results are applicable to choose nanofluids along with other critical parameters for the desired heat transport. They performed simulations for wider spectrum of parameter ranges and proposed heat transport correlations in different flow regimes. Later, Kumar and Kalam2 made numerical simulations of convective flow, thermal transport analysis and reported the discrepancies existing in the results of Davis and Thomas1, and suggested new correlations to predict the thermal transport rates. Convective flow of different liquids in an annular enclosure has been experimentally investigated by Prasad and Kulacki3 for three different aspect ratios and by fixing the ratio of outer to inner radius, known as radius ratio, 7. Sankar and co-workers9 made detailed investigations to analyze the impacts of thermal sources on buoyant convective motion of air in a discretely heated porous and non-porous annulus and observed discrete heating could enhance thermal transport compared to complete heating of wall. Later, Wang et al.10 investigated transient buoyant flow in the same geometry and reported new correlations to predict the thermal transport rates. The size and positional influence of thermal sources on hydrodynamic stability has been numerically examined by Mebarek-Oudina11 in an upright annular domain. Recently, Husain and Siddiqui12 made an experimental analysis of unsteady buoyant convective flow of water in tall and narrow annular region, and also presented theoretical simulations through a commercial software package. It is worth to mention that the above investigations mainly addresses the buoyant flow and associated transport processes in a vertical annular chamber without taking account of wall thickness effect.Buoyant thermal transport of conventional fluids as well as nanofluids\u00a0(NFs) in various finite-sized geometries has been widely investigated through theoretical simulations and experimental visualizations. This is mainly due to the direct relevance of these geometries in many vital applications ranging from cooling of electronic components to safety measures of pertinent devices, e.g., nuclear reactors. In particular, amongst the finite-sized geometries, the annular space formed by two vertical co-axial cylindrical tubes with different heating of side boundaries and insulated horizontal surfaces is considered as a suitable model problem aptly describing the physical configuration in many applications. David and Thomas15. Thermal transport analysis of different NFs in finite shaped geometries have also received a great amount of attraction due to the requirement of effective cooling of electronic equipments17. One of the earliest attempt to investigate the buoyant motion of Al18. They performed extensive numerical simulations by considering wide spectrum of parameter ranges and proposed thermal transport correlations for square and annular geometries. Cadena-de la Pe19 conducted experiments to analyze cooling mechanisms of oil-based nanoliquids by considering two different NPs and found thermal transport enhancement with NFs. The impacts of discrete thermal sources of different lengths and locations on buoyant motion of NFs in an annular domain reveals interesting flow features and enhanced thermal transport as compared to uniform or complete heating21. Recently, Keerthi and Sankar22 presented numerical simulations to reveal the consequences of different non-uniform heating of annular boundaries on the convective motions of Cu-based NF and identified an appropriate heating condition to enhance the thermal dissipation rates. The convective motions of various NFs in horizontal and tilted annular configurations with and without fins have also been reported24.The addition of nano-sized particles (NPs) in conventional liquids could effectively enhance the thermal transport rates and is substantiated through the predictions made by many theoretical simulations and experimental observations25 presented detailed analysis on thermal transport enrichment for Cu-based NFs in a square geometry and proposed a theoretical model and heat transport correlations to estimate nanofluid thermal performance. Later, this study was extended by Jou and Tzeng26 by taking NP dispersion into consideration and aspect ratio. Many investigations analyzed the buoyant motion and thermal dissipation of different NFs in two-dimensional plane geometries by considering various models for fluid properties and identified an appropriate model for thermal transport enhancement29. Oztop and Abu-Nada30 addressed the idea of choosing the type of nanofluid for flow behavior and thermal transport enhancement. The type of thermal boundary condition greatly influences the convective thermal transport characteristics which has been discussed in detail by Basak and Chamkha31. Through numerical predictions it has been observed that utilizing nanofluid in an enclosure predominantly improves convective heat transfer32. Roy33 examined nanofluid buoyant motion in the annular section between a square geometry and three distinct interior geometries, such as circular or elliptical or rectangular cylinder and found the inner shapes has profound impacts on thermal dissipation rates compared to a square geometry. Using combined Lagrangian and Eulerian modeling, Sharaf et al.34 investigated the convective motion and nanoparticle dissemination in a microchannel formed by parallel plates and brought out inaccuracies in the existing nanofluid model. The impacts of three different arrangements of conductive baffles on nanofluid motion and associated thermal behavior in a square geometry has been performed by Bendaraa et al.35 and noticed that the fin location has vital role in effective controlling of the flow movement and thus thermal dissipation rates. Buoyant nanofluid motion and the associated thermal dissipation rates are highly sensitive to shape of chosen geometry. In many applications, the geometrical configuration is not regularly-shaped and the convective transport rates can be effectively controlled through a vital geometrical parameter arising in non-regular geometries37. A detailed review and discussion on various constraints affecting nanofluid flow behavior and heat dissipation rate in different geometries and passages have been reported39. The above research works mainly focused on the convective flow of NFs but, the studies pertaining to the rheology of NFs are also very important in the application point of view. Experimental studies on rheological properties and the behavior of gold-NPs with poly (vinylidene fluoride) was examined in detail by Susrutha et al.40. Also, great amount of investigation on rheology and stability of NFs was addressed by Ram and co-workers42. The fascinating properties of magnetic NFs and its applications in magnetic resonance imaging, chromatography and many more has been illustrated in detail by Singh and Ram43.Among the finite shaped enclosures, rectangular and square geometries have been widely used in analyzing the nanofluid buoyant motion by considering various constraints affecting the flow and thermal transport mechanisms. Khanafer et al.44 in a square geometry by considering three different wall conduction models. For larger thermal gradients, they observed asymmetric flow field and non-uniformity in temperature along the interface between solid and fluid. Ben-Nakhi and Chamkha45 performed numerical analysis to understand the influence of a slim tilted baffle on conjugate buoyant convective motion in a square geometry having finite thickness on three boundaries. In a 2D square section, with thickness on its side wall, the change in flow motion and thermal behavior of liquid gallium subjected to an externally imposed tilted magnetic force and wall conductivity was examined by Belazizia et al.46 and reported that magnetic angle is a crucial parameter in controlling thermal transport. The impact of width of conductive walls and thermal conductivity ratio on natural convection in a porous square was analyzed by Saeid47. A detailed investigation on conjugate buoyant motion in finite porous geometry has been addressed by considering discrete heating effects48.In many practical situations, such as thermal bridge, heat barrier, design of thermal insulation, thermo couple design, gas turbine blade cooling, furnace design, design and sizing of heat exchangers, aerospace applications, the impact of wall thermal conduction should be taken into consideration, otherwise leads to inaccuracies in the prediction of flow movement and thermal behavior. Therefore, the impact of wall conduction on buoyant fluid motion and associated thermal removal from the hot boundary have received substantial attention by many theoretical and experimental analysis. In this direction, one of the pioneering and detailed study was made by Kaminski and Prakash49 and non-inclined51 square geometry was numerically analyzed in the presence and absence of magnetic field. By adopting Buongiorno\u2019s model, Sheremet and Pop52 analyzed the Brownian movement and thermophoresis effect of NFs for a vast range of critical parameters and determined the range of parameters at which the chosen model could be used. Alsabery et al.53 discussed the impacts of non-uniform thermal conditions on nanofluid buoyant motion in a square geometry with thick bottom wall. The conjugate flow and thermal behavior of NFs undergo predominant changes due to the presence of protruding source or block in a finite geometry55. Ghalambaz et al.56 addressed the conjugate buoyant motion and thermal transport of hybrid NFs in a square geometry and discussed the impacts of all key parameters. Reddy and Narasimham57 performed numerical simulations to study combined conduction-convection in an enclosed annular region between inner heated rod and an outer cylinder for vast ranges of thermal conductivity ratios and presented thermal transfer correlations. Later, conjugate buoyant transport in a porous material placed in the annular region between two solid cylinders was numerically analyzed by Badruddin et al.58. Recently, John et al.59 made a detailed review on conjugate thermal transfer analysis covering various applied and theoretical aspects.Conjugate buoyant motion and transport rate due to the presence of a solid block in an inclinedWe made a meticulous and systematic literature survey on conjugate buoyant convection of base fluids as well as NFs in different shapes of finite geometries by considering most of the additional constraints. From the detailed survey of theoretical and experimental investigations, we have noticed that the conjugate buoyant motion and thermal transport behavior of NFs inside the enclosed annular region has not been analyzed so far. Therefore, keeping the applications involving thermal bridge or heat barrier in mind, a detailed numerical investigation is carried out to explore the impacts of various key parameters on flow and thermal behavior of three different NFs in the annular geometry having finite thickness at the inner cylinder.The geometrical structure, as portrayed in Fig. mentclass2pt{minim20In the present study, thermophysical properties of NFs are described as below:nf, f and p represents the nanofluid, fluid and nanoparticle, respectively. Applying the following transformations,Here, the subscripts By introducing two-dimensional stream function quations can be eThe initial and boundary conditions in dimensionless form are;The thermal dissipation rates are measured through the average Nusselt numbers along the solid wall 60. These FDM based techniques reduce the PDEs to a system of linear algebraic FD equations with tridiagonal structure and using tri-diagonal matrix algorithm (TDMA), the solutions are obtained. We have performed the grid independence trials by considering five different grid sizes, varying from sparse to finer grids, as shown in Table The coupled and nonlinear partial differential equations (PDEs) and associated supplementary conditions governing the physical processes are numerically solved by utilizing\u00a0a suitable implicit finite difference method (FDM). In particular, the transient PDEs, such as vorticity and temperature equations are discretized using alternating direction implicit (ADI) method and successive line over relaxation (SLOR) method is adopted to solve steady-state stream function equation18, displayed in Table Ra values. An additional quantitative comparison of flow and thermal contours in a square geometry containing Al28 analysis is exhibited in Fig. The current simulations are tested with different benchmark data present in the literature. Firstly, the global heat transfer rate for an annular geometry containing Alentclass1pt{minimaIn the present analysis, the combined conduction-convective flow and associated thermal transport analysis is performed in the solid and annular regions. The dimensionless parameters arising in this investigation, varied over wide spectrum of values, Ra on flow and thermal contours for three different NFs and base-fluid by keeping Ra to a maximum chosen value RaRaRa, the temperature difference between the vertical walls increases which leads to more convection in the fluid region. Thus, the isotherms become well distorted at higher Ra and this indicates that the conduction heat transfer at lower Ra has been changed to convective heat transfer for Ra, the isotherms are horizontally skewed in the fluid region due to convection-dominant state and larger thermal gradients are noticed near the solid\u2013fluid interface. Similar isothermal structure pattern is detected for all the samples.Figures Kr on streamlines and isotherms is depicted in Fig. Kr increases, the isotherms are near stratified state and the flow pattern also changes. For Kr, a strong temperature stratification exists and the buoyant nanofluid motion reveals an enhanced flow strength.In Figs. see Fig. . For lowThe influence of solid wall thickness on buoyant flow and thermal contours is presented in Fig. The variation in buoyant flow and thermal structure due to nanoparticle concentration is discussed in Fig. Ra, Kr, Ra and Kr on overall thermal transport rate at the wall and interface are presented in Fig. Ra caused by increasing the temperature difference or altering the Kr value. For all three NFs as well as base fluid, the Kr. The thermal dissipation rate at the wall is comparatively higher for base fluid compared to NFs. Though the nanofluid occupied in annular region is not in direct contact with the hot inner wall, the global dissipation rate at solid boundary is slightly influenced by the choice of nanofluid. This can be anticipated from the thermal condition imposed at the interface, which carries the influence of NPs used. On contrast, the heat transport rate at the interface strongly depends on the choice of NP. Further, among the three NPs used in the analysis, Cu-based nanofluid produces enhanced heat dissipation as compared to AlNu enhances with an increment in Ra at all conductivity ratios except for Ra. For The thermal dissipation rate from the annular boundary to interface and in turn to the surrounding NFs is highly influenced by various parameters such as mentclasspt{minimaRa on overall heat transport rate at the wall and interface for the three NFs and base fluid significantly promotes the heat transport through the wall. Hence, convection is enriched and the thermal transport through the interface is enhanced for higher Kr. For given value of An increase in the solid wall to nanofluid thermal conductivity ratio (Kr and The addition of nano-sized particles to base fluid enhances the thermal dissipation at the solid\u2013fluid interface and percolates the nanofluid fluidity. The total heat transport rate for all three typical NFs enhances with an increase in nanoparticle concentration. For any value of nanoparticle concentration, Ra, Kr and For given values of Ra, Kr, the upper portion of interface exhibits higher temperature.To study the thermal dissipation and flow behavior throughout the domain, the temperature variations along the interface is analyzed. For chosen Ra, Kr and For minimal wall thickness, the choice of higher values of Conjugate buoyant convective motion in an annular geometry with a solid inner cylinder is numerically analyzed, with examples of the annular region filled with aqueous NFs of Cu, Al"} +{"text": "Background and Objectives: Substantial evidence links social connectedness prospectively to cognitive aging outcomes, but there is little agreement about the social processes or mechanisms that drive this relationship. This study evaluated nine measures of social connectedness, focusing on two distinct forms of social enrichment \u2013 access to an expansive and diverse set of loosely connected individuals and integration in a supportive network of close ties . Research Design and Methods: This study used egocentric social network and clinical cognitive data from 311 older adults in the first wave of the Social Networks in Alzheimer Disease (SNAD) study. Linear regressions adjusting for gender, age, education, and depression symptoms were used to estimate the association between nine measures of social connectedness and global cognitive function, verbal memory, and attention. Results: Measures indicative of social bridging were consistently associated with better cognitive outcomes, while measures of social bonding largely produced null effects. Discussion and Implications: These findings suggest that the protective benefits of social connectedness for cognitive function and memory may operate primarily through a cognitive reserve mechanism that is driven by irregular contact with a larger and more diverse group of peripheral others. Population-level interventions that promote the cultivation of social bridging relationships and activities may have benefits for cognition later in life."} +{"text": "In the past 2 decades the concept of stem cell niches, referring to the cell types neighboring stem cells in their microenvironment, have been gaining momentum and biological appreciation . Vasculaex vivo reproduce a vascularized bone marrow on a chip model. This special issue topic, composed of seven review articles, provides an overview of all these themes and aspects ranging from embryonic and adult basic biology studies, to translational studies and recent technological advancements.Bone marrow endothelial cells associated with malignant leukemic conditions provide hematopoietic tumor cells with sheltering microenvironments accommodating tumor resistance to chemotherapeutic and irradiation therapies and participate in tumor escape from immune surveillance, consenting leukemic relapse. Yet, this tight relationship between blood forming stem cells and vascular blood vessel forming endothelial cells begins at a very early embryonic developmental stage when a special type of hemogenic endothelial cells give rise to primitive and definitive hematopoietic cells responsible for the early waves of hematopoiesis. Moreover, already at this stage neighboring endothelial cells which do not specify to hematopoietic cells provide a supportive niche to this developmental process . OverallThe emergence and maintenance of the hematopoietic system relies on the source of a specialized sub-type of hemogenic endothelial cells and at the same time on the incoming guiding signals from neighboring vascular endothelial niche. Hematopoiesis is differentially regulated during development and intimately related to niche specialized endothelial cells in its infancy. Heck et al. provide a comprehensively review of the current evidence on embryonic hematopoiesis and discuss the role of specialized vascular beds in the generation and expansion of hematopoietic stem and progenitor cells . StudiesDuring adulthood, hematopoiesis occurs primarily in the bone marrow, where hematopoietic stem and progenitor cells reside in close contact with blood vessels, namely sub-types of arteriolar, sinusoidal, and transitional capillary ECs. In recent years, several studies have better characterized the heterogeneity of the bone vasculature and its functional impact in bone physiology and hematopoiesis. The role of specialized blood vessels in the adult bone is discussed by Hendriks et al., who have previously described the type-H endothelium, an endosteal vascular subtype that is important for bone maintenance and turnover. The authors review the organization of the bone vasculature in detail and discuss the current evidence on how bone marrow vascular niches contribute to bone repair and homeostasis via interaction with hematopoietic and mesenchymal stromal cells .In addition to the key role of blood vessels in homeostasis, vascular environments are affected and influence disease states. Mosteo et al. focus on the role of the bone marrow vascular niches in myeloid hematologic malignancies, namely acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) . The autStucker et al. present a larger picture of how the bone marrow vascular niches are remodeled in allostasis . The autOne of the key pathways involved in the interaction between endothelial cells and hematopoiesis is the Notch signaling pathway, which is the subject of analysis by Huang et al. The authors review how Notch is involved in hematopoietic lineage differentiation and in leukemia and attempt to reconcile the contradictory evidence for the importance of Notch signaling in adult HSC maintenance .in vivo imaging will deepen our understanding of the vascular niche and resolve standing questions.Despite being known and studied in depth for decades, only recently the bone marrow microenvironment has been dissected at a single cell level thanks to recent technological advancements, providing the possibilities for dissecting tissues at this resolution. Dolgalev et al., made a concise synopsis of the recent work done in the field, highlighting the molecular features of the bone marrow microenvironment at single cell resolution, emphasizing the most significant differences in tissue dissection for acquisition of cellular material, sequencing and analysis techniques, and computational approaches . The bioin vitro or in vivo. Several experimental systems have been implemented and have displayed the feasibility of bioengineering bone marrow-like tissues, supported by cells of mesenchymal origin. Despite being largely disregarded in the first models, vascular endothelial cells have gradually been included in these constructs. Bessy and colleagues have reviewed the field of bone-tissue bioengineering with a particular focus on vascular implementation and integration (As recent technological advances have allowed a thorough characterization of the cellular and matrix components of the vascular bone marrow niche, modelling capabilities have followed up with the aim of reproducing 3D bone marrow-like structures, which can support normal and malignant hematopoiesis either egration . The fieIn summary, our research topic brings forward the most recent advancements in the research area of the hematopoietic stem cell niche, highlighting the fact that endothelial and blood cells are bound together for life from the early time points of embryogenesis, throughout adulthood and aging, during homeostasis and disease, tightly regulating and affecting each other\u2019s fate choice decisions. This multidisciplinary field of studies combining hematopoiesis and vascular biology, is rapidly moving forward, thanks to recent technological advances, gaining insights and major relevance to hematological diseases. As it gains momentum, more and more basic scientists as well as clinicians begin to appreciate the translational potential and the novel therapeutic approaches that can be developed based on the basic biological findings presented in this review collection. We predict that in the upcoming years this research topic will continue to rapidly evolve and attract scientific and clinical interest leading to major discoveries further contributing to better biological understanding of intra-tissual cellular interactions and advancing clinical approaches to treat disease."} +{"text": "The analysis of human pathogens requires a diverse collection of bioinformatics tools. These tools include standard genomic and phylogenetic software and custom software developed to handle the relatively numerous and short genomes of viruses and bacteria. Researchers increasingly depend on the outputs of these tools to infer transmission dynamics of human diseases and make actionable recommendations to public health officials . In orde Augur originally existed as an internal component of the nextflu and NextTo address these issues, we refactored the original Augur scripts into a toolkit of individual subcommands wrapped by a single command line executable, augur. With this approach, we followed the pattern established by samtools and bcftBy implementing the core components of Augur as a command line tool, we were able to rewrite our existing pathogen analyses as straightforward bioinformatics workflows using existing workflow management software like Snakemake . Most paThe modular Augur interface has enabled phylogenetic and genomic epidemiological analyses by academic researchers, public health laboratories, and private companies. Most recently, these tools have supported the real-time tracking of SARS-CoV-2 evolution at global and local scales . This su"} +{"text": "Differential gene expression and gene ontology analysis showed that hotspots were enriched in gene sets associated with DNA replication, cell cycle, and ligand receptor interaction. Genome and exome analysis suggested hotspots and coldspots to have similar mutational profiles. However, a limited number of hotspot-specific mutations and fusion transcripts indicated that hotspot tumor cells developed from coldspot cells and point at the potential role of hotspot driver genes in glioblastoma. Our findings reveal that hotspots in glioblastomas represent a more advanced stage of molecular evolution than coldspots.Glioblastoma is one of the most aggressive cancers, but the molecular evolution is still not fully understood. We used PET imaging combined with deep sequencing of glioblastoma biopsies at both the RNA and DNA levels to get a deeper insight into molecular evolution. In the clinical setting, PET imaging provides information about metabolically active tumor areas, but the molecular interpretation is unclear. Our primary objective was to perform an intratumoral spatial comparison of biopsies from potentially aggressive and less aggressive areas in glioblastomas according to PET scans. Additionally, tissue from the tumor periphery was included. We used MRI,"} +{"text": "This study aims to find relevant factors influencing the intention to use exoskeletons for exercise (IEE) among older adults and to analyze the moderating effect of frailty. The sample of this study is 310 people (65 or older) without cognitive impairment who completed an online survey. The intention to use exoskeletons was measured with three questions from the Senior Technology Acceptance Model (STAM). Potential relevant factors comprise sociodemographic characteristics, physical and psychological health, exercise, attitude towards aging, and social relationship. Linear regression analyses showed that depressive symptoms, regular exercise, attitude towards aging, and social participation were significantly related to IEE. People with more depressive symptoms and a negative attitude towards aging are more likely to have a higher level of IEE. People who exercise regularly and actively participate in social activities showed a higher level of IEE. Subgroup analyses were performed based on the frailty status measured with Korean Groningen Frailty Indicator (K-GFI). Among people without frailty (N=177), regular exercise, and social participation were positively related to IEE. The number of chronic diseases and social participation was positively related to IEE among people with frailty (N=133). The results of this study implied that poor health conditions lead to an increased need for exoskeletons. The results of this study also suggested that exercise and social participation work as facilitating factors in the context of gerontechnology acceptance. Results of subgroup analyses suggested that influencing factors on IEE can vary depending on the physical functional status."} +{"text": "Cognition is influenced by the neighborhood social and physical environment, but the underlying mechanisms by which neighborhood environment affects cognition are unclear. We tested the hypothesis that sleep mediates the effects between environmental exposures and cognition. We employed structural equation modeling to examine interrelationships among neighborhood social and physical environment, actigraphic sleep characteristics, and global cognition in a sample of older adults from Round 2 of the National Social Life, Health, and Aging Project. Results indicated that participants with better cognition lived in salutary social environments and less disruptive physical environments . The mediation hypothesis was partially supported. Time spent awake after sleep onset mediated the social environment-cognition relationship, but sleep characteristics did not mediate the physical environment-cognition relationship. Future work should identify other environmental influences on sleep and cognition in aging to inform public health intervention priorities."} +{"text": "The present study aimed to examine the effects of regular exercise on attitude towards using exoskeletons and the mediating effects of technology anxiety and perceived usefulness among Korean older adults. Data was collected through online recruitment in February 2021. The sample comprised 310 people who did not report dementia. The dependent variable was the attitude towards using technology, especially lower limb exoskeleton robots for exercise. The independent variable, regular exercise, was coded as a binary variable. The mediating variables were technology anxiety and perceived usefulness measured by the sum of three questions about exoskeleton robots, respectively. Gender, age, education level, and household income were included as control variables. The mediating effect was estimated by serial path analysis and bootstrapping . Results showed the total effect of regular exercise was significant and the total indirect effect of it was significant. There was no significant direct effect of regular exercise on the attitude towards using technology. The association between regular exercise and the attitude of using technology was completely mediated by perceived usefulness . Although technology anxiety had no mediating effect alone, the serial mediating effect via the path from technology anxiety to perceived usefulness was significant . This study will be the first empirical study to examine the effects of health habits by expanding the senior technology acceptance model for older adults in Korea."} +{"text": "Higher fasting blood glucose level than postprandial level can be seen in variety of conditions in both normal population and diabetics. Various modifiable factors along with underlying condition of patient behind such laboratory picture are discussed in this article. In clinical laboratories, daily numerous blood samples are processed for estimation of fasting blood glucose (FBG) level and postprandial blood glucose (PPBG) level. It is found in some cases that postprandial level of blood glucose is remarkably lower than that of fasting level.Being unsatisfied with the laboratory result, patient or sometimes clinician wants to recheck the blood glucose level in next laboratory. This is because of common perception that PPBG level must be higher than FBG level. But the repeated investigation yields similar type of result. FBG may be higher than the PPBG in both diabetics and healthy population. Many modifiable factors may be the cause for this laboratory finding along with underlying conditions of such patient.The aim of the present article is to aware healthcare providers about the factors that can cause FBG level higher than PPBG.2 Careful attentions to these modifiable factors by both clinician and laboratory staff are essential to ensure accurate glucose measurement.Blood glucose level primarily depends upon individual characters like type and quantity of food intake, physical activity and the body's metabolic response. Pre-analytical factors that affects blood glucose level are smoking, caffeinated drinks, use of hypoglycemic drugs, heavy exercise, anxiety and delay in sample processing.The organ that is responsible for fasting value of blood glucose is liver whereas it is the pancreas that is responsible for PPBG value. Several hours after dinner, blood glucose level drops leading to decrease in insulin level and rise in glucagon level. Glucagon is responsible for maintaining adequate blood glucose level in fasting condition via activation of metabolic pathways like gluconeogenesis and glycogenolysis in liver. Higher FBG level is due to increase in glucagon to insulin ratio as seen in diabetes, where liver is involved in excess glycogen breakdown and gluconeogenesis. Despite having sufficient insulin, individual may have higher FBG value which is mainly due to insulin resistance that is the commonest cause of impaired fasting glucose tolerance and diabetes mellitus.Apart from this underlying disturbed homeostatic response of person, various modifiable factors have effect on FBG level. Higher FBG is mainly due to high carbohydrate meal at bedtime or not enough diabetic medication. The anxious individual with disturbed sleep may also have high FBG. Furthermore, the lesser known entities like Dawn phenomenon and Somogyi effect also contribute to higher FBG in the morning. These are the body's response to hypoglycemia by release of counter regulatory hormones like glucagon, epinephrine and cortisol which can be treated by altering type and time of meal and medication.36 Chewing and eating slower can reduce the reactive glucose surge post meal. Other causes of lower PPBG includes gastroparesis seen in diabetic patient which an alter the rate and amount of food passing into small intestine causing erratic changes in blood sugar level. Some people deliberately eat less or eat non-carbohydrate meal before testing for PPBG level.Immediately after food intake, insulin is released from pancreas that maintains blood glucose by activating glycolysis pathway along with suppression of glycogenolysis and gluconeogenesis pathway. The common cause of decreased postprandial glucose level is intake of antidiabetic medication and strenuous activity before sampling. Individuals with lesser PPBG level than FBG should be evaluated for possibility of meal induced hypoglycemia also known as reactive hypoglycemia. Various causes for this are high insulin sensitivity, exaggerated response of glucagon-like peptide-1, defects in counter regulatory hormones like glucagon and massive weight reduction.7It should be noted that fasting and postprandial glucose level help us adjust the dose of diabetic medications properly and glycated hemoglobin (HbA1c) helps to know whether there is an overall control so as to prevent complications. Due to individual variation of FBG and PPBG and large imprecision in analysis, some researchers have advocated the use of HbA1c only for diabetes diagnosis.It is essential to understand that laboratory error, though present in few cases is not always the cause for higher fasting blood glucose level than postprandial level. Healthy subjects with such laboratory finding should be followed for possibility of getting diabetes mellitus type 2 and should be advocated for lifestyle change along with dietary modification. In diabetics, changing the medication dosage, form or time should be considered along with counseling for aforementioned factor that affects laboratory result."} +{"text": "How proteins properly fold and maintain solubility at the risk of misfolding and aggregation in the cellular environments still remains largely unknown. Aggregation has been traditionally treated as a consequence of protein folding (or misfolding). Notably, however, aggregation can be generally inhibited by affecting the intermolecular interactions leading to aggregation, independently of protein folding and conformation. We here point out that rigorous distinction between protein folding and aggregation as two independent processes is necessary to reconcile and underlie all observations regarding the combined cellular protein folding and aggregation. So far, the direct attractive interactions between cellular macromolecules including chaperones and interacting polypeptides have been widely believed to mainly stabilize polypeptides against aggregation. However, the intermolecular repulsions by large excluded volume and surface charges of cellular macromolecules can play a key role in stabilizing their physically connected polypeptides against aggregation, irrespective of the connection types and induced conformational changes, underlying the generic intrinsic chaperone activity of cellular macromolecules. Such rigorous distinction and intermolecular repulsive force-driven aggregation inhibition by cellular macromolecules could give new insights into understanding the complex cellular protein landscapes that remain uncharted. Cellular proteins navigate diverse conformational landscapes including folding, misfolding and aggregation in the cellular environments where polypeptides are physically connected to (or surrounded by) crowded cellular macromolecules with large excluded volume and attractive/repulsive surface area ,2,3,4. SIn contrast to the prevailing view, however, the intermolecular attractive interactions between proteins leading to aggregation can be generally inhibited by the intrinsic and extrinsic factors, independently of protein folding and conformation. For example, charges are the major determinants dictating solubility or aggregation inhibition of molecules including chemicals, cellular macromolecules and colloids in the aqueous phase due to intermolecular repulsions including direct repulsions and desolvation penalty ,10. The The hydrophobic interactions between chaperones and their substrates have been known to be important for the substrate recognition and binding ,20. ThesWe here point out the necessity of rigorous distinction between protein folding (or misfolding) and aggregation as two independent processes for properly integrating protein folding, misfolding and aggregation and the potential importance of the intermolecular repulsive force-driven aggregation inhibition underlying the generic intrinsic chaperone activity of cellular macromolecules including chaperones.In contrast to the prevailing view treating aggregation as a consequence of protein folding (or misfolding), they need to be rigorously distinguished as two independent processes to properly integrate them and to underlie the effects of the intrinsic and extrinsic factors on the combined protein folding and aggregation without conceptual conflict or misunderstanding.The protein folding properties and the direct attractive interactions between proteins and cellular macromolecules can be described with a single protein molecule whereas aggregation is difficult to explain or predict with the behaviors of a single molecule. The relationship between protein folding and aggregation can be well illustrated and visualized using a single protein in the GroEL/ES chamber . In the Such independency can be further demonstrated. The importance of the factors to stabilize proteins against aggregation was mentioned in the Introduction. When these factors are considered only for one fixed state among unfolded, misfolded and folded states of proteins, the factors are not related to the intramolecular conformational change between them at all. Protein folding and conformational change cannot address why, for example, unfolded (misfolded or folded) conformers maintain their solubility against aggregation in given environments. Indeed, the unfolded proteins maintain their solubility mainly by their charged (or hydrophilic) moieties. Similarly, the solubility maintenance and aggregation of folded proteins are independent of protein folding. Moreover, aggregation monomers are generally treated as hard-spheres or structurally invariants in aggregation studies . In thisThe necessity of the rigorous distinction between protein folding (or misfolding) and aggregation as two independent processes can be further illustrated in the case of Janus faced molecular chaperones, the core molecules at the interfaces of protein folding, misfolding and aggregation. Cellular proteins can continuously undergo the kinetic/thermodynamic partitioning between protein folding and aggregation even before folding ,13. ProdThe Anfinsen\u2019s thermodynamic hypothesis is a tenet of protein folding that the native structures of proteins are thermodynamically most stable under the physiological conditions and thus fold spontaneously . The relWhen protein folding and aggregation are treated as the two independent, combined intramolecular and intermolecular reactions , this moThe magnitude of steric and electrostatic repulsions can overwhelm that of stabilizing attractive interactions for biomolecular assembly and binding. The excluded volume of molecules is a constraint for all biomolecular assembly and binding; for example, the excluded volume of a single hydrogen atom cannot be violated. Conformational space violating excluded volume cannot be accessible to proteins . ConsistTransfer a charged residue from water to hydrophobic core can generate a large desolvation penalty up to 19 kcal/mol ,58. ConsThe following reasons further support the intermolecular repulsive force-driven aggregation inhibition by cellular macromolecules. Aggregation is a multimolecular assembly of polypeptides that brings involved molecules in close proximity to each other increasing the repulsions between molecules; aggregation is neither unimolecular nor bimolecular reaction. Furthermore, it can be specific ,63. AggrThe intermolecular repulsions exhibit the following unique features, underlying the generic intrinsic chaperone activity of cellular macromolecules as mentioned previously . First, E. coli Hsp70 homolog) molecules can induce the expansion of their bound substrates or unfolding, rescuing the kinetically trapped intermediates . Th. Th17]. The chaperones and folding catalysts including Hsp60, Hsp70, Trigger factor, Spy, protein disulfide isomerase and peptidyl prolyl isomerase strongly prevent the aggregation of their fused proteins in cis ,85,86,87The generic intrinsic chaperone activity of cellular macromolecule can be harnessed for the development of therapeutic strategies for the aggregation-associated diseases. The polypeptides involved in the diseases are physically (directly or indirectly) connected to a myriad of cellular macromolecules including domains and other proteins. Such cellular macromolecules possibly exerting the chaperone effect on their connected polypeptides can be drug targets as suggested previously . ConsistA general feature of the cellular environments is the physical connection of polypeptides with a myriad of cellular macromolecules with large excluded volume and attractive/repulsive surface area. So far, the effects of cellular macromolecules including chaperones on the combined protein folding and aggregation have been mainly understood through the lens of the protein folding properties and the direct attractive interactions between cellular macromolecules and polypeptides. In contrast to the prevailing view, we here point out that it is critical to rigorously distinguish between protein folding (or misfolding) and aggregation as two independent processes in order to properly integrate them. Due to the independency between protein folding and aggregation, the intrinsic and extrinsic factors independently affect protein folding and aggregation. Moreover, this new view rationalizes the generic intrinsic chaperone activity of cellular macromolecules by the intermolecular repulsive force-driven aggregation inhibition. The rigorous distinction between protein folding and aggregation and the intermolecular repulsive force-driven aggregation inhibition can give new insights into how proteins maintain solubility in the presence of misfolding and aggregation at the proteome level in the cellular environments.The cellular protein landscapes in the protein science community have been mainly understood in the structure formation (including binding) and the pathway analysis of it, based on the attractive interactions stabilizing structures and binding to date. This trend can be blind to the intermolecular repulsive force-driven inhibition against the structural formation such as aggregation. For example, there is no consideration of the obvious charge effect on protein solubility in the chaperone concept and proteostasis concept that mainly handle the solubility maintenance of proteins against aggregation. Moreover, the intermolecular repulsions of megadalton-sized ribosomes with supernegative surface charges in terms of aggregation is not considered as described in the macromolecular tethering although the intermolecular repulsions of a single charged amino acid on aggregation is considered. It is rather shocking that, so far, cellular macromolecules have been mainly understood such as this ribosome case in terms of aggregation, based on protein folding and attractive interactions. The diverse cellular protein landscapes can be largely affected by the intermolecular repulsive forces of bulky cellular macromolecules physically interacting proteins. Therefore, the destabilizing intermolecular repulsive forces of cellular macromolecules, distinct (but fully compatible with) from conformational change, conformational entropy and attractive interactions, need to be considered in order to describe the diverse cellular protein landscapes consistently and accurately."} +{"text": "Assintomatic infundibula stricture is a late complication of percutaneous nephrolithotomy (PCNL) and can have serious consequences. Parsons et al in previThe rigid nephroscopy can usually reach the renal pelvis when the puncture is made in the lower pole but reaching upper pole calyces and interpolar calyces without placing undue torque on the renal parenchyma can be challenging, especially in obese patients with low-lying kidneys because of hindrance from the iliac crest. In these cases a steeper torque associated with a large expansion orifice may result in the formation of scar tissue and stricture.This prospective study investigated the impact of PCNL on retrograde intra-renal surgery (RIS) outcomes found a rate of infundibula stricture much higher than those previously described, reaching a quarter of operated patients, probably due to the factors described above .We conclude that, in addition to previous imaging exams, the surgeon must be prepared to find and treat the infundibula stricture in patients previously submitted to PCNL."} +{"text": "Emotions help guide our everyday choices in complex life situations. We are more likely to continue to perform certain tasks or to prefer certain places/situations if they induce a positive emotional valence, while avoiding those that induce negative valence. This type of emotional processing can also greatly affect memories, with emotionally salient events more likely to be remembered long-term. Such emotional processing is dependent on a widely distributed set of brain regions and neurocircuits that respond to both intrinsic and extrinsic factors. Dysregulation of these emotional processing pathways can lead to a wide variety of serious mental health disorders. Therefore, determining how intrinsic and extrinsic factors can alter emotional processing is likely to provide key understanding of the development of many mental health issues.Coker et al. reviewed the current literature examining how diets high in fat can alter key neuronal circuitries and neurotransmitter systems involved in emotional processing, how diets can alter insulin and glucose regulation, and how these seemingly disparate systems may interact in the context of alcohol use. In particular, this review focuses on the novel concept that high fat diets may impact neurocircuitry that is often associated with alcohol use disorder. Since high fat diet and alcohol intake often result in activation of overlapping circuits, this article highlights two important views: (1) binge consumption of high fat diets can sensitize increased alcohol intake and thus diet may be a risk factor for development of alcohol use disorders; and (2) high fat diets can be used to mitigate or offset neurocircuit dysregulation during alcohol withdrawal and serve to reduce alcohol intake overall. In addition to neurocircuit changes, diet and alcohol can also alter gut microbiome, which has also been shown to be involved in regulation of emotional processing. In accordance with the hypothesis that the microbiome plays an important role in altering behavioral indices of emotion regulation, Dauge et al. provided novel experimental data showing that treatment with a probiotic formula can decrease anxiety-like and depressive-like behaviors in rodent models of maternal stress and genetic stress sensitivity. Other extrinsic factors described in this collection can alter activity in brain regions known to be involved in emotional processing.The goal of this article collection is to provide an update on how diverse factors, either intrinsic or extrinsic in nature, can alter neural pathways involved in emotional processing. Articles within this collection describe a number of factors that may modulate emotional regulation and result in behavioral changes. Two articles focused on the role of diets in emotional behaviors. Javanbakht et al. utilized a clinical laboratory model of fear conditioning and instructed extinction learning. Their findings indicate that subregions of the prefrontal cortex and parahippocampus gyrus show increased activation during extinction learning. Using the left ventromedial prefrontal cortex as a seed region, the authors found increased prefrontal cortex activity during extinction learning was associated with significant co-activation of the dorsal medial prefrontal cortex, parahippocampus, insula, and amygdala. Other articles in this collection utilizing preclinical models or analysis of the literature confirm the importance of the prefrontal cortex (Brockway and Crowley) and the amygdala , and further indicate that the bed nucleus of the stria terminalis (Giardino and Pomrenze) and paraventricular nucleus of the thalamus are also critically important for regulation of emotional memories and behaviors. Within these brain regions, a number of signaling systems are proposed to be critical for emotional regulation. This is especially important in brain regions which have highly heterogenous cell-types with potential overlapping neurotransmitter and neuropeptide content, like the bed nucleus of the stria terminalis, or in brain regions like the paraventricular nucleus of the thalamus that has multiple cell types across anatomical subregions. Determining how these cell types coordinate emotional memory under typical and dysregulated conditions will be critical as the field continues to develop.Emotional processing is thought to involve distributed networks of brain regions. In this article collection, Brockway and Crowley). Many of these peptides are co-released from GABAergic neurons in the prefrontal cortex and appear to be responsible for regulating the activity of both local circuits within the prefrontal cortex and the activity of glutamatergic projection neurons. Dao et al. examined how somatostatin neurons in the prefrontal cortex, basolateral and central amygdala, and bed nucleus of the stria terminalis were altered following forced abstinence from alcohol in preclinical models. This work showed that alcohol abstinence increased somatostatin neuron activity in the prefrontal cortex which may dampen overall prefrontal cortex local network activity while somatostatin neuron activity in the bed nucleus of the stria terminalis was also altered. These findings appeared to be more pronounced in female mice compared to male mice, suggesting distinct sex differences within this model. Sex differences were also shown in a study in this collection by Anderson et al. examining a subset of GABAergic neurons in the prefrontal cortex containing parvalbumin. The authors found that genetic deletion of g-protein coupled inwardly rectifying potassium (GIRK) channels from parvalbumin neurons throughout the brain resulted in increased time in the open arms of the elevated plus maze in both males and females, but an increase in immobility episodes in the forced swim test only in males. While the authors found sex differences in reversal learning models, modulation of GIRK expression in parvalbumin neurons did not seem to alter these behaviors. Modulation of GIRK expression resulted in larger afterhyperpolarization of prefrontal cortex parvalbumin containing GABAergic neurons in both sexes but this resulted in increased action potential firing only in male mice. These findings further highlight the importance of examining sex differences as the field continues to develop.Studies to examine neuronal subtype function on behavior are underway in the prefrontal cortex, as highlighted by two studies within this collection. Both clinical and preclinical evidence suggests that a number of neuropeptides, including neuropeptide Y, corticotropin releasing factor, somatostatin, and endogenous opioids, are critical for emotional memory (In summary, the articles of this collection highlight the complexities of understanding emotional processing. Such complexities are due to numerous factors, such as distributed neural networks, various levels of neuronal processing, and multiple neurotransmitter and neuropeptide systems. Studies in this collection describe how these factors are altered by intrinsic and extrinsic influences, such as stress, diet, or drug exposure, that can all lead to altered signaling within the distributed network of brain regions involved in emotional regulation. While future studies will be needed to further delineate such mechanisms, the articles in this collection provide novel avenues for these critically important studies to explore.YS wrote and edited the manuscript.This work was supported by NIH grants AA026865 and AA022937.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Amaranthus genus.Adapting agriculture to global climate change, shifting patterns in food consumption, fulfilling the priorities of national and international programs, and instability in agricultural research funding trends will all be crucial challenges in the coming decades. Over the past 50 years, food supplies worldwide have trended toward increased homogeneity and interdependence on a limited number of major crop commodities genes. Trehalose-6-phosphate has emerged as an important signaling compound for plant growth and is known to help some plants withstand long periods of desiccation (Paul et al., Amaranthus and other crop species.In comparison, Amaranthus species are available (Clouse et al., Deb et al. have contributed a valuable new reference genome of a superior local landrace variety of A. hypochondriacus from India. The significance of this study is not only a reference genome more suitable for breeding South Asian varieties of A. hypochondriacus, but also in demonstrating a methodology that could be applied to other local landraces and orphan crops in developing countries. This study is a welcome addition and complements previous efforts by Wu and Blair (Although genomic resources for several cultivated and weedy nd Blair and Stetnd Blair in genotNardo et al. reviews progress in this area over the last decade focusing on amaranth's promising role as a functional food with antihypertensive properties. Amaranth contains several bioactive compounds, including encrypted peptides with inhibitory functions against enzymes of the Renin-Angiotensin-Aldosterone System, which are targets of commonly prescribed pharmaceutical drugs for controlling hypertension. These bioactive compounds show promise for formulation of novel functional foods, but the authors also address the challenges related to demonstrating biological activity in complex food matrices.Many studies have explored the chemical composition of amaranths revealing an exceptional nutritional balance compared to staple crop species. In this Research Topic, Altogether, the papers presented in this Research Topic highlight the multidimensional benefits of both grain and vegetable amaranths and will facilitate interdisciplinary research for more climate-resilient varieties of orphan crops for sustainable food production across the world and improved human health among vegetarians and low-income consumers dependent on grain based diets.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "This study investigated whether older Americans with physical disability were vulnerable to three types of economic insecurity and two types of food insecurity during the early months of the COVID-19 pandemic. We evaluated the extent to which associations are moderated by three personal characteristics and two pandemic-specific risk factors . Data were from a random 25 percent subsample of the Health and Retirement Study participants who completed a COVID-19 module administered in 2020. Our analytic sample included 3,166 adults aged 51 and older. We estimated logistic regression models to document the odds of experiencing each hardship. Persons with three or more functional limitations reported significantly higher odds of both types of food insecurity, and difficulty paying regular and medical bills, relative to those with no limitations. After controlling for health conditions, effects were no longer significant for paying medical bills, and attenuated yet remained statistically significant for other outcomes. Patterns did not differ significantly on the basis of the moderator variables. Older adults with more functional limitations are vulnerable to economic and food insecurity during the pandemic, potentially exacerbating the physical and emotional health threats imposed by the pandemic. Our findings reveal an urgent need to promote policies and procedures to protect older adults with disability from economic and food insecurity. Supports for older adults with disability should focus on logistical as well as financial support for ensuring food security."} +{"text": "These observations, bolstered by analysis based on kinetic modeling of the time course of recurrence following initial events, suggest that acute stroke patients experience an underlying vulnerable state that quickly transitions to a more stable state. Some evidence also supports the benefits of early treatment with direct-acting oral anticoagulants in cardioembolic stroke and of continuation or early initiation of statin therapy in atherosclerotic stroke. Treatment of ischemic stroke should address the transient vulnerable state that follows the initial event, employing measures aiming to avert early recurrence of thromboembolism and to promote stabilization of vulnerable arterial plaque. These measures constitute In the hospital care of acute ischemic stroke patients, initial clinical management is tightly focused on interventions aimed to reverse ischemia through induced reperfusion and to limit early complications of brain infarction. Investigations are undertaken to rapidly explore potential mechanisms of stroke, and planning for discharge quickly begins, with selection of the appropriate rehabilitation program to meet the patient's needs. Careful consideration of preventing a subsequent stroke is often relegated to the ambulatory setting. Instead, secondary prevention needs to be considered acutely, as the highest risk for recurrent stroke is typically in the first several days following an initial ischemic event , 2. RiskEarly secondary stroke prevention trials generally had enrollment windows extended for months following the ictus, missing early detection of stroke recurrence. Exceptions were the Chinese Acute Stroke Trial and the Analyses of the CHANCE and POINT trials have confirmed that the benefits of dual antiplatelet therapy over aspirin alone accrued entirely in the first few weeks following stroke, while the small excess bleeding risk accompanying dual antiplatelet therapy continued at an approximately constant rate over the entire duration of the study period , 10. Forpost-hoc analysis of the CHANCE trial data found that the risk of recurrent stroke was substantially greater in those patients with intracranial atherosclerosis as the probable mechanism of stroke and that risk reductions of dual antiplatelet therapy were numerically confined to this group, though the interaction of subgroup with treatment effect did not reach significance following ischemic stroke in atrial fibrillation is the focus of ongoing trials. Existing evidence shows that anticoagulation with DOACs in the early period (3\u20135 days) following ischemic stroke at least can be applied with a low frequency of associated symptomatic intracranial hemorrhage events , 22. AnaCervical carotid artery disease raises an additional dilemma regarding acute secondary prevention: unstable plaque in the internal carotid artery is well-recognized to lead to a very high risk for recurrent stroke, particularly in the early period following initial stroke or TIA , and yetA subgroup of cervical carotid stroke patients has a distinctive pattern of crescendo TIA or stroke-in-evolution, often due to hypoperfusion resulting from severe carotid stenosis, with progressive symptoms unresponsive to medical stabilization, and a high risk of severe stroke outcome. These observations have driven a trend toward earlier carotid revascularization in selected cases of unstable ischemia, with acceptable complication risks reported in a large observational study of carotid endarterectomy performed within 48 h of onset of TIA or stroke-in-evolution . HoweverOne-quarter to one-third of ischemic strokes remain unexplained after standard inpatient etiologic evaluations. Many of these cases have features strongly pointing to an embolic mechanism of stroke. These cases have been categorized as \u201cEmbolic stroke of undetermined source,\u201d or ESUS, and the supposition that many of these events are occurring due to cardioembolism has led to testing of anticoagulation as a potentially more efficacious method of secondary prevention than aspirin. Thus far, randomized trials have not shown any superiority of DOACs over aspirin for secondary prevention following ESUS , 28. TheThough the role of statins in long-term secondary prevention in stroke of presumed atherosclerotic mechanism is well-established, data regarding early initiation of statin therapy are limited. A large retrospective study showed that patients on statins prior to stroke hospitalization had improved post-stroke survival, especially when statins were restarted with 2 days of the stroke, whereas statin withdrawal at the time of the stroke was associated with increased mortality . A smallacute secondary prevention. Clear evidence has established the efficacy of dual antiplatelet therapy with clopidogrel and aspirin and has suggested a possible role for ticagrelor. In atrial fibrillation-related stroke, early institution of anticoagulant therapy with DOACs may also safely prevent an initial wave of stroke recurrence. Statin treatment during and after stroke admission is associated with lowered mortality and dependency following the stroke and is generally indicated for long-term secondary prevention. Further investigations will need to explore ways to promote plaque stabilization following initial atheroembolic events from ruptured plaque, perhaps the chief entity accounting for the vulnerable state transiently following an initial ischemic event. Efforts aimed at preventing early stroke recurrence have long-term consequences for patients, including averting cognitive impairment, a frequent consequence of incident and recurrent lacunar stroke (acute secondary prevention in the transition between acute treatments and long-term preventative care.Driven by recent clinical trials examining the early hours following the initial stroke, management of acute stroke and TIA has begun to address r stroke , 34. HosZB and JB developed the concept for this article. JB wrote the first draft and edited further drafts. ZB and SM reviewed and revised the article. All authors agree to be accountable for the content of the work.This work was internally funded through academic support of the Department of Neurology of the University of Chicago.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "It is well known that seagrass meadows sequester atmospheric carbon dioxide, protect coasts, provide nurseries for global fisheries, and enhance biodiversity. Large-scale restoration of lost seagrass meadows is urgently needed to revive these planetary ecosystem services, but sourcing donor material from natural meadows would further decline them. Therefore, we advocate the domestication and mariculture of seagrasses in order to produce the large quantities of seed needed for successful rewilding of the sea with seagrass meadows. We provide a roadmap for our proposed solution and show that 44% of seagrass species have promising reproductive traits for domestication and rewilding by seeds. The principle of partially domesticating species to enable subsequent large-scale rewilding may form a successful shortcut to restore threatened keystone species and their vital ecosystem services. Seagrass meadows provide multiple global and local ecosystem services, including carbon sequestration , high stochasticity , and natural fragmentation . Seagrasses cope with these hurdles by the power of large numbers: large shoot numbers to reach densities that reduce the impact of physical stress and small-scale stochasticity, large meadow areas to generate positive feedback loops at landscape scale, and large numbers of surrounding meadows with dispersing seeds to recolonize meadows lost in large-scale stochastic events. From population dynamic theory, it is known that this combination of strong positive feedback loops and stochasticity inevitably leads to intermittent local population extinctions, meaning that persistence in an area depends on reintroductions from nearby populations within the same metapopulation and landscape scale for which sufficient data was available . This resulted in 12 species that are highly suitable potential candidates for domestication and rewilding and 7 that are intermediately suitable preparing for domestication and mariculture is not much, given that land-based agriculture has already a history of thousands of years and agricultural techniques still improving. Although seagrass restoration with return of nearly all functions can be achieved within 10\u201320 years (Orth et al. In conclusion, domestication to enable rewilding could become an important strategy to restore keystone species in a changing world, shaping valuable ecosystems and their services and goods. For seagrasses, a domestication trajectory could start with the species with high seed production and short life cycles selected in this review. The proposed domestication of seagrass to enable rewilding may likely exceed budgets traditionally assigned to nature restoration projects by orders of magnitude but will also be more profitable. Rather, investments should be part of budgets required for climate change mitigation, agricultural innovations, and land and sea use transitions in the future era.biab092_Supplemental_FilesClick here for additional data file."} +{"text": "The aim of this study was to perform a systematic review for previous publications that have assessed the incidence, risk factors, and favorable procedures to prevent and manage falls among cancer survivors of elderly and older adults.This systematic review was undertook using PubMed, SCOPUS, Web of Science, Medline, and Cochrane Database of clinical studies and systematic reviews to determine the incidence, risk factors, favorable inpatient and outpatient management, and non-pharmacological interventions for falls among elderly and older adult patients with cancer from 2010 to October, 2020.After the comprehensive screening, clinical studies, meta-analysis, systematic reviews, and established guidelines were included in this review. Only 5 clinical studies (3 randomized and 2 single-arm studies), 5 systematic reviews, and 6 established guidelines were considered eligible. The five systematic reviews provide risk factors of falls and the 6 guidelines provide assessment & prevention modalities of falls, however, the 6 clinical studies provide the non-pharmacological intervention for falling among cancer survivors. Many factors associated are demonstrated among wide range of elderly individuals. Earlier falls were reliably listed as an important risk factor of falls in the two inpatient and outpatient environments including both general older people and geriatric cancer populations.This review concludes that the assessment of falls among older individuals with cancer is the most important way for determining who could need additional observation and treatment program. Health professions involving physical therapy and occupational therapy have an important function for promoting health well-being in elderly and older adults with cancer. Fall is a critical health issue in the elderly and older adult people Cancer is identified an aging disease. The growing number of aged population combined with incidence of cancer may regard a predictable sixty-seven increasing in the prevalence of cancer among older people in 2030.6Accordingly, recent studies should identify the whether the falls risks will be grown among elderly and older adult patients with cancer, and identify the factors associated with falls among those susceptible individuals. Therefore, we conducted a systematic review to assess the rate, risk factors, and proper interventions of falls among elderly and older adult patients with cancer.According to the guidelines and framework of PRISMA checklistIdentical provisions and keywords (in differing arrangements) were included in the exploring for concepts of cancer, elderly, older adults, falls, risk factors of falls, prevention of falls, and screening. The search was limited to the English language.References which indexed in the articles were also utilized to recognize additional researches. Regarding the factors associated with falls among cancer survivors, the search strategy was arranged in accordance with indoor and outdoor environments (despite a number of the guidelines is relevant to both settings) as the risk factors associated with falls are not essentially similar. Guidelines were also sorted according to the inpatient and outpatient setting because fall risk factors are not necessarily universal across locations.Clinical studies were included to detect the non-pharmacological interventions in the treatment of falls among cancer survivors. Regarding consistency, the evidence levels of interferences declared by the strategy were transformed in accordance with the following criteria: 1) systematic reviews of randomized studies, 2) randomized studies/observation studies with impressive impacts, 3) non-randomized cohort studies/prospective studies, and 4) case reports and case-control studies.From the comprehensive screening, clinical studies, meta-analysis, systematic reviews, and established guidelines were included in this review. 5 clinical studies (3 randomized and 2 single-arm studies), 5 systematic reviews, and 6 established guidelines were considered eligible. The five systematic reviews provide risk factors of falls and the 6 guidelines provide assessment & prevention modalities of falls, however, the 6 clinical studies provide the non-pharmacological intervention for falling among cancer survivors.Five systematic reviews provided the risk factors of falls among elderly and older adults with cancer Some reviews and guidelines have demonstrated the favorable interventions for falls in the inpatient environments,18Inpatient management; as demonstrated in 23Outpatient management; as detailed in 17Other recommendations were provided for preventing falls such as the frequent assessment of falls22Nutrition and physical exercise therapy showed an improvement in cancer care field.We conducted the current systematic review to assess the risk factors and proper interventions for falls among elderly and older adult patients with cancer. The findings showed that the falls history is the commonest risk factor for falling among elderly and older adults suffering cancer whether inpatient or outpatient settings. Consequently, elderly individuals have to be assessed for recent falls when happened. Despite the variations of interventions were recommended, assessing falls each medical visit, particularly in the outpatient or outdoor settings as the aged people are commonly suffering from quick functional impairments related to the development of cancer disease.Twenty percent of elderly individuals are experiencing disturbance in activity daily livings when exposing to chemotherapy.The several strategies of falls management were highly recommended by the reviewed guidelines. Combination between exercise intervention and the multifactorial evaluation and treatment also is highly commended for preventing and managing falls among elderly people, particularly experiencing cancer.35Physical therapy assessment has a key role for proper evaluation of the musculoskeletal system, especially physiotherapists who have expertise in assessment of falls and have the sufficient skills for creating safe exercise programs for preventing falls among elderly individuals.38Fall among elderly and older adult patients with cancer is growing as the number of aged people is continuously increased. The current review provides the common risk factors of falls and the efficient modalities for preventing falls in those individuals according to the published systematic reviews and the created guidelines.This review concludes that the assessment of falls among older individuals with cancer is the most important way for determining who could need additional observation and treatment program. Health professions involving physical therapy, occupational therapy, and exercise intervention have an important function for promoting health well-being in elderly and older adults with cancer. However, future studies examining the different effects of tailored technology-based training and traditional exercise intervention are required to achieve the most desired benefits in preventing falls among elderly and older adults."} +{"text": "Development of reliable and valid measurements to quantify biological aging is a critical frontier geroscience. Originating in accumulations of molecular changes, biological aging undermines resilience within cellular networks and organ systems, driving disease, disability, and mortality. Measurements of biological aging have been proposed at several molecular and physiological levels of analysis. But agreement between measures implemented at different levels of analysis is low. The timing at which aging processes manifest at different levels of biological organization may vary, with the result that signs of aging manifest in one level of analysis are not yet observable in another. And different aging processes may be most apparent in different molecular levels of analysis. In midlife humans, aging-related changes are manifest at multiple molecular and physiological levels, making this population ideal for development of measurements that integrate information across levels of analysis to more precisely quantify the state and pace of biological aging."} +{"text": "Prospective memory, the ability to remember to execute an intention in the future, is crucial for the performance of many everyday tasks important for independent living. Prospective memory abilities decline with age, and older adults living with mild cognitive impairment (MCI), cognitive impairment due to traumatic brain injury (TBI), and cognitive impairment due to stroke are especially susceptible to prospective memory failures. The goal of the Digital Reminders for Everyday Activity Memory (DREAM) project is first to establish proof of concept for an adaptive cognitive aid to support the prospective memory of older adults with various cognitive impairments, and then establish proof of product in studies examining the use of a working prototype within the lab and within participants\u2019 homes. Data will be presented from initial work verifying product requirements through engagement with stakeholders, including subject matter experts, older adults with cognitive impairments, and their care partners."} +{"text": "ABSTRACT IMPACT: Measuring and analyzing qualitative and quantitative traits using phenomics approaches will yield previously unrecognized heart failure subphenotypes and has the potential to improve our knowledge of heart failure pathophysiology, identify novel biomarkers of disease, and guide the development of targeted therapeutics for heart failure. OBJECTIVES/GOALS: Current classification schemes fail to capture the broader pathophysiologic heterogeneity in heart failure. Phenomics offers a newer unbiased approach to identify subtypes of complex disease syndromes, like heart failure. The goal of this research is to use data-driven associations to redefine the classification of the heart failure syndrome. METHODS/STUDY POPULATION: We will identify < 10 subphenotypes of patients with heart failure using unsupervised machine learning approaches for dense multidimensional quantitative and qualitative data extracted from an integrated health system electronic health record. The heart failure subphenotypes we identify from the integrated health system electronic health record will be replicated in other heart failure population datasets using unsupervised learning approaches. We will explore the potential to establish associations between identified subphenotypes and clinical outcomes . RESULTS/ANTICIPATED RESULTS: We expect to identify < 10 mutually exclusive phenogroups of patients with heart failure that have differential risk profiles and clinical trajectories. DISCUSSION/SIGNIFICANCE OF FINDINGS: We will attempt to derive and validate a data-driven unbiased approach to the categorization of novel phenogroups in heart failure. This has the potential to improve our knowledge of heart failure pathophysiology, identify novel biomarkers of disease, and guide the development of targeted therapeutics for heart failure."} +{"text": "Esophageal cancer (EC) is an aggressive malignancy and a major health burden documented as the sixth most common cause of cancer mortality worldwide . Over 80The African ESCC corridor , which sThere is an apparent lack of genomic studies on ESCC on African populations, therefore the genetic etiology is poorly understood and implementation of genomic medicine for ESCC remains elusive. The striking geographical distribution of ESCC suggests that ESCC etiology is multifactorial, with shared and locally relevant environmental and genetic risk factors. There are several mutational signatures in ESCC that have been linked to environmental exposures, including tobacco smoking and alcohol consumption . It is, . These studies had several limitations: 1) small sample sizes leading to poor statistical power; 2) no cohort studies; and 3) no standardized methods of data collection, reporting, or analysis. In addition, the studies did not correct for population structure in cases and controls, which is particularly relevant in African populations known for high levels of genomic diversity , Johannesburg Cancer study activity but, surprisingly, not of tobacco smoke.Genomic analysis of tumor tissues by DNA and RNA sequencing in large-scale global projects such as the Cancer Genome Atlas (TCGA) has led A recent study investigGenomic studies provide critical information about the pathobiology of diseases, which improves our understanding of the risk and heritability of ESCC, risk prediction for populations and individuals, and contributes to cancer prevention . ESCC geGenomics can be used as a tool to address health disparities in cancer . There abroader characterization of the genomic diversity of African individuals to understand human ancestry and improve health\u201d (A recent study explored health\u201d . It remaThe Pan-Cancer Analysis of Whole Genomes Consortium performed the most comprehensive meta-analysis of cancer genomes to date, using 2,658 tumors and 38 tissues . Of thesThe lack of investment in genomic medicine in Africa has led to most genomic medicine knowledge being founded on genomes of European ancestry, despite African populations displaying higher levels of genetic diversity. A major barrier to implementing genomic research in Africa is inadequate infrastructure including poorly equipped facilities, erratic power supply, inadequate biotechnology and information technology infrastructure as well as the high cost of genomics tools and the costs associated with implementing genomic medicine . These aAfrican genomes harbor the most genetic diversity and variation, and yet are the least genetically characterized. This means that genetic variants of medical relevance remain unknown . For ESCFurthering genomic medicine in Africa requires leveraging existing infrastructure and learning from the extensive experience of current genomic medicine implementations in other countries . This reGenomics is an invaluable approach in providing unbiased information about the pathogenesis of ESCC. The information could be used to predict risk, screen asymptomatic individuals, diagnose more accurately and develop targeted treatments. We are still far from being able to implement genomic medicine for ESCC in Africa since genomic information on African ESCC patients is very limited."} +{"text": "Mexican immigrants make up an increasing proportion of the US population 65 and older. Whereas this population has among the lowest rates of disability at working ages, there is growing evidence of high rates of disability at older ages, findings which contradict what mechanisms of selection, namely the \u201csalmon bias,\u201d would predict. However, largely due to data limitations disability rates between those who stay in the US into older ages and those who return to Mexico are rarely compared. Here two waves of data from the US based Health and Retirement Study and the Mexican Health and Aging Study are combined to create a novel dataset that enables an interrogation of the widely held assumption of negative selection on health among return migrants. Investigating three measures of functional limitation and disability, results show higher prevalence of disability for stayers as compared to both younger and older returnees. These results are robust to controls for childhood background, adult socioeconomic status, and migration related variables and hold for those who immigrated during different immigration policy regimes. These findings are novel not only because they stand in opposition to previous assumptions about the direction of health selective return migration, but also because they mean that those remaining in the United States into older ages are among the most vulnerable."} +{"text": "Although a number of studies have examined relationships between religiosity and social attitudes, less is known about how these relationships change over the life course using a multidimensional construct of religiosity among Baby Boomers. A multidimensional construct of religion allowed us to take a more person-centered approach to religiosity, whereby we examine the association between Baby Boomers with different types of religiosity and the trajectories of their political and gender role attitudes over a period of transition from early to later adulthood. We selected 798 young-adult Baby Boomers from the 1971 wave (mean age: 19 years) of the Longitudinal Study of Generations (LOSG) and tracked their political and gender role attitudes through until the 2016 wave (mean age: 64 years). Using latent class analysis, we identified four latent religious typologies: strongly religious, weakly religious, liberally religious, and privately religious. We found that Baby Boomers in the strongly religious class reported the most conservative political and gender role attitudes among the four classes over this period of transition. Baby Boomers in the privately religious class were conservative in their political and gender role attitudes than those in the weakly religious class. The liberally religious group generally reported the second most conservative political attitudes among the four identified groups, but reported the least conservative gender role attitudes of the four groups. Findings suggest that early religiosity may serve as a significant predictor affecting political and gender role attitudes throughout the adult life course."} +{"text": "Highlighted Research Paper:In Vivo, by Haiwen Chen, Richard H. Roth, Elena Lopez-Ortega, Han L. Tan, and Richard L. Huganir.AMPA Receptors Exist in Tunable Mobile and Immobile Synaptic Fractions Information processing in the nervous system emerges from complex temporal and spatial interactions between fast excitatory synaptic neurotransmission and modulatory signals from other neurochemicals. A critical property of excitatory synapses is that they undergo bidirectional changes in synapse strength in response to experience to encode relevant information for future recall. This process is referred to as Hebbian plasticity and is aHomeostatic plasticity is primarily accomplished through altering the number and composition of excitatory neurotransmitter receptors found at postsynaptic sites . Glutamain vitro, generally using fluorescence recovery after photobleaching or FRAP. In these experiments, AMPA receptors are labeled with a fluorescent tag that allows receptors to be tracked during live imaging. A segment of plasma membrane containing AMPA receptors is then photobleached through excessive illumination, and researchers measure the time and extent to which the fluorescent signal recovers in the bleached region. A rebound in fluorescence within the bleached membrane segment indicates that AMPA receptors diffused into the region following photobleaching. Estimates of AMPA receptor diffusion using in vitro FRAP experiments have been highly variable, ranging from estimates that anywhere between 20% and 100% of AMPA receptors are mobile within the plasma membrane (in vitro preparations may alter the biology that exists in vivo. Resolving these inconsistencies is of profound importance as it can point to which mechanisms of homeostatic plasticity predominate within the brain.Until recently, AMPA receptor motility in the plasma membrane had only been studied membrane . Such dieNeuro provide the first in vivo estimate of AMPA receptor mobility in the plasma membrane. In experiments with a high degree of technical difficulty, Chen and colleagues used in utero electroporation to tag AMPA receptors with fluorescent probes and implanted mice with cranial windows for two-photon in vivo imaging once they reached adulthood. They then performed FRAP experiments by photobleaching synaptic spines and measuring the fluorescence recovery in the visual and motor cortices. In both regions, roughly 50% of the fluorescent signal recovered following quenching, suggesting that a significant proportion of AMPA receptors are immobile at basal states in live animals.New results by Many CNS disorders are characterized by changes in synapse strength and network excitability that could involve alterations in AMPA receptor mobility. Exposure to significant stress, particularly in early life, is one of the strongest risk factors for developing pathologic brain conditions and stress hormones can alter synaptic transmission and plasticity . To testin vivo exist in a state of intermediate AMPA receptor motility that maximizes the dynamic range over which synapse strength can be bi-directionally modulated. Furthermore, the finding that corticosterone treatment significantly altered these dynamics indicates that systemic factors associated with different physiological states can have immediate and profound impacts on synapse function and network scaling. These rigorous in vivo data provide a critical foundation for future in vivo and in vitro studies of AMPA receptor dynamics aimed at revealing the mechanisms underlying physiological and pathologic synaptic and network function in numerous contexts.In summary,"} +{"text": "Communicating about antimicrobial resistance (AMR) and antimicrobial stewardship (AMS) requires technical knowledge, consideration of audience values and appropriate identification of communication strategies for multiple audiences. Within the context of animal agriculture, communicating about AMR represents an important and complex endeavour for veterinarians, governmental agencies, producers and the industry to convey policy and practice information regarding the use of antimicrobials in food animals.To assess the science communication challenges related to AMR by identifying the motivations, goals and struggles of animal agriculture stakeholders when communicating about AMR and AMS.N\u200a=\u200a80) completed a workshop on science communication, including small group meetings with oral/written comments collected. Participants included veterinarians, government agency representatives, industry stakeholders and producers.Participants attending a meeting on AMR communication in animal agriculture (Results indicated participants believed providing more accurate information would resolve misunderstanding and concern about AMR to other stakeholders, counter to recommendations of science communicators. Other participants noted beliefs about the utility of stories in trying to explain how AMS is normative and consistent with the values of all parties interested in animal agriculture. Participants noted the importance of public engagement, even if the participants\u2019 perceived target audiences did not include the public.Communicating about AMR and AMS in animal agriculture contexts provide unique challenges. Few evidence-based recommendations are available for science communicators in these contexts and more research is needed to improve the quality of communication about AMR and AMS in animal agriculture. Farmers and producers, those who manage and run operations where animals may be treated with antibiotics, may perceive their stakeholders to be retailers and consumers who buy their product, veterinarians who treat their animals and government officials who might draft regulations producers must follow. Each of these stakeholder groups has unique obligations and limitations related to AMR. For example, veterinarians must adhere to regulations from government agencies, discuss treatment plans for clients and serve as a public-facing group given the visibility of their profession to mainstream audiences. Similar complexities exist for other animal agriculture stakeholders whose diverse obligations, audiences and communication goals require varied, and effective, science communication strategies. At present, few studies examine how the many stakeholder groups in animal agriculture manage and address communication challenges relevant to AMR.The current study reports the outcomes of an interactive, in-person workshop focused on improving science communication about AMR among animal agriculture stakeholders. The objective of the workshop evaluation reported here was to increase understanding about the communicative challenges facing animal agriculture stakeholders and provide a foundation for improving AMR communication efforts in the future.N\u200a=\u200a80) responded to prompts about (i) why communication about AMR is important to their job; (ii) the audience with which they wanted to better communicate about AMR; (iii) a challenging AMR communication situation faced in the past; (iv) the cause of said communication challenge; and (v) how to improve communication efforts in the future.Participants in this study were science communication workshop attendees at a national antibiotic symposium hosted by the National Institute of Animal Agriculture. The workshop included participants representing five stakeholder groups by the public across multiple stakeholder groups.All stakeholder groups indicated the need to improve consumer/public understanding of AMR and AMS at varying levels of priority. Policymakers were the only other audience segment of interest mentioned by most groups.Most participants, across groups, indicated a lack of knowledge (of some audience) hindering communication attempts. Unfamiliarity with animal agriculture practices and policies was another frequently cited source of communication challenges.Participants noted inconsistent messaging, the complexities of AMR policies and concerns, and lack of consumer knowledge as drivers of communication challenges. Other reasons for challenges included beliefs about media messages influencing myths and misperceptions and that animal agriculture messaging often focuses more on precision/accuracy than clarity.ineffective in science communication.Many participants believed using stories and analogies focusing on shared values and emotions might be a useful approach. Other participants advocated for a deficit model approach, relying on the provision of information to the target audience to correct a perceived knowledge deficit. While this strategy remains a popular and oft-cited approach for public outreach, it has been found to be consistently The current study suggests that agricultural stakeholders are aware of the considerable challenges in communicating about AMR to audiences of interest. Many responses for improving communication aligned with strategies that science communicators advocate . However, there were still participants who favoured simply filling the perceived gap in knowledge related to AMR and AMS, which science communication research has shown repeatedly to be unproductive. Findings from this study suggest a need for more engagement between animal agriculture stakeholder groups and social scientists who could provide recommendations/training about communication and public engagement theory and practice that move beyond the deficit model. Moreover, the breadth of opinions and issues addressed by these stakeholders highlights the need for more nuanced approaches to communication/outreach with a diversity of stakeholder groups with animal agriculture interests. Without a larger evidence base, AMR communication will continue to be a challenge, hindering progress toward widespread adoption of AMS behaviours. Evidence-based recommendations will improve communication and facilitate behaviour change that contributes to AMS efforts across animal health contexts."} +{"text": "To understand the genetic basis and the selective forces acting on longevity, it is useful to employ ecologically diverse individuals of the same species, widely different in lifespan. This way, we may capture the experiment of Nature that modifies the genotype arriving at different lifespans. Here, we analyzed 76 ecologically diverse wild yeast isolates and discovered wide diversity of lifespan. We sequenced the genomes of these organisms and analyzed how their replicative lifespan is shaped by nutrients and transcriptional and metabolite patterns. By identifying genes, proteins and metabolites that correlate with longevity across these isolates, we found that long-lived strains elevate intermediary metabolites, differentially regulate genes involved in NAD metabolism and adjust control of epigenetic landscape through conserved, rare histone modifier. Our data further offer insights into the evolution and mechanisms by which caloric restriction regulates lifespan by modulating the availability of nutrients without decreasing fitness."} +{"text": "This study aimed to examine the buffering effect of neighborhood social cohesion on the association of social isolation and suicidal ideation among Korean older people. The sample was older adults who were 65 years old or older and participated in the Korea Health Survey 2017 collected by the Center for Disease and Prevention . Social isolation was measured with three indicators: living-alone, contact isolation , and participation isolation . Neighborhood social cohesion was measured with two indicators: trust in neighbors and the welfare budget ratio to represent social capital and social inclusion capabilities, respectively. Multilevel logistic regression analyses were performed to estimate the dynamic relationships between social isolation, neighborhood social cohesion, and suicidal ideation. Results of the main effect indicated that social isolation is a significant risk factor for suicidal ideation and neighborhood social cohesion works as a protective factor against suicidal ideation. Results of cross-level interactions showed that the welfare budget ratio moderated the association between participation isolation and suicidal ideation . The negative effect of participation isolation was reduced as the welfare budget ratio of the neighborhood increased. Neighborhood social cohesion indicators did not moderate the association between the remaining types of social isolation and suicidal ideation. The evidence from this study highlights the importance of social welfare expenditures when building suicide prevention interventions and age-friendly communities."} +{"text": "Ample research suggests that musical interventions have the potential to boost social connection, engender positive emotions, and potentially buffer against depression in people with dementia (PwD). Here, our focus concerns expanding the present body of knowledge by quantifying the benefits of a music-based nonpharmacological intervention. The Voices in Motion (ViM) choir is an intergenerational sociocognitive lifestyle intervention designed to support caregivers and PwD. Over the course of 18 months, the well-being of PwD and caregiver dyads were rigorously assessed using an intensive repeated measures design. This project set out to determine whether positive change in the social dimensions of health ameliorates depression in PwD. Multilevel modeling was employed to examine longitudinal change within and between individuals. SC significantly predicted intraindividual change , with a predictive trend for between person differences . On occasions when PwD reported more SC, relative to their own baseline, they also reported fewer depressive symptoms. The effect associated with WB was significant at the between-person level . Our analysis suggests that a lifestyle intervention targeting psychological health and wellbeing may also contribute to the depressive signs and symptoms in PwD. As the current health care system is forced to adapt to social distancing and constant precautionary measures, it is crucial to understand and potentially harness the protective effects of modifiable lifestyle factors."} +{"text": "The Arkansas Geriatric Education Collaborative (AR\u2019s GWEP) embraces, nurtures, and encourages students with a passion for caring for older adults. Each year five geriatric scholars are chosen from across the spectrum of health services schools to enhance their geriatric knowledge and experience. Requirements focus on geriatric academic and community-based opportunities. However, these opportunities drastically changed with the pandemic. Therefore, the students became very innovative as they trudged forward to meet and exceed the scholar objectives. They participated in various virtual events to fulfil their academic and community participation requirements. They worked together to develop and implement an interdisciplinary final project that marketed to and engaged rural isolated older adults in a fun educational event aimed at preventing social isolation in older adults and caregivers. Students learned how to connect to and bridge the digital divide with isolated rural older adults."} +{"text": "Older adults prefer to age in place, to live independently while maintaining social connection and engagement with the community. Though older adults can encounter barriers to these goals, social and assistive domestic robots hold promise for promoting independence and online/offline social engagement. However, social robots must be designed to meet their needs and preferences. Open questions remain regarding how to facilitate the development of trust and acceptance in robot support. We investigated the associations between robot social characteristics, sociability, trust, and acceptance for instrumental activities of daily living. We used an online survey to assess older adults\u2019 perceptions towards social and assistive robots. Robots with more social abilities were rated as more acceptable and trustworthy across different task types. We discuss design implications that may promote the development of robot trust and acceptance by older adults, and ultimately help enable aging in place and social engagement."} +{"text": "The goals of this narrative review are to provide a brief overview of the muscle and tendon adaptations to eccentric resistance exercise and address the applications of this form of training to aid rehabilitative interventions and enhance sports performance. This work is centered on the author contributions to the Special Issue entitled \u201cEccentric Exercise: Adaptations and Applications for Health and Performance\u201d. The major themes from the contributing authors include the need to place greater attention on eccentric exercise mode selection based on training goals and individual fitness level, optimal approaches to implementing eccentric resistance exercise for therapeutic purposes, factors that affect the use of eccentric exercise across the lifespan, and general recommendations to integrate eccentric exercise in athletic training regimens. The authors propose that movement velocity and the absorption or recovery of kinetic energy are critical components of eccentric exercise programming. Regarding the therapeutic use of eccentric resistance training, patient-level factors regarding condition severity, fitness level, and stage of rehabilitation should govern the plan of care. In athletic populations, use of eccentric exercise may improve movement competency and promote improved safety and performance of sport-specific tasks. Eccentric resistance training is a viable option for youth, young adults, and older adults when the exercise prescription appropriately addresses program goals, exercise tolerability, and compliance. Despite the benefits of eccentric exercise, several key questions remain unanswered regarding its application underscoring the need for further investigation. Eccentric muscle actions\u2014which yield net force production during active muscle lengthening\u2014remain both a scientific curiosity and a ubiquitous element of mobility and task performance. Over 90 years have passed since A. V. Hill and his prot\u00e9g\u00e9, Wallace Fenn, provided keen insights into what physiologists now regard as the \u201cnegative Fenn effect\u201d, whereby a given force produced through eccentric muscle actions requires lower metabolic cost in comparison to isometric and concentric muscle actions . IncremeJournal of Functional Morphology and Kinesiology addresses some of the evidence gaps concerning the mechanisms of muscle and tendon adaptations to eccentric exercise and the emerging applications of this unique form of exercise. In this introduction to the Special Issue, the editors present a narrative review highlighting the major themes from the contributing authors. These collective works make important distinctions across multiple modes of eccentric exercise, examine the adaptations to active muscle lengthening for therapeutic purposes, consider the use of eccentric exercise across the lifespan, and provide recommendations to integrate eccentric exercise in athletic training regimens.Importantly, the unique characteristics of eccentric muscle actions have stimulated interest in the use of eccentric exercise in a wide variety of experimental and applied settings. The application of eccentric exercise has evolved from a model to induce muscle damage under laboratory conditions, to selected forms of strengthening exercise used to enhance sports performance, and most recently as an approach to identify musculoskeletal injury risk in sport and as a form of therapeutic exercise for clinical and athletic populations ,9,10. De++ mediated changes in the stiffness of sarcomeric proteins such as titin [The net force generated during active muscle lengthening occurs when the external resistance exceeds momentary force produced by the agonist muscle ,11. Ecceas titin ,12,13.Lindstedt model of a spring in series with a damper, these eccentric exercise categories are largely defined by the function of kinetic energy [(1)Recovery of Kinetic Energy: Activities that potentiate force production via ballistic movements involving maximal acceleration with very short surface contact time. These repetitive activities facilitate the recovery of elastic recoil energy and contribute to the coupling phases of the stretch-shortening cycle (SSC) [le (SSC) ,16.(2)Absorption of Kinetic Energy: Activities that typically result in the deceleration of angular joint velocity during non-ballistic movements. These activities result in eccentric force production and the absorption of kinetic energy which is dissipated as heat [ as heat ,17.Muscle performance during activities that emphasize active muscle lengthening is influenced by angular joint velocity, instantaneous muscle stiffness, as well as the timing and magnitude of the external resistance or imposed force . Stan Lic energy ,10,15:, the question of how eccentric exercise should be integrated into overall sports training is still less well understood. In particular, some of the primary questions practitioners may continually grapple with include: (1) how to limit the degree of delayed onset muscle soreness and fatigue post eccentric training, (2) what type of eccentric training should be used with their athletes across different phases of the periodization plan, and (3) how a variety of athlete characteristics such as age, sex, sport and training history may influence what constitutes their optimal form of eccentric training. Two recent papers have reviewed the relevant literature in an attempt to provide an overview of the potential benefits of eccentric training for team sport and yout(1)While inertial flywheel training can be an effective form of eccentric overload training, the magnitude of the eccentric peak force is influenced by the effort and intention of the trainee, with trainees with more experience in flywheel training producing greater peak eccentric force . This ma(2)There is the possibility of a velocity specificity of eccentric training , in whicMcNeil and colleagues conducte(1)Consistent practicing of progressively more challenging hopping and jumping tasks by athletes, in which landing mechanics are emphasized. This focus on landing mechanics is important so athletes develop the ability to absorb eccentric forces and improve their movement competency. This approach facilitates improved safety and performance of complex motor skills involved in sport-specific tasks.(2)Eccentric hamstring strength development should be emphasized to improve youth athletes running and jumping performance and reduce the risk of injury while performing these motor tasks. Such training could involve the Nordic hamstring curl as well as more hip extensor dominant hamstring exercises such as 45\u00b0 hip extensions. All of these eccentric hamstring exercises can significantly increase eccentric strength and muscle fascicle lengths , with su(3)Inertial flywheel training is another option to increase eccentric strength for youth athletes, with some studies demonstrating such exercises produced significant improvements in youth athletes\u2019 jumping, sprinting and change of direction ability. However, low intensity flywheel exercise should be performed initially using flywheels with lower inertia wheels than that used with adult athletes in the same sport.Drury et al. performeIt was also apparent that Drury et al. were awaJournal of Functional Morphology and Kinesiology Special Issue entitled \u201cEccentric Exercise: Adaptations and Applications for Health and Performance\u201d. This Special Issue features a total of 8 papers, encompassing 28 different affiliations, with authors from 7 different countries spanning Europe, Australia, and North America.The purpose of this narrative review is to provide a brief overview of the muscle and tendon adaptations to eccentric resistance exercise and consider the applications of this form of training in rehabilitation and athletic performance settings. The key papers featured in this work are from contributors to the Recent special journal issues and systematic reviews concerning eccentric exercise have focused on the mechanisms associated with tissue adaptations to chronic active muscle lengthening stimuli, spinal and supraspinal control of eccentric muscle actions, biomarkers of post-eccentric muscle action damage, use of eccentric exercise training for rehabilitative purposes, and the low energy expenditure relative to force output during eccentric muscle actions ,22,24,66Journal of Functional Morphology and Kinesiology Special Issue entitled \u201cEccentric Exercise: Adaptations and Applications for Health and Performance\u201d adds to a growing literature supporting eccentric exercise as a viable option across the lifespan and in sport performance for enhancing force characteristics, injury prevention, and improved functional capacity. Importantly, despite the positive findings outlined in this Special Issue, several key questions remain unanswered regarding the application of eccentric exercise underscoring the need for further investigation.Rational direction for the wider use of eccentric exercise with athletic populations may be taken from the works of Drury et al. and McNe"} +{"text": "Certain neural processes that underlie addiction are also central to parenting, notably stress and reward. Parenting interventions that incorporate the unique context of caregivers with addiction have demonstrated some success: However, real-world implementation of evidence-based interventions can be difficult with this population. Video feedback interventions are an especially promising approach to reach parents who experience barriers to participation, particularly caregivers with addiction. A translational neuroscientific approach to elucidating the mechanisms of change in these interventions will aid the delivery and success of this method and advance theory surrounding parenting in the context of addiction. Along these lines, we provide an example of one video feedback intervention, Filming Interactions to Nurture Development, that will serve as such a mechanistic experiment. Caregivers of young children constitute a notable proportion of the population of individuals with substance use disorders. Increasing rates of substance use, particularly opioid use, in this subgroup reflect an already-emergent public health concern that hasThe significance of these consequences has fueled research examining the intersectionality of substance use and parenting . ParentaUnderstanding the mechanisms underlying the interaction between parenting and addiction provides useful knowledge for identifying intervention targets that promote healthy parent and child outcomes. Although those mechanisms can be studied at multiple levels , investigating the neurobiological correlates of parenting processes that mediate responsive caregiving in the context of addiction draws upon the wealth of knowledge provided in these separate literatures elicit reward responses, and stress often precedes subsequent use . In the Activation of stress and reward neural circuitry across these contexts plausibly induces a mutually informed interaction wherein system responses in one context impact the response in another . AlthougThe dysregulation of these stress and reward systems associated with addiction must be considered alongside the neuroendocrine changes elicited by the onset of parenthood. Research on the maternal brain suggests that rising levels of hormones correspond with stress and reward circuit activation central to sensitive caregiving . This ciIn addition to the impact of general addiction processes, the type of drug used can impart unique physiological changes. While there is little research on the effect of extended opioid use on parental brain circuitry, the role of endogenous opioids in maternal stress and emotion regulation and reward processing highlights the importance of investigating that effect .As shown in A reward-stress dysregulation model of addiction and parenting proposed by Instances of household instability and child neglect along with co-occurring mental health difficulties underscore the need for effective interventions for parents with addiction . DespiteAlthough dual treatment for substance use and parenting results in improvements in both domains , directiMany interventions for parents with substance use disorders are based on attachment and relational theories, integrating varying aspects of caregiver responsivity, mentalization, emotion and stress regulation, and mindfulness to improve parent and child outcomes. Examples include Relational Psychotherapy Mothers\u2019 Group , PracticVideo feedback has been employed in parenting interventions where caregiver-child interactions are filmed. Videos are useful for capturing the reciprocal influence parents and children exert on each other. Trained therapists use recordings to replay and personalize feedback to parents. This method allows researchers to highlight parenting skills in a naturalistic environment, often in participants\u2019 homes. Although the specificity of this intervention approach varies, many video feedback interventions aim to encourage supportive interactions between parents and their children. A review of 29 experimental studies revealed that video feedback interventions successfully resulted in a change of maternal sensitivity and more positive parent and child behaviors .Given the disruption of maternal sensitivity in many parents with addiction, this style of intervention might be especially well suited for substance-using parents. However, the true measure of intervention effectiveness does not end within a research context but extends to the feasibility of disseminating and evaluating that intervention in community settings for those who could benefit most. Barriers to accessing treatment are a primary concern for parents with addiction and often have roots in systemic inequalities and racism prevalent in society . The natResearch on video feedback interventions containing proposed mechanisms of change helps discern employable components to further explore and integrate into interventions for caregivers with substance use disorders. Although there is overlap among hypothesized mechanisms, distinct interventions have not targeted mechanisms uniformly. A cursory comparison of different video feedback interventions illustrates this. PuP uses psychoeducation and mindfulness skill building to target the proposed mechanisms of change: parental emotion regulation, representation quality, and mentalization about own and child\u2019s emotions . SimilarThese video interventions have yielded improvements in parenting and substance use behaviors . HoweverFilming Interactions to Nurture Development is a strength-based video feedback intervention with a clearly proposed conceptual model, protocol, and potential to achieve notable impact at scale. FIND was designed to primarily target responsive caregiving and consequently improve caregiver and child outcomes. This design is informed by research on serve and return interactions that are critical to healthy development, a process where caregivers provide contingent, supportive responses to child-initiated cues . Almost Across 10 sessions with a family (five filming sessions and five coaching sessions), coaches share video compilations of positive micro-social interactions between parent and child to encourage parents to identify and increase the frequency of specific serve and return components . Further details of the program can be found in Emerging evidence suggests that FIND is particularly effective for high-adversity families. A preliminary study with low-income fathers provides support for FIND\u2019s conceptual model that caregiver and child improvements occur through increases in responsive parenting . FathersParents with opioid addiction tend to experience difficulty understanding and reacting to child cues, exhibiting greater irritability and decreased responsiveness compared to other parents . Gaps inCurrently, a randomized clinical trial of FIND is being conducted with 200 mothers in opioid use treatment or recovery with children aged 0\u201336 months. Half the parents are assigned to a control condition, which includes alternating child development information sessions and supportive observations of caregiver-child interaction. This study will both evaluate the effect of FIND on responsive caregiving and test whether observed changes in parenting and addiction circuitry, which have considerable overlap , accompaInvestigating the neurocognitive mediators of responsive caregiving improvements and subsequent outcomes allows for more informed intervention alteration and adaptation in real-world contexts. Many evidence-based interventions fail to achieve impact when delivered at scale, and others only yield modest effects and fail to support families at highest risk . For subThe design process employed in developing FIND was intended to proactively tackle large-scale dissemination concerns of both scalability and real-world efficacy for high-risk populations. FIND\u2019s descriptive, as opposed to analytical, coaching delivery permits more people to implement the program, enhancing scalability. Parents of addiction may respond particularly well to the specific, strength-based nature of the program which directly addresses non-drug reward hypo-responsivity by increasing the inherent rewards of parenting without imposing feelings of shame or guilt that might accompany skill-learning present in other interventions. Previous research suggests that participation increases responsive caregiving at lower doses than many existing interventions , possiblThe need for effective resources and interventions for caregivers with addiction necessitates carefully planned research that acknowledges their shared and unique contexts. The reciprocal influence model posits that drug-induced brain changes are implicated in a cluster of cognitive, behavioral, and affective caregiver changes that directly impact child interactions and consequently create a high-stress parenting environment that increases risk for further drug use. Such models, informed by the neurobiology of shared processes, have potential to be more efficient and scalable than those without a clearly proposed and tested mechanism.Building, testing, and disseminating effective interventions for this population are complicated by ongoing challenges. Individuals come in with varying skills and may be experiencing concurrent and related stress or adversity. One intervention cannot be made to suit all caregivers and some caregivers may need more or less support. Continued research that connects the growing knowledge of neurobiology related to caregiving and substance use with mechanistic intervention evaluation will allow scientists to investigate what works, why, and for whom.The original contributions presented in the study are included in the article/supplementary material, and further inquiries can be directed to the corresponding author.PF and A-MB conceived the idea. A-MB and KM wrote the manuscript. All authors contributed to the final version of the manuscript.The authors gratefully acknowledge grant P50 DA048756 from the National Institute on Drug Abuse to PF.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "The process of recruiting, enrolling, and retaining older adults in research studies has been challenging, even prior to the COVID-19 pandemic. This symposium presents research conducted and lessons learned on recruiting, enrolling, and retaining older adults, including those with cognitive impairment. Insights are provided on what techniques are most beneficial for improving rates of research participation, spanning time prior to and during the pandemic. The first presentation reports on qualitative perspectives of persons living with dementia and their caregivers as to what helped them decide to enroll into a clinical trial together. The second presentation speaks to how variations in incentive payment allocations played a role in consent decisions of patients with amnestic mild cognitive impairment and their study partners. The third presentation discusses the effectiveness of an adapted framework and strategies to increase the recruitment and retention of older Latinos with Alzheimer\u2019s Disease and Related Dementias (ADRD) into a clinical trial. The fourth presentation shares techniques for recruiting older adults for a survey study during the pandemic. The fifth presentation defines challenges during a longitudinal study when the pandemic and other natural disasters occurred and strategies for success. Taken together, these presentations will inform researchers on techniques that could be used to improve recruitment, enrollment, and retention of older adults in clinical research."} +{"text": "New developments in medical technology span the breadth of the healthcare environment providing new solutions for therapies, diagnostics, and imaging. Healthcare is a billion dollar market which drives the development and progression of healthcare technologies to the clinic. The innovative approaches which involve novel tools and technologies form the basis for this translation. Exciting areas highlighted by this new Journal, such as Cardiovascular Medtech, Nano-Based Drug Delivery, Medtech Data Analytics, Pharmaceutical Innovations, Regulatory Affairs and Regenerative Technologies represent key examples where step changes in healthcare solutions are being addressed. In each one of these sectors and across sectors, there are major challenges which we can identify.Probably the biggest underlying global challenge which requires a new \u201cmind set\u201d is maintaining a high quality of life for our aging populations. Across the globe, people are living longer and requiring new solutions to address life as an aged citizen. Regenerative technologies and robotics are highlighting a new era of how we maintain a healthy life through a millennial lifespan. Soft robotics and tissue engineering provide potential reparative solutions. New innovative technologies can help to maintain healthy lives in our aging populations by addressing major chronic and acute clinical conditions. Scientific disciplines in biology and molecular approaches have revealed the potential for new drugs and treatments, however, there are still significant gaps in the enabling technologies and supporting medical technology devices which need addressing. Recent viral pandemics such as COVID 19 have demonstrated clearly the need for new medical technologies to fight disease such as portable ventilators and respiratory assistive devices useable throughout the world in developed and underdeveloped countries. These future technologies require the skillsets of a diverse academic base crossing many scientific and engineering communities. In addition, to bring new approaches to the clinic, many facets of the field must be determined and defined to the standards and rigor of the scientific, regulatory and clinical communities. With the increase in innovative technologies and regenerative therapies aiming for the clinic, there are key challenges in delivery systems, metrology, quantitative and computational modeling, data throughput, multimodal approaches for the characterization of disease and treatments, physiological and biochemical monitoring of clinical treatments and tools, technology integration and automation.Over the past 10 years, the scale of healthcare therapies is reducing with \u201cnanotechnologies\u201d providing exciting opportunities. Examples of nanotechnologies include drug delivery systems with smaller and more targeted approaches, nanomagnetic solutions with nanoparticles for imaging and treatments such as hyperthermia in cancer. The ability to modify materials rapidly at small length scales using techniques such as laser direct printing and other 3D printing modalities provides opportunities for unique capabilities in the fabrication of medical devices .Coping with the complexity of tissues and organs alongside the issues of multi morbidity in patients requires new approaches in targeting and specificity of drugs and other medical devices. Design for additive manufacturing (DfAM) aims to utilize the complexity of human systems for the development of medical devices. DFAM provides enhanced performance in our ability to generate biomaterials with complex geometrical designs at the micro-scale . New nanin silico tools (Stratification of patient populations is presenting a new era of personalized medicine. How we stratify patients requires new tools and diagnostic capabilities . How we co tools . The phaEarly screening for disease prevention rather than end stage treatment of degeneration has been proposed as a key solution for us to tackle long term conditions . New advSurgical procedures in cardiovascular, opthamology and other major organs are evolving and improving with clinically validated protocols. Precision surgical tools combined with robotics and virtual surgeries provide the supporting technology advances in this area. New technologies have reached the clinic in minimally and non-minimally invasive, transluminal endoscopic, and single site surgeries .Innovations in assisted devices are building mobility in our physically impaired populations. Advances in materials, electronics and designs are revolutionizing our ability to support and mobilize this community. The role of tissue mechanics and mechanotransduction has been identified in rehabilitation and provides a future area for new forms of rehabilitation regenerative therapies .Stem cell therapies and regenerative medicine require significant support in the form of enabling technologies to reach the clinic. To deliver regenerative medicine therapies involves scalable production and application of standardized clinical grade biotherapies. The delivery is underpinned by effective supply chain capabilities combined with manufacturing and sourcing . These eNew challenges include how to assess advances in therapies using health technology assessments which are tailored for new fields such as gene therapy or cell therapies. The expansion of medical technology in our hospitals has not kept pace with patient safety. Assessments and safety requirements play an important role in protecting against risk of failure. Evidence suggests that pioneer entrants in medical technology may take significantly longer than follow on products which can be related to novel assessments and lack of regulatory guidelines in some cases .Finally, large databases of patient data are being captured in hospitals which if accessed provide wealth of information about disease treatment and prevention. Handling data sets and analysis of data has become a major growth area of interest globally . Mobile To tackle these challenges, the Med Tech field needs to work as a community celebrating their new high quality approaches and integrating them across organ sectors. This new journal, Frontiers in Medical Technology, will provide a forum for these disparate communities to come together and publish their articles in an open access format for dissemination. Reaching out to the clinician, clinical scientist, academic, engineering and commercial worlds, we aim to provide an on-line forum for high quality pier reviewed publications which spearheads new innovations in a global field and demonstrates their relevance in a clinical setting.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The effects of gender and marital status on accrued debt in retirement planning becomes an urgent concern because unmarried women face greater financial challenges in retirement than their counterparts. This study used data from the National Financial Capability Study (NFCS), designed by FINRA. We identified debt that influences retirement planning among a sample of pre-retirees, aged 51 to 61 years, and consider the associations of gender, marital status, debt, and retirement planning. Our results indicated that mortgage debt and credit card debt were negatively associated with retirement planning for women. Having a retirement account is positively associated with retirement planning and it also mediates the relationship between credit card debt and retirement planning. We urge women and financial planning executives to take time during the pre-retirement years to assess their various forms of debt and determine how it affects retirement planning objectives given current marital status."} +{"text": "Dear Editor,2. Sadly, efforts towards reducing maternal mortality in Sub-Saharan Africa have been inadequate. Pregnant women go through birthing at home and in mission houses because of poverty and poor transportation facilities to healthcare centers. In addition, poor staffing and lack of essential drugs and equipment in the healthcare centers contribute to poor obstetric healthcare delivery3.The highest rates of maternal and infant mortality have been recorded continuously in Sub-Saharan Africa because pregnant women in this region have difficulty receiving expert emergency obstetric care due to the delay in seeking appropriate medical help, delay in getting to an appropriate health facility, and delay in receiving expert medical help after reaching the appropriate health facility4. According to the World Health Organization, Five Emergency Obstetric care facilities including at least one comprehensive facility should serve a population of about 0.5 million people5. Meeting the obstetric care needs of pregnant and postpartum women should start from the foundation. Pregnant women in communities should be assisted by the midwife to develop a birth preparedness and complications readiness plan with the knowledge that every pregnant woman is at risk of developing complications. A key aspect of this is making pregnant women aware of danger signs in pregnancy while having a transportation plan in case they experience any of the danger signs.Pregnant women should have access to emergency obstetric care and should be attended by skilled health personnel, either a doctor, nurse, or midwifeNurses and midwives operating at every level of the healthcare delivery system should always be prepared to attend to emergency obstetric cases. The SHARP principle is a recommended format for midwives providing basic emergency obstetric care, which is expanded as:Seek help when attending to emergencies;Have what you need, including the pregnancy history, test results, sutures for episiorrhaphy, and sterile instruments for assisted delivery;Activate emergency responses such as administration of uterotonics, antibiotics, and anticonvulsants for required cases;Refer cases requiring comprehensive emergency obstetric care such as Caesarian section and blood transfusion to the nearest comprehensive healthcare center;Prepare the pregnant woman for surgery, specifically for nurses and midwives in centers providing comprehensive emergency obstetric care.Meeting the emergency needs of pregnant women is a collaborative effort of the community, the skilled healthcare provider, and health systems. Investments should be made to ensure that primary healthcare centers are continuously equipped with essential resources to meet the ever-growing demand for obstetric care in Sub-Saharan Africa. Maternal mortality is painful and no woman should die in the process of bringing another human to life. While efforts are continuously made to reduce maternal mortality in the Sub-Saharan African region, midwives should continue to strive to meet the emergency needs of pregnant and postpartum women to reduce maternal mortality."} +{"text": "Cardiovascular disease remains the leading cause of death worldwide despite significant advances in our understanding of the disease and its treatment. Consequently, the therapeutic potential of cell therapy and induction of natural myocardial regeneration have stimulated a recent surge of research and clinical trials aimed at addressing this challenge. Recent developments in the field have shed new light on the intricate relationship between inflammation and natural regeneration, an intersection that warrants further investigation. Ischemic heart disease (IHD) affects more than 197 million people worldwide and accounts for the greatest number of years of life lost in the world . The cosredirect resident cells of the myocardium to adopt a cardiomyocyte (CM) fate themselves. The connection between the acute inflammatory response and myocardial regeneration is an emerging area of interest.There are two general strategies for cardiac regeneration after myocardial infarction (MI) currently under investigation. The first is direct transplantation of stem cells to the injured myocardium, which is an area of active study with many recent clinical trials . The secEfforts to capitalize on the regenerative potential of stem cells to repair or restore injured myocardium have been ongoing since the 1990s. After Loren Field\u2019s group demonstrated the feasibility of grafting syngeneic CMs into recipient myocardium without rejection, first in mice and thenBy the year 2000, trials in humans had begun. Phillippe Menasch\u00e9\u2019s team injected skeletal myoblasts into the scarred myocardium of patients undergoing coronary artery bypass grafting (CABG) in a Phase 1 trial . After aGiven the accessibility and low cost of bone marrow-derived stem cells, there was a rush to initiate clinical trials using these heterogeneous progenitors despite limited evidence that they could regenerate infarcted myocardium. Indeed, several of these trials showed no clinically significant improvement over CABG alone . The reipost hoc analysis, this group did show a modest benefit in temporary weaning from LVAD compared to the control group, suggesting there is a differential response among the various etiologies of heart failure. The differential effect of MPCs on patients in this trial with ischemic versus non-ischemic heart failure implies that there may be potential therapeutic benefit, perhaps via different mechanisms than initially believed.Nonetheless, some wondered if cell therapy may still have clinical utility that is simply not reflected in multifactorial metrics such as EF, and that perhaps including more acutely ill patients in future studies would reveal a signal . In 2014Inconsistent results from clinical trials of stem cell transplantation may be related to ambiguity about the putative mechanism. Evidence from several studies suggest that the beneficial effects of cell therapy may be attributable to paracrine signaling induced by the transplanted progenitor cells, rather than direct repopulation of the injured myocardium . SpecifiSuspecting alternative mechanisms for the findings of earlier studies on cell therapy for IHD, one of the most elegant studies to support the paracrine hypothesis came from Vagnozzi and Molkentin . CellulaWhile It remains unclear whether the findings of the Vagnozzi study and those of previous clinical trials are on the mechanistic continuum of natural myocardial regeneration seen in neonatal small mammals, or if it is a non-specific antifibrotic damage-control strategy employed by the cell which is parallel to but does not result in natural regeneration, as it appears to be in the axolotl . FurtherThe distinct challenge in reprogramming mature CMs in cell cycle arrest is our relative knowledge deficit surrounding the mechanisms for releasing CM cell cycle arrest. Native CM proliferation and migration into injured territories occurs physiologically in small and large mammalian neonates , b. HoweAlthough the adult mammalian heart is unable to regenerate to any significant extent, neonatal mammals have the capacity to regenerate viable myocardium following MI in the early days of life , b. It fEfforts to harness the natural regenerative capacity have focused on releasing CMs from cell cycle arrest via a variety of approaches. Releasing cell cycle arrest has been attempted with overactivation of cell cycle activators such as cyclin D2, which led to enhanced angiogenesis and remuscularization in the MI border zone . SimilarAs evidence mounted that the findings in the cell therapy clinical trials were more likely related to paracrine signaling induced by transplanted cells rather than engraftment, some groups began attempting to recapitulate the responsible signaling pathways without the technical challenges of engrafting billions of cells. After MI, the acute inflammatory response attracts macrophages, fibroblasts, and T cells to the infarct zone. These cells clear debris from apoptotic cells and remodel the extracellular matrix. In turn, potent chemoattractants such as stromal cell-derived factor 1\u03b1 (SDF) recruit endothelial progenitor cells to the infarct territory and promote angiogenesis . By usinInterpreting the Unsurprisingly, excessive proliferation or inappropriate depletion of resident cardiac macrophages after acute MI can impair myocardial regeneration in mice and resuWhile this review focuses on cell therapy and paracrine signaling approaches to myocardial regeneration, innovative approaches in other fields such as hydrogels, biophysics, neurohormonal modulation, and tissue engineering have also yielded promising advancements toward the common goal of myocardial regeneration. The exponential pace of discovery of new genes, small molecules, and proteins that promote various steps of myocardial regeneration has identified many promising avenues of research. The neutral results of clinical trials investigating cell therapy for IHD may be partially explained by the emergence of an alternative inflammatory mechanism underlying the rescue of ventricular function after MI. It appears that the small therapeutic benefit of cell therapy is more likely related to endogenous inflammatory and wound-healing pathways, rather than direct replacement of the damaged myocardium with viable cardiomyocytes. This is a significant paradigm shift in the pursuit of myocardial regeneration after injury. Therapies targeting individual stimuli for regeneration have shown potential for success but have fallen short of the robust physiologic regenerative response seen in neonatal mammals. Nonetheless, repopulating the infarcted myocardium with viable, non-arrhythmogenic CMs remains the ultimate goal, and recent work in animal models on natural regeneration remains a promising field for further investigation. Future progress will likely depend upon interdisciplinary collaborations, including bioengineers, immunologists, cell biologists, and physicians to develop multifaceted therapeutic strategies that integrate bioengineering and developmental biology techniques.YJW and HW conceptualized the manuscript which was written by SE, and edited and revised the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "This paper reports on the the challenges faced and coping strategies employed community-based care providers in a mid sized city in the Pacific Northwest in the midst of the Covid 19 pandemic. Researchers from a Palliative Care Institute conducted six online focus groups using the zoom platform. The project aimed at gathering important information on the experiences of caregivers as well as providing a virtual space where caregivers could support each other. A purposive sampling technique was used to gather data where participants were not chosen randomly but because they could best answer the research question. Membership of the focus groups included representatives from skilled nursing facilities, home-care agencies, elder law services, memory-care facilities, adult family homes, medical supply facilities, chaplains and nutritionists. Data gathered from the focus group were transcribed. A constant comparison method of analysis were employed and categories and themes were created from open coded data. Six key themes were identified which included: dealing with the impact of social isolation on caregiver-client relationships, assessing personal risk when dealing with clients living with dementia, facing challenges seeking continuing employment, struggling with social support and self care, using technology for professional and personal support and grappling with the challenges reentering a face to face environment once the pandemic is controlled.. Findings point to the importance developing and sustaining technological innovations that support workforce retention, fostering communication between the larger community, care providers and clients in various care settings and planning for safe reentry into a post Covid world."} +{"text": "Social networks and family support are known to have benefits for many older adults globally, and India is no exception. However, the exact nature of the impact of these factors on depression in the Indian population remains largely unexplored. Considering the aging Indian population and changing socio-cultural landscape, it is important to identify the role of social engagement and neighborhood factors in the mental health needs of these older adults. To address this need, this study aimed to identify predictors of depressive symptoms among individuals aged 45+ years from four states in India. Data were taken from the Longitudinal Aging Study in India (LASI) pilot survey in 2010, focusing on the influence social activities, family factors and neighborhood satisfaction variables have on depressive symptomatology. A hierarchical multiple regression analysis was conducted and found that residing in a southern state ; lower life satisfaction ; having more living children , less frequently or never visiting friends and relatives and not liking the neighborhood were predictors of depressive symptoms. These findings are consistent with limited extant literature on the importance of family and social engagement as predictors of depressive symptoms in this population. Future research should focus on qualitatively examining the interaction between depressive symptoms and social engagement within this population, thereby helping develop targeted interventions, measure outcomes and long term, community engagement-based prevention programs."} +{"text": "Dear Editor,We read with great interest the systematic review and meta-analysis by Tavares et al. which aimed to provide \u2018best evidence\u2019 by evaluating the safety and efficacy of vacuum therapy and comparing vacuum therapy to stent treatment for anastomotic leakage.In our view, interpretation of comparative analyses on anastomotic leakage in currently available literature is problematic for three reasons. First, most studies report very little leakage characteristics and patient parameters at leak diagnosis . However, these parameters may be crucial to understand the wide-ranging clinical presentation of anastomotic leaks. In addition, these parameters affect treatment decisions, and thus need to be corrected for during comparative analyses to reduce confounding bias. Second, the fact that the treatment strategy of anastomotic leakage is usually a combination of multiple interventions is often overlooked by studies focusing on a specific treatment modality. Whilst endoluminal vacuum therapy by itself may be viewed as a strategy (i.e. combining drainage and defect closure), stent treatment is rarely a complete treatment strategy. Additional interventions (e.g. drainage of fluid collections) performed synchronously for management of anastomotic leaks are often not reported. Third, selection of patients in current studies may complicate interpretation of comparative analyses. For example, the largest study included by the meta-analysis introduced selection bias by excluding patients who underwent surgical treatment after failure of endoluminal vacuum therapy or stent treatment.,The authors used the proper scientific tools to assess the risk of bias and quality of evidence of the included studies.The search for more evidence on anastomotic leakage treatment efficacy continues and the scientific community is eagerly awaiting evidence supporting a specific treatment for anastomotic leakage in order to improve outcomes of leak treatment. A tool to correct for leakage characteristics and patient parameters at time of diagnosis of the leak is currently being developed and may be used to reduce the risk of confounding bias in future studies."} +{"text": "In response to the Hong Kong Principles for assessing researchers, this Formal Comment argues that it is time to take gender and diversity considerations seriously in the pursuit of fostering research integrity; this requires acknowledging and reshaping the influence of research assessment criteria on researcher representation. PLOS Biology this past July. The principles concern research institutions\u2019 assessment of researchers according to responsible research criteria. The HKP value issues ranging from complete reporting and open science to a diversity of other essential research tasks .The Hong Kong Principles (HKP) for assessing researchers , a produWe applaud this initiative and believe it is an important step forward because it directly addresses a root cause of many issues that erode research integrity: the unfair reward structures and perverse incentives that researchers encounter . ReformiWe were surprised that HKP explicitly refrain from considering gender and other issues related to diversity and inclusiveness in researcher assessment. They rather state that, \u201c[t]hese themes require an assessment of a group of researchers when making decisions about funding allocations or human resources policies. Furthermore, these issues concern the social justice and societal relevance of research rather than research integrity.\u201d (p. 9) . We disaFirst, we challenge the assertion that gender and diversity issues concern social justice and societal relevance of research rather than research integrity. Such a strong distinction between societal relevance and research integrity is difficult to justify; although the field of research integrity was traditionally narrowly defined as pertaining to misconduct issues, it is increasingly acknowledged as addressing general issues of research quality, relevance, and reliability . FurtherSecond, in our view, current researcher assessment practices are funding allocation schemes or human resource policies of research institutions, which affect individual researchers and systematically disadvantage entire groups of researchers, including women and those from a minority background . For insOur plea to the research integrity community is to take gender and diversity considerations seriously, especially in the pursuit of fostering research integrity. This means researcher assessment approaches which acknowledge that systemic disadvantages can be introduced or exacerbated with individual assessment criteria and which contribute toward improving representation within research teams and across seniority levels."} +{"text": "The aim of this study was to identify pre-discharge risk factors associated with early inpatient readmission in general adult service users, with a particular focus on modifiable factors. We hypothesised that stability prior to discharge would reduce readmission to inpatient services within 90 days.Early readmission to inpatient psychiatric services is a poor outcome for service users, staff and the healthcare system. A variety of clinical, demographic and system factors, mostly non-modifiable, have been investigated previously. The identification of pre-discharge and particularly modifiable factors associated with readmission would give an opportunity for intervention and changes in policy.272 medical records of all admissions within an 8 month period to a NHS inner city psychiatric inpatient service were reviewed to identify factors associated with readmission within 90 days of discharge. The data were analysed by simple comparison, calculation of odds ratios and logistic regression.26% of service users were readmitted to the mental health trust within 90 days of discharge. Incidents and psychotropic medication change in the week before discharge were significantly associated with readmission, as were the number of previous admissions, and comorbid substance misuse. Successful overnight leave was found to be significantly protective against readmission .The ability to predict those at high risk for readmission means they can be targeted for interventions and it can also help develop best practice around inpatient care and the discharge process. The novel findings in this study of pre-discharge modifiable risk factors such as stability and successful overnight leave could have significant implications in discharge planning policy."} +{"text": "Considerable scholarly attention has been directed at increasing social isolation and loneliness during the COVID-19 pandemic, and their adverse impact on later life psychological well-being. Notably absent is the focus on financial hardship in the context of overlapping unprecedented economic and public health crisis. It is unclear whether loneliness continues to differ across different levels of financial hardship even amidst immense uncertainty, social isolation, and anxiety induced by the pandemic. Based on our nationwide web-based survey of adults aged 50 years and older (n=1861), we used ordinal logistic regression to examine the influence of financial hardship on loneliness and assessed the role of socioeconomic status (SES), emotional support, and health status in contributing to such influence. We found significantly higher odds of greater loneliness among individuals who reported experiencing greater financial hardship. Among two measures of SES, only household income contributed substantially to the influence of financial hardship on loneliness. We documented significantly lower emotional support and greater health disadvantage among individuals experiencing greater financial hardship. Consideration of emotional support and health status explained the remaining influence of financial hardship, due to their association with both financial hardship and loneliness. Despite a sense of shared vulnerability and social isolation across the general population, our findings suggest that SES inequalities in later life loneliness are maintained even in the midst of the pandemic."} +{"text": "Caregiver burden has negative effects on health outcomes and quality of life. Meanwhile, safety protocols during the COVID-19 pandemic created immediate impacts on informal caregiving with increasing burden on family caregivers. Our primary purpose was to describe the impacts of the pandemic on caregiver burden among informal caregivers, and their sudden shift in roles as a result. This review describes emerging effects on various aspects of health and explores future directions to support informal caregivers. A streamlined search was conducted to fit the scope of this review, with key terms determined to identify relevant publications. Common research databases and mainstream resources were utilized. We focused on research published since March 2020 to align with the timing of the pandemic in the US. Early research suggests that the pandemic has worsened caregiver burden among informal family caregivers. Reported health impacts include greater stress, pain, depression, sleep problems, and irritability, decreased social connectedness and quality of life. Informal family caregivers face negative health outcomes and distress as a result of greater caregiver burden and intensity during the COVID-19 pandemic. Immediate solutions are needed to alleviate this growing burden and provide ongoing support. Future work should explore the potential of boosting positive resources such as resilience and purpose to ease caregiver burden."} +{"text": "The availability and accessibility of international orthopedic care have increased dramatically over recent decades . A promiThe act of traveling across international borders in pursuit of healing is as old as civilization itself, with travel to India during ancient times for Ayurvedic treatments giving way to the practice among the middle classes of nineteenth century Europe of visiting spa destinations to \u201ctake the waters,\u201d often for the purpose of relieving chronic arthralgia . The medThe elective nature of many orthopedic procedures, coupled with their high cost in developed economies, account for the growing importance of orthopedic tourism . MedicalThe lack of an accredited international registry limits our understanding of the true volume, movement patterns, and complications associated with orthopedic tourism. The international branch of the US-based Joint Commission, a not-for-profit organization, accredits medical services around the world, but many medical tourism services operate outside its remit . MoreoveThere is a paucity of authoritative evidence regarding the quality of care and clinical outcomes of procedures performed on orthopedic tourists. A systematic review of surgical tourism by Foley et\u00a0al. reported complication rates as high as 56% including wound infection, poor functional outcome, and adverse cardiovascular events . The risJudicious patient selection and medical optimization are key determinants of the outcome of orthopedic surgical procedures. Both facets of care are at risk of being compromised in the context of orthopedic tourism. The lack of continuity of care and multidisciplinary preoperative care and follow-up by medical tourism providers, as well as the medicolegal complexities at play in foreign jurisdictions in cases where surgical negligence is alleged, should be carefully considered by prospective orthopedic tourists. While insurance policies do exist that cover surgical procedures performed in different jurisdictions and domestic health-care costs arising from complications in returning tourists, it is likely that many orthopedic tourists, in line with other international travellers, do not purchase such insurance . WhetherThe impact of orthopedic tourism on host countries also deserves our attention. While some national governments, such as the Malaysian government, actively promote their medical tourism industries abroad , the posInternationalization of orthopedic surgery involves not only the movement of patients but also of practitioners. Surgical volunteerism, or short-term surgical trips, is a term used to describe teams from developed countries embarking on \u201csurgical missions\u201d to low- and middle-income countries (LMICs) to deliver high-quality surgical care that is otherwise unavailable to local patients. The nature of the trip varies depending on the primary clinical needs in the region. Orthopedic expeditions range from acute trauma care necessitated by major disasters to missions where elective joint arthroplasty provides the main focus of the surgical travellers. The successful establishment of organizations such as Operation Rainbow and Orthopedics Overseas reflects the success of orthopedic surgeons\u2019 efforts to provide care in LMICs. The major earthquake that struck Haiti in 2010 resulted in 150,000 deaths and 300,000 people injured, inspired over 500 American Academy of Orthopedic Surgeons and Orthopedic Trauma Association volunteer surgeons. Organizations such as Partners in Health were instrumental in coordinating the acute trauma care response . OperatiThe successful execution of an orthopedic surgical mission is challenging and requires methodical preparation. First, the safety of the surgical team is of paramount importance. Volunteers are exposed to multiple risks including threats to personal safety and infectious diseases. Due diligence in preparation for the trip includes appropriate travel vaccination and malaria chemoprophylaxis where the risk demands it and familiarization with the region and meticulous planning with host hospital groups to implement security measures and provide adequate accommodation. The procurement of sustainable equipment must also be arranged . A uniquInternational volunteerism is fraught with ethical and legal considerations, and these must be addressed before any orthopedic mission. Historically, the \u201cblitz surgery\u201d model aimed to maximize the number of operative procedures performed. However, this approach led to a high rate of adverse clinical outcomes owing to a lack of continuity of care, inadequate supplies, and surgeons performing operations outside their scope of expertise. The development of guidelines for international surgical volunteers has shifted the focus of missions to the education of local surgeons, appropriate patient selection, and continuity of care . The legThe globalization of orthopedic care has created educational opportunities for medical students, orthopedic trainees, and surgeons in both receiving and visiting countries. Establishing residential placements overseas in resource-poor settings may help orthopedic trainees deal with occupational burnout and expose them to a variety of unfamiliar orthopedic presentations. However, it is important that a symbiotic relationship is nurtured in which trainees are actively involved in educating health-care workers in their host hospital . MedicalGovernance of orthopedic practice pertaining to orthopedic tourism and orthopedic volunteerism is challenging. The COVID-19 pandemic has temporarily grounded many international travellers and dramatically reduced the number of elective orthopedic procedures being performed worldwide. The pandemic will undoubtedly have a negative impact on the movement of orthopedic tourists and on developing regions that depend on surgical volunteerism. The medical profession should advocate for international COVID-19 vaccine equity to prevent rising global health-care inequalities and ensure the continued success of globalized orthopedic care. While the potential for disjointed care exists for orthopedic tourists, the joint effort of volunteer orthopedic surgeons who travel to low-resource destinations to provide care is to be encouraged.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article."} +{"text": "Positive aspects of caregiving (PAC) are positive appraisals that caregivers report about their role such as feeling appreciated or important, and may increase with caregiver adaptation over time. We aimed to examine differences in PAC by caregiving duration and social engagement, controlling for measures of distress. A total of 283 African American or White caregivers from the Caregiving Transitions Study with a wide range of caregiving durations were included in our analysis. We used multivariable linear regressions to model total PAC score on years of caregiving and social engagement , adjusting for age, sex, race, marital status, relationship to care recipient, dementia status of care recipient and measures of distress . Caregivers with higher social engagement reported significantly higher PAC while caregivers with longer duration of care reported marginally higher PAC in most analytic models. African American caregivers reported higher PAC compared to White caregivers. Dementia caregivers reported lower PAC than non-dementia caregivers in models that adjusted for demographic variables and social network size, but the association was attenuated with the addition of caregiving strain. In summary, higher social engagement and longer care duration were associated with higher PAC after adjusting for demographic variables and measures of distress. Future studies should aim to understand how caregivers shift appraisal to positive aspects of their role and explore implementation of interventions targeting PAC in order to improve the caregiving experience."} +{"text": "Sleep complaints and disorders are one of the most common disturbances to health and well-being in later life. Evening electronic media use has been shown to influence the subsequent quantity and quality of sleep, but most research focused on younger age groups who are more likely to use new media to replace or complement traditional mass media such as television. To investigate how different types of evening media use is related to sleep in later life, we used ecological momentary assessment data from the Daily Experiences and Well-being Study to examine how evening computer use and television viewing affect subsequent sleep hours and perceived sleep quality. Across all evening assessments, 43% of the evenings were spent using computers, and 80% of the evenings were spent watching television. Findings from a series of within-between random effects models indicated that evening computer use and television viewing had independent associations with sleep quantity and quality. That is, older adults reported fewer hours of sleep, more difficulty falling asleep, and worse overall sleep quality on nights following the evening computer use. In contrast, evening television viewing was associated with feeling less tired the next day morning. The results highlight the continued presence of television viewing in older adults\u2019 daily lives and their distinction from general computer use. The social context in which older adults watch television in the evening may potentially explain how different electronic media use influences sleep in later life."} +{"text": "The progressive decline of resilience during the aging process across multiple functional systems suggests basic biological mechanisms of regulation. We exploited a primary cell model to identify markers of cellular resilience or the ability of cells in culture to respond and return to homeostasis following acute challenge including metabolic, oxidative, or proteostatic stress. Using primary fibroblasts from minimally-invasive skin biopsies of genetically heterogeneous mice, we are able to determine individual cellular resilience as well as the normal lifespan and healthspan of each donor. Our studies suggest donor age and sex affect cellular resilience and that this measure of resilience can predict functional outcomes in some interventional studies. While longevity studies continue, these studies point to a potential highly important marker of healthspan and longevity as well as a model to delineate the biology of resilience in animal and translational models."} +{"text": "The National Association for Geriatric Education (NAGE) is a non-profit organization representing geriatric and gerontology programs, including Health Services and Resource Administration funded Geriatric Workforce Enhancement Programs (GWEPs), and Geriatric Academic Career Awardees (GACAs). NAGE responded to the renewed call to address systemic racism and racial inequities by forming a Diversity and Racial Equity Workgroup. The Workgroup explored ways to disseminate educational resources, support members to address racial inequities among older adults, promote increased diversity of the geriatrics/gerontology workforce, and support public policy initiatives that address racism and health disparities. Initial outputs include creating a Diversity and Racial Equity resource page, identifying liaisons to the Workgroup from each NAGE Committee to ensure impact across the organization, and organizing collaborations across GWEPs and GACAs to share successful initiatives. Future plans include education and advocacy with members and collaborating organizations to address systemic racism and racial health inequities impacting older adults."} +{"text": "Clinical studies suggest an association between EWB and the risk or progression of AD. However, the mechanistic link and causal relationship between EWB and AD remain unknown, due to limited experimental access and control of the underlying human brain processes. Animal models offer genetic control of AD mutations and neural circuit analysis tools, but subjective feelings of EWB cannot be assessed through self-report. To study EWB across species, we adopt a theoretical framework that views emotions as central brain states that respond to exteroceptive or interoceptive stimuli and cause multiple cognitive, somatic and behavioral changes. Recent neuroanatomical and functional imaging studies have identified evolutionarily related brain circuits in the encoding and regulation of central emotional states in animals. Dr. Wang will review progress in elucidating the functional activities of these circuits and discuss the challenges and opportunities to link these neural representations to EWB and AD related pathological progression."} +{"text": "Community-dwelling multi-morbid older adults are a vulnerable population for medication safety-related threats. We interviewed a sample of these older adults recruited from local retirement communities and from primary care practices to learn their perceptions of barriers and enablers for their medication safety. The present study is part of the Partnership in Resilience for Medication Safety (PROMIS) study. One of the aims of this project is to identify barriers and opportunities to improve older adults' medication safety. These interviews were conducted during COVID-19 pandemic conditions. Results from this qualitative study suggest that trust between these older adults and their healthcare providers is an essential component of medication safety. Overarching themes include disruptions in medication management, caregivers caring for each other, patient safety practices or habits, and medication management literacy. Participants also shared strain due to lack of skills to navigate telemedicine visits, trust in Primary Care Providers (PCPs) and pharmacists to prescribe and dispense safely for them, reliance on PCPs and pharmacists to give essential information about medications without having to be asked. Our interviews illustrated large variations in older adults\u2019 perceived role in medication safety, with some developing expertise in understanding how medications work for them and how long-term medications should be periodically reviewed. The types of information needs and supports from PCPs were likely different. Understanding these barriers and enablers for safe medication management can help us develop medication safety improvements for this vulnerable population."} +{"text": "The COVID pandemic has impacted access to care, particularly for older, homebound persons living with dementia (PwD). At the beginning of the pandemic, our interdisciplinary team introduced a home-based medical care program (HBMC) to address chronically ill and homebound PwD and caregivers\u2019 needs to promote aging in place. The purpose of this presentation is to describe PwD and caregiver service use and experiences with Virginia at Home (VaH) HBMC during the pandemic. All PwD participating in VaH program are offered home telehealth access with necessary devices. We will discuss telehealth access and use and dyad-care provider communication across up to 20 dyads to facilitate continuity of care. These data are supplemented by qualitative interviews with dyads presenting needs, preferences, and experiences accessing and using services across the first six months of program launch. We will conclude with a discussion of participant-informed program alterations to facilitate optimal overall care and outcomes."} +{"text": "Older adults with cognitive impairment and multiple other chronic conditions often have polypharmacy which increases their risks of medication related cognitive effects, adverse drug events, hospitalization and death and leads to higher health care costs. Deprescribing, the process of reducing or stopping potentially inappropriate medications may improve outcomes for those older adults with cognitive impairment and multiple chronic conditions. The OPTIMIZE trial examined whether a primary care-based, patient- and family-centered intervention educating and activating patients, family members, and clinicians about deprescribing reduces numbers of chronic medications and potentially inappropriate medications for older adults with dementia or mild cognitive impairment and multiple chronic conditions. We explored the mechanisms of intervention effectiveness through post hoc qualitative stakeholder interviews and surveys with 15 patients, 7 family caregivers, and 28 clinicians. All stakeholder groups endorsed the acceptability of the intervention. Success of the intervention was affected by contextual factors including prior knowledge and openness to deprescribing, cognition and prognosis. Positive outcomes included patients and care partners scheduling specific appointments to discuss deprescribing and providers remembering to consider deprescribing in cognitively impaired older adults. Recollection of intervention materials was inconsistent over time but highest shortly after intervention delivery. The time required to mail intervention materials to patients prior to a scheduled appointment limited the reach of the intervention by excluding persons with rapidly scheduled appointments. Our work identifies key learnings in intervention roll out which can guide future translation of our intervention to other settings and other pragmatic intervention studies in this vulnerable population."} +{"text": "Dementia family caregivers often show deep devotion and a strong sense of purpose and duty toward their relatives needing care. The concept of grit, which includes aspects of commitment, purpose, perseverance, and resilience, is a novel theoretical approach to expanding understanding of dementia family caregiver strengths amidst the challenges they face. Multiple psychosocial and contextual factors are likely to interact with and influence grit among these caregivers. This symposium addresses commitment to the family dementia caregiver role, willingness to embrace the stressful work of caregiving, and perseverance in finding ways to sustain caregiving roles under typical and adverse circumstances. Blieszner focuses on associations between grit and stressors and strains that challenge caregiver well-being and jeopardize continued caregiving. Wilks considers the impact of spiritual support on sustaining resilience among Caucasian and African American dementia caregivers. McCann explores caregivers\u2019 responses to changes in informal support and social interactions available to assist with home care tasks over the course of the COVID-19 pandemic. Albers examines the strengths and resources caregivers draw upon to manage the challenges of caring for and supporting a relative in long-term residential care during the pandemic. Collectively, these presentations provide new insights into the range of influences on aspects of grit and circumstances in which grit sustains caregiving. Discussant Margrett considers the value of the concept of grit for furthering understanding of caregivers\u2019 abilities to manage typical and unique challenges in their caregiver roles and offers suggestions for future research and interventions to enhance grit among dementia family caregivers."} +{"text": "Frailty is often described as being an increased vulnerability to the effects of stressors. There is little research investing how frailty may act as either a mediator or participate in interactions in the associations between risk factors and chronic disease. We will present novel analyses of the Canadian Longitudinal Study on Aging, focusing on the 30,000 study participants who underwent serial physical evaluations at one of 11 data collection sites between 2011 and 2018. Using the 4- way decomposition method elaborated by Vanderweele, we investigate the role of grip strength, as a component of physical frailty, in the effect of cardiovascular risk factors on the atherosclerotic burden of individuals (measured using carotid intima media thickness). Our findings clarify the mechanisms underlying of grip strength in the associations between cardiovascular risk factors and carotid intima media thickness."} +{"text": "The ongoing COVID-19 pandemic has underscored the need to optimize care for one of the most affected sectors: older adults in nursing homes and more specifically highly vulnerable populations such as residents with dementia. Research developed in collaboration with stakeholders can optimize impact, relevance, and trustworthiness of study findings thereby informing advances in care. Yet, evidence on stakeholder driven research for enhancing dementia care is limited. This symposium will provide examples of stakeholder-driven research questions that were addressed with stakeholder engagement. First, we will present current evidence about the perspectives of caregivers, including those from communities of color. The second presentation will discuss the perspective of clinical training stakeholders responsible for supporting system-wide clinical program implementation and their experiences with early and later adopter nursing homes within the context of a clinical trial. The third presentation will address the perspective of policy makers and payers via the effect of state-mandated dementia training on resident outcomes. The fourth and final present the findings from a study that examined how nursing home stakeholders responded to a payor requirements for pharmacy services and the relationship between that response and patient outcomes. We will conclude the session with a discussion of stakeholder-engagement methods and recommendations for future nursing home research, which champions stakeholder collaboration."} +{"text": "Although a causal association remains to be determined, epidemiologic evidence suggests an association between hearing loss and increased risk of dementia. If we determine the association is causal, opportunity for targeted intervention for hearing loss may play a fundamental role in dementia prevention. In this discussion, we summarize current research on the association between hearing loss and dementia and review potential casual mechanisms behind the association . We emphasize key areas of research which might best inform our investigation of this potential casual association. These selected research priorities include examination of the causal mechanism, measurement of co-existing hearing loss and cognitive impairment and determination of any bias in testing, potential for managing hearing loss for prevention of dementia and cognitive decline, or the potential to reduce dementia-related symptoms through the management of hearing loss. Addressing these research gaps and how results are then translated for clinical use may prove paramount for dementia prevention, management, and overall health of older adults. Hearing loss is the leading potentially modifiable risk factor for dementia; up to 8% of global dementia cases are estimated as being attributable to hearing loss , 2020. FEven with our expanding knowledge of the association between hearing loss and dementia, significant gaps in our understanding persist. In this article, we aim to (1) provide a foundational understanding of hearing loss presentation and diagnosis; (2) review current hearing loss epidemiology (3) provide context to the existing research on the relationship between hearing loss and dementia to guide dementia prevention and intervention recommendations or research; (4) discuss the leading theories on the pathways behind the hearing-dementia association; and (5) present four crucial areas for future research. With the demographic changes in the coming decades, we conclude with calls for inter-disciplinary collaboration and posit a unique opportunity to alter the landscape of cognitive aging and dementia care. Understanding the role and presentation of hearing loss in the adult population allows for better appreciation of where the field of auditory science may fit into a broader picture of dementia prevention and interventions.The act of hearing involves two inter-related processes and components of the auditory system \u2013 the peripheral auditory system and the central auditory system and addiThe peripheral auditory system includes the outer ear (pinna), ear drum (tympanic membrane), middle ear bones , and cochlea . These cThe most common clinical tool for measurement of peripheral hearing acuity in adults is pure tone audiometry , with reFollowing passage through the peripheral auditory system, the electrical signal created by the cochlea is sent to the auditory nerve where it is then decoded by the brain . CentralMeasurement of central auditory function is often completed through the presentation of speech within the presence of increasing volume of selected types of background noise or specialized tests of central auditory processing ability that involve specific tasks like listening to degraded or temporally modified speech . HoweverAge-related hearing loss (ARHL), also known as presbycusis, accounts for the largest percentage of hearing loss cases around the world and presents as a gradual decrease in hearing ability. The outer hair cells and other sensory cells in the cochlea are progressively damaged and unable to regenerate . The resThe impact of a given pattern of hearing function as represented on the audiogram on communicative performance may vary widely from individual to individual . An indiHearing loss currently impacts an estimated 20% of the global population, or more than 1.5 billion people . By 2050Globally, the cost of unaddressed hearing loss is estimated at over $980 billion annually . EconomiThe prevalence of hearing loss varies by non-modifiable factors such as certain identified syndromes and genetic factors . AdditioAdditional potential causative risk factors for hearing loss across the life course have also been identified . While mHistorically, hearing loss has been considered a benign component of the aging process resulting primarily in impaired communication. However, research over the last few decades has highlighted hearing loss as a precipitating factor for additional functional and neuropsychiatric disorders in older adults and has spurred changes in thought within the medical and public health community . ImportaThe expected rise in dementia cases around the world requires action on dementia prevention and intervention across innovative and multi-disciplinary channels to meet the pressing societal and health needs. With no known dementia cure, epidemiologic research then seeks to discern risk factors associated with the progression of dementia pathology, progression of dementia symptoms, or with dementia diagnosis to delay or minimize the impact of clinical symptoms . If we cIn this review, we highlight evidence of the association and potential causal effect primarily within studies utilizing completed objective measures of auditory function . While consideration of self-reported hearing is important, it integrates aspects of not only peripheral auditory function but also of an individual\u2019s perceived hearing and communication ability, incorporating environmental and communication demands, mental health, listening motivation and expectations, and central auditory function.Heterogeneity in study methodology and design creates challenges to synthesize data from hearing and cognition research. Heterogeneity exists across audiometric and cognitive parameters as well as sample sizes, populations studied, and consideration of confounders, to name a few. Within auditory science, heterogeneity includes aspects such as differing means to define hearing loss, pure tone frequencies used, or how hearing ability is categorized. For cognitive research, variability in the neurocognitive tests used, domains investigated, utilization of cognitive screeners, patient or physician report, and ways of defining cognitive change all create obstacles for evidence synthesis.Lancet Commission vs. consideration of those with a moderate or greater hearing loss (PTA > 40 dB HL) as the hearing-impaired group likely constitutes different comparison groups and underlying idea of what is a hearing \u201closs\u201d across different studies.A previous meta-analysis found thVaried measures of cognition used have also placed challenging demands on synthesis of prior results. A plethora of validated neurocognitive assessments exist both across cognitive domains and as global screeners. Variation in domain, mode of administration, if accommodations for hearing loss were considered, whether cognitive status was determined by provider or proxy report exist across studies, among others. While the importance of evaluating cognitive ability in multiple ways should not be ignored due to the complexity of cognitive processing and complex diagnostic presentation, synthesis of results across studies remains aloof.While an association between cognitive decline/dementia and peripheral auditory function is well established , the relPrior systematic reviews have revealed mixed quality and potential bias in previous work on central auditory function and cognition . Dryden early marker as a measure of central auditory function. The DSI presents a meaningless but grammatically correct sentence to each ear simultaneously and the listener is to then identify the sentences, with designated systematically differing modes of reporting the sentence items . This diInvestigation of various means to define and measure central auditory function suggest an association with subjective memory complaints/impairment . In a smAcross measures of central auditory processing, an association has been observed between biomarkers such as CSF tau, cortical thickness and volumetric measures of AD-related brain regions , althougDue to low-risk auditory rehabilitation tools such as hearing aids, hearing loss in older adults is readily considered modifiable and therefore makes it a worthy target of interest among dementia risk factors. The current limited use of hearing aids and challenges with accessibility of hearing devices and services have been a focus of both health research and public policy in recent years , bringinThe complexities and interdependence between central auditory function and cognitive processing present challenges for causal inference. Therefore, current hypotheses of mechanistic pathways predominantly view peripheral hearing loss as a potential cause of dementia and consider central auditory function as a marker of cognitive decline. Current hypotheses of the causal mechanistic pathways have been well articulated in other works . ClarifyA growing body of evidence indicates prolonged sensory deprivation has an adverse effect on the brain, with enduring changes to brain structure and function. Due to auditory deprivation from ARHL, neural deafferentation, cortical re-allocation for support of other processes, and atrophy in brain regions important for speech perception processing may occur. The resultant reorganization may add to existing brain pathology at the detriment of general cognitive performance by altering critical brain regions which could otherwise be utilized for higher-level cognitive processing. Reduced gray matter density and reductions in temporal lobe volume are observed in those with peripheral hearing loss , as prolWhile the sensory deprivation hypothesis suggests physical changes to the brain due to prolonged hearing loss which subsequently impacts cognitive processing, the information degradation hypothesis proposes the association stems from increased demands on cognitive processing in order to compensate for impoverished sensory input. The additional processing required to compensate for degraded auditory perception draws on the same resources needed for other higher-level cognitive processing and semantic encoding . These iAlternatively, both hearing loss and cognitive impairment may merely stem from the same underlying mechanism . Given tAPOE \u03b54) has shown no association with hearing loss genetic determinants exist may provide further insight toward additional avenues of a common cause between hearing loss and dementia are thought to contribute toward the association , these fIdentification of research priorities given the transdisciplinary scope of study on hearing and dementia will aid in achieving foundational dementia research goals: to advance our identification of subgroups of adults who may present greater risk for cognitive decline/dementia or suggest novel options for intervention or prevention. Numerous pressing research questions and additional perspectives on the importance of these questions prevail . Here weGiven the varied temporal contributions of each proposed mechanistic pathway, determination of which pathway(s) serve as the primary driver behind the association is vital. This determination may allow for improved study design and planning and well as more informed clinical intervention to delay or prevent the onset of cognitive symptoms and delay the progression along or alter the trajectory of the clinical course of dementia. With the current insufficient evidence to declare hearing loss has an independent effect on cognitive impairment for older adults, how we should intervene on hearing loss, when to do so, and if such interventions are effective in decreasing or delaying dementia risk will all largely depend on the underlying mechanism. We know the presentation of dementia symptomatology is heterogeneous across individuals even with the same underlying pathology. We have yet to determine by what manner hearing loss may influence a potential buffer which delays/prevents the presentation of symptoms in some individuals yet fails do so in others, leading to earlier symptomatology.If the association between hearing loss and dementia is only due to a common cause, the potential for directly delaying or preventing changes in the presentation of dementia symptoms or pathology through hearing would be extremely limited as the underlying cause would remain untreated. The research intervention focus would ultimately turn toward the underlying common confounder, which could then have downstream effects for hearing and cognition. However, the use of hearing management such as hearing aids may support cognition through indirect pathways like improving social engagement and communication yet decreasing cognitive load and strain on central auditory function through improvement of peripheral auditory input, directly preventing dementia would remain elusive.A direct effect of hearing loss on cognitive function is inferred with the sensory-deprivation and information degradation hypotheses. A long-term versus short term-effect is implied depending on the proposed pathway, yet both advocate that hearing loss, and notably untreated hearing loss, leads to downstream consequences for cognitive resources with important implications for approaches to intervention. The sensory deprivation hypothesis posits structural and functional changes in the brain due to lack of auditory stimulation. Therefore, preemptive identification of hearing loss and early adoption of treatment strategies which delay or prevent deafferentation or atrophy within the auditory or sensory regions of the brain are essential to prevent lasting structural damage. Importantly, auditory rehabilitation to prevent structural and functional changes in the brain through sensory deprivation may even have benefit at later stages of hearing loss by delaying additional neural reorganization or atrophy. For comparison, the information degradation hypothesis strongly supports hearing intervention at any time in the disease process. With restoration of the integrity of auditory stimuli via rehabilitation or hearing management, the cognitive demands and utilized cognitive resources for speech and environmental awareness would in theory be reduced, allowing for cognitive resources to again be allocated to overall cognitive processing and compensation.It is imperative we determine how to disentangle CAD and cognitive decline if we are to consider its use in targeting prevention efforts or early identification of subgroups at greater risk for cognitive decline. How to differentiate between changes in cognitive processing and CAD, the temporality between each processing condition, and whether CAD may serve as an early marker for specific subtypes of dementia remains a challenging barrier for characterizing the link between hearing loss and dementia. While the majority of research to date has focused on the association between hearing loss and Alzheimer\u2019s disease since the most common form of dementia and pathology observed, distinctions in association with other dementia pathologies is paramount. The dependence and entanglement of both forms of hearing on higher-level cognitive functioning stirs question of how to interpret the role of each process along the auditory pathway. If CAD may serve as an early marker of dementia remains to be determined.As stated, it is likely multiple mechanistic pathways are involved in the hearing-dementia association. Determining if one pathway serves as the primary driver, or if the pathway is unique to the individual may provide an opportunity for a person-centered approach to dementia prevention and intervention. Furthermore, while not mutually exclusive, determining the role of central vs. peripheral hearing in the hearing-dementia association will further inform research and clinical use of hearing and prevention or as an early marker of dementia.A goal of any neurocognitive test battery is to accurately measure cognitive function for all individuals. Yet the validity of cognitive assessments inherently depends on an individual\u2019s auditory or visual ability to access test materials. This interdependence has led some to question whether there is a bias or confounding introduced by a sensory impairment during cognitive testing for older adults . An inveWhile exclusion of those with severe sensory loss from testing might ensure completion of evaluations, this exclusion limits our understanding of the role of sensory loss in cognition. One way to assess cognitive function among those with hearing loss may be to utilize cognitive test batteries that are administered via visual modality rather than auditory. However, this strategy does not fully address issues that arise among those with dual sensory impairment .An alternative approach to address sensory loss when administering cognitive assessments is to consider accommodations for the sensory loss . If an iRecent decades have seen an accumulation of evidence for the impact of treating hearing loss on cognitive decline or dementia. Our observational studies have provided foundational and pivotal insights into the hearing-dementia association, however, evidence of causality for decreased or delayed cognitive decline due to hearing aid use is more challenging. From a neurocognitive perspective on this investigation, challenges include selection effects of older adults into studies. Individuals who pursue and obtain a hearing aid are generally a select group of adults\u2014 often with higher education, higher income, and greater health seeking behaviors\u2014 all of which are considered protective factors for cognitive decline .Many barriers to obtaining hearing aids still exist within the United States and must be considered within the context of existing research on the use of hearing aids as dementia prevention or intervention. Hearing aid and aural rehabilitation services are not covered under Medicare or many private insurances, placing the cost of the device and services (often $1000 or more) on the individual and family. Further, an audiologic evaluation and aural rehabilitation appointments are not currently available through direct-access to patients under some American insurances, but require referral from a primary care physician or specialist . This adWithout understanding the mechanism(s) behind the hearing-dementia association, it is challenging to determine how and when is best to intervene on cognitive decline and dementia. Evidence for treatment of hearing loss throughout the dementia continuum is growing, yet many questions remain. Evidence of efficacy, effectiveness and cost efficiency will aid in determining the best aural rehabilitation choices for prevention \u2014 all areas with extensive gaps in evidence for hearing loss and dementia.In addition to potentially serving as a dementia prevention strategy, hearing aids may present opportunity for intervention for neuropsychiatric symptoms (NPS) at all stages of dementia and negative health outcomes associated with NPS . BreakdoAdditional work is needed to determine how best to provide auditory rehabilitation for adults with cognitive impairment. A recent study suggestsWhile hearing aids serve as the most prominent means of hearing intervention, other means of aural rehabilitation are available such as personal amplifiers, general assistive listening devices, or auditory training strategies. Research is limited on the use of these alternative strategies for treatment of hearing loss along the dementia continuum, yet determination of a variety of accessible alternative strategies is fundamental for providing communication ability and social engagement for older adults. Hearing aids may not be feasible for some older adults and likely do not meet the listening needs of many adults when used as the only form of rehabilitation. As mentioned, adaptation to increased auditory stimuli requires extensive cortical adjustment which may overwhelm some individuals without proper counseling and consideration. Non-technology driven alternative strategies require Importantly, the use of hearing aids has a primary role in management of peripheral hearing loss, contributing to the focused effort of public health research on peripheral rather than central hearing ability and the association with cognitive decline/dementia. If the pathway linking hearing to cognition is related (directly or in part) due to central auditory processing and ability, the use of hearing aids as a prevention and intervention option for dementia will have minimal effect given the state of current technology and auditory processing treatments. While hearing aid use may not delay the progression of dementia pathology if the association is due to a common cause, as stated above the use of hearing aids may still indirectly support intervention of progression of the clinical presentation of dementia symptoms through indirect pathways such as decreased cognitive load and improved social stimulation. Future advances in hearing aid technology which may better address cognitive and central auditory demands may provide even greater benefit. Currently, evidence for the role of central auditory processing and central hearing disorders for early identification of dementia will have heightened importance and emphasize the need for consideration of greater use in neuropsychological and medical evaluations.if hearing or vision may serve as an early marker of dementia- a point which has yet to be determined and has received minimal study driving the association between hearing and dementia, consideration of sensory loss during cognitive testing or in care strategies for those with dementia or dementia prevention, and targeted future directions of research can have a significant impact on prevention and intervention strategies for older adults. The interdependent and synergistic processes of hearing and cognition require careful approach for research and clinical care. The current limitations in dementia treatment necessitate innovative approaches for dementia intervention. Identification of additional early markers of dementia, a potential role of central auditory function with continued research may aid in this process, as well as inform optimal strategies for hearing management itself. Considering the presence of other conditions, like hearing loss, and optimizing our strategies to evaluate and treat hearing loss could diminish the risk of adverse outcomes and enhance health and quality of life for older adults.DP was responsible for the initial drafting, editing, and formatting. EO, NR, FL, and JD contributed to content and editing. All authors contributed to the article and approved the submitted version.NR reports being a scientific advisory board member of Shoebox Inc and Neosensory. FL reports being a consultant to Frequency Therapeutics, speaker honoraria from Caption Call, and being the director of a public health research center funded in part by a philanthropic gift from Cochlear Ltd to the Johns Hopkins Bloomberg School of Public Health. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "Objectives: Immigration is a stressful life event, and immigrants commonly experience loneliness, a risk factor for depression. However, little is known about how and whether older immigrants\u2019 perceived stress exposure/appraisals mediate the association between loneliness and depressive symptoms. Further, this study explores whether familial relationships moderate the indirect or direct effects of the mediation models. Method: This study uses the 2012 Health and Retirement Study from a sample of 719 immigrants age 57 and older. A series of moderated mediation analyses were conducted across the total number of stress exposure and eight stress appraisal domains. Results: The findings indicate that the total number of stress exposure and five domains of stress appraisals mediate the association between loneliness and depressive symptoms. In addition, the perceived negative strain from family moderated the mediating effect of health problems and housing problems in the relationship between loneliness and depressive symptoms. Discussion: This study suggests that negative relationships with family may increase upsetting in stress appraisals on health and housing problems, which turn in increased depressive symptoms for lonely older immigrants. Practitioners need to assess older immigrants\u2019 stressors and family relationships to understand their loneliness and depressive symptoms."} +{"text": "This paper makes connections between social policies of retirement, migrant worker\u2019s migration experience, and migrant workers\u2019 retirement savings. Using insight from the political economy of aging and stress theory, this paper links the macro levels of understanding with the micro levels of work and aging experiences for migrant workers. Using binary logistic regression with a sample of 699 Chinese migrant workers from three emigration provinces , this paper explores four specific aspects of migrant worker\u2019s migration experience in relation to their retirement savings: financial status; length of employment; social support, and levels of hopefulness. Findings reveal that migrant workers with better financial status, social support, and higher level of hopefulness towards future are more likely to have retirement savings as compared to their counterparts. Discussions linking the macro and micro levels of social policies were provided. Policy implications were discussed."} +{"text": "There is an error in the third paragraph of the Introduction. The correct paragraph is: In people with hearing loss using assistive hearing technologies the ability to process ILD and ITD is limited [15]. Binaural summation effect, head shadow effect, and squelch effect are significantly smaller than in listeners with normal hearing [7]. The high variability in assistive technology parameters, e.g., processing times and channel numbers, and the asymmetry of hearing performance between the ears often result in bad outcome because of the wrong input in the auditory system caused by the hearing devices. Also synchronization technologies does not always help. Therefore, measuring binaural effects is challenging . The publisher apologizes for the error."} +{"text": "To review the existent literature base regarding Black and Minority Ethnic (BAME) groups care pathway into and experience of care and treatment within secure services. This includes any differences (between BAME and majority ethnic groups) in rates of sentencing, sectioning, length of stay, received treatment and use of restrictive practice. Our overarching aim is to highlight the severe lack of research in this area and the corresponding need for increased research to both consolidate and progress the existing evidence base in order to inform and improve culturally competent service provision.Research suggests that BAME groups have an increased risk of involuntary psychiatric care, longer-stays within services and higher rates of re-admission. Several explanations have been proposed for this observed disparity, however few of these proposed explanations have provided sufficient or consistent supporting evidence.A review of both quantitative and qualitative research regarding BAME groups within secure services was conducted. Approximately twenty journal articles, literature reviews and meta-analysis published between 1988 and 2019 were included. The current study should be considered a snapshot and not reflective of the full extent of published literature on the subject. For inclusion, studies should have been conducted in either a forensic mental health setting or a prison and differentiate a minimum of two ethnic groupsResearch suggest that BAME individuals continue to experience an increased risk of involuntary psychiatric care, longer stays within secure services and higher rates of re-admission. Whilst many explanations for this disparity have been proposed, few have provided adequate supporting evidence. The ongoing lack of research within this field has led to a limited evidence base from which to inform culturally competent practice. The research which has been conducted has tended to produce inconsistent findings, in part due to the reliance on small scale studies with limited generalisability. Research within this area has been further complicated by varying definitions of culture and ethnicity across studies, leading to some suggestion that the issue of ethnic inequalities and pathways to care, has been misconceptualised. This highlights a critical need for increased research efforts to:Understand why BAME individuals are at increased risk of involuntary psychiatric care, and how this disproportionate risk can be addressedExplore potential disparities in the care and treatment of BAME individuals within services and how this might impact upon higher rates of re-admissionAscertain how best to improve culturally competent service provision."} +{"text": "The Virginia Geriatric Education Center\u2019s GWEP recruited 195 of Virginia's 273 eligible nursing homes, using two Project ECHO Nursing Home Training Centers located at George Mason University and Virginia Commonwealth University. These sessions promoted collaboration, allowed for sharing of successes and challenges, and nurtured quality improvement projects. Our next steps are to survey Virginia\u2019s nursing homes to see if they are interested in future ECHO sessions with other topics. We plan to share these results with the Institute for Healthcare Improvement so that we may be able to continue to enhance this national network of Training Centers with faculty and staffing dedicated to quality assurance and performance improvement. The program has initiated new collaborations with nursing homes across many healthcare disciplines, strengthened connections between nursing homes and research institutions, and will help foster innovative ways to collaborate in this post-pandemic virtually connected world."} +{"text": "Retinal vein changes, which can be observed on clinical exam or ophthalmic imaging, are promising non-invasive biomarkers for elevated intracranial pressure (ICP) as a complement to other markers of high ICP including optic nerve head swelling. Animal and human studies have demonstrated increase in retinal vein pressure associated with elevated ICP mediated by increase in cerebral venous pressure, compression of venous outflow by elevated cerebral spinal fluid pressure in the optic nerve sheath, and compression of venous outflow by optic nerve head swelling. Retinal vein pressure can be estimated using ophthalmodynamometry. Correlates of retinal vein pressure include spontaneous retinal venous pulsations, retinal vein diameter, and retinal vein tortuosity. All of these have potential for clinical use to diagnose and monitor elevated ICP. Challenges include diagnostic prediction based on single clinical measurements and accurate assessment of retinal vein parameters in cases where optic nerve head swelling limits visualization of the retinal veins. Elevated intracranial pressure (ICP) is a pathophysiological state, detection of which is relevant to the diagnosis of neurological and neurosurgical diseases such as brain tumors, cerebral venous sinus thrombosis, and idiopathic intracranial hypertension (IIH). Monitoring of ICP is relevant to mitigating the risk of vision loss due to optic nerve dysfunction caused by elevated ICP. However, current methods for measurement of ICP are limited to invasive techniques. Ophthalmic changes are promising non-invasive biomarkers of elevated ICP since they can be seen on clinical exam and ophthalmic imaging.Papilledema, swelling of the optic nerve head due to axoplasmic stasis in the retinal ganglion cells that form the optic nerve, is a downstream effect of high ICP . AccordiRetinal vein changes are promising biomarkers of elevated ICP because, like optic nerve changes, they are observable on clinical exam and ophthalmic imaging but, unlike optic nerve appearance, change rapidly following ICP changes. There are early data to support the potential of retinal vein changes as a biomarker to aid in diagnosing and monitoring high ICP states.To consider retinal vein measurements as potential markers of elevated ICP, it is necessary to understand the broader landscape of parameters that influence retinal vein appearance. As with all blood vessels, retinal veins are compliant tubes. Their appearance is based on anatomical branching pattern, compliance of the vessel wall, pressure on the outside , and pressure of their contents . Blood pressure and flow are determined by upstream pressure, downstream pressure, and resistance. For retinal veins, the relevant pressures are central retinal artery pressure and central retinal venous pressures with resistance being mainly in the retinal arterioles. However, these pressures do not exist in isolation and are impacted by upstream and downstream vascular pressures and resistances.Elevated ICP impacts retinal veins through three mechanisms. First, it is associated with changes in downstream cerebral venous pressures. Second, elevated pressure in the cerebral spinal fluid (CSF) in the subarachnoid space inside the optic nerve sheath exerts external pressure on the central retinal vein as it exits the eye, which increases vascular resistance. Finally, elevated pressure in the CSF in the subarachnoid space compresses the retinal ganglion cells in the optic nerve, and the feeding arteriolar supply causes papilledema to develop. Papilledema also exerts external pressure on the central retinal vein which increases vascular resistance.Non-human primate studies of acute ICP elevation have confirmed the first two mechanisms with the following observations. Superior ophthalmic vein pressures are elevated in association with ICP elevation . IncreasObservation of pathological retinal findings in humans with elevated ICP support an association between high ICP and elevated retinal venous pressures in humans. Examples include venous stasis retinopathy and retiFirst developed in the early twentieth century, ophthalmodynamometry involves application of force to the external eye and observing the retinal vessels as force is increased. The force at which a vessel collapses is indicative of pressure in the upstream vessel . The comEarly use of ophthalmodynamometry focused on arterial pressure measurements. More recently, multiple studies of ophthalmodynamometric measurements in patients undergoing invasive ICP monitoring have shown ICP and retinal vein pressure to be highly correlated , 12. HowSpontaneous retinal venous pulsations, visualized as an oscillation in retinal vein diameter, often near the optic disc margin, are a result of IOP and ICP oscillations leading to transmural pressure oscillations causing partial collapse of the vein . When reThe detection of spontaneous retinal venous pulsations is often used as a clinical screening tool to rule out elevated ICP, although it is an imperfect one with the presence of spontaneous retinal venous pulsations assessed by an expert examiner having sensitivity approaching 90% to exclude high ICP but specificity of <20% to detect high ICP . Some ofThe diameter of a compliant tube increases as transmural pressure is increased , and accQualitative and quanThe largest study of retinal vein diameter in IIH was performed in conjunction with the IIH Treatment Trial (IIHTT), a randomized controlled trial of acetazolamide + weight loss intervention vs. placebo + weight loss intervention in 165 subjects with IIH, papilledema, and mild vision loss . At basevia downstream venous pressure increases and optic nerve sheath pressure increases, the additional mechanism of papilledema causing downstream venous resistance increases may be a stronger factor. However, this does not negate the potential of retinal vein diameter as a marker of ICP elevation. Rapid retinal vein changes following CSF pressure lowering . This reflects retinal vasculature distortion by papilledema including obscuration of vessels and hemorrhages obscuring the branching pattern and illustrates a practical challenge in the use of peripapillary retinal vein measures as biomarkers of ICP.In compliant tubes, increases in pressure initially cause an increase in diameter but subsequently cause an increase in tortuosity . RetinalThere are multiple retinal vein findings that relate to ICP and show promise as clinical biomarkers of elevated ICP to complement those already used in clinical care. These include ophthalmodynamometry to measure retinal vein pressure, detection of spontaneous retinal venous pulsations, measurement of retinal vein diameter, and measurement of retinal vein tortuosity. Future research is needed to advance these to clinical care beyond a qualitative screening test as spontaneous retinal venous pulsation detection is currently used. Effort is needed to better understand the factors causing measurement variability and to develop measurement techniques less susceptible to failure due to papilledema.There are multiple parameters impacting retinal vein pressure and direct/indirect measurements of this. While many of these have been identified, how they combine with each other to impact measurements has not been elucidated. Ophthalmodynamometric , non-humDistortion of the optic nerve and peripapillary retina by papilledema introduces a technical challenge when translating retinal vein measurement techniques developed for application in situations without optic nerve swelling. Potential solutions to improve feasibility of measurements include measurement of vessels distant from the optic nerve, for example by examining macular vessels or using widefield imaging.HM contributed to conception and design of the study and wrote the manuscript.This study was supported by National Institutes of Health R21 EY 031726 and P30 EY 026877, Unrestricted Grant from Research to Prevent Blindness to the Stanford Department of Ophthalmology.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past collaboration with one of the author, HM.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher."} +{"text": "The ongoing COVID-19 pandemic has underscored the need to optimize care for one of the most affected sectors: older adults in nursing homes and more specifically highly vulnerable populations such as residents with dementia. Research developed in collaboration with stakeholders can optimize impact, relevance, and trustworthiness of study findings thereby informing advances in care. Yet, evidence on stakeholder driven research for enhancing dementia care is limited. This symposium will provide examples of stakeholder-driven research questions that were addressed with stakeholder engagement. First, we will present current evidence about the perspectives of caregivers, including those from communities of color. The second presentation will discuss the perspective of clinical training stakeholders responsible for supporting system-wide clinical program implementation and their experiences with early and later adopter nursing homes within the context of a clinical trial. The third presentation will address the perspective of policy makers and payers via the effect of state-mandated dementia training on resident outcomes. The fourth and final present the findings from a study that examined how nursing home stakeholders responded to a payor requirements for pharmacy services and the relationship between that response and patient outcomes. We will conclude the session with a discussion of stakeholder-engagement methods and recommendations for future nursing home research, which champions stakeholder collaboration."} +{"text": "While the separate effects of socioeconomic status and engaging in leisure activities on cognition have been well documented, their interaction effect has rarely been examined. After examining life course socioeconomic status (SES) on cognitive impairment in old age, this paper is focused on exploring the interaction effects between life course SES and leisure activities. We use data from the Chinese Longitudinal Healthy Longevity Survey, which covers five waves of interviews of adults aged 65 or older between 2002 and 2014. Cognitive impairment is measured by the Chinese version of Mini-Mental Status Examination. Two sets of variables are used to reflect an older person\u2019s life course SES in childhood and adulthood, respectively. Seven leisure activities are included in this analysis. We adopt the lagged independent variable approach and a Generalized Linear Mixed Model to examine the association between leisure activity and cognitive impairment over time. Results show that there is an independent impact of SES in both childhood and adulthood on cognitive decline in Chinese older population. Furthermore, as the focus of this study, there are substantial interactions between life course SES and engaging in leisure activities with a consistent pattern: those of higher life course SES enjoy extra benefits from engaging in leisure activities. The interactions between life course SES and leisure activities promise a competing approach accounting for cognitive health inequality among older adults."} +{"text": "Personality reflects the influence of older adults\u2019 past experiences on their tendencies to engage in certain behaviors and generate emotions. An increasing number of studies have focused on the expression of personality in older adults\u2019 everyday life. Specifically, personality features have been associated with daily activities, affect reactivity, and mood. This symposium draws on Ecological Momentary Assessments and longitudinal analysis to understand how personality is manifested in daily life, and how daily emotional experiences accumulate over time to influence physical health. Lee and colleagues examine how personality is associated with daily activities and find that extraversion is positively associated with activity diversity in two adult samples. Pasquini and colleagues consider the within-person fluctuations in personality traits and demonstrate the possibility of using daily behaviors and affect as markers of extraversion and neuroticism. Zhang and Fingerman assess how positive and negative moods concurrently change in reaction to daily social contacts and confirm that narcissism moderates such associations. Finally, this symposium also focuses on the cumulative effect of daily emotions on physical health. Leger and colleagues address the long-term association between personality and physical health and identify the mediating role of negative reactivity to daily stressors. Collectively, the presentations provide an in-depth analysis of personality\u2019s impact on concrete daily behaviors and emotions, as well as their profound long-term effect on physical health. Our discussion outlines future research directions and highlights how inter-individual differences, simultaneous life events, and social interactions intertwine to influence individuals\u2019 behaviors that occur in natural settings."} +{"text": "Multimorbidity describes the accumulated burden of chronic disease. Multimorbidity erodes physiologic reserve, increasing the risk of frailty, disability and death. Most older adults have at least one chronic health condition by age 65. Once established, many age-related conditions progress and accumulate with age. Geroscience holds that there are key biologic pathways that explain the increase with age in multimorbidity, frailty and disability Translation of geroscience principles to human studies requires careful assessment of biomarkers of these pathways and multisystem outcomes. In this symposium, translational researchers in geriatric medicine and gerontology will present current work to elucidate biologic underpinnings of aging and potential intervention targets. We will address whether blood biomarkers of aging processes are prognostic using combinatorial techniques and explore the potential for proteomics to identify novel pathways for health aging. New insights into the role of inflammation will be discussed with an emphasis on its relationship to multimorbidity. Brain aging will be considered with respect to the interactions between external stressors and resilience evaluating the role of ketone bodies which have immunomodulatory effects particularly on innate immune cells. Finally, the role of multimorbidity as an intervention target and potential intermediate outcomes including biomarkers will be presented with discussion of next steps needed to realize the potential for translational geroscience clinical trials to improve health span."} +{"text": "Blood has been widely investigated to discover biomarkers and gain insights into the biology of aging and age-related diseases. Its protein composition provides insights into complex biological processes, as proteins are often direct regulators of cellular pathways. In clinical trials, selected proteins have been used as primary and secondary endpoints, but recent methodological developments allow the measurement of thousands of proteins with very high sensitivity and specificity. In two phase 2 clinical trials testing the safety, tolerability, and feasibility of infusions of the plasma fraction GRF6019 in Alzheimer's disease (AD), we measured more than 7000 proteins in plasma over the course of the clinical trials. Differential trajectories analysis revealed groups of proteins and pathways that were responding to GRF6019. Several pathways were relevant to the biology of aging and AD and our study suggests that deep proteomics profiling can inform on specific biological processes responding to treatment in clinical trials."} +{"text": "Homeless populations require spaces and services that take into account their life trajectories. The Aging in the Right Place - Environmental Checklist (AIRP-ENV) is an environmental audit tool developed by our team to evaluate the accessibility and overall design features of housing targeted for aging individuals experiencing homelessness. Researchers in Vancouver, Calgary and Montreal employed this tool in 2021 to evaluate environmental features in selected promising practices to identify built environment factors that promote aging in the right place. Preliminary findings reveal the following themes across sites: access to communal and recreational spaces encourage social inclusion and meaningful recreation opportunities; barrier-free built environment features foster independence and safety; and access to services and amenities encourage community mobility. Findings demonstrate a need to employ a broader evaluative lens that incorporates psycho-social factors to gain a nuanced understanding of aging in the right place for older adults who have experienced homelessness."} +{"text": "Prediction of neurodevelopmental outcomes after preterm birth has interested neonatologists and health care workers involved in follow\u2010up of children born preterm for decades. Whereas many studies demonstrate evidence regarding prediction of childhood outcomes in the motor domain, prediction of cognitive skills lags behind. Two new studies add to this evidence by reporting moderately strong associations between the scores on the Hammersmith Infant Neurological Examination (HINE) in infancy and cognition later on.The associations found have also been demonstrated in several studies regarding the predictive value of General Movement Assessment (GMA) for later cognition.The connection between early findings in the motor domain and later cognitive skills is very interesting. In typically developing children born at term, motor development stimulates interaction with the environment, resulting in advancing development of various cognitive skills, by creating new learning opportunities.The cause of the coocurring motor and cognitive delay could be different between children born early preterm and moderate\u2010to\u2010late preterm. With advancing gestational age, the disruptions of brain development are less severe, but the associations are still moderately strong.The findings in both studies have important clinical implications. Lower scores on the HINE may identify children born preterm at risk for cognitive delay, enabling interventions aimed at improving later cognition to start earlier than at present. It is tempting to conceive interventions that improve certain movements and postures because these were the items of the HINE that were associated most strongly with attainment of cognitive skills. Whether this indeed improves cognition in children born preterm should be the subject of future longitudinal studies."} +{"text": "Pediatric burn patient family needs have many similarities to adult burn patients. However, based on our abstract Family Needs of Adult & Pediatric Burn Patients study from 2013 to 2018, there is a difference. We found our desire to preserve the pediatric burn patient family members as the \"safe, comforting person\" prevented them from learning all the necessary skills to be the successful caregivers once the child was discharged.An integrative review is conducted using a literature search from EBSCOhost, CINAHL, Scopus, Medline, and PubMed. We found very little information addressing this specific concern for our pediatric burn population. However, there is a lot of literature discussing how to involve pediatric family members with other childhood diseases and the benefits of making pediatric family members a part of the treatment team. We shared our literature findings along with the results of responses we got from our Family Needs of Adult & Pediatric Burn Patients study with our Shared Decision-Making (SDM) Council and implemented our new practice.An informal interview results showed much improved pediatric burn family member satisfaction. By the time the family takes the burn child home, they demonstrate proficient dressing change skills along with the knowledge of how to manage their pain, itch, nutritional needs, and how to contact their care team as needed.While most of us know the importance of family centered care, putting this concept into practice need more structured approaches and administrative support. Unit based SDM Council and Journal Club can help to keep our nursing staff, especially the new hires to embrace this practice."} +{"text": "This presentation hypothesizes that an innovative collaboration by the adult generations will be necessary to enable conditions needed for family success in a longevity society. Unprecedented challenges of parents and grandparents are examined. Reasons why adults have to regard youth as a source of learning about their unique experiences in an age-separated society are explained. International curriculum development studies to support families of children from birth through adolescence are described. A curriculum that provides a common knowledge base about child and adolescent guidance is proposed to harmonize efforts of adults to support younger relatives. Curriculum for retirees should focus on continuing responsibilities other generations expect of them, learning about the lives of younger family members, and gaining awareness of parenting practices to reinforce lessons. Training volunteers in assisted living and long-term care facilities to be indigenous leaders of grandparent classes is discussed as a practical way to offer relevant learning and improve social support. Instruments are examined that assess ethnic relationships between adult generations, adults and adolescents, and track results of education intervention."} +{"text": "Multidisciplinary approaches to conservation and wildlife management are often effective in addressing complex, multi-factor problems. Emerging fields such as conservation physiology and conservation behaviour can provide innovative solutions and management strategies for target species and systems. Sensory ecology combines the study of \u2018how animals acquire\u2019 and process sensory stimuli from their environments, and the ecological and evolutionary significance of \u2018how animals respond\u2019 to this information. We review the benefits that sensory ecology can bring to wildlife conservation and management by discussing case studies across major taxa and sensory modalities. Conservation practices informed by a sensory ecology approach include the amelioration of sensory traps, control of invasive species, reduction of human\u2013wildlife conflicts and relocation and establishment of new populations of endangered species. We illustrate that sensory ecology can facilitate the understanding of mechanistic ecological and physiological explanations underlying particular conservation issues and also can help develop innovative solutions to ameliorate conservation problems. Animals possess a variety of sensory systems that perceive salient features of the environment and facilitate critical, fitness-enhancing decisions . SensoryInsights from sensory ecology have important implications for conservation and management of wildlife with connections to the emerging disciplines of conservation behaviour and consAlthough ecological research on visual and auditory senses has been conducted for nearly a century , only inHere, we present a comprehensive overview of the benefits to wildlife conservation and management that emerge from an understanding of sensory ecology and use the term \u2018wildlife\u2019 broadly to include all animal taxa. We review three major sensory modalities as well as less understood modalities and present case studies highlighting sensory ecology approaches relevant to conservation and management. In particular, we discuss case studies where sensory ecology has been demonstrated to successfully benefit a conservation problem see , and alsVision as a sensory modality can be defined not only as the ability to detect and respond to light stimuli, but also the ability to detect spatial structure and form an image . Light iIn this section we review visual ecology research for five major taxa that has benefited conservation and wildlife management. Amphibian vision has been relatively understudied for the context of conservation , and thuBirds are visually oriented animals whose cone photoreceptor cells also have pseudoorganelles (oil droplets) that can enhance color discrimination . Color pMolothrus ater) visual system to safe breeding areas (Gyps fulvus) to nest on cliffs that had not been chosen as nesting sites by this species for ~60\u00a0years that exploits ultraviolet vision to search for lichens and other food sources in dark winter periods under night lighting conditions to increase 6-fold compared with unlit conditions to green, red and blue light (Acipenser fulvescens: Anguilla rostrata: It has been known for some time that white or mercury vapour light (a high intensity discharge lamp) can be an effective repellant or attractant for various fish species . HoweverDrosophila melanogaster (Bicyclus anynana) for selecting mates (e.g. Melanophila acuminata), which use infrared to detect forest fires from distances indicating suitable low-risk places for females to lay eggs , seaward migration following emergence occurs predominantly during the night and hatchlings rely on light from the horizon above the sea to guide them to water . Reptile and amphibian auditory ecology has been relatively understudied in the context of conservation, and thus we do not discuss these taxa in this section . AnthropAvian species often rely heavily on hearing for a number of behaviours including hunting/foraging, predator avoidance, territorial defense and conspecific attraction for reproductive purposes . Avian hSialia mexicana) and a significant reduction in hatching success in noisy sites compared with control, quiet sites (Seiurus aurocapilla: Turdus merula) song to earlier hours of the morning to avoid rush hour traffic causing sleep deprivation for the bird , and this can have a number of negative consequences for bird species in many contexts . For exathe bird .Vireo atricapilla), a territorial songbird, was attracted to suitable habitat sites that were uninhabited by the species by playing recordings of the bird\u2019s song. The researchers were successful at attracting birds to the experimental sites where the bird song was played, compared with control sites where no black-capped vireos were attracted over the same time period. In this example, the researchers attracted birds to sites where the brood-parasitic brown-headed cowbird (Molothrus ater) was controlled, and thus higher nesting success was seen compared with nearby black-capped vireo populations in uncontrolled habitats (Sturnus vulgaris), and results showed an 82% reduction in the number of starlings at airfields with sonic nets compared with control areas. Previously we discussed how avian vision can be exploited to make aircraft more visible to birds to reduce airstrikes, and perhaps using a combination of approaches, and targeting more than one sense (multisensory approaches), may be more effective at either repelling species from unsuitable dangerous habitats, or attracting species to more suitable habitats.Conservation practitioners can also exploit bird auditory ecology to influence habitat selection behaviour to guide birds to settle in more appropriate areas. In a study by habitats . SimilarMyotis myotis), potentially interfering with signal reception and processing. Natural gas compressor stations reduce pallid bat activity levels by as much as 40% at louder stations compared to quieter ones (Trachops cirrhosus) can shift to active echolocation from passively listening for frog vocalizations when anthropogenic noise is present (Dipodomys stephensi), traffic noise not only masked foot-drumming signals but also served as an acoustic model that kangaroo rats appeared to mimic without reducing target Atlantic cod (Gadus morhua) catches in Danish gillnet fisheries , although the stress response was not seen when kelpfish were exposed to a constant source of sound indicating that the variability in sound pollution may be a more important factor than its presence alone (Pomacentrus amboinensis) exposed to motorboat noise also show signs of physiological stress and, as a result, have a reduced ability to evade predators in North America, including into the Laurentian Great Lakes found near loud roadways (Cryptotympana takasagona) found in louder environments (Gryllus bimaculatus) to orient to male auditory calls odours without physical contact with the source and is oIn this section, we will discuss how chemosensory ecology, in particular olfaction and gustation, can be exploited in conservation and wildlife management. Research has led to the development of highly effective animal control techniques through creating species-specific olfactory traps. Examples include controlling pest, invasive or overabundant species, and mitigating human\u2013wildlife conflicts. The majority of the literature on pest control through exploiting olfactory systems focuses on insects as various species are common pests in agriculture and vectors for diseases, and thus there is a strong need to control their populations in some instances predation on threatened hooded plover (Thinornis rubricollis) eggs, model eggs that mimicked those of the hooded plover were produced and treated with a CTA-inducing chemical is one such method used to manipulate the behaviour of an individual. Through this method, individuals are taught to associate certain food items with a negative taste experience. True CTA has been successfully used to reduce predation of endangered bird eggs. In one study that aimed to reduce red fox females release sexpheromones that attract males for reproduction purposes. These goats were introduced by humans to the Galapagos archipelago where they quickly established a fast-growing population that had destructive effects on native biota and eventually demanded eradication of the population (Capra hircus) were controlled through predator olfactory deterrents. Canis lupus dingo), lion (Panthera leo) and tiger (P. tigris) odors, which could have implications to shift goat grazing areas to other areas where they may not be causing as much damage or competition with endangered native species. Olfactory predator deterrents have also been shown to be successful with a number of other species including certain marsupials , a threatened primate species are invasive species to the Laurentian Great Lakes and are destructive parasites of valued sport fishes. Researchers found that male sea lamprey release a mixture of sex pheromones and identified several components (Sex pheromones in species of invasive fish have been successfully exploited to control populations of some species. Sea lamprey (Lymantria dispar) is an invasive species in the United States that feeds on many woody plants and has devastating effects on forests that can detect its prey, the flatfish (Pleuronectes platessa), using only electrical stimuli but not sandbar sharks in both natural and labortary settings offspring provide their parents with increased information (Schizocosa stridulans) courtship behaviour that includes both visual and seismic signals only integrated vibrational and olfactory sexual stimuli from males when they are reproductive, which aids in finding the specific location of reproductive males and nest sites (Coccinella septempunctata) are multimodal signals comprising visual and chemical warning signals (Bombus impatiens), allowing individuals to learn and detect more rewarding flowers faster , finding that squirrels were less responsive to auditory predator signals, and instead increased their alertness to obtain more visual cues. Sciurus carolinensis). Assessing how human development, and planned development, affects multisensory perception in animals will allow a more comprehensive measurement of the impacts of such development on affected animals as the only species for which sensory ecology has been studied with applications for conservation. Despite a relatively small amount of research in the field of applied sensory ecology, we do observe certain taxonomic biases . SpecifiTo improve communication and collaboration across sensory ecology, physiology and conservation science fields there is a need for increased research efforts demonstrating sensory-based conservation strategies, and a clear understanding of conservation needs (see Every organism lives in its own sensory world, each perceiving the environment through different sensory organs. Knowledge of how and what different organisms perceive has helped us understand seemingly counter-intuitive, maladaptive behaviours including birds colliding with moving vehicles ("} +{"text": "Over the past 5 years, advanced assisted reproductive technologies (ARTs), such as mitochondrial replacement therapies (MRTs) and heritable human genome editing (HHGE), have raised global policy concerns and fears of \u2018unregulated\u2019 proliferation. Yet, few innovations are ever truly unregulated and more often fall within the scope of one or more pre-existing regulatory regimes, a process referred to as \u2018inherited regulation\u2019. While the United Kingdom has enacted new legislation to specifically authorize and closely regulate MRTs, many jurisdictions will likely default to current oversight systems to manage advanced ARTs. This article evaluates and compares how several jurisdictions have already used four types of inherited regulatory regimes to manage MRTs and HHGE. Cases are drawn from jurisdictions where inherited regulatory interventions on advanced ARTs have taken place and include jurisdictions closely connected with those cases (Mexico and Spain). When accounting for political, cultural, and religious contexts, many of these inherited regimes offer promise as starting points for governance of advanced ARTs, yet each will require further adjustments and tailoring to adequately manage the benefits and risks of these powerful innovations. Technology has long influenced how and when human reproduction can occur, transforming and being transformed by everything from social values to economic structures in the process. Yet, over the past four-and-a-half decades, the actual or potential role of technology in reproduction has rapidly expanded.These advanced ART techniques move beyond IVF and related methods by manipulating gametes, embryos, or even somatic cells at the organelle, genomic, or gene expression levels, ultimately producing a viable embryo biologically related to the intended parents. Advanced ART techniques began to arise over two decades ago with reproductive cloning and ooplasmic transfer, although the controversies they provoked resulted in legislative and regulatory actions to block their use in many jurisdictions.In this article, we trace how multiple states have already used available regulatory systems to steer the use of, or prohibit, certain advanced ART techniques. Scholars have already begun to make comparisons of several states\u2019 approaches to one type of advanced technique, MRTs, addressing the matters of how jurisdictions conceptualize and categorize the technology or whether states have or will enact novel regulatory regimes.In this article, we find evidence of jurisdictions taking multiple different approaches to using existing regulatory structures and instruments to manage advanced ARTs, and we argue that effectively using these regimes will require policymakers to thoughtfully, and incrementally, tailor their requirements to advanced ARTs. For some jurisdictions, this will require coordinating multiple inherited regimes, potentially at multiple levels of government. Section II provides an overview of two nascent advanced ARTs, which have already seen clinical use, before Section III introduces the theoretical framework of inherited regulation. Five case studies of inherited regulatory interventions on advanced ARTs are presented in Section IV, followed by a comparison and discussion of these cases in Section V. Concluding thoughts and implications for policy strategies around advanced ARTs and inherited regulation are set out in Section VI.Two broad classes of advanced ARTs have recently seen clinical applications, with others currently under development. The first, MRTs, have gained prominence for their potential to prevent some mitochondrial diseases.MRTs offer technologies to avoid such diseases by matching the mtDNA of a healthy donor woman with the nuclear DNA of the two intended parents, allowing parents to have a healthy, biologically related child. Prominent techniques include pronuclear transfer (PNT), maternal spindle transfer (MST), and polar body transfer (PBT), where PNT and one form of PBT require a fertilized egg to be discarded but MST and the other PBT variant do not.Alongside their potential benefits, these MRT methods also present potential health risks and ethical concerns. Various mitochondrial-nuclear interactions occur in healthy cells, so pairing the intended parents\u2019 nuclear genome with donor mitochondria could result in safety issues if potentially harmful mismatches occur.A second advanced ART which has already seen clinical application is heritable human genome editing (HHGE).Various stakeholders have raised multiple safety and effectiveness risks on the potential use of HHGE, including leading scientists Jennifer Doudna and Feng Zhang,Myriad social and ethical concerns have also risen to meet the realistic potential of HHGE. These range from challenges over equitable access, human enhancement, and medical tourism to the rightful place of biomedicine in reproduction and the fundamental meaning of human dignity or self.Other advanced ARTs are being developed, though appear to be substantially farther from clinical application than MRTs and HHGE at this time. These might include potentially transformative innovations such as in vitro gametogenesis or artificial womb technology,Nascent technologies frequently incite legal, ethical, and policy challenges by posing novel benefits and risks\u2014real or perceived\u2014unanticipated by current systems of governance. The speed of innovation often appears to accelerate as a technology begins to emerge and its uses become more apparent, yet government entities create new legal norms at a relatively constant rate. The result is a \u2018pacing problem\u2019, where the governing activities of legislative and regulatory bodies increasingly lag behind technological innovation.More often, existing regulatory regimes can, and do, apply to emerging technologies. The question is therefore about the efficacy of the current regime in achieving its stated policy goals and addressing emergent concerns rather than whether or not the technology and/or its products fall within the scope of existing regulation.Discourse on inherited regulation has focused on both the degree of coverage and the efficacy of past regimes for emerging technologies. Regarding coverage, inherited regimes may apply to new technologies depending on the scope of both the existing, written rules themselves, and on the interpretation of those standards. For example, an existing regime may cover the products of an emerging technology (ie product regulation), but not the novel processes involved in their production (ie process regulation), as is common in the USA.When assessing an inherited regime\u2019s fitness (ie efficacy) for an emerging technology, it becomes critical to interrogate the goals, assumptions, and structures underlying the existing regulatory system.Evaluating fitness in regulatory inheritance therefore requires examining entire regimes, not just individual rules or standards. Levi-Faur defines a regulatory regime as the collection of all norms, values, assumptions, procedures, and actors engaged in regulation within a particular industry, sector, or space.Coverage and fitness can inform the extent to which inherited regulations will capture emerging technologies with appropriate goals and tools, however, evaluating the success of an inherited regulatory regime will also require looking to empirical evidence. Assessing regulatory interventions based on inherited regimes will therefore require analyzing the implementation of and compliance with the inherited oversight system. Implementation efforts will depend both on the quality of a regulator\u2019s information gathering, as failing to detect the use of an emerging technology within their jurisdiction will prevent applying standards to its use, and on the enforcement strategy selected.Analyzing how well an inherited regulatory regime can govern an emerging technology therefore can be described as involving at least four components: coverage, fitness, implementation, and compliance. This article will proceed by using fairly established normative criteria\u2014effectiveness and legitimacy\u2014to assess and compare the performance of inherited regulatory interventions on advanced ARTs across five cases. Effectiveness of regulation measures, in relative terms, how well oversight activity achieves its policy goals while legitimacy describes the degree and character of social, moral, and political support behind the regulatory actions and institutions.Advanced ARTs pose numerous, complex policy challenges. Balancing health and social risks across generations against potentially powerful benefits to individuals, families, and health care systems calls for robust regulatory oversight. However, the regulatory inheritance discourse and lessons from other emerging technologies suggests that most jurisdictions will not establish new regimes specifically tailored to manage advanced ARTs.Only one state has thus far constructed a novel regulatory regime for an advanced ART. In 2015, the United Kingdom became the first jurisdiction to enact legislation authorizing and setting out a new regulatory regime for MRTs.The new MRT legislation empowered the HFEA to license qualified clinics seeking to provide MST or PNT techniques, solely to prevent mitochondrial diseases, where licensed clinics must further apply to regulators for approval to perform each treatment.While a handful of jurisdictions, including Australia and Singapore, are debating enacting similar regulatory regimes for MRTs,In September 2016, news that the first baby had already been born following an MRT treatment sparked a global debate over the technology.Despite media attention in 2016 on a statement from a member of the clinical team that the procedure occurred in Mexico because the state has \u2018no rules\u2019 on MRTs, Palacios-Gonz\u00e1lez and Medina-Arellano point to relevant regulatory frameworks at both the federal and local levels.In 2017, the US Food and Drug Administration (FDA) took action by sending Dr Zhang a letter detailing the clinic\u2019s violations of US medical products\u2019 regulations.Currently, MRTs cannot lawfully be performed in the US, though the techniques are not specifically illegal. While the US National Academies recommended, in 2016, that clinical studies of MRTs to prevent mitochondrial diseases could proceed once evidence suggested adequate safety and efficacy, conditioned on using only male embryos initially, this plan has not yet moved forward.The FDA has signaled it would oversee MRTs with its drug and biologics regulatory regimes should the appropriations rider be lifted, and FDA\u2019s CBER cited drug and biologics rules when taking its enforcement action against the New Hope Fertility Center in 2017.Though not publicly known at the time, a clinic in Greece received state approval to move forward with MRT clinical trials only days before the announcement of the first MRT birth in New York.While most ART regulation in the EU occurs at the national level, some supranational legislation may apply to advanced ARTs such as MRTs. Most notably, Article 90 of the EU Clinical Trials Regulation, replacing the earlier Directive 2001/20/EC, prohibits clinical trials of medical products \u2018which result in modifications to the subject\u2019s germ line genetic identity\u2019.Further, Greece and Spain (but not the United Kingdom) have both ratified the Oviedo Convention, a multilateral agreement through the Council of Europe setting international norms on human rights in the biomedical context.Spain has an ART regulatory regime grounded in legislation from 2006, which establishes a licensing and registry system for ART clinics, basic standards for research and practice, and sanctions for noncompliance.Greece also has an existing regulatory regime for ARTs, overseen by the Greek National Authority of Assisted Reproduction, where ART treatments may only be performed to treat infertility or prevent serious heritable disease in a child.The existing Greek ART regulatory regime appears to grant the National Authority the powers necessary to approve a clinical trial for MRTs to treat infertility (and likely for the intended use of avoiding disease as well). The legislative provisions requiring regulatory approval before research leading to a pregnancy and mandate that ART interventions should treat infertility or prevent a heritable disease, alongside the absence of a direct prohibition on techniques involved in MRTs, should enable the approval of investigational MRTs at licensed ART clinics in Greece. While the Hellenic National Bioethics Commission recommended against clinical trials of MRTs in 2017,The second known birth from an MRT occurred in January 2017 at the Nadiya Clinic in Kiev, Ukraine.While the exact regulatory status of the clinical research is murky, the Nadiya Clinic claims to have received authorization to conduct a clinical trial from the Ministry of Health of Ukraine via a local hospital.While Ukraine does not currently have comprehensive ART legislation,Other ART-related law in Ukraine potentially applicable to advanced ARTs do not appear to capture MRTs. Though Ukrainian legislation specifically forbids human reproductive cloning, the language is likely too narrow to apply to other forms of advanced ARTs.As the Darwin Life-Nadiya group claims to have received approval from the Ministry of Health to conduct a clinical trial on MRTs, Ukrainian health research regulations should also apply. Generally, Ukrainian health legislation provides basic requirements for medical research such as informed consent.Furthermore, the National Academy of Sciences of Ukraine appears to have taken a rare step by providing ethical review for the Darwin Life-Nadyia group\u2019s MRT clinical trial, although ethical approval came nearly 2 years after the first birth in Ukraine was reported.When making the decision, our Committee resolved that, according to all international acts, every person has the right to reproduction. The main setback for development of reproductive nuclear transfer techniques is the uncertainty of impact of this technology on a future child\u2019s health. Considering it, we are not able to answer this question without conducting the experimental study on condition of patients\u2019 consent and their understanding of possible risks.The rationale provided suggests interests in reproductive autonomy were judged to outweigh safety concerns for consenting patients in approving the clinical trial, particularly in light of the uncertainty around safety risks.In 2003, a scientific conference abstract unexpectedly reported that the first pregnancy derived from PNT had been successfully established for a woman in China.The National Health Commission (NHC), the current successor to the Ministry of Health, functions as the national ART regulator for China and all ART clinics must undergo certification and monitoring by the agency to offer services.CCR5 gene in embryos from couples where the biological father was HIV-positive, given the gene\u2019s role in HIV transmission, allegedly to decrease the risk of infection to the children throughout life.In late November 2018, Antonio Regalado at the MIT Technology Review broke news that a group in China had performed HHGE with CRISPR-Cas9 tools, leading to the birth of twins and (later discovered) at least one other child.In performing HHGE, Dr He and his team appear to have violated not only the 2003 guidelines on embryo modification but also several other guidelines on ethical review and biotechnological research safety.The Chinese regulatory response to this case of advanced ARTs also relied on criminal law; in part, in response to political pressure from the international community to take definitive action against He.In response to the 2018 incident, China issued new regulations on HHGE, in mid-2019, which would be more directly enforceable than ministerial guidance.CCR5 gene with CRISPR tools.Only months after the He Jiankui incident, a scientist from Russia announced that he also intended to transfer gene-edited embryos to patients. In a statement to \u2018Nature\u2019 published in June 2019, Dr Denis Rebrikov revealed a strong intent to perform HHGE with a similar plan to Dr He\u2019s, again targeting the While Russia does not have a dedicated ART regime, its general health statute creates a right to ART treatment and broadly empowers the government to approve and restrict ART protocols.In October 2019, responding to international pressures and in the shadow of the He Jiankui incident, the Russian Ministry of Health extended its 2012 order on ART protocols to preclude the clinical use of HHGE.In the wake of the Ministry\u2019s decision, Rebrikov expressed disappointment but signaled he would not proceed without regulatory approval.These five cases of regulatory interventions on advanced ARTs with inherited regimes exemplify how jurisdictions can extend existing rules to emerging technologies. However, the legal question of whether current regimes can be extended is different from the normative inquiry into how well inherited regulation operates\u2014and with what consequences. Previous literature analyzing inherited regulation has focused on nanotechnologies, finding that several jurisdictions successfully applied or extended their available regulatory regimes but with questionable fitness for managing the novel products.This section will assess the five case studies presented above interpreting current regulatory norms. The degree to which an inherited regime can cover new technological spaces will depend on the scope and targets of existing rules and political support for formally or informally applying those rules instead of crafting new ones.First, the most common type of inherited regime applied to emerging reproductive technologies were existing ART regulatory systems. Extending these systems reflected a pragmatic choice by policymakers, as the scope of these regimes often readily captured the new techniques. However, the differences in the breadth and scope of the ART regimes in each case required some jurisdictions to perform more interpretive work than others in defaulting to these regimes. For example, Spain\u2019s system of national and local approval for any new reproductive technique and Greece\u2019s national regulatory approval before clinics conduct human research represented the most robust ART regimes, readily capturing MRTs.Second, two jurisdictions did or could use criminal law to oversee advanced ART activity: China and Mexico.Third, Mexico and Ukraine achieved different extents of coverage for advanced ARTs with human subjects research regulation, although these regimes can only address research and not clinical/commercial uses of the techniques. Mexico\u2019s rules should prohibit the study of any new ART technique unless it treats infertility, which should readily cover MRTs intended to prevent disease and HHGE and benefit from a national regulatory agency to enforce them.Finally, only the USA elected to extend products regulation to advanced ARTs, with the FDA enforcing drug and biologics rules on MRTs and signaling those norms would also apply to HHGE.More generally, coverage in several cases struggled to cope with medical tourism, as national or subnational regimes could not easily apply transnationally.Pertaining to the theory of inherited regulation, several cases demonstrate that extending existing regulatory regimes to an emerging technology is not merely a passive process or an inevitable result. Rather, an emerging technology will only inherit a prior regime through actors in the regulatory community actively (re)interpreting available regulatory norms to apply in unforeseen settings, constituting an inherently political and contestable process.The case studies saw four different types of inherited regulatory regimes applied to achieve coverage of advanced ARTs. However, the degree of coverage achieved and the appropriateness of an existing regime are two separate and equally important questions. Determining the fitness of an inherited regime requires normative inquiry into how appropriate its assumptions, values, and goals are for managing the benefits and risks\u2014including short- and long-term\u2014associated with an emerging technology.Five jurisdictions extended ART regulation, which generally seeks to promote the safety of patients and children, effectiveness of treatments, and certain ethical principles or social values such as reproductive autonomy.Human research subjects and ART regulatory regimes both seek to promote safe and ethical uses of ARTs, yet their different assumptions reduce the fitness of the former. Broadly, human subjects regimes aim to ensure that research is conducted consistent with applicable bioethical principles and that the rights of participants or communities are protected.Only the USA defaulted to a pre-existing system of medical products regulation for advanced ARTs, although it is notable that the USA lacks a national system of ART oversight. Medical products regulation shares both safety and effectiveness goals with ART regulation but makes different assumptions with impacts on fitness. Though both use technical rulemaking and enforcement, products regimes typically assume that products will indeed enter the market once safety and performance thresholds have been met.China and Mexico both had criminal law applicable to advanced ARTs, though we argue that criminal law offers poor fitness for the oversight of these technologies. Criminal law generally examines behavior through a moral lens, with common rationales such as deterrence of or retribution for acts perceived as immoral.More broadly for inquiry on inherited regulation, these cases also demonstrate that jurisdictions may at times have multiple pre-existing regimes from which to select when managing an emerging technology, and each regime type may have different fitness considerations. Mexico, Ukraine, and China each had two types of regulatory regimes applicable to advanced ARTs, and China took enforcement measures through both its ART regulatory framework and its criminal legal system.Further, determining whether and how to activate potentially overlapping inherited regimes will inevitably introduce coordination problems into the use of inherited regulation, both within and across different levels of government.The effectiveness and legitimacy of inherited regulatory regimes depend not only on their coverage and fitness for the new technology (or product) but also on how policymakers implement the inherited system and how regulated actors respond. Factors, such as whether and how regulators communicate substantive expectations to regulatees and monitor conduct, procedural actions taken in enforcement, and political environment, may all modulate policy outcomes when using an inherited regime.First, one trend observed in the cases was that early, honest communication between regulators and regulated entities on how inherited regimes would apply to advanced ARTs led to more positive outcomes. For example, regulatees in the Greece and Russia cases both took affirmative measures to contact regulators before proceeding with advanced ARTs, signaling their knowledge that existing requirements could apply and some level of respect for the relevant regulatory authorities. Communicating with officials in advance afforded regulators an opportunity to consider whether and how to extend existing rules to cover the advanced ART, avoiding snap decisions and regulatory outcomes perceived as unpredictable. The Institute of Life\u2019s MRT activities appear to have remained within the scope of what Greek regulators approved, illustrating an effective inherited regulatory intervention which still allowed an advanced ART to proceed. Dr Rebrikov in Russia expressed disappointment at the Ministry of Health\u2019s decision to block HHGE but did appear to accept the outcome as being legitimate.By contrast, the regulatees in China appeared to be unaware that inherited regimes could cover their use of HHGE. The team\u2019s proud announcement of their achievement with the advanced ART, to the apparent surprise of health officials, suggests the team failed to communicate with the NHC or other officials about their plans.However, willful noncompliance and insufficient monitoring were still possible after regulators communicated their substantive expectations to the public at large. The US FDA publicly stated in early 2016 it would not approve MRTs after US lawmakers had removed their budget to do so, setting a clear expectation for ART researchers and clinicians within the jurisdiction.Second, decisions around how to implement inherited regulatory interventions for advanced ARTs occurred against the backdrop of domestic and global political tides. China received intense criticism from the international scientific and political communities after HHGE was performed within its jurisdiction, and Hurlbut argues that China applied harsh sanctions from criminal law to appease external actors and restore its reputation as much as to achieve internal policy goals.Third, two of the cases involved enforcement for violations of inherited regulatory norms, each adopting a different enforcement style. Enforcement approaches can vary along several dimensions, including along a spectrum from persuasion and capacity-building to coercive and deterrent sanctions, with more responsive styles beginning with softer approaches and escalating if compliance is not achieved.These examples illustrate how different styles of enforcement are possible after regulators achieve coverage with an inherited regime, providing another potential source of flexibility in the use of existing regimes for emerging technologies. In terms of effectiveness, both enforcement styles succeeded in halting and deterring undesired advanced ART activity in their respective jurisdictions.These conclusions from observations of inherited regulation in action suggest that scholars and analysts should broaden their scope of inquiry to build more complete assessments of how an inherited regime performs and the political dynamics involved. While attention to inherited regulation in the past has highlighted the role of pre-existing standards and their fitness,This article has demonstrated how two rapidly emerging advanced ARTs are not truly \u2018unregulated\u2019 and reviewed case studies of several jurisdictions that have already applied existing regulatory tools to MRT and HHGE techniques. Greece, Russia, and the USA have experienced reasonable success in using inherited regulation to effectively achieve policy goals for advanced ARTs while retaining perceived legitimacy. China effectively achieved its goals, although its implementation may have suffered from diminished perceived predictability, while Ukraine appears to have struggled to attain robust, transparent regulation despite coverage with an existing regime. Comparing and evaluating these responses illustrate both the potential utility and challenges of leveraging existing regulatory regimes and offer lessons to other jurisdictions for managing advanced ARTs.With advanced ARTs beginning to rouse global policy debates, stakeholders and policymakers should be cognizant of inherited regulation as a policy tool to achieve normative goals for managing advanced ARTs. This could be especially true in jurisdictions with limited political appetite to craft new regulatory systems. While the United Kingdom\u2019s moves to deploy a novel regulatory framework is commendable, only a handful of jurisdictions such as Australia and Singapore appear likely to follow this approach in the short term.Adopting an inherited regulatory approach to advanced ARTs can also provide opportunities for international cooperation or transnational coordination in managing this emerging space. The Russia case with HHGE illustrates how global institutions such as the WHO can influence how states extend their existing oversight regimes and could play a capacity-building or orchestrating role in the future, if desired by states. In 2019, the WHO signaled its interest in coordinating, or supporting the coordination of, national-level regulatory responses to HHGE and could perform a similar role for other advanced ARTs.This article has also argued that some types of existing regulatory regimes may facilitate better outcomes, while others may require greater adjustments to meet the governance challenges presented by advanced ARTs. All four types of inherited regimes were able to achieve coverage of advanced ARTs, although the depth of regulation enabled by each regime type and the fitness of their goals and assumptions for advanced ARTs varied widely. Perhaps, unsurprisingly, those jurisdictions with pre-existing and robust ART regulatory regimes offered the highest fitness once coverage was achieved, as these regimes\u2019 normative goals and regulatory tools provided high capacity to identify and manage the benefits, risks, and uncertainties of emerging reproductive technologies. Notably, some policy recommendations for emerging reproductive technologies such as longitudinal studies of health outcomes,This study holds several implications for the theory of inherited regulation as well,As advanced ARTs continue to develop and find clinical applications, or even nonmedical uses, the need for robust governance of these innovations will only grow. Inherited regulation offers one instrument and broader strategy for policymakers to consider for establishing meaningful oversight of these emerging technologies, drawing on lessons from other jurisdictions as the implementation continues and new information on advanced ARTs arise. Weighing the strengths and weaknesses of applying inherited regulation, and its political acceptability, against other available policy tools should aid decision-makers at all levels of government in selecting prudent paths forward.The authors gratefully acknowledge the Carnegie Corporation of New York, which generously funded our research in this article through the Andrew Carnegie Fellows Program. The authors would like to thank Professors Eleni Kosta and Sida Shen (Zhengzhou University Law School) for valuable comments and suggestions on earlier drafts of this article.The authors have no conflict of interest to report.Carnegie Corporation of New York"} +{"text": "For decades, life course and stress process scholars have documented that negative, stressful experiences in childhood have consequences for health across the life course. One aspect of the childhood adversity that deserves more research attention is childhood disability. Children with disabilities experience higher levels of psychological distress compared to their peers and having a disability can negatively impact traditional markers of the transition to adulthood . At present, there is limited evidence regarding the impact of childhood disability on mental health over multiple years of adulthood. This study applies random effects models to nationally representative data from five waves (2008-2016) of the Health and Retirement Study , to examine how experiencing disability before the age of 16 shapes depressive symptoms over multiple years of adulthood. Given known gender differences in mental health, the models are stratified by gender to examine how the association between childhood disability and adult mental health varies by gender. Preliminary results suggest that experiencing a childhood disability is associated with different patterns of depressive symptoms in adulthood. Men who experienced childhood disability report more depressive symptoms in adulthood, net of sociodemographic, adult health, and childhood disadvantage covariates. Women who experienced childhood disability report more depressive symptoms in adulthood, net of all covariates except for childhood depression. Next steps are to conduct age-based growth curve models using Stata\u2019s mixed function to estimate whether childhood disability influences baseline and growth of depressive symptoms in adulthood."} +{"text": "This qualitative study examines online consumer reviews for experiences of racism in US hospitals among patients. The inability to measure interpersonal racism at the local level has limited the ability to improve racist patient experiences within health care. Prior work has demonstrated consumer reviews\u2019 unique ability to highlight novel concepts not captured in traditional performance metrics and to impact consumer hospital selection.3 Consumer reviews offer an opportunity to understand subjective perceptions of racism in health care in an unstructured and anonymous format. To demonstrate the potential role of consumer reviews in studying interpersonal racism in health care, we explored reviews of hospitals to better understand how consumers perceive and report racism.Racial disparities, the result of structural and interpersonal racism, represent a complex phenomenon present in all domains of health care.SRQR) reporting guideline.This qualitative study was deemed exempt by the University of Pennsylvania institutional review board and informed consent was not required because of the public and retrospective nature of the consumer reviews. This study followed the Strengthening the Standards for Reporting Qualitative Research it is feasible to identify acts of interpersonal racism in health care using qualitative methods on consumer reviews, (2) racism in health care can involve critical organization personnel outside of the clinical staff, and (3) racism can be bidirectional, affecting both patients and hospital employees. These detailed reviews likely represent the tip of the iceberg, and future efforts to supplement this data with existing hospital-based reporting measures, such as human resources reports, may help to further explore concepts such as patient-to-employee racism. Additionally, experiences of interpersonal racism are just one aspect of racism in health care, and future work is needed to couple the subjective measures of interpersonal racism with objective measures of structural racism to establish a hospital quality composite metric of racism. This study\u2019s findings are limited by the low frequency of reviews citing racism, limited information on reviewer race, and additional context about reported experiences."} +{"text": "Dear Editor,We thank Dr. Lauro and Prof. Sapienza for their thoughtful correspondence to our publication on endovascular revascularization in patients with acute mesenteric ischemia, where we report our experience on 40 consecutive patients who underwent stent implantation after acute mesenteric ischemia secondary to thrombosis of the proximal celiac or superior mesenteric artery . We founHowever, as highlighted by the guidelines of the World Society of Emergency Surgery and in tIn order to account for confounding variables and obtain clear actionable insight, a strict patient selection for studies evaluating the outcome of different treatment options for mesenteric ischemia is paramount to get clear evidence in future. In this context, establishing national or international patient registers may accomplish larger study populations and better data to improve the overall level of evidence regarding the treatment of patients with different causes of mesenteric ischemia.We fully agree with the correspondent in that a seamless, fast inter-disciplinary treatment of patients with suspected or proven mesenteric ischemia is of key importance to improve outcome of these patients. Such inter-disciplinary decision making and treatment is certainly best achieved in dedicated intestinal stroke centers, but also in larger tertiary care hospitals where interventional radiologists offer the same 24/7 emergency treatment service as surgeons do."} +{"text": "Older adults are more likely to be prescribed opioids and to suffer from opioid-related harms. Despite growing concerns about opioid misuse in older adults, providers and health care systems often struggle with approaches that would effectively manage opioid use and reduce opioid misuse in older adults. To address this issue, the Agency for Healthcare Research and Quality funded a four-year project to work with primary care practices in developing and testing innovative strategies for opioid management in older adults. To develop a change package that will inform learning collaboratives where primary care practices will be encouraged to test new or modified strategies in managing opioids in older adults, Abt, the contractor, first completed an environmental scan to identify existing resources/tools. Identified resources/tools were vetted by an expert panel and appropriate items were used to develop a change package consisting of nine high-leverage change (HLC) strategies . In the change package, multiple key activities that accompany each HLC strategy are presented as examples of strategies that could be implemented to bring about the selected HLC. Primary care practices participating in learning collaboratives will use the change package to guide the development and testing of strategies to manage opioids in their older adults, which will inform the development and refining of a compendium of strategies to best reduce harms of opioid use in older adults."} +{"text": "Patients are increasingly using complementary therapies, often for chronic conditions. Asthma is the most common chronic condition in the UK. Previous research indicates that some asthma patients experience gaps in their NHS care. However, little attention has been given to how and why patients and parents of children with asthma use complementary therapies and the implications for NHS care.Qualitative study, comprising 50 semi-structured interviews with a purposeful sample of 22 adults and 28 children with asthma (plus a parent), recruited from a range of NHS and non-NHS settings in Bristol, England. Data analysis was thematic, drawing on the principles of constant comparison.A range of complementary therapies were being used for asthma, most commonly Buteyko breathing and homeopathy. Most use took place outside of the NHS, comprising either self-treatment or consultation with private complementary therapists. Complementary therapies were usually used alongside not instead of conventional asthma treatment. A spectrum of complementary therapy users emerged, including \"committed\", \"pragmatic\" and \"last resort\" users. Motivating factors for complementary therapy use included concerns about conventional NHS care (\"push factors\") and attractive aspects of complementary therapies (\"pull factors\"). While participants were often uncertain whether therapies had directly helped their asthma, breathing techniques such as the Buteyko Method were most notably reported to enhance symptom control and enable reduction in medication. Across the range of therapies, the process of seeking and using complementary therapies seemed to help patients in two broad ways: it empowered them to take greater personal control over their condition rather than feel dependant on medication, and enabled exploration of a broader range of possible causes of their asthma than commonly discussed within NHS settings.Complementary therapy use reflects patients' and parents' underlying desire for greater self-care and need of opportunities to address some of their concerns regarding NHS asthma care. Self-management of chronic conditions is increasingly promoted within the NHS but with little attention to complementary therapy use as one strategy being used by patients and parents. With their desire for self-help, complementary therapy users are in many ways adopting the healthcare personas that current policies aim to encourage. Asthma is the most common chronic disease in the UK, constituting a considerable burden to patients, their families and the National Health Service (NHS) . Many asUse of complementary therapies is increasing in the UK and in other western countries, often for chronic conditions ,9. Most UK estimates of the prevalence of complementary therapy use for asthma vary widely, from 6% to 70%, with variations probably due to methodological problems in the studies ,15. For The clinical evidence is inconclusive regarding the effectiveness of complementary therapies for asthma, with systematic reviews noting the paucity of high quality randomised controlled trials -21. GiveQualitative studies of complementary therapy use indicate that patients use such therapies because of dissatisfaction with conventional medicine, perceived harmful effects of conventional treatments, desire for a more holistic approach and greater philosophical congruence with complementary therapies ,23. LimiIn addition to mapping the range of views of complementary therapies among patients and parents of children with asthma, both users and non-users of complementary therapies, the main aims of this study were threefold:\u2022 To investigate why and how patients and parents of children with asthma use complementary therapies as part of their coping strategies.\u2022 To explore their experiences of the impact of complementary therapies on their condition.\u2022 To consider the implications of the findings for the overall delivery of high quality asthma care within the NHS.Qualitative methods were used and the study took place in Bristol (England) during 2004. The Central and South Bristol Research Ethics Committee approved the study.The overall sampling strategy was purposeful aiming tSampling comprised various stages. First we recruited two contrasting general practices, one in an affluent suburb with potential local access to private complementary therapy clinics (practice A), and one in a deprived inner city area with access to a subsidised complementary therapy service via the practice (practice B). Along with a patient information sheet and covering letters signed by the GP and the research team, a brief screening questionnaire on complementary therapy use was sent to a random sample of 100 patients from each practice. Patients included were aged seven plus, with an asthma diagnosis, and a prescription for asthma medication in the past 12 months. The initial sample size was based on an estimate of the proportion likely to respond to a community survey, to give a reasonable pool of patients to purposefully sample a heterogenous sample for interviews. In practice A, 32 patients returned questionnaires (32%), with 28 agreeing to be contacted for an interview. In practice B, 22 returned questionnaires (22%), with 17 agreeing to be contacted. From these, a sub-sample of patients with a range of ages and gender, both non-users and users of various complementary therapies were selected.Subsequently, a purposeful sample of asthma patients and parents from a respiratory clinic at a children's hospital, a NHS homeopathic hospital, and private complementary therapists were approached via a doctor, nurse or therapist. They were given the same covering letters and information sheet and asked to indicate whether they were willing to be contacted by the research team. Those known to be complementary therapy users were selected as this stage, as data saturation had been reached with non-users from the general practices.Semi-structured interviews were conducted by AS in participants' homes. A flexible topic guide was used, allowing participants to introduce new issues, and incorporating new lines of questioning in response to emerging themes as data collection and early analysis progressed . Broad tPreliminary analysis commenced alongside early interviews and progressed iteratively. A thematic approach was used, guided by the principles of constant comparison . \"Open\" Fifty interviews were conducted. The numbers of patients from each setting and their characteristics (socio-demographic and complementary therapy use) are shown in table A summary of reasons for non-use of complementary therapies emerging from interviews with non-users is provided in table Complementary therapies were used in a range of ways by patients and parents, varying in the degree to which they played a role in patients' self-management of their health. Broadly speaking, complementary therapy users fell into three categories. First, complementary therapies were the first port-of-call, and the NHS the last resort, for a minority of participants who held \"alternative\" philosophical beliefs about health that often differed from those underpinning conventional medicine (\"committed users\"). While these patients and parents ideally wanted alternatives to conventional asthma medication, and had a preference for non-pharmaceutical treatments, none had stopped taking their prescribed medication, recognising the potential dangers of doing so. Other participants had a more pragmatic approach towards complementary therapies, seeking various treatments and self-help strategies to improve asthma symptoms and related health issues alongside their prescribed medication, without a strong philosophical preference for complementary therapies (\"pragmatic users\"). Finally, a small group of participants were using complementary therapies somewhat in desperation, after trying conventional treatments and finding them to be ineffective at managing their or their child's condition. Primarily, these were patients for whom medication had escalated, often with limited benefit for controlling symptoms (\"last resort users\"). Table This paper will focus on findings from the thirty-one participants using complementary therapies for asthma (twelve adults and nineteen child-parent pairs), as these provide the richest data to address the main study objectives. The themes presented are supported by data reflecting the full range of expressed views tables , 6, 7, 8The first broad theme concerns the ways in which complementary therapies are accessed and used, which fall into two categories: routes into complementary therapies and the nature of complementary therapy use.The complementary therapies used for asthma are summarised in table The second broad theme concerns reasons for complementary therapy use, which fall into two categories: \"push factors\" from conventional medicine and \"pull factors\" from complementary therapies.\"Push factors\" from conventional medicine can be viewed as problematic aspects of NHS care that cause asthma patients or parents to look elsewhere for help or self-taught. The main valued benefit was enhanced control over breathing without recourse to medication, along with reduced medication use (both preventative and \"relievers\"). While complementary therapies were not always experienced as effective for asthma symptoms, participants usually reported broader personal benefits from trying other ways of managing their condition. These fall into two categories: the benefits of self-help and taking control, and the exploration of a broader range of causes of asthma.A key beneficial opportunity that complementary therapy use provided was to empower patients to help themselves . They wanted more advice on preventative self-help strategies to enhance their general health and reduce their \"susceptibility\" to asthma , along with less routine reliance on drug-based asthma management within their NHS care.In parallel with using non-drug strategies, participants often self-managed asthma medication, aiming to reduce doses or frequency of use when possible. Parents often did this because they wondered if maintaining the prescribed dose masked underlying improvements in their child's condition. However, a tension between reducing medication and awareness of the potentially life-threatening nature of asthma was expressed and was experienced as a difficult pathway to navigate.The second benefit of complementary therapy use was the provision of opportunities to explore a wider range of causes of asthma than usually discussed within their NHS care . However, complementary therapy consultations were valued not only for giving longer time, but for the quality of that time, and for the acknowledgement that health problems such as asthma do not always have clear-cut, \"scientific\" answers.Wider philosophical concerns about a \"sticking plaster\" approach within conventional medicine were also sometimes expressed. NHS care was perceived to be generally good at addressing patients' presenting symptoms, but poor at addressing deeper underlying causes of illness . Through more holistic treatments, some patients and parents were exploring broader questions about their or their children's health that conventional medicine seemed unable to answer.Complementary therapy use for chronic conditions is increasing in the UK. This study offers a qualitative account of why and how patients and parents of children with asthma are using complementary therapies and the perceived impact of complementary therapies on their condition. It highlights how that, with the exception of small pockets of NHS provision, patients and parents of children with asthma are primarily using complementary therapies outside of the NHS, identifying and accessing services via informal networks of personal contacts. It suggests that patients are using complementary therapies alongside not instead of conventional asthma treatment, with a spectrum of types of complementary therapy users, including \"committed\", \"pragmatic\" and \"last resort\" users.Previous studies have identified problems that patients perceive with their asthma care, for example gaps in information about medication ,4. Our fPatients' and parents' desire for a more \"holistic\" approach to asthma supports the findings of previous research that asthma patients using a complementary therapy wish to be treated as \"a whole person\" and addsWhat are the implications of the findings for the overall quality of asthma care? Health policy makers and providers increasingly encourage patients with chronic conditions to take responsibility for their health and reduce their dependence on healthcare systems ,34, illuCurrent quality indicators for asthma management in primary care focus on various quantitative measures at a practice level, for example percentages of asthma patients who have had a review in the past fifteen months, or who smoke and who have received smoking cessation advicer . While tHealth professionals often express reservations about complementary therapies, including concerns about lack of evidence of effectiveness, safety and the quality of complementary therapists' practice ,40. WithThe \"push factors\" for complementary therapy use identified in this study indicate several areas of NHS asthma care that could be improved. In particular, patients' and parents' concerns about long-term medication use reveal the need for greater discussion of the risks and benefits of conventional asthma treatment within NHS consultations. Furthermore, whatever an individual clinician's attitudes to complementary therapies might be, this study suggests that more open communication with patients and parents about complementary therapy use may be valuable. Initiating a conversation about complementary therapies could allow patients' and parents' concerns about conventional treatment, and the reasons why they are turning to complementary therapies, to be discussed, in order to improve their NHS care. This might enable concerns about both conventional and complementary treatments to be aired \u2013 both patients' concerns regarding conventional treatment and professionals' concerns about complementary therapies .A challenge for NHS practitioners is how to facilitate greater communication about complementary therapy use within asthma consultations, when patients may not disclose such self-care because of fears about health professionals' responses . One simHealth professionals may feel uncomfortable initiating discussions about complementary therapies if they feel they lack relevant knowledge to advise patients, or if they perceive them to be ineffective or unsafe. However, patients exercise their autonomy and make decisions about healthcare often independent of the evidence-based medicine principles that so govern NHS practice . Thus, aResources are beginning to be developed to aid clinicians in their search for information on the effectiveness of complementary therapies. An example is the CAMEOL database funded by the Department of Health, which coIn qualitative terms the findings of this study are likely to be transferable to asthma patients and parents using complementary therapies from similar backgrounds and settings in other parts of the UK. The majority of complementary therapy users were female, mirroring findings of previous research. Patients from ethnic minorities were under-represented. Other authors have begun to explore attitudes to complementary therapies among South Asians with asthma and mothers of children with asthma from various ethnic backgrounds ,25. ExamComplementary therapy use among patients with chronic conditions is increasing. Patients and parents of children with asthma are turning to complementary therapies because of various concerns about conventional NHS asthma care and because of attractive aspects of complementary therapies. Breathing techniques such as the Buteyko Method are of particular interest to patients and parents, and are experienced by some as beneficial for enhancing breathing control and enabling reduction in asthma medication. The process of seeking and using complementary therapies appears to help patients in two broad ways \u2013 empowering them to take greater personal control over their condition and enabling exploration of a broader range of causes of asthma than are discussed within their NHS care.While health professionals often express reservations about the clinical value of complementary therapies, complementary therapy use seems to be indicative of an underlying desire among patients and parents for greater self-care and need for opportunities to address their concerns regarding NHS asthma care. Self-management of chronic conditions is increasingly promoted within the NHS but to date there has been little recognition of the role that complementary therapies may play in patients' own self-management strategies. With their desire for greater self-help, complementary therapy users are in many ways adopting the healthcare personas that current policies aim to encourage. Openness to self-management and a desire to take responsibility for one's health are qualities that could fruitfully be nurtured across other patient groups beyond complementary therapy users, to the advantage of both NHS professionals and patients.EAT is a consultant homeopathic physician at one of the recruitment settings used for this study. The authors have no other competing interests.All authors contributed to the design, analysis and writing-up of this study. AS was responsible for day-to-day management and conduct of the study, conducted the interviews, led the analysis and produced the first draft of the manuscript. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:"} +{"text": "Several studies carried out during the past two decades have investigated the effect of dietary and surgical manipulation on pancreatic growth and carcinogenesis. Diets high in trypsin inhibitor stimulate pancreatic growth and increase the formation of preneoplastic lesions and carcinomas in the rat pancreas. Cholecystokinin (CCK) is the key intermediary in this response, since both natural and synthetic trypsin inhibitors increase circulating levels of the hormone and CCK antagonists largely prevent these changes. Fatty acids enhance pancreatic carcinogenesis in both rats and hamsters, whereas protein appears to have a protective role in the rat, but to increase tumour yields in the hamster. Several surgical operations affect the pancreas. Pancreatobiliary diversion and partial gastrectomy stimulate pancreatic growth and enhance carcinogenesis, probably by means of increased CCK release. Complete duodenogastric reflux has similar effects on the pancreas but the gut peptide involved is gastrin. Although massive small bowel resection increases pancreatic growth, the marked reduction in caloric absorption probably explains its failure to enhance carcinogenesis. CCK and enteroglucagon might work in concert to modulate the tropic response of the pancreas to small bowel resection. In the pancreas, as in the large intestine, hyperplasia appears to precede and predispose to neoplasia."} +{"text": "Papua New Guinea is the only endemic country in the Western Pacific Region that has not yet introduced a countrywide programme to eliminate lymphatic filariasis. However, on Misima Island in Milne Bay Province, government and private sectors have collaborated to implement a pilot elimination programme. Although interim evaluation indicated that the programme has been parasitologically successful, an appreciation that sustainable health gains depend on understanding and accommodating local beliefs prompted this qualitative study.We investigated Misima community members knowledge and attitudes about lymphatic filariasis and the elimination programme. A combination of focus groups and key informant interviews were used to explore participants perceptions of health; knowledge of the aetiology and symptoms of filariasis, elephantiasis and hydrocele; attitudes towards the disease and mass drug distribution; and the social structure and decision-making protocols within the villages.pom\") a major health problem but were generally positive about mass drug administration campaigns. A variety of conditions were frequently and incorrectly attributed to filariasis. Participants expressed the belief that individuals infected with filariasis always had visible manifestations of disease.Focus group discussions proved inferior to key informant interviews for gathering rich data. Study participants did not consider lymphatic filariasis (\"A common misconception was that taking drugs during campaigns provided long-term immunity against disease. The role of mosquito vectors in transmission was not generally appreciated and certain clinical presentations, particularly hydrocele, were associated with supernatural forces. Multiple adverse events were associated with mass drug administration campaigns and most study participants mentioned community members who did not participate in campaigns.Important issues requiring educational intervention and elimination activity modification in the Misima region were identified during this study. Research outcomes should assist Papua New Guinea in developing and implementing a national elimination strategy and inform discussions regarding the appropriateness of current elimination strategies. DrowsinPeople felt dizzy and weak. They felt like sleeping and rested after the distribution\".\"The majority of villagers indicated that affected individuals managed their own side effects by resting and sleeping. A number of \"adverse events\" reported actually represent benefits particularly passage of worms and altered but improved health state.A variety of benefits were attributed to the Filariasis Elimination Programme. Eight of the sixteen focus groups indicated that they could never get sick with filariasis because the tablets had made them immune. One individual stated:\"The benefit of the drug distribution is that people are now living in good health and they believe that they will never get sick with filariasis because they have taken the pills to prevent.\"Half the focus groups associated continued good health with participation in the elimination programme. A participant commented:\"We feel that this programme is good because since this started we have had no attack of pom and we have been kept healthy\".Three groups mentioned that the tablets cured other sicknesses:\"People are living in good health and this pill has cured some illness apart from pom\".One key informant questioned the ongoing value of the programme \u2013 given that filariasis was no longer perceived as a concern. Nevertheless he indicated his continued willingness to take the pills as a preventive measure against the disease returning:\"I myself cannot say the distribution of the filariasis tablets has done any good to us because I have never seen pom in my village. Maybe if we did not take the tablets somebody might get the sick but since we have taken the tablets this sickness will not get us. That is the good thing about the tablets.\"\"pom\" to describe LF strongly indicates that local understandings of the disease are confined to outward gross manifestations of elephantiasis. In the course of this study we were left with the belief that locals had a poor understanding of micro-filarial infection and indeed the role of the mosquito as the vector.Misima islanders participating in this study did not spontaneously identify lymphatic filariasis as an important current health concern. This may be due to the low prevalence of elephantiasis in the region or may reflect community definitions of disease . The empThe greater importance placed on access to adequate health facilities and life-threatening infectious diseases has also previously been identified in LF endemic areas . In otheAs respondents only associated filariasis with the chronic signs of LF, including hydrocoele and elephantiasis, it is not surprising that the declining prevalence of these disease manifestations was associated with perceived low personal risk. Although MDA campaigns were generally viewed positively, there were early warning signs of wanting commitment with drug-associated adverse events identified as a constraining factor. A similar trend has been detected in other countries including Thailand, India and Haiti where fever, dizziness and nausea have been associated with MDA campaigns ,18,19.The limited appreciation of the role of vectors found is not unusual in areas where elimination has relied on MDA campaigns ,14,21. CWhile traditional hierarchical community structures persist with power for decision making residing with a limited number of traditional leaders, drug distribution programmes may remain successful despite different understandings of LF in the affected communities. To date, the Misima campaign has relied very heavily on the assumption that by working through local traditional decision making structures, compliance will remain high. However, to achieve sustainable improvements in health, efforts to bridge the gap between local health knowledge systems and western biomedical models will become increasingly important. The importance ascribed to supernatural influences and limited understanding of the biomedical model of disease transmission appears to influence participation in disease control efforts and treatments both in PNG and in other contexts ,17. WhilAs has been discussed earlier, the quality and depth of information gathered using the question outlines developed as part of a standardised multi-centre protocol. Important limitations included language barriers, limited ability of the instrument to provide in-depth understandings of cultural norms and practices, and short time prescribed. Focus group discussions were constrained by the need for an interpreter. The cumbersome process of translation and back translation, focus group participants apparent concern about providing incorrect responses despite reassurances that all responses were valid and an observed preference in all focus groups to establish consensus before providing a group response, influenced data-collection. These limitations did not permit a thorough exploration of local understandings of LF, its origins or relevant community behaviour. A thorough understanding of all of these elements is essential for the development of appropriate educational materials which, in addition to achieving longer term sustainability, foster a balance between western and local health knowledge systems.Many of the questions included in the standardised multi-centre protocol were developed for populations where chronic manifestations of LF are still common, which is not the case on Misima Island. The large number of prompts relating specifically to elephantiasis and hydrocoele leave limited time to probe more subtle presentations and respondents often indicated that these questions were irrelevant. While interview questions presupposed a shared definition of LF, respondents had difficulty relating to the bio-medical interpretation of the disease that underpinned the question outline.Furthermore, because of the low prevalence of the disease in the region, individuals struggled to remember the details of their past experiences, if any, with the disease. Some modification of the assessment instrument in accordance with local disease epidemiology and understandings is essential. Despite these constraints, our experience suggests that richer data resulted from in-depth interviews with key informants than focus group discussions.This investigation identified knowledge gaps requiring educational intervention, perceptions and community behaviours that may require modifications in LF elimination activity in the Misima region. These findings will be of value in Papua New Guinea as the national LF elimination strategy is developed and implemented. Although compliance and community satisfaction with the LF elimination programme in Misima appeared high, there was a need for an effective education programme focusing on LF transmission and prevention. The central necessity of community involvement in developing educational strategies that reflect local understandings and interpretations of the disease should not be overlooked.A particular concern was that Misima islanders associated LF infection only with the chronic visible manifestation of filariasis and other unrelated diseases. Another potentially detrimental belief is that tablet consumption provides lifelong immunity against contracting infection and this may contribute to the neglect of personal vector control measures. Sustainable LF treatment and prevention interventions require a broad understanding of local disease perceptions, including mode of transmission, consequences of infection and means of prevention.The author(s) declare that they have no competing interests.SW, PL, WM, DD conceived the study and developed the study design. Fieldwork and data collection was conducted by JC, BS. Principal dataanalysis was performed by SW and JC. All authors contributed to interpretation of results and manuscript preparation."} +{"text": "Although airborne influenza viruses were not measured, 1997 hospital admission records at Alta Floresta, Brazil, showed that influenza incidence was highest during the burning season .Influenza viruses and various non-pigmented bacteria are killed by UV-B wavelengths in sunlight . BiomassHuman cases of avian influenza in Thailand and Vietnam peaked during the winter burning seasons of 2003 and 2004 . AssuminHuman cases of avian influenza in Thailand and Vietnam since December 2003 have peaked during both the rainy season and the burning season. Thus, periods of prolonged cloudiness and severe smoke pollution could play a role in initiating avian and other influenza outbreaks by attenuating the solar UV-B that might otherwise suppress influenza viruses in outdoor air exposed to sunlight. The transmission of avian influenza to people during these periods is enhanced by the fact that poultry raised for human consumption are often kept within several meters of where people live ."} +{"text": "The internet combined with browser-based graphics, animation and streaming media offer a unique opportunity to reach rural students in both synchronous and asynchronous modes, while simultaneously augmenting the resources to students attending class in person.This presentation will showcase a semester long course in the undergraduate Nursing curriculum at East Carolina University School of Nursing. The three-hour weekly course utilized streaming media, graphics and animation to educate nursing students. Results:The case study will highlight the production management that went into the development and the problems encountered and solved. Evaluations of both residential and remote students were compared showing little difference in retention.Animations and project management will be broken down into their development components and processes will be explained."} +{"text": "For more than 30 years transthoracic external cardioversion has been an established method for the restoration of sinus rhythm in patients with persistent atrial fibrillation. It was first described by Lown in 1963 ,4, thereThe method of internal cardioversion for restoration of sinus rhythm using transvenous electrodes has been reported in several animal ,7 and huThe initial human data has been collected using two separate catheter for internal cardioversion. Though this approach demonstrated some advantages, there are also clear disadvantages, such as lack of ventricular backup stimulation in cases of post shock bradycardia, prolonged fluoroscopy time and the need for venous access via primarily the lower limb. These disadvantages increase the risk of bleeding complications, especially in patients with anticoagulation.Recently published data have demonstrated the benefit of a single lead catheter with two shock arrays on a balloon guided pulmonary artery catheter, when compared to the previous two catheter technique . OptionaFor cardioversion with this new device an electrode configuration in the right atrium and left pulmonary artery is suggested. A randomized trial could demonstrate that this configuration provides a homogeneous electrical field for effective cardioversion, and slightly higher energy requirements compared to a lead position in the right atrium and distal coronary sinus , as descVentricular backup pacing is an important safety tool, not only for a subgroup of patients with post shock bradycardia, but also for bradycardia after the administration of antiarrhythmic drugs or beta-blockers. The possibility of post shock atrial pacing also offers new therapeutic options in preventing the early recurrence of atrial fibrillation. Immediately after cardioversion 60% of all patients develop premature atrial contractions . Recentl For internal cardioversion of atrial fibrillation an electrode position with the distal tip in the left pulmonary artery is currently used preferably . Due to Though the design of the cardioversion catheter is similar to a regular Swan-Ganz balloon catheter, the cardioversion catheter offers the additional facilities of cardioversion, cardiac pacing and, in the newest generation of these electrode systems even haemodynamic measurements by means of thermodilution. These qualities render the cardioversion catheter suited for application in the electrophysiological laboratory as well as in emergency and intensive care settings. More than 30 % of patients undergoing cardiovascular surgery develop persistent atrial fibrillation . In thes"} +{"text": "Epidemiological and experimental studies suggest that androgens influence colonic carcinogenesis. We investigated the effects of hormonal manipulations on colonic tumour development, tumour and mucosal histopathology, and epithelial proliferation in macroscopically normal colonic mucosa in male rats, after induction of chemical colon carcinogenesis by subcutaneous injections of azoxymethane (AOM). Chemical castration with cyproterone acetate, but not surgical castration, resulted in increased colonic tumorigenesis, which was accompanied by decreased crypt length, decreased number of cells per crypt, and increased crypt epithelial mitotic index in the right colon. Chemically castrated rats also had crypt hyperplasia and increased numbers of dysplastic foci in the left colon which were not seen with surgical castration. By contrast, rats given testosterone after surgical castration showed decreased colonic tumorigenesis with an increased proportion of tumours in the left colon and lower percentage of tumours with invasion. The grossly normal mucosa of the testosterone-substituted castrated rats showed decreased crypt length in the right colon similar to the other groups of castrated rats, but no significant increase in mitotic index. Our results suggest that the anti-androgenic progestin cyproterone is a potent enhancer of colonic tumorigenesis and epithelial proliferative abnormalities after AOM administration. Exogenous testosterone after castration alters tumour distribution and characteristics and suppresses epithelial proliferative abnormalities. Finally, androgen effects on the colonic mucosa are more prominent in the right than in the left colon, suggesting different influences of hormones on the epithelium of these anatomical sites."} +{"text": "We measured the clonogenic growth of 110 breast cancer samples obtained from 107 patients with advanced disease. We determined clonogenicity under conventional conditions and under conditions supplemented with growth factors and hormones that target breast tissue. After a median follow-up period of 6 years we analyzed our data to determine if and to what degree clonogenic growth of metastatic breast tumours was related to the survival of patients. We found that tumour clonogenicity and patient survival correlated weakly, particularly if compared to the strong correlations of patient survival with either performance status or tumour bulk. Furthermore, an association between tumour clonogenicity and patient survival was visible only for clonogenicity that was determined under hormone-supplemented conditions, and only for tumour lesions that formed 50 or more colonies per 500,000 cells cultured. Thus, we conclude that clonogenic growth of breast tumour samples incompletely reflects the tumour features that determine the course of advanced disease."} +{"text": "Understanding the role\u00a0(particularly the mechanisms of action) that physical activity plays in the development of hypertension among blacks is important for risk reduction efforts and public policy actions, especially because blacks bear the highest burden of hypertension, and cross-sectional studies suggest that physical activity may be associated with reduced hypertension in blacks . We therWe performed a qualitative, systematic review of cohort studies examining the relationship between physical activity and incident hypertension among blacks. We searched for articles in Medline from January 1966 to February 2005, examined all potentially relevant articles, and reviewed the reference lists of those articles. Fourteen studies assessed physical activity and incident hypertension in all populations. Most studies were conducted among whites and were conducted in the United States; four studies were conducted in countries other than the United States and did not include blacks, and four other studies included blacks but one did not report the estimate of the physical activity\u2013hypertension association by race. Only three studies met our inclusion criteria.Overall, cohort studies confirmed the positive effects of physical activity on hypertension among whites. Five studies found that among whites, physical activity reduced hypertension in univariate analyses but not after adjusting for other covariates, such as age, body mass index, and alcohol intake. Univariate analyses of one study found a relationship between physical activity and hypertension among blacks ; no suchHowever, the three studies have limitations that threaten internal and external validity. One limitation is possible nondifferential misclassification of physical activity levels due to poor physical activity ascertainment ,4. To ilWe would conclude from the published evidence that physically active blacks are not at a reduced risk for hypertension, but we recognize the numerous limitations of the research. Cohort studies did, however, report a biologically plausible inverse association of physical activity with hypertension risk. Widening the criteria of our review to include evidence from cross-sectional studies and controlled clinical trials suggestsHealthy People 2010 \u2014 reducing the proportion of adults with hypertension and eliminating health disparities overall.\u00a0Additional cohort studies and controlled clinical trials are needed to examine physical activity and incident hypertension among blacks. Longitudinal mechanistic research designs that include the mediating variable of physical activity to hypertension are essential for researchers to develop effective hypertension risk reduction interventions and for policymakers to implement informed and effective policies. This may put us closer to reaching the aims of"} +{"text": "A year ago, reproductive biologists and general public were astonished with evidence reported by Johnson et al. in Nature 428:145 that mammalian ovaries possess persisting large germline stem cells, which allegedly enable follicular renewal in adult females. Recently, the same research group declared such view obscure, and reported that mammalian oocytes originate from putative germ cells in bone marrow and are distributed by peripheral blood to the ovaries (Cell 122:303). While neglecting available data on the germ cell origin from the ovarian surface epithelium (OSE) in adult mouse and human females and complexity of follicular renewal in humans, the authors widely extrapolated their observations on formation of allogeneic oocytes after bone marrow (or blood) transplantation in ovaries of adult mice treated with cytostatics to clinical implications in the public media. Yet, the resulting outcome that such allogeneic oocytes may enable the propagation of ovarian cycles is a poor alleviation for the women with ovarian infertility. Women lacking primary follicles, or carrying follicles with low quality eggs persisting in aging ovaries, are not concerned about the lack of menstrual cycles or ovarian steroids, but about virtually no chance of having genetically related children. Johnson et al. also reported that the germ cell formation in bone marrow disappears in ovariectomized mice. Such observation, however, raises solid doubts on the bone marrow origin of oocytes. Since germ cells developing from the OSE cells of adult human ovaries during periodical follicular renewal are known to enter blood vessels in order to enable formation of primary follicles at distant ovarian sites, they also contaminate peripheral blood and hence bone marrow. Better knowledge on the complexity of follicular renewal in humans and exploration of a potential of human OSE cells to produce new oocytes in vitro are essential for novel approaches to the autologous treatment of premature ovarian failure and age induced ovarian infertility. The claim that female germ cells in adult mammals (mice and humans) originate from bone marrow and are delivered to the ovaries via the blood stream is anothAfter facing immediate critique, which indicated that such large cells rather resemble earlier described superfluous oocytes leaving mouse and human ovaries ,4, the TTo explore an idea on the extragonadal origin of germ cells in adult mammalian females, one will compare observations in animals with and without ovaries. Johnson et al. did and reported: In the absence of ovaries the evidence of germ cell formation in bone marrow completely disappears. However, instead of realizing that this observation is a perfect evidence on ovarian origin of germ cells, which enter the ovarian blood stream and, therefore, some of them bone marrow too, the authors surprised the reader with an additional uncovering: \"The results from the ovariectomy experiments lend further support to the existence of a novel communication loop between the ovaries and bone marrow that may regulate the extent of de novo oocyte production each cycle\" .If Johnson et al. are more respectful for the available literature, they will consider that the germ cells derived from ovarian surface epithelium (OSE) utilize blood vessels for colonization of distant targets during follicular renewal , and henCuriously, although Johnson et al. are apparently aware of relevant literature, the studies on the germ cell and oocyte origin from OSE and follicular renewal in adult mouse ,6 and huTwo highly distinguished American pioneers of modern reproductive physiology in 1920s and 1930s, Edgar Allen and Herbert M. Evans, concluded their studies of oogenesis and follicular renewal in adult mouse ovaries as follows: \"A cyclical proliferation of the germinal epithelium (OSE) gives rise to a new addition of young ova to the cortex of the adult ovary at each normal oestrous period\" and \"NewWhat Johnson et al. have recently shown is that the mouse ovaries lacking primary follicles after treatment with cytostatics exhibit follicles with allogeneic oocytes following bone marrow or peripheral blood transplantation from distinct mouse donors. The concomitant immunosuppression may enable allogeneic oocytes to develop, either from the donor-derived circulating ovarian germ cells, or due to the transplantation of immune-system related cells (blood monocytes and lymphocytes), which accompany as ovarian macrophages and T lymphocytes the development of germ cells from some OSE cells in adult and fetaRecently, we suggested animal experiments comparing the effect of autologous vs. allogeneic white (nucleated) blood cell concentrate (buffy coat) transfusions for induction of follicular renewal after chemotherapy in order to determine possible advantage of the former against the latter procedure . Yet, compared to the small laboratory rodents with available clusters of primitive granulosa cells resembling human fetal ovaries , a re-coin vitro production of new autologous eggs from the OSE cells of human ovaries [in vitro fertilization and utilization of embryos for intrauterine implantation, may represent more suitable variant for providing genetically related children to women with ovarian infertility, worth of consideration and further exploration.However, the age limitless ovaries -10, and"} +{"text": "The objective of this systematic review was to evaluate the impact of pharmacist delivered community-based services to optimise the use of medications for mental illness. Twenty-two controlled (randomised and non-randomised) studies of pharmacists' interventions in community and residential aged care settings identified in international scientific literature were included for review. Papers were assessed for study design, service recipient, country of origin, intervention type, number of participating pharmacists, methodological quality and outcome measurement. Three studies showed that pharmacists' medication counselling and treatment monitoring can improve adherence to antidepressant medications among those commencing treatment when calculated using an intention-to-treat analysis. Four trials demonstrated that pharmacist conducted medication reviews may reduce the number of potentially inappropriate medications prescribed to those at high risk of medication misadventure. The results of this review provide some evidence that pharmacists can contribute to optimising the use of medications for mental illness in the community setting. However, more well designed studies are needed to assess the impact of pharmacists as members of community mental health teams and as providers of comprehensive medicines information to people with schizophrenia and bipolar disorder Mental Health Services in New South Wales [Mental and behavioural disorders are estimated to account for 12% of the global burden of disease . Health th Wales .The appropriate use of medications is central to the effective management of mental illnesses, however, there is evidence that psychotropic medications are often used inappropriately ,7. Eldercommunity-based services to optimise the use of medications for mental illness.The World Health Organization (WHO) has recognised including pharmacists as active members of the health care team as one approach to improving psychotropic medication use . The Natnd quarter 2005) were searched using text words and MeSH headings including: pharmacy, pharmacists, pharmaceutical care, pharmaceutical services, mental disorders, mentally ill persons, depression, schizophrenia, psychotic disorders, antidepressive agents, psychotropic drugs, benzodiazepines, anxiety and antipsychotic agents. Reference lists of retrieved articles were checked for additional studies not identified in the original database search. If the abstract clearly indicated that the study did not relate to pharmaceutical services provided by pharmacists to optimise the use of medications for mental illness, or if the study was conducted in an acute inpatient or hospital setting, then the study was excluded at this stage.Medline (1966-April 2005), Embase (1994-April 2005), PsychInfo (1985-April 2005), Cinahl (1982-April 2005), International Pharmaceutical Abstracts (1970-April 2005) and the Cochrane Controlled Trials Register that reported the provision of services by pharmacists in community and residential aged care settings were considered. This included trials specifically conducted for individuals with a mental illness, or that reported outcomes in terms of changes to mental health symptoms, and studies of medication reviews and education initiatives to optimise the use of medications commonly prescribed for mental illness. Papers that reported pharmacists' activities as part of multidisciplinary teams were included where a pharmacist or pharmacists provided a service specifically related to optimising the use of medications for mental illness. Studies of pharmacists' interventions in residential aged care facilities were included, because community pharmacists frequently provide services to residential aged care facilities, but studies evaluating pharmacists' services in hospital inpatient or acute care settings were excluded. Studies without control groups, before and after studies, descriptive studies, results of postal surveys and qualitative interviews were excluded, as were studies to optimise medication use that did not involve a service provided by pharmacists. Each study meeting the criteria outlined above was assessed on the basis of study design, service recipient, country of origin, intervention type, number of participating pharmacists, methodological quality and outcome measurement. An overview of the literature search strategy and review procedure is presented in Figure The literature search identified 59 papers that reported or discussed community pharmacy services to optimise the use of medications for mental illness. Twenty-two papers reported the results of studies that met the inclusion criteria for the review. Studies that met the inclusion criteria were approximately equally divided between services provided to consumers n = 10) , discharge medication counselling, and medication monitoring at a community mental health centre. Pharmacist delivered services provided to other health professionals included medication reviews and outreach education activities designed to optimise prescribing. Several medication review studies reported impacts of pharmacists' interventions in terms of changes in prescribing of medications commonly used to treat mental illness and/or changes in mental health symptoms, but were not specifically targeted to people with a mental illness. Several small studies of pharmacists' medication review activities specifically conducted for people with a mental illness did not meet the review inclusion criteria ,22,41,42Three papers reported results of community pharmacists' medication counselling sessions for people commencing non-tricyclic antidepressant therapy in The Netherlands -55. InteFour studies reported patient education and treatment monitoring services for people prescribed antidepressant medications in the United States -59. The Three studies investigated the effect of pharmacist delivered services to community mental health centres and outpatients' clinics -62. In aIn a study of patients discharged home from hospital after admission for relapse of schizophrenia in Malaysia, those identified as having poor medication adherence were allocated to receive pharmacist medication counselling or standard care . The impA study that evaluated the impact of providing mental health patients with a pharmacist generated medication care plan at the time of discharge found that patients with care plans were less likely to be readmitted to hospital than those without, however, this result was not statistically significant . InformaComponents of medication review services provided by pharmacists include comprehensive medication history taking, patient home interviews, medication regimen review, and patient education . MedicatIn a randomised controlled study of pharmacist conducted domiciliary medication reviews in the United States there were significant declines in the overall numbers and monthly cost of medications, but no significant difference in cognitive or affective functioning between the intervention and control groups . This maTwo additional cluster randomised controlled studies of pharmacists' medication reviews in residential aged care facilities demonstrated significant reductions in the number and cost of medications prescribed -70. In oIn the Netherlands, pharmacotherapy meetings to optimise prescribing are undertaken as part of routine clinical practice by groups of local community pharmacists and general medical practitioners. A cluster randomised controlled trial of inter-professional (pharmacotherapy) meetings to discuss prescribing of antidepressant medications resulted in a significant reduction in the prescribing of highly anticholinergic antidepressants to elderly people by 40% compared to a control group of practitioners that did not receive the prescribing support . In compFour additional studies evaluated the impact of pharmacists' educational visits to general medical practitioners to optimise the prescribing of benzodiazepines and other psychotropic medications commonly prescribed for mental illness -75. The Given the extent of mental illness in the community and in aged care, and the fact people with mental illness frequently report concerns about their prescribed medications, services directed toward optimising the use of medications for mental illness fulfil an important public health need. As evidenced by the large number of papers excluded from this review, many studies of community pharmacy services to optimise the use of medications for mental illness have been descriptive, lacked parallel control groups or have been qualitative in nature. The controlled studies included in this review provide some evidence of the potential value of including pharmacists in mental health care across a range of settings and patient populations.Studies included in the review utilised a range of randomisation techniques, however, the review did not attempt to characterise the quality of the randomisation beyond whether randomisation occurred at the patient, practice or residential aged care facility level. The majority of the studies involved less than five pharmacists, and 10 out of the 22 papers described interventions where just one pharmacist was involved. Studies involving small numbers of pharmacists may have good internal consistency, but the results obtained may not be generalisable to outcomes of services provided by the wider pharmacy profession. In several studies the pharmacists' interventions were components of multidisciplinary team approaches to improving mental health care. The challenge of evaluating complex and multi-factorial interventions, which by their nature depend on the context in which the intervention takes place, has been described .Five studies assessed the impact of pharmacists' provision of medicines information and treatment monitoring for people commencing antidepressant therapy. Three of the five studies demonstrated that involvement of the pharmacist was associated with a significant improvement in medication adherence and/or medication use rates when measured using an intention to treat analysis. One further study demonstrated significant improvements in medication adherence among patients who received three pharmacist counselling sessions; however, this was not significant when measured using an intention to treat analysis. Given the high rates of antidepressant discontinuation during the first three months of treatment, pharmacists have a potentially important role in providing medicines information and conducting treatment monitoring for those patients at high risk of medication non-adherence. No studies of pharmacists' treatment monitoring for people commencing antidepressant therapy compared monitoring provided by pharmacists to monitoring conducted by other health professionals. A separate study of antidepressant treatment monitoring conducted by nurses also demonstrated improved medication adherence .Despite people with psychotic disorders having reported unmet medicines information needs, relatively few controlled studies assessed community pharmacy services for users of antipsychotic medications. Other studies have suggested that service provision by pharmacists may be limited by not having access to patients' medical histories , a lack Pharmacist conducted medication management reviews appear a valuable strategy to identify potential medication related problems among people taking medications for a mental illness. The included studies demonstrated that such reviews can reduce the numbers of potentially inappropriate psychotropic medications used for mental illness prescribed to elderly people in residential aged care settings. Only one study made the link between a reduction in psychotropic medication use and improved adherence to national prescribing guidelines . The valEducational visiting has been shown to modify prescribing behaviour . The revThe review of the international literature highlights the range of pharmaceutical services provided by community pharmacists in Australia that are potentially well suited to assisting patients and prescribers optimise the use of medications for mental illness. These data show that medication counselling and treatment monitoring conducted by pharmacists can improve medication adherence among people commencing antidepressant therapy. Pharmacist conducted medication reviews and resulting recommendations to optimise medication regimens may reduce the numbers of potentially inappropriate medications for mental illness prescribed to elderly people. This review of the available published evidence supports the continued expansion of pharmaceutical service delivery to people with mental illness, but identified the need for further well-designed research in specific areas. Future studies are needed to assess the cost-effectiveness and clinical implications of pharmacists working as members of multidisciplinary community mental health teams, and as providers of pharmaceutical services to people with psychotic disorders.SB conducted the literature search and wrote the manuscript. AJM assisted in the literature search and in the writing of the manuscript. PA proof read drafts of the manuscript. PW and TFC participated in the conceptualisation of the review and assisted in the writing of the manuscript."} +{"text": "Objective: To evaluate the functional capacity of granulocytes and monocytes from pregnant and nonpregnant women in relation to group B streptococcus (GBS) colonization status. Methods: Engulfment of fluorescent GBS by peripheral blood phagocytes from GBS-colonized and noncolonizedwomen was measured by flow cytometry. Intracellular superoxiode generated in response to GBS challenge tomonocytes and granulocytes enriched from peripheral blood of these women was also measured by flowcytometry, and extracellular superoxide was determined by colorimetric assay.Results: Monocytes and granulocytes from pregnant, GBS-colonized women engulfed significantly greaternumbers of GBS than phagocytes from pregnant, noncolonized women. No difference in intracellular superoxideproduction was detected between any of the groups of women; however, monocytes from pregnant, colonizedwomen released significantly more superoxide into the extracellular milieu than did granulocytes from the samewomen. No differences in extracellular release of superoxide were observed among noncolonized womenwhether they were pregnant or not.Conclusions: Monocytes from pregnant, colonized women engulf more GBS and release more of the superoxideinto the extracellular environment, where it is unlikely to be an effective defense mechanism against intracellularbacteria. This suggests that components of the innate immune system that should serve in a protective role mayfunction suboptimally, thereby contributing to the colonization process by GBS."} +{"text": "Neisseria meningitidis B, Reverse Vaccinology has strongly enhanced the identification of vaccine candidates by replacing several experimental tasks using in silico prediction steps. These steps have allowed scientists to face the selection of antigens from the predicted proteome of pathogens, for which cell culture is difficult or impossible, saving time and money. However, this good example of bioinformatics-driven immunology can be further developed by improving in silico steps and implementing biologist-friendly tools.Since a milestone work on in silico identification of the best vaccine candidates from whole proteomes of bacterial pathogens. The software integrates multiple robust and well-known algorithms for protein analysis and comparison. Vaccine candidates are ranked and presented in a html table showing relevant information and links to corresponding primary data. Information concerning all proteins of the analyzed proteome is not deleted along selection steps but rather flows into an SQL database for further mining and analyses.We introduce NERVE (New Enhanced Reverse Vaccinology Environment), an user-friendly software environment for the .After learning from recent years' works in this field and analysing a large dataset, NERVE has been implemented and tuned as the first available tool able to rank a restricted pool (~8\u20139% of the whole proteome) of vaccine candidates and to show high recall (~75\u201380%) of known protective antigens. These vaccine candidates are required to be \"safe\" (taking into account autoimmunity risk) and \"easy\" for further experimental, high-throughput screening (avoiding possibly not soluble antigens). NERVE is expected to help save time and money in vaccine design and is available as an additional file with this manuscript; updated versions will be available at All authors read and approved the final manuscript."} +{"text": "Because genetic predisposition probably plays an important role in the aetiology of most of childhood cancers, studies of second primaries occurring after these cancers may be particularly informative about possible common genetic mechanisms in both of these cancers. We have studied the incidence of thyroid tumours occurring after cancer in childhood in a cohort of 592 children treated before 1970. Among these children, six later developed a thyroid carcinoma, and 18 developed a thyroid adenoma. Radiation doses received to the thyroid by each of the irradiated children have been estimated using individual radiotherapeutic technical records. Thyroid carcinomas and thyroid adenomas were five times more frequent after irradiation for neuroblastoma than after irradiation for any other first cancer. This ratio did not depend on sex, nor on time elapsed since irradiation, nor on dose of radiation received for the thyroid gland. This result suggests that there is a common mechanism for the occurrence of neuroblastoma and of differentiated thyroid tumour."} +{"text": "Cryptic species are two or more distinct but morphologically similar species that were classified as a single species. During the past two decades we observed an exponential growth of publications on cryptic species. Recently published reviews have demonstrated cryptic species have profound consequences on many biological disciplines. It has been proposed that their distribution is non-random across taxa and biomes.We analysed a literature database for the taxonomic and biogeographical distribution of cryptic animal species reports. Results from regression analysis indicate that cryptic species are almost evenly distributed among major metazoan taxa and biogeographical regions when corrected for species richness and study intensity.This indicates that morphological stasis represents an evolutionary constant and that cryptic metazoan diversity does predictably affect estimates of earth's animal diversity. Our findings have direct theoretical and practical consequences for a number of prevailing biological questions with regard to global biodiversity estimates, conservation efforts and global taxonomic initiatives. These discoveries continue to increase exponentially and raise a number of general questions, such as: How frequent are cryptic species? Are cryptic species evolutionary young? Is morphological stasis upon speciation more often found in environmental extremes, such as the tropics, the artic or the deep sea? A recent review proposed that the distribution of cryptic species is non-random across taxonomic groups and biomes, which might have substantial consequences for biodiversity assessments, macroecology, biogeography, conservation management and evolutionary theory which yielded 2207 entries. Even though the term sibling species has also the slightly different connotation of recent divergence , it is uBoth authors planned the study and drafted the manuscript. MP retrieved and analysed the data."} +{"text": "Serum and early morning urine specimens were obtained from 62 patients. The levels of beta human chorionic gonadotrophin (BhCG) in both serum and urine were estimated simultaneously in all cases. At the time of estimation 43 patients had transitional cell carcinoma of the bladder, one had transitional cell carcinoma of the renal pelvis and three had carcinoma in situ . Raised serum and urinary levels were found in only three patients, all of whom had poorly differentiated or metastatic transitional cell carcinoma of the bladder. This observation is in accordance with previous studies. In one of these patients, who underwent transurethral resection of her bladder tumour, the urinary levels returned to within normal limits post resection. An additional three patients had elevations of serum BhCG. Two of these three patients had poorly differentiated transitional cell carcinoma present at the time of estimation and one had no sign of recurrence. Using immunoperoxidase staining a retrospective study was undertaken to stain all available sections belonging to patients studied to observe whether BhCG was being produced by the respective tumours. Twelve well differentiated, nine moderately well differentiated and seven poorly differentiated specimens were available. In no case was evidence of BhCG production demonstrated in these tumours despite its presence being demonstrable in positive controls. We confirm the production of BhCG associated with bladder tumours, a feature correlated with poorer differentiation. Studies employing larger patient numbers are necessary to clarify the role of this tumor marker in patients with well differentiated bladder tumours."} +{"text": "Restriction of fetal growth and compromise of fetal wellbeing remain significant causes of perinatal death and childhood disability. At present, there is a lack of scientific consensus about the best strategies for predicting these conditions before birth. Therefore, there is uncertainty about the best management of pregnant women who might have a growth restricted baby. This is likely to be due to a dearth of clear collated information from individual research studies drawn from different sources on this subject.A series of systematic reviews and meta-analyses will be undertaken to determine, among pregnant women, the accuracy of various tests to predict and/or diagnose fetal growth restriction and compromise of fetal wellbeing. We will search Medline, Embase, Cochrane Library, MEDION, citation lists of review articles and eligible primary articles and will contact experts in the field. Independent reviewers will select studies, extract data and assess study quality according to established criteria. Language restrictions will not be applied. Data synthesis will involve meta-analysis (where appropriate), exploration of heterogeneity and publication bias.The project will collate and synthesise the available evidence regarding the value of the tests for predicting restriction of fetal growth and compromise of fetal wellbeing. The systematic overviews will assess the quality of the available evidence, estimate the magnitude of potential benefits, identify those tests with good predictive value and help formulate practice recommendations. Restriction of fetal growth and compromise of its wellbeing remain significant causes of perinatal death and childhood disability -3. TheseScreening and diagnosis of fetal growth restriction (FGR) and prediction and monitoring for compromise of fetal wellbeing in a clinical setting includes a combination of patients' characteristics, symptoms, physical signs and tests, which form the basis of clinical care. For instance, methods employed to screen for and detect FGR might include obtaining previous history of small babies, recording symphyseal fundal height on a customised growth chart and estimating fetal weight with ultrasound . SimilarThe term FGR (related term IUGR or intrauterine growth retardation) and SGA are often used interchangeably, but some times erroneously. Appreciation of the difference between smallness of fetus as a consequence of intra-uterine constraint as opposed to that resulting from normal smallness is central to understanding the meaning of FGR and the accuracy of tests to predict FGR. SGA refers to any fetus that falls below a defined size . It represents a heterogeneous group comprising of fetuses that have failed to achieve their growth potential (true FGR) as well as fetuses that are constitutionally small due to an inherent low growth potential. Only about half of SGA fetuses have FGR. It is FGR that is likely to be associated with childhood disability; normal constitutional smallness is expected to be of no clinical consequence. Hence a good fetal growth test will be expected to accurately identify fetuses that have true FGR, distinguishing FGR from SGA alone.A distinction has earlier been made between tests that measure fetal size or growth (e.g. biometric tests) and those that assess fetal wellbeing . Tests oThe reference criteria for confirmation of growth restriction and compromise of wellbeing are different and our project will deal with this issue in a methodologically sound manner. Many tests have been purported to be predict stillbirth, birth hypoxia and neonatal complications . To careTimely prediction of growth restriction and compromise of fetal wellbeing is of essence in antenatal care. Without accurate prediction, clinicians are handicapped. Wrong or delayed prediction puts baby at risk of an adverse outcome whereas correct prediction provides an opportunity to optimise care. If high-risk groups are accurately and efficiently identified, they could benefit from monitoring of wellbeing and appropriate interventions such as steroid administration and timely delivery. However, decision-making is hampered due to lack of precise information on estimates of risk, a situation that can be ameliorated with a comprehensive systematic review of the literature. Research in prevention of complications of growth restriction itself will benefit form identification of high-risk groups with accurate tests as these may be enrolled in clinical trials with an improved likelihood of providing robust evidence of effectiveness.To generate a set of the most accurate tests for predicting restriction of fetal growth and compromise of its wellbeing, systematic reviews of test accuracy studies will be conducted with the following objective:To obtain summary estimates of accuracy of available antenatal tests for predicting restriction of fetal growth and compromise of fetal wellbeing.Literature will be identified using:\u2022 General bibliographic databases including MEDLINE (PubMED) and EMBASE (Ovid)\u2022 Specialist electronic databases: The Cochrane Library , MEDION\u2022 Contact with individual experts and those with an interest in this filed to uncover grey literature\u2022 Contact with manufacturers of tests\u2022 Hand-searching of selected specialist journals\u2022 Checking of reference lists of relevant review articles and papers that will be eligible for inclusionTwo searches will be performed, the first looking at prediction and diagnosis of FGR and the second at compromise of fetal wellbeing. The comprehensive search strategies will aim to find all primary studies reporting in the accuracy of any test (or test combinations) used to predict or diagnose fetal growth restriction and/or compromise of fetal wellbeing. The search for FGR may be viewed as additional file Studies will be selected for inclusion in the reviews using the selection criteria based on population, index test, reference standard and study design of interest.Population: Pregnant women any health care setting, any level of risk.Diagnostic tests: Tests will be prioritised on the basis of clinical relevance after consultation with experts in the field. allowing generation of 2 \u00d7 2 tables of accuracy. Case series <10 cases and case-control studies defined by reference standard outcome (birth weight measurement) will be excluded, these study designs have been shown to be associated with bias 32][[32][31][[[32][31]The author(s) declare that they have no competing interests.RKM developed the protocol, developed the searches and data management, will participate in selection, inclusion, quality assessment and data extraction of papers for the reviews, will perform statistical analysis. KSK led the grant application secured from Wellbeing of Women charity, developed the protocol and will advise RKM in all of her work as the general project supervisor. SCR developed the protocol, will provide clinical expertise and review of manuscripts for publication. AC helped develop the protocol. JK helped develop the protocol, will provide advice on methodology and statistical analysis and review of manuscripts for publication. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:Search strategy for tests to predict/diagnose fetal growth restriction. Word document detailing search strategy for Medline, Embase and Cochrane library used in systematic reviews of diagnostic accuracy of tests to predict/diagnose fetal growth restriction.Click here for file"} +{"text": "There are several very obvious and simple solutions for eliminating the \"Pitfalls\" and for minimizing the risk of occurrence of any perioperative complications associated with placement of chronic indwelling central venous access devices in cancer patients. The first is the utilization of a venous cutdown approach, such as the cephalic vein or the external jugular vein, which essentially eliminates potentially life-threatening perioperative complications, such as pneumothorax and injury to the great vessels (with or without associated hemothorax). The second is the selective and appropriate utilization of intraoperative venography for defining the central venous anatomy and for providing a venous roadmap in those particularly challenging cases in which difficulties are encountered during chronic indwelling central venous access device placement. The placement of chronic indwelling central venous access devices in cancer patients remains an essential service not infrequently provided by many practicing surgical oncologists . AlthougIn a recently published article featured in International Seminars in Surgical Oncology on June 5, 2007, entitled \"Pitfalls in Portacath location using the landmark technique: case report\", Wyles et al [Two particularly useful venous cutdown approaches for placement of chronic indwelling central venous access devices in cancer patients are the cephalic vein cutdown approach ,4 and thThe venous cutdown approach represents an easy, safe, and highly useful avenue for selectively and appropriately performing intraoperative venography during challenging central venous access cases . Such a Wyles et al inferredIn conclusion, consideration of a venous cutdown approach, as well as selective and appropriate utilization of intraoperative venography, represent very obvious and simple alternative solutions for eliminating the \"Pitfalls\" and for minimizing the risk of occurrence of any perioperative complications associated with placement of chronic indwelling central venous access devices in cancer patients.The author(s) declare that they have no competing interests.The author organized, wrote, and edited all aspects of this manuscript. He approved the final version of this manuscript."} +{"text": "Influenza and pneumococcal vaccination are recommended for a number of clinical risk groups including patients treated with major immunosuppressant disease modifying anti-rheumatic drugs. Such immunisation is not only safe but immunogenic in patients with rheumatic diseases. We sought to establish dual vaccination rates and significant influencing factors amongst our hospital rheumatology outpatients.We audited a sample of 101 patients attending hospital rheumatology outpatient clinics on any form of disease modifying treatment by clinical questionnaire and medical record perusal. Further data were collected from the local immunisation coordinating agency and analysed by logistic regression modelling.Although there was a high rate of awareness with regard to immunisation, fewer patients on major immunosuppressants were vaccinated than patients with additional clinical risk factors against influenza or streptococcus pneumoniae . The presence of additional risk factors was confirmed as significant in determining vaccination status by logistic regression for both influenza and streptococcus pneumoniae . The diagnosis of rheumatoid arthritis was also found to be a significant factor for pneumococcal vaccination . There was a negative trend suggesting that patients on major immunosuppressants are less likely to be immunised against pneumococcal antigen .Influenza and pneumococcal immunisation is suboptimal amongst patients on current immunosuppressant treatments attending rheumatology outpatient clinics. Raising awareness amongst patients may not be sufficient to improve vaccination rates and alternative strategies such as obligatory pneumococcal vaccination prior to treatment initiation and primary care provider education need to be explored. Influenza infection is responsible for considerable morbidity and mortality in epidemic years , whilst Patients were eligible for inclusion if they were on DMARD treatments including systemic corticosteroids (over 20 mg per day for at least 1 month in the last 12 months) and biologic therapy whilst attending a doctor or nurse-led adult rheumatology outpatient clinic at our district general hospital. No exclusion criteria were specified. A single page questionnaire gathering information on general practitioner, age, gender, rheumatological diagnosis, significant comorbidities, current treatment, vaccination awareness, vaccination status and underlying motive for vaccine refusal if applicable was created to standardise data collection amongst auditors. A large practice was defined as a general practice at which more than 6 audit patients were registered. Whilst the questionnaire was not formally validated prior to the study, its design was discussed with our clinical audit department and then reviewed in the initial stages of the project. No questionnaire modifications were deemed necessary and the audit was continued as initially planned. Our patient recruitment strategy was designed to maximise the number of audited patients over a short period of time. To this end, questionnaires were simultaneously distributed to two nurse practitioners, two specialist registrars and one consultant in our rheumatology department in September 2006. Individual auditors then consecutively screened and selected for audit suitable patients attending their respective outpatient clinics until a predefined target of 100 audited patients was achieved in October 2006. Data were collected from patient interview and available hospital records by individual auditors at the time of clinical review. There were no recorded instances of refusal to participate in our audit by a patient. Additional corroborative information was sought from the immunisation coordinating Lancashire and South Cumbria Agency, Preston, UK. This was released to our clinical audit department after formal approval by our appointed Caldicott guardian in charge of patient data protection, merged with interview data and then released in anonymised format to the investigators. Formal approval to carry out this audit was sought and granted by our clinical audit department. The Statistical analysis was performed using software supplied by Minitab Inc, USA and Creostat HB, Sweden.The main characteristics of our sample of 101 patients are summarised in table We compared the vaccination profile of patients with and without additional risk factors according to their use of major immunosuppressant DMARDs as shown in Table We investigated the factors influencing immunisation amongst our sample of patients by logistic regression modelling using presence of additional risk factor, size of general practice, diagnosis of rheumatoid arthritis, major immunosuppressant drug therapy and gender as predictor variables. Results are displayed in tables In the case of influenza vaccination the presence of an additional risk factor was the only significant factor influencing the odds ratio for immunisation, whilst a trend was apparent for large practices . There was no detectable effect of major immunosuppressant use.Significant factors influencing pneumococcal vaccination included a diagnosis of rheumatoid arthritis and the presence of additional risk factors . There was a notable negative trend for the odds ratio with major immunosuppressant use .Given the increased susceptibility to infection amongst patients with inflammatory rheumatic diseases and the potential to counteract this risk with influenza and pneumococcal vaccination, it is important to ascertain the effect that current education and immunisation practice are having on rheumatology patients.Our audit has shown a high rate of immunisation awareness amongst our patients as could be expected from our unit's policy of routinely counselling patients starting disease modifying treatments and providing written drug information leaflets. A small number of patients on minor immunosuppressant DMARD therapy and without additional risk factors requiring immunisation believed they needed vaccinating and this was reflected in their rate of vaccination offer and uptake. Information on risk factors was collected by direct patient questioning with access to clinical records during patient consultation, and it would seem unlikely that any major risk factors would have been missed in the audit process thus raising the possibility that the perceived immunosuppressant effects of rheumatic illness or the perceived risk of minor immunosuppressant drug therapy may be affecting patients' and their family physicians' immunisation strategies. The first possibility is supported by finding rheumatoid arthritis to be a significant factor influencing pneumococcal vaccination rates through our logistic regression model. A number of our patients will inevitably eventually turn to major immunosuppressant DMARDs as rescue therapies and we are therefore not concerned by what appears to be over-vaccination on the part of our general practitioner colleagues.Patients who are on major immunosuppressants are nevertheless less commonly offered vaccination or vaccinated as compared to patients with other risk factors despite the high levels of patient awareness and uptake suggesting that a proportion of our high risk patients are not actively pursuing known immunisation advice nor being correctly identified by their family physicians. Notwithstanding our small audit sample size, there is even a trend suggesting that major immunosuppressant use may be an independent negating factor in the setting of pneumococcal vaccination. Interestingly, patients belonging to larger general practices with higher numbers of rheumatology patients are likely to achieve better coverage for influenza immunisation and this may suggest that organisational factors in individual practices may play an important role here.As influenza vaccination is seasonal, it would be impractical and difficult given our limited resources to offer annual immunisation directly in our rheumatology outpatient clinics when there are funded agencies dedicated to this purpose operating within our area. There is also a concern that patients could unnecessarily be vaccinated more than once by different providers and for these reasons we maintain that responsibility for immunisation should continue to rest with primary care providers. As immunosuppressant therapy is mostly initiated in rheumatology outpatient clinics, one possible approach to improve current practice and perhaps immunisation efficacy would be to routinely request patient vaccination prior to rather than after the initiation of major immunosuppressant therapy as we do at present. Whilst feasible for pneumococcal vaccine, this approach may be limited by the availability of influenza vaccine outwith the immunisation calendar. We would therefore also recommend contacting primary health care providers before the start of each annual immunisation season to raise general awareness about the need to vaccinate any patient on major immunosuppressant therapy in order improve targeting of existing rheumatology patients in the community.Rheumatology outpatients are not being appropriately targeted by the influenza and pneumococcal vaccination efforts on the part of primary care physicians. Raising patient awareness is not sufficient to ensure optimal immunisation thus calling for alternative strategies on the part of rheumatology services to improve vaccination coverageThe author(s) declare that they have no competing interests.ES proposed, designed, performed statistical analysis and wrote the first draft report of the audit study. WM approved, contributed to the design, took part in the data collection and edited the first draft report. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:"} +{"text": "Serum leptin variation is commonly associated with fat percentage (%), body mass index (BMI), and activity. In this investigation, we report population differences in mean leptin levels in healthy men as well as associations with fat % and BMI that are independent of these factors and reflect likely variation resulting from chronic environmental conditions.Serum leptin levels, fat %, and BMI were compared between lean American distance runners and healthy Ache Native Americans of Paraguay. Mean levels were compared as were the regressions between fat %, BMI, and leptin. Comparisons were performed between male American distance runners and highly active male New World indigenous population in order to determine whether significant population variation in leptin is evident in physically active populations living under different ecological circumstances independent of adiposity and BMI.While the Ache were hypothesized to exhibit higher leptin due to significantly greater adiposity , leptin levels were nonetheless significantly higher in American runners . Significant differences in the association between leptin and fat % was also evident between Ache and runner men. Although fat % was significantly related with leptin in runners fat % was negatively related in Ache men .These results illustrate that chronic ecological conditions in addition to activity are likely factors that contribute to population variation in leptin levels and physiology. Population variation independent of adiposity should be considered to be an important source of variation, especially in light of ethnic and population differences in the incidence and etiology of obesity, diabetes, and other metabolic conditions. Leptin is a polypeptide hormone that is secreted primarily by adipose tissue and acts as a lipostat to the hypothalamus affecting numerous aspects of physiology including metabolism, immune function, and reproduction . While lAlthough adiposity is a major source of variation in leptin levels, significant population variation is evident with leptin being significantly lower in non-industrialized populations compared to more developed communities -9. The sTo determine whether differences in the association between leptin and adiposity extend also to Ache men, this investigation compares Ache male leptin with a group of comparable adiposity in a developed society, American runners. The significance of this comparison is gain insights into ethnic variation in leptin physiology and to provide a greater understanding of the etiology of metabolic syndrome among Native American groups ,13. BothLeptin and anthropometric data was collected from the Ache by the author and compared with pre-exercise control measures from runners reported in Hickey et al. . SpecifiDespite significantly higher body fat percentage , Ache leptin was significantly lower than runners . There was no significant difference in BMI or age Figures . In addiThe hypothesis that leptin should be higher in the group exhibiting greater adiposity was not supported in this investigation. In addition, the hypothesis that leptin should be positively associated with adiposity is only evident among American runners. Therefore other sources of leptin variation, particularly among the Ache, need to be considered. The exact mechanisms that underlie population variation independent of adiposity remain unclear, however genetic differences between populations, chronic environmental influences such as maternal/fetal or childhood nutritional status, and acute lifestyle differences such as diet and physical activity may be contributory. Since American runners were chosen due to their leanness and physical activity compared to the Ache, it is unlikely that acute differences in daily lifestyle patterns related to adiposity and physical activity were a factor in this study.Genetic differences in the Ob gene that codes for leptin as well as its receptor are also possible sources of variation. For example among Taiwanese aboriginal populations, greater incidences of obesity were associated with the G-2548A polymorphism in the promoter region of the leptin gene and the Gln223Arg (Q223R) polymorphism of the leptin receptor gene . Similarth percentile compared to American pregnant women) (unpublished data). However clearly further data on pregnancy and leptin are needed among the Ache.McMillen and colleagues have emphasized the potential role of early developmental processes that may affect leptin and adipose physiology later in adulthood. They suggest high maternal BMI may lead to greater circulating glucose in fetuses and altered adipocyte metabolism during childhood, ultimately leading to greater leptin levels in adulthood and a propensity towards obesity . HoweverIn addition, a comparison of leptin between well-fed Italian and undernourished Gambian boys and girls revealed that Gambian children exhibited consistently lower leptin even after controlling for BMI . Animal In adults, leptin levels and adipose tissue production rates exhibited a more prominent decline in fasted lean women compared to fasted obese women , while fhigher among active tuberculosis patients compared to controls. Treatment elevated leptin levels even higher. Schwenk et al. [Immunological stress, while not quantified in this study, likely differed between Ache and American runner men. Chronic and acute infections affect and are influenced by leptin levels ,35. Speck et al. also repWhile leptin likely serves as a fat cell mass/energy signal to the central nervous system, acute underfeeding can dramatically lower systemic leptin independent of changes in adipose tissue mass . This isForaging populations are excellent models for assessing the evolutionary implications of exercise physiology. Assessments of physical performance of the Ache have provided evolutionary physiologists with important insights into human biology and their responses to physical activity, both recreational and non-recreational . Indeed,The significant non-pathological range of variability in leptin and other metabolic hormones merits greater awareness and appreciation on the part of human biologists. Moreover, the growing incidence of obesity, metabolic syndrome, and diabetes, along with increasing population heterogeneity due to immigration, strongly advocates that diagnostic and research clinicians would surely benefit from recognizing the importance of leptin variation independent of adiposity.While adiposity has been repeatedly shown to be central to leptin production and circulating levels, we have provided further evidence that leptin levels exhibit a significant range of variation independent of somatic condition, most importantly adiposity. Leptin production rate varies in association with environmental conditions and contributes to population variation. Further research is necessary to ascertain the potential implications for differences in the incidence and etiology of obesity, diabetes, and other metabolic disorders among ethnicities and populations.The authors(s) declare that they have no competing interests.Dr. Richard G. Bribiescas initiated the research question addressed in this manuscript, performed the field collection and conducted the laboratory analysis of the Ache hormonal and anthropmetric data, performed the statistical analysis, as well as contributed to the preparation and editing of the manuscript. He also initiated and procured the grants necessary to collect the Ache data.Dr. Matthew S. Hickey contributed to the collection and laboratory analysis of the American runner hormonal and anthropometric data. He also assisted in the preparation and editing of the manuscript. Both authors were involved with the preparation and editing of the final manuscript."} +{"text": "By analogy with combination chemotherapy, endocrine agents with different mechanisms of action have been combined in the treatment of patients with advanced breast cancer. The clinical use of tamoxifen+aminoglutethimide+hydrocortisone showed no clinical benefit over the individual use of tamoxifen or aminoglutethimide+hydrocortisone. The endocrine changes occurring in postmenopausal patients as a consequence of their treatment with tamoxifen+aminoglutethimide+hydrocortisone have been examined. Suppression of gonadotrophin and oestrogen levels and increased levels of sex hormone binding globulin were observed. These changes might be expected to be of benefit in the treatment of advanced breast cancer, and do not explain the lack of clinical benefit in combining the treatments. Non-responders to this combination therapy had higher levels of oestrone and dehydroepiandrosterone sulphate whilst on treatment than responders, confirming previous observations in patients treated with aminoglutethimide+hydrocortisone."} +{"text": "Ser/Thr/Tyr kinases (STYKs) commonly found in eukaryotes have been recently reported in many bacterial species. Recent studies elucidating their cellular functions have established their roles in bacterial growth and development. However functions of a large number of bacterial STYKs still remain elusive. The organisation of domains in a large dataset of bacterial STYKs has been investigated here in order to recognise variety in domain combinations which determine functions of bacterial STYKs.Using sensitive sequence and profile search methods, domain organisation of over 600 STYKs from 125 prokaryotic genomes have been examined. Kinase catalytic domains of STYKs tethered to a wide range of enzymatic domains such as phosphatases, HSP70, peptidyl prolyl isomerases, pectin esterases and glycoproteases have been identified. Such distinct preferences for domain combinations are not known to be present in either the Histidine kinase or the eukaryotic STYK families. Domain organisation of STYKs specific to certain groups of bacteria has also been noted in the current anlaysis. For example, Hydrophobin like domains in Mycobacterial STYK and penicillin binding domains in few STYKs of Gram-positive organisms and FHA domains in cyanobacterial STYKs. Homologues of characterised substrates of prokaryotic STYKs have also been identified.The domains and domain architectures of most of the bacterial STYKs identified are very different from the known domain organisation in STYKs of eukaryotes. This observation highlights distinct biological roles of bacterial STYKs compared to eukaryotic STYKs. Bacterial STYKs reveal high diversity in domain organisation. Some of the modular organisations conserved across diverse bacterial species suggests their central role in bacterial physiology. Unique domain architectures of few other groups of STYKs reveal recruitment of functions specific to the species. The list of predicted STYKs used for further analysis has been arrived at after careful cross-referencing between the results of these methods as well as manual scrutiny for a variety of factors such as length of the kinase domains and presence of critical functional residues. Kinase catalytic domains of the PKLA were aligned using CLUSTALW. Manual decisions are taken considering the presence/absence of functional motifs and the lengths of putative kinase domains. Those kinase-like sequences without functional residues, such as an aspartate in the catalytic base position, are segregated separately and are not considered for the detailed analysis. Number of such sequences in various genomes is provided in Table We have employed multiple sensitive sequence search and analysis methods PSI-BLAST , IMPALA Domain assignment to the non-catalytic regions of the kinase containing genes has been carried out using the HMM search methods by querying each of the kinase containing sequences against the 6190 protein family HMMs available in the Pfam database . Trans-mThe 3-dimensional structures were superimposed using STAMP .AK performed the computational sequence analysis and modelling. AK and NS conceived the study and participated in its design and coordination. Both the authors read and approved the final manuscript.Data files comprising of the description of protein kinases and homologues encoded in genomes of organisims considered in the current analysis are provided as supplementary information accompanying this article. Each additional data file lists the gene identifiers, length, and domain arrangement of protein kinases and homologues identified in the current analysis.Click here for file"} +{"text": "Intakes of starch, non-starch polysaccharides (NSPs), protein and fat have been compared with colorectal cancer incidence in 12 populations worldwide. There were strong inverse associations between starch consumption and large bowel cancer incidence . There was no significant relation with NSPs, although the association with large bowel cancer incidence was still significant when NSP was combined with resistant starch (RS) to give an estimate of fermentable carbohydrate . The relationships between starch, RS and NSPs and cancer incidence remained statistically significant after adjusting for fat and protein intakes. The strong inverse associations found here suggest a potentially important role for starch in protection against colorectal cancer and correspond with the hypothesis that fermentation in the colon is the mechanism for preventing colorectal cancer. Measures of both starch and NSPs need to be included in future epidemiological studies of diet and bowel cancer."} +{"text": "GATA4, ZFPM2, NR2F2 and WT1, and signaling pathway components, including members of the retinoic acid pathway. Mutations in these genes affect diaphragm development and can have pleiotropic effects on pulmonary and cardiac development. New therapies, including fetal endoscopic tracheal occlusion and prenatal transplacental fetal treatments, aim to normalize lung development and pulmonary vascular tone to prevent and treat lung hypoplasia and pulmonary hypertension, respectively. Studies of the association between particular genetic mutations and clinical outcomes should allow us to better understand the origin of this birth defect and to improve our ability to predict and identify patients most likely to benefit from specialized treatment strategies.Congenital diaphragmatic hernias (CDHs) and structural anomalies of the diaphragm are a common class of congenital birth defects that are associated with significant morbidity and mortality due to associated pulmonary hypoplasia, pulmonary hypertension and heart failure. In \u223c30% of CDH patients, genomic analyses have identified a range of genetic defects, including chromosomal anomalies, copy number variants and sequence variants. The affected genes identified in CDH patients include transcription factors, such as Summary: In this Review, Kardon et al. discuss the complex etiology of congenital diaphragmatic hernia, as revealed by comprehensive genomic analyses and modeling in mice, and highlight the need for new therapies to treat this developmental disorder. Birth defects represent some of the most complex challenges in medicine. A structural problem in one organ can have associated comorbidities in many other systems because defects in one organ, such as the heart or diaphragm, can affect the development or function of another, such as the lungs or because the structural defect is part of a multisystem genetic syndrome . The hetBochdalek hernia: A developmental diaphragmatic defect that involves the lumbocostal triangle at the posterior-lateral chest wall; clinicians often use this term to imprecisely describe many types of CDH.Congenital diaphragmatic hernia (CDH): Diaphragmatic hernias that involve the posterior-lateral diaphragm and present in newborns with respiratory distress.Ductus arteriosus: Fetal anatomical shunt between the pulmonary and systemic circulation. In CDH patients with severe pulmonary hypertension, the ductus arteriosus is often kept open by treatment with a prostaglandin E1 (PGE1) infusion to decrease the workload on the right ventricle.Eventration: Abnormally thin diaphragm usually associated with muscularization defects.Fetal endoscopic tracheal occlusion (FETO): Fetal surgical procedure in which the trachea is occluded to cause fetal lung fluid accumulation, which induces the stretching and possibly accelerated development of the lungs.Morgagni hernia: A hernia that occurs in the anterior diaphragm just posterior to the sternum. These hernias are not usually discovered in newborns, and are not usually associated with pulmonary hypoplasia.Pleuroperitoneal folds (PPFs): Transient pyramidal structures at the base of the embryonic thoracic region that give rise to the muscle connective tissue and central tendon of the diaphragm.Pulmonary hypertension: High blood pressure in the vascular system of the lungs. CDH patients often have cardiopulmonary failure that is marked by severe pulmonary hypertension.Pulmonary hypoplasia: Lungs that are small due to abnormal development, as seen in patients with CDH.The diaphragm is a skeletal muscle that normally separates the thoracic and abdominal cavities and is essential for respiration. Defects in diaphragm development are common, occurring in about 1 in 3000 births worldwide , and areRecent advances, including decreased sequencing costs and the ability to make mouse models more easily, have allowed researchers to study CDH more effectively, leading to new insights into the genetic and developmental contributors to CDH, which we review here. We also discuss the cardiopulmonary consequences of CDH, and the available and emerging treatment options.The diaphragm consists of two muscle domains. The costal diaphragm is a domed sheet of muscle composed of a radial array of muscle fibers, which extends from the ribs to a central tendon . The cruSevere CDH that presents at birth is usually associated with co-morbidities in other organs . ApproxiCurrently, the clinical management of CHD largely consists of supportive care with surgical repair of the diaphragm postnatally. This care includes respiratory support with positive \u2018gentle\u2019 ventilator pressures, modulation of the pulmonary vascular system, measures to prevent right-heart failure by allowing for patent ductus arteriosus shunting . An impode novo mutations constitute a significant fraction of the genetic alterations predisposing babies to developing CDH. Mutations in particular CDH-associated genes or chromosomal regions are incompletely penetrant for CDH (GATA6) and nuclear receptor subfamily 2 group F , have also been associated with other congenital anomalies, including congenital heart disease and pancreatic agenesis and single-gene mutations. CDH can be caused by chromosomal anomalies . After uGATA4 , FRAS1-r) FREM1; , fibrill2; STRA6 and FBLN6 , insertions and deletions (indels), or large CNVs are expected to contribute significantly to the etiology of these cases. Studies of trios of unaffected parents with CDH-affected children identified, via cytogenetic and microarray analyses, de novo pathogenic CNVs (affecting one or more genes) in 4% of CDH patients (de novo (as well as inherited) SNVs, indels and CNVs. Using WES on 39 trios of unaffected parents and CDH children, the DHREAMS study (http://www.cdhgenetics.com/dhreams-study.cfm) identified an excess burden of de novo variants that are likely to disrupt or be deleterious to genes highly expressed during diaphragm development in mice has also implicated mesothelial cells associated with PPFs as a cellular source of CDH to mark and follow the fate of these structures during development. Most studies have relied on analyses of histologically stained sections whose orientations are not uniform. Future progress will be enhanced by the whole-mount analysis of embryos in which structures that give rise to the diaphragm are labeled with specific antibodies or Cre alleles.The complexities of early diaphragm development pose a major barrier to discovering whether common pathways or processes underlie the development of CDH. While three embryonic structures play vital roles in diaphragm development, other structures, such as the posthepatic mesenchymal plate (PHMP), could be important . There iLung defectsPremature arrest of airway branchingDecreased number and size of alveoliLong-term obstructive and restrictive lung diseaseAirway hyper-reactivityAbnormal diffusion capacityPulmonary vascular defectsPulmonary hypertensionPremature arrest of arterial branchingDecreased proximal vessel sizeDecreased alveolar capillary densityIncreased vascular smooth muscle thicknessEctopic positioning of vascular smooth muscleDecreased response to vasodilating cuesIncreased circulating vasoconstrictorsCardiac defectsIncreased incidence of congenital heart diseaseDecreased size of left-sided structuresDuctal and intra-cardiac shuntRight heart dysfunction/failureAlthough abnormal diaphragm development is the defining hallmark of CDH, the high rate of mortality and the long-term disability of CDH patients are largely due to abnormal lung and pulmonary vasculature development and function, which cause lung hypoplasia and pulmonary hypertension Dillon . In CDH Normal lung development depends on the regulation of mechanical forces within the chest and lungs . HoweverGATA4 and ZFPM2 in CDH patients and mice lead to defects in diaphragm development and CDH and Slit mouse mutants. ROBO and SLIT proteins are best known for their function in axon guidance and angiogenesis limited the response of these patients to tracheal occlusion. However, reaching such a conclusion is difficult without knowing the baseline mortality rate in patients undergoing this procedure in the absence of pathogenic CNVs can be life-saving. For example, it is now common practice to maintain an open ductus arteriosus see see . In addiAlthough we have made significant advances in improving the outcomes of CDH patients \u2013 through improved prenatal diagnosis and the use of interventions such as FETO and ECMO \u2013 the morbidity and mortality of CDH remains high, especially in patients who have other associated anomalies. Advances in genomics, coupled with functional studies in animal models, are increasingly identifying the causes of CDH in both familial and sporadic cases. Through these approaches, we are beginning to elucidate the mechanisms and molecular pathways that are responsible for diaphragm and lung development abnormalities in CDH patients. A key challenge will be to understand which molecular pathways are most commonly disrupted and contribute to diaphragm and lung defects in CDH. An additional challenge will be to understand what causes the phenotypic variability and different clinical outcomes of CDH patients (or their mouse model counterparts) who share the same genetic mutation. We believe that the combined efforts of clinical investigators and developmental biologists will lead to new insights into the etiology of CDH that will improve patient prognosis and care as well as identify future targets for therapy."} +{"text": "Several imaging and neurophysiological assessments are used to characterize both neural injury and neural function after stroke. These measures can inform clinical practice, map longitudinal changes, and guide therapeutic interventions. Electroencephalography (EEG) is one technique that measures neural function and can provide detailed assessment of spontaneous and task-related cortical oscillatory function. Neural oscillations reflect synchronized activity of large populations of cortical neurons which are fundamental for network communication and information processing. Although not currently a routine clinical assessment following stroke, EEG is a sensitive measure of cortical function and subsequent neural changes resulting from brain insults such as cerebral ischemia, and therefore has potential for wider clinical use.Recently, Wu et al. investigWu et al. reportedAn important application of EEG is the ability to investigate neural oscillations in specific frequency bands. Insight into the functional significance of different frequency oscillations may provide an additional source of neurophysiological information. For example, previous stroke studies suggest delta oscillations originate from the region of the obstructed cerebral artery, reflecting reduced regional cerebral blood flow . MG is supported by an NHMRC-ARC Dementia Research Development Fellowship (1102272).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Decades of research have documented continuous tension between anthropocentric needs and the environment\u2019s capacity to accommodate those needs and support basic human welfare. The way in which society perceives, manages, and ultimately utilizes natural resources can be influenced by underlying environmental ethics, or the moral relationship that humans share with the natural world. This discourse often centers on the complex interplay between the tangible and intangible benefits associated with nonhuman nature , both of which are relevant to public health. When ecosystem degradation is coupled with socio-demographic transitions, additional concerns related to distributional equity and justice can arise. In this commentary, we explore how environmental ethics can inform the connection between the ecosystem services from green space and socially just strategies of health promotion. A transformative perspective on public health requires insight from the environmental field . From HaFor many scholars, especially economists and environmental scientists, anthropocentric conversations about nature\u2019s value typically revolve around the benefits it provides to people, which are often described as ecosystem services. Through this lens, the value of nature is often assessed through factors and processes that generate tangible outputs affecting human health and wellbeing ,8,9. SucNature provides an array of ecosystem services that highlight inextricable links between humans and the ecosystems that support their health . The ecoWhile many scholars acknowledge the fundamental importance of access to quality health care, ecosystem services from green spaces also enhance characteristics of place in ways that influence determinants of health and ultimately encourage health promotion . In theiOne of the most fundamental issues in environmental ethics is the debate regarding the valuation of nonhuman nature ,28. WhilHow might the concepts of ecosystem services and environmental ethics be integrated? In a recent study, Bull et al. conducteIn order to fully realize nature\u2019s vital role in public health, Horton et al. encouragThe environmental justice movement, which stemmed from concerns that environmental burdens were disproportionately located in minority communities and economically impoverished neighborhoods , also seA critical component underlying both environmental justice and health equity is the broader social ethics concept of distributive justice. Rawls advocateAccess to green spaces was not initially considered in traditional environmental justice research, but this paradigm has expanded to consider equitable access to parks and other health-promoting natural amenities ,48. For Simultaneous integration of these concepts can be challenging, however. In their article on ethical responsibilities related to environmental health, Jameton and Pierce outlinedOther research has examined the convergence of ethics in ecosystem and health management. Humphreys et al. articulaEnvironmental ethics and environmental justice are the transformative lenses through which ecosystem services are leveraged to yield sustainable health outcomes for individuals from all backgrounds. Cultivation of an environmental ethic may support the valuation and ultimate conservation of important ecosystem services from both anthropocentric and biocentric/ecocentric perspectives. Similarly, strengthening the ethical foundation of justice concerns can support effective policy implementation and concerns related to environmental injustice , thereby"} +{"text": "For decades, microbiologists have considered uncertainties as an undesired side effect of experimental protocols. As a consequence, standard microbial system modeling strives to hide uncertainties for the sake of deterministic understanding. For decades, microbiologists have considered uncertainties as an undesired side effect of experimental protocols. As a consequence, standard microbial system modeling strives to hide uncertainties for the sake of deterministic understanding. However, recent studies have highlighted greater experimental variability than expected and emphasized uncertainties not as a weakness but as a necessary feature of complex microbial systems. We therefore advocate that biological uncertainties need to be considered foundational facets that must be incorporated in models. Not only will understanding these uncertainties improve our understanding and identification of microbial traits, it will also provide fundamental insights on microbial systems as a whole. Taking into account uncertainties within microbial models calls for new validation techniques. Formal verification already overcomes this shortcoming by proposing modeling frameworks and validation techniques dedicated to probabilistic models. However, further work remains to extract the full potential of such techniques in the context of microbial models. Herein, we demonstrate how statistical model checking can enhance the development of microbial models by building confidence in the estimation of critical parameters and through improved sensitivity analyses. Since the work of Monod , simple Reductionist modeling approaches have generally been parameterized from data gleaned from laborious bench experiments. However, contemporary next-generation sequencing (NGS) approaches provide unprecedented characterization of the diversity of microbial communities, yet because feedbacks between biotic and abiotic systems are inherently nonlinear and complex, mathematical models of microbial guilds interacting with their environment are required. Current models have been developed along the lines of systems biology approaches , 5 or trWithin microbial models, these uncertainties can be accounted for by machine learning techniques in the validation process while improving standard validation techniques. Standard validation is usually performed using a sufficiently large number of model simulations, but the precise number is left to the acumen of the modeler, which is not a satisfying guarantee with respect to the precision and correctness of the analyses. In contrast, the precision and correctness of SMC methods are formally certified by using statistical results to compute the required number of model simulations. Moreover, SMC methods are tailored for the analysis of models that incorporate uncertainties Instead of fixing parameter values to their mean observed values and performing sensitivity analysis of one parameter at a time . ConsequModel parameters are often difficult to measure because microbial communities encapsulate an array of trait data leading to wide ranges in parameter values. Moreover, identifying a distribution of parameter values, for instance, trait parameter values for models of microbe-mediated biogeochemical processes remains a difficult task. One could overcome this difficulty by considering a slight modification of the SMC paradigm to decipher the global set of parameters (with uncertainties) that best fit the experimental data . While tUncertainties in parameter values are inherent to models built from experimental data. Instead of doing our best to rule out these uncertainties through deterministic modeling, we advocate that they should be incorporated into the models via the development of dedicated probabilistic modelings. Originally developed for software applications, statistical verification of such models will enhance the accuracy of model validation while also bringing formal evidence of the correctness of the approach. In addition, the future development of dedicated SMC methods will be the necessary steps to estimate parameter values with uncertainties, ensuring the satisfaction of desired properties, which represents the next methodological block for modeling quantitatively microbial systems from genes to ecosystems."} +{"text": "NCR (neutron capture radiography) may be used successfully for the imaging of one of the stable isotopes of a few chemical elements and for labelling experiments using these stable isotopes. Other physical techniques compete with NCR. However, NCR can remain extremely useful in a certain number of cases, because it is usually more easily done and is less expensive than the other techniques."} +{"text": "The sense of smell is a complex chemosensory processing in human and animals that allows them to connect with the environment as one of their chief sensory systems. In the field of functional brain imaging, many studies have focused on locating brain regions that are involved during olfactory processing. Despite wealth of literature about brain network in different olfactory tasks, there is a paucity of data regarding task design. Moreover, considering importance of olfactory tasks for patients with variety of neurological diseases, special contemplations should be addressed for patients. In this article, we review current olfaction tasks for behavioral studies and functional neuroimaging assessments, as well as technical principles regarding utilization of these tasks in functional magnetic resonance imaging studies."} +{"text": "Early life adversity has been identified as a potentially causal factor in the development of mental disorders. Little is known, however, about the association between various types of early life adversities and social cognitive function in adults with major psychiatric disorders, such as schizophrenia, borderline personality disorder, bipolar disorder and major depressive disorder. We conducted a systematic review aimed at elucidating possible underlying cognitive mechanisms that may form the pathway between early life adversities and social cognitive dysfunction.Relevant studies were identified via electronic and manual searches of the literature, and included peer reviewed English language articles published up to May 2017. Quality of individual articles was assessed using the quality evaluation scale.A total of 15 studies were included in the systematic review with the quality assessment scores ranging from 2 to 5 (out of 6). The majority of the studies demonstrated that various types of early life adversities, specifically physical neglect, emotional and sexual abuse and insecure attachment, are significantly associated with social cognitive function.Presented in the context of an attachment model, we conclude that childhood adversity results in poor internal working models, selective attention towards emotional stimuli and greater difficulties with emotional self-regulation. The importance of these findings for development of interventions which diminish the adverse effects of childhood maltreatment on social cognition is discussed."} +{"text": "Defining the basic mechanisms behind regeneration requires comparison to both development and homeostasis. How is organ size achieved in animals during normal development, and how is it reconstituted in animals capable of regenerating organs and body parts lost to injury? Are the mechanisms regulating size and allometry evolutionarily conserved? In recent years, discoveries in the fields of signalling, physiology, developmental biology and regeneration using a growing and diverse collection of model organisms have begun to shed mechanistic insight into these problems. Growth, central to embryonic development, tissue homeostasis and regeneration, was the unifying concept at the recent Molecular and Cellular Basis for Growth and Regeneration Keystone meeting. As a feature shared by all three states , the inclusion of growth proved highly successful, creating an inclusive, unifying and ultimately stronger meeting through its breadth and depth , the second Keystone meeting focusing on regeneration, and you find a room full of scientists applying modern technology to these age-old questions. The first regeneration meeting, in 2011, notably united work from many regenerative organisms.nd depth . While c2 to a developing story about neuromast deposition in embryonic development. The promotion of proliferation by Wnts in conjunction with the suppressive role of Notch in regeneration is notably different in early zebrafish development. Alejandro S\u00e1nchez Alvarado also used juxtaposition of development, homeostasis and regeneration to shed light on two stories, one unpublished on ontogeny of stem cells in planarian embryos (Schmidtea mediterranea) and another on mechanisms of their maintenance and repopulation under challenge in adult worms.3 Plants were represented by Kenneth Birnbaum, who discussed single cell RNAseq methods to understand patterning in regenerating Arabidopsis root tips, finding regeneration largely recapitulated embryonic developmental stages.4 In a final, beautiful example, Joachim Wittbrodt unified development, growth, and regeneration through his description of medaka eye morphogenesis using live imaging. He not only demonstrated how eye morphogenesis behaves much like gastrulation, but also explored how adult stem cells remodel during scalar lifetime growth through elegant modelling of physical constrains.5By directly comparing development and regeneration, we can begin to understand each process respective of the other. Although in the recent past we may have accepted a distinct definition of development, it is becoming increasingly clear the lines between embryonic development, regeneration, wound healing, homeostasis and even tumorigenesis are becoming significantly blurred. These interwoven relationships and framework for investigation was clearly represented at this meeting. One example came from Tatjana Piotrowski, who discussed work comparing recently published roles of Notch and Wnt in zebrafish lateral line neuromast regeneration6 Matt Gibson presented the highly regenerative sea anemone Nematostella vectensis as a key model for understanding epithelial morphogenesis and growth regulation through an evolutionary lens using live imaging. Other talks that utilised sophisticated imaging techniques include complementary talks given by Aaron Mertz from Elaine Fuch\u2019s lab and Valentina Greco. Aaron Mertz described newly published work detailing how live imaging with a spinning disc microscope revealed spatial organisation of the developing mouse epidermis.7 Valentina Greco used two photon confocal imaging to reveal striking spatiotemporal kinetics of cell migration and proliferation of intact and wounded epidermis in live adult mice.8 Elena Ezhkova shed light on the epigenetics regulating murine skin cell differentiation.9Live imaging was also used to capture regenerative responses and initiation of growth in other organisms and contexts. Ken Poss described a newly developed technique of time-lapse clonal imaging with overlaid reconstruction of multiple clones, suggesting considerable heterogeneity in adult stem cells in the regenerating zebrafish tail fin.10 How adult cells in a tissue maintain their number was addressed by Jayaraj Rajagopal, who used insult to basal lung cells in the mouse to reveal adult stem cells provide a niche for their progeny, ensuring tissue homeostasis and regeneration.11 Both Rajagopal and David Moore took this idea of plasticity and addressed growth with respect to tumorigenesis.Thinking about regenerative growth with respect to developmental growth begs another comparison: regenerative growth versus homeostatic growth control/maintenance. Maintaining or achieving homeostatic growth control is important in the context of wounding, regeneration and tumorigenesis. This universality underlines the need for a plastic response by adult somatic cells to sense their environment and respond appropriately. Like Valentina, Joseph Rodgers used response to injury in the adult mouse as a paradigm to investigate the reentry of quiescent cells into the cell cycle.hoxb1a locus in zebrafish.12 Understanding how histone modifications work to establish different transcriptional states in stem cells was addressed by Elisabeth Duncan from the S\u00e1nchez Alvarado lab in describing her work on how different H3K4 histone methyltransferases have different genomic targets in planarian neoblasts.13 Taking a macroscopic view of the nucleus, Julie Baker focused on the relationship between nuclear architecture and regeneration and presented visually striking unpublished work describing chromatin remodelling in early Xenopus wound response and regeneration. Finally, Antonio Giraldez presented compelling work from Ariel Bazzini looking at the role of codon usage in regulation of the maternal to zygotic transition in zebrafish.14 This work unveiled a novel regulation of gene expression operating through codon optimality, a concept that will likely be of great interest to many.Individual cellular behaviors underpin growth and regenerative tissue responses and, in turn, are driven by regulation of transcription and translation. Probing the mechanism of cell fate specification through transcriptional regulation, Charles Sagerstr\u00f6m discussed recent work describing how poised Tale factors control transcription of the 15 Jochen Rink also discussed work aiming to understand how long-range gradient patterning relates to scaling in planaria.In thinking about mechanisms governing growth and scaling in developmental contexts, morphogen signalling gradients often come to mind first. Eric Hill, in Chris Petersen\u2019s laboratory, addressed how Wnt and Notum contribute to brain size scaling in planaria.Drosophila. At the level of single cell division, Marco Gonzales Gaitan explained work on microtubules and diffusion-based mechanisms of asymmetric division in sensory precursor cells.16 Norbert Perrimon described unpublished work focusing on mechanical regulation of homeostasis in the gut epithelium via osmoregulation and mechanotransduction. Also on the whole tissue level, Yohanns Bella\u00efche described patterning of cell division across the dorsal thorax using a combination of large scale live imaging and modelling, revealing the Hertwig rule is enforced through tricellular junctions.17Alternatively, but not mutually exclusive to morphogen gradients, the idea of forces mediated through adhesion and cytoskeletal elements to inform and enforce growth was also showcased using several tissues in 18\u201320Expanding creatively on both large-scale modelling and the idea of forces playing integral roles in growth and patterning, L. Mahadevan described an elegant modelling approach to the relationship between form and function at the meso-scale level of organs. Work out of his laboratory focuses on spatiotemporal growth and pattern formation. Both mathematical models and diverse physical models were used to reveal the physical basis for patterning in a variety of tissues from pollen tubes to the mouse brain.21 The idea of trans-species variation also drove Richard Schneider\u2019s talk, which demonstrated through elegant neural crest cell transplants that jaw size is cell autonomous across avian species.22Taking a broader perspective, several engaging talks applied molecular mechanisms to evolutionary questions of growth, pattern, shape and function. Hopi Hoekstra commenced the meeting with an engaging keynote describing unpublished work on the mechanisms of patterning among and across rodent species.23 Elaine Ostrander also described intra-specie variation on perhaps the best documented and most relatable of examples: the many breeds of domestic dog. Her lab harnesses the benefits of large-scale comparative genomics with well-documented AKC pedigrees to uncover the molecular basis for breed differences like fur, jaw and leg length and body size.24Conversely, variation within species was addressed by Arkat Abzhanov, whose lab impressively uses a wide range of approaches from fieldwork to modelling to elucidate mechanisms of regulation in beak growth and shape in Darwin\u2019s finches.25 The second addressed a deeply fundamental question: what makes humans human? This work used comparative genomics to identify human-specific loss of regulatory DNA and then mouse genetics to demonstrate its functional consequences on the neocortex.26What can we learn by comparing adaptations within a species versus differences that define species? David Kingsley incorporated both intra- and inter-species variation into a beautiful two-part story about important roles the loss of regulatory DNA has in evolutionary changes in vertebrates. The first story described selective pressure driving drastic phenotypic changes to marine sticklebacks through loss of regulatory regions when populations are isolated in fresh water.Drosophila gut regeneration after infection with bacteria.27 In larval development, Andreas Bergman talked about work linking reactive oxygen species and immune cells known as hemocytes to apoptosis-induced proliferation in the eye imaginal disc.28 Duojia Pan discussed recent work revealing the hippo pathway functions in the innate immune response through Yorki promoting IkB transcription in a Toll-mediated bacterial response.29 In a closely related talk, Laura Johnston presented work on Toll and cell competition in the Drosophila wing.30The breadth and timeliness of this meeting captured several emerging themes. One variable that likely affects development, homeostasis, wound healing and regeneration is the immune response. A field in its own right, how the immune response affects and is integrated into growth and regeneration emerged as a high interest area. Bruce Edgar discussed the roles of Egf, Ras and MapK signalling pathways in Drosophila, as Nadia Rosenthal discussed the balancing act of inflammatory scarring versus cell replacement and regeneration in both axolotl limbs and the mammalian heart, in which macrophages have an integral role.31 Shishir Biswas, from Ashley Seifert\u2019s group, also discussed the interesting tradeoff between scarring and epimorphic regeneration in describing his current work comparing expression of the matrisome between the scarring Mus musculus and the regenerating Acomys cahirinus (African spiny mouse).The link between immunity, regeneration and growth was not limited to 32 This meeting captured several instances in which endoreplication had functional roles. Bruce Edgar discussed regulation of enterocyte endoreplication and work out of Wallace Marshall\u2019s lab from Pranidhi Sood described a single celled, macro-nucleated organism capable of regeneration, Stentor coeruleus. However, two talks really explored the relationship between ploidy and spatial problem-solving by differentiated cells. Mary Baylies discussed size and scaling of multinucleate Drosophila larval muscles, which assemble through fusion events and the positioning of their endoreplicated nuclei.33 Her presentation of polyploid nuclear spatial territories during developmental growth was a delightful juxtaposition to what happens in response to injury of post mitotic adult tissue; Vicki Losick presented elegant work in the adult Drosophila epidermis describing how ventral abdominal wounds are sealed using a combination of cell fusion/ syncytium formation and polyploidy.34Another emerging theme was the role of endoreplication in tissue growth, repair and regeneration. Despite knowledge of polyploidy for over a century, our understanding of its physiological function in diverse organisms still remains to be understood. It is clear that endoreplication is coupled to large cell size and differentiated cells, suggesting polyploidy serves some specialized function.Regeneration and growth both pose complex problems that require consideration with respect to development, homeostasis and disease to begin to fully understand how each work. The Keystone meeting on Molecular and Cellular Basis for Growth and Regeneration effectively leveraged the integration of a host of models and diverse perspectives from different fields, biological scale, and techniques to address common questions and provide a platform for integral discussion of both advances and difficulties. As we\u2019ve thankfully long passed the point of integration and overlap of scientific approach disciplines , the current challenges facing the fields of regeneration and growth (and others) are what host of tools are out there and what methods on the sliding scale of molecular to evolutionary biology can and should one apply to their own problem. It is not a surprise that some of the best new ideas come from passing comments and wildly different ideas and perspectives. The breadth of this meeting provided a stage ripe for these types of moments and showcased topics like immunity and endoreplication as areas we will need to keep in mind when approaching growth and regeneration. It will be grand to see this meeting grow further and continue to generate ideas and collaborations."} +{"text": "Multiple sclerosis (MS) is a neurodegenerative disorder characterized by an inflammatory autoimmune disease process in the central nervous system (CNS) . MS presThere is a need for development of a unified taxonomy to help define what people experience when they report fatigue , 11. An Kluger et al. presenteThe purpose of this paper is to convey the limitations of current fatigue assessments for evaluating task performance fatigability in rehabilitative settings for PwMS. Additionally, we call for the development of clinical tests which can measure the influence of state variables on the trait characteristic of performance fatigability as it relates to function and quality of life.The fatigue severity scale (FSS) and fatigue impact scale (FIS) are questionnaires of self-reported fatigue. Both tests are the current primary clinical outcome measures for objectively measuring fatigue symptoms in MS. For example, Latimer-Cheung et al. examinedHistorically, PwMS were discouraged from participating in regular exercise to avoid exacerbating fatigue . There hReframing how investigators characterize fatigue in MS may guide subsequent research efforts within this area of inquiry. Enoka and Duchateau have proIn a rehabilitative setting, clinical assessments of fatigability should be associated with functional tasks of daily living. Steens et al. , 27 haveOur stance is that the development of clinical assessments, which manipulate state variables under fatiguing tasks, is the most direct way to evaluate the trait characteristic of fatigue on functional performance. Of key importance is designing tests which can best mimic functional requirements of daily living. Current functional exams of performance in MS are not strongly associated with fatigue as a trait characteristic \u201322. TestAssessment of muscle morphology as a state variable may also provide valuable insights concerning performance fatigability. Previous work by Kent-Braun et al. and WensFurther evaluation of the impact of modulating state variables on fatigability in clinical rehabilitation settings will be challenging. The current trend of measuring multiple state variables of fatigue at once has masked the clinically significant changes that can occur through interventions . HoweverFatigue is a vague symptom that defies simple characterization. Due to this ambiguity, there is a need for quantifiable clinical measures of performance fatigability as they relate to the rehabilitation of PwMS. Assessing fatigability may be critical for understanding the relationship between an individual\u2019s function and reported fatigue symptoms. Performance-based fatigability testing provides an in-depth view of muscle function as a state variable related to activities of daily living and mobility. With focused clinical testing, rehabilitation professionals can track the response to interventions and make recommendations on specific exercise prescriptions for PwMS. Taking these steps will help clinicians guide PwMS toward the goals of minimizing debilitating fatigue, improving functional performance, and enhancing their quality of life.BS and MH-L were responsible for the conceptual idea; performed the literature review; prepared the figure; drafted the manuscript; edited and revised the manuscript critically for important intellectual content; and approved the final draft.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "We interpret this double dissociation as part of a more general phenomenon of psychic tone similarly dissociated with regard to hemispheric control, including mood, psychomotor baseline, speech rate, and even immunity. The behavioral significance of this psychic tone is to modulate approach versus avoidance behavior.Brain topographical studies of normal men have have shown that sexual excitation is asymmetric in the brain hemispheres. Group studies of patients with unilateral epileptic foci and other studies of patients with unilateral brain lesions have come to the same conclusion. The present study reviewed previously published single case reports of patients with frank hypo or hypersexuality subsequent to a unilateral brain lesion. Hyposexual patients tended to have left hemisphere lesions , and hypersexual patients tended to have right hemisphere lesions ("} +{"text": "Ovarian cancer screening has been described in scientific reports ,2,3,4, aFroyman and collaborators have assessed and compared the performance of different ultrasound-based International Ovarian Tumor Analysis (IOTA) strategies and subjective assessment for the diagnosis of early stage ovarian malignancy. This important study establishes that the approaches that are taken present a good discrimination between early stage ovarian malignancy and benign abnormalities of the ovary .Baldwin and co-investigators have realized that oophorectomy confers protection against ovarian cancer to the population that has undergone this surgical procedure. As a consequence, risk estimates of ovarian cancer must be adjusted for this protection so that true risk is not underestimated. When these adjustments were made, the rates of ovarian cancer were substantially higher when salpingo-oophorectomy was considered .Ore and associates have examined how frequently and confidently healthy women report symptoms during surveillance for ovarian cancer. They found that the frequency of symptoms relevant to ovarian cancer was more than two hundred times higher than the occurrence of ovarian cancer and that 80.1% of women expressed confidence in the symptoms they reported .Miller and her investigational team compared complications of surgical intervention for participants in the Kentucky Ovarian Cancer Screening Program to results from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial (PLCO). They report that complications resulting from surgery performed in the Kentucky Ovarian Cancer Screening Program were infrequent and significantly fewer than reported in the Prostate, Lung, Colorectal and Ovarian Cancer Screening trial. Complications observed were mostly minor (93%) and were more common in cancer versus non-cancer surgery .Ormsby and collaborators present arguments in favor of serial ultrasonography as an alternative to immediate surgery so that any benign abnormality will have the opportunity to resolve. Ultimately, this report presents arguments relative to the benefits of surveillance .Ed Pavlik presents ten critical considerations for ovarian cancer screening, some of which have not been realized in published ovarian screening study reports. These considerations are presented in depth along with illustrations of how they impact the outcomes of ovarian cancer screening trials. These considerations highlight effects that have an important bearing on ovarian screening outcomes and their interpretations .Michael Andrykowski presents considerations that have psychological and behavioral impacts on individuals participating in ovarian screening. His findings suggest that a \u201cnormal\u201d screening test result can have psychological benefits, including increased positive affect and beliefs in the efficacy of screening. Moreover, any psychological or behavioral harms attributable to ovarian cancer screening are generally very modest in severity and duration, and might be counterbalanced by psychological benefits accruing to women who participate in routine ovarian cancer screening and receive normal test results .Koshiyama and collaborators present current issues that are related to ovarian cancer and screening. They report that the efficacy of ovarian cancer screening may be higher in Asia than in Europe and the USA. These investigators review the re-analysis of PLCO screening data when cancers presenting more than one year after screening are excluded and show a significant survival benefit in the PLCO screening. They highlight their views by considering the difficulties of detecting Type II ovarian carcinomas .Chris Smith examines the effects that ovarian cancer has on patients and their families. The rigors of treatment conspire with the inevitability of recurrence in the eyes of this first year resident in Obstetrics and Gynecology. He postulates that in the absence of effective therapies, early detection holds the greatest promise .Fred Ueland relates the 50 year history of biomarkers and ultrasound in the context of ovarian cancer. He emphasizes the serial application of both biomarkers and ultrasound. Importantly, he looks to what the future may bring with regard to the utilization of biomarkers and ultrasound in routine patient exams .Taken together, these authors have provided both original data and overviews of ovarian cancer screening studies that enhance the present interpretation of this type of screening."} +{"text": "Although histomorphology has made significant advances into the understanding of cancer etiology, classification and pathogenesis, it is sometimes complicated by morphologic ambiguities, and other shortcomings that necessitate the development of ancillary tests to complement its diagnostic value. A new approach to cancer patient management consists of targeting specific molecules or gene mutations in the cancer genome by inhibitory therapy. Molecular diagnostic tests and genomic profiling methods are increasingly being developed to identify tumor targeted molecular profile that is the basis of targeted therapy. Novel targeted therapy has revolutionized the treatment of gastrointestinal stromal tumor, renal cell carcinoma and other cancers that were previously difficult to treat with standard chemotherapy. In this review, we discuss the role of histomorphology in cancer diagnosis and management and the rising role of molecular profiling in targeted therapy. Molecular profiling in certain diagnostic and therapeutic difficulties may provide a practical and useful complement to histomorphology and opens new avenues for targeted therapy and alternative methods of cancer patient management. The management of patients with cancer has always been a challenge to those working in the healthcare field. Despite significant research and practical advances that were made over the past few decades, the war against cancer is far from being over. Classic approaches to cancer treatment include a combination of surgery, radiotherapy, chemotherapy and hormonal therapy. With modern techniques and therapeutic options, the mortality and morbidity from cancer have decreased significantly in the past two decades. However, problems of therapy resistance and tumor progression and recurrence still plague many cancer survivors. The current treatment approach is based on a diagnosis of cancer that is rendered after pathologic analysis of the tumor and its characteristics. The process of histopathologic visualization of tumor cells, herein referred to as histomorphology, is the cornerstone of the pathologist labeling of a tumor as carcinoma, sarcoma or melanoma and is the basis of cancer treatment Advances in histopathology, which were largely fueled by curiosity regarding tumor morphology, have led to the development of an array of pathologic nomenclatures and classifications of different tumors.KIT mutations and related genetic aberrations in gastrointestinal stromal tumor (GIST), chronic myeloid leukemia and other c-kit expressing tumors. In many instances, the presence of KIT mutations in a tumor is equivalent to responsiveness to imatinib mesylate. Targeting KIT or other tyrosine kinase receptors has been at the epicenter of this exponential genomic research, and has opened new avenues in cancer classification and management.In the past few decades, numerous research discoveries have been made in identifying genetic aberrations that have resulted in better understanding of the pathogenesis of malignancies and have allowed for more refined tumor diagnosis. The demonstration of specific genes mutations, fusion transcripts and chromosomal translocations has been of pivotal importance in the diagnosis of numerous cancers particularly sarcomas, some other solid tumors, lymphomas and leukemias. Genetic events in tumors result in the over-expression of signaling transduction pathways that regulate tumor proliferation, growth and spread. The link between genetic aberrancies and activation of signaling pathways and the mapping of different growth factors and their receptors have been elucidated in many tumors. These advances have allowed for more accurate diagnosis as well as exploration of novel therapeutics that target these genetic events and signaling pathways. The research on targeted therapy was sparked by discovery of imatinib mesylate and its broad anti-tumor effects , 2. ThisHistomorphology is an ancient technique that has been essential in the identification and the diagnosis of all types of benign and malignant tumors. A portion of the patient's tumor tissue is fixed for several hours and subjected to histological processing technique that includes paraffin-embedding, microtome-sectioning and staining with hematoxylin and eosin stains that pathologists have been using for over a century , 4. The in situ hybridization and digital pathology, all of which still rely on histomorphology and have added extra costs to patient's care [Histomorphology has been valuable in the assessment of tumor topography and cellular morphology and in the classification and nomenclature of variety of disease entities. It also adds value to patients' management by identifying certain prognostic indicators such as lymphovascular invasion, infiltration of adjacent organs, necrosis, and mitotic rate. However, since the invention of light microscope in the sixteenth century and the discovery of hematoxylin and eosin stains more than a century ago, the process of histomorphology has remained as such without much change , 4, 6, 7t's care , 9. FurtCancer diagnosis often requires ancillary tests, such as immunohistochemistry and flow cytometry. These tests are performed in independent laboratory settings that incur additional costs. Immunostained slides and special stains typically cost the patient approximately $50 per single slide for in-house tests and an average of $200 per send-out test [There is no clear and direct scientific relationship existing between the tumor morphology and the response to therapy. The current classification of tumors vastly depends on histomorphology which has hampered any novel attempt to reclassify disease process or substantially develop new avenues in patient's management. Classifying malignancies into benign and malignant is sometimes ambiguated by the concepts of intermediate tumors, low grade malignancies, very low risk cancers and other tumors of variable clinical behaviors.Some pathologists and treating physicians regard cancers as discrete morphologic entities whereas, in reality, cancer is a continuous disease process. Attesting to the latter fact, are the recent classifications of new diagnostic entities with intermediate morphological features that fall between two classic entities, such as ganglioneuroblastoma, B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, B-cell lymphoma with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and transitional liver tumors that resemble hepatoblastoma and hepatocellular carcinoma \u201313. ExamCancer histomorphology has become increasingly complex. Over the past few decades, the complexity of pathologic classification of cancers and the more vivid description of histomorphologic variants have substantially increased, fueled in part by the accumulation of rare consultation cases. Good examples include papillary thyroid carcinoma that has 12 variants, meningioma with 15 morphologic variants, and invasive breast carcinoma which has 20 described morphologic subtypes . The subInterpretation of histopathologic specimens can be subjective. A variable degree of discordance exists among pathologists in the interpretation of specimens depending on the specimen type and the expertise of the pathologist. A recent study published in the Journal of American Medical Association (JAMA) has reflected on the high degree of disagreement among breast pathologists and on the fact that their diagnosis may exhibit an inter-observer variability in up to 25% of cases . The appEWS/FLI1 chromosomal translocation and KIT/PDGFR mutations are indispensable in confirming the diagnosis of Ewing's sarcoma and GIST respectively. Furthermore, molecular tests often provide valuable information about the patient's prognosis and expected survival outcome. Combination of molecular and immunohistochemical tests has resulted in the molecular subclassification of medulloblastoma and breast cancer [FLT3 mutations in acute myeloid leukemia, exon 11 mutations in GIST tumors and alpha thalassemia x-linked protein (ATRX) and isocitrate dehydrogenase expression in brain gliomas is clinically useful to identify aggressive cancers of different prognosis and help guide appropriate chemotherapy [Molecular cancer studies have expanded beyond understanding tumor pathogenesis to the clinical laboratory setting where tests are occasionally requested to assist in the diagnosis of various tumors and aid in the patient's management. The identification of specific genetic events in tumors has fueled the development and rapid growth of molecular diagnostic tests that are based on polymerase chain reactions, immunohistochemistry or other simple techniques. The identification of t cancer . The ideotherapy \u201319. Thesotherapy . NotwithEWS gene rearrangements in Ewing's sarcoma, desmoplastic round cell sarcoma, extraskeletal myxoid chrondrosarcoma, myxoid liposarcoma, clear cell sarcoma and several other cancers [KIT mutations and KIT protein expression has been identified in numerous tumors including GIST and other tumors unrelated to GIST [SMAR CB1 (INI-1) deletions are increasingly being identified in multiple tumors [ALK-rearranged, KIT-mutated, EWS-rearranged, and INI-1 deleted. Similarly, the identification of translocations and shared gene signatures has provided for the reclassification of rhabdomyosarcomas (RMS) into fusion-positive RMS and fusion negative-RMS, which includes embryonal RMS and fusion negative alveolar RMS [The expansive research into cancer genetic background has led to the identification of shared genetic events in tumors with diverse histologic appearances. These findings have prompted researchers and pathologists to consider classifying these tumors according to their \u201cgenomic signature\u201d or \u201cgenetic profile\u201d. A good example is the identification of cancers Similarly to GIST . Such tue tumors . Thus, tolar RMS . Table 1KIT mutations occur in benign entities such as mastocytosis as well as malignant tumors such as GIST. These tumors are treated differently regardless of the underlying genetic events. In these instances, identifying molecular events, without histomorphology, cannot predict the tumor's biologic behavior.An interesting observation is that some genetic mutations are identified among tumors of various biologic behaviors including benign tumors, low grade and high grade malignancies. Targeted therapy is based on the inhibition of up-regulated mutational events and signaling pathways in cancers. Numerous cell growth factors and their receptors converge on the PI3K/Akt/mTor pathway and other intracellular pathways, which are widely activated in numerous cancers . PreclinIn most cases, targeted therapy is offered to patients after the failure of routine or standard chemotherapy. Clinical trials are commonly conducted on patients previously heavily treated by conventional chemotherapy or on patients whose tumors have progressed despite adequate chemotherapy. In few instances, initial treatment with targeted therapy is offered for tumors which are considered to be resistant to conventional chemotherapy. In this regard, targeted therapy has revolutionized the treatment of renal cell carcinoma and GIST , 28. TheBCR/ABl translocation in chronic myeloid leukemia, and KIT mutations in imatinib-responsive GIST [BRAF mutation testing for variable tumors like melanoma and craniopharyngioma and anaplastic lymphoma kinase (ALK) inhibitors and epidermal growth factor receptors in various subtypes of lung cancer [Not all tumors respond to the same targeted therapy and thus predictive tests are needed to identify patients and tumors that are most likely to respond to that particular inhibitory therapy . This seive GIST . Additiog cancer , 33.Numerous other tumors are lagging behind in the discovery and standardization of similar predictive tests. Immunohistochemical tests provide some promise as predictive tests Figure but lackBiologic pathways and genetic events in cancers are multiple and reveal complex interactions that affect tumor pathogenesis at different levels including initial tumorigenesis, sustained proliferation, inhibition of apoptosis, invasion and metastasis. Each tumor is expected to over-express specific genetic components or biologic pathways that are unique to the tumor, i.e. \u201cmolecular profile\u201d. However, standard genomic or molecular profiling yields massive amount of data that are non-essential and difficult to decipher and less than 20% of such data can be described as clinically relevant . Only a Molecular profiling has been used in large clinical centers for the targeted therapy treatment of tumors that are resistant to standard chemotherapy, progressed or metastasized despite adequate chemotherapy and in patients who do not tolerate standard chemotherapy . In suchversus malignant tumors with high accuracy in all cases but can significantly complement tumor morphology in the overall diagnostic and therapeutic assessment of cancer.Molecular profiling can also offer insight into tumor classification. For example, osteosarcoma and Ewing's sarcoma and a variety of other sarcomas over-express IGF1R. Hence, these tumors can grouped together and treated with IGF1R inhibitors , 51. TheResistance to treatment is a common phenomenon in treating patients with cancer and can develop de novo or during the course of treatment. The development of targeted therapy has also been confounded by resistance that extended to the use of second- or third-generation molecular therapies. Although resistance to targeted therapy may be due to several pharmacologic and molecular aberrations within the tumor cells, the delay in starting such treatment until failure of previous chemotherapy may account for some of the de novo resistance mechanisms. However, an option exists for initiating targeted therapy based solely on the tumor's TMP and without prior chemotherapy. Targeted therapy is frequently considered as the last reserve in the fight against cancer and has seldom ever been tested as an initial treatment choice. Initiating treatment with targeted therapy in lieu of standard chemotherapy has been accomplished in the treatment of gastrointestinal stromal tumors, renal cell carcinomas and few other tumors that are known to be natively resistant to standard chemotherapy , 28. FolThe use of imaging technologies such as Computed Tomography and Positron Emitted Tomography has already influenced early cancer detection and management . Future The use of molecular diagnostic tests provides a strong argument for evidence-based practice of medicine and yields a logical correlation between the molecular profile and response to targeted therapy. In combination with histomorphology, these methods can significantly complement cancer diagnosis. Non-histologic molecular diagnostic tests can be performed on the patient's tumor tissue directly or on cells harvested from body fluids and include techniques based on DNA/RNA, protein assay methods, and biologic assay methods Figure . Next geIn cancer management, the toxicity and related healthcare costs associated with the use of personalized targeted therapy are less pronounced than those of standard chemotherapy. Serious toxicities have been rarely reported, that generally reflected poor patient selection due to lack of reliable predictive tests. The selective use of cancer agents directed against a specific molecular target on cancer cells has been reported to be associated with a lower incidence of toxicity and lower healthcare costs compared with the use of less-specific targeted agents, including general angiogenesis inhibitors and chemotherapeutic agents . Thus, tConceivably, the use of molecular diagnostic tests is currently associated with the requirement for large amounts of tissue that are needed for different techniques, including precious fresh or frozen tumor tissue . In contThe high cost and the lengthy turnaround time have thus far limited the widespread use of next generation sequencing platforms and their clinical applications. The price cost of DNA sequencing and microarray tests is currently fairly high , and varPDGFRB rearrangement\u201d, B-cell lymphoma with IRF4 rearrangement and high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement [Given the drawbacks in cancer histomorphology and molecular profiling, there are currently no perfect methods to guide cancer treatment. However, the field of therapeutic pathology and its role in the treatment of cancer is continually evolving. Cancer histomorphology will likely continue to be the basis of cancer diagnosis and management and reconcile with the growing trend in molecular diagnosis and targeted therapy by offering a combined or integrated tumor classification scheme. A more affordable approach would be to limit molecular testing to the identification of certain therapeutic and prognostic biomarkers. In this scheme, a basic morphologic cancer diagnosis is followed by ancillary immunohistochemical or other tests that may offer prognostic or therapeutic information Figure . The Colangement . While tComprehensive molecular profiling based on next generation sequencing methods is currently routinely not practical but may be helpful in certain clinical situations:To detect targetable mutations in otherwise difficult to treat, chemoresistant or metastatic tumors. In these cases, identifying tumor TMP from metastatic specimens is more important than tumor profiling from initial diagnostic specimens . The praTo provide targetable options for tumors than could not be histologically adequately classified. In these situations, targeted therapy may be offered as an initial treatment option. This is particularly helpful in pediatric cancers where the robust genomic sequencing methods have helped solve the diagnostic odyssey and alleviate parents' anxiety \u201382. SeveTo determine the origin of a metastatic tumor of unknown primary , 87. GenTo provide a refined diagnosis in cases of undifferentiated malignancies. In a recent transcriptome analysis of 19 undifferentiated sarcoma of the thorax, identifying SMARCA4 mutations has placed these tumors along with malignant rhabdoid tumors rather than lung carcinomas .To detect circulating genetic material or tumor cells in liquid biopsies from patients with metastatic disease ;versus histomorphology in the management of cancer patients. However, with wider availability of molecular tests and development of successful targeted therapy, the role of cancer histomorphology may gradually decrease giving way to laboratory-based molecular tests that may be interpreted by molecular pathologists and non-MD scientific personnel.With future advances in test costs and turnaround time, tumor profiling methods may become more affordable and practical and offer more opportunities in therapeutic pathology. There are at the present not enough data to show the life cost benefit of pure molecular profiling The development and applications of cancer profiling methods will be the cornerstone of targeted cancer research offering novel methods of cancer classification and treatment. Comprehensive or limited cancer profiling offers an alternative approach to treat patients with difficult cancers and can supplement or supersede classical management methods such as histomorphology and chemotherapy. The success of this approach will be further appreciated through the growing research in targeted therapy and the development of accurate and less expensive molecular diagnostic tests that accurately predict the response to targeted therapy. Given the rapid pace in which advances in tumor diagnostics are expanding, pathologists, researchers and clinicians should be willing to consider novel ways of approaching cancer treatment."} +{"text": "Patient satisfaction with healthcare has clear implications on service use and health outcomes. Barriers to care seeking are complex and multiple and delays in seeking care are associated with significant morbidity and mortality. We sought to assess the relationship between water, sanitation and hygiene (WASH) provision in healthcare facilities (HCF) and patient satisfaction/care seeking behaviour in low-income and middle-income countries. Pubmed and Medline Ovid were searched using a combination of search terms. 984 papers were retrieved and only 21 had a WASH component warranting inclusion. WASH was not identified as a driver of patient satisfaction but poor WASH provision was associated with significant patient dissatisfaction with infrastructure and quality of care. However, this dissatisfaction was not sufficient to stop patients from seeking care in these poorly served facilities. With specific regard to maternal health services, poor WASH provision was the reason for women choosing home delivery, although providers\u2019 attitudes and interpersonal behaviours were the main drivers of patient dissatisfaction with maternal health services. Patient satisfaction was mainly assessed via questionnaires and studies reported a high risk of courtesy bias, potentially leading to an overestimation of patient satisfaction. Patient satisfaction was also found to be significantly affected by expectation, which was strongly influenced by patients\u2019 socioeconomic status and education. This systematic review also highlighted a paucity of research to describe and evaluate interventions to improve WASH conditions in HCF in low-income setting with a high burden of healthcare-associated infections. Our review suggests that improving WASH conditions will decrease patience dissatisfaction, which may increase care seeking behaviour and improve health outcomes but that more rigorous research is needed. A WHO/Unicef report (2015) highlighted the lack of adequate water, sanitation and hygiene (WASH) provision in many healthcare facilities (HCF)\u00a0in low-income and middle-income countries (LMIC).Patient satisfaction and care seeking behaviour have been extensively used to monitor and improve the quality of care.The evidence on the contribution of poor WASH to patient dissatisfaction and care seeking behaviour is unclear.This systematic review sought to assess the relationship between WASH in HCF and patient satisfaction/care seeking behaviour in LMIC.Our findings showed that WASH status was not the main driver of patient satisfaction as other factors were more significant to users.Nevertheless, poor WASH provision was associated with significant patient dissatisfaction and stopped women from seeking care at maternity services.This is the first systematic review to be published on this topic.Inadequate WASH provision in HCF in LMIC may increase the risk of healthcare-associated infections (HCAI).Beyond the HCAI burden, poor WASH provision may increase patient dissatisfaction and limit care seeking behaviour, leading to adverse health outcomes.Improving WASH provision in HCF should be prioritised as a means of addressing HCAI but also to address patient satisfaction and encourage timely care seeking.Global best practice guidelines combined with concerted action at the national policy level would support progress in ensuring adequate WASH provision in HCF in LMIC.The water, sanitation and hygiene (WASH) attributable burden of disease is large and concentrated within low-income and middle-income countries (LMIC). A total of 842\u2009000 diarrhoeal disease deaths were attributed to inadequate WASH in 145 countries.4\u20136Healthcare-associated infections (HCAI) are a major challenge in LMIC, where it has been estimated that the risk is 2\u201320 times higher than in developed countries.The barriers to care seeking are characterised using the three delays model developed by Thaddeus and Maine19Care seeking barriers are multiple and include caretakers\u2019 failure to identify early danger signs that should trigger appropriate care\u00a0seeking behaviour, cost , distance to the facility, impediments related to weather or social unrest, lack of supervision for other children at home, lack of transport and, particularly relevant to this review, dissatisfaction with the quality of care.The review methods are reported in accordance with the \u2018Preferred Reporting Items for Systematic Reviews and Meta-Analyses\u2019 (PRISMA)10.1136/bmjgh-2017-000648.supp1Supplementary file 1Pubmed and Medline Ovid were searched in March 2016 for articles published in English after the year 2000 using the search terms outlined in Relevant data were extracted from all included papers using a standardised form. These data were: geographic location, type of study, type of healthcare facility, intervention (if any) and main findings. All quantitative and qualitative findings were recorded. Data were summarised narratively and no meta-analysis was conducted because of the heterogeneity between studies and use of different indicators of patient satisfaction.This systematic review assessed the effect of WASH in HCF on two quality of care outcomes: patient satisfaction and care seeking behaviour. Although WASH was rarely the primary focus of the included studies, all included some assessment of WASH conditions in HCF and their impact on patient satisfaction and/or care seeking behaviour.The search strategy retrieved 984 articles . After rThe level of satisfaction with WASH provision was reported in most studies. However, some studies reported on composite indicators of patient satisfaction and these were also noted. The papers were categorised according to the type of healthcare system, in particular, findings for maternity services were presented separately. Additionally, three papers investigated improvement interventions.Several papers reported patient dissatisfaction rates with WASH in non-maternal health service. Woldeyohanes and colleagues assessed patient satisfaction with in-patient services in Ethiopia and reported 81.5% were dissatisfied with toilet cleanliness .25 A stuKhamis and colleagues investigated patient satisfaction with quality of care in an outpatient department in Tanzania using perception and expectation questions and calculating mean gap score between the two components.30Mohammed and colleagues assessed the responsiveness of healthcare services for insured patients in Nigeria.32In a study investigating quality of care and contraceptive use in Kenya, 78.5% of facilities had running water; however, facility infrastructure and patient satisfaction indicators were not associated with contraceptive use.Glick investigated the reliability of exit surveys frequently used to assess patient satisfaction.34Nine out of 21 studies focused on WASH conditions specifically around maternal health services, covering antenatal, delivery and postnatal care. Srivastava and colleagues conducted a systematic review investigating determinants of women\u2019s satisfaction with maternal healthcare in developing countries and covered all three dimensions: structure, process and outcome.35Steinmann and colleagues assessed women\u2019s satisfaction with latrines and hand washing stations in rural India and their impact on care seeking behaviour.36Mbwele and colleagues investigated the quality of neonatal healthcare in Tanzania.39Gabrysch and colleagues reported that women criticise dirty toilets, lack of water and aseptic practices, highlighting combined shortcomings in personal interaction, medical care and hygiene.34Developing accreditation standards in Ugandan hospitals was investigated by Galukande and colleagues.One paper investigated a criteria-based audit to improve a maternity unit in Malawi, where an initial audit resulted in the formulation of recommendations and a second audit 3\u2009months later would report on any observed improvements.45Patient satisfaction is a good indicator of quality of care provided and impacts on care seeking behaviour. In the reviewed studies, inadequate WASH in HCF was associated with increased patient dissatisfaction and was even a barrier to service use in some settings (most notably maternity services). This systematic review of current evidence has informed a conceptual model of patient dissatisfaction, detailing relevant factors and repercussions of low patient satisfaction . In thisThe limitations of this study include a relatively small publication window (2000\u20132016), which was chosen to exclude historic (or outdated) WASH provision and a search strategy that could have been further optimised to retrieve all relevant papers. Potential further limitations are the difficulty of retrieving eligible LMIC research, likely to be published in national journals not indexed in the databases searched and studies are not necessarily indexed properly (particularly regarding LMIC status/country\u2009affiliation). Finally, the studies included were mostly cross-sectional with potentially biased outcome measures and perhaps more importantly no study designed to specifically assess the causal effect of WASH provision on patient satisfaction and/or care seeking behaviour was found. The limitations of some of the included studies are related to study design, such as small sample size, lack of randomisation and patient recruitment procedures, as well as outcome measures such as heterogeneous indicators of patient satisfaction and potentially biased findings.This review focused on WASH and patient satisfaction/care seeking because of the large disease burden associated with delayed care seeking. The link between perceived quality of care and attendance at HCF was supported by several studies and the WHO recommends the evaluation of patients\u2019 satisfaction for the improvement of HCF.44The evaluation of patient satisfaction is usually performed using patient questionnaires, administered at either the HCF or households. It has been shown that exit questionnaires tend to overestimate patient satisfaction level due to courtesy bias .47The availability of skilled birth attendants is crucial to provide emergency obstetric care and reduce maternal and newborn mortality.The importance of WASH in HCF extends beyond patient satisfaction and care seeking behaviour because inadequate WASH may also be associated with a significant burden of HCAI. Poor sanitary conditions and hand hygiene in hospital settings would result in several gastrointestinal and opportunistic infections. Unfortunately, poor hand washing practices around birth are still prevalent and continue to pose risks to mother and baby. In an observational study, the proportion of birth attendants who washed their hands prior to assisting with delivery was 24% in India, 69% in Bangladesh and 32% in Nepal.The provision of adequate WASH in HCF is important to protect vulnerable populations and reduce HCAI. However, WASH provision is still inadequate in many HCF in LMIC. This systematic review assessed the impact of WASH provision on care seeking behaviour and patient satisfaction. Our review suggests that improving WASH conditions will decrease patience dissatisfaction, which may increase care seeking behaviour and improve health outcomes but that more rigorous research is needed."} +{"text": "The immune pathogenesis story of schizophrenia is gathering momentum, with increasing evidence from genetic, circulating biomarker and neuropathological studies. New treatment approaches are being trialled. However immune dysfunction is not unique to schizophrenia, and circulating proinflammatory biomarkers identified in schizophrenia have also been identified in bipolar disorder and major depressive disorders. Similarly, in recent times there has been an increasing recognition of commonality across categorical diagnoses at a symptom level; as RDoC criteria acknowledge. For example, depressive symptoms are common in schizophrenia, hallucinations and delusional beliefs common in mood disorders and anhedonia a cross diagnostic challengeThis presentation will include data of altered circulating pro-inflammatory markers from recently completed meta-analysis in first episode psychosis, established schizophrenia and bipolar disorder, highlighting the potential pluripotent inflammation pathway to mental disorders and outline a circulating cytokine profile at the onset and development of mental disorder as related to symptom specific profiles.Data on circulating inflammatory makers as related to symptom profiles cross-sectional and longitudinally will also be presented from the recently concluded NIHR funded BeneMin (The Benefits of Minocycline on negative symptoms in early phase psychosis) study.Future research should recognise co-morbidity, adopt a dimensional approach, or investigate symptom specific biomarkers at early stages of illness with numbers large enough to explore an immune specific clinical profile. This knowledge is essential in the developing story of inflammation and psychosis with the most potential in decades to translate into tailored effective treatment options."} +{"text": "The development of nanoscale molecular probes capable of diagnosis, characterization, and clinical treatment of disease is leading to a new generation of imaging technologies. Such probes are particularly relevant to inflammation, where the detection of subclinical, early disease states could facilitate speedier detection that could yield enhanced, tailored therapies. Nanoparticles offer robust platforms capable of sensitive detection, and early research has indicated their suitability for the detection of vascular activation and cellular recruitment at subclinical levels. This suggests that nanoparticle techniques may provide excellent biomarkers for the diagnosis and progression of inflammatory diseases with magnetic resonance imaging (MRI), fluorescent quantum dots (QDs), and surface enhanced Raman scattering (SERS) probes being just some of the new methodologies employed. Development of these techniques could lead to a range of sensitive probes capable of ultrasensitive, localized detection of inflammation. This article will discuss the merits of each approach, with a general overview to their applicability in inflammatory diseases."} +{"text": "Key to this process is a critical balance of intrinsic developmental patterning and context-dependent environmental signaling events that configures astrocyte phenotype. Indeed, emerging lines of evidence indicate that persistent cues from neighboring cells in the mature CNS cooperate with early patterning events to promote astrocyte diversity. Consistent with this, manipulating Sonic hedgehog (Shh), Notch and fibroblast growth factor (FGF) signaling in the adult brain, have profound effects on the structural, morphological and physiological state of mature astrocytes. These pathways may become disrupted in various neurological diseases and contribute to CNS pathology. This mini-review article focuses on how context-dependent environmental cues cooperate with intrinsic developmental patterning events to control astrocyte diversity in vivo in order to promote healthy brain function.Astrocytes play essential roles in nearly all aspects of brain function from modulating synapses and neurovasculature to preserving appropriate extracellular solute concentrations. To meet the complex needs of the central nervous system (CNS), astrocytes possess highly specialized properties that are optimized for their surrounding neural circuitry. Precisely how these diverse astrocytes types are generated Astrocytes are critical non-neuronal cells of the central nervous system (CNS) that maintain precise environmental conditions for neurons and their connections. The complex structural and molecular properties of astrocytes enable these cells to play major roles including extracellular ion maintenance, neurotransmitter recovery and regulation of cerebrovasculature. Of particular interest for this mini-review article is the protoplasmic astrocyte which has a sponge-like appearance and closely interfaces with neurons, synapses and cerebrovasculature. These cells are extremely complex, enveloping neuronal cell bodies and synapses with fine processes, and surrounding blood vessels with endfeet. These processes are loaded with specific molecular machinery allowing these cells to fulfill many functions including removing neurotransmitters and ions, secreting neuroactive substances that regulate synapses, regulating energy substrates and exchanging nutrients with vasculature.Astrocytes were initially defined by their star-shaped morphology in the 19th century. Today, however, it is more greatly appreciated that astrocytes display an array of morphological and functional features that reflect the brain circuitry in which they surround. In some regions of the CNS, astrocyte morphology is so dramatically different that it can be used to identify the boundaries of anatomical regions of the retina show a number of specific properties tailored to retinal function such as fluid transport and protecting the system from oxidative stress during photoreception of the cerebellar cortex are another example of an astrocyte that deviates from the classical star-shaped morphology. BG are morphologically polarized astrocytes with their soma closely associated with those of neighboring Purkinje cells (PC). Elaborate processes extend through the molecular layer (ML) and envelope synapses within the dense neuropil of the ML. Along with their unique morphology comes a specialized gene expression profile optimized for dealing with the dense glutamatergic innervation of the ML. BG express high levels of proteins used to detect and manage extracellular glutamate including the glutamate transporters EAAT2/GLT1 and EAAT1/GLAST as well as calcium permeable ionotropic glutamate receptors composed of GluA1 and GluA4 subunits. The expression of AMPA receptors is required for BG detection of glutamate and fine motor coordination is the central regulator of circadian rhythm. Cell-autonomous cycles of gene expression define the 24-h cycle in the absence of external cues. Recent findings show that astrocytes of the dSCN are critical regulators of the length of the circadian cycle and bone morphogenetic protein (BMP) segregate the spinal cord into defined progenitor domains. Each progenitor domain gives rise to sequential populations of neurons and astrocytes with specific properties and locations . BG and VAs are derived from the same progenitor pool signaling pathway is involved in many processes including the morphological elaboration of drosophila astrocytes generating further astrocyte diversity; and (2) maintaining healthy, non-reactive astrocyte phenotypes. Further studies are needed to understand the fine balance between these scenarios and reveal potential new mechanisms allowing astrocytes to transition from a healthy to a disease state. Ultimately, understanding how astrocyte heterogeneity is generated will allow us to better understand fundamental properties of the CNS and potentially improve brain/spinal cord function following injury or disease.WTF conceived, researched and wrote this review. KM assisted in writing and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer HH and handling Editor declared their shared affiliation."} +{"text": "Over the years, the role of the radiologist within the multidisciplinary team has evolved remarkably, with imaging providing crucial information for patient management. Through close collaboration with referring clinicians, most radiology practices now strive for their radiology reports to provide the maximum value for individualized patient care . TherefoIn general, structured reporting allows information to be more easily extracted and improves communication with clinicians. In addition, the use of structured reporting reduces ambiguous terms and errors due to use of speech recognition systems, typically seen with narrative reports, which could lead to misinterpretation and in turn impact patient management . FurtherAiming at enhancing the quality and efficiency of radiology reports, the Radiology Society of North America (RSNA) and the European Society of Radiology (ESR) have jointly formed the Template Library Advisory Panel (TLAP) . TLAP prSeveral studies have analyzed the value of structured reporting, most of them focusing on various oncological applications \u20137. BrookThe study by Franconeri and colleagues investigTemplate reporting improves the consistency of radiology reports and assures a terminology accepted by everyone involved in patient care. Selection of the clinically important features that determine patient management and treatment selection is crucial and best done in consultation with the clinical management team. In fact, the study by Franconeri and colleagues proves t"} +{"text": "Instability of the knee is a common finding in patients with congenital limb deficiency. The instability can be attributed to soft tissue abnormalities, frontal, sagittal or rotational deformity of the lower limb and bony dysplasia of the patella or of the femoral condyles. In most of the cases, these pathomorphologic changes stay asymptomatic in daily activity. However, instability can appear during deformity correction and bone-lengthening procedures, leading to flexion contracture or subluxation of the knee.A review of pediatric orthopaedic literature on different factors of knee instability, state-of-the-art treatment options in congenital limb deficiency and in cases of lengthening-related knee subluxation is presented and the authors\u2019 preferred treatment methods are described.Leg lengthening and deformity correction in patients with congenital limb deficiencies can be achieved with various techniques, such as guided growth, monolateral or circular external fixation and intramedullary lengthening nails. Radiographic assessment and clinical examination of the knee stability are obligatory to estimate the grade of instability prior to surgical procedures. Preparatory surgery, as well as preventive measures such as bracing, bridging of the knee and intensive physical therapy, can help to avoid subluxation during lengthening in unstable knees.Adequate surgical techniques, preventive measures and early detection of signs of subluxation can lead to good functional results in patients with congenital limb deficiency. An unstable knee can be observed in various congenital deformities and appears to be one of biggest challenges in deformity correction and lengthening.Congenital deformities which result in knee instability are longitudinal deficiencies such as congenital femoral deficiency (CFD) and fibular hemimelia (FH) or tibial hemimelia. Depending on the severity of the deficiency, the instability can be detected in early infancy or later during life, sometimes without clinical significance.The correction of axial malalignment and leg length discrepancy is crucial in the treatment of patients with congenital longitudinal deficiencies. Severe deformities such as valgus or varus deviations, as well as rotational malalignment, can exaggerate knee instability and maltracking of the patella.Children with severe CFD and FH may need multiple deformity correction or lengthening procedures during growth to reduce axial malalignment and leg length discrepancy. Various methods such as monolateral fixators, circular hexapod fixators and intramedullary lengthening nails have been developed. However, irrespective of the applied lengthening method, knee instability in congenital limb deficiency can unmask and can lead to knee subluxation as a severe complication.Prevention of subluxation during lengthening in patients with congenital knee instability can be achieved with bridging of the knee with monolateral or circular fixators. Intensive physical therapy and bracing may prevent knee subluxation during lengthening using intramedullary nails.As mild knee subluxation can easily go unrecognised on X-rays , clinicaCommon classifications of congenital limb deficiency are the classifications according to Paley and Standard and PappIn CFD and FH, specific pathomorphologic changes of the knee have been described . PotentiSome authors estimate that 95% of FH have an absent ACL . AbnormaManner et al. developeOther authors made similar findings regarding the ACL and PCL changes in CFD and FH , 10.Besides these pathomophologic changes within the knee, the knee stability is also influenced by axial malalignment with severe valgus deformity increasing maltracking of the patella and hyperlaxity of the overused medial collateral ligaments.daily activity in most of the cases of CFD and FH [It remains unclear which patients with CFD or FH suffer from knee instability in daily activity or mild sports activity. Despite the pathoanatomy and signs of instability in physical examination, many authors conclude that there might be no or only insignificant instability in D and FH , 11, 12.congenital cruciate aplasia may lead to retropatellar pain and meniscus injury [Others state that the s injury , as wellThere is not much data on functional outcome in daily activity or in sports participation of patients with congenital limb deficiency. Crawford et al. presenteInstability in daily activity or sports.Knee pain, meniscal damage or degenerative changes.Complications during bone lengthening or deformity correction (flexion contracture or knee subluxation).Recurrence of axial malalignment after deformity correction .However, depending on the severity of the knee instability in congenital deformity, different problems can occur:ACL reconstruction in congenital deficiencies of the lower limb are rare. This might be mainly because most of the patients do not complain of instability in daily activity. Furthermore, intraarticular ACL reconstruction in the absence of a femoral notch is challenging.Reports on arthroscopic Gabos et al. describeFigueroa et al. presenteAs severe knee instability is treated with comprehensive knee reconstruction in early childhood , the indication for arthroscopic ACL repair in congenital cases is rare. In the older child with symptomatic knee instability, other reasons for instability such as axial malalignment have to be corrected before considering a cruciate ligament repair.preparatory surgery is often done before the age of 4\u00a0years [Knee stability can be reconstructed in early age with complex reconstruction surgery of the knee to achieve good stability for daily activity and for future lengthening procedures. This 4\u00a0years .A multitude of soft tissue procedures to reconstruct knee stability have been developed.superknee procedure described by Paley and Standard [The most comprehensive procedure in congenital knee instability is the Standard . This meStandard and supeexternal fixation devices for deformity correction and bone lengthening have been developed.Various Grill and Dungl reportedHexapod systems for external fixators such as the Taylor spatial frame or the Ortho-SUV frame enable more accurate deformity correction than the Ilizarov frame [ov frame , 19. Howbridging of the knee with a circular frame . An accurately placed hinge at the centre of rotation of the knee between the femoral and tibial frame allows safe lengthening and enables controlled mobilisation of the knee joint . Knee subluxation occurred in 13% and bridging of the knee and the use of an articulated external fixator was recommended .Especially in the most severe knee deformity with aplasia of the cruciate ligament and ball and socket joint configuration, the frontal plane instability can lead to recurrence of axial malalignment after deformity correction .motorised intramedullary lengthening nails can be a preferable option.In moderate deformities with no or mild clinical instability, The nails show faster rehabilitation with higher knee range of motion, better callus formation and less complications compared to external fixation .The development of new motorised intramedullary lengthening nails enables deformity correction and limb lengthening with higher patient satisfaction and comfort than with external fixators .The use in congenital limb deficiency has been described for the FITBONE nail , 24\u201326, The limitations of lengthening nails should be kept in mind, as severe cruciate aplasia and joint incongruity can lead to subluxation. Cases of subluxation during lengthening with motorised intramedullary lengthening nails have been reported , 28.Shabtai et al. presenteWe use the PRECICE nail in congenital deformity without or with minor instability in combination with an above-knee orthosis Fig.\u00a0c and weeGuided growth can be particularly helpful as a joint-sparing procedure to reduce the extent of other more invasive surgical techniques and wearing time of these braces. In the presence of significant knee instability in lower limb deficiency, lengthening with external fixation and bridging of the knee remains the gold standard of treatment.signs of subluxation as early as possible to prevent the knee from sustaining severe damage.The prediction of an individual\u2019s risk for subluxation in patients with CFD/FH remains difficult or impossible. It is necessary to detect Flexion contracture of the knee can occur during lengthening and can be resolved by decreasing the lengthening rate or intensive physical therapy in most of the cases. However, acute or severe flexion contracture in congenital limb deficiency may indicate knee subluxation and should be followed closely.Knee range of motion during lengthening procedures of the femur with external fixation is limited during treatment and needs several months to recover . Flexionstop the lengthening procedure. An existing bridging of the joint should be re-evaluated to ensure the correct position and configuration.In the case of severe flexion deformity or subluxation, it is advisable to temporarily reverse programmes (shortening). Acute shortening might be advisable in severe and especially in acute subluxation to manage that complication.Motorised nails such as the PRECICE and PhenConservative treatment with physical therapy [ therapy , 28 and therapy was reposurgical procedures such as simultaneous corrective osteotomy with arthroscopic ACL repair [Furthermore, various L repair , PCL recL repair , soft tiL repair to treatL repair , 17. MosConsequences of subluxation and residual knee flexion deformity can be severe with functional leg length discrepancy (despite the prior lengthening procedure), anterior knee pain and inability to weight bear due to knee instability (Fig.\u00a0ity Fig.\u00a0c.Knee joints of patients with congenital limb deficiencies show individually highly variable grades of instability. The knee function in daily activity seems to be nearly normal, even with knee abnormalities such as cruciate ligament aplasia and dysplasia of the joint surfaces. The instability might be relevant in sports activity, but further studies on this topic are needed. However, special attention is necessary prior to lengthening and deformity correction. Preoperative radiographic assessment is essential and clinical assessment of instability is obligatory. The development of new lengthening devices enabled us to correct congenital limb deficiencies with higher patient satisfaction and comfort. Irrespective of the applied method, high functional outcome can only be achieved by obeying the general rules of leg lengthening, with the highest aim of preventing the joint sustaining any damage during the lengthening procedure. In cases of severe flexion contracture or knee subluxation during lengthening, we recommend to stop lengthening or transiently shorten the bone to protect the knee joint from further damage. Intensive physical therapy and the use of a knee extension brace can help to prevent and treat subluxation. Adequate surgical techniques, preventive measures and early detection of signs of subluxation can lead to good functional results in patients with congenital limb deficiency."} +{"text": "We report the investigation of the organisation of proper names in two aphasic patients (NBC and FBI). The performance of both patients on spoken word to written word matching tasks was inconsistent, affected by presentation rate and semantic relatedness of the competing responses, all hallmarks of a refractory semantic access dysphasia. In a series of experiments we explored the semantic relatedness effects within their proper name vocabulary, including brand names and person names. First we demonstrated the interaction between very fine grain organisation and personal experience, with one patient with a special interest in the cinema demonstrating higher error rates when identifying the names of actors working in a similar film genre than those working in different genres . Second we compared directly two potential principles of semantic organisation \u2013 taxonomic and thematic. Furthermore we considered these principles of organisation in the context of the individuals' personal knowledge base. We selected topics matching the interests and experience of each patient, namely cinema and literature (NBC) and naval history (FBI). The stimulus items were arranged in taxonomic arrays , thematic arrays , and unrelated arrays . We documented that different patterns of taxonomic and thematic organisation were constrained by whether the individual has limited knowledge, moderate knowledge or detailed knowledge of a particular vocabulary. It is suggested that moderate proper name knowledge is primarily organised by taxonomy whereas extensive experience results in a more detailed knowledge base in which theme is a powerful organising principle."} +{"text": "Radical cystectomy has become a standard and effective treatment for muscle-invasive bladder cancer, however, the role and appropriate extent of a concomitant lymphadenectomy continues to evolve. We performed a detailed review of the English medical literature pertaining to the historical development and rationale for an extended lymphadenectomy in patients undergoing radical cystectomy. An historical perspective of lymphadenectomy and an anatomic account of bladder lymphatic drainage are presented. The boundaries and technique of an extended lymphadenectomy are also highlighted. Autopsy and contemporary survival data are presented to suggest that a more extensive lymphadenectomy has both prognostic and therapeutic utility. Furthermore, the stage of the primary bladder tumor, total number of lymph nodes removed, and the lymph node tumor burden are shown to be important prognostic variables in patients undergoing cystectomy with pathologic evidence of lymph node metastasis. Radical cystectomy provides not only excellent local cancer control with low pelvic recurrence rates, but also the best long-term survival. Radical cystectomy with an appropriate extended lymphadenectomy, while surgically more challenging, does not significantly increase the morbidity or mortality of the procedure. Although the absolute limits of the lymph node dissection remain to be determined, there is an evolving body of data to support that an extended lymphadenectomy provides further diagnostic and therapeutic benefit."} +{"text": "Eating in response to negative emotions (EE) may be an explanatory factor of the weight regain of many dieters. This narrative review presents evidence on possible causes of EE and the association of EE with depression and obesity and discusses implications of these findings for the treatment of obesity.Possible causes of EE are high dietary restraint, poor interoceptive awareness, alexithymia, emotion dysregulation and a reversed hypothalamic pituitary adrenal (HPA) stress axis. EE may be the outcome of inadequate parenting or depressive feelings in interaction with genetic susceptibility. There is also robust evidence that EE is a mediator between depression and obesity.The association of EE with depression and poor emotion regulation skills suggests that the treatment of obese people with high EE should not focus on calorie-restricted diets but on emotion regulation skills. The DEBQ (Dutch Eating Behavior Questionnaire) enables such a matched treatment of obesity. In a pilot study of a group dialectical behaviour therapy (DBT), a cognitive behaviour therapy adapted for obese emotional eaters with modules on mindfulness , emotion regulation and distress tolerance . DBT appA high degree of external eating, unsupported by a high degree of emotional eating, points to a sensitivity to external food cues. Although mindfulness approaches were also shown to be effective for external eaters with obesity , the theIn people with low scores on emotional or external eating, but with high scores on restrained eating, also the past history of body weight and weight fluctuation should be taken into account, as should be the tendency towards restrained breaking (disinhibition or failure of restraint) or bingeing. For example, underweight in combination with severe dieting may point to anorexia nervosa, while a history of large weight fluctuation in combination with severe dieting and tendencies towards restraint breaking may indicate bulimia nervosa. However, if a person has always been overweight, he or she may be better of accepting his or her heavy build than to continuously starving him or herself. In approaches such as Health at Every Size and Intuitive eating, the focus is on health and adaptation and getting into contact with feelings of hunger and satiety .Possible mechanisms of distress-induced emotional eating are poor interoceptive awareness, high alexithymia and a blunted HPA axis stress response (as indicated by a blunted cortisol stress response). Inadequate parenting and a high degree of depressive feelings may, in interaction with a genetic vulnerability, be associated with increases in emotional eating during adolescence. Emotional eating may also act as a mediator between depression and body mass index or weight gain. This finding is of interest for both obesity interventions and interventions for atypical depression. A matched treatment approach of obesity is suggested, an approach that matches the treatment to the specific eating style of the individual. Matched treatment of obesity may provide a new pathway to more permanent weight loss or maintenance of body weight ."} +{"text": "Drosophila circuit and cellular mechanisms employed in this circuit, with vertebrate systems, suggests that the identified cell signaling mechanisms may be conserved for neural circuit function related to nutrient sensing by central neurons. The ideas proposed are potentially relevant for understanding the molecular basis of metabolic disorders, because these are frequently linked to nutritional stress.All organisms can respond physiologically and behaviorally to environmental fluxes in nutrient levels. Different nutrient sensing pathways exist for specific metabolites, and their inputs ultimately define appropriate nutrient uptake and metabolic homeostasis. Nutrient sensing mechanisms at the cellular level require pathways such as insulin and target of rapamycin (TOR) signaling that integrates information from different organ systems like the fat body and the gut. Such integration is essential for coordinating growth with development. Here we review the role of a newly identified set of integrative interneurons and the role of intracellular calcium signaling within these neurons, in regulating nutrient sensing under conditions of nutrient stress. A comparison of the identified The ability of an organism to sense nutrients in its environment is closely linked to survival Lam, . NutrienNutrients are macromolecules required for catabolic and anabolic processes in the cell. Organisms have evolved varying strategies to sense nutrients from their external environment, as their individual nutritional requirements maybe different in Drosophila and the Adenosine 5\u2032-Monophosphate-activated Protein Kinase (AMPK) pathways Hardie, . Togethea Figure where moa Figure . The mNSa Figure . These cDrosophila, where the fat-body and endocrine tissues like the corpora cardiaca in the ring gland, along with the mid-gut are considered as the predominant tissue systems for metabolic regulation , regulate the integration of external nutrient information with appropriate developmental transitions , an intracellular calcium release channel; stromal interaction molecule (STIM), an endoplasmic reticular calcium sensor; Orai, a plasma-membrane localized calcium channel also referred to as the Store-operated calcium entry (SOCE channel); transient receptor channels (TRPs) that bring in extracellular calcium in response to a range of intracellular signals; as well as two-pore channels that mediate changes in levels of cytosolic calcium in response to extracellular stimuli, first appeared in the unicellular choanoflagellates, which precede multicellularity or receptor tyrosine kinases (RTKs), binds to the IP3R on the endoplasmic reticulum and leads to elevated cytosolic calcium by calcium release from ER stores in neuronal networks or in the insular cortex and needs to be investigated. It would also be interesting to test if neural components in the spinal cord regulate hypothalamic circuits given that spinal inputs are known to regulate the PVH (Geerling et al., Drosophila that integrates nutrient availability with developmental check-points, suggests that it may be a precursor of a more evolved mammalian spinal cord-hypothalamic circuit.The glutamatergic interneurons identified recently by us (Jayakumar et al., 3R signaling might allow context dependent modulation of nutrient sensing pathways. It could be speculated that the timing of ecdysteroid peaks during third instar larval progression are the result of integration of nutritional information and serve as additional checkpoints. The ecdysone receptor is thought to represent the insect equivalent of nuclear receptors that function in mammals for endocrine regulation of different physiological functions (Thornton, 3R mediated calcium release and associated SOCE in multicellular organisms might function to enable neuronal networks to appropriately adapt their physiological response to changes in their environmental conditions.Though the mechanism by which varying classes of nutrients are sensed differ among multicellular organisms, intracellular signaling cascades like IPSJ researched and wrote the manuscript. GH critically revised the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer TKH declared a shared affiliation, though no other collaboration, with one of the authors SJ to the handling Editor."} +{"text": "According to the Linguistic Niche Hypothesis , limited semantic transparency of lexical items and formulaic idioms, reduced compositional structure, and less sophisticated syntactic devices are found among isolated human groups living in small, close-knit communities with higher proportions of native speakers who share considerable amounts of knowledge globularization, but around 100\u201350 kya enhanced domestic features in our species also facilitated the emergence of the social and technological complexity of exoteric societies. At the same time, the extended juvenile period and enhanced parenting brought about by self-domestication supported teaching behaviors that facilitate learning of the complex linguistic systems that underpin behavioral modernity.AB-B and VK conceived and wrote the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "We here review the collision risks posed by large-bodied, flocking geese to aircraft, exacerbated by recent major increases in northern hemisphere goose populations and air traffic volume. Mitigation of goose\u2013aircraft strike risks requires knowledge of local goose movements, global goose population dynamics and ecology. Airports can minimise goose strikes by managing habitats within the airport property, applying deterrents to scare geese away and lethal control, but goose migration and movements at greater spatial scales present greater challenges. Habitat management outside of airports can locally reduce goose attractiveness of peripheral areas, but requires stakeholder involvement and coordination. Information on bird strike rates, individual goose movements and goose population dynamics is essential to understand how best to reduce the risk of goose strikes. Avian radar provides tactical information for mitigation measures and strategic data on local patterns of goose migration and habitat use. In the face of expanding air traffic, goose distributions and populations, these threats need to be integrated with other local, national and international stakeholder involvement to secure viable solutions to multiple conflicts. Branta canadensis are increasing globally and present a disproportionate challenge around airports where aircraft are vulnerable during approach, landing and take-off Dolbeer . Geese cAirport operators are responsible under national and international legislation for mitigating the risks of bird strikes involving geese, and have used a variety of tools to achieve this aim. This is becoming particularly important given the rapid increases in some goose populations (see below) and the average 5.8% annual increase in global air traffic passengers between 2005 and 2016 Statista culminatThe hazards presented to the aviation industry by geese are further exacerbated by rising goose populations in North America and Europe which elevate risks concerned is fundamental for developing recommended mechanisms and best practice for reducing bird strike risk.Migratory geese that breed in northern latitudes, but winter further south, pose a different set of challenges to local or resident birds that spend the greater balance of their annual cycle in one region for managers tasked with maintaining aviation safety. Migrant geese may pass through airspace infrequently, as they transit between breeding and wintering grounds; however, they may do so at altitudes where they are difficult to manage by ground personnel and in numbers that increase the likelihood of a damaging strike. Hence, the potential to manage the serious collision risks associated with migrating geese usually lies well outside of the area of influence of airport authorities. In such circumstances, all that can be done is to observe movements and alert pilots to these via the Automatic Terminal Information Service (ATIS) and/or direct communication with Air Traffic Controllers. When wintering grounds are juxtaposed with an airport, migrant geese can represent a persistent and significant risk. In contrast, local or resident birds may commute regularly between different elements in the landscape around the airport and represent a year-round hazard, but may be more predictable in their movements and more amenable to local management.Branta leucopsis that breed in the Russian Arctic and the Baltic, and winter around North Sea coasts. This population has shown exponential increase in recent years and exceeded 1.2 million individuals in 2015 (Fox and Madsen Copenhagen Airport at Kastrup (Denmark) experiences both migrant geese and resident geese. An example of a genuine migrant species is the barnacle geese Sturnus vulgaris, gulls and shorebirds; Brough and Bridgman Most airports in Europe and North America maintain extensive areas of grassland between runways and taxiways to ensure pilot and general visibility, allow for emergency passage of aircraft straying from paved areas and enable rapid access for emergency vehicles to all areas has proved successful at small scales, although effective and relatively inexpensive in the short term, they often require frequent re-applications to maintain effectiveness , combined acoustic\u2013visual deterrents (pyrotechnics), visual deterrents and deployment of potential predators based on arguments put forward to justify them in relation to air safety concerns. The International Civil Aviation Organisation (ICAO) recommends a 13-km radius safety zone around an airport centre point for the basis of an effective wildlife management plan ICAO . Within Chen caerulescens caerulescens nesting in the Russian arctic migrate along the Pacific Coast in fall to wintering areas in British Columbia (Canada), Washington, Oregon and California (United States of America). Migration is prolonged from October to December, and thousands of birds remain on the Fraser River delta (British Columbia) all winter . Monitoring of goose movements was undertaken using radar before and after the agreement was reached between Schiphol and local farmers, and these data showed a reduction in the number of goose movements over the airfield . As lakes and wetlands are likely to attract geese and other waterfowl for foraging, loafing and night roosts, objection to new wetland restoration projects has been both appropriate and provided an administrative mechanism to avoid conflict in the vicinity of airports. In Denmark, where the recommendations from ICAO are implemented in the provisions of domestic legislation, airports have successfully objected to lake and wetland projects, when applied for these concerned areas within 13\u00a0km of the airports when other mechanisms have failed, especially when dealing with resident populations of geese . The process of finding effective solutions to the conflicts these patterns pose to airport safety necessitates the active involvement of many diverse stakeholders. Local information about goose ecology is required to make informed management decisions and to assess and validate actions. Several potential sources of data relating to goose ecology in the vicinity may be available to airport authorities and their stakeholder partners, and mechanisms to generate such data can and need to be established. However, it is of fundamental importance to identify the specific data needs before initiating data collection.Anser albifrons) observed over-flying or settling at Copenhagen Airport have increased exponentially and the airport managers need to join with consortia of other stakeholders in collaborating towards attaining the goal of maintaining the highest levels of regional aviation safety. This can be achieved by joining with much larger initiatives that contribute to solving the problems posed by increasing goose populations. Such a major initiative requires a scale-dependent set of mechanisms, starting at finding strategic solutions to conflict at the flyway level, but focussing ultimately for delivering solutions at the site level. Such a process requires an openness and willingness of all parties to work together with mechanisms to gather appropriate data sources and establish a shared understanding of the available data, a process that has been described by Tombre et al. in relatThere remain considerable improvements to be made at the regional level, where collaboration is required to engage regional stakeholders and raise awareness of the risk that geese pose to aircraft operations, including the worst-case consequences of an incident. This awareness, built upon an agreed acceptance of the current data, can be used to build a framework of cooperative management that helps to address goose issues on lands within the vicinity of the airports that are outside its jurisdiction.Stakeholders involved should include local governments with jurisdiction over public green spaces, agricultural managers (if present in the vicinity of the airport), other private landowners with goose habitat on their properties and environmental organisations. Efforts should be made to discuss the differing interests of each stakeholder group to reach understandings and to unite interests (Tombre et al. Geese represent an adaptable suite of species that have shown themselves well able to thrive within the mosaic of post-industrial human-modified landscapes, especially agricultural landscape and amenity grasslands. The risk of goose strikes to aviation safety has been an unintentional consequence of goose management efforts as well as the major expansion in the air transport industry over the past century. The long-distance migratory nature of many goose populations, both regionally and internationally, necessitates the collaboration of stakeholders at multiple levels (see Madsen et al."} +{"text": "Schizophrenia is possibly the most stigmatised of all mental disorders. It has been argued that the label of schizophrenia itself has become stigmatically charged through over a century of association with misleading and sensationalist representations in news media and pop-culture. There has, therefore, been considerable recent debate on the topic of changing the label of schizophrenia. Label change advocates argue that public stigma about schizophrenia would be reduced should the label be replaced with either an eponymous or descriptive alternative. However, few empirical studies to date have directly investigated this possibility. Moreover, no known single study has investigated the effects of descriptive and eponymous relabelling of schizophrenia on public stigma as a function of symptomatology and illness phase. The current study aimed to fill this gap in the literature.Australian university students participated in the study by reading a brief vignette depicting a protagonist with schizophrenia, and by subsequently completing a number of stigma measures. Participants were randomly allocated to vignette conditions that varied systematically by disorder label (schizophrenia vs eponymous label vs descriptive label), symptoms (positive vs negative symptoms), and illness phase (active vs remittent symptoms). Stigmatised thoughts, attitudes, and behaviour were measured using the Social Distance Scale and selected items forming six factors from the Attributional Questionnaire . Socially desirable response bias and familiarity with mental illness were controlled using the Marlow-Crowne Social Desirability Scale , and Level-of-Contact Report .Data was analysed with a series of ANCOVA and ANOVA analyses. No group differences in either SDS or AQ scores were observed as a function of disorder label. Positive symptoms were observed to elicit significantly greater levels of fear/dangerousness responses and endorsement of forced treatment when compared to negative symptoms. However, negative symptoms elicited significantly greater anger responses. While only these isolated differences on stigma measures were observed for symptom profile contrasts, vignettes depicting an active illness phase elicited significantly greater levels of stigma on the SDS and most AQ factors when compared with vignette conditions depicting a symptomatically remittent protagonist. Lastly, no statistically significant interactions were observed between labels, symptomatology and illness phase.The results suggest that diagnostic label change may not be an effective strategy to reduce public stigma about schizophrenia in western countries. It is important to note, however, that public stigma elicitation is just one of the numerous considerations as regards the utility of label change, and that others, such as consumer perspectives, hold value independent of the current findings. The current findings also highlight that the symptomatology and illness phase of schizophrenia are likely to be implicated in eliciting public stigma about the disorder, and are worthy of further attention. While the current study investigated these phenomena at the broad symptom profile level, future research should investigate individual symptoms and their subtypes discretely, in order to inform a comprehensive, symptom-focussed model of elicited public stigma pertaining to schizophrenia."} +{"text": "Molecular imaging with Positron Emission Tomography (PET) has the unique capability of examining molecules in the brains of human subjects in real time. This has been well exploited in the study of dopaminergic transmission in schizophrenia. The results have on one hand confirmed some predictions, and on the other hand they have brought up unexpected findings, that have the potential to affect drug development in a major way.PET studies of dopamine release, synthesis, storage, receptors and transporters across labs and different experiments will be reviewed to extract findings that differ from preconceived notions. These have the capability of re-focusing drug development based on new evidence.Expected findings that PET studies have confirmed are those of striatal dopaminergic excess, measured as enhanced presynaptic release capacity and presynaptic enzymatic synthesis capacity. Also expected was hypodopaminergic transmission in the dorso-lateral prefrontal cortex.The unexpected findings from PET have been as follows: 1) the striatal excess is most predominant in the associative striatum, rather than the limbic striatum. 2) hypodopaminergia is generalized to all extrastriatal areas of the brainThese observations of opposite presynaptic dopaminergic dysfunction between striatal and extrastriatal regions suggest that the striatal excess may not be driven by activity levels of midbrain DA cells but may result from abnormal striatal local regulation of presynaptic DA release, affecting specifically the associative striatum, region which shows largest magnitude of excess DA. Furthermore alterations in dopaminergic signaling in opposing directions may have a dual effect on learning across functional domains by weakening learning from salient or relevant signals and reinforcing stimulus independent signals, thus explaining different symptom domains.More work is needed to understand the cellular mechanisms of dopaminergic dysfunction in schizophrenia. The evidence presented here, while limited, highlights the challenges of drug development in the absence of real in vivo information from patients, and the need for multidisciplinary cross talk to address these challenges."} +{"text": "NaP as the major current contributing to the pacemaking property of RVLM presympathetic neurons.Despite several studies describing the electrophysiological properties of RVLM presympathetic neurons, there is no consensus in the literature about their pacemaking property, mainly due to different experimental approaches used for recordings of neuronal intrinsic properties. In this review we are presenting a historical retrospective about the pioneering studies and their controversies on the intrinsic electrophysiological property of auto-depolarization of these cells in conjunction with recent studies from our laboratory documenting that RVLM presympathetic neurons present pacemaking capacity. We also discuss whether increased sympathetic activity observed in animal models of neurogenic hypertension (CIH and SHR) are dependent on changes in the intrinsic electrophysiological properties of these cells or due to changes in modulatory inputs from neurons of the respiratory network. We also highlight the key role of I Presympathetic neurons located in the rostral ventrolateral medulla (RVLM) are responsible for generating the sympathetic drive to the cardiovascular system and ultimately determine cardiac output and vascular resistance Dampney, . OriginaAdditional evidence about the relevance of RVLM in the maintenance of baseline arterial pressure was provided in a study by Guertzenstein and Silver , in whicin vivo confirming the involvement of these cells in the cardiovascular regulation the network theory suggesting that the activity of these neurons is dependent on the balance of tonic excitatory and inhibitory synaptic inputs arising from other brain regions. Although, different studies have documented the presence of excitatory and inhibitory inputs to RVLM neurons , reduced the excitatory neurotransmission using glutamate-receptor antagonist (kynurenic acid) and recorded the firing frequency of RVLM neurons using extracellular recordings. Intracisternal injection of kynurenic acid increased the firing frequency of functionally identified barosensitive neurons. On the other hand, several studies documented that microinjections of kynurenic acid into RVLM produced no major changes in the sympathetic nerve activity , we observed that all RVLM presympathetic neurons fire spontaneously and the frequency of these cells were heterogeneous ranging from 8 to 22 Hz, with depolarized (\u221252 mV) and hyperpolarized (\u221263 mV) values of membrane potential and spontaneously hypertensive (SH) rats, show a significant increase in sympathetic tone, more recently we became directly involved with this important issue. Our studies were designed to analyze whether RVLM neurons, from juvenile-adult animals, present an enhancement in their spontaneous firing frequency and whether this enhancement is responsible for the sympathetic overactivity and hypertension observed in CIH and SH rats. To reach these goals, we used s Paton, . This prs Paton, . Althougs Paton, , 2014.in situ approach, in the presence of synaptic blockade RVLM neurons from CIH rats presented no changes in their resting membrane potential, firing frequency and input resistance. Thus, the intrinsic properties of RVLM presympathetic neurons in brainstem slices from juvenile rats exposed to CIH were similar to those observed in neurons from control rats, as we observed in in situ preparations of CIH and SH rats. Although, our findings indicate that RVLM presympathetic neurons are pacemakers, our studies using two experimental models of neurogenic hypertension (CIH and SH) also indicate that the increased firing frequency of these cells is not due to changes in their intrinsic properties RVLM presympathetic neurons have intrinsic mechanism that allow them to behave as pacemaker neurons; and (2) the increased respiratory modulation to these neurons is mainly due to excitatory drives , which in turn may influence the firing frequency of neurons as suggested by Pierrefiche et al. abolished the spontaneous activity of these cells .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "This review will introduce the concept of toll-like receptor (TLR)\u2013mediated glial activation as central to all of the following: neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects . Attenuation of glial activation has previously been demonstrated both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. Here we demonstrate that selective acute antagonism of TLR4 results in reversal of neuropathic pain as well as potentiation of opioid analgesia. Attenuating central nervous system glial activation was also found to reduce the development of opioid dependence, and opioid reward at a behavioral (conditioned place preference) and neurochemical level of analysis. Moreover, a novel antagonism of TLR4 by (+)- and (\u02d7)-isomer opioid antagonists has now been characterized, and both antiallodynic and morphine analgesia potentiating activity shown. Opioid agonists were found to also possess TLR4 agonistic activity, predictive of glial activation. Targeting glial activation is a novel and as yet clinically unexploited method for treatment of neuropathic pain. Moreover, these data indicate that attenuation of glial activation, by general or selective TLR antagonistic mechanisms, may also be a clinical method for separating the beneficial and unwanted actions of opioids, thereby improving the safety and efficacy of their use."} +{"text": "Obstructive sleep apnoea syndrome is a type of sleep-disordered breathing that affects 1 to 5% of all children. Pharyngeal and palatine tonsil hypertrophy is the main predisposing factor. Various abnormalities are predisposing factors for obstructive sleep apnoea, such as decreased mandibular and maxillary lengths, skeletal retrusion, increased lower facial height and, consequently, increased total anterior facial height, a larger cranio-cervical angle, small posterior airway space and an inferiorly positioned hyoid bone. The diagnosis is based on the clinical history, a physical examination and tests confirming the presence and severity of upper airway obstruction. The gold standard test for diagnosis is overnight polysomnography. Attention must be paid to identify the craniofacial characteristics. When necessary, children should be referred to orthodontists and/or sleep medicine specialists for adequate treatment in addition to undergoing an adenotonsillectomy. Obstructive sleep apnoea syndrome (OSAS) is defined as a type of sleep-disordered breathing (SDB) characterized by partial and/or complete upper airway obstruction that affects normal ventilation Obstructive sleep apnoea (OSA) is estimated to affect 1 to 5% of all children Adenoid and tonsil hypertrophy are more prevalent between 3 and 6 years of age At birth, the face is approximately 40% of the adult size, and it increases to 65% by 3 years of age. Facial growth is only completed after puberty. Facial growth is influenced mainly by genetic factors, but environmental aspects such as the breathing pattern may also contribute to growth Nasal breathing in children may induce a correction of craniofacial growth and the adequate development of other functions, such as chewing and swallowing Various craniofacial deformities are predisposing factors, including decreased mandibular and maxillary lengths, skeletal retrusion, increased lower facial height and, consequently, increased total anterior facial height, a larger cranio-cervical angle, decreased posterior airway space and an inferiorly positioned hyoid bone A positive correlation exists between the severity of the breathing pattern as measured by the apnoea and hypo-apnoea index and changes in dentofacial development. Dental arch abnormalities can be explained by long-term changes in the head, mandible and tongue positions In a recent meta-analysis, Katyal Children with OSAS often have cognitive problems, disturbed sleep, delayed learning, social performance disorders, bruxism and enuresis. The diagnosis is based on clinical history, a physical examination and tests confirming the presence and severity of the obstruction The gold standard for the diagnosis is overnight polysomnography, which is currently the only reliable diagnostic modality that can discern SDB from primary snoring Advanced technologies, such as computed tomography and magnetic resonance imaging, are currently used to evaluate the anatomical characteristics of the upper airway and craniofacial structures. However, the traditional cephalometric method is the most practical technique and is frequently used in clinical practice due to its easy access, low cost and low radiation exposure One misleading problem in assessing craniofacial morphology using a lateral cephalogram is that patients are conscious, in an upright position and have occluded teeth. Paediatric SDB typically worsens in the supine position when muscle hypotony occurs while sleeping. Further investigations are required to address the relationship between craniofacial morphology and paediatric SDB in all three dimensions The treatment is based upon the severity of obstructive apnoea. The practice guidelines established by the American Academy of Pediatricians proposes an adenotonsillectomy as the first line of therapy for childhood OSAS Changing the breathing pattern from oral to nasal early in adolescence may benefit the craniofacial dimensions during growth However, the structural problems in many children with SDB are not fully solved after an adenotonsillectomy, and a risk exists for a slow but progressive reappearance of OSA symptoms The recurrence is typically not immediate and may occur during the pubertal period and after the mean age at which dentoskeletal development reaches approximately 90% of its adult final growth These findings raise important issues regarding the efficacy of an adenotonsillectomy and further suggest that overnight polysomnography should be routinely implemented Given the impact on a child\u2019s health, determination of these predictor factors is important to prevent and manage SDB. If a health professional notices signs and symptoms SDB, the young patient should be referred to a sleep medicine specialist and to an orthodontist if dentoskeletal abnormalities are present In adults, continuous positive airway pressure therapy is the first line of treatment for patients with OSAS. This procedure prevents upper airway collapse and relieves symptoms but has poor compliance. An alternative is maxillomandibular advancement, which enlarges the pharyngeal space and is often performed with genioglossus advancement to decrease the amount of tongue blockage during sleep Further standardization of research methods is recommended, including the establishment and acceptance of valid definitions for normal breathing, SDB and OSA Craniofacial morphology plays an important role in SDB in children. It is also associated with the recurrence of snoring and OSA after an adenotonsillectomy at later ages, including in teenagers and adults. Attention must be paid to identify these characteristics. When necessary, children should be referred to orthodontists and/or sleep medicine specialists for adequate treatment in addition to undergoing an adenotonsillectomy.Authors make substantial contributions to conception and design of this manuscript. Bozzini MF participated in drafting and writing this review article and together with Di Francesco RC revised it critically for important intellectual content. Both authors approved the final version of the manuscript to be submitted."} +{"text": "Children with special health care needs receive less oral care than the normal population, inspite of the high level of dental diseases among them. They are at an increased risk for oral diseases throughout their lifetime. This paper reports a case of a toddler with congenital unusual thick convolutions of the cortex resulting in a condition called pachygyria. Intra oral examination showed multiple abscesses with poor oral hygiene. As the patient was lacking cooperative ability, treatment of full mouth rehabilitation as needed. The parents were advised for regular dental check-ups and informed about maintenance of good oral hygiene. This case report demonstrates the importance of oral hygiene maintenance of special children and also about their short and long term dental treatment protocol for maintaining good oral health. Key words:Pachygyria, general anaesthesia, special child, health care needs, preventive measures. American Association of Pediatric Dentistry defines special health care needs as \u201cany physical, developmental, mental, sensory, behavioral, cognitive, or emotional impairment or limiting condition that requires medical management, health care intervention, and/or use of specialized services or programs\u201d . Such inA 3-year old male patient reported to the department of Paediatric and Preventive Dentistry with the chief complaint of decayed teeth in lower left and right back teeth region. The patient showed signs of both physical and mental retardation. Medical history revealed that the child was diagnosed with Pachygyria since birth and has seizures, developmental delay, poor muscle tone and control and difficulty with feeding/swallowing. The child was under sodium valproate and clobazam medications and this was the patient\u2019s first dental visit.Since the child fell under lacking cooperative ability according to Wright\u2019s classification 1975), usual clinical and radiographic examinations were not possible on the dental chair. Intra-oral examination was done in knee-to-knee position which revealed extensive carious lesions involving all the primary molars and anterior teeth. Dento-alveolar abscesses were noticed in relation to maxillary right first molar [54], mandibular left and right first molars [74 and 84]. All the teeth were covered with dental plaque and food debris along with minimal gingival enlargement (Figs. 975, usuaUnder general anaesthesia oral prophylaxis was done using hand scaling instruments to get a clear view of the carious extensions on all the teeth. Glass ionomer restorations were placed in the maxillary and mandibular anterior teeth . Pulpectomy was done followed by composite restorations in maxillary upper right lateral incisor and canine [53 and 52]. Incision and drainage was done in the above mentioned teeth that had dentoalveolar abscesses. Pulpectomy was done followed by stainless steel crowns in the maxillary and mandibular first and second primary molars . Although the remaining crown structure of the pulpectomised teeth were not optimal, stainless steel crowns were placed to help in mastication (Fig. The prominent symptoms seen with Pachygyria are the most important etiologic factors causing severe dental caries. Developmental delays make them uncooperative for tooth brushing leading to plaque accumulation and limiting exposure to topical fluorides. They may also be exposed more frequently to medications and sugar sweetened beverages . DecreasAmerican Academy of Pediatric Dentistry\u2019s guideline on Caries Risk Assessment have categorised them under High risk for physicians and other non-dental health care providers and Moderate risk for dental providers . AttitudKeeping in mind the importance of prevention, a vigorous approach to preventive measures such as oral hygiene practices, dietary advice and fluoride supplements are required. Dentists should take the responsibility and offer their services in prevention of dental disease in children with special health care needs by establishing communication with the authorities responsible for welfare of these individuals and involve themselves in the total health care . InvolunManagement of dental diseases in children with special health care needs should be aimed at both short and long term treatment options. Short term treatment options are focused to control the disease progression and long term options are advised and taught to parents for preventing the recurrence of the disease."} +{"text": "Overall Abstract: Current treatments for schizophrenia (SCZ) are partially effective in treating positive symptoms, but many patients are refractory to available medications and they are ineffective in the treatment of negative symptoms and cognitive impairment. There is a tremendous need to develop novel approaches to the treatment of SCZ that have broader efficacy and fewer adverse effects than existing dopamine D2 receptor and mixed D2/5-HT2A antagonists. To achieve fundamental breakthroughs that provide efficacy for refractory patients and across multiple symptom domains, it will be critical to rely on rigorous studies in SCZ patients that guide development of novel treatment approaches. Major recent advances in the genetics, imaging, and molecular pathophysiology of SCZ point to new potential treatment strategies, and may guide patient selection and outcome measures. Speakers in this symposium will summarize examples of translational studies that may offer novel therapeutic approaches that have the potential to fundamentally change the standard of care for SCZ patients. Jeff Conn will summarize recent genetic studies that point to loss of function mutations in two novel G protein-coupled receptors in SCZ patients, and the discovery of novel positive allosteric modulators for these receptors that are providing a strong proof of concept for advancing selective agents to clinical evaluation in patients, including those that bear these specific mutations. Brian Dean will then review clinical studies showing that a subgroup of SCZ patients show a marked loss of cortical muscarinic M1 receptors and translational studies suggesting that selective activators of M1 receptors could provide benefits in treating this disorder. In addition, he will summarize changes in molecular cytoarchitecture in the cortex of subjects with SCZ that provide important insights in considering M1 activators as a treatment strategy. Clare Beasley , will review mounting evidence from postmortem tissue that implicates immune dysregulation and the complement system in SCZ and the potential utility of complement inhibitors in the treatment of this disorder. Finally, Anissa Abi-Dargham will discuss recent advances in the use of molecular imaging for discovery of patients with alterations in specific targets that may guide clinical development. Specifically, imaging studies suggest that nigro-striatal dopaminergic projections may play a more important role relative to mesolimbic dopaminergic projections than previously appreciated, and suggest a blunting of dopamine release in extra-striatal areas. These observations can be linked to clinical treatment response or particular domains of pathology and fit nicely with new data suggesting that activation of targets outlined in the first presentation selectively inhibit dopaminergic signaling in nigrostriatal but not in other dopaminergic pathways. In summary, this panel will highlight new therapeutic leads derived from novel insights gathered through imaging, genetic and molecular studies of SCZ patients."} +{"text": "Antimicrobial resistance (AMR) is a global health challenge and developing countries are more vulnerable to the adverse health impacts of AMR. Health care workers including pharmacists can play a key role to support the appropriate use of antimicrobials in developing countries and reduce AMR.The aim of this review is to investigate the role of pharmacists in the appropriate use of antibiotics and to identify how the pharmacists\u2019 role can be enhanced to combat AMR in developing countries.The databases MEDLINE, EMBASE, Web of Science and Google Scholar were searched for articles published between 2000 and the end of August 2017 that involved studies on the role of pharmacists in developing countries, the expanded services of pharmacists in patient care in developed countries and pharmacists\u2019 contributions in antimicrobial use in both developed and developing nations.In developing countries pharmacists role in patient care are relatively limited. However, in developed nations, the pharmacists\u2019 role has expanded to provide multifaceted services in patient care resulting in improved health outcomes from clinical services and reduced health care costs. Success stories of pharmacist-led programs in combating AMR demonstrates that appropriately trained pharmacists can be part of the solution to overcome the global challenge of AMR. Pharmacists can provide education to patients enabling them to use antibiotics appropriately. They can also provide guidance to their healthcare colleagues on appropriate antibiotic prescribing.This review highlights that appropriately trained pharmacists integrated into the health care system can make a significant impact in minimising inappropriate antibiotic use in developing countries. Strengthening and enhancing the pharmacists\u2019 role in developing countries has the potential to positively impact the global issue of AMR. Antimicrobial resistance (AMR) is a serious global health challenge . It is pPharmacists are important members of the healthcare team and they play a major role in medicine use and the provision of advice regarding appropriate medicines use . EducatiNumerous studies have highlighted that inappropriate medication practices are relatively common in the community and hospital settings of developing countries \u201315. For Several reviews have addressed and proposed possible solutions to the challenge of AMR in developing countries , 22. HowA literature search was conducted to identify articles, published between 2000 and the end of August 2017 that involved studies on antimicrobial use or AMR involving pharmacists in community and hospital settings of developing countries using databases such as EMBASE, MEDLINE and Web of Science.The following \u2018Medical Subject Headings\u2019 (MeSH) terms were used to search articles: (Antibiotics.mp.) OR OR OR AND (Community pharmacy.mp. or Pharmacies) OR (Community Pharmacy Services/ or Pharmacists/ or community pharmacist.mp.) OR OR AND AND (Attitude OR Perception OR Barriers).The following keywords were used to search articles in Web of Science: AND (\u201cCommunity pharmacy\u201d OR \u201cCommunity pharmacist\u201d) AND . Google Scholar was also used to search for articles with the appropriate keywords. Cross-references of articles identified using these databases were also searched. National pharmacy journals of developing countries were also searched for relevant articles.This review focuses on three main areas; firstly, the current role of pharmacists in developing countries; secondly, pharmacists\u2019 services in patient care in developed countries; and, thirdly, success stories involving pharmacists that optimised antibiotic use and reduced AMR in both developed and developing nations. Articles were scrutinised to identify those that addressed the above. Only articles and abstracts published in English were included in the review. This will not limit this review, because authors have searched different national journals from developing countries which publishes articles in English and available online.The challenges and barriers related to pharmacists\u2019 roles in pharmaceutical care in developing countries identified from recently published research articles are presented in Table\u00a0 Practicing pharmacists providing pharmaceutical care services are central to coordinating and optimising medicines among healthcare professionals, patients and the general public is presented in Fig. Role of pharmacists\u2019 in enhancing antibiotic use and combating AMR from recently published studies in developing and developed countries are presented in Table Significant progress in delivering pharmaceutical care services by the pharmacists has occurred within the pharmacy profession in the past few decades. There is a notable shift from medicine supply roles to pharmacist-delivered patient-centred services for the purpose of improving rational use of medications and ultimately enhancing the quality of life of patients. In many developed nations, pharmaceutical care services as a practice based profession was introduced many years ago. These developed nations are now experiencing the positive outcomes of the expanded roles of pharmacists, which directly impact patient care and quality use of medicines. However, in many developing countries, pharmaceutical care services are still limited to traditional pharmacy practices such as procurement of drugs, extemporaneous compounding, dispensing of prescriptions and selling of medicines. Therefore, an understanding the expanded roles of pharmacists in the current rapidly changing healthcare system of developed countries and the benefits they can bring is important for the development of healthcare systems in developing countries. One of the major outcomes of enhanced pharmacists\u2019 roles is the more appropriate use of antibiotics among health care professionals, patients in different settings of care and the general public. The importance of pharmacist-led antibiotic stewardship programs has long been recognised in the developed nations. The establishment of well qualified and trained pharmacy workforce in developing countries has the potential to reduce antibiotics overuse and misuse.The pharmacy profession still has an emerging professional status in developing countries . PharmacThere are numerous challenges and barriers faced by pharmacists in developing countries to implement and maintain sustainable pharmaceutical care services , 27, 30.If pharmacists are to provide patient care services in developing countries, it is essential to remove these major barriers . These cExtended pharmacists\u2019 roles are well established in the developed nations . PharmacAn example of an expanded pharmacist roles includes clinical pharmacist activities in Australian hospital emergency departments (ED) . ED mediIn developed nations, pharmacists\u2019 role has expanded to provide a variety of services including pharmacovigilance activities , pharmac., 2007 [Pharmacists\u2019 contribution in optimal antimicrobial use is an essential component in the fight against growing AMR. Many developed countries have achieved success with the implementation of antimicrobial stewardship (AMS) programs that include pharmacists. , 79 AMS ., 2007 , clearly., 2007 , 33\u201342. ., 2007 .In contrast, developing countries have not yet implemented pharmacist-led initiatives such as pharmacist-led AMS programs . In thesHence, there is a necessity to ensure suitably qualified pharmacists in developing countries through delivery of high quality and expanded pharmacy education. Education on infectious diseases, their management and AMR should be given increased attention in the pharmacy curriculum. The resultant knowledge, behaviours and skills should be evaluated prior to qualification and continuing professional development in this therapeutic area maintained if developing countries are to avoid the negative impact of inappropriate antibiotic utilization and AMR that is forecast in the developing countries in the near future .To our knowledge, there have been few reviews of the actual or potential role of pharmacists in developing countries that combat the challenge of AMR. This review explored the current situation of pharmacists in developing countries, the role of pharmacists in pharmaceutical care in the developed world and the success stories of pharmacist-related interventions in advancing prudent antibiotic use. This review highlights significant justification for enhancing pharmacists\u2019 roles in developing countries and the steps that should be taken by these countries to achieve these expanded pharmacists\u2019 roles. This review was limited to studies published in English, and therefore relevant studies published non-English languages would have been missed.Given the emerging nature of pharmaceutical care services, some developing countries have incorporated pharmaceutical care courses, such as clinical pharmacy, albeit in their infancy, within the national pharmacy curriculum . HoweverFurthermore, pharmacists can provide their services and support to physicians, nurses and other healthcare professionals to optimize antibiotic use, provide updated information about antibiotics and the adverse drug effects of antibiotics and monitor antibiotic use within healthcare settings. Establishing collaborative team based relationships between physicians and pharmacists will allow for improved patient outcomes . AntibioWhile the evidence for expanded pharmacist roles in developed countries is robust and generally translatable, it is nevertheless important that local evaluation of interventions by appropriately educated and trained pharmacists occurs. Factors related to success and failure of local programs will need to be identified to inform further program development and implementation. Importantly, programs expanding clinical pharmacist services are likely to be assisted with local and national policy and appropriate remuneration. Initiatives such as guideline development will also assist these programs. Although this review has focussed on pharmacist education and training, the training of other healthcare professionals also requires evaluation and possible overhaul. Education that highlights the benefits of health care provision when providers are team players will be advantageous.As has occurred in developed countries, the provision of qualified trained pharmacists and pharmacist integration into healthcare systems has the potential to make a significant impact on inappropriate antibiotic use in developing countries. Although this is only one of a number of interventions necessary to overcome the problem of catastrophic AMR in developing countries, it is achievable. Studies from developed countries have demonstrated that cost-effective optimal patient outcomes are achieved when pharmacists roles are enhanced within the health care system, when they are recognised as part of the health care team to provide advice on the rational and safe use of medicines, and university curricula and continuing professional education provide theoretical and practical knowledge and skills regarding the quality use of medicines. Antimicrobial stewardship involving pharmacists should be established in hospitals to ensure judicious and appropriate antimicrobial use. Adoption of these strategies will assist developing countries overcome their increased vulnerability to growing AMR."} +{"text": "The process of intercellular communication seems to have been a highly conserved evolutionary process. Higher eukaryotes use several means of intercellular communication to address both the changing physiological demands of the body and to fight against diseases. In recent years, there has been an increasing interest in understanding how cell-derived nanovesicles, known as extracellular vesicles (EVs), can function as normal paracrine mediators of intercellular communication, but can also elicit disease progression and may be used for innovative therapies. Over the last decade, a large body of evidence has accumulated to show that cells use cytoplasmic extensions comprising open-ended channels called tunneling nanotubes (TNTs) to connect cells at a long distance and facilitate the exchange of cytoplasmic material. TNTs are a different means of communication to classical gap junctions or cell fusions; since they are characterized by long distance bridging that transfers cytoplasmic organelles and intracellular vesicles between cells and represent the process of heteroplasmy. The role of EVs in cell communication is relatively well-understood, but how TNTs fit into this process is just emerging. The aim of this review is to describe the relationship between TNTs and EVs, and to discuss the synergies between these two crucial processes in the context of normal cellular cross-talk, physiological roles, modulation of immune responses, development of diseases, and their combinatory effects in tissue repair. At the present time this review appears to be the first summary of the implications of the overlapping roles of TNTs and EVs. We believe that a better appreciation of these parallel processes will improve our understanding on how these nanoscale conduits can be utilized as novel tools for targeted therapies. Intercellular communication and the exchange of biological information between cells and organs is considered one of the sophisticated means of cellular coordination which modern eukaryotes have evolved to meet the needs of body physiology Lai, . Cells uIn the absence of direct physical contact, cells may convey biological messages in paracrine fashion through secreted factors such as cytokines, chemokines, and secreted growth factors has designated a generalized term extracellular vesicles (EVs) to represent heterogeneous populations of vesicles and is required for TNT formation discovered by Rustom and colleagues containing vesicles, as well as intercellular exchange of B7-2 (CD86) molecules and MHC-II which represent novel pathways of intercellular communication and immunoregulation . Similarly, molecular transport via EVs represents phenotypic and functional changes in recipient cells. Therefore, dissemination of various forms of cytoplasmic cargo mediated by TNTs and EVs exhibits multifaceted roles in human physiology and pathological states including immunomodulation, infectious diseases, neurodegenerative disorders, cancer progression, cellular homeostasis, and repair process that will be discussed in sections below.Increasing body of evidence has demonstrated the contribution of EVs in immunomodulation and inflammatory responses both during normal physiology as well as pathological states . For instance, Tau and other prion-like proteins promote the formation of TNTs between neurons and thus their own intercellular transfer via TNTs which results in prion-like propagation of Tau assemblies and propagation of neurodegenerative pathology Figure . AstrocyAdditionally, fibrillar \u03b1-synuclein (\u03b1-syn) aggregates in lysosomal vesicles are transported between neurons via TNTs indicating the role of TNTs and lysosomes in the progression of synucleinopathies was expressed in infected cells and transferred to uninfected recipient cells via TNTs. Particularly, the increased fluorescent activity was observed in recipient cells indicating the functional transmission of NV1066 virus expressed eGFP from affected to na\u00efve cells such as cytarabine and daunorubicin treatment has been shown to inhibit TNT formation (Omsland et al., The transfer of mitochondrial or mtDNA between mammalian cells including stem cells and mitochondria associated bioenergetics are increasingly being considered more dynamic process than previously thought (Spees et al., The contribution of TNTs in lysosomal transfer from endothelial progenitor cells to stressed endothelial cells has been attributed in reducing premature senescence and vasorelaxation (Yasuda et al., TNT-mediated communication between MSCs and renal tubular cells with extensive spontaneous intercellular exchange of cytoplasmic material contributes to renal physiology (Plotnikov et al., EVs are currently a focus of intensive interest in understanding their role in intercellular communication, dissemination of bioactive cargo, and their contribution in the progression of various diseases. Albeit, TNTs are comparatively less described nonetheless, they hold a great potential not only in studying cellular communication but also their multifaceted roles in disease progression and tissue repair. Given the fact that they transport organelles and regulate cellular bioenergetics; TNTs could be best exploited in treating organelle specific diseases in particular those associated with mitochondrial and lysosomal disorders.Better understandings on the roles of nanotubes in tumor-stromal cross-talk could help to identify new selective targets for cancer therapeutics. Therefore, interfering with central routes of intercellular cross-talk via these membranous cellular tubes and EVs in separate or simultaneously could offer strong potential to explore novel strategies for directed therapy. If we develop mechanistic insights into the formation of TNTs and release of EVs, modes of cargo transfer, and their functional consequences; TNTs and EVs might one day be used as vectors of drug delivery against multiple diseases.Both authors participated in conceptualizing, writing, and critical review of the draft and agreed to final version before submission.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Oxidative stress constitutes a mechanism of injury seen in many disease processes . Increas2 utilization from dysfunctional mitochondria may represent the generator of fundamental abnormalities in critical illness.An increased oxidative burden can affect several cellular components. A potentially notable impact in critical illness is the alteration of mitochondrial function which may be pivotal in states of increased oxygen demand or hypoperfusion, that is, shock/sepsis. Indeed, there is evidence suggesting that the severity of mitochondrial dysfunction following increased oxidative stress correlates with the severity of sepsis and has been associated with adverse outcomes in septic patients . The patThose abnormalities at the cellular level may have significant implications in the function of organs which are frequently impaired in critical care patients such as the heart or the kidneys. Increased oxidative stress can induce ultrastructural and functional changes in cardiomyocytes that may result in altered electrical properties and compromised contractility. Intriguingly, experimental treatment with antioxidant vitamins alleviated both the systemic and myocardial inflammatory cytokine responses and decreased myocardial apoptosis . On the This special issue may stimulate our effort to thoroughly understand the underlying mechanisms of oxidative stress and to reveal its impact on organ functions and systemic homeostasis. The increasing knowledge of its pathogenesis and impact on several aspects of critical illness may provide further insight in our perception of the development and management of critical illness and in the evaluation of novel concepts of treatment at the clinical level. As always, this constitutes a work in progress with exciting prospects.Demosthenes MakrisPeter R. MertensEvangelia DounousiGregory GiamouzisSaad Nseir"} +{"text": "Eleusine coracana (L.) Gaertn.] lags far behind. It is an important staple in several semi-arid and tropical regions of the world with excellent nutraceutical properties as well as ensuring food security in these areas even during harsh environment. This review highlights the importance of finger millet as a model nutraceutical crop. Progress and prospects in genetic manipulation for the development of abiotic and biotic stress tolerant varieties is also discussed. Although limited studies have been conducted for genetic improvement of finger millets, its nutritional significance in providing minerals, calories and protein makes it an ideal model for nutrition-agriculture research. Therefore, improved genetic manipulation of finger millets for resistance to both abiotic and biotic stresses, as well as for enhancing nutrient content will be very effective in millet improvement.Crop growth and productivity has largely been vulnerable to various abiotic and biotic stresses that are only set to be compounded due to global climate change. Therefore developing improved varieties and designing newer approaches for crop improvement against stress tolerance have become a priority now-a-days. However, most of the crop improvement strategies are directed toward staple cereals such as rice, wheat, maize etc., whereas attention on minor cereals such as finger millet [Key message: Apart from the excellent nutraceutical value of finger millet, its ability to tolerate various abiotic stresses and resist pathogens make it an excellent model for exploring vast genetic and genomic potential of this crop, which provide us a wide choice for developing strategies for making climate resilient staple crops. Agriculture productivity is adversely affected with serious impact on production and productivity due to uneven weather conditions increased temperature and less availability of irrigation water. Global climate change together with the rapidly increasing population is mounting considerable pressure on agriculture sector to produce more food from less land. The anticipated increase in temperature will mostly affect the hot tropics, mainly populated by developing countries as they are likely to suffer maximum loss in food production . Even inThus development of varieties with enhanced nutraceutical value and improved stress tolerance has been one of the priority areas of research these days. Modern crop improvement techniques such as genomics-assisted breeding and genetic engineering play important role in understanding the complexities of stress response and tolerance as well as in providing measures for enhanced crop productivity. However, one of the possible solutions to counter these tribulations can be identifying and improving native crops that are highly adaptive to local climate, have high nutritive value and can efficiently withstand biotic and/or abiotic stresses. Although it is difficult to find a single staple food crop that fulfills all the major criterions, the wide variety and diversity of local food crops (such as minor millets) provide us a choice of such climate resilient crops .Most world population depends upon cereals as their staple food. Wheat, rice and corn have been the preferred cereals, whereas millets have largely been neglected, more so in the aftermath of green revolution. Millets represent a diverse group of small-seeded grasses grown for food, feed or forage . They coEleusine coracana), foxtail millet , kodo millet , proso millet (Panicum miliaceum), barnyard millet (Echinochloa spp.), and little millet (Panicum sumatrense), and all of them are known for their unique traits and nutritional values that negatively affect its nutrient values by reducing the digestibility of nutrients and mineral absorptions . These aEleusine is derived from the Greek goddess of cereals, \u201cEleusine\u201d while the common name finger millet indicates \u201cfinger-like\u201d branching of the panicle. As such, it may be one of the oldest indigenous domesticated tropical cereals in Africa. It is a highly productive crop that can thrive under a variety of harsh environmental conditions, and is also organic by default. It can be grown on low fertility soils and is not dependent on the use of chemical fertilizers, hence, is a boon for the vast arid and semi-arid regions . India has the largest collection of finger millet germplasm followed by Ethiopia . Functional genomics has led to the identification of several nutritionally important genes including those encoding calcium transporters and seed storage proteins. De novo RNA sequencing technology has been used to sequence the finger millet grain-filling stages transcriptome . Such studies can reveal the evolutionary relationship between species and may be useful in predicting key genes playing role in abiotic stress tolerance. Indeed, extensive similarities have been known to be shared across plant genomes of even distantly related species . OrtholoAgrobacterium-mediated transformation of finger millet using shoot explants was established by mtlD gene from bacteria. Further, efforts have been made to understand the role of monodehydroascorbate reductase, a key anti-oxidant enzyme, in finger millet under different abiotic stresses .The genetic improvement of finger millet through transgenic technology has, however, been inadequate regardless of its significance as a nutraceutical crop and also that improved stress tolerance along with superior grain yield has been a priority area of research for this crop . The twostresses . Krishnastresses . In thisolerance . Recentlolerance and calcolerance . Since, Figure 1). Proteomics is another important functional genomic approach that has been demonstrated its utility in identifying novel stress responsive proteins that could be exploited for improving stress tolerance of important agricultural crops. Under stress various ion transporters and signaling cascades and regulatory proteins are activated, knowledge of the proteins involved in these processes can give insights into the unique characteristics of small millets that can be exploited for crop improvement \u03b1-amylase (Escherichia coli Rosetta2 (DE3) cells and reported a significant increase in rbi transcript accumulation in leaves of finger millet when infected with Rhizopus oryzae and Curvularia lunata.Several bioactive and AFPs that are induced in response to pathogen attack have been identified and characterized in millets during the past few years . Prolami-amylase . SimilarMagnaporthe grisea (anamorph Pyricularia grisea) is one of the major limiting factors for the production and productivity in finger millets. Identification of QTLs/genes linked to important physiological traits such as blast resistance will be useful for molecular breeders to introgress those genes into locally well adapted germplasm. In this effort, molecular markers linked to blast resistance were identified, which could be used to develop blast resistant genotypes through marker assisted selection . Likewise, FMBLEST32 and RM262 were found to be associated to all finger millet blast diseases by both the approaches. The SSR marker UGEP53 was associated to finger blast by explaining the 10.5% of phenotypic variance . Thus, the genetic improvement of finger millet for increased grain yield by imparting resistance to fungal diseases and other biotic stresses is a priority. Understanding the molecular mechanisms of resistance in the finger millet grain will play key role in developing robust resistance against various pests and pathogens. One of the major constraints toward developing increased resistance to pathogens has been the relatively low level of resistance obtained when a single plant antifungal gene is used. The obvious strategy thus is to identify the combinations of such genes that will provide resistance against a broad spectrum of pathogens.Advances in recombinant DNA technology and molecular tools have remarkably assisted in establish finger millet as a model to understand plant\u2013microbe interactions. The initial work on finger millet transformation was carried out by coarse cereal rather referred as a nutri-cereal or as a nutraceutical crop and is seen as a potential solution for malnutrition and hidden hunger worldwide. Apart from its excellent nutritional value, its ability to tolerate various abiotic stresses and resist pathogens make it an excellent model for exploring vast genetic and genomic potential of this otherwise important crop and related cereal grasses. These properties thus on the whole make finger millet an ideal model for studying genomics and a plausible source for gene mining for complex traits.Finger millet is no more called a Brachypodium genome sequence, and on-going genomics program in finger millet and pearl millet will be of great help for the abiotic and biotic stress tolerance research in these minor cereals. High throughout sequencing platforms will not only be able to overcome the complexity of large and complex finger millet genome but will also help to understand the regulation of stress tolerance at transcriptional, post-transcriptional and epigenetic levels. An integration of various advanced high throughput omics strategies will definitely revolutionize finger millet research with the large-scale identification of stress responsive genes/proteins/metabolites that could potentially be used for crop improvement. Potential candidate genes responsible for high yield, biotic and abiotic stress tolerance and those involved in high mineral accumulation isolated from finger millet can also be utilized for improving other cereal crops through transgenic approaches or genomics-assisted breeding and pave way for the development of designer crops for a better and sustainable future. Production of transgenic crops expressing functional foreign genes has to be expanded to millets as well in order to produce transgenic finger millet varieties expressing foreign genes of agronomic importance, which will be very helpful in improving millet production by conferring resistance to both biotic and abiotic stresses. Development of a super cereal in the future may also be possible by incorporating various agronomically important traits into the genome of a single finger millet genotype. Thus utilization of current advances in molecular breeding and genetic engineering together with advanced Omics technologies will definitely prove useful in improving the present scenario of research in finger millet.Molecular biology and biotechnology has proved to be a promising tool for imparting stress tolerance in economically important plants, however, until now the progress is limited among millets mainly due to lack of appropriate genomic resources in these crops. However, with the availability of sorghum, foxtail millet and AK conceptualized the manuscript. SMG, SA, NM, and CL wrote the manuscript. AP assisted and CL, SP and JK edited the manuscript. SMG and AK contributed in critically revising the draft and updating the manuscript for publication. All authors read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Severe lower extremity trauma as a devastating combat related injury is on the rise and this presents reconstructive surgeons with significant challenges to reach optimal cosmetic and functional outcomes. This study assessed early reconstructions of complex lower extremity battlefield soft tissue wounds. This was a prospective case series study of battled field injured patients which was done in the Department of Plastic Surgery, Baqiyatallah University of Medical Sciences hospitals, Tehran, Iran between 2013-2015. In this survey, 73 patients were operated for reconstruction of lower extremity soft tissue defects due to battlefield injuriesSeventy-three patients ranging from 21-48 years old (mean: 35 years) were enrolled. Our study showed that early debridement and bone stabilization and later coverage of complex battlefields soft tissue wounds with suitable flaps and grafts of lower extremity were effective method for difficult wounds managements with less amputation and infections. Serial debridement and bone stabilization before early soft tissue reconstruction according to reconstructive ladder were shown to be essential steps. In this regard, optimal management of battlefield injuries to the lower extremity poses significant challenges to plastic surgeons. It is necessary to be a close cooperation between orthopedic and plastic surgeons for best management of battlefield injuries. Blast injuries are usually contaminated and composite in nature, concomitant trauma to vital organs usually exists and in time delivery to referral centers might also be significantly delayed due to the overwhelming number of the injured in the combat zone.2 Consequently, poor wound healing, chronic pain, heterotopic ossification and multiple drug resistant of wound infections are the leading complications associated with severe extremity injuries in the battlefield.3 Moreover, with the ever-growing advances of military technologies, more devastating and extensive war related injuries are on the rise.4Trauma places a massive burden on national economies and costs countries billions of dollars each year in healthcare system, law enforcement and productivity.5 Due to all these reconstructive difficulties and despite remarkable advancements of limb salvage procedures, in some cases amputation and use of advanced prosthetics remain a more feasible and beneficial alternative.6 Here, the challenges and proposed solutions regarding successful soft tissue reconstruction of the battlefield lower extremity trauma regarding to increase in terrorist attacks and increasing of civilian populations that are injured in such casualties were studied.Satisfactory surgical outcomes are not just limited to cosmetic aspects and functional demands of the lower extremities must also be surgically addressed.In a case series study of battlefield injured patients which was done in the Department of Plastic Surgery, Baqiyatallah University of Medical Sciences hospitals, Tehran, Iran between 2013-2015. All patients filled out the consent form before enrollment and the study protocol was approved by the Ethic Committee of Baqiyatallah University of Medical Sciences. In this survey, 73 patients were operated for reconstruction of lower extremity soft tissue defects due to battlefield injuries. The patients who referred for reconstruction of lower extremity defects were at the level of knee to foot. The characteristics of reconstructive procedures were shown in In some situations, blood supply of this muscle was damaged and in these conditions, fasiocutenous gastrecnimus flap was used in complex wounds and the result was good . In mid Seventy-three patients of 21-48 years old (mean: 35 years) were included in this study. Our study showed that early debridement and later bone stabilization coverage of complex battlefields soft tissue wounds of the lower extremity were effective method for complicated wounds management with less amputation and infections. Also, in any anatomic defects special vascularized flaps near to defects with or without skin grafts revealed good results . In addiFor reconstruction of wrist and proximal foot complex wounds, reverse sural flap was accompanied with functional results, and for complicated forefoot defects, toe fillet flap instead of foot amputation lead to better functional results. No significant complications after early managements of these complex lower extremity battlefield injuries during our survey were noticed. It is necessary to undertake a close cooperation between orthopedic and plastic surgeons for best management of battlefield injuries because these wounds were complex (contaminated and composite in nature) and were different from usual civilian accidents.7 Currently, no reliable scoring system exists to predict the success rate of limb salvage procedures in management of foot and ankle war injuries. The reliability of scoring systems like Mangled Extremity Severity Score (MESS) to predict the likelihood of limb salvage has been questioned.7 In a large prospective study, the clinical utility of different lower-extremity injury-severity scoring systems was assessed in 556 patients. The predictive power of MESS, the Nerve Injury, Ischemia, Soft-Tissue Injury, Skeletal Injury, Shock, and Age of Patient Score (NISSSA), the Limb Salvage Index (LSI), the Hannover Fracture Scale-97 (HFS-97) and the Predictive Salvage Index (PSI) were compared. The researchers reported low sensitivity and suggested that these scoring systems should be used with caution when deciding the fate of limbs damaged by high-energy mechanisms.8Compared with the civilian injuries, combat related trauma has been reported with significant worse salvage outcomes.9 In most cases and in absence of contraindications, it is logical to try salvation techniques initially. Decisions about amputation could be later finalized, considering the functional outcomes, patients\u2019 preferences and cost-effectiveness analyses.10 Strategies to prevent wound infection and preservation of the remaining viable structures should be seriously taken into consideration in each reconstructive step. Early, extensive and serial wound debridement remains a mainstay of successful soft tissue reconstruction of war injuries. Due to the high-energy mechanism and high risk of contamination of blast injuries, tissues tend to devitalize and the reconstruction efforts have to be delayed enough to allow for sequential and aggressive debridement.11In contrast with these findings, a number of studies with smaller sample size or retrospective design indicated a higher sensitivity and specificity of MESS as a simple and available scoring system.12 Debridement is very important in these injuries, our preferred method is serial conservative debridement until cleaning and good vascularized bed for reconstruction, this is especially important for early skin graft coverage. We did early management of these wounds with good results. Despite possible problems in detecting perfusion and viability of the affected tissues, some experts suggested use of tourniquets in order to minimize excessive blood loss in serial debridements. However, tourniquet must be released at the end of each debridement procedure to reassess the remaining tissues and the need for further debridement.In wounds with bone exposure or more complicated wounds that need the vascularized flap for coverage, debridement is also important; but in these wounds, early coverage with flap is very important due to prevention of secondary complications such as osteomyelitis. Another important point is fixation and stabilization of any bone injury before soft tissue reconstruction, of course; secondary procedures on bone such as bone graft must be conducted after good soft tissue coverage and healing of the wounds . 13 we did not use a delay reconstruction in our cases. Important factors that determined the timing and type of reconstructive procedures in lower extremity war injuries were hemodynamic stability, concomitant trauma, exposed vascular structures and severity of the injury. Providing rapid cover for the repaired vascular structures using myocutaneous or muscle flaps was of great importance.14The timing and reconstruction success rate of combat related injuries of the lower extremity were previously determined showing that acceptable infection rates and low rates of flap loss, despite reconstruction of wounds in the sub-acute period within one week and three months of injury.15There are several procedures for distal lower extremity reconstruction. In some cases, primary repair after debridement was the only surgery that was needed in superficial soft tissue injuries spit thickness skin grafts that were harvested preferably from intact limb as a good choice, but in some cases; combined procedures including skin grafts and some variety of flaps were necessary. Nerve damage usually can manage at the same time of soft tissue reconstruction or delayed repair and is dependent to wound condition and severity of damage.15 A recent systematic review of the literature reported trauma as the most common indication of the distally based sural fasciocutaneous flap. This flap has been used most frequently to cover heel, ankle and foot defects, respectively.16A variety of pedicled and free flaps could be used to cover the lower extremity war wounds. Reverse sural fasciocutaneous flap as a safe and quick pedicled flap requires no microvascular expertise. This flap is based on sural vessels and is a versatile option covering the lower limb wounds particularly in patients suffering multiple trauma or vascular pathologies.17 Gastrocnemius and soleus flaps could be used to cover the wounds around the knee and in cases of extensive damage to the lower extremity, a combination of both flaps have been recommended.18 We have shown combination of medial gastrocnemius faciocutenous and soleus muscle flap as vascularized flaps for large proximal leg defect with bone exposure due to explosion injured patient, reversed superficial peroneal neurocutaneous island flap that has been reported as an excellent alternative flap in soft tissue reconstruction of the ankle and foot as previously described.19Rectus abdominis myocutaneous flaps have historically remained a mainstay of reconstructive procedures in lower abdomen, groin and anterior thigh defects. However, alternatives including pedicled anterolateral thigh flap have been reported as superior alternatives with promising results and less donor site morbidity.20We explain soft tissue reconstruction of the distal lower limb defects in four parts. These parts are forefoot, midfoot, hindfoot and ankle-distal leg. The reconstructive surgeon have to consider the reconstructive ladder for any surgery in these parts, this means that simple procedures have complex reconstructions according to severity of blast trauma . Combat related trauma of the forefoot usually leads to complete or partial amputation of toes. Various reconstructive techniques according to reconstructive ladder could be used based on the toes involved to reach excellent functional and cosmetic outcomes. Big toe reconstruction is of value in maintaining good stability during gate and should be considered a priority. Free peroneal and scapular flaps have been tried with acceptable cosmetic and functional outcomes in post-traumatic reconstruction of the big toe.21 Dorsalis Pedis Adipofascial Perforator (DPAP) flap has been anatomically studied as another possible alternative in big toe reconstruction. Yet, its effectiveness remains to be verified by further clinical studies.22 Amputation is frequently preferred over the salvage of the lesser toe to prevent unnecessary extra challenge to the surgical team. However, reconstructive techniques using autogenous bone grafting with external fixation exist with satisfactory outcomes were reported in case series.23Also, use of free vascularized bone graft of the supracondylar region of the femur has been described with excellent outcome in cases of segmental bone defects of the great toe.24 Another important issue in reconstruction of the forefoot defects is maintaining the dorsal foot and ankle contour for shoe fitting. In order to address this issue, distally based adipofascial flap with skin graft could be utilized with minimum donor site morbidity, optimal aesthetic and functional results.25 Distally based lateral supramalleolar adipofascial flap has also been used to cover the dorsal foot and ankle surface in this regard.26Use of autologous hemi-toe osteochondral graft is another possibility with excellent reported functional improvements in reconstruction of interphalangeal joints.27 Yet, as previously discussed, a combination of factors complicate management of combat related trauma and as a result, optimal techniques used in the civilian setting might not properly work in soft tissue reconstruction of war injuries.10Midfoot blast injuries might result in open comminuted fractures and high potential of serious complications should be considered before selecting the ideal surgical approach. Open reduction and internal fixation is the standard approach in management of severe tarsometatarsal fractures of civilian foot and ankle trauma.28 However, some reports suggest persistent morbidity despite proper and in time use of external fixation in midfoot crush injuries.29 In another approach, successful use of saphenous cross-leg flap with modified Masquelet technique in reconstruction of extensive medioplantar defect was reported. Following saphenous cross-leg flap, corticocancellous iliac bone graft was used to reconstruct the medial cuneiform deformities.30External fixation as an alternative with satisfactory short and long-term outcomes is commonly practiced in military medicine in reconstruction of the severe open ankle and foot fractures in combat zone. This technique is superior to the conventional civilian approach regarding its applicability in face of poor recourses and less surgical insult to the severely damaged soft tissues.31 The hind foot defects are the most difficult to reconstruct successfully and are infamous with high rates of complications and final amputation, particularly if open calcaneal fracture is present. Informed early decision about amputation should be discussed with the patients before reconstruction procedures; as many limb salvage efforts would fail in these patients due to poor functional outcomes, osteomyelitis and infection. Size, location, fracture type and severity in addition to mechanism of injury could predict amputation risk in war-related calcaneal fractures. Amputation could lead to improved activity levels and reduced pain compared with the demanding salvage protocols in these cases.32In addition, a viable soft tissue coverage of the distal lower limb was reverse sural artery fasciocutaneous flap that has been reported with acceptable outcomes in carefully selected patients.33 Finally, if patient prefers limb salvage gracilis or suralis flaps with free skin grafts could be considered for soft tissue reconstruction of the calcaneal fractures.34 we have also shown reconstruction of complex hindfoot wound after mine explosion defect with reverse sural flap (A special pattern of hind foot trauma faced in war zone is caused by anti-vehicle mines and is referred to as \u201cdeck-slap\u201d injury. Review of the literature highlights devastating nature of these injuries and low chance of returning to military duties due to poor functional outcomes.ral flap .35 We used medial gastrecnimus free flap in complex heel wound due to mine explosion. In reconstruction of ankle and distal leg, posterior tibial perforator flap, revers sural flap and lateral supramalleolar skin flap based on supramalleolar artery provided a wide variety of reconstructive options in management of the distal lower limb soft-tissue defects. Use of free flaps is more reliable than distally based fasciocutaneous flaps in patients with poor vascularity of the lower limb or in cases with extensive defects.36 Soft tissue reconstruction of combat related lower extremity injuries poses significant challenges to the plastic and orthopedic surgeons. In addition, great patience and expertise are necessary to achieve most satisfactory aesthetic and functional patient-oriented outcomes. So serial debridement and bone stabilization before early soft tissue reconstruction according to reconstructive ladder is an essential step. As discussed earlier, reverse sural flap is considered a versatile option in optimal management of lower leg defects especially in maleolar defects, heel reconstruction, hindfoot and also midfoot reconstructions, we used this flap frequently for these reconstructions. This flap has a large arc of rotation and could be safely used, free of significant pressure to cover defects that are more extensive."} +{"text": "Escherichia coli (EPEC) as a model system, Hazen and colleagues used 9 isolates representing 8 lineages and 3 phylogroups to find that isolates with similar genomic sequences exhibit similarities in global transcriptomes under conditions of growth in medium that induces virulence gene expression, and they found variation among individual isolates.Archetypal pathogenic bacterial strains are often used to elucidate regulatory networks of an entire pathovar, which encompasses multiple lineages and phylogroups. With enteropathogenic Escherichia coli (EPEC) as a model system, Hazen and colleagues used 9 isolates representing 8 lineages and 3 phylogroups to find that isolates with similar genomic sequences exhibit similarities in global transcriptomes under conditions of growth in medium that induces virulence gene expression. They also found variation among individual isolates. Their work illustrates the importance of moving beyond observing regulatory phenomena of a limited number of regulons in a few archetypal strains, with the possibility of correlating clinical symptoms to key transcriptional pathways across lineages and phylogroups.Archetypal pathogenic bacterial strains are often used to elucidate regulatory networks of an entire pathovar, which encompasses multiple lineages and phylogroups. With enteropathogenic Escherichia coli diarrheal pathovar (a set of strains with similar characteristics) of global significance (E.\u00a0coli (EPEC) strains in different media and phases of growth, as well as under conditions of adherence to epithelial cells in culture. Under conditions mimicking those associated with pathogenesis, they observed coordinate regulation of key metabolic and virulence genes (Hazen et al. examined whether global transcriptome similarity can be correlated to genetic relatedness of phylogenetic lineages of an ificance . Previouce genes . Thus, tce genes . Differice genes , 4. HereHazen and colleagues concluded that the number of genetically similar lineages that have similar global transcriptomes is greater than the number of dissimilar lineages that have similar global transcriptomes. Their report also illustrates the subtleties of global transcriptomes across different isolates and lineages, and perhaps that represents the more significant observation. The diversity that they observed was due to genetic variation but also to variation in the regulatory control of key virulence genes and to subtleties and contradictions, in contrast to results shaped by limitations of technology or approach. The regulatory variation is likely adaptive for the pathogen. To illustrate this point, only 21 conserved core genes were significantly differentially expressed in all 9 of the EPEC isolates under virulence-inducing versus noninducing conditions. The list included metabolic genes but lacked most of the virulence genes thought to be regulated under these conditions. Through genomics and transcriptomics, we will gain a better understanding of the consistencies and inconsistencies across the different EPEC lineages and, ultimately, a clearer picture of the regulatory networks necessary to cause disease. Their work highlights that an integrative and inclusive approach to improve our understanding of the greater pathovar is not only possible but imperative.E.\u00a0coli pathovar to be described, was isolated in 1969 and has been studied as a prototypical strain over several decades, as a model pathogen causing diarrhea in children. This work by Hazen et al. reminds us of the historical and practical importance of studying prototypical isolates, clearly illustrates the limitations of this approach, and opens a new door to a much greater understanding of transcriptional control of bacterial disease. Many researchers around the globe study EPEC pathogenesis, including those investigating virulence gene expression, but all the isolates studied most likely contain genetic and regulatory variation compared to the original isolate due to genetic differences and laboratory passage over time (The E2348/69 strain of typical EPEC, the first ver time . FurtherE.\u00a0coli lineages are transmitted and cause disease outbreaks.As pointed out by the authors, we can begin to investigate whether clinical symptoms can be correlated with differences in transcriptional regulation and to understand why some lineages might be bystanders as opposed to true pathogens and why some lineages are associated with more-severe disease than others. With genome sequencing providing information about gene content and single nucleotide polymorphisms and RNA-Seq analysis routinely available to understand transcriptomes, some researchers have suggested that we can now move beyond the pathovar distinction for diagnostic purposes . If thei"} +{"text": "Editorial on the Research TopicThe Developments of Hybrid Surgical Strategies for Congenital Heart DiseaseOver the last few decades, we have witnessed a significant improvement in the outcomes of congenital cardiac surgery and a huge expansion in interventional cardiology techniques for the treatment of congenital heart disease. Nevertheless, a considerable number of patients fall into a gray area in which on the one hand conventional surgery has an unsatisfactory risk, and on the other hand an interventional cardiology procedure is not feasible because of technical limitations.A hybrid operation is defined as a procedure carried out by means of a combination of surgical and interventional strategies. If we consider the abovementioned gray area, a hybrid operation can be seen as a surgical procedure whose unsafe steps are dealt with interventional techniques; similarly, we could define it as an interventional procedure whose technical issues are overcome or reduced by one or more surgical steps.Having broadly defined hybrid surgery, some more detailed definitions are needed to better understand the rationale behind it.From a surgical perspective, duration of cardiopulmonary bypass and cardioplegic arrest of the heart are two of the main determinants of perioperative risk, which is directly correlated with them . This geFrom an interventional cardiology perspective, technical issues are related to limited size range of the available devices and awkward catheter manipulation in the context of the complex anatomy typical of congenital heart disease. Hence, the surgical portion of a hybrid operation aims at overcoming size limitations and providing a more direct access for catheter-based procedures.Being able to limit surgical risk has not only therapeutic implications but it also affects preoperative assessment process and, potentially, surgical indication. Therefore, the availability of a hybrid option broadens the spectrum of patients who can be treated successfully, including extremely high-risk individuals.The purpose of this research topic is providing an overview of the most important clinical problems that can be addressed with a hybrid approach in pediatric and adult congenital heart disease. It consists of four papers exploring different applications of hybrid surgery in this field.Suleiman et al.).In their review on hybrid pulmonary valve replacement after surgery for tetralogy of Fallot, Suleiman and colleagues reported current outcomes of surgical and percutaneous pulmonary valve replacement, highlighting drawbacks for both approaches. They also illustrated the potential advantages of hybrid pulmonary valve replacement according to experiences from the Bristol Heart Institute and the Rush University Medical Center, providing technical insights in terms of operative strategy and reporting published data supporting their practice .Rapetto and coworkers published a short series of three cases of adult patients with congenital heart disease that were managed successfully with a hybrid surgical approach. All patients had undergone previous cardiac operations for different reasons; they were then deemed unsuitable for conventional reoperative surgery requiring cardiopulmonary bypass and cardioplegic arrest due to comorbidities, impaired ventricular function or both (Gupta and Amin).Gupta and Amin reviewed the most popular hybrid congenital heart operations, specifically focusing on stage I Norwood procedure, ventricular septal defect closure, pulmonary valve replacement, and aortic balloon valvuloplasty. For each procedure, they briefly summarized the rationale for patient selection, technical aspects, and clinical outcomes, and also pointing out that the collaboration among different specialists is the necessary premise for satisfactory results .Finally, McLennan and colleagues reported a case of an infant with combination of aortic coarctation and aortic valvar stenosis, treated by surgical aortic coarctation repair and hybrid aortic balloon valvuloplasty through carotid artery cutdown. The two steps were performed as a combined procedure in a hybrid operating theater, with coarctation repair immediately followed by valvuloplasty. The authors also reviewed previously published outcomes of surgical and interventional treatments for these conditions, highlighting the excellent surgical results of conventional surgery for aortic coarctation but also pointing out the drawbacks of cardiopulmonary bypass and cardioplegic arrest in neonates needing open heart operations . The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Prevention of thrombotic disorders has priority over treatment. There are only two pathologically relevant tests which are suitable for measuring the overall thrombotic status both in experimental conditions and in humans. The Global Thrombosis Test (GTT) and the Global Parallel-Plate Thrombosis Test can detect the pathologically relevant global thrombotic status. These tests have been successfully used for monitoring the effect of antithrombotic drugs and for developing novel antithrombotic agents. By using GTT, varieties of fruits, vegetables, and regular physical exercise have been tested for the effect on global thrombotic status. This review discusses the published evidence for the benefit of diet of selected fruit and vegetable varieties and doing regular physical exercise on improving thrombotic status. Future clinical trials monitored by GTT or Global Parallel-Plate Thrombosis Test could decide on the effectiveness of an experimentally proven antithrombotic diet with regular physical exercise in the prevention of thrombotic diseases. Prevention of deadly diseases like heart attack or stroke is more effective than treating patients with already progressed disease. Epidemiologic studies raised the possibility that eating healthy food and doing physical exercise may prevent thrombotic diseases. To create an \u2018antithrombotic diet\u2019, fruits and vegetables should be selected and the benefit of diet and exercise should be monitored in people. We found that the Global Thrombosis Tests are useful\u00a0for both selection of antithrombotic diet components and monitoring thrombotic status of individuals. Large epidemiological study in the USA found that the risk of coronary heart disease in adults depends on the consumption of healthful and unhealthful plants . In thiset\u00a0al. found that antithrombotic activity of fruits and vegetables classified as \u2018healthy\u2019 is still depend on the tested varieties. Accordingly, varieties of the same fruit or vegetable can be antithrombotic, prothrombotic or without effect on thrombotic status [By testing native blood using the shear-induced\u00a0GTT, Yamamoto\u00a0c status . The antc status ,76. ThusEpidemiological and clinical studies suggested that regular exercise is an efficient way to prevent arterial thrombotic diseases . The recThe requirement of starting the tests within 15\u201320\u00a0s after withdrawal of blood samples mandates experienced operator or phlebotomist, and organization that the instrument should be near to the tested person. It is the latter which is most difficult to ensure, as in the present clinical practice blood samples are taken, stored and tested later in different laboratories.The concept of preventing arterial thrombotic disorders by long-term intake of an experimentally proven antithrombotic diet and monitored regular physical exercise is challenging and intriguing. The key to success is finding test(s) capable of monitoring thrombotic status under pathologically relevant conditions. In contrast to common platelet function or coagulation tests currently in use, the shear-induced global thrombosis and thrombolysis test and the global parallel-plate thrombosis test performed with native (nonanticoagulated) blood are suitable for screening fruit and vegetable varieties for antithrombotic effect. The use of these tests under experimental conditions can result in establishing an antithrombotic diet. Having found the pathologically relevant tools of testing and monitoring thrombotic status of individuals, future work should be focused on organizing large scale and monitored trials involving healthy people, and those who are at risk of atherothrombotic diseases and cardiovascular events. The outcome of such trials may justify the everyday consumption of an antithrombotic diet with regular physical exercise, and this would be a simple and economical way of prevention of arterial thrombotic diseases.Interest in prevention of thrombotic disorders by antithrombotic vegetable varieties and physical exercise is increasing. Pathologically relevant point-of-care global tests for the assessment of global thrombotic status are badly needed.The Global Thrombosis Test enables the simultaneous measurement of platelet reactivity to high shear stress, platelet procoagulant and endogenous fibrinolytic activity. This technique proved to be suitable for screening fruits and vegetables for antithrombotic effect, making possible to establish an antithrombotic diet and also to individualize the need of physical exercise in people at risk of thrombotic events. The Global Parallel-Plate Thrombosis Test enables also the simultaneous measurements of platelet activation, coagulation and fibrinolytic activities during thrombus formation.Global Thrombosis Test-monitored or Global Parallel-Plate Thrombosis Test-monitored large scale trials are needed to verify the beneficial effect of an antithrombotic diet with regular physical exercise in the prevention of arterial thrombotic events."} +{"text": "Hepatitis C is associated with more deaths in the United States than 60 other infectious diseases reported to CDC combined. Despite curative hepatitis C virus (HCV) therapies and known preventive measures to interrupt transmission, new HCV infections have increased in recent years to NNDSS in 2015 and U.S. Census data. Existing state laws in all states related to access to clean needles and syringes by persons who inject drugs were reviewed using the legal database WestlawNext. Once the relevant laws were identified, the legal findings were corroborated with findings from the Syringe Distribution Laws data set on LawAtlas.Three types of laws related to access to clean needles and syringes were researched: 1) authorization of syringe exchange programs; 2) the scope of drug paraphernalia laws; and 3) retail sale of needles and syringes. Two independent analysts qualitatively assessed the laws based on the presence of five elements in each type of law, and the potential impact of these elements on access to clean needles and syringes, in a method similar to other legal analyses had the most comprehensive laws related to prevention; each state had laws that authorized syringe exchange without jurisdictional limitations, removed barriers to possessing and distributing syringes and needles through drug paraphernalia laws, and explicitly allowed for the retail sale of syringes to persons who inject drugs .Twenty-four states had restrictive Medicaid treatment policies that required some period of sobriety to receive HCV treatment through Medicaid, including 11 of the states with the least comprehensive set of laws related to prevention. Sixteen states had permissive Medicaid HCV treatment policies that did not require a period of sobriety or only required screening and counseling to receive HCV treatment through Medicaid . Among tOnly three states had both a most comprehensive or more comprehensive set of laws and a permissive Medicaid treatment policy that might affect access to both HCV preventive and treatment services for persons who inject drugs.The creation and implementation of law can be used to achieve public health objectives, including infectious disease prevention and control, and legislation can be an effective tool to address public health threats faced by a state\u2019s residents , West Virginia had less comprehensive laws, and Kentucky and Massachusetts had more comprehensive laws. However, some of these laws did not take effect until 2015, suggesting that some laws might have been enacted in response to the increased HCV prevalence in these states.In addition to legal strategies aimed at primary prevention, state Medicaid policies can either facilitate or hinder access to HCV treatment services for persons who inject drugs incidence that can be attributed to injection drug use. Some states have used public health laws and treatment policies to reduce the risk for transmission of HCV infections among persons who inject drugs.In 2015, seventeen states were characterized as having acute HCV incidence rates above the national average. In an analysis of state laws governing access to safe injection equipment and Medicaid policies related to sobriety requirements for approval of HCV treatment for persons who inject drugs, only three states had state laws and Medicaid policies capable of comprehensively preventing and treating HCV among persons who inject drugs.This report can be used as a tool for states in establishing laws and policies to address increases in HCV incidence in their own jurisdictions, and as a source of data for evaluating the long-term impact of these laws and policies. State laws that increase access to syringe exchange programs and clean needles and syringes, and policies that facilitate access to HCV treatment through state Medicaid programs can reduce HCV transmission risk."} +{"text": "Strengthening Laboratory Management Toward Accreditation (SLMTA) is a competency-based management training programme. Assessing health professionals\u2019 views of SLMTA provides feedback to inform program planning, implementation and evaluation of SLMTA's training, communication and mentorship components.To assess laboratory professionals\u2019 and hospital chief executive officers\u2019 (CEOs) perceptions and attitudes toward the SLMTA programme in Ethiopia.A cross-sectional descriptive survey was conducted in March 2013 using a structured questionnaire to collect qualitative data from 72 laboratory professionals and hospital CEOs from 17 health facilities, representing all regions and two city administrations in Ethiopia. Focus groups were conducted with laboratory professionals and hospital administration to gain insight into the strengths and challenges of the SLMTA programme so as to guide future planning and implementation.Ethiopian laboratory professionals at all levels had a supportive attitude toward the SLMTA programme. They believed that SLMTA substantially improved laboratory services and acted as a catalyst for total healthcare reform and improvement. They also noted that the SLMTA programme achieved marked progress in laboratory supply chain, sample referral, instrument maintenance and data management systems. In contrast, nearly half of the participating hospital CEOs, especially those associated with low-scoring laboratories, were sceptical about the SLMTA programme, believing that the benefits of SLMTA were outweighed by the level of human resources and time commitment required. They also voiced concerns about the cost and sustainability of SLMTA.This study highlights the need for stronger engagement and advocacy with hospital administration and the importance of addressing concerns about the cost and sustainability of the SLMTA programme. These issues have fostered distrust in laboratory data amongst clinicians, reinforcing cycles of inadequate investment in laboratory systems. However, with recent emphasis on improving access to testing so as to meet the needs of expanded treatment and prevention programmes for HIV and other major diseases, the demand for diagnostics in resource-limited settings has increased substantially.3Laboratory services are an integral part of clinical decision-making and contribute to various aspects of health services, including the making of diagnostic and therapeutic decisions for patients, as well as disease monitoring and prevention.4 As a result, the World Health Organization\u2019s Regional Office for Africa has suggested that member countries improve the performance standards of their laboratories by implementing laboratory quality management systems (LQMS), establishing intermediate quality level goals and working toward accreditation in a stepwise manner.5Laboratory accreditation is used widely in developed countries to encourage and document improvements in the quality and reliability of test results. However, for laboratories in developing countries accreditation is a daunting challenge that only a handful of public laboratories in Africa have surmounted.The laboratory network in Ethiopia is organised according to size and scope: health centre laboratories, hospital laboratories, regional reference laboratories and national reference laboratories. The Ethiopian Public Health Institute (EPHI), formerly known as the Ethiopian Health and Nutrition Research Institute, developed its first laboratory Master Plan in 2005 with a focus on building laboratory systems in the country. One of the strategic objectives was to expand and strengthen the national LQMS.7 In 2010\u20132012, Ethiopia implemented the SLMTA programme in two cohorts with a total of 45 laboratories, comprising national and regional reference laboratories, referral hospital laboratories and district hospital laboratories throughout the country.8 Hiwotu et al. detail SLMTA implementation in Ethiopia, documenting substantial improvements to laboratory quality.9To accelerate the implementation of the LQMS, Ethiopia adopted the Strengthening Laboratory Management Toward Accreditation (SLMTA) programme, a competency-based management training programme that uses a series of short didactic courses and work-based learning projects to bring about immediate and measurable laboratory improvements and to prepare laboratories for accreditation.10 However, no study has yet been published assessing the attitudes of healthcare professionals toward the programme. This study aimed to assess laboratory professionals\u2019 and hospital chief executive officers\u2019 (CEOs) perceptions and attitudes toward SLMTA programme implementation in Ethiopia in order to provide feedback for programme planning, implementation, communication and mentorship activities.Since its introduction in 2009, SLMTA has been implemented in 617 laboratories in 47 countries.11 A total of 72 people \u2013 55 laboratory professionals (three to four per facility) and 17 hospital CEOs (one per facility) \u2013 were surveyed using questionnaires tailored to each group of respondents and four additional hospitals in larger regions. All hospitals included in the survey had participated in the Ethiopian Hospital Management Initiative and hospital CEOs had received Master of Hospital Administration degrees through the Ministry of Public Health as part of this programme.pondents . Hard anTwo focus groups representing 12 of the 17 facilities were conducted, each with five laboratory quality officers and three laboratory managers . In two-\u00ae Excel, after which descriptive statistics were used to present the findings. Qualitative data were analysed by transcribing and categorising responses.Quantitative data were entered and analysed using MicrosoftData collected from the eight regional laboratory managers showed an overwhelming agreement on the importance of the SLMTA programme. All of the participants agreed that the programme had brought substantial improvements to the quality of laboratory services, one saying that SLMTA was \u2018a catalyst for healthcare reform\u2019 in Ethiopia. Respondents reported that stock outs of reagents were reduced, data management systems were improved and interruption of service resulting from equipment problems was minimised.Respondents cited the commitment and participation of trained laboratory personnel, the national implementing unit and other implementing partners as major driving forces in the successful implementation of the SLMTA programme. All participating laboratory managers agreed that SLMTA has helped to accelerate improvements in laboratory networking, sample referral systems, competency of laboratory professionals through need-based trainings, laboratory equipment maintenance and electronic or paper-based data management.Despite the significant benefits of the SLMTA programme, two of the eight respondents indicated that laboratory quality improvements were not as large as they had expected. The main challenges they faced in implementing the programme included high turnover of trained staff, inconsistent and inadequately-trained mentors and a lack of awareness regarding the importance of SLMTA at some facilities.The respondents recommended further training for laboratory staff and sensitisation workshops for medical directors and hospital CEOs. For sustainable SLMTA implementation throughout the country, respondents suggested national strategic planning and empowerment of regional laboratories to oversee the programme in their respective regions.Of the 47 facility laboratory managers and quality officers surveyed, 40 (85%) viewed the SLMTA programme as being a critical step in the laboratory quality improvement process. All participants reported that SLMTA impacted every laboratory process and believed that positive and sustainable changes had occurred at all levels of the laboratory. They reported more confidence about the procedures to follow as well as a better understanding of the tests they performed, and felt that they were given more responsibilities for laboratory quality improvement processes.Thirty-five (74%) of the participants reported satisfaction with the SLMTA training methods and that they gained important knowledge and experience. The remaining 12 (26%) respondents had various complaints about the training methods. For example, one respondent (Participant 03) reported that \u2018the programme was launched without availing computers and providing basic computer skill training\u2019 as there were no computers available at the training facility.w]e were spending so much of our time preparing different documents that had no potential impact on the quality of laboratory services\u2019 (Participant 01).Half of the participating quality officers and laboratory managers related that, even though SLMTA demanded more resources than were currently available, improvements and changes were vital for their laboratories. They reported that the ministry planned to provide the resources necessary for accreditation preparation. The other half indicated that SLMTA\u2019s value for accreditation preparation was low in comparison to the resources and time required to implement. One said, \u2018 beyond our ability and capacity before.\u2019 (Participant 16)\u2018Vaccination and safe waste disposal are coming true in our facility, [A majority of the focus group participants agreed that the programme required more resources and time than they had anticipated. One participant said:\u2018Even though I have no doubt of the importance of SLMTA for my country, the programme requires more resources which will hinder implementation in resource-limited situations.\u2019 (Participant 04)On the other hand, some participants did not notice the cost of SLMTA, since the programme is mainly funded by support from the government and implementing partners.Participants expressed great concern about sustainability. All agreed on its importance, but noted that neither EPHI nor the implementing partners who initiated SLMTA in Ethiopian laboratories had designed strategies for sustaining the programme. Health facility management and the regional health bureau were not made aware of the need and cost of implementing and sustaining SLMTA. Furthermore, the roles of facility management and of the regional health bureau have not been clearly defined; this complicates the issue, since participants believe that sustaining the SLMTA programme is the responsibility of the government.Participants agreed that sufficient action had not been taken to decentralise responsibility from the government to the management at their facilities, primarily because of a lack of regular communication between management at the facilities and EPHI. They recommended that all stakeholders, including laboratory management, facility management, EPHI and implementing partners, maintain close communication in order to share the responsibility of sustaining the SLMTA programme.Participants agreed that regular mentorship as part of the SLMTA programme was important, but noted that this component was absent in some of their facilities. Major concerns included deficiencies in the number of trained mentors, uncoordinated planning between EPHI and regional facilities and lack of awareness of the importance of mentorship for quality management systems. Participants pointed out that the time allocated for mentorship was insufficient and that there were inconsistent skill levels amongst mentors. One shared her experience:\u2018Even though we have limited mentorship services, we have tremendous knowledge and experience from mentors that improves our facility performance.\u2019 (Participant 06)The majority of the discussants agreed that implementing partners have played an important role in SLMTA execution. They have worked in collaboration with EPHI on capacity-building activities, such as renovation of laboratories, donation of modern laboratory equipment and provision of mentorship and basic training to laboratory staff on safety and quality management. One regional hospital representative shared:\u2018The role of partners in the SLMTA programme was an essential piece for SLMTA implementation in our facility.\u2019 (Participant 15)However, some participants argued that the role of partners should be to build capacity and focus on short-term solutions, rather than to provide long-term support for SLMTA. One participant expressed concerns that partners have provided \u2018a lot of support, but there was no joint planning between facilities and partners\u2019 (Participant 10). Other participants wanted to take on more of the responsibility, saying:\u2018We want the help of partners based on our plans and requirements.\u2019 (Participant 09)Common challenges identified included lack of commitment from facility management and laboratory staff, turnover of trained staff, insufficient regular mentorship, inadequate laboratory infrastructure, lack of awareness of the importance of the SLMTA programme and scarce resources. Other impediments included frequent equipment malfunction due to power interruption and lack of coordination between implementing partners and EPHI.The attitudes of laboratory personnel in this study were generally supportive of the SLMTA programme. They recognised that SLMTA fundamentally restructured laboratory operations, heightened the confidence of laboratory professionals, improved data management systems and reduced turnaround times, equipment down times and supply lead times. Study participants agreed that the programme resulted in substantial improvements to the quality of laboratory services, laid the foundation for the implementation of an integrated pharmaceutical logistics information system and served as a catalyst for total healthcare reform and improvement in Ethiopia. Laboratory staff concerns focused on the issues of retention of trained staff, lack of regular mentor visits and resource requirements with regard to SLMTA implementation.Hospital CEOs were more sceptical of SLMTA and raised concerns regarding programme costs and the prolonged process associated with implementation. In addition, many hospital CEOs did not have a clear understanding of the benefits of the SLMTA programme and most of those in hospitals whose laboratories remained at the zero-star level at the exit audit did not believe that the value of the improvements merited the human resources and time consumed. The roles of hospital management and regional health bureaus should be afforded greater attention in the implementation of SLMTA. Overall, the greatest concern was the cost and sustainability of SLMTA.12 Two of the 17 studies identified focused on the laboratory personnel\u2019s perceptions towards accreditation. Both studies found that most of the respondents preferred to work in an accredited laboratory because accreditation increased their confidence in the procedures they followed. However, the majority had concerns about the cost of accreditation and whether it had an effect on the quality of laboratory results.Previous studies have found similar results. Alkhenizan and Shaw conducted a systematic review of the global literature on the attitude of healthcare professionals toward accreditation.The interface between laboratories and clinicians is important, as clinicians play a critical role in the use of laboratory services and test results; however, physicians and nurses were not interviewed in this study. An evaluation of their attitudes toward laboratory services before and after SLMTA implementation and their perspective on SLMTA in general would provide additional relevant information.Laboratory professionals had a positive attitude toward SLMTA implementation in Ethiopia, seeing it as a driving force for substantial improvements in sample referral linkage, laboratory commodity management and laboratory data management systems. Half of the hospital CEOs were positive about the programme, whilst the other half, mainly those with low-scoring laboratories, were sceptical, highlighting the need for stronger engagement with hospital administration in order to address concerns about cost and sustainability. Future studies focusing on the cost-benefit of the SLMTA programme and long-term sustainability of results within SLMTA laboratories, as well as of the programme as a whole, would be beneficial."} +{"text": "Recent studies indicated that the Zika virus genome could be detected in the amniotic fluid and the fetal brain, which confirms that the virus can cross the placental barrier. Secretory autophagy or exosome pathways may participate in this virus transfer. Autophagy modulators regulate autophagosome formation or membrane fusion with lysosomal vesicles and therefore inhibit viral nucleocapsid releasing or virus transfer to the fetus hypothetically. However, some autophagy modulators may enhance virus replication. Autophagy inhibitors may arrest placental development; while exaggeration of autophagy in human placenta may be associated with the fetal growth restriction. Therefore, autophagy modulators should be used carefully due to their complex clinical effects. Alternatively, exosome-specific inhibitors might be also considered, although their safety of both maternal and fetal conditions must be carefully assessed before any advancement to human clinical trials. A widespread epidemic of Zika virus (an emerging mosquito-borne flavivirus) infections was found in Central and South America recently. The main concern is the significant increasing of microcephaly in the fetus born to the mother of Zika virus infection pathways, may enhance antigen presentation and processing and improve maintenance of memory CD8 cytotoxic T lymphocytes after influenza virus infections Fedson, . CarbamaAmong the common autophagy stimulators, only rapamycin (a mTORC1 inhibitor) has been shown to inhibit exosome release evidently may be only one of the complex mechanisms of Zika virus penetration through the placental barrier. Zika virus infection triggers apoptosis and vascular damages in the placenta, which may increase the permeability of the placenta (Miner et al., When Zika virus has penetrated the placenta, it may damage the fetal brain directly or indirectly, because of its neurotropic property (Mlakar et al., ZZ contributed to the discussion of ideas and helped with the writing. ZL contributed to the discussion of ideas and the writing. SY conducted the literature search and drafted the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer IEC and handling Editor declared their shared affiliation and the handling Editor states that the process nevertheless met the standards of a fair and objective review."} +{"text": "This paper reports the synthesis and UV sensing characteristics of a cellulose and ZnO hybrid nanocomposite (CEZOHN) prepared by exploiting the synergetic effects of ZnO functionality and the renewability of cellulose. Vertically aligned ZnO nanorods were grown well on a flexible cellulose film by direct ZnO seeding and hydrothermal growing processes. The ZnO nanorods have the wurtzite structure and an aspect ratio of 9 ~ 11. Photoresponse of the prepared CEZOHN was evaluated by measuring photocurrent under UV illumination. CEZOHN shows bi-directional, linear and fast photoresponse as a function of UV intensity. Electrode materials, light sources, repeatability, durability and flexibility of the prepared CEZOHN were tested and the photocurrent generation mechanism is discussed. The silver nanowire coating used for electrodes on CEZOHN is compatible with a transparent UV sensor. The prepared CEZOHN is flexible, transparent and biocompatible, and hence can be used for flexible and wearable UV sensors."} +{"text": "Rheumatic valve disease, a consequence of acute rheumatic fever, remains endemic in developing countries in the sub-Saharan region where it is the leading cause of heart failure and cardiovascular death, involving predominantly a young population. The involvement of the mitral valve is pathognomonic and mitral surgery has become the lone therapeutic option for the majority of these patients. However, controversies exist on the choice between valve repair or prosthetic valve replacement. Although the advantages of mitral valve repair over prosthetic valve replacement in degenerative mitral disease are well established, this has not been the case for rheumatic lesions, where the use of prosthetic valves, specifically mechanical devices, even in poorly compliant populations remains very common. These patients deserve more accurate evaluation in the choice of the surgical strategy which strongly impacts the post-operative outcomes. This report discusses the factors supporting mitral repair surgery in rheumatic disease, according to the patients' characteristics and the effectiveness of the current repair techniques compared to prosthetic valve replacement in developing countries. Although mitral valve repair (MVR) has become the treatment of choice in degenerative etiology, the fundamentals of this surgery promoted by Carpentier were devA literature search was conducted in medical databases Pubmed and Google Scholar using the following combination of keywords: \"rheumatic heart disease\", \"mitral valve repair\", \"mitral valve replacement\", \"developing countries\", \"anticoagulation\". There were no restrictions to language, date of publication or publication status. All identified citations were critically evaluated to establish the possible relevance of the articles for inclusion in the review. A total of 46 papers were finally analyzed. The bibliographies of the articles in hand were used to find other references. Attention was given to articles comparing the outcomes of mitral valve repair and replacement for rheumatic heart disease.According to estimates of the World Health Organization, about 16 million people are affected by RHD worldwide, with a high prevalence among young populations in developing countries . The subIt is widely ascertained that PVR reduces life expectancy, especially in children and young adults regardless of native valve pathology, due to prosthetic valve-related complications \u201322. A reClinical and surgical patterns of rheumatic mitral valve disease may differ between patients from western and southern regions. In the developed countries, patients are often older, some with previous surgical or percutaneous procedures for mitral disease especially for valve stenosis . These pThe high rate of failure and reoperation associated with MVR in rheumatic aetiology has been commonly argued to favour PVR in this disease. This thinking developed during the early era of mitral reconstruction techniques, as various studies had reported suboptimal repair results , 33. ThePerioperative management of patients' undergoing valve surgery has also improved, with more accurate pre-operative assessment of valve function, routine use of intraoperative transoesophageal echocardiography, and better myocardial protection strategies. The surgeons can be less concerned with cross-clamping duration and may first attempt MVR and then PVR only in case of suboptimal repair. Furthermore, many experts have shared their methods to assess repair feasibility and to prevent failure. Gupta and colleagues describeMore than fifty years ago, Frater said, \"A patient with a mitral prosthesis is a patient for life,\" emphasizIntroducing his paper CarpentiAdvantages of mitral valve repair over prosthetic valve replacement in degenerative etiology are well established;Mitral valve repair in rheumatic disease is associated with high rate of failure and reoperation as compared to degenerative disease;Management of patients with prosthetic valves is challenging in developing regions for the limited financial and medical facilities especially for anticoagulation control.Rheumatic mitral lesions in young patients are often amenable to repair;Recent experiences of rheumatic mitral repair have reported improved freedom from failure and reoperation on the long term as compared to earliest studies;With few exceptions, the management of patients with prosthetic valves especially mechanical valves in the Sub-Saharan regions remains challenging."} +{"text": "Radiologic imaging of the newborn detected prenatally with hydronephrosis should follow a systematic approach. Upper and lower urinary tract imaging should be performed in most cases in order to determine the etiology and gauge the use of future imaging. An overview of renal ultrasound, voiding cystourethrography, renal scintigraphy, and magnetic resonance urography in the setting of antenatal hydronephrosis are discussed."} +{"text": "This article provides a description of an agricultural household survey data of rice growers collected in Ecuador between October 2014 and March 2015. The household survey was implemented using a structured questionnaire administered among 1028 households in the main rice production areas of Ecuador . Information collected was provided by household heads and included household and plot level data. The survey information includes household socio-demographic characteristics , farm characteristics , rice management practices , and rice production and utilization . Additional socio-economic context variables were also recorded such as government subsidies to rice production, participation in rural organizations, and food security related questions. The dataset contains a total of 6288 variables among numeric, categorical and string variables. The dataset is shared publicly on the Harvard dataverse site and provide access to questionnaires, the complete data and a brief report. Specifications tableValue of the data\u2022The dataset with detailed plot level information can be used to characterize rice farming systems in Ecuador and parametrize and develop rice crop models to evaluate biotic and abiotic effects on production.\u2022The dataset can be used to estimate the level of adoption of different rice varieties and agronomic practices in Ecuador, and analyze factors influencing adoption of agricultural innovations in the rice sector. This analysis could support a better targeting of agricultural extension programs.\u2022The dataset contains key variables to estimate productivity and livelihood impacts of using agricultural innovations that would inform agricultural policies in the rice sector.1The dataset described in this article was collected in the coastal region of Ecuador between November 2014 and April 2015. Ecuador is one of the most important rice producing countries in Latin America and where improved rice technologies have been widely promoted The dataset recorded information about household characteristics , rice production , land ownership and tenure, other crops farmed, production decision making disaggregated by gender , productive assets endowment, measurements of poverty level (using the Progress out of Poverty Index) and food security (using consumption during the last 24\u202fh and week), access to credit and public services, and climate change perceptions.The survey was collected by interviewing the farm household head . In addition to the complete data, a variable dictionary describing labels and the questionnaire used for data collection are available in the Harvard dataverse. Identification variables such as farmer's name, GPS coordinates, and community names were removed and they are available only upon request .Fig. 1Ma2) formats.Following"} +{"text": "This paper reviews the effects of single and repetitive transcranial magnetic stimuli (rTMS) delivered to one cortical area and measured across distributed brain regions using electrophysiological measures , functional neuroimaging and behavioural measures. Discussion is restricted to changes in excitability in the primary motor cortex and behaviour during motor tasks following transcranial magnetic stimulation delivered to primary motor and premotor areas. Trains of rTMS have lasting effects on the excitability of intrinsic and corticofugal neurones, altering the responsiveness of local and remote sites. These effects lead to distributed changes in synaptic activity at rest, and during a range of motor tasks. It is possible to impair or improve performance following rTMS, but for most simple motor tasks performance is unaltered. Changes in distributed activity observed with functional imaging during motor behaviour may represent compensatory activity, enabling maintenance of performance; stimulation of additional cortical areas appears to impair performance. A detailed understanding of the distributed changes in excitability following rTMS may facilitate future attempts to modulate motor behaviour in the healthy brain and for therapeutic purposes."} +{"text": "Making the diagnosis of pulmonary tuberculosis in children can be difficult because microbiological confirmation is not often achieved. Diagnosis is therefore often based on clinical features in combination with chest radiograph findings. Chest radiographs can demonstrate lymphadenopathy of the hilar and para-tracheal regions on the anteroposterior view, and subcarinal lymphadenopathy on the lateral view. However poor interobserver agreement has been reported for radiologist and clinician assessment of lymphadenopathy. This might reflect the lack of standardised imaging criteria for diagnosis as well as radiologists\u2019 objectives for achieving sensitivity rather than specificity. In this paper the authors provide a pictorial aid of chest radiographs in children with culture-confirmed tuberculosis to help clinicians identify lymph node enlargement in primary pulmonary tuberculosis. This collection of images comprises chest radiographs accompanied by schematics and either CT or MRI scan confirmation of pathological lymph node enlargement at the positions commonly affected in tuberculosis. Making the diagnosis of pulmonary tuberculosis in children can be difficult because microbiological confirmation is not often achieved . DiagnosDespite their many limitations, chest radiographs demonstrate lymphadenopathy of significant size at the hilar and para-tracheal regions on the anteroposterior view and in the subcarinal region on the lateral view , 8. EnlaCT is considered the modality of choice for identifying mediastinal and hilar lymphadenopathy , 10 and In the context of standardising the interpretation of chest radiographs of children with suspected pulmonary tuberculosis in clinical practice, it can be useful to have a pictorial aid of chest radiographic images in children with culture-confirmed tuberculosis and definite lymphadenopathy confirmed through cross-sectional imaging. This could act in a similar manner to the templates of images used in other areas of diagnostic imaging where standardisation of imaging features for diagnosis is vital, such as asbestosis scoring on chest radiograph and ovarconcave outwards and the space between the main intersecting vessels should be empty of soft-tissue masses. There should be no compression of the major bronchi.Figure convex appearance [Right hilar lymphadenopathy is seen on the anteroposterior radiograph as a lobulated density occupying the hilum and obliterating the hilar point , resulting in an outwardly pearance . Figure Because of the presence of a thymus and other normal structures making up the mediastinum, lymphadenopathy superimposed on these can be masked on the anteroposterior radiograph . LymphadLeft hilar lymphadenopathy is reported less often in children because it only becomes obvious on anteroposterior chest radiographs when it projects beyond the left cardiac margin . Left hiLeft paratracheal lymphadenopathy is not often identified in isolation and is usually reported when the whole anterior mediastinum is involved. Figure It has been demonstrated that because infant airways are smaller and more pliable than others they can be more easily compressed by enlarged hilar lymph nodes . This maNormal lateral chest radiographs should not demonstrate any oval soft-tissue densities dorsal or inferior to the lower trachea (near the carina) and bronchus intermedius. Normal soft-tissue densities of the vascular structures, the main pulmonary arteries and posterior aspect of the aortic arch should form an upside-down horseshoe above the level of the carina, while only diverging linear and branching smaller vessels should be seen below this Fig. 7)7). The pLateral radiographs are considered useful and therefore are still obtained for detecting lymphadenopathy in children with suspected tuberculosis. Lymphadenopathy is characteristically identified as lobulated mass-like density posterior and inferior to the bronchus intermedius , 8. LympThis pictorial review represents a comprehensive collection of chest radiographic signs of tuberculous lymphadenopathy with explanatory schematics and accompanying cross-sectional imaging confirmation, and is intended to aid clinicians who interpret chest radiographs in children with suspected pulmonary tuberculosis. It is also hoped that the publication of a pictorial standard of the appearances of obvious lymphadenopathy on chest radiographs confirmed with cross-sectional imaging in children with culture-confirmed primary pulmonary tuberculosis serves to improve interobserver agreement in the interpretation of chest radiographs for the diagnosis of pulmonary tuberculosis in children."} +{"text": "Neuropsychiatric disorders constitute a large global burden of disease; yet the neural mechanisms of emotional and social cognitive disturbances in patients are not yet fully understood .Anhedonia is an underlying critical feature of neuropsychiatric disorder but has remained little understood since first being introduced by Theodore Ribot in 1896 as the \u201cinability to experience pleasure\u201d , emotional traits in ADHD, borderline and antisocial personality disorder into a related cluster of mental conditions.Cognition interacts with emotion to play a major role in those at risk for developing neuropsychiatric disorders. In particular Sallin et al. describe investigations into resignation syndrome, which is long-standing disorder predominately affecting psychologically traumatized children and adolescents in the midst of a strenuous and lengthy migration process. They evaluate several hypotheses including stress and culture-bound psychogenic catatonia, and show how models of predictive coding and in particular negative expectations could explain the down-regulation of higher order and lower order behavioral systems in vulnerable individuals.Still, some neuropsychiatric disorders are not fully understood. BDNF Val66Met genotype and adolescent depressive symptoms (Xia and Yao).Genetic factors are also important for the development of neuropsychiatric disorders. Xia and Yao conducted a systematic review of the genes involved in adolescent depression and found positive association between Durieux et al.). They used mice to test that striatal glutamate levels can be shifted by N-acetylcysteine and found that the treated animals were significantly less active and more anxious in the open field test.Animal models can potentially provide new insights into the neural mechanisms of neuropsychiatric disorders. Durieux and colleagues tested the hypothesis that the known imbalance between excitatory glutamate and inhibitory GABA transmission found in some neuropsychiatric disorders can be indirectly modulated through glial mechanisms .Still, studies on human participants are likely to be more informative and objective measurements of relevant impairments are urgently needed. In order to address this, Bland and colleagues developed a standardized test battery, comprised of existing, adapted and novel tasks, to assess four core domains of affective cognition in order to facilitate and enhance treatment development and evaluation in a broad range of neuropsychiatric disorders but only recent developments in methods including probabilistic tractography and whole-brain computational modeling enabled Van Hartevelt and colleagues to identify the Hebbian-like changes in structural connectivity induced by long-term deep brain stimulation .The treatment of neuropsychiatric disorder has a long history but the development of deep brain stimulation (DBS) for the treatment of Parkinson's disease is relatively recent and found that weaker intra- and inter-network functional connectivity of the salience network was linked to higher trait anxiety among adolescents, which may underlie altered salience processing and cognitive regulation.Anxiety is a significant neuropsychiatric problem, especially in adolescence. Geng and colleagues investigated adolescents' susceptibility to trait anxiety (Gawda and Szepietowska). They found significant differences during the performance of more complex tasks between individuals with low anxiety and those with high anxiety.Similarly, Gawda and Szepeitowska investigated the brain activity in low/high-anxious adult groups of participants based on measures of trait anxiety .Adolescents are also prone to develop compulsive behaviors which include various forms of behavioral addictions .Borderline personality disorder is another important neuropsychiatric disorder linked with differences in brain activity. Using EEG, Van Elst and colleagues found significant intermittent rhythmic delta and theta activity in patients compared to controls . This reveals a new dimension to this brain region in processing exclusion and contributing to mental health outcomes in those vulnerable to depression.Depression has been strongly linked to social functioning .In more evidence of how depression is linked to impaired social functioning, Young and colleagues found that depression reduces psychomotor performance and alters affective movements in caregiving interactions based on salient affective sounds .More evidence of changes in social cognition was unearthed in a neuroimaging study of voice perception and handedness which showed that a polymorphism specifically affects voice-specific brain function . They found that different dimensions of schizotypy are correlated with brain regions involved in social cognitive abilities.Finally, Wang and colleagues used neuroimaging to examine participants with different risk for psychosis .Problematic hypersexual behavior is a compulsive behavioral compulsive disorder defined as the continuous participation in sex acts with little or no control over excessive sexual compulsivity and behavior despite the awareness of the associated negative outcomes. Seok and Sohn used neuroimaging to study a group of hypersexual individuals and found significant differences compared to controls, which are consistent with other behavioral addictions .Hoarding disorder is another compulsive disorder, characterized by the excessive acquisition and retention of goods with limited or no value, leading to significantly cluttered living spaces, and significant associated distress and life impairment. Vickers and colleagues used behavioral methods to investigate hoarding disorder and found that individuals in the high hoarding group were more impatient for consumables than for monetary reward, which suggest a specific, potent desire for consumable rewards . They found that high impulsivity is associated with increased metabolism within the fronto-insular network.Tahmasian and colleagues used positron emission tomography to investigate correlations between glucose metabolism and impulsivity in patients with Parkinson's disease .The anticipation of reward is an important component of the pleasure system which can become unbalanced in neuropsychiatric disorders, especially in adolescence. Li and colleagues used neuroimaging to investigate anticipatory pleasure in healthy adolescents and found that activity in the mesolimbic pathway during the anticipation of monetary reward could to some extent be predicted by subjective anticipatory pleasure .Anticipation of reward has been studied in the context of delayed discounting and intertemporal decision-making. Ludwig and colleagues used neuroimaging to uncover the neural correlates of delay discounting during reward delivery and found that impulsivity and subclinical anxious-depressive traits are related to stronger neural responses for winning immediate relative to delayed rewards \u201d of the Chinese Academy of Sciences (XDB02030002), the National Science Fund China , the Beijing Training Project for Leading Talents in S&T (Z151100000315020). MK is supported by an ERC Consolidator Grant CAREGIVING (n.615539).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Biochemical and pharmacological studies have identified the structure of leukotrienes, the pathways that lead to their synthesis, and the signaling events they trigger when they interact with their cognate receptors. A privileged interaction exists between these lipid mediators and another group of molecules essential for inflammation and immune modulation, namely, cytokines. Whereas leukotrienes can trigger the synthesis and release of selected cytokines in distinct cell populations, many cytokines can affect cellular responsiveness to leukotrienes by modulating leukotriene receptor expression. As we progressively begin to unravel these complex interactions, new areas of cell-cell communication and eventual therapeutic interventions will emerge."} +{"text": "Cases of Zika virus were recently detected in Luanda, Angola, a major travel hub in Africa. The risk of Zika virus transmission throughout the continent from Angola is evaluated.Travel volumes were assessed using monthly passenger-level flight data from Luanda to all locations throughout Africa. Travel data was superimposed onto seasonal environmental suitability maps that predict the potential for subsequent Zika virus transmission.Windhoek, Maputo, Durban and Kinshasa have the greatest potential for Zika virus introduction and transmission during the southern hemisphere summer months, and Nairobi during the northern hemisphere summer months. Aedes mosquito vectors. Although the current Pan-American outbreak strain is caused by the Asian genotype, the virus has recently been detected in at least three African settings: Guinea-Bissau (African genotype), Angola (genotype yet to be determined)1 and Cape Verde (Asian genotype). The African ZIKV genotype has also been known to be circulating in West Africa at low levels for the last few decades, possibly supported by a sylvatic cycle,2 although there are suggestions that the ZIKV stain currently circulating in the Americas has significantly higher infectivity.3 The more recent cases in urban areas of Angola are of potential concern. Angola is a major gateway between Africa and South America with significant connectivity via air travel and is a plausible location for ZIKV re-introduction.4 Furthermore, Angola, its neighbours, and much of the continent is vulnerable to arboviral infections year-round due to conducive climate conditions, and many countries have sub-optimal surveillance systems in place for disease detection. Should Angola become a focal point for ZIKV introduction, directing limited public health resources to strengthen surveillance and control measures in that country, while also predicting where subsequent regional and continental transmission may occur could help mitigate ZIKV-related complications.Zika virus (ZIKV), originally endemic to parts of Africa and Asia, has now spread throughout most of Latin America and the Caribbean, and has infected millions of individuals. Infections with Zika virus are typically mild, although data emerging from the current epidemic confirmed that the infection is associated with significant birth defects and Guillain\u2013Barr\u00e9 syndrome, and that it can be transmitted sexually. ZIKV has spread internationally due to the movement of infected individuals and autochthonous transmission is now occurring in several regions that have suitable conditions, namely the appropriate climate and 1 to all locations throughout Africa. We analysed all airport destinations and corresponding volumes of travellers for the period of October 2015 to September 2016 using worldwide ticket sales data from the International Air Transport Association. To estimate the potential for local virus transmission arising from ZIKV introduction, we then combined predictions of local monthly variation in ZIKV transmission suitability,4 and show seasonal variation in local transmission risk for the 10 most visited African cities from Luanda, Angola.We analysed monthly passenger-level flight data from Luanda (where two ZIKV cases were recently detected)Aedes aegypti suitability for subsequent ZIKV transmission. Areas that have high risk of ZIKV introduction and potential for local transmission are Windhoek, Maputo, Durban and Kinshasa . Transmission potential is expected to shift to the northern hemisphere during their spring and summer months. In this analysis, Nairobi had both the highest potential of ZIKV introduction reflected by the number of arriving passengers coupled with suitable environmental potential for local transmission followed by Addis Ababa (Ethiopia), which experienced a significant increase in passengers in the months of November to January Figure . Johannen Figure .5 Prior studies evaluating the potential for ZIKV introduction or re-introduction to African and Asia-Pacific settings highlighted Angola as being of increased risk of importation during the months of November to April given the confluence of travel patterns from epidemic locations (from Brazil in particular) and congruent seasonal environmental conditions suitable for ZIKV transmission in the arrival locations of these passengers.4 Our results reveal the potential for distant spread of ZIKV from Angola throughout the African continent via air travel, highlighting that Namibia and Mozambique are at highest risk for importation and subsequent transmission. Beyond continental spread via air travel, spread of the virus via land travel is possible, as recently observed with yellow fever cases spreading from Angola to the Democratic Republic of Congo.6 Unfortunately, the limited diagnostic, surveillance and public health infrastructure in many at-risk African settings poses several challenges, including providing quality maternal care and mosquito control efforts. Recent advances in rapid and even portable genomic sequencing of arboviruses could improve surveillance, but currently there a dearth of data evaluating the burden of illness in African settings.7It is currently unclear if the cases of ZIKV detected in Angola are of the African or Asian lineage. Genetic data could help with answering this question and elucidate whether the detection of these cases is indicative of local transmission. If so, there are presumably more unreported cases. This is of concern for pregnant women or women considering pregnancy, given the association between ZIKV infection and foetal complications.It is unclear what the underlying extent of protective immunity to ZIKV exists in African settings. It is also unclear whether the African genotype provides some or any cross-protection against the epidemic Asian strain. These two unknown issues have the potential to significantly influence transmission dynamics of ZIKV in Africa. Regardless of the genotype circulating in Angola, these recently discovered cases have been suggested to be the result of local transmission. This further highlights the potential of arboviruses to spread locally and regionally in African settings, requiring a coordinated public health response.Supplementary DataClick here for additional data file.Supplementary DataClick here for additional data file.Supplementary DataClick here for additional data file.Supplementary DataClick here for additional data file.Supplementary DataClick here for additional data file."} +{"text": "Tai Chi is defined here as a combination of Chinese philosophy, martial and healing arts. Tai Chi is a form of physical activity that is carried out at either a light or moderate intensity. The practice of Tai Chi integrates mental concentration and breathing control ,2. We fiFrom the point of clinical cancer diagnosis one may be categorized as a cancer survivor. There are approximately 14.1 million cancer survivors, across all cancer types, worldwide and this figure is expected to rise to 24 million by 2035 [Regular physical activity is assocA recent systematic review of controlled trials of physical activity in cancer survivors identified 16 interventions to increase physical activity levels post treatment, of which only six demonstrated statistically significant impacts . Likewiset al. [A key barrier to physical activity participation in cancer survivors is the sensation of debilitating fatigue. However, meta-analytic data from randomized controlled trials of physical activity in cancer survivors of mixed diagnoses (but mostly breast cancer) show improvements in many outcomes that are of particular importance to patients, including reductions in cancer-related fatigue . This pret al. have proTai Chi , a form of Qigong, is an exercise that originated in ancient China and is a combination of Chinese philosophy, martial and healing arts . The ComTo date, Tai Chi has shown feasibility and improved physical and psychological outcomes among older adults, patients with chronic conditions and breast cancer survivors. A recent meta-analysis synthesized randomized controlled trial (RCT) on the effect of Tai Chi on treatment-related outcomes in breast cancer survivors . A totalIn addition to the potential benefits on physical fitness and psychological health, Tai Chi may negate the deleterious cognitive side effects of cancer and its treatment. Tai Chi incorporates the practice of meditation ,2. This Tai Chi is accessible to most people and does not require special facilities or expensive equipment. Tai Chi is an understudied but promising tool to increase light physical activity levels with additive meditative benefits in cancer survivors and thus improving survival outcomes . The mechanisms of such impact and the potential of scaled-up Tai Chi implementation in cancer survivors are largely unknown. Given the likelihood for high acceptability of Tai Chi among this particularly vulnerable population, with their distinctive challenges and the potential positive impact on survival, research is urgently needed to uncover and understand mechanistic pathways for Tai Chi to improve cancer survival and to ultimately become part of routine care. Research is also required on the development of robust Tai Chi interventions for this population . We encourage research into all areas of cancer survivorship and Tai Chi."} +{"text": "Depression and anxiety symptoms are reported to be common among university students in many regions of the world and impact on quality of life and academic attainment. The extent of the problem of depression and anxiety among students in low- and middle-income countries (LMICs) is largely unknown. This paper details methods for a systematic review that will be conducted to explore the prevalence, antecedents, consequences, and treatments for depression and anxiety among undergraduate university students in LMICs.Studies reporting primary data on common mental disorders among students in universities and colleges within LMICs will be included. Quality assessment of retrieved articles will be conducted using four Joanna Briggs critical appraisal checklists for prevalence, randomized control/pseudo-randomized trials, descriptive case series, and comparable cohort/case control. Meta-analysis of the prevalence of depression and anxiety will be conducted using a random effects model which will generate pooled prevalence with their respective 95% confidence intervals.The results from this systematic review will help in informing and guiding healthcare practitioners, planners, and policymakers on the burden of common mental disorders in university students in LMICs and of appropriate and feasible interventions aimed at reducing the burden of psychological morbidity among them. The results will also point to gaps in research and help set priorities for future enquiries.CRD42017064148PROSPERO Poor mental health among university students has been a cause of concern globally. A previous systematic review indicated that university students have higher rates of depression than the general population . PrevaleFactors implicated in psychological morbidity among students include academic pressure, demanding workloads , worry aPsychological distress among students may adversely influence their academic performance and quality of life and may What is the documented prevalence of depression or anxiety among university students in LMICs?Which sociodemographic and curricular factors are associated with depression or anxiety among university students in LMICs?What are the reported short and medium term consequences of depression or anxiety among university students in LMICs?This systematic review will be conducted in an effort to answer the following key questions:This study protocol is structured in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). The PRISMA contains a 27-item checklist which is aimed at facilitating the development and reporting of robust systematic review protocols . The sysPubMed, PsychINFO, EMBASE and African Index Medicus, BIREME, LILACS, and MEDLINE databases will be searched for studies reporting primary data on common mental disorders (depression and/or anxiety) among students in universities and colleges within LMICs. For this study, LMICs will be defined using the World Bank Country Lending Group list for the year 2017 .In light of the paucity of studies in LMICs, no time restrictions will be imposed on the search. Controlled vocabulary terms will be appropriately incorporated for each database. We will use the terms to search for three main concepts namely (1) undergraduate university/college students, (2) prevalence of depression or anxiety, and (3) low- and middle-income countries. A full search strategy for one database is displayed in Studies will be included if they report the prevalence of depression or anxiety among university/college students undertaking undergraduate degree programs. Study types will include descriptive and analytical studies such as cross-sectional and longitudinal studies, case-series analysis, and randomized control trials that include data on prevalence of depression or anxiety. We will include studies in all languages, which will be translated into English. Due to paucity of research on depression or anxiety in most LMICs, the studies will not be excluded based on how they measured depression or anxiety since it is important to understand how these conditions are being measured in different settings.Two reviewers will independently screen titles and then abstracts of included articles using a piloted data extraction sheet . ExampleThe Joanna Briggs Institute (JBI) Prevalence Critical Appraisal tool The JBI critical appraisal checklist for randomized control/pseudo-randomized trialsThe JBI critical appraisal checklist for descriptive/case seriesThe JBI critical appraisal checklist for comparable cohort/case control.All retrieved papers eligible for selection will undergo an assessment process conducted by two independent reviewers. Standardized critical appraisal tools will be utilized in the quality assessment. In this study, four critical appraisal tools will be These tools were developed primarily for use in systematic reviews. Where there are disagreements between the two reviewers, a third reviewer will be engaged and discussions among the three reviewers will be used to resolve the differences.Meta-analysis of the prevalence of depression and anxiety among university students will be conducted using a random effects model which will generate pooled prevalence with their respective 95% CIs. Analyses will be conducted in Stata 14. The results from the review will be summarized and presented in text, This systematic review will be conducted as the initial step of a longitudinal study on common mental disorders among university students in Zimbabwe. The review aims to explore the prevalence, antecedents, and consequences of depression and anxiety among university students in LMICs. The results from the review will inform and guide health care practitioners and researchers on appropriate and feasible interventions aimed at enhancing the psychological well-being of undergraduate students in resource-constrained settings."} +{"text": "Following the discovery in the late 1980s that hard tissues such as bones and teeth preserve genetic information, the field of ancient DNA analysis has typically concentrated upon these substrates. The onset of high-throughput sequencing, combined with optimized DNA recovery methods, has enabled the analysis of a myriad of ancient species and specimens worldwide, dating back to the Middle Pleistocene. Despite the growing sophistication of analytical techniques, the genetic analysis of substrates other than bone and dentine remain comparatively \u201cnovel\u201d. Here, we review analyses of other biological substrates which offer great potential for elucidating phylogenetic relationships, paleoenvironments, and microbial ecosystems including (1) archaeological artifacts and ecofacts; (2) calcified and/or mineralized biological deposits; and (3) biological and cultural archives. We conclude that there is a pressing need for more refined models of DNA preservation and bespoke tools for DNA extraction and analysis to authenticate and maximize the utility of the data obtained. With such tools in place the potential for neglected or underexploited substrates to provide a unique insight into phylogenetics, microbial evolution and evolutionary processes will be realized. Equus quagga), which had died ~140 years previously )The move towards whole genome approaches and NGS technologies yields significantly more data than have traditional sequencing methods, with much of this data made up of increasingly short DNA fragments. As bioinformatic methods improve, we will recover ever more genomic and metagenomic information from unconventional substrates, including increasingly high-resolution information on genetic traits underlying local adaptations , and pheGreater understanding of DNA preservation and degradation within various materials and their implications for selecting the most appropriate material for destructive analysis;Developing appropriate multi-proxy approaches for authenticating ancient genetic data;Raising awareness of the common pitfalls of aDNA analysis on atypical substrates that may be unfamiliar to many \u201cmodern\u201d genetic laboratories entering the field.The past three decades of aDNA analysis have witnessed the recovery of genetic material from a wide range of ancient tissues and artifacts, including inorganic matrices once thought to be barren of surviving DNA . Further optimization of DNA extraction and analytical techniques, coupled with high-throughput and single-molecule sequencing will catalyze research in this area, allowing greater access to the often low-template, highly damaged DNA retained within these substrates. Nevertheless, these new technology-driven opportunities also present some challenges that need to be addressed, including: Evidence for progress in these areas is already apparent\u2013over 45% of the studies reviewed above had either method development or modeling DNA degradation as their primary research goal. A richer understanding of the potentials and pitfalls associated with the genetic analysis of these unconventional substrates will ultimately lead to more robust scientific results and more ethically informed decisions on sampling these irreplaceable historical resources."} +{"text": "Arterial stiffness is an important predictor of risk for incident cardiovascular events. Impaired endothelial function has been related to arterial cyclic stress, large artery stiffness and remodeling. MRI has been used to noninvasively measure local aortic strain and distensibility, and regional pulse wave velocity (PWV) of the proximal aorta. We investigated the relationship between aortic size and stiffness and tissue factor pathway inhibitor (TFPI) that is an endogenous inhibitor of the procoagulant tissue factor/factor VIIa complex, known as a marker of endothelial cell dysfunction in a large population free from overt cardiovascular disease.Multi-Ethnic Study of Atherosclerosis (MESA) participants with MRI parameters and TFPI measures at baseline (2000-2002) were studied. A phase contrast cine gradient echo sequence with ECG gating was performed to evaluate aortic size and through-plane flow. Images of the ascending and descending aorta were obtained in the transverse plane perpendicular to the aortic lumen at the level of the right pulmonary artery. Aortic sagittal oblique plane with black blood sequence was acquired to measure the distance from the ascending and descending aorta planes. Aorta analysis was performed using a validated automated software . Brachial blood pressures were obtained during MRI. Linear regression models were used to evaluate the association between aortic size and aortic stiffness parameters and TFPI after adjusting for demographics and cardiovascular risk factors including age and systolic blood pressure.A total of 552 participants were included in this cross-sectional study. Table Our observations indicate that higher TFPI is independently related to reduced aortic strain and distensibility assessed by MRI, beyond the effects of age and cardiovascular risk factors including blood pressure. This suggests that increased local proximal aortic stiffness is independently associated with endothelial damage and dysfunction in humans free from overt cardiovascular disease."} +{"text": "Our findings suggest that there is a convincing relationship between suicidal behaviour and cannabis use, the latter awakening depressive experiences. Suicidal behaviour and cannabis use are major public health problems and require a multidimensional approach with culturally competent preventive interactions. School based prevention programmes are necessary at the levels of parent-teacher partnership and classroom intervention. The treatment of adolescent disorders remains a major challenge of the future. Double disorders such as cannabis use and suicidal behaviour are uncharted areas and need novel approaches.Cannabis use and suicidal behaviour are causes of adolescent morbidity and mortality worldwide. Changing trends in these behaviours in younger age groups, higher incidence, gender differences and sociocultural variations present an enormous challenge. There is no consensus whether these complex relationships are either a direct or an indirect effect due to other mental disorders, or a social response of disclosure of drug taking habits to family members and school authorities. This paper reviews the epidemiology of suicidal behaviour and cannabis use among adolescents and looks at the relationship of these behaviours regionally and internationally. The Caribbean islands have an established use of cannabis with higher suicidal rates, which provides an ideal setting to investigate the interrelationship of these disorders. Preliminary research findings in Trinidad indicate high rates of cannabis use among school students with higher rates in vocational schools compared to grammar schools. Utilising the CAPE questionnaire, depressive and psychotic experiences were common findings in adolescent cannabis users with a significant preponderance of depressive experiences ("} +{"text": "On January 16, 2018, CDC was notified by the Florida Department of Health of potential rabies virus exposure in two persons believed to be residents of Switzerland. Rabies virus infections cause a fatal encephalitis, and persons exposed to the virus are advised to receive postexposure prophylaxis (PEP) as soon as possible . The couple confirmed handling the bat with their bare hands but did not report being bitten. The couple also confirmed that no other persons approached the bat during the time it was in their possession. The couple was advised to begin PEP, which was started the same day (January 25).Since January 2017, CDC\u2019s Poxvirus and Rabies Branch has used the IHR national focal point network to issue health alerts regarding potential rabies virus exposures in 12 persons. The IHR health alerts have resulted in at least four persons receiving potentially lifesaving treatment for rabies .The decision to notify the Swiss IHR national focal point was made after considering the severity of rabies virus infections in exposed persons, despite the lack of identifiable information available. This event illustrates the usefulness of the WHO IHR national focal point network for communicating binational, time-sensitive public health information. The Swiss Federal Office of Public Health was rapidly able to employ effective messaging to identify the persons at risk.The IHR national focal point network maintained by WHO can be activated outside of pandemic situations to strengthen international public health relationships; communicate valuable, time-sensitive information; and strengthen global health capacity through coordinated response efforts. The CDC examples since January 2017 highlight the increasingly multinational nature of rabies virus exposure investigations, the collateral benefit of having the WHO IHR national focal point system in place, and the willingness of IHR signatories to expand its application to urgent situations, even those involving a small number of persons."} +{"text": "Oleuropein, a polyphenolic compound enriched in olive oil and leaves of the olive tree, has attracted scientific attention in recent years because of a variety of reported health benefits. While the mechanisms by which oleuropein functions stigated , more stOleuropein is best known for its blood pressure-lowering effect. When administered via intraperitoneal or intravenous injections, oleuropein significantly reduces systolic and diastolic blood pressure in animal models. The ability of oleuropein to lower blood pressure may justify the traditional use of olive leaf in the treatment of mild to moderate hypertension. Our recent study provides significant insight into the mechanism whereby oleuropein reduces blood pressure. We find that oleuropein protects the hypothalamus from oxidative stress by improving mitochondrial function through activation of the Nrf2-mediated signaling pathway [Beyond hypertension, oleuropein has been shown to have cardioprotective, anti-inflammatory, antioxidant, anti-cancer, anti-angiogenic and neuroprotective functions, and thus may be of therapeutic potential for a variety of human disorders. Oleuropein reduces oxidative damage in the substantia nigra of aged rats, a region of the brain that is most affected by neurodegeneration in Parkinson's disease . OleuropDespite the many benefits of oleuropein, considerations about detrimental effects in certain individuals should not be neglected. Oleuropein may exacerbate low blood pressure in individuals who already have low blood pressure. Oleuropein could also interact with other pharmaceutical drugs that are designed to lower blood pressure or regulate diabetes. Patients should consult their physician before use and keep their physician informed of each medication being used in order to avoid additive or antagonistic drug interactions and side effects.The unexpected benefits and unique properties of oleuropein provide ample rationale for continued use and study of this key component of the Mediterranean diet to promote human health. Future studies are needed for a more comprehensive understanding of the cellular networks involved in the diverse protective effects of oleuropein."} +{"text": "Recent advances in research are modifying our view of recovery after nervous system damage. New findings are changing previously held concepts and providing promising avenues for treatment of patients after stroke. This review discusses mechanisms of neuronal injury after brain ischemia and the attempts to study neuroprotection options based on such mechanisms. It also considers measures available at present to improve outcome after stroke and presents new areas of research, particularly stimulation techniques, neurogenesis and trophic factors to enhance recovery. In order to improve outcomes, medications that may be detrimental to recovery should be avoided, while symptomatic therapy of problems such as depression, pain syndromes and spasticity may contribute to better results. Continued surveillance and early treatment of complications associated with acute stroke, along with supportive care remain the mainstay of treatment for stroke patients in the recovery phase. Present research on limiting brain damage and improving recovery and plasticity enhance the prospects for better clinical treatments to improve recovery after stroke."} +{"text": "This book provides an overview on current progress in various orthopaedic subspecialties. It is the collaborative product of three main editors and 55 experts from different parts of the world with the support of SICOT .The content covers congenital, developmental and degenerative conditions, trauma, growth and infection related disorders, and clinically relevant basic scientific research. Congenital abnormalities affecting the limbs remains a great challenge to orthopaedic surgeons, but development in this field is swinging from amputation and prosthetic fitting to bone and soft tissue reconstruction due to better understanding of underlying pathology and improvement in surgical techniques. Management of congenital talipes equinovarus (CTEV) has changed dramatically favouring non-operative approach (Ponseti technique), while early surgical intervention for brachial plexus birth palsy (BPBP) is gaining popularity with better defined indications. An update on management of cerebral palsy children stresses the importance of disease categorization and single event multilevel surgery (SEMLS) approach.A few chapters are dedicated to provide comprehensive review of various spine conditions. They include management of sagittal and coronal spine deformity, disc disease, Tuberculosis, osteoporotic fracture and metastasis.Femoro-acetabular impingement (FAI) has recently been recognized as a source of hip pain and a cause for early osteoarthritis. Hip arthroscopy and surgical hip dislocation are some of the newly developed procedures for evaluation and treatment of this condition. In addition to updates on surgical fixation for femur neck and distal radius fractures, a chapter is assigned for review of the role of functional nonoperative treatment for humerus fracture.There is a good review on surgical options and implant selection for degenerative disease of major joints, with special focus on younger patients and those with early osteoarthritis. Parallel to improvement in survival rate among patients with malignant musculoskeletal tumours, there has been increasing preference for limb salvage with the use of endoprosthesis or biological reconstruction. One chapter describes the basic principles of organising a screening program, and reviews the practice of screening for scoliosis and developmental dysplasia of hip. Finally, another chapter provides an update on autologous chondrocyte implantation (ACI) and non-cell-based approaches to cartilage repair.Most of the progress described in this book are related to innovation of surgical techniques and better understanding of disease processes, rather than on improvement in implant designs or biomaterial. Although some of the recommendations may not be based on strong clinical evidence, they provide the general orthopaedic surgeons with some ideas about the direction of future advancement.I would like to recommend this book to general orthopaedic surgeons who are interested to keep pace with the rapid development in orthopaedics. Even for those who have already subspecialized, updates by experts in the respective field will still be beneficial."} +{"text": "Intrauterine growth restriction (IUGR) is a fetal pathology which leads to increased risk for certain neonatal complications. Furthermore, clinical and experimental studies revealed that IUGR is associated with a significantly higher incidence of metabolic, renal and cardiovascular diseases (CVD) later in life. One hypothesis for the higher risk of CVD after IUGR postulates that IUGR induces metabolic alterations that then lead to CVD.This minireview focuses on recent studies which demonstrate that IUGR is followed by early primary cardiovascular alterations which may directly progress to CVD later in life. Intrauterine growth restriction (IUGR) affects 3\u20137% of all newborns. As a consequence of maternal, placental or fetal pathology the fetus cannot fully exploit its growth potential . While tNewborns with IUGR exhibit significantly increased morbidity immediately after birth . Later in life former IUGR-patients were found to have a significantly higher incidence of renal, cardiovascular and metabolic diseases, the same ailments that are also the most frequent causes of morbidity and mortality in the western world \u20135.The underlying mechanisms leading from fetal undersupply to the development of diseases in adulthood are not fully understood. In this context Barker et al. hypothesize that intrauterine undernutrition compromises growth and differentiation of organs during the vulnerable phase of fetal development that results in persistent alterations of the organism and leads to the development of secondary diseases later in life \u20138.The shortage of nutrients during fetal development observed in IUGR is commonly replaced by an adequate nutrient supply after birth. The hypothesis of the \u201cthrifty phenotype\u201d\u00a0considers the mismatch between intrauterine and postnatal supply with nutrients in IUGR individuals to be the underlying cause of secondary pathologies. In a fetus adapted to shortage of nutrients during intrauterine development postnatal hyperalimentation leads initially to excessive catch up growth and later to metabolic, cardiovascular and renal diseases .As IUGR is associated with a higher incidence of metabolic syndrome, it appears conceivable that cardiovascular dysfunction observed after IUGR is secondary to diabetes, dyslipidemia or hypertension . HoweverIn the heart, a number of studies revealed myocardial alterations induced by IUGR, that can be detected long before the onset of metabolic disease and arterial hypertension. IUGR affected cardiac development and significantly reduced the number of cardiomyocytes at the time of birth , 14. StuMoreover, assessment of inflammatory and profibrotic markers revealed an early induction of the expression of transforming growth factor beta (TGF-\u00df), connective tissue growth factor (CTGF) and microfibrillar matrix molecules in the myocardium of juvenile IUGR animals without evidence of metabolic syndrome . This suIUGR-induced metabolic disease (including dyslipidemia and insulin resistance) may likewise indirectly lead to atherosclerosis . In addiBut even in the absence of experimental vascular disease, primary vascular alterations were detected in normotensive IUGR animals: A significantly increased expression of connective tissue growth factor (CTGF) was observed in aortas of neonatal animals after IUGR. Collagen I and collagen IV deposition in the aorta was more prominent in juvenile IUGR animals . Recent IUGR favors the development of secondary cardiovascular diseases later in life which are among the most frequent causes of morbidity and mortality and constitute a significant proportion of healthcare-related expenditures in the western world. Cardiovascular disease appears not only to be a consequence of metabolic syndrome, but also caused by direct effects on cardiac and vasculature structure and function in individuals with IUGR. A more detailed knowledge of underlying disease mechanisms is likely to advance prevention and treatment of IUGR and its complications, and thereby improve long-term outcomes for patients with IUGR."} +{"text": "The application of functional imaging to study painful sensations has generated considerable interest regarding insight into brain dysfunction that may be responsible for functional pain such as that suffered in patients with irritable bowel syndrome (IBS). This review provides a brief introduction to the development of brain science as it relates to pain processing and a snapshot of recent functional imaging results with somatic and visceral pain. Particular emphasis is placed on current hypotheses regarding dysfunction of the brain-gut axis in IBS patients. There are clear and interpretable differences in brain activation following somatic as compared with visceral noxious sensation. Noxious visceral distension, particularly of the lower gastrointestinal tract, activates regions associated with unpleasant affect and autonomic responses. Noxious somatic sensation, in contrast, activates regions associated with cognition and skeletomotor responses. Differences between IBS patients and control subjects, however, were far less clear and interpretable. While this is in part due to the newness of this field, it also reflects weaknesses inherent within the current understanding of IBS. Future use of functional imaging to examine IBS and other functional disorders will be more likely to succeed by describing clear theoretical and clinical endpoints."} +{"text": "Patients with a left ventricular assist device (LVAD) have increased risk of gastrointestinal (GI) bleeding. They are prone to develop angiodysplasia of the small intestine, and have a higher risk of bleeding as these patients are all required to be on permanent therapeutic anticoagulation. Here we report a case of a critically ill 55-year-old male on pressors and inotropes with an LVAD, who successfully underwent an antegrade double balloon enteroscopy (DBE). Patients with a left ventricular assist device (LVAD) are at increased risk for gastrointestinal (GI) bleeding with 20% of patients experiencing at least one episode , 2. ApprA 55-year-old male with dilated cardiomyopathy, atrial fibrillation, internal cardiac defibrillator, end-stage renal disease on hemodialysis, and iron deficiency anemia was transferred to our institution for LVAD placement. Esophagogastroduodenoscopy (EGD) and colonoscopy performed 4 months prior to LVAD placement to evaluate iron deficiency anemia were unremarkable. The patient remained hospitalized after HeartWare LVAD placement due to a complicated course including fungemia, ventricular arrhythmias, and aspiration pneumonia resulting in cardiac arrest and intubation from which he subsequently recovered. Three months after LVAD placement, the patient was transferred to the intensive care unit (ICU) for septic shock and required norepinephrine and dobutamine infusions for vasopressor and inotropic support. The following day, the patient developed maroon colored stools in the setting of aspirin and therapeutic anticoagulation with decrease in hemoglobin (Hgb) from 9 to 6 g/dL. He was transfused six units of red blood cells (RBCs). Urgent EGD and colonoscopy without bowel preparation demonstrated bilious fluid in the duodenum and blood throughout the terminal ileum and colon; however, the bleeding source could not be identified. Given suspicion for a small bowel source of bleeding, a PillcamSB capsule study was performed. The patient continued to demonstrate signs of active GI bleeding and a tagged RBC scan was performed concurrently, revealing active blood loss from the small bowel. Mesenteric angiogram of the cBleeding in patients with LVADs is likely to become a more frequently encountered problem given their increasing usage as destination therapy and bridge to transplantation. Evaluation of the small bowel appears to be of particular importance among LVAD patients given that there is increased small bowel angiodysplasia and up to 65% of patients have unidentified source of bleeding despite upper and lower endoscopy . The higThese procedures theoretically carry a higher risk compared to endoscopy and colonoscopy given the prolonged procedure and sedation time, repeated episodes of scope advancement and withdrawal with resultant pressure and mobilization of the small bowel in the upper abdomen. The LVAD driveline, which connects the LVAD to the external controller and power source, travels through the upper abdomen creating the potential of disrupting the driveline during deep enteroscopy. There is also concern that a capsule study may interfere with LVAD functioning and vice versa.Review of the literature reveals that 62 capsule studies and 28 deep enteroscopies have been performed in LVAD patients. There has been one prior documented DBE performed in an LVAD patient while th"} +{"text": "Infant and child facial cues influence perceptions and ratings in the Hypothetical Adoption Paradigm as well as actual parental care. A previous study demonstrated that infant and child facial cues of low body weight negatively influenced adults' ratings. The current study sought to replicate and expand on those results by presenting adults with normal faces as well as faces that were digitally altered to display high or low body weight. Cues of abnormal body weight significantly, and negatively, influenced adults ratings of adoption preference, health, and cuteness. Effect sizes were larger for cues of high body weight. Thus, infant and child facial cues of abnormal body weight may represent a relative risk factor to the quality of adult care obtained by children with abnormal body weight."} +{"text": "Transient epileptic amnesia (TEA) is a recently recognised syndrome of epilepsy in which the principle manifestation of seizures is recurrent episodes of isolated memory loss. In this article, we describe the clinical and cognitive profile of this emerging syndrome, and present new data that provide at most weak support for its proposed relationship to cerebrovascular disease. TEA is often associated with two unusual forms of interictal memory impairment: accelerated long-term forgetting and remote memory impairment. We discuss the clinical and theoretical implications of these relatively novel cognitive deficits."} +{"text": "OPRM1), catechol-O-methyltransferase (COMT), and prepronociceptin (PNOC) with a shorter length of hospital stay and less need for treatment in neonates exposed to opioids in utero. Consistently falling genomic sequencing costs and computational approaches to predict variant function will permit unbiased discovery of genomic variants and gene pathways associated with differences in maternal and fetal opioid pharmacokinetics and pharmacodynamics and with placental opioid transport and metabolism. Discovery of pathogenic variants should permit better delineation of the risk of developing more severe forms of NAS. This review provides a summary of the current role of genomic factors in the development of NAS and suggests strategies for further genomic discovery.Significant variability has been observed in the development and severity of neonatal abstinence syndrome (NAS) among neonates exposed to prenatal opioids. Since maternal opioid dose does not appear to correlate directly with neonatal outcome, maternal, placental, and fetal genomic variants may play important roles in NAS. Previous studies in small cohorts have demonstrated associations of variants in maternal and infant genes that encode the \u03bc-opioid receptor ( An epidemic of neonatal abstinence syndrome (NAS) currently exists due to dramatic increases in prenatal opioid exposure. Significant variability has been noted in the incidence and severity of NAS among neonates exposed to prenatal opioids. The promise of precision medicine has prompted increasing interest in discovery of genomic variants that could better predict the development and severity of NAS and suggest new therapeutic approaches for both prevention and treatment \u20133. Althoboth mother and infant are associated with severity of NAS (OPRM1), catechol-O-methyltransferase (COMT), and prepronociceptin (PNOC) were associated with differences in neonatal outcomes . While the SNPs chosen for study are known to have important physiologic roles in opioid drug response and withdrawal in adults, the effect sizes of these SNPs have been modest and have not had a significant impact on clinical practice to evaluate the predicted function and frequency of both common and rare SNPs in genes known to be associated with heritable addiction or alterations in drug metabolism. Falling sequencing costs will permit complete genomic resolution for discovery of clinically actionable genomic variants in individual mother/infant dyads. This approach should avoid the need to rely on linkage disequilibrium or imputation. Unbiased whole exome or genome sequencing would permit the evaluation of the contributions of rare variants in both recognized and unrecognized genes to NAS severity. The statistical challenges associated with rare variant discovery may be partially addressed by using family study design to reduce the contributions of highly diverse genomic backgrounds to phenotype and multiple confounding co-variables present in case\u2013control studies. Examining infants with the extremes of NAS severity may also improve statistical power to identify relevant genomic variants ((A)If we can establish high-risk genetic profiles in young women, can we then limit opioid exposure?(B)Can we establish low-risk genetic profiles in young women and safely wean them off their medication-assisted treatment without an increased risk of relapse?(C)If high-risk profiles are found in pregnant women, can we intervene and modify risk factors such as limiting cigarette smoking and polypharmacy?(D)With high-risk profiles identified in neonates, could we administer low doses of opioids immediately after birth and limit the development and severity of NAS?(E)If lower risk profiles are identified in neonates, could we send them home earlier and carefully follow them up as an outpatient?(F)Can pharmacogenomics identify optimal treatment strategies for the mother and her neonate?(G)If genetic risk factors can be combined with clinical and demographic variables, can we develop \u201crisk assessment\u201d models that can be applied to neonates, older children, and adults to determine the risk of addiction following exposure to opioids ?Extension of current SNP-based studies of the genomics of NAS may benefit from leveraging available, diverse large exome and genome databases (e.g., variants . A revievariants . Standarvariants , 22. Devvariants , 24. Finvariants will be variants , 12. ForThese are some of the potential benefits of a more precision medicine-guided approach that could be adopted with rapid development of novel genomics methodologies. What is most important is sufficient funding, and legislative efforts are currently driving this innovation and offer a path forward to address NAS in this highly vulnerable population.FC and JD conceptualized and drafted the entire manuscript; DW contributed data analysis.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer, TF, and handling editor declared their shared affiliation, and the handling editor states that the process nevertheless met the standards of a fair and objective review."} +{"text": "The field of oncology is currently undergoing a paradigm shift. Advances in the understanding of tumor biology and in tumor sequencing technology have contributed to the shift towards precision medicine, the therapeutic framework of targeting the individual oncogenic changes each tumor harbors. The success of precision medicine therapies, such as targeted kinase inhibitors and immunotherapies, in other cancers have motivated studies in brain cancers. The high specificity and cost of these therapies also encourage a shift in clinical trial design away from randomized control trials towards smaller, more exclusive early phase clinical trials. While these new trials advance the clinical application of increasingly precise and individualized therapies, their design brings ethical challenges . We review the pertinent ethical considerations for clinical trials of precision medicine in neuro-oncology and discuss methods to protect patients in this new era of trial design. Precision medicine has garnered attention in the public sphere since President Barack Obama declared it a national priority as part of a major US public health initiative. This new paradigm builds on the idea that cancers that harbor certain oncogenic mutations may be particularly susceptible to therapies that specifically target the aberrant proteins created by these mutations. As next-generation sequencing techniques have begun to uncover some of the mutations that drive the formation and growth of various cancers, applying this new therapeutic framework has the potential to revolutionize cancer management.BRAF, has been shown to reduce tumor burden and to improve overall survival in melanoma patients [EGFR [The last decade has seen many innovations in the usage of targeted therapies. Vemurafenib, a targeted kinase inhibitor of the B-Raf protein variant produced by a V600E point mutation in patients . Similarts [EGFR , 3. Prects [EGFR . Indeed,ts [EGFR \u20137.The successes and potential of precision medicine have also introduced new challenges not only related to clinical care, but also to ethics of clinical research. While there remains little doubt of the potential improvements in efficacy with precision medicine, characterizing and understanding these challenges can uphold the standards of patient autonomy, respect, and protection. In this discussion, we review pertinent ethical challenges to early phase clinical trials in precision medicine.New trials of targeted therapies are tested in patients whose cancers harbor the specific mutations those therapies target. This design makes recruitment for large-scale randomized clinical trials (RCTs) exceedingly difficult since patients selected for a trial will not only need to share the same cancer and stage, but must share similar oncogenic mutations as well. Clinical trial design will reflect the specificity and expense of targeted therapy as it shifts from large RCTs towards early phase testing in n-of-1 and small cohort trials. For rare brain tumors, recruiting large cohorts of patients with the similar genomic profiles becomes nearly impossible, so early phase trials circumvent the challenge of relatively low prevalence of brain cancers but introduce new ethical challenges that must be addressed.Advances in NGS have made these problems especially relevant as they have provided individual patients and their providers the ability to assess the genomic composition of their tumors to optimize their management . These tWe focus this discussion on the most salient ethical challenges to early phase clinical trials in neuro-oncology, including informed consent, societal value, generalizability, institutional oversight, vulnerable patient selection, and justice. These ethical issues are relevant considerations in other types of trials, though the costs, specificity, and prerequisite of NGS of precision medicine trials raise novel concerns that are compounded by the relatively low prevalence of brain cancers and potential cognitive changes.Physicians must secure informed consent before sequencing patients\u2019 tumors for entry into trials of targeted therapy. Informed consent requires physicians to explain details about the benefits and risks of a procedure or therapy accurately and understandably to patients. The rapidly changing landscape of genomic medicine requires physicians to understand the theory of precision medicine and be familiar with various therapies in order to inform patients of their options. Physicians differ in their levels of knowledge and experience with precision medicine, which may preclude the ability to provide adequate informed consent . Even foInformed consent requests must incorporate options for communicating incidental findings. In the clinical trial context, NGS will be used to screen for specific oncogenes that determine entry into a trial. It may also reveal the presence of incidental mutations in the same or different genes . The outThe four types of incidental findings in NGS are genetic variants that are medically actionable for the patient, medically actionable for the patient\u2019s family but not the patient, associated with disease but not currently medically actionable, and of unknown significance . Non-disThe disclosure of gene variants that accurately predict the development of diseases that cannot be prevented or managed may cause patient psychological distress, but allow them to adjust their life plans around this illness. Gene variants of unknown medical significance are also possible outcomes of NGS. Their disclosure likely carries no utility but may be stored in a medical record in case its significance becomes uncovered. Developing NGS technologies that only probe for mutations of interest for each individual trial circumvents the discovery of incidental findings altogether, but may be financially prohibitive and impedes the discovery of medically actionable variants. Each of these four potential scenarios must be clearly delineated in the informed consent process, and oversight committees should consider how to inform patients about the different types of incidental findings and how to create opt-in or opt-out systems for their disclosure.The format in which informed consent is obtained must efficaciously communicate detailed descriptions of oncogenes of interest, targeted therapies, and potential incidental findings. The process must also be concise enough for patients to complete it without confusion or fatigue from the complex knowledge and different options they must weigh. Multidisciplinary teams can help design resources for patients and physicians to aid in this process; for example, genetic counselors may aid oncologists in communicating complex genetic information and implementing flexible consent processes . Tiered Each individual targeted therapy requires significant financial investment for research and development and is applicable to a narrow spectrum of patients, limiting its societal value . An arguBRAF in melanoma led to the development of B-Raf inhibitors that years later, have shown potential efficacy in craniopharyngioma [There are also reasons to believe that despite the high up-front costs of a targeted precision therapy, it provides societal benefit beyond its immediate application as a therapy for a specific cancer. One such example is \u201cdrug repositioning\u201d, the concept that drugs designed to target an aberrant protein in one cancer can be applied to other cancers with the same molecular disruption. For example, study of the V600E mutation in ryngioma . Early pryngioma .RCTs often enroll dozens or hundreds of patients, providing high enough enrollment to allow for detailed statistical analysis of the effects of the new treatment. Smaller cohorts often have limited generalizability as the confidence interval for any measure of an outcome varies inversely with cohort size. In practical terms, a clinician determining whether to prescribe a new targeted therapy to a patient based on the results of a trial with two enrollees may be unable to determine whether their patient will respond similarly to those enrollees. If those enrollees also responded differently to the therapy despite having the same mutational profile, the clinician cannot accurately predict which enrollee the patient would respond more similarly to. Brain pathologies also face the unique challenge that therapeutics must cross the blood brain barrier.The goal of precision medicine is to provide patient-specific therapies that maximize outcomes, including minimizing toxicity. However, even if multiple small trials show no evidence of toxicity for patients receiving a specific therapy, physicians cannot accurately determine potential toxicities without evidence from large and longitudinal cohort studies . As withInstitutional oversight is a requirement for clinical research. In the United States, any research that uses human test subjects requires Institutional Review Board (IRB) approval. The role of the IRB includes determining if there is enough preclinical evidence to justify a trial in humans.The specificity of targeted therapies could increase the difficulty of accumulating sufficient preclinical evidence to justify any trial. In vivo testing would require the development of animal models of cancers that match the specificity of all study populations\u2019 genomic signatures, which may be unfeasible. New experimentation protocols and emerging technologies such as ex vivo organoids and analytical data modeling can mitigate this problem, but ultimately, oversight committees must set strict and consistent evidential standards to warrant approval. Additionally, oversight committees have a role in ensuring that the therapeutics that were developed for other cancers and tested in neuro-oncology trials achieve therapeutic levels in the brain by crossing the blood brain barrier without increasing risk of systemic toxicity. Testing therapies that have not been proven to achieve therapeutic levels in the brain would bring further ethical challenges related to patient safety.Last, the proliferation of early phase trials threatens to bring less oversight; it is much more manageable for an oversight committee to follow a large trial than many small trials, especially as the distinction between research and individualized care becomes less clear. Oversight committees will need to adapt to these anticipated changes to ensure appropriate adjustments that maintain sufficient oversight. While the function of these committees will remain the same, their structure should reflect the increasing number and complexity of these trials.Neuro-oncologic patients enrolling in trials require protections given vulnerabilities inherent to brain disease and to potentially having refractory cancers. Brain pathologies and their therapies may subtly alter a patient\u2019s decision-making capacity. The poor prognoses of many brain cancers may incentivize patients to explore experimental treatments. These problems are exacerbated for late-stage patients and those with refractory disease, such that these vulnerable patients may become the most eager group to join trials. This is especially problematic for Phase 1 trials, but also has implications for trials with therapeutic intent, which constitute the majority of precision medicine trials.Equitable participant selection seeks to prevent the exploitation of vulnerable patients in clinical trials. Even though studies are being designed to test targeted treatments upfront, experimental targeted therapies are also tested in patients whose cancers remain refractory to traditional therapeutic modalities. Even though the primary goal of many precision medicine trials is related to care, at the same time, most investigators also have the goal to generate knowledge to improve management of future patients with similar disease profile as their enrollees. This implies that trial investigators should not continually seek the most desperate patients as enrollees only to then prioritize prescribing the tested therapy to healthier eligible patients. Ensuring that the characteristics of trial enrollees reflect their intended beneficiaries becomes more difficult to accomplish in small cohorts, so care must be taken to carefully define enrollee criteria and generalizability of a study.The selection criteria for early phase targeted therapy trials will include specific genetic data that necessitate access to genetic sequencing technologies and the expertise to interpret genetic data. Patients of low socioeconomic status may not have equal access to these resources that are often located in advanced tertiary care institutions . ConsequIt is important to note that just recruitment is a challenge in all clinical trials. The requirement of NGS technologies in addition to standard studies like MRI brings an additional impediment for patients of lower socioeconomic status. Therapies specific for genetic mutations that are more common in patients of low socioeconomic status due to certain environmental exposures may therefore never be developed, which would propagate these patients\u2019 exclusion from precision medicine. Therefore, patients from lower socioeconomic backgrounds require increased protection to ensure their access to and representation within these trials , 25.Genomic data gathered for these trials might also risk unfair treatment of enrollees by societal actors. The Genetic Information Nondiscrimination Act enacted in 2008 provides broad prohibitions for health care insurance and employer from discriminating based on known genetic predispositions for future disease. It is not all-encompassing; for example, insurers may request genetic data to determine whether to cover certain procedures . DespiteThere has been a surge in early phase trials of precision medicine that target mutations specific to individual tumors. These therapies hold immense potential to improve outcomes in neuro-oncology, but it is necessary to consider the implications of the changes associated with these trials, including their high costs and small cohort sizes, to protect patients and uphold scientific standards. Ethical considerations for clinical trials of precision therapies include informed consent, vulnerable patient protection, societal value, generalizability, institutional oversight, and justice. While each of these present problems for early phase trials of targeted therapies, trial design can adapt to ensure ethical standards are met.Obtaining informed consent provides major challenges towards these trials due to the difficulty of communicating information and the handling of incidental findings. Innovative informed consent structures such as tiered and multi-disciplinary approaches to educate patients will aid in this process . In a reWhile long-term societal value of an innovation is difficult to predict, the clinical and scientific benefits from targeted therapies should be recorded and analyzed to determine their true cost-effectiveness. This can be done by unbiased third-party institutions with the expertise to conduct economic analyses in biomedical fields. Societal value also depends on researchers\u2019 clearly defining the generalizability of each trial as they become smaller and more specific, including specific mutations and demographic details. Adjustments in trial end-points and statistical methodology will aid in achieving higher societal value and more precise generalizability. End-points may include biomarker values, radiographic change, and symptomatic control in additional to traditional end-points like 1\u00a0year progression-free survival. Small sample size statistics such as Bayesian probabilistic modelling may also aid in analyzing results .The composition of oversight committees will need to reflect the diversity of the geneticists, oncologists, and biologists who contribute to the development of targeted therapies. Patients and their representatives may also provide input to determine the priorities and agenda of the development of precision medicine to increase public trust and involvement and improve equitability , 31.Likewise, trial participants themselves should be representative of society and should not be limited to only those who can afford access. Patient and community advocacy groups may develop infrastructure to help patients of low SES gain access to these trials, whether by easing the burdens of physically accessing tertiary centers, enrolling patients in affordable insurance plans, and so on. The integration of genomic results into patients\u2019 medical records must come with protections against genetic discrimination by employers, insurers, and other institutions . EthicisThese trials have specific, ethically pertinent impacts on the families of trial enrollees. The potential for an enrollee\u2019s NGS to uncover findings that impact family members directly impinges on family members\u2019 autonomy and privacy. An opt-in system, whereby family members could affirm their desire to learn of clinically relevant inheritable variants they are at risk for, would protect autonomy but may require burdensome coordination by the patient. Family members that do not or cannot complete this request could be assumed to have opted in to be informed of the potential that they harbor medically actionable variants as most people desire to ascertain information that could improve or elongate their lives . Knowled-positive glioblastoma with currently over 200 centers participating. The ACT IV study has been a successful model of a multicenter RCT of a precision medicine in neuro-oncology, but is not without challenges. As broader networks of trial investigators are necessary for these types of trials, this will raise novel ethical issues, including limitations to generalizability and societal value from inter-institutional inconsistencies in patient selection, treatment, imaging, and pathologic analysis. In addition, this trial structure complicates the coordination, standardization, and implementation of institutional and central oversight.Novel trial design paradigms may mitigate many of the ethical challenges. For instance, large-scale multi-institutional studies increase sample size, thereby increasing the societal value and generalizability of a study. The larger patient pool also allows for enrollment of demographically and socioeconomically diverse cohorts, thereby addressing concerns for justice. An example is the ACT IV study, a double-blind RCT of rindopepimut for EGFRvIIIOther emerging clinical trial designs that might mitigate some of the ethical challenges include blinded single participant \u201con\u2013off\u201d studies, increased enrollment from community centers, seamless phase II/III studies, and Bayesian adaptive randomization models amongst other solutions that also bring their own new ethical challenges . CombinaWhile these are largely beyond the scope of this analysis, NGS and precision medicine raise challenging ethical questions regarding information sharing and management after the completion of trials. Incidental findings with unknown clinical significance discovered by NGS in these trials may potentially be studied to determine their role in health and disease. The prospective usage of incidental findings should ideally be assessed prior to enrollment and included in informed consent requests. Retrospective usage of such data should also require informed consent to protect patients from discrimination and respect their privacy.We acknowledge the meritorious scientific background of early phase trials: decades of molecular biology and genomics research settings have yielded findings that have dramatically elongated patient survival and improved quality of life for cancer patients. Increasingly precise therapies have the potential to benefit neuro-oncologic patients immensely. However, as oncological management transitions to increased specificity and personalization, ethical analysis of these changes and adaptation of researchers and IRBs to new standards are imperative to protect patients."} +{"text": "A 45 years female presented with a complain of something coming out through her anus since one year, which comes on straining and reduces only after manual intervention. She had also, a history of constipation with occasional blood and mucus discharge in the stool. On examination, she was found to have full thickness rectal prolapse, which comes out on straining and reduces only after pushing it manually. With a diagnosis of complete rectal prolapse grade III, she underwent abdominal suture rectopexy and now she is doing well after six months of follow-up. One of the very close differential diagnosis of complete rectal prolapse is prolapsed internal hemorrhoid. Both can present with similar symptoms with similar clinical grading, but management is completely different. Diagnosis of both these conditions is critical and mostly based on clinical findings. The differentiating point between a rectal prolapse and internal hemorrhoid lies in the orientation of the mucosal folds. Rectal prolase usually has circular folds where as internal hemorrhoids have radial folds (C). This is because, hemorrhoids are collections of submucosal, fibrovascular, arterio-venous sinusoids mostly seen in the left lateral, right anterolateral and right posterolateral region of anal canal. While rectal prolapse is the intussusception of whole circumference of the rectal wall through the anal canal which presents with circular folds of rectal mucosa. This image presents a classic case of complete rectal prolapse with an image of a prolapsed internal hemorrhoid to understand the differentiating points of these two very common clinical conditions."} +{"text": "Global food security requires a major re-focusing of plant sciences, crop improvement and production agronomy towards grain legumes (pulse crops) over coming decades, with intensive research and development to identify climate-resilient species and cultivars with improved grain characteristics. Labs contributing to this special issue have undertaken research and breeding to improve pulse crops, together with innovative production agronomy which contributes to the sustainability of cropping systems. The reviews and research together form an invaluable resource for the research community and policymakers.The value of pulses in food cultures around the world is well known, and calling them \u2018little marvels\u2019 is apt , not least because of their significant health benefits . HoweverRecognizing that increasing the global production of grain legumes has the potential to provide a sustainable solution to food and protein security, significant efforts are currently being made to increase genomic resources and apply innovative breeding techniques to improve the yield and nutritional quality of legume crops, together with enhanced resilience to climate change. Production agronomy and crop rotation approaches could also be intensified to address the associated economic and environmental challenges. The papers presented in this special issue bear testimony to the urgent need for the intensification of basic and applied research into grain legumes, which will form a cornerstone of future food and nutritional security and a global web of biodiversity.et al. captures valuable genes from wild relatives and moves them into the breeding programme by crossing the genetically diverse exotic lines with elite lines, creating evolving gene banks. The new rapid-cycle plant breeding method will have long-term benefits for all plant breeders, and could help to adapt and develop climate-ready crops, but the immediate challenge is to validate the results in commercial pulse crops.Several papers in the issue highlight the development of genetic resources that will unleash significant untapped potential for genetic improvement. The development of effective phenotyping and breeding approaches is a challenge for the less-well studied grain legumes in particular. Modern breeding efforts to improve yield, disease resistance and quality are constrained by a low level of genetic diversity in breeding programmes. Large genetic diversity exists in seeds of grain legumes held in gene banks, but these are not fully used in active breeding programmes. Vicia faba) genome are provided by As one of the five major crops, soybean is the most widely planted and highest-yielding grain legume have outcrossing characteristics, and rely to some extent on pollination by animal vectors. Climate change and associated extreme weather events such as sudden episodes of high temperature during flowering can affect reproductive success in grain legumes, directly through physiological damage and indirectly by affecting plant\u2013pollinator interaction. Some grain legume species such as faba bean and pigeon pea (Tylosema esculentum) for the first time.As a protein staple in the diet of many of the world\u2019s poorest, pulses are nature\u2019s gemstones because they are protein packed and nutritious. However, in many cases relatively little is known about the biology of the plethora of \u2018orphan\u2019 legume crops that contribute to human and animal diets. Many unique functions of grain legumes take place beneath the soil. These plants offer the promise of more sustainable use of nitrogen fertilizers in crop systems through their ability to fix atmospheric nitrogen in symbiotic root nodules. The process of bacteroid infection in legume roots that culminates in the formation of symbiotic nodules is summarized by The papers in this special issue describe, consider and discuss the state of our developing knowledge and understanding of important topics within legume biology, as well as identifying key areas where more knowledge is urgently needed such as an absence of comprehensive genomic information and intensive breeding efforts. In the past 50 years, global cereal production has almost tripled while pulse production has only increased by about 60% . Prepare for more from these little marvels in the future."} +{"text": "Cyclodextrins encapsulate and electrostatically bind to lipophilic molecules. The exterior of cyclodextrins are water-soluble and maintain aqueous solubility despite encapsulation of non-aqueous soluble molecules. This unique ability to encapsulate lipophilic molecules and maintain water solubility confers numerous pharmacologic advantages for both drug delivery and removal. Cyclodextrins, a component part of supramolecular chemistry, may be in its infancy of anesthetic application but recent advances have been described as novel and revolutionary. A review of current research coupled with an understanding of cyclodextrin properties is necessary to fully appreciate the current uses and future potentials of these unique molecules."} +{"text": "Widespread acceptance of laparoscopic urology techniques has posed many challenges to training urology residents and allowing postgraduate urologists to acquire often difficult new surgical skills. Several factors in surgical training programs are limiting the ability to train residents in the operating room, including limited-hours work weeks, increasing demand for operating room productivity, and general public awareness of medical errors. As such, surgical simulation may provide an opportunity to enhance residency experience and training, and optimize post-graduate acquisition of new skills and maintenance of competency. This review article explains and defines the various levels of validity as it pertains to surgical simulators. The most recently and comprehensively validity tested simulators are outlined and summarized. The potential role of surgical simulation in the formative and summative assessment of surgical trainees, as well as, the certification and recertification process of postgraduate surgeons will be delineated. Surgical simulation will be an important adjunct to the traditional methods of surgical skills training and will allow surgeons to maintain their proficiency in the technically challenging aspects of minimally invasive urologic surgery."} +{"text": "Microorganisms represent the largest proportion of the Earth's biodiversity and play an essential role in ecosystem processes, providing functions that ultimately sustain all of life was the dominant control of nutrient loss from smallholder tropical agriculture. Both studies emphasize the necessity of further research on incorporating microbial dynamics into plantation management to improve productivity while mitigating soil fertility loss. Xiong et al. observed that sustainable agricultural management regimes, such as crop rotation, of commercially important crops in tropical regions significantly increased soil fungal diversity and might be a meaningful strategy to prevent vanilla Fusarium wilt disease.Some contributions to this Research Topic have focused on how land management practices impact microbially-mediated processes in tropical soils through the alteration of microbial communities. Belden et al.Finally, one of the biggest threats facing frog populations in montane tropical systems is a lethal skin disease caused by a chytrid fungus. The composition of the frog skin microbiota can strongly influence many facets of frog health and disease resistance. Field survey data published as part of our Research Topic has demonstrated that the frog skin microbiota is producing broadly similar sets of anti-fungal metabolites across different host species and sites In summary, the contributions to this Research Topic showcase the current knowledge regarding microbial ecology in tropical ecosystems, identify many challenges and questions that remain to be addressed and open up new horizons in our understanding of the environmental and anthropological factors controlling microbial communities in these important ecosystems.SP produced the first draft of the editorial, and all authors edited the editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Overall Abstract: Aberrant bodily self experiences are highly salient and disruptive to individuals with schizophrenia. Given that these self disturbances are already present at prodromal stage, persist throughout the course of illness, and impact functional outcome, they should be precisely targeted for intervention. However, in contrast to the prominence of auditory hallucination in schizophrenia research, bodily self disturbances have been largely neglected. This symposium aims to bridge this gap with new theoretical and experimental advances that allow us to capture the full extent of the phenomenology, and at the same time, mechanistically specify the etiology and nature of self disorders with an eye toward implementing new treatments.Nelson & Sass will present their revised theory of self disturbances in schizophrenia that reconciles phenomenology with neuropsychological and empirical evidence. Raballo and Poletti will present a comprehensive analysis of recent developmental psychopathological studies of self disorders in the schizophrenia spectrum. Giersch and colleagues provide the crucial experimental evidence for the close link between weakened temporal expectancy and the disruption of continuous and unitary self in schizophrenia. Temporal expectancy helps to link and transform a chain of discrete events into our perceptual experience of continuous flow of time, but it is disrupted in schizophrenia. These results point toward potential intervention strategies. Park and colleagues present exteroceptive, proprioceptive and interoceptive contributions to abnormal mapping of bodily sensation and peripersonal space in the schizophrenia-spectrum and argue that the core problems may lie in prediction coding errors across multisensory systems. Potential intervention may lie in studying trained \u201csensorimotor experts\u201d (athletes) who show precise and sharpened awareness of embodied sensations. The discussant (Ferri) will integrate these findings to highlight a new framework and multi-level approaches for understanding the etiologies of self disturbances in the schizophrenia-spectrum."} +{"text": "It has been reported that sea surface temperature (SST) anomalies, flow intensity and mesoscale ocean processes, all affect sardine production, both in eastern and western boundary current systems. Here we tested the hypothesis whether extreme high and low commercial landings of the Brazilian sardine fisheries in the South Brazil Bight (SBB) are sensitive to different oceanic conditions. An ocean model (ROMS) and an individual based model (Ichthyop) were used to assess the relationship between oceanic conditions during the spawning season and commercial landings of the Brazilian sardine one year later. Model output was compared with remote sensing and analysis data showing good consistency. Simulations indicate that mortality of eggs and larvae by low temperature prior to maximum and minimum landings are significantly higher than mortality caused by offshore advection. However, when periods of maximum and minimum sardine landings are compared with respect to these causes of mortality no significant differences were detected. Results indicate that mortality caused by prevailing oceanic conditions at early life stages alone can not be invoked to explain the observed extreme commercial landings of the Brazilian sardine. Likely influencing factors include starvation and predation interacting with the strategy of spawning \u201cat the right place and at the right time\u201d. In eastern boundary current systems (EBC), interdecadal variability of sardine populations can be related to both sea surface temperature (SST) anomalies and flow intensity . During suggesteThe ecological relevance of the spawning sites within the SBB suggested by for the The hypothesis that remains to be tested is whether it is possible to clearly determine the optimum oceanic conditions that would favour high commercial landings of the Brazilian sardine within the SBB. Or, alternatively, if extremely low landings could be result of specific unfavourable conditions. Fluctuations in fish abundance can be explained by migration, year-class success, fishing and stock-recruitment relationships and adult trophic interactions . In a reIn this paper, we use an individual based modelling (IBM) approach to look for differences in eggs and larvae mortality resulting from oceanic conditions prior to extreme Brazilian sardine landings. This investigation fills an important gap in our understanding of the Brazilian sardine ecology not addressed by previous research , 6. We fSardinella aurita in the Senegalese-Mauritanian region sho sho9] shDespite the limitations imposed by our modelling scheme, namely the lack of some important ecological interaction mechanisms such as predation or cannibalism, our results added a much-needed physical element to our understanding of the Brazilian sardine dynamics. Our modelling scheme realistically simulated increased initial larval mortality caused by temperature, and showed that mortality by advection becomes an important process depending on the spawning strategy. Most importantly though is that oceanic variability alone, particularly during the early developmental stages of the Brazilian sardine, has not proven to be sufficient to explain the recorded extreme fish landings.The use of a hydrodynamic numerical model to simulate environmental conditions, associated with individually tracked particles mimicking the biophysical behavior of fish eggs and larvae, is critical for a balanced analysis of the spawning process. The spatial structure of sardine eggs and larvae is influenced by the possibility of entraining different hydrodynamic regimes. It is also important to be able to test alternative hypotheses from which one can draw more realistic inferences from different, though possible, spawning scenarios.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file."} +{"text": "Editorial on the Research TopicSexual Dimorphism in Glucose and Lipid MetabolismLundsgaard and Kiens; Varlamov et al.) and are more prone to develop pathological alterations in glucose and lipid metabolism (Lundsgaard and Kiens). Thus, understanding how sex influences energy metabolism might hold key answers to how obesity related diseases can be prevented. Therefore, the aim of this research topic is to give an overview of the current knowledge on sexual dimorphisms in glucose and lipid metabolism. The articles are mainly focused on knowledge obtained in humans using different tracer studies. Overall, the data point toward a complex role of sex hormones where the sexual dimorphisms depend on the metabolic status of the individual. This includes that women in the prandial and postprandial state utilize more carbohydrate than men to meet energy needs (Lundsgaard and Kiens), whereas during prolonged fasting or exercise women rely more on fat oxidation than men . As reviewed by Hedrington and Davis, women endure lower blood glucose levels than men during prolonged fasting. This seems a consequence of a blunted central nervous system efferent response that in turn results in lower plasma levels of counter regulatory hormones and lower hepatic glucose output (Hedrington and Davis).Apart from the sexual dimorphism in when carbohydrates are preferred to meet energy needs, there are also sex differences in blood glucose levels seem to contribute to the android (upper body)/gynoid (lower body) fat distribution . However, there are sex differences in adipose tissue lipolysis during fasting and exercise, where women have a higher whole body lipolytic rate and higher plasma FFA levels than men . In the postabsorptive state, most plasma triacylglycerol (TAG) is found in very low density lipoproteins (VLDL) secreted by the liver. Women have lower plasma levels of VLDL-TAG than men, which is due to a higher clearance rate of TAG by skeletal muscle .As reviewed by on Table , whereasVarlamov et al.; Hedrington and Davis). Importantly, as reviewed by Lundsgaard and Kiens, the evidence for higher insulin sensitivity in female skeletal muscle stands stronger than the potential sexual dimorphism in whole body insulin sensitivity. Most studies investigating sex differences in insulin sensitivity have been conducted in healthy, lean individuals, thus leaving its significance in obese a largely unanswered question . In the study by Ter Horst et al., severely obese men had lower hepatic insulin sensitivity than BMI and age matched women, suggesting that targeting the liver when treating type-2-diabetes is particularly important in men.Insulin sensitivity is often measured as whole body insulin sensitivity and both no difference between men and women, and women having higher whole body insulin sensitivity than men have been reported . Overall both estradiol and testosterone deficiency affects energy metabolism in a manner suggesting that both hormones have a protective role against obesity and insulin resistance , with estradiol having the most pronounced effects (Santosa and Jensen). However, excess of both hormones, such as seen in women using oral contraceptives (excess exogenous estrogen) or women with PCOS (excess androgen), promotes insulin resistance (Lundsgaard and Kiens), and the beneficial effect of sex hormone repletion is generally unresolved (Santosa and Jensen).How sex influences energy metabolism is highly complex and as pointed out in the review by In all, the articles underline the significance of sex differences in energy metabolism and show the importance of studying obesity related diseases in a sex-specific manner as conclusions made in one-sex studies only apply to that particular sex. Furthermore, much knowledge can be gained by understanding why premenopausal women despite a higher fat mass, remains less susceptible to obesity related diseases.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The UWH cannot explain why filling the incubation period with a light cognitive demand task has more incubation effect than filling it with rest or a demanding task. The DPT explains this by assuming that performing an undemanding task ensures that both unconscious and conscious processes are recruited during incubation, whereas resting makes incubation an entirely conscious process and performing a demanding task makes it entirely unconscious because cognitive resources are depleted by the task (Sio and Ormerod, Secondly, the DPT can account for both insightful incubation and certain incubation-related phenomena in divergent thinking, such as the superiority of immediate incubation. Gilhooly argued tFinally, the DPT can explain the inverted-U shaped relationship between unconscious thoughts and creative performance (Yang et al., WS and YY discussed the study and co-wrote this comment. WS and YY revised this comment according to the reviewers' comments. All authors have read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "One of the fundamental goals of object recognition research is to understand how a cognitive representation produced from the output of filtered and transformed sensory information facilitates efficient viewer behavior. Given that mental imagery strongly resembles perceptual processes in both cortical regions and subjective visual qualities, it is reasonable to question whether mental imagery facilitates cognition in a manner similar to that of perceptual viewing: via the detection and recognition of distinguishing features. Categorizing the feature content of mental imagery holds potential as a reverse pathway by which to identify the components of a visual stimulus which are most critical for the creation and retrieval of a visual representation. This review will examine the likelihood that the information represented in visual mental imagery reflects distinctive object features thought to facilitate efficient object categorization and recognition during perceptual viewing. If it is the case that these representational features resemble their sensory counterparts in both spatial and semantic qualities, they may well be accessible through mental imagery as evaluated through current investigative techniques. In this review, methods applied to mental imagery research and their findings are reviewed and evaluated for their efficiency in accessing internal representations, and implications for identifying diagnostic features are discussed. An argument is made for the benefits of combining mental imagery assessment methods with diagnostic feature research to advance the understanding of visual perceptive processes, with suggestions for avenues of future investigation. Traditional object recognition research frequently focuses on bottom\u2013up processing of visual stimuli, proceeding from the detection of stimulus properties by the retinal cells to electrical transduction and consummate neural response. This vein of research has been successful in identifying physiological and neural pathways involved in the detection and processing of visual object properties leading to cognitive perception. Visual mental imagery therefore represents a flow of information opposite to that of visual perceptual phenomena; one which requires a departure from traditional bottom\u2013up perspectives in order to be fully understood.Why are certain images, or subcomponents of images, visualized more clearly than others, and what does this suggest about the process of perceptual viewing? Such questions remain to be answered in any conclusive or specific manner, and it is the goal of this review to evaluate possible avenues for working toward an explanation. By improving the precision with which we identify the visual content of mental imagery, a more complete appreciation of its interactive relationship with visual perception may be achieved, thereby leading to enhanced conclusions regarding the creation of cognitive representations.With the advent of enhanced technologies and improved testing methods, visual mental imagery research has progressed from mere speculation on a largely inaccessible, theoretical phenomenon to an effective and valid field of research with a rich empirical background. Increasing numbers of studies have demonstrated the functional role of visual imagery in a variety of tasks, such as memory , creativMental imagery offers a unique advantage over visual perception in that the amount of potential information available during later recall of a stimulus is far less than the amount available during perceptual viewing of the same stimulus. By definition, mental imagery refers to the ability to experience familiar or novel visual stimuli in the absence of appropriate concurrent physical stimulation . BecauseNatural limitations of attention and storage capacity during the process of transduction from the sensory to perceptual level are bound to result in the loss and distortion of some visual information. In other words, the amount of information available during visual recall is both quantitatively and qualitatively diminished compared to the perceptual state. Despite this, numerous empirical studies have demonstrated that it is possible to understand, name, and describe the properties of an object through mental imagery alone e.g., . TherefoThe goal of this review is to suggest that visual mental imagery, the contents of which have undergone a natural filtration process to sift out object information that is irrelevant for recognition or categorization in a given scenario, holds significant potential for identifying object features that are critical for perceptual recognition. These features, referred to as distinguishing or diagnostic features, are visual components with classificatory significance that facilitate fast and efficient object recognition . Due to (1)reviewing the prominent behavioral and neuroimaging methods that have been used to successfully access mental visual representations;(2)evaluating the potential of each method for identifying diagnostic features based on the efficiency and specificity they have been shown to achieve;(3)suggesting possible directions and implications for exploring distinguishing features through mental imagery in future research.The significance of object features in visual perception has long been acknowledged. In one of the oldest and most well-known theories emphasizing the importance of distinct visual parts, Despite the extensive literature regarding the role of visual features in object perception, the precise extent to which various individual features contribute to recognition remains inconclusive. Some theories speculate that distinguishing features play a critical role in facilitating efficient object identification and categorization. These unique informative visual components expedite the determination of object identity within a specific context by allowing the observer to quickly and effectively discriminate amongst probable alternatives . SimilarThe existence of distinguishing features in visual perception and their role in object recognition have received some empirical support, although the findings are by no means definitive. Originally thought to play an integral role in novel viewpoint recognition, diagnostic features supported a counter argument to the structural description theory suggested by The tendency for particular features to receive increased allocation of attention, along with their potential to aid fast and efficient object recognition across dynamic scenarios, supports the plausible perceptual and cognitive significance of distinguishing features. These findings also suggest that essential distinguishing features are likely to remain relatively intact in mental representations for several reasons:(1)their classificatory significance decreases the likelihood that they are filtered out as irrelevant information during the initial encoding of a mental representation;(2)it is reasonable to predict that distinguishing features represent a significant proportion of semantic object information within a spatially condensed visual unit;(3)their cognitive relevance presumably increases their robustness against the information degradation and bias effects that occur between the visual perception and mental image generation stages.Therefore, distinguishing object features are a prime candidate for empirical study in that they are simplified, reliable units that represent or anchor the larger, more complex mental representation of a visual stimulus. To illustrate, consider the example of a hammer. Most likely, an image of a hammer comes to mind as the word is read. Are there parts or features that seem clearer than others? Consider a simple recognition experiment in which a participant is shown an image of a hammer, with the metallic hammerhead portion removed. It is unlikely that a vaguely defined wooden handle would \u201cactivate\u201d (as reflected in any given measure of interest) one\u2019s conception of a hammer as efficiently as the whole object, with hammerhead intact. If the manipulation were reversed, however, with the handle removed and the hammerhead retained, one would expect much greater \u201cactivation\u201d of the abstract concept of \u201chammer,\u201d along with it all of the associations that concept entails because diagnostic features facilitate efficient perceptual category classification via uniquely discriminating visual features, neural activity that supports category classification may be related to diagnostic feature information, thus indicating that component-based visual information is directly represented through neural substrates;(2)because the exact locations within the neural visual processing stream at which distinguishing features are represented remains unclear, it can be assumed that diagnostic feature content may exist in either high or low visual areas.Despite mental imagery being a difficult and abstract concept to target, several self-report questionnaire instruments have demonstrated successful and reliable measurement of various aspects of visual representations. Of particular note are the widely used Vividness of Visual Mental Imagery Questionnaire VVIQ; and its At least one questionnaire instrument has attempted to target specific shape information represented within visual mental images. The Mental Imagery Scale MIS; was desiThe Object-Spatial Imagers Questionnaire OSIQ; approachThere are several advantages and drawbacks to employing questionnaires in the study of mental imagery. On the one hand, surveys allow a large amount of detailed data to be collected in a relatively short amount of time, much more so than physiological or biological measures; the questionnaires described above contain 32 items on average. All items consist of a simple Likert scale rating ranging from 5 to 7 steps. In addition, these measures require very little in the way of technical skills or eligibility criteria, making the instruments accessible to a broad and representative population. The reliability of self-report responses of this type is also supported by behavioral results indicating that individuals tend to have reliable and accurate metacognition of their own imaginative experiences . HoweverDespite these shortcomings, the high level of proficiency with which written questionnaires have been shown to access the mental imagery construct warrants their consideration as reflectors of distinguishing features in mental imagery. In order to best take advantage of the benefits provided by their time-efficient and portable format, questionnaires assessing the specific shape structure of visualized images may best be applied to a large group of respondents. Using an extensive population reduces the influence of individual biases and representational preferences on responses. Any significant patterns observed within and across responses could then be identified and targeted for further, more in-depth, analyses. In the meantime, indicators of individual preferences such as the Psi-Q and OSIQ should be considered for use as covariates when measuring partial object information in mental imagery, regardless of the primary methodology employed. Even perceptual biases revealed through drawings may be insightful for inferring the visual aspects which receive the most attention during encoding, thus suggesting features of greater relative cognitive import. If diagnostic features are highly informative for the identity of a given object, patterns among the features or shape aspects reported by a large and varied group hold potential for identifying naturally occurring diagnostic object features. Although the distinguishing features captured by questionnaires would most likely be limited to spatially discrete, nameable object components, these data could then be used to guide further empirical research to evaluate the quality, reliability, and validity of these components as perceptual diagnostic features.Gestural motor movements have also been explored as an indicator of mental object representation content. Following an established link between functional motor actions and tool use, one such study investigated whether an individual could acquire functional object representations merely by imagining the use of novel objects and visualizing the appropriate corresponding hand gestures . ParticiThe findings yielded by the study performed by The implicit connection between gestural actions and the cognitive understanding of objects holds intriguing potential for the study of distinguishing features, but it is subject to significant weaknesses as well. Similar to questionnaires, motor behavior tasks provide a non-invasive, inexpensive method by which to assess distinguishing object parts that inform natural interactive behaviors. However, such testing is considerably more time-consuming than survey administration, and the resulting data require complex scoring and careful interpretation. In order to avoid confounds of novelty and inexperience, investigations of motor behavior regarding distinguishing features may best be applied to ecologically valid objects with which participants have had previous physical interactions. Categorical classification as implicated by specific gestures may allow for efficient object decoding based upon observation alone . HoweverEye movements associated with imaginary visual tasks are similar to those observed during perceptual tasks. Spontaneous eye movements during visualization of a scene reflect directional patterns comparable to those associated with perceptual viewing . ParticiThe prediction of an association between mental imagery content and concurrent oculomotor movements is by no means a novel one, and it has received empirical support dating back several decades . In a diAlthough the precise nature of the relationship between saccades and object perception is still debated, there is some evidence that saccades index attention to specific object features during visual search. Eye tracking data suggest that saccadic patterns are influenced by peripheral object information acquired during visual search, thus reflecting attention to particular visual features based on available object information . Early fThere are several limitations that must be considered when applying eye movement tracking to the study of object feature detection, both in perceptual and imaginary tasks. The first of these is the potential confound of covert attention, during which an observer allocates increased cognitive attentional resources to a particular location in the visual field without executing a saccadic eye movement . The abiNonetheless, the relationship between oculomotor movements and spatial locations may be used to the advantage of object feature research. If discrete object features were equated to independent, distinct spatial locations, similar to the design employed by A large number of neuroimaging studies suggest that distinguishing object information is represented at the neural level and can therefore be detected by brain recording equipment. Data collected from fMRI have been used to successfully decode both object identity and category classification of not only visually perceived stimuli, but mentally generated images as well . PerceptThe impressive precision and flexibility with which fMRI data have been shown to capture specific feature information support the possibility that distinguishing object components are reflected in neural activity associated with mental imagery, thereby providing a direct means of accessing diagnostic features through mental representations. If distinguishing features truly are sufficient for category classification, as theory suggests, they may be significant contributors to the neural patterns observed in studies such as those described above. In order to test this, categorical stimuli that are found to elicit similar patterns of neural activation could be systematically segmented into a collection of visual component parts has been used to study mental representations as expressed through electrical neural activity e.g., . ResearcThe word cue approach employed to manipulate the experimental mental imagery condition in Functional near-infrared spectroscopy (fNIRS) is a relatively new technology that is rapidly gaining popularity due to its portability and flexibility of experimental application. This system combines the spatial sensitivity of fMRI with the convenience and temporal resolution of EEG through non-invasive measurement of the diffusion rate of near-infrared light as it is projected through the skull. Recordings collected from fNIRS are influenced by the relative concentration of oxygenated and deoxygenated hemoglobin in cortical blood flow, and are thus conceptualized as an indirect measurement of neural activity . This coA study of visual processing in infants employed fNIRS in an investigation of the neural correlates underlying object individuation . Using aSeveral concerns remain when considering fNIRS as a measure of mental imagery. On the one hand, a relatively established body of work investigating motor imagery may hold clues for guiding future application of this technology to object representations. The bulk of this literature focuses on decoding motor imagery for application to brain-computer interface technology see , which pThe investigation of mental imagery through brain activity is clearly advantageous in that these methods do not require individuals to explicitly communicate their private mental experiences. Despite the demonstrated success of neurophysiological recording methods in accessing mental imagery, there are still several limitations that must be considered when examining their implications for identifying distinguishing features in object representations. For example, similar to the stimulus set utilized by Although results from fNIRS studies show limited ability to categorize motor imagery and visual perceptual processes, there are several concerns that affect this area of research as applied to feature detection in object mental imagery. First, the nature of infrared light penetration employed by fNIRS restricts recordings to areas of cortex lying closely beneath the skull approximately 2\u20133 cm below the cortical surface . FortunaAn additional advantage of neuroimaging methods is that their data lend themselves to a wide range of statistical analyses which allow interpretations of complex activation patterns to identify correlations between visual and semantic information. Many of these techniques, including MVPA and support vector machine learning, allow multiple factors to be considered when correlating brain activity with category information see . The varOverall, fMRI neural recordings of perceptual and mental visual processing hold great potential for indexing distinguishing features in object representations, whereas EEG and fNIRS appear to be weaker methods. The sensitivity to object content demonstrated by fMRI data clearly suggests their utility for accessing the discrete visual elements necessary for distinguishing amongst different object categories. Results from EEG reflect partial imagery effects in brain wave dynamics, but current work is limited to general and disparate effects in holistic vs. non-holistic effects. In addition, there is reason to believe that fNIRS technology may be capable of recording mental imagery as expressed within adult primary visual cortical regions. However, more work remains to be done before fNIRS can be confidently applied to imaginary representations in either the motor or object imagery domains. Considering that fNIRS and EEG are highly compatible and improve accuracy when used together to investigate perceptual processes e.g., , combiniTable 1). The early, underdeveloped state of this field favors a systematic methodological approach capable of capturing a broad range of information. In order to achieve this, measurement approaches should be combined with the aim of capitalizing on methodological strengths and compensating for weaknesses, with an emphasis for collecting large and varied amounts of data. Here, overall implications and the utility of each method for exploring distinguishing features in visual imagery are summarized and suggestions are made for future directions.The aim of this review is twofold: to propose that mental imagery is an advantageous and valid method for assessing diagnostic object features, and to demonstrate that, in spite of the present lack of direct investigations of diagnostic features within mental imagery, evidence of their relationship and the tools best suited to their study are suggested by existing literature. Each measurement method offers its own unique advantages and weaknesses for exploring the role of diagnostic visual components in object processing it facilitates rapid growth of the relatively undeveloped area of semantically labeled visual features;(2)it allows important individual differences in imagery generation style to be identified and considered when interpreting supplementary, indirect measurements;(3)it lends insight into the cognitive processes revealed by self-report, which may provide informative, concrete links between semantic classification and biological activity, thereby augmenting interpretations drawn from physiological or neurological recordings.Studies of motor movement behavior implicate a significant relationship between goal-directed actions and mental representations that is mediated by the functional end of manipulable objects. When acquired without physical practice, however, this relationship appears to be limited to large-scale, goal-directed behaviors that are expected to produce an appropriate consequence. Because precise motor behaviors such as grip have not been shown to share a direct correlation with imagery-acquired mental representations, this approach may only appropriate for items that are associated with obvious and unique goal-directed movements, such as tools. Nevertheless, the observed correlation between spatially discrete, structural object components and motor behavior supports the likelihood that distinct features exist in mental representations, and that cognitively significant features may be indirectly expressed through physical actions.Eye tracking findings indicate that saccades are similar across perceptual viewing and mental imagery states, and thus reflect meaningful cognitive processes. Although saccadic eye movements in either condition may implicate attention to spatial location more so than individual features, this relationship may be exploited for the benefit of diagnostic feature research. If object features were to be reliably equated with distinct spatial locations in a manner that does not artificially modify the holistic representation of an object, saccadic eye movements may allow a more direct index of attention to salient object features rather than spatial location, which can then be tested for classificatory utility. In addition, such a method may pre-empt possible confounds of covert attention by requiring overt eye movements in order to fixate discrete features. This approach could be applied to perceptual object recognition tasks, the results of which could guide and be compared to analogous mental imagery investigations. A straightforward assessment of diagnostic features across perceptual and imagery conditions such as this may lead to further insight into the broader interactions between object features, perceptual processing, and mental imagery.Neural activity recordings obtained through fMRI constitute the most established area of research regarding internal visual images. This method provides a direct index of mental imagery content while avoiding the complications associated with verbal or visual translation of private mental experiences. Category classifications achieved via blood-oxygen-level dependent fluctuations as measured by fMRI strongly implicate the presence of diagnostic feature information in mental images, as well as their expression through neural activity. Distinct patterns of activity associated with particular categories of imagined objects have been identified and found to remain stable across individuals. Overall, fMRI techniques show notable promise for advancing the understanding of the role of diagnostic object features in object representations via the underlying neural mechanisms of mental imagery. Preliminary findings from EEG studies also suggest that holistic and non-holistic imagery of partial object components may be reflected in brain wave dynamics, but specific feature information has yet to be identified, suggesting it may be best combined with methods such as fMRI. The detailed level of specificity accomplished through fMRI is limited by its lack of temporal resolution, whereas EEG is limited by spatial resolution.Perceptual work conducted with fNIRS provides inconclusive evidence regarding hemodynamic responses as a reliable indicator of imagery-related activity. Although perceptual research employing fNIRS is still in its early stages, studies of object individuation and motor imagery suggest potential for future application of fNIRS to mental imagery events. Unfortunately, near-infrared is currently limited to the shallow cortical regions involved in visual processing, and the reliability of hemodynamic response for neural decoding remains to be validated. In order to accommodate the widely distributed and varied neural correlates of mental imagery formation, fNIRS should be combined with broader measurement instruments such as EEG or fMRI in order to aid effective indexing of visualized object features.The methods and findings reviewed in this article are intended to support the feasibility and value of exploring perceptual diagnostic features through visual mental representations. Internal visual experiences, which occur in the absence of perceptual input, have the potential to be uniquely informative for understanding the manner in which visual information is transformed and translated to produce semantically meaningful object representations. By taking advantage of the natural information filtration processes imposed by the physical and cognitive limitations of human visual and neuronal systems, it is possible to access a great deal of semantic information via a condensed, concentrated source, in the form of distinguishing features. Mental imagery offers significant benefits over direct perceptual evaluations in that, during natural perceptual viewing, the potential amount of identifying object information is far greater than when an object is recalled through imagery alone, in part because irrelevant information has been discarded \u2013 or, at least, deemphasized \u2013 in mental representations. By studying object recognition solely as it occurs during perceptual processes, the researcher is forced to consider an inordinate amount of possibilities when determining the properties of a stimulus most essential to its identification. However, this procedure poorly reflects natural visual processes. By approaching visual perception from the level of its ultimate goal \u2013 the mental representation \u2013 and evaluating the relationship between the initial input and its final output, the investigator may reach a more complete and accurate understanding of the interaction between vision and cognition.SR developed the concept, conducted the research, and wrote the text of this manuscript.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer DL and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review."} +{"text": "Cancers are the second leading cause of death among children 5 to 14 yr, after accidents . Delay iThe overall incidence of childhood cancer in Tehran metropolitan area was 176 per 1000000 . Fig. 1 In following former pivotal evidence about childhood cancer epidemiology, some reported registry-based studies and regional surveys shows finding as follow: increasing trend in thyroid cancer in all age group except children patients , the incSome evidence from other regions was as follow: the relative percentage of the lymph nodes and skin cancer in Western countries in boys was nearly twice of figures in girls . In the In contrast to cancers in adults, there are more challenges and pitfalls in childhood cancers. Small percentage of them has known preventable and modifiable risk factors. Radiation exposure is well established as a cause of childhood cancer because more than half of century it is identified that an association between exposure to medical radiation in pregnancy and risk of leukemia in offspring . ConstraAccording to scare evidence about childhood cancer epidemiology, future studies in Iran should provide evidence about etiology, effectiveness of screening tools and treatment modalities and validity and completeness registries in this context."} +{"text": "Currently many facets of genetic information are illdefined. In particular, how protein folding is genetically regulated has been a long-standing issue for genetics and protein biology. And a generic mechanistic model with supports of genomic data is still lacking. Recent technological advances have enabled much needed genome-wide experiments. While putting the effect of codon optimality on debate, these studies have supplied mounting evidence suggesting a role of mRNA structure in the regulation of protein folding by modulating translational elongation rate. In conjunctions with previous theories, this mechanistic model of protein folding guided by mRNA structure shall expand our understandings of genetic information and offer new insights into various biomedical puzzles. With regards to the full contents of genetic information, the answer to this fundamental question in biology has been frequently updated as newly emerging techniques and growing data constantly challenge our existing understandings . On one Commonly known as \"the second half of genetic code\", a vast in silico prediction for the structure of ribosome-bound mRNA. Recently, this viewpoint has altered due to the latest technical innovations, especially ribosome profiling to explore all possibilities and choose the native conformation .The complexity of protein folding have been conventionally summarized as the Levinthal's paradox. It states that the number of possible conformations of a small protein (around 100 residues) was so large that it would require more time than the lifespan of universe . More recently, new genomic data were used for directly testing the connection between mRNA structure and protein folding by comparison among genes . Using pCollectively, new genomic data of ribosome profiling and mRNA secondary structure suggested a mechanistic model , where tIn conclusion, elucidating the regulatory role of mRNA secondary structure for protein folding shall expand our understandings of the full contents of genetic information and the molecular mechanisms of its phenotypic expression. Gaining such insights offers broad implications for biological researches. For example, combined with proper bioinformatic algorithm for designing mRNA structure, it is bound to enhance our capability of expressing functionally heterologous proteins in cells. The generality of this regulatory role has raised questions on the neutrality of synonymous variations in coding sequences for molecular evolutionary analyses. The regulatory role of mRNA structure in protein folding has become the only model capable of explaining the stronger mRNA secondary structures in highly expressed genes . It offeDetailed modeling of co-translational folding modulated by mRNA structure can help us predict or interpret the phenotypic effects and elucidate the underlying mechanisms of synonymous variations ubiquitous in human genome . ImplicaGreat appreciations were extended to Yong-Gang Yao, Gong-Wang Yu, Heng Zhang and two anonymous reviewers for valuable comments."} +{"text": "We will try to demonstrate that laparoscopic radical nephrectomy could be the new gold standard treatment for renal cell carcinoma with the aid of the current reports exploring the advantages and disadvantages of laparoscopic radical nephrectom overopen surgery.Reported perioperative outcomes like operating time, blood loss, postoperative analgesia requirement, and length of hospital stay and duration of convalescence had been found to be in favor of laparoscopic radical nephrectomy. Some technical issues like approach of laparoscopic technique , removal of dissected specimen and need for lymph node dissection had been also discussed in detail in this review. Besides, oncological safety of laparoscopic radical nephrectomy had been explored. The overall five-year disease free survival rates of laparoscopic radical nephrectomy in recent series were found to be over 90%. All of the series including the present one at least confirmed the oncological efficacy of LRN as compared with open surgical approach. The contemporary review of the literature documents clearly demonstrated the perioperative benefits of laparoscopy compared to the open approach. Nevertheless, the development, however, more safe and reliable technique in laparoscopy is necessary for tumor extraction. Recent studies confirmed the long-term similar cancer control results of laparoscopic radical nephrectomy with open surgery. Despite some technical modifications by the different groups, it can be stated that laparoscopic radical nephrectomy is the new gold standard treatment modality for patients with localized renal cell carcinoma."} +{"text": "Recent advances in neurogenomics have allowed exploration of the brain on a previously unprecedented scale. The development of genomic technologies combined with neurobiology tools has given rise to discoveries that have transformed our understanding of brain connectivity , 2 and tRAB10 that provide resilience to Alzheimer\u2019s disease in \u2018high-risk\u2019 individuals, suggesting that this gene could be a promising therapeutic target. The approach used in this study could be repurposed to identify rare variants associated with resilience to other complex diseases [In this special issue on Disease Neurogenomics, we sought to capture novel insights into the impact of genetic and genomic variation with a special focus on neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. The articles published in this issue present advances that bridge the gap between genomics and neurobiology to improve our understanding of disease risk and the translational potential for diagnostic and therapeutic opportunities. In the study by Kauwe and colleagues, which formed part of the Alzheimer\u2019s Disease Neuroimaging Initiative, the authors identified rare variants in diseases .DOCK8/KANK1 duplications were shared by the five disorders, providing a CNV map that could be used to elucidate common molecular pathways across these heterogeneous phenotypes [Neurodevelopmental and neuropsychiatric disorders represent a spectrum of heterogeneous disorders with degrees of shared genetic etiology , 7. Hakoenotypes , 7.Although rare CNVs are known to play a role in schizophrenia, their impact in the context of intelligence quotient (IQ) within these patients is unclear. Bassett and colleagues showed that the burden of pathogenic CNVs in schizophrenia differs between IQ subgroups in a community sample of adults . They reThe functional impact of de novo mutations are of particular interest in neurodevelopmental disorders given their prevalence in patients. Eichler and colleagues review the state of neurodevelopmental disorders in the context of de novo mutations (DNMs), including CNVs, highlighting patterns of DNM enrichment and cell type-specific convergence in the brain . The autIn order to further understand the overlap between schizophrenia and four other neurodevelopmental disorders, Stahl and colleagues developed an extended pipeline called extTADA to analyze rare exonic variants from whole exome sequence data. This pipeline could derive insights into the genetic complexity of rare variation in schizophrenia versus other neurodevelopmental disorders and novel risk genes .Mapping the genetic architecture of complex diseases is being intensively investigated via multiple routes. Neuroimaging genomics is one of these routes, which aims to map genetic variation to brain structural phenotypes. Jahanshad and colleagues highlight emerging pathways associated with neural phenotypes and discuss the need for refined brain mapping to localize variation to specific tissue layers and subfields .Risk prediction in these diseases is difficult because of the polygenic nature of complex disorders; however, application of polygenic risk scores (PRS) is a widely used approach that has predictive power for case-control status . GelerntTogether, these collective efforts further our understanding of disease risk and the underlying neurobiology of complex brain disorders. We must continue in the direction of integrated, interdisciplinary, and open research in order to uncover the mechanisms by which genetic and genomic variation influence disease initiation and progression in these highly heterogeneous conditions; such a direction will only improve our ability to stratify patients to develop more informed diagnostic and therapeutic approaches."} +{"text": "There is renewed interest in the relationship between early childhood trauma and risk of psychosis in adulthood. Trauma and stressful events in childhood and adolescence are known to be more prevalent among individuals with schizophrenia and other psychotic disorders than in the general population. Furthermore, other findings support the role of childhood trauma as a socio-environmental risk factor for psychotic symptoms, and research on the potential etiological relationship between trauma/stressful events in childhood/adolescence and psychotic disorders is evolving. The aim of the current study was to examine relations among all items and domains of childhood trauma and schizophrenic symptoms in patients with schizophrenia. The relationship between types of trauma and their association with psychotic symptoms was analysed.In this study, we collected data from 50 schizophrenic patients . All patients met the DSM 5 criteria for schizophrenia. Psychotic symptoms were measured by the Positive and Negative Syndrome Scale (PANSS). Trauma and stressful events in childhood and adolescence were assessed using the Childhood Trauma Questionnaire (CTQ).We found significant correlations between emotional and sexual abuse, emotional neglect and denial scale in CTQ with positive symptoms of the PANSS .Meanwhile, no correlations were found between CTQ domains neither with negative symptoms nor with general psychopathology scale of the PANSS.This study showed that childhood trauma could be a predictor factor for developing positive symptoms in schizophrenia. Most studies found similar results, showing a correlation between childhood trauma and hallucinations in schizophrenia. A correlation between childhood trauma and agressive behaviours was also described in litterature. These results went along with the stress sensitization model where the HPA axis is over-active and excessively reactive to the subsequent environemental stressors causing positive symptoms of the disease."} +{"text": "Empathy is a complex interpersonal process thought to be impaired in individuals with schizophrenia spectrum disorders. Past studies have mainly used questionnaires or performance-based tasks with static cues to measure cognitive and affective empathy. In contrast, we used an Empathic Accuracy Task (EAT) designed to capture the more dynamic aspects of empathy by using video clips in which perceivers continuously judge emotionally charged stories of various targets. We compared individuals with schizophrenia to healthy controls on the EAT and assessed correlations among the EAT and three other commonly used empathy tasks.Patients (n=92) and healthy controls (n=42) matched for age and education, completed the EAT, the Interpersonal Reactivity Index, the Questionnaire of Cognitive and Affective Empathy and the Faux Pas task. Differences between groups were analyzed and correlations were calculated between empathy measurement instruments.The groups differed in EAT performance, with controls outperforming patients. A moderating effect was found for the emotional expressivity of the target: while both patients and controls scored low when judging targets with low expressivity, controls performed better than patients with more expressive targets. Though there were also group differences on the cognitive and affective empathy questionnaires (with lower scores for patients in comparison to controls), EAT performance did not correlate with questionnaire scores. Reduced empathy performance did not seem to be part of a generalized cognitive deficit, as differences between patients and controls on general cognition was not significant.Individuals with schizophrenia benefit less from the emotional expressivity of other people than controls, which contributes to their impaired empathic accuracy. The lack of correlation between the EAT and the questionnaires suggests a distinction between self-report empathy and actual empathy performance. To explore empathic difficulties in real life, it is important to use instruments that take the interpersonal perspective into account."} +{"text": "Drosophila neural stem cells (neuroblasts). New work from the Cabernard lab has now uncovered a molecular pathway for this essential component of cell division asymmetry.The ability of progenitor stem cells to divide asymmetrically allows for the production of diverse daughter cell fates. This process typically follows the sequential steps of cortical cell polarity and mitotic spindle positioning to ensure unequal distribution of molecular fate specifying factors. For divisions that produce daughter cells that are also of different sizes, an additional requisite is the asymmetric displacement of non-muscle Myosin II and site of cleavage furrow ingression. Previous work had demonstrated that the apical polarity complex functions in a spindle-independent pathway for such asymmetric cleavage furrow establishment in Drosophila neuroblasts as a model system, Tsankova, et al. [Again employing , et al. have rev"} +{"text": "Results from our field study show that the regulation of the foraging gene in harvester ants occurs at two time scales: levels of foraging mRNA are associated with ontogenetic changes over weeks in worker age, location and task, and there are significant daily oscillations in foraging expression in foragers. The temporal dissection of foraging expression reveals that gene expression changes in foragers occur across a scale of hours and the level of expression is predicted by activity rhythms: foragers have high levels of foraging mRNA during daylight hours when they are most active outside the nests. In the experimental study, we find complex interactions in foraging expression between task behaviour and light exposure. Oscillations occur in foragers following experimental exposure to 13 L : 11 D (LD) conditions, but not in brood workers under similar conditions. No significant differences were seen in foraging expression over time in either task in 24 h dark (DD) conditions. Interestingly, the expression of foraging in both undisturbed field and experimentally treated foragers is also significantly correlated with the expression of the circadian clock gene, cycle. Our results provide evidence that the regulation of this gene is context-dependent and associated with both ontogenetic and daily behavioural plasticity in field colonies of harvester ants. Our results underscore the importance of assaying temporal patterns in behavioural gene expression and suggest that gene regulation is an integral mechanism associated with behavioural plasticity in harvester ants.Task allocation among social insect workers is an ideal framework for studying the molecular mechanisms underlying behavioural plasticity because workers of similar genotype adopt different behavioural phenotypes. Elegant laboratory studies have pioneered this effort, but field studies involving the genetic regulation of task allocation are rare. Here, we investigate the expression of the Sociamalvolio, a gene involved in manganese transfer and sucrose responsiveness )foraging mRNA do not necessarily translate to protein activity differences in vivo. Future experiments should examine expression patterns in FOR protein in brains of foragers versus workers of other task groups. Additionally, in situ studies of RNA levels will elucidate whether the differential regulation of foraging is limited to particular brain areas in particular task groups, or during particular stages of behavioural maturation. A study of the ant Pheidole pallidula indicates that the spatial distribution of the foraging protein in the brain differs between minor and major workers of this species [foraging-sensitive regions of the brain involved in the transitions between tasks in harvester ant workers that could be determined by immunohistochemical analyses.Gene expression and the presence of species . Thus, tforaging expression underscores the potential importance of this gene in the development of behavioural plasticity in social insect workers [foraging gene is highly conserved in the Hymenoptera, with little evidence for functional evolution in amino acid sequence [The flexibility in the regulation of workers . The forsequence . It appesequence ,3,74\u2014to"} +{"text": "Subclinical psychotic experiences are present in approximately 5% of adults and 7.5% of adolescents from the general population. Whilst the majority of these experiences are transitory, individuals who report subclinical psychotic experiences are at greater risk developing psychotic spectrum disorders, as well as other adverse outcomes. It is now well established that there is an inverse association between psychosocial functioning and (subthreshold) psychotic experiences in both clinical and non-clinical populations, however the mechanisms which drive this association are unclear. Adolescents with subclinical psychotic experiences are more likely to use maladaptive coping strategies and less likely to use adaptive ones. Given that coping styles are potentially modifiable, clarifying how coping may mediate the association between subclinical psychotic experiences and functioning could provide an important avenue for psychosocial intervention. In the current study we aimed to determine whether the association between subclinical psychotic experiences and psychosocial functioning is mediated by coping style. We conducted a within study replication in two large adolescent samples from the general populations of Australia and the United Kingdom.723 adolescents from Melbourne, Australia, and 239 adolescents from Birmingham, UK, took part in the study. Subclinical positive psychotic experiences were measured using the Community Assessment of Psychic Experiences (CAPE). The Coping Inventory for Stressful Situations (CISS) assessed three different coping styles; task oriented (adaptive) styles and emotion and avoidance oriented styles. Functioning was measured via the Multidimensional Assessment of Functioning Scale (MAFS), which assesses general, family, and peer functioning. Mediation analysis was conducted using the PROCESS macro for SPSS.Subclinical psychotic experiences were strongly associated with reduced general and family functioning, and to a lesser extent with reduced peer functioning. Higher subclinical psychotic experiences were associated with lower task (adaptive) and avoidance oriented coping and increased emotion oriented coping. Task and emotion oriented coping were found to significantly mediate the relationship between subclinical psychotic experiences and all three types of functioning in both the Melbourne and the Birmingham samples. Avoidance oriented coping was found to significantly mediate subclinical psychotic experiences and peer functioning in the Melbourne sample only. Avoidance oriented coping was not found to mediate subclinical psychotic experiences with general or peer functioning in either sample.Given that 17% of children and 7.5% of adolescents experience subclinical psychotic experiences and that these experiences are associated with reduced functioning, high levels of distress, and suicidal ideation, introducing classroom based learning about coping strategies in schools may encourage the adoption of more positive coping strategies earlier. Additionally, the findings of the present study have important clinical treatment implications, as they suggest that techniques which increase levels of adaptive coping and reduce levels of maladaptive coping (in particular emotion-oriented styles) may help to break the cycle between subclinical psychotic experiences, functional decline, and eventual need for care."} +{"text": "The purpose of this study was to measure retinal vessel caliber and to examine early changes in macular thickness using optical coherence tomography (OCT). We evaluated to what extend vascular caliber and macular thickness differed between patients with type 2 diabetes mellitus without diabetic retinopathy compared with healthy individuals. 26 diabetic patients without diabetic retinopathy and 26 normal participants without any retinal and optic nerve diseases underwent ophthalmic examination, fundus photography, and OCT imaging. Temporal inferior retinal vessel diameters were measured using OCT. Also, we measured macular thickness in nine ETDRS subfields using Cirrus OCT. The mean age in the diabetic group was 61.5 years and in the control group, 55.5 years. Wider retinal arterioles and venules were found in patients with diabetes compared with healthy subjects . In patients with type 2 diabetes mellitus, central macular thickness was significantly thinner than that of control eyes . Our results support the hypothesis that the association between vascular damage and structural changes of the neuroretina is an early indicator of retinal impairment in patients with diabetes without diabetic retinopathy. Diabetic retinopathy (DR) is a frequent ocular complication and one of the leading causes of blindness in developed countries. DR is common in the first 5 years duration of type 1 diabetes and all the patients with type 2 diabetes have some form of DR after 20 years from the onset [3]. Thus, a protocol is needed to identify the individuals at great risk of blindness, before permanent changes in the retina occur. We need objective and reproducible tests for screening, early diagnosis and treatment evaluation of diabetic retinopathy. According to World Health Organization (WHO), more than 422 million people worldwide have diabetes mellitus (DM), and the number is increasing with an expected number of 552 million by 2030 [4]. Recent studies suggest that neurodegeneration plays an important role in the pathogenesis of DR [5]. Histological studies of autopsy samples have revealed that the alternation of the metabolic pathways in diabetes can potentially cause neural cell degeneration in the retina . Some of the studies reported that the neural loss might occur before any visible signs of vascular changes. Animal studies have shown that, in early stages of retinopathy, neural apoptosis, loss of ganglion cell bodies and glial reactivity can be observed . The interaction between regulation of blood flow and neural activity is considered to be involved in the pathophysiologic mechanism of DR, and is described as neurovascular coupling . For many years, diabetic retinopathy was considered a form of vasculopathy. The osmotic stress from hyperglycemia is the pathophysiological mechanism of increased intraretinal vascular permeability and variable degrees of intraretinal capillary closure, resulting in macular edema and ischemia [12]. OCT images can be used to qualitatively assess pathological changes of the retina or to make quantitative measurements, in vivo . Recently, Spectral Domain OCT has been used to measure retinal vessel diameter . OCT has become an important tool for screening, diagnosis and treatment evaluation of diabetic retinopathy [12]. Optical coherence tomography (OCT) is used for quantitative analysis of retinal architecture and provides detailed scans of retinal structure with a high resolution, retinal thickness, choroid and optic disc morphometry [17]. Several groups have shown that total retinal thickness is decreased in patients with no or minimal DR compared with healthy controls [18]. OCT measures the structural composition of the neuroretina and can assess retinal neurodegeneration. Studies have shown that vascular parameters such as venular dilation and larger arteriolar caliber are associated with DR . Fundus photography excluded from the study eyes with diabetic retinopathy. Mydriatic Zeiss camera was used to acquire optic disc centered fundus color photographs with a stereoscopic 35-degree field, according to the Fundus Photograph Reading Center procedure . Another study suggested that localized areas of retinal thickening can be found in initial stages of diabetic retinopathy [31]. One report found that fovea was significantly thinner with a longer duration of disease in a patient with no or mild DR [32]. Two other groups concluded that the pericentral retinal thickness was significantly decreased and reported a subnormal Rarebit Fovea Test result in patients with minimal DR . Because OCT evaluates the morphology of the retina, retinal neurodegeneration can be assessed clinically. Only a few clinical studies have investigated the neurogenic damage in patients with diabetes. The first study reported an increased retinal thickness of the superior nasal quadrant of the macula in patients with DR compared with patients without DR and controls . With an increase in the duration of DM, neuronal abnormalities are the cause for reduced RNFL thickness. If neuronal abnormalities develop before the increase of vascular permeability, these changes may explain the thinner macular thickness in early stages of diabetes. Further studies are needed to determine if changes in RNFL are the cause of the reduction in macular thickness. Several studies reported that retinal neuronal abnormalities are present in the early stages of diabetes [In the early stage of diabetes, the retinal vascular caliber and central macular thickness, measured with OCT, are altered in patients without diabetic retinopathy. Both arterioles and venules are wider in diabetic patients compared with healthy subjects. Central fovea thickness is reduced in patients with diabetes mellitus. We used OCT to study the human retina in vivo and non-invasively. We concluded that the retinal vessel caliber changes combined with structural retinal neurodegeneration might be an early indicator of retinal impairment in diabetes, before clinical evidence of diabetic retinopathy.We believe that intraretinal examination with OCT might help understand the macular pathophysiology and might become an important diagnostic tool in diabetic patients with no clinical evidence of retinopathy.Conflict of interest statementThe authors declare that they have no conflict of interest."} +{"text": "All craniate chordates have inner ears with hair cells that receive input from the brain by cholinergic centrifugal fibers, the so-called inner ear efferents (IEEs). Comparative data suggest that IEEs derive from facial branchial motor (FBM) neurons that project to the inner ear instead of facial muscles. Developmental data showed that IEEs develop adjacent to FBMs and segregation from IEEs might depend on few transcription factors uniquely associated with IEEs. Like other cholinergic terminals in the peripheral nervous system (PNS), efferent terminals signal on hair cells through nicotinic acetylcholine channels, likely composed out of alpha 9 and alpha 10 units . Consistent with the evolutionary ancestry of IEEs is the even more conserved ancestry of Chrna9 and 10. The evolutionary appearance of IEEs may reflect access of FBMs to a novel target, possibly related to displacement or loss of mesoderm-derived muscle fibers by the ectoderm-derived ear vesicle. Experimental transplantations mimicking this possible aspect of ear evolution showed that different motor neurons of the spinal cord or brainstem form cholinergic synapses on hair cells when ears replace somites or eyes. Transplantation provides experimental evidence in support of the evolutionary switch of FBM neurons to become IEEs. Mammals uniquely evolved a prestin related motor system to cause shape changes in outer hair cells regulated by the IEEs. In summary, an ancient motor neuron population drives in craniates via signaling through highly conserved Chrna receptors a uniquely derived cellular contractility system that is essential for hearing in mammals. Afferent fibers bring information into the CNS. Afferents develop from neural crest or placode-derived sensory neurons of spinal and cranial ganglia fibers bring information to the PNS. Efferents develop in vertebrates from basal plate-derived motor neurons and axons project either through ventral roots , or dorsal roots . Efferent fibers reach striated muscle fibers or neural crest-derived visceral ganglia of the autonomic system. Efferents use acetylcholine as the primary transmitter with variable additional transmitters. Efferents, branchial, visceral, and most ocular cranial motor neurons require Phox2a and/or 2b for their normal development innervation. The efferent innervation of the craniate retina is highly variable and appears to reflect the original connection of the diencephalic brain that evolved into the vertebrate retina of craniate chordates connects to peripheral target organs via two sets of nerve fibers comprising the peripheral nervous system (PNS):This review will provide evidence for the evolutionary and developmental reorganization of FBMs to IEEs that terminate on hair cells carrying an ancient nicotinic acetylcholine receptor predates chordates. Indeed, the molecular origin of these receptors occurred over 1 billion years ago. Recent cladistic analysis indicates a rapid multiplication and molecular diversification into several subunits around 800 million years ago in brainstem of mice (Pattyn et al., In summary, IEE develop initially in close proximity or overlapping with FBMs, share molecular cues with FBMs, but segregate through differential projection of axons outside and inside the brain as well as differential longitudinal and radial migration, including migration and or projection of axon branches across the floor plate. Candidate transcription factors are identified that may guide the differential projection and migration of IEEs but more work is needed to support those notions.The close proximity and initial molecular similarity of the IEEs to the FBMs (Roberts and Meredith, Xenopus laevis embryos caudally to the trunk to replace a somite (Elliott and Fritzsch, Motor neurons can be experimentally rerouted to become IEE to the ear by transplanting ears in In addition to visceral motor neurons acquiring a novel target (Espinosa-Medina et al., The conserved nature of the cholinergic receptor associated with hair cells that closely resembles ancestral pentameric cholinergic receptors (Li et al., A chance event that captured already existing chordate FBM axons (Fritzsch and Northcutt, Together, these data imply that the formation of IEEs may have two evolutionary and developmental significant steps:It remains unclear how developmental reorganization evolved an ear out of distributed mechanosensory cells (Fritzsch et al., BF Conceived and wrote a partial initial draft, KE completed the draft and edited.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Neuroimaging techniques have been developed as important tools to investigate brain dysfunctions that underlie mental disorders. In particular, modern functional magnetic resonance imaging (fMRI) holds the promise to provide neurofunctional biomarkers for improved diagnosis, prognosis, and optimized treatment of schizophrenic and affective disorders.Neurofunctional connectivity MRI using advanced experimental paradigms permits targeted investigation of the functional integrity of brain systems involved in the pathomechanisms of schizophrenic and affective disorders. From these investigations, pathophysiologically relevant neuroimaging biomarkers can be derived for differential diagnosis and tailored treatment selection.Possible neuroimaging biomarkers will be presented for the prediction of development and clinical course of schizophrenic and affective disorders as well as for the prediction of individual treatment responses. Further, recent neuroimaging findings on possible pathophysiological subtypes of schizophrenic and affective disorders will be discussed.These findings from functional neuroimaging studies may help to foster the development of precision medicine in psychiatry."} +{"text": "Assisted reproductive technology with intracytoplasmic sperm injection (ICSI) is becoming an international panacea for couples struggling with infertility. The increasing popularity of these techniques and the data generated has given us a better understanding of the efficacy, consequences and costs of these procedures. There still remain many unanswered questions and controversies surrounding the use of IVF and ICSI. Increased experience, better refinement of these techniques and clearer indications for IVF and ICSI will inevitably minimize the risks associated with this procedure."} +{"text": "Since its inception four decades ago, both the clinical and technologic aspects of continuous renal replacement therapy (CRRT) have evolved substantially. Devices now specifically designed for critically ill patients with acute kidney injury are widely available and the clinical challenges associated with treating this complex patient population continue to be addressed. However, several important questions remain unanswered, leaving doubts in the minds of many clinicians about therapy prescription/delivery and patient management. Specifically, questions surrounding therapy dosing, timing of initiation and termination, fluid management, anticoagulation, drug dosing, and data analytics may lead to inconsistent delivery of CRRT and even reluctance to prescribe it. In this review, we discuss current limitations of CRRT and potential solutions over the next decade from both a patient management and a technology perspective. We also address the issue of sustainability for CRRT and related therapies beyond 2027 and raise several points for consideration. Continuous renal replacement therapy (CRRT) was developed originally as an alternative for hemodynamically unstable acute renal failure (ARF) patients who could not tolerate conventional hemodialysis , 2. The While CRRT is now a mainstay therapy in the vast majority of large ICUs around the world, this modality can be challenging to implement at some institutions and significant opportunity for improvement exists . CliniciIn the most recent Acute Dialysis Quality Initiative (ADQI) consensus conference, the participants rightly identified the need for CRRT patient management to align with the current focus on personalized medicine. In this regard, the ADQI participants proposed the term \u201cprecision CRRT\u201d in calling for technology to be applied on an individualized basis rather tBased on the landmark study performed by Ronco et al. and seveThe clinical relevance of urea as a toxin per se is very much an open question, especially in light of large prospective studies performed in patients with end-stage renal disease (ESRD), and many experts give credence to the potential importance of other uremic toxin classes , 21. HowFor the future, we believe the incorporation of effluent urea nitrogen measurements, first through clinical protocols and thenRecent data have cast doubt on the use of conventional ESRD-based criteria for RRT initiation in AKI patients . NeverthWe believe the concept of demand/capacity imbalance, proposed recently by Mehta and colleagues , 32, wilThe concept of demand/capacity balance will also be useful to guide decisions about renal recovery and RRT cessation. The ADQI group has recommended explicitly that RRT should be discontinued if kidney function has recovered sufficiently to reduce the demand\u2013capacity imbalance (current and expected) to acceptable levels . We beliWhile awaiting the results from clinical trials, we also believe further progress will be made by 2027 in the clinical application of biomarkers , 36, notSevere fluid overload continues to be a common trigger for CRRT initiation, especially in septic shock patients who have received aggressive volume resuscitation in the face of worsening renal function . A quantEven while approaches designed to assess fluid overload and quantify fluid responsiveness are refined , we predThe increased prevalence of sepsis-associated severe AKI over the next decade will result in the need for antibiotic therapy in an increasingly greater percentage of CRRT patients . The lacA series of recent prospective trials have demonstrated that regional citrate anticoagulation (RCA) significantly reduces the risk of hemorrhage for patients treated with CRRT (in comparison with heparin) . The majIn parallel with advances in RCA, we believe manufacturers will continue in the pursuit of developing antithrombogenic membranes that either minimize or obviate the requirement for anticoagulation during CRRT. Surface-modified versions of the AN69 membrane have beeFinally, another issue related to thrombogenicity during CRRT is from the perspective of catheter use. Catheter thrombosis is a very common treatment complication, resulting in decreased therapy delivery and contributing to significant morbidity and cost. Recent data suggest that use of a surface-modified catheter (in comparison with a standard unmodified polyurethane catheter) results in a longer catheter life and less dysfunction (as measured by blood flow rate) . We beliOne of the current factors potentially limiting outcome improvements and further dissemination of the therapy is the lack of standardization for CRRT. A specific limitation that contributes to this lack of standardization is an insufficient evidence base\u2014the current confusion regarding the timing of CRRT initiation is a good example. As such, we predict that both randomized and pragmatic clinical trials performed over the next decade will address such critical issues and improve therapy standardization.Another major factor limiting therapy standardization is the lack of consensus CRRT quality metrics. Rewa et al. are currThe technical limitations of current CRRT machines make efficient management of patient and treatment data difficult in some respects . As oppoA dynamic CRRT program also implies the ability to use information technology beyond the real-time phase for longer-term purposes. At present, CRRT machine data are not routinely stored in an accessible warehouse, rendering impossible the systematic generation of reports for review by the clinical team. We predict that by 2027 clinicians will routinely be able to assess historical trends on a facility-level basis, especially those related to the basic quality metrics mentioned earlier, or to use these data for quality assurance purposes. Moreover, these data will facilitate design and implementation of pragmatic trials, including registries. Again, patient-level data from the EMR will supplement technical data.2 [While several extracorporeal approaches have been used as adjunctive therapies for organ failures beyond AKI , 54\u201360, ilation) , 58 and ilation) , 60 techAs is the case with data analytics and information management, CRRT is lagging behind many other therapies with respect to technology \u201cdown-sizing\u201d. The incorporation of microfluidics, micromechanics, and nanotechnology is driven by the desire not only to decrease the physical footprint of medical technologies (thus enhancing portability) but also to extend their applicability to greater numbers and subsets of patients . We predOne clear example of this trend within the renal replacement field is the development of wearable dialysis and ultrafiltration devices, on which several investigative groups have made significant progress during the past decade , 63. WhiThe recent development of a CRRT device specifically designed to treat pediatric AKI patients is a more immediate-term example of technology miniaturization. While treatment of pediatric AKI with CRRT has grown substantially over the past decade , pediatrThe need for efficient processing of data in the management of critically ill AKI patients has been highlighted during a recent ADQI conference focused on the implications of \u201cbig data\u201d for this population . While tThe cost of medical care for both chronic diseases and acute conditions is increasingly being scrutinized by government agencies and payers, in both the developed and the developing world. Because the societal costs of treating relatively small numbers of patients with ESRD are disproportionately high, health economic analyses and cost-effectiveness studies are now performed frequently upon the introduction of new chronic dialysis therapies. While visibility for the costs of treating AKI seems to be low and few health economic assessments have been performed, it is a costly disorder , 70. RecAnother important consideration is the general affordability of acute RRT in the future. In the developed world, acute RRT costs typically are not an important factor due to widespread health insurance coverage and relatively generous reimbursement policies. On the other hand, hospital reimbursement and patient self-payment policies vary considerably across the developing world , resultiA final consideration over the next decade is the need to begin developing acute dialysis techniques designed to provide sustainability beyond 2027. One of the major environmental footprints associated with most extracorporeal dialysis modalities is the generation of large masses of plastic disposables, including filters and tubing sets. The development of miniaturized technologies, including wearable devices, would be an important advance in addressing this problem. Another important dialysis-related environmental footprint is the large volume of fluid generated as waste . Both soAs the utilization of CRRT and ancillary therapies in the management of critically ill patients increases, their limitations have become more evident to many clinicians. These limitations apply both to the manner in which patients are clinically managed and how the technology is used. We have critically assessed these problems and rendered predictions about the manner in which they will be solved over the next decade. While we have tried to prognosticate on several topics, we have not attempted to address certain contentious issues that we believe will continue to be debated even in 2027. For example, we believe questions about the optimal CRRT mode and nutr"} +{"text": "Dental paresthesia is loss of sensation caused by maxillary or mandibular anesthetic administration before dental treatment. This review examines inferior alveolar block paresthesia symptoms, side effect and complications. Understanding the anatomy of the pterygomandibular fossa will help in understanding the nature and causes of the dental paresthesia. In this review, we review the anatomy of the region surrounding inferior alveolar injections, anesthetic agents and also will look also into the histology and injury process of the inferior alveolar nerve. Allod2et al. [Paresthesia is defined as altered sensation exhibited as numbness, burning or tingling of patient skin . The etiet al. , reporteInferior alveolar or lingual nerve paresthesia , 16 is aThere is a wide variety of anesthetic agents used in dental procedures. Articaine is the anesthetic of choice used in many dental practices . Its useGaffen and Haas (2009) reportedet al (1999) [There are numerous studies that present an array of clinical cases of prolonged lingual and mandibular anesthesia . Loss ofl (1999) found thThird molar extractions are very common procedures in most dental practices. Many complications might result from third molar extractions including bleeding, pain, swelling, dry socket, trismus and paresthesia , 21. TheIt was reported in 31 out of 134 cases of paresthesia, patients had felt an \u201celectric shock\u201d sensation at the time of anesthetic administration which miIt has been suggested that dental injection complications might be due to neurotoxicity and concentration of anesthetic agent used or simplTo understand the nature of dental paresthesia and their relationship with the site of inferior alveolar or mandibular nerve blocks, dentists need to appreciate the anatomy of pterygomandibular fossa which will be described in this next section.3Understanding the anatomy of pterygomandibular fossa is crucial for dentists since it is the target space for local anesthetic administration prior dental treatment. Key structures that are present in pterygomandibular fossa include lingual nerve, inferior alveolar nerve and nerve to the mylohyoid. The sphenomandibular ligament and the interpterygoid fascia are also integral structures that define this area , 29. TheThere is a considerable amount of literature regarding anatomical variations in pterygomandibular fossa especially the inferior alveolar nerve . Variantet al., 2010 [Lingual nerve injury has been reported in some cases of inferior alveolar nerve blocks , 16. In The location of lingual nerve in cadavers\u2019 study done by Kiesselbach and Chamberlain, 1984 was foun4et al 2003 [Inferior alveolar nerve has a structure of any typical peripheral nerve with three layers of epineurium, perineurium and endoneurium that sur al 2003 have fouDifferent imaging techniques have been used to determine the level of neuronal injury . PanoramThe etiology of paresthesia following dental procedure is still mysterious. Anatomical variations concerning the location of the lingual and inferior alveolar nerve, and variant branches of the nerve or the presence of multiple mandibular canals might be a possible cause for dental paresthesia. The histology of the lingual and inferior alveolar nerve and the number of fascicles surrounding these nerves are also very important factors in understanding the reasons behind paresthesia affecting these nerves."} +{"text": "Snail intermediate hosts play active roles in the transmission of snail-borne trematode infections in Africa. A good knowledge of snail-borne diseases epidemiology particularly snail intermediate host populations would provide the necessary impetus to complementing existing control strategy.This review highlights the importance of molecular approaches in differentiating snail hosts population structure and the need to provide adequate information on snail host populations by updating snail hosts genome database for Africa, in order to equip different stakeholders with adequate information on the ecology of snail intermediate hosts and their roles in the transmission of different diseases. Also, we identify the gaps and areas where there is need for urgent intervention to facilitate effective integrated control of schistosomiasis and other snail-borne trematode infections.Prioritizing snail studies, especially snail differentiation using molecular tools will boost disease surveillance and also enhance efficient schistosomaisis control programme in Africa.The online version of this article (10.1186/s40249-018-0401-z) contains supplementary material, which is available to authorized users. Please see Additional file Snails are invertebrate animals, belonging to the Phylum Mollusca. This group of organisms (except slug) possess a unique feature, known as \u201cshell\u201d which is a major characteristic of the group . The snaSome snails are medically important because they transmit disease-causing trematodes in humans and other animals . Most ofFirstly, the continued transmission of snail-borne trematode infections in most endemic areas is facilitated by the presence and distribution , 7 of thSecondly, poor access to basic infrastructure by most inhabitants living in endemic settings and the Several studies have been done to unravel the identity of the \u201csupposed enemy\u201d whose influence is of great public health importance and with pronounced burden amongst people living in marginalized settings of the tropic and sub-tropic regions \u201312.Therefore, it is important to develop the platform that will monitor and identify snail distribution and infected snails, to help improve control efforts of the diseases caused by snail-borne trematodes. Also, a lot of achievements have been recorded in the identification of some snail hosts of medical and veterinary importance using both morphological and molecular approaches \u201316 and tThere are continued efforts at improving the development of biomarkers that are effective in differentiating schistosome parasites and also provide insights into factors influencing host-parasites compatibilities on local scales , 18.Despite all the efforts, it is obvious that more reliable genomic information is required for snail intermediate hosts populations to help improve control programmes , 20 partGreat tasks lie ahead and more commitment is required to ensuring the elimination of schistosomiasis from endemic regions of Africa.Though, snail hosts studies are crucial especially in Africa as we prioritize NTDs elimination but only few studies have established snail hosts differentiation on local scales , 22, 23.Therefore, it is imperative to provide adequate information on snail host population structure and diversity both on national and continental scales using molecular approaches in order to strengthen control programmes in Africa. Such information is important for reliable decision making and efficient control implementation. This should be a pre-requisite for setting up effective control programmes that will be supported by active surveillance response system in endemic areas especially in sub-Saharan Africa where the disease burden is enormous but control efforts are limited due to poor funding and lack of political will.As suggested by Rollinson et al. that a gThis paper summarize the available information on the progress made in controlling schistosomiasis transmission through snail intermediate hosts studies using molecular approaches and also identify areas where actions are required to be taken for effective integrated control efforts to be achieved in Africa.The predominant snail intermediate hosts implicated for transmitting schistosome parasites in Africa is shown in Table Schistosoma mansoni and S. haematobium are responsible for intestinal schistosomiasis and urinary schistosomiasis respectively [S. haematobium is located in the venous plexus and it drains the infected person\u2019s urinary bladder while S. mansoni is located in the mesenteric veins and it drains both the large and small instestines.The male and female adult schistosome worms dwell inside the blood stream of humans. ectively Fig. 1)SchistosoS. haematobium) and the lumen of the intestine (S. mansoni) and are released into the environment with urine or feces. The accumulation of eggs deposited in the venules cause its blockage and this burst the veins and allows eggs and blood to access the urinary bladder and the intestine and this leads to the characteristic symptom of blood in urine and feces. When the eggs are released into the freshwater bodies, they hatch into miracidia and penetrate a suitable snail intermediate host of the genus Bulinus or Biomphalaria , both serve as snail hosts of S. haematobium and S. mansoni respectively. The schistosome parasites develop and multiply into the infective cercariae within the snail hosts and are released into the water bodies by the snails. Humans become infected when they have contact with waterbodies that are infested with active cercariae [Schistosome eggs equipped with spines are deposited by the female schistosome parasites into the small venules of the portal and perivesical systems. The eggs migrate towards the bladder and ureter ribosomal gene (rRNA), and the mitochondrial cytochrome oxidase I (COI) have created robust and reliable taxonomy which haB. forskalii, Bi. pfeifferi and B. truncatus using molecular methods in N\u2019Djamena, Chad [B. globosus, B. forskalii, Bi. pfeifferi, Lymnaea natalensis and Indoplanorbis exutus) of trematode parasites in Nasarawa State, north central, Nigeria using mitochondrial gene cytochrome oxidase I (cox1). The study assessed the phylogenetic relationship of these snails and established that B. globosus from Nasarawa State, Nigeria clusters with B. globosus sequence data from other West African countries such as Burkina Faso, Senegal and Niger when BLAST, using nucleotide blast homology on genbank forming a monophyletic lineage but forms paraphyletic relationship with B. globosus species from East Africa. B. forskalii also followed similar pattern, as it cluster to form a monophyletic relationship with species from Burkina Faso (Mogtedo barrage), Niger (Tondia) and Senegal (Thiekeene Hulle) while Bi. pfeifferi from Nigeria clustered with Bi. pfeifferi species from Senegal (Lake De Guirs), Kenya (Kibwezi), Uganda (Lake Albert) and Zimbabwe (Chiweshe) to form a monophyletic relationship. Indoplanorbis exutus formed a paraphyletic relationship with species from Asia. Information is lacking on the phylogenic status of Indoplanorbis exutus and Lymnaea natalensis from Africa, there is need to prioritize the establishment of reliable genome database for these snails across Africa considering their veterinary importance. Similarly, [Bulinus truncatus using PCR-RFLP technique and assessed their infection status with Dra I gene repeat in Southwest Nigeria while [B. globosus, B. forskalii, B. camerunensis and B. senegalensis in schistosomiasis endemic communities of Ogun state, Southwestern Nigeria through the application of PCR-RFLP on the snails ribosomal ITS region.Though the use of molecular approaches in differentiating snail hosts population structure have been applied on local scales across Africa but it is yet to be fully explored. For instance, identifina, Chad . Comprehmilarly, characteia while establisDraI and sm17 in the early detection of S. haematobium and S. mansoni in infected snail intermediate hosts of the Bulinus sp. and Bi. pfeifferi respectively have helped strengthen snail surveillance and boost schistosomiasis control efforts [DraI PCR and Sh110 SmSl PCR were effective in differentiating schistosome parasites that infected snails within the Bulinus group in Morocco [Molecular tools application is not limited to elucidating relationships across snail hosts taxa. The application of PCR efforts , 34. Als Morocco . Table 4The need to meet the goals of schistosomiasis elimination prompted the pursuit of an integrated control approach , 36 and It is observed that environmental factors play significant role in the population size of snail host\u2019s natural populations. The effects of these environmental conditions greatly affect gene flow between populations and induces important variations in population size . Their hBulinus snails from different ecological zones across Cameroon, Egypt and Senegal revealed high genetic diversity within Bulinus populations sampled from the three countries with the highest diversity observed within populations of B. forskalii and B. senegalensis [Biomphalaria pfeifferi in Madagascar which was reported to have high level of inter-population variation [Biomphalaria choanomphala along Lake Victoria covering Tanzania, Kenya and Uganda. The study identified consistent parasitism as the major influencing factor [Biomphalaria species of African origin were derived from the neotropical natives and that proto-Biomphalaria glabrata is the progenitor of the African species through the trans-Atlantic colonization of Africa.The investigation of snail genetics role in trematode parasite infections variation using molecular approaches is vital to understanding their epidemiology. The assessment of the genetic differentiation of galensis , but thiariation . Utiliziariation , showed g factor indicateS. mansoni in Bi. alexandrina population from Egypt that refractory character within the snail hosts population is hereditary and therefore advised that snails that are actively resistant to schistosome parasites should be cultured to encourage biological control of snail intermediate hosts in a natural population.Findings have shown that schistosome parasites development inside the snail host is influenced by both the host and parasite genes , 47. ThiFurthermore, it was established that snail hosts infection with schistosome parasites is species specific and often localized , effortsMore importantly, it is necessary to encourage the extensive study of snail genome differentiation on a large scale due to the current global changes that have led to changes in the modification of the geographical distribution of species prompting hybridization, such hybridization is already known to occur in schistosomes and offspring have been shown to have superior virulence and invasive capacities . This isLarge-scale assessment of snail intermediate hosts genome will create the platform to determine the degree of variability among and within snail populations across the continent and give an overview of schistosomiasis distribution in Africa with current realities.Determination of snail intermediate hosts population genetics and diversity using biomarkers is shown in Fig. 3Though, molecular approaches to differentiating snail intermediate hosts are key to combating the menace of this debilitating disease in Africa . HoweverFirstly, snail identification using shell morphology and bionomics studies are essential to understanding the distribution pattern of snail hosts and transmission dynamics of schistosomiasis and other disease causing snail-borne trematodes at local scales across the continent , 54. We Secondly, the application of Geographical Information System (GIS) and remote sensing technologies to map and define the spatial limits of snail hosts distribution is an important area that requires utmost attention. Though it has been applied in some parts of Africa on local scales \u201357, but Thirdly, there is urgent need to aggresively create awareness by educating the larger society especially people in the endemic areas through the mass media and other communication platforms on the importance of these planorbid snail hosts in schistosomiasis epidemiology. Experience in the field have shown that most locals who live around waterbodies in most endemic settings have little or no knowledge of the snails and are not aware of the danger their presence poses to their well-being. Hence, it is important to consistently create awareness on snail hosts control. The locals should be equipped with information that will spur them to ensuring that the snails does not thrive in their environment and also be mandated to urgently report snail hosts presence in any waterbody around their domain to the relevant health authorities promptly.Eichhornia crassipes within and around waterbodies enhance the occurrence, distribution and abundance of snail hosts because it serves as a good source of food, provide shelter and oviposition sites for the snails [In addition to the aforementioned three gaps on snail biology, there are other areas that requires attention. This includes effort to put infrastructure in place or consistently modify the environment to discourage the continued presence and distribution of snail hosts and schistosomiasis transmission in most endemic countries. The environment in most endemic countries are characterized by factors that influence the distribution of snail hosts of schistosome parasites as a result of poor environmental management \u201362. The e snails \u201365. Envie snails , 67. TheDespite the public health significance of schistosomiasis globally especially in Africa where about 95% of global schistosomiasis is concentrated , 69, theThe challenge of insufficient supply of praziquantel due to scarcity of funds and the resistance of schistosome parasites to the drug of choice led to tThis might also be attributed to the perceived negative impact that niclosamide, the molluscicide of choice have on fishes, an important protein source and means of generating income for people living in rural settings. Therefore, it is advised that the molluscicide formulation be improved to ensure that it has less negative impact on the environment and biodiversity , but retPhytolacca dodencandra and Millettia thonningii and some other plants with similar properties [. The distribution of these molluscicidal plants in areas identified as schistosomiasis hotspots in endemic areas will help curtail the distribution of snail hosts. However, it is important to effectively monitor the plants when cultivated in large scale because of their toxic properties.The exploration of the molluscicidal properties of plants such as operties should bThe use of biological techniques for snail hosts control is long overdue in Africa, measures should be taken to effectively apply natural predators or encourage biotechnological methods to induce infecundity in the snails . Figure The elimination of schistosomiasis and other trematode parasite infections will receive a great boost when snail hosts studies and effective snail control programme are prioritized. There is urgent need to set-up reference laboratories and other platforms that will encourage qualitative snail intermediate hosts and schistosomiasis researches and also facilitate early diagnosis of schistosomiasis cases. It is imperative to encourage capacity building through training and re-training of scholars, health workers and different stakeholders in Africa on snail hosts identification using both morphological and molecular approaches.Additional file 1:Multilingual abstracts in the four official working languages of the United Nations. (PDF 514 kb)"} +{"text": "Valuable insights into the role played by visual experience in shaping spatial representations can be gained by studying the effects of visual deprivation on the remaining sensory modalities. For instance, it has long been debated how spatial hearing evolves in the absence of visual input. While several anecdotal accounts tend to associate complete blindness with exceptional hearing abilities, experimental evidence supporting such claims is, however, matched by nearly equal amounts of evidence documenting spatial hearing deficits. The purpose of this review is to summarize the key findings which support either enhancements or deficits in spatial hearing observed following visual loss and to provide a conceptual framework that isolates the specific conditions under which they occur. Available evidence will be examined in terms of spatial dimensions and in terms of frames of reference . Evidence suggests that while early blind individuals show superior spatial hearing in the horizontal plane, they also show significant deficits in the vertical plane. Potential explanations underlying these contrasting findings will be discussed. Early blind individuals also show spatial hearing impairments when performing tasks that require the use of an allocentric frame of reference. Results obtained with late-onset blind individuals suggest that early visual experience plays a key role in the development of both spatial hearing enhancements and deficits. Our sense of vision provides us with the most detailed information about the spatial configuration of our environment. This visual dominance stems in part from the brain receiving high-resolution spatial information directly from the retina that is coded topographically throughout the visual pathway. While other modalities extract spatial information in a similar manner , they are body-centric and do not provide reliable information beyond personal and peripersonal space . However, there are exceptions to this rule, such as when using sensory-substitution devices to translate visual information into tactile input that can be perceived, for instance, on either the tongue or the back e.g., . The audsensory compensation hypothesis whereby blind individuals develop exceptional perceptual abilities within their remaining sensory modalities to compensate for the visual loss . In contrast, however, the blind display more accurate localization in peripheral auditory space, particularly for sound sources straddling the interaural axis .A seminal study identified a marked difference in spatial hearing ability between early blind and sighted individuals when having to localize sounds under monaural listening conditions . The spectral cue hypothesis, however, is challenged by spatial hearing findings in the vertical plane. Although localization ability in the vertical plane is also believed to rest primarily on spectral cues , early bAuditory depth perception has not been as extensively studied as localization, but there are nonetheless some emerging trends in sighted individuals can improve auditory localization is at odThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The global expansion of the aquaculture industry has brought with it a corresponding increase of novel viruses infecting different aquatic organisms. These emerging viral pathogens have proved to be a challenge to the use of traditional cell-cultures and immunoassays for identification of new viruses especially in situations where the novel viruses are unculturable and no antibodies exist for their identification. Viral metagenomics has the potential to identify novel viruses without prior knowledge of their genomic sequence data and may provide a solution for the study of unculturable viruses. This review provides a synopsis on the contribution of viral metagenomics to the discovery of viruses infecting different aquatic organisms as well as its potential role in viral diagnostics. High throughput Next Generation sequencing (NGS) and library construction used in metagenomic projects have simplified the task of generating complete viral genomes unlike the challenge faced in traditional methods that use multiple primers targeted at different segments and VPs to generate the entire genome of a novel virus. In terms of diagnostics, studies carried out this far show that viral metagenomics has the potential to serve as a multifaceted tool able to study and identify etiological agents of single infections, co-infections, tissue tropism, profiling viral infections of different aquatic organisms, epidemiological monitoring of disease prevalence, evolutionary phylogenetic analyses, and the study of genomic diversity in quasispecies viruses. With sequencing technologies and bioinformatics analytical tools becoming cheaper and easier, we anticipate that metagenomics will soon become a routine tool for the discovery, study, and identification of novel pathogens including viruses to enable timely disease control for emerging diseases in aquaculture. Traditionally, the diagnosis of viral diseases has been dependent on cell culture in which viruses exhibit cytopathic effects (CPE) and immunoassays based on antibodies having the binding specificity for the virus to be diagnosed , has emerged not only as a powerful tool able to enhance our understanding of the host response to infection and other fish species in Asia were first reported in the 1970s and yet the virus was first characterized in 1990 and several other shrimp viral diseases reached high epidemic levels before their etiological agents were identified and characterized that had just aborted on San Miguel Island , South American sea lions (Otaria flavescens) , and bottlenose dolphins (T. truncates) , which causes mortality within 4\u20136 days after hatching , asp (Aspius aspius), round goby (Neogobius melanostomus), monkey goby (Neogobius fluviatilis), and roach (Rutilus rutilus) showing clinical signs of a cauliflower-like disease and a novel seadornavirus resembling the mammalian Banna virus from freshwater carp baitfish using NGS. The majority of viruses shown in Table Recently identified pathogenic viruses of fish include the circovirus isolated from barbell fish (Frafantepenaeus duorarum hepatopancreas), which is a commercially important farmed shrimp species. One virus clone had a 403 nt insert encoding the RNA-dependent-RNA polymerase (RdRp) partial sequence while the other contained a 236 nt insert encoding a capsid protein partial sequence. Phylogenetic analysis showed that the capsid sequence was 43\u201351% similar to the shrimp nodaviruses, Macrobrachium rosenbergii nodavirus (MrNV) and P. vannamei nodavirus (PvNV), which causes white tail disease in prawns (M. rosenbergii), and muscle necrosis disease in shrimp (Litopenaeus vannamei) Table also ideAsterias forbes) virus (AFSSV) as the causative agent of a wasting disease condition linked to high mortality in the Forbes sea stars. On the other hand, Andrade et al. and bottle-nose dolphins (Tursiops tuncatus) are widely used as recreation animals. And as such, these animals are kept in marine parks where they are used in circus shows and other activities because of their intelligence and easy trainability. Given their close contact with humans, it has become expedient that their disease profile is determined both for public health reasons and for the sake of providing timely healthcare when they become infected with different diseases. Recently, Ng et al. (Phoca vitulina richardsii). Kluge et al. and South America fur seal . From the South America fur seals they identified seal anellovirus 5 (SaV5), and Troque teno salophus virus 1 (TTZV) while in the Subantarctic seal fur picornaviruses were identified namely Fur seal sakobuvirus (FSSV) having 50% amino acid identity resemblance to the Feline sakobuvirus A (FSVA). In addition, rotaviruses were identified from the subantarctic fur seals with 45\u201369% amino acid homology with group C rotaviruses. The identification of rotaviruses from Fur seals has important public health implications given that these animals are commonly found on coastal areas of South America where they attract a lot of tourism where they could serve as a source of zoonotic infections to tourists. These findings suggest that viral metagenomics can be used to obtain disease profiles for aquatic animals as well as profiles of zoonotic pathogens found in marine mammals. Table Captive marine mammals such as the Californian sea lions to identify SealAV. Hewson et al. (Enhydra lutris Nereis) that constitute the assemblage of complete viral genomes. As for viral diagnostics, it can be used to identify etiological agents of single infections, co-infections, and tissue tropism. It can also be used for disease surveillance by profiling viruses infecting in different host species and determining disease prevalence in selected host species. As for quasispecies analyses, metagenomics analysis can help identify segments of the viral genome prone to genetic diversity and the conserved segments. Hence, viral metagenomics can be used as multifaceted tool for the identification of novel viruses, phylogenetic analyses, diagnosis of single and co-infection, tissue tropism, and disease surveillance. Moreover, it has been shown that metagenomics analyses can be used to study the epidemiology of viruses outside their susceptible hosts using environmental samples (Munang'andu, de novo assembly, sequencing biases and low sequencing depth. These observations further consolidate the notion that verification of viral metagenomics data can be a difficult challenge.In this review, we have shown that viral metagenomics is a proactive diagnostic tool able to enhance the discovery of novel pathogenic viruses in aquaculture. In terms of the discovery of novel viruses, the de novo assembly of viral sequences is that they sometimes form chimeric contigs made of artificially combined reads that are not easy to identify. Hence, the bulk of uncharacterized viral sequences, sometimes referred to as the \u201cdark matter of metagenomics,\u201d limits our ability to identify novel pathogens using this tool given that new viruses without homologous sequences in public databases are likely not to be identified. Kim and Bae (de novo assembly to ensure that only long reads are produced for easy of taxonomical classification of viruses.Another important challenge faced in viral metagenomics analysis is that a large proportion of viral sequences generated using this tool remain uncharacterized mainly because they have no similarity with any known sequences in common databanks. Rosario et al. generate and Bae compared and Bae who also and Bae showed tde novo assembled genomes have not been investigated in detail (Mokili et al., Finally, another important challenge faced with viral metagenomics analysis is that the accuracy of the methods used for aligning the All authors listed participated have made substantial, direct and intellectual contribution and approved publication of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Glial cells, previously thought to have generally supporting roles in the central nervous system, are emerging as essential contributors to multiple aspects of neuronal circuit function and development. This review focuses on the contributions of glial cells to the development of auditory pathways in the brainstem. These pathways display specialized synapses and an unusually high degree of precision in circuitry that enables sound source localization. The development of these pathways thus requires highly coordinated molecular and cellular mechanisms. Several classes of glial cells, including astrocytes, oligodendrocytes and microglia, have now been explored in these circuits in both avian and mammalian brainstems. Distinct populations of astrocytes are found over the course of auditory brainstem maturation. Early appearing astrocytes are associated with spatial compartments in the avian auditory brainstem. Factors from late appearing astrocytes promote synaptogenesis and dendritic maturation, and astrocytes remain integral parts of specialized auditory synapses. Oligodendrocytes play a unique role in both birds and mammals in highly regulated myelination essential for proper timing to decipher interaural cues. Microglia arise early in brainstem development and may contribute to maturation of auditory pathways. Together these studies demonstrate the importance of non-neuronal cells in the assembly of specialized auditory brainstem circuits. Our ability to localize sound sources relies in large part on specialized circuitry in the auditory brainstem. Unlike other sensory modalities, such as the visual and somatosensory systems, in which spatial information is encoded in the sensory epithelium, the cochlea is unique in that it instead contains an orderly representation of frequency selectivity. This frequency map is conveyed through spiral ganglion cells to the brainstem, and interaural time and intensity differences are computed through specialized circuitry in the superior olivary complex. The development of these specialized neural pathways requires coordination of multiple molecular and cellular mechanisms. Several classes of axon guidance molecules have been identified that contribute to the formation of synaptic connections with precisely selected targets. Emerging evidence has shown that several classes of glial cells, including astrocytes, oligodendrocytes and microglia, play important roles in nervous system development Stevens, . Here weIn vertebrates, sound stimuli are transduced in the ear, where auditory hair cells in the cochlea are spatially ordered according to their preferred stimulus frequency. Hair cells synapse onto peripheral processes of cochlear ganglion cells, whose central processes enter the brainstem through the eighth cranial nerve (nVIII) and contact the cochlear nuclei, preserving tonotopy. Birds and mammals both use interaural time differences (ITDs) and interaural level differences (ILDs) to varying degrees to infer the locations of sound sources in space.The chick pathway, shown in Figure Several additional organizing features enhance the function of the NM-NL pathway in ITD computation Ohmori, . CoincidGlial cells are found throughout the auditory brainstem during the formation and maturation of the NM-NL pathway and are well positioned to contribute to most of the spatially ordered features of the auditory circuitry described above. Astrocytes are seen in the brainstem when NM and NL are still part of a common cell group known as the auditory anlage, at about embryonic day (E) 8. Glial fibers express the intermediate filament vimentin, a marker for radial glia. At E10, when NM-NL connections form, vimentin expression is limited to the dorsal region of NL -positive astrocytes coincides with this process, and we tested the effect of GFAP-positive astrocyte conditioned medium (ACM) on dendritic maturation in an organotypic auditory brainstem slice culture that permitted repeated imaging of individual labeled dendrites , are seen in VCN and MNTB during the first postnatal week in mice , a specific marker that broadly labels astrocytes (Cahoy et al., A distinct population of glial cells, the microglia, also populate the auditory brainstem nuclei at early ages (Dinh et al., Glial cells form close associations with the calyx of Held. In mature animals, the calyx has a fenestrated morphology, with astrocytic processes labeled in openings in the calyx (Ford et al., While GBC projections to MNTB are usually limited to the contralateral side, early unilateral removal of the cochlea leads to loss of VCN neurons on the lesioned side Trune, and subsWhile specialized auditory pathways engage glial cells for their mature function, glial cells also contribute significantly to the assembly of these pathways. Recent studies have shown roles for glial cells in synaptogenesis and dendrite maturation. Additionally, developmental regulation of myelination and internode distance are critical factors in establishing conduction times required for temporal processing in sound localization pathways of birds and mammals. While much remains to be discovered on the mechanisms of neuron-glial communication in these developmental processes, progress has been made determining the effects of this communication at numerous points of contact. Glial cells are integral components of functioning auditory brainstem pathways. These recent studies suggest that subpopulations of glia contribute to brainstem development and to their integration into these circuit elements.KSC drafted and edited the manuscript and prepared figures. EWR contributed to revision of the manuscript and preparation of figures.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "To systematically review the association between intergenerational social mobility and leisure-time physical activity (LTPA) in adulthood, in order to assess all published evidence relating to the hypothesis that adults socially mobile between childhood and adulthood will have different levels of LTPA than those in the same socioeconomic group across life.A systematic review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were identified by searching databases and reference lists. Eligible studies examined associations between any indicator of social mobility, based on at least one measure of parental socioeconomic position (SEP) and one measure of own adult SEP, and LTPA in adulthood.13 studies comprising a total of 44\u2005000 participants from the UK, Finland, Sweden, Australia, USA and Brazil were included. Participants were aged 16\u201370\u2005years and were from population-based surveys, occupational cohorts and primary care registries. Most studies (n=9) used occupational class measures to identify social mobility; education (n=4) and income (n=1) were also used. There was consistent evidence in nine of the 13 studies that stable high socioeconomic groups tended to report the highest levels of participation in LTPA and stable low socioeconomic groups the lowest. Upward and downwardly mobile groups participated in LTPA at levels between these stable groups.Cumulative exposure to higher SEP in childhood and adulthood was associated with higher LTPA in adulthood. Thus, a potential outcome of policies and interventions which aim to minimise exposure to socioeconomic adversity may be increased LTPA among adults.CRD42016036538. Regular physical activity improves physical health and mental well-being and reduces risk of chronic diseases including cardiovascular disease.Intergenerational social mobility, that is, changes in the level of SEP of offspring in adulthood when compared with their parents', may also be related to LTPA during adult life. Several alternative hypotheses have been proposed to explain how changes in SEP across life may relate to LTPA in adulthood. For example, adult LTPA may be predominantly influenced by socialisation effects of childhood SEP (origins hypothesis) or mostly by those of current SEP (destination hypothesis).11Studies of other cardiovascular disease risk factors generally find evidence of cumulative additive effects.This systematic review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelinesProspective and retrospective cohort studies published in English examining the association between changes in SEP from childhood to adulthood and LTPA in adulthood were included. Eligible measures of intergenerational social mobility were those derived based on at least one measure of childhood SEP \u226418\u2005years) and one comparable measure of adult SEP,\u2005years anEmbase (from 1980), MEDLINE (from 1946) and PsycINFO (from 1806) were searched up to October 2015 using keywords 10.1136/jech-2016-208052.supp2supplementary file S2Of 1199 unique citations retrieved from database searches, 13 studies reported in 17 publicationsStudy characteristics are summarised in Parental SEP was prospectively ascertained in five studies . ChangesMost studies present estimates of LTPA as prevalence across stable and mobile socioeconomic groups . StatistIn men and women from the 1946 British birth cohort National Survey of Health and Development),23Differences in physical activity27More pronounced age and sex-adjusted differences in prevalence of sports and exercise were found across social mobility groups of the Scottish Health Survey 2003 when compared with those reported above.29Mean reported exercise hours in the West of Scotland Collaborative Study tended to be highest in the stable high and lowest in the stable low groups.34Australian men and women aged 26\u201336 remaining in the highest and lowest educational groups between childhood and adulthood had the highest and lowest prevalence of LTPA, respectively, while socially mobile groups had levels in between these stable groups.This systematic review included findings from 13 studies (reported in 17 publications). It found that intergenerational stability and mobility of SEP was consistently associated with LTPA in adulthood. Of 11 studies that examined intergenerational stability and upward and downward mobility of SEP, nine found similar patterns of association. These suggested that stable high socioeconomic groups reported the highest levels of LTPA and stable low socioeconomic groups the lowest, and that both socially mobile groups participated in LTPA at levels closer to the stable high SEP group. The other two of these 11 studies found no associations. In addition, there were no differences in prevalence of LTPA in the remaining two studies both of which compared physicians who were upwardly mobile with those who had stable high SEP.The greatest differences in LTPA were between those groups stable in the same SEP and this supports an accumulation of additive effects hypothesis whereby continued exposure to a certain SEP in childhood and adulthood cumulatively alters probability of LTPA.49This review's findings also suggest that transitioning to more advantaged SEP in adulthood may partially offset the influence of low childhood SEP on less LTPA in adulthood shown in previous reviews.10In assessing the published evidence it is important to consider methodological factors which may influence interpretation. An important limitation of most analyses identified was that they were unadjusted for potential confounders even though certain factors might influence social mobility and LTPA. Related to this, none of the studies described whether the upwardly socially mobile participated in LTPA more, and the downwardly mobile participated in LTPA less, than expected relative to the SEP group they joined which may have indicated selection effects and so helped differentiate genuine effects of social mobility from those due to confounding.Most studies relied on recall of childhood SEP which could lead to misclassification due to recall errors and subsequently underestimate associations.All studies relied on participant reports to assess LTPA and although such methods are well suited to capturing LTPA,Our systematic review has several important strengths that include the use of a protocol, following of established guidelines, searching of multiple databases and reference lists, and assessment of search results and included studies by pairs of independently working reviewers which helps prevent errors in screening and data extraction. Despite our efforts to locate all published studies, a wider search may have identified additional studies . In addition, we did not search for unpublished studies and we could not formally test for evidence of publication bias as we did not perform a meta-analysis. However, potential publication bias may have been minimised by inclusion of all studies even where associations of interest were not the primary aim.A better understanding of the mechanisms through which socioeconomic circumstances might influence LTPA is required. Studies with repeat assessments of SEP could test alternate hypotheses relating life course SEP to LTPA.The findings of this review suggest that policies and interventions aimed at minimising exposure to socioeconomic adversity69\u201378Recent systematic reviews have reported associations between lower socioeconomic position (SEP) in childhood and less leisure-time physical activity (LTPA) in adulthood.The association between intergenerational social mobility and LTPA in adulthood has not previously been systematically reviewed.This is the first systematic review of published evidence on the association between intergenerational social mobility and adult LTPA.Cumulative exposure to higher SEP in childhood and adulthood was associated with higher LTPA among adults from different countries.Policies which aim to minimise exposure to socioeconomic adversity at any point in life may have the potential to improve LTPA status in adulthood.This systematic review of intergenerational social mobility associations with adult LTPA included 13 studies and found that those in stable high socioeconomic groups reported the highest levels of participation in LTPA and those in stable low socioeconomic groups the lowest, and that socially mobile groups participated in LTPA at levels between these stable groups. Thus, policies which aim to minimise exposure to socioeconomic adversity may result in improved LTPA levels."} +{"text": "Consciousness is a central concept in epileptology, relevant to the understanding of both focal and generalized seizures. Within focal seizures, impairment of consciousness has long been considered as the main criterion differentiating complex partial seizures (CPS) from simple partial seizures With the development of improved tools for investigating human brain function, new insights into the brain mechanisms of altered consciousness in CPS have become available. This paper reviews the existing literature on how the currently available methods can be used to address the fundamental issue of how CPS alter consciousness."} +{"text": "Joint fibrosis affects many synovial joints causing stiffness and pain. The mechanism of joint fibrosis remains unknown, although genetic factors may contribute. Defects in maintenance of telomere length resulting from impaired telomere repair have been shown to cause lung and liver fibrotic disease. Here we tested the hypothesis that joint fibrosis and other soft tissue fibrotic conditions are also associated with telomere length.5,200 participants in the TwinsUK registry had data on telomere length (measured by qPCR) and the traits of interest and fibrotic conditions .Multivariable logistic regression analyses showed a significant association between telomere length and fibrotic conditions even after taking age into account. No association was found between TJR and telomere length.These findings suggest that defects in telomere repair contribute to joint fibrosis, and that fibrosis shares a common mechanistic pathway in different organs. Therapeutic strategies to combat telomere shortening may offer novel treatments for fibrotic joint disease. Using the TwinsUK registry of monozygotic and dizygotic twins , we haveThe process of fibrosis is characterized by the deposition of a dense, disorganized extracellular matrix of collagen . In fibrRecent research suggests that defects in telomere maintenance involving the telomerase reverse transcriptase (TERT) gene cause liver and lung fibrotic disease . It is uParticipants were selected from the TwinsUK registry on the aMean leukocyte telomere length (LTL) was measured using a qPCR-based technique as part of a larger study using the TwinsUK cohort as previously described . Full deLogistic regression analysis was used to determine the association between the three traits of interest and telomere length. Adjustment was made for age, sex, BMI and smoking status. The cluster option in Stata was used to adjust for family relatedness . This inLogistic regression analysis was performed with telomere length as the predictor variable , for eacHere we report a significant association between telomere length and the presence of fibrotic joint disease in a large sample taken from the NIHR BRC TwinsUK BioResource. This suggests that impaired telomere maintenance may contribute to the development of joint fibrosis. Currently our understanding of the pathogenesis of joint fibrosis is poorly understood and consequently treatment options are severely limited. Measurement of TL by qPCR is a robust method and these twin TL data have previously contributed to the identification of new genetic loci associated with reduced TL in a genome-wide association study. In addiAnalysis of this observational study has limitations. Firstly, diagnosis of fibrotic joint disease relied on patient-reported data. However, the incidence of these conditions was found to be similar to previous studies ,17. SecoOther fibrotic conditions such as liver cirrhosis and pulmonary fibrosis have been shown to have a genetic disposition, with mutations seen in the TERT gene responsible for telomere maintenance and repair . As a reS1 MethodA detailed description of the qPCR method used to measure telomere length is provided together with relevant references.(DOCX)Click here for additional data file."} +{"text": "Cyclic Nucleotide Phosphodiesterase (PDE) comprise a family of 11 enzymes that hydrolyze cyclic nucleotides. PDEs aid in the regulation of secondary messengers, cyclic adenosine monophosphate (cAMP), and cyclic guanosine monophosphate (cGMP), through the degradation of phosphodiester bonds (Huang et al., Until recently, there was little knowledge about the expression of PDEs in the inner ear (Huang et al., in vitro (Kranz et al., The discovery of these various PDEs in the inner ear suggest that they play a crucial role in the auditory system Figure and can The future of PDE research could thus have vast implications in the field of hearing loss. Future studies should focus on deciphering the molecular mechanisms of the PDE pathways in the cochlea as well as how increasing and decreasing cAMP/cGMP levels influence inner ear homeostasis. In particular, further studying PDE5, PDE4D, and PDE3B inhibitors and their exact ototoxic properties at varying concentrations could provide insight on whether these drugs have beneficial or harmful effects on the auditory system and hearing. Once these ototoxic properties are thoroughly understood, medicinal doses can be administered or reduced accordingly. If reduction is not an option, the consequent step would involve changing the biochemical properties and structures of these PDE inhibitors to maintain their therapeutic purposes while reducing their ototoxicity.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Retinal microvascular imaging is an especially promising application of high resolution imaging since there are increasing options for therapeutic intervention and need for better structural and functional biomarkers to characterize ocular and systemic vascular diseases.Adaptive optics scanning light ophthalmoscopy (AOSLO) is an emerging technology for improving in vivo imaging of the human retinal microvasculature, allowing unprecedented visualization of retinal microvascular structure, measurements of blood flow velocity, and microvascular network mapping. This high resolution imaging technique shows significant potential for studying physiological and pathological conditions of the retinal microvasculature noninvasively.This review will briefly summarize the abilities of in vivo human retinal microvasculature imaging in healthy controls, as well as patients with diabetic retinopathy, retinal vein occlusion, and sickle cell retinopathy using AOSLO and discuss its potential contribution to scientific research and clinical applications. The retina has one of the highest metabolic demands per unit weight of any tissue in the human body , making Recently, advances in high resolution imaging techniques such as adaptive optics and optical coherence tomography angiography (OCTA) have expanded our ability to map the living human retinal vasculature noninvasively without the use of exogenous contrast agents \u20138. In paTraditionally, confocal AOSLO has allowed direct visualization of microscopic structures of the human retina with unprecedented contrast and resolution , 14, 19.Recently, the options of adaptive optics microscopic imaging have been expanded through the use of multiply scattered light with nonconfocal detection schemes . The general principles and applications of this technique have been described in detail elsewhere , 26\u201330. Since it was introduced by Novotny and Alvis in 1961, intravenous fluorescein angiography (IVFA) has been the clinical gold standard for assessing retinal vascular disease . It prodConfocal AOSLO FA performed with oral administration of fluorescein has an ability to image the microscopic detail of the retinal vasculature with greater resolution and contrast than with conventional imaging . CompariNonconfocal AOSLO coupled with motion contrast processing reveals maps of retinal microvasculature perfusion with detail comparable to confocal AOSLO FA, but without the need for any exogenous contrast agent . This imOCTA imaging is a new and emerging technology based on motion contrast with widespread clinical potential for mapping the retinal vasculature, detecting retinal vascular abnormalities and monitoring disease progression Fig.\u00a0e. SimilaDespite their advantages, AOSLO and OCTA are relatively new to the clinic and not yet considered routine techniques for imaging retinal vasculature. As with any new technology, the accuracy and reproducibility of AOSLO and OCTA must be tested in order to establish their validity and suitability for routine clinical implementation. These investigations are especially critical prior to initiation of cross-sectional or longitudinal studies of pathological microvascular change. Since accuracy and reproducibility have yet to be established, such studies must be conducted to define normative anatomic and physiologic standards before we can reliably assess disease states. In addition, comparative analyses between AOSLO and OCTA may be instructive regarding the significance of vascular patterns observed and their relationship to various vascular abnormalities.Currently, there are a variety of cross-sectional AOSLO studies which describe the structural and functional changes to the retinal capillaries in patients with vasculopathies , 42\u201347. Diabetic retinopathy is the most prevalent retinal vascular disease, causing visual impairments in 7.6 million Americans age 40 and older . It typiRetinal vein occlusion is second only to diabetic retinopathy as a cause of retinal vascular morbidity . Branch Currently, there are only few AOSLO studies on retinal vascular occlusion. Using a commercially-available confocal AOSLO, Akagi-Kurashige et al. observed that retinal capillaries were more dilated and tortuous in patients with branch retinal vein occlusion . In patiSickle cell retinopathy is a major complication of sickle cell disease that can lead to visual impairment. Sickle cell disease is caused by a point mutation on the beta globin gene, which limits erythrocyte deformity and reduces membrane elasticity . These rAs revealing as AOSLO cross-sectional imaging has been for displaying the details of microvascular change, its capability for non-invasive recording of longitudinal data is even more extraordinary, providing insight into the natural progression of microangiopathies. The ability to track capillary perfusion and microaneurysms longitudinally allows the opportunity to develop metrics of vascular change and apply them as biomarkers to help stage disease progression and assess treatment response \u201366. FiguFigure\u00a0Longitudinal vascular imaging of a 49-year-old female with proliferative diabetic retinopathy is shown in Fig.\u00a0Despite the AOSLO\u2019s extraordinary ability to extend our view into the microworld, current instrumentation and protocols have limitations that prevent its widespread clinical use. It is very time-consuming to acquire images, due to its limited field of view, and can be very fatiguing for patients. Furthermore, the optics of the AOSLO exaggerates sensitivity to media opacities, higher refractive errors, fixation stability, and tear film quality, and demands exceptional subject cooperation. Image processing, montaging and analysis are also very labor intensive and time consuming due to lack of automated techniques. Hopefully future advances in speed and tracking will expand its ability to image more challenging eyes, and software advances will make results more rapidly available in a clinically relevant time course.AOSLO provides unprecedented views of the retinal vascular network down to the capillary level, revealing microscopic vascular features that are not consistently visible with current clinical ophthalmic imaging instruments. This high resolution imaging technique also shows significant potential for studying physiological and pathological features of the retinal vasculature in the living human eye. Its ability to noninvasively track subclinical vascular changes over time opens new vistas onto the dynamic evolution of certain diseases and provides a more sensitive examination of clinical interventions."} +{"text": "We investigated social cognition and theory of mind in patients with schizophrenia and in patients with frontotemporal dementia in order to elucidate the cognitive mechanisms involved in the breakdown of these skills in psychiatric and neurological patients. Our tasks included videotaped scenarios of social interactions depicting sincere, sarcastic and paradoxical remarks, as well as lies. We found impaired performance of the schizophrenia group on all theory of mind conditions despite their intact understanding of sincere statements. In contrast, the FTD group performed poorly only when they had to rely on paralinguistic cues indicating sarcasm or lies, and not on paradoxical remarks or sarcasm when given additional verbal cues. Our findings suggest that, while current deficits in social and interpersonal functioning in patients with FTD may reflect a decrement in previously acquired skills, similar deficits in patients with schizophrenia may reflect an altogether inadequately learned process."} +{"text": "A series of emerging pathogen outbreaks during the past 24 months have commanded the public\u2019s attention and have exposed gaps in our preparedness to rapidly respond to these challenges. For example, the disease prevention and vector control response to the introduction and local spread of Zika virus infection in the United States is being blunted and hampered by congressional discord. Also, relying on legislation for emergency funds for each outbreak (rather than having a dedicated budget for preparedness and response to infectious disease outbreaks) is problematic. That said, previous zoonotic pathogen crises provide valuable insights into best practices, and herein, we detail the role of museum biorepositories in disease outbreak investigations. In addition to providing wide taxonomic sampling, museums and associated databases critically tie discoveries of new pathogens to permanent host records and samples and to a series of other informatics resources that facilitate future exploration, tracking, and mitigation of novel zoonotic pathogens. Because a fundamental requirement for the designation of a new pathogen is precise identification of the reservoir taxon , we advoApodemus agrarius) as the reservoir host of Haantan virus, the prototype virus of the genus Hantavirus in the family Bunyaviridae [Peromyscus maniculatus) in the southwestern US [Approximately 40 years have passed since the identification of the striped field mouse . Therefore, in-depth knowledge of potential hosts, their taxonomic affinities and relationships, and geographic distributions is vital . We recoAlthough the fundamental utility of host voucher specimens and frozen tissue collections is recognized and has been championed by a few disease ecologists , wide acField collections of natural history specimens often arise through dynamic collaborations that are capable of producing a diverse array of preparations and associated data with precise spatial and temporal stamps that facilitate myriad investigations. When properly archived and digitally captured, museum databases are capable of linking diverse kinds of \u201cbig data.\u201d This biorepository nexus can be a powerful tool for research in pathogen discovery, environmental change, and host\u2013reservoir dynamics. Spatially broad and temporally deep archives of ultra-frozen tissues represent unparalleled infrastructure for virologists, as demonstrated through the retrospective surveys for Sin Nombre hantavirus and subsMaintains spatially broad, temporally deep and site-intensive archives of ultra-frozen vertebrate tissuesPermanently links host specimens and tissues, microbial and host genetic sequences, associated publications, and other related data or materialsEnsures that pathogen reservoir identity is not lost due to taxonomic revisionEstablishes best practices for loan agreements and specimen trackingFacilitates inclusion of museum catalog numbers in GenBank accessions prior to accepting manuscripts for publicationNecessitates long-term institutional commitment to support personnel and physical infrastructureRequires periodic inventory of the number and condition of biospecimens"} +{"text": "External beam radiotherapy (EBRT) is the most treatment used in solid tumors as nearly 50% of cancer patients receive curative EBRT in the world. Its success depends mainly on the total dose homogeneously delivered within the target volume. Nevertheless, EBRT inevitably exposes surrounding normal tissues and may cause late and sometimes irreversible toxicities depending on different cells or tissues . Interactions between cells or compartmental tissues and the immune system via cytokines produce inflammatory and pro-fibrotic reactions. Cell depletion, inflammation, repopulation and remodeling are reminiscent of the wound healing process leading to different severities of late deterministic effects .Stratifying patients according to the toxicity risk and modulating EBRT dose would provide a valuable tool for personalized EBRT . Many efEBioMedicine, Kerns and colleagues and patients clearly at risk of developing more late effects defined as very sensitive . In termIn conclusion, there is no doubt that personalized radiotherapy driven by companion tests of radiotoxicity but also of tumor radioresponse will be the standard of care in the near future as it is already the case for targeted therapies in medical oncology. One size will no longer fit all!The authors declare that they have no competing interest regarding this manuscript."} +{"text": "Both preclinical and human research suggest that cannabidiol (CBD) has antipsychotic properties. This study assessed the safety and effectiveness of CBD in patients with schizophrenia.Patients with schizophrenia (n=88) were randomized to receive CBD (1000 mg/day) or placebo alongside their existing antipsychotic medication for 6 weeks. Participants were assessed before and after treatment using the PANSS, BACS, GAF scales, and the CGI Improvement and Severity scales.Compared those given placebo, patients treated with CBD had lower levels of positive psychotic symptoms , and were more likely to have been rated by clinicians as improved and as not severely unwell . Patients who received CBD also showed trends for greater improvements in cognitive performance and in overall functioning . There was no difference in the frequency of CBD of adverse events between CBD and placebo.These data suggest that CBD has beneficial effects in patients with schizophrenia and is not associated with significant adverse effects."} +{"text": "The current progress using the human embryonic stem cell (hESC) model system has provided much insight into the early origins of the hematopoietic and endothelial lineages, particularly the elusive hemangioblast. Recently, the cellular hierarchy and molecular regulation controlling hematopoietic commitment have been further elucidated. These findings not only provide new insights into early human development, but also advance the knowledge required to develop techniques capable of generating a given cell type for potential clinical applications. This review will focus on the latest advances using the hESC model system, capitalizing on the well-established mouse embryonic stem cell model system, as a means to investigate the lineage commitment events underlying the early embryonic development of human hematopoietic and endothelial cells."} +{"text": "Eretmochelys imbricata) in the eastern Pacific Ocean use foraging grounds in the region of their natal beaches, a pattern we term natal foraging philopatry. Our findings confirm that traditional views of natal homing solely for reproduction are incomplete and that many marine turtle species exhibit philopatry to natal areas to forage. Our results have important implications for life-history research and conservation of marine turtles and may extend to other wide-ranging marine vertebrates that demonstrate natal philopatry.The complex processes involved with animal migration have long been a subject of biological interest, and broad-scale movement patterns of many marine turtle populations still remain unresolved. While it is widely accepted that once marine turtles reach sexual maturity they home to natal areas for nesting or reproduction, the role of philopatry to natal areas during other life stages has received less scrutiny, despite widespread evidence across the taxa. Here we report on genetic research that indicates that juvenile hawksbill turtles ("} +{"text": "The long-term survival and quality of life of patients on hemodialysis is dependant on the adequacy of dialysis via an appropriately placed vascular access. The native arteriovenous fistula (AV fistula) at the wrist is generally accepted as the vascular access of choice in hemodialysis patients due to its low complication and high patency rates. It has been shown beyond doubt that an optimally functioning AV fistula is a good prognostic factor of patient morbidity and mortality in the dialysis phase. Recent clinical practice guidelines recommend the creation of a vascular access (native fistula or synthetic graft) before the start of chronic hemodialysis therapy to prevent the need for complication-prone dialysis catheters. A multidisciplinary approach, including nephrologists, surgeons, interventional radiologists, and nurses should improve the hemodialysis outcome by promoting the use of native AV fistulae. An important additional component of this program is the Doppler ultrasound for preoperative vascular mapping. This approach may be realized without unsuccessful surgical explorations, with a minimal early failure rate, and a high maturation, even in risk groups such as elderly and diabetic patients. Vascular access care is responsible for a significant proportion of health care costs in the first year of hemodialysis. These results also support clinical practice guidelines that recommend the preferential placement of a native fistula."} +{"text": "The sale of unproven stem cell interventions (SCIs) by commercial entities has proliferated in highly developed countries, most notably in the USA. Yet, there have been few criminal prosecutions and regulatory enforcement actions against providers who have violated laws and best practice standards due to the lack of resources and legal ambiguity. While the stem cell research community has invested much in protecting patients and preventing the growth of this industry, some patients are seeking remedies under civil law to hold stem cell clinics responsible for fraudulent practices. Several patients have filed lawsuits against providers demanding compensation for physical injuries caused by unproven treatments and financial losses due to fraud and false advertising. Lawsuits can be used as a tool not only to compensate plaintiffs but also to achieve positive public health and policy outcomes. In this paper, we explore the value of a public health litigation strategy as a countermeasure against the exploitative practices of the unproven SCI industry by analyzing stem cell lawsuits and comparing them with other major public health litigation efforts. We argue that stem cell lawsuits complement other approaches to reining in unsafe practices. In particular, stem cell lawsuits could intensify publicity and raise awareness of the harms of unproven treatments, set legal precedent, reshape the media narrative from one focused on the right to try or practice to one highlighting the need for adequate safety and efficacy standards, and encourage authorities to turn their attention to policy reform and enforcement. However, recent reports show a significant rise of clinics in economically developed countries, including the USA, UK, Australia, and Japan,4 calling into question whether robust regulatory frameworks are sufficient to rein in these practices. Although active enforcement with more stringent penalties might be an effective countermeasure, the current trend in the USA and other countries focuses on developing pathways for accelerated or conditional approval of regenerative medicine products, rather than a move toward more regulation.5 Indeed, most US states have enacted Right to Try legislation,6 and the US Senate recently passed the federal Trickett Wendler Right to Try Act,7 which may restrict regulatory authorities\u2019 ability to exert control over companies selling unproven SCIs. In the absence of government oversight of private sector firms, patients and consumers may need to look elsewhere to protect their interests. Civil litigation provides a means for patients who feel they have been harmed by undergoing a SCI to seek redress and compensation from providers and may also motivate government and industry to address the issue on a larger scale.The direct-to-consumer marketing of unproven stem cell interventions (SCIs) has emerged amid a complex and highly dynamic social, economic, and legal-regulatory environment.8 In this paper, we compare the identified cases to other public health litigation efforts and outline the advantages and shortcomings of civil law in protecting the health of consumers in this context. We argue that civil litigation is a potentially effective tool against businesses marketing unproven SCIs and outline how this can be achieved. We provide several considerations for members of the stem cell research community to support patients seeking legal recompense.We identified 9 individual and class action lawsuits filed by 19 named injured patients against providers offering SCIs using the LexisNexis and Westlaw databases, as well as Google.com. We excluded cases involving noninvasive cosmetic products, lawsuits that did not involve an injured plaintiff suing a clinic or clinician for damages, and cases in which the injury was not caused by the SCI. A more diverse list of cases involving stem cells that includes other claims, such as intellectual property and vendor contract disputes, has been compiled elsewhere.The small but growing number of individual and class action lawsuits filed against stem cell clinics include claims of product liability, misrepresentation of fact, false advertising, lack of informed consent, and financial elder abuse Table . The inc10 While the subject matter in these cases varies widely, tort litigation has had the effect of attracting public attention, shaping the media narrative, uncovering information, and giving issues greater prominence on agency agendas, eventually altering industry practices.Public health litigation has been used in tobacco-related illness, gun violence, and the clergy abuse scandal among others, not only to compensate injured plaintiffs but also to achieve positive public health and policy outcomes.11 As the media narrative grew, more individuals came forward to file lawsuits refocusing attention on institutional responsibility, rather than solely on individual defendants. Although the primary goal of public health litigation is to compensate victims, it had the additional effect of increasing awareness and prompting governments and others, including the US Conference of Catholic Bishops, to investigate the issue and amend policies to strengthen enforcement and prosecution efforts to prevent future incidents.11 While lawsuits against stem cell clinics are not to target a single institution as in the clergy abuse context, several clinics do form conglomerates that might help in uncovering fraudulent business practices instituted across clinics.Public health litigation has been implemented in various ways based on the context of harm and with varying success. In the context of the clergy sexual abuse scandal, where this public health litigation strategy achieved positive outcomes, successful litigation garnered media attention, identifying sympathetic plaintiffs, generating moral outrage, and mobilizing support for victims.12 The fear of tort liability may provide sufficient incentive for compliance and minimize the occurrence of unethical practices.9The threat of financial liability for wrongdoing is the primary means by which civil law governs behavior in the private sector. Despite calls for stepping up enforcement efforts, the US Food and Drug Administration (FDA) is currently restricted in its ability to identify and target clinics operating in apparent violation of regulations.13 the impact of these messages is being overwhelmed by clinics advertising treatments as panaceas for treatment-resistant and chronic conditions14 and political advocacy groups demanding easier access to unproven treatments as a matter of patient rights. Litigation may impact the broader conversation about unproven SCIs by drawing attention to negative outcomes and engendering moral outrage on behalf of vulnerable and sympathetic plaintiffs. Plaintiffs will receive public sympathy because they typically have debilitating diseases and turn to clinics as a last resort. Additionally, stem cell lawsuits may reframe the media narrative shifting the focus away from the patients\u2019 right to try and instead toward misconduct by providers, holding them accountable and highlighting the need for adequate safety and efficacy testing of experimental products.In addition to having a direct financial impact on clinics, stem cell lawsuits may help raise public awareness and influence public policy, particularly if there is a high volume of cases. Although public awareness and education campaigns publicize predatory practices of some stem cell clinics,9 Lawsuits could help identify wrongdoers and contribute to effective enforcement against such clinics.As seen with lawsuits against tobacco companies, another major benefit of stem cell lawsuits is uncovering previously undisclosed information about a provider\u2019s practices through the discovery process, which may trigger FDA investigations.9Finally, and perhaps most importantly, cases against providers may catch the attention of the media leading other victims to come forward and likewise file suit\u2014similar to what happened in the clergy abuse context. Despite evidence of injury, very few patients publically report suffering negative impacts. There may be several complex reasons for patient silence; perhaps it is due to embarrassment or fear of reprisal from their patient community or perhaps they themselves do not view their overall experience as negative. However, if enough lawsuits are filed, the debate will be thrust into the public eye forcing policy makers and administrative agencies to do more to address the proliferation of clinics operating outside accepted scientific and medical standards.15 The complaint relied primarily on false advertising and misrepresentation claims, alleging that StemGenex (1) misrepresented satisfaction ratings on its website by stating that no patients were dissatisfied despite being presented with evidence to the contrary, and (2) advertised its treatment as providing a benefit without any evidence of efficacy.15 The Court allowed the misrepresentation of customer satisfaction claims to proceed but dismissed the claims based on a misrepresentation of efficacy. According to the Court, plaintiffs cannot prevail on a claim for fraud under California Consumer Protection Laws when there is merely a lack of evidence that a SCI will work; plaintiffs only have a viable fraud claim if they can provide positive scientific evidence both that the SCIs do not work and the clinic knew about it.15 The burden of proof is on the plaintiff to show that the SCIs are demonstrably ineffective and that the defendant provided them in spite of this scientific evidence. The Court also dismissed the plaintiffs\u2019 claim that the defendants violated the human experimentation law by failing to obtain adequate informed consent for treatment. The Court found that the SCIs offered by StemGenex would not be considered \u201cmedical experimentation\u201d, which is defined in the law as an intervention \u201cnot reasonably related to maintaining or improving the health of the subject\u201d.16 Because the SCI was related to maintaining or improving health, it fell outside the scope of the California law.Most lawsuits to date have reached a settlement with no substantive ruling or court opinion on the merits of the claims raised. However, in one current proposed class action case, Moorer v. StemGenex, the court decided that some claims lack merit, while others potentially have merit and could proceed to trial.17 This document names five plaintiffs individually in the lawsuit but proposes there are likely hundreds more plaintiffs who would be included in the lawsuit if the Court decides to certify the class. The Court\u2019s ruling in dismissing some claims does not mean that they would not be viable in other states. As more courts issue opinions on the merits of certain claims in different jurisdictions, attorneys will be better able to identify strategies most likely to be successful in future cases.Initial complaints often include several theories of liability, and therefore dismissal of some claims, with the option of amending and refiling them, is not necessarily a \u201closs\u201d for plaintiffs. In response to the ruling, the plaintiff submitted a Fourth Amended Complaint relying on false misrepresentation of patient satisfaction ratings.18 and Bioheart, Inc.19 in 2015, plaintiffs raised product liability claims alleging that the company retrieved adipose tissue and injected it bilaterally into their respective eyes to treat macular degeneration resulting in severe and permanent damage.20 Unlike the StemGenex case, these cases alleged actual physical injury caused by the SCIs and claimed that the company failed to ensure both the safety of its products and that the products would successfully accomplish what they were marketed to do, namely, treat macular degeneration.19 Such cases may have a stronger basis for liability, relying on physical injury rather than financial injury and claiming that the advertised therapies are actively harmful, not merely ineffective.Other lawsuits that resulted in settlement alleged different claims that may also be found to have merit. For example, in two cases against US Stem Cell, Inc. However, most lawsuits filed against clinics to date have ended in settlement or voluntary dismissal with no court opinion to offer judicial analysis of the claims Table . It is m21 In this case, the plaintiff successfully sued a private stem cell clinic for failing to discuss the risks of infusing mesenchymal stem cells, particularly in light of the patient\u2019s preexisting medical conditions. According to the court, the plaintiff was not adequately informed of the risks prior to undergoing the procedure and was awarded the costs of therapy as well as an additional 500,000 yen (~4188 USD) in damages.21 Although the US administrative and legal systems differ greatly from Japan\u2019s, this case demonstrates the global relevance of legal efforts to protect patients from unproven SCIs and offers insight into the way in which the medical community can respond.While there is little legal precedent in the USA, one case in Japan serves as an example of a successful civil lawsuit resulting in a judgment against a stem cell clinic.22 Non-disparagement clauses and arbitration agreements in service contracts are increasingly being used by businesses to shield reputations and limit liability. While the use of civil law as an instrument for patients seeking restitution can impact and alter business practices, having a more comprehensive approach involving litigation, federal drug and professional regulation, and public education is likely to have a collective social impact to reign in unethical practices.24While lawsuits are likely to be effective in combating unethical stem cell clinics, the nature of the SCI industry may make it difficult for civil litigation alone to counter the current growth trend. The primarily online marketing presence of the industry and geographical mobility of providers makes it simple for providers to alter practices to evade prosecution or skip payment. While judgments could be entered against clinics, jurisdictional limitations may render successful plaintiffs unable to collect damages from defendants who relocate overseas. Therapeutic statements can be worded suggesting efficacy without making any binding promises, and the nature of web marketing allows for the rapid revision of legally problematic claims. Clinics have begun seeking ways to limit their customers\u2019 avenues for legal recourse through the inclusion of waivers and disclaimers in informed consent documents and on websites.25 and in the USA,27 with most recent efforts by the FDA against clinics in California and Florida.12 Yet despite notable efforts by the FDA through investigation and drafting clearer guidance, clinics in the USA continue to offer unproven SCIs under incorrect claims of regulatory compliance28 or may relocate to a more permissive regulatory environment.29 Press coverage of lawsuits may raise awareness and draw the FDA\u2019s attention to unethical stem cell business practices. Public health litigation may also raise the specter of unproven stem cell treatments and could result in greater allocation of resources toward FDA\u2019s regulatory and enforcement efforts. Additionally, lawsuits can prompt state medical boards to investigate and discipline those physicians who practice beyond their scope.Regulatory efforts have been modestly successful in the closure of clinics abroadIncreased media exposure combined with the development of sophisticated health literacy strategies might sway some patients from turning to unproven SCIs. Patients with untreatable or refractory conditions, who may believe they have little to lose, may ignore warnings from physicians or patient advocacy groups and instead incur substantial costs and attempt unproven SCIs even with slim to no chances of improvement. While there may be a perception among some patients that clinics engaged in misconduct are simply \u201cbad apples\u201d, public education campaigns may gain greater traction when accompanied by media exposure and regulatory efforts. Raising awareness may motivate patients to further scrutinize clinics by demanding more information and proof of efficacy of SCIs or possibly reconsider the entire venture. Additionally, given that social support can impact self-efficacy and health behavior, broader public awareness about the dangers of unproven treatments among families and friends of patients may further influence patients\u2019 perspectives on the risks of unproven SCIs.30 The success of anti-smoking campaigns took a combination of health litigation efforts against \u201cbig tobacco\u201d, regulatory and policy efforts to limit smoking, and public health literacy to make a significant impact on rates of smoking.32 Combining legal, regulatory, and educational efforts offer a powerful strategy that when applied in concert could effect public policy change and stifle the burgeoning SCI industry.Influencing the health of a population requires a combination of legal, regulatory and educational efforts.34Litigation should be accompanied by coordinated efforts of scholars, patient advocacy groups, and scientists within the stem cell research community. Public outreach efforts to communicate the ethical and legal concerns to patients should continue. Efforts to raise awareness and share legal strategies with legal practitioners through bar association journals and continuing education programs will inform lawyers about harmful practices so they may better serve their clients. Scholars and stem cell scientists can provide expert testimony where appropriate regarding the state of stem cell research. Finally, patient advocacy groups should continue to provide education and outreach to reinforce the message that many SCI businesses offer scientifically baseless interventions that are unlikely to help patients or society.nothing to lose in trying an unproven SCI, there is a real risk of losses to the patients themselves, to others suffering from intractable medical conditions, and to society. Civil litigation efforts, in conjunction with increased regulatory enforcement and public education campaigns, may convincingly show patients and society that there are real and significant harms from unproven SCIs, and this strategy may complement the arsenal of efforts focused on reining in this industry.A sufficient number of stem cell lawsuits can have a strong impact in stifling the unproven SCI industry by permitting patients to recover damages incurred, raising public awareness and political support, and stopping harmful business practices. While successful cases leading to judgment for plaintiffs will be most effective, settled lawsuits may also garner attention by demonstrating the need for policy changes and greater FDA oversight. As lawsuits increase, more victims are likely to join the growing chorus of advocates pushing to stop the spread of unapproved SCIs. While patients may believe they have"} +{"text": "Three theories of apical dominance, direct, diversion, and indirect, were proposed in the 1930s to explain how auxin synthesized in the shoot apex might inhibit axillary bud outgrowth, and thus shoot branching. The direct and diversion theories of apical dominance have been investigated in detail, and they are replaced with the current auxin transport canalization and second messenger theories, respectively. These two current theories still cannot entirely explain the phenomenon of apical dominance. Although there is ample evidence that the inhibition of bud outgrowth by auxin from the shoot apex is linked to stem elongation and highly branched auxin biosynthesis or signaling mutants are dwarf, the third theory proposed in the 1930s, the indirect theory, that explains apical dominance as auxin-induced stem growth indirectly inhibits bud outgrowth has been overlooked. The indirect theory did not propose how a growing stem might inhibit bud outgrowth. Recent discoveries indicate bud dormancy in response to intrinsic and environmental factors in diverse species is linked to enhanced growth of the main shoot and reduced sugar level in the buds. Since a growing stem is a strong sink for sugars, and sugar is indispensable for shoot branching, the indirect theory of apical dominance might now be explained as auxin-induced stem growth inhibits bud outgrowth by diverting sugars away from buds. Detailed study of the indirect theory and the effect of source\u2013sink status on dormancy and outgrowth of axillary buds will advance our knowledge of apical dominance and shoot branching in plants. Figure 1) \u2013 were proposed to explain the phenomenon of apical dominance does not fully restore apical dominance indicating factors other than auxin inhibit bud outgrowth in intact plants mutant of Arabidopsis . Plants grow through production of successive phytomers. Each phytomer has a leaf, a node, an internode and an axillary bud. In eudicots such as pea that display strong apical dominance, stem internodes elongate during the vegetative phase but buds do not grow . When the growing shoot apex is decapitated, bud outgrowth begins immediately. A method known as shoot inversion in Ipomoea nil (morning glory) promotes bud outgrowth by suppressing the elongation of the stem section below the shoot tip . Once the shoot apex transitions to flowering phase, internodes begin to elongate and the tillering phase ends is associated with an increase in plant height and up-regulation of genes marker for sucrose deprivation in the buds mutant of maize branch profusely while the height of the main shoot is not significantly different from the wild type . In maize, the length of internodes is negatively correlated to the number and size of ears that develop from axillary buds (tin) wheat mutant is defective in the timing of development of internodes . Intrinsic and environmental factors besides auxin that promote the growth and development of new sink organs including stem internodes and reproductive organs could also inhibit shoot branching indirectly by limiting sugars available for bud outgrowth. On the other hand, dwarfism in the absence of either auxin or strigolactones might stimulate shoot branching by making excess sugars available for growing buds. Therefore, shoot branching might be an unintended consequence of source\u2013sink relationships and result from an overflow of sugars to axillary buds that cannot be utilized by the main shoot. While bud outgrowth depends on sugar supply from the main shoot, subsequent growth of the developing branch depends on an ample supply of nutrients and water from the roots. Nutrients are also one of the major factors determining the source\u2013sink status, and thus indirectly regulate shoot branching.It is well established that during apical dominance auxin from the shoot apex inhibits bud outgrowth indirectly without entering into buds. The two current theories of apical dominance, auxin transport canalization, and second messenger, describe processes in the main shoot in response to auxin from the shoot apex, including an increase in the level of strigolactones and a decrease in the level of cytokinins, leading to enhanced stem growth and formation of vascular tissues. Therefore, apically derived-auxin stimulates the growth of stem internodes in the main shoot and internode growth, which is a strong sink, inhibits buds indirectly by depriving sugars necessary for their growth (The plant source\u2013sink relations is regulated by intrinsic and environmental factors making shoot branching a complex trait that cannot be predicted easily without considering the growth and developmental status of the whole plant and prevailing environmental conditions. Reappraisal of the source\u2013sink status in shoot branching mutants and wild-types and systematic study of the effect of source\u2013sink status of the main shoot on dormancy and outgrowth of axillary buds might advance our knowledge of the physiological basis of apical dominance and shoot branching in plants. Future studies should accurately determine the sink or source status of an organ being manipulated. For example, the cotyledons in pea contribute to seed germination. The nutrient reserve and biomass of the cotyledons are exhausted within the first 10 days after sowing, during which the plant transitions from heterotrophic to autotrophic growth . ExperimBesides their role in shoot branching, sugars are also important in many other aspects of plant growth and development including phase transitions from juvenile to adult and from vegetative to flowering . TherefoTHK conceived the idea and wrote the paper.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Exome sequencing represents targeted capture and sequencing of 1\u20132% of \u2018high-value genomic regions\u2019 (subset of the genome) which are enriched for functional variants and harbors low level of repetitive regions. We discuss here an overview of exome sequencing, ways to approach plant exomes, and advantages and applicability of this powerful approach in deciphering functional regions of genomes. Though initially this approach was developed as an alternative to whole genome sequencing (WGS), but the multitude of benefits conferred by sequence capture via hybridization approaches created a niche for itself to solve many of biological riddles, particularly for resolving phylogenetic distances. The technique has also proved to be successful in understanding the basis of natural and induced molecular variation, marker development and developing genomic resources for complex, wild and non-model species, which are still intractable for WGS efforts. Thus, with profound applications of this powerful sequencing strategy, near future is expected to witness a collective expansion of both techniques, i.e., sequence capture via hybridization for evolutionary and ecological research and WGS approaches for its universal accessibility. Completion of an Arabidopsis plant genome sequence in 2000 marked a major breakthrough in the sequencing era. Further progress in deciphering of large and complex genomes of crop species is a reflection of the advancement of sequencing technologies that are commonly referred to as NextGen sequencers along with the evolution of more powerful data analysis tools.Polyploidization has played a critical role during evolution in shaping the complex genomes of important crop species viz. Wheat, Brassica etc., and has resulted in large genome sizes with exceptionally high repeat content, heterozygosity and presence of closely related homeologous genes in large gene families. This poses significant challenge for whole genome sequencing (WGS) and resequencing in many such plant lineages. Several strategies such as reduction of genome complexity, sequencing of diploid progenitors and sequencing of sorted and purified chromosome arms are thus deployed to gain chromosome specific insight into genomes of complex polyploids . One impExome sequencing restricts attention only to the genomic fraction that encodes for mRNA and eventually a phenotype, and is thus considered to be adequate to explain the molecular origin of genetic variation . Coding sequences represents only 1\u20132% of genome depending on species and compTwo technological alternatives available for hybridization based exome capture are: array/chip- based capture and In sFigure 1). Certain factors such as mode and quality of processing of input DNA sample, number of targets, coverage depth for each target, probe design and GC content holds certain advantages over its comparable approaches, like RNA sequencing, that is sometimes limited by the bias of transcript abundance and also dependent on tissue and stage while exome sequencing permits exploration of the genes and alleles. Similarly, sequencing of gene rich regions by methylation filtration method is limited by the minimum control a researcher can execute on specific target regions especially during genotyping of diverse germplasm in parallel. While exome analysis is a probe-based enrichment approach that targets specific regions rather than random euchromatic regions. Other methodologies viz., EST sequencing, high Cot DNA selection are lessExome sequencing serves a great advantage when WGS is either not practical or necessary and as an adjunct to later. It allows affordable dissection of subregions of complex genomes and reduction of non-pertinent repetitive sequences to confer several benefits over WGS: (a) multiplexing of more samples for a given sequencing space, (b) sequencing of targeted informative regions reduces the complexity of data analysis, (c) identification of functional molecular markers, (d) useful platform to collect genomic data at population level for evolutionary and phylogeny studies, (e) existing databases provides functional context for exome identified SNPs through transcript/exon annotation in contrast to SNPs identified outside coding regions through genotyping based sequencing which are not easily annotated , and (f)Though high-depth WGS is considered as a gold standard for sequencing and re-sequencing purposes as it can access and interrogate all regions of genomes, exome sequencing still forms an alternative method of choice for the trait or target specific studies. It has demonstrated its potential in generating genome wide data for species such as black cotton wood , pine N, and sugPhylogenetic studies rely on the information content of homologous genomic regions across diverse taxonomic groups. Due to general conservation of exons of protein coding sequences as well as their inherent variability in third codon position, probes designed from the same ensures the efficacy of target capture in reference species and also holds potential to extend their capture across diverse taxas to resolve topologies at moderate to deep evolutionary time scales. Introns are generally targeted to analyze phylogeny at or below the species level. Apart from probe design, loci under consideration, target number, size and its properties, population size and time scale under study are other important determinants to consider during phylogeny analysis using sequence capture.Table 1) ability to enrich for degraded DNA samples obtained from museums or herbariums; (b) reduced sequencing of contaminant DNA from paleontologiocal samples; (c) targeted approach to reduce genome complexity relative to anonymous loci produced by restriction enzymes based approaches; (d) multiplexing offers broader sampling and deep coverage relative to WGS to target phylogenetically informative loci to resolve topologies with increased resolution in a cost effective manner without involving complexities of data analysis and storage at whole genome scale; and (e) deep coverage of targeted and unlinked loci allows to accommodate for more variation in probe designs to generate family wide sets of probes that ensures high resolution and strong bootstrap values for phylogenetic trees . These fTable 1) . AdditioHordeum taxa and reported utility of multilocus species level phylogeny without sequencing whole genomes. Thus, the approach permits to target variation in much broader gene pool by accommodating a large number of genomes to be sequenced with less complexity in data analysis, in comparison to resequencing of whole genomes of same number of genotypes.Though, initially most of the targeted sequencing effort to define phylogenetic relations were directed toward plastome or ribosomal DNA sequences, recently, Table 1) namely in (a) investigation of the molecular basis of natural variation and induced mutation, (b) identification of new genetic markers and rare variants, (c) and as an effective alternative for genomics studies of non-model and related wild species.Apart from phylogenetic studies, WES also holds a wide applicability for crop improvement (H. vulgare and H. bulbosum for alien introgressions (1, black cotton wood (B. napus (One of the first successful application of sequence capture was to enrich for 2.3 Mb chromosome interval and set of dispersed 43 genes in maize and subsressions . Exome ston wood and pineton wood so as toton wood . Exome cton wood and alsoton wood . Thus, iton wood , thus deton wood . SimilarB. napus open aveSaccharum complex has been captured successfully (Cross capturing of exomes using probes of related species have been effectively applied for less resourced species. Extensive collinearity shared between sorghum and sugarcane genic regions was explessfully to charaSuitability of exome capture to identify induced variants through mutagenesis to investigate gene function has been successfully demonstrated in many crops. Exome resequencing of four selected soybean mutants arose through fast neutron radiation confirmed presence of deletions . Exon caExome sequencing via hybridization, holds high potential for its applicability in phylogenetic studies and genomic studies that require resequencing of multiple individuals of species with large and complex genome sizes. Few considerations have been raised for WES in terms of benefits conferred by WGS approaches, i.e., more consistent genome coverage, uniform distribution of sequencing quality parameters, identification of a large number of variants and absence of reference sequence bias generated by probes usage. But even in the near future, when prices of WGS will become at par with that of sequence capture via hybridization, the latter approach is much anticipated to sustain given its practical utilities for solving specific biological queries that rely on target sequencing. Resequencing of genomes of individuals in a mapping population/multiple accessions or cultivars of plants with large and complex genomes cannot be routinely employed and poses technical challenges in handling of robust informatics data. To its rescue, sequencing of sub-genomic regions is an effective alternate in terms of cost and efforts to achieve an equivalent depth of coverage, particularly for studies that do not require access to whole genomes.PK and KG have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Botulinum toxins are well known for their ability to disrupt neurotransmission and cause muscle paralysis. Recently, urologists have discovered their beneficial effects in patients with neurogenic and overactive bladder conditions. This review is intended to provide a quick overview for urologists of the structure, function, and clinical uses of botulinum neurotoxin A in the lower urinary tract."} +{"text": "During 2014, cutaneous lesions were reported in dairy cattle and farmworkers in the Amazon Region of western Colombia. Samples from 6 patients were analyzed by serologic and PCR testing, and results demonstrated the presence of vaccinia virus and pseudocowpox virus. These findings highlight the need for increased poxvirus surveillance in Colombia. Poxviridae family comprises large double-stranded DNA viruses that infect a wide range of invertebrate and vertebrate animals, including humans and Parapoxvirus , are considered zoonotic viruses because their infections usually arise from human contact with infected domestic or sylvatic animal species (The Orthopoxviruses (OPXVs) gained considerable attention in the past because variola virus fatally infected millions of persons worldwide for centuries. However, in 1980, smallpox became the first infectious disease to be eradicated, resulting from vaccination campaigns involving several VACV strains and Solita (patient 6) in the department of Caquet\u00e1 ; Table iAll serum samples were tested by ELISA for OPXV IgG and IgM as described . An ELISA56R gene from patients 2 and 5 were amplified by PCR, sequenced according to the manufacturer\u2019s instructions and amplified by using PCR with generic and specific poxvirus primers as previously described (12). OPequenced , and comequences Table 1. equences , panel Ap37K gene by PCR and PCPV (2 patients). Lesions caused by poxviruses affected the hands and forearms and disappeared within weeks without treatment. However, by limiting the patients\u2019 daily activities, the infections had substantial negative impacts on the economies of dairy farmworkers and their local communities.The disease burden of poxvirus infections in Colombia has not been estimated. However, anecdotal communications and data suggest it might be a serious and increasing health problem because farmworkers and healthcare personnel are not trained to recognize the disease and prevent subsequent transmission. The rapid spread of poxviruses could be facilitated by farmworkers performing daily milking activities at several farms and trading cattle. Also, factors such as human-to-human and fomite transmission, a growing susceptible population, and an unknown animal reservoir might increase the potential risk for infection at the community level. The serious consequences that poxvirus infections could have on immunocompromised persons (Studies focused on determining the prevalence of poxvirus infections, risk factors for disease, and the geographic distribution of poxvirus strains are needed to understand the disease burden and guide effective prevention and control measures and educational outreach. Analysis and characterization of VACV and PCPV complete genomes could provide clues to explain their emergence and recent evolutionary histories, and research aimed at identifying the domestic animal hosts and wildlife reservoirs of poxviruses could further our understanding of their natural transmission cycles.A56R and p37K reference genes used in phylogenetic analyses.Description of methods and information on the"} +{"text": "Humor can provide a method of coping with a variety of stressful situations. Training of humor-related skills has proven effective in clinical samples, although humor training in patients with schizophrenia is relatively rare.In the present study, patients with schizophrenia have been randomly assigned to either a training of humor abilities or a training of social skills. Training effects on measures of psychopathology, psychosocial functioning and stress were compared between groups.Preliminary analyses revealed that level of negative symptoms, stress and psychosocial dysfunction were significantly reduced in the humor group over the course of the training.These results suggest that humor training may improve important clinical and functional outcomes in patients with schizophrenia."} +{"text": "Orgasm is one of the most intense pleasures attainable to an organism, yet its underlying mechanisms remain poorly understood. On the basis of existing literatures, this article introduces a novel mechanistic model of sexual stimulation and orgasm. In doing so, it characterizes the neurophenomenology of sexual trance and climax, describes parallels in dynamics between orgasms and seizures, speculates on possible evolutionary origins of sex differences in orgasmic responding, and proposes avenues for future experimentation. Here, a model is introduced wherein sexual stimulation induces entrainment of coupling mechanical and neuronal oscillatory systems, thus creating synchronized functional networks within which multiple positive feedback processes intersect synergistically to contribute to sexual experience. These processes generate states of deepening sensory absorption and trance, potentially culminating in climax if critical thresholds are surpassed. The centrality of rhythmic stimulation for surpassing these thresholds suggests ways in which differential orgasmic responding between individuals\u2014or with different partners\u2014may serve as a mechanism for ensuring adaptive mate choice. Because the production of rhythmic stimulation combines honest indicators of fitness with cues relating to potential for investment, differential orgasmic response may serve to influence the probability of continued sexual encounters with specific mates. Given that reproduction is the bottom line of evolutionary fitness, it is unsurprising that orgasm would be a source of intense pleasure frequently involves synchronized rhythmic production of related somatic, visceral, visual, auditory, olfactory, or gustatory signals. The synchronous information from these various sensory modalities provides multiple potential channels for entrainment of an individual nervous system, with potential for interpersonal entrainment if multiple nervous systems are simultaneously entrained to the same source of rhythmic stimulation evidence for deactivation of areas of cortex related to higher-order cognition and executive functions, including frontal and midline structures may be adaptive for species with sophisticated cognitive abilities, because it allows greater flexibility in releasing the powerfully rewarding mechanisms underlying sexual trance and orgasm. More specifically, although rhythmic capacity may be an honest indicator of organismic fitness that contribute to sexual climax .In considering the evolutionary bases of sex differences in orgasm, it is important to remember that males and females of many species confront different challenges and opportunities with respect to reproductive success indiscriminately, and it should be similarly unsurprising that many women have a large number of contingent factors that influence the frequency and quality of their orgasms individuals, and in particular, women (Garcia et al., This is not to say that male orgasm \u2013 and bonding, given sufficient kindling of incentive motivation (Pfaus et al., The above account is not meant to imply that every aspect of orgasmic expression directly contributes to reproductive success. Animals as intelligent and behaviorally flexible as humans have found numerous ways to deploy rhythmic pleasure for personal enjoyment and social desires (Merker, Morley, & Zuidema, What is orgasm? This article has attempted to provide a multilevel evolutionary explanation involving enabling conditions, plausible neurophysiological mechanisms, and experiential as well as behavioral impacts of entrainment through rhythmic sexual activity. Much work remains to be done in order to adequately characterize this profound and fundamental experience. Future researchers may wish to contemplate the different evolutionary life history strategies that could be enabled by adjusting parameters for orgasmic responding in males and females, as these are likely to be continuous with sexual incentive motivation and capacity for bonding to one or more sexual partners on various timescales. In sex \u2013 as in so many other aspects of life \u2013 timing is everything."} +{"text": "To investigate the ability of an automated fluorescent analyzing system to detect microsatellite alterations, in patients with bladder cancer. We investigated 11 with pathology proven bladder Transitional Cell Carcinoma (TCC) for microsatellite alterations in blood, urine, and tumor biopsies. DNA was prepared by standard methods from blood, urine and resected tumor specimens, and was used for microsatellite analysis. After the primers were fluorescent labeled, amplification of the DNA was performed with PCR. The PCR products were placed into the automated genetic analyser and were subjected to fluorescent scanning with argon ion laser beams. The fluorescent signal intensity measured by the genetic analyzer measured the product size in terms of base pairs. We found loss of heterozygocity (LOH) or microsatellite alterations in all the patients by using fluorescent microsatellite analysis and an automated analyzing system. In each case the genetic changes found in urine samples were identical to those found in the resected tumor sample. The studies demonstrated the ability to detect bladder tumor non-invasively by fluorescent microsatellite analysis of urine samples. Our study supports the worldwide trend for the search of non-invasive methods to detect bladder cancer. We have overcome major obstacles that prevented the clinical use of an experimental system. With our new tested system microsatellite analysis can be done cheaper, faster, easier and with higher scientific accuracy."} +{"text": "The advent of clinically useful robotic devices to facilitate reconstructive laparoscopic surgery in pediatric urology opens new doors to minimally invasive procedures. Previously limited by the challenge of delicate suturing and reconstruction using conventional laparoscopic instruments, robotic assistance offers a more rapid climb up the learning curve. Initial procedures that have been safely and efficaciously performed with robotic assistance include nephrectomy, partial nephrectomy, pyeloplasty, and antireflux surgeries. These techniques and their outcomes will be reviewed, as well as some of the challenges still posed by this methodology."} +{"text": "Converging evidence for an essential function of the lateral hypothalamus (LHA) in the control of feeding behavior has been accumulating since the classic work conducted almost 80 years ago. The LHA is also important in reward and reinforcement processes and behavioral state control. A unifying function for the LHA across these processes has not been fully established. Nonetheless, it is considered to integrate motivation with behavior. More recent work has demonstrated that the LHA is also required when cognitive processes, such as associative learning and memory control feeding behavior, suggesting it may serve as a motivation-cognition interface. Structurally, the LHA is well positioned within the cerebral hemisphere, with its extensive connectional network across the forebrain-brainstem axis, to link motivational and behavioral systems with cognitive processes. Studies that examined how learned cues control food seeking and consumption have implicated the LHA, but due to methodological limitations could not determine whether it underlies motivation, learning, or the integration of these processes. Furthermore, the identification of specific substrates has been limited by the LHA\u2019s extraordinary complexity and heterogeneity. Recent methodological advancements with chemo-and opto-genetic approaches have enabled unprecedented specificity in interrogations of distinct neurons and their pathways in behaving animals, including manipulations during temporally distinct events. These approaches have revealed novel insights about the LHA structure and function. Recent findings that the GABA LHA neurons control feeding and food-reward learning and memory will be reviewed together with past work within the context of the LHA function as an interface between cognition and motivation. Learning and motivation are both necessary for the survival of a mammalian organism and their neural substrates have been studied extensively. But these processes have been considered somewhat independently and how they are integrated at a neural circuitry level remains an important area of inquiry . Additionally, a recent study found that some ORX neurons express GAD1 are believed to mediate food motivation (measured by approach behavior) vs. consumption, based on their distinct activation patterns indicated that they mediate food seeking behavior (operant responding for sucrose reward) but not the chow consumption or compulsive locomotion that were observed after stimulation of total LHAGABA neurons LHA neurons are critical in feeding control over insular cortex (AI) processing during responding to food cues (Livneh et al., Recent technologies, which enabled selective interrogations of specific neurons and their circuitries, have greatly advanced the field. These methods have revealed a novel LHA function in learning and memory and identified cell-specific substrates and their pathways in the control of feeding behavior. They are also revealing another dimension of LHA structural complexity. Future work will require thoughtful synergies across genetic, anatomical, and behavioral approaches to unearth the organization of the LHA structure and how it functions to control feeding and other motivated behaviors.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The most common cause of lower urinary tract obstruction in male infants is posterior urethral valves. Although the incidence has remained stable, the neonatal mortality for this disorder has improved due to early diagnosis and intensive neonatal care, thanks in part to the widespread use of prenatal ultrasound evaluations. In fact, the most common reason for the diagnosis of posterior urethral valves presently is the evaluation of infants for prenatal hydronephrosis. Since these children are often diagnosed early, the urethral obstruction can be alleviated rapidly through catheter insertion and eventual surgery, and their metabolic derangements can be normalized without delay, avoiding preventable infant mortality. Of the children that survive, however, early diagnosis has not had much effect on their long-term prognosis, as 30% still develop renal insufficiency before adolescence. A better understanding of the exact cause of the congenital obstruction of the male posterior urethra, prevention of postnatal bladder and renal injury, and the development of safe methods to treat urethral obstruction prenatally are the goals for the care of children with posterior urethral valves[1]."} +{"text": "Background Plants depend on their root systems to acquire the water and nutrients necessary for their survival in nature, and for their yield and nutritional quality in agriculture. Root systems are complex and a variety of root phenes have been identified as contributors to adaptation to soils with low fertility and aluminium (Al) toxicity. Phenotypic characterization of root adaptations to infertile soils is enabling plant breeders to develop improved cultivars that not only yield more, but also contribute to yield stability and nutritional security in the face of climate variability.Scope In this review the adaptive responses of root systems to soils with low fertility and Al toxicity are described. After a brief introduction, the purpose and focus of the review are outlined. This is followed by a description of the adaptive responses of roots to low supply of mineral nutrients [with an emphasis on low availability of nitrogen (N) and phosphorus (P) and on toxic levels of Al]. We describe progress in developing germplasm adapted to soils with low fertility or Al toxicity using selected examples from ongoing breeding programmes on food and forage/feed (Brachiaria spp.) crops. A number of root architectural, morphological, anatomical and metabolic phenes contribute to the superior performance and yield on soils with low fertility and Al toxicity. Major advances have been made in identifying root phenes in improving adaptation to low N (maize), low P (common bean) or high Al .Conclusions Advanced root phenotyping tools will allow dissection of root responses into specific root phenes that will aid both conventional and molecular breeders to develop superior cultivars. These new cultivars will play a key role in sustainable intensification of crop\u2013livestock systems, particularly in smallholder systems of the tropics. Development of these new cultivars adapted to soils with low fertility and Al toxicity is needed to improve global food and nutritional security and environmental sustainability. Plants colonized the land around 450 to 490 Mya . This rest century. Low soil fertility including low availability of nutrients and problems such as soil acidity and associated Al toxicity limits agricultural productivity by restraining crops from reaching their yield potential. Excessive use of fertilizer in developed countries, including China, pollutes the air and water and contributes to climate change and environmental degradation. Low soil fertility in developing countries is a primary constraint to food security and economic development. Additionally, water availability often limits crop growth in most agricultural systems. Increasing the efficiency of plants in acquiring soil resources is a key approach to improve crop yields and to reduce the dependence of farmers on fertilizers or irrigation and phosphorus (P), soil acidity-related Al toxicity, and salinity] and insufficient water availability are probably the biggest cause of a persistent gap between potential and realized crop productivity, particularly in developing countries in the tropics. The nutrients that soils naturally supply to plants come from the dissolution of primary and particularly weatherable minerals. About 36 % of the tropics has soils with low (<10 %) reserves of weatherable minerals in their sand and silt fraction, which constitute nutrient capital reserves . The proGeneral symptoms of crop plants due to low soil fertility or mineral toxicity include poor emergence; slow growth; seedling and adult plant stunting; leaf chlorosis and bronzing; reduced overall growth and dry-matter production; delayed and prolonged flowering and maturity; flower and pod abortion; low harvest index; reduced seed weight; deformed and discoloured seeds; and severe yield loss. Root growth, development and distribution across the soil profile are adversely affected by soil chemical constraints . ImprovePlant adaptation to infertile soils has complex inheritance and is affected by the growing environment, and consequently the genetic and physiological mechanisms leading to improvements in adaptation have been difficult to identify and to quantify. However, understanding the mechanisms by which plants adapt to infertile soils is critical for creating efficient strategies to develop stress-resistant cultivars for the sustainable intensification of production systems.The most successful approaches to improving crop adaptation to infertile soils have historically used field-based evaluations to identify tolerant genotypes, followed by breeding and selection of cultivars that combine performance in stressful environments with other desirable plant attributes. One aspect of germplasm improvement is to identify morphological, physiological and biochemical mechanisms by which plants adapt to soils with low fertility and Al toxicity. Defining specific mechanisms of adaptation to these soil constraints can contribute to the development of high-throughput phenotyping protocols improving the efficiency of genetic improvement programmes.Three major soil constraints for crop and forage production in developing countries are low N and P availability and soil acidity-induced Al toxicity. Soil nutrients can be relatively mobile or immobile . NitrogeThe phenotype of an organism is fundamentally a manifestation of its genotype\u2019s interaction with its environment and common bean (Phaseolus vulgaris L.) and one major forage/feed crop, brachiaria (Brachiaria spp.). We highlight the importance of developing a robust understanding of root adaptations to design superior root ideotypes to match the environment. We conclude by discussing the challenges and opportunities for 21st-century breeding to design soil stress-resilient crop and forage cultivars for sustainable intensification of crop\u2013livestock systems leading to improved food and nutritional security and environmental sustainability.The aim of this paper is to review the state of our understanding of the adaptive responses of root systems to soils with low fertility focusing on P and N limitations and soil acidity-related Al toxicity with the objective to develop strategies for the breeding of crops to acid, Al-toxic soils with low fertility with complex soil-related constraints. We first describe the adaptive responses of roots to low supply of mineral elements (with a particular emphasis on low N and P availability in soil) and toxic level of Al in soil. We then discuss the progress in developing germplasm adapted to soils with low fertility and Al toxicity using examples from ongoing breeding programmes. The case studies selected include two major food crops, maize among species for effective performance under low fertility soil conditions . Each kiPlant root adaptive growth in response to low availability of macro- and micronutrients depends on a wide range of variables such as nutrient forms, availability, concentration, localization and nutrient behaviour in soil, as well as the nutrient status of the plant . Root grA number of root system responses contribute to plant adaptation to low-fertility soils .Table 2\u22121 and losses due to low soil fertility are estimated at over 1\u00b712 million tonnes every year . Crucially for farmers, these varieties also perform well under well-fertilized conditions, whilst several carry resistance to maize lethal necrosis, a devastating viral disease spreading through eastern Africa. IMAS is aiming to raise maize yields by 50 % and benefit up to 60 million maize farmers in eastern and southern Africa. It will be a major challenge to quantify the relative contribution of root adaptations to low N stress and the improved yield of these varieties in farmers\u2019 fields.In eastern and southern Africa, the IMAS (Improved Maize for African Soils) project (coordinated by Dr B. Das of CIMMYT) has established the world\u2019s largest low-N screening network for maize, with 25 sites in ten countries and a total of over 120 000 experimental plots. In 2014, partners in the IMAS project developed 41 maize cultivars that respond better to low amounts of N fertilizer and these are due for release in nine African countries through 24 seed companies in soil (Long-term research using common bean has contributed to defining root phenes and their role in enhanced soil exploration and P acquisition . In comml traits . The idecy (PAE) . It incocy (PAE) . EfficieIn addition to root system architectural traits, root morphological traits such as root length, diameter, surface area and volume, presence of root hairs, and length of root hairs contribute to inter- and intra-specific variation in PAE. The formation of root cortical aerenchyma, which converts living cortical tissue to air space through programmed cell death, improves PAE by reducing the metabolic cost of soil exploration . A cost\u2013An increase in PAE by mobilization of P in the rhizosphere can be achieved by increased production and secretion of organic acids and enzymes such as phosphatases and ribonucleases in the rhizosphere in marker-assisted breeding encoding traits for crop PAE have been identified , with Al being toxic by binding to the walls of outer cells, which directly inhibited their loosening in the elongation zone. They also found that an alteration in the biosynthesis and distribution of ethylene and auxin was a second, slower effect. Their study demonstrated the importance of focusing on root traits related to cell wall composition as well as mechanisms involved in wall loosening to overcome the deleterious effects of soluble Al.Research conducted over the past two decades on the physiology, genetics and molecular biology of plant Al resistance and toxicity has shown that Al resistance can be achieved by mechanisms that exclude Al from the root apex apoplast (Al exclusion) and/or by mechanisms that enable plants to tolerate Al in the symplast (Al tolerance) novel Al tolerance genes have been identified involving modifications to the carbohydrate composition of the root cell wall, leading to reduced wall Al accumulation; (5) other Al tolerance mechanisms involve the identification of novel Al uptake transporters, including Nrat1 in rice and aquaporins (which mediate plasma membrane and tonoplast Al accumulation in an Al accumulator); (6) major Al tolerance loci that have been pivotal in breeding strategies targeting crop adaptation to Al-toxic soils are determined primarily by the plasma membrane transporters conferring Al-activated organic acid release (ALMTs and MATEs); and (7) there is breeding potential in exploring the genetic determinants of transcriptional regulation of ALMT1 and MATE genes in addition to those underlying other Al tolerance mechanisms.Differential genotypic response to Al stress is the basis of identification of new sources of Al resistance and contributes to improved understanding of the mechanisms of Al resistance. Phaseolus coccineus L.) germplasm accession G35346 showed high shoot vigour in an acid soil in the field and superior root elongation in Al-toxic soil and hydroponic systems in the greenhouse tolerated an approximately five-fold higher level of Al than poorly adapted Brachiaria ruziziensis Germain & Evrard (ruzigrass), even though the resistance of ruzigrass was comparable with that of wheat, triticale and maize genotypes that were previously classified as Al-resistant (Brachiaria hybrids are developed using B. decumbens with high adaptation to low P and Al-toxic acid soils combined with B. brizantha (A. Rich.) Stapf with its high level of resistance to spittlebug, a major insect pest (B. humidicola (Rendle) Schweick (koroniviagrass) are being developed that are not only highly adapted to low-fertility acid soils but are also highly tolerant to poorly drained soils with constitutive formation of RCA in their root systems (Interspecific ect pest . IntraspP. arundinacea. Bulbous canarygrass is one of the most important sown perennial grasses used in south-eastern Australia due to its high productivity and drought tolerance . HoweverLucerne is the most widely grown forage legume in the world. Its productivity is affected by reduced root growth due to soil acidity and Al toxicity (The above comparison of relative differences in Al resistance in different food and forage crops indicates that there is a large gap between the level of Al in soil solution that wheat can tolerate versus the level that forage crops such as bulbous canarygrass or signalgrass can tolerate. Identification of genes responsible for greater level of Al resistance in forage crops can contribute to further improvement of Al resistance in food crops.An ideotype is a plant with an ideal phenotype that combines the desirable traits and mechanisms predicted to enable its adaptation to a target environment. A crop ideotype is a model plant that is expected to yield more when developed as a cultivar . Ideotyp2. The root ideotype for topsoil foraging for P combines several desirable root phenes (+ and organic compounds, greater exudation of phosphatases, and greater phosphate uptake capacity of root cells. A shallow root system will be beneficial to maximize P acquisition in a low P soil while deep root system will improve nitrogen and water acquisition, particularly in deep soils (The SCD root ideotype proposed for efficient N acquisition combines several root phenes (ep soils . Deep roAn integrated improvement of root adaptations to problem soils is necessary to improve crop productivity on low-fertility acid soils rather than considering individual nutrient stresses separately. Thus, we need a common ideotype with phenotypic plasticity to respond to several constraints simultaneously. The aim of this common ideotype could be not only to improve nutrient and water acquisition and resistance to high Al, but also to optimize the balance between internal use of carbon resources for structural development, and the benefits gained from such investments in terms of the fraction of photosynthates that are translocated to economical products. By definition this should lead to better yield, and is useful only if it leads us to focus on the factors that maximize both biomass production and harvest index.Low soil fertility and Al toxicity in particular limit biomass accumulation. Based on a modelling exercise, Multiple soil stress factors often co-occur in farmers\u2019 fields. Roots that are stunted by Al toxicity are inefficient in absorbing both nutrients and water and Al-resistant plants may be more drought-resistant and require lower inputs of lime and P fertilizer than less resistant genotypes (Interactions of a particular stress with other factors in the environment, especially other stresses, complicate the selection for stress tolerance . While tThis review shows that considerable progress has been made in the last decade in improving knowledge of root adaptations to soils with low fertility and Al toxicity. Developing the right root system to cope with soil fertility and toxicity constraints in each production environment will be a major research challenge.Low N-adapted maize genotypes have few crown roots and acquire more N from deep soil strata. These genotypes also have the ability to form high RCA to improve plant growth under low-N conditions by decreasing root metabolic costs, thereby enhancing soil exploration and N acquisition from deep soil strata.Pup1 showed a dramatic increase in PAE when grown in P-deficient soils.Phosphorus acquisition efficient common bean genotypes develop more adventitious roots, shallower basal roots, and longer, denser root hairs. Traits including root hair length, adventitious rooting and basal root growth angle under low P availability were shown to be under control of multiple QTL. Architectural trade-offs for P and water acquisition have been demonstrated for root growth angle. Genotypes with deeper basal roots had superior growth under water stress while genotypes with shallower basal roots have superior growth under low P conditions. Rice lines developed using QTL, Significant advances have been made in defining the mechanisms of Al resistance in different crops and forages using Al-resistant and Al-sensitive cultivars. Major Al tolerance loci are determined primarily by the plasma membrane transporters conferring Al-activated organic acid release.The genetic control of stress tolerance is often complex, requiring a combination of several different mechanisms to achieve significantly elevated levels of stress tolerance. In these cases, gene discovery and efficient marker-assisted gene pyramiding technologies will be important.Physiological and molecular studies on breeding populations provide a path towards the identification of physiological mechanisms and genomic regions contributing to root system responses to low soil fertility and Al toxicity, which in turn could lead to the isolation of genes contributing to changes in individual root phenes. Major advances have been made in developing screening methods at laboratory, greenhouse and field level to evaluate differences in root phenes for tolerance to N and P deficiency and Al resistance. Using these screening methods, it is possible to make further advances in breeding or agronomic evaluation of crops and forages for improved root adaptation to soil fertility constraints. Advanced root phenotyping tools will address major knowledge gaps to dissect the root responses into specific root phenes that will aid breeders to develop superior crop and forage cultivars. These new cultivars will play a key role in sustainable intensification of crop\u2013livestock systems, particularly in developing countries. Development of these new cultivars is essential to improve global food and nutritional security.A major challenge is to define the interactions between different soil constraints and their influence on root adaptations so that cultivars with adaptation to soils with low fertility and Al toxicity can be developed through breeding. Dissection of differences in individual root phenes as influenced by mineral element deficiency or toxicity could explain differences in field performance between genotypes. The key to detecting subtle changes in growth is to be familiar with whole plant development and plasticity responses to stress conditions.Combining a number of root architectural, morphological, anatomical and metabolic phenes for improved adaptation to soils with low fertility and Al toxicity will require multidisciplinary approaches. It is critical to cross-validate and integrate information from breeding, agronomy, physiology, soil science, plant nutrition and molecular genetics. Collaboration between breeders and physiologists contributes to defining appropriate root phenes that can serve as selection criteria for breeding, and to help design selection schemes and methods to address major soil constraints . Expertsin vivo will help to design cultivars with optimum root systems for soils with low fertility and Al toxicity. Field studies of mapping populations or association panels are needed to identify key root traits and underlying genes that are able to enhance nutrient acquisition beyond the level present in current cultivars.Major technological advances have been made in recording images of root systems and for characterizing root phenes under laboratory (2 or RILs coupled with statistical linkage analysis could improve the efficiency of molecular breeding for improved root level adaptation to stress factors.A broader view is needed to implement an integrated multidisciplinary approach to make progress in breeding for improved root adaptations for stress resistance. An integrated improvement of resistance to different stresses is likely to be more productive than considering them in isolation (Recent advances in translational genomics and the development of molecular tools for breeders have revolutionized plant improvement strategies by integrating complex biological data to inform genomics-assisted breeding approaches ("} +{"text": "On April 23, 2016, the Democratic Republic of the Congo (DRC) Ministry of Health reported an outbreak of yellow fever. As of May 24, 2016, among 41 confirmed yellow fever cases, 31 (75.6%) had occurred in Kongo Central Province, in the western part of the country bordering Angola , complete case report forms, and send forms weekly to both provincial officials and a national expert committee for vaccine pharmacovigilance. Although a provisional classification of AEFIs by severity is made at peripheral and provincial levels at the time of an initial investigation, responsibilities at the national level are to guide the investigation of suspected serious AEFIs, classify them according to standard AEFI cause\u2013specific definitions, recommend additional testing of biologic specimens if warranted, and determine causality.Because identification of AEFIs through passive surveillance is limited by low reporting rates in Kongo Central Province (estimated <50%), active surveillance for AEFIs after receipt of yellow fever vaccine was piloted in the Matadi Health Zone after the campaign. Results obtained through active surveillance were compared with the results from the existing routine passive AEFI reporting system integrated into the Expanded Program on Immunization (EPI), which was established in the late 1970s to ensure that infants/children and mothers have access to routinely recommended vaccines.Surveillance of Adverse Events Following Immunization Against Yellow Fever that occurs after immunization (\u226430 days after the receipt of yellow fever vaccine) and which is not necessarily causally related to receipt of the vaccine. An active retrospective search to identify AEFIs was conducted at two referral health facilities in the Matadi Health Zone. Data were collected using the national EPI AEFI case investigation form, which was revised based on recommendations in the World Health Organization\u2019s field guide, AEFIs identified through this comprehensive review were compared with those detected through passive surveillance during the immunization campaign to assess the completeness and representativeness of passive surveillance data. Overall, 15 AEFIs were identified by active surveillance among approximately 2,800 patient records reviewed at the two targeted referral hospitals, including eight AEFIs previously reported during the immunization campaign . Two AEFThis enhanced surveillance program found that the passive yellow fever AEFI system failed to identify half of all AEFIs that were identified through active surveillance, including all of the serious AEFIs. The national expert committee for vaccine pharmacovigilance will validate all AEFIs identified through this evaluation; however, discrepancies between AEFIs identified through this pilot active surveillance and through passive surveillance highlight the need for an organized and active data collection system to supplement the lack of sensitivity of passive AEFI detection during a mass immunization campaign ("} +{"text": "Strict spatiotemporal control of trafficking events between organelles is critical for maintaining homeostasis and directing cellular responses. This regulation is particularly important in immune cells for mounting specialized immune defenses. By controlling the formation, transport and fusion of intracellular organelles, Rab GTPases serve as master regulators of membrane trafficking. In this review, we discuss the cellular and molecular mechanisms by which Rab GTPases regulate immunity and inflammation. Eukaryotic cells have membrane bound organelles that are essential for maintaining cellular organization and performing highly dynamic and specialized functions. These processes, which depend on the transfer and exchange of cargo between different organelles, require communication within cells and between cells and their environment, while maintaining the distinct identities of these compartments. Regulated transport and trafficking of intracellular vesicles is required to achieve these highly coordinated and spatiotemporally regulated events . Activation of these pattern recognition receptors on the plasma membrane leads to different signals than when the receptors are activated by microbial components localized in the lumen of endocytic vesicles family of small GTPases regulates vesicular transport and determines organelle identities, thereby functioning as central players in regulating the intracellular and cell-cell communication required to generate and maintain cellular homeostasis are recognized by pattern recognition receptors (PRRs) on the surface of immune cells. This recognition induces intracellular signaling pathways responsible for inflammatory immune responses to its vacuole, events not associated with the human-restricted S. typhi. These observations imply that some Rab GTPases can contribute to host specificity stimulation have suggested the importance of Rab37 in regulated exocytosis to autophagosomes to restrict their replication and a protease, respectively and promote evasion of Rab32-dependent host immune responses, favoring bacterial survival class I molecules from Rab11 positive endosomal recycling compartments (ERC) is a type of inflammatory bowel disease (IBD) characterized by a chronic inflammation of the gastrointestinal tract (Landy et al., In vivo studies with knock-out mice have demonstrated antimicrobial roles for Rab20 (Schnettger et al., in vivo models remain largely undefined. Extending findings from in vitro studies to in vivo models will be crucial in understanding the roles of other Rab proteins in immune responses.In the last few years it has become evident that Rab GTPases, by regulating fundamental cellular processes, also regulate many important aspects of immune responses. Whereas some processes such as phagosome maturation and antigen presentation are well described, it is often not considered that secretion of cytokines relies on exocytosis; a membrane trafficking pathway regulated by Rab GTPases among other molecules. In addition, the expression of Rab GTPases is heavily regulated by cytokines, and there is a network of Rab proteins linked to various inflammatory processes that include Rab20 and Rab32. Future work will define the molecular basis of Rab gene expression during disease and their role during infection and immunity. All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Myocardial contrast echocardiography (MCE) has an established role in left ventricular assessment by improving the ventricular opacification and endocardial border definition especially in patients with sub-optimal echocardiographic images. With advances in cardiac ultrasound imaging technology and the development of new contrast agents, the clinical utility of this technique has greatly expanded to include assessment of coronary reperfusion in the setting of acute myocardial infarction, determination of myocardial viability within infarct zones as well as assessment of coronary microcirculation and flow reserve in patients with microvascular coronary disease. Improvements in image quality with intravenous contrast agents can facilitate image acquisition and enhance delineation of regional wall motion abnormalities at peak levels of exercise. Numerous studies have confirmed the clinical utility of contrast enhancement during echocardiographic studies, particularly in patients undergoing stress testing. In this paper, we explore the evidence in support of MCE and its potential clinical applications. Our review aims to summarize (1) the basic principles of myocardial contrast echocardiography including recent advances in the ultrasound technology and contrast agents (2) its clinical applications in the diagnosis of cardiovascular diseases and finally, (3) its potential role in risk stratification and assessment of microvascular perfusion in patients with hypertensive heart disease. Recent developments in contrast agents and acoustic technology have opened new opportunities in the clinical applications of myocardial contrast echocardiography (MCE). Beyond evaluation of cardiac structures and function, MCE can provide much needed insight into myocardial perfusion and thus permit a better understanding of pathophysiologic mechanisms in patients with abnormal LV function. This role appears to have specific advantage in patients with microvascular disease particularly in the absence of concomitant epicardial coronary artery disease. In this paper we briefly describe recent advances in the technology of MCE and potential application of these new advances in the evaluation of patients with hypertensive heart disease.Early use of contrast in echocardiography was necessitated by the need to better visualize cardiac anatomy. Since the initial description of echocardiographic contrast effect in the aortic root by Gramiak and Shah more than four decades ago , signifiTo a large extent the ability of contrast agents to opacify and hence allow the evaluation of the LV has been made possible by the introduction of sonication by Feinstein et al in 1984 .\u00a0SonicatThe availability of stable microbubbles and the current performance limits of ultrasound imaging and Doppler techniques have encouraged the growth of contrast echocardiography in clinical practice. By increasing the signal to noise ratio, ultrasound contrast agents have greatly improved the sensitivity and specificity of diagnostic ultrasound imaging. Routine clinical applications have been found in the study of myocardial ischemia during functional stress testing, endocardial border delineation and evaluation of valvular flows. Perhaps the most exciting potential clinical utility of contrast echocardiography is in the evaluation of microvascular flows and \u201cno-reflow\u201d phenomenon.\u00ae, an earlier generation contrast agent was found to be effective in achieving adequate LV opacification in 81% of cases and improving LV endocardial definition in 83% of patients [Chamber opacification and improved endocardial border delineation allow for accurate assessment of LV volume and hence a more precise estimation of cardiac function. In phase III clinical trials, Albunexpatients . Crouse patients have alspatients have dempatients reported\u00ae was the first commercially available contrast agent. Developed by sonication of 5 % albumin solution, Albunex\u00ae has excellent myocardial opacification on intracoronary injection but does not opacify left ventricle after intravenous injection [\u00ae, FS069 (Optison\u00ae) and DMP-115 (Definity)\u00ae).The micro-bubbles in these newer generation contrast agents contain larger molecular weight gases with low diffusion capacity thus creating stable bubbles which do not dissolve in blood. They enter the myocardium intact permitting effective backscatter and ultimately satisfactory visualization of the left ventricular cavity as well as the myocardium after intravenous injection thus allowing one to directly evaluate myocardial perfusion [Albunexnjection . After injection . The sigerfusion , 17. Thierfusion , collateerfusion , 20 as werfusion , 21.\u00ae), a phase-shift colloid belongs to the newer class of fluorocarbon based ultrasound contrast agents offering better endocardial border delineation and LV opacification. Clinical investigations have thus far shown promise with EchoGen and other new generation contrast agents in visualization and localization of myocardial perfusion defects at rest by producing a negative contrast effect. Unlike albumin, a less stable contrast agent, the microbubbles produced by EchoGen, Optison and Definity persist in the LV for much of systole and are able to make multiple passes through the portal vein. The microbubbles are small, uniform and stable and thus survive transpulmonary transit, allowing for circulation in the vascular system and enabling imaging of small blood vessels and tissues [Perflenapent emulsion at 2 years in patients with asymptomatic LV systolic dysfunction , 47. SymIn hypertensive patients with symptoms of heart failure but preserved LV systolic function and no evidence of valvular, pericardial or primary myocardial disease, LV diastolic dysfunction is an important condition and commonly, the culprit. In addition to confirming a normal LV ejection fraction and excluding structural heart disease, the demonstration of abnormal trans-mitral Doppler spectrum is important for echocardiographic diagnosis. However, a pseudo-normal Doppler spectrum may be seen when abnormalities of relaxation, compliance and restrictive physiology coexist. The use of Valsalva maneuver and a careful recording of the pulmonary vein Doppler spectrum can help unmask diastolic dysfunction -56. In pMyocardial contrast echocardiography is an ideal imaging tool for the assessment of coronary microcirculation . MCE canMicrovascular flow may be abnormal in hypertensive heart disease especially in the setting of LVH, and may indeed produce angina symptoms even in the absence of significant epicardial coronary artery disease. By defining the region of abnormal microvascular flow or perfusion with MCE, it is possible to quantify the extent of myocellular damage , 60. TheMyocardial contrast echocardiography is able to demonstrate, not only the presence or absence of microvascular perfusion, but can quantify myocardial blood volume and microvascular reserve , 64. WheCoronary blood flow reserve is dependent on the inherent vasodilatory properties of the coronary microvasculature and blooCurrently, only 2 contrast agents (Albunex and Optison) are approved for use in the USA by the Food and Drug Administration (FDA). These agents are approved for the indication of left ventricular opacification and enhanced endocardial border delineation, but not for myocardial perfusion. In line with earlier observations by Marwick et al , review Perhaps, the most promising future application of myocardial contrast echocardiography is in the routine clinical evaluation of myocardial perfusion, coronary, and intramyocardial blood flow. It is expected however that, that with the level of interest and research currently in progress, our understanding of ultrasound-contrast interaction will witness an exponential growth and would spur refinements in machine technology that ultimately will lead to routine clinical application of this technique in patients with microvascular disease such as those with Hypertensive Heart Disease.MCE will undoubtedly continue to gain prominence in the evaluation and management of cardiovascular diseases. It is uniquely positioned to fill a major void in the non-invasive assessment of microvascular flows particularly in patients with hypertensive heart disease and associated co-morbidities. With continued progress and refinements in acoustic technology and contrast agents, these potential applications will soon be translated to routine clinical use."} +{"text": "Cholesterol granuloma (CG) is the outcome of the foreign body type of response to the accumulation of cholesterol crystals and is frequently present in conjunction with chronic middle ear diseases. Recently, cases of CG in jaws have been reported, but still, very few cases have been found of CG in dental literature. This article presents three rare cases of CG in the wall of odontogenic cysts emphasizing on its possible role in expansion of the associated lesion and bone erosion. It also lays stress on the fact that more cases of CG should be reported so that its nature and pathogenesis in the oral cavity become more perceivable. Cholesterol granuloma (CG) is a histopathological entity that is characterized by collection of numerous cholesterol clefts, which are associated with foreign body giant cells, foam cells, and hemosiderin filled macrophages . Most co calcifying odontogenic cyst with cholesterol granuloma was made for the same in private dental clinic but after extraction the swelling persisted. On palpation, swelling was soft and fluctuant in nature extending from the buccal vestibule till midline of the hard palate. FNAC was attempted but the mass bled profusely. CT scan revealed a huge expansile, well demarcated, and osteolytic mass extending from maxilla into the maxillary sinus. A provisional diagnosis of keratocystic odontogenic tumor (KCOT) was made. Surgical enucleation of the cyst was performed and the tissue was sent for histopathological examination. The sections revealed proliferation of cystic odontogenic epithelial lining with palisaded hyperchromatic columnar nuclei, stellate reticulum like areas, and sheets of abundant ghost cells. Surrounding connective tissue stroma showed mature collagen bundles. Abundant hemorrhagic areas and fibrin deposits were evident both in fibrous wall and in cystic lumen. Also visible both in the connective tissue and in cystic lumen were abundant cholesterol clefts and hemorrhagic areas. Focal areas of ghost cell formation were also visible in the stroma surrounded by foreign body giant cells and hemosiderin pigmentation. Thus, based on this a final diagnosis ofwas made . dentigerous cyst with cholesterol granuloma was made was made. The cyst was surgically enucleated and the histopathology revealed nonkeratinized stratified squamous cystic epithelial lining, 2-3-cell layer thick, which showed proliferation in few areas associated with underlying inflammation. In the connective tissue cystic capsule, mixed inflammatory cell infiltrates with areas of hemorrhage were evident. A part of the tissue revealed abundant cholesterol clefts in the cystic capsule in association with multinucleated giant cells. Based on this a diagnosis ofwas made .A 47-year-old male reported with complaint of pain in lower left posterior mandible for past two days. He gave history of swelling on this side since two months. Mild swelling was present on left side of mandible, which was hard on palpation and nontender. Intraorally the swelling was soft in consistency and painful with a slight opening present on crest region through which yellowish green color discharge was noticed. Computed tomography revealed a well-defined radiolucency (30 \u00d7 14\u2009mm in size) present on left angle of mandible region with 38 displaced near the inferior border of the mandible. Incisional biopsy was sent for histopathological evaluation which revealed cystic lining of varying thickness, nonkeratinized stratified squamous in nature with few areas of mucus metaplasia. Connective tissue capsule was fibrocellular with vascular channels and mild inflammatory cell infiltrate and a diagnosis of dentigerous cyst was made. After this the excised tissue was sent which after repeated regrossing and tissue sectioning did not show any cystic lining. The connective tissue stroma was ectomesenchymal and fibrocellular with abundant cholesterol clefts and chronic inflammatory cell infiltrate .CG histopathologically depicts a large collection of longitudinal cholesterol clefts that are formed at the site of cholesterol crystals because of dissolution of crystals at the time of tissue processing and is embedded in fibrous granulation tissue with surrounding foreign body type of multinucleated giant cells and macrophages filled with hemosiderin . After aAn ambiguity has always persisted regarding the terminology of CG in the oral cavity, as Bhaskar, Wood, and Goaz described a lesion in the jaw with similar histopathological features but termed it cholesteatoma . StatingCG should be considered in clinical-radiographic differential diagnoses of odontogenic cysts or tumors. Netto et al. reported a case of mandibular CG mimicking a dentigerous cyst .The cholesterol crystals are reported to occur more commonly in inflammatory cysts, especially in radicular cysts. Lowest incidence was reported in noninflammatory cysts such as odontogenic keratocyst . In all The pathogenesis of CG is controversial as many possible mechanisms have been proposed to explain it but no clear consensus has been made. CG is formed due to irritant effect of accumulated cholesterol crystals as a result of the breakdown of blood, inflammatory tissue, or exudate. They attract foreign body giant cells and thus cause fibrosis . Our casThe buildup of cholesterol crystals in the cyst wall and cystic fluid could result from the disintegrating red blood cells of stagnant blood vessels within the lesion, circulating plasma lipids, or fatty degeneration of connective tissue in a cavity blocked by inflammation . Our casCG could lead to expansion of the lesion with which it is associated. Almada et al. reportedCG is considered as a nonspecific histopathological reaction to cholesterol crystals rather than a clinical or pathological entity. As its clinical and radiographic characteristics are nonspecific, it should be considered in differential diagnosis of odontogenic cyst and tumors and histopathological analysis is essential for a correct final diagnosis of CG. Due to paucity of the intraoral reported CG cases the true nature and pathogenesis are still ambiguous. There also persists confusion on the terminologies and distinctiveness of CG reported in the oral cavity and ear. More CG cases of the oral cavity should be brought to light so that their unique identity could be revealed and elaborated upon."} +{"text": "Senescence-associated proteolysis in plants is a complex and controlled process,essential for mobilization of nutrients from old or stressed tissues, mainly leaves,to growing or sink organs. Protein breakdown in senescing leaves involves manyplastidial and nuclear proteases, regulators, different subcellular locations anddynamic protein traffic to ensure the complete transformation of proteins of highmolecular weight into transportable and useful hydrolysed products. Proteaseactivities are strictly regulated by specific inhibitors and through the activationof zymogens to develop their proteolytic activity at the right place and at theproper time. All these events associated with senescence have deep effects on therelocation of nutrients and as a consequence, on grain quality and crop yield. Thus,it can be considered that nutrient recycling is the common destiny of two processes,plant senescence and, proteolysis. This review article covers the most recentfindings about leaf senescence features mediated by abiotic and biotic stresses aswell as the participants and steps required in this physiological process, payingspecial attention to C1A cysteine proteases, their specific inhibitors, known ascystatins, and their potential targets, particularly the chloroplastic proteins assource for nitrogen recycling. Leaf senescence is a physiological process critical for plant survival. It ischaracterized by the dismantling of cellular structures, massive degradation ofmacromolecules and efficient relocation of nutrients from senescing leaves to growingtissues or sink organs .Protein breakdown is one of the most important catabolic processes associated with leafsenescence with an essential role in nutrient recycling, especially nitrogen. Changes inthe temporal expression pattern of proteases take place not only in nuclei but also inchloroplasts and mitochondria to cooperatively ensure protein degradation into aminoacids, amides and ammonium , sucrose starvation, dark, cold, heat, drought,salt, or wound. Moreover, pathogen infection and phytophagousarthropod infestation can also promote or alter senescence . There aSAG12 was alsoinduced during the HR against viruses and bacteria against incompatible bacteria and fungi as well as interactions with viruses assays using barley cystatins and cathepsin L-likeCysProt fused to moieties of the green fluorescent protein marker (GFP). Theformation of a CysProt-cystatin complex has also been reported in senescent spinachleaves . It includes the formation of a primary fluorescent catabolite in theplastid, followed by isomerization to produce non-fluorescent catabolites in thecentral vacuole (HvPap-1 CysProt barley lines grown underdarkness (unpublished data). Proteolysis associated with senescence provides freepeptides or amino acids and redistributes them within the plant. Degradation ofplastidial proteins represents the main source of nitrogen remobilization, and moststudies have been focused in this organelle rather than in the other cellcompartments concentrations are also affectedby alterations in the senescence process .To cope with this dilemma it is important to balance the agronomical or economicconsequences with the quality of the end-product. For barley grains, low protein contentis desirable in malting processes to obtain beer whereas high protein content isdesirable to be used for animal feeding. Moreover, slow grain filling associated withdelayed senescence implies an increased probability of damage by environmental factorssuch as heat and drought stress and drought during the later stages of crop development. ManipulStrong indications from multiple studies indicate that prevention of prematuresenescence induced by biotic/abiotic stresses may be the key in engineering stresstolerance. This review compiled the current knowledge on different aspects related todegradation of proteins as part of the leaf senescence mediated by different stresses,and their potential effects on crop yields. Future research should be done to acquiremore precise information about protease action and protease targets and to increaseknowledge concerning the traffic of hydrolysed proteins from their original subcellularlocations via specialized vesicles to the central lytic vacuole. Clarifying how proteaseactivity is regulated by a specific inhibitor may contribute to understand the balancebetween recovery from stress and excessive protein degradation resulting in cell death.Overall, research is needed to encompass the complete set of information in order tounderstand why, how, where and when leaf senescence is produced. The final goal will beto control the impact of senescence in agriculture keeping in mind the current andfuture effects of extreme weather events related to climate changes."} +{"text": "In this issue we are publishing two reviews, eleven original papers, one history note andone case report.Wajman et al. analyzed the influence of cultural phenomena on behavior andon cognition and functional realms. The authors concluded that continual research inthis area is essential to understand differences in performance on neuropsychologicaltests among culturally and linguistically different populations.Takada reviewed the genetics of monogenic frontotemporal dementia, an areawhere several novel discoveries in the last decade have furthered our knowledge and mayhave an impact on the future diagnosis and treatment of these conditions.Tiel et al. performed a systematic review on the neuropsychiatric symptomsof vascular cognitive impairment and included 13 papers in their analysis. The authorsfound that subcortical and cortical-subcortical vascular dementia were describedpredominantly with apathy and depression, whereas neuropsychiatric symptoms were lessfrequent in vascular cognitive impairment without dementia.Damin et al. designed a 22-item questionnaire to identify individuals withnormal cognition, mild cognitive impairment (MCI) and dementia in Brazil. TheQuestionnaire of Cognitive Change was able to classify individuals into these threegroups with high accuracy, even after reducing the number of questions to eight.Jacinto et al. carried out a transcultural adaptation of an instrumentdeveloped in the United Kingdom for assessing the knowledge and attitudes of physicianstowards dementia. After adaptation to the Brazilian context, the instrument wasconsidered adequate for future validation and use in Brazil.Ramanan et al. investigated category and phonemic verbal fluency tasks inthe discrimination of AD from MCI and bvFTD. The numbers of responses and switches incategory fluency were able to differentiate AD from MCI in most cases, but verbalfluency tests proved insufficient to discriminate AD from bvFTD.De Paula et al. used modified versions of the verbal fluency tests toevaluate specific aspects of the executive functions. The authors found that a modifiedversion in which the participant had to give the name of an animal followed by a fruit(as word pairs|) was a more specific measure of cognitive flexibility than other verbalfluency tests.Serrao et al. used a Lexical Decision Test in three groups of elderly:healthy individuals, patients with MCI and with AD. Although there were differences inthe cognitive tests, the Lexical Decision Test did not differ among the three groups,showing that this test may be used for measuring premorbid intelligence quotient(IQ)Sposito et al. evaluated a large cohort of Brazilian elderly to investigatethe relationship between engagement in advanced activities of daily living andperformance on the domains of the Mini-Mental State Examination. The authors found anassociation of engagement in advanced intellectual and social activities with bettercognitive performance.Silveira and Mansur analyzed the discourses of normal and aphasic subjectswhen narrating three selected fairy tales. The number of propositions was lower inaphasic individuals and the three stories were able to differentiate between control andaphasic individuals based on the macrostructure of the discourse.Muller et al. conducted a systematic review on executive functions as apotential neurocognitive endophenotype in anxiety disorder diagnosis using several databases. Executive dysfunctions were considered a neurocognitive endophenotype inobsessive-compulsive disorder. The authors concluded that further studies on executivefunctions in other anxiety disorders are needed.Artigas et al. presented data showing that attending a support group forParkinson disease patients was associated with better quality of life scores and fewersymptoms of depression, anxiety and social phobia when compared to Parkinson diseasepatients who did not attend a support group.Kessels et al. investigated verbal and visuospatial working memory in mildcognitive impairment (MCI) and in Alzheimer\u2019s disease (AD). This study showed thatworking memory deficits are present in both MCI and AD, but that impairments are notalways evident on all working memory tests.Engelhardt and Grinberg revisited the papers published by Alois Alzheimer onvascular brain diseases to find that he had identified and described three groups ofvascular brain diseases that are the main forms we currently recognize as responsiblefor Vascular Cognitive Impairment.Simabukuro et al. reported a case with a long course of psychiatric diseasediagnosed as Bipolar Affective Disorder that evolved to encephalitis caused byantibodies against NMDA receptor. The possibility of a relapsing autoimmune disorder ortwo conditions was discussed.Ricardo Nitrini Editor-in-Chie"} +{"text": "Some patients suffering from the same neuropsychiatric disorder may have no overlapping symptoms whilst others may share symptoms common to other distinct disorders. Therefore, the Research Domain Criteria initiative recognises the need for better characterisation of the individual symptoms on which to focus symptom\u2010based treatment strategies. Many of the disorders involve dysfunction within the prefrontal cortex (PFC) and so the marmoset, due to their highly developed PFC and small size, is an ideal species for studying the neurobiological basis of the behavioural dimensions that underlie these symptoms.Here we focus on a battery of tests that address dysfunction spanning the cognitive (cognitive inflexibility and working memory), negative valence and positive valence (anhedonia) systems pertinent for understanding disorders such as ADHD, Schizophrenia, Anxiety, Depression and OCD. Parsing the separable prefrontal and striatal circuits and identifying the selective neurochemical modulation (serotonin vs dopamine) that underlie cognitive dysfunction have revealed counterparts in the clinical domain. Aspects of the negative valence system have been explored both at individual\u2010 (trait anxiety and genetic variation in serotonin transporter) and circuit\u2010based levels enabling the understanding of generalisation processes, negative biases and differential responsiveness to SSRIs. Within the positive valence system, the combination of cardiovascular and behavioural measures provides a framework for understanding motivational, anticipatory and consummatory aspects of anhedonia and their neurobiological mechanisms. Together, the direct comparison of experimental findings in marmosets with clinical studies is proving an excellent translational model to address the behavioural dimensions and neurobiology of neuropsychiatric symptoms. \u00a9 2016 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 77: 328\u2013353, 2016 One in five people will suffer from a neuropsychiatric disorder at some point in their life and neurochemically specific toxins , or temporarily, by infusions of drugs through indwelling cannulae. This will also prove an advantage when applying state\u2010of\u2010the\u2010art molecular and imaging techniques to neural circuit analysis of cognition and emotion, including optogenetics , negative valence and positive valence (anhedonia) systems, as defined by RDoC Fig. . Since sImpairments within the cognitive systems are prominent in disorders such as schizophrenia, obsessive\u2010compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD). These disorders may share a range of cognitive impairments including deficits in cognitive flexibility and inhibitory response control and aspects of working memory Morice, . Such deCognitive flexibility is the ability to adapt mental strategies and actions to the changing contingencies and conditions of the environment and ventrolateral prefrontal cortex (vlPFC), studies in marmosets revealed their differential contribution to these two forms of cognitive flexibility , generally shows a significant impairment in OCD patients , they can easily become maladaptive and deleterious once left unregulated. Pathological anxiety, affecting more than 28% of the general population that results in reduced gene expression has been linked to a high trait anxiety phenotype on anxious behavior. The low gene expressing, high trait anxious marmosets displayed an anxiogenic response in contrast to the anxiolytic response of the high gene expressing, low trait anxious marmosets [Santangelo et al., SCL6A4 genetic variation in the latter and vlPFC on fear and anxiety. At face value, the effects of both lesions seemed almost identical, increasing anxiety as measured by the human intruder test, increasing innate fear in response to a snake stimulus [Fig. The question remains as to what is the distinct contribution of these two prefrontal regions to the anxiety phenotype, the answer of which will help to stratify anxiety disorders and develop targeted treatments. Besides the failure to regulate negative emotions, patients with anxiety and depression often make poor decisions. Because they are particularly sensitive to negative information, they tend to perceive threat with increased intensity and are more risk averse components. The latter is seldom measured in studies of reward processing in animals or an empty food box (CS\u2212). Changes in behavioral and cardiovascular arousal during the CSs were assessed both after a single extinction session, in which the decline in conditioned cardiovascular arousal was measured following omission of the expected reward and after reversal of the reinforcing contingencies, in which the previous CS\u2212 became the CS+, and vice versa. So far this revised version has been used to study the contribution of the antOFC to the regulation of appetitive Pavlovian conditioning. Marmosets with excitotoxic lesions of the antOFC failed to show the normal decline in the conditioned systolic blood pressure response after reward omission, instead showing a prolonged arousal response. Moreover, upon reversal, antOFC lesioned animals were much slower to reverse their blood pressure response. Significantly, even when the cardiovascular response was successfully reversed, conditioned behavior was not and the Wellcome Trust (TWR) and was performed within the Behavioral and Clinical Neuroscience Institute, University of Cambridge, funded jointly by the Wellcome Trust and MRC. LO is supported by an MRC studentship. We thank Stacey Jackson, Ian Bolton and Adrian Newman for advice on illustration and figure formatting."} +{"text": "Intra-articular adipose tissue deposits known as articular fat pads (AFPs) are described to exist within synovial joints. Their assumed role in normal joint biomechanics is increasingly objectivized by means of advanced methods of functional imaging. AFPs possess structural similarity with body subcutaneous white adipose tissue (WAT), however, seems to be regulated by independent metabolic loops. AFP dimension are conserved during extreme WAT states: obesity, metabolic syndrome, lipodystrophy, and cachexia. Hoffa fat pad (HFP) in the knee is increasingly recognized as a major player in pathological joint states such as anterior knee pain and osteoarthritis. HFP contains numerous population of mesenchymal and endothelial progenitors; however, the possible role of mature adipocytes in the maintenance of stem cell niche is unknown. We propose that AFP is an active component of the joint organ with multifunctional roles in the maintenance of joint homeostasis. Endowed with a rich network of sensitive nervous fibbers, AFPs may act as a proprioceptive organ. Adipokines and growth factors released by AFP-resident mature adipocytes could participate in the maintenance of progenitor stem cell niche as well as in local immune regulation. AFP metabolism may be locally controlled, correlated with but independent of WAT homeostasis. The identification of AFP role in normal joint turnover and its possible implication in pathological states could deliver diagnostic and therapeutic targets. Drug and/or cell therapies that restore AFP structure and function could become the next step in the design of disease modifying therapies for disabling joint conditions such as osteoarthritis and inflammatory arthritis. White adipose tissue (WAT) is increasingly recognized as a multifunctional, metabolically active organ . The evoMature adipocytes together with WAT resident macrophages are active players in local and systemic immune response by releasing pro-inflammatory cytokines and adipokines that orchestrate local and central pathways of the innate immune system . The endWhite adipose tissue is widely distributed in almost the entire body subcutaneous region, in organs and hollow viscera of the abdominal cavity, in mediastinum as well as in several muscle groups functioning as a thermal insulator and shock absorber. Its role in mechanical protection has been related to the lax extracellular matrix (ECM) structure and to the important capability to recover from mechanical deformation .White adipose tissue structure and function varies with body distribution. Subcutaneous fat presents distinct cellular and sec-retory profile compared to visceral fat . RegionsHowever, despite WAT heterogeneity in structure and function, its responsiveness appears to be closely correlated by similar, if not the same, neuroendocrine and biochemical pathways. Shared biochemical profile during pathological states obesity and metabolic syndrome at one pole and lipodystrophy and cachexia at the opposite pole draws the picture of a body-wide organ functioning as an organismal network with possible site-specific adaptive particularities.An interesting and potentially important WAT location has been, surprisingly, largely neglected. AFPs have been mainly mentioned in the context of pathological joint states (such as knee pain and osteoarthritis\u2014OA) or as a This paper will introduce the hypothesis of AFP as an internal homeostatic joint regulator, in possible relation but distinctive from body WAT function and balance. We propose that AFP is a specialized tissue of the joint organ contributing to its homeostasis by releasing bioactive molecules implicated in cell and ECM growth, turnover, and repair. AFP biomechanical role and its function in joint homeostasis are intertwined and might be locally regulated and systemically coordinated. AFP might act by converting information about joint biomechanics into biochemical cues that contributes to regulating the homeostasis of all articular tissues.Commonly, intra and periarticular fat deposits are included within the category of joint adjacent supportive structures together with menisci and ligaments. Such structures, described to be heterogeneously present in some joints are thought to contribute to joint stability and to function as a shock absorber .Possibly the largest AFP in humans, the infrapatellar fat pad of the knee joint, known as Hoffa\u2019s fat pad (HFP) is one oIn the hip joint, a relatively recently identified structure placed at the anterior head\u2013neck junction of the upper femur has AFP characteristics and is sought to be a source of femoroacetabular impingement . Fat padArticular fat pads were described to be present superior and inferior to lumbar facet joints from which fat-filled synovial folds project between the articular surfaces the superior being intracapsular between the ligamentum flavum and the lamina while the inferior remains extracapsular lying on the back of the lamina below and communicates with the joint through a hole in the inferior capsule. Lumbar facets AFPs can be identified by computer tomography scans. Lumbar facets AFPs enlargement is sought to be associated with degenerative changes and capsular laxity of the facet joints .Intermetacarpal fat pads have been described to be adipose structures located between the heads of the second, third, fourth, and fifth metacarpal bones, filling the spaces between the palmar fascia and its deep expansions. They are proposed to act as protection from shear forces during gripping, to protect neurovascular finger bundles, and to contribute to neurological symptoms when inflamed or injured .The development of modern imagistic such as ultrasound and arthroscopy made possible not only the identification of previously unknown AFPs location but enabled as well direct visualization, dynamic assessment, and quantification of their biomechanical role within the joint.It is noteworthy to mention that historically, \u201csynovial fat pads\u201d were regarded as the sources of synovial fluid (SF). AFPs were denominated harversian glands and thought to produce substances that \u201coil\u201d the joint surface. Currently, the name is kept only in regard with the acetabular floor AFP (known as harversian fat). The attributed physiological role in joint lubrication was only later replaced by an assumed mechanical filler-cushioning function.The existence of physiological particularities of the intra-articular deposits distinguishing this tissue from widespread subcutaneous fat was suspected by anatomists as late as the middle of the twentieth century. Despite the structural similarity to body-wide WAT, AFPs persist even during advanced states of malnutrition, when all other deposits are depleted. This observation raised the hypothesis that such tissue might possess yet unexplored particular ultrastructural and secretory features of potential importance for joint function .However, the study of fat pat deposits seem to have fallen into oblivion until late 1990s when sports physicians and physiotherapists become interested in its involvement in producing joint pain. Reports related almost, if not completely to HFP, are stressing out the involvement of its rich nervous network and abundant substance P fibers in producing anterior knee pain in various pathological states , 19, 24.in vivo and in vitro . In the absence of relevant information, AFP contribution to the homeostasis of the normal joints remains unknown. Conversely, AFP involvement in pathological joint conditions is increasingly stressed out and suggests a local regulatory mechanism in close dialog with the well-known inflammatory milieu that characterizes such diseases. The interplay between AFP biomechanical and secretory function may serve as a turning point between joint dynamics, axis, and alignment and the control of local metabolism, under the influence but possible distinct from body nutritional status. Deciphering the cross talk between AFP as a bio mechanic sensory organ that responds by modulating joint organ turnover and controlling local inflammation could contribute to increased understanding of joint functioning.Tissue niches are known to control site-specific stem cell function, governing their transition from quiescence to proliferation and maturation. Mature adipocytes were shown to contribute to the maintenance of stem cell niche in various locations and to generate niches for other cell types. Mature adipocytes within bone marrow were shown to inhibit hematopoetic stem cell engraftment . Conversin vitro suggesting a conserved cartilage progenitor pool might exist within the tissue that trigger stem cell activation or an indirect immune-mediated contribution could be involved. Indeed IL-10-producing type 1 regulatory T cells (Tregs) were shown to modulate the activity of mice MSCs in a mice model of RA . FurtherBy far the most investigated AFP, HFP begins to develop in humans starting with the 11th gestational week from the mesenchymal tissue below the patella, between the cruciate and the patellar ligaments . Its strHFP is a very sensitive structure due to the presence of peptidergic C-fibers, nerve fibers staining positive for substance P that areAs it is the case with synovial tissue, HFP is the stage of immune cells invasion during OA and RA that triggers production of pro-inflammatory and pro fibrotic cytokines from local activated macrophages. After the initiation of joint degradation, cartilage breakdown molecules could activate monocytes and trigger innate immunity mechanisms . HFP-resThe role of WAT produced adipokines in the initiation and aggravation of inflammatory processes at systemic level as well as within the joint is well established. Leptin, adiponectin, and resistin were reportedly found in SF of OA and RA patients at concentrations that differ from blood levels. Such pro-inflammatory mediators could be produced by HFP by an independent locally regulatory mechanism that is not correlated with body fat and nutritional status.Pertaining to the largest joint in the body, HFP contribution to knee pain and pathological conditions is increasingly recognized. If, however, there is a connection between biomechanical joint misbalance and HFP function in contributing and sustaining joint inflammatory milieu, has not yet been established. Dynamic biomechanical studies could elucidate if potential HFP function as a proprioceptive sensor correlates with its secretory role and contributes to both joint organ maintenance. Its perturbed functional states could generate targets for complex joint re-balancing.Obesity and metabolic syndrome are currently recognized to generate systemic and peripheral pro- inflammatory status. Moreover, OA has been proposed to be a metabolic disease associated with the chronic low-grade inflammation that defines obesity and metabolic syndrome and with the impaired cartilage homeostasis in the context of lipid and glucose abnormalities . Far lesLipodystrophy is defined as the acquired or genetically induced partial or complete loss of metabolically active WAT. Age or disease-associated cachexia are wasting syndromes associating severe fat and muscle loss . As a coArticular fat pad deposits remain quantitatively unmodified during extreme WAT states as a possible mechanism for preserving the joint homeostasis and hence enabling the body to remain mobile and to interact with the surroundings. In turn, preservation of mobility and the capability to engage in physical activities are mandatory for self-adjusting the equilibrium in multiple hierarchical systems inside and outside the body. AFP acting as a biomechanical sensor could adjust joint organ homeostasis by means of physical activity. Systemic WAT extremes are prevented and/or adjusted by mobility and so is the organism ability to interact within its ecosystem. Obviously, at the extremes, obesity and advanced wasting states overcome articular joint capability to self-adjustment by imposing severe external restrictions in mobility. Morbid obesity but as well lipodystrophy and cachexia mechanically restrict joint movements either by excessive body weight or by muscle wasting. Systemic or local inflammatory status and insulin resistance overcome the capability of AFP to maintain intra-articular homeostasis. Here, complex intervention that addresses both systemic conditions and intra-articular AFP impairment are needed.Recently, intra-articular therapies using SVF and/or adipose tissue administration in OA joints are reporting favorable results in the management of knee OA , 62; howWe propose that AFP is an active component of the joint organ with multifunctional roles in maintenance of joint homeostasis. AFP rich network of sensitive nervous fibbers could act as a sensory organ possible involved in proprioception having role in acquiring information about joint axis, stability, and dynamics. Endocrine and paracrine secretion of adipokines and GFs AFP mature adipocytes could participate to joint organ turnover being involved in the maintenance of progenitor stem cell niche, cell renewal, and differentiation as well as local immune regulation. Local immune residents such as macrophage and Tregs are involved in balancing cellular growth and respond to pathological stimuli by controlling joint organ inflammatory status. While correlating with body-wide WAT status, AFP could possess genetic particularities as well as an independent mechanism of local control. Genetic and metabolic profiling of AFT could possibly result in description of molecular particularities that define distinct disease phenotypes. A metabolic-based classification of OA could result in predicting therapeutic response to existent preventive and therapeutic methods .In vivo monitoring of AFP function in animal models could elucidate its role within normal joint organ functioning and discriminate the contribution to the occurrence and progression of diseases. Bioinformatics analysis and computational modeling could identify currently unknown pathways involved in AFP functioning, eventually identifying AFP as an internal homeostatic system that connects joint biomechanics with structural maintenance mechanisms, correlated with systemic WAT but independently regulated. Cell therapies that aim to restore AFP structure and function could become the next step in delivering disease modifying therapies for disabling joint conditions such as OA and RA. Intra-articular therapies using adipose tissue derivatives might act by triggering AFP secretory and/or biomechanical role in regenerating joints structure and function.Further studies are needed to assess the biomechanical and molecular particularities of AFP in normal and diseased joints during normal and extreme WAT conditions. Cellular components as well as sensory fibers and ECM should be the subject of comparative investigation in both normal and pathological joint states as well as during normal and WAT pathological states. Using omics technologies at the single-cell level, complete AFP genetic and epigenetic profiling could be performed potentially deriving targets for future therapies. The presence and biomechanical importance AFP deposits are increasingly revealed due to the use of new and improved advanced dynamic imaging. Historically thought to possess a role in joint physiology by assumed production of joint lubricants, AFP metabolic role has been largely disregarded. WAT is increasingly recognized as an important endocrine organ with impact in body homeostasis. The similarity between WAT and articular fad pad regarding structure, cellularity, and composition invites to the reconsideration of its role in the maintenance of normal joint homeostasis. Methods that are designed to locally restore the functionality of the intra-articular adipose tissue could represent an effective modality to re balance joint homeostasis, improve joint function, and restore body mobility. This will derive important consequences for the treatment not solely for joint diseases but for extreme WAT misbalances\u2014obesity, metabolic syndrome, age, and disease-associated wasting.LL contributed to formulating and launching the hypothesis presented in this manuscript FZ-E contributed to gathering literature data and orienting manuscript writing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Syphilis transmitted from mother to child is second only to malaria as a leading cause of preventable stillbirth.The World Health Organization (WHO) strategy for the elimination of congenital syphilis prioritized commitment and advocacy at the highest levels, alongside promoting increased access to and quality of maternal and newborn health services, improved coverage of syphilis testing and treatment in pregnancy and ongoing surveillance, monitoring and evaluation of targets.Integration of syphilis prevention with HIV control programmes offers the opportunity to expand coverage of syphilis testing and treatment among populations at risk for both infections, particularly among pregnant women, who bear the highest burden of adverse outcomes. Aligning elimination efforts may also contribute to strengthening the health system and saving costs.New technology has increased the feasibility of integrated testing. For example, the development of rapid dual HIV/syphilis test kits has enabled additional syphilis intervention opportunities within clinical settings. This kit allows simultaneous testing for both infections on a single cartridge. A systematic review has shown that the field performance of rapid dual HIV/syphilis tests is comparative to laboratory reference testing.,,While improved diagnostic tools may improve efficiency and testing coverage, securing and maintaining strong political commitment is also critical to programme success. China has succeeded in increasing syphilis testing and treatment for pregnant women nationally, and for high-risk groups in some areas, by strategically integrating syphilis control with HIV \u2013 an issue that receives both political attention and resources in the country."} +{"text": "Mucormycosis is an invasive and aggressive opportunistic fungal infection that usually presents with rhinocerebral or pulmonary involvement and rarely involves the gastrointestinal tract. The disease is acute with mortality rate up to 100%. A 68-year-old male was undergoing treatment at a local hospital for COPD exacerbation with IV steroids and antibiotics. Two weeks into his treatment he suddenly developed massive upper GI bleeding and hemodynamic instability that necessitated transfer to our tertiary care hospital for further treatment and management. An urgent upper endoscopy revealed multiple large and deep gastric and duodenal bulb ulcers with stigmata of recent bleeding. The ulcers were treated endoscopically. Biopsies showed fibrinopurulent debris with fungal organisms. Stains highlighted slightly irregular hyphae with rare septa and yeast suspicious for Candida. The patient was subsequently placed on fluconazole. Unfortunately, the patient\u2019s general condition continued to worsen and he developed multiorgan failure and died. Autopsy revealed disseminated systemic mucormycosis. Most of the cases of gastrointestinal mucormycosis were reported from the tropics and few were reported in the United States. The disease occurs most frequently in immunocompromised individuals. The rare incidence of GI involvement, acute nature, severity and the problematic identification of the organisms on biopsies make antemortem diagnosis challenging. Treatment includes parenteral antifungals and debridement of the infected tissues. Gastroenterologists should be aware of this rare cause of gastrointestinal bleeding and understand the importance of communication with the reviewing pathologist so that appropriate, and often lifesaving, therapies can be administered in a timely manner. Mucormycosis is an invasive and aggressive opportunistic fungal infection that usually presents with rhinocerebral or pulmonary involvement and rarely involves the gastrointestinal tract. The disease is acute with mortality rate up to 100%. Herein we describe a rare case of disseminated invasive mucormycosis that presented with massive upper GI bleeding.A 68-year-old male was undergoing treatment at a local hospital for COPD exacerbation with IV steroids and antibiotics. Two weeks into his treatment he suddenly developed massive upper GI bleeding and hemodynamic instability that necessitated transfer to our tertiary care hospital for further treatment and management.Candida. The patient was subsequently placed on fluconazole.An urgent upper endoscopy revealed multiple large and deep gastric and duodenal bulb ulcers with stigmata of recent bleeding. The ulcers were treated endoscopically with epinephrine injection and bipolar cautery, and proton pump inhibitor therapy was initiated. Biopsies obtained from the gastric mucosa showed fibrinopurulent debris with fungal organisms. Periodic acid-Schiff and Grocott\u2019s methanamine silver stains were performed which highlighted slightly irregular hyphae with rare septa and yeast suspicious for Unfortunately, the patient\u2019s general condition continued to worsen and he developed multiorgan failure including: altered mental status, respiratory failure, thyroid storm, atrial fibrillation, renal failure, and pancytopenia. He died 2 weeks later due to multiorgan failure at which time an autopsy revealed disseminated systemic mucormycosis with necrotizing hemorrhagic infarctions in the stomach , 2, lungMucormycosis refers to several different diseases caused by fungi in the order Mucorales, which includes the species Mucor, Rhizopus, Absidia and Cunninghamella , 2, ubiqThe most common clinical presentation of mucormycosis is rhinocerebral and pulmWhen gastrointestinal tract is involved, mucormycosis can present with nonspecific symptoms such as abdominal pain, nausea, and vomiting ; howeveEndoscopically, gastric mucormycosis can have the appearance of a white, fibrinous growth or be asDiagnosis is challenging, especially on scant tissue samples, and is complicated by distortion of the organism during tissue retrieval and processing. Significant pathological expertise is required to make the diagnosis . If therHofman et al. observedInterpretation of tissue cultures in these patients is a complicated and slow process. The organism is a common laboratory contaminant and may be destroyed during tissue processing rendering false positive and negative results, respectively . OrganisMost of the cases of gastrointestinal mucormycosis were reported from the tropics; however, the disease is increas\u00adingly becoming an iatrogenic and/or nosocomial problem in industrialized nations and receSystemic amphotericin B is the mainstay of treatment. Reversal of underlying medical disease and often surgical debridement of the infected tissues are necessary for successful management .Most of the cases of gastrointestinal mucormycosis were reported from the tropics and few were reported in the United States. The disease occurs most frequently in immunocompromised individuals. The rare incidence of GI involvement, acute nature, severity and the problematic identification of the organisms on biopsies make antemortem diagnosis challenging. Treatment includes parenteral antifungals (amphotericin B) and debridement of the infected tissues. Advances in medical therapies have improved survival for many disease states which have resulted in an ever increasing number of immunocompromised patients. It is likely that we will see a corresponding increase in the incidence of Mucormycosis. Gastroenterologists should be aware of this rare cause of bleeding gastric and duodenal ulcerations and understand the importance of communication with the reviewing pathologist so that appropriate, and often lifesaving, therapies can be administered in a timely manner."} +{"text": "We report two contrasting cases of diabetic retinopathy to illustrate vascular and retinal abnormalities in this condition. In the first case, mild diabetic retinopathy is diagnosed in an asymptomatic patient with diabetes mellitus of recent onset. The second patient has severe diabetic retinopathy, causing vision loss as a consequence of poor metabolic control."} +{"text": "The relationship of age and symptoms with the performance on verbal learning and memory tasks in schizophrenia could provide useful information for optimizing and individualizing the efforts to remediate the cognitive impairments of patients.During a cross-sectional study, 97 medicated and stabilized patients with chronic schizophrenia , which were consecutively referred to our Unit, were assessed using the Hopkins Verbal Learning Test (HVLT) and the Positive and Negative Syndrome Scale (PANSS). A linear regression analysis was conducted in order to investigate the effect of symptoms and age on HVLT performance.Increased age and total PANSS symptoms were associated with worse total recall (raw scores) . The effect of symptoms on HVLT total recall was significant for positive , negative , but not for general psychopathology symptoms . Further analyses revealed the significant negative correlations of total symptoms with the performance in immediate recall during the first HVLT trial , and age during the second and third HVLT immediate recall trials. Both total symptoms and age were significantly negatively correlated with the performance in recognition discrimination (raw scores) . We failed to find any significant correlation between either age or symptoms with delayed recall.Age and symptoms are associated with immediate verbal learning and memory impairments but not with deficits in verbal delayed recall in schizophrenia. The effects of medication remain to be explored in future analyses. Cognitive remediation programmes against verbal learning deficits in individuals with schizophrenia should take into account their age as well as their symptomatology."} +{"text": "This article provides a review of the effects of activation of muscarinic and nicotinic receptors on the physiological properties of circuits in the hippocampal formation. Previous articles have described detailed computational hypotheses about the role of cholinergic neuromodulation in enhancing the dynamics for encoding in cortical structures and the role of reduced cholinergic modulation in allowing consolidation of previously encoded information. This article will focus on addressing the broad scope of different modulatory effects observed within hippocampal circuits, highlighting the heterogeneity of cholinergic modulation in terms of the physiological effects of activation of muscarinic and nicotinic receptors and the heterogeneity of effects on different subclasses of neurons. Besides its role as a neurotransmitter in the peripheral nervous system, acetylcholine (ACh) in the central nervous system mainly acts as a neuromodulator by modulation of neuronal excitability, presynaptic release probability, postsynaptic responsiveness and synaptic plasticity. Thereby, ACh plays an important role in modulating cortical circuit activity. Empirical evidence indicates a role for ACh in normal physiological cognitive functions including attention to sensory stimuli GABAergic neurons leading hippocampal rhythmic activity structures coincides with changes in hippocampal rhythmic activity paced by the rhythmic activity of the GABAergic MSDB neurons 3 and (\u03b13)2(\u03b24)3 channel compositions is an ionotropic receptor built as a homo- or heteromeric pentamer, which can be activated pharmacologically by the drug nicotine and functions as a non-selective, excitatory cation channel recorded from CA3 neurons in rat hippocampal slices channels, Dasari and Gulledge while ACin vitro positive Schaffer collateral associated and basket cells at the terminals of CCK+ basket cells, resulting in reduced GABA release vs. nicotinic (17%) mediated changes in membrane potential, and only 3% of interneurons had mixed responses in PV+ basket cells, and these sAHPs are reduced by bath application of muscarine make up approximately 40% of all GABAergic interneurons. However, this is a heterogeneous group of functionally distinct interneuron subtypes. For example, in the hippocampus alone, there are at least three functionally and morphologically distinct populations of PV+ interneurons has been observed to increase the frequency of IPSPs in downstream pyramidal cells, but these effects vary greatly depending on brain region and cortical layer. Postsynaptic observations of IPSPs in hippocampus show that muscarinic modulation increases the frequency of spontaneous IPSPs but decreases the amplitude of evoked IPSCs positive interneurons led to the recruitment of nearly 20% of excitatory cells demonstrating the powerful extent of VIP+ activity on the local network. There is still some debate as to whether this disinhibition acts more globally or more locally, since there is more recent evidence that VIP+ cells project within a narrow vertical column and serve to \u201copen holes in the blanket of inhibition\u201d , a retrograde signaling mechanism, where endocannabinoids are released from depolarized pyramidal cells act on upstream CB1 receptors on CCK+ basket cells to transiently reduce the frequency of GABA vesicle release. Notably, this phenomenon is highly accentuated when muscarinic receptors on CCK+ basket cells cause larger than baseline IPSP frequencies and postsynaptic depolarization amplitudes in CA1 pyramidal cells was added to the slice in order to enhance synaptic release of ACh. Imaging of calcium activity in the barrel cortex of mice in vivo revealed that astrocytes exhibited elevated intracellular calcium levels during the induction of LTP . In this review we will focus our discussion on AD and epilepsy, but see Higley and Picciotto for a re+ neurons was found to be reduced along the entire length of the basal forebrain in aged vs. young rats plaques, as well as intracellular neuropil threads and neurofibrillary tangles consisting of twisted filaments of hyperphosphorylated tau protein, which also accumulates in the extracellular space after neuronal death readily induces epileptic seizures and may lead to status epilepticus, resulting in spontaneous recurrent seizures following a latent period of epileptogenesis (Friedman et al., Epilepsy is not a singular disease entity, but a group of neurological disorders characterized clinically by an enduring predisposition to generate epileptic seizures (Fisher et al., As reviewed here, physiological data demonstrates robust neuromodulatory effects of the activation of muscarinic and nicotinic receptors within cortical circuits including the hippocampal formation. These modulatory effects appear important to the encoding of new information, based on changes in network circuit dynamics as reviewed in previous articles (Hasselmo, All authors conceived and wrote the review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Overall Abstract: As expanding genetic studies increasingly demonstrate that both rare variants of large impact and common variants of small effect contribute to schizophrenia, it becomes increasingly critical that we unravel how these risk factors interact within and between the diverse cell types populating the brain. While mouse models are uniquely suited for demonstrating how aberrant function of single gene products contribute to aberrant neuronal function or behavior, genetic studies of penetrance and complex gene interactions are nearly impossible to address using inbred mouse lines. Similarly, the lack of human post-mortem tissue, coupled with the inability to conduct functional experiments in patient cells, has to date left us with a very limited understanding of how rare and common variants impact gene expression or cellular function. Our panelists have each developed human induced pluripotent stem cell (hiPSC)-based models for the study of predisposition to neuropsychiatric disease, establishing a new mechanism by which to systematically explore the impact of rare and common putative causal variants in human cells.Given the heterogeneity of schizophrenia and the limited cohort sizes feasible with hiPSC-based cohorts, our panelists will share their successes and struggles in developing cohorts defined by shared clinical or genetic features. They will discuss both the molecular and phenotypic insights they have uncovered, in neurons and glia, from case/control and genetically-edited isogenic cohorts. Our discussant will focus on integrating these findings into consortia-led datasets generated from recent genomic and post-mortem studies of large schizophrenia cohorts. Our overall objective is to consider the role of hiPSC-based studies in dissecting the genetic origins of schizophrenia, validating causal variants identified through ongoing genetic analyses, and serving as a personalized medicine approach to screen for novel therapeutics with which to prevent or reverse disease course."} +{"text": "Carotid arterial system tortuosity is comparatively less common than its variations in branching patterns and termination. Tortuous common carotid artery is often associated with risk of injury during surgical procedures in the neck region, and such injuries usually occur during tracheotomy . LoopingThe occurrence of multiple loops of carotid vessels presented in this case is unique and has not yet been reported. These loops may decrease blood flow to certain regions of the head and neck, when in certain positions. Knowledge of these unusual loops may be important in diagnostic, therapeutic, radiological, and surgical techniques."} +{"text": "Neisseria gonorrhoeae is one of the most prevalent sexually transmitted infections worldwide. This obligate human pathogen has been extensively studied in vitro, where bacterial factors that are known to contribute to gonococcal disease and their regulation are relatively well defined. However, these in vitro experimental conditions only loosely replicate the host specific environment encountered by the bacteria in vivo. We recently reported on the complete gonococcal transcriptome expressed during natural human mucosal infection using RNA-seq analysis. Gene transcripts expressed in vivo (in vivo expressed factors) included genes encoding antibiotic resistance determinants, and a large number of hypothetical genes. A comparison of the gonococcal transcriptome expressed in vivo with the corresponding strain grown in vitro identified sets of genes regulated by infection, including those regulated by iron and the transcriptional regulatory protein Fur. We highlight here the role of Fur and gonococcal-specific regulatory processes important for infection and pathogenicity. We have determined that the genes controlled by Fur follow the same expression pattern in vivo as described previously in vitro, confirming Fur's regulatory role during infection. Collectively, these studies provide new insights into how bacterial fitness and pathogenicity are modulated during human mucosal infection. This article reviews how combining transcriptomics on pathogens from naturally infected hosts and other mechanistic studies can improve our understanding the genes involved in bacterial pathogenesis and how they are regulated. Neisseria gonorrhoeae is the causative agent of the sexually transmitted infection gonorrhea, the second most common reportable disease in the USA. According to the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO), there are approximately 800 000 new cases of gonorrhea in the USA and 106 million cases worldwide each year proteins interactions with host cells overcomes some of these limitations and the Fur-regulated tbpA/B and fbpA genes were expressed in mucosal samples obtained from men and women with uncomplicated gonorrhea and novel proteins that could represent new therapeutic targets and the ferric binding protein (fbp) is indirectly activated by Fur and has been shown to be important for intracellular survival in endocervical cells via AKT kinase activation and iNOS in vitro and other oxidative species as antimicrobial compounds and the gonococcus has adapted mechanisms that enable the organism to survive within PMNs . Further analysis of these unique data sets obtained from infected male and female subjects will define gonococcal adaptions during natural mucosal infection, a long-term goal of our studies. Taken together, these studies offer powerful new insights into the pathobiology of N. gonorrhoeae and will not only lead to a better understanding of the mechanisms of gene regulation employed by N. gonorrhoeae during infection, but ultimately will allow for the identification of novel virulence factors and consequently expand the potential for preventive and therapeutic strategies against N. gonorrhoeae infection.Current studies are focused on gonococcal transcriptional profiles expressed during infection in men. These studies have revealed a divergence in both the disease presentation in men and women, and gonococcal transcriptional programmingConflict of interest. None declared."} +{"text": "Postmortem studies demonstrate glial cell loss while the in vivo imaging data reveal disturbed glial functioning and altered white matter microstructure. Molecular studies report on altered gene expression of glial specific genes. In sum, the clinical findings provide ample evidences on glial pathology and demonstrate that all major glial cell types are affected. However, we still lack convincing theories explaining how the glial abnormalities develop and how exactly contribute to the emotional and cognitive disturbances. Abnormal astrocytic functioning may lead to disturbed metabolism affecting ion homeostasis and glutamate clearance, which in turn, affect synaptic communication. Abnormal oligodendrocyte functioning may disrupt the connectivity of neuronal networks, while microglial activation indicates neuroinflammatory processes. These cellular changes may relate to each other or they may indicate different endophenotypes. A theory has been put forward that the stress-induced inflammation\u2014mediated by microglial activation\u2014triggers a cascade of events leading to damaged astrocytes and oligodendroglia and consequently to their dysfunctions. The clinical data support the \u201cgliocentric\u201d theory, but future research should clarify whether these glial changes are truly the cause or simply the consequences of this devastating disorder.Depressive disorders are complex, multifactorial mental disorders with unknown neurobiology. Numerous theories aim to explain the pathophysiology. According to the \u201cgliocentric theory\u201d, glial abnormalities are responsible for the development of the disease. The aim of this review article is to summarize the rapidly growing number of cellular and molecular evidences indicating disturbed glial functioning in depressive disorders. We focus here exclusively on the clinical studies and present the Depressive disorders are a leading cause of disease burden globally and for the Depressive Disorders. All these terms mean larger categories and include several disorders. Here, we occasionally need to use the old terminology, since the majority of the studies have been done before the DSM-5. Most of the clinical studies discussed here involved patients either with Major Depressive Disorder (MDD) or with BD.in vivo imaging studies documenting reduced activity and volume shrinkage in the prefrontal cortex (PFC) of depressed patients , thus, some scientists question their scientific soundness. But in fact most of the Finally, we should note here that there are also negative findings on glial cell numbers in the literature thus, a theory had been put forward proposing that depressive disorders are the consequence of the disturbed astrocytic functioning microglia was significantly increased in depressed suicides and found that glial cell numbers were significantly reduced in the parietal cortex studies reveal reduced volumes of specific brain areas in depression , functional magnetic resonance imaging (fMRI), proton magnetic resonance spectroscopy (1H-MRS) and positron emission tomography (PET) imaging. Here, we summarize the in vivo clinical findings documenting glial abnormalities in patients with depressive disorders.18F-deoxyglucose by astrocytes is associated with neuronal activity , regulation of synaptic development and maturation and maintenance of the blood brain barrier levels in the context of mood disorders which is a key component of the glutamatergic system and expressed by neurons and astrocytes measures the magnitude of directionally varying diffusion restriction effect, while mean diffusivity (MD) represents the average diffusion coefficient in all direction.Oligodendroglia provides support and insulation to axons by creating the myelin sheath. Consequently, oligodendrocyte pathology can cause abnormal development, demyelination or reduction of myelinated axons. Oligodendrocyte abnormalities can be investigated A significant number of DTI studies found robust FA reductions in the corpus callosum and in several frontal and temporal regions and associated with macromolecular concentration. Hence, increased MTR in the white matter indicates remyelination, whereas decreased MTR indicates demyelination , Choline (Cho), myo-inositol (mI), Glutamate (Glu)/Glutamine (Gln) and Creatine (Cr). NAA plays a role in various cellular functions such as osmoregulation, energy homeostasis and possibly also in myelin production was significantly increased by the magnitude of 30% in the PFC, ACC and insula using [18F] FEPPA radiopharmaceutical was higher in the ACC and insula of MDD patients with suicidal thoughts compared to patients without such intention. They also provided the first evidence that increased TSPO may be more associated with suicidality than the MDD diagnosis itself . Based on this, it was proposed that some microglia can induce apoptosis while others stimulate adult neurogenesis may account for the contradictory results can induce profound inflammatory response and interacts with serotonin metabolism and increases glutamate which all in turn can result in depressive mood . In line with this, a postmortem study reported reduced densities of glutamine synthetase expressing astrocytes in specific cortical gray matter areas in MDD in the hippocampus of depressed patients Are these glial changes represent the cause or the consequence of the disease? (2) Do these glial abnormalities relate to each other, or are they present in different subgroup of patients? Some argue that the different glial abnormalities are connected to each other. It has been proposed that the microglia mediated inflammatory processes can damage the oligodendrocytes and disrupt glutamate homeostasis by impairing astrocytic functions (Mechawar and Savitz, in vivo imaging data.BC had the concept and wrote the parts on the cellular and molecular findings. SAN wrote the parts on the The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Hyperinflation is a cardinal feature of COPD associated with reduced daily physical activity and increased mortality. Although bronchodilators and pulmonary rehabilitation have some effect many patients with COPD remain highly symptomatic.The most established treatment is lung volume reduction surgery and results from the NETT trial show improved survival in appropriately selected patients with upper lobe predominant disease and low exercise capacity which are sustained out to at least 7 years. There is a Grade A evidence for LVRS in ARTS/ERS COPD guidelines and patients should be being systematically assessed for potential suitability. The risk of adverse outcomes in modern practice appears to be less than in the NETT. The cost/QALY of LVRS is between $40,0000 and $50,000.Various other techniques are being assessed either to reproduce the effects of surgery with potentially fewer side effects or to enable lung volume reduction in different populations. Endobronchial valves prevent air entering a target lobe causing atelectasis and improving the function of other areas of lung. They do not work in the presence of interlobar collateral ventilation which occurs if the interlobar fissures are not intact. The BeLieVeR-HIFi and Dutch STELVIO studies have shown that valve placement improves lung function, exercise capacity and quality of life. They reduce dynamic hyperinflation, improve oxygen kinetics and chest wall synchrony and may produce a survival benefit. The estimated cost per QALY of endobronchial valves is 25,000 Euros.Airway coils tension the target area of lung preventing airway collapse and have shown promise in early results although sustained effects are modest. Other approaches are the use of steam to shrink target areas through contraction fibrosis and the use of fibrin glue.Airway bypass techniques should work in the presence of collateral ventilation but are limited by problems keeping them patent, so benefit is very short-lived.As the evidence base and experience with patient selection for different therapies develops it is important for patients with potentially treatable emphysema to be discussed in a multidisciplinary meeting including chest physicians, radiologists and surgeons."} +{"text": "Emergency medicine residency programs offer Emergency Medical Services (EMS) curricula to address Accreditation Council for Graduate Medical Education (ACGME) milestones. While some programs offer advanced clinical tracks in EMS, no standard curriculum exists. We sought to establish a well-defined EMS curriculum to allow interested residents to develop advanced clinical skills and scholarship within this subspecialty.Core EMS fellowship trained faculty were recruited to help develop the curriculum. Building on ACGME graduation requirements and milestones, important elements of EMS fellowship training were incorporated into the curriculum to develop the final document.The final curriculum focuses on scholarly activities relating to the four core areas of EMS identified by The American Board of Emergency Medicine and serves as an intermediary between ACGME graduation requirements for education in EMS and fellowship level training.Standardization of the EMS scholarly track can provide residents with the potential to obtain competency beyond ACGME requirements and prepare them for success in fellowship training and/or leadership within EMS on graduation. Emergency Medical Services (EMS) provides the initial medical evaluation and treatment for patients with acute medical emergencies. Patients with emergent conditions benefit from initial triage, treatment, and stabilization performed by pre-hospital providers resulting in both improved short and long-term clinical outcomes -2. TradiEmergency medicine training programs need a defined foundational curriculum in EMS, including on and off-line medical control, medico-legal aspects, communications, disaster management, and EMS structure, to ensure graduation of physicians competent in EMS medicine. Despite prior publications relating to EMS curricular design and the minimum training requirements determined by the Accreditation Council for Graduate Medical Education (ACGME) for emergency medicine residents specific for EMS, the training experiences completed by residents are variable -5. Such As with the specialty of emergency medicine, it will be years before the supply of EMS subspecialists meets the demand. Rural areas and uncompensated or poorly compensated EMS coverage areas will continue to face challenges in the recruitment of EMS trained medical directors. The National Association of EMS Physicians (NAEMSP) position statement on physician medical direction in EMS recommends that physicians be board certified or board prepared in emergency medicine with an active clinical practice and completion of an EMS fellowship. In addition, the NAEMSP statement lists training or significant experience in the clinical practice of pre-hospital EMS and the provision of both direct and indirect medical direction as requirements for EMS medical directors.\u00a0The statement includes the\u00a0requirement of knowledge in the broad array of pre-hospital medicine design, laws, and operation that exceed the minimum training required by the ACGME for emergency medicine residency completion .\u00a0OverallResident education and interest are the key to improving this situation. Presently, many ACGME graduating residents fail to meet NAEMSP recommendations for EMS directorship. Therefore, we need to enhance resident education and interest in this subspecialty.\u00a0By providing interested emergency medicine residents a focused track in EMS during their training, we might see improvement in not only the number of graduates pursuing fellowship training but also success and productivity of EMS fellows.\u00a0For residents who choose not to pursue fellowship training, niche based training during residency may strengthen their job application and foster interest in local involvement in EMS medicine .The purpose of the curriculum proposed in this report is to describe a structured curriculum that bridges the gap between minimum ACGME requirements for emergency medicine residents in EMS and the requirements for EMS fellowship training.\u00a0The goal of our longitudinal scholarly track in EMS medicine is to promote scholarship within EMS while encouraging residents to pursue continued training within the subspecialty.\u00a0Core education faculty members involved in our EMS curriculum were recruited along with interested residents to structure a scholarly track based on our current experience, ACGME requirements, and NAEMSP guidelines. A local needs assessment is institutionally variable in regards to available and necessary resources. At our institution, we identified EMS fellowship trained faculty mentorship, developed dedicated and available didactic time, and identified local EMS agencies able to participate in the curriculum. To ensure the curriculum was goal-directed, clear goals Table and objeThe final curriculum was established with additional requirements in the four core areas of EMS medicine: Clinical Aspects of EMS Medicine, Medical Oversight of EMS, Quality Management and Research, and Special Operations. The curriculum includes administrative, research, clinical, and educational domains expanding upon the basic residency requirements outlined by the ACGME Table .Collectively, the advanced track curriculum includes an additional 36 hours of EMS didactics, completion of defined EMS-related competencies, and required scholarly and quality improvement projects focused on EMS. Didactic sessions were based upon the Ohio American College of Emergency Physicians Medical Director's Course and the selected textbook readings provided in the appendix.Learners will receive biannual formative evaluation letters completed by track mentors providing detailed feedback in regards to track participation and specific opportunities for improvement. An annual summative review evaluation letter will be provided highlighting their performance and completion of scholarly track requirements. Ongoing annual assessment of the program will be performed by a focus group consisting of resident participants, residency program leadership, and track mentors. Identified opportunities for improvement will be addressed by a specific detailed plan developed by the focus group.The ACGME requirements for EMS training during an emergency medicine residency help establish a minimum competency in this domain. The implementation of an EMS specific advanced track curriculum can augment a program\u2019s traditional curriculum and provide expanded opportunities for resident learners . EducatiThe proposed curriculum presented builds upon ACGME emergency medicine requirements and mirrors aspects of the EMS Fellowship Guidelines . The EMSWe believe that in using the aforementioned format, we will produce residents with an enhanced competence in EMS, either ready to enter the workforce as a leader and participate in the activities of local EMS agencies or to excel in EMS fellowship programs. There are some emergency medicine residency programs that have EMS scholarly tracks in place, but no published standard curriculum exists. As with any curriculum, ongoing evaluation and refinement will be required . Future The main limitation of our curriculum design is the lack of prospective data looking specifically at outcomes such as resident satisfaction, scholarly output, or numbers of residents who graduate seeking fellowship in EMS or leadership opportunities in the field. Because the needs assessment is specific to our program, it will be difficult to generalize to other institutions; therefore, each program should perform its own needs assessment based on available resources. Moving forward, it is our goal to look at such data.\u00a0We also hope to collaborate with other institutions to ultimately develop a best practice for broad application.A focused EMS scholarly track permits interested residents to acquire further experience in EMS medicine, including the administrative tasks required in practice. Although a subset of residents may continue to build on the knowledge base acquired through an\u00a0EMS advanced track via a dedicated EMS fellowship, a scholarly track allows others to graduate residency with an enhanced ability to further develop their professional goals and serve as leaders in their local EMS medicine community. Given that no standard EMS advanced track curriculum exists, we attempted to define such a curriculum for standardized implementation. Future studies assessing the impact of the curriculum on learner satisfaction and EMS-based competency will be performed to determine areas of curricular improvement."} +{"text": "Craniofacial development is an extraordinarily complex process requiring the orchestrated integration of multiple specialized tissues such as the surface ectoderm, neural crest, mesoderm, and pharyngeal endoderm in order to generate the central and peripheral nervous systems, axial skeleton, musculature, and connective tissues of the head and face. How do the characteristic facial structures develop in the appropriate locations with their correct shapes and sizes, given the widely divergent patterns of cell movements that occur during head development? The patterning information could depend upon localized interactions between the epithelial and mesenchymal tissues or alternatively, the developmental program for the characteristic facial structures could be intrinsic to each individual tissue precursor. Understanding the mechanisms that control vertebrate head development is an important issue since craniofacial anomalies constitute nearly one third of all human congenital defects. This review discusses recent advances in our understanding of neural crest cell patterning and the dynamic nature of the tissue interactions that are required for normal craniofacial development."} +{"text": "Early diagnosis is an important aspect of contemporary cancer prevention and control strategies, as the majority of patients are diagnosed following symptomatic presentation. The nature of presenting symptoms can critically influence the length of the diagnostic intervals from symptom onset to presentation , and from first presentation to specialist referral . Understanding which symptoms are associated with longer diagnostic intervals to help the targeting of early diagnosis initiatives is an area of emerging research. In this Review, we consider the methodological challenges in studying the presenting symptoms and intervals to diagnosis of cancer patients, and summarize current evidence on presenting symptoms associated with a range of common and rarer cancer sites. We propose a taxonomy of cancer sites considering their symptom signature and the predictive value of common presenting symptoms. Finally, we consider evidence on associations between symptomatic presentations and intervals to diagnosis before discussing implications for the design, implementation, and evaluation of public health or health system interventions to achieve the earlier detection of cancer. Diagnosing cancer earlier is a critical aim of contemporary cancer control policies. Screening interventions can achieve asymptomatic detection but are currently only available for a limited number of cancer sites, and their effectiveness is further constrained by limited sensitivity and both suboptimal and unequal uptake. This means that the majority of cancer patients continue to be diagnosed following symptomatic presentation, for whom timely diagnosis is associated with better clinical and patient-reported outcomes Box 1symptom signature and diagnostic difficulty.In this Review, we make frequent use of two terms: Symptom signature denotes the nature and relative frequency of symptoms (or symptom combinations) reported at presentation by patients later diagnosed with a particular cancer diagnostic difficulty (of a given cancer site) has previously been used to characterize cancer sites as \u201charder-to-suspect\u201d or \u201ceasier-to-suspect\u201d based on the profile of presenting symptoms The term Alt-text: Box 1Substantial variation in measures of diagnostic timeliness exists between patients with different cancers We discuss methodological challenges in capturing data on symptoms at presentation and intervals to diagnosis and subsequently examine the symptom signatures of cancer sites and how this relates to diagnostic difficulty . DiagnosFinally, we summarize available evidence on the association between symptomatic presentations and diagnostic intervals and discuss how this evidence could inform the design of early diagnosis interventions.Capturing information on symptoms is challenging, as the majority cannot be objectively observed and their appraisal by individuals is influenced by sociocultural factors such as level of education and health literacy (including awareness of likely cancer symptoms), cancer fear, or fatalism Similar challenges exist when measuring prediagnostic intervals experienced by cancer patients. Existing methods rely on the validity of the recall of particular dates of significance along the diagnostic pathway including the date of symptom onset, the date of first relevant symptomatic presentation (help-seeking), and the date of first referral to secondary care Box 2Self-reported symptom information.Information on presenting symptoms can be directly elicited from patients through semistructured interviews Patients may be prompted to identify their presenting symptoms from a predefined list (symptom recognition) or to describe them without any prompting , which can affect the degree of recall inaccuracies or bias. Prompting patients to consider their symptom status in respect of calendar \u2018landmark\u2019 dates may be helpful Records-based symptom information.Alternatively, information on presenting symptoms can be recorded during healthcare encounters and captured as part of the patients' health records In principle, studies collecting symptom information from patient records are less prone to the risk of selection and recall bias, as information on presenting symptoms is collected prospectively and prior to diagnosis for all patients. However, such methods critically rely on the symptoms both being elicited during the consultation and being accurately recorded; in many instances, these assumptions may not be met Alt-text: Box 2Two principal study designs have been described to examine diagnostic intervals: collecting self-reported information from patients and extracting information from patients' health records Box 3MethodologyWe searched for studies describing the frequency of presenting symptoms of cancer patients based on either primary care records or prospectively collected self-reported information, supplemented by expert knowledge of relevant evidence. Studies describing self-reported symptoms captured retrospectively (after diagnosis) were excluded due to the high risk of bias. Studies on pediatric, teenager, and young adult cancer patient populations and studies based in low- and middle-income settings were excluded as they were deemed not comparable. All retrieved studies providing evidence regarding the symptom signature of a cancer site were additionally examined for information on associations between symptoms and diagnostic intervals.There is no standard assessment tool for risk of bias in observational nonrandomized studies, and so we developed a risk of bias tool based on the REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) and the Quality Assessment of Diagnostic Accuracy Studies 2nd version (QUADAS-2) checklists Summary of findingsWe identified a total of 41 studies including information on presenting symptoms for 16 cancer sites . All included studies were based in the UK and were mostly case-control or cohort studies examining the predictive value of symptoms: for such studies, the sample size and symptom frequency relevant to cases (and not controls) were extracted. Of the included studies, 18 (44%) had low risk of bias across all examined dimensions, while 11 studies had high risk of bias across two dimensions (study population and symptom information) (Table S2). Nearly all studies focused on single cancer sites, with the exception of colorectal, esophagogastric, and renal tract cancers, which were treated as single entities, respectively No evidence on the frequency of presenting symptoms before diagnosis could be identified for the following 12 cancers: laryngeal cancer; liver cancer; melanoma; mesothelioma; oral cancer; penile cancer; sarcoma; small intestinal cancer; testicular cancer; thyroid cancer; vaginal cancer; and vulval cancer.Of the 41 studies included in the Review, only four also contained evidence on associations between individual symptoms and intervals to diagnosis Alt-text: Box 3Understanding the nature and relative frequency of presenting symptoms associated with different cancer sites is necessary before investigating how symptoms may influence diagnostic timeliness. We therefore reviewed the literature to examine the symptom signature of common and rarer cancers see and presIn this category, we consider several cancers where the majority of patients present with one symptom with adequately strong association with a given cancer . For example, the majority of women diagnosed with breast cancer initially present with a breast lump, which is associated with a relatively high predictive value for cancer; see Likewise, the symptomatic presentations of thyroid cancer, melanoma, testicular cancer, penile cancer, vaginal cancer, vulval cancer, and sarcoma are also narrow and are likely to have meaningfully high predictive values, although empirical documentation of the symptom signatures of these cancers is limited In this category, we consider cancer sites characterized by a broad symptom signature. For some cancers, this includes certain alarm symptoms , while for other cancers, presenting symptoms are chiefly nonspecific .Many common cancers have broad symptom signatures consisting of multiple symptoms, of which only few (e.g. one or two) are alarm symptoms that are strongly predictive of cancer. For example, eight studies report rectal bleeding, which has relatively high predictive value, as a common presenting symptom of colorectal cancer, although estimates vary substantially (16%-60%) We identified six studies describing the frequencies of the presenting symptoms of pancreatic cancer (Table S3.9) Current data on the symptom signatures of esophageal and gastric cancers are limited to studies that describe them in combination (Table S3.7) Likewise, ovarian cancer has a symptom signature encompassing a broad spectrum of abdominal symptoms, although existing evidence tends to be based on smaller study populations due to the low incidence of this cancer (Table S3.8) Some cancers have broad symptom signatures comprising almost entirely symptoms of low predictive value. Results from four studies indicate that hematological cancers have such symptom signatures, comprised of vague or nonlocalizing symptoms such as fatigue and weight loss or common complaints such as back pain (Table S13-15) Although a proportion of patients with brain cancer are diagnosed after an acute event such as a seizure or neurological deficit, most patients are thought to initially experience nonspecific symptoms, with very low predictive value [87]. AcTo date, there has been limited examination of individual cancer symptoms and time to diagnosis. The majority of available evidence is based on the analysis of health records, and symptoms are often aggregated into broad categories for analysis. For example, patients with alarm symptoms across a range of cancers have been shown to experience shorter diagnostic intervals (time from symptomatic presentation to diagnosis) compared to those with nonalarm symptoms Box 4Data from three SYMPTOM studies in England on lung, colorectal, and pancreatic cancers provide some early insights into variation in intervals to diagnosis by individual symptoms The multicenter DECCIRE study used a comparable design to collect information on the diagnostic process for 795 colorectal cancer patients in Spain The presenting symptoms of breast cancer and associated patient and primary care intervals have been examined using primary care data in England Alt-text: Box 4Available evidence on individual symptoms and diagnostic timeliness is currently limited to four cancers and is derived from study designs that combine prospectively collected patient information with primary and secondary care records, or examine data collected as part of clinical audit initiatives see . ExpandiMeasuring presenting symptoms and intervals before the diagnosis of cancer in patient populations is challenging. Currently, there are two main approaches: self-report versus records-based information. We identified 41 population-based studies describing information on the symptom signatures of 16 common and rarer cancers. Based on our findings, we described these symptom signatures as narrow , broad comprising cancers with some highly predictive symptoms , or broad comprising cancers characterised by mostly nonspecific symptoms. Evidence on how presenting symptoms relate to prediagnostic intervals was limited, but emerging findings indicate notable variation that could be used to guide interventions.We have reviewed the interrelated concepts of symptom signature and diagnostic difficulty, the latter being an expression of symptom-specific predictive values. It should be acknowledged however that organizational or system factors can also influence the difficulty of diagnosis of a particular cancer site. For example, both the availability and the accessibility of different clinical investigations may influence the diagnostic difficulty of a cancer. Full blood counts can be more readily ordered than paraprotein studies in primary care; therefore, leukemia may be investigated with a lower threshold of cancer suspicion than myeloma and has lower overall diagnostic difficulty. Given the likely variation across countries in diagnostic activity and access to investigations, international comparisons through collaborative efforts such as the International Cancer Benchmarking Partnership (ICBP) could be valuable Further, some presenting symptoms such as jaundice are likely to represent advanced disease. In these patients, diagnostic difficulty could be minimal, but expediting their diagnosis may not necessarily lead to favorable clinical outcomes or alter prognosis. Understanding associations between symptoms and stage at diagnosis is an important area for future research There was substantial variation in reported symptom frequencies between studies, reflecting the heterogeneity in how symptom information was reported, extracted, and collated. Optimizing data capture by improving the application of existing clinical coding systems (and physician compliance) is important, particularly as novel technologies such as machine learning and natural language processing are used to extract information from electronic health records a priori) either from relevant literature or clinical guidelines. Rarer or less-specific symptoms might not have been captured and reported symptom frequencies may not be fully representative of the symptomatic patient population. Examining all presenting symptoms of a cohort of cancer patients without prior restrictions can bring valuable insights Many of the studies included in this Review investigated patients with prespecified symptoms (identified Most patients with cancers characterized by a narrow symptom signature (such as breast and bladder cancer) experience relatively short intervals to help-seeking Postpresentation, patients with alarm symptoms are likely to benefit from fast-track diagnostic assessment pathways In conclusion, the diagnostic difficulty of a cancer is closely tied to its symptom signature. Expanding current scientific knowledge about the nature of presenting symptoms and how they are associated with diagnostic intervals will further our understanding of mechanisms that influence the diagnostic pathway at patient, healthcare professional, and system levels. Doing so will strengthen the evidence base to support the development and implementation of public health and healthcare interventions promoting early diagnosis, thereby resulting in improved outcomes for cancer patients.UK Department of Health [grant number no. 106/0001]. This work was part of the program of the Policy Research Unit in Cancer Awareness, Screening and Early Diagnosis. The Policy Research Unit in Cancer Awareness, Screening, and Early Diagnosis receives funding for a research program from the Department of Health Policy Research Programme. It is a collaboration between researchers from seven institutions . G. L. is supported by a Cancer Research UK Advanced Clinician Scientist Fellowship [grant number: C18081/A18180]. F. M. W. is supported by a National Institute for Health Research (NIHR) Clinician Scientist award. The views expressed are those of the authors and not necessarily those of the Department of Health, Cancer Research UK, or NIHR.This work was supported by a grant from the"} +{"text": "Bone targeted treatments have transformed the quality of life and physical functioning of patients with metastatic bone disease and, in certain circumstances, have been shown to prevent the development of bone metastases and improve survival. However, the steps in development of these agents have been somewhat disjointed and based on good fortune as well as scientific endeavour and rational clinical development.Although bisphosphonates were first synthesised in the late 19th century, initial usage was restricted to a range of industrial processes and their potential clinical relevance was not appreciated until the late 1960s The early trials focused on the use of etidronate and clodronate with some success In the 1980s, small trials with oral clodronate and oral pamidronate had suggested useful effects on skeletal morbidity in breast cancer and multiple myeloma In the late 1990s, more potent bisphosphonates were developed; both oral ibandronate and intravenous zoledronic acid were evaluated with the latter showing slight superiority over pamidronate for breast cancer patients There have been great strides in our understanding of the biology of bone metastases and the regulation of bone cell function. This included the discovery of RANK ligand For several decades there has been interest in the potential of bone-targeted agents, through their profound effects on bone physiology, to modify the process of metastasis and have effects on important disease outcomes such as recurrence and survival In a recent initiative with the Early Breast Cancer Clinical Trials Group (EBCTCG), individual patient data from around the world were collected to enable a meta-analysis of 18,766 women included in randomised trials that evaluated the effect of an adjuvant bisphosphonates on breast cancer outcomes Denosumab also has some beneficial effects on the underlying disease with evidence of modest activity in delaying the development of bone metastases in prostate cancer patients with rising PSA levels despite androgen deprivation therapy (ADT) Finally, the knowledge obtained from studies of bone-targeted treatments in osteoporosis has been applied to the cancer setting. Many patients, notably breast cancer patients receiving aromatase inhibitors or experiencing chemotherapy induced premature menopause and men with prostate cancer receiving ADT experience rapid bone loss due to the resultant suppression of circulating oestradiol levels and are at increased risk of fragility fractures. Both bisphosphonates In the future we can expect to see the currently available bone-targeted agents applied increasingly widely across multiple disease settings with further gains in quality of life and, potentially in some disease settings, improvements in disease outcomes with fewer bone recurrences and improved patient survival. Additionally, new bone-targeted agents such as radium-223 are already being incorporated into the management of advanced prostate cancer"} +{"text": "Neutrophils are the most abundant leukocyte in humans and they are among the first white cells recruited to infected tissues. These leukocytes are essential for the innate immune response to bacteria and fungi. Inasmuch as neutrophils produce or contain potent microbicides that can be toxic to the host, neutrophil turnover and homeostasis is a highly regulated process that prevents unintended host tissue damage. Indeed, constitutive neutrophil apoptosis and subsequent removal of these cells by mononuclear phagocytes is a primary means by which neutrophil homeostasis is maintained in healthy individuals. Processes that alter normal neutrophil turnover and removal of effete cells can lead to host tissue damage and disease. The interaction of neutrophils with microbes and molecules produced by microbes often alters neutrophil turnover. The ability of microbes to alter the fate of neutrophils is highly varied, can be microbe-specific, and ranges from prolonging the neutrophil lifespan to causing rapid neutrophil lysis after phagocytosis. Here we provide a brief overview of these processes and their associated impact on innate host defense. Neutrophils are the primary cellular defense against infections caused by bacteria and fungi. These phagocytes are the most numerous leukocyte in humans and are mobilized rapidly from the bloodstream and/or bone marrow reserves to infected tissues. At sites of infection, neutrophils phagocytose microbes, which in turn are killed by reactive oxygen species (ROS) and antimicrobial peptides and proteases , and this process is accompanied by nuclear chromatin condensation, DNA fragmentation, and cytoplasmic vacuolation delay neutrophil spontaneous apoptosis, effectively increasing neutrophil numbers during early stages of inflammation and thus providing ample opportunity for clearance of invading pathogens are elicited by many conditions, including interaction with microbial pathogens. NETs can form from viable cells or by cytolysis, and are characterized by filamentous web-like structures that consist of extruded DNA that are ornamented with neutrophil granule enzymes and histones to elongated hyphae or large sporulating structures such as the Coccidioides immitis spherule (~10\u2013200 microns). Particle size is an additional and important consideration for efficient neutrophil phagocytosis. Consistent with the opportunistic lifestyle, there are numerous reports indicating that fungal pathogens such as Candida albicans are readily ingested and killed by neutrophils works through the lipoxin A4 receptor (ALX or FPLR-1) that paradoxically induces anti-inflammatory signals while simultaneously accelerating the rate of phagocytosis of parasites by neutrophils of promastigotes becomes apoptotic with impaired phagocytic capacity and ROS production has been reported in blood samples of patients with visceral leishmaniasis has been shown to activate nuclear factor-kappa B (NF-\u03baB) and phosphatidylinositol 3-kinase (PI3K), which subsequently increases expression and stabilization of Mcl-1 protein and ultimately results in inhibition of neutrophil apoptosis . Possible outcomes for neutrophils following interaction with bacteria, fungi, parasites, and viruses are summarized in Figure All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer WMN and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review."} +{"text": "Rates of morphological evolution vary across different taxonomic groups, and this has been proposed as one of the main drivers for the great diversity of organisms on Earth. Of the extrinsic factors pertaining to this variation, ecological hypotheses feature prominently in observed differences in phenotypic evolutionary rates across lineages. But complex organisms are inherently modular, comprising distinct body parts that can be differentially affected by external selective pressures. Thus, the evolution of trait covariation and integration in modular systems may also play a prominent role in shaping patterns of phenotypic diversity. Here we investigate the role ecological diversity plays in morphological integration, and the tempo of shell shape evolution and of directional asymmetry in bivalved scallops.Overall, the shape of both valves and the magnitude of asymmetry of the whole shell are traits that are evolving fast in ecomorphs under strong selective pressures , compared to low rates observed in other ecomorphs . Given that different parts of an organism can be under different selective pressures from the environment, we also examined the degree of evolutionary integration between the valves as it relates to ecological shifts. We find that evolutionary morphological integration is consistent and surprisingly high across species, indicating that while the left and right valves of a scallop shell are diversifying in accordance with ecomorphology, they are doing so in a concerted fashion.Our study on scallops adds another strong piece of evidence that ecological shifts play an important role in the tempo and mode of morphological evolution. Strong selective pressures from the environment, inferred from the repeated evolution of distinct ecomorphs, have influenced the rate of morphological evolution in valve shape and the magnitude of asymmetry between valves. Our observation that morphological integration of the valves making up the shell is consistently strong suggests tight developmental pathways are responsible for the concerted evolution of these structures while environmental pressures are driving whole shell shape. Finally, our study shows that directional asymmetry in shell shape among species is an important aspect of scallop macroevolution.The online version of this article (10.1186/s12862-017-1098-5) contains supplementary material, which is available to authorized users. It has long been observed that rates of morphological evolution vary across different taxonomic groups \u20133 and vaEcological hypotheses feature prominently in observed differences in phenotypic evolutionary rates across lineages. Transitioning from one ecological niche to another can promote changes in the tempo of morphological evolution by either limiting morphological diversification or substantially accumulating change e.g., , 21\u201324).\u201324.21\u201324In some cases, external selection pressures can act differentially on separate traits of the same individual, resulting in variability in the rates of phenotypic evolution within organisms e.g., , 33\u201336).\u201336.33\u201336Morphological evolution of bivalved scallops (Pectinidae) is strongly influenced by ecological niche shifts \u201346, and The scallops are also an attractive system with which to examine evolutionary morphological integration. The bivalve shell is a simple modular system comprised of two valves attached with a hinge on the dorsal side. This two-valved arrangement poses an interesting challenge to studying morphological evolution, as bivalved animals can have both object symmetry as well as matching symmetry . Note thHere we investigate the role ecological diversity plays in morphological integration and tempo of shell shape evolution and directional asymmetry in scallops. We estimate the magnitude of morphological integration in scallop shell shape across species, and examine how the strength varies among ecomorphs to understand how the complex shell is evolving in response to changing ecological demands. Then we estimate the tempo of evolution in three traits: the left valve shape; the right valve shape; and the difference in shape between valves (amount of asymmetry), which is a trait representing the whole shell. With these estimates, we test whether the tempo of morphological change differs among ecomorphs, and whether there are within-shell differences in rates . We predict substantial differences of morphological integration and tempo among ecomorphs because of the differing functional constraints imposed by the life habit, the degree of exposure each valve contends with, and the different roles of the left and right valves. Further, we expect particularly high rates of morphological change and stronger integration in gliding and recessing species because these ecomorphs have been previously identified to be under strong natural selection \u201346. We cWe sampled shells from 1081 adult individuals for 123 species and spanning the range of ecomorphs of the first PLS axis of each valve. The rPLS was calculated for all 86 species using species mean shapes, as well as for each ecomorph (excluding the single nestling species). Each test was statically assessed by a permutation procedure (1000 permutations each). To test whether the strength of integration differs between ecomorphs, we compared their effect sizes (Z-scores), which provides a standardised measure of the strength of integration in each dataset for formal quantitative comparisons ).Pedum spondyloideum, is an obligate commensal, where the scallop settles on and then becomes encased as the living scleractinian corals grows around it [With respect to the pace of evolutionary change, the tempo of the three shell traits along the branches of the phylogeny all present a similar pattern among ecomorphs: rates are high in gliding, recessing and nestling species, while comparatively low for the other ecomorphs. This is particularly conspicuous in the shape of the right valve and thus overall shell asymmetry Figs.\u00a0 & 4. Theround it . Within round it . Higher round it , which sAP M\u00f8ller and A Pomiankowski proposedFinally, placing our results here in the context of a growing body of macroevolutionary work on scallops \u201346 proviOur study on scallops adds another strong piece of evidence that ecological shifts play an important role in the tempo and mode of morphological evolution. The results presented here suggest that strong selective pressures from the environment, inferred from the repeated evolution of distinct ecomorphs, have influenced the rate of morphological evolution in scallop valve shape and the magnitude of asymmetry between left and right valves. We observed strong morphological integration between the two valves comprising the shell, and this is consistent across all ecomorphs, which suggests there are distinct, evolutionarily conserved developmental pathways responsible for the concerted evolution of these structures even though environmental pressures are driving whole shell shape. In conclusion, an interplay and morphological integration and directional asymmetry in shell shape among species have played an important role in scallop macroevolution."} +{"text": "Humans have modified planet Earth extensively, with impacts ranging from reduced habitat availability to warming temperatures. Here we provide an overview of how humans have modified the nutritional physiology and ecology of wild organisms, and how nutrition is vital to successful conservation practices. in situ and ex situ conservation. Though we find that the changes in the nutritional ecology and physiology of wildlife due to human alterations are typically negative and largely involve impacts on foraging behaviour and food availability, the extent to which these will affect the fitness of organisms and result in evolutionary changes is not clearly understood, and requires further investigation.Over the last century, humans have modified landscapes, generated pollution and provided opportunities for exotic species to invade areas where they did not evolve. In addition, humans now interact with animals in a growing number of ways (e.g. ecotourism). As a result, the quality (i.e. nutrient composition) and quantity (i.e. food abundance) of dietary items consumed by wildlife have, in many cases, changed. We present representative examples of the extent to which vertebrate foraging behaviour, food availability and digestive physiology have been modified due to human-induced environmental changes and human activities. We find that these effects can be quite extensive, especially as a result of pollution and human-provisioned food sources (despite good intentions). We also discuss the role of nutrition in conservation practices, from the perspective of both In the last century, humans have modified the global landscape to accommodate the growing human population . As a reIn recent years, two fields of nutrition have grown significantly . They arin situ and ex situ conservation. We focus on vertebrates given their imperilled status , and consider how each of these modifications may affect the acquisition, availability and digestion of food for vertebrates. We additionally present representative examples that demonstrate the extent to which humans can impact the nutrition of wild vertebrates. We address how nutrition has been used in the context of Humans have altered the planet in many ways including through climate change, pollution, habitat alteration and the introduction/translocation of new species is affected by both body size and climatic indices had reduced capture rates of benthic prey and slower growth rates consumed a lower diversity and abundance of benthic prey and had lower condition (Lepomis macrochirus) showed reduced feeding rates under increased turbidity increased feeding on plankton at low turbidity but decreased feeding at high turbidity (Rutilus rutilus) . TurbidiPlatorchestia smithi) and littering . Zebra mussels modify the concentration of nutrients and the community of algae in whole ecosystems (Bufo marinus) were introduced to deal with plant pests, but their presence has had many unintended consequences. For example, northern trout gudgeon (Mogurnda mogurnda) exposed to cane toad tadpoles showed reduced rate of consumption of native tadpoles (Carassius auratus) and common carp (Cyprinus carpio), increase water turbidity through the mechanical actions of foraging, thus affecting the foraging success of other aquatic species (see \u2018Pollution\u2019 section) spend less time foraging when exposed to traffic noise was largely unaffected by low frequency sounds which are typical of cargo ships and oil development infrastructure (Fringilla coelebs) to increase vigilance (scanning for predators) and decrease food intake (Gasterosteus aculeatus) . Howeveruleatus) . The conuleatus) , but fewHaematopus ostralegus) led to less time spent foraging and reduced food intake for the parents, and decreased the proportion of food allocated to the chicks (Circus aeruginosus), disturbance by fisherman, passers-by, dogs, and vehicles also resulted in lower food provisioning and higher nutritional stress in chicks (Ursus arctos) showed minimal effects of human presence as they altered their behaviour to maintain food intake and body condition were disturbed, they often abandoned kills, spent less time at the kill when they stayed and consumed less meat (Cervus elaphus) fled in response to skiers, often moving upslope to areas with poorer quality vegetation rarely fed at salmon carcasses when disturbed while glaucous-winged gulls (Larus glaucescens) fed more, indicating gulls were more wary of the dominant heterospecific than of people or on purpose spent less time foraging and had higher reproduction but also increased aggression while feeding on garbage (Papio anubis) with access to garbage also spent less time foraging and had higher body condition and lower levels of parasite infection than naturally-foraging groups (Cyanocitta stelleri) utilizes anthropogenic food at campsites, and though the effects on the jay\u2019s nutrition are not known, access to this food source may result in increased predation on the endangered marbled murrelet (Brachyramphus marmoratus) . Many cosmopolitan opportunistic species such as gulls, rats and foxes have benefited greatly from these food subsidies, showing improved body condition and reduced susceptibility to pathogens (reviewed in moratus) . When fomoratus) . Thus thPapio ursinus) where these injuries also hindered their foraging efficiency aims to manage and protect species in natural habitats (Notiomnystis cincta) with carbohydrates to increase reproductive success (Macaca tonkeana) can help reduce damaging crop raiding behaviours , which was put under the Endangered Species Act in 1989 due to huge population declines , it is increasingly apparent that the importance of ex situ conservation is growing, as extinction rates continue to rise and are exacerbated by climate change hatchlings and juveniles grew more rapidly when fed diets high in protein than when fed lower protein diets (Odocoileus hemionus), diets supplemented with feed concentrates, oats and barley resulted in increased body mass and antler size, as well as earlier breeding and a decrease in fawn mortality to learn the location of food is essential to the growth and reproductive success of vertebrates. In fact, the physiological component of reproduction and sexual behaviour is extremely sensitive to the intake of metabolic fuels . ProteinBox 2.Panthera tigris) are a globally endangered species that have suffered huge population losses as a result of human presence Tigers (Box 3.Strogops habroptilus) is a large, flightless parrot endemic to New Zealand. It was put on the critically endangered list in 1989, largely due to catastrophic population declines caused by introduced mammalian predators (Image by Milena Scott)The kakapo ; and they now ingest more pollutants than they used to. All of these changes to nutritional intake can influence the reproductive capacity, growth and overall survival of wild animals. Our current understanding of the long-term effects of such modifications are poorly understood, and we urge for more research to consider the impacts that changing nutrition may have on animals in the long term as part of a broader conservation physiology approach . By undeThis work was supported by the Natural Sciences and Engineering Research Council of Canada [315 774-166] and the Canada Research Chairs program. D.R. is supported by Australian Research Council Linkage Grant [Project ID: LP 140100235]."} +{"text": "Cylindrospermopsis raciborskii, and the biomass of macrozooplankton and microbial food web components did not increase. In October, the same addition of nutrients stimulated growth of small edible Lyngbya spp., and there were coincident increases in biomass of macrozooplankton and components of the microbial web. Past generalizations that cyanobacteria blooms inhibit growth of other food web components may not always hold true.During two controlled enclosure experiments using water from a subtropical lake, the plankton food web displayed a highly variable response to combined addition of nitrogen and phosphorus. In July, the nutrients stimulated growth of"} +{"text": "Brazil, Chile, Colombia,and Mexico are well positioned to build this workforce. Role implementationbarriers include lack of role clarity, legislation/regulation, education, funding,and physician resistance. Strong nursing leadership to align APN roles with policypriorities, and to work in partnership with primary care providers and policymakers is needed for successful role implementation. given the diversity of contexts across nations, it is important to systematicallyassess country and population health needs to introduce the most appropriatecomplement and mix of APN roles and inform implementation. Successful APN roleintroduction in Latin America and the Caribbean could provide a roadmap forsimilar roles in other low/middle income countries. We examined literature related to APN roles, their global deployment, and APNeffectiveness in relation to universal health coverage and access to health. Theexamination of APN roles was limited to the clinical nurse specialist (CNS) and thenurse practitioner (NP). The article begins with a summary of the WHO\u2019sUniversal health coverage aims to strengthen health care delivery systems to promoteaccess to care and improve health outcomes especially for disadvantaged populations.It involves the financing of health systems to ensure 1. the availability ofcomprehensive and high quality health services including promotion, prevention,treatment, rehabilitative and palliative care; and 2. equitable access to theseservices, regardless of social circumstances, without risk of financial hardship-Although much progress has been made in Latin American countries to improve healthcare and implement varied financial models for universal health coverage, equitableaccess to health and essential primary health care remains elusive for millions ofpeople in the region) emphasized the need to develop specialized nursing and APN roles withthe core competencies to meet population health and health services needs inrevitalized primary health care systems. PAHO echoed this recommendation withResolution CD 52.R13 to include advanced practices nurses as one part of an overallstrategy to increase the primary health care workforce in Latin America,-Recognition of the need to strengthen primary health care worldwide dates back to theDeclaration of Alma-Ata in 1978 and has been reinforced in subsequent policies suchas the WHO Resolution WHA62.12-The International Council of Nurses (ICN), defines an advanced practice nurse as a\u201cregistered nurse who has acquired the expert knowledge base, complex decision-makingskills and clinical competencies for expanded practice, the characteristics of whichare shaped by the context and/or country in which she/he is credentialed to practice.A master\u2019s degree is recommended for entry level\u201d-The impetus for APN roles is contextually driven at the country and/or organizationallevel. Internationally, this has resulted in some confusion about what constitutesthe role and a plethora of role titles. One international survey identified 52different APN role titles such as the clinical nurse specialist (CNS), nursepractitioner (NP), advanced practice nurse, nurse specialist, nurse consultant, nursemidwife, and nurse anesthetist-The actual extent of global APN role deployment is not known. The introduction of APNroles is at different stages of development across countries and inconsistentmechanisms for regulating and thus identifying nurses in the role, make it difficultto monitor and track practice patterns. According to the ICN-,,,-Improving health outcomes and increasing access to health care in rural and remotecommunities and for vulnerable populations in urban communities have been initial drivers for the introduction of NPsin primary health care settings-,-APN roles are at an early stage of development in Latin America and theCaribbeanAt this time, Latin American countries at the greatest state of readiness tointroduce APN roles for primary health care are Brazil, Chile, Colombia and Mexico.Nursing leaders from these countries recently met with their counterparts from Canadaand the United States to determine strategies for development of APN competencies andcurricula,,-,--,Barriers to the introduction of APN roles in Latin America and Caribbean countriesare similar to those reported in the international literature including role clarity,legislation, regulation, education programs and resources, funding, and physicianresistance,,,,,,Other challenges for introducing APN roles for primary health care in most LatinAmerican countries is a general shortage of nurses and a high proportion oftechnically trained nurses compared to degree preparedprofessional nurses in the workforce to draw on for further developmentUniversal health coverage is dependent on adequate financing which is difficult toachieve for all countries, but especially those with low and middle incomes, due torising health care costs. In Latin America and the Caribbean, inadequate financing ofuniversal health coverage in some countries has contributed to a mix of public andprivate insurance plans, high out-of-pocket expenses and inequitable access to timelyand high quality care for the unemployed, poor and vulnerable populationsOne strategy is to offset the costs of financing universal health care coverage bygaining efficiency in health care. The WHO has provided ten recommendations forreducing the 40% of health care spending that is wasted through inefficiency,--Multiple systematic reviews have demonstrated that CNSs and NPs are safe andeffective health care providers. In relation to health care service use, CNSs and NPsmay achieve cost savings through: shorter hospital lengths of stay and reducedhospital readmissions for the elderly and patients transitioning from hospital tohome,,,,--Relevant to appropriate staff mix, as substitutes for other providers to address workforce shortages, CNSs and NPs achieve equal or betterhealth outcomes and satisfaction with care in inpatient and outpatient settings andfor transitional care,--Other studies indicate that CNSs help support the development of a motivatedworkforce by promoting staff satisfaction,-Compared to usual care, CNSs and NPs also improve access to health by achievingbetter health outcomes for a broad range of patient populations in varied practicesettings. Older adults receiving APN care in ambulatory care for dementia or chronicheart failure or those in long term care settings have reduced mortality rates andimproved health outcomes related to depression, aggressive behavior, incontinence,and pressure ulcers-If the process is done well, the introduction of APN roles in Latin America and theCaribbean could provide a roadmap or template for introducing these roles in low andmiddle income countries where few such roles exist. To achieve optimal impact forimproving universal health coverage and access to health, a systematic approach toAPN role introduction is required to determine patient populations and communitieswith unmet health and health service needs and where the greatest gains in healthoutcomes, health care efficiency and health systems improvement can be madeThe framework also applies principles for effective health human resource planning todetermine the type of APN role, the optimal complement and mix of other health careproviders, and how the role will interact with other health care team members toachieve identified goals and related outcomes-,-Given the overall shortage of nursing and other provider roles in primary health carein most countries, it will be important to consider the introduction of APN roleswithin the context of creating a primary health care workforceThe PEPPA framework also integrates planning steps to identify potential barriers andoptimize enablers to effective APN role implementation related to stakeholder and APNeducation, recruitment and retention, and health care policies including legislationand regulationAs outlined above, there are a multitude of systematic reviews of the internationalliterature, predominately from high income countries, confirming that CNSs and NPsare safe and effective health care providers. Within the context of APN roleintroduction in Latin America and the Caribbean, research and the use of otherevaluation methods will be required to ensure the effective use, optimalimplementation and long-term sustainability of these roles. A major challenge in someLatin American countries is the lack of good baseline workforce and health caresystem data to inform the introduction and design of APN roles and to supportsubsequent evaluationsThere is a substantive body of international evidence about the positive impact of APNroles for improving patient health outcomes, quality of care and health systemefficiency. The implementation of these roles can address country needs to improveuniversal health coverage and universal access to health in Latin America and theCaribbean. Several middle and high income Latin American countries with access tograduate nursing education are posed to introduce these roles. Other important elementsin place to support APN role introduction in these countries include the alignment ofAPN outcomes with health care policies for primary health care reform and a developingcoalition of nursing leaders across health care, academic, and health policy sectorsboth within and external to Latin American countries. Further expansion to engage otherintersectoral leaders will be required to move the APN agenda forward."} +{"text": "The Editorial on the Research TopicThird-Generation Neuroimaging: Translating Research into Clinical UtilityAs yet, no reliable structural or functional brain marker has been univocally associated with any psychiatric disorder, and no clinical applications have been developed in psychiatric neuroimaging \u20134. ThereSilverstein et al.), autism spectrum disorder , or suicidal behavior , or how they may help to predict the cognitive enhancing effect of pharmacological agents across disorders (van Amelsvoort and Hernaus) or psychotherapeutic interventions in patients with ADHD and schizophrenia and comorbid substance misuse problems . However, one article also emphasizes the importance of further second-generation imaging to investigate specific symptoms in a systematic manner before third-generation imaging can be informed (de Cates and Broome). Further contributions are suggesting advanced optical topography , 18F-FDG PET , or EEG microstates or beta oscillation analyses (Ghorashi and Spencer) as promising approaches to guide third-generation imaging across disorders or in schizophrenia , while others argue for the fusion of multimodal imaging modalities . Multimodal approaches, which integrate brain activation and connectivity patterns with metabolic measurements, are also proposed to gain a better understanding of the neuropathology underlying basic symptom in psychosis . The current Research Topic also reveals the clinical utility of machine learning methods using multimodal imaging data in identifying individuals at high risk for psychosis and predicting outcomes across psychiatric populations , as well as of real-time fMRI in treating symptoms of PTSD and auditory\u2013verbal hallucinations in schizophrenia . Finally, this topic outlines a theoretical framework how Hierarchical Bayesian Models of functional neuroimaging data may help to establish diagnostic test in autism spectrum disorder .The aim of this research topic is to provide the field with an overview of current third-generation neuroimaging approaches in translational psychiatry that is hoped to improve and create therapeutic options for psychiatric diseases. This Research Topic includes articles indicating the potential of specific network connectivity analyses for inferring on the pathophysiological mechanisms of schizophrenia (This issue is intended to provide a useful framework for further third-generation imaging investigations aiming at predicting clinical outcomes, such as transition, remission, and treatment responses in early phases of different psychiatric diseases. These types of analyses might help to improve and develop novel therapeutic scenarios. We would like to thank all the authors and reviewers for their valuable contributions, as well as the Editorial Office for their help in the editing process.All authors listed have made substantial, direct, and intellectual contribution to the work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Functional Magnetic Resonance Imaging (fMRI) has consistently highlighted impaired or aberrant functional connectivity across brain regions of autism spectrum disorder (ASD) patients. However, the manifestation and neural substrates of these alterations are highly heterogeneous and often conflicting. Moreover, their neurobiological underpinnings and etiopathological significance remain largely unknown. A deeper understanding of the complex pathophysiological cascade leading to aberrant connectivity in ASD can greatly benefit from the use of model organisms where individual pathophysiological or phenotypic components of ASD can be recreated and investigated via approaches that are either off limits or confounded by clinical heterogeneity. Despite some obvious limitations in reliably modeling the full phenotypic spectrum of a complex developmental disorder like ASD, mouse models have played a central role in advancing our basic mechanistic and molecular understanding of this syndrome. Recent progress in mouse brain connectivity mapping via resting-state fMRI (rsfMRI) offers the opportunity to generate and test mechanistic hypotheses about the elusive origin and significance of connectional aberrations observed in autism. Here we discuss recent progress toward this goal, and illustrate initial examples of how the approach can be employed to establish causal links between ASD-related mutations, developmental processes, and brain connectional architecture. As the spectrum of genetic and pathophysiological components of ASD modeled in the mouse is rapidly expanding, the use of rsfMRI can advance our mechanistic understanding of the origin and significance of the connectional alterations associated with autism, and their heterogeneous expression across patient cohorts. Despite caveats, in the next few years the approach is poised to offer breakthroughs in our understanding of the pathogenesis of ASD-related connectivity aberrancies, possibly bringing some order to the intricate and often contradictory body of research detailing connectional alterations in patient populations.AG conceived and wrote the manuscript with input from AL.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Major depressive disorder (MDD) affects a significant number of adolescents today. Its consequences mandate close attention in clinical practice. While tricyclics and monoamine oxidase inhibitors (MAOIs) have been used infrequently and with questionable efficacy, selective serotonin reuptake inhibitors (SSRIs), particularly fluoxetine, consistently have been shown to be of benefit in treating outpatient adolescents with MDD. Despite some success with other drugs in its class, fluoxetine remains the only SSRI that is FDA approved for treatment of children and adolescents with depression. A review of recent studies is presented, including the controversy regarding the relationship of antidepressants and suicidal behavior in this patient population."} +{"text": "Kocuria are Gram-positive cocci of the family Micrococcacceae that are ubiquitous in the environment and part of the normal skin and oral flora in humans. A paucity of cases have been reported of Kocuria as human pathogens and there are currently no evidence-based guidelines for managing these uncommon infections.Species of the genus Kocuria that required line removal despite antimicrobial therapy.We present two paediatric cases of central line infections with species of the genus Kocuria are uncommon human pathogens that have rarely been reported to cause opportunistic infections in both adult and paediatric populations. The cases presented here add to the growing body of literature documenting the pathogenicity of these organisms and the possible need for line removal to achieve clinical cure in central line-associated bacteraemia caused by species of the genus Kocuria. Species of the genus Kocuria are Gram-positive cocci of the family Micrococcaceae that are non-motile, catalase-positive and coagulase-negative. They are ubiquitous in the environment and part of the normal skin and oral flora of humans and other mammals and thus blood cultures were collected from her dialysis catheter and she was admitted to the inpatient floor and empirically started on vancomycin and gentamicin. Gentamicin was discontinued on hospital day 2 upon identification of a Gram-positive organism from a positive central line blood culture from admission. The organism was identified as Kocuria kristinae and was persistently isolated from her dialysis catheter for six consecutive days despite treatment with vancomycin on his complete blood count. Blood cultures were drawn from his broviac catheter and peripherally, and cefepime and vancomycin were started for presumed line infection. Cefepime was discontinued on hospital day 2 upon identification of a Gram-positive organism from blood cultures drawn both from his line and peripherally during his admission to the hospital. Thereafter, daily blood cultures were obtained. He defervesced on hospital day 2 but his blood cultures were continuously positive for Kocuria varians for six days despite treatment with vancomycin and infective endocarditis in immunocompromised hosts breakpoint interpretations for in vitro susceptibility testing of Kocuria isolates. Monotherapy with vancomycin, piperacillin/tazobactam, oxacillin or ciprofloxacin and combination therapy with teicoplanin and vancomycin, ciprofloxacin and clindamycin, and ceftriaxone and ofloxacin have been used successfully in case reports (Kocuria (\u22121 and 1.0 mcg ml\u22121), both patients continued to have positive blood cultures for Kocuria necessitating central line removal. Both patients cleared their bacteraemia after line removal and had favourable outcomes.Due to the limited number of reports available, there are no guidelines for management of Kocuria have been rarely reported to cause opportunistic infections in both adult and paediatric populations. It is likely that many laboratories are misidentifying species of the genus Kocuria as coagulase-negative Staphylococcus or Micrococcus due to the biochemical similarities among these species and laboratory protocols requiring minimal workup of these organisms. With newer organism identification methods, such as matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry, becoming widespread across clinical microbiology laboratories, previously unknown pathogen-disease associations will be uncovered. The cases described here add to the growing body of literature documenting the pathogenicity of species of the genus Kocuria and the possible need for central line removal for achieving clinical cure in Kocuria central venous catheter-associated bacteraemia infections.In conclusion, species of the genus"} +{"text": "Penisetum glaucum (L) R. Br.] is a hardy cereal crop grown in the arid and semiarid tropics where other cereals are likely to fail to produce economic yields due to drought and heat stresses. Adaptive evolution, a form of natural selection shaped the crop to grow and yield satisfactorily with limited moisture supply or under periodic water deficits in the soil. Drought tolerance is a complex polygenic trait that various morphological and physiological responses are controlled by 100s of genes and significantly influenced by the environment. The development of genomic tools will have enormous potential to improve the efficiency and precision of conventional breeding. The apparent independent domestication events, highly outcrossing nature and traditional cultivation in stressful environments maintained tremendous amount of polymorphism in pearl millet. This high polymorphism of the crop has been revealed by genome mapping that in turn stimulated the mapping and tagging of genomic regions controlling important traits such as drought tolerance. Mapping of a major QTL for terminal drought tolerance in independent populations envisaged the prospect for the development of molecular breeding in pearl millet. To accelerate genetic gains for drought tolerance targeted novel approaches such as establishment of marker-trait associations, genomic selection tools, genome sequence and genotyping-by-sequencing are still limited. Development and application of high throughput genomic tools need to be intensified to improve the breeding efficiency of pearl millet to minimize the impact of climate change on its production.Pearl millet [ The unfolding climate change; a rise in global average temperature caused mostly by increasing concentrations of greenhouse gasses in the atmosphere is expected to increasingly distress crop production in many parts of the world. An estimated 41% of the land area of the world constitutes arid and semiarid zones characterized by a very stochastic environment , suboptiPenisetum glaucum (L) R. Br.] is a hardy cereal crop grown in the adverse climatic conditions of the arid and semiarid tropics where other cereals are likely to fail to produce economic yields. It is the staple food and fodder crop of millions of rural families in the hottest and driest environments of Africa and Indian subcontinent. As its cultivation is predominantly practiced on marginal lands under unirrigated condition, environmental stresses mainly drought and heat are the two most important production constraints that it faces.Pearl millet has been developed in pearl millet to capture wider genetic variations of traits . A strucFigure 3). However, MAGIC has disadvantage mainly in resource utilization as it takes longer time and more resources to develop. The population is also likely to show extensive segregation for developmental traits, limiting their use in the analysis of complex traits.Multi-parent advanced generation intercross (MAGIC) population was proposed for genome-wide association mapping for the identification of major genes, QTL, and potentially novel loci associated with important traits . The anaThe MAS uses molecular markers in linkage disequilibrium with major QTL that are tightly linked with the QTL and inherited together. The recent extension of marker-assisted selection is genomic selection where geGenomic selection has been used for improvement of quantitative traits in several different crops with effective training population design. Being an orphan crop, pearl millet has not been evaluated yet for the selection strategy using breeding values. It was preferred to major QTL to accurately predict the genetic value of breeding lines using genome-wide high-throughput DNA markers information . The majGenotyping-by-sequencing (GBS) is the most widely used low-cost whole-genome marker profiling platform for a robust simultaneous marker discovery and genotyping . This inA recent molecular diversity and population structure analysis of 500 pearl millet accessions in two diversity panels using GBS discovered 83,875 SNPs that revealed the prevalence of high genetic diversity in accessions from Senegal as compared to the world collections . Rapid Lde novo transcriptome assemblies for the development of array-based , exome say-based or the s1. The project of sequencing the pearl millet genome selected an important ancestral genotype of many seed parents of pearl millet hybrids in use for forage and grain in the USA as well as dual-purpose hybrids in India, Tift23D2B1.The pearl millet genome sequence provides a genetic blueprint of the species and presumed to facilitate the development of genomic tools that would expedite the development of improved cultivars through the application of marker-assisted breeding. It also facilitate marker-trait association studies and identification of candidate genes for important quantitative traits such as yield and tolerance to stresses like drought. With the overall objective to sequence the pearl millet genome, ICRISAT spearheaded an informal International Pearl Millet Genome Sequencing Consortium (IPMGSC) that brought together several leading research organizations in genome sequencing, crop genomics, and pearl millet researchThe project successfully assembled large clean sequence data from whole genome shotgun sequencing (WGS) raw data . It is eIn pearl millet, there were several independent domestication events resulted in four different races , enrichiThe progress toward developing genomic resources for the application of NGS in pearl millet is promising but much awaits to implement genomics-assisted breeding to expedite the breeding for drought tolerance. With the development of such genomic tools, identification as well as development of improved genotypes is destined to become easier and faster. High density maps construction for fine mapping and candidate gene identification, integration with the genome sequence, and QTL detection needs to be strengthened. A shift from bi-parental to multi-parental and germplasm based association mapping platforms with the application of genomic tools can accelerate discovery of allelic variants that fast pace pearl millet improvement for drought tolerance.Cost effective high throughput genotyping platforms are readily applicable in a diploid pearl millet genome. However, the respectable genome size should be taken into consideration in the process of selection for a genotyping method. The newly popularized exome-capture may reduce the extent of DNA sequence data handled and also leads to the identification of functional markers. Further, the advanced marker-assisted selection strategy that captures small-effect quantitative trait loci and breeding value needs to be given due emphasis for hybrid breeding. A release of the pending genome sequence would have paramount importance in the development and application of the aforementioned genomic tools for mapping and QTL detection. Integration of genome sequences with the consensus linkage map would increase the identification of genes underlying the QTL detected for drought tolerance.DS conceived the idea and prepared the draft of the manuscript. RY edited the draft manuscript and contributed relevant information included in the review.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Dutch policies have advocated sustainable commodity value chains, which have implications for the landscapes from which these commodities originate. This study examines governance and policy options for sustainability in terms of how ecosystem services are addressed in cocoa, soy, tropical timber and palm oil value chains with Dutch links. A range of policies addressing ecosystem services were identified, from market governance to multi-actor platforms (roundtables) and public governance (policies and regulations). An analysis of policy narratives and interviews identified if and how ecosystem services are addressed within value chains and policies; how the concept has been incorporated into value chain governance; and which governance options are available. The Dutch government was found to take a steering but indirect role in all the cases, primarily through supporting, financing, facilitating and partnering policies. Interventions mainly from end-of-chain stakeholders located in processing and consumption countries resulted in new market governance, notably voluntary sustainability standards. These have been successful in creating awareness of some ecosystem services and bringing stakeholders together. However, they have not fully addressed all ecosystem services or stakeholders, thus failing to increase the sustainability of value chains or of the landscapes of origin. We argue that chains sourced in tropical landscapes may be governed more effectively for sustainability if voluntary, market policy tools and governance arrangements have more integrated goals that take account of sourcing landscapes and impacts along the entire value chain. Given the international nature of these commodities. These findings have significance for debates on public-private approaches to value chain and landscape governance. Green economic growth requires embracing (and reconciling) national and cross-boundary policy issues such as climate change, poverty and equity, trade and value chains. As part of that agenda, the Dutch government has promoted considering ecosystems and ecosystem services generally in value chains for \u201cenhanced biodiversity, water and food security, poverty alleviation and human well-being\u201d has integrated the concept of environmental services in its value chain approach. The ecosystem services concept is seen as capable of bridging natural and social sciences and economics, conservation and development, and public and private policy risk of producer failure , often defined selectively by different policy instruments. Of the policy documents, only the Natural Capital Agenda , marketed as a public-private partnership, supported by government financing; a closed co-governance solution to conserve and maintain ecosystem services. Sustainability challenges for business were framed as an opportunity to strengthen the competitive position of the Netherlands, particularly in recent policy documents.Ecosystem services are positioned in different governance arrangements. The main policy document providing the most extensive information on ecosystem services is the 2008\u20132011 Biodiversity policy\u2014the oldest of the documents\u2014where ecosystem services are introduced with reference to the Millennium Ecosystem Assessment. Ecosystem services were predominantly associated with markets and payment mechanisms, while biodiversity was associated with sustainable trade chains. The policies strongly emphasize markets and stimulate attempts to define the economic value of ecosystem services. The policy documents suggest that the main cause of ecosystem degradation is due to the costs of losing biodiversity and ecosystem services not having market prices. This externalization of ecosystem costs resulted in attempts to define the economic value of ecosystem services so that they can be internalized, at least partly, into chain activities. This led to a focus on economic policy measures such as the Sustainable Trade Initiative standards which demonstrated the sustainability credentials of products. These developments implied a change in the framework conditions in which the value chains operated.The third frame relates to market governance, with certification as one of the main mechanisms used to promote more sustainable chains. It has been the main approach in which ecosystem services were either specifically named or implied. Among the voluntary sustainability standards promoted as tools to implement the Dutch policy, only the Forest Stewardship Council (FSC) and Forest Certification for Ecosystem Services (ForCES) certification explicitly mention ecosystem services. The certification standards used in the cocoa, soy and palm oil chains mention only specific services such as genetic resources, erosion regulation and water quality, but do not use the term ecosystem services. Experiments with the use of payments for ecosystems (PES) in the cocoa chain and reducing emissions from deforestation and forest degradation (REDD+) in the timber chain are the only other examples of market-led policy instruments which explicitly allude to ecosystem services.The 2010\u20132015 Sustainable Trade Action Plan IDH discusseThe Dutch policies to increase the sustainability of commodity value chains mirror global trends. Sustainability policies have been implemented by the UNDP Green Commodity Program since 2009 in eleven countries concerning the palm oil, cocoa, coffee, pineapple, fisheries, soy and beef chains UNDP and in GHow are ecosystem services incorporated into the Dutch-linked value chains?This section successively provides an overview of the eight cases that address ecosystem services in the four value chains, the actors driving the change, and where in the chain and how ecosystem services were addressed Table ; how theTable Multi-stakeholder involvement and partnerships between private sector, non-government and civil society organizations, and research institutes were the most common approach to trigger and implement changes in chain governance, with examples found in all the chains Table . The majWhich governance options are available to increase the sustainability of international value chains by addressing ecosystem services?This section presents the results according to the three research questionsThe cases in the previous sections show that a range of governance arrangements and policy approaches have been used in tropical commodity value chains ending in the Netherlands. The main policy approaches used have been endorsing, partnering and facilitating. Both government and non-government actors were incorporated into new governance arrangements used to stimulate and support changes toward more sustainable chains, with ecosystem services mostly implicitly, except for four cases and explicitly addressed. Initially, pressure from civil society played a major role in developing more sustainable value chain practices. Companies and NGOs often worked together in establishing and defining production standards (van Tulder Some interviewees (notably CSOs and some private sector actors) raised questions about whether framework conditions were addressed considering the indirect role of the Dutch government and limited involvement of governments of countries of origin. It was noted that the reliance on market governance using certification standards, meant that impacts are most prevalent in origin landscapes, but this is where the Dutch government and its agencies have little authority.A third of the interviewees noted that a stronger combination of both statutory \u201ccommand and control\u201d and voluntary instruments would allow higher standards to be developed through voluntary mechanisms. Regulations would enable minimum standards to be set to ensure complete chain and sector coverage, which is currently lacking Value chain actors need to collaborate to develop clear, coherent and integrated strategies that make the role of ecosystem services and landscapes in global commodity value chains explicit in policy concepts such as \u201csustainable inclusive growth\u201d, \u201cnatural capital\u201d, and \u201cgreen economic growth\u201d;(ii)Governments in consumer countries can re-consider the mix of policy instruments, using market governance certification \u201ccarrots\u201d and incentive-based \u201csticks\u201d (such as tax incentives and public procurement) to stimulate new partnerships and initiatives with regulation to ensure full chain, sector and landscape coverage to defined standards;(iii)Governments can more explicitly create standards for ecosystem services in their procurement criteria to stimulate how these services are addressed in origin landscapes;(iv)Governments in end-of-chain countries can re-consider the mix of policy instruments used, expanding from the focus on voluntary product certification to alternative instruments which support the private sector to respond to market opportunities for ecosystem services, for example incentivizing demand through fiscal incentives;(v)Governments from sourcing regions and consumer countries should jointly discuss with standards organizations how a more explicit inclusion of ecosystem goods and services in the landscapes from which they originate can be addressed in voluntary sustainability standards;(vi)Bringing together stakeholders with a landscape focus and commodity focus and voluntary standard platforms such as the ISEAL Alliance, operating at multiple levels where value chains and landscapes intersect, could also better integrate ecosystem services into the different segments of a chain more effectively;(vii)Making use of the interconnections between products and experiences across chains and origin landscapes could provide valuable multi-level, cross-sectoral information, as could government involvement in certification schemes\u2014such as FSC and UTZ\u2014which take a \u201cbeyond the chain\u201d integrated landscape approach, to provide insights for all types of chain actors, particularly, consumers, origin country governments and smaller enterprises) into the costs and benefits of maintaining ecosystem services as part of sustainable chains and origin landscapes;(viii)Sectoral ministries should ensure a coherent approach when using indirect policy tools that facilitate and endorse ecosystems services to take an integrated landscape approach;(ix)Policy possibilities should be explored to influence how ecosystem services are impacted in other stages in the chain than the current focus on origin countries. The processing and consumption stages which take place in end-of-chain countries where the sphere of influence and range of policy options available is greater for consumer country governments such as the Netherlands;(x)Consumer and origin country governments should increase collaboration to develop, implement and enforce policies and governance that stimulates sustainable production practices;(xi)European processing and consumer country governments could collaborate more to address sustainable chains, both bilaterally and regionally (the European Union) to ensure a level playing field and to stimulate demand for products which address ecosystem services all along their value chains and not just in the sourcing landscape;(xii)More evidence is needed of the impact of governance arrangements and particularly certification at landscape level and how it maintains or enhances ecosystem services, with internationally agreed upon impact indicators.Based on these findings, the following suggestions were made by interviewees and by the authors, of options to further integrate sustainable use and maintenance of ecosystem services into tropical commodity value chains, directed toward all stakeholders in the value chains :Over the past decade, policymakers in the Netherlands together with private sector and societal organizations, have experimented with different governance arrangements to address the sustainability of international commodity value chains with strong Dutch links. The result has been rapidly shifting policies and on-the-ground practices relating to sustainability of the value chains in general, and increased attention to enhancing the maintenance of ecosystem services specifically. Challenges have included making ecosystem services explicit in policy and governance arrangements and engaging with all value chain actors, particularly consumers and origin country governments, with all types of private sector actors. The cases highlight that organizing multi-actor involvement in international value chains is seen as a critical factor for the success and acceptance of sustainability initiatives addressing ecosystem services, such as voluntary standards and certification.The Dutch cases show how the government created incentives for actors to address ecosystem services in international commodity value chains politically feasible, using endorsing, facilitating and partnership policies. However, the main approach used\u2014market governance\u2014has had limits in terms of effectiveness, sector uptake and impact to date, with the business incentives to invest in internalizing these concepts not clear for all private sector actors. Chains sourced in tropical landscapes may be governed more effectively for sustainability if the voluntary, market policy tools and governance arrangements used have more integrated goals that take account of sourcing landscapes and impacts along entire value chain. Given the limitations of market governance, governance arrangements that more fully support the transition to value chains that address the entire range of ecosystem services impacted by commodity production and trade and create a level playing field for all market players are needed. Scoones et al. stress tIt is increasingly recognized that we need to go further and go one step beyond current policies and governance practices: \u201cBeyond certification\u201d Barry to certi"} +{"text": "Sperm cryopreservation has been utilized routinely for over 40 years to preserve fertility in men undergoing cancer therapy and allow conception for infertile couples. This article provides a concise and up-to-date review of the literature and covers the latest advances in sperm cryopreservation and its array of clinical indications. Over recent years, the scope of clinical indications used for sperm cryopreservation has expanded widely. Consequently, more patient groups are eligible for sperm freezing, requiring specialist resources and higher running costs. Although sperm cryopreservation prior to cancer therapy is readily available in many countries, referral rates by oncology specialists and levels of patient engagement with cryopreservation services are both reported as low. Furthermore, sperm banking continues to raise ethical issues such whether sperm donation should be anonymous and whether sperm can be utilized posthumously by the surviving partner without consent from the patient. This review focuses on the technological advances and ethical controversies in sperm cryopreservation, and how better understanding of these issues could lead to improved access to fertility preserving treatment for patients. Sperm cryopreservation (\u201csperm freezing\u201d) has been used widely since the 1970s to treat couples with infertility. Sperm freezing is principally used to store sperm in patients undergoing cancer therapy and play a vital role in treating couples with infertility. However, several other clinical applications for sperm freezing have emerged in recent years. Furthermore, sperm banking remains an emotive subject raising ethical debates in society. This article aims to provide a concise and contemporary review summarizing the major clinical applications, challenges and future avenues for sperm freezing.The first human live birth using frozen sperm was reported in 1953 following short-term storage of semen in dry ice ,3. SpermThe simplest method of producing a semen sample for sperm banking is masturbation; however, other techniques are available if this is not possible. Disposal penile vibratory stimulation devices are noninvasive and simple . ElectroPre-freeze semen parameters have been shown to be an accurate predictor of post-thaw sperm motility and viability . HoweverNumerous studies have investigated whether advanced sperm selection techniques to improve post-thaw semen quality, mainly focused on selection of sperm by hyaluronanic acid binding; however, a recent Cochrane review was unable to recommend their routine use . Sperm wMalignancy is the major indication for sperm banking. Testicular cancer, Hodgkin\u2019s lymphoma and leukemia confer higher risks of male infertility when compared with other tumor types . Rates oA survey in the UK revealed that only 38% of oncology physicians provided patients with cancer with written information about fertility; contributory factors included having insufficient time to discuss sperm freezing, a lack of knowledge and poor perceived success of fertility preservation . FurtherThere are currently no recommended approaches to protect spermatogenesis in patients undergoing chemotherapy . SeveralSperm freezing is an established tool in the management of couples with infertility, and the scope of its clinical applications is widening rapidly. Autologous sperm freezing is commonly utilized to provide a backup sample for patients with severe oligospermia undergoing intracytoplasmic sperm injection (ICSI). Sperm retrieved during epididymal sperm aspiration or testicular biopsy may be frozen if the procedure cannot be performed synchronously with egg retrieval during ART. Sperm banking may also be provided by a sperm donor when no suitable sperm can be produced by the patient. Other indications for sperm donation may include preventing vertical transmission of an infectious or genetic condition, and fertility treatment for single women or women in same-sex relationships ,71. Men A recent meta-analysis suggested that the prevalence of transgender individuals is 4.6/100,000 in the populations studied . Nearly Sperm retrieval and freezing may be required in patients for whom ejaculation is not possible. Spinal cord injury (SCI) causes erectile dysfunction, anejaculation and reduced semen quality . AbdominIt is generally accepted that patients at high risk of infertility from cancer therapy should be offered sperm freezing. However, there is a paucity of data guiding how the patient and clinician should decide upon the duration of sperm freezing; clinical practice therefore varies and may depend on clinical requirements and funding. In the UK, the Human Fertilisation and Embryology Authority (HFEA) allows patients with persistent infertility to consent for sperm freezing for up to 55 years . HoweverSperm freezing poses several ethical issues which must balance the needs of the donor, recipient and resulting offspring. Anonymity of sperm donation has been standard practice in many countries , but theThe numbers of offspring sired from single donors is also a common ethical concern due to the risks of unintentional consanguinity. Guidelines from the Practice Committee of ASRM and Practice Committee of Society for Assisted Reproductive Technology recommend that sufficient records should be maintained to limit the utilization of sperm from single donors; in a population of 800,000 they recommended that no more than 25 live births result per donor . In the It is routine practice that frozen sperm may be used posthumously by a named partner following the written permission of the patient. However, the question of whether posthumous retrieval and use of sperm by the surviving partner of a patient be permitted without written permission, remains a subject of debate. Sperm remain viable in situ up to 36 h following death , and canMature sperm begin to appear in the ejaculate during puberty. Although sperm suitable for freezing can be collected in any boy with pubertal development, a recent study of 12\u201317 year old boys suggested that cryopreservation was most feasible in those older than 13 years . SurvivaSperm banking is an established and effective mode of preserving fertility in at-risk patients and for treating couples who would otherwise be unable to conceive. However, evidence suggests that access to fertility preservation services could be improved; closer collaboration between clinicians and sperm bank providers is required to ensure patients with cancer can benefit from referral in a timely fashion. It is also important to consider that widening access to sperm banking facilities is likely to have implications for the treatment costs in affected patients. While malignancy is the most common indication for fertility preservation, the large number of conditions, risk factors and treatments having the potential to impair sperm function requires all healthcare providers to enquire about the reproductive wish of their patients, with a view to minimize potential negative effects on fertility. Perhaps the biggest challenge relevant to sperm banking is the ever-expanding list of indications in which it has become incorporated. Regulations for sperm banking were formulated historically to treat men with cancer or heterosexual couples with infertility. The clinical landscape of sperm banking has already changed dramatically, which is illustrated by the increasing utilization of cryopreservation by homosexual and transgender couples. Furthermore, we cannot exclude that further developments such as genetically modifying gametes will become a reality in the future. Further research is needed to develop technologies for fertility preservation prior to puberty, to predict and perhaps prevent long-term gonadal toxicity following cancer therapy, and to refine established policies to deliver the greatest clinical impact for patients."} +{"text": "Medication nonadherence is known to limit the effectiveness of available therapies; however, little is known specifically about medication adherence in people with psoriasis. Medicines self\u2010management can feel onerous to those with dermatological conditions due to the nature of therapies prescribed and many individuals with psoriasis experience additional challenges such as physical and psychological comorbidities that place significant additional demands on individuals and may undermine adherence. Viewing nonadherence to medication as an outcome of limited personal coping resources and conflicting goals may help to explain medication nonadherence.To explore individuals\u2019 perspectives of their psoriasis, medication and its management.Twenty people with psoriasis were recruited from community samples in England and interviewed in\u2010depth about their perceptions of their psoriasis, medication, and adherence to medication and self\u2010management advice. Data were analysed using Framework Analysis.Participants reported that adhering to recommended treatment regimens conflicted with the management of the physical and psychological demands of living with psoriasis. Medication usage was viewed as a source of unresolved emotional distress and, for some, resulted in poor self\u2010reported adherence, which included medication overuse, underuse and rejection of prescribed therapies. Perceived lack of engagement by clinicians with participants\u2019 self\u2010management difficulties was viewed as an additional source of stress and distress.Adhering to medication in psoriasis can be an additional source of considerable emotional distress. We interpreted some episodes of nonadherence to psoriasis medication as rational attempts by individuals to minimize distress and to gain control over their life. What's already known about this topic?Although common, little is known about factors contributing to nonadherence to therapies used in psoriasis.What does this study add?Illness and medication beliefs and associated mood influence medication nonadherence.Attempts to adhere can undermine people's ability to manage their emotional distress.For some patients, following prescribed medication regimens adds to rather than relieves psoriasis\u2010associated distress.What are the clinical implications of this work?Some occurrences of nonadherence to medication in psoriasis should be recognized as a strategic decision by the patient to reduce distress and to gain control.Assessing patients\u2019 beliefs and mood, and identifying potentially conflicting health goals may help to support medication adherence. A purposive sampling strategy was used to obtain a diverse demographic and clinical group. Of 75 invitations sent to potential participants, 36 people demonstrated interest and were sent further details, with a final sample of 20 people recruited from the support website n = 4 and froDuring October 2011 and February 2012, data were collected via face\u2010to\u2010face, in\u2010depth cognitive interviews with participants at a location convenient for them . Interview questions about medication use were based on the self\u2010reported adherence items from the Medication Adherence Report Scale (MARS),Individuals were recruited and interviewed sequentially with analysis being undertaken after each three to four interviews, and additional questions added to the interview guide if new relevant themes were identified. Data saturation (no new themes emerging) was achieved after 20 interviews, constituting the final sample for this study. Mean duration of the interviews was 90 min. They were conducted, audiorecorded and transcribed verbatim by R.J.T. Informed consent was obtained from all participants prior to data collection. Research Ethics Committee approval was obtained (reference 11059).Data were analysed based on the principles of Framework Analysis.One researcher (R.J.T.) undertook the preliminary analysis with the interpretative component undertaken using secondary validation by a second author (L.C.). The multidisciplinary research team comprising researchers from diverse professional backgrounds including psychology, dermatology and pharmacy, engaged in ongoing discussion to improve the transferability and credibility of the findings. The quality and transparency of this research was guided by the Standards for Reporting Qualitative Research (SRQR) recommendations.The analysis produced four overarching themes and subthemes Table .Adherence to psoriasis therapies depleted personal coping resources, including time and motivation available for other illness tasks Table . ParticiAdherence to psoriasis therapies conflicted with the management of other illness tasks Table . Particiincrease psoriasis severity and resistance to medication, which served to perpetuate feelings of anxiety. The inability to use alternative psoriasis therapies due to existing contraindications generated a sense of unwanted medication dependency and lack of long\u2010term psoriasis control that served to increase anxiety and negative expectations of the future course of psoriasis and its management.Perceived poor control of symptoms and the unpredictable response to topical therapy was a source of internal conflict and distress and led participants to question the necessity of their therapy. Furthermore, some questioned whether topical therapy usage could consequences of psoriasis were perceived as stressful and contributing to symptom severity. Participants viewed this vicious psoriasis\u2013stress cycle as particularly difficult, resulting in beliefs of limited or no control and feelings of frustration or hopelessness. Participants also expressed the belief that stress interacted with medication response; some believed stress could interfere with the efficacy of topical therapies, which maintained feelings of limited control and distress. In addition, psoriasis therapies and efforts to adhere to them were also viewed as inherently stressful because of their impact on daily life.Stress was viewed as a causal factor of psoriasis and exacerbating flares. In addition, the psychological and social despite medication usage, perpetuated feelings of limited control and psychological distress. The unattractive effects of topical therapies were constant reminders of the visibility of their condition and its psychological and social consequences. Furthermore, the perceived visibility and noticeability of topical therapy usage conflicted with the strong desire to hide the condition from others, amplifying concerns about the negative reactions of others. Many participants felt they had to conceal their condition from the general public, as well as from their family, close friends and spouse/partner. However, while recognizing the importance of topical therapies, participants found usage of them challenged their need to conceal their condition; participants described topical therapies as a burden to themselves , and also to their partners or close family members.The experience of relapsing and remitting flares was a key factor in participants\u2019 inability to adjust to their psoriasis. The experience of unpredictable flares, perceived symptom severity.Adherence to psoriasis therapies depleted personal resources and conflicted with the management of other illness tasks. Despite these challenges and self\u2010reported distress, some participants reported continuing to use their psoriasis therapy as advised to help control disease and improve quality of life Table . Howeverduration of topical application), interspersed with topical therapy underuse, which appeared to be intentionally compensatory for lack of regular therapy use. For those who were using their topical therapies regularly, topical therapy overuse was done in order to address uncertainty about topical therapy efficacy and gain control over troubling symptoms.Managing the time\u2010consuming nature of topical therapies was difficult and for some, this ongoing depletion of personal resources (including time and effort) resulted in the decision to have \u2018treatment holidays/breaks\u2019. Some participants actively chose to underuse their topical therapy to avoid experiencing ongoing conflict. Thus, topical therapies were used only when their psoriasis flares were perceived to be severe and requiring immediate symptom management. This strategically nonadherent behaviour enabled individuals to regain a manageable balance of addressing psoriasis symptoms and medication concerns while diminishing the impact of topical therapies on daily life, feelings of uncertainty and distress. Some participants had sporadic topical therapy overuse (increasing the For some participants, heightened medication concerns, feelings of low controllability and dissatisfaction with the management of symptoms resulted in the decision to prioritize mood management and other illness tasks and use alternative therapies, which included the use of indoor ultraviolet radiation exposure in the form of tanning beds.Participants experienced medication use to be challenging and distressing, but participants believed this was rarely acknowledged in clinic Table . ParticiWe undertook an in\u2010depth study of patient perspectives in treatment decision making and adherence to therapy in psoriasis. We found that individuals\u2019 reported beliefs about their psoriasis and medication and associated mood played a crucial role in medication adherence. One notable finding is that medication underuse and overuse were influenced by distinct beliefs about psoriasis and psoriasis medication. Medication underuse seemed to be driven by concerns about the potential for adverse effects, perceived poor control of symptoms and feelings of anxiety. Medication overuse was influenced by experiences of unpredictable flares during medication usage, perceptions of uncertain treatment effectiveness and frustration.These results suggest nonadherence to psoriasis medication may be a function of depleted personal resources and of conflicting demands or priorities, differing aspects of what is known as self\u2010regulation failure.The need to manage psoriasis symptoms with prescribed medication conflicted with the need to manage concerns about adverse effects. Perceived uncertainty about treatment effectiveness and views that they had little control over symptoms added to internal conflict. Participants reported stress as a cause and trigger of psoriasis, and described ongoing struggles between their need to limit exposure to stressors and their desire to use psoriasis therapies perceived as stressful. Furthermore, the use of visible topical therapies undermined their desire to hide their condition from others. These challenges resulted in unresolved emotional distress, little perceived control and high levels of uncertainty. Findings reflected other evidence that highlighted perceived lack of support from healthcare providers, especially within general practice management,Despite these challenges, some people reported continuing to use their psoriasis therapy as prescribed, although this led to continued high levels of unresolved distress. Others managed this distress by adjusting their medication usage based on perceived symptom severity, resulting in medication nonadherence, both medication underuse and overuse. A further group chose to reject their prescribed medication altogether and seek support from alternative sources.Factors influencing medication adherence in psoriasis are largely unknown, with few studies exploring the role of patient perspectives in treatment decision making.The majority of participants recruited were using topical therapies and thus the findings may not be transferable to individuals whose treatment included more complex regimens. We acknowledge the potential for sampling bias; self\u2010reported distress and illness and medication burden in this study could be due to participants primarily being recruited through support groups. Additionally, levels of adherence disclosed by the participants were self\u2010reported rather than assessed by an objective measure. Despite these limitations, our qualitative methods have provided new insights and a richer understanding of factors that influence adherence in psoriasis and individuals\u2019 perceptions of the challenges of treatment decision making, which have not been captured in previous survey studies. The SRQR guidelinesWe suggest using a nonjudgmental approach that recognizes barriers to adherenceTable S1. Cognitive interview topic guide.Click here for additional data file.Video S1. Author videoClick here for additional data file."} +{"text": "Acute ureteral obstruction produces renal damage and complications that are proportional to the severity and length of the obstruction. Anatomic diagnosis of the obstruction may be insufficient to manage the patient. Intravenous urogram (IVU) is the method usually advised by radiologists to obtain functional information, but requires iodinated contrast agents. IVU anatomic information is superior to anatomic information obtained with renal scintigraphy, but normally the physician already has the anatomic information (unenhanced CT or ultrasound). A renal scan offers better physiologic information than the IVU, has neither adverse effects nor complications, is accurate to confirm or discard significant ureteral obstruction, and depicts obstruction complications. This paper presents a patient with spontaneous urine extravasation secondary to acute renal obstruction who is diagnosed with renal scintigraphy. The authors describe the scintigraphic signs of extraperitoneal, diffuse perinephric, urine extravasation and emphasize the role of renal scintigraphy in diagnosis and follow-up of renal colic."} +{"text": "Survival to adulthood for people with Spina Bifida now exceeds 85% due to improvements in medical and surgical management. Rates remain lower than expected for community participation, healthy lifestyle choices, employment and independent living. The importance of transition programming to help adolescents with disabilities prepare for adult life roles is now understood. Literature currently is mainly conceptual or descriptive, but informs the process of developing transition program models. The need for competent and effective adult care providers is discussed. Both the transition to adulthood and the transfer of care to adult care clinics are important and distinct components of spina bifida lifespan care."} +{"text": "This review examines the literature during the past 10 years about suicide risk and suicide during adolescence and young adulthood of individuals with eating disorders. Epidemiological surveys are summarized, including suicide rates, parasuicidal behaviors, associated risk factors, and comorbid psychopathology. Critical implications for the comprehensive assessment and treatment planning, including safety considerations, are discussed. Two clinical cases of women with long-standing eating disorders are described to highlight both the pragmatic considerations and the complex clinical challenges of working with patients with eating disorders who become suicidal. The potentially life-threatening issues of safety have not received sufficient attention, neither in the medical literature nor by the treating clinicians. All health care professionals who are treating patients with an eating disorder must be keenly aware of the serious risks of suicidal behavior and of suicide in this population."} +{"text": "Aneuploidies have diverse phenotypic consequences, ranging from mental retardation and developmental abnormalities to susceptibility to common phenotypes and various neoplasms. This review focuses on the developmental defects of murine models of a prototype human aneuploidy: trisomy 21 . Murine models are clearly the best tool for dissecting the phenotypic consequences of imbalances that affect single genes or chromosome segments. Embryos can be studied freely in mice, making murine models particularly useful for the characterization of developmental abnormalities. This review describes the main phenotypic alterations occurring during the development of patients with T21 and the developmental abnormalities observed in mouse models, and investigates phenotypes common to both species."} +{"text": "Cortical information processing is structurally and functionally organized into hierarchical pathways, with primary sensory cortical regions providing modality specific information and associative cortical regions playing a more integrative role. Historically, there has been debate as to whether primary cortical regions mature earlier than associative cortical regions, or whether both primary and associative cortical regions mature simultaneously. Identifying whether primary and associative cortical regions mature hierarchically or simultaneously will not only deepen our understanding of the mechanisms that regulate brain maturation, but it will also provide fundamental insight into aspects of adolescent behavior, learning, neurodevelopmental disorders and computational models of neural processing. This mini-review article summarizes the current evidence supporting the sequential and hierarchical nature of cortical maturation, and then proposes a new cellular model underlying this process. Finally, unresolved issues associated with hierarchical cortical maturation are also addressed. The concept of cortical hierarchy has been widely recognized for years !]) and is a measure of neural network performance -based imaging studies characterizing cortical developmental trajectories in humans (Walhovd et al., In conclusion, the evidence for hierarchical cortical maturation in humans appears to be quite robust, and there is directly related evidence from animal research to support hierarchical cortical maturation (Jacobson, TC planned and wrote the manuscript and BH critically evaluated it. Both authors contributed to the ideas related to the content.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Second Resident Duty Hours in the Learning and Working Environment Congress. We describe the joint process used by ACEP and CORD to capture the opinions of emergency medicine (EM) educators on the ACGME clinical and educational work hour standards, formulate recommendations, and inform subsequent congressional testimony.The American College of Emergency Physicians (ACEP) and the Council of Emergency Medicine Residency Directors (CORD) were invited to contribute to the 2016 Accreditation Council for Graduate Medical Education\u2019s (ACGME) In 2016 our joint working group of experts in EM medical education conducted a consensus-based, mixed-methods process using survey data from medical education stakeholders in EM and expert iterative discussions to create organizational position statements and recommendations for revisions of work hour standards. A 19-item survey was administered to a convenience sample of 199 EM residency training programs using a national EM educational listserv.A total of 157 educational leaders responded to the survey; 92 of 157 could be linked to specific programs, yielding a targeted response rate of 46.2% (92/199) of programs. Respondents commented on the impact of clinical and educational work-hour standards on patient safety, programmatic and personnel costs, resident caseload, and educational experience. Using survey results, comments, and iterative discussions, organizational recommendations were crafted and submitted to the ACGME.EM educators believe that ACGME clinical and educational work hour standards negatively impact the learning environment and are not optimal for promoting patient safety or the development of resident professional citizenship. The Accreditation Council for Graduate Medical Education (ACGME) aims to assure a safe learning environment for residents, in part by trying to mitigate fatigue-related medical errors and promote learner wellness.5Even before these revisions, studies evaluating the benefit of work hour limitations demonstrated mixed outcomes.18Resident Duty Hours in the Learning and Working Environment Congress in March 2016. The ACGME invited 64 national organizations to submit position papers with recommendations to improve the work hour standards and the learning environment, from which 56 were invited to provide oral testimony to the Congress. The American College of Emergency Physicians (ACEP) and the Council of Emergency Medicine Residency Directors (CORD) were invited to testify on behalf of emergency medicine (EM). In 2017 the ACGME used this input to revise their common program requirements in an effort to improve the learning and working environment for residents.5In an attempt to improve resident education, the ACGME held its second Resident Duty Hours in the Learning and Working Environment Congress.With this article, we describe the processes and outcomes by which ACEP and CORD collaborated and jointly explored the state of opinion of EM educators on the ACGME\u2019s clinical and educational work hour standards, and developed recommendations for the 2016 ACGME What do we already know about this issue?ACGME duty hour standards have been in place since 2003. Their effects on the EM learning environment have not been extensively reported.What was the research question?We sought to gain the perspectives of EM educators and make recommendation regarding the future of ACGME work hour standards.What was the major finding of the study?Aside from promoting resident wellness, EM educators largely perceive current work hour standards to have a negative impact on patient safety and the educational experience.How does this improve population health?Future revisions of ACGME clinical and work hour standards should aim to prioritize all aspects of the learning environment.In response to the ACGME request for organizational position papers and recommendations on resident learning and the working environment, ACEP and CORD engaged in parallel but collaborative efforts to generate informed, consensus-based responses from both organizations. The University of Virginia Institutional Review Board reviewed the completed project retroactively and deemed this descriptive report to be exempt from review.In 2016 an 11-member working group of experts in graduate medical education (GME) and EM residency training convened and engaged in iterative discussions to offer EM\u2019s recommendations for future changes to the dimensions of resident work hour requirements and standards governing key aspects of the learning and working environment. Work group members were purposefully selected through an unstructured discussion process by ACEP academic affairs committee leaders for their understanding of, and expertise in, GME and to assure diverse opinions on the learning environment from programmatic, institutional, and national perspectives.Following broad discussion and commentary, the work group developed and administered a 19-item survey to gain feedback regarding the impact of existing ACGME duty hour standards on EM programs in the areas of patient care and safety (five items), programmatic and personnel costs (six items), consultant and EM resident caseload (four items), and educational experience (four items). Respondents were asked to rate the impact of the 2011 ACGME duty hour standards on a bi-directional 5-point Likert scale from significant negative impact to significant positive impact. Comments were solicited within each area of impact .The survey was distributed to a convenience sample of EM GME stakeholders via the CORD organizational email listserv for EM residency programs. This listserv has participation from each of the 167 allopathic and 32 osteopathic accredited EM training programs. These 199 EM GME programs average five listserv members per program for a total listserv membership of 1,034. Members include departmental chairs, vice-chairs, program directors, associate program directors, educational faculty, and program coordinators. We performed survey data analysis using simple descriptive statistics. Comparative statistics were used to highlight significant differences as appropriate. We identified representative comments in each of the four impact areas to exemplify perceived impact in each of the areas.Informed by relevant resources,The work group was comprised of four women, four active program directors and six past program directors. All members contributed substantially to the iterative discussions. One hundred fifty-seven EM educational leaders responded to the survey representing 15.2% of the broader listserv membership. Ninety-two of the 157 respondents were program directors, yielding a targeted response rate for EM program directors of 46.2% (92/199). Demographic data, professional positions, and geographic locations of respondents are listed in The impact of the ACGME duty hour standards is reported to have had a majority negative effect in all four domains , although the magnitude of negative impact was least in most of the education experience categories. The only positive impact found was fostering resident work-life balance and wellness. Representative comments selected from 233 completed text fields pertaining to individual areas of impact are presented in Informed by feedback from EM GME educators, our collaborative, consensus-based process found that the ACGME clinical and educational work hour standards are believed to have overall negative effect on the balance of patient safety and the educational experience. EM educators believe broad work hour regulations have adversely impacted the number of patient handoffs, length of stay, boarding, resident case load, hospital costs, and faculty work load in GME. In addition, the ability of training programs to deliver an effective didactic curriculum and assure resident professional citizenship and accountability has been hampered. The only areas of perceived positive impact were resident wellness and a program\u2019s ability to foster it.EM educators believe that ACGME work hour standards have historically fallen short of their intended outcomes for patient safety and the educational experience, compromising residency programs\u2019 ability to maintain an ideal learning environment.Residency training programs commit to promoting a supportive educational learning environment. In doing so, programs must balance the resident training experience and educational opportunities with resident wellness and patient safety to create a meaningful and effective educational experience. The ACGME strives to ensure this optimal balance through established work- hour standards for residents.EM educators encourage the ACGME to consider specialty specific work hour standards allowing for greater alignment of work hour regulations with individual specialty workflow.Patient safety is known to be adversely affected by fatigued decision-making, excessive transitions of care, and, in the emergency department (ED), prolonged length of stay and departmental boarding.Resident and faculty attendance at didactic conferences is critical and necessitated by ACGME program requirements.Both schedule alterations necessary to comply with work hour standards and monitoring of clinical and educational hours have had an additional economic impact on institutions. First, the cost of replacing off-service trainees who are repatriated to their home training programs to fulfill service obligations can be substantial. There are no specific data to determine the amount lost; however, surrogate costs are available. For example, providing just eight hours of care daily by advanced practice providers in the ED can result in substantial costs to a department or organization. It stands to reason that similar effects are felt by other specialties as their resident workforce hours are decreased. Institutions potentially need to re-allocate dollars to fund coverage for changes created by the duty hour standards, shifting funding away from educational programs. Thus, a system has been created by which there is less funding for education without a definitive increase in patient safety or training effectiveness.EM educators still believe the ACGME must explore ways to decrease the programmatic administrative burden of monitoring work hour standards compliance.Given the increased administrative burden of logging and monitoring resident time, many residency programs have needed to expand their administrative support.EM educators encourage the ACGME to consider greater flexibility in clinical and educational work hour standards to promote resident wellness while allowing for the greater development of professional citizenship.Another significant concern is the notion that the current emphasis on work hour monitoring appears to engender a \u201cclock punching\u201d mentality, de-emphasizing service, professional citizenship, and personal investment in one\u2019s craft \u2013 all critical components of professional development for physicians. Though current requirements allow for continuous work hour limitation exceptions when caring for sick patients, the need to document explanations for these exceptions imposes additional administrative burdens on residents, often resulting in a punitive effect rather than rewarding desired behavior. Currently, two large studies investigating the impact of flexible duty hours on resident training are granted work hour waivers.28The second trial, Individualized Comparative Effectiveness of Models Optimizing Patient Safety and Resident Education (iCOMPARE), is also a large, multi-institutional study designed to evaluate the efficacy and safety of less restrictive work hours in internal medicine training programs.In spring 2017, the ACGME announced revisions to subsections of the common program requirements pertaining specifically to the regulation of the learning and working environment.Our informed consensus-based process for developing recommendations for the ACGME was limited in several ways. First, our survey instrument was primarily derived using input from workgroup members with expertise in EM and medical education, and their personal experience and understanding of the literature. Given the significant time constraint imposed by the ACGME for each organization\u2019s formal position paper, our survey was informed by a limited literature review and we were not able to confirm response process validity by piloting the survey for readability and clarity. It is possible that important topics were misunderstood or excluded from the survey instrument. However, while the overall survey response rate was low (15.2%), the response rate from program directors\u2014those most likely to be familiar with ACGME regulations and their effect on trainees\u2014was better (46.2%). Still, with less than 50% of program directors responding to the survey, there is the potential that our conclusions do not accurately represent all program directors\u2019 opinions, despite including input from the broader GME community.Additionally, open comments were solicited and reviewed by the work group allowing for all opinions to be considered. Next, with an average of 5.2 listserv members per program, any given institution could have answered the survey more than once. The respondent characteristics suggest that there was broad response, but there is still a possibility that over-representation from one institution may have affected the survey results. Next, we recognize the possibility of bias affecting our results. The survey instrument was created by a group of medical education experts, all of whom work (or have worked) within the ACGME program requirements. While survey categories and questions could have been biased towards outcomes favored by the workgroup based on their collective experience, the creation of the initial survey instrument was guided by existing relevant literature. Moreover, there was diverse input from several EM stakeholders and qualitative responses were reviewed and incorporated into iterative discussion minimizing the risk of any bias from the small work group. Lastly, our qualitative commentary data was not formally coded, but rather iteratively discussed by the expert working group to inform commentary and to derive position statements and recommendations.Emergency Medicine educators believe that ACGME clinical and educational work hour standards have historically negatively impacted the learning environment and do not optimally promote patient safety or the development of resident professional citizenship. EM educators hope that the 2017 revisions to the ACGME clinical work and education standards prioritize all aspects of patient safety, resident wellness, and the ideal learning environment."} +{"text": "This study was conducted to assess factors that influence use of antenatal care services with both quantitative and qualitative designs. Methods used were structured questionnaire interviews and focus group discussions in the Kampung District, Kampot Province in Cambodia with a volunteer sample of 260 postnatal mothers. The outcome measure was factors influencing use of antenatal care services. The results showed that first-time mothers (primigravidas) were more likely to use antenatal services than multiparous mothers . Mothers with some school education used antenatal services more than those with no school education . Mothers engaged in professional occupations by virtue of their higher levels of educational attainment were more likely to use antenatal services than those engaged in agriculture . Use of antenatal care services was higher in the districts whose health centers were supported by a foreign nongovernmental organization as compared to other districts with no such support . Although services were generally inadequate, those that existed were underutilized by the mothers. Major factors influencing use of services include distance, lack of transport, and lack of awareness of the benefits of antenatal care by the mothers, thus resulting in a general notion that antenatal care is only important when problems occur during pregnancy. It is concluded that for remote villages, mobile antenatal clinics should be provided to improve access, and greater emphasis should be placed on health educating the mothers about the potential benefits of antenatal care, with special attention to multiparous mothers and those from the lower socio-economic class, among whom use of antenatal services was lowest."} +{"text": "This review outlines the anatomy of the obturator nerve and the indications for obturator nerve block (ONB). Ultrasound-guided ONB techniques and unresolved issues regarding these procedures are also discussed. An ONB is performed to prevent thigh adductor jerk during transurethral resection of bladder tumor, provide analgesia for knee surgery, treat hip pain, and improve persistent hip adductor spasticity. Various ultrasound-guided ONB techniques can be used and can be classified according to whether the approach is distal or proximal. In the distal approach, a transducer is placed at the inguinal crease; the anterior and posterior branches of the nerve are then blocked by two injections of local anesthetic directed toward the interfascial planes where each branch lies. The proximal approach comprises a single injection of local anesthetic into the interfascial plane between the pectineus and obturator externus muscles. Several proximal approaches involving different patient and transducer positions are reported. The proximal approach may be superior for reducing the dose of local anesthetic and providing successful blockade of the obturator nerve, including the hip articular branch, when compared with the distal approach. This hypothesis and any differences between the proximal ONB techniques need to be explored in future studies. Obturator nerve block (ONB) is commonly performed to prevent sudden thigh adduction during transurethral resection of bladder tumor (TURBT) \u20133, to prThe obturator nerve arises from the anterior rami of the second, third, and fourth lumbar nerves. The nerve descends through psoas major and emerges from the medial border of this muscle. The obturator nerve then runs along the lateral wall of the lesser pelvis and extends to the anterior thigh after passing through the obturator canal. During its course, the obturator nerve divides into anterior and posterior branches. In a cadaveric study, bifurcation of these two main branches of the obturator nerve was determined to be intrapelvic (23.22%), within the obturator canal (51.78%), or in the medial thigh (25%) . The antThe obturator nerve is situated directly adjacent to the lateral wall of the bladder during TURBT when the irrigation fluid used in this procedure fills the bladder. Any electrical stimulation caused by tumor resection involving the bladder may induce sudden adductor muscle contraction, which may lead to perforation of the bladder accompanied by extravesical spread of the tumor and even injury to the obturator artery \u20133, 22. SThe knee joint capsule is partially innervated by the obturator nerve , 20. In The hip joint receives sensory innervation from branches of the femoral, obturator, superior gluteal, and sciatic nerves, as well as the nerve to quadratus femoris . Among tGroin and thigh pain frequently arises from the articular branch of the obturator nerve, whereas trochanteric pain arises from the articular branch of the femoral nerve . The nerPersistent hip adductor spasticity is a major complication of spinal cord injury, traumatic brain injury, cerebral palsy, and multiple sclerosis. Hip adductor spasticity causes hip joint deformity, pain, and scissoring of the hips, which prevents maintenance of perineal hygiene, leading to breakdown and infection of the skin in patients requiring long-term care. Some case series have reported that ONB using a neurolytic agent is effective for treatment of hip adductor spasticity in both adult and pediatric patients , 11, 25.As described above, the obturator nerve provides no cutaneous innervation in more than half of individuals; therefore, successful ONB can be achieved despite a lack of sensory block at the medial thigh and/or knee. The success of ONB is evaluated by confirming a decrease in adductor muscle strength using a sphygmomanometer as described by Lang et al. . Using tIn recent times, ultrasound guidance has been used to improve the success rate and safety profile of peripheral nerve blocks, including ONB. The success rate of landmark-based nerve stimulation-guided ONB in prevention of adductor muscle contraction during TURBT has been reported to be between 84% and 96% , 33. A nMany ultrasound-guided ONB approaches have been reported and can be classified as distal or proximal.The distal approach is defined as one in which the anterior and posterior branches of the obturator nerve are blocked separately by two injections of local anesthetic directed toward the interfascial planes where each branch lies. Patients are placed in the supine position with the thigh slightly abducted and externally rotated. An ultrasound transducer is placed at the inguinal crease and perpendicular to the skin Figures to identSudden adductor muscle contraction during TURBT might occur even if an ONB using the distal approach is correctly performed because of various patterns of ramification of the obturator nerve when it terminates in the adductor muscles . In otheTaha reported that ultrasound-guided injection of local anesthetic into the interfascial plane between the pectineus and obturator externus muscles successfully produces blockade of both the anterior and posterior branches of the obturator nerve . YoshidaThe same patient and transducer positions were used in the reports published by Anagnostopoulou et al. , Taha 2, and LinAkkaya et al. evaluated a further proximal approach in both cadaveric and clinical studies . Using tMost recently, Yoshida et al. have described a new approach for proximal level ONB . This apNerve stimulation guidance is not always used to perform proximal level ONB procedures because injection of local anesthetic into the interfascial plane between the pectineus and obturator externus muscles, which can be easily identified using ultrasound, provides successful ONB. This interfascial plane is seen as a hyperechoic thick fascia under ultrasound guidance, while the obturator nerve itself can also be seen as a hyperechoic thick structure within this fascia. Therefore, it may be difficult to distinguish the nerve from the interfascial plane under ultrasound guidance alone in some cases. Because an intraneural injection within the perineurium requires a higher injection force than one outside the perineurium, it would be helpful to monitor the injection pressure during ONB, especially in cases without peripheral nerve stimulation, to avoid intrafascicular injection of local anesthetic and the concomitant risk of neurologic complications \u201348.Technical differences between the above-mentioned ultrasound-guided ONB approaches are summarized in The superiority of ultrasound-guided ONB techniques over landmark-based ONB techniques has not yet been validated by a prospective comparative trial, although theoretically ultrasound guidance would improve the success rates and safety profiles of peripheral nerve blocks. Various approaches for ultrasound-guided ONB have been reported; however, there has been no study comparing the advantages or disadvantages of these approaches in any respect . The proximal approaches for ONB would be superior to a distal approach for reducing the minimum local anesthetic dose required to achieve blockade and for providing successful blockade of the hip articular branch of the obturator nerve. Nevertheless, this is still a hypothesis that needs to be tested. Further study in a large population would be required to assess the safety of these techniques.Fluoroscopy guidance was used to perform percutaneous radiofrequency lesioning and pulsed radiofrequency treatment of the obturator nerve for hip joint pain in previous case series reports , 9. ThesVarious ultrasound-guided ONB techniques have been reported and can be classified according to whether the approach is distal or proximal. The proximal approach, which comprises a single injection of local anesthetic into the interfascial plane between the pectineus and obturator externus muscles, would be superior for reducing the minimum dose of local anesthetic required and for achieving successful blockade of the obturator nerve, including the hip articular branch, when compared with the distal approach. Nevertheless, this hypothesis should be validated in future studies. The pros and cons of each proximal ONB technique also need to be evaluated in a randomized controlled trial."} +{"text": "Results revealed that the condition of the immediate forest surrounding was the most important variable influencing visitors\u2019 landscape preferences. Visitors preferred healthy mature forest stands and disliked forests with substantial dead wood. The number of visitors was the most important social factor influencing visitor landscape preferences. Differences in the influence of physical and social factors on visual preferences existed between study sites. Findings suggest that both visual forest conditions and visitor use management are important concerns in addressing landscape preferences for beetle-impacted forest recreation areas.Extensive outbreaks of tree-killing insects are increasing across forests in Europe and North America due to climate change and other factors. Yet, little recent research examines visitor response to visual changes in conifer forest recreation settings resulting from forest insect infestations, how visitors weigh trade-offs between physical and social forest environment factors, or how visitor preferences might differ by nationality. This study explored forest visitor preferences with a discrete choice experiment that photographically simulated conifer forest stands with varying levels of bark beetle outbreaks, forest and visitor management practices, and visitor use levels and compositions. On-site surveys were conducted with visitors to State Forest State Park in Colorado ( Dendroctonus ponderosae) in North America and the spruce bark beetle (Ips typographus) in Europe are increasing due to climate change and other factors ?Do preferences vary by the location of the impacted forest stands in the landscape (near-view to far-view)?What trade-offs do visitors make between physical and social factors of forest recreation sites, and which attributes influence visitors\u2019 preferences most?Are there differences in landscape preferences between forest visitors to sites with different bark beetle impacts and to German and U.S. forest recreation sites?The following research questions guided the study:The study was conducted in two U.S. state parks\u2014State Forest State Park in Colorado and Lake Bemidji State Park (LBSP) in Minnesota\u2014and in Harz National Park (HNP) in Germany Table . The sitPinus contorta), which accounts for 60% of all tree cover at the park, were killed by the mountain pine beetle (Dendroctonus ponderosae) (COSP Colorado State Forest State Park (COSP) is located in the high country of north-central Colorado, 128\u2009km from Fort Collins. The park covers forestland west of the Medicine Bow Mountain Range and into the northern end of the Never Summer Range. Its alpine lakes, trails, and developed and backcountry sites attract visitors for a number of summer and winter recreational activities. About 95% of lodgepole pine (ae) COSP . Currentae) COSP .Pinus resinosa), white pine (Pinus strobus), and jack pine (Pinus banksiana). A 2007\u20132008 infestation by pine engraver beetles (Ips pini) primarily impacted jack pine and red pine in smaller stands .LBSP is located in the pine moraine region of northwest Minnesota. The park affords a variety of land and water-based recreation opportunities. Coniferous species include red pine (Picea abies). Since its designation as a national park in 1990, the major objective has been to accelerate recovery of the natural vegetation through both active forest management and by natural processes. A policy of \u201cnon-management\u201d of spruce monocultures in the core zone has led to significant spruce bark beetle outbreaks (Ips typographus). Bark beetles are only managed in a 500-m buffer zone from the park boundary in order to avoid spreading to neighboring private forests and along hiking trails , user groups , and number of dogs and dog walkers\u2019 behavior . A visitor management measure, the presence or absence of a trail sign prohibiting bicycling, was also employed. The sign prohibiting bicycling was always combined with a 100% proportion of hikers in the scenarios.The exact combination of the attribute levels of the DCE depended on an underlying asymmetric orthogonal fractional factorial design closed canopy scenario followed by a natural rejuvenation. The higher preference for an intervention strategy found in this study may pose a challenge for natural management of protected areas if management restrictions exist. Management could intensify educational efforts about bark beetles and their role in ecological processes and dynamics of forest ecosystems to explore whether this could increase the acceptance of successional stages with high amounts of dead trees. An effective communication strategy to address the associated issues could be the provision of information along hiking trails and around tourism facilities in and near impacted forest stands. So far, limited research exists on the influence of knowledge on visitor perceptions of bark beetle-impacted forests participants dislike a high number of trail users national differences and (2) social site conditions. A near-view forest stand with the same structures but showing pines with yellow tree foliage was less preferred in the U.S. study sites, especially in Colorado, compared to German visitors, while German visitors were more concerned about spruce beetle impacts. Previous studies have shown that the color of foliage has an influence on people\u2019s preferences for trees and forests (Buhyoff et al. Previous research on recreational forests is limited on whether and how visitor preferences for social conditions might differ nationally or internationally. Similar to this study, existing research reveals differences in preferred social conditions between forest visitors from different countries (Arnberger et al. Dogs and dog walker behavior played no or a marginal role in this study; only HNP visitors disliked the presence of dogs. Compared to other studies in the urban context (Arnberger et al. As such, it may be that the study site with its specific visitor structure is more relevant than nationality in terms of preferences for or attitudes toward social attributes. Given that none of our study sites were urban, future research may compare preferences of forest visitors in one country along a gradient from urban to rural, to examine whether degree of urbanization/ruralness may influence preferences for recreation site conditions.This study found that physical and social attributes of bark beetle-impacted forests influenced visitors\u2019 preferences, with the condition of the immediate forest surrounding being the most influential. We suggest that forest managers and planners need to be aware of how forest insect impacts can affect recreation setting preferences as increasing outbreaks of forest insects may occur due to climate change and global trade. If forest recreation sites are heavily impacted by forest insects, then their attractiveness will diminish and visitors may avoid visiting such forest environments, leading to reductions in tourism revenues and loss of other cultural ecosystem services, as well as the potential for crowding or conflict at other recreational sites if users shift locations.Based on this study, forest recreation managers in areas with beetle impacts have several options to maintain the quality of recreation experience for their visitors. Management, remediation, or intervention activities that focus on the forest setting proximate to the recreation areas may have high potential to address visitor perceptions and preferences. Several studies support the notion that to provide information of the issues to visitors increases their interests and understanding of what they see. This is especially true in protected areas and in places where outbreaks are natural disturbance regimes in forests. It is important to understand factors that influence changes to public perception of bark beetle outbreaks. Landscape esthetics are of particular concern among visitors as landscape appearance influences visitor experience and the frequency of subsequent visitation (Sheppard and Picard"} +{"text": "The interest towards research in hearing loss and ear disease has seen a great and progressive increase in the light of the continuous increase in the number of challenging research articles. Although hearing loss is a worldwide health problem and its socioeconomic burden is globally significant, nonregenerative hair cells in the cochlea and difficult drug delivery to the inner ear hindered progress in the field of hearing recovery . HoweverThis special issue brings together 10 research articles and review article which nicely illustrate the wide spectrum of basic inner ear research and its related research about central auditory pathway. While some cutting-edge researches about neuroimaging study of central pathway including auditory cortex and higher cognitive function were illustrated, basic inner ear studies using many kinds of animal models were also described. In detail, diabetic mice, gerbil hearing loss model with aminoglycoside administration, and specifically devised early progressive hearing loss model were introduced. This special issue also includes deriving significant clinical implication, predicting the surgical outcomes from the data of cochlear implant recipients. Finally, the art of nanomedicine was thoroughly reviewed in the field of inner ear research.The collection of papers published in this special issue nicely covers all the fields of hearing science including basic molecular study, imaging study, and clinical implication study and we hope that it will attract the interests of a large number of basic researchers as well as clinicians aiming at improving the treatment of hearing loss.Yong-Ho ParkSung K. MoonKenneth H. LeeJeong-Han Lee"} +{"text": "Reverse Segond fracture is an uncommon avulsion fracture of the tibial attachment of the deep portion of the medial collateral ligament of the knee. We report a reverse Segond fracture associated with anterior cruciate ligament tibial avulsion fracture and anteromedial tibial rim fracture. Unlike previous reports, the combination of reverse Segond fracture, anteromedial tibial rim fracture, and anterior cruciate ligament avulsion fracture was not associated with posterior cruciate ligament injury, posterolateral corner injury, or tibial plateau fracture. This new combination of injuries provides better understanding of the mechanisms of ligamentous injuries of the knee and highlights the importance of meticulous assessment of these injuries for accurate diagnosis and subsequent management. Reverse Segond fracture is an avulsion fracture of the medial proximal tibia, caused by the deep portion of the medial collateral ligament (MCL). It was first described by Hall and Hochman in 1997 [In the few cases reported, reverse Segond fracture has been associated with multiple knee injuries including tibial plateau fractures, medial meniscal root tears, and cruciate ligament tears or avulsion fractures \u20136. All rWe report a case in which a reverse Segond fracture was associated with anteromedial rim fracture and ACL avulsion fracture, without associated injuries in PCL, PLC, or tibial plateau. We believe this case report provides new insights to deeply understand the mechanisms of ligamentous injuries of the knee.A 19-year-old man, involved in a motorcycle road traffic accident, presented with a painful swollen left knee. The injured knee had never been significantly injured before. According to the patient's description, he hit a pedestrian during driving a motorcycle which made him lose balance and fall to the ground on his left side where his left knee was injured secondary to a direct trauma to the flexed knee, with the motor bike on top potentially causing a valgus moment at the knee. Clinical examination was evident for medial laxity and ACL failure. Tibial eminence fracture and reverse Segond fracture were seen on anteroposterior and lateral radiographs . ComputeExamination under anaesthesia confirmed ACL and MCL laxity. Intraoperatively, the deep portion of the MCL with its avulsed bony fragment and the anteromedial rim fracture were repaired using nonabsorbable transosseous sutures. Open reduction and fixation of the avulsed ACL were achieved using nonabsorbable pullout sutures . A hingeReverse Segond fracture is an avulsion of the deep capsular component of the MCL. It has been associated with PCL , 3, 6 orAnteromedial tibial rim fractures have been associated with PCL and PLC injuries \u201310. ThisThe current case demonstrates three tibial avulsion fractures within the same injury. To our knowledge, this combination of injuries, without tibial plateau fracture or PCL or PLC disruption, has never been reported. The exact mechanism of injury that led to this pattern of avulsion fractures is hard to prove. The potential mechanism of injury that led to that combination of injuries is consistent with the hypothesis of Peltola et al. that valWe draw attention to the fact that injuries around the knee may result in a spectrum of bony and/or ligamentous disruptions. Vigilance and meticulous assessment of these types of injuries is essential for accurate diagnosis and subsequent management."} +{"text": "The biomechanical roles of both tendons and ligaments are fulfilled by the extracellular matrix of these tissues. In particular, tension is mainly transmitted and resisted by protein fibers, whereas compression is opposed by water-soluble glycosaminoglycans (GAGs). GAGs spanning the interfibrillar spaces and interacting with fibrils through the interfibrillar proteoglycans also seem to play a part in transmitting and resisting tensile stresses. Both tendons and ligaments showing similar composition, but different functional roles and collagen array, exhibit periodic undulations of collagen fibers or crimps. Each crimp is composed of many knots of each single fibril or fibrillar crimps. Fibrillar and fiber crimps play a mechanical role in absorbing the initial loading during elongation of both tendons and ligaments, and in recoiling fibrils and fibers when tissues have to return to their original length. This study investigated whether GAGs covalently attached to proteoglycan core proteins directly affect the 3D microstructural integrity of fibrillar crimp regions and fiber crimps in both tendons and ligaments. Achilles tendons and medial collateral ligaments of the knee from eight female Sprague-Dawley rats (90 days old) incubated in a chondroitinase ABC solution to remove GAGs were observed under a scanning electron microscope (SEM). In addition, isolated fibrils of these tissues obtained by mechanical disruption were analyzed by a transmission electron microscope (TEM). Both Achilles tendons and medial collateral ligaments of the rats after chemical or mechanical removal of GAGs still showed crimps and fibrillar crimps comparable to tissues with a normal GAG content. All fibrils in the fibrillar crimp region always twisted leftwards, thus changing their running plane, and then sharply bent, changing their course on a new plane. These data suggest that GAGs do not affect structural integrity or fibrillar crimp functions that seem mainly related to the local fibril leftward twisting and the alternating handedness of collagen from a molecular to a supramolecular level."} +{"text": "Prostate cancer continues to be a significant public health issue worldwide, particularly in countries where men have life expectancies long enough to clinically manifest the disease. In many countries, it remains one of the leading causes of cancer-related morbidity and mortality.Although significant progress has been made over the past few decades, many elements regarding the diagnosis and management of patients with prostate cancer remain enigmatic. In this Prostate Cancer special issue, our expert authors present and examine clinically relevant topics and look ahead to future research."} +{"text": "Cancer diagnosis coupled with emotional impact converge to create one of the most difficult physical and emotional periods of life. Cancer treatment causes plethora of short and long term complications which can be so debilitating that patient may interrupt treatment. Pretreatment oral assessment and supportive oral care during and after cancer therapy can increase quality of life and supportive care costs.Study was conducted on 189 patients receiving cancer therapy. Patients were subjected to clinical assessment and findings were recorded in specially designed proforma and complete oral (objective and subjective) and constitutional findings were recorded.Among the patients undergoing chemotherapy in both groups, prevalence of oral findings was found to be highest with methotrexate whereas constitutional symptoms was found to be highest with doxyrubicin. Whereas in radiotherapy patients subjective and objective oral symptoms increased from 10th - 30th fractionated dose of radiations and then subsequently decreased and constitutional symptoms were found to be consistent in all fractionated dosages with lowest at 50th fraction. Under combined chemo and radiotherapy patients, constitutional symptoms were highest than the oral findings.Cancer therapy can greatly damage the normal tissues and diminish patients quality of life and often leads to serious clinical sequelae. Therefore, therapy induced damage should be anticipated and prevented whenever possible and managed early. Head and neck cancer treatment primarily involves three modalities namely surgery, radiotherapy and chemotherapy, administered alone or in combination. Chemotherapy along with surgery or radiotherapy for advanced disease causes a plethora of short and long-term oro and oropharyngeal squeal. These complications are complex, dynamic pathobiological processes that lower the quality of life and predispose patients to serious clinical disorders.Most common adverse effects of these therapies includes mucositis, local or systemic infection, salivary gland dysfunction, taste alteration and pain, which later lead to secondary complications such as nutritional disorder, xerostomia or hemorrhage .These treatment modalities not only destroy cancer cells but normal cells also and tissues with high rates of proliferation namely hair follicles, gastrointestinal tract and oral cavity -4.Therapy based oral complications are due to high cellular turnover rates of the oral mucosa, a diverse and complex microflora, and trauma to oral tissues during normal oral function and often results in epithelial and glandular destruction and inflammation.Complications are so debilitating that patients may tolerate only lower less-effective doses of therapy, may postpone treatments or will discontinue treatment entirely. Considerable number of studies has been reported demonstrating varied adverse effects on oral mucosa due to cancer therapy but very few articles are reported depicting individual effects of drug and fractionation of radiation therapy causing stomatotoxicity.Thus the present study was conducted to evaluate the impact of cancer therapy regimens on individual well being and to establish relationship between chemotherapeutic drugs and oral side effects and also to evaluate relative effect of fractions of radiations on oral mucosa. Our objective was to characterize from the patient\u2019s perspective, the consequences resulting from cancer therapy.Hospital based survey performed on 189 patients with the age range of 16 - 70 years who were undergoing chemo and radiotherapy at Jawaharlal Nehru Cancer Hospital and Research Centre, Bhopal (MP).The study group comprised of 86 patients in group I (head and neck cancer cases: HNCC) and 103 patients in group II (other than head and neck cancer cases: OHNCC). Distribution of patients undertaking various treatments is given in Patients in each group were subjected to clinical assessment with prior consent from concerned authority followed by recording of findings in specially prepared performa to assess subjective and objective oral hard and soft tissue findings along with constitutional symptoms in response to chemo and radiotherapy .Oral complications due to chemotherapy were analyzed with respect to most commonly administered chemotherapeutics drugs in both group I and II. Radiotherapy associated complications were recorded correlating with fraction of radiation dose in group I alone and findings was also evaluated in patients undergoing combined therapy (chemo and radiotherapy) in both groups and results were tabulated in excel sheet for analysis.As the chemotherapeutic drugs administrated were common to both the groups, results were tabulated together. Prevalence of subjective and objective oral findings in both the groups was found to be highest with methotrexate (28.16% and 51.43%) and lowest with Paclitaxel drug (26.78% and 44.79%) respectively. Whereas constitutional symptoms was found to be highest with doxyrubicin (55.91%) and minimum with cisplatin (52.04%) . WhereasCases of regionally advanced disease in both group I and II after surgical intervention, have undergone combined chemo and radiotherapy in which constitutional symptoms were highest when compared to oral findings . HoweverPrevalence of oral complications from drug and radiation due to cancer therapy lies in the limited literature and potentially had unreported. Cancer therapy adverse effects results from two mechanism: a direct effect of the drug or irradiation on the oral mucosa (direct stomatotoxicity) or an indirect result of myelosupresion from drug or radiation therapy (indirect stomatotoxicity) . The dirThese complications may result in significant morbidity, treatment delays, dose reductions, and nutritional deficiencies , 10-12. Trends in the treatment of HNCC have led to an increasing use of chemotherapy with RT and the development of more intense RT regimens . FractioEffects of tumorcidal doses of radiation on healthy oral mucosa are divided into acute type, which occurs during treatment or shortly afterwards (2 - 3 weeks) and chronic types may occur months or even years after therapy .Previous studies reveal occurrence of oral mucositis in 97% and 100% of HNCC receiving conventional fractionated and altered fractionation RT radiotherapy respectively, which is in accordance with our study. In this study, only group I patients received radiotherapy without chemotherapeutic drugs after surgical intervention and showed increasing incidence of oral side effects from 10th - 30th fractions of radiation, whereas it decreased with advancing fractions this finding can be substantiated by the fact that as RT continues, a steady state between death and regeneration of mucosal cells could occur because surviving cells are produced at an increased rate.Combined chemo and radio therapy is now considered standard for most locally advanced tumors in both the cancer groups. Chemotherapy can be given prior to radiation therapy or alongside with radiation therapy. The toxicities of this combined therapy are essentially the same as with radiation alone but they develop more rapidly and severe, when they reach maximum level and these patients will be more immunosuppressed than those receiving radiation therapy alone. Therefore suspicion of oral infection should be high which includes odontogenic, candidal and herpes simplex infections. However in contrast, the present study showed high predilection for constitutional symptoms when compared to oral findings in both group I and II patients. So to this end the study illustrate the debilitating nature of mucosal injury in patients with cancer therapy and the need for new and effective therapies for oropharyngeal mucositis.Cancer therapy though cures the disease, can also greatly damage oral tissues and cause other systemic adverse effects. So a standard assessment tools and optimal prophylactic or therapeutic agents, emphasis on frequent and meticulous oral care are important for reducing the severity of oral complications. Adverse effects may be minimized by introducing prior biological response modifiers, cytoprotective drugs, tissue-sparing radiation technique and surgical advances."} +{"text": "During gross anatomy head and neck laboratory session, one dissection group observed an abnormal anatomic variation in the posterior cranial fossa of a 94-year-old male cadaver. The internal occipital crest was not aligned with internal occipital protuberance and groove for superior sagittal sinus. It seemed that the internal occipital protuberance was shifted significantly to the right side. As a result the skull was overly stretched in order to connect with the internal occipital ridge. These internal skull variations of occipital bone landmarks can influence the location of adjacent dural venous sinuses and possibly influence cerebrospinal fluid flow. Similar anatomical anomalies have been attributed to presence of hydrocephalus and abnormalities in cisterna magna. The posterior cranial fossa is posteriorly enclosed by the occipital bone. Internal occipital crest and internal occipital protuberance are prominent anatomical landmarks of the floor of the midsagittal plane of posterior cranial cavity. The internal occipital protuberance is identified as an elevated part of cruciform eminence which divides the occipital bone into four fossae: two upper cerebral fossae and two lower cerebellar fossae. The groove of transverse sinus separates the upper cerebral fossae from the lower cerebellar fossae. The groove for superior sagittal sinus is superiorly located to the protuberance. An elevated ridge that begins from the internal occipital protuberance down to the foreman magnum is the internal occipital crest, which also serves as attachment site for the falx cerebelli. Normally, the internal occipital crest, protuberance, and groove for superior sagittal sinus are aligned in a straight line. Occipital protuberance and internal occipital crest, as a group, are closely related to dural venous sinuses and binding of falx cerebri and falx cerebelli. Internal occipital crest traces the occipital sinus to the confluence of the sinus, located next to the internal occipital protuberance. These sinuses are located within layers of dura maters. Internal occipital protuberance is an important landmark where confluences of the transverse, occipital, and superior sagittal sinuses meet and falx cerebri and falx cerebelli folds attach.An obvious misalignment of the internal occipital protuberance and internal occipital crest was observed during a head and neck laboratory session for dental school students. It was noticed in a 94-year-old cadaver who died from malignancy of the prostate, ischemic heart disease, and cirrhosis of liver. To reveal the internal bony landmarks, horizontal cuts were made through temporal bone, frontal bone, and occipital bone of the skull using a schissel and a hammer . The intInternal occipital crest misalignment with internal occipital protuberance has been reported in the literature as a byproduct of select brain pathologies. According to a case report by Pozzati et al., 1979 , there wIn conclusion, further morphometric studies and clinical analysis are needed in order to reveal whether these skull/brain asymmetries are normal neuroanatomical variations or caused by certain brain pathologies."} +{"text": "Nutrition Journal, one of BioMed Central\u2019s open access journals. Diet is among the leading risk factors for morbidity and mortality globally [This editorial introduces a revised and refreshed scope for globally . This siNutrition Journal will prioritize manuscripts reporting on novel and high-impact research shedding light on factors that influence eating patterns among diverse populations, and studies that elucidate relationships between eating patterns and health and disease outcomes. We also welcome intervention research, including controlled trials but also natural experiments that uncover successes and challenges in implementing strategies to improve eating patterns among populations, including interactions between policies and programs and contextual factors. Within these areas, we invite manuscripts reporting on research conducted with various populations across the lifecycle and in diverse settings. Considered is research within public and population health, as well as in clinical settings and among individuals with chronic disease risk factors or endpoints.With its refreshed scope, Dietary assessment is fundamental to much nutrition research. With the refreshed scope, the journal places a more explicit focus on methodological considerations. We encourage authors to peruse publicly-available resources \u20134 relateIn all papers reporting on studies including the measurement of dietary intake, we encourage perusal of the checklist associated with the nutritional epidemiology extension of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement, known as STROBE-Nut . AlthougStudy protocol manuscripts will be considered in light of the aim of increasing transparency of methodology such that findings can be interpreted appropriately. Publication of protocols is also intended to contribute to the harmonization of methods across studies so the resulting evidence can be synthesized in a meaningful way. The journal thus welcomes the submission of manuscripts describing protocols for cohort studies and controlled trials, including studies designed to provide baseline data to enable leveraging natural experiments to offer novel insights. As above, within such papers, we seek detailed descriptions of the dietary methods and measures used to assess dietary exposures and outcomes and the considerations weighed in arriving at these methods and measures, as well as the planned use of statistical approaches to mitigate error in dietary data. Protocols for randomized controlled trials should be accompanied by the checklist corresponding to the SPIRIT Statement , 11.The journal will continue to consider systematic reviews and meta-analyses that adopt robust methods for the identification of relevant literature and abstraction of results. Authors of such papers should consult the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statemenFinally, given that publication in the peer-reviewed literature is only one of many approaches to dissemination with reach limited to particular audiences, the journal also encourages the submission of papers advancing the science of knowledge translation in the area of nutrition evidence, both to health professionals and members of the public.With our refreshed scope, we are embracing a theme of holism. The journal has a strong tradition of publishing research reporting on the impact of specific dietary constituents on risk factors for disease. We will continue to consider such studies provided a clear rationale is articulated, but encourage researchers to consider eating patterns more holistically given increasing recognition that it is the combination of foods and beverages we consume rather than particular nutrients or other dietary components in isolation that influence our health . Thus, wGiven our focus on advancing our understanding of nutrition and its influences in populations, the journal does not publish animal studies.Nutrition Journal is an open access, broad scope journal that focuses on human and population nutrition. All articles published by Nutrition Journal are made freely and permanently accessible online immediately upon publication, without subscription charges or registration barriers. Nutrition Journal operates an open peer-review system, which increases transparency and accountability through the identification of reviewers. Additional details regarding article types and submission guidelines can be found at https://nutritionj.biomedcentral.com/.Nutrition Journal. Our vision is to create a journal recognized for publishing high-quality human nutrition research with a focus on transparency and robustness of methods, particularly those used for measuring dietary exposures and outcomes and related dietary phenomena.We are very pleased to invite you to submit your research manuscripts to"} +{"text": "The sea lamprey is invasive to the Laurentian Great Lakes and managers have exploited the unique physiology of this basal vertebrate to control their populations and rehabilitate the Great Lakes ecosystem and fishery. Sea lamprey control is an example of conservation physiology successfully addressing a critical natural resource problem. Petromyzon marinus) control in the Laurentian Great Lakes of North America is an example of using physiological knowledge to successfully control an invasive species and rehabilitate an ecosystem and valuable fishery. The parasitic sea lamprey contributed to the devastating collapse of native fish communities after invading the Great Lakes during the 1800s and early 1900s. Economic tragedy ensued with the loss of the fishery and severe impacts to property values and tourism resulting from sea lamprey-induced ecological changes. To control the sea lamprey and rehabilitate the once vibrant Great Lakes ecosystem and economy, the Great Lakes Fishery Commission (Commission) was formed by treaty between Canada and the United States in 1955. The Commission has developed a sea lamprey control programme based on their physiological vulnerabilities, which includes (i) the application of selective pesticides (lampricides), which successfully kill sedentary sea lamprey larvae in their natal streams; (ii) barriers to spawning migrations and associated traps to prevent infestations of upstream habitats and remove adult sea lamprey before they reproduce; and (iii) the release of sterilized males to reduce the reproductive potential of spawning populations in select streams. Since 1958, the application of the sea lamprey control programme has suppressed sea lamprey populations by ~90% from peak abundance. Great Lakes fish populations have rebounded and the economy is now thriving. In hopes of further enhancing the efficacy and selectivity of the sea lamprey control programme, the Commission is exploring the use of (i) sea lamprey chemosensory cues to manipulate behaviours and physiologies, and (ii) genetics to identify and manipulate genes associated with key physiological functions, for control purposes. Overall, the Commission capitalizes on the unique physiology of the sea lamprey and strives to develop a diverse integrated programme to successfully control a once devastating invasive species.Sea lamprey ( Petromyzon marinus) control programme in the Laurentian Great Lakes of North America , one of the most commercially valuable species and one of the top predators was especially hard-hit because it is the preferred host of the sea lamprey by treaty in 1955 to coordinate fisheries management, implement a research programme to promote the rehabilitation of Great Lakes fisheries, and develop and implement a sea lamprey control programme. By the early 1960s, a sea lamprey control programme was developed through Commission-sponsored research. Annual application of sea lamprey control that continues today has reduced sea lamprey abundance from peak levels by nearly 90% across the lakes and allowed for the rehabilitation of fish stocks, in particular lake trout Fig. . SuccessSuccess of any pest control programme lies in gaining an intimate understanding of the biology and ecology of the target organism. After the sea lamprey invasion, scientists began collecting this knowledge by first determining the sea lamprey life cycle Fig. and distScientists at the time realized the best chance to control sea lamprey was during its stream-dwelling stages as either larvae or adults where they are relatively concentrated and their distributions are known. With this knowledge in hand, scientists began conducting research to understand the physiological vulnerabilities of the sea lamprey in hopes to ultimately develop sea lamprey control techniques to exploit these vulnerabilities. Since the 1950s, a suite of successful sea lamprey control techniques have been developed and refined with ongoing research. The control techniques in use today include lampricides, barriers to spawning migrations, traps and sterile male releases. These techniques are highlighted next along with the key physiological research responsible for their development and refinement.During the 1950s, scientists began searching for pesticides that could kill larval sea lamprey in their natal streams before they metamorphosed and migrated to the lakes to feed on fishes. Successful development of any pesticide lies in its selective toxicity to the target organism. For sea lamprey, the pesticide (lampricide) should kill larval sea lamprey, but have minimal effects on other species that reside in the same habitats. During the development of lampricides, nearly 10 000 mostly organic compounds were screened for their selective toxicity to sea lamprey . Two comEarly speculation, based on studies from similarly structured compounds, was that TFM disrupts oxidative phosphorylation leading to rapid energy depletion , but it Oncorhynchus mykiss; Selectivity of TFM appears to be associated with differences in the ability of sea lamprey and other fishes to detoxify and excrete TFM after biotransformation through the process of glucuronidation . The mosAdditional physiological research identified key environmental variables that affect TFM toxicity and selectivity. In particular, pH was found to have an inverse relationship with TFM toxicity . TFM toxThe original discovery of TFM and niclosamide led to the creation of a highly effective, large-scale, lampricide application protocol, which has been refined over 60+ years based on further physiological research to increase its effectiveness and selectivity. Even though much has been learned about the mode of action of lampricides, particularly TFM, elucidation of exactly how TFM and niclosamide disrupt oxidative phosphorylation could provide further information to enhance current lampricide treatments and insights into the identification and development of more effective and selective lampricides. Although the effects of lampricides on stream macro-invertebrates has been studied , researcBefore the development of lampricides, some of the earliest control tactics exploited the adult sea lamprey's strong instinct to swim upstream , includiMost purpose-built sea lamprey barriers have adult sea lamprey traps either integrated into their design or placed along their face Fig. . These tSea lamprey barriers are critically important to the sea lamprey control programme. In fact, sea lamprey control would likely not exist if it were not for sea lamprey barriers, especially those built for other purposes that protect thousands of kilometres of streams from sea lamprey infestation. The increase in the amount of lampricide needed to control sea lamprey in the absence of these barriers would likely not be economically feasible. Nevertheless, the need for sea lamprey barriers can conflict with the ecosystem and fishery restoration goals of allowing native fish passage to historical habitats to rehabilitate their populations. Additionally, although traps serve a critical assessment function for sea lamprey control, their potential as a control tactic has not yet been fully realized . ResearcThe release of sterilized males, a technique first developed for insects , has beeN-methylphosphinothioic amide -Bisazir; was an eBisazir; . BisazirBisazir; , howeverBisazir; . ImportaBisazir; ; 1978, aBisazir; . MaintaiThe sterile male release technique was first field tested in Lake Superior streams and the St. Marys River from 1991 to 1996 and was Although the sterile male release technique is currently not being deployed, it still remains a viable sea lamprey control option for low density populations. Valuable lessons were learned during the technique's previous deployments and a reCurrent sea lamprey control relies exclusively on lampricides and barriers, two technologies that can have significant negative impacts on non-target organisms. Even though ongoing physiological research continues to sharpen the effectiveness and selectivity of these techniques, there is a strong desire to develop new, innovative techniques that could provide levels of effectiveness and selectivity yet to be seen and prevent catastrophic population increases if one of the current techniques is rendered ineffective (e.g. development of lampricide resistance). Two avenues of research, chemosensory cues and genetics, have shown strong potential for the development of effective and selective sea lamprey control tactics and are discussed below. Other aspects of sea lamprey, non-target organism and host fish physiologies are being explored with the intent of further integrating and advancing sea lamprey control, but are not highlighted in this article.The use of chemosensory cues such as pheromones and alarm substances has long been suspected of potentially being useful for sea lamprey control purposes . AlthougThe adult sea lamprey's reproductive journey begins with finding suitable spawning streams while navigating vast expanses of open water. Adult sea lamprey do not home , but insSea lamprey complete sexual maturation while migrating within streams. Male sea lamprey typically precede females in migrating to spawning areas consisting of gravel/cobble substrate and cool, well-oxygenated water . Males bMost recently, investigations of the importance of alarm cues to sea lamprey reproductive fitness have begun. Alarm cues can be odours produced by both dead or alive conspecifics and heterospecifics and are hypothesized to function in sea lamprey as a way to assess risk, for instance, predatory risk, the risk of choosing poor habitat conditions and the risk of choosing streams in which spawning has already occurred (sea lampreys die after spawning). In support of this hypothesis, conspecific odours from deceased sea lamprey have been shown to induce avoidance and flight responses in adult conspecifics ; Fig. 10Chemosensory cues have been proposed to be integrated into the sea lamprey control programme in several ways, including trapping of adults, redistribution of adults to areas that would reduce fitness , communication disruption via agonists and antagonists, and population assessment . Adult tGenetic technologies have been hypothesized to hold considerable promise for the control of invasive fishes and wereOne possible mechanism in which sea lamprey control could be achieved through genetic manipulation is gene knockdown. Morpholinos are one potential gene knockdown technique . MorpholAnother gene manipulation approach that has recently advanced is exploitation of the CRISPR/Cas system . The CRIAnopheles gambiae; Cyprinus carpio) to create all male offspring in hopes of eradicating local invasive populations to distort sex-ratios for control purposes in mosquitos . Finally, physiological knowledge gained through the sea lamprey control programme could also be conversely used to inform conservation of sea lamprey in their native range where they are imperiled. Clearly, sea lamprey control in the Laurentian Great Lakes of North America is a successful example of conservation physiology."} +{"text": "Structured interventions on lifestyle have been suggested as a cost-effective strategy for prevention of cardiovascular disease. Epidemiologic studies demonstrate that dietary salt restriction effectively decreases blood pressure, but its influence on cardiovascular morbidity and mortality is still under debate. Evidence gathered from studies conducted in patients with primary aldosteronism, essential hypertension, or heart failure demonstrates that long-term exposure to elevated aldosterone results in cardiac structural and functional changes that are independent of blood pressure. Animal experiments and initial clinical studies indicate that aldosterone damages the heart only in the context of an inappropriately elevated salt status. Recent evidence suggests that aldosterone might functionally interact with the parathyroid hormone and thereby affect calcium homeostasis with important sequelae for bone mineral density and strength. The interaction between aldosterone and parathyroid hormone might have implications also for the heart. Elevated dietary salt is associated on the one hand with increased urinary calcium excretion and, on the other hand, could facilitate the interaction between aldosterone and parathyroid hormone at the cellular level. This review summarizes the evidence supporting the contribution of salt and aldosterone to cardiovascular disease and the possible cardiac and skeletal consequences of the mutual interplay between aldosterone, parathyroid hormone, and salt. Arterial hypertension is the most frequent modifiable cardiovascular risk factor. The NHANES has estimated a prevalence of hypertension of 30% among the adult population, and that approximately 85% of people between 55 and 65 years will develop hypertension within their lifetime . BecauseEvidence gathered in the last decades indicates that, in addition to the well-known renal tubular actions, aldosterone regulates many cellular functions. These cellular effects of aldosterone result in the regulation of specific responses including tissue remodeling, hypertrophy, and fibrosis . In factIncreasing evidence indicates that, beyond its cardiovascular effects, aldosterone excess might affect also mineral metabolism and have specific relevance for calcium homeostasis \u201315. BecaThe association between dietary salt consumption, hypertension, and cardiovascular disease has long been the subject of important epidemiological studies. Because of significant discrepancies among the findings of these studies, this association remains under debate .Dietary salt consumption has long been associated with blood pressure regulation. In fact, hypertensive patients have been classified as \u201csalt-resistant\u201d or \u201csalt-sensitive\u201d depending upon their blood pressure response to an oral or intravenous salt load. Salt is distributed in the extracellular fluid and, as such, participates in blood pressure regulation . The effThe relationship between dietary salt intake and blood pressure was initially investigated in the International Study of Salt and Blood Pressure (INTERSALT) population study . This stDespite the evidence supporting the contribution of salt to blood pressure regulation, the potential benefits of dietary salt restriction on cardiovascular morbidity and mortality are uncertain. The association of daily salt intake, as assessed by urinary sodium excretion, with a composite outcome of cardiovascular events and mortality was prospectively investigated in a 3-year follow-up study . An incrLandmark studies have tested the effects of aldosterone antagonists on patients with systolic cardiac failure reporting a highly significant decrease in mortality as compared to placebo and suppPrimary aldosteronism is associated with cardiac changes that might reflect the ability of inappropriately elevated circulating aldosterone to cause myocardial damage beyond that induced by high blood pressure itself. Longitudinal retrospective studies have shown that patients with primary aldosteronism have a greater risk of atrial fibrillation and coronary artery and cerebrovascular disease than matched patients with essential hypertension \u201332. AlsoBecause of the relevance of left ventricular hypertrophy and diastolic dysfunction in patients with essential hypertension, the possible contribution of circulating aldosterone to these cardiac changes has been extensively investigated. Initial observations indicated that aldosterone antagonists decrease left ventricular mass in patients with essential hypertension and left ventricular hypertrophy , 39 and In 44 elderly patients with cardiac failure and preserved ejection fraction, eplerenone improved left ventricular diastolic function more than conventional treatment . In the The hypothesis of an interplay between dietary salt and aldosterone in causing cardiac damage was extensively supported by the findings of animal studies , 9. SomeIn the clinical setting, observations on the contribution of salt to aldosterone-mediated cardiac damage are restricted to a few studies . In a poAn interaction between components of the renin-angiotensin-aldosterone system and hormones involved in calcium homeostasis was initially suggested in patients with salt-sensitive hypertension by Resnick et al. and has In support of the close interplay existing between PTH and aldosterone, recent evidence indicates that type-1 PTH receptors are expressed in aldosterone-producing adenomas and explThe interplay between salt, aldosterone, and PTH has received robust support from experimental animal studies. Treatment of rats with aldosterone and 1% dietary salt increases urinary and intestinal calcium excretion causing hypocalcemia and increased PTH secretion . In thesIn the setting of heart failure, aldosterone secretion is increased as a result of renin-angiotensin axis activation and causes salt and fluid retention. The inappropriate elevation of aldosterone for the salt status increases urinary and intestinal calcium losses with subsequent activation of PTH production . This exRobust scientific evidence demonstrates a relationship between salt intake and blood pressure and supports the benefits of salt restriction in hypertension. Conversely, the possible benefits of dietary salt restriction on cardiovascular outcomes are still debated because intervention studies and cumulative analyses have not been able to provide thoroughly convincing results. Current evidence unquestionably supports the view that elevated aldosterone causes cardiovascular damage well beyond what could be expected just from blood pressure elevation. Animal studies clearly indicate that aldosterone-dependent cardiac damage is strictly dependent on the salt status and this view is corroborated by the results of some human studies. A close interaction between aldosterone, calcium, and PTH has been demonstrated that is dependent on the salt status both in healthy subjects and in disease states. This complex interplay of salt with aldosterone and PTH might contribute to the development and progression of organ damage in patients with primary aldosteronism or primary hyper-PTH, in patients with heart failure, and in subjects with dietary salt excess. These observations might have important therapeutic implications inasmuch as dietary salt restriction, aldosterone blockers, calcimimetic drugs, and PTH receptor blockers might prove beneficial for cardiovascular and bone protection in these conditions. The effects of all these interventions will have to be tested in appropriately designed studies."} +{"text": "Dementia is a debilitating and life-altering disease which leads to both memory impairment and decline of normal executive functioning. While causes of dementia are numerous and varied, the leading cause among patients 60 years and older is Alzheimer\u2019s disease. The gold standard for Alzheimer\u2019s diagnosis remains histological identification of amyloid plaques and neurofibrillary tangles within the medial temporal lobe, more specifically the entorhinal cortex and hippocampus. Although no definitive cure for Alzheimer's disease currently exists, there are treatments targeted at preserving cognition and memory while delaying continued loss of function. Alzheimer's disease exists along a spectrum of cognitive decline and is often preceded by Mild Cognitive Impairment (MCI). Patients with MCI demonstrate memory loss and cognitive impairment while still continuing normal activities of daily living, and are considered to be at increased risk for developing Alzheimer's Dementia. Identifying patients with prodromal states of Alzheimer's dementia such as MCI may allow initiation of appropriate treatment planning and delay of cognitive decline. Therefore, the need for a non-invasive early biomarker for the detection of Alzheimer's disease has never been greater. Multiple neuroimaging methods utilizing visual rating scales, volumetric measurements, and automated methods have been developed to identify, quantify, and track anatomic sequelae of Alzheimer\u2019s Disease."} +{"text": "A 45-year-old female patient with left-sided lobular carcinoma in situ underwenWhat are the challenges of breast augmentation after autologous reconstruction?What factors determine survival of free flaps?What has often been suggested in literature to increase flap safety during augmentation with pedicle division?Are there recommended wait periods after free tissue breast reconstruction before pedicle divisions can be safely performed?Breast reconstruction combining implants with autologous tissue has been performed in the past. Combining autologous and implant-based methods for breast reconstruction allows for reduction in the risk of wound breakdown and infectionSurvival of free flaps is initially based on the vascular pedicle, but other factors contribute to survival after a period of time, including closing of arteriovenous shunts,Although multiple clinical studies and reports demonstrate reliance on the vascular pedicle, there have been reports of flap survival after early division or compromise of the vascular pedicle.However, Enajat et alIn this case, the patient desired additional volume that autologous tissue was not able to provide. Therefore, alloplastic implantation was pursued and division of the pedicle provided the advantage of allowing for proper subpectoral placement and medialization of the implant. We demonstrate that an alloplastic implant can be added at a second stage with autologous breast reconstruction utilizing TUG free flap, and the vascular pedicle can be safely divided after 6 months to allow for optimal placement of the implant."} +{"text": "Transgender persons are at high risk for human immunodeficiency virus (HIV) infection; in a recent analysis of the results of over nine million CDC funded HIV tests, transgender womenBRFSS is an annual, state-based, random-digit\u2013dialed cellular and landline telephone survey of the noninstitutionalized U.S. adult population.Pooled data collected in 2014 and 2015 were used to compare demographic characteristics and HIV testing among transgender and cisgender respondents. Cisgender men who reported sexual orientations of gay or bisexual represent a group at high risk for HIV infection and men (66.9%) had a higher prevalence of ever testing than their white counterparts . Among transgender women, the highest prevalence of ever testing (68.5%) was reported by those who had ever received a diagnosis of a depressive disorder . After aDespite the high risk for HIV infection previously reported among transgender populations, nearly two thirds of transgender women and men in the sample reported never testing for HIV, which is consistent with evidence suggesting that many HIV-infected transgender women are not aware of their status , which reduced the precision of HIV testing estimates. Second, BRFSS transgender data are only representative of transgender persons in the 28 jurisdictions that participated in the optional module and therefore cannot be generalized to the entire U.S. transgender population. Third, the measure of gender identity might incorrectly classify transgender respondents who self-identify simply as man or woman rather than transgender man or woman, which would potentially underestimate the number of transgender persons in the sample. Finally, because BRFSS does not ask questions about HIV status or sexual risk behaviors, the analytic sample might have included respondents who are already living with HIV infection or who are not at risk for HIV infection and therefore would be less likely to have tested for HIV in the past year or at all.The findings of this analysis indicate suboptimal rates of HIV testing among transgender women and men. The population-based estimates in this report can serve as a baseline for future monitoring of testing trends among transgender persons. Intensified and expanded use of culturally appropriate recruitment methods by public health officials might enhance activities to reach transgender women and men and increase the rates of testing. CDC is currently working to enhance the capacity of community-based organizations to provide targeted HIV testing in addition to other prevention and support services to transgender persons who are at risk for or have newly diagnosed HIV. These programs and other innovative approaches are needed to improve delivery of HIV testing and other prevention services to transgender persons.Transgender persons are at high risk for HIV infection. CDC recommends that persons at high risk for HIV infection be screened for HIV at least annually, but transgender persons are not specified in the current recommendations, and current nationwide HIV testing rates for transgender persons are unknown.This analysis of 2014 and 2015 Behavioral Risk Factor Surveillance System data showed that transgender women and men self-reported a lower prevalence of HIV testing (both ever and in the past year) compared with gay and bisexual men whose gender identities match their sex assignments at birth (cisgender). Transgender women and men self-reported testing at levels similar to cisgender heterosexual men and women.Transgender women and men reported current HIV testing levels that were inconsistent with their HIV risk profiles. Innovative, tailored approaches might be needed to reach transgender persons who are not being reached by existing HIV prevention strategies that focus on other key populations, such as gay, bisexual, and other men who have sex with men."} +{"text": "This article discusses the use of enteral nutrition in the management of stroke. Stroke is a major source of disability, including dysphagia. The clinical manifestation of swallowing difficulties in stroke patients may lead to malnutrition which has implications for health status and clinical outcomes including morbidity, mortality and cost to the health service. The prevalence of malnutrition following an acute stroke could range from 8% to 34%. Therefore, the need to develop and implement the use of enteral nutrition support in stroke patients becomes pertinent. A range of enteral feeding tubes and feeding methods may be used to support stroke patients who are unable to meet their nutritional requirements through oral intake alone, although each of these approaches has its merits and limitations. Based on this review, there is evidence that enteral nutrition support is a useful method of providing nutrition for patients with dysphagia following a stroke in order to enhance their nutritional status and promote their health. However, there are challenges in the use of enteral tube feeding in these patients. Enteral nutrition provides support to individuals who are unable to meet their nutritional requirements through oral intake alone. Most of these individuals have neurological conditions, such as stroke, which impact the swallowing process, causing dysphagia. Irrespective of the underlying medical condition, nutrition support products provide protein, energy, minerals and vitamins. These products can be given as oral nutritional supplements (ONS), when there are no contraindications, such as dysphagia, or may be delivered via enteral feeding tubes . There aThe National Institute for Health and Care Excellence (NICE) guideline applied The consequences of stroke may be profound and can include impaired mobility, communication, dysphagia, and depression . Stroke While 20% of patients following a stroke may require enteral tube feeding during the acute phase, 8% will require long-term enteral tube feeding for more than six months . The pro2), those with unintentional weight loss (>10% within the last six months) and those who have eaten little or no food in the last five days or may eat little or no food for five days or longer [The National Institute for Health and Care Excellence (NICE) guideline states tr longer .Validated screening of people at risk of malnutrition involves the use of the malnutrition universal screening tool (MUST) which defines the risk of malnutrition as low risk (score 0), medium risk (score 1) and high risk (score 2 or above) . This wiWhen a patient has failed a swallow test and is unable to safely tolerate oral fluids or food, an NGT should be inserted within 24 h ,21. If aThe role of nutrition support services is to treat the underlying cause of malnutrition or manage the high risk of malnutrition . An inteIn hospital, the nutritional status of patients following a stroke can deteriorate and malnutrition following admission has been observed to be associated with case fatality and poor functional status . DecisioThere are medical indications for NGT and PEG tube insertions and these include people with acute stroke who are unable to tolerate adequate nutrition and fluids orally . A furthIn a recent study, ischemic stroke patients with dysphagia were compared with patients with normal swallowing ability . Based oThe implication of these studies would suggest that there are merits and limitations with the use of enteral feeding tubes in dysphagic patients following a stroke. Poor outcomes reported included patients with a PEG tube being at greater risk of developing pressure sores than those with NGT, possibly due to reduced mobility and different nursing approaches . An addeAn important element of care during enteral tube feeding is the provision of regular oral hygiene, frequent replacement of the NGT and enhanced input by a physiotherapist through mobilisation of sedentary stroke patients . These aInsertion of a NGT in patients following a stroke is complex due to their communication difficulties, inability to swallow and possible confusion . TherefoThe FOOD Trial Collaboration found a positive impact of the provision of early enteral nutrition on mortality . The outThe benefits of early initiation of enteral nutrition in patients following a stroke who are in a coma has been explored, and Yamada concludeDiarrhoea is a common problem that is associated with enteral tube feeding and may further exacerbate the condition of patients following a stroke who are already at risk of malnutrition . The durEnteral nutrition support is a useful method of providing nutrition for patients with dysphagia following an acute stroke in order to meet their nutritional requirements. This could be delivered by means of a NGT or PEG feeding tube. Although there are advantages in these methods of enteral tube feeding, difficulties remain."} +{"text": "Since 2010, the World Health Organization has recommended universal malaria diagnostic testing to guide treatment of febrile illness as a fundamental component of malaria case management \u2013 examintour de force. The resulting publications demonstrate program-relevant observations. Access to malaria diagnostic testing was poor and wildly inequitable shortly following the universal diagnosis policy \u2013 particularly in peripheral health facilities. None of the nationwide surveys showed the promised reductions in ACT consumption at a population level, at least not at first. Moreover, countries varied greatly in terms of what impact malaria diagnostic testing had on fever management overall. While clinical guidelines for antibiotic use appeared straightforward, they still required considerable judgment on the part of health workers \u2013 who were frequently left feeling unsupported, especially when malaria test results were negative. Once malaria diagnostic testing had become established, however, a majority of health workers adapted to using the results to guide malaria-specific treatment. But antibiotic overtreatment was common, especially among children testing negative for malaria, and was influenced by the presence of other symptoms such as cough or difficult breathing. Arriving at each of these discrete findings, Dr. Johansson establishes an approach that she and others can revisit as new evidence and experience accumulate.Johansson and her colleagues \u20137 interrWhile each of the four specific papers stands on its own, Johansson's skill really shines in the front matter and discussion that bring these disparate approaches into sharp focus and point toward program action. The works are linked by a thoughtful conceptual framework that emphasizes access, facility readiness, and clinical practice. The diffusion of innovations theory affords a useful perspective from which Johansson and her colleagues consider their findings in light of rapid and ongoing changes in policy and practice. She also contextualizes malaria RDT implementation in the integrated management of childhood illness and challenges the dominant focus on malaria-related commodities and outcomes. She ends by advancing the case that malaria diagnostics represent an underappreciated opportunity for malaria-specific investments to contribute to broader systems strengthening efforts.The implications of Johansson's studies for future work are varied. There is still much to be done before malaria diagnosis becomes universally available and applied. This will require a further commodity shift so that RDTs can greatly outnumber ACT treatments. But there is good evidence now that despite some initial concerns health workers can quickly adjust to making malaria treatment decisions on the basis of a diagnostic test. The situation is far less clear for the management of non-malarial fevers, and more thought is needed to rationalize treatment decisions and antibiotic prescribing in this setting. It would also be troubling if the fledgling confidence in malaria RDTs were undermined by concern over focal reports of malaria parasite populations undetectable by the most common testing platform . The glotrack (Finally, malaria policy makers would be well-advised to accept Dr. Johansson's challenge and recognize the important opportunity universal malaria diagnostic testing presents for enhancing health systems through malaria investments. This should include a more comprehensive program to address children who test negative, including the right guidance, commodities, and support to empower health workers to treat them adequately. Another important direction would be to ensure that the information created by wider application of malaria RDTs was captured and reported through improved surveillance systems. Johansson's title only partially references WHO's T3 strategy for scaling up malaria diagnosis: test, treat, and track . CapturiGlobal policy and procurements for malaria diagnostics still lean heavily toward the disease-specific Millennium Development Goals. By encouraging the malaria community to embrace the systems strengthening potential of its investments, Dr. Johansson also points us toward closer alignment with the more cross-cutting elements of the Sustainable Development Agenda. Let's take her up on it."} +{"text": "Triticum aestivum L.) were investigated in field experiments. Selective sequential extraction procedures revealed that application of pond sediment in soil increases the labile pools of the studied heavy metals . Risk assessment codes concluded that Cu and Pb were in the high-risk zone in both pond sediment and soil amended with pond sediment, whereas Zn and Cu were found in the medium-risk zone for control soil. Heavy metal accumulation by wheat straw and grain was significantly increased through application of pond sediment. However, metal accumulation did not thwart the enhancement of wheat yield when pond sediment was applied. Health risk indexes of analyzed heavy metals were found to be within the Indian permissible limit for foodstuffs. Pond sediments help to fortify wheat grain by increasing the concentration of Zn and Cu as a source of micronutrients in the diet. However, a significant increase of Pb in wheat grain through pond sediment could be a health concern for its long-term application. Therefore, pond sediment would be a valuable resource for agriculture as an alternative organic supplement, but long-term use may require the cessation of the excavated sediment as agricultural landfill in order to restrict heavy metal contamination through it.The risks of heavy metal accumulation and the dynamics related to roadside pond sediment application in comparison to control of winter wheat ("} +{"text": "Congenital duodenal obstruction (CDO) in children is a kind of common upper gastrointestinal malformation with various pathological types, caused by the abnormal embryonic development, including duodenal stenosis and atresia, annular pancreas. CDO in children is often manifested as abdominal distension, frequent and severe bilious vomiting; such children often need to receive the operation to establish the continuous digestive tract, and to be fasted after operation to reduce the risk of anastomotic fistula. Therefore, the postoperative nutritional support appears particularly important. The jejunal nutrient tube has been increasingly used in child and adult critical patients in recent years \u20132, so asThe present study investigated the role of jejunal nutrient tube in postoperative enteral nutrition support for child patients with CDO.The clinical data of 17 child patients with CDO (observation group) receiving surgical treatment and intraoperative placement of jejunal nutrient tube for early enteral nutrition from January 2013 to June 2017 were analyzed retrospectively. Fifteen child patients with CDO (control group) receiving laparoscopic surgery but without undergoing the enteral nutrition via jejunal nutrient tube in our hospital were selected. The perioperative period, postoperative complications and changes in some nutritional indexes were compared between the two groups. Informed consent was taken from the participants and the study was approved by the hospital authorities.P<0.05). The increase ranges of serum total protein, albumin and body weight after operation in observation group were significantly larger than those in control group (P<0.001).All of 17 child patients \u20133 in obsEN refers to the injection of nutrients required for the body to maintain the basic functions or growth and development into the patient\u2019s intestine through different ways, replacing the gastric digestive function, which can provide necessary nutritional support for child patients with gastric digestive dysfunction .With the understanding of the EN in children and the update of catheter material and inserting technique, EN via jejunal nutrient tube in children has been gradually recognized by Chinese Society of Parenteral and Enteral Nutrition . In this"} +{"text": "Populations affected by humanitarian emergencies may require unique strategies to ensure access to life-saving vaccines and attain sufficiently high population immunity to interrupt virus circulation. Vaccination strategies among displaced populations should not be an afterthought and must be part of the vaccine-preventable disease eradication and elimination initiatives from the start. According to the UN High Commissioner for Refugees (UNHCR), there were 59.5 million forcibly displaced persons worldwide by the end of 2014 due to persecution, conflict, generalized violence, or human rights violations, and this number is only expected to increase with numerous ongoing global conflicts [There are a number of VPD eradication and elimination initiatives taking place worldwide. Eradication is defined as the permanent reduction to zero of the worldwide incidence of infection caused by a specific agent as a result of deliberate efforts; whereas elimination is the reduction of the incidence of a specified disease to zero in a defined geographic area . Among tGlobal VPD eradication and elimination initiatives are resource intensive in terms of finance and human resources. Experiences with GPEI and MRI have shown that populations displaced due to humanitarian emergencies can increase the risk of VPD outbreaks and thereby adding to the resources needed to meet VPD eradication and elimination goals \u201310. AlthThe spread of VPDs among displaced populations and susceptible host communities has not been limited to the Middle East. A 2013 outbreak of polio in refugee camps along the Kenya Somalia border spread into the surrounding communities resulting in reactive vaccination efforts in both the camps and non-camp populations . OutbreaVarious guidance documents for vaccination efforts in acute humanitarian emergencies are currently available , 14 TradUnless plans are made upfront to include displaced populations in national and regional VPD control efforts, global eradication and elimination goals may not be achieved within the targeted time frame. Vulnerable populations affected by humanitarian emergencies may require unique strategies to ensure that these populations have access to life-saving vaccines and attain sufficiently high population immunity to interrupt virus circulation. The Global Vaccine Action Plan (GVAP) 2011\u20132020 highlights, in its third strategic objective, the importance of ensuring equitable access of vaccines to all people including those in humanitarian crises and conflict zones . GVAP ca"} +{"text": "These advantages generate great potential for the clinical applicability of NIRS as a means of evaluating muscle dysfunction in clinical populations.The ability to sustain submaximal exercise is largely dependent on the oxidative capacity of mitochondria within skeletal muscle, and impairments in oxidative metabolism have been implicated in many neurologic and cardiovascular pathologies. Here we review studies which have demonstrated the utility of Near-infrared spectroscopy (NIRS) as a method of evaluating of skeletal muscle mitochondrial dysfunction in clinical human populations. NIRS has been previously used to noninvasively measure tissue oxygen saturation, but recent studies have demonstrated the utility of NIRS as a method of evaluating skeletal muscle oxidative capacity using post-exercise recovery kinetics of oxygen metabolism. In comparison to historical methods of measuring muscle metabolic dysfunction Specifically, mitochondria have been widely recognized for their ability to produce cellular free energy in the form of adenosine triphosphate (ATP) through oxidative phosphorylation. Oxidative phosphorylation is an oxygen-dependent biochemical process which converts biological fuels to ATP and functions as the primary mechanism of energy production at rest and during aerobic exercise. Skeletal muscle energy demands can increase 100-fold during exercise, and the ability to sustain submaximal exercise is largely dependent on the production of ATP via mitochondrial oxidative phosphorylation , quantify mitochondrial content, and evaluate enzyme activity levels in excised tissue samples. Indeed, these techniques provide important information related to specific mtDNA mutations and mitochondrial enzyme deficiencies, and therefore, play a critical role in the diagnosis and characterization of various mitochondrial diseases can be used in a similar manner to measure the recovery of oxygen metabolism following a brief bout exercise as an assessment of mitochondrial oxidative capacity = End \u2212 \u0394 \u00d7 ekt\u2212 often results in deactivation of skeletal muscle below the level of injury. The loss of chronic skeletal muscle activation can lead to muscle atrophy and changes in muscle phenotype which may impede the rehabilitation processes and increase cardiometabolic risk Shields, . The phySkeletal muscle in persons SCI has also demonstrated considerable plasticity is an autoimmune disease which causes degradation of myelin and axonal damage in the central nervous system (CNS). The demyelination of axons impairs neural transmission in the CNS which can impede voluntary muscle activation and motor control is a progressive neurological disease characterized by the degradation of motor neurons in the CNS. While the damage to cerebral, spinal, and peripheral neurons has been implicated in the progression of ALS, there is increasing evidence suggesting that skeletal muscle mitochondria are also directly affected by the pathology is a progressive condition associated with poor quality of life and multiple comorbidities. In addition, reduced exercise capacity is common in persons with HF, but the link between the pathophysiology of HF and exercise intolerance is unclear is associated with survival , suggesting that other factors may be involved is an autosomal recessive genetic disease which results in dysfunction of the CF transmembrane conductance regulator (CFTR) protein. CFTR is a chloride ion channel that plays a critical role in the regulation of mucus in the airway, and persons with CF experience deficiencies in clearance which can result in chronic bacterial infections and inflammation is progressive condition characterized by reduced airflow during pulmonary ventilation resulting from thickening of airways, reduced alveoli elasticity, and chronic inflammation MacNee, . COPD isIn vitro studies of respiratory chain function in humans with FRDA have found 84% reduction in complex I and 77% complex III activity in cardiac muscle, but no significant reduction was found in skeletal muscle is a mitochondrial disease caused by a genetic mutation of the FRDA gene. Alterations of the FRDA gene sequence can disrupt production of the mitochondrial protein frataxin, and studies have shown that persons with FRDA have lower levels of frataxin , the noninvasive nature of the technique permits multiple measurements to be performed in close proximity tissue sample responsible for changes in mitochondrial capacity. For example, NIRS cannot identify changes in mitochondrial volume, substrate utilization, or dysfunction within the electron transport system. Indeed, the mechanisms underlying mitochondrial dysfunction are different depending on the pathology, and future studies may be strengthened by combining NIRS with Recent studies have demonstrated the utility of NIRS in the evaluation of mitochondrial dysfunction in persons with neurological, autoimmune, cardiovascular, and mitochondrial diseases. NIRS provides an affordable, versatile, and noninvasive technique for evaluating mitochondrial oxidative capacity of skeletal muscle in clinical populations.TW performed literature review and composed manuscript. KM designed and revised manuscript.KM is the president of Infrared RX. The other author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Despite growing efforts to understand the role of the microbiota in airway disease, mechanisms that link microbial community dysbiosis to chronic inflammation remain elusive. Our laboratory is interested in how altered microbiota composition or function influences airway inflammatory diseases, including chronic rhinosinusitis, asthma, and cystic fibrosis. in vitro and in vivo experimental validation. An increased understanding of the role of the microbiota in chronic airway inflammation will ultimately lead to the rational development of therapeutics aimed at manipulation of microbiota composition or activity to treat these important and costly diseases. In this perspective, I discuss our current research investigating the microbiology and ecology of the airway microbiome.Despite growing efforts to understand the role of the microbiota in airway disease, mechanisms that link microbial community dysbiosis to chronic inflammation remain elusive. Our laboratory is interested in how altered microbiota composition or function influences airway inflammatory diseases, including chronic rhinosinusitis, asthma, and cystic fibrosis. Given the tight interplay between host-associated microbes and host immunity, the potential for translational microbiome research to guide clinical decisions and novel therapeutics is becoming better appreciated. We hope to advance our understanding of the ecology of airway disease through integrating multiple omics assays and WhetherAn emerging body of evidence indicates that local mucosal microbial composition and function are related to the host immune response in the airways and at oCRS often exists in a setting of concomitant lower airway disease . Two exain vitro and in disease models. Layering of multiomics assays will permit identification of the primary microbial producers and the molecules that mediate microbiome-host interactions underlying chronic inflammation. The resolution achieved through metagenomic sequencing will capture the functional genomic potential and strain level diversity of bacteria, fungi, and viruses in patients with CRS. The power of this approach was recently demonstrated in a study of atopic dermatitis that influence dendritic-cell\u2013T-cell interactions, leading to suppression of anti-inflammatory Foxp3+ CD25+ CD4+ Treg cells (A second goal of my laboratory is to identify microbiota-derived molecules that promote the selection of pathogenic microbial communities and drive specific inflammatory profiles. Bacteria and fungi coinhabit the human body, and the microbial interactions within niche-specific microbiomes can influence health and disease. Bacterial cocolonizers can directly affect fungal morphology, growth, virulence, and attachment to host epithelia or other microbes . We are rmicutes . Recent eg cells . Future eg cells . Other bGiven the tight interplay between the microbiota and host immunity, the potential for microbiome research to guide clinical decisions and novel therapeutics is becoming better appreciated. Advances in our understanding of the microbial mechanisms that drive disease and maintain host immune homeostasis will facilitate the development of strategies for microbiome manipulation, which holds great potential for treating a myriad of human diseases. I anticipate that the next 5\u00a0years will bring advances in our understanding of the ecology of airway disease through a systems biology approach facilitated by the application of layered multiomics paired with experimental validation.Like other translational microbiome projects, we hope to understand how dysbiotic microbiotas drive inflammation and develop strategies to manipulate these communities. At this juncture, we should use caution when developing therapeutics designed to manipulate microbiotas before we fully understand the mechanisms driving disease and microbial interactions. Premature efforts could lead to ineffective treatment because we do not yet understand the complexity of microbial interactions that could lead to increased host inflammatory responses or virulence. Microbiotas in peripheral organs, such as the gut, may also influence airway health. Experimental evidence suggests that manipulation of the GI microbiota can alleviate or prevent allergic airway disease . HoweverAs a field, we should develop and embrace multiomics approaches that integrate information from metagenomes, metabolomes, and metatranscriptomes to obtain a more comprehensive understanding of the microbiological and ecological processes that govern microbial community function within a niche. This will inform our design of future microbiota-targeted therapeutics, including whether keystone or foundation species are appropriate, whether the goal of probiotics should be stable engraftment or transient colonization of a niche, and whether a single species or a consortium of taxa should be transferred to treat disease."} +{"text": "Genetic sequencing of malignancies has become increasingly important to uncover therapeutic targets and capture the tumor's dynamic changes to drug sensitivity and resistance through genomic evolution. In lung cancers, the current standard of tissue biopsy at the time of diagnosis and progression is not always feasible or practical and may underestimate intratumoral heterogeneity. Technological advances in genetic sequencing have enabled the use of circulating tumor DNA (ctDNA) analysis to obtain information on both targetable mutations and capturing real-time Darwinian evolution of tumor clones and drug resistance mechanisms under selective therapeutic pressure. The ability to analyze ctDNA from plasma, CSF, or urine enables a comprehensive view of cancers as systemic diseases and captures intratumoral heterogeneity. Here, we describe these recent advances in the setting of lung cancers and advocate for further research and the incorporation of ctDNA analysis in clinical trials of targeted therapies. By capturing genomic evolution in a noninvasive manner, liquid biopsy for ctDNA analysis could accelerate therapeutic discovery and deliver the next leap forward in precision medicine for patients with lung cancers and other solid tumors. In the current era of precision medicine, molecularly targeted therapies against oncogene driven lung cancers have been shown to achieve initial response rates of up to 70% . UnfortuLiquid biopsies can be obtained with relative ease from plasma (blood volume needed: 10\u201320\u2009mL) , lumbar Each analysis method has its own diagnostic niche. Digital PCR is rapid, allows for quantitation of mutant alleles at very low concentrations, and is relatively inexpensive. However, it requires a priori knowledge of the specific mutations of interest and cannot be used to detect rearrangements unless the exact genomic breakpoint is known, and multiplex analysis of more than a few mutations is challenging . Hybrid EGFR T790M in plasma of patients with EGFR mutant lung cancers treated with erlotinib, which accounts for the majority of treatment failures [ EGFR T790M, including osimertinib which has recently gained FDA approval and has been adopted as a standard of care [ EGFR C797S and L798I mutations, as well as previously described mechanisms such as MET amplification, and activating mutations in PIK3CA have been identified and/or characterized by sequencing of plasma ctDNA [Beyond simply reflecting the information obtained by invasive tissue biopsies, ctDNA analysis may offer a more comprehensive and integrated view of systemic evolution of cancer across multiple sites. Discordance of mutational status in primary and metastatic lesions has been shown to be as high as 28% and 24% in (NSCLC) . Additio (NSCLC) \u201322, 25. In addition to defining driver mutational status in the metastatic setting, ctDNA analysis can also be applied to analysis of differences in tumor composition between the central nervous system (CNS) and the periphery, a phenomenon well characterized recently by Brastianos et al. . In a stSeveral studies suggest that malignancy involving the CNS, be it a primary CNS tumor or a metastatic lesion, poses a unique challenge for acquisition of ctDNA representative of the central lesion in the peripheral blood as shed material may not predictably cross the blood-brain barrier (BBB) , 39. De Given the noninvasive nature of liquid biopsy and the rapidly improving methodologies for detecting ctDNA, the ability for real-time minimally invasive monitoring of the emergence of resistance mechanisms is quickly becoming a reality. Therefore, we advocate for the incorporation of ctDNA analysis in clinical trials of targeted therapies for the systematic interrogation of genomic evolution of lung cancers. Continued clinical research is vital as we incorporate ctDNA into everyday clinical practice. Researches in optimization of timing, frequency, and choice of liquid biopsy testing in the clinical setting along with the ongoing technical refinements that are expected to bring down the cost of genetic sequencing from ctDNA are keys to help mitigate the financial toxicity for patients in the future. By capturing genomic evolution, ctDNA analysis could accelerate therapeutic discovery and deliver the next leap forward in precision medicine for patients with lung cancers and other solid tumors."} +{"text": "Distributed networks of interacting brain systems\u2014rather than a single area\u2014are usually involved in the execution of a specific cognitive task. Recent advances in neuroimaging techniques now allow us to see how these interacting brain regions are integrated and cooperate with each other to prosecute cognitive operations statistical dependencies between brain regions and has been extensively studied to characterize brain networks at rest. However, understanding the precise mechanisms mediating cognitive processes depend on directed information flow within brain networks. Thus, the current research topic focuses on mapping psychopathology with (directed) effective connectivity analysis, which models causal interactions among brain regions. We attempt to further improve current understanding of the neural mechanisms of major neuropsychiatric disorders by exploring how signals are transmitted differently from one region to another in healthy controls and patients. This comparison may help explain the pathophysiology and psychopathology seen in these disorders\u2014at a network and possibly synaptic level.In this research topic, we invited world-renowned experts to present their recent work that have utilized various models of directed connectivity; including psychophysiological interactions (PPI), Granger causality (GC), and dynamic causal modeling (DCM) to investigate directed connectivity in healthy subjects and patients with neuropsychiatric disorders. The papers in this research topic further our knowledge of the neurobiological mechanisms underlying neurological and psychiatric disorders. We will see that young people with OCD exhibit increased dorsal anterior cingulate cortex (dACC) modulatory effects during the performance of working memory tasks . There is also new evidence suggesting that neurodegenerative disorders like Parkinson's disease and Huntington's disease are characterized by impaired causal interactions of the motor control system speaking to the interesting notion that age-dependent neural mechanisms may be important for understanding aberrant belief states associated with psychopathology. Interestingly, abnormalities in brain effective connectivity are also seen clearly in resting state in subjects with schizophrenia , smoking addiction , idiopathic generalized epilepsy and cocaine users . In addition, it is exciting to see that effective connectivity analysis may furnish a new framework to understand fatigue and depression . We believe these findings have the potential to invigorate and advance our understanding of the neurobiological mechanisms of major neuropsychiatric disorders, thus improving the prevention, diagnosis and treatment of these disorders.huntingtin protein selectively targets striatal spiny projection neurons . For example, methods that use detailed biophysical modeling based on canonical microcircuits and neural mass models for functional MRI data protein-network-phenotype mappings will be crucial for the early diagnosis and development of interventional therapies for slowing and preventing dementia. In psychiatry, computational modeling has already given a birth to the new field of computational psychiatry that constitutes a new paradigm for translational research and clinical decision making (Montague et al., All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "In this study, the Tn916CN and the Tn916ExFr in oral streptococci and enterococci were determined using droplet digital PCR (ddPCR). In addition, we investigated the fitness cost associated with new acquisition of Tn916 in a selected oral streptococci and enterococci strains. Amelioration of fitness cost and mechanism(s) to mitigate fitness loss were evaluated by ddPCR and next generation sequencing (NGS). We found the ddPCR is superior to southern blot to determine Tn916CN. It was also found that both the excision rate of Tn916 and its autonomous replication increase because of antimicrobial challenge. Loss of bacterial fitness was usually associated with multiple acquisitions of Tn916. It is concluded that amelioration of fitness cost is achieved after a few hundred generations and by maintaining one copy of Tn916 in bacterial genome under no selection pressure.The Tn916 and other related elements are broad host range conjugative transposons that are widely spread in bacteria. These elements contribute to the spread of antibiotic resistance genes (ARG) between bacterial species. Variation in the Tn"} +{"text": "It has not yet been definitively demonstrated that preoperative evaluation of women with stress urinary incontinence (SUI) with urodynamic testing (UDS) enhances surgical outcomes. Nonetheless, UDS is frequently utilized in the assessment of women with SUI in the hopes that results will shed light on preoperative risk factors for failure or postoperative voiding dysfunction. Poorer outcomes for stress incontinence surgery are primarily attributed to intrinsic sphincter deficiency (ISD), detrusor overactivity (DO), and voiding dysfunction. The ability of UDS to identify and characterize those parameters reliably remains under investigation. Furthermore, debate continues regarding the association of each of those factors with postoperative success for various SUI procedures. Since UDS is invasive, costly, and not always available, it is imperative that its benefit be carefully explored. In this review, we discuss the value of UDS in identifying risk factors for poor outcome and how those risk factors are associated with surgical failure."} +{"text": "Despite considerable efforts from multiple laboratories worldwide, highly specific inhibitors of autophagy for clinical use are not yet available. Lysosomal inhibitors are being employed instead, in spite of multiple limitations that are summarized herein. Levy and colleagues have recently provided a comprehensive and balanced overview on the therapeutic potential of autophagy-targeting agents for cancer therapy . Indeed,in vitro and in vivo by autophagy-independent mechanisms [Chloroquine and hydroxychloroquine have been extensively tested as antineoplastic agents in preclinical and clinical settings with promising results , 5, but chanisms \u20139.Another potential issue with using chloroquine and hydroxychloroquine for oncological indications is linked to their immunosuppressive effects . Indeed,The development of truly specific pharmacological inhibitors of autophagy for clinical use will shed additional light on the actual therapeutic potential of this approach for the management of neoplastic conditions. We surmise that refined targeted strategies will have to be conceived to focus the therapeutic effects of autophagy inhibitors on cancer cells as anticancer immune responses remain fully operational."} +{"text": "Recent advances from microbiome and host response mechanistic studies indicate that periodontitis is not a bacterial infection in the classical sense but rather results from dysbiosis owing to a breakdown in host-microbe homeostasis. Accordingly, periodontitis is induced in susceptible hosts by a polymicrobial community, in which different members have distinct roles that converge synergistically to enhance colonization, nutrient procurement and persistence in an inflammatory environment. Keystone pathogens \u2013 the colonization of which is facilitated by accessory pathogens \u2013 initially subvert the host response leading to the emergence of a dysbiotic microbiota, in which pathobionts overactivate the inflammatory response and cause periodontal tissue destruction. Inflammation and dysbiosis positively reinforce each other because inflammatory tissue breakdown products are used as nutrients by the dysbiotic microbiota, thereby contributing to its persistence and chronic inflammation. These concepts have important implications for novel therapeutic approaches, including strategies for microbial community manipulation and targeted modulation of the host response to limit destructive inflammation and reverse the microbial immune subversive tactics that fuel dysbiosis."} +{"text": "Use of indocyanine green angiography in microsurgical subinguinal varicocelectomy - lessons learned from our initial experience.Dr. Chak-Lam et al., from China, produce an elegant manuscript that describe the use of intraoperative indocyanine green angiography with infrared fluorescence operative microscope in microsurgical subinguinal varicocelectomy that potentially allows an early identification as well as preservation of testicular artery .The main goal of varicocelectomy is to preserve testicular function and initiate pregnancy in infertile couples . AlthougMost infertility experts prefer the subinguinal approach that is performed through an incision below the external inguinal ring obviating the need to open the aponeurosis of the external oblique which causes less pain . HoweverPrevious studies reported that multiple spermatic arteries are identified in approximately 40% of the spermatic cords during microsurgical varicocelectomy at the subinguinal level , 6. JaroIn the present study, the authors found a low average number of arteries using intraoperative indocyanine green angiography compared to published data mentioned above. These findings could be explained by an aggressive manipulation of the vessels during dissection that can lead to spasm, making it difficult to achieve the ideal indocyanine green perfusion especially in secondary tiny arteries. In addition, the present study has some limitations that must be addressed before we can conclude that a combination of subinguinal microsurgical varicocelectomy and indocyanine green angiography may decrease the incidence of artery injury during varicocele repair. For example, the authors did not compare the benefits of this new technique with conventional microsurgical procedures. Also, the number of patients studied is too small to draw definite conclusions. However, the authors must keep in mind that current results highlight how the continued investigation appears worthwhile and additional research is needed to better clarify whether all these technological advances is likely to improve testicular function, seminal parameters or even fertility potential.In conclusion, the testicular artery is the largest artery supplying the testicle and its ligation during varicocele repair may exert deleterious effects on testicular function. Thus, there is growing support for artery sparing techniques and accidental arterial injury during varicocelectomy should be avoided with all effort possible. Current available data indicates that preoperative parameters are not predictive of the number of testicular arteries identified at the time of surgery. As a result, the application of technological advances during varicocelectomy including optical magnification, microsurgery skills, vascular Doppler and indocyanine green angiography should be alternative options to achieve maximal preservation of the arterial blood supply to the testes."} +{"text": "Congenital Zika virus (ZIKV) infection impacts fetal development and pregnancy outcomes. We infected a pregnant rhesus macaque with a Puerto Rican ZIKV isolate in the first trimester. The pregnancy was complicated by preterm premature rupture of membranes (PPROM), intraamniotic bacterial infection and fetal demise 49 days post infection . Significant pathology at the maternal-fetal interface included acute chorioamnionitis, placental infarcts, and leukocytoclastic vasculitis of the myometrial radial arteries. ZIKV RNA was disseminated throughout fetal tissues and maternal immune system tissues at necropsy, as assessed by quantitative RT-PCR for viral RNA. Replicating ZIKV was identified in fetal tissues, maternal uterus, and maternal spleen by fluorescent in situ hybridization for viral replication intermediates. Fetal ocular pathology included a choroidal coloboma, suspected anterior segment dysgenesis, and a dysplastic retina. This is the first report of ocular pathology and prolonged viral replication in both maternal and fetal tissues following congenital ZIKV infection in a rhesus macaque. PPROM followed by fetal demise and severe pathology of the visual system have not been described in macaque congenital ZIKV infection previously. While this case of ZIKV infection during pregnancy was complicated by bacterial infection with PPROM, the role of ZIKV on this outcome cannot be precisely defined, and further nonhuman primate studies will determine if increased risk for PPROM or other adverse pregnancy outcomes are associated with congenital ZIKV infection. We also identified clusters of gram positive cocci in the fetal esophageal lumen . There were multiple areas of alveoli with type II pneumocyte hyperplasia, with multifocal expansion of the alveolar septa with fibrin. The trachea, primary and secondary bronchi, however, had normal respiratory epithelium.ZIKV RNA localization was evaluated by ISH and mFISH on selected tissues with high vRNA burden as determined by qRT-PCR . Fig 9 pIn this report of an adverse pregnancy outcome following ZIKV infection in a rhesus macaque, we describe fetal demise following suspected PPROM, fetal and maternal ZIKV burden, and significant ocular pathology in the fetus. ZIKV RNA was widely distributed throughout fetal tissues at necropsy, including in the cerebrum and ocular tissues. ZIKV vRNA was also identified in maternal lymph nodes and maternal spleen at the time of necropsy (49 dpi). Replication competent virus was identified by ISH for the presence of negative and positive strand RNA in fetal and maternal tissues. Although no brain pathology was noted, abnormal histology was observed in multiple fetal tissues including alveolitis and pneumocyte hyperplasia in fetal lung tissue, and severe ocular abnormalities. Both fetal ocular pathology and fetal demise have been described in human reports of ZIKV infection and demonstrate parallels between human and NHP CZS.This is the first report of rupture of membranes and fetal demise in an NHP model of congenital ZIKV infection. We presume that maternal membranes ruptured by 42 dpi because we detected amniotic fluid markers in the urine at this time point, and identified high vRNA burden in this urine sample, despite absence of detectable maternal viremia at this time. It is possible that ZIKV RNA in the urine may represent vaginal secretions and not amniotic fluid leakage. ZIKV RNA has been detected in vaginal secretions collected by swab sampling up to 14 days after infection in humans and nonhA week after detection of ZIKV RNA in the pan-collected urine/amniotic fluid mixture, abdominal ultrasound evaluation found no fetal heartbeat and the fetus and dam were submitted for necropsy. There was no chronic villitis, which would be expected for viral induced changes. However, sections of the decidua and myometrium revealed a pronounced leukocytoclastic vasculitis involving the smooth muscle walls of the radial and spiral arteries. This is significant because this type of vasculitis is not expected in cases of bacterial infection, but does occur as a response to viral infections associated with cutaneous vasculitis (hypersensitivity vasculitis) . CutaneoS. epidermidis from amniotic fluid was minimal. This was a surprise because we expected to find histologic evidence of bacteria throughout the placenta and parts of the fetus that were exposed to amniotic fluid. Therefore, we considered the possibility of S. epidermidis environmental contamination in the amniotic fluid culture. Indeed, neutrophilic inflammation in the chorionic plate that is sterile has been described in human cases of PROM [Although there was fibrinopurulent material surrounding the fetus in the uterine cavity and gram positive cocci in the esophagus, multiple sections of placenta and all other fetal tissues had no histologic evidence of bacterial colonization. The growth of of PROM . Sterile of PROM and male of PROM . TherefoClosely associated with this fetal demise is the occurrence of PPROM. Although it is not possible to determine if the amniotic membranes ruptured because of ZIKV infection or bacterial placentitis, the finding of PPROM followed by fetal demise also occurs during human prenatal ZIKV infection . It coulCongenital ocular abnormalities are strongly associated with human prenatal ZIKV infection, as demonstrated by the high frequency (up to 55%) of ocular disease in human infants with first trimester prenatal infections . There iAn ocular coloboma is a congenital lesion associated with a failure in the closure of the embryonic (ocular) fissure causing defects of one or more ocular structures . The defect is essentially a bare sclera with the overlying retinal pigmented epithelium, retina or choroid missing . It may In our previous study, we identified optic nerve gliosis in the two-first trimester infections , but didZIKV RNA was detected throughout fetal tissues, affecting multiple organ systems , and replication competent virus was identified in fetal lung tissue 49 dpi via negative and positive strand RNA ISH. Remarkably, ZIKV RNA was also detected in maternal lymph nodes at 49 dpi and replication competent virus was identified in the lymph node tested. The presence of vRNA does not imply that the virus is replicating or may be transmissible. However, the detection of negative strand RNA by ISH and its colocalization with positive strand vRNA is confirmation of replication competent virus, and the finding of infectious virus in fetal and maternal tissues 49 dpi could have important implications for transmission. The fact that replication competent ZIKV is still present in an adult lymphoid-associated tissue at 49 dpi is critical to understanding the risk involved with organ transplantation, although with the caveat that viral persistence may be longer in pregnancy. Viral persistence is not explained by a lack of maternal humoral immune response since the dam developed neutralizing antibodies at concentrations similar to our previous NHP studies of ZIKV infections , 60.We do not know to what extent ZIKV infection of the fetus directly contributed to fetal demise, since this case is complicated by PPROM with acute chorioamnionitis. Extended exposure of the fetus to ZIKV is most likely responsible for the ocular pathology observed, and there is no literature of which we are aware which suggests that bacterial infection results in ocular malformations. The substantial viral burden in the fetal membranes also supports the hypothesis that ZIKV contributed to PPROM. The detection of replicating ZIKV intermediates in membranes and fetal tissues at the time of fetal demise also suggests that active ZIKV infection was ongoing up until fetal demise.In summary, we describe a case of congenital ZIKV infection with severe ocular and uteroplacental pathology complicated by bacterial infection and fetal demise following apparent PPROM. The fetal ocular pathology recapitulates defects seen in human CZS. This is the first report of an adverse pregnancy outcome and fetal pathology in an NHP infected with ZIKV strain PRVABC59. Additional NHP studies with sham-infected animals as appropriate controls will be needed going forward to better define the baseline incidence of adverse pregnancy outcomes. This case report highlights the range of outcomes present in the macaque model along with our earlier NHP pregnancy studies and suppS1 FigA) H&E image of the fetal esophagus. B) Gram stain of a section of the fetal esophagus epithelial surface, where gram positive cocci were abundant.(TIF)Click here for additional data file.S2 Fig(TIF)Click here for additional data file.S1 Table(TIF)Click here for additional data file.S2 Table(TIF)Click here for additional data file."} +{"text": "Postmortem studies in schizophrenia show well-replicated neuronal differences in the prefrontal cortex (PFC), specifically showing lower dendritic spine density in upper-layer cortical pyramidal neurons. Animal models that recapitulate features of psychosis also show lower dendritic spine density and synapse number in the PFC, with a more pronounced effect in upper-layer cortical neurons. Furthermore, the decrease in dendritic spines and synapses in animal models have been shown to be reversible with antipsychotic treatment. Results from postmortem brains, animal models and in vitro rodent cultures provide a strong impetus to test the hypothesis that dendritic spine biology plays an important role in the biology of schizophrenia and in mediating the effects of antipsychotic medications.To extend these findings, we studied cortical neurons generated from subjects with schizophrenia. We reprogrammed induced pluripotent stem cells (iPSCs) from human subjects with schizophrenia and from matched healthy controls. We differentiated human iPSCs along the forebrain lineage to generate mature cortical neurons. We developed a robust experimental approach to delineate and quantify spines in the dendrites as well as methods to outline and measure the spines in order to classify the different spine types. We also developed methodology for functional characterization of individual neurons using calcium imaging in the cortical neuron cultures.We found that cortical neurons generated from the iPSCs of schizophrenia patients had a lower density of dendritic spines when compared to cortical neurons generated from the iPSCs of healthy control subjects. We also delineated the different composition of spine types in cortical neurons from schizophrenia patients when compared to those from healthy control subjects. In cortical neurons from schizophrenia subjects, we found that clozapine exposure in vitro leads to a robust increase in dendritic spine density.We found that cortical neurons from iPSCs of schizophrenia subjects recapitulate the dendritic spine differences reported in postmortem brains of schizophrenia subjects. Moreover, we found that human cortical neurons from schizophrenia subjects show increased dendritic spine density when exposed in vitro to clozapine. The ability to delineate cellular features related to disease biology in iPSC-derived neurons opens the door to understand the pathophysiology of schizophrenia and lay the foundations for the development of novel therapeutics."} +{"text": "Prescription opioid dependence has reached epidemic proportions in the U.S. and internationally . OverdosResearch has identified brain regions specifically associated with psychological processes underlying craving and substance use. A few studies have investigated cue reactivity \u20137, and aYet, critical to our understanding of the neurobiology of chronic prescription opioid use is defining brain connectivity, that is, how the brain regions interact as opposed to focusing on the functionality of individual regions of interest in isolation. There are only two brain connectivity studies that have examined functional connectivity in the brain of the POD patients ,13. RestHowever, the effects of long term prescription opioid use on the large scale brain networks that have implications in drug addiction have not been examined. These large scale brain networks include default mode network ; saliencThe literature cited above suggests the following directions for future neurocognitive research on prescription opioid addiction. First, studies would do well to include a multimodal assessment of structural and functional brain changes in prescription opioid users\u2019 brain networks including DCPN. This would be achieved by using functional MRI and structural Diffusion Tensor Imaging (DTI) techniques and structural, functional and effective connectivity analysis to understand changes in brain networks due to long term prescription opioid use. It would also be important for future researchers to collect for the first time the structural, functional and effective connectivity data between the regions within different brain networks in PODs and matched controls. Data collection should be geared toward developing both pharmacologic and behavioral therapies in the treatment of relapse prevention in individuals with prescription opioid use disorder. Finally, translational constructs linking research to clinical applications should be explicated. Specifically, how therapies can be developed from brain connectivity research to change the neuroplasticity within the DCPN and other large brain networks. Restoring normal functioning of these networks holds promise in promoting abstinence from drug use in this high-risk population."} +{"text": "We review the performance of 35 published and 121 newly designed primers targeting the nirS and nirK genes, against sequences from complete genomes and 47 metagenomes from three major habitats where denitrification is important. There were no optimal universal primer pairs for either gene, although published primers targeting nirS displayed up to 75% coverage. The alternative is clade-specific primers, which show a trade-off between coverage and specificity. The test against metagenomic datasets showed a distinct performance of primers across habitats. The implications of clade-specific nir primers choice and their performance for ecological inference when used for quantitative estimates and in sequenced-based community ecology studies are discussed and our phylogenomic primer evaluation can be used as a reference along with their environmental specificity as a guide for primer selection. Based on our results, we also propose a general framework for primer evaluation that emphasizes the testing of coverage and phylogenetic range using full-length sequences from complete genomes, as well as accounting for environmental range using metagenomes. This framework serves as a guideline to simplify primer performance comparisons while explicitly addressing the limitations and biases of the primers evaluated.The detection of NO-forming nitrite reductase genes ( Microorganisms carry out the cycling of inorganic nitrogen, which includes numerous reactions catalyzed by different enzymes present in a diverse range of bacterial, archaeal and fungal taxa. Nitrite reduction is a key step in the nitrogen cycle and is considered a branching point due to its role in several N-cycle pathwaysnirS and nirK, coding for the nitric oxide (NO)-forming nitrite (NO2\u2212) reductases NirS and NirK respectively, are commonly used as molecular markers for denitrifying communities, and to a lesser extent for anammox since more specific molecular targets exist2\u2212 to NO, they are two non-homologous proteins that differ significantly in their evolution89nir genes and other functional genes relies heavily on both the existence of extensively tested primers targeting universally conserved regions, and on the availability of comprehensive, reliable and curated reference databases.Taxonomic molecular markers like the 16S rRNA gene do not provide sufficient information to capture the functional ecology of microbial communities at a detailed level, particularly when studying processes such as nitrite reduction as part of the denitrification pathwaynirS and nirK were first designed from the few sequences available in the late 1990\u2019s12nir genes arose early in evolution there is a high substitutional load in their sequences that makes primer design difficult. Consequently, primer bias and non-specificity have been pointed out recurrently1516nir genes obtained from genomes have shown that commonly used primer sets do not cover poorly studied clades within their phylogeniesnir sequence clades, similar to what was done for the nosZ gene encoding the nitrous oxide reductaseet al.nirS; Thaumarchaea, Eukarya and Firmicutes in nirKnir clades. Prompted by this, we designed novel primer sets and performed updates on the specificity and inclusiveness of the existing sets. In addition, we review the usage of clade-specific primers for nir genes in denitrification and discuss problems with the interpretation of results using clade-specific primers, both for quantification of nir genes and analysis of diversity and composition of denitrifiers. Our approach includes an in silico analysis of 35 available nirS and nirK primers as well as 121 new primers designed in this study and was facilitated by the recent publication of robust and comprehensive phylogenies for both genesPrimers targeting nirS and 79 nirK primers displayed a higher coverage than previously published primers, whereas those for nirK only did so with prohibitively high degeneracy , though this of course depends on the complexity of each environment. This approach is similar in concept to that outlined by Kushwaha nir genes.The growing number of sequences deposited in databases makes the development and continuous update of primer sets a bottleneck in microbial ecology of denitrifiers, other nitrite reducers and functional groups in general, as estimates of coverage and specificity of primer sets require comprehensive phylogenetic analyses of highly divergent sequences and demonstration of their performance using environmental samples. Traditionally, primer evaluation has included the demonstration of successful amplification in a number of strains known to harbor the gene and sequencing of a few environmental samples1418nir gene diversity and abundance in the environment will require multiple complementary primer sets, despite the issues discussed here. This does not represent a larger effort than the implementation of novel methods targeting microbial communities like synthetic long readsnir primer pairs in our study can be used as a reference along with their environmental specificity as a coarse guide for primer selection and future primer design. Furthermore, researchers can avoid the potential pitfalls of nir gene analyses by implicit incorporation of currently known biases and theoretical contingencies into primer selection and experimental design, combined with the explicit acknowledgement of such issues in ecological interpretations of results.We conclude that an exhaustive description of nirS and nirK primers, we used the most up to date, comprehensive and robust phylogenies published by Graf et al.nirK and nirS sequences from complete genomes using the automatic structure guided alignment implemented in t-coffee expressonirS and 79 nirK primer candidates .Publisher\u2019s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations."} +{"text": "While the effects of the CAS on blood coagulation measured as activated partial thromboplastin time shortening are well documented, genetic mutations that result in deficiencies in the expression of either plasma prekallikrein (PPK) or factor XII (FXII) are not associated with spontaneous bleeding or increased bleeding risk during surgery. Deficiencies in these proteins are often undiagnosed for decades and detected later in life during routine coagulation assays without an apparent clinical phenotype. Increased interest in the CAS as a potentially safe target for antithrombotic therapies has emerged, in large part, from studies on animal models with provoked thrombosis, which have shown that deficiencies in PPK or FXII can reduce thrombus formation without increasing bleeding. Gene targeting and pharmacological studies in healthy animals have confirmed that PPK and FXII blockade does not cause coagulopathies. These findings support the conclusion that CAS is not required for hemostasis. However, while deficiencies in FXII and PPK do not significantly affect bleeding associated with peripheral wounds, recent reports have demonstrated that these proteins can promote hemorrhage in the retina and brain. Intravitreal injection of plasma kallikrein induces retinal hemorrhage and intracerebral injection of PKal increases intracranial bleeding. PPK deficiency and PKal inhibition ameliorates hematoma formation following cerebrovascular injury in diabetic animals. Moreover, both PPK and FXII deficiency are protective against intracerebral hemorrhage caused by tissue plasminogen activator-mediated thrombolytic therapy in mice with thrombotic middle cerebral artery occlusion. Thus, while the CAS is not required for hemostasis, its inhibition may provide an opportunity to reduce hemorrhage in the retina and brain. Characterization of the mechanisms and potential clinical implications associated with the effects of the CAS on hemorrhage requires further consideration of the effects of PPK and FXII on hemorrhage beyond their putative effects on coagulation cascades. Here, we review the experimental and clinical evidence on the effects of the CAS on bleeding and hemostatic mechanisms.The contact activation system (CAS) exerts effects on coagulation The contact activation system (CAS) represents a group of plasma proteins, including factor XII (FXII), plasma prekallikrein (PPK), and high molecular weight kininogen (HK) that promotes inflammation and coagulation upon contact of blood with an activating surface or protease , 2. CAS The acute effects of the CAS on coagulation have been primarily attributed to FXIIa-mediated activation of FXI and thereby the intrinsic coagulation pathway leading to fibrin generation. Although the biochemical roles of PKal and FXIIa as upstream triggers for the intrinsic coagulation system were recognized over 50\u2009years ago , the cliHemostasis is the process that prevents blood loss following vascular injury. The mechanisms of hemostasis involve both serial and parallel events, mediated by the interactions between circulating factors in blood with components of activated or injured vascular tissue. Given the critical nature of hemostasis, the system has evolved both redundant and reinforcing mechanisms that facilitate both rapid and stable cessation of blood loss. The sequence of events and the relative contributions and requirements of individual coagulation components may vary according to the affected tissue and type of injury, and possibly also the animal species. While thrombosis and hemostasis share a host of coagulation factors, the etiology of these processes has important distinctions, which may create therapeutic opportunities to selectively target thrombosis without affecting hemostasis.Although animal models do not fully recapitulate the complexity of human physiology and disease, studies on animals with targeted deficiencies in coagulation factors have provided insight into contributions of individual components of coagulation in hemostatic mechanisms. Multiple approaches are used to quantify hemostatic responses in rodents, including tail tip bleeding, cuticle bleeding, and tail vein transection assays. Deficiencies in FXII and PPK in healthy animals exert little or no effect on tail bleeding time despite aPTT prolongation Table , in contin vitro and contribute to thrombosis in animal models, are not associated with a bleeding diathesis. However, while surgical interventions provide a general assessment of hemostasis, it does not fully model the potential contributions of the CAS in all hemorrhagic conditions. Indeed, recent studies have suggested that the CAS may play an important role in hemorrhage in the retina and brain in certain diseases (Deficiencies in downstream factors in the intrinsic cascade (such as FIX and FXI) result in bleeding disorders, demonstrating their role in physiological hemostasis. Paradoxically, deficiencies in the CAS factors FXII, PPK, or HK, which trigger coagulation diseases , 20, 30.via glycoprotein VI (GPVI) receptors to exposed basement membrane collagen at the site disrupted endothelium to initiate platelet aggregation. This process leads to tethering and activation of platelets, additional platelet receptor-collagen interactions, and platelet plug formation. GPVI play a critical role in normal hemostasis, and its deficiency results in abnormal platelet-responses to collagen and mild bleeding tendency provides the basis for the aPTT, a clinical clotting assay, which is widely used to assess the integrity of the intrinsic pathway and to monitor anticoagulation with heparin. Deficiencies in FXII, PPK, and HK results in markedly prolonged aPTT and no increases in spontaneous bleeding or impairment in hemostasis Table . NormaliIn humans, PPK deficiency is not associated with hemostatic disorders, indicating PKal is not required for hemostasis. Although some case reports have associated FXII deficiency with prothrombotic events, a clinical study failed to demonstrate a significant correlation between increased risk of thrombosis and FXII deficiency . GirolamC1-inhibitor is the primary endogenous inhibitor of both PKal and FXIIa. HAE is a rare genetic disease caused by deficiencies in C1-INH concentration (Type I) or C1-INH activity (Type II) . HAE has3 model of thrombosis. Antibody 14E11 binds FXI and interferes with FXI activation by FXIIa, suggesting that thrombus formation in this model requires FXI activation by FXIIa. These data have generated interest in developing strategies to therapeutically inhibit FXIIa and contact activation to treat or prevent thromboembolic disorders. Interestingly, thrombosis protection in mice was greater with FXII deficiency than with FXI deficiency, suggesting that FXII may exert effects on coagulation that do not require FXI ; the leading cause of vision loss in working-age adults in most developed countries . Proteomin vitro studies have shown that PKal binding to collagen interferes with its effects on GPVI-mediated platelet activation, these findings suggest that PKal may decrease platelet plug formation, which plays an early step in hemostasis.Diabetes and hyperglycemia are associated with increased ICH and worse clinical outcomes following a cerebrovascular accident \u201398. DiabTissue plasminogen activator is the only approved treatment for thrombotic stroke . While iThese findings have suggested that the CAS may either worsen vascular damage or impair hemostasis in the cerebral vasculature following tPA administration. Studies using human plasma have shown that tPA\u2019s effects on the CAS are mediated by plasmin , which hvia activation of the intrinsic coagulation cascade promotes clot stabilization and growth. Feedback activation of FXI by thrombin contributes to clot stabilization and may explain the lack of dependence of hemostasis on FXII and PPK. PKal has been implicated in promoting spontaneous microvascular bleeding and the impairment of collagen-induced platelet activation. Pharmacological blockade of PKal has been shown to provide beneficial effects on cerebral hemostasis in animal models. Although inhibition of the CAS reduces provoked arterial and venous thrombosis in animal models, the clinical significance of the CAS in thrombosis is not yet available. The clinical indications for targeting the CAS for thrombosis will require the identification of thrombotic processes that are dependent on the CAS, which potentially include interactions with artificial surfaces and disease processes that generate factors that activate FXII. In addition, inhibition of the CAS may provide an opportunity to reduce cerebral hemorrhage, which is one of the primary concerns of increased bleeding risk associated with current antithrombotics.Currently available anticoagulants used for prevention or treatment of thromboembolic events all target enzymes of the coagulation cascade that are essential for the formation of fibrin, a protein necessary for controlling injury-related blood loss. As a result, currently used anticoagulants increase the risk of bleeding and are associated with an increase risk in potentially life-threatening hemorrhage . BleedinFS and EF performed literature searches and wrote the manuscript.EPF is an employee of KalVista Pharmaceuticals Inc. . FS declares no competing financial interests."} +{"text": "The first reports of phonological, surface and deep dyslexia come from orthographies containing quasi-regular mappings between orthography and phonology including English and French. Slovakian is a language with a relatively transparent orthography and hence a mostly regular script. The aim of this study was to investigate impaired oral reading in Slovakian. A novel diagnostic procedure was devised to determine whether disorders of Slovakian reading resemble characteristics in other languages. Slovakian speaking aphasics showed symptoms similar to phonological dyslexia and deep dyslexia in English and French, but there was no evidence of surface dyslexia. The findings are discussed in terms of the orthographic depth hypothesis."} +{"text": "Platelets occupy a central role in the maintenance of hemostasis by adhering to sites of vascular injury and facilitating thrombin generation, which leads to the formation of a fibrin clot. Patients with hemophilia exhibit defective thrombin generation secondary to reduced plasma factor concentrations, which can lead to excessive and sometimes life-threatening bleeding. Individuals differ greatly with respect to platelet function and platelets from different individuals differ inherently in their ability to enact thrombin generation, the key coagulative process that is deficient in hemophilia. Similarly, some patients with hemophilia seem to bleed less often than others despite exhibiting similar plasma factor levels. The biologic factors that underlie this phenotypic variability remain poorly understood, but evidence is reviewed supporting a role for platelets and platelet-related factors in modifying bleeding tendency in patients with hemophilia and potential directions for further clinical research in this area are discussed."} +{"text": "In recent years, psychosocial functioning has received a lot of attention with discussions around its importance in terms of early identification of illness, prediction of outcome, and targeting of treatment. Regardless of diagnostic outcome, both groups of individuals at ultra-high risk for psychosis (UHR) and those with a first episode of psychosis (FEP) show a wide range of functional outcomes. In light of these clinical outcomes, effort has been made to identify neuroanatomical markers for functioning and functional outcome independent of diagnostic status. The present study aimed to increase insight into the association of brain volume with psychosocial functioning in the early stages of (psychotic) illness by investigating the association between grey matter volume and current levels of social and occupational functioning (SOFAS) in healthy individuals, those with emerging mental health problems (EMH), UHR individuals, and those with a FEP.Twenty nine healthy controls , 27 EMH individuals , 31 UHR individuals , and 31 FEP individuals were recruited from mental health services, through posters, social media and opportunity sampling, in the wider area of Birmingham, UK. They underwent magnetic resonance imaging at the Birmingham University Imaging Centre and completed the Social and Occupational Functioning Assessment Scale . Images were analysed using the CAT12 toolbox in SPM12. Grey matter volumes were examined controlling for age, gender and total intracranial volume.Compared to healthy controls, EMH individuals displayed a pattern of grey matter volume reduction in association with reduced functioning scores in medial prefrontal and cingulate areas. The areas spanning volumetric differences between the two groups in their association with SOFAS scores were similar to those identified in previous work investigating the association between brain volume and functional outcome in UHR individuals but were more widespread and disperse. Similar areas of association were observed in UHR and FEP individuals compared to healthy controls but here the pattern was much more specific and more pronounced in the FEP group than the UHR group in the comparison with healthy controls.The present findings provide novel evidence that while those in the early stages of psychotic illness present a unified pattern of association between psychosocial functioning scores and grey matter volume, those with EMH present with a more pronounced but more dispersed pattern, possibly reflecting a more disperse diagnostic outcome. This indicates specificity with psychotic illness in the association between psychosocial functioning and brain volume and suggests importance concerning our ability to predict outcome and target interventions. In addition, it provides support for the recent focus on functioning in addition to distinct diagnostic categories."} +{"text": "In recent years, there have been many advances in the treatment of superficial bladder cancer. Standard intravesical chemotherapeutic agents can now be delivered more effectively thanks to new technological advances in drug delivery. Local microwave hyperthermia and electromotive drug administration are of particular interest. Research has also shown that different combinations of drugs and sequential drug delivery of two or more different drugs for differing periods of time also increase the effectiveness of possible treatments of superficial bladder cancer. Furthermore, new chemotherapeutic drugs for intravesical use are being investigated in various clinical trials, with gemcitabine showing particularly promising results. Also in the pipeline are new approaches to treatment such as gene therapy, but these will need to be developed much more before they become part of routine practice."} +{"text": "Youth with rheumatologic diseases have a high prevalence of comorbid mental health disorders. Individuals with comorbid mental health disorders are at increased risk for adverse outcomes related to mental health as well as their underlying rheumatologic disease. Early identification and treatment of mental health disorders has been shown to improve outcomes, but current systems of care fall short in providing adequate mental health services to those in need. Pediatric rheumatologists are uniquely positioned to provide mental health screening and intervention for youth with rheumatologic diseases due to the frequency of patient encounters and ongoing therapeutic relationship with patients and families. However, additional training is likely required for pediatric rheumatologists to provide effective mental health care, and focusing efforts on providing trainees with mental health education is key to building competency. Potential opportunities for improved mental health education include development of clinical guidelines regarding mental health screening and management within pediatric rheumatology settings and incorporation of mental health didactics, workshops, and interdisciplinary clinic experiences into pediatric rheumatology fellowship curricula. Additional steps include mental health education for patients and families and focus on system change, targeting integration of medical and mental health care. Research is needed to better define the scope of the problem, determine effective strategies for equipping pediatric rheumatologists with skills in mental health intervention, and develop and implement sustainable systems for delivery of optimal mental health care to youth with rheumatologic diseases. Beyond the long-established detrimental impact that chronic disease has on an individual\u2019s mental health, we now appreciate that the relationship between chronic physical disease and mental illness is bidirectional . As suchChildren with chronic diseases have a higher prevalence of mental illness \u20135, and yDiscrepancies in reported prevalence of mental health disorders in this population are potentially due to small sample sizes with limited generalizability and the varying use of symptoms, screeners, or diagnosis codes to define mental health disease. These limitations and the overall paucity of existing data regarding mental health comorbidities across pediatric rheumatologic diseases emphasize the need for further research to describe better the burden of mental health disorders in this patient population. Large collaborative studies that draw on diverse demographics of patients will be important in defining the scope of the problem and understanding risk factors for mental health disorders in youth with rheumatologic diseases.Preliminary studies show that mental health disorders adversely impact quality of life, development, and disease outcomes in youth with rheumatologic diseases. Understanding these effects can illuminate strategies to optimize overall care. In youth with JIA, depression has been associated with higher disease activity, worse pain, worse general health, greater functional disability, and overall lower health related quality of life (HRQL) scores , 23. In While the scope of the problem of mental illness in youth with rheumatologic diseases has yet to be fully investigated, studies of other pediatric chronic diseases indicate that mental illness can lead to poor outcomes during childhood , 26\u201329 aThe impact of mental health disorders on rheumatologic diseases has been more robustly studied in adults than in children. In adults with SLE, depression is cited as the most significant predictor of poor health-related quality of life , 36, andFortunately, early recognition and treatment of mental health disorders improves outcomes. In small, randomized controlled trials cognitive behavioral therapy was found to lower levels of functional disability and reported depressive symptoms in adolescents with fibromyalgia and imprGiven the impact of mental health disorders on health outcomes and the effectiveness of psychological interventions, the United States Preventive Services Task Force and the Canadian Network for Mood and Anxiety Treatment recommend screening adolescents for depression , 61. TheThis situation might be acceptable if access to pediatric mental health providers were not exceedingly limited. Workforce data from the American Academy of Child and Adolescent Psychiatry indicates that there are approximately 8300 practicing child and adolescent psychiatrists in the US with over 15 million youth in need of one . AdditioThus, the current systems of care fall short in terms of meeting the mental health needs for youth with rheumatologic diseases. In a survey by the Childhood Arthritis and Rheumatology Research Alliance (CARRA), which includes pediatric rheumatologists from both US and Canada, 52% of surveyed members reported inadequate symptom identification; and 45% reported inadequate treatment of depression and anxiety in adolescents with SLE, identifying limited staff resources and availability of mental health providers as top barriers to mental health intervention . These bThe increased risk of mental health disorders in youth with rheumatologic diseases and their impact on clinical and psychosocial outcomes, as well as the shortage of mental health providers, underscore the need for pediatric rheumatologists to be proficient in addressing mental health needs for these vulnerable patients. Pediatric rheumatologists are optimally positioned to improve mental health intervention due to the frequency and intensity of their patient-provider interactions. Youth with SLE and MCTD have on average twice the number of rheumatology visits compared to primary care visits, and one study found youth with SLE and depressive symptoms to have fewer primary care visits than youth with SLE and no depressive symptoms . FurtherTo begin closing the mental health care gap for youth with rheumatologic diseases, pediatric rheumatologists must feel adept in the screening and initial management of mental health disorders. Symptoms of mental health disorders are often subtle and can be easily overlooked despite multiple interactions between youth with chronic conditions and the health care system. Thus, pediatric subspecialists need to learn how to implement formal screening methods into routine clinical care, effectively communicate with patients, families, and other providers regarding mental health, and assist with establishing and sustaining appropriate mental health intervention.Current training program requirements outlined by the Accreditation Council of Graduate Medical Education simply call for adequate resources for an education in mental health and social services . The AmeTherefore, current training programs likely insufficiently prepare pediatric rheumatologists to manage mental health comorbidities in youth with rheumatologic disease. In a CARRA survey of 130 pediatric rheumatologists, two-thirds reported formal mental health training only in medical school and nearly 10% reported no training at all. Importantly, the respondents with higher levels of mental health training perceived a lower frequency of barriers to mental health screening, and greater than 90% of respondents expressed interest in further mental health training . These dThe most basic measure to tackle this educational need might be to provide guidelines for mental health screening to pediatric rheumatologists. The American Diabetes Association and the American College of Gastroenterology both issued 2017 guidelines for standards of medical care in diabetes and preventive care in inflammatory bowel disease, respectively, that include recommendations for routine depression and anxiety screening , 78. SucFor pediatric rheumatology trainees, mental health education could be delivered in didactics within fellowship core curricula or offered in workshops at academic conferences. However, mastery of the skills to elicit information on the symptoms of a mental health disorder in a patient interview likely requires more intensive instruction from behavioral health specialists. Dedicated rotations in behavioral health clinics could provide this needed education if protected time for trainees and mental health providers is secured. Furthermore, training pediatric rheumatologists in the setting of interdisciplinary clinics, where rheumatology and behavioral health trainees work side by side, may offer the most comprehensive opportunity to educate providers and improve mental health care in pediatric rheumatology. While it potentially involves restructuring the way care is provided to patients, it has been proven to be effective for enhancing pediatric resident education in the management of behavioral health problems and improving collaboration between pediatricians and behavioral health specialists . AccordiFurther research is needed to develop effective education programs that will optimize mental health care for youth with rheumatologic diseases. The National Academy of Medicine has outlined a research agenda to support an integrative mental health training paradigm with attention to the following topics: comparative studies of different structural configurations of the interface of pediatric medical care and behavioral health support; development of quality indicators that assess competencies for integrative team training and that lead to improved health outcomes for children; and study of new integrative training models for children with chronic disorders . StudiesEarly and ongoing mental health education for patients and families of youth with rheumatologic diseases is essential to help increase mental health awareness and normalize attention to mental health as part of the overall care of youth with rheumatologic diseases. Normalization of mental health care is critical in reducing stigma and fear, both of which have been reported by youth with SLE and their parents as common barriers to seeking mental health treatment . PartnerIncreasing the availability of peer support groups and networks also has the potential to improve mental health education of youth with rheumatologic diseases. Specifically, the iPeer2Peer Program, a novel online peer mentoring program for adolescents with JIA developed by investigators in Canada, improved participants\u2019 perceived ability to manage their disease compared to controls . SimilarWhile improved mental health education for both pediatric rheumatologists and patients and their families is necessary, education alone is insufficient. Sustainable systems for the delivery of mental health services must be developed. Dedicated application of implementation science principles and quality improvement methodology has been successfully utilized to improve mental health care for youth with other chronic diseases . FundingThe prevalence and burden of mental health disorders in youth with rheumatologic diseases is high. The evidence from pediatric and adult literature of rheumatologic diseases indicates that mental illness has a pervasive impact on multiple areas of health behaviors, disease outcomes, and quality of life. Improved identification and early treatment of mental health disorders may improve outcomes in this population, and pediatric rheumatologists are well situated to provide mental health screening and offer early intervention. Additional training for pediatric rheumatologists is necessary to enable provision of effective mental health care. Potential educational strategies include the development of clinical guidelines for mental health screening within pediatric rheumatology settings and revision of pediatric rheumatology fellowship cuuricula to include mental health didactics, workshops, and clinical experience in behavioral health. Improved education of patients and families is also essential in order to increase awareness of and normalize inclusion of mental health as part of overall care. Future work should focus on developing and implementing sustainable systems for the delivery of mental health care alongside medical care for youth with rheumatologic diseases. Increased advocacy for mental health resources and research funding is needed to support the above initiatives."} +{"text": "De novo root regeneration (DNRR) is a type of plant regeneration to produce adventitious roots upon wounding or stress , adventitious roots could usually be regenerated by two ways: adventitious roots could be formed directly from detached leaf explants when cultured on B5 medium without added hormones can form adventitious roots from callus expression for the fate transition from regeneration-competent cells to root founder cells expression for the fate transition from root founder cells to root primordium in direct DNRR, and therefore the regenerated root number is limited . The endogenous auxin keeps a high level in the root primordium and its level decreases during patterning. The rooting process usually does not stop between initiation and patterning. However, during indirect DNRR, the priming and initiation steps of cell fate transition are quite dramatic and fast, and numerous regeneration-competent cells are induced to form founder cells that then divide to become newly formed callus following stimulation with high levels of exogenous auxin. Auxin is enriched in many callus cells, and therefore numerous adventitious roots could be observed when auxin is removed in indirect DNRR. In the newly formed callus, the high level of exogenous auxin in CIM prevents callus from patterning, resulting in disruption of the recognition of the tissue anatomy and keeping callus cells without pre-specific fate. Removal of auxin from the medium allows callus into the patterning step.WOX11, WOX5, LBD16 and other markers and phenotype analysis of mutants are important in studying different types of rooting in the future.Overall, we believe that direct DNRR and indirect DNRR share similar cell fate transition steps but have different auxin sources and behavior. Further studies on genetic and epigenetic regulations of direct and indirect DNRR will improve our understanding of the two ways of adventitious rooting at the molecular level. We cannot exclude the possibility that adventitious roots can also initiate from differentiated cells via cell fate reprogramming. Cell lineage analysis using JY, WL, JL, PQ, and LX designed the research. JY, WL, and JL conducted the research. LX wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Area Health Education Centers provide health professional students the opportunity to explore the benefits of practicing in a rural and underserved location. The status of health conditions in chronic disease patients residing in impoverished regions of the US provides the chance to understand the factors that are responsible for constant inadequate outcomes in underserved and rural communities. Many limiting barriers to positive health outcomes occur in disproportionate numbers in the Southern Black Belt. Students should consider participating in rural and underserved clerkships, and ultimately a career as a health care provider in a poor health outcome region. In addition, promising programs to help implement patient-centered evidence-based interventions can tackle current chronic disease issues commonly encountered by health professionals who work with diverse patient populations. Through community-based training, financial assistance , and partnerships throughout various counties, Area Health Education Centers (AHECs) provide valuable opportunities for all future health-professional students who are interested in pursuing careers in impoverished areas.AHECs were created by US Congress in 1972 to address health professional shortage, increase health providers in rural and underserved communities, and create educational opportunities for students in training .Clerkships provide health professional students the chance to spotlight various aspects of rural and underserved health care careers and understand the implications of educational training in certain locations for future professional options. The implementation of health care practices in rural areas across the US is necessary to reduce emergency room visits, support appropriate health behaviors, and control chronic medical conditions before they progress in severity.The term \u201cBlack Belt\u201d is used to identify areas of the Deep South in the US because of the prevalence of its dark soil and high percentage of African American communities . The BlaMultiple areas across the United States contain medically underserved populations that possess a higher than average percentage of poor health outcomes. Many of these vulnerable communities are in rural locations, where access to crucial resources is limited, gaps between physician and patient exist, and the frequency of chronic disease is significantly higher than in other parts of the country. Rural and underserved clerkships can provide students with an exceptional awareness of ways to influence successful health outcomes, particularly for individuals who can understand the importance of balancing literacy problems, emotional factors, physical issues, and medication adherence to influence preventive medicine in areas that need it most. The final goal of training is to essentially reduce increased costs on the current health care system and produce a network of health professionals dedicated to improving the status of chronic conditions in vulnerable communities.Training in a rural and underserved environment is beneficial in many ways. Rural and underserved areas not only help students in training gain a solid comprehension of the factors that are responsible for poor health outcomes in susceptible populations, but also provide the opportunity to bridge the gap between healthcare professionals and ill patients. Training provides appreciation of cultural variations and perceived stigma prevalent in communities like the Southern Black Belt. Students can understand the importance of diversity and engaging in partnerships with community members to help reduce any communication barriers that might exist. Incentive programs are constantly being implemented for providers or students interested in pursuing a career as a rural or underserved primary-care physician. Successful experiences can increase the likelihood of eventually practicing in similar areas. In addition, many training sites can offer future health professionals the opportunity to incorporate new and innovative developments into practice when treating patients residing in impoverished areas.Many advances have been made in the past, and creating models of care tailored to each patient can provide promising results in isolated communities. Telemedicine employs technology, health care providers, and evidence-based models to address the barrier of geographical separation between a patient and provider in rural and underserved communities . PatientCommunity Health Workers (CHWs) can address health disparities dominant in a variety of rural and underserved locations comparable to the Southern Black Belt. CHWs serve as lay leaders in rural communities, and emphasize the importance of preventing disease and promoting health . Many CHThe National Health Service Corps (NHSC) is well known for its efforts to reduce health care costs by increasing the prevalence of primary-care providers in rural and underserved areas across the US. The organization evaluates the conditions of locations by calculating a health professional shortage area (HPSA) score. The NHSC program participants then contribute time back into communities to help deliver quality care. Financial incentives in the form of scholarships or loan repayments help students pay for school and other relevant expenses. Implementing these programs not only offers the chance to engage in community-based experiences, but also allows future health professionals to experience and understand the factors that are causing poor health outcomes in some of the most deprived areas across the nation. These factors must be considered when designing individualized care for patients who are constantly trapped in a cycle of barriers that negatively impact proper health maintenance, behaviors, and outcomes.Various factors influence medical students\u2019 primary care or specialty career choices, including gender, race/ethnicity, socioeconomic status, previous rural or urban residence, perceptions, and interest acquired during medical school clerkships , 9. TherMedical students should participate in clerkship experiences funded through AHEC centers across the nation. Teaching opportunities in underserved and rural populations can help alleviate the burden of increased health care costs and poor health outcomes in susceptible regions, such as the Southern Black Belt. Increasing the number of practicing health care providers in communities affected by health disparities and social determinants of health can mitigate some of these concerns. More awareness about the benefits associated with medical student clerkship programs can promote rural and underserved community career options through a variety of means, including financial incentives funded by organizations like the NHSC. Future advancements in the disciplines of telemedicine and CHWs can further influence quality health care in impoverished communities with poor health outcomes."} +{"text": "Verdict on tracing exact place of drowning is a part of medico-legal investigation. This question often stands when circumstances remain unclear about true drowning place. Usually, when a dead body rises from the bottom of drowning site, it will appear near to the point where it had actually disappeared but rapid current may carry a body to real distance from the exact place of death before any major obstruction. Forensic methodology has suggested qualitative as well as quantitative comparison of diatoms recovered in dead body and reference water samples to corroborate drowning as cause of death and locating precise place of drowning. Collection of wrong reference water samples from drowning site can also hamper the investigation process. Since, the distributions of different genera in certain extents relate particular water where the death due to drowning might have taken place; therefore, the present attempt was made to understand diatom distribution in five water bodies of Haryana with reference to diatom growth factors. This research data represents diatomological profiles of selected sites for possible application of forensic diatomology. Both, the light and scanning electron microscopy identified diatoms. It is envisioned that this data report is informative enough for the experts to plan future strategy for investigating mysteries associating place of drowning. Specifications TableValue of the data\u2022Little is known about the diatomological mapping of fresh water bodies of Haryana.\u2022Diatomological information produced here provides a baseline data which can aid future efforts in investigation of the diatom diversity present in Haryana.\u2022Data provide details of the strategy for the forensic and medicolegal experts to trace the informative pathway dealing with questioned drowning place.\u2022These data are also useful for researchers working in the field of archaeology, botany and environment sciences for water quality assessment and environmental change.1Data provided in this article revealed diversity of diatom depending upon properties of habitat water and prevailing climatic conditions of water bodies from varied localities of Haryana .2Water samples were collected from Morni Hills Tikkar Taal Lake, Panchkula; Tilyar Lake, Rohtak; Jawaharlal Nehru Canal, Rohtak; Kharawad Village Well, Rohtak; and Suraj Kund, Faridabad. The first sampling was conducted during winter season in the month of December 2013. The schedule was continued following spring (March), summer (June) and autumn (September) seasons in 2014. Changes in the physical characteristics of these water bodies have been depicted in Earlier mentioned protocols"} +{"text": "A range of strategies to improve pharmaceutical care has been implemented by population health management (PHM) initiatives. However, which strategies generate the desired outcomes is largely unknown. The purpose of this paper is to identify guiding principles underlying collaborative strategies to improve pharmaceutical care and the contextual factors and mechanisms through which these principles operate.The evaluation was informed by a realist methodology examining the links between PHM strategies, their outcomes and the contexts and mechanisms by which these strategies operate. Guiding principles were identified by grouping context-specific strategies with specific outcomes.In total, ten guiding principles were identified: create agreement and commitment based on a long-term vision; foster cooperation and representation at the board level; use layered governance structures; create awareness at all levels; enable interpersonal links at all levels; create learning environments; organize shared responsibility; adjust financial strategies to market contexts; organize mutual gains; and align regional agreements with national policies and regulations. Contextual factors such as shared savings influenced the effectiveness of the guiding principles. Mechanisms by which these guiding principles operate were, for instance, fostering trust and creating a shared sense of the problem.The guiding principles highlight how collaboration can be stimulated to improve pharmaceutical care while taking into account local constraints and possibilities. The interdependency of these principles necessitates effectuating them together in order to realize the best possible improvements and outcomes.This is the first study using a realist approach to understand the guiding principles underlying collaboration to improve pharmaceutical care. In order to provide high quality care while keeping health care systems affordable and accessible, many countries are moving toward a population-based approach. The assumption underlying a population-based approach is that to achieve better population health and quality of care and a reduction in cost growth (Triple Aim (TA); Improving pharmaceutical care was one of the first subjects addressed within the monitored Dutch PHM initiatives. In recent years, health care insurance companies had tried different policies, such as outcome-based funding for effective prescription of medicine by general practitioners, in an attempt to improve the quality of pharmaceutical care and to control the cost of medicines. However, the expenditure on pharmaceutical care barely dropped , contexts (C), mechanisms (M) and outcomes (O). The main focus of traditional realist evaluations is on generating or testing theories by focusing on how particular contexts (C) trigger changes in the reasoning and behavior of human actors (mechanisms (M); S) that are associated with specific outcomes (O) . In our This realist evaluation included several iterative stages: engagement of experts and reference panels; data collection; and analyzing, synthesizing and interpretation of data. As per realist evaluations\u2019 methodology and in line with the RAMESES standards , representatives of health care insurers and patient organizations, and project and program managers). For three PHM initiatives, individual interviews were held with a program manager or pharmacist .To become familiar with the intervention improving pharmaceutical care and the PHM region, the authors collected additional data such as pharmaceutical toolkits describing the agreements and procedures regarding the new multidisciplinary approach to pharmaceutical care, which were developed by the PHM initiatives. Also during the kick-off meeting, participants were asked to share their experiences with the new strategies PHM initiatives practiced.A semi-structured interview guide was used to support the interview process (available on request). At two points during the interview, all interviewees were asked to write down their lessons regarding which strategies worked or failed in improving collaboration on pharmaceutical care. The first time was at the start of the interview enabling the discussion about these lessons during the focus group or during the individual interview. The second time was after the presentation of the eight components of the CAHN framework, enabling interviewees to add lessons that came to mind upon viewing the eight components. All lessons were discussed, and additional information regarding strategies, contextual factors, underlying mechanisms and outcomes were retrieved during the interviews. The interviews were audio recorded and transcribed verbatim.In realist evaluations, analysis, synthesis and interpretation of the data tend to occur alongside each other during the evaluation process . Data anThe research team and reference panels reflected and commented upon the whole research process. In addition, a researcher outside the research team (LB) verified the analysis, synthesis and interpretation process. Furthermore, results were presented and discussed during a feedback meeting with representatives of four of the participating PHM initiatives and one PHM initiative that did not participate in this study. Finally, based on this feedback, the guiding principles and accompanying contextual factors and mechanisms were debated and refined within the research team.Ethics approval from the Psychological Ethical Review Committee at Tilburg University (EC-2015.54) was received in October 2015.A total of ten guiding principles enhancing collaboration to improve pharmaceutical care were identified. The strategies as well as the contexts and mechanisms by which these guiding principles operate are shown in [\u2026] Many single projects [aiming to improve pharmacy care] in the past have failed, and now we aim for sustainable regional collaboration based on health, quality and costs. So there is a vision behind it which is the driving force behind everything we are going to do in the future.PHM initiatives implemented two different strategies to organize agreement on and commitment to a coordinated intervention including multidisciplinary collaboration regarding pharmaceutical care see . First, Second, five PHM initiatives facilitated stakeholders to jointly develop a business plan for substituting brand for generic medicines including a new financial incentive model (e.g. shared-savings contract). A contextual factor enabling this strategy was a growing sense of urgency mainly from the health care insurance companies to counter ongoing high prescriptions of expensive drugs with little effect on health improvement. For the providers, this growing sense of urgency was also fueled by the fact that failing to cooperate would have negative financial consequences . This contextual factor induced feelings of problem ownership and encouraged stakeholders to reach agreement and commitment regarding lowering of prescription rates of expensive drugs and changes in ways of working, capacity and finance. However, in four PHM initiatives, other contextual factors such as corporate restructuring of stakeholders\u2019 organizations hindered the process of agenda setting and the timing of engagement of individual organizations. Consideration of strategic, financial and substantive arguments at the board level of participating organizations took more time. In these organizations, prioritizing between what they regarded as a small-scale project and their own restructuring process delayed the process of gaining agreement and commitment to multidisciplinary collaboration on pharmaceutical care.PHM initiatives fostered cooperation and representation at steering committee level to encourage leaders of regional care groups, hospitals and pharmacies to invest in multidisciplinary collaboration on pharmaceutical care. This study identified two strategies. The first strategy was that PHM initiatives sought opportunities to stimulate multidisciplinary collaboration (five PHM initiatives). Within the context of expected positive revenues gained through the introduction of shared savings contracts, this strategy enabled leaders to cooperate for three reasons. First, leaders felt obliged to prove that a multidisciplinary approach to pharmaceutical care could be successful. Given the historically disappointing results of a mono-disciplinary approach to improve pharmaceutical care, multidisciplinary agreement on lowering the prescription rates of expensive drugs and enhancement of drug safety guaranteed these quick wins. Second, leaders reasoned that these quick wins could give them the opportunity to create a financial buffer to support future projects within the PHM initiatives. Lastly, they presumed that cooperation would increase the visibility of PHM initiatives on a regional and national level.[\u2026] at an early stage, you often need representatives that are supported by their organizations and have the capability to think strategically. After 3 or 4 meetings you also need knowledge [\u2026] this issue is insufficiently recognized [\u2026].The second strategy was installing the right people at the right time in the right place . PHM initiatives differed in the way they organized representation of pharmacists depending on which knowledge (content or strategic) was needed during the process. Pharmacists were represented in the steering committee of the PHM initiative (four PHM initiatives), or regional legal entity (one PHM initiative). In addition, all PHM initiatives organized representation of pharmacists at the project level, and some had an additional steering group for this specific intervention:Representation of pharmacists at the level of the steering committee of PHM initiatives increased the possibility to channel and discuss problems and to adjust policy regarding pharmaceutical care. Consequently, the involvement of pharmacists in other projects of the PHM initiatives increased. However, pharmacists felt less involved when only represented on a lower level. On the other hand, representation in a project group led to pharmacists investing more time and in-depth knowledge in the project in comparison to participation in the steering committee. The regional legal entity combined the best of both worlds: generating more involvement and visibility of pharmacists in regional projects and more investment of time and expertise.All PHM initiatives used a layered governance structure for escalation and facilitation purposes to direct and enable multidisciplinary collaboration. The governance structure of most PHM initiatives comprises a steering committee, one or more working groups and sometimes an executive or management committee. Two strategies were identified. First, all PHM initiatives made conscious use of information within the layered governance structure for escalation or facilitation purposes. This strategy was profitable within the context of solving problems for which additional background information or exchange of information at a certain level within the governance structure was needed. Managers, for instance, learned more about the professional, organizational or regional sensitivities and interests during steering committee meetings. Consciously using information for escalation and facilitation purposes helped to generate commitment to modify prescription behavior and adjust ways of working in line with the agreed upon pharmaceutical protocol.Second, all PHM initiatives made conscious use of the skills and influencing power of PHM managers and professional experts for escalation or facilitation purposes within the layered governance structure. In situations where professionals had different paces of adjusting to the new multidisciplinary working processes, this strategy worked positively for those colleagues who had worked alongside each other for years. By having PHM managers confront professionals on their pace of adjustment to the new ways of working, instead of having colleagues confronting each other, it was ensured that professional relationships were not put under pressure. In contexts in which stakeholders had different interests and levels of commitment within the layered governance structure, the same strategy generated confidence mechanisms among stakeholders. Stakeholders were of the opinion that PHM managers and professional experts such as medical specialists who, at the same time, hold a professorship were more capable of highlighting the differences and similarities in interests and commitment due to their so-called independent position within the layered governance structure. They were assumed to know the different organizational cultures and to have good communication and persuasion skills. The contribution of PHM managers and experts\u2019 ability to enhance confidence levels was an important precondition to direct PHM initiatives toward multidisciplinary collaboration and thus for launching the pharmacy intervention (six PHM initiatives).For example with regard to the lipid level, there is a difference between general practitioners and cardiologists with respect to the cut-off values that should be pursued.Six PHM initiatives applied three strategies to ensure awareness at all levels about the need to improve pharmaceutical care, thus allowing the development of new pharmaceutical protocols and working processes. First, PHM initiatives organized continuous interaction and communication between health care insurance companies, regional care providers and patient organizations. The managers played an important role in the execution of this strategy by serving as a link between parties and by organizing discussions . A contextual factor enabling this strategy was the development of a pharmacy toolkit, which enabled discussions regarding guidelines and scientific knowledge, and health care insurance claims data. These discussions generated several mechanisms. First of all, they enabled the re-examination of existing pharmacotherapies with the intention of reducing costs without losing the quality of care. Furthermore, these discussions generated taking into account multiple medical guidelines , which, although evidence-based, sometimes contradicted each other:[\u2026] differences become transparent and negotiable during discussion. Sometimes we reached an agreement, sometimes not. Most of the time consensus was reached. Also negative emotions became apparent. In the past, differences were often not understood, people felt that others did not cooperate but did not know why.Discussing differences made stakeholders more aware of each other\u2019s point of view. Despite these differences, consensus regarding new pharmaceutical protocols was reached. Lastly, the discussions also stimulated the re-examination of existing working processes and professional roles in order to modify them in line with the new multidisciplinary pharmacy protocol (five PHM initiatives). For example, agreements were reached about the time frame within which patients had to be informed, the number of substitution consultations that should be executed and who was responsible for drafting the pharmaceutical advices and for the substitution consultations:A second strategy was making use of existing consultation situations. An enabling contextual factor of this strategy was the pre-existing quality of consultations between medical specialists, general practitioners, pharmacists, physician assistants and patients (three PHM initiatives). Joining existing consultation situations in which people already knew and trusted each other created a safe situation for discussing medication policies and ways of working. Consequently, creating awareness for needed changes was easier than in situations where trust levels were low (three PHM initiatives).A third strategy in the same context generated similar mechanisms. PHM initiatives developed information leaflets and made information available in waiting rooms to support communication with patients of the new medication policy. Discussing this information in a trusted environment increased awareness of patients that a generic drug would have the same, or even better results with lower costs, and reduced feelings of mistrust toward the new drug efficacy (five PHM initiatives).PHM initiatives organized interpersonal links to establish openness to (new) knowledge, ideas and a more multidisciplinary perspective regarding pharmaceutical care to support changes in norms, values and ways of working. This study recognized three strategies and one enabling contextual factor influencing these three strategies. This contextual factor was the already increased collaboration within primary care and between primary and secondary care. For instance, for years most general practitioners and pharmacists were engaged in pharmacotherapy consultation groups and knew each other on a personal level. Two strategies were identified. The first strategy of PHM initiatives was joining these already existing consultations (five PHM initiatives) and second was organizing regional multidisciplinary meetings to share best practices or the pharmacy protocols that were developed (four PHM initiatives).The third strategy PHM initiatives undertook was to include a range of different professionals in these regional meetings. These strategies enhanced trust, recognition and acknowledgment of each other\u2019s contribution and scientific knowledge (two PHM initiatives). In three PHM initiatives, continuous sharing of experiences in the region led to installment of a regional multidisciplinary pharmaceutical committee .PHM initiatives created a learning environment that supported the use of measurements within a feedback loop (plan-do-check-act). This study identified two strategies. First, PHM initiatives organized data input and/or new tools to match the information needs of professionals . Until then, health care insurance claims data provided insufficient insight into the degree of improvement of prescription practices due to, for example, a lack of a historical overview and insufficient insight for general practitioners into repeat prescriptions of medical specialists . Also the time frame within which changes in prescriptions were reflected in the data and the level of feedback was insufficient (five PHM initiatives). These contextual factors enabled the strategy to enhance motivation of professionals to engage in the feedback loop.Second, to support data input and tool development, PHM initiatives organized capacity and knowledge of data technology, data analysis and synthesizing data into meaningful information. Information was seen as important in creating awareness of inefficient pharmaceutical care. Insufficient capacity and knowledge put pressure on professionals and health care insurance companies to establish either internal or external capacity and knowledge to support data input and tool development. The former meant either health care insurance companies (four PHM initiatives) or professionals themselves (one PHM initiative) took the lead in organizing capacity and knowledge. Professional control led to an immediate enhancement of the level and frequency of data feedback. Two PHM initiatives organized external capacity and knowledge. In one of these PHM initiatives, this resulted in the development of a business-intelligence tool that links selected data from pharmacy, primary care and laboratory registries in order to track and decrease the use of high-cost, low-quality services for specific diseases.PHM organized shared responsibility for multidisciplinary improvement of regional pharmacy care. This study recognized two strategies. First, five PHM initiatives organized a new incentive design for multidisciplinary responsibility to improve pharmaceutical care. Contextual factors enabling this strategy were the fact that the old incentive design did not fit the new multidisciplinary agreement of PHM initiatives. Also, leaders felt an urgent need to improve pharmaceutical care, as they were not pleased with negative financial incentives for not following the formulary . In addition, leaders expected shared savings to encourage multidisciplinary responsibility by letting stakeholders share realized savings that were associated with certain results (e.g. X% brand converted into generic within certain time frame). However, a constraining contextual factor of the strategy was the difference in basic principles of professionals and organizations that became apparent during the development of the pharmacy protocol, such as differences in cut-off values and scores or setting of the benchmark . For instance, teaching hospitals only wanted to be benchmarked with other teaching hospitals, as their patient population is very different from community hospitals. PHM initiatives took these differences into account while designing these new incentive designs.The second strategy was to organize an adherence design, based on social forces like peer reviewing in which general practitioners, pharmacists and medical specialists discussed each other\u2019s results. Because stakeholders were dissatisfied with pre-existing individual and regional prescription rates of expensive drugs, peer reviewing induced a shift to multidisciplinary accountability resulting in a higher participation rate of providers than mono-disciplinary accountability (five PHM initiatives). Also, peer reviewing in a multidisciplinary context prompted strong feelings of motivation for achieving better performances, especially if stakeholders already had positive experiences with the plan-do-check-act cycle (five PHM initiatives).If you look at the price of Spiriva for COPD patients, sixty percent of the low budget medication is Spiriva [\u2026]. But the patent of Spiriva expires this year [\u2026] Now the costs are 80 or 90 euros and this can drop to a couple of euros [\u2026].PHM initiatives implemented two financial strategies to strive for the best pharmacy therapy for the lowest price, given the market context. First, two PHM initiatives took into account market factors and trends of pharmaceutical products such as prices, applicability of products and expiration dates of patents to define the pharmacy formulary. On the basis of this formulary, health care insurance companies negotiated with manufacturers on the basis of efficiency and quality:For asthma/COPD products, we looked per interchangeable groups of medicines on the basis of qualitative criteria. How medicine should be applied played an important role in this choice. [\u2026] And now the insurer is asking the pharmaceutical market to react on this formulary. The manufacturers don\u2019t know the formulary content, but were asked to provide the best possible price. If manufacturers are lower in price than the ones on the formulary, and the quality of the medicine does not differ much, then such a manufacturer can still end up on the formulary. In this way we try to combine quality with efficiency.The insurance companies successfully challenged manufacturers to lower pricing rates per serving in order for them to be included into the formulary. Although the formulary gave financial and qualitative advantages, it was also criticized for reducing the freedom of choice of medicine:For CVRM you can make estimates how much risk you want to take. [\u2026] You cannot change everything at once, so you would like to discuss with patients \u2018if you lose five kilos the chance of getting a heart attack will be reduced with 10%, and if you stop smoking then it will drop with another 30%, and when you take your medicine the chances will reduce even further with another 5%. So what is feasible for you? By bringing together data with regard to clinical outcomes, patient preferences and financial data e.g. option 1 would be the cheapest solution and option 3 would lead to a financial break even.Second, two PHM initiatives organized financial insight to support treatment options, starting with people with multimorbidity. Within the context of striving for the best pharmaceutical therapy for the lowest price, this strategy induced deliberate use of financial outcomes and combining this data with clinical data and patient preferences:As a result, PHM initiatives were capable of weighing individual treatment options as well as improving health care purchasing processes in the regional market (two PHM initiatives). Although combining data raised political concern related to privacy laws and regulations, one PHM initiative derived legitimacy for the experiment based on support expressed by a visiting political delegate.PHM initiatives organized mutual gains to develop a financial buffer and put the initiative \u201con the map.\u201dThis study identified two strategies. The first strategy of PHM initiatives was to focus on \u201clow-hanging fruit\u201d to gain quick wins. Because leaders expected positive revenues gained through the introduction of shared savings contracts, several distribution scenarios of potential savings were under debate at the start of the intervention. One of these scenarios was directing all savings back to the professionals executing the intervention . However, discussions in society at large about unequal distribution of bonuses influenced the debate. Three PHM initiatives were motivated to funnel net savings back to serve as a financial buffer for future interventions that would benefit the health of the regional community.The second strategy of PHM initiatives was to enhance the visibility of the PHM initiatives . Improving pharmaceutical care was just the first intervention of a growing regional PHM program as initiatives wanted to address medical and social determinants of health of the regional community. The pressure of PHM initiatives to work toward a comprehensive regional program led to a focus on achieving financial wins (four PHM initiatives). These quick wins not only symbolized successful regional multidisciplinary collaboration, but also the potential of PHM initiatives to continue their journey and enhance their regional and national visibility.Although we have made agreements to provide integrated care, we face the current fragmented funding streams. So, integrated agreements were unraveled into separate pieces in order for them to be separately funded in line with the existing system. This is not easy, it took tremendous effort to get organizations support the integrated regional approach.PHM initiatives implemented two strategies. First, PHM initiatives indicated at the earliest possible moment when existing regulations did not match new regional agreements. Four PHM initiatives stated that a constraining contextual factor for this strategy was the \u201cpreference policy\u201d of health care insurance companies. Although health care insurance companies agreed to the regional pharmaceutical formulary of PHM initiatives, in hindsight, one medication group did not match the national preference policy of insurance companies. This contextual factor led to risk factors at the level of the treatment relationship, as PHM initiatives assumed all medicines within the formulary would be reimbursed. Providers sometimes had to deal with dissatisfaction of patients due to the miscommunication about reimbursement of medicine. Furthermore, PHM initiatives risked damaging the accountability relationship between the insurance company and the initiatives. Although, eventually, the national preference policy was adjusted to the regional policy regarding the aforementioned medication group, providers were only reimbursed from this moment onwards. Other constraining contextual factors were the existing walls regarding funding systems between sectors and disciplines:This factor led to the unraveling of the multidisciplinary agreements to adhere to current financial systems.Furthermore, as health care insurance companies tended to stick to their own contract and not follow the contract of the other health care insurers in the same region, the second strategy of PHM initiatives was to reduce ambiguity with regard to which policy, and thus which contract, was preferred in the region . This strategy was especially important when there were two or more health care insurers with a similar or at least substantial market share in PHM regions. Regulations about contracting of insurance companies were regarded by leaders of PHM initiatives as a constraining contextual factor as insurance companies could contract care provision as they saw fit. This factor led PHM initiatives to require clarity of the non-preferred insurance company at the earliest possible stage to reduce uncertainty in financial revenues, reduce additional administrative burdens and reduce the risk of lack of support for the intervention .This study identified ten guiding principles for the organization of regional collaboration to improve pharmaceutical care in line with the TA goals: create agreement and commitment based on a long-term vision; foster cooperation and representation at board level; use the layered governance structure; create awareness at all levels; enable interpersonal links at all levels; create a learning environment; organize shared responsibility; adjust financial strategies to the market context; organize mutual gains; and align regional agreements with national policies and regulations. The strategies underlying each guiding principle interact with various contextual factors and thereby trigger different mechanisms that influence collaboration to improve pharmaceutical care. Furthermore, the guiding principles are interdependent. Therefore, it is necessary to develop and implement them together in order to realize the greatest improvements and outcomes.Reflecting on the guiding principles, two types of guiding principles can be identified: guiding principles 1-5 predominantly represent the people management side of improving collaboration. Guiding principles 6-10 relate predominantly to the technical conditions of improving collaboration. Both types of guiding principles are interdependent as is in line with previous work (For guiding principles 1-5 to be effective, it is important that regional stakeholders get to know each other and gain awareness of shared regional problems in order to be able to develop a long-term regional vision. This requires contexts highlighting mutual dependence of regional stakeholders which is in line with Guiding principles 6-10 are consistent with the literature on the importance of learning environments in times when roles and working practices, professional and organizational status are in flux e.g. , but thaThis study adopted an evaluation method based on realist principles. This approach provides insights that other forms of synthesizing evidence would not have given (Improving pharmaceutical care was in most Dutch PHM initiatives the first step in a large program of change to build multiorganization and multisector collaborations designed to address both medical and social determinants of health for regional populations. Elements such as developing a multidisciplinary business plan, executing a multidisciplinary regional approach, building and improving relationships, and experimenting with new forms of funding such as shared savings contracts formed the basis for future regional collaboration to align prevention, care and welfare services. The current PHM guiding principles provide health system leaders and policy makers the necessary ingredients to choose strategies that will lead to the intended outcomes given local, regional and national constraints and opportunities. Considering the broader ambitions of PHM initiatives, future research in the guiding principles, the underlying strategies and accompanying contexts and mechanisms by which these guiding principles operate is necessary. The guiding principles are part of an ongoing process of sharing knowledge and experiences. The Dutch Monitor of Pioneer Sites Population Management will continue to monitor the Dutch PHM initiatives as they add new stakeholders and populations and seek to grow their PHM programs. In addition, we will gain insight into the learning experiences of four international PHM initiatives in 2017-2018. As a result, we will be able to enrich the current guiding principles and identify new ones, and as such will contribute to the international debate and learning with regard to the organization of collaboration across public health, health care, social care and community services.There are many factors stimulating collaboration to improve pharmaceutical care in the Dutch PHM initiatives. The ten guiding principles identified in this study will support health system leaders and policy makers to design, implement or improve strategies fostering collaboration with the aim of improving pharmaceutical care. The guiding principles must be developed and implemented together in order to realize the greatest improvements and outcomes. Health system leaders can use these principles in the contexts of their own regional setting and identify which activities and policies make most sense, given regional constrictions and chances. Improving pharmaceutical care is an incremental process. Continuous sharing of practices and understandings in implementing the guiding principles will lead to improved pharmaceutical care."} +{"text": "Early identification of dysplasia remains a critical goal for diagnostic endoscopy since early discovery directly improves patient survival because it allows endoscopic or surgical intervention with disease localized without lymph node involvement. Clinical studies have successfully used tissue autofluorescence with conventional white light endoscopy and biopsy for detecting adenomatous colonic polyps, differentiating benign hyperplastic from adenomas with acceptable sensitivity and specificity. In Barrett's esophagus, the detection of dysplasia remains problematic because of background inflammation, whereas in the squamous esophagus, autofluorescence imaging appears to be more dependable. Point fluorescence spectroscopy, although playing a crucial role in the pioneering mechanistic development of fluorescence endoscopic imaging, does not seem to have a current function in endoscopy because of its nontargeted sampling and suboptimal sensitivity and specificity. Other point spectroscopic modalities, such as Raman spectroscopy and elastic light scattering, continue to be evaluated in clinical studies, but still suffer the significant disadvantages of being random and nonimaging. A recent addition to the fluorescence endoscopic imaging arsenal is the use of confocal fluorescence endomicroscopy, which provides real-time optical biopsy for the first time. To improve detection of dysplasia in the gastrointestinal tract, a new and exciting development has been the use of exogenous fluorescence contrast probes that specifically target a variety of disease-related cellular biomarkers using conventional fluorescent dyes and novel potent fluorescent nanocrystals . This is an area of great promise, but still in its infancy, and preclinical studies are currently under way."} +{"text": "Creative cognition is frequently described as involving two primary processes, idea generation and idea selection. A growing body of research has used transcranial direct current stimulation (tDCS) to examine the neural mechanisms implicated in each of these processes. This literature has yielded a diverse set of findings that vary depending on the location and type of electrical stimulation employed, as well as the task\u2019s reliance on idea generation or idea selection. As a result, understanding the interactions between stimulation site, polarity and task demands is required to evaluate the potential of tDCS to enhance creative performance. Here, we review tDCS designs that have elicited reliable and dissociable enhancements for creative cognition. Cathodal stimulation over the left inferior frontotemporal cortex has been associated with improvements on tasks that rely primarily on idea generation, whereas anodal tDCS over left dorsolateral prefrontal cortex (DLPFC) and frontopolar cortex has been shown to augment performance on tasks that impose high demands on creative idea selection. These results highlight the functional selectivity of tDCS for different components of creative thinking and confirm the dissociable contributions of left dorsal and inferior lateral frontotemporal cortex for different creativity tasks. We discuss promising avenues for future research that can advance our understanding of the effectiveness of tDCS as a method to enhance creative cognition. Creative cognition\u2014cognition manifesting in ideas that are both novel and useful Barron, \u2014compriseThe neuroscientific exploration of creative cognition has focused on brain regions that support creative idea generation and selection using functional neuroimaging and electrophysiological measures. Recent inquiries have also used transcranial direct current stimulation (tDCS) to provide causal evidence for the role of specific brain areas in each of these processes. tDCS is the application of a constant, low-level electrical current to the cortex through surface electrodes positioned on the scalp to modulate the excitability of neurons within a region of interest . Thus, understanding the relationship between task demands and stimulation montages is required to evaluate the potential of tDCS to enhance creative performance. Here, we survey the effects of tDCS on creative cognition, drawing particular distinctions between the generative and selective processes and the corresponding stimulation designs under which enhancements in creative performance can be achieved.reducing cortical excitability of left inferior frontotemporal cortex through cathodal tDCS required or their reliance on the retrieval of semantic information. For example, establishing and breaking a mental set in problems involving visual reasoning was a primary component of the studies by Chi and Snyder , 2012, breduction of excitability of left DLPFC would have been antithetical to theories that implicate this region in creative idea selection. Critically, enhancements did not extend to a separate verbal fluency task, a measure of creativity that is primarily generative. Increased DLPFC activity may not be enough to induce changes in performance on tasks that rely more heavily on idea generation, suggesting that other regions have a more critical role in highly generative forms of creative thought.Contrary to creative idea generation, creative idea selection requires task-directed thoughts and integration of semantically distant concepts. When approaching a creative problem, one must be able to effectively direct their thoughts towards a specific goal and evaluate the suitability of potential solutions before choosing the optimal one depending on context and task demands. One appealing neural target for creative thinking that relies on such selective processes is dorsolateral PFC (DLPFC), which has been widely linked to executive function, including promotion of task-relevant thoughts and suppression of inappropriate ones , whereas the latter task more strongly taxes the generative resources. However, instructing participants to think creatively introduces additional selectivity demands\u2014particularly for the verb generation task. When participants were asked to think creatively, they needed to inhibit more common, prepotent responses and select more semantically distant options. With this greater focus on idea selection, potentiating left frontopolar cortex produced greater enhancements compared to the uncued\u2014and less selective\u2014conditions. Our study showed that, without a cue to think creatively, anodal tDCS to left frontopolar cortex was not associated with enhanced performance on the otherwise non-selective verb generation task can augment creative idea selection. These results support the effectiveness of this particular study design in which stimulation type and location interact with task context (increased demands on selectivity) to produce significant behavioral gains for creativity performance.Creative cognition likely relies on two primary operations, idea generation and idea selection. Although most measures of creative thought involve\u2014to an extent\u2014both of these processes, the growing literature on tDCS interventions to promote creative thinking suggests that creative idea generation and idea selection involve inherently different mechanisms with distinct neural bases. This review article outlined tDCS designs that have elicited dissociable creative enhancements on each of these processes. Cathodal stimulation over the left inferior frontotemporal cortex, a region implicated in inhibitory control and the maintenance of mental templates, has been associated with improvements on tasks that rely primarily on idea generation, without significantly changing performance on tasks that rely primarily on idea selection. In contrast, anodal tDCS over left DLPFC and frontopolar cortex\u2014brain regions that likely contribute to goal-directed thought and informational integration\u2014can augment performance on tasks that impose high demands on creative idea selection, without significant consequences for tasks that rely primarily on creative idea generation.in vivo neurobiological mechanisms of tDCS: the effects of tDCS may be functionally specific, because the stimulation may affect mechanisms that are already undergoing neural plasticity and The John Templeton Foundation (ID 51971).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Uddanam is a lush green region with rich coconut and cashew plantations in Srikakulam district, Andhra Pradesh state, India. An unknown number of people living in this area have a chronic kidney disease of unknown etiology, a disease that mostly affects farmers and agricultural workers.An increased prevalence of chronic kidney disease has been observed in several geographical areas across the world over the past two decades.,,Unpublished cross-sectional estimates from Uddanam suggest that the prevalence of chronic kidney disease of unknown etiology is between 40% and 60% . This range is nearly three times higher than the national prevalence of 17.2%.Many scientific communities are exploring the causes of chronic kidney disease of unknown etiology in Uddanam region.,,Lessons learnt from other regional nephropathies could facilitate more focused research. For instance, the Sri Lankan nephropathy studyUddanam nephropathy is a public health issue in India and sharing expertise across disciplines and countries is needed to accelerate knowledge dissemination, guide the research agenda and help establish its causes. However, it is challenging for India to engage in sustained research, given constrained resource, research capabilities and national policy initiatives. WHO could support these efforts by contributing to reshaping the research agenda and calling for collaboration between clinicians, researchers, epidemiologists, toxicologists, agriculture scientists, social scientists, hydrologists and governmental and nongovernmental organizations, including those who work for the Epidemic Intelligence Service. Local and national governments should strengthen the implementation of available interventions for early detection and management of chronic kidney disease of unknown etiology. They should also prioritize the provision of safe drinking water and food in affected areas and promote sustainable agricultural practices based on current knowledge and evidence until researchers have established the exact cause of this chronic disease. Paramedical personnel trained in renal care, as well as social workers, should also provide social and psychological support to patients, families and communities. All these interventions should be regularly evaluated to assess their impact and adapt them if needed.If policy-makers do not undertake such steps until a cause is established, people of Uddanam are potentially more at risk of acquiring the disease and patients already having chronic kidney disease of unknown etiology will be at risk of death. The experience of Sri Lanka shows that the scientific community needs to collect data in a comprehensive manner and analyse these thoroughly to increase the chances of finding the cause of Uddanam nephropathy."} +{"text": "Invasive populations are often associated with low levels of genetic diversity owing to population bottlenecks at the initial stages of invasion. Despite this, the ability of invasive species to adapt rapidly in response to novel environments is well documented. Epigenetic mechanisms have recently been proposed to facilitate the success of invasive species by compensating for reduced levels of genetic variation. Here, we use methylation sensitive-amplification fragment length polymorphism and microsatellite analyses to compare levels of epigenetic and genetic diversity and differentiation across 15 sites in the introduced Australian house sparrow population. We find patterns of epigenetic and genetic differentiation that are consistent with historical descriptions of three distinct, introductions events. However unlike genetic differentiation, epigenetic differentiation was higher among sample sites than among invasion clusters, suggesting that patterns of epigenetic variation are more strongly influenced by local environmental stimuli or sequential founder events than the initial diversity in the introduction population. Interestingly, we fail to detect correlations between pairwise site comparisons of epigenetic and genetic differentiation, suggesting that some of the observed epigenetic variation has arisen independently of genetic variation. We also fail to detect the potentially compensatory relationship between epigenetic and genetic diversity that has been detected in a more recent house sparrow invasion in Africa. We discuss the potential for this relationship to be obscured by recovered genetic diversity in more established populations, and highlight the importance of incorporating introduction history into population-wide epigenetic analyses."} +{"text": "Adolescent developmental issues, such as mental health problems, substance abuse, and egocentric behavior, of university students are examined. This conceptual review generally shows that although there are related issues among university students deserving greater attention, there is a general lack of systematic prevention or positive youth development programs adopting the principle of universal prevention. In contrast to the abundance of universal adolescent prevention and positive youth development programs specifically designed for high school students, similar programs are grossly lacking in the university educational context. This paper highlights the factors contributing to such negligence in university education and the possible strategies that can be adopted to help university students develop in a holistic manner."} +{"text": "Prostate cancer is now the most commonly diagnosed solid tumor in American men, due in part to widespread screening and aggressive diagnostic practices. Prostate cancer autopsy studies show the uniquely high prevalence rates of small, indolent tumors in men dying of other causes. These findings have led to increased concern for the overdetection and overtreatment of prostate cancer. Active surveillance for prostate cancer allows one to limit prostate cancer treatment with concomitant risks of treatment-related morbidity to the men who will benefit the most from aggressive therapies. Several tools have been developed in treated and surveyed men to assist physicians in selecting men with potentially indolent tumors amenable to active surveillance. Recent published results describe institutional experiences with active surveillance and delayed selective therapy for men with low-grade, early prostate cancer. Although median follow-up from these studies is relatively short, the outcomes appear favorable. Data from these reports provide information for selecting men for this approach, as well as for following them over time and determining triggers for further intervention. Ongoing clinical trials with watchful waiting and active surveillance for prostate cancer will ultimately provide improved evidence for managing early, localized disease."} +{"text": "CDC has updated its interim guidance for U.S. health care providers caring for infants with possible congenital Zika virus infection does not rule out infection. Serologic testing is affected by timing of sample collection: a negative immunoglobulin M (IgM) serologic test result does not rule out infection because the serum specimen might have been collected before the development of IgM antibodies, or after these antibodies have waned. Conversely, IgM antibodies might be detectable for months after the initial infection; for pregnant women, this can make it difficult to determine if infection occurred before or during a current pregnancy. In addition, cross-reactivity of the Zika virus IgM antibody tests with other flaviviruses can result in a false-positive test result, especially in persons previously infected with or vaccinated against a related flavivirus, further complicating interpretation American College of Obstetricians and GynecologistsAssociation of Maternal and Child Health ProgramsAssociation of Public Health LaboratoriesAssociation of State and Territorial Health OfficialsCouncil of State and Territorial EpidemiologistsFamily VoicesMarch of DimesNational Association of County and City Health Officials National Association of Pediatric Nurse PractitionersPublic health organizationsCalifornia Department of Public HealthCounty of San Diego Health and Human Services AgencyDepartment of Health of Puerto RicoFlorida Department of HealthNew York City Department of Health and Mental HygieneTexas Department of State Health ServicesFederal agenciesAdministration for Children and FamiliesCenters for Disease Control and PreventionCenters for Medicare & Medicaid ServicesMaternal and Child Health Bureau, Health Resources and Services AdministrationNational Institute of Child Health and Human Development, National Institutes of HealthOffice of the Assistant Secretary for Preparedness and ResponseThis updated interim guidance is based on current, limited data about Zika virus infection, the interpretation of individual expert opinion collected during the Forum, and knowledge about other congenital infections, and reflects the information available as of September 2017. As more information becomes available, this guidance will be updated.The optimal assays, specimens, and timing of testing for congenital Zika virus infection are unknown. A few reports have described infants with clinical findings consistent with possible congenital Zika syndrome but with negative laboratory results , which measures virus-specific neutralizing antibodies, can be used to help identify false-positive results Developmental monitoring and screening using validated screening tools recommended by the American Academy of Pediatrics (http://pediatrics.aappublications.org/content/137/1/e20153596)Vision screening as recommended by the American Academy of Pediatrics Policy Statement \u201cVisual System Assessment in Infants, Children, and Young Adults by Pediatricians\u201d and assistance with Zika virus diagnosis, testing, and counselingNeurologist by age 1 month for comprehensive neurologic examination and consideration for other evaluations such as advanced neuroimaging and EEGOphthalmologist for comprehensive eye exam by age 1 monthClinical geneticist for confirmation of the clinical phenotype and evaluation for other causes of microcephaly or congenital anomaliesEarly intervention and developmental specialistsFamily and supportive servicesAdditional possible consultations, based on clinical findings of the infant:Endocrinologist for evaluation of hypothalamic or pituitary dysfunction and consideration for thyroid testingLactation specialist, nutritionist, gastroenterologist, or speech or occupational therapist for evaluation for dysphagia and management of feeding issuesOrthopedist, physiatrist, or physical therapist for the management of hypertonia, clubfoot or arthrogrypotic-like conditionsPulmonologist or otolaryngologist for concerns about aspirationThe initial clinical evaluation, including subspecialty consultations, can be performed before hospital discharge or as an outpatient, taking into account hospital capabilities and needs of the family. Transfer to a facility with access to pediatric subspecialty care typically is not necessary unless there is an urgent clinical need. Health care providers should maintain vigilance for the appearance of other clinical findings associated with congenital Zika syndrome. Diaphragmatic paralysis should be considered in an infant who develops respiratory distress or failure or who fails to wean from a ventilator. Infant feedings should be monitored closely, and if there are signs of swallowing dysfunction, such as difficulty breathing with feeding, coughing or choking during feeding, or extended feeding times, an assessment for dysphagia should be performed , there is no laboratory evidence of congenital Zika virus infection , and the clinical evaluation is normal, then congenital Zika virus infection is unlikely. Infants should continue to receive routine pediatric care, and health care providers should remain alert for any new findings of congenital Zika virus infection.This heterogeneous group includes mothers who were never tested during pregnancy as well as those whose test result could have been negative because of issues related to timing or sensitivity and specificity of the test. Because the latter issues are not easily discerned, all mothers with possible exposure to Zika virus during pregnancy who do not have laboratory evidence of possible Zika virus infection, including those who tested negative with currently available technology, should be considered in this group.Laboratory testing. Laboratory testing for congenital Zika virus infection is not routinely recommended for infants born to mothers in this category based on the unknown risk for infection; the lower likelihood of congenital Zika virus infection as a result of the declining prevalence of Zika virus infection; and limitations of infant laboratory testing. If abnormal findings are identified, these infants should receive further evaluation, including evaluation and testing for congenital Zika virus infection.Clinical evaluation and management. Infants without clinical findings consistent with congenital Zika syndrome born to mothers without laboratory evidence of possible Zika virus infection during pregnancy should have a standard evaluation ; and maternal factors, including the presence and timing of symptoms, and type, location, and length of possible Zika virus exposure. Older infants in whom maternal Zika virus exposure was not assessed at birth and who are evaluated later might also have more clinical data available to guide the evaluation. If findings consistent with congenital Zika syndrome are identified at any time, referrals to the appropriate specialists should be made, and subsequent evaluation should follow recommendations for infants with clinical findings consistent with congenital Zika syndrome .While much has been learned about congenital Zika syndrome, limitations of laboratory testing exist and the full spectrum of congenital Zika virus infection is not yet known. Similar to other congenital infections, prenatal diagnostic evaluation can inform the clinical evaluation of infants with possible Zika virus exposure. Current CDC guidance regarding prenatal diagnosis is reviewed below (Ultrasound. Routine screening for fetal abnormalities is a component of prenatal care in the United States. Comprehensive ultrasound examination to evaluate fetal anatomy is recommended for all women at 18\u201322 weeks\u2019 gestation (Questions remain about optimal timing of ultrasound among pregnant women with possible maternal Zika virus exposure. Abnormalities have been detected anywhere from 2 to 29 weeks after symptom onset (Amniocentesis. The role of amniocentesis for the detection of congenital Zika virus infection is unknown. Data regarding the positive and negative predictive values and optimal timing for amniocentesis are not available. Reports of the correlation between positive Zika test results in amniotic fluid and clinical phenotype or confirmatory infant laboratory testing are inconsistent (Summary of prenatal diagnosis of congenital Zika virus infection. Given the limitations in the available screening modalities and the absence of effective interventions to prevent and treat congenital Zika virus infection, a shared decision-making model is essential to ensure that pregnant women and their families understand the risks and benefits of screening in the context of the patient\u2019s preferences and values. For example, serial ultrasound examinations might be inconvenient, unpleasant, and expensive, and might prompt unnecessary interventions; amniocentesis carries additional known risks such as fetal loss. These potential harms of prenatal screening for congenital Zika syndrome might outweigh the clinical benefits for some patients; therefore, these decisions should be individualized ("} +{"text": "The Lancet Commission and the Global Health Workforce Alliance reported that professional education has generally not kept up the pace of health care challenges. Sub Saharan Africa needs an effective and efficient nursing education system to build an adequate, competent and relevant nursing workforce necessary for the achievement of Sustainable Development Goals. The Plan of Action for Scaling up Quality Nursing and Midwifery Education and Practice for the African Region 2012 - 2022 provided a framework for scale up of nurses and midwives. This integrative review examined literature on nursing education challenges and solutions in Sub Saharan Africa to inform development of a model for improving the quality, quantity and relevance of nursing education at local level.A search of PubMed, Medline on EBCSOhost and Google Scholar was conducted using key words: nursing education, challenges, solutions and/ or Africa. Published works from 2012 to 2016 were reviewed to explore reports about challenges and solution in nursing education in Sub Saharan Africa. Full texts of relevant studies were retrieved after reading the tittles and abstracts. Critical appraisal was undertaken and the findings of the relevant studies were analysed using thematic analysis.Twenty articles and five grey sources were included. Findings of the review generally supports World Health Organisation framework for transformative and scale up of health professions education. Six themes emerged; curriculum reforms, profession regulation, transformative teaching strategies, collaboration and partnership, capacity building and infrastructure and resources. Challenges and solutions in nursing education are common within countries. The review shows that massive investment by development partners is resulting in positive development of nursing education in Sub Saharan Africa. However, strategic leadership, networking and partnership to share expertise and best practices are critical.Sub Saharan Africa needs more reforms to increase capacity of educators and mentors, responsiveness of curricula, strongly regulatory frameworks, and availability of infrastructure and resources. The review adds to the body of knowledge to enhance efforts of stakeholders in the improvement of the quality, quantity and relevance of nursing education in Sub Saharan Africa. Sub Saharan Africa continues to report poor health indicators with challenged health systems due to growing burden of diseases including HIV/ AIDS and non-communicable diseases and a severe shortage of health care workers \u20134. ShortThere is a global consensus that nurses and midwives constitute the majority of the global health workforce and the largest health care expenditure . Nurses Traditionally, nursing and midwifery education has been offered at stand-alone training institutions with more emphasis of production of lower level cadre. Many countries including Malawi, Zambia, Kenya, Zimbabwe still have majority of their nurses at technician level than registered nurse level. However, nursing and midwifery education in Africa has shown signs of development over the past two decades. World Health Organization reportedHowever, literature still report lack of necessary competencies among graduates due to lack of strategic leadership to drive transformation , unrespoThe Plan of Action for Scaling up Quality Nursing and Midwifery Education and Practice for the African Region 2012 \u2013 2022 provided a framework for scale up of nurses and midwives in the region. The purpose of this study was to review literature on status of nursing education in Sub Saharan Africa to inform development of a model for improvement of quality, quantity and relevance of nursing education at local level.The researchers were informed by the works of Whittemore and Knafl which haThe research problem emanated from a Norwegian Church Aid (NCA) funded National Nursing Education Research Conference and anecdotal notes from nursing education stakeholders who identified shortage of nursing workforce and growing concerns of poor quality of nursing care because of inefficiencies in the nursing education system. The review was guided by the following research questions: what is the status of nursing education in Sub Saharan Africa, and what are the solutions or innovations being taken to improve nursing education?A search of PubMed, MEDLINE, Academic search complete, health sources on EBCSOhost and Google scholar was conducted using the key words; nursing education, challenges, solutions, innovations AND Africa. The inclusion criteria for electronic records included primary source and peer reviewed reports on nursing education in Sub Saharan Africa. The review included literature from 2012 to 2016 to capture what has been reported during the period after the Plan of action for Scaling up Quality Nursing and Midwifery Education and Practice for the African Region 2012 \u2013 2022. Peer reviewed records were targeted to ensure integrity of findings because they already have a level of scrutiny. The review also included a search of grey literature as well as extensive consultation with nursing education experts to identify relevant documents. Key stakeholders including nurse educators, nursing education policy makers were individually approached to voluntarily provide material they knew would be relevant including program documents, project reports and progress reports on nursing education. The process of the integrative review is presented in Fig. Records were evaluated for their authenticity, methodological quality and informational value. A structured data extraction and quality appraisal checklist was utilized on each record for information extraction based on the Critical Appraisal Skills programme Checklist. Initially records were selected based on their titles. Abstracts of selected titles were analysed to assess their relevance to the study question. Only abstracts that addressed nursing education challenges and solutions in Africa after 2012 were subjected to a full text review. Full text records that did not meet the appraisal process were excluded from the review. Relevant bibliographies from the identified records were also reviewed.Thematic analysis was used to analyse data. Data was extracted and coded into manageable framework. This was then displayed to convert extracted data from individual sources into a display that assembles around particular variables or subgroups. Extracted data was compared item by item so that similar data was categorised and grouped together. An iterative process of examining data displays to facilitate distinction of patterns, themes, variations and relationships was done using a comparison method. Conclusions were then drawn from the data. To ensure reliability of the review, the articles and the appraisal forms were independently reviewed by two colleagues. Findings from the researchers and the independent evaluators were compared and discussions were held to reach an agreement.The search conducted yielded a total of 1434 records. One thousand two hundred and eighty seven (1287) records were obtained from EBSCOhost database, 58 records from PubMed and 84 from Google scholar and 5 grey records obtained from experts. One thousand three hundred and eighty (1380) abstracts were excluded either because they addressed nursing education outside Sub Saharan Africa or addressed education of health professions in general. Twenty nine (29) full text reports were excluded from the study because they neither addressed the challenges nor the solutions of nursing education. Majority of the records addressed perceptions and experiences of nursing students with the nursing training. Finally, twenty (20) records and five (5) grey material were finally included in the review (Table\u00a0Six themes emerged from the review namely; curriculum reforms, professional regulation, transformative teaching strategies, collaboration and partnership, capacity building and infrastructure and resources.Health care reforms alter the environment in which nurses and other health care workers practice. The review found that in Sub Saharan Africa, emphasis on primary care, emerging of new health challenges, increasing burden of disease significantly demand need for curriculum reforms \u201323. MtheMtshali and Gwele developeWithin the changing face of nursing education, key issues in Sub Saharan Africa related to professional regulation include notions of specialist and advanced practice, accountability and autonomy, competence, supervision, continuing education and delegation . McCarthAppiagyei et al. observedWe found that the complexity of healthcare demands and practice environment require a coordinated and collaborative approach to training of health professionals including nurses. However, the review show that nurses\u2019 engagement in policy making is still complex and contested . EvidencWe found that the changing learning environment, competition for learning opportunities and limitations in terms of clinical support pose challenges for professional nurses to perform their multifaceted role . ProfessChallenges facing nursing education in Sub Saharan Africa demands strong committed leadership to see mutual goals and strategic contribution and effective use of resources . BuildinThe complex environment in nursing education demands that academic managers, leaders and players continually monitor the ever- evolving, complex system of the professional tripartite: nursing education, research and practice. Nursing leaders have been challenged to spearhead a successful translation of scientific knowledge that links nursing education to professional practice in the delivery of high quality health care. Jooste and Jasper reportedCapacity building also surrounds around the issue of faculty ability to prepare a generation of relevant graduates , 37. TheWe found that lack of infrastructure, absence of trained human resources experts and lack of material resources posed big challenges to nursing education among Sub Saharan African countries , 40. WitThis integrative review has attempted to synthesize relevant published work on nursing education in Africa and made recommendations towards improving the quality, quantity and relevance of nursing education in Su Saharan Africa. Despite the reported severe shortage and maldistribution of nurses between and within countries, nurses remain the single largest available group of available health workers. This positions nurses to be global leaders in driving the quality of health care delivery especially in low \u2013resource settings . NumerouA curriculum is at the heart of every educational enterprise . The chaNursing plays a key role in the coordination and integration of care and services from other providers . ReformsNursing as a profession has a unique system of rules an principles to regulate its members and demonstrate its responsibility to society . The chaInternational Council of Nurses identifiMany health professional training programs have mostly maintained classroom teaching. These short term lectures and seminars have proved not to be effective in diversifying skills md competencies of health workers including nurses . The revNurse educators need to examine what they do in and out of classroom to continue to be effective, current and relevant. With the focus on community health demands, training initiatives should prioritise the acquisition of competencies through sustained mentorship and supervision, simulation rather than through ad hoc short term lectures and seminars , 63.In some instances a disjuncture between nursing leadership and front line nurses has been reported , 65. WorCareful planning of students learning experiences between academia and practice is imperative to ensure that students get maximum benefits from their training. Current reforms in nursing education demands sharing of knowledge and information. Partnerships between academia and practice can contribute significantly towards a vibrant healthcare system. Effective academic practice partnerships can reduce the theory practice-gap thereby improving patient safety, reducing medical errors, strengthening practice setting and cushioning faculty shortage , 68. AcaAcademic practice partnerships provide a platform for partners to capitalize on each other\u2019s expertise. This also improves access to a broader array of clinical experiences for students. Students receive adequate clinical support that is blended with expertise from both academic knowledge and practice competencies. Evidence supports that mentorship provided by clinical personnel is critical to students\u2019 training outcomes . QualityWorld Health Organization highlighHealth worker shortage in Sub Saharan Africa is a result of many causes which include past investment shortfalls in pre- service training, international migration, career changes among health workers, premature retirement and morbidity and mortality . ExperieThis review shares useful information for improving nursing education among stakeholders worldwide. The major limitation of the study was that it only focused on literature from Sub Saharan Africa.Nursing and midwifery remains the backbone of the healthcare system worldwide. Continued efforts to improve training of nurses and midwives will ensure improved health outcomes. Effective nursing education will ensure provision of competence based practice among nurses. More research on nursing education will help to improve practice standards in nursing and midwifery.The integrated review highlights that majority of countries within Sub Saharan Africa are experiencing common challenges ranging from strained training institutions due to increased enrolments, inadequate faculty capacity, lack of infrastructure and resources, high demand for clinical training sites. To ensure improved quality and quantity of production, developmental partners have increased allocation of financial resources for infrastructure and teaching and learning material. Efforts are being done to expand number of clinical sites, build faculty capacity and increase collaboration with clinical institutions for clinical instructors and mentors. Curriculum reforms are being implemented to reposition the nursing workforce for a competence based approach, community based education and inter-professional training. Clinical simulation and technology based teaching strategies are on the increase to accommodate the demands for new ways of teaching and learning."} +{"text": "The trigeminal nerve and heart are strongly related through somato-autonomic nervous reflexes that induce rapid changes in cardiovascular function. Several trigeminal reflexes have been described, but the diving and trigeminocardiac reflexes are the most studied. The heart is a target organ dually innervated by the sympathetic and parasympathetic systems. Thus, how cardiac function is regulated during the trigeminal reflexes is the result of the combination of an increased parasympathetic response and increased, decreased, or unaltered sympathetic activity. Various hemodynamic changes occur as a consequence of these alterations in autonomic tone. Often in the oxygen-conserving physiological reflexes such as the diving reflex, sympathetic/parasympathetic co-activation reduces the heart rate and either maintains or increases blood pressure. Conversely, in the trigeminocardiac reflex, bradycardia and hypotension due to parasympathetic activation and sympathetic inactivation tend to be observed. These sudden cardiac innervation disturbances may promote the generation of arrhythmias or myocardial ischemia during surgeries in the trigeminal territory. However, the function and mechanisms involved in the trigeminal reflexes remain to be fully elucidated. The current review provides a brief update and analysis of the features of these reflexes, with special focus on how the autonomic nervous system interacts with cardiovascular function. Physiological or pathological stimulation of the trigeminal nerve can trigger sudden cardiovascular disturbances with the characteristic features of a nervous reflex . AlthougThese reflexes represent somato-autonomic responses where the trigeminal nerve is the afferent pathway, the vagus and sympathetic nerves are the efferent pathways, and numerous brainstem nuclei serve as integration centers . AlthougThe trigeminocardiac reflex is a brainstem reflex that has been demonstrated both clinically and experimentally . Schallevia a combination of parasympathetic activation and sympathetic inhibition. Using a different experimental model in rabbits breathing spontaneously, Kumada et al. , their cardiovascular responses may differ depending on the sympathetic/parasympathetic interaction . As alreSome studies have clarified the factors that condition trigeminal stimulation responses. First, the type of stimulus triggering the reflex should be taken into consideration. Pressor responses are frequently reported, indicating an increase in the peripheral sympathetic tone in response to physiological stimuli, such as irritation of the nasal mucous membrane or stimuThe second aspect to consider is the administration of different analgesics and anesthetics that may modulate the trigeminal\u2013vagal reflexes in variable and unpredictable ways \u201329. ThisThe last aspect to consider is species differences. In diving animals such as seals, the diving reflex increases sympathetic tone and allows preservation of blood pressure within physiological ranges. In humans, however, the sympathetic response of the diving reflex is more intense and may increase blood pressure to critical values .via electrocardiogram, which confirmed the presence of profound co-activation during the nasopharyngeal reflex (Bradycardia and blood pressure modifications are the most evident hemodynamic changes induced by these reflexes. The sudden changes that occur in these reflexogenic adaptations may impact patients with cardiovascular disease, inducing severe and sometimes lethal complications. Various authors reported complications in patients with coronary disease, and severe arrhythmias such as asystole and ventricular fibrillations as a consequence of the trigeminocardiac reflex during neurosurgeries , 35. Altl reflex . IntenseWe previously demonstrated that short-term vagal electro-stimulation in rabbits can generate critical changes in myocardial oxygen consumption in the context of coronary ischemia and reperfusion . It is iStimulation of the trigeminal nerve or the territories innervated by its branches can trigger deep hemodynamic changes due to neurogenic somato-autonomic responses such as the diving and trigeminocardiac reflexes. Although they can act as extremely efficient oxygen-conserving reflexes, the sudden disturbances of cardiovascular autonomic tone can often generate electrical instabilities, predisposing to cardiac arrhythmias and myocardial ischemia. Differences in hemodynamic responses to trigeminal stimulation depend upon the antagonistic or synergistic interaction of the sympathetic and parasympathetic systems. Future investigations will be needed to understand the molecular mechanisms and functional purposes of the trigeminal reflexes. This knowledge is of paramount importance for appropriate management of patients affected during surgeries in the trigeminal territory.BB brought the manuscript to fruition through the collection of historical and current trends in trigeminal reflexes and composed early drafts of the manuscript and figure. JK contributed to each section including major revisions, current trends, and research in each aspects of the manuscript. EB and ND contributed to revisions and facilitated with manuscript editing and figure assembly. RG provided critical feedback and manuscript revisions, significant intellectual commentary on the manuscript, and final approval of the version to be published.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Effective brachial plexus blockade requires a thorough understanding of the anatomy of the plexus, as well as an appreciation of anatomic variations that may occur. This review summarizes relevant anatomy of the plexus, along with variations and anomalies that may affect nerve blocks conducted at these levels. The Medline, Cochrane Library, and PubMed electronic databases were searched in order to compile reports related to the anatomy of the brachial plexus using the following free terms: \"brachial plexus\", \"median nerve\", \"ulnar nerve\", \"radial nerve\", \"axillary nerve\", and \"musculocutanous nerve\". Each of these was then paired with the MESH terms \"anatomy\", \"nerve block\", \"anomaly\", \"variation\", and \"ultrasound\". Resulting articles were hand searched for additional relevant literature. A total of 68 searches were conducted, with a total of 377 possible articles for inclusion. Of these, 57 were found to provide substantive information for this review. The normal anatomy of the brachial plexus is briefly reviewed, with an emphasis on those features revealed by use of imaging technologies. Anomalies of the anatomy that might affect the conduct of the various brachial plexus blocks are noted. Brachial plexus blockade has been effectively utilized as a component of anesthesia for upper extremity surgery for a century. Over that period, our understanding of anatomy and its variations has improved significantly. The ability to explore anatomy at the bedside, with real-time ultrasonography, has improved our appreciation of brachial plexus anatomy as well."} +{"text": "Our hypothesis is that, in a concomitant chronic ACL and PCL injury, posterior capsular contracture and abnormal reattachment of torn ACL will result in less clinical and subjective laxity, preoperatively. The aim of this study is to review a cohort of patients who had undergone PCL reconstructive surgery and compare the preoperative clinical assessments with and without anesthesia with arthroscopic finding of ACL. This is to assess the accuracy and reliability of clinical ACL laxity tests in detecting ACL tear in chronic ACL and PCL injury.An anterior cruciate ligament (ACL) injury may be diagnosed by clinical examination and radiological investigation using magnetic resonance imaging or by arthroscopy. An anterior cruciate ligament (ACL) injury may be diagnosed by clinical examination and radiological investigation using magnetic resonance imaging (MRI) or by arthroscopy.This study was a retrospective analysis of all 38 patients with chronic PCL tear (> 6 weeks post injury), who underwent PCL reconstruction in 2012 and 2013 in our center. In all the cases, the clinical diagnosis of chronic PCL with or without ACL injury was made after examination by the senior author through three clinical examinations comprising (1) Lachman test,Data was collected from 38 patients who were diagnosed and underwent PCL reconstruction surgery to the knee. Seventeen cases had ACL and PCL injury, while 21 cases had combined multiligament injuries involving ACL, PCL, and collateral ligaments. The cohort of patients reviewed consisted mainly of males, aged between 26 and 35, and injuries were mainly due to motor vehicle accidents . Of theWe found that in chronic PCL injury knees the accuracy of preoperative clinical examination for ACL laxity with or without anesthesia is low. Although preoperative examination under anesthesia is more sensitive compared with the preoperative examination without anesthesia, it was still less accurate based on the intraoperative arthroscopic findings. Preoperative test without anesthesia was virtually ineffective in indicating ACL tears in patients with ACL tear, with two of three clinical examinations yielding no indication of ACL tears in any patient. This may be due to the posterior capsular contracture in chronic PCL injury or an abnormal reattachment of torn ACL. Muscle relaxation during the examination under anesthesia might also influence the findings. We believe that our findings should be borne in mind when examining a knee with chronic PCL injury of a possible concomitant ACL injury.In chronic PCL injury, preoperative examination with or without anesthesia alone may give an inaccurate finding to determine the diagnosis and grading of ACL laxity. The diagnosis and management of ACL injuries should be based on the history, clinical examination, and arthroscopic findings. MRI should be interpreted with caution as the reattached ligament may be confused with a partially injured or uninjured ligament."} +{"text": "Classical trigeminal neuralgia (TN) is a chronic pain disorder that has been described as one of the most severe pains one can suffer. The most prevalent theory of TN etiology is that the trigeminal nerve is compressed at the root entry zone (REZ) by blood vessels. However, there is significant evidence showing a lack of neurovascular compression (NVC) for many cases of classical TN. Furthermore, a considerable number of patients who are asymptomatic have MR evidence of NVC. Since there is no validated animal model that reproduces the clinical features of TN, our understanding of TN pathology mainly comes from biopsy studies that have limitations. Sophisticated structural MRI techniques including diffusion tensor imaging provide new opportunities to assess the trigeminal nerves and CNS to provide insight into TN etiology and pathogenesis. Specifically, studies have used high-resolution structural MRI methods to visualize patterns of trigeminal nerve-vessel relationships and to detect subtle pathological features at the trigeminal REZ. Structural MRI has also identified CNS abnormalities in cortical and subcortical gray matter and white matter and demonstrated that effective neurosurgical treatment for TN is associated with a reversal of specific nerve and brain abnormalities. In conclusion, this review highlights the advanced structural neuroimaging methods that are valuable tools to assess the trigeminal system in TN and may inform our current understanding of TN pathology. These methods may in the future have clinical utility for the development of neuroimaging-based biomarkers of TN. Trigeminal neuralgia (TN), characterized by excruciating attacks of electric shock-like unilateral facial pain, has been described as one of the most severe pains one can experience. There are an estimated 15,000 new cases of TN diagnosed in the United States each year and with greater awareness and better diagnostic criteria, recent studies suggest that this is likely an underestimate , the symptoms occurred with every pain attack can also be a source of severe pain to assess anatomical characteristics and patterns of NVC, brain gray matter volume and cortical thickness (CT) and diffusion imaging (diffusion tensor images (DTI)) to assess brain white matter and trigeminal nerve microstructure.Structural MRI is widely used in both clinical practice and research. However, MRI for research typically involves specialized protocols and post-processing techniques. Structural MRI for TN research uses Structural MRI can be used to test whether NVC sufficiently explains TN etiology. Some have argued that NVC cannot be the only cause of TN because blood vessels are often seen in the vicinity of the trigeminal nerve on routine autopsy or even on conventional MRI scans of unaffected nerves or in asymptomatic individuals without any TN ; moderate (NVC with vessel covering <20% of the nerve circumference); simple . In general, the shape of the tensor carries information about the three-dimensional character of the water molecules\u2019 diffusion. There are several measures of tissue microstructure that can be derived from these eigenvalues, the most widely used being fractional anisotropy , RD corresponds to diffusion perpendicular to the main diffusion direction (average of \u03bb2 and \u03bb3), and MD measures the local magnitude of diffusion regardless of direction . These other measures of tissue microstructure have been linked to specific pathophysiological mechanisms such as demyelination, neuroinflammation and edema thinning normalized towards the level of healthy controls following effective neurosurgical treatment for TN (DeSouza et al., While many patients experience excellent outcomes from TN treatments, some experience minimal pain relief. That is, there is individual variability with regard to patient responsiveness to treatment. Since conventional clinical diagnostic measures cannot predict which patients will benefit from a given treatment approach for TN, neuroimaging may be an effective tool to noninvasively provide brain-based biomarkers to support the optimal treatment selection for individual TN patients. We previously established that TN is associated with subtle, yet widespread abnormalities in brain structure as measured by morphometric and microstructural measures of brain gray matter and white matter (DeSouza et al., Machine learning approaches based on neuroimaging data have been used to distinguish physical and social pain/rejection (Woo et al., While the predictive accuracy of a classification algorithm based solely on morphological measures is cautioned (Labus et al., in vivo and inform our understanding of trigeminal nerve and brain abnormalities in TN.In this review, we have provided structural neuroimaging evidence to support peripheral theories of TN etiology and pathophysiology, showed a role for the CNS in TN pain, and discussed implications for the use of potential neuroimaging-based biomarkers to predict treatment response. It is becoming increasingly understood that TN pathophysiology is associated with both trigeminal nerve and brain abnormalities. While future studies are needed to assess the extent to which these abnormalities are the cause or consequence of TN, it is clear that structural MRI methods offer a valuable means to noninvasively examine the trigeminal system DDD: concept and design for manuscript content; critical revision of the manuscript for important intellectual content. MH and KDD: concept and design for manuscript content; interpretation of findings; critical revision of the manuscript for important intellectual content; supervising.DDD reports no disclosures. MH is the surgical co-director of the Gamma Knife Centre at the Toronto Western Hospital and has received financial contributions from the Canadian Institutes of Health Research and the Trigeminal Neuralgia Association of Canada. KDD reports no disclosures."} +{"text": "Perineural invasion is an underrecognized route of metastatic spread along the nerve bundles within the nerve sheath into the surrounding tissues. It hinders the ability to establish local control as tumour cells can traverse along nerve tracts well beyond the extent of any local invasion rendering them inoperable and unresectable. Perineural invasion is a marker of poor prognosis. Oral submucous fibrosis with oral cancer constitutes a clinicopathologically distinct disease. Our case highlights an enigmatic presentation of oral submucous fibrosis and its coexistence with oral cancer presenting with unusual neurological disturbance of the inferior alveolar nerve and facial nerve and diffuse widening of the mandibular canal. The objective of this case report is to enumerate the significance of perineural invasion in determining the course of the disease and necessitate the need for future studies that can shed light on molecular mediators and pathogenesis of perineural spread. The mandibular canal widening is an unusual presentation related only to a few pathologic conditions affecting the lower jaw. Loss of cortical bone surrounding the mandibular canal appears as wide radiolucency on a radiograph, inferred as canal widening . GeneralPerineural invasion (PNI) is considered as a distinct third mode of tumour metastasis for oral squamous cell carcinoma (OSCC) together with lymphatic and blood vessel invasion . It can A 48-year-old man with a swelling on the right side of his face below the lower lip reported to our Department of Oral and Maxillofacial Surgery. He presented with a six-month history of nonhealing ulcer in the right side of the buccal mucosa with an extraoral draining sinus and dysphagia for one month .In addition, he also presented with a two-month history of inability to close his right eye and deviation of the corner of the mouth to the left side followed by numbness in the lower lip and chin region. General health status of the patient and blood and urine analyses were unremarkable. Extraoral examination confirmed the classical signs of lower motor neuron type facial nerve palsy which included absence of wrinkles on the forehead, lagophthalmos of the right eye positive bells sign, flattening of the nasolabial fold , and devIntraoral examination revealed an erosive lesion approximately 6 \u00d7 2\u2009cm in size, extending from the angle of the mouth on the right side anteriorly up to the retromolar trigone posteriorly. The floor was covered with a pseudomembranous slough, with rolled edges and erythematous margins. On palpation, there was induration, tenderness, and the presence of fibrous bands . Soft, dThe panoramic radiograph revealed the presence of generalized bone loss with diffuse uniform enlargement of the mandibular canal, starting from the mandibular foramen to the mental foramen . SphericIncisional biopsy of the right buccal mucosa confirmed the clinical diagnosis of squamous cell carcinoma of right gingival-buccal sulcus. Histopathology sections revealed pleomorphic tumour cells with individual cell keratinization and dense peritumoural inflammatory response. Representative histological section demonstrating PNI (Modified Liebig Type A Classification) and infiltration of the epineurium was also seen , 10 FigThe treatment plan included full-thickness, wide local excision of buccal mucosa, segmental mandibulectomy, and modified radical neck dissection preserving internal jugular vein, spinal accessory nerve, followed by reconstruction with the free fibula graft using reconstruction plate. The resected specimen showed well differentiated squamous cell carcinoma with margins and nodes free of tumour. Adjuvant radiotherapy was planned considering the PNI.Perineural invasion is well defined when at least 33% of the circumference of the nerve is surrounded by tumour cells. The biologic mechanism of PNI pathogenesis remains elusive with postulations that it relates to reciprocal signaling interactions and the intrinsic capacity of tumour cells to retort to signals within the peripheral nerve and promote invasion .PNI is \u201ca tropism of tumour cells for nerve bundles in the surrounding tissues\u201d . It is oP < .0001).PNI is an important predictor for outcome of patients with SCC of the oral cavity and oropharynx. It is significantly associated with tumour differentiation, lymph node metastasis, depth of invasion, locoregional recurrence, and distant metastasis. Rahima et al. concludeThe centrifugal and centripetal propagation of squamous cell carcinoma along the perineural space can demonstrate intracranial spread and jeopardise the available treatment options.PNI in adenoid cystic carcinoma is well recognized; however, it should also be corroborated in oral squamous cell carcinoma specimens that have of late demonstrated PNI. The presence of PNI can connote a late stage disease and is a hallmark of subclinical invasion that can necessitate the need for aggressive resection, coincident management of neck lymph nodes, and the addition of adjuvant therapy. Targeted drug therapy for PNI in oral cancer is still at its infancy and can be a boon in the years to come. Patients with oral cancer often undergo adjuvant radiation for pathologically high risk features including positive nodal disease, extracapsular spread, and positive tumour margins. Excluding these high risk features, PNI is an independent risk factor necessitating the need for adjuvant radiation .Widening of the mandibular canal is a classical sign of neurofibromatosis but it has been unusual so far in oral cancer. Intraosseous schwannomas may sometimes cause distension of the inferior alveolar canal; they typically produce well-defined unilocular radiolucency mimicking an odontogenic cyst or a tumour. The other causes of mandibular canal widening like perineuroma, multiple endocrine neoplasia syndrome type 2b, vascular leiomyoma, arteriovenous malformation, and traumatic neuroma have been reported in the literature .The persistent paraesthesia of lower lip and chin region is a warning sign of a tumour or a malignancy compressing or invading the nerve.Sphenopalatine ganglionJunction of the chorda tympani and the lingual nerveParotid gland along the auriculotemporal branch of the mandibular nerveKoivisto et al. (2016) [Facial nerve and the trigeminal nerve are assumed to form a synapse at three strategic locations:et al. 20 [16] advThe prognostic utility of PNI with respect to the diameter of the nerves is debated with conflicting results being reported from different series of cases. It has been postulated that the stroma of the perineural sheath promotes tumour growth, with the perineural space as a conduit for tumour growth. In view of this large diameter, nerves closer to the surgical margins may be associated with recurrence . ContrarOral squamous cell carcinoma often presents with a nonhealing exophytic/endophytic ulcer fixed to the underlying skin or the mucosa. This case differs from its usual presentation by its aggressive nature, multiple neural invasion, synchronization of submucous fibrosis and oral cancer, and diffuse widening of the mandibular canal. PNI is an independent risk factor for occult metastasis along with depth of invasion, size of primary tumour, differentiation, and immunosuppression. Further studies are warranted to elucidate its molecular biology of pathogenesis, histopathological pattern of PNI, and its significance in the prognosis. With a better understanding of the mechanisms involved, we can progress to develop therapeutic agents that can target this form of intriguing tumour spread."} +{"text": "Bleeding from antral and duodenal varices is anuncommon feature in patients with portal hypertension.We report a patient with cirrhosis and portalvein thrombosis, who had a massive bleed fromantral and duodenal varices. Bleeding was controlledwith endoscopic injection of varices usinghistoacryl. Endoscopic treatment and the relativelyuncommon occurrence of antral and duodenalvarices are highlighted."} +{"text": "Throughout the 20th century, the mission of local and state public health departments broadened from infectious disease prevention and control to encompass maternal and child health, immunizations, food and water safety, environmental health, and chronic disease prevention -3. Now iThe Institute of Medicine has recommended that \"each state have a department of health that groups all primarily health-related functions\" . It furtNineteen respondents believed that mental health issues fit best under \"community health\" on the public health agenda, but all the respondents acknowledged that public health professionals should promote mental health in the context of public health issues. Although the survey indicates that states want their public health models to encompass mental health, funding and administrative barriers exist. Federal funding for state mental health services is separate from that for state public health departments and provides little support for prevention services. States have few incentives to integrate physical and mental public health care. Funding for mental illness prevention comes from limited state and county resources. These factors discourage integration of services and do not recognize the vital role that mental health plays in chronic disease outcomes.In 2004, California voters passed Proposition 63 , which supports the integration of primary care and mental health. The purposes of this law were to 1) define serious mental illness as a condition deserving priority attention, including prevention and early-intervention services and medical and supportive care; 2) reduce the long-term adverse effect for people and state and local budgets resulting from untreated serious mental illness; 3) expand successful, innovative service programs ; 4) make state funds available to provide services that are not already covered by federally sponsored programs; and 5) develop services that are best practices and subject to local and state oversight. Proposition 63 finances county-based mental health programs to expand overall services, including prevention and early-intervention programs. These investments will support the growth of capacity for more integration of mental health and primary care, thus establishing new practice models that will be worth watching. The California Mental Health Directors Association has reported that several counties are using their Proposition 63 dollars to fund integration of mental health and primary care programs. For example, San Diego County has established new mental health services in a primary care diabetes clinic that serves a large Latino population to treat and prevent depression and diabetes in an integrated approach.To support integration, state and local health departments and mental health departments must take a more active role in developing specific strategies and identifying system-level support to begin working together. For example, pilot projects could be developed that use integrative approaches to encourage local mental health providers to collaborate with public health providers and increase access to mental health treatment for racial and ethnic minorities. Such efforts could address disparities among minorities who are not accessing mental health treatment. Health departments could also better inform the public of the role that mental health plays in overall prevention and treatment of many chronic diseases. Both public health and mental health providers need training to increase their understanding that there is no health without mental health. Furthermore, public health and mental health professionals should work together to convince funders that integration of public health and mental health is important to overall health. Through this effort, national legislation, policies, and funding could begin to provide incentives for public health and mental health integration."} +{"text": "Determining the presence or absence of neurovascular involvement by a malignant musculoskeletal neoplasm is animportant aspect of local tumor staging. This article discusses issues concerning such assessments made by diagnosticimaging techniques, including factors inherent to the patient and those related to imaging technology. The distinctionbetween tumor contact and tumor encasement is emphasized and illustrated."} +{"text": "Drug discovery today includes considerable focus of laboratory automation and other resources on both combinatorial chemistry and high-throughput screening, and computational chemistry has been a part of pharmaceutical research for many years. The real benefit of these technologies is beyond the exploitation of each individually. Only recently have significant efforts focused on effectively integrating these and other discovery disciplines to realize their larger potential. This technical note will describe one example of these integration efforts."} +{"text": "Despite recent advances in hepatic surgery, resectionof the cirrhotic liver continues to be fraughtwith high morbidity and mortality rates. As a result,for many patients requiring resection of HCC thepostoperative course is complicated and the probabilityof cure is diminished by coexisting cirrhosis.In this review, we discuss the characteristicsof the cirrhotic liver which make it poorly tolerantof resection and the most common complicationsthat follow such surgery. The main purpose of thispaper is to review recent attempts to identify interventionsthat might be beneficial to cirrhotic patientsundergoing resection. These interventions includeassessment of liver reserve, advances in surgicaltechnique, and improvement in liver function andregeneration."} +{"text": "Specialisation in spinal services has lead to a low threshold for referral of cervical spine injuries from district general hospitals. We aim to assess the capability of a district general hospital in providing the halo vest device and the expertise available in applying the device for unstable cervical spine injuries prior to transfer to a referral centre.The study was a postal questionnaire survey of trauma consultants at district general hospitals without on-site spinal units in the United Kingdom. Seventy institutions were selected randomly from an electronic NHS directory. We posed seven questions on the local availability, expertise and training with halo vest application, and transferral policies in patients with spinal trauma.The response rate was 51/70 (73%). Nineteen of the hospitals (37%) did not stock the halo vest device. Also, one third of the participants were not confident in application of the halo vest device and resorted to transfer of patients to referral centres without halo immobilization.The lack of equipment and expertise to apply the halo vest device for unstable cervical spine injuries is highlighted in this study. Training of all trauma surgeons in the application of the halo device would overcome this deficiency. In the United Kingdom (UK), most spinal trauma presents to district general hospitals where on-site spinal units are unavailable. Patients need to be transferred to tertiary care centres for definitive surgical management.Unstable cervical spine injuries require adequate immobilisation to prevent or limit neurological sequelae during transport. Methods of immobilisation of the injured cervical spine include cervical orthotics , head cervical orthotics (Philadelphia collar and Miami-J collar), cervical traction, and halo-vest immobilisation. The halo vest is the most rigid of all cervical orthoses , and repAlthough this is an effective and relatively safe procedure , Kang anWe investigated the capability of UK district general hospitals regarding the familiarity and confidence of application of the halo vest traction device among the orthopaedic staff, availability of the device, and the implications this may have for training and service delivery in light of the ongoing restructuring of spinal services towards tertiary spine centres.A survey was conducted at 70 UK district general hospitals with designated acute trauma admission status. Eligible centres were identified randomly using an electronic NHS directory.Hospitals with on-site spinal units were excluded. Individual orthopaedic trauma consultants were contacted by a postal questionnaire to assess the level of service provision with regard to halo vest application.The questionnaire was in a simple tick-box style format and assessed whether the hospitals in which the consultants were employed stocked halo vest equipment routinely, their level of confidence to apply halo devices to adult and paediatric trauma patients, and whether they had received adequate training in application or had recent experience in halo vest application.In addition, participants were asked about referral protocols and problems encountered with referral of patients with cervical spine injuries to tertiary spine centres.Results are presented as absolute numbers and proportions together with 95% binomial exact confidence intervals (CI), where appropriate.Altogether, 51/70 consultants responded to the questionnaire, for a response rate of 73%.Nineteen (37%) of 51 district hospitals no longer routinely stocked emergency halo-vest equipment. Just 33/51 of the consultants stated that they would feel confident to apply this device even when available both in adults and children, while the remaining did not feel confident either because of inadequate training or lack of recent experience.Twenty consultants did not receive adequate training in applying the halo vest device. Only fifteen had applied a halo vest in the past two years.Most surgeons had a low threshold in referring patients to tertiary spinal units despite inherent risks associated with transfer of an unstable cervical injury with suboptimal immobilisation . This was despite one quarter of clinicians encountered referral difficulties such as inappropriate delays or problems obtaining specialist advice.Cervical spine injuries can have serious neurological consequences. Patients with these injuries require adequate immobilisation to prevent or limit neurological deterioration during transfer to tertiary spine centres and definitive surgical fixation.The key factor in immobilising the cervical spine is the rigidity of the applied device. Cervical and head-cervical orthoses still allow for variable motion of the cervical segments and therefore are not suitable in patients with unstable cervical spine injuries. Studies assessing the stabilising effects of different cervical orthoses showed the halo-vest device to be the most rigid ,6.The treatment of unstable cervical spine injuries with the halo vest is an established procedure. The halo traction device was first devised by Perry and Nickel in 1959 to overcome problems encountered while using the Minerva plaster for treating unstable cervical spine fractures . The halThe halo vest can be used for both intermediate and definitive treatment of cervical spine injuries, as well as immobilisation after surgical fixation of cervical spine fractures . It may The halo ring is made of graphite or metal with pin fixation on the frontal and parieto-occipital areas of the skull. Development of lightweight composite material led to the design of radiolucent rings compatible with magnetic resonance imaging. Restriction in cervical motion depends on the fit of the halo vest, since improper fit can allow 31% of normal spine motion. The halo vest is the weak link in terms of motion control. Compressive and distractive force can occur with variable fit of the vest. Motion restrictions provided by the halo include the following: limits flexion and extension by 90 to 96%, limits lateral bending by 92 to 96%, limits rotation by 98 to 99% .When compared to cervical traction using skull tongs the halo-vest device keeps patients mobile and reduces respiratory problems. This is specifically advantageous in elderly patients who have a higher incidence of upper cervical spine injuries .Despite its efficacy in immobilising the cervical spine, the halo vest device has its own problems. Complications like pin loosening, pin site infection, discomfort at pin sites, dysphagia, prolonged bleeding at pin sites, and dural puncture have been reported in the literature . This caAlthough in the UK most spinal trauma cases present initially to district general hospitals, our study shows a trend not to stock the halo device in one third of these hospitals. This would mean immobilisation of potentially unstable cervical spine injuries by other, less rigid cervical orthoses. When the halo device was available, only two thirds of the trauma surgeons were confident in applying one. Previously, this would have been considered a prerequisite trauma skill for practicing orthopaedic surgeons in hospitals providing acute services. There now appears to be a wide variation in the provision of this essential service throughout the UK, with a high proportion of trauma units having neither the resources nor clinical expertise to manage these injuries. As the management of spinal trauma becomes more specialised, this is likely to affect service delivery and training, and has important safety implications.One limitation of our study is that, although the sample population was selected randomly, it may still not be representative of all district general hospitals in the UK. Also, the overall sample size and response rate may further limit firm conclusions. Finally, we did not collect data on demographic and professional backgrounds of the respondents and their institutions.Apart from these limits, our study has created an awareness of the existing level of application skill and availability of the halo vest traction device. No comparable study is available in the literature, and it may be of interest to perform similar surveys in other countries.We recommend training all trauma surgeons in the indications, technique of application, and possible complications of the halo vest device.Specialisation of spinal services has serious implications on the initial management of cervical spine trauma in district general hospitals without on-site spinal units. The lack of equipment and expertise to apply the halo vest device for unstable cervical spine injuries in this set up is highlighted. We recommend training of all trauma surgeons in the application of a halo vest device and making this device available for use.The author(s) declare that they have no competing interests.UR was involved in reviewing the literature, drafting the manuscript and proof read the manuscript. JCS was involved in collecting data, reviewing the literature, drafting the manuscript and proof read the manuscript. AS is the senior author and was responsible for final proof reading of the article. All authors have read and approved the final manuscript."} +{"text": "Bos taurus) has now been analyzed by the Bovine Genome Sequencing and Analysis Consortium and the Bovine HapMap Consortium, which together represent an extensive collaboration involving more than 300 scientists from 25 different countries.The draft genome sequence of cattle ( BioMed Central group of journals published in April 2009, appropriately, the Year of the Ox. A full list of companion papers and other materials can be found at [The cattle genome ,2 was orfound at . These rAt present, there are approximately 3.4 billion domesticated cattle, buffalo, sheep and goats in the world which provide a major source of protein nutrition for 6.6 billion humans . About tThe growth of domesticated ruminant populations, especially cattle, has mirrored the rapid expansion of the human population. More than 800 cattle breeds have been selected by humans since domestication for different economic, social and religious reasons and these represent an important world heritage and a unique scientific resource .The cattle genome sequence fills an evolutionary void among mammalian genome sequences as it is the first complete high coverage genome sequence from the Cetartiodactyl order of eutherian mammals which first appeared ~60 million years ago when grasslands began to cover large parts of the earth's surface. The order includes ~220 species of even-toed ungulate mammals , hippopotamus and 88 cetacean species . The Cetartiodactyla have adapted to an extraordinary diversity of terrestrial and aquatic environments. Cattle are representative of the Ruminantia, a phylogenetically distant clade to humans and rodents, the two most intensively investigated mammalian species. The evolutionary relationships between these three mammalian groups are well positioned to inform genome similarities and differences in each group and comment on mammalian biology. The evolution of genome organization, particularly the expansion and contraction of paralogous gene families and the molecular bases for economically important adaptive traits of ruminants such as lactation, metabolism, reproduction and disease resistance, are all important scientific issues that can explicitly be addressed by comparative analysis of the cattle genome with other mammalian genomes.The unique biology of ruminants was a predominant factor influencing the decision to sequence the cattle genome . RuminanThe assembled 7.1\u00d7 cattle genome sequence primarily represents DNA from a single inbred female Hereford animal, L1 Dominette ,14. In aWhat has the initial analysis of the bovine genome sequence revealed? Evolutionary breakpoint regions in mammalian chromosomes, which define the boundaries of conserved syntenic blocks of sequence, are associated with considerable evolutionary plasticity in mammals. Large segmental duplications are over-represented and some types of repetitive sequence elements are selectively enriched or excluded in these regions ,16. MoreMilk is exquisitely formulated to suit the differing developmental needs of newborn mammals. Analysis of the genes encoding proteins present in bovine milk and the genes expressed in mammary tissue during the lactation cycle provide the first comprehensive overview of lactation genomics . The intSeveral of the companion papers focused on changes in the organization of specific gene families in the bovine lineage and their potential impact on ruminant biology. Compared with humans and rodents, there are significant changes in the organization of several immune gene families exemplifMetabolic reconstruction analysis revealed that most genes encoding metabolic enzymes are conserved in mammals however in cattle a few gene losses compared with other mammalian species were identified . These eThe Bovine HapMap Consortium analysed the frequency of over 37,000 SNP in 497 cattle from 19 geographically and biologically diverse cattle breeds . The resst century \u2013 efficient and sustainable production systems with smaller environmental footprints.Although these collective studies generated a multitude of discoveries, this is only the beginning of a much larger body of future research that will be catalyzed by the availability of the bovine genome sequence and haplotype map. The genome sequence will be refined, reanalyzed and integrated with biological data in ways we can not yet imagine to examine fundamental questions relating to the linkage between genes and cattle phenotypes, the reasons for the evolutionary success of ruminants, the history of cattle domestication, and the mechanisms of mammalian evolution, to name but a few. The availability of very large well managed cattle populations and sire based breeding systems will accelerate the discovery of genes contributing to complex traits of direct relevance to humans such as energy partitioning, muscle formation, milk production and disease resistance. Undoubtedly, the bovine genome sequence and haplotype map will revolutionize the beef and dairy industries by providing genetic and genomic tools to help address the pivotal livestock issues of the 21"} +{"text": "Anatomic distortion and displacement of hilar structures due to liver lobe atrophy and hypertrophy occasionally complicates the surgical approach for biliary stricture repair. Benign biliary stricture following hepatic resection deserves special consideration in this regard because the inevitable hypertrophy of the residual liver causes marked rotation and displacement of the hepatic hilum that if not anticipated may render exposure for repair difficult and dangerous. Three patients with biliary stricture after hepatectomy illustrate the influence of hepatic regeneration on attempts at subsequent stricture repair. Following left hepatectomy, hypertrophy of the right and caudate lobes causes an anteromedial rotation and displacement of the portal structures. After right hepatectomy, the rotation is posterolateral, and a thoracoabdominal approach may be necessary for adequate exposure. Radiographs obtained in the standard anteroposterior projection may be deceptive, and lateral views are recommended to aid in operative planning."} +{"text": "A pathogen may emerge as an important public health problem because of changes in itself or its transmission pathways. Alternatively, a microorganism may emerge as a pathogen or acquire new public health importance because of changes in host susceptibility to infection. Factors influencing host susceptibility within the population as a whole include increases in the number of immunocompromised patients; increased use of immunosuppressive agents, particularly among persons receiving cancer chemotherapy or undergoing organ transplantation; aging of the population; and malnutrition. In considering the emergence of foodborne pathogens and designing interventions to limit their spread, the susceptibility of these population subgroups to specific infections should be taken into account."} +{"text": "Mitochondrial fractions isolated from tumours induced with the respiratory inhibitor rotenone lack respiratory control, oxidative phosphorylation, are partially or totally insensitive to cyanide and have a near-normal content of respiratory carriers. These characteristics are more similar to those of mitochondria from atrophic mammary gland than to those of mitochondria from spontaneous mammary adenomas. Thus, the characteristic structural and biochemical mitochondrial alteration of rotenone-induced tumours would represent a lack of mitochondrial differentiation as the tumour develops from the atrophic mammary gland. Slices of rotenone-induced tumours are insensitive to oligomycin and dinitrophenol, thus indicating that glycolysis would be their sole source of metabolic energy."} +{"text": "CJD. vCJD remains restricted to date to MM homozygosity on codon 129. It remains to be determined whether this genotype is dictating a shorter incubation period.A comparison of the pathological profiles of two spongiform encephalopathies with a similar presumptive route of infection was performed. Archival kuru and recent variant Creutzfeldt\u2013Jakob disease (vCJD) cases reveal distinct lesional differences, particularly with respect to prion protein, suggesting that the strain of agent is important in determining the phenotype. Genotype analysis of the polymorphism on codon 129 reveals (in conjunction with updated information from more kuru cases) that all three genotypes ) are detected in kuru with some preference for MM homozygosity. The presence of valine does not therefore appear to determine peripheral selection of PrP CJD immunohistochemistry, where there was a much greater PrP load in all brain areas in vCJD than in kuru, with the exception of the cerebellar granular layer (CJD (Neuropathological comparison of vCJD and kuru revealed that these diseases show distinct differences, particularly with PrPar layer . The patar layer . A compayer (CJD than witThe underlying differences in neuropathological profiles were thought to be in keeping with the different clinical features in these two disorders. Although both diseases exhibit prominent cerebellar ataxia, vCJD lacks the chronic emotional lability characteristic of kuru, and is characterized instead by psychiatric and sensory symptoms at onset with subsequent myoclonus and other movement disorders followed by dementia and akinetic mutism (CJD, as previously postulated to account for the high frequency of a valine 129 in other cases of iatrogenic CJD (The 11 cases of kuru showed a homogeneous pattern of prion protein deposition with an accentuation of cerebellar changes. Of the five cases in which the codon 129 could be assessed, there were two MM and three VV genotypes (M, methionine; V, valine;"} +{"text": "In environmental circles, nanomaterials have aroused concern because, even as their use burgeons, their impact on animal and plant life remains largely unknown. Moreover, scientists studying the environmental effects of nanomaterials might unknowingly be putting their own health at risk The National Institute for Occupational Safety and Health, which conducts research on workplace safety, has no recommended exposure limit guidelines for nanomaterials, and the Occupational Safety and Health Administration has no permissible exposure limit specific to engineered nanomaterials. However, recent animal toxicology studies suggest nanomaterials may cause specific adverse health effects. For example, carbon nanotubes have been shown to induce inflammation and oxidative stress in animal models.To assess the magnitude of potential exposure in a laboratory setting, a team of researchers measured the amount of carbonaceous nanomaterials (CNMs) released into the air during routine material handling and processing tasks in standard environmental matrices such as artificial river water. The authors evaluated nanomaterial releases using real-time particle counters and transmission electron microscopy.The research team found that CNMs became airborne when they were handled and weighed in the lab. Smaller structures, with an aerodynamic diameter of less than 1 \u03bcm, scattered more readily than larger particles.A surprise finding was the substantial release of CNMs during sonication, a common laboratory process used to break apart agglomerates of nanomaterials into aqueous dispersions. Sonication produced a CNM-containing mist that could be inhaled by workers or that could leave CNMs on laboratory surfaces after the water evaporated. The extent of release during sonication was increased when natural organic matter was added to the solution, as is often done to simulate conditions in the environment. Hydrophobic CNMs exhibited higher airborne particle number concentrations during handling than during sonication, whereas hydrophilic CNMs exhibited the opposite trend.These findings contradict the belief that risks of exposure are minimized when working with nanomaterials in liquid suspensions. The authors believe this field case study is the first to demonstrate the release of CNMs during sonication and also the first to detail nanomaterial release in an environmental laboratory. They caution that more robust statistically based experimental research is needed to evaluate CNM exposure among laboratory workers. Until then, they urge researchers working with nanomaterials to use appropriate personal protective equipment in the laboratory and to adopt adequate engineering controls to minimize their exposure."} +{"text": "Until recently the public water supply to Worksop contained high concentrations of nitrate. An epidemiological study has revealed that, compared with low nitrate control towns, Worksop has an increased death rate from gastric cancer. The possible role of the bacterial production of nitrosamines in the aetiology of these stomach cancer deaths is discussed."} +{"text": "The use of 5-aminolaevulinic acid (ALA) is gaining increasing attention for photosensitization in photodynamic therapy of superficially localized tumours. The aim of this work was to determine the kinetics of porphyrin generation in tissues after topical application of ALA delivered in different vehicles on the skin overlying the tumour and normal skin of mice. Maximal accumulation was found in tumour 3 h after ALA application in both cream and lotion preparations. Normal and overlying tumour skin tissues showed different kinetic patterns, reflecting histological changes when the latter is invaded by tumour cells. Liver, kidney, spleen and blood porphyrins also raised from basal levels, showing that ALA and/or ALA-induced porphyrins reach all tissues after topical application. During the first 24 h of ALA topical application, precursors and porphyrins are excreted by both urine and faeces. ALA lotion applied on the skin overlying the tumour induced higher accumulation of tumoural porphyrins than cream, and lotion applied on normal skin appeared to be the most efficient upon inducing total body porphyrins. This work has demonstrated the great influence of the formulation of ALA vehicle on penetration through the skin. Knowledge of the kinetics of porphyrin generation after different conditions of ALA application is needed for the optimization of diagnosis and phototherapy in human tumours. \u00a9 1999 Cancer Research Campaign"} +{"text": "Chlamydia trachomatis, and the epidemiology and clinical spectrum of chlamydial disease, the magnitude ofmorbidity from human chlamydial infections remains an important public health concern. Controlof chlamydial disease will likely depend on a multidisciplinary approach, including the developmentof immunoprophylactic or immunotherapeutic strategies. Reasonable progress has been made inunderstanding specific immune mechanisms that contribute to host immunity in experimental modelsof chlamydial infection. However, studies of human immunity have not been so successful. Thisis particularly evident in that studies to address the development and role of mucosal immuneresponses to urogenital chlamydial infections have not been forthcoming. The following review isa brief summary of our current knowledge of protective immunity to chlamydial urogenital infectionsof females. It is not meant to be exhaustive, but instead to touch upon aspects of protective immunitythat have been described in both human and experimental animal models of chlamydialinfection.Despite significant advances in our understanding of the biology and antigenic structure of"} +{"text": "Improvements in donor screening and testing and viral inactivation of plasma derivatives together have resulted in substantial declines in transfusion-transmitted infections over the last two decades. Most recently, nucleic acid testing techniques have been developed to screen blood and plasma donations for evidence of very recent viral infections that could be missed by conventional serologic tests. Nonetheless, the blood supply remains vulnerable to new and reemerging infections. In recent years, numerous infectious agents found worldwide have been identified as potential threats to the blood supply. Several newly discovered hepatitis viruses and agents of transmissible spongiform encephalopathies present unique challenges in assessing possible risks they may pose to the safety of blood and plasma products."} +{"text": "Preventing Chronic Disease address the following topics: public health policy , more effective outreach to the low-income population or more generous eligibility criteria (positive), or both.Do the measures stand alone or are they aggregated into an index or summary measure? The articles differ in the extent to which they recommend aggregation. The outcomes and inequalities articles , the rapid development of health information technology, the extent of administrative data systems, data linkage and integration, and the potential for modeling. Several questions have bearing on data decisions and choice of metrics.Do the available data correspond to the geographic level of the intervention? This question is particularly relevant to community-level interventions because many national surveys do not have sufficient sample sizes to produce local estimates. As the health behaviors article points out (ints out , even ifints out would maHow timely are the data? Rewarding performance requires recent data that are released on a regular basis. The need for current data may affect strategies for addressing small sample sizes in communities; aggregating data over several years to boost sample size limits the sensitivity of a measure to detect changes in response to an intervention.Are the measures reliable and valid? Although the articles mention the need for reliability and validity, they do not indicate how they would assess the measures that they propose.Can the measures be produced for population subgroups? Tracking racial/ethnic, socioeconomic, and other disparities requires far more extensive data and much larger survey sample sizes than does monitoring population health overall. These data demands pose substantial challenges for identifying and tracking disparities at the community level.Are indirect methods of estimation appropriate? New tools for indirect estimation, including data integration and linkage, Bayesian estimation, and systems modeling, offer potential strategies for developing community-level estimates, including estimates for subpopulations. The environment article ( article providesShould data reporting be part of an incentive-based population health improvement system? This idea was raised in a recent Institute of Medicine report on addressing disparities in health care quality ( quality and deseAs policy makers consider strategies to promote improvements in population health, measurement may provide powerful incentives for change, but selecting reliable and valid health metrics that can be tracked consistently across communities is challenging. The 7 articles in this issue illustrate many of the complexities that policy makers must consider in selecting such metrics, and the articles lay the groundwork for ongoing discussions on this topic."} +{"text": "During 1968-1980, 1176 women aged 16-50 years with newly diagnosed breast cancer and a like number of matched controls were interviewed at 9 teaching hospitals in London and Oxford and asked about their use of oral contraceptives. The results were reassuring. A few statistically significant differences in oral contraceptive use were found between the breast cancer and control groups, but the data were subdivided in many ways so that some \"significant\" differences would have been expected through the play of chance alone. Certainly no patterns of risk emerged which would suggest that any of the associations were causal. It must be stressed, however, that the data are still sparse in some important subcategories--for example, only small numbers of both cases and controls had prolonged oral contraceptive use before their first term pregnancy. For this reason, it is important that information on the possible relationship between pill use and breast cancer should continue to be collected. Women who had never used oral contraceptives presented with appreciably more advanced tumours than those who had been using oral contraceptives during the year before detection of cancer, while past users were in an intermediate position. These differences in staging were reflected in the pattern of survival. Possible explanations for these observations include \"surveillance bias\" among oral contraceptive users leading to earlier diagnosis and a beneficial biological effect of oral contraceptives on tumour growth and spread. Women with breast cancer reported never having used any method of contraception and heavy cigarette smoking significantly less often than controls. We could find no obvious explanation for the former observation, but suspect that the latter reflects the unrepresentative smoking habits of our hospital controls rather than a protective effect of smoking against breast cancer."} +{"text": "Drug treatment with sulphasalazine or 5-aminosalicylic acid improved the enteritis score and attenuated TNBS induced oedema formation and LTB4 production. The applicability and relevance of this new model are discussed with respect to drug development and basic research of inflammatory bowel diseases.An enteritis, based on a delayed-type hypersensitivity reaction, was induced in TNBS sensitized rats by multiple intrajejunal challenge with TNBS via an implanted catheter. This treatment induced chronic inflammation of the distal small intestine characterized by intense hyperaemia, oedema and gut wall thickening as assessed by macroscopic scoring and weighing a defined part of the dissected intestine. Histologically, the inflammatory response included mucosal and submucosal cell infiltration by lymphocytes and histiocytes, transmural granulomatous inflammation with multinucleated cells and activated mesenteric lymph nodes. Ex vivo stimulated release of the inflammatory mediator LTB"} +{"text": "Few tumour types have received as much molecular analysis as breast cancer over the past 10 years. Impressive progress has been made in the analysis and interpretation of genomic data sets, the identification of novel mechanisms of breast cancer susceptibility, growth and development and the parallel integration of these molecular data to test novel therapeutic approaches for patients with this disease within clinical trials. This book, edited by Giordano and Normanno with individual chapters from experts in the field, successfully integrates this diverse field of progress within one volume, suitable for both medical professionals with an interest in breast cancer management and scientists with an interest in translational oncology. The book covers an impressive field, guiding the reader through scientific developments in breast tumour biology, cell-cycle control and growth factor signalling, to the complexities of stromal/tumour interactions, mammary gland development and stem cell biology, through to the clinical implications of basic research.A consistent feature of the book is the elegant way in which the reader is led from the basic science observations underpinning the evidence through to the clinical implications of bench-side research. Several chapters review developments in the field from a clinical practice perspective. Chapter 3 explores the implications of developments in breast cancer genetics and its application in clinical practice, succinctly explained by Russo and colleagues. The authors cover a broad field, describing the molecular portrait of breast cancer using microarray analysis of gene and microRNA expression and the difficulties implementing such techniques into clinical practice, recently emphasised by Modelling breast cancer using transgenic mice is discussed in detail in chapter 7 by Dillon and Muller. The authors present structured and balanced examples supporting the use of animal models while expressing caution concerning the key differences between mouse and human mammary stromal tissue, patterns of cancer spread and the predominant oestrogen receptor negativity of most animal models. A future vision of developments in this field is presented, through the modelling of stromal/tumour interactions and the design of animal models that more robustly reflect hormone receptor profiles and patterns of spread witnessed in human breast cancer.\u03b2 signalling and the Jekyll and Hyde character of this signalling cascade in breast cancer mediating both tumour suppressor and oncogenic pathway activation and how this may impact on the successful targeting of this network. Szyf reviews epigenetic modification through the modification of gene expression through regional DNA hypermethylation in chapter 10. DNA methylation is associated with the silencing of tumour suppressor gene expression and widespread hypomethylation patterns involving metastasis-associated genes are commonly witnessed in solid tumours. This chapter presents a balanced view associated with therapeutic strategies aimed at modulating methyltransferase activity in breast cancer, detailing the complexity of this process mediated by the DNA methyltransferase family and their targeting to specific DNA positions through interaction with sequence recognition factors. The author discusses practical considerations when attempting to influence the activity of this process, as although DNA methyltransferase blockade may activate tumour suppressor gene expression, the paradoxical activation of metastasis-associated gene expression could also be unleashed.The final four chapters of the book discuss novel targets in breast cancer, their therapeutic implications and clinical trial considerations when developing drugs targeting these molecules. Lee and colleagues discuss the complexities of TGF-Chapter 11, \u2018Signal transduction inhibitors in the treatment of breast cancer\u2019 by Maiello and colleagues, discusses the clinical trial results associated with the specific targeting of growth factor receptor pathways in breast cancer. Despite the excitement of the introduction of such strategies into clinical trial development in breast cancer, the authors emphasise that clinical activity associated with notable monotherapy strategies has been disappointing. Redundancy of growth factor signalling pathways and inter-patient tumoural heterogeneity are likely to contribute to these disappointing results.Breast Cancer in the Post-Genomic Era will be highly relevant to both scientists and oncology health professionals requiring a practical overview of the field of translational breast cancer medicine.The only potential criticism of such a book is the rate at which this field is progressing and how rapidly a second edition is required to keep up with developments. Perhaps the second edition will consider the impact of next-generation sequencing technologies on our understanding of the complexity of breast cancer tumourigenesis and tumour heterogeneity and the post-genomic functional annotation of the breast cancer genome using RNA interference strategies. In summary,"} +{"text": "Tirapazamine (SR 4233), a bioreductive drug selectively toxic towards hypoxic cells, is presently in phase II clinical trials. Since it would not be expected that all tumours would respond equally to the drug, we are exploring ways of predicting the response of individual tumours. In this study we have tested whether the comet assay, which measures DNA damage in individual cells, can provide a simple, surrogate end point for cell killing by tirapazamine. We examined the relationship between the cytotoxicity of tirapazamine under hypoxic conditions and tirapazamine-induced DNA strand breaks in murine and human tumour cell lines. These results were compared with the relationship between tirapazamine cytotoxicity and another measure of the ability of cells to metabolise tirapazamine; high-performance liquid chromatography (HPLC) analysis of tirapazamine loss or formation of the two electron reduction product SR 4317. The correlation between the hypoxic cytotoxic potency of tirapazamine and DNA damage was highly significant . A similar correlation was observed for hypoxic potency and tirapazamine loss , while the correlation between hypoxic potency and SR 4317 formation was not significant . The hypoxic cytotoxicity of tirapazamine in vitro can therefore be predicted by measuring tirapazamine-induced DNA damage using the comet assay. This approach holds promise for predicting the response of individual tumours to tirapazamine in the clinic."} +{"text": "Background. Subcentimeter pulmonary nodules are being detected with increasing frequency in patients with sarcoma due to the greater use of chest CT, the advent of helical CT scanning and multidetector scanners, and the attendant decrease in image section thickness.Assessing the clinical significance of these pulmonary nodules is of particular importance in sarcoma patients, due to the frequent occurrence of pulmonary metastasis from sarcomas. Purpose. This article reviews the technical advances that have contributed to the increased detection of subcentimeter pulmonary nodules, statistics about subcentimeter pulmonary nodules and options for evaluating such nodules."} +{"text": "The spatial distribution of new cases of lymphoma occurring in Yorkshire between 1978 and 1982 has been studied. Administrative districts were used as the basis for analysis and differences in age standardised incidence rates between districts were determined. Excessive rates for NHL were found to occur in Scarborough, York and Leeds districts. In addition an analysis contrasting broadly urban and rural districts showed an excess of NHL in rural areas, particularly of the follicular subtypes."} +{"text": "Over the last half-century both the identification of the causes of diseases and the use of inorganiccompounds to treat such conditions have been considerably enlightened through our emerging capabilities toidentify the pivotal chemical species involved. The \u2018duty of care\u2019 placed upon scientists to protect theenvironment from manufactured chemicals and to limit their effects upon humans therefrom is best realisedfrom a speciation knowledge database. This paper discusses categorising chemicals in terms of theirpersistence, bioaccumulation, and toxicities and uses speciation information to optimise desirable effects ofchemicals in several applications such as the manufacture of pulp for paper and in the foliar nutrition ofcrops. Simultaneously, the chemical wasting side effects of industrial overdosing is easily avoided ifspeciation approaches are used. The move towards new environmentally friendly ligand agents is describedand methods of finding substitute agents to replace nonbiodegradableEDTA. The geosphere migration of metals through the environment is discussed in terms ofspeciation. Future objectives discussed include improved means of communicating speciation-basedrecommendations to decision makers."} +{"text": "Polyamines, such as putrescine and spermine, are naturally occurring substances intimately associated with normal and neoplastic growth. High levels are found in cancer patients and are associated with tumour growth. Experiments with V79 hamster cells cultured in vitro have demonstrated that the presence of putrescine and spermine can significantly reduce the cytotoxicity of the commonly used chemotherapy agent cis-DDP. These data may have clinical implications."} +{"text": "A high proportion of females of the C3H strain of mice develop tumours of the mammary gland which are caused by mouse mammary tumour virus (MMTV) transmitted through the milk. We have examined whether administration of mouse interferon (IFN) to nursing mothers and/or their suckling offspring only during the period of nursing, can affect the incidence of tumours developing in these animals. In two separate experiments, animals receiving IFN by direct injection while suckling, and remaining virgin showed a marked and statistically significant decrease in tumour incidence. Mice receiving the same or a tenfold higher dose of IFN while lactating showed no such reduction in tumour incidence, even if they had also received IFN while suckling. The results suggest that IFN can affect the initial establishment of the MMTV infection in suckling mice sufficiently to delay tumour development provided the animals are not exposed to the hormonal stimulus of pregnancy and lactation."} +{"text": "The recent decade has witnessed many landmark observations, which have added to the scientific credentials of Ayurveda.It is however believed that instead of a retrospective approach of looking into the Ayurveda through the scientific reappraisals, a prospective approach through primary understanding of Ayurveda followed by a search into scientific linkage would be more appealing. This article brings the simplified yet scientific decoding of the core concepts of Ayurveda that form the framework of this ancient science of health. The 21st century has marked the beginning of a new era, receptive to eastern healthcare philosophy through positive attitudes.Contrary to the global scene, Ayurvedic schools in India consistently urge for scientific rooting of Ayurvedic principles. A connotation of linking science and Ayurveda is well perceived by Ayurvedic physicians in India, and schools like Banaras Hindu University (BHU) have pioneered this thought. What prevented this thought from becoming a reality? A poor scientific appraisal of Ayurvedic principles among Indian scientific community eventually resulted in a poor interdisciplinary collaboration between science and Ayurveda. This subsequently led to a premature demise of this thought until it has been resurrected recently with stronger evidence to rely on. Thinking of effective utilization of Ayurveda through a better understanding of its fundamentals is the recent realization. Fortunately, this realization has given rise to a spurt of an impulsive and argumentative pro-Ayurvedic generation as its eventuality. Global d7omne vivum ex ovo (every living thing comes from a pre-existing living thing) before arriving finally at theory of biopoiesis. A biopoiesis theory ultimately proposed for a three-step transition between non-livings to living earth. These transitional stages are postulated as:How did life evolve on Earth? This is the question stirring the human mind all through the ages. Initial proposals of spontaneous generation soon transformed into 1. Origin of biological monomers; 2. Origin of biological polymers and 3. Evolution of cells from polymers.Revisiting the recent understanding of origin of life through an Ayurvedic viewpoint surprisingly explores a remarkable clarity and similarity of postulates.Nasato vidyate bhavo, na bhavo vidyate satam (non- existence cannot give rise to existence) as an Ayurvedic version to omne vivum ex ovo (every living thing comes from a pre-existing living thing). This dictum argues for the omnipresence of formative substances of life since eternity.Avyakta (invisible) and reached to Vyakta (visible) stage after passing through number of intermediaries.Origin of life process began from Elaborating its postulates about origin of life, Ayurveda, fundamentally proposes a few dictums, which are equally re-phrasable to their modern contexts of origin of life. These dictums are:Sattva, Rajas and Tamas (Triguna) symbolizing the physical properties prevalent to the primitive earth. Sattva, the foremost of Triguna, symbolizes the energy required for creation, Rajas, the second of Triguna symbolizes the particle movements and Tamas finally symbolizes inert material having a capacity to convert into new forms under the constant influence of Sattva and Rajas.Ayurveda proposes for an omnipresence of basic building blocks of life in the universe suggesting that beginning of synthesis is subject to the availability of optimal conditions. This justifies the life process to begin only a few billion years ago despite availability of the basic materials since eternity. Primitive earth was proposed to be characterized by Sattva, Rajas and Tamas to that of conditions available to primitive earth that acted decisively to begin the actual process of origin of life Rasa , Virya (potency), Vipaka (post- digestion property) and Prabhava and all these are needed to fully understand the complete pharmacological effect of a substance. The Rasa and corresponding attributes of a substance, independently or in coherence are used in Ayurveda for identifying the pharmacological effect and subsequently for the clinical usage of a medicine. Different Rasa have also been described to produce variable effects on functions of dosha. This makes the consideration of dosha and rasa of a medicine very crucial in the practice Ayurvedic medicine [Besides medicine .Prakriti led to a search for possible classification of people on their Prakriti based on theirgenetic make up.[prakriti as is conceived in Ayurveda.[The 21st century began with a few landmark observations that helped decisively to rediscover the lost links between modern Science and Ayurveda. This period has also proposed certain new models to comprehend Ayurvedic fundamental tenetson grounds acceptable to the Western world. The evol make up. These stAyurveda.Rasa), after taste (Vipaka), special effects (Prabhava) and pharmacological impacts (Guna) of medicinal plants.[Bhasma preparations as novel nano-technological applications. Typical features of Ayurvedic Bhasma have been recently demonstrated through transmission electron microscopy and atomic force microscopy.[Swarna (Gold) bhasma principally constituted of globular gold particle of 56\u201357 nm. Interestingly, the same study also revealed Swarna bhasma to be devoid of any other heavy metal or organic material by its screening through Atomic Absorption Spectroscopy (AAS) and Infrared Spectroscopy (IS).[Bhasmas, has been confirmed in another study,[Bhasma preparations. Pyrgiotakis (2007), with the help of Raman spectroscopy, has demonstrated the effect of Yashada (Zinc) bhasma on intracellular DNA and proteins of the treated human lung adenocarcinoma cell line (A549).[Bhasma preparation is largely attributed to the number and type of Puta used in its making. Increased incinerations, therefore, are able to reduce particle size and subsequently give rise to increased efficacy to a given Bhasma.[Reappraisal of Ayurvedic phytochemistry gives a strong support to the Ayurvedic fundamental constructs about the taste (l plants. Ayurvedicroscopy. A furtheopy (IS). This stuopy (IS). The nanoer study, where ite (A549). Another e (A549). It is obn Bhasma.Shodhana (biopurification), which are proposed to reduce drug toxicities through manual, physical or organic ways. Efficacy of Shodhana methods in reducing toxicity and enhancing safety of ayurvedic preparations was tested as early as in 1981 when Singh et al. demonstrated an improved pharmacological property and reduced toxicity in a Shodhana treated Vatsanabha (aconite) sample.[Shodhana for their relative efficacy. In this study, Aconite processed with cow urine was found more effective and less toxic compared to other methods of Shodhana.[The toxicity of certain Ayurvedic formulations has become a potential limiting factor towards its globalization. Ayurvedic classic texta have taken a serious note of the potential toxicity of certain herbs, minerals and metals. A strict GMP observation is recommended to overcome inherent toxicity of these preparations. Traditionally, ayurvedic drugs are purified through ) sample. Throat aShodhana. UnfortunRasayana is one such concept having an extensive potential applications. Rasayana drugs are described to have anti-aging effects. Labhopayo hi shastanam rasadinam rasayanam, is statement from the Charaka Samhita (Chikitsa sthana i/i/8) that says that Rasayana,are agents thatare supportive to the qualitative improvement of tissues. A qualitative improvement here essentially refers to the functional and constitutional specifications of a tissue altered by age. Such an enhanced tissue would have optimal functions and also withstand premature aging consequent to its impaired quality. Therefore, anti-aging seems to be the secondary outcome of the Rasayana, subsequent to qualitative up-gradation and stabilization of cellswhich is its primary function. Sharangdhara's statement rasayanam cha tajghyeyam yajjaravyadhi vinashanam is more apt for its description of the use of Rasayanas in Jaravyadhi (progeria), Jara (aging) and Vyadhi (disease).Ayurveda also presents some unique clinical applications of its fundamental concepts. Rasayana drugs are said to produce their beneficial effect more promptly in conditions where a suboptimal quality of tissue is leading to its premature aging and suboptimal functioning. In healthy people where the tissue aging is in connotation to the physical age, Rasayana can offer only a little to help.It is for this reason that, Rasayana drugs are proposed to promote tissue longevity through some more novel mechanisms likeReduction of toxin/ metabolic waste load within the cell through their reduced production or increased scavenging, ensuring efficient use of energy within the cell, thus requiring less substrate consumption leading to reduced energy requirement and reduced waste production, initiation of micro-repair by providing essential nutrients by participating in regeneration directly or through promotion of latent enzyme systems.[ systems.et al. have added to the understanding of antioxidant action of a few Rasayana herbs of Ayurveda. The mechanism of action proposed for these herbs include suppression of free radical formation, break- chain initiation, break-chain propagation, reconstitution of membrane and repair damage.[The studies of Devasagayam r damage.Sarpagandha (Rouwolfia serpentina), till today is the only molecule that blocks vesicular monoamine transporters (VMAT). This generalized blockage exposes biogenic amines to degradation by monoamine oxidize (MAO) leading to their depleted levels. This recent understanding of reserpine uniquely explains the classical indication of Sarpagandha for Unmad (mania) patients and also explains how its use may lead to biogenic amine depletion and subsequently to depressive episodes.An approach to understand Ayurvedic pharmacology within a molecular perspective is the recent segment of interfacing between Ayurveda and molecular science. Reserpine, the active alkaloid of Ayurveda is often sought as a therapy for cancer patients. There are several common features between the ayurvedic concept of cancer and modern science. Anti-cancer medicines currently used inactivate or activate specific molecules or cell signaling pathways. Within the last three decades, cancer causing genes called oncogenes, cancer-suppressing genes (tumor suppressor genes), cancer growth factors , cancer-promoting enzymes and cancer-causing protein kinases have been identified as targets. Although these targets were not known 5000 years ago, the components of herbs used at that time now appear to target these molecules. For instance, nuclear factor kB, which has been known to play a major role in tumorigenesis, is targeted by the components of several herbal remedies described in Ayurveda. Similarly; several herbs have been described in Ayurveda that can suppress either expression of COX-2 or its activity.There are several more postulates and sporadic works, which strongly present Ayurveda in a scientific and understandable manner to a receptive mind. Thus it is felt that a reappraisal of Ayurveda in light of fundamental science and its advances would be immensely helpful to perceive Ayurveda in true scientific fervor.This article discussed a few important leads from basics of Ayurveda in light of their possible scientific correlates to reappraise them in tune to contemporary knowledge.The very core of Ayurveda is formed from some very basic concepts e.g. panchabhautic theory, the prakriti concept which is used to describe the predisposition to and prognosis of disease as well as governs the choice of the therapy, balance and imbalance of the three dosha in the development of disease. Interestingly, Ayurveda further expands on these theories to plan interventions that would correct the imbalance. The actions of medicines are described through their various properties based inherently on their elemental composition. It is the need of the hour to use modern technology to explore the relevance of these concepts, so that they may be interpreted in light of contemporary scientific language to offer modern health care."} +{"text": "The relationships between response to chemotherapy of advanced breast cancer and the histological type, grade, elastosis content and DNA ploidy of the primary tumours were examined using paraffin-embedded tissue derived from 125 patients. Higher response rates were seen amongst tumours with a high elastosis content and those that were diploid. However, selection of patients with advanced breast cancer for chemotherapy will not be assisted significantly by an assessment of these features in the primary tumour."} +{"text": "Paired mushroom bodies, an unpaired central complex, and bilaterally arranged clusters of olfactory glomeruli are among the most distinctive components of arthropod neuroarchitecture. Mushroom body neuropils, unpaired midline neuropils, and olfactory glomeruli also occur in the brains of some polychaete annelids, showing varying degrees of morphological similarity to their arthropod counterparts. Attempts to elucidate the evolutionary origin of these neuropils and to deduce an ancestral ground pattern of annelid cerebral complexity are impeded by the incomplete knowledge of annelid phylogeny and by a lack of comparative neuroanatomical data for this group. The present account aims to provide new morphological data for a broad range of annelid taxa in order to trace the occurrence and variability of higher brain centers in segmented worms.Immunohistochemically stained preparations provide comparative neuroanatomical data for representatives from 22 annelid species. The most prominent neuropil structures to be encountered in the annelid brain are the paired mushroom bodies that occur in a number of polychaete taxa. Mushroom bodies can in some cases be demonstrated to be closely associated with clusters of spheroid neuropils reminiscent of arthropod olfactory glomeruli. Less distinctive subcompartments of the annelid brain are unpaired midline neuropils that bear a remote resemblance to similar components in the arthropod brain. The occurrence of higher brain centers such as mushroom bodies, olfactory glomeruli, and unpaired midline neuropils seems to be restricted to errant polychaetes.The implications of an assumed homology between annelid and arthropod mushroom bodies are discussed in light of the 'new animal phylogeny'. It is concluded that the apparent homology of mushroom bodies in distantly related groups has to be interpreted as a plesiomorphy, pointing towards a considerably complex neuroarchitecture inherited from the last common ancestor, Urbilateria. Within the annelid radiation, the lack of mushroom bodies in certain groups is explained by widespread secondary reductions owing to selective pressures unfavorable for the differentiation of elaborate brains. Evolutionary pathways of mushroom body neuropils in errant polychaetes remain enigmatic. Annelida is an ancient phylum that comprises over 16,500 described species. Its members inhabit nearly all biotopes in marine environments, and occupy fresh water and moist terrestrial habitats , they pArctonoe vittata GRUBE, 1855 and Nereis vexillosa GRUBE, 1851, where they relay information to mushroom body neuropils is an eostomium and relaIn this account, the general term 'unpaired midline neuropil' is applied to hitherto unspecified neuropils that span the midsagittal plane of the brain; the term does not imply homology between individual unpaired midline neuropils encountered in different species.Nereis diversicolor, where the unpaired midline neuropil consists of a small, crescent-shaped fiber tangle with no apparent internal differentiation and Bergen (Norway), respectively, and aided in collecting and determining polychaete specimens. CMH, CHGM, CT, and RL all contributed to writing the manuscript. All authors read and approved the final manuscript."} +{"text": "Science, Naqvi et\u00a0al. demonstrated that smoking addiction is disrupted by damage to the insula cortex. This suggests that brain circuits mediating interoception also contribute to craving states.Awareness of one's physiology is an important component of emotion. How might these processes be related to addiction? In a recent issue of Science provides strong evidence that interoceptive processes within insula cortex underlie craving associated with nicotine addiction.Addictions hijack brain systems controlling emotional and motivational behavior that are fundamental to adaptive survival. Feeling states, such as craving, are the experiential component of motivational behavior, representing consciously accessible expressions of motivational need. Primary feeling states represent an elegant means of maintaining physiological homeostasis; feelings such as hunger, cold, or thirst motivate nutrient absorption (facilitating thermoregulation and rehydration) and may be considered homeostatic emotions. Evolutionary development of emotional systems within social environments may explain a hierarchy of feelings, where more complex emotions can anticipate potential social challenges to homeostatic and internal integrity and contribute to mnemonic reinforcement of adaptive behaviors. Motivational stimuli such as emotive cues engender involuntary bodily responses . The interoceptive feedback of these dynamic bodily reactions directly influences feeling states and affective experience. This process is central to influential peripheral theories\u00a0of emotion e.g., . CorrespThe addictive nature of tobacco smoking is illustrated by the difficulty smokers experience in quitting, despite the fact that deaths attributable to tobacco smoking are predicted to reach 6.4 million per year by 2015 . CravingAddiction neuroscience has been valuably informed by animal models. Processes that characterize addiction, such as habit learning and reward signaling, are supported by dopaminergic mechanisms within striatal and prefrontal circuitry . The neuWithin the primate brain, interoceptive information relays via thalamus to insula cortex where sequential rerepresentations permit associative integration with other processing streams . In humainterpretative models of emotion where the actual emotion that is experienced arises from interpretation of the perceived context in which bodily arousal changed (In our own laboratory, the link between interoception and insula activity has been observed in a number of contexts: including covariation of right anterior insula activity with sympathetic electrodermal activity during gambling or, in studies of patients with peripheral autonomic neuropathy, an attenuation of right insula activity in the absence of autonomic reaction during effortful behavior or during the processing of threat (reviewed in changed . In a fu changed . The stu changed and seco changed interoceIn addition to insula cortex, anterior cingulate and orbitofrontal cortices are also anatomically and functionally associated with integrated autonomic control and are sensitive to interoceptive signals . Damage A number of laboratories, including our own, are attempting to dissect the neural mechanisms that support and mediate interactions between conscious perception, interoceptive control, and emotional feelings. In parallel, studies of the functional neurobiology of the cognitive control of anxiety and the facilitation of motivational \u201cunlearning\u201d and extinction highlight the importance of affective neuroscience to clinical therapeutics. In the study by Naqvi and coworkers, the effects of insula lesions on smoking addiction are reminiscent of an \u201cinteroceptive agnosia\u201d arising from disruption of viscerosensory representations . Their sWhy did not all smokers with insula lesions quit? Obviously a number of factors play a role in the maintenance of addiction, only some of which are usefully explained at the neural level. Of these, alterations in striatal dopaminergic reward-related processing are well recognized to play a critical role. The degree to which reward/goal-selection processes and interoceptive awareness of craving differentially contribute to drug-seeking behavior is not known. One important next step in further understanding the interplay between the multiple neural systems mediating addiction would be"} +{"text": "The past has taught us many lessons about risk from environmental exposures. For example, the lack of full scientific proof concerning the adverse effects of asbestos and the delay of precautionary action had devasting consequencies to human health . If asbeIn conclusion, concerning the exposure to electromagnetic fields, the precautionary principle should be applied to protect humans from environmental effects of non-thermal mechanisms."} +{"text": "Drug screening trials and general treatment of solid tumours in advanced cancer patients have been concerned only with the site of primary origin, regardless of where metastases might have seeded. Since the environment for tumour growth can differ appreciably at various anatomical sites, an investigation was undertaken to determine the effect of metastatic site on response to chemotherapy. Data from 1961 to 1965 of the screening trials of the Eastern Clinical Drug Evaluation Program were utilized. Response and location data extensive enough for analysis represented 6 sites of primary origin and 6 metastatic site groups, totalling 1687 lesions. Analysis of percentage reduction in tumour size after chemotherapy regimens of up to 60 days revealed a significant amount of variation associated with metastatic sites and a non-significant amount associated with sites of primary origin. Advanced primary tumours showed marked variation in responsiveness and some showed a difference in response to different drug groups. Generally, metastases responded better than the advanced primaries from which they were derived, except for those from breast tumours."} +{"text": "Objective: Nerve regenerative is a complex problem and cell therapy strategies are being developed to enhance axonal regeneration. One approach is to transplant peripheral myelin\u2013forming cells (Schwann cells or olfactory ensheathing cells) that can secrete neurotrophic factors and participate in remyelination of regenerated axons. The objectives of this report are to first review the basic regeneration properties of myelinated axons. Next, to review studies that show functional improvement after transplantation of peripheral myelinating cells in the injured spinal cord. The final objective is to review recent studies using this approach as an adjunct cell therapy for microsurgical repair of peripheral nerve. Methods: Schwann cells and olfactory ensheathing cells were transplanted into injured spinal cord and peripheral nerve. In the microsurgical repair studies, rat sciatic nerves were repaired with epineural sutures (10.0). Olfactory ensheathing cells were transplanted in the experimental group at the time of repair. Histological and behavioral assessment was carried out at 5 weeks postsurgery. Results: Experimental transplantation of olfactory ensheathing cells at the time of microsurgical repair of peripheral nerve leads to increased axonal regeneration across the repair site and improved functional outcome. Conclusions: Olfactory ensheathing cells can integrate and participate in neural repair in both spinal cord and peripheral nerve. They promote axonal sprouting and contribute to remyelination associated with appropriate axon nodal sodium channel clustering necessary for proper impulse conduction. These experimental observations suggest that adjunct cell transplantation with microsurgical repair should be considered as a possible tool in peripheral nerve repair. Damage to peripheral nerve fibers often results in axonal loss and demyelination followed by regeneration and remyelination under optimal conditions with the possibility of at least some functional recovery. In the central nervous system (CNS), unassisted axonal regeneration is at best rare. Much recent work now indicates that this difference between peripheral nervous system (PNS) and CNS axonal regeneration is the result of both permissive factors present in the PNS and active inhibitory factors present in the CNS. Indeed, knowledge of these differences has encouraged research to develop novel strategies to enhance axonal regeneration. After nerve repair, clinical results are often disappointing and experimental approaches to enhance functional recovery are on their way. These include focal application of neurotrophic factors, blockade of axonal regeneration inhibitory molecules, and cell transplantation. In this article, we review the basic organization of peripheral axons and discuss current experimental strategies using transplantation of peripheral myelin\u2013forming cells to enhance axonal regeneration and remyelination both in the spinal cord and in microsurgical nerve repair.Peripheral myelinated axons FigA are myeThe node of Ranvier is the short segment of axon between adjacent Schwann cells and is the site of action potential generation. The internode distance of a large myelinated axon can be as long as a millimeter, but the node of Ranvier is typically only several microns in length Fig B. The ac2 of the nodal membrane and the internodal membrane has a sodium channel density \u03bcof about 25/\u03bcm2.2, which is insufficient to generate an action potential. There are numerous sodium channel subtypes with different electrical properties.Much work indicates that sodium channels, the molecular batteries generating the action potential, are present at the node in relatively high concentration. Experiments using radiolabeled saxitoxin have estimated the relative density of sodium channel at the mammalian node and internode.When the axon is severed by nerve injury, the axon diebacks a millimeter or two from the injury site and the distal segment degenerates, a feature known as Wallerian degeneration.NGFR, are considerably upregulated on Schwann cells.NGFR expression after contact with regenerating axons.Nerve growth factor (NGF) is produced by target tissues both of sympathetic neurons and of sensory nerves.After a delay of a day or two, the proximal stump of the cut nerve gives rise to axonal sprouts that will extend either on the surface of Schwann cells or to the inner laminin-rich surface of the basal lamina of the Schwann cells columns (bands of B\u00fcngner). If the proximal and distal segments of the nerve appose each other, regenerating axons may grow through these Schwann cell \u201cscaffolds\u201d and make contact with peripheral targets with the possibility of some functional recovery. Typically, several axonal sprouts issue from a single regenerating fiber and grow within a single Schwann cell column, but after target contact, all but one of the sprouts dieback leaving a single fiber making contact with a peripheral target. The regenerated fiber is then myelinated by Schwann cells within the tube and conduction velocity is increased to appropriate levels.16If the regenerating axon sprouts do not reach and elongate through the trophic distal Schwann cell tube, they will grow in a more random manner and can form a neuroma.Long-tract axons in the mammalian spinal cord do not normally regenerate for an appreciable distance within the denervated host tract after they are transected. This is likely because of a lack of the permissive environment that the Schwann cell provides in peripheral nerve24NGFR. Interest has focused on these cells because olfactory epithelial neurons are continuously replaced and regenerate peripheral axons in the adult.31Recent attention has focused on transplants of cultured olfactory ensheathing cells (OECs) into injured spinal cordOEC transplantation can enhance regeneration of transected spinal cord axons and improve forepaw reaching behaviorAlthough endogenous Schwann cells play an important role in the regeneration of peripheral nerve, transplantation of Schwann cells, or OECs, could in principle assist the regenerative process. For example, if severed nerve is surgically reapposed, it may take time for the endogenous Schwann cells to appropriately differentiate and organize to provide an optimal regenerative environment. Cultured Schwann cells transplanted to the apposition site could facilitate the regenerative process. Importantly, the newly formed nodes of Ranvier of the regenerated axons expressed sodium channel subtype Nav 1.6,Although peripheral myelinating cells were first used to encourage axonal regeneration in the spinal cord, more recently, transplantation of OECs has been considered as an adjunct for peripheral nerve repair. The rationale is that they may provide a scaffold for axons to regenerate as well as trophic support and directional cues.41The next question was whether transplantation of peripheral myelinating cells at the time of microsurgical repair could improve functional outcome. In a recent article, we demonstrated that OECs transplanted at the time of microsurgical nerve repair enhanced nerve regeneration and functional outcome.Experimental work indicates that peripheral nerve has a remarkable capacity to regenerate after injury. Reasons include the permissive environment produced by reactive Schwann cells in the distal nerve segment and the lack of axonal inhibitory proteins. Schwann cells not only provide a structural scaffold for regeneration by contributing to the bands of B\u00fcngner but also are a rich source of neurotrophic support, including NGF. When appropriate alignment of proximal and distal stumps of cut nerve occurs, the probability of correct nerve-target reestablishment is increased. When regenerating peripheral nerves are blocked from reacting target and neuroma formation occurs, the regenerating axonal sprouts become maladaptive and contribute to pain and paresthesias including phantom limb pain in the case of limb amputation. Several experimental strategies including focal neurotrophin treatment and cellular transplantation are being studied in the laboratory to optimize both surgical nerve repair and dysesthesias. The use of peripheral myelin\u2013forming cells into areas of spinal cord injury results in improved functional outcome, and clinical studies are ongoing. More recent experimental work indicates that the transplantation of OECs into the site of microsurgical nerve repair leads to improved regeneration and functional outcome. An important challenge is to translate the recent advances in regeneration biology to novel surgical interventional approaches in the treatment of nerve injury."} +{"text": "Epidemiological studies point to a strong and possibly causal association of psychiatric and neurological disorders with cardiovascular disease (CVD). Mechanistic links between these co-occurring illnesses are not well understood. Better insight into their relationship could help identify novel diagnostic markers and therapeutic targets. For successful translation of basic biomedical research into clinical practice, analyses of postmortem human tissues are essential. However, current tissue banks dedicated to psychiatric and neurological research collect only brain tissue samples deemed most important to the institution's participating investigators. While this practice is often dictated by budget constraints, restricted tissue storage space and other practical reasons, it limits the ability of the biological research community to access and study multiple organ systems relevant to cardiovascular and neuronal systems dysfunction. This problem is worsened when clinical records pertaining to coexistent systemic pathology are not available. To promote further understanding of co-occurring CVD and psychiatric/neurological disorders, efforts should be made to support tissue banks that harvest heart, coronary arteries, and aorta samples as well as brain tissue, from the same subjects. A growing awareness of the links between diseases of the cardiovascular system and pathologies of the central nervous system, including psychiatric and neurological disorders, has promulgated interest in understanding the pathophysiological mechanisms underlying these associations . It is aExtensive efforts have been made to elucidate the role of elevated serum cholesterol, APOE4 genotype, heart disease, and cerebral hypoperfusion in the pathogenesis of AD ; howeverA prominent example of comorbid psychiatric and cardiovascular disorders is the association between depression and coronary heart disease (CHD). Depression is associated with increased cardiovascular morbidity and mortality and withIt is conceivable that studies using postmortem brain and heart/vascular tissues from the same subject would be advantageous to the cardiovascular psychiatry/neurology research; however such samples are not harvested together routinely from autopsies of normal and diseased adults. Considering the complexity of current brain banking efforts , 12, it Several issues should be considered before initiating the extension of an existing brain bank into a multiorgan bank. First, a detailed and comprehensive protocol would have to be formulated to ensure standardized sampling procedures from multiple organs. Next, a dedicated and adequate source of funding must be secured; tight budgets combined with insufficient personnel and tissue storage capacities of most brain banks in the USA and abroad restrict large scale storage of harvested tissues. Finally, greater efforts must be made to promote collaborations of basic and clinical neuroscientists with experts in CVD. These collaborations are invaluable in the light of the co-occurrence of cardiovascular and psychiatric/neurological disorders as well as the progressive multisystem dysfunction that accompanies cognitive decline in many elderly individuals. By expanding our existing brain tissue banks to accommodate the emerging need for a multiorgan/tissue oriented research, multidisciplinary collaborations would be fostered to provide broader insight into the disease process. This could be achieved by requesting improved funding for such initiatives, along with matching education and outreach efforts to ensure greater public support for such projects."} +{"text": "Seeding of tumour in the needle track following percutaneous needle biopsy of liver neoplasms is rarelyreported. We describe two such cases following the needle biopsy of an hepatocellular carcinoma andsecondary colorectal carcinoma respectively. The risk of needle track recurrence of liver tumours shouldnot be regarded as insignificant. The diagnosis of liver neoplasms may be achieved by non-invasivemodalities, and their needle biopsy should be reserved for cases not amenable to surgical resection."} +{"text": "Health policy and systems research (HPSR) has been identified as critical to scaling-up interventions to achieve the millennium development goals, but research priority setting exercises often do not address HPSR well. This paper aims to (i) assess current priority setting methods and the extent to which they adequately include HPSR and (ii) draw lessons regarding how HPSR priority setting can be enhanced to promote relevant HPSR, and to strengthen developing country leadership of research agendas.Priority setting processes can be distinguished by the level at which they occur, their degree of comprehensiveness in terms of the topic addressed, the balance between technical versus interpretive approaches and the stakeholders involved. When HPSR is considered through technical, disease-driven priority setting processes it is systematically under-valued. More successful approaches for considering HPSR are typically nationally-driven, interpretive and engage a range of stakeholders. There is still a need however for better defined approaches to enable research funders to determine the relative weight to assign to disease specific research versus HPSR and other forms of cross-cutting health research.While country-level research priority setting is key, there is likely to be a continued need for the identification of global research priorities for HPSR. The paper argues that such global priorities can and should be driven by country level priorities. Failing or inadequate health systems are one of the main barriers to scaling-up interventions towards the achievement of the millennium development goals and therResearch priority setting is acknowledged to be a key function of national health research systems and is perceived to be an important process in terms of ensuring the alignment of research funding with national evidence needs . IdeallyMuch of HPSR is context specific and thus the role of national health authorities in setting HPSR priorities is particularly important. However, in many developing countries, significant funding for HPSR comes from external sources, and while HPSR research priorities should be set at the national level, there is likely to be a continued need for information about HPSR priorities at the global level. Indeed there are several current developments for which sound priority setting processes are required. For example, the Intergovernmental Working Group on Public Health, Innovation and Intellectual Property prepared a global strategy and plan of action on essential health research to address conditions affecting developing countries disproportionately. The first element of the strategy involves prioritizing research and development needs, in part by \"formulating explicit prioritized strategies for research and development at country and regional and inter-regional levels\" . In lighA substantial amount of previous work on priority setting processes for health research has been conducted ,9-11, bu\u2022 To explore current priority setting methods and the extent to which they adequately include HPSR\u2022 To draw lessons regarding how HPSR priority setting can be enhanced to strengthen developing country leadership of research agendas, and to promote relevant HPSRThis paper does not set out to provide a comprehensive review of previous health research priority setting processes, which can be found elsewhere -12. It sPriority setting processes can be distinguished by a number of inter-linked factors including:-Level: \u2022 they may aim to set research priorities at global, national, sub-national or institutional levels.Comprehensiveness\u2022 : some priority setting processes focus on relatively narrow sub-sets of research questions , whereas others aim to set research priorities for the whole of the health sector, others still may situate health research priorities within the broader context of scientific investment and research priorities in other fields.The balance between technical versus interpretive approaches\u2022 : priority setting processes within the health sector may be predominantly technical in nature, dominated by quantifiable epidemiologic or other needs and costs data, or more interpretive assessments, dominated by the consensus views of informed participants . Other 2SystematInformation needs of target audiences - Priority setting exercises need to take their target audience into account [- account . The appUnderstanding the implications of HPSR capacity constraints for the identification of research priorities. The fact that few priority setting processes properly address health systems research is one reason why funding for the field has been relatively limited. However another factor undermining funding for HPSR, that could perhaps be better taken account of in priority setting processes, is the weak capacity to conceptualize, develop, and implement HPSR in low and middle income countries. Good analyses are needed of how limited research capacity shapes the nature of research priorities, and how HPSR priority setting could also address capacity strengthening so as to strike a balance between investments in direct research funding and in capacity development.- The authors declare that they have no competing interests.MKR and SCB conceived of the study and designed the study. MKR conducted the literature review. MKR and SCB wrote the paper. Both authors have read and approved the final manuscript."} +{"text": "A survey of Genbank entries for complete microbial genomes reveals that the majority donot conform to the Genbank standard. Typical deviations from the Genbank standardinclude records with information in incorrect fields, addition of extraneous and confusinginformation within a field, and omission of useful fields. This situation results from twoprincipal causes: genome centres do not submit Genbank records in the proper form andthe Genbank, EMBL and DDBJ staffs do not enforce the database standards that theyhave defined."} +{"text": "A new, simple and sensitive low pH ELISA method has been developed to measure serum levels of tumour associated antigens detectable by monoclonal antibodies HMFG1 and HMFG2. We examined sera from healthy controls, patients with neoplastic and non-neoplastic conditions of breast, liver and gastrointestinal tract. The majority of patients with metastatic breast cancer had elevated serum antigens compared to healthy controls or patients with benign breast disease . There was no discrimination using these assays between patients with neoplastic and non-neoplastic conditions of liver and gastrointestinal tract. This new method promises to be of value in the assessment and management of patients with breast cancer."} +{"text": "Worldwide, breast cancer is the most frequent malignancy among females. Its incidence shows a trend towards an increase in the next decade, particularly in developing countries where less than of 5% of resources for cancer management are available. In most breast cancer cases systemic cancer treatment remains a primary management strategy. With the increasing costs of novel drugs, amidst the growing breast cancer rate, it can be safely assumed that in the next decade, newly developed cancer drugs will become less affordable and therefore will be available to fewer patients in low and middle income countries. In light of this potentially tragic situation, a pressing need emerges for science-based innovative solutions.In this article, we cite examples of recently published researches and case management approaches that have been shown to lower overall treatment costs without compromising patient outcomes. The cited approaches are not presented as wholly inclusive or definitive solutions but are offered as effective examples that we hope will inspire the development of additional evidence-based management approaches that provide both efficient and effective breast cancer treatmentWe propose a \"win-win\" initiative, borne in the year of 2008 of strategic information sharing through preparatory communications, publications and our conference presentations. In the year 2009, ideas developed through these mechanisms can be refined through focused small pilot meetings with interested stakeholders, including the clinical, patient advocate, and pharmaceutical communities, and as appropriate (as proposed plans emerge), governmental representatives. The objective is to draw a realistic road map for feasible and innovative scientific strategies and collaborative actions that could lead to resource sparing; i.e. cost effective and tailored breast cancer systemic treatment for low and middle income countries.The intended result would assure sustained affordability and accessibility in breast cancer systemic therapy for patients in low and middle income countries. As an added benefit, the example of breast cancer could be expanded to include other cancers in diverse settings around the world. By the year 2020, 70% of the twenty million new cancer cases will occur in countries that collectively have only five percent of the global resources for cancer control . Breast This trend provides every indication that the need for systemic anticancer agents will continue to increase over the next ten years. The pharmaceutical companies are developing increasingly expensive novel anticancer molecules with no indication that the rapidly escalating cost of new treatments will ease in future. Improvements in the overall and disease-free survival rates and quality of life are not commensurate with the soaring costs of cancer treatment.The major markets for the leading pharmaceutical industry are in the United States, Western Europe and Japan; and while these regions may be able to meet the increased cost of treatment, it can be safely assumed that the cost of novel anticancer drugs will continue to expand as an insurmountable obstacle to care for an ever greater proportion of cancer patients in Low and Middle Income Countries (LMCs) where the majority of the world's population live. This discomforting reality confronts us with difficult challenges that merit the spirited engagement of regional and international health leaders.Breast Cancer, with its predictable increase in incidence, and multiple available, effective treatment options provides an excellent starting point for developing economically sustainable cancer control strategies that could be tailored in LMCs for other forms of cancer as well.It is our aim to establish a scientific initiative to expand availability of resource sparing Breast Cancer Systemic Therapy (BCST) and hope that such strategy may meet the demand for effective, affordable breast cancer care for patients who would otherwise be left without scientifically valid treatment options.This communication reviews examples of recent and ongoing scientific researches and suggestions that could lead to lower costs of BCST without compromising overall patient outcomes. These findings, this summary, and subsequent detailed publications, and conference presentations can provide a basis for pilot meetings to launch a \"win-win\" scientific initiative based on cooperation and collaboration of stakeholders; whereby markets are created or maintained for effective cancer therapies, and patients are assured access to these interventions regardless of where in the world they reside.A trial of 9-weeks of trastuzumab treatment has been compared to 52 weeks treatment. Both arms were similar in outcome . We assu\u00ae) trastuzumab lies in the saturation of deoxcytidine kinase which occurs after short infusion at conventional doses. This enzyme is needed for conversion of gemcitabine into its active form gemcitabine triphosphate. While short usual infusion leaves most of the drug unmetabolized, prolonged infusion apparently leads to a higher intracellular concentration of the active metabolite [The encouraging response of phase I-II trials of low dose gemcitabine in prolonged infusion in the treatment of certain solid cancers, e.g. non small cell lung cancer, breast, pancreas and bladder cancers deserves further investigation. The explanation for these responses caused by low doses (of 250 mg and 180 mg/m\u00ae) at no cost to patients with chronic myelogenous leukemia (CML) or gastrointestinal stromal tumor (GIST) in 81 countries who would not otherwise have access to comprehensive reimbursement for the treatment[is a worldwide program to provide imatinib (Glivectreatment. This exAromatase inhibitors (AI), when given as interrupted course, probably would also be effective as continuous therapy after prior tamoxifen and/or AI treatment. The hypothesis is that AI interrupted courses may cause estrogenic stimulation and enhance response of residual resistant cells. We citeAccording to recent studies, it is shown that lapatinib when taken orally with food -not on an empty stomach as cited frequently\u2013yields an increased plasma level. Lower oral doses administrated with food and with grapefruit juice could effectively inhibit the enzyme CYP3A and thereby could provide comparable effect. Up to 80% of the dose and the cost of the drug could be reduced by this approach [- There are greater possibilities in using oral cancer drugs [er drugs . The oraThe following concise points relate to what some refer to as \"the essential and conventional\" systemic cancer drugs:Fortunately, the pharmaceutical arsenal of \"essential and conventional systemic anticancer drugs\" still constitutes the basis of this treatment modality. In addition, these conventional drugs are relatively inexpensive. For breast cancer the list would include CMF , FAC , Tamoxifen and Ovarian ablation.Innovative strategic thinking and approaches should be encouraged to improve the availability and accessibility of first-line systemic anticancer treatments as part of the comprehensive breast cancer control plan for underserved countries. An example of novel chronology and mode of drug administration that tests additional mechanisms of actions and indications is the metronomic use of prolonged, low oral doses of cyclophosphamide and methotrexate as palliative breast cancer treatment . While aoffer the possibility of less expensive treatment. However, the quality and bioequivalence of generics used in developing countries should be assured by regulations or developing a transparent system for international testing. To overcome difficulties in achieving large scale feasibility in quality control, we suggest working at the small scale level to test random samples or pilot settings upon invitation from the local authorities in some developing countries.Tamoxifen requires enzymatic activation by CYP 450 enzymes for the formation of clinically relevant metabolites 4-OH-tamoxifen and endoxifen which both have a greater affinity to the estrogen receptors and ability to inhibit cell proliferation when compared to the parent drug. The key enzyme in this bio-transformation is the CYP2D6. Recent pharmacological and clinical pharmacogenetics evidence suggests that genetic variants and drug interaction by CYP2D6 inhibitors influence plasma concentration of active tamoxifen metabolites and thereby improve treatment outcome of breast cancer patients treated by adjuvant tamoxifen . It is sAnother approach would be to help develop the required infrastructure for the clinical research and trials with pragmatic goals that would be ideally suited to LMCs, few suggestions for this are:a) To tailor treatment to patients, community and tumor factors .b) To address economic considerations, cost-effectiveness and quality of life issues within each community or region.c) To test innovative combinations or different schedules of administration of older (and relatively cheaper) drugs that might lead to previously improved therapeutic index or applicability to specific societies. Such investigations usually are not supported by pharmaceuticals companies and international conferences, although they might be of benefit to science and cancer patients in LMCs.d) To test new uses of a relatively old and less expensive drugs (as earlier cited in the use of Cisplatin in triple negative breast cancer patients).e) Conducted with appropriate ethical guidelines and international oversight, clinical research would provide broader and more transparent access to novel drugs, and would enhance professional education and training in LMCs. Such an approach would assist companies in streamlining the development of new drugs.), we propose \"The win-win initiative\". It starts with communications and publications. Then, we propose to hold small pilot working meetings with representatives of interested parties and willing leading pharmaceutical companies. Next, we would look to larger meetings and collaborative actions with a broader range of participants.On behalf of ICEDOC's Experts in Cancer without borders (ICEDOC is The International Campaign for Establishment and Development of Oncology Centers The goals of this approach include:\u2022 To create a Think Tank or what Franklin Roosevelt described as \"A Brain Trust\", opened for innovative scientific thoughts and ideas that could lead to cost -effective systemic treatment for more breast cancer patients in LMCS.\u2022 To develop a strategy to coordinate ongoing efforts and initiatives.\u2022 To recommend areas of innovative clinical research that address the needs of LMCs\u2022 To identify key components and infrastructure needs in LMCs to support research\u2022 To determine the key barriers to pharmaceutical companies in investing in LMCs research and provide a strategy to overcome those barriers.-Investment in creating infrastructure will create new markets-Old drugs can bring new profits and its use may pave ways for novel drugs.The outcome of the communications and meeting for the year 2009 would be a road map for the win-win initiative\u2022 An actionable strategy opened for contribution, collaboration and coordinating efforts and ideas.\u2022 Formation of a collaborative task force group that aims at more availability and affordability of systemic cancer therapy in LMCs.\u2022 A published report on recommended research and key components.\u2022 A proposal of pilot projects.Finally, no leadership role, or claim to invention is being made. There are many key players and stakeholders in the world. Coordination and cooperation are needed.The author declares that they have no competing interests."} +{"text": "Epidemiological evidence indicates that mammographic dysplasia is associated with an increased risk of breast cancer, particularly in premenopausal women. To examine biochemical associations with mammographic dysplasia we have compared premenopausal women with different patterns of the breast parenchyma on mammography. One group had extensive radiological dysplasia (n = 30) and the other no dysplasia (n = 16). Both groups were recruited from mammographic units in the same way and then compared according to epidemiological risk factors, anthropometric measures, nutrient intake and plasma levels of oestradiol, progesterone and prolactin obtained in both follicular and luteal phases of the menstrual cycle as well as total plasma cholesterol and lipid fractions. Women with mammographic dysplasia were found to be leaner, more often nulliparous and to consume more alcohol than women without these radiological changes. Mammographic dysplasia and a family history of breast cancer were found to be independently associated with significantly higher levels of high density lipoprotein cholesterol (HDL-C) after taking into account the possible confounding effects of percentage body fat, parity and consumption of alcohol and dietary fat. Triglyceride levels were also independently associated with a family history of breast cancer. We conclude that further investigation is warranted of the role of plasma lipids in relation to breast cancer risk."} +{"text": "We tested environmental data from remote sensing and geographic information system maps as indicators of Sin Nombre virus (SNV) infections in deer mouse (Peromyscus maniculatus) populations in the Walker River Basin, Nevada and California. We determined by serologic testing the presence of SNV infections in deer mice from 144 field sites. We used remote sensing and geographic information systems data to characterize the vegetation type and density, elevation, slope, and hydrologic features of each site. The data retroactively predicted infection status of deer mice with up to 80% accuracy. If models of SNV temporal dynamics can be integrated with baseline spatial models, human risk for infection may be assessed with reasonable accuracy."} +{"text": "Periodontal therapy deals with many aspects of the supporting structures, including the prevention and repair of lesions of the gingival sulcus. Endodontics deals primarily with disease of the pulp and periapical tissues. The success of both periodontal and endodontic therapy depends on the elimination of both disease processes, whether they exist separately or as a combined lesion. The relationship between periodontal and endodontic disease has been a subject of speculation for many years. This paper aims at presenting a comprehensive review of several aspects of perio-endo lesions. The tooth, the pulp tissue within it and its supporting structures should be viewed as one biologic unit. The interrelationship of these structures influences each other during health, function and disease. The interrelationship between periodontal and endodontic diseases has aroused much speculation, confusion and controversy. The relationship between the periodontium and the pulp was first discovered by Simring and Goldberg in 1964.Three main pathways have been implicated in the development of periodontal-endodontic lesions, namely :Dentinal tubulesLateral and accessory canalsApical foramenPulpal and periodontal problems are responsible for more than 50% of tooth mortality. Periodon5Pulpal and periodontal tissues are closely related and the disease transmission between these two lesions has been demonstrated by many studies, which showed significant microbiological similarities between infected root canals and advanced periodontitis.\u201310 OtherThe possible pathways for ingress of bacteria and their products into theanatomical pathways are vascular pathways such as the apical foramen and the lateral canals and tubular pathways.The most important among the Apical Foramen: The pulp and periodontal tissues are derived from highly vascular mesenchymal tissues of the tooth germ. The blood supply maintains a connection between these tissues via the apical foramen and lateral canals throughout the development of the tooth. The apical foramen is the principal and most direct route of communication between the periodontium and the pulp. Although periodontal disease has been shown to have a cumulative damaging effect on the pulp tissue, total disintegration of the pulp is only a certainty if bacterial plaque involves the main apical foramen, compromising the vascular supply. Following necrosis of the pulp, various bacterial products like enzymes, metabolites, antigens etc. reach the periodontium through the apical foramen, initiating and perpetuating an inflammatory response there. This results in destruction of periodontal tissue fibers and resorption of the adjacent alveolar bone. External resorption of the cementum can also occur concurrently.Lateral canals: In addition to the apical foramen, which is the main avenue of communication, there are a multitude of branches connecting the main root canal system with the periodontal ligament. These root canal ramifications were first described nearly 100 years ago by Preiswerk (1901). These ramifications are now currently termed as \u2018accessory canals\u2019. The term accessory canal is now used to describe any ramification that connects the root canal system to the periodontal ligament. Acc Acc26] APrimary endodontic lesionPrimary periodontal lesionPrimary endodontic lesion with secondary periodontal involvementPrimary periodontal lesion with secondary endodontic involvementTrue combined lesionAn acute exacerbation of a chronic apical lesion on a tooth with a necrotic pulp may drain coronally through the periodontal ligament into the gingival sulcus. This condition may clinically mimic the presence of a periodontal abscess. In reality, however, it would be a sinus tract originating from the pulp that opens into the periodontal ligament. Primary endodontic lesions usually heal following root canal therapy. The sinus tract extending into the gingival sulcus or furcation area disappears at an early stage, if the necrotic pulp has been removed and the root canals are well sealed.These lesions are caused primarily by periodontal pathogens. In this process, chronic periodontitis progresses apically along the root surface. In most cases, pulpal tests indicate a clinically normal pulpal reaction. There is frequently an accumulation of plaque and calculus and the presence of deep pockets may be detected.If a primary endodontic lesion remains untreated, it may become secondarily involved with periodontal breakdown. Plaque accumulation at the gingival margin of the sinus tract leads to plaque induced periodontitis in this area. When plaque and calculus are detected, the treatment and prognosis of the teeth are different from those of the teeth involved with only endodontic disease. The tooth now requires both endodontic and periodontal treatment.Primary endodontic lesion with secondary periodontal involvement may also occur as a result of root perforation during root canal treatment, or where pins and posts may have been misplaced during restoration of the crown. Symptoms may be acute, with periodontal abscess formation associated with pain, swelling, pus or exudates, pocket formation, and tooth mobility. A more chronic response may occur without pain, and involves the sudden appearance of a pocket with bleeding on probing or exudation of pus.Root fractures may also present as primary endodontic lesions with secondary periodontal involvement. These typically occur in root canal treated teeth, often with posts and crowns. The signs may range from a local deepening of periodontal pocket to a more acute periodontal abscess formation.The apical progression of a periodontal pocket may continue until the apical tissues are involved. In this case, the pulp may become necrotic as a result of infection entering through lateral canals or the apical foramen. In single-rooted teeth, the prognosis is usually poor. In molar teeth, the prognosis may be better. Since not all the roots may suffer the same loss of supporting tissue, root resection can be considered as a treatment alternative.If the blood supply circulating through the apex is intact, the pulp has good prospects for survival. It has been reported that pulpal changes resulting from periodontal disease are more likely to occur when the apical foramen is involved. In these cases, bacteria originating from the periodontal pocket are the most likely source of root canal infection.The treatment of periodontal disease can also lead to secondary endodontic involvement. Lateral canals and dentinal tubules may be opened to the oral environment by scaling and root planning or surgical flap procedures. It is possible for a blood vessel within a lateral canal to be severed by a curette and for the microorganisms to be pushed into the area during treatment, resulting in pulp inflammation and necrosis.True combined endodontic periodontal disease occurs less frequently than other endodontic-periodontal problems. It is formed when an endodontic lesion progressing coronally joins an infected periodontal pocket progressing apically. The degrDiagnosis of primary endodontic disease and primary periodontal disease usually present no clinical difficulty. In primary periodontal disease, the pulp is vital and responsive to testing. In primary endodontic disease, the pulp is infected and nonvital. However, primary endodontic disease with secondary periodontal involvement, primary periodontal disease with secondary endodontic involvement, or true combined diseases are clinically and radiographically very similar. Accurate diagnosis can be achieved by careful history taking, examination and the use of special tests . The extThe following steps in diagnosis, aids in deciding an appropriate treatment plan:Examination of soft tissues, alveolar mucosa and attached gingiva is done for any inflammation, ulcerations or sinus tracts. The teeth are examined for any caries, defective restorations, erosions, abrasions, cracks, fractures, and discolorations like \u2018pink spot\u2019 which is indicative of internal resorption. Magnifying loupes and operating microscope can be used for enhanced magnification and illuminationRadiographic examination aids in detection of carious lesions, extensive or defective restorations, pulp caps, root fractures, periradicular radiolucencies, thickened periodontal ligament and alveolar bone loss. Radiographic changes can be detected only after inflammation or bacterial by-products originating from the dental pulp cause sufficient demineralization of the cortical bone. Initially, periradicular bone resorption from endodontic origin is confined to only cancellous bone. Therefore, it is difficult to identify bone loss caused due to endodontic disease in the initial stages. However, periodontal disease causing alveolar bone loss and the presence of calculus can be effectively detected by radiographs.Teeth with vital pulps will react to cold test with sharp brief pain response that usually does not last more than few seconds. An intense and prolonged pain response often indicates pulpal changes and irreversible pulpitis. Lack of response may indicate pulp necrosis.The presence of a deep solitary pocket in the absence of periodontal disease may indicate the presence of a lesion of endodontic origin or a vertical root fracture. Periodontal probing helps in differentiating between endodontic and periodontal disease. It can also be used to track a sinus resulting from an inflammatory periapical lesion that extends cervically through the periodontal ligament space. In periodontal lesions, numerous defects are present throughout the mouth and subgingival calculus can be detected.Before the commencement of any kind of advanced restorative work to treat a perio-endo lesion, the prognosis of the tooth should be considered carefully. Whether there is a functional need for the tooth, whether the tooth is restorable after the lesion has been treated and whether the patient is suitable for a lengthy, costly and invasive treatment are factors that should be taken into consideration. If any of these factors are deemed negative, extraction is the treatment of choice.When the pulp is nonvital and infected, conventional endodontic therapy alone will resolve the lesion. Surgical endodontic therapy is not necessary, even in the presence of large periradicular radiolucencies and periodontal abscesses. If primary endodontic lesions persist, despite extensive endodontic treatment, the lesion may have secondary periodontal involvement or it may be a true combined lesion.In case of secondary periodontal involvement, root canal therapy is instituted immediately and the cleaned and shaped root canal is filled with calcium hydroxide paste, which has bactericidal, anti inflammatory and proteolytic property, inhibiting resorption and favoring repair. It also inhibits periodontal contamination of instrumented canals via patent channels connecting the pulp and periodontium before periodontal treatment removes the contaminants. Treatment results should be evaluated after two to three months and only then should periodontal treatment be considered. This allows sufficient time for initial tissue healing and better assessment of the periodontal condition. Prognosis of primary endodontic disease with secondary periodontal involvement depends on periodontal treatment and patient response.Primary periodontal lesions should be treated first by proper hygiene phase therapy. Poor restorations and any developmental grooves that are difficult to be altered and make oral hygiene maintenance problematic for the patient should be removed. Periodontal surgery is performed after the completion of hygiene phase therapy. Pulpal pathology may be induced while carrying out periodontal therapy in lesions involving the furcation area. Periodontal therapy may consist of procedures that attempt to treat periodontal pockets and promote regeneration. The techniques used include new attachment techniques, gingivectomy, apically displaced flap, removal of the tooth side of pocket by tooth extraction or by hemisection or root resection. In such cases, root canal therapy is not indicated unless pulp vitality test results show change. Re-evaluation must be performed periodically after therapy to check for possible retrograde endodontic problems. The prognosis is entirely dependent on the periodontal therapy, in such cases. Early stage periodontal lesions with secondary endodontic involvement may present as reversible pulpal hypersensitivity, which can be treated purely by periodontal therapy. Periodontal treatment removes noxious stimuli, and secondary mineralization of dentinal tubules allows the resolution of hypersensitivity. If pulpal inflammation is irreversible, root canal treatment is carried out, followed by periodontal treatment. In some cases, periodontal surgical intervention is advantageous.The prognosis of periodontal lesions is poorer than endodontic lesions and is dependent on the apical extensions of the lesion. A favorable endodontic prognosis is obtained only when the tooth is in a closed and protected environment. As the lesion advances the prognosis approaches that of a true combined lesion.True combined lesions are treated initially as for primary endodontic lesions with secondary periodontal involvement. Prior to surgery, palliative periodontal therapy should be completed and root canal treatment carried out on the roots to be saved. The prognosis of a true combined perio-endo lesion is often poor or even hopeless, especially when periodontal lesions are chronic, with extensive loss of attachment. Root amputation, hemisection or bicuspidization may allow the root configurations to be changed sufficiently for a part of the root structure to be saved. The prognosis of an affected tooth can also be improved by increasing bony support, which can be achieved by bone grafting and guided tissue regeneration. These advanced treatment options are based on responses to conventional periodontal and endodontic treatment over an extended time period.Iatrogenic lesions like perforation during root canal instrumentation or preparation of the canal for post and core, require a surgical approach or sealing through an access cavity with a zinc oxide eugenol, glass ionomer or mineral trioxide aggregate sealing material immediately.The periodontal-endodontic lesion develops by extension of either periodontal destruction apically combining with an existing periapical lesion or an endodontic lesion marginally, combining with an existing periodontal lesion. From the diagnostic point of view, it is important to realize that as long as the pulp remains vital, although inflamed or scarred, it is unlikely to produce irritants that are sufficient to cause pronounced marginal breakdown of the periodontium.Inflammatory processes in the periodontium associated with necrotic dental pulp and periodontal disease have an infectious etiology. The essential difference between the two disease entities is their respective source of infection. Rarely will established endodontic lesions involve the marginal periodontium, unless they are developing close to the bone margin. A potential pathway for infectious elements in the root canal in such instances may be lateral canals.Acute manifestations of root canal infections can result in rapid and extensive destruction of the attachment apparatus. Abscesses may drain off in different directions, either through a sinus tract along the periodontal ligament space or through extra osseous fistulation into the gingival sulcus or pocket. Following proper endodontic therapy, these lesions should be expected to heal without a persistent periodontal defect.Many studies in the literature indicate that combined periodontal and endodontic therapy is essential for successful healing of a periodontal-endodontic lesion. It has been said that either endodontic or periodontic treatment alone would not lead to a satisfactory prognosis, if both disease entities are present and that both must be considered together.30 Hiatt The effect of periodontal inflammation on the pulp is controversial and conflicting studies abound.2033\u201336 I2037Treatment and prognosis of primarily endodontic and primarily periodontal disease is very straightforward. However, prognosis of combined forms of the lesions is more difficult to predict. Endodontic therapy is more predictable and completion of this therapy before periodontal procedures has a positive effect on periodontal healing. The most guarded prognosis is given for true combined lesions. In general, assuming that endodontic therapy is adequate, what is of endodontic origin will heal. However,"} +{"text": "Dear Sir,In response to the query raised by Dr. Taksande and his colleague on our pThe patient had mental retardation.The echocardiogram with Doppler showed cardiomegaly with thickened mitral and tricuspid valves."} +{"text": "Several diseases are known or suspected to be associated with altered levels of hormones and growth factors that may influence breast cancer risk. To elucidate this possibility, we studied the relationship between 23 medical conditions or procedures and breast cancer risk by means of data from a multicentric case-control study conducted between 1991 and 1994 in six Italian areas. The study included 2569 histologically confirmed incident cases of breast cancer and 2588 control women admitted to the same hospitals as cases for a variety of acute conditions unrelated to known or suspected risk factors for breast cancer. After allowance for education, parity and body mass index, elevated odds ratios (ORs) emerged for history of diabetes mellitus in post-menopausal women , hypertension in pregnancy and breast nodules . Risk decreases were associated with ovarian ablation for ovarian cysts and with thyroid nodules but not with the combination of any type of benign thyroid disease. While most examined conditions seemed unrelated to breast cancer risk, the association with late-onset diabetes is of special interest as it suggests a role of hyperinsulinaemia and insulin resistance in breast cancer promotion. It also points to preventive lifestyle modifications."} +{"text": "African nations, for example, have experienced rapid urbanization as well as tremendous expansion in industry and technology in an attempt to raise living standards and keep pace with the global community. But this trend has also exposed these nations to numerous modern environmental health hazards (MEHHs)\u2014health threats that tend to accompany rapid development in the absence of health and environmental safeguards. A review of the scientific literature suggests that such hazards have added considerably to Africa\u2019s disease burden and are increasing in public health significance The authors wrote that ongoing exposures to emerging MEHHs may soon rival the contributions of more traditional hazards\u2014including malaria, poor access to safe drinking water, and lack of basic sanitation\u2014that have long troubled Africa. Furthermore, poor and malnourished populations may be more vulnerable to the impacts of MEHHs, given that malnutrition increases susceptibility to toxicologic challenges. According to the United Nations Industrial Development Organization, Africa\u2019s pollution intensity (pollution generated per unit of production output) is among the highest in the world.Reviewing published epidemiologic, exposure, and environmental studies of chemical agents, the researchers noted ongoing occupational and nonoccupational exposures to organochlorine pesticides such as DDT and to heavy metals such as lead and mercury. All these pollutants are known to persist in the environment and accumulate in the food chain over time, as confirmed by biomonitoring studies of farmworker populations in several African nations. The authors also presented evidence of existing and emerging air toxics issues related to both indoor and outdoor air pollution, pervasiveness of toxic chemicals in consumer products (such as arsenic and chromium in canned beverages), and inadequate management of domestic and industrial waste streams.Relatively robust exposure data for lead showed elevated body burdens in African populations exposed to lead-bearing soil, dust, and paint, offering suggestive evidence of ongoing exposures to MEHHs at biological levels associated with adverse health impacts. Some studies found elevated body burdens of mercury in exposed populations such as miners, workers involved in ore processing, children who resided in mining communities, and women who habitually used soaps that contain high concentrations of inorganic mercury (such soaps are marketed as skin and hair lighteners). However, very few body burden studies have provided conclusive evidence of the relationship between heavy metal exposures and increased disease risks in African populations.Management of MEHHs in many African nations has long been hampered by a lack of various safeguards for environmental health, such as stable institutions, adequate infrastructure, monitoring capacity, and regulatory frameworks. The researchers proposed that MEHHs should occupy a priority spot on Africa\u2019s public health and policy agenda, and emphasized that future public health policy should consider these newer environmental health risks in tandem with other longstanding public health issues."} +{"text": "Duncan Clark and Howard Moss identify obstacles to alcohol-related screening and treatment for adolescents and propose policy solutions. Adolescent binge drinking and related disorders are worldwide public health problems For over a decade, governmental and professional organizations such as the World Health Organization (WHO), the US Surgeon General, the American Medical Association, and the American Academy of Pediatrics have called on health care practitioners to become more involved in providing screening, brief intervention, and referral for treatment (SBIRT) for adolescent drinkers Evaluate alcohol use as a routine part of risk behavior assessmentRecognize signs and symptoms of alcohol abuseDiscuss the hazards of alcohol useStrongly advise patients against the use of alcoholDiscourage parents from allowing underage drinking at homeRefer patients for further assessment and treatment as indicatedMost SBIRT recommendations do not take into consideration developmental changes that occur during the course of adolescence. For example, the WHO recommendations to health care practitioners providing SBIRT to young people are intended to apply to patients aged 10 through 24 years In our opinion, age-related emphases on promoting alcohol abstinence and identifying binge drinkers would improve the developmental specificity and applicability of SBIRT approaches. Particularly in younger adolescents, alcohol abstinence should be the SBIRT goal. In middle adolescence, screening for binge drinking would provide a focus for prevention activities and would also identify most adolescents with an AUD. Exclusively focusing on AUD is appropriate for patients in late adolescence.Several screening methods that target AUD have been developed for adolescents. Screening approaches recently studied include those based on alcohol use frequency Very brief screening methods have been described with promising results. Using one question on the frequency of drinking episodes, a threshold of three or more episodes per month was found to identify adolescents with AUD at 90% sensitivity and 84% specificity Our view is that none of the available screening methods has been shown to have the full complement of characteristics that would warrant widespread use. In addition to inconsistent psychometric results, the AUDIT and CRAFFT multi-item questionnaires utilize administration and scoring procedures that may not readily integrate into typical clinical practices. Additional research is needed to develop and validate very brief screening methods that may be applied by interview or questionnaire methods and may thus be readily incorporated into current and future clinical practices. Furthermore, the exclusive focus on AUD may miss opportunities to identify at-risk adolescents. Screening methods for patients in early and middle adolescence should incorporate the assessment of alcohol use patterns to facilitate preventive interventions.Interventions for the prevention and initial treatment of AUD in adolescents have been tested in a variety of health care settings, including emergency departments and college health clinics Encouraging results have been recently reported with some brief interventions implemented in health care settings. An approach called motivational interviewing was compared to feedback only in 198 adolescents and young adults with problem alcohol use seen in a US emergency department In our opinion, the extensive training and office intervention time required by motivational interviewing makes this approach unlikely to be adopted in primary care clinics or emergency departments. A consensus is needed to define the operating constraints in such settings that need to be considered in designing brief interventions. Web-based approaches may be more feasible, and additional research is needed to develop and test computer-assisted interventions for adolescents seen in health care settings.Relatively few major studies have examined the effects of treatment approaches on alcohol consumption outcomes for adolescents with AUD In our opinion, comprehensive treatment programs have been shown to be effective. The extent to which the less comprehensive treatment typically available is effective remains unclear. Even in the most affluent nations, there are shortages of specialized treatment programs and providers qualified to provide comprehensive treatment for adolescents with AUD Some adolescents have expressed apprehension that revealing their alcohol use may lead to conflicts with parents and other adverse consequences Clear practice policies regarding parental disclosure need to be established and communicated to parents and adolescents. Procedures for billing must ensure that confidential information is not inadvertently breached by billing codes and statements. The development and implementation of electronic data collection approaches may also improve adolescents' disclosure.In an evaluation of SBIRT for alcohol-related problems in 12 countries in Europe, Asia, and the Western Pacific, the WHO cites lack of governmental support and insufficient reimbursement as important obstacles to implementation In our opinion, insufficient support for alcohol-related SBIRT is evident in many countries. In the US, health insurance reimbursement rates and actual payments are typically insufficient, relative to the skills and time required, to fully support SBIRT practices. Fiscal and administrative support for SBIRT activities needs to reflect the resources required to provide these services.Health care practitioners have been exhorted to routinely provide SBIRT to underage drinkers by international, governmental, and professional organizations. Our evaluation of the status of these efforts indicates that substantial obstacles need to be overcome for this aspiration to be realized. In our view, these obstacles and their solutions are relevant in most of the countries facing significant problems with adolescent alcohol involvement. Our proposed solutions include a broader developmental perspective, the development of more effective prevention and intervention methods, and the provision of increased support for SBIRT services. SBIRT goals for adolescent patients need to be expanded from an exclusive focus on AUD to alcohol abstinence promotion and binge drinking prevention. Screening and assessment methods applicable in typical clinical practice settings need to be developed and validated. Brief interventions that are effective and feasible in typical health care settings need to be developed. While acknowledging that the interventions offered in the adolescent addiction treatment system are often imperfect, more comprehensive and systematic information about available local resources need to be accessible to health care practitioners. Confidentiality concerns need to be managed to facilitate adolescent participation. Adequate support for health care practitioners undertaking these challenging tasks will also be required. Despite these obstacles, many practitioners have been willing to provide SBIRT to their adolescent patients. Widespread routine implementation of SBIRT for underage drinkers in health care settings will occur when the clinical value of improved screening and brief intervention methods have been verified, adolescents may confidentially provide valid reports of their alcohol involvement without fear of reprisals, adolescent-focused addiction treatment services become more available and affordable, and health care practitioners are fairly compensated for these efforts."} +{"text": "A small (approximately 30) but varied group of organic and inorganic compounds appear to be carcinogenic in both humans and experimental animals. A much larger number and wider variety of chemical carcinogens, primarily synthetic organic compounds, are known for experimental animals. These agents include a small (approximately 30) and varied group of metabolites of green plants and fungi. Many more of these carcinogens must exist in the living world. As with the synthetic carcinogens, the majority of these naturally occurring carcinogens are procarcinogens that require metabolic conversion into reactive electrophilic and mutagenic ultimate carcinogens. These strong electrophiles combine covalently and non-enzymatically with nucleophilic sites in DNAs, RNAs, proteins, and small molecules in target tissues. One or more of the DNA adducts appear to initiate carcinogenesis in an irreversible manner. The subsequent promotion step leading to gross tumours may be completed by further administration of carcinogen or by treatment with non-carcinogenic promoters. Roles for the RNA and protein adducts in the carcinogenic process have not been excluded. Recent data on the metabolic activation and reactivity in vivo of the naturally occurring carcinogens ethyl carbamate and certain of the alkenylbenzene spice flavours are illustrative of these principles. These agents can initiate the carcinogenic process in male mouse liver with small doses given prior to weaning. Subsequent growth of the liver and male hormonal factors appear to function as promoters leading to gross hepatic tumors after one year. Reactive electrophilic metabolites of ethyl carbamate and of safrole and estragole and their nucleic acid adducts formed during initiation in mouse liver have been characterized."} +{"text": "The growth of mouse bone marrow colonies in agar diffusion chambers (ADCs) was evaluated using host mice injected with saline or with cyclophosphamide (CY) before chamber insertion. The mice pretreated with cyclophosphamide proved more effective hosts than control mice, indicating that cyclophosphamide causes the elaboration of a stimulating factor acting on colony precursor cells. Assays of the factor for colony stimulating activity against mouse bone marrow cells in agar culture in vitro suggest that potentiation may be due to a slight temporary increase in the level of colony stimulating factor (CSF) in the chamber environment, although a parallel increase was not detected in the serum. Stem cell recovery from the ADCs, measured by spleen colony formation, suggests that the stimulus may act by increasing differentiation at the level of the pluripotential stem cell."} +{"text": "Patients with obstructive jaundice have an increased perioperative complication rate. Sepsis, bleeding, wound problems, renal and liver malfunction are all seen in these patients. Assessment of immune function has been an active research area in these patients. This review will examine various aspects of immune functions in obstructive jaundice, discuss the recent research results and controversies and then go on to discuss the relevant mediators of immune function and some possible implications for treatment."} +{"text": "These sera did not, however, block the cytotoxicity of lymph node cells from tumour immune rats for cells of the immunizing tumour. In addition, the tumour specific rejection antigens and embryonic antigens have been shown to have dissimilar locations in tumour cells.The tumour specific antigens and tumour associated embryonic antigens expressed on chemically induced rat hepatomata and sarcomata have been shown to be different by means of blocking antibody studies. Serum from multiparous female rats contained blocking antibody which protected both tumour and embryo cells from the"} +{"text": "Adenosine deaminase has been assayed in lymphocytes, granulocytes and erythrocytes from 45 patients with haematological malignancies. Activities were uniformly low in lymphocytes from patients with chronic lymphocytic leukaemia. Variable, but abnormal activities were frequently found in multiple myeloma, untreated lymphoma and leukaemic reticuloendotheliosis. High values were observed in lymphocytes from patients with lymphoma during intensive combination chemotherapy. ADA levels in lymphocytes were not correlated with levels in granulocytes or erythrocytes. ADA was elevated in blasts of patients with acute lymphocytic and myelogenous leukaemias but the ranges of activities per cell were so similar that ADA assay is unlikely to be of major help in distinguishing the two diseases."} +{"text": "Various grafts have been used in the treatment of urinary incontinence and pelvic prolapse. Autologous materials such as muscle and fascia were first utilized to provide additional anatomic support to the periurethral and pelvic tissues; however, attempts to minimize the invasiveness of the procedures have led to the use of synthetic materials. Complications such as infection and erosion or extrusion associated with these materials may be troublesome to manage. We review the literature and describe a brief overview of grafts used in pelvic floor reconstruction and focus on the management complications specifically related to synthetic materials.We performed a comprehensive review of the literature on grafts used in pelvic floor surgery using MEDLINE and resources cited in those peer-reviewed manuscripts. The results are presented.Biologic materials provide adequate cure rates but have associated downfalls including potential complications from harvesting, variable tissue quality and cost. The use of synthetic materials as an alternative graft in pelvic floor repairs has become a popular option. Of all synthetic materials, the type I macroporous polypropylene meshes have demonstrated superiority in terms of efficacy and fewer complication rates due to their structure and composition. Erosion and extrusion of mesh are common and troublesome complications that may be managed conservatively with observation with or without local hormone therapy, with transvaginal debridement or with surgical exploration and total mesh excision, dependent upon the location of the mesh and the mesh type utilized.The ideal graft would provide structural integrity and durability with minimal adverse reaction by the host tissue. Biologic materials in general tend to have fewer associated complications, however, the risks of harvesting, variable integrity of allografts, availability and high cost has led to the development and use of synthetic grafts. Synthetic grafts have a tendency to cause higher rates of erosion and extrusion; however, these complications can be managed successfully. The use of graft materials in pelvic floor reconstruction is now a common practice. The evolution of grafts from autologous muscle and fascia has produced new materials that will hopefully prove to be efficacious and durable. This review aims to provide an overview of the different materials available for use in pelvic floor surgery and to discuss the potential complications, in particular erosion and extrusion, associated with synthetic materials.The decision to use a graft in the repair of the pelvic floor is based on a number of factors including the tissue quality of the patient, history of previous repairs and concomitant procedures to be performed. The ideal material should be strong, sterile, permanent, nonallergenic, inert, free of risk of infection, infectious transmission, erosion and extrusion and affordable. In 1997,in vivo tissue remodeling and reduced erosion rates. Tab Tab18] TAs discussed previously, erosion or extrusion of the mesh is thought to be associated with the type of synthetic material used. However, patient factors such as poorly controlled diabetes mellitus, tobacco use, prior history of pelvic irradiation, repeat procedures and vaginal estrogen status may also contribute to poor wound healing and subsequent infection, erosion or extrusion. Some studies have suggested that concomitant hysterectomy may be an additional risk factor for extrusion of the sacrocolpopexy mesh.31 SurgicWhile repairs requiring greater dissection tend to have higher rates of complications, the placement of slings via the transvaginal versus transobturator route do not appear to play a significant role in the risk of erosion or extrusion in the literature available to date. Prospective randomized trials that compare sling placement techniques are currently in progress.de novo stress urinary incontinence, urgency, hematuria or urinary tract infection or obstruction. In the experience of the authors, physical exam findings can usually identify extrusion of mesh components on pelvic exam. However, in cases of high suspicion without visualization of extruded mesh, exam under anesthesia may be necessary. It is of utmost importance to evaluate the urinary tract with cystourethroscopy to rule out erosion of material into the bladder or urethra, particularly if the patient presents with hematuria, recurrent urinary tract infections, irritative or obstructive symptoms, de novo urgency or bladder stones. In addition, we have noted from our own experience that over 30% of patients with vaginal extrusions required exam under anesthesia in order to adequately identify their extrusion sites, demonstrating the importance of a high index of suspicion for extrusion in those with clinical indications.Patients who present with vaginal extrusion or urinary tract erosion may demonstrate a variety of symptoms, but they may be completely asymptomatic. Usual presenting symptoms include vaginal discharge, pain, dyspareunia, complaints of pain from the partner during intercourse, Management is based on the type of material, presence of infection and location of erosion or extrusion. From our own experience and from review of the literature, we have found that extrusion of Type I polypropylene mesh into the vagina may be managed conservatively with abstinence from sexual intercourse, local estrogen replacement therapy and antibiotics if associated infection is noted.33 The cl1Persistent infection or failure to epithelialize over a type I mesh warrants complete mesh excision . The appVaginal extrusion of type II, III and IV meshes generally requires complete excision due to higher risks of infection and poor healing rates. As with type I mesh, excision may be performed transvaginally if the exposed graft can be removed completely with adequate debridement and reapproximation of vaginal epithelium. Ironicalet al. Of 14 patients that presented with complications following pubovaginal sling placement, two were noted to have erosion of mesh into the bladder and both were managed by endoscopic sling and/or suture removal. At one month follow-up, both patients' symptoms had resolved and both were continent.[Erosion into the urinary tract mandates complete removal of mesh regardless of mesh type . Erosionontinent. One mustUrinary tract erosion of mesh that has been used in sacrocolpopexy may be addressed via laparoscopy or laparotomy with retroperitoneal graft excision.et al. In a review of nine patients who presented with erosion of graft material into the urethra, three were from synthetic grafts that were excised and repaired as described. At a mean follow-up of 30 months, no urethral erosion or fistulas occurred, however, stress incontinence recurred in two of the three patients.[et al recommend urethral catheter drainage for two weeks with a pull-out cystourethrogram at the time of catheter removal.[Urethral erosions require urethrolysis with graft explantation. Urethral debridement followed by primary repair and multilayer closer with a Martius flap has been described by Amundsen patients. Clemens removal.et al report three patients with mesh noted in the bladder following pubovaginal placement of polypropylene mesh tape. All three underwent successful laparoscopic removal of the mesh and at six months follow-up, two of the three patients continued to have complaints of stress and urge incontinence without further mesh erosion into the bladder.[et al describe three cases of vaginal mesh extrusion following abdominal sacrocolpopexy treated by transvaginal endoscopic excision of mesh. All three patients continued to have excellent support with adequate tissue healing at follow-up (six weeks to one year).[et al. Two cases of bladder erosion following TVT were managed using cystoscopic excision combined with traction from laparoscopic grapsers through a small suprapubic port. One of the patients had follow-up office cystoscopy at six weeks that showed appropriate resolution with no persistent mesh in the bladder.[Newer techniques have been described in the treatment of mesh extrusion and erosion. Laparoscopic excision of mesh associated with bladder erosion and transvaginal endoscopic removal of mesh after sacrocolpopexy have been described.36 Pikaarne year). A techni bladder.Continence rates following mesh removal have been variable and often dependent on the amount of dissection performed and presence of infection. Reported rates of continence have ranged from 42-100%.343834Synthetic mesh has become a popular option for pelvic reconstruction. The potential complications of urinary tract erosion and vaginal extrusion are dependent on multiple factors including mesh type and patient tissue integrity. However, review of short and intermediate term data from the literature has shown that amongst synthetic grafts, type I mesh provides durable results with the fewest rates of erosion and extrusion. In addition, viable management options for vaginal extrusion include conservative approaches such as observation with or without local estrogen administration. While all materials, synthetic and biologic alike, have advantages and disadvantages in the treatment of pelvic floor disorders, synthetic materials may provide a safe and cost-effective alternative for pelvic reconstructive surgery."} +{"text": "The results from an international survey of 15 major cancer centres have clarified how randomization is being implemented in cancer trials. As regards the mechanics of obtaining treatment assignment for each patient a system of telephone registration to a central randomization office was widely used. We also advise formal checks for patient eligibility immediately before treatment assignment, and subsequent written confirmation of randomization to the investigators. As regards statistical methods, stratification of randomization by one or two prognostic factors is commonplace. Most centres used the standard approach of random permuted blocks within strata though some others used \"dynamic\" institution-balancing or \"minimization\" methods instead. The value of stratified allocation is chiefly for the trial's credibility in having comparable treatment groups, rather than for statistical efficiency. One should avoid overstratification and use only the really important prognostic factors. One essential is that randomization should in practice work for every patient, so undue complexity is to be avoided."} +{"text": "Statistically significant correlations have been demonstrated between carcinogenic activity, toxicity and number of carbons per molecule for an extensive set of nitrosamines. Such correlations, involving only bulk molecular properties indicate that the chemical nature of the alkyl substituents need not be the sole determinants of carcinogenic activity. These structure-activity relationships can be used to estimate carcinogenic activity with some degree of confidence."} +{"text": "Understanding how people of diverse cultural backgrounds have traditionally used plants and animals as medicinal substances during displacements is one of the most important objectives of ethnopharmacological studies. An ethnopharmacological survey conducted among migrants living in the Southeast Atlantic Forest remnants is presented herein.Ethnographical methods were used to select and interview the migrants, and botanical and zoological techniques were employed to collect the indicated resources.Impatiens hawkeri W. Bull., Artemisia canphorata Vill., Equisetum arvensis L., Senna pendula (Humb. & Bonpl. ex Willd.) H.S. Irwin & Barneby, Zea mays L., Fevillea passiflora Vell. and Croton fuscescens Spreng)] and the two animals (Atta sexdens and Periplaneta americana) that showed maintenance of use among migrants during their displacement in Brazilian territory, have not been studied by pharmacologists yet.We interviewed five migrants who described knowledge on 12 animals and 85 plants. Only 78 plants were present in Diadema, they belong to 37 taxonomic families; 68 were used exclusively for medicinal purposes, whereas 10 were reported to be toxic and/or presented some restriction of use. These taxa were grouped into 12 therapeutic categories based on the 41 individual complaints cited by the migrants. While the twelve animal species were used by the migrants to treat nine complaints; these were divided into six categories, the largest of which related to respiratory problems. None of the animal species and only 57 of the 78 plant species analysed in the present study were previously reported in the pharmacological literature; the popular knowledge concurred with academic findings for 30 of the plants. The seven plants [Thus, they should be highlighted and focused in further pharmacology and phytochemical studies, since the persistence of their uses can be indicative of bioactive potentials. Cultural mixing mediated by the migration of people around the world has generated increasing interest in recent years within the field of ethnopharmacology . Medicin2 and the two animals (Atta sexdens and Periplaneta americana) that showed maintenance of use among migrants during their displacement in Brazilian territory, have not been studied by pharmacologists yet. These species should be highlighted in further investigations because the maintenance of use during human migrations can be indicative of bioactive potential.The seven plants [This work also demonstrates the impossibility of sharing benefits related to property rights with cultures under certain circumstances, as the dynamic use of natural resources presents particularly varied influences. The interviewed migrants had passed through several Brazilian cities and were exposed to distinct vegetation and cultures. In this migration, they have passed on and incorporated knowledge in an intensive exchange where formulas and uses are mixed and re-invented as a result of contact between cultures.The authors declare that they have no competing interests.Author DG performed the fieldwork. Author MVD identified the animal specimens. Author ER supervised the research works. All authors drafted, wrote, read and approved the final manuscript."} +{"text": "This is possibly due to exogenous polyamine salvage from the host, which replenishes the intracellular polyamine pool. This implies that disruption of polyamine metabolism as an antimalarial chemotherapy strategy may require targeting both polyamine biosynthesis and transport simultaneously. In the absence of a clear understanding of the uptake mechanism of polyamines into Plasmodium falciparum parasites, polyamine transport into both the infected erythrocytes and parasites isolated from the erythrocyte were investigated using radioisotope flux techniques. While the characteristics of transport of putrescine into infected erythrocytes (iRBC) were similar to those of transport into uninfected erythrocytes (RBC) spermidine uptake occurred via the new permeability pathways (NPP) induced by the parasite in the erythrocyte membrane. Once inside the erythrocyte cytoplasm, both putrescine and spermidine are taken up by the parasite via a temperature- and glucose-dependent, saturable process. The uptake of both these polyamines was competed for by other polyamines and biosynthesis inhibition led to increased total uptake of both putrescine and spermidine. Polyamine uptake was pH dependent with uptake increasing with increasing pH, but did not appear to be coupled to the Na+ or K+ gradients. Membrane potential perturbations influenced polyamine uptake, consistent with the transport being an electrogenic process.Polyamines are present at high levels in proliferating cells, including cancerous cells and protozoan parasites and the inhibition of their synthesis has been exploited in antiproliferative strategies. Inhibition of the malaria parasite's polyamine biosynthetic pathway causes cytostatic arrest in the trophozoite stage but does not cure"} +{"text": "We report a case of a patient presenting with neuropsychiatric manifestations secondary to paradoxical embolismUnexplained rapid onset of confusion with amnesia and minimal neurological deficits can be a manifestation of various systemic causes of which stroke, either ischemic or hemorrhagic, is one. Thorough and systematic evaluation of these patients can be highly rewarding in terms of optimizing patient outcome. We report the case of a 45-year-old woman whose initial presentation was with acute onset of confusion, memory loss with personality change and headaches. A differential diagnosis of systemic illness and cerebral pathology was entertained. She was empirically treated for neurological infection. Brain imaging revealed bilateral thalamic and cerebellar infarction. Further evaluation with an aim to define the etiology, revealed the diagnosis of Patent Foramen Ovale with paradoxical embolism. The differential diagnosis of unexplained rapid onset of confusion, amnesia with minimal motor neurological deficits and relevant appropriate investigations are discussed in this case report.This case highlights the importance of recognising the atypical manifestations of posterior fossa stroke. In young patients presenting with non-focal neuropsychiatric manifestations, paradoxical embolism, secondary to patent foramen ovale is a possible cause. Confusion is a common cause of admission in the older population. Though not as common in younger patients, unexplained rapid onset of confusion with amnesia and minimal neurological deficits can be a manifestation of various systemic causes of which stroke, either ischemic or hemorrhagic, is one. Thorough and systematic evaluation of these patients can be highly rewarding in terms of optimizing patient outcome.A 45-year-old woman was admitted with acute onset of short-term memory loss, intermittent headaches, dizzy spells and an obvious change in personality which had progressed over a ten day period. Intermittent vomiting, confusion and unsteadiness were also reported. These symptoms worsened over the three days prior to admission. Her past medical history included an episode of herpes simplex virus infection about one month earlier. A non-smoker, she consumed alcohol in moderation.On examination, she had disorientation of time and place and her mini mental score was found to be 2/10. Confusion with nominal aphasia was also noted. She was apyrexial. Cardiovascular, respiratory and gastrointestinal system examination was unremarkable. Neurological examination showed normal power and tone in both arms and legs with normal symmetrical deep tendon reflexes. Her gait, coordination, cranial nerve and fundus examination were normal.Investigations revealed a normal full blood count and unremarkable routine biochemical tests and inflammatory markers. Contrast enhanced CT of the brain showed low attenuation areas adjacent to the anterior ends of both thalami. Appearances were reported as an unusual form of cerebral infarctions and it was suggested that other pathology could not be ruled out.Examination of CSF revealed isolated lymphocytosis. Glucose and protein were normal. Polymerase Chain Reaction (PCR) tests for herpes simplex virus and varicella zoster were negative.Electroencephalogram (EEG) recordings showed intermittent low frequency activity suggesting focal abnormality of cortical function, probably associated with a vascular or structural lesion but no clear evidence of encephalitis or epileptiform activity. On MRI scan Figure of the hOver a period of two weeks there was a progressive worsening of confusion, with increasing agitation, memory impairment and personality change. With deterioration in Glasgow Coma Scale (GCS), the possibility of other systemic causes was considered. She was empirically treated for encephalitis and/or viral meningitis and a possibility of vasculitis was considered, for which a trial of methylprednisolone and cyclophosphamide was given without any significant benefit. Further investigations, looking for a possible systemic cause, by an autoantibody screen including anti-neutrophil cytoplasmic antibodies and a vasculitic screen was reported as normal.A saline contrast transthoracic echo confirmed a diagnosis of Patent Foramen Ovale (PFO) as a significant number of microbubbles appeared in the left atrium within 3 cardiac cycles of their appearance in the right atrium and this was facilitated with valsalva release. Further assessment for atrial septal separation was not done with transesophageal echocardiogram because of the above positive findings from the transthoracic echocardiogram.A diagnosis of embolic basilar artery ischemic stroke with thalamic and cerebellar infarcts secondary to paradoxical embolism via the PFO was made. She was started on aspirin and clopidogrel and later anticoagulated with warfarin before she underwent percutaneous device closure.There are three treatment options in patients with a presumed paradoxical embolism and PFO.1. Antiplatelet therapy with aspirin2. Oral anticoagulation with warfarin3. Surgical or percutaneous device closureDespite the growing evidence for association between PFO and atrial septal aneurysm with paradoxical embolism causing neurological events there is no consensus as how to treat a cryptogenic stroke and none of the above treatments have been evaluated in randomised controlled trials.There was a gradual improvement over four weeks and subsequently the patient went on to have a complete recovery without any neurological or physical residual effects.Later she underwent percutaneous endovascular closure of the PFO with a Biostar device. In our patient percutaneous device closure was used because of her young age and absence of deep vein thrombosis or procoagulant state. It was felt inappropriate to leave the patient on life long warfarin with all the risks that anticoagulation might entail. Our patient had further follow up after the device closure of the PFO and had had no further episodes of transient ischaemic attack or any recurrence of stroke.The incidence of cerebellar infarction in a series of patients with stroke is approximately 1.5% . The comNater et al reported an increased frequency of posterior circulatory stroke in patients with patent foramen ovale and atrial septal aneurysm . CardioeThe functional anatomy of the cerebellum and thalamus needs to be addressed in order to better understand the spectrum of clinical features that can be seen in stroke involving these structures.Cerebellar pathology commonly shows important motor signs and less evident cognitive dysfunction. But various studies have strDysarthria and ataxia are prominent in infarcts involving the area supplied by the superior cerebellar artery, whereas lesions involving the inferior cerebellar artery, especially the posterior inferior cerebellar artery, lead to vertigo, headache and vomiting . The othSimilarly the thalamic blood supply is derivTherefore behavioral and cognitive problems are recognized manifestations of both cerebellar and thalamic infarcts involving the anterior or paramedian nucleus.Sometimes encephalitis if relatively focal in distribution can look exactly like an infarct on neuroimaging. The typical appearance of encephalitis with the involvement of the medial temporal lobes is sometimes difficult to differentiate and occasionally cerebritis can also mimic infarction .The clinical picture in our patient though still manifesting within the spectrum of features of cerebellar with posterior inferior cerebellar artery territory and thalamic stroke involving the anterior nucleus was difficult to correlate with the diagnosis. This was because the cognitive impairment overshadowed, and was the predominant clinical manifestation, with there being minimal motor impairment. The other differential diagnoses that need to be ruled out by appropriate investigations are meningitis, encephalitis and vasculitis.The clinical picture in our patient was neuropsychiatric manifestations without any focal deficits. The symptoms of confusion, memory impairment and personality changes pointed more towards a non-focal neurological cause. After a systematic evaluation, the diagnosis of posterior fossa stroke due to paradoxical embolism was made. This case highlights the importance of thorough evaluation, to rule out systemic causes, while at the same time bearing in mind that it could be an atypical presentation of stroke, especially involving the cerebellum and thalami. The investigations should be directed towards evaluating the etiology in a stepwise manner, to optimise patient care and outcome.Anti-neutrophil cytoplasmic antibody (ANCA), Glasgow coma scale (GCS), Magnetic resonance imaging (MRI), Computed tomography (CT), Patent foramen ovale (PFO)The author(s) declare that they have no competing interests.All authors have contributed equally and have given approval of the version to be published.Written informed consent was obtained from the patient for the publication of the case report and accompanying images. A copy of the written consent is available for review by the Editor-in Chief of this journal."} +{"text": "Outbreak investigations, an important and challenging component of epidemiology and public health, can help identify the source of ongoing outbreaks and prevent additional cases. Even when an outbreak is over, a thorough epidemiologic and environmental investigation often can increase our knowledge of a given disease and prevent future outbreaks. Finally, outbreak investigations provide epidemiologic training and foster cooperation between the clinical and public health communities."} +{"text": "To examine the relationship of dietary and serum vitamin A to the risk of cervical dysplasia, a case-control study was conducted in Miyagi, Japan. Cases were 137 women who were found by Papanicolaou test screening and histological examination provided by Miyagi Cancer Society between October 1987 and September 1988 to have cervical dysplasia. Controls were selected from participants of the general health examination provided by the Society and individually matched to cases on age and screening date. The consumption of retinol or carotene-rich foods during the past 7 days was assessed at interview. Information was also collected about other risk factors of cervical dysplasia, such as reproductive histories and sexual behaviour. The mean serum retinol levels were significantly lower among cases compared with controls, although dietary intake levels of retinol and carotene were not different between the two groups. When examined by tertile, the risk of cervical dysplasia was significantly higher among women in the highest tertile of dietary vitamin A level. An inverse association was observed between serum retinol level and risk of cervical dysplasia, although it did not achieve statistical significance."} +{"text": "Adenosine deaminase has been measured in the blast cells of 36 patients with acute lymphoblastic, acute myeloid, chronic myeloid and chronic myeloid blast crisis leukaemia. Particularly high levels were found in acute lymphoblastic and chronic myeloid blast crisis patients. The measurement of ADA may be useful diagnostically in the undifferentiated acute leukaemias and in detecting the early onset of blast crisis in chronic myeloid leukaemia. Possible reasons for the elevation of ADA in malignant cells are discussed."} +{"text": "Recent reports of strong selection of mitochondrial DNA (mtDNA) during transmission in animal models of mtDNA disease, and of nuclear transfer in both animal models and humans, have important scientific implications. These are directly applicable to the genetic management of mtDNA disease. The risk that a mitochondrial disorder will be transmitted is difficult to estimate due to heteroplasmy\u2014the existence of normal and mutant mtDNA in the same individual, tissue, or cell. In addition, the mtDNA bottleneck during oogenesis frequently results in dramatic and unpredictable inter-generational fluctuations in the proportions of mutant and wild-type mtDNA. Pre-implantation genetic diagnosis (PGD) for mtDNA disease enables embryos produced by in vitro fertilization (IVF) to be screened for mtDNA mutations. Embryos determined to be at low risk can be preferentially transferred to the uterus with the aim of initiating unaffected pregnancies. New evidence that some types of deleterious mtDNA mutations are eliminated within a few generations suggests that women undergoing PGD have a reasonable chance of generating embryos with a lower mutant load than their own. While nuclear transfer may become an alternative approach in future, there might be more difficulties, ethical as well as technical. This Review outlines the implications of recent advances for genetic management of these potentially devastating disorders. One in 400 people carries pathogenic mitochondrial DNA (mtDNA) mutations Chorionic villus sampling has been extremely successful in preventing recurrence of Mendelian genetic diseases, but not for maternally inherited diseases, caused by mutations in the mtDNA, because of the problem of heteroplasmy Heteroplasmy is one reason why the clinical severity of mtDNA disorders is highly variable and can progress with time. In mtDNA disease patients the level of mutant mtDNA commonly Factors that affect segregation of mtDNA variants include the biological fitness of dividing cells, the mutant load, and any differences between wild-type and mutant mtDNA in the rate of replication and degradation. While accumulation of mutant mtDNA can sometimes be attributed to genetic drift Analysis of segregation of mtDNA mutants in tissue culture often uses \u201ccybrid\u201d technology, where mtDNA-free immortalized cells are fused with cytoplasm containing the mitochondria under investigation. Because such cells are aneuploid, some investigators dismiss this model as non-physiological Genetic counseling of women who are carriers of mtDNA diseases is complex because the dose of mutant mtDNA transmitted to offspring may be determined by the so-called \u201cmitochondrial bottleneck\u201d Recent studies have carefully quantified mtDNA copy number of individual cells during mouse development In humans, although the meiotic division is initiated in the germline of the developing foetus during the last trimester of pregnancy, primary oocytes remain arrested in the first stage of the meiosis during the years between birth and puberty. In women of reproductive age, a group of oocytes is selected to grow and resume meiosis every cycle of \u223c28 days. In most cases this results in the production of a single developmentally competent oocyte. It is possible that clonal expansion of a subpopulation of mtDNA during folliculogenesis in mice (between the stages of primary and mature oocyte) may correspond to the mitochondrial bottleneck Three studies suggest that there is selection against detrimental mtDNA mutants in the mouse germline. One group developed a mouse with mtDNA rearrangements modelling Kearns-Sayre syndrome PolgA, and this generates high levels of point mutations in the mtDNA. The homozygous founder female mice were crossed with wild type and transmitted multiple mtDNA mutations (on average 30 mutations per first generation mouse) to their offspring who were heterozygous for the PolgA mutation. Subsequent backcrossing eliminated the mutant PolgA allele and hence mtDNA mutants were passively transmitted without generating further mutations. It was thus possible to observe and compare the segregation of multiple different mtDNA mutations in a single lineage. Neutral mutations that do not alter the protein sequence undergo less selection than those that do. Purifying selection can therefore be compared with neutral drift by the relative frequency of such mutations. Clonal selection against deleterious mutations occurred in a remarkably short time frame. Indeed, many deleterious mutations were eliminated within four generations. However, selection was stronger and occurred more rapidly against mutations in genes encoding mRNAs than tRNAs. This may be linked to the apparently high frequency of pathogenic human mtDNA mutations that are identified in tRNAs Another group investigated the transmission of randomly generated mtDNA mutations in a mouse model of mtDNA disease A third study, focussing on two pathogenic mtDNA point mutations, again demonstrates selection in mouse But what is the basis of the selection seen in mice and potentially in humans? Only 30% of oogonia established during fetal life develop into matured oocytes, the remainder undergoes apoptosis A second possible mechanism for selecting against mutant mtDNA is selection at the organelle level. The number of mtDNA copies per mitochondrion in germ cells is thought to be as few as one or two molecules, in comparison to eight or so in somatic cells A third possible mechanism is specific to oocytes, based on a structure known as the Balbiani body or the mitochondrial cloud Whatever the underlying mechanism, something occurring during early oogenesis and/or folliculogenesis seems to provide a degree of selection against mutant mtDNA molecules. Studies by Sato et al. Genetic management of patients with mtDNA disease depends on understanding both germline segregation and the physiological basis of the bottleneck. However, the published human data where oocytes are compared with load in maternal post mitotic tissues are minimal Oocyte donation would avoid all the problems associated with the presence of mutant mtDNA, but there is a shortage of oocyte donors. Pre-implantation genetic diagnosis for mitochondrial disease could be the best option for patients carrying high levels of mutant mtDNA While PGD clearly has enormous promise for women with sub-clinical levels of mtDNA mutations Since Dolly the sheep was created by fusing an adult somatic cell with a recipient enucleated oocyte, producing in Dolly mtDNA inherited not from the somatic cell donor but the recipient oocyte Recently, Tachibana et al. A different procedure, ooplasm donation (cytoplasm from a donor oocyte), offers an alternative Will any of these procedures be viable alternative strategies to more conventional genetic management? Nuclear transfer sounds simple and seems effective in mice In conclusion, the many ethical, scientific, and pragmatic problems have been a major impediment in the genetic management of mtDNA diseases. Recent experiments on animals suggest that nuclear transplant holds future promise. Currently, the most ethical course of action may be to weigh-up the uncertainties and use new approaches such as PGD in an attempt to help these distressed families."} +{"text": "Adisruption of the dynamic equilibrium of the healthy vagina may have significant sequelae, leading to chronic or serious conditions. Therefore, all cases of vaginitis should be accurately diagnosed and appropriately treated."} +{"text": "The phylogenetics of the genus Alphavirus have historically been characterized usingpartial gene, single gene or partial proteomic data. We have mined cDNA andamino acid sequences from GenBank for all fully sequenced and some partiallysequenced alphaviruses and generated phylogenomic analyses of the genus Alphavirusgenus, employing capsid encoding structural regions, non-structural coding regionsand complete viral genomes. Our studies support the presence of the previouslyreported recombination event that produced the Western Equine Encephalitis clade,and confirm many of the patterns of geographic radiation and divergence of themultiple species. Our data suggest that the Salmon Pancreatic Disease Virus andSleeping Disease Virus are sufficiently divergent to form a separate clade fromthe other alphaviruses. Also, unlike previously reported studies employing limitedsequence data for correlation of phylogeny, our results indicate that the BarmahForest Virus and Middelburg Virus appear to be members of the Semliki Forestclade. Additionally, our analysis indicates that the Southern Elephant Seal Virusis part of the Semliki Forest clade, although still phylogenetically distant from allknown members of the genus Alphavirus. Finally, we demonstrate that the wholeRubella viral genome provides an ideal outgroup for phylogenomic studies of thegenus Alphavirus."} +{"text": "Endocardial lesions are caused not only by inflammatory processesbut also by myocardial ischemia, resulting in endocardialthrombosis and cerebral embolism. We deviced a method for directvisualization of endocardial damages by a novel dye imagecardioscopy with Evans blue and examined its feasibility inpatients with heart disease. The dye was injected into the leftventricle before and after endomyocardial biopsy. Endocardialsurface was stained in dark blue in 63% of patients withangina pectoris before biopsy. After biopsy, the biopsied portionswere stained in blue in all. The results indicate that endocardiumis damaged even in apparently intact LV in patients with ischemicheart disease and that endomyocardial biopsy causes severeendocardial damages."} +{"text": "The many diverse functions executed by the central nervous system (CNS) are mirrored in the diverse shapes, connections, and firing patterns of its individual neuronal cell types. Furthermore, distinct neurological diseases are the result of defects in specific neuronal cell types. However, despite the significance of this cellular diversity underlying brain function and disease, we know relatively little about the genes that contribute to purposeful differences among regions and cell types within the brain. A major challenge in this endeavor is the paucity of markers that define the many regions and cell types thought to exist. Cataloging the neuronal cell types and cell- and region-specific marker genes requires novel avenues that enable researchers to define gene expression profiles of brain regions and individual neurons and to apply this information to understand functional and structural properties in the normal and diseased brain. Functional genomic approaches such as gene expression profiling offers the exclusive opportunity to glimpse the detailed inner workings of distinct neuronal cell types. Recent studies have applied microarray technology in unique and novel ways to understand the molecular mechanisms that underlie such neuronal diversity and their potential role in brain diseases. A major challenge in understanding brain development and function is the enormous complexity of the central nervous system (CNS). The complexity of the mammalian brain is reflected in the diverse cell types of its neuronal constituents - their vastly different morphologies, synaptic connections and functional properties. Recent reviews have discussed in detail the working definition of a neuronal cell type based on various criteria , 2 and wSince the introduction of microarray technology and the establishment of the field of functional genomics almost fifteen years ago -5, reseaIn answering this question, it is critical to understand why gene expression profiling in the brain is so important in the first place. The human genome contains approximately ~30,000 genes ,14 the fhttp://www.knockoutmouse.org/) to knock-out every gene in the mouse genome will provide an amazing database of information to mined with regard to understanding candidate genes from expression profiling approaches in brain function and disease.In the past few years, significant progress has been made in our understanding of brain organization by the application of functional genomic approaches to characterize gene expression in defined cell types . In geneBelow I provide a review of published studies analyzing gene expression in defined neuronal populations or specific brain regions with emphasis on recent studies that have led to the identification and characterization of candidate genes involved in brain function and disease \u2013 a goal for which expression profiling was expected to have a major impact a decade ago. In addition, I highlight novel approaches to analyze gene expression data and follow-up studies that have moved beyond the usual end-point of generating lists of candidate genes.From the beginning, reports of gene expression profiling in human brain tissues revealed interesting insights into diseases of the brain. For example, gene expression profiling of prefrontal cortical tissue from age-matched pairs of schizophrenic and control subjects showed a decrease in messages encoding proteins involved in the regulation of presynaptic function correlated with the schizophrenia subjects . The basIn general, gene expression studies aimed at identifying transcripts present in subsets of neurons or expressed at low levels are complicated by the cellular heterogeneity of the brain . For exaThis general issue led to the application of biostatistical approaches such as linear modeling and regression analysis of microarray data to \u2018deconvolute\u2019 expression profiles derived from whole brain regions . In thisdifferentiation by antagonizing Nmyc-mediated proliferation [Ultimately, this study identified groups of genes representing the early specification of granule neuron precursors (GNPs), the proliferation of this cellular pool, and finally the later stages of granule neuron differentiation . While sferation . That isWith regard to brain disease, previous studies showed that aberrant Shh signaling contributes to cerebellar tumors in both mice and humans and Nmycbetween brain regions, this strategy takes advantage of the inherent variability associated with gene expression profiles that exist within brain regions \u2013 that is, biological replicates from a single brain region - to define higher-order relationships among gene products. Using this approach, Oldham and colleagues defined gene coexpression relationships in microarray studies generated from specific human brain regions. Comparison of conserved gene modules from different brain regions then led to the identification of coexpressed genes that correspond to distinct cell types including neurons, oligodendrocytes, astrocytes and microglia [More recently, other bioinformatics methods such as systems biological approaches have been developed to identify groups of genes, or \u2018modules\u2019, with highly correlated expression levels in brain regions . To defiicroglia , demonstThe application of WGCNA to normal and diseased brain might then provide a means to reveal biological relationships of the phenotypic source of the observed transcriptome changes not apparent with traditional analysis of differential gene expression. For example, despite the fact that Alzheimer\u2019s disease is the most common and well studied neurological disorder of the elderly, no coherent picture of the pathology underlying this disease has emerged from previous microarray expression studies in part due to artifacts associated with collection of postmortem samples or with different microarray platforms often resulting in non-overlapping gene lists . Miller In addition to bioinformatics approaches, other avenues of research were applied early on to understand gene expression in neuronal cell types. Early reports were successful in generating expression profiles from single neurons isolated by laser capture microdissection (LCM) for microarray expression analysis , 41; howAn alternative strategy to circumvent the need to analyze individual cells is to isolate pools of defined neuronal subtypes labeled by transgenic or tracer injection methods (reviewed in ). For inin vivo and compared their gene expression to two other pure populations of cortical projection neurons: callosal projection neurons and corticotectal projection neurons [In addition, other methods such as fluorescent activated cell sorting (FACS) have been used successfully to isolate labeled neuronal cell types (reviewed in ). For ex neurons . The ide neurons , providiIn more recent studies, these same authors then went on to show that Ctip2 also plays a role in striatal medium spiny neurons (MSN) differentiation and development . MSNs arOther studies have pursued similar methods to isolate defined neuronal populations using FACS but with different methods to label the cells (reviewed in ). For exThe results of this study might impact brain disorders of the basal ganglia by the identification of candidate genes to follow-up on in future studies. Interestingly, two of the most promising identified genes (Dock3 and Slc35d3) have some known association with movement disorders. Dock3 has been implicated in one family with an attention deficit and hyperactivity disorder (ADHD)-like clinical syndrome while SlA common concern for using approaches such as FACS and LCM is that these cell isolation techniques themselves might actually introduce variability into the resulting expression data. It will be useful therefore to compare the results from studies utilizing different approaches to isolate samples but from the same brain region and disease. For example, Parkinson's disease is caused by a progressive loss of the midbrain dopamine (DA) neurons in the substantia nigra. Moran and colleagues analyzed brain tissue from clinically well-documented and pathologically documented cases of sporadic Parkinson's disease to define expression profiles corresponding to medial and lateral substantia nigra . After eIn contrast, Simunovic and colleagues used LCM to isolate dopaminergic neurons from the substantia nigra of control subjects and individuals with idiopathic Parkinson's disease matched for age and postmortem interval followed by microarray analysis to document gene expression changes .Both studies identified genes previously implicated in Parkinson\u2019s disease based on published literature , 51. In A particularly interesting idea is to molecularly \u2018tag\u2019 the mRNA population within a defined neuronal subtype to allow selective analysis of a particular cell type of interest. For example, Von Stetina and colleagues profiled gene expression throughout the nervous system in worms by generating a stable, chromosomally integrated transgenic line expressing an epitope-tagged poly-A binding protein throughout the nervous system . Such taIn addition, deep sequencing methods allow direct ultra-high-throughput sequencing of RNA, which can then be mapped back to the genome (reviewed in ). HoweveThe past decade has witnessed three orders of magnitude increase in the information available regarding microarrays and gene expression in the brain. While we have just begun to make significant inroads into the characterization of candidate genes identified in the various expression profiling studies, clear evidence emerges demonstrating the potential impact of these and other approaches. However, moving from gene lists, coexpression modules, or \u2018hub\u2019 genes to function in brain disorders still remains a major challenge in most expression profiling studies. Transcriptome studies by definition are correlation based, not causative. Thus, researchers pursuing expression studies should first have a plan mapped out for future research to determine how one will demonstrate function of potential candidate genes identified in their experiments.A particularly important avenue of future research is the simultaneous genome-wide analysis of gene expression and genetic variation to map genetic factors that underlie individual differences in quantitative levels of expression . In theEven though to date there are no publications utilizing this methodology to identify genes that influence brain disease progression, a modification of this method has been applied to mouse inbred strains to identify genes that influence the volume of the amygdala, a brain region that regulates emotion . In this"} +{"text": "Endothelin (ET) peptides perform several physiological, vascular,and nonvascular functions and are widely distributed in a numberof tissues. They are altered in several disease processes includingdiabetes. Alteration of ETs have been demonstrated in organsof chronic diabetic complications in both experimental and clinicalstudies. The majority of the effects of ET alteration in diabetesare due to altered vascular function. Furthermore, ET antagonistshave been shown to prevent structural and functional changes inducedby diabetes in animal models. This review discusses the contributionof ETs in the pathogenesis and the potential role of ETantagonism in the treatment of chronic diabetic complications."} +{"text": "Macrophages are major cellular inhabitants of cycling and pregnant mammalian uteri. Their densities and patterns of tissue distribution in this organ fluctuate in concert with levels of circulating female sex steroid hormones, estrogens and progesterone, and their production of various effector molecules also may be hormonally regulated. Hormonal control may be achieved by direct binding to receptors or by indirect pathways where hormones modulate production of various autocrine and paracrine cytokines and growth factors that then target toresident macrophages and influence their secretory profiles. In this paper, we marshall evidence supporting the concept that progesterone acts as a powerful negative regulator of these versatile cells, reducing their migration into the uterus and impairing their ability to produce potent effector molecules such as nitric oxide that could interfere with the success of pregnancy."} +{"text": "Plasmodium, or design of human vaccines emulating mosquito resistance to the parasite, require extensive knowledge of processes involved in immune responses and of microevolutionary mechanisms that create and maintain variation in immune responses in wild vector populations. The recent realization of how intimately and specifically mosquitoes and Plasmodium co-evolve in Nature is driving vector molecular biologists and evolutionary ecologists to move closer to the natural setting under the common umbrella of \u2018Ecological immunology\u2019.More than a century after the discovery of the complex life cycle of its causative agent, malaria remains a major health problem. Understanding mosquito\u2013malaria interactions could lead to breakthroughs in malaria control. Novel strategies, such as the design of transgenic mosquitoes refractory to Plasmodium-infected mosquitoes. In the past decade, research on the mosquito immune response has been particularly dynamic, focusing on identifying mosquito genes giving resistance to Plasmodium infection using gene mapping, and also focusing on characterizing immune defence mechanisms through gene expression analyses. This area of research benefited tremendously from the completion of the Anopheles gambiae genome and from advances in genomics and transcriptomics, such as the development of microarray technology and RNAi gene silencing, resulting in a rapidly expanding body of literature.A key to interrupting human malaria transmission lies in unravelling the physiological and molecular mechanisms characterizing Plasmodium parasites and the costs and benefits of mounting an immune response to such an infection. From an evolutionary point of view, strong immune defence responses might not always be advantageous to malaria vectors and understanding why some mosquitoes develop an infection whereas others do not could be as important to our understanding of malaria transmission as describing the immune defence mechanisms themselves have shown that parasite-mediated costs begin to be incurred within hours of infection, when nitric oxide synthase (NOS) transcription is upregulated in the midgut epithelium An. stephensi with Plasmodium berghei, a non-natural host\u2013parasite combination An. gambiae/Plasmodium yoelii nigeriensisExperimental infections of Plasmodium-infected mosquitoes, but several studies have shown that infection sometimes affects survivorship and fecundity Constitutive immune defences are a first line of defence directed against a broad array of pathogens and are constantly activated. (ii) Inducible defences are specific and are switched on in response to a particular threat Drosophila melanogaster in which selection for increased encapsulation ability against parasitoids resulted in constitutive costs in the form of reduced larval competitive ability and lower survival rate Aedes aegypti, selection for early and late pupation resulted in correlated changes in body size and melanization response, revealing trade-offs between those traits Trade-offs are a major cause of constitutive and inducible immune defence costs and, in their simplest form, arise when energetically costly immune responses compete with resources or with a particular gene product required for other important functions Plasmodium parasites induces the transcription of several immune-related molecules An. stephensi infected with P. bergheiIn Anophelines, microarray studies have shown that the invasion of the mosquito midgut and salivary glands by An. gambiae, artificial stimulation of the phenoloxidase cascade and antimicrobial peptide production results in a reduction in egg production owing to the induction of apoptosis in cells of the follicular epithelium and subsequent resorption of eggs Similarly, the phenoloxidase cascade responsible for the melanotic encapsulation of parasites in insects produces phenol intermediates that are cytotoxic to the individual An. gambiae refractory strains has no match in nature. By contrast, melanization of P. falciparum is rarely observed in East African mosquito populations Most of the advances discussed above were obtained through studies based on laboratory models of malaria infection. Consequently, the upregulation of immune genes that these studies describe might not always accurately mirror the upregulation operating in natural associations Plasmodium genotypes, on the environment and, importantly, on the way that their genotype responds to changes in the environment; a phenomenon known as phenotypic plasticity inducible immunity are thought to be the main reason for the maintenance of susceptibility in natural populations et al.et al.Anopheles Plasmodium-responsive leucine-rich repeat 1 protein (APL1) was responsible for this strong inducible defence against PlasmodiumSinden Plasmodium should be fitter than their resistant high malaria season counterpart, creating seasonal cycles in the frequency of resistance alleles. To date few field studies have attempted to correlate variation in environmental characteristics with variation in immune responses The environment in which wild mosquito populations live is highly variable in time and in space. There is strong evidence from laboratory systems that genetic and environmental factors interact to determine the fitness of infected and non-infected individuals such that different genotypes might have higher fitness in different environmental conditions . EnvironPlasmodium genotypes (An. gambiae families and natural mixed-infection P. falciparum isolates suggest that such interactions could have an important role in nature Another source of variation in immune defence that leads to cycles in allelic frequencies is frequency-dependent selection. Laboratory studies support the idea that the outcome of infection depends on the host and enotypes , Box 4. Plasmodium interactions remains in its infancy and this review should serve as a strong incentive for re-examining the effects of genetic and environmental factors on Plasmodium infections using controlled laboratory experiments based on natural mosquito\u2013Plasmodium associations. Future transcriptomic and metabolomic studies based on similar experimental designs will further bolster our understanding of the underlying mechanisms leading to variation in immune responses in natural populations. The challenge of the field of ecological immunology is to design tractable field studies that incorporate the multiple ecological factors that are essential for determining the course of an infection. The complexity of the infected mosquito phenotype can easily turn experiments into exercises in confounding factors and correlative interpretations. However, despite these difficulties, describing population-level processes occurring between Plasmodium and mosquito hosts remains a priority and a key component in our quest to resolve the malaria problem.Despite years of research, relatively little is known about microevolutionary processes that create and maintain variation in immune responses in wild mosquito populations. The ecological immunology of mosquito\u2013"} +{"text": "As part of a Congressional initiative begun in 1999 to upgrade national public health capabilities for response to acts of biological terrorism, the Centers for Disease Control and Prevention (CDC) was designated the lead agency for overall public health planning. A Bioterrorism Preparedness and Response Office has been formed to help target several areas for initial preparedness activities, including planning, improved surveillance and epidemiologic capabilities, rapid laboratory diagnostics, enhanced communications, and medical therapeutics stockpiling The military has formally assessed multiple agents for their strategic usefulness on the battlefield In June 1999, a meeting of national experts was convened to 1) review potential general criteria for selecting the biological agents that pose the greatest threats to civilians and 2) review lists of previously identified biological threat agents and apply these criteria to identify which should be evaluated further and prioritized for public health preparedness efforts. This report outlines the overall selection and prioritization process used to determine the biological agents for public health preparedness activities. Identifying these priority agents will help facilitate coordinated planning efforts among federal agencies, state and local emergency response and public health agencies, and the medical community.On June 3-4, 1999, academic infectious disease experts, national public health experts, Department of Health and Human Services agency representatives, civilian and military intelligence experts, and law enforcement officials (see footnote) met to review and comment on the threat potential of various agents to civilian populations. The following general areas were used as criteria: 1) public health impact based on illness and death; 2) delivery potential to large populations based on stability of the agent, ability to mass produce and distribute a virulent agent, and potential for person-to-person transmission of the agent; 3) public perception as related to public fear and potential civil disruption; and 4) special public health preparedness needs based on stockpile requirements, enhanced surveillance, or diagnostic needs. Participants reviewed lists of biological warfare or potential biological threat agents and selected those they felt posed the greatest threat to civilian populations.The following unclassified documents containing potential biological threat agents were reviewed: 1) the Select Agent Rule list, 2) the Australian Group List for Biological Agents for Export Control, 3) the unclassified military list of biological warfare agents, 4) the Biological Weapons Convention list, and 5) the World Health Organization Biological Weapons list were placed in Category C. These agents will be addressed nonspecifically through overall bioterrorism preparedness efforts to improve the detection of unexplained illnesses and ongoing public health infrastructure development for detecting and addressing emerging infectious diseases Vibrio cholera and Shigella spp. (the cause of shigellosis) would be easier than the mass production of anthrax spores, the public health impact of widespread dissemination would be less because of the lower morbidity and mortality associated with these agents. Although the infectious doses of these bacteria are generally low, the total amount of bacteria that would be required and current water purification and food-processing methods would limit the effectiveness of intentional large-scale water or food contamination with these agents.Agents were categorized based on the overall evaluation of the different areas considered. Although use of conventional weapons such as explosives or firearms is still considered the most likely means by which terrorists could harm civilians Salmonella contamination of salad bars in The Dalles, Oregon, in 1984 Most evaluations of potential risk agents for biological warfare or terrorism have historically been based on military concerns and criteria for troop protection. However, several characteristics of civilian populations differ from those of military populations, including a wider range of age groups and health conditions, so that lists of military biological threats cannot simply be adopted for civilian use. These differences and others may greatly increase the consequences of a biological attack on a civilian population. Civilians may also be more vulnerable to food- or waterborne terrorism, as was seen in the intentional Category A agents are being given the highest priority for preparedness. For Category B, public health preparedness efforts will focus on identified deficiencies, such as improving awareness and enhancing surveillance or laboratory diagnostic capabilities. Category C agents will be further assessed for their potential to threaten large populations as additional information becomes available on the epidemiology and pathogenicity of these agents. In addition, special epidemiologic and laboratory surge capacity will be maintained to assist in the investigation of naturally occurring outbreaks due to Category C \u201cemerging\u201d agents. Linkages established with established programs for food safety, emerging infections diseases, and unexplained illnesses will augment the overall bioterrorism preparedness efforts for many Category B and C agents.The above categories of agents should not be considered definitive. The prioritization of biological agents for preparedness efforts should continue. Agents in each category may change as new information is obtained or new assessment methods are established. Disease elimination and eradication efforts may result in new agents being added to the list as populations lose their natural or vaccine-induced immunity to these agents. Conversely, the priority status of certain agents may be reduced as the identified public health and medical deficiencies related to these agents are addressed . To meet the ever-changing response and preparedness challenges presented by bioterrorism, a standardized and reproducible evaluation process similar to the one outlined above will continue to be used to evaluate and prioritize currently identified biological critical agents, as well as new agents that may emerge as threats to civilian populations or national security.Risk-Matrix Analysis Process Used to Evaluate Potential Biological Threat Agents"} +{"text": "We analyzed retrospectively the use of Physician Desk Reference Database searches to identify epidemics of tularemia, nephropathy, Pogosta disease, and Lyme disease and compared the searches with mandatory laboratory reports to the National Infectious Diseases Register in Finland during 1995. Continuous recording of such searches may be a tool for early detection of epidemics."} +{"text": "A molecular hallmark of cancer is the presence of genetic alterations in the tumoral DNA. Understanding how these alterations translate into the malignant phenotype is critical for the adequate treatment of oncologic diseases. Several cancer genome sequencing reports have uncovered the number and identity of proteins and pathways frequently altered in cancer. In this article we discuss how integration of these genomic data with other biological and proteomic studies may help in designing anticancer therapies \"a la carte\". An important conclusion is that next generation treatment of neoplasias must be based on rational drug combinations that target various pathways and cellular entities that sustain the survival of cancer cells. A critical step towards defining a correct personalized anticancer therapy is the identification of the genes and pathways altered in the tumour of the patient, and the elucidation of their particular oncogenic role. The success of molecular studies in identifying potential molecular targets for therapeutic intervention is exemplified by the developments in the treatment of chronic myelogenous leukaemia (CML) . This diin vitro establishment. On the other side, sequencing of acute myeloid leukaemia (AML) samples have identified 10 mutations in protein-coding mRNAs [In designing proper anticancer therapies the clinical and the preclinical researchers face several important questions: How many genetic alterations exist in a tumour? How many of them are responsible of promoting tumour growth? How many should be targeted to eradicate the tumour? The availability of technologies that allow large scale sequencing and genomics analyses of several tumours, together with strong bioinformatics tools and functional studies are contributing to answering these questions. Recent studies on the molecular profiling of breast and colon ,8, lung ng mRNAs ,18. AddiBy using bioinformatics analyses those authors indicated that most of the mutations in an individual breast or colon tumour were silent in terms of favouring tumour progression . These aAdditional studies carried out in glioblastoma multiforme (GBM) ,13 and pEGFR/HER1, CCNE1, or KRAS. In addition, the paper describes a novel player in lung cancer pathophysiology, the NKX2-1 gene product, a transcription factor implicated in the formation of lung pneumocytes. Knocking down the expression of this protein in NCI-H1925 lung cancer cells decreased their ability to grow in an anchorage-dependent manner, indicating that this protein may represent a novel lung cancer promoting oncogene, and an interesting novel therapeutic target. Another report analyzed somatic mutations of 623 genes in 188 lung cancer samples [KRAS or EGFR were mutated in a substantial proportion of patients; but, in addition, several other genes not formerly associated to lung cancer were identified, and included tumour suppressors , as well as tyrosine kinase genes . Of note, 132 of the 188 tumours had at least one mutation in genes that participate in MAPK signalling. Also, mutations in multiple genes of the Wnt pathway were observed in 29 of the 188 samples. Frequent mutations were also detected in DNA damage response genes, including TP53, and ATM. This clustering of mutations in certain pathways which play a role in oncogenesis points to the possibility of interfering with them for the treatment of lung tumours. Moreover, from a more ample perspective the molecular studies mentioned above open outstanding possibilities in terms of better focusing on certain targeted therapies for these tumours, based on drugs that target components of the identified signalling pathways. Another report confirmed the relevance of p53 and Rb in lung cancer [In lung cancer, using single nucleotide polymorphism (SNP) arrays, Weir et al. analyzed samples . These gg cancer . Here thAn ample study of somatic copy number alterations performed on 3131 tumour samples, and also using high resolution SNP arrays identified a median of 12 gains and loses in each patient tumour . FrequenA strategy that has been recently developed to massively identify potentially useful therapeutic targets is based on functional genomics studies using RNA-interference (RNAi) screenings. In one such functional screen based on the knockdown of 2,924 genes selected for their potential implication in tumour generation/progression, Schlabach et al. identified between 80-150 gene products important for tumour survival/proliferation . Of themIn addition to finding potentially useful drug targets, these RNAi-based functional genomic screens have also been used to uncover mechanisms of drug resistance. Bernards and colleagues explored proteins involved in trastuzumab resistance in breast cancer and identified PTEN as one of the principal proteins whose lack of function was linked to trastuzumab resistance , in agrein vitro whose in vivo manipulation could be highly toxic. It is therefore mandatory to proceed into in vivo testing the manipulation of those targets targeting in cancer have offered insights into the convenience of complementing the genomic data with proteomic studies to establish efficient anticancer therapies. Stommel et al. analyzedIn line with those findings, two additional reports showed the importance of targeting multiple RTKs in breast and lungWhile the above mentioned studies offer unquestionable useful information about relevant targets for therapeutic intervention in cancer, several factors that can limit the efficacy of targeted therapies must be considered. One is the presence of molecular heterogeneity within a particular tumour . The welAnother factor that limits the efficacy of targeted agents is the presence of parallel activation of downstream pathways. A well characterized example is the preclinical identification of the lack of antitumor activity of agents against RTKs when mutations at the K-RAS and PI3K genes were present ,44. TranAnother important tumour component that is gaining importance as a targettable cell type is the stromal compartment. In multiple myeloma, a disease characterized by the accumulation of tumoral plasma cells, the interaction of these cells with the stroma is expected to be critical for sustaining survival of the myelomatous cells, and to provide drug resistance . MoreoveThe power of high scale \"omics\" analyses coupled with the ample portfolio of targeted drugs under clinical development and already approved offers hope for a more effective and individualized anticancer therapy. It is rewarding to observe that sophisticated genomic, proteomic and biological studies reinforce the already known clinical strategy of using drug combinations to treat cancer patients Figure . The molIn conclusion, recent results using new \"omic\" techniques support the future use of targeted drug combinations for the treatment of solid tumours. In our opinion to increase the efficiency of this process, it is critical to reach a close collaboration between academia, the pharmaceutical and biotechnological companies as well as regulatory authorities to develop rationale studies with drug combinations based on strong preclinical data.The authors declare that they have no competing interests.Both authors contributed equally to the writing of the paper. Both authors also read and approved the final manuscript."} +{"text": "Since its introduction into clinical practice in 1967, selective variceal decompression by means of a distalsplenorenal shunt (DSRS) has become one of the more commonly performed portal-systemic shuntingprocedures in the treatment of variceal hemorrhage throughout the world. In addition to selectivedecompression of gastroesophageal varices, the DSRS provides the advantages of preservation of portalperfusion of the liver and maintenance of intestinal venous hypertension. Many large, uncontrolledseries and the majority of controlled randomized studies have demonstrated a lower incidence ofencephalopathy after the DSRS than after nonselective shunt procedures. A secondary advantage of theDSRS is that the hepatic hilum is avoided, thus making subsequent liver transplantation a lessformidable procedure. None of the studies have shown an advantage to this shunt with respect to longtermsurvival in patients with alcoholic cirrhosis. However, some of the large, uncontrolled series haveshown that survival is significantly improved in patients with non-alcoholic cirrhosis compared tononselective shunt procedures in the same population. Controlled trials comparing the DSRS toendoscopic sclerotherapy have shown that chronic endoscopic variceal sclerosis is an appropriate initialtherapy for most patients as long as shunt surgery is readily available if sclerotherapy fails."} +{"text": "We present an ontology for describing genomes, genome comparisons, their evolutionand biological function. This ontology will support the development of novel genomecomparison algorithms and aid the community in discussing genomic evolution. Itprovides a framework for communication about comparative genomics, and a basisupon which further automated analysis can be built. The nomenclature definedby the ontology will foster clearer communication between biologists, and alsostandardize terms used by data publishers in the results of analysis programs.The overriding aim of this ontology is the facilitation of consistent annotation ofgenomes through computational methods, rather than human annotators. To thisend, the ontology includes definitions that support computer analysis and automatedtransfer of annotations between genomes, rather than relying upon human mediation."} +{"text": "The pancreatic cancer continues to represent an important problem, as a cancer with extremely poorprognosis. To date more than 16 chemicals have been shown to induce pancreatic tumors, in animal models. Thetumors developed in rats are essentially of acinar type and those in hamsters mostly of ductal type.Many studies proved the direct or indirect role of hormonal and dietary factors in pancreatic cancer.The development of alternative treatments according to biological and biochemical steps of carcinogenesisis available as adjuvant treatment. We present herein an overview of current experimental and clinical results in order to understand theevolution, histogenesis and biological behaviour of pancreatic cancer."} +{"text": "The global nature of the threat posed by new and reemerging infectious diseases will require international cooperation in identifying, controlling, and preventing these diseases. Because of this need for international cooperation, international law will certainly play a role in the global strategy for the control of emerging diseases. Recognizing this fact, the World Health Organization has already proposed revising the International Health Regulations. This article examines some basic problems that the global campaign against emerging infectious diseases might face in applying international law to facilitate international cooperation. The international legal component of the global control strategy for these diseases needs careful attention because of problems inherent in international law, especially as it applies to emerging infections issues."} +{"text": "Estimations of the activities of various enzymes in clinical samplesare routine tasks for clinical chemists. Most of this work is doneby automatic analysis. The reference ranges against which patients'results are interpreted, however, have generally been defined in termsof manual methods and the conditions of a manual method cannotbe reproduced in automated systems. This paper describes thepossibility of translating the results of enzyme analysis into acommon currency through the use of enzyme reference materials ascalibrators."} +{"text": "The demonstration that hexamethylphosphoramide (HMPA) possesses potent carcinogenic properties has raised doubts about the safety of exposure to other phosphoric amides. In order to define a suitable short-term test with which to evaluate such analogues, the response of the Salmonella typhimurium mutation assay of Ames and cell transformation assay of Styles to HMPA and 3 selected analogues has been studied. These analogues were the related leukaemogen phosphoramide, the putative non-carcinogen, phosphoric trianilide and N.N'N''-trimethylphosphorothioic triamide, a compound of unknown and hitherto unpredictable properties. While both tests found the trianilide negative, the Ames test failed to detect phosphoramide as positive and gave an erratic and predominantly negative response to HMPA. In contrast, the transformation assay found both phosphoramide and HMPA positive. This test response profile indicates that the transformation assay is the preferred test with which to evaluate analogues of HMPA for potential carcinogenicity. Some structural requirements for potential carcinogenicity within this class of compounds are tentatively deduced."} +{"text": "The spleens of rats bearing methylcholanthrene induced sarcomas are enlarged. This applies both to primary and to isotransplanted tumours. The spleen enlarges with increasing tumour size.Splenomegaly is induced by skin homograft rejection, but spleen sizes do not reach those seen during tumour growth, even when the animals are chronically exposed to homologous skin. Sensitization of animals with small tumour homografts gives spleen sizes even greater than those of primary tumour growth.Spleen histology in tumour bearing animals is comparable with that of homograft rejection.The relation of splenomegaly to the presence of tumour specific antigen is discussed. The suggestion is advanced that the spleen size during tumour growth is determined by the product of reaction to foreign antigen, and of reticuloendothelial (phagocytic) activity."} +{"text": "Xenopus embryonic cardiac neural crest progenitors results in a wide spectrum of both structural and functional congenital heart defects, the actual functional mechanism of the cardiac neural crest cells within the heart is poorly understood. Neural crest cell migration and appropriate colonization of the pharyngeal arches and outflow tract septum is thought to be highly dependent on genes that regulate cell-autonomous polarized movement . Once the migratory cardiac neural crest subpopulation finally reaches the heart, they have traditionally been thought to participate in septation of the common outflow tract into separate aortic and pulmonary arteries. However, several studies have suggested these colonizing neural crest cells may also play additional unexpected roles during cardiovascular development and may even contribute to a crest-derived stem cell population. Studies in both mice and chick suggest they can also enter the heart from the venous inflow as well as the usual arterial outflow region, and may contribute to the adult semilunar and atrioventricular valves as well as part of the cardiac conduction system. Furthermore, although they are not usually thought to give rise to the cardiomyocyte lineage, neural crest cells in the zebrafish (Danio rerio) can contribute to the myocardium and may have different functions in a species-dependent context. Intriguingly, both ablation of chick and Xenopus premigratory neural crest cells, and a transgenic deletion of mouse neural crest cell migration or disruption of the normal mammalian neural crest gene expression profiles, disrupts ventral myocardial function and/or cardiomyocyte proliferation. Combined, this suggests that either the cardiac neural crest secrete factor/s that regulate myocardial proliferation, can signal to the epicardium to subsequently secrete a growth factor/s, or may even contribute directly to the heart. Although there are species differences between mouse, chick, and Xenopus during cardiac neural crest cell morphogenesis, recent data suggest mouse and chick are more similar to each other than to the zebrafish neural crest cell lineage. Several groups have used the genetically defined Pax3 (splotch) mutant mice model to address the role of the cardiac neural crest lineage. Here we review the current literature, the neural crest-related role of the Pax3 transcription factor, and discuss potential function/s of cardiac neural crest-derived cells during cardiovascular developmental remodeling.Although it is well established that transgenic manipulation of mammalian neural crest-related gene expression and microsurgical removal of premigratory chicken and"} +{"text": "The efferent vessel of hepatocellular carcinoma (HCC) and the mechanism and pathogenesis of the high frequency of intrahepatic metastasis in HCC has not yet been clarified. Three hundred ninety-three resected specimens of HCC were examined for tumor thrombosis in the portal vein and the hepatic vein: 231 tumors \u22645 cm in diameter were examined for the relationship between mode of tumor spread and tumor size. Efferent vessels in HCC were identified by direct injection of radiopaque material into the tumor in 23 resected liver specimens and by percutaneous infusion of radiopaque media into tumor nodules in 8 patients. The mode of tumor spread in HCC progressed from capsular invasion to extracapsular invasion, then to vascular invasion, and finally to intrahepatic metastasis. There was a strong statistical correlation between the presence of intrahepatic metastasis and portal vein thrombosis . Radiopaque material injected directly into 23 resected tumors entered only the portal vein in 17 tumors and into both the portal and hepatic veins in 6 tumors. In all 8 patients with unresectable lesions, radiopaque media injected percutaneously into tumor nodules flowed only into the portal vein. These findings suggest that intrahepatic invasion by HCC may occur through the portal vein as an efferent tumor vessel."} +{"text": "Cuscuta L. (Convolvulaceae), commonly known as dodders, are epiphytic vines that invade the stems of their host with haustorial feeding structures at the points of contact. Although they lack expanded leaves, some species are noticeably chlorophyllous, especially as seedlings and in maturing fruits. Some species are reported as crop pests of worldwide distribution, whereas others are extremely rare and have local distributions and apparent niche specificity. A strong phylogenetic framework for this large genus is essential to understand the interesting ecological, morphological and molecular phenomena that occur within these parasites in an evolutionary context.The genus Cuscuta using sequences of the nuclear ribosomal internal transcribed spacer and plastid rps2, rbcL and matK from representatives across most of the taxonomic diversity of the genus. We use the phylogeny to interpret morphological and plastid genome evolution within the genus. At least three currently recognized taxonomic sections are not monophyletic and subgenus Cuscuta is unequivocally paraphyletic. Plastid genes are extremely variable with regards to evolutionary constraint, with rbcL exhibiting even higher levels of purifying selection in Cuscuta than photosynthetic relatives. Nuclear genome size is highly variable within Cuscuta, particularly within subgenus Grammica, and in some cases may indicate the existence of cryptic species in this large clade of morphologically similar species.Here we present a well-supported phylogeny of Cuscuta are homoplastic and are of limited use in defining true evolutionary groups. Chloroplast genome evolution seems to have evolved in a punctuated fashion, with episodes of loss involving suites of genes or tRNAs followed by stabilization of gene content in major clades. Nearly all species of Cuscuta retain some photosynthetic ability, most likely for nutrient apportionment to their seeds, while complete loss of photosynthesis and possible loss of the entire chloroplast genome is limited to a single small clade of outcrossing species found primarily in western South America.Some morphological characters traditionally used to define major taxonomic splits within Cuscuta have been described, and they are distributed widely on every continent except Antarctica ). A different set of taxa was used for rpoA, which is missing in all sampled members of subgenus Grammica. A user tree, based on highly supported nodes of the bootstrap consensus tree in Figure atpE and rpoA not shown). Synonymous and non-synonymous branch lengths were first calculated with no constraints under the MG96, HKY 3, 4 codon model. Next, a tree with all branches constrained to the same non-synonymous to synonymous ratio was optimized, and a likelihood ratio test (LRT) was performed to determine whether the unconstrained tree had a significantly better likelihood. Likelihood parameters were then reoptimized for trees with the non-synonymous to synonymous rate ratio constrained differently for various clades . Clades examined in this manner for atpE, rbcL and rps2 were the Convolvulaceae clade (Ipomoea + Cuscuta), all Cuscuta, all Cuscuta except subgenus Monogyna and the clade comprising the three sampled species of subgenus Grammica. For rpoA, clades examined were Convolvulaceae, Cuscuta, subgenus Cuscuta and Cuscuta nitida. LRTs were confined to testing only hypotheses of change at these nodes of interest rather than performing numerous additional tests and thereby increasing the chance of Type I error.Aligned datasets for Cuscuta species and a photosynthetic outgroup from which some loci were extracted for this study and which were used extensively for primer design. CWD participated in design and coordination of the research and extensively edited the manuscript. All authors read and approved the final manuscript.JRM collected PCR data, performed analyses and wrote the manuscript. KA performed flow cytometry nuclear genome size estimation. JVK and JLB helped produce complete plastid genome sequences for two"} +{"text": "Neuroblastoma cells express the polysialylated form of the neural cell adhesion molecule (NCAM), which normally becomes restricted to a few neural tissues after embryogenesis. In this study, we investigated serum levels of polysialylated NCAM in 14 children with different grades and stages of neuroblastoma using an immunoluminescence assay, and compared the results to 269 healthy control subjects. Simultaneously, the polysialylated NCAM content of the tumours was determined by immunohistochemistry. Serum levels were dramatically elevated (more than sixfold) in children with advanced stages and fatal courses of disease, whereas children with differentiated tumour types and limited disease had low or normal levels. Serum concentrations correlated with the polysialylated NCAM content of the tumours, and they decreased during successful therapy. We therefore suggest polysialylated NCAM to be a useful marker monitoring childhood neuroblastoma."} +{"text": "Parvoviridae. Previously identified members of this genus are pathogens of bovines and canines. A parvovirus of human origin was recently discovered and called human bocavirus because it is closely related to bovine parvovirus and canine minute virus. Human bocavirus is associated with respiratory tract infections, particularly in infants and young children.Genus in the family"} +{"text": "Currentdata further corroborate our previous findings that steps akin to antigen processing andpresentation are clearly important in the induction of immune responses in lowervertebrates like fish, in a manner similar to that seen in mammalian systems.Consequently, it would appear that many immune functions among the diverse taxa ofvertebrates are remarkably conserved.Studies were conducted to address further the role(s) of antigen processing andpresentation in the induction of immune responses in a phylogenetically lowervertebrate, specifically a teleost, the channel catfish. In particular, studies were aimed atdetermining the subcellular compartments involved in antigen degradation by channelcatfish antigen-presenting cells (APC) as well as ascertaining the reexpression ofimmunogenic peptides on the surfaces of APC. The results showed that exogenousprotein antigens were actively endocytosed by APC as detected by flow cytometry. Useof radiolabeled antigen and subcellular fractionation protocols also showed that antigenlocalized in endosomes/lysosomes. Furthermore, there was an apparent redistributionof antigen between these organelles and the plasma membrane during the course ofantigen pulsing. Functional assays for the induction of"} +{"text": "Colon cancer is the second leading cause of cancer deaths in the western world. If detected early, colorectal cancer is one of the most treatable forms of cancer. Unfortunately, very few people are screened. N-myristoyltransferase (NMT) catalyzes myristoylation of various proteins including oncoproteins. We have demonstrated earlier the alteration of NMT activity during the progression of colorectal cancer and established NMT as a putative therapeutic target for cancer.Peripheral blood samples and bone marrow were collected from the colon cancer patients and azoxymethane induced colonic tumor rats and their controls respectively. NMT activity and expression was determined as reported earlier. Immunohistochemical studies were carried out using standard procedures.In this study we demonstrate for the first time altered expression and localization of NMT in the peripheral blood and bone marrow in colon cancer patients. Immunohistochemical analysis revealed weak to negative staining for NMT in peripheral blood mononuclear cells (PBMC) of controls, whereas strong positivity was observed in PBMC colon cancer patients. In addition, we observed that NMT was localized mostly in the nuclei of the bone marrow (BM) mononuclear cells of the colon cancer patients, whereas NMT remained cytoplasmic in the control bone marrow specimens.The strikingly different NMT expression offers the basis of a potential adjunct investigative tool for screening or diagnosis of patients at risk for or suspected of having colon cancer. Furthermore, altered localization of NMT in BM of tumor bearing hosts may serve as an added investigative tool for the diagnostic purpose. One unit of NMT activity was expressed as 1 pmol of myristoyl peptide formed per min.[eviously . The assSDS-PAGE was carried using standard procedures and Western blot analysis was performed as described previously and probIn thirty weeks all the animals' injected with azoxymethane developed at least two tumors in colon with a maximum of four in two cases. Control rats appeared healthy without any colon tumors. These tumors ranged from adenomas (polyp) to highly invasive tumors.We have established NMT as a putative therapeutic target for colon cancer . To examThe strikingly different NMT expression offers the basis of a potential adjunct investigative tool for screening or diagnosis of patients at risk for or suspected of having colon cancer. Furthermore, altered localization of NMT in BM of tumor bearing hosts may serve as an added investigative tool for the diagnostic purpose. To assess the specificity of the test we performed immunohistochemical staining of the peripheral blood from a chronic lymphocytic leukemic (CLL) patient. Interestingly, NMT staining was negative in the lymphoid cells of the CLL patient (data not shown). A preclinical trial is underway involving larger sample size of patients and healthy controls to validate NMT as blood marker for the diagnosis of colon cancer.AS, RKS and University of Saskatchewan currently hold provisional US patent for this work.All authors have read and approved the final manuscript. A Shrivastav conceived, designed, carried out the studies and drafted the manuscript. SV carried out the studies and drafted the manuscript. A Saxena participated in the immunohistochemical analysis. JD participated in the design of the study. RS conceived the study, and participated in its design and coordination and helped to draft the manuscript. All authors have read and approved the final manuscript."} +{"text": "A method for estimating both structural and functional vascular volumes in murine sarcomas is described. Intact vessels were demonstrated by the presence of laminin, a basement membrane-associated antigen, using an immunofluorescent technique, and functional vessels in the same sample by prior injection with the DNA binding dye Hoechst 33342. No significant vascular effects were seen after melphalan but a very pronounced decrease in both functional and structural vascular volume was seen after MISO. Combined chemotherapy of a murine sarcoma with melphalan and MISO induced a rapid decrease in the functional vascular volume, and there was a resumption of blood flow prior to measurable regrowth. The fully regrown tumour retained the vascular characteristics of untreated tumours of similar size."} +{"text": "The clinical effects of levocabastine occur rapidly and are predominantly due to local antihistaminic effects at the site of application. Clinically, levocabastine is well tolerated with an adverse effect profile comparable with that of sodium cromoglycate and placebo. As might be expected from the route of drug administration, local irritation is the most frequent adverse event seen with levocabastine eye drops and nasal spray with an incidence comparable with that in placebo-treated controls. Intranasal application of levocabastine has been shown to have no adverse effect on ciliary activity both in vitro and in vivo, while ocular administration has not been shown to have any significant or consistent adverse effect in both animal and human studies. At therapeutic doses, levocabastine appears to be devoid of significant systemic activity producing no apparent effects on cardiovascular, psychomotor and cognitive function. Since levocabastine undergoes little hepatic metabolism, and only low plasma levels of the drug are attained following topical administration, drug interactions are unlikely.Levocabastine is a highly potent and selective H"} +{"text": "The ability of human tumour cells to form colonies in soft agar is enhanced by the presence of autologous phagocytic/adherent cells. We investigated the effect of irradiation on the ability of the adherent cells to support human tumour colony formation. Relatively low doses of irradiation significantly increased the growth enhancing ability of adherent cells in 17/19 cases. The possibility that the enhancement was mediated by inactivation of radiosensitive contaminating lymphocytes was explored. Depletion of T lymphocytes from unirradiated adherent cells by a monoclonal antibody and complement resulted in little overall change in tumour colony growth. However, elimination of only the suppressor subset (OKT8+) of T lymphocytes resulted in increased colony growth relative to control values obtained with unirradiated adherent cells. In contrast, depletion of T lymphocytes from irradiated adherent cells by a pan T monoclonal antibody and complement decreased colony formation. Thus, the ability of irradiated macrophages to enhance tumour colony growth appeared to be mediated by a T lymphocyte. The effect of irradiation on isolated populations of macrophages and T lymphocytes was also examined. The enhanced ability of irradiated adherent cells to support tumor colony growth appeared to have been due to treatment of T lymphocytes alone. The results indicate that both adherent macrophages and lymphocytes may influence the growth of clonogenic human tumour cells."} +{"text": "Genetic make up had been known to influence pharmacokinetics and pharmacodynamics of psychotropic medications. Time separation in evolutionary trend in Africans, Orientals and Caucasians had been thought a possible explanation for the observed racial variation in activities of Cytochrome P 450 (CYP 450) enzymes, which are responsible for metabolism of psychotropic and other medications in human. Past studies on pharmacokinetics and pharmacodynamics of antipsychotic medications and socio-cultural factors influencing response to antipsychotic medications had consistently giving an inkling of possible racial difference in symptoms response to antipsychotic medications. Another growing body of evidence subscribing to possible racial difference in psychotic symptoms response to antipsychotic medications is the observed variation in antipsychotic medications prescription pattern and dosage across races and regions. Empirical observation had shown that dosage prescription pattern of antipsychotic medications in most Sub-Saharan African countries deviates from the standard prescription guidelines published for use in western parts of the world. Studies coming from the United States (U.S) had consistently reported a higher dosage of antipsychotic medications prescription for African-American patients compared to their Caucasian counterparts. Research on East Asia Psychotropic Prescription (REAP) study had also identified high dosage antipsychotic medications prescription pattern well above the recommended dose of 1,000 mg Chlorpromazine equivalent per day as common practices in some East Asian countries.The pertinent question is why the apparent differences in dosage prescription practices across races and regions? The possibility of racial differences in psychotic symptoms response to antipsychotic medications rather than clinicians' prescription attitudes was entertained.Future carefully controlled studies might be needed to test the proposed hypothesis of racial differences in psychotic symptoms response to antipsychotic medications.There might be actual racial influence on psychotic symptoms response to antipsychotic medications. If future carefully controlled studies uphold the hypothesis of racial differences in psychotic symptoms response to antipsychotic medications, there might be need to draw up new treatment or prescription guidelines that would put into consideration variations in genetic make up and consequent racial differences in psychotic symptoms response to antipsychotic medications. Genetic make-up had been known to influence metabolism and utilization of psychotropic medications -4. GenetIn the past two decades, review of literature on pharmacokinetics and pharmacodynamics of psychotropic medications and socio-cultural influences on response to psychotropic medications in different races had consistently pointed an exploratory search light at possible variation in racial symptoms response to psychotropic medications -10. VariPrescription pattern and dosages of antipsychotic medications prescribed varies from one patient to another, from one professional to another, from one clinical institution to another and from one region to another . EmpiricIt had also been found that African-Americans compared to their Caucasian counterparts often received antipsychotic medications for a longer period of time as maintenance treatment for Bipolar Affective Disorders (BAD) ,17. BothThe reasons for the difference between the prescription pattern in African-American and their Caucasian counterparts in above studies -18 couldTherefore, a possible explanation is that at the same level of severity of psychotic symptoms as measured by any standardized rating scale, African-Americans and black Africans of Sub-Saharan African descent might require a higher dosage of antipsychotic medications compared to their Caucasian counterparts for resolution of their psychotic symptoms. This difference may lie in varied pharmacogenetic effects in metabolism and utilization of antipsychotic medications in different races of the world.The argument of racial differences as it affects the effective therapeutic dosage of antipsychotic medications in treatment of psychosis is given a further weight by Sim et al study , which rThere is need to explore the possible explanations for the apparent racial and regional differences in dosage prescription pattern of antipsychotic medications.It had already been noted that prescribing practices might vary from one professional to another and from one region to another . This maThe possible argument against differences in prescribing practices being a function of training background could be found in literature coming from the United States (US), where training of mental health professionals is regulated by a uniform body and can be presumed to be a uniform training background. In these literatures -18, it hTherefore, the significant difference in dosage prescription pattern and longer term use of antipsychotic medications observed in African-Americans and black Africans in Sub-Saharan Africa compared to their Caucasian counterparts may not be solely explained by variation in training backgrounds of attending mental health professionals in these regions of the world.Socio-cultural acceptability of patients with symptoms of mental illness may vary according to symptoms presentation. Patients with depressive symptoms are likely to be more accepted and coped with than patients that present with psychotic symptoms, while patients that present with psychotic symptoms without aggression are tend to be more accepted and coped with than patients that present with psychotic symptoms and aggression.The socio-cultural acceptability and unacceptability of patients' symptoms affect directly and indirectly the prescription pattern and practices. Famuyiwa noted thRelating Barbui et al findingsThen, the zeal to curtail aggression and potential dangerousness in a patient presenting with psychotic symptoms may be the reason behind the dosage prescription of antipsychotic medication well above the recommendation in standard prescription guidelines. This may also explain poly-pharmacy and common use of depot antipsychotic medications among African-American and black African patients from sub-Saharan Africa that had been noted in some studies ,18-21.Another possible explanation for differences in dosage prescription pattern of antipsychotic medications that had been found in the above studies ,13,16-21Having been established that genetic variation have some influence on pharmacodynamics and pharmacokinetics of psychotropic medications -4, thereThe deviation in dosage prescription practices from prescription guidelines published for use in western parts of the world ,15 in moConsidering the presence of other confounding factors like availability and cost of antipsychotic medications, health care financing systems among other factors which may vary in different regions of the world and can contribute to the observed difference in prescription pattern and dosage of antipsychotic medications across races and regions, the need for further studies is apparent to confirm or refute the hypothesis of racial difference in psychotic symptoms response to antipsychotic medications. These studies would be necessary to unravel the actual reason behind the observed difference in dosage of antipsychotic medication prescription that existed among black Africans, African-Americans, Orientals and their Caucasian counterparts. Controlled studies, utilizing pharmacogenetic testing, standardized psychotic symptoms resolution assessment method and serum level measurements of antipsychotic medications during treatment might be able to provide a definitive answer to the puzzling question of observed differences in dosage of antipsychotic medication prescription across races and regions. Actual racial differences in psychotic symptoms response to antipsychotic medications due to genetic variations might be the underpinning factor.If the hypothesis of racial differences in psychotic symptoms response to antipsychotic medications is upheld by future studies, there might be need to draw up new prescription or treatment guidelines that would take into consideration variations in genetic make-up and consequent racial differences in psychotic symptoms response to antipsychotic medications.The author declares that they have no competing interests.MOB conceived and wrote the manuscript. The author read and approved the final draft of the manuscript."} +{"text": "Cell fusion has been used to analyse the genetic determinants of metastasis at the cellular level. Highly metastatic mouse melanoma cells were fused with diploid mouse lymphocytes and a range of hybrid clones isolated and tested for tumorigenicity and metastatic potential by s.c. injection into newborn, histocompatible, sublethally-irradiated mice. Although almost all clones tested were tumorigenic, most had considerably reduced metastatic potential. This suggests that tumorigenicity and metastasis are determined by different genetic elements. Histological examination of primary tumours produced by metastatic and non-metastatic hybrid cell lines showed that an essential step in the production of metastases is the separation of tumour cells from the main tumour mass and their movement into the surrounding tissues. The primary tumours of a metastatic hybrid cell line showed local invasiveness whereas those of a non-metastatic cell line did not."} +{"text": "The provision of ambulatory care by major retailers is small but growing, providing speedy attention to consumers with minimal wait times and no appointments necessary. Users of these clinics are satisfied with the care they receive. Primary care physicians have opposed retail clinics, concerned that conditions will be misdiagnosed, opportunities to address comorbidities and risk behaviors will be missed, necessary follow-up care will be delayed or absent, and the profit motive will lead to cutting corners. Public health is now being challenged to capitalize on the advantageous possibilities these clinics can offer, such as serving uninsured patients, while remaining vigilant regarding potential hazards, such as financial pressures that could negatively affect health care quality, continuity, and accessibility. Public health has long maintained a sibling rivalry of sorts with its flashier, more popular sister \u2014 medical care. Population-based, prevention-oriented interventions are often overshadowed by medical treatments geared toward the curative needs of individual patients. The widely cited statistic that public health accounts for less than 3% of health-related spending in the United States is frequDespite some latent jealousies and important differences in priorities and perspectives, public health workers have historically collaborated with physicians and other health care providers to improve the health of individuals and communities. The nature and strength of this partnership has evolved over the years but has been characterized by a mutual recognition of the utility, value, and interdependency of the medical and public health models 2). Som. Som2). Clinic sponsors and other proponents argue that retail clinics provide needed (and carefully targeted) services in a responsive and cost-efficient manner to people who would otherwise have limited access to health care . EvidencRetail clinic users also appear to improve access for the underserved. Mehrotra et al found thPrimary care physicians have been quite vocal in their opposition to retail clinics . ConcernConcerns that financial imperatives will negatively affect health care quality, continuity, and accessibility are by no means unprecedented, but they take on renewed poignancy in light of the disruptive innovation potentially posed by retail clinics. Similar issues were raised as managed care became more prevalent and imposed escalating financial pressure on health care providers . The curThe real effect of retail clinics on patient care, and on population-based services that intersect with medicine, depends on how widely this care model is used and the ways in which these clinics relate to conventional primary care and public health. In addition to worrying about jeopardizing the quality and continuity of patient care and the financial health of existing safety net providers, public health professionals also worry about less publicized issues, such as disease surveillance compliance, disease screening opportunities, health education capacities, and appropriate use of antibiotics. Will retail clinics participate in vaccination registries? Assess conjugate pneumococcal vaccination status for children with otitis media? Comply with influenza vaccine recommendations in the event of a shortage? Provide appropriate antibiotic treatment? Convey tobacco use cessation guidance to adult patients with pharyngitis? Recommend diabetes screening to the overweight patient with a urinary tract infection? These specific inquiries raise the larger question: Are partnerships with public health compatible with the retail clinic business model?Tensions between profit motives and humanitarian goals in health care are not new. Private outpatient medical practices have always operated as small businesses, but traditionally the professional ethics of independent health care practitioners have been perceived to mediate the potentially pernicious influence of commerce . PrevailAs the independence and decision-making authority of individual professionals are diminished within large corporate bureaucracies, critics worry that both the quality of patient care and commitment to the public good will suffer. Some limited evidence exists to support these concerns. For example, physicians with an ownership stake in their practice are more likely to provide charity care than those employed by a private practice .Public health has an important role to play in monitoring the consequences of changing health care delivery models and organizational structures, but appropriate watchfulness should not prevent public health officials from exploring and initiating collaborative opportunities with these new commercial partners. As the nature of medical practice evolves, public health must continue to seek ways to harness the reach and creativity of new corporate stakeholders. These opportunities are likely to take on a variety of forms \u2014 some will prove viable, while others will fail to be realized.In many respects, the goals and structure of retail clinics appear to align quite well with public health objectives. Retail clinics have the potential to make a variety of value-added contributions to the traditional medical\u2013public health partnership. Several characteristics of these care sites could be marshaled to improve population health outcomes.The retail clinic business model is firmly grounded in a sophisticated understanding of what consumers want and how they make decisions. The marketing advantages of on-site clinical services may be more appealing to retailers than the discrete profits these clinics generate. These services draw customers to the retail location, trigger demand for related products such as pharmaceuticals and over-the-counter drugs, and help establish a \"wellness\" brand for the retailer. Retailers invest heavily in multiple forms of marketing, including mass media advertising, direct mailings, in-store promotions, coupons, and niche marketing techniques. Public health can explore ways to leverage these marketing goals and competencies to design and implement collaborative social marketing campaigns related to clinical preventive services, risk behaviors, and health promotion messages.These types of public\u2013private partnerships have a proven track record in health promotion. For example, the Back to Sleep campaign to reduce sudden infant death syndrome received a substantial boost from Proctor and Gamble, which contributed marketing expertise to the campaign and aided in message dissemination . Retail To maintain an acute awareness of consumer preferences, retail businesses invest substantial resources in information technology and data-gathering activities. These efforts are oriented toward who buys what where, when, and why. But these consumer monitoring techniques also have the potential to provide valuable information for public health research and practice.Public health has begun piloting methods to use consumer product data for syndromic surveillance. Additional forms of data sharing and collaborative monitoring hold tremendous promise. For example, most retail clinics use electronic medical records. These electronic data can be shared with conventional primary care providers and incorporated into existing registries and emerging surveillance methods while protecting patient privacy. Another example is self-guided patient education through computer kiosks, which has been tested in physician and social service offices and could be adapted for the retail clinic setting.Retail clinics are typically staffed by nurse practitioners, and clinic operators have noted that the quality and communication skills of the clinical staff are central to achieving consumer satisfaction. The premium placed on employing highly competent clinicians with superior interpersonal skills suggests that these retail clinic employees could be valuable allies in disseminating disease prevention and health promotion messages.Retail distributors have tremendous reach given their strategic locations proximate to population growth centers. They are highly efficient in inventory tracking and management. Mass merchandisers analyze customer flow and movement throughout their stores and are skilled in directing foot traffic toward promotional displays. These skills could be used in planning for emergency mass prophylaxis and for carrying out routine, universal treatment services such as annual influenza vaccination campaigns.Corporate interests represent an influential constituency for public policy makers. Inculcating public health priorities into the public policy agenda of corporate stakeholders substantially improves the likelihood that these objectives will be achieved.Some healthy skepticism is warranted in the pursuit of these opportunities. Public health advocates should remain mindful that corporate partners are primarily driven by profit motives. But strong communication and interactive exchange between public health and commercialized medicine can reveal \"win-win\" opportunities. Corporate branding and public relations goals may align well with health improvement objectives. Some public health professionals may find it challenging to make peace with their own reluctance to acknowledge the legitimacy of commercial interests. Similarly, retail partners may need assistance in overcoming their own perceptions about the bureaucratic burdens of working with government agencies. Competitive tensions among corporate partners must also be acknowledged. Public health will need to be receptive to all interested, appropriate partners and avoid exclusive partnering arrangements.The history of public health is defined by the field's ability to adapt and respond to the evolving threats to human health that have emanated from a changing environment. The health care industry's increasing emphasis on financial returns (which transcends the emergence of retail clinics) and the proliferation of new care delivery models pose new threats and opportunities for public health. The field is now being challenged to capitalize on advantageous possibilities while remaining vigilant regarding potential hazards. Such dexterity will require both open minds and open eyes; ready for that macchiato?"} +{"text": "During exocytosis, chemical transmitters stored in secretory vesicles can be released upon fusion of these intracellular organelles to the plasma membrane. In this process, SNARE proteins that form a ternary core complex play a central role. This complex could provide the means for generation/storage of energy necessary for driving the fusion of vesicular and plasma membranes. Recently, the amount of energy for (dis)assembly of the ternary complex has been measured using various experimental approaches, including atomic force microscopy, the surface force apparatus, and isothermal titration calorimetry. The obtained measurements are in good agreement with the calculated energy required for membrane fusion achieved by theoretical modeling approaches. Whether the energy expenditure to form the ternary SNARE complex can be utilized towards membrane fusion and/or docking/tethering of vesicles to the plasma membrane still remains one of the key contemporary issues in biophysics and neuroscience."} +{"text": "Recently, the Food and Drug Administration placed a \"black box\" label on etanercept, and other tumor necrosis factor inhibitors used to treat childhood arthritis, warning of the risk of malignancies. The Food and Drug Administration made their decision based on a review of 48 cases of malignancies identified worldwide in children treated with tumor necrosis factor inhibitors for inflammatory bowel disease, sarcoidosis, and juvenile idiopathic arthritis. Recently, an article in Pediatric Rheumatology demonstrated that there may not be an increased risk of cancer in children with juvenile idiopathic arthritis treated specifically with the tumor necrosis factor receptor fusion protein, etanercept. There are many confounding issues regarding whether or not etanercept increases the risk of malignancy, specifically lymphomas, above the background rate of cancer in children with juvenile idiopathic arthritis who are not being treated with biologic agents. Whether or not it was appropriate for the Food and Drug Administration to lump cancer patients with underlying granulomatous diseases (inflammatory bowel disease and sarcoidosis) with children with juvenile idiopathic arthritis is explored herein. Moreover, the amalgamation of etanercept with anti-tumor necrosis factor monoclonal antibodies is another point of contention. What is clear is that there is much that is currently unknown to be able to convincingly demonstrate a substantial risk of cancer in children with juvenile idiopathic arthritis treated with etanercept. Conversely, there is ample evidence demonstrating remarkable benefit of etanercept in treating juvenile idiopathic arthritis. Physicians treating childhood arthritis should weigh these potential risks and benefits with patients and their families discussing the current limitations in available data regarding the risk of cancer in children treated with etanercept for juvenile idiopathic arthritis. The bench to bedside transition of tumor necrosis factor (TNF) inhibitors has been a truly remarkable breakthrough in the treatment of both adult and pediatric chronic inflammatory arthritis, and no less worthy than awarding the 2003 Lasker Clinical Medical Research Award to Drs. Feldman and Maini . The firMcCroskery and colleagues identified 18 malignancies worldwide among children who received etanercept, and 3 of these remain unconfirmed . The potVery recent independent preliminary studies have suggested that biologic na\u00efve JIA patients experience an approximately 2- to 3-fold increased risk of cancer ,9, and aWhat does seem likely, however, is a risk of developing hepatosplenic T cell lymphomas in children with inflammatory bowel disease (IBD) treated with a combination of azathioprine or 6-mercaptopurine (6-MP), and a monoclonal antibody (mAb) directed against TNF . AlthougIt is often difficult for the FDA to choose when to alert the public about a potential drug-related safety issue as they rarely have adequate information to make definitive conclusions at the time of the warning. However, it remains questionable whether or not the FDA should have lumped different classes of TNF inhibitors and different patient populations with differing malignancies together and placed a generic black box warning on the TNF inhibitors for malignancy risk, particularly in the setting of JIA patients treated with etanercept. For rare diseases and rare events, it is extremely difficult to determine causality. Accordingly, interested parties have called for the creation of a consolidated registry to monitor the long-term safety of pediatric rheumatology treatments . Until tAbbreviations are defined in the text where first used.The authors declare that they have no competing interests.RQC researched the subject and drafted the manuscript.TB researched the subject and modified the manuscript accordingly.Both authors read and approved the final manuscript."} +{"text": "The conservation of gene order among prokaryotic genomes can provide valuable insight into gene function, protein interactions, or events by which genomes have evolved. Although some tools are available for visualizing and comparing the order of genes between genomes of study, few support an efficient and organized analysis between large numbers of genomes. The Prokaryotic Sequence homology Analysis Tool (PSAT) is a web tool for comparing gene neighborhoods among multiple prokaryotic genomes.PSAT utilizes a database that is preloaded with gene annotation, BLAST hit results, and gene-clustering scores designed to help identify regions of conserved gene order. Researchers use the PSAT web interface to find a gene of interest in a reference genome and efficiently retrieve the sequence homologs found in other bacterial genomes. The tool generates a graphic of the genomic neighborhood surrounding the selected gene and the corresponding regions for its homologs in each comparison genome. Homologs in each region are color coded to assist users with analyzing gene order among various genomes. In contrast to common comparative analysis methods that filter sequence homolog data based on alignment score cutoffs, PSAT leverages gene context information for homologs, including those with weak alignment scores, enabling a more sensitive analysis. Features for constraining or ordering results are designed to help researchers browse results from large numbers of comparison genomes in an organized manner. PSAT has been demonstrated to be useful for helping to identify gene orthologs and potential functional gene clusters, and detecting genome modifications that may result in loss of function..PSAT allows researchers to investigate the order of genes within local genomic neighborhoods of multiple genomes. A PSAT web server for public use is available for performing analyses on a growing set of reference genomes through any web browser with no client side software setup or installation required. Source code is freely available to researchers interested in setting up a local version of PSAT for analysis of genomes not available through the public server. Access to the public web server and instructions for obtaining source code can be found at An analysis of gene order conservation is commonly performed in genomic comparison studies of microbial genomes. Several tools for visualizing and comparing gene order on a whole genome scale have been developed for identifying genomic rearrangements and to infer phylogenetic relationships between genomes -3. Gene Researchers frequently perform comparative genomics studies between a selected set of closely related genomes to investigate genomic differences responsible for distinct characteristics. Several tools that have been developed with features to assist researchers with comparing genomic neighborhoods between genomes therefore focus on comparisons among only a small set of genomes -14. ManyWe have developed the Prokaryotic Sequence homology Analysis Tool (PSAT), a web based tool that utilizes a large database of pre-calculated sequence homologs for analysis of genomic neighborhoods among large numbers of bacterial genomes. A PSAT web server is publicly available to provide researchers around the world with access to the tool's comparative analysis utilities immediately, without any software installation or setup. Several other websites have been developed with similar designs, utilizing custom databases populated with gene and homology data from multiple bacterial genomes and providing a set of analysis tools through a web interface. Some examples include MicrobesOnline, Prolinks, STRING and the TIGR Comprehensive Microbial Resource (CMR), each with its own set of comparative genomics features -19. A coWe describe here how we generate the data to populate the database utilized by the PSAT web server. We then provide an overview of the source code developed for generating the web interface for query and display of results. Researchers interested in running a local version of PSAT can download the freely available source code and follow similar methods to create and populate their own database for studying unpublished genomes or genomes not yet added to our public PSAT tool.Protein and sequence files for published bacterial genomes are downloaded from NCBI . The proSeveral freely available Perl modules (available from CPAN ) are usePSAT users use the tool's web interface to select a single reference genome to perform comparisons with over five hundred bacterial genomes publicly available through NCBI. Because protein sequence homologs have been pre-computed and stored in an optimized database, retrieval of homologs among such large numbers of genomes using various querying options is quick. For the selected gene of interest and each of its homologs in the result set, PSAT generates and aligns a visualization graphic of the genomic neighborhood. Each gene in the reference genome is assigned a color, and any homolog found in the displayed region of a comparison genome is color coded to correspond with the appropriate reference gene. The coloring of homologs is designed to help researchers easily identify regions of conserved gene order across several genomes, providing support for gene orthology or functional gene clusters. To facilitate examination of gene neighborhoods, popups activated when hovering the mouse over each drawn gene provide users with gene details such as gene name, locus tag, and description, as well as any relevant BLAST hit details. A zoom tool is also available for comparing genomic regions of different sizes, ranging from 1 to 100 kb. To assist researchers with exploration of large amounts of results, features are available for scrolling through the images generated for each comparison genome to align with the reference genome, selecting to remove genomes from the visualization, or reordering the results based on BLAST hit scores or using PSAT's homolog cluster scoring system.The PSAT homolog cluster score for a selected gene is defined as the number of contiguous homolog neighbors found in conserved order surrounding the homolog match for this gene in another genome. Homologous protein sequences are determined by BLAST alignment with a uThe PSAT display draws all genomic features to scale, including intergenic distances, and uses color to represent homologous genes in the compared genomes to facilitate identification of conserved gene clusters, rearrangements, insertions, deletions and sequence inversion. In the graphical display of each genome, which is aligned with the 5' end of the query gene, PSAT distinguishes the homologs with a common color (the rest of the genes are grey). For the purpose of identifying conserved gene clusters, this method of display presents some advantage over coloring genes based on role categories or otheOur experiences performing and assisting other researchers with comparative genomics studies inspired the development of PSAT. We were therefore able to identify multiple scenarios that we had encountered in such studies in which PSAT was or would have been helpful. Using these scenarios as examples, we demonstrate here some of the uses of PSAT and evaluate the tool's utility in assisting with particular tasks. We also discuss some of our plans for developing the tool further.Francisella tularensis subspecies novicida U112, for example, revealed that the gene FTN_0453 does not have any BLAST hits in the other Francisella genomes. PSAT results indicated, however, that the gene is homologous to genes of other bacterial genera including Shewanella and Vibrio. Although the sequence identity between FTN_0453 and these homologs is modest, the PSAT visualization graphic also indicated the gene may be involved in a potential gene cluster pair in s Figure . The obstabolism .The PSAT web server's database of gene annotations and sequence homologs enables the tool's efficient genomic neighborhood comparative analysis and visualization features. The public server is currently loaded with a selected set of reference bacterial genomes published through NCBI. We plan to continue to load additional published genomes into the tool in order to more broadly support researchers studying different bacterial organisms. We also recognize the importance of keeping the genome data used by the public server up to date. We are therefore also implementing an automated system for updating the database as new or modified genome annotations become available through NCBI.PSAT was originally designed for exploring homologs within genomic neighborhoods to analyze gene order and identify potential gene clusters among several genomes. We recognize, however, that the database of genes and protein sequence homologs that was built for this purpose could be utilized for several other types of genomic analyses. We plan to, for example, leverage the database to add a query interface to retrieve homology statistics from various genomes. Enabling researchers to determine the proportion of genes in a reference genome that have homologs in several other genomes can provide a rough comparison of genomic similarity and phylogenetic distances. Another feature we plan to implement is a querying method utilizing homology data for determining a putative set of genes that are unique to a particular set of genomes. This kind of analysis can help researchers identify a list of potential genes that appear, for example, in a set of genomes belonging to virulent strains of a bacterium, yet not in a set of genomes belonging to avirulent strains of the same bacterium.As the number of bacterial genomes being sequenced, annotated, and published quickly increases, so does the potential for researchers to perform interesting comparative studies based on the available genomic data. The PSAT web tool can be helpful for such comparative genomics studies by providing researchers with an original interface to explore and compare the genomic neighborhoods of multiple prokaryotic genomes. Essential features of the tool include efficient retrieval of homologs between large numbers of genomes, a graphical visualization of homologs within genomic neighborhoods for analyzing gene order conservation, and options for ordering and filtering results based on various properties to facilitate exploration of large result sets. We have demonstrated how PSAT can be used to help identify gene orthologs, detect a loss of function in a genome under study, and discover potential biological associations between genes.Burkholderia, Escherichia, Francisella, Salmonella, Pseudomonas, and Yersinia genera, against over five hundred other bacterial genomes available on NCBI. The PSAT source code is also freely available for researchers to easily set up local versions of PSAT to perform analyses of other genomes, including those not yet released to the public. Please visit the PSAT website for more information.Our publicly available PSAT web server currently supports analysis of reference genomes from a subset of published bacterial genomes, including selected genomes from the Project name: PSATProject home page: Operating systems: Platform independent for accessing the public web server; Linux (or possibly other Unix variants) for local installationsProgramming language: PerlOther requirements: Javascript enabled web browser for accessing the public web server; Apache web server and PostgreSQL database for local installationsAny restrictions to use by non-academics: noneCF designed and wrote the application, and drafted the manuscript. LR advised on biological aspects of the application and helped draft the manuscript. MW and MR assisted in the computational architecture design. MB conceived of the application, coordinated its design and helped to draft the manuscript. All authors read and approved the final manuscript."} +{"text": "A number of rare human inherited syndromes are associated with apparent defects in DNA repair and a greatly increased frequency of cancer. Cell lines derived from such individuals phenotypically resemble certain bacterial mutant strains that have increased sensitivity to radiation or chemical agents and well characterised repair defects. This analogy provides leads for unravelling the molecular alterations in such cancer-prone human cells. The inducibility of DNA repair enzymes is also reviewed. Exposure of bacteria to alkylating agents, or oxygen radicals, causes the overproduction of several novel and interesting repair activities, and the induced bacteria provide an abundant source of these proteins for purification and biological characterisation. Enzymes with the same defined specificities are often present in human cells, presumably serving the same functions as in microorganisms, but these activities are only constitutively expressed at low levels."} +{"text": "Projects creating gene expression atlases at unprecedented scales for the embryonic fruit fly as well as the embryonic and adult mouse already involve the analysis of hundreds of thousands of high resolution experimental images mapping mRNA expression patterns. Challenges include accurate registration of highly deformed tissues, associating cells with known anatomical regions, and identifying groups of genes whose expression is coordinately regulated with respect to both concentration and spatial location. Solutions to these and other challenges will lead to a richer understanding of the complex system aspects of gene regulation in heterogeneous tissue.Many important high throughput projects use in situ expression imagery and performing subsequent analysis. We use a non-linear, information theoretic based image registration technique specifically adapted for mapping expression images to anatomical annotations and a method for extracting expression information within an anatomical region. Our method consists of coarse registration, fine registration, and expression feature extraction steps. From this we obtain a matrix for expression characteristics with rows corresponding to genes and columns corresponding to anatomical sub-structures. We perform matrix block cluster analysis using a novel row-column mixture model and we relate clustered patterns to Gene Ontology (GO) annotations.We present an end-to-end approach for processing raw in situ experiments.Resulting registrations suggest that our method is robust over intensity levels and shape variations in ISH imagery. Functional enrichment studies from both simple analysis and block clustering indicate that gene relationships consistent with biological knowledge of neuronal gene functions can be extracted from large ISH image databases such as the Allen Brain Atlas and the Means drawn from the mean zero class are given a variance drawn from the interval and for the means drawn from the random class we draw a variance uniformly from . Such matrices have similar statistics to our brain atlas data matrix and other DNA microarray experiments. Table after an initial hierarchical clustering of a larger 46 \u00d7 400 microarray data matrix. Importantly, these hand assigned row column clusters indeed exhibit approximately block constant structure. For the following experiments we randomize this matrix, apply the algorithms described in the previous section and use the hand labeled class assignments as the ground truth. Table In these experiments we compare the algorithms described in the previous sections for the task of automatically determining the class assignments that were used to create figure First, when performing joint row-column cluster analysis one must of course have reason to believe that block constant structure exists in the underlying data. However, figure The authors declare that they have no competing interests.MJ performed the image processing and functional enrichment analysis. CP conceived of and implemented the block clustering analysis. CP, ELM and DK directed the research and contributed to the writing of the manuscript. RTZ provided information on mouse neurobiology."} +{"text": "We have analysed samples from 20 patients with acute myeloid leukaemia for microsatellite alterations by comparing constitutional DNA and DNA from leukaemic samples. Twelve microsatellites were amplified by PCR and investigated for novel bands, indicative of microsatellite instability, or for loss of heterozygosity. Out of 215 paired amplifications, no additional bands were observed at any locus in any of the samples analysed and loss of heterozygosity was found only as four loci from three patients. These results suggest that microsatellite alterations are very uncommon in acute myeloid leukaemia."} +{"text": "Ornithodoros sonrai can be naturally infected with the causative agent.African swine fever is a highly contagious disease of pigs in Africa. Although its persistence in Senegal may be caused by asymptomatic carriers involved in the domestic transmission cycle, we demonstrated that the soft tick Asfaviridae virus, and usually results in acute hemorrhagic fever in susceptible animals with mortality rates up to 100% in some herds (African swine fever (ASF) is one of the most severe diseases of pigs in Africa. It is caused by African swine fever virus (ASFV), an Phacochoerus aethiopicus) or bushpigs (Potamochoerus spp.) and soft tick vectors of the Ornithodoros moubata complex or in a domestic cycle that involves pigs of local breeds with or without tick involvement of PCR products confirmed a 100% relationship with ASFV. One sample was positive by repeated analysis. Three samples showed doubtful results when retested by PCR, which indicated low virus titers.ng sites . Specimes of ASF , panel Aexamined , panel Bexamined . The farO. sonrai is naturally infected with ASFV. Although these preliminary results suggest a role for O. sonrai in persistence of ASFV within a sylvatic cycle, only experimental infections will enable formal testing of O. sonrai as a reservoir and competent vector for AFSV. Additional tick sampling and virus detection analyses are also being conducted to estimate its natural prevalence of infection. If one considers that the ability of pathogens to infect a wide range of hosts is a risk factor for disease reemergence (To our knowledge, this study demonstrated for the first time that O. sonrai colonizes mainly rodent or insectivore burrows with high humidity and a cool temperature favorable for its development and survival. It is rare that such favorable microhabitats are near pigpens and enable ticks to feed on pigs instead of small mammals inhabiting burrows. In addition, heterogeneous and relatively low infestation rates for such microhabitats have been shown in a previous study (O. sonrai. To more clearly quantify contacts between ticks and domestic pigs or warthogs and assess their effect on ASF transmission, analyses of mammalian cytochrome B in tick blood meals and detection of antibodies to tick saliva in serum samples of pigs and warthogs are being conducted.Although contact between soft ticks and domestic pigs has been confirmed in villages in this study, this contact is considered limited."} +{"text": "Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy is a rare recessive autoimmune disorder caused by a defect in a single gene called AIRE (autoimmune regulator). Characteristics of this disease include a variable combination of autoimmune endocrine tissue destruction, mucocutaneous candidiasis and ectodermal dystrophies. The development of Aire-knockout mice has provided an invaluable model for the study of this disease. The aim of this review is to briefly highlight the strides made in APECED research using these transgenic murine models, with a focus on known roles of Aire in autoimmunity. The findings thus far are compelling and prompt additional areas of study which are discussed."} +{"text": "The advent ofimproved imaging methods and the expansion of interventional radiology however, combined withadvances in surgical technique, has produced a change in attitude towards this tumour. The availableworld literature since 1960 has been reviewed and is presented in this article. However, whilst theoutlook for diagnosis and treatment is improving, clearly the association with cholelithiasis (between45% and 100%), is a cause for concern particularly with the advent of treatments which leave gall bladder mucosa and residual fragments of stone"} +{"text": "Significant numbers of mast cells have been demonstrated histologically around the periphery of the invasive rat mammary adenocarcinoma 13672NF. The number of mast cells at microfoci along the tumour:host tissue junction was significantly greater than that found in normal mammary tissues, and few mast cells were detected within the tumour itself. Mast cell degranulation, often associated with disruption and lysis of the connective tissue matrix, was a common feature in later stages of tumour proliferation. When soluble products derived from purified rat peritoneal mast cells were added to monolayer cultures of rat stromal fibroblasts or tumour cells they stimulated a significant increase in total collagenase production, and the mast cell products were also capable of activating the latent collagenases thus produced. Histological examination indicated that degradation of local collagenous matrix was a common feature of mast cell degranulation, an observation possibly explained by the release of mast cell enzymes and/or the potential of this cell to modulate the expression of collagenolytic activity by surrounding cells. These observations suggest that, at least in some tumours, mast cells contribute to the connective tissue breakdown commonly associated with tumour invasiveness and metastatic spread."} +{"text": "This is possibly due to exogenous polyamine salvage from the host, which replenishes the intracellular polyamine pool.Polyamines are present at high levels in proliferating cells, including cancerous cells and protozoan parasites and the inhibition of their synthesis has been exploited in antiproliferative strategies. Inhibition of the malaria parasite's polyamine biosynthetic pathway causes cytostatic arrest in the trophozoite stage but does not cure This implies that disruption of polyamine metabolism as an antimalarial chemotherapy strategy may require targeting both polyamine biosynthesis and transport simultaneously.Plasmodium falciparum parasites, polyamine transport into both the infected erythrocytes and parasites isolated from the erythrocyte were investigated using radioisotope flux techniques.In the absence of a clear understanding of the uptake mechanism of polyamines into While the characteristics of transport of putrescine into infected erythrocytes (iRBC) were similar to those of transport into uninfected erythrocytes (RBC) spermidine uptake occurred via the new permeability pathways (NPP) induced by the parasite in the erythrocyte membrane.Once inside the erythrocyte cytoplasm, both putrescine and spermidine were taken up by the parasite via a temperature- and glucose-dependent, saturable process. The uptake of both these polyamines was competed for by other polyamines, and biosynthesis inhibition led to increased total uptake of both putrescine and spermidine.Polyamine uptake was pH dependent with uptake increasing with increasing pH, but did not appear to be coupled to the Na+ or K+ gradients. Membrane potential perturbations influenced polyamine uptake, consistent with the transport being an electrogenic process."} +{"text": "Basedupon the presence or absence of bleeding on probing (BOP), which isa marker for the disease activity, there were higher levels of theenzyme activity in BOP positive, than in negative sites. When theBOP positive sites became negative after periodontal therapy, theenzyme activity decreased dramatically to almost undetectablelevels. There were no significant differences between the activitybefore and after treatment when the BOP positive sites remainedunchanged. These results suggest that the activity in GCF reflectsperiodontal disease conditions and that it can be used as a markerfor disease activity.The activity of phospholipase A"} +{"text": "Seventy-one patients suffering from acute myeloid leukaemia (AML) who were already in complete remission and had already received one further course of cytotoxic drugs as consolidation therapy were randomised to receive maintenance chemotherapy alone or the same maintenance chemotherapy plus immunotherapy with BCG and irradiated allogeneic blast cells. The duration of first remission was slightly, but not significantly, longer in those patients who received immunotherapy. This was true also for the duration of survival after relapse. Comparison with other series suggested that the effect of such immunotherapy on duration of survival after relapse is probably real, but did not clearly indicate whether or not any real difference in the first remission duration existed."} +{"text": "Advances in pig gene identification, mapping and functional analysis have continued to make rapid progress. The porcine genetic linkage map now has nearly 3000 loci,including several hundred genes, and is likely to expand considerably in the next fewyears, with many more genes and amplified fragment length polymorphism (AFLP)markers being added to the map. The physical genetic map is also growing rapidlyand has over 3000 genes and markers. Several recent quantitative trait loci (QTL)scans and candidate gene analyses have identified important chromosomal regionsand individual genes associated with traits of economic interest. The commercial pigindustry is actively using this information and traditional performance informationto improve pig production by marker-assisted selection (MAS). Research to studythe co-expression of thousands of genes is now advancing and methods to combinethese approaches to aid in gene discovery are under way. The pig's role inxenotransplantation and biomedical research makes the study of its genome importantfor the study of human disease. This review will briefly describe advances made,directions for future research and the implications for both the pig industry andhuman health."} +{"text": "Postoperative renal dysfunction is a relatively common and one of the serious complications of cardiac surgery. Though off-pump coronary artery bypass surgery technique avoids cardiopulmonary bypass circuit induced adverse effects on renal function, multiple other factors cause postoperative renal dysfunction in these groups of patients. Acute kidney injury is generally defined as an abrupt and sustained decrease in kidney function. There is no consensus on the amount of dysfunction that defines acute kidney injury, with more than 30 definitions in use in the literature today. Although serum creatinine is widely used as a marker for changes in glomerular filtration rate, the criteria used to define renal dysfunction and acute renal failure is highly variable. The variety of definitions used in clinical studies may be partly responsible for the large variations in the reported incidence. Indeed, the lack of a uniform definition for acute kidney injury is believed to be a major impediment to research in the field. To establish a uniform definition for acute kidney injury, the Acute Dialysis Quality Initiative formulated the Risk, Injury, Failure, Loss, and End-stage Kidney (RIFLE) classification. RIFLE, defines three grades of increasing severity of acute kidney injury \u2013 risk (class R), injury (class I) and failure (class F) \u2013 and two outcome classes (loss and end-stage kidney disease). Various perioperative risk factors for postoperative renal dysfunction and failure have been identified. Among the important preoperative factors are advanced age, reduced left ventricular function, emergency surgery, preoperative use of intraaortic balloon pump, elevated preoperative serum glucose and creatinine. Most important intraoperative risk factor is the intraoperative haemodynamic instability and all the causes of postoperative low output syndrome comprise the postoperative risk factors. The most important preventive strategies are the identification of the preoperative risk factors and therefore the high risk groups by developing clinical scoring systems. Preoperative treatment of congestive cardiac failure and volume depletion is mandatory. Avoidance of nephrotoxic drugs and prevention of significant hemodynamic events that may insult the kidney are essential. Perioperative hydration, aggressive control of serum glucose, haemodynamic monitoring and optimization of ventricular function are important strategies. Several drugs have been evaluated with inconsistent results. Dopamine and diuretics once thought to be renoprotective has not been shown to prevent renal failure. Mannitol is probably effective if given before the insult takes place. Some of the newer drugs like fenoldopam, atrial natriuretic peptide, N-acetylcysteine, clonidine and diltiazem have shown some promise in preventing renal dysfunction but more studies are needed to establish their role of renoprotection in cardiac surgery. Postoperative renal dysfunction is are latively common and one of the serious complications of cardiac surgery. Renal dysfunction or failure occurs nearly in 8% of all patients undergoing myocardial revascularization16Although serum creatinine (Cr) is widely used as a marker for changes in glomerular filtration rate (GFR), the criteria used to define renal dysfunction and acute renal failure (ARF) is highly variable-4468When using RIFLE criteria for assessment of renal dysfunction, two large retrospective studies indicate the incidence of acute kidney injury (AKI) after cardiac surgery is about 15% to 20%177Several studies have examined the risk factors associated with the development of postoperative renal failure. Most patients at increased risk for postoperative renal dysfunction can be identified before their surgical procedures. Certain preoperative risk factors have been repeatedly associated with an increased risk of ARF1The pathologic changes in the kidney of patients with ARF following OPCAB are largely assumed to be due to acute tubular necrosis which is usually confirmed by granular casts in the urine. Hypoxia-ischemia is the predominant cause of perioperative ARF and results from low renal blood flow due to a reduced cardiac output; from regional factors reducing renal blood flow; or from disturbances of intrarenal blood flow related to inflammation, sepsis or toxinPrevention of postoperative renal dysfunction after OPCAB needs knowledge of identifying the preoperative risk factors. Several groups have developed clinical scoring systems that help to predict the risk23Several drugs have been tried in attempting to reduce postoperative renal dysfunction with inconsistent results. Loop diuretics increase renal cortical blood flow414954606265The development of renal dysfunction after cardiac surgery is an independent predictor of poor outcome. We must develop a standard definition of ARF that is sensitive and specific to determine the true incidence of this complication, permit an accurate assessment of ARF on outcomes, and allow comparison of patients across centers. Early preventive measures may be a way of reducing postoperative ARE. Thus, sensitive markers of renal injury are desirable for early intervention to diminish and minimize the perioperative renal insults. Some recent studies demonstrate that sensitive markers of tubular injury may be altered much earlier than a rise in serum creatinine and may allow us to define the time points when injury occurs72"} +{"text": "Until recently, West Nile (WN) and Kunjin (KUN) viruses were classified as distinct types in the Flavivirus genus. However, genetic and antigenic studies on isolates of these two viruses indicate that the relationship between them is more complex. To better define this relationship, we performed sequence analyses on 32 isolates of KUN virus and 28 isolates of WN virus from different geographic areas, including a WN isolate from the recent outbreak in New York. Sequence comparisons showed that the KUN virus isolates from Australia were tightly grouped but that the WN virus isolates exhibited substantial divergence and could be differentiated into four distinct groups. KUN virus isolates from Australia were antigenically homologous and distinct from the WN isolates and a Malaysian KUN virus. Our results suggest that KUN and WN viruses comprise a group of closely related viruses that can be differentiated into subgroups on the basis of genetic and antigenic analyses."} +{"text": "Castrate female rats given weekly applications of DMBA to the genital tract and treated additionally with growth hormone, insulin or alloxan (to induce diabetes) are heavier and have more sarcomatous and epithelial cervico-vaginal neoplasms than intact animals under the same experimental conditions. Promotion of carcinogenesis and gain in body weight are independent phenomena caused by castration in the medicated rats. Growth hormone is most effective in enhancing body weight in all animals, but least as regards tumour formation. It reduces the incidence of sarcomas in intacts, but raises that of epithelial neoplasms, and promotes both types of neoplasms in castrates. The highest incidence of cervico-vaginal epithelial and sarcomatous tumours occurs in spayed diabetics.Squamous celled epitheliomas of the vulva are not affected by castration or additional medication, while basal celled neoplasms tend to be more frequent in intacts than in castrates and particularly numerous in intact failed diabetics. Vulval sarcomas are usually rare but are increased in numbers in diabetic and in insulin treated intacts.Granular myoblastomas of the cervico-vaginal tract occur in intacts only and particularly in diabetics and those medicated with growth hormone or insulin."} +{"text": "Restricted expression of oncofetal fibronectin mRNA in the tissues of thyroid papillary and anaplastic carcinoma has recently been shown by both Northern blot analysis and reverse transcriptase polymerase chain reaction (RT-PCR). Oncofetal fibronectin mRNA can be a target of gene diagnosis and targeted gene therapy, provided it is expressed in all cancer cells in the tissues. To investigate this criterion in thyroid cancer tissues, we measured their expression of oncofetal fibronectin mRNA using in situ hybridization. An abundant expression of oncofetal fibronectin mRNA was found in all the observed cancer cells of six papillary carcinomas and an anaplastic carcinoma, but not in the tissues of normal thyroid, Graves' disease, adenomatous goitre, follicular adenoma, follicular carcinoma or medullary carcinoma. This result encourages us to establish gene diagnosis of thyroid papillary and anaplastic carcinomas by detecting oncofetal fibronectin mRNA in biopsies."} +{"text": "Ovarian mucinous cysts, but not ovarian cysts of other histological types, contain common antigens with normal gastric mucosa. By immunodiffusion, antigens of both extracts give identical reactions. Immunofluorescence experiments localize these antigens in the epithelial coat of ovarian mucinous cysts and in the mucous cells of the surface epithelium of the fundic and pyloric gastric mucosa."} +{"text": "The second British Stomach Cancer Group trial was a prospective randomised controlled trial of adjuvant radiotherapy or cytotoxic chemotherapy after gastrectomy for adenocarcinoma. It recruited between 1981 and 1986. No survival advantage has been demonstrated for the patients receiving either type of adjuvant therapy compared with those undergoing surgery alone. We report on 436 patients randomised into the trial together with 203 patients, who did not fulfil the trial criteria, referred to the trial. A univariate (log-rank) analysis of pathological factors obtained from the local referring centres showed that tumour size, macroscopic type, number os sites involved, depth of invasion, involvement of resection lines and lymph nodes and histological grade were significant determinants of survival. Histological review by two experienced histopathologists found that the Lauren classification and histological grade, but not the Ming classification, were significant prognostic factors. The degree of lymphocytic and eosinophilic infiltration and presence of dysplasia assessed by one of the pathologists showed a significant correlation with survival. However, inter-observer correlation for these histological parameters and grade was poor. Multivariate analysis identified only depth of invasion, resection line and nodal involvement as significant independent pathological variables influencing survival. This study confirms the need for expert preparation of the resected specimen to obtain the important information on depth of invasion and nodal status and also reveals some variation in histological assessment, particularly grading, in gastric carcinoma."} +{"text": "Spontaneous regression of metastatic renal cell carcinoma is rarely observed. A case of suspected spontaneous regression of pulmonary metastases following nephrectomy for histologically proven renal cell carcinoma without systemic treatment is presented along with a brief review of the literature. A 60 year old man, who was under regular haematological follow-up because of myelofibrosis, presented at a routine clinic visit complaining of increasing shortness of breath, weight loss and lethargy. Clinical examination of the chest was normal but a chest x-ray (CXR) showed multiple lung lesions consistent with metastatic deposits figure . A stagiThe patient underwent laparoscopic cytoreductive nephrectomy without complications and agreed to have immunotherapy with alpha-interferon. Histology revealed clear cell renal cell carcinoma. Six weeks following the operation, just prior to commencing immunotherapy, he attended the haematology clinic as routine follow-up. His initial symptoms had completely resolved and a repeat chest radiograph on that day showed clear lungs with no evidence of metastatic deposits figure . AlthougRenal cell cancer accounts for 2% of all cancers and its incidence is steadily rising. It usually presents in late adult life and is more common in males than females. Although they are associated with Von Hippel-Lindau disease, adult polycystic kidney disease and multicystic nephroma, most renal cell cancers develop spontaneously .The patient may present with urological symptoms such as haematuria or flank pain or with an abdominal mass or alternatively with systemic manifestations, such as anaemia and fever, or symptoms of metastatic disease and other rare phenomena .Approximately 20% to 30% of patients with renal cell carcinoma present with metastatic disease, and 20% to 40% of patients undergoing nephrectomy for clinically localized disease will develop metastasis [However, a group of patients with advanced disease have experienced improvements in survival, which is partly related to the introduction of immunotherapeutic approaches and a better understanding of the role and timing of cytoreductive nephrectomy. Although the benefits of immunotherapy have been displayed repeatedly by several studies, controversy has existed as to the need for adjunctive nephrectomy in treating metastatic patients. Removal of the malignant kidney may be of palliative benefit in some settings of metastatic renal cell carcinoma . There hThere have been case reports in the literature that describe spontaneous regression of metastatic renal cancer ,7-12.Bumpus described the first reported case of spontaneous regression of metastatic renal cell carcinoma in 1928 . MetastaThe rarity of the observation and the heterogeneity of the clinical circumstances in which spontaneous regression of disease occurs do not provide the opportunity for insight into the pathophysiologic mechanism or into the capability for the identification of potential candidates for regression. Although no single mechanism can completely account for this phenomenon, it can be speculated that resection of the primary tumour may result in removal of a prometastatic or growth factor secreted by the tumour and/or promotion of apoptosis might be involved. Immunologic factors almost certainly play a role in some cases of spontaneous tumour regression and perhaps removal of bulk tumour enables or stimulates the immune system to control residual disease. Other theories include hormonal changes, trauma and changes in blood supply (via inhibition of angiogenesis by cytokines) .It is important to recognize the existence of this clinical entity, which, although rare, might provide another argument in favour of surgical intervention or immunological treatment of metastatic renal cancer. The observation itself should also provide encouragement and drive to pursue immunologic as well as other investigations of the disease.The authors declare that they have no competing interests.SV conceived of the case.PAV and KL drafted the manuscript.BM finalized the manuscript.All authors have read and approved the final manuscript."} +{"text": "Before performing any eye procedure:Wash your hands (and afterwards too)Position the patient comfortably with his/her head supportedAvoid distraction for yourself and the patientEnsure good lightingAlways explain to the patient what you are going to do.To remove ingrowing eyelashes (trichiasis)To prevent corneal abrasionMagnification (magnifying loupe)Torch or flashlightGauze swabsLocal anaesthetic eye dropsEpilation forcepsA helperExplain the procedure and advise the patient that it will cause some very brief discomfortThe patient, helper, and examiner should be positioned appropriately. The helper can hold the torch Figure .Instil the local anaesthetic eye dropsUsing magnification, identify the eyelashes which need epilating Figure For lower eyelashes:ask the patient to look up, fix his/her gaze, and keep stillwith an index finger, gently hold down the lower eyelidFor upper eyelashes:ask the patient to look down, fix his/her gaze, and keep stillwith a thumb, gently ease the upper eyelid up against the orbital rimWith the epilation forceps in the other hand, hold the ingrowing eyelash close to its base and pull gently forward to pluck it out Figure Repeat until all ingrowing lashes are epilatedBetween each epilation, wipe the eyelash off the forceps with a clean swab Figure Reassure the patient when all ingrowing lashes have been removed and advise him/her not to rub the eye."} +{"text": "In a clinical investigation of observed postoperative survival, 563 patients have been registered for primary surgical treatment of colorectal cancer since 1974. The potential prognostic factors examined within the first days of hospitalization for primary resection included age of the patients, operability, location of the tumour, tumour extension and the preoperative serum CEA level. Statistical treatment of the data revealed that each of the clinical parameters except tumour location covers ranges associated with highly significant differences in survival of the patients. The preoperative serum CEA level gave prognostic information in addition to operability or tumour extension. The prognostic significance of the preoperative CEA level was still evident when selected subgroups of patients with distinct resectability and tumour extension were examined. The results indicate that the preoperative serum CEA level is an independent prognostic parameter."} +{"text": "The influence of leukaemic cells on the colony formation of human bone marrow cells was studied in vitro as an extension of our previous work . An extract of leukaemic bone marrow cells significantly suppressed colony forming ability of the normal bone marrow cells, whereas an extract of normal bone marrow cells did not suppress it except in two cases. The suppressive effect of normal bone marrow cells, however, was obviously less intense than that of leukaemic cells. This suppressive effect was dose dependent and was fairly stable to heat treatment. These results suggest that leukaemic bone marrow cells contain factor(s) which suppress normal colony formation."} +{"text": "Renal physiology has often been the most difficult topic for students to grasp and provides pedagogical challenge to educators. It has an inherent difficulty associated with it (intrinsic cognitive load). This inherent difficulty may not be altered by an instructor by didactic lecture or by static slides without animation (extraneous cognitive load) and it then becomes difficult for the student to understand core concepts in renal physiology like renal regulation of acid-base balance through ion exchange .The first example is that of typical conventional diagram provided in almost all physiology text books. To learn from these diagrams learners must split their attention between various arrows to understand and grasp ion exchange. This is a typical example of Split-attention effect (extraneous cognitive load) and eludes elucidation as it has to be decoded mentally to which many learners may not be adept at and also our working memory capacity is limited. The later slides depicting \"Integrated example\" enhances learning because embellished with animations and displayed sequentially, it guides the learner's attention through the worked example.The linguistic invention-animation-based lectures (ABL) as a protologism was first used by us in 2009. Majority of the students agreed that ABL helped to sustain interest, visualize concepts better, remembering facts, applying knowledge and understanding better different aspects of physiology teaching .Students dislike both transparencies and static PowerPoint slides for the monotony and lack of interest it generates among both the teacher and student. There is richness that occurs while incorporating multisensory modalities as part of ABL . It is aselecting relevant words and images, organizing words and images into coherent verbal and visual models, and integrating the corresponding components of the verbal and visual models [According to a cognitive theory of multimedia learning, active learning occurs when a learner engages in the cognitive process of l models .ABL, therefore, as a pedagogical tool in renal physiology is a metacognitive strategy that assists learners and minimizes working memory load and promotes meaningful learning. More ABL as instructional design decrease extraneous cognitive load during learning, and refocus that learner's attention toward germane materials, increasing germane (schema related) cognitive load. Carefully crafted hypotheses and well-matching experiments will go a long way to providing insight into the true value of animations as pedagogical tools."} +{"text": "The kinds of computational techniques described here have been widely applied in other areas of immunology, including the innate response PLoS Computational BiologyImmunological Reviews (216) devoted to quantitative modeling of immune responses.The immune system acts across multiple scales involving complex interactions and feedback, from somatic modifications of DNA to the systemic inflammatory reaction. Computational modeling provides a framework to integrate observational data collected from multiple modes of experimentation and insight into the immune response in health and disease. This Message attempts to illustrate how different computational methods have been integrated with experimental observations to study an immunological question from multiple perspectives by focusing on a very particular, though fundamental, component of adaptive immunity: B cells and affinity maturation . B cellsThe adaptive immune system operates by clonal selection. A preformed repertoire of diverse Ig receptors for antigen is clonally distributed among a finite but large number of B cells. These receptors are generated by a somatic recombination process that brings together a number of interchangeable gene segments present in the DNA. Recombination signals (RSs) associated with each segment help determine the efficiency of segment pairing, but high variability both across and within species has made experiments difficult to interpret. Computational models have been used effectively to exploit the correlation structure of known RSs to predict recombination efficiency and to recognize new RSs Foreign antigens are recognized by individual B cells that happen to have receptors that bind, with the threshold for activation being set low, since in general these chance \u201cfits\u201d between receptor and pathogen will have weak interactions. During the course of an immune response, Ig receptors that initially bind antigen with low affinity are modified through cycles of somatic mutation and affinity-dependent selection to produce high-affinity memory and plasma cells. Somatic mutation is a process unique to B cells responding to antigen that results in a mutation rate that is 7\u20138 orders of magnitude above normal background (and thus often referred to as hypermutation). Identifying somatic mutations in experimentally derived Ig receptor sequences is critical to understanding this process, but can be challenging since the germline sequence for individual B cells is chosen stochastically during cell maturation in the bone marrow and thus is not known a priori. Imprecision in the recombination process, and the action of various enzymes that can add or delete nucleotides during rearrangement, further compounds this problem. Hidden Markov models and other computational approaches have been instrumental to predict germline sequences, including the most likely combination of gene segments involved http://imgt.cines.fr), which contains a wealth of sequence information, including the germline Ig genes of several species and links to analysis tools.Analyzing the interaction between somatic hypermutation and germline codon usage in the Ig receptor has provided insight into strategies used by the immune system to adapt to pathogenic challenge. In general, more mutable codons are used in the complementary determining regions (CDRs), where most contact residues for antigen binding are found, and less so in framework (FW) regions, which provide the structural backbone of the receptor The mutation patterns in experimentally derived Ig sequences provide a kind of fossil record for the affinity maturation process, and can furnish important evidence of antigen-driven selection. The most common tests for selection compare the observed frequency of replacement mutations to their expected frequency under the null hypothesis of no selection. Elevated frequencies indicate positive selection, while decreased levels indicate negative selection with significance determined by a binomial test Low sensitivity is another problem that plagues methods for detecting selection. Additional information may be extracted from B cell lineage trees , which depict the relationships between groups of B cells that share a common ancestor (often generated from microdissection experiments). Unlike the case for phylogenetic trees, the relatively small number of mutations and sequences means there are often few ambiguities in creating these trees. Monte Carlo simulation approaches have been used to link the topological properties of B cell lineage trees to underlying biological processes such as somatic hypermutation p and undergoes apoptosis at rate d. To model BrdU labeling, this population is split into unlabeled (BU) and labeled (BL) subsets:s) and 100% labeling efficiency.Affinity maturation involves extensive proliferation and death. Accurate rate measurements for these processes can help determine their relative contribution to the preferential expansion of higher-affinity B cell mutants. Dividing cells can be labeled using bromodeoxyuridine (BrdU), a thymidine analog that gets incorporated into DNA during S phase. The fraction of labeled cells is tracked during BrdU administration and following withdrawal using flow cytometry. To interpret these data, Bonhoeffer et al. Similar kinds of population dynamic models have been developed to help interpret experiments using the cell dye carboxyfluoroscein succinimidyl ester (CFSE) The biological mechanisms underlying the preferential expansion of rare higher-affinity B cell mutants are largely unknown. Population dynamic models including somatic hypermutation and selection can be used to explore the consequences of different hypotheses. Indeed, such modeling played an important role in suggesting that a process involving cyclic re-entry was necessary to achieve efficient affinity maturation The spatial structure of the germinal center is thought to play an important role in affinity maturation, and many models include multiple compartments. However, it has only recently become possible to visualize the spatiotemporal dynamics of immune responses in vivo using \u201cintravital multi-photon microscopy,\u201d which allows tracking of individual cells in the lymph nodes and germinal centers Modeling and computational approaches have been widely applied to problems in immunology, and are finding increasing applications as experiments become more quantitative and seek to extract information on kinetics. Virtually all of the top immunology journals now publish papers with significant computational components, which was not the case just a few years ago. In some ways, this success presents a challenge for those looking to get started in the field. Leading computational immunology research groups often publish their work in domain-specific experimental journals and present at biology conferences, so finding and following state-of-the-art research requires tracking several journals and becoming familiar with many different areas of biology."} +{"text": "Periodontal diseases are microbial induced chronic inflammatory conditions characterized by infiltration of leukocytes, loss of connective tissue, alveolar bone resorption, and formation of periodontal pockets. In response to periodontal pathogens, the leukocytes (PMN) elaborate destructive oxidants, proteinases and other factors. The balance between these factors, the antioxidants and endogenously synthesized antiproteinases determine the extent of periodontal damage. Diabetes mellitus is a metabolic disorder. Most of the complications of diabetes are due to hyperglycemia. Persons with diabetes are at a greater risk for periodontal disease Malnutrition is characterized by marked tissue depletion of antioxidant nutrients and impaired acute phase protein response to infections resulting in impaired healing. Diabetes mellitus also alters the micronutrient levels. Malnutrition is characterized by marked tissue depletion of antioxidant nutrients and impaired acute phase protein response to infections resulting in impaired healing. Malnutrition, which usually involves concomitant deficiencies of several essential macro and micro nutrients, therefore, has the potential to adversely influence the prognosis of periodontal infections. Objectives:This study has been conducted to evaluate and compare the serum levels of vitamin C, zinc and copper in diabetic and healthy individuals with periodontitis.In this case control study 60 subjects inclusive of both sexes were selected and divided into 3 groups of 20 each. Group 1 comprised of 20 subjects with type 2 diabetes mellitus and periodontal disease, Group 2 comprised of 20 healthy subjects with periodontal disease. And Group 3 comprised of 20 healthy subjects without periodontal disease. Venous blood samples were collected and centrifuged at 3000rpm for 15 minutes and the superanatant serum is collected to measure the vitamin C, zinc and copper levels. The vitamin C levels of clinical samples were measured using spectrophotometric quantitation (dinitrophenyl hydrazine method) and zinc and copper levels were measured using atomic absorption spectrophotometry.The results showed that the levels of vitamin C and zinc decreased and copper levels increased in diabetic patients with periodontits compared to healthy individuals with periodontitis.It may be reasonable to suggest vitamin and/or mineral supplements for patients whose nutrition might be inadequate. Future research should focus on an evaluation of which nutrients may help to prevent the onset and progression of periodontal disease Periodontitis is a term used to describe an inflammatory process, initiated by the plaque biofilm that leads to loss of periodontal attachment to the root surface and adjacent alveolar bone and which ultimately results in tooth loss. The primary etiological agent is specific, predominantly gram negative anaerobic or facultative bacteria within the subgingival biofilm. These bacteria have the ability to activate host defense mechanisms, which breakdown epithelia and other structures of gingiva and periodontium, while at the same time inactivating repair systems.Although now it has been unanimously accepted that periodontal disease is the resultant of an interaction between microbial plaque and the resultant inflammatory and immunological changes within the periodontal tissues, it is also recognized that the nature and severity of this interaction in turn may be modified by many systemic factors, including hormonal changes, nutritional deficiencies, blood dyscrasias, drug ingestion, aging or a compromised immune system.The vitality of the periodontal tissues, in both health and disease, depends strongly upon an adequate source of essential nutrients being available to the host. The epithelium of the dento-gingival junction and the connective tissue are among the most dynamic tissues in the body. The maintenance of these tissues and, therefore, the integrity of periodontium is dependent upon adequate supply of proteins, carbohydrates, fats, vitamins and mineral salts. A chronic deficiency in the availability of one or more of these nutrients may be expected to produce pathological alterations in the periodontal tissues.The food we eat contains nutrients. Nutrients can be considered major or minor, as determined by the amounts consumed in our diet. Major nutrients are consumed in gram quantities and they include protein, carbohydrates, lipids. Micro nutrients are required in milligram to microgram quantities and include vitamins and minerals.Periodontal diseases are the result of bacterial infections to the gingival tissues. Therapy to decrease the levels of oral microorganisms can reduce gingivitis and stabilize periodontitis. Although dietary components play a major role in the pathogenensis of dental caries, diet plays primarily a modifying role in the progression of periodontal disease. A periodontal lesion is essentially a wound, and sufficient host resources must be available for optimal healing to take place.et al. in 2003 reviewed the literature on the use of specific nutrients to prevent and/or treat periodontal diseases and concluded that although treatment of periodontal disease with nutritional supplementation has minimal side effects, the data on its efficacy are limited. Diabetes mellitus is a group of complex multisystem metabolic disorders characterized by a relative or absolute insufficiency of insulin secretion and or concomitant resistance to the metabolic action of insulin on target tissues.The exact mechanism by which nutritional deficiencies modify periodontal destruction has not yet been precisely defined. The effect of nutrition on the immune system and its role in periodontal disease has been recently reviewed. Nevia Diabetes mellitus is a major health problem in the world. Approximately 5% of the diabetics are classified as Type- 1(IDDM), a condition characterized by abrupt onset at any age, destruction of pancreatic islet cells, and dependence on exogenous insulin. The more prevalent form of diabetes is Type- 2 (NIDDM), a condition which often develops over a period of time, involves reduced responsiveness of tissues to circulating insulin, and is often controlled by diet or oral hypoglycemic drugs. Both types are characterized by hyperglycemia, hyperlipidemia, and associated complications.Hyperglycemia is a hallmark of diabetes mellitus as are its chronic metabolic complications. Periodontitis has been recognized as the sixth major complication of diabetesAmong the systemic factors, the relationship between periodontal disease and diabetes mellitus has been studied extensively. Many investigators, in their epidemiological, experimental and clinical studies have reported that the severity of periodontal diseases is significantly greater among diabetics than in non- diabetics. Malnutrition has been suggested as a cause of diabetes mellitus. Numerous studies have found alterations in micronutrient status of patients with diabetes mellitus, and in some studies deficiency of certain minerals or vitamins has been correlated with presence of diabetic complications. However, the exact pathogenetic role of malnutrition in diabetes mellitus has been disputed.Hence this study has been designed to estimate and compare the micronutrient levels of vitamin C, zinc and copper in diabetic patients and healthy individuals with periodontitis.A study to compare the serum levels of copper, zinc and magnesium in diabetic patients concluded that diabetes can alter copper and zinc levels. Perturbations in mineral metabolism are more pronounced in diabetic populations. But it is not clear whether differences in trace element status are a consequence of diabetes or alternatively, whether they contribute to the expression of disease.A case control study was conducted to evaluate the serum metal status in patients with noninsulin diabetes mellitus. They concluded that diabetics had lower zinc levels and higher copper levels than controls. There is also evidence of significant difference in metal status between diabetic patients with or without specific complications. This further indicated that patients with noninsulin diabetes mellitus have distinct changes in their metal status, and these perturbations are associated with some diabetic complications.A study was conducted to evaluate the effect of dietary intake of vitamin C and the presence of periodontal disease. Dietary intake showed a statistically significant relationship between with periodontal disease status, as measured by clinical attachment loss. Those taking the lowest levels of vitamin C had the greatest negative clinical effect on their periodontal tissues.Lack of vitamin C has been related to an increased risk of periodontal disease in a clinical study. The serum levels of vitamin C were significantly lower in peridontitis patients compared to healthy controls; consumption of grape juice for two weeks led to an increase in plasma vitamin c levels and reduced gingival sulcus bleeding scores.A study was conducted to evaluate the serum zinc levels and severity of periodontal disease. It concluded that patients with decreased zinc levels had increased alveolar bone resorption.A study was conducted to evaluate serum copper concentrations in diabetic individuals and healthy individuals. The results concluded that serum copper levels are higher in diabetic patients than healthy individuals.To estimate the level of vitamin c, zinc and copper in serum of diabetes mellitus patients with periodontitisTo estimate the level of vitamin c, zinc and copper in serum of healthy individuals with and without periodontitisTo compare the level of vitamin c, zinc and copper in serum of Type 2 diabetes mellitus patients and healthy individuals with periodontitisThe subjects for this study were selected from the outpatients, Department of Periodontics, A.B. Shetty Memorial Institute of Dental Sciences, Deralakatte, MangaloreThe study was designed as a case\u2013control study comprising of 60 subjects, inclusive of both sexes and were divided into three groups of 20 patients each:Group I: 20 patients of Type 2 Diabetes Mellitus with periodontal diseaseGroup II: 20 healthy subjects with periodontal diseaseGroup III: 20 healthy individuals without periodontal diseasePatients categorized as Type 2 diabetes mellitus should haverandom blood glucose \u2265 200 mg/dl with symptoms such as polyuria, polydipsia, polyphagiafasting blood glucose \u2265 126 mg/dlPatients with periodontal disease havinggeneralized clinical attachment loss\u2265 5mm measured with a Williams periodontal probebleeding on probingControls who are periodontally healthyPatients who had not undergone any periodontal surgery for at least six months prior to samplingAll measurements and samples are taken before starting any periodontal therapyHistory of any antibiotic therapy within six months prior to studyHistory of any systemic disease for the control groupHistory of any systemic disease other than diabetes for the test groupSubjects who are pregnant and pre eclampticSubjects with a history of smoking, tobacco consumptionSubjects with vitamin supplementsSubjects who regularly use mouth washesVenous blood samples were collected and centrifuged at 3000 rpm for 15 minutes and the supernatant serum is collected to measure the vitamin c, zinc and copper levels. The vitamin C levels of clinical samples are measured using spectrophotometric quantitation (dinitrophenly hydrazine method) and zinc and copper levels is measured using atomic absorption spectrophotometryA study was conducted at the Department of Periodontics, A.B. Shetty Memorial Institute of Dental Sciences, Mangalore to evaluate and compare the serum micronutrient status in diabetic patients and healthy individuals with periodontitis.t test was used for statistical analysis. The student P value less than 0.0001 in diabetic patients and healthy individuals with periodontitis.On a global basis, malnutrition is the most wide spread cause for immunosuppression in humans. Several lines of evidence strongly suggest that chronically malnourished individuals constitute a special risk group for severe and at times unique periodontal pathologies. The commonest types of periodontal lesions are inflammatory lesions elicited by specific pathogens in dental plaque. When exposed to infections or inflammatory agents, the host responds not only by mounting appropriate specific and nonspecific immune responses but also by initiating a well characterized series of metabolic adjustments. Inflammatory stimuli from dental plaque promote release of reactive free radicals and also elicit metabolic changes that are modulated by potent soluble mediators known as cytokinesDeficiency of vitamin C, zinc and copper increases susceptibility to infection, impair the function of neutrophils and macrophages, reduces antibody -mediated, cell- mediated, phagocytic and delayed type of hypersensitivity reactions and depletion of antioxidants.The pathogenesis of periodontal disease is complex because it reflects a combination of the initiation and maintenance of the chronic inflammatory process by a diverse microbial flora and its numerous bacterial products. The subsequent host response to this infection mediates a complex cascade of tissue destructive pathways.Additional factors contributing to this multifaceted local disease process in the oral cavity include a number of systemic diseases, especially diabetes that can exaggerate the host response to the local microbial factors, resulting in unusually destructive periodontal breakdown.An abundance of information accumulated from studies on the complications of diabetes and periodontal disease has revealed that a hyperactive innate immune response may be the antecedent of both diseases, which probably have a synergistic effect when they coexist in the host.Experimental evidence in diabetes mellitus patients has suggested that micronutrient deficiency leads to glucose intolerance. Serum content of copper increased and vitamin C and zinc levels were lower in diabetics than non-diabetics. These alterations may contribute to some of the complications of diabetes and there is a place for judicious replacement of micronutrients in diabetic patients with demonstrated deficiencies.In our study the results show that serum vitamin C and zinc levels were lower and copper levels were higher in diabetic patients with periodontitis when compared to healthy individuals with periodontitis.It is reasonable to consume a nutritionally adequate diet to help maintain host resistance and the integrity of the periodontal tissues. A good diet contributes to both good general health and good oral health. There is, however, insufficient evidence to justify treatment with vitamin and mineral supplementation in the adequately nourished individual. Periodontal disease is an infectious disease that can be treated and prevented by the elimination of dental plaque in the adequately nourished individual. However, it may be reasonable to suggest vitamin and /or mineral supplement for patients whose nutrition might be inadequate. Future research should focus on an evaluation of which nutrients may help to prevent the onset and the progression of periodontal disease."} +{"text": "The emergence of physician owned specialty hospitals focusing on high margin procedures has generated significant controversy. Yet, it is unclear whether physician owned specialty hospitals differ significantly from non physician owned specialty hospitals and thus merit the additional scrutiny that has been proposed. Our objective was to assess whether physician owned specialty orthopedic hospitals and non physician owned specialty orthopedic hospitals differ with respect to hospital characteristics and patient populations served.We conducted a descriptive study using Medicare data of beneficiaries who underwent total hip replacement (THR) and total knee replacement (TKR) in 29 physician owned and 8 non physician owned specialty orthopedic hospitals during 1999\u20132003. We compared hospital characteristics of physician owned and non physician owned specialty hospitals including procedural volumes of major joint replacements (THR and TKR), hospital teaching status, and for profit status. We then compared demographics and prevalence of common comorbid conditions for patients treated in physician owned and non physician owned specialty hospitals. Finally, we examined whether the socio-demographic characteristics of the neighborhoods where physician owned and non physician owned specialty hospitals differed, as measured by zip code level data.Physician owned specialty hospitals performed fewer major joint replacements on Medicare beneficiaries in 2003 than non physician owed specialty hospitals , were less likely to be affiliated with a medical school , and were more likely to be for profit . Patients who underwent major joint replacement in physician owned specialty hospitals were less likely to be black than patients in non physician owned specialty hospitals , yet physician owned specialty hospitals were located in neighborhoods with a higher proportion of black residents . Patients in physician owned hospitals had lower rates of most common comorbid conditions including heart failure and obesity (P < .05 for both).Physician owned specialty orthopedic hospitals differ significantly from non physician owned specialty orthopedic hospitals and may warrant the additional scrutiny policy makers have proposed. The emergence of specialty hospitals focusing on narrow procedural aspects of medicine has generated widespread controversy. One area of controversy has been the allegation by critics that specialty hospitals preferentially admit low-risk patients without demonstrating improvements in risk-adjusted outcomes ,2. RecenAnother area of controversy has centered on the precise definition of a specialty hospital and, in particular, the importance of physician ownership of specialty hospitals as a differentiating factor. Critics of specialty hospitals claim that physician ownership of hospitals is extremely concerning because it creates incentives for physicians to take steps to increase utilization of their facilities , thereby driving up healthcare costs ,6. SuppoAn understanding of potential similarities and differences between physician owned and non physician owned specialty hospitals is of more than academic interest since legislators at both the state and federal levels have responded to the specialty hospital controversy by proposing legislation banning physician ownership of hospitals ,9. WhileWe used Medicare Part A administrative data and American Hospital Association Annual Survey data to answer the following questions: 1) Do physician owned and non physician owned specialty orthopedic hospitals differ with regards to important hospital characteristics including bed size, teaching status, or nurse staffing levels; 2) Do physician owned and non physician owned specialty hospitals differ with respect to the demographic characteristics and comorbidity of the patient populations that they serve; 3) Do physician owned specialty hospitals and non physician owned specialty hospitals differ with respect to the socio-demographic characteristics of the neighborhoods where the hospitals are located.th Clinical Modification (ICD-9-CM) procedure codes (81.51 for primary THR and 81.53 revision THR: 81.54 for primary TKR and 81.55 for revision TKR). The Part A files contain data for Medicare patients discharged from acute care hospitals with the exception of Medicare managed care enrollees. Data elements from the MedPAR data include: patient demographics; primary and secondary diagnoses and procedures, as captured by ICD-9-CM codes; and patients' zip codes of residence. Additional hospital-level information was obtained from the 2003 American Hospital Association Annual Survey, including hospital teaching status, hospital ownership , total number of hospital beds, and hospital registered nurse (RN) staffing. Zip code level socio-demographic information was obtained by linking patients' zip codes to zip code level data available from the 2000 US Census data ) and non physician owned (75% [n = 6]) specialty hospitals were located in urban areas as measured by a rural-urban commuting area of 1 . We alsoOur findings suggest that physician owned and non physician owned specialty orthopedic hospitals differ significantly both in terms of hospital characteristics and the patient populations they serve. Physician owned hospitals tend to be smaller than non physician owned hospitals, are less likely to be affiliated with medical schools, and are more likely to be for-profit. In addition, physician owned specialty hospitals admit Medicare patients who are slightly younger and have fewer comorbid conditions than non physician owned specialty hospitals. Finally, physician owned specialty hospitals are located in zip codes that are less affluent and have a higher proportion of black residents than non physician owned specialty hospitals, though these differences were not statistically significant.A number of our findings are important and merit further comment. Prior studies have demonstrated that specialty hospitals tend to be smaller and less likely to have academic affiliations than general hospitals ,22. LikeThe findings with regard to hospital location are also interesting. Given the prominent role that hospital location could be expected to play in hospital choice, it would be reasonable to expect that the socio-demographic characteristics of the patients admitted to physician owned and non physician owned specialty hospitals would reflect the socio-demographics of the neighborhoods in which these hospitals are located. Thus, our finding that physician owned specialty hospitals admit less affluent patients as measured by the patients' zip codes of residence makes sense because the physician owned specialty hospitals are located in less affluent neighborhoods than the non physician owned hospitals. Conversely, our finding that physician owned specialty hospitals admit a smaller proportion of black patients than non physician owned specialty hospitals despite being located in zip codes with a greater proportion of black residents is somewhat difficult to explain. One possibility is that black patients are choosing not to go to physician owned specialty hospitals, while another is that the physicians who treat black patients are consciously referring these patients to other facilities. Alternatively, it is well documented that blacks have shorter life expectancies than white patients; thus, many blacks may actually die before reaching the age of Medicare eligibility , and thereby depressing the proportion of black patients in the Medicare population .These findings have a number of important implications for the ongoing policy debate over specialty hospitals. At the most basic level, our findings suggest that legislative efforts to ban physician investment in specialty hospitals are likeFirst, banning physician investment in specialty hospitals would have the potential to stifle benefits that may result from physician ownership of hospitals. Potential benefits that have been cited include improved patient outcomes, improved hospital efficiency and cost savings, and enhanced patient satisfaction; some of these purported benefits are substantiated by published data, while others remain hypothetical . For exaSecond, while a ban on physician investment in hospitals would be likely to curtail the growth in physician owned specialty hospitals, it would do little to slow the growth in non physician owned specialty hospitals. Across the United States hospitals faced with stagnant reimbursement and growing numbers of uninsured and under-insured patients are expanding their efforts to grow profitable service lines . In turnThis study has a number of important limitations that should be discussed. First, our assessment of physician ownership of specialty hospitals dichotomized specialty hospitals into physician owned and non physician owned groups. In actuality, it is well recognized that the financial relationships between physicians and specialty hospitals are highly variable . Some hoIn summary, the current study provides evidence that physician owned specialty hospitals differ significantly from non physician owned specialty hospitals, both in terms of hospital characteristics and in terms of the patient populations they serve. Banning physician investment in \"whole hospitals\" is likely to be effective in limiting growth in the largest subgroup of specialty hospitals, but also has the potential to limit innovation in the hospital delivery system.The author(s) declare that they have no competing interests.PC had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed equally to this analysis and approved the final manuscript.The pre-publication history for this paper can be accessed here:"} +{"text": "Nsp), which facilitated the host shift of Pieridae butterflies onto Brassicales host plants ~80 Myr ago.A molecular population genetics understanding is central to the study of ecological and evolutionary functional genomics. Population genetics identifies genetic variation and its distribution within and among populations, it reveals the demographic history of the populations studied, and can provide indirect insights into historical selection dynamics. Here we use this approach to examine the demographic and selective dynamics acting of a candidate gene involved in plant-insect interactions. Previous work documents the macroevolutionary and historical ecological importance of the nitrile-specifier protein . Nsp exhibits unexpectedly high amounts of amino acid polymorphism, unequally distributed across the gene. The vast majority of genetic variation exists within populations, with little to no genetic differentiation among four populations on two continents. A comparison of synonymous and nonsynonymous substitutions in 70 randomly chosen genes among P. rapae and its close relative Pieris brassicae (Large Cabbage White) finds Nsp to have a significantly relaxed functional constraint compared to housekeeping genes. We find strong evidence for a recent population expansion and no role for strong purifying or directional selection upon the Nsp gene.Here we assess the microevolutionary dynamics of the Nsp gene in P. rapae are dominated by recent population expansion and variation in functional constraint across the repeated domains of the Nsp gene. While the high amounts of amino acid diversity suggest there may be significant functional differences among allelic variants segregating within populations, indirect tests of selection could not conclusively identify a signature of historical selection. The importance of using this information for planning future studies of potential performance and fitness consequences of the observed variation is discussed.The microevolutionary dynamics of the Studying plant-insect interactions provides an opportunity to investigate the coevolution of species on a molecular, ecological, and evolutionary level. While ecologists are interested in the overall dynamics and interactions between plants and their insect herbivores, biochemical and molecular level studies focus on the genes and gene products that actually interact between these species groups . EcologiNsp) )Nsp protein will be necessary in order to understand the observed excess amino acid variation. In sum, while regions of relaxed constraint certainly harbor more variation, this does not mean such variation is neutral. Indeed, much of the known amino acid variation affecting the kinetics of metabolic enzymes is located upon the surface of enzymes .-64.Nsp pNsp gene appear to be a mixture of demographic effects (population expansion and high migration) coupled with variation in functional constraint across the gene. Patterns of nucleotide diversity and indirect molecular tests for historical selection reject strong local adaptation, as well as directional and strong purifying selection. Rather than taking the absence of clear signatures of historical selection upon the Nsp gene as conclusive evidence for no fitness variation among alleles, we recognize the limitation of such indirect approaches and remain curious as to the functional effects of the extremely high amount of amino acid diversity. Thus, this study provides a foundation for the design and insightful use of molecular markers for genetic variants whose ecological performance and fitness can be characterized in the field (e.g. [The microevolutionary dynamics at the ld (e.g. ).P. rapae. If this allelic variation has functional consequences, the effects are likely to be environmentally dependent and potentially small. As such, future studies will need very large sample sizes for many families across a range of potentially relevant conditions. Families can be sampled from the field as ovipositing females and will contain sufficient diversity for study. In addition, individuals will need to be sampled during larval stages in order to provide access to the cDNA of the Nsp gene, as the entire coding sequence must be sequenced for no single polymorphic site will suffice to characterize Nsp allelic variation. Only with functional study of the identified genetic variation can we begin to conclusively assess the extent to which the observed variation at Nsp plays an ongoing role in the microevolutionary dynamics of P. rapae and its interaction with the highly variable chemical defense system of their Brassicales hostplants.We now know that there is an exceptional amount of amino acid variation within nearly every population of HH-F carried out the molecular laboratory work, with the help of HV. HH-F and CW analyzed the raw data and performed the statistical analyses, CW conducted the ABC analysis. HH-F and CW designed the study and wrote the manuscript. HV and DH participated in its design and helped draft the manuscript. All authors participated in the writing and approved the final version.Additional Figures and Tables. Figure S1: Comparison of synonymous and nonsynonymous site changes in the NSP domains; Table S1: Summary statistics for molecular tests of selection; Table S2: Summary statistics for MK test; Tree file from GARD output; Pieris species cDNA comparison datatable for dN/dS analysis.Click here for file"} +{"text": "Sir,et al were added to our models.In a recent interesting study by P trend=0.03). This is contrary to the findings of Monroe et al, who observed a significant increase in risk of breast cancer with greater consumption of grapefruit in this subgroup.Stratification by BMI did not alter the breast cancer risk with either grapefruit or grapefruit juice intake. However, stratification by hormone therapy showed a significant decrease in risk of breast cancer with greater intake of grapefruit in women who never used hormone therapy .Furthermore, the association between grapefruit (not grapefruit juice) intake and breast cancer risk differed significantly by oestrogen and progesterone receptor status of the tumours. No association was observed in women with oestrogen and progesterone receptor positive cancers. However, in women with oestrogen and progesterone receptor negative cancers, there was a significant decrease in breast cancer risk with increased consumption of grapefruit , oestrone , or oestrone sulphate .We also examined cross-sectionally the relationship between consumption of grapefruit and grapefruit juice and plasma levels of oestrogens among 701 postmenopausal women not using hormone replacement. No significant correlation was observed for plasma oestradiol (Our findings do not support an adverse effect of consumption of grapefruit or grapefruit juice on risk of breast cancer or on endogenous hormone levels."} +{"text": "Childless women were not at increased risk compared to childbearing , as neither were women with 0\u20131 children compared to women with at least three children . In conclusion, we found no inverse assciation between childbearing and oesophageal adenocarcinoma.The male predominance of oesophageal adenocarcinoma might be explained by oestrogen protection in women. If true, female patients might have sex hormonal disturbances rendering impaired fertility. The influence of childbearing on the risk of oesophageal adenocarcinoma was investigated in a Swedish population-based case ( The striking male predominance among patients with adenocarcinoma of the oesophagus and gastro-oesophageal junction (cardia) remains entirely unexplained . DetectiThe design and organisation of our case\u2013control study has been described in detail elsewhere and 141 female control persons participated. Reasons for nonparticipation among cases were mainly physical or mental disorders or early death, while most nonparticipating controls declined to participate. Some characteristics of the case and control participants are presented in This study did not supply any evidence of a reduced risk of oesophageal or cardia adenocarcinoma related to fertility as measured by childbearing.Although we included virtually all female cases of oesophageal and cardia adenocarcinomas throughout Sweden during a 3-year period, and we combined these tumour sites into one, the sample size was too limited to rule out moderate associations. The point estimates were all confidently close to unity, however, which supports our interpretation that childbearing does not strongly reduce the risk of developing these tumours. Moreover, if our hypothesis was true, we would expect strong effects that should be possible to reveal in the study. The similar sex ratios of oesophageal and cardia adenocarcinomas justified combining these tumours in the analyses. Moreover, their risk factor profiles are similar, although not identical . SeparatThe rarity of oesophageal and cardia adenocarcinoma among women has virtually prohibited epidemiological research of the risk factors for these tumours among females separately. In the absence of known risk exposures that are sufficiently skewed between the sexes, sex hormonal influence has been hypothesised as playing a key role . HoweverIn conclusion, our hypothesis of an inverse relation between childbearing and risk of oesophageal or cardia adenocarcinoma was not supported in this study. However, this finding should not discourage further research of sex hormones in the aetiology of these tumours. A role for sex hormones cannot be excluded on the basis of the available data. The mystery of the male predominance among patients with oesophageal and cardia adenocarcinoma needs to be solved in future research."} +{"text": "Urine of normal rats, pregnant animals and animals bearing chemically induced hepatoma was tested with antisera to foetoproteins by the double immunodiffusion technique. Antigens were not detected in the urine of normal rats. Alpha-foetoprotein was demonstrated in the urine of pregnant rats and hepatomabearing animals."} +{"text": "Anastrozole is the first aromatase inhibitor to show a significant survival advantage over megestrol acetate in post-menopausal women with advanced breast cancer. The rationale for extending the use of aromatase inhibitors to the treatment of early breast cancer is based on the efficacy observed in the advanced setting, combined with good tolerability and a convenient dosing regimen. Furthermore, oestrogen deprivation by ovarian ablation (similar to oestrogen antagonism with tamoxifen) is already established as an effective adjuvant treatment in premenopausal women with modality breast cancer. Anastrozole produces a profound suppression of plasma oestrogen levels which is greater than that obtained with earlier aromatase inhibitors or megestrol acetate. This could account for the differences in clinical efficacy seen between anastrozole and megestrol acetate. In terms of benefits over other endocrine agents, anastrozole causes significantly less weight gain than megestrol acetate; it does not have the partial agonist activity of tamoxifen, and is unlikely to lead to tumour stimulation in patients resistant to tamoxifen or to exert proliferative effects on the endometrium. The lack of oestrogen agonist activity, however, may possibly have detrimental effects on bone mineral density and blood lipid profile. Current clinical trials are investigating the efficacy and safety of anastrozole in the early breast cancer setting. The results of these trials will help to determine whether anastrozole has any benefits over tamoxifen, the current treatment of choice in post-menopausal women with early breast cancer."} +{"text": "Urokinase plasminogen activator (uPA) is a serine proteinase that has been suggested to play an important role in cancer invasion and metastasis. It binds to a specific membrane receptor denominated uPA receptor (uPAR). uPA activates plasminogen to form plasmin, which participates in tissue degradation and proteolysis. Binding of uPA to its receptor accelerates UPA's own activation from pro-uPA, enhancing the activity of the uPA/uPAR cascade. Using immunohistochemistry and Northern blot analysis, we analysed the role of uPA and uPAR in 30 human pancreatic cancers. Immunohistochemical analysis demonstrated moderate to strong immunostaining of both factors in most pancreatic cancers. Cancer lesions with signs of invasion exhibited the strongest immunohistochemical signals for both factors. In addition, in desmoplastic areas adjacent to the cancer cells, moderate uPA and uPAR immunoreactivity was detectable. Northern blot analysis revealed a sixfold and a fourfold increase in uPA and uPAR mRNA levels in pancreatic cancer, respectively, in comparison with normal controls (P<0.01). Correlation of the Northern blot data with the clinical parameters of the patients indicated that patients with concomitant overexpression of uPA and uPAR had a shorter post-operative survival than patients in whom only one or none of these factors were overexpressed (P<0.002). Our data suggest that uPA and uPAR may serve as prognostic markers in human pancreatic cancer and that the marked overexpression of both factors may create an environment that enables pancreatic cancer cells to invade surrounding tissues."} +{"text": "The permanent proliferation arrest, distended morphology and other phenotypic features characteristic of cellular senescence can be triggered by telomere attrition (replicative senescence) and various stresses such as activated oncogenes or genotoxic treatments (premature senescence). Physiological relevance of cellular senescence is apparent from its emerging roles in aging, in tumor pathogenesis as an inducible barrier to tumor progression, and in response to radiotherapy and chemotherapy . MechaniRelevant findings preceding this study include the recent demonstration of cytokine signaling pathways involved in drug-evoked senescence , and theConsidered within the context of other data in the field, these new results help us"} +{"text": "Cell and gene therapy clinical trials began more than 40 years ago. At some institutions cellular therapy laboratories were started to support marrow transplantation. These early laboratories removed red blood cells and plasma from aspirated bone marrow that was used for allogeneic transplants, cyropreserved autologous marrow, depleted T cells from allogeneic grafts and depleted leukemic or cancerous cells from autologous grafts . At otheFor many years cellular and gene therapies were primarily highly experimental therapies which were developed and used in highly specialized academic health care centers. Now these forms of therapies are used in numerous clinical trials throughout the US and worldwide. While the field has advanced, progress has been slow. Some therapies have not been effective and some have been associated with unacceptable adverse out comes. However, both cell and gene therapies have now become important potential therapies for incurable diseases.Hematopoietic stem cell transplants have changed dramatically and have become very successful for hematopoietic reconstitution. Hematopoietic stem cell transplants now make use of marrow, mobilized peripheral blood stem cells and umbilical cord blood for transplants involving HLA matched siblings and unrelated subjects as well as autologous transplants. Recently, there have been important advances in immune therapy of cancer. Immune therapy for melanoma protocols that involve TIL make use of lymphodepletion and autologous CD34+ cell rescue have been reported to result in a greater than 50% objective clinical response rates . Gene thin vitro.The successful clinical results of some cellular and gene therapy clinical trials and the increased understanding of immunology, cancer, and stem cell biology have lead to the development of many potential new therapies. Natural killer (NK) cells and dendritic cells (DCs) are important parts of many cancer immune therapy investigational protocols. Genetically engineered T cells and DCs are being tested for immune therapy for cancer. Vectors containing tumor reactive T cell receptors are being introduced into T cells. Chimeric receptors containing antibodies specific to antigens expressed by leukemic cells along with T cell costimulatory molecules are being transferred into T cells that are being used therapeutically. Artificial antigen presenting cells are being made by introducing costimulatory molecules into cell lines and these cells are being used to expand cytotoxic T cells Regenerative medicine is an emerging new field. Marrow and mobilized PBSCs injected into ischemic myocardium was been reported to increase cardiac function . MeschenTranslational studies have been and will continue to be critical to progress in cellular and gene therapy. The converging nature of gene therapy, immune therapy for cancer, HSC transplantation, regenerative medicine and tissue engineering make the rapid and widespread exchange of information essential. The goal the JTM Cell and Gene Therapy Section is to advance this field by reporting the results of translational medicine studies and by being a forum for the exchange and discussion of new information, ideas and hypothesis. We welcome contributions from all those participating in this field; clinicians, scientists, and engineers from academia, industry and the regulatory community."} +{"text": "Interventional pneumology includes both bronchological and vascular methods of diagnosisand therapy, especially in emergency situations such as pulmonary hemorrhage. Inmassive pulmonary hemorrhage bronchological diagnosis is required to determine the siteand extent of bleeding, as well as angiography of bronchial arteries, and of pulmonaryarteries. Bronchus occlusion by aid of balloon catheter or double lumen tube are holdingmeasures until definitive surgery or embolization of bronchial or pulmonary arteries canbe performed. The paper suggests a close relationship between bronchoscopic and angiographicdiagnosis and therapy in case of severe pulmonary bleeding."} +{"text": "In the United States, consumer demand for new foods and changes in eating habits and food safety risks are affecting the food processing industry. The population is becoming older on average; moreover, consumers want fresh and minimally processed food without synthetic chemical preservatives. To address the need for safer food and compete for consumer acceptance, manufacturers are exploring new food processing and preservation methods."} +{"text": "We report a classical case of branch retinal artery occlusion (BRAO) in the acute setting and review the literature relating to the diagnostic, therapeutic and prognostic facets of this condition. BRAO can cause sudden visual loss and is not an infrequent presentation to emergency medical services. BRAO may indicate predisposing and related conditions capable of significant morbidity and mortality. Although current therapeutic practices in the acute setting are of uncertain benefit, conservative measures may be attempted in the emergency room by a nonophthalmologist with the aim of dislodging the causative embolus. Regardless of the current means of acute management, anitplatelet therapy and cardiovascular risk management remain the mainstay of treatment for BRAO. The potential for life-threatening systemic associations necessities investigation and multidisciplinary input. A BRAO occurs when a branch of the central retinal artery becomes occluded, preventing perfusion of an area of the inner layers of the retina. Emboli are the most common cause and subsequent ischemia results in intracellular oedema secondary to cellular injury and necrosis. Presentation is with sudden onset, painless loss of monocular vision. Issues relating to acute presentation and management of BRAO will be reviewed here.Mr F, a 67-year-old man with a history of coronary and peripheral atherosclerotic disease, presented to the emergency department complaining of a sudden and painless loss of the inferior field of vision in his right eye, initially noted on closure of his left eye 12 h previously. Mr F had an unremarkable medical history, save for having been a smoker for 40 years and having had angina and subsequent coronary angioplasty and placement of stent 6 years previously. His general practitioner had put him on simvastatin, aspirin and quinapril hydrochlordide. Bedside examination confirmed an inferior altitudinal defect of his right eye. There was no relative afferent pupillary defect and Snellen visual acuity measured 6/9 in both eyes. Systems examinations were noncontributory and bedside observations fell within normal parameters. Fundoscopy findings are shown in Sudden, painless, partial loss of vision in the context of the above clinical signs is suggestive of a branch retinal artery occlusion (BRAO) with macular sparing. The photograph shows a hypopigmented ischemic area of the retina, superior and distal to a large yellow, refractile cholesterol embolus: A \u201cHollenhorst plaque\u201d . RetinalEchocardiography and carotid Doppler studies are recommended as emboli frequently arise from atheromatous plaques or thrombi at the carotid bifurcation, internal carotid artery or cardiac valvular structures. Fasting The goal of treatment in the acute setting is to cause sufficient fluctuation in intraocular pressure to propel an embolus distally along the circulation to a less vital area of supply. Conservative treatment can be attempted in the emergency department and includes intravenous acetazolamide and ocular massage. Anterior chamber paracentesis is frequently performed by ophthalmologists but is of uncertain benefit. More invSudden visual loss secondary to retinal arterial occlusion may be the first manifestation of significant atherosclerotic or other systemic disease. Given that persons with retinal emboli are at an increased risk of stroke-related death, a thorough medical and ophthalmological work-up is crucial not only in attainment of diagnosis but also in identification and subsequent treatment of underlying systemic disease. At present, acute management remains an area of controversy as there is no proven treatment for BRAO."} +{"text": "In the December 2007 Forum article on the links between food additives and hyperactivity, Environmental Health Perspectives (pectives .According to Herndon and the FDA should seriously consider what the late Philip Handler said about balancing risks and benefits:A sensible guide would surely be to reduce exposure to hazard whenever possible, to accept substantial hazard only for great benefit, minor hazard for modest benefit, and no hazard at all when the benefit seems relatively trivial. The FDA has never clarified the health benefits of artificial food colors."} +{"text": "Several medicinal plants have been described to be beneficial for cardiac ailments in Ayurveda like Ashwagandha and Arjuna. Ashwagandha-categorised as Rasayanas, and described to promote health and longevity and Arjuna primarily for heart ailments. coronary artery disease, heart failure, hypercholesterolemia, anginal pain and can be considered as a useful drug for coronary artery disease, hypertension and ischemic cardiomyopathy.Withania somnifera (Ashwagandha) and Terminalia arjuna (Arjuna) individually and as a combination on maximum velocity, average absolute and relative Power, balance, maximum oxygen consumption (VO2 max) and blood pressure in humans.There are no scientific clinical studies showing effect of both these drugs on exercise performance after regular administration when given as supplements The present study was therefore designed and performed to assess the effects of Withania somnifera, 10 received standardized bark extract of Terminalia arjuna and the rest of the 10 received standardized root extract of Withania somnifera in addition to bark extract of Terminalia arjuna both. Both the drugs were given in the form of capsules (dosage 500mg/day for both the drugs). Ten participants received placebo (capsules filled with flour). All the subjects continued the regimen for 8 weeks. All variables were assessed before and after the course of drug administrationForty normal healthy. Subjects were recruited after written informed consent was obtained. Institutional Ethics Committee permission was also obtained. Thirty participants were assigned to experimental group of which 10 received standardized root extracts of Withania somnifera increased velocity, power and VO2 max whereas Terminalia arjuna increased VO2 max and lowered resting systolic blood pressure. When given in combination, the improvement was seen in all parameters except balance and diastolic blood pressure.Our study showed that Withania somnifera may therefore be useful for generalized weakness and to improve speed and lower limb muscular strength and neuro-muscular co-ordination. Terminalia arjuna may prove useful to improve cardio-vascular endurance and lowering systolic blood pressure. Both drugs appear to be safe for young adults when given for mentioned dosage and duration. There is renewed interest in traditional medicines because of a perception of lower incidence of side effects. The World Health Organization (WHO) estimates that 80 percent of the world\u2019s population presently uses herbal medicines for some aspect of primary health care. Several Withania somnifera (WS), also known as Ashwagandha, Indian ginseng, or winter cherry, has been an important herb in the Ayurvedic and indigenous medical systems for over 3000 years. The roots of the plant are categorised as Rasayanas, and described to promote health and longevity by augmenting defenses against disease, arresting the ageing process, revitalizing the body in debilitated conditions and thus creating a sense of wellbeing..When Terminalia arjuna and Withania somnifera (group III) was the most effective in reducing systolic blood pressure (4.37%), which is highest significant reduction in systolic blood pressure between groups followed by group II (4.22%) that consumed only Terminalia arjuna. There is no significant difference were seen for any other parameters Without training or excessive physical exertion, Terminalia arjuna was found to be effective in reducing resting systolic blood pressure in healthy young adults.When results between groups were compared the group which was given both Withania somnifera treated group followed by the group that received both Withania somnifera and Terminalia arjuna. Average absolute power was found to be improved most in the Withania somnifera and Terminalia arjuna group, followed by Withania somnifera group and Terminalia arjuna group respectively. Withania somnifera and Terminalia arjuna were equally effective in improving relative power of the lower limbs. The maximum oxygen consumption capacity was effectively increased in those subjects, who were given Withania somnifera and Terminalia arjuna in combination followed by those who were given just Terminalia arjuna.The maximum velocity was found to be improved the most in the The present study was limited to an 8 week period on healthy young adults. The future research should focus on longer treatment duration, dose finding as well as gender specific effects of the drugs. Further studies are also required to assess whether the drugs can improve other physical parameters and to see the effectiveness in elite sports persons so that in future these drugs can be given as ergogenic elements.Withania somnifera may therefore be useful for generalized weakness and to improve speed and lower limb muscular strength and neuro-muscular co-ordination. Terminalia arjuna may prove useful to improve cardio-vascular endurance and lowering systolic blood pressure. Both drugs appear to be safe for young adults when given for mentioned dosage and duration."} +{"text": "We have employed molecular probes produced from DNA fragments of human papillomavirus, cloned into prokaryotic vectors, to detect virus nucleic acid sequences in extracts of human oral tissues. The study was conducted with duplicate coded snap-frozen tissue biopsies from which frozen sections had been taken to accurately assess the pathology of each particular sample. The results show that a large proportion of the oral biopsies contained DNA which hybridized to the viral DNA probes, even under conditions of high stringency. The presence of virus did not correlate with neoplasia in the tissues examined, but HPV like sequences were found in a high proportion (80%) of biopsies taken from areas of keratosis and lichen planus and also in 41 to 46% of normal and tumour tissues."} +{"text": "Studies were conducted of the in vivo therapeutic potential of compounds which induce the differentiation of Friend leukaemia cells (FLC) in vitro. DBA2/J mice were inoculated with Friend leukaemia cells grown in tissue culture and at various times thereafter were treated with either N-methylacetamide, dimethylacetamide, or tetramethylurea. While survival was only occasionally prolonged, in every study these agents significantly inhibited leukaemia cell proliferation in the spleen and to a lesser extent in the marrow. These agents had no effect on the rate of proliferation of FLC growing subcutaneously nor on the proliferation of myeloid leukaemia in RFMS mice. These studies indicate that the administration of inducing agents to mice bearing Friend leukaemia can alter the proliferation characteristics of the leukaemia cells and hence suggest that these agents may have therapeutic potential."} +{"text": "Hazards in our indoor environments have been recognized since biblical times. The advice in Leviticus 14:33\u201348 for treating mold infested houses has contemporary meaning in the recent World Health Organization (WHO) document on damp and moldy indoor spaces . The risToday concerns about indoor air quality in developed countries have found expression in green building guidelines, smoking bans, and product standards. Nevertheless, indoor problems persist because of faulty construction, complex building systems, deferred maintenance, new formulations of products and a growing recognition that our homes contribute to our body burden of chemicals. Increased time spent indoors and reduced air exchange rates have increased personal exposure to many compounds originating indoors. Residential environments have the potential to be critical sources of chemical exposures through their release from building materials, household furnishings, and a wide range of consumer products. This diversity of exposures mirrors the dramatic rise in the development and production of synthetic chemicals globally since the 1950s . Many ofWe live in an ever more complicated and connected world. A sustainable path for the built environment will depend on our wise use of resources as well as the protection of human health. Energy consumed to build and operate buildings is an obvious component of greenhouse gas reduction strategies. Ambitious energy conservation programs should not lose sight of the lessons learned 40 years ago when sealing buildings with reduced ventilation led to sick building syndrome, combustion source problems and mold with associated health and productivity losses. A warmer atmosphere has already brought increasing weather variability with increased frequency of extreme precipitation and hot spells. For non-air-conditioned homes, warmer nighttime temperatures and prolonged heat events are likely to alter indoor comfort due to the retained thermal mass of the structures, inducing heat stress. Increased humidity and excessive precipitation will lead to dampness in indoor environments and may exacerbate problems with mold. With insight from past indoor air lessons and precautionary use of untested synthetic chemicals, our indoor environments still to be built might offer climate adapted sanctuaries that promote health and reduce carbon emissions.We are encouraged by recent WHO efforts to focus attention on issues related to housing and health, as well as the U.S. Surgeon General\u2019s recent Call-to-Action on Healthy Homes . We reco"} +{"text": "For malaria parasites, exposure to drugs is now an integral, human-induced, part of their ecology that exerts substantial selective effects on their traits. Currently used drugs often do not eliminate transmission, which enables evolution of traits that are beneficial for parasites. The appearance and spread of resistance mutations that protect parasites through direct interactions with drug molecules are well documented and often assumed to underlie treatment failures. However, this is just one example of how parasites can minimise their vulnerability to drugs. Other parasite traits that parasites have evolved independently of drugs can also provide indirect protection from drugs. Both lab and field data suggest that such traits can influence parasite survival and transmission in drug treated malaria infections.(Plasmodium chabaudi) to test if virulence can confer protection to parasites in drug-treated infections. Mice were infected with genetically similar virulent or avirulent genotypes (CWvir orCWavir), with or without an additional competing genotype (DK). Parasites were then exposed to drugs and we compared parasite survival, production of gametocytes and, in a subset of infections, transmission to mosquitoes.We used a rodent malaria model 1 or artemisinin, and produce more gametocytes than genetically related avirulent parasites. The survival and gametocyte production benefits for the virulent parasites held fora range of drug doses, duration of treatment and for drugs with different modes of action.We show virulent parasites better survived treatment with pyrimethamine2. I will discuss how to overcome the challenge of translating our laboratory findings to natural infections in humans and how to integrate our epidemiological and evolutionary findings into a framework for malaria control.Drug sensitivity can be virulence dependent, leading to a survival and transmission advantage for virulent parasites. If these results are general across parasite genotypes and species, this has consequences for the evolutionary trajectories of parasites resulting from continued population-wide exposure to drugs"} +{"text": "We have analysed the relationship of blood eosinophil count and serum eosinophil cationic protein (ECP) levels in patients with acute and chronic idiopathic urticaria. The ECP levels and eosinophil counts were measured in the peripheral blood of 15 patients with acute urticaria, 25 with chronic idiopathic urticaria and 10 normal healthy subjects. Blood eosinophil counts and serum ECP levels increased in all patients with acute urticaria. Concerning patients affected by chronic urticaria, taking into account the recrudescence of the disease at the moment of taking the blood sample, only symptomatic patients showed increased eosinophil blood values whereas serum ECP levels were increased both in symptomatic and asymptomatic patients. Furthermore, serum ECP levels in chronic urticaria did not correlate with the peripheral eosinophil counts, as they did in acute urticaria. The results of the present study indicate that eosinophils may play a role in the inflammatory mechanisms in patients with acute and chronic urticaria showing a positive correlation between serum ECP levels and disease activity."} +{"text": "Purpose. This review summarizes the more prevalent soft tissue tumours arising in the retroperitoneum and highlights some recent fundamental and diagnostic developments relevant to mesenchymal tumours. Discussion. The retroperitoneum is an underestimated site for benign and malignant neoplastic disease, and represents the second most common site of origin of primary malignant soft tissue tumours (sarcomas) after the deep tissues of the lower extremity. In contrast to the predominance of benign soft tissue lesions over malignant sarcomas elsewhere, retroperitoneal mesenchymal lesions are far more likely to be malignant. The differential diagnosis is primarily with the more common lymphoproliferative and parenchymatous epithelial lesions arising in this area, and with metastatic disease from known or unknown primary sites elsewhere.The most prevalent mesenchymal tumours at this site are of a lipomatous, myogenic or neural nature.Their generally late clinical presentation and poorly accessible location provides numerous clinical challenges; optimal radiological imaging and a properly performed biopsy are essential cogs in the management route. Histopathological diagnosis may be complicated, but has been aided by developments in the fields of immunohistochemistry and tumour (cyto)genetics. Despite significant advances in oncological management protocols, the prognosis remains generally less favourable than for similar tumours at more accessible sites."} +{"text": "Despite a flourishing biomedical and global health industry Teens from racial and ethnic backgrounds underrepresented in the biomedical sciences consider a myriad of intrinsic and extrinsic factors as they approach college age Global Health has been defined as \u201cthe area of study, research and practice that places a priority on improving health and achieving equity in health for all people worldwide\u201d This study was conducted according to the principles expressed in the Declaration of Helsinki. Seattle BioMed researchers received written informed consent from 2005-07 BioQuest Academy parents to have their minor children participate in the 2005-07 Academy sessions and for the collection and subsequent analysis of students' verbal and written responses to pre-, post- and focus group tools. With federal grant support, the revised 2008-09 study protocol was approved by the Western Institutional Review Board (WIRB #20071499) to also include permission to collect and analyze student interview responses. Taken together, all study participants and/or their legal guardians have provided written or tape recorded (by the members of the Center for Research and Learning) informed consent for the collection and subsequent analysis of student verbal and written responses.High school students from increasingly larger pools of racially diverse applicants from public, private and parochial schools across Washington State learn of the Academy and the online application process through multiple avenues. Most students learn of the program by attending half-day field trips to Seattle BioMed with their teacher, while other applicants get program information by targeted recruitment. Since 2005, a total of 169 high school juniors, in groups of 10\u201312, have enrolled in the BioQuest Academy from increasingly larger pools of applicants see . Strategvar2csa gene segments procured from geographically disparate Plasmodium isolates Anopheles mosquito dissection to gene expression analysis of Mycobacterial latency, are listed in The BioQuest Academy largely takes place within a biosafety-level-2-rated dedicated education laboratory located within Seattle BioMed. Institute and partner organization scientists mentor the students under the direction of BioQuest staff\u2014who are also veterans of the biotechnical and biomedical industry and analyzed for means, standard deviations and statistically significant differences. As a complement to the student feedback collected proximal to the Academy, students also participated in follow-up interviews during their first year of college concerning Academy outcomes and activities, as well as future coursework, career options and connections with Seattle BioMed. The open nature of the interview allowed the students to expand upon their experiences during the Academy and reflect on the impact that the program had on their college coursework and career aspirations. Longitudinal tracking was additionally supported by direct interaction by email, phone and Facebook\u2122-mediated discourse between program staff and students. Data collected during participant interviews were qualitatively analyzed through constant comparison methods to identify themes and major categories of response. BioQuest staff collected and analyzed the number of public inquiries made with regards to BioQuest Academy programming, as well as teacher and family attendance at Seattle BioMed scientific lectures and BioQuest Academy website visitation metrics as a reflection of community interest infectious disease.Seattle BioMed leadership launched a mosaic of precollege outreach modules as the BioQuest Program in 2004 to address to anticipated workforce challenges and to increase community engagement around neglected diseases of global concern. Since launching the program in 2005 BioQuest modules involve the participation of 100\u2013120 Seattle BioMed scientists per year and deliver activities and curriculum of varying duration and rigor all relating to Seattle BioMed research focus. Each year, greater numbers of students apply for our programs see , 10\u201315% Seattle BioMed training and advocacy objectives, vital to the mission of Seattle BioMed as well as national biomedical workforce diversification goals, have been advanced by the development of the Academy precollege program. The results of data gathering instruments and ongoing dialog with graduates demonstrate that the BioQuest Academy immersion program impacts students' attitudes toward science and significantly increases students' knowledge of infectious disease and biomedical careers. Targeted recruitment strategies are attracting increasing numbers of students from a spectrum of ethnicities and races to apply and participate. Student longitudinal trends related to college enrollment, college persistence and overall interest in biomedical and health-related fields are consistently higher than national trends, regardless of an increasingly diverse student cohort, suggesting that Academy students depart better prepared to successfully navigate post-secondary endeavors and subsequently address the long term labor needs of the biomedical community. As graduates apply for and participate in Seattle BioMed discovery research programs as undergraduates, they frequently state that their experience in the Academy as the place where their affinity for the Institute mission began and the reason why they sought employment and volunteer opportunities at Seattle BioMed. In addition to advancing Institute training goals, colleagues from our clinical trials teams appreciate the exposure that their programs get through BioQuest. Last year alone, over 600 students and teachers who accessed BioQuest programming were shown authentic recruitment and regulatory content related to the Institute's genetically attenuated parasite vaccine approach. Interactive and educational conversations through BioQuest resulted in numerous inquiries to the Seattle BioMed Malaria Clinical Trials Center website and staff regarding opportunities for trials enrollment [unpublished statistics]. Data and ongoing dialog with graduates demonstrate that providing precollege students with structured access to practicing scientists and authentic research environments within the context of advancing global health has proven to be a robust means of both increasing the visibility of health disparities. As graduates integrate infectious disease content into their community service projects or declare their predilection for global health related post-secondary learning and training opportunities they are influencing the development of baccalaureate programming. Influential community stakeholders from across the public and private sectors Since launching its doors in 1976 Seattle BioMed has included post-secondary, scientific training opportunities for students. Since 2005, and the launch of the BioQuest Academy, increasing numbers of Seattle BioMed investigators have hired Academy students to join their research teams as undergraduates . Providing precollege students with structured access to practicing scientists and authentic research environments within the context of advancing global health has proven to be a robust means of both increasing the visibility of health disparities, refining adolescent preconceptions of research and producing scientists and leaders who can passionately address the challenges of global disease and inequity and, one day, deliver a healthier world."} +{"text": "An increased awareness of the impact of group B streptococcus (GBS) infection on neonataloutcome has prompted several seemingly discordant committee recommendations. Intrapartumantibiotics are effective in reducing the risk of neonatal morbidity when administered to a colonizedwoman who has a clinical condition that places her neonate at high risk for early-onset sepsis.However, less is known about the efficacy of prophylactic antibiotics in the colonized woman whodoes not have obvious risk factors. Some authorities have suggested that providers refrain fromadministering intrapartum antibiotics to colonized women who do not have any of these risk factors,primarily due to concerns about potential adverse reactions, selection of resistant pathogens, andcost-effectiveness. These recommendations may conflict with the desires of an informed womanwho weighs the real, albeit low, risk for serious neonatal disease against the lower perceived riskof adverse maternal sequelae from allergic reactions to the antimicrobial agents. Selective prophylaxisfor GBS disease that is limited to the colonized parturient with risk factors has the potentialfor creating conflict because maternal beneficence-based obligations of the physician may be atodds with maternal autonomy-based obligations. We believe that, given all currently availableinformation, providers have a moral obligation to discuss GBS screening and treatment issues withpatients. The potential for conflict between patient and physician at the time of delivery can beminimized through the use of preventive ethics, allowing patients to develop advance directivesregarding intrapartum management within the confines of reasonable and cost-effective care. Untila consensus is reached among experts, the most prudent approach would be to address such issuesproactively and individualize care based upon the overall estimation and anticipation of risk as wellas the patient's specific desires."} +{"text": "Actinomyces.A 22-year-old female patient presented for further evaluation and second opinion of chronic, long standing tearing, discharge and swelling of right lower lid since three years. She had been diagnosed and treated in other hospitals for naso-lacrimal duct obstruction and advised to go for dacryocystorhinostomy. Examination showed best corrected visual acuity of 20/20 in both eyes. Right eye revealed lower canalicular swelling and pouting of the punctum . On gentPrimary chronic canaliculitis is an uncommon disease of the proximal lacrimal system that can be overlooked in terms of misdiagnosis and inappropriate management. It mightActinomyces israelii is the most common causative agent encountered in canaliculitis, but other bacteria (Fusobacterium and Nocardia species), fungi and viruses should also be considered as a cause.[ a cause.The differential diagnosis of chronic canaliculitis includes; migration of silicone punctal plug, chronic conjunctivitis or even rarely carcinoma of the lacrimal canaliculus.Although very few literature reports showed that intracanalicular irrigation with broad spectrum antibiotics may obviate the need for surgical management in treating chronic canaliculitis, canalicular debridement in the form of canaliculotomy and expression of all concretions is still the mainstay of treatment and more effective than conservative management.4"} +{"text": "Behaviour is shaped by environmental challenge in the context of homoeostatic need. Emotional and cognitive processes evoke patterned changes in bodily state that may signal emotional state to others. This dynamic modulation of visceral state is neurally mediated by sympathetic and parasympathetic divisions of the autonomic nervous system. Moreover neural afferents convey representations of the internal state of the body back to the brain to further influence emotion and cognition.Neuroimaging and lesion studies implicate specific regions of limbic forebrain in the behavioural generation of autonomic arousal states. Activity within these regions may predict emotion-specific autonomic response patterns within and between bodily organs, with implications for psychosomatic medicine. Feedback from the viscera is mapped hierarchically in the brain to influence efferent signals, and ultimately at the cortical level to engender and reinforce affective responses and subjective feeling states. Again neuroimaging and patient studies suggest discrete neural substrates for these representations, notably regions of insula and orbitofrontal cortex.Individual differences in conscious access to these interoceptive representations predict differences in emotional experience, but equally the misperception of heightened arousal level may evoke changes in emotional behaviour through engagement of the same neural centres. Perturbation of feedback may impair emotional reactivity and, in the context of inflammatory states give rise to cognitive, affective and psychomotor expressions of illness. Changes in visceral state during emotion may be mirrored in the responses of others, permitting a corresponding representation in the observer. The degree to which individuals are susceptible to this \u2018contagion\u2019 predicts individual differences in questionnaire ratings of empathy. Together these neuroimaging and clinical studies highlight the dynamic relationship between mind and body and help identify neural substrates that may translate thoughts into autonomic arousal and bodily states into feelings that can be shared. Homoeostasis is a pervasive guiding principle: Motivations arise from physiological need to preserve the integrity of the organism, via processes including thermoregulation, maintenance of fluid and nutrient balance and avoiding the consequences of noxious stimuli. Thus, the way we process or react to our environment depends on our internal bodily state. For example if we are thirsty or hungry, the manner in which we behave toward food stimuli differs and biases perceptions, hedonics, cognitions and memory. Motivations drive behaviour, while changes in the internal state of the body anticipate, facilitate or accommodate the consequences of motoric action. The result is a system in a state of dynamic flux internally that contributed to physical and social interaction with the external environment.As a consequence, salient events and emotive stimuli in our environment influence our internal bodily state. The automaticity of these physiological reactions, particularly to threat, suggests an independence of emotional reaction from \u2018rational\u2019 thoughts. The James\u2013Lange theory of emotion proposes that emotional feelings arise from the mind perception of bodily changes in response to emotive stimuli to \u2018colour\u2019 our thoughts . ArguablInteraction between bodily reactions and cognitive processes has remained toward the periphery of psychological science, and still all too often treated as a confound. Commonly a single metric of autonomic nervous function may be used as an objective index of mental processing, but the response itself is treated as an interesting epiphenomenon rather than integral to the cognition or emotion. Nevertheless, the functional impact of two-way communication between mind and body has long been recognized with implications for fields such as psychosomatic medicine. Damasio and colleagues reinvigorated the field with observations in brain lesioned patients and healthy individuals that led to the formulation of the Somatic Marker Hypothesis: Cognitive processes such as decision-making are guided by central feedback of bodily arousal responses brain imaging enables measurement across whole brain of local haemodynamic changes that reflect local neural activity. The technique has reasonable spatial (a few millimetres) and temporal resolution (seconds), limited by the distribution and responsivity of cerebral arterioles. Within these constraints, fMRI has permitted some significant advances in understanding brain processes supporting cognition and emotion . Combini2215O positron emission tomography (PET) studies, typically contrasted performance of a task containing cognitive/emotional process of interest with a control task that was similar in terms of sensorimotor performance requirements but lacked the \u2018extra\u2019 element. Radiolabelled water accumulated where there was more brain activity. From the outset functional neuroimaging of the brain has tended to reveal increased activity in dorsal anterior cingulate cortex when people are engaged in demanding tasks. Brain imaging experiments, particularly HUsing first PET and later fMRI, my research within R. Dolan's laboratory, and the research of others has highlighted the close relationship between dorsal anterior cingulate activity and enhancement of autonomic arousal. In the first set of studies, healthy subjects performed mental arithmetic and a motor exercise task (isometric handgrip). Dorsal anterior cingulate activity was enhanced when performing the effortful versions of each of these tasks. More conclusively, activity within the dorsal anterior cingulate cortex correlated with increases in blood pressure induced by mental or physical effort (i.e. independent of task) . These fElectrodermal activity is an interesting autonomic measure to psychophysiology in that it reflects sympathetic neural responses independent of direct parasympathetic control or circulating factors such as adrenaline. Evoked electrodermal responses were central to the formulation of the Somatic Marker Hypothesis by Damasio and co-workers. Lesion and stimulation studies have particularly helped map the brain regulation of this pure sympathetic index of cognitive-autonomic integration. One such study highlighted the hierarchy of descending electrodermal control . In humaactively selected which gamble they wanted to play, heart rate increased, both in anticipation of the outcome and in response to the feedback given at outcome. Notably the genual and dorsal anterior cingulate cortex was engaged at outcome reflecting both the agency and the autonomic state accompanying that agency during motivational decision-making; i.e. gambling task performance. In particular, one such study revealed activity within the dorsal anterior cingulate cortex in anticipation of the outcome of risky decisions that reflected both the degree of risk in the decision and the electrodermal arousal in anticipation of the outcome of the decision (a judgment as to whether a playing card would be followed by a higher or lower card) Fig. 1BBFig. 1B.t agency .A further example of the integration of brain and autonomic response comes from a study of the Stroop interference task. Dorsal anterior cingulate cortex has been strongly implicated in executive function. A functional system centred around the dorsal ACC for rapid detection and signalling of cognitive and behavioural errors was identified using depth electrodes in the human brain . Such fiTogether these studies link autonomic arousal to decision-making anticipation of outcome and processing outcomes beyond effort and point to the anterior cingulate cortex as a mediator of changes in sympathetic arousal coupled to effortful and evaluative processing. While low-level autonomic explanations account in part for task-related activity during cognitive behaviour; dorsal anterior cingulate engagement appears in the context of attentional engagement and volitional task performance that engender peripheral physiological changes. These effects are apparent across different autonomic axes, yet the different locations of concurrent cingulate cortical activity appear to reflect both task differences and the particular autonomic response that was measured.3Anterior cingulate activity is further associated with generation of sympathetic autonomic responses in the context of emotional processing; again there appears to be some relation to the nature of the task and with the precise autonomic response measured. One study examined the effects of emotional processing on the cardiac responses induced during a forewarned reaction time task. Forewarned reaction time tasks induce predictable changes in both brain activity and autonomic bodily response. A warning stimulus (cue) signals that the participant should respond to the next imperative stimulus with a reaction time response. In the period between cue and imperative stimuli, there is an orienting response to the cue stimulus followed by cardiac deceleration prior to the imperative stimulus and response. An electrocortical potential also occurs during this anticipatory interval, indicative of thalamocortical excitability and ascribable in part to dorsal cingulate activation e.g. . The emoThe emotional effect observed on heart rate was consistent with those observed in other contexts: notably Ekman et al.'s studies on differential autonomic responses to emotion . The bas4The internal state of the body influences the way we think and feel. Primary or basic emotions originate in states of physiological imbalance, including inflammation and pain. The physiological readiness of the body shapes the execution of particular behaviours linking cognitive and emotional processes to more dynamic changes in bodily state. The influence of transient arousal responses on aspects of affect and cognition is embodied within Damasio's Somatic Marker Hypothesis which proposed that emotional feelings originate in representations particular within somatosensory cortices . EmpiricAn imaging study using a heart beat detection task revealed engagement of anterior cingulate insula and somatosensory cortices when people focus on their internal bodily processes. Awareness and sensitivity to the occurrence of individual heart beats was revealed by how well people distinguished the presence of a heart-note delay in auditory tones triggered by individual heart beats. Across participants, activity and even the grey matter volume within one brain region, right anterior insular cortex, predicted differences in interoceptive sensitivity . The lin5Both visceral stimulation and general perturbations in interoceptive state modulate activity within similar brain centres. Direct gastrointestinal stimulation of oesophagus or large bowel enhances activity with cingulate and insula cortex (even in the absence of pain) . ExperimObservations in patients with spinal cord lesions and from a single patient treated with vagus nerve stimulation for depression also highlight a role of ventromedial prefrontal cortex in the integration of afferent visceral sensory information perturbed by interference with spinal and vagus nerve routes . Surpris6Afferent information from the viscera influences stimulus processing even at the level of individual heart beats . At syst7The representation of afferent information from the viscera and to emerge as consciously accessible emotional feelings appears to be supported at a neural level through the activity of right anterior insula cortex. In fact the perception of internal state of arousal may be influenced but false feedback. In an imaging study, participants were fed back auditory tones which they were led to believe represented their heart beating. During the course of the experiment they were required to judge the emotional \u2018intensity\u2019 of neutral happy and angry faces while undertaking or not undertaking blocks of isometric handgrip exercise. Behaviourally, the participants rated neutral faces as more intense/salient when they heard a heart beat trace consistent with arousal that would normally accompany exercise, but were not exercising. The change in rating of neutral faces due to false feedback arousal was reflected in activity changes in the right anterior insula and amygdala . These o8The neural integration of cognitive, affective and autonomic response has been proposed to be a guide to adaptive social behaviour . ChangesOne set of studies examined the impact of pupillary signals on emotional processing . StudentThese observations show a contagion of autonomic responses in emotional processing, highlighting automatic mirroring only in the context of sadness perception that influences the judgment of sadness in a manner related to individual differences in empathy for others. Moreover the findings highlight the presence of organ specificity in emotional autonomic responses that are integrated with cognitive and emotional aspects of empathy within a discrete neural system.9Together these neuroimaging and clinical studies highlight the dynamic relationship between mind and body and help identify neural substrates that may translate thoughts into autonomic arousal and bodily states into feelings that can be shared. By combining functional MRI with autonomic monitoring during performance of cognitive and emotional tasks one can tease apart the mechanisms of interaction that arise from an embodied mind. Certain patterns to the neural integration of affect cognition and visceral response are evident. Firstly, the notion that autonomic processes and control is confined to brainstem must be dismissed. Secondly a discrete set of cortical brain regions, including anterior cingulate and anterior insula orchestrates the response and representation of bodily states in specific behavioural contexts. The midline \u2018generator\u2019 system is likely to interact closely with the lateral \u2018representational\u2019 system . Nuclei Despite anatomical evidence for hierarchical organization of this system, low-level autonomic changes can impact directly on high-level cognitive functions, and at the same time cognitive representation of anticipated or misperceived arousal can impact on peripheral and early stages of emotional response. Together these neuroimaging and clinical studies highlight the dynamic relationship between mind and body and help identify neural substrates that may translate thoughts into autonomic arousal and bodily states into feelings that can be shared. The extension of these findings to detail the fundamental psychophysiological processes and basis for differences in phenotypical expression across individual is anticipated to lead to novel interventions that will have real impact in the field of psychological and psychosomatic medicine."} +{"text": "Complete genome sequences of important bacterial pathogens and industrial organisms hold significant consequences and opportunities for human health, industry and the environment. Addressing biological and clinical problems through genome sequence based approaches offers many commercial opportunities. The aftermath of whole genome sequencing has revealed new insights into evolution of bacterial lifestyles including strategies for adaptation to new niches and overcoming competitors. Whole genome sequences representing more than 1500 prokaryotic organisms combined with the dozens (to hundreds) of strain re-sequencing projects are posing mind boggling problems on the optimal utilization of the resultant \u2018omic\u2019 datasets. Consequently, microbiologists are confronted with the challenge to translate these data into better human and animal healthcare solutions and pursue basic research approaches to interpret the data in ecological and evolutionary perspectives. New informatic approaches towards optimal utilization, holistic integration and meaningful interpretation of the genome sequence data are extremely necessary.Whole genome sequence analysis of prokaryotes is fundamentally important in understanding human infections, development of diagnostics and vaccines, biodefense studies, antimicrobial target identification and drug design. Rapid advances in sequencing technology have provided the capability to quickly and cheaply produce several hundreds of prokaryotic genomes each year.The next generation sequencing platforms hold promise to further reduce time and cost of whole genome sequencing. Multiple species of bacteria and hundreds of strains thereof are being sequenced every year, thanks to cutting edge approaches such as re-sequencing wherein genome sequence of a reference organism is used as a scaffold to direct analysis of several different strains Comparison of genomic sequences has revealed mechanism of changes in bacterial lifestyles. We have learned how species have evolved strategies to survive and compete as part of adaptation to their preferred hosts, habitats or niches. Genomic comparison of multiple species and strains has facilitated insights into adaptive mechanisms leading to host or tissue tropism. Such inferences however need to be tested functionally and thus the need for integration of genome data with cues obtainable from downstream \u2018omic\u2019 experiments that have sampled a variety of conditions or treatments. New informatic approaches are emerging which are capable of integrating genomic and functional datasets and also making use of data available through published resources. The emergence of e-Science, Semantic Web, and Science 2.0 approaches hold a lot of promise for holistic data integration and meaningful interpretation of community genomics and microarray experiments in an interactive and collaborative fashion. The present overview discusses some of these issues and ideas in relation to the \u2018PLoS ONE prokaryotic genomes collection\u2019.Comparative genomics of whole genome sequences of many different pathogenic and commensal forms of microorganisms have improved our perception of the mechanisms of pathogenesis and the transition between pathogenic and non-pathogenic varieties within the same species. It is becoming increasingly evident that distinct genomic differences found in different microbes have a definite impact on pathogenic potential, adaptation to parasitic lifestyles and host/tissue tropism. Some examples in this context are discussed.Acinetobacter has enabled comparison in a more general context to tease apart likely genetic changes that enabled adaptation of Acinetobacter species to specific environments In the case where different species of the same genus represent diverse lifestyles it is imperative to have sampled genome sequences from varieties of all forms. For example, the availability of three complete genome sequences from Brachyspira hyodysenteriaeBrachyspira, and that are supposed to have facilitated adaptation and survival of the bacterium within the intestines, belonged mostly to classically \u2018enteric type\u2019 of organisms, rather than to other spirochaetal relatives of BrachyspiraAnother interesting lifestyle has been deciphered from the genome sequence of Mycobacterium indicus pranii (MIP) together with molecular phylogenetic analyses Mycobacterium avium intracellulare complex that did not prefer parasitic adaptation but a free living life-style. Further analysis suggests a shared aquatic phase of MIP with the early pathogenic forms of Mycobacterium, well before the latter diverged to form \u2018specialist\u2019 bacterial parasites. This information has an important bearing on our understanding of mycobacterial evolution.Whole genome sequencing and analysis of Yersinia pestis which originated from its closest relative Y. pseudotuberculosisBrucella ovis whose genome is shorter than the classical zoonotic strains via pseudogenization and degradation that has happened concomitant to the narrowing of its host range; it infects only sheep B. ovisB. ovis genome has been the presence of increased number of transposable elements thus hinting towards frequent shuffling of its genome Genomic downsizing and streamlining has been a dominant evolutionary trend in mycobacterial genome evolution that perhaps shapes their host-range and tissue tropism giving rise to \u2018specialist\u2019 lineages Streptococcus (GAS). Recently, a study analyzing twelve sequenced GAS genomes Variation in gene content, especially the flexible or unstable part of the genome such as mobile elements and genomic islands, has been shown to influence phenotypes such as virulence and antimicrobial resistance. This is especially true for some of the biomedically significant organisms such as the Group A http://www.jgi.doe.gov/programs/GEBA/). This program aims at filling the genomic gaps pertaining to bacterial and archaeal branches of the tree of life while using the tree itself as a guide to identify which target microorganisms need to be sequenced completely. Some of the potential benefits of the GEBA project include identification of new protein families across different lineages of bacterial phyla so as to provide a comparative genomics and proteomics platform towards annotation of forthcoming genomes and microbiomes of the same or different phyla. Also, it will facilitate improved phylogenetic anchoring of metagenomic data-sets besides providing better understanding of the processes underlying the evolutionary diversity and functional stratification of different microbes inhabiting various different niches in the environment.A wide variety of microbial sequencing projects having been completed or being implemented throughout the world has created a rich and diverse \u2018mega-database\u2019 of microbial genomes. However, to fully gauge the prevailing diversity and stratification patterns of all bacterial species, it will be required to sequence hundreds and thousands of genomes representing all branches and lineages within the bacterial and archaeal part of the tree of life wherein each of the phylum provides an opportunity to capture evolutionary footprints of billions of years. It is estimated that there are at least 35 different phyla of bacteria according to the rRNA gene sequence based tree of life Many of the pathogenic bacterial species are monomorphic meaning that they present very little diversity upon genetic fingerprinting or limited sequence profiling. Gaining insights into their dispersal patterns, evolutionary genetics, emergence and reemergence in different communities and catchments poses a great challenge for molecular epidemiologists. Multiple genome sequences from across strains of a single species offer more fine scale resolution of genetic differences that enable tracking and identification of species and development of additional genetic markers.in-situ gene duplication strategies to shape an optimal repertoire of the genes and elements to support a successful lifestyle Prokaryotes evolve largely by horizontal gene acquisition, vertical genome reduction and Steptococcus agalactiae for example Helicobacter pylori, termed the \u2018plasticity region cluster\u2019, could be useful in adaptation to a particular host population Novel genes constantly emerge from newly sequenced replicate genomes Another important reason to sequence replicate genomes of a prokaryotic species entails need to study chronological evolution of bacterial pathogens within their hosts. The nature and extent of genetic polymorphisms accumulated in the genome of bacterial pathogens across wide timescales and during the colonization of different host niches are not known. The advantages of polymorphisms linking to fitness in pathogens or commensals need additional in-depth studies. While some studies have explored chronological strain diversity through genetic fingerprinting Leptospira interrogans whose genome sequences enabled significant insights into the question as to how virulence evolves during the traverse of pathogens from one intermediate host to the other. This has been facilitated through comparative genomics with saprophytic L. biflexa genome sequence With complete genomes of multiple variants of a closely related group (genus or species), it is possible to test evolutionary hypotheses based on the core genes of the group. The phylogenetic relatedness of such core genes could then be harnessed to examine larger collection of strains by multilocus sequence typing (MLST). This genome sequence based approach has already revolutionized molecular epidemiology and evolutionary genetics of many bacterial pathogens as previously reviewed Bacillus subtilisLeaving aside genetic diversity of naturally occurring populations, important differences in the isolates of even a single laboratory strain might be highly significant in genetic experiments. Using whole genome sequence determination, several important polymorphisms were detected in replicate genomes of a single strain of Developing the computational infrastructure necessary to support data analysis and formulation of tools and resources is necessary to fully utilize the wealth of genomic information. Novel data integration capabilities in a community genomics environment are likely to give rise to cutting-edge platforms. However, availability of processed data to feed into such platforms will depend on the speed and accuracy with which the genomic raw data and assemblies are processed. It is noteworthy to mention the success of subsystems approaches wherein annotation servers have been developed that are capable of processing 20\u201350 prokaryotic genomes daily. Such tools as the RAST server via a semantic web approach in silico or a \u2018virtual\u2019 laboratory in silico experimentation across grids of international networks Processed genomic information as above is likely to make up excellent inputs for the systems that exploit the power of collaborative grid computing aimed at integration of information that links organisms through their genes and gene products http://www.nextbio.com) routinely extract, integrate and compare information and observations contained in publications while juxtaposing colossal amounts of disparate, biological or clinical and \u2018omic\u2019 data from public and proprietary sources, regardless of data type and origin. Other tools such as Ondex http://ondex.sourceforge.net/).Academic institutions and publicly funded research consortia are generating large sets of \u2018omic\u2019 data that are capable of serving collaborative groups across different disciplines. With the cutting-edge approaches as discussed above, it will be possible to facilitate these groups to bring in and compare their sets of data with other experimental results and pathways available in the public domain. Web tools based on these concepts , it is possible to quickly exchange experimental results and their interpretations across different platforms. This in turn simplifies utilization and processing of genomic information contained in research publications so that details such as decipherment of novel pathways or evolutionary relationships etc. could be discussed globally and interpreted through community genomics environments.via information from external sources that discuss and link to the results, such as citations from PubMed Central, Google Scholar and Scopus; evaluations and ratings at Faculty of 1000; bookmarks from social networking sites such as CiteULike and Connotea; and blog posts from experts and readers in the field. Just like other PLoS content, it will be possible to make utilization of individual articles interactive for the users (human or machine) to harness elements of research and associated content in the form of relevant discussions (and raw data posted in response to a discussion). This content can be processed in a variety of computational formats such as graphs or networks that can be inspected visually, cured manually or mined computationally. Linking therefore the secondary contents and Science 2.0 based enhancements to published information and their subsequent harnessing through different knowledge-platforms is likely to underpin formation of new ideas and insights in a more holistic and interdisciplinary manner. Such novel theses in the form of alternative or even more provocative interpretations could ultimately be linked back to the original genome sequences thus completing a cycle of information sharing through Open Access.To this end, \u2018PLoS ONE prokaryotic genomes collection\u2019 represents a novel initiative to compile a permanent archive of all important articles describing whole genome sequence based biology of prokaryotic organisms. This collection of articles will facilitate understanding of the biology and lifestyle of the underlying organisms not only through main contents of articles but also"} +{"text": "We believe the prevention of infection-related adverse pregnancy outcome is the most important focus for obstetricians today. An emphasis upon immunization of susceptible women, prevention of transmissible disease by modification of patient behavior, and identification and treatment of silent infections should become standards of practice. This will require educational initiatives for physicians and their patients as well as continued clinical trials to determine costs and effectiveness."} +{"text": "Troponin elevation is usually synonymous with acute coronary syndrome (ACS). Although sensitive for ACS, the elevation of serum troponin, in the absence of clinical evidence of ischemia, should prompt a search for other etiologies of myocardial necrosis. In fact, elevated values of troponin are correlated with myocardial necrosis even though it does not discriminate the mechanism involved. We report a series of seven patients (age range 18-67 years), who presented with complaints of chest discomfort and were found to have regular supraventricular tachycardia (5 patients) and one patient each with atrial fibrillation and ventricular tachycardia. All these patients had elevated troponin I and underwent coronary angiography that revealed normal epicardial coronary arteries. This is first case series in which all patients underwent coronary angiography and none of the patients was hemodynamically unstable at the time of presentation. Patients with elevated troponin due to conditions other than ACS can receive inappropriate and delayed definitive diagnosis and treatment. Troponin elevation usually signifies some myocardial damage and is associated with significant obstructive coronary artery disease. There are multiple conditions that can cause elevation of troponin besides myocardial ischemia like sepsis, renal failure, decompensated heart failure, pulmonary embolism, coronary vasospasm, prolonged hypotension and tachycardias associated with hypotension to mention few. Although there have been multiple case reports of troponin elevation associated with tachycardias, coronary artery disease was ruled out either by stress test or by coronary angiography. We report a case series of 7 patients with different kinds of tachycardias and troponin elevation who underwent coronary angiography and were hemodynamically stable.Six patients of supraventricular tachycardias of different duration and one case of sustained ventricular tachycardia were found in our database. All cases presented with palpitations and chest discomfort of different duration. Patients underwent routine laboratory investigations and all of them had two-dimensional echocardiography. All patients were found to have elevated troponin I. There were three cases of accessory pathway mediated tachycardia (AVRT), two cases of atrioventricular-nodal reentrant tachycardia (AVNRT) and one case each of atrial fibrillation (AF) with fast ventricular response and ventricular tachycardia (VT). All patients underwent coronary angiography and had normal coronary arteries. Five patients (3 AVRT and 2 AVNRT) underwent successful radiofrequency ablation. One with atrial fibrillation was subsequently cardioverted after coronary angiography and placed on sotalol. The patient who presented with ventricular tachycardia was placed on amiodarone and had a biventricular ICD implanted for non-ischemic cardiomyopathy. All patients had elevation of Troponin I . Table 1The joint committee of the European Society of Cardiology, the American College of Cardiology, and the American Heart Association has accepted the measurement of troponin T and I in serum as the standard biomarker for the diagnosis of acute myocardial infarction and for diagnosis and management of acute coronary syndromes -3. HowevAll patients in our series underwent coronary angiography and had normal epicardial vessels. None of our patient was hemodynamically unstable and therefore the troponin rise in our series was a direct result of tachycardia.The exact mechanism for troponin elevation during a tachycardia remains unknown. However, the most likely mechanism may be shortening of diastole with subsequent subendocardial ischemia . CoronarThe patients admitted within the framework of tachyarrhythmia without hemodynamic instability, the decision whether to obtain serum markers of myocardial ischemia should cover a comprehensive clinical context. Patients with elevated troponin due to conditions other than ACS can receive inappropriate and delayed definitive diagnosis and treatment."} +{"text": "Benign laryngeal disorders result in dysphonia because of effects on glottic closure and thevibratory characteristics of the true vocal fold. Treatment is initially directed at reversingmedical conditions and patterns of abuse with surgery reserved for unresolving lesions resultingin troublesome dysphonia. Benign lesions that require surgery are excised as precisely aspossible sparing overlying mucosa and the underlying vocal ligament. Vocal fold scarring iscurrently best treated by augmentation procedures, and atrophy may be compensated for bymedialization thyroplasty or by adding bulk to the affected folds. Application of currentknowledge of laryngeal histology and physiology is prerequisite to endoscopic surgicalintervention."} +{"text": "Based on recently reported data that fructose ingestion is linked to arterial hypertension, a model of regulatory loops involving the colon role in maintenance of fluid and sodium homeostasis is proposed.In normal digestion of hyperosmolar fluids, also in cases of postprandial hypotension and in patients having the \"dumping\" syndrome after gastric surgery, any hyperosmolar intestinal content is diluted by water taken from circulation and being trapped in the bowel until reabsorption. High fructose corn sirup (HFCS) soft drinks are among common hyperosmolar drinks. Fructose is slowly absorbed through passive carrier-mediated facilitated diffusion, along the entire small bowel, thus preventing absorption of the trapped water for several hours.Here presented interpretation is that ingestion of hyperosmolar HFCS drinks due to a transient fluid shift into the small bowel increases renin secretion and sympathetic activity, leading to rise in ADH and aldosterone secretions. Their actions spare water and sodium in the large bowel and kidneys. Alteration of colon absorption due to hormone exposure depends on cell renewal and takes days to develop, so the momentary capacity of sodium absorption in the colon depends on the average aldosterone and ADH exposure during few previous days. This inertia in modulation of the colon function can make an individual that often takes HFCS drinks prone to sodium retention, until a new balance is reached with an expanded ECF pool and arterial hypertension. In individuals with impaired fructose absorption, even a higher risk of arterial hypertension can be expected. Despite wide range of daily salt and water ingestion, sodium and fluid homeostasis is maintained through orchestrated action of aldosterone, ADH, ANP and other humoral mediators. Actions of angiotensin II and aldosterone include vasoconstriction; increased glomerular filtration with sodium reabsorption and potassium secretion in the distal tubule; increased thirst and ADH secretion . Beside The whole picture has recently become more complex when fructose ingestion was reported as an independent dietary risk factor of arterial hypertension . It has per se is closely linked to hypertension, data reported by Jalal et al. do not suggest that obesity play an intermediary role in the reported hypertension - HFCS consumption link.In other words, although obesity This theoretic paper is an attempt to interpret the reported link of fructose ingestion and arterial hypertension by proposing a model of increased sodium absorption in the large bowel, due to stimulation of aldosterone secretion by osmotic loads in the upper digestive tract.Many isotonic \"sport\" drinks contain low amounts of carbohydrate (near 6%) and electrolytes . VariousHigh fructose corn syrup (HFCS) is produced by splitting starch into glucose molecules that are partially enzymatically converted to fructose. Typical HFCS for soft drinks contains 55% fructose and 45% glucose. In comparison to pure sucrose solutions, the HFCS soft drinks contain twice as many osmotically active molecules for the same amount of sugar. Reported sugar content data of non diet soft drinks -11 rangeWines and beers have even higher osmotic values , mainly Similar to kitchen salt, oligosaccharides and particularly monosaccharides are all osmotically active molecules. From the beginning of duodenum throughout the rest of the small intestine, normal digestion sustains the osmotic pressure of the intestinal contents equal to the plasma , with noThe presence of hypertonic concentration of salt and/or small sugar molecules in the gut requires some intestinal fluid to dilute the gut content to isotonicity. Intact starch is not osmotically important since it is a huge molecule, but during enzymatic digestion of starch, many small molecules form and act as osmotic particles. Water follows absorption of osmotically active molecules and this process maintains isotonicity of intestinal content along the small bowel. + movement for their absorption from the gut. This net solute transport is important when considering the quantity of water that can be moved into the blood stream. Both glucose and galactose are in the small intestine absorbed with sodium by active cotransporters SGLT 1, so any water from drinks containing these sugars can be absorbed into the body circulation in less than two hours [Due to cotransport with sodium across the mucosal membrane, many sugars and amino acids depend on the Na wo hours -15. In nThe consequence of these differences in transport is that rapid rehydration requires solutions that contain glucose and sodium, while slower water absorption can be expected after ingestion of drinks that contain sucrose. One half water will rapidly follow the glucose absorption, but the rest is following the slow fructose absorption.Three clinical topics are related to the dilution of intestinal content due to osmotic forces. The first is postprandial hypotension that is, at least partially, caused by osmotic water traffic into the intestinal lumen .Second in diarrheal patients, hypertonic drinks with a high sugar concentration can worsen diarrhea, as they draw water out of the body and into the intestine and, thus should never be used for peroral rehydration , and theThe last example is often in patients following gastric surgery, where a sudden hyperosmotic load in the small bowel can cause the \"dumping syndrome\", due to uncontrolled, rapid entry of hypertonic gastric content into the small intestine, under which so much water moves into the gut that significant circulatory hypovolemia and arterial hypotension result .Here proposed model is based on the idea that ingestion of hypertonic fluid transiently affects the body fluid balance due to fluid shifts needed for the intestinal content dilution. This reduction of fluid volume in circulation stimulates aldosterone secretion and increases sodium absorption in colon and reabsorption in kidneys.Common fluids in our diet are listed in Table Due to the highest initial osmolarity, the HFCS soft drink is an important osmotic challenge Table . IngestiWater retained in the small bowel until sugar reabsorption is temporary sequestrated from the body fluid compartments. Larger trapped fluid volumes (as expected after ingestion of HFCS soft drinks) can lead to increased renin secretion and sympathetic activity, as seen in postprandial hypotension ,17. ReniIngestion of other hypertonic liquids from Table A similar situation is expected with a sucrose containing soft drink. Initially, dilution does not take much water, due to mild hypertonicity of sucrose drink. Eventually, sucrose is enzymatically split in glucose and fructose and new osmotic particles take some additional water, but the amount is reduced by simultaneous reabsorption of these two sugars, particularly of glucose. So, only a limited and transient increase in ADH and aldosterone secretion can be expected.Although highly hyperosmolar ,12, ethaHere presented interpretations suggest that it might be important how an individual takes carbohydrates or salt. It seems that the best way to avoid the reported risk of hypertension from HFCS drinks is to dilute them with fresh water before ingestion, or to drink adequate volume of fresh water immediately after the HFCS drink. Any isotonic, or hypotonic combination of food and drinks that slowly releases both salt and sugars might help avoid risk of arterial hypertension, due to small volume of initially trapped fluid.As of May 2010, PubMed lists some 150 papers considering HFCS in various settings. Some of them are discussing relations between HFCS ingestion and blood levels of metabolic hormones , aiming to link HFCS to obesity and to the metabolic syndrome . Since tHere proposed model predicts subtle and transient changes in the circulatory volume after the ingestion of hypertonic HFCS drink. So, only a slight increase in aldosterone blood levels can be expected between one and four hours after ingestion. In other words, the risk of future hypertension would be higher in individuals that take HFCS drinks in regular intervals, along meals, in concordance with Jalal et al. . A plausThe author declares that they have no competing interests."} +{"text": "Oncorhynchus mykiss) disrupts dominance hierarchies within groups of native Atlantic salmon . The genetic and molecular actors underlying phenotypic plasticity are poorly understood.Ecological and evolutionary changes in native populations facing invasion by exotic species are increasingly reported. Recently, it has been shown that competition with exotic rainbow trout (versus subordinate juvenile Atlantic salmon in presence or absence of a competitive rainbow trout.Here, we aimed at identifying the genetic and molecular actors contributing to this plastic loss of dominance hierarchies as well as at identifying genes implicated in behaviours related to social dominance. By using microarrays, we compared the genome-wide gene transcription profiles in brains of dominant Adding the trout competitor resulted in dominant and subordinate salmon being more similar, both behaviourally and at the level of brain gene transcription patterns. Genes for which transcription levels differed between dominant and subordinate salmon in the absence of exotic trout were mainly over-expressed in dominant salmon and included genes implicated in protein turnover, neuronal structural change and oxygen transport.Our study provides one of the few examples demonstrating a close interplay between behavioural plasticity and gene transcription, therefore contributing to the understanding of the molecular mechanisms underlying these processes in an ecologically relevant context. Oncorhynchus mykiss) are native to tributaries of the Pacific Ocean in Asia and North America, but have been introduced for food or sport in many locations throughout the world Salmo salar), as well as the phenotypic correlation between several behaviours Biological invasion of species outside their native range is among the most important factors contributing to the ongoing biodiversity crisis Research in behavioural physiology and genetics has allowed the identification of several candidate genes and endogenous molecules modulating aggressive, territorial or dominance-related behaviours to test whether gene expression differences would reflect the plastic loss of dominance hierarchies in juvenile Atlantic salmon competing with rainbow trout. Particularly, we tested the hypotheses that (i) social hierarchies within pairs of Atlantic salmon changed in the presence of rainbow trout and (ii) changes in gene expression correspondingly occurred.The present study aimed at identifying genes regulating behaviours related to social dominance but also at understanding the association between gene expression and behavioural plasticity in the ecological context of species invasion. Hence, we compared, using a 16 006-gene salmonid microarray, the genome-wide gene transcription profiles of dominant ad libitum with commercial fish food pellets before experiments started.We used young-of-the-year (YOY) Atlantic salmon and rainbow trout caught by electrofishing in the Malbaie River . In the sympatric section of the river, both species occupied similar macro-habitats and micro-habitat overlap increased as fish grew see . In SeptBehavioural experiments were all performed simultaneously using 12 artificial channels made of transparent Plexiglas . The chai.e., subordinate or dominant) of individuals within each salmon pair was evaluated. Dominance was measured following the methodology described by Sloman et al. The behavioural experiment was performed in three steps. First, following introduction of the fish in the aquaria, the status of dominance . All possible interaction terms were considered.During the experiment, one subordinate fish died in the intraspecific competition treatment; the number of replicates was then five instead of six for this treatment. To evaluate whether the social hierarchies within pairs of Atlantic salmon changed after the addition of rainbow trout, we compared the behavioural repertory of dominant and subordinate Atlantic salmon before (second step of the experiment) and after the addition of a competitor in the aquaria. Instead of analysing each behavioural variable independently, we used a multivariate analysis of variance with repeated measures MANOVAR, to test TRIZOLReagent using a Diax 100 homogeniser (Heidolph instruments). Total RNA was extracted as previously described bkoopuvic.ca), and contain 16,006 salmonid cDNA clones, the great majority of which (99.8%) are not replicated. However, a same gene can be represented on the chip by several different cDNA clones Following the behavioural experiment, all fish were anaesthetised and whole brains were taken from both salmon of each initial pair. Brains were immediately frozen in liquid nitrogen, and later homogenised individually in Signal detection and data preparation was done as previously reported As previously reported, rainbow trout strongly disrupt the social hierarchy between subordinate and dominant juvenile Atlantic salmon [9]. IndOnly one gene showed significant transcription level differences between dominant and subordinate salmon that had been exposed to a rainbow trout at the P<0.005 significance threshold, which is less than expected by chance alone. This gene was hence considered as a false positive and therefore not interpreted any further. By contrast, the comparison of dominant and subordinate fish in a purely intraspecific competition context revealed more significant differences than expected by chance . This absolute value must however be interpreted cautiously since estimation of the expected number of false positives from the total number of spots analyzed might be misleading as a same gene can be represented by several spots (same or different ESTs) and the expression of many genes is expected to be correlated, which cannot be accounted for in the analysis. It is also noteworthy that all of the differentially expressed transcripts at P<0.005 appeared over- rather than under-transcribed in dominant individuals which corroborates the results of previous transcriptomic experiments which have documented gene transcription differences implicated in aggressive behaviour \u221215 and an informative name during the array annotation process. The functions of the remaining candidates are discussed in the following section.This study identified genes implicated in behavioural differences related to social dominance, which contributes to the understanding of the relationship between gene expression and behavioural plasticity in the context of competitive interactions between native and invasive species. Namely, our results provide evidence for the differential transcription of 27 different genes between dominant and subordinate salmon. Additionally, the greater degree of similarity in the behaviour of subordinant and dominant salmon in presence of the exotic competitor see also reflecteAdmittedly, the use of a microarray not specific for brain cDNA to analyse gene expression in the brain is not without limitations versus subordinate salmon in mouse and may insure ubiquitin stability within neurons Drosophila strains selected for aggressive behaviour (see versus dominant rainbow trout kelch-like 1 in dominant salmon could be implicated in increased structural changes in neurons or in organizing newly formed neurons. In the same way, brain lipid-binding protein, also over-expressed in dominant versus subordinate salmon (Three genes implicated in protein degradation were over-transcribed in dominant e salmon . The expiour see encodes iour see . This geiour see . While be salmon , is a faTo conclude, our study provides one of the few examples demonstrating a close interplay between behavioural plasticity and changes in gene expression in an ecologically relevant context. Behavioural plasticity is a key mechanism for animals facing rapid ecological changes such as species invasion"} +{"text": "Laparoscopic surgery has greatly developed recently and is becoming a standard operative procedure because of the important advantages it offers, namely less tissue trauma, decreased postoperative pain, as well as shorter hospital stay with minimized postoperative morbidity and mortality. It offers patients major medical and economical advantages over laparotomy.2 that is required for the procedure. Laparoscopy may lead to possibly harmful cardiovascular and respiratory alterations that could possibly be harmful for the patient. Numerous studies have focused on the effects of intraperitoneal CO2 insufflation and its systemic absorption on cardiovascular, respiratory and on the derangement of the acid-base balance, all of which can potentially impair the cerebral perfusion.Laparoscopic surgery, although enjoying ever-increasing popularity and presenting new anaesthetic challenges, can be potentially hazardous due to the intraperitoneal insufflation of CO2 alterations (CO2 reactivity) has been analyzed profoundly. Nevertheless, there are only few references regarding the alterations in the cerebrovascular dynamics after CO2 insufflation into peritoneal cavity during laparoscopic surgery and the effect of such insufflation on cerebral blood flow velocities (CBFV) and cerebral oxygenation (rSO2). It has been reported that CO2 insufflation can produce adverse cerebrovascular effects, although this has not been extensively studied. Cerebral blood flow (CBF) increases during pneumoperitoneum in head-up or head-down positions due to the rise of arterial CO2 partial pressure (PaCO2). This increase in the CBF could be dangerous if laparoscopy is performed in patients with cerebral disease, reduced intracranial compliance or impaired cerebral physiology.The normal cerebrovascular response to CO2 reactivity, two homeostatic mechanisms important for the control of CBF, are impaired by pathology and some drugs commonly used during anaesthesia.It is well known that anaesthetic agents have variable effects on cerebral circulation. Consequently, the choice of the anaesthetic regimen could be important in laparoscopic surgery in order to minimize the adverse cerebrovascular response. Cerebral autoregulation mechanism and CO2 reactivity, CBFV and cerebral autoregulation seem to remain intact during sevoflurane administration or during propofol induced isoelectric electroencephalogram (EEG).Regarding the type of anaesthetic agent used, it is already known that inhalation anaesthesia's effects on CBF depend on the balance between its indirect vasoconstrictive action, secondary to flow metabolism coupling and its direct vasodilatory properties. COAlthough the central nervous system is the primary endpoint of most general anaesthetic it is still the least monitored organ in clinical anaesthesiology. In the last decade, technological research has expanded the application of near infrared spectroscopy to allow continuous, non-invasive and bedside monitoring of cerebral oxygen saturation providing accurate information on the balance between brain oxygen supply and demand. Several To date, monitors of cerebral function including electroencephalography, jugular bulb mixed venous oxygen saturation and transcranial doppler either require an invasive procedure or are not sensitive enough to effectively identify patients at risk for cerebral hypoxia. Near-infrared spectroscopy is a noninvasive device that uses infrared light, a technique similar to pulse oximetry, to penetrate living tissue and estimate brain tissue oxygenation by measuring the absorption of infrared light by tissue chromophores. This tec2 insufflation or any potential decrease in the oxygenation of the brain. By selecting the proper anaesthetic agent or by using specific surgical manoeuvres, possessing protective properties, regarding cerebrovascular dynamics can minimize the potential negative effects of pneumoperitoneum, hypercarbia and haemodynamic fluctuations on cerebrovascular balance.[The cerebrovascular system can undergo adaptive changes during laparoscopic surgery. Thus, it is important to anticipate increase in the CBFV after CO balance. MonitoriClearly, further studies are needed to enlighten the necessary measures for preventing possible alteration of CBFV and of brain oxygenation during specific operations in Trendelenbourg position, such as in laparoscopic surgery, especially in patients with cardiovascular and cerebral derangement. Nevertheless, routine use of rSO2 monitoring during laparoscopic surgery could actually guide anaesthesia and surgical plan in order to improve the patient outcome and shorten hospital stay. A simple noninvasive device as near infrared spectroscopy has the potential for optimizing the anaesthesiologists' and the surgical team's plans to the real needs of one of our main targeted organs: the brain."} +{"text": "The Environmental Protection Act has created a growing need forthe measurement and assessment of trace emissions to the environment. This encompasses three main areas of ground, water and the atmosphere. The need to achieve lower emissions has placed a large burden on analytical techniques, particularly in the areas of trace analysis to ppb and ppt levels. Chromatographic techniques are widely used for assessment and measurement of emissions in all three areas. Enhanced detectors using mass spectrometry principles are available to lower detection limits, but these are expensive. Standard chromatography detectors can be used for trace analysis,but this often leads to extensive sample preparation stages to achieve low detection limits. This paper describes the techniques developed by Thomas Swan & Company to introduce a cost effective way of lowering detection limits. The approach takenmeets both BATNEEC and BPEO constraints."} +{"text": "All drugs reduced eicosanoid release globally. It is concluded that cAMP mediated drugs interfere with arachidonic acid metabolism at a site proximal to the branching into lipoxygenase and cyclo-oxygenase pathways.In this study the question was addressed whether cAMP mediated drugs induce a differential reduction of branches of the arachidonic acid metabolism rather than a global reduction of eicosanoid synthesis. The isolated lungs of actively sensitized rats were employed to study prostaglandin and leukotriene release in the presence and absence of the cAMP mediated drugs theophylline, milrinone, sulmazole, isobutyl-methylxanthine and salbutamol. The release of eicosanoids as measured by RIA was predominantly basal and continuous, with a mild antigen induced stimulation only for TXB"} +{"text": "We cytogenetically investigated six osteoid osteomas, one osteoblastoma and one aggressive osteoblastoma, and observed clonal structural changes in one osteoid osteoma and in the aggressive osteoblastoma. Clonal chromosome changes had not been reported previously in osteoid osteoma, whereas the only reported chromosome change in osteoblastoma was different from the one presented here."} +{"text": "Total knee arthroplasty represents a common orthopedic surgical procedure. Achieving proper alignment of its components with the predrilled patellar and tibial peg holes prior to polymerization of the bone cement can be challenging.After establishing the femoral, patellar and tibial bone cuts, the cancellous bone around the tibial keel, as well as the peg holes for the patella and femoral components are marked with methylene blue using a cotton swab stick. If bone cement is then placed onto the cut and marked bone edges, the methylene blue leaches through the bone cement and clearly outlines the tibial keel and predrilled femoral and patellar peg holes. This allows excellent visualization of the bone preparations for each component, ensuring safe and prompt positioning of TKA components while minimizing intraoperative difficulties with component alignment while the cement hardens.The presented technical note helps to improve the accuracy and ease of insertion when the components of total knee arthroplasty are impacted to their final position. The prevalence of degenerative joint disease has seen a considerable increase due to general aging of the population -3. TotalIn the present technical note, we describe a simple modification prior to cementation of TKA components to ensure alignment of patella peg holes, tibial keel, and femoral prosthesis. This surgical technique can be performed in as little as 30 seconds. It thus marginally prolongs the surgical case while helping to avoid intraoperatively repositioning maneuvers of implant components.The standard TKA technique is pursued according to the surgeon's preference. Once the femoral, patellar and tibial bone cuts are established and the knee is balanced correctly, the cut bone surfaces are prepared for cementation in the choosen standard fashion. At this point, the cancellous bone around the tibial keel, as well as the peg holes for the patella and femoral components are marked with methylene blue using a cotton swab stick. Figure The presented technique allows for excellent visualization for the appropriate placement of each component in its prepared location Figure . IntraopTotal knee arthroplasty is a frequently performed surgical procedure . HoweverHowever, as the alignment of each component is highly depended on the location of predrilled peg holes, the presented technique can only allow better visualization for component implantation. As a result, rotational accuracy and alignment cannot be improved when predrilled peg holes are rotationally malaligned. In addition, surgeons routinely applying the cement to the prosthesis prior to component placement will not benefit from the described technical trick.This small change in technique prior and during cementation may prevent intraoperative complications and struggles with optimizing the implant alignment during the 6-10 minute time-window until the PMMA cures , and theThe authors declare that they have no competing interests.WBL, MRD and SJM designed the manuscript. MAF and SJM wrote the manuscript. All authors approved the final version of this review."} +{"text": "Many older Americans have decided to remain in the labor market beyond the traditional retirement age, suggesting the need for companies to consider human resource initiatives to retain and support the aging workforce. Applying active aging concepts, which emphasize older adults\u2019 active roles through participation in social and economic activities for healthy later life, to the workplace could be helpful for developing programs that enhance the health, well-being, and work outcomes of older workers. Despite the expected benefits of active aging at work for older workers\u2019 overall well-being, little research has been conducted on what personal and team factors impact on outcomes of active aging at work; what mechanism exists in the links between factors and outcomes in the contemporary workplace. The current study tested the validity of an active aging framework using the Age and Generations Study data. We analyzed responses of 508 American workers aged 50 and older using structural equation modeling. Results showed that perceived self-efficacy was a strong predictor of engagement, mental health, and performance, whereas perceived leader equity predicted only engagement. Also, work engagement was powerful mechanism for promoting older adults\u2019 mental health; engagement mediated the relationship between perceived self-efficacy and the relationship between leader equity and mental health. The findings highlight how important it is for employers to invest in human capital, suggesting human resource programs should focus on strategies that target older adults\u2019 engagement through tailored self-efficacy programs and diversity leadership training programs. Such attempts would contribute to the well-being of older workers."} +{"text": "Pain and pain management is a growing concern for older adult patients and their health care providers. Upwards of 50% of older adults report having bothersome pain and 75% of these individuals report having pain in more than one location. Persistent pain is associated with decreased physical function, depression, isolation, and a decreased quality of life. Managing chronic pain in the setting of an opioid crisis requires special knowledge about the aging body so that medications can be used safely and effectively; and adjuvant therapies such as PT or acupuncture can be maximized. This segment of the symposium will review common challenges faced by primary care providers when managing chronic pain in older adults: the natural physiologic changes that occur in the aging body, co-morbid chronic diseases which can complicate pain syndromes, and assessing pain in cognitively impaired patients."} +{"text": "The IPUMS Data in Aging Research symposium will showcase aging research that is possible using freely available population-level data accessible via IPUMS. This session will feature papers that use IPUMS data in novel ways to examine aging-related topics including living arrangements, widowhood and divorce, paths toward retirement, intergenerational effects of interventions on later life outcomes, and time use of caregivers. In addition to the common threads of work and family, these papers all represent innovative contributions to aging research based on census and nationally-representative survey data. The potential value of these types of data for studying aging may not be immediately apparent to all researchers. By combining papers on an array of topics from a variety of data sources, this symposium highlights exemplar papers that demonstrate the types of novel research possible using public use census and survey data."} +{"text": "Unrepairable comminuted fractures of the radial head Mason type III or type IV have poor outcomes when treated by open reduction and internal fixation. Radial head resection has been proposed as good option for surgical treatment, while in the last decades, the development of technology and design in radial head prosthesis has increased efficacy in prosthetic replacement. The present review was conducted to determine the best surgical treatment for comminuted radial head when ORIF is not possible. Better outcomes are reported for radial head arthroplasty in terms of elbow stability, range of motion, pain, and fewer complications compared to radial head excision. Nevertheless, radial head resection still can be considered an option of treatment in isolated radial head fractures with no associated ligament injuries lesion of ligaments or in case of older patients with low demanding function. Surgical treatment for comminuted and unrepairable fractures of the radial head may be challenging. These types of fractures are often associated with multiple ligamentous injuries amounting to elbow instability. Radial head resection has been proposed as good option for surgical treatment, while in the last decades, the development of technology and design in radial head prosthesis has increased efficacy in prosthetic replacement.The radial head is a secondary valgus stabilizer of the joint and it is involved in transmission of axial force load through the elbow during flexion . It is aThe purpose of this review was to investigate the current literature on surgical treatment of unrepairable comminuted radial head fractures Mason type III or type IV to assess results and indications for radial head replacement or resection.We searched in PubMed electronic database the words AND ((artrhoplasty) OR (prosthesis)) AND ((resection) OR (excision)). The guidelines for preferred reporting items for systematic reviews and meta-analysis (PRISMA) were used . We seleWe extracted relevant data from the selected articles: type of study, number of patients, age, follow-up, type of surgery performed, clinical results , and radiographic results.The database search identified 152 potentially relevant articles. Abstracts have been analyzed following inclusion and exclusion criteria and a total of 29 papers were selected for the present review. Most of retrospective studies on metal radial head prosthesis have been published in the last ten years in comparison to a lack of studies for radial head excision in the last two decades. Moreover, few articles on comparison of the two surgical techniques have been found. Because of heterogeneity in level of evidence, surgical technique, type of implants, and rehabilitation protocol, we did not perform statistical data analysis. Articles selected are reported in From our review of literature clinical results for radial head replacement are reported in Most common radiological modifications include osteoarthritic changes of ulnohumeral joint, capitellum wear for oversizing of radial head prosthesis, periarticular heterotopic ossifications, and radiolucency lines around the stem. Some modifications in radiographic appearance seem to not correlate directly with clinical symptoms: bone resorption around the prosthesis does not correlate with loosening of the prosthesis and does not affect clinical scores. Marsh reports Complications describeRetrospective studies on radial head resection have a longer follow-up and clinical and radiological results are reported in Finally, few papers compare radial head resection and radial head arthroplasty , 35 wherFrom our review of literature almost all the retrospective studies on radial head arthroplasty report convincing results in terms of elbow stability, range of motion, and pain. Nevertheless, papers on radial head resection report good clinical outcomes in isolated radial head resection with no associated ligament injuries. Few papers compare the two techniques with no substantial differences in terms of clinical outcomes at medium and long follow-up."} +{"text": "Informal caregivers provide 80% of the care needed to support community-dwelling older adults with dementia. Over time caregivers often face adverse effects on their health, quality of life and well-being; particularly those caring for someone with dementia. This study examines the impact of participation in the Voices in Motion (ViM) choir on caregiver burden, mood and quality of life. A measurement burst approach was used to investigate intraindividual variability on key psychosocial and health indicators. Results indicate that choir participation significantly improves caregiver well-being and quality of life. Findings suggest that choirs offer significant caregiver support and respite. The discussion focuses the public policy and on the potential economic implications which suggests a shift is needed in the services available to older adults with dementia and their caregivers."} +{"text": "As the proportion of older adults in the world\u2019s total population continues to grow, the deleterious downstream health economic outcomes of age-related hearing loss are steadily becoming more prevalent. While recent research has shown that age-related hearing loss is the single greatest modifiable risk factor for dementia, the rate of hearing aid use remains low in many countries across the globe. Reasons for poor uptake are multifactorial and likely involve a combination of factors, ranging from increasing costs of hearing aid technology to lack of widespread insurance coverage. This paper aims to first identify the current state of hearing aid access across the world using eight representative countries as examples. We then provide recommendations on how to facilitate greater access to hearing aids for consumers by addressing areas in regulation, technology, reimbursement, and workforce."} +{"text": "Congenital unilateral agenesis of the internal carotid artery (ICA) is a rare anomaly. Due to proper sufficient collateral circulation via the circle of Willis most cases are asymptomatic, but patients can also present with ischemic or hemorrhagic cerebrovascular insults. The absence of the bony carotid canal is essential to differentiate this anomaly from chronic ICA occlusion. Awareness of this situation by clinicians and radiologists is essential because these patients have an increased incidence of various intracranial pathologies. We report two cases of this rare developmental congenital abnormality occurring in two young patients and describe the presentation, diagnosis, determined developmental causes, imaging findings, and complications. The anomalies of the internal carotid artery (ICA) related to developmental defects can be categorized as follows: agenesis ; aplasia ; or hypoplasia . These aIn this article we report two cases of right internal carotid agenesis in a young female patient with nonspecific neurological findings and in a young male patient who presented with both nonspecific and specific neurological findings.A 19-year-old female patient with a few days history of severe headache, dizziness, nausea, vomiting and syncope was admitted for cranial CT examination. Her physical and neurological examinations were normal and her medical history was unremarkable. The color Doppler sonography revealed absence of the right ICA and a changing flow pattern of common carotid artery, from a low peripheral resistance pattern proximally into a high peripheral resistance pattern similar to that seen in the external carotid artery distally Figure . The braA 27-year-old male patient with an unremarkable medical history presented with acute onset of severe headache, dizziness and disequilibrium, and left sided weakness. Unenhanced CT revealed a hypodense lesion in the right thalamic and subthalamic region about 1 cm in diameter and an absent right ICA and bony carotid canal Figure . CranialAgenesis of ICA firstly reported by Tode in 1787 reportedThe reported frequency is low, but as most patients are asymptomatic, the condition probably underreported. The vast majority of reported asymptomatic cases with ICA agenesis are one-sided, although there are scarce papers of asymptomatic cases of bilateral ICA agenesis . DiffereThe agenesis of ICA is associated with a higher incidence of intracranial aneurysms, transsphenoidal encephaloceles, and an extensive rete mirabilis (vascular network interrupting the continuity of an artery or vein in the tissue) in the cranial base 6. The cl23532The ophthalmic artery has a sophisticated embryogenesis, which is closely related to with the development of the internal carotid artery . AccordiIn patients with unilateral or bilateral ICA agenesis three types of collateral pathway have been described. The most-common type of these collateral circulations is the fetal type, in which the ipsilateral anterior cerebral artery and the ipsilateral medial cerebral artery are supplied by the normal contralateral ICA through the anterior communicating artery and by the basilar artery through an ipsilateral dominant posterior communicating artery respectively . In the 6Congenital agenesis of the ICA is a rare, usually asymptomatic, vascular anomaly. Although most patients are asymptomatic rarely, they can be presented with some neurological disorders including intracranial hemorrhage or ischemia. To our knowledge an intracranial ischemia as in our second case is a very rare complication. The goals of imaging when suspecting ICA agenesis are: confirming the diagnosis by evaluating the bony carotid canal, identifying the type of the collateral circulation, assessing the presence of associated anomalies and ruling out acute complications including intracranial hemorrhage and ischemic lesions. MRI and MR angiography coupled with CT and color Doppler sonography allow accurate diagnosis. It is also beneficial for the educating of the patients and families about the benign feature of the disease and the oncoming implications, as well as the potential complications.The authors declare that they have no competing interests."} +{"text": "We will then concisely review how organoids have been used to study human pathogens, how new genetic and bioengineering tools are being applied to organoid research, and how this integration has allowed researchers to elucidate mechanisms of human development and disease. Finally, we will briefly discuss remaining challenges in the field and how they can be addressed. HPSC derived organoids are promising new model systems which hold the potential of unlocking unknown mechanisms of human gastrointestinal development and disease.In recent years, advances in human pluripotent stem cell (hPSC) biology have enabled the generation of gastrointestinal (GI) organoids which recapitulate aspects of normal organ development. HPSC derived gastrointestinal organoids are comprised of epithelium and mesenchyme and have a remarkable ability to self-organize and recapitulate early stages of human intestinal development. Furthermore, hPSC derived organoids can be transplanted into immunocompromised mice which allows further maturation of both the epithelium and mesenchyme. In this review, we will briefly summarize work from model systems which has elucidated mechanisms of GI patterning and how these insights have been used to guide the differentiation of hPSCs into organoids resembling small intestine and colon. We will succinctly discuss how developmental principles have been used to promote maturation of human intestinal organoids (HIOs) In the past decade, organoid models have revolutionized the study of the gastrointestinal (GI) epithelium \u20134. OrganStudies in model organisms such as frog, mouse and chick are the foundation for directing human pluripotent stem cells toward desired tissue fates . Human iThe generation of HIOs from hPSCs can be difficult to reproduce without proper training and experience. Suboptimal seeding density of hPSCs can result in the generation of definitive endoderm incapable of undergoing 3D morphogenesis into mid/hindgut spheroids. To circumvent this, several groups have generated HIOs by simply passaging WNT and FGF treated DE monolayers as clumps \u201317. WhenEscherichia coli (E. coli) . Bacteriin vivo including neurons and glial cells. NCC differentiation and organization into ENS was supported by the HIOs which expressed the chemoattractant factors glial cell derived neurotrophic factor (GDNF) and endothelin 3 (EDN3). The resulting neurons were solely excitatory and displayed a spontaneous calcium efflux indicating a neuronal activity. The complexity of the neuronal system was further enhanced after in vivo transplantation resulting in the emergence of inhibitory neurons in addition to the excitatory neurons.The smooth muscle layers of the intestine are innervated by the enteric nervous system which allows for peristalsis. The development of the smooth muscle layers in transplanted HIOs suggested that HIOs could be innervated . The entex vivo. Upon receiving a neuronal stimulus, HIOs with an ENS exhibited contractile waves similar to peristalsis in human intestines suggesting a neuromuscular communication. Additionally, the NCC derived inhibitory neurons integrated into the smooth muscle layers to control tissue relaxation by releasing the neurotransmitter nitric oxide (NO). Furthermore, the presence of ENS following transplantation of the HIOs resulted in decreased expression of markers of differentiated epithelial cell types and increased epithelial proliferation in the HIOs. The generation of innervated intestinal tissue is a significant advancement since it could allow for the replacement of damaged intestine with a tissue which is competent to induce peristalsis.To functionally test the ability of HIOs with an ENS to produce peristalsis, electrical stimulation was applied to transplanted HIOs in vitro lack maturity and thus have limited applications for studying intestinal physiology (in vitro maturation of these organoids (in vitro. The authors were able to identify Interleukin 2 (IL-2) as the crucial factor secreted by Jurkat cells which allowed the maturation of the HIOs in vitro. The transcriptomic profile of co-cultured and IL-2 treated HIOs more closely resembled the human adult small intestine. Functional maturation was also evident in the matured HIOs as assessed by their ability to establish barrier function, transport chemotherapeutic drugs and transport glucose. Additionally, matured HIOs expressed functional cystic fibrosis transmembrane conductance regulator (CFTR) and were capable of swelling in response to forskolin, an assay designed to screen for Cystic Fibrosis therapeutic drugs mice which lack lymphocytes and have normal intestinal development.HIOs grown ysiology , 22. To rganoids . Surprisic drugs , 25. TheInitial analysis of HIOs revealed that they were comprised of proximal and distal small intestinal tissue even within the same organoid suggesting additional signaling might be required for proper patterning of HIOs . In ordein vitro culture, HCOs generated colon enriched cell types such as mucin 5B (MUC5B) expressing goblet cells and the colon specific enteroendocrine hormone insulin like 5 (INSL5) following induced expression of NEUROG3. After renal transplantation into immunocompromised mice, HCOs retained the expression of SATB2, lacked GATA4 expression and lacked small intestinal cell types such as GIP expressing enteroendocrine cells and Paneth cells. In contrast, transplanted HIOs expressed GATA4 and contained small intestinal cell types such as Paneth cells and small intestinal enteroendocrine hormones such as Ghrelin, Motilin, and GIP. These studies demonstrated the utility of hPSC-derived organoids for studying mechanisms of anterior-posterior patterning.In another study, M\u00fanera et al. demonstrated that a transient activation of BMP signaling was sufficient to induce the expression of posterior Homeobox (HOX) genes and confer a colonic identity on human gut tube cultures . Furtherin vitro models for viral replication are scarce. HIOs have offered some hope as they have been shown to allow limited replication of clinical isolates of rotaviruses and noroviruses producing Escherichia coli O157:H7, and Clostridium difficile. Bacterial pathogens can be microinjected into the lumen of HIOs to study the effect of the pathogens on the epithelium and mesenchyme of HIOs. These studies demonstrated that HIOs recapitulate responses to bacterial pathogens including internalization of bacteria, increased secretion of mucus, epithelial barrier disruption and induced pro-inflammatory cytokine expression allows the generation of patient specific iPSCs . Using tThe generation of HIOs can be an inefficient process which could limit their scalability. To address this shortcoming, Arora et al. investigated the impact of spheroid number, size and morphology on organoid yield and found the last two parameters to be the key features that help identify spheroids which are most likely to generate organoids . By devein vitro. In addition, the authors were able to demonstrate that HIOs grown in this hydrogel could be orthotopically transplanted and could improve mucosal wound healing in the colon of immunocompromised mice . This plin vitro culture. In addition, single cell RNA sequencing of HIOs compared to fetal intestine should allow the identification of cell types which are differentially absent or present in HIOs compared to human fetal intestine.Although morphologically HIOs undergo transitions similar to those that occur in mammalian embryos, the molecular changes associated with these transitions remain unresolved. Future experiments directly comparing HIOs to human fetal and postnatal intestine from several stages of development will determine the relative age of an HIO at any timepoint during the AD and JM helped to write and edit the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Reflectance confocal microscopy (RCM) is a optical imaging technique that affords an horizontal view of the skin until superficial dermis. RCM uses a laser light, at near infrared wavelength (830 nm), as a source of coherent monochromatic light which penetrates the tissue and illuminates a single point.Microscopic tissue elements reflect light with different refractive indices resulting in white structures on a black background. Given the high reflective index of melanin and keratin this non-invasive imaging tool can have an important application in the diagnosis of skin cancer. Though an \u201coptical biopsy\u201d allows physicians to visualize the skin lesion to a depth of 200 microns with subcellular resolution, improving diagnostic accuracy of dermoscopic equivocal cutaneous lesions .If combined with clinical and dermoscopic diagnosis, RCM can enhance the accuracy of differentiating between benign and malignant skin neoplasms . RCM canDespite its utility in skin cancer diagnosis the diffusion of RCM in clinical practice is circumscribed mainly around academic medical centers. Moreover, the daily use of RCM is limited by its cost and knowledge gap amongst dermatologist .Before performing RCM at a safe level physicians need a dedicated training, that is not available although the numerous publications in literature about this topic .Farnetani et al. showed tIn RCM the images are in gray scale and the interpretation of RCM skin images requires specific knowledge of histomorphological features rather than direct translation of clinical and dermoscopic skills. Consequently, this makes RCM difficult to perform in a routine clinical setting.Unlike dermoscopy, which has rapidly spread as a screening technique among dermatologists of all generations, currently RCM is rarely used outside teaching hospitals. Dermoscopy is based on the description of colors and structures, whereas RCM morphologic features are similar to those observed within a diagnostic pathology setting . MoreoveAlso images visualization is more pertinent to the dermatopathology since in RCM there is an acquisition both in planes oriented parallel to the skin surface and both in depth through stack of images.ex vivo confocal microscopy; this new technique allows real-time microscopic examination of freshly excised cutaneous tissues. This technology has been introduced in Mohs dermatologic surgery in particular for the evaluation of the surgical margins of basal cell carcinomas but shows a possible application in breast and brain surgery. Ex vivo confocal microscopy could save two-thirds of processing time compared with conventional analysis of Mohs surgery, as processing and sectioning times are eliminated. Moreover, the procedure does not impair further histopathology evaluation on frozen or paraffin sections.The above considerations indicate that RCM, in our opinion, may reach more widespread acceptance and utilization among pathologists/dermatopathologists rather than clinical dermatologists. To this regard, a recent article reports in vivo and ex vivo RCM should primarily be used to assist pathologists/dermatopathologists in the classical histopatological and immunohistochemical diagnosis of skin cancer and, consequently, should not be considered a clinical tool for dermatologists.In conclusion, we believe that both AF and MA wrote the manuscript. The final version of the manuscript was approved by all coauthors.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Sex differences in the incidence, prevalence, and clinical presentation of neurodegenerative diseases have been previously documented, however, sex differences in how individuals with neurodegenerative diseases access the health system remain understudied. Clinical trials and observational studies often do not report data stratified by sex, which limits the understanding of sex-related differences in persons with neurodegenerative diseases. This session will highlight both opportunities and methodological challenges researchers face when undertaking sex and gender research in persons with neurodegenerative diseases using two case studies: 1) sex differences in health service utilization prior to a diagnosis of Amyotrophic Lateral Sclerosis (ALS); and 2) sex differences in care needs and survival among persons who are admitted to a nursing home after a stroke. The findings of these studies may support the development of guidelines and care plans to meet the needs of men and women with neurodegenerative disorders in varied care settings."} +{"text": "Using qualitative interpretative phenomenological analysis and semi-structured interviews, we explored transit mobility needs and its impact on well-being and quality of life among late-life Asian Indian immigrants. Using inductive and deductive methods, we analyzed qualitative data collected from 18 participants. Four themes emerged specific to the influence of contextual factors on transportation mobility barriers among participants. Findings suggest that cultural and individual attitudes combined with the \u2018built environment\u2019 hinder participation at the temple and other cultural and religious activities and increase dependence on adult children. The reciprocal fit between transit mobility needs, access to culturally familiar environments and the built environment is critical to freedom, independence, and healthy aging for diverse older adults. Research at the intersection of global aging and transportation mobility requires equal grounding in a range of justice principles in the pursuit of sustainable transportation options for diverse older adult populations."} +{"text": "The role of the pharmacist in healthcare has evolved greatly over the last half-century, from dispensing to providing direct patient-oriented activities not associated with dispensing. However, pharmacist-led healthcare services in Sri Lanka must undergo reform to fully take advantage of their expertise and training in medicine management and related outcomes in Sri Lankan patients. As befits a profession\u2019s role development and value, professional and educational standards for pharmacists need ongoing development and growth. Currently, university curricula and continuing professional education in Sri Lanka require further development and optimisation to provide the theoretical and practical knowledge and skills regarding quality use of medicines and patient-oriented care. Furthermore, pharmacists\u2019 roles in Sri Lankan hospital and community pharmacist settings need to be recognised and should include the pharmacist as an integral part of the multidisciplinary healthcare team in Sri Lanka. Studies from developed countries and some developing countries have demonstrated that expanded pharmacists\u2019 roles have had a significant positive cost-effective impact on the population\u2019s health. Therefore, the availability of qualified Sri Lankan pharmacists trained to deliver expanded professional services accompanied by greater pharmacist integration into healthcare delivery is crucially important to ensure quality use of medicines within the Sri Lankan healthcare system and optimise the medication-related needs of Sri Lankans. Pharmacy is a major health discipline that contributes to the development of a country . PharmacIn order to achieve the ultimate goal of improving the healthcare services of a nation, the pharmacy profession should be committed to continuously improving its knowledge and quality of practice. The aim of this chapter is to highlight the need to strengthen the roles of pharmacists in Sri Lanka. Further, this chapter will describe the importance of pharmaceutical care services, the current scenario of pharmacists\u2019 roles in hospital and community pharmacies in Sri Lanka and how further augmentation of pharmacy education can produce competent pharmacists able to deliver enhanced pharmaceutical care across all Sri Lankan healthcare settings and ultimately optimised patient self-management of medicines. The role of the pharmacist around the world has evolved greatly over the last decades, expanding from dispensing activities to enhanced direct patient-care tasks, administrative activities and public health functions. Pharmaceutical care aims to provide responsible and careful medication therapy to achieve optimal medication outcomes and increase patient satisfaction in an integrated health system that ultimately improves the quality of a patient\u2019s life . HoweverOfficial Sri Lankan reports have made recommendations for the improvement of pharmaceutical care services in both hospital pharmacy and community pharmacy settings, albeit with little fruition . CurrentPharmaceutical care services in the hospital setting promote appropriate medicine use and cost-effective prescribing and enhance medication safety . EnhanceIn recent years, developing countries such as Malaysia , Taiwan There are only a few studies and reports in the literature discussing Sri Lankan hospital pharmacy and pharmaceutical care service delivery. Currently, only a small number of pharmacists are employed in Sri Lankan hospitals , and phaA high prevalence of preventable medication errors (35.5%) related to incorrect dosing regimens and inappropriate documentation for prescribed or administered medications inpatient records has been reported in Sri Lankan hospitals . This reUsing pharmacists to provide pharmaceutical care services in hospitals and recognising them as part of the healthcare team may improve access to comprehensive medicines information for patients and clinicians and enhances the ability for pharmacists to develop close collaborative relationships with prescribers and other healthcare professionals . FurtherCommunity pharmacists play a vital role in healthcare provision . CommuniIn developed countries, community pharmacy services are well recognised and utilised , and theBy contrast, community pharmacy services offered in developing countries are typically confined to traditional practices of dispensing with a business-oriented approach and a liIn Sri Lanka, privately-owned community pharmacies are the main source of medicines, and dispensing is mostly undertaken by pharmacists and drug retailers ,56. CurrThe absence of a qualified and trained pharmacist in the community pharmacy setting is the mains reason for many of the observed inappropriate dispensing practices in Sri Lankan community pharmacies. Remuneration and recognition are two concerns for qualified pharmacists to seek work opportunities elsewhere . GuideliThere is a considerable need for healthcare services provided by community pharmacies in Sri Lanka and an urgency to undergo reforms to meet the changing needs of medicines users and align with international standards of practice. Apparently, most of the medication use and supply occurs in community-based settings , so it iFurthermore, community pharmacists can play a key role in optimising medicines use to help achieve the quality use of medicines in the community. Importantly, pharmacists\u2019 contributions to healthcare need to be recognised. There is an urgent need to strengthen community pharmacists\u2019 role in Sri Lanka. To achieve this, policy changes in the healthcare system for pharmacists should be considered for adoption in Sri Lanka. Remuneration and recognition for the extended roles that a pharmacist can play (beyond supplying medicines) are critical in order that qualified pharmacists achieve their full scope of practice in community pharmacies. Pharmacists with the appropriate education and training can assist both healthcare professionals and patients in using medications wisely ,74,75. FPharmacy undergraduate education in Sri Lanka is a predominantly science-based university course. If pharmacy education is to keep pace with current and future changes in practice, then pharmacy training must become more patient-focused, embracing elements of clinical and therapeutics training. There is a necessity to provide knowledge and skills on pharmaceutical care through pharmacy curriculum at undergraduate level . A primaThe next imperative is to provide postgraduate (PG) level training for pharmacists in Sri Lanka. These PG courses can be introduced as M. Pharm in Clinical Pharmacy or M. Pharm in Hospital Pharmacy or PhD in Pharmacy. Postgraduate courses focusing on the management of diseases and the development of quality use of medicines in Sri Lankan universities could be an additional strategy. Currently, pharmacy graduates undertake PG studies in allied fields, such as chemistry, since graduates do not have access to research or PG studies in the field of pharmacy or pharmacy practice. There are currently no academic institutions in Sri Lanka that offer postgraduate degrees in the pharmacy discipline, and this has meant Sri Lankan qualified pharmacists who wish to further their postgraduate pharmacy career need to undertake postgraduate studies abroad. To date, relatively few pharmacists have obtained Masters or PhD qualifications in pharmacy. This hampered development of pharmacy leaders with a wider range of competencies, knowledge and skills necessary for the development of future healthcare services in Sri Lanka presents pharmacy graduates with a significant barrier to their future academic and professional development and is a major challenge for the development of Sri Lankan pharmacy practice. It is essential that research and PG programmes in pharmacy-related fields are introduced. These future initiatives will not only provide benefits for the graduate pharmacists but will also have an important impact on the future development of pharmacy leaders and the pharmacy profession in Sri Lanka and optimise the appropriate, safe and effective use of medicines by Sri Lankans.It is also equally important to analyse the contents of pharmacy curricula of undergraduate and postgraduate pharmacy programmes in other countries, which excel in pharmacy practice, such as Australia . AustralAdditionally, continuous professional development courses and programs for practising pharmacists are another important strategy requiring establishment in Sri Lanka. Continuous professional education, using workshops, seminars and online courses is another important means to improve appropriate medication use and dispensing practices in Sri Lanka. These educational strategies could have a direct influence on patient-centred practices of pharmacists in Sri Lanka. If pharmacists are to consider providing enhanced pharmaceutical care services in future, then using the teaching and training of pharmacy practice at undergraduate level as well as maintaining the currency of their skills and knowledge through continuous professional courses will help to strengthen the role of pharmacists in Sri Lanka.In Sri Lanka, pharmacists are currently underutilised, and their potential roles in patient-care can be viewed as a missed opportunity for optimising the health of the nation\u2019s population. There is a greater need for Sri Lankan pharmacists to extend their services to offer pharmaceutical care. This could lead to the identification and resolution of drug-related problems, improved medication adherence, improved medication safety and enhanced patient care. To effectively and continually offer these services, national policies will need to be developed and enacted to provide some remuneration and recognition for the service. Several studies have demonstrated that the expanded role of pharmacists delivering cost-effective optimal patient care has a significant impact on the healthcare system of a nation. Therefore, the pharmacist\u2019s role should be strengthened to deliver pharmaceutical care services in Sri Lanka."} +{"text": "Renal blood flow occurs both in series and parallel. While all the blood entering the kidney first enters the renal cortex, two distinct populations of nephrons give rise to remarkably different post\u2010glomerular capillary circulations. Superficial and mid\u2010cortical nephrons give rise to the cortical peritubular capillary network, a web of capillaries that supplies the cortical parenchyma and supports reabsorption of the bulk of the glomerular filtrate. In contrast, the majority of juxta\u2010medullary nephrons, whose afferent arterioles arise near the corticomedullary junction, give rise to vascular bundles containing descending vasa recta capillaries that supply blood to the renal medulla. Some of these descending vasa recta traverse all the way to the tip of the papilla, before looping around to giving rise to ascending vasa recta capillaries. Descending vasa recta on the periphery of these vascular bundles give rise to the dense plexus of capillaries that supply the medullary parenchyma. The relatively low rate of perfusion and the looped structure of the medullary circulation limit the washout of solutes including NaCl and urea in this region, maximizing the ability to form concentrated urine.Since the observation by Trueta et\u00a0al. that renMuch of the controversy regarding the role of renal hemodynamic changes toward disease likely arises from the difficulties associated with studying regional renal hemodynamic changes. While the kidney is perfused by a single artery, making measurement of total renal blood flow relatively simple, the parallel nature of the renal circulation makes quantifying regional hemodynamic changes difficult, particularly in the deeper less accessible areas such as the renal outer\u2010medulla. Further, most techniques utilized to quantify regional renal hemodynamics require prolonged anesthesia of the animal and exposure of the kidney, factors that undoubtedly have major effects of renal perfusion. Many techniques also lack the sensitivity to adequately quantify changes in regional kidney blood flow, particularly within the small post\u2010capillary vessels of the cortical peritubular circulation and post\u2010glomerular medullary capillaries.The microfil technique, in which the renal circulation perfused with silicone rubber before dissolving the renal parenchyma, has provided an enormous amount of information regarding renal hemodynamics. Vascular casts of the renal circulation have been utilized to visualize the complex tubular vascular relationships that support renal function as well as understand the actions of vasoactive stimuli on glomerular afferent and efferent arteriole diameters (Denton et\u00a0al. In this issue, Fan et\u00a0al. describe"} +{"text": "Evidence shows that education is strongly associated with cognitive functioning; however, few studies have examined the effect of education on cognitive decline among older adults with very limited education. Our study analyzed six waves of panel data from the Longitudinal Study of Older Adults in Anhui Province, China. We estimated two-level multilevel models of cognitive functioning for older adults age 60+, sampled using probability sampling strategy. We found that having formal schooling was positively associated with better cognitive functioning. Older adults with formal schooling had slower decline in cognition and the gap in cognition between the literate and illiterate widened with age. These findings highlight the role of early life experience in affecting cognitive function in later life and suggest that disadvantages in cognitive functioning accumulate throughout the life course for persons with no formal education."} +{"text": "What evidence exists that this phenomenon occurs in human patients with retinal degeneration, and what is the ultimate effect of spontaneous hyperactivity in the output neurons, the retinal ganglion cells? Here I summarize abnormalities of visual perception among patients with retinal degeneration that may arise from hyperactivity. Next, I consider the disruption of neural encoding and anatomic connectivity that may result within the retina and in downstream visual centers of the brain. I then consider how specific characteristics of hyperactivity may distinguish various forms or stages of retinal degeneration, potentially helping in the near future to refine diagnosis and/or treatment choices for different patients. Finally, I review how consideration of these features may help optimize pharmacologic, gene, stem cell, prosthetic or other therapies to forestall visual loss or restore sight.Hereditary retinal degenerations result from varied pathophysiologic mechanisms, all ultimately characterized by photoreceptor dysfunction and death. Hence, much research on these diseases has concentrated on the outer retina. Over the past decade or so increasing attention has focused on concomitant changes in complex inner retinal neural circuits that process visual signals for transmission to the brain. One striking abnormality develops before the ultimately profound anatomic disruption of the inner retina. Highly elevated spontaneous activity was first demonstrated in central nervous system visual centers An ever-widening variety of genetic defects and biophysical mechanisms is recognized to cause progressive dysfunction and death of photoreceptors: hereditary retinal degenerations. Beyond this is an even broader array of neurologic and systemic disorders whose manifestations include retinal degeneration.Gradual loss of vision in these patients is, of course, expected as the primary light-sensing cells of the retina fail, and so scientific attention in these diseases long has focused on photoreceptors. Yet beyond these cells the neural circuits of the inner retina perform a tremendous amount of visual processing before information about the world we see is \u201ccompressed\u201d and sent to visual centers in the brain. Arguably, the retina itself may be considered a structure of the central nervous system (CNS), a perspective that may be helpful to understand its normal function and deterioration with disease.Up to 70% of patients with retinal degenerations report an impressive variety of visual symptoms beyond a simple scotoma . These range from photopsias and scintillations to complex formed hallucinations to imagined scenes or awakened visual memories , reflectThe more complex of these abnormal visual perceptions may be considered a form of the Charles Bonnet syndrome originally described in 1760 in a patient with severe bilateral cataracts, but also reported for other forms of severe bilateral visual loss . In suchHow might this spontaneous hyperactivity among RGCs affect the vision of patients with retinal degeneration? It is easy to speculate that irregularly occurring bursts of such activity in RGCs, either individually or among groups of RGCs, would generate brief flashes of light, and that characteristics might vary substantially depending upon which functional type of RGC(s) were active at any given moment . AlternaHowever, it now is widely accepted that a simple rate code cannot carry all the visual information conveyed by the retina to the brain . A varieenhance visual perception: a principle known as stochastic resonance , Cep290 and Rpe65 but also substantial reorganization of circuitry and electrophysiologic functioning of the inner retina, culminating in abnormal output of RGCs. This includes an increase in background spontaneous activity originating from multiple sites, from the level of photoreceptors, horizontal cells, and bipolar cells to the output level of RGCs. The aberrant activity often is rhythmic and oscillatory and may affect changes in neural connectivity and function in further downstream visual centers of the CNS.The discovered background spontaneous hyperactivity of RGCs may help explain the variety of phosphenes and other visual phenomena experienced by many patients in some stages of retinal degeneration. It may also degrade normal visual perception, but alternatively might actually improve perception under certain conditions . Individual visual processing pathways may be selectively affected, causing specific distortions in visual perception, and even translate to complex visual phenomena \u2013 including formed hallucinations \u2013 at a cortical level. Because of disruptions in normal developmental maturation of these retinal circuits, early identification and treatment of these disorders may be critical for developing therapies that ultimately are more effective. Finally, basic mechanisms identified to date do suggest some further avenues to explore in order to improve clinical testing of patients, for both diagnosis and the identification of optimal candidates for specific treatments in clinical trials.There is a great deal yet to be learned about the clinical implications of these findings for patients with retinal degeneration. However, studies of animal models such as those in this Research Topic highlight a variety of key features of this reorganization and suggest previously unrecognized mechanisms that may explain patients\u2019 symptoms. Because certain of these characteristics appear to be disease-specific, they also may help to diagnose specific disorders earlier and more accurately. For example, current clinical tests such as low-contrast visual acuity charts may be adapted to assess for intrinsic \u201cequivalent noise\u201d and potentially quantify disease stage, perhaps even predict treatment responses in individual patients. Ultimately, deeper understanding of the inner retina\u2019s reorganization may pave the road to more mechanistically targeted therapies and provide more specific tests to screen for optimal subjects in clinical trials of new and evolving treatments.SS reviewed relevant literature, wrote and revised the manuscript, read and approved the submitted version.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Helicopter EMS (HEMS) teams may perform a variety of clinical, managerial and transport functions during major incident management. Despite national and international variations in HEMS systems, the rapid delivery of HEMS personnel with advanced skills in major incident management and clinical scene leadership has been crucial to the delivery of an effective medical response at previous incidents. This document outlines the Best Practice Advice of the European HEMS and Air Ambulance Committee (EHAC) Medical Working Group on how HEMS and Pre Hospital Critical Care teams may maximise the positive impact of their resources in the event of Major Incidents.Narrative literature review and expert consensus.To ensure a safe, coordinated and effective response, HEMS teams require suitable, proportionate and up to date major incident plans that are integrated into the major incident plans of other regional emergency and healthcare services. Role specific protocols, training and equipment should be adapted to the expected HEMS role in the major incident plan and likely regional threats. System and incident factors will influence HEMS utilisation during the major incident response and can include patient and staff transfer, equipment resupply, aerial assessment, search and rescue, clinical leadership and advanced care. During the recovery phase of a major incident there is a need to ensure restoration of conventional service and address the welfare of involved HEMS personnel. Standardised reporting of major incidents is strongly recommended for clinical governance, legal and research reasons.The rapid delivery of HEMS personnel with advanced skills in Major Incident management and clinical scene leadership is crucial to the delivery of an effective medical response at Major Incidents. A major incident can be defined as an incident that requires the mobilisation of extraordinary emergency medical service (EMS) resources and is identified as a major incident in that system , 2. MajoHelicopter EMS (HEMS) teams may perform a variety of clinical, managerial and transport functions during major incident management. Helicopters have the capability to bring specialised teams and equipment to incident scenes, transport patients, provide search and rescue services, and perform overhead surveillance. When a site is remote or conventional access routes are compromised, helicopters may be the only way to transport personnel, equipment and patients to and from an incident .HEMS services differ nationally and internationally in the medical expertise of team members, aviation platform, funding model and integration into state EMS. Despite these variations, the rapid delivery of HEMS personnel with advanced skills in Major Incident management and clinical scene leadership has been crucial to the delivery of an effective medical response at previous Major Incidents \u20136.This document outlines the Best Practice Advice of the EHAC Medical Working Group on how HEMS and Pre Hospital Critical Care teams may maximise the positive impact of their resources in the event of Major Incidents. This document is intended to compliment and not supplant existing local and international Major Incident guidance.Fixed-wing Air Ambulance rarely have a role in the initial response phase of Major Incidents, but are often used for secondary/interhospital transport to relieve local hospital capacity or transport patients to definitive care in the development and conclusion phase of a Major Incident response. The EHAC Medical Working Group have decided to not describe fixed-wing Air Ambulance separately in this document, but recommend that the same Best Practice Advise be valid for fixed-wing as for HEMS.HEMS units require a suitable, proportionate and up to date Major Incident plan that includes medical, aviation, and technical aspects. Further, support services e.g. communication, fuel and resupply should also be integrated into the service planLocal Major Incident plans should include clear pre-defined roles, responsibilities and command of HEMS medical personnel and helicopter utilisationHEMS Major Incident plans must be integrated with the Major Incident plans of other local medical and non-medical emergency services including fire, police and militaryInformation on capability, capacity, landing site and contact details should be available to HEMS teams and their control centres for regional and supra-regional hospitals to facilitate patient distribution and optimise surge capacityDepending upon regional threat, HEMS teams may require formal planning cooperation with tactical law enforcement units to ensure team safety, helicopter base security and efficient clinical care in non permissive environmentsConsider maintaining units in reserve or delaying HEMS deployment until incidents are declared to avoid HEMS resources from becoming fully committed to potential or minor incidents at the expense of casualties at decompensated sites. Reserve assets also maintain the ability to respond to multiple incident sites and ensure that conventional activity can be fully resumed at the conclusion of the incident Ensure robust communication methods between HEMS teams and other emergency services exist to allow interoperability and a cohesive responseEstablish efficient communication cascades within HEMS systems to ensure teams can be mobilised and coordinated in the event of a major incidentHEMS medical personnel must complete a recognised Major Incident management training course that allows operational integration with local emergency servicesHEMS operational staff must ensure that they are familiar with the HEMS and local Major Incident plansMajor Incident exercises should be conducted on a regular basis together with other rescue services, in accordance with local statutory requirements, to confirm operational familiarity with plans and identify deficits Training in tactical, chemical, biological or radiation operational safety should be provided to HEMS teams that are expected to provide immediate patient triage and care or if no alternative tactical medical team exists , 9]9]Anticipate the provision of equipment and drug requirements of mass casualty incidents sufficient to deploy multiple equipped HEMS teams in exceptional circumstances Provide Personal Protective Equipment (PPE) to allow safe working in a Major Incident environment with conventional scene hazardsRisk evaluate for the likelihood of Chemical, Biological, Radiation, Nuclear or Explosive (CBRNE), ballistic or specific local scene hazards and consider stocking sufficient risk specific PPE, logistics and detection equipment to allow the safe deployment of multiple teamsConsider the routine carriage of back-up communications equipment due to the multifactorial potential for conventional communication network failurePrepare items such as triage labels, action cards, event logs, etc. in accordance with local protocols to facilitate the organisation and documentation of Major IncidentsSupport structures like maintenance, supplies, transfusion services, human resources, public relations and communications departments are all integrated parts of operational HEMS units and should be embedded in major incident plans to maintain resilience in prolonged operations.http://www.legislation.gov.uk/ukpga/2004/36/contents. Moreover, healthcare organisations have a legal duty of care for their employees and must appropriately equip and prepare them to work in such rare, high risk but foreseeable circumstances. Failure to adequately train or protect staff has resulted in severe short and long term health consequences for medical staff at incidents such as the sarin attacks in Tokyo [Major incident planning, training, resources and exercises are not only central to the delivery of an effective emergency response but are legal requirements in some countries in Tokyo , 11 and in Tokyo . Conversin Tokyo .The medical management of a Major Incident will be guided by local and international protocols . The focPrimary and secondary patient transferTransfer of emergency service staff to and between major incident sitesDeployment and resupply of medical equipmentAerial assessment of Major Incident scenesAccess to remote sitesSearch and rescueWhere multiple emergency services deploy helicopters into an uncontrolled airspace there must be predetermined procedures to coordinate activity and ensure aviation safetyOrganisations operating HEMS must have Standard Operating Procedures (SOPs) for incidents involving multiple HEMS units in uncontrolled airspace that ensure clear command, control, communication and safetyThe safety of HEMS crews should be prioritised when landing in unsurveyed landing sitesConsider the risk from the cause and consequence of the Major Incident, such as ongoing fire, explosion, toxic chemicals, flooding, weather, building collapse, terrorist activity and secondary attacks directed at emergency responders Authority for helicopter deployment should be coordinated by systems familiar with the logistical and clinical capability of the HEMS asset to ensure safe and efficient utilisationContingency plans for regional and supra-regional major incident control centres should be established to mitigate the risk of local command centre communication overload or failureHEMS team may be required to assume medical command of major incident management due to geography, speed of response, medical seniority or predefined Major Incident roleHEMS teams should contribute to the situational awareness of scene command with intelligence collected from the air and recognise that visual information from flight to and from the scene can be valuable for critical decision making in the scene commandDeliver regular site report updates to the regional system control centre to allow effective utilisation of available assetsWhen possible, HEMS personnel should operate in their usual teams and aviation platforms to minimise risk due to inter service variations in operational proceduresHEMS teams often have extensive regional knowledge of the health care system and can utilise this knowledge in scene command decision makingFacilitate scene coordination by wearing labels that clearly state designated Major Incident role and responsibility e.g. Casualty Clearing Station officer, Medical Major Incident Commander etc.In accordance with local Major Incident training protocols, responsibility for scene command, safety, communication and safety may take precedence over the personal delivery of medical care to individual casualtiesHEMS teams must be able to organise and implement dynamic triage at each stage of the Major Incident response according to national or local triage systemsHEMS teams must be able to systematically prioritise casualties for treatment and transport. This is a vital element in the efficient management of Major IncidentsHEMS teams must follow the same triage system as local resources if a national triage system is not in place or when operating in cross border incidentsRapid application of simple interventions, such as tourniquet control of massive haemorrhage and recovery position for airway obstruction, may be superior to definitive clinical management of individual patients when managing large numbers of patients with limited resources or in a non permissive environment The appropriate level of patient care may change during phases of a Major Incident and as a patient is moved away from direct danger into an increasingly permissive and safe environmentImplementation of advanced medical procedures, such as intubation, requires situational judgement to ensure that it does not further endanger the individual patient and impair the care delivered to other unattended victimsDecision making on helicopter transfer of patients will be influenced by many event specific factors and may be inappropriate if the helicopter is better deployed to convey staff and equipment. This may change during different phases of the responseHelicopter evacuation may allow primary transfer to distant specialist care ) or inter-hospital transfers to appropriately distribute patients for definitive careHEMS teams may be required to use a knowledge of regional resources and specialist centres to distribute patients according to need and capacityA systematic review of the utilisation of HEMS during the early response to major incidents demonstrated that, in addition to their conventional patient treatment and transport functions, these resources have been used in a diverse range of roles at previous incidents . This diEffective triage and major incident management by skilled pre hospital physicians has been demonstrated to reduce critical mortality and over triage rates . ApproprHEMS teams should plan to rapidly regain operational activity to meet conventional need and to respond to further related incidentsHEMS teams that have been involved in major incident scene management should be relieved when the mission is over to allow for rest, debriefing and psychological supportTeam debriefing and psychological support should be available to HEMS membersContemporaneous records of Major Incident events and decision making must be preserved to inform later investigation and analysis and in accordance with local regulations or lawsTeams should be encouraged to write statements of Major Incident events soon after the incident to promote accurate recording and recollection of eventshttp://majorincidentreporting.net)A standardised Major Incident reporting template should be completed (A recent systematic literature review found little or no systematic reporting of the utilisation of HEMS in the early medical management of major incidents . This coDespite the predominant focus upon minimizing the physical risk to emergency responders at Major Incidents, there is a significant evidence base demonstrating psychopathological sequelae . Critica"} +{"text": "We draw on outstanding recent research to substantiate factors driving pro-environmental food purchasing behavior. Throwing light on purchasing behavior for environmentally sustainable foods, our study highlights the relevance of consumer trust and motivations in organic product markets together with individuals' perceived value and willingness to buy such items throughout the choice behavior and decision-making process. Our findings prove that most aspects influencing consumers' attitudes for and choices of organic foods are related to their trust and perceptions of the nutritional benefits such products provide. The insights gained from our research extend present knowledge concerning consumer behavior and purchase intention for environmentally sustainable products. The chief gaps and issues identified by the review cover the variety of organic food consumer purchase intentions and behaviors, including the relative environmental performance of organic food production and the link between the motivational values and attitudes concerning the consumption of non-chemical products. Apart from sustainable agriculture and upsides of organic farming, the main disadvantages are as follows: recycling and aligning with natural operations does not necessitate chemical inputs, but organic food is more prohibitive as farmers do not obtain significant crop productivity out of their land, while organic goods may have a price of up to 40% more (production expenses are steeper because farmers demand more labor force), marketing and distribution are not streamlined as organic products are delivered in diminished volumes, food disorders may occur more frequent, and chemical-free agriculture cannot produce sufficient nutrients that the world's population requires to live on. The purpose of this research is to examine the consistent shift of consumer predispositions and behavior toward food with diminished detrimental health and environmental effects , focusinThe present study provides evidence that safety, nutritional, and health features shape readiness to pay a high price for enviWhen shopping for a product, purchasers encounter various information that can only influence their preferences if they consider it . Food buAschemann-Witzel and Zielke insist tGarcia and Teixeira write thKonuk reveal tThere is a growing body of evidence showing that consumers' values shape their attitude and intention to eat additive-free food . DecidinTaufique and Vaithianathan hold thaRana and Paul suggest Petrescu et al. state thOrganic crop farmers in underprivileged regions generally do not have adequate access to certification and markets . OrganicHealth issues are the leading incentive of consumers buying organic products . AttitudHidalgo-Baz et al. indicateGineikiene et al. show thaPuska et al. state thAssessment of organic output developed on yield correlations of sets of equivalent crops cultivated non-chemically or using nitrogen fertilizer is unsuccessful in identifying the land that is to be designated to vegetables for biological nitrogen fixation by vegetables to provide nitrogen for the cultivation of non-vegetable crops. The resultant reduced portion of land operational for cereal crops diminishes the entire output of organic agriculture, being unsatisfactorily productive to nourish the present or predictable world population growth . OrganicThe above literature throws light on purchasing behavior for environmentally sustainable foods. Such empirical evidence supports the belief that organic product labeling can have a pivotal function in decision-making by exertBased on an extensive review of recent and relevant literature, our study indicates that organic food production and consumption offer health and sustainability upsides. Current gaps in the research include the consequences of prolonged chemical-free agriculture on soil-derived greenhouse gas emissions, the advancement of circular economic systems, management routines and crops that can adjust to the influence of climate change, bioenergy production associated with organic farming systems, plant breeding and genetics as a manner to substitute chemical inputs, and the use of big data and artificial intelligence in organic agriculture as a groundbreaking way out to cut down agrochemicals and procedures that deteriorate the agroecosystem. Future beneficial research should examine the economic effectiveness of sustainable organic farming hotspots, the nutritional value of organic food products and its subsequent impact on human health, the greenhouse gas emissions and energy efficiencies of organic production systems, the regeneration of biodiversity through environmentally harmonized food production, and decisional aspects motivating farmers to engage in organic agriculture.All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Older Veterans living in rural areas often do not have access to geriatrics team care; rural frontline providers and teams may need support to address the needs of older adults with complex chronic conditions. GRECC Connect aims to link up geriatric teams at Geriatric Research, Education and Clinical Centers (GRECCs) and rural clinics to provide geriatric consultation remotely through clinical video telehealth (CVT) and other means. GRECC Connect is established in twelve GRECCs across the country with links to rural clinics in their catchment area; consultations led to identification and meeting of care needs of older adults with complex conditions, improving medication use and reducing older adults\u2019 need for travel to long distances for consultation. In this presentation, we review the experience of establishing connections with rural clinics, impact on older adult care and adaptations needed to address local needs and contexts."} +{"text": "To the editor,We read with interest the recent paper by Urkmez et al examining the effects of urethroplasty on erectile and orgasmic function .The authors report a prospective study involving 60 males who underwent buccal graft substitution, penile skin flap or anastomotic urethroplasty by a single surgeon and report the outcomes on both erectile and orgasmic function using the international index of erectile function (IIEF) score.The authors conclude by stating that urethroplasty does not affect erectile, sexual or orgasmic function irrespective of surgery type, stricture location or length but acknowledge the limitations of the study including the lack of validated questionnaires.This study does highlight one of the challenges for urethral surgeons: measuring sexual outcomes following urethroplasty. As endoscopic management of recurrent stricture disease moves towards formal urethroplasty with better long term success rates, assessing outcomes remains paramount from a patient and surgical perspective. To date, there have been limited attempts at developing specific patient reported outcomes (PROMS) for anterior urethral reconstruction . The firHistorically, a successful outcome following urethroplasty was based on the need for secondary intervention to improve outflow symptoms but outcomes should be all inclusive and evaluate psychological, voiding and sexual outcomes as well as quality of life with a specific, validated questionnaire.Breyer et al have published preliminary data on the development of a patient specific outcome measure, the 32 item Urethral Stricture Symptoms and Impact Measure (USSIM), which will further address both voiding and sexual symptoms following urethroplasty , 11.Undoubtedly, as the assessment of urethYours Sincerely,Authors"} +{"text": "The mesolimbic hypothesis has been a central dogma of schizophrenia for decades, positing that aberrant functioning of midbrain dopamine projections to limbic regions causes psychotic symptoms. Recently, however, advances in neuroimaging techniques have led to the unanticipated finding that dopaminergic dysfunction in schizophrenia is greatest within nigrostriatal pathways, implicating the dorsal striatum in the pathophysiology and calling into question the mesolimbic theory. At the same time our knowledge of striatal anatomy and function has progressed, suggesting new mechanisms via which striatal dysfunction may contribute to the symptoms of schizophrenia. This Review draws together these developments, to explore what they mean for our understanding of the pathophysiology, clinical manifestations, and treatment of the disorder. Techniques for characterising the mesostriatal dopamine system, both in humans and animal models, have advanced significantly over the past decade.In vivo imaging studies in schizophrenia patients demonstrate that dopaminergic dysfunction in schizophrenia is greatest in nigrostriatal as opposed to mesolimbic pathways.Better understanding of striatal structure and function has enhanced our insight into the neurobiological basis of psychotic symptoms.The role of other neurotransmitters in modulating striatal dopamine function merits further exploration, and modulating these neurotransmitter systems has potential to offer new therapeutic strategies. Schizophrenia is a syndrome consisting of positive symptoms , negative ones (including flattened affect and lack of motivation), and cognitive ones. Dysregulated dopaminergic modulation of striatal function is fundamental to many models that seek to explain the mechanisms underlying the symptoms of schizophrenia In this paper, we review how advances in neuroscientific methods have improved our understanding of striatal structure and function. We then examine the evidence regarding striatal dysfunction in schizophrenia, and discuss how recent findings suggest a re-evaluation of prior hypotheses may be required. Finally, we ask what these developments mean for our understanding of the clinical manifestations and treatment of the disorder.The striatum is an integral part of the corticobasal ganglia circuitry. Extensive work mapping its pathways, as summarised below, suggests that it acts as an integrative hub for information processing in the brain.limbic Recent methodological advances have further refined our understanding of corticostriatal architecture In addition to its widespread cortical connectivity, the striatum has extensive bidirectional connections to the midbrain A. The deResting state functional magnetic resonance imaging (fMRI)diffusion tensor imagingMany of these more recent findings on striatal connectivity have been demonstrated only in rodents to date, and interspecies differences must be borne in mind when seeking to draw parallels with primate and human anatomy B [14]. HIn summary, it appears that, in addition to well-established parallel pathways, there also exists, across species, a high degree of pathway crossing and information funnelling, with regions in the associative striatum acting as integrative hubs. Furthermore, there appear to be a variety of pathways allowing for bidirectional information transfer across the striatum.Recent advances have refined understanding of striatal neurochemistry. In this section, we consider these findings and their implications for mechanisms by which abnormalities of nondopaminergic neurotransmitter systems may contribute to dopaminergic dysfunction. We also discuss their relevance for developing new treatment approaches to normalise striatal dopamine function and possibly treat schizophrenia without requiring dopamine D2/3 receptor blockade.Most dopamine neurons have the potential to release GABA as a cotransmitter, and a smaller proportion corelease glutamate. This cotransmission varies across the striatum, and can moderate the reciprocal relationship between dopaminergic and cholinergic neurons Corticostriatal neurons synapse upon cholinergic interneurons, which in turn modulate dopamine neurons via nicotinic receptors situated on these dopamine neurons, thereby mediating the corticostriatal control of striatal dopamine release et al. demonstrated that the extrapyramidal side effects of antipsychotic medications may primarily result from the blockade of D2 receptors on cholinergic interneurons indirect pathway MSNs, both due to the direct effect on these neurons, and as a result of increased acetylcholine-mediated activation of M1 receptors on the MSNs, occurring as a result of D2 blockade on cholinergic interneurons \u2013fMRI studies also provide evidence that striatal dopamine has a broader role than simply encoding reward prediction errors, and is associated with the function of cortical salience networks The activity of mesostriatal dopamine neurons has been shown to signify the discrepancy between expected and actual rewards, which has been termed the reward prediction error amphetamine sensitisation encourages habit formation, and it is the dorsal striatum that is implicated in the habitual responses to drug cues experienced by addicts Striatal function along a ventral\u2013dorsal axis is also relevant to habit formation. During the learning of action\u2013outcome pairings, performance is goal directed and sensitive to changes in outcome values. After extensive training, however, performance moves to a stimulus\u2013response mode that is inflexible, and no longer responds to changes in outcome. This evolution of behaviour from contingency-dependent learning to habitual responding has been associated with a shift from ventral to dorsal striatal processing positive psychotic symptoms Early postmortem studies investigating striatal dopaminergic abnormalities produced inconsistent results. Initial studies measured concentrations of dopamine, and while some reported an association between schizophrenia and increased concentrations specifically in the More recently, no differences between patients and controls in terms of either density of dopaminergic terminals in vivo. Radiolabelling of the dopamine precursor l-dihydroxyphenylalanine enables the measurement of its uptake and conversion in dopamine neurons to give an index of dopamine synthesis capacity. Alternatively, imaging the competition between endogenous dopamine and radioligands specific to postsynaptic dopamine receptors can determine baseline levels of dopamine (following depletion of endogenous dopamine using compounds such as \u03b1-methylparatyrosine), as well as the magnitude of dopamine release .PET allows quantification of the dopamine system Meta-analysis of studies using these PET and single photon emission computed tomography (SPECT) techniques shows that there is a robust increase in striatal dopamine synthesis and release in psychosis Early PET and SPECT studies of presynaptic dopamine function could distinguish anatomical subdivisions of the striatum but lacked sufficient resolution to accurately distinguish between functional subdivisions. Accordingly, these studies reported outcomes for the whole striatum or anatomical subdivisions. However, the subsequent development of higher resolution PET scanners has enabled the assessment of striatal functional subdivisions as well. The first studies to report on these subdivisions in patients with schizophrenia found that the greatest differences in dopamine function were within the associative striatum, with differences in the limbic subdivision not reaching statistical significance clinical high risk (CHR) of psychosis also found the greatest abnormality to be in the associative striatum Studies investigating presynaptic dopamine function in individuals at In a multimodal study, frontal activation during a working memory task was shown to correlate inversely with associative striatum dopamine synthesis capacity in a CHR group in vivo neuroimaging studies have provided evidence that dopaminergic dysfunction in schizophrenia is greatest within dorsal, as opposed to ventral regions of the striatum.In summary, in contrast to the mesolimbic theory, An ongoing question is how the neurobiological abnormalities identified in patients translate to the diverse psychopathology with which they present. We now suggest several mechanisms whereby striatal dysfunction could contribute to the clinical manifestations of the disorder. It is important to note, however, that many of these proposals are speculative at this stage, and furthermore, that schizophrenia is a heterogeneous disorder and no single brain region or neurotransmitter is likely to be able to account for all symptoms in all patients.Theoretical models linking biological substrates to phenomenological experience in psychosis have frequently built upon the finding that mesostriatal dopamine signalling is involved in marking the salience of environmental stimuli Existing models have proposed that delusions then develop secondary to cognitive processes attempting to construct a coherent explanation for these unusual experiences. Historically, however, discussions regarding the phenomenology of delusions have emphasised form of thought over content. Delusional form is characterised by a certainty of conviction, that is accompanied by an inability to shift perspective, and an imperviousness to counterargument Another finding of relevance to theories of aberrant salience attribution in schizophrenia is the following one. A stimulus, even if initially lacking inherent salience, once paired with dopaminergic activity, maintains the ability to evoke dopaminergic activity over time The striatum, and specifically areas of the associative striatum, can be viewed as an integrative hub. Regions of the caudate receive inputs from nearly the entire cortex inappropriate affect. However, this has yet to be definitively tested.Given that the striatum performs an integrative role, functional disruption secondary to aberrant dopamine signalling may lead to the associative impairments observed in schizophrenia. Based on preclinical models, it has been proposed that the underlying pathophysiology in schizophrenia represents a combination of increased aberrant spontaneous phasic dopamine release, and a reduction in adaptive phasic release in response to relevant stimuli Regionally targeted dopamine signalling enables the precise selection of specific behaviours over others, and collaterals between direct and indirect pathway MSNs efference copy is an internally generated replica of an outgoing motor signal, that has the effect of dampening sensory perceptions occurring as a result of the motor act, encouraging it to be perceived as self-authored and avoiding attribution to an external agent. The possibility, therefore, that disruption of efference copy mechanisms could contribute to passivity phenomena has long been suggested An Efference copies accompanying internally generated motor cortex activity travel via pyramidal tract neurons to the dorsal striatum thought echo. Inner speech is in certain respects a motor act, in that it is thought to result from motor plans for speech that are subsequently aborted In addition to motor passivity phenomena, a similar mechanism may contribute to auditory hallucinations related to inner speech, such as Efference-copy mechanisms, however, are less likely to account for auditory hallucinations that are phenomenologically unrelated to inner speech, and a predictive coding framework, which is a more generalisable model, seems more relevant in this context. Predictive coding refers to the idea that the brain compares prior expectations with new sensory evidence, and uses the discrepancy between the two (the prediction error) to update its model of the world. The certainty regarding one\u2019s prior expectation is described as the precision of that prediction. Both the extent of the difference between prior and sensory data, and the precision of these determine the magnitude of the prediction error It addition to the role that striatal dopamine signalling plays in the development of positive symptoms, several mechanisms have been suggested for its contribution to the cognitive and negative symptoms of the disorder as well.in vivo imaging evidence for a deficit in cortical dopamine transmission has emerged Cognitive impairments in schizophrenia have been suggested to result from cortical hypodomaminergia; an idea supported by the importance of cortical dopamine signalling for prefrontal related cognition in vivo studies showing that reduced connectivity of the associative striatum and substantia nigra is related to the severity of cognitive deficits in schizophrenia Striatal hyperdopaminergia could conceivably result in cognitive impairments either by disrupting signalling between the frontal cortex and associative striatum, or by potentially driving cortical dopamine dysregulation There is also evidence that striatal dysfunction may contribute directly to negative symptoms. Studies using probabilistic learning tasks have shown that negative symptoms in individuals with schizophrenia may be related to impaired reward-based learning In this section we consider the implications of the evidence discussed earlier for the development of new treatments for schizophrenia that are not D2 receptor blockers and that might address the striatal dopamine dysfunction seen in the disorder.As previously discussed, studies have shown that the magnitude of dopaminergic abnormalities in schizophrenia varies across the striatum, with the most marked dysfunction seen in the associative striatum. These findings suggest that anatomically selective modulation of dopamine function is preferable The existing mechanistic understanding of striatal circuitry points at some possible therapeutic approaches that could allow more anatomically precise modulation of striatal dopamine function. One such mechanism, as discussed earlier, is muscarinic modulation of striatal dopamine release. Preclinical studies have shown that M4 positive allosteric modulators (PAMs) act on striatal MSNs to specifically inhibit dorsal striatum dopamine release via endocannabinoid signalling in vivo imaging evidence consistently suggests that the major abnormality in dopamine function in schizophrenia is located within the dorsal rather than the limbic striatum. Increasing knowledge regarding the structure, function, and neurochemistry of the striatum has improved our understanding of how these dopaminergic abnormalities may lead to symptoms. While these developments highlight potential pathways for the development of new treatments, the translation of these advances to meaningful clinical interventions, remains a significant challenge (See Outstanding Questions).Outstanding QuestionsIs anatomically precise modulation of dopamine signalling within the striatum possible? The variation across the striatum both in terms of dopamine receptor distributions, and of the mechanisms that control striatal dopamine and striatal function, suggests that it may be, but this remains to be tested.Do endocannabinoids, GABAgeric, cholinergic, and glutamatergic interventions have therapeutic potential given their role in modulating striatal function?Do primary striatal abnormalities exist in schizophrenia, or is dysfunction entirely secondary to upstream pathology? Genes associated with schizophrenia, overlap significantly with genes expressed by MSNs but not with those expressed by dopamine neurons. Abnormalities such as patch-matrix differentiation, or ones associated with cholinergic interneurons might also contribute to striatal dysfunction in schizophrenia. Recently, greater densities of afferent excitatory synapses have been found in the NAcc of individuals with schizophrenia, this could, via the feedforward mechanisms discussed A, drive Are specific symptoms associated with dopamine dysregulation in specific striatal loci? For instance, are verbal hallucinations associated with dopaminergic abnormalities in striatal regions displaying connectivity to the secondary auditory cortex? Are motor symptoms associated with the motor striatum?What is the optimal striatal parcellation? Preclinical findings suggest current atlases may oversimplify the picture, and point at the importance of improving our understanding of striatal connectivity. Could we improve our ability to characterise striatal dopamine dysfunction by using individual participant functional or anatomical connectivity to parcellate the striatum in multimodal studies of schizophrenia?Recent RM declares no financial conflicts of interest. AA-D has received research support from Pierre Fabre, Otsuka, Forest, Pfizer, and Neurocrine; served on advisory boards of Roche, Otsuka, Lundbeck; and given lectures sponsored by Otsuka. She is an advisor and holds shares in System 1 Biosciences and in Storm Biosciences. ODH has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Astra\u2013Zeneca, Autifony, BMS, Eli Lilly, Heptares, Jansenn, Lundbeck, Lyden-Delta, Otsuka, Servier, Sunovion, Rand and Roche. Neither Dr Howes nor his family have been employed by or have holdings/a financial stake in any biomedical company."} +{"text": "In this review, we evaluate evidence for the hypothesis that developmental changes in emotion regulation tendencies during adolescence depend on the maturation of affective control. Affective control refers to the application of cognitive control to affective contexts, that is, the capacity to attend and respond to goal-relevant affective information, while inhibiting attention and responses toward distracting affective information. The evidence suggests that affective control develops throughout adolescence into adulthood. However, the developmental trajectory appears not to be uniform across different facets of affective control. In particular, the capacity to inhibit attention and responses to distracting affective information may be reduced during adolescence relative to childhood and adulthood. Focusing on the association between affective control and emotion regulation development in adolescence, the research reviewed supports the notion of affective control as a cognitive building block of successful emotion regulation. Good affective control appears related to fewer ruminative tendencies in adolescence as well as more frequent and successful reappraisal in older adolescents. Lower use of habitual suppression, itself a type of affective inhibition, shows an association with updating capacity. We conclude by discussing the implications of these findings for mental health and the potential mental health benefits associated with improving affective control. Adolescents experience greater affective fluctuations, higher levels of negative mood, and are more sensitive to the experience of positive, rewarding experiences than are adults and children . A subseThe first part of this review defines emotion regulation before focusing on studies exploring developmental changes in affective control in adolescence , who experienced higher levels of interference from negative material on a working memory updating task, demonstrated less efficient increases in positive affect following reappraisal in everyday life information presented in control tasks. For example, high ruminators not only have lower levels of affective control capacity, but the tendency to ruminate may further increase the affective significance of negative material and consequently augment its interference potential.The literature reviewed supports our proposal of affective control as a cognitive building block of successful emotion regulation. This conclusion highlights the need for longitudinal research exploring the codevelopment of affective control and emotion regulation across adolescence. The findings from studies using different affective control paradigms, which assess affective inhibition, updating and shifting, suggest that affective control is not a unitary construct, and that each component may show a different developmental trajectory.This review has focused on the typical development of affective control and emotion regulation. A major motivation to understand the typical development of the cognitive and neural architecture underlying emotion regulation is to study individual differences, as this might shed light on the development of poor emotion regulation tendencies, which constitute a core causal pathway to mental health problems in adolescence . AffectiTraining studies have shown in adolescents and young adults that affective control can be improved and that the gains in affective control are associated with improved emotion regulation and reduced mental health symptoms e.g., . The proThe current review predominantly focused on the association between affective control and emotion regulation tendencies. That is, habitual use of specific emotion regulation strategies. However, emotion regulation capacity, that is the ability to successfully implement situationally adaptive emotion regulation strategies, has also been shown to improve with age and shouonline supplemental materials for recommended additional readings on this topic.Please refer to the 10.1037/emo0000695.supp"} +{"text": "There are published variants of the floating elbow injury which include ipsilateral diaphyseal humeral fracture, proximal ulna fracture with proximal radioulnar joint disruption, and ipsilateral diaphyseal humeral fracture with elbow dislocation and both bones forearm fracture. We present the case of a 21-year-old woman whose left arm became caught between the side of a waterslide and adjacent rocks at a park. She sustained a torsional and axial loading injury to her left upper extremity resulting in ipsilateral humeral shaft and Galeazzi fractures. The combination of ipsilateral humeral shaft and Galeazzi fractures resulted in a rare floating elbow variant. Prompt open reduction and internal fixation of both fractures and early range of motion of the elbow and wrist resulted in an excellent clinical and radiographic result. Floating elbow injuries and their variants should be promptly recognized as early anatomic reduction, and rigid internal fixation can allow for good elbow function with minimization of stiffness. The combination of humeral shaft and forearm fractures results in a \u201cfloating elbow\u201d injury which requires open reduction and internal fixation of all fractures to allow for preservation of elbow joint motion and minimization of stiffness \u20133. VariaA 21-year-old previously healthy woman, a college student, was on a waterslide at an amusement park, when her left arm became caught between the side of the waterslide and adjacent rocks. She sustained a forceful twisting and loading injury to her left upper extremity which resulted in a severe pain and deformity to her left arm, forearm, and wrist. She was brought by ambulance to our emergency department. On physical exam, her injuries were closed, her arm and forearm compartments were soft, and she was neurovascularly intact. Radiographs of the humerus, forearm, and wrist demonstrated a left distal third humeral shaft fracture as well Within 24 hours of admission, the patient underwent open reduction and internal fixation of both her humeral shaft and radial shaft fractures. The decision was made to reduce and fix the humeral shaft first. The humeral shaft fracture was amenable to reduction and fixation with an extraarticular locking plate through a posterior approach with the patient in the lateral decubitus position. Because of the manipulation of the forearm, which may be required during reduction and plating of the humerus, we chose to avoid fixation of the radius and the possible transfixion of the distal radioulnar joint until after the operation on the humeral shaft was completed.The surgery was performed under general anesthesia. The patient was positioned on a radiolucent table in the lateral decubitus position with the left arm which was supported over a foam roller. The left upper extremity was then prepped and draped, and 2 grams of cefazolin was administered prior to incision. The Gerwin-Hotchkiss approach was used to access the posterior half of the distal humerus and radial nerve . A longiThe patient's postoperative course was unremarkable. The splint was removed at one week, and gentle elbow and wrist active and passive range of motion exercises were begun. At 12 weeks follow-up, radiographs demonstrated healing of the humeral and radial shaft fractures. At this time, elbow, forearm, and wrist strengthening exercises were performed for 6 weeks. At final follow-up 1 year postoperatively, radiographs demonstrated healed humeral and radial shaft fractures in anatomic position with stable reduction of the distal radioulnar joint Figures . The patFloating elbow injuries traditionally refer to ipsilateral diaphyseal humeral fracture and diaphyseal ulna and radius fractures , 3. ThesThere are few series which evaluate the outcomes of operative treatment of floating elbow injuries. All of the patients in earlier case series had traditional floating elbow injuries with diaphyseal fractures of the humerus ulna and radius , 3. YokoMore recent case series have included floating elbow variants including ipsilateral diaphyseal humeral fracture with proximal ulna fracture, and proximal radioulnar joint disruption (Monteggia fracture); ipsilateral diaphyseal humeral fracture, elbow dislocation, and diaphyseal ulna and radius fracture; and distal humerus fractures with intraarticular fractures of the olecranon or radial head , 7. JockDitsios and colleagues retrospectively reviewed 19 patients with floating elbow injuries and reported variants in their series including humerus shaft or distal humerus fractures and an intra-articular fracture of the olecranon and/or the radial head. They included three patients with humeral shaft and Galeazzi fractures and classified them as traditional fracture patterns. Two of these cases were distal third humeral shaft fractures (Holstein-Lewis pattern) with radial nerve palsy. At a mean follow-up of 26 months, the final arc of motion in the entire cohort was 88.9\u00b0 , and 11 patients 58%) had good-excellent results. Because the three cases of humeral shaft with Galeazzi fracture were not separately analyzed, it is unclear if the results of this subgroup are different from those of the traditional floating elbow pattern [8% had goWe report here a very rare floating elbow variant with fracture of the humeral shaft, fracture of the radial shaft, and distal radioulnar joint disruption . Ipsilateral humeral shaft and Galeazzi fracture is a floating elbow pattern that should be recognized as an atypical pattern distinct from the traditional pattern in which the wrist joint is intact. Disruption of the distal radioulnar joint and the potential effect of this injury on wrist function adds an additional variable not present with the traditional fracture type that must be addressed in order to obtain good functional outcomes."} +{"text": "When parents decide how much to invest in current versus future offspring and how many offspring to divide their current investments between, the optimal decision can be affected by the quality of their partner. This differential allocation (DA) is highly dependent on exactly how partner quality affects reproductive costs and offspring benefits. We present a stochastic dynamic model of DA in which females care for a series of clutches when mated with males of different quality. In each reproductive event, females choose the size and number of offspring. We find that if partner quality affects reproductive costs, then DA in total reproductive investment occurs only via changes in the number of offspring. DA in the optimal size of the offspring occurs only if partner quality affects the offspring benefit function. This is mostly in the form of greater female investment per offspring as male quality decreases. Simultaneously, we find that adaptive DA increases the number of offspring, and thus the amount of total investment, as male quality increases. Only certain model scenarios produce the positive DA in offspring size seen in empirical studies, providing a predictive framework for DA and how partner quality affects reproductive costs and offspring benefits. How a pIn conclusion, we challenge empiricists to test our model by assessing partner effects on both total reproductive effort and on offspring size versus number in the same systems. Crucial information is also required concerning likely partner effects on offspring fitness functions versus parental cost functions to allow comparisons against the appropriate DA models predictions . Lastly,"} +{"text": "Saving for retirement should begin with the first job, but preparation with respect to determining a specific retirement age and plans for post-retirement life, generally occurs closer to the retirement date. However, among those who provide care for family or close friends who are elderly and/or have disabilities, retirement preparation may take a back seat to more pressing current concerns. While we know quite a lot about patterns of saving for retirement and the factors that influence those patterns, we know little about retirement expectations and patterns of thinking about and planning for the broader retirement experience, particularly among caregivers. This paper uses data from the 2008-2016 rounds of the nationally-representative 1979 National Longitudinal Survey of Youth to examine retirement expectations and five areas of retirement preparation among employed adults (ages 51-59 in 2016) who are or are not providing care for someone in or out of their household. Longitudinal analysis finds significantly lower retirement preparation among adults caring for someone inside versus outside the household, as well as significantly lower preparation activities among female versus male caregivers. Caregiving influences employment and, in turn, the types of retirement accounts held by men and women. Although caregiving is associated with decreased retirement savings among both men and women who have pension accounts, retirement preparation activities in 2008 and 2012 are associated with higher retirement savings in 2016."} +{"text": "This contribution studies the roles of grandparents in caring for grandchildren in skipped generation households, from gender perspective. Historical studies often focus on health and economic status of older adults generally, without distinguishing older adult women whose responsibilities are often undervalued. Such assessments assume that both grandparents engage in caring for grandchildren, being the joy of old age. Highlighting women\u2019s roles will ensure proper design and implementation of policies to enhance improvement in overall well-being of skipped generation households in Nigeria. The economic value of this is high. Using detailed data from three major states in Nigeria, - Imo, Lagos and Kano (representing each of the major ethnic groups) this study provides a detailed picture of the areas of women\u2019s responsibilities in skipped generation households, using both quantitative and qualitative methodologies. The quantitative study employed structured questionnaire to collect primary data while the qualitative technique employed the use of in-depth interviews and focus group discussions. The older adult participants are grouped into three; less than sixty five years, between sixty five and eighty and those above eighty years of age. The study reveals that social norms and expectations impact the lives of older adults, ensuring that responsibilities sharing in skipped generation households are strongly impacted by gender roles. The paper concludes that in order to ameliorate the difficulties and challenges faced in performing these roles, governments and other organizations need to put the realities in the skipped generation households into consideration during planning processes."} +{"text": "Prior research suggests that neighborhoods with predominantly minority and low-income individuals have decreased access to high quality hospitals, primary care physicians, and nursing homes. The purpose of this study is to determine if low quality Home Health Agencies (HHAs) are concentrated within more disadvantaged neighborhoods, while high quality HHAs cluster in more affluent neighborhoods. We characterize neighborhoods by racial and ethnic composition, and the proportion of residents below the federal poverty line; and HHAs according to their star ratings. We conduct a national, observational descriptive study using data from the 2017 HH Compare and American Community Survey. Predominantly black neighborhoods are served by the highest proportion of unrated and low-rated HHAs, while predominantly white neighborhoods have the highest proportion of high quality HHAs. This study signals and potential explanation for why minorities and duals receive care from lower quality HHAs. Such knowledge may help inform reimbursement and incentive practices."} +{"text": "Social support provides important benefits following widowhood. One context promoting social support throughout life may be the military, where benefits extend to both service members and their spouses. A substantial proportion of older men served in the military, so many widowed women today were married to veterans. We tested two hypotheses: 1) surviving military spouses will experience lower persistent loneliness following widowhood compared to their nonmilitary counterparts, and 2) this benefit is explained by increased emotional and structural social support. Our study uses the Health and Retirement Study (HRS) to examine changes in loneliness following widowhood among spouses of veterans and nonveterans. We used OLS regression and mediation tests to address our hypotheses. Overall, results supported our hypotheses. Widows of veterans reported lower levels of loneliness following widowhood compared to nonveteran widows . Emotional and structural social support mediated the relationship between veteran status of the deceased spouse and loneliness. Specifically, the beneficial effect of veteran status was reduced by almost 50% and became nonsignificant. Our findings suggest the military may facilitate lifelong cultivation of social support that flows not only to veterans but also to their families. These findings are suggest that the military may offer important opportunities to cultivate emotional and structural social supports that enhance the ability of veteran wives to more readily adjust to widowhood. Additionally, they emphasize the importance of having social support in later life when faced with adversity, as it seems to ameliorate some of the negative effects."} +{"text": "Ageism refers to stereotypes about and prejudice against individuals on the basis of age. Ageism among young adults may be different than other forms of intolerance simply because age changes; that is, young adults will grow older, and they will eventually become a member of what is presently an outgroup . The purpose of this study was to investigate whether ageism among young adults (N = 623) is more closely associated with future-oriented variables or whether ageism more closely resembles an outgroup attitude, which like other outgroup attitudes is mitigated by knowledge about and quality of contact with those outgroup members. Bivariate correlations found that knowledge of aging, quality of contact with older adults, and optimism were associated with lower ageism. In a multiple regression analysis, only knowledge about aging and quality of contact with older adults were associated with lower ageism. Overall, the results suggest that ageism represents more of an outgroup attitude rather than a future-oriented attitude. These results support the contact hypothesis in that knowledge of aging and quality of contact with older adults were associated with lower ageism among young adults. Education about aging and quality contact with older adults may be effective ways to reduce ageism among young adults."} +{"text": "Robot pets of varying degrees of sophistication are advertised as ideal companions for older adults, with claims that they support their emotional and cognitive needs. A new generation of robot pets is emerging equipped with internet connections, recognition software, surveillance capacity, and AI platforms to mimic desired aspects of animal-human relationships. This paper draws upon promotional materials gathered at the Consumer Electronics Show 2019 and interviews with robot designers, to probe what the robotization of human-animal relationships tells us about shifting notions of companionship through the life course. The argument is that robot pets are inscribed within discourses that instrumentalize human-animal-technology entanglements and position digital technologies as idealized solutions to perceived age-related problems. Theoretical ideas from animals studies add a creative dimension to aging studies to explore what the societal enthusiasm for robot pets reveals about our understanding of the lived material and relational worlds of older adults."} +{"text": "Atmospheric nitrogen deposition has been shown to affect both the structure and the function of heathland ecosystems. Heathlands are semi-natural habitats and, as such, undergo regular management by mowing or burning. Different forms of management remove more or less nutrients from the system, so habitat management has the potential to mitigate some of the effects of atmospheric deposition. Data from a dynamic vegetation model and two field experiments are presented. The first involves nitrogen addition following different forms of habitat management. The second tests the use of habitat management to promote heathland recovery after a reduction in nitrogen deposition. Both modelling and experimental approaches suggest that plant and microbial response to nitrogen is affected by management. Shoot growth and rates of decomposition were lowest in plots managed using more intensive techniques, including mowing with litter removal and a high temperature burn. Field data also indicate that ecosystem recovery from prolonged elevated inputs of nitrogen may take many years, or even decades, even after the removal of plant and litter nitrogen stores which accompanies the more intensive forms of habitat management."} +{"text": "Hematopoietic stem cells (HSCs) are the best studied of the tissue-specific stem cells. By definition, HSCs have long been regarded as restricted to formation of blood cells of both the lymphoid and myeloid lineages. HSCs residing in the bone marrow microenvironment have self-renewal capacity and can repopulate the hematopoietic system of irradiated transplant recipients for the lifetime of the individual. Therefore, HSCs are extremely important targets for gene therapy applications aimed toward the treatment of inherited and acquired blood disorders. However, recent studies have suggested that a subpopulation of HSCs may have the ability to contribute to diverse cell types such as hepatocytes, myocytes, and neuronal cells, especially following induced tissue damage. Preclinical amelioration of liver disease and myocardial infarcts by HSC-enriched bone marrow cell populations raises the possibility that HSC transplants have the potential to provide therapeutic benefit for a wide variety of diseases. These surprising findings contradict the dogma that adult stem cells are developmentally restricted. Extrapolation of these findings to the clinic will be facilitated by prospective identification of the stem cells that possess this developmental plasticity. Furthermore, characterization of the signaling pathways and molecular determinants regulating the remarkable transdifferentiation capacity of these stem cells may provide insight into novel approaches for modulating frequency of differentiative potential."} +{"text": "This symposium will provide an update on older adult nutrition policy, including background on the issues of older adult malnutrition and food insecurity. The federal policy update will include discussion of the Older Americans Act nutrition programs and their reauthorization progress, older adult programs under the US Department of Agriculture, and advances in nutrition services being made in healthcare programs such as Medicare Advantage and managed long-term care services and supports. It will also discuss funding for federal older adult nutrition programs and their sustainability moving forward."} +{"text": "Subjective age has been extensively researched as a predictor of physical and mental health outcomes in older adulthood. However, the mechanisms behind subjective age have not yet been established and reasons for longitudinal changes are unclear. Selective engagement theory proposes a connection between increases in objective and subjective cognitive costs and motivation to engage future resources. Costs are influenced by personal resources, mainly physical and mental health. These changes in costs may also influence subjective experiences of the aging process. For example, aging attitudes have been shown to partially mediate the associations between resources and both motivation and activity engagement . Using the Health and Retirement Study (HRS) data, changes in resources were hypothesized to predict changes in subjective age across 8 years. More specifically, reductions in resources were predicted to be associated with older subjective ages over time. This relationship was expected to be mediated through aging attitudes. Results indicate an association between changes in resources and changes in subjective age over time in the expected direction. Changes in resources were partially mediated by aging attitudes. However, resources function differently in predicting changes in subjective age based on the resource and chronological age of the participant. These findings provide more guidance as to the mechanisms behind subjective age and may offer theoretical guidance for future work looking at understanding changes in subjective age."} +{"text": "The long time from exposure to potentially harmful chemicals until breast cancer occurrence poses challenges for designing etiologic studies and for implementing successful prevention programs. Growing evidence from animal and human studies indicates that distinct time periods of heightened susceptibility to endocrine disruptors exist throughout the life course. The influence of environmental chemicals on breast cancer risk may be greater during several windows of susceptibility (WOS) in a woman\u2019s life, including prenatal development, puberty, pregnancy, and the menopausal transition. These time windows are considered as specific periods of susceptibility for breast cancer because significant structural and functional changes occur in the mammary gland, as well as alterations in the mammary micro-environment and hormone signaling that may influence risk. Breast cancer research focused on these breast cancer WOS will accelerate understanding of disease etiology and prevention.Despite the plausible heightened mechanistic influences of environmental chemicals on breast cancer risk during time periods of change in the mammary gland\u2019s structure and function, most human studies of environmental chemicals are not focused on specific WOS. This article reviews studies conducted over the past few decades that have specifically addressed the effect of environmental chemicals and metals on breast cancer risk during at least one of these WOS. In addition to summarizing the broader evidence-base specific to WOS, we include discussion of the NIH-funded Breast Cancer and the Environment Research Program (BCERP) which included population-based and basic science research focused on specific WOS to evaluate associations between breast cancer risk and particular classes of endocrine-disrupting chemicals\u2014including polycyclic aromatic hydrocarbons, perfluorinated compounds, polybrominated diphenyl ethers, and phenols\u2014and metals. We outline ways in which ongoing transdisciplinary BCERP projects incorporate animal research and human epidemiologic studies in close partnership with community organizations and communication scientists to identify research priorities and effectively translate evidence-based findings to the public and policy makers.An integrative model of breast cancer research is needed to determine the impact and mechanisms of action of endocrine disruptors at different WOS. By focusing on environmental chemical exposure during specific WOS, scientists and their community partners may identify when prevention efforts are likely to be most effective. Despite the considerable personal and societal burden from breast cancer, primary prevention efforts encounter challenges. Unlike other cancers that are linked to a predominant risk factor . FoBreast cancer etiology appears to be driven in part by perturbations to breast tissue as well as alterations of the mammary gland micro-environment during critical windows. Here we briefly summarize breast tissue changes occurring during each WOS, review evidence that addresses environmental carcinogenesis during each WOS, and outline the motivation for ongoing research on the chemicals and metals targeted in BCERP.The prenatal period is a particularly vulnerable WOS because breast tissue begins to develop in the embryonic stage when epidermal cells in concert with embryonic mesenchyme become breast buds \u201318. FastPregnancy and birth cohorts reveal possible associations between environmental chemicals during the prenatal period and breast cancer. The Child Health and Development Studies (CHDS) found high levels of maternal exposure to dichlorodiphenyltrichloroethane (DDT) during pregnancy increased the daughters\u2019 later breast cancer risk to age 52 nearly fourfold compared to daughters of women with low levels of exposure Table\u00a0 25]. Al. Al25]. Another class of chemical exposures of concern during the prenatal WOS is polycyclic aromatic hydrocarbons (PAH). PAH are produced as a result of combustion of hydrocarbons. Some of the common sources of PAH exposure include consuming grilled meats and certain other food items , inhalinLike DDT and other organochlorines, PAH are lipophilic and stored in fat tissue including breast tissue . Most PAdelayed median puberty endpoints by 5\u201311\u2009months when comparing extreme categories of exposure and per- and polyfluoralkyl substances (PFAS) on breast development and breast density. PFAS are used in many commercial products because of their non-stick, stain-resistant, and waterproof characteristics. Sources of human exposure include production facilities, firefighting training, consumer products, diet, and drinking water. Dietary sources include seafood and foodPregnancy is another period of rapid breast tissue and micro-environmental changes during which susceptibility to environmental exposures may increase the risk of breast cancer . During In mice, there is a greater than 100-fold increase in the number of mammary epithelial cells during pregnancy demonstrating the rapid changes that occur in mammary tissue. Despite the rapid proliferation, a full-term pregnancy renders the mammary epithelium resistant to tumorigenesis subsequent to the pregnancy. This is observed in studies of exposure to carcinogens , 97\u201399 aEpidemiologic evidence directly linking environmental exposures during pregnancy and breast cancer risk arises from the previously mentioned prospective CHDS which measured PCB and DDT soon after pregnancy and confirmed breast cancer diagnoses with medical records. Relative risk estimates for breast cancer comparing upper to lower quartiles of 16 individual PCB congeners ranged from 0.2 to 6.3; a composite score of exposure was associated with an odds ratio of 2.8 (95% CI 1.1\u20137.1) showed that the increased incidence of breast cancer with use of exogenous estrogen and progesterone \u2013127 was PBDE are a class of over 200 organohalogenated compounds widely used as flame retardants and may modulate steroidogenesis including expression of aromatase \u2013136. BPAMetalloestrogens are metals that activate the ER, leading to estrogen-like changes. Metalloestrogens are prevalent environmental contaminants with multiple routes of human exposure. They often accumulate in tissues and organs . MBCERP members are examining whether exposure to PBDEs, BPA, or selected metals during the menopausal transition is associated with breast cancer risk in humans, and evaluating potential mechanisms to explain these associations in rodent models.The long time between exposures during the early WOS and breast cancer occurrence has multiple implications for breast cancer research. First, because many environmental exposures are stored long-term in adipose tissue, even compounds now banned, such as DDT and PBDE, may continue to be relevant for breast cancer risk. Bioaccumulation of lipophilic chemicals and their long-term storage also means studies incorporating biomarkers in breast tissue need to consider both the effects on adipose tissue as well as epithelial and stromal tissues.Second, because it may be decades after the relevant windows of exposure before breast cancer is diagnosed, the examination and validation of intermediate biomarkers of response, apparent closer to the timing of exposure and before diagnosis, are imperative, particularly in prospective human studies. BCERP first started as a cohort study of the environmental exposures that may accelerate puberty. The main outcome of the cohort study was based on Tanner Stages . As BCEROne intermediate outcome is mammographic breast density (MBD), defined as the fraction of connective and glandular tissue to adipose tissue on a mammogram \u2013181. MBDLittle is known of the drivers of breast tissue changes across adolescence, early adulthood, and the menopausal transition and thus the contributors to breast density. Most of what is known about normal breast tissue characteristics is from mammography data in women over 40\u2009years of age. In women under 40\u2009years, two alternative imaging methods have been used to assess breast composition including three studies of magnetic resonance imaging (MRI) in women aged 15\u201330\u2009years \u2013190 and Given the changes in mammary tissue architecture and hormone signaling during the prenatal, pubertal, pregnancy, and menopausal transition windows, these critical time periods may reflect windows of heightened risk. Thus, measuring the impact of environmental chemical and metal exposures during these WOS is essential to understand their roles in breast cancer risk; these issues have not been addressed by the majority of epidemiologic studies to date.Experimental studies in cell lines and animals are providing causative mechanistic links between environmental exposures and altered mammary carcinogenesis, particularly during key WOS. Increasingly, epidemiologic studies are able to link the human exposure of chemicals and metals during relevant WOS through the use of intermediate breast outcomes including specific breast tissue characteristics and breast density in adolescence and adulthood to address the challenge of long latency time posed in cancer research.For many of the studies described here, community engagement strengthens the research design as well as the dissemination and implementation of study findings. To address knowledge gaps and accelerate translation of environmental breast cancer research findings related to WOS, BCERP integrates basic and population researchers with communication scientists and representatives of community-based organizations Fig. . CommuniAlthough the median age when women are diagnosed with breast cancer is 62\u2009years , primary"} +{"text": "Forensic anthropology involves diverse applications of anthropological knowledge to medico-legal problems. While the applications are evidence-driven, the available scientific methodology and foundation have developed through decades of research and experience. The roots of this field are anchored in comparative human anatomy but methodology has developed through experimentation, the assemblage of documented collections and databases and thoughtful research design. While forensic anthropology represents a mature scientific field, it continues to evolve and advance through new, innovative global research. Much of this progress is fuelled by issues encountered in casework. The unique evidence and problems presented in forensic cases call for the very best scientific approaches available. Usually, the correct approaches and solutions can be found in the existing scientific literature. However, sometimes the unique issues presented by the casework cannot be addressed adequately with the existing techniques. These situations stimulate forensic anthropologists to seek new solutions through targeted research.This Special Issue presents research advances in several areas of forensic anthropology that have sustained rapid, recent progress. While our journals continually reveal new information in all aspects of forensic anthropology, several areas of investigation have registered particularly strong academic interest featuring innovative research.Successful recovery and analysis of DNA has dramatically affected many areas of forensic science. In the field of forensic anthropology, molecular analysis can yield highly accurate information regarding the sex of the individual represented and provide positive identification . MoleculWhile the merits and contributions of DNA analysis are profound, many related issues express the need for new, innovative research and technological development. Frequently, evidence submitted for forensic anthropological analysis is not in pristine condition. In many cases, recovered remains are incomplete and/or extremely degraded due to criminal activity and/or taphonomic factors. Some site investigations produce only small fragments where even species is not apparent. Decisions need to be made regarding what areas of bone or tooth should be examined. Since DNA analysis is an expensive and destructive process, these decisions are critical and can affect the outcome of the case. Of course, decisions regarding the type of DNA analysis also are critical and largely driven by both the availability of the antemortem information and the nature of the evidence. Experimentation and casework experience have greatly improved approaches to these issues.Deaths related to the global movement of undocumented people across national borders present major forensic challenges. Even within countries, identification of citizens can be difficult with incomplete evidence and lack of information regarding missing persons. These problems are greatly exacerbated when different countries are involved and the international movement of the person represented is not registered officially. Such cases call for extraordinary investigation, thoughtful forensic analysis and international communication. These efforts can strain the available local resources and often fall short of positive identification.Recent years have witnessed remarkable efforts to address the identification of deceased, undocumented border crossers. These initiatives have involved international cooperation, careful exhumation procedures, comprehensive anthropological analysis and new techniques such as isotope analysis to identify the likely regions/countries of origin.The entire process of forensic anthropological investigation begins with the procedures of search, detection and recovery. Improper or inadequate detection and recovery of human remains can compromise the downstream analysis and interpretation. While the traditional techniques of surface survey and excavation continue to be needed, new approaches, especially those using advanced technology offer significant advances.Search procedures can be especially challenging when only very general information is available regarding the likely location of human remains. Topographic features can present limitations, especially with dense vegetation and other ground cover. Investigations of humanitarian and human rights issues can present special search and recovery challenges when information suggests that wells, cisterns, sewer systems, mass graves or disposal in water were involved. Confronted with these problems, researchers have devised innovative new approaches to improve the probability of success.Secondary deposits of human remains or those that have sustained significant disturbance involve loss of normal bone articulation patterns. When multiple individuals are involved, the resulting commingling presents challenges to determine the number of persons represented and to assemble remains of individuals for analysis, identification and return to families. Traditional approaches to commingling problems have involved sorting by the type and side (left or right) of bone, age at death, bone size and maturation, sex and pathological conditions. In some skeletal assemblages, taphonomic indicators can be helpful as well.Once obvious sorting has been completed, questions persist regarding bone morphology related to individuals. Could a robust femur relate to a robust humerus and represent one individual? Recent advances in commingling analysis address this issue. New databases and computerized techniques establish the probabilities that different bones could relate to the same individual. Applications refine the determination of the number of individuals represented and facilitate analysis aimed at identification.A primary function of anthropological analysis relates to the interpretation of bone trauma. Anthropologists must differentiate the skeletal alterations representing perimortem trauma from those relating to antemortem injury, developmental features or postmortem and taphonomic factors. Assessment of the biomechanical factors involved plays a key role in any interpretation. Knowledge of biomechanical principles is required to explain fracture patterns and other alterations likely related to perimortem trauma. Interpretation of bone trauma can be challenging. Such challenges have led to greater understanding of the principles involved and experimental work designed to improve interpretation.Major new initiatives in forensic anthropology have focused on decomposition research. Experiments involving both humans and non-human animals have revealed great detail about the process and variation of soft tissue decomposition and hard tissue alteration. In general, such research has elucidated the many factors that influence both the nature and timing of the decomposition process. Clearly temperature and location have long been regarded as key factors. Research has also indicated that soil conditions, moisture, body composition, body condition, presence of clothing or enclosures, funerary treatment and many other factors can influence the process. Such information is needed to properly assess time since death and post-mortem events related to criminal activity.In 1965, Ellis R. Kerley publishe3 photosynthetic pathway or a C4 pathway and the herbivores that fed upon them. Analysis of nitrogen isotopes provides insight into the trophic level of human diet. In anthropological studies of ancient populations, such information is crucial to interpretations of dietary and horticultural practices.For decades, analysis of elemental stable isotopes has offered key anthropological information related to diet. Stable carbon isotopes recovered from human tissues have revealed if diet focused on plants with a CRecently, researchers have applied the concepts of isotopic analysis to examine the geographical origin of human remains. When unidentified human remains are recovered in forensic contexts, investigators question if they represent someone who lived in the area of recovery or from somewhere else. This question is especially relevant in cases involving terrorism and unidentified possible migrants. Using a battery of stable isotope analyses, researchers can determine if the isotopic signatures from the unknown match local baseline data. If not, attempts can be made to determine from what geographic area the unknown originated. This exciting new area of forensic science investigation depends on the assemblage of baseline data from appropriate geographic regions.Forensic anthropologists relate to issues of facial imaging in facial approximation, craniofacial photographic superimposition and interpretations of surveillance images. Facial approximation refers to the process of estimating the living facial image of a person from the evidence presented by a recovered skull. This technique is used to reach out to the public for leads in missing persons that could culminate in identification using other methods.Craniofacial photographic superimposition involves comparing a facial photograph of a missing person with a recovered skull. This technique is used primarily to exclude when photographs are available of a missing person thought perhaps to be represented by the recovered remains.Recent research has focused on enhanced use of computers and related technology, as well as targeted efforts to clarify the relationship between soft and hard tissues. Facial approximation continues to represent a blend of art and science; however, recent advances have strengthened the scientific foundation.Forensic Sciences Research focus on overviews of the published literature on these topics. They also share results from the latest innovative research on these key areas of forensic anthropology applications.Articles in this Special Issue of"} +{"text": "Cells exist in dynamic three\u2010dimensional environments where they experience variable mechanical forces due to their interaction with the extracellular matrix, neighbouring cells and physical stresses. The ability to constantly and rapidly alter cellular behaviour in response to the mechanical environment is therefore crucial for cell viability, tissue development and homeostasis. Mechanotransduction is the process whereby cells translate mechanical inputs into biochemical signals. These signals in turn adjust cell morphology and cellular functions as diverse as proliferation, differentiation, migration and apoptosis. Here, we provide an overview of the current understanding of mechanotransduction and how septins may participate in it, drawing on their architecture and localization, their ability to directly bind and modify actomyosin networks and membranes, and their associations with the nuclear envelope. Therefore, living cells have acquired exquisite mechanisms that enable them to constantly and rapidly respond to mechanical forces, with cellular responses as diverse as migration, proliferation, differentiation and apoptosis bundles .Septins are a large family of guanosine triphosphate (GTP)\u2010binding proteins that are evolutionarily and structurally related to the Ras guanosine triphosphatase (GTPases) promotes the assembly of septin filaments promotes the formation of well\u2010bundled actin rings to ensure efficient contraction of the actomyosin ring (ARHGEF18), via its N\u2010terminal domain, thereby inhibiting RhoA signalling and actin SF formation , display increased mechanosensitivity, with cells failing to resolve the final stage of cytokinesis on stiff matrices but not on soft matrices , as well as measurements of PM tension with different septin network conformations.However, it remains unknown whether septins participate in mechanosensing and mechanotransduction at stretch\u2010activated channels and cilia. Future work will therefore require experiments directly testing the role septins in relaying mechanical cues picked up by cilia or PM deformation. This may require experiments directly studying the effect of septins on ion channel conformation and downstream signalling interacts with HIF1Considering the effects of mechanical cues on cancer cell malignancy, cell differentiation and EMT, it is important to further study the role of septins in these processes from a mechanical perspective. Changes in septin expression have been observed in cancers, and septins have already been shown to be important for cancer cell invasion and survival (Angelis & Spiliotis, These analyses will be complicated by the fact that cells contain several septins and septin isoforms, and that there is significant heterogeneity in the effects of septins and their isoforms on cellular behaviour (Connolly et al., Finally, classical mechanobiology techniques will be required to assess the role of septins in mechanotransduction. These include traction force analysis, and measurements of cell and nuclear shape and mechanical properties. In particular, it would be interesting to decipher the links between septins and key nodes in mechanotransduction such as FAs and LINC complexes. Are these interactions indirect through septin\u2010mediated actomyosin organization, or could septins play a direct role in signal transduction at these points?"} +{"text": "This study investigated the association between intergenerational transfer and self-rated health (SRH) using data collected from 323 older Chinese immigrants in Honolulu and 752 Chinese older adults in Wuhan. We also explored the mediating role of resilience and the moderating role of gender in linking the associations. Findings show, for both study sites, receiving greater emotional support was associated with increased levels of SRH and this association was partially explained by resilience for females but not for males. For country differences, receiving economic support was negatively associated with SRH whereas providing economic support was positively associated with SRH for males but not for females in Honolulu. In Wuhan, receiving housework support was negatively associated with SRH for females but not for males. These findings indicate that future studies need to consider country differences as well as the impact of acculturation when examining intergenerational transfers and health among Chinese older adults."} +{"text": "Researchers have used positron emission tomography (PET) to study the interrelationships of structural, metabolic, and functional brain changes following alcohol consumption as well as during withdrawal and abstinence. This technique is based on the fact that blood flow and energy metabolism tend to increase in parts of the brain undergoing increased activity and to decrease in brain tissue that is diseased or damaged. PET detects such changes by tracking the distribution within the brain of radioactive chemicals that have been injected into the blood. Because of its sensitivity, PET can detect early functional deficits in the brain before structural changes are apparent. PET has documented gradual recovery of cognitive functions with continued abstinence. In addition, PET data has been used to investigate possible mechanisms for some of alcohol 3s effects and to provide additional evidence for the heritability of alcoholism. AlcoholismResearchers have obtained these measurements using various imaging methods, including magnetic resonance imaging (MRI) techniques and single-photon emission computed tomography (SPECT). These methods are described in Blood flow and energy metabolism tend to increase in parts of the brain undergoing increased activity and to decrease in brain tissue that is diseased or damaged. PET detects these changes by tracking the distribution within the brain of chemicals known as tracers, which are injected into the blood. These tracers are rendered radioactive by being chemically combined with radioactive variants of elements found naturally in the human body. Special cameras surrounding the subject\u2019s head track the radioactive tracer as it moves through the brain\u2019s bloodstream. A computer translates the resulting data into color-coded images.PET has had two major applications to date. First, PET can measure blood flow for the entire brain or for specific regions within the brain . Second, PET can measure brain energy metabolism by tracking the distribution of the radiolabeled tracer fluorodeoxyglucose (FDG), a variation of glucose. Because glucose is normally the brain\u2019s sole energy source, the distribution of FDG in the brain reflects relative energy metabolism in different brain regions.Acute exposure to alcohol may produce brain impairments ranging from visible signs of intoxication to decreased performance in specialized tests of cognitive function. Many tracer studies using techniques other than PET have reported decreased CBF in alcoholics , the higher of the two alcohol doses increased the RCBF in both the prefrontal cortex and the right temporal cortex . The incAlcohol\u2019s tendency to increase blood flow in the right, rather than the left, temporal cortex is consistent with results of neuropsychological and electroencephalographic tests in which alcohol predominantly affected the functions of the right half of the cerebrum .The constriction and dilation of blood vessels caused by alcohol make it difficult to assess the relation between CBF data and brain function . Conversincreased CBF in the frontal cortex as it decreased frontal metabolism and enlargement of the ventricles . The sigThe alcoholic subjects in the studies cited above were not actively drinking. This raises the question of brain structure and function during the phases of withdrawal and recovery from alcoholic drinking episodes. Many researchers have used PET to investigate withdrawal and recovery in alcoholics, but studies have yielded conflicting results. Two PET studies reported decreased brain energy metabolism , whereasBy 60 days after last consuming alcohol, the alcoholics\u2019 brain metabolic rates were comparable to those of the control subjects except for persistently low metabolic rates in the alcoholics\u2019 basal ganglia. Significantly, no patients in the study exhibited abnormal movements typical of basal ganglia disorders, although such movements may occur transiently during alcohol withdrawal .Additional experiments have detAll brain functions involve communication among nerve cells, which in turn requires the expenditure of energy. Thus, the energy metabolism measured by PET in a given region reflects to some extent the level of communication among local nerve cells as they perform their specific functions. Communication between adjacent nerve cells generally involves the release of chemical messengers called neurotransmitters. A message is \u201creceived\u201d when a neurotransmitter temporarily attaches, or binds, to its receptor protein in the surface of a nerve cell.\u00ae), known to increase the effects of GABA, to 12 nonalcoholic and 10 recently detoxified alcoholic subjects. Lorazepam decreased whole brain energy metabolism in both groups.The neurotransmitter gamma-aminobutyric acid (GABA) regulates brain function by inhibiting nerve cell communication. Research suggests that GABA may contribute to the intoxicating effects of alcohol and the development of alcoholism . TherefoThe nonalcoholic and alcoholic subjects showed similar responses to lorazepam in occipital and cerebellar metabolism, whereas the alcoholic subjects exhibited significantly less of a response to lorazepam in the thalamus, basal ganglia, and orbitofrontal cortex. The blunted metabolic response to lorazepam in alcoholics is consistent with decreased GABA receptor function. Analysis of the data suggests that blunting of the effects of lorazepam in these specific brain regions in alcoholics may be a consequence of alcohol-related changes in cerebellar metabolism . Such chThe blunted response of brain metabolism to lorazepam in alcoholics may result from chronic alcohol use. Alternatively, the blunted response may represent a genetic trait associated with preexisting vulnerability to alcoholism. For example, children of alcoholics show a blunted response to various signs and symptoms of alcohol administration compared with subjects with no family history of alcoholism . The GAB\u00ae), a sedative belonging to the same class as lorazepam . Both groups of subjects received increasing doses of diazepam (25 to 100 micrograms per kilogram [\u03bcg/kg]) or a placebo on 2 days at least 1 week apart. The researchers assessed the effects of diazepam using two eye-movement tasks that objectively measured benzodiazepine effects. The FHP\u2019s displayed significantly less diazepam effects on eye movements than the FHN\u2019s. Effects increased as the dose increased.A study by Researchers have used PET measurements of blood flow and energy metabolism to identify brain regions affected by alcohol and to investigate mechanisms of alcohol-induced cognitive and behavioral impairment. Because of its sensitivity, PET can detect early functional deficits in the brain before structural changes can be detected. Thus, PET studies have shown that alcohol withdrawal changes regional brain metabolism in alcoholics in the absence of neurological or psychological impairment. PET has also documented gradual recovery of cognitive functions with continued abstinence.The cerebellum appears to be one of the areas of the brain most sensitive to alcohol. Alcohol-related changes in cerebellar metabolism might help explain the lack of control over drinking associated with alcoholism. Cerebellar metabolism and drug response, as revealed by PET, suggest that abnormal GABA receptor function may help characterize subjects with family histories of alcoholism."} +{"text": "Background: Studies have shown that participation in community-based self-management education programs can result in improved healthful behaviors , improved health status , and decreased days in the hospital. Problem: One of the understudied factors thought to influence efficacy in community based self-management programs is the presence and impacts of multiple chronic conditions on participants within community based behavioral health program populations. Multiple chronic diseases when scaled collectively can be considered as a participant\u2019s individual disease burden to be included in other analyses. Methodology: This investigation explores possible ways disease burden associates with such important constructs as participant personal characteristics and participant confidence in controlling impacts of their disease symptoms and participant preferences for use of various methods of coping with disease impacts. Outcomes: Results indicate a complex pattern of relationships between such factors as personal characteristics of program participants and their perceived mastery over the impacts of their disease symptoms, and their preferred mechanisms for coping. Implications: program designers and managers can better understand the differential influences of disease burden on participants analyzed with their personal characteristics and their preferential uses for coping mechanisms and their perceived ability to withstand the added burdens of multiple chronic diseases."} +{"text": "Forests are one of the most important global vegetation types, serving functions from supporting healthy watershed, to wildlife habitat, and economic industries through their harvesting and tourism value. Understanding and mitigating threats to these resources is therefore of great societal importance. Forest pests are among the most pertinent and obvious threats to forest health, with their impacts amplified by contemporary issues such as climate change and global trade , which primarily attacks ash trees, the redbay ambrosia beetle (Xyleborus glabratus) infesting members of the laurel family (Lauraceae), and the Asian longhorned beetle (Anoplophora glabripennis) and polyphagous shot hole borer (PSHB), which are capable of infesting a wide range of tree species , and those infesting a narrow range of hosts (such as A. planipennis and X. glabratus) at the same time. For example, of 298 spruce bark beetles sampled during an outbreak in Finland, more than two fungal species were concurrently found on over 40% of individuals , can form part of an integrated strategy. These regulate insect communication and can be utilized as potential repellents against beetles at outbound transport points or increase the efficacy of luring traps (Kandasamy et al., Managing increasingly disturbed forests will be an important global challenge moving forward. While significant research effort has been devoted to understanding and mitigating the effects of insect pests on forest health (Vega and Hofstetter, Fundamental baseline information on the diversity and frequency of most insect-fungal associations is currently lacking. Such information is important for recognizing novel vector-fungi associations, which have the potential to cause serious forest damage (Ploetz et al., While important advances have been made in understanding the impacts of fungal pathogens associated with forest insect pests, many pertinent questions remain and we hope this article will help stimulate research to investigate them.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "This Research Topic covers the dynamics of emotional labor and its related outcomes and antecedents in various settings. Recent consumer and service management research increasingly focuses on the role of emotions and emotional labor in service delivery and, at the same time, employees' emotional status. Frontline employees in various settings are expected to display certain emotions and suppress others in their daily interactions not only with customers but also with their managers or supervisors in order to comply with their job requirements and organizational expectations. As a result, consumers are also coping with their level of emotional acceptance when purchasing goods or receiving services, such as comfort or discomfort. Thus, this topic can be approached from both within the business and from consumer perspectives, or beyond.Park et al., investigate the relationship between the felt emotional dissonance and prosocial behavior with four experiments suggesting higher emotional dissonance serially influences perceived lack of control, emotional exhaustion, lowered sympathy for others' feeling, and subsequently lower willingness to help others.There are 10 manuscripts in this Research Topic. First, despite the growing body of research on the emotional labor of service providers, little has been known about the social consequences of emotional labor by exploring double roles of emotional laborer as a consumer. Drawing on emotional dissonance theory, Jeong et al., investigate a conceptual model articulating the nature of customer expectations and satisfaction over services with several emotional factors. Five propositions about consumer emotional service expectations as a primary antecedent toward confirmation, perceived quality, and satisfaction are provided. As moderators, two dimensions of consumer detection of emotional labor are imposed on each of the relationships. Evidence demonstrates the roles of emotional service expectation in service confirmation and satisfaction. The moderating effects of consumer detection of employees' emotional strategies are limited to the relationship between emotional service expectation and confirmation in the hotel/restaurant industry. Zhang et al., examine how employee surface acting relates to their sabotage to customers through the mediating role of emotional exhaustion. Also, they explore the moderating roles of coworker exchange and leader-member exchange using the conservation of resources theory and social exchange theory as conceptual frameworks, and find that coworker exchange buffers the positive effect of surface acting on emotional exhaustion. In addition, the study stresses the effect of surface acting on employee harmful behaviors, the potential underlying mechanism, and boundary conditions to mitigate the negative consequences. Lee et al., explore the relationship between employees' expression of emotional labor and perception of customer feedbacks touching how the perception of customer feedback affects emotional exhaustion in order to understand how emotional exhaustion affects job satisfaction and turnover intentions. The result suggests that employees with better understanding of their own emotions who experience a more significant negative effect when there is a discrepancy between what they feel and how they should act.Three manuscripts focus on the emotional relationship between consumers and service providers. Oh et al., examines the relationship between corporate social responsibility (CSR) perception and emotional labor strategies, and the effects of the interaction between CSR perception and moral identification on emotional labor strategies indicating main effect of CSR perception on emotional labor strategies. The results find CSR perception of employees is positively related to deep acting revealing employees' views on their organization's social responsiveness and morality affect their emotional labor strategies. Also, affective organizational commitment and moral identifications mediate the relationship between CSR perception and surface acting but not between CSR perception and deep acting. Lee et al., focus bond and fit toward emotional labor within organization. The manuscript examines the influences of relationship bonds on emotional labor through person-organization fit (P-O fit) and the moderating effects of collectivism between P-O fit and emotional labor in the financial industry identifying financial, social, and structural bonds enhanced P-O fit that improves deep acting. This study not only suggests the empirical evidence identifying the process of relationship bonds influencing emotional labor but also expands the scope of study by examining moderating roles of collectivism in cultural psychology aspect.Within the organizational level, there are six articles. Based on social identity theory, Huang et al., investigate school teachers' emotional labor process and the consequential outcomes for their well-being examining the roles of two antecedents, namely, teachers' perceptions of display rules and self-monitoring tendencies. The results show that self-monitoring generally have stronger, though maladaptive, effects than display rule perceptions on individuals' use of emotional labor strategies and well-being. Both self-monitoring and display rule perceptions are positively related to two emotional labor strategies concluding self-monitoring may be less beneficial than previously thought. Knowledge-based service workers' display rule perceptions and deep acting may not necessarily be harmful to their well-being but reflect their role identification and commitment. Han et al., investigate the effects of level of emotional labor and its impact of emotional labor on organizational trust and organizational commitment with college administrative staffs with 3 factors as determinants of emotional labor.Two manuscripts focus on knowledge-based service providers. Cho and Cho examine the internal state of employees' emotion how people anticipate negative emotion when faced with an uncertain outcome and try to manage their expectation. While extant research streams remain equivocal on whether managing expectation always succeeds, this research examines situations in which setting a low expectation can have an adverse emotional impact and ways to alleviate this negative emotional consequence using goal setting and false-feedback paradigm. Choi et al., explore rather negative consequences of emotional problem in workplace taking a holistic approach associating the concept of bullying with firm-level performance as well as stakeholders' responses in the market analyzing whether and how market investors react to the news of corporate harassment by top officials of publicly listed firms in Korea. The results find significantly negative stock price reactions to news of corporate bullying and harassment.We wish to express our great appreciation to the authors of this special issue for their enthusiasm and scholarly achievements. Although the individual manuscripts reflect considerable variations in focus and perspectives, we genuinely believe that there is a tremendous cohesive message for a better understanding of the filed of emotional labor and consider applying various theories to further developing effective employee retention strategies and enhancing the well-being of all stakeholders in the service delivery process.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Hahn asserts It is worth considering how our own backgrounds in ecological research might have biased our attention away from fundamental aspects of evolutionary toxicology. For many who study wild populations, there is a sense of obligation to suggest applications for research findings, even if those suggestions might be out of touch with practice. This premium for applied relevance can neglect the critical role and value of scientific curiosity and fundamental research (Courchamp et\u00a0al., Ultimately, the most comprehensive understanding in toxicology might best be achieved through dual pursuits of both basic research and applied research. As Hahn notes, even applied toxicology is fundamental in nature. We suggest further that applied insights can help inform basic insights. For instance, novel conditions or objectives in applied contexts might help elucidate novel mechanisms underlying toxicological responses. Thus, the relationship between applied research and basic research in toxicology is one of mutual benefit, each inspiring the other and leading to the advancement of knowledge.We appreciate the important and balanced perspective put forth by Hahn and are encouraged that our special issue on Evolutionary Toxicology is prompting consideration of the diverse value of the role of evolutionary concepts in toxicology. We look forward to future discoveries and syntheses that await this vibrant and multidisciplinary field."} +{"text": "Cat management is often discussed in terms of population reduction, with trap-neuter-return (TNR) campaigns commonly organized to manage unowned urban cat populations. However, long-term effectiveness is only possible if positive neutering practices are continued by local residents. Here we discuss how implementing TNR within a wider framework of social engagement has the potential to tackle cat overpopulation and instill long-term positive behavior change toward them. We demonstrate how community engagement pre-TNR can help establish a baseline of the attitudes, knowledge and behavior concerning cats. Using a case study, we explore whether this information can be linked with positive intended behavior based on intentions to arrange for neutering of unowned cats. Structural equation modeling indicated that negative attitudes toward cats and reduced knowledge around neutering reduced the likelihood of positive intended behavior. This result was underpinned by the indirect effects of perceptions of unowned cats and reduced understanding of their needs. Utilizing these results alongside an understanding of the values and motivation of the community allows for tailored and targeted education and intervention. In turn, this addresses the underlying knowledge gaps and perceptions regarding cat welfare. This framework can help address the challenge of cat management because it: (1) takes an integrative approach to identifying the motivations of communities to take responsibility for unowned cats; (2) changes the structure of the social environment, encouraging positive neutering practices for unowned cats. In turn this improves the impact and longevity of TNR campaigns whilst promoting positive welfare change for unowned and owned cats; and (3) appreciates that opinions are likely to vary hugely between areas, therefore providing an adaptable community level approach. Human behavior change is fundamental to tackling anthropogenic problems, both globally and locally. The unowned cat overpopulation problem in urban areas is one such issue, largely a function of socio-demographic parameters \u20133, humanThe dynamic nature of unowned cat populations, influenced by constant immigration, and emigration , necessiAssuming the provision of affordable neutering services, the capacity of local people to arrange neutering for their cat and/or for unowned cats in their community, will still be strongly influenced by their perceptions and beliefs. Some studies have shown that the intention to neuter unowned cats is predicted by religious beliefs, attitudes toward neutering and beliefs about personal capacity . AdditioHere we propose a modeling framework to identify key factors underpinning positive neutering behavior in a community. We illustrate the potential for TNR campaigns to not only have short-term operational benefit but, through community engagement and behavior change interventions, also the potential to empower a community to ensure the continuation of positive neutering practices for the cat population as a whole. We provide an example of how a modeling approach can unravel the beliefs underpinning a positive intended behavior, and how this could potentially be used for further community engagement.Education often forms the focus of any campaign to bring about behavior change, whether based on health, conservation or animal welfare. A plethora of models exist that set out to provide a deeper understanding of the psychological processes underpinning behavioral change. However, it is increasingly recognized that knowledge alone is insufficient, because many other factors influence behavior change including self-efficacy , social Individual behavior can be driven by three essential components; capability, opportunity and motivation, termed the COM-B model Table . CapabilThere are nine intervention functions: Education, Persuasion, Incentivisation, Coercion, Training, Enablement, Modeling, Environmental Restructuring, and Restriction .\u201d\u201cIt has given me advice on how to deal with a stray cat.\u201dWithout continued neutering within the community, TNR work is at risk of failing to make significant progress in urban areas and its long-term impact jeopardized . We highWe found that intended behavior toward cats was primarily driven by attitudes toward cats in general. Perceptions about unowned cats also shaped attitudes, suggesting there are higher order cognitions that strongly influence behavioral intentions. This result is not dissimilar from previous studies , which fRespondents knowledge was the second predictor of intentions. More than half of respondents were either unsure or agreed that female cats should be allowed to have a litter prior to being neutered and that related cats would not mate with each other. This result is consistent with previous studies that identified poor owner knowledge of feline reproduction . AdditioEarly engagement with the community prior to and during TNR operations had the additional operational benefit of identifying perceived areas of high unowned cat density. This is valuable as unowned densities have been found to vary dramatically even across a short distance . AdditioAs our case study shows, the combination of survey instruments with modeling approaches can inform how best to approach community engagement and interventions. The hierarchical relationships among variables would have been missed if a multiple linear regressions were used. The modeling framework presented here is easily extended to incorporate a range of behavioral concepts and provides the basis to explore different behavioral hypothesizes. The adaptability of this approach is desirable as barriers and motivations will vary across communities and depend on the sociodemographic context , therefoIn highly deprived areas, the barriers to unowned cat management will also encompass broader community problems. Going forward, this community engagement could spark wider collaborations with other stakeholders and human agencies, such as housing authorities and foodbanks. Providing interventions that work together and address community problems will help empower individuals encouraging positive behavior. For example, offering social support has shown to be important for behavior change in other contexts \u201331, but We have highlighted the importance of accounting for anthropogenic factors when determining appropriate interventions to ensure the long-term benefit of TNR campaigns. Our case study revealed the drivers of behavioral intention go far beyond a lack of awareness alone and that attitudes, perceptions and knowledge are all significant drivers. Studies that fail to account for specific barriers around helping unowned cats within a community may not effectively increase the capacity for people to help unowned cat populations and prevent cat overpopulation more generally. This study adds to the increasing understanding that targeted interventions are necessary for behavior change. We therefore recommend further consideration of the social context within which TNR is often implemented and ultimately application of similar approaches across other urban areas around the world.All questionnaires were optional, and respondents were advised they did not need to take part and could withdraw involvement at any point. This study was carried out in accordance with the recommendations of University of Bristol's Ethics Policy and Procedure. The protocol was approved by University of Bristol Faculty of Health Science Research Ethics Committee approval number 38661.JM coded the models, ran the analysis and wrote the paper. JC motivated the research, manages the Cat Watch project and commented on drafts. MF provided constructive input into the development of the project and commented on drafts.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "This session reports on older LGBT adults\u2019 perspectives of roles that pets played in relation to older adults\u2019 aging-in-place experiences. The goal of this study is to advance understanding of the role of pets in the lives of older LGBT adults living in rural communities. The qualitative study used individual, semi-structured interviews with 11 older adults residing in rural Appalachia. Individuals were recruited using purposive sampling techniques, including recruitment through LGBT friendly service providers, a lesbian listserv, and snowball sampling. The majority of respondents reported that pets played a role in social support and some in social capital. One respondent described a utilitarian relationship with animals that is important to understanding the roles animals may play in rural communities in terms of \"belongingness\". After reviewing study findings, we will provide recommendations for including information about pets in formal social service delivery systems and conclude with implications for future research."} +{"text": "As the gender divide among family caregivers closes, it is important to understand whether and how men and women differently experience caregiving. For example, literature suggests that employed family caregivers experience burden and health outcomes differently than unemployed caregivers, but less is known about how these factors affect men and women differently. Using data from Caregiving in the U.S., 2015 (source: AARP and NAC), this study reliably modelled the effect of multiple threats to good health within the caregiving role . In the analysis, several moderated relationships were observed using data from 816 working caregivers. In the full sample, the relationship between objective caregiving burden (hours of care and counts of ADLs/IADLs) and self-reported health status was altered by financial strain. In the high burden condition, relatively poor health was progressively related to increasing levels of financial strain controlling for traditional covariates. In separate analyses for males and females, this moderated relationship was discovered to be limited to female caregivers. Physical and emotional strain did not moderate the relationship between burden and health. Several covariates related to employment conditions behaved differently across models and are presented and discussed in relation to financial strain as a determinant of caregiver health. These findings shed light on gender-based differences in caregiver outcomes, and suggest that interventions aimed at assessing and improving caregiver health should account for the financial strain experienced particularly by women."} +{"text": "Although previous studies have extensively investigated the cross-sectional relationship between social engagement and depressive symptoms in late life, longitudinal studies have produced mixed results. Furthermore, studies on the associations between these two concepts among aging African Americans are few. Using a sample of 1688 older African Americans adults from waves 1 and 7 of the National Health and Aging Trends Study , the present study investigates the longitudinal associations between social engagement and depressive symptoms across seven years. Structural equation modeling was used to test cross-lagged relationships between the variables. Findings suggest that social engagement at baseline significantly predicted subsequent depressive symptoms and social engagement. Depressive symptoms at baseline, however, were not significantly associated with subsequent social engagement. These findings suggest that low social engagement in older African Americans is directly associated with increased depressive symptoms over time, but not vice versa. The implications of these findings are discussed in relation to the barriers of social engagement for older African Americans and its effects on their mental health."} +{"text": "The tubers were harvested and analyzed for total flavonoids, total phenolics, antioxidant activity and cyanogenic glucoside content. Total phenolic and flavonoid compounds were determined using the Folin-Ciocalteu assay and aluminium chloride colorimetric method, respectively. Different sources of fertilizer, varieties and their interactions were found to have a significant effect on phytochemical content. The phenolic and flavonoid content were significantly higher (p < 0.01) in the vermicompost treatment compared to mineral fertilizer and EFB compost. The total flavonoids and phenolics content of vermicompost treated plants were 39% and 38% higher, respectively, than those chemically fertilized. The antioxidant activity determined using the DPPH and FRAP assays were high with application of organic fertilizer. Cyanogenic glycoside levels were decreased with the application of organic fertilizer. Among the two types of compost, vermicompost resulted in higher nutritional value of cassava tubers. Medan variety with application of vermicompost showed the most promising nutritional quality. Since the nutritional quality of cassava can be improved by organic fertilization, organic fertilizer should be used in place of chemical fertilizer for environmentally sustainable production of better quality cassava. A field study was conducted to determine the effect of organic and mineral-based fertilizers on phytochemical contents in the tubers of two cassava varieties. Treatments were arranged in a split plot design with three replicates. The main plot was fertilizer source and sub-plot was cassava variety (Medan and Sri Pontian). The amount of fertilizer applied was based on 180 kg K Manihot esculenta Crantz) has the ability to grow on the poorest soils and left to compete with weeds. This ability has led many to think that cassava, either when grown alone or as an intercrop does not require high soil fertility and does not respond to fertilizer application. Farmers do not fertilize cassava because they are assumed to be content with the minimal yields obtained from using limited inputs or even from their infertile soils. The indifference towards low productivity can be attributed to the low and unstable prices of cassava tubers. However, fertilizer requirements for optimum yield in cassava is determined by the soil fertility status of the farmland, cropping system, and the rainfall pattern during the growing season \u00d7 100. The determination of the total antioxidant activity in the extract using the FRAP assay followed after a modified method reported by . ExtractThe alkaline picrate method of was usedIn summary, it can be concluded that nutrient sources can have significant effects on antioxidant activity and phenolic metabolites in cassava. Organic fertilizer should be used in place of chemical fertilizer for environmentally sustainable production of better quality cassava. The results indicated that application of vermicompost and empty fruit bunch compost can enhance the antioxidant activities of field grown cassava. Application of inorganic fertilizer increased the level of cyanide in cassava. Medan variety with application of vermicompost showed the most promising nutritional quality. Phytochemical composition was significantly improved with the application of organic fertilizer and vermicompost showed better effects than EFB compost."} +{"text": "Dear Editor,Colorectal cancer is the third most common malignancy worldwide and the fourth most leading cause of cancer deaths. Colorectal cancer has become a real public health issue in both developed and developing countries .High intake of red and processed meat has been also linked to an increased risk of several cancers. Recently, Rosato et al. 2017) analyze017 analyIn the present letter, we summarize the recent studies carried out to investigate the association between red and processed meat intake and colorectal cancer risk (Table 1The author declares no conflict of interest."} +{"text": "Sharing Opinions and Advice about Research (Project SOAR), funded by PCORI, trained individuals living in under-resourced and underserved communities how to evaluate and provide advice to scientists about recruitment procedures, survey items, and intervention components for implementation in their communities. Moreover, graduate students learned community-based participatory research (CBPR) procedures and interacted with communities in implementing their own research projects. Students worked with the urban Holt community in western Alabama on issues of food insecurity due to pollution and concerns about growing vegetables and herbs in the soil. Students participated in the Potted Plant Project and plant give away, collecting questionnaire and health data. Students reported finding the fluid nature of research during this community event both stressful and rewarding. Students also identified how familiarity with CBPR procedures enhanced their clinical service provision in the community. Discussion will focus on future graduate training needs in implementation of CBPR."} +{"text": "This presentation will discuss the findings and implications from a mixed-methods study examining the impact of support services for caregivers of persons living with Dementia in their faith community. Caregivers and persons living with dementia participating in religious activities report numerous psychosocial benefits. Faith communities are the primary social network for older adults, with 48% of older adults attending religious services at least once weekly. Results will highlight specific opportunities for local congregations to foster spiritual connection and meaningful engagement with caregivers of persons living with Dementia. Findings will also describe key considerations and pathways for social work practitioners, researchers, and religious leaders to better serve older adults in their communities by providing education and strengths-based interventions in the context of local congregations. These findings have the potential to increase the reach of such programs to diverse, underserved populations."} +{"text": "Abstract The choice of healthcare facility by older persons is an important factor in their healthcare seeking behavior, and this can be associated with a number of factors. This study investigated the relationship between social support and healthcare facility choice of older persons in Nigeria. Other factors associated with the choice of healthcare facilities by older persons were also identified. Quantitative data were collected from a sample of 3,696 elderly aged 60 years above who were selected through multi-stage systematic random sampling. Binary logistic regression analysis revealed that older persons who received social support were more likely to seek treatment in formal healthcare facilities, while older persons who did not receive any form of social support were more likely to seek treatment in informal healthcare facilities. Membership of social or religious groups was found to be a predictor of health seeking behavior among the older adults. Sex, age, level of education, and ability to handle activities of daily living (ADL), and ease of access to the nearest health facility, were found to be significantly associated with choice of healthcare facilities. The article concludes that there is need for conscious planning to provide formal supports to ease access of older persons to available health facilities. Such facilitation should include financial support and removal of existing physical and cultural barriers to health care utilization by older persons."} +{"text": "Since 1998 the Hartford Institute for Geriatric Nursing has offered a summer program designed to accelerate the development of research projects and trajectories for young scientists. This interprofessional program brings faculty and scholars together from across the globe representing all healthcare disciplines. In the week long program, scholars benefit from expert presentations and daily mentoring sessions with experts in gerontological research. In this symposium, scholars will discuss strategies they have used to successfully move from ideas for research, to development of proposals, conduct of research projects and planning career trajectories. We will present differing mentoring strategies and available mentoring opportunities for gerontological-focused scientists. Each scholar will present their work with topics including optimal medication management to sustain home placement: use of adaptive dance to improve mood and function in persons with Alzheimer\u2019s disease; facilitating positive attitudes toward older adults in nursing students; the use of mindfulness to reduce symptoms of urinary incontinence; and, a novel intervention to reduce pressure ulcers in the nursing home."} +{"text": "Dental practitioners may encounter bifid mandibular canals upon radiographic assessment, and may not understand the true extent of this presentation. The presentation of a bifid mandibular canal poses difficulties when carrying out dental procedures, including administration of mandibular block anaesthesia, oral surgical procedures of the lower third molars, orthognathic surgery and implant placement. Therefore it is of paramount importance that general dental practitioners be aware of the radiographic appearance, as incorrect diagnosis of this rare presentation can lead to detrimental consequences. The purpose of the communication is to draw dental practitioner\u2019s attention to the variations of bifid mandibular canals and ensure practitioners interpret radiograph correctly to make an informed diagnosis and eliminate the risk of damage and discomfort in the event of surgical treatment being carried out. It is advised that dental practitioners refer for further imaging such as a cone beam scan for greater understanding of the anatomical variation. Key words:Bifid mandibular canal, inferior alveolar nerve, bilateral bifid mandibular canal. RadiogrA 63-year old male patient, reported to the Dental clinic with multiple missing teeth who requested a replacement with fixed prosthesis. Panoramic radiograph was advised which revealed an incidental finding of a bilateral bifid mandibular canal Fig. . To the Panoramic radiographs detect mandibular canals in a two dimensional aspect, however when anatomical variations are present, depicting bi-dimensional images can be challenging . Dental Cross sectional CBCT provide dental practitioners important information regarding the mandibular canal and its precise trajectory, which allows for the precise localisation of the duplicated canal to eliminate the risk of potential nerve injury . A CBCT Carter and Keen developeBifid mandibular canals require much attention prior to surgical planning, understanding the location and configuration of mandibular canal variations is important for preoperative planning to alter and modify the procedure and take extra precautionary measures to prevent extensive damage to the nerve and surrounding tissues ,6,13.The most common problem that arises with the presence of a bifid mandibular canal is inadequate local anaesthesia ,14. AdmiDental practitioners need to undertake third molar extractions and surgical procedures in the molar area with a bifurcation with caution as it is possible to have a second neurovascular bundle which has the potential to be damaged during extraction and invasive dental procedures, causing paraesthesia, dysesthesia, anaesthesia, neuroma development and can lead to significant bleeding following the procedure ,11-13.Implants are another surgical procedure carried out by dentists and other dental specialists, with inadequate insight of the three-dimensional aspect of the anatomy of the jaw/canal, the IAN can be traumatised by penetration of the drill preceding implant placement . This coOnce anatomical variation has been detected, the practitioner can alter local anaesthetic technique and preoperative design for surgical procedures in order to reduce pain, discomfort and ultimately damage to the affected area ,9,11-13.Bifid mandibular canals are too commonly unrecognised by practitioners on standard panoramic radiographs, this anatomical variation is of significant importance for surgical procedures and it is of utmost importance that dental practitioners are well educated in their presentation and be able to correctly diagnose this variation to enable adequate surgical planning in the region. It is strongly recommended when practitioners come across what is believed to be a true bifid canal that a CBCT is taken as these radiographs allow for greater accuracy in the diagnosis of anatomical variations in the jaw which reduces the incidence of nerve injury and damage to the neurovascular bundle."} +{"text": "In early October 2014, 7 months after the 2014\u20132015 Ebola epidemic in West Africa began, a cluster of reported deaths in Koinadugu, a remote district of Sierra Leone, was the first evidence of Ebola virus disease (Ebola) in the district. Prior to this event, geographic isolation was thought to have prevented the introduction of Ebola to this area. We describe our initial investigation of this cluster of deaths and subsequent public health actions after Ebola was confirmed, and present challenges to our investigation and methods of overcoming them. We present a transmission tree and results of whole genome sequencing of selected isolates to identify the source of infection in Koinadugu and demonstrate transmission between its villages. Koinadugu's experience highlights the danger of assuming that remote location and geographic isolation can prevent the spread of Ebola, but also demonstrates how deployment of rapid field response teams can help limit spread once Ebola is detected. On 25 May 2014, the first confirmed case of Ebola virus disease (Ebola) was reported in Sierra Leone . Koinadu2 but has a relatively small population of 265\u00a0765 based on the 2004 census . Th. Th14]. Early investigations in Fankoya revealed suspected Ebola deaths in early September. However, due to limited resources of burial and surveillance teams, CIFs were not routinely collected for deceased persons until 20 October. During 5 September through 17 December, a total of 56 potentially Ebola-related deaths were reported in Nieni including 16 suspected, eight probable and 32 confirmed Ebola cases. Burial information was missing for 26 deaths (which occurred before CIFs were routinely collected); it is assumed these burials were performed in the community by friends and family members. For 30 deaths for whom burial information was recorded, 26 (87%) were buried safely by a trained burial team and four (13%) were buried by the community using traditional practices. The majority of these deaths took place after intensification of staff and other resources.Investigation of Ebola in Koinadugu, a particularly remote area, determined that Ebola was likely to have been introduced to Koinadugu weeks to months prior to confirmation of Ebola in the district. Whole genome sequencing results suggest the initial route of Ebola transmission into Koinadugu was from within Sierra Leone rather than a cross-border transmission. However, based on inferred phylogenetic relationships, Koinadugu likely had multiple introductions of Ebola during the course of the Ebola outbreak. Of note, whole genome analysis demonstrates that while closure of international borders was associated with decreased transmission, international cross-border transmission still occurred . Our invAccess issues, resource limitations and logistical constraints of remote villages are a challenge to outbreak responses and can lead to delayed identification of Ebola-related morbidity and mortality with increased potential for spread to other communities. These challenges have been identified in previous haemorrhagic fever outbreaks, and intervention strategies to overcome these challenges have been noted by previous articles. Information collected about the decrease in number of days from symptom onset to case report completion and the increase in the percent of confirmed case patients for whom CIFs were completed shows how intensive surveillance and enhanced response efforts may improve key responses. During the West Africa Ebola outbreak, which primarily affected urban areas, the challenges of rural environments in Liberia similar to Koinadugu were noted to interfere with Ebola epidemic control \u201320. In rActivities undertaken in Nieni to control the Ebola outbreak were similar to the objectives of Liberia's national strategy. After confirming Ebola cases in Nieni Chiefdom, the DHMT and international partners attempted to increase case finding, improve isolation measures, decrease time to receipt of laboratory results and expedite transfer of confirmed Ebola cases to ETUs. It should be noted that prior to establishment of field-based, rotating surveillance and laboratory teams in Nieni and the Kumala CCC, no confirmed cases from Nieni survived long enough to be transported to an ETU. After these measures were put in place the majority of newly identified suspected patients survived long enough for transport to an ETU, and several patients returned to their villages after ETU discharge. Our data also showed an increase in case reporting and decrease in reporting delays after intensified outbreak response efforts were started.et al. [We determined by verbal autopsy that several cycles of unusual illnesses and deaths which were likely to have been Ebola had occurred approximately 6 weeks before the first reported Ebola case in this district. These findings emphasise the importance of assessing surveillance in silent areas in order to promptly detect ongoing transmission and rapidly implement response measures. Surveillance gaps in Sierra Leone resulting in Ebola-infected persons coming to the attention of health authorities only after they died were also reported by Crowe et al. . In respIn addition to Ebola containment and infection prevention strategies, there was a targeted community effort to raise Ebola awareness and decrease stigma related to the disease. The support of Nieni's Paramount Chief of the outbreak response was integral to the successful containment of Ebola. In remote areas where Ebola response activities are limited, integration of existing political and public health structures into response efforts might improve community enthusiasm for participation in the response .et al. describe the social networking of rural communities in Sierra Leone including the complexities and importance of familial lineages and traditional practices of marriage and funerals with regards to the current Ebola outbreak [Similar to earlier Ebola outbreaks and other areas affected by the Ebola outbreak in West Africa, burial preparation, funeral practices and travel to neighbouring villages contributed significantly to the spread of Ebola in Nieni chiefdom , 24. Whooutbreak . VillageLimitations of our investigation include incomplete case reporting, particularly at the beginning of the outbreak. Although the initial investigation teams uncovered 22 suspicious deaths, time, logistical and political constraints did not allow for an exhaustive evaluation. When combined with initial delays in identifying cases, a significant spike in case reports followed community notification about the first confirmed case. We believe a more gradual progression of Ebola onsets likely occurred than suggested by the epidemic curve. Similarly, focused interventions in Nieni chiefdom resulted in improved case-finding and were not necessarily emblematic of increased transmission in the area.The experience in Koinadugu highlights the danger of assuming that remote location and geographic isolation can prevent the spread of Ebola, and further, that absence of case reports reflects the absence of transmission. People remain mobile and social networks drive the spread of diseases like Ebola regardless of geopolitical boundaries.Nieni chiefdom's case study underscores the importance of active surveillance for early detection of Ebola and is a call for increased preparedness of rural populations. The ability to (1) set up surveillance using standard case definitions and prompt reporting and (2) quickly enact outbreak control strategies in remote areas is critical for early containment of Ebola . A polic"} +{"text": "In migratory birds, early arrival on breeding sites is typically associated with greater breeding success, but the mechanisms driving these benefits are rarely known. One mechanism through which greater breeding success among early arrivers can potentially be achieved is the increased time available for replacement clutches following nest loss. However, the contribution of replacement clutches to breeding success will depend on seasonal variation in nest survival rates, and the consequences for juvenile recruitment of hatching at different times in the season. In particular, lower recruitment rates of late\u2010hatched chicks could offset the benefits to early arrivers of being able to lay replacement clutches, which would reduce the likelihood of replacement clutch opportunities influencing selection on migratory timings. Using a simulation model of time\u2010constrained capacity for replacement clutches, paramaterized with empirically\u2010derived estimates from avian migratory systems, we show that greater reproductive success among early\u2010arriving individuals can arise solely through the greater time capacity for replacement clutches among early arrivers, even when later renesting attempts contribute fewer recruits to the population. However, these relationships vary depending on the seasonal pattern of nest survival. The benefits of early arrival are greatest when nest survival rates are constant or decline seasonally, and early arrival is least beneficial when nest success rates increase over the breeding season, although replacement clutches can mitigate this effect. The time benefits of early arrival facilitating replacement clutches following nest loss may therefore be an important but overlooked source of selection on migratory timings. Empirical measures of seasonal variation in nest survival, renesting, and juvenile recruitment rates are therefore needed in order to identify the costs and benefits associated with individual migration phenology, the selection pressures influencing migratory timings, and the implications for ongoing shifts in migration and breeding phenology. Declines in breeding success with date of arrival on the breeding grounds have been widely demonstrated in many species which were constant throughout the season. As these models showed that the effects of renesting were greatest at intermediate levels of nest survival (see Section to 0.9 w2.4In simulations in which replacement clutches were possible (up to a maximum of one or three attempts), the lay date of renesting attempts was determined by first assigning a nest failure date to each failed attempt, by sampling at random from a distribution of numbers of days between laying and failure of nesting attempts Figure d, and ad2.5The probability of offspring recruitment into the breeding population for each successful nesting attempt (one hatched offspring per successful attempt) was estimated as a function of hatch date Figure . Hatch dEach of the 15 simulations was run 100 times, from which the arrival date, mean lay date of successful nests, mean annual number of nesting attempts, mean annual number of successful nesting attempts, mean annual recruitment probability and lifetime number of recruits over the 10\u2010year period was calculated for each individual.33.1As nest survival rates increase, the number of successful nesting attempts increases, and the capacity to lay multiple replacement clutches results in a higher number of successful nesting attempts Figure a. The in3.2Five scenarios of seasonal variation in nest survival rates were modeled Figure , top rowSeasonal variation in nest survival rates can alter the influence of replacement clutch capacity on breeding phenology and success Figure e\u2013t. SeasSustained seasonal increases in nest survival rates Figure i can intWhen nest survival rates are low at the start of the season and either increase to a plateau Figure m or decrThus, replacement clutches can drive benefits of early arrival even when patterns of nest survival vary seasonally, and seasonal declines in recruitment probability can enhance benefits of early arrival and replacement clutches, even when nest survival rates increase through the breeding season.4Declines in breeding success with date of arrival date on the breeding grounds have been widely reported, and a range of potential drivers have been proposed , while very low nest survival rates lead to the majority of first nests and replacement clutches failing (again limiting the benefit of renesting). Our models did not include opportunities to achieve more than one successful nesting attempt within a season but producing multiple broods would be likely to produce similar benefits to early arrival as laying replacement clutches. The probability of laying replacement clutches is also likely to be influenced by length of the breeding season and consequently to vary with latitude. However, replacement clutches can occur even at high arctic latitudes replacement clutches delay offspring fledging Figure . QuantifA striking feature of migratory populations is that, despite the apparent benefits of early arrival on the breeding grounds, the timing of spring migration within populations is typically characterized by high levels of between\u2010individual variation but very low levels of within\u2010individual variation (individuals are typically highly repeatable in their timing of migratory journeys; Alerstam, Hake, & Kjell\u00e9n, 5In summary, early arrival of migratory birds on breeding grounds can potentially lead to higher reproductive success solely as a result of the greater time available for laying replacement clutches, should early nesting attempts fail. These patterns persist across a range of seasonal patterns in nest survival rates and even when later nesting attempts are less likely to produce successful recruits. These benefits of replacement clutches are most apparent at intermediate nest survival rates, as very high or very low rates of nest loss will render replacement clutches unsuccessful or unnecessary, respectively. Advances in the timing of spring migration are occurring in many species at present, and there is evidence for population declines being associated with a lack of these shifts in timing (Gilroy et al., None declared.All authors conceived the ideas and designed the methodology. CAM performed the simulation modeling and JAG and CAM led the writing of the manuscript. All authors contributed to the writing of the manuscript and gave final approval for publication.\u2009Click here for additional data file."} +{"text": "Breathing constantly adapts to environmental, metabolic or behavioral changes by responding to different sensory information, including afferent feedback from muscles. Importantly, not just respiratory muscle feedback influences respiratory activity. Afferent sensory information from rhythmically moving limbs has also been shown to play an essential role in the breathing. The present review will discuss the neuronal mechanisms of respiratory modulation by activation of peripheral muscles that usually occurs during locomotion or exercise. An understanding of these mechanisms and finding the most effective approaches to regulate respiratory motor output by stimulation of limb muscles could be extremely beneficial for people with respiratory dysfunctions. Specific attention in the present review is given to the muscle stimulation to treat respiratory deficits following cervical spinal cord injury. Experimental studies of respiratory modulation via peripheral muscles can be divided into two overlapping groups: (i) investigation of functional interactions between locomotor and respiratory neural circuits and (ii) studying the effect of muscle afferent activation on cardio-respiratory system during exercise.Many experimental studies have demonstrated that locomotion is functionally linked to respiration by coupling between central pattern generators (CPGs) for stepping and breathing . This coIn the experimental setup to study afferent inputs from limb muscles to respiratory system, activation of muscle afferents can be achieved by nerve, muscle or dorsal roots electrical stimulation as well as by passive or active limb movements or stretch .During experimental stimulations of limb muscle afferents, two major effects on respiration can be observed: entrainment of breathing and hyperpnoea. During entrained breathing the respiratory rhythm resets and follows the frequency of stimulus applied to muscle afferents , whereasThe supraspinal respiratory network is organized into several brainstem compartments that extend from the lower medulla to the pons have demonstrated inhibitory effect of hindlimb afferent stimulation on phrenic a rapid increase in total ventilation at the exercise onset; (2) a transient phase with a further continuous increase of ventilation; and (3) the final steady phase characterized by plateaued ventilation . The rapAnatomical and electrophysiological studies have shown that high threshold (III/IV type) muscle afferents have direct and non-direct projections to the lower brainstem including the NTS , reticulIn addition, polysynaptic ascending spinal pathways activated by somatic muscle afferents include the spino-reticular tracts. Spino-reticular neurons project to reticular structures in the vicinity of the ventrolateral medulla and can Stimulation of different muscles (hindlimb vs. forelimb or flexors vs. extensors) may have different effects on respiration during locomotion or exercise. Moreover, prior studies indicate that even activation of the same muscle can have inconsistent effects between animal species . This isHuman studies suggest that the magnitude of cardiovascular and respiratory response during exercise might depend on the mass of a muscle involved . TherefoAnother consideration is that, even within lower limb muscles, there is a specific pattern of distribution of different type fibers. Deep extensor lower limb muscles predominantly contain type 1 fibers when more peripheral muscles have a higher proportion of type 2 fibers. This is correlated with the recruitment of muscles during locomotion: deep muscles are activated during postural standing and walking, while peripheral muscles are activated through running and jumping . TherefoOverall, the published experimental results suggest that targeting the muscles with a larger mass and containing a higher proportion of type 2 fibers can be more effective to elicit cardio-respiratory responses. Worth noting again, however, is that type 2 fibers are more susceptible to fatigue .Therapies based on repetitive limb movements and stimulation are becoming more recognized in treating respiratory dysfunctions in people with different medical conditions. For example, upper limb exercising was incorporated in pulmonary rehabilitation for patients with chronic obstructive pulmonary disease (COPD) and demonstrated a reduction in dyspnea episodes . In indiClinical studies also suggest that stimulation of limb muscles may be employed for respiratory rehabilitation in people with spinal cord injuries (SCI). Repetitive activation of the impaired respiratory system by peripheral muscle stimulation might retrain spared neural networks (activity-based therapy) and improve their function post-SCI . This acHowever, cervical level SCIs are the most devastating and often impair the majority of motor functions below the injury, including paralysis/paresis of both, lower and upper limbs. Treadmill rehabilitation in tetraplegic individual represents a huge logistical and economic burden. Therefore, using FES of upper extremities in people with cervical SCI could be a more suitable alternative. This type of rehabilitation is non-invasive (cutaneous electrode placement), requires less personnel and can be applied in a home environment. Arm-cranking exercise assisted by FES is one oOverall, despite a significant number of experimental and clinical studies, the detailed mechanisms of respiratory control by stimulation of peripheral muscles in the intact and, especially, injured spinal cord are still unclear and require more thorough investigations. An understanding of these mechanisms will help to develop improved stimulation paradigms and devices for limb FES in combination with different exercises, targeting the most effective choice of muscles to enhance respiratory plasticity and recovery in individuals with cervical SCI and other respiratory dysfunctions. As neural engineering advances the field of neural interfacing, we can expect to see even greater improvements in these described results, with better strategies for improving breathing.NS, VM, and TB made a substantial contribution to the drafting, figure making and discussion of this work and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Introduction: Linear scleroderma en coup de sabre is a localised inflammatory disorder of the skin causing sclerosis in a linear distribution affecting the head and neck. We describe the case of a patient with progressive linear scleroderma en coup de sabre with unusual manifestations involving dental destruction and high T2 signal changes on magnetic resonance imaging (MRI) of the brain in the parenchyma below the area of scleroderma.Case description: This 36\u2009year old female first noticed an area of hair loss at 25\u2009years old and was referred to dermatology and diagnosed with linear scleroderma en coup de sabre. She had no systemic features of connective tissue disease and antinuclear antibody testing, anticentromere antibody and extractable nuclear antigens were all negative. Despite topical treatment the area of linear scleroderma progressed and the patient was commenced on penacillamine. A year after her initial diagnosis, she developed an abnormality of her gums and teeth and maxillofacial review identified right upper incisor periodontal loss and radiograph confirmed local bone loss. Histopathology of the upper labial gingivae showed atrophied stratified squamous epithelia and chronically inflamed collagenous connective tissue in keeping with linear scleroderma. Pencillamine was later discontinued due to pregnancy, and the skin changes continued to spread causing disfigurement. The patient underwent psoralen and ultraviolet A radiation (PUVA) treatment and multiple reconstructive surgical procedures. Systemic disease modifying treatment was retried with oral methotrexate under the care of rheumatology but unfortunately with no efficacy and was therefore later withdrawn. The patient began suffering with headaches at the time of her initial presentation in 1997 and underwent an MRI brain scan which was unremarkable. She went on to develop diplopia which was thought to be due to enopthalmos secondary to the local involutional soft tissue changes around the orbit. The patient then underwent a further MRI scan in 2013 due to ongoing headaches and poor memory which revealed ipsilateral high T2 signal changes in the right corona radiata down to the lentiform nucleus and in the right internal capsule, below the area of linear sclerosis. Neurological investigations in the joint neurology and rheumatology clinic including computer tomography (CT) angiography have been unremarkable and it is felt this area of abnormality in the parenchyma is another manifestation of her linear scleroderma en coup de sabre. She has ongoing intermittent headaches but no further neurological symptoms. She has had a number of repeat MRI brain scans which show no progression of the parenchymal changes, and she remains under close monitoring with a multitude of specialities including rheumatology, neurology, dermatology, ophthalmology and plastic surgery.Discussion: Linear scleroderma en coup de sabre is often considered to be a condition affecting the skin, in contrast to systemic sclerosis which has much broader manifestations in terms of other organ involvement. However this patient\u2019s case highlights the fact that this condition is not just skin deep but can affect underlying soft tissue, the orbit, teeth, bone and brain parenchyma. Involution of the cranial bones and hemifacial atrophy is a documented complication of linear scleroderma but dental complications are rarely reported in the literature. Ipsilateral changes on brain imaging have previously been reported in patients with linear scleroderma. Patients may present with seizures, headache or other neurological manifestations such as hemiparesis. Case reports describe oligoclonal bands in the cerebrospinal fluid of patients with such radiological changes, pointing towards an underlying inflammatory pathology. Inflammation has been confirmed in one case report in which a patient underwent brain biopsy showing low grade localised vasculitis, however other case reports describe sclerosis with no inflammation on brain biopsy. Intravenous steroids and cyclophosphamide have been used to successfully treat progressive neurological complications, in terms of symptomatic and neuro-radiological improvement, again suggesting an inflammatory pathology.Key Learning Points: This case highlights the importance of considering the wider manifestations of linear scleroderma en coup de sabre, including intracerebral pathologies when patients with this condition present with neurological symptoms and signs.Disclosure: J. Jade: None. M. Hadjivassiliou: None. M. Akil: None."} +{"text": "Lesbian, gay, bisexual, trans and intersex (LGBTI) people experience significant health inequalities. Located within a European Commission funded pilot project, this paper presents a review of the health inequalities faced by LGBTI people and the barriers health professionals encounter when providing care.A narrative synthesis of 57 papers including systematic reviews, narrative reviews, meta-analyses and primary research. Literature was searched in Cochrane, Campbell Collaboration, Web of Science, CINAHL, PsychINFO and Medline. The review was undertaken to promote understanding of the causes and range of inequalities, as well as how to reduce inequalities.LGBTI people are more likely to experience health inequalities due to heteronormativity or heterosexism, minority stress, experiences of victimization and discrimination, compounded by stigma. Inequalities pertaining to LGBTI health(care) vary depending on gender, age, income and disability as well as between LGBTI groupings. Gaps in the literature remain around how these factors intersect to influence health, with further large-scale research needed particularly regarding trans and intersex people.Health inequalities can be addressed via changes in policy, research and in practice through health services that accommodate the needs of LGBTI people. With improved training to address gaps in their knowledge of LGBTI health and healthcare, health professionals should work in collaboration with LGBTI people to address a range of barriers that prevent access to care. Through structural change combined with increased knowledge and understanding, services can potentially become more inclusive and equally accessible to all. Moreover, there is a significant lack of research regarding how to address these inequalities. Indeed, in 2016 this journal noted the need for greater international research to inform LGBT public health initiatives.Therefore, this global review was undertaken as part of an EU-funded pilot project that aimed to explore the sources of and modalities for reduction of LGBTI health and healthcare inequalities by determining: (i) what are the causes of LGBTI health inequalities? (ii) What is known about the health inequalities faced by LGBTI people as it relates to healthcare settings? (iii) What is known about the health inequalities of LGBTI people on vulnerable intersections ? (iv) What are the potential barriers faced by health professionals when providing care for LGBTI people and how can these barriers be addressed?A narrative synthesis design was used to search global literature systematically. This design was chosen due to the complex exploratory nature of the review which aimed to establish \u2018what is known\u2019 about LGBTI health and healthcare inequalities as well as produce a synthesis of current thinking that cuts across the field offering new perspectives and new areas for further research, training and policy development. Whilst such a review may not necessarily provide answers to addressing explicit health problems in given settings, it can nevertheless help policy makers, researchers and practitioners address concerns that occur across the data.Systematic searches were carried out using six electronic databases . Additional databases were excluded to prevent duplication. Google Scholar was searched in English and the references of included papers were then checked to identify further relevant articles.Database searches were conducted using various combinations of key words and MeSH terms for the three main areas of interest: health inequalities, the study population (LGBTI people) and health professionals .Although some of the search terms used medicalize and or pathologize sexualities, gender identities and sex characteristics, these terms were included to ensure the broadest coverage and to expand retrieval. To maximize the number of relevant studies, literature searches were conducted in two parts see focussinPapers were considered for inclusion if they: (i) were primary research studies; (ii) reviews, systematic reviews or meta-analyses; (iii) were published from 2010 onwards to ensure the most recent studies were captured ; and (iv) were published in English. All editorials, commentaries, non-research and theoretical papers were excluded.Eligibility for inclusion was assessed initially (by the first author) by screening all identified papers and reports based on titles and abstracts. The full text was then obtained for all selected articles and a second screening performed to determine final eligibility was agreed between the first and second author. Any discrepancies/disagreements were resolved in consultation with the third author. The data extraction process is summarized in The first database search on health inequalities and LGBTI people cultural and social norms that preference and prioritize heterosexuality;,,,,Health inequalities occur in a context where heterosexuality prevails as the norm.,,,,,,,Discrimination and prejudice sanction the behaviour of those who deviate from commonly accepted norms. The impact of discrimination is described in minority stress theory, the leading narrative explaining the health inequalities of LGBTI people.,Health inequalities were experienced differently between LGBTI groups and spanned both physical and mental health. LGB people reported significantly worse physical health compared to the general population with gay men showing an increased incidence of long-term conditions that restricted their activities of daily living. Conditions included musculoskeletal problems, arthritis, spinal problems and chronic fatigue syndrome,,LGB people are at a higher risk of developing certain types of cancer at a younger age.,,In relation to mental health, significant inequalities exist with LGBT people being twice to three times more likely to report enduring psychological or emotional problems compared to the general population.,,,Whilst accessing treatment and care, LGBTI people were more likely to report unfavourable experiences. General concerns were around communication with health professionals and overall dissatisfaction with treatment and care provided.,Like LGBT people, some intersex people experience isolation due to stigma, discrimination or rejection from others.,,In contemporary health and social care literature, it is well understood that there is a strong relationship between the social determinants of health inequalities and health outcomes.,Health professionals faced a range of challenges when caring for LGBTI people including heteronormativity where heterosexuality is upheld as the status quo or gender normativity where the male-female binary is retained as the norm.When LGBTI people were recognized, or their lives and partnerships were acknowledged, they were more likely to be open and disclose their identity (\u2018come out\u2019) or to share relevant health-related information.,,,,,,,,,Further barriers occurred where health professionals lacked appropriate knowledge regarding the lives and related health needs of LGBTI people or where health professionals lacked the appropriate culturally specific skills necessary to meet their needs.This review has established \u2018what is known\u2019 about the health inequalities of LGBTI people and where change in practice or further research is needed. By identifying these gaps, the findings and recommendations can be of value for health policy makers, practitioners and researchers to help reduce these inequalities.,,,,,,,,Recommendations stemming from this review include the need to address high rates of anal cancer in gay and bisexual men, by introducing anal screening programmes to ensure early detection.,,,,,,,Very little research specifically considers how more than one factor intersect to influence the health outcomes of LGBTI people. Further research is needed to understand fully and document the potential impact of intersectionality. Where this kind of research did exist, studies showed that living in rural areas, being on a low income,,,,,,,,,,,,,Key but achievable changes are needed in healthcare to address the barriers that prevent access to care.This review has made an important contribution to the field of health inequalities experienced by LGBTI people. Nevertheless, two key limitations should be noted. First, as a narrative synthesis, studies included were not assessed for quality and thus caution must be applied regarding interpretation and generalizability. Second, some of the studies reported in this review combined health profiles for lesbian and bisexual women, or gay and bisexual men or LGB people without considering the health inequalities of each individual group. In other words, our analysis revealed that studies commonly collapsed sexual minorities into a single group. Although combining data can be useful for analytical purposes, it may blur important issues specific to distinct groups and in some cases it was not possible to tease out such distinct issues. Future research designs should differentiate between LGBTI people to ensure analysis can be conducted separately without presuming their issues are the same in ways that neglect intersectional differences.cky226_Supplementary_DataClick here for additional data file."} +{"text": "A voluminous literature empirically proves the significant relationship between social participation and elderly mental health. Further analysis discovers the different behavior between rural and urban elderly. Despite the importance of taking into account regional inequality, gender disparity which explains the inconsistent empirical results across countries, is sometimes negligible from the discussion. This study aims to investigate the link of social participation in voluntary activity and community regular meeting to depressive symptom among the elderly in Indonesia. Separated analysis based on gender is also conducted to examine the extent to which social activities could explain the depressive symptom disparity between male and female elderly. Data from Indonesia Family Life Survey 2007 and 2014 were analyzed using logistic regression. Sample of 2994 and 2917 respondents aged 60 and over in 2007 and 2014 respectively are combined as pooled cross-sectional data instead of panel data to deal with the large reduction of sample size due to mortality. To minimize the potential endogeneity, covariates are included in the model such as residence location, living arrangement, socio-economic status, and health condition. The results indicate that economic condition, chronic disease, and difficulty on instrumental activity daily living (IADL) play a significant role in depressive symptom among Indonesian elderly, regardless of the gender. Surprisingly, social participation that is widely believed in strengthening mental health is statistically significant for female sample only. Moreover, the contrast sign of voluntary participation and community regular meeting coefficients indicate a special behavior between these two activities."} +{"text": "Honey bees are one of the treasures in the world. An increase of waveform communication leads to good information exchange ofmankind. In the biological view, it causes a lot of side effects and lifestyle changes in other living organisms. The drastic changes arecausing the natural imbalance in the ecosystem and become a global issue. There are significant reasons for bee colony collapse disorder(CCD) like pesticides, disease and climate change. Recent studies reveal that a cell phone tower and mobile phone handset are also causingside effects to honey bees due to radiation emission. Most of the researchers concentrated on biological and behavioral changes in a honeybee due to radiation effects. For that, the real-time radiation levels have experimented but the different technical perspectives such asradiation emission levels, handset radiation emission measures and multi-sources of radiation are needed to be considered during research.This study aimed to provide possible research extensions of colony collapse disordercaused by cell tower and mobile handsets. Honey bees are small insects which play a vital role in agriculture.Honeybees are essential partners of pollination for successful yieldin agriculture. Recent declines in honey bee populations andincreasing demand for insect-pollinated crops raise concerns aboutpollinator shortages. It happens due to pesticides, monoculturalcrop practices etc. The existing experimental studies contributed much more in CCDresearch area. The overall work investigation is classified in threemajor categories namely honey bee radiation study in hives, theimpact of the life cycle of honey bees caused by EMF radiation,CCD caused by cell towers.The first criteria are well explored and the studies confirmed theradiation effects arepossible for CCD due to mobile handsets. Thewaggling dance, foraging, and navigation behavior of honey beesare destructed due to radiation emission of mobile phones. Iselectromagnetism one of the causes of the CCD? A work plan fortesting this hypothesis, Marie-Claire Cammaerts (2017) Study of radiation influences in a life cycle of honey bees:Most of the studies focused on behavioral change in honey beesdue to EMF radiation. Some significant contributions are in queenand its hatching measures. Changes in honeybee behavior andbiology under the influence of cell phone radiations,VedParkashSharma and Neelima R. Kumar (2010), made a significant study ofhoney bees during radiation exposure and revealed remarkableoutcomes of their work Only a few of the studies are done about EMFradiation in celltowers. The cell tower and multiple cell towers in the same locationcan have the possibility of colony collapse. The mobile phone withrespect to its density and battery level also be considered. For thatSAR and Connect values will be used as the measuring parameters.Effect of electromagnetic radiations on brooding, honey productionand foraging behavior of European honey bees, Pramod mall andYogeshKumar 2014) made an experimental study and resulted thatthere is an insignificant change in honey bee colony byelectromagnetic radiation made an Based on the several experimental studies the following possibleresearch areas can be explored in technological view.Most of the studies concentrated in EMF radiation of Mobilehandsets with CCD. The EMF emission of cell towers must beconsidered as a serious problem and lot research is needed in thatarea. Multiple cell towers installed in the same location is alsoconsidered. Whereas each tower may emit radiation in permissiblelimits but overall radiation should be measured and CCD issue tobe explored. Cell towers with high-density population producehigh radiation in both cell towers and mobile phones.Radiation Emission of Mobile handsets and Battery powerThe mobile handset with less battery power and low signal rangecauses high radiation exposure. The distinct tower location areas,especially in forest areas must be explored. Experimentation shouldbe done periodically during radiation and some studies done onlywith mobile handsets nearby hives.The radiation shielded honey boxes may use to protect the hivesfrom high radiation exposure. The other preventive mechanismsare also being considered like planting Trees and gardens. The lessnumber of trees and plants insists bees to collect honey from longdistances. Hence it is affected by environmental factors and failedto return their hives. If trees are available in frequent distances,then it can be avoided. The urban areas can be gardened in publicareas like park etc.Daniel Favre (2017), an Independent researcher revealed that theexperimental data about CCD and honey bees research with respectto EMF must be shared and contributed to the researchers forfurther exploration of research in that area. The experimental datacan be used as a data set to predict accurate results usingcomputation techniques. Another important point is experimentaldata are the strong shreds of evidence for radiation occurrence sothat the impact of radiation can be known to the society. The dataset can be stored in public storage medium as online databases or incloud storage. So, that it is available and accessible globally.The present investigations were undertaken significant studies inCCD and radiation effects. The perspective of this proposed studyto enable researchers to extend their research work from atechnological point of view. The existing studies show bothnegative and non-negative impacts of radiation. whereas the nonnegativestudies need to confine that there is standard provenevidence for the destruction of bee colony due to radiation. Whenthe studies have supporting data with technological evidence thenit can be considered as a blueprint for researchers and socialworkers to insist the authorities to standardize the regulations tocontrol and maintain the radiation emissions by cell towers andmobile handsets."} +{"text": "Despite the value of spinal cord stimulation (SCS) in treating some patients with focal neuropathic pain, technological advances in stimulator design and treatment protocols have not correlated with significant improvements in clinical outcomes. This may be because incomplete understanding of the mechanisms underlying SCS precludes improvement in clinical efficacy. In this brief review, we (a) review phenomenological effects of SCS, (b) review the literature on proposed spinal sites of action of SCS and (c) propose a novel hypothesis of mechanism of action.Dorsal columns, dorsal roots and dorsal horns have each been proposed as spinal sites of action of SCS. We suggest that evidence in favour of the dorsal columns or dorsal roots as the primary mediators of SCS is weak and propose that the dorsal horn is the crucial site of action. Furthermore, we hypothesize that, based on their location, and neurochemical and morphological properties, dorsal horn islet cells may mediate the effects of SCS.The precise spinal mechanisms of action of SCS are still unknown. Dorsal horn islet cells have properties that position them to play a key role in analgesic effects of electrical stimulation. Understanding the mechanisms responsible for positive SCS effects are needed for successful translation into clinical dividends.We review possible spinal mechanisms of action of spinal cord stimulation for neuropathic pain, proposing that direct modulation of dorsal horn neurons is crucial. We suggest that mechanistic insights are needed for translation into more favourable clinical outcomes. There are many unanswered questions raised by this hypothesis that can start to be addressed using methodologies in rodents once islet cells can be genetically targeted (like other spinal cord neurons, e.g. Chopek et al., 3The general phenomenology of neuropathic pain in patients and the therapeutic effects and limits of SCS for the treatment of neuropathic pain have been well described. To advance electrical stimulation therapies further, animal models aimed at studying neuronal circuits underlying neuropathic pain and how these circuits are modulated by SCS will undoubtedly provide invaluable understanding (see Linderoth and Foreman, None.RMB and MPJ worked together to identify studies relevant to the topic and draft the manuscript. RMB designed the study concept, and critically revised the manuscript."} +{"text": "The field of patient safety in surgery has seen dramatic improvements in the new millennium . OngoingAs of today, there remains a critical gap of knowledge in many of these areas. For instance, we must learn more about our patients\u2019 nutritional behaviors, diagnostic measures to identify specific nutritional deficits, and the efficacy of nutritional interventions. Over the last decades, the surgical community has made great strides in developing safe surgical techniques allowing for the successful treatment of many surgical conditions, which prior had to be left untreated. Looking forward, we must retain a strict focus on quality research and innovative strategies aimed at further minimizing the risk of postoperative wound complications as we are striving to improve surgical outcomes and patient safety in surgery."} +{"text": "The majority of U.S. older adults are overweight or obese. Social relationships are a key factor linked to obesity among younger age groups, but there are no known investigations of these modifiable risk factors older for adults. This study examined the association between quantitative and qualitative indicators of social relationships and waist circumference among middle-aged and older adults. We also examined whether psychosocial and health behavior characteristics mediate and/or moderate these relationships. Using the 2006 and 2010 waves of the Health and Retirement Study, a series of regression models were estimated to examine the longitudinal association between social relationships and waist circumference in age stratified samples . Results for those age 50 to 64 indicated that higher positive social support and lower negative social support were associated with lower waist circumference over time. For those age 65 and older, lower negative social support and higher loneliness were associated with lower waist circumference over time. Further, daily exercise and anxiety were observed to be mediators of these associations; both variables also acted as moderators. Findings from this study highlight the need for healthcare providers to assess older adults\u2019 levels of social support and loneliness in order to achieve a more comprehensive understanding of wellness. The results also underscore the importance of developing intervention programs that provide widespread and ample opportunities for older adults to engage socially, particularly those that incorporate or encourage physical activity and healthy eating."} +{"text": "Community health workers can play an important role in health education and ante-natal care that will help reduce the number of preterm births. As members of their communities, they are best placed to advise and support parents and extended families in reducing the risk of ROP and visual loss.Preterm births are an important public health concern worldwide due to the resultant morbidities. Survival of premature babies has improved largely due to improved neonatal care services. However premature infants are at greater risk of cerebral palsy, developmental delays, hearing and vision related issues.Retinopathy of prematurity (ROP) remains one of the leading causes of childhood blindness worldwide. Recent estimates show that worldwide 32,000 infants become blind or visually impaired due to ROP. Most of the ROP blind infants are born in countries in Asia.Community health workers are members of communities where they provide preventive, promotional and rehabilitation care to other members. The community health workers in India areAuxiliary nurse midwife (ANM)Anganwadi worker (AWW) andAccredited social health activist (ASHA worker).They play a crucial role in the health care system especially in maternal and child health care and thus can help in prevention of blindness due to ROP.Commonly known as ANM, they are a village level female health worker who is the first contact person between community and health services. ANMs are regarded as the grassroots workers in health organisation pyramid.Anganwadi centers are government run mother and child care center in villages in India. The anganwadi workers ensure antenatal and postnatal care for pregnant women, nursing mothers and immediate diagnosis and care for new born children. Monitoring regular health and medical check-ups for women and children is one of their key responsibilities.ASHA workers are local women trained to act as health educators and promoters in their communities. Their tasks include motivating women to give birth in hospitals, bringing children to immunisation clinics, encouraging family planning, treating basic illness and injury with first aid, keeping demographic records and improving sanitation.Community health workers serve as a key communication pathway between the healthcare system and the rural population, especially in reducing preterm deliveries and in prevention of ROP in babies born too soon. Preterm deliveries can be reduced by working on modifiable risk factors such as maternal nutrition, pregnancy planning, birth spacing etc. ROP blindness can be reduced by expanding and improving screening and treatment services at medical colleges and district hospital sick newborn care units (SNCUs) and neonatal intensive care units (NICUs). The community health workers play a key role in preventing ROP blindness in three different stages:Reducing preterm deliveriesPrevention of ROP in preterm babiesScreening and treatment services for ROPChild marriage has lasting consequences on girls, from their health, education and social development perspectives which often last well beyond adolescence. It has been found that teenage mothers are three times more likely to deliver preterm babies and twice as likely to deliver low birth weight (LBW) babies compared to older mothers (21 Yrs to 34 Yrs).It is likely that when the space between births is short, there will be depleted nutrition in new mothers, as these women do not get enough time to recover before getting pregnant again. Therefore, after a birth, the interval before attempting a new pregnancy should be at least 24 months to reduce the risk of adverse maternal and infant outcomes.Maternal undernutrition is still a major problem in India. In populations with food insecurity and high rates of maternal undernutrition, balanced protein energy supplementation may improve foetal growth and reduce the risk of foetal and neonatal death.Prenatal maternal stress, depression and anxiety are found to be related to preterm labour.ASHA workers can help in educating pregnant women about regular antenatal check-ups and the importance of periodic follow-up. This aids in monitoring for hypertension, diabetes, infections etc, which if properly managed may reduce preterm deliveries. The community health workers play a role in birth preparedness which consists of preparing the mother, family and community for delivery and potential complications. They should encourage and increase the percentage of hospital deliveries which are safe for the mother and child.With a preterm birth, the focus shifts to prevention of ROP and other morbidities. A well- trained health worker anticipates and prepares to minimise the morbidities that may ensue. Risk factors like poor weight gain, infection etc if tackled properly can prevent ROP related childhood blindness.A significant reduction in the risks of mortality, respiratory distress syndrome and intraventricular haemorrhage have been confirmed after administering antenatal steroids in babies delivered before before 34 weeks gestation.It has been found that exclusive breastfeeding for six months starting within an hour after birth may prevent ROP. Health workers can help in explaining to mothers the importance and advantages of exclusive breast feeding. There are several significant short term and long term benefits of breastfeeding preterm infants. Neurodevelopmental outcomes are also proven to improve with early and exclusive breastfeeding.As sepsis in preterm infants leads to increased risk of ROP, infection control procedures like personal hygiene can be clearly explained to mothers. Small yet significant measures such as bathing regularly and washing all clothes used for the baby can be easily explained to the mothers in the local language. Educating family members along with the mother on washing hands thoroughly before touching the baby and keeping surroundings clean help in keeping infections under control.Hypothermia is another concern in the management of pre-term infants. Kangaroo mother care (KMC) involves direct and continuous skin to skin contact between infant and mother. It helps in preventing hypothermia, improving weight gain and reducing incidence of infection. The procedure and benefits of KMC when explained clearly to the mothers, help in improving survival and decrease ROP. Along with KMC, the ASHA workers can also show proper swaddling of babies and keeping babies warm.Community health workers should be made aware that all the babies born too soon (<34 weeks) and small (<2000grams) who have been admitted to SNCU/NICU should undergo first eye screening for ROP before 30 days of birth. They are best placed to motivate parents to take their preterm infant for ROP eye screening to a trained ophthalmologist nearest to them. Educating parents about the disease with the help of visual aids like flash cards or posters of the disease and how it leads to blindness helps in reaching out to illiterate population in a better way. Health workers can also encourage parents to take the baby for ROP screening before they are 30 days old.Community health workers can help parents understand that ROP is a disease with a narrow time period between detection and treatment and that treatment cannot be delayed. Counselling parents and their families about laser photocoagulation can also be done by a community health worker.The most common challenge faced in management of ROP is lack of compliance and follow-up. Though the initial screening is done when the baby is in NICU, parents especially in rural areas do not come back for follow-up. As ROP is a disease which requires multiple visits the ASHA workers can help in tracking pre-term infants in their communities and motivating parents to go for follow up visits. Educating parents about long term effects a pre-term birth can have on the eyes is also important, to encourage them to attend for follow up. Simple language must be used in training the ASHA workers so they can effectively counsel parents.Community health workers can play an important role in health education and ante-natal care that will reduce the number of premature babies born. They also have an important role in advising and supporting the mothers of preterm babies in order to reduce the risk of ROP and visual loss."} +{"text": "Respiratory motor failure is the leading cause of death in spinal cord injury (SCI). Cervical injuries disrupt connections between brainstem neurons that are the primary source of excitatory drive to respiratory motor neurons in the spinal cord and their targets. In addition to direct connections from bulbospinal neurons, respiratory motor neurons also receive excitatory and inhibitory inputs from propriospinal neurons, yet their role in the control of breathing is often overlooked. In this review, we will present evidence that propriospinal neurons play important roles in patterning muscle activity for breathing. These roles likely include shaping the pattern of respiratory motor output, processing and transmitting sensory afferent information, coordinating ventilation with motor activity, and regulating accessory and respiratory muscle activity. In addition, we discuss recent studies that have highlighted the importance of propriospinal neurons for recovery of respiratory muscle function following SCI. We propose that molecular genetic approaches to target specific developmental neuron classes in the spinal cord would help investigators resolve the many roles of propriospinal neurons in the control of breathing. A better understanding of how spinal circuits pattern breathing could lead to new treatments to improve breathing following injury or disease. Respiratory failure is the leading cause of death in spinal cord injury (SCI) . For example, activation of fictive locomotion in isolated brainstem/spinal cord preparations can cause an increase in phrenic burst frequency as well as entrainment of locomotor and respiratory periods through its effects on spinal neurons of the locomotor CPG as well as coupling the respiratory and locomotor cycles derived propriospinal neurons as a potential therapy to restore respiratory motor function. For example, iPSC derived V2a and V3 neurons have been generated from mouse or human cells as well as the regularity of motor bursts specific classes of propriospinal neurons have been valuable tools to investigate the function of neurons within circuits. These tools will continue to be useful as we investigate mechanisms of neuroplasticity that promote recovery of function following injury. Overall, a better understanding of the circuitry that controls breathing in uninjured animals and the changes that occur following injury should lead to new therapies to improve breathing.SC, WA, and VJ wrote the article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Recently, researchers have been exploring successful aging in rural communities of Alaska as it is experienced by Alaska Native Elders. Due to outmigration based on economic, medical, or familial influences, many Alaska Native elders leave their home communities to live in urban settings in Alaska, even though research suggests that most elders would like to remain in their home communities to grow old. Very little is known about the relocation process and how it impacts an elder\u2019s views on successful aging. While established protective factors in rural communities involve family and extended family members, community, subsistence, and traditional activities, there is little knowledge of which protective factors exist in urban settlements supporting successful aging. This exploratory, qualitative study presents the protective factors of successful aging in the context of relocation of Alaska Native Elders from rural to urban dwellings. A life course approach and discourse analysis were used to analyze individual interviews asking how Alaska Native Elders experienced relocation and how successful aging was experienced similarly and differently in rural and in urban settings. A community-based participatory approach allowed for collaboration between researchers and communities as equal partners at all phases of the process, both contributing their expertise to enhance understanding of successful aging and supportive factors. Access to informal supports and meaningful community engagement were more important to rural Elders, and access to health care services and family engagement were important to Elders in urban communities. Challenges remain for Elders in urban environments to establish a sense of community."} +{"text": "To the author's knowledge, this is the first reported case in the literature of a supraseptal ethmoid sinus cell, located between the nasal septum and ethmoid roof. Such a cell, while rare, should be recognized and dissected carefully to prevent skull base injury and cerebrospinal fluid leak. Variant cells such as Onodi, Haller, and Kuhn cells can present a challenge when performing sinus surgery. Herein, we present a previously undescribed ethmoid cell lying superior to the nasal septum and inferior to the ethmoid roof.To the author's knowledge, this is the first reported case of an ethmoid sinus cell superior to the nasal septum and inferior to the ethmoid roof/ethmoid skull base. The previously described ethmoid sinus cells, including Onodi cells ,Herein, we report a male patient with chronic rhinosinusitis and a left supraseptal ethmoid sinus cell who underwent functional endoscopic sinus surgery. Preoperative imaging demonstrated the cell and intraoperative navigation combined with careful endoscopic dissection facilitated thorough dissection of the cell without injury to the overlying ethmoid skull base.2A Hispanic male patient in his mid\u201050s presented with chronic rhinosinusitis symptoms including postnasal drainage, facial pressure, and nasal congestion. He was treated with maximal medical therapy including 21\u00a0days of oral antibiotic therapy and intranasal steroids and had persistent symptoms at a follow\u2010up visit. Post\u2010treatment imaging demonstrated mucosal thickening in the maxillary and ethmoid sinuses consistent with chronic rhinosinusitis. The computed tomography (CT) of the sinuses also demonstrated an unusual supraseptal ethmoid sinus cell pneumatizing into the area between the superior aspect of the midnasal septum and the ethmoid roof. Figure During the endoscopic sinus surgery, the left supraseptal ethmoid sinus cell was identified Figure . The cel3A thorough knowledge of paranasal sinus anatomy and associated anatomical variations is necessary to avoid incomplete dissection and complications when operating on the paranasal sinuses via the endoscopic approach. Familiarity with the ethmoid air cells and their variations helps prevent injury to nearby structures such as the anterior and posterior ethmoid arteries, the cribriform plate and fovea ethmoidalis, the orbital floor, and the optic nerves.The ethmoid bone develops from the nasal capsule via ossification of the perpendicular plate of the ethmoid and the bilateral ethmoid labyrinths.As with other well\u2010described variant ethmoid cells, the supra\u2010ethmoid sinus cell is clinically significant as its superior boundary is the central ethmoid skull base. Its unusual location makes recognition of this cell important, as dissection through the superior aspect of the supraseptal ethmoid cell may result in leakage of cerebrospinal fluid through the central ethmoid roof. Adequate dissection of the supraseptal ethmoid cell, if diseased or opacified, prevents persistent opacification of the cell or obstruction of posterior ethmoid cells by the supraseptal ethmoid cell.To our knowledge, this specific ethmoid variant cell has not been previously described in the literature. In reviews of hundreds of preoperative maxillofacial CT scans, this patient had the single example of this particular ethmoid sinus cell noted by this author. The location of this particular ethmoid cell variant inferior and medial to the anterior ethmoid artery should be noted to avoid injury to the anterior ethmoid artery as it crosses the ethmoid roof Figure F. The ceNone declared.MRG: fulfilled the criteria and should qualify for authorship. MRG: conception and design, data acquisition, drafting the manuscript, and approving the revised and final version of the manuscript. The author has managed the manuscript submission process.This case report was determined to be exempt by the SUNY Upstate Institutional Review Board. The patient gave informed written consent to publish de\u2010identified information and clinical and radiographic images."} +{"text": "Objective: To describe an infrequent instance of sphenoid sinus mucocele presenting as retrobulbar optic neuritis and highlight the value of imaging in the diagnosis and treatment plans.Methods: A woman aged 26 noted a sub-acute decrease in vision in the right eye, which mimicked optic neuritis. Magnetic resonance imaging (MRI) indicated a large mass in the sphenoid sinus, which was in favor of mucocele. Results: Endoscopic sphenoidotomy and marsupialization of the mucocele were carried out, and the diagnosis was confirmed by pathology. The patient was also administered a high dose of corticosteroid, upon which progression of the disease was halted. Unfortunately, no significant improvement in vision was achieved.Conclusions: This report emphasized the important role of imaging in differentiating between different causes of optic neuropathies. A high level of clinical skepticism along with appropriate imaging studies can help diagnose rare causes. With timely management, gratifying results may be achieved. They are frequently misdiagnosed and can result in complications because of their vicinity with important structures. Their most common presentation is headaches and the second common is visual disturbance (65%) [2]. Further complications are ocular palsy , exophthalmos, and pituitary gland dysfunctions in rare cases. We describe an unusual incident of sphenoid sinus mucocele masquerading retrobulbar optic neuritis.Sphenoid sinus mucoceles occur infrequently and have a prevalence of one percent of all paranasal sinus mucoceles . Also, a compressive effect of the posterior ethmoid or the sphenoid sinus\u2019s mucocele on the optic nerve can cause optic neuropathy. In Sphenoid mucocele, the vision deficit may be due either to the accumulation effect of the enlarging mucocele resulting in a disruption in the blood stream of the optic nerve or to the involvement of the optic canal causing unilateral, gradually proceeding to loss of vision, which can result in optic degeneration [4-6]. Other potential causes of optic neuritis during sinus diseases are allergic reactions and autoimmune demyelination of the optic nerve as a result of infectious organisms [4]. The function of paranasal sinus in the occurrence of optic neuritis is controversial. Sinusitis and mucoceles can cause optic neuritis by theoretically numerous ways. One is the direct spread of inflammation to the optic nerve via bony structures of sinus cavity neighboring with optic nerve dural sheath [7].Computed Tomography (CT) scan is necessary for evaluating the optic canal and the adjacent paranasal sinuses in patients with sinus diseases accompanied with visual disturbances. In CT-scans we can find signs of sinusitis, abscesses formation, mucoceles or any dehiscences or destructions in posterior sinus walls [8]. It presents as a cystic homogenous lesion in relation to the paranasal sinuses. MRI is essential to find the extent of the mucocele as well [7]. Orbital MRI of our patient indicated a homogenous cystic lesion in the right sphenoid sinus with invasion to the sinus walls and optic nerve, which was suggestive for mucocele.A bulky mucocele generates a typical radiographic feature of an engorged deformed sinus with a bony defect showing a protrusion into the adjoining structures. MRI image of the nose and paranasal sinuses is vital to corroborate the diagnosis of mucocele [9]. In 2008, Pelaz et al. presented two cases of reversible optic neuritis due to sphenoid sinus disorders, which reverted in one case with surgical treatment and in the other with steroid-based treatment [10]. In 2012, Gupta et al. reported an instance of retrobulbar optic neuritis attributable to sphenoid sinus mucocele. In this case, early surgical excision of the mucocele brought about thorough recuperation from the lesion and improvement in contrast sensitivity and visual field [11]. In 2013, Sharifi et al. reported three instances of sudden blindness as a result of isolated sphenoid sinus mucocele and retention cyst. After the endoscopic removal of the mucoceles, total vision and visual field recovery in two cases and partial recovery in the third were achieved [12]. In 2014, Selvakumar et al. presented a rare instance of sphenoethmoidal mucocele leading to bilateral optic neuropathy and unilateral sixth nerve palsy. After the surgical excision of the mucocele, the vision was recovered and they observed thorough resolution of the sixth nerve palsy [13]. Any surgical approach should focus on reducing the size of mucocele to reduce the compressive effect of the lesion on the optic nerve. Treatment involves marsupialization or surgical excision of the mucocele, often resulting in rapid secession of some ophthalmic manifestations especially third nerve palsy, but with a smaller effect on visual impairments [9]. Regarding our patient, she had a small improvement in visual acuity throughout the follow-up period (from count fingers at forty centimeters to one meter) and mild visual field improvement in the right eye. However, after three months of her clinical presentation, optic atrophy arose in the affected eye, regardless of medical and surgical therapy of mucocele and optic neuritis.Unfortunately, the visual acuity and visual field defects rarely improve after mucocele surgical removal and only one fifth of the patients with visual impairment due to sphenoid sinus mucocele experience improvement of visual acuity to > 20/ 40 after surgery, during follow-up visits. But early surgical excision is necessary to limit the visual impairment complications [There are few case reports regarding optic neuropathy due to sphenoid sinus mucoceles. Prompt diagnosis, referral, and treatment could recover the optic neuropathy and the vision may improve, but when the proper treatment is delayed, the prospects will not be promising. Neuroimaging studies ought to be supposed vital in cases of retrobulbar neuritis even in the incidence of a solitary typical feature."} +{"text": "The positive association between midlife occupational complexity and cognitive functioning in older age is well documented. Much less is known about the underlying neural mechanisms and whether occupational stress may accelerate neurocognitive aging. According to the BOSS model , occupational exposures may serve as long-term protective and risk factors that influence the rate and extent of neurocognitive decline in aging . We present findings from three independent samples linking different occupational exposures with brain volume in cognitively healthy older adults. We discuss the findings in the context of cognitive reserve and brain maintenance. Our findings suggest that occupational activities need to be acknowledged as an important factor in lifespan cognitive and brain development and warrant further research, with a possible outcome of workplace interventions aimed at optimizing neurocognitive aging."} +{"text": "Heliconius butterflies, Heliconius melpomene and H. cydno. They identified three small genomic regions highly associated with mate preference, one of which was adjacent to a gene for the preferred trait, and two of which were not. Their findings illustrate that mate preference may be influenced by a small number of genes, while providing support for multiple hypotheses for the genetic architecture of assortative mate preferences.Animals display an astonishing array of diverse colors and patterns, and animals also exhibit preferences for these diverse, species-specific traits when choosing a mate . It is hypothesized that in order for both preference and trait to be species specific, alleles for a trait and the preference for that trait must be inherited together and hence maintained as linked loci. This linkage could be maintained by three different genetic architectures: (A) the genes responsible for a species-specific preferred trait also directly influence preference for that trait; (B) genes producing preference and the preferred trait are not identical but are instead in close physical proximity in the genome; and (C) genes for preference and the preferred trait are nonadjacent but are inherited together due to selection. Merrill and colleagues test these hypotheses by performing large-scale genetic mapping of mating behavior using hybrids of two sympatric species of This Primer explores how a study of courting behavior in Heliconius butterflies sheds light on the genetic architecture of reproductive isolation, and provides new insights into the often elusive genes for mate preference. Humans have been interested in describing and defining species since the days of Aristotle. For the last millennia, two questions related to species delimitation and speciation that have plagued scientists are which animals choose to interbreed, and why animals that could interbreed choose not to do so. One behavior often associated with the maintenance of species boundaries is assortative mate preference, in which individuals preferentially mate with individuals of the opposite sex that share a number of common characteristics \u20133. TheseBecause assortative mate preferences often play an important role in speciation, the traits used by individuals to select mates are often species specific and tend to coincide with traits we (humans) use to delimitate species. Such species-specific traits are generally heritable and genetically determined, which makes identifying the genes responsible for their variation relatively straightforward. However, the traits used in mate selection are only half of the assortative mating story. Determining causal genetic variation for observed variation in mating preferences, the other half of the assortative mating tango, has proven much more difficult.One challenge in identifying genes underlying variation in mate preference is that the trait is inherently transient, because it is only expressed, and can therefore only be measured, when an individual is actively seeking a mate . Moreover, mate preference itself is wonderfully complex, with individuals considering combinations of multiple desirable traits when selecting a mate . TherefoHeliconius butterflies. Over the last 20 years, a handful of studies in Drosophila have illustrated how species-specific genetic variation can lead to species-specific variation in mate preference, providing confirmation that genetic variation may underlie observed species-specific variation in mate preferences and subsequent assortative mating . Therated by .Simultaneously, population geneticists and evolutionary biologists studying morphological variation in sister and incipient species have developed three hypotheses for the genetic architecture underlying genes for mate preference and genes for the traits animals prefer ,3,5,12. Heliconius butterflies to identify small regions of the genome highly associated with assortative mate preference (quantitative trait loci [QTLs] of large effect) in male H. melpomene and H. cydno butterflies. In these butterflies, males use the visual appearance of female wing patterns to determine which individual to approach and court. Avian predators also use the visual appearance of Heliconius wing patterns to assess potential butterfly toxicity and determine prey choice [H. melpomene males preferring females with red bands on their forewings, and H. cydno males preferring females with white bands on their forewings [optix being largely responsible for the presence or absence of red on the forewings of H. melpomene [aristaless 1 being largely responsible for the presence or absence of white on the forewings of H. cydno [WntA and cortex, are also known to influence color patterning in the wings of these butterflies [Here, Merrill and colleagues take advy choice , making orewings Fig 1D)Heliconiuelpomene , and ariH. cydno . Two othterflies ,24 and tAlthough it may seem unrealistic to expect a single gene to influence both preference and preferred trait, wing color patterning genes in butterflies are particularly good candidates for this role. Wing color patterning genes in butterflies influence pigment production and placement . SomH. melpemene and H. cydno butterflies. They then crossbred H. melpomene and H. cydno butterflies and tested the preferences of hybrid males. Lastly, they made careful use of the offspring of backcrosses (offspring of hybrids paired with either purebred H. melpomene or H. cydno) to facilitate the identification of small genomic regions highly associated with male preference for female forewing band colors. This strategy allowed them to identify three loci of large effect for male assortative mating and represents one of the first descriptions of the genetic architecture underlying assortative mating outside of Drosophila. Of the three large-effect loci responsible for variation in male preference, one was adjacent to, and potentially contains, the wing patterning gene optix, whereas the other two loci are not adjacent to any known wing patterning genes [To identify loci of large effect for male assortative mate preference, Merrill and colleagues first conducted a series of mate choice trials using ng genes .optix influences both wing pattern and preference or whether the gene associated with that particular preference locus is adjacent to optix, thereby determining whether the same gene is influencing both preference and the preferred trait in this system. However, the authors have made great strides in identifying the genetic architecture underlying assortative mate preference by definitively demonstrating that genes of large effect for mate preference can be maintained in high LD with genes for the preferred trait (wing pattern in this case) in the absence of physical proximity.These findings are significant for a few reasons. First, they illustrate that assortative mate preference can be driven by a small number of genes of large effect. Second, they provide support for multiple hypotheses for the genetics of assortative mate preference. Future functional work is needed to determine whether Heliconius butterflies and the enzyme CRISPR associated 9 (Cas-9), components of the bacterial immune system, to target and edit precise locations in the genome [Drosophila provide evidence for both [Merrill and colleagues\u2019 findings represent a large step forward in our understanding of the genetics of assortative mate preference but also highlight some remaining questions on this topic. First, in spite of concerted efforts by the research community studying assortative mate preference in a wide range of animal species\u2014from guppies to zebra finches to ies and opte genome ), couplefor both , but theIn addition to the outstanding questions on the genes and neurological mechanisms underlying assortative mating and preference diversity described above, the fundamental question of the primary genetic architecture underlying assortative mate preference and speciation events remains: which genetic architecture is most commonly associated with assortative mate preference and subsequent speciation events? Is it (A) single gene for trait and preference, (B) two adjacent genes for trait and preference, or (C) two physically unlinked genes maintained in high LD? This is perhaps the low-hanging fruit of big questions in assortative mate preference research and will hopefully be answered in the near future as genomic data become available for numerous sister species with previously described assortative mate preferences."} +{"text": "Recent systematic reviews have highlighted a paucity of rigorous evidence to guide water, sanitation and hygiene (WASH) interventions in humanitarian crises. In June 2017, the Research for Health in Humanitarian Crises (R2HC) programme of Elrha, convened a meeting of representatives from international response agencies, research institutions and donor organisations active in the field of humanitarian WASH to identify research priorities, discuss challenges conducting research and to establish next steps. Topics including cholera transmission, menstrual hygiene management, and acute undernutrition were identified as research priorities. Several international response agencies have existing research programmes; however, a more cohesive and coordinated effort in the WASH sector would likely advance this field of research. This report shares the conclusions of that meeting and proposes a research agenda with the aim of strengthening humanitarian WASH policy and practice. Over the last decade, numerous scoping and systematic reviews have concluded that water, sanitation and hygiene (WASH) interventions in humanitarian crises can yield important health and social benefits for vulnerable affected populations \u20138. Howevn\u00a0=\u20096) than other areas of public health [This paucity of evidence is reflected in guideline recommendations for humanitarian WASH programmes, such as the SPHERE standards , which ac health .In November 2016, during the 7th Emergency Environmental Health Forum (EEHF) in Kathmandu, Nepal .The objective of the meeting was to identify key public health research priorities for humanitarian WASH research, informed by response agency, research institution and donor organisation perspectives, to strengthen policy and practice. Momentum for the meeting was supported by concurrent funding initiatives for health in humanitarian crises research such as the R2HC, the\u00a0Humanitarian Innovation Fund (HIF) and the\u00a0Humanitarian Evidence Programme (HEP). We have published this report of the\u00a0meeting to expand the discussion beyond those who attended and to stimulate much-needed research interest and investment in the field of humanitarian WASH.The main outcomes of the meeting are presented below under three sub-headings: Research Priorities for Humanitarian WASH; Challenges with Conducting Research in Humanitarian Crises and Moving the Humanitarian WASH Research Agenda Forward.WASH for the prevention and control of choleraTo understand the relative importance of cholera transmission in the domestic and public domains and implications for effective humanitarian WASH responsesTo rigorously assess the effectiveness of conventional WASH interventions on cholera transmission in humanitarian crisesMenstrual hygiene management (MHM)To identify effective culturally appropriate MHM interventions for women and girls affected by humanitarian crisesTo identify social and cultural barriers to safe MHM interventions among women and girls affected by humanitarian crisesTo design and test strategies to integrate MHM interventions for different response phases (e.g. acute and post-acute phase)Coordination of Oral Cholera Vaccine (OCV) and WASH interventionsTo evaluate the relative effectiveness of combined WASH and OCV versus OCV alone on cholera transmission in different settings and for different populations (e.g. in endemic versus epidemic settings)To design and test strategies for coordinating and targeting WASH and OCV interventions in different settings and for different populations (e.g. in endemic versus epidemic settings)Strengthening the design and targeting of hygiene kits in WASH programmesTo determine the most appropriate products to be included in hygiene kits in different responses phases (e.g. acute and post-acute phase)To understand the utilisation of hygiene kits and evaluate their effectiveness to control infectious disease outbreaks WASH in moderate/severe acute malnutrition programmesTo identify appropriate WASH interventions to include in programmes for management of child moderate acute malnutrition (MAM) and severe acute malnutrition (SAM) in humanitarian crisesTo evaluate the effect of combined WASH and MAM/SAM interventions on reduce relapse rates, duration of treatment and overall mortality among children in humanitarian crisesWASH-related enteric disease and transmissionTo ascertain aetiology of childhood diarrhoeal disease in humanitarian settings and other symptomatic and asymptomatic consequences of faecal oral diseasesShigella, pathogenic E. coli) which present a high burden in given humanitarian crisesTo assess dominant transmission routes for specific diarrhoeal diseases in populations affected by humanitarian crisesStrengthening the sanitation component of humanitarian WASH programmesTo design and evaluate behaviour change interventions to increase sanitation uptake in humanitarian crisesTo design and evaluate novel sanitation technologies for use in the acute phase of humanitarian crisesTo design and evaluate novel technologies and approaches to improve sanitation uptake among vulnerable populations, including people with disabilities and young children, in humanitarian crisesWASH as part of the effective transition between emergency and developmentTo evaluate the impact of strategies for improved coordination amongst WASH response agencies and between WASH and health sectors on performance indicatorsTo describe and evaluate current coordination mechanisms for transitionary handover of WASH services from response agencies to national government and/or other development actorsTen key research priorities were identified by the attendees reflecting operational, research and donor perspectives:Participants shared their current research programmes and related how this work had been initiated and developed. A wide range of research activities were shared but these efforts were largely independent and uncoordinated, with topics reflecting individual organisation\u2019s mandates rather than broader strategic or sectoral areas of interest or concern. Participants remarked that it might not be feasible or even desirable for all agencies to adhere to a common research agenda due to organisational priorities, although a common agenda might help to guide future research activities, donor investments and research collaborations.Humanitarian crises, by definition, provide a challenging context for undertaking research. Most often in crises, affected populations have acute needs, response agencies operate under severe logistical constraints, and the socio-political environment is often unstable. Resources and opportunities for research in these settings are limited, particularly more intensive research involving differing standards of care and experimental interventions. Organisations undertaking research need to plan in advance, often significantly ahead of an actual emergency yet remain pragmatic and adaptive when research is executed.Difficult to secure ethical approval rapidlyLimited investment in research and resources not readily availableChallenges in reconciling interests and needs of response agencies and research institutions with regard to what constitutes \u201csufficient rigour\u201dConflicting timelines of response efforts and research protocolsLack of staff trained in research methods within humanitarian organisationsWeak connections between research, and policy and practice functions within agenciesLimited public data sharing, and publication of internal evaluationsThere was consensus on the importance of research and the need to strengthen the evidence base for these interventions but also a recognition that dedicated efforts are needed to support uptake of findings within and across sector agencies.Many of the response agencies present had specific programmes to train staff and increase research outputs. Examples included the Centers for Disease Control and Prevention (CDC) \u201cEpidemiology for WASH\u201d training programme, the \u201cUsing evidence for WASH\u00a0policy and practice\u201d course run between UNICEF and the London School of Hygiene and Tropical Medicine (LSHTM) and other WASH-specific training programmes run internationally ,\u00a0the M\u00e9dA notable challenge remains in establishing and maintaining connections from research findings and teams operating in-country. The group recognised that research uptake needs careful consideration in dedicated training programmes in order to build local capacity for research and evaluation and as an advocacy tool across the humanitarian\u00a0WASH, health, nutrition and shelter sectors. Revisions to guidelines and manuals needs to be evidence-based with Specific, Measurable, Achievable, Relevant and Time-Related (SMART) indicators to aid monitoring and evaluation. Participants noted that a cultural shift is required within most organisations to carry out and incorporate research within\u00a0their programmes or to build linkages with agencies who have that technical expertise.Engage with the wider humanitarian WASH community: A survey will be undertaken amongst response agencies with active WASH programmes to map the current and future research activities and to identify research priorities. Full engagement with field staff as well as international managers is necessary to foster buy-in and identify relevant research objectives. Immediate opportunities to broaden the dialogue on this agenda are the 2018, and ongoing editions of, the Emergency Environmental Health Forum (EEHF), the Water Engineering Development Centre (WEDC), and the University of North Carolina (UNC) Water and Health conferences.Knowledge Sharing: Greater efforts will be made to disseminate publications, advertise training opportunities, publicise relevant calls for proposals and share information on ongoing research activities. Identified opportunities for this include the nascent Technical Working Group (TWiG) within the Global WASH Cluster and the use of existing repositories for published and non-published research outputs including those within the Global WASH Cluster platform [platform and otheplatform , 22.Engagement of all members of the Global WASH Cluster was flagged as important to establish a representative view and ensure the involvement of the broader group of those involved in the humanitarian WASH response. This meeting was intended to gauge interest and undertake initial discussions on the direction for future WASH in humanitarian crises research. The group made two commitments towards sustaining momentum on this agenda:The scale, duration and complexity of humanitarian crises is increasing , with a"} +{"text": "The formation and subsequent recall of coherent episodes from our past relies on the ability to parse the continuous stream of experience in our daily lives into meaningful chunks or segments . This seThe events we experience and remember are often complex and unfold over time, but neuroimaging studies of episodic memory have typically used isolated static stimuli. Despite providing tight control over what is seen, and for how long, there is clearly a disconnect between classic laboratory tests of episodic memory and the construction of event representations in everyday life. Therefore, researchers have sought to use stimuli that are more dynamic and naturalistic, such as discrete film-clips lasting a few seconds. Such studies have found that hippocampal activity increases at the immediate offset of clips and is greater for remembered versus forgotten episodes . The autThe Journal of Neuroscience may also support different aspects of event memory . SpecifiA key unanswered question is what these increases in hippocampal activity at event boundaries represent. As suggested above, they may be interpreted as a rapid replay of the just encountered event to create a cohesive representation . AlternaIn summary,"} +{"text": "Misuse of opioids is a national crisis affecting the social and economic welfare of communities throughout the U.S. and is particularly rampant in rural America. Older adults are far too frequently excluded from consideration of those who are affected by the opioid epidemic. While rural older adults may not suffer the highest per capita rate of opioid overdose deaths, they are deeply affected by the problem. In their youth and middle adulthood, many older adults used their bodies for labor. At older ages, they experience multiple chronic conditions and high rates of chronic pain for which opioids and related prescription and non-prescription drugs are often the treatment of choice. Also and far too frequently, older people become easy targets for abuse by persons needing resources to feed their addiction. This symposium focuses on elder abuse associated with opioid and related substance misuse. Zanjani\u2019s presentation provides the context of rurality and drugs and alcohol as a precursor to elder abuse. The second paper by Teaster and colleagues examines trends in APS cases of elder abuse in which the perpetrator is a substance user and identifies perpetrator and victim characteristics predictive of different types of substantiated abuse. Using APS case notes, Roberto and colleagues characterize cases of elder abuse in rural Kentucky in which the perpetrator used opioids and related substances. Robert Blancato and Brian Lindberg will discuss presenters\u2019 collective findings by weaving together concepts of rurality, addiction, and elder abuse and recommending strategies for prevention, intervention, and policy."} +{"text": "Due to the rising prevalence of mental illness in nursing homes (NHs), the US Congress passed the 1987 Pre-Admission Screening and Resident Review (PASRR) mandate, which aims both to limit inappropriate institutionalization of people with mental illness and to ensure that they are served appropriately when living in NHs. Although the PASRR is a federal mandate, states have considerable flexibility in implementing it, resulting in considerable variation across states. This study explores the Commonwealth of Massachusetts\u2019 policies on admission and care of individuals with mental illness in NHs, focusing on implementation of PASRR regulations. Semi-structured phone interviews were conducted with key informants identified through purposive snowball sampling (N=8). Key informants included representatives from NHs, the State Mental Health Authority, state Medicaid office, and independent contractors and an academic expert. Data were analyzed using qualitative content analysis. Participants agreed that the PASRR tools efficiently identified and screened people with mental illness -- thus achieving PASRR\u2019s first aim, but that the regulations did not successfully ensure appropriate services. Interviewees also identified a lack of services and options for diversion of people with mental illness into the community. Nursing home informants noticed a disconnect between the various supervising departments and felt instructions were unclear on the administration of the tool. This work builds a case for a national study to understand how PASRR implementation varies across states, resulting in variations in the proportion of people with mental illness admitted and served in NHs."} +{"text": "This ESPO Presidential Symposium features a multidisciplinary perspective and recent scientific advances made by early career researchers from each of the GSA scientific sections. They will provide examples of how their work is addressing ways to build and maintain networks in aging and gerontological workforce. These talks will span research on the age-associated transcriptional networks , enhancing care for persons with dementia using a professional healthcare network , ways to maintain care networks in nursing home residents , exploring the impact of social isolation in older adults on the Autism Spectrum and reflections on a project that linked aging education and student involvement within the aging network at the state level . These talks will demonstrate the diversity of aims, strategies, methodologies, and tools employed across disciplines. In addition, these early career researchers will share how they use networks in their own disciplines to advance their science with the goal of building an independent program of research. We will conclude with a discussion on ways to identify synergies across different fields and promote strategies for successful cross-discipline collaboration."} +{"text": "One question asked by generations of gerontology doctoral students is what types of employment can be secured after completing the PhD in Gerontology. The Gerontology Education Longitudinal Study (GELS) has surveyed graduate students and alumni of the various doctoral programs in order to understand the career trajectories of graduates. Of 102 alumni surveyed in 2014 (42% response rate), the majority (60%) were not working with other people who had degrees in gerontology, yet 51% report working with at least some people who have experience with aging and older adults. On the job, graduates say that their duties require knowledge and mastery of public policy issues, health and medical aspects related to aging, and psychological theories. As aging experts, it is inherent in their work to combat ageism and reduce age-related stereotypes. As such, gerontologists are using substantive content expertise within their careers and serving as experts in aging."} +{"text": "Reliable protocols for measuring subsurface fluxes of water and chemicals need to be developed.Determining the interaction and impact of surface runoff and subsurface flow processes on the environment has been hindered by our inability to characterize subsurface soil structures on a watershed scale. Ground penetrating radar (GPR) data were collected and evaluated in determining subsurface hydrology at four small watersheds in Beltsville, MD. The watersheds have similar textures, organic matter contents, and yield distributions. Although the surface slope was greater on one of the watersheds, slope alone could not explain why it also had a nitrate runoff flux that was 18 times greater than the other three watersheds. Only with knowledge of the subsurface hydrology could the surface runoff differences be explained. The subsurface hydrology was developed by combining GPR and surface topography in a geographic information system. Discrete subsurface flow pathways were identified and confirmed with color infrared imagery, real-time soil moisture monitoring, and yield monitoring. The discrete subsurface flow patterns were also useful in understanding observed nitrate levels entering the riparian wetland and first order stream. This study demonstrated the impact that subsurface stratigraphy can have on water and nitrate (NO"} +{"text": "Presently, multiple potential biomarkers have been introduced following many prospective studies , 2. HoweGiven the inevitably valuable role of biomarkers in the diagnosis of gastric cancer and their role in developing personalized medicine, clinicians strive to continue studying potential candidates; thus, identifying pitfalls before designing biomarker studies is valuable for patient participants and outcomes of such studies. Finally, the investigation of the mechanisms underlying the involvement of circular RNAs in the development of gastric cancer in patients of diverse ethnicities is another challenging but worthwhile undertaking\u2014which is also lacking in the field."} +{"text": "Over the past few years, our knowledge of how ecological interactions shape the structure and dynamics of natural communities has rapidly advanced. Plant chemical traits play key roles in these processes because they mediate a diverse range of direct and indirect interactions in a community-wide context. Many chemically mediated interactions have been extensively studied in industrial cropping systems, and thus have focused on simplified, pairwise and linear interactions that rarely incorporate a community perspective. A contrasting approach considers the agroecosystem as a functioning whole, in which food production occurs. It offers an opportunity to better understand how plant chemical traits mediate complex interactions which can enhance or hinder ecosystem functions. In this paper, we argue that studying chemically mediated interactions in agroecosystems is essential to comprehend how agroecosystem services emerge and how they can be guaranteed through ecosystem management. First, we discuss how plant chemical traits affect and are affected by ecological interactions. We then explore research questions and future directions on how studying chemical mediation in complex agroecosystems can help us understand the emergence and management of ecosystem services, specifically biological control and pollination. It is well known that plant mediated interactions strongly influence the structure of natural communities . ResourcPlant-mediated interactions have been studied in agricultural systems due to the impact that herbivores, pathogens and pollinators have on plant production, and the mechanisms behind plant resistance, tritrophic interactions and pollinator attraction are well known . HoweverThe integration of knowledge from chemical ecology into agroecology has been slow in the last decades, with a few notable exceptions , 2014. CWhen secondary metabolites produced by plants are perceived by other organisms they acquire ecological functions and become subjected to selective pressures . Some ofThe fact that plant chemical traits such as VOCs have many functional roles makes them candidates for research and technology for agriculture. However, we still lack knowledge about the ecological consequences of the manipulation of plant chemical traits in a multitrophic and evolutionary context. Experimental manipulation of HI-VOCs emission by plants in the field, for example, is usually planned considering predators and parasitoids of herbivores as target receivers of these signals . HoweverIn this paper, we propose that studying chemically mediated interactions structured by VOCs and phytochemical diversity in agroecosystems is essential to understand how ecosystem functions emerge and can be enhanced in these systems. We explore broad research questions and future directions on how chemical ecology can be studied in diversified agroecosystems and discuss its applications in two of the most studied agroecosystem services: pollination and biological control. By highlighting these perspectives, we hope to help comprehend how chemical ecology can be integrated in agroecosystem management.Ecological interactions are responsible for providing important agroecosystem services. A goal of chemical ecology should be to help us understand these interactions so that agroecosystems can be managed more efficiently. To achieve this goal, a rigorous application of ecological theory is necessary. It is also fundamental to investigate traditional diversified agroecosystems that have been developed over thousands of years. Traditional cropping systems hold substantial amounts of information that detailed ecological study can make available more generally. For this purpose, we highlight two general interlinked questions that we think will be relevant in guiding future research.(1)What are the mechanisms that generate phytochemical diversity in agroecosystems? Agroecosystem diversification can affect phytochemical diversity through three major paths: (1) planned taxonomic diversity, i.e., the plants chosen for inclusion in the agroecosystem; (2) associated diversity, which comprises the organisms that spontaneously appear in the agroecosystem; and (3) changes in plant chemistry resulting from induced responses to environmental cues such as biotic interactions and abiotic stress. Understanding the relevance of each of these processes for chemically mediated interactions is fundamental if we want to comprehend the ecological processes supporting agroecosystem function. VOC-mediated plant-plant interactions are promising candidates for these studies since it is known that they affect plant growth and defense , 2003. I(2)How does plant chemistry help modulate the interaction web in diversified agroecosystems? Research that focuses on pairwise interactions and/or linear tritrophic chains could lead to underestimation of the impacts of plant chemistry on interaction webs . AgroecoThe two topics highlighted above emphasize the mechanisms that generate phytochemical diversity and how plant chemistry affects the entire web of interactions. An integration of these two aspects is required to comprehend the emergence of agroecosystem services. This approach could provide knowledge to improve the quality of agroecosystem services through more efficient ecosystem management . We can therefore analyze how different agroecosystem management practices affect the community structure and the plant chemical traits specifically related to ecological processes that guarantee such services . In the The perspectives discussed on how plant chemistry can mediate ecological interactions in a community-wide agroecosystem context lead us to propose a series of research questions to comprehend the emergence of agroecosystem services. We focus on the application of chemical ecology to the study of pollination and biological control.(1) What are the relative roles of taxonomic diversity, biotic interactions and abiotic stress in generating phytochemical diversity in agroecosystems?(2) How does phytochemical diversity of VOCs affect pollinator diversity, flower-pollinator interaction webs and plant reproductive output?(3) Do VOC-mediated plant-plant interactions have an effect on floral biology and agricultural production?(4) How does phytochemical variation resulting from taxonomic plant diversity, biotic interactions and abiotic stress affect the natural enemies of herbivores in agroecosystems?(5) How do VOC-mediated plant-plant interactions make plants more resistant or susceptible to herbivores and affect the structure of interaction webs?(6) Are there trade-offs between cascading effects of induced plant responses on biological control and pollination at the agroecosystem level?(7) Can knowledge of phytochemical traits be applied to improve crop combinations?Agroecosystem diversification, through management of flower strips, for example, has shown that increasing plant diversity is positively associated with the richness and abundance of pollinators, pollination, and fruit production . MoreoveThe landscape of VOCs can be influenced by plant diversity and also by biotic interactions. For example, herbivore-induced changes in plant physiology can affect flower odor and pollFloral volatiles are also important in plant-plant communication. They are produced and emitted at higher rates than vegetative VOCs, with over than 1700 known compounds. These compounds can vary quantitatively and qualitatively between species or between floral states within a species (i.e., pollinated vs. unpollinated flowers emit different signals; It is also important to ask how phytochemically diverse environments affect the structure of plant-pollinator interaction webs. Each plant has specific floral traits that promote pollinator visitation while limiting non-pollinating visitors, a mechanism known as floral filtering . VOCs plResearchers have applied chemical ecology primarily in the study of individual pest species focused on pairwise interactions . HoweverPlant chemistry influences pest incidence by affecting plant localization and selection by herbivores or throuDespite research focused on the behavior of individual predators and parasitoids in response to volatiles in the laboratory, their response to volatiles in diverse odor backgrounds remains to be studied . VOC sigPlant-plant communication mediated by volatiles has rarely been included in biocontrol studies . It is kDesmodium spp. among crop plants to act as \u2018push\u2019 components by emitting VOCs repellent to stemborers. Simultaneously, Napier grass is planted surrounding the crop as \u2018pull\u2019 components to chemically attract egg laying stemborers. Additionally, allelopathic compounds emitted by Desmodium spp. prevent the emergence of Striga ssp., a parasitic plant of maize and sorghum (Push-pull technology is an example of how chemical ecology has been integrated to small-scale farming to improve pest and weed management . An exam sorghum . The suc sorghum .Push-pull studies have broken new ground on communication between plants and plants and the third trophic level in diversified agroecosystems. A major goal should be to understand whether specific plant chemical traits have consistent effects in enhancing biological control across systems. This could lead to predictions of the effects of plant combinations on pest incidence based on VOC profiles. This information can be used to plan taxonomic and interaction diversity in agroecosystems.Chemical ecology has long focused on providing technological products for industrial agriculture, but it is now beginning to be recognized that small-scale agroecological systems have great potential to sustainably guarantee food security, particularly to the most vulnerable populations . Such smAll authors contributed equally to the conception, literature search, and writing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Treating fungal infections in the central nervous system (CNS) remains a challenge despite the availability of new antifungal agents. Therapy is limited by poor understanding of the kinetic properties of antifungal drugs in the CNS compounded by lack of data for many agents. In some cases, clinical response rates do not correspond to data on drug concentrations in the cerebral spinal fluid and/or brain parenchyma. In order to better characterize the use of antifungal agents in treating CNS infections, a review of the essential principles of neuroPK are reviewed. Specific data regarding antifungal drug concentrations in the cerebral spinal fluid and brain tissue are described from human data where available. Alternative dosing regimens and the role of antifungal drug concentration monitoring in treating fungal infections in the CNS are also discussed. Having a better understanding of these key concepts will help guide clinicians in determining the best treatment courses for patients with these devastating infections. Invasive fungal infections in the central nervous system (CNS) are particularly difficult to treat and are associated with high morbidity and mortality rates. These infections often attack patients immunosuppressed by underlying disease states, such as human immunodeficiency virus (HIV) or their treatments including antineoplastic agents. Recently, patients with less severe pathology receiving immune-modulating biologic agents have also emerged as a group at risk of CNS fungal infections.Antifungal drug therapy is the cornerstone of management of fungal infections in the central nervous system. The unique challenges of drug penetration to the site and the variability of pharmacokinetic and dynamic characteristics between agents and individual patients further complicate the successful treatment of these life-threatening infections. This review summarizes many principles which should be considered when administering antifungal treatment for CNS disease.The key to determining the ability of an individual antifungal agent to treat infections of the CNS is describing drug exposure within the CNS or neuroPK. Similar to more traditional pharmacokinetics, this is a description of the absorption, distribution, metabolism and elimination of drug within the CNS. The ability to obtain repeated sampling, or any sampling at all from the CNS , interstitial fluid and brain tissue) of patients undergoing treatment significantly limits data to guide the best practices in this area.The CSF is a protected site separated from traditional blood circulation by two primary barriers. The interstitial fluid of brain parenchyma is separated from blood circulation by the blood\u2013brain barrier (BBB), while CSF is separated from blood circulation by the blood\u2013CSF barrier (BCSFB) ,2. The lThere are several drug characteristics that are associated with optimal entry into the CNS. These include lipophilicity, which allows maximal penetration through the lipid bilayer surrounding the CNS. Lipophilicity is measured as the octanol-water partition coefficient and is expressed as log P. Values between 0 to 1 are considered optimal for CNS penetration . The secDistribution within the CNS is a key component to ultimate drug availability at the target site. There is no restrictive barrier between interstitial fluid of the brain parenchyma and the CSF, therefore, once penetrating the CNS, the drug can move fluidly between these spaces . HoweverDrug clearance from the CNS can also affect drug availability. A drug is cleared from the CNS by two main mechanisms: reverse diffusion across the blood brain barrier, often employing transport mechanisms, and drainage of interstitial fluid into venous blood . The latAs with traditional pharmacokinetic principles, many factors can alter neuroPK parameters. These include patient factors associated with underlying disease, such as immunosuppression, altered protein binding secondary to protein deficiency, and changes in drainage rates into venous blood by concomitant medications . CNS perOne of the most discussed infection-related parameters affecting CNS drug exposure is meningeal inflammation. It is thought that inflammation results in a leakier BBB and decreases return clearance into venous blood ,18. AddiUnderstanding the neurologic pharmacokinetic effects of the various antifungal agents allows for better prediction of which agents will allow adequate CNS exposure to treat fungal disease at this sequestered site. However, treatment recommendations and guidelines for managing CNS fungal infection, as discussed throughout the rest of this issue, place much greater weight on clinical experience for managing the disease. Data regarding CNS penetration from human (where available) and animal models are depicted in Amphotericin B and associated lipid formulations remain the cornerstone of treatment for many CNS fungal infections . Data haSimilarly, there is significant clinical experience with fluconazole for treating CNS disease based on the favorable kinetic profile in the CNS for this agent. Recently, voriconazole has also emerged as a reasonable treatment option for CNS disease and has been associated with successful treatment in many patient populations ,24.Many other newer antifungal agents lack experience in treating CNS disease and do not offer adequate CNS exposure to justify veering away from current standards of care. This is especially true for the echinocandin agents that have isolated evidence of successful treatment, but only at doses higher than those traditionally given and/or in combination with other agents ,2. NearlThe other articles in this issue focus on treating specific fungal infections in the CNS and provide greater detail on agent selection and dosing.Given the limitations of a systemic drug reaching the CNS, direct administration of antifungal agents into the CNS has been attempted. The majority of data with this approach is with administration of amphotericin B deoxycholate via the intrathecal route ,57. ReceIntra-ventricular administration may help mitigate differential CSF drug distribution between lumbar and ventricular CSF, as previously described. This can be accomplished by administration via an Ommaya\u2122 reservoir, a device invented to circumvent the limitation of lumbar drug administration for the treatment of CNS disease . Using tDirect administration to the site of infection certainly has many theoretical advantages, including eliminating the complex issues surrounding CNS penetration. This circumvents the need for drug absorption into the CNS but does not change the other pharmacokinetic considerations required of antifungal therapy in the CNS. Most notably, drug elimination through routine CSF draining to the venous blood supply can lead to quickly declining drug concentrations . ToxicitMonitoring drug concentrations for antifungal drugs has become more common practice over the past decade . For allThere are several antifungal agents that can successfully be used to treat CNS fungal infections today. However, each antifungal agent possesses unique kinetic and dynamic properties that impact its ability to successfully treat infections in the CNS. Understanding key considerations to the challenge of delivering antifungal drugs to the CNS is essential for the successful treatment of this patient population."} +{"text": "Recruitment of older adults and/or their family caregivers for participation in research is challenging. This process is further complicated by population or procedure-specific factors that can impede recruitment efforts. The purpose of this symposium is to describe various recruitment challenges and solutions as well as strategies used to engage older adults and family caregivers in research. Dr. Glenna Brewster will present recruitment strategies used for a multisite telehealth intervention for caregivers of persons living with dementia. Dr. Todd Monroe will examine barriers and solutions for recruitment and retention of persons with Alzheimer\u2019s disease for neuroimaging studies. Dr. Karen Moss will share strategies used to recruit family caregivers of African American older adults with dementia for end-of-life research. Dr. Shiva Prasad will share strategies to recruit LGBT older adults to a study on exploring the idea of an LGBT online senior center, and Dr. Karen Rose will describe stigma associated with recruiting persons with Alzheimer\u2019s disease and other dementias, and their family caregivers, including best practices from the literature coupled with lessons learned from experiences. Shared strategies and solutions will assist researchers in identifying and addressing recruitment challenges and help to ensure recruitment of diverse groups of older adults and/or family caregivers for studies that use various research methodologies, including leveraging the power of professional and community-based networks. Increasing research participation will yield the knowledge necessary for improving health outcomes for older adults and their family caregivers living with serious chronic illnesses such as Alzheimer\u2019s disease and related dementias."} +{"text": "Enhanced Recovery After Surgery (ERAS) is a multidisciplinary approach to the care of surgical patient. ERAS protocols are multimodal perioperative care pathways designed to achieve early recovery after surgical procedures by maintaining preoperative organ function and reducing the profound stress response following surgery . ERAS stThe overall goal of this research topic is to examine ERAS protocols and their implementation in different settings. The issue contains a series of review articles as well as original research articles.Stojanovic et al. present the evidence that application of ERAS program reduces the length of hospital stay, decreases the surgical, and non-surgical complications in the postoperative period, and improves the overall outcome in patients undergoing vascular surgery. Having reviewed recent literature, Dinic et al. highlight potential procedures and techniques that might be incorporated into the ERAS program after thoracic surgery. Golic et al. conducted a retrospective analysis of nine cases of patients who developed flail chest following blunt trauma, and were treated with early osteo-fixation of the chest wall and postoperative epidural analgesia. The authors concluded that surgical stabilization and epidural analgesia reduced ventilator support, shortened intensive care unit stay, and reduced medical costs. Vukovic and Dinic analyzed the components of ERAS protocols in urologic surgery. They concluded that there are still very few guidelines for ERAS protocols in urology and emphasize the importance of preoperative medical optimization, epidural analgesia, and nutritional management.Recent studies suggest that ERAS protocol can be successfully applied in vascular surgery. In a narrative review article, Jovanovi\u0107 et al. comprehensively explain the role of sedation, analgesia, early oral intake, and early mobilization as integrative parts of SICU ERAS concept implementation.The idea of incorporating ERAS protocols in surgical intensive care unit (SICU) setting has great potential for promoting enhance recovery of SICU patients. Simi\u0107 et al. in their review focus on the importance of postoperative analgesia in children. The authors describe the utility of continuous peripheral blocks (CPNB) for complete and prolonged postoperative analgesia of pediatric patients.Sivevski et al. provide an in-depth review of the available data from the literature as well as evidence-based recommendations considering the concept of low dose spinal anesthesia for patients undergoing gynecological surgery. An interesting result of the study is that there was no respiratory depression in geriatric patients receiving 100 \u03bcg of spinal morphine. This study also highlights the hemodynamic stability of elderly patients who received low-doses of intrathecal bupivacaine in combination with opioids.Pujic et al. developed a survey tool of 22 questions with multiple choice answers that was sent by email to all hospitals in Serbia that provide obstetric services. The questionnaire asked whether ERAS protocols had been formally adopted for surgical patients and about their use in patients undergoing cesarean delivery (CD). Responses were obtained from 46 of 49 hospitals . ERAS protocols were in use in 11 of 46 (24%) of surveyed hospitals and 63% of the time the responsibility for patients counseling was shared between the obstetrician and anesthesiologist. However, even ERAS hospitals reported a higher number of discharges after 3 days compared to surveys of UK hospitals where the majority of women are discharged within 2 days of their CD.Akerman et al. conclude that improved early oral intake and early mobilization can be more easily achieved with good pain control hereof QLB has a great potential in this area of ERAS.Quadratus lumborum block (QLB) is a new form of the abdominal wall block which is relatively easily performed thanks to clear ultrasound anatomic markers. QLB is safe and has found its place in multimodal postoperative pain therapy in patients undergoing abdominal surgery, gynecological and obstetric procedures, and orthopedic interventions on hips, whether interventions are performed in general or spinal anesthesia, both in adults and in children. In summary, this issue discusses particular aspects of ERAS protocols and an anesthesiologist's role in preoperative, intraoperative, and postoperative strategies for different surgical interventions and in different patient groups.IB and IV have made a substantial contribution to the work and approved the final version of the manuscript to be published.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Optical coherence tomography angiography (OCT-A) represents the most recent modality in retinal imaging for non-invasive and depth-selective visualization of blood flow in retinal vessels. With regard to quantitative OCTA measurements for early detection of subclinical alterations, it is of great interest, which intra- and extra-ocular factors affect the results of OCTA measurements. Here, we performed OCTA imaging of the central retina in 65 eyes of 65 young healthy female and male participants and evaluated individual physical fitness levels by standard lactate diagnostic using an incremental maximal performance running test. The main finding was that OCTA measurements of the foveal avascular zone (FAZ) area were associated with physical fitness. Using multivariate regression analysis, we found that running speed at the individual lactate threshold, a marker strongly associated with aerobic performance capacity, significantly contributed to differences in FAZ area . The data indicates that smaller FAZ areas are likely observed in individuals with higher aerobic exercise capacity. Our findings are also of interest with respect to the potential use of retinal OCTA imaging to detect exercise-induced microvascular adaptations in future studies. Within the last few years, optical coherence tomography angiography (OCTA) has contributed insight to various retinal diseases by qualitative visualization of blood flow in the back of the eye. One of tSince OCTA algorithms detect blood flow based on the OCT signal scattered or reflected by moving red blood cells, one important parameter recently reported by Yang and colleagues is the hematocrit level, which significantly affects the flow signal particularly in narrow capillary vessels localized in the macula or at the optic nerve head (ONH). IntraocuRecently, our group contributed data on long-term changes in ocular perfusion measured by OCTA in response to a controlled physical training intervention. Thus, weTherefore, the aim of this study was to evaluate if and to what extent physical fitness affects OCTA measures of ONH and macular blood perfusion in healthy adults.Sixty-five young healthy moderately trained female and male students of the University\u2019s Physical Education Department were recruited at the Institute of Sports Medicine of the University Hospital Muenster in May 2017 as reported elsewhere. All partAll investigations were performed in accordance with the declaration of Helsinki and after the approval of the ethical committee of the medical association Westfalen-Lippe and the Westphalian Wilhelms-University of Muenster . Prior to subjects\u2019 participation in the study, written informed consent was obtained. Inclusion criteria were age > 18 years, a health certificate as mandatory to study at the University\u2019s Physical Education Department and a valid maximal performance exercise test (see below). Participants with diagnosis of any cardiovascular disease, use of cardiovascular medication or diagnosis of arterial hypertension were not eligible to participate. Any ocular pathology in the medical history as well as any pathologic alteration in structural OCT scans led to exclusion. Since axial length affects OCTA measurements of FAZ due to magnification effects particularly in higher aberrations of axial length , particimax). The test was performed indoors at ambient temperature (18\u201322\u00b0C) on a synthetic 200 m running track in groups of 4 individuals as described elsewhere. in case of non-normal distribution. Data were tested for normal distribution using Kolmogorov-Smirnov test. Correlation analysis was performed using Pearson Product-Moment Correlation. For OCTA parameters showing statistically significant correlations with physical fitness measures, multiple linear regression was performed. P-value was set to 0.05.max, speed immediately before test termination due to fatigue) were comparable to previously reported data in similar age groups .Exemplary performance data including the determination of the IAT and Vmmol\u00b7L-1 . Since pNo signs of pathologic ocular alteration were observed in structural OCT scans or OCTA images of any analyzed individual and parameters obtained were comparable to published data reporting on healthy individuals of identical age. SSI of amax) with OCTA parameters are presented in max as well as IAT were detected . No other OCTA parameters were significantly associated with exercise performance. Scatter plots and linear regressions showing the correlation between FAZ area and performance parameters (i.e. IAT and Vmax) are presented in Results of the initial correlation analysis of physical performance and age, an association which has already been reported in previous histologic studies suggesting that histologically normal maculae show a decrease in density and diameter of choriocapillaris vessels with advancing age.The current study evaluated if OCTA measurements of ocular blood flow at the posterior pole are associated with physical performance measures in young healthy adults. We found that physical fitness defined by running speed at individual anaerobic lactate threshold (IAT) was inversely correlated with the foveal avascular zone (FAZ) area.max). Both exercise parameters are strongly correlated and depend largely on cardiopulmonary fitness attained by regular physical activity and exercise training. While testing methods for maximal exercise performance may (at least in part) be actively or involuntarily influenced by the tested individual and the observer, blood lactate-based measures such as the IAT are considered as reliable and objective parameters for endurance exercise performance. They can neither be influenced by the participant nor by the trainer and are determined after completion of the test. It is important to note that our study group included females and males not matched for physical fitness. However, we did not detect an effect of sex on the FAZ area although, in the multivariate analysis, sex nearly missed statistical significance. In addition, subgroup analysis of females and males did not show significant correlations between IAT/ Vmax and FAZ. With regards to these results and the unbalanced sex-ratio in our cohort, future studies are required to determine the influence of sex and physical fitness on OCTA parameters. This is also of relevance since there is ongoing discussion in the current literature concerning potential sex effects on FAZ area.[The more precisely and unaffected from influencing factors quantitative OCTA imaging can be performed, the more effectively and sensitively natural history studies and interventional clinical trials can detect changes in ocular perfusion that may be associated with onset or progression of disease. In this regard, the identification of intra- and extra-ocular factors, which affect blood flow properties and thus OCTA measurements is of central interest.\u201310 We haFAZ area.,28With respect to the interpretation of OCTA-derived inter-individual FAZ data, it is important to note that current commercial OCTA devices do not correct area measurements for changes in image size magnification. Thus, the actual size of the FAZ area imaged depends on the combined magnification of the camera and the analyzed eye. Garway-Heath et al. compared different methods to correct for the magnification of the eye and concluded that using axial length to correct for magnification error was a practicable approach. ConsisteSo far, a number of studies have reported normative data for FAZ area size and vascular densities based on OCTA imaging in healthy individuals of different age ranges. A subgroup analysis of macular OCTA data of subjects between 20\u201339 years of age reported data very similar to our findings. Multivarmax, correlated with FAZ area size in the univariate linear regression model. However, only IAT reached statistical significance in the multivariate regression analysis. This observation might indicate that aerobic exercise capacity or regular exercise training performed to improve aerobic performance affects FAZ measurements to a greater extend then maximal exercise performance capacity. Compared to other known effectors, the effect of individual fitness on the FAZ area in OCTA appears rather moderate, particularly in comparison to the known effect of the spherical equivalent. However, also moderate effects may have biological relevance and this finding should also be interpreted with respect to the narrow range of physical fitness in our young and healthy population. The range of physical fitness in the overall population is considerably large and future studies are needed to investigate the effect of physical fitness and regular physical activity on OCTA measurements including the FAZ area in population-based studies. Of note, no associations were detected for the investigated FD parameters, indicating that FAZ parameters are sensitive to physical activity and training over the entire range of physical performance capacity while significant effects on FD may only be detected in response to physical training in sedentary individuals. Notably, long-term training effects seem to differ from acute physical activity effects in that FDrPP, which has been shown to decrease immediately after exercise, was not associated with physical fitness in the current analysis.[Since OCTA data with information on regular physical activity or training status of the analysed participants is missing from the literature, we can only interpret our data within the findings of our own analysis. Interestingly, both performance parameters, IAT and Vanalysis.,11The above described observations may be explained by different effectors including local factors causing vasodilation. For instance, retinal vasomotor function is, as part of the cerebral circulation, largely dependent on local nitric oxide (NO) production.,32 AsymmSeveral limitations may exist for the current study. A significant effect of haematocrit on the decorrelation signal using 45%, 40% and 32% haematocrit blood samples has been described in an ex-vivo model.. FurtherIn conclusion, we provide evidence that OCTA measurements of FAZ are associated with physical fitness. In detail, smaller FAZ areas were observed in individuals with higher aerobic exercise capacity determined by IAT.At this point, future OCTA studies are not required to be corrected for physical activity patterns. The detected effect was moderate and based on a young and healthy group of moderately trained individuals. Follow-up studies must confirm the presented results and aim to include larger groups with wider age ranges and greater diversity in physical fitness.The better we understand which intra- and extra-ocular variables affect OCTA measurements, the more reliable and more exact findings will be provided, also with regard to the association of retinal perfusion and pathology and the determination of potential surrogate markers at early asymptomatic disease stages."} +{"text": "Dry mouth is a common condition among older adults that negatively influences oral health, general health, and quality of life. The role of psychosocial factors in oral health conditions and diseases remains largely unknown. We examined the relationship between perceived stress and dry mouth among US older Chinese adults and further investigated the moderating role of social support from different sources in the relationship. Data came from baseline of the Population Study of Chinese Elderly in Chicago between 2011 and 2013 . Stepwise logistic regression models with interaction terms were used. More perceived stress was significantly associated with a higher likelihood of reporting dry mouth. Friend support was protective against dry mouth. The effect of perceived stress on dry mouth varied by levels of family and friend support. To prevent or reduce dry mouth, interventions need to consider perceived stress and social support in this growing population."} +{"text": "Although families have always cared for their aging members, changes in contemporary society have added to the stress and challenges of providing daily care and support for relatives experiencing physical and/or cognitive decline. Personal characteristics, geographic location, and family structures and relationships influence beliefs about family care; thus, recognizing differences within and across families is crucial for developing culturally informed caregiving programs and practices. This symposium focuses on four diverse groups of caregivers. Recognition of caregiving cultures and the barriers caregivers encounter is the central theme of all four papers. Using daily diary interviews and GIS data, Savla and colleagues discuss the unique cultural and geographical challenges caregivers in rural Appalachian Virginia face when caring for a family member with dementia. J. Angel employs quantitative and qualitative data from two nationally representative datasets to discuss the effects of immigration on family structures and caregiving for Mexican-American older adults with dementia. Miyawaki and her colleagues provide a profile of caregivers of older Vietnamese refugees, the resources they use and support structures they rely on. Finally, Roberto and Savla expand the definition of family caregivers to include extended and fictive kin who are providing dementia care and provide an in-depth view of the circumstances that influence the responsibilities they assumed, the type of care they provide, and the coping strategies they use. Dr. Rosemary Blieszner will discuss the presenters\u2019 collective findings considering their unique caregiving practices and beliefs as well as the common grounds between the different races, regions and relationships."} +{"text": "Publicly available gene expression datasets deposited in the Gene Expression Omnibus (GEO) are growing at an accelerating rate. Such datasets hold great value for knowledge discovery, particularly when integrated. Although numerous software platforms and tools have been developed to enable reanalysis and integration of individual, or groups, of GEO datasets, large-scale reuse of those datasets is impeded by minimal requirements for standardized metadata both at the study and sample levels as well as uniform processing of the data across studies. Here, we review methodologies developed to facilitate the systematic curation and processing of publicly available gene expression datasets from GEO. We identify trends for advanced metadata curation and summarize approaches for reprocessing the data within the entire GEO repository. Gene expression datasets are accumulating rapidly in public repositories such as the NCBI\u2019s Gene Expression Omnibus (GEO) BioPortal manual curation, 2) automated natural language processing (NLP), and (3) inferring metadata directly from the gene expression profiles. In the subsequent sections, we describe recent activities within these three categories signatures from CD34+ cells that cluster with While manual curation through crowdsourcing produces, in general, high-quality annotations, this approach has other drawbacks besides lack of scalability. Curators make mistakes and produce inconsistent annotations in borderline cases techniques such as named-entity recognition (NER) and document classification to the textual descriptions of GEO studies is an attractive alternative for curating GEO metadata manually. NLP has been intensively applied to extract structured elements from the free-text of biomedical research publications over the past two decades for this task . AL is a meta-algorithm for ML that learns to intelligently select examples (data points) for the underlying supervised ML algorithm to train and generalize more efficiently . These search engines are powered by machine readable metadata that is hosted on dataset landing pages by the data repository using standards such as schema.org guiding principles have been proposed to improve the groundwork needed to support the reuse of scientific data (Wilkinson et al. While the curation of metadata and the unified metadata models are important, optimal and uniform data processing pipelines, such as Recount2 (Collado-Torres et al. Public gene expression data repositories such as GEO harbor enormous capacity for knowledge discovery. Outstanding progress has been achieved in developing methodologies and tools to facilitate the improved curation and reuse of those datasets in the past few years. However, there is still opportunity to develop better approaches to further advance the quality of GEO\u2019s metadata and data. With the FAIR guiding principles, the resultant improved curated public gene expression datasets will be integrated into an ecosystem of biomedical datasets and knowledge-bases for advancing biological discovery and for accelerating therapeutics development."} +{"text": "This study examines the roles of daily stress processes as a possible mediator of how life course socioeconomic inequality is reproduced in day-to-day experiences and creates disparities in clinical risk for rapid kidney function declines in adulthood. Data are from 1174 middle and older adults who participated in the MIDUS study wave 2 and Refresher. We found significant pathways that childhood SES was associated with education and adult SES, adult SES was associated with exposure to daily stressors and daily stressor reactivity to negative affect, positive affect, and somatic symptom. In turn, higher report of daily somatic symptom and lower report of daily positive affect were associated with higher CKD risk factors. Finally, childhood SES was directly associated with CKD risk factors. Childhood SES is associated with clinical risks for rapid kidney function decline through direct association and life course accumulation."} +{"text": "Pupillometry research has experienced an enormous revival in the last two decades. Here we briefly review the surge of recent studies on task-evoked pupil dilation in the context of cognitive control tasks with the primary aim being to evaluate the feasibility of using pupil dilation as an index of effort exertion, rather than task demand or difficulty. Our review shows that across the three cognitive control domains of updating, switching, and inhibition, increases in task demands typically leads to increases in pupil dilation. Studies show a diverging pattern with respect to the relationship between pupil dilation and performance and we show how an effort account of pupil dilation can provide an explanation of these findings. We also discuss future directions to further corroborate this account in the context of recent theories on cognitive control and effort and their potential neurobiological substrates. Try to solve the problem and watch your pupil at the same time, a rather difficult exercise in divided attention. After a few attempts, almost everyone is able to observe the pupillary dilation that accompanies mental effort.\u201d Daniel Kahneman, Every day we encounter situations that demand goal-directed behavior and the control over our automatic, impulsive reactions. The ability to exert cognitive effort in these situations is highly important evoke significantly smaller pupil dilations than Go trials trials as compared to congruent trials on the Stroop task system. More specifically, it has been proposed that the LC receives input from brain areas that detect task demands such as the ACC, and that its efferent projections influences the levels of neural gain throughout the cortex, including frontal and parietal regions important for cognitive control (Aston-Jones & Cohen, Similarly, acetylcholine has been proposed to play an important role in compensatory effort to keep up task performance under challenging conditions (Sarter, Gehring, & Kozak, The norepinephrine and acetylcholine systems receive projections from the anterior cingulate cortex which has been proposed to monitor the environment for cognitive conflict and demands (Botvinick et al., The studies reviewed here show that pupil dilation can be used as an indirect index of effort in cognitive control tasks. Across the domains of updating, switching and inhibition, studies show that pupil dilation closely responds to changes in task demands and in some cases predict improved task performance. Future work that integrates other physiological indices of cognitive effort with neuroimaging techniques is needed to advance our understanding of the intricate role of brain and body mechanisms that underlie cognitive effort."} +{"text": "August 20\u201324, 2018, marks the fifth annual Contact Lens Health Week. In collaboration with partners from clinical, public health, industry, and regulatory sectors, CDC is promoting healthy contact lens wear and care practices to reduce the risk for eye infections among the approximately 45 million persons in the United States who wear contact lenses. Research after outbreaks of rare but serious eye infections in the United States has indicated that these infections occur most often in contact lens wearers who do not take proper care of their contact lenses, indicating a need to promote safer wear and care ( MMWR reviews cases of contact lens\u2013related eye infections associated with sleeping in contact lenses. Other reported habits in addition to sleeping while wearing lenses were swimming while wearing lenses and not replacing lenses and storage cases as often as recommended. Some of the patients sought care in an emergency department where it is more costly to receive care, and some of the infections led to serious adverse health outcomes.A report in this issue of Contact lenses can pose an infection risk, especially if they are not worn and cared for properly. Practicing proper contact lens hygiene is important for keeping contact lens wearers\u2019 eyes healthy.https://www.cdc.gov/contactlenses.Additional information on Contact Lens Health Week and the proper wear and care of contact lenses is available at CDC receives an annual contribution from the Contact Lens Institute to support CDC\u2019s Healthy Contact Lens Program. The Contact Lens Institute had no involvement in the drafting or review of this report."} +{"text": "In addition, pain chronicity, with its centralmechanisms, such as neuroplasticity and central sensitization, as well as theparticipation of psychogenic factors, makes it especially challenging to gain a completeunderstanding of the pathophysiology of these disorders(2).Temporomandibular disorders (TMDs) are widely described as heterogeneous conditionsaffecting the temporomandibular joint (TMJ) and masticatory muscles. However, TMD is ahighly generic term, referring to a group of disorders arising from the muscles(myogenic TMDs) or the joint (arthrogenic TMDs). The most common arthrogenic TMDs areanterior disc displacement of the articular discs and TMJ osteoarthritis. Each of thosedisorders has a complex pathophysiology and multiple risk factors, which interact indifferent ways in each individualRadiologiaBrasileira(3) makes important contributions to the understanding ofinternal TMJ disorders, mainly due to the large number of joints studied. The authorsdemonstrated that changes indicative of osteoarthritis were more common on the articularsurfaces of TMJs with anterior articular disc displacement than on those of TMJspresenting normal articular disc positioning, corroborating the findings of previousstudies involving considerably smaller samples. The study of interest, conducted byBedran et al.(3),presents interesting data regarding the osseous alterations of the articular eminenceand the articular fossa, findings that are highly relevant, considering that thoseanatomical sites are often neglected in the analysis of internal TMJ disorders onimaging examinations. However, despite the timely presentation of the data and theimportant contribution of that study to a better understanding of the internal disordersof the TMJ, the study design precludes any reliable inferences regarding temporal orcausal relationships between or among the different types of internal TMJ disorders.The article \"Changes in temporomandibular joint anatomy, changes in condylar translation,and their relationship with disc displacement: magnetic resonance imaging study\"published in the previous issue of (4)indicated that the risk of degenerative changes is 2.0 times higher in cases of anteriordisc displacement with TMJ reduction and 4.4 times higher in cases of anterior discdisplacement without TMJ reduction. Dias et al.(5) demonstrated that degenerative changes are8.25 times more likely to occur in cases of anterior disc displacement without TMJreduction. However, other authors have suggested that bone alterations caused by TMJosteoarthritis would lead to an incompatibility between the articular disc and themandibular condyle, with consequent anterior disc displacement of the TMJ, which wouldalso explain the higher prevalence of anterior disc displacement in degenerative TMJdisorders(6).In addition, it has been hypothesized that osteoarthritis and anterior disc displacementof the TMJ represent distinct entities, given that there are cases of osteoarthritis inTMJs with normal disc position and cases of TMJs with anterior disc displacement and nobone changes. Another important issue that must be discussed is whether anterior discdisplacement and TMJ osteoarthritis share the same risk factors, such as joint overload,which would also help explain the frequent concomitant presence of the two disorders inthe same joint(4).The causal relationship between osteoarthritis and anterior disc displacement of the TMJis still not well understood. It has been suggested that a change in the position of thearticular disc would lead to an increased mechanical load on the TMJ, thus contributingto the development of osteoarthritis. That theory is usually corroborated by data fromstudies demonstrating the association between the two disorders (osteoarthritis andanterior disc displacement of the TMJ). The study conducted by Roh etal."} +{"text": "Vulvodynia is an idiopathic chronic pain disorder and a leading cause of dyspareunia, or pain associated with sexual intercourse, for women. The key pathophysiological features of vulvodynia are vaginal hyperinnervation and nociceptor sensitization. These features have been described consistently by research groups over the past 30 years, but currently there is no first-line recommended treatment that targets this pathophysiology. Instead, psychological interventions, pelvic floor physiotherapy and surgery to remove painful tissue are recommended, as these are the few interventions that have shown some benefit in clinical trials. Recurrence of vulvodynia is frequent, even after vestibulectomy and questions regarding etiology remain. Vestibular biopsies from women with vulvodynia contain increased abundance of immune cells including macrophages as well as increased numbers of nerve fibers. Macrophages have multiple roles in the induction and resolution of inflammation and their function can be broadly described as pro-inflammatory or anti-inflammatory depending on their polarization state. This state is not fixed and can alter rapidly in response to the microenvironment. Essentially, M1, or classically activated macrophages, produce pro-inflammatory cytokines and promote nociceptor sensitization and mechanical allodynia, whereas M2, or alternatively activated macrophages produce anti-inflammatory cytokines and promote functions such as wound healing. Signaling between macrophages and neurons has been shown to promote axonal sprouting and nociceptor sensitization. This mini review considers emerging evidence that macrophages may play a role in nociceptor sensitization and hyperinnervation relevant to vulvodynia and considers the implications for development of new therapeutic strategies. Vulvodynia is a chronic pain disorder, usually characterized by pain localized to the vaginal entrance macrophages to M2 (CX3CR1high/Ly6C-) phenotype has been shown following phagocytosis of muscle cell debris, and whereas M1 macrophages coculture promoted proliferation of muscles cells, coculture with M2 macrophages stimulated cell growth. The critical role of macrophages is highlighted by observations that macrophage depletion at the time of injury prevents muscle repair to M2 (CD206+) macrophages compared to healthy controls, and this ratio correlated with measures of radiographic joint disease (Liu et al., The shift from M1 to M2 phenotypes appears critical for resolution of protective hyperalgesia associated with the acute inflammatory response. Spinal cord injury, a condition frequently associated with prolonged neuropathic pain, results in a sustained increased abundance of M1 phenotype cells in the spinal cord (Kigerl et al., Since vulvodynia is a condition affecting women, sex-related differences regarding nerve-immune cell interactions regulating nociceptive signaling are important to consider. Sex differences in clinical pain are well established, including higher prevalence of chronic pain among women compared to men, greater sensitivity of women to multiple measures of experimentally induced pain and different analgesic responses to opioid drugs (Bartley and Fillingim, Microglial promotion of spinal cord neuron hyperexcitability in models of neuropathic and inflammatory pain appears more important in males than females. Intrathecal LPS to activate microglia produces allodynia only in male mice (Sorge et al., In summary, data from human studies and animal studies investigating chronic inflammatory, neuropathic and cancer pain, all support the view that macrophage phenotype may be an important peripheral factor influencing pain sensitivity. Additionally, there is evidence M2 macrophages promote analgesia. In a model of peripheral neuropathic pain, application of cultured M2 macrophages to the injured nerve reduced mechanical pain sensitivity (Pannell et al., In vitro studies show distinct effects of M1 and M2 macrophages on neuronal growth and survival (Kigerl et al., Macrophage to neuron signaling may promote axonal sprouting and hyperinnervation. Pronounced and persistent hyperinnervation has been described following inflammation in skin (Reynolds and Fitzgerald, Cutaneous hyperinnervation induced by plantar injection of complete Freund\u2019s adjuvant is accompanied by abundant angiotensinogen and renin production in macrophages and T cells (Chakrabarty et al., The ability of macrophages to induce nerve sprouting is shown in sympathetic hyperinnervation following myocardial infarction in a mechanism involving their production of NGF (Hasan et al., Injury models indicate that actions of NGF mediated by macrophages may be sustained for prolonged periods. In the intervertebral disc injury model, injured discs contain increased abundance of macrophages, NGF mRNA and NGF protein 1 day following injury, and all three measures continue to be substantially increased 28 days following injury (Nakawaki et al., For many years lack of suitable models of vulvodynia was a major barrier to the development of treatments that specifically target the pathophysiology of the disease. Recently developed models of vaginal hyperinnervation in rats and mice are an important advancement (Farmer et al., However, a significant body of research demonstrates macrophages can contribute to hyperinnervation and nociceptor sensitization in multiple pathological conditions. Therapeutic approaches that target angiotensin signaling, putatively involving macrophages, appears promising in addressing key pathological features of vulvodynia. As with other organs in the body, the composition of embryonically and adult-derived macrophage subpopulations in the vagina is not yet clear, nor the extent to which local proliferation and circulating monocytes replenish and expand populations within a tissue in homeostatic and disease states. This could have implications on the effectiveness of interventions targeting monocyte migration or proliferation of subtypes of macrophages, in addition to factors altering macrophage polarization state. Studies clearly show macrophages are highly dynamic and can transition between polarization states that have distinct effects on nociception, suggesting they are a potential target for interventions to modulate pain sensitivity. Modulation of the microenvironment by interventions including exercise, can alter macrophage phenotype and shift the balance of their functions and potentially protect against the development of chronic pain.CB designed and drafted the manuscript. CB, DM and RH contributed to manuscript critical revision and read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Adiponectin, the most abundant secreted adipokine, has received great attention from the scientific community since its discovery . The hugThis Special Issue, entitled \u201cMechanisms of Adiponectin Action\u201d, shows the pleiotropic role of adiponectin by presenting three research articles and seven reviews focused on recent findings about adiponectin in different target tissues. The Special Issue contains two reviews about adiponectin in skeletal muscle, a classical adiponectin target tissue, in which the hormone affects both metabolic and regeCollectively, the papers reported in this Special Issue reinforce the idea that adiponectin plays an important role at the systemic level and that hypoadiponectinemia is associated with many diseases. The exogenous administration of adiponectin has often beneficial effects in diseased tissues, suggesting that the planning of new drugs able to activate adiponectin signaling could be a new tool for the amelioration of several pathologies."} +{"text": "OBJECTIVES/SPECIFIC AIMS: Expanded Access is an avenue for patients with no available treatment options to access investigational drugs and devices for clinical therapy. This process requires physicians treating these patients to submit requests to the FDA and the local IRB, processes which are typically unfamiliar to clinicians. METHODS/STUDY POPULATION: With the goal of reducing burden and ensuring access to investigational products, Michigan Medicine established the Expanded Access Oversight Committee in January 2015. This committee brought together key stakeholders to develop appropriate policy and infrastructure to support these requests. RESULTS/ANTICIPATED RESULTS: Outcomes from this committee have resulted in a uniform process with a single point of entry for interested physicians and patients. With standardized policy implemented across the institution, a revised IRB application has been developed that is more tailored to Expanded Access and an informed consent document has been developed specific to the clinical use of investigational therapies. To ensure timely execution of these agreements, the contracts office has streamlined the process for negotiating Expanded Access agreements with manufacturing companies. Further development has begun with the Michigan Clinical Research Unit to provide space for clinical visits in Expanded Access cases, allowing for initiation of outpatient therapy. These changes have allowed Michigan Medicine to support triple the number of Expanded Access requests, including more than 45 Expanded Access requests in fiscal year 2018. DISCUSSION/SIGNIFICANCE OF IMPACT: Institutional support for Expanded Access requests within a large academic medical center is feasible and can increase access to investigational therapies bfor patients."} +{"text": "The goal of most older adults is to live independently in their own homes, for as long as possible. There are many advantages to aging in place for the individual, but also challenges as changes in cognitive and physical health can occur over time. Especially for older adults living alone, tracking these changes is critical for early intervention and prevention. The relatively easy availability of consumer technology may provide one mechanism for monitoring older adults in their homes. We designed a pilot study to test the feasibility and acceptability of using wearable sensors (Fitbit sensors), in conjunction with automated interactive voice recognition technology (Amazon Echo), to monitor older adults\u2019 physical and cognitive health during daily activities. Participants were recruited from a housing complex for older adults with low income. They were interviewed about health monitoring technology before and after a 2-week measurement period during which they were expected to wear the Fitbit daily and interact with the Amazon Echo for 8 consecutive days. Feasibility challenges included limited skill in Echo interactions, remembering to do the assessments, and charging/uploading Fitbit data. Qualitative analysis of interviews revealed generally positive attitudes about technology, but low comfort operating the devices. These preliminary findings suggest that with additional training for older adults, sensors and voice recognition technologies could have significant roles in maintaining older adult quality of life by contributing to early detection of decline and timely intervention."} +{"text": "Strength and balance exercise programmes are effective in reducing the rate and risk of falls but uptake and adherence to community based programmes are low. Exergaming technology may be a promising tool to increase exercise uptake and adherence among seniors due to their motivational features. As yet, there is little published on the views of older people and therapists of their experiences of using Exergames to reduce falls in assisted living facilities that may inform implementation. This study is the qualitative component of a cluster randomized controlled trial that investigated the use of purpose-built strength and balance Exergames in community-dwelling older people in 18 assisted-living facilities in the UK. Data collection included 36 hours\u2019 observation, semi-structured interviews with 5 physiotherapists, assistants and researchers, and 13 focus groups with residents of assisted living facilities who had participated in a 12 week Exergame programme. Transcribed data were analysed using thematic content analysis to identify themes arising from older users\u2019 and therapists\u2019 experiences of using the Exergames. Findings suggest that the senior users enjoyed using the strength and balance Exergames and reported physical, psychological and social benefits. Although some games were generally favoured, there was no overall consensus on game preferences although social components, feedback, music and colourful animation appeared to increase the appeal of the Exergames. This is the first study exploring older users and therapists\u2019 perceptions of exergames in assisted living facilities and provides valuable insight into the barriers, facilitators, contextual factors and perceived benefits or drawbacks following 12 weeks use."} +{"text": "Pancreatic cancer is one of the leading causes of cancer-related death in the United States and survival outcomes remain dismal despite significant advances in molecular diagnostics and therapeutics in clinical practice. The microenvironment of pancreatic cancer carries unique features with increased desmoplastic reaction and is infiltrated by regulatory T cells and myeloid-derived suppressor cells which negatively impact the effector immune cells. Current evidence suggests that stellate cell-induced hypovascular stroma may have direct effects on aggressive behavior of pancreatic cancer. Preclinical studies suggested improvement in drug delivery to cancer cells with stroma modifying agents. However these findings so far have not been confirmed in clinical trials. In this article, we elaborate current-state-of-the science of the pancreatic cancer microenvironment and its impact on molecular behavior of cancer cells, chemotherapy resistance and druggability of stroma elements in combination with other agents to enhance the efficacy of therapeutic approaches. Pancreatic cancer is one of the most challenging cancers among gastrointestinal malignancies due to various factors including aggressive molecular behavior driven by the loss of multiple tumor suppressor genes , 2, lackThe pancreatic cancer microenvironment harbors unique characteristics that directly impact the molecular behavior of cancer cells. It is known to be relatively dense and enriched by pancreatic stellate cells which prIn this article, we discuss potential impacts of the pancreatic cancer microenvironment on therapeutic approaches and targetability of this dense tumor stroma to optimize the efficacy of treatments for this aggressive disease.Chemotherapy resistance, one of the key causes for the aggressive nature of this disease was attributed to multiple factors related to tumor characteristics such as epithelial-to-mesenchymal transition (EMT) , increasAt this juncture, studies combining stroma modulating agents in combination with cytotoxic agents have not demonstrated significant activity to change current clinical practice. Phase III trial of PEGPH20 with gemcitabine and nab-paclitaxel will likely provide more understanding on targetability of pancreatic cancer stroma in combination with cytotoxic agents. Future studies focusing on characterization of desmoplasia and its cause-effect relationship with pancreatic cancer stem cells may shed further light on druggability of the pancreatic cancer microenvironment in combination with cytotoxic agents.Targeted therapy in pancreatic cancer has not substantially achieved progress particularly due to its complex signaling network and rebound activation of alternative growth signaling pathways . ErlotinThe efficacy of immunotherapy in pancreatic cancer has been widely studied in preclinical and clinical studies. However, at this time the benefit of immunotherapy appears to be limited to only microsatellite instability-high (MSI-H) pancreatic cancer patients who had an objective clinical response with pembrolizumab in a phase II clinical trial . Single At this juncture, the pancreatic cancer microenvironment remains a dilemma for scientists particularly due to contradictory findings from reported preclinical and clinical studies. Current evidence fails to substantially support the notion of using stroma modifying agents to enhance cytotoxic drug delivery in pancreatic cancer. It is important to note that chemoresistance of pancreatic cancer is not solely related to the dense and fibrotic microenvironment and there are intrinsic factors that are associated with reduced sensitivity to cytotoxic agents as discussed above. Notably, phylogenesis of pancreatic cancer is not independent of its microenvironment and a high degree of hypoxia led by desmoplasia likely impacts the evolutionary expression profile throughout the development of cancer. Therefore, reversal of fibrotic stromal tissue without additive strategies targeting chemoresistant cancer cells will likely not be effective on the aggressive behavior of pancreatic cancer and may also lead to detrimental outcomes. However, targeted agents that are proven to be \u201chighly\u201d effective on multidrug resistant cancer cells may be an approach that can be investigated in preclinical studies and can be further examined in clinical trials if highly promising. Further studies on molecular biology for pancreatic cancer are also warranted to better understand the mechanisms leading to chemoresistance, which may trigger new approaches for targeted therapies in combination with stroma modulating agents.The efficacy of immunotherapy in pancreatic cancer has been so far disappointing in MSS patients. The lack of clinical response may partially be explained by the microenvironment, which is predominantly infiltrated by immune suppressive cells such as Tregs and MDSCs. Strategies targeting stroma and immune regulatory cells have not yielded significant clinical response at least partially due to hypoimmunogenic nature of pancreatic cancer. Cancer vaccines which are designed to prime immune cells and optimize the tumor microenvironment have not led to significant clinical progress due to rebound activation of inhibitory signals on cytotoxic T cells such as PD-1. The additive role of immune checkpoint inhibitors to GVAX is currently being investigated which may lead to a measurable anti-cancer immune response. Stromal remodeling therapies may also enhance the generation of secondary and tertiary lymphoid structures and potentiate the anti-cancer effect if combined immunotherapy approaches achieve substantial clinical response.To date, the unique features of the pancreatic cancer microenvironment have been extensively studied. However, the complexity of interaction between the microenvironment and cancer cells remains to be better characterized. The failure of stroma modifying agents revealed that we have not yet comprehended exact consequences of this dual interaction on the development and progression of pancreatic cancer. Although the current state of the science regarding the complex microenvironment of pancreatic cancer has not revealed druggable targets, ongoing and future studies may shed more light to unknowns of this complex interaction and uncover more facts on this dilemma which may provide further therapeutic tools to scientists and physicians to advance treatment options for this malicious disease."} +{"text": "Populations of minority older adults will continue to increase at an accelerated pace in the coming decades. As such, it is increasingly important to disseminate minority aging education and research topics in spaces that will prepare gerontology scholars to address the needs of diverse elders. This symposium will highlight efforts to diversify academic spaces by scholars engaged in minority aging education and research. The first presentation describes a service-learning pedagogical approach to teaching minority aging topics to graduate students. It will discuss how a gerontological social work course seeks to offer real-world learning experiences through community partnership. The second presentation discusses an experiential learning pedagogical approach to teaching social determinants of health to graduate students at a historically Black university and highlights how to apply theoretical concepts to creating community needs assessments and health promotion programming for the local community. The third presentation discusses efforts to teach undergraduate students about older LGBT individuals, who represent a growing group of minority elders. This presentation advocates for the use of various strategies for integrating both research and pedagogical approaches to increase knowledge and awareness of LGBT aging topics. The last presentation focuses on the promotion and dissemination of scholarship produced at minority-serving institutions (MSI) through the creation of a new open-source journal. This presentation describes publication challenges for tenure-track MSI faculty and developed opportunities for inclusiveness of such scholarship. The symposium discussant will summarize these challenges, opportunities, and implications to promote minority-focused gerontological topics in academia."} +{"text": "The benefits of early referral to hospice services have been well documented. However, late admissions and short hospice stays are ongoing issues that are often barriers to improving terminally-ill persons\u2019 and the caregivers\u2019 quality of life and the quality of care. Using ordered logistic regression, this study analyzed the length of stay of 7,307 patients who died in 2015 while receiving care in the largest hospice agency in the DC metro region. Cancer diagnoses and residence in a higher median income neighborhood were associated with shorter lengths of stay. Female sex, older age, and residence in a lower median income neighborhood were associated with longer lengths of stay. The findings indicate that differences in demographic and diagnostic characteristics likely affect hospice length of stay."} +{"text": "Orofacial cancers result in facial deformities and impairment of vital functions and are often lethal. These aggressive solid tumors exhibit great heterogeneity between them and show distinct and exclusive molecular alterations that deregulate the function of important signaling pathways. The Notch signaling pathway is involved in the initiation and development of orofacial cancers. Increasing evidence suggests that Notch molecules may have a dual function in cancer, acting either as oncogenes or tumor suppressor genes. Crosstalk between Notch and other signaling pathways provides a critical multidirectional control in these cancers. Protein phosphorylation is activated in cancers and therefore novel drugs inhibiting phosphorylation events (kinase inhibitors) are increasingly used in the treatment of cancers. Another pharmacological strategy is the selective targeting of Notch signaling in order to eliminate the cancer stem cells using monoclonal antibodies against specific regions of the Notch molecules. Organoids, \u201corgan-on-a-chip\u201d devices and single-cell genomic analyses could be used for further investigations and preclinical studies in orofacial cancers. Organoids can be used to study complex interactions between the various cells lines in orofacial cancers, as well as for the preclinical screening of novel drugs. Microfluidic culture systems, also called \u201corgans-on-chips,\u201d can be used to model cancer cell behavior within orofacial tissues and their environment. These chips also enable to vary drug delivery and composition in a controlled manner in order to study cancer tissue responses to various pharmaceutical anticancer products. Single-cell RNA-seq analyses allow exploring the genetic and functional heterogeneity of orofacial cancers at a cellular resolution, thus revealing new insights into tumor composition and drug resistance. These important technological developments and the innovative therapeutic strategies demonstrate significant promise and generate enthusiasm and optimism within the oncology community.cyclin D1 gene and region 7p11 that encodes epidermal growth factor receptor (EGFR) are the sixth most common cancers diagnosed worldwide and can result in facial deformities and impairment of vital functions such as swallowing, speech, and taste could be used in combination with chemotherapy or immunotherapy in order to reprogram cancer stem cells and sensitize to chemotherapy (Albiges et al., Notch is a key player in regulating cancer stem cell maintenance and mobility during metastasis (Artavanis-Tsakonas and Muskavitch, Although these recent findings have contributed to a certain molecular understanding of HNSCCs regulation, further investigations on the differences between HNSCCs and other cancer types and subtypes would surely increase the chances to treat better this disease. Genetically modified and humanized mouse models have been used to test epigenetic regulators and other candidates in HNSCCs (Porcheri et al., All these exciting recent developments generate enthusiasm and optimism within the medical community that selective targeted HNSCCs therapies will continue to improve and significantly extend patients' lives.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "African American men experience extremely high levels of social and psychological stress from unfavorable social and economic circumstances emerging from institutional discrimination and unfair treatment. Stress has been linked to disproportionate risks for illness, disease and premature mortality among this population. But, few studies have examined how African American men manage or cope with stress, and even fewer have assessed how their coping responses have implications for their health. Faith has been considered a stress coping strategy and a growing number of studies explore how religiosity and spirituality have implications for health outcomes. No studies to our knowledge have examined how faith impacts stress and its influence on the health among African American men. The purpose of this chapter is to demonstrate how faith has implications for socio-biologic interactions associated with elevated risk for disease and premature death among this marginalized population."} +{"text": "Aging is a complex trait is controlled by multiple genetic and environmental factors. Genome-wide screens in invertebrate organisms have led to the identification of hundreds of genes, whose deletion or knockdown can dramatically increase lifespan. Many of these genes represent conserved signaling pathways and biological processes suggesting that they might be involved in the regulation of mammalian aging. Nevertheless, the mechanistic basis by which the majority of these long-lived gene deletions extend lifespan remains poorly understood. Using yeast Saccharomyces cerevisiae as a model system, we employ systems biology network analysis of transcriptomic and protein expression data to build a detailed translational regulatory network of aging in yeast and identify genetic interactions among various aging pathways. Through these studies we expect to gain understanding how the regulatory networks are perturbed with aging, which could provide important insights into human disorders associated with the old age."} +{"text": "There are numerous potential applications for validated passive sampling techniques to measure persistent organic pollutants (POPs) in the atmosphere, but such techniques are still in their infancy. Potential uses include: monitoring to check for regulatory compliance and identification of potential sources; cheap/efficient reconnaissance surveying of the spatial distribution of POPs; and deployment in studies to investigate environmental processes affecting POP cycling. This article reviews and discusses the principles and needs of passive sampling methodologies. The timescales required for analytical purposes and for the scientific objectives of the study are critical in the choice and design of a passive sampler. Some techniques may operate over the timescales of hours/days, others over weeks/months/years. We distinguish between approaches based on \"kinetic uptake\" and \"equilibrium partitioning\". We highlight potentially useful techniques and discuss their potential advantages, disadvantages, and research requirements, drawing attention to the urgent need for detailed studies of sampler performance and calibration."} +{"text": "Clostridioides difficile infection, antimicrobial stewardship strategies including de-escalation protocols and stopping antimicrobials in non-infective cases should be a fundamental component of sepsis quality improvement initiatives.Sepsis and antimicrobial stewardship programmes coexist in tension, as they can appear to have apparently opposing messages around antimicrobial prescribing. In the era of increasing antimicrobial resistance (AMR), there is a need for greater alignment between sepsis and antimicrobial stewardship governance and management programmes. Antimicrobial therapy is an essential part of sepsis management with a focus on time-dependent recognition and resuscitation pathways.Media framing of sepsis and AMR has been identified as influencing public expectation of antimicrobial prescribing as well as health professionals\u2019 perceptions of optimal prescribing strategies. Sepsis media reports tend to use well-recognised triggers that increase public interest. These include emotive personal narratives that commonly centre on young patients, and which identify immediate solutions that are within the power of individual health professionals and the public . In contrast, AMR is framed as a vague threat affecting future patients and involving multiple actors, often under the \u2018One Health\u2019 umbrella.High-profile stories of preventable deaths from sepsis can lead people to potentially overestimate the frequency that an infection could be sepsis.The first step in sepsis management pathways is recognition of patients with sepsis; however, this itself is challenging. Sepsis is a subjective clinical rather than a laboratory diagnosis and recognition can be difficult, especially early in the clinical presentation when symptoms are non-specific and laboratory results are pending. This means clinicians must act before the results of investigations are available. While the majority of experienced clinicians report confidence in applying sepsis definitions, only a minority successfully identified sepsis case vignettes in an experimental test of their diagnostic accuracy.Current antimicrobial stewardship guidance aims to strike a balance between promptly managing suspected infection and avoiding antimicrobial overuse. Recommendations include the development of bespoke guidelines based on local AMR epidemiology to standardise antimicrobial prescribing, a blended learning approach to antimicrobial stewardship education, standardised antimicrobial consumption surveillance and close liaison with the diagnostic laboratory.C. difficile infection rates.Sepsis and antimicrobial stewardship initiatives are frequently implemented by different teams and individuals within healthcare organisations, resulting in lack of alignment of goals and activities. Hospitals in the USA were mandated to report compliance with the \u2018SEP-1\u2019 sepsis bundle from late 2015.While both the drive to tackle sepsis and antimicrobial stewardship initiatives represent efforts to implement evidence into practice and improve the quality of healthcare, the respective healthcare messages need to be more integrated. Sepsis and antimicrobial stewardship cannot be discussed in isolation and should be portrayed as two sides of the same coin. The terminology and framing used in relation to sepsis and AMR in the media and messages promoted through public health campaigns also need to be considered. Achieving an appropriate balance requires reframing AMR as an immediate problem with consequences for individual practitioners and patients. Furthermore, inappropriate antimicrobial prescribing should be framed as a public health threat and a patient safety issue. This should include highlighting positive effects of more targeted prescribing, including the reduction of individual side effects such as hospital-acquired, multidrug-resistant infections. Following principles from behavioural economics when formulating these health messages could help to balance perceptions of sepsis and antimicrobial stewardship and could help to achieve a \u2018recognition of necessity\u2019 to change prescribing approaches. Within healthcare organisations, there is a need for local alignment of sepsis and antimicrobial stewardship programmes, with coordinated responsibilities and consistent messages. In the future, new technologies enabling real-time, near-patient diagnosis of sepsis and identification of antimicrobial susceptibilities of the associated infection will be crucial to reducing uncertainty and the need for empirical prescribing decisions prone to bias. It will therefore require combined efforts from clinicians including sepsis and antimicrobial stewardship experts and social science researchers to influence policy makers, journalists and the public."} +{"text": "It is well-established that there is a critical shortage of trained health care staff who can deliver high-quality behavioral health services to persons with dementia. The development of innovative professional training curricula, and effectively implementing and sustaining such programs, is a key element in addressing this workforce crisis. This symposium highlights cutting-edge efforts being conducted across the continuum of care, to train health care professionals to support optimal behavioral health for persons with dementia. In the outpatient setting, Wyman et al. present data from a survey of mental health clinicians on their perspectives about working with persons with dementia and caregivers, revealing critical gaps in knowledge and skills to target in continuing education programming. Wray and colleagues focus on integrated behavioral health in primary care, discussing how geriatric experts can most effectively contribute to improved assessment and treatment within this setting. Koepp presents an innovative program to transform outpatient mental health care for persons with dementia through provider training and consultation. In the residential care setting, Reinhardt and colleagues report on the implementation of a comprehensive approach to the alleviation of behavioral health problems through training direct care staff in person-directed care in nursing homes. Finally, Karel et al share how VA interprofessional nursing home teams learn and sustain an evidence-based program to address behavioral concerns among residents with dementia. The discussant will lend a deep expertise in research and policy related to the geriatric workforce to her remarks on the presentations."} +{"text": "Accelerating global and regional environmental changes are likely to favor species that can rapidly adapt to new conditions. Long-lived, clonal species whose reproduction is mainly asexual have long been thought to possess a relatively low potential for adaptation. However, the potential for transmitting responses to environmental change between vegetative generations within clones could compensate for lack of natural selection based on sexual reproduction that is widely introduced in Europe. They suggest that epigenetic-based transgenerational inheritance may be relevant for adaption and evolution of P. nigra clones in contrasting or rapidly changing environments. Shi et al. reported that invasive populations of Alternanthera philoxeroides in China exhibit extremely low variation in DNA sequence, but high epigenetic diversity. They suggest that epigenetic variation may compensate for the loss of genetic variation in this invasive species and thus contribute to their success in novel environments.Three papers focus on the ecological significance of epigenetic regulation responses for clonal plants to different natural habitats. In a forum paper, Dong et al. tested effects of parental soil nutrient environments on offspring performance of the highly invasive, clonal herb A. philoxeroides at both the individual ramet level and the level of the whole generation of ramets. They provide novel evidence that the magnitude of parental environmental effects varied at different plant levels, and depended on propagule provisioning. Li et al. examined effects of parental shade environments on growth, morphological and physiological traits of a stoloniferous herb Centella asiatica. They found that transgenerational plasticity through both morphological and physiological flexibility was triggered across clonal generations of C. asiatica subjected to high/low light treatments, and such effects allowed offspring ramets to present adaptive phenotypes in response to the prevailing light environments. Fan et al. showed that physiological connection with parental ramets of a desert clonal shrub Calligonum mongolicum in favorable conditions can alleviate stress on offspring ramets exposed to wind erosion.Three papers report parental environmental effects on offspring fitness of clonal plants. Gonz\u00e1lez et al. examined the generality of transgenerational environmental effects in the clonal plant Trifolium repens with five genotypes and five types of parental environments. They found that transgenerational environmental effects were highly genotype-specific and common in some genotypes, and potentially under epigenetic control. Baker et al. set up two glasshouse shade environments for an inbreeding plant Polygonum persicaria, and measured ecological important traits of their isogenic offspring in both environments. They found that the adaptive effects of parental shading were pronounced and highly significant for seedlings growing under shade, and such effects were mediated by DNA methylation status of parent plants, rather than changes to propagule provisioning.Two papers consider the variation in transgenerational environmental effects among genotypes. Transgenerational environmental effects in sexually reproduced species have received considerable attention, but such effects in clonal plants have begun to attract interest. Researchers are recently attempting to advance understanding of the mechanisms for transgenerational environmental effects between vegetative generations, in the context of environmental variation. Clonal plants are widely distributed in nature and dominate a number of plant communities and ecosystems around the world. Therefore, knowledge of transgenerational environmental effects is important to understand how clonal plants can adapt efficiently to the ongoing, rapid change at both global and regional scales in natural environments. We hope the publication of this research topic will stimulate more studies on this important issue in the coming years.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The incidence of cutaneous melanoma has risen faster than any other malignancy worldwide.Biomarkers of disease help to stratify patients for different cancer treatments. The neutrophil\u2013lymphocyte ratio (NLR) represents the host systemic inflammatory response to cancer and is strongly associated with survival, recurrence, metastatic burden, and treatment response.We observed that a low NLR (<\u20092.5) was associated with over twice the risk of death from melanoma.Although we made substantial efforts to mitigate the risks of methodological biases in our work, further prospective work is needed to define the associations between localized melanoma and hematological biomarkers.The use of adjuvant immunotherapy for resected stage III/IV disease is now commonplace. Trials of neoadjuvant immunotherapy in high-risk resectable and oligometastatic melanoma prior to resection are now underway,Ultimately, multivariable modeling of biomarkers will improve the selection of patients for different treatments. To implement this type of \u2018personalized cancer treatment\u2019 and improve the management of melanoma, we must share data derived from international collaborations and exploit modern computational methods of modeling big data."} +{"text": "This paper reviews and compares demographic, socioeconomic, behavioral (including diet) characteristics and heath phenotypes of centenarians in China and Italy. The results revealed that the interactions between familial longevity and any one of the three environmental factors were significantly associated with the three health outcome indicators at old ages. We discovered that the effects of these environmental factors on the health outcome indicators were substantially stronger among elders who had no family history of longevity compared to centenarians\u2019 children who likely carry genes and/or inherited healthy behavior and better lifestyle from long-lived parents."} +{"text": "Nursing home stays often represent a time of change for residents and their social networks . Nursing home residents may be experiencing exacerbations of medical conditions, changes in physical functioning, and/or cognitive impairment. These changes often preclude the resident from returning to their pre-admission level of functioning, resulting in the need for adjustments for both residents and their social network. However, nursing home staff and residents/caregivers frequently have different expectations for post-discharge functioning. This may be the result of inadequate or unclear communication on the part of nursing home staff and/or residents and caregivers being unable or unwilling to internalize the information. The lack of shared expectations can leave residents and caregivers unprepared, creating unanticipated caregiving burdens for the social network and unwanted outcomes for the resident. We conducted interviews with 14 resident/caregiver dyads who experienced care transitions from VA nursing homes to examine expected and actual functioning and activities post-discharge. Using a qualitative content analysis approach, we identified several themes including marital strain related to mismatched expectations, impact of physical changes on Veterans\u2019 social functioning, and differences between planned and actual post-discharge activities. We will discuss the importance of clear communication about expectations throughout the nursing home stay. We will also provide suggestions for improving discharge care planning to ensure creation of shared expectations and timely communication to allow residents and their social networks to adequately prepare for nursing home discharge."} +{"text": "Bilateral vestibulopathy has had several names, paralleling growing numbers of publications and interest in its pathophysiology and treatment. The condition was formerly Dandy syndrome, eponymously associated with neurosurgeon Walter Dandy who worked at the Johns Hopkins Hospital from 1918 to 1946. Having developed expertise in vestibular schwannoma surgery, Dandy became interested in vestibular nerve section to treat Meniere's disease. He achieved early success at controlling vertigo in patients with Meniere's disease after unilateral sectioning of the vestibular nerve, and then began performing bilateral vestibular nerve section. The first descriptions of the consequences of this surgery were in 1936 by neurologist Frank Ford and neuro-ophthalmologist Frank Walsh, who both worked with Dandy at the Johns Hopkins Hospital .Although we understand the implications of cutting both vestibular nerves today, at the time, many clinicians had a poor knowledge of the role of the vestibular system. A popular notion held that the vestibular system was vestigial. Prominent English physician Edmund Hobhouse noted in a 1924 Lancet editorial: \u201cWe are driven to the somewhat painful conclusion that in the semicircular canals man possesses a beautiful and complex mechanism which has been superseded by higher development, and whose only positive function now is to produce some of the most disabling and distressing symptoms which the human body can experience; moreover, this mechanism is so bound up with the organ of hearing that it is impossible to remove it without inflicting the penalty of deafness .\u201d If vesHain et al. for comprehensive review). Surgery is no longer a common cause of bilateral vestibulopathy, and the etiology of bilateral vestibulopathy is more varied than once believed (Kattah). Fortunately, idiopathic cases of bilateral vestibulopathy are becoming less common. Authors in this issue have identified new causes such as amiodarone (G\u00fcrkov) and environmental toxicities like a type of military jet fuel . Others highlighted here include an accumulation of iron called superficial siderosis , as well as central vestibular lesions that can mimic peripheral ones .This research topic highlights the significant progress our field has made since Ford and Walsh's first descriptions of Dandy syndrome allow us to identify patterns of bilateral vestibular impairment . For instance, patients with Wernicke's encephalopathy, show a predominantly horizontal semicircular canal impairment . We also now have evidence for sequential episodes of superior vestibular neuritis leading to bilateral vestibulopathy . Rotatory chair testing may have new applications as well, by combining gain and time constant in a new variable to help determine the severity of bilateral vestibulopathy and to track progress during treatment .New diagnostic tests like video head impulse testing (vHIT) and vestibular-evoked myogenic potentials , they can be incapacitated by oscillopsia and unstable gait. Articles in this research topic show that patients with bilateral vestibulopathy depend heavily on other sensory cues such as vision and proprioception , and that covert saccades are triggered in order to decrease symptoms of oscillopsia . Vestibular physical therapy can be helpful. Lehnen et al. emphasize the importance of head motion while Ellis et al. propose newer cognitive interventions to improve self-motion perception.Many patients with bilateral vestibulopathy suffer, and although these patients may be spared spinning vertigo and have similar rates visual height intolerance to the general population (Lucieer et al. and Anson et al. report early work toward developing new validated outcomes measures for bilateral vestibulopathy. We must also better understand the causes of bilateral vestibulopathy and establish clear diagnostic criteria. Recently the committee for the classification of vestibular disorders of the Barany society has made an important first step, defining the condition as bilateral vestibulopathy and publishing consensus diagnostic criteria (New medical and surgical treatments are being investigated, including gene therapy to regrow hair cells and vestibular implantation. In order to determine whether new treatments are effective, well-defined and properly developed outcome measures are needed. criteria . The manBW and AT jointly contributed to this editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Symptoms of insomnia are associated with symptoms of depression and anxiety in older adults, yet less is known about the impact of specific forms of insomnia . We explored how insomnia type predicted symptoms of anxiety and depression in older adults . We hypothesized that onset and maintenance insomnia would have stronger relations to depression and anxiety than terminal insomnia. Regression analyses indicated that onset insomnia was the only significant predictor of anxiety symptoms, and maintenance was the only significant predictor of depressive symptoms. Thus, our findings suggest that despite overlap between depression and anxiety, insomnia may have different mechanisms of affecting each disorder. Implications for the treatment of anxiety and depressive symptoms by addressing insomnia problems will be discussed."} +{"text": "Published literature addressed public health aspects and associated risks with MG and necessity of public health preparedness as the responsibility of public health authorities 5. There are several concerns regarding MG from the viewpoint of public health authorities including risk of spreading infectious diseases by participants worldwide 6.Mass gathering (MG) is defined as \"any type of organized or spontaneous occasion that attracts sufficient numbers of peoples to strain the planning and response sources of the city or nation hosting the event\" st FIFA world cup, 2018, was hosted by Moscow, Russian Federation from Jun 14, 2018, to Jul 15, 2018. This large sporting event attracted large number of visitors from around the world. Public health authorities of hosting countries are responsible for public health events including potential outbreaks, which may occur during such type of MG. As WHO recommended, hosts of international and large MG should improve public health preparedness to prevent and mitigate the impact of potential public health emergencies with international concerns such as Middle East respiratory syndrome coronavirus (MERS-CoV) and similar infectious diseases 7.Different types of MG include religious, cultural and sporting ones are held by hosting countries throughout word. Recently the 219. Moreover, the spread of some health events which originated from hosted country may extend to home community once participants return to their own countries. This consideration is a serious challenge to countries, which departed MG participants when they affected by an infectious disease with long incubation period 6.In the process of a MG, the concentration of people may impact the local health systems. Public health authorities of such MG host country should follow critical proposed elements, including implementation syndromic surveillance systems or enhances surveillance systems, educating participants on occurred health events and other activities according to relevant guidelines in light of situationPublic health authorities of hosting countries of both sporting and religious MG are advised to consider the risk of spreading infectious diseases especially MERS-CoV. As a specific suggestion regarding Hamadan 2018 event, Hamedan capital of Asian tourism, public health authorities of Hamadan Province are suggested to consider similar requirements. In case of sporting events, it is strongly recommended to use FIFA or other federation's website as an opportunity to educate interested visitors on hand hygiene, respiratory hygiene practices and infection prevention measures."} +{"text": "Climate change poses a serious threat to efforts by developing countries to ensure food security and poverty reduction. The National Development goals of South Africa envisage the agricultural sector as a key driver for job creation and economic growth. This article seeks to investigate the adaptive capacity of the Ncunjane farming community in Msinga, KwaZulu-Natal in response to drought spells of 2010 and 2014. This article draws on data collected using both qualitative and quantitative methods in 2011 and later in 2015 with the data analysed through the Statistical Package for Social Science to determine significant correlations between variables. Analysis of the vulnerability and adaptive capacity is performed using conceptual framework. This study found that both smallholder farmers who engaged in livestock and crop production have experienced high cattle mortalities and stagnant crop productivity, which in turn put pressure on already constrained disposable household income because of increased food costs and agricultural input costs, particularly supplementary animal feed. Cattle owners were more vulnerable to drought because of poor risk management and thus became highly dependent on government to provide drought relief. Application for government drought relief was found not to be effective in cases of large herds of cattle. Variability of rainfall and prolonged heat spells has a significant impact on the sustainability of smallholder mixed-farming systems, leaving agriculture as a highly questionable form of livelihood for rural farming communities such as Msinga. The article recommends strengthened institutional mechanisms so that stakeholders should play a more meaningful role within provincial and local agriculture in leveraging government support but places emphasis on the adoption of innovative strategies that can potentially yield significantly resilient smallholder mixed-farming systems in the wake of climate variability. Climate change is generally regarded as a threat to efforts by developing countries to ensure food security and poverty reduction Province where extreme drought conditions were experienced by the farming fraternity during the growing season of 2014 through to late 2015, which had a more pronounced effect on the small-scale enterprises characterised by limited resources. Smallholder producers raised concerns over exorbitant agricultural input costs and the protracted period of low returns on production. The worse impact was on dry land conditions with smallholder producers experiencing increased crop losses and high cattle mortality rates because of a lack of adequate feed and water. In response, the KZN Provincial Department of Agriculture and Rural Development implemented a Drought Relief Plan to assist farmers by subsidising animal feed while the Department of Water and Sanitation provided much needed water to communities , manure and being sold to get immediate cash. These farming systems are commonly characterised by low production, poor access to productive assets such as infrastructure and credit among households with permanent jobs contributing 10.48% to household disposable income Mthembu . Agricullobola, for ceremonial slaughter, for hides that are used to make traditional clothing, for meat and for sales and hardy cattle breeds and goat production.Consider agroecological principles such as agroforestry, conservation agriculture or climate-smart agriculture.More strategic policy\u2013related and programme-related recommendations include the following:Train public extension and advisory services, animal health practitioners including social workers on climate change and adaption by society from a social, ecological and economic perspective. This calls for investment in employee capacity building and equipping them with the appropriate working tools or resources.Government to promote climate-smart innovations such as greenhouses and hydroponics through subsidies and low-interest loan facilities.Strengthen institutional mechanisms and promote intergovernmental relations for successful implementation of government drought relief support programmes.Encourage public\u2013private partnerships to leverage support for producers affected by climate change or drought.Research institutions to prioritise climate-smart innovations.Strengthen use of ICT and social networks through increased investment in rural ICT infrastructure, broadband and development of affordable, user-friendly applications.Adaptation presents producers with prospects for growth within agriculture in the awakening impact of climate change given that over time producers will eventually fully comprehend climate change and begin thriving in the advantages that comes with it."} +{"text": "Current guidelines recommend that survivors achieve regular physical activity and reduced inactivity to attenuate cancer and mortality risk and to promote quality of life. Optimal ways of obtaining physical activity or measuring how much exercise has been achieved continues to be a challenge, especially among older adults and cancer survivors. Our symposium will provide insights using big data to understand population level patterns of activity and potential benefits for survivors, examining implications for survival and key health outcomes, including multimorbidity and functional limitations. We will also discuss social and environmental determinants that may be important for older survivors in designing community interventions, especially in rural communities. These include considerations related to the built environment and social support to promote leisure-time physical activity in older survivors."} +{"text": "The combination of sensory and cognitive impairment is increasingly prevalent among older adults and may be an important driver of healthcare cost due to functional disability and reduced self-care. This presentation focuses on the relationship between hearing and/or vision impairment and cognitive impairment with hospital admissions and healthcare cost using data from the Medicare Current Beneficiary Survey, a nationally representative sample of community-dwelling adults. We show that the presence of sensory impairment is associated with increased risk of hospitalization regardless of dementia status. In adjusted models, annual total healthcare costs were generally higher among those with sensory impairments compared to those without sensory impairments. We will also discuss work related to the development of a prognostic model that provides estimates of hospitalization risk among older adults with self-reported hearing and/or vision impairment. This model may help inform allocation of health care resources to those at highest risk for adverse outcomes."} +{"text": "The proportion of the European population aged >65 years is expected to be 25% by 2030, with 20% of the global population projected to be obese by 2030 . UnderstThe effects of ageing on the contractile function of skeletal muscle has been thoroughly investigated, categorised by a reduction in both isometric strength and concentric power when quantified in both absolute and relative terms . The effBased on this understanding, if obesity effects on skeletal muscle function were to complement the responses seen with ageing, an additive effect would result in more substantial implications for locomotor function and health-related fitness. The small body of evidence that has explored this indicates poorer stair ascent and descent, impaired balance, a slower more tentative gait pattern and difficulties moving (activities of daily living) in sarcopenic obese individuals compared to aged lean counterparts . MoreoveStudies examining the contractile performance of isolated muscle have been important in informing our understanding of the muscle ageing response and have more recently been used to provide insight into the effect of obesity on muscle function. An isolated muscle model allows researchers to quantify direct muscle responses, distinguish fibre type-specific differences and allow a more accurate measurement of muscle quality. It has also been proposed that isolated muscle models provide a more accurate measure of fatigue resistance when comparing obese and normal weight experimental groups Recent research from our lab examininFuture work is required to understand the effects of chronic obesity (greater than the 9 weeks used in our study on isolated muscle function to provide a more accurate representation of long duration age-related weight gain. This, in combination with work examining the mechanistic changes that account for obesity-associated changes in aged muscle function, is important in developing therapeutic strategies to combat the detrimental effects of sarcopenic obesity on health-related fitness."} +{"text": "Scoliosis can be defined as complex spinal deformities, including thoracic kyphosis and spinal rotation, where the rotation of the entire spine causes a lateral curvature and asymmetry , 2. ScolOverall, 134 female primary school students participated in the \u201cScoliosis Early Screening and Prevention Program\u201d conducted by Incheon National University (INU) in 2015. The study population included 74 adolescents with idiopathic scoliosis and 60 healthy adolescents .The study was conducted after receiving the necessary consent from the students and the parents. All participants provided written informed consent, and the Institutional Review Boards at approved the study INU.A 3-dimensional spine structure analysis and plantar pressure device was used to measure and compare the factors that affect spinal deformity and the rotation of center of pressure in the static standing posture. These instruments allowed accurate and rapid measurements to be obtained since they were performed by surface tomography using a rasterized video method on four anatomical landmarks on the back of the body. The device provided data that were objective and highly reproducible without the risk of radiation exposure . We usedThe adolescents with idiopathic scoliosis showed statistical significance in scoliosis angle, kyphotic angle, and asymmetric angle of pelvic inclination compared to the healthy adolescents. The form of idiopathic scoliosis in adolescents is closely associated with deformities such as thoracic kyphosis and pelvic asymmetry. Moreover, significance was found in the rotational angle of the center of plantar pressure, indicating that spinal deformity influenced the static standing posture. Based on our findings, regular scheduled, systematic, early screening is needed to maintain proper posture in adolescents in their growing stages are also needed for public health."} +{"text": "The gut microbial community (Gut microbiota) is known to impact metabolic functions as well as immune responses in our body. Diet plays an important role in determining the composition of the gut microbiota. Gut microbes help in assimilating dietary nutrients which are indigestible by humans. The metabolites produced by them not only modulate gastro-intestinal immunity, but also impact distal organs like lung and brain. Micro-aspiration of gut bacteria or movement of sensitized immune cells through lymph or bloodstream can also influence immune response of other organs. Dysbiosis in gut microbiota has been implicated in several lung diseases, including allergy, asthma and cystic fibrosis. The bi-directional cross-talk between gut and lung (termed as Gut-Lung axis) is best exemplified by intestinal disturbances observed in lung diseases. Some of the existing probiotics show beneficial effects on lung health. A deeper understanding of the gut microbiome which comprises of all the genetic material within the gut microbiota and its role in respiratory disorders is likely to help in designing appropriate probiotic cocktails for therapeutic applications. The human microbiota is constituted by the microbial communities residing in various body sites considerably differs from infants who are formula-fed that are capable of digesting plant polysaccharides to yield SCFAs , which modulate the host immune system promote recruitment as well as maturation of immune cells which provide protection against inflammatory response . Butyrate works as an inhibitor of histone deacetylases (HDAC) and promotes acetylation of histone H3 at the promoter of the gene encoding FOXP3 increases All the above-mentioned findings corroborate that gut and lung are intricately linked organs which influence each others' homeostasis.Perturbation of the normal gut microbiota may be associated with development of experimental asthma and other respiratory disorders, as demonstrated in animal models B cells in significant numbers. Recent findings indicate that GALT-DCs can act as \u201cantigen presenting cells\u201d (APCs), thereby influencing differentiation and antibody secretion in B cells constitutes inductive as well as effector sites which are defined on the basis of their functional properties and anatomy. The immune cells migrate from these mucosal inductive to effector sites through the lymphatic system targeting the mucosa, plasma cells produce dimeric immunoglobulin A which are secreted by epithelia expressing polymeric Ig receptor in T as well as B cells and thereby boost their migration to small intestine destined to home into specific sites, interact with high endothelial venules (HEVs) on these effector sites is correlated with an increased risk of asthma in 2\u20137 years old Finnish children and higher risk of developing atopy/asthma in neonates patients show reduced microbial diversity as well as increased intestinal inflammatory markers is in confirmation with a similar decrease observed in patients with allergic responses. This indicates the potential of utilizing this pathway (and bacteria possessing it) in early diagnosis of respiratory diseases. Further, these bacteria can find potential applications as probiotics for treatment of several lung diseases like allergy, COPD, asthma, etc. The influence of dietary intake on butyrate production highlights a link between nutrition and lung immunity.A fiber rich diet changes not only the intestinal microbiota, but also affects the lung microbiota, indicating influence of nutrition on lung immunity as well as regulating innate immunity using toll-like receptors and the corresponding signaling pathways , the tumor is observed to be controlled to an equal efficacy as that seen with PDL1 specific antibody therapy. This PDL1 specific antibody therapy has shown promise in the treatment of advanced Non-small Cell Lung Cancer as well as other genera including Enterococcus and Streptococcus. The placebo comprised of products having the same acidity and taste, but which lacked live microorganisms. The trials showed no significant differences in several laboratory parameters between the probiotic treated groups and the placebo treated individuals pathway for diagnosis and assessment of lung diseases. In addition, our observation can be utilized for designing potential probiotic cocktails for treatment of lung disorders. Thus, the information based on the interactions amongst host genetics, diet and microbiota can be potentially used for designing personalized precision approaches for prevention as well as treatment of lung disorders.SA and SM designed the review and drafted the manuscript. Both authors approved the final version of the manuscript for submission.SM and SA are employed by company Tata Consultancy Services Ltd., (TCS) and are part of TCS Research. Both authors declare no competing interests. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript."} +{"text": "We have known for some time that being bullied was associated withchildren\u2019s and adolescents\u2019 adjustment difficulties andwell-being. In recent years, we have come to recognise that the impact ofchildhood bullying victimisation on the development of mental healthproblems is more complex. This paper aims to review the evidence for anindependent contribution of childhood bullying victimisation to thedevelopment of poor outcomes throughout the life span, including mental,physical and socioeconomic outcomes, and discuss the implications for policyand practice.Existing research indicates that (a) being bullied in childhood isassociated with distress and symptoms of mental health problems. This largebody of evidence supports actions aimed at reducing the occurrence ofbullying behaviours; (b) the consequences of childhood bullyingvictimisation can persist up to midlife and, in addition to mental health,can impact physical and socioeconomic outcomes. These new findings indicatethat interventions should also focus on supporting victims of bullying andhelping them build resilience; (c) research has identified some factors thatpredispose children to be targeted by bullying behaviours. These studiessuggest that public health interventions could aim at preventing childrenfrom becoming the target of bullying behaviours from an early age.It is a truism to emphasise that further work is needed to understandwhy and how young people\u2019s aspirations are often cut short by thisall too common adverse social experience. In parallel, we must developeffective strategies to tackle this form of abuse and its consequences forthe victims. Addressing bullying in childhood could not only reducechildren\u2019s and adolescents\u2019 mental health symptoms but alsoprevent psychiatric and socioeconomic difficulties up to adulthood andreduce considerable costs for society. There is little doubt today that being bullied is an adverse and stressfulexperience that casts a shadow on children\u2019s and adolescents\u2019well-being and development. But this has not always been the view. After severalyears of general scepticism about the true impact of bullying victimisation, it isonly recently that researchers, mental health professionals and policy makers havestarted to pay attention to the potentially harmful consequences of being bullied inearly life. This change in perception is reflected in different ways. First, thenumber of publications on the topic of bullying has grown exponentially since theearly 1990s see . ThisacThis review paper aims to summarise findings on the impact of being bulliedfrom population-based samples with prospective measures of bullying victimisation inchildhood or early adolescence. It emphasises longitudinal studies that examinedmental health and other outcomes up to adulthood, and considers how these findingsmay influence policy and practice. It also aims to provide pointers for futureresearch. This review paper does not report on children who bully others or focus onthe dyadic relationship between them and their victims. It does not focus onbullying victimisation among specific groups such as children with developmentaldisorders or disabilities, for example. This paper considers bullying as a globalform of abuse and does not distinguish specific types of bullying victimisation.This review paper is timely in light of the emphasis of current policies on youthmental health. It summarises the body of evidence so far on one of the mostprevalent risk factors for mental health problems in childhood and adolescence. Italso builds upon review papers published recently on the long-term outcomes of beingbullied and expapeer victimisation and bullyingare often used interchangeably, peer victimisation is not equivalent to bullying.For example, it is not bullying when two people of about the same strength quarrelor fight, but it is peer victimisation. An especially important feature of bullyingis the power imbalance between those who perpetrate bullying behaviours and theirvictims. Strength, number or size of those involved can place the victims at adisadvantage. The power imbalance can also be more subjective and difficult tocapture, involving factors such as popularity, intelligence or disabilities. It canalso be determined by the environment: a child who just joined a new school may beat risk of being bullied by others, as would a child belonging to a minority group.Dan Olweus, the founder of research on bullying, argued that the power imbalance isbest determined by the victims themselves (2013). Victims of bullying can also bullyother vulnerable youths. \u2018Bully/victims\u2019 represent a small butdistinct group of children who are involved in bullying both as a perpetrator and asa victim. The distinction between bullying and peer victimisation may appear trivialor pedantic but it is important when investigating the consequences of this form ofabuse. By definition, victims of bullying represent a group of individuals who, forvarious reasons, are less likely to retaliate when confronted with abusivebehaviours from their peers. They constitute a heterogeneous and vulnerable groupwho might be likely to experience adversity, adjustment difficulties or even mentalhealth problems at some point in their lives, despite the experience of bullying. Itis therefore reasonable to question whether the sheer act of being bullied trulycontributes to poor outcomes among the victims, and if so, how.Bullying victimisation is the repeated occurrence of abuse between peoplefrom the same age group where an imbalance of power makes it difficult for thevictims to defend themselves ,2013. BDetermining the impact of childhood bullying victimisation onchildren\u2019s and adolescents\u2019 mental health and well-being, as well asreducing the occurrence of bullying behaviours, are important for several reasons.First, bullying is common world-wide among children and adolescents. A survey ofchildren in nearly 40 countries indicated that approximately 13% of 11-year-oldsreported being the victims of bullying . PrevaleAs with victims of crimes or assaults, children and adolescents are likely toget upset when targeted by abusive behaviours. Young victims can manifest signs ofpsychological distress such as being tearful or irritable, losing motivation andexperiencing sleep problems. These could be considered as temporary reactions to astressful event and would normally recede with appropriate support when exposure tobullying behaviours cease. Documented reactions associated with bullyingvictimisation include being unhappy at school, difficulties in school adjustment andpoor school perceptions , facing Victims of bullying can also manifest symptoms of psychological distresscommonly associated with psychopathology. Studies have found that bullied youthshowed an increased risk of self-harm and suicidal ideation , and espLongitudinal study designs are instrumental for establishing the extent towhich being the victim of bullying is a contributing risk factor to the developmentof mental health problems. Establishing temporal priority \u2013 what come first,bullying victimisation or poor mental health \u2013 is an essential first step.Indeed, one important alternative hypothesis that must be ruled out is that earlymental health symptoms account for both an increased risk for being targeted bybullying behaviours and also for later psychopathology. Findings so far have shownthat over and above early signs of poor mental health prior to bullyingvictimisation, being bullied in childhood or in adolescence is associated with newsymptoms/diagnoses of mental health problems, and especially with later symptoms ofanxiety and depression . These sThe extent to which being the victim of bullying contributes to thedevelopment of mental health problems in childhood and adolescence has criticalimplications for prevention and intervention efforts. Although these strategies areimportant to safeguard the human rights of children, reducing bullying behaviourcould be an expensive and ineffective way of decreasing children\u2019s earlysymptoms of poor mental health if being bullied is spuriously associated with pooroutcomes. Strong and robust tests supporting the assumption that being bullied inchildhood can actually contribute to mental health problems remain sparse. Onereason for this is the limits of observational studies most commonly used to examinethe outcomes associated with being bullied in childhood and adolescence. Randomisedcontrolled trials would allow proper testing for a possible causal role of bullyingvictimisation, but randomly assigning children to bullied and nonbullied conditionsis not an option for obvious ethical reasons. Researchers therefore have to resortto using alternative study designs and statistical methods to strenThree longitudinal studies have used the discordant MZ twin design to testthe robustness of the impact of being bullied in childhood on mental healthoutcomes. A first study from the Environmental Risk (E-Risk) Longitudinal Twin Study showed tDespite these strong findings, not all bullied children end up developingmental health problems. Studies testing the modifying effect of variables onoutcomes associated with bullying victimisation are also important. First, thisresearch may help disentangle and characterise subgroups of youth who are mostlikely to develop problems as a consequence of being bullied. There are a fewexamples of such studies focusing on biological factors. One study showed thatvariation in the serotonin transporter (5-HTTLPR) gene, involved in mood regulationand depression, moderates children\u2019s emotional problems in response tobullying victimisation: frequently bullied children with the SS genotype were atgreater risk for developing emotional problems than were children with the SL or LLgenotypes . AnotherSecond, studies of social factors can help identify targets forinterventions aimed at reducing symptoms of mental health problems. One studydemonstrated that most bullied young adolescents do not engage in self-harmingbehaviours, but those who did were more likely to have a family member who hadattempted/completed suicide, compared to those who did not self-harm . They weThe evidence reviewed thus far indicates that being bullied in childhood isnot only associated with signs of psychological distress but also with symptoms ofmental health problems in childhood and adolescence. These findings support actionsto stop bullying behaviours in order to reduce suffering in youth and prevent thedevelopment of mental health problems. Such actions are already in place.To date, relatively little is known about the longterm impact of bullying,as only a few longitudinal studies with prospective measures of bullyingvictimisation in childhood have followed participants into adult life.\u2018Long-term\u2019 is characterised here not only by the age of theparticipants when outcomes were assessed, but also by the time lag between exposureto bullying victimisation and mental health problems. So far, four longitudinalcohorts have documented the adult outcomes of childhood bullying victimisation, atleast 10 years apart, with adequate consideration for childhood mental healthproblems and other confounders. The Epidemiologic Multicenter Child PsychiatricStudy is a prospective nationwide birth cohort study from Finland . InformaThis limitation was addressed in an accelerated population-based study withoutcome measures collected during research-based assessments, the Great SmokyMountain Study from North Carolina in the United States . InformaThe long-term impact of childhood bullying victimisation was furtherinvestigated in National Child Development Study (NCDS), or the 1958 British CohortStudy, a 50-year prospective followup of a UK birth cohort . InformaN = 30) and the reporting period covering mostly theadolescent years, may explain the dissimilarity in the conclusions.The fourth birth cohort study partially corroborates the pattern of findingsobserved so far. The Christchurch Child Development Study is a longitudinalexamination of 1265 individuals born in Christchurch New Zealand, in 1977 . Data onThe findings reported here are based on observational data and thus do notallow causal inferences. The consistency of the findings across the four cohorts is,however, compelling. These studies (a) used prospective measures of bullyingvictimisation in childhood and later outcomes in adulthood; (b) controlled formental health problems in childhood, indicating that bullying victimisationcontributes either to the onset or worsening of mental health problems in lateryears; (c) accounted for a range of confounders that might also explain poor lateroutcomes in young victims of bullying, including childhood IQ, parental SES, otherforms of adversities and gender; and (d) are representative of the populations offour different countries. Conclusions from these studies cannot be ignored. Takentogether, these findings suggest that the impact of bullying on the young victimsmay persist once the bullying has long stopped. Tackling bullying behaviours may notonly reduce children\u2019s and adolescents\u2019 mental health symptoms andadjustment difficulties, but also prevent psychiatric problems in adulthood.Furthermore, if symptoms persist beyond the childhood and adolescent periods, thisindicates that support to young victims, even after the bullying has stopped, isnecessary to reduce the long-term burden of mental health difficulties among youngvictims of bullying.The long-term impact of bullying victimisation explored by the fourlongitudinal cohorts described above was not limited to mental health problems.Focusing on outcomes in the adult years opens up the possibility of examining arange of life domains more difficult to study in childhood or adolescence. These arephysical health, criminal and socioeconomic domains.Examining physical health outcomes associated with bullying victimisationamong children and adolescents is challenging as most chronic diseases arerelatively rare at this young age and risk indicators may still be latent. Withhigher prevalence rates of diseases, the midlife period offers the possibility ofrobustly exploring these long-term outcomes. Findings from NCDS indicated that beingbullied in childhood was associated with self-ratings of poor general health at age50 and thisCriminal outcomes have been associated with bullying victimisation, but morespecifically with bully/victims. Boys who both were frequently bullied by others andwho also bullied others in childhood had an increased risk for repeated offendingwhen they were aged 16\u201320 years according to the Finnish National PoliceRegister data . This riThe impact of bullying victimisation has further been found to extend toeconomic hardship, social relationships and perceived quality of life in the adultyears. Individuals who had been bullied in childhood had difficulties keeping jobsin young adulthood andwereThe consistency of findings with regard to poor physical and socioeconomicoutcomes observed among victims of bullying, across ages and across cohorts, isagain striking. It is important to note, however, that poor long-term outcomes wereobserved especially for those who were frequently or chronically bullied inchildhood, and in the case of criminal outcomes, more often among those who werebully/victims. Taken together, these findings suggest that childhood bullyingvictimisation is not only associated with individual suffering but could also belinked to considerable costs for society given its pervasive impact on physical,criminal and socioeconomic outcomes. Some studies have already pointed out theconsequences of childhood bullying victimisation on the health care system. TheFinnish birth cohort showed that participants who were frequently bullied inchildhood were more likely to have received psychiatric hospital treatment and usedpsychiatric medications at age 24, over and above psychopathology prior to bullying. These eSimilar to children and adolescents who suffered from maltreatment, youngvictims of bullying may need support to overcome their difficulties facing thisstressful situation. Appropriate interventions may be as simple as schools andfamilies acknowledging the impact of being bullied to prevent normal reactions ofdistress from developing into mental health problems . StudiesThe evidence supporting the persistent impact of bullying victimisation onpoor outcomes up to adulthood is intriguing. However, the developmental processesthat translate childhood bullying victimisation into poor outcomes up to adulthoodremain unclear. How can abusive behaviours perpetrated by other pupils andclassmates leave marks observable well into adult life? We need a betterunderstanding of these interactive processes to identify specific targets forintervention programmes aimed at reducing the harmful outcomes of being bullied andbuilding resilience among young victims.5-HTTLPR compared to their nonbullied cotwins in the mesolimbic dopamine pathway to explain socialaversion among mice exposed to repeated aggression and offer anopportunity to explore biological mechanisms in more depth. For example, anexperiment on mice demonstrated the role of brain-derived neurotropic factor. This framework lists 11 principles to assistschools in providing a safe environment to their pupils. These include: promotecare, respect and cooperation and value diversity; recognise the critical importanceof preservice and ongoing professional development in creating a safe and supportiveschool environment; focus on policies that are proactive and oriented towardsprevention and intervention; and take action to protect children from all forms ofabuse and neglect. Comparisons of cross-sectional data across 4 years indicate thatrates of bullying have only moderately declined and reports from staff suggest poordevelopment and implementation of the NSSF strategies .Findings from the United States are somewhat more encouraging. A recentstudy examined the effectiveness of the antibullying legislation using data from 25different states. Students living in a state complying to at least one guidelinerecommended by the Department of Education had a 24% reduction in reporting of beingbullied .FindingA study reported on the changes in bullying behaviours, mental health andmental health service use in Finland . A compeNumerous school-based prevention and intervention programmes have emerged inrecent years with the aim of reducing bullying behaviours. Such programmes varywidely with regard to their focus and methods of delivery. For example, someinterventions target the implementation of new curriculum. They commonly includevideotapes, lectures and discussions around the topic of bullying with the aim ofpromoting attitudes against bullying and prosocial behaviours. They are usuallylimited in time and in outreach by involving mostly classrooms for a few weeks.Instead, a whole-school approach implements rules and sanctions school wide, trainsteachers in methods for handling bullying, teaches conflict resolution strategiesand offers counselling support. It also involves a wide range of people includingall pupils, teachers, school staff, families and when possible, communities.Examples of such programmes are the well-known Olweus Bullying Prevention Program and the KiVa was built from two lines of research, one on aggressive and bullyingbehaviours and one on the participant roles of bullying . This inSystematic reviews have evaluated the effectiveness of antibullyingprogrammes more generally and provide encouraging findings with slightly greaterreduction in bullying behaviours than bullying victimisation and associated pooroutcomes . OverallIt might be considered controversial to investigate early factors that couldincrease the risk of children and adolescents becoming victims of bullying. Thisendeavour goes against a general assumption that bullying has nothing to do with theunfortunate victims, but all to do with the perpetrators of bullying behaviours.However, the search for these predictors is central to our understanding of theimpact of being bullied in childhood. It is crucial for research to account forthese factors when determining later outcomes associated with being bullied inchildhood. From a prevention perspective, it is also imperative to identifycharacteristics that render children vulnerable for bullying victimisation .Although prospective longitudinal studies remain the exception in this lineof research, findings indicate that both contextual and individual factors areassociated with youths\u2019 risk of being bullied. A meta-analytic investigationand empirical studies have reported that being the victim of bullying, includingbeing a bully/victim, is associated with a range of factors including male gender,young age, low social competence, difficulties solving social problems and socialrejection/isolation . In lineThe role of families has also been emphasised as an important factorassociated with the risk of being bullied : lowparTwins studies have pushed further the search for factors associated withbeing bullied by showing it is partly heritable. One study found that geneticinfluences accounted for over two-thirds of individual differences inchildren\u2019s bullying victimisation during the first 2 years of their formalschooling . This fiThe mechanisms explaining how specific characteristics and environmentstranslate into a risk for children being bullied are not fully understood: anxiousand depressed children may be perceived as easy targets who will not retaliate whenother children are abusive towards them. Aggressive children may attract hostilityfrom other children. Contextual factors may also influence child characteristics,which in turn affect their risks for being bullied. For example, one study has shownthat individual characteristics including aggressiveness, social isolation, academicperformance, prosocial behaviour and dislikability accounted for the effect ofsocial circumstances on preadolescents\u2019 risks for being bullied . HoweverThere is no such thing as a profile for the typical young victim ofbullying. In addition to contextual and individual factors, circumstances such asmoving to a new school or starting to wear glasses may also put some children atrisk of being bullied. However, evidence indicates that youths from deprivedsocioeconomic backgrounds, who have previously experienced violence victimisationand who already show a vulnerability for developing mental health problems have anincreased risk of being bullied, via both genetic and environmental pathways. Thisbody of research has identified individual and contextual factors among children andadolescents that contribute at making them potential victims of bullying. It isimportant for prevention strategies to consider these factors because they couldbecome targets of fruitful early interventions to stop some children from beingbullied in the first place.A public health approach aimed at preventing vulnerable children frombecoming the targets of bullying may be an effective strategy to reducesociety\u2019s burden related to bullying. For example, instructing young children skills for facingadversity and standing up to bullying may contribute to reducing this form of abuse.Prevention programmes aimed at building resilience could also benefit young childrenlikely to be exposed to this form of abuse. Providing children with tips on how tomake and keep friends may be an example of such intervention and thisThe evidence reviewed above provides strong and robust support for anindependent contribution of childhood bullying victimisation to the development ofpoor outcomes throughout the life span, including mental, physical and socioeconomicoutcomes. However, several important questions remain unanswered. Here are afew.First, there are increasing concerns about the impact of cyberbullying andInternet harassment. This form of abuse deserves careful attention given thewidespread use of social media by young people today. While it is not clear whetherharassment on the Internet and social media is a true form of bullying , it has been associated with symptoms ofmental health problems (for a review see Second, considerable attention has been focused on bullying in the childhoodand adolescent years. Bullying also takes place among adults with potentiallydamaging consequences, domestic violence potentially being one such example. Someresearch has been conducted among specific groups such as prisoners but thisThird, the role of genetic factors has been neglected when it comes tounderstanding the impact of being bullied in childhood. It is important to considergenetic influences to fully recognise the extent to which bullying affects pooroutcomes in later years and identify most at-risk groups. It is also important toexplore the genetic influences that contribute to the risk of being bullied. Thismay provide fruitful avenues for preventing young children from being bullied in thefirst place. As an example, the use of polygenic risk scores could help identifyheritable characteristics associated with the risk of being bullied at a youngage.Fourth, the examination of the outcomes associated with childhood bullyingvictimisation should not be limited to individual consequences and could be extendedto societal impacts, including institutions and systems. Emerging studies on themental health service use are good examples. Research could include measures of theconsequences of bullying victimisation on health institutions, social services andthe education system. In addition, studies could also include measures of economicimpact.Fifth, developing new innovative and rigorous research designs remainscrucial despite the strong evidence reviewed above showing that being bullied inchildhood can have a significant harmful impact. The use of natural experiments andother innovative study designs to support causal inferences of the role of bullyingvictimisation could strengthen current evidence. The use of animal models, whereresearchers can exercise greater control over the environment, can help unravel themechanisms behind poor outcomes associated with being bullied. Modifications inanimal social hierarchies are well suited to examine the impact of bullyingvictimisation and easily allow the observation of associations between changes insocial status and changes in outcomes. Natural experiments such as the discordantmonozygotic twin design also have the potential to strengthen conclusions bycontrolling for a wide range of confounding factors including genetic influences.Better control of confounding variables and especially other forms of victimisationis also crucial. The use of propensity score models could heSixth, there is a lack of neuroimaging findings on structural and functionalbrain differences among children and adolescents\u2019 victims of bullying. Basedon recent review of studies in youths who experienced maltreatment , wewoulBased on existing evidence thus far, bullying should be considered asanother form of childhood abuse alongside physical maltreatment and neglect. Severalrigorous studies reviewed above provide strong and robust support for an independentcontribution of childhood bullying victimisation to the development of poor outcomesthroughout the life span, including mental, physical and socioeconomic outcomes.Further research is needed to better understand the mechanisms explaining theemergence and the persistence of these poor outcomes. In the meantime, effortsfocusing on stopping bullying behaviours should not only be supported but also bewidened to provide appropriate help to the young victims and prevent children andadolescents from becoming the target of bullying."} +{"text": "Understanding the resident experience is a critical step to creating a sustainable and replicable model of affordable resident-centered housing with supportive services programs. This study thus draws lessons from focus groups with participants in the R3 program for designing and implementing such initiatives in affordable senior housing. Findings indicate that the R3 program brings value to residents: they benefit from reliable information on health-related issues, as well as emotional support and assistance with accessing appropriate care. By focusing on prevention and ensuring timely access to services, findings suggest how the intervention could promote seniors living independently longer and lower health system costs. Results also suggest ways to improve the effectiveness of housing with services programs, including providing clarity regarding the purpose of the program, its components and staffing, building trust between program staff and residents, addressing concerns about privacy and confidentiality, and implementing a multipronged marketing and promotion strategy."} +{"text": "Osteochondral lesions (OCL) of the talus involve both articular cartilage and subchondral bone of the talar dome. This term refers to a wide spectrum of pathologies including mild bone marrow contusion as well as severe osteoarthritis resulting from long standing disease. Although Magnetic Resonance Imaging (MRI) at 1.5 Tesla is the leading cross-sectional modality for detection and staging of OCL, lack of spatial resolution hampers accurate assessment of thin articular cartilage. Cone Beam Computed Tomography (CBCT) arthrography is better suited for precise staging of cartilage lesions. The purpose of this pictorial review is to illustrate the strength of each imaging method. Osteochondral lesions (OCL) of the talus are defined as any damage involving both articular cartilage and subchondral bone of the talar dome. This term covers a wide spectrum of pathologies including (sub)chondral contusion, osteochondritis dissecans, osteochondral fracture and osteoarthritis resulting from longstanding disease. Subchondral bone involvement can be manifested by bone marrow edema (BME), fracture, sclerosis and/or cyst formation. Cartilage damage may have a variable imaging appearance ranging from a small fissure, a distinct defect, flap formation or delamination. The majority of those lesions occur in active patients and are related to trauma. The location of the lesion at the talus is related to the mechanism of the injury and direction of the applied force Figure .Osteonecrosis can develop when the lesion\u2019s vascularity is disrupted. The articular surface of the talus is large and its blood supply is critical in the watershed areas explainiAccurate staging of cartilage lesions is of utmost importance, as this will have a major impact on the treatment strategy and ultimate prognosis. Unstable lesions \u2013 if left untreated \u2013 predispose for early osteoarthritis. Arthroscopic evaluation of the cartilage is regarded as the gold standard , but dueSchematic drawing shows the basic anatomy of the talocrural joint Figure . On plaiFor staging of OCL of the talus several grading systems have been proposed. The first system of classification has been reported by Berndt and Harty in 1959 , includiDue to the widespread use of fluid-sensitive sequences on MRI, even subtle foci of BME may be seen adjacent to a cartilage defect, particularly in acute or subacute OCL lesions. On the other hand, although MRI a very useful and sensitive technique for evaluation of the subchondral compartment (showing either BME or cyst formation), the precise depth and extent of the overlying cartilage lesion is often not accurately staged. In adult patients, the depth of the cartilage lesions is often understaged Figures and 4.Because the plasticity of the cartilage in children and adolescents is higher than in adults, OCL lesions in young patients are often characterized by isolated subchondral bony changes without overlying cartilage disruption Figure .An alternative MRI staging system has been proposed by Mintz et al. iStage 1 lesions are due to bone marrow contusion. MRI is the most sensitive method to depict this stage without any correlating signs on CR or CBCT with injection of intraarticular contrast. Articular cartilage lining remains homogenous without any signal changes , complex (one lesion with variable depth of the lesion) or multifocal .CBCT, which was first introduced for preoperative evaluation of dental implants, is currently also used for musculoskeletal applications. It uses a conical X-ray beam and flat-panel detector collecting all volumetric data in one rotation of the gantry. It combines high spatial resolution, relatively low radiation dose and low equipment cost and is useful for evaluation of trauma of small bones and joints, particularly when there is clinical suspicion for a fracture despite negative plain radiographs . The equDue to its noninvasiveness, absence of radiation exposure and its ability to visualize associated concomitant soft tissue abnormalities, MRI is the initial technique for exclusion/confirmation of an osteochondral lesion of the ankle. Additional CBCT-Arthrography is, however, very useful for more accurate cartilage staging and should be considered in those clinical scenarios where arthroscopic treatment of the lesion is considered."} +{"text": "Whole genome sequencing (WGS) plays an increasing role in communicable disease control through high-resolution outbreak tracing, laboratory surveillance and diagnostics. However, WGS has traditionally relied on microbial culture in order to obtain pathogen specific DNA for sequencing. This has severely limited the application of whole genome sequencing on pathogens with fastidious culturing requirements. In addition, the widespread adoption of culture-independent diagnostic tests has reduced availability of cultured isolates for confirmatory testing and surveillance. These recent developments have created demand for the implementation of techniques enabling direct sequencing of microbial genomes in clinical samples without having to culture an isolate. However, sequencing of specific organisms from clinical samples can be affected by high levels of contaminating DNA from the host and other commensal microorganisms. Several methods have been introduced for selective lysis of host cells and/or separate specific organisms from a clinical sample. This review examines the different approaches for sample preparation that have been used in diagnostic and public health laboratories for metagenomic sequencing. Escherichia coli (The ability to perform high-throughput whole genome sequencing (WGS) on infectious agents has revolutionized research into microbial genomics \u20133. WGS hhia coli . The curhia coli \u201314. HoweMolecular-based culture independent diagnostics test (CIDT) methods offer significant advantages for diagnostic microbiology laboratories, the most important being a reduction in cost and an decrease in turn-around-time \u201317. The Metagenomics offers unbiased sequencing of all DNA in a clinical sample without culturing individual bacterial isolates [reviewed in ]. The apThe shotgun metagenomics has been applied for pathogen discovery or to uncover the etiology of an unrecognized infection , 24. MetBrucella in cerebrospinal fluid (CSF) from a patient with partially treated meningitis where the causative agent could not be determined via traditional microbiological methods targeting common neurotropic pathogens present unique and specific challenges reflecting their matrix and concentrations of the target pathogen and resident microflora. Samples like urine and swabs will have low target pathogen cell counts making it difficult to extract a high concentration of genomic DNA (gDNA). In contrast, human stool samples are comprised of a complex matrix of fibers, enzymes, undigested parts, and other inhibitors which have to be removed during DNA extraction . Both stThere are three key challenges of sequencing microbial organisms directly from a sample: (i) contamination of host DNA and other microorganisms, (ii) low cell abundance of the target organism present in the sample, and (iii) presence of DNA amplification inhibitors and other confounding variables in the clinical sample matrix. Therefore, several complementary methods have been developed to reduce the presence of host DNA or separate out the microbial DNA. Afterwards usually an enrichment method is then used to address the low microbial DNA. Noteworthy, the DNA enrichment process can increase the risk of selection bias. The key pre-treatment methods for metagenomics are summarized in Figure Chlamydia trachomatis directly from genital swabs and bacterial load as few reads were obtained for the pathogen of interest both in this example and from the CSF case mentioned previously selectively targets methylation sites in eukaryotic DNA and binds it to magnetic beads. This approach was used to directly sequence 13 samples . Withouteviously . The sucMycobacterium tuberculosis from respiratory specimens was based on osmotic lysis, where a large volume of sterile water is added to a sputum sample to increase the osmotic pressure and cause human cells to burst while leaving the more robust M. tuberculosis cells intact and salt buffer (5.5 M NaCl). Nanopore sequencing also has the significant advantage of providing real time data acquisition and analysis compared to the Illumina platform, allowing for fast turnaround time of clinical results.Another study demonstrated an improved method of human cell depletion over the Molysis kit . The metXT) originally for the enrichment of specific regions of large eukaryotic genomes for deep sequencing of a selected subset of genes to capture and amplify mycobacterial DNA , which target only s genome . Thereforial DNA , which rrial DNA .Risk of laboratory contamination and enrichment biases are of particular concern as the use of highly sensitive clinical metagenomics becomes more widespread. Possible sources of DNA contamination include extraction reagents and columns, PCR reagents and library preparation reagents , 59. AnoTwo significant objectives must be achieved to facilitate the implementation of metagenomics into public health laboratory surveillance and outbreak investigations. Firstly, the analytical sensitivity of metagenomic methods should be improved and validated . This evMetagenomics has yet to be implemented into routine diagnosis and few long term studies have been conducted. However, future advancements in sequencing technology will most likely be the deciding factor as to when metagenomics will be integrated into public health surveillance. Sensitivity of shotgun metagenomics will improve as new sequencing platforms are released that can efficiently generate longer sequencing reads with higher depths. In addition due to the various sample types and data analysis methods available, laboratories will need to clearly define the intended clinical usage and range of pathogens that will be detected as this will greatly impact the choice of methodology for sample preparation and DNA extraction.NB and RR complied and wrote the manuscript. VT and VS were involved in review and editing.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The glycogen storage diseases (GSDs) are a group of inherited metabolic disorders that result from a defect in any one of several enzymes required for either glycogen synthesis or glycogen degradation. The traditional diagnostic approach is based on the invasive hepatic or muscle biopsies, which are neither cost effective nor convenient. Molecular (gene testing) has emerged over the course of past few years as a robust alternative diagnostic tool, which not only confirms the diagnosis of GSDs but also clearly differentiates the types of GSDs allowing the initiation of the type-specific appropriate treatment for the particular type of GSDs. The aim of this update is to highlight the limitations of undertaking a liver biopsy for the diagnosis of GSDs; and to further describe the pros of the molecular testing for better patient centered care. A distinct group of inherited metabolic disorders caused by a defect of the enzymes involved in glycogen synthesis, degradation, or regulation are classified under the umbrella term of glycogen storage diseases (GSDs). Several studies have reported the overall GSD incidence to be approximately 1 case per 20000-43000 live births.1Glycogen is the storage form of glucose and the chief source of non-oxidative glucose disposal. It is most copiously present in the liver and muscle cells, in addition smaller amounts are present in brain, heart, kidney, adipose tissue and erythrocytes. It serves to maintain glucose homeostasis in the liver whereas provides substrates for the adenosine triphosphate (ATP) in the muscles.2The GSDs can be classified on the basis of organ affected and the enzyme deficiency involved. On the basis of target organ involved GSDs are comprised of three broad groups including; hepatic type of GSDs, muscles type of GSDs and the group affecting both liver and muscles. Each group has several different types; caused by defect of a different enzyme or a transporter, which is encoded by a different gene .From a clinician\u2019s perspective the hepatic group of GSDs often has an easily recognizable clinical phenotype usually apparent as doll-like facies, failure to thrive/short stature, hepatomegaly and the biochemical features of fasting ketotic hypoglycemia, lactic academia, raised alanine transaminase with or without hypertriglyceridemia and hyper-uricemia.In Pakistan the conventional diagnostic approach towards hepatic types of GSDs includes recognition of clinical symptoms followed by biochemical work up and ultimately the more invasive liver biopsy to reveal features consistent with fatty change, nuclear hyper-glycogenation and fibrosis. Additional electron microscopy and enzyme studies on the liver tissue are required to specify the type of GSDs. Neither the electron microscopy nor the enzyme assays for GSDs are locally available, which compromises the diagnostic yield of liver biopsy for diagnosing GSD in local setting. The liver biopsy has the following limitations, some of which are specific to Pakistan:\u2022 Controversial diagnostic accuracy for GSDs with lack of specificity based on light microscopy only.\u2022 The procedure is invasive with serious complications including pain, hemorrhage, bile peritonitis, penetration of abdominal viscera, pneumothorax, and even death.4\u2022 The high cost including multiple clinic visits, anesthesia reviews and procedure cost.\u2022 Lack of centers with trained staff with sufficient experience for performing liver biopsy, further adds to the constraints especially for patients in smaller cities with limited technical expertise available.\u2022 Usually 30\u201340 mg of tissue or four cores of hepatic tissue including about 15 mg of snap-frozen hepatic tissue in liquid nitrogen is required for all the studies necessary including light microscopy, electron microscopy and enzymes analysis to make a definitive diagnosis.5\u2022 Specialized laboratories offering enzyme studies for hepatic GSDs are not available in Pakistan thus liver tissues are needed to be out-sourced to overseas laboratories in completely frozen condition with very vigilant temperature control, which is extremely challenging and chances of losing the precious hepatic tissue collected after an invasive procedure are very high.\u2022 Electron microscopy on the hepatic tissue, which is required for the diagnosis of GSDs is not readily available at most diagnostic centers in the country owing to its high cost.\u2022 The treatment is aimed at specific type of GSDs, which is not possible based on only histo-pathological findings of hepatic tissue on light microscopy without the enzyme testing, which is not available in Pakistan.On the other molecular testing, which was previously only performed to supplement enzyme activity analysis and confirm equivocal results has now become the principal diagnostic tool for GSDs.\u2022 Non-invasive compared to the liver biopsy.\u2022 High diagnostic accuracy as molecular methods minimize false positive test results by targeting the specific gene of interest.\u2022 Molecular testing clearly differentiates between different types of GSDs allowing physicians to initiate specific type-based treatment of GSDs and organizing the specific type-based surveillance plan, which varies significantly for various GSDs.\u2022 Ease of sample transportation to the laboratory without vigilant temperature control.\u2022 Automated analyzers are available and a single trained pathologist can report numerous samples.\u2022 Short turnaround times, which is 48 hours.\u2022 Cost-effective, as the cost of next-generation sequencing (NGS) allowing analysis of multiple genes in a single DNA sample is around $278.\u2022 Provision of reliable prenatal diagnosis and carrier testing by offering targeted familial variant testing to at-risk couples and carrier testing for family members.Early diagnosis of GSDs is imperative for initiation of appropriate treatment and achieving better prognosis. Owing to the nonspecific clinical presentation of GSDs and the lack of specific biomarkers to differentiate various types of GSD, NGS has become the first line diagnostic tool for the evaluation of GSD. NGS depends on massive molecular parallelization and allows analyzing multiple genes at the same time in a single DNA sample, it is a rapid and a much cost-effective way of not only diagnosing GSD but also differentiate different types of GSDs in absence of the invasive procedure of liver biopsy.In context of NGS instrumentation availability, a wide variety exists e.g. MiniSeq and Miseq from Illumina, Ion Torrent from Life Technologies Thermo Fischer Scientific and MinION from Oxford Nanopore etc. These differ primarily in terms of cost, capacity, principle chemistry and read length, DNA library preparation and run time. On the basis of feasibility, the Illumina MiSeq is the most popular sequencer due to its relatively low cost, significantly low error rate and capacity to deliver the moderate throughput required by most centers.7From a local perspective, measurement of enzyme activity suffers from logistic issues and is technically more challenging alongside a dearth of laboratory expertise. Furthermore, enzyme analysis is usually not reliable in detecting heterozygous carriers of a disease. These testing modalities are often very laborious, time consuming and require a pre-selection by clinical phenotype for targeting the specific enzyme.In line with the best practices, the undertaking of molecular testing for suspected cases with GSDs, by outsourcing the samples abroad to accredited laboratories has been a standard practice at our institute. For this purpose, the extracted DNA samples from peripheral (whole) blood specimen is outsourced for NGS based GSDs panels, with ease of transportation at room temperature.The capacity and capability to perform molecular testing using NGS is available in Pakistan. NGS equipment and proficient molecular pathologists and molecular geneticists are present at few centers locally, but molecular testing for GSDs is currently not offered in the country. In most clinical settings, the pediatricians and pediatric metabolic geneticists outsource NGS molecular testing to various accredited centers abroad, offering GSDs panels. However, the expertise of local molecular pathologists and molecular geneticists can be easily nurtured in this respect; and the widespread use of molecular testing of GSD can be achieved with its added distinct advantages.BA conceived, designed the idea and did final review of the manuscript, is responsible for integrity of research.SA did literature review and manuscript writing."} +{"text": "The presence and characteristics of cognitive alterations in children and adolescents affected by migraine have been largely under-investigated. Childhood and adolescence are key periods for personal growth and academic achievements, and migraine-related cognitive deficits may interfere with functioning levels across several settings. A careful analysis of cognitive impairment in the context of migraine is pivotal for making informed decisions on the most appropriate care pathways.We therefore critically evaluated the results of research studies conducted to date on cognitive function in children and adolescents affected by migraine using the Pubmed database. The literature search was limited to original articles published in English language and focused on current research trends. We operationally defined cognitive processing as the range of individual cognitive functions assessed by neuropsychological studies. Our analysis, which did not include findings on cognitive processing assessed by neurophysiological measures for methodological consistency, led us to formulate the opinion that young patients affected by migraine may present with specific cognitive deficits.An early neuropsychological study on young patients with migraine was conducted in 1989 on a group of 20 children affected by migraine without aura, aged between 7 and 11. The authors of this study did not identify clinically relevant impairment in cognitive performance, with the exception of impaired functioning in short and long-term memory tasks can be difficult to summarize when studying associations to sensitive areas, such as cognitive changes in children. Despite our efforts to reduce methodological heterogeneity by focusing on neuropsychological studies only, the available literature shows a wide variability and it is difficult to conduct meta-analyses of association risk. The inconsistency of the findings poses considerable limitations to any conclusions about association risks, however it is possible to outline future research strategies to address unanswered questions. Specifically, future studies should be conducted on larger and more homogeneous cohorts of patients, using standardized neuropsychological batteries encompassing the broad spectrum of cognitive functions. Multicenter studies involving the coordinated research activity of specialist clinics might allow to achieve adequate standards in terms of both statistical power and inter-rater reliability. Ideally, longitudinal studies on large cohorts of patients in transition from childhood to adolescence could be conducted to assess cognitive functions and associated clinical variables across crucial developmental trajectories. Considering also that migraine is a cronic condition that tends to persist into adolescence and adulthood, it is important to recognize effective intervention that could prevent long term cognitive impairments. Finally, further studies are needed both to clarify uncertainties and to evaluate possible changes in cognitive symptoms following targeted interventions, as compared to traditional treatments for migraine .All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Continuing changes in the world\u2019s climate put the older adult population more at risk than other age groups. Multiple circumstances such as disasters and environmental events brought about by climate change impair the ability of older adults to maintain healthy physical and psychological well-being. Unfortunately, during these times, public and individual emergency preparation plans often fall short of having the needed resources to reach out and offer assistance to older adults. Co-sponsored by the Environmental Gerontology and Disasters and Older Adults Interest Groups, four presenters will highlight multiple circumstances where older adults face serious physical and psychological consequences as a result of climate change issues: 1) the loss of electrical power and its impact on hypothermia and hyperthermia in older adults, 2) the loss of basic public health services after Hurricane Maria and its contribution to older adults\u2019 reduced psychological well-being including increased levels of suicide, 3) homeless older adults experiencing a disaster and their resulting increased need for resources, and 4) older adults in the path of violent tornadoes and their ability to cope on their own. These presenters will discuss actions, interventions, and development of emergency disaster preparation plans that would be beneficial for older adult response and recovery. The fifth paper will review the theoretical backgrounds of and previous studies on Anthropocene with a focus on climate change policy and practice. Collectively, these papers will address various means by which older adults are affected by climate change and optimal practices to speed recovery."} +{"text": "This paper will discuss the Older Americans Act nutrition programs and their reauthorization progress, older adult programs under the US Department of Agriculture, and advances in nutrition services being made in healthcare programs such as Medicare Advantage and managed long-term care services and supports. It will also discuss funding for federal older adult nutrition programs and their sustainability moving forward."} +{"text": "The Florida Department of Elder Affairs (DOEA) provides programs and services for over 65,300 older people and adults with disabilities. These individuals are uniquely vulnerable and may be disrupted, displaced, and disoriented during the natural disasters common to Florida. DOEA clients are homebound or dependent upon community-based services to provide supervision or direct assistance to perform basic self-care. Often, clients are unable to complete personal care independently, which makes sheltering in place a unique challenge, yet they can only evacuate with special transportation and support arrangements in the shelter. It is critical to DOEA to accurately predict clients likely to be seriously affected by storms, plan for relocation before an event, and arrange for the provision of extended care after. DOEA responded by utilizing ArcGIS mapping software to join client residence locations to evacuation zone polygons and developed a methodology to prioritize clients with personal and functional barriers to evacuation. Proven during Hurricane Michael (2018), local emergency managers were able to use this tool to complete wellness checks on survivors before outside aid arrived. This initiative is evolving with the challenges posed by each storm season. Hurricane Dorian (2019) required the addition of latitude and longitude of client locations for when traditional street navigation became unavailable. Importing and overlaying primary data on secondary emergency management resources is a strategy that could be replicated by other organizations that have similar needs to reconcile individual locations in context of local threats, making this methodology transferrable to other disaster and flood-prone communities."} +{"text": "The purpose of the study was to identify the sequence of violence that ensues after breaking bad news and develop a contextual model of breaking bad news and develop a model contextual for Pakistan.A qualitative exploratory study was conducted using Six FGDs and 14 IDIs with healthcare providers working in the emergency and the obstetrics and gynecology departments of tertiary care hospitals of Karachi, Pakistan. Data was transcribed and analyzed to identify emerging themes and subthemes using thematic content analysis.Impatience or lack of tolerance, lack of respect towards healthcare providers, unrealistic expectations from healthcare facility or healthcare staff were identified as main reasons that provoked violence after breaking bad news. A conceptual five step model was developed to guide communication of bad news by the health care providers. On initial testing the model was found to be effective in de-escalation of violence.Communication of bad news requires application of specific approaches to deal with contextual challenges for reducing violence against healthcare. During past few decades Pakistan has seen an increase in the number of incidents of violence targeting the general population.A multicenter study conducted in Karachi, in 2015 found that 66% of HCPs had experienced or witnessed at least one incidence of violence in last 12 months.6Studies have identified that effective communication of health related information to patients and their families can reduce violence against healthcare.11A qualitative study of experiences of healthcare providers regarding breaking bad news analyzed bad and good experiences separately and identified that interpersonal communication skills and specific training of healthcare providers regarding breaking bad news predominantly influenced outcomes of breaking bad news.A qualitative exploratory study was conducted in August, 2016 in tertiary healthcare settings of Karachi to identify the reasons for violence related to breaking bad news and suggestions of participants in its management. Six Focus Group Discussions (FGDs N=45) and 14 in depth interviews were conducted with purposive sampling of HCPs working in the departments of Emergency, Obstetrics and Gynecology and Medicine of six public and private sector hospitals which included Jinnah Postgraduate Medical Centre, Civil Hospital, Ziauddin Hospital, Sindh Government Hospital-Korangi, Sindh Government Hospital-Lyari and Sindh Government Hospital-Malir. The respondents included; doctors, nurses, residents, dispensers and paramedics from seven public and private tertiary care hospitals. Using theoretical sampling the data collection was stopped when saturation was reached.Semi structured interview guides were used after pre-testing. All the FGDs and IDIs were video-recorded and audio-taped. Data was transcribed and translated into \u201cEnglish\u201d by a language expert. The transcripts of IDIs were discussed with the respondents to ensure the reliability and authenticity of the data.Data was analyzed using thematic content analysis. Both \u2018manifest content\u2019 and \u2018latent content\u2019 (underlying meaning) of the text were analyzed. The principal investigator (PI) and two co-investigators analyzed the data independently to identify codes and themes, which were finalized with consensus.Ethical approval for the proposed study was obtained from Institutional Review Board (IRB) of Jinnah Sindh Medical University and relevant health care settings. Informed consent was taken from all study participants before the IDI or FGD.The study identified a number of reasons for violence against healthcare in response to breaking bad news. The causes of violence were classified as client and provider related causes. The client related causes included impatience or lack of tolerance, lack of respect towards healthcare providers, unrealistic expectations from healthcare facility or healthcare staff. A HCP from emergency department of a public sector hospital mentioned;\u201cViolence occurs when people become emotional in response to adverse health outcomes \u201c, .The provider-related causes included: bad attitude of HCPs towards patients and attendants, lack of timely communication, inability to counsel patients/attendants and appropriate preparation for undesirable outcomes. One study participant said;\u201cIncompetency to counsel patients and their families and bad attitude of doctors with staff and attendants causes violence in healthcare settings\u201d. (Nurse Supervisor).The study participants suggested various strategies to help reduce violence in healthcare settings related to receiving bad news. Training in communication especially breaking bad news was suggested by most participants a postgraduate trainee said;\u201cTraining of health care providers in communication skills may help in reducing violence\u201d.Most of the healthcare providers emphasized that violence in healthcare settings can be reduced by implementing specific patient-communication protocols. Based on the themes and subthemes emerging from data analysis a context specific training module was developed to train HCPs for effective and safer communication of sensitive information or breaking bad news. This model offers a contextualized stepwise approach to be used by healthcare providers for effective communication of bad news while ensuring healthcare providers` safety as well. Currently, this model is being implemented in some tertiary care teaching hospitals of Karachi and the effectiveness of the entire training on de-escalation of violence was found to be effective which also included the model on breaking bad news.14This is the first study which specifically explored ways to effectively manage breaking bad news in the local context. Our study identified lack of communication skills and empathic attitude among healthcare providers that resulted in violence against healthcare. This is in concurrence with the study done in Pakistan with residents related to breaking bad news.17Our proposed model also emphasizes that training on communication skills is also important while implementing the step-wise approach for breaking bad news to patients and or their attendants. Our model has some similar characteristics/ constructs with a previous model Known as \u201cSPIKE Strategy\u201d for breaking bad news by Buckman. The SPIKE strategy focuses on demonstration of empathic attitude while recognizing and addressing emotions at receivers` end and is not specifically designed for communication of bad news.18SPIKE does not offer essential guidance about identifying the right person for breaking the bad news in case many attendants are present. This in our opinion is very important in the context of Pakistan where families visit their patients in groups due to cultural practices and limited health literacy. Moreover, unstable political environment and extremism increases possibility to encounter political or religious mobs at hospitals and requires a specific strategy to deal with a larger group of emotionally heightened people.A number of studies have identified the crucial role of cultural values and context for patient-centered communication in improving patient satisfaction and psychological well-being.Similarly, our model advocates using simple language and avoiding use of medical jargon while breaking the bad news to ease the uptake of information at receivers` end which is also supported by SPIKES.Consequently, this study proposes first ever health communication model for Pakistan and provides evidence based guidelines to break bad news effectively in the context of Pakistan and similar cultures. Inclusion of study participants from healthcare settings frequently involved in breaking bad news from multiple hospitals of metropolitan city of Karachi increases trustworthiness of study findings. Analysis of data by more than two researchers establishes the credibility of the finding. Although the effectiveness of the model has not been tested independently but the effectiveness of de-escalation of violence training was found to be positive which also included training on breaking bad news model.14The adaptation of this contextual model is dependent on basic communication skills of the healthcare providers; hence, this calls for basic trainings in communication along with adaptation of this contextual model. This model mainly addresses challenges of breaking bad news in emergency conditions in one episode and does not provide specific guidelines about role of frequent consultations to break the bad news if patient or attendants are not well prepared to receive the complete news or information as suggested by Dean and Willis.19Incorporating socio-cultural context in patient communication can improve their satisfaction and compliance to the information provided. The five step Model of Breaking bad news is a contextual model and can be tried in Pakistan and similar countries with local adaptation."} +{"text": "Family caregivers are at the forefront of managing dementia but are not routinely included in discussions about prognosis and are often poorly prepared to engage in surrogate decision-making. Few interventions target advance care planning in primary care, which is where most persons with dementia are initially diagnosed and medically managed. SHARING CHOICES proactively engages family and support advance care planning in primary care by normalizing advance care planning discussions, clarifying the role of the family during interactions with primary care clinicians, providing ongoing access to a non-clinician trained to lead advance care planning conversations, facilitating registration for the patient portal enable and extending electronic interactions and information access to family caregivers, and providing education and resources about dementia for clinic staff. This presentation will discuss refinement of the SHARING CHOICES protocol and facilitators and challenges of executing a pragmatic trial of this type across two large primary care systems."} +{"text": "As the number of people affected by dementia increases, it is essential that caregivers are provided resources and communities educated on how to engage and support people living with dementia. Supporting caregivers and providing education about dementia-friendly communities are key components of the Geriatric Workforce Enhancement Programs. This symposium will provide examples of GWEP projects which foster dementia-friendly communities and support caregivers. Additionally, recent and current legislation targeting dementia and caregivers will be presented."} +{"text": "Prescribing antibiotics to patients represents an ethical dilemma for physicians since the current health needs of the patients have to be balanced with concerns for long term containment of antimicrobial resistance in the community. Overuse of antibiotics is a major pathway for development of antimicrobial resistance. In resource-poor settings a complex social reality can influence antibiotic prescribing behavior among physicians which apparently violates the conventional biomedical ethics principles especially beneficence and justice. These social factors include patient socioeconomic class, patient demand for antibiotics, competition among practitioners and conflict of interest arising from the physician\u2019s social relationship with his/her patient. Current approaches for combating antimicrobial resistance in the developing countries are inadequate in factoring and dealing with those irrational prescription practices which are driven predominantly by subtle violation of medical ethics as opposed to blatant economic and professional profiteering. Prescription of antibiotics presents an ethical dilemma for physicians since the current health needs of patients have to be balanced with concerns for their safety due to adverse effects and restricting antimicrobial resistance (AMR) throughout the community - 2. TheClinical judgment influenced by patients\u2019 socioeconomic statusWhile prescribing antibiotics, especially in resource-poor settings, physicians often have to rely upon clinical evaluation alone in the absence of adequate diagnostic support. Empirical therapy is not always unwarranted; however, the high cost of investigations like blood/urine culture and sensitivity testing, which are not affordable or easily accessible for poor patients, can influence the physician\u2019s behavior . SimilarPatient demand for antibioticsThere is global evidence that physicians can be pressured into prescribing antibiotics even against their clinical judgment . PatientConflict of interests and biasEven during unavoidable empirical therapy, narrow-spectrum antibiotics should be prescribed as opposed to broad-spectrum antibiotics, even though nonclinical and social factors can influence the type of antibiotic prescribed. It is ethically appropriate for physicians to write prescriptions for their family members to cure short-term minor problems, that is, if they possess the necessary expertise to treat the condition . NeverthIn developing countries, current approaches to containing AMR focusing on prescription audits, sensitization and training of physicians tend to rely upon clinical worldviews in which pharmaceutical incentives and the urge for gratifying patient expectations preclude rational antibiotic prescribing - 12. Ne"} +{"text": "A growing body of literature found that attitudes towards aging is related to individual\u2019s health among older adults. This paper aims to examine the relationship between negative attitudes towards aging and self-rated health among Chinese older adults living in Honolulu (N=400) and Wuhan (N=552) and explore the moderating roles of resilience and gender. Results showed that the positive relationship between attitudes towards aging and self-rated health was moderated by resilience such that higher levels of resilience weakened this association significantly and substantially, implying its stress-buffering role. Both the positive focal relationship and the moderating effect appeared to be stronger among older adults in Honolulu than their peers in Wuhan. For gender differences, the moderating effect of resilience was only significant for males in Honolulu and females in Wuhan, indicating that males in Honolulu and females in Wuhan may rely heavily on psychological resources such as resilience in coping with stressors."} +{"text": "Levels of ultraviolet B radiation (UVBR), a potent immunosuppressant, have increased in parts of the world due to anthropogenic thinning of the Earth\u2019s protective ozone layer. However, little is known about how UVBR influences amphibian immune function, or if increased UVBR exposure can contribute to disease emergence in susceptible species. Amphibian populations the world over are under threat of extinction, with as many as 40% of assessed species listed as threatened under IUCN Red List criteria (a significantly higher proportion than other vertebrate group). Amongst the key threats to amphibian species is the emergence of novel infectious diseases, which have been implicated in the catastrophic amphibian population declines and extinctions seen in many parts of the world. The recent emergence of these diseases coincides with increased ambient levels of ultraviolet B radiation (UVBR) due to anthropogenic thinning of the Earth\u2019s protective ozone layer, raising questions about potential interactions between UVBR exposure and disease in amphibians. While reasonably well documented in other vertebrate groups , the immunosuppressive capacity of UVBR and the potential for it to influence disease outcomes has been largely overlooked in amphibians. Herein, we review the evidence for UVBR-associated immune system disruption in amphibians and identify a number of direct and indirect pathways through which UVBR may influence immune function and disease susceptibility in amphibians. By exploring the physiological mechanisms through which UVBR may affect host immune function, we demonstrate how ambient UVBR could increase amphibian susceptibility to disease. We conclude by discussing the potential implications of elevated UVBR for inter and intraspecific differences in disease dynamics and discuss how future research in this field may be directed to improve our understanding of the role that UVBR plays in amphibian immune function. Batrachochytrium dendrobatidis (Bd) in 1998 have recently increased in prevalence. Ranaviruses have now been detected in more than 70 amphibian species in 20 countries forms a part of the solar electromagnetic spectrum (wavelength range 280\u2013320 nm). Although the majority of solar UVBR reaching the outer atmosphere is absorbed by stratospheric ozone, a small amount does reach the Earth\u2019s surface . SpatialUVBR is a powerful natural stressor because it can interact with a range of biological molecules and is capable of causing extensive cellular and molecular (DNA and protein) damage . At the Bd-related amphibian declines have occurred in montane environments to low levels of UVBR for 3 days did not increase susceptibility to Bd or subsequent mortality. Likewise, Bd when Rana cascade larvae were exposed to UVBR and Bd simultaneously. UVBR exposure has also been linked to reduced Bd susceptibility in larvae of Bufo bufo (Bd susceptibility in green tree frog (Litoria caerulea) larvae . Differences in the source of the UVBR , UVBR dose, the timeframe of exposure, life history stage at the time of exposure and species influence amphibian UVBR exposure outcomes also have diurnal juvenile and adult stages for which UVBR exposure may be harmful. In the subsequent sections of this review, we will explore how UVBR exposure influences immune defences early in development . We will show that UVBR can act directly on components of the innate and adaptive immune systems, as well as indirectly influencing immune function through impacts on other physiological systems or by influencing the capacity of other environmental stressors to affect immune function , along with glucocorticoids, play a major role in the timing and control of tissue development and metamorphosis . UVBR exoles and . Indeed,oles and . Conceivoles and , so therImmune responses and resistance to pathogens and parasites are physiologically demanding . EnergetBd than those exposed to low/no UVBR as larvae. These findings indicate that early developmental exposure to UVBR has long-term ramifications for amphibian immune function and disease susceptibility. Further work is required to understand the mechanistic basis for the latent effects of UVBR exposure on amphibians, and how UVBR dose, intensity and the timing of exposure can influence latent immunosuppression.The effects of UVBR on amphibian immune function may not manifest immediately, which may mask the potential risk from this stressor. Juvenile amphibian immune function can be significantly influenced by environmental stressors experienced during the larval period, including pond drying and dietary stress . Given tLimnodynastes peronii larvae (unpublished data). The accumulation of UVBR-associated DNA damage underpins the immunosuppressive nature of UVBR in mammals of disease-related amphibian population declines. Understanding the role that elevated UVBR levels may have played and may continue to play, in the emergence or exacerbation of amphibian diseases is, therefore, important.Bd) was subsequently shown to be the proximate cause of many of these declines, the possibility that increased UVBR may have contributed to the emergence and epidemiology of the disease has remained largely unexplored. Elevated UVBR has been largely neglected from major environmental models of Bd-related declines because of a lack of data on natural UVBR levels in the amphibian\u2013pathogen microenvironment. UVBR levels are difficult to accurately quantify and can vary enormously, over both space and time, as a consequence of solar distance and angle, vegetation cover, cloud thickness and levels of dissolved organic matter in water and the clicking froglet (Crinnia signifera), have been identified as highly virulent vectors of Bd capable of harbouring and spreading the fungus to more susceptible species in their environments . While in this review we have focused on the potential for UVBR to disrupt amphibian resistance pathways, tolerance of pathogens is increasingly recognised as an important immune strategy for managing host\u2013pathogen interactions . While pGlobal UVBR levels have increased by between 2 and 6% since the middle of the last century and are"} +{"text": "Total joint arthroplasties (TJA) are today considered highly successful operations. Total hip arthroplasty (THA) was the pioneering surgical procedure that preCosts associated with the burden of TJA are increasing , relatedWell-established joint replacement National Registries have been developed by scientific societies and governments worldwide and have confirmed a prolonged service life of these implants , validatThe number and severity of TJA-related complications remind us of the complexity and seriousness of these surgical procedures. While many patients perform remarkably well without any complications, the risks are often not well-understood by the patient at the time of informed consent. The prognosis of the complicated procedure jeopardizes the expectations of those patients suffering complications. The readmission rate after TJA provides a valid measurement of early complications. This has been associated with comorbidities and is one of the most important reasons for increased costs. Readmission rates 30 or 90 days after surgery range from 5% to 10% [More information from clinical studies is available today about the diagnosis and treatment of joint arthroplasty complications. Both medical and surgical complications may be equally important in altering the patient outcome of TJA. Prophylaxis of complications, early diagnosis and specific treatment may improve this outcome. Therefore, basic research on new technologies or epidemiological, clinical and registry studies on complications and adverse events after TJA related to patient factors or surgical issues ,12 are cThe influence of renal function in postoperative complications , the pot"} +{"text": "Climate change places many older adults at unique risk for adverse, potentially life-threatening consequences. Compared to younger adults, older adults are more susceptible to the effects of extreme weather events and at greater risk for heat stroke and hypothermia. With advanced age, some people have vulnerabilities, such as social isolation and physical and mental health conditions that predispose them to a greater level of danger. Loss of power, that leaves people without functioning cooling or heating systems, can cause death because it exacerbates preexisting medical conditions and impairs thermoregulatory function for those with medical illnesses or taking certain medications. Many older adults who function independently may not self-identify as being vulnerable and take necessary precautions to remain safe. This presentation will describe recent research that found that many older adults are unaware of hypothermia and hyperthermia symptoms and the actions needed to maintain health and life."} +{"text": "Clostridium difficile (CDI) is the most common healthcare associated infection (HAI), and it causes particularly high morbidity and mortality among older adults. While risk factors for this deadly HAI have been explored at the patient and facility levels, less is known about transmission between facilities. Recent literature suggests that more patient transfers to a hospital are correlated with elevated CDI levels. However, this work excludes skilled nursing facilities (SNFs), although SNFs are a major contributor of older adult patients to hospitals. We use multiple large data sets to make progress in filling several existing knowledge gaps. First, we construct and analyze healthcare facility networks using transfers of Medicare beneficiaries in the Minimum Data Set 3.0 and Medicare claims data from New Mexico, New York, Connecticut, and Colorado. We evaluate the role of SNFs in networks through the volume and frequency of patient flows in and out of individual hospitals. We also assess the level of interaction between facilities of different sizes, locations, and types. Second, using the Healthcare Cost and Utilization Project State Inpatient Databases, we examine whether a hospital CDI outbreak is predictive of CDI incidence across a network of hospitals, using multiple existing metrics of CDI incidence, noting strengths and weaknesses for each. These two aims lay the foundation for future work to examine the relationship between patient transfers and the distribution of outbreaks. Such work may be able to identify facilities that present the greatest CDI risk to older adults across a facility network."} +{"text": "Annals of Oncology, Spiteri et al. [The evolution of divergent subpopulations of cancer cells within the same tumour has been proposed to underlie the development of treatment resistance and the recurrence of malignancy across multiple tumour types . In thisi et al. utilise GBM is the most common primary brain malignancy in adults characterised by a devastating prognosis and a lack of effective therapeutic options. Since the 1970s, treatment has consisted of maximal resection followed by focal external beam radiotherapy , and morFollowing initial radical therapy, tumour recurrence inevitably occurs and is the predominant source of mortality in these patients . ClinicaThe genomic architecture of untreated GBM was revealed through genomic sequencing studies such as The Cancer Genome Atlas (TCGA) , 10 idenInsights into the temporal evolution of GBM have been revealed by profiling matched therapy naive and recurrent tumours, revealing significant heterogeneity in both somatic mutations and copy number alterations at relapse . Thus, sIDH1 wildtype GBM and 1 patient with IDH1 mutant anaplastic astrocytoma. They performed multi-region whole-exome sequencing from the primary tumour mass, SVZ and infiltrative margin collected using fluorescent guided resection and, in two cases, matched tissue from a second surgery at local relapse were available for comparison and PEACE which afford the highest resolution sampling to better understand the evolutionary history underlying this devastating disease and inform future therapeutic targets both molecular and immunogenic."} +{"text": "This symposium will highlight the implementation of nutrition, body composition and functional assessment in vulnerable older adults. Understanding the barriers and enablers of implementing traditional nutrition screening and assessment tools, nutrition focused physical examination, body composition analysis, functional assessment and biomarkers can aid researchers in the design of pragmatic nutrition studies in vulnerable older adults. DiMaria-Ghalili will provide an introduction to overall nutrition assessment in community-dwelling older adults and present lessons learned in regards to nutrition assessment protocols from an ongoing clinical trial. Starr will discuss the issues surrounding nutrition screening and assessment in high-risk older adults undergoing abdominal surgery. A comparison of data on different nutrition screening and assessment tools in older adults undergoing abdominal surgery will be presented. Batsis will discuss the controversies and challenges in body composition assessment focusing on sarcopenic obesity. Data highlighting the different diagnostic criteria of sarcopenic obesity and diagnostic accuracy will be presented. The link between overall nutrition status and physical function on health outcomes is emerging in older adults. Bales will discuss the types of physical function assessment tools used in studies of older adults and discuss her findings on the impact of higher protein intake on functional outcomes. The symposium will conclude with a discussion led by Locher on practical implications of integrating best assessment techniques into clinical practice."} +{"text": "This symposium will explore role that paid caregivers play in the health and team-based healthcare of older adults living in the community. The large and growing workforce of paid caregivers witness the changes in health status, chronic health needs, and psychosocial stressors of the older adults they care for. Yet existing research on paid caregivers has largely been limited to workforce issues such as recruitment, retention, and job satisfaction. The unique potential of paid caregivers to impact the health of their clients remains largely unstudied. The first presenter will describe results from qualitative interviews with seriously ill older adults and their long-time paid caregivers that found that paid caregivers perform a wide variety of health-related tasks in the course of their routine care. The second presenter will describe results from focus groups with paid caregivers that found that though not a part of the official care plan, paid caregivers provided deliberate cognitive, emotional, and social care that sought to improve their clients\u2019 \u201ctotal\u201d health. The third presenter will outline the rationale for and development of an educational intervention aiming to improve paid caregiver\u2019s ability to provide care to patients with heart failure. Finally, the fourth presenter will discuss the limited role paid caregivers currently play in the healthcare team. She will then highlight key policy, educational, and clinical recommendations to promote further paid caregiver integration in the healthcare team."} +{"text": "Physiology and ecology are intimately linked; thus, ecological observations can be strengthened by an understanding of organismal physiology. Through a symposium entitled \u201cApplications of Physiological Ecology in Elasmobranch Research\u201d at the 2017 American Elasmobranch Society meeting, we demonstrated the strengths of collaborative efforts across disciplines for informing conservation efforts. A strength of physiological ecology is its incorporation of aspects of both species\u2019 ecology and physiology; this holistic approach is needed to address current and future anthropogenic stressors affecting elasmobranch fishes that range from overexploitation to the effects of climate change. For example, physiology is one of several key determinants of an organism\u2019s ecological niche . The fundamental role of physiology in niche determination led to the development of the field of physiological ecology. This approach considers physiological mechanisms in the context of the environment to understand mechanistic variations that beget ecological trends. Physiological ecology, as an integrative discipline, has recently experienced a resurgence with respect to conservation applications, largely in conjunction with technological advances that extended physiological work from the lab into the natural world. This is of critical importance for species such as elasmobranchs , which are an especially understudied and threatened group of vertebrates. In 2017, at the American Elasmobranch Society meeting in Austin, Texas, the symposium entitled `Applications of Physiological Ecology in Elasmobranch Research\u2019 provided a platform for researchers to showcase work in which ecological questions were examined through a physiological lens. Here, we highlight the research presented at this symposium, which emphasized the strength of linking physiological tools with ecological questions. We also demonstrate the applicability of using physiological ecology research as a method to approach conservation issues, and advocate for a more available framework whereby results are more easily accessible for their implementation into management practices. Physiology has traditionally been studied from the biochemical to organismal level, without consideration for the effects of or interaction with aspects of the organism\u2019s habitat, which include both abiotic and biotic factors. In this limited scope, our understanding of physiological mechanisms does not account for physiological variability that is attributable to ecological factors when extrapolating laboratory experiments to field settings. Likewise, ecological studies cannot fully explain patterns of animal behaviour without considering the underlying physiological mechanism(s) that influence those observations. Physiological ecology integrates the physiology of organisms within the context of their environment and evolutionary histories ; thus, iPerspective\u2014has the potential to improve our understanding of the intricate relationship between physiology and ecology in elasmobranch fishes and how it can be applied to conservation and management.The field of physiological ecology has experienced a recent resurgence as advances in technology expand the capability to incorporate physiological measurements into ecological studies that address conservation concerns in species of interest . BecausePhysiological ecology has the potential to play an important role in conservation by furthering our understanding of the connection between underlying physiological mechanisms and ecological observations and patterns . ComparePerspective, we summarize key concepts and tools presented by the speakers that demonstrate the need to examine results from a physiological ecology perspective and how doing so can potentially further conservation and management applications. We outline the state of knowledge in the fields of (i) metabolism and energy use, (ii) thermal physiology, (iii) sensory ecology and neuroecology, providing a broad overview of available methods and tools and outline key future directions and questions for the field of elasmobranch physiological ecology. While we recognize this Perspective cannot encompass all applications of physiological ecology research, we hope it can foster the development of this field to address the sensitive conservation needs of many elasmobranch species.The application of new methods and technologies to elasmobranch research naturally leads to increased linkages between disciplines as both ecological and physiological perspectives are needed to interpret data in meaningful, biologically relevant ways . HoweverAerobic scope\u2014the difference between maximum aerobic metabolic rate and standard metabolic rate (i.e. minimum metabolic rate)\u2014forms a dynamic connection between ecology and physiology, as it governs the rate at which organisms assimilate resources from the environment into available energy for metabolism, growth and reproduction . As popuGinglymostoma cirratum), lemon sharks (Negaprion brevirostris) and blacktip sharks (Carcharhinus limbatus) in conjunction with laboratory calibrations. Metabolic rate for these species can now be predicted using accelerometry in the field are unique among elasmobranch fishes for their ability to retain metabolically generated heat through the presence of counter-current heat exchangers, or in situ shifts sensitivity to that of conspecifics during the mating season, whereas decreasing androgen concentrations at the end of the mating season shifts sensitivity towards that of prey items that make seasonal migrations to the `White Shark Caf\u00e9\u2019 in the eastern Pacific Ocean and white sharks, are characterized by relatively large olfactory bulbs and optic tecta, highlighting the importance of long-distance olfactory and visual cues when foraging for highly mobile and patchily distributed prey in the open ocean and those requiring integration of multiple sensory systems, such as vision, olfaction and electroreception as in hammerhead sharks , hammerhead sharks, stingrays (Myliobatiformes) and filter-feeding species such as whale sharks , increased pigmentation in the skin and ocular lens protect against oxidative damage from radiation in high-UV habitats . However, other methods can also be used to address these types of questions. Here, we highlight the utility of both novel and traditional techniques that provide alternative perspectives for investigating the physiological ecology of elasmobranch fishes.Over the past three decades, molecular genetic tools have rapidly advanced and have increased the amount of data that can be obtained from an individual sample. In particular, the development of high-throughput sequencing (HTS) technologies and associated bioinformatic analyses has increased the capacity of genetic tools to answer a wide variety of physiological and ecological questions , can now be inferred through metagenomics/barcoding. For example, microbial communities living within or on the bodies of elasmobranch fishes can be assessed through HTS shotgun sequencing, with the added capability to also assess individual and population health and environmental condition , is an exciting application of HTS genomic tools. Since the regulation of gene expression is one of the primary cellular mechanisms governing metabolism and physiological processes, functional genomics will aid our understanding of how physiology relates to ecology in elasmobranch fishes. Functional genomics has been used to determine the molecular mechanisms behind endothermy , reprodu13C, \u03b415N) of a tissue is affected by tissue break down and regrowth (e.g. tissue turnover), which in turn is influenced by an individual\u2019s metabolism and/or growth at particular life stages that governs how quickly ingested prey items are assimilated and converted into tissue biomass has traditionally been viewed exclusively as an ecological tool, due to its past utility to study trophic ecology and the movement of marine species or influenced by anthropogenic activities . Unlike stable isotopes, which follow predictable patterns through et al. in review). This results from either higher rates of feeding, feeding on more calorically dense prey items, or both. Other physiological factors include sex differences. Females offload contaminants to their young .While contaminant signatures can be used as ecological markers, physiology also plays a role in influencing contaminant accumulation. Not only does the location of feeding (ecology) influence contaminant uptake, but physiological factors also dictate feeding rate. For example, elasmobranch fishes with higher aerobic metabolic rates tend to have higher concentrations of organic contaminants compared to other pelagic shark species were attributed to its feeding in the deeper mesopelagic food web . Detrimental effects of these responses can be mitigated through modifications of fishing practices, such as electromagnetic deterrents that limit interactions of sharks with pelagic longline gear . WithoutIn addition to fishing pressure, climate change presents a challenge for many species as niches of both prey and predators are likely to shift geographically according to species-specific physiological abilities, habitat preferences and metabolic demands. Increasing water temperatures are predicted to increase metabolic rates .Mobula spp.) even though they may not face the highest risk of extinction or be the best candidates to answer particular research questions. Therefore, we argue that future work must carefully select study species and develop appropriate model organisms; it is our hope that the Physiological Ecology Symposium at the 2017 Annual Meeting of the American Elasmobranch Society and this Perspective spur continued discussion between ecologists and physiologists as to how to integrate their respective disciplines to enhance our understanding of the biology of sharks, skates and rays as well as to improve conservation efforts for many members of this group of vertebrates that are simultaneously threatened and understudied species.Finally, ecological and conservation field-based research on elasmobranch fishes tends to focus on the largest and most charismatic species (e.g. white sharks and"} +{"text": "Domestic wastewater pollution in environmental waters or water reuse supplies represents a threat to public health because of high concentrations of diverse pathogens associated with human excreta . Since iCapsicum spp.), and its presence in human feces originates from the consumption of infected peppers, which are frequently used in processed pepper products . PMMEscherichia coli and enterococci), a group of bacteria that are native to the guts of animals. FIBs are the most affordable and commonly used fecal pollution indicators in the world. Unfortunately, FIB presence does not always correlate with human pathogens and/or human health risks, especially in the case of human enteric viruses , 2612, 2In addition to being a viral indicator for water quality monitoring purposes, PMMoV holds potential as a surrogate for enteric viruses in the assessment of food safety . AlthougFrom the serendipitous discovery that plant viruses dominate human feces, PMMoV has emerged as a unique surrogate for enteric viral pathogens with proven applications for monitoring microbial water quality, (waste)water treatment efficiency, and food safety (summarized in ). Curren"} +{"text": "The number of publications on mathematical modeling of cancer is growing at an exponential rate, according to PubMed records, provided by the US National Library of Medicine and the National Institutes of Health. Seminal papers have initiated and promoted mathematical modeling of cancer and have helped define the field of mathematical oncology (Norton and Simon in J Natl Cancer Inst 58:1735\u20131741, Mathematical modeling in cancer has a long history as reviewed in multiple publications and the National Cancer Institute (NCI) in the USA, the Engineering and Physical Sciences Research Council (EPSRC) and Cancer Research UK, the German Cancer Research Center (DKFZ), and multinational frameworks within the European Union. Several mathematical modeling research groups and even mathematical oncology departments have become established in cancer centers and medical schools around the world. As a result, we begin to witness the translation and evaluation of mathematical model-derived treatment protocols in prospective clinical trials in liquid biopsies. In contrast to statistical models that correlate random variables (such as pre-treatment tumor size with treatment outcome), mathematical modeling simulates the dynamics of the tumor and their underlying mechanisms. Therefore, the data of putative biomarkers for mechanistic modeling should be temporally resolved.The change of the putative biomarker over time is described using dynamic models such as mechanistic differential equations or cellular automata or agent-based models . If only temporal data are available, ordinary differential equations (ODE) are often sufficient. Partial differential equations (PDE) should only be used if spatio-temporally resolved data are available, or temporal dynamics alone are insufficient to explain the observed biomarker dynamics. The number of model variables and parameters should be determined with utmost care and limited based on the available data. Information criteria offer invaluable analyses to balance model complexity with degrees of freedom Akaike .3.Calibrate model with existing dataIf longitudinal data are limited , non-mechanistic or statistical models may be considered that simulate the dynamics of the biomarker without resolution of the underlying mechanisms. Such models, however, will have limited ability to predict novel treatment protocols beyond considerations for treatment holidays.The mathematical model is only suitable to simulate and predict novel treatment protocols if it can fit and predict the data of known therapies. If possible, model parameters should not be taken from the empirical wisdom or the literature but derived from the data within realistic bounds. A variety of machine learning and established statistical methods are already available to identify model parameters for simple models. To further aid in parameter estimation for larger models and across multiple data sets, however, major advances are still required to reliably calibrate mathematical models. Model analysis should be performed to test parameter identifiability and biologically important bounds must be honored. Additionally, when comparing predicted responses to innovative treatments with the data, one can only draw conclusions about the evaluated regimes. To claim \u2018optimal therapy,\u2019 rigorous optimal control approaches and an exhaustive analysis should be provided.Mathematical oncology has contributed significant scientific insights into the dynamics of tumor growth and treatment response and is uniquely positioned to help map the multidimensional treatment response space (Enderling et al."} +{"text": "Immigration and acculturation process in host society have been closely linked to health consequences among the immigrant populations. However, it has been inadequately examined regarding its relationships with cognitive outcomes. Data were drawn from PINE Study. Linear regression analyses were used to examine associations between acculturation levels and cognitive performance. After adjusting for potential confounding variables, higher levels of acculturation were associated with better cognitive performance. More specifically, higher levels of acculturation in aspects of media use and ethnic social relations were associated with better cognitive performance, whereas it has no significant association with the language preference aspect. Research and practice addressing health disparities and cognitive impairment should leverage efforts to provide culturally relevant resources to less acculturated populations in the US. More longitudinal studies are needed to clarify the influence of acculturation on cognitive performance and its mechanism."} +{"text": "Pigs are proven models for biomedical studies due to their anatomical and physiological similarities with humans. Pig models have increasingly been validated for mimicking human diseases Prather, . The seqThese considerations led Schook et al. to develIn addition to sarcomas, other cancers have been developed to date using the OCM platform: hepatocellular carcinoma (HCC) and pancreatic cancer (PA) , since immunosuppressed swine present several characteristics that closely resemble human PTLD. The authors reported their attempt to establish an immortal cell line that could induce PTLD when inoculated into the same inbred line animals.Gutierrez et al. have presented the potential applications and advantages of using pigs, particularly minipigs, as indispensable large animal models in fundamental and clinical research, including the development of therapeutics for inherited and chronic disorders including cancers. The authors have reviewed examples of naturally occurring conditions in pigs that closely mimic those affecting humans as well as examples of induced swine models of diseases and established engineered pig models .Overgaard et al. have shared original research regarding the use of pigs as a large animal model for cancer vaccine development. Their work demonstrated that the pig model is highly appropriate for addressing the questions related to optimal adjuvant composition and vaccine formulations. The authors investigated whether it is possible for pigs to generate immune responses to cancer antigens RhoC and IDO, using three different adjuvants . The results showed that all adjuvants tested were capable of generating some cytotoxic T lymphocytes (CTL) response to the cancer antigens following peptide immunization. These findings support the further use of the pig as a large animal model for vaccine development against human cancer.Clark et al. have demonstrated that BRCA1 inactivation in pig cells promotes transformation and thus serves as a model for human cancers. The authors established an immortalized porcine breast cell line and stably inactivated BRCA1 using miRNA. The cell line developed the characteristics of breast cancer stem cells and exhibited a transformed phenotype. These results validate the concept of using pigs as a model to study BRCA1 defects in breast cancer and establish the first porcine breast tumor cell line.Bourneuf has reviewed melanoma genetics, discussing some of the most common mutations found in this type of tumor in humans. Examples of melanoma animal models have also been discussed, with emphasis on the porcine MeLiM model. This work suggests that the spontaneous tumor progression and regression occurring in these models could shed light on the interplay between endogenous retroviruses, melanomagenesis, and adaptive immune response.Combined, the studies on this research topic have demonstrated that pigs are proven useful models for cancer studies including in (1) the development of genetically engineered pigs by using different technologies like TALENs, CRISPRs, transposons, and the Cre-Lox system; and (2) models for myeloid, lymphoid, breast, and melanoma cancers. Thus, the porcine genome sequence coupled with somatic cell cloning has led to the development of innovative porcine cancer models to support translational cancer research.TC and FS are responsible for organizing the materials and writing this editorial. LR and LS are responsible for proofreading this editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Kidney transplantation for end-stage renal disease remains the preferred solution due to its survival advantage, enhanced quality of life and cost-effectiveness. The main obstacle worldwide with this modality of treatment is the scarcity of organs. The demand has always exceeded the supply resulting in different types of donations. Kidney donation includes pure living related donors, deceased donors, living unrelated donors , paired kidney donation and more recently compensated kidney donation. Ethical considerations in live donor kidney transplantation have always created a debate especially when rewarding unrelated donors. In this paper, we examine the problems of financially driven kidney transplantation, the ethical legitimacy of this practice, and propose some innovative methods and policies that could be adopted to ensure a better practice with accepted ethical guidelines. Living related kidney donation evolved significantly between 1960s and 1970s and became a routinely acceptable practice . The gapThe most commonly accepted method of live kidney donation, altruism, remains insufficient since it does not help halt the illegal buying and selling of kidneys . AltruisIn 2008, the Transplantation Society in Turkey organized the International Summit on Transplant Tourism and Organ Trafficking. The Summit released the Istanbul Declaration which emphasizes the importance of preventing organ trafficking and transplant commercialism and encourages legitimate transplantation protocols . HoweverThe American Society of Transplantation's Live Donor Community of Practice organized a Consensus Conference on Best Practices in Live Kidney Donation in 2014 . The groIn this review, we highlight the different types of kidney donation and emphasize the ethical dilemmas in financial rewards for living kidney donors, and discuss the reasons for the emerging of compensation in donation with a focus on some known models of compensation for unrelated kidney donation as practiced by some countries.A comprehensive search was made on Pubmed for studies, review papers and meta-analyses discussing different types of kidney donation, financially driven kidney transplantation and the ethics revolving around compensation. The inclusion criteria were based on the most relevant, most recent and most cited studies present in Pubmed. A summary table of the studies is presented in a The Middle East region features some insufficiencies in the transplantation mechanism. These comprise inadequate preventive medicine, uneven health infrastructure, and poor awareness in the general public and medical community about organ donation. Severe organ shortage and political instability have resulted in major unethical practices such as transplant tourism and organ trafficking , even thSeveral studies were conducted to poll the opinion of the general public, health professionals and patients in regards to this issue. Questionnaires completed by medical and nursing staff at West London Renal Transplant Center showed that the highest acceptable mode of donation reported by the participants was from blood related donors 100%) followed by non-blood relatives and friends (92.6%) and strangers (47.2%). Direct financial rewards were not considered an important motive by the majority of participants wherein a substantial minority favored direct financial returns 0% follow. An inteSince the greatest obstacle in kidney transplantation is the limited availability of deceased / living kidney donors, all possible solutions to increase access to kidney transplant should be taken into consideration before resorting to paid donation. This has given rise to another type of donation known as kidney paired donation (KPD) that has been established to prevent commercial transplantation . It takeNumerous transplant centers have adopted this program with amounted increase in transplant numbers. For instance, in the US the number of paired kidney exchanges has increased from 2 in 2000 to 400 transplants annually . In IndiThe KPD program requires a national database that is absent in some countries like in India, in addition to lack of coordination between transplant centers . There aThe past decade has witnessed an upsurge in innovative mechanisms for living kidney donation such as altruistic donation, KPD, donor chains and exchange programs . HoweverIf it is already taken for granted that financial rewards for organ donation are pernicious and accordingly prohibited by laws worldwide, why do these rewards still receive heightened attention? Why are they practiced clandestinely? What are the reasons behind the rise of compensation in kidney donation? Possible explanations include: surge of commercial kidney transplants even in the presence of strict rules against them, limited success of altruistic donations and incapability of governments to secure organs through organized networks. Only under exceptional conditions, does the human being exhibit willingness for uncompensated transfers and generosity to others? . AltruisThere is a major argument against compensation of living unrelated kidney donation. It revolves around the concept of commodification. This argument assumes that there are limits to what can be sold and since organs are valuable and priceless then this means that they cannot be sold. Once a kidney is put into marketplace, it denies the definite valuable organ of a human being and denies his / her dignity and worth . The argWhat would seem a good solution to end the malevolent practice of kidney trafficking? In an attempt to explore the reasons donors propel to sell their organs, a primary overall factor appears: poverty. To compensate for such unethical practices, adopting a regulated system incorporated with financial incentives can help eliminate commercial transplants. This can be done when KPD has failed for a specific donor. An example of such a successful program is the Iranian model, initiated in 1988 and governed by a charitable organization called the Dialysis and Transplant Patients Association (DATPA). The DATPA provides compensation for those who provide kidneys without the need for a broker or mediator since the government covers for the hospital expenses, immunosuppressive drugs and provides award and health insurance to the unrelated donor .The concept of financial incentives was grouped in three categories. The first class focuses on the subject of compensation, wherein the donor is covered for the incurred detriments such as medical tests and examinations, health insurance, etc. This is important because many of the donors may not have insurance to cover for their tests and out-of-pocket expenses are linked to more extensive medical care in the long term . The secWhat would be the benefits of a system that adopts a model similar to the Iranian model? Ghods elaborates this topic by addressing several concerns that could be raised by opponents of this type of donation. Patient and graft survival rates, as well as donor morbidity and mortality in Iran have comparable results when compared to conventional transplant centers in the country, since all donors are positively selected and screened for diseases . The IraOn the other hand, the Hamad Medical Corporation (HMC) has initiated the Doha Donation Accord (DDA) in 2010 which aims at meeting the needs for transplantation as to discourage patients from undergoing unsafe practices abroad . The DDAIf countries decide to adopt a model that provides financial reward to donors, payment should be governed by a balanced, objective and multidisciplinary body which determines standardized protocols for donors and recipients as well as a uniform fee . If counKidney transplantation is currently the accepted mode of renal replacement therapy, which provides long-term and robust survival advantage . A drawb"} +{"text": "The study examined gender differences in the impact of living alone and intergenerational support on depressive symptoms among Mexican American older adults. The sample included 335 parent-adult child dyads which were nested within 92 Mexican American respondents in a city in West Texas. Each respondent reported their specific relationships with each child. The results from clustered regression showed that men provided and received less intergenerational support than women, but their depressive symptoms were more susceptible to living alone and different types of intergenerational support. Factors such as living alone, and receiving instrumental support were related to higher levels of depressive symptoms among Mexican American older men than among in their female counterparts, whereas emotional closeness with children was associated with lower level of depressive symptoms in men than in women. The findings can be used to develop and target a gender-specific approach for depression interventions among older Mexican Americans."} +{"text": "Integrated care is the coordination of general and behavioral health and is a highly promising and practical approach to improving healthcare delivery and patient outcomes. While there is growing interest and investment in integrated care implementation internationally, there are no formal guidelines for integrated care implementation applicable to diverse healthcare systems. Furthermore, there is a complex interplay of factors at multiple levels of influence that are necessary for successful implementation of integrated care in health systems.Guided by the Exploration, Preparation, Implementation, Sustainment (EPIS) framework , a multiple case study design was used to address two research objectives: 1) To highlight current integrated care implementation efforts through seven international case studies that target a range of healthcare systems, patient populations and implementation strategies and outcomes, and 2) To synthesize the shared and unique challenges and successes across studies using the EPIS framework.The seven reported case studies represent integrated care implementation efforts from five countries and continents , target a range of clinical populations and care settings, and span all phases of the EPIS framework. Qualitative synthesis of these case studies illuminated common outer context, inner context, bridging and innovation factors that were key drivers of implementation.We propose an agenda that outlines priority goals and related strategies to advance integrated care implementation research. These goals relate to: 1) the role of funding at multiple levels of implementation, 2) meaningful collaboration with stakeholders across phases of implementation and 3) clear communication to stakeholders about integrated care implementation.Not applicable. In recent decades, integrated care has received increased attention globally. Policymakers, providers, payers, and healthcare consumers propose that integrated care holds promise in facilitating healthcare improvements , 2. A glOver 175 definitions for integrated care exist , as wellA complex interplay of factors integral to integrated care implementation exist. A commentary paper discussing the implementation of integrated care noted several factors impacting implementation . BarrierThis complexity necessitates considering multiple levels of influence including patients who access healthcare, providers who deliver care, organizations that provide the infrastructure for healthcare, and policymakers influencing the funding and processes of care delivery . The EPIThe EPIS framework was used to pursue two objectives. The first was to highlight current integrated care implementation efforts through international case studies targeting different healthcare systems, patient populations and implementation outcomes. The second objective was to synthesize the shared challenges and successes across our case studies and propose an agenda of priorities and critical implementation strategies for integrated care implementation generalizable across countries and healthcare systems.N\u00a0=\u20097) is conceptualized as a \u201ccase\u201d [This study used an explanatory multiple case study design to illuminate shared and unique implementation processes present in contemporary integrated care implementation efforts across different countries and contexts. The core research team invited researchers targeting integrated healthcare implementation in North America (United States of America [USA]), Europe (United Kingdom [UK]), South America (Peru), Asia (Israel) and Africa (Nigeria) to contribute a case study. The intention was to include case studies that represented unique implementation efforts across the EPIS phases, that focused on heterogenous patient populations, and targeted a range of outer and inner context factors to highlight the unique, and at times, consistent challenges and successes at different points of integrated care implementation. This approach incorporates the four main features of multiple case study designs : 1) a coa \u201ccase\u201d , 22 in la \u201ccase\u201d .After identifying lead research investigators who agreed to contribute a case study, the core research team and investigators completed a 1\u20132 page summary of the implementation effort based on a shared template used to collect, organize, and communicate characteristics for each case study. See Table\u00a0Because a random sampling approach is not recommended for multiple case study designs , 23, we Case studies are presented in order of their EPIS phase of implementation. Although implementation efforts may include activities across multiple phases, case studies representing efforts that are in the early stages of the EPIS framework are presented first, while case studies that are further along in implementation are presented last. Outer and inner context factors, as well as bridging and innovation factors, for integrated care implementation are discussed.To meet the healthcare needs of growing numbers of older people, this project targets implementation of a co-designed integrated care model for community dwelling older adults with frailty in SouthA number of challenges, successes and lessons learned with regard to implementation of integrated care for older adults with frailty were identified through a multi-stakeholder qualitative study. First, providers working in different parts of the healthcare system shared an understanding that integrated care for older adults with frailty involves different providers working in effective multi-disciplinary teams across different care organizations and sectors to deliver patient-centered, holistic, and coordinated health and social care. A number of care professionals perceived that there were improved relationships between providers working in health and social care. Despite these improved relationships, there persisted limited care coordination and teamwork of providers across health, social and voluntary care sectors. Most service users and caregivers demonstrated difficulty conceptualizing integrated care. Some understood it as improved coordination of health and social care services, whilst others viewed integrated care as continuity of care with a trusted professional who knew them well and had the right information and resources to access and navigate the system. Perceived barriers to integrated care implementation among stakeholders related to organizational or system coordination factors , and individual characteristics .The goal of the \u201cAccess To Tailored Autism INtegrated Care\u201d (ATTAIN) study isThis project aims to implement an integrated care approach (collaborative care) to improve screening and care for common perinatal mental health disorders in Vietnam, a lower-middle income country with a significant focus by national policy makers on the delivery of healthcare through public health systems. Perinatal mental health disorders are more prevalent in Vietnam than in high-income countries, and integrating mental health care with primary perinatal health care activities is essential . This prSeveral implementation themes have characterized this integrated care effort. A critical implementation driver was the existing federally-supported effort to initiate screening and treatment for depression. This national policy initiative was an opportunity to leverage regional resources for the pilot implementation study. The primary challenge to implementation was identification of additional funding sources for the participation of external experts and health services researchers to support the pilot and evaluation.Clalit) clinic, in northern Israel. Numerous outer and inner context factors influenced implementation of integrated behavioral health in the Tivon clinic. The primary outer context influence was the financial restructuring of mental health services through the 2015 mandate. Stakeholder commitment and engagement, together with organizational inertia, were key inner context factors aiding implementation. The HMOs hired trained personnel , many of whom had previously worked for the Ministry of Health. In addition, the Tivon clinic designated a room for behavioral health providers to facilitate integration.This project focuses on implementation of integrated behavioral healthcare in Israel following a mental health insurance reform in 2015 that transferred responsibility for the provision of mental healthcare from the Israeli Ministry of Health to the four major health maintenance organizations (HMO) health plans . While tThroughout implementation in the Tivon clinic, several challenges and some successes emerged. While there was hope for increased communication and cooperation between the primary care providers and the behavioral health staff, this collaboration was never realized. There are two potential reasons for this unrealized hope: (1) the Tivon clinic was only provided with one psychiatrist despite promises of also being provided with a social worker and therapist, and (2) psychiatric services were only offered once every 2 weeks, precluding the psychiatrist from joining weekly staff meetings. Additional challenges remain regarding availability of services, largely associated with the concentration of mental health professionals in the large cities and inequities in distribution based on social economic and socio-political factors. Despite ongoing challenges, successes should be acknowledged. For example, there has been a transfer of responsibility for some of the less serious mental health illnesses from psychiatry to primary care. Additionally, relative integration of physical and mental health services has been achieved in some clinics across Israel \u201338, withThe Scaling up Care for Perinatal Depression for Improved Maternal and Child Health (SPECTRA) project used a task sharing approach to integrate care for perinatal depression into primary maternal care where the largest proportion of Nigerian women receive maternal and child health services. Integrating mental health services into routine primary/maternal care such that non-physician health care providers deliver the bulk of essential mental health care service under the support and supervision of physicians or psychiatric nurses is commonly agreed as the most effective way to bring care to those in need , 40. TheMidwife-led continuity models of care have been demonstrated to provide greater benefits for women and babies, with no adverse effects, when compared to other models of care for women during pregnancy, birth, and early parenting . This caMost Innovative Collaboration\u2019 Award.The identified inner and outer context factors informed selecting more than 20 evidence-based implementation strategies of service delivery at the Family Care Center (FCC) at Memorial Hospital of Rhode Island, USA, provides an example of an integrated care implementation. The FCC offers integrated multidisciplinary services for patients across the lifespan. PCMHs have demonstrated effectiveness in cost savings by reducing hospital and emergency department visits, mitigating health disparities, and improving patient outcomes \u201350.Several outer and inner context factors were key in facilitating the FCC\u2019s progression into the Sustainment phase of PCMH implementation. Key outer context factors include a history of transdisciplinary, and legislative, initiatives to improve United States healthcare and patient health outcomes . SeveralWhile the FCC has been able to sustain the PCMH model of service delivery, areas for improvement reported by FCC faculty and resident physicians include ongoing challenges of limited time, feeling/being under resourced, limited staffing, and payment systems that do not adequately support the PCMH model. Despite these challenges, several successes deserve acknowledgement. Many faculty and resident physicians described the widespread knowledge of the PCMH within the FCC, and the integration of some structures and processes to facilitate integration, as successes.A growing number of integrated care efforts have demonstrated both positive and equivocal outcomes . To maxiFive key outer context factors were identified across the case studies. (1) The first key shared outer context factor related to patient/client characteristics, specifically, the degree to which specified patient populations had been identified as the targets for integrated care and greater levels of socio-political support to improve care for these groups. (2) Secondly, leadership was critical for implementation, particularly the engagement of higher-level leaders and state authorities who can determine priorities for healthcare reform efforts. Recent work has shown that both strong system level and clinic level leadership predict EBP sustainment . (3) The(4) The fourth shared outer context factor related to the extent and nature of patient/client advocacy and involvement. Our case studies revealed that consensus from stakeholders about prioritizing integrated care implementation and the voice of service users are critical at all stages of implementation. National healthcare agencies like the US Agency for Health Research and Quality and fede(5) Finally, inter-organizational environment and networks were identified as an important outer context factor shaping integrated care implementation. Many of the case studies mentioned the role of the electronic health record in facilitating (if shared across systems) or impeding (if incompatible) integration across service systems. Related to cross-service system communication, the extent to which primary and specialty care services were co-located, available and/or accessible to service users was an important consideration. In some cases, the extent of meaningful and collaborative communication was influenced by perceptions of the potential for loss of confidentiality or release of personal health information. This was particularly salient for mental health providers who may be reluctant to share patient records with other non-mental health providers due to the sensitive information about the client\u2019s mental health experiences.Five inner context factors were particularly relevant across the case studies. (1) Individual characteristics of service providers related to their knowledge, education or professional training in integrated care, as well as their confidence as a provider of integrated care, were key inner context factors shared across cases studies. This was sometimes shaped by insufficient clarity about the roles and functions of providers involved in integrated care delivery. It was also shaped by service provider\u2019s understanding and prioritization of healthcare needs of the population targeted. (2) Several organizational characteristics were important for adoption and implementation of integrated care approaches across different health populations. These included the integrated care implementation climate , 56 (def(5) Finally, organizational staffing processes, like shifting employees\u2019 roles and responsibilities to facilitate integrated care implementation and sustainment, emerged as a fifth shared inner context factor. This could take the form of transitioning nursing staff to nurse care managers to review high risk patient lists, outreach, and coordinate care. This factor also relates to individual characteristics of service providers and their attitudes towards shifting their roles and functions to facilitate integrated care.There was one primary bridging factor identified as key to integrated care implementation across all the case studies. This bridging factor was establishing and involving a community-academic partnership with theThere was one primary innovation factor identified: the degree of fit between the integrated care innovation and the system(s), organisation, provider, and patient/client groups. Fit was shaped by several elements of the contextual implementation environment including: the magnitude of siloed care prior to integrated care implementation; the extent to which stakeholders perceived that integrated care was an aspiration but discordant with the reality of care delivery; the perception that the role and identity of physician is more narrowly focused on medical/acute conditions rather than the \u201cwhole\u201d patient (a core principle of integrated care); the extent of (collaborative) communication between providers, leaders, stakeholders from different service systems; and service user characteristics, including the complexity of their healthcare needs for target populations .Based on these outer, inner, bridging and innovation factors, we propose an agenda of three broad goals to advance research in integrated care implementation.As with most implementation efforts in health service contexts, funding is a vital condition for successful transformation of healthcare delivery. At the outer context level, national and international research funding agencies can support the establishment of integrated care implementation by prioritizing funding for integrated care implementation research programmes, including funding for early and later phases of the implementation process. At the system-level, bridging strategies can reinforce priorities for integrated care implementation and can be communicated through incentives, mandates, and encouragement, and monitoring of national or local policy that communicates and reinforces the goal of adoption and implementation of integrated care approaches . While iThis goal can be achieved through several strategies. One example is through establishment of a community-academic partnership to plan Implementation climate for integrated care could be targeted by developing organizational mission statements that discuss integrated care or selecting employees for their prior experience working in integrated care settings. Another strategy is explicitly targeting leadership to support integrated care implementation . IntegraThere are several strengths balanced with some limitations of this research. While systematic reviews exist demonstrating the effectiveness of integrated care approaches , limitedSeveral limitations are of note. The primary limitation of this research is the snowball sampling strategy to select case studies. This sampling strategy was selected for several reasons but it may have resulted in the inclusion of case studies that are not representative of all integrated care implementation efforts. To mitigate this effect, we intentionally sought out integrated care researchers who were conducting implementation research in a range of high income and low-to-middle income countries that were focused on a variety of service systems and patient populations. In addition, some potential contributors were excluded from inclusion if it was felt that they would lead to excessive redundancy between case studies. We believe that we have provided a fairly broad range of examples. Though the sampling effort may have limitations, we believe the conclusions presented have broader applicability beyond the integrated care implementation efforts included in this paper. Within this effort to include a range of integrated care examples, we acknowledge that we sought out researchers who are leading or who are involved in integrated care program implementation. Commonly, integrated care programs do not involve researchers and are often implemented in care contexts that limit the feasibility of engaging researchers and community members in community-academic partnerships. An additional limitation is that we did not include an independent evaluator to assign or review the work described in each case study to the specific domains of the EPIS framework. However, we employed an iterative qualitative analytic approach that provided all research leads of the case studies and the lead EPIS framework developer the opportunity to review and refine the operationalization and application of the EPIS domains and phases to each case study.This multiple case study design highlights research from five countries in pursuit of implementing integrated care models in a range of service systems for various patient groups. Synthesis of case study descriptions revealed common themes related to the outer, inner and bridging/innovation contexts that informed our proposed agenda to advance the research in integrated care implementation. The primary goals within our proposed agenda relate to 1) the role of funding at multiple levels of implementation; 2) fostering meaningful collaboration with stakeholders across phases of implementation; and 3) clear communication about integrated care implementation.Additional file 1. Full Text Case Studies. These are the full case studies based on the standard template (see Table"} +{"text": "Myths and stereotypes of sex in late life prevail . Unless the workforce is adequately prepared and knowledgeable to address the sexual health needs of older adults, it is difficult to disrupt ageism that contribute to discrimination against older adults. Methods: We evaluated a two-day experiential workshop designed for students to develop factual community resources and educational materials related to sex and aging. Results: Using content analysis, we examined open-ended responses from 41 students. We identified three themes that depicted the value of experiential learning, specifically for this taboo topic. Students (1) increased awareness of late life sexual health and behaviors, (2) demonstrated comfort and creative strategies to discuss sex, and (3) appreciated the opportunity for transferable pre-professional skill development. Discussion: Providing pre-professional training helped close the knowledge gap about basic gerontological issues and issues specific to sexual health and sexual behaviors in late life. Students perceived the flipped classroom and collaborative structure of this experiential workshop as beneficial and practical for their learning and professional preparation. They developed skills for translating knowledge into practical resources that likely will transcend professions. Emphasizing the potentially uncomfortable topic of sex and aging provided students an opportunity to increase their comfort when addressing issues they will experience in their various professions. It is critical for gerontology educators to identify strategies to deliver sex and aging education among professionals to enhance interactions with older adults."} +{"text": "Plants can produce different phenotypes when exposed to different environments. Understanding the genetic basis of these plastic responses is crucial for crop breeding efforts. We discuss two recent studies that suggest that yield plasticity in maize has been under selection but is controlled by different genes than yield. Figure 1; Phenotypic plasticity is phenotypic variation that results from the complex relationships between an individual\u2019s genotype (G) and the environment (E), including management decisions, in which it is grown. The ability of a single genotype to produce different phenotypes in different environments is termed phenotypic plasticity. The amount of phenotypic change across environments describes the degree of plasticity. When this change is far from zero, the phenotype is plastic; when this change is near zero, the phenotype is stable. Phenotypic plasticity is a characteristic of an individual genotype; when variation for plasticity exists within a population, it is termed genotype-by-environment interaction (GxE) . Responses to this macroenvironmental variation are termed plasticity . By contThe adaptive significance of phenotypic plasticity is situational . For exaConsequently, accounting for plastic responses in applications such as plant breeding is critical because plants are sessile and must respond to the environments in which they are grown. Breeders have approached this challenge in two ways . First, post hoc manner and QTLs that only have effects in certain environments (gene regulation model) . ControvMaize is an ideal model and crop species in which to study phenotypic plasticity. It was domesticated in the lowlands of southwestern Mexico and subsequently adapted to highland and temperate environments . FurtherSTF and low nucleotide diversity) between 30 temperate and 30 tropical inbred maize lines along with a control group of SNPs that exhibited no such evidence. These SNPs were used to test the amount of phenotypic variation among 858 temperate maize hybrids that could be explained by SNP-environment interactions within each group. They found that high STF SNPs explained an average of 8.1% of the GxE variance for yield compared to 18.7% for low STF SNPs. High STF SNPs also explained less genetic variance for yield than low STF SNPs. This suggests that selection, especially in genomic regions showing high differentiation between temperate and tropical germplasm, has increased yields in temperate environments at the expense of the amount of GxE variation associated with yield that is explained by those SNPs. This reduction in GxE variance could be the result of increased uniformity in either the yield plasticity or yield stability of modern temperate maize germplasm. Because breeders have heavily selected for yield stability in modern temperate maize, To address this question, 1, will be required to test this hypothesis.If loci for yield and yield stability are genetically linked, selection for yield would be expected to affect allele frequencies at loci for yield stability and vice versa. Because breeders have selected for both yield and yield stability, the simultaneous reduction in genetic and GxE variances explained by putatively selected genomic regions suggests that these regions contain genetically linked genes for yield and yield stability where the favorable alleles for both traits are in coupling linkage. Simultaneous selection for yield and yield stability by breeders has been remarkably successful; for example, modern commercial hybrids have improved drought tolerance while also increasing yields in well-watered and drought conditions . HoweverAdditionally, yield integrates plastic responses to multiple abiotic and biotic stresses; the genes that mediate each plastic response may or may not be linked to yield-related genes and/or each other, increasing the complexity of breeding decisions when selecting for adaptive loci for particular combinations of environmental conditions. This view of yield as a function-valued trait of multiple environmental factors has a rich theoretical background , but manIdentifying such loci will allow for the identification and selection of desirable recombinants in elite breeding germplasm. However, if the findings of Further experiments to identify adaptive variation in maize paired with emerging technologies present an opportunity to improve yields not only by increasing average yield but also by maintaining and manipulating genetic variation that helps individuals maximize productivity across different environments. New cultivars can then be tailored to expected future conditions and agronomic practices in their target performance environments. Such an approach could not only create higher-yielding cultivars that exploit favorable conditions but also higher-yielding, stable cultivars that provide predictable yields in challenging environments where subsistence farming is often found.All authors contributed to the writing and editing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Alcoholics often suffer from motor incoordination resulting from alcohol-related cerebellar damage. However, the effect of cerebellar structural damage on cognitive functioning has not been clearly demonstrated. It is not known if the relationships observed between cerebellar damage and functional impairments persist with abstinence from alcohol. Cell death may cause permanent loss of function, whereas tissue shrinkage without permanent cell loss might represent the potential for recovery. This article examines research on the interrelationship of alcohol-related abnormalities in cerebellar structure and function. Research such as this may provide knowledge to guide future rehabilitation efforts. One of the most widely recognized signs of acute alcohol intoxication is staggering gait. The motor incoordination element of intoxication is routinely assessed by highway patrol officers when they use standard tests of stance imbalance (otherwise known as gait ataxia) and eye-hand incoordination.The obvious signs of gait and coordination disturbance demonstrated by these simple tests usually resolve once the person has become sober. However, careful study of alcoholicsIn addition to its role in controlling movement, the cerebellum may play an important role in the acquisition of motor skills and the cognitive processes that control movement . The cerThis article reviews current knowledge on the motor and cognitive processes controlled or facilitated by the cerebellum and describes damage to the cerebellum associated with long-term alcoholism. The article then explains how researchers are seeking to relate this damage both to problems with balance and motor coordination and to some of the characteristic cognitive deficits associated with alcoholism.The term cerebellum comes from the Latin and means \u201clittle brain.\u201d Although it is only about one-tenth the weight of the cerebrum, it contains about as many nerve cells (approximately 5 billion for each structure) . The cerThe vermis lies between and in front of the cerebellar hemispheres. It has 10 lobules and is named for its wormlike appearance. Damage to the vermis can result in poor control of posture and upright position, ataxia , and dysarthria (irregular and explosive cadence of speech). The superior (upper) lobules of the vermis are especially involved with refinement of coordination and postural stability of the legs and trunk. The more inferior (lower) lobules support coordinated movement of the arms.Nerve cells in the cerebellum communicate with nerve cells in the cerebrum, brain stem, and spinal cord, including regions involved in cognitive functions, such as spatial and other sensory perception, problem-solving, organization, and planning. Skilled performance of motor tasks involves timing, feedback from visual and sensory cues, coordination, and learned patterns or dynamics of movement that allow movements to be made quickly, smoothly, and relatively effortlessly . These fThe cerebellum may contribute to cognitive functions carried out primarily by the cerebrum. These functions include certain aspects of verbal learning as well Cerebellar degeneration is common in alcoholics . ResearcStructures at the base of the cerebellum also may be affected by excessive alcohol consumption . These rCerebellar volume loss is confirmed by neuroimaging techniques that provide quantitative measurement of the different tissue types of the brain. Studies using computed tomography and magnetic resonance imaging (MRI)Cerebellar shrinkage is most notable in older alcoholics with at least a 10-year duration of alcoholism . WhetherThe demonstration that increasing doses of alcohol are associated with increasing severity of an impairment would provide important evidence that the impairment is alcohol related. However, this type of alcohol dose-response relationship has been difficult to demonstrate for cerebellar impairment. In one study , degree Signs of ataxia can wax and wane corresponding with periods of alcoholic drinking and abstinence, providing evidence for specific adverse effects of alcohol on motor coordination. Abstinent alcoholics may show improvement in balance and periIn one study , alcoholA functional neuroimaging study used positron emission tomography (PET) to study the ability of the brain regions to incorporate glucose, the brain\u2019s primary energy source. This study revealed that alcoholic patients with ataxia showed hypometabolism (lower than expected glucose uptake by the brain) in the superior cerebellar vermis, whereas alcoholics without ataxia did not show cerebellar hypometabolism . These rGenetics also may play a role in alcohol-related motor deficits. Using PET, Neuroimaging might help clarify the relationship between cerebellar structural and functional changes during abstinence. A similar approach has been applied to the cerebrum, where researchers have used neuroimaging techniques to track the progression and recovery of volume loss during periods of active drinking and abstinence . HoweverAlcoholics often exhibit cognitive deficits in visuospatial processing and problem-solving (reviewed in An MRI study identified significant cerebellar shrinkage in detoxified patients with chronic alcoholism . These rThe combined disorders of balance and visuospatial ability put alcoholics at increased risk of falls and other accidents. This may be especially true of older alcoholics . Such acThe reversibility of cerebellar structural changes is not known, and it is not known if the relationships observed between cerebellar damage and functional impairments persist with abstinence. To the extent that the structural change represents cell death, it may be permanent, and function may not recover. Tissue shrinkage without permanent cell loss may account for variance in the correlation between cerebellar structural and functional impairment and might represent the potential for recovery. Future investigations will need to focus on the reversibility and interrelationship of alcohol-related abnormalities in cerebellar structure and function. Results of such studies may lead to knowledge regarding the potential for recovery and guide future rehabilitation efforts."} +{"text": "Herbivore\u2010induced plant volatiles (HIPVs) are an important cue used in herbivore location by carnivorous arthropods such as parasitoids. The effects of plant volatiles on parasitoids have been well characterised at small spatial scales, but little research has been done on their effects at larger spatial scales. The spatial matrix of volatiles (\u2018volatile mosaic\u2019) within which parasitoids locate their hosts is dynamic and heterogeneous. It is shaped by the spatial pattern of HIPV\u2010emitting plants, the concentration, chemical composition and breakdown of the emitted HIPV blends, and by environmental factors such as wind, turbulence and vegetation that affect transport and mixing of odour plumes. The volatile mosaic may be exploited differentially by different parasitoid species, in relation to species traits such as sensory ability to perceive volatiles and the physical ability to move towards the source. Understanding how HIPVs influence parasitoids at larger spatial scales is crucial for our understanding of tritrophic interactions and sustainable pest management in agriculture. However, there is a large gap in our knowledge on how volatiles influence the process of host location by parasitoids at the landscape scale. Future studies should bridge the gap between the chemical and behavioural ecology of tritrophic interactions and landscape ecology."} +{"text": "The 2018 European Molecular Biology Laboratory (EMBL) Experimental and Evolutionary Approaches to Yeast and Other Organisms conference brought together researchers addressing fundamental questions in microbial evolutionary systems biology. Topics spanning evolution in the wild and the lab to molecular mechanisms of adaptation and ecological interactions between species were covered. Here, we highlight key themes that emerged from this meeting and summarize new and unpublished results that were presented. For the sake of brevity, we describe only oral presentations even though the quality of the poster presentations was excellent. We identified five major themes that encompassed the majority of presentations.Every two years, biologists who span disciplines from evolutionary to synthetic biology and work with organisms ranging from yeast to humans, congregate above the German town of Heidelberg at the European Molecular Biology Laboratory (EMBL) to report on recent progress. In October 2018, the 5S. cerevisiae strains has provided a great resource for understanding the evolutionary history of this species in Torulaspora delbrueckii points toward a model in which HO originated from the only intein-containing gene in yeast, VMA1. Its fusion to a zinc finger domain provides the protein sequence specificity and ability to integrate into empty alleles. Another exception was described by Anne-Ruxandra Carvunis, who summarized recent progress in understanding de novo gene birth, a process that generates proto-genes without ancestral gene modification. This process was initially thought to be extremely rare but has become a subject of greater interest following the identification of some 2,000 proto-genes by ribosome profiling data truly allows for scientific exchange, discussion and for establishment of new collaborations. Future topics for the 2020 meeting might include microbial ecology, food microbiology and industrial applications. The EMBL meeting has established itself as the preeminent forum for reporting progress in our understanding of microbial evolution and ecology. We look forward to making the pilgrimage to Heidelberg in two years and the continuing evolution of this essential meeting."} +{"text": "Technology offers powerful tools for meeting the increasing needs of older adults and caregivers. The Geriatric Workforce Enhancement Program recognizes the important role technology will play in service delivery and training by fostering innovation to meet local training and healthcare needs. This symposium will review the innovative models and strategies GWEPs are utilizing to improve care including Project ECHO, remote monitoring, and telehealth. The policy implications of these models will be presented, including current legislative action to support technology and innovation in the care of older adults."} +{"text": "Online discussion platforms have the potential to support or even improve older adults\u2019 well-being. Nonetheless, potential health benefits are often shaped by the usability of such platforms. Improving usability is imperative to maximize these potential benefits. As a part of a qualitative analysis of a study of an online community for older adults with frailty symptoms, we developed and refined a coding scheme targeting usability. The scheme was derived by reviewing contemporary literature on user experience, usability, and health information technology in older adults. Our review revealed challenges to apply commonly used terms to summarize our qualitative data. For example, the concept of perceived usability has different meanings and definitions in existing frameworks as they pertain to user engagement and technology adoption than usability in an online discussion context for older adults. Because none of the meanings of usability fully encompassed the breadth of this concept for older users, we developed a coding scheme that is practical and captures a broad range of older adults\u2019 perceptions of usability. Through qualitative analysis of the online discussion content using the newly developed coding scheme, new themes emerged such as confusing layout , insufficient instruction or training (trouble posting discussions), unwanted results , and memory issues and cognitive burden. This presentation describes the process of developing a coding scheme, illustrates nuances of meanings in concepts related to usability, and presents preliminary results of our qualitative analysis."} +{"text": "OBJECTIVES/SPECIFIC AIMS: The goal of this pilot study is to provide a reliable anatomical algorithm for the measurement of adipose tissue within the pelvic cavity as a predictor of prostate cancer aggressiveness and recurrence after radical prostatectomy. METHODS/STUDY POPULATION: We will conduct a retrospective analysis of men treated with radical prostatectomy between 2012 and 2016 at the VA Caribbean Health Care System. Clinical variables, pathology reports, and computed tomography will be reviewed. Pelvic and periprostatic fat (PF) will be measured to determine association between PF and cancer aggressiveness and recurrence. RESULTS/ANTICIPATED RESULTS: We expect a positive association between PF and cancer aggressiveness and recurrence among patients who underwent radical prostatectomy. DISCUSSION/SIGNIFICANCE OF IMPACT: Measurement of subcutaneous and PF within the pelvic cavity can provide a reliable anatomical measure which can be used as a proxy measure to identify those with higher risk of recurrence and develop better prevention and treatment strategies, especially in Hispanic men."} +{"text": "Molecular factors and pathways promoting human longevity and healthy aging can potentially delay or prevent multiple chronic diseases and conditions, but identifying such factors that can be pharmacologically targeted requires an integrated multidisciplinary approach. We describe the design of the five research projects and three cores of the Longevity Consortium (LC) and how their cooperative research is designed to discover molecular factors and pathways that can predict healthy human aging and longevity, associate with extreme human lifespan, show relevance to chronic age-related conditions, respond to interventions to slow aging in mice, and show evidence for association with lifespan across species. A systems biology approach is undertaken to identify common molecular features across human traits and organisms, and a chemoinformatics approach to link molecular targets to candidate healthy aging interventions. The LC results are made publicly available and we provide funding opportunities to the scientific community to support pilot projects."} +{"text": "Flowering plants display a large spectrum of seed architectures. The volume ratio of maternal versus\u00a0zygotic seed tissues changes considerably among species and underlies different nutrient-storing strategies. Such diversity arose through the evolution of cell elimination programs that regulate the relative growth of one tissue over another to become the major storage compartment. The elimination of the nucellus maternal tissue is regulated by developmental programs that marked the origin of angiosperms and outlined the most ancient seed architectures. This review focuses on such a defining mechanism for seed evolution and discusses the role of nucellus development in seed tissues and nutrient partitioning at the light of novel discoveries on its molecular regulation. Tissue partitioning is the driving force that shapes the development of different seed structures. The relative contribution of each tissue to the final seed mass varies considerably among species and underlies different nutrient-storing strategies. Tissue partitioning is achieved through cell elimination programs that regulate the degeneration of one tissue in favor of another Ingram . The nucRecent discoveries on the molecular regulation of nucellus elimination have given an insight into the process of seed tissues partitioning. Here, we discuss them in the context of angiosperm seed natural diversity. Finally, we review nutrient transport and accumulation in the nucellus across different seed architectures to present seed tissue and nutrient partitioning as two coherent and inextricably linked aspects of seed development.Angiosperm ovules have been classified according to their nucellus position and thickness Endress . A firstAustrobaileya scandens seeds drives early seed growth and is then eliminated by the endosperm, whose further development determines final seed size and progresses in a distal\u2013proximal fashion to achieve the loss of 50% of its cells by 8 DAF. A few layers of proximal nucellus cells persist and expand with the rest of the ovules to form a gate between chalaza and endosperm till embryo maturity and Multicopy Suppressor of IRA1 (MSI1) are also expressed in the nucellus and seed coat and autophagy. Furthermore, a papain-type KDEL-tailed cysteine endopeptidase (CysEP), involved in PCD of vegetative tissues, has been shown to be expressed in the distal nucellus undergoing degeneration Polycomb Group (PcG) proteins on nucellus degeneration in wheat, barley, and sorghum.In cereals, the nucellus accounts for most of the grain volume at anthesis and it is eliminated after fertilization in a centripetal fashion. At grain filling, only the outermost nucellus cell layer (nucellus epidermis) and a few nucellus cell layers overlaying the ovule vascular trace at the chalazal side are retained and undergo PCD more or less rapidly according to the species. The chalazal nucellus of maize grains appears as compact layers of dead cells with limited plasmodesmata connections gene revealed a mechanical interaction between nucellus and endosperm. Maize grains mutated for the Mn1 gene show a gap between the nucellus cells, which are rapidly emptied of their nuclear and cytoplasmic material, and the endosperm. Such a gap is not due to cell death but to an underdeveloped endosperm that results in over-expanded nucellus cells, thus suggesting that the endosperm exercises a mechanical force on the nucellus genes responsible for sucrose import in sink tissues (Bagnall et al. By contrast, the nucellus of wheat and barley is simplastically connected to the placenta and the nucellar projection develops transfer cells, thus expanding the nutrient unloading zone and facilitating transfer (Radchuk et al. Brachypodium grains develop a smaller nucellar projection than barley and wheat, but display a thicker nucellus epidermis which has been proposed to play an active role in nutrient transport (Ellis and Chaffey MADS29 expression, highlighting the active role of the rice nucellus in transferring nutrients to the endosperm (Nayar et al. Rice and The role of the nucellus in perispermic seeds changes from nutrient-transport facilitator to long-term nutrient sink. The perisperm of quinoa seeds accumulates mostly starch while undergoing PCD (Lopez-Fernandez and Maldonado The evolution of seed storage tissues in angiosperms has been a \u201cbattle\u201d between endosperm and nucellus development. Both tissues can store starch and become the main source of energy for embryo germination. Indeed, the nucellus of perispermic seeds parallels the endosperm of endospermic seeds at both morphological and functional levels. Nevertheless, most angiosperm seeds evolved mutually exclusive growth of nucellus and endosperm. The nucellus offers an easier system of nutrient storage simplastically connected to the placenta. By contrast, the endosperm couples nutrient storing to fertilization, thus possibly avoiding energy waste in case of unsuccessful fertilization.Whereas we have a better understanding on seed nutrient transport and tissue elimination, the next challenge will be to address how nutrient and tissue partitioning are coordinated at the molecular level.JL reviewed the role of MADS box genes in nucellus development. EM wrote the rest of the paper in consultation with JL."} +{"text": "Japan has four stand alone abuse prevention laws, including child abuse (enforced in 2000), domestic abuse (2001), elder abuse (2006) and abuse for people with disabilities (2011). These laws are distinctive in that they aim to prevent abuse, not merely to address abuse after it occurs. This paper compares components of these four abuse prevention laws, delineating major strengths and weaknesses of the elder abuse prevention law in comparison to the other three. The analysis considers both institutional and domestic settings and suggests possible improvements of elder abuse prevention law that need to be made. Evidence for this analysis is supplied through examination of trends abuse using longitudinal data (2012-2017) collected by Japan\u2019s Ministry of Health, Labour and Welfare. The analysis shows commonalities in trends in the four abuse categories. For example, the number of abuse cases has risen over time despite the dissemination and implementation of abuse prevention training, program implementation, and public outreach. Differences include reporting \u2013 police more often report abuse cases of children and people with disabilities, while elder abuse cases are more often reported by professional staff members responsible for dealing with elder abuse cases. Although some amendments have been made to the child abuse and domestic abuse prevention laws, no amendments have been made to the elder abuse prevention law despite the requirement to review its success. Needed revisions include provisions of protection orders and temporary shelters to protect elder victims from abusers as soon as possible."} +{"text": "As populations worldwide are living longer, the impact of neurodegenerative diseases on health resource utilization is expected to increase. Providing care to older adults with neurodegenerative diseases is challenging, and requires adequate supports across multiple health sectors including community, acute care and nursing home settings to allow individuals to maximize their quality of life. The Ontario Neurodegenerative Disease Research Initiative (ONDRI) is a collaborative research program that aims to improve diagnosis, treatment and management of neurodegenerative diseases including Alzheimer\u2019s disease and related dementias, Parkinson\u2019s disease, Amyotrophic Lateral Sclerosis (ALS), and Vascular Cognitive Impairment. Using population-based linked health administrative and clinical databases--covering over 14 million individuals residing in the province of Ontario, Canada-- the ONDRI health services research platform will address knowledge gaps regarding the health service utilization and outcomes of older adults with neurodegenerative diseases and impacts on family and care partners. Access to over two decades of historical health administrative data on a large population of older individuals uniquely positions our collaborative to examine trajectories of health system use as well as rare neurodegenerative diseases which have been previously understudied. The health services research platform is embedded within a larger ONDRI network of biomedical researchers, provincial decision-makers and health system stakeholders. Our research findings will inform health system planning and interventions to support older adults to live independently in the community. This session will explore how health administrative databases may be used to address knowledge gaps regarding health service utilization and outcomes in older persons with neurodegenerative diseases."} +{"text": "This study investigated the association between widowhood and depressive symptoms and the extent to which the association is contingent upon immigration status, functional limitations, financial strains, and intergenerational support, among older Mexican Americans. A sample of 344 parent-child dyads reported by 83 older adults in a city of West Taxes completed the measures for socioeconomic status and depressive symptoms. Clustered regression analysis showed that widowhood elevated the risk of depressive symptoms. Living with functional limitations, having more children and residing in the same city with children exacerbated the adverse effects of widowhood on depressive symptoms. Residing in the same city with children increased the detrimental effects of widowhood on the depressive symptoms among men, whereas this pattern did not appear among women. The findings highlight the heterogeneity of depressive symptoms among the widowed Mexican American older adults."} +{"text": "This presentation reports findings from on different translation approaches that embedded into the community two evidence-based interventions for family caregivers of people with dementia. CarePRO was embedded into the community after completion of a clinical trial, whereas EPIC was embedded from the program\u2019s inception. CarePRO is a group and telephone coach call intervention targeting family caregivers and EPIC is a group dyadic intervention for both early-stage people and their care partners. Available in English and Spanish, these programs are still being delivered across two states through community-based organizations. Findings from both CarePRO and EPIC demonstrate significant levels of participant benefit . Presenters will share lessons learned from the translation process regarding design modifications, training and supervision of interventionists, participant recruitment and retention, and adaptation of outcome assessments."} +{"text": "Sudden Cardiac Death (SCD) is the leading cause of cardiovascular death in dialysis patients. This review discusses potential underlying arrhythmic mechanisms of SCD in the dialysis population. It examines recent evidence from studies using implantable loop recorders and from electrophysiological studies in experimental animal models of chronic kidney disease. The review summarizes advances in the field of non-invasive electrophysiology for risk prediction in dialysis patients focusing on the predictive value of the QRS-T angle and of the assessments of autonomic imbalance by means of heart rate variability analysis. Future research directions in non-invasive electrophysiology are identified to advance the understanding of the arrhythmic mechanisms. A suggestion is made of incorporation of non-invasive electrophysiology procedures into clinical practice.Key Concepts:\u2013 Large prospective studies in dialysis patients with continuous ECG monitoring are required to clarify the underlying arrhythmic mechanisms of SCD in dialysis patients.\u2013 Obstructive sleep apnoea may be associated with brady-arrhythmias in dialysis patients. Studies are needed to elucidate the burden and impact of sleeping disorders on arrhythmic complications in dialysis patients.\u2013 The QRS-T angle has the potential to be used as a descriptor of uremic cardiomyopathy.\u2013 The QRS-T angle can be calculated from routine collected surface ECGs. Multicenter collaboration is required to establish best methodological approach and normal values.\u2013 Heart Rate Variability provides indirect assessment of cardiac modulation that may be relevant for cardiac risk prediction in dialysis patients. Short-term recordings with autonomic provocations are likely to overcome the limitations of out of hospital 24-h recordings and should be prospectively assessed. Chronic kidney disease affects 5\u20137% of the global population and is associated with a 10-fold increase in cardiovascular mortality. Over 2 million people worldwide are on renal replacement therapy . DespiteIt has been shown that renal dysfunction increases the risk of ventricular arrhythmias in patients with underlying ischaemic heart disease. After a first myocardial infarction, the presence of CKD stage 3 was found to be associated with a sixfold increase in odds of developing VF independently of traditional cardiovascular risk factors . AdvanceAlthough CKD often coexists with coronary artery disease , SCD is Furthermore, whereas the increased risk of ventricular arrhythmias due to advanced CKD in the context of severe ischaemic cardiomyopathy has been confirmed , the undRisk stratification strategies to identify dialysis individuals who are at high risk of SCD are lacking. This is despite them attending hospital or satellite facilities for their dialysis treatment three times weekly and having clinical observations and blood tests more often than any other out-patient group. Because of this, it is recognized that non-invasive electrophysiology could serve the unmet clinical need for risk prediction in this population . DescripThis review summarizes the recent evidence from the use of ILRs in HD patients and electrophysiological studies in animal models of CKD, exploring the potential underlying arrhythmic mechanisms. It also presents the evidence from the use of non-invasive electrocardiography in dialysis patients focusing on QRS-T angle and HRV and concludes with suggestions for future directions of research.Since 2015, five studies using ILR in asymptomatic HD patients have been published Table 1Table 1. Although these studies provide novel information, this should be interpreted with caution. The scarcity of available information about the prevalence of bradyarrhythmias from long-term monitoring in asymptomatic patients need to be taken into consideration.Previous studies using 24-h recordings in healthy individuals have shown a high prevalence of bradycardias (heart rate 40 beats/min or less) during sleep at 24% in males aged 22\u201327 years . With adThe participants in the HD ILR studies were not young and, despite the lack of knowledge regarding the normal incidence of bradycardias in HD patients and notwithstanding the small number of relatively low cardiovascular risk participants and the heterogeneity amongst the studies, these investigations show a high burden of bradyarrhythmias in HD patients with preserved ejection fraction. This potentially contributes substantially to the overall burden of SCD. Consistent with the HD ILR studies, a recent epidemiological study that investigated registry data of 28,471 dialysis patients showed tElucidating the underlying mechanisms of bradycardias and their relationship to SCD has important clinical implications relating to the required routine screening, to the decisions of potential use of beta blockers, and/or to considerations of potential interventions such as pacemaker insertion.Electrolyte shifts, especially pre-dialysis hyperkalaemia, have been implicated as potential triggers of bradyarrhythmias particularly at the end of the long interdialytic interval in a typical 3 dialysis session week. The electrophysiological role of hyperkalaemia in triggering bradyarrhythmias is likely potentiated by the presence of underlying structural abnormalities in the conduction system and/or abnormal cardiac autonomic regulation of the pacemaker activity that prevent adequate heart rate reactions in response to physiological stress. Cardiac valve calcification may affect the cardiac conduction system and has also been implicated in bradyarrhythmias . It is hThe potential contribution of obstructive sleep apnoea to bradyarrhythmias in dialysis patients merits attention. Sleep apnoea is typically characterized by episodes of bradycardia as shownThe high rate of AF in the HD population is another important finding and may be linked to increased risk of SCD. Evidence suggests that AF may be associated with SCD in cardiac patients and in tAnimal models have been used to investigate the pre-arrhythmic substrate and the mechanisms of arrhythmias in CKD .Ito was reduced in epicardial cardiomyocytes in CKD rats compared to controls, and associated with decreased transmural gradient of Ito. Similar to the previous study, increased heterogeneity of repolarization occurred independently of the cardiac fibrosis that was observed at similar levels in CKD and normal rats . Both models demonstrated a high incidence of arrhythmias accompanied by increased interstitial fibrosis and decreased Cx43 expression in the heart.The first two animal investigations suggest The observation that the relationship between subcutaneous nerve activity, a surrogate of sympathetic tone, and heart rate was different in CKD rats compared to normal rats is in keeping with human studies describing abnormal autonomic cardiac modulation in CKD.However, fundamental electrophysiological differences exist between rodents and large mammals , making The standard 12 lead ECG is an essential clinical tool in CKD and dialysis patients . It is cThe QRS-T angle is an established marker of global repolarization heterogeneity that canAn increased QRS-T angle has been associated with echocardiographic left ventricular hypertrophy , decreasDifferent groups have used different methods for the calculation of the QRS-T angle that are summarized in Racial, and previously described sex differences should aThe mechanisms linking abnormal repolarization heterogeneity with clinical outcomes and cardiac structure and function abnormalities remain unclear and will need to be assessed in prospective studies.Sympathetic overactivation has short and long-term proarrhythmogenic effects and may play a role in the pathogenesis of arrhythmic deaths in CKD patients. Sympathetic activation impacts on cellular channel activity increasing repolarization heterogeneity and playSympathetic nerve activity, assessed by microneurography of the peroneal nerve, increases with declining renal function and is eThe baroreflex regulation has also been shown to be impaired in CKD. In dialysis patients, impaired baroreflex sensitivity was shown to be associated with vascular calcification and arterial stiffness indicatiDirect measurement of the autonomic system with microneurography poses practical challenges and is not suitable for clinical practice. Nevertheless, indirect measurements are possible by assessing HRV . HRV is Many groups have used HRV methodology in dialysis patients. A pubmed search using the terms HRV and dialysis returns 122 studies with the first one published already in 1986 . AbnormaFrequent daily HD has been shown to improve components of HRV . PreservDespite the consistent results confirming the value of HRV in CKD patients, major challenges exist in extrapolating associations from these studies and incorporating HRV measurements into clinical practice. The main challenge is related to the sensitivity of HRV to environmental influences and the need for strict standardization, particularly for 24-h ECG recordings, which is practically impossible when the recording is performed in the outpatient setting.For the purposes of standardized assessment, several studies used short term recordings around or during the dialysis procedure, i.e., a period with relatively standardized environment characterized by volume and electrolyte shifts that provoke the autonomic system in a predictable manner. It is known that patients who exhibit excessive intradialytic decline in systolic blood pressure have higher risk of cardiovascular and overall mortality . The patStudies using short term intradialytic ECG monitoring have shown that HRV parameters are influenced by the rate of volume removal during dialysis and by tFew studies have used short term HRV assessment during autonomic postural, provocations in HD patients. In the study by Genetic differences might contribute to the differences in reported HRV response to autonomic provocations. A recent study in 114 HD patients suggesteTwo small studies have reported reasonable reproducibility of HRV measurements from intradialytic recordings .Recent ILR studies have shown an important relative contribution of bradyarrhythmias to sudden death in dialysis patients. However, these studies did not include incident dialysis patients with high cardiovascular risk that may be more vulnerable to ventricular tachyarrhythmias. Future large studies with long term ECG monitoring in incident dialysis patients are needed to elucidate the precise incidence and underlying arrhythmic mechanisms of SCD. These studies should aim at developing risk stratification strategies for both tachyarrhythmic and bradyarrhythmic risks. Tachyarrhythmic risk is mainly related to static and dynamic ventricular repolarization abnormalities and it is possible that repolarization patterns and changes related dialysis induced fluid and electrolyte shifts prior to the fatal arrhythmias may be important for its prediction. On the contrary, bradyarrhythmic risk is mainly related to cardiac periodicity and is likely to be influenced by autonomic system abnormalities including sleep apnoea.The ECG signals should be regularly interrogated during the course of such studies and treatment for significant bradyarrhythmias should be offered. Non-invasive surface long term ECG technology with sufficient memory that can record continuous high quality ECG signal could serve the dual purpose of potentially fatal or final rhythm detection and data acquisition for risk profiling for both tachyarrhythmias and bradyarrhythmias. In addition, non-invasive continuous long term ECG monitoring devices that can be attached and exchanged during a dialysis visit may facilitate the recruitment of high risk incident patients who may not wish to attend additional hospital visits or undergo invasive procedures.Research protocols should include detailed cardiovascular, genetic and sleep disorder phenotyping.These studies, in addition to clarifying the prevalence of bradyarrhythmias and ventricular arrhythmias, will provide important information about the burden of AF and its potential association with SCD. An association between AF and increased risk of SCD has been shown in cardiac patients and may The QRS-T angle assessment has substantial potential to be used as a descriptor of uremic cardiomyopathy. It can also be easily incorporated into clinical practice. In the first instance, the different methodological approaches need to be rigorously tested and compared in existing large ECG databases of CKD and dialysis patients to determine the best methodological approach to the angle expression. This should be based on a multicenter collaboration between clinical research teams and bioengineers. Such collaborative effort can help determine normal reference values and increase our understanding of racial and gender differences in the CKD and dialysis populations.Furthermore, it is important for the clinical and research community and industry partners in ECG manufacturing to understand the importance of collecting high quality ECGs and storing them in easily accessible formats in orderIn the field of HRV and assessment of cardiac autonomic modulation, further research is required to standardize the measurements in dialysis patients. Short-duration tests with autonomic provocations could overcome methodological shortcomings of 24-h outpatient ambulatory ECG recordings. These assessments can be organized around the dialysis treatment in order to minimize a patient\u2019s inconvenience and be suitable to be incorporated into regular clinical practice in the future. HRV measurements may be useful for both bradyarrhythmic and tachyarrhythmic risk stratification. The value of cardiac autonomic modulation assessment during standardized autonomic provocations for prediction of significant bradyarrhythmias should be prospectively investigated.On the other hand, ECG acquisition during autonomic provocations has the potential to yield important prognostic information for tachyarrhythmias, while at the same time characterizing cardiac autonomic regulation measured by HRV and by dynamic repolarization profiles. Short duration continuous ECG measurements with standardized controlled provocations can be used to assess dynamic changes of the QRS-T angle during different stages of cardiac autonomic status; this has been shown to strengthen risk prediction in cardiac patients . This tyNon-invasive electrophysiology has an important role in CKD patients. Close collaboration across the disciplines of biomedical engineering, clinical cardiology and nephrology is required to bridge the gaps between available technological tools, research efforts and clinical translation in arrhythmic complications of CKD.DP: concept, design, drafting article, and critical revision of article. KH and SS: critical revision of article. DG and PK: concept and critical revision of article. MM: concept, design, and critical revision of article.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Metastasis of malignancies to the brain, including parenchymal and leptomeningeal disease, represents a common neurological complication in cancer patients , 2. CurrFranchino et al. describe different detection methods, including magnetic resonance imaging (MRI), computed tomography, positron emission tomography (PET) as well as advanced imaging techniques commonly used in the diagnosis, treatment planning, and follow-up of patients with brain metastases. The authors also introduce more sophisticated methods of tumor analysis to detect circulating biomarkers in body fluids such as blood and cerebrospinal fluid, and their use in monitoring treatment response and tumor progression. The benefits and impacts on prognosis of different commonly used therapeutic approaches are discussed, including more recent clinical trials featuring immunotherapies such as checkpoint inhibitors.The study of tumor cell metastasis to the brain or leptomeninges has developed into an intensely researched area, as it has the potential to provide selective targets for developing therapeutic strategies for brain metastases. In this Research Topic, we have organized a collection of review and original research articles that will hopefully help the readers gain insight into different aspects of cancer metastases to the CNS. In an overview of brain metastasis, Han and Brastianos describe novel approaches in genomic testing such as the use of cell-free circulating tumor DNA in the cerebrospinal fluid in the study of brain metastases. The authors focus on recent advances in genomic profiling of brain metastases and current knowledge of targeted therapies in the management of brain metastases from cancers of the breast, lung, colorectum, kidneys, and ovaries as well as melanoma. Identification of genomic alterations found in brain metastases and targeted therapies against these mutations represent an important research area that could potentially bring improved outcomes for patients with brain metastases.In the era of precision medicine, choice of cancer treatment has been increasingly prescribed based on the molecular or genomic properties of the individual cancer. in vitro assays. Despite their extensive use, these assays have limitations in the study of complex host/tumor cell interactions throughout metastasis. In this respect, animal models represent a versatile tool to examine anatomical barriers (such as the blood brain barrier), stromal/environmental factors, genetic factors, and the immune response. Singh et al. discuss the development of patient-derived xenograft (PDX) models for brain and leptomeningeal metastasis through injection of patient tumor cells into an appropriate microenvironment. These PDX models have been shown to maintain their molecular signatures and recapitulate the heterogeneous nature of the original patient tumor, providing some advantages over genetically engineered mouse models. These models have contributed significantly to our understanding of CNS metastasis, and will play a pivotal role in the identification and testing of potential therapeutic agents.Brain metastasis and leptomeningeal spread are process that can be partially recapitulated through Contreras-Z\u00e1rate et al. developed and characterized a PDX model of breast cancer brain metastasis. The investigators obtained freshly resected brain metastases from breast cancer and implanted tumor cells in the mammary fat pad of female immune-deficient recipients. The xenografts retained critical clinical markers and gene expression profiles of parental tumors. Importantly, intra-cardiac injection of dissociated cells from xenografts led to tumors in the brain parenchyma within 8\u201312 weeks, suggesting that xenografts derived from brain metastases maintain the capacity to colonize the brain. These novel xenografts represent heterogeneous and clinically relevant models to study the biology of brain metastasis and to test drugs in therapeutically relevant settings.Despite improvements in systemic therapies, brain metastasis of breast cancer is associated with dismal survival with limited and non-specific treatment options. Study of breast cancer brain metastases and preclinical tests have relied mostly on injection of a few breast cancer cell lines; however, this approach suffers from a lack of tumor heterogeneity observed clinically and limited use for therapeutic studies due to their rapid progression following transplantation. Wasilewski et al. discuss our current understanding of the contribution of reactive astrocytes to brain metastasis. Emphasis is placed on the signaling pathways and interactions that play a crucial part in the communication with metastatic cancer cells (Andreou et al. examined microglial/macrophage activation in a mouse model of breast cancer brain metastasis. Microglia can differentiate along the proinflammatory pathway to upregulate cytokine levels and acquire the ability to mediate an immune response against tumor cells. Alternatively, microglia can develop an anti-inflammatory phenotype that promotes angiogenesis and tumor growth. The authors identified populations of both proinflammatory and anti-inflammatory microglia/macrophages. The investigators further demonstrated that selective depletion of this microglia/macrophage population significantly reduced metastatic tumor burden and increased apoptosis. These findings suggest that microglia/macrophages are important effectors of the inflammatory response in brain metastases. Hence targeting the anti-inflammatory pathway in microglia/macrophages may offer therapeutic opportunities for patients with brain metastases.Indeed, PDX models recapitulate many characteristics of breast cancer brain metastases including active angiogenesis and astroglial activation. Conversely, unlike other sites for tumor dissemination such as liver or bone, astrocytes represent a major cell type that come into contact with cancer cells during brain metastasis. In response to cancer cells that metastasize to the brain, astrocytes undergo further differentiation and activation to affect the survival and growth of disseminated cancer cells within the CNS. er cells . In addiTreatment options for intracerebral seeding of cancer cells are limited and lacking specificity. The molecular and cellular makeup of brain metastases usually differs from that of the primary tumors, as well as from metastases at other sites. Molecular detailing of metastatic cancer cell penetration, seeding, and outgrowth in the brain will contribute to the discovery of innovative cancer therapies.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Numerous studies have examined the strategy of tight glucose control (TGC) with intensive insulin therapy (IIT) to improve clinical outcomes in critically ill adults and children. Although early studies of TGC with IIT demonstrated improved outcomes at the cost of elevated hypoglycemia rates, subsequent studies in both adults and children have not demonstrated any benefit from such a strategy. Differences in patient populations, variable glycemic targets, and glucose control protocols, inconsistency in attaining these targets, heterogeneous intermittent sampling, and measurement techniques, and variable expertise in protocol implementation are possible reasons for the contrasting results from these studies. Notably, differences in modes of nutrition support may have also contributed to these disparate results. In particular, combined use of early parenteral nutrition (PN) and a strategy of TGC with IIT may be associated with improved outcomes, while combined use of enteral nutrition (EN) and a strategy of TGC with IIT may be associated with equivocal or worse outcomes. This article critically examines published clinical trials that have employed a strategy of TGC with IIT in critically ill children to highlight the role of EN vs. PN in influencing clinical outcomes including efficacy of TGC, and adverse effects such as occurrence of hypoglycemia and hospital acquired infections. The perspective afforded by this article should help practitioners consider the potential importance of mode of nutrition support in impacting key clinical outcomes if they should choose to employ a strategy of TGC with IIT in critically ill children with hyperglycemia. Clinical trials of tight glucose control (TGC) with intensive insulin therapy (IIT) to improve outcomes in critically ill adults and children have promised much, but delivered little. While the first studies in critically ill adults in surgical intensive care units (ICUs) demonstrated improvements in mortality and morbidity from TGC with IIT , 2, lateStress hyperglycemia commonly occurs in critically ill children, even in those with previously normal glucose homeostasis \u201325. OverThe mode of nutrition support in the ICU can also exacerbate stress hyperglycemia . CriticaIn turn, stress hyperglycemia can affect the delivery of nutrition during critical illness in a variety of ways. Stress hyperglycemia may influence the ability to provide consistent or adequate EN during critical illness due to delayed gastric emptying and slowing down of gut motility . Stress Stress hyperglycemia during critical illness thus results in the rapid availability of glucose as a fuel for metabolic processes occurring in vital organs in the body. During the acute phase of critical illness coinciding with high metabolic demands, stress hyperglycemia may be adaptive to favor survival. However, during the chronic phases of critical illness, persistence of stress hyperglycemia may reflect impaired allostasis with potential for harm from increased oxidative damage due to propagation of the proinflammatory response, and impaired cellular repair and tissue healing . Though Early studies of TGC with IIT in critically ill children focused on children with severe burns and very low birth weight neonates \u201356. SubsPublished meta-analyses of studies of TGC with IIT in critically ill children have not observed any benefits from this strategy \u201359. In 2In the single-center surgical and medical adult ICU studies of TGC with IIT from Leuven, early use of PN for nutrition support was heavily favored during ICU admission , 3. Per In the pediatric Leuven study (similar to the adult Leuven studies), PN was started at ICU admission (in the form of 20% intravenous dextrose solutions) while attempts were made to start EN as soon as feasible based on the underlying condition . On averThe mode of nutrition support (EN or PN) is a key variable that has important implications for the efficacy and safety of TGC with IIT in both adults and children. In the single center Leuven adult studies, the aggressive early initiation of PN to rapidly reach goal energy needs by 48\u201372 h following admission may have aggravated the problem of stress hyperglycemia and risk of worse outcomes in a population of critically ill adults with high prevalence of pre-existing diabetes mellitus. Consequently, the strategy of TGC with IIT may have proven beneficial in this setting . In contA published meta-analysis by Marik et al. in 2010 took into account mode of nutrition support (EN vs. PN) using meta-regression techniques to control for proportion of intravenously delivered calories from PN . This meIn published studies of TGC with IIT in critically ill children till date, less granular information is available regarding timing, intensity, duration and mode of nutrition support. This limits our ability to provide detailed analyses of interaction of mode of nutrition support and TGC with IIT on clinical outcomes similar to adult studies. Similar to the adult studies, the pediatric studies also vary in nutrition support practice which makes direct comparisons challenging. The pediatric Leuven study demonstrated benefits of TGC with IIT coupled with a nutrition support strategy that relied mainly on early PN . In contThe important question for practitioners is whether any one mode of nutrition support\u2014EN or PN\u2014is superior to another to improve outcomes in critically ill adults and children. In critically ill adults, early EN initiation compared to early PN initiation did not reduce mortality or reduce secondary infections, but was associated with more digestive complications and hypoglycemia , 64. BasIn summary, studies of TGC with IIT have demonstrated varying results due to numerous methodological and target population differences, but an important factor that may often go underappreciated is the mode of nutrition support in the form of either EN or PN, or a combination of the two. Specifically, when PN is the favored mode of nutrition support, TGC with IIT may be associated with improved outcomes compared to usual care, as usual care in this setting of early PN may be associated with more harm from uncontrolled hyperglycemia. In contrast, when EN (or predominantly EN) is the favored mode of nutrition support, TGC with IIT may be associated with equivocal or worse outcomes compared to usual care, as usual care in this setting of early EN may be more beneficial with maintenance of gut function and processes involved in autophagy. While pediatric data surrounding the interaction of mode of nutrition support and TGC with IIT is limited, the practitioner should consider the potential importance of mode of nutrition support in impacting key clinical outcomes, if they should choose to employ a strategy of TGC with IIT to manage critically ill children. Future studies of TGC with IIT should use targeted indirect calorimetry for more accurate estimation of energy needs, and ensure targeted protein delivery to meet minimum threshold goals. Such studies should also incorporate better decision making support for nutrition delivery and glucose control in the form of protocol-driven algorithms and continuous glucose monitoring technologies to ensure consistency in key variables that affect outcomes in this critically ill population.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Few investigations have explored the potential impact of the Affordable Care Act on health disparity outcomes in states that chose to forgo Medicaid expansion. Filling this evidence gap is pressing as Congress grapples with controversial healthcare legislation that could phase out Medicaid expansion. Colorectal cancer (CRC) is a commonly diagnosed, preventable cancer in the US that disproportionately burdens African American men and has substantial potential to be impacted by improved healthcare insurance coverage. Our objective was to estimate the impact of the Affordable Care Act on colorectal cancer outcomes and economic costs among African American and White males in North Carolina (NC), a state that did not expand Medicaid. We used an individual-based simulation model to estimate the impact of ACA on three CRC outcomes and economic costs among African American and White males in NC who were age-eligible for screening (between ages 50 and 75) during the study period, years of 2013\u20132023. Health exchanges and Medicaid expansion improved simulated CRC outcomes overall, though the impact was more substantial among AAs. Relative to health exchanges alone, Medicaid expansion would prevent between 7.1 to 25.5 CRC cases and 4.1 to 16.4 per 100,000 CRC cases among AA and White males, respectively. Our findings suggest policies that expanding affordable, quality healthcare coverage could have a demonstrable, cost-saving impact while reducing cancer disparities. Our nation is embattled over the future of its healthcare system. Public concern has been mounting about the potential impacts of an ACA repeal on populations at risk for health and healthcare disparities. In addition to expanding private healthcare coverage, ACA legislation afforded states a historic opportunity to expand Medicaid to childless adults with incomes at or below 138 percent of the federal poverty level (FPL) . ExpandeFindings from a notable quasi-experimental study suggested that the most significant gains in health insurance coverage are attributable to full ACA implementation with Medicaid expansion as opposed to ACA implementation alone . AlthougAnalysis of policy alternatives can be challenging with conventional statistical and econometric methods because they require observed data, yet our current datasets fail to provide the full scope of measures required, do not allow us to estimate unobserved scenarios , and are unable to capture downstream impacts on cancer incidence and mortality. In contrast, significant insights about the potential impacts of ACA and Medicaid expansion on health disparities can be gleaned from individual-based simulation. Individual-based simulation models estimate population-level outcomes over time using information about a population\u2019s demographic structure and behaviors, which are shaped by context. The models provide flexibility for integration of diverse sources of data and estimate plausible projections of future health outcomes. Many studies have demonstrated the utility of individual-based simulation models for exploring population-level impacts of policy interventions . IndividWe use CRC as a test case because it is one of the most commonly diagnosed, preventable cancers in the US , represeExpansion states are experiencing an uptick in CRC screening (+4.3 percentage points) among adults ages 50\u201364 . Thus, nWe used an individual-based simulation model to estimate CRC screening, stage-specific incidence, and deaths among African American and White males in NC. A more comprehensive overview of the simulation model is published elsewhere . BrieflyUsing a combination of health insurance claims and Behavioral Risk Factor Surveillance System (BRFSS) data, we differentiate factors affecting probability of individual receipt of alternative CRC screening modalities and the predicted probability of compliance into the simulation model based on individual sociodemographic factors of race, gender, and insurance type as well as county-level factors affecting practice patterns and distance to endoscopy centers , 26. ForWe used the RTI Synthetic Household Population, which provides an accurate sociodemographic representation of households and persons throughout the US . For ourWe compared the claims-based simulation model\u2019s predicted probability of being up-to-date with CRC screening to the percent of NC residents aged 50\u201375 years who reported being up-to-date with CRC screening in biannual data from the BRFSS survey from 2002 to 2012 . The BRFWe modeled a control scenario to provide a baseline in the absence of ACA policy changes . The BRFSS data indicated that from 2002 to 2014, the percent up-to-date initially increased and then leveled off around 2012. Thus, for the control scenario , we assumed CRC screening compliance probabilities remained stable after 2012.We simulated five ACA policy scenarios. We simulated one scenario to evaluate the potential impact of increased insurance coverage through the implementation of the ACA\u2019s health exchange insurance marketplaces only, beginning in 2014. We simulated four policy scenarios to evaluate the potential impact of Medicaid expansion if NC had expanded in 2014.To model the impact of the health insurance marketplaces, we used NC BRFSS data to determine the probability of an individual becoming newly insured in 2014 based on sex, age, income, race, and marital status, accounting for secular trends. To implement insurance change in the simulation model, we assigned a probability of obtaining healthcare coverage in 2014 to individuals who were uninsured prior to 2014 that matched the probabilities observed in BRFSS data. We assumed that increases of health insurance coverage in 2014 were due to both the newly available health insurance marketplace enrollments and an increase in public awareness about Medicaid coverage . Thus, iIn the Medicaid expansion scenarios, we utilized the same probabilities from the ACA scenario to determine whether an uninsured individual became newly insured in 2014. In addition, we identified uninsured individuals who fit eligibility guidelines for Medicaid under the expansion income and household size limits. We evaluated four hypothetical scenarios based on assumptions of enrollment among eligible individuals (low or high) and CRC screening compliance rates among newly insured individuals (low or high). We assessed enrollment rates in other states that expanded Medicaid and set the low and high rates to be comparable to the range observed . We set low and high compliance rates to be the same as rates for individuals covered through Medicaid or private insurance, respectively . Thus, low and high compliance rates represent the most conservative and most generous estimates, respectively.We sought to estimate increased clinical care costs of screening and potential decreases in downstream costs of cancer treatment\u2013a payer perspective, though we aggregate payers to focus on the overall balance of clinical costs. Costs for fecal testing ($6) and colonoscopy ($631) were based on Medicare reimbursement rates . CRC treGiven the large number of individuals simulated, we ran 5 replications of the model for each of the control and policy scenarios and compared the control scenario to each of the policy scenarios. We used the model to estimate the percent of African American and White males up-to-date with CRC screening, lifetime CRC cases prevented by stage, and lifetime CRC deaths prevented. We assessed the percent up-to-date with CRC screening in NC overall and by the Area Health Education Center\u2019s (AHEC) regions. The regions were chosen because the AHEC agencies in each provide educational programs and services to improve health with a focus on underserved populations. We assessed the costs of CRC screening and the initial phase of treatment of the cohort of African American and White males. Costs were discounted using the conventional annual 3 percent rate .The control and all ACA policy scenarios resulted in an increase over time in the percent up-to-date with CRC screening among both White and African American males . By 2018The ACA health exchange and Medicaid expansion policy scenarios had larger relative impacts on CRC screening rates for African American males than for White males and resulted in decreased disparities. In the control scenario, the disparity gap in CRC screening rates between African American and White males increased in all but one of nine major regions of NC . In contThe ACA health exchange and Medicaid expansion scenarios prevented more CRC cases and deaths among both the African American and White male cohorts compared to the control scenario, but the impact was diminished in Medicaid expansion scenarios with low compliance. In all scenarios, the impacts of ACA health exchanges and Medicaid expansion were more substantial among African Americans than Whites . CompareThe ACA health exchange and Medicaid expansion policy scenarios all incurred higher initial costs compared to the control scenario, but all policy scenarios were cost-saving in the long-term for both African American and White males . Based oThe ACA policy scenarios resulted in higher per person costs for African American than White males in the short term, but the cumulative cost savings per person were also substantially higher for African Americans over the long-term . For exaOur findings show that increased insurance coverage due to ACA health exchanges is likely to improve CRC screening and reduce CRC incidence and death over time with substantial cost-savings, highlighting the significant need for policies that stabilize health insurance markets. Medicaid expansion may also hold untapped potential to further reduce persistent CRC disparities in non-expansion states. Using NC as a case example, our simulation model predicted increases in the percent-up-to-date with CRC screening due to Medicaid expansion among African Americans who are disproportionately at risk for CRC morbidity and mortality. Population-level impact of expanding Medicaid eligibility in NC could result in hundreds of CRC deaths averted among non-Hispanic White and African American men. Such state-level achievements in CRC screening uptake would help to advance our nation\u2019s progress towards the National CRC Roundtable\u2019s goals of increasing CRC screening to 80% and preventing new CRC cases and deaths in every community . Our resMany holdout states attribute their decision to forgo Medicaid expansion because of concerns over long-term costs and sustained federal commitment to Medicaid cost-sharing . Yet, weWe concede that eliminating CRC disparities will require broader attention to the social determinants of health and personal health behaviors that help catalyze them. While we recognize that reductions in CRC incidence and mortality will not be fully achieved by expanding health insurance access, our findings suggest Medicaid expansion represents a \u201clow hanging fruit\u201d policy opportunity to reduce disparities. We are especially encouraged that even in the most conservative policy scenarios, CRC screening rates improved among all men and disparities were reduced. Even more encouraging was the finding suggesting that policy interventions like Medicaid expansion might also save American lives\u2013an unquantifiable population health gain.There are important limitations to consider when interpreting results from this study. Although the model differentiated rates of adenoma incidence by race and age, it assumes that the anatomic distribution and progression of CRC is the same between African Americans and Whites. There are studies that indicate there may be differences in genetic susceptibility, anatomic locations, and aggressiveness of tumors between African Americans and Whites \u201341. Yet,Given our intent to assess the balance of clinical care costs overall, the model did not attribute costs by payer and makes simplifying cost assumptions. The study does not provide information on the distribution of costs between private and public funders. We did not include costs of administering ACA or Medicaid expansion, as the effects of each extend far beyond the focus of this analysis (CRC outcomes). However, including some component of administration costs would diminish the potential cost savings. To be conservative and focus on more proximal costs, we only included the initial phase (12 months) of treatment costs following a CRC diagnosis (and did not include the costs of continuing surveillance and end-of-life care). Including the initial phase only renders cost savings estimates lower than they are actually likely to be. Finally, evidence is only now emerging about enrollment in new healthcare coverage options due to ACA and adherence to CRC screening, and we had to make assumptions about the future uptake of insurance and adherence to screening in NC over time. We attempted to provide scenarios of Medicaid expansion that provide a plausible range of potential outcomes.The ACA and its provisions for Medicaid expansion resulted in increased insurance coverage for lower income men\u2013a group traditionally ineligible for Medicaid. Medicaid expansion in holdout states like NC has the potential to reduce racial CRC disparities among men, which will likely worsen in the absence of policy interventions. Our investigation advances our understanding of the prospective, long-term benefits of ACA and Medicaid expansion in reducing preventable CRC morbidity and mortality. Our results suggest that leveraging opportunities created by Medicaid expansion to increase access to early CRC detection and screening in one state may save hundreds of lives. The national impact of ACA\u2019s health exchanges and Medicaid expansion on CRC mortality is likely much larger. Future studies should replicate similar simulation research in other states and estimate the potential impact of various proposed healthcare reform policies on additional health outcomes. The need for such evidence is critical to state and national policymakers as they contemplate newly proposed legislation that will drastically change health insurance markets and Medicaid coverage and alter our nation\u2019s capacity to reduce health disparities in populations vital to our capacity to compete in the global marketplace."} +{"text": "Necrotizing Enterocolitis (NEC) is one of the most devastating gastrointestinal diseases in neonates, particularly among preterm infants in whom surgical NEC is the leading cause of morbidity. NEC pathophysiology occurs in the hyper-reactive milieu of the premature gut after bacterial colonization. The resultant activation of the TLR4 pathway appears to be a strongly contributing factor. Advancements in metagenomics may yield new clarity to the relationship between the neonatal intestinal microbiome and the development of NEC. After a century without effective directed treatments, microbiome manipulation offers a promising therapeutic target for the prevention and treatment of this devastating disease. Worldwide, sepsis is the third leading cause of neonatal mortality , the most well studied of which are Toll-Like Receptors (TLR). The TLRs recognize microbial associated molecular patterns (MAMPs) Rhee . PatternAfter birth, the neonatal gut receives its first large scale challenge of MAMPs activating TLR plays a critical role in the development of NEC \u2013 its activation leads to mucosal injury and reduced epithelial repair. Furthermore, TLR4 is upregulated in the premature gut as compared to the gut of the full term neonate and heterogeneous populations studied- including a wide range of post gestational ages at which NEC develops Hosny .Gammaproteobacteria with a decrease in other bacterial species . Interestingly, while milk samples from mothers who underwent elective cesarean sections varied in bacterial composition from milk samples from mothers who experienced vaginal delivery, the microbiome in the breast milk of mothers who underwent nonelective cesarean sections was similar to the microbiome of milk among mothers with vaginal deliveries. This suggests that maternal stress and hormones influence breast milk microbiome more directly than mode of delivery (Cabrera-Rubio et al. In addition to helping shape the intestinal microbiome by nutrient selection, breast milk has its own microbiome which evolves over time. Initially colostrum contains Enterobacteriaceae, Bacteroides, and Clostridium in their stools compared to infants who receive breast milk. The effect on breast versus formula feeding on the levels of the Bifidobacterium species are less clear with some studies finding significantly reduced amounts in formula fed infants and other studies showing no difference at all (Penders et al. After birth, breast fed infants are first colonized with aerobic or facultative anaerobic bacteria followed by a bloom of anaerobic bacteria. Formula fed infants\u2019 gastrointestinal microbiomes differ by having fewer anaerobes and a plethora of gram negative bacteria (Le Huerou-Luron et al. Antibiotic exposure has a large impact on the neonatal microbiome delaying the colonization of beneficial bacteria and reducing the diversity of the intestinal microbiome, both factors which are thought to predispose the neonate to NEC (Torrazza and Neu Proteobacteria and limits the diversity of the fecal microbiome. These alterations may predispose an infant to NEC (Gupta et al. Acid suppression therapy has a known impact on the preterm microbiome. Gupta et al. demonstrated that the use of H2 blockers in premature infants shifts the microflora pattern towards Bifidobacterium breve (Costeloe et al. Given the link between dysbiosis and NEC, altering the microbiome is a promising target for future therapies (Vongbhavit and Underwood Research over the last decade has demonstrated the importance of the gut microbiome on human health and disease. Microbiome alterations have been associated with a vast array of diseases ranging from cardiovascular disease to colorectal cancer, obesity, diabetes, and rheumatoid arthritis (Shreiner et al. There are three major options for an approach to microbiome-based therapies: additive, subtractive, or modulatory therapies. Additive therapy includes the manipulation of the microbiome by supplementing the microbiome of the host with either specific strains of organisms or groups of natural or engineered microorganisms. Subtractive therapy involves the removal of specific deleterious members of the microbiome to cure disease. Modulatory therapies involve administration of nonliving agents, called prebiotics, to modify the composition or activity of the host microbiome (Mimee et al. Probiotics are discussed in detail above. However, before probiotics can routinely be used in the prevention of NEC, dose, strain, and timing of administration need to be standardized. Probiotics might require regulatory approval for use in the neonate before they can become standard of care. In addition to commercially available probiotics the development of genetically engineered probiotics are underway, although this process is still in its infancy. Bacterial cells could be altered to allow recombinant expression of therapeutic biomolecules. This would overcome issues with bioavailability and drug inactivation with oral administration. Protein synthesis of the therapeutics could be tied to conditions associated with the disease (Mimee et al. Quantitative metagenomics can be used to directly map the human gut microbiome. In the future this could be used for risk detection Ehrlich . CurrentIn summary, NEC is among the most common and lethal gastrointestinal diseases that plague premature infants and results in high short and long term morbidity and mortality. The pathogenesis of this complex disease has been studied for decades but only recently have advancements underscored the importance of the intestinal microbiome. The intestinal microbiome can have both a protective or a pathogenic role in preventing or contributing to the development of NEC. Achieving a healthy complement of commensal bacteria can help protect the preterm infant from gut inflammation and injury leading to necrotizing enterocolitis. Although much work lies ahead in order to translate the lessons learned in the laboratory to clinical practice, the manipulation of the intestinal microbiome is a promising strategy for the prevention of necrotizing enterocolitis."} +{"text": "Mutualistic plant\u2013microbial functioning relies on co-adapted symbiotic partners as well as conducive environmental conditions. Choosing particular plant genotypes for domestication and subsequent cultivar selection can narrow the gene pools of crop plants to a degree that they are no longer able to benefit from microbial mutualists. Elevated mineral nutrient levels in cultivated soils also reduce the dependence of crops on nutritional support by mutualists such as mycorrhizal fungi and rhizobia. Thus, current ways of crop production are predestined to compromise the propagation and function of microbial symbionts, limiting their long-term benefits for plant yield stability. The influence of mutualists on non-native plant establishment and spread, i.e. biological invasions, provides an unexplored analogue to contemporary crop production that accounts for mutualistic services from symbionts like rhizobia and mycorrhizae. The historical exposure of organisms to biotic interactions over evolutionary timescales, or so-called eco-evolutionary experience (EEE), has been used to explain the success of such invasions. In this paper, we stress that consideration of the EEE concept can shed light on how to overcome the loss of microbial mutualist functions following crop domestication and breeding. We propose specific experimental approaches to utilize the wild ancestors of crops to determine whether crop domestication compromised the benefits derived from root microbial symbioses or not. This can predict the potential for success of mutualistic symbiosis manipulation in modern crops and the maintenance of effective microbial mutualisms over the long term. Plants establish beneficial symbiotic interactions with microbes that sustain plant nutrition and growth. These interactions are crucial for the stability of crop yields, particularly those of legumes. Likewise, in natural ecosystems symbioses facilitate the establishment and spread of invasive plant populations, to which microbes confer similar benefits as in crops. This manuscript builds on the parallelism between microbial symbioses in crops and invasive plants to develop a new framework. This framework can inform whether modern crops preserve the ability to obtain symbiotic benefits from microbes, and whether breeding programs could target symbioses for future plant production. Rapid climate change and the need to utilize resources more efficiently call for crops that are able to cope with perturbation and stress while supporting stable yields. Root microbial mutualists such as arbuscular mycorrhizal fungi legumes rely heavily on eco-physiological flexibility conferred by symbioses with microbes , (ii) legume productivity is highly dependent on cultivation practices, weather events, and edaphic and climatic conditions and (iii) compared to other crops, legumes have received less attention by breeders and therefore may have significant potential for improving yield and resilience to environmental unpredictability.Eco-evolutionary experience describes the historical exposure of an organism to biotic interactions over evolutionary timescales . In the Cropping under edaphic and climatic conditions different from those during domestication and breeding is analogous to plant\u2013mutualist co-invasions in novel environments, where symbiotic benefits mediate the success of plant establishment and spread . AlthougAcacia; The idea that the EEE of plant\u2013mutualist interactions can influence plant success in novel environments has been used to explain the invasiveness of Australian acacias and high soil nutrient levels under cultivation and breeding are known to have compromised the nutritional and growth-promoting benefits of mycorrhizal and rhizobial symbioses Inocula of microbial mutualists are prepared from modern cultivars and crop wild ancestor(s) in an initial trapping or soil conditioning phase as in plant\u2013soil feedback experiments by growing the respective plants in their soil of origin . Enriched and specific inocula can be obtained in the form of surface-sterilized roots and root nodules (in case of rhizobia).Treatments under common garden conditions, we specify which ecological and evolutionary aspects of plant\u2013microbe functioning are being tested under each treatment. In Measurements, we outline which features of plant growth responses, symbiotic functioning and evolutionary processes could be addressed with this experimental approach.(B) These inocula are then applied to modern crop cultivars grown in common garden-type experiments under sterilized and non-sterilized soil conditions. This design allows for inferences to be made on plant-symbiont compatibility and the effectiveness of ancestral symbionts in absence and presence of other soil biota. In (A) Generation of mutualist inoculum by soil conditioning/symbiont trapping.(B) Inoculation with microbial symbionts from the conditions under cultivation and the distribution range of the wild ancestor(s).Treatments under common garden conditions :As in trap culturing and the conditioning phase of plant\u2013soil feedback experiments, inocula can be obtained by growing wild crop ancestors in their native soils and by isolating their root-associated microbial mutualists. These can be used to inoculate modern cultivars growing in sterile cultivated soils, as a way to test their ability to recruit and benefit from these putative ancestral symbionts . Based ode novo domestication or genetic engineering are viable options . With symbiont partner specialization comes predictable symbiotic associations and C. CThe most likely encountered scenarios are those in which symbiont selectivity and responsiveness to symbiosis have been decoupled. Crops may have switched to new mutualistic partners, being unable to take advantage of the benefits offered by their ancestral mutualists. Such changes in crop EEE can thus render active microbiome management unnecessary . Bread wDespite a growing body of research on eco-evolutionary dynamics and their implications for plant\u2013mutualist interactions in novel environments, relatively little attention has been paid to their role in crop development (Current efforts to manipulate entire microbiomes ("} +{"text": "Vascular smooth muscle cells (VSMCs) are the predominant cell type in the blood vessel wall and normally adopt a quiescent, contractile phenotype. VSMC migration is tightly controlled, however, disease associated changes in the soluble and insoluble environment promote VSMC migration. Classically, studies investigating VSMC migration have described the influence of soluble factors. Emerging data has highlighted the importance of insoluble factors, including extracellular matrix stiffness and porosity. In this review, we will recap on the important signalling pathways that regulate VSMC migration and reflect on the potential importance of emerging regulators of VSMC function. Cell migration begins at the earliest stages of life and it continuous as a fundamental process for survival at the plasma membrane. Upon stimulation, cofilin is dephosphorylated to sever actin filaments and promote actin polymerisation complex and nuclear lamina have surprisingly emerged as regulators of cell migration. The NE is comprised of a double lipid bilayer that forms a physical barrier between the cytoplasm and nuclear interior how biophysical signalling and intercellular coupling between the cytoskeleton and nucleus contributes to VSMC migration; and (2) the role of insoluble factors, including matrix stiffness and porosity. Biophysical signalling and insoluble cues are known to change during ageing and vascular disease. Therefore, unravelling the mechanistic role of these changes will potentially identify novel therapeutic pathways to manipulate VSMC migration in ageing and vascular disease."} +{"text": "The aim of this study is to explore the barriers and enablers of deprescribing from the perspectives of home care nurses, as well as to conduct a scalability assessment of an educational plan to address the learning needs of home care nurses about deprescribing. This study employed an exploratory qualitative descriptive research design, using scalability assessment from two focus groups with a total of eleven home care nurses in Ontario, Canada. Thematic analysis was used to derive themes about home care nurse\u2019s perspectives about barriers and enablers of deprescribing, as well as learning needs in relation to deprescribing approaches. Home care nurse\u2019s identified challenges for managing polypharmacy in older adults in home care settings, including a lack of open communication and inconsistent medication reconciliation practices. Additionally, inadequate partnership and ineffective collaboration between inter-professional healthcare providers were identified as major barriers to safe deprescribing. Further, home care nurses highlighted the importance of raising awareness about deprescribing in the community, and they emphasized the need for a consistent and standardized approach in educating healthcare providers, informal caregivers, and older adults about the best practices of safe deprescribing. Nurses in home care play a vital role in medication management and, therefore, educational programs must be developed to support their awareness and understanding of deprescribing. Study findings highlighted the need for the future improvement of existing programs about safer medication management through the development of a supportive and collaborative relationship among the home care team, frail older adults and their informal caregivers."} +{"text": "Evidence-based interventions for persons with dementia and their caregivers are important to improve both their quality of life and quality of care. Conducting rigorous clinical trials is essential to build evidence, guide research, and inform clinical practice. Clinical trials involve multifaceted phases which present opportunities and challenges to the research team. In this presentation, we discuss obtaining consent, gathering information to inform refinement of an intervention, adaptation of an intervention, and fidelity checks to ensure the rigor of intervention delivery. The first session will discuss initial challenges faced when consenting nursing home residents with dementia and tailored approaches to enhance clinical trial enrollment. The second session will share highlights of usability testing of a novel mobile app to refine and improve its ease in a future clinical trial of use for persons with dementia and their caregivers. The third session will describe findings from focus groups that generated recommendations for culturally adapting an intervention to promote quality of life among older Latinos with dementia. The final session will discuss the advantages, disadvantages and ethical considerations of in-person fidelity monitoring during a home-based intervention clinical trial involving persons with dementia and their caregivers. Together, these presentations describe the complex nature of implementing clinical trials and highlight the important lessons learned to strengthen study implementation."} +{"text": "The retirement landscape is transformed by the shifting of risk and responsibility to individuals, who are increasingly responsible for their retirement security. Many factors lead to indebted and overleveraged American households. Specifically, nearly 40% of Americans approaching retirement are heavily indebted. Understanding the role of secured and unsecured debt in retirement planning becomes an urgent concern because debt is highly related to well-being in retirement among a growing number of older Americans. We focus on pre-retirees because these individuals have time to earn an income and plan ahead before they commit to a fully retired lifestyle. Utilizing data from the 2015 National Financial Capability Study, we identified the secured and unsecured debt that influences retirement planning among a national sample of pre-retirees, aged 51 to 61 years. Regression and mediation analyses were used to examine the relationship between debt and retirement planning and to identify the mediating effect of having a retirement account on the relationship between unsecured and secured debt and retirement planning. Our results indicated that mortgage debt and credit card debt were negatively associated with retirement planning. Having a retirement account is positively associated with retirement planning and it also mediates the relationship between credit card debt, specifically, and retirement planning. In conclusion, we urge individuals and financial planning executives to take time during the pre-retirement years to assess various forms of debt and determine how it is affecting their retirement planning objectives. And policy-makers should address the challenges faced by indebted pre-retirees."} +{"text": "Nurses draw from their experiences and intuition to detect changes in patient condition, patterns of patient behaviors, and evidence of distress. In the nursing home setting, nurses care for residents with dementia and manage challenging behavioral and psychological symptoms of dementia (BPSD), and may rely on informed intuition to assess and capably respond to such behaviors. To date, no observational method has been developed to discern nurse-resident interactions that identify expert nurses who effectively address BPSD. It is not known if or how nurses in this setting use intuition to make clinical judgments and decisions to manage BPSD events. Using an ethogram approach, we developed an observational tool and spot interview method to discern BPSD events, background and proximal factors and nurse responses to BPSD. Pilot observations took place over three nursing shifts to identify nurse-resident interactions during BPSD events using the observation tool. Nurse-resident interactions were followed by spot interviews with each nurse to clarify their responses to BPSD. Semi-structured interviews were conducted with nurse participants to further develop an interview guide and identify elements of nurse intuition. The pilot study affirmed the feasibility of gaining access to facilities with residents with BPSD, of nurse comfort with field observation and interviews, and established preliminary construct validity of the \u201cexpert nurse.\u201d Verification of the utility of this observation and interview method permit further examination of effective nurse engagement with nursing home residents with BPSD, informs our understanding of nurse intuition and permits further exploration of the broader context of BPSD."} +{"text": "This review covers previous and current literature on the impact of forensic anthropologists on the positive scientific identification of human remains and aims to provide an understanding of what information a forensic anthropologist can contribute to an investigation. Forensic anthropologists looking to identify human remains study traits of the skeleton and any orthopedic devices present. In order to obtain a positive scientific identification, evidence that is both sufficiently unique to the individual and comparable to available antemortem data from that individual must be found. The increased availability of radiographs, scans and implants in recent decades has facilitated the identification process. When these records are unavailable, other techniques, such as craniofacial superimposition and facial approximation, can be employed. While these methods may assist the identification process, they are most useful for exclusion of certain individuals and gathering leads from the public. Forensic anthropologists have heavily relied on the skull and its complexities for identification \u2013 typically focusing on the frontal sinus and other unique traits. Post-cranial remains can provide important information about bone density, possible disease and other characteristics that may also be utilized. Techniques used to positively identify individuals are not limited to medicolegal death investigations, and have been useful in other legal contexts. In the future, a team approach, utilizing all the information gathered by multiple forensic scientists \u2013 including forensic anthropologists \u2013 will most likely become more common. Positive scientific identification of human remains recovered in a medicolegal context represents a central goal of forensic anthropology analysis. Many facets of anthropological activity, including search and recovery, determining species, estimation of sex, age at death, stature, time since death, and ancestry and detection of unique anatomical features produce information used to narrow the search of missing persons. Ultimately, forensic anthropologists contribute to positive scientific identification either directly, or through the wealth of supplemental information provided. Direct contributions involve assessment of a variety of anatomical features and comparison with antemortem information, usually revealed through radiography and related imagery.Types of identification include tentative, circumstantial, presumptive and positive types . The firPositive identification represents a much higher level of probability and involves a two-step process. First, anatomical features must be discovered that are shared between the examined evidence and the known antemortem information relating to a particular individual. Second, the analyst must determine that the features being compared are sufficiently unique to enable the identification. In addition, any differences must be noted and explained in a satisfactory manner. When errors are made in identification they usually fall into two categories: (1) differences are considered as evidence for exclusion that actually represent other factors, and (2) shared features are presented in support of identification with insufficient consideration of their uniqueness. Great caution is needed in interpretation since misidentification can lead to tragic consequences.Contributions of forensic anthropologists to identification are especially needed and valuable in the analysis of extensively decomposed and/or skeletonized human remains. Experimental research reported by Sauerwein et\u00a0al. indicateProper recovery, documentation and assessment of the biological profile of human remains are essential elements leading to positive identification . DetailsThe unique features needed for positive identification can be provided by surgical procedures, especially those generating devices that remain in the skeletal tissue . For exaMany orthopedic devices recovered with human remains may present information revealing the manufacturer . Some deForensic anthropologists have found these inorganic materials fundamental in their cases. For example, Bennett and Benedix report pWhen lacking surgical modifications, anthropologists must look for organic anomalies or unique traits in skeletal remains. The classic text of Stewart discusseDental features frequently provide information needed for identification . ForensiComparative antemortem information is usually available through radiographs and related imagery. Murphy and Spruill report tCraniofacial superimposition compares features of a recovered skull thought to be of medico-legal interest with antemortem photographs of a missing person who might be represented by the remains. This technique may be employed when positive identification has not been accomplished through molecular analysis, dental reconstruction comparison or anthropological radiographic assessment . UsuallyDorion notes thFacial approximation represents the attempt to produce a facial likeness of an individual from a skull. While the method cannot be used for positive identification directly, the image produced can be used to communicate with the public in an effort to gather information on missing persons who might be represented by the recovered remains. Major advances in methodology include new population data of soft tissue depth, new guidelines of assessing facial features and innovative computerized approaches . AlthougAlthough facial approximations have been reported to be useful in gathering information relative to identification, Stephan and Cicolini reportedTechniques of facial approximation are improving with enhanced information regarding the relationship of facial hard and soft tissues and more sophisticated computer technology. Despite these advancements, facial approximation does not represent a method of positive scientific identification. However, the generated image may prove useful to assist public communication that the remains of someone with particular visual and demographic characteristics have been recovered.While other methods have led to tentative identifications, distinctive features present on the skeleton allow for a more certain classification. The skull frequently has provided the unique information needed for positive scientific identification in anthropological analysis for two primary reasons: (1) historically, considerable research has focused on the skull revealing great variation of many anatomical features, and (2) antemortem radiographs and related imagery frequently are available for the head and may include multiple views. As noted by Smith et\u00a0al. , skull iAlthough many features of the human skull display extensive variation and thus are useful for individual identification, many investigators have focused on the frontal sinus. This sinus located superior to nasion in the area of the supraorbital ridges displays remarkable variation ranging from minimal presence to large labaryinthion formations. Apparently reflecting environmental and developmental influences, even identical twins display morphological differences in frontal sinus expression .As early as 1921, Sch\u03cbller called aAlthough most early comparative studies of frontal sinus morphology utilized in medicolegal applications featured pattern recognition, metric and more sophisticated statistical treatments have been introduced as well. Kirk et\u00a0al. introducNoting the growing demands from the legal arena for increased quantification and probability assessment of features used in identification, Christensen applied Skeletal remains from the post-cranial skeleton also present abundant anatomical features useful for identification if corresponding antemortem radiographs can be located. Post-cranial bones may be less affected by animal scavenging and other postmortem factors . GeneralAlthough contributions of forensic anthropologists to positive scientific identification usually involve recovered skeletal remains, similar techniques can be applied to medicolegal issues involving the living. Fenger et\u00a0al. report hAlthough anthropologists frequently apply their skills to individual skeletal features, ultimately identification represents a team effort . Apart fCritical evaluation of past progress reveals trends likely to produce future advances. Technological advances clearly represent key potential for enhanced capability in positive scientific identification. The images generated by computerized tomography (CT) reveal much more skeletal detail than those previously available from conventional radiography. The rapidly advancing technology available for imagery clearly will contribute to major advances.Recent years have witnessed increased scrutiny of the forensic sciences in the legal arena. Constructive criticism has stimulated research focus on probability assessment, cognitive bias, error analysis and the general scientific foundation of forensic applications. Future analyses of features contributing to positive scientific identification must relate accurately the probabilities involved. Those involved in the identification process must guard against cognitive bias that might impact assessment. Research must attempt to define the uniqueness of features commonly involved in skeletal identifications. Concepts of \u201cmatch\u201d and \u201cconsistency\u201d likely will be replaced with more precise statements of probability and associated error. More sophisticated statistical analyses predictably will become apparent in the research designs targeting methods of identification.The team approach discussed above likely will become more commonplace in the identification procedure. Individual techniques and statistical analysis present individual probabilities of identification. The team approach offers the potential for combined probabilities that should enhance the identification effort.Identification benefits from the training and experience of anthropologists conducting the analysis. Internationally, the best and brightest students are becoming increasingly attracted to the field of forensic anthropology. This surge of academic interest and dedication bodes well for the future of forensic anthropology and for methodology of positive scientific identification."} +{"text": "Dear Editor, Recently, Cadenas and colleagues reported that the endothelial lipase (LIPG) is upregulated during oxidative stress and supports survival of cells that are no longer able to generate a sufficient supply of fatty acids by de novo synthesis . LIPG iIn the present study, Cadenas and colleagues used overexpression and knockdown strategies to demonstrate that LIPG enables breast cancer cell lines to utilize circulating lipoproteins to synthetize and store triglycerides in lipid droplets . MoreovProgression of tumors is a complex process that involves genes controlling proliferation , immune"} +{"text": "These propagules are then used in research, agriculture, and ecological restoration. There are many examples from other microbial systems that long-term in vitro propagation leads to domesticated strains that differ genetically and functionally. Here, we discuss potential consequences of in TRC propagation on AM fungal traits, and how this may affect their functionality. We examine weather domestication of AM fungi has already happened and finally, we explore whether it is possible to overcome TRC-induced domestication.Transformed root cultures (TRC) are used to mass produce arbuscular mycorrhizal (AM) fungal propagules Domestication of plants and animals has been a hallmark of the Anthropocene , resultiSaccharomyces cerevisiae created yeasts without the ability to reproduce sexually or survive outside of laboratory conditions fungi are obligate biotrophs that participate in an ancient symbiosis with plants . ThroughSidebar#1Agrobacterium rhizogenes into the genome of a host plant plasmid of the parasite st plant . The Ri st plant . The roovia TRC represents strong selection pressure on fungi and represents a form of domestication, through changes to nutrient limitations, microbial consortia, and reduced host variation. Such selection pressure may lead to reduced genetic diversity and mutualistic quality.Currently, commercial AM fungal inocula are used both in horticulture and field applications . Many ofR. irregulare DAOM197198) .via nitrogen fertilization) can select for rhizobia or tomato (Solanum lycopersicum)]. While gene activation in the early stages of colonization are preserved among hosts when maintained under long-term lab conditions. In addition, there is evidence of sequence loss in spores of an isolate of a Glomus coronatum when maintained in cultures compared to field originated spores benefit. Copious spore production over nutritional benefit is a trade-off that seems to be preserved even when this isolate is grown in pots with a variety of different hosts ; Heterobasidion); Neurospora)] Diverse nucleotypes in spores may prevent the loss of genetic variation and functional diversity in the case of population reduction or ensure maintenance of genetic information when new populations are established from few propagules (prevent genetic drift through founder effects).Heterokaryosis, first coined by Gigaspora sp., also plays an important ecological role, since newly germinating spores can connect to the pre-established network prior interacting with a host, gaining an important survivorship benefit , nucleotype diversity may be maintained through anastomosis in wild populations of closely related AMF . For AM benefit .via karyogamy and meiosis. Although it is still not yet clear under which conditions the dikaryons proceed to karyogamy and meiosis aka to sexual reproduction showed a 78-fold increase in fungal metabolite production compared to the pure culture of the fungus (Coprinopsis cinerea and Gongronella sp.) produced 900 times increased oxidation activity compared to pure cultures can induce colonization ability and stimulate the spore production of AM fungi every 4 years alleviates this bottleneck fungi can lose their symbiotic ability and eventually fail to colonize plant roots if maintained ong term . Growingttleneck . The re- strains . Similarbilities . Furtherian host showing in vitro propagation alters AM fungal morphology, genetics, and functioning, meaning that domestication of such strains is in progress or has occurred. While mass production of AM fungal propagules is needed for a sustainable inoculant industry, in vitro propagation may bring unwanted changes to the cultured isolates. If domestication reduces the isolate\u2019s ability to anastomose, these fungi would have a fitness disadvantage in the field. Alternatively, if the unnatural environment of TRC creates strains that are less beneficial in natural conditions, but these isolates are still able to anastomose with native fungi, such isolates may impact negatively on the gene pool of natural populations. It is important to further examine the effects of domestication on AM fungi and predict how changes could greatly affect the environment following inoculation with such strains.There is clear evidence that continuous No datasets were generated or analyzed for this study.MH and VK conceptualized the work and shared the writing and revision of the MS. MH and VK approved the publication of the MS in its current form. MH and VK agreed to be accountable for all aspects of the work including accuracy or integrity of any part of the work.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "This presentation will analyze the growing precarity of life for older Americans emanating from austerity budgets and privatization of public services. As governments at every level continue to look for ways to reduce social and health spending and cut taxes they are also pursuing privatization through contracts with for-profit firms to provide regulated social and health services. The presentation will discuss how these trends toward greater precarity in old age relate to Streecks\u2019 concept of the Consolidation State in Western neoliberal political economies. The Consolidation State serve the interest of capital, especially finance capital by implementing austerity budgets, preserving low taxes on wealth, prioritizing the financing of deficits/debt and privatizing public services and assets. Such policies put health care, long term care and other programs supporting older persons in jeopardy, creating a glide path toward the extension of precarious employment into a precarious retirement for millions of older people."} +{"text": "Development of simple and versatile synthetic methodologies for these nanomaterials has been the key in diversifying macromolecule based medical therapy and treatment. This review highlights the advancement from conventional \u201conly one function\u201d to multifunctional nanomedicine. It is achieved by synthetic elaboration of multivalent platforms in miktoarm polymers and dendrimers by physical encapsulation, covalent linking and combinations thereof.To address current complex health problems, there has been an increasing demand for smart nanocarriers that could perform multiple complimentary biological tasks with high efficacy. This has provoked the design of tailor made nanocarriers, and the scientific community has made tremendous effort in meeting daunting challenges associated with synthetically articulating multiple functions into a single scaffold. Branched and hyper-branched macromolecular architectures have offered opportunities in enabling carriers with capabilities including location, delivery, imaging M. M148]. The concept of combined therapeutics with diagnosis (theranostics) has recently become an integrated part of drug delivery systems, specifically for the treatment of high morbidity diseases such as cancer . The strThe presence of ample surface groups at the periphery of dendrimers provides a platform for the chemical conjugation of drug molecules with suitable functional groups. The attachment of multiple copies of same therapeutic agent on a single nanocarrier results in enhancement of therapeutic response due to synergistic or multivalency effect. In addition, the attachment of targeting agents and solubilizing polymers along with the bioactive molecules can even further improve the pharmacokinetic profile. The drug bound to nanocarrier diffuses slower than the free drug, thus, increasing its blood circulation time providing an opportunity to interact with targeting tissues. Dendrimers can be synthetically articulated to carry a well-defined payload of therapeutic molecules. Although physical encapsulation of drug molecules in the dendrimers is possible, but only a few molecules of drugs can be encapsulated even in the case of high generation dendrimers with well-defined internal cavities. Furthermore, the covalent attachment of the drug molecules provides better control in terms of their release which can only take place through physiological trigger either by chemical or enzymatic cleavages of the bonds attaching the drugs to the nanocarriers . The druin vivo studies 3 [(PCL)3-(PDEAEMA-b-PPEGMA)3] as pH sensitive micelles for the delivery of DOX [et al. has designed and reported a multifunctional star-shaped micellar system combining active targeting ability and redox responsive behavior to deliver the drug to the solid tumor with high therapeutic efficiency with minimum exposure to healthy tissues [In vivo studies demonstrated that these active-targeting and redox responsive multifunctional micelles possessed better antitumor activity and higher safety to normal tissues as compared to the redox-insensitive micelles.A continuous effort is being made to effectively design drug delivery systems with improved therapeutic efficacy and minimum side effects. Recently, the research is focused on developing stimuli-sensitive nanomaterials, which can respond to specific internal or external environmental fluctuations and trigger the drug release. A variety of stimuli have been studied for drug delivery applications including, pH, temperature, light, enzymes, and redox . For insy of DOX . The stu tissues . The micIt is becoming increasingly clear that nanocarriers will constitute an integral part of a therapeutic intervention in the future. The imagination of a chemist in designing and articulating their structures has paved the way for their translation into nanomedicine. The control offered by branched and hyperbranched structures in their design provides ample opportunities in placing any desired combination of functions into a single scaffold. These materials have offered great potential to develop materials with improved therapeutic efficacy including target specificity, controlled drug release, lower therapeutic doses and minimum exposure to normal tissues. This programmability of dendrimers and miktoarm stars is the key in developing highly efficient architectures with unique capabilities. The synthetic elaboration of dendrimers has reached a stage where one could easily adapt them to include chosen cores, branches and functional groups at surfaces. It provides freedom in incorporating a spatial distribution of diverse functionalities including therapeutic, targeting and imaging agents. With the ability to adapt to the needs of drug molecules, we can easily enable physical encapsulation or covalent linking and combinations thereof, in dendrimers and miktoarm stars. A hybrid combination of the latter two platforms may hold a better future, and a direction that can be explored. This review has highlighted the progress made in developing novel nanocarriers based on branched and hyperbranched architectures for nanomedicine. Much focus is currently being directed at taking the next step and bridging the gap to put these macromolecules into practice. Chemists are standing up to the challenge, and we are beginning to see translation of the structures elaborated by them, through a careful design and mix of adaptable features, into clinical studies. This will be achieved by synthetic adaptation of these nanostructures to industrial needs, knowledge of their safety, therapeutic efficacy, and a detailed understanding of their physico-chemical behavior."} +{"text": "OBJECTIVES/SPECIFIC AIMS: Our study seeks to answer the following questions: (1) To determine whether higher numbers of gravidity and parity are associated with a decreased risk of mild cognitive impairment or dementia; (2) To determine whether higher numbers of gravidity and parity are associated with a decreased risk of amyloid deposition by PET MRI. METHODS/STUDY POPULATION: Our study population includes all female study participants in the Atherosclerosis Risk in Communities (ARIC) study who did not have a diagnosis of dementia before enrollment. Participants were also required to have been evaluated for cognitive impairment in the ARIC-NCS ancillary study, or to have received an MRI PET scan of their brain as part of the ARIC-PET ancillary study. Baseline information on the gravidity and parity of all the women was recorded at initial enrollment. We use statistical analyses and epidemiological measures to explore our study questions. For our first question, we use logistic regression to evaluate the association of gravidity and parity as two separate ordinal variables using adjudicated mild cognitive impairment (MCI) and dementia. For our second question, we use logistic regression to evaluate the association of gravidity and parity with amyloid positivity. We use STATA for our statistical analyses. RESULTS/ANTICIPATED RESULTS: We hypothesize that increased gravidity and parity will have either no effect or a protective effect against MCI, dementia, and amyloid deposition. Our preliminary analyses show that older age of a woman at first pregnancy and at first live birth are both positively correlated with increased incidence of cognitive impairment. No relationship was found between these surrogates of lifetime estrogen exposure and cerebral amyloid deposition. DISCUSSION/SIGNIFICANCE OF IMPACT: Multiple basic science and clinical research studies have shown that estrogen exposure has an effect on cognitive function, likely through a complex interplay of multiple physiologic systems. Our study expands the research in this area by using a large, established epidemiologic cohort to examine gravidity and parity as important factors in lifetime estrogen exposure as they relate to cognitive impairment and amyloid plaque deposition."} +{"text": "August 19\u201323, 2019, marks the sixth annual Contact Lens Health Week. In collaboration with partners from clinical, public health, industry, and regulatory sectors, CDC is promoting healthy contact lens wear and care practices to reduce the risk for eye infections among the approximately 45 million persons in the United States who wear contact lenses. Studies conducted following outbreaks of rare but serious eye infections in the United States have found that these infections occur most frequently in contact lens wearers who do not take proper care of their contact lenses, indicating a need to promote safer wear and care (MMWR reviews reported provision and receipt of contact lens wear and care recommendations among providers and patients in the United States (A report in this issue of https://www.cdc.gov/contactlenses.Additional information on Contact Lens Health Week and the proper wear and care of contact lenses is available at"} +{"text": "Central nervous system neurons become postmitotic when radial glia cells divide to form neuroblasts. Neuroblasts may migrate away from the ventricle radially along glia fibers, in various directions or even across the midline. We present four cases of unusual migration that are variably connected to either pathology or formation of new populations of neurons with new connectivities. One of the best-known cases of radial migration involves granule cells that migrate from the external granule cell layer along radial Bergman glia fibers to become mature internal granule cells. In various medulloblastoma cases this migration does not occur and transforms the external granule cell layer into a rapidly growing tumor. Among the ocular motor neurons is one unique population that undergoes a contralateral migration and uniquely innervates the superior rectus and levator palpebrae muscles. In humans, a mutation of a single gene ubiquitously expressed in all cells, induces innervation defects only in this unique motor neuron population, leading to inability to elevate eyes or upper eyelids. One of the best-known cases for longitudinal migration is the facial branchial motor (FBM) neurons and the overlapping inner ear efferent population. We describe here molecular cues that are needed for the caudal migration of FBM to segregate these motor neurons from the differently migrating inner ear efferent population. Finally, we describe unusual migration of inner ear spiral ganglion neurons that result in aberrant connections with disruption of frequency presentation. Combined, these data identify unique migratory properties of various neuronal populations that allow them to adopt new connections but also sets them up for unique pathologies. Most central nervous system (CNS) neurons become postmitotic near either the ventricle or the pia mater of the brain, typically through the cell division of a radial glia cell, whereas all peripheral nervous system (PNS) neurons are derived either from neural crest or peripheral placodes . After eDepending on the nuclear translocation, the leading process may develop into a dendrite or may transform partially into the axon . For exaThis overview shows that various migration trajectories can generate unique neuronal populations that are separated from other populations with closely associated spatial and temporal origins through their final topology and associated unique input and output properties. While molecular networks of glial cell migration begin to emerge , in partAtoh1-cre-induced Smo preferentially transforms the EGL into a rapidly growing MB with distinct patterns of innervation that are partially conserved across vertebrates . These mThe fibers to the superior rectus division of CNIII branch upon entry into the orbit, indicating that the migration and branching pattern are two unique aspects specific to this population of motor neurons. This is important as this branching was recently shown to explain a human eye movement defect, congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Specifically, it was found that a mutation in a human tubulin associated transporter, Kif21a, causes stalling of oculomotor nerve fiber axons destined to reach the superior rectus and levator palpebrae. In this disease since the muscle fibers are not innervated, they turn into connective tissue in humans as well as in a mouse model of this human disease . In addiFacial branchial motor (FBM) neurons are motor neurons that inn1). Mutations in transcription factor AP2-alpha [TFAP2A] are underlying this variably penetrant, dominantly inherited syndrome . Unfortunately, identifying the unique function of Gata3 in inner efferent guidance and migration requires unique deletion only in the inner ear efferents as Gata3 is also essential for cochlear development and the intestine (enteroendocrine cells), it seems very unlikely that a human pathology will ever be encountered matching this specific phenotype. Nevertheless, the resulting mouse pathology is extremely informative to reveal the molecular basis of frequency specific hearing and the limitations of physiological refinement of frequency specific sound perception as specific case of sensory map formation hearing, physiological tests can reveal the effect of disorganized innervation on frequency specific hearing by tuning curves. In principle, one of two outcomes were expected: the topographical wiring will be corrected for by the frequency specific filtering mechanisms or the miswiring of the cochlea onto cochlear nuclei results in aberrant tuning curves. Clearly, the tuning properties of central auditory neurons are abnormal and show in most cases only weak if any tuning properties at all. Combined these data suggest that migration and pathfinding in spiral ganglion neurons depend on Neurod1 that regulates the molecular basis of Schwann cell interaction both to read the stop signal and to navigate in a topographical specific way to establish the connectional substrate for tonotopic, frequency specific hearing. Given the complexity of the mouse mutants needed to have viable mice with the specific targeted deletion of ormation .In summary, we present four cases of migration related CNS and PNS pathologies that correlate specific migrations with defined pathologies or connection details of distinctly migrating populations. While much of the presented data are at the level of correlation, at least one case shows that migration, fiber guidance and overall wiring critically depends on a single transcription factor that also plays a crucial role in one of the other cases of neuronal migration, Neurod1. It remains to be shown, how other transcription factor(s) affect the differential migration and projection of the two other populations presented here, and what is the molecular nature of cellular interactions with surrounding glia fibers that direct the process growth and direction and level of translocation.BF conceived the review. KE, GP, JD, and JK contributed the images and parts of writing. KE, GP, JD, MH, and JK reviewed and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The threatened eastern wolf is found predominantly in protected areas of central Ontario and has an evolutionary history obscured by interbreeding with coyotes and gray wolves, which challenges its conservation status and subsequent management. Here, we used a population genomics approach to uncover spatial patterns of variation in 281 canids in central Ontario and the Great Lakes region. This represents the first genome-wide single nucleotide polymorphism (SNP) dataset with substantial sample sizes of representative populations. Although they comprise their own genetic cluster, we found evidence of eastern wolf dispersal outside of the boundaries of protected areas, in that the frequency of eastern wolf genetic variation decreases with increasing distance from provincial parks. We detected eastern wolf alleles in admixed coyotes along the northeastern regions of Lake Huron and Lake Ontario. Our analyses confirm the unique genomic composition of eastern wolves, which are mostly restricted to small fragmented patches of protected habitat in central Ontario. We hope this work will encourage an innovative discussion regarding a plan for managed introgression, which could conserve eastern wolf genetic material in any genome regardless of their potential mosaic ancestry composition and the habitats that promote them. Neutral theory provides a strong foundation for the application of conservation genetics, which identifies evolutionary distinct lineages that are vulnerable to genetic erosion or extinction due to reductions in population sizes ,2,3. HisIsland species have been used as archetypal evolutionary models representing the consequences of isolated populations that can persist despite low effective population sizes ,6,7,8. HCanis anthus ) complex . Their rThe viewpoint described above prioritizes conserving genetic diversity across a gradient of admixed individuals. Adopting this view, canids of varying wolf and coyote ancestry should be conserved on the Ontario landscape to maintain unique eastern wolf genetic material and maximize evolutionary potential. A second viewpoint prioritizes ecological function and seeks to conserve roles that rare species play in ecosystems . In the We find that eastern wolves represent a unique genomic cluster that is geographically isolated to patchy regions of central Ontario and possibly southern Quebec, with a general increase in admixture outside of protected areas. Their unique genetics provides a solid foundation to identify them as a conservation priority, especially given their low effective population size and degree of isolation. Further genomic assessment of canids in southern Quebec would help clarify the extent of the eastern wolf range outside of Ontario. Moving forward, conservation of the eastern wolf genome would benefit from the connection of current protective zones across the Ontario landscape."} +{"text": "Promoting engagement in social activities may be an intervention that prevents or delays cognitive impairment. Nevertheless, little is known about social engagement among people with mild cognitive impairment. We aim to examine patterns of social engagement among people with mild cognitive impairment and to assess whether factors under four domains of the WHO's ICF model are associated with patterns. Data were drawn from the 2010 Health and Retirement Study. The final sample comprised 1,227 people with Cognitive Impairment No Dementia (CIND). Latent class analysis and multinomial logistic regression were utilized. Three patterns of social engagement were identified: informal social engagement only, formal and informal social engagement, and low social engagement. At least one factor from each domain was associated with the probability of class membership. Our findings suggest that social engagement is heterogeneous among people with CIND and that some groups of people with CIND have possibilities of engaging in more social activities, especially in formal social activities. Results also indicate that providing informal social resources may be essential for social programs designed specifically for people with CIND to promote their formal social engagement. Future study is needed to examine possible differences in outcomes across groups with similar patterns of social engagement."} +{"text": "Sepsis is a leading cause of morbidity and mortality in children with a worldwide prevalence in pediatric intensive care units of approximately 8%. Fluid bolus therapy (FBT) is a first line therapy for resuscitation of septic shock and has been a recommendation of international guidelines for nearly two decades. The evidence base supporting these guidelines are based on limited data including animal studies and case control studies. In recent times, evidence suggesting harm from fluid in terms of morbidity and mortality have generated interest in evaluating FBT. In view of this, studies of fluid restrictive strategies in adults and children have emerged. The complexity of studying FBT relates to several points. Firstly, the physiological and haemodynamic response to FBT including magnitude and duration is not well described in children. Secondly, assessment of the circulation is based on non-specific clinical signs and limited haemodynamic monitoring with limited physiological targets. Thirdly, FBT exists in a complex myriad of pathophysiological responses to sepsis and other confounding therapies. Despite this, a greater understanding of the role of FBT in terms of the physiological response and possible harm is warranted. This review outlines current knowledge and future direction for FBT in sepsis. The worldwide burden of sepsis in pediatric intensive care in terms of morbidity and mortality remains high and is a key healthcare priority \u20133. FluidData supporting current pediatric sepsis guidelines are limited. Recommendations in relation to FBT have been based on small case control studies and animal data, mostly from two-three decades ago \u201311. Few Clinicians aim to identify patterns of circulatory dysfunction in septic shock that include myocardial dysfunction, systemic vasodilatation, and hypovolaemia . This geThis review outlines the current understanding of the role of FBT in children with sepsis and recent research direction.The global burden of sepsis and septic shock is high in pediatric intensive care units (PICUs) with prevalence studies suggesting mortality rates ranging from 6 to 25% , 27. TemThere are very few large scale epidemiological or randomized studies of FBT in pediatric septic shock . SeveralA large US adult study of the interaction between fluid administration on day 1 and mortality from sepsis showed increased severity adjusted mortality and cost for each liter above 5L; in the presence of shock, mechanical ventilation or both . LeismanThe pathophysiology and haemodynamic patterns in septic shock are complex, dynamic and not easily determined clinically. The pathophysiological hallmarks of septic shock are cytokine and nitric oxide mediated inflammation, activation of the coagulation cascade, manifesting as myocardial, endothelial, and organ dysfunction . TherapeClinical signs of septic shock such as tachycardia, hypotension, impaired skin perfusion, while readily identifiable and indicative of shock, are difficult to rely upon to indicate hypovolaemia or volume responsiveness. Yet these are commonly the triggers or targets available to clinicians in the first hours of pediatric sepsis management. More advanced tools such as echocardiography or invasive haemodynamic monitoring can assist in deciphering myocardial dysfunction from a hyperdynamic circulation as well as volume responsiveness, however even these, as static measures lack predictive accuracy . Their aBlood pressure and heart rate are the most highly rated clinical signs among pediatric intensivists , ED physCapillary refill time (CRT) is a simple bedside test universally regarded as a marker of inadequate perfusion and dehydration in children and a specific adjunct sign of shock , 51. In Several studies describe the haemodynamic patterns in children with septic shock, often following an initial dose of FBT commonly referred to as \u201cfluid refractory shock.\u201d Deep et al. showed distinct patterns of \u201ccold' and \u201cwarm\u201d shock amongst 36 children with community acquired and hospital acquired sepsis with early and sustained abnormalities in haemodynamic values . An IndiClearly a spectrum of circulatory phenotypes exists, overlap and evolve in the initial stages of septic shock in children. The ability of clinicians to recognize these entities early and repeatedly on the basis of predominantly clinical signs, commence therapies and use clinical, biochemical, echocardiographic, and perhaps microcirculatory markers to judge response to therapy outlines the complex nature of sepsis resuscitation and teasing out the role of one therapeutic intervention.Imaging of the microcirculation to measure the number of perfused capillaries and capillary density can assess the microvascular response to sepsis and therapy. It is performed in intensive care patients with a sublingual camera using side-stream dark field video-microscopy of the sublingual circulation. Alterations in the microvasculature include reduction in capillary density and microvascular blood flow , 60. MicPerhaps, in time, assessment of the phenotypic subtypes of septic shock may extend beyond clinical signs and haemodynamic measured and include genetic markers . Until t2) 5 min following a fluid bolus that had dissipated by 60 min to a lower baseline than pre bolus . The results were consistent across all pre-specified subgroups including malaria, anemia (hemoglobin concentration < 50 mg/l), coma and lactic acidosis (lactate >5 mmol/l). These results generated much interest and debate surrounding the role of FBT in high-income countries and mortality. The degree to which FBT contributes to fluid accumulation in children is not well established. The association of fluid overload and harm is consistent in a broad spectrum of critically ill children including those following congenital heart disease surgery \u201390, acutp < 0.001). Roughly two-thirds received only 1 further bolus. There were no differences in hospital or PICU based outcomes. The authors concluded that lower than expected severity of illness precludes conduct of a larger study. The Canadian study aims to determine whether early vasoactive therapy, compared to usual fluid resuscitation practice (up to 60 ml/kg of isotonic fluid) reduces time to shock reversal and organ dysfunction. Adult data have shown that fluid restrictive resuscitation can reduce FBT administration. The CLASSIC study randomized 151 adults with septic shock and showed a significant reduction of resuscitation fluid at 5 days but no difference in total administered fluid but a trend toward lower fluid accumulation and tissue dysoxia (lactate elevation) are key features. A study in ANZ showed that these features are easily identifiable early and can accurately discriminate children at risk of death, albeit once admitted to an intensive care unit . Recent Trials of restrictive fluid therapy will require a clinically significant separation of administered fluid volume. Vasoactive agents such as adrenaline or noradrenaline can be administered peripherally and are suitable alternate interventions. Adrenaline being more inotropic with vasoconstrictor activity would be the optimal agent. In most instances, central venous access would not be readily available and hence dilute peripheral administration would be required. The administration of peripheral adrenaline presents several issues warranting consideration. Initial titration of adrenaline would occur using non-invasive blood pressure monitoring and, in the presence of shock, would require clear pathways and ceiling doses to either enable weaning or mandate early intensive care interventions. The entry point of recruitment would need to occur when initial therapy for reversing shock are insufficient. Otherwise one risks exposing a large group of children to an intervention (or comparison therapy) that may not have been indicated thereby exposing a proportion of children to excessive therapy. The presence of septic shock and administration of 20 ml/kg of FBT and a decision to administer further resuscitation would be an example of suitable inclusion criteria.Appropriate outcomes for studies of FBT in sepsis will be an important consideration for trial designs. The desired range of outcomes should include mortality, measures of organ dysfunction, need for intensive care resources as well as outcomes specific to fluid therapy. Markers of tissue oxygenation, tissue oedema and endothelial dysfunction have also been included as secondary endpoints in current study designs. The sample size required to show a 5\u201310% difference in outcomes have been suggested to be up to 1,500 participants (FBT has been the frontline recommended therapy in sepsis management guidelines for several decades without a body of evidence supporting its appropriate use. Increasing attention has now turned to the potential consequences of excessive fluid therapy in the context of evidence suggesting harm. This has made the time ripe to further investigate the role of this long standing, fundamental intervention in pediatric sepsis. Restrictive fluid resuscitation is currently at the forefront of alternative strategies being investigated. Whether this approach is safe, feasible and effective in reducing excessive fluid therapy and can be shown to independently improve meaningful outcomes in children with septic shock remains to be seen.The author confirms being the sole contributor of this work and has approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Anthropogenic climate change induces unprecedented variability in a broad range of environmental parameters. These changes will impact material properties and animal biomechanics, thereby affecting animal performance and persistence of populations. Climate change implies warming at the global level, and it may be accompanied by altered wind speeds, wave action, ocean circulation, acidification as well as increased frequency of hypoxic events. Together, these environmental drivers affect muscle function and neural control and thereby movement of animals such as bird migration and schooling behaviour of fish. Altered environmental conditions will also modify material properties of animals. For example, ocean acidification, particularly when coupled with increased temperatures, compromises calcified shells and skeletons of marine invertebrates and byssal threads of mussels. These biomechanical consequences can lead to population declines and disintegration of habitats. Integrating biomechanical research with ecology is instrumental in predicting the future responses of natural systems to climate change and the consequences for ecosystem services such as fisheries and ecotourism. Here, we summarise how the dominant environmental changes associated with climate change can impact the biomechanics and movement of organisms. Anthropogenic climate change will dominate ecosystem flux for the next decades if not centuries. The recent literature has given a much clearer picture of the expected impacts of global warming on physiological performance and thermal tolerance of environmental variability that affects performance and ultimately reproductive success. Migrating birds, for example, are exposed to local variation at their breeding and overwintering grounds and to global variation as a result of migration, and together these will determine reproductive success . The comNerita atramentosa) . Ocean wWarmer waters are often associated with low oxygen concentrations . TheoretIn terrestrial environments, climate change can alter wind speeds . The ter2 causes an energetic constraint and allocation trade-off that curtails growth, and it reduces the calcium carbonate building blocks essential for calcification ."} +{"text": "Social isolation has been shown to associate with negative health outcomes including depression and stress. For family caregivers of older adults, the demands on the caregiver often are associated with increasing feelings of loneliness and decreased social contact. The degree to which the caregiver\u2019s social isolation is related to the complexity of the caregiving situation remains unknown. Through a cross-sectional analysis of 526 family caregivers from the Family Caregiver Alliance client record database, an association has been established between care recipient functional decline and caregiver social isolation. Social isolation was measured through the Lubben Social Network Scale and functional decline was measured through ADL/IADL reporting. Covariates controlled for in the analysis included caregiver ethnicity, duration of caregiving, adult child status, caregiver education, care recipient income, and hours per week caregiving. Family caregivers of care recipients with higher functional decline experienced elevated odds of social isolation as compared to family caregivers of care recipients with little to no functional decline. The results from this study highlight the need for medical personnel and non-profit actors to anticipate social isolation as a risk factor for family caregivers of older adults given the care recipient is experiencing functional decline."} +{"text": "The quest for new and improved therapies for glioblastoma (GB) has been mostly unsuccessful in more than a decade despite significant efforts. The few exceptions include the optimization of classical alkylating chemotherapy by including lomustine in the first line regimen for GB with a methylated MGMT promoter and tumor treating fields , 2. The What consequences do these findings have for clinical traials with inhibitors of EGFR or mTOR signal transduction? To fully exploit the potential of inhibitors, biomarkers have to be developed to identify tumors with defective wiring of signal transduction. Additionally, these findings may influence the potential armamentarium for combinatorial drug treatment. A direct combination with drugs that cause local hypoxia or nutrient deprivation like antiangiogenic drugs might result in reciprocal annulations of effects. Depending on the half life and pharmacokinetics of the drugs, stepwise treatment algorithms could be an option to prevent antagonistic effects. While glioma-associated microglia/macrophages (GAMs) can make up for more than half of the cells of a GB tumor, the role of signal transduction inhibitors on GAMs has only marginally been addressed but may nevertheless influence treatment efficacy. It is interesting to note that GBs with more extensive microglia infiltration appeared more responsive to EGFR inhibition with the EGFR antibody nimotuzumab . This maThese considerations give reason for cautious optimism that, while the path to clinical development of EGFR and mTORC1 inhibitors for GB treatment has certainly been strenuous, the advancement of understanding of the wiring of GB signal transduction will eventually reveal actionable targets at least in some tumor and patient subgroups."} +{"text": "Immunosenescence creates a challenge in developing vaccines tailored for older adults. Recent advances in immunology, molecular biology and systems vaccinology have enabled greater understanding of the innate and adaptive immune mechanisms behind vaccine responses in adults. Novel approaches to vaccine design for this population include adjuvant technology. New knowledge and accumulating experience enables evidence-based selection of the right antigen and adjuvant combination leading to the discovery and development of better and/or newer innovative vaccines specifically tailored to protect against pathogens responsible for infectious diseases resulting in significant morbidity and mortality in older adults. For example, the recent licensure of several vaccines formulated with a new generation of adjuvants to help protect older adults against influenza, hepatitis B and herpes zoster (shingles). This evidence-based approach to the development of adjuvanted vaccines addressing immunosenescence is a primary prevention strategy to develop and maintain the functional ability that enables wellbeing in older age."} +{"text": "As the US population ages, the prevalence of Alzheimer\u2019s Disease (AD) and related dementias is expected to increase, making dementia prevention efforts a major public health priority. Impaired sleep and circadian rhythms, along with other lifestyle factors, have emerged as important modifiable disease risk factors\u2014recent studies demonstrate the importance of sleep in preventing the development of key biomarkers for AD/dementia pathology. In this symposium, we will highlight findings on the associations of sleep, circadian rhythm disruptions, and daytime activity patterns on development of cognitive decline and dementia, exploring not only the mechanisms driving these associations, but the potential impact of sleep and lifestyle interventions in promoting healthy brain aging. The symposium consists of four presentations which use data from large national cohort studies. First, we will present analyses on patterns of 24-hour (circadian) activity rhythms and incident dementia risk. The second presentation will present findings pertaining to understanding the link between sleep disturbance and inflammation . The third will examine whether detailed daytime activity patterns associate with imaging-based brain volumes, independent of sleep disturbance. The final presentation will explore whether initiation of sleep disorder treatments may have the potential to change trajectories of cognitive performance as individuals age. Overall, the symposium will highlight the importance of sleep and activity patterns to brain health and stimulate discussion about improving sleep and circadian disruption as a target for dementia prevention efforts."} +{"text": "There is overwhelming evidence that the highest burden of disease worldwide is concentrated in low and middle-income countries (LMICs) and responsible for the high mortality in these countries . This hiThe existing contextual barriers to undergraduate research are complex and interrelated and can include:Poor research infrastructure: poor research production in Cameroon can grossly be associated to the weak and unavailable functional research infrastructures at the institutional level. Most public and private institutions lack the commitment to investment in research structures, making research practice unrealistic with poor student referral and uptake into health research.Poor study facilities: undergraduate training institutions in Cameroon are substandard with inadequate training facilities. Observed in these institutions are outdated and under-resourced library stocks, lack of computers, poor internet and e-libraries limiting access to research literature. Good research questions, protocols, appraisal and review of current literature are unrealizable without easy access to the literature.Lack of proper mentorship: the observed attitude, knowledge, and practices of faculty lead, and those assuming research supervisory roles in our undergraduate training institutions in Cameroon leaves little to be desired by students. The missing track record of many providing guidance leaves students with a univocal view of research as a graduation requirement. This attitude has left students with the inability to appraise and engage in health research. The situation is further compounded by incompetent assessors, whose main motivation is pecuniary rather than the core values of the supposed exercise.Late introduction of students to the research process: all undergraduate training programs for biomedical students tend to have a research course. The course is often introduced late during training and directed towards the final year project or thesis. Coupled with tight training programs, students work within a short time under pressure on research projects. The associated pressure and lack of clarity of the research process have led many to hate research.Lack of funding and promotion: high-quality research is unthinkable without appropriate funding. Lack of institutional and national frameworks to promote research among young researchers and students also halts the promotion of research culture in Cameroon. Many faculties and supervisors lack funded projects that may enroll students into practical research during training.Lack of journals: the rare availability of institutional and national journals coupled with the financial obligations for publications by journals constitute research barriers. Furthermore, some international journals rarely accept manuscripts originating from lesser well-known authors [ authors .To improve health research in undergraduates, it is mandatory to reconsider making positive changes to the presenting of contextual barriers. Strengthening existing research infrastructures and creating new ones from the national framework to operational research units at the clinical site is non-elective. This may be a good investment to target health problems effectively in the near future. Such establishments may engage interested students early into clinical research. Accreditation/supervision of training institutions for biomedical students should be comprehensive and rigorous. All approved institutions should meet the minimum training standards with all the necessary study facilities for high quality training and research. Only adept enthusiastic teachers/lecturers should be assigned for research supervision. Hence, training institutions may make it as a target for all lecturers assuming a supervisory role to publish on a regular basis as this may naturally benefit the students as they advance their career. There is a need to revisit our crowded training programs with early introduction of the research process to allow graduates to embrace the tenets of research early during training. Early understanding of the research process may translate to increase research engagement during training and in future. Early enrollment of students into research and journal clubs in biomedical institutions may further consolidate this research attitude. Such units may look for partnership with active collaborators to promote research . PromotiBarriers to undergraduate biomedical students' research in Cameroon can be much improved if training institutions invest into research. Practical efforts to changing student attitude towards research from a graduation requirement to a problem solving skill during training are necessary.The author declares no competing interests."} +{"text": "Drosophila melanogaster, neural crest cell migration in chick and Xenopus embryos, and posterior lateral line primordium (pLLP) migration in zebrafish. The pLLP is a group of about 100 cells that begins migrating around 22 hours post-fertilization along the lateral aspect of the trunk of the developing embryo. During migration, clusters of cells are deposited from the trailing end of the pLLP; these ultimately differentiate into mechanosensory organs of the lateral line system. As zebrafish embryos are transparent during early development and the pLLP migrates close to the surface of the skin, this system can be easily visualized and manipulated in vivo. These advantages together with the amenity to advance genetic methods make the zebrafish pLLP one of the premier model systems for studying collective cell migration. This review will describe the cellular behaviors and signaling mechanisms of the pLLP and compare the pLLP to collective cell migration in other popular model systems. In addition, we will examine how this type of migration is hijacked by collectively invading cancer cells.Cellular migration is necessary for proper embryonic development as well as maintenance of adult health. Cells can migrate individually or in groups in a process known as collective cell migration. Collectively migrating cohorts maintain cell-cell contacts, group polarization, and exhibit coordinated behavior. This mode of migration is important during numerous developmental processes including tracheal branching, blood vessel sprouting, neural crest cell migration and others. In the adult, collective cell migration is important for proper wound healing and is often misappropriated during cancer cell invasion. A variety of genetic model systems are used to examine and define the cellular and molecular mechanisms behind collective cell migration including border cell migration and tracheal branching in Cellular migration is necessary both during development and adulthood and has been widely studied in populations of cells that migrate independently. However, cells can also migrate in groups in a process known as collective cell migration. During collective cell migration, cells maintain cell-cell contacts, exhibit both morphological and behavioral polarization and interact with neighboring cells within the collective to affect each others behavior. This process is important during the morphogenesis of multiple organ systems, as well as during wound healing in adults. In addition, invading cancer cells exhibit many hallmarks of collective cell migration.Collectives can be organized in a variety of different forms, including loose chains or strands, tight clusters, tubes, or epithelial sheets Figure . Neural D.melanogaster . During border cell migration a group of cells delaminates from the follicular epithelium of the D.melanogaster egg chamber and migrates across the chamber toward the developing oocyte is a group of around 100 cells that migrates along the lateral aspect of the trunk of the embryo during embryogenesis Figure . The pLLCells within the pLLP display differential morphology and different states of differentiation depending on their location and can be generally designated as leader or follower cells. The leading third of the pLLP is comprised of 2\u20133 tip cells of mesenchymal character and less differentiated epithelial cells Figure . The remIn addition to differences in morphology, leader and follower cells within the pLLP show differences in their fate. As the pLLP migrates it deposits proto-NMs every 5\u20137 somites. At the onset of migration the pLLP contains 2 to 3 proto-NMs; however, by the end of migration the pLL consists of 5\u20136 NMs and the terminal cluster of NMs Figure . Newly gcxcl12a is uniformly expressed and Fgf (trailing region) signaling interacts with the Notch3 receptor on neighboring cells within the proto-NM and inhibits expression of atoh1a, in neighboring cells therefore specifying them as supporting cells and supporting cells, whereas E-cadherin is only expressed in the hair cell progenitor cell signal take on the role of the leader cell , the chimeric pLLP stopped and tumbled until mutant cells were \u201cpushed back\u201d and excluded from this leading region found in blood samples of patients Figure Zeidman. SubsequXenopus express high levels of the ligand CXCL12 Figure Wang et. FurtherBased on the similarities between collective invasion and collective cell migration, we can use models of collective cell migration during development to discern mechanisms used by tumor clusters during metastasis. For example, as Lef1 is upregulated at the invasive fronts of both lung and colorectal invasive cancers and canonical Wnt signaling via Lef1 is active in the leading region of the pLLP we can use the leading region of the pLLP as a model for collective cancer invasion. We can study cellular adhesion, protrusive behavior, and cell-ECM interactions using the pLLP model to identify cellular mechanisms that promote cancer front migration and metastasis. Identification of cellular pathways that act downstream of Lef1 in the pLLP may provide clues as to how these factors are misregulated during invasive cancers that show increased Lef1 expression at their leading edge. Thus, further insights gained through studies of pLLP leading edge behavior could provide insight into how these invasive clusters promote metastasis.Collective cell migration is a widely used developmental process that initiates and promotes morphogenesis of many different organ systems. While collectives are organized into a variety of different forms, they often share similar cellular strategies. Collectives are guided by leading cells that sense and respond to the extracellular environment, specifically chemotactic cues. These chemotactic cues are then transmitted through specific signaling pathways to initiate molecular changes that guide migration as well as differentiation. Insights gained from studying mechanisms of collective cell migration can be used to identify mechanisms by which invasive cancers hijack developmental machinery to promotemetastasis.HO wrote the manuscript. AN edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Cellular aging is a complex process that involves many interwoven molecular processes. Studies in model organisms have identified many individual genes and factors that have profound effects on lifespan. However, how these genes and factors interact and function collectively to drive the aging process remains unclear. We investigated single-cell aging dynamics throughout the replicative lifespans of S. cerevisiae, and found that isogenic cells diverge towards two aging paths, with distinct phenotypic changes and death forms. We further identified specific molecular pathways driving each aging fate and revealed that these pathways interact and operate dynamically to enable an early-life switch that governs the aging fate decision and the progression towards death. Our work uncovers the interconnected molecular pathways that drives the aging process and opens up the possibility of designing interventions that simultaneously target multiple network nodes, instead of single genes, to more effectively extend the healthspan."} +{"text": "The septo\u2013hippocampal pathway adjusts CA1 network excitability to different behavioral states and is crucially involved in theta rhythmogenesis. In the medial septum, cholinergic, glutamatergic and GABAergic neurons form a highly interconnected local network. Neurons of these three classes project to glutamatergic pyramidal neurons and different subsets of GABAergic neurons in the hippocampal CA1 region. From there, GABAergic neurons project back to the medial septum and form a feedback loop between the two remote brain areas. In vivo, the firing of GABAergic medial septal neurons is theta modulated, while theta modulation is not observed in cholinergic neurons. One prominent feature of glutamatergic neurons is the correlation of their firing rates to the animals running speed. The cellular diversity, the high local interconnectivity and different activity patterns of medial septal neurons during different behaviors complicate the functional dissection of this network. New technical advances help to define specific functions of individual cell classes. In this review, we seek to highlight recent findings and elucidate functional implications of the septo-hippocampal connectivity on the microcircuit scale. Knowing the structural and functional connectivity of specific brain regions is essential to understand the link between behavior and neuronal activity. A highly interconnected brain region contains the medial septum and the diagonal band of Broca (MSDB) within the basal forebrain. Among others, it receives inputs from the hippocampus, the amygdala, the supra-mammillary nuclei, the thalamus and the ventral tegmental area and projects to the entire hippocampal formation, the amygdala, the ventral tegmental area and the hypothalamus to the hippocampus arise from cholinergic neurons, providing the main source of acetylcholine release in the hippocampus interneurons, with their somata and dendrites located in stratum oriens and their axonal projections in stratum radiatum and lacunosum moleculare, display fast nicotinergic excitation in response to cholinergic input from the medial septum , the neuropeptide somatostatin and the presence of cyclic nucleotide gated hyperpolarization activated ion channels (HCN; Freund GABAergic projections from the medial septum predominately target hippocampal GABAergic interneurons expressing parvalbumin Freund . One maiThe input strength from putative GABAergic septal neurons to hippocampal interneurons as well as the theta power increases during running episodes (Kaifosh et al. GABAergic neurons in the hippocampus not only receive strong GABAergic input from the medial septum but they can also project back to the medial septum (Alonso and K\u00f6hler The GABAergic neurons projecting from the medial septum to the hippocampus are predominantly parvalbumin positive. In contrast, the GABAergic neurons projecting from the hippocampus to the septum are predominantly somtatostatin-expressing neurons (Jinno and Kosaka In vivo long-range GABAergic neurons in the hippocampus display rhythmic firing; however, they are not forming a uniform group regarding their discharge patterns (Katona et al. In this review, on septo\u2013hippocampal interaction that by far could not cover the full extent of the literature, we pointed out the properties and specific roles of major medial septal cell types and their projections. Cholinergic medial septal neurons do not couple to theta oscillations but their firing rates during theta oscillations are elevated. Acetylcholine is thought to suppress oscillations in other frequencies than theta and is released during exploration and associative learning tasks (Vandecasteele et al. Glutamatergic septal neurons activate hippocampal interneurons in stratum oriens before and during movement. Their activity rates are elevated during locomotion and correlated to the animal\u2019s running velocity. Thereby, they provide a speed signal to the CA1 pyramidal neurons and may serve to adjust hippocampal excitability to the vigor of future and ongoing locomotor activity. The local glutamatergic network within the medial septum may provide the coupling of hippocampal theta oscillations to the running velocity. The medial septum is located in a central position in the locomotion-initiation circuitry and is well interconnected with subcortical regions on the input and output level see Fig. b.GABAergic septal projections to the hippocampus predominantly terminate on GABAergic parvalbumin positive neurons in the hippocampus. They synchronize and entrain the local inhibitory, mainly perisomatically innervating interneuron population to the theta rhythm. In this way, they rhythmically disinhibit the pyramidal neuron population and are main contributors to theta generation in the hippocampus. GABAergic input from the medial septum furthermore carries information about the intensity of sensory stimuli. The reciprocity in the GABAergic connection between the hippocampus and the medial septum may serve to ensure the binding and synchrony of both brain areas in a brain state-dependent manner see Fig. c.Neurons in the medial septum innervate hippocampal pyramidal neurons to adjust their excitability directly. Furthermore, a variety of CA1 interneurons is targeted to orchestrate the hippocampal network activity in many facets. The diversity of innervation patterns, time-courses of activation and rhythmic firing properties of these interneurons makes them perfect relay stations for fine-tuning the hippocampal network excitability during changes of the behavioral state. Inhibitory projections from the medial septum target mostly the PV-positive hippocampal interneurons for rhythmogenesis. Excitatory septo\u2013hippocampal projections target the group of somatostatin-positive stratum oriens interneurons, including the O-LM interneurons. The medial septum has at least two ways to provide excitation to these neurons, first via glutamatergic and second, via cholinergic, projections; somatostatin-positive interneurons stand out for several reasons: Somatostatin-positive interneurons can project to all hippocampal layers and thereby control the excitation from the temporo-ammonic and the Schaffer collateral pathway (Fuhrmann et al."} +{"text": "Racial health disparities have been observed across the lifecourse. While some studies have attributed these disparities to underlying biomedical differences, a large body of research supports a sociocultural etiology. In this symposium we will demonstrate that observed racial differences in health outcomes are associated with sociocultural factors, and demonstrate effective strategies for assessing race and racial differences in qualitative and quantitative analyses. We will share an overview of health disparities and aging, highlighting the National Institute on Aging\u2019s Health Disparities Research Framework. After this introduction, four speakers will present scientific projects that exemplify the breadth and depth of research assessing health disparities and social determinants of health across the lifecourse. Dr. Brown will present qualitative work on how social determinants are positively addressed through exercise. Dr. Chiles Shaffer will present findings demonstrating the contribution of financial burden and lower education to racial differences in healthy aging. Dr. Noppert will present evidence highlighting the structural influences that underlie the association between education and metabolic health focusing on differences by race and gender. Dr. Thierry will present research on the association between neighborhood characteristics and telomere length with a focus on heterogeneity by race and urban/non-urban residence. Finally, Dr. Hill will provide an overview of the four presentations and facilitate questions and discussion."} +{"text": "Loneliness is prevalent among older adults and is associated with adverse outcomes for health and mortality. Additionally, researchers have suggested that loneliness may cause a person to direct attention inward and become preoccupied with bodily symptoms which may subsequently lead to health anxiety. However, little extant research has examined the association among older adults. In this study, we proposed a loneliness model of hypochondriasis in which loneliness contributes to hypochondriasis through intolerance of uncertainty and anxiety. Healthy, community-dwelling older adults completed an interview survey. Loneliness was associated with higher hypochondriasis and had an indirect effect on hypochondriasis through intolerance of uncertainty and anxiety. Lonelier older adults may have an activated threat system which prompts greater intolerance of uncertainty and anxiety and thereby results in greater hypochondriasis."} +{"text": "Objective: There are very few studies reporting the techniques utilized in penile replantation. Of those in literature, many agree that the use of microvascular technique results in better outcomes. The most common complications are skin necrosis and venous congestion, which are even higher in replants without arterial supply. Methods: This study describes a case of self-inflicted penile amputation treated with microsurgical replantation and managed postoperatively with hyperbaric oxygen therapy and Cialis , and SPY angiography. The penile replant had extensive skin necrosis, which prevented a sufficient clinical evaluation of the replanted penis. Serial SPY angiography was performed to assess tissue viability, following hyperbaric oxygen therapy and Cialis treatment. Results: SPY angiography was critical to the decision making of the operating team in the management of this case of penile replantation. Conclusions: The use of SPY angiography prevented the patient from undergoing revision amputation and allowed for a safe and successful penile replantation. The transection was 2 cm from the base of the penile shaft, and the distal amputated part was preserved appropriately. and hyperbaric oxygen therapy (HBOT) were initiated 72 hours after amputation and 58 hours after replantation. Due to the fact that this replant had no arterial anastomoses, HBOT was additionally vital as it would help increase blood flow to the penis. After HBOT and Cialis, physical examination still yielded no answers but repeat SPY angiography showed increased tissue perfusion at the distal tip of the glans which prompted continuation of the Cialis and HBOT. and lack of identifiable arteries possibly lead to a higher risk of skin necrosis. Chou et alSPY angiography allowed the operating team to objectively assess the improvements made with HBOT and Cialis and justified the extensive and aggressive treatment with HBOT. Without the use of SPY angiography, the complete full-thickness necrosis of the penis, which provided an extremely difficult evaluation, would have probably resulted in a reoperation or phallic reconstruction. SPY angiography allowed for a reliable and objective method of assessing tissue viability, preventing reoperation, and allowing the team to take a more conservative approach, thereby increasing patient safety.Successful penile replantation is critical to patients both physically and mentally. Microvascular surgical repair is the preferred method; however, the lack of an arterial anastomosis can still result in a successful replantation. The use of SPY in the immediate postoperative period helped manage complications and reduced the need to make management decisions based on insufficient clinical evidence. SPY angiography provided reliable objective data regarding tissue perfusion, after hyperbaric oxygen and Cialis therapy, and prevented the patient from undergoing unnecessary revision amputation. The ability to continually evaluate the replantation enabled the operating team to manage the skin necrosis conservative and ultimately resulted in a functional and cosmetically well-appearing penis."} +{"text": "A 33-year old woman underwent a right mastectomy with bilateral deep inferior epigastric perforator (DIEP) flap reconstruction. Intraoperative discovery of a dislocated catheter prevented us from using the internal mammary vein (IMV) for anastomosis. With the aid of the venous congestion algorithm, we elected to anastomose the superficial inferior epigastric vein (SIEV) to the retrograde descending branch of the IMV stump.Which vessels are used in DIEP anastomosis?What is the proposed algorithm to address intraoperative venous congestion?What considerations were made in selecting vessels for anastomosis in our patient?What is the anatomy of chemotherapy catheter placement and what are the rates of dislocation?Recipient vessels for microvascular anastomosis in DIEP flap breast reconstruction include the internal mammary, thoracodorsal, and circumflex scapular vessels. Of these 3, the IMV and the internal mammary artery (IMA) have diameters most compatible with those of deep inferior epigastric vessels and thus are the most commonly used recipient vessels.2Venous drainage of the lower abdomen skin and subcutaneous tissue occurs primarily through the superficial venous system and secondarily through the deep venous system, with perforating veins interconnecting the 2 systems. When congestion occurs, assessed by the presence of an engorged and tense SIEV, a second anastomosis can be performed to ensure proper venous draining. An algorithm has been designed for choosing this second anastomosis.We present the case of a 33-year-old female patient status post left mastectomy with chemotherapy and radiation therapy . With ouPatients with breast cancer often require chemotherapy infusion, which can be administered by central venous catheters (CVCs). The preferred vein for a CVC is the right internal jugular vein (IJV) for its straight course to the right side of the heart and the lowest risk of venous stenosis and thrombosis.In the case of a known displaced catheter, we recommend preoperative imaging (chest computed tomography with contrast) to identify the catheter placement. With prior identification of the catheter or in an intraoperative discovery, such as in our case, following an intraoperative algorithm for the alleviation of venous congestion will help guide the surgeon in choosing the appropriate vessels for anastomosis."} +{"text": "Human kidneys are most spectacular organs. They have a busy life with filtering well over 100 liters of fluid every day and a few million liters over the course of a life. Not only is proper renal function essential for water and electrolyte balance and excretion of toxic substances in mammals, but our kidneys have amazing additional roles regarding blood pressure regulation and stimulation of red blood cell renewal. Those diverse functions are achieved by an array of different renal cell types, forming a complex tissue architecture. The \u201cbuilding plan\u201d ensuring formation and maintenance of these amazing organs lies within our genes and tiny changes within this renal map will have devastating consequences within this fine-tuned building of blood vessels, glomeruli, and tubules. It therefore comes to no surprise that in children and adolescents, genetic defects are the most common cause for end stage renal disease.Frontiers in Pediatrics we aim to give the reader interested in pediatric nephrology a broad overview over a variety of genetic kidney diseases and recent developments in clinical fields, from a research point of view as well as from a patient's perspective.Over the last years there has been outstanding progress in the knowledge about genetic kidney diseases, including the identification of multiple disease-associated genes and insights into the cellular pathophysiology. These developments have profoundly changed our understanding of genetic kidney diseases and our therapeutic approaches to (pediatric) patients suffering from these disorders. In this research topic on Genetic Kidney Diseases of Childhood published in Kemper and Lemke). Further, genetic research in combination with cell biology and biochemistry approaches has revealed multiple novel components of the glomerular filtration barrier, greatly improving our biological understanding in general (Hagmann and Brinkkoetter). Novel experimental approaches including work on model organisms like Drosophila melanogaster or Danio rerio as described in two manuscripts of the research topic have further contributed to unravel the molecular mechanisms resulting in the clinical presentation of nephrotic syndrome and the histology of e.g., focal and segmental glomerulosclerosis .Amongst the most common heriditary renal disorders with childhood onset are glomerular diseases. The discovery of genetic origins of steroid resistant nephrotic syndrome has provided great diagnostic progress and dramatically influenced the therapeutic pathway for affected families, protecting affected children from unnecessary and unsuccessful immunosuppressive treatments . This study has interestingly revealed that changes in collagen genes may underly a substantial number of patients with focal and segmental glomerulosclerosis as also described by an independent group . While podocyte-focussed research has received a lot of attention during the last years, genetic defects of the glomerular basement membrane thus represent a substantial cause for glomerular disease (Chew and Lennon).The observational Podonet-approach follows a large international cohort of patients and describes genotype-phenotype correlations , Meckel Gruber syndrome (MKS), or von Hippel Lindau syndrome (VHL).Hartill et al.), MKS , or VHL (Kim and Zschiedrich), approaches to diagnosis and treatment of cystic kidney diseases in adults (M\u00fcller and Benzing), and current opinions on the use of gastrostomy tube insertion in children with ARPKD . A topic of ongoing debate is the question whether children of patients suffering from ADPKD should undergo early diagnosis or not. These children are at a 50% risk of having inherited the genetic variants responsible for ADPKD, a disorder that typically develops over decades. It has not yet been fully established whether children benefit from early diagnosis or whether the e.g., psychosocial burden of an early diagnosis outweighs benefits. Two manuscripts in the research topic deal with different aspects of ADPKD in children . The genetic and cellular changes underlying ADPKD are summarized in an additional manuscript .The management of pediatric patients with cystic kidney diseases remains a clinical challenge as no causative treatment options are available to date. The research topic at hand discusses some important aspects and presents state-of-the-art knowledge, including current and potential future ways of managing BBS . Two additional manuscripts describe current collaborative research consortia that aim to link the findings of genetics and cellular biology with a deep clinical phenotyping and biobanking in order to set the basis for evidence-based clinical recommendations and future translational research approaches for cystic kidney diseases .Over the last years a lot of attention has been paid to a specific cellular organelle, whose dysfunction has been linked to the development of cystic kidney disease. This organelle is the primary cilium, an antennae-like structure on the cellular surface that seems to be involved in the sensing of the extracellular environment. As cilia can be found on multiple cell types, it is plausible that cystic kidney diseases frequently present with extrarenal manifestations as in nephronophthisis and nephronophthisis-associated diseases. A manuscript of this research topic summarizes the molecular mechanisms and the genetic basis resulting in Nephronophthisis Cystinosis (B\u00e4umner and Weber), magnesium transport defects or inherited disorders with kidney stone formation . Genetic diagnosis has not only provided opportunities of highly specialized clinical care and genetic counseling of at-risk and carrier individuals but also offers for the first time causative treatment options such as for cystinosis where cysteamine therapy has now been implemented.Likewise, an array of defective genes has been identified to date to cause renal tubular dysfunction, leading to diverse phenotypes in human such as Bartter syndrome , resulting from basal membrane defects or defects involving the heart and the kidneys The latter often but not always result from cilia dysfunction, however the precise underlying molecular mechanisms, e.g., cell signaling pathways defective, have not been understood. Last but not least, patients with congenital anomalies of the kidney and urinary tract (CAKUT) can present with complex syndromal appearances as described for individuals harboring PBX1 mutations and kidney function seems to be regulated by programming events very early in life that likely result in long-term modulation of gene function in the kidney .Inherited renal diseases with childhood onset can be manifestations of syndromal disease patterns with multiple organ systems involved such as in case of ciliopathies like BBS or MKS. Other examples include rare conditions affecting the skin and the kidneys (This research topic provides a concise overview about current state-of-knowledge and outlook on future developments with respects to the diverse landscape of inherited childhood onset renal diseases.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.ML has received honoraria for scientific lectures from Pfizer. Representing the University Hospital of Cologne, ML has been counseling Otsuka in an advisory board. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Modifiable health behaviors, such as physical activity and sleep quality are important for cognition throughout life. A growing body of research also suggests that engaging in enough physical activity is important to sleeping well. One recent study found that sleep efficiency mediates the relationship between physical activity and cognition. It is still unknown whether other metrics of sleep quality are mediators. The present study tested mediation in the second wave of the Midlife in the United States (MIDUS) study. Using the PROCESS macro for SPSS, we found that those who were more physically active fell asleep faster, and had better executive functioning. In addition, those who were more physically active reported waking up fewer times during the night, and had better executive functioning and self-rated memory. Discussion will focus on the moderating role of gender and distinctions between findings with different measures of sleep, physical activity, and cognition."} +{"text": "Head and neck surgeries can perturb normal structures of neck muscles and nerve innervations, which are supposed to function in harmony to allow complicated process like swallowing. It is still likely that cricopharyngal dysfunction emerges years after the head and neck surgeries.We report a case with history of left unilateral vocal cord immobility and development of dysphagia and aspiration 2\u00a0years after radical thyroidectomy with neck lymph nodes dissection and medialization thyroplasty. Cricopharyngeal dysfunction was impressed and was confirmed with visualization of cricopharyngeal narrowing segment in radiographic contrast swallow examination. The patient was treated successfully by cricopharyngeal myotomy, achieving long-term relief in our 4\u00a0years of follow up.Our case of delayed cricopharyngal dysfunction after radical thyroidectomy and medialization thyroplasty shows that it is important to follow up swallowing functions after patients with UVCI undergo medialization thyroplasty. In the event of delayed manifestation of cricopharyngeal function, it can still be treated successfully by cricoharyngeal myotomy, achieving long term relief of dysphagia. Cricopharyngeal dysfunction is a disorder caused by failure of the cricopharyngeus muscle in upper esophageal sphincter (UES) to relax during swallowing and thereby causing oropharyngeal dysphagia [Unilateral vocal cord immobility (UVCI) caused by recurrent laryngeal nerve injury often results in problems with dysphonia, aspiration, and swallowing difficulties. It is often the phonatory problems that prompt patients to seek medical attention , and medysphagia . Open crysphagia . It alsoWe report a case who suffered from left unilateral vocal cord immobility after radical thyroidectomy with neck lymph nodes dissection and type I thyroplasty for the treatment of phonatory insufficiency. The patient developed dysphagia and aspiration 2\u00a0years after the surgeries, and the patient was treated successfully by cricopharyngeal myotomy, achieving long-term relief of symptoms in our 4\u00a0years of follow up. This case adds to our experience that oropharyngeal dysfunction can be a delayed manifestation of head and neck surgeries, and appropriate surgical intervention after onset of symptoms can still achieve ideal relieve without adverse effects.A 62-year-old woman was diagnosed of thyroid cancer and received total thyroidectomy with left neck lymph nodes dissection . The patient suffered left unilateral vocal cord immobility after the surgery, and she received type I thyroplasty with vocal cord medialization 1\u00a0month after the thyroid and neck dissection surgery as treatment for her phonatory insufficiency. The patient did not receive further chemotherapy or radiation therapy, and no evidence of residual thyroid cancer or recurrence had been noted in her follow ups. There was no complaint of swallowing difficulty and aspiration before and after the neck operations. However, it was 2\u00a0years after the last previous operation of thyroplasty that she progressively developed oropharyngeal dysphagia with frequent coughing and aspiration. Physical and neurological examinations were unremarkable. Endoscopy and cervical computed tomography (CT) revealed no structural abnormality. A videotaped barium radiographic study (videoesophagraphy) showed a narrowing segment at the level of the cricopharyngeus muscle with partial dilation of the proximal esophageal segment and the external branch of the superior laryngeal nerve (EB-SLN). After branching from the vagus nerve and coursing back to the larynx, the recurrent laryngeal nerve divides into an external branch providing motor function to the four intrinsic laryngeal muscles, and an internal branch with only sensory activity for the glottis. It has been well characterized that injury to the recurrent laryngeal nerve results in ipsilateral vocal immobilization which leads to impaired phonation, aspiration, and even breathing difficulty. Another nerve in the larynx that also contributes to deglutition process is superior laryngeal nerve. The superior laryngeal nerve consists of two branches: the internal laryngeal nerve (sensory), which supplies sensory fibers to the supraglottis, and the external laryngeal nerve (motor), which innervates the cricothyroid muscle. It is well understood that the activation of SLN tilts the thyroid cartilage and tenses the vocal cord by modifying the distance between the cricoid and the thyroid cartilages. Vocal fold tension and thickness influence the frequency of the vibration . Injury Medialization thyroplasty in patients with unilateral vocal cord immobilization (UVCI) allows better apposition of the two vocal cords during phonation, and it is generally considered a phonosurgical procedure for voice augmentation. Patients with UVCI are also likely to have swallowing difficulty especially if it is related to recurrent laryngeal nerve damage, because recurrent laryngeal nerve at least partially innervates the proximal cervical esophagus . Study bIt is highly probable that our case has suffered left recurrent laryngeal nerve injury with evidence of left vocal cord immobility after the neck surgery for thyroid cancer, and the patient showed hoarseness and aspiration episodes in correlation with left vocal palsy. However, it is hard to obtain objective evidence of superior laryngeal nerve injury or its wellness from the patient, because intraoperative identification of SLN is not routinely done, and there is no standard SLN examination postoperatively. It has become a matter of our concern because, from this case, we have unanswered questions that whether injury to the superior laryngeal nerve combined with injury to the recurrent laryngeal nerve would affect a patient\u2019s dysphagia severity, and its\u2019 correlation with corresponding treatment plans. Studies show that Zenker\u2019s diverticulectomy and diverticlopexy are associated with high risks of recurrent laryngeal nerve paralysis, and surgical combination with cricopharygeal myotomy shows lower recurrence rate . AlthougAlthough radiographic appearance of cricopharyngeal bar, or cricopharyngeal narrowing in our patient, does not directly corroborate criciopharyngeal dysfunction, cricopharyngeal muscle is the primary muscle of the upper esophageal sphincter (UES) which needs to relax to allow the bolus to enter the esophagus. If the UES opening is limited in width or impaired in coordination, truncation of the bolus and residue can lead to aspiration when the airway reopens for breathing. Cricopharyngeal muscle receives dual innervations from the glossopharyngeal nerve (CN IX) via the pharyngeal plexus and the recurrent laryngeal nerve (CN X). We have known that recurrent laryngeal nerve has been injured in our patient, therefore, it strongly suggests that cricopharyngeal narrow seen in our patient correlates with our patient\u2019s dysphagia after eliminating structuration abnormality in the esophagus and pharynx. Treatment options for cricopharyngeal dysfunction include injection of botulinumm toxin, dilatations, and surgical myotomy of the muscle . We arraOur case of delayed cricopharyngal dysfunction after radical thyroidectomy with neck lymph nodes dissection and medialization thyroplasty shows that it is important to follow up swallowing functions after patients with UVCI undergo medialization thyroplasty. The procedure might cause progression of glottic insufficiency in swallowing. In the event of delayed manifestation of cricopharyngeal function after medialization thyroplasty can still be treated successfully by cricoharyngeal myotomy, achieving long term relief of dysphagia."} +{"text": "There is a growing field of evidence that individuals experiencing homelessness are disproportionately impacted by climate change due to factors like exposure to the elements, lack of resources and services, as well as disenfranchisement and stigma; all while experiencing greater occurrences of environmental injustice. Given that there are distinct needs for older individuals experiencing homelessness when affected by disasters, this study will report salient themes identified from qualitative interviews with five residential shelters on considerations they incorporate when disaster planning for their older residents. Thematic analysis revealed older age and homelessness have serious implications for planning, responding and in the recovery of disasters. Challenges to finding accessible transitional and permanent housing, limitations to workforce re-entry, increasing income inequality between classes, limitations to mental health services and policies, and cultural justifications for criminalizing poverty and homelessness contribute to our collective understanding of disaster vulnerability when older adults experience homelessness."} +{"text": "Metalworking fluid (MWF) is a complex mixture used during machining of metal objects and usually contains substances including biocides, corrosion inhibitors, metal fines, tramp oils, and biological contamination , 2. WateA comparative cross-sectional study was conducted among metal machinists at Malaysia between 2014 and 2015 and focused on the dermal exposure to MWF and the consequences on dermal health of the workers in production section compared to workers in other work sections. The total participants of 398 workers who provided the consent to participate, 297 were randomly selected from production sections and 98 form other sections such as administration, financial, general store and others. The workers were exposed to MWF through direct dermal contacts.The study was approved by the Ethics Committee for Research involving human subjects at Universiti Putra Malaysia (UPM).The dermal exposure level to MWF was considerably higher among production sections workers than workers from other sections particularly on hands, forearms, and front torso . The comAmong the MWF exposed workers, those with dermal health disorders have showed poor compliances with occupational health and safety regulations such as wearing gloves, washing hands to the elbow at least 5 times per day, cleaning working zone and taking off the working uniform immediately after work . We recommend further studies to empower the workers to play a key role in protecting their health by increasing their awareness towards the health risks of exposure to MWF and to enhance their application of the above safety methods consistently and properly."} +{"text": "Despite a growing focus on rural ageing, international literature in this field remains underdeveloped in critical and interdisciplinary perspectives. Reflecting traditional divisions across geographic, gerontological and health literatures, how we understand experiences of growing older in rural settings can still be characterised by a narrow, applied approach. This has implications for our capacity to disentangle multifaceted lived realities from rural contexts, and macro socio-economic and structural environments. There then remains questions about the ways in which the study of rural ageing needs to develop to direct policy, research and practice agendas to be a more critical reflection of these complexities. This symposium aims to draw together interdisciplinary critical perspectives on ageing and rurality as a means to advance this development. It will consider different theoretical approaches and major cross cutting challenges in relation to rural ageing. Burholt and Scharf will examine how critical gerontology has raised awareness of the heterogeneity of rural ageing across social justice elements of demography, resources, recognition and representation. Keogh and Walsh address these same elements in relation to the empirical intersection of exclusion and change in the production of a new rurality for older people. Cutchin and Rowles present a pragmatist theoretical perspective to encapsulate the essence of rural integration within an ever-changing milieu. Poulin et al. offer a critical approach to rural gerontological health that emphasizes intersectionality in the formation and development of older adult health. Herron and Skinner explore the intersectional construction of dementia and mental health in rural settings for older adults."} +{"text": "Despite improvements in diagnosis and treatment of intracranial aneurysms (IA), subarachnoid hemorrhage caused by rupture of IAs remains a devastating disease. While traditional risk factors, such as aneurysm size, morphology, smoking and hypertension, partially account for intracranial aneurysm rupture risk, many patients fall into a grey-zone in whom identification of additional novel modifiable risk factors and biomarkers may be beneficial and lead to improved outcomes.Although recent evidence suggests that hypocalcemia and hypomagnesemia are significantly associated with the extent of bleeding in patients with ICH, and the role of magnesium has been studied in the context of post-aSAH complications and outcome, the role of calcium and magnesium in the context of risk of aneurysm rupture is unknown \u20133. ThereAlthough we cannot infer causality with a biomarker association study and further prospective trials are needed to confirm these findings, the identification of biomarkers such as hypocalcemia and hypomagnesemia that are associated with rupture may provide insights into novel disease mechanisms with potential therapeutic implications."} +{"text": "There is a paucity of research that seeks to understand why race disparities in health across the life course remain elusive. Two such explanations that have been garnering attention is stress and discrimination. This symposium contains papers seeking to address the impact of discrimination or stress on health or health disparities across the life course. First, Brown and colleagues examine black-white differences in the number of reported chronic stressors across five domains their appraised stressfulness, and their varying associations with anxiety and depression among a diverse sample of older adults using data from 6,019 adults ages 52+ from the 2006 HRS. Race and appraisal interactions show that blacks and whites report similar increases in anxiety and depressive symptoms with appraisal. Second, Tobin and colleagues investigate the impact of early life racial discrimination (ELRD) on mental health among Black adults. Using data from 618 participants in the Nashville Stress and Health Study, these investigators found that childhood and adolescent ELRD were positively associated with adult distress. Also, individuals who experienced childhood ERLD had 88% lower odds of adult MDD than individuals with no ELRD. Cobb and colleagues examine the cross-sectional association between everyday discrimination and kidney function among older adults in HRS. The authors report that after adjusting for demographic characteristics, everyday discrimination was associated with lower mean eGFR. The relationship between everyday discrimination and kidney function was not explained by biospsychosocial factors. This collection of papers provides insights into how discrimination or stress impacts health in middle to late life."} +{"text": "Increasing attention has been given to direct associations of general parenting styles with children's obesity. General parenting styles refer to the broad emotional context reflecting childrearing across situations and domains do not exist in low SES groups. This is remarkable as parents are particularly important for younger children and low SES groups have increased vulnerability to young childhood obesity behavior that are more proximal to parenting than weight status and not easily assessed in survey studies. For instance, Lucas-Thompson and colleagues focused on general parenting and found that observed limit setting (but not observed warmth or self-reported parenting style) was related to the healthfulness of food choices during grocery shopping (Lucas-Thompson et al., or children (Engel et al., Moreover, EMA studies are important because they can distinguish between short-term fluctuations in weight-related parenting practices and the causes and consequences of these fluctuations. Research has shown that parenting can vary across time and context. A recent EMA study by Berge et al. revealedTo conclude, this commentary provides argumentations for changing focus from evaluating direct links between general parenting and child obesity to conceptualizing general parenting style as a contextual factor and potential moderator of the impact of specific weight-related parenting practices on children's eating behavior and obesity risk. Future naturalistic studies should include measurements of children's behaviors, which are more proximal to parenting than weight status. Moreover, innovative and personalized EMA studies with experimental parts among both children and parents simultaneously may yield better understanding of the interactions between weight-related parenting practices and general parenting influences.JL drafted and shortened the paper. SK oversaw paper process and reviewed the paper. ES reviewed the paper and added literature and references. JV added critical arguments and reviewed the paper. JF reviewed and edited the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "The close interlink between physical and mental health outcomes has long been recognised in gerontological research. Mental-physical comorbidities \u2013 the presence of at least one physical health long term condition, and at least one mental health-related long term condition are common in older age individuals. Numerous studies have shown a positive association between the prevalence of multimorbidity and age so, as the population of older individuals in developed nations continues to grow, multimorbidity is likely to become increasingly higher in ageing populations. A major goal in current gerontological neuropsychology and neuroepidemiological research is to better understand how interindividual differences in cognitive and mental health in old age emerge. Cognitive reserve (a marker of brain resilience) may come into play when facing stressors that affect cognitive decline and mental health, such as suffering from chronic diseases. We present data from three different longitudinal studies of ageing i) the Lothian Birth Cohort of 1921, ii) PREVENT and iii) the English Longitudinal Study of Ageing from the United Kingdom. These studies are ideally placed to address key research questions related to mental ageing, psychological health, terminal decline and their determinants. We explored the following objectives: 1) to investigate the association between an increasing number of chronic physical conditions, medication and mental disorders 2) to assess the role of childhood intelligence and education on the terminal decline in later life 3) to investigate the associations between different markers of cognitive reserve and dementia"} +{"text": "Over the past decade, important scientific advances have revolutionized the field of stem cell biology through the remarkable discovery of reprogramming somatic cells into induced pluripotent stem cells (iPSCs). These advances allowed to achieve the long-standing ambition of modelling human disease in a dish and, more interestingly, paved the way for unprecedented opportunities to translate bench discoveries into new therapies and to come closer to a real and effective stem cell-based medicine. The possibility to generate patient-specific iPSCs, together with the new advances in stem cell differentiation procedures and the availability of novel gene editing approaches and tissue engineering, has proven to be a powerful combination for the generation of phenotypically complex, pluripotent stem cell-based cellular disease models with potential use for early diagnosis, drug screening, and personalized therapy. This review will focus on recent progress and future outcome of iPSCs technology toward a customized medicine and new therapeutic options.A comprehensive understanding of the molecular basis and mechanisms underlying cardiac diseases is mandatory for the development of new and effective therapeutic strategies. The lack of appropriate CVDs are considered multi-faceted disorders, since both genetic and environmental factors play a fundamental role in their onset and progression. Patho-physiologically, CVDs are associated with heart dysfunction and cardiomyocytes (CMs) death, generation of fibrosis and scar tissue, and abnormal ventricular remodeling . Cardiomin vitro .These properties make PSCs a precious and irreplaceable platform for a variety of biomedical applications, such as the study of early stages of development biology , diseaseBased on this knowledge and potential, human embryonic stem cells (hESCs) became rapidly and progressively more and more exiting since they were first isolated in 1998 . AlthougDisease modeling has relied mostly on the use of mouse models genetically modified for knockout or disease-specific mutations in the gene of interest. Despite animal models have provided interesting information, mice are genetically different from humans and may not provide a comprehensive knowledge on how mutations affect the onset and the development of human disease. Understanding the molecular basis of disease has allowed the identification of targets and signaling pathways that might represent potential candidates against which scientists can develop new therapeutic strategies. Moreover, therapeutics that showed encouraging results in animals often did not provide any improvement in humans. The lack of human cellular models for disease modeling has delayed our know-how regarding the molecular mechanisms underlying disease and even more the possibility to discover effective cures for currently untreatable disorders. Human stem cells-based disease models offer the advantage for a more refined comprehension of disease mechanisms that in turn is the way to unveil new therapeutic targets. Modeling early onset childhood disease results very successful because stem cells allow to faithfully recapitulate phenotype during early stage of differentiation . To date+ cells have been used in clinical trials for autologous transplantation in patients with MI showing an improvement of cardiac perfusion and left ventricle function during the short-term follow-up; unfortunately, long-term follow-up did not reveal any cardiac advantage [Despite significant advances in prevention, diagnosis, and treatment of CVD, in the most severe cases there is no other way than heart transplantation. Numerous strategies have been developed and various cell types have been investigated to serve as potential source to replace damaged or dead cardiomyocytes. Stem cell therapy (SCT) represents a promising way addressed to the treatment of ischemic cardiomyopathy and is the only alternative to heart transplantation . Cell thdvantage . Based odvantage . Unfortudvantage , while odvantage . MI is udvantage . Strategdvantage . Adiposedvantage but agaidvantage . Overall+) [+) [+ cells [de novo differentiation and cell fusion with resident host cardiomyocytes [For a long time the adult heart has been considered an organ with any regenerative capacity. This wrong belief has changed with the identification of cardiac progenitor cells that have the function to maintain a certain degree of cardiomyocytes turnover . During +) , insulin+) [+) , c-Kit+ [+ cells , have be[+ cells ,54. Wang[+ cells . CSCs inmyocytes . Altogetmyocytes ,58. Unfomyocytes . The incThe ability of adult stem cells to repair damaged myocardial tissue has been mainly evaluated in preclinical models but only a few of them have reported promising data and were further employed in clinical trials. Apart from their safety, adult stem cells only showed marginal beneficial in cardiac regeneration capability pointing to the need to develop new therapeutic strategies.+ cardiac progenitor cells were embedded into a fibrin scaffold and injected in patient with severe HF. The procedure reported a 10% increase of the left ventricle ejection fraction (LVEF) and improvement of the symptoms without complications such as or tumor formation [A potential novel method is the possibility to generate cardiomyocytes from pluripotent stem cells that, compared to other cell types employed in clinical trials and animal models, are master cells with master properties such as self-renewal and capability to evolve into cells and tissues of the three primary germ layers. Self-renewal is a property owned of specific cells that can divide indefinitely and form cell progeny indistinguishable from it. Under the right circumstances, a PSC can produce specialized cell types, both in vivo and in vitro. After this development stage is over, the stem cell-derived differentiated cell no longer has the potential to develop further. Besides their potential to give rise to all different cell types, PSCs have the advantage to be expanded and cultured for long time without losing their pluripotency. ESCs are pluripotent stem cells derived from the inner cell mass early stage embryo. The first human ESC line was isolated in 1998 by Thomson and collaborators and has ormation . Despiteormation .The discovery, in 2007, that pluripotent stem cells can be generated from adult somatic cells has revolutionized stem cell biology and opened a great interest in their potential therapeutic application in heart diseases offeringThe concept of cellular reprogramming has been further improved with the manipulation of cellular identity as shown by the direct conversion of fibroblasts to cardiomyocytes without going through an intermediate state in a process named direct differentiation or trans-differentiation. Srivastava and collaborators have demonstrated the generation of functional cardiomyocytes by retroviral delivery of three cardiac transcription factors, Gata4, Mef2c, and Tbc5 (GMT) into murine fibroblasts. The same author used genetic lineage tracing to demonstrate that non-myocytic cells in murine heart can be converted into cardiomyocytes by in vivo delivery of GMT after coronary ligation and that this strategy has the potential to reduce the infarct size . This prCell engraftment after myocardial injection still remains a big goal to be achieved. The presence of less expandable scar areas compromises the viability of injected cells and advances in tissue engineering are currently oriented to the generation of heart tissues that can be implanted onto the infarcted region. Different extracellular matrix (ECM) such as Matrigel, fibrin, and collagen are currently under investigation. Tissue engineering aims to the generation of 3D cardiac tissue with a complex ECM structure similar to that of native human heart . Three-dDespite the morphological and functional similarities between iPSCs and ESCs, different studies have also reported the existence of important dissimilarities ,75,76. ISeveral studies have attempted to develop strategies able to generate more mature iPSC-derived cardiomyocytes . Beyond SCN5A as causative of cardiomyopathy, while corrected cells showed normal channel activity [New advances are based on the combination of iPSC technology with genome-editing technology, such as zinc-finger nuclease (ZFN) or clustered regularly interspaced short palindromic repeats- (CRISPR-) associated 9 (Cas9) system. The genome editing technology enables the generation of genetically modified patient-specific iPSCs to elucidate gene function and mechanisms of human cardiac diseases or targeted gene(s) causing disease correction . CRISPR/activity . RestoraDespite substantial advances and exciting discoveries, cardiac regeneration still remains an unmet ambition. Investigating the mechanisms by which different stem cell types govern the regeneration of infarcted heart is of utter importance for the development and discovery of new therapeutic strategies. The advances in stem cell technology, together with the knowledge of the endogenous mechanism involved in organ repair, has revolutionized the basis of the progress of regenerative attitude. The possibility to use stem cells to repair damaged cardiac tissue involves indirect and paracrine mechanisms. The latter includes the direct cardiac differentiation of injected SCs and their integration into the myocardium to compensate loss of CMs or endothelial cells. iPSCs technology has become a powerful tool for investigating the developmental biology and the pathophysiological mechanisms of various genetic cardiac diseases. Understanding how diseases develop and which are the signaling pathways and mechanisms responsible opens the way for the discovery of new targets against which scientists can develop now curative molecules and new therapeutic strategies. Additionally, iPSCs have significantly evolved for developing strategies for their potential use in future cell therapy and regenerative medicine. Heart transplantation represents the end stage of severe cardiac failure: the procedure is not at all simple and many patients have no chance of getting cardiac transplantation because of very restricted accessibility of hearts donors and other complications involved. Stem cell-based therapy for cardiac regeneration thus represents a new potential way to overcome injured heart, but many significant concerns need to be further investigated and determined. The challenge is now the understanding how this technology can be translated to real clinical application through optimization of differentiation and purification steps. Often, the discoveries with the greatest therapeutic benefits present the most difficult challenges; this is particularly true for pluripotent stem cells. Researchers are attempting to learn ways of controlling the development process of pluripotent stem cells into the many different cell types in the human body. Another current challenge is that the cells used in research are rejected from a person\u2019s body due to their immune system. iPSCs have the potential to be used for the treatment of many diseases but new strategies attempting to overcame their current technical issues need to be developed. When this is achieved than iPSCs can really represent the hope for many people suffering of cardiac diseases."} +{"text": "While preregistration has gained increasing acceptance for quantitative, particularly experimental, studies, its relevance and implementation for qualitative research has only recently been proposed. This presentation provides an overview of the very recent and ongoing debate on the potential benefits and costs of implementing preregistration for qualitative research. The presentation summarizes the debates about whether and how preregistration will lead to greater transparency in qualitative research, explores the implications of preregistration for qualitative research, identifies some of the costs incurred in preregistering qualitative studies, describes the inaccurate assumptions about qualitative research that are repeatedly embedded in calls for preregistration, and identifies some likely, unintended consequences of adopting the same approaches employed or proposed for quantitative studies. Acknowledging the importance of greater transparency and reduced publication bias for all research, including qualitative studies, questions about transparency that qualitative researchers must urgently address are also suggested."} +{"text": "The World Health Organization (WHO) estimates that 466\u00a0million people experience moderate or higher levels of hearing loss and that this number could double by 2050 if the current demographic trends continue.Prevention of deafness and hearing lossFortunately, many of the causes that lead to hearing loss can be avoided through preventative public health actions. Those who experience hearing loss can benefit from early identification and intervention. Hearing aids, cochlear implants, use of sign language and assistive technologies are some of the available options to ensure that no one lives with unaddressed hearing loss. The 2017 World Health Assembly Resolution ,These challenges can be tackled through the integration of ear and hearing care into health systems as part of universal health coverage (UHC). In 2015, when the United Nations General Assembly adopted the sustainable development goals, WHO and its Member States committed to achieve UHC by 2030.\u2013,,,,This theme issue draws further attention towards this topic, highlighting the impact of unaddressed hearing lossWorld report on hearing, which will recommend a package of evidence-based interventions for improving ear and hearing care through health system strengthening.The theme issue sets the stage for the First Membership Assembly of the World Hearing Forum, which will take place this December at WHO headquarters in Geneva, Switzerland."} +{"text": "The new framework of resilient aging has gained its importance in recent years. This symposium provides new findings on resilience and health among the Chinese population. Using data collected among 430 Chinese older adults in Honolulu, the first presentation examines resilience as an explanatory mechanism linking neighborhood social environment and well-being. Results showed that neighborhood cohesion was positively related to psychological well-being and life satisfaction. Resilience contributed to a substantial portion of the associations. Using the same data, the second presentation examines the association between immigrant status and oral health related quality of life (OHQoL) and the moderating role of resilience. Findings showed that U.S.-born Chinese immigrant older adults had better OHQoL than their foreign-born Chinese American counterparts. Resilience was positively associated with OHQoL for the former but not for the latter. The third paper presents findings from the same dataset along with a survey of 800 older adults in Wuhan, China. The positive relationship between attitudes towards aging and self-rated health (SRH) was found to be moderated by resilience such that higher levels of resilience weakened this association substantially. Both the positive focal relationship and the moderating effect appeared to be stronger among participants in Honolulu. Using both datasets, the fourth paper investigates patterns of intergenerational transfer and their relationships with SRH as well as the meditating effect of resilience. Findings highlighted the beneficial health effects of receiving emotional support from adult children as well as the mediating role of resilience for older females in both study sites."} +{"text": "Newborn stem cell banking began with the establishment of cord blood banks more than 25 years ago. Over the course of nearly three decades, there has been considerable evolution in the clinical application of stem cells isolated from newborn tissues. The industry now finds itself at an inflection point as personalized medicine and regenerative medicine continue to advance. In this review, we summarize our perspective on newborn stem cell banking in the context of the future potential that stem cells from perinatal tissues are likely to play in nascent applications. Specifically, we describe the relevance of newborn stem cell banking and how the cells stored can be utilized as starting material for the next generation of advanced cellular therapies and personalized medicine. In September of 2018, the umbilical cord blood transplant and newborn stem cell banking communities celebrated the 30th anniversary of the first hematopoietic stem cell (HSC) transplant using cord blood as a graft for a patient with Fanconi\u2019s anemia. The successful demonstration that cord blood is capable of reconstituting a patient\u2019s blood and immune system, coupled with the confirmation that cord blood can be cryopreserved for later use, led to the establishment of cord blood banks, and thus the newborn stem cell banking industry, in the early 1990s [It is widely recognized that additional perinatal tissues routinely discarded as medical waste contain nonhematopoietic cells with potential therapeutic value. For example, mesenchymal stromal cells (MSCs) can be isolated from placental tissue, umbilical cord tissue, and amniotic fluid. With the exception of amniotic fluid, which is obtained during an elective amniocentesis, these tissues are collected in a noninvasive procedure following birth of the neonate and would otherwise be discarded. Concomitant cryopreservation of multiple newborn tissues from the same donor has beeCertain maternal and neonatal parameters associated with cord blood quality, such as gestational age and birth weight, can be used by public banks to optimize donor selection in an effort to increase likelihood of utilization and as part of managing costs associated with tissue procurement . The celMore than 40,000 hematopoietic stem cell transplants using cord blood have been performed during the last three decades . In thisThere is also considerable interest in exploring cord blood as a therapeutic intervention in nonhematopoietic indications. In the mid-2000s, researchers began investigating cord blood in acquired neurological indications. Pilot and clinical trials enrolling pediatric patients with conditions such as cerebral palsy, autism spectrum disorder, and acquired hearing loss have confirmed the safety, and in some patients evidence of efficacy, of administering minimally manipulated cord blood cryopreserved in an autologous setting ,17,18,19A recent review of clinical trials employing perinatal tissue-derived products in advanced cell therapy identified 281 clinical studies registered between 2005 and 2015, and acquired neurological conditions or disorders was the second most common category of diagnosis behind trials in hematology or oncology with manipulated cell types . Of moreCryopreserved perinatal tissues are also being explored for their capacity to augment established uses of cord blood in traditional transplant medicine. For example, monocytes isolated from cryopreserved cord blood are used to manufacture a cell therapy product aimed to augment cord blood transplantation in the setting of inherited demyelinating conditions of the central nervous system . FurtherInterest in exploring cryopreserved newborn stem cells in regenerative applications has continued to increase over the past decade. The mechanism by which the therapeutic cells exert their effects in many of these exploratory studies is theorized to involve immunomodulation and paracrine-based signaling facilitating endogenous tissue repair rather than direct cell replacement or engraftment. The evolving landscape of clinical trials in regenerative medicine utilizing umbilical cord tissue, placental tissue, and minimally manipulated cord blood has been recently reviewed in depth by others, as have approaches to ex vivo cord blood expansion and efforts to improve outcomes following cord blood stem cell transplantation in adult recipients for cord blood. The public banking community has repeatedly pointed out that the process for achieving licensure is both onerous and costly, negatively impacting the costs of collecting, storing, and distributing cord blood units . One facWith a positive safety profile to date, the use of cord blood cells in regenerative medicine applications appears poised to increase the number of clinical settings in which the cells can be considered as part of a therapeutic intervention, as discussed above. This rapid evolution for potential indications outside of hematopoietic reconstitution has the potential to greatly influence the utilization rate of cord blood units from the public inventory. Each bank, though, would need to be approved for releasing cord blood units for new indications by performing the requisite clinical studies, which public banks have neither the resources nor the commercial initiative to do. Private cord blood banks are indirectly affected by this issue due to a lack of comparability studies. To our knowledge, only one controlled study in a regenerative medicine application has directly compared infusion of autologous cord blood to allogeneic unrelated cord blood from a public cord blood bank . Should Commercial institutions in adjacent business areas are likely to influence the near-term financial sustainability of public cord blood banks. Companies such as Gamida Cell Ltd, Fate Therapeutics, and others are focused on expansion technologies and approaches for improving the efficiency of homing and engraftment of cord blood stem cells. While applicable to both private and publicly banked units, public banks are likely to benefit most from successful clinical translation if these technologies increase utilization of units that would otherwise fail to meet cell dose thresholds. Nohla Therapeutics is taking a different approach by developing off-the-shelf, ex vivo expanded products from cord blood units to provide a short-term hematopoietic bridge following transplant of an unmanipulated cord blood graft. If successful, Nohla\u2019s product could help improve outcomes in patients undergoing a cord blood transplant. These technologies address current challenges in cord blood hematopoietic stem cell transplantation and their success could increase utilization rate from the public inventory, which in turn would help bolster the financial health of public banks. Public cord blood banks also have the opportunity to diversify revenue streams through creative outsourcing of inventory that is unlikely to be used as a graft for hematopoietic reconstitution. Blood banks collecting and distributing peripheral blood for use in transfusion medicine have already begun a similar shift as they look to capitalize on ancillary material or products that have expired. Likewise, the increasing demand for human platelet lysate as a supplement for use in routine cell culture has led to a niche market for blood banks. Public cord blood banks are exploring the applicability of donated cord blood in nascent technologies, such as chimeric antigen receptor T-cell (CAR-T) products. Importantly, a single cord blood unit is often sufficient for CAR-T, and for these and other similar immunotherapies, the cells are only required for a short time. Because units are HLA-typed at the time of processing, there is also a great deal of interest in utilizing inventory from public cord blood banks to create a haplobank of HLA-homozygous induced pluripotent stem cells (iPSCs); proof-of-concept studies have demonstrated the feasibility of this approach for populations in various geographical locations . Private newborn stem cell banks are also interested in exploring the application of cord blood in the evolving field of immunotherapies and more than minimally manipulated products. Clinical studies initiated in the mid-2000s sought to determine the potential of nonmanipulated cryopreserved cord blood in Type 1 diabetes. Consistent with the results of clinical trials in acquired neurological injuries, autologous infusion of cord blood in patients with Type 1 diabetes was confirmed to be safe and feasible both alone and when administered alongside daily vitamin D and docosahexaenoic acid ,30. InveThere is increased clarity on potential application of privately banked stem cells outside of the established uses in HSC transplants. Early recognition of the interest and anticipated utilization of MSCs across a variety of clinical settings garnered the interest of the private banks as an opportunity to leverage infrastructure and technology platforms to provide storage of umbilical cord tissue as a service under the collection and manufacturing model already established as part of private cord blood banking. Similarly, private institutions led the industry in the banking of placental tissue. Although efforts are underway , publicFor cord blood, clinical outcomes of transplants are influenced by the graft characteristics, including nucleated cell dose, stem cell dose, and HLA match, while the impact of the volume reduction processing technology used in preparing cord blood for cryopreservation is less evident, assuming that units selected meet appropriate criteria for the individual recipient and appropriate methods for thawing are followed ,37. WhilThe proliferation of private cord blood banks in the early 2000s led to market saturation in many geographical regions. Mergers and acquisitions subsequently led to consolidation in the private banking industry. It is estimated that over the last decade, the number of European banks decreased by one-third through consolidation activity . The merHybrid banks were originally met with resistance from the banking community based on perceived conflicts of interest for the donor. More recently, there has been greater acceptance of the hybrid model, with several institutions demonstrating that private banking can be used to offset costs for altruistic public donations without deterring from the donor pool. Companies such as StemCyte International have found stability in the consumer market while also providing donated cord blood units for use in unrelated recipients. As evidenced by the acquisition of the hybrid bank CORD:USE by the private bank Cryo-Cell International, mergers and acquisitions also present an opportunity to enter into new market sectors, such as public banking, while limiting the potential financial risks of de novo development. Some industry activities meanwhile capitalize on infrastructure expertise and capacity for biobanking as a logical extension of services. For example, Cord Blood Registry was acquired and merged with California Cryobank. The newly established California Cryobank Life Sciences Platform provides newborn stem cell banking alongside reproductive tissue services. Celularity Inc., a spinout of Celgene, is developing placenta-derived allogeneic immuno-oncology and regenerative products while offering cryopreservation of umbilical cord and placental tissues through the private arm LifeBank USA. Celularity also acquired CariCord, a private cord blood bank affiliated with ClinImmune laboratories, presumably in part to augment biosourcing capabilities for future placenta-derived products. Within the United States, the health care system is critical to long-term economic stability for newborn stem cell banking. Health care coverage of the costs associated with collection and cryopreservation of newborn tissues for future use and establishing insurance reimbursement once clinical efficacy and cost calculations are established in regenerative medicine applications would provide for economic incentives for all invested parties and help the industry meet the increasing demand for precision health care. Outside of establishing legislation mandating education by health care providers for expecting families, efforts to lobby Congress have thus far been unsuccessful. The Cord Blood Association, a nonprofit organization comprised of stakeholders across the banking industry, advocates on behalf of the community to advance relevant legislation and modifications to the regulatory framework and may be a more effective approach than previous efforts. Emerging technologies have the potential to influence the direction of newborn stem cell banking; both public and private banking institutions will need to identify a strategic path in order to position themselves favorably for the long term. Public and private banks are actively exploring ways to augment their model from providing storage of a minimally manipulated cellular product to one that recognizes the promise in companion products and provides starting material for downstream applications . It is a"} +{"text": "There has been growing interest in the use of community-based participatory research (CBPR) in gerontology. Photovoice, one of several qualitative methods utilized in CBPR, pairs participants with photography to identify and represent issues of importance. This paper explores photovoice as a tool for meaning making and preserving a \u2018sense of place\u2019 in a gentrifying context in New York City. Older residents describe pending neighborhood displacement due to gentrification using photographs. Using these themes and a range of visual media, older adults mobilize preservation and resistance efforts to gentrification. The paper concludes with implications and directions for future research."} +{"text": "With the increasing occurrences of disasters throughout the world, researchers, communities, and organizations have become interested in how the use of social networks during and after a disaster can ease the psychological recovery of older adults who are affected by traumatic disaster events such as hurricanes and wildfires. This symposium will focus on the power of social networks and highlight the importance of preparedness, informal and formal groups, and interventions to assist recovery of older adults. First, Dr. Judith Phillips will present data on how informal and formal social network groups affected the psychological well-being of older adults who experienced exposure to multiple wildfires. Second, Dr. Denise Eldemire-Shearer will address how both formal and informal social network groups in Jamaica are informed and mobilized to provide support to older adults on the island during hurricanes and other water-related disasters. Third, Dr. Lisa Brown will introduce the Skills for Psychological Recovery intervention and provide an overview and modifications needed when using with older adults; she will also demonstrate an exercise. Fourth, Dr. Debra Dobbs will present themes examining the role of community engagement in hurricane preparedness which were gathered from focus groups and interviews with assisted living administrators in Florida. Lastly, Dr. Mary Helen McSweeney-Feld will address how voluntary organizations active during disasters aid older adults with disaster relief efforts. Together these presenters will provide evidence of the power of various social networks that will lessen the vulnerability of older adults after disasters."} +{"text": "The psychological construct of generativity encompasses a person\u2019s motivation to leave a legacy for future generations by investing in acts that will outlive the self . Lewis and Allen (2017) outlined the importance of generativity within AN cultures (caring for the future of our youth) and expanded Erikson\u2019s western-based definition by adding the indigenous cultural generativity component to describe and incorporate Alaska Native specific cultural elements. These culturally based elements involve giving back to family and community including guidance and teaching of future generations . Generativity within western societies accentuates independent achievements and successes more than the notion to care for future generations. This study is part of a larger community-based, exploratory, study between researchers and communities to explore successful aging that included 42 Alaska Native Elders in the Norton-Sound subregion, 21 Alaska Native Elders from the Aleutian Pribilof Islands, and 26 Elders from the Bristol Bay region. Qualitative interviews explored the participant\u2019s life, influences on aging well, and their aging process. Thematic analysis was used to investigate the impact of generativity on successful aging was used to establish codes and main themes based on the three different cultural regions of Alaska. The findings suggest that generativity promotes successful aging. Elders who live in communities that promote community engagement, support family and school activities, and maintain and/or revitalize culture and traditions reported increased emotional well-being. Results can guide communities to incorporate or support cultural activities that promote generative activities and meaningful engagement which fosters successful aging."} +{"text": "Sarcoptes scabiei in all forms of parasite included adult female, nymph stage and eggs. One of the patients spouse was also infested by Sarcoptes and appeared mild clinical symptoms. The disease was diagnosed with Norwegian scabies and the patients were successfully treated with topical 5% permethrin ointment for two weeks continuously. Overall, Norwegian scabies should be considered in immune- compromised patients with contaminated areas.Norwegian scabies (hyperkeratosis scabies) is an acute form of skin disease seen in immune-compromised patients. This study aimed to describe two cases of Norwegian scabies from Ahvaz, southwest of Iran in 2015. Two patients included a 55 year old man with renal transplant history and a 49 yr old man with diabetic mellitus and autoimmune disease, complained of dermatitis lesions and itching with sever hyperkeratosis, several macula and papules on neck and armpits for one-month duration were referred to a Iran Zamin Medical Diagnostic Laboratory in Ahvaz, Southwestern Iran in 2015. Patients were referred for fungal examination. Scraping from the crusted lesions of skin and slide preparation with 20% KOH was done. Microscopic examination presented that huge infestation of Sarcoptes scabiei var. hominis belonged to Stigmata order. Sarcoptes mites\u2019 barrow skin and lay several eggs in the canals and then nymph stages leave the canals and appear in surfaces for few days. In this time they can easily be transmitted to other persons who have close contact with infected one.Human scabies is caused by an ectoparasite mite called Sarcoptes mite for rapidly distribution in body and presents a generalized infestation. Clinical signs included hyperkeratosis and skin crusting, severe itching and forming secondary infection that causes septicemia and mortality in untreated patients have been completely observed by the authors."} +{"text": "An accurate understanding of one\u2019s abilities and limitations allows adaptive response to the challenges that are faced in daily life. However, older adults may over or under estimate their actual abilities. The Daily Balance Project examined the intraindividual dynamics of older adults\u2019 perceived balance with objective measures of balance and physical activity. For 30 consecutive days, following a comprehensive fall risk assessment, 20 older adults rated their balance confidence at that moment and then performed five standardized balance assessments measured via smartphone accelerometer held to their chest. Physical activity was measured with an activity monitor. Baseline measurements of fall risk differentiated the extent of intraindividual variation and co-variation of balance and physical activity. For some participants, actual and perceived balance became more closely aligned as the study progressed. The implications of the findings for life-span perspectives on aging and fall prevention are discussed."} +{"text": "People with dementia (PwD) receive most of their health care in primary care, yet timely recognition and optimal management of dementia in that setting continues to be challenging. Implementation of primary care medical home models in the Veterans Health Administration (VHA) holds promise for improving quality and coordination of dementia care through interprofessional collaboration. Integrating behavioral health providers (BHPs) into primary care may help to support the care of people with dementia and their families. However, most integrated BHPs have a generalist training background and likely require professional education to address the unique needs of patients with dementia. We will describe findings from a national VHA education needs survey of integrated BHPs and an in-depth qualitative study examining primary care for PwD in two large VHA healthcare systems. We will discuss how geriatric experts can serve as trainers to address current gaps in primary care of PwD."} +{"text": "Perhaps because the public is not well-versed on the biological and medical facts of dementia , or the life experiences and capabilities of persons living with dementia , dementia is one the most feared and stigmatized terminal illnesses , typically resulting in social isolation . Similar to personal dementia fear , dementia worry has been associated with suicide ideation , which is a predictor of accepting attitudes toward physician-assisted suicide . Findings from the development and testing of a conceptual model of social comfort indicated that people with higher levels of PBK had higher levels of social comfort towards persons with dementia . The present study is a secondary analysis of data obtained from Wisconsin residents through an online platform and community outreach efforts to examine whether individuals with higher levels of PBK have lower levels of PDF. A hierarchical linear regression revealed that PBK and BK were significant predictors of PDF . However, when controlling for age and knowing a friend or family member with dementia , only PBK remained a significant predictor . Results suggest that enhancing PBK through interactions with people living as well as possible with dementia could reduce PDF."} +{"text": "Obligately asexual organisms tend to occur at higher altitudes or latitudes and occupy larger ranges than their obligately sexual relatives\u2014a phenomenon called geographical parthenogenesis. Some facultatively parthenogenetic organisms that reproduce both sexually and asexually also exhibit spatial variation in reproductive mode. Theory suggests that sexual conflict and mate limitation can determine the relative frequency of sex in facultative parthenogens, but the effect of these dynamics on spatial distributions is unknown. Here, we use individual-based models to investigate whether these dynamics can generate local differences in the reproductive mode in a facultatively parthenogenetic metapopulation occupying an environmental gradient. We find that selection for resistance and high fecundity creates positive epistasis in virgin females between a mutant allele for parthenogenesis and alleles for resistance, resulting in female-biased sex ratios and higher resistance and coercion towards the productive \u2018core\u2019 of the metapopulation. However, steeper environmental gradients, which lead to lower density and less mating at the \u2018edge\u2019, generate female bias without promoting coercion or resistance. Our analysis shows that local adaptation of facultatively parthenogenetic populations subject to sexual conflict and productivity gradients can generate striking spatial variation suggesting new patterns for empirical investigation. These findings could also help to explain the rarity of facultative parthenogenesis in animals.This article is part of the theme issue \u2018Linking local adaptation with the evolution of sex differences'. The pDespite this predicted advantage, the evolution of parthenogenetic forms within obligately sexual lineages rarely results in the complete extinction of sex. More frequently, sexual and asexual relatives coexist within the same range while occupying distinct geographical areas or ecological niches. For example, asexuals tend to have larger ranges or more marginal distributions at higher latitudes or altitudes than their sexual counterparts ,5, and oper se could provide advantages that drive geographical differences in reproductive mode )xpanding . Interesxpanding , suggestaltitude , but malaltitude . In JapaTimema stick insects 31]). WheWe test these predictions using an individual-based model that simulates the invasion of a sexual metapopulation by facultatively asexual mutants across a range of ecological and genetic conditions. We investigate how sexual conflict interacts with other factors associated with geographical parthenogenesis\u2014including colonization via uniparentality, ecoclines in productivity and probability of dispersal\u2014to drive spatial differences in facultatively parthenogenetic populations. Specifically, we ask what conditions and dynamics lead to the evolution of female-biased sex ratios that result from higher rates of facultative parthenogenesis at either the range core or edge, and whether female bias is associated with higher levels of resistance and/or coercion.2.(a)n \u00d7 n patches each, where n = 20 and each patch possesses no more than one individual) arranged in a row with explicit boundaries to allow edge effects , and ith resistance allele carried by a female . The relative values of these phenotypes determine whether mating takes place . Our use of a polygenetic architecture is motivated by the observation that coercion and resistance phenotypes frequently comprise numerous morphological, physiological and behavioural characteristics probably controlled by multiple loci )P generated comparable results (compare P allele and to clearly determine the contribution of resistance to spatial distributions of parthenogenesis. In itself, this polygenic architecture probably had little effect on selection for parthenogenesis in our model, but larger effects could occur if resistance loci reside on multiple chromosomes. We also assumed that resistance and coercion traded off against reproductive success in similar ways for each sex. Assuming a different cost structure might alter expected outcomes because larger costs of resistance might constrain the evolution of high resistance genotypes and therefore limit rates of parthenogenesis.We assumed that the mutant allele for facultative parthenogenesis arose in a large proportion of the core population and at a single point in time in order to limit the effects of genetic drift. However, although such a high rate of mutation is biologically improbable, the initial frequency of the allele did not appear to affect evolutionary outcomes as very low and very high initial frequencies of Previous work suggests that linkage disequilibrium between resistance alleles and alleles for parthenogenesis, generated by epistasis for fitness between resistance and the capacity for parthenogenetic reproduction, could play an important role in the establishment of parthenogenetic populations . ResultsFacultatively parthenogenetic animals offer valuable opportunities to understand the factors that contribute to the maintenance of loss of sexual reproduction, and may therefore hold clues to resolving the paradox of obligate sex . But why"} +{"text": "Recent efforts to better understand voluntarism as fundamental to how rural communities are meeting the challenges of population ageing have highlighted ageing rural volunteers, and the attendant burden of older voluntarism, as key issues for ageing in place of rural residents and ageing rural community sustainability. Drawing on a case study of a volunteer-based rural library in Ontario, Canada, this study examines the experiences of older volunteers, the challenges of sustaining volunteer programs, and the implications of older voluntarism for rural community development. Findings from interviews and focus groups with library volunteers, staff, board members and community stakeholders demonstrate how the experiences of older volunteers and challenges of older voluntarism affect rural community development. The results reveal how participation, well-being, conflict and territoriality associated with older voluntarism contributes to \u2018contested spaces of older voluntarism\u2019 whereby older volunteers negotiate their rights and responsibilities associated with ageing and volunteering in rural communities."} +{"text": "The additional tissues examined include cerebral spinal fluid, intestines and lymph nodes. We provide a comparison contrast analyses of the data across anatomical compartments tested in these studies to reveal where peripheral blood analyses reflect outcomes in other tissues as well as where the data reveal differences between tissue outcomes. We also summarize the current knowledge on these topics and highlight key open questions that need to be addressed experimentally to move the HIV cure research field closer to the development of an intervention strategy capable of eliciting long-term antiretroviral free remission of HIV disease.HIV reservoirs persist in infected individuals despite combination antiretroviral therapy and can be identified in secondary lymphoid tissues, in intestinal tissues, in the central nervous system as well as in blood. Clinical trials have begun to explore effects of small molecule interventions to perturb the latent viral infection, but only limited information is available regarding the impacts of HIV cure-related clinical interventions on viral reservoirs found in tissues. Of the 14 HIV cure-related clinical trials since 2012 that have evaluated the effects of small molecule interventions Despite years of successful combination antiretroviral therapy (cART), viral replication rebounds almost inevitably in all HIV infected individuals upon cART cessation . This istoll-like receptor (TLR) agonists] and examining HIV persistence in tissues. Specifically, we review the impacts of such interventions on mechanisms that regulate HIV persistence in vivo as well as the immunological and virological impacts of these interventions in tissues other than peripheral blood. Other HIV cure related interventions including gene therapy approaches, stem cell transplants, antiretroviral intensification, therapeutic vaccines and broadly neutralizing antibody infusions have recently been reviewed elsewhere , panobinostat or the TLR9 agonist MGN1703 , 2019a. ex vivo harboring an HIV provirus that matched plasma-derived rebound viruses isolated following analytical treatment interruption (in vivo in HIV infected individuals.While the direct s clones , 2018. Trruption . Thus, tWe recently examined the clonality of persistent virus in lymph nodes and compared these sequences to replication competent viruses that rebounded during an analytical treatment interruption . We examin vivo in the setting of cART. Advancement of the HIV cure research agenda will benefit from a continued push to seek detailed explorations of infected cells both derived from peripheral blood as well as from organ sources. Thus, there is strong impetus to continue examining multiple organs in such trials.Understanding the regulation of HIV reservoir persistence is a high priority in the HIV cure research field. Since 2012, 14 HIV cure-related clinical trials have been published where the objective was to test the impacts of small molecule interventions designed to either cause infected cells to become visible to the immune system for clearance or to improve the ability of the immune system to clear infected cells. These clinical studies have yielded new insights into the effects of the interventions on the regulation of HIV persistence, particularly related to clonal populations of latently infected cells. In four of the trials, efforts were made to define the impacts of the respective intervention in the central nervous system, intestinal tissues and/or lymph nodes. Data from these four trials reveal key similarities between the peripheral blood and the organs. Furthermore, they highlight that observations made in peripheral blood are not always fully representative of the impacts made by interventions in the organs which also harbor persistent HIV reservoirs. Such differential responses highlight the importance of defining the impacts of curative strategies in all relevant organ systems including those reviewed herein as well as other applicable tissues such as spleen and bone marrow. With improved methods for analyzing tissue reservoirs, investigators will begin to overcome the limitations in studies that are due to the extreme rarity and heterogeneity of HIV infected cells PD wrote the first draft the manuscript. OS and MT helped to wrote the manuscript. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "It is hypothesized that older adults are more influenced by environmental factors due to reduced tolerance to stressors and greater cumulative exposure. The role of environmental factors in brain and cognitive aging, specifically, has not been well studied. In this symposium, we highlight novel work at the interface of the environment and the brain in aging. The presentations assess varying aspects of the environment/brain interface within three cohorts. Two of the presentations focus on the environment as a risk factor for brain or cognitive aging. Sara Godina will present analyses of neighborhood socioeconomic status and neuroimaging markers of brain atrophy within the Health ABC Study, with the aim of understanding documented associations of neighborhood socioeconomic status with cognitive function. Jessica Finlay will present data from the REGARDS study linking weather conditions with cognitive changes. Climate influences social and physical activities and could thereby, impact cognitive aging. The brain also serves to process and integrate environmental data in order to direct behaviors in an adaptive manner. Two of the presentations assess how cognitive aging may impact individuals\u2019 interactions with the environment. Using residential histories of participants in the Cardiovascular Health Study, Jonathan Platt will explore how cognitive trajectories change in relation to changes in residence. These analyses will demonstrate how residential changes may be either supportive or detrimental to cognitive aging. Finally, Andrea Rosso will present data from the Health ABC that demonstrates how cognitive aging may determine the vulnerability of older individuals to environmental influences on mobility declines."} +{"text": "Also, we discuss the pertinent literature related to the state of the art of drug incorporation of NPs with antibacterial properties inside TNTs, along with the promising future perspectives of in situ drug delivery systems aggregated to biomedical implants.The fast evolution of surface treatments for biomedical implants and the concern with their contact with cells and microorganisms at early phases of bone healing has boosted the development of surface topographies presenting drug delivery potential for, among other features, bacterial growth inhibition without impairing cell adhesion. A diverse set of metal ions and nanoparticles (NPs) present antibacterial properties of their own, which can be applied to improve the implant local response to contamination. Considering the promising combination of nanostructured surfaces with antibacterial materials, this critical review describes a variety of antibacterial effects attributed to specific metals, ions and their combinations. Also, it explains the TiO Biomedical implants have their most critical moment of integration to living tissues when their biomaterial first contacts the human cells and local microorganisms , which substantially alter the physico-chemical properties of the implant surface making it friendlier to human bone cells and promoting potential antibacterial properties , presenting potential properties than B. subtilis (gram-positive bacteria). Conversely, Yoon et al. not only to their TNTs but into their coatings as well. Chitosan coatings incorporated with GFs presented better results in terms of cell adhesion, bone cell proliferation and increase in the expression of bone formation markers in vitro (Abarrategi et al. The combination of loaded TNTs with a drug-incorporated surface coating might represent an attractive possibility for in loco treatment of a failing and/or compromised implanted device. However, studies investigating this possibility are scarce and, when available, still at early stages, and so far there is no single definition in terms of the best surface coating material or the ideal drug to be implemented for these purposes in vivo.One attempt to investigate the possibilities involving surface coating association with TNTs drug delivery system was related to late local antibiotic-release activation (Wang et al. In conclusion, the present overview critically analyzed the significant diversity of drugs, metals and NPs presenting antibacterial properties and their functionalization on TNTs surfaces, depicting a wide range of these potential metals and drugs used in biomedical implants and related advanced research regarding their biocompatibility and potential antibacterial effects.2 nanotubes surfaces show a large energy area for immobilization and subsequent functionalization of nanoparticles, preserving its biocompatibility and mechanical stability. Many strategies to incorporate NPs and drugs to implant surfaces have been presenting promising preliminary results in combating bacteria that cause infections in the human, and especially where biomedical implants may be placed.TiOIt has been suggested by some investigations that the drug delivery system applied to TNTs might be successful and has promising early results. Even though a large part of these reported studies represent in vitro evidence, the pathway for clinical trials involving concepts on the application of drug delivery TNTs has already been suggested, followed by more extensive cytotoxicity tests and in vivo observations to firstly ensure their biologic safety.The possibility of decreasing the application of systemic antibiotics usually associated with side effects to patients for an in situ usage seems to be one of these drug-loaded TNTs most advantageous properties, since their association with surface coatings may keep a drug and/or NP active for a long-term gradual release once needed. Further investigation in vivo should be performed to establish the proper advantages and efficacy linked to the in situ application of antibiotics in biomedical implants compared to systemic drug administration.Finally, the use of functionalized TNTs aiming a localized release of antibiotic drugs and bactericide NPs has presented promising early results and should be further explored aiming future medical applications. The possibilities related to local infection control may positively influence the outcome of a major biomedical problem related to implant loss and/or disfunction. With established protocols regarding adequate drug dose and production optimization, this technology can play an important role into further increase the clinical success of biomedical implants in the near future."} +{"text": "Chronic migraine is a highly disabling disease with a great impact on socioeconomic functioning and quality of life of migraine patients. Chronic migraine usually evolves from episodic migraine that gradually increases in attack frequency, supporting the view of migraine as a spectrum disorder. Pathophysiological mechanisms responsible for migraine chronification are not fully understood. Likewise episodic migraine, chronic migraine patients show widespread functional and structural alterations of cortical and subcortical pain-related brain areas. However, chronic migraine patients experience a more pronounced dysfunction of the pain inhibitory network and an increased sensitization of the central pain pathways, which might explain the higher susceptibility to migraine attacks. Imaging studies have highlighted that brain regions with a key role in migraine attack generation, like the pons and hypothalamus, might also be involved in migraine chronification. Whether brain alterations are biomarkers that predispose migraine patients to chronification or reflect adaptive or maladaptive responses to the increasing headache frequency is still a matter of debate. The central mechanisms of action of chronic migraine preventive treatments and imaging biomarkers that could predict patients' treatment response have also been explored. In this new era of migraine treatments, a better understanding of chronic migraine pathophysiology will pave the way for the development of new improved treatments specifically designed for chronic migraine patients. Chronic migraine is a highly disabling disease. Relative to episodic migraine, patients with chronic migraine have greater headache-related impact on socioeconomic functioning and worse quality of life . AccordiPathophysiological mechanisms responsible for migraine chronification are not fully understood. Patients with chronic migraine might have a lower sensory threshold and an increased susceptibility to migraine attacks . CentralPain experience is a complex process involving sensory, affective, and cognitive brain networks. Similar to previous findings in episodic migraine patients , an alteSeveral studies , 30, 34 Whether these functional and structural alterations are the consequence of the recurrence of headache attacks or might predispose to chronic migraine is still a matter of debate. Some studies demonstrated functional , 20 and Dynamic functional , 26 and Quantitative MRI techniques have shown increased iron deposition in the periaqueductal gray, red nucleus, and basal ganglia in migraine patients and patients with chronic daily headache \u201340. A hiA further unanswered question is whether neuroimaging alterations are common to episodic and chronic migraine patients or are specifically involved in migraine chronification. There is evidence showing a more pronounced dysfunction of the pain inhibitory and thalChronic migraine is also associated to more extensive brain structural alterations. Schwedt and colleagues reportedIn migraine patients, the perception of the headache pain can be exacerbated by the exposure of lights. There is evidence showing that photic signals coming from the retina can converge on thalamic trigeminovascular neurons that project to cortical areas involved in the processing of pain and visual perception. Thus, supporting the link between the visual and trigeminal pain processing system . InteresAlthough our understanding of the pathophysiology of migraine has progressed over the last years, where exactly migraine attacks originate is still an unresolved question. Several studies demonstrated a selective activation of the dorsal pons during spontaneous , 44 and Recent MRI studies have pointed the attention to the role of the hypothalamus in migraine attack generation. Positron emission tomography and funcDifferent regions of the hypothalamus seem be involved in the onset of the migraine attack and in migraine chronification. Chronic migraine patients with and without medication overuse showed a selective increased activity of the anterior hypothalamus during trigeminal painful stimulation and in aRelative to episodic migraine, an increased activation of the hypothalamus seems to facilitate the recruitment of cortical areas involved in pain processing in chronic migraine patients .In conjunction with functional alterations, structural plasticity of the anterior hypothalamus has been demonstrated in patients with chronic migraine. A hypothalamic volume lower than 1.43 ml had a good diagnostic accuracy for chronic migraine with sensitivity of 81% and specificity of 100% .Imaging techniques can provide new insights into the central mechanisms of action of treatments commonly used for chronic migraine. A positron emission tomography study showed sNow that new mechanism-based treatments specific for migraine are available a better prediction of treatment response might facilitate the selection of the most appropriate treatment for each patient. Chronic migraine patients who responded to OnabotulinumtoxinA treatment, as evidenced by reversal from a chronic to an episodic state, had distinct patterns of morphometric and functional alterations in pain processing areas compared to those patients who did not respond . The ideSignificant advances in our understanding of chronic migraine pathophysiology have been made over the last years. Neuroimaging findings support the view that migraine is a spectrum disorder, with clinical and pathophysiological features that can progress over time. Chronic and episodic migraine share similar functional and structural alterations in brain regions implicated in the generation of the migraine attack and in pain processing. However, chronic migraine patients experience a more pronounced dysfunction of the pain inhibitory network and an increased sensitization of the central pain pathways, which might explain the higher susceptibility to migraine attacks. Whether brain alterations are biomarkers that predispose migraine patients to chronification or reflect adaptive or maladaptive responses to the increasing headache frequency is still debated. Longitudinal studies including large sample size of patients with episodic and chronic migraine are warranted. Future studies combining multimodal data, such as functional MRI, structural MRI and electroencephalographic data, might help us to achieve a better understanding of chronic migraine pathophysiology. In the future, imaging patterns that predict whether an episodic migraine patient will evolve to a chronic form should be identified. This might lead to an early prevention of migraine transformation. In this new era of migraine treatments, a better understanding of chronic migraine pathophysiology will pave the way for the development of new improved treatments specifically designed for chronic migraine patients.MF and RM contributed to the study concept and drafting/revising the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Racial and ethnic inequities in health among older adults in the U.S. are well documented. A substantial amount of the health literature focuses on physical and mental disparities; however, less research has examined racial and ethnic differentials in subjective, self-rated health (SRH). Prior research has documented racial and ethnic inequities in SRH, though mechanisms by which these disparities occur are still largely unknown. One potential mechanism by which these disparities may arise is through unequal access to psychosocial resources through variability in social networks. Utilizing data from the 2006 Health and Retirement Study (HRS) along with the 2006 HRS Psychosocial and Lifestyle Questionnaire, the current study seeks to explore racial and ethnic differentials in SRH from a social network perspective. Ordinal logistic regression is used to predict SRH by race and Hispanic ethnicity potentially mediated by possession and number of friends, frequency of contact with friends, and psychosocial and subjective well-being. Results indicate that older black adults are less likely to rate their health in a higher category of SRH than older white adults, and this relationship is not significant for other racial groups and Hispanics. Additionally, psychosocial and subjective well-being and frequent written-communication with friends are found to significantly predict better SRH. The results suggest that feeling well mentally is crucial for SRH, but equally important is regular contact with friends. Further research should employ more robust measures of social networks to elucidate the role that network composition plays in predicting SRH for racial and ethnic minorities."} +{"text": "Aboriginal and Torres Strait Islander peoples suffer higher rates of food insecurity and diet-related disease than other Australians. However, assessment of food insecurity in specific population groups is sub-optimal, as in many developed countries. This study tailors the Healthy Diets ASAP methods protocol to be more relevant to Indigenous groups in assessing one important component of food security. The resultant Aboriginal and Torres Strait Islander Healthy Diets ASAP methods were used to assess the price, price differential, and affordability of healthy (recommended) and current diets in five remote Aboriginal communities. The results show that the tailored approach is more sensitive than the original protocol in revealing the high degree of food insecurity in these communities, where the current diet costs nearly 50% of disposable household income compared to the international benchmark of 30%. Sixty-two percent of the current food budget appears to be spent on discretionary foods and drinks. Aided by community store pricing policies, healthy (recommended) diets are around 20% more affordable than current diets in these communities, but at 38.7% of disposable household income still unaffordable for most households. Further studies in urban communities, and on other socioeconomic, political and commercial determinants of food security in Aboriginal and Torres Strait Islander communities appear warranted. The development of the tailored method provides an example of how national tools can be adapted to better inform policy actions to improve food security and help reduce rates of diet-related chronic disease more equitably in developed countries. Poor diet is now the major preventable risk factor contributing to the burden of disease globally . In AustFew Australians <4%) consume diets consistent with the Australian Dietary Guidelines (ADGs) % consume. The conGood nutrition is underscored by food security. This is when \u201call people, at all times, have physical, social and economic access to sufficient, safe and nutritious food that meets their dietary needs and food preferences for an active and healthy life\u201d . Food seOne specific barrier to food security in Australia is believed to be the relative expense of healthy foods. This is particularly the case, among low socioeconomic groups ,15,16,17However, past food price surveys in Australia have applied a wide variety of \u2018food basket\u2019 costing tools and methods and resuThe Healthy Diets ASAP methods protocol was developed to assess, compare and monitor the price and affordability of healthy and current diets among the general population in Australia ,23. The In addition to application at international and national levels, the \u2018optimal\u2019 approach of the INFORMAS diet price and affordability framework has the The Healthy Diets ASAP methods protocol for application with the Australian population as a whole has been reported in detail elsewhere . The proPart one of the Healthy Diets ASAP methods protocol covers the development of two diet pricing survey tools. These are the current diet pricing tool and the healthy (recommended) diet pricing tool. The current diet pricing tool comprises the mean fortnightly intake of specific foods and drinks reported in the AHS 2011\u20132013, expressed in grams or millilitres, by each age/gender group corresponding to the four individuals comprising a reference household in the AHS 2011\u20132013 . The amoIn the second part of the Healthy Diets ASAP methods protocol pertaining to household income, median household income is sourced from national Australian census data which provide a total (gross) amount per household per week (i.e. before taxation). To estimate household income at time points between the five-yearly census, national wage price indexes (published quarterly) are applied .The indicative low (minimum) income for the household is calculated from minimum wage and welfare payments provided by the Department of Human Services ,31. A seAffordability of the healthy and current diets for the reference household is determined by comparing the cost of each diet with the median (gross) household income and with the indicative low (minimum) disposable income of low income households per fortnight. Internationally, a benchmark of 30% of income has been used as a cut-off point to indicate affordability of a diet ,21.The aim of this study was to modify and test the Healthy Diets ASAP methods protocol to be more relevant to the Aboriginal and Torres Strait Islander population. It developed methods and tools to assist others to apply the approach in order to compare the price, price differential and affordability of healthy (recommended) and current diets of Aboriginal and Torres Strait Islanders living in different locations with other population groups in Australia.It was not necessary to amend the Healthy Diets ASAP healthy (recommended) diet pricing tool to adapt the Healthy Diets ASAP methods protocol for application with Aboriginal and Torres Strait Islander groups as the Australian Dietary Guidelines already include culturally-appropriate and commonly available food and drink options and are similar at broad food group level for both Aboriginal and Torres Strait Islanders and non-Indigenous people .However, the Healthy Diets ASAP current diet pricing tool required modification to reflect the mean intake of each relevant Aboriginal and Torres Strait Islander age and gender group in the National Aboriginal and Torres Strait Islander Nutrition and Physical Activity Survey component of the AHS 2011\u20132013 . This waIn relation to assessment of household income, it was not necessary to adapt the Healthy Diets ASAP methods protocol to determine the median (gross) household income in Aboriginal and Torres Strait Islander communities in remote areas as census data is reported for relevant Statistical Areas (SA2). However, assumptions regarding characteristics of the household members were reviewed in relation to any welfare and taxation policies specific to Aboriginal and Torres Strait Islander people and/or to those people living in remote locations in order to better reflect Aboriginal and Torres Strait Islander households living in remote areas for the calculation of indicative low (minimum) disposable income ,32. The Prices of food and drinks were collected in five community stores on the Anangu Pitjantjatjara Yankunytjatjara (APY) Lands of South Australia using thUnder the Healthy Diets ASAP pricing collection methods protocol, several discretionary food prices are collected from commercial premises outside of a supermarket, including for pizza, hamburger, beef pie and hot chips. As such premises were not available in the remote communities, relevant prices were collected from the store\u2019s hot takeaway section, or if not available, for frozen pizza, frozen hamburger and frozen pies, as these items were commonly heated by the purchaser in a microwave at the store for immediate consumption. Frozen potato chip prices were not collected however, due to the large price differential between a single serve of hot chips and the significantly larger bag of frozen chips, and the requirement for more complex cooking methods than microwaving. Alcohol prices were not collected as the communities are \u2018dry\u2019 and alcohol was not available for sale.Price data were double entered by ML into data entry and analysis Excel\u00a9 spreadsheets developed for the Healthy Diets ASAP methods protocol ,33. If tMedian (gross) household income data from the Community Profile for the APY Lands SA2 was tranThe QUT University Human Research Ethics Committee assessed this study as meeting the conditions for exemption from Human Research Ethics Committee review and approval in accordance with section 5.1.22 of the National Statement on Ethical Conduct in Human Research (2007); the exemption numbers are 1500000161 and 1800000151. All data were obtained from publicly available sources and did not involve human participants.The reported consumption ratio calculated by comparing the reported dietary intakes of each food group, and relevant components, by Aboriginal and Torres Strait Islanders with theThe reported consumption ratios were applied to calculate the amounts of foods and drinks comprising the Aboriginal and Torres Strait Islander Healthy Diets ASAP current diet pricing tool as presented in The amounts of foods and drinks comprising the Aboriginal and Torres Strait Islander Healthy Diets ASAP healthy (recommended) diet pricing tool are preThe Community Profile for the APY Lands SA2 states that the median weekly household income in 2016 was $AUD1150 and the average household contained 3.8 people . The AusThe method to determine the indicative low (minimum) disposable household income was modified to include in the underlying assumptions that theThe mean (\u00b1 standard deviation) cost of the healthy diet was $AUD827.63 (\u00b1 $42.24) in the five remote Aboriginal communities surveyed.The cost of the current diet in the five remote Aboriginal communities using the Healthy Diets ASAP methods protocol and Aboriginal and Torres Strait Islander Healthy Diets ASAP methods, and the difference between the two, are presented in Using the Aboriginal and Torres Strait Islander Healthy Diets ASAP methods, the cost of a healthy diet was 24% less than the cost of the current diet. If the original Healthy Diets ASAP methods protocol was used, the cost of the healthy diet was 16% less than the current diet.Using the Healthy Diets ASAP methods protocol, the proportion of the total cost of the current diet derived from discretionary foods and drinks was 56.5%. This figure was 62.0% when the Aboriginal and Torres Strait Islander Healthy Diets ASAP methods were used.The total cost of the current diet was $AUD66.97 per fortnight (7%) more expensive when the Aboriginal and Torres Strait Islander specific methods were used rather than the original Healthy Diets ASAP methods protocol for the whole population . The maiThe affordability of healthy diet and the current diets determined by both the Healthy Diets ASAP methods protocol and the Aboriginal and Torres Strait Islander Healthy Diets ASAP methods in five remote Aboriginal communities are shown in Food insecurity is a key factor contributing to the high double-burden of malnutrition experienced by Indigenous Australians . HoweverAdjustment of the whole-of-population Healthy Diets ASAP current diet pricing tool by the reported consumption ratio method, proved to be a simple, expedient method to customise the tool for application in remote Aboriginal and Torres Strait Islander communities, particularly as it did not require redevelopment of the original data collection tools. However, this method does rely on the availability of quality dietary (food and drink) intake survey data for both the whole population at the national level and for specific population groups, which may not always be available, even in developed countries .The total cost of the current diet was 7% more expensive when the Aboriginal and Torres Strait Islander specific methods were used rather than the original Healthy Diets ASAP methods protocol for the whole population. This was due to differences in the reported intakes of foods and drinks that contributed substantially to the current diet in Aboriginal and Torres Strait Islander groups compared with the broader Australian population. Major differences were seen for sugar-sweetened drinks contributing most (69%) of the additional expense, and reported intakes of fruit and vegetables (which were 30% less than the broader population) reducing the current diet costs by 19%, when determined by the Aboriginal and Torres Strait Islander Healthy Diets ASAP methods.While data on median (gross) household income of Aboriginal and Torres Strait Islanders specifically are not readily available, the use of median (gross) household income from the relevant 2016 Census data Community Profiles did provTesting demonstrated that it is feasible to apply the Aboriginal and Torres Strait Islander Healthy Diets ASAP methods stores in remote communities. However, further studies would be required to test utility of the approach in urban centres. Among other differences, remote community stores, stock a much smaller range of items than supermarkets in urban areas. In this study there were four instances where the listed food item in the pricing tool was unavailable in any size or brand. Each store outlet surveyed in the five remote communities operates as a general store selling fresh fruit, vegetables, meat, bread, frozen foods, pantry items, and other goods. Four of the stores also sold a range of hot takeaway food items. Some food items were available only in sizes much smaller than stated on the price collection data sheet; for example, plain yoghurt is listed as 1kg on the Healthy Diets ASAP food price data collection sheet, but was only available in 200g tubs in three of the five stores. This contributed to the high standard deviation in the cost of the food groups observed where larger items were missing, particularly the milk, yoghurt and cheese food group. Conversely, as part of the nutrition policy in place in the five stores surveyed, the price of 600mL bottled water is mandated at $AUD1.00, so that for this item the standard deviation of prices across the five stores was zero.Testing of the Aboriginal and Torres Strait Islander Healthy Diets ASAP methods supported the notion that the approach has acceptable face validity in providing assessment of the price, price differential and affordability of current and healthy (recommended) diets of Aboriginal and Torres Strait Islander groups living in remote communities. The results were consistent with expectations arising from consideration of the reported dietary intake data of the two different populations ,7 and thConsistent with similar surveys, particularly in Australia where the GST of 10% is not applied to basic, healthy foods ,23,24,25Despite these promising findings, further scrutiny showed that healthy diets would be unaffordable due to the low household incomes in the communities surveyed. When assessed by the Aboriginal and Torres Strait Islander Healthy Diets ASAP methods, healthy diets would cost over 35% of median (gross) household income and nearly 39% of indicative low (minimum) disposable household incomes in these communities, compared to the international affordability benchmark of 30% of disposable household income ,21. The high level of food insecurity and food stress in these communities was confirmed, as the current diet cost over 43% of median (gross) household income and nearly 48% of indicative low (minimum) disposable household incomes when assessed by the Aboriginal and Torres Strait Islander Healthy Diets ASAP methods.The tailored Aboriginal and Torres Strait Islander Healthy Diets ASAP methods were more sensitive than the original Healthy Diets ASAP methods protocol in revealing the current degree of food security in the communities surveyed. If the tailored methods developed and tested in this study had not been used, the severity of food security issues in the remote Aboriginal communities surveyed would have been partially masked, and valuable data relevant to potential policy actions would have remained undetected.Worryingly, while 41% of the energy intake of the diet was derived from discretionary choices , applicaThese results highlight that, given the high proportion of food insecurity and diet-related disease in Aboriginal and Torres Strait Islander groups, nothing should be done to risk increasing the price differential of healthy to discretionary food and drinks in remote Aboriginal communities, as this could act as a further barrier to healthy diets. While better understanding of price elasticities and access to income entitlements in remote communities would be useful, the findings also suggest that investigation into the nature and effect of drivers of food choice other than price, such as housing, access to educational and employment opportunities, availability and functionality of food preparation/cooking facilities, transport, convenience, product placement in stores, promotion, advertising and food preferences appears warranted.Similar to the original Healthy Diets ASAP methods protocol, there are several inherent limitations in the Aboriginal and Torres Strait Islander Healthy Diets ASAP methods. Given that the approach is based on the reported mean dietary intakes of select age and gender groups of Aboriginal and Torres Strait Islanders at the national level, the diet pricing tools should be considered as reference instruments and the cost of the current diet is unlikely to be the same as actual expenditure on food and drinks by all Aboriginal and Torres Strait Islander people or households currently .All diet pricing tools should ideally include foods that are culturally acceptable, commonly consumed and widely available. Whilst the amounts of the foods included in the diet survey pricing tools are reflective of the respective food and food group consumption of Aboriginal and Torres Strait Islander groups reported in the AHS 2011-13 at the tNo adjustments were made to account for the marked under-reporting in the AHS 2011-13 ,6. Nor wThe Aboriginal and Torres Strait Islander Healthy Diets ASAP methods tailor nationally-standardised diet price and affordability method protocols to improve applicability to Indigenous Australians. The method incorporates relevant household income data and reported dietary intakes of Aboriginal and Torres Strait Islander groups to more appropriately assess, compare, monitor and benchmark the price, price differential and affordability of current and healthy (recommended) diets in different communities. The development of the tailored Aboriginal and Torres Strait Islander Healthy Diets ASAP methods provides an example of how standardised national tools can be adapted at sub-population and regional levels to provide better data to inform policy actions to improve food security and help reduce rates of diet-related disease more equitably in developed countries."} +{"text": "Older adults have increased risk of social isolation, loneliness, and cognitive functioning decline, but the relationships among these factors are not conclusive. We used the 2011 and 2012 waves of the harmonized China Health and Retirement Longitudinal Study to: 1) measure the association between social isolation and cognitive functioning among Chinese older adults within their cultural context, and 2) investigate the potential mediation mechanism of loneliness on this association. Specifically, we applied a multiple indicator multiple cause approach to determine whether the construct of social isolation is well defined by four indicators . We used structural equation modeling to examine the direct and indirect effects among variables of interest. The results demonstrated that three indicators of social isolation were significantly associated with cognitive functioning . The indirect effect of social isolation on cognitive functioning through loneliness was significant , indicating loneliness was an important mediator. After controlling for the indirect effect of loneliness, the direct effect of social isolation on cognitive functioning remained significant , suggesting a partial mediation effect. Our study confirms that social isolation contributes to cognitive functioning decline among Chinese older adults and that loneliness plays a mediating role. The findings suggest maintaining social relations and coping with feelings of loneliness are beneficial to older adults\u2019 cognitive functioning."} +{"text": "The paper highlights alternative strategies available to participants in research interviews, including engaging with personal experience of loneliness or avoidant tactics such as digression, projection onto others or claiming ignorance of the topic. The data point towards complicating factors including a reluctance to disclose loneliness as a socially undesirable phenomenon, as well as difficulties in articulating the complexities of this topic. These considerations remind researchers of the need for reflection on the use of qualitative interviews when investigating loneliness and other difficult aspects of personal experience."} +{"text": "In health care and senior housing and care, the challenge of meeting diverse regional workforce needs is increasingly important in higher education. Educators within gerontology are rising to this challenge using multiple platforms, including online education . This poster presents the life cycle of a traditional face to face introductory level graduate gerontology course which was transitioned to a fully online course. This transition was achieved using a structured course development process based on nationally recognized online course quality standards by Quality Matters (QM). Utilizing a team approach, the process incorporated faculty (subject matter experts and course developers), instructional designers, and professional staff in distance education, faculty teaching support, and online learning specialists. QM standards serve to assure quality online instruction, with the goal of providing students with a positive and successful online learning experience. Analysis of this case highlights the role of Certified (QM) peer reviewers who have expertise in Gerontology and can serve as the connector of online gerontology courses offered within programs, between institutions, and globally. Recommendations are presented to improve the pedagogical quality of online courses to attract and retain students in gerontology and aging studies courses. The case for building an initial network of online course peer reviewers to strengthen online teaching and learning within the gerontology profession will be made."} +{"text": "This presentation will cover recent advances in machine learning applied to large claims databases involving medical disparities. First, we will describe methods involving the enrichment of existing claims data with social determinants of health from census data, where variables are imputed from one dataset to another, ultimately resulting in clinical models with enhanced predictive performance. Second, we will discuss the inclusion of variables representing imaging signs from MRI and CT exams, presenting large scalability and interobserver reliability, representing a method that can be used to enrich large state and national registries through the use of image recognition. Finally, we will discuss novel protocols for Natural Language Processing involving a combination of rule-based creation of corpora for radiology and discharge reports, with highly accurate deep learning methods for concept extraction and classification."} +{"text": "Adequate economic resources ensure that older adults\u2019 basic needs are met and facilitate a healthier lifestyle. Hardship signals unfulfilled needs experienced by individuals lacking adequate economic resources. Despite well-documented associations between indicators of hardship and self-rated health, little is known about whether hardship has the same impact on self-rated health across age groups. The purpose of this study was to investigate the association between hardship and self-rated health among older adults and determine whether this association differed by age. Employing data from the 2014 Survey of Income and Program Participation, we conducted logistic regression analysis to examine the association between hardship and self-rated health among adults age 55 and older in the United States, and the moderating effect of age on this relationship. Analyses were weighted using replicate weights provided by the survey. Indicators of hardship were dichotomized . Analyses indicated that individuals who were unable to pay utility bills, unable to pay rent or mortgage, or who experienced food insecurity had lower odds of reporting good/very good/excellent health relative to those not experiencing these hardships. The association between hardship and self-rated health was shown to be less substantial among the oldest cohort (age 75 and older) relative to younger adults. Hardship is directly relevant to health outcomes as it represents the consequence of unfulfilled needs experienced by individuals lacking adequate economic resources. This study contributes to our understanding of the role of age in the association between hardship and self-rated health."} +{"text": "Recently, the US Food and Drug Administration and European Medicines Agency issued warnings on the use of dolutegravir and darunavir/cobicistat for treatment of pregnant women living with human immunodeficiency virus (HIV). It took 3\u20135 years to identify the risks associated with the use of these antiretroviral drugs, during which time pregnant women were exposed to these drugs in clinical care, outside of controlled clinical trial settings. Across all antiretroviral drugs, the interval between registration of new drugs and first data on pharmacokinetics and safety in pregnancy becoming available is around 6 years. In this viewpoint, we provide considerations for clinical pharmacology research to provide safe and effective treatment of pregnant and breastfeeding women living with HIV and their children. These recommendations will lead to timelier availability of safety and pharmacokinetic information needed to develop safe treatment strategies for pregnant and breastfeeding women living with HIV, and are applicable to other chronic disease areas requiring medication during pregnancy. The time period between registration of antiretroviral drugs and first pregnancy data becoming available should be shortened. We provide considerations on how to effectively evaluate aspects of clinical pharmacology required for safe and effective treatment to optimize pharmacotherapy during pregnancy and breastfeeding. A large observational study detected a 0.9% risk of neural tube defects (NTDs) in infants delivered by women receiving dolutegravir around conception or early in the first trimester of pregnancy. This was considered a substantial risk relative to 0.1% NTDs observed with other antiretrovirals . This ober Cmin) , 8. In Oer Cmin) .These reer Cmin) . Doluteger Cmin) . DespiteIn the past decade, the FDA and EMA have continued to emphasize the need for inclusion of women (pregnant and nonpregnant) in clinical development programs, issuing guidance for industry on how to conduct pharmacokinetic and pharmacodynamic studies in pregnant and lactating women, as well as on establishing pregnancy registries . There iDespite efforts to promote postmarketing surveillance and investigate the pharmacokinetics and safety of antiretroviral agents during pregnancy , data frIn July 2018, the World Health Organization (WHO) Paediatric Antiretroviral Working Group launched a toolkit for research and development of paediatric antiretroviral drugs and formulations, which aims to guide industry on approaches for accelerating the development of antiretrovirals for children and pregnant and lactating women . In thisAlthough there are clearly ethical considerations when including pregnant and breastfeeding women in clinical trials, it can also be considered unethical not to test new drugs in pregnant women in a controlled setting. In practice, once new drugs are approved in adults, their use rapidly expands to include pregnant and breastfeeding women, exposing more mothers and infants to these potential risks than would have occurred in the context of a clinical trial.Essential elements of pregnancy-related clinical pharmacology are the direct and indirect drug effects on the fetus. Indirect drug effects, such as increased risk of preterm labor or impaired glucose homeostasis, may have profound effects on fetal well-being. Also, many drugs cross the placenta, resulting in exposure of the fetus, with potential toxicity. Exposure during the first trimester may impact fetal organogenesis and result in teratogenicity. Exposure later in pregnancy may put the fetus at risk for impairments of growth and development or harm to specific organ systems. Fetal exposure to antiretroviral drugs may also provide beneficial effects such as preexposure prophylaxis that may aid in preventing perinatal HIV transmission . Short- Pregnancy is associated with a wide range of physiological, anatomical, and biochemical changes that substantially impact the pharmacokinetics of therapeutic agents , 26. ProPhysiologically, placental transfer is the main determinant of fetal exposure during pregnancy . HoweverAfter delivery, infants can also be exposed to antiretrovirals through breast milk. Transmission of HIV from mother to child in the postnatal period via breast milk remains a major contributor to perinatal transmission rates in low- and middle-income countries, where women commonly breastfeed for \u08d92 years. The provision of maternal antiretroviral therapy during the breastfeeding period has been shown to significantly reduce breast milk HIV transmission, by reducing breast milk HIV concentrations and/or by providing prophylaxis to the infant through ingestion of antiretroviral drugs present in breast milk . HoweverRegulatory authorities and ethics committees should incentivize and support inclusion of pregnant women in premarketing clinical trials for compounds with potential for use in pregnancy. Ethically acceptable strategies for conducting research on HIV treatment and prevention during pregnancy are being studied in the Pregnancy and HIV/AIDS: Seeking Equitable Study (PHASES) project . PHASES Dedicated clinical pharmacology studies in pregnant and lactating women can be initiated once initial phase 2 safety and efficacy data have been demonstrated in nonpregnant adults. These studies could include the women from premarketing trials and continue to include more pregnant women for adequate power with respect to a prespecified clinical endpoint, for example, undetectable viral load at delivery. The studies may be opportunistic or interventional , and may be performed by academia, the pharmaceutical industry, or a collaboration between both. To accelerate inclusion rates and include women in the setting where the disease is most prevalent, these studies should be performed in relevant populations in both high-income and low- and middle-income country settings. Centers of excellence should be established in low- and middle-income countries.Antiretroviral clinical pharmacology studies in pregnant and lactating women should be executed according to the highest standards and requirements. These studies should include intensive pharmacokinetic sampling over a dosing period in the third trimester of pregnancy (minimum), second and first trimesters (if possible), and a postpartum reference curve for intrasubject comparison (at least 4 weeks postpartum). Furthermore, random sampling during the entire pregnancy to support population pharmacokinetic modeling is highly recommended. Unbound plasma concentrations should be determined for highly protein-bound drugs (>80% bound). Collection of cord and maternal blood samples at delivery will allow assessment of placental transfer of the drugs in vivo. Antiretroviral infant washout samples following delivery should be collected, especially for drugs with a long half-life and those metabolized by enzymes not fully developed in newborns . These pharmacology studies should also collect efficacy and safety data, and should be included in global pregnancy registry databases.Postpartum lactating women should be included in clinical trials to allow assessment of breast milk transfer from mother to infant. Breast milk sampling can be done randomly during the 3 phases: colostrum (starts secreting around 24 weeks of gestation), transitional (days 2\u20133 postpartum), and mature milk phase (days 10\u201314 postpartum). To assess transfer rates into breast milk, maternal blood, breast milk, and infant blood should be collected at around the same time randomly after medication intake. Collection of full curves may not be necessary .Placental transfer should be studied during the preclinical phases of drug development using techniques such as in vitro\u2013in vivo extrapolations or ex vivo human cotyledon perfusion models. This will lead to early indications of whether drugs are likely to transfer through the placenta and reach the infant at potentially toxic levels. Such studies will require cooperation between academia and the pharmaceutical industry, as perfusion models are typically set up in academic hospitals, due to the limited time window between collection of placentas and start of perfusion.Furthermore, basic and clinical research exploring the mechanisms of the pregnancy effect on maternal drug exposure, as well as the mechanisms behind transfer of drugs across the placenta and into breast milk, is needed to make physiologically based pharmacokinetic models of pregnancy more accurate and robust.Although safety of antiretroviral therapy and pregnancy outcomes should be closely monitored during pharmacokinetic studies that include pregnant women, pharmacovigilance with postmarketing pregnancy surveillance studies, preferably global in scope, will still be necessary to delineate low-frequency adverse pregnancy outcomes. If all pregnancy outcomes of the first exposures to drugs during pregnancy are registered (>1000 as an indication), safety signals may be picked up at an early stage after licensure, without delaying access to the new compounds for women of childbearing potential.Inadequate drug exposure with the use of cobicistat-boosted drugs in pregnancy could have been recognized earlier if pregnancy pharmacokinetic studies had been performed at an earlier stage of drug development or if outcomes of initial pregnancies exposed after licensure had been registered. Regulatory requirements for obligatory studies in pregnancy should not delay the registration process or the availability of new drugs for women of childbearing potential, if these studies are routinely incorporated into the drug development process. Regulatory incentives may help successfully ease the transition to performance of initial pregnancy pharmacology studies as part of drug development and obligatory registration of pregnancy outcomes after licensure.An approach based on the considerations outlined here and in the WHO toolkit for research and development of pediatric antiretroviral drugs and formulations will facilitate the timelier availability of safety and pharmacokinetic information needed to develop safe treatment strategies for pregnant and breastfeeding women living with HIV. This approach is also applicable to other chronic disease areas where medication during pregnancy is required, such as diabetes mellitus, epilepsy, and autoimmune diseases. Cross-sector efforts are needed to accelerate research and ensure that protecting women and their babies does not delay their access to universal health coverage."} +{"text": "An emerging area of research within public health is the interaction between parents and their children for the promotion of physical activity. Higher levels of daily physical activity may not only improve physical health but also yield better academic performance by improving cognitive skills, classroom behavior, and academic achievement within the pediatric population. However, no theoretical model has yet been proposed to interrelate constructs of parental engagement and support, physical activity, and academic performance within the pediatric population. Here, we: 1) summarize salient research related to pediatric physical activity and academic performance, parents\u2019 physical activity engagement with their children, and the role of parental support in child academic performance; 2) propose a theoretical model interrelating parent physical activity engagement and support, physical activity, and academic performance (PESPAAP); 3) identify features of the proposed model that support its potential merit; and 4) provide potential future research directions and potential analyses that can be undertaken to support, modify, or disprove the proposed theoretical model. The proposed PESPAAP model provides a logically sound model that can be modified or expanded upon to improve applicability and generalizability and can be used as a framework to help align testable hypotheses for studies examining these interrelationships. Parents play a vital role in their children\u2019s physical, emotional, and mental development . ChildreA line of research that manifests from a conceptual extension of these findings is how parents\u2019 active engagement in the promotion of physical activity can positively impact specific facets of their child\u2019s academic performance. Additionally, the link between physical activity and academic performance may be confounded by the level of a parent\u2019s support in their child\u2019s academic pursuits as previous studies have shown parental involvement being a predictor of child academic success ,16. PareResearch in the behavioral sciences is most often guided by theory and hypotheses about observed phenomena. Research not aligning to a theory lacks direction and is said to lack a theoretical framework to base the study upon. A theory is a provisional set of interrelated concepts that structure a systematic view of phenomena for the purpose of expanding or predicting ,18. A thAccording to Wacker , definitIn recent decades, the positive relationships between health behaviors, particularly physical activity, with cognitive functioning has been well explored within the pediatric population ,21,22,23In addition to impacting physiological mechanisms that may improve cognitive skills and abilities ,29,30, pThere also may be interplay between physical activity and the health-related fitness domain of cardiorespiratory endurance that links to both cognitive functioning and academic achievement ,38. PrevPrograms derived for the promotion of pediatric physical activity recommend that parents and families be engaged with children to provide them enjoyable and developmentally appropriate opportunities to participate ,12. CorrStudies have shown that when parents are involved and engaged in the promotion of physical activity of their children, physical activity interventions tend to yield greater efficacy ,14. MetaThe link between pediatric physical activity and academic performance has been well supported in the recent literature; however, as recommended by the Centers for Disease Control and Prevention, further testing this relationship is a research priority ,57. A poThe proposed theoretical model of parent engagement and support, physical activity, and academic performance (PESPAAP) is presented in Parent physical activity engagement is the lone primary exogenous construct in the proposed theoretical model and serves as an antecedent for child and adolescent physical activity. Parent physical activity engagement is when one or both parents help to improve their child\u2019s opportunities for and participation in physical activity either during school or within out-of-school settings . Parent Child and adolescent physical activity and correlates is the mediator construct within the proposed PESPAAP theoretical model. Physical activity is any bodily movement that increases caloric expenditure above resting caloric expenditure . PhysicaAcademic performance is comprised of different facets that may influence student success at school, including cognitive skills, classroom behavior, and academic achievement . CognitiParent academic support is a potential exogenous construct within the proposed theoretical model that can also relate to child and adolescent academic performance. Parent academic support is when one or both parents share responsibility with teachers to help their children learn and meet educational goals . This poThree feedback loops have been proposed impacting both parental physical activity engagement and parental academic support. These feedback loops may facilitate either positive or negative spirals of engagement that will further facilitate continual high or low levels of child and adolescent physical activity and correlates and/or academic performance. An example of positive feedback facilitating a positive spiral of engagement is a higher level of child or adolescent physical activity providing positive feedback to parents to continually engage in physical activity behavior with their children. This positive feedback will continually maintain higher levels of physical activity and may support continual higher levels of academic support via the child and adolescent physical activity and academic performance relationship. An example of negative feedback facilitating a negative spiral of engagement is lowered levels of child and adolescent physical activity providing negative feedback to parents that leads to disengagement in the participation of physical activity with their children. The negative spiral of engagement will lead to continual lower levels of child and adolescent physical activity that may negatively affect academic performance. These positive and negative spirals of engagement can also be applied to academic performance affecting parental physical activity engagement and academic performance affecting parental academic support. Feedback loops and spirals of engagement can be modified or disrupted through intervention targeting salient variables representing a respective construct.Uniqueness). Although the proposed theory\u2019s conservatism is questionable due to the possibility of modification or refutation through empirical research, it has potential for broad generalizability for studies examining these interrelationships by applying to both children and adolescents, families of varying socioeconomic strata, race/ethnicities, and cultures. It is also a model rich with potential research questions that can be addressed using various cross-sectional, longitudinal, experimental, and non-experimental research designs and questions that can be tested using broad moderator variables such as sex, age, and/or socioeconomic status (Fecundity). Although mediated mechanisms are present in the proposed theoretical model, we believe parsimony does exist within the model by use of a limited number of constructs to explain the interrelationships, partially by collapsing child and adolescent physical activity as a concept that encapsulates both observed physical activity and motivational factors that contribute to its engagement. As described in the prior section, many of the interrelationships have evidence for validity or have logical and plausible explanations of the relationships ; however, there is still much uncertainty regarding the strength and potential impact of the relationships, which manifests a degree of empirical riskiness. Finally, abstraction is present within the model because there are many smaller and internally consistent concepts/relationships represented and integrated into the larger model .Wacker proposedA number of future research directions arise from the proposed theoretical model. As stated previously, the link between physical activity and academic performance has been established using cognitive skill, classroom behavior, and academic achievement endpoints ,46,72. WThe feedback mechanisms proposed within the theoretical model have been mostly unexamined, especially the link between academic performance and parent physical activity engagement. Given past research, it is theoretically plausible that higher levels of academic achievement may yield a positive spiral of engagement with parent physical activity promotion for their children ,79,80; hThe proposed PESPAAP model displays a number of relationships that can be tested in whole or in part. The link between parent physical activity engagement, child and adolescent physical activity, and academic performance can be tested using a mediation model. Within mediation models direct, indirect, and total effects should be tested, including the communication of the percentage of total effect mediated. The link between child and adolescent physical activity and academic performance is potentially confounded by parent academic support. Parent academic support could be used as a control variable if it is indeed thought of as a potential confounder between child and adolescent physical activity and academic performance to hold its effect constant on a respective academic performance outcome. To strengthen and possibly expand the variables used in PESPAAP, use of other mediators may be included in path analyses, including salient physical activity motivational variables in addition to measured physical activity behaviors. Additionally, because child and adolescent physical activity is a broad construct, examining different assessment metrics and time segments will provide more specific information, especially within the mediating models. Sedentary behavior may also play a role in these interrelationships. Analyzing both sedentary behaviors and physical activity within the context of a constrained time-use framework can be tested using CoDa. A more comprehensive examination of PESPAAP, including the covariance between parent physical activity engagement and academic support and the latent construct of academic performance, may be addressed using Structural Equation Modeling (SEM) having both structural and measurement components. Bi-directional relationships and feedback mechanisms can be tested using mediation analysis/SEM reversing direction arrows within the model and comparing parameter estimates and model fit accordingly. Longitudinal analysis of these relationships may provide stronger evidence for directionality of effects.In this paper we proposed a theoretical model to link parent engagement in the promotion of child and adolescent physical activity with child and adolescent academic performance. We proposed that this link is a potential mediated relationship using observed physical activity behaviors and/or physical activity motivational factors as potential mediators within the relationship pathway. We also proposed that the relationship between child and adolescent physical activity and academic performance may be confounded by parental support for academic performance. Feedback loops were incorporated into the model to identify potential feedback mechanisms facilitating positive or negative spirals of parental engagement. The proposed theoretical model has a number of features that support its potential merit including a theoretical model being rich with potential research questions that can be addressed using a variety of research designs among a variety of different pediatric and adult populations. Our hope is that PESPAAP provides a logically sound model that can be modified or expanded upon and can be used by researchers as a framework to align testable hypotheses involving these interrelationships."} +{"text": "Biomedical research is gaining ground on human disease through many types of \u201comics\u201d, which is leading to increasingly effective treatments and broad applications for precision medicine. The majority of disease treatments still revolve around drugs and biologics. Although food is consumed in much higher quantities, we understand very little about how the human body metabolizes and uses the full range of nutrients, or how these processes affect human health and disease risk. Nutrient composition databases are used by dietitians to describe common consumer food products, but these fail to identify chemicals with the same nomenclature as metabolic pathways in basic life sciences research and with far less precision. Consumer-oriented nutrient compositions often describe generic substances (e.g. Sugars) while scientific reporting is often much more specific . Integrating these two fields of research presents a difficult challenge for novel applications of precision nutrition.This data set provides a manually curated collection of nutrient identifiers from the USDA\u2019s Nutrition Data Bases and maps them to PubChem (a resource for cheminformatics and drug discovery research), biomedical literature records in PubMed using Medical Subject Headings, biological pathways using the Chemical Entities of Biological Interest ontology. Biomedical research is gaining ground on human disease through many types of \u2018omics, leading to increasingly effective treatments and broad applications for precision medicine. However, the majority of disease treatments still revolve around drugs and biologics. Food is consumed in much higher quantities and yet we understand very little of the specifics about how the human body metabolizes and uses nutrients, and how these processes affect human health and disease. Understanding this better is one of the primary goals of the Plant Pathways Elucidation Project (P2EP) .The P2EP Knowledgebase aims to collect and integrate data from food crops, nutrients, biochemical pathways and reactions, and human health and disease. This is a large undertaking that will require years of effort and data collection starting with genome assembly for many crop plants, and gene mapping and annotation to determine pathway representation. In order to jumpstart the informatics component of this project, we have integrated existing consumer-oriented nutrient composition databases with life sciences and biomedical resources.Nutrient composition databases , 3 oftenNutrition intersects various biomedical domains: basic science research, biomedical literature, and drug discovery and cheminformatics. There are many biological pathways resources such as the Gene Ontology and ReacOur baseline sample of nutrient identifiers and names were extracted from multiple USDA Nutrient Databases. The primary resource was the Standard Reference 28 . TogetheThe list of Nutrient Identifiers and Names were given to two student interns of the Plant Pathways Elucidation Project (P2EP) . The stuThe prior techniques were then repeated for assignment to Medical Subject Headings (MeSH) descriptors . When muFinally, links to the PubChem Compound database were colInterestingly, none of the resources annotated contains a complete matching to all of the USDA Nutrients listed. Twenty-nine of the NDB nutrients have no annotations to ChEBI, MeSH, or PubChem. While in some cases this can be attributed to the generic consumer-oriented nutrient classifications , the remaining instances may be classifications that warrant further consideration into the scientific databases. Now that this resource exists, we can do further research into the properties and connections of these nutrients and find more information about the effects of both known and uncharacterized phytochemicals on human health.The high specificity of scientific terminology does not map cohesively to the current level of ambiguity in the Nutrition Composition databases. While it is not immediately obvious that adding new generic terminology to existing resources like ChEBI or MeSH is beneficial, adding more comprehensive lists of chemical variations with similar bioavailability would be desirable for increasing utility and accessibility of more diverse data sets."} diff --git a/PMC_clustering_682.jsonl b/PMC_clustering_682.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..3318d63e17b311a748d76d4f610782f29153c9e7 --- /dev/null +++ b/PMC_clustering_682.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:1d8b147fe29729cd95e65a2aa42f8983f54efc20f76f4daed0e284dbf0c6021a +size 88766282 diff --git a/PMC_clustering_683.jsonl b/PMC_clustering_683.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..100f43065a4eb7b97249914f9080e33c7f1dc420 --- /dev/null +++ b/PMC_clustering_683.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:d28e24b2638c84cccb28e7146a85df129a4ccf4b14ce2c24c917847cd9b94b84 +size 46456925 diff --git a/PMC_clustering_684.jsonl b/PMC_clustering_684.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..91f9557729ad6ac441b8083804666a0cdf76f59a --- /dev/null +++ b/PMC_clustering_684.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:4ef35c1face763c3d219424ab3a824fb48af1ce9a5e6fe916bf32ca71989d97e +size 86438808 diff --git a/PMC_clustering_685.jsonl b/PMC_clustering_685.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..0d5c3acfa9cd97c08d0ce07e5ec692f25f4d4517 --- /dev/null +++ b/PMC_clustering_685.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:08ec2503422803b2165bd365103d16dcb9bf3c2e1a47f494bae8461954369dd3 +size 67611130 diff --git a/PMC_clustering_686.jsonl b/PMC_clustering_686.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..da444439e8d448a263f84ba9093cbd58dae0bb9e --- /dev/null +++ b/PMC_clustering_686.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:89ab8112b657f4e8f1c1f7fe21911b992e67c7c5231a8d5ecc2b6151e8c9d25b +size 54163324 diff --git a/PMC_clustering_687.jsonl b/PMC_clustering_687.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..cc6fb841d62cb4e41d3455a1f54b2d60681910f9 --- /dev/null +++ b/PMC_clustering_687.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:a7298e8d82c1b30391dfbb6187e5f3ba0384eb12605645ded1bec942123aae8e +size 76703297 diff --git a/PMC_clustering_688.jsonl b/PMC_clustering_688.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..7a7f01c8a3c19e62e572635f59e0283c07b399e6 --- /dev/null +++ b/PMC_clustering_688.jsonl @@ -0,0 +1,579 @@ +{"text": "This article has been corrected: Due to errors during figure assembly, the representative image of normal tissues in Figure 7E control group is incorrect. The correct Figure 7, obtained using the authors\u2019 original data, is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.105222-105237. https://doi.org/10.18632/oncotarget.22160Original article: Oncotarget. 2017; 8:105222\u2013105237."} +{"text": "JCI Insight. 2019;e129270. https://doi.org/10.1172/jci.insight.129270Original citation: JCI Insight. 2021;6(4):e148169. https://doi.org/10.1172/jci.insight.148169Citation for this retraction: JCI Insight editorial policy prohibits falsification and misrepresentation of data.Following a review by the Swedish National Board for Assessment of Research Misconduct, it was determined that a serious breach of good scientific practice in the form of falsification occurred during the pseudocoloring of scanning electron micrographs in this article. The National Board determined that the serious deviation from good research practice was not intentionally committed and concluded that no research misconduct occurred. The paper is being retracted because"} +{"text": "In the Materials and Methods section, the indicated concentration of the siRNAs in the working dilution was incorrect. It should read 10 \u03bcM (not mM).https://www.sommerlab.org/fileadmin/uploads/RNAi_soaking_Alex.pdfA step-by-step protocol has been made available at the following link:"} +{"text": "R. Soc. Open Sci.7, 200266. (Published online 8 July 2020). (doi:10.1098/rsos.200266)This correction has been published due to an error in a collection permission of biological specimens in the Methods section. In \u00a72.1 Study area, it was stated that:Universidad del Rosario provided the field permit from ANLA 63257\u20132014. All collections were done on public land.This has been updated to:Universidad de Santander (UDES) provided the collection permit from ANLA 01749. All collections were done on public land."} +{"text": "This article has been corrected: The authors requested the replacement of panel C of Figure 3 because they reversed the inscriptions on this panel.This correction does not change the content of the publication. The corrected Figure 3 is provided below.https://doi.org/10.18632/aging.102637Original article: Aging. 2020; 12:481\u2013501."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-75162-x, published online 27 october 2020Correction to: The original version of this Article contained errors.Information on the Data Availability was incomplete. Therefore, the original Data Availability text,\u201cThe normalized and non-normalized feature tables are available in supplementary data\u201d.Now reads,https://www.ncbi.nlm.nih.gov/bioproject/PRJNA684000\u201d.\u201cThe normalized and non-normalized feature tables are available in supplementary data. The raw metagenomics sequence data is available at This has now been corrected in the PDF and HTML versions of the Article."} +{"text": "Scientific Reportshttps://doi.org/10.1038/srep38657, published online 12 December 2016Correction to: In this Article, Baikun Li is incorrectly listed as corresponding author. The correct corresponding author for this Article is Xing Yuan.Correspondence and request for materials should be addressed to yuanx@nenu.edu.cn."} +{"text": "METRN) in colorectal cancer has not been reported previously. We aimed to explore the relationship between METRN and colorectal cancer (CRC) prognosis.The role of meteorin , disease\u2010free (DFS), and disease\u2010specific survival (DSS) rates were determined by Kaplan\u2013Meier analysis and analyzed by log\u2010rank test.Data were retrieved from the Gene Expression Omnibus database. Gene expression values were log2 transformed and normalized by quantile normalization. Missing values were imputed with the R impute package. Differentially expressed genes were analyzed using the R limma package. METRN was expressed at a higher level in CRC (p\u00a0=\u00a0.0011) than in normal tissues, especially in advanced stages (p\u00a0=\u00a0.0343). METRN expression levels were higher in the MSI (dMMR) subtype (p\u00a0<\u00a0.001) and usually with BRAF mutations (p\u00a0<\u00a0.0001). METRN overexpression was associated with poor prognosis and low OS (p\u00a0=\u00a0.01014), DFS (p\u00a0=\u00a0.0146), and DSS (p\u00a0<\u00a0.0001) rates.METRN overexpression is a predictive factor for poor prognosis in patients with CRC. Overexpression of meteorin (METRN) is associated with colorectal cancer and can predict poor prognosis of colorectal cancer. It was first described in 2004 protein, which is homologous to METRN, have been implicated as biomarkers of hematological and endocrine diseases. Nevertheless, there are few studies on the role of METRN in CRC, and the relationship between METRN expression and CRC patients\u2019 prognosis remains unclear. Therefore, to explore the role of METRN in CRC, we performed a retrospective analysis using data from the Gene Expression Omnibus (GEO) database. We found that METRN expression was upregulated in CRC and the overexpression of METRN was associated with poor prognosis of patients with CRC. Based on these results, we suggest that METRN may be used as a biomarker for the prognosis of CRC.Meteorin . The following search strategy was used: (metrn OR meteorin) AND . We downloaded the original data from the GEO database datasets, http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE23878, http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE33113, http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE17536, http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE14333, http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE13067, http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE13294, http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE39582, and http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE37892.CRC patient data and RNA\u2010seq expression data were downloaded from the Gene Expression Omnibus and microsatellite stability (MSS) subtypes in the http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE13067 and http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE13294 datasets, respectively. The association of METRN expression level with the histopathological grading of tumors was also analyzed in the http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE17536 dataset. Moreover, the relationship between METRN expression level and BRAF and KRAS mutations was analyzed in the http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE39582 dataset. In addition, overall survival (OS), disease\u2010free survival (DFS), and disease\u2010specific survival (DSS) curves were generated using the Kaplan\u2013Meier method, and these data were analyzed for statistical significance using a log\u2010rank test in the http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE17536 and http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE37892 datasets. In the above analyses, p\u2010values less than 0.05 indicated statistical significance.R software was used for data analysis. We used the affy package (R language) to read and process these data. Data were log2 transformed, and the missing values were filled in with the impute package. Differentially expressed genes were filtered out using the limma package. Probes were matched to their corresponding genes using annotation files. We compared the expression levels of 33.1METRN between CRC tissues and normal tissues and found that METRN was expressed at significantly higher levels in CRC tissues CRC than in proficient mismatch repair (pMMR) CRC can be used as the basis of risk stratification. There is ample evidence that patients with dMMR have a lower risk of recurrence and longer survival time than those with pMMR (Sargent et al., METRN was found to be a significant predictor of OS, DSS, and DFS, with rates of survival being negatively correlated with METRN expression. This suggested that METRN expression is a significant risk factor in patients with CRC. A previous study reported that METRNL could alleviate lipid\u2010induced inflammation and insulin resistance via AMPK or PPAR\u03b4\u2010dependent pathways (Jung et al., AMPK and PPAR\u03b4 signaling pathways play important roles in CRC. AMPK has an important autophagy\u2010inducing effect during the treatment of tumors, including CRC tumors, and this can be regulated by redox modification under oxidative stress (Kim, Kundu, Viollet, & Guan, METRN may be involved in regulating CRC prognosis through the above mechanisms.In survival analysis, METRNL levels may be associated with endothelial dysfunction (El\u2010Ashmawy, Selim, Hosny, & Almassry, METRN expression may be involved in regulating the function of colorectal endothelial cells. Another study found that METRN is highly expressed in early embryos during gastrulation and is crucial for mesoendoderm development (Kim et al., METRN regulates the function of colorectal endothelial cells.In addition, it has been reported that low serum METRN might be a prognostic indicator in patients with CRC, we did not explore the possible mechanism of METRN\u2019s involvement in CRC regulation. Therefore, we cannot completely confirm the specific role of METRN in CRC. Additional studies are recommended to explore the role of METRN in CRC. Since there are no previous reports on the relationship between METRN and CRC, our results will play a guiding role for future studies.Although our study revealed that METRN was closely associated with advanced CRC stage and predicted poor clinical outcomes. Therefore, our results may have a more detailed reference value for the prognosis of patients with CRC in the future clinical practice.In conclusion, overexpression of The authors have no conflict of interest to declare."} +{"text": "In these times, reflection on the learning processes from the past is initiated. All non\u2010pharmaceutical public health countermeasures currently being taken against the COVID\u201019 outbreak are based on experience gained from past pandemics over the last several centuries,https://trends.google.com) revealed marked increases in searches for Spanish flu on the web and on news pages in March and April 2020 , the number of listed scientific studies per 100,000 citations using the search terms Spanish flu or influenza 1918 in their abstract/title reached an all\u2010time high in 2020 ; Formal analysis ; Investigation ; Methodology ; Supervision (lead); Visualization ; Writing\u2010original draft ; Writing\u2010review & editing . Jo\u00ebl Floris: Conceptualization ; Formal analysis ; Investigation ; Methodology ; Visualization ; Writing\u2010original draft ; Writing\u2010review & editing .https://publons.com/publon/10.1111/irv.12806.The peer review history for this article is available at 1Giles\u2010VernickT, CraddockS, GunnJ. Influenza and Public Health. Learning from Past Pandemics. London: Earthscan from Routledge; 2015:293.2WebbJLA. The historical epidemiology of global disease challenges. Lancet. 2015;385:322\u2010323.257138333MurrayCJ, LopezAD, ChinB, FeehanD, HillKH. Estimation of potential global pandemic influenza mortality on the basis of vital registry data from the 1918\u201320 pandemic: a quantitative analysis. Lancet. 2006;368:2211\u20102218.171890324MorensDM, DaszakP, TaubenbergerJK. Escaping Pandora\u2019s Box \u2014 Another Novel Coronavirus. N Engl J Med. 2020;382:1293\u20101295.321016605TaubenbergerJK, KashJC, MorensDM. The 1918 influenza pandemic: 100 years of questions answered and unanswered. Sci Transl Med. 2019;11(502):eaau5485.31341062"} +{"text": "Nature Communications 10.1038/s41467-018-06394-9, published online 02 October 2018.Correction to: The original version of this article contained errors in the deposition locations of data and code.The original Data availability statement read:https://github/theunissenlab/soundsig. Tutorials with example data are found in https://github/theunissenlab/BioSoundTutorials. The complete library of vocalizations is available at: https://drive.google.com/drive/folders/1etvuPjaNHV9oFPgUAuLxP3bk1aWfj3Pl?usp=sharing. The behavioral data and behavioral analysis code are available from the corresponding authors upon reasonable request.\u201d\u201cThe custom Python code used to calculate the acoustical features is available as the BioSound class in sound.py found in The correct version replaces this with:https://github.com/theunissenlab/soundsig. Tutorials with example data are found in https://github.com/theunissenlab/BioSoundTutorial. The complete library of vocalizations is available at Figshare: 10.6084/m9.figshare.11905533.v1. The behavioral data and behavioral analysis code are available from the corresponding authors upon reasonable request.\u201d\u201cThe custom Python code used to calculate the acoustical features is available as the BioSound class in sound.py found in The original version also included the incorrect Github URLs in the first paragraph of the \u2018Acoustical analysis\u2019 section of the Methods:https://github/theunissenlab/soundsig; BioSound Tutorials with examples are found in https://github/theunissenlab/BioSoundTutorials).\u201d\u201cAll acoustical features were obtained using custom Python code from the Theunissen lab .\u201d\u201cAll acoustical features were obtained using custom Python code from the Theunissen lab (BioSound class in sound.py found in These have been corrected in both the PDF and HTML versions of the Article."} +{"text": "The erratum corrects a misspelled author surname. The correct spelling is Pasarikovski.This article [J. Biomed. Optics, 25(3), 035003 (2020), doi: This article was corrected on 9 April 2020."} +{"text": "Correction to: BMC Infect Dis (2020) 20:909https://doi.org/10.1186/s12879-020-05534-1Following publication of the original article , the autThe correct captions are given below.The correct caption for Fig. 1 is: \"Classification of pyoverdine and pyocyanin producer by qualitative observational method. a, pyoverdine producer strain; b, pyocyanin producer strain\"Pseudomonas aeruginosa strains isolated from patients with VAP and from patients with other infections . PBS was used as a positive control for larvae survival. *Statistically differences were found between VAP and non-VAP P. aeruginosa (p <\u20090.001) using the log-rank test\u201d.The correct caption for Fig. 2 is: \"Survival curves for Galleria mellonella larvae after infection with The original article has been"} +{"text": "This article has been corrected: While reviewing the database for this study, the authors discovered that the Tunel staining data for all 6 panels in 49338-49350. https://doi.org/10.18632/oncotarget.17638Original article: Oncotarget. 2017; 8:49338\u201349350."} +{"text": "This article has been corrected: The Acknowledgements section has been updated. The proper text is as follows:ACKNOWLEDGMENTSSG was supported by CHRIM operating grant, Health Science Foundation general operating grant and Research Manitoba New Investigator operating grant. MJ\u0141 kindly acknowledges the support from LE STUDIUM Institute for Advanced Studies through its Smart Loire Valley General Program, cofunded by the Marie Sklodowska-Curie Actions, grant #665790.24857-24868. https://doi.org/10.18632/oncotarget.25324Original article: Oncotarget. 2018; 9:24857\u201324868."} +{"text": "Figs barbaros.yet@hacettepe.edu.tr.The corresponding author\u2019s email address is incorrect. The correct email address for Dr. Barbaros Yet is:"} +{"text": "Scientific Reports 10.1038/srep33735, published online 27 September 2016Correction to: This Article contains an expired email address for Santosh Anand. Correspondence and requests for materials should be addressed to santosh.anand@gmail.com."} +{"text": "This review article focuses on that topic.Because of the propensity for https://link.springer.com/article/10.1007/s00253-018-09577-yStreptomyces strains to inhabit soil near plants and to stimulate their health and growth.This mini\u2010review focuses on the ability of https://microbewiki.kenyon.edu/index.php/Streptomyces_lividansS. lividans but also Streptomyces in general. S. lividans is used industrially as a protein secretion host.This page discusses not only https://bacdive.dsmz.de/search?search=streptomyces&submit=Streptomyces strains that can be obtained from the collection.This strain collection website contains information on thousands of https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgiStreptomyces strains, as well as isolates that have not been studied in detail.This NCBI site lists well\u2010studied http://strepdb.streptomyces.org.uk/cgi-bin/dc3.pl?accession=AL645882&start=4291472&end=4302043&iorm=map&width=900Streptomyces.This database was made to share resources for those studying Actinobacteria, with a focus on https://phagesdb.org/hosts/genera/4/Streptomyces species.This database focuses on bacteriophages infecting https://www.nature.com/articles/s41597-020-0395-9Streptomyces genomes and their mining for novel biosynthetic gene clusters.This recent paper describes the sequencing of thirty new https://www.genome.jp/kegg-bin/show_organism?org=scoStreptomyces coelicolor is a model Streptomyces species, and this database page links to the genome, metabolic networks and enzymes of the organism.https://www.microbiologyresearch.org/content/streptomycesStreptomyces bacteria.This scientific society page provides a good overview of https://www.sciencedirect.com/science/article/pii/S0944501314000573Streptomyces isolates.This study describes a protocol and results from the use of Matrix\u2010Assisted Laser Desorption/Ionization Time\u2010Of\u2010Flight Mass Spectrometry (MALDI\u2010TOF\u2010MS) for identifying https://biocyc.org/SCO/organism-summary?object=SCOThis database page contains information on the metabolism and enzymes of the organism.https://www.ncbi.nlm.nih.gov/genome/?term=streptomycesStreptomyces genomes. At this time, there are 3740 genome assemblies.This database page provides links to information on https://mbio.asm.org/content/10/5/e01533-19Streptomyces, leading to a large diversity of genomes over time.Insertions and deletions occur commonly in https://www.sciencedirect.com/science/article/pii/S2001037020303135Streptomyces species.This mini\u2010review discusses approaches for the identification for secondary metabolite biosynthetic gene cluster in https://scholars.unh.edu/cgi/viewcontent.cgi?article=2307&context=thesisStreptomyces genomes.This master\u2019s thesis describes approaches for conducting bioinformatics analyses of https://mibig.secondarymetabolites.org/queryStreptomyces and their products are prominently featured in the database.This database contains information on biosynthetic gene clusters broadly."} +{"text": "JNCI. J Natl Cancer Inst (2019), doi: 10.1093/jnci/djz075.Erratum to \u201cRadiogenomics Consortium Genome-Wide Association Study Meta-Analysis of Late Toxicity After Prostate Cancer Radiotherapy\u201d by Sarah L Kerns et al. In this article, the name of Sarah L. Kerns should be displayed as Sarah L. Kerns*, indicating that Dr. Kerns contributed equally to this work. The Publisher regrets the error."} +{"text": "This article has been corrected: There was an error during the assembly of the bottom panel of 20813-20824. https://doi.org/10.18632/oncotarget.15343Original article: Oncotarget. 2017; 8:20813\u201320824."} +{"text": "Senses (2020). doi:https://doi.org/10.1093/chemse/bjaa034), published on 22 May 2020. Due to an error in the script used to create subsections of This is a correction notice for article bjz034 (DOI:"} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-58000-y, published online 29 January 2020Correction to: This Article contains an error in the Statistical Analysis section where,\"R scripts used for the analysis are available in Supplementary Files 2\u201310.\"should read:https://doi.org/10.5281/zenodo.3763407 and https://github.com/jgrembi/DIETFITS_GutMicrobiotaPlasticity\"\"R scripts used for the analysis are available at"} +{"text": "This article has been corrected: This article has been corrected: Due to errors during image selection, identical images were used for panels D and E in 2Mohamed M. NasefThe authors declare that these corrections do not change the results or conclusions of this paper.3472-3490. https://doi.org/10.18632/oncotarget.26930Original article: Oncotarget. 2019; 10:3472\u20133490."} +{"text": "R. Soc. Open Sci.7, 191561. (Published Online 8 April 2020). (doi:10.1098/rsos.191561)This correction refers to an error in the funding statement. Grant number 31972587 for the National Natural Science Foundation of China had not been listed. This has now been corrected."} +{"text": "Dr. Feng\u2019s email address is: chfeng@kmu.edu.tw. The publisher apologizes for the error.There is an error in the author byline. Authors Wu-Chien Chien, Chia-Hsien Feng, and Pauling Chu should be noted as contributing equally to this work as corresponding authors. Dr. Chien\u2019s email address is:"} +{"text": "This webpage put up by the company AgBiome highlights several of their microbial control agents. For example, \u201cHowler\u201d is composed of a http://www.biocomes.eu/biological-control/This website discusses biocontrol for sustainable farming and forestry. It is fairly basic but has useful videos and information explaining the basic elements of biocontrols.https://www.novozymes.com/en/advance-your-business/agriculture/crop-production/biocontrolNovozymes is a large enzyme producer that also markets bacteri and fungi that target damaging pests that decrease crop yields in agriculture.https://link.springer.com/article/10.1007%252Fs10526-017-9831-yThis journal article discusses different aspects of getting more biocontrol agents on the market. This includes more engagement with farmers and the public, and better mechanisms for going through regulatory approval.http://www.angelfire.com/wizard/kimbrough/Textbook/FungiAsBiocontrolAgents_blue.htmIn addition to bacteria, numerous fungal strains are useful in controlling crops pests. This website contains many such examples.https://www.ncbi.nlm.nih.gov/pubmed/29362088This review article discusses microbial biocontrol broadly, with some emphasis on microbiome aspects of microbial amendments onto plants and soils.https://ec.europa.eu/eip/agriculture/sites/agri-eip/files/8_eip_sbd_mp_biocontrol_final.pdfThis page from eip\u2010agri discusses the economics, the microorganisms, and the potential impacts of microbial biocontrols.http://www.bt.ucsd.eduBacillus thuringiensis produces a parasporal protein crystal that is toxic to certain insects. This has been recognized for many decades and so B. thuringiensis is one of the first biocontrol agents to be widely used commercially. This website provides a good overview.https://link.springer.com/article/10.1007/s10526-019-09964-yThis review article makes the point that biocontrol regulations in Europe generally treat biocontrol microbes as dangerous and prone to become dominant in the environment. Arguments against that view are provided.https://www.aphis.usda.gov/aphis/ourfocus/planthealth/import-information/permits/regulated-organism-and-soil-permits/biological-control-organism-permitsThis page discussed and provides documents for movement of biocontrol agents. It is a page of the United States Department of Agriculture.https://biotechnologie.rivm.nl/sites/default/files/2017-11/Future%2520introductions%2520of%2520genetically%2520modified%2520microbial%2520biocontrol%2520agents%2520in%2520the%2520EU.pdfThis report describes activities in genetic engineering of biocontrol agents and asks if current Europen Union legislation is currently adequate for proper risk assessment.http://www.rcsb.org/structure/1W99Aedes and Anopheles mosquitoes.This site contains the deposited X\u2010ray structure and information on the protein toxic to the larae of https://springerplus.springeropen.com/articles/10.1186/s40064-016-1780-xFusarium verticillioides.This article desribes the isolation and characterization of different bacteria that can protect corn from infectivity of https://microbewiki.kenyon.edu/index.php/Bacillus_thuringiensisBacills thuringiensis ecology, metabolism, and utility in biocontrol.This Microbe Wiki pages covers https://www.nature.com/articles/s41598-019-56741-zThis study compares biocontrols to more traditional copper fungicide for treating grapevine leaves susceptible to fungal infections.https://www.g3journal.org/content/10/3/881Bacillus strains.This study examined the genomes of and possible virulence factors produced by different nematicidal"} +{"text": "Scientific Reports 10.1038/srep08331, published online 09 February 2015Correction to: This Article contains errors.The sequencing data underlying the study had been previously deposited on the institutional server. The authors have now additionally deposited it in GenBank, under accession code QDGY00000000. The Data Availability section should therefore read:Data Availabilityhttp://spxy.tust.edu.cn/duxj/index.html and in GenBank under accession code QDGY00000000.The genome sequence data and RNA-seq data generated in this project are available at"} +{"text": "The anomalous vessel was retrospectively identified on chest computed tomography (CT) scan. A thoraket Fig. . The veiket Fig. and requket Fig. .Appropriate written informed consent was obtained for publication of this case report and accompanying images."} +{"text": "Given that these foods are often indigenous and linked to culture, these are important considerations as food biotechnology becomes more prevalent in developing countries.https://en.wikipedia.org/wiki/List_of_microorganisms_used_in_food_and_beverage_preparationThis page contains a very long list of genera and species of bacteria involved in food and beverage production and indicates the food they they produce.https://www.wikilectures.eu/w/Micro-organisms_in_FoodsThis page briefly covers microbes involved with foods in different ways, as: human pathogens, spoilage agents or in production or processing.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956270/Enzymes are widely used in the food industry. Some have their origins from microbial systems. Others are originally from plants or animals but are biosynthesized in microbes recombinantly.https://www.annualreviews.org/doi/abs/10.1146/annurev-food-022811-101219This is a helpful review article althought its content may only be available through university libraries.https://fbt.ethz.ch/research.htmlThis laboratory studies food biotchnology and complementary gut microbial metabolism, with the goal of oprimizing nutrition and human health.https://archive.bio.org/articles/biotechnologys-impact-food-ingredientsThis website is put out by the Biotechnology Innovation Organization, or Bio. It briefly deals with major contemporary issues in food biotechnology.https://www.sciencedaily.com/releases/2019/02/190201130624.htmWet processing of coffee utilizes a microbial fermentative step. Lactic acid bacteria play a role, as do other bacteria, in that process.https://www.globenewswire.com/news-release/2019/05/23/1841415/0/en/Food-Biotechnology-Market-value-to-hit-45-Billion-by-2025-Global-Market-Insights-Inc.htmlThis business report concludes that the food biotechnology market is growing rapidly and is predicted to reach $45 billion by the year 2025.https://www.nature.com/subjects/food-microbiologyNature publishers is a compendium of recent peer\u2010reviewed publications in Nature journals related to food microbiology.This page by https://network.bepress.com/life-sciences/food-science/food-biotechnology/This page of the Food Biotechnology Commons links to numerous open source articles related to food biotechnology.https://www.biotech.wisc.edu/docs/default-source/outreach-documents/biotechandfood.pdf?sfvrsn=dd91ec28_2This extension report focuses on food and agricultural biotechnology.https://www.liebertpub.com/doi/full/10.1089/ind.2016.0011GRAS stands for \u201cGenerally Regarded As Safe.\u201d Enzymes made from food safe organisms would be safe to use for food applications.https://academic.oup.com/femsle/article/349/2/77/533643Lactobacillus acidophilus was originally isolated from the human intestinal tract and is today an important strain for yogurt and other dairy products.https://www.ncbi.nlm.nih.gov/genome/genomes/1099?Lactobacillus acidophilus strains.This page of the National Center for Biotechnology Information (NCBI) links to the genome sequences and related data for many"} +{"text": "The erratum corrects a grant number listed in Acknowledgments section of the original article. J. Biomed. Opt.24(1), 017001 (2019) doi: 10.1117/1.JBO.24.1.017001] was originally published on 8 January 2019 with an erroneous grant number in the Acknowledgments section. The original grant listed was NSF PFI: BIC 11631146; the correct grant number is NSF PFI: BIC 1631146.This article [The error was corrected on 31 December 2020."} +{"text": "Scientific Reports 10.1038/srep15414, published online 21 October 2015Correction to: This Article contains an incorrect version of the Supplementary Information file. The correct Supplementary Information file has been provided below.Supplementary Information."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-019-44350-9, published online 28 June 2019Correction to: The original version of this Article contained an error. A Data Availability section was originally not included \u2013 it now appears as below:https://figshare.com/authors/Rebecca_Pratt/8485863Raw data generated for this study has been deposited at an online open access repository \u201cFigshare\u201d and can be accessed via this link: Following are the individual DOIs for raw data for each tissue:https://doi.org/10.6084/m9.figshare.11891760Adipose: https://doi.org/10.6084/m9.figshare.11892111Liver: https://doi.org/10.6084/m9.figshare.11892279Brain: In addition, there were errors in Figure S2 of the updated supplementary file, where the CTR images for Green Fluorescence and Red Fluorescence corresponding to DAPI were incorrect. In the revised Supplementary Figure\u00a02, the representative cluster for images (green fluorescence and red fluorescence) within each group now correctly identifies with their corresponding DAPI images. These corrections do not affect the findings of the original article. Specifically, the following representative images have been replaced in Supplementary Figure\u00a02: Green and Red Fluorescence images of Liver tissue for Control and WD groups; Green and Red Fluorescence images of Brain tissue for Control, WD and WD-Lenti-Adiponectin-GFP groups.These errors have now been corrected in the HTML and PDF versions of the Article, and in the accompanying Supplementary Information file."} +{"text": "Scientific Reports 10.1038/s41598-020-57674-8, published online 24 January 2020Correction to: The original version of this Article contained a typographical error in the Abstract.\u201cMAESTRO can gather data using cloud storge for further research and in-depth analysis.\u201dnow reads:\u201cMAESTRO can gather data using cloud storage for further research and in-depth analysis.\u201dAdditionally, the following statement was previously omitted from the Results and Discussion section:https://lcas.lincoln.ac.uk/owncloud/index.php/s/9L0zwZgjsTJMCcn.\u201d\u201cThe mobile App can be downloaded from the following link: Finally, in the Materials and Evaluation section:https://lcas.lincoln.ac.uk/owncloud/index.php/s/gGiGUxhYTmPV1vKGHCID.\u201d\u201cThe dataset can be downloaded from the following link: now reads:https://lcas.lincoln.ac.uk/owncloud/index.php/s/gGiGUxhYTmPV1vK.\u201d\u201cThe dataset can be downloaded from the following link: These errors have now been corrected in the PDF and HTML versions of the Article."} +{"text": "There is an error in the article title. The correct title is: Measuring agency with an adaptive sensorimotor task. The publisher apologizes for the error.https://doi.org/10.1371/journal.pone.0244113The correct citation is: Wang S, Rajananda S, Lau H, Knotts JD (2020) Measuring agency with an adaptive sensorimotor task. PLoS ONE 15(12): e0244113."} +{"text": "This article has been corrected: The Funding information has been updated as follows:This project was supported by the National Natural Science Foundation of China .109632-109645. https://doi.org/10.18632/oncotarget.22759Original article: Oncotarget. 2017; 8:109632\u2013109645."} +{"text": "This article has been retracted: Authors concluded that the experimental results are not solid enough to support their conclusions. Thus, they have made the decision to retract the article upon the agreement of all listed authors. . https://doi.org/10.18632/aging.103485Original article: Aging. 2020; 12:14418\u201314433."} +{"text": "The treatment includes current coronavirus vaccine development.https://www.nytimes.com/interactive/2021/health/bharat\u2010biotech\u2010covid\u201019\u2010vaccine.htmlWhile the most rapidly developed SARS\u2010CoV\u20102 vaccines use RNA technology, this article describes a vaccine developed by using beta\u2010propiolactone to kill the virus particles that constitute the antigen.https://builtin.com/healthcare\u2010technology/biotechnology\u2010effective\u2010coronavirus\u2010vaccineThis article, written at the start of the 2019 coronavirus pandemic, describes the different types of vaccines than can now be developed: genetically engineered viruses, DNA vaccines and mRNA vaccines.https://www.nature.com/articles/s41587\u2010019\u20100385\u20107The first Zaire Ebola virus vaccine was approved in November, 2019. The vaccine uses a vesicular stomatitis virus that expresses an Ebola surface glycoprotein.https://www.frontiersin.org/articles/10.3389/fimmu.2018.01963/fullThis is a journal review article that discusses viral vector, DNA and m\u2010RNA based vaccines.https://www.cell.com/trends/biotechnology/fulltext/S0167\u20107799(19)30050\u20102This review article deals specifically with the development of vaccines directed against pathogenic bacteria. It proposes the application genomic methodologies to accelerate the process of strain selection for vaccine development.https://www.bharatbiotech.com/blog/vaccines/the\u2010emergence\u2010of\u2010inactivated\u2010vaccines/This blog on a commercial website covers types of vaccines: inactivated pathogens, live\u2010attenuated pathogens, sub\u2010unit and nucleic acid\u2010based, and toxoid vaccines.https://www.frontiersin.org/articles/10.3389/fimmu.2018.02315/fullThis comprehensive review article deals largely with bacterial vaccines and also discussed the use of genomics in strain selection and the use of monoclonal antibodies.https://www.cytivalifesciences.com/en/us/solutions/bioprocessing/knowledge\u2010center/bacterial\u2010vaccine\u2010manufacturingThis webpage describes the characterization and purification of bacterial capsular polysaccharides for use in vaccine production.https://weekly.biotechprimer.com/vaccines\u2010powerful\u2010simplicity/This news article describes the different types of SARS\u2010CoV\u20102 virus vaccines that have been worked on and the companies that are doing that research.https://www.cdc.gov/vaccines/pubs/pinkbook/prinvac.htmlThis government website deals with vaccines in the context of the human immune response.https://www.historyofvaccines.org/index.php/content/articles/different\u2010types\u2010vaccinesThis webpage covers a history of vaccine development and the principle organisms and viruses the vaccines are directed against.https://bioscience.lonza.com/lonza_bs/US/en/vaccine\u2010manufacturingThis commercial website deals with the process of vaccine manufacturing.https://www.usp.org/sites/default/files/usp/document/our\u2010impact/covid\u201019/standards\u2010for\u2010quality\u2010vaccines.pdfVaccine manufacture requires standard reagents and procedures. This website deals with these methods and materials that constitute quality control for vaccine development.https://www.nature.com/subjects/recombinant\u2010vaccineNature research page offers a compendium of references and links to further information on recombinant vaccines.This https://www.news\u2010medical.net/health/What\u2010are\u2010the\u2010Different\u2010Types\u2010of\u2010Vaccines.aspxThis article describes the different types of vaccines and the microorganisms and viruses that each are used with.https://www.frontiersin.org/articles/10.3389/fimmu.2019.02997/fullThis article discusses the influenza hemagglutinin vaccine. This article describes efforts to overcome the variability of the hemagglutinin head region to stay one step ahead of the virus.https://www.ncbi.nlm.nih.gov/books/NBK537197/This article deals with the mechanism of action and administration of influenza vaccines.https://www.hiv.gov/hiv\u2010basics/hiv\u2010prevention/potential\u2010future\u2010options/hiv\u2010vaccinesThis website describes efforts to develop a vaccine against HIV.https://www.ncbi.nlm.nih.gov/books/NBK545173/The DPT vaccine is comprised of inactivated diphtheria and tetanus toxins and pertussis antigens.https://www.ncbi.nlm.nih.gov/books/NBK559008/Clostridium tetani requires a tetanus vaccine, as described in detail here.Possible exposure to the toxin produced by https://pubmed.ncbi.nlm.nih.gov/33388125/Streptococcus type III capsular polysaccharide.This paper deals with vaccine development using the"} +{"text": "Scientific Reports 10.1038/s41598-020-74076-y, published online 08 October 2020Correction to: The Acknowledgements section in this Article is incomplete.https://doi.org/10.17862/cranfield.rd.13006631.v1.\u201d\u201cThe authors would like to acknowledge supports from Cametics Ltd., the UK EPSRC funded research . This publication has emanated from research conducted with the financial support of Science Foundation Ireland (SFI) under Grant Number SFI 13/IA/1833 & SFI 16/RC/3918, co-funded by the European Regional Development Fund. The authors are also grateful to Mr. Jim Hurley and Mr. Ben Hopper from Cranfield University for strong and continuous technical supports throughout the research. The underpinning data can be accessed at should read:https://doi.org/10.17862/cranfield.rd.13006631.v1.\u201d\u201cThe authors would like to acknowledge supports from Cametics Ltd., the UK EPSRC funded research . This publication has emanated from research conducted with the financial support of Science Foundation Ireland (SFI) under Grant Number SFI 13/IA/1833 & SFI 16/RC/3918 and Foundation for Polish Science (FNP) under Grant Number First TEAM/2016\u20131/7, co-funded by the European Regional Development Fund. The authors are also grateful to Mr. Jim Hurley and Mr. Ben Hopper from Cranfield University for strong and continuous technical supports throughout the research. The underpinning data can be accessed at"} +{"text": "Nitric oxide acts as a cotransmitter in a subset of dopaminergic neurons to diversify memory dynamics. Published 17, November 2019https://github.com/alexdobin/STAR/blob/master/docs/STARsolo.md) in conjunction with a new release of the genome annotation from Flybase to generate more accurate transcript counts from our sequencing reads. The changes to our published data are minor and all the statistical conclusions are consistent between the original and revised datasets. The changes do not alter any of our conclusions or require revision of the published figures. Nonetheless, we would like to update the Supplementary file 1 to provide the most accurate data for future use. The analysed data was updated at NCBI Gene Expression Ombnibus. The accession number GSE139889 remains the same as in the original publication (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE139889).We improved our RNA-seq analysis pipeline using the STARsolo aligner .Sequencing adapters were trimmed from the reads with Cutadapt prior to alignment with STAR to the Corrected:https://github.com/alexdobin/STAR/blob/master/docs/STARsolo.md) to the Drosophila r6.34 genome assembly on Flybase .Sequencing adapters were trimmed from the reads with Cutadapt prior to alignment with the STARsolo aligner (The following reference was added:GitHub.\u00a02.7.5a. https://github.com/alexdobin/STARDobin\u00a0A.\u00a02020.\u00a0STARsolo: mapping, demultiplexing and quantification for single cell RNA-seq.\u00a0The article has been corrected accordingly."} +{"text": "Correction to: BMC Public Health 16, 431 (2016)https://doi.org/10.1186/s12889-016-3069-yIt was highlighted that in the original article the CompIncorrectThe authors declare that they have no competing interests.CorrectJun Fukuyoshi and Akio Yonekura are the founders of Cancer Scan Co. Ltd. Yoshiki Ishikawa a director at Cancer Scan Co. Ltd. The other authors declare that they have no competing interests."} +{"text": "Nucleic Acids Research, 2020, https://doi.org/10.1093/nar/gkaa451The first version of this article inadvertently neglected to include Ting Gong as third author. This has now been corrected online. The authors regret the error."} +{"text": "Correction to: Cell Death and Disease10.1038/cddis.2015.282 published online 10 December 2015This Article was originally published without the accompanying Supplementary figures. The Supplementary figures are provided below."} +{"text": "Correction to: BMC Public Health 12, 760 (2012)https://doi.org/10.1186/1471-2458-12-760It was highlighted that in the original article the CompIncorrectThe authors declare that they have no competing interests.CorrectJun Fukuyoshi and Akio Yonekura are the founders of Cancer Scan Co. Ltd. Yoshiki Ishikawa a director at Cancer Scan Co. Ltd. The other authors declare that they have no competing interests."} +{"text": "Int J Epidemiol 2020;49:486\u201396. doi: https://doi.org/10.1093/ije/dyz265First published online: 16 January 2020, The originally published version of this article contained errors in the numbering of all references from reference 40 onward. This has now been corrected and OUP apologizes for the error."} +{"text": "Scientific Reports 10.1038/srep19233, published online 18 January 2016Correction to: The website on which the data underlying this study was stored is no longer maintained. The data is now deposited in zenodo, with a 10.5281/zenodo.3662895. As such, in the Abstract,http://www.ucbioinformatics.org/metabenchmark.html\u201d\u201cData sets and results are freely available from should read:https://zenodo.org/record/3662895#.XkMnZnUzbRI\u201d\u201cData sets and results are freely available from"} +{"text": "The following information is missing from the Funding statement: VBO and MA was supported by the European Research Council (Project LipidArrays).The full Funding statement should now read:https://www.britishinfection.org/). SAJ and KP was supported by Medical Research Council and Department for International Development Career Development Award Fellowship MR/J009156/1 (http://www.mrc.ac.uk/). SAJ was additionally supported by a Krebs Institute Fellowship (http://krebsinstitute.group.shef.ac.uk/), Medical Research Foundation grant R/140419 and Medical Research Council Center grant (G0700091). SAR and CL were supported by a Medical Research Council Programme Grant (MR/M004864/1) (http://www.mrc.ac.uk/). RCM, EB, SN and RJE were supported by a Lister Fellowship (www.lister-institute.org.uk/), Medical Research Council Project Grant (MR/J008176/1) (http://www.mrc.ac.uk/). RCM, EB and SAJ were additionally supported the European Research Council Consolidator Award \u201cMitoFun\u201d (https://erc.europa.eu/). HMK and JT were supported by a Canadian Institutes of Health Research, grant # OME-142884, http://www.cihr-irsc.gc.ca/. VBO and MA were supported by a Wellcome Trust grant 094143/Z/10/Z https://wellcome.ac.uk/funding and the European Research Council (Project LipidArrays). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.RJE was supported by a British Infection Association postdoctoral fellowship ("} +{"text": "This article has been corrected: The authors made the mistake in Funding information. The correct Funding is provided below. This correction does not change the content of the publication.. https://doi.org/10.18632/aging.103301Original article: Aging. 2020; 12:10873\u201310895."} +{"text": "The data availability paragraph in Materials and Methods should read as follows.Volume 4, no. 1, e00011-19, 2019, SRP142224. The coassembly and its annotation are available on IMG (https://img.jgi.doe.gov/) under taxon OID 3300014983, MAGs are available from IMG as specified by their taxon OIDs in Table 1, and raw sequences of the 16S V3-V4 rRNA gene amplicon surveys are available on NCBI SRA under ID SRP066190. The metagenome reconstructed 16S rRNA gene sequence of R. aquaticus LMG 30558 is available from NCBI GenBank under reference ID MW131457. The 16S rRNA gene sequence of the R. aquaticus LMG 30558T isolate is available from NCBI GenBank under reference ID MW138094. MAGs are also available from DDBJ/ENA/GenBank under accession IDs SAIV00000000 (R. aquaticus), SAIW00000000 (Bacteroidetes sp. MAG1), and SAIX00000000 (Bacteroidetes sp. MAG2). The versions described in this paper are versions SAIV01000000, SAIW01000000, and SAIX01000000. The draft genome assembly of the R. aquaticus LMG 30558T isolate is available from NCBI GenBank under ID JADDOJ000000000. Flow cytometry data are publicly available on FlowRepository under ID FR-FCM-ZYFM. The data analysis for this article is available at https://github.com/rprops/Ramlibacter--CW. The Anvi\u2019o profile database is available at https://doi.org/10.6084/m9.figshare.6170420, and the Anvi\u2019o pangenome analysis is available at https://doi.org/10.6084/m9.figshare.6170117. Supplemental information and figures are available at https://doi.org/10.6084/m9.figshare.7577636. R. aquaticus LMG 30558T cultures are available from the BCCM (ID LMG 30558) and DSMZ (ID 110366) culture collections.Raw sequence reads are available on NCBI SRA under identifier (ID) or accession no."} +{"text": "Correction to: BMC Pregnancy Childbirth (2020) 20:196https://doi.org/10.1186/s12884-020-02886-zFollowing publication of the original article , we haveDr. Michelle Sholzberg has received honoraria for advisory boards from Pfizer. Dr. Yulia Lin has received research grants from Novartis and consulting fees from Pfizer. The remaining authors declare that they have no competing interests."} +{"text": "This article has been corrected: Due to errors during figure assembly, the wrong transwell image was used for the lower left panel of 1084-1095. https://doi.org/10.18632/oncotarget.6744Original article: Oncotarget. 2016; 7:1084\u20131095."} +{"text": "The correct name is Kamala Thriemer. Additionally, the affiliation listed for Thomas A. Weppelmann is incorrect. Affiliation 38 should therefore read:"} +{"text": "This article has been corrected: The funding information has been updated. The correct listing is given below:This work was supported by the European Research Council [grants number 310649 and 825076].386-398. https://doi.org/10.18632/oncotarget.27438Original article: Oncotarget. 2020; 11:386\u2013398."} +{"text": "Future Science OA due to substantial overlap with a previously published article:The following article has been retracted from Future Sci. OA doi: 10.2144/fsoa-2020-0006 (2020).Retracted article: Beri K. Exploring the microbiome and mindfulness connection. Yale J. Biol. Med. 89(3), 397\u2013422 (2016).Previous article: Schnorr SL, Bachner HA. Integrative therapies in anxiety treatment with special emphasis on the gut microbiome. Future Science OA regret any negative consequences this publication might have caused in the scientific and medical communities.The author and editors of"} +{"text": "An additional affiliation is missing for the first author. Moein Khajehnejad is also affiliated with: Faculty of Information Technology, Monash University, Melbourne, Australia.Moein.khajehnejad@monash.edu.The corresponding author\u2019s email address is incorrect. Dr. Khajehnejad 's correct email address is:"} +{"text": "Int J Epidemiol 2020;49:619\u201328. doi: https://doi.org/10.1093/ije/dyz268First published online: 18 January 2020, The originally published version of this article contained some errors in the setting of some equations (see below). These have now been corrected. OUP apologises for this error."} +{"text": "Scientific Reports 10.1038/s41598-019-38683-8, published online 14 February 2019Correction to: This Article contains a typographical error in the Data Availability section where,https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE117795 and enter token gzahweaipbslfqx into the box.\u201d\u201cThe single cell RNA sequencing data reported in this paper were deposited in NCBI Gene Expression Omnibus (GEO) under the accession number GSE118932. To review, go to should read:https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc= GSE118932.\u201d\u201cThe single cell RNA sequencing data reported in this paper were deposited in NCBI Gene Expression Omnibus (GEO) under the accession number GSE118932. To review, go to"} +{"text": "Scientific Reports 10.1038/srep39491, published online 21 December 2016Correction to: The Article contains an error in the Data Availability section, where the accession code is missing the BioProject prefix \u201cPRJNA\u201d. The correct accession is PRJNA283427. As such, this section should read:Data Availabilityhttp://www.ncbi.nlm.nih.gov/bioproject) under BioProject number PRJNA283427.The sequence data from this study have been submitted to NCBI BioProject ("} +{"text": "This article has been corrected: The pRb blots in HCT116 and HT29 in Figure 3B were inadvertently duplicated during the assembly of the figure. The corrected Figure 3 is shown below. The authors declare that these corrections do not change the results or the conclusions of this paper.5216-5232. https://doi.org/10.18632/oncotarget.23749Original article: Oncotarget. 2018; 9:5216\u20135232."} +{"text": "Correction to: Experimental & Molecular Medicine 10.3858/emm.2009.41.9.072 Published online 29 May 2009After online publication of this article, the authors noticed an error in the Fig. The authors apologize for any inconvenience caused."} +{"text": "This article has been retracted: The Program for Promotion of Research Integrity (PPRI), Academia Sinica, Taiwan, after twenty months of extensive and thorough investigation, has concluded that this paper should be RETRACTED, because of evidence showing that Dr. Ching-Shih Chen manipulated sixteen (16) images.https://ae.daais.sinica.edu.tw/site/datas/detail/2036/30/183/194/0The investigation reports can be downloaded from this link (the two PDFs at the bottom of the page): https://www.sinica.edu.tw/en/news/6469The Academia Sinica\u2019s news release in English can be found here: https://www.sinica.edu.tw/ch/news/6469The Chinese version of the news release can be found here: Ohio State University officials reported that Dr. Ching-Shih Chen had manipulated images in at least 14 papers in different journals, eight of which required retraction.As of today, 11 papers of Dr. Ching-Shih Chen were retracted from different journals.1796-1807. https://doi.org/10.18632/oncotarget.6427Original article: Oncotarget. 2016; 7:1796\u20131807."} +{"text": "This article has an addendum: Signed HIPPA forms from the parents of the 2 patients who were alive at the time of manuscript submission were obtained.551-557. https://doi.org/10.18632/oncotarget.26560Original article: Oncotarget. 2019; 10:551\u2013557."} +{"text": "Open Biol.5, 150126 (Published online 1 December 2015). (https://doi.org/10.1098/rsob.150126)c,d)). This paper has been identified among of a set of papers that present significant text and data duplication and therefore the data reported in this article are unreliable. The authors have not been able to supply the raw data as requested, thus, the editors consider the conclusions of this article to be invalid. The authors have not responded to correspondence about this retraction.Following an investigation, we have found duplicates in the figures presented (notably fig. 5. \u2018The mechanism of viral miRNA editing in virus infection\u2019 panels (https://royalsocietypublishing.org/doi/10.1098/rsob.200165.The image integrity standards and policies for the journal can be found here: Jonathon Pines FRSOpen Biology.Editor-in-Chief,"} +{"text": "Microbe\u2010based drug delivery.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895346/This review targets microbe\u2010based drug delivery with the goal of providing site\u2010specific medical benefits to patients.Synthetic microbes as drug delivery systems.https://pubs.acs.org/doi/10.1021/sb500258bThis article examines potential developments in medicine for using microbes to diagnose disease, produce therapeutics in situ, and deliver medicines.Microbial\u2010fabricated nano\u2010systems.https://www.frontiersin.org/articles/10.3389/fchem.2021.617353/fullThis is a broad treatment on the formulations of microbes with metals, polysaccharides, and other agents for making nano\u2010scale delivery agents.Modes of therapeutic delivery.https://www.cell.com/trends/microbiology/fulltext/S0966\u2010842X(22)00249\u20109This review discusses bacterial therapeutics and vaccines, with a focus on those moving into clinical trials.Bacteria and anti\u2010cancer drugs.https://www.sciencedirect.com/science/article/pii/S0168365920303849This review article highlights the use of bacteria or bacterial derivatives as drug carriers for cancer therapy.Bacterial drug delivery IP.https://www.wipo.int/wipo_magazine/en/2014/04/article_0002.htmlThis interesting article in the World International Patent Organization (WIPO) magazine discusses a microbial drug patented for the treatment of gastrointestinal disorders.Bacterial lysing systems in cancer therapy.https://www.nature.com/articles/s41467\u2010021\u201026367\u20109Salmonella\u2010derived delivery system to induce lysis and release proteins specifically into tumour cells.This article deals with the use of a Bacteria and medical implants.https://www.mdpi.com/2079\u20104983/13/4/173This deals with bacterially responsive drug delivery for the release of antibacterial compounds at the site of implants to mitigate against infections.Anti\u2010microbial peptide delivery.https://agris.fao.org/agris\u2010search/search.do?recordID=US202000140612Nano\u2010scale drug delivery systems are being investigated for the delivery of bacterially produced toxins called bacteriocins."} +{"text": "Correction to: Pediatric Rheumatology (2023) 21:4810.1186/s12969-023-00831-wThe consent for publication section in the original publication was incorrect. The incorrect and correct information is listed in this correction article. The original article has been updated.IncorrectNot applicable.CorrectPublication consent was obtained from all participants."} +{"text": "Edit 3, tag the DOI as ext-link with type=doi rather than uri Phil. Trans. R. Soc. B377, 20200455. (Published online 15 November 2021) (https://doi.org/10.1098/rstb.2020.0455)https://doi.org/10.1098/rstb.2022.0476 [This is an update to the Expression of concern (Published online 26 December 2022):The journal's editorial team wish to update readers on this investigation which isongoing.The authors acknowledge that there are problems with the analyses in this paper, andthey are currently re-analysing the data. The response will be independentlyreviewed and either a correction or retraction will be published in due course."} +{"text": "CMNPD Databasehttps://www.cmnpd.orgThe Comprehensive Marine Natural Products Database (CMNPD) is an open\u2010access resource focussed on marine natural products research.Screening using the CMNPDhttps://www.mdpi.com/2075\u20101729/13/6/1298in silico screening methods for identifying acetylcholinesterase inhibitors using the Comprehensive Marine Natural Products Database (CMNPD).This paper describes MarinLithttps://marinlit.rsc.orgMarinLit is a site dedicated to literature and compound information related to marine natural products research.Marine natural product databaseshttps://onlinelibrary.wiley.com/doi/full/10.1002/biot.201800607This review article highlights dedicated and tangentially related databases that could prove useful for those studying marine natural products. It focusses on freely available resources.PeruNPDBhttps://www.biorxiv.org/content/10.1101/2023.01.15.524152v1This preprint describes an effort to focus on local marine natural products of Peru. Similar efforts are ongoing for Mexico, Brazil, India and China.Marine natural products in clinical usehttps://pubmed.ncbi.nlm.nih.gov/36005531/Only a limited number of marine natural products reach the clinical stage of development, and this review focusses on those.Antifouling marine natural productshttps://www.frontiersin.org/articles/10.3389/fmars.2022.858757/fullSociety invests considerable resources in preventing the build\u2010up of marine life on ships, harbour docks and offshore installations, often using toxic agents such as tributyltin. This article advocates for the use of biological controls to the problem.Marine natural products at Scrippshttps://scripps.ucsd.edu/research/topics/natural\u2010products\u2010chemistryStudies on marine natural products are highlighted by this webpage offered by the Scripps Institution of Oceanography and the University of California at San Diego.Marine natural products cataloguehttps://www.medchemexpress.com/NaturalProducts/marine\u2010natural\u2010products.htmlThis commercial site offers a collection of marine natural products that may be purchased for screening purposes.Marine natural products GRChttps://www.grc.org/marine\u2010natural\u2010products\u2010conference/2024/Gordon Research Conferences discuss cutting edge research in different fields and this one to be held in 2024 focusses on marine natural products.Marine natural product databaseshttps://d4\u2010pharma.com/marine\u2010natural\u2010products\u2010database\u2010for\u2010drug\u2010discovery/This blog post describes the creation of a data compilation from more than 20,000 articles dealing with marine natural products.Sustainable production of marine natural productshttps://www.frontiersin.org/articles/10.3389/fmars.2023.1188090/fullFrontiers special issue on marine biotechnology and bioproducts.This is an Editorial article highlighting different papers submitted for a Metagenomics for marine secondary productshttps://journals.asm.org/doi/10.1128/spectrum.01501\u201023In this report, long\u2010read DNA sequencing was used to determine the biosynthetic capacity of prokaryotes in surface waters of the Yellow Sea.Marine natural product toolhttps://www.biorxiv.org/content/10.1101/2021.01.20.427441v1This preprint details the development of a toolbox for identifying a broad range of biosynthetic gene cluster domains in metagenomic data.Secondary products in the Arctic Oceanhttps://www.microbiologyresearch.org/docserver/fulltext/mgen/7/12/mgen000731.pdf?expires=1697161491&id=id&accname=guest&checksum=C11D8730189C277E67AF0FD38348586DHere is reported metagenomic sequencing of Arctic Ocean planktonic microbiomes and mining for novel biosynthetic gene clusters of natural products.Biosynthetic potential of the global oceanhttps://www.nature.com/articles/s41586\u2010022\u201004862\u20103This study examined around 10,000 microbial genomes from marine sources that yielded approximately 40,000 biosynthetic gene cluster, most of which were characterized as being novel.From ocean to medicinehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460513/Antibiotics summarized reports appearing after 2014 and dealing with marine bacteria and their utility for the production of novel natural products.This review article in the journal"} +{"text": "Machine learning clinical decision support for interdisciplinary multimodal chronic musculoskeletal pain treatment By Zmudzki F and Smeets RJEM (2023) Machine learning clinical decision support for interdisciplinary multimodal chronic musculoskeletal pain treatment. Front. Pain Res. 4:1177070. doi: 10.3389/fpain.2023.1177070A Corrigendum on r.smeets@maastrtichtuniversity.nl\u201d The correct email address is: \u201cr.smeets@maastrichtuniversity.nl\u201dIn the published article, there was a mistake in the corresponding author email address for author Rob J. E. M. Smeets. The email was incorrectly displayed as \u201cThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Adaptive responses and transgenerational plasticity of a submerged plant to benthivorous fish disturbance. Ecology and Evolution, 13, 1\u201312. In the recent article by Li et al. (2023), the citation for \u2018glmm.hp\u2019 R package for statistical analysis is incorrect. The correct reference is as follows:https://doi.org/10.1093/jpe/rtac096.Jiangshan Lai*, Yi Zou, Shuang Zhang, Xiaoguang Zhang. Lingfeng Mao.2022. glmm.hp: an R package for computing individual effect of predictors in generalized linear mixed models. Journal of Plant Ecology 15(6):1302\u20131307. We apologize for this error."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-32568-7, published online 03 April 2023Correction to: The original version of this Article contained an error in the Data availability section, where the GEO accession number was omitted.https://www.ncbi.nlm.nih.gov/geo/). The whole genome sequencing data generated in this study have been submitted to the NCBI SRA database (https://www.ncbi.nlm.nih.gov/bioproject/) under accession number PRJNA832117, reviewer's accession link:\u00a0https://dataview.ncbi.nlm.nih.gov/object/PRJNA832117. All original code has been deposited at Github .\u201d\u201cAll raw and processed sequencing data generated in this study have been submitted to the NCBI Gene Expression Omnibus , under accession number GSE201435. The whole genome sequencing data generated in this study have been submitted to the NCBI SRA database (https://www.ncbi.nlm.nih.gov/bioproject/), under accession number PRJNA832117: https://dataview.ncbi.nlm.nih.gov/object/PRJNA832117. All original code has been deposited at Github .\u201d\u201cAll raw and processed sequencing data generated in this study have been submitted to the NCBI Gene Expression Omnibus (GEO; The original Article has been corrected."} +{"text": "This article has an addendum: Research funding was obtained from the Albany College of Pharmacy and Health Sciences, Scholarship of Discovery Fund.284-293. https://doi.org/10.18632/oncotarget.28397Original article: Oncotarget. 2023; 14:284\u2013293."} +{"text": "Due to a production error, there was a mistake in Supplementary material as published. The incorrect Data Sheet was published, omitting Figures A1 and A2 The correct Data Sheet can now be found under the original articles link: https://www.frontiersin.org/articles/10.3389/fnins.2023.1171417/full#supplementary-materialDue to a production error, there was a mistake in the The publisher apologizes for this mistake. The original article has been updated."} +{"text": "This study looked broadly at plasmids to better understand their composition and distribution as a function of environment.https://www.sciencedirect.com/science/article/pii/S1369527422000364The studies described here investigate how microbial communities alter conjugative plasmid transfer and persistence.https://www.addgene.org/search/catalog/plasmids/?q=pseudomonasPseudomonas. It includes plasmid maps and other useful information.This commercial site contains a large list of plasmids suitable for research with https://royalsocietypublishing.org/doi/10.1098/rstb.2020.0461This opinion piece discusses the role of plasmids in vertical and horizontal transfer and how plasmids might modulate their hosts for their own benefit in some instances.https://blog.addgene.org/plasmids-101-positive-and-negative-selection-for-plasmid-cloningThe blog post here discusses the basics of using plasmids for negative and positive selection purposes.https://www.nature.com/articles/s41467-019-10600-7This paper describes how plasmids might persist over evolutionary time scales without having selectable markers associated with the plasmid.https://pubs.acs.org/doi/10.1021/acssynbio.0c00466Escherichia coli Nissle 1917 natively contains two plasmids, the plasmids are maintained without selection, and they can be engineered for molecular engineering.This report documents that https://phys.org/news/2022-12-reassemble-plasmid-genes-diverse-environmental.htmlEscherichia coli, Pseudomonas putida, Bacillus subtilis and Saccharomyces cerevisiae.This news article describes research in which an environmentally\u2010derived plasmid was engineered to be highly promiscuous. It could transfer between an https://journals.asm.org/doi/epub/10.1128/microbiolspec.plas-0033-2014Here is reviewed plasmids and molecular parts of vectors than can be used for engineering purposes.https://www.addgene.org/vector-database/query/The Vector database currently has 4,399 entries with information on vector backbones. It is compiled by Addgene but the resources are from third party sources and are not their commercial plasmids. There is a link to search Addgene plasmids for those interested.http://www.geneinfinity.org/sp/sp_plasmidsandvectors.htmlThis page provides links to collections of plasmid and vector resources.https://www.snapgene.com/plasmidsThis site contains plasmid annotations and sequences with a focus on cloning vectors from different commercial sources.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581055/pdf/961.pdfAs more microbes are subjected to genome sequencing, and particularly with metagenome sequencing, it is becoming more important to separately identify plasmid DNA from chromosomal DNA.https://www.ebi.ac.uk/genomes/plasmid.htmlWhile this page is not being updated, it still has a useful collection of microbial plasmid sequences."} +{"text": "Funding statement. The project grant reference 2020/00183/001 is wrong. The correct Funding statement appears below.In the published article, there was an error in the"} +{"text": "Correction to: International Journal of Legal Medicine (2023)https://doi.org/10.1007/s00414-023-02999-yThe original article published with inverted author names. Family name was captured first instead of given name. This is now correctly presented here.The original article has been corrected."} +{"text": "Mining terpene synthaseshttps://biotechnologyforbiofuels.biomedcentral.com/articles/10.1186/s13068\u2010022\u201002189\u20109Terpenes are an industrially important and highly abundant class of natural products. This review discussed mining of soil microbial genomes for genes encoding known and novel terpenoid compounds.Metagenomic analysis for new pectinaseshttps://biotechnologyforbiofuels.biomedcentral.com/articles/10.1186/s13068\u2010017\u20100885\u2010yThis study looked a specific microbiome connected to apple compost to find new pectinolytic enzymes.Repurposing CRISPRi for metagenomic mininghttps://www.nature.com/articles/s41587\u2010022\u201001563\u20100Nature Biotechnology describes a new CRISPR\u2010interference method to rapidly mine metagenomic and genomic sequences. This journal is not available without subscription, but is available through many institutional libraries.This study in Metagenomic mining for natural productshttps://www.biorxiv.org/content/10.1101/2021.01.20.427441v1.fullThis article on a preprint server for biological studies describes a tool for rapid mining of microbial biosynthetic gene clusters.Mining enzyme diversityhttps://link.springer.com/referenceworkentry/10.1007/978\u20103\u2010319\u201031421\u20101_216\u20101This review book chapter focuses on metagenomic mining for new enzyme diversity.Microfluidics and metagenome mininghttps://www.liebertpub.com/doi/10.1089/crispr.2022.0054This paper describes a high\u2010throughput, microfluidic method to enrich rare sequences in a metagenomic mixture.Mining hidden biosynthetic potentialhttps://www.nature.com/articles/s41467\u2010021\u201024133\u20105Nature Communications, focused on mining for secondary metabolites.This is a review article in an open\u2010source journal, Long\u2010read metagenomics of marine microbeshttps://journals.asm.org/doi/10.1128/spectrum.01501\u201023Long\u2010read sequencing is important for discovering biosynthetic gene clusters, which are often comprised of dozens of contiguous genes.Hunting down enzymeshttps://elifesciences.org/digests/70021/hunting\u2010down\u2010enzymesThis magazine style article describes tools for analysing genomes to find new enzymes that modify DNA.MGnify databasehttps://www.ebi.ac.uk/metagenomicsMGnify is a database and platform that can be used to assemble, analyse and archive microbiome\u2010derived nucleic acid sequences.MGnify genomeshttps://www.sciencedirect.com/science/article/pii/S0022283623000724This recent paper describes MGnify Genomes, an extension of the MGnify database. This resource includes the increasing availability of biome\u2010specific metagenome\u2010assembled genomes (MAGs).Metagenome submission guidehttps://www.ncbi.nlm.nih.gov/genbank/metagenome/This page offers information for submitting metagenome project sequences to the National Center for Biotechnology Information (NCBI)."} +{"text": "The sentences:early stopping with a patience of ten epochs. early stopping with a patienceof 10 epochs. (page 5947)should be:early stopping if no improvement was obtained afterten non-consecutive epochs.https://github.com/molML/MoleculeACE.Using a patience of 10 epochs (as erroneouslystated previously)does not affect the conclusions of the paper. The corresponding resultscan be found in the dedicated GitHub repository at the following URL:"} +{"text": "Due to a production error, the Data Availability Statement that was originally published was incorrect.The Data Availability Statement is:https://www.ebi.ac.uk/ena/browser/view/PRJEB59277\u201d.\u201cThe original contributions presented in the study are publicly available. This data can be found here: The publisher apologizes for this mistake.The original version of this article has been updated."} +{"text": "Biofilms and continuous chemical catalysishttps://www.sciencedirect.com/science/article/pii/S0167779912000741This article discussed biofilms as a mechanism for production of chemicals, particularly fine chemicals. It has extensive coverage of methods for analysing biofilms.Catalytic biofilmshttps://www.ufz.de/index.php?en=42201This is the page of an academic group studying catalytic biofilms.Engineered biofilm catalystshttps://gtr.ukri.org/projects?ref=BB%2FI006834%2F1This page describes a project to use engineered biofilms for the production of fine chemicals and pharmaceuticals.Pseudomonas biofilm biotransformationshttps://www.jmb.or.kr/journal/view.html?volume=23&number=2&spage=195Pseudomonas biofilm bioreactor that catalysed the conversion of ethylene glycol to glycolic acid over 2 months of continuous operation.This article describes a Polymer biofilms for biocatalysishttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC9528183/In some cases, the most catalytically useful bacteria are not adept at forming biofilms naturally. This study addressed that issue by demonstrating different methods of making polymer\u2010induced biofilms.Anammox biofilm reactorhttps://pubs.acs.org/doi/10.1021/acsestwater.0c00107Anammox microbes have been shown to be very useful in industrial nitrogen removal from wastewaters. This paper describes the development and operation of a flow\u2010through Anammox biofilm reactor.Trickle\u2010bed production of acetic acidhttps://www.frontiersin.org/articles/10.3389/fenrg.2022.842284/fullAn industrially useful biotechnological process involves the use of acetogenic bacteria to convert inexpensive gaseous chemicals into acetic acid. This paper describes a trickle\u2010bed reactor designed for this purpose.Chemical imaging in biofilmshttps://pubs.acs.org/doi/10.1021/acs.est.2c05027This report describes sensitive mass spectrometric methods for imaging chemicals within biofilms.Contaminant effects on biofilmshttps://www.frontiersin.org/articles/10.3389/fmicb.2020.526545/fullThis study examined the effects of nutrients and pharmaceuticals on biofilms.Biofilms in the biorefineryhttps://www.sciencedirect.com/science/article/pii/S0734975021000720This review describes the use of the natural ability of microbes to form biofilms in wastewater treatment and large\u2010scale chemical conversions into products.Productive biofilmshttps://onlinelibrary.wiley.com/doi/full/10.1002/jctb.7208This excellent review article describes the most industrially relevant microorganisms and reactor designs for productive industrial biofilm conversions."} +{"text": "Scientific Reports 10.1038/s41598-023-43276-7, published online 26 September 2023Correction to: In the original version of this Article Filip Machaj was incorrectly listed as a corresponding author. The correct corresponding author for this Article is Tomasz Kazimierz Wojdacz. Correspondence and request for materials should be addressed to tomasz.wojdacz@pum.edu.pl.The original Article has been corrected."} +{"text": "In the originally published versions of the below-listed manuscripts, an acknowledgement was missing: \u201cThis paper is part of the David F. Dinges Festschrift Collection. This collection is sponsored by Pulsar Informatics and the Department of Psychiatry in the Perelman School of Medicine at the University of Pennsylvania.\u201dThis error has been corrected.List of all affected DOI URLs:https://doi.org/10.1093/sleepadvances/zpac034https://doi.org/10.1093/sleepadvances/zpac040"} +{"text": "Pseudo-feeders as a red flag for impending or ongoing severe brain damage in Vein of Galen aneurysmal malformation By Saliou G and Buratti S. (2022) Front. Pediatr. 10:1066114. doi: 10.3389/fped.2022.1066114An Erratum on An omission to the funding section of the original article was made in error. The following sentence has been added: \u201cOpen access funding was provided by the University of Lausanne\u201dThe original version of this article has been updated."} +{"text": "Regulatory T cells promote functional recovery after spinal cord injury by alleviating microglia inflammation via STAT3 inhibition by Rui Liu et al., https://doi.org/10.1111/cns.14161.The cover image is based on the Original Article"} +{"text": "Withdrawal: https://onlinelibrary.wiley.com/doi/10.1002/npr2.12343 ), has been withdrawn by agreement between the authors, the journal Editor in Chief, Tsuyoshi Miyakawa and John Wiley & Sons Australia, Ltd. The Withdrawal has been agreed because the patient revoked consent to the publication.The above article, published online on 07 May 2023 in Wiley Online Library (wileyonlinelibrary.com) as Early View ("} +{"text": "Spatial resolution of cellular senescence dynamics in human colorectal liver metastasis by Ombretta Garbarino et al., https://doi.org/10.1111/acel.13853Cover legend: The cover image is based on the Research Article"} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-35585-8, published online 23 May 2023.Correction to: In the original version of this Article, Rezvan Dadras was incorrectly listed as a corresponding author. The correct corresponding author for this Article is Parham Sadeghipour, as well as Mona Alimohammadi. Correspondence and request for materials should be addressed to psadeghipour@hotmail.com or mona@alimohammadi.co.uk.The original Article has been corrected."} +{"text": "This erratum corrects the following:J Appl Clin Med Phys. 2022; 22: 175\u2013181. https://doi.org/10.1002/acm2.13234Ferris WS, Culberson WS, Smilowitz JB, Bayouth JE. Effects of variable\u2010width jaw motion on beam characteristics for Radixact Synchrony\u00ae. John E. Bayouth reports ownership interest in a company that provides consulting services on image\u2010guided radiation therapy technology . He/(his employer) received travel reimbursement/speaking fees from ViewRay Inc. The remaining authors have no conflicts of interest to disclose."} +{"text": "Nucleic Acids Research, 2023; gkad678, https://doi.org/10.1093/nar/gkad678In the originally published version of this manuscript, the Graphical Abstract contained an error. The correct version of the Graphical Abstract is include here:This error has been corrected online."} +{"text": "This article has an addendum: The melanoma registry database of the Department of Dermatology has been partially supported by an unrestricted grant to the University of Zurich from Amgen, Novartis, BMS, MSD and Pierre Fabre. The study itself required no external funding.1370-1379. https://doi.org/10.18632/oncotarget.28333Original article: Oncotarget. 2022; 13:1370\u20131379."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-39930-9, published online 07 August 2023Correction to: In the original version of this Article, Titaporn Supasri was omitted as a corresponding author. Correspondence and requests for materials should also be addressed to titaporn@narit.or.thThe original Article has been corrected."} +{"text": "All authors have agreed to thefollowing requested changes:In the Author Contributions, YaoyiXing\u2019s name was misspelledas \u201cXaoyi Xing.\u201d The corrected paragraph is includedin this Correction.http://www.ebi.ac.uk/pride/archive/projects/PXD037367.The PRIDE public repository details forthe raw files for thiswork were omitted from the original paper. The raw files can be foundat"} +{"text": "Biol. Lett.19, 20230152 (Published online 20 September 2023). (https://doi.org/10.1098/rsbl.2023.0152)Since initial publication, changes have been made to the author list to correct author names, affiliations and general spelling on the Publisher's website. This does not affect the results of the paper. The list of affiliations can be found in the electronic supplementary material ."} +{"text": "Correction to: Folia Microbiologica https://doi.org/10.1007/s12223-023-01059-7The original version of the Supplementary Information file unfortunately contained an error. The Supplementary Information file was published without accepting track changes. The corrected Word file with accepted track changes for Supplementary data has been provided.The original Supplementary Information file has been corrected.Supplementary file1 (DOCX 536 KB)Below is the link to the electronic supplementary material."} +{"text": "Printing sporeshttps://pubmed.ncbi.nlm.nih.gov/31792444/This abstract links to a paper, a commentary, similar articles and papers citing this paper. The focus of the paper was on embedding spores within hydrogels.Bacterial spores ecology and biotechnologyhttps://pubmed.ncbi.nlm.nih.gov/30798805/This links to an abstract and provides additional links to related papers. The main paper is a review article that highlights applications of spores and calls for more work on the ecology of spores and their role in the environment.Bacillus sporesApplications of https://journals.asm.org/doi/10.1128/aem.01096\u201020Bacillus subtilis spores. Topics include recycling enzymes, drug delivery and applications in materials science.This review article highlights the applications of Bacillus sporesBioengineered https://pubs.acs.org/doi/10.1021/acssynbio.0c00578This study explored the engineering of the spore forming and releasing processes while using a minimum of genetic modifications.Spore surface displayhttps://www.jmb.or.kr/journal/view.html?doi=10.4014/jmb.1807.06066This paper reviews the most important aspects of spore surface display systems with a particular focus on its applications.Bacillus journal club: Sporeshttps://www.linkedin.com/pulse/bioprinting\u2010bacillus\u2010subtilis\u2010spores\u2010daniel\u2010zeiglerBacillus spore imprinting and offers additional ideas as to how that technology could be used.This post discusses a paper describing Engineering sporeshttps://academiccommons.columbia.edu/doi/10.7916/53g9\u2010y771This page links to a doctoral thesis that presents details on the engineering of spore processing to express a heterologous protein in the spore protective coat.Mechanisms of spore germinationhttps://pubmed.ncbi.nlm.nih.gov/37125461/Bacillus and Clostridium species spores. The major focus was on food sterilization.This study examined Spore delivery systemshttps://www.mdpi.com/2218\u2010273X/13/6/947This review article discusses the potential applications for spore delivery mechanisms to make new mucosal surface vaccines.Spore germination receptorshttps://www.cell.com/trends/microbiology/fulltext/S0966\u2010842X(23)00165\u20108While spores are relatively dormant, they must have sensing mechanisms to know when they can acquire specific environmental nutrients that will allow them to germinate. This article discussed these mechanisms.How spores come back to lifehttps://www.sciencedaily.com/releases/2023/04/230427173433.htmScience that reports on spore sensing mechanisms and germinations.This news article highlights a paper in the journal Fabrication of inhalable sporeshttps://www.sciencedirect.com/science/article/abs/pii/S0378517312002852This paper does not use biological spores but takes inspiration from natural spore delivery into lungs to generate nanomaterials for drug delivery.Artificial sporeshttps://www.nanowerk.com/spotlight/spotid=27711.phpThis is a synopsis of a paper describing artificial spores. The procedure described is to coat living cells with various materials to make a more stable, long\u2010lasting biological material."} +{"text": "Campylobacter spp., France . The article has been corrected online (https://wwwnc.cdc.gov/eid/article/29/3/22-1417_article).The author order was incorrect in Multicenter Retrospective Study of Vascular Infections and Endocarditis Caused by"} +{"text": "Sci., 2023, https://doi.org/10.1039/d2sc06040j.Correction for \u2018Radical ring-opening polymerization of sustainably-derived thionoisochromanone\u2019 by Emily A. Prebihalo The authors regret that incorrect details were given for ref. 28 in the original article. The correct version of ref. 28 is given below as ref. The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-44680-9, published online 13 October 2023Correction to: In the original version of this Article, Zahra Atlasbaf was omitted as a corresponding author. Correspondence and requests for materials should also be addressed to atlasbaf@modares.ac.ir.The original Article has been corrected."} +{"text": "Biol. Lett.19, 20220475. (Published online 18 January 2023) (doi:10.1098/rsbl.2022.0475)The primary affiliation institution metadata details for author Benjamin Lecorps has been changed from the University of British Columbia to the University of Bristol. This has now been corrected on the publisher's website."} +{"text": "The Funding statement contains an error. The correct Funding statement is:MF was supported by fellowships from The European Horizon 2020 Framework Programme, H2020-MSCA-IF-2020\u2013101030203/GENMAINEVO (https://ec.europa.eu/), the Human Frontier Science Program\u2014LT000786/2016-L (https://www.hfsp.org/), the European Molecular Biology Organization\u2014ALTF 485\u20132015 (https://www.embo.org/) and the Associazione Italiana per la Ricerca sul Cancro\u2014iCARE 17957 (https://www.airc.it/). AWM was supported by grants from the National Institute of General Medical Sciences\u2014GM43987/RO1 (https://www.nigms.nih.gov/), the National Science Foundation\u2014#1764269 (https://www.nsf.gov/) and the Simons Foundation\u2014#594596 (https://www.simonsfoundation.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."} +{"text": "In the published article, there was an error in the named corresponding authors, and author Anamika Mishra was erroneously excluded. The corrected corresponding author list appears below.Katrina M. Morris* - katrina.morris@roslin.ed.ac.uk; katrina.m.morris345@gmail.comAnamika Mishra* - reach2anamika@yahoo.comThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "This article has been corrected: The Grant Support information has been updated. Please see the paragraph below:CAPES - Coordination for the Improvement of Higher Education Personnel.This research was supported by the Sao Paulo Research Foundation and the National Council of Technological and Scientific Development . This manuscript also received funding from 43016-43032. https://doi.org/10.18632/oncotarget.5513Original article: Oncotarget. 2015; 6:43016\u201343032."} +{"text": "The Data Availability statement is incomplete. The complete statement should read:https://www.ukbiobank.ac.uk/register-apply/) with applications. The ARIC datasets used for the analyses in this manuscript were obtained from dbGaP through dbGaP accession study number phs000280.v3.p1. All summary statistics for Gene-Fish Oil Interactions are publicly available on figshare (https://doi.org/10.6084/m9.figshare.14171069.v1). Key computational scripts are available here: https://github.com/michaelofrancis/FishOil-Lipid-Interaction. All other relevant data are within the manuscript and its Supporting information files.Individual-level genetic and phenotypic data cannot be shared publicly because of participant privacy. Data are available from the UK Biobank Institutional Data Access / Ethics Committee study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institute of Health, Department of Health and Human Services, under contract numbers . The authors thank the staff and participants of the ARIC study for their important contributions. Funding for the ARIC Gene Environment Association Studies (GENEVA) was provided by National Human Genome Research Institute grant U01HG004402 (E. Boerwinkle). The datasets used for the analyses in this manuscript were obtained from dbGaP through dbGaP accession study number phs000280.v3.p1."} +{"text": "Due to a production error, a correction has been made to the Data Availability Statement. The paragraph now reads:https://www.ebi.ac.uk/eva/, PRJEB65581.\u201d\u201cThe original contributions presented in the study are publicly available. This data can be found here: European Molecular Biology Laboratory's European Bioinformatics Institute (EMBL-EBI), European Variation Archive (EVA), The publisher apologizes for this mistake. The original article has been updated."} +{"text": "The Data Availability statement is incomplete. The complete statement should read:https://www.ncbi.nlm.nih.gov/bioproject/) under the accession numbers PRJNA653772 and PRJNA945849, respectively. All other relevant data are in the manuscript and Supporting Information files.RNA-seq and ChIP-seq data have been deposited at BioProject ("} +{"text": "Nature Communications 10.1038/s41467-023-40126-y, published online 24 July 2023Correction to: The original version of this article contained an error where Rohit K. Jangra and Zhongde Wang were not listed as corresponding authors and their email addresses rohit.jangra@lsuhs.edu and zonda.wang@usu.edu were not included. This has been corrected in both the PDF and HTML versions of the Article."} +{"text": "JCI Insight. 2018;3(19):e121123. https://doi.org/10.1172/jci.insight.121123Original citation JCI Insight. 2023;8(13):e173086. https://doi.org/10.1172/jci.insight.173086Citation for this retraction: JCI Insight of data misrepresentation in this article, discovered in the process of internal review. In particular, natural history controls without surgical intervention were admixed with data from rats randomized to receive surgical placebo infusion, without correct attribution. The authors have indicated that the conclusions of the article may be valid; however, the corresponding author and the institution deemed the data misrepresentation sufficiently substantive to request retraction. Therefore, JCI Insight is retracting this article.The Smidt Heart Institute of Cedars-Sinai Medical Center recently notified"} +{"text": "Modulation effects of different treatments on periaqueductal gray resting state functional connectivity in knee osteoarthritis knee pain patients by Jun Zhou et al., https://doi.org/10.1111/cns.14153.The cover image is based on the Original Article"} +{"text": "This article has been retracted: Due to defects in the experimental results and methods, the conclusions of this paper are invalid. The authors were unable to verify or replicate the experiments. As a result, with the agreement of all authors, Oncotarget has decided to retract this paper.109238-109246. https://doi.org/10.18632/oncotarget.22652Original article: Oncotarget. 2017; 8:109238\u2013109246."} +{"text": "Escherichia coli\u2010associated follicular cystitis in dogs: Clinical and pathologic characterization. J Vet Intern Med. 2023;37(3):1059\u20101066. doi:In the originally published article, the author's name Katarina Eskola was spelled incorrectly. This has been corrected in the version of record on Wiley Online Library.The authors regret for this error."} +{"text": "J Clin Invest. 2023;133(10):e165228. https://doi.org/10.1172/JCI165228Original citation: J Clin Invest. 2023;133(13):e173110. https://doi.org/10.1172/JCI173110Citation for this corrigendum: EGFP and AAV-Cre were inverted. The correct figure part is below. The HTML and PDF files have been updated online. The authors have stated that this correction does not change any of the conclusions made.In the original version of The authors regret the error."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-023-40562-2, Published online 22 August 2023Correction to: The original version of this Article contained an error in the Data availability section where the link to the dataset was incorrect.https://doi.org/10.15482/USDA.ADC/1529269.\u201d\u201cRaw sequence reads have been deposited to NCBI Sequence Read Archive under the accession PRJNA95317. Other data and R analysis has been deposited at the USDA NAL Ag Data Commons at now reads:PRJNA957317. Other data and R analysis has been deposited at the USDA NAL Ag Data Commons at https://doi.org/10.15482/USDA.ADC/1529269.\u201d\u201cRaw sequence reads have been deposited to NCBI Sequence Read Archive under the accession The original Article has been corrected."} +{"text": "The word \"mechanisms\" was misspelled in the title of the article. The correct title is: Network Bursting Dynamics in Excitatory Cortical Neuron Cultures Results from the Combination of Different Adaptive Mechanisms. The correct citation is: Masquelier T, Deco G (2013) Network Bursting Dynamics in Excitatory Cortical Neuron Cultures Results from the Combination of Different Adaptive Mechanisms. PLoS ONE 8(10): e75824. doi:10.1371/journal.pone.0075824"} +{"text": "Successful treatment depends on early and accurate diagnosis . Therefoto blood . This noto blood . Studyinto blood . It woul"} +{"text": "Figure 1 has some arrows that are missing from the image. Please see the correct version of the figure at the following link:http://plosone.org/corrections/pone.0047343.g001.cn.tif"} +{"text": "Dr. Huiping Yan is co-corresponding author with Dr. Li Wen. Dr. Huiping Yan can be reached at the email address yhp503@vip.sina.com"} +{"text": "For the article by Michael Aquino et al., p. 1499, the correct title is \u201cProtective Behavior Survey, West Nile Virus, British Columbia.\u201dhttp://wwwnc.cdc.gov/eid/article/10/8/03-1053_article.htm.The corrected article appears online at We regret any confusion this error may have caused."} +{"text": "There was an error in the Funding statement. http://www.973.gov.cn/AreaAppl.aspx], National Water Pollution Control and Management Technology Major Project (2012ZX07101-010) [http://nwpcp.mep.gov.cn/] and State Key Laboratory of Freshwater Ecology and Biotechnology (2011FBZ07) [http://eastlake.ihb.ac.cn/]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The correct statement is: This study was jointly supported by the National Basic Research Program of China (973 Program) (2008CB418101) ["} +{"text": "There were errors in author names in the citation. The correct citation is: Koschwanez JH, Foster KR, Murray AW (2011) Sucrose Utilization in Budding Yeast as a Model for the Origin of Undifferentiated Multicellularity. PLoS Biol 9(8): e1001122. doi:10.1371/journal.pbio.1001122"} +{"text": "The version of Figure 5 in the article was incomplete.http://www.plosone.org/corrections/pone.0071561.g005.tifThe complete version of the figure is available here:"} +{"text": "PLoS ONE 8(11): e81213. doi:10.1371/journal.pone.0081213 The word \"treatment\" was incorrectly spelled in the Title of the article. The correct Title is: \"Association of"} +{"text": "The word \"Hierarchical\" is misspelled in the article title. The correct title is: Mapping Informative Clusters in a Hierarchical Framework of fMRI Multivariate Analysis. The correct citation is: Xu R, Zhen Z, Liu J (2010) Mapping Informative Clusters in a Hierarchical Framework of fMRI Multivariate Analysis. PLoS ONE 5(11): e15065. doi:10.1371/journal.pone.0015065"} +{"text": "IJMS[i.e., the galectins. These errors have been amended in an amended version of the manuscript, which is available from the International Journal of Molecular Sciences website. The authors and publisher apologize for the inconvenience.The authors wish to add this correction on their paper published in IJMS. Galectihttp://www.mdpi.com/1422-0067/13/12/17294/s1.The corrected version can be accessed at:"} +{"text": "KBS has supported the long-term demographic and behavioral studies at RPPN-FMA with funds from NSF , the National Geographic Society , the Liz Claiborne and Art Ortenberg Foundation (http://www.lcaof.org), Fulbright Foundation (http://www.fulbright.org), Sigma Xi Grants-in-Aid (http://www.sigmaxi.org), Grant 0000213 from the Joseph Henry Fund of the NAS , WWF (http://www.wwf.org), L.S.B. Leakey Foundation (http://www.leakeyfoundation.org), Chicago Zoological Society (http://www.brookfieldzoo.org), Lincoln Park Zoo Neotropic Fund (http://www.lpzoo.org), Margot Marsh Biodiversity Foundation, Conservation International (http://www.conservation.org), and the Graduate School of the University of Wisconsin-Madison (http://www.grad.wisc.edu). PBC and CSA were supported by CNPq and Petrobras (http://www.petrobras.com.br) scholarships, respectively. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This work was sponsored by Minist\u00e9rio do Meio Ambiente \"PROBIO - MMA/BIRD/GEF/CNPq\" ("} +{"text": "This website gives the name of the producing organism as a http://www.gumtech.com/products/GuarReplace.phpGuar gum is a plant polysaccharide that is used in foods and, most recently, in hydraulic fracturing to produce oil and gas. There is an ongoing search to find replacements due to the huge volumes required for the latter application.http://en.wikipedia.org/wiki/Xanthan_gumXanthomonas campestris that is widely used in the food industry, as described in this Wikipedia entry.Xanthan gum is a polysaccharide secreted by the bacterium http://www.polysaccharides.us/aboutlevan_background.phpLevan is a polysaccharide made of fructose that is unusual by packing into a highly stable spherical structure. This website describes many of the properties and used of the polymer.http://www.mycology.adelaide.edu.au/Fungal_Descriptions/Hyphomycetes_(dematiaceous)/Aureobasidium/This fungus produces the exopolymer pullulan.http://www.elicityl-oligotech.com/?fond=rubrique0026;id_rubrique=30Spirulan, produced by certain strains if filamentous cyanobacteria, is an acidic, sulfated polysaccharide.http://www.biopharma.novozymes.com/en/products/hyaluronic-acid/Pages/default.aspxHyaluronan is an important biomedical polymer. Its sources have been limited and its recombinant production is an important development."} +{"text": "The name of the first author was given incorrectly. The correct name is: Simone Del Fabbro. The correct citation is: Del Fabbro S, Nazzi F (2013) From Chemistry to Behavior. Molecular Structure and Bioactivity of Repellents against Ixodes ricinus Ticks. PLoS ONE 8(6): e67832. doi:10.1371/journal.pone.0067832."} +{"text": "The following funders provided living stipends for author Eric Patterson:http://www.arcsfoundation.org/Achievement Rewards for College Scientists: http://www.onr.navy.mil/Office of Naval Research Grant #10230702:"} +{"text": "Listeria monocytogenes Infection in Israel and Review of Cases Worldwide, by Y. Siegman-Igra et al., an error appears in the discussion section. The corrected sentence appears below and online at http://wwwnc.cdc.gov/eid/article/8/3/01-0195_article.htmInThe case-fatality rate in the collected data on nonperinatal infection was 36% .We regret any confusion this error may have caused."} +{"text": "There is an error in Table 2. The entry cov squared sVdotA in the left-hand column should not be squared. The correct version of Table 2 can be viewed here: http://www.plosone.org/corrections/pone.0053216.001.cn.tifThe correct version of the legend of Table 2 can be viewed here:"} +{"text": "In Table 4, the symbols that denote the traps were negative have accidentally been omitted. Furthermore, the table's symbol legends at the bottom are misaligned. Please see the corrected Table 4 here:http://www.plosntd.org/corrections/pntd.0001822.t004.cn.tif"} +{"text": "The TCGA data analyzed here are available through dbGAP, accession phs000178.v8.p7 (http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000178.v8.p7).\"The authors wish to publish the following erratum for the Acknowledgements Statement: \"The results published here are in whole or part based upon data generated by The Cancer Genome Atlas pilot project established by the NCI and NHGRI. Information about TCGA and the investigators and institutions who constitute the TCGA research network can be found at"} +{"text": "This blog to discusses differences in annotation tools and offers information on new tools.http://blog.tshw.de/wp-content/uploads/2009/03/Applied-Metagenomics-Presentation.pdfThis set of PowerPoint slides gives some examples of application of metagenomic studies of microbes.http://www.biotechnologyforbiofuels.com/content/pdf/1754-6834-4-23.pdfThis study describes mining of metagenomic data for novel glycohydrolases that might be useful to deconstruct plant biomass and produce biofuels.http://www.ecolyse.com/microbeid.phpThis company offers services using metagenomics to monitor microbial populations with respect to biofouling, biocide effectiveness and hydrogen sulfide production; support services for drilling industries.http://www.hydrocarbonmetagenomics.comPotential applications of the hydrocarbon metagenomics project are in oil sands remediation and stimulating coal bed methane generation.http://www.spe.org/jpt/print/archives/2011/11/11Microbes.pdfThis article highlights microbiology relevant to the oil industry and includes such methods as metagenomic analysis.http://www.sciencemag.org/content/336/6086/1253Microbes in the gut influence the efficacy or activation of oral drugs. This page links to an article discussing how metagenomics could help in this assessment.http://metapath.cbcb.umd.eduThis project was initiated to analyse metabolic pathways reconstructed from metagenomic data.http://www.sciencedirect.com/science/article/pii/S1043661812001545This article reviews literature on our current understanding of how complex microbial consortia degrade xenobiotic compounds in soil, water and the human intestine and the application of metagenomics to aid in these studies."} +{"text": "Diabetic Retinopathy for the comprehensive ophthalmologist. Walker J.http://drcobook.com. Please note that the book is now three years old and that new information has become available, in particular about intravitreal injections. However, the book also covers timeless topics such as informed consent and diabetes control.This book will be available in electronic format on the new Community Eye Health Update CD, due out with the December 2011 edition of this journal. Look out for your free copy! The book is also available for purchase or free download (nine PDF files of 14-59MB each) from Diabetes grading scheme: International Clinical Diabetic Retinopathy And Diabetic Macular Edema Disease Severity Scales. International Council of Ophthalmology, October 2002.http://archive.icoph.org/standards/gdrp.htmlPatient information about diabetic retinopathy www.retinalscreening.nhs.uk/userFiles/File/diabeticRetinopathyFacts.pdfPatient information about a DR screening programme: examples in several languages www.dhsspsni.gov.uk/public_health_diabetic_retinopathyDetailed patient information about screening for DR www.retinalscreening.nhs.uk/userFiles/File/EyeScreeningForDiabetes.pdfPatient information about laser treatment www.retinalscreening.nhs.uk/userFiles/File/PreparingForLaserTreatmentDR.pdf"} +{"text": "There were multiple errors in the Author Contributions statement. The Author Contributions statement should read: \"Conceived and designed the experiments: NP JV. Performed the experiments: NP WD SR AC. Analyzed the data: NP WD SR TVL. Contributed reagents/materials/analysis tools: AC SR. Wrote the paper: NP WD JV.\"In addition, a funding organization was incorrectly omitted from the Funding Statement. The following sentence should be included in the Funding Statement: \"T.V.L. is a post-doctoral fellow of the Fund for Scientific Research Flanders (FWO).\""} +{"text": "Tragelaphus strepsiceros)\u201d by Andrew A. Cunningham et al., errors occurred in the title.In the article entitled \u201cDistribution of Bovine Spongiform Encephalopathy in Greater Kudu (The corrected title appears below:Tragelaphus strepsiceros).Bovine Spongiform Encephalopathy Infectivity in Greater Kudu (http://wwwnc.cdc.gov/eid/article/10/6/03-0615_article.htm.The corrected article appears online at We regret any confusion this error may have caused."} +{"text": "Regarding the paper \u2018Individual and contextual factors influencing patient attrition from antiretroviral therapy care in an urban community of Lusaka, Zambia\u2019 by Maurice Musheke, Virginia Bond and Sonja MertenJournal of the International AIDS Society Supplement 1. Citation: http://www.jiasociety.org/index.php/jias/article/view/17366 \u2223 http://dx.doi.org/10.7448/IAS.15.3.17366Published in Table 1 are not clear. The correct table is displayed belowThe categories in"} +{"text": "There was an error in the corresponding author designation. Bosiljka Tasic and Liqun Luo are both corresponding authors. Bosiljka Tasic's e-mail address is bosiljka.tasic@gmail.com. Liqun Luo's published e-mail address was incorrect; lluo@stanford.edu is correct."} +{"text": "In Table 1, the wrong PDB codes were associated with the chemical structures shown . Please use the corrected version of Table 1 at the following link:http://www.plosone.org/corrections/pone.0040147.t001.cn.docx"} +{"text": "The Supporting Figures are currently provided as CDR files and the Supporting Tables and Protocol are provided as WPD documents. For any readers unable to access these files types, the authors have provided PDF files of all Supporting Information files.Figure S1Quantifying Potential Bias in the Magnitude of Selection Gradients Caused by Pseudoreplication. Mean sexual selection gradients on eight logcontrast male CHCs from three geographic populations are presented. For each population, mean selection gradients were estimated from 1,000 bootstrap replicates each of two subpopulations composed of 128 males randomly sampled from the population of 256 males. In subpopulation A, 64 trials were randomly selected, and both the chosen and rejected males were used. In subpopulation B, a single male (chosen or rejected) was sampled from each of the 128 trials. The line is a one-to-one line.doi:10.1371/journal.pbio.0030368.sg001Click here for additional data file.Figure S2Quantifying Potential Bias in the Significance Level of Selection Gradients Caused by Pseudoreplication. Mean significance levels for the sexual selection gradients on eight logcontrast male CHCs from three geographic populations estimated from 1,000 bootstrap replicates of subpopulations A and B as described in doi:10.1371/journal.pbio.0030368.sg002Click here for additional data file.Table S1Standardized Linear and Nonlinear Sexual Selection Gradients on the Eight Male CHCs for Each of the 12 Populations.doi:10.1371/journal.pbio.0030368.st001Click here for additional data file.Table S2Media Recipes for the Three Treatment Environments.doi:10.1371/journal.pbio.0030368.st002Click here for additional data file.Protocol S1Pseudoreplication and Multiple-Choice Mating Trials.doi:10.1371/journal.pbio.0030368.sd001Click here for additional data file."} +{"text": "The article has been corrected online (http://www.cdc.gov/eid/content/17/4/645.htm).References were misnumbered in the article Complete Sequence and Molecular Epidemiology of IncK Epidemic Plasmid Encoding"} +{"text": "Figures 2 and 4 are corrupted in the HTML article. Please use the following links to access the proper versions of these figures.Figure 2: Figure 4: Figure 3 incorrectly refers to \"Anas clypeata\" in the diagram. This has been replaced with \"Anas sibilatrix\". The correct figure can be seen at the following link:http://plosone.org/corrections/pone.0063334.g003.tif"} +{"text": "The last author, Kevin Pethe, should be noted as a Corresponding Author for the article. The last author's email address is: kevin.pethe@ip-korea.org"} +{"text": "Identifying functions for all gene products in all sequenced organisms is a central challenge of the post-genomic era. However, at least 30-50% of the proteins encoded by any given genome are of unknown or vaguely known function, and a large number are wrongly annotated. Many of these \u2018unknown\u2019 proteins are common to prokaryotes and plants. We set out to predict and experimentally test the functions of such proteins. Our approach to functional prediction integrates comparative genomics based mainly on microbial genomes with functional genomic data from model microorganisms and post-genomic data from plants. This approach bridges the gap between automated homology-based annotations and the classical gene discovery efforts of experimentalists, and is more powerful than purely computational approaches to identifying gene-function associations.Among Arabidopsis genes, we focused on those that (i) are unique or belong to families with no more than three members, (ii) occur in prokaryotes, and (iii) have unknown or poorly known functions. Computer-assisted selection of promising targets for deeper analysis was based on homology-independent characteristics associated in the SEED database with the prokaryotic members of each family. In-depth comparative genomic analysis was performed for 360 top candidate families. From this pool, 78 families were connected to general areas of metabolism and, of these families, specific functional predictions were made for 41. Twenty-one predicted functions have been experimentally tested or are currently under investigation by our group in at least one prokaryotic organism . Ten additional predictions have been independently validated by other groups. Discovering the function of very widespread but hitherto enigmatic proteins such as the YrdC or YgfZ families illustrates the power of our approach.Our approach correctly predicted functions for 19 uncharacterized protein families from plants and prokaryotes; none of these functions had previously been correctly predicted by computational methods. The resulting annotations could be propagated with confidence to over six thousand homologous proteins encoded in over 900 bacterial, archaeal, and eukaryotic genomes currently available in public databases. Accurate characterization of as many genes as possible is a central challenge of the post-genomic era and an essential precondition for progress in systems biology . But thihttp://www.genomesonline.org), the numbers of unknown genes continue to increase )http://theseed.uchicago.edu/ (see http://TheSEED.org for access to data relating to the SEED Project) was the main comparative genomics platform of this study. This database hosts all validated and proposed functional predictions developed in the course of this study for 78 genes families analysed in this study.The SEED genomic database and software suite , publiclgene attributes and organism attributes , which provide valuable non-homology based clues for functional predictions for uncharacterized genes.The SEED organizes genomic data in the form of subsystems covering all organisms rather than on an organism-by-organism basis. Subsystems are developed and maintained by experts to capture the current status of knowledge of specific biological processes in model, well characterized organisms and to project this knowledge to other species via comparative genomics and metabolic reconstruction techniques . Each suhttp://theseed.uchicago.edu/FIG/SubsysEditor.cgi. They are regularly updated to accommodate newly sequenced bacterial genomes as well as novel experimental data and other relevant data as they become available.All Subsystems created in this study, as well as over 1300 resident subsystems in SEED encoding all aspects of microbial physiology and metabolism are available on the public SEED server at http://www.nmpdr.org/FIG/wiki/view.cgi/FIG/SigGenes). This tool identifies gene families that are common to a selected group of genomes, or those that differentiate one group of genomes from another. Annotations for paralog families were made using physical clustering when possible or by building phylogenetic trees using the ClustalW tool [Phylogenetic occurrence profiles were analysed using the Signature Genes tool on the NMPDR server and KEGG (http://www.genome.jp/kegg) [http://www.brenda-enzymes.info/) [Engine http://www.sbg.bio.ic.ac.uk/phyre/) [http://pfam.sanger.ac.uk) [http://www.arabidopsis.org/) [Saccharomyces Genome Database http://www.yeastgenome.org) [http://www.microbesonline.org/) [http://ecogene.org/) [E. coli genes and metabolism (http://biocyc.org/ECOLI/) [http://genome.kazusa.or.jp/cyanobase) [Pseudomonas genome database (http://www.pseudomonas.com/) [http://rhodobase.org/index.php). Collections of Arabidopsis global expression and proteomics data with on-line tools for visualization and analysis: ATTED (http://www.atted.bio.titech.ac.jp/) [http://csbdb.mpimp-golm.mpg.de/csbdb/dbxp/ath/ath_xpmgq.html, [http://bioinfo.ucr.edu/projects/Unknowns/external/express.html); Genevestigator (https://www.genevestigator.com) [http://ppdb.tc.cornell.edu/) [http://www.rcsb.org/pdb/home/home.do) [We also used the bioinformatic tools and resources at NCBI (jp/kegg) , BRENDA s.info/) , PHYRE (/phyre/) , the Pfar.ac.uk) , and speis.org/) ; SGD (Saome.org) ; Microbene.org/) ; EcoGenene.org/) ; EcoCyc /ECOLI/) ; Cyanobaanobase) ; Pseudomas.com/) ; and Rho.ac.jp/) ; Golm Trgq.html, -33); PEDtor.com) -33; PPDBll.edu/) ; PDB, Thhome.do) .Methods for the three experimental validation vignettes described above are already, or soon will be, described in the authors\u2019 publications.The authors declare that they have no competing interests.V de C-L and ADH conceived the study and, with SG, carried out the bioinformatic and function prediction work, and drafted the manuscript. RO and AW participated in the bioinformatic analysis. BEY, MB, IKB, CH-B, LJ, AL-N, AP, and JCW performed the experimental validation experiments. BEY participated in manuscript preparation. All authors read and approved the final manuscript.Gene families shared between plants and prokaryotes: unique Arabidopsis genes (1A), paralogous Arabidopsis gene families with 2 members (1B), paralogous Arabidopsis gene families with 3 members (1C).Click here for filehttp://www.theseed.org/Papers/20101120/.Gene families shared between plants and Prokaryotes, that were linked to general areas of metabolism and physiology, or associated with more specific potential functions. All additional files table were also made available on: Click here for file"} +{"text": "In this review, following a description of candidate gene prioritisation, we summarise the approaches to single nucleotide polymorphism (SNP) prioritisation and discuss the tools available to assess functional relevance of the risk variant with consideration to its genomic location. The strategy and the tools discussed are applicable to any study investigating genetic risk factors associated with a particular disease. Some of the tools are also applicable for the functional validation of variants relevant to the era of GWAS and next generation sequencing (NGS).The candidate gene approach has been a pioneer in the field of genetic epidemiology, identifying risk alleles and their association with clinical traits. With the advent of rapidly changing technology, there has been an explosion of Candidate gene studies have been at the forefront of genetic association studies i.e. identifying risk variants associated with a particular disease. Candidate gene studies are relatively cheap and quick to perform, and are focused on the selection of genes that have been in some way related to the disease previously and thus come with prior knowledge about gene function. The candidate gene approach begins with selection of a putative candidate gene based on its relevance in the mechanism of the disease (trait) being investigated . This ishttp://hapmap.ncbi.nlm.nih.gov/) [http://www.1000genomes.org/) [In silico initiatives which take into account LD and compile tag SNPs and haplotypes can be very helpful in circumventing this.Candidate gene association studies have been criticised on some aspects, but these can be duly overcome by the range of new tools and resources developed to this end. One such aspect is non-replication of results. One of the major issues for non-replication of the results involves population stratification, which can easily be circumvented by considering a replication study using an independent and random cohort of test and control populations, which reduces the chance of occurrence of a similar admixture showing similar patterns of variations . The manih.gov/) and 1000es.org/) , providees.org/) ,8. Falsees.org/) and/or bes.org/) . In siliin silico tools to evaluate all aspects of the candidate gene and the prioritised SNPs in a strategic manner.Considering these aspects along with cumulative effect of multiple loci and complex disease heterogeneity, a fine tuning of the candidate gene approach has been sorted after ,9. Complin silico methods are applicable to the functional analysis of data generated through various candidate gene association studies or for variants identified through post-GWAS fine mapping studies and/or next-generation sequencing.This review intends to summarize current bioinformatics tools and literature available for the purpose of selecting a candidate gene for disease association studies and the genetic variants such as SNPs, from these candidate genes de novo, or from within a linkage peak. Some of these http://www.ihop-net.org/UniPub/iHOP/) [http://pubcrawler.gen.tcd.ie/) [http://www.biovista.com/bea/) [http://www.ingenuity.com) is a depot of manually reviewed, enriched and sorted information of biological interactions and functional annotations, provided to the user through powered products like IPA\u00ae, iReport\u00ae in a contextual interface, also linking out to the original articles.Recent data mining software advancements have catered substantially to growing research needs making it much easier to cope with the initial phase of searching through the enormous amounts of literature present online and keeping constantly updated in order to intelligently select a candidate gene. Tools provided by iHOP Web services (b/iHOP/) enables tcd.ie/) enables om/bea/) is uniquhttp://www.reactome.org) [http://www.litinspector.org) [http://www.netpath.org/index.html) [http://predictivenetworks.org/) [http://www.genego.com/) technology facilitates pathway analysis to find interacting molecules and subsequent interactions relevant to the investigated trait or disease. Ingenuity IPA also considers pathway analysis in its package. Another website ToppGene suite (http://toppgene.cchmc.org/) [Analysing participating pathways is an important aspect of any gene\u2019s functional analysis strategy. In this view, REACTOME (ome.org) is a crotor.org) and NetPex.html) allow onks.org/) integratmc.org/) , providehttp://www.esat.kuleuven.be/gpp), links out to 33 current computational tools for this purpose, such as GeneRank, GeneWanderer, Caesar, SNPs3D and GeneDistiller among many others. This resource compares many online computational tools and thus, provides an efficient and comprehensive guide to help the user develop a suitable gene prioritisation strategy, and is highly recommended.Finding candidate genes for further investigation, also defined as gene prioritisation has been covered in detail elsewhere . The hoshttp://www.ncbi.nlm.nih.gov/omim) [http://www.phenopred.org/) [https://www.oncomine.org) [in silico gene function prediction relevant to cancer study, with their efficacy in suitably classifying uncharacterised cancer genes based on current knowledge from online databases has been given by Hu et al.[Functional analysis of a gene is incomplete without a brief investigation for any existing disease associations. OMIM\u00ae, Online Mendelian Inheritance in Man\u00ae (ov/omim) is a dated.org/) is anothine.org) providinHu et al..http://www.ncbi.nlm.nih.gov/Entrez) [http://www.ensembl.org) [Kallikrein15 (KLK15) gene locus, where a SNP (rs266851) closely located (15\u00a0kb downstream) to a novel exon, renders increased susceptibility to ovarian cancer survival and is predicted to play a role in alternative mRNA splicing [KLF6 gene polymorphism, called IVS1 -27\u00a0G\u2009>\u2009A, i.e. the IVS\u0394A allele giving rise to an additional DNA binding site and increased expression of three alternative spliced transcripts of the gene [http://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/) [http://genome.ucsc.edu/) [http://genome.ucsc.edu/ENCODE/) [Once a thorough assessment of literature and a holistic view of interacting pathways to the gene of interest have been considered, one is ready to focus on the gene composition and sequence. A gene locus can be analysed for various attributes. Many popular, consistently well updated and publically available databases provide genetic and functional information of a gene and its locus, which are advantageous to consider during SNP selection. Prior knowledge of the gene\u2019s functional and structural elements within and those in its periphery can elicit a better understanding of the putative function of the gene variants. Comprehensive sites such as Entrez Gene (/Entrez) and Ensembl.org) host an splicing . Another a SNP rs6851 clossc.edu/) is an exENCODE/) which ishttp://genome.lbl.gov/vista) [http://enhancer.lbl.gov/) [http://rviewer.lbl.gov/) [http://genepipe.ncgm.sinica.edu.tw/variowatch/main.do) [To assist in probing the functional importance of candidate genes while prioritising them, the VISTA Genome Browser (v/vista) gives tobl.gov/) , which ibl.gov/) , a tool main.do) which rehttp://www.ncbi.nlm.nih.gov/projects/genome/assembly/grc/).Various high-end computational resources developed in the last decade are freely available online and are updated continuously, although some limitations exist. Tools which rely on Gene Ontology (GO) to characterise information are limited because the GO annotation is an ongoing process, and cannot provide a full picture. Also, it shows a bias towards well known, better characterised diseases and research terms, hence, making the search miss on what could otherwise be functionally relevant to the gene under investigation . Thus toA consolidated account of all the above mentioned resources is provided in Additional file Once the relevance of the candidate gene and the spread of its functional elements have been noted, the next step is cataloguing the SNPs present in the candidate gene, in its regulatory sequences , and in its surrounding regions which might have long distance effects on the gene function (eg. enhancers). A demonstration of this step and its context can be found in a recent review by us focussed on cataloguing all SNPs important to the Kallikrein gene locus .et al.[http://www.ncbi.nlm.nih.gov/snp) [http://genome.wustl.edu/pub/software/polyscan/) [http://bioq.saclab.net/) [https://cgsmd.isi.edu/dbsnpq/) [http://snpper.chip.org/) [http://www.cisreg.ca/) although the link is not currently functional [http://variantgps.nci.nih.gov/cgfseq/pages/snp500.do) [http://variantgps.nci.nih.gov/cgfseq/pages/home.do). ANNOVAR (http://www.openbioinformatics.org/annovar/) [http://snpinfo.niehs.nih.gov/) [Some resources which facilitate scouring the gene locus for submitted variants have been reviewed extensively by Coassin et al. such as gov/snp) ,38. Polylyscan/) can be uab.net/) enables dbsnpq/) providesip.org/) , one of nctional . This isnctional . A databp500.do) hosted bnnovar/) enables ih.gov/) providesr2, where r is the correlation coefficient between two loci with alleles in association [http://distild.jensenlab.org/[http://www.sanger.ac.uk/resources/software/gliders/) [http://snp.istech21.com/snpanalyzer/2.0/) [http://www.broad.mit.edu/mpg/snap/) [http://www.genes.org.uk/software/LD-software.shtml[Linkage disequilibrium is a phenomenon where alleles associate at different loci non-randomly; carrying with them conserved combinations of SNPs. The most widely recognised measure for LD is ociation . A gene ociation . Analysiociation ; becauseociation ,49. Recenlab.org/, GLIDERSliders/) , SNPAnaler/2.0/) further g/snap/) further are.shtml.http://hapmap.ncbi.nlm.nih.gov/) took the initiative of genotyping sections of human populations worldwide to bring the haplotype map, and accelerate the search for Haplotypes and tag SNPs to narrow down on statistically significant, reviewed disease associated loci, while understanding the patterns of genetic distribution in humans from diverse regions [http://www.broad.mit.edu/mpg/haploview/) [Haplotypes can be defined as evolutionary conserved segments of DNA inherited together. It is at these regions that tag SNPs and LD effects are observed; such that genotyping one SNP in a locus can determine the effects of many others. The international HapMap project ( regions . It currloview/) takes itin silico analysis of the respective functional changes they might bring in cellular processes.Following the identification of candidate SNPs and a peripheral analysis of their location in the genome, focussed computational tools designed to specifically understand downstream effects of SNPs depending on their genomic context and placement can be considered, thus, enabling in depth http://www.ensembl.org/info/docs/variation/vep/index.html) [SNPs are classified according to their location in the gene locus, which also most times dictates the functional downstream effects of the SNP and willex.html) found wiKLK3 gene is implicated in high association to prostate cancer susceptibility, and rs1126497 with a C/T polymorphism in epithelial cell adhesion molecule (EpCAM) in its exon 3 has been linked to increased risk of breast cancer in chinese populations [A nsSNP affect protein sequence and structure, and can affect its functionality depending on the position of the change and the amino acid it replaces. Usually such changes differ in the degree of deleterious effect they cause, with highly deleterious SNPs already being filtered out by nature through natural selection . Thus, ahttp://www.snps3d.org/) [http://ls-snp.icm.jhu.edu/ls-snp-pdb/) [http://modbase.compbio.ucsf.edu) [http://polydoms.cchmc.org) [http://www.uniprot.org/) [http://snpeffect.switchlab.org/) [http://pupasuite.bioinfo.cipf.es/) [Annotation of protein structure can be performed by resources such as SNPs3D (3d.org/) . LS-SNP/np-pdb/) lets onecsf.edu) goes onehmc.org) to predihmc.org) . UniProtot.org/) providesab.org/) , and Pupipf.es/) . These, ipf.es/) and refeipf.es/) .et al. [et al.[http://babylone.ulb.ac.be/popmusic/) [http://profile.mutdb.org/) [http://genetics.bwh.harvard.edu/pph2/) [http://sift.jcvi.org/) [http://provean.jcvi.org/) [Recent advancements in forecasting the effects of amino acid substitutions in protein sequence train computational tools to learn and then predict downstream effects of protein variants. These programs are trained by using either disease-associated alleles in databases or by experimentally varying amino acid substitutions to check for functional changes . Many reet al. , albeit . [et al. classify. [et al., for exapmusic/) checks fdb.org/) predictsdb.org/) ,77, and db.org/) . PolyPheu/pph2/) and SIFTvi.org/) are two vi.org/) is a toohttp://www.cbs.dtu.dk/services/NetPhos/) [http://prosite.expasy.org/) [Lately, variants affecting the post translational protein modifications have received attention, in their potential role in disease causation. Post translational modifications can be reversible or irreversible changes made to a protein after its translation, changing its function by changing protein structure and dynamics or by altering a binding site on it, thus playing an important role in signal transduction pathways and modulating a protein\u2019s cellular role . Close tetPhos/) is a toosy.org/) can be uKeeping the wide range of available products in mind, protein prediction tools should be assessed for the method they follow to determine protein structure variations and the functional causal effect. This can be done by reading their respective manuscripts in detail, and to determine if that method suits, and is the best one for the investigation.et al.[Eukaryotic gene expression involves multiple steps: gene transcription, processing of RNA through splicing mechanisms, translation into a protein product, post-translational modifications and subsequent protein activity. The majority of gene expression regulation takes place within genetic elements modulating it, like enhancers and silencers, TFBS and splicing sites. The intricacies with which sequence variation give rise to gene expression defects have been covered by Wang et al.. Many coa) SNPs in regulatory elementsSNPs within the regulatory elements of the gene can disrupt gene expression by altering TFBS, influencing the strength of enhancers and promoters, making these SNPs of prime importance to be considered for candidate gene association studies . Below, et al.[Putative genetic regulatory elements such as promoter regions, TFBS, CpG islands over-seeing gene expression, along with microRNA binding sites, are extremely crucial locations where a SNP can cause widespread expression variations and potential disease causing effects, perhaps in a tissue specific nature. Examples of such genetic alterations are discussed by Werner et al.. Informaet al.. An initet al.,86. Suchet al..http://tfbind.hgc.jp/) [http://www.genomatix.de/matinspector.html) [http://www.cbrc.jp/research/db/TFSEARCH.html) [http://bio.chip.org/mapper) [http://www.genomics.csse.unimelb.edu.au/product-is-rSNP.php) [http://www.regulomedb.org/index) [http://bioconductor.org/ which is itself a rich source of multi-purpose bioinformatic tools, takes into account chromatin features along with tag SNP and linked SNPs from the 1000 genomes project to spew out functionally important SNPs specific to non-coding regions [Analysis of the regulatory regions involves starting at a few well known websites to find TFBS such as TFBIND (hgc.jp/) , MatInspor.html) , TFSEARCCH.html) , MAPPER /mapper) and alsoSNP.php) and Regug/index) , which s regions . A rare regions .http://datam.i2r.a-star.edu.sg/ereV3/index.html) [http://jaspar.genereg.net/) [http://zlab.bu.edu/~mfrith/cister.shtml) [et al.[In certain hormone mediated diseases such as cancer, hormone response elements have causal relations with aberrant hormonal modulations . Thus, pex.html) and JASPeg.net/) to charar.shtml) can be u) [et al. for a sihttp://www.mirbase.org/) [http://www.bigr.medisin.ntnu.no/mirsnpscore/) [http://cmbi.bjmu.edu.cn/mirsnp) [http://www.microrna.org/) [http://compbio.uthsc.edu/miRSNP/) [http://www.patrocles.org/) [A recent class of powerful functional elements, which play an extensive role in the genomic regulation as a part of epigenetic mechanisms in the cell, are microRNAs . Their dse.org/) is a micse.org/) . Mirsnpspscore/) is a dat/mirsnp) providesna.org/) , which amiRSNP/) and Patres.org/) . A compab) eQTLcis acting eQTLs are those located near the target genes and have a direct influence on its gene regulation, whereas trans acting eQTLs are located away from the target region and show an indirect remotely regulated gene expression [Expression quantitative trait loci (eQTL) mapping is a technique which uses results from two high throughput techniques, i.e. genome wide gene expression analysis and the GWAS to define an association between a particular genomic loci variant with a changed gene expression pattern, thus, attributing specific genetic regulatory roles to candidate SNPs in the gene locus -114. cispression .http://web.bioinformatics.ic.ac.uk/eqtlexplorer/) [http://statgen.ncsu.edu/eQTLViewer/) [http://comptox.unc.edu/fastmap.php) [http://www.cs.washington.edu/homes/suinlee/lirnet/) [Software developed towards facilitating mining of genetic expression and variant associations include eQTL Explorer, eQTL Viewer, FastMap and Lirnet. Bioinformatics concepts relating to eQTL have been reviewed in . eQTL Explorer/) as an adplorer/) and QTL plorer/) , enablesViewer/) uses Scamap.php) , developlirnet/) uses a lRecent advances in high-throughput experimental technologies like whole-genome gene expression profiling, the genome wide association studies (GWAS), next generation DNA, RNA sequencing and CHIP-seq scan the genome for disease associated genetic variants and add knowledge to gene function, regulation, SNP prioritisation resources ,124. TheThe authors declare that they have no competing interests.JB conceived the idea. RP collated the information on all in silico tools and associated websites with input from JB. RP and JB wrote the manuscript. JAC critically reviewed the manuscript. All authors read and approved the final manuscript.List of useful web-tools for candidate gene selection and SNP mapping ,37,39-46Click here for fileSNP Effects and functional analysis -80,83,84Click here for file"} +{"text": "We have repeated the multi-variant statistical analysis of the original data with StatView software. This analysis produced different values for the risk ratios and 95% confidence intervals for variables other than age. The corrected Table four is presented below (table p values are unchanged, thus the original conclusions of the article are not altered.Correction : It was ow table . The p vThe pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/11/488/prepub"} +{"text": "Table S1's accession list is currently missing the accession numbers. Please see the correct version of Table S1 with the accession numbers at the following link:http://www.plosone.org/corrections/pone.0042932.cn.s001.doc"} +{"text": "There was an error in the sixth author's name. The correct name is Steven M. Lewis. The corrected author contributions are: \"Conceived and designed the experiments: ACH RAC MRR. Performed the experiments: ACH TCO RAC MW JSE SML CCE LT CLC SAK. Analyzed the data: ACH RAC JRC SLM PMP DMC MRR. Contributed reagents/materials/analysis tools: ACH TCO RAC MW JSE SML CCE LT CLC SAK. Wrote the paper: ACH TCO RAC MW JSE SML CCE LT CLC SAK JRC SLM PMP DMC MRR.\""} +{"text": "Paper to correct:10.1111/j.1752/4571.2012.00239.xSerbezov, D. et al. 2012. Life history and demographic determinants of effective/census size ratios as exemplified by brown trout . Evolutionary Applications. doi: Erratum:Palstra et al. 2009 was unfortunately omitted from the following sentences in the Discussion. The corrected sentences are:\u2013 \u2018Iteroparity, which can be viewed as a \u2018bet-hedging\u2019 strategy to deal with environmental uncertainty, thus might be an effective strategy in such a system which might regularly experience years with poor recruitment and low number of breeders \u2019.\u2013 \u2018The evolutionary implications of effective population size therefore depend on detailed knowledge of its interactions with life history and population dynamics. These insights may be attained only through carefully considering age structure in empirical investigations of Ne \u2019Omitted Reference: Palstra, F. P., M. F. O'Connell, and D. E. Ruzzante. 2009. Age structure, changing demography and effective population size in Atlantic salmon . Genetics 182:1233\u20131249 doi: 10.1534/genetics.109.101972.x"} +{"text": "Fusarium oxysporum. Please see the corrected Table 4 here: http://plosone.org/corrections/pone.00065093.t004.cn.tifIn the last row of Table 4, in the column labeled 'Fungal Species', question marks appear in place of"} +{"text": "There was an error in the author byline. The correct byline should read: the Huntington Study Group COHORT Investigators. Author E. Ray Dorsey remains corresponding author of the article. The correct citation is: the Huntington Study Group COHORT Investigators (2012) Characterization of a Large Group of Individuals with Huntington Disease and Their Relatives Enrolled in the COHORT Study. PLoS ONE 7(2): e29522. doi:10.1371/journal.pone.0029522"} +{"text": "As a result, the URL for this paper has changed from http://www.jmir.org/2013/11/e240/ to http://www.jmir.org/2013/10/e240/. No content changes were made.A correction notice has been sent to PubMed. This was done before submission to Pubmed Central and other full-text repositories."} +{"text": "Nucleic Acids Res. 2012; 40, 6001\u20136015. doi:10.1093/nar/gks311The authors wish to apologize for an error in their article. The correct Sequence Read Archive accession number is SRP010386, not SRP008250.This correction does not influence the validity of the results and conclusions of this article."} +{"text": "Mycobacterium lentiflavum in Drinking Water Supplies, Australia . The article has been corrected online (www.cdc.gov/eid/content/17/3/395.htm).References were misnumbered in the Appendix Table of the article"} +{"text": "Clostridium botulinum. From the Latin botulus, \u201csausage,\u201d the disease was first recognized in Germany in persons who had eaten tainted sausage and was originally called \u201csausage poisoning.\u201dFood poisoning with neurotoxicity caused by eating food contaminated with http://www.epi.hss.state.ak.us/pubs/botulism/bot_03.htmSources: Dorland\u2019s illustrated medical dictionary. 30th ed. Philadelphia: Saunders; 2003 and Botulism in Alaska [monograph on the Internet]. [cited 2005 Aug 26]. Available from"} +{"text": "Due to errors introduced during the production process, some equations do not display correctly.http://plosone.org/corrections/pone.0050440.e004.cn.tif [^]The upper limit in Equation 4 is not in the correct place. The correct equation can be viewed here: http://plosone.org/corrections/pone.0050440.004.cn.tif [^]The \"If-Then-Else\" statement that follows Equation 6 has incorrect symbols. The correct equation can be viewed here: In the Methods section, in the last paragraph of the subsection \"Virtual chain-tape rugosity\", the in-text reference for Equation 1 is incorrect. The text reading \"equ:chainrgsty\" should instead read \"Equation 1\"."} +{"text": "There is a value that was incorrectly stated in the main text and several values that were incorrectly stated in Table 1. Please see the corrections to these values in the document at the following link:http://www.plosone.org/corrections/pone.0049461.001.cn.pdf"} +{"text": "The name of one of the authors of this manuscript was missAll authors have no competing interests.All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/14/95/prepub"} +{"text": "IJMS[The authors wish to add this correction on their paper published in IJMS. The firhttp://www.mdpi.com/1422-0067/13/12/17290/s1.The corrected version can be accessed at:"} +{"text": "In Table 1, the symbols that denote the traps were negative have accidentally been omitted. Furthermore, the table's symbol legends at the bottom are misaligned. Please see the corrected Table 1 here:http://www.plosntd.org/corrections/pntd.0001822.t001.cn.tif"} +{"text": "These include http://microbewiki.kenyon.edu/index.php/BiocontrolThis site provides a broad definition of microbial biocontrol agents and gives several examples of these agents.http://www.bt.ucsd.edu/index.htmlB. thuringiensis in agriculture and has nice graphics, some animations and links to further information.This site focuses on the use of http://www.anbp.orgThis website is put up by the professional trade organization of manufacturers of biocontrol pest management agents. It contains information pertaining to news, events and new research findings.http://www.ibma.ch/pg_microorganisms_mbca.htmlThis website is an international association dedicated to the proper use of biocontrol agents for the benefit of industry and society.http://www.angelfire.com/wizard/kimbrough/Textbook/FungiAsBiocontrolAgents_blue.htmThis site discusses many crop diseases and how they can be controlled biologically. It contains many useful photographs to illustrate the disease-causing agents, the plants they attack, and the fungi that control the diseases.http://www.biocontrol.entomology.cornell.eduThis site contains information, photographs and links relevant to biological control agents commonly used in North America.http://www.epa.govt.nz/new-organisms/popular-no-topics/Pages/biological-control-agents.aspxThis site contains information on insect and fungal biocontrol agents approved for usage in New Zealand.http://www.epa.gov/pesticides/biopesticides/pips/regofbtcrops.htmThis webpage details the history of EPA regulatory actions on Bt crops used in the United States.http://www.cipm.infoThis site is dedicated to fostering integrated pest management practices that includes the use of microbial biocontrol agents.http://en.wikipedia.org/wiki/LUBILOSAThis site describes a research program focused on developing a biological control, typically via fungi, for locust infestations.http://bioenergy.asu.edu/photosyn/courses/bio_343/lecture/insect.htmlThis chapter from a course contains information on microbial biocontrols for insects.http://en.wikipedia.org/wiki/BiopesticideThis site defines biopesticides as living agents, typically bacteria or fungi, or natural product chemicals that control pests.http://en.wikipedia.org/wiki/Biological_pest_controlWhile this Wikipedia page appears similar in name to the one above, it offers a different perspective, dealing with biological pest control from an ecological standpoint."} +{"text": "Nobel laureate Stanley B.Prusiner, American neurologist and biochemist, coined the word prion in 1982 todescribe the noninfectious agents he proposed as the cause of scrapie. Prusinernoted that, \u201cBecause the dominant characteristics of the scrapie agentresemble those of a protein, an acronym is introduced to emphasize thisfeature\u2026 the term \u2018prion\u2019 (pronounced pree-on)is suggested.\u201d Prions are now recognized as etiologic agents of othertransmissible spongiform encepalopathies, including bovine spongiform encephalopathyand Creutzfeld-Jakob disease.Sources: Dorland\u2019s Illustrated MedicalDictionary. 31st ed. Philadelphia: Saunders; 2007; The Nobel Prize in Physiology orMedicine 1997: Stanley B. Prusiner [cited 2011 Oct 25]; http://nobelprize.org/nobel_prizes/medicine/laureates/1997/prusiner-autobio.html;Prusiner SB. Novel proteinaceous infectious particles cause scrapie. Science.1982;216:136\u201344From"} +{"text": "This project was recently funded to explore this paradigm.http://onlinelibrary.wiley.com/doi/10.1002/elsc.200900093/abstractThis paper describes a bacterium that grows on methane and produces copious amounts of polyhydroxy butyrate.http://arpa-e.energy.gov/?q=arpa-e-events/biological-technologies-methane-liquid-fuels-workshopThis page contains notes from a workshop at which approaches were discussed for converting methane to liquid biofuels, largely by biological mechanisms.https://biblio.ugent.be/publication/3166868This page links to a dissertation focused on studies of methanogenic communities with the goal of mitigating against atmospheric methane release.http://microbewiki.kenyon.edu/index.php/Methylococcus_capsulatusMethylococcus capsulatus is a methanotrophic bacterium that has been well studied and is one of two major experimental model systems for understanding the biochemistry of methanotrophy.http://biocyc.org/MOB3B/organism-summary?object=MOB3BMethylosinus trichosporium is a methanotrophic bacterium that has been well studied and is one of two major experimental model systems for understanding the biochemistry of methanotrophy. This BioCyc page contains metabolic reconstruction information derived from the genome-sequencing project for this organism.http://www.calystaenergy.com/index.phpCalysta is a commercial entity that has the goal of converting methane to fuels and chemicals via biological processes using methanotrophic bacteria.http://www.greencarcongress.com/2013/09/20130919-arpae.htmlThis page contains a list and a description of projects funded by ARPA-E that are focused on converting natural gas to liquid fuels.http://www.ncbi.nlm.nih.gov/pubmed/23765894This paper shows methane oxidation by a non-methanotrophic bacterium containing an alkane monooxygenase enzyme.http://www.ncbi.nlm.nih.gov/pubmed/20107985Deoxyribonucleic acid sequencing can be used to identify methanotrophic community signatures that might be indicative of natural gas being below the surface in a given region.http://genomea.asm.org/content/1/4/e00053-13.fullMethylmicrobium buryatense 5G is a fast-growing methanotrophic bacterium, and thus it may have commercial value; this study describes its genome sequence.http://en.wikipedia.org/wiki/Methane_monooxygenaseThis general article describes properties of both the soluble and particulate methane monooxygenases.http://www.rcsb.org/pdb/explore.do?structureId=1YEWThis Protein Data Bank (PDB) page has links to structural information for the membrane-bound copper-containing methane monooxygenase found within methanotrophic bacteria.http://www.rcsb.org/pdb/results/results.do?qrid=80EA0197&tabtoshow=CurrentThis PDB page has links to structural information for the cytoplasmic iron-containing methane monooxygenase found within methanotrophic bacteria.http://www.brenda-enzymes.org/php/result_flat.php4?ecno=1.14.18.3This BRENDA pages contains extensive information regarding the properties of particulate methane monooxygenase, including its substrate range.http://www.brenda-enzymes.org/php/result_flat.php4?ecno=1.14.13.25This BRENDA pages contains extensive information regarding the properties of the soluble methane monooxygenase, including its broad substrate range.http://www.ucalgary.ca/mehrotra/files/mehrotra/2011-Hettiarachchi-Hettiaratchi-Mehrotra-Kumar-EnvironmentalPollution.pdfEnvironmental methane releases are of growing concern because of increases in oil extraction from oil sands and via hydraulic fracturing. One method of detailing with methane emissions where gas harvesting is not possible is to use methane biofilters."} +{"text": "EHP. Environ HealthPerspect 123(4):A78; http://dx.doi.org/10.1289/ehp.1509968Schroeder JC, Booker SM. 2015. New developments at Published online 1 April 2015EHP.In the original version of this editorial Shaun Halloran\u2019s previous employer wasincorrectly stated as the American Society of Chemical Engineers. Mr. Halloran wasemployed by the American Society of Civil Engineers before coming toEHP regrets the error."} +{"text": "CDC is collaborating with the U.S. Environmental Protection Agency to urge U.S. residents to pay attention to their local air quality during Air Quality Awareness Week, April 28\u2013May 2, 2014. May also is Asthma Awareness Month, and May 6 is World Asthma Day.Asthma sufferers are particularly affected by air pollution. One in 12 U.S. residents (approximately 25.5 million persons) currently has asthma, and nine persons in the United States die from asthma-related complications every day and Enviroflash e-mail service (http://www.enviroflash.info).Daily air quality forecasts and current conditions for 400 U.S. cities are available at http://epa.gov/airnow/airaware/index.html. Information on Asthma Awareness Month is available at http://www.epa.gov/asthma/awareness.html. Additional information about asthma is available from CDC at http://www.cdc.gov/asthma.Information on Air Quality Awareness Week is available at"} +{"text": "The U.S. Department of Health and Human Services, CDC, state and local health departments, and other health agencies will observe National Influenza Vaccination Week December 7\u201313, 2014, with educational and promotional activities scheduled across the country. The observance was begun in 2005 to highlight the importance of annual influenza vaccination and to foster greater use of influenza vaccine in the months of December, January, and beyond. As of November 14, 2014, approximately 139.7 million doses of 2014\u201315 seasonal influenza vaccine had been distributed to vaccination providers in the United States (The Advisory Committee on Immunization Practices recommends influenza vaccination for all persons aged \u22656 months . Influenhttp://www.cdc.gov/flu/nivw/index.htm, whereas general materials regarding influenza vaccination are available at http://www.cdc.gov/flu/freeresources. Additional information and resources for health care professionals are available at http://www.cdc.gov/flu/professionals. End of season vaccination coverage estimates for the 2013\u201314 influenza season are available at http://www.cdc.gov/flu/fluvaxview.Educational materials, web tools, and CDC\u2019s planned activities for National Influenza Vaccination Week are available at"} +{"text": "Nature Communications7, Article number: 10945 10.1038/ncomms10945 (2016); Published: 03102016; Updated: 05042016Peter.Rez@asu.edu) or to H.C. (Hagai.Cohen@Weizmann.ac.il).'The author Hagai Cohen is incorrectly omitted from the list of corresponding authors. The corresponding authors are Peter Rez and Hagai Cohen. The correct information for correspondence is: \u2018Correspondence and requests for materials should be addressed to P.R. ("} +{"text": "The online information includes estimates of the percentage of persons vaccinated during July 2012\u2013May 2013, for each state, for each U.S. Department of Health and Human Services region, and for the United States overall.Final state-specific influenza vaccination coverage estimates for the 2012\u201313 season are now available online at FluVaxView (http://www.cdc.gov/flu/fluvaxview/interactive.htm) with state-specific estimates and are complemented by an online summary report (http://www.cdc.gov/flu/fluvaxview/coverage-1213estimates.htm) with national estimates.Analyses were conducted using National Immunization Survey data for children aged 6 months\u201317 years and Behavioral Risk Factor Surveillance System data for adults aged \u226518 years. Estimates are provided by age group and race/ethnicity. These estimates are presented in an interactive report ("} +{"text": "During 1990\u20132010, the age-adjusted esophageal cancer death rate decreased 38% for black men and 47% for black women aged \u226565 years. For white men in this age group, the rates increased 26% during 1990\u20132002 and stabilized during the rest of the decade; for white women the rates stayed nearly the same. In 2010, esophageal cancer death rates were nearly 40 per 100,000 population for white and black men aged \u226565 years and nearly 10 per 100,000 population for white and black women in the same age group.Sources: CDC. National Vital Statistics System. Available at http://www.cdc.gov/nchs/data_access/vitalstatsonline.htm.http://www.cdc.gov/nchs/hdi.htm.CDC. Health Data Interactive. Available at http://wonder.cdc.gov.CDC. CDC WONDER. Available at"} +{"text": "During 2009\u20132011, males were more likely than females to have met both the aerobic activity and muscle strengthening guidelines, regardless of race/ethnicity. Non-Hispanic white and non-Hispanic black males were more likely to have met the aerobic activity and muscle strengthening guidelines compared with Hispanic and Asian males. Non-Hispanic white females were more likely to have met both guidelines compared with non-Hispanic black, Hispanic, and Asian females.Sources: CDC. National Health Interview Survey, 2009\u20132011.http://www.cdc.gov/nchs/hdi.htm.CDC. Health Data Interactive. Available at"} +{"text": "In the article \u201cPublic Health and Rare Diseases: Oxymoron No More,\u201d boxed text was omitted because of a technical error.http://www.cdc.gov/pcd/issues/2016/15_0491.htm. We regret any confusion or inconvenience this error may have caused.The correction was made to our website on January 15, 2016, and appears online at"} +{"text": "Nature Communications6: Article number: 10342 10.1038/ncomms10342 (2015); Published: 01202016; Updated: 02222016Eli.Rothenberg@nyumc.org) or to M.D. mario.delmar@nyumc.org).'The author Eli Rothenberg was incorrectly omitted from the list of corresponding authors in this Article and authors Julia Gorelik and David Feny\u00f6 were incorrectly listed as corresponding authors. Furthermore, Julia Gorelik, David Feny\u00f6, Eli Rothenberg and Mario Delmar should have been listed as having jointly supervised the work. The correct information for correspondence is: \u2018Correspondence and requests for materials should be addressed to E.R."} +{"text": "Arthritis affects an estimated 50 million U.S. adults and contCommon arthritis stereotypes suggest that arthritis only affects older adults and that it is inevitable and untreatable. However, arthritis can affect persons at any age, including children, and most persons with arthritis are aged <65 years . Furtherhttp://www.cdc.gov/arthritis. Additional information is available from the Arthritis Foundation ( http://www.arthritis.org ) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases ( http://www.nih.gov/niams ).Information about ways to help manage arthritis is available at"} +{"text": "There are errors in the Funding section. The correct funding information is as follows:http://www.nsfc.gov.cn), Natural Science Foundation of Jiangsu Province (BK2012202) (http://www.jstd.gov.cn/), Chinese Postdoctoral Science Foundation (2013M540518) (http://res.chinapostdoctor.org.cn/BshWeb/index.shtml), Jiangsu Provincial Postdoctoral Science Foundation (1302080C) (http://www.jsbsh.gov.cn/), National 973 Program (Grant No 2010CB428902) (http://www.most.gov.cn/), and Applied Basic Research Project of Suzhou (SYN201306) (http://www.szkj.gov.cn/default.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This work was supported by National Natural Science Foundation of China (NNSFC31400091) (The publisher apologizes for the error."} +{"text": "In the article \u201cA Customizable Model for Chronic Disease Coordination: Lessons Learned From the Coordinated Chronic Disease Program,\u201d 2 figures were omitted because of a technical error.http://www.cdc.gov/pcd/issues/2016/15_0509.htm. We regret any confusion or inconvenience this error may have caused.The correction was made to our website on March 31, 2016, and appears online at"} +{"text": "In the crystal, complex cations are arranged in hexa\u00adgonally packed rows parallel to [010], with the chloride counter-anions situated in between. The inter\u00adactions between cations and anions are mainly ionic in nature.In the complex cation of the title salt, [CrCl(C DOI: 10.1107/S1600536814015852/wm5034Isup2.hklStructure factors: contains datablock(s) I. DOI: Click here for additional data file.10.1107/S1600536814015852/wm5034fig1.tif. DOI: The asymmetric unit of the title compound, with the atom-numbering scheme and displacement ellipsoids drawn at the 30% probability level.Click here for additional data file.10.1107/S1600536814015852/wm5034fig2.tif. DOI: The crystal structure of the title compound in a perspective view along [100].1012642CCDC reference: crystallographic information; 3D view; checkCIF reportAdditional supporting information:"} +{"text": "Database 2014 (2014), doi:10.1093/database/bau047, pp. 1\u20136http://www.retina-international.org/.The author incorrectly supplied the URL for the Mutation Database of Retina International. The correct link is The author apologizes for this mistake."} +{"text": "The referenceVan den Huevel-Panhuizen, M. (2012). Mathematics education research should come more often with breaking news. Paper presented at the Freudenthal Institute for Science and Mathematics Education, Utrecht University.should be:http://www.mnd.su.se/polopoly_fs/1.76181.1329229188!/menu/standard/file/svendPedersenLecture_120205.pdfVan den Heuvel-Panhuizen, M. (2012). Mathematics education research should come more often with breaking news. Lecture on the occasion of receiving the Svend Pedersen Lecture Award 2011. Stockholm: Stockholm University, Department of Mathematics and Science Education, 1 February. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "November is National Epilepsy Awareness Month. Epilepsy is a brain disorder characterized by recurrent seizures; it affects approximately 2.3 million adults in the United States .The CDC Prevention Research Centers\u2019 Managing Epilepsy Well (MEW) Network includes U.S. universities, the Epilepsy Foundation, and other epilepsy groups . The MEWhttps://www.epilepsyfoundation.org/livingwithepilepsy/webease/index.cfm) shown to improve some epilepsy self-management outcomes is available at http://www.cdc.gov/epilepsy and @mewnetwork on Twitter.Several MEW Network programs are available. WebEase is an Internet-based program (outcomes . UPLIFT outcomes , with trepilepsy with tra"} +{"text": "Nucleic Acids Res. 2014 Mar;42(5):2945\u201357. doi: 10.1093/nar/gkt1289.In Figure The authors wish to apologise to the readers and publisher for this error."} +{"text": "Scientific Reports5: Article number: 1494110.1038/srep14941; published online: 10092015; updated: 02082016.http://srv00.recas.ba.infn.it/editing\u2019 which was incorrectly given as \u2018 http://srv00.ibbe.cnr.it/editing/\u2019. These errors have now been corrected in the PDF and HTML versions of the Article.The original version of this Article contained typographical errors in the inosinome database link \u2018"} +{"text": "March 26 is Diabetes Alert Day, which is dedicated to raising awareness about type 2 diabetes, its risk factors, and its prevention. Type 2 diabetes, which can be prevented or delayed through lifestyle changes such as losing weight and increasing physical activity, accounts for 90%\u201395% of all diabetes cases in the United States .http://www.cdc.gov/diabetes/prevention/prediabetes.htm) is a helpful resource that uses answers to a few simple questions about weight, age, family history, and other risk factors to indicate a person\u2019s risk for developing type 2 diabetes.Information about type 2 diabetes and ways to prevent it is available from numerous sources. The Prediabetes Risk Test (http://www.cdc.gov/diabetes/prevention/index.htm) is working with partners in communities across the United States to establish effective lifestyle change programs for persons at high risk for type 2 diabetes. Lifestyle change programs are listed by state at http://www.cdc.gov/diabetes/prevention/recognition/registry.htm#program. The Just One Step tool , created by the National Diabetes Education Program, a joint program of the CDC and the National Institutes of Health, provides helpful tips for making lifestyle changes.The CDC-led National Diabetes Prevention Program (http://www.cdc.gov/diabetes/atlas) provide data on trends in diagnosed diabetes , obesity, and leisure-time physical inactivity in the United States. Additional information about diabetes control and prevention is available at http://www.cdc.gov/diabetes.CDC\u2019s Diabetes Interactive Atlases ("} +{"text": "Low (mjlow@umich.edu) are co-corresponding authors for this article.The corresponding author information is incomplete. Marcelo Rubinstein ("} +{"text": "Scientific Reports6: Article number: 2344010.1038/srep23440; Published online: 03222016; Updated: 04292016The Acknowledgements section in this Article was omitted. The Acknowledgements should read:\u201cWe thank Dr. Kausik Chakraborty for thought provoking discussion. BSC0121 is duly acknowledged for providing support for this work. BLP acknowledges CSIR, India for providing fellowship.\u201d"} +{"text": "Summary of Notifiable Diseases \u2014 United States, 2013 . The publication criteria used for the 2013 finalized tables are listed in the \u201cPrint Criteria\u201d column of the NNDSS event code list, available at http://www.cdc.gov/nchs/nvss/bridged_race/data_documentation.htm#vintage2012. Population estimates for territories are 2012 estimates from the U.S. Census Bureau , bridged-race , Hispanic ethnicity , and sex (vintage 2012), prepared under a collaborative arrangement with the U.S. Census Bureau. Population estimates for states are available at"} +{"text": "In 2012, 20% of residential care communities used EHRs. Greater proportions of communities with larger numbers of beds used EHRs compared with communities with fewer beds. Communities with >100 beds (36%) were more than three times as likely as communities with 4\u201310 beds (11%) to use EHRs.Source: National Study of Long-Term Care Providers, 2012. Available at http://www.cdc.gov/nchs/nsltcp.htm."} +{"text": "Anaplasma phagocytophilum should be replaced by Haemaphysalis longicornis. The article has been corrected online (http://wwwnc.cdc.gov/eid/article/20/6/14-0003_intro.htm).In the first paragraph of the article Novel Phlebovirus with Zoonotic Potential Isolated from Ticks, Australia ,"} +{"text": "High qun overuse. Labelinn overuse. We poinsed study; secondl"} +{"text": "Scientific Reports6: Article number: 2896210.1038/srep28962; published online: 07012016; updated: 08192016.PyImageQualityRanking software source code has been omitted from the Methods section under subheading \u2018Image Quality Ranking Software\u2019. It should read:In this Article, the PyImageQualityRanking software\u2019s source code can be downloaded from https://bitbucket.org/sakoho81/pyimagequalityranking/. The software is distributed as a standard Python package, which contains an automatic setup script for easy installation. A convenient command line interface is provided for controlling various measures. For further details, please refer to the software documentation at https://bitbucket.org/sakoho81/pyimagequalityranking/wiki/Home.\u201d\u201cThe"} +{"text": "Three of the author names appear incorrectly in this published article.The fourth author\u2019s name is missing a space. The correct name is Sergio Li Calzi.The fifth author\u2019s name is spelled incorrectly. The correct name is Chandra Jadhao.The sixth author\u2019s initials are incorrect in the author contributions. The correct author contributions for \"Performed the experiments\" are: YPRJ SH QQ.The correct citation is:+ Cells in Diabetic Individuals Involves Hypoxic Desensitization and Impaired Autocrine/Paracrine Mechanisms. PLoS ONE 9(4): e93965. doi:10.1371/journal.pone.0093965Jarajapu YPR, Hazra S, Segal M, Li Calzi S, Jadhao C, et al. (2014) Vasoreparative Dysfunction of CD34"} +{"text": "Streptococcus suis Serotype 5 in Pig Farmer . The article has been corrected online (http://wwwnc.cdc.gov/eid/article/20/3/13-0535_article).The name of author Magnus Rasmussen was misspelled in the article Septic Arthritis Caused by"} +{"text": "Luk and Kenneth MC Cheung should be noted as corresponding authors. Dr. Luk may be contacted at hrmoldk@hku.hk. Dr. Cheung may be contacted at cheungmc@hku.hk.The Corresponding Author in the author list is incorrect. The publisher apologizes for the error. The 8"} +{"text": "K. Kojima and B. Gueorguiev contributed equally to the article. The article has since been corrected online.In the article \u201cBiomechanical Evaluation of Interfragmentary Compression At Tibia Plateau Fractures In Vitro Using Different Fixation Techniques: A CONSORT-compliant article,"} +{"text": "Scientific Reports6: Article number: 22583; 10.1038/srep22583 published online: 03032016; updated: 05202016.In this Article, the Accession codes were omitted from the Additional Information section:http://www.ncbi.nlm.nih.gov/bioproject/PRJNA305241). BAM files were included in Banana Genome Hub and can be visualized with genome browser of the (http://banana-genome-hub.southgreen.fr/jbrowse_ma1).Data availability: The short reads of RNA-seq were deposited in NCBI\u2019s Sequence Read Archive (SRA) database with accession numbers from SRX1473480 to SRX1473497 ("} +{"text": "Scientific Reports6: Article number: 2473510.1038/srep24735 published online: 04192016; updated: 06272015.http://pfp.biosino.org/pfp\u2019 which was incorrectly given as \u2018http://pfp.biosino.org/\u2019. These errors have now been corrected in the PDF and HTML versions of the Article.The original version of this Article contained typographical errors in the Predict Functional Phosphosites website \u2018"} +{"text": "The term haplotype is used incorrectly throughout the manuscript. The correct term should be type.The term haplotype is used incorrectly in the article title. The correct title is: HLA Typing from RNA-seq Data Using Hierarchical Read Weighting. The correct citation is: Kim HJ, Pourmand N (2013) HLA Typing from RNA-seq Data Using Hierarchical Read Weighting. PLoS ONE 8(6): e67885. doi:10.1371/journal.pone.0067885"} +{"text": "From 2000 to 2010, HIV disease death rates decreased approximately 70% for both black and white men aged 25\u201344 years. Rates decreased by 53% for black men aged 45\u201354 years and 34% for white men aged 45\u201354 years. Throughout the period, HIV disease death rates for black men were at least six times the rates for white men.Sources: CDC. National Vital Statistics System. Available at http://www.cdc.gov/nchs/data_access/vitalstatsonline.htm."} +{"text": "The stated Author Contributions for Elliot W. Abrams and Tripti Gupta are incomplete. In addition to contributing reagents/materials/analysis tools, both of these authors also conceived and designed experiments, performed experiments and analyzed data. The correct author contributions for this manuscript are as follows:Conceived and designed the experiments: XG DG EW MCM FP EWA TG. Performed the experiments: XG DG EW CH JLG ED TY AA EWA TG. Analyzed the data: XG DG EW JLG TY EWA TG. Contributed reagents/materials/analysis tools: EWA TG FLM MCM. Wrote the paper: XG EW MCM FP."} +{"text": "Davide Gabellini is a Dulbecco Telethon Institute Senior Scientist.The following information is missing from the Funding section: Additionally, this study was supported by the Italian Telethon Foundation (http://www.afm-telethon.com/); the ERA-Net for Research on Rare Diseases (http://www.erare.eu/); the European Research Council (http://erc.europa.eu/); the Italian Epigenomics Flagship Project (http://www.epigen.it/); the Italian Ministry of Health and the FSHD Global Research Foundation . Additionally, this study was supported by the Italian Telethon Foundation (https://www.telethon.it/en/). Davide Gabellini is a Dulbecco Telethon Institute Senior Scientist.The complete, correct funding information is as follows: This work was supported by the Association Fran\u00e7aise contre les Myopathies ("} +{"text": "Needing help with routine activities increased steadily with age for all racial/ethnic groups. Non-Hispanic blacks were more likely to need help with routine activities compared with Hispanics and non-Hispanic whites among those aged 45\u201374 years. Among adults aged 45\u201354 years, Hispanics were least likely to need help with routine activities. However, the pattern changes among adults aged \u226575 years; Hispanics and non-Hispanic blacks were both more likely to need help with routine activities than non-Hispanic whites.Sources: CDC. National Health Interview Survey, 2011.http://www.cdc.gov/nchs/hdi.htm.CDC. Health Data Interactive. Available at"} +{"text": "Our aim is to detect the infection by Toscana virus (TOSV) and other Phleboviruses in the sera and cerebro-spinal fluid (CSF) of patients with meningitis in Tunisia. We examined various species of phlebotomus present in Tunisia to determine whether or not a direct relationship exists between cases of meningitis and the viruses circulating in the insect vectors.Patients with the meningeal syndrome were tested for anti-TOSV IgM and IgG using an indirect Enzyme-Linked Immunosorbent Assay (ELISA) and for the presence of TOSV and other Phleboviruses using a RT-PCR test.An entomological study was carried out using CDC light traps to trap sandflies in different bioclimatic zones of Tunisia. Collected sandflies were tested by RT-PCR for the presence of TOSV and other Phleboviruses and subsequently by viral isolation on Vero cells.Of 263 patients were tested using ELISA of which 12.16% (n = 32/263) were IgM positive for anti TOSV. Of these 32 patients, 78% (n = 25/32) were IgG positive. 12.86% (n = 18/140) of the CSF samples tested by RT-PCR were positive for the Toscana virus.One CSF sample tested by RT-PCR revealed the presence of Sandfly Fever Sicilian Virus (SFSV). The Punique virus was identified in one sandfly pool.This study confirms, for the first time, that TOSV is involved in a neurological disorder in North Africa. The incidence of this involvement in Tunisia conforms with observations made in other Mediterranean countries. Moreover, for the first time, a molecular approach was used to detect SFSV in a Tunisian patient displaying neurological symptoms.The online version of this article (doi:10.1186/s12879-014-0598-9) contains supplementary material, which is available to authorized users. Phlebotomus perniciosus and P. perfiliewi are present . Som. Som5]. TOSV has a segmented RNA genome composed of 3 units: L (large), M (medium), and S encoding the viral proteins -14]. A . A 14]. The well-known difficulty of directly diagnosing acute viral neurological infections is due to a short viremic phase with a low viral load during clinical symptomatology that generally corresponds to the period of hospitalization and clinical sampling . The virA study conducted in Morocco showed the presence of TOSV in the sandfly vectors; however no data on human epidemiology were published . In TuniThe objective of this work was to detect infection by TOSV and other Phleboviruses in the sera and cerebo-spinal fluid of subjects with meningitis during the summer. We examined various phlebotomus species circulating in Tunisia to prove the existence of a direct relationship between cases of meningitis and virus circulation in the vector.3) from different regions of Tunisia were admitted to Tunisian hospitals. Bacterial and fungal cultures of CSF samples tested negative. Suspecting a viral aetiology, the clinical virology laboratory of the Pasteur Institute of Tunis systematically searched for enteroviruses, herpes simplex virus, and West Nile virus, but the analysis proved negative. Samples (sera and CSF) collected from the 331 patients were examined for TOSV or other Phleboviruses infection.Between June 2011 and November 2012, 331 patients with meningeal syndrome , in phosphate-buffered saline (PBS) (pH 7.2) and incubated overnight at 4\u00b0C. Human sera were diluted at 1:100 in PBS-TM . Each assay included two negative and two positive control sera. Goat anti-human IgM and Goat anti-human IgG (Fc-specific) peroxidase conjugated antibody was diluted at 1:1000 for sera and at 1/10 for CSF and added to each well. A color reaction was developed by adding a substrate solution containing 3,3\u2032,5,5\u2032-tetramethylbenzidine (TMB) . The reaction mixture was incubated for 75 min. at 37\u00b0C at each step, and washed extensively with PBS-Tween. H2SO4 was added at a final concentration of 1 N to stop the reaction. All serum samples were tested in duplicate with viral and negative control antigens ,22]. Th. Th22]. RNA extraction and RT-PCR: RNA extraction was performed using the NucleoSpin RNA II kit following the manufacturer's instructions. Eluted RNA was collected and stored at -80\u00b0C when not immediately used.RT-PCR and nested PCR were performed using degenerated primer pairs specific for TOSV L genomic segment as described by Sanchez-Seco et al. with somCapture of phlebotomine sandflies: Using CDC light traps , phlebotomine sandflies were captured after dusk and until dawn from June to November (2011 and 2012), the period and time when they are active in Tunisia, in the regions where patients showed clinical AMM enriched phosphate-buffered saline (PBS). Two hundred \u03bcl of ground solution were used for total RNA purification with the RNeasy Plus Mini kit as per the manufacturer's instructions. RT-nested PCR was performed to detect TOSV in sandflies as described above.Viral isolation on Vero cells (ATCC CCL-81) was performed on some PCR-positive sandfly pools, as described by Sanchez-Seco et al. , with miwww.DnaBaser.com) to obtain optimal sequence alignment files. A BLAST analysis at the NCBI database was made to retrieve sets of homologues exhibiting high scores to the L gene of TOSV.Specific TOSV detection was carried out by sequencing PCR products as described previously . The PCRTo build phylogenetic tree, the maximum parsimony method cStatistical differences among the groups were determined using Pearson's Chi-square test. To calculate the Chi2, the Epi Info v.6.04 was used. A probability (P) value of less than 0.05 was considered statistically significant.The sequences generated in this study have been deposited in the DNA Data Bank of Japan (DDBJ) under accession numbers [DDBJ: AB904897 to AB904924 and AB905360 to AB905362].From the 331 patients (1-81 years old), 140 CSF samples and 191 sera were tested for Phlebovirus infection. CSF samples (n = 72) were tested by both PCR and enzymatic immunoassay (ELISA) to detect specific IgM. The remaining (n = 68) were tested only by PCR because only limited amount of materials were available from sera reactive individuals. All 191 sera were tested using ELISA.95% [8.47%-16.74%]) tested positive for anti-TOSV IgM: the prevalence of TOSV IgM was detected in 13.6% (26/191) of the serum samples and 8.3% (6/72) of the CSF samples. The different rates detected in sera and CSF samples were not significant (p = 0.24). Geographically, most positive samples came from Tunis (n = 10), Mahdia (n = 7) and Bizerte (n = 6) while the balance (n = 9) came from ten other governorates were positive with both phlebovirus-generic and TOSV-specific primer sets. The TOSV-positive samples were from Tunis (n = 14), Bizerte (n = 2), Mahdia (n = 1) and Sfax (n = 1). Moreover, one sample was sequenced that had tested positive with the NPhlebo2 pair of primers but negative with the specific TOSV primers Atos2. Of the samples tested, 72 CSF samples were investigated by both RT-PCR and ELISA: two of these samples (2.7%) had antibodies reactive to the TOSV antigen, six of the 72 CSF samples (8.3%) were positive by PCR and negative by ELISA, one (1.3%) was negative by nested PCR and positive by ELISA for anti-TOSV IgM and IgG, while 63 (87.5%) were negative by both methods.Of the 140 CSF samples tested by RT-PCR, 18 were sequenced using primers specific for Phlebovirus (NPhlebo2) and TOSV (ATos2).15 sequences (from 120-180 sequenced nt) were obtained with Atos2 set primers [DDBJ: AB904897 to AB904911] and three sequences (from 200-250 sequenced nt) were obtained with NPhlebo2 set primers The BLAST analysis on the National Center for Biotechnology Information website retrieved a unique hit consisting of the TOSV polymerase gene with a 98-99% identity score with French , 95-97% with Moroccan [GenBank:JN832571] and 95% with Tunisian [GenBank:JX867537] strains of TOSV.Only one CSF-derived amplicon sequenced [DDBJ: AB905361] was similar (98%) to the published sequence of the Sandfly Fever Sicilian Virus (SFSV) [GenBank: EF095551] derived from sandflies collected in Algeria .Of the 19 CSF-derived amplicons that were sequenced:Six sequences [DDBJ: from AB904912 to AB904917] and five sequences were obtained with NPhlebo2 set primers [DDBJ: from AB904920 to AB904924]. The BLAST analysis revealed 98-99% identity with French and 95-97% with Moroccan [GenBank: JN832571] TOSV strains.In an effort to isolate the virus for more significant sequence information, we randomly selected eight pools, including those that were positive with only the Nphlebo2 primer set, and seeded them onto Vero cells to grow the virus. Only a single sample showed a marked cytopathic effect after eight days. The BLAST of culture-derived PCR product [DDBJ: AB905362] was strongly homologous (95%) with the Punique virus strain PI-B4-2008 [GenBank: JF920133] from Tunisia.Of the 12 pool-derived amplicons that were sequenced:In a maximum parsimony analysis based on the alignment of the L segment of TOSV, a phylogenetic tree was constructed from sequences of the TOSV isolate obtained from GenBank Figure using a The clinical manifestations of the TOSV infection are the same as those provoked by several other neurotropic viral agents, and require a rapid, sensitive laboratory diagnosis for confirmation. Serological techniques such as ELISA are useful for assaying specific IgM as a marker of an acute infection. In this study, a serological investigation for the TOSV infection was performed (in house-ELISA) on 263 samples that included sera (n = 191) and cerebrospinal fluids (n = 72) collected from patients with AMM from different regions of Tunisia. TOSV infection was recorded in 12.1% of the patients affected by meningitis during the summer, since anti-TOSV IgM were detected. IgG antibodies against TOSV were detected in 78.1% of the IgM-positive cases. The remaining 21.9% of IgM positive but IgG negative cases could reflect a very early phase of infection. Similar results were observed in Turkey where IgG and IgM antibodies were reactive with TOSV in 10.4% and 8.2% of the sera respectively, while only 4% were reactive for both IgG and IgM . The detThe overall 12.1% TOSV seroprevalence rate is quite similar to the rate observed in Tunisia by Bahri et al. , who attDespite the limitation of serological tests, viral RNA detection has been established as a powerful tool and an effective alternative for identifying acute TOSV infections ,31]. Th. Th31]. With respect to the samples tested by serological and molecular techniques (72 of 140), the discrepancies in the results observed using these two diagnostic methods can be explained either by assays' different sensitivities or by the timing of drawing CSF samples. Similar finding were reported in Anatolia, Turkey where TOSV IgM was identified via indirect immunofluorescence test in only four of the 16 TOSV RNA positive samples .The PCR amplicons were directly sequenced to confirm the TOSV genome and, possibly, to identify the viral strain circulating in Tunisia. However, due to the short sequences obtained with the primers Atos2 and NPhlebo2+ (126bp), we could not identify the strain of TOSV precisely.Nevertheless, the sequences obtained correspond to those described in Morocco , France In this study, using RT-PCR, we also identified the presence of SFSV in the CSF sample of one febrile patient with meningoencephalitis from the Sousse region, situated in the lower semi-arid bioclimatic zone. SFSV have infrequently been implicated in central nervous system infections. However, the presence of symptoms and the detection of viral RNA confirmed that the Sousse patient suffered from an acute infection with SFSV from which he completely recovered. Similar cases of SFSV infection were described in a patient returning from vacation in Tunisia who was suffering from fever, headache, rigor, nausea, joint pains and a maculopapular . In addiIn earlier serological studies conducted in Tunisia, neutralized antibodies against SFSV were detected in 1.3% of tested sera . By usinP. papatasi, P. perniciosus and P. perfiliewi are widespread in Tunisia where they transmit leishmaniasis to dogs and humans ,[46,[46P. pand Spain .P. perniciosus collected in Medjez el Bab, located in the Beja governorate of Tunisia's upper semi arid bioclimatic zone. Recently described in Tunisia by Zhioua et al. [In the effort to isolate the virus from Phlebotomine pools by viral cultures, we isolated only the Punique virus from one pool of a et al. , this phP. perniciosus and P. perfiliewi). Global changes, including climate change, land use changes and mainly livestock development, may influence the density and future distribution of sandfly species. This may, in turn, have implications for the epidemiology of sandfly-borne Phleboviruses and create new risk areas and potential at-risk human populations. Consequently, surveillance programs should be designed to prevent the spread of sandflies in Tunisia.Several unexplained cases of meningitis recorded every summer in Tunisian hospitals are confirmed as being due to TOSV. A sporadic case is attributed to SFSV. Indeed, the RNA of these viruses was detected in CSF from patients with neurological symptoms and in sandfly vectors (TOSV should be considered an emergent viral pathogen that threatens healthy populations in Tunisia by causing seasonal aseptic meningitis. Clinicians should be aware of the role of TOSV and other Phleboviruses in cases of meningitis and RT-PCR should be considered a useful tool for their identification in clinical samples.Links to accession numbers in the DDBJAB904897http://getentry.ddbj.nig.ac.jp/getentry/na/AB904897/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904898http://getentry.ddbj.nig.ac.jp/getentry/na/AB904898/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904899http://getentry.ddbj.nig.ac.jp/getentry/na/AB904899/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904900http://getentry.ddbj.nig.ac.jp/getentry/na/AB904900/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904901http://getentry.ddbj.nig.ac.jp/getentry/na/AB904901/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904902http://getentry.ddbj.nig.ac.jp/getentry/na/AB904902/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904903http://getentry.ddbj.nig.ac.jp/getentry/na/AB904903/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904904http://getentry.ddbj.nig.ac.jp/getentry/na/AB904904/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904905http://getentry.ddbj.nig.ac.jp/getentry/na/AB904905/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904906http://getentry.ddbj.nig.ac.jp/getentry/na/AB904906/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904907http://getentry.ddbj.nig.ac.jp/getentry/na/AB904907/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904908http://getentry.ddbj.nig.ac.jp/getentry/na/AB904908/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904909http://getentry.ddbj.nig.ac.jp/getentry/na/AB904909/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904910http://getentry.ddbj.nig.ac.jp/getentry/na/AB904910/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904911http://getentry.ddbj.nig.ac.jp/getentry/na/AB904911/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904912http://getentry.ddbj.nig.ac.jp/getentry/na/AB904912/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904913http://getentry.ddbj.nig.ac.jp/getentry/na/AB904913/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904914http://getentry.ddbj.nig.ac.jp/getentry/na/AB904914/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904915http://getentry.ddbj.nig.ac.jp/getentry/na/AB904915/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904916http://getentry.ddbj.nig.ac.jp/getentry/na/AB904916/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904917http://getentry.ddbj.nig.ac.jp/getentry/na/AB904917/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904918http://getentry.ddbj.nig.ac.jp/getentry/na/AB904918/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904919http://getentry.ddbj.nig.ac.jp/getentry/na/AB904919/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904920http://getentry.ddbj.nig.ac.jp/getentry/na/AB904920/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904921http://getentry.ddbj.nig.ac.jp/getentry/na/AB904921/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904922http://getentry.ddbj.nig.ac.jp/getentry/na/AB904922/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904923http://getentry.ddbj.nig.ac.jp/getentry/na/AB904908/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB904924http://getentry.ddbj.nig.ac.jp/getentry/na/AB904908/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB905360http://getentry.ddbj.nig.ac.jp/getentry/na/AB905360/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB905361http://getentry.ddbj.nig.ac.jp/getentry/na/AB905361/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10AB905362http://getentry.ddbj.nig.ac.jp/getentry/na/AB905362/?format=flatfile&filetype=html&trace=true&show_suppressed=false&limit=10OF: collected samples, performed molecular and data analysis and drafted the manuscript; YM and GGS: participated to molecular and data analysis; LA, NH and HT: coordinated human sample collection and collected clinical data; MGC and AB: supervised the study and reviewed the manuscript. All authors read and approved the final manuscript."} +{"text": "National HIV Testing Day, June 27, promotes the importance of testing in detecting, treating, and preventing human immunodeficiency virus (HIV) infection. HIV testing is the essential entry point to a continuum of prevention, health care, and social services that improve the quality of life and the length of survival for persons with HIV . Recent MMWR includes a report presenting estimates of the prevalence of diagnosed and undiagnosed HIV infections by state during 2008\u20132012.In 2011, an estimated 1.2 million persons were living with HIV infection in the United States; an estimated 86% were diagnosed with HIV, 40% were engaged in HIV medical care, 37% were prescribed ART, and 30% achieved viral suppression (http://www.cdc.gov/features/HIVtesting. Basic testing information for consumers is available at http://www.cdc.gov/hiv/basics/testing.html.Additional information on National HIV Testing Day is available at http://www.cdc.gov/hiv/testing. CDC\u2019s guidelines for HIV testing of serum and plasma specimens are available at http://www.cdc.gov/hiv/testing/laboratorytests.html.Additional information on HIV testing for health professionals is available at"} +{"text": "The second author\u2019s last name is incorrectly displayed in the citation. The publisher apologizes for the error.10.1371/journal.pone.0150953The correct citation is: Leighton GM, Vander Meiden LN (2016) Sociable Weavers Increase Cooperative Nest Construction after Suffering Aggression. PLoS ONE 11(3): e0150953. doi:"} +{"text": "The publisher apologizes for this error.Dr. Sing Chan is incorrectly listed as corresponding author. The correct corresponding author is Calvin Q. Pan ("} +{"text": "During 2009\u20132011, approximately 41% of adults aged \u226565 years reported their health to be excellent or very good. The percentage reporting excellent or very good health was higher among those in families with higher income compared with families with lower income. Non-Hispanic whites aged \u226565 years were more likely to report excellent or very good health at each income level compared with Asians, Hispanics, or non-Hispanic blacks.Sources: National Health Interview Survey, 2009\u20132011. Available at http://www.cdc.gov/nchs/nhis.htm.http://www.cdc.gov/nchs/hdi.htm.CDC. Health Data Interactive. Available at"} +{"text": "Nucleic Acids Res. 2014 Jun;42(11):7461\u201372. doi: 10.1093/nar/gku387.The authors have accidently duplicated the ZFN-AAVS1-LONG panel in Figure This error does not affect the results or conclusion of the article.The authors wish to apologise to readers for the inconvenience caused."} +{"text": "There are errors in the published S1 FileTable A. Exclusion criteria for genetic testing in patients with a first degree relative with a pacemaker. Table B. HaloPlex NGS depth of coverage for Coriell and pacemaker samples.Table C. Selected HGMD and nonHGMD VUSs in pacemaker patients. Table D. Pacemaker variants filtering analysis and classification (number of variants). Table E. HGMD variants with disease association in pacemaker patients. Table F. Major co-morbidities at the time of pacemaker implantation in patients with ICCD or SSS without structural heart disease. Table G. Variant annotation file description. Table H. HGMD initial variant classification. Table I.Primers for Sanger/Big Dye variant confirmation. Table J. HaloPlex intra-run performance.Table K. Overall Performance of SNP variant calling in genotype known Coriell samples. Table L. Selective analyses of SNP performance in Coriell samples.(DOCX)Click here for additional data file."} +{"text": "National Infant Immunization Week (NIIW) will be observed April 20\u201327, 2013. An annual event since 1994, NIIW brings together local and state health departments, national immunization partners, and health-care professionals across the country to hold community activities and events highlighting the importance of protecting infants from vaccine-preventable diseases through immunization.Although immunization rates for vaccines routinely recommended for children remain at or near record highs, recent outbreaks of measles and pertussis in the United States underscore the importance of maintaining high immunization rates by successfully addressing parents\u2019 questions and concerns about childhood vaccines . This yehttp://www.cdc.gov/vaccines/events/niiw. Additional information about World Immunization Week is available at http://www.who.int/campaigns/immunization-week/2013/en/index.html.Additional information about NIIW is available at"} +{"text": "CTCCCATGCGCCGTTTG.In Table 1, the Primer/Probe sequence for Tryps_KS-rev is incorrect. The correct sequence is:"} +{"text": "Scientific Reports5: Article number: 10370; 10.1038/srep10370 published online 05192015; updated: 02152016http://immusort.bjmu.edu.cn/.\u2019 which was incorrectly given as \u2018 http://202.85.212.211/Account/ImmuSort.html.\u2019 These errors have now been corrected in the PDF and HTML versions of the Article.The original version of this Article contained typographical errors in the ImmuSort database link \u2018"} +{"text": "Acinetobacter venetianus JKSF02 was isolated from contaminated sediment in eastern Houston, Texas along the San Jacinto River. This microorganism specializes in n-alkane degradation and is well suited for bioremediation of the petroleum hydrocarbon deposited throughout the region by shipping and industrial activity from the Houston Ship Channel. Acientobacter venetianus, designated A. venetianus JKSF02. A. venetianus is a Gram-negative, oxidase-negative bacterium that was initially characterized for notable phosphotriesterase activity against organophosphate insecticides as part of an Environmental Sampling Research Module undertaken by University of Houston biotechnology undergraduates (A. venetianus RAG-1T (http://www.bioinformatics.babraham.ac.uk/projects/fastqc/) and filtered using BBTools (http://sourceforge.net/projects/bbmap). Paired-end reads were then assembled into a total of 87 contigs with the Spades 3.6.2 program (de novo annotation was performed with Prokka (http://www.ncbi.nlm.nih.gov/genome/annotation_prok/). The metabolic pathways of aromatic and heterocyclic compounds were examined through KEGG databases project has the project accession no. LSVC00000000. This version of the project (01) is LSVC01000000, and consists of sequences LSVC01000001 to LSVC01000087.The"} +{"text": "There is a growing gap between amount of proteomic data and availability of tools for their analysis . While smultiCleverMachine (multiCM), is an extension of the cleverMachine approach annotation output. While GO statistics are important to characterize the functional role of proteins, their interpretation is difficult without further downstream processing . In. InC. elroteomes , we foun binding .Fig. 3PmultiCM allows feature classification and the cleverGO provides clustering through semantic relationships. We illustrated the performances of both multiCM and cleverGO using examples related to RNA-binding abilities of S. cerevisiae chaperone substrates [S. cerevisiae, M. musculus and H. sapiens [C. elegans [In this work, we introduced two innovative approaches to compare multiple protein datasets using physico-chemical properties and GO annotations: the bstrates , physico sapiens and the elegans . In all As shown in the examples, we are particularly interested in understanding the relationship between nucleic-acid binding ability and structural disorder and aggregation. Indeed, previous studies indicate that RNA secondary structures , especiamultiCM for prediction of structural disorder, aggregation and nucleic-acid binding ability [In conclusion, theoretical approaches for prediction of protein features, such as those integrated in the ability \u201353, will ability , 55 and ability , 56\u201358.multiCM and cleverGO are available at http://www.tartaglialab.com/cs_multi/submission and http://www.tartaglialab.com/GO_analyser/universal.The http://www.tartaglialab.com/cs_multi/tutorial and http://www.tartaglialab.com/GO_analyser/tutorial. Documentation files are deposited at http://service.tartaglialab.com/static_files/algorithms/clever_machine/documentation.html.Tutorials can be accessed at"} +{"text": "To present two cases of food allergy with unusual presentation and discuss the diagnostic approach in childrenCase # 1: Girl, 11, afflicts right lower quadrant pain for 3 months. BackgroundPrematurity, atopy . Sister and atopic mother. Physical examination: exquisite tenderness in the right iliac fossa, bilateral Cord colic pain. Dry skin. Laboratori data:all hematology is normal. Examination of normal urine, serial parasitological (-). EDN (eosinophil derived neurotoxin) fecal> 3210 ng / ml (VN <360NG / ml). Colonoscopy:ILNH, ileal lymphoid nodular hyperplasia. Food allergy Score: 9Case No. 2: Boy, 9 years. Pain in right lower quadrant , abdominal pain for three months located in the right iliac fossa, a predominantly nocturnal and radiating to right thigh. A child psychiatrist prescribes antidepressants. Personal BackgroundMixed Breastfeeding from birth. Atopy: asthma, atopicdermatitis, infantcolic. Family history: Mother allergic to foods, presents father rhinitis. Physical examination: bilateral colic Rope. Tenderness in the right iliac fossa. Lab: Immunoglobulin E 160.5 IU / mL Colonoscopy lymphoid hyperplasia in distal ileum. Score of foodallergy: 11.Both cases improve with hypoallergenic diet.The presence of lymphoid nodular hyperplasia and family and / or personal history of atopy severe gastrointestinal symptoms may be due to food allergy. The elimination diet is diagnostic and therapeutic turn.Written informed consent was obtained from the patients for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal."} +{"text": "Blood cultures were negative probably due to the previous administration of antibiotics. Transthoracic and transesophageal echocardiographic examinations revealed vegetations on the anterior mitral leaflet with pseudoaneurysm formation, which had ruptured to the left ventricle, and moderate to severe mitral regurgitation .http://jthc.tums.ac.ir/index.php/jthc/article/view/518/425Video 4. Vegetation on the anterior aortic wall prolapsing to the proximity of the right coronary ostium on transesophageal echocardiography (short-axis view).http://jthc.tums.ac.ir/index.php/jthc/article/view/518/426"} +{"text": "Motivation: Public archives contain thousands of trillions of bases of valuable sequencing data. More than 40% of the Sequence Read Archive is human data protected by provisions such as dbGaP. To analyse dbGaP-protected data, researchers must typically work with IT administrators and signing officials to ensure all levels of security are implemented at their institution. This is a major obstacle, impeding reproducibility and reducing the utility of archived data.Results: We present a protocol and software tool for analyzing protected data in a commercial cloud. The protocol, Rail-dbGaP, is applicable to any tool running on Amazon Web Services Elastic MapReduce. The tool, Rail-RNA v0.2, is a spliced aligner for RNA-seq data, which we demonstrate by running on 9662 samples from the dbGaP-protected GTEx consortium dataset. The Rail-dbGaP protocol makes explicit for the first time the steps an investigator must take to develop Elastic MapReduce pipelines that analyse dbGaP-protected data in a manner compliant with NIH guidelines. Rail-RNA automates implementation of the protocol, making it easy for typical biomedical investigators to study protected RNA-seq data, regardless of their local IT resources or expertise.Availability and Implementation: Rail-RNA is available from http://rail.bio. Technical details on the Rail-dbGaP protocol as well as an implementation walkthrough are available at https://github.com/nellore/rail-dbgap. Detailed instructions on running Rail-RNA on dbGaP-protected data using Amazon Web Services are available at http://docs.rail.bio/dbgap/.Contacts: anellore@gmail.com or langmea@cs.jhu.eduSupplementary information:Supplementary data are available at Bioinformatics online. These include physical security of computing infrastructure, restricting inbound internet access, multi-factor authentication (MFA) and password policies, encryption of data, enforcing the principle of least privilege and logging data access. For many investigators, the guidelines pose a practical challenge: institutional computer clusters may not be compliant, requiring IT policy revisions or intervention by IT administrators.The Database of Genotypes and Phenotypes (dbGaP) (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-086.html) allowing investigators to request permission to transfer to and analyse dbGaP data in compliant clouds provides a convenient alternative: investigators can use protocols and software tailored for secure analysis of dbGaP data in a commercial cloud, bypassing local infrastructure issues.The recent NIH announcement units called instances and software comes pre-installed on standard disk images selected at launch time.https://aws.amazon.com/1000genomes/ and https://aws.amazon.com/public-data-sets/tcga/). Input data, intermediate results and final results can all be kept in cloud storage before final results are downloaded or browsed. AWS also provides guidance on secure analysis of protected genomic data (see https://d0.awsstatic.com/whitepapers/compliance/AWS_dBGaP_Genomics_on_AWS_Best_Practices.pdf).Amazon Web Services (AWS) is a popular choice for genomics data analysis. Key datasets such as 1000 Genomes, TCGA and ICGC are hosted in AWS storage, allowing researchers to use cloud-enabled tools without copying data across the internet Rail-dbGaP, a protocol for analyzing dbGaP data in the cloud using Elastic MapReduce (EMR), an AWS service; and (ii) the v0.2\u2009line of our Rail-RNA tool (http://hadoop.apache.org) cluster consists of a master instance and several worker instances. The Rail-dbGaP security architecture . A VPC is a logically isolated unit of the cloud providing a private network and firewall. The connection with the cloud storage service is via a \u2018VPC endpoint,\u2019 which ensures that data transferred never leaves the data center.Inbound traffic is restricted via security groups. A security group is essentially a stateful firewall. A master security group for the master instance and a worker security group for worker instances prevent initiation of any connection to the cluster except by essential web services.Data are encrypted at rest. During cluster setup, before any sensitive data has reached the cluster, each instance runs a preliminary script (\u2018bootstrap action\u2019) that uses Linux Unified Key Setup (LUKS) (https://guardianproject.info/code/luks/) to create an encrypted partition with a keyfile. The key is randomly generated on each instance and never exposed to the user. Temporary files, the Hadoop distributed file system and buffered output to the cloud storage service are all configured to reside on the encrypted partition via symbolic links. Files written to cloud storage are also encrypted. On S3, this is enforced by creating a bucket policy (i.e. rules governing user access to the bucket) barring uploads that do not use server-side encryption.Data are encrypted in transit. Worker instances download dbGaP data using SRA Tools (http://ncbi.github.io/sra-tools/), ensuring encryption of data transferred from dbGaP to the cluster. Secure Sockets Layer (SSL) is enabled for transfers between cloud storage and the cluster as well as between cloud storage service and compliant local storage to which an investigator saves results.Identities are managed to enforce the principle of least privilege. The principle of least privilege prescribes users have only the privileges required to perform necessary tasks. In the Rail-dbGaP protocol, an administrator uses multi-factor authentication, grants the user only necessary privileges and constrains the user to set up a password satisfying NIH security best practices at http://www.ncbi.nlm.nih.gov/projects/gap/pdf/dbgap_2b_security_procedures.pdf.Audit logs are enabled. These record logins and actions taken by the user and on the user\u2019s behalf, including API calls made by processes running on the cluster. On AWS, audit logs take the form of CloudTrail logs stored in encrypted S3 buckets.https://github.com/nellore/rail-dbgap, and Rail-RNA v0.2.x may be downloaded at http://rail.bio. We used the Rail-dbGaP protocol to align 9662 paired-end RNA-seq samples obtained by the GTEx consortium (Supplementary Material. Scripts for reproducing our results are available at https://github.com/nellore/runs/tree/master/gtex.The Rail-dbGaP protocol is implemented in the v0.2\u2009line of Rail-RNA. Detailed instructions on implementation are available at"} +{"text": "A 23-year-old woman referred to our echocardiography laboratory for follow-up transthoracic echocardiography (TTE). She had undergone perimembranous ventricular septal defect closure with the Amplatzer device one month previously. Right catheterization before VSD closure revealed no right ventricular outflow tract (RVOT) stenosis. At the time of echocardiography, she was asymptomatic. TTE showed increased wall thickness and a narrowed RVOT (10 mm at diastole and 6 mm at systole) with a turbulent flow at device replacement . AlthougTo watch the following videos, please refer to the relevant URLs:Video 1. Hypertrophy of the anterior wall of the right ventricular outflow tract in the parasternal short-axis view at the level of the aortic valve and the ventricular septal defect device occluder in two-dimensional echocardiographyhttp://jthc.tums.ac.ir/index.php/jthc/article/view/779/503Video 2.Turbulent flow at the right ventricular outflow tract at the ventricular septal defect device site in color-flow Dopplerhttp://jthc.tums.ac.ir/index.php/jthc/article/view/779/502"} +{"text": "This funding was received by LM.The following information is missing from the Funding section: Funding was provided by the University of Glasgow (http://www.epsrc.ac.uk/Pages/default.aspx) through the Doctoral Training Centre (DTC) in Medical Devices, University of Strathclyde (http://www.strath.ac.uk/simd/dtc/). This funding was received by CAM. Funding was also provided by the University of Glasgow (http://www.gla.ac.uk) LKAS scholarship (http://www.gla.ac.uk/services/postgraduateresearch/scholarships/kelvinsmith/). This funding was received by LM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.The complete, correct Funding statement is: Funding was provided by the Engineering and Physical Sciences Research Council (EPSRC) ("} +{"text": "In August 2014, physicians at Children\u2019s Hospital Colorado in Aurora, Colorado, noted a cluster of cases of acute limb weakness among children tested positive: eight (20%) for EV-D68 and nine (22%) for eight other enterovirus/rhinovirus types. Of the 19 patients whose upper respiratory tract samples were obtained <14 days from respiratory illness onset, 10 (53%) were positive: seven (37%) for EV-D68 and three (16%) for rhinoviruses. Laboratory testing for other pathogens is ongoing.http://www.cdc.gov/flu/protect/habits/index.htm. If a child appears to have a sudden onset of weakness in arms or legs, caregivers should contact a health care provider to have the child assessed for possible neurologic illness. Health care providers are encouraged to report patients meeting the case definition to their state or local health department. Health departments should report patients with illness meeting the case definition to CDC using a brief patient summary formlimbweakness@cdc.gov). Additional information is available at http://www.cdc.gov/ncird/investigation/viral/sep2014.html.On November 7, CDC published interim clinical management considerations, summarizing expert opinion based on current evidence on management and care of children with acute flaccid myelitis . CDC con"} +{"text": "The MNIST data set is available at (http://yann.lecun.com/exdb/mnist/) and the CIFAR10 data set is available at (http://www.cs.toronto.edu/~kriz/cifar.html). The software binaries and source code are deposited to GitHub (https://github.com/rafaelcp/figmn).The Data Availability Statement for this paper is incorrect. The correct Data Availability Statement is: Data are available at Figshare ("} +{"text": "Biochim. Biophys. Acta. 2012 Aug; 1820 (8):1205\u20131213. doi: 10.1016/j.bbagen.2011.10.003. Epub 2011 Oct 13. Review. PMID: 22020049]. The authors regret not having detected their error and apologise to the readers of the Journal for any confusion this may have caused.The authors and the journal retract the 9 February 2012 article cited above. This article is a duplicate of an article that had been previously submitted for publication in another journal [Molecular structure and target recognition of neuronal calcium sensor proteins, Ames, J. B., Lim, S.,"} +{"text": "Regarding the paper \u2018HIV Vaccine Awareness Day: sustaining the momentum\u2019 by Kathleen M MacQueen, Mitchell Warren.Journal of the International AIDS Society, Citation: MacQueen KM and Warren M. Journal of the International AIDS Society 2016, 19:21202. http://www.jiasociety.org/index.php/jias/article/view/21202 \u2223 http://dx.doi.org/10.7448/IAS.19.1.21202Published in Reference 6 is missing in the reference list, and should be cited in the text according to the following: \u201cThis is no different than the requirements for advancing research on a cure for HIV [6], on new methods \u2026\u201d.The correct reference list is displayed below."} +{"text": "Maria Marino (maria.marino@uniroma3.it) are the corresponding authors.The corresponding authors are not noted in the HTML version of the paper. Dr. Filippo Acconcia ("} +{"text": "Temnothorax curvispinosus. The correct title is: Visual Navigation during Colony Emigration by the Ant Temnothorax curvispinosus. The second sentence of the Abstract should read: \u201cWe evaluated the roles of both modalities during colony emigration by Temnothorax curvispinosus. The correct citation is: Bowens SR, Glatt DP, Pratt SC (2013) Visual Navigation during Colony Emigration by the Ant Temnothorax curvispinosus. PLoS ONE 8(5): e64367. doi:10.1371/journal.pone.0064367In the title and Abstract of this article, the wrong species name is given. The correct species name is"} +{"text": "Nucl. Acids Res. 43 (8): 4039\u20134054. doi: 10.1093/nar/gkv252The authors wish to draw attention to an error in their published article.In Figure The findings and conclusion of the article remain valid.The authors apologise to readers for this error and any inconvenience caused."} +{"text": "Dear Editor,ADHD predicts future substance abuse/dependence . In the"} +{"text": "May is Arthritis Awareness Month. Arthritis affects an estimated 52.5 million U.S. adults , is a cohttp://www.cdc.gov/arthritis/interventions/physical-activity.html). Increased availability of WWE programs in community settings for adults with arthritis will help them reduce their pain and improve their health.Although physical activity can help reduce joint pain and disability among those with arthritis, only one in 10 persons with arthritis meet HHS physical activity guidelines of 150 minutes of moderate activity per week Walking http://www.cdc.gov/arthritis. Additional information is available from the Arthritis Foundation (http://www.arthritis.org) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (http://www.niams.nih.gov).Information about ways to help manage arthritis is available at"} +{"text": "The in vitro mass spectrometry proteomics data have been deposited at the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD003806 (http://www.ebi.ac.uk/pride/archive/projects/PXD003806).The following information is missing from the Data Availability section: The"} +{"text": "Present: Due to a technical error, the following author names were indexed incorrectly in PubMed: Piris MA and Vaqu\u00e9 JPCorrect: The abbreviation has been updated to reflect correct spelling of these authors' names. The publisher sincerely apologizes for this oversight25452-25465. doi: 10.18632/oncotarget.4545.Original Article: Oncotarget. 2015; 6:"} +{"text": "Due to an error in the production process, the labels for panel D in http://dx.doi.org/10.5061/dryad.pq482.The Dryad DOI in the Data Availability Statement links out incorrectly. The correct Dryad link is"} +{"text": "Published 12 September 2014House T. 2014. Epidemiological dynamics of Ebola outbreaks. In the published article text, a term was omitted from Equation 2. This equation read:It should have read:The article has now been corrected."} +{"text": "The 7th annual Global Handwashing Day will be observed October 15, 2014. This observance increases awareness and understanding of handwashing with soap as an effective and affordable way to prevent disease around the world.Handwashing with soap has an important role to play in child survival and health. Approximately 2.2 million children aged <5 years die each year from diarrheal diseases and pneumonia, the top two causes of death among young children globally . HandwasAlthough persons around the world clean their hands with water, few use soap to wash their hands. Washing hands with soap removes bacteria much more effectively .http://www.cdc.gov/features/globalhandwashing. General handwashing information is available from at http://www.cdc.gov/handwashing. Information on water-related hygiene is available at http://www.cdc.gov/healthywater/hygiene/index.html.Additional information on Global Handwashing Day is available from CDC at"} +{"text": "World Health Day and the 50th anniversary of the World Health Organization (WHO) will be observed April 7. The focus of World Health Day this year is high blood pressure (hypertension). Although preventable, high blood pressure remains a leading risk factor for heart disease and stroke and a major cause of morbidity and mortality worldwide . Globallhttp://million-hearts.hhs.gov/docs/mh_smbp.pdf) and Spanish-language materials to improve health among Hispanics (available at http://millionhearts.hhs.gov/resources/toolkits.html#spanishtoolkit).CDC is working to help persons control blood pressure in multiple ways, including the Million Hearts initiative. Million Hearts aims to prevent 1 million heart attacks and strokes by 2017. In addition, CDC recently released a guide to strategies to improve blood pressure control for public health practitioners (available at http://www.who.int/world-health-day/en. Additional information regarding hypertension and CDC\u2019s sodium reduction initiative is available at http://www.cdc.gov/bloodpressure, http://millionhearts.hhs.gov, and http://www.cdc.gov/salt.Additional information on World Health Day is available at"} +{"text": "The publisher apologizes for the error.The second author\u2019s name is spelled incorrectly. The correct name is: William J. Crowther. The correct citation is: Nabawy MRA, Crowther WJ (2015) A Quasi-Steady Lifting Line Theory for Insect-Like Hovering Flight. PLoS ONE 10(8): e0134972. doi:"} +{"text": "Equal contribution should have been assigned. The first two authors, Zhiwei Wang and Yu Chen, should be noted as contributing equally to this work and are both first authors.wangyining@pumch.cn), Huadan Xue (bjdanna95@hotmail.com) and Zhengyu Jin (jin_zhengyu@163.com).There is an error in the corresponding author designation. The correct corresponding authors are: Yining Wang ("} +{"text": "We present a Markov chain Monte Carlo approach to sequence assembly that instead generates distributions of assembly hypotheses with posterior probabilities, providing an explicit statistical framework for evaluating alternative hypotheses and assessing assembly uncertainty. We implement this approach in a prototype assembler, called Genome Assembly by Bayesian Inference (GABI), and illustrate its application to the bacteriophage Because our approach is computationally expensive, our current tests are limited to the small but well-studied genome of the http://www.illumina.com/systems/miseq/scientific_data.ilmn). Aavailable as To demonstrate the feasibility of the MCMC approach, we have implemented a prototype assembler called Genome Assembly by Bayesian Inference prior distribution could be used if nothing is known about the genome to be assembled. Since To evaluate the mixing and convergence of our MCMC sampler, we ran three independent chains and compared their traces and split frequencies, as is common practice for other applications of MCMC Overall, the standard deviation in edge frequencies between the chains decreased with additional sampling, indicating that the independent chains converged to the same posterior distribution . The splGABI provides multiple ways for summarizing the results of an MCMC analysis and is built on top of BioLite, a light-weight bioinformatics framework with rich diagnostics and reporting capabilities . The repde novo point-estimate assemblies generated by the String Graph Assembler de novo point-estimate assemblies and will have associated information on the confidence in various aspects of its sequence and structure. In addition, MCMC assembly provides new opportunities for investigators who are interested not only in the certainty of a particular inference (e.g. an ALE https://bitbucket.org/mhowison/gabi/src/master/phix-test). Here, we provide brief comments on the technical details.The results presented were generated with GABI version 0.2.0 and are recomputable using included scripts processors and 24 GB of memory. CPU-hours were calculated as total walltime across all nodes, multiplied by 8 CPUs per node.ftp://webdata:webdata@ussd-ftp.illumina.com/Data/SequencingRuns/PhiX/PhiX_S1_L001_R1_001.fastq.gz and ftp://webdata:webdata@ussd-ftp.illumina.com/Data/SequencingRuns/PhiX/PhiX_S1_L001_R2_001.fastq.gz, accessed 2013 Apr 26). Using the bl-filter-illumina tool from BioLite, we chose the first 2,000 read pairs that did not contain known Illumina adapter sequences and that had mean quality score greater than 37 (Phred-33 scoring). This procedure is available in the script https://bitbucket.org/mhowison/gabi/src/master/phix-test/00-subset-data.sh.We started with 8.36 Gb of paired-end reads of maximum length 251 bp from Illumina https://github.com/jts/sga/blob/master/src/examples/sga-ecoli-miseq.sh). To assemble with Velvet, we used the included VelvetOptimiser tool to sweep coverage and cutoff parameters for a https://bitbucket.org/mhowison/gabi/src/master/phix-test/01-assemble.sh.To assemble the overlap graph to a string graphFirst, we recursively and completely trimmed all tips (edges with an incidence of one), because the To determine whether to accept a proposed assembly hypothesis, we calculate the odds ratio If this ratio is greater than 1, the new assembly is automatically accepted. If it is less than 1, it is accepted with probability R. The process is then repeated until there is a stationary distribution of assemblies in the sample, which occurs when the frequency of assembly attributes does not change with additional sampling.File S1X174 sequence data. A subset of 2,000 paired-end reads drawn from Illumina MiSeq sample data (http://www.illumina.com/systems/miseq/scientific_data.ilmn ).(ZIP)Click here for additional data file."} +{"text": "Xin-Ping Zhang should be noted as co-corresponding author with Dr. Ke Zhao. Dr. Zhang\u2019s email address is: http://www.nsfc.gov.cn/) and the Guangdong Provincial Natural Science Foundation .There are errors in the Funding section. The correct funding information is as follows: Funding for this work came from the Natural Science Foundation of China (No. 50871039,"} +{"text": "Summary of Notifiable Diseases \u2014 United States, 2012 for 2012. These data will be published in more detail in the http://wwwn.cdc.gov/nndss/document/nndss_event_code_list_2012.pdf. In addition, only cases from reporting jurisdictions where the nationally notifiable disease is reportable are published. The NNDSS website is updated annually to include the latest national surveillance case definitions approved by the Council of State and Territorial Epidemiologists for classifying and enumerating cases of nationally notifiable infectious diseases.Policies for reporting NNDSS data to CDC can vary by disease or reporting jurisdiction depending on case status classification . The publication criteria used for the 2012 finalized tables are listed in the \u201cPrint Criteria\u201d column of the NNDSS event code list, available at http://www.cdc.gov/nchs/nvss/bridged_race/data_documentation.htm#vintage2011 as of June 13, 2013. Population estimates for territories are 2012 estimates from the U.S. Census Bureau , bridged-race, , Hispanic origin , and sex (vintage 2011), prepared under a collaborative arrangement with the U.S. Census Bureau. Population estimates for states are available at"} +{"text": "AoB PLANTS5: plt045; doi:10.1093/aobpla/plt045Bajpai D, Inderjit. 2013. Impact of nitrogen availability and soil communities on biomass accumulation of an invasive species. The author has supplied the following corrected version of Figure"} +{"text": "Saccharomyces cerevisiae Cells. PLoS ONE 10(3): e0120702. doi:10.1371/journal.pone.0120702. The journal apologizes for this error that was introduced during the typesetting process.The fourth author\u2019s name is spelled incorrectly. The correct name is Maria Bretner. The correct citation is: Krol K, Brozda I, Skoneczny M, Bretner M, Skoneczna A (2015) A Genomic Screen Revealing the Importance of Vesicular Trafficking Pathways in Genome Maintenance and Protection against Genotoxic Stress in Diploid"} +{"text": "These findings have added significance with the current concern over honeybee colony collapse disorder.This study identified bee honey crop and microbiota as a rich source of novel lineages of lactic acid bacteria, notably http://nar.oxfordjournals.org/content/early/2015/10/25/nar.gkv1093This paper describes the design and use of tools for modifying lactic acid bacteria. The tools are then used to make variations in the nisin biosynthetic pathway.http://www.nature.com/ismej/journal/v10/n3/full/ismej2015134a.htmlCaenorhabditis elegans, uses odorant binding proteins to sense lactic acid bacteria by virtue of the diacetal fermentation product that they make as part of their normal metabolism.This interesting article demonstrates that the bacteriovorous nematode worm, http://www.medscape.com/viewarticle/828358Staphylococcus epidermidis.Lactic acid bacteria are described here to inhibit a common skin inhabitant, The latter organism is important to control and it has been shown to be a opportunistic pathogen upon wounding of the skin.http://www.cmbi.ru.nl/lab_secretome/This database is stated to serve for comparative analysis of the predicted secretomes of lactic acid bacteria.http://www.nature.com/ncomms/2015/150929/ncomms9322/abs/ncomms9322.htmlThis article describes the comparative genomic analysis of 231 lactic acid bacteria.http://www.extension.iastate.edu/wine/lactic-acid-bacteria-and-wine-spoilageLactic acid bacteria can have various effects on wine, some desirable and some undesirable. They are responsible for malolactate fermentation which can enhance the flavor of wines. In other cases, they can cause extensive wine spoilage."} +{"text": "A latina nr mordens appears incorrectly throughout the article and in the article title. The correct species name should be Alatina nr mordens. The correct citation is: Courtney R, Seymour J (2013) Seasonality in Polyps of a Tropical Cubozoan: Alatina nr mordens. PLoS ONE 8(7): e69369. doi:10.1371/journal.pone.0069369. The publisher apologizes for this error.Due to an error introduced during the typesetting process, the species name"} +{"text": "The authors wish to acknowledge that the software package associated with our Research Article , under tThe software code from GoSemSim is used We have now updated our software package such that it is licensed under a compatible GPL version 2 licence, and revised the package to give the appropriate attribution.We apologize for any inconvenience this oversight may have caused.Availability and RequirementsProject name: ppiPre.Project home page:http://cran.r-project.org/web/packages/ppiPre/index.html.Operating system(s): Platform independent.Programming language: R.Other requirements: None.License: GPL-2.Any restrictions to use by non-academics: None."} +{"text": "MMWR in Brief Republished in American Journal of Public Health,\u201d on page 908, in the second paragraph, the first Internet link in the third sentence was incorrect. The sentence should read as follows: \u201cThat summary was republished online by AJPH on October 8 (available at http://ajph.aphapublications.org/doi/pdf/10.2105/AJPH.2014.10411e13 ), along with an editorial describing the collaboration (available at http://ajph.aphapublications.org/doi/pdf/10.2105/AJPH.2014.302321 ).\u201dIn the Notice to Readers, \u201c"} +{"text": "Regarding the Invited Review Article \u2018Psychotherapies for PTSD: what do they have in common?\u2019 by Ulrich Schnyder et al.6: 28186 - http://dx.doi.org/10.3402/ejpt.v6.28186Published in European Journal of Psychotraumatology 2015. Citation: European Journal of Psychotraumatology 2015, In the paragraph headed \u201cThomas Elbert, Maggie Schauer, and Frank Neunert (Narrative Exposure Therapy)\u201d one of the names were incorrectly spelt.The correct name is Frank Neuner (not Frank Neunert). The correct heading is displayed below.Thomas Elbert, Maggie Schauer, and Frank Neuner (Narrative Exposure Therapy)"} +{"text": "Congenital tracheal diseases are less common than congenital cardiac.They contain two lesions: anomaly and stenosis. They may associate with other congenital lesions especially pulmonary artery sling. Tracheal stenosis is the main factor causing airway obstruction. Depend on the degree of tracheal stenosis, clinical manifestation ranges from having some episodes of stridor to severe respiratory failure and death. Reconstruction surgery is the method of choice for severe cases.Retrospective review congenital tracheal disease cases that underwent reconstruction surgery for over two years (from Aug. 2013 to Feb. 2015). Tracheal stenosis parts were managed using slide tracheoplasty technique. As for other congenital lesions, only pulmonary sling was reconstructed, together with tracheoplasty.16 patients were operated. Ages range from 3 - 12 months (average: 7.9). Other congenital lesions include: sling: 12/16; ring: 1/16; VSD: 2/16; no anus: 2/16. Result is excellent in 14 cases: good in one. Mortality: 1.Reconstruction surgery is feasible for congenital tracheal diseases. Result is excellent. Slide tracheoplasty should be applied in all cases to manage tracheal stenosis parts. Segments resection is not recommended for any part of the trachea."} +{"text": "Upon publication of this article it has bhttp://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.\u00a9 2015 Pears et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ("} +{"text": "Wang's email address was spelled incorrectly. The correct email address is wang.hang@zs-hospital.sh.cn. The article has since been corrected online.In the article \u201cThe Zhongshan Score: A Novel and Simple Anatomic Classification System to Predict Perioperative Outcomes of Nephron-Sparing Surgery\u201d,"} +{"text": "Both the spelling of the corresponding author's name, as well as the designation are incorrect in the original correction. The corresponding author of this article is Hamid Reza Khankeh.Correction: Challenges for Resuming Normal Life After Earthquake: A Qualitative Study on Rural Areas of Iran. PLOS Currents Disasters. 2015 Mar 9. Edition 1. doi: 10.1371/currents.dis.7118c63570e15df3cc033090ea4e0120.View Original Correction"} +{"text": "Intuitive understanding of hypothetical genes\u2019s signal peptide, transmembrane helix (TH) domain and LipoP box of any pathogenic microorganisms is a prerequisite for the rational development of drugs and vaccine candidates. A protein harboring these sequences may serve as receptor and conveyer for various biostimulations generated during host-pathogen interaction. Identification and annotation of these proteins may help in designing of novel drug or developing new vaccine candidates to control CT infections.http://bmbpcu36.leeds.ac.uk/cgi bin/sig_pred), siglanlP4.0 , TMpred (http://www.ch.embnet.org/software/TMPRED_form.html), TMHMM (http://www.cbs.dtu.dk/services/TMHMM/) and LipoP box (http://www.cbs.dtu.dk/services/LipoP/).We have retrieved whole sequence of CT serovar D/UW-3/CX from NCBI database. To identify secreted proteins, TH domain and lipoP box, we have exploited the following online softwares: sigpred have signal peptide as well as TH domain. Additionally, among five, four proteins also have lipoP box. Harboring TH domain sequences suggests that they may have either membrane spanning, extracellular or intracellular domain which may help in host-pathogen interactions and/or signal transduction. It is also possible that these proteins may be secreted and thereby induces host immune responses but it will need further validation.We consider that CT149, CT605, CT623, CT823 and CT858 may be secreted outside the pathogen and should be explored further to understand the pathogenesis of CT."} +{"text": "MMWR reports related to the Ebola outbreak and response are now available in French. Beginning this week, the reports can be accessed on the MMWR website at http://www.cdc.gov/mmwr. Readers with questions pertaining to reports in French can send them to e-mail, mmwrq@cdc.gov.Selected MMWR in Brief is a new feature that provides summaries of serial publications periodically on the MMWR website at http://www.cdc.gov/mmwr/mmwr_briefs.html. The feature was piloted with two postings in November 2013.MMWR is collaborating with the American Journal of Public Health (AJPH), which will republish the MMWR in Brief summaries. The first republished summary is for the report, \u201cOutbreaks of Acute Gastroenteritis Transmitted by Person-to-Person Contact \u2014 United States, 2009\u20132010.\u201d That summary was republished online by AJPH on October 8 (available at http://ajph.aphapublications.org/doi/pdf/10.2105/AJPH.2014.302301 ), along with an editorial describing the collaboration (available at http://ajph.aphapublications.org/doi/pdf/10.2105/AJPH.2014.302321 ).Beginning this month,"} +{"text": "The authors inadvertently omitted the accession numbers for PacBio sequence runs on the Staphylococcus aureus and Escherichia coli isolates. These accession numbers are available from http://www.ebi.ac.uk/ena under the study accession number PRJEB10032 (see E.\u00a0coli strains described in the paper have been deposited and are available from BEI Resources (https://www.beiresources.org/) and the Belgium Co-ordinated Collections of Microorganisms (http://bccm.belspo.be/).Volume 6, no. 3, doi:"} +{"text": "The following information is missing from the Funding section: Kanugula acknowledges CSIR for providing the Senior Research Fellowship. Please view the complete funding statement here.http://dbtindia.nic.in/index.asp), and SMiLE-CSC-0111 and EpiHeD-BSC-0118 (http://csirhrdg.res.in/). Kanugula acknowledges CSIR for providing the Senior Research Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This work was supported by No.BT/PR9637/BRB/10/582/2007 (Additionally, the titles for"} +{"text": "The U.S. Department of Health and Human Services, CDC, state and local health departments, and other health agencies will observe National Influenza Vaccination Week December 8\u201314, 2013, with educational and promotional activities scheduled across the country. The observance was begun in 2005 to highlight the importance of annual influenza vaccination and to foster greater use of influenza vaccine in the months of December, January, and beyond. As of November 15, 2013, approximately 126 million doses of 2013\u201314 seasonal influenza vaccine had been distributed to vaccination providers in the United States (The Advisory Committee on Immunization Practices recommends influenza vaccination for all persons aged \u22656 months . Influenhttp://www.cdc.gov/flu/nivw/index.htm, whereas general materials regarding influenza vaccination are available at http://www.cdc.gov/flu/freeresources. Additional information and resources for health-care professionals are available at http://www.cdc.gov/flu/professionals. Current influenza vaccination coverage estimates are available at http://www.cdc.gov/flu/fluvaxview.Educational materials, web tools, and CDC\u2019s planned activities for National Influenza Vaccination Week are available at"} +{"text": "The author wishes to make the following correction to this paper . Due to Figure 1. Regional map of Ghana. Source: MAGELLAN Geographics, 1992 [15].with:Figure 1. Regional map of Ghana. Source: Ezilon, 2009 [15].The updated reference for thishttp://www.ezilon.com/maps/africa/ghana-maps.html (accessed on 12 February 2016).15. Ghana Map\u2014Political Map of Ghana. Available online: The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "Brain. 2022;145(5): 1576\u20131578. https://doi.org/10.1093/brain/awac142Fatemeh Geranmayeh. Cholinergic neurotransmitter system: a potential marker for post-stroke cognitive recovery, In the originally published version of this manuscript, the schematic Figure\u00a01 resulted in some confusion. The figure and associated legend have now been updated."} +{"text": "Nature Communications 10.1038/ncomms4650, published online 11 April 2014Correction to: Since the publication of this work, Shelly A. Wanamaker has changed their name from Shelly A. Trigg. This has now been amended."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-17386-7, published online 01 August 2022Correction to: In the original version of this Article, Mohamed S. Hasanin was omitted as a corresponding author. Correspondence and requests for materials should also be addressed to sido_sci@yahoo.com.The original Article has been corrected."} +{"text": "In the article entitled \u201cSkin eruption involving bilateral breasts following radiation therapy for invasive ductal carcinoma of the left breast\u201d , by Belzer et al., the correct answers to the questions were missing and have been provided below.Chronic radiation dermatitisInflammatory breast cancerCellulitisCarcinoma en cuirasseRadiation-induced morphea (RIM)/LS overlapCorrect answer: 5. Radiation-induced morphea (RIM)/LS overlap.A. RIM typically develops during RTB. RIM is dependent on radiation doseC. RIM may extend beyond the radiation fieldD. RIM is a precursor to angiosarcomaE. RIM typically demonstrates atypical fibroblasts and vascularectasia on pathologyCorrect answer: C. RIM may extend beyond the radiation field.A. Ultrasound of the breastB. Punch biopsy of affected skinC. Serum anti-nuclear antibodyD. Serum anti-scleroderma-70 (topoisomerase 1) antibodyE. No diagnostic tests indicatedCorrect answer: B. Punch biopsy of affected skin."} +{"text": "The systems biology markup language (SBML) is an extensible standard format for exchanging biochemical models. One of the extensions for SBML is the SBML Layout and Render package. This allows modelers to describe a biochemical model as a pathway diagram. However, up to now, there has been little support to help users easily add and retrieve such information from SBML. In this application note, we describe a new Python package called SBMLDiagrams. This package allows a user to add a layout and render information or retrieve it using a straightforward Python API. The package uses skia-python to support the rendering of the diagrams, allowing export to commons formats such as PNG or PDF.github.com/sys-bio/SBMLDiagrams). Users can install the package using the standard pip installation mechanism: pip install SBMLDiagrams.SBMLDiagrams is publicly available and licensed under the liberal MIT open-source license. The package is available for all major platforms. The source code has been deposited at GitHub (Bioinformatics online. The systems biological markup language (SBML) . The following is an example that illustrates some simple operations.SBMLDiagrams can be used to read and edit the layout and render of an existing SBML model which can be subsequently exported to an updated SBML model. A variety of color formats (as well as opacity) are supported including decimal RGB, HEX string and all the HTML names (import SBMLDiagrams# load SBML from a file (or string)df = SBMLDiagrams.load(\u2019mymodel.xml\u2019)print(df.getNodeSize (\u201cATP\u201d))print(df.getReactionFillColor (\u201cENOLASE\u201d))df.setNodeTextPosition df.setNodeFillColor df.setNodeTextFontColor df.setReactionLineThickness newSbmlStr = df.exportpypi.org/project/skia-python/). Users can export the SBML networks as PNG, JPG or PDF files. The visualization is based on skia-python df = SBMLDiagrams.load(r.getSBML)df.autolayoutdf.drawdf.draw will display the network at the console. Users can also save the figure to a file, for instance, df.draw(output_fileName = \u2019fileName.pdf\u2019).For most Python IDEs, Autolayout is provided by NetworkX and is useful when an SBML model has no layout information. By use of drawing primitives it is also possible to specify networks that use some aspects from SBGN (pypi.org/project/SBMLDiagrams/) and installed using the standard pip mechanism: pip install SBMLDiagrams. The package is fully documented as https://sys-bio.github.io/SBMLDiagrams/.SBMLDiagrams is available as a pip package (btac730_Supplementary_DataClick here for additional data file."} +{"text": "Microbial electrochemical systemshttps://www.frontiersin.org/articles/10.3389/fenvs.2020.00044/fullThis systematic review article provides a broad and historical description of microbial electrochemical systems.Enzyme and microbial electrochemistryhttps://pubs.acs.org/doi/10.1021/acsmeasuresciau.2c00042This tutorial review focuses on the interactions between enzymes, microbes and electrodes. It also covers electroanalytical methods.Microbial fuel cellshttps://www.sciencedirect.com/topics/biochemistry\u2010genetics\u2010and\u2010molecular\u2010biology/microbial\u2010fuel\u2010cellThis page contains a compendium of journal articles, books and book chapters dealing with microbial fuel cells.Microbially\u2010based green electronicshttps://www.sciencedirect.com/science/article/pii/S0167779920303309Some microbes produce nanometer\u2010diameter protein strands that conduct electricity. This report describes their being examined for potential incorporation into electronic devices.Bioelectrosynthesishttps://link.springer.com/book/10.1007/978\u20103\u2010030\u201003299\u20109The link is to a book on electrochemical biosensors, biosynthesis, bioleaching, artificial photosynthesis and other related topics.Electrobiotechnologyhttps://dechema\u2010dfi.de/en/Topics+_+Projects/Electro+biotechnology.htmlThis site describes a large number of research projects related to the field of electro biotechnology.Microbial electrochemical technologieshttps://www.water.imdea.org/scientific\u2010infrastructure/pilot\u2010plants/microbial\u2010electrochemical\u2010technologiesThis page describes lab scale and field bioreactors that use microbial electrochemistry for projects such as wastewater treatment and the removal of pollutants.Increasing electrical conductivity in bacteriahttps://phys.org/news/2023\u201001\u2010bacteria\u2010generated\u2010nanowires\u2010soil\u2010oceans.htmlThis publication describes bacteria that transmit current through protein nanowires and how a dramatic increase in conductivity can be generated by light.Microbial electrochemistry terminologyhttps://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=4704024707debc15e61af0f60800ef8664c639d1This article introduces terminology and classification systems that derives from the interfacing of microbiology and electrochemistry.The International Society for Microbial Electrochemistry and Technology (ISMET)https://is\u2010met.orgISMET is an international society that links researchers working in different fields of science and engineering to consider questions related to microorganisms and electrodes.Microbial electrochemistry for bioremediationhttps://www.electra.site/wp\u2010content/uploads/2020/06/No.6\u2010paper.pdfThis article provides a review of biolectrochemical systems that are focused on bioremediation applications."} +{"text": "The IAPB Vision Atlas website isa compilation of the latest data and evidence relevant to all those who believe that in the 21st Century no one should have to live with avoidable blindness or sight loss - from eye conditions many of which can be easily treated or prevented and for which cost-effective solutions are readily available.The IAPB Vision Atlas is designed around two main sets of data: the estimates of the burden of blindness and visual impairment made by the Vision Loss Expert Group (VLEG) and national level performance against the key indicators laid out in the World Health Assembly resolution 66.4 \u2018Universal Eye Health: a Global Action Plan 2014 \u2013 2019\u2019 (the GAP).http://atlas.iapb.orgDo visit it here: www.lshtm.ac.uk/study/masters/mscphec.html or email Romulo.Fabunan@Lshtm.ac.uk10 fully funded scholarships available for Commonwealth Country Nationals. Course aims to provide eye health professionals with the public health knowledge and skills required to reduce blindness and visual disability in their setting. For more information visit: Eye Banking Course: New international qualification course for eye bankers. Suitable to all service and experience levels. The Specialist Certificate course starts in September 2017 (with option to work towards Graduate Certificate afterwards). Expressions of Interest via: http://commercial.unimelb.edu.au/custom-education/courses/eyebankingsc or please contact Heather Machin, Subject Coordinator, via: heather.machin@unimelb.edu.auwww.health.uct.ac.za or email chevron.vanderross@uct.ac.zawww.kcco.net or contact Genes Mng'anga at genes@kcco.netWrite to the Training Coordinator, Lions Medical Training Centre, Lions SightFirst Eye Hospital, PO Box 66576-00800, Nairobi, Kenya.Tel: +254 20 418 32 39admin@cehjournal.orgContact Anita Shah web@cehjournal.org or visit www.cehjournal.org/subscribewww.cehjournal.orgwww.facebook.com/CEHJournalhttps://twitter.com/CEHJournal"} +{"text": "Due to a production error, the DOI for this article was incorrectly registered as 10.3389/fpsyg.2023.1041016. The correct DOI for the article is 10.3389/fpsyg.2022.1041016.The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Please remember to self\u2010claim your CPD and retain your supporting evidence. Answers will be available via the QR code and online at J Med Radiat Sci. https://doi.org/10.1002/jmrs.576a. Major discrepancy unlikely to lead to an adverse outcome for the patientb. Major discrepancy that would lead to adverse outcomes for the patientc. Complete agreementd. Minor discrepancyThe diagnostic agreement scoring criteria describes Category 2 as:a. Acceptableb. Goodc. Highd. LowWhich of the following level of agreement was found between the radiographers/sonographers and radiologist's reports in this study?a. Obstetricb. Abdomenc. Musculoskeletald. DopplerThe most common ultrasound examinations undertaken by the radiographers/sonographers were:a. Bowel obstructionb. Intussusceptionc. Abdominal massd. Urinary tract infectionA clinical indication for paediatric examinations included suspected:a. This study involved only two remote primary healthcare centres, hence results from this study should not be generalised to metropolitan regions.b. The sample size was too small to produce accurate results, and more cases are required to increase the statistical power.c. The radiographers/sonographers involved in this study received formal training in definitive ultrasound reporting, hence results from this study should not be generalised to the whole profession.d. The range of ultrasound examinations was not varied enough to produce accurate results, hence more anatomical sites should be included in future studies.Which of the following was identified as a limitation of this study?Williams I, Baird M, Schneider M. (2022) Recommended further reading:1.Br J Radiol 2013; 86(1021): 20120112. https://www.birpublications.org/doi/10.1259/bjr.20120112.Hardy M, Snaith B, Scally A. The impact of immediate reporting on interpretive discrepancies and patient referral pathways within the emergency department: a randomised controlled trial. 2.Radiography 2012; 18(2): 90\u201395: https://doi.org/10.1016/j.radi.2011.06.002.Kelly BS, Rainford LA, Grey J, McEntee MF. Collaboration between radiological technologists (radiographers) and junior doctors during image interpretation improves accuracy of diagnostic decisions. www.asmirt.org/news-and-publications/jmrsScan this QR code to find the answers, or visit"} +{"text": "This article has been retracted: Figure 6B contains an image previously published in an earlier paper from another journal. The authors have been unable to retrieve their original experimental data, nor can they produce the necessary ethics approval documentation. Based on these deficiencies, all authors have agreed to retract this paper from Oncotarget.103785-103796. https://doi.org/10.18632/oncotarget.21792Original article: Oncotarget. 2017; 8:103785\u2013103796."} +{"text": "JCI Insight. 2022;7(21):142805. https://doi.org/10.1172/jci.insight.142805Original citation: JCI Insight. 2023;8(2):168446. https://doi.org/10.1172/jci.insight.168446Citation for this corrigendum: Cheng-Yi Lee has requested to be removed from the author list, and the corresponding author has agreed. The revised author list is shown above, and the author and affiliation lists in the PDF and HTML versions have been updated accordingly."} +{"text": "This article has been retracted: During its investigation, Oncotarget requested the original data for this paper from the authors. The authors state: \u201cAfter investigation, we determined that some original data were lost and we cannot repeat the results, making data interpretation difficult and conclusion unreliable.\u201d All authors have therefore agreed to the retraction of this paper from Oncotarget.11989-11998. https://doi.org/10.18632/oncotarget.22857Original article: Oncotarget. 2018; 9:11989\u201311998."} +{"text": "Plant Physiology, https://doi.org/10.1104/pp.15.00552In the originally published version of this manuscript, a funding statement was omitted fromthe Acknowledgements. The Acknowledgements should have included the following statement: \u201cMRCwas funded by project BIO2014-59092-P funded by MINECO/AEI and FEDER.\u201dThese details have been corrected only in this correction notice to preserve the publishedversion of record."} +{"text": "This article has an addendum: This study proceeded with institutional IRB approvals at each participating cancer center. Due to the retrospective nature of this project, a waiver of informed consent was approved by each of the listed local IRBs.257-270. https://doi.org/10.18632/oncotarget.28178Original article: Oncotarget. 2022; 13:257\u2013270."} +{"text": "Due to a production error, the DOI for this article was incorrectly registered as 10.3389/fmicb.2023.1083467. The correct DOI for the article is 10.3389/fmicb.2022.1083467.The publisher apologizes for this mistake. The original article has been updated."} +{"text": "Cell Research 10.1038/s41422-021-00477-x, published online 19 February 2021Correction to: We apologize for the mistake of correspondence email address of Wei Xie. The correct information is as follows. This correction does not affect the conclusion of the work.Correspondence: Wei Xie (xiewei121@tsinghua.edu.cn) or Lei Li (lil@ioz.ac.cn)"} +{"text": "This article has an addendum: Written informed consent was obtained from all patients. The study protocol was approved by an independent ethics committee or institutional review board at each site.2172-2181. https://doi.org/10.18632/oncotarget.27612Original article: Oncotarget. 2020; 11:2172\u20132181."} +{"text": "Correction to: Graefe's Archive for Clinical and Experimental Ophthalmologyhttps://doi.org/10.1007/s00417-022-05569-xIn the published version of this article, the author names presentation is incorrect.The correct presentation is provided below.D KiesslingC RenningsM HildA LappasTS DietleinGF RoesslerRA WidderThis is being corrected in this publication."} +{"text": "This article has been corrected: Authors Kenneth S. Zaret and Erica L. Carpenter contributed equally as corresponding authors. The footnote to the author list indicating both individuals as co-corresponding authors was unintentionally omitted. The proper footnote is shown below:**Co-corresponding authorsIn addition, the paper\u2019s title has been corrected to read, \u2018THBS2 as a prognostic biomarker for patients diagnosed with metastatic pancreatic ductal adenocarcinoma.\u2019 The authors declare that these corrections do not change the results or conclusions of this paper.2266-2272. https://doi.org/10.18632/oncotarget.28099Original article: Oncotarget. 2021; 12:2266\u20132272."} +{"text": "Correction to: Behavior Genetics.10.1007/s10519-022-10114-x.In the original version of this article, unfortunately the article note was missed. The article note should be displayed as \u201cDr. Jean-Baptiste Pingault and Dr. Fr\u00fchling Rijsdijk are shared senior authors\u201d. This has been corrected by publishing this correction article. The original article has been corrected."} +{"text": "Adenoviridae includes non-enveloped viruses with linear dsDNA genomes of 25\u201348\u2009kb and medium-sized icosahedral capsids. Adenoviruses have been discovered in vertebrates from fish to humans. The family is divided into six genera, each of which is more common in certain animal groups. The outcome of infection may vary from subclinical to lethal disease. This is a summary of the ICTV Report on the family Adenoviridae, which is available at ictv.global/report/adenoviridae.The family T=25 icosahedral particles. The capsid consists of 240 non-vertex (hexon) and 12 vertex capsomers (penton). The latter consist of the penton base and a protruding fiber protein trimer , persistent interstitial infection in the kidney and haemorrhagic cystitis. Mastadenovirus infections in animals are common, but disease usually appears only when predisposing factors are present . Canine ictv.global/taxonomy. Genus and species demarcation is based mainly on phylogenetic criteria but also on genome organization and biological characteristics. Genus Mastadenovirus: >50 species ; Aviadenovirus: >14 species (birds); Atadenovirus: >9 species ; Siadenovirus: >7 species ; Ichtadenovirus: 1 species (white sturgeon); Testadenovirus: 1 species (red-eared slider) [Current taxonomy: slider) .Adenoviridae: ictv.global/report/adenoviridae.Full ICTV Report on the family sites.google.com/site/adenoseq.Sequenced adenoviruses:"} +{"text": "J Clin Invest. 2019;129(10):4523\u20134538. https://doi.org/10.1172/JCI128865Original citation: J Clin Invest. 2022;132(11):e161565. https://doi.org/10.1172/JCI161565Citation for this erratum: Streptococcus pneumoniae (Spn) carriage\u2013 (Spn\u2013) and carriage+ (Spn+) were inverted. The correct figure panels are below. The HTML and PDF versions of the figure have also been updated.During the preparation of this manuscript, the labels for JCI regrets the errors.The"} +{"text": "The course aims to provide eye health professionals with the public health knowledge and skills required to reduce blindness and visual disability. For more information visit www.cehjournal.org/Lessons-from-the-USAID-Child-Blindness-ProgrammeUSAID Child Blindness Programme partners have identified areas that have the greatest impact on on project sucess, including recording gender data to ensure equitable access. Read more on admin@cehjournal.orgContact Anita Shah web@cehjournal.org or visit www.cehjournal.org/subscribewww.cehjournal.orgwww.facebook.com/CEHJournalhttps://twitter.com/CEHJournal"} +{"text": "This article has an addendum: This observational study was summarized from clinical data, therefore the patients\u2019 informed consents were waived. This study was approved by the Ethics Committee.4069-4078. https://doi.org/10.18632/oncotarget.23861Original article: Oncotarget. 2019; 10:4069\u20134078."} +{"text": "Due to a production error, the DOI for this article was incorrectly registered as 10.3389/fpsyg.2023.1031566. The correct DOI for the article is 10.3389/fpsyg.2022.1031566.The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Consent was added to this article: Patient consent was required and obtained. The authors received approval from the Medical University Ethics committee to perform the genetic studies presented.708-718. https://doi.org/10.18632/oncotarget.27914Original article: Oncotarget. 2021; 12:708\u2013718."} +{"text": "Now, there is a growing awareness that these emergencies are dealt with better when overseen by a more senior consultant. The British Emergency Eye Care Society was founded in 2013 to bring together practitioners who provide acute ophthalmology services in the UK to improve practice and promote excellence in patient care. To find out more, visit http://bit.ly/CoM18RPA total of 350 members of over 100 global and local eye health organisations recently met in India at the International Agency for the Prevention of Blindness (IAPB) Council of Members meeting in Hyderabad, India. On the agenda was Universal Health Coverage and eye health, technology, and partnerships in eye care. A round-up with videos and photos from the different meetings are available online at www.lshtm.ac.uk/study/masters/mscphec.html or email romulo.fabunan@lsthm.ac.ukFully funded scholarships are available for Commonwealth country nationals. The course aims to provide eye health professionals with the public health knowledge and skills required to reduce blindness and visual disability. For more information visit The ICEH Open Education for eye care programme offers a series of online courses in key topics in public health eye care. All the courses are free to access and include: Global Blindness, Eliminating Trachoma, Ophthalmic Epidemiology: Basic Principles and Application to Eye Disease.More free courses coming! Certification also available.http://iceh.lshtm.ac.uk/oer/For more information visit admin@cehjournal.orgContact Anita Shah web@cehjournal.org or visit www.cehjournal.org/subscribewww.cehjournal.orgwww.facebook.com/CEHJournalhttps://twitter.com/CEHJournal"} +{"text": "Scientific Reports 10.1038/s41598-022-23891-6, published online 10 January 2023Correction to: In the original version of this Article, Klaudiusz Szczepaniak was incorrectly listed as a corresponding author. The correct corresponding author for this Article is Maciej Grzybek. Correspondence and request for materials should be addressed to maciej.grzybek@gumed.edu.pl.The original Article has been corrected."} +{"text": "The third author\u2019s name is spelled incorrectly. The correct name is: AJ Harris. The correct citation is:https://doi.org/10.1371/journal.pone.0257575Zhu ZX, Nizamani MM, Harris A, Wang HF (2021) Anthropogenic factors are stronger drivers of patterns of endemic plant diversity on Hainan Island of China than natural environmental factors. PLOS ONE 16(9): e0257575. The publisher apologizes for the error."} +{"text": "This article has been retracted: Oncotarget requested the original data for this paper to address concerns regarding image duplication. The authors were unable to retrieve the data. As a result, all authors have agreed to the retraction of this paper from Oncotarget. The University was notified about the issues with the paper.52960-52974. https://doi.org/10.18632/oncotarget.17674Original article: Oncotarget. 2017; 8:52960\u201352974."} +{"text": "The International Pediatric Ophthalmology and Strabismus Council and The Department of Pediatric Ophthalmology at The Red Cross War Memorial Children's Hospital, Cape Town are proud to announce the 2018 ROP Africa Symposium.Date: 3\u20134 September 2018Venue: Surgical Skills Training Centre, Red Cross War Memorial Children's Hospital, Cape Town, South Africajbaker9@uic.eduMark your calendars for this international 2-day clinical conference and hands-on workshop for ophthalmologists and neonatologists caring for infants with retinopathy of prematurity. For more details, contact: Jenny Baker at Fully funded scholarships are available for Commonwealth country nationals. The course aims to provide eye health professionals with the public health knowledge and skills required to reduce blindness and visual disability.www.lshtm.ac.uk/study/masters/mscphec.html or email romulo.fabunan@lsthm.ac.ukFor more information visit ICEH Open Education for eye care programme offers a series of online courses in key topics in public health eye care. All the courses are free to access.Courses:Global Blindness, Eliminating Trachoma, Ophthalmic Epidemiology Basic Principles (1) and Application to Eye Disease (2).More free courses coming! Certification also available.http://iceh.lshtm.ac.uk/oer/For more information visit admin@cehjournal.orgContact Anita Shah web@cehjournal.org or visit www.cehjournal.org/subscribewww.cehjournal.orgwww.facebook.com/CEHJournalhttps://twitter.com/CEHJournalMay 13th to May 19th 2018To increase awareness about Retinoblastoma every year seven days from the second Sunday in May is celebrated as \u2018World Retinoblastoma Awareness Week\u2019, this year it will be celebrated from"} +{"text": "J Clin Invest. 2019;129(12):5294\u20135311. https://doi.org/10.1172/JCI129448Original citation: J Clin Invest. 2023;133(2):e168084. https://doi.org/10.1172/JCI168084Citation for this corrigendum: The authors recently became aware that representative illustrations presented in Supplemental Figure 7A might be mistaken for original data. As this schematic was used strictly for demonstrative purposes, it has been removed from the figure for clarity. A tabular representation of the experimental findings is provided in Supplemental Table 3. The supplemental document has been updated online."} +{"text": "This article has been retracted: Oncotarget requested the original data for this paper to address concerns regarding image duplication. The authors were unable to retrieve the data. As a result, all authors have agreed to the retraction of this paper from Oncotarget.39756-39792. https://doi.org/10.18632/oncotarget.5476Original article: Oncotarget. 2015; 6:39756\u201339792."} +{"text": "This article has been corrected: The authors corrected the Data sharing section. The correct text is presented below.Data sharinghttps://www.ncbi.nlm.nih.gov/geo/ from 04-14-23 following an embargo from the date of publication to allow for commercialization of research findings.The data that support the findings will be available in Gene Expression Omnibus at"} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-10876-8, published online 05 May 2022Correction to: The Data Availability section in the original version of this Article was omitted.It now appears as below:Data availabilityhttps://www.ncbi.nlm.nih.gov/bioproject/?term=PRJNA783029).All genomic data is available from the NCBI Sequence Read Archive under BioProject #PRJNA783029 (The original Article has been corrected."} +{"text": "In the original publication , there wThe correct Legendhttps://icnts2008.bo.infn.it (accessed on 15 December 2021). Reprinted with permission from Lluis Font (2008).Figure 3. Diagram of the sources (brown square boxes), processes (green round boxes), and parameters that a global dynamic radon model must consider. The time-dependent parameters are in blue. Figure by Font L, available at"} +{"text": "Correction to: Clinical Rheumatologyhttps://doi.org/10.1007/s10067-022-06263-3The original published version of the above article contained incorrect Key Points. The authors requested to note the following corrected points.The Key Points of the article should be:Key Points:1. HPLC-MS identified increased serum Kyn/Trp ratio in DM patients, which positively correlated with levels of muscle enzymes and inflammatory markers and was downregulated upon treatment.2. Cox regression analyses identified ln(Kyn/Trp) as an independent prognostic predictor of mortality in DM.3. Monitoring intrinsic immune regulation function should be considered a potential therapeutic target in DM patients.Instead of:Key Points:1. HPLC\u2013MS identified increased serum Kyn/Trp ratio in DM patients, which positively correlated with levels of muscle enzymes and inflammatory markers and was downregulated upon treatment.2. More attention to psychological status is needed in RA patients.3. Cox regression analyses identified ln(Kyn/Trp) as an independent prognostic predictor of mortality in DM.The original article has been corrected."} +{"text": "Correction: Microbiome 9, 137 (2021)https://doi.org/10.1186/s40168-021-01078-xhttp://www.rummeta.com\" found in the Availability of Data and materials section leads to an incorrect site. The new URL should be \"http://rummeta.njau.edu.cn/.\"In the original article , it has The original article has been updated."} +{"text": "Data availability statement. The correct Data Availability statement appears below.In the published article, there was an error in the https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE205535.\u201d\u201cSupplemental material for this article can be found at The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated."} +{"text": "Diversity of commercial probiotic strains.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430388/In response to incomplete labels, this study cultured common strains from 21 different commercial probiotic preparations and sequenced the genomes.Viability of probiotic strains.http://www.ijpmbs.com/uploadfile/2020/0622/20200622030828608.pdfThis study investigated the ability of microbes in probiotic products to survive strong acid conditions. This was done to learn about potential survival in the acid portions of the digestive tract.Probiotics: NIH.https://www.nccih.nih.gov/health/probiotics\u2010what\u2010you\u2010need\u2010to\u2010knowThis is a basic, but useful, site on all aspects of probiotics, bacteria, products, and usage statistics. It is put out by the U.S. National Institutes of Health.Whole genome analysis of probiotic strains.https://bmcgenomics.biomedcentral.com/articles/10.1186/s12864\u2010021\u201007539\u20109This study examined the genes in the genomes of commercially\u2010relevant probiotic bacterial strains. The focus was on their identification of genes putatively involved in toxin production, other virulence factors, and antibiotic resistance.Comparative genomics of probiotic strains.https://www.frontiersin.org/articles/10.3389/fmicb.2019.00712/fullThis study looked at genomes to gain better insights into species diversity, risks and impacts of traditional probiotic microbial species on gut microbiomes.Probiotics and metabolic landscapes.https://www.biorxiv.org/content/10.1101/2021.06.20.449192v1.fullLactobacillus, Lactococcus, Leuconostoc, Oenococcus, Pedicoccus, and Streptococcus.This study looks at the genomes and metabolism of probiotic lactic acid bacteria. Lactic acid bacteria are defined as members of the following genera: Gut persistence of a probiotic strain.https://journals.asm.org/doi/10.1128/JB.01637\u201007A major goal of probiotic formulations is to provide some lasting benefits to gut microbiomes. This study dealt with the identification of genes associated with long\u2010term persistence in the gut.How probiotics affect the microbiota.https://www.frontiersin.org/articles/10.3389/fcimb.2019.00454/fullThis is a review article on the basics of probiotics with an emphasis on their effects on the gut microbiota.Regulating microbiome manipulation.https://www.nature.com/articles/s41591\u2010019\u20100451\u20101This comprehensive review discusses both over the counter probiotics and those prescribed for specific diseases. It takes the view that potential risks are largely being overlooked.Global probiotics market.https://www.prnewswire.com/news\u2010releases/at\u20108\u20104\u2010cagr\u2010probiotics\u2010market\u2010size\u2010is\u2010expected\u2010to\u2010reach\u2010usd\u2010108\u201016\u2010billion\u2010to\u20102028\u2010by\u2010globally\u2010says\u2010brandessence\u2010market\u2010research\u2010301497707.htmlThis site reports the global value of the probiotic business market, expected growth, and major companies involved. It also provides links to further information."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-72895-7, published online 25 September 2020Correction to: The original version of this Article contained an error in the link in the Data Availability section where,https://submit.ncbi.nlm.nih.gov/subs/sra/ and received submission code of SUB5704553.\u201d\u201cAll the data analyzed or generated during this study are included in this article. This Sequence Read Archive (SRA) submission has been released on 2020-07-01. The data that support the findings of this study are deposited at now reads:https://trace.ncbi.nlm.nih.gov/Traces/study/?acc=PRJNA549052 and received submission code of SUB5704553.\u201d\u201cAll the data analyzed or generated during this study are included in this article. This Sequence Read Archive (SRA) submission has been released on 2020-07-01. The data that support the findings of this study are deposited at The original Article has been corrected."} +{"text": "This article has an addendum: Patient consent was required and obtained. This study was approved by the Russian Research Centre of Radiology and Surgical Technologies Ethics Committee .3723-3729. https://doi.org/10.18632/oncotarget.27757Original article: Oncotarget. 2020; 11:3723\u20133729."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-020-70932-z, published online 20 August 2020Correction to: The Data Availability section in the original version of this Article was omitted. The Data Availability section now reads:Data availability:https://www.ncbi.nlm.nih.gov/sra/?term=prjna886666.The datasets generated during and analysed during the current study are available in BioProject, at The original Article has been corrected."} +{"text": "JCI Insight. 2019;4(17):e130402. https://doi.org/10.1172/jci.insight.130402Original citation: JCI Insight. 2023;8(4):e169516. https://doi.org/10.1172/jci.insight.169516Citation for this retraction: JCI Insight of concerns regarding the identity of the antibodies used in Figure 2. JCI Insight previously issued a corrigendum to update the source of the TRESK and CCK-AR antibodies used for immunocytochemistry; however, the antibodies listed in the corrigendum were not correct (JCI Insight is retracting this article.The University of Michigan recently notified correct . The ins"} +{"text": "Correction: BMC Plant Biol 23, 34 (2023)https://doi.org/10.1186/s12870-022-03974-2Funding section.Following the publication of the original article , the autThe current Funding reads:Limonium spp. (Plumbaginaceae) from Morocco Atlantic coast\u2019. Computational resources were partially provided by INCD funded by FCT and FEDER under the project 01/SAICT/2016 n\u00b0 022153.This work was supported by Portuguese national funds through Fundacao para a Ciencia e a Tecnologia (www. fct. pt/) projects PTDC/AGRPRO/4285/2014, LEAF UI/AGR/04129/2013 and UIDB/00329/2020 , grants PTDC/AGRPRO/4285/BD/2014 , attributted to FPM, and PTDC/AGRPRO/4285/BM/2014 and PhD Scholarship ref. UI/BD/153730/2022 (wet-lab work) attributed to SIRC. The Linnean Society of London through the Percy Sladen Memorial Fund provided a grant to ADC for fieldwork in the project \u2018Taxonomic reassessment of The correct Funding should read:UIDB/00239/2020 (CEF), under the Scientific Employment Stimulus\u2014Individual Call \u20142021.01107.CEECIND/CP1689/CT0001 (IM). The Linnean Society of London through the Percy Sladen Memorial Fund provided a grant to ADC for fieldwork in the project \u2018Taxonomic reassessment of Limonium spp. (Plumbaginaceae) from Morocco Atlantic coast\u2019. Computational resources were partially provided by INCD funded by FCT and FEDER under the project 01/SAICT/2016 n\u00b0 022153.This work was supported by Portuguese national funds through Fundacao para a Ciencia e a Tecnologia (www. fct. pt/) projects PTDC/AGRPRO/4285/2014, LEAF UI/AGR/04129/2013 and UIDB/00329/2020 , grants PTDC/AGRPRO/4285/BD/2014 , attributted to FPM, and PTDC/AGRPRO/4285/BM/2014 and PhD Scholarship ref. UI/BD/153730/2022 (wet-lab work) attributed to SIRC The correction does not have any effect on the results or conclusions of the paper. The original article has been"} +{"text": "Sample preparation is and will always be the most important step in chemical analysis. Numerous techniques, methods, methodologies and approaches are published in the literature offering a wide range of analytical tools to the lab practitioner.Analytical scientists all over the world try to develop protocols for a plethora of analytes in various sample matrices.In the last decade, sample pre-treatment advances followed green chemistry and green analytical chemistry demands, focusing on miniaturization and automation, using the lowest possible amounts of organic solvents.The question is how far we have gone until now as well as what the future perspectives are.To answer this question, analytical chemists were invited to share their experience in the field and report on the recent advances in sample preparation approaches.Eleven excellent manuscripts were the outcome of our invitation including four review articles and seven original research articles in the first edition of the Special Issue \u201cSample Preparation-Quo Vadis: Current Status of Sample Preparation Approaches\u201d.The second edition is a collection of ten significant contributions to the field of sample preparation. It includes two highly interesting and comprehensive review articles and eight innovative research articles.https://www.mdpi.com/1420-3049/27/9/2953 (accessed on 31 July 2022)).Jos\u00e9 S. C\u00e2mara et al. present a comprehensive overview on the Green Extraction Techniques as Advanced Sample Preparation Approaches in Biological, Food, and Environmental Matrices (https://www.mdpi.com/1420-3049/26/18/5612 (accessed on 31 July 2022)).Aliya Nur Hasanah et al. report on the Factors Affecting Preparation of Molecularly Imprinted Polymer and Methods on Finding Template-Monomer Interaction as the Key of Selective Properties of the Materials (https://www.mdpi.com/1420-3049/26/15/4461 (accessed on 31 July 2022)).A feature paper on the Multi-Element Analysis Based on an Automated On-Line Microcolumn Separation/Preconcentration System Using a Novel Sol\u2013Gel Thiocyanatopropyl-Functionalized Silica Sorbent Prior to ICP-AES for Environmental Water Samples is presented by Natalia Manousi et al. (https://www.mdpi.com/1420-3049/27/4/1435 (accessed on 31 July 2022)).Microwave-Assisted Extraction Coupled to HPLC-UV Combined with Chemometrics for the Determination of Bioactive Compounds in Pistachio Nuts and the Guarantee of Quality and Authenticity is proposed by Natasa P. Kalogiouri et al. (https://www.mdpi.com/1420-3049/26/11/3101 (accessed on 31 July 2022)).Mariana N. Oliveira et al. propose the Application of Bar Adsorptive Microextraction for the Determination of Levels of Tricyclic Antidepressants in Urine Samples (https://www.mdpi.com/1420-3049/26/8/2350 (accessed on 31 July 2022)).Micro Salting-Out Assisted Matrix Solid-Phase Dispersion: A Simple and Fast Sample Preparation Method for the Analysis of Bisphenol Contaminants in Bee Pollen is presented by Jianing Zhang et al. ).A Simple and Reliable Dispersive Liquid-Liquid Microextraction with Smartphone-Based Digital Images for Determination of Carbaryl Residues in https://www.mdpi.com/1420-3049/26/14/4325 (accessed on 31 July 2022)).Maria S. Synaridou et al. present a Fluorimetric Analytical method for the determination of Five Amino Acids in Chocolate (https://www.mdpi.com/1420-3049/27/8/2602 (accessed on 31 July 2022)).Stefani Fertaki et al. report on the Measuring Bismuth Oxide Particle Size and Morphology in Film-Coated Tablets (https://www.mdpi.com/1420-3049/27/10/3279 (accessed on 31 July 2022)).Panagiota Papaspyridakou et al. report a Comparative Study of Sample Carriers for the Identification of Volatile Compounds in Biological Fluids Using Raman Spectroscopy (https://susy.mdpi.com/academic-editor/special_issues/process/1103908.The Guest Editors wish to thank all authors for their fine contribution and invite analytical chemists to submit their relative work to the third edition until the 31st of January 2023. For more information, the readers are advised to visit the site:"} +{"text": "Journal of Antimicrobial Chemotherapy (https://academic.oup.com/jac/issue/76/Supplement_2), roman numeral page numberprefixes (ii) were omitted in error. This error has been corrected. The publisher apologizesfor the error.In the originally published versions of articles in Volume 76, Supplement 2 of"} +{"text": "Due to a production error, the DOI for this article was incorrectly registered as 10.3389/fpsyg.2023.954876. The correct DOI for the article is 10.3389/fpsyg.2022.954876.The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "Information includes isolation origin, and links to related data.This site provides information on 590 isolated https://bacdive.dsmz.de/search?search=PseudomonasPseudomonas in the BacDive database provides information on strains currently and previously designated as Pseudomonas spp.A search of https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgiPseudomonas strains. The majority do not list a species designation.This site of the National Center for Biotechnological Information contains a very large collection of https://bmcmicrobiol.biomedcentral.com/articles/10.1186/s12866\u2010020\u201002058\u20101P. putida KT2440 grow aerobically. This modeling study indicates that implementation of anerobic respiration in that organism would require extensive sets of additional genes.Model pseudomonad like https://bmcmicrobiol.biomedcentral.com/articles/10.1186/s12866\u2010021\u201002420\u2010xP. chlororaphis is being effectively used as a biological control agent in agriculture for preventing fungal diseases of crops.http://eawag-bbd.ethz.ch/servlets/searchPseudomonas\u201d gives a large set of microorganisms and the biodegradation or biocatalysis pathway for which they have been studied.A search of the Biocatalysis/Biodegradation Database with the term \u201chttps://www.frontiersin.org/articles/10.3389/fmicb.2021.660134/fullPseudomonas strains show diverse capacity to deal with stresses through making protective substances, enlisting chaperones, altering membranes and resisting solvents. These properties can make them more robust for biotechnological applications."} +{"text": "The Developmental Origins of Health and Disease (DOHaD) hypothesis emphasizes how effects of prenatal or perinatal environmental exposures can determine later-life human health and disease . While tWith recent technological advancements in genomic research, several next-generation sequencing-based omics techniques can be used to detect genome-wide epigenetic changes. These techniques include chromatin immunoprecipitation (ChIP-seq) and DNasPetroff et al. showed how phthalates and common phthalate replacement chemicals are associated with DNA methylation in newborns in a sex-specific manner (https://www.frontiersin.org/articles/10.3389/fgene.2022.793278/full); Guo et al. developed statistical approaches that correlated neonatal exposures including phenols, pesticides, phthalates, flame retardants, and air pollutants with DNA methylation changes in children and their corresponding cognitive, behavioral, and mental health outcomes (https://www.frontiersin.org/articles/10.3389/fgene.2022.871820/full); and Song et al. showed how prenatal ambient air pollution exposures during pregnancy are associated with decelerated epigenetic aging in the newborns (https://www.frontiersin.org/articles/10.3389/fgene.2022.929416/full).Three of the studies, using children from the ECHO longitudUlloa et al. identified several genes that have an altered DNA methylation pattern in children exposed to 2\u20138.5\u00a0\u03bcg/L MeHg and confirmed these DNA methylation changes in several of the genes by exposing SH-SY5Y neuroblastoma cells to 8 or 40\u00a0nM MeHg (https://www.frontiersin.org/articles/10.3389/fgene.2022.993387/abstract). In a human study with adult men, Maggioet al. showed how elevated exposures to persistent endocrine disrupting compounds can impact the sperm methylome in regions associated with autism spectrum disorder (https://www.frontiersin.org/articles/10.3389/fgene.2022.929471/full). Finally, two studies investigated differences in microRNAs with environmental exposures, in non-human models: Yang et al. showed how four differentially expressed microRNAs mediate insecticide tolerance in Spodoptera frugiperda (https://www.frontiersin.org/articles/10.3389/fgene.2021.820778/full); and Zhang et al. conducted miRNA expression analysis in Bemisia tabaci under insecticide tolerance to assess stable reference genes for qPCR analyses (https://www.frontiersin.org/articles/10.3389/fgene.2022.899756/full). These studies contribute to the burgeoning progress in understanding mechanisms of long-term toxicity and epigenetic effects upon environmental exposures.In an EWAS using umbilical cord blood from a seperate cohort,"} +{"text": "Consent was added to this article: Informed consent was obtained from each patient and the study was approved by our institution.576-582. https://doi.org/10.18632/oncotarget.28222Original article: Oncotarget. 2022; 13:576\u2013582."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-03879-4, published online 07 January 2022Correction to: In the original version of this Article, Deepa Subramaniam Nachimuthu was incorrectly listed as a corresponding author. The correct corresponding author for this Article is Saritha Balasubramaniyan. Correspondence and requests for materials should be addressed to sarithabme89@gmail.com.The original Article has been corrected."} +{"text": "Scientific Reportshttps://doi.org/10.1038/srep43253, published online 24 February 2017Correction to: http://bebgteam.net/resources. The correct hyperlink is https://gitlab.com/icm-institute/burguiere/publications/2017_scirep_mondragonburguiere.This Article contains an error in the Methods section, under the subheading \u201cSoftware access\u201d, where the hyperlink to external data is incorrectly given as"} +{"text": "Please remember to self\u2010claim your CPD and retain your supporting evidence. Answers will be available via the QR code and online at J Med Radiat Sci. https://doi.org/10.1002/jmrs.607Education of referrers on essential information for referring cliniciansDevelop artificial intelligence tools to interrogate the electronic health record (EHR) for the required informationEncourage radiographers to conduct a full assessment of the patient prior to scanningEncourage radiologists to review the electronic health record (EHR) for every patientWhat do the authors of this study see as the next step in improving clinical information in CT requests?Generate discussion among a group of peopleGain a consensus among a panel of expertsFacilitate online focus groupsObserve participants and collect data using researchers' five sensesWhich of the following is most correct? Delphi studies are used toSmoking historyPresence of fever/febrileDuration of presenting symptomsHuman immunodeficiency virus (HIV)/blood\u2010borne virus (BBV) statusWhich of the following was an essential item of clinical information for CT Chest scan referrals?Medication historyRecent travel historyFamily history of cancerHistory of prior abdominal pathologyWhich of the following was an essential item of clinical information for CT Abdomen referrals?Full blood countLocalising neurologyHistory of intravenous drug useHistory of emergency department presentationsWhich of the following was an essential item of clinical information for CT Multi\u2010Trauma (CT Trauma Series) referrals?Castillo C, Steffens T, Livesay G, Sim L, Caffery L. (2022) Recommended further reading:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111406/.Boulkedid R, Abdoul H, Loustau M, Sibony O, Alberti C. Using and Reporting the Delphi Method for Selecting Healthcare Quality Indicators: A Systematic Review. Wright JM, editor. PLoS ONE [Internet]. 2011 Jun 9;6(6): e20476. Available from: https://onlinelibrary.wiley.com/10.1002/jmrs.424.Castillo C, Steffens T, Sim L, Caffery L. The effect of clinical information on radiology reporting: A systematic review. Journal of Medical Radiation Sciences. 2020 Sep;68(1). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896008/.Bardach SH, Real K, Bardach DR. Perspectives of healthcare practitioners: An exploration of interprofessional communication using electronic medical records. Journal of Interprofessional Care. 2017 Feb 2;31(3):300\u20136. Available from: www.asmirt.org/news-and-publications/jmrsScan this QR code to find the answers, or visit"} +{"text": "Treenome Browser is a web browser tool to interactively visualize millions of genomes alongside huge phylogenetic trees.cov2tree.org, or at taxonium.org for user-provided trees. Source code and documentation are available at github.com/theosanderson/taxonium and docs.taxonium.org/en/latest/treenome.html.Treenome Browser for SARS-CoV-2 can be accessed at Bioinformatics online. Huge genomic datasets are increasingly common and widely available. The ongoing coronavirus disease 2019 pandemic has particularly stressed existing bioinformatic infrastructure for the analysis of genomic data. We developed UShER . Gingr curated by the UCSC Genome Browser to render the mutations along the genome, which exploits WebGL to render large datasets much more quickly than traditional approaches for web visualization. This phylogenetically informed process displays on screen the complete set of amino acid and/or nucleotide substitutions in every leaf genome without explicitly enumerating the mutations in each genome, increasing rendering speed and reducing memory usage panel. Annotations are loaded into Treenome Browser automatically for the global SARS-CoV-2 tree at cov2tree.org. We use the UCSC Genome Browser API to fetch each bigBed and bigWig annotation file curated by UCSC for SARS-CoV-2 . These annotations and user-provided annotation files are displayed by JBrowse 2. Treenome Browser is implemented in React as a feature addition to the Taxonium project. Source code is available at https://github.com/theosanderson/taxonium/tree/master/taxonium_web_client.The reference genome and annotation tracks are displayed in an interactive JBrowse 2 (Buels btac772_Supplementary_DataClick here for additional data file."} +{"text": "The Collaborative Cross and the Diversity Outbred mouse populations are related multiparental populations, derived from the same 8 isogenic founder strains. They carry >50\u00a0M known genetic variants, which makes them ideal tools for mapping genetic loci that regulate phenotypes, including physiological and molecular traits. Mapping quantitative trait loci requires statistical and computational training, which can present a barrier to access for some researchers. The QTLViewer software allows users to graphically explore Collaborative Cross and Diversity Outbred quantitative trait locus mapping and related analyses performed through the R/qtl2 package. Additionally, the QTLViewer website serves as a repository for published Collaborative Cross and Diversity Outbred studies, increasing the accessibility of these genetic resources to the broader scientific community. Multiparental populations MPPs; improve The CC and the DO were bred from the same 8 strains: A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ . The CC Mouse experiments support the collection of multiple types of data on the same individuals, including physiological traits and molecular assays (e.g. gene expression) across multiple tissues. Integrative approaches like mediation analysis can be used to delineate the relationships among traits with shared QTLs (https://qtlviewer.jax.org), an interactive QTL mapping webtool built for both CC and DO that utilizes the R/qtl2 package to perform QTL mapping as well as variant association mapping based on the founder strain genotypes. QTLViewer can perform mediation analysis for QTL through -omic traits to identify candidate causal mediators of physiological trait QTL. The primary goal of QTLViewer is to allow users to interactively perform and visualize QTL mapping for publicly available CC and DO datasets, and so, QTLViewer represents a data repository that can be also downloaded for further investigation. This software will empower researchers to analyze and explore CC and DO data while facilitating access to relevant data and findings from others across the community.The R/qtlcharts software providedThe QTLViewer is an interactive web application designed to interactively perform and visualize QTL mapping and related analyses in experimental CC or DO data. We make use of modern computing tools, such as application programming interfaces (APIs) and Docker containers, to make QTLViewer efficient, portable, and extendable.https://www.docker.com/\u2014v18.09.3 last accessed 06/13/2022) images that are managed with Docker-Compose (https://docs.docker.com/compose/\u2014v1.23.2 last accessed 06/13/2022). The user interface is contained in the churchilllab/qt2lweb container (v1.0.0), which is a Python (v3.6.9) web application that processes all requests made by the user. Each request is parsed and analyzed to determine which analyses need to be performed.The QTLViewer is comprised of 3 Docker (https://restrserve.org/\u2014v0.4.1 last accessed 06/13/2022). All data returned from these APIs are in JSON format. Since some requests require longer time to complete than others, we use another instance of the churchilllab/qtl2web container to manage them. We utilize Celery (https://docs.celeryproject.org/\u2014v4.47 last accessed 06/13/2022) with a Redis (https://redis.io/\u2014v6.2 last accessed 06/13/2022) backend as a task queue.All computational requests are performed by the churchilllab/qtl2rest container (v0.1.0). This container loads data upon startup and listens to Web API calls via RestRserve and processed by the churchilllab/qtl2web container. A dialog box with a spinning wheel is displayed to the end-user to show that the request is being processed. The request is parsed to determine which APIs need to be called. There could be one to many API calls per request. Those API calls are bundled together and submitted to the task queue for processing. Once the task queue receives the request, a unique ID is generated and sent back to the web page. The web page parses the unique ID and begins polling the task queue until the task is complete or an error occurs. While the web page is polling the task queue for a status, the API calls are submitted to the churchilllab/qtl2rest container for computational analyses. When all API calls are complete, the task queue bundles the data together and marks the job as complete. The background polling that has been happening on the web page see that the job is complete, removes the dialog box, and processes the JSON data to display the appropriate graphs and data.A diagram illustrating the implementation process is shown in https://www.ensembl.org last accessed 06/13/2022) that provides a web API to retrieve genomic information. Ensimpl extracts the necessary data from Ensembl and creates efficient SQLite (https://www.sqlite.org/ last accessed 06/13/2022) databases for querying purposes. The databases are separated by Ensembl release and species (mouse and human). The web API is written in Python utilizing FastAPI (https://fastapi.tiangolo.com/ last accessed 06/13/2022) framework. The API functionality provides search, genomic location lookup, gene lookup, and gene history.QTLViewer relies on a set of tools that facilitate the analyses of MPPs. Ensimpl (v 1.0.0) is a customized small version of Ensembl (https://churchilllab.jax.org/foundersnps last accessed 06/13/2022). The Founder SNP database is a custom version of the Sanger SNP VCF files that have been processed via a Python script and stored in an SQLite (https://www.sqlite.org/ last accessed 06/13/2022) database. The SNP genomic location and allele calls for the 8 founder strain alleles are stored. A custom Strain Distribution Pattern is stored for easy query and dissemination of data. Currently, GRCm38 (https://www.ncbi.nlm.nih.gov/assembly/GCF_000001635.20/ last accessed 06/13/2022) release 1410 and 1505 are supported.In addition to Ensimpl, QTLViewer also utilizes a Founder SNP Database (https://highcharts.com last accessed 06/13/2022) which is built on D3 LOD peaks can be viewed by changing the Plot type select box. Additional information on specific QTLs can be interactively accessed by hovering and clicking on the points in the grid. The plot supports pan and zoom features.The QTL mapping features of the QTLViewer are flexible and tailored to different types of data. For -omics data, such as transcripts and proteins, an vailable , which sLOD Peaks grid or select a trait in the text search. Genome-wide LOD plots are useful to visualize peaks on the genome associated with the phenotype of interest. For example, the LOD plot for the gene Sfi1 reveals a clear expression QTL (eQTL) on chromosome 13 at 65\u2009Mb (Sfi1 is located on chromosome 11. Information about each LOD score may be accessed by hovering. The Plots select box will switch between additive and factor-interactive QTL models. Clicking on a locus of interest (i.e. the peak LOD score) is used to drive additional analyses on the locus, which are visualized as plots in the lower panel. These analyses include estimation of founder allele effects, mediation of the locus effect through -omic traits, and SNP association mapping in the locus region.To visualize a genome-wide LOD plot for a specific trait, users should click on a point from the at 65\u2009Mb , which iSfi1 show a biallelic pattern driven by lower expression from the CAST/EiJ and C57BL/6J alleles compared to higher expression from the other alleles association mapping is useful to identify genetic variants of interest in the QTL region. To perform this analysis, users should click the LOD plot . This wiot . Correlation tab adjacent to the Profile Plot tab will show the correlation of the element of interest with any other element in the data . If users are interested in this type of analysis, they should scroll down to the bottom left corner of the screen, under the Plot tab . The prothe data . The toohe table . The valith Sfi1 . The gentor Rsl1 . The negpression .Download Data on the top of the page . The QTLViewer software is version controlled and available from GitHub .Users can access the QTLViewer webpage at https://churchilllab.jax.org/ensimpl (last accessed 06/13/2022) and https://churchilllab.jax.org/foundersnps (last accessed 06/13/2022), respectively. The Docker containers code can be found at https://github.com/churchill-lab/qtl2web (last accessed 06/13/2022), https://github.com/churchill-lab/qtl2rest (last accessed 06/13/2022), and https://github.com/churchill-lab/ensimpl (last accessed 06/13/2022). The Docker images are available at https://hub.docker.com/r/churchilllab/qtl2web/tags (last accessed 06/13/2022), https://hub.docker.com/r/churchilllab/qtl2rest/tags (last accessed 06/13/2022), and https://hub.docker.com/r/churchilllab/ensimpl/tags (last accessed 06/13/2022). The source code for QTL mapping analysis through R/qtl2 package can be found at https://github.com/rqtl/qtl2 (last accessed 06/13/2022).The supporting tools Ensimpl and SNPDB are available online at https://churchilllab.jax.org/qtlviewer/JAC/DOHeart (last accessed 06/13/2022) and at figshare under accession number https://doi.org/10.6084/m9.figshare.12378077.The aging heart data analyzed here to demonstrate the QTLViewer functions can be found online at G3 online.This work was supported by the Jackson Laboratory Cube Initiative and grant funding from the National Institute of Health (NIH): R01GM070683 (GAC and KWB), F32GM134599 (GRK), R01DK101573 (MPK), and RC2DK125961 (MPK). This work was also supported by the University of Wisconsin\u2013Madison, Department of Biochemistry and Office of the Vice Chancellor for Research and Graduate Education with funding from the Wisconsin Alumni Research Foundation (MPK).None declared.jkac146_Supplementary_DataClick here for additional data file."} +{"text": "Following publication of the original article , the autThe incorrect name is: Health Services Organization.The correct name is: Health Standards Organization.The incorrect reference is:https://healthstandards.org/public-reviews/clinical-governance/.Health Services Organization. CAN/HSO 1003:2021 Clinical governance standard\u2014public review. Health Services Organization; 2010. The correct reference is:https://healthstandards.org/public-reviews/clinical-governance/.Health Standards Organization. CAN/HSO 1003:2021 Clinical governance standard\u2014public review. Health Services Organization; 2010. The original article has been"} +{"text": "This year, the call to action we encourage you to use is \u201cMake Vision Count\u201d. In 2010, just over 28% of the world's population were affected by Myopia (shortsightedness). This is predicted to rise to 34% by 2020 and nearly 50% by 2050. In 2014, approximately 422 million people \u2013 or 8.5% of adults worldwide \u2013 were living with diabetes, compared to 108 million in 1980. Low- and middle-income countries account for approximately 75% of the global diabetes burden. Approximately one in three people living with diabetes have some degree of Diabetic Retinopathy (DR) and one in 10 will develop a vision-threatening form of the disease.communications@iapb.org if you want to receive World Sight Day promotional material like posters, balloons and ribbons.This World Sight Day, let's get the numbers out, so we know where we stand. Do write to www.iapb.org/wsd17/promotional-materialYou can download print quality logos for World Sight Day, here: MSc Public Health for Eye Care, London School of Hygiene & Tropical Medicine 10 fully funded scholarships available for Commonwealth Country Nationals. Course aims to provide eye health professionals with the public health knowledge and skills required to reduce blindness and visual disability in their setting. For more information visit: www.lshtm.ac.uk/study/masters/mscphec.html or email romulo.fabunan@lshtm.ac.ukOnline International Eye Bank Qualification course \u2013 Now accepting applications for the September intake of the Graduate Certificate and shorter Specialist Certificate. Apply and enquire via: http://commercial.unimelb.edu.au/custom-education/courses/eyebankinggcadmin@cehjournal.orgContact Anita Shah web@cehjournal.org or visit www.cehjournal.org/subscribewww.cehjournal.orgwww.facebook.com/CEHJournalhttps://twitter.com/CEHJournal"} +{"text": "J Clin Invest. 2022;132(7):e148667. https://doi.org/10.1172/JCI148667Original citation: J Clin Invest. 2022;132(19):e165107. https://doi.org/10.1172/JCI165107Citation for this corrigendum: http://genomics.cicbiogune.es/CANCERTOOL/index.html), the two panels included in The authors recently became aware that, following the recent update of Cancertool breast cancer dataset (OSM in the Wang (20) dataset did not reveal a significant association with disease-free survival and disease-free survival (DFS) data for breast cancer patients based on OSM mRNA expression in the METABRIC (19) and Wang (20) datasets were analyzed and represented using the CANCERTOOL interface (59) in combination with cBioPortal .The authors regret the errors."} +{"text": "J Clin Invest. 2020;130(1):335\u2013344. https://doi.org/10.1172/JCI129937Original citation: J Clin Invest. 2022;132(11):e161852. https://doi.org/10.1172/JCI161852Citation for this corrigendum: P values, but not the effect sizes and directionalities. The authors have stated that all conclusions of the paper remain the same.The authors recently became aware that the standard errors for the diabetes group were incorrect in Supplemental Table 9. The supplemental data PDF has been updated with the correct information. This correction affected the The authors regret the errors."} +{"text": "Scientific Reports 10.1038/s41598-022-22913-7, published online 26 October 2022Correction to: In the original version of this Article, Kah\u2011Wee Ang and Yong\u2011Wei Zhang were omitted as corresponding authors. Correspondence and requests for materials should also be addressed to kahwee.ang@nus.edu.sg and zhangyw@ihpc.a-star.edu.sgThe original Article has been corrected."} +{"text": "This addendum was issued to note clinical trial registration numbers for the following publications. In line with strengthening journal guidelines on adhering to the ICMJE guidelines on specifying clinical trial registration for interventional studies, the following manuscripts declare their clinical trial registration numbers. Prospective registration was not mandated by the funding agencies at start of the study and thus, retrospective registration was done by the author(s).https://doi.org/10.4069/kjwhn.2022.09.22Kim SH. Development and effects of a webtoon education program on preventive self-manage\u00adment related to premature labor for women of childbearing age: a randomized controlled trial. Kore\u00adan J Women Health Nurs. 2022;28(3):250-263. \u2192 KCT0008015https://doi.org/10.4069/kjwhn.2021.06.07Kim SM, Ahn S. Development and application of a self-transcendence enhancement program for the well-being of elderly women living alone in Korea. Korean J Women Health Nurs. 2021;27(2):128-140. \u2192 KCT0008010The clinical trial registration number has also been updated to the manuscript PDF and online access.Korean Journal of Women Health Nursing strongly recommends prospective registration of interventional health studies."} +{"text": "Adv. Sci. 2023, 10, 220343310.1002/advs.202203433DOI: In the originally published article, Table Some primer sequences did not match their names in primer lists due to re\u2013sorting in the table. The corrected Table Supporting InformationClick here for additional data file."} +{"text": "Correction to: European Journal of Applied Physiology 10.1007/s00421-022-05058-3.The original version of this article unfortunately contained a mistake. The given name and family names of five author were incorrectly structured.The correct given name and family names should be:Helen McGuire.Kenneth Graham.Jason Siegler.Corinne Caillaud.Kate M. Edwards.The original article has been corrected."} +{"text": "European Journal of Public Health, 2021; https://doi.org/10.1093/eurpub/ckab171In the originally published version of this manuscript, author forenames and surnames were swapped in error. These errors have been corrected online."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-98796-x, published online 28 September 2021Correction to: The Data Availability section in the original version of this Article was omitted. The Data Availability section now reads:Data Availability:https://zenodo.org/record/6367404#.YkRbTajTXIV.The datasets generated during and analysed during the current study are available in Zenodo, at The original Article has been corrected."} +{"text": "Fully funded scholarships are available for Commonwealth country nationals. The course aims to provide eye health professionals with the public health knowledge and skills required to reduce blindness and visual disability.www.lshtm.ac.uk/study/masters/mscphec.html or email romulo.fabunan@lsthm.ac.ukFor more information visit ICEH Open Education for eye care programme offers a series of online courses in key topics in public health eye care. All the courses are free to access.Courses:Global Blindness, Eliminating Trachoma, Ophthalmic Epidemiology Basic Principles (1) and Application to Eye Disease (2).More free courses coming! Certification also available.http://iceh.lshtm.ac.uk/oer/For more information visit admin@cehjournal.orgContact Anita Shah web@cehjournal.org or visit www.cehjournal.org/subscribewww.cehjournal.orgwww.facebook.com/CEHJournalhttps://twitter.com/CEHJournal"} +{"text": "JCI Insight. 2021;6(10):146849. https://doi.org/10.1172/jci.insight.146849Original citation: JCI Insight. 2023;8(3):168732. https://doi.org/10.1172/jci.insight.168732Citation for this corrigendum: For this article, we used the Michigan Neuropathy Screening Instrument combined index (MNSI index) to measure neuropathy longitudinally in 141 Pima American Indians. We were contacted by the authors who developed the MNSI index and were notified of an error in their published manuscript .Specifically, the cutoff reported by Herman et al. to determine neuropathy was incorrect. The corrected cutoff for neuropathy is MNSI index > 2.5407, rather than MNSI index > 3.2516. While we primarily used the continuous MNSI index in our paper, we also reported the prevalence that met this cutoff during each year of follow-up. In light of this information, we reanalyzed our data with the corrected cutoff.The text in Results and Methods is corrected as follows:At baseline, 32.9% of participants met the cutoff for neuropathy (MNSI index > 2.5407 ), which generally increased during follow-up .To provide additional clinical context to our primary neuropathy measurement, we also determined the number of participants meeting the predefined cutoff for neuropathy based on the MNSI index (MNSI index > 2.5407) (66)."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-24946-4, published online 01 December 2022Correction to: The Data availability section in the original version of this Article was incomplete.https://usda.library.cornell.edu/concern/publications/rn301137d (United States Department of Agriculture), https://nass.usda.gov/Research_and_Science/Cropland/Release/index.php (United States Department of Agriculture Cropland Data Layer), and https://prism.oregonstate.edu (Parameter-elevation Regressions on Independent Slopes Model Climate Group). Our source code to process and combine these data sources, as well as the resulting combined dataset itself, is part of the Supplementary Information.\u201d\u201cThe raw data that support the findings in this paper are openly available at now reads:https://usda.library.cornell.edu/concern/publications/rn301137d (United States Department of Agriculture), https://nass.usda.gov/Research_and_Science/Cropland/Release/index.php (United States Department of Agriculture Cropland Data Layer), and https://www.prism.oregonstate.edu/ (Parameter-elevation Regressions on Independent Slopes Model Climate Group). Our source code to process and combine these data sources is available at: https://github.com/LucaIns/honey_bee_loss_US_scirep, and the resulting combined dataset is part of the Supplementary Information.\u201d\u201cThe raw data that support the findings in this paper are openly available at The original Article has been corrected."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-13840-8, published online 15 June 2022Correction to: In the original version of this Article, Fateh Abolfazl was incorrectly listed as a corresponding author. The correct corresponding author for this Article is Seyed Davar Siadat. Correspondence and request for materials should only be addressed to d.siadat@gmail.com.The original Article has been corrected."} +{"text": "Openness toward organizational change is central to employees\u2019 responses to organizations\u2019 strategic actions. This study aims to assess the validity evidence of the Openness Toward Organizational Change Scale (OTOCS) by examining the internal structure of the measure and its relations with other variables such as quality of work life, burnout, job satisfaction, and work engagement. A cross-sectional study was conducted using total sample of 1,175 workers, with 565 workers from Portugal and 610 from Brazil. The data provided satisfactory validity evidence based on the internal structure: the expected dimensionality was confirmed, acceptable levels of reliability were found, and measurement invariance was achieved among countries and sex. The measure also demonstrated satisfactory validity evidence based on the relations to other variables, being negatively associated with burnout and positively associated with work engagement, job satisfaction and quality of work. The OTOCS proved to be a relatively short self-report measure with satisfactory validity evidence to be used among Brazilian and Portuguese workers. Work engagement is described as energetic involvement with work reflecte was seleLimeSurvey ). The modification indices were investigated, and a correlation path between item\u2019s 2 and item\u2019s 4 residuals was added to the model . The modified model presented an acceptable fit to the data from the merged samples (\u03c72(4) = 96.363, p < .001, \u03c72/df = 24.090; n = 1,175; CFI = .976; NFI = .975; TLI = .940; SRMR = .058; RMSEA = .140; P(rmsea) \u2264.05) < .001, 90% CI ). All OTOCS\u2019 factor loadings were statistically significant (p < .001). There were no items removal. The minimum item loading for the OTOCS was.34. Consequently the fit for the separated samples was also acceptable (2(4) = 35.349, p < .001, \u03c72/df = 8.837, n = 610; CFI = .985; NFI = .983; TLI = .962; SRMR = .051; RMSEA = .113; P(rmsea) \u2264.05) = .001, 90% CI ; Sample 2: \u03c72(4) = 64.087, p < .001, \u03c72/df = 16.022, n = 565; CFI = .967; NFI = .965; TLI = .918; SRMR = .067; RMSEA = .163; P(rmsea) \u2264.05) < .001, 90% CI ). RMSEA is known to be overestimated for models with few degrees of freedom ). The UWES-9 second-order model obtained an acceptable fit, after constraining the variance of the first-order factor dedication to 0.01 in order to avoid negative variance (\u03c72(25) = 441.365, p < .001, \u03c72/df = 17.65; n = 1,103; CFI = .998; NFI = .998; TLI = .997; SRMR = .041; RMSEA = .123; P(rmsea) \u2264.05) < .001; 90% CI ). The OLBI second-order model presented an acceptable fit to the data (\u03c72(89) = 1,390.029, p < .001, \u03c72/df = 15.618; n = 1,104; CFI = .979; NFI = .977; TLI = .975; SRMR = .074; RMSEA = .115; P(rmsea) \u2264.05) < .001; 90% CI ). After adding one correlation among items\u2019 3 and 5 residuals the SIJS presented a very good fit to the data (\u03c72(4) = 11.529, p = .021, \u03c72/df = 2.882; n = 1,102; CFI = .999; NFI = .999; TLI = .999; SRMR = .022; RMSEA = .041; P(rmsea) \u2264.05) = .647; 90% CI .All the measurement models of each of the OTOCS criterion related variables were tested. The QWLS hierarchical model presented acceptable fit = 1,390.029, p < .001, \u03c72/df = 15.618; n = 1,103; CFI = .979; NFI = .977; TLI = .975; SRMR = .074; RMSEA = .115; P(rmsea) \u2264.05) < .001; 90% CI ) showing a large and positive correlation ) presenting a medium and positive correlation ) the correlation was small ) the obtained correlation was large Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1:\u00a0YesReviewer #2:\u00a0Partly**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1:\u00a0YesReviewer #2:\u00a0No**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data\u2014e.g. participant privacy or use of data from a third party\u2014those must be specified.The Reviewer #1:\u00a0YesReviewer #2:\u00a0No**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1:\u00a0YesReviewer #2:\u00a0No**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1:\u00a0Dear colleagues,I\u2019ve recently had the opportunity to review the manuscript \u201cOpenness Toward Organizational Change Scale (OTOCS): Validity Evidence from Brazil and Portugal\u201d. I have appreciated your manuscript that I consider as consistent and well done.I have some concerns and comments. I hope they are useful to you to move forward.Please describe with more details:1) the construct of Openness Toward Organizational Change Scale as measured by OTOCS, in relationship with the item contents.2) Why do you adopt the 5-item version?3) the psychometric qualities of OTOCS that literature presents4) why do you accept the models even if the RMSEA indexes are very unfair?5) why do you assume Weighted Least Squares Means and Variances (WLSMV) estimator?6) some lines of organization interventions when there is a low level of Openness Toward Organizational ChangeReviewer #2:\u00a0I am sympathetic to value of a Portuguese language version of commonly used scales in organizational research. The authors have provided evidence of the psychometric properties of a variety of commonly used scales including Engagement and Openness to Change. What puzzles me is this: why is the focus of this paper Openness to Change when none of the other indicators used pertain to that topic.The present version uses a two-country sample of Portuguese speaking individuals and surveys them using a questionnaire that contains a mixed bag of common scales in organizational research. Yet the focus of the paper is the phenomenon of Openness to Change and the suitability of this particular translation of a common scale to assess it. The convenience samples in Brazil and Portugal do not appear to involved organizations undergoing a systematic or planned organizational change. Despite the assertions of the authors, Openness to Change is a construct largely targeting change recipients to understand the role of individual predispositions in shaping their change responses. Not only is there no evidence that change is occuring in the organizations from which participants are derived, but there is no measure of change-related perceptions, processes/interventions or outcomes.This paper could easily have been written with a focus on engagement, for example, and then the psychometric properties of that scale could be the central story. If change-related experiences are not assessed we do not know whether the Openness to Change measure functions in the typical context in which it is used. It is true that engagement and stress are measured in lots of contexts and it may be better to refocus the present report on Portuguese translations of common organizational measures, and downplay the focus on change, since the sampling strategy is not tied to change experiences.Methodologically, I am concerned that there is no change context studied, limiting the information provided regarding the explanatory power of the Portuguese version of Openness to Change for change research. I also am concerned with idiosyncratic adjustments made in the interdependencies among items in order to engineer good fit. I recognize that tools are available in various structural equation programs to enhance conventional indicators, but this is a practice not widely accepted. It would be better to report the non-engineered and engineered indicators of fit and talk through the sensitivity of observed effects to these adjustments.So, I am suggesting that a connection between organizational change and the present survey and sample design is not yet established. Can you make a better case, perhaps through additional change-related measures, or further evidence regarding the change experience of your sample?I suggest as an alternative a focus on the Portugeuse language assessment of common organizational survey measures. I do not know this literature but in trying to find contributions that can be made by the current data set that possibility comes to mind.**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article digital diagnostic tool,\u00a0 16 Mar 2021Manuscript ID: PONE-D-20-29649\u201cOpenness Toward Organizational Change Scale (OTOCS): Validity Evidence from Brazil and Portugal\u201dReviewer 1###########################################################Reviewer 1\u2019s comments###########################################################I\u2019ve recently had the opportunity to review the manuscript \u201cOpenness Toward Organizational Change Scale (OTOCS): Validity Evidence from Brazil and Portugal\u201d. I have appreciated your manuscript that I consider as consistent and well done.I have some concerns and comments. I hope they are useful to you to move forward. ****************************************************************************Authors\u2019 response ****************************************************************************Thank you for your careful reading of the manuscript. Responses to your questions and concerns are below.###########################################################Reviewer 1\u2019s comments###########################################################Please describe with more details:1) the construct of Openness Toward Organizational Change Scale as measured by OTOCS, in relationship with the item contents. ****************************************************************************Authors\u2019 response ****************************************************************************We added to pages 6-7:\u201cThe original five-item scale assesses respondents\u2019 favorable attitudes toward change in the organization and the absence of resistance or rejection of change. Researchers have used the scale to measure specific changes [10] or potential changes [31].\u201dPlease describe with more details:###########################################################Reviewer 1\u2019s comments###########################################################2) Why do you adopt the 5-item version? ****************************************************************************Authors\u2019 response ****************************************************************************We added (page 6):\u201cThe 5-item version focuses on respondents\u2019 favorableness toward change in a relatively succinct manner. Its length is convenient when the practitioner/researcher wants to measure openness toward organizational change along with other constructs. The 5-item unidimensional measure offers a good balance between length and psychometric properties.\u201d###########################################################Reviewer 1\u2019s comments###########################################################Please describe with more details:3) the psychometric qualities of OTOCS that literature presents ****************************************************************************Authors\u2019 response ****************************************************************************Psychometric properties of the OTOCS obtained from other studies was added to the manuscript (page 7):\u201cThe OTOCS has previously showed good validity evidence in different studies . In terms of its dimensionality, it has shown a stable number of items and dimensions. The original study suggested retaining five items from a set of eight items [10]. Other authors used the pool of eight items from the original study and retained seven of them [33]. Wanberg and Banas [28] used a 7-item modified version of the original OTOCS, suggesting two latent factors. Chawla and Kelloway [32] used the 8-item version assuming a single latent factor. Recent research has implemented the original 5-item version (one-factor structure) [31]. In terms of reliability, the OTOCS presented good evidence. Since its original study (\u03b1 = .80) [10], the unidimensional version of the OTOCS presented good reliability estimates , ranging from \u03b1 = .83 [32] to \u03b1 = .97 [33]. Since none of the existing studies assessed measurement invariance across groups within OTOCS, there is no evidence of any kind regarding this type of psychometric property. The evidence pertaining to the relations to other variables is consistent, namely in terms of convergent evidence. Positive moderate correlations with work engagement [31], organizational identification [10], trust, procedural justice, communication, and participation [32] were found. And positive strong correlations with need for achievement and quality information [10] were also reported.\u201d###########################################################Reviewer 1\u2019s comments###########################################################Please describe with more details:4) why do you accept the models even if the RMSEA indexes are very unfair? ****************************************************************************Authors\u2019 response ****************************************************************************The RMSEA is one of the various possible goodness-of-fit indices with some known particularities, namely, it depends on sample size and model misspecification, and model degrees of freedom . The SRMR presents evidence to be generally accurate across all conditions . Nevertheless, other goodness-of-fit indices were used in conjunction to assess models\u2019 adequacy.The OTOCS model presents a particularly small number of degrees of freedom and thus can be more exposed to the RMSEA under optimal performance in models with few degrees of freedom.We added this, information to the data analysis section:\u201cIt is known that for models with few degrees of freedom RMSEA too often falsely indicates a poor fitting [81]. RMSEA performance also depends on sample size and model misspecification . The SRMR presents evidence of being generally accurate across all conditions . Nevertheless, the evaluation of the goodness-of-fit of the tested models will be based on the evidence provided by all mentioned indicators in conjunction.\u201d###########################################################Reviewer 1\u2019s comments###########################################################Please describe with more details:5) why do you assume Weighted Least Squares Means and Variances (WLSMV) estimator? ****************************************************************************Authors\u2019 response ****************************************************************************We added on page 19:\u201cThe WLSMV was chosen because it does not require multivariate normality as an assumption and also because all items of the used psychometric instruments have an ordinal response scale.\u201d###########################################################Reviewer 1\u2019s comments###########################################################Please describe with more details:6) some lines of organization interventions when there is a low level of Openness Toward Organizational Change****************************************************************************Authors\u2019 response ****************************************************************************The importance of assessing employees\u2019 openness toward change at anytime, even if a planned change is not imminent, is fairly well expressed by Malik and Garg [5]:\u201c\u2026technological transformations put immense pressure on employees since they encounter frequent changes in roles and responsibilities and reskill constantly to gear up with new lines of reporting and modifications in IT operations. This necessitates these firms to prepare their employees to adopt to change rather than retaliate against it. IT organizations thus need to ensure that their employees adapt effectively to these change processes and elicit affective commitment to change.\u201dAlthough Malik and Garg focus on the tech industry, knowledge of employees\u2019 orientation toward planned change or incremental changes related to adapting to everyday work challenges can provide insight into a range of factors \u2013 past management actions, employees\u2019 attitude formation, work unit flexibility, etc.As so, we added the following lines to the manuscript:Page 29-30\u201cIt is important to note in this study burnout levels were associated with the general possibility of organizational change, not before or after the implementation of change. Given stress among employees is a common reaction of the organizational change [9], it is important for firms to assess employee attitudes toward such changes [101]. It almost goes without saying that the existence of high stress levels is never a good starting point for organizational change [18]. On top of possible resistance to change, strained workers have less resources to produce positive views and participate in planned organizational change [17].\u201dPage 31\u201cAt the same time, there is considerable value in measuring employees\u2019 openness to change when a planned change is not ongoing or imminent [101]. Information about their attitude toward change in general can provide insights regarding employee overall adaptability, past management actions, variation in employee attitudes from one unit to another, or work unit flexibility.\u201d###############################################################################################################Reviewer 2###########################################################Reviewer 2\u2019s comments###########################################################I am sympathetic to value of a Portuguese language version of commonly used scales in organizational research. The authors have provided evidence of the psychometric properties of a variety of commonly used scales including Engagement and Openness to Change. ****************************************************************************Authors\u2019 response ****************************************************************************Thank you for your careful reading of the manuscript. Responses to your questions and concerns are below.###########################################################Reviewer 2\u2019s comments###########################################################What puzzles me is this: why is the focus of this paper Openness to Change when none of the other indicators used pertain to that topic. The present version uses a two-country sample of Portuguese speaking individuals and surveys them using a questionnaire that contains a mixed bag of common scales in organizational research. Yet the focus of the paper is the phenomenon of Openness to Change and the suitability of this particular translation of a common scale to assess it. ****************************************************************************Authors\u2019 response ****************************************************************************Your comment raises two important issues, one of which is brought up several times.First, one issue concerns the paper\u2019s orientation vis a vis impending/current change processes.There is great value in scales that assess employees\u2019 attitudes about change when planned change is ongoing or imminent. In these contexts, the openness to change scale may provide insight into employee responses during a change or provide a comparison of attitudes from one time point and a second time point. There is also considerable value in measuring employees\u2019 openness to change when a planned change is not ongoing or imminent. Information about their attitude toward change in general can provide insights regarding employee overall adaptability, past management actions, variation in employee attitudes from one unit to another, work unit flexibility, etc.A number of authors have measured openness to changes when organizational change was not imminent. Here are a few: Chai et al. [6] \u2013 use the Miller et al., [7] scale, Korean sample, no imminent change context;Danish et al., [8] \u2013 use the Wanberg and Banas [9] scale that incorporates the Miller et al., [7] scale, Indian sample, no imminent change context;Malik and Garg [5] \u2013 use the Herscovitch and Meyer [10] affective commitment to change scale, Indian sample, no imminent change context;Gori and Topino [11] \u2013 use the Di Fabio and Gori [12] scale on acceptance of change, Italian sample, no imminent change context.Second, the \u201cmixed bag of common scales in organizational research\u201d provides convergent evidence with those constructs. Importantly, the relationship of the OTOC measure with job satisfaction, quality of work life, burnout, and work engagement scales provide a point of comparison to prior research, in keeping with the Standards for Educational and Psychological Testing [13]. A natural next step for research is to assess concurrently the OTOCS\u2019 convergent and discriminant validity, which we include in the Discussion section.###########################################################Reviewer 2\u2019s comments###########################################################The convenience samples in Brazil and Portugal do not appear to involved organizations undergoing a systematic or planned organizational change. Despite the assertions of the authors, Openness to Change is a construct largely targeting change recipients to understand the role of individual predispositions in shaping their change responses. Not only is there no evidence that change is occuring in the organizations from which participants are derived, but there is no measure of change-related perceptions, processes/interventions or outcomes.****************************************************************************Authors\u2019 response ****************************************************************************As noted above, we did not intend to test the effectiveness of interventions based on their collaborators\u2019 levels of OTOC.An important element in the paper is the responses of Portuguese and Brazilian workers to the OTOCS, given their cultural similarities and differences.The reviewer brings up an interesting aspect, which was added to the future research agenda with the OTOCS. The use of criterion measures (i.e. test-criterion evidence) can be assessed with two approaches (predictive or concurrent). Predictive evidence (indicates the strength of the relationship between test scores and criterion scores that are obtained at a later time) e.g. OTOCS relationships with measures of the effectiveness of organizational change. Concurrent evidence (obtains test scores and criterion information at about the same time) e.g., relationships of OTOCS with change-related perceptions.###########################################################Reviewer 2\u2019s comments###########################################################This paper could easily have been written with a focus on engagement, for example, and then the psychometric properties of that scale could be the central story. If change-related experiences are not assessed we do not know whether the Openness to Change measure functions in the typical context in which it is used.****************************************************************************Authors\u2019 response ****************************************************************************We appreciate the reviewer\u2019s focus on change-related experiences as well as the value of assessing the relationship of engagement along with the OTOCS. As noted earlier, we note the importance of convergent validity investigations as both a limitation of the current study and a direction for future research. A chief goal of the manuscript was to assess the psychometric properties of the instrument .Another aim of future investigations is to examine employee openness to change in Portuguese-language countries in a longitudinal research design under relevant interventions. For instance, longitudinal measurement invariance can be tested to assess the stability of the measurement structure of the OTOC, a point now included as future research.###########################################################Reviewer 2\u2019s comments###########################################################It is true that engagement and stress are measured in lots of contexts and it may be better to refocus the present report on Portuguese translations of common organizational measures, and downplay the focus on change, since the sampling strategy is not tied to change experiences.Methodologically, I am concerned that there is no change context studied, limiting the information provided regarding the explanatory power of the Portuguese version of Openness to Change for change research.****************************************************************************Authors\u2019 response ****************************************************************************Thank you for your suggestion. However, we clarify in the manuscript that the objective of the manuscript was not to study the levels of organizational change among workers in the different phases of an organizational change intervention, but to study the psychometric properties of the OTOCS instrument.Given the use of the original Miller et al. [7] scale in both change contexts and non-change contexts, the present study provides evidence of the OTOCS\u2019 psychometric properties and responses from the two country samples.We also suggest that future research must approach the predictive evidence of the OTOCS.###########################################################Reviewer 2\u2019s comments###########################################################I also am concerned with idiosyncratic adjustments made in the interdependencies among items in order to engineer good fit. I recognize that tools are available in various structural equation programs to enhance conventional indicators, but this is a practice not widely accepted. It would be better to report the non-engineered and engineered indicators of fit and talk through the sensitivity of observed effects to these adjustments.****************************************************************************Authors\u2019 response ****************************************************************************In an effort for the reader to understand the effort to discern the best fit of the data, the manuscript reports the initial analysis and subsequent modification indices both in terms of effect size and statistical significance:\u201cThe original OTOCS structure provided a mediocre fit for data obtained with the merged samples (\u03c72(5) = 319.298, p < .001, \u03c72/df = 63.860; n = 1,175; CFI = .918; NFI =.917; TLI = .837; SRMR = .105; RMSEA = .231; P(rmsea) \u2264 .05) < .001, 90% CI ].210; .253.117; .165 however the included modification is justifiable by the fact that both items belong to the same factor and due to both items being negatively worded [100]. The use of reversed items has its trade-offs, and its use should be cautioned .\u201d###########################################################Reviewer 2\u2019s comments###########################################################So, I am suggesting that a connection between organizational change and the present survey and sample design is not yet established. Can you make a better case, perhaps through additional change-related measures, or further evidence regarding the change experience of your sample?****************************************************************************Authors\u2019 response ****************************************************************************We appreciate your perspective and effort to strengthen the study by positioning the relevance of the OTOCS in light of a current or impending organizational change.We also suggest, as noted earlier, there is value in measuring employees\u2019 openness to change when a planned change is not ongoing or imminent.To quote Malik and Garg [5] regarding the importance of studying employees\u2019 attitude toward change in IT companies, \u201ctechnological transformations put immense pressure on employees since they encounter frequent changes in roles and responsibilities and reskill constantly to gear up with new lines of reporting and modifications in IT operations. This necessitates these firms to prepare their employees to adopt to change rather than retaliate against it. IT organizations thus need to ensure that their employees adapt effectively to these change processes and elicit affective commitment to change.\u201d###########################################################Reviewer 2\u2019s comments###########################################################I suggest as an alternative a focus on the Portugeuse language assessment of common organizational survey measures. I do not know this literature but in trying to find contributions that can be made by the current data set that possibility comes to mind.****************************************************************************Authors\u2019 response ****************************************************************************Thank you for your suggestion to enhance the potential contribution of this data set to Portuguese-speaking individuals and organizations. We will seek to incorporate this idea in future studies.+++++++++++++++++++++++++++++++++++++++++++++++++++++++++++References1. MacCallum RC, Browne MW, Sugawara HM. Power analysis and determination of sample size for covariance structure modeling. Psychological Methods. 1996;1: 130\u2013149. doi:10.1037/1082-989X.1.2.1302. Chen F, Curran PJ, Bollen KA, Kirby JB, Paxton P. An empirical evaluation of the use of fixed cutoff points in RMSEA test statistic in structural equation models. Sociological Methods & Research. 2008;36: 462\u2013494. doi:10.1177/00491241083147203. Maydeu-Olivares A, Shi D, Rosseel Y. Assessing Fit in Structural Equation Models: A Monte-Carlo Evaluation of RMSEA Versus SRMR Confidence Intervals and Tests of Close Fit. Structural Equation Modeling: A Multidisciplinary Journal. 2018;25: 389\u2013402. doi:10.1080/10705511.2017.13896114. Shi D, Maydeu-Olivares A, Rosseel Y. Assessing fit in ordinal factor analysis models: SRMR vs. RMSEA. Structural Equation Modeling: A Multidisciplinary Journal. 2020;27: 1\u201315. doi:10.1080/10705511.2019.16114345. Malik P, Garg P. The relationship between learning culture, inquiry and dialogue, knowledge sharing structure and affective commitment to change. Journal of Organizational Change Management. 2017;30: 610\u2013631. doi:10.1108/JOCM-09-2016-01766. Chai DS, Song JH, You YM. Psychological ownership and openness to change: The mediating effects of work engagement, and knowledge creation. Performance Improvement Quarterly. 2020;33: 305\u2013326. doi:10.1002/piq.213267. Miller VD, Johnson JR, Grau J. Antecedents to willingness to participate in a planned organizational change. Journal of Applied Communication Research. 1994;22: 59\u201380. doi:10.1080/009098894093653878. Danish RQ, Asghar J, Ahmad Z, Ali HF. Factors affecting \u201centrepreneurial culture\u201d: The mediating role of creativity. Journal of Innovation and Entrepreneurship. 2019;8: 1\u201312. doi:10.1186/s13731-019-0108-99. Wanberg CR, Banas JT. Predictors and outcomes of openness to changes in a reorganizing workplace. Journal of Applied Psychology. 2000;85: 132\u2013142. doi:10.1037/0021-9010.85.1.13210. Herscovitch L, Meyer JP. Commitment to organizational change: Extension of a three-component model. Journal of Applied Psychology. 2002;87: 474\u2013487. doi:10.1037//0021-9010.87.3.47411. Gori A, Topino E. Predisposition to change is linked to job satisfaction: Assessing the mediation roles of workplace relation civility and insight. International Journal of Environmental Research and Public Health. 2020;17: 1\u201316. doi:10.3390/ijerph1706214112. di Fabio A, Gori A. Developing a new instrument for assessing acceptance of change. Frontiers in Psychology. 2016;7: 1\u201310. doi:10.3389/fpsyg.2016.0080213. American Educational Research Association, American Psychological Association, National Council on Measurement in Education. Standards for Educational and Psychological Testing. Washington, DC, USA: American Psychological Association; 2014.AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 30 Mar 2021Openness Toward Organizational Change Scale (OTOCS): Validity Evidence from Brazil and PortugalPONE-D-20-29649R1Dear Dr. Mar\u00f4co,We\u2019re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you\u2019ll receive an e-mail detailing the required amendments. When these have been addressed, you\u2019ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they\u2019ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact Kind regards,Mariagrazia BenassiAcademic EditorPLOS ONEAdditional Editor Comments :Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the \u201cComments to the Author\u201d section, enter your conflict of interest statement in the \u201cConfidential to Editor\u201d section, and submit your \"Accept\" recommendation.Reviewer #1:\u00a0All comments have been addressedReviewer #2:\u00a0All comments have been addressed**********2. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1:\u00a0YesReviewer #2:\u00a0Yes**********3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1:\u00a0YesReviewer #2:\u00a0Yes**********4. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data\u2014e.g. participant privacy or use of data from a third party\u2014those must be specified.The Reviewer #1:\u00a0NoReviewer #2:\u00a0Yes**********5. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1:\u00a0YesReviewer #2:\u00a0Yes**********6. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1:\u00a0Dear authors, I have appreciated your improvments and think the paper is fair to be published.Best RegardsReviewer #2:\u00a0I accept your responses to my concerns and am persuaded by your arguments. I have no further comments.**********what does this mean?). If published, this will include your full peer review and any attached files.7. PLOS authors have the option to publish the peer review history of their article : Validity Evidence from Brazil and Portugal Dear Dr. Mar\u00f4co:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact plosone@plos.org. If we can help with anything else, please email us at Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staffon behalf ofDr. Mariagrazia Benassi Academic EditorPLOS ONE"} +{"text": "Correction to: BMC Health Serv Res 21, 667 (2021)https://doi.org/10.1186/s12913-021-06659-yFollowing publication of the original article , the autThe incorrect author name is: Ahmed Ehsanur RahamnThe correct author name is: Ahmed Ehsanur RahmanIn addition, the corresponding email has been changed from eshanur@icddrb.org to ehsanur@icddrb.org.The author group and corresponding email have been updated in this correction article and the original article has been"} +{"text": "Scientific Reportshttps://doi.org/10.1038/srep36975, published online 11 November 2016Correction to: https://www.ncdc.noaa.gov/paleo-search/study/21350.The Supplementary Information published with this Article contains errors where four Supplementary data tables are omitted from the final file. This data is now available in the NOAA database, and can be accessed using the link:"} +{"text": "Int J Epidemiol 2019, doi: https://doi.org/10.1093/ije/dyz150First published online: 19 July 2019, In the originally published version of this article, the funding section was missing. This has since been added."} +{"text": "GigaScience published the article \u201cDissectionof soybean populations according to selection signatures based on whole-genomesequences,\u201d by Jae-Yoon Kim and colleagues: https://doi.org/10.1093/gigascience/giz151. In 2020, the editorsreceived credible information about attribution problems with the source of the data inthe article and subsequently alerted the readers with a statement of concern: https://doi.org/10.1093/gigascience/giaa040. A full institutionalinvestigation has now been completed, which has concluded that research misconduct wascarried out. As a result, this article is being retracted by the editors andauthors.In December 2019,"} +{"text": "JAC-Antimicrobial Resistance 2021; https://doi.org/10.1093/jacamr/dlab051JAC-Antimicrobial Resistance 2021; https://doi.org/10.1093/jacamr/dlab053JAC-Antimicrobial Resistance 2021; https://doi.org/10.1093/jacamr/dlab054JAC-Antimicrobial Resistance 2021; https://doi.org/10.1093/jacamr/dlab055JAC-Antimicrobial Resistance 2021; https://doi.org/10.1093/jacamr/dlab056In the original published versions of these articles, in the Transparency declarations, \u201cThis article forms part of a Supplement sponsored by Shionogi Europe.\u201d, should have read \u201cThis article is part of a promotional Supplement developed and sponsored by Shionogi B.V. The accompanying video formed part of an educational webinar for which the author received a speaking honorarium.\u201dThis has now been corrected in the published versions of the articles. The authors apologize for this error."} +{"text": "Blood pressure variability and outcome in acute severe stroke: A post hoc analysis of CHASE\u2014A randomized controlled trial by Jingjing Zhao et al., https://doi.org/10.1111/jch.14090.The cover image is based on the Original Paper"} +{"text": "The second and third authors\u2019 names are incorrect. The correct name for the second author is Buyun Dai and the correct name for the third author is Yuanping Deng.https://doi.org/10.1371/journal.pone.0250268The correct citation is: Jian X, Dai B, Deng Y (2021) The robust estimation of examinee ability based on the four-parameter logistic model when guessing and carelessness responses exist. PLoS ONE 16(4): e0250268."} +{"text": "PLOS ONE article that was retracted on February 9, 2021 [Salvelinus genus, or Salvelinus sp. (GenBank accession: GCF_002910315.2).This article cites a 9, 2021 because The draft genome reported in was one https://www.ncbi.nlm.nih.gov/bioproject/PRJNA530256/). Custom scripts and sample information can be found in supplemental files and via GitHub: https://github.com/KrisChristensen/OrthologyBetweenSpecies.The retracted article was also"} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-021-93266-w, published online 05 July 2021Correction to: In the original version of this Article, author Salma Jamal was omitted as a corresponding author. Correspondence and requests for material should also be addressed to salmajamal@jamiahamdard.ac.in.The original Article and accompanying Supplementary Information file have been corrected."} +{"text": "This article has been corrected: The CONFLICTS OF INTERESTS section has been updated as shown below:K.C. Anderson is on the advisory board of Celgene, Gilead, Millennium and Bristol Myers Squibb; and is a scientific founder with financial interest in Acetylon, Oncopep and C4 Therapeutics. JB is a scientific founder with financial interest in Acetylon.80109-80123. https://doi.org/10.18632/oncotarget.19019Original article: Oncotarget. 2017; 8:80109\u201380123."} +{"text": "J Clin Invest. 2018;128(6):2613\u20132625. https://doi.org/10.1172/JCI98769Original citation: J Clin Invest. 2022;132(6):e159825. https://doi.org/10.1172/JCI159825Citation for this retraction: JCI of concerns regarding Figures 4I and 7A and indicated that an independent panel investigation concluded that these figures contain data fabricated by Mark Smyth. In accordance with the institutional recommendation, the JCI is retracting this article.QIMR Berghofer Medical Research Institute recently notified the Journal\u2019s decision to retract the paper. The remaining authors abstained from commenting or could not be reached.Amelia Roman Aguilera, Matthias Braun, Ailin Lepletier, and Kyohei Nakamura have agreed with the"} +{"text": "Chinese Journal of Lung Cancer 1 due to disagreement between authors.We would retract our article from Challa KIRAN and Ponnala DEEPIKAAug, 2012https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969376"} +{"text": "In addition, emerging integrative or hybrid methods (I/HM) are producing structural models of huge macromolecular machines and assemblies, sometimes containing 100s of millions of non-hydrogen atoms. The performance requirements for visualization and analysis tools delivering these data are increasing rapidly. Significant progress in developing online, web-native three-dimensional (3D) visualization tools was previously accomplished with the introduction of the LiteMol suite and NGL Viewers. Thereafter, Mol* development was jointly initiated by PDBe and RCSB PDB to combine and build on the strengths of LiteMol (developed by PDBe) and NGL (developed by RCSB PDB). The web-native Mol* Viewer enables 3D visualization and streaming of macromolecular coordinate and experimental data, together with capabilities for displaying structure quality, functional, or biological context annotations. High-performance graphics and data management allows users to simultaneously visualise up to hundreds of (superimposed) protein structures, stream molecular dynamics simulation trajectories, render cell-level models, or display huge I/HM structures. It is the primary 3D structure viewer used by PDBe and RCSB PDB. It can be easily integrated into third-party services. Mol* Viewer is open source and freely available at Experimental methods to determine the three-dimensional 3D) structures of biomolecules are continuously improved and produce molecular complexes from models with various resolutions that span multiple scales and can be dynamic throughout an experiment. By combining data from complementary experimental techniques including macromolecular crystallography (MX), nuclear magnetic resonance (NMR), 3D electron microscopy (3DEM), small-angle scattering (SAS), chemical crosslinking, or integrative/hybrid methods (I/HM), 3D structural models of large macromolecular systems can be determined ,2. Such D structuhttps://www.khronos.org/webgl/) and their surrounding ecosystem offer good support for the development of modular libraries and components. In summary, the web provides a unique opportunity to develop a common library and a set of tools for accessing, analysing, and visualizing macromolecular data.Web platforms, both mobile and desktop, have become an increasingly popular and essential tool for performing these tasks. Embracing advances in web browser technology provides the means for creating scalable molecular graphics and analysis tools with near-instant access to any available data. Web-based tools are platform-independent and require little or no local software installation, making them available to virtually everyone in both the scientific and non-scientific community, reaching an audience larger than ever before. Moreover, these technologies Viewer, part of the Mol* open source project developehttps://github.com/molstar).The purpose of Mol* Viewer is to enable web-based molecular visualization and analyses by providing a common library for the rapid and efficient development of tools and services for the structural biology/bioinformatics community. Examples include showing experimental/validation-related data for macromolecular models; displaying various annotations for macromolecular models providing biological context, including SCOP , PFAM 1, UniProtMol* Viewer can visualize markedly larger molecular systems than other currently available web visualization tools. Due to built-in BinaryCIF , decomprMol* inherits many LiteMol suite and NGL Viewer features, as described in their respective articles. Here, we highlight some of its new and improved features:Advanced User Interface: access to many capabilities of the underlying Mol* library for fully creating molecular scenes with custom visuals and colourings.High-quality rendering: advanced rendering options for beautiful images and improved perception of details, such as lighting , outlines, fog/depth cue, and ambient occlusion \u2018shadows\u2019 which darken crevices occluded from ambient light selection menu to help with navigating the structure and making selections.Alignment of molecules: sequence-guided pairwise alignment of two or more structures and ligand alignment by manual selection of corresponding atoms.Measurements and labels: geometric measurements and their labelling.Session state saving: save the current molecular scene to reload it later.Animation export: video export of molecular dynamics simulations, rotating molecules, and 3D state transitions (such as zooming to a binding site).Screenshots: custom-sized, high-resolution, anti-aliased screenshots with preview, automatic cropping, and transparent background support.Built-in data loading and annotations: includes support for loading data from RCSB PDB and PDBe MX and 3DEM density servers, wwPDB validation reports, and RCSB PDB assembly symmetry.Mol* Viewer is currently able to load and visualize many file formats with 3D structures:Structures (https://mmcif.wwpdb.org/pdbx-mmcif-home-page.html) (including BinaryCIF encoded), pdb (ftp://ftp.wwpdb.org/pub/pdb/doc/format_descriptions/Format_v32_letter.pdf), pdbqt (http://autodock.scripps.edu/faqs-help/faq/what-is-the-format-of-a-pdbqt-file), gro , sdf (https://discover.3ds.com/sites/default/files/2020\u201308/biovia_ctfileformats_2020.pdf), mol (https://discover.3ds.com/sites/default/files/2020\u201308/biovia_ctfileformats_2020.pdf), mol2 (http://chemyang.ccnu.edu.cn/ccb/server/AIMMS/mol2.pdf), CIF-core (https://www.iucr.org/resources/cif/dictionaries/cif_core).ructures : PDBx/mmVolumes: ccp4/mrc/map (http://svn.cgl.ucsf.edu/svn/chimera/trunk/libs/VolumeData/dsn6/brix-1.html), cube (http://paulbourke.net/dataformats/cube/), dx , BinaryCIF , dcd (https://www.ks.uiuc.edu/Research/namd/2.14/ug.pdf), psf (topology) .Generic triangle geometries: ply (http://gamma.cs.unc.edu/POWERPLANT/papers/ply.pdf).Adding support for additional formats is usually a straightforward process.https://www.typescriptlang.org/) was used for the development of the web application, WebGL (https://www.khronos.org/webgl/) for hardware-accelerated 3D rendering, and the standards of the open web platform (https://www.w3.org/standards/) for the whole tool. The React framework (https://reactjs.org/) was used to implement the application's UI.TypeScript . The structures can be static or dynamic (e.g.\u00a0a molecular dynamic trajectory). It can visualize large mesoscopic models (e.g.\u00a0Genome3D , cellPACThe high quality and applicability of Mol* Viewer was shown by a large number of integrations of it into scientific tools and databases. Mol* Viewer was integrated into PDBe and RCSB PDB as the primary 3D viewer where it is actively used by thousands of users daily. Moreover, Mol* Viewer was incorporated into many other resources, including PDBe-KB , PDB-DevMol* Viewer is a powerful web application for the visualization and analysis of molecular data. Its visualization capabilities far exceed other currently available web visualization tools. Mol* Viewer's speed and robustness allow the fast and intuitive visualization of molecular data ranging from atomistic models from PDB or MD simulations up to hybrid models with hundreds of thousands of residues, mesoscale cellPACK with tens of millions of atoms, or 3D Genome data. Furthermore, Mol* Viewer offers advanced selection and superimposition functionalities. It also offers a rich set of visualization models and colouring types. Last but not least, Mol* Viewer can save a visualization state operated by this web app.https://molstar.org/ or can be integrated into other web applications. Its source codes are available on GitHub at https://github.com/molstar.Mol* Viewer can be used from its webpage https://molstar.org/, under the MIT license, a permissive Open Source license, to facilitate code sharing and collaboration. The code is available on GitHub at https://github.com/molstar. Mol* Viewer can be readily embedded into any scientific web application.Mol* Viewer is available for free at https://doi.org/10.6084/m9.figshare.12040257.v1 and (Data for Figure 7.v1 and . Data fo7.v1 and . Data fo7.v1 and ."} +{"text": "Adv. Sci. 2021, 8, 200110010.1002/advs.202001100DOI: In the originally published article, the first name and family name of the third author were mixed\u2010up. The corrected author byline is presented here."} +{"text": "Bioinformatics (2019) doi:http://dx.doi.org/10.1093/bioinformatics/bty922In the originally published version of this manuscript, there was an error in the \u2018Availability and implementation\u2019 section of the Abstract.guanine.evolbio.mpg.de/complexityThe URL for the browser tracks should be: This detail has been corrected only in this corrigendum to preserve the published version of record."} +{"text": "Rheumatology Advances in Practice 2020. doi:10.1093/rap/rkaa021\"This paper originally erroneously published with the rkab028_Supplementary_DataClick here for additional data file."} +{"text": "Following publication of the original article , the autThere are 3 corresponding authors, including Ms. Xinyi Huang (xinyihuang1210@163.com), Dr. Anyi Chen (chenay@cqmu.edu.cn), and Prof. Dr. Jianjiang Xue (jianjiangxue@163.com).The original article has been"} +{"text": "Mol. Biol. Evol. doi: 10.1093/molbev/msaa311In the originally published version of this manuscript, amendments were inadvertently made without author approval prior to publishing, making key data incomprehensible to the reader. The errors have now been corrected."} +{"text": "Cell Death and Disease 10.1038/cddis.2016.139, published online 26 May 2016Correction to: nd. The original article has been corrected.The original version of this article unfortunately contained a mistake in an author name. The correct author name is GW Dorn 2"} +{"text": "The authors wish to make a change to the published paper . In Tablhttps://www.mdpi.com/2073-4360/13/13/2088.The manuscript will be updated, and the original will remain online on the article webpage:"} +{"text": "In the original publication the email addresses of corresponding authors have not been displayed. The correct email addresses of corresponding authors are provided in this correction. Fang-Cheng Li (sjwklfc@126.com), Fei Hu (neuron111@163.com), Min-Hua Luo (luomh@wh.iov.cn)."} +{"text": "The authors regret that contact details for the corresponding authors were not provided. The corrected contact details for the corresponding authors are provided below.wuxingzhi@usts.edu.cn (Xingzhi Wu), yjy2010@suda.edu.cn (Junyi Yang), ylsong@hit.edu.cn (Yinglin Song).* Corresponding author. E-mail addresses: The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers."} +{"text": "Adv. Sci. 2019, 6, 1801927https://doi.org/10.1002/advs.201801927In the originally published article, there are errors found in Figures\u00a0The correct figures panels are presented below. The corrections do not affect the results or conclusions of this work. The authors apologize for any inconvenience this may have caused.Supporting InformationClick here for additional data file."} +{"text": "Following the publication of the original article , the authttps://dataverse.scholarsportal.info/dataset.xhtml?persistentId=doi:10.5683/SP2/OAXHHZInformation about the original data used in that article is viewable at:"} +{"text": "DOI 10.26508/lsa.201900309.Published online 13 February 2019. In the original version of this article, a factual error occurred in The authors apologize for this error."} +{"text": "Discovery and Preclinical Development of Orally Active Small Molecules That Exhibit Highly Selective Follicle Stimulating Hormone Receptor Agonism by Nataraja S., Yu H., Guner J. and Palmer S. (2021). Front. Pharmacol. 11:602593. doi: 10.3389/fphar.2020.602593An erratum on Due to a production error, The publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "JAC-Antimicrobial Resistance 2021; https://doi.org/10.1093/jacamr/dlab026In the author list, the name \u2018E. Nwanko\u2019 should have appeared as \u2018E. Nwankwo\u2019. This has now been corrected in the published version of the article.The authors apologize for this error."} +{"text": "It is no longeraccessible at http://snpcurator.science.uu.nl/ but can be found at http://tdslab.nl/snpcurator/.Since this paper has published, the SNPcurator, which was previously hosted on"} +{"text": "The correct hyperlink is: \u2018http://doi.org/10.5255/UKDA-SN-854821\u2019.The authors wish to make the following corrections to their published paper . The hypThe corrected Data Availability Statement should be: Data Availability Statement: Data available in a publicly accessible repository. The data presented in this study are openly available in UK Data Service at http://doi.org/10.5255/UKDA-SN-854821 . Demographic data have been removed from the publicly accessible file to ensure participant anonymity.The authors would like to apologize for any inconvenience caused to the readers by these changes. The change does not affect the results or conclusions of the study."} +{"text": "Mol. Biol. Evol. doi:10.1093/molbev/msab044Supplementary data files unrelated to this article were published alongside this paper. The correct supplementary data files have now replaced the incorrect files online."} +{"text": "For more information, please see this retraction notice: https://doi.org/10.1093/nargab/lqad028.This article has been retracted and replaced under a new DOI at"} +{"text": "Following publication of the original article , the aut*Correspondence: bq_fan@139.com; fwfei1974@njmu.edu.cn.The original publication lists the contacts as followed: *Correspondence: fwfei1974@njmu.edu.cn; bq_fan@139.com.However, the correct order of contacts is: This is due to Dr. Fan being the main corresponding author.The original article has been updated to reflect the correct order."} +{"text": "The original version of this article unfortunately contained a mistake. In abstracts section, Clinicaltrials.gov registration should be NCT02041975 (22/01/2014).The original article has been corrected."} +{"text": "Due to the author\u2019s figure errors, the authors expect to make corrections and the correct figures are as below:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6000507"} +{"text": "Scientific Reports 10.1038/s41598-022-06017-w, published online 07 February 2022Correction to: In the original version of this Article, Jaros\u0142aw Domaradzki was incorrectly listed as a corresponding author. The correct corresponding author for this Article is Dawid Ko\u017alenia. Correspondence and request for materials should be addressed to dawid.kozlenia@awf.wroc.pl.The original Article has been corrected."} +{"text": "In https://www.hsph.harvard.edu/pgda/data/.Further, the posted code treats income using ranked categories. Code has been updated to treat income using the mid-points of income categories or the lowest value for the highest category and is available at"} +{"text": "Scientific Reportshttps://doi.org/10.1038/srep27911, published online 15 June 2016Correction to: This Article contains errors.For Fig. 6C, the lanes shown for JNK are incorrect. The correct Fig.\u00a0In addition, full blots for the data presented were omitted in the original Article. They have been included in the attached Supplementary Information file.Supplementary Information."} +{"text": "Following publication of the original article , it was https://pactr.samrc.ac.za/) with study Trial No. PACTR201811640750761.Trial registration: The trial was also registered with the Pan African Clinical Trial Registry (Where it should read:Trial registration: The trial was also registered with the ISRCTN registry with study Trial No. PACTR201811640750761.It said:The original article has been updated accordingly."} +{"text": "Scientific Reports 10.1038/s41598-021-93284-8, published online 07 July 2021Correction to: In the original version of this Article, Sam Van Haute and Sami Ghnimi were omitted as corresponding authors. Correspondence and requests for materials should also be addressed to sam.vanhaute@ghent.ac.kr and sghnimi@isara.fr.The original Article has been corrected."} +{"text": "Due to a production error, the corresponding authors were listed in the incorrect order. They should be listed as follows:Tian Lifmmult@foxmail.comZubing Meiherrmayor@126.comXueliang Wuwuxl@hebeinu.edu.cnThe publisher apologizes for this mistake. The original version of this article has been updated."} +{"text": "This study examined microorganisms known to be recalcitrant to storage and examined drying conditions that would lead to the best outcomes.https://www.thermofisher.com/us/en/home/industrial/microbiology/microbiology\u2010learning\u2010center/storing\u2010bacterial\u2010samples\u2010optimal\u2010viability.htmlThis commercial website provides a good overview of different bacterial storage methods, the temperatures they require and the effects on bacteria generally.https://www.nature.com/articles/s41598\u2010019\u201038588\u20106Chlorella vulgaris as an example and showed that ultra\u2010low temperature and nitrogen control were important factors in maintaining viability.Increasingly, algal storage is becoming industrially relevant. This study used https://www.intechopen.com/books/probiotics/different\u2010methods\u2010of\u2010probiotics\u2010stabilizationThis report describes a wide range of methods for preparation and storage of probiotic bacterial starter cultures.https://link.springer.com/article/10.1007/s00253\u2010017\u20108706\u20106Arthrobacter chlorophenolicus A6 that biodegrades chlorophenols. They examined methods like air\u2010drying in media such as vermiculite, to store bacteria for use in bioremediation.This study examined https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227486Given the increasing interest in metagenomic studies of gut microbiomes, accurate and reproducible comparative data often requires maintaining microbial viability while storing stool samples. This study examined storage conditions in this context.https://onlinelibrary.wiley.com/doi/full/10.1002/mbo3.1046This study describes the use of a guanidine thiocyanate based medium to stabilize microbial DNA in gut microbiome sample for shipping, storage and later sequencing.https://link.springer.com/article/10.1007/s00294\u2010019\u201001036\u2010zTrehalose has been known to prevent cellular protein\u00a0damage by acting as a chemical chaperone, but it might also diminish protein acetylation and glycation.https://sfamjournals.onlinelibrary.wiley.com/doi/10.1111/1751\u20107915.12880This review article discusses methods for maintaining high viability in microbial inoculant cultures for use in agriculture.https://patents.google.com/patent/US8011132B2/enRhizobium, Bradyrhizobium, Bacillus, Azotobacter and Azospirillum species. This patent deals with the storage of these types of bacteria in liquid inoculants on seeds.Numerous genera of bacteria have been shown to provide benefits to plant growth and those include: http://www.esalq.usp.br/lepse/imgs/conteudo_thumb/Life\u2010and\u2010death\u2010of\u2010dried\u2010prokaryotes.pdfThis classic paper focuses on the underlying molecular mechanisms of desiccation resistance and sensitivity in prokaryotes.https://www.biorxiv.org/content/10.1101/2021.02.06.430066v1.fullThis preprint deals with desiccation tolerant bacteria in cold adapted dry environments where water is in a solid state during almost the entire year."} +{"text": "Scientific Reportshttps://doi.org/10.1038/s41598-022-05064-7, published online 19 January 2022Correction to: In the original version of this Article, Rong Xu was incorrectly listed as a corresponding author. The correct corresponding author for this Article is Beifu Wang. Correspondence and request for materials should be addressed to wangbeifu@126.com.The original Article has been corrected."} +{"text": "Fugh-Berman and colleagues surveyed medical journals' policies and practices on advertising. Pharmaceutical products, they say, dominate journals' advertising pages, creating conflicts of interests. Peer-reviewed medical journals are generally considered to be a source of unbiased and reliable information about drugs. But at the same time, most medical journals contain advertisements, almost all of which are for drugs, and which are, by their very nature, biased toward promoting sales of that drug. In this article, we address the purpose and effects of journal advertising, the possible reasons for pharmaceutical product domination of advertising pages, and the current policies and practices of representative journals. We also make recommendations for change.Advertisements are intended to increase or maintain market share for targeted products. Pharmaceutical companies value print advertisements because they increase sales effectively . In a suhttp://www.rxpromoroi.org/rapp/index.html). Another industry study of 45 advertising campaigns found that journal advertising returned US$3.05 for advertising of unique products and US$2.46 for advertising of competitive established products campaign.\u201d He suggests: \u201cLet professional messages complement consumer messages. The copy platform and graphics should work together for all those times the patient will not remember the brand name but might remember the art or headline\u201d . The autIt is clear why drug companies advertise in medical journals, but why do they dominate display advertising pages? In other words, why do journals appear to publish advertisements for drugs much more frequently than for cars, computers, vacations, or other products of potential interest to doctors?New England Journal of Medicine (NEJM), theJournal of the American Medical Association (JAMA), Annals of Internal Medicine , PLoS Medicine, American Family Physician, theLancet, theBMJ, theCanadian Medical Association Journal, and theMedical Journal of Australia. Multispecialty journals were chosen because they receive the most advertising revenue. According to PERQ/HCI, in 2002, US$220,982,000 was spent on advertising in multispecialty journals, almost ten times the amount spent on the runner-up, internal medicine journals products\u201d through a special, addense version ofJAMA that contains an average of \u201c64 ad pages and 102 editorial pages\u201d were aware that their subscription toThe Lancet was sponsored by a pharmaceutical company. Moreover, one half also recalled, on anunaided [bold text in the original quotation] basis, the name of the sponsoring company\u201d delivers your product with your distinct message to thousands of physicians a week\u201d . TheNEJM also offers to \u201cconduct complimentary research for you among sponsored subscribers to validate the success of your program\u201d .Theompany\u201d . \u201cArm yoJAMA, theArchives journals, andAmerican Medical News), more than twice the US$17.5 million received from subscriptions [Journal advertisements generate profits not only for pharmaceutical companies and medical journals, but also for the physician organizations that publish the journals. In 1996, five of six physician organizations raised 10% or more of their total annual revenue from pharmaceutical company advertising in affiliated medical journals; the proportion of total revenues ranged from 2.1% to 31.3% . The AMAiptions .By accepting only advertisements for drugs and medical devices, medical journals have accepted an exclusive and dependent relationship with corporations. Perhaps the distance between the prescribing physician and the purchase of the advertised product contributes to the perception that drug advertisements in journals are somehow more professional than advertisements for goods hawked directly to the consumer. However, all advertising campaigns are designed to create positive feelings about a brand, to saturate a targeted population's environment with a brand name, and to sell the product.In consumer magazines, article content often caters to, or is ordered by, advertisers, and publishing articles that displease advertisers can financially jeopardize the publication. Medical journals are similarly prone to leash-yanking by advertisers.Annals criticized the accuracy of advertisements in journals [A 1995 survey of North American journal editors found that 12% noted conflicts between advertisers' wishes and editorial decisions, and 21% reported that they had no control over advertisements . In 1992ournals . Severalournals , costingournals . Ensuingournals .At times, advertising departments appear to influence editorial decisions.Annals expressed concern about a planned editorial on high drug costs. These concerns were allayed when the editor invited a commentary from the Pharmaceutical Research and Manufacturers Association , which commissioned a piece from a conservative thinktank, the American Enterprise Institute for Public Policy Research [Dialysis and Transplantation explained to an author that although the author's article had passed both editorial and peer review, the marketing department had rejected it [At times, advertising departments appear to influence editorial decisions. In 2001, the advertising department ofmerica) . In 2004cted it . The joucted it .Several authors have suggested that dependence on drug advertising endangers the independence of medical journals and haveBMJ USA has folded because \u201cit has fallen victim to the widespread downturn in US pharmaceutical advertising and has become financially unsustainable for the BMJ Publishing Group\u201d [Dependence on a single industry can be financially disastrous for a journal that displeases its corporate funders. Dependence on prescription drug advertising is also financially risky, as the journal risks closure if it can't attract sufficient revenue\u2014indeed, Group\u201d . AcceptiPLoS Medicine, for example, uses a business model that includes support from foundations, from institutional memberships, and from asking research funders to pay a publication charge for accepted research papers (http://www.plos.org/support/index.html).Another option is to eschew journal advertising altogether. Some journals refuse to advertise drugs or devices, depending instead on other sources of income. The non-profit journalClinicians rely on medical journals for scholarly articles and the latest information on drugs and devices. Advertisements in these journals are unreliable sources of information, since they \u201ceducate\u201d physicians to prescribe the newest, most expensive drugs .The scholarly nature of journals confers credibility on both articles and advertisements within their pages. By exclusively featuring advertisements for drugs and devices, medical journals implicitly endorse corporate promotion of the most profitable products. Advertisements and other financial arrangements with pharmaceutical companies compromise the objectivity of journals.The primary obligation of industry is to make money for its stockholders. The primary obligation of journals should be to physicians and their patients, who depend on the accuracy of information within these publications. Medical journals should not accept advertisements from pharmaceutical companies, medical device companies, or other industries \u201crelevant to medicine.\u201dJournal of the American Medical Association:http://pubs.ama-assn.org/misc/jamarates.pdfThe New England Journal of Medicine:http://nejmadsales.org/media/pdfs06/06USRateCard.pdf;http://nejmadsales.org/incentives/advertisingopportunities/minidemo.html;http://nejmadsales.org/incentives/research.html#journal;http://nejmadsales.org/faq/index.htmlMedical Journal of Australia:http://www.mja.com.au/classifieds/Advtg_index.htmlBMJ:http://www.bmjpg.com/advertisingCanadian Medical Association Journal:http://www.cmaj.ca/pdfs/cmaj.pdfLancet:Thehttp://www.elsmediakits.com/ratecards/LANCET_display06.pdfAmerican Family Physician:http://www.aafp.org/PreBuilt/afp_ratecard_2006.pdfAnnals of Internal Medicine:http://www.acponline.org/journals/advert/annals_rates06.pdfPLoS:http://www.plos.org/support/index.htmlMedical Marketing and Media:http://www.mmm-online.com/content/fileadmin/files/mediainfo/onesheet.pdfForbes:http://www.forbesmedia.com/forbes/forbrates.phpVogue:http://www.srds.com/listinglink/advertisinginfo/vogueArchitectural Digest:http://www.condenastmediakit.com/ad/genrates.cfmTravel and Leisure:http://www.tlmediakit.com/nat_rates06.cfmBusiness Week:http://mediakit.businessweek.com/PDFNew England Journal of Medicine:http://nejmadsales.org/media/pdfs06/06USRateCard.pdf;http://nejmadsales.org/incentives/sponsorship.htmlMedical Journal of Australia:http://www.mja.com.au/classifieds/Advtg_index.htmlCanadian Medical Association Journal:http://www.cmaj.ca/misc/advertising.shtml;http://www.cma.ca/index.cfm/ci_id/25274/la_id/1.htm#restrictionsPLoS Medicine:http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.0010022;http://www.plos.org/support/index.htmlAnnals of Internal Medicine:http://www.acponline.org/journals/advert/annals_rates06.pdf;http://www.acponline.org/journals/advert/pharm/start_acp.pdfAmerican Medical Association:http://pubs.ama-assn.org/misc/adprinciples.pdfBMJ:http://www.bmjpg.com/advertisingLancet:Thehttp://www.elsmediakits.com/ratecards/LANCET_display06.pdfAmerican Family Physician:http://www.aafp.org/PreBuilt/afp_ratecard_2006.pdfAll Web sites accessed between 2005 December 23 and 2006 January 3."} +{"text": "DOI: 10.1371/journal.ppat.0020008PLoS Pathogens, vol 2, issue 1:In http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide). The accession numbers are DQ497165\u2013DQ497182.The data upon which Figures 1 and 2 are based had not been deposited in a publicly available repository at the time of publication. Readers can now access the data at Genbank ("} +{"text": "PLoS Biology, volume 4, issue 8: DOI: 10.1371/journal.pbio.0040255In The figure caption is missing a credit. The caption should read as follows: A model based on growth trajectories estimated from fossils provides evidence that dinosaurs were reptiles whose body temperatures increased with body size. (Painting: Skye White)."} +{"text": "The authors provide a targeted review of national pandemic influenza plans from the developed and developing world, describing national variations in prioritization of vaccines and antiviral medications. Recognizing the potential severe impact of pandemic influenza, the World Health Organization (WHO) urges every country to develop or maintain an up-to-date national influenza preparedness plan, and provides guidance on plan content . WHO guiPrioritization of scarce pharmaceutical resources that could ultimately delay the spread of a pandemic or lower overall incidence is of particular importance to planning at the national level. Because of costs and manufacturing limitations, these critical resources are likely to be scarce and will require evidence-based rationing. At current capacity, we cannot expect to vaccinate more than 14% of the world's population within a year of a pandemic . BecauseUntil recently, developing countries were unlikely to secure supplies of oseltamivir. Today, generic drug manufacturers in Bangladesh, Algeria, India, and China produce oseltamivir, some for local use as determined in official agreements and some for use in areas without patent protection . It seemDespite the growing availability of pharmaceutical resources, the planning community has yet to conduct a critical analysis of distribution strategies. A study from April 2006 that reviewed national pandemic influenza plans briefly touched on prioritization among a myriad of competing issues. Furthermore, it focused exclusively on the European region, reviewing a total of 21 plans . Given tWe obtained a total of 50 pandemic influenza plans. We identified these plans through Web sites that compile lists of plans (39 plans), contacts at national influenza centers (five plans), Google searches (five plans), and personal contacts (one plan). We subsequently excluded three plans that were not available in the selected languages, and two plans (Sierra Leone and Namibia) that focused exclusively on avian influenza preparedness. Our final sample contained 45 national pandemic influenza plans, 19 from developed and 26 from developing nations .Three plans were from low-income nations, a World Bank\u2013defined category with 59 total members. The subset sample (see http://www.who.int and http://www.undg.org). We used Google to identify links to documents on ministry of health Web sites\u2014search keywords included \u201cpandemic,\u201d \u201cinfluenza\u201d (as well as synonyms and foreign-language translations), \u201cplan,\u201d and names of countries. Lastly, we contacted the WHO National Influenza Centers for 83 countries, and requested access to official pandemic influenza plans. The search process occurred between February 6, 2006, and April 20, 2006.We searched for pandemic influenza plans on official Web sites that compile planning documents from World Bank sources . We clasThe subset sample included one plan from Africa, one from Australia, three from North America, seven from Central and South America, 16 from Europe, and 17 from Asia\u2013Pacific. As of April 20, 2006, 18 (40%) nations had identified cases of H5N1 in bird populations . The datGoals of pharmaceutical interventions were recorded for 21 plans. Although the wording varied slightly, three goals appeared in various combinations. These goals were reduction of morbidity and mortality (21 plans), continued maintenance of essential services (13 plans), and minimization of social and economic impacts (13 plans). Within their plans, 18 (40%) nations\u201415 developed and three developing\u2014included a modeled scenario to estimate pandemic impact in terms of morbidity and mortality. Estimated attack rates ranged from 10% to 50% (Greece and the UK), with seven nations modeling several different attack-rate scenarios. Stated mortality rates ranged from 0.37% to 2.5%, and four nations specifically based assumptions on worst-case scenarios derived from the 1918 pandemic.There were 14 (74%) developed and 14 (54%) developing nations that prioritized population groups to receive vaccine in a pandemic (p = 0.18), and 12 (63%) developed and 10 (38%) developing nations that prioritized population groups to receive antivirals (p = 0.10) . No natiOf the 28 nations that prioritized vaccine, high-risk individuals were prioritized most frequently, followed by health-care workers and essential services workers\u2014a category which may include health-care workers depending on a nation's definition . CertainThree options guided the antiviral distribution strategies detailed in 22 plans: pre-exposure prophylaxis, postexposure prophylaxis, and treatment of influenza cases within 48 hours of onset of illness. Seven (32%) nations did not differentiate among these strategies in allocating resources. Eleven (50%) plans indicated that the treatment of cases would be preferred over prophylaxis for groups such as health-care workers. Among the four nations that allocated antivirals for prophylaxis over treatment, two were from the developing world. The UK plan, which prioritized treatment over prophylaxis, reasoned that long-term prevention at the population level was not an efficient use of resources. Serbia's plan prioritized prophylaxis because the 48-hour time window required for effective treatment was considered too narrow.Health-care workers were consistently ranked at the top of the vaccine and antiviral priority lists . Eleven Of the 25 subset plans, 14 described the composition of the high-risk category . Twelve Of 25 plans, 13 (52%) provided rationales for the inclusion of certain priority groups. Two plans explained the exclusion of certain groups . Plans justified the prioritization of health-care workers for the following reasons: (1) they are at increased risk of acquiring infection and/or passing it to vulnerable patients ; (2) they perform essential services, enable the treatment of those affected by disease, and are required for quality medical care and good patient outcomes ; and (3) their availability reduces morbidity and mortality .Furthermore, plans justified the inclusion of children for the following reasons: (1) since children transmit influenza, prioritizing this group is consistent with the goal of containment , and (2) children may have a great risk of infection and severe illness depending on the circulating strain (Brazil and Thailand). Canada's plan explained its exclusion of children, stating that this group is at the lowest risk of developing severe outcomes from influenza during annual epidemics, and absence from school does not have the direct economic impact that illness in adults has. The US plan excluded children because in prior pandemics and epidemics, this group has been at low risk for hospitalization and death.This study provides the first description of pandemic influenza prioritization decisions in both the developed and the developing world. Although WHO recommends that nations set priority groups for both vaccine and antiviral distribution , about 3Fewer nations prioritized antivirals (49%) than vaccine (62%). This is an unexpected finding since antivirals may be the first\u2014and, perhaps, the only\u2014pharmaceutical intervention available to many countries in a pandemic . BecauseThe nations that prioritized vaccines and antivirals varied considerably in their allocation decisions, and in several instances, chose to deviate from WHO guidelines. This variation cannot be explained with respect to stated goals; rather, we must look to differences in interpretation of evidence or sociocultural factors. It seems nations were equally divided with respect to children, with 47% prioritizing children for vaccine against WHO recommendations. WHO states, \u201cThere is no evidence that the use of inactivated vaccine in children will reduce the spread of a pandemic in the community, and this strategy is not recommended\u201d . The decSince these models were not available when most of the plans were written, the decision to prioritize children may also reflect different sociocultural values, suggesting that purely epidemiology-based guidelines are insufficient in priority setting. Planners can specifically research and consider alternatives to preferential vaccination that both recognize the moral imperative to prioritize children and achieve optimal public health impact. Argentina (2006)Australia (June 2005) http://www.health.gov.au/internet/wcms/publishing.nsf/Content/ohp-pandemic-ahmppi.htmAustria (September 2005) http://www.bmgf.gv.at/cms/site/attachments/3/6/8/CH0019/CMS1126084167391/pandemieplanh3neu.pdfBahrain (November 2005) http://ai.moh.gov.bh/BahrainPlan.aspBolivia (October 2005)Brazil (September 2005) http://portal.saude.gov.br/portal/arquivos/pdf/plano_flu_english.pdfCanada (September 2004) http://www.phac-aspc.gc.ca/cpip-pclcpi/index.htmlChile (September 2005) http://www.minsal.cl/ici/pandemiainfluenza/ pandemiainfluenza.htmlChina (Unlisted) http://www.undg.org/content.cfm?id=1598Cuba (October 2005) http://www.undg.org/content.cfm?id=1552Czech Republic (April 2004) http://www.who.int/csr/disease/influenza/czechplan.pdfFiji (November 2005)France (January 2006) http://www.grippeaviaire.gouv.fr/IMG/pdf/Plan_version_anglaise.pdfGermany (July 2005) http://www.rki.de/cln_006/nn_225576/DE/Content/InfAZ/I/Influenza/influenza__node.html__nnn=trueGreece (October 2005) http://www.who.int/csr/disease/influenza/nationalgreece.pdfHong Kong (February 2005) http://www.chp.gov.hk/files/pdf/flu_plan_framework_en_20050222.pdfHungary (September 2003) http://www.who.int/csr/disease/influenza/Pandemic_preparedness_plan_Hungary.pdfIndia (December 2005) http://www.undg.org/content.cfm?id=1684Ireland (2002) http://www.doh.ie/pdfdocs/panflu.pdfIsrael (January 2006)Japan (October 1997) http://www.mhlw.go.jp/english/topics/influenza/index.htmlLithuania (Sept 2005)http://www.vvspt.lt/aktai/gripas/2005%2009%2020%20GRIPO%20PLANO%20VERT.docMexico (Unlisted) http://www.dgepi.salud.gob.mx/pandemia/planpp.htmMontenegro (October 2005) http://www.mzdravlja.cg.yu/vijesti.php?akcija=rubrika&rubrika=188Nauru (Aug 2005) http://www.spc.int/phs/PPHSN/Outbreak/Influenza/Pand-Preparedness-plans-Pacific-countries.htmNew Caldonia (October 2005) http://www.dass.gouv.nc/static/infoPratique/documents/PandemieGrippePlanActionNouvelleCaledonie20042005version131005.PDFNew Zealand (November 2005) http://www.moh.govt.nz/moh.nsf/ea6005dc347e7bd44c2566a40079ae6f/5f5694e4a5736dd2cc256c55000788a3?OpenDocumentNorway (July 2003) http://www.dep.no/archive/hdvedlegg/01/08/Influ041.pdfPalau (October 2005) http://www.spc.int/phs/PPHSN/Outbreak/Influenza/Palau_Flu_Plan_Final_Draft_103105.pdfPhilippines (October 2005) http://www.undg.org/content.cfm?id=1671Poland (2005) http://www.gis.gov.pl/index.php?option=com_content&task=category§ionid=10&id=28&Itemid=61&lang=iso-8859-2Serbia (October 2005) http://www.zdravlje.sr.gov.yu/downloads/pdf_e/Influenza%20Preparedness%20Plan.pdfSingapore (December 2005) http://www.moh.gov.sg/corp/hottopics/influenza/detail.doSlovak Republic (August 2001) http://www.who.int/csr/disease/influenza/Pand_Plan_SR_AJ.pdfSouth Africa (Unlisted) http://www.undg.org/content.cfm?id=1528Spain (May 2005) http://www.msc.es/ciudadanos/enfLesiones/enfTransmisibles/docs/PlanGripeIngles.pdfSwitzerland (March 2005) http://www.bag.admin.ch/influenza/01120/01134/index.htmlThailand (May 2005) http://thaigcd.ddc.moph.go.th/AI_Nationalplan_en_05_07.htmlTimor Leste (November 2005) http://www.undg.org/content.cfm?id=1551United Kingdom (October 2005) http://www.dh.gov.uk/PolicyAndGuidance/EmergencyPlanning/PandemicFlu/fs/enUruguay (Unlisted) http://www.undg.org/content.cfm?id=1572United States (November 2005) http://www.hhs.gov/pandemicflu/planVenezuela (January 2006) http://www.msds.gov.ve/msds/modules.php?name=Content&pa=showpage&pid=422West Bank/Gaza (2005) http://www.healthinforum.net/files/misc/nat_avian_plan.pdfYemen (October 2005) http://www.undg.org/content.cfm?id=1608It is notable that despite the influence of sociocultural factors on decisions, priority-setting rationales always referred to epidemiology-based arguments. None of the plans prioritized children as a special group in need of protection, and plans seldom mentioned ethics in the context of resource allocation. Within the 25 plan subset, only five referred to concepts of equity and fairness in allocation decisions, and two referred to consultation with ethicists.In the absence of an explicit WHO guideline, more than half the nations that prioritized vaccine distribution developed a tiered (ranked) strategy, revealing another example of variation. It may seem that the more well developed a ranked prioritization scheme is, the more prepared a nation is to deal with resource scarcity; however, the use of tiers may have both positive and negative consequences in view of the uncertainty associated with the actual characteristics of an emerging pandemic. While prior discussion of groups and their relative importance can lead to greater public acceptance at the time of a pandemic, the effect of reordering groups to reflect new evidence (during a crisis) is unclear. Emergency planners have further cautioned against planning in great detail in the face of uncertainty , an unceNations were urged by WHO to estimate the impact of a pandemic , yet onlThere was some notable variation in the prioritization of key government decision makers, such as politicians. Of the nations that prioritized vaccine, 40% included key decision makers, and several more nations prioritized this group within the essential services category. Interestingly, when key decision makers appeared in rankings, this group ranked near the top of the list for vaccine (Tiers 1 and 3), but at the bottom for antivirals (Tier 7).Our study highlights several unresolved issues. First, variation in priority setting may or may not represent a problem to be corrected, and may reflect concrete variation in local conditions. If this is the case, nations may disregard further WHO guidance that is not country specific, in addition to evidence-based.Second, nations should be clearer with respect to the different antiviral strategies of treatment and pre or postexposure prophylaxis. Seven of 22 nations that prioritized antivirals did not differentiate among these strategies in allocating resources. Most countries that did differentiate, however, preferred treatment.Third, if an antiviral stockpile is donated to a developing nation for the purpose of curbing a global pandemic at its source or for a humanitarian purpose, it is unclear at this time whether prioritization would follow a national prioritization scheme or one dictated by the donating body. Nations should plan for the use of national and potentially donated resources if they are willing to yield some control to a donating body.Finally, it is unclear why vaccine and antiviral medications have been singled out for prioritization when many critical resources are likely to be scarce. Further guidance should address whether additional schemes for ventilators, N95 masks, and hospital beds are necessary, and should explore the special considerations involved in their distribution.Our study had several limitations. First, we were restricted to nonprobability sampling because it was unclear how many countries have in fact developed written pandemic influenza plans. Our search strategy may be less effective at capturing the plans of developing nations, which may not publish plans on the Internet. Second, pandemic influenza plans are dynamic documents in various stages of revision. Any analysis that takes a snapshot of the state of planning has a certain shelf-life. Third, it is unclear how well any description of the level of planning detail actually captures the concept of preparedness; many of the plans noted that prioritization schemes are subject to change based on emerging epidemiology and social conditions, thus emphasizing the fact that flexibility is indispensable to preparedness.Finally, because of variation in plan format, use of language, foreign-language translation, and the subjective nature of any categorization of diverse elements, our ability to represent the intent of planners is limited. Because of limited resources, we were unable to contact planners in each country and verify findings. In theory, however, the plans should stand as self-explanatory documents that clearly state pandemic policy.Attention to prioritization and its ethical implications may help to reduce death and disease burden, and minimize political destabilization and claims of injustice. Comparative analyses of national pandemic influenza plans provide a lens to reveal previously underaddressed considerations that can play a significant role in international preparedness against this global infectious disease threat."} +{"text": "PLoS Biology, volume 2, issue 11: DOI: 10.1371/journal.pbio.0020363In http://www.microrna.org/ contains the updated information with changes flagged. We thank Dr. Denman for pointing out this error to us.We incorrectly named the products of two genes, gamma actin and betaAPP, as FMRP ligands because of a misreading of Table 1 from ["} +{"text": "Am J Trop Med Hyg 96:758 (https://doi.org/10.4269/ajtmh.16-0831a), there was an error in the author list. Pagliano Pasquale and Ascione Tiziana should have appeared as Pasquale Pagliano and Ascione Tiziana. The journal regrets the error.In"} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following positions:\u2022 Scientific Officer Epidemic Intelligence (SRS)\u2022 Medical Library Specialist (RMC)http://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxThe deadline for application is 28 November 2016. For detailed information on the job descriptions, requirements and the application procedure, please visit the ECDC website at:"} +{"text": "Staphylococcus aureus strains isolated from milk samples from clinically healthy cows in the Russian Federation. Four of them were determined to be sequence type 97 (ST-97), and one was determined to be ST-22. All the strains are characterized by their genome possessing genes that code for enterotoxins and cytotoxins.We present here the draft genome sequences of five Staphylococcus aureus is a component of normal human and animal microflora. It is now often associated as a cause of mastitis development . Whole-genome sequencing was performed using the Ion Torrent semiconductor technique with an Ion Proton sequencer, with coverage depths from 114 to 186\u00d7 for each genome. De novo contig assembly was performed using Newbler GS de novo assembler v.3.0. As a result, we obtained 51 to 56 contigs for each genome (http://rast.nmpdr.org) (https://www.ncbi.nlm.nih.gov/genomes/static/Pipeline.html). In genotyping analysis, S. aureus strain 17 was classified as sequence type 22 (ST-22), and another four strains were classified as ST-97 by multilocus sequence type (MLST) analysis (https://cge.cbs.dtu.dk/services/MLST/) . In addiS. aureus associated with mastitis. A more detailed report from a full comparative genomic analysis will be included in a future publication.Thus, despite the fact that our strains were isolated from clinically healthy cows, we identified genes for virulence factors of The GenBank accession numbers for these five genome sequences are listed in"} +{"text": "Scientific Data 4:170050 doi: 10.1038/sdata.2017.50 (2017); Published 11 April 2017; Updated 30 May 2017The financial support for this Data Descriptor was not fully acknowledged. The Acknowledgements should have included the following: S.I.H. is funded by a Senior Research Fellowship from the Wellcome Trust [095066]."} +{"text": "The third author's name was not hyphenated and the citation was incorrect. The correct name is: Constance Barazzone-Argiroffo.10.1371/journal.pone.0163217The correct citation is: Stollar F, Gervaix A, Barrazone-Argiroffo C (2016) Safely Discharging Infants with Bronchiolitis from an Emergency Department: A Five Step Guide for Pediatricians. PLoS ONE 11(9): e0163217. doi:"} +{"text": "Sensors [http://www.mdpi.com/1424-8220/17/5/1075. The authors wish to correct Sensors , doi:10.The authors apologize for any inconvenience caused to readers by these changes. The manuscript will be updated, and the original will remain online on the article webpage with a reference to this Erratum."} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following position:Senior Expert Microbiologyhttp://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxThe deadline for application is 29 May. For more information, visit the ECDC website:"} +{"text": "Retraction: Due to the authors\u2019 negligence during the preparation of this manuscript for submission, it contains a plethora of data errors. Authors sincerely apologize for their mistakes and wish to retract their manuscript.Footnotes: The online version of the original article can be found under doi.4760-4772. doi: 10.18632/oncotarget.13587.Original article: Oncotarget. 2017; 8(3):"} +{"text": "Correction to:Prostate Cancer and Prostatic Diseases (2016); doi:10.1038/pcan.2016.7; advance online publication 12 July 2016Following publication, the authors noticed that the conflict of interest statement was incomplete. The omitted information appears below.DB is the director of SmartTarget Ltd. (UK company number 09847173), a medical device company the markets prostate image fusion software."} +{"text": "Brucella neotomae Infection in Humans, Costa Rica . The article has been corrected online (https://wwwnc.cdc.gov/eid/article/23/6/16-2018_article).A subhead was missing and layout was incorrect in the Table for"} +{"text": "Retraction: Due to an error, Fig1 was previously published in another paper. The original source was never cited. The authors sincerely apologize for this error..Footnotes: The online version of the original article can be found under doi.doi: 10.18632/oncotarget.13127.Original article: Oncotarget. 2016 Nov 4."} +{"text": "This article has been corrected: The updated Grant information is provided below:GRANT SUPPORTRF-2013-02354985) and in part by funds obtained through an Italian law that allows taxpayers to allocate 0.5 percent share of their income tax contribution to a research institution of their choice.This work was supported by Associazione Italiana per la Ricerca sul Cancro , by Ministero della Salute (Ricerca Finalizzata 2013 https://doi.org/10.18632/oncotarget.7262Original article: Oncotarget. 2016; 7:12731-12747."} +{"text": "The brochure is well\u2010prepared and highlights important publications dealing with analyzing microbiomes for their impact on human health.https://www.nature.com/articles/nrgastro.2017.29This review article poses the question as to if and when it will be possible to modulate gut microbiomes to better manage gastrointestinal diseases.http://www.mdpi.com/journal/nutrients/special_issues/microbiome-human-healthThis webpage is the entry point to a special journal issue covering different aspects of microbiomes and human health.https://hmpdacc.orgThis major page of the U.S. National Institutes of Health deals with their funded human microbiome projects. The data consists of analyzing five different major body sites and using 16S and shotgun sequencing methods.https://commonfund.nih.gov/hmpThis site from the U.S. National Institutes of Health hosts research resources to aid in the study of human microbiomes and their role in health and disease.http://www.metahit.euMetaHIT stands for metagenomics of the human intestinal tract and this is the main website for this project funded by the European Commission with 13 partners from industry and universities.https://www.broadinstitute.org/hmp/human-microbiome-projectThis site describes the human microbiome projects of the Broad Institute of MIT and Harvard University.https://onlinelibrary.wiley.com/doi/full/10.1111/1751-7915.12699This review article highlights the potential for using human microbiome data in forensics and criminal investigations.https://www.nature.com/articles/nbt.3960In all metagenomic studies, sampling methods are critical to obtain representative DNA for sequencing. Differences in sampling can yield different results and so this study addresses standardization of sampling methods.https://weekly.biotechprimer.com/the-microbiome-magnified/This site lists and describes some of the commercial players in developing human microbiome science.http://blog.signals-analytics.com/microbiome-on-the-rise-12-companies-to-watch-1This page tracks a good number of companies involved in human microbiome science and shows where their products are in the developmental cycle.http://www.enterome.frEnterome is a company focused on the development of microbiome\u2010derived biomarkers and drugs for treating cancer.https://www.fiercebiotech.com/topic/microbiomeThis is a general site following business developments at many companies focused on human microbiome research and development.https://www.ventureradar.com/keyword/MicrobiomeThis site covers human microbiome companies from the perspective of the venture funding community.http://www.mbiome.comThis is the site for a company that is focused on therapies to maintain health by modulating the human gastrointestinal microbiome.https://www.evolvebiosystems.comThis company is focused on therapies to positively modulate the newborn gut microbiome, that plays a critical role in proper immune and metabolic development.https://www.vedantabio.comVedanta Biosciences is involved in the rational design of medicines based on human commensal bacteria.http://www.serestherapeutics.comSera Therapeutics is looking to use live bacteria to treat human diseases."} +{"text": "Road traffic crashes are the world's leading cause of death among persons aged 15\u201329 years and the leading cause of death among U.S. teens aged 16\u201319 years Global Road Safety Week is May 8\u201314, 2017. This year\u2019s theme is \u201cSaveLives #SlowDown\u201d with a focus on speed management and preventing speed-related injuries and deaths and 11.2 . The resolution acknowledges these targets and calls for action to reduce road traffic deaths and injuries as a pressing development priority (http://www.who.int/violence_injury_prevention/publications/road_traffic/SlowDown_Days/en/. Additional information about U.N. Global Road Safety Week is available at https://www.unroadsafetyweek.org/en/home. Additional information about motor vehicle safety is available at https://www.cdc.gov/motorvehiclesafety/.Additional information about #SlowDown is available at"} +{"text": "Biochemia Medica 2017;27(2): 342-49. DOI: https://doi.org/10.11613/BM.2017.037.This is a correction for Since the publication of this article, the authors have noticed that the surname of the second author in the byline was published incorrectly. The correct byline is presented above. The authors apologize for any inconvenience caused to the readers."} +{"text": "Erratum for: Braz J Med Biol Res | doi: 10.1590/1414-431X20175831Brazilian Journal of Medical and Biological Research The Journal would like to correct the order of the authors for correspondence in the article \"Primary cultures of mouse small intestinal epithelial cells using the dissociating enzyme type I collagenase and hyaluronidase\" that was published incorrectly in volume 50 no. 5 (2017) in the The correct order of the authors for correspondence is:mingliang_2015@sina.com> | J. Cui: Correspondence: L. Ming: <"} +{"text": "Chronic obstructive pulmonary disease (COPD), which includes emphysema and chronic bronchitis, makes breathing difficult for the 16 million U.S. residents who have received a diagnosis of COPD and millions more who are not aware that they have it (https://www.cdc.gov/copd and from NHLBI at https://www.nhlbi.nih.gov/health/educational/copd.November is National COPD Awareness Month, an observance supported by NHLBI\u2019s COPD: Learn More, Breathe Better campaign. More information about COPD is available from CDC at"} +{"text": "The corresponding authors of this paper should be listed as follows:dufourya@msu.eduYann S. Dufour, thierry.emonet@yale.eduThierry Emonet, The Data Availability statement should read as follows:https://github.com/dufourya/SwimTracker. The code used for the FAST experiment is available at https://github.com/ dufourya/FAST. The data are available publicly at https://dx.doi.org/10.6084/m9.figshare.3593046 or upon request by contacting the corresponding authors at dufourya@msu.edu and thierry.emonet@yale.edu.The code used for single-cell tracking is available at The Acknowledgments section should read as follows:We thank Adam Waite for improvements of the SwimTracker code, and Adam Waite and Setsu Kato for comments on the manuscript. We thank Victor Sourjik and Sandy Parkinson for their generous gifts of strains.The publisher apologizes for these errors."} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following positions:Senior Expert Vaccine-preventable Diseases Senior Expert Pedagogy and Adult Learninghttp://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxThe deadlines for application are 24 April and 25 April 2017, respectively. For more information, visit the ECDC website:"} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following position:Head of Section Communication and Public Relationshttp://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxThe application deadline expires on 23 October. For more information, please visit the ECDC website:"} +{"text": "Information about TARGET can be found at http://ocg.cancer.gov/programs/target.The following information is missing from the Acknowledgments section: The results published here are in part based upon data generated by the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative managed by the NCI. The data used for this analysis (phs000218.v15.p5.c1) are available at"} +{"text": "September is National Food Safety Education Month. One of CDC\u2019s food safety objectives is to raise awareness about healthy practices to prevent food poisoning. Every year in the United States, an estimated one in six persons (48 million persons) become ill, and 3,000 die from eating contaminated food (https://www.cdc.gov/foodsafety/education-month.html. Information on preventing food poisoning can be found at https://www.cdc.gov/foodsafety/groups/consumers.html.Information about CDC\u2019s activities related to Food Safety Education Month can be found at"} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following position:\u2022 Scientific Editor Eurosurveillance (RMC)http://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxThe deadline is 28 November 2016. For more information, visit the ECDC website:"} +{"text": "The online information includes estimates of the cumulative percentage of persons receiving influenza vaccination through the end of each month during July 2016\u2013May 2017.Final 2016\u201317 influenza season vaccination coverage estimates for selected local areas, states, U.S. Department of Health and Human Services regions, and the United States overall are available online at FluVaxView (https://www.cdc.gov/flu/fluvaxview/interactive.htm) and are complemented by an online summary report (https://www.cdc.gov/flu/fluvaxview/coverage-1617estimates.htm).Analyses were conducted using National Immunization Survey\u2013Flu influenza vaccination data for children aged 6 months\u201317 years and Behavioral Risk Factor Surveillance System influenza vaccination data for adults aged \u226518 years. Estimates are provided by age group and race/ethnicity. These estimates are presented in interactive reports ("} +{"text": "MMWR Serial Publications are now using ScholarOne Manuscripts, an online system for manuscript submissions. This system provides comprehensive workflow management and streamlines the submission process for Recommendations and Reports, Surveillance Summaries, and Supplements.The https://mc.manuscriptcentral.com/mmwr-sp. Additional information on how to submit through ScholarOne Manuscripts is available at https://www.cdc.gov/mmwr/serial_submissions.html.ScholarOne Manuscripts allows manuscripts to be transmitted electronically and makes manuscript files accessible to editors through the submission site. All manuscripts for the Serial Publications must be submitted through ScholarOne Manuscripts at"} +{"text": "It covers sources, substrates, inhibitors, kinetics and other characteristic features of the enzymes.https://biocyc.orgBio/Cyc is an umbrella for different databases focused on metabolic pathways and genomes. It can be used to look at specific biocatalysis reactions or can be focused on the metabolism of specific microorganisms.http://accelrys.com/products/datasheets/biocatalysis.pdfThis is a commercial database that is focused on the use of enzymes and microorganisms for chemical synthesis, which might offer advantages of selectivity, efficiency and greater environmental friendliness.https://envipath.orgEnviPath is a database that focuses on microbial degradation of organic chemicals in the environment.http://identifiers.org/registry?query=enzymeThis page created by the European Bioinformatics Institute contains numerous links to sites and databases relevant to biocatalysis.http://www.genome.jp/kegg/kegg.htmlThe KEGG databases cover many aspects of cell function. It has extensive coverage of biochemical reactions, genes and enzyme nomenclature.http://www.ebi.ac.uk/thornton-srv/databases/CSA/The catalytic site atlas compiles information on enzyme active sites and catalytic residues as derived from the X\u2010ray structures of enzymes.http://www.enzyme-database.orgThis enzyme database is organized along the lines of the Enzyme Commission classification system of enzyme reaction types.http://peroxibase.toulouse.inra.frPeroxidases are useful enzymes and this website focuses on peroxidase enzymes, both their sequences and their reactions.http://www.cazy.orgThere are many commercially\u2010relevant reactions with carbohydrates and this database is dedicated to information on carbohydrate\u2010active enzymes.http://biocatalysis.uni-graz.at/sites/links.htmlThis page contains numerous links to sites on chemistry and biochemistry that is relevant to biocatalysis.https://biocatnet.deThe BioCatNet is a site that contains links to a collection of family\u2010specific enzyme databases, with a focus on enzymes of interest for biocatalysis.https://www.rcsb.orgThe Protein DataBank (PDB) is a major resource for information on protein structures, typically determined by X\u2010ray crystallography or NMR methods.http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl?pdbcode=index.htmlPDBsum is a pictorial database providing a visual overview of material from the PDB, showing protein, ligands, metals, etc.http://www.au-kbc.org/beta/bioproj2/Lipases have proven to be very versatile on the synthesis and chiral resolution of molecules, particularly in the pharmaceutical industry. This database focuses on information pertaining to lipases.http://pfam.xfam.orgThe Pfam database focuses on protein sequences within large protein families. It represents the data using multiple sequence alignments and hidden Markov models.https://cyped.biocatnet.deCytochrome P450 enzymes are highly versatile because of their broad specificity and engineerability. This site focuses on a broad range of cytochrome P450 enzymes."} +{"text": "To The Editor Helicobacter pylori and iron deficiency (H. pylori infection and iron deficiency anemia in patients with celiac disease. But the conclusion of this study was that H. pylori infection and iron deficiency anemia is poorly reflected in practice to celiac disease patients (H. pylori eradication and provided evidence for a cause-effect relation between H. pylori and iron deficiency anemia (H. pylori infection with anemia, or bouth (H. pylori infection was considered a risk factor for anemia due to iron deficiency, mainly in children and adolescent groups with high iron requirements (H. pylori infection (H. pylori infection in patients with celiac disease and iron deficiency.Early studies have not revealed a link betweenficiency . A recenpatients . Howevery anemia . Mild enor bouth .\u00a0 H. pylirements . In sevenfection . Therefo"} +{"text": "After the publication of the article , the aut1* and Wei Jiang3*Correct corresponding author order: Binghe XuCorrect correspondence: xubinghe@medmail.com.cn; wjiang6138@cicams.ac.cnPlease note that the above author list and corresponding emails have been updated."} +{"text": "Email: gorodkin@rth.dklars.juhl.jensen@cpr.ku.dkCorrespondence may also be addressed to Email: This has been corrected online, and the publisher apologizes for the error."} +{"text": "Scanpy is a scalable toolkit for analyzing single-cell gene expression data. It includes methods for preprocessing, visualization, clustering, pseudotime and trajectory inference, differential expression testing, and simulation of gene regulatory networks. Its Python-based implementation efficiently deals with data sets of more than one million cells (https://github.com/theislab/Scanpy). Along with Scanpy, we present AnnData, a generic class for handling annotated data matrices (https://github.com/theislab/anndata). SEURAT [MONOCLE [SCDE/PAGODA [MAST [CELL RANGER [SCATER [SCRAN [SCANPY\u2019s Python-based implementation is easy to interface with advanced machine-learning packages, such as TENSORFLOW [Simple integrated analysis work flows for single-cell transcriptomic data have beeSEURAT , MONOCLE[MONOCLE , SCDE/PAE/PAGODA , MAST [5L RANGER , SCATER [SCATER , and SCRR [SCRAN . HoweverNSORFLOW .SCANPY integrates the analysis possibilities of established R-based frameworks and provides them in a scalable and modular form. Specifically, SCANPY provides preprocessing comparable to SEURAT [CELL RANGER [TSNE [PHENOGRAPH [MONOCLE 2 [WISHBONE [o SEURAT and CELLL RANGER , visualiER [TSNE , 12, graER [TSNE \u201315 and dER [TSNE , 16, 17,ENOGRAPH \u201320, idenENOGRAPH , which cENOGRAPH with MONONOCLE 2 , and WISWISHBONE [https://github.com/theislab/scanpy_usage/tree/master/170505_seurat). Benchmarking against the more run-time optimized CELL RANGER R kit [https://github.com/theislab/scanpy_usage/tree/master/170503_zheng17) [https://github.com/theislab/scanpy_usage/tree/master/170522_visualizing_one_million_cells). Thus, SCANPY provides tools with speedups that enable an analysis of data sets with more than one million cells and an interactive analysis with run times of the order of seconds for about 100,000 cells.In a detailed clustering tutorial of 2700 peripheral blood mononuclear cells (PBMCs), adapted from one of ER R kit , we demozheng17) . Moreovehttps://github.com/theislab/scanpy_usage/tree/master/170502_haghverdi16), the simulation of single cells using literature-curated gene regulatory networks based on the ideas of [https://github.com/theislab/scanpy_usage/tree/master/170430_krumsiek11), and the analysis of deep-learning results for single-cell imaging data [https://github.com/theislab/scanpy_usage/tree/master/170529_images).In addition to the mentioned standard clustering-based analyses approaches, we demonstrate the reconstruction of branching developmental processes via diffusion pseudotime as in thideas of and variables , and unstructured annotations. As SCANPY is built around that class, it is easy to add new functionality to the toolkit. All statistics and machine-learning tools extract information from a data matrix, which can be added to an ANNDATA object while leaving the structure of ANNDATA unaffected. ANNDATA is similar to R\u2019s EXPRESSIONSET [ANNDATA objects on disk, a format independent of platform, framework, and language. This allows operating on an ANNDATA object without fully loading it into memory\u2014the functionality is offered via ANNDATA\u2019s backed mode as opposed to its memory mode. To simplify memory-efficient pipelines, SCANPY\u2019s functions operate in-place by default but allow the optional non-destructive transformation of objects. Pipelines written this way can then also be run in backed mode to exploit online-learning formulations of algorithms. Almost all of SCANPY\u2019s tools are parallelized.With SSIONSET , but supSCANPY introduces a class for representing a graph of neighborhood relations among data points. The computation of neighborhood relations is much faster than in the popular reference package [SCANPY\u2019s tools reuse a once-computed, single graph representation of data and hence, avoid the use of different, potentially inconsistent, and computationally expensive representations of data. package . This is package , 28, 29.SCANPY\u2019s scalability directly addresses the strongly increasing need for aggregating larger and larger data sets [SCANPY can be easily developed further and maintained by a community. The transfer of the results obtained with different tools used within the community is simple, as SCANPY\u2019s data storage formats and objects are language independent and cross-platform. SCANPY integrates well into the existing Python ecosystem, in which no comparable toolkit yet exists.ata sets across data sets . Moreovehttps://github.com/linnarsson-lab/loompy) was proposed for HDF5-based storage of annotated data. Within a joint effort of facilitating data exchange across different labs, ANNDATA now supports importing and exporting to loom (https://github.com/linnarsson-lab/loompy). In this context, we acknowledge the discussions with S. Linnarson, which motivated us to extend ANNDATA\u2019s previously static to a dynamic HDF5 backing. Just before submission of this manuscript, a C++ library that provides simple interfacing of HDF5-backed matrices in R was made available as a preprint [During the revision of this article, the loom file format [FASTPROJECT (https://github.com/YosefLab/FastProject) [ACCENSE (http://www.cellaccense.com/) [SPRING (https://github.com/AllonKleinLab/SPRING) [http://d3js.org D3.js for the actual visualization and Python only for preprocessing\u2014the trajectory inference tool SCIMITAR (https://github.com/dimenwarper/scimitar), the clustering tool PHENOGRAPH (https://github.com/jacoblevine/PhenoGraph) [MIMOSCA (https://github.com/asncd/MIMOSCA)[UMIS for handling raw read data [ECLAIR (https://github.com/GGiecold/ECLAIR) [FLOTILLA (https://github.com/yeolab/flotilla), which comes with modules for simple visualization, simple clustering, and differential expression testing. Hence, only the latter provides a data analysis framework that solves more than one specific task. In contrast to SCANPY, however, FLOTILLA is neither targeted at single-cell nor at large-scale data and does not provide any graph-based methods, which are the core of SCANPY. Also, FLOTILLA is built around a complicated class STUDY, which contains data, tools, and plotting functions. SCANPY, by contrast, is built around a simple HDF5-backed class ANNDATA, which makes SCANPY both scalable and extendable (law of Demeter).Aside from the highly popular o/scLVM) , 47, whiProject) , ACCENSEse.com/) , and SPR/SPRING) \u2014the lattnoGraph) , the sin/MIMOSCA), UMIS , and theSCANPY\u2019s and ANNDATA\u2019s open-source code are maintained on GITHUB and published under the BSD3 license.SCANPY and ANNDATA are released via the Python packaging index: https://pypi.python.org/pypi/scanpy and https://pypi.python.org/pypi/anndata.https://github.com/theislab/scanpy_usageand summarized here: Cell Ranger R kit [https://github.com/theislab/scanpy_usage/tree/master/170503_zheng17.Analyzing 68,579 PBMCs Fig.\u00a0 in a comhttp://satijalab.org/seurat/pbmc3k_tutorial.htmland one of Seurat\u2019s tutorials [https://github.com/theislab/scanpy_usage/tree/master/170505_seurat.Clustering and identifying cell types, adapted from and benchmarked with utorials : https:/https://github.com/theislab/scanpy_usage/tree/master/170522_visualizing_one_million_cells.Visualizing and clustering 1.3 million cells (Fig.\u00a0https://github.com/theislab/scanpy_usage/tree/master/170502_haghverdi16.Reconstructing branching processes via diffusion pseudotime : https:/https://github.com/theislab/scanpy_usage/tree/master/170430_krumsiek11.Simulating single cells using gene regulatory networks : https:/https://github.com/theislab/scanpy_usage/tree/master/170529_images.Analyzing deep-learning results for single-cell images : https:/Demonstrations and benchmarks discussed in the main text are all stored at The data sets used in demonstrations and benchmarks are three data sets from 10x Genomics.Programming language: PythonOperating system: Linux, Mac OS and Windows"} +{"text": "Present: Due to a production error, proper equal contribution credit for the first and second authors was erroneously eremoved from the published version.Corrected: The proper contributions are listed below. The publisher sincerely apologizes for this oversight.27966-79. doi: 10.18632/oncotarget.4626.Original article: Oncotarget. 2015; 6(29):"} +{"text": "Scientific Reports 10.1038/s41598-017-08833-x, published online 25 August 2017Correction to: The version of this Article previously published omitted Chan Hee Park as a corresponding author. The correct corresponding authors for this Article are Cheol Sang Kim & Chan Hee Park. Correspondence and request for materials should be addressed to chskim@jbnu.ac.kr or biochan@jbnu.ac.kr. This error has now been corrected in the HTML and PDF versions of the Article."} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following position:Senior Expert Applied Molecular Epidemiologydc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxhttp://ecThe deadline for the application is 28 Aug 2017. For more information, visit the ECDC website:"} +{"text": "November is National Diabetes Month. Approximately 114 million U.S. persons are living with diabetes (30 million) or prediabetes (84 million) (https://DoIHavePrediabetes.org). CDC also joined forces with CBS Television Stations in a television and digital miniseries, \u201cYour Health with Joan Lunden and CDC,\u201d to provide information about diabetes prevention and control (https://www.cdc.gov/diabetestv/index.html). More information is available at https://www.cdc.gov/diabetes.Working with partners, CDC plays an important role in preventing or delaying the onset of type 2 diabetes, preventing complications of diabetes, and improving health and quality of life for persons with diabetes. The National Diabetes Statistics Report, 2017 ("} +{"text": "PMCID: PMC 5391228 PMID: 28278492http://www.aging-us.com/article/101186/textIn this article, the last and first name of corresponding author is mixed up: Gw\u00e9na\u00eblle Catheline.The correct citation of this author is:"} +{"text": "Present: The published funding information is incomplete.Correct: Additional funding information is given below.FundingThis project has received funding from the European Union\u2019s Seventh Framework Programme for research, technological development and demonstration under grant agreement nr 602856 (EEC) and nr 278742 (EUROSARC).18875-90. doi: 10.18632/oncotarget.4303Original article: Oncotarget. 2015; 6:"} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following positions:\u2022 Head of Section Communication Support (PHC)\u2022 Legal Advisor (RMC)http://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxThe deadline is 17 October 2016. For more information, visit the ECDC website:"} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following position:\u2022 Head of Section Public Health Training (PHC)http://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxThe deadline is 14 November 2016. For more information, visit the ECDC website:"} +{"text": "Fumihiro Arizumi appeared incorrectly as Arizumi Fumihiro. Dr. Shinichi Inoue appeared incorrectly as Inoue Shinichi. Dr. Toshiya Tachibana appeared incorrectly as Tachibana Toshiya. Dr. Keishi Maruo appeared incorrectly as Maruo Keishi. Dr. Shinichi Yoshiya appeared incorrectly as Yoshiya Shinichi.In the article, \u201cA sewing needle in contact with the cervical dura mater and vertebral artery: A case report\u201d,"} +{"text": "Database (2018), doi: 10.1093/database/bay003In the original article, the wrong author name was indicated next to the \u2018Correspondence may also be addressed to\u2019 section. It should have read as follows:lars.juhl.jensen@cpr.ku.dk*Corresponding author: Tel +45 35325025; Email: gorodkin@rth.dkCorrespondence may also be addressed to Jan Gorodkin. Tel: +45 35333578; Email: This has now been corrected online. The Publisher apologizes for the error."} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following position:Expert Outbreak ResponseThe deadline for the application is 16 August 2017. For more information, visit the ECDC website:http://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspx"} +{"text": "The online information includes estimates of the cumulative percentage of persons vaccinated by the end of each month, from July 2013 through May 2014, for select local areas, each state, each U.S. Department of Health and Human Services region, and the United States overall.Final 2013\u201314 influenza season vaccination coverage estimates are now available online at FluVaxView (http://www.cdc.gov/flu/fluvaxview/interactive.htm ) and complemented by an online summary report (http://www.cdc.gov/flu/fluvaxview/coverage-1314estimates.htm).Analyses were conducted using National Immunization Survey influenza vaccination data for children aged 6 months\u201317 years and Behavioral Risk Factor Surveillance System data for adults aged \u226518 years. Estimates are provided by age group and race/ethnicity. These estimates are presented in an interactive report ("} +{"text": "The third author\u2019s name is cited incorrectly. The publisher apologizes for the error.10.1371/journal.pone.0130853The correct citation is: Rose SB, Spalek K, Abdel Rahman R (2015) Listening to Puns Elicits the Co-Activation of Alternative Homophone Meanings during Language Production. PLoS ONE 10(6): e0130853. doi:"} +{"text": "Correction to:Molecular Psychiatry advance online publication, 12 July 2016; doi:10.1038/mp.2016.97The ninth author\u2019s name was presented incorrectly. It should have been listed as LF Jarskog."} +{"text": "Burkholderia pseudomallei. Outbreaks are uncommon and can generally be attributed to a single point source and strain. We used whole-genome sequencing to analyse B. pseudomallei isolates collected from an historical 2-year long case cluster that occurred in a remote northern Australian indigenous island community, where infections were previously linked to a contaminated communal water supply. We analysed the genome-wide relatedness of the two most common multilocus sequence types (STs) involved in the outbreak, STs 125 and 126. This analysis showed that although these STs were closely related on a whole-genome level, they demonstrated evidence of multiple recombination events that were unlikely to have occurred over the timeframe of the outbreak. Based on epidemiological and genetic data, we also identified two additional patients not previously associated with this outbreak. Our results confirm the previous hypothesis that a single unchlorinated water source harbouring multiple B. pseudomallei strains was linked to the outbreak, and that increased melioidosis risk in this community was associated with Piper methysticum root (kava) consumption.Melioidosis is a tropical disease caused by the bacterium HPD, highest posterior density; indel, small insertion/deletion; MLST, multilocus sequence typing; PFGE, pulsed-field gel electrophoresis; SLV, single-locus variant; SNP, single-nucleotide polymorphism; SRA, Sequence Read Archive; ST, sequence type; TMRCA, time since the most recent common ancestor; WGS, whole-genome sequencing.Whole genome sequencing data have been deposited into the Sequence Read Archive or the European Nucleotide Archive:http://www.ebi.ac.uk/ena/data/view/ERR311046ERR311046, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3525374SRR3525374, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3525385SRR3525385,\u2009https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3525386SRR3525386, http://www.ebi.ac.uk/ena/data/view/ERR311049ERR311049, http://www.ebi.ac.uk/ena/data/view/ERR311050ERR311050, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3525387SRR3525387, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3525399SRR3525399, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3525400SRR3525400, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3525401SRR3525401, http://www.ebi.ac.uk/ena/data/view/ERR311053ERR311053, http://www.ebi.ac.uk/ena/data/view/ERR311054ERR311054, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR5260553SRR5260553, Burkholderia pseudomallei. B. pseudomallei rarely transmits person-to-person, with infections almost exclusively acquired by contact with contaminated water or soil. Due in part to this restricted transmission, melioidosis outbreaks are uncommon, and are typically caused by a single bacterial strain that can be linked to a contaminated point source shared by multiple individuals. In this study, we revisited a historical melioidosis outbreak on a remote Australian island by applying whole-genome sequencing (WGS) to better understand the aetiology of this outbreak. Our analysis shed new light on the outbreak, clarifying transmission patterns and confirming that the outbreak was caused by multiple B. pseudomallei strains. In addition, we identified cases not previously known to be associated with this outbreak. Our study provides another example of the utility of WGS for understanding the origin and risk factors associated with bacterial outbreaks.The tropical disease melioidosis is caused by the soil-dwelling bacterium Burkholderia pseudomallei is a Gram-negative soil-borne bacterium and the aetiological agent of melioidosis, a disease endemic in northern Australia and South-East Asia that is becoming increasingly recognized elsewhere and 6 49 (n=1) . ST-125 eviously , the comn=5), ST-126 (n=6) and ST-149 (n=2) strains. Nine isolates were from eight case cluster patients (two isolates were from one patient), two were environmental isolates that matched with MLST to clinical cases and the remaining two were from melioidosis patients living in two separate communities, each located ~100\u2009km from the remote island case cluster, who had not originally been linked to the case cluster but were identified as also being infected with ST-125 strains through the course of the Darwin Prospective Melioidosis Study and a gePiper methysticum, and its use is a known risk factor for melioidosis [B. pseudomallei [The ST-125 isolates obtained from the two patients not originally identified as part of the case cluster (MSHR0286 and MSHR0436) were remarkably similar to other ST-125 isolates on the whole-genome level, differing by only two and five variants, respectively . Despiteioidosis . The strB. pseudomallei isolates derived from the soil identified a putative link between the environmental soil isolate (MSHR0503) and the clinical isolate from P110 (MSHR0356), both of which were identified as ST-149. However, WGS analysis showed that these strains differed by 57 variants (29 SNPs and 28 indels), indicating that the soil-borne ST-149 population is diverse and that the infecting strain was not sampled at the time. Interestingly, this patient was one of only two involved in the outbreak who did not have a history of recent kava consumption, supporting that this patient likely did not contract melioidosis from the water supply, but was an isolated, endemic case contracted from contaminated soil that occurred concurrently with the outbreak. The only other patient to not list kava as a risk factor presented with septic shock and died shortly after hospital admission, with history of kava use not ascertained.MLST of the B. pseudomallei, with one water sample and six soil samples yielding viable cultures [B. pseudomallei cultures through a single-colony bottleneck prior to culture storage and genotyping, a strategy that has potentially masked the presence of a genetically heterogeneous population. The clinical history of this outbreak points to an environmental reservoir for ST-125, which may have existed as a mixed population within the community water supply and was simply not identified due to sampling methodology. Subsequent to the recognition of contamination of the water supply with B. pseudomallei, the community water supply was remediated and chlorinated. While sporadic endemic cases of melioidosis are still documented from that region, there have been no further cases with ST-125 or ST-126.Due to the historic nature of the outbreak, the soil and water samples collected for the investigation were not preserved for later analysis, so could not be revisited for this study. Fortunately, sampling efforts performed shortly following the outbreak were relatively comprehensive, and involved collection and testing of 87 soil samples and 35 water samples. Of these, only seven were positive for cultures . Both STB. pseudomallei population that had contaminated the unchlorinated community water supply, which was then unwittingly ingested by multiple community members over a 2 year period. Concurrent with this outbreak, two sporadic cases occurred in this remote community, most likely due to exposure to contaminated soil. Our study provides an important demonstration of the additional epidemiological and evolutionary insights gained from WGS compared with traditional genotyping methodologies.In conclusion, we report, to the best of our knowledge, the first documentation of a heterogeneous melioidosis case cluster characterized using WGS. This high-resolution method enabled the investigation of genome-wide strain relatedness and the contribution of recombination in epidemiologically linked SLVs, and in combination with epidemiological evidence, identified kava use as either the probable point source of infection or an associated risk factor. Given the genetic diversity of infecting isolates, this case cluster was likely caused by a polyclonal http://www.ebi.ac.uk/ena/data/view/ERR311046.ENA, accession no. ERR311046, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3525374.NCBI SRA, accession no. SRR3525374, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3525385.NCBI SRA, accession no. SRR3525385, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3525386.NCBI SRA, accession no. SRR3525386 http://www.ebi.ac.uk/ena/data/view/ERR311049.ENA, accession no. ERR311049, http://www.ebi.ac.uk/ena/data/view/ERR311050.ENA, accession no. ERR311050, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3525387.NCBI SRA, accession no. SRR3525387, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3525399.NCBI SRA, accession no. SRR3525399, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3525400.NCBI SRA, accession no. SRR3525400, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR3525401.NCBI SRA, accession no. SRR3525401, http://www.ebi.ac.uk/ena/data/view/ERR311053.ENA, accession no. ERR311053, http://www.ebi.ac.uk/ena/data/view/ERR311054.ENA, accession no. ERR311054, https://trace.ncbi.nlm.nih.gov/Traces/sra/?run=SRR5260553.NCBI SRA, accession no. SRR5260553,"} +{"text": "Data availability for article :https://www.ebi.ac.uk/ega/home.The raw sequence data have been deposited into European Genome-phenome Archive (EGA) with accession number EGAS00001000776 =>. https://www.ncbi.nlm.nih.gov/geo/)The raw sequence data have been deposited into Gene Expression Omnibus (GEO) with accession number GSE87340."} +{"text": "In github.com/FernandoMarcon/PKS-Test.In the Program availability section, the URL provided is incorrect. The correct URL is"} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following position:Expert Public Health Training and Capacity Buildinghttp://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxThe deadline for application is 10 April 2017. For more information, visit the ECDC website:"} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following position: Expert Hepatitis B/C http://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxThe deadline for application is 27 March 2017. For more information, visit the ECDC website:"} +{"text": "We report here the complete genome sequence of an avian metapneumovirus (aMPV) isolated from a tracheal tissue sample of a commercial layer flock. The complete genome sequence of aMPV-A/chicken/Brazil-SP/669/2003 was obtained using MiSeq sequencing. Phylogenetic analysis of the complete genome classified the isolate as avian metapneumovirus subtype A. Pneumoviridae, genus Metapneumovirus) (Avian metapneumovirus (family movirus) is the vmovirus) , 3. The movirus) and confmovirus) . SamplesThe virus was isolated in chicken embryo-related cells after three passages. The cell supernatant sample was pretreated according to a previous study . Afterwahttp://www.bioinformatics.babraham.ac.uk/projects/fastqc). Cutadapt version 1.3 . Cell cuent tool . All reaMF093139.The complete genome sequence of aMPV-A/chicken/Brazil-SP/669/2003 has been deposited in GenBank under accession number"} +{"text": "The complete statement is:The Data Availability statement for this paper does not include a GEO accession number for the RNA-seq data presented. These data are available from the GEO database (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE84386). All other relevant data are within the paper and its Supporting Information files.The RNA-seq data are available from the GEO database ("} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following positions:Expert Data Management/ Knowledge ManagementExpert Vaccine-preventable Diseaseshttp://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxThe deadlines for application are 18 April and 24 April 2017, respectively. For more information, visit the ECDC website:"} +{"text": "Trial Registration:https://clinicaltrials.gov/ct2/show/NCT00977418. The publisher apologizes for the error.There is an error in the penultimate sentence of the Abstract. The correct sentence is:"} +{"text": "Present: Due to the authors\u2019 negligence during the preparation of this manuscript for submission, it contains a plethora of data errors. Authors sincerely apologize for their mistakes and wish to retract their manuscript.Correct: The online version of the original article can be found under doi.68151-68155. doi: 10.18632/oncotarget.11902Original article: Oncotarget. 2016; 7:"} +{"text": "MSM represent approximately 2% of the U.S. population and acquired immunodeficiency syndrome (AIDS) on gay, bisexual, and other men who have sex with men (MSM) . Information about National Gay Men\u2019s HIV/AIDS Awareness Day is available at https://www.cdc.gov/features/ngmhaad.CDC supports a range of measures to reduce HIV infection among MSM ("} +{"text": "MMWR will publish several Surveillance Summaries on topics that highlight rural health issues. The MMWR Rural Health Series is available at https://www.cdc.gov/mmwr/rural_health_series.html. Two recently published reports (During 2017,"} +{"text": "Present: The wrong symbol font was used in preparation of the PDF version of this manuscript.Correct: The PDF was replaced with the correct version. Please see the original manuscript for download link.31153-65. doi: 10.18632/oncotarget.8866.Original article: Oncotarget. 2016; 7:"} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following position:\u2022 Expert Epidemic Intelligence (SRS)http://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxThe deadline is 6 March 2017. For more information, visit the ECDC website:"} +{"text": "BMJ 2015;350:g7873, doi:10.1136/bmj.g7873) was mistakenly published under the CC BY NC licence initially online and in the March 2015 academic print issue, and should have been published under the CC BY licence. The online version has since been corrected.This Research article ("} +{"text": "Information about funding source was omitted from the Acknowledgments section of the article \u201cProvision of Clinical Preventive Services by Community Pharmacists,\u201d which was released on October 27, 2016. This research received no specific grant from any funding agency in the public, commercial, or nonprofit sectors. The statement was added to the article on November 16, 2016.http://www.cdc.gov/pcd/issues/2016/16_0232.htm. We regret any inconvenience this omission may have caused.The corrected article appears online at"} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following position:\u2022 Senior Expert Emerging and Vector-borne Diseases (SRS)http://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxThe deadline is 23 January 2017. For more information, visit the ECDC website:"} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following position:\u2022 Senior Expert Public Health Emergency Preparedness Unithttp://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxFor detailed information on the job description, requirements and the application procedure, please visit the ECDC website at:"} +{"text": "Although being missed from the printed version, the same was included in the online version of the issue and can be read at http://www.jaypeejournals.com/eJournals/ShowText.aspx?ID=6229&Type=FREE&TYP=TOP&IN=~/eJournals/images/JPLOGO.gif&IID=471&isPDF=YESIn the last issue of Euroasian Journal of Hepato-Gastroenterology (EJOHG), that is , the article"} +{"text": "MMWR at no cost directly from CDC each week will no longer receive them. This decision was reached after careful consideration of the costs of printing and mailing. Distribution of printed copies of MMWR serial publications was discontinued in 2011 (Effective August 1, 2014, subscribers who currently receive printed copies of MMWR publications are available at no cost online at http://www.cdc.gov/mmwr. Readers desiring to have electronic copies of MMWR publications e-mailed to them automatically can subscribe online at http://www.cdc.gov/mmwr/mmwrsubscribe.html. Printed copies of the MMWR Weekly and serial publications are available by subscription from the Massachusetts Medical Society and from the U.S. Government Printing Office at http://www.cdc.gov/mmwr/order.html.All"} +{"text": "National HIV Testing Day, June 27, highlights the importance of testing in detecting, treating, and preventing human immunodeficiency virus (HIV) infection. Awareness of HIV infection through HIV testing is the first step to prevention, health care, and social services that improve quality of life and length of survival monitors behaviors among populations at risk for acquiring or transmitting HIV infection. Recent NHBS data indicate that persons at risk for HIV infection who had ever received testing for HIV are testing at shorter intervals than in the past (https://www.cdc.gov/features/HIVtesting. Basic testing information for consumers is available at https://www.cdc.gov/hiv/basics/testing.html. Additional information on HIV testing for health professionals is available at https://www.cdc.gov/hiv/testing. CDC\u2019s guidelines for HIV testing of serum and plasma specimens is available at https://www.cdc.gov/hiv/guidelines/testing.html.Additional information on National HIV Testing Day is available at"} +{"text": "Acinetobacter baumannii is an important opportunistic pathogen in global health care settings. Its dissemination and multidrug resistance pose an issue with treatment and outbreak control. Here, we present draft genome assemblies of six multidrug-resistant clinical strains of A. baumannii isolated from patients admitted to one of two major hospitals in Kuwait. Acinetobacter baumannii has steadily raised concerns in the medical field over the past decade as one of the most dangerous multidrug-resistant (MDR) human pathogens in health care settings and conflict zones complex across the entire genome . In ordeA. baumannii, three isolates each from Al-Sabah Hospital and Farwaniya Hospital (http://www.bioinformatics.babraham.ac.uk/projects/fastqc), and low-quality sequences were removed from the ends using FASTX trimmer (http://hannonlab.cshl.edu/fastx_toolkit/). Retained high-quality reads were assembled de novo using Velvet 1.2.10 , were grt 1.2.10 . Assemblt 1.2.10 . The conn France (GenBankrain AYE .All genome sequences discussed here were submitted to NCBI under BioProject number PRJNA380997 and are available with the accession numbers listed in"} +{"text": "Staphylococcus aureus and Lipopolysaccharide Modulate Gene Expressions of Drug Transporters in Mouse Mammary Epithelial Cells\u2013Correlation to Inflammatory Biomarkers.There is an error in the article title. The publisher apologizes for the error. The correct title is: Staphylococcus aureus and Lipopolysaccharide Modulate Gene Expressions of Drug Transporters in Mouse Mammary Epithelial Cells\u2013Correlation to Inflammatory Biomarkers. PLoS ONE 11(9): e0161346. doi:10.1371/journal.pone.0161346The correct citation is Yagdiran Y, Tallkvist J, Artursson K, Oskarsson A (2016)"} +{"text": "Caballeronia ptereocthonis comb. nov.\u201d to \u201cCaballeronia ptereochthonis comb. nov.\u201d and \u201cBurkholderia ptereocthonis\u201d to \u201cBurkholderia ptereochthonis\u201d. The corrected Table In the original article, there was a spelling mistake in a species name contained in Table Also, an additional section titled \u201cDescription of New Species Combinations\u201d was added to the original article. The section contains a short protologue for each proposed novel combination to conform to the rules of the Bacterial Code of Nomenclature. The protologues appear below.The authors apologize for this error. The original article has been updated.Caballeronia arvi (ar'vi. L. gen. n. arvi of a field).Burkholderia arvi Peeters et al., 2016.Basonym: Caballeronia with very high support.The description is as provided in Peeters et al. . AnalysiT (= CCUG 68412T = MAN34T).The type strain is LMG 29317Caballeronia arationis (a.ra.ti.o'nis. L. gen. n. arationis from a field).Burkholderia arationis Peeters et al., 2016.Basonym: Caballeronia.The description is as provided in Peeters et al. . PhylogeT (=CCUG 68405T).The type strain is LMG 29324Caballeronia calidae .Burkholderia calidae Peeters et al., 2016.Basonym: Caballeronia.The description is as provided in Peeters et al. . PhylogeT (=CCUG 68408T).The type strain is LMG 29321Caballeronia catudaia .Burkholderia catudaia Peeters et al., 2016.Basonym: Caballeronia.The description is as provided in Peeters et al. . Our anaT (=CCUG 68411T).The type strain is LMG 29318Caballeronia concitans .Burkholderia concitans Peeters et al., 2016.Basonym: Caballeronia.The description is as provided in Peeters et al. . AnalysiT (=CCUG 68414T = AU12121T).The type strain is LMG 29315Caballeronia fortuita .Burkholderia fortuita Peeters et al., 2016.Basonym: Caballeronia.The description is as described in Peeters et al. . Our anaT (=CCUG 68409T).The type strain is LMG 29320Caballeronia glebae .Burkholderia glebae Peeters et al., 2016.Basonym: Caballeronia.The description appears in Peeters et al. . AnalysiT (=CCUG 68404T).The type strain is LMG 29325Caballeronia hypogeia .Burkholderia hypogeia Peeters et al., 2016.Basonym: Caballeronia.The description appears in Peeters et al. . Our anaT (=CCUG 68407T).The type strain is LMG 29322Caballeronia pedi .Burkholderia pedi Peeters et al. 2016.Basonym: Caballeronia.The description is listed in Peeters et al. . The anaT (=CCUG 68406T).The type strain is LMG 29323Caballeronia peredens .Burkholderia peredens Peeters et al., 2016.Basonym: Caballeronia.The description is as discussed in Peeters et al. . Our anaT (=CCUG 68415T = NF100T).The type strain is LMG 29314Caballeronia ptereochthonis .Burkholderia ptereochthonis Peeters et al., 2016.Basonym: Caballeronia.The description appears in Peeters et al. . The anaT (=CCUG 68403T).The type strain is LMG 29326Caballeronia temeraria .Burkholderia temeraria Peeters et al., 2016.Basonym: Caballeronia with high support.The description of this species appears in Peeters et al. . The anaT (=CCUG 68410T).The type strain is LMG 29319Caballeronia turbans .Burkholderia turbans Peeters et al., 2016.Basonym: Caballeronia.The original species description appears in Peeters et al. . Our anaT (=CCUG 68413T = HI4065T).The type strain is LMG 29316The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} +{"text": "Present:ACKNOWLEDGMENTSThe authors gratefully acknowledge the data production teams at the Genome Sciences Centre.Corrected:ACKNOWLEDGMENTShttp://cancergenome.nih.gov.The authors gratefully acknowledge the data production teams at the Genome Sciences Centre. The results published here are in whole or part based upon data generated by The Cancer Genome Atlas managed by the NCI and NHGRI. Information about TCGA can be found at 25930\u201348. doi: 10.18632/oncotarget.8412.Original article: Oncotarget. 2016; 7(18):"} +{"text": "There are errors in the Author Contributions. The correct contributions are: Investigation: INO AOA ASL BWO. Supervision: INO AOA. Writing\u2013review & editing: BWO INO AOA ASL AL. The second, third and fourth authors, Amy S. Labar, Adebayo Lamikanra and Aaron O. Aboderin, should not have been attributed equal contribution to this work."} +{"text": "This article contains data related to the research articles \"Spatial and Temporal Analysis of Gene Expression during Growth and Fusion of the Mouse Facial Prominences\" Specifications TableValue of the data\u2022The data is a statistically robust and extensively verified multidimensional gene expression resource for mouse facial development.\u2022By comparing the transcriptome across age, prominence and tissue layer, the data provide a valuable tool for studying the complex process of craniofacial development.\u2022The data could contribute to interpretation of gene expression data in mouse mutants.\u2022The data could contribute to interpretation of clinical genetic data pertaining to facial development, morphology and orofacial cleft pathogenesis.12 scale) . Each ge2 scale) .Fig. 1To22.1http://www.ncbi.nlm.nih.gov/geo) with the accession number GSE7759.Details of data collection and capture were described previously in 2 expression signal values, and 2) Detection Above Background (DABG) with unmodified perfect match (PM) intensity values to calculate p-values for the probability of reliable signal detection. The DABG values were used to make \u05f3Absent/Present\u05f3 Detection calls, such that an expression value is called Present if the DABG p-value\u22640.05, and called Absent otherwise. Transcript identifiers were annotated by gene name, gene description and database identifiers using the Affymetrix-provided annotation file MoGene-1_0-st-v1.na31.mm9.transcript.csv. Only data for transcript identifiers associated to a named gene are used for display in the html pages (25468 transcript identifiers corresponding to 23160 distinct gene symbols). All data from our analysis are MIAME compliant and are available via GEO (http://www.ncbi.nlm.nih.gov/geo) with the accession number GSE62214.For separated ectoderm and mesenchyme datasets, the raw image data from the array scans were processed using the apt-probeset-summarize command from the Affymetrix Power Tools (APT) software suite, with options \"-a rma -a pm-only,dabg\" to perform 1) Robust Multi-array Average (RMA) with background correction, quantile normalization, and median polish summarization in order to get log2.21)Mammalian Phenotypes: downloaded 30 Dec 2013 from ftp://ftp.informatics.jax.org/pub/reports/index.html#pheno; see files ftp://ftp.informatics.jax.org/pub/reports/VOC_MammalianPhenotype.rpt and ftp://ftp.informatics.jax.org/pub/reports/MGI_PhenoGenoMP.rpt2)KEGG Pathways: downloaded Feb 2011 from http://www.kegg.jp/kegg/download/)3)InterPro Domains: downloaded 30 Dec 2013 from ftp://ftp.informatics.jax.org/pub/reports/MGI_InterProDomains.rpt4)Gene Ontology: downloaded 30 Dec 2013 from ftp://ftp.informatics.jax.org/pub/reports/index.html#go; see files ftp://ftp.informatics.jax.org/pub/reports/gene_association.mgi and ftp://ftp.informatics.jax.org/pub/reports/go_terms.mgiData for each gene were visualized using custom scripts in the R language"} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following position:Expert Mathematical Modellinghttp://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxThe deadline for application is 19 May. For more information, visit the ECDC website:"} +{"text": "Treponema pallidum subsp. pertenue, is an important public health problem in many tropical countries.T. pallidum particle agglutination assay (Haemophilus ducreyi may cause clinically similar ulcers.T. pallidum pertenue DNA. Both serological and molecular tests have a major role to play in the World Health Organization yaws eradication campaign.Yaws, caused by"} +{"text": "In www.addgene.org), with the following catalog numbers: pEpic #84372; pEpic_Lite #84373.The correct plasmids and their sequences have been deposited with Addgene ("} +{"text": "In 2017, National Child Passenger Safety Week is being observed during September 17\u201323. In the United States, motor vehicle\u2013related injuries are a leading cause of death among children (https://www.cdc.gov/motorvehiclesafety/child_passenger_safety and the National Highway Traffic Safety Administration at https://www.safercar.gov/parents/index.htm. Campaign promotional materials in English and Spanish are available at https://www.trafficsafetymarketing.gov/get-materials/child-car-safety/child-passenger-safety-week.As part of National Child Passenger Safety Week, September 23 has been designated \u201cNational Seat Check Saturday.\u201d On this day, drivers with children who ride in car seats or booster seats are encouraged to visit a child safety seat inspection station to have a certified technician inspect their car seat for proper installation and proper use, free of charge. Additional information and an inspection station locator are available from CDC at"} +{"text": "Here we present three packages which aim to simplify such procedures. The ontologyIndex, ontologyPlot and ontologySimilarity are all available on the Comprehensive R Archive Network website under https://cran.r-project.org/web/packages/.Bioinformatics online. It implements Resnik\u2019s and the Medical Research Council programme grant MC_UP_ 0801/1 (D.G. and S.R.).Conflict of Interest: none declared.Supplementary DataClick here for additional data file."} +{"text": "During 2010\u20132012, 30% of adults aged \u226565 years living in nonmetropolitan areas had no natural teeth, compared with 21% of those living in metropolitan areas. The percentage of adults aged \u226565 years with no natural teeth was higher in nonmetropolitan areas than in metropolitan areas in all regions of the United States. In both metropolitan and nonmetropolitan areas, the West had the lowest percentage of adults with no natural teeth.Sources: National Health Interview Survey, 2010\u20132012. Available at http://www.cdc.gov/nchs/nhis.htm.http://www.cdc.gov/nchs/hdi.htm.CDC. Health Data Interactive. Available at Reported by: Ellen A. Kramarow, PhD, ekramarow@cdc.gov, 301-458-4325."} +{"text": "This article has been corrected: The updated Acknowledgments and Funding information is provided below:ACKNOWLEDGMENTS AND FUNDINGThis study was supported by grants from the National Natural Science Foundation of China (No. 81401989). Guangzhou Science and Technology Plan Projects (No. 201400000001-4).https://doi.org/10.18632/oncotarget.14839Original article: Oncotarget. 2017; 8:15242-15251."} +{"text": "Please access the data at either of the following links:The Data Availability statement for this paper is incorrect. The correct statement is: Our study data files are publicly deposited in the University of Massachusetts Medical School\u2019s institutional repository, http://dx.doi.org/10.13028/M27P4Qhttp://escholarship.umassmed.edu/pediatrics_data/4/"} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following position:Deputy Head of Unit, Surveillance and Response Support UnitThe deadline for the application is 20 June 2017. For more information, visit the ECDC website:http://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspx"} +{"text": "Erratum to:npj Genomic Medicine (2017); doi:10.1038/s41525-017-0014-7; Published 26 April 2017This article contained typographical errors within the Availability of data and material section:https://github.com/ngreenwald/publications/Lab_Stuff/High_Grade_Meningioma.All code used for analysis is available at Now reads:https://github.com/ngreenwald/Publications/tree/master/High_Grade_Meningioma.All code used for analysis is available at This error has now been corrected in the HTML and PDF versions of this Article."} +{"text": "Clostridium difficile PCR Ribotype 027, Europe , the Figure contained errors. The correct version appears in the online version of this article (available from www.cdc.gov/EID/content/14/9/1485.htm) and is reprinted below.In Clindamycin-Resistant Clone of We regret any confusion these errors may have caused."} +{"text": "The following funding information was omitted. MC also received Fondazione Cariplo grant 2005-1166 (to S.Canevari)."} +{"text": "Correction to:British Journal of Cancer (2002), 87, 982\u2013988. doi:10.1038/sj.bjc.6600583triennial percentage change. Similarly, all the corresponding age-specific AAPCs in Table 2 are average triennial percentage change.The average annual percentage change (AAPC) as quoted in the paper currently says 3.61%. This figure is actually for the average The authors apologise for any inconvenience this may have caused."} +{"text": "Artemisia genipi, A. glacialis, and A. umbelliformis) should be seriously reconsidered in terms of sustainability, given the limited availability of these species, even though their collection is culturally salient in the entire study area.A gastronomic and medical ethnobotanical study was conducted among the Occitan communities living in Blins/Bellino and Chianale, in the upper Val Varaita, in the Piedmontese Alps, North-Western Italy, and the traditional uses of 88 botanical taxa were recorded. Comparisons with and analysis of other ethnobotanical studies previously carried out in other Piemontese and surrounding areas, show that approximately one fourth of the botanical taxa quoted in this survey are also known in other surrounding Occitan valleys. It is also evident that traditional knowledge in the Varaita valley has been heavily eroded. This study also examined the local legal framework for the gathering of botanical taxa, and the potential utilization of the most quoted medicinal and food wild herbs in the local market, and suggests that the continuing widespread local collection from the wild of the aerial parts of Alpine wormwood for preparing liqueurs ( In recent years, only a few ethnobotanical researches in the Alps have focused on the interaction between plant resources and human societies within ethnic minority groups -6. This Furthermore, the Alps represent one of the most interesting but least studied regions in Europe, particularly with regard to the exploration of tangible and intangible cultural heritage related to TK of plants, even though the potential outputs of such researches could be important in sustainability projects focused on organic farming, home gardens, local foods, eco-tourism, eco-gastronomy, and eco-museology; and even though climate change may have a tremendous impact on Alpine biodiversity and related ethnobotanical resources .Although a number of ethnobotanical inventories were compiled during the past 50 years in a few other Occitan -20, FranThe aims of this study were therefore:\u2022 to record the food and medical ethnobotanical knowledge of the Occitans living in the upper Varaita valley ;\u2022 to compare the collected data with those available in the ethnobotanical literature of other Alpine valleys in Piedmont and surrounding areas , and to point out the eventual occurrence of a specific \"Occitan\" ethnobotany;\u2022 to suggest local plant resources of particular interest for sustainable small-scale agricultural/gathering activities and eco-tourism activities.The presence of a single \"Occitan\" culture/language is one of the most disputed issues in European ethnolinguistics , given tth Century from the French side, and in the 19th and most of the 20th century it saw much intensive smuggling activity.The focus of this study, the Varaita valley, is located in the Western Alps in the Piedmont region, Cuneo province, in North-Western Italy figure . The valAt present, only mainly elderly persons still live year round in the upper part of the Valley. Bellino (1480 m a.s.l.) includes the hamlets of \u00c7elle, Chiazale, Chiesa Fontanile, Pleyne, Ribiera, and Sant'Anna, and has the status of a municipality. Chianale , and the subassociation Junipero-Arctostaphyletum cembretosum . The total rainfall is 854 mm/yr ; the climate is sub-littoral alpine, with some continental characteristics [Regarding vegetation, the upper Varaita valley presents mainly the association eristics .The local economy of the upper valley is based on traditional agro-pastoral activities (cow breeding), but this is carried out in only a minor way. There is some tourism, especially in the summer . Almost all of the few middle-aged and younger members of the community are employed in the lower part of the valley. Traditional cultivation of local staples had disappeared by the 1970's and home gardens these days are managed as a secondary activity only.Ethnobotanical investigations of the upper Varaita Valley figure , in the Flora d'Italia [Prior informed consent (PIC) was obtained verbally before commencing each interview, and ethical guidelines adopted by International Society of Ethnobiology were fold'Italia , and syd'Italia . Voucher\u00ae Excel, and a descriptive comparison was conducted with ethnobotanical data available in the scientific literature . HowAll the quoted botanical taxa (n = 88), including their related recorded local names and traditional gastronomic and/or medicinal uses, are reported below. We have included in brackets the voucher specimen codes and the quotation index .Achillea herba-rotta All. (Asteraceae). Wild. Canam\u00eco, Rua. Dried flowering aerial parts (figure s figure : tea or Achillea millefolium L. (Asteraceae). Wild. Ervo taiouro. Dried flowering aerial parts: tea as an anti-haemorrhoidal (humans) or an anti-diarrheic (cattle). Fresh aerial parts: topically applied as a cicatrizing agent. (CHI-ETA) ++Alchemilla vulgaris (Rosaceae). Wild. Gunnellettes . Dried leaves: use not recalled. Traded in the past. +Allium cepa L.(Alliaceae). Cultivated. Seoulo. Fresh bulbs: consumed in salads and as a seasoning in the local cuisine. +++Allium porrum L. (Alliaceae). Cultivated. Por. Fresh whole plant: traditionally consumed mixed in a kind of maize polenta. +Allium sativum L. (Alliaceae). Cultivated. Ai. Fresh bulbs: as a seasoning in the local cuisine (rare). In the past made into necklaces and worn by children as a treatment for worms. ++Allium schoenoprasum L. (Alliaceae). Wild. Poureto. Fresh leaves: added in pancakes (bignes) as a seasoning. To be avoided by cows and sheep, as the milk takes on a horrible taste. (CHI-POU) +++Antennaria dioica (L.) Gaertn. (Asteraceae). Wild. Piot de chat. Dried flowering aerial parts: tea as a digestive. Traded in the past. +Arnica montana L. (Asteraceae). Wild. Strugnarelo. Dried flowers: macerated in alcohol or in oil and applied externally for treating bruises. Traded now and in the past. (CHI-STR) +++Artemisia absinthium L. (Asteraceae). Wild. Erbio bioncho, Ousenzo. Dried aerial parts: put in cattle stables and in wardrobes as an anti-parasitic or to drive away moths. Tea used as an anti-hypertensive, digestive, and an antihelminthic (for children). (CHI-BIO) +++Artemisa genipi Weber (Asteraceae) Figure . Wild. GArtemisia glacialis L. (Asteraceae) Figure . Wild. GArtemisia umbelliformis Lam. (Asteraceae) Figure . Wild anArtemisia vulgaris (Asteraceae). Wild. Artumiso. Dried aerial parts: tea used as an emmenagogue (women) and to facilitate calving (cows). (CHI-ART) +++Avena sativa L. (Poaceae). Cultivated in the past. Aveno. Fruit used as fodder for animals. +Boletus spp. (Boletaceae). Wild. Boulet. Fruiting body: consumed (rare). +Brassica oleracea L. (Brassicaceae). Cultivated. Chaoul. Fresh aerial parts: consumed in soups and as fodder for animals. Often harvested during the snow season and stewed with anchovies (sancraou). ++Bunium bulbocastanum L. (Apiaceae). Wild. Gravaioun. Fresh tubers: eaten raw, or boiled, also in the dough of the ravioles . These uses are recalled as occurring only in the past. +Carlina acaulis L. (Asteraceae). Wild. Chardousso. Fresh flower receptacle as a snack. Dried flowering aerial parts are hung on the outside door year round and used to forecast weather. (CHI-CHA1) ++Carum carvi L. (Apiaceae). Wild. Chimmel, Serieis. Dried fruits: tea or macerated in alcohol as a digestive. Added to food as a seasoning . (CHI-SER) +++Cetraria islandica (L.) Acharius (Parmeliaceae). Wild. Gratacoul. Dried thallus: tea as a bechic. Traded in the past. (CHI-GRA) ++Chelidonium majus L. (Papaveraceae). Wild. Erbo de Santo Mario. Fresh latex: topically applied for treating warts. (CHI-ESM) +Chenopodium bonus-henricus (Chenopodiaceae). Wild. Bies, Zerbes, Orle . Fresh young leaves: consumed boiled in soups and in omelettes. Also preserved in salt. Fodder for cows (reputed to be good as a \"cleansing\" agent). Topically applied for treating skin inflammation caused by stinging nettle. (CHI-BIE) +++Cirsium acaule Scop. (Asteraceae). Wild. Vazanel. Fresh flower receptacle, consumed raw as a snack. +Cirsium arvense (Asteraceae). Wild. Choussio. Fresh young leaves: boiled in soups. (CHI-CHO) +Cirsium spinosissimum (L.) Scop. (Asteraceae). Wild. Chardousso. Fresh flower receptacles as a snack. Dried flowering aerial parts are hung on an outside door year round and used to forecast weather. (CHI-CHA2) ++Cynodon dactylon (L.) Pers.(Poaceae). Wild. Gramoun. Roots: tea as a depurative. (CHI-GRA) +Echium italicum L. (Borraginaceae). Wild. Erbo vieio. Fresh young leaves: boiled in soups. +Fagopyrum esculentum Moench. (Polygonaceae). Cultivated in the past. Furmetin, Pignoulet. Fruits: ground into flour and used as the main ingredient in the local polenta, often prepared by alternating layers of polenta with layers of local cheese (tumo) and butter, or sometimes even adding potatoes and leeks. +++Fragaria vesca L. (Rosaceae). Wild. Ambourses , Mourso. Fruits: consumed as a snack. (CHI-MOU) ++Gentiana acaulis L. (Gentianaceae). Wild. Chaousso de cucu. Dried leaves: tea as a digestive and anti-hypertensive. Dried flowers: macerated in alcohol or wine, as a digestive. (CHI-CHC) +++Gentiana lutea L. (Gentianaceae). Wild. Ergensano. Dried roots (reis): macerated in wine, as a digestive, for \"cleansing blood \"/depurative, or \"to make the blood thinner\". Decoction used to enhance rumination in cows. (CHI-ERG) +++Heracleum sphodylium L. (Apiaceae). Wild. Turmel. Fresh aerial parts: to be avoided as fodder . (CHI-TUR) +Hordeum vulgare L. (Poaceae). Cultivated in the past. Uerge.polenta (poouties). Folk species: Epl\u00e0, Pel\u00e1. Fruits: roasted and ground, in decoction, as a \"coffee substitute\". ++Folk species: Brins, Brens. Fruits: crushed and used as fodder for hens; the bran used as fodder for cattle. Traditionally consumed as main ingredient in a particular kind of Hypericum perforatum L. (Hypericaceae). Wild. Erbo di San Juan. Fresh flowering aerial parts: macerated in oil for treating burns. (CHI-ESJ) +Juglans regia L. (Juglandaceae). Semi-domesticated. Nounzal (tree). Kernels: pressed to obtain the oil, which was commonly used in the past in the local cuisine. +Juniperus communis L. (Cupressaceae). Wild. Chais. Dried fruits: used as a seasoning or macerated in grappa as a digestive. (CHI-CHI) ++Laburnum alpinum (Mill.) Bercht. & J. Presl (Leguminosae). Wild. Albourn. Fresh flowering aerial parts (bindareles): put in the hen house to deter lice and flies. (CHI-ALB) ++Larix decidua Mill. (Pinaceae). Wild. Melze, Merze. Resin: topically applied as a cicatrizing agent. (CHI-MEL) +++Lathyrus sp. (Leguminosae). Wild. Lioum. Seeds: ground and the flour used in the past for preparing a kind of polenta. +Lens culinaris Medik. (Leguminosae). Cultivated in the past. Lentie . Seeds: in soups, or traditionally consumed as main ingredient in a particular kind of polenta (poouties). ++Linum usitatissimum L. (Linaceae). Cultivated in the past. Lin. Seeds: as fodder for calves. Mixed with water, heated and externally applied on the chest for treating colds and coughs. +Malva neglecta Wallr. and M. sylvestris L. . Wild. Rioundelo. Fresh leaves: tea, also used in gargles, as an anti-inflammatory. Boiled in soups. (CHI-RIU) +++Mentha spicata L. (Lamiaceae). Cultivated in home gardens. Mento. Fresh leaves: tea as a digestive. Also as a seasoning for pancakes (bignes). ++Myrrhis odorata (L.) Scop. (Apiaceae). Wild. Charvei. Aerial parts: to be avoided as they are \"poisonous\". (CHI-CHV) +Narcissus poeticus L. (Liliaceae s.l.). Wild. Susarelo, Joes de mel, Fior del mel. Flowers: sucked as a snack . (CHI-SUS) +Nasturtium officinale R. Br. (Brassicaceae). Wild. Creissentin. Fresh leaves: consumed in salads. (CHI-CRE) +Nepeta cataria L. (Lamiaceae). Wild. Erbo da chat. Dried aerial parts: tea as a mild tranquillizer. Traded in the past. +Onobrychis montana DC. (Leguminosae). Wild. Sparsei. Fresh and dried aerial parts: highly valued fodder for animals. (CHI-SPA) +Petasites hybridus (L.) P. Gaertn., B. Mey & Scherb. (Asteraceae). Wild. Chapus. Fresh leaves: fodder for hens. (CHI-CHP) ++Peucedanum ostruthium (L.) W.D.J. Koch (Asteraceae). Wild. Algrot. Fresh root (reis): decoction or directly administered crushed and mixed with salt as a digestive (for cattle and sheep). (CHI-ALG) +++Pinus cembra L. (Pinaceae). Wild. Elvio. Seeds: pressed to obtain oil (in the past). Cones: macerated in alcohol as a digestive. (CHI-ELV) +++Piper nigrum L. (Piperaceae). Not local; bought in shops. Pepe. Dried fermented fruits: boiled in milk and butter for treating coughs. +Plantago lanceolata L. and P. major L. (Plantaginaceae). Wild. Piantai. Dried leaves: tea as an appetizer and digestive . Fresh leaves: topically applied with cream from cows' milk and bread or clay as a suppurative . (CHI-PIA1/CHI-PIA2) ++Polygonum bistorta L. (Polygonaceae). Wild. Zonbuines , Lingo boino, Linboina. Fresh young leaves: consumed in soups. (CHI-ZON) +++Prunus avium L. (Rosaceae). Semi-cultivated. Serieses . Fresh fruits: consumed raw as a snack. +Prunus domestica L. (Rosaceae). Semi-cultivated. Brigne . Fresh fruits: consumed raw. +Rosa canina L. (Rosaceae). Wild. Bouchier, Bouchiet. Dried pseudofruits: tea as an anti-diarrhoeic. Ground and added to bread dough in the past. (CHI-BUC) ++Rubus ideaus L. (Rosaceae). Wild. Amurse . Fresh fruits: eaten raw or processed into home-made jams. +++Rumex acetosa L. and R. acetosella L. (Polygonaceae). Wild. Setou. Fresh leaves. eaten raw as a snack. (CHI-SET1 and CHI-SET2) +Rumex alpinus L. (Polygonaceae). Wild. Gravasso, Ravasso. Fresh leaves: topically applied as a cicatrizing agent. Fresh leaves and stems: fodder for cattle. Fresh stems: eaten raw with salt as a snack or boiled like asparagus; occasionally used in soups . (CHI-GRA) ++Sambucus nigra L. (Caprifoliaceae). Wild. Sambuc. Fresh fruits: wine and jams (only in the lower part of the studied area). +Secale cereale L. (Poaceae). Cultivated in the past. Seil. Fruits: flour. Widely used in the past as main ingredient for bread, and also for the local home-made noodles, courzeitin, and a porridge-like preparation based on milk and butter, panado. +++Sedum album L. (Crassulaceae). Wild. Salabron. Fresh aerial parts: topically applied for treating skin inflammation caused by stinging nettle. (CHI-SAL) +Solanum tuberosum L. (Solanaceae). Cultivated. Trufes . Fresh tubers: consumed boiled; traditionally added to the dough of the local dumplings (ravioles). +++Sorbus aria (L.) Cratz. (Rosaceae). Wild. Alier. Fresh fruits : eaten after natural fermentation on straw. Once dried, ground and added to bread dough (in the past). +Sorbus aucuparia L. (Rosaceae). Wild. Pizzera. Fresh fruits: to be avoided by humans but appreciated by wild birds. +Tanacetum vulgare L. (Asteraceae). Wild and semi-domesticated. Archebuse. Fresh leaves: macerated in alcohol as digestive. (CHI-ARC) +++Taraxacum officinale Weber (Asteraceae). Wild. Mourioun. Fresh leaves: consumed in salads or boiled. (CHI-MOU) +++Thymus pulegioides L. s.l. (Lamiaceae). Wild. Serpour, Serpoul. Dried leaves: tea as a digestive, for treating sore-throats, or as a diuretic. As a seasoning in the local cuisine . (CHI-SER) ++Tragopogon pratensis L. (Asteraceae). Wild. Barbouch, Barbabouch. Fresh flower buds and young leaves: consumed raw or boiled. (CHI-BAR) +++Tussilago farfara L. (Asteraceae). Wild. Pupettes. Dried flowers: tea as a bechic. Traded in the past. (CHI-PUP) +Urtica dioica L. and other U. species (Urticaceae). Wild. Urtio. Fresh leaves: consumed in soups or frittata. Tea as a diuretic . (CHI-URT) +++Vaccinium myrtillus L. (Ericaceae). Wild. Aize. Fresh fruits: consumed raw or processed in jams or cordials. +++Vaccinium uliginosum L. (Ericaceae). Wild. Poumarette . Fresh fruits: often mixed with V. myrtillus fruits, consumed raw or processed in jams or cordials (less popular than V. myrtillus fruits) ++Vaccinium vitis-idaea L. (Ericaceae). Wild. Petemerlet. Fresh fruits: raw as a snack. ++Valerianella sp. . Wild. Salzet. Fresh young leaves: consumed in salads. (CHI-SAL) +Veratrum album L. (Liliaceae s.l.). Wild. Varaire. Roots: topically applied as an anti-lice treatment for calves. (CHI-VAR) +Verbascum nigrum L. (Schrophulariaceae). Wild. Nevioun. Flower: tea as a bechic. (CHI-NEV) +Veronica allionii Vill. (Schrophulariaceae). Wild. Jaspertero. Dried flowering, aerial parts: tea . Decoction given to cows . Traded in the past. (CHI-JAS) +++Veronica beccabunga L. (Schrophulariaceae). Wild. Seiraset. Fresh leaves: consumed raw in salads. (CHI-SER) +Vicia faba L. (Leguminosae). Cultivated in the past. Faves . Seeds: traditionally consumed as main ingredient of a particular kind of polenta (poouties). +Viola odorata L. (Violaceae). Wild. Vioulette . Dried leaves: tea for treating colds and coughs (low dosage). Fresh leaves: boiled in soups. Traded in the past. (CHI-VIO) ++Vitis vinifera L. (Vitaceae). Vinegar. Purchased in the surrounding lower areas. Poultice mixed with clay: externally as a suppurative. ++Zea mais L. (Poaceae). Cultivated. Meliga. Seeds: ground into flour and used as main ingredient for a particular kind of local polenta. +++Unidentified taxon. Wild. Erbo dousso. Fresh aerial parts. Boiled in soups. +Unidentified taxon. Wild. Gialinettes, Gialinettes grasses . Fresh aerial parts: boiled in soups. ++Unidentified taxon. Wild. Ontu. Root: decoction given to calves to treat digestive problems. +Table Artemisia genipi, A. glacialis, A. umbelliformis). This term has probably Savoyard origins, and is derived from the Latin Dianae spicum [The term genep\u00ec/g\u00e9n\u00e9p\u00ec is applied in the Western Alps to diverse species of locally growing Alpine wormwood (esp. English) .genep\u00ec in the Western Alps has never been recorded specifically or systematically, although scattered notes have occurred in Alpine ethnobotanical studies over the last few decades and the home-made liqueur . According to locals in the upper Varaita valley, the specific occurrence in the recipe of A. genep\u00ec is crucial for achieving a superb tasting alcoholic beverage.All our informants, however, were very keen to underline the difference in taste between the industrial genep\u00ec . In the past this species was probably heavily exploited by the locals in Chianale, who used to sell it to local distilleries both on the plain of Piedmont and on the French side (often smuggled across secondary pathways over the Alps that were passable with donkeys only). Informants in Chianale recalled how this activity provided the inhabitants with their most important income from a few decades after World War II. There is probably still some illegal gathering of this species that provides additional cash to the people of the mountain. A few informants told us that the income that can be derived from gathering genep\u00ec can reach 15-20 thousand Euros every summer for one single household.Locals in the upper Varaita valley continue to gather the flowering tops of In table genep\u00ec species cannot be recommended, however sustainable gathering of other local plant resources that are widely available in the area, could be a very interesting way to complement the eco-touristic activity, that is quite exclusively concentrated during the summer months, thereby providing an important source of income for the few remaining inhabitants.It is clear that further exploitation of the Achillea herba-rotta, Arnica montana, Carum carvi, Chenopodium bonus-henricus, Tanacetum vulgare, Taraxacum officinale, and Tragopogon pratensis.Traditional food and medical uses of 88 local plants were recorded in the upper part of the Varaita valley. Analytical comparisons with other ethnobotanical studies previously carried out in other Piemontese and surrounding areas have shown that: a) traditional knowledge has been heavily eroded in the Varaita valley, and b) approximately one fourth of the quoted botanical taxa were also recorded in earlier surveys conducted in other Occitan valleys in the Italian Alps. Furthermore, the continued widespread local collection from the wild of the aerial parts of Alpine wormwood for the preparation of liqueurs should be seriously reconsidered in terms of sustainability, given the limited availability of these species even though this collection is culturally salient in the entire study areas, On the other hand interesting potentialities for the local market could be tested for other widely available wild species, such as The authors declare that they have no competing interests.AP and MEG have collected the data in the field; AP has analyzed the data and drafted the conclusions. All authors read and approved the final manuscript."} +{"text": "After the publication of this work , we becaWe regret any inconvenience that this oversight may have caused.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/10/311/prepub"} +{"text": "Few web-based sites related to contrast media in radiology and imaging, available at the moment, are reviewed below.Introduction to Intravenous Radiographic Contrast is a concise summary of the subject by Romell Dhadha. Featured as a part of the Department of Radiology Short Clerkship: Lectures at University of Iowa, the material is available at http://www.radiology.uiowa.edu/Radshortclerkship/RadShortClkship/LectureNotes/Dhada.htm.A Simple Guide to the Basics of Contrast Media is available in the form of Guide notes at http://www.e-radiography.net/contrast_media/contrast_media_introduction.htm. The material includes iodinated intravascular contrast agents, barium sulfate, computerized tomography (CT) contrast agents, biliary contrast agents and reactions, allergic emergencies.eMedicine, comprehensive educative material on radiographic iodinated contrast media is obtainable at http://www.emedicine.com/radio/byname/contrast-medium-reactions-recognition-and-treatment.htm.From Chest Xray.com deals concisely with radiology contrast at http://www.chestx-ray.com/Practice/Contrast.html. The following sections are covered: general, non-ionic vs ionic, risk factors, severity of reactions, renal toxicity, screening creatinine and treatment. Incidentally, the portal chest Xray.com at http://www.chestx-ray.com/ covers areas related to research, education, practice and resources.The webportal Contrast Media in Diagnostic Radiology from the Textbook of Radiology at http://www.medcyclopaedia.com/library/radiology/chapter07.aspx is an up-to-date feature from Medcyclopaedia\u2122. Medcyclopaedia\u2122 is a \u201cunique combination of a scientific library and a handy toolbox on the internet.\u201d In addition, the site features the complete online edition of The Encyclopaedia of Medical Imaging, the complete online edition of A Global Textbook of Radiology, GE Healthcare's Expanded Medical Imaging Glossary, clinical cases for training purposes and a complete e-learning solution in normal imaging anatomy.Symposium on Ultrasound Contrast for Radiological Diagnosis titled Bubbles in Radiology - The State of the Art is available at http://www.sunnybrook.utoronto.ca/bubble/. The site requires a mandatory registration. Additionally, \u2018A Handbook of Contrast Echocardiography\u2019 authored by Harald Becher and Peter N Burns is available at http://www.sunnybrook.utoronto.ca/EchoHandbook/. Within this, there is an Interactive Glossary of Contrast Ultrasound at http://www.sunnybrook.utoronto.ca/EchoHandbook/bookindex.htm.A Controversies and Consensus in Imaging and Interventions is a journal for medical imaging professionals, focusing on current issues in radiology, imaging and interventional radiology/cardiology and CT radiology. This website, sponsored by an educational grant from GE Healthcare, has a section on contrast media that is available at http://www.c2i2.org/contrast_media.asp.Issues in Contrast and CT Angiography with Multislice CT is featured in Applied Radiology (Mar 2002), accessible at http://www.appliedradiology.com/backissues/issue.asp?ID=71, after a compulsory registration. The material covers important topics such as optimizing contrast use in multislice CT, fast CT in neurological imaging: contrast issues, contrast multiplies cardiac CT applications, CTA of extremities: new approaches to scanning, contrast use, new contrast administration protocols: safety considerations. A panel discussion is also available at the end.An educative supplement on Guidelines and manuals on the use of contrast media in radiology are issued periodically from reputed professional bodies. Currently available comprehensive references includeAmerican College of Radiology Contrast Manual on Contrast Media version 6/2008, which is available at http://www.acr.org/SecondaryMainMenuCategories/quality_safety/contrast_manual.aspx.ACR Practice Guideline for the Use of Intravascular Contrast Media, which is accessible at http://www.acr.org/s_acr/bin.asp?CID=541andDID=12241andDOC=FILE.PDF.European Society of Urogenital Radiology (ESUR) Guidelines on Contrast Media, available from http://www.esur.org/fileadmin/Guidelines/ESUR_2007_Guideline_6_Kern_Ubersicht.pdf.Royal College of Radiology Standards for Iodinated Intravascular Contrast Agent Administration to Adult Patient, available from http://www.rcr.ac.uk/docs/radiology/pdf/IVcontrastPrintFinal.pdf.Review Articles/Citations on Contrast media in Radiology: There are numerous articles on contrast media in radiology available from various journals. From these, a handy \u2018must read\u2019 list of review articles on this subject, published in recent times and available online, is given below in MR - Technology Information Portal (MR-TIP.com) was reviewed earlier in the Aug 2007 issue of this journal. Recently, a similar online database covering ultrasonography, titled UltraSound - Technology Information Portal is on offer at http://www.us-tip.com/serv1.php?type=ldir.The online database US-TIP.com \u201cis a global information resource aimed at people with professional interests in medical ultrasound technology for imaging and/or therapy.\u201d US-TIP.com, at its home page, links to a US-TIP Resource-Database that contains currently around 1600 entries. Within this are absorbing sections on UltraSound Technology, Knowledge 3D and 4D UltraSound, Contrast Agents, various examinations, History of UltraSound, Image Quality Artifacts, Probes Transducers and UltraSound Physics. Relevant to the topic of this web review, from the above two information portal sites, contrast agents is covered at http://www.mr-tip.com/serv1.php?type=db1anddbs=Contrast%20Agents and http://www.mr-tip.com/serv1.php?type=db1anddbs=Contrast%20Agents and http://www.us-tip.com/serv1.php?type=db1anddbs=Ultrasound%20Contrast%20Agents.EduRad at http://www.edurad.in/index.php is an online initiative aimed at integrating and improving the education of Radiologists by using a professional approach towards the organization of academic programs.Created by Dr. Bharat Parekh, Dr. Deepak Patkar and Dr. Jignesh Thakkar, the portal offers a wide range of web-based education for radiologists. After a mandatory registration, the website offers educative material on Case Reports, Image Gallery, Techno Watch, Classifieds, CME Events, Archives, Teaching Files, Radiology Learning Centre, Online Lectures and Past Conferences (Archives), Live Webcast-Interactive and DMRE (Part-I) lecture series on power point.Wiki is a special type of web site that enables a group of users to collectively edit, expand, revise, and create content. Wikipedia at http://www.wikipedia.org/ is a free encyclopedia of information created with a notable difference, in that, anyone can edit the information and therefore participate to create an online collaborative reference. What's more, the edited material is assessed for quality and verity by a \u201cbehind the scene\u201d moderator group comprising of experts and voluntary professionals.A Medical Wikis are the medical equivalent of Wikipedia. They are hosted with an aim to offer comprehensive, veritable and up-to-the-minute information from a single point and that too on a large scale. Medical Wikis are emerging on the net as this List of Medical Wikis at http://davidrothman.net/list-of-medical-wikis/suggests. How far would they evolve and progress, what innovative features would they offer a decade from now, what are the advantageous spinoffs emerging from such websites and what is the endpoint in such websites are some of the hazardous questions that mystifyingly stare at us.Nevertheless, when it comes to the discipline of radiology, the following Radiology Wikis are available at the moment:RadiologyWiki at http://www.radiologywiki.org/wiki. This site has a radiology image search functionally similar to ARRS Goldminer, Yottalook and Google image search. Titled Ajax, this filtered radiology image search engine is available at http://www.radiologywiki.org/w/index.php?title=AJAX_Search.RadsWiki at http://www.radswiki.net/main/index.php?title=Main_Page. This site has many sections, including those on named fractures, radiology in movies, differential diagnosis and a list of signs in radiology.Diagnostic Radiology Wikibooks is an open-content textbook collection at http://en.wikibooks.org/wiki/Diagnostic_Radiology.wikiRadiography at http://www.wikiradiography.com/ is an radiography resource on the web with sections on Applied Radiography written by M. J. Fuller, General Radiography, Computed Tomography, U/S, MRI and Mammography Homepages."} +{"text": "After publication of this work , we becaWe regret any inconvenience that this inaccurate information might have caused.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/10/571/prepub"} +{"text": "The fifth word of the title was misspelled. This also affect the article's citation. The correct title should be: Computational Modelling of Genome-Wide Transcription Assembly Networks Using a Fluidics Analogy. The corrected citation is: Azmy YY, Gupta A, Pugh BF (2008) Computational Modelling of Genome-Wide Transcription Assembly Networks Using a Fluidics Analogy. PLoS ONE 3(8): e3095. doi:10.1371/journal.pone.0003095"} +{"text": "Int. J. Mol. Sci. recently [We found an error in our paper published in the recently : on pageWe apologize for any inconvenience caused to the readers."} +{"text": "P values in the article, \"Employer Adoption of Evidence-Based Chronic Disease Prevention Practices: A Pilot Study,\" were expressed incorrectly. The P values are located in Table 3 of the manuscript and should have been expressed as \"P > .99,\" not \"P < .99.\" Corrections were made to our website on August 7, 2008, and appear online at www.cdc.gov/pcd/issues/2008/jul/07_0070.htm. We regret any confusion or inconvenience this error may have caused.Because of an editing error, 2"} +{"text": "R. Soc. open sci.5, 181565. (Published Online 23 October 2018). (doi:10.1098/rsos.181565)There is an error in the second sentence of the Introduction in the published paper. The sentence should read: \u2018As(V) is also capable of retaining negative charge in its phosphate analogue arsenate\u2026\u2019."} +{"text": "Correction to: Exp. Mol. Med.50, e460 (2018). 10.1038/emm.2017.301; Published Online 23 March 2018.After online publication of this article, the authors noticed an error in the Figure section. The correct statement of this article should have read as below.In the article cited above, incorrect figure was placed in Fig.\u00a0The corrected material is printed below. Other parts of this article remain unchanged. The authors apologize for any inconveniences they may have caused."} +{"text": "Systematic reviews offer high quality, evidence-based guidance to health professionals. These reviews address myopia and its complications.www.who.int/hinariCochrane Eyes and Vision (CEV) is an international network of individuals working to prepare, maintain and promote access to systematic reviews of interventions to treat or prevent eye diseases or visual impairment, and reviews of the accuracy of diagnostic tests. Systematic reviews are summaries of the best available evidence and are designed to answer a specific research question. The reviews featured here are published in the Cochrane Library, which is available free of charge in low- and middle-income countries via the Hinari Programme. www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004916.pub3Date: December 2011. Update due in 2019.Key findings: Anti-muscarinic topical medication slows the progression of myopia in children. Adverse effects include light sensitivity and near blur.www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD005023.pub3Date: February 2018Key findings: Vision screening plus provision of free spectacles improves the number of children who have and wear the spectacles they need compared with providing a prescription only.www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD004765.pub2/Date: March 2007Key findings: The effect of laser photocoagulation to treat choroidal neovascularisation due to myopia is uncertain. Adverse effects include enlargement of the atrophic laser scar which is potentially vision threatening.www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD011160.pub2Date: December 2016Key findings: Low and moderate-certainty evidence that people receiving anti-vascular endothelial growth factor have a better outcome in terms of visual acuity compared with no treatment, photodynamic therapy or laser. Adverse effects occurred rarely."} +{"text": "This quiz is designed to help you test your own understanding of the concepts covered in this issue, and to reflect on what you have learnt.www.cehjournal.orgWe hope that you will also discuss the questions with your colleagues and other members of the eye care team, perhaps in a journal club. To complete the activities online \u2013 and get instant feedback \u2013 please visit Tick ALL that are TRUEa. False. It is essential to control the pre-operative inflammation before operating \u2013 preferably for 3 months or more. b. True. c. False. Different IOL materials promote varying levels of fibrotic response. d. False. In uveitis, combined surgery gives a very low success rate for the trabeculectomy.a. False. Poor diabetic control has long term implications but will not affect the outcome of surgery. b. True. c. True. d. True.a. True. b. False. Dispersive viscoelastics spread themselves onto the endothelium creating a protective coating. c. True. d. False. Effective surgery with the technique you are most familiar with is likely to minimise endothelial damage.a. False. Dilation starts to wear off after a few hour. Starting dilating drops one prior to surgery is probably optimal. b. True. c. False. Bimanual pupil stretching should be adequate in most cases and involves no extra cost to the hospital other than slightly longer surgical time. d. True."} +{"text": "This article has been corrected: During production, the ending page number for this article was listed incorrectly. The page count has now been adjusted to show the proper pagination.https://doi.org/10.18632/oncotarget.457Original article: Oncotarget. 2012; 3:345-356."} +{"text": "The third author, Dr. Dieter Lukas, should be included as a Corresponding Author. Dr. Lukas\u2019 email address is:"} +{"text": "This article has been corrected: Due to errors in image preparation, the IP blots in Fig. 3A contained identical images. These duplicates have now been replaced. The proper Figure 3A is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.46034-46046. https://doi.org/10.18632/oncotarget.17682Original article: Oncotarget. 2017; 8:46034\u201346046."} +{"text": "Nucleic Acids Research, 2018, https://doi.org/10.1093/nar/gky1222The Authors apologize for an error in reference which sh"} +{"text": "Correction to: Cell Discovery (2016) 210.1038/celldisc.2016.45 Published online 6 December 2016The original version of this article unfortunately contained a mistake. The given and family name of Andres Klein Szanto is incorrect. The correct name is Andres J Klein-Szanto.The original article has been corrected."} +{"text": "Due to an editorial error, the Data Availability Statement containing the raw sequences was erroneously omitted from the article. The publisher apologizes for the mistake.PRJNA497709 (https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA497709).All sequence data from this study has been deposited on NCBI under BioProject accession no."} +{"text": "Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point\u2010in\u2010time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14751. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein\u2010coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid\u20102019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC\u2010IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands ( The ligand binding domain is placed on the extracellular surface of the plasma membrane and separated from the functional domain by a single transmembrane\u2010spanning domain of 20\u201025 hydrophobic amino acids. The functional domain on the intracellular face of the plasma membrane has catalytic activity, or interacts with particular enzymes, giving the superfamily of receptors its name. Endogenous agonists of the catalytic receptor superfamily are peptides or proteins, the binding of which may induce dimerization of the receptor, which is the functional version of the receptor.Amongst the catalytic receptors, particular subfamilies may be readily identified dependent on the function of the enzymatic portion of the receptor. The smallest group is the particulate guanylyl cyclases of the natriuretic peptide receptor family. The most widely recognized group is probably the receptor tyrosine kinase (RTK) family, epitomized by the neurotrophin receptor family, where a crucial initial step is the activation of a signalling cascade by autophosphorylation of the receptor on intracellular tyrosine residue(s) catalyzed by enzyme activity intrinsic to the receptor. A third group is the extrinsic protein tyrosine kinase receptors, where the catalytic activity resides in a separate protein from the binding site. Examples of this group include the GDNF and ErbB receptor families, where one, catalytically silent, member of the heterodimer is activated upon binding the ligand, causing the second member of the heterodimer, lacking ligand binding capacity, to initiate signaling through tyrosine phosphorylation. A fourth group, the receptor threonine/serine kinase (RTSK) family, exemplified by TGF\u2010\u03b2 and BMP receptors, has intrinsic serine/threonine protein kinase activity in the heterodimeric functional unit. A fifth group is the receptor tyrosine phosphatases (RTP), which appear to lack cognate ligands, but may be triggered by events such as cell:cell contact and have identified roles in the skeletal, hematopoietic and immune systems.A further group of catalytic receptors for the Guide is the integrins, which have roles in cell:cell communication, often associated with signaling in the blood.1.1http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=699\u2013 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=686\u2013 http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=687\u2013 1http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=334, the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=303 family and the http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=14. Within this group of records are described Type I cytokine receptors, typified by interleukin receptors, and Type II cytokine receptors, exemplified by interferon receptors. These receptors possess a conserved extracellular region, known as the cytokine receptor homology domain (CHD), along with a range of other structural modules, including extracellular immunoglobulin (Ig)\u2010like and fibronectin type III (FBNIII)\u2010like domains, a transmembrane domain, and intracellular homology domains. An unusual feature of this group of agents is the existence of soluble and decoy receptors. These bind cytokines without allowing signalling to occur. A further attribute is the production of endogenous antagonist molecules, which bind to the receptors selectively and prevent signalling. A commonality of these families of receptors is the ligand\u2010induced homo\u2010 or hetero\u2010oligomerisation, which results in the recruitment of intracellular protein partners to evoke cellular responses, particularly in inflammatory or haematopoietic signalling. Although not an exclusive signalling pathway, a common feature of the majority of cytokine receptors is activation of the JAK/STAT pathway. This cascade is based around the protein tyrosine kinase activity of the Janus kinases (JAK), which phosphorylate the receptor and thereby facilitate the recruitment of signal transducers and activators of transcription (STATs). The activated homo\u2010 or heterodimeric STATs function principally as transcription factors in the nucleus. Type I cytokine receptors are characterized by two pairs of conserved cysteines linked via disulfide bonds and a C\u2010terminal WSXWS motif within their CHD. Type I receptors are commonly classified into five groups, based on sequence and structual homology of the receptor and its cytokine ligand, which is potentially more reflective of evolutionary relationships than an earlier scheme based on the use of common signal transducing chains within a receptor complex.Cytokines are not a clearly defined group of agents, other than having an impact on immune signalling pathways, although many cytokines have effects on other systems, such as in development. A feature of some cytokines, which allows them to be distinguished from hormones, is that they may be produced by \u201cnon\u2010secretory\u201d cells, for example, endothelial cells. Within the cytokine receptor family, some subfamilies may be identified, which are described elsewhere in the Guide to PHARMACOLOGY, receptors for the Type II cytokine receptors also have two pairs of conserved cysteines but with a different arrangement to Type I and also lack the WSXWS motif.1IL2RG, http://www.uniprot.org/uniprot/P31785), though IL\u20104 and IL\u20107 receptors can form complexes with other receptor chains. Receptors of this family associate with Jak1 and Jak3, primarily activating Stat5, although certain family members can also activate Stat1, Stat3, or Stat6. Ro264550 has been described as a selective IL\u20102 receptor antagonist, which binds to IL\u20102 . Mutations of RET and GDNF genes may be involved in Hirschsprung's disease, which is characterized by the absence of intramural ganglion cells in the hindgut, often resulting in intestinal obstruction.Inhibitors of other receptor tyrosine kinases, such as et al. (2013) GDNF, NGF and BDNF as therapeutic options for neurodegeneration. Pharmacol. Ther. 138: 155\u201075 https://www.ncbi.nlm.nih.gov/pubmed/23348013?dopt=AbstractPlusAllen SJ et al. (2017) Biology of GDNF and its receptors \u2010 Relevance for disorders of the central nervous system. Neurobiol. Dis. 97: 80\u201089 https://www.ncbi.nlm.nih.gov/pubmed/26829643?dopt=AbstractPlusIb\u00e1\u00f1ez CF Expert Opin. Ther. Targets20: 193\u2010208 https://www.ncbi.nlm.nih.gov/pubmed/26863504?dopt=AbstractPlusMerighi A. (2016) Targeting the glial\u2010derived neurotrophic factor and related molecules for controlling normal and pathologic pain. Integrins are unusual signalling proteins that function to signal both from the extracellular environment into the cell, but also from the cytoplasm to the external of the cell. The intracellular signalling cascades associated with integrin activation focus on protein kinase activities, such as focal adhesion kinase and Src. Based on this association between extracellular signals and intracellular protein kinase activity, we have chosen to include integrins in the \u2018Catalytic receptors\u2019 section of the database until more stringent criteria from NC\u2010IUPHAR allows precise definition of their classification.2+ ion in the I or I\u2010like domain that is essential for ligand binding. Other cation binding sites may regulate integrin activity or stabilise the 3D structure. Integrins regulate the activity of particular protein kinases, including focal adhesion kinase and integrin\u2010linked kinase. Cellular activation regulates integrin ligand affinity via inside\u2010out signalling and ligand binding to integrins can regulate cellular activity via outsidein signalling.Integrins are heterodimeric entities, composed of \u03b1 and \u03b2 subunits, each 1TM proteins, which bind components of the extracellular matrix or counter\u2010receptors expressed on other cells. One class of integrin contains an inserted domain (I) in its \u03b1 subunit, and if present , this I domain contains the ligand binding site. All \u03b2 subunits possess a similar I\u2010like domain, which has the capacity to bind ligand, often recognising the RGD motif. The presence of an a subunit I domain precludes ligand binding through the \u03b2 subunit. Integrins provide a link between ligand and the actin cytoskeleton . Integrins bind several divalent cations, including a Mghttp://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6584 (\u03b1IIb\u03b23) for short term prevention of coronary thrombosis, (2) http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7437 (\u03b14\u03b27) to reduce gastrointestinal inflammation, and (3) http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6591 (\u03b14\u03b21) in some cases of severe multiple sclerosis.Several drugs that target integrins are in clinical use including: (1) Collagen is the most abundant protein in metazoa, rich in glycine and proline residues, made up of cross\u2010linked triple helical structures, generated primarily by fibroblasts. Extensive post\u2010translational processing is conducted by prolyl and lysyl hydroxylases, as well as transglutaminases. Over 40 genes for collagen\u2010\u03b1 subunits have been identified in the human genome. The collagen\u2010binding integrins \u03b11\u03b21, \u03b12\u03b21, \u03b110\u03b21 and \u03b111\u03b21 recognise a range of triple\u2010helical peptide motifs including GFOGER (O = hydroxyproline), a synthetic peptide derived from the primary sequence of collagen I ) and collagen II ).Laminin is an extracellular glycoprotein composed of \u03b1, \u03b2 and \u03b3 chains, for which five, four and three genes, respectively, are identified in the human genome. It binds to \u03b11\u03b21, \u03b12\u03b21, \u03b13,\u03b21, \u03b17\u03b21 and \u03b16\u03b24 integrins10.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6749 is a glycosylated hexamer composed of two \u03b1 , two \u03b2 and two \u03b3 subunits, linked by disulphide bridges. It is found in plasma and alpha granules of platelets. It forms cross\u2010links between activated platelets mediating aggregation by binding \u03b1IIb\u03b23; proteolysis by thrombin cleaves short peptides termed fibrinopeptides to generate fibrin, which polymerises as part of the blood coagulation cascade.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6754 is a disulphide\u2010linked homodimer found as two major forms; a soluble dimeric form found in the plasma and a tissue version that is polymeric, which is secreted into the extracellular matrix by fibroblasts. Splice variation of the gene product generates multiple isoforms.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6746 is a serum glycoprotein and extracellular matrix protein which is found either as a monomer or, following proteolysis, a disulphide \u2010linked dimer.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6753 forms an integral part of the mineralized matrix in bone, where it undergoes extensive posttranslation processing, including proteolysis and phosphorylation.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6755 is a glycoprotein synthesised in vascular endothelial cells as a disulphide\u2010linked homodimer, but multimerises further in plasma and is deposited on vessel wall collagen as a high molecular weight multimer. It is responsible for capturing platelets under arterial shear flow (via GPIb) and in thrombus propagation (via integrin \u03b1IIb\u03b23).Platelets28: 40\u201042 https://www.ncbi.nlm.nih.gov/pubmed/27715379?dopt=AbstractPlusClemetson KJ. (2017) The origins of major platelet receptor nomenclature. et al. (2000) Structural basis of collagen recognition by integrin alpha2beta1. Cell101: 47\u201056 https://www.ncbi.nlm.nih.gov/pubmed/10778855?dopt=AbstractPlusEmsley J et al. (2016) The complexity of integrins in cancer and new scopes for therapeutic targeting. Br. J. Cancer115: 1017\u20101023 https://www.ncbi.nlm.nih.gov/pubmed/27685444?dopt=AbstractPlusHamidi H et al. (2016) The integrin adhesome network at a glance. J. Cell. Sci. 129: 4159\u20104163 https://www.ncbi.nlm.nih.gov/pubmed/27799358?dopt=AbstractPlusHorton ER et al. (2016) Integrin\u2010based therapeutics: biological basis, clinical use and new drugs. Nat Rev Drug Discov15: 173\u201083 https://www.ncbi.nlm.nih.gov/pubmed/26822833?dopt=AbstractPlusLey K et al. (2017) A proteomics view on integrin\u2010mediated adhesions. Proteomics17: https://www.ncbi.nlm.nih.gov/pubmed/27723259?dopt=AbstractPlusManninen A et al. (2017) Integrins as Therapeutic Targets: Successes and Cancers. Cancers (Basel)9: https://www.ncbi.nlm.nih.gov/pubmed/28832494?dopt=AbstractPlusRaab\u2010Westphal S http://www.ncbi.nlm.nih.gov/pubmed/20303872?dopt=AbstractPlus]) participate in the innate immune response to microbial agents, the stimulation of which leads to activation of intracellular enzymes and regulation of gene transcription. PRRs express multiple leucine\u2010rich regions to bind a range of microbially\u2010derived ligands, termed PAMPs or pathogen\u2010associated molecular patterns or endogenous ligands, termed DAMPS or damage\u2010associated molecular patterns. These include peptides, carbohydrates, peptidoglycans, lipoproteins, lipopolysaccharides, and nucleic acids. PRRs include both cell\u2010surface and intracellular proteins. PRRs may be divided into signalling\u2010associated members, identified here, and endocytic members, the function of which appears to be to recognise particular microbial motifs for subsequent cell attachment, internalisation and destruction. Some are involved in inflammasome formation, and modulation of IL\u20101\u03b2 cleavage and secretion, and others in the initiation of the type I interferon response.Pattern Recognition Receptors Toll\u2010like receptors (TLRs)Nucleotide\u2010binding oligomerization domain, leucine\u2010rich repeat containing receptors \u2010like receptors)RIG\u2010I\u2010like receptors (RLRs)http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1620 and http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=1621Non\u2010catalytic PRRshttp://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=942 (ALRs)http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=945http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=929http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2843 (RAGE)http://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlus]) share significant homology with the interleukin\u20101 receptor family and appear to require dimerization either as homo\u2010 or heterodimers for functional activity. Heterodimerization appears to influence the potency of ligand binding substantially . TLR1, TLR2, TLR4, TLR5, TLR6 and TLR11 are cell\u2010surface proteins, while other members are associated with intracellular organelles, signalling through the MyD88\u2010dependent pathways (with the exception of TLR3). As well as responding to exogenous infectious agents, it has been suggested that selected members of the family may be activated by endogenous ligands, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4953 [http://www.ncbi.nlm.nih.gov/pubmed/10623794?dopt=AbstractPlus].Members of the toll\u2010like family of receptors Toll and Toll\u2010like receptor signalling in development. Development145: https://www.ncbi.nlm.nih.gov/pubmed/29695493?dopt=AbstractPlusAnthoney N et al. (2015) International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. Pharmacol. Rev. 67: 462\u2010504 https://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlusBryant CE et al. (2017) Innate Immune Receptors as Competitive Determinants of Cell Fate. Mol. Cell66: 750\u2010760 https://www.ncbi.nlm.nih.gov/pubmed/28622520?dopt=AbstractPlusFranz KM et al. (2016) Toll\u2010like receptors and chronic inflammation in rheumatic diseases: new developments. Nat Rev Rheumatol12: 344\u201057 https://www.ncbi.nlm.nih.gov/pubmed/27170508?dopt=AbstractPlusJoosten LA et al. (2018) Targeting toll\u2010like receptor 4 signalling pathways: can therapeutics pay the toll for hypertension? Br. J. Pharmacol. https://www.ncbi.nlm.nih.gov/pubmed/29981161?dopt=AbstractPlusNunes KP et al. (2017) Toward a structural understanding of nucleic acid\u2010sensing Toll\u2010like receptors in the innate immune system. FEBS Lett. 591: 3167\u20103181 https://www.ncbi.nlm.nih.gov/pubmed/28686285?dopt=AbstractPlusZhang Z http://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlus]) share a common domain organisation. This consists of an N\u2010terminal effector domain, a central nucleotidebinding and oligomerization domain , and C\u2010terminal leucine\u2010rich repeats (LRR) which have regulatory and ligand recognition functions. The type of effector domain has resulted in the division of NLR family members into two major sub\u2010families, NLRC and NLRP, along with three smaller sub\u2010families NLRA, NLRB and NLRX [http://www.ncbi.nlm.nih.gov/pubmed/18341998?dopt=AbstractPlus]. NLRC members express an N\u2010terminal caspase recruitment domain (CARD) and NLRP members an N\u2010terminal Pyrin domain (PYD).The nucleotide\u2010binding oligomerization domain, leucine\u2010rich repeat (NLR) family of receptors leading to signalling through NF\u03baB and MAP kinase. Activation of NLRC4 (previously known as IPAF) and members of the NLRP3 family, including NLRP1 and NLRP3, leads to formation of a large multiprotein complex known as the inflammasome. In addition to NLR proteins other key members of the inflammasome include the adaptor protein ASC and inflammatory caspases. The inflammasome activates the pro\u2010inflammatory cytokines http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4974 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4983 Upon activation the NLRC family members NOD1 (NLRC1) and NOD2 (NLRC2) recruit a serine/threonine kinase http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4731 [http://www.ncbi.nlm.nih.gov/pubmed/16407889?dopt=AbstractPlus], http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4719, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4954 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4865 [http://www.ncbi.nlm.nih.gov/pubmed/20303873?dopt=AbstractPlus].NLRP3 has also been reported to respond to hostderived products, known as danger\u2010associated molecular patterns, or DAMPs, including Loss\u2010of\u2010function mutations of NLRP3 are associated with cold autoinflammatory and Muckle\u2010Wells syndromes.http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2793 which can be found in the \u2018Inhibitors of apoptosis (IAP) protein family\u2019 in the http://www.guidetopharmacology.org/GRAC/ReceptorFamiliesForward?type=OTHER section of the Guide.This family also includes et al. (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16: 407\u201020 https://www.ncbi.nlm.nih.gov/pubmed/27291964?dopt=AbstractPlusBroz P et al. (2015) International Union of Basic and Clinical Pharmacology. XCVI. Pattern recognition receptors in health and disease. Pharmacol. Rev. 67: 462\u2010504 https://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlusBryant CE et al. (2017) NOD1 and NOD2: Beyond Peptidoglycan Sensing. Trends Immunol. 38: 758\u2010767 https://www.ncbi.nlm.nih.gov/pubmed/28823510?dopt=AbstractPlusKeestra\u2010Gounder AM et al. (2017) Epithelial Cell Inflammasomes in Intestinal Immunity and Inflammation. Front Immunol8: 1168 https://www.ncbi.nlm.nih.gov/pubmed/28979266?dopt=AbstractPlusLei\u2010Leston AC Nat Rev Gastroenterol Hepatol15: 721\u2010737 https://www.ncbi.nlm.nih.gov/pubmed/30185915?dopt=AbstractPlusMan SM. (2018) Inflammasomes in the gastrointestinal tract: infection, cancer and gut microbiota homeostasis. et al. (2018) NOD1 and NOD2 in inflammation, immunity and disease. Arch. Biochem. Biophys. https://www.ncbi.nlm.nih.gov/pubmed/30578751?dopt=AbstractPlusMukherjee T et al. (2017) Synthetic agonists of NOD\u2010like, RIG\u2010I\u2010like, and C\u2010type lectin receptors for probing the inflammatory immune response. Future Med Chem9: 1345\u20101360 https://www.ncbi.nlm.nih.gov/pubmed/28776416?dopt=AbstractPlusNielsen AE http://www.ncbi.nlm.nih.gov/pubmed/25081315?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25829385?dopt=AbstractPlus]. They function as RNA helicases (EC 3.6.4.13) using the energy from ATP hydrolysis to unwind RNA.There are three human RIG\u2010I\u2010like receptors (RLRs) which are cytoplasmic pattern recognition receptors (PRRs) of the innate immune system. They detect non\u2010self cytosolic double\u2010stranded RNA species and and 5\u2032\u2010triphosphate single\u2010stranded RNA from various sources and are essential for inducing production of type I interferons, such as IFN\u03b2, type III interferons, and other anti\u2010pathogenic effectors .Transmembrane guanylyl cyclases are homodimeric receptors activated by a diverse range of endogenous ligands. GC\u2010A, GC\u2010B and GC\u2010C are expressed predominantly in the cardiovascular system, skeletal system and intestinal epithelium, respectively. GC\u2010D and GC\u2010G are found in the olfactory neuropepithelium and Gr\u00fceneberg ganglion of rodents, respectively. GC\u2010E and GC\u2010F are expressed in retinal photoreceptors. Family members have conserved ligand\u2010binding, catalytic (guanylyl cyclase) and regulatory domains with the exception of NPR\u2010C which has an extracellular binding domain homologous to that of other NPRs, but with a truncated intracellular domain which appears to couple, Aureobasidium species, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4952, acts as an antagonist at both GC\u2010A and GC\u2010B receptor s [http://www.ncbi.nlm.nih.gov/pubmed/1674870?dopt=AbstractPlus]. GC\u2010D and GC\u2010G have been reported to be activated intracellularly by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9164 and guanylyl cyclaseactivating protein . GC\u2010D and GC\u2010G may be activated by atmospheric levels of CO2 through the formation of intracellular bicarbonate ions . GC\u2010G may be activated at cooler temperatures (20\u201025\u00b0C) through apparent stabilisation of the dimer [http://www.ncbi.nlm.nih.gov/pubmed/25452496?dopt=AbstractPlus].The polysaccharide obtained from fermentation of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2509)\u2010sensitive (soluble) guanylyl cyclase (GTP diphosphate\u2010lyase (cyclising)), http://www.genome.jp/kegg\u2010bin/search_brite?option=\u2010a&search_string=4.6.1.2, is a heterodimer comprising a \u03b21 subunit and one of two alpha subunits giving rise to two functionally indistinguishable isoforms, GC\u20101 (\u03b11\u03b21) and GC\u20102 (\u03b12\u03b21) . A haem group is associated with the \u03b2 subunit and is the target for the endogenous ligand http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2509, and, potentially, carbon monoxide [http://www.ncbi.nlm.nih.gov/pubmed/9003762?dopt=AbstractPlus].Nitric oxide Molecular Physiology of Membrane Guanylyl Cyclase Receptors. et al. (2015) Extending the translational potential of targeting NO/cGMP\u2010regulated pathways in the CVS. Br. J. Pharmacol. 172: 1397\u2013414 https://www.ncbi.nlm.nih.gov/pubmed/25302549?dopt=AbstractPlusPapapetropoulos A et al. (2017) The multifaceted role of natriuretic peptides in metabolic syndrome. Biomed. Pharmacother. 92: 826\u2013835 https://www.ncbi.nlm.nih.gov/pubmed/28599248?dopt=AbstractPlusSanthekadur PK et al. (2016) Thirty Years of Saying NO: Sources, Fate, Actions, and Misfortunes of the Endothelium\u2010Derived Vasodilator Mediator. Circ. Res. 119: 375\u201096 https://www.ncbi.nlm.nih.gov/pubmed/27390338?dopt=AbstractPlusVanhoutte PM et al. (2016) The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment. Clin. Sci. 130: 57\u201377 https://www.ncbi.nlm.nih.gov/pubmed/26637405?dopt=AbstractPlusVolpe M et al. (2018) Guanylate cyclase\u2010C as a therapeutic target in gastrointestinal disorders. Gut67: 1543\u20131552 https://www.ncbi.nlm.nih.gov/pubmed/29563144?dopt=AbstractPlusWaldman SA http://www.ncbi.nlm.nih.gov/pubmed/11357143?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/17575237?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/2158859?dopt=AbstractPlus]. In the human genome, 58 RTKs have been identified, which fall into 20 families [http://www.ncbi.nlm.nih.gov/pubmed/20602996?dopt=AbstractPlus].Receptor tyrosine kinases (RTKs), a family of cellsurface receptors, which transduce signals to polypeptide and protein hormones, cytokines and growth factors are key regulators of critical cellular processes, such as proliferation and differentiation, cell survival and metabolism, cell migration and cell cycle control .All RTKs display an extracellular ligand binding domain, a single transmembrane helix, a cytoplasmic region containing the protein tyrosine kinase activity , with juxtamembrane and C\u2010terminal regulatory regions. Agonist binding to the extracellular domain evokes dimerization, and sometimes oligomerization, of RTKs . This leads to autophosphorylation in the tyrosine kinase domain in a trans orientation, serving as a site of assembly of protein complexes and stimulation of multiple signal transduction pathways, including RTKs are of widespread interest not only through physiological functions, but also as drug targets in many types of cancer and other disease states. Many diseases result from genetic changes or abnormalities that either alter the activity, abundance, cellular distribution and/or regulation of RTKs. Therefore, drugs thatmodify the dysregulated functions of these RTKs have been developed which fall into two categories. One group is often described as \u2018biologicals\u2019, which block the activation of RTKs directly or by chelating the cognate ligands, while the second are small molecules designed to inhibit the tyrosine kinase activity directly.http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00500000269785 are Class I receptor tyrosine kinases [http://www.ncbi.nlm.nih.gov/pubmed/12520021?dopt=AbstractPlus]. https://www.genenames.org/data/gene\u2010symbol\u2010report/#!/hgnc_id/HGNC:3430 appears to act as an essential partner for the other members of the family without itself being activated by a cognate ligand [http://www.ncbi.nlm.nih.gov/pubmed/9130710?dopt=AbstractPlus]. Ligands of the ErbB family of receptors are peptides, many of which are generated by proteolytic cleavage of cell\u2010surface proteins. HER/ErbB is the viral counterpart to the receptor tyrosine kinase EGFR. All family members heterodimerize with each other to activate downstream signalling pathways and are aberrantly expressed inmany cancers, particularly forms of breast cancer and lung cancer. Mutations in the EGFR are responsible for acquired resistance to tyrosine kinase inhibitor chemotherapeutics.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4848 has been used to label the ErbB1 EGF receptor. The extracellular domain of ErbB2 can be targetted by the antibodies http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5082 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5046 to inhibit ErbB family action. The intracellular ATP\u2010binding site of the tyrosine kinase domain can be inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4947 , http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4941, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4920 and tyrphostins http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4863 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4862.et al. (2016) Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy. Cancer Sci. 107: 1179\u201086 https://www.ncbi.nlm.nih.gov/pubmed/27323238?dopt=AbstractPlusKobayashi Y http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5012 and the related insulin\u2010like growth factors (IGF) activate Class II receptor tyrosine kinases [http://www.ncbi.nlm.nih.gov/pubmed/12520021?dopt=AbstractPlus], to evoke cellular responses, mediated through multiple intracellular adaptor proteins. Exceptionally amongst the catalytic receptors, the functional receptor in the insulin receptor family is derived from a single gene product, cleaved post\u2010translationally into two peptides, which then cross\u2010link via disulphide bridges to form a heterotetramer. Intriguingly, the endogenous peptide ligands are formed in a parallel fashion with post\u2010translational processing producing a heterodimer linked by disulphide bridges. Signalling through the receptors is mediated through a rapid autophosphorylation event at intracellular tyrosine residues, followed by recruitment of multiple adaptor proteins, notably https://www.genenames.org/data/gene\u2010symbol\u2010report/#!/hgnc_id/HGNC:6125 (http://www.uniprot.org/uniprot/P35568), https://www.genenames.org/data/gene\u2010symbol\u2010report/#!/hgnc_id/HGNC:6126 (http://www.uniprot.org/uniprot/Q9Y4H2), https://www.genenames.org/data/gene\u2010symbol\u2010report/#!/hgnc_id/HGNC:10840 (http://www.uniprot.org/uniprot/P29353), https://www.genenames.org/data/gene\u2010symbol\u2010report/#!/hgnc_id/HGNC:4566 (http://www.uniprot.org/uniprot/P62993) and https://www.genenames.org/data/gene\u2010symbol\u2010report/#!/hgnc_id/HGNC:11187 (http://www.uniprot.org/uniprot/Q07889).The circulating peptide hormones http://www.uniprot.org/uniprot/P08833, http://www.uniprot.org/uniprot/P18065, http://www.uniprot.org/uniprot/P17936, http://www.uniprot.org/uniprot/P22692, http://www.uniprot.org/uniprot/P24593), which sequester the IGFs; overexpression of IGFBPs may induce apoptosis, while IGFBP levels are also altered in some cancers.Serum levels of free IGFs are kept low by the action of IGF binding proteins , which lacks classical signalling capacity and appears to subserve a trafficking role [http://www.ncbi.nlm.nih.gov/pubmed/2964083?dopt=AbstractPlus]. INSRR, which has a much more discrete localization, being predominant in the kidney [http://www.ncbi.nlm.nih.gov/pubmed/1530648?dopt=AbstractPlus], currently lacks a cognate ligand or evidence for functional impact. Antibodies targetting IGF1, IGF2 and the extracellular portion of the IGF1 receptor are in clinical trials.There is evidence for low potency binding and activation of insulin receptors by IGF1. IGF2 also binds and activates the cation\u2010independent mannose 6\u2010phosphate receptor combine as homo\u2010 or heterodimers to activate homo\u2010 or heterodimeric PDGF receptors. SCF is a dimeric ligand for KIT. Ligands for CSF1R are either monomeric or dimeric glycoproteins, while the endogenous agonist for FLT3 is a homodimer.Type III RTKs include PDGFR, CSF\u20101R (Ems), Kit and FLT3, which function as homo\u2010 or heterodimers. Endogenous ligands of PDGF receptors are homo\u2010 or heterodimeric: PDGFA, PDGFB, VEGFE and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5687 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5697 ; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5702 and AC220 , as well as pan\u2010type III RTK inhibitors such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5713 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5711 [http://www.ncbi.nlm.nih.gov/pubmed/15606337?dopt=AbstractPlus]; 5\u2032\u2010fluoroindirubinoxime has been described as a selective FLT3 inhibitor [2].Various small molecular inhibitors of type III RTKs have been described, including http://www.ensembl.org/Homo_sapiens/Gene/Family/Genes?family=ENSFM00440000236870 are homo\u2010 and heterodimeric proteins, which are characterized by seven Ig\u2010like loops in their extracellular domains and a split kinase domain in the cytoplasmic region. They are key regulators of angiogenesis and lymphangiogenesis; as such, they have been the focus of drug discovery for conditions such as metastatic cancer. Splice variants of VEGFR1 and VEGFR2 generate truncated proteins limited to the extracellular domains, capable of homodimerisation and binding VEGF ligands as a soluble, non\u2010signalling entity. Ligands at VEGF receptors are typically homodimeric. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5085 is able to activate VEGFR1 homodimers, VEGFR1/2 heterodimers and VEGFR2/3 heterodimers. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5086 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5314 activate VEGFR1 homodimers, while VEGFC and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5088 activate VEGFR2/3 heterodimers and VEGFR3 homodimers, and, following proteolysis, VEGFR2 homodimers.http://www.ncbi.nlm.nih.gov/pubmed/12443771?dopt=AbstractPlus], Ki8751 [http://www.ncbi.nlm.nih.gov/pubmed/15743179?dopt=AbstractPlus] and ZM323881, a novel inhibitor of vascular endothelial growth factor\u2010receptor\u20102 tyrosine kinase activity [http://www.ncbi.nlm.nih.gov/pubmed/12483548?dopt=AbstractPlus] are described as VEGFR2\u2010selective tyrosine kinase inhibitors. Bevacizumab is a monoclonal antibody directed against VEGF\u2010A, used clinically for the treatment of certain metastatic cancers; an antibody fragment has been used for wet age\u2010related macular degeneration.The VEGFR, as well as VEGF ligands, have been targeted by antibodies and tyrosine kinase inhibitors. DMH4 [http://www.ncbi.nlm.nih.gov/pubmed/21711248?dopt=AbstractPlus].Fibroblast growth factor (FGF) family receptors act as homo\u2010 and heterodimers, and are characterized by Ig\u2010like loops in the extracellular domain, in which disulphide bridges may form across protein partners to allow the formation of covalent dimers which may be constitutively active. FGF receptors have been implicated in achondroplasia, angiogenesis and numerous congenital disorders. At least 22 members of the FGF gene family have been identified in the human genome [11]. Within this group, subfamilies of FGF may be divided into canonical, intracellular and hormone\u2010like FGFs. FGF1\u2010FGF10 have been identified to act through FGF receptors, while FGF11\u201014 appear to signal through intracellular targets. Other family members are less well characterized . PD161570 is an FGFR tyrosine kinase inhibitor [http://www.ncbi.nlm.nih.gov/pubmed/9488112?dopt=AbstractPlus], while http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5037 has been described to inhibit FGFR1 and FGFR3 [http://www.ncbi.nlm.nih.gov/pubmed/10987832?dopt=AbstractPlus].Splice variation of the receptors can influence agonist responses. http://www.ncbi.nlm.nih.gov/pubmed/21132015?dopt=AbstractPlus].The PTK7 receptor is associated with polarization of epithelial cells and the development of neural structures. Sequence analysis suggests that the gene product is catalytically inactive as a protein kinase, although there is evidence for a role in Wnt signalling .http://www.ncbi.nlm.nih.gov/pubmed/20407211?dopt=AbstractPlus], while ANA12 has been described as a noncompetitive antagonist of BDNF binding to trkB [http://www.ncbi.nlm.nih.gov/pubmed/21505263?dopt=AbstractPlus]. GNF5837 is a family\u2010selective tyrosine kinase inhibitor [http://www.ncbi.nlm.nih.gov/pubmed/24900443?dopt=AbstractPlus], while the tyrosine kinase activity of the trkA receptor can be inhibited by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4946 and tyrphostin http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4863 [http://www.ncbi.nlm.nih.gov/pubmed/7683492?dopt=AbstractPlus].Small molecule agonists of trkB have been described, including LM22A4 [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3548 binding to a http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=25 thereby forming a cell\u2010surface multiprotein complex [http://www.ncbi.nlm.nih.gov/pubmed/21078818?dopt=AbstractPlus].Members of the ROR family appear to be activated by ligands complexing with other cell\u2010surface proteins. Thus, ROR1 and ROR2 appear to be activated by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5319 forms a complex with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5320 to activate MuSK [http://www.ncbi.nlm.nih.gov/pubmed/18848351?dopt=AbstractPlus].The muscle\u2010specific kinase MuSK is associated with the formation and organisation of the neuromuscular junction from the skeletal muscle side. Thus far, no selective MuSK inhibitors have been described.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5315 , a serine protease inhibitor. MST1, the ligand of RON, is two disulphide\u2010linked peptide chains generated by proteolysis of a single gene product.HGF receptors regulatematuration of the liver in the embryo, as well as having roles in the adult, for example, in the innate immune system. HGF is synthesized as a single gene product, which is post\u2010translationally processed to yield a heterodimer linked by a disulphide bridge. The maturation of HGF is enhanced by a serine protease, HGF activating complex, and inhibited by http://www.ncbi.nlm.nih.gov/pubmed/22924734?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5057 is an inhibitor of the HGF receptor [http://www.ncbi.nlm.nih.gov/pubmed/14500382?dopt=AbstractPlus], with the possibility of further targets [http://www.ncbi.nlm.nih.gov/pubmed/17595299?dopt=AbstractPlus].PF04217903 is a selective Met tyrosine kinase inhibitor .AXL tyrosine kinase inhibitors have been described .A number of tyrosine kinase inhibitors targeting RET have been described [http://www.ncbi.nlm.nih.gov/pubmed/21132015?dopt=AbstractPlus].The \u2018related to tyrosine kinase receptor\u2019 (Ryk) is structurally atypical of the family of RTKs, particularly in the activation and ATP\u2010binding domains. RYK has been suggested to lack kinase activity and appears to be involved, with FZD8, in the Wnt signalling system . Other collagen receptors include glycoprotein VI (http://www.uniprot.org/uniprot/Q9HCN6), leukocyte\u2010associated immunoglobulin\u2010like receptor 1 (http://www.uniprot.org/uniprot/Q6GTX8), leukocyte\u2010associated immunoglobulin\u2010like receptor 2 (http://www.uniprot.org/uniprot/Q6ISS4) and osteoclast\u2010associated immunoglobulin\u2010like receptor (http://www.uniprot.org/uniprot/Q8IYS5).The tyrosine kinase inhibitors of DDR, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4903 is a tyrosine kinase inhibitor, anti\u2010cancer drug targeting ALK and ROS1.http://www.ncbi.nlm.nih.gov/pubmed/9444961?dopt=AbstractPlus], giving rise to the name AATYK (Apoptosis\u2010associated tyrosine kinase); while over\u2010expression induces differentiation in neuroblastoma cells [http://www.ncbi.nlm.nih.gov/pubmed/10837911?dopt=AbstractPlus].The LMR kinases are unusual amongst the RTKs in possessing a short extracellular domain and extended intracellular domain (hence the \u2018Lemur\u2019 name reflecting the long tail). A precise function for these receptors has yet to be defined, although LMR1 was identified as a potential marker of apoptosis [As yet no selective inhibitors of the LMR family have been described.http://www.ncbi.nlm.nih.gov/pubmed/23742252?dopt=AbstractPlus].The LTK family appear to lack endogenous ligands. LTK is subject to tissue\u2010specific splice variation, which appears to generate products in distinct subcellular locations. ALK fusions created by gene translocations and rearrangements are associated with many types of cancer, including large cell lymphomas, inflammatory myofibrilastic tumours and non\u2010small cell lung cancer .Similar to the LMR RTK family, STYK1 has a truncated extracellular domain, but also displays a relatively short intracellular tail beyond the split kinase domain. STYK1 Spatial and Temporal Regulation of Receptor Tyrosine Kinase Activation and Intracellular Signal Transduction. Annu. Rev. Biochem. 85: 573\u201397 https://www.ncbi.nlm.nih.gov/pubmed/27023845?dopt=AbstractPlusBergeron JJ et al. (2016) Immunotherapy of cancer: from monoclonal to oligoclonal cocktails of anti\u2010cancer antibodies: IUPHAR Review 18. Br. J. Pharmacol. 173: 1407\u201324 https://www.ncbi.nlm.nih.gov/pubmed/26833433?dopt=AbstractPlusCarvalho S et al. (2017) Targeting the hepatocyte growth factor/Met pathway in cancer. Biochem. Soc. Trans. 45: 855\u2013870 https://www.ncbi.nlm.nih.gov/pubmed/28673936?dopt=AbstractPlusDe Silva DM et al. (2017) Angiopoietin\u2010Tie signalling in the cardiovascular and lymphatic systems. Clin. Sci. 131: 87\u2013103 https://www.ncbi.nlm.nih.gov/pubmed/27941161?dopt=AbstractPlusEklund L Pharmacol. Ther. 177: 1\u20138 https://www.ncbi.nlm.nih.gov/pubmed/28185914?dopt=AbstractPlusKatayama R. (2017) Therapeutic strategies and mechanisms of drug resistance in anaplastic lymphoma kinase (ALK)\u2010rearranged lung cancer. Gene614: 1\u20137 https://www.ncbi.nlm.nih.gov/pubmed/28267575?dopt=AbstractPlusKazlauskas A. (2017) PDGFs and their receptors. et al. (2016) EGFR as a Pharmacological Target in EGFR\u2010Mutant Non\u2010Small\u2010Cell Lung Cancer: Where Do We Stand Now? Trends Pharmacol. Sci. 37: 887\u2013903 https://www.ncbi.nlm.nih.gov/pubmed/27717507?dopt=AbstractPlusKe EE et al. (2016) Overcoming drug resistance to receptor tyrosine kinase inhibitors: Learning from lung cancer. Pharmacol. Ther. 161: 97\u2013110 https://www.ncbi.nlm.nih.gov/pubmed/27000770?dopt=AbstractPlusKuwano M Pharmacol. Ther. 174: 1\u201321 https://www.ncbi.nlm.nih.gov/pubmed/28167215?dopt=AbstractPlusLee DH. (2017) Treatments for EGFR\u2010mutant non\u2010small cell lung cancer (NSCLC): The road to a success, paved with failures. et al. (2017) Receptor Tyrosine Kinases: Translocation Partners in Hematopoietic Disorders. Trends Mol Med23: 59\u201379 https://www.ncbi.nlm.nih.gov/pubmed/27988109?dopt=AbstractPlusNelson KN et al. (2016) Mechanisms and regulation of endothelial VEGF receptor signalling. Nat. Rev. Mol. Cell Biol. 17: 611\u201325 https://www.ncbi.nlm.nih.gov/pubmed/27461391?dopt=AbstractPlusSimons M et al. (2017) ROR\u2010Family Receptor Tyrosine Kinases. Curr. Top. Dev. Biol. 123: 105\u2013142 https://www.ncbi.nlm.nih.gov/pubmed/28236965?dopt=AbstractPlusStricker S et al. (2017) Exploiting receptor tyrosine kinase co\u2010activation for cancer therapy. Drug Discov. Today22: 72\u201384 https://www.ncbi.nlm.nih.gov/pubmed/27452454?dopt=AbstractPlusTan AC et al. (2017) VEGF Receptor Tyrosine Kinases: Key Regulators of Vascular Function. Curr. Top. Dev. Biol. 123: 433\u2013482 https://www.ncbi.nlm.nih.gov/pubmed/28236974?dopt=AbstractPlus\u00c1lvarez\u2010Aznar A http://www.genome.jp/kegg\u2010bin/search_brite?option=\u2010a&search_string=2.7.11.30, respond to particular cytokines, the transforming growth factor \u03b2 (TGF\u03b2) and bone morphogenetic protein (BMP) families, and may be divided into two subfamilies on the basis of structural similarities. Agonist binding initiates formation of a cell\u2010surface complex of type I and type II RSTK, possibly heterotetrameric, where where both subunits express serine/threonine kinase activity. The type I receptor serine/threonine kinases are also known as activin receptors or activin receptor\u2010like kinases, ALKs, for which a systematic nomenclature has been proposed (ALK1\u20107). The type II protein phosphorylates the kinase domain of the type I partner , causing displacement of the protein partners, such as the FKBP12 FK506\u2010binding protein https://www.genenames.org/data/gene\u2010symbol\u2010report/#!/hgnc_id/HGNC:3711 (http://www.uniprot.org/uniprot/P62942) and allowing the binding and phosphorylation of particular members of the Smad family. These migrate to the nucleus and act as complexes to regulate gene transcription. Type III receptors, sometimes called co\u2010receptors or accessory proteins, regulate the signalling of the receptor complex, in either enhancing or inhibitory manners. TGF\u03b2 family ligand signalling may be inhibited by endogenous proteins, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4933 , which binds and neutralizes activins to prevent activation of the target receptors.Receptor serine/threonine kinases (RTSK), http://www.ncbi.nlm.nih.gov/pubmed/18692464?dopt=AbstractPlus]. Some are known to form disulphide\u2010linked homo\u2010 and/or heterodimeric complexes. Thus, inhibins are \u03b1 subunits linked to a variety of \u03b2 chains, while activins are combinations of \u03b2 subunits.Endogenous agonists, approximately 30 in man, are often described as paracrine messengers acting close to the source of production. They are characterized by six conserved cysteine residues and are divided into two subfamilies on the basis of sequence comparison and signalling pathways activated, the TGF\u03b2/activin/nodal subfamily and the BMP/GDF (growth/differentiation factor)/MIS (M\u00fcllerian inhibiting substance) subfamily. Ligands active at RSTKs appear to be generated as large precursors which undergo complexmaturation processes . The authors confirmed the selectivity of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6049 to inhibit TGF\u03b2 signalling through ALK4, ALK5, ALK7 [http://www.ncbi.nlm.nih.gov/pubmed/14978253?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4907 inhibits BMP signalling through ALK2 and ALK3, it also inhibits AMP kinase [http://www.ncbi.nlm.nih.gov/pubmed/11602624?dopt=AbstractPlus].An appraisal of small molecule inhibitors of TGF\u03b2 and BMP signalling concluded that TGF\u03b2 pathway inhibitors were more selective than BMP signalling inhibitors Budi EH et al. (2016) Immunoregulation by members of the TGF\u03b2 superfamily. Nat. Rev. Immunol. 16: 723\u2010740 [https://www.ncbi.nlm.nih.gov/pubmed/27885276?dopt=AbstractPlus]Chen W et al. (2016) Molecular switches under TGF\u03b2 signalling during progression from cardiac hypertrophy to heart failure. Br. J. Pharmacol. 173: 3\u201014 [https://www.ncbi.nlm.nih.gov/pubmed/26431212?dopt=AbstractPlus]Heger J et al. (2015) Regulators and effectors of bone morphogenetic protein signalling in the cardiovascular system. J. Physiol. (Lond.)593: 2995\u20103011 [https://www.ncbi.nlm.nih.gov/pubmed/25952563?dopt=AbstractPlus]Luo JY et al. (2015) Structural determinants of Smad function in TGF\u2010\u03b2 signaling. Trends Biochem. Sci. 40: 296\u2010308 [https://www.ncbi.nlm.nih.gov/pubmed/25935112?dopt=AbstractPlus]Macias MJ et al. (2016) Targeting BMP signalling in cardiovascular disease and anaemia. Nat Rev Cardiol13: 106\u201020 [https://www.ncbi.nlm.nih.gov/pubmed/26461965?dopt=AbstractPlus]Morrell NW et al. (2015) Targeting the TGF\u03b2 pathway for cancer therapy. Pharmacol. Ther. 147: 22\u201031 [https://www.ncbi.nlm.nih.gov/pubmed/25444759?dopt=AbstractPlus]Neuzillet C Nat Rev Rheumatol13: 155\u2010163 [https://www.ncbi.nlm.nih.gov/pubmed/28148919?dopt=AbstractPlus]van der Kraan PM. (2017) The changing role of TGF\u03b2 in healthy, ageing and osteoarthritic joints. https://www.genenames.org/data/gene\u2010symbol\u2010report/#!/hgnc_id/HGNC:11283) to activate signalling cascades. Family members bind components of the extracellular matrix or cell\u2010surface proteins indicating a role in intercellular communication.Receptor tyrosine phosphatases (RTP) are cell\u2010surface proteins with a single TM region and intracellular phosphotyrosine phosphatase activity. Many family members exhibit constitutive activity in heterologous expression, dephosphorylating intracellular targets such as Src tyrosine kinase Pleiotrophin and its receptor protein tyrosine phosphatase beta/zeta as regulators of angiogenesis and cancer. Biochim. Biophys. Acta1866: 252\u2010265 [https://www.ncbi.nlm.nih.gov/pubmed/27693125?dopt=AbstractPlus]Papadimitriou E et al. (2017) Targeting Tyrosine Phosphatases: Time to End the Stigma. Trends Pharmacol. Sci. 38: 524\u2010540 [https://www.ncbi.nlm.nih.gov/pubmed/28412041?dopt=AbstractPlus]Stanford SM http://www.ncbi.nlm.nih.gov/pubmed/23840967?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26008591?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/25169849?dopt=AbstractPlus].Dysregulated TNFR signalling is associated with many inflammatory disorders, including some forms of arthritis and inflammatory bowel disease, and targeting TNF has been an effective therapeutic strategy in these diseases and for cancer immunotherapy Kalliolias GD et al. (2016) Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases. Pharmacol. Ther. 159: 110\u20109 https://www.ncbi.nlm.nih.gov/pubmed/26808166?dopt=AbstractPlusOlesen CM et al. (2017) Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nat. Rev. Cancer17: 352\u2010366 https://www.ncbi.nlm.nih.gov/pubmed/28536452?dopt=AbstractPlusvon Karstedt S"} +{"text": "Bioinformatics, (2018) https://doi.org/10.1093/bioinformatics/bty357The author wishes to apologize for a mistake in The paper has been corrected online."} +{"text": "This article has been corrected: Due to errors during image assembly, the western blotting results of b-tubulin for Bax and Bak in PEO1 cells, shown in Figure 2A, were accidental duplicate images. The corrected Figure 2A is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.1354-1368. https://doi.org/10.18632/oncotarget.13817Original article: Oncotarget. 2017; 8:1354\u20131368."} +{"text": "Correction to: Cell Death and Disease10.1038/cddis.2017.215 published online 01 June 2017Following the publication of this article, the authors noticed that Fig."} +{"text": "This article has been corrected: Due to errors in figure preparation, panels A and B of Figure 4 were accidentally duplicated. The corrected Figure 4 is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.76108-76115. https://doi.org/10.18632/oncotarget.18551Original article: Oncotarget. 2017; 8:76108\u201376115."} +{"text": "This article has been corrected: During processing of the data, the image sets of cells in Fig.1B were mistakenly combined. The correct Figure 1B is shown below. The authors declare that this correction does not change the results or conclusions of this paper.39184-39195. https://doi.org/10.18632/oncotarget.5508Original article: 2015; 6:39184\u201339195."} +{"text": "There is a mistake in the second author\u2019s name. The correct name is: Mansi. The correct citation is:https://doi.org/10.1371/journal.ppat.1006587Kushwaha NK, Mansi, Chakraborty S (2017) The replication initiator protein of a geminivirus interacts with host monoubiquitination machinery and stimulates transcription of the viral genome. PLoS Pathog 13(8): e1006587."} +{"text": "This article has been corrected: Due to errors in image processing, Figure 2C contains an image from the wrong cell line (GBC-SD cells). The corrected Figure 2C is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.47052-47063. https://doi.org/10.18632/oncotarget.16789Original article: Oncotarget. 2017; 8:47052\u201347063."} +{"text": "Gastroenterology Report, 2016, 4(2): 165\u2013167. https://doi.org/10.1093/gastro/gou081.The author of the above paper wishes to notify the reader that in the original article Figure 3 appeared incorrectly. The Figure appears correctly below. None of the findings or conclusions were affected by this error. The paper has been corrected online."} +{"text": "Bio\u2010based plastics derive from non\u2010petroleum biological resources. Biodegradable plastics degrade via exposure to naturally occurring microbes and may be bio\u2010based or made from petroleum.https://www.plasticseurope.org/en/about-plastics/what-are-plastics/large-family/bio-based-plasticsThis review article discussed starch blends, poly\u2010lactic acid, bio\u2010polyethylene terephthalate, bio\u2010polyethylene and polymers from bio\u2010based succinic acid.https://en.wikipedia.org/wiki/BioplasticThis Wikipedia entry provides a fairly comprehensive overview of bio\u2010based plastics.https://ensia.com/features/bioplastics-bio-based-biodegradable-environment/This article provides a good overview of the source and production of bioplastics, and it also considers marketability of these materials.https://www.organixsolutions.com/compostable-bioplasticsThis post describes both bio\u2010based and compostable (biodegradable) polymers. For example, the carbon in bio\u2010based plastics such as poly\u2010lactic acid is typically derived from corn starch. There are examples of petroleum based polymers that are biodegradable.https://www.plasticstoday.com/sustainability/study-asks-why-switch-biobased-plastics-taking-so-long/73993200161277One highlight of this article is reference to a new market study on bio\u2010based polymers. Fundamentally, bio\u2010based polymers have not seen very widespread use due to cost and lack of manufacturing scale.https://greenliving.lovetoknow.com/Type_of_Biodegradable_PlasticThis popular press type article gives an excellent description of a range of biodegradable polymers.https://www.cell.com/trends/biotechnology/fulltext/S0167-7799(19)30089-7This review article describes multiple bio\u2010based polymers and the role of microbial cells and enzymes in the production and recycling of polymers.https://www.labiotech.eu/features/bioplastics-2019-feature/This article focuses on the total market for plastics, and the increment of bioplastics, both currently and in projected years.https://onlinelibrary.wiley.com/doi/abs/10.1002/pen.25083This paper describes a method for extrusion or spray coating of natural and synthetic insect repellents into poly\u2010lactic acid fibres.https://www.energy.gov/eere/amo/plastics-or-fibers-bio-based-polymersThis page focuses on the energy and carbon emissions savings that can be attributed to the use of bio\u2010based polymers such as polylactic acid.https://www.usda.gov/media/blog/2018/09/19/new-industrial-revolution-plasticsThis optimistic article discussed the potential for increases in bio\u2010based plastics. It posits that the global bioplastic packaging market is anticipated to grow at a rate of 18% between 2017\u20102025.https://www.mdpi.com/journal/molecules/special_issues/Biodegradable_PolymersMolecules, focused entirely on different aspects of \u2018Advances in Biodegradable Polymers\u2019.This link is to a special issue of the journal https://www.frontiersin.org/articles/10.3389/fmats.2019.00151/fullThis article specifically focuses on the use of biodegradable polymers for applications in conservation of cultural heritage materials.https://www.degruyter.com/view/j/epoly.2019.19.issue-1/epoly-2019-0041/epoly-2019-0041.xmlBiodegradable polymers have important applications for controlled delivery of drugs, or in sutures where only limited material lifetime is desirable.https://pubs.acs.org/doi/10.1021/acs.macromol.9b00430Cyclopropenium\u2010based biodegradable polymers are useful cationic polymers that traditionally have not been viewed as biodegradable. The current report describes the synthesis of biodegradable members of this class.http://www.imedpub.com/scholarly/biodegradable-polymers-journals-articles-ppts-list.phpThis webpage provides a compendium of recent journal articles related to biodegradable polymers.https://csp.umn.eduThe Center for Sustainable Polymers is funded by the United States National Science Foundation and is committed to research, education and public outreach related to the sustainable production and use of polymeric materials."} +{"text": "In this paper, we establish two Lyapunov inequalities for some half-linear higher order differential equations with anti-periodic boundary conditions. Our result improves that obtained by Wang (Appl. Math. Lett. 25:2375\u20132380,"} +{"text": "This article has been corrected: Due to errors in figure preparation, the image of 22Rv1 displayed in Figure 1B is incorrect. The corrected figure is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.1341-1353. https://doi.org/10.18632/oncotarget.6372Original article: Oncotarget. 2016; 7:1341\u20131353."} +{"text": "The first and fourth authors\u2019 names are published incorrectly in the article XML. The correct name for the first author is Anne Ahrendt Bjerregaard. The correct indexing in PubMed should read Bjerregaard AA. The correct name for the fourth author is Sjurdur Frodi Olsen. The correct indexing in PubMed should read Olsen SF.https://doi.org/10.1371/journal.pmed.1002911The correct citation, therefore, should read: Bjerregaard AA, Halldorsson TI, Tetens I, Olsen SF (2019) Mother\u2019s dietary quality during pregnancy and offspring\u2019s dietary quality in adolescence: Follow-up from a national birth cohort study of 19,582 mother\u2013offspring pairs. PLoS Med 16(9): e1002911."} +{"text": "This article has been corrected: The correct Grant support information is given below:GRANT SUPPORTWe thank Tonghui Ma for his technical help and Xinyu Liu for helpful discussions. This work was supported by Science & Technology department of Shanghai (13411950901), Zhejiang Provincial Nature and Science Foundation (NSF) grant for \u201cOutstanding Youth\u201d(No.LR15H100001 to RT).https://doi.org/10.18632/oncotarget.9543Original article: Oncotarget. 2016; 7:35643-35654."} +{"text": "This article has been corrected: Due to an error during image assembly, in figure 2B the images shown for the 293T cell lines are incorrect. The proper images are shown below. The authors declare that these corrections do not change the results or conclusions of this paper.https://doi.org/10.18632/oncotarget.13656Original article: Oncotarget. 2017; 8:808\u2013818."} +{"text": "Dr Uduak Udom of Nigeria, the World Council of Optometry's immediate past president and a friend of the Community Eye Health Journal, has passed away after a long and courageous battle with illness. Read more about her remarkable career here: http://bit.ly/UduakUdomDr Frank Green (UK) is remembered for his work providing ophthalmology services to refugees in Myanmar and Thailand. He performed over 20,000 cataract operations and trained selected Karen refugees to perform cataract surgery. Read more here: http://bit.ly/DrFrankGreenThe Eye Book: an Illustrated Guide for Patients. Orbis has produced a book to support doctors, nurses and allied health personnel when they discuss eye diseases and conditions with patients, parents, family members and caregivers. Available for free download from Cybersight at https://cybersight.org/portfolio/the-eye-book-an-illustrated-guide-for-patients/www.lshtm.ac.uk/study/masters/mscphec.html or email romulo.fabunan@lsthm.ac.ukFully funded scholarships are available for Commonwealth country nationals. For more information visit training@lionsloresho.org or call/message +254 728 970 601 or +254 733 619 191.Courses begin every six weeks and cost US $1,000 for training and approximately US $1,000 for accommodation. Email The ICEH Open Education for eye care programme offers a series of online courses in key topics in public health eye care. All the courses are free to access. More free courses coming! Certification also available. For more information visit http://iceh.lshtm.ac.uk/oer/Contact Anita Shahadmin@cehjournal.orgSubscribe to our mailing listweb@cehjournal.org or visit www.cehjournal.org/subscribeVisit us onlinewww.cehjournal.orgwww.facebook.com/CEHJournalhttps://twitter.com/CEHJournal"} +{"text": "Scientific Datahttps://doi.org/10.1038/sdata.2017.139, published online 03 October 2017.Correction to: The Data Descriptor incorrectly states the formula used to calculate the Bliss additivity score in the Data analysis subsection of the Methods. The correct equation is listed below:"} +{"text": "This article has been corrected: Due to production mistake the wrong Figure 2 was posted in this paper. The authors declare that this correction does not change the results or conclusions of this paper. The correct Figure 2 is provided below.3650-3667 . https://doi.org/10.18632/aging.102004Original article: Aging. 2019; 11:3650\u20133667."} +{"text": "The prevalence of diagnosed HIV infection among Hispanics/Latinos is approximately twice that among non-Hispanic whites found that a significantly higher percentage of women (78%), compared with men (54%), were living in poverty (https://www.cdc.gov/hiv/group/racialethnic/hispaniclatinos/index.html.National Latinx AIDS Awareness Day is an opportunity to encourage increased HIV prevention activities among Hispanics/Latinos. CDC supports testing; linkage to, and engagement in, care and treatment; and other efforts to reduce the risk for acquiring or transmitting HIV infection among Hispanics/Latinos. Additional information is available at"} +{"text": "This article has been corrected: The correct Funding information is given below:FUNDINGThis work was supported by the Wellcome Trust/DBT India Alliance Fellowship [grant number IA/CPHI/14/1/501485] awarded to Dr Nikhil Patkar. Initial part of the study (8 colour FCM) was funded by a Lady Tata Memorial Trust Grant awarded to Prof Navin Khattry.https://doi.org/10.18632/oncotarget.26400Original article: Oncotarget. 2018; 9:36613-36624."} +{"text": "Correction to: Cell Death & Disease10.1038/cddis.2017.273, published online 8 June 20171], the authors became aware of an error in Fig. Following publication of this article ["} +{"text": "The registration toolkit is available at https://sites.google.com/site/myronenko/research/mirt. Image data and simulation results has been incorporated at the open repository http://simvascular.stanford.edu/downloads/public/open_data/zebrafish_PLOSCompBio_2017/The Data Availability statement for this paper is incorrect. The correct statement is: All image segmentation, cardiac model construction and finite element software is available as part of the SimVascular open source project at"} +{"text": "This article has been corrected: During manuscript editing according to the reviewers' comments, the tubulin control for cyclin D1 in Figure 4A right panel was accidentally misplaced. The corrected Figure 4A is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.2148-2163. https://doi.org/10.18632/oncotarget.13236Original article: Oncotarget. 2015; 6:2148\u20132163."} +{"text": "This article has been corrected: Due to errors in image assembly, a western blot (TSC2) in Figure 3B was accidentally duplicated. The corrected Figure 3 is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.34552-34564. https://doi.org/10.18632/oncotarget.16602Original article: Oncotarget. 2017; 8:34552\u201334564."} +{"text": "This article has been corrected: The correct Funding information is given below:FUNDINGThis meta-analysis has been financially supported by the National Natural Science Foundation of China (No. 81472682 and No. 81572538) and the Science Foundation of Tianjin (No. 16JCZDJC34400).https://doi.org/10.18632/oncotarget.21971Original article: Oncotarget. 2017; 8:102361-102370."} +{"text": "This article has been corrected: The correct figures are given below:The authors declare that these corrections do not change the results or conclusions of this paper.103710-103730. https://doi.org/10.18632/oncotarget.21780Original article: Oncotarget. 2017; 8:"} +{"text": "The correct Data Availability Statement is: Summary statistic GWAS meta-analysis results for the combined dataset excluding 23andMe are available at https://doi.org/10.17863/CAM.36024. The most significant 10,000 SNPs for the meta-analysis including 23andMe are available at https://doi.org/10.17863/CAM.36024.In the Data Availability Statement, the URL does not fully match the data described. The URL should be: There is an error in S2 Table(XLSX)Click here for additional data file."} +{"text": "The European Centre for Disease Prevention and Control (ECDC) invites applications for the following positions:Head of Disease Programme Emerging and Vector-borne DiseasesExpert Medical EntomologyExpert Infectious Diseases EpidemiologyScientific Officer Surveillancehttp://ecdc.europa.eu/en/aboutus/jobs/Pages/JobOpportunities.aspxThe deadlines for the applications vary. For more information, please visit the ECDC website:"} +{"text": "The authors would like to draw the reader's attention to an error in the following article:Respirology Case Reports, 5 (2), e00215. https://doi.org/10.1002/rcr2.215.Tomioka, H. and Takada, H. (2017) Treatment with nintedanib for acute exacerbation of idiopathic pulmonary fibrosis. Dr Hirohito Takada's last name was misspelt.The correct spelling is: Hirohito Takata.The authors apologize for this error and any confusion it may have caused."} +{"text": "Dr. Wang\u2019s email address is: wningli@163.com.The first author, Jialiang Zhao, is incorrectly noted as the corresponding author. The correct corresponding authors are Quanfu Ye and Ningli Wang. Dr. Ye's email address is:"} +{"text": "Sensors [https://www.mdpi.com/1424-8220/18/10/3562. The following corrected table should be used with incorrect references removed from original. The corrected table does not change the scientific results. The correct references are used in the original manuscript. The manuscript will be updated and the original will remain online on the article web page, with a reference to this Erratum.The authors wish to correct Sensors , doi:10."} +{"text": "This article has been corrected: The control data used in the assembly of Figure 5 was incorrect. After reviewing all of the raw data, an updated Figure 5 was created and is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.13671-13687. https://doi.org/10.18632/oncotarget.3701Original article: Oncotarget. 2015; 6:13671\u201313687."} +{"text": "Pharmaceutical Biology.Sanjib Bhattacharya (2017). Medicinal plants and natural products in amelioration of arsenic toxicity: a short review, http://dx.doi.org/10.1080/13880209.2016.1235207The above article was first published online with the below errors:The author\u2019s name should be 'Sanjib Bhattacharya' instead of 'Sanijb Bhattacharya'."} +{"text": "A growing number of beta\u2010lactone molecules are showing anticancer and antibiotic activities.http://www.secondarymetabolites.org/mining/This page contains a compilation of secondary metabolite gene mining tools with links to the original databases.http://esnapd2.rockefeller.edueSNaPD stands for environmental Survey of Natural Product Diversity which is a tool to analyse crude metagenomic samples or bacterial culture collections for natural product gene clusters.http://napdos.ucsd.eduThis is a tool for finding natural product genes, particularly those encoding C and KS domains.https://bitbucket.org/chevrm/sandpumaThis tool is focused on finding genes and proteins involved in the biosynthesis of non\u2010ribosomally synthesized peptides.https://arts3.ziemertlab.comARTS stands for Antibiotic Resistant Target Seeker. It is a tool to screen secondary metabolites gene cluster for resistance genes.https://fungiminions.shinyapps.io/FunGeneClusterS/This bioinformatics tool is focused on accurate prediction of secondary metabolite gene clusters in filamentous fungi.https://academic.oup.com/bioinformatics/article/32/8/1138/1744063This article describes a tools to search for islands of enriched cluster motifs and nearby anchor genes.https://magarveylab.ca/prism/#!/prismThis tool accepts sequences and then searches genomes for encoded natural products.http://biosyn.nih.go.jp/2ndfind/This is a web\u2010based tool for finding natural product biosynthetic gene clusters.http://www.bldb.euThe beta\u2010lactamase database compiles information on sequences and structural biological information on beta\u2010lactamases.https://card.mcmaster.caThis antibiotic resistance database has information on genes, proteins and phenotypes.http://bioinf-applied.charite.de/supernatural_new/This database is very comprehensive, containing records of more than 300,000 natural products.http://bidd2.nus.edu.sg/NPASS/This database contains information on natural products, source organisms, biological targets and activities reports.http://zinc.docking.org/browse/catalogs/natural-productsThis site compiles links to information on natural product databases and commercial sources.https://pubchem.ncbi.nlm.nih.govPubChem is a large database if chemical maintained by the National Center for Biotechnology Information. While it is not confined to natural products, there are many contained within, and it is strong on biological activity of molecules, which is particularly useful for natural products."} +{"text": "Melissa M. Cushing should have been listed as senior author. Ljljana V. Vasovic provided assistance with the article. The article has been corrected online ("} +{"text": "Nucleic Acids Research,2019, gkz1110,\u00a0https://doi.org/10.1093/nar/gkz1110https://github.umn.edu/schmidt-lab/SPINE) was inaccessible to users outside their institution. The repository has been moved to the public Github: https://github.com/schmidt-lab/SPINE.The authors had not realized that the Github enterprise server (These corrections do not affect the results or conclusion of the article.The published article has been updated."} +{"text": "It points out that microbes are the preferred source for these enzymes due to a lower cost and more consistent means of production.https://www.elsevier.com/books/biotechnology-of-microbial-enzymes/brahmachari/978-0-12-803725-6This is the website for a book dealing with the production and industrial applications of microbial enzymes.https://www.liebertpub.com/doi/full/10.1089/ind.2016.0011Bacillus subtilis.GRAS stands for Generally Regarded As Safe. It is the standard for regulatory approval of substances expected to become an additive to a food product, including enzymes. To be be considered safe, food enzymes are typically produced in host organisms, that are deemed to be GRAS, such as https://www.intechopen.com/books/food-industrial-processes-methods-and-equipment/microbial-pectic-enzymes-in-the-food-and-wine-industryPectic enzymes are widely used in the food industry, largely dealing with beverages derived from fruits and vegetables.https://www.scitechnol.com/peer-review/metagenomics-prospective-in-biomining-the-microbial-enzymes-f8DZ.php?article_id=7172For many enzyme applications, there is interest in discovering new enzymes with properties preferred over the existing enzymes. Metagenomic sequencing is a source for finding new sequences and enzymes.http://biosciences.dupont.comThe DuPont industrial biosciences site deals with all bioscience products. Enzymes are a major component, and DuPont is one of the world's largest enzyme producers.https://www.novozymes.com/-/Project/Novozymes/.../Enzymes_at_work.pdfThis web pamphlet is a little dated but provides an excellent overview of many commercial enzymes and their specific applications in industry.https://www.basf.com/global/en/products/cross-industry-solutions/enzymes.htmlThe large chemical company BASF also has a major enzyme division, and this website highlights their activities.https://www.codexis.comCodexis focuses on enzyme modifications for industrial purposes. In many cases, especially for pharmaceutical applications, enzyme reactivity toward a specific synthetic intermediate needs to be improved to become cost\u2010effective.https://www.bio.org/sites/default/files/David%20Ager.pdfDSM is a large traditional chemical company that has developed extensive proficiency with enzyme\u2010based catalysis.https://www.amano-enzyme.comAmano is a specialty enzyme company that started in Japan in 1899 as a pharmaceutical company.https://www.crunchbase.com/organization/enzyme-2#section-overviewLike all biotech products, they must meet regulatory compliance to go to the market. A new industry is emerging to help other companies rapidly and efficiently meet regulatory compliance.https://www.businesswire.com/news/home/20180628006408/en/Global-Enzymes-Market-Report-2018-Analysis-TypeThis website is an entry to market information on the enzyme industry and prospects for growth.https://www.mordorintelligence.com/industry-reports/global-industrial-enzymes-market-industryThis website is on current and future projected market information on the enzyme industry.http://www.rcsb.org/pdb/results/results.do?tabtoshow=Current&qrid=1C55793EThese webpages link to X\u2010ray structure information on a major industrial protease. There have been many modifications of this enzyme and there are 297 structures available for the search on \u2018subtilisin.\u2019https://www.aspergillus.org.uk/content/efficacy-different-commercial-phytase-sources-and-development-phosphorus-release-curvePhytases are used in animal nutrition to release phosphate from phytic acid.https://www.slideshare.net/reshvenkatesh/glucose-isomeraseThis slideshare provides information on glucose isomerase. Glucose isomerase in an important industrial enzyme, typically used in immobilized form to produce high\u2010fructose corn syrup."} +{"text": "This article has been corrected: Due to errors in image processing, there were misplaced images in Figure 2. An updated Figure 2 using the original data is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.87246-87256. https://doi.org/10.18632/oncotarget.13531Original article: Oncotarget. 2016; 7:87246\u201387256."} +{"text": "This article has been corrected: Due to errors in figure processing, the image in miR-125b mimics group at 0h is exactly the same as the NC group in Figure 5B. The corrected Figure 5B is attached. The authors declare that these corrections do not change the results or conclusions of this paper.2105-2119. https://doi.org/10.18632/oncotarget.23249Original article: Oncotarget. 2018; 9:2105\u20132119."} +{"text": "In addition to the current commonly used enzymes, it contains information of emerging enzymes of interest.http://www.novozymes.com/-/media/Project/Novozymes/.../Enzymes_at_work.pdfThis web brochure produced by Novozymes provides many examples of industrial enzymes, their origins and applications.http://www1.lsbu.ac.uk/water/enztech/detergent.htmlThis web article is a little dated but it nevertheless provides a good overview of how enzymes are used on washing formulations.https://www.aasv.org/shap/issues/v18n2/v18n2p90.htmlPhytase is an enzyme that releases phosphate from phytate, a hexaphosphate ester of inositol. Because much phosphate in grain and seeds is stored in phytate, phytase enzyme is added to animal feed to help release phosphate from the feed.https://www.ocl-journal.org/articles/ocl/pdf/2017/04/ocl170015.pdfLipases, mostly obtained from fungi, is used extensively in industry. Major uses are in detergents and in food oil processing.https://www.heraproject.com/files/22-F-07_PROTEASE_HERA_Final%20Edition%20(unsecured%20-%20PDFA-1b).pdfBacillus. It is used in laundry, dishwashing and contact lens cleaning applications. The current document contains much information relevant to the industrial use of subtilisin.Subtilisin is a protease, originally obtained from strains of https://www.chemistryworld.com/podcasts/chymosin/3007682.articleChymosin is an important enzyme used in the conversion of milk to cheese. It was originally obtained from the digestive tracts of young ruminant animals. More recently, it is produced in recombinant form by microbial fermentation processes.https://microbialcellfactories.biomedcentral.com/articles/10.1186/s12934-016-0507-6Trichoderma reesei.Cellulases are important industrial enzymes in biomass conversion. A major organism long studied for it enzymes for degrading cellulose is the fungus https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769773/This review article discusses the uses of amylases, mostly in converting various food products such as starches in corn, wheat, rice, and tapioca. A very large process currently is the conversion of corn starch to glucose by amylase coupled to the isomerization of glucose to fructose.https://www.researchgate.net/publication/315803185_Xylanases_and_their_industrial_applications_A_reviewThis Research Gate website contains an abstract on xylanases and a link to the full review article on the topic.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347563/This review article covers enzymes used in the production of semi\u2010synthetic beta\u2010lactam antibiotics. The major focus is on protein expression and engineering.https://www.creative-enzymes.com/similar/glucose-isomerase_319.htmlGlucose isomerase, also known as xylose isomerase, is widely used in the production of high\u2010fructose corn syrup.https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/pectinasePectinases are widely used in producing clarified fruit juices. The pectinases hydrolyze linkages in the pectic substance found in the cell walls of plants.https://www.novozymes.com/enNovozymes is a major enzyme producing company, headquartered in Denmark.http://biosciences.dupont.comDuPont is a very large producer of enzymes with currently 900 commercial products on the market.https://www.dupont.com/products-and-services/industrial-biotechnology/industrial-enzymes-bioactives/primagreen.htmlMany enzymes are used in textile processing and clothing finishing. This website addresses are group of enzymes used in those applications.http://animalnutrition.dupont.com/productsservices/feed-enzymes/Animal nutrition enzymes are largely derived from bacteria and aid in the animal digestion of their foods. The enzymes are principally phytase, proteases, and carbohydrate hydrolyzing enzymes.https://www.basf.com/global/en/products/cross-industry-solutions/enzymes.htmlThe German chemical company BASF made a large entry into industrial enzymes with the the purchase of the Verenium Corporation.https://www.amano-enzyme.com/uk/about-company/Amano produces microbial enzymes for use in food, supplement, and medical diagnostic industries."} +{"text": "Correction to: Cell Death & Disease10.1038/cddis.2016.452 published online 5 January 2017Since publication of this article, the authors have noticed that there were errors in Fig."} +{"text": "Scientific Reports 10.1038/srep08397, published online 23 February 2015Correction to: The Supplementary Information published with this Article contains errors. In Supplementary Tables The correct Supplementary Information file is provided below.Supplementary Information"} +{"text": "This article has been corrected: Due to errors in image processing, the representative image of TRAP staining in RANKL+HP d1 is incorrect. The proper Figure 1 is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.1868-1884. https://doi.org/10.18632/oncotarget.22930Original article: Oncotarget. 2018; 9:1868\u20131884."} +{"text": "Bioscience Reports (2017) vol. 37, BSR20170984; https://doi.org/10.1042/BSR20170984The author Shengjun Ma was omitted from the Author Contribution section of the published version of this article. S.M. reviewed the manuscript and put forward valuable suggestions for revision."} +{"text": "The authors wish to make a change to the published paper . In Secthttp://www.mdpi.com/2073-4360/9/12/638.The manuscript will be updated and the original will remain online on the article webpage"} +{"text": "MMWR found that overall, 38.9% of the U.S. population had ever tested for HIV infection, including 46.9% in the 50 local jurisdictions with the majority of diagnoses and 35.5% in the seven states with disproportionate occurrence of HIV in rural areas. To control HIV transmission, health care providers and public health practitioners need to develop HIV testing strategies to reach segments of the population that have never tested for HIV infection and offer at least annual testing of persons at risk for infection.National HIV Testing Day, observed each year on June 27, highlights the importance of testing in detecting, treating, and preventing human immunodeficiency virus (HIV) infection. Early diagnosis is critical to controlling HIV transmission in the United States (https://www.cdc.gov/features/HIVtesting. Basic testing information for the public is available at https://www.cdc.gov/hiv/basics/testing.html. Additional information on HIV testing for health professionals is available at https://www.cdc.gov/hiv/testing. CDC\u2019s guidelines for HIV testing of serum and plasma specimens are available at https://www.cdc.gov/hiv/guidelines/testing.html.Additional information on National HIV Testing Day is available at"} +{"text": "Please see the complete captions for The URL where data for Patient F can be found is missing from the captions of S4 Tablehttps://doi.org/10.5281/zenodo.1419151; https://doi.org/10.5281/zenodo.192398.Contingency table formed using the average of all the training sessions. S4 Table data is located at (XLSX)Click here for additional data file.S5 Tablehttps://doi.org/10.5281/zenodo.1419151; https://doi.org/10.5281/zenodo.192400.Contingency table formed using the average of all the feedback sessions. S5 Table data is located at (XLSX)Click here for additional data file.S2 Fighttps://doi.org/10.5281/zenodo.1419151; https://doi.org/10.5281/zenodo.192398; https://doi.org/10.5281/zenodo.192400.Receiver operating characteristic (ROC) curve of the binary support vector machine (SVM) classifier. (A) Training and (B) feedback sessions. Each circle in the ROC curve space represents false positive rate (FPR) versus true positive rate (TPR) for each session. Sessions with the same coordinate points in the ROC space are represented by concentric circles. The red star along with the coordinate points in the ROC space represent FPR versus TPR of all the sessions combined. In the figure panels A and B, the x-axis is the FPR and the y-axis is TPR. The thick diagonal line dividing the ROC space represents chance level. Points above the diagonal represent good classification results (better than random); points below the line represent poor classification results (worse than random). S2 Fig data is located at (JPG)Click here for additional data file."} +{"text": "This article deals with these evolutionary aspects.https://www.biorxiv.org/content/10.1101/365023v1.fullThe rhizosphere refers to the root region of plant microbiomes whereas phyllosphere refers to the above\u2010ground portion of plants that make another habitat for microbes.https://jgi.doe.gov/functional-genomics-database-for-plant-microbiome-studies/This page describes efforts to catalog plant beneficial bacteria to aid in understanding of the interactions and to potentially engineer plant microbiomes.http://www.earthmicrobiome.orgThe Earth microbiome is broader than plant systems. But plant microbiomes is one of the type of environments covered from a metagenomic perspective.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4752285/This big picture article is expansive but mostly deals with ways to study associations between strains in complex plant microbiomes.https://www.agri-pulse.com/articles/10740-bayer-moving-ahead-with-plant-microbiome-companyThis site describes the formation of a joint venture between Bayer and Ginkgo Bioworks to form Joyn Bio, a company dedicated to develop biological nitrogen fixation solutions for agriculture.https://www.ventureradar.com/keyword/Plant%20microbiomeThis business website highlights different companies with technology trained on understanding and engineering plant microbiomes for agriculture. The site provides a short synopsis and a link to the commercial site.https://agbiome.comAgbiome studies bacteria in the plant microbiome in an effort to develop natural controls against agronomic pests such as pathogenic fungi, insects and mites.https://www.pivotbio.comPivot Bio is focused on engineering bacteria for continuous derepression of nitrogen fixation genes and overcoming other functional control. The major goal is to develop bacteria that associate with corn plant roots and supply nitrogen to the plant."} +{"text": "Cell Death & Disease ; 10.1038/cddis.2017.449; published online 5 Oct 2017.Correction to: The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information."} +{"text": "This article has been corrected: In Figure 5E, the pictures for X2KO bottom left and bottom right were mistakenly taken from the same assay dish. A revised Figure 5 using the original raw data is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.1525-1538. https://doi.org/10.18632/oncotarget.26689Original article: Oncotarget. 2019; 10:1525\u20131538."} +{"text": "The original version of the article contained a mistake. The accession number has been incorrectly published in the \u201cAvailability of data and materials\u201d section.The number is given below and has been corrected with this erratum.The datasets generated and analysed during the current study are available in the MG-RAST repository with identification numbers described in Additional file 4.https://zenodo.org/record/1194340 (DOI: 10.5281/zenodo.1194340).The NCBI shotgun metagenomes are BioProject id: PRJNA435511. Draft bacterial genomes are available at"} +{"text": "Cell Death & Disease; 10.1038/cddis.2017.287; published online 29 June 2017.Correction to: The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information."} +{"text": "This article has been corrected: The authors wish to make the readers aware of an error in the actin blot of 10251-10270. https://doi.org/10.18632/oncotarget.2500Original article: Oncotarget. 2014; 5:10251\u201310270."} +{"text": "The issues underlying this phenomenon are discussed in this review.The \u201caverage\u201d enzymes shows a http://science.sciencemag.org/content/355/6322/289In natural evolution over the span of earth life history, enzymes adapted to operate under lower temperature in most contemporary environments. The mechanisms of this adaption has relevance to understanding evolving enzymes for greater stability and temperature change.https://www.genengnews.com/gen-news-highlights/easy-evolution-accelerates-enzyme-engineering/81255966This news article describes a method of gene amplification and mutation to accelerate obtaining beneficial mutations.https://www.biorxiv.org/content/early/2018/08/23/399154This review takes a theoretical approach and concludes that the best fit for models suggest selection for stability and activity simultaneously.http://www.jbc.org/site/thematics/enzyme_evolution/Journal of Biological Chemistry in which all of the articles deal with enzyme evolution.This page provides the overview for a special issue of the https://www.sciencedirect.com/science/article/pii/S2001037014600908Most studies focus on the methods of DNA manipulation relevant to directed evolution. This review focuses on the choice of host organism to use for the procedures.https://journals.plos.org/plosone/browse/directed_evolutionThis page shows a collection of directed evolution papers in the journal.https://sequencing.roche.com/en/technology-research/technology/directed-evolution.htmlThis Roche page highlights a primer on directed evolution and a link to relevant products.https://www.bsse.ethz.ch/bpl/research/directed-evolution.htmlThese pages provide good information and references pertaining to laboratory directed evolution.http://fhalab.caltech.eduThis is the webpage for Nobel laureate Frances Arnold's laboratory with links to research, papers and laboratory personnel. Arnold's lab has been a leader in developing directed evolution methods.https://www.springer.com/us/book/9781493910526This is a methods and procedures paper in a general methods book.https://dash.harvard.edu/handle/1/33840714This page links to a doctoral thesis for the topic indicated.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430392/Enzyme transformations related to pharmaceutical development is largely based on non\u2010natural reactions,\u00a0and directed evolution is almost invariably required to generate enzymes with requisite specificity and rates."} +{"text": "Xanthoparmelia farinosa under optical and electron microscopy. Mycology. https://doi.org/10.1080/21501203.2017.1367333Garc\u00eda RA, Rosato VG. 2017. Observations of the development of Xanthoparmelia farinosa was set incorrectly as Xanthoria farinosa in the title and abstract. This has now been corrected in both the print and online versions.When the above article was first published online, the species name The authors apologize for this error."} +{"text": "The authors wish to make the following corrections to this paper :Changes in AcknowledgementDue to a lapse, some important contents were missed in the Acknowledgement section from the original article .Acknowledgments: The authors would like to thank the support by the Fund of the National Natural Science Foundation of China under Grant No. 61601135 and Natural Science Foundation of Heilongjiang Province of China under Grant No. QC201706802. Additionally, the Vaihingen data set was provided by the German Society for Photogrammetry, Remote Sensing and Geoinformation (DGPF) : http://www.ifp.uni-stuttgart.de/dgpf/DKEPAllg.html. The experimental SVM program comes from libsvm-3.1-[FarutoUltimate3.1Mcode]. Faruto and liyang, LIBSVM-faruto Ultimate Version, a toolbox with implements for support vector machines were based on libsvm, 2011. Software is available at http://www.matlabsky.com. Chih-Chung Chang and Chih-Jen Lin, LIBSVM: a library for support vector machines, 2001. Software is available at http://www.csie.ntu.edu.tw/~cjlin/libsvm. The experimental SAE program comes from the rasmusbergpalm-DeepLearnToolbox-9faf641 toolkit. Software is available at https://github.com/rasmusbergpalm/DeepLearnToolbox.][The authors would like to apologize for any inconvenience caused to the readers by these changes."} +{"text": "Recently, we were questioned about thNew England Journal of Medicine, Cell, and Nature [http://www.partek.com/publications). Also, it is recommended by the NIH (https://ostr.cancer.gov/btep/software/partek).Partek and RLE plot were provided by Yang's group. There is no unqualified sample in GSE32537 and GSE3d Nature , 5. Topihttp://www.chem.agilent.com/cag/bsp/products/1color/OnecolorPerformanceposter_finaldraft.pdf), and we found no unqualified samples.According to the samples from GSE10667 and GSE5"} +{"text": "The publishers regret to announce that the above paper was published with the incorrect article number.The correct citation details are as follows:BJPsych Open 2019; 5(2): e19. https://doi.org/10.1192/bjo.2019.3.Pybus K, Pickett KE, Prady SL, Lloyd C, Wilkinson R. Discrediting experiences: outcomes of eligibility assessments for claimants with psychiatric compared with non-psychiatric conditions transferring to personal independence payments in England. This has now been updated in the original article online.The publisher sincerely apologises for this error."} +{"text": "This article has been corrected: During production, the ending page number for this article was listed incorrectly. The page count has now been adjusted to show the proper pagination.https://doi.org/10.18632/oncotarget.1795Original article: Oncotarget. 2014; 5:1101-1110."} +{"text": "Due to a typesetting error, the Data Availability statement for this paper is incomplete. The publisher apologizes for the error.http://dx.doi.org/10.17605/OSF.IO/36RQC (https://osf.io/36rqc/).The complete Data Availability statement is: All data and analysis files are available from the Open Science Framework:"} +{"text": "L. Lai, is incorrectly noted as the corresponding author. The correct corresponding author is Nan Qin. Dr. Qin\u2019s email address is:"} +{"text": "This article has been corrected: The correct GEO number information is given below:Data acquisitionSlides were scanned with the Microarray Scanner using the following default settings: dye channel = green, scan resolution = 3 \u03bcm, PMT = 100%, and 20 bit. Data were extracted with Feature Extraction v.10.7 (Agilent Technologies). Raw data were normalised with the quantile algorithm of GeneSpring v.12.6.1 (Agilent Technologies). The microarray data presented in this article have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) and are accessible through GEO Series accession number GSE118039.https://doi.org/10.18632/oncotarget.18138Original article: Oncotarget. 2017; 8:47876-47889."} +{"text": "This article has been corrected: The labelling for equal first authorship is given below:* These authors contributed equally to this workhttps://doi.org/10.18632/oncotarget.5734Original article: Oncotarget. 2015; 6:38967-38982."} +{"text": "This article has been corrected: Due to errors during image assembly, the RFP-ELL1 merged image in Figure 4B is incorrect. The proper Figure 4 is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.29245-29254. https://doi.org/10.18632/oncotarget.8588Original article: Oncotarget. 2016; 7:29245\u201329254."} +{"text": "The Data Availability statement for this paper is incorrect. The publisher apologizes for this error.http://doi.org/10.5281/zenodo.3245408The correct Data Availability statement is: This research work relies on surface velocity fields that can be freely downloaded from the following repository: Magaldi, Marcello G., Mantovani, Carlo, and Cosoli, Simone (2019). Current velocities measured by HF radars in Gulf of Trieste\u2014April 2012 [Data set]. Zenodo."} +{"text": "Nucleic Acids Res., 2018, https://doi.org/10.1093/nar/gky1034This article has been updated to correct an error in the author's name."} +{"text": "Borage is an herb crop that is an important source of gamma\u2010linolenic acid.https://www.novozymes.com/en/advance-your-business/agriculture/crop-productionNovozymes is a global leader in industrial\u2010scale enzymes. This commercial page describes their interests in microbial processes for promoting plant growth and productivity, including seed treatments.http://cardycropsolutions.com/uploads/planting_soybeanbiologicalmicrobialseedtreatments.pdfThis commercial article provides a good overview of the overall process of, and developments in, microbial seed coatings. The experimental part focuses on soybean.https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0205200Neonicotinoid pesticides are increasingly being used to treat seeds to prevent damage from pests such as aphids. This study examined the effect of neonicotinoinds on microbes.https://www.corteva.us/products-and-solutions/seed-treatments.htmlThis website describes commercial products. In the process, it provides good insights into the types and manner of microbial seed protection.https://agriculture.basf.com/us/en/Crop-Protection/Poncho-VOTiVO-2-0.htmlThis site highlights an ongoing trend of combining an insecticide and a microbe on the same seed for enhanced survival and performance.https://www.nature.com/articles/s41598-019-42865-9Seeds are transmitters of microbes into a soil upon planting. The transmission can be for beneficial or detrimental bacteria. This study looked at pathogen transmittal and how the pathogens might be out\u2010competed by other microbes.https://www.agriculture.com/crops/the-science-behind-microbial-and-biological-productsThis popular science article gives a good overview of this field of research and highlights some of the researchers working in the field.http://www.acceleronsas.com/Solutions/BioEnhancers/Pages/Acceleron-BioAg.aspxThis is a commercial website, but information on the products highlights important features of microbial seed treatments.http://www.syngenta-us.com/crop-protection/seed-treatmentThis website highlights the seed treatment products of the agricultural products company Syngenta.https://patents.google.com/patent/WO2017087939A1/enThis patent describes methods for encapsulating microorganisms in a polymer gel on seeds and the utility of such processes.https://patentscope.wipo.int/search/en/detail.jsf?docId=US243315432This patent focuses on formulations, specifically the most effective microbial combinations for particular seed treatments.https://headsupst.com/crops/soybean-crops/This page highlights an approval of microbial seed treatment for pest control by a regulatory body, in this case the U.S. Environmental Protection Agency.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738727/Bacillus strain and it effects on cotton seedlings.This publication describes a specific type of seed treament, a particular https://link.springer.com/content/pdf/10.1007%2F978-94-011-4926-6_8.pdfThis extensive review article is somewhat dated but it provides a good, comprehensive description of many aspects of coating microbes onto seeds.https://www.frontiersin.org/articles/10.3389/fmicb.2017.00011/fullThis study details an approach of applying a benefical microbe to flowers with the effect of ultimately transmitting the microbe to harvested seeds.https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176930This paper described a method for using electrospinning to nanoimmobilize microbes for subsequent seed applications."} +{"text": "Gastroenterology Report, 2019;7:146\u20139. https://doi.org/10.1093/gastro/goz005The original version of this article contained a mistake in the authors' affiliations; this has now been corrected. The publisher would like to apologize for this mistake."} +{"text": "This article has been corrected: The correct figure 4 is given below:The authors declare that this correction does not change the results and conclusions of this paper.26573-26590. https://doi.org/10.18632/oncotarget.15719Original article: Oncotarget. 2017; 8:"} +{"text": "Aging Cell, 2019;18:e12841. https://doi.org/10.1111/acel.12841Ogrodnik M, Salmonowicz H, Gladyshev VN. Integrating cellular senescence with the concept of damage accumulation in aging: Relevance for clearance of senescent cells. m.ogrodnik@newcastle.ac.uk)\u201d to \u201c(Ogrodnik.Mikolaj@mayo.edu).\u201dIn the article \u201cIntegrating cellular senescence with the concept of damage accumulation in aging: Relevance for clearance of senescent cells,\u201d the corresponding author would like to change his email address from \u201c(The author would like to apologize for the inconvenience caused."} +{"text": "Antimicrobial peptides are increasingly deemed to be important in biotechnology for their animal and human therapeutic potential.http://aps.unmc.edu/AP/structure.phpThis site contains a database of peptides, prediction tools and classification schema. Overall, it is a comprehensive resource on the topic.http://www.camp.bicnirrh.res.inThis collection focuses on sequence patterns and HMMs for antimicrobial peptides and provides links to major databases such as UniProt and PubMed.http://www.cryst.bbk.ac.uk/peptaibolThis site focuses on a specific class of antimicrobial peptides known as peptaibols. These peptides are typically derived from fungi.http://csb.cse.yzu.edu.tw/dbAMP/This database is particularly useful for identifying antimicrobial peptides using transcriptomic and proteomic data.https://dbaasp.orgThis database specializes in modeling structures of antimicrobial peptides to help predict therapeutic potential for these compounds.http://www.rcsb.org/structure/1CIXThis record in the Protein DataBank has information and structural coordinates for techystatin A, an antimicrobial peptide from horseshoe crab.https://www.researchgate.net/figure/Four-structural-classes-of-antimicrobial-peptides-A-a-helical-structure-of-human_fig1_281555477This page from the Research Gate site posts information on a specific collection of antimicrobial peptides from animal origin.https://www.rcsb.org/structure/2MJQThis record in the Protein DataBank has information and structural coordinates for antimicrobial peptide anoplin that is embedded in diphosphatidylcholine micelles. Anoplin is an antimicrobial peptide from a species of wasp.https://www.mdpi.com/2218-273X/8/1/4/htmThis review article explores antimicrobial peptides, especially from the standpoint of providing a replacement of some antibiotic therapies where resistance is rising.https://www.frontiersin.org/articles/10.3389/fphar.2018.00281/fullThis article discusses the use of antimicrobial peptides for surface injuries such as skin wounds.http://gprobiotics.comGeneral Protobiotics is a biotechnology company exploring commercial use of antimicrobial peptides in the poultry industry, as a replacement for antibiotics. The use of antibiotics in animal agriculture is increasingly being constrained.https://www.hycultbiotech.com/products/innate/antimicrobialpeptidesThis biotechnology company sells a variety of antimicrobial peptides, largely for research purposes.https://www.grc.org/antimicrobial-peptides-conference/2019/This Gordon Research Conference is designed to host high\u2010level discussion of antimicrobial peptides, with a particular focus on their potential efficacy in human and veterinary medicine.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829097/An important area of antimicrobial peptide research is understanding structure/function correlations. This is discussed here in the context of designing more effective, faster\u2010acting peptides.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989729/Antimicrobial peptides largely exert their effects in membranes. This study uses molecular dynamics simulations to better understand the interactions between the peptides and specific membrane components.https://en.wikipedia.org/wiki/Antimicrobial_peptidesThis Wikipedia entry provides a particularly good tutorial on many aspects of antimicrobial peptides.https://www.sciencedirect.com/science/article/pii/S1876162318300282This review focuses on biophysical and computational methods for studying antimicrobial peptides."} +{"text": "Biochemia Medica 2018;28(2):020501. DOI: https://doi.org/10.11613/BM.2018.020501This is a correction of Since the publication of this article, the authors have noticed that the"} +{"text": "This article has been corrected: The correct figure The authors declare that these corrections do not change the results or conclusions of this paper.https://doi.org/10.18632/oncotarget.9717Original article: Oncotarget. 2016; 7:43390-43400."} +{"text": "Salmonella enterica subsp. enterica serovar Typhimurium WG49 is widely used for enumeration of F-specific RNA (F-RNA) coliphages in water. Salmonella enterica subsp. enterica serovar Typhimurium WG49 is widely used for enumeration of F-specific RNA (F-RNA) coliphages in water. Escherichia coli WG5 is broadly used for the detection and enumeration of somatic coliphages in water samples. We report here the genome sequences of these bacterial strains used in South Africa under ISO methods 10705-1 and 10705-2. Escherichia coli. Different E. coli strains have been used as phage hosts in laboratory assays. Some researchers advocate the use of a specific local strain for each country. However, E. coli strain WG5 is broadly used under standardized protocols and is E. coli . Followihttps://www.bioinformatics.babraham.ac.uk/projects/fastqc/). Reads of quality lower than 35 and lengths less than 45\u2009nt were filtered with Sickle and subjected to Nextera XT DNA library preparation according to Illumina (USA) instructions. Normalized libraries were run on an Illumina MiSeq sequencer . Read quality was evaluated with FastQC . The genome sequences have been deposited at DDBJ/ENA/GenBank under accession no. PXZB00000000 for Salmonella Typhimurium WG49 and PYBI00000000 for E. coli WG5. The versions described in this paper are PXZB01000000 for Salmonella Typhimurium WG49 and PYBI01000000 for E. coli WG5.The whole-genome shotgun sequencing is described in the GenBank BioProject no. PRJNA434049. Raw reads are available from the Sequence Read Archive (SRA) (accession no. SRR6804879 for"} +{"text": "This article has been corrected: An image duplication error occurred in Figure 5E, in which a selected image was inadvertently pasted in the incorrect panel. The proper Figure 5E is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.647-659. https://doi.org/10.18632/oncotarget.26567Original article: Oncotarget. 2019; 10:647\u2013659."} +{"text": "This article has been corrected: The correct figure The authors apologize for the oversight. The authors declare that this correction does not affect the description, interpretation, or the original conclusions of the manuscript.https://doi.org/10.18632/oncotarget.21882Original article: Oncotarget. 2017; 8:101952-101964."} +{"text": "A 2011 Institute of Medicine report and the CDC Guideline for Prescribing Opioids for Chronic Pain (https://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm). Better public education regarding expectations, beliefs, and understanding about pain are all important. Additional measures include professional education and training for better, comprehensive, and integrated pain management.A report on chronic pain in this issue (https://www.hhs.gov/opioids/about-the-epidemic/hhs-response/better-pain-management/index.html.Better pain management is also a major element in addressing the current opioid crisis. Persons living with pain need safer and more effective alternatives for pain management. Additional information is available at"} +{"text": "Stanley, is deceased. Philip M. Kihaule will serve as corresponding author moving forward. Dr. Kihaule\u2019s contact information is:"} +{"text": "National Latinx AIDS Awareness Day, October 15, is observed each year to focus on the continuing and disproportionate impact of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) on Hispanics/Latinos in the United States. In 2017, 26% of newly diagnosed HIV infections occurred in Hispanics/Latinos (An analysis of the behaviors of Hispanic/Latino MSM included in CDC\u2019s National HIV Behavioral Surveillance system found that nearly 75% reported having had condomless anal sex during 2017 (https://www.cdc.gov/hiv/group/racialethnic/hispaniclatinos/index.html and https://www.cdc.gov/hiv/group/msm/hispanic-latino.html.National Latinx AIDS Awareness Day is an opportunity to encourage increased HIV prevention efforts among Hispanics/Latinos. CDC supports testing, linkage to and engagement in care and treatment, and other efforts to reduce the risk for acquiring or transmitting HIV infection. More information is available at"} +{"text": "Scientific Reports 10.1038/s41598-019-38595-7, published online 05 February 2019Correction to: The Acknowledgements section in this Article is incomplete.\u201cJ.E. was funded by the Research Institute for Development (IRD). We are particularly grateful to Timothy H. Druitt for constructive scientific discussions. We warmly thank A. Folch and one anonymous reviewer for constructive comments.\u201dshould read:\u201cJ.E. was funded by the Research Institute for Development (IRD). We are particularly grateful to Timothy H. Druitt for constructive scientific discussions. We warmly thank A. Folch and one anonymous reviewer for constructive comments. We thank the European project EUROVOLC (grant number 731070), A.C. also acknowledges the Italian MIUR project Premiale Ash-RESILIENCE.\u201d"} +{"text": "Correction to: Cell Death & Disease; 10.1038/cddis.2017.463; published online 12 October 2017.The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information."} +{"text": "Table S1 has now been updated.http://dev.biologists.org/content/146/6/dev173146.supplemental.The updated supplementary data are now available online at The authors apologise to readers for this mistake."} +{"text": "This article has been corrected: Due to errors during figure assembly, the image used in Figure 3C is incorrect. In addition, the image for Figure 3A contains accidental duplication of FACS panels. The proper Figure 3 is shown below. The authors declare that these corrections do not change the results or conclusions of this paper.825-846. https://doi.org/10.18632/oncotarget.26582Original article: Oncotarget. 2019; 10:825\u2013846."} +{"text": "Almost 30 million babies worldwide are born prematurely or become ill annually and need specialized care to survive. Formalized collaborative practice agreements (CPA) between clinical pharmacists and physicians have been put forward as a means for improving the overall medicating experience in many patient populations, including children. This report briefly describes opportunities for collaboration using examples from countries on each continent where CPA is established in professional governance documents and standards. It also provides resources in the form of a toolkit for countries and pharmacist\u2013physician collaborators to authorize and form CPAs to provide comprehensive medication management (CMM) for children and youth with special health care needs (CSHCN). Almost 30 million babies worldwide are born prematurely or become ill annually and need specialized care to survive . The Conhttps://www.who.int/maternal_child_adolescent/child/en/), UNICEF (https://www.unicefusa.org/), International Pharmaceutical Federation , or Commonwealth Fund publications. Countries listed in this report serve as examples of the scope of regulatory and practice scenarios and processes that could be applied in the developing world. To estimate whether a particular country has the capacity for CMM through CPA, an internet search was performed using the following search terms: children, pediatrics, clinical pharmacy, collaborative practice, collaborative care, pharmacist prescribing (PhP), partnership for care, board of pharmacy, pharmacy council, pharmacy guild, pharmaceutical society, regulatory, medication review, medication management, medication access, scope of practice, and each continent. While an Internet search may be limited as far as creating a comprehensive survey of practice expectations worldwide, the authors realized that a search of this nature may not capture all possible activity in other countries. In addition, the report was limited to English language websites and those that could be translated. The toolkit provides tools and resources for potential collaborators to assess the value of closer collaboration in practice for the benefit of patients, including children. Moreover, the expansion of clinical pharmacy education within universities may be an indicator of an evolving societal expectation for collaborative CMM practice. Readers are referred to In South Africa, pharmacists are registered with the South African Pharmacy Council. While pharmacists in hospital practice may contribute to antimicrobial stewardship programs , provide pharmacokinetic advice , or service anticoagulant clinics, they are unable to alter doses or order laboratory tests on their own . Domain https://www.pharmcouncil.co.za/)South African Pharmacy Council (SAPC) (https://www.pssa.org.za/)Pharmaceutical Society of South Africa (https://www.sasocp.co.za/)South African Society of Clinical Pharmacy and case write ups and logs are required for advanced practice .http://www.hsa.gov.sg/content/hsa/en/Health_Products_Regulation/Manufacturing_Importation_Distribution/Overview/Audit_Licensing_and_Registration_Of_Pharmacies.html)Health Sciences Authority Singapore Pharmacy Council Therapeutics Products Division (http://www.pss.org.sg/)Pharmaceutical Society of Singapore Pharmacy Specialists Accreditation Board The Royal Dutch Pharmacists Association (https://www.kinderformularium.nl/)Kinderformularium states that pharmacy professionals work in partnership or collaboration with patients and others on the health care team . Just thhttps://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency)Medical and Healthcare Products Regulatory Agency The European Medicines Agency (http://www.pharmacyregulation.org/registration/registration-pharmacy-premises)General Pharmaceutical Council (http://www.rpharms.com/home/home.asp)Royal Pharmaceutical Society of Great Britain (https://www.pgeu.eu/en/pgeu/members.html)Pharmaceutical Group of the European Union British National Formulary for Children Medsafe (http://www.psnz.org.nz/)Pharmaceutical Society of New Zealand (http://www.pharmacycouncil.org.nz/index.asp)Pharmacy Council (http://www.pgnz.org.nz/)Pharmacy Guild of New Zealand for estimating cardiovascular, diabetes, obstructive sleep apnea, and skin cancer risk using standardized tools (see links below). Pharmacists also provide vaccinations (Standard 11), minor ailments service (Standard 12), disease state management (Standard 13), medication review (Standard 14), dose administration aid (Standard 15), and harm minimization (Standard 16) in a collaborative fashion .http://www.tga.gov.au/)Therapeutic Goods Administration, Department of Health and Aging (http://www.guild.org.au/)The Pharmacy Guild of Australia (http://www.psa.org.au/)The Pharmaceutical Society of Australia International Health Care System Profiles-Australia Clinical Information Access Portal of New South Wales Brazilian Society of Pharmacists and Community Pharmacies (http://www.cff.org.br/userfiles/file/_PROFAR_kit_Livro_corrigido.pdf)Support Program for Pharmaceutical Care in Healthcare National Health Surveillance Agency (Useful links on collaborative practice and regulation:The purpose of this toolkit is to aid countries and clinical pharmacists around the world in identifying opportunities to develop more formalized collaborative practices between clinical pharmacists and other prescribers for managing the medications of children. Progress related to CMM and CPA in the developed world may be applicable in other jurisdictions and settings."} +{"text": "Soc Cogn Affect Neurosci (2018), 1327.https://doi.org/10.1093/scan/nsy101DOI: Footnotes indicating that the first two authors contributed equally have been added to the article."} +{"text": "This article has been corrected: Due to errors in image preparation, two panels in Figures 4 and 5 were accidentally duplicated. The corrected Figures 4 and 5 are shown below. The authors declare that these corrections do not change the results or conclusions of this paper.1284-1305. https://doi.org/10.18632/oncotarget.26641Original article: Oncotarget. 2019; 10:1284\u20131305."} +{"text": "A reference is omitted from the second sentence of the third paragraph under the subheading \u201cInteroceptive awareness and sexual concordance\u201d in the Introduction section.The sentence should read: In a sample of 26 women, the noticing subscale of the Multidimensional Assessment of Interoceptive Awareness scale (MAIA) [34] was related to greater sexual concordance .https://doi.org/10.1016/j.jsxm.2016.09.018The reference is: Handy AB, Meston CM. Interoceptive awareness moderates the relationship between perceived and physiological genital arousal in women. J Sex Med. 2016;13:1907\u20131914."} +{"text": "JC-F was a postgraduate fellow with a CONACYT fellowship No. 589318 (http://www.conacyt.gob.mx).\u201d The publisher apologizes for the error.The Funding section is incorrect. The complete, correct funding information is: \u201cThis work was supported by the Instituto Polit\u00e9cnico Nacional (IPN) Project No. SIP 20181110 ("} +{"text": "Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point\u2010in\u2010time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.14749. Ion channels are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein\u2010coupled receptors, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid\u20102019, and supersedes data presented in the 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC\u2010IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.The Concise Guide to PHARMACOLOGY 2019/20 is the fourth in this series of biennial publications. The Concise Guide provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands ( Many ion channels are gated by voltage but others are relatively voltage\u2010insensitive and are gated by second messengers and other intracellular and/or extracellular mediators. As such, there is some blurring of the boundaries between \u201cion channels\u201d and \u201cligand\u2010gated channels\u201d which are compiled separately in the Guide. Resolution of ion channel structures, beginning with K channels [http://www.ncbi.nlm.nih.gov/pubmed/9525859?dopt=AbstractPlus] then Cl channels [http://www.ncbi.nlm.nih.gov/pubmed/11796999?dopt=AbstractPlus] and most recently Na channels [http://www.ncbi.nlm.nih.gov/pubmed/21743477?dopt=AbstractPlus] has greatly improved understanding of the structural basis behind ion channel function. Many ion channels share several structural similarities. These channels are thought to have evolved from a common ancestor and have been classfied together as the \u201cvoltage\u2010gated\u2010like (VGL) ion channel chanome\u201d (see [http://www.ncbi.nlm.nih.gov/pubmed/16382097?dopt=AbstractPlus]). Other ion channels, however, such as Cl channels, aquaporins and connexins, have completely different structural properties to the VGL channels, having evolved quite separately.Ion channels are pore\u2010forming proteins that allow the flow of ions across membranes, either plasma membranes, or the membranes of intracellular organelles [http://www.ncbi.nlm.nih.gov/pubmed/17139284?dopt=AbstractPlus]. However, the advent of novel, faster screening techniques for compounds acting on ion channels [http://www.ncbi.nlm.nih.gov/pubmed/18356919?dopt=AbstractPlus] suggests that these proteins represent promising targets for the development of additional, novel therapeutic agents for the near future.Currently, ion channels (including ligand\u2010gated ion channels) represent the second largest target for existing drugs after G protein\u2010coupled receptors , 5\u2010HT3 , ionotropic glutamate and P2X receptors and the inhibitory, anion\u2010selective, GABAA and glycine receptors . The nicotinic acetylcholine, 5\u2010HT3, GABAA and glycine receptors are pentameric structures and are frequently referred to as the Cysloop receptors due to the presence of a defining loop of residues formed by a disulphide bond in the extracellular domain of their constituent subunits . However, the prokaryotic ancestors of these receptors contain no such loop and the term pentameric ligand\u2010gated ion channel (pLGIC) is gaining acceptance in the literature [http://www.ncbi.nlm.nih.gov/pubmed/19646860?dopt=AbstractPlus]. The ionotropic glutamate and P2X receptors are tetrameric and trimeric structures, respectively. Multiple genes encode the subunits of LGICs and the majority of these receptors are heteromultimers. Such combinational diversity results, within eachclass of LGIC,in a widerangeof receptors withdiffering pharmacological and biophysical properties and varying patternsof expression within the nervous system and other tissues. The LGICs thus present attractive targets for new therapeutic agents with improved discrimination between receptor isoforms and a reduced propensity for off\u2010target effects. The development of novel, faster screening techniques for compounds acting on LGICs [http://www.ncbi.nlm.nih.gov/pubmed/18356919?dopt=AbstractPlus] will greatly aid in the development of such agents.By convention, the LGICs comprise the excitatory, cationselective, nicotinic acetylcholine [3 receptor (NC\u2010IUPHAR Subcommittee on 5\u2010Hydroxytryptamine (serotonin) receptorsnomenclature as agreed by the [http://www.ncbi.nlm.nih.gov/pubmed/7938165?dopt=AbstractPlus]) is a ligand\u2010gated ion channel of the Cys\u2010loop family that includes the zinc\u2010activated channels, nicotinic acetylcholine, GABAA and strychnine\u2010sensitive glycine receptors. The receptor exists as a pentamer of 4TM subunits that form an intrinsic cation selective channel [http://www.ncbi.nlm.nih.gov/pubmed/18761359?dopt=AbstractPlus]. Five human 5\u2010HT3 receptor subunits have been cloned and homo\u2010oligomeric assemblies of 5\u2010HT3A and hetero\u2010oligomeric assemblies of 5\u2010HT3A and 5\u2010HT3B subunits have been characterised in detail. The 5\u2010HT3C , 5\u2010HT3D and 5\u2010HT3E subunits , like the 5\u2010HT3B subunit, do not form functional homomers, but are reported to assemble with the 5\u2010HT3A subunit to influence its functional expression rather than pharmacological profile . 5\u2010HT3A, \u2010C, \u2010D, and \u2010E subunits also interact with the chaperone RIC\u20103 which predominantly enhances the surface expression of homomeric 5\u2010HT3A receptor [http://www.ncbi.nlm.nih.gov/pubmed/20522555?dopt=AbstractPlus]. The co\u2010expression of 5\u2010HT3A and 5\u2010HT3C\u2010E subunits has been demonstrated in human colon [http://www.ncbi.nlm.nih.gov/pubmed/21192076?dopt=AbstractPlus]. A recombinant hetero\u2010oligomeric 5\u2010HT3AB receptor has been reported to contain two copies of the 5\u2010HT3A subunit and three copies of the 5\u2010HT3B subunit in theorderB\u2010B\u2010A\u2010B\u2010A[http://www.ncbi.nlm.nih.gov/pubmed/16116092?dopt=AbstractPlus], butthis is inconsistent with recent reports which show at least one A\u2010A interface . The 5\u2010HT3B subunit imparts distinctive biophysical properties upon hetero\u2010oligomeric 5\u2010HT3AB versus homo\u2010oligomeric 5\u2010HT3A recombinant receptors , influences the potency of channel blockers, but generally has only a modest effect upon the apparent affinity of agonists, or the affinity of antagonists which may be explained by the orthosteric binding site residing at an interface formed between 5\u2010HT3A subunits . However, 5\u2010HT3A and 5\u2010HT3AB receptors differ in their allosteric regulation by some general anaesthetic agents, small alcohols and indoles . The potential diversity of 5\u2010HT3 receptors is increased by alternative splicing of the genes HTR3A and E . In addition, the use of tissue\u2010specific promoters driving expression from differenttranscriptional start sites has beenreported for theHTR3A, HTR3B,HTR3D and HTR3E genes, which could result in 5\u2010HT3 subunits harbouring different N\u2010termini . To date, inclusion of the 5\u2010HT3A subunit appears imperative for 5\u2010HT3 receptor function.The 5\u2010HT3A subunit, or the receptor native to human tissues. Significant changes introduced by co\u2010expression of the 5\u2010HT3B subunit are indicated in parenthesis. Although not a selective antagonist, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5458 displays multimodal and subunit\u2010dependent antagonism of 5\u2010HT3 receptors [http://www.ncbi.nlm.nih.gov/pubmed/19131665?dopt=AbstractPlus]. Similarly, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4323, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2298, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4051, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2366 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1862 are not selective for 5\u2010HT3 receptors (e.g.[http://www.ncbi.nlm.nih.gov/pubmed/21059362?dopt=AbstractPlus]). The anti\u2010malarial drugs http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4252and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2510 exerta modestly more potent block of 5\u2010HT3A versus 5\u2010HT3AB receptor\u2010mediated responses [http://www.ncbi.nlm.nih.gov/pubmed/18311193?dopt=AbstractPlus]. Knownbetterasa partial agonistof nicotinic acetylcholine \u03b14\u03b22 receptors, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5459 is also an agonist of the 5\u2010HT3A receptor [http://www.ncbi.nlm.nih.gov/pubmed/21775477?dopt=AbstractPlus]. Human , rat [http://www.ncbi.nlm.nih.gov/pubmed/7509203?dopt=AbstractPlus], mouse [http://www.ncbi.nlm.nih.gov/pubmed/1718042?dopt=AbstractPlus], guinea\u2010pig [http://www.ncbi.nlm.nih.gov/pubmed/9463477?dopt=AbstractPlus] ferret [http://www.ncbi.nlm.nih.gov/pubmed/10884508?dopt=AbstractPlus] and canine [http://www.ncbi.nlm.nih.gov/pubmed/16647053?dopt=AbstractPlus] orthologues of the 5\u2010HT3A receptor subunit have been cloned that exhibit intraspecies variations in receptor pharmacology. Notably, most ligands display significantly reduced affinities at the guinea\u2010pig 5\u2010HT3 receptor in comparison with other species. In addition to the agents listed in the table, native and recombinant 5\u2010HT3 receptors are subject to allosteric modulation by extracellular divalent cations, alcohols, several general anaesthetics and 5\u2010hydroxy\u2010 and halidesubstituted indoles .Quantitative data in the table refer to homooligomeric assemblies of the human 5\u2010HTet al. (2014) Nausea and the quest for the perfect anti\u2010emetic. Eur. J. Pharmacol.722: 108\u201021 https://www.ncbi.nlm.nih.gov/pubmed/24157981?dopt=AbstractPlusAndrews PL et al. (2015) From Chemotherapy\u2010Induced Emesis to Neuroprotection: Therapeutic Opportunities for 5\u2010HT3 Receptor Antagonists. Mol. Neurobiol.52: 1670\u20101679 https://www.ncbi.nlm.nih.gov/pubmed/25377794?dopt=AbstractPlusFakhfouri G et al. (2016) 5\u2010HT3 receptors: Target for new antidepressant drugs. Neurosci Biobehav Rev64: 311\u201025 https://www.ncbi.nlm.nih.gov/pubmed/26976353?dopt=AbstractPlusGupta D et al. (1994) International Union of Pharmacology classification of receptors for 5\u2010hydroxytryptamine (Serotonin). Pharmacol. Rev.46: 157\u2010203 https://www.ncbi.nlm.nih.gov/pubmed/7938165?dopt=AbstractPlusHoyer D et al. (2015) A review of fluorescent ligands for studying 5\u2010HT3 receptors. Neuropharmacology98: 31\u201040 https://www.ncbi.nlm.nih.gov/pubmed/25892507?dopt=AbstractPlusLochner M et al. (2014) Molecular mechanisms of 5\u2010HT(3) and NK(1) receptor antagonists in prevention of emesis. Eur. J. Pharmacol.722: 26\u201037 https://www.ncbi.nlm.nih.gov/pubmed/24184669?dopt=AbstractPlusRojas C NC\u2010IUPHARnomenclatureas agreed by [http://www.ncbi.nlm.nih.gov/pubmed/25287517?dopt=AbstractPlus]) are members of a Na+ channel superfamily that includes the epithelial Na+ channel (ENaC), the FMRF\u2010amide activated channel (FaNaC) of invertebrates, the degenerins (DEG) of Caenorhabitis elegans, channels in Drosophila melanogaster and \u2019orphan\u2019 channels that include BLINaC [http://www.ncbi.nlm.nih.gov/pubmed/10457052?dopt=AbstractPlus] and INaC [http://www.ncbi.nlm.nih.gov/pubmed/10767424?dopt=AbstractPlus] that have also been named BASICs, for bile acidactivated ion channels [http://www.ncbi.nlm.nih.gov/pubmed/24365967?dopt=AbstractPlus]. ASIC subunits contain two TM domains and assemble as homo\u2010 or hetero\u2010trimers to form proton\u2010gated, voltage\u2010insensitive, Na+ permeable, channels . Splice variants of ASIC1 [termed ASIC1a [http://www.ncbi.nlm.nih.gov/pubmed/9062189?dopt=AbstractPlus], ASIC1b [http://www.ncbi.nlm.nih.gov/pubmed/9707631?dopt=AbstractPlus] and ASIC1b2 (ASIC\u03b22) [http://www.ncbi.nlm.nih.gov/pubmed/11588592?dopt=AbstractPlus]; note that ASIC1a is also permeable to Ca2+] and ASIC2 and ASIC2b [http://www.ncbi.nlm.nih.gov/pubmed/9368048?dopt=AbstractPlus]] have been cloned. Unlike ASIC2a (listed in table), heterologous expression of ASIC2b alone does not support H+\u2010gated currents. A third member, ASIC3 [http://www.ncbi.nlm.nih.gov/pubmed/9261094?dopt=AbstractPlus], has been identified. A fourth mammalian member of the family (ASIC4/SPASIC) does not support a proton\u2010gated channel in heterologous expression systems and is reported to downregulate the expression of ASIC1a and ASIC3 . ASIC channels are primarily expressed in central and peripheral neurons including nociceptors where they participate in neuronal sensitivity to acidosis. They have also been detected in taste receptor cells (ASIC13), photoreceptors and retinal cells (ASIC1\u20103), cochlear hair cells (ASIC1b), testis (hASIC3), pituitary gland (ASIC4), lung epithelial cells (ASIC1a and \u20103), urothelial cells, adipose cells (ASIC3), vascular smooth muscle cells (ASIC1\u20103), immune cells and bone (ASIC1\u20103). A neurotransmitter\u2010like function of protons has been suggested, involving postsynaptically located ASICs of the CNS in functions such as learning and fear perception , responses to focal ischemia [http://www.ncbi.nlm.nih.gov/pubmed/17127388?dopt=AbstractPlus] and to axonal degeneration in autoimmune inflammation in a mouse model of multiple sclerosis [http://www.ncbi.nlm.nih.gov/pubmed/17994101?dopt=AbstractPlus], as well as seizures [http://www.ncbi.nlm.nih.gov/pubmed/18536711?dopt=AbstractPlus] and pain . Heterologously expressed heteromultimers form ion channels with differences in kinetics, ion selectivity, pH\u2010 sensitivity and sensitivity to blockers that resemble some of the native proton activated currents recorded from neurones .Acid\u2010sensing ion channels inhibits ASIC1a by increasing the affinity toH+and promoting channel desensitization . PcTx1 has little effect on ASIC2a, ASIC3 or ASIC1a expressed as a heteromultimer with either ASIC2a, or ASIC3 but does inhibit ASIC1a expressed as a heteromultimer with ASIC2b [http://www.ncbi.nlm.nih.gov/pubmed/21715637?dopt=AbstractPlus]. PcTx1 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10305 potentiate ASIC1b currents . ASIC1containing homo\u2010 and heteromers are inhibited by Mambalgins, toxins contained in the black mamba venom, which induce in ASIC1a an acidic shift of the pH dependence of activation [http://www.ncbi.nlm.nih.gov/pubmed/23034652?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10306 is highly selective for ASIC1a with very little activity at ASIC1b. It inhibits channel activation and is very slowly reversible [http://www.ncbi.nlm.nih.gov/pubmed/28320941?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4135 most potently blocks homomeric ASIC3 channels, but also ASIC2b+ASIC3, ASIC1b+ASIC3, and ASIC1a+ASIC3 heteromeric channels with IC50 values of 117 nM, 900 nM and 2 \u03bcM, respectively. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4135 has no effect on ASIC1a or ASIC2a+ASIC3, however, it does potentiate ASIC1b and ASIC2a homomers in the low micromolar range(1\u201010\u03bcM) . http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4135however also inhibits voltage\u2010gated Na+ channels . IC50 value for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4116 was determined using high throughput electrophysiology on human ASIC3 expressed in HEK293 cells [http://www.ncbi.nlm.nih.gov/pubmed/22778804?dopt=AbstractPlus]. The pEC50 values for proton activation of ASIC channels are influenced by numerous factors including extracellular di\u2010 and poly\u2010valent ions, Zn2+, protein kinase C and serine proteases . Rapid acidification is required for activation of ASIC1 and ASIC3 due to fast inactivation/desensitization. pEC50 values for H+\u2010activation of either transient, or sustained, currents mediated by ASIC3 vary in the literature and may reflect species and/or methodological differences . The transient ASIC current component is Na+\u2010selective (PNa/PK of about 10) whereas the sustained current component that is observed with ASIC3 and some ASIC heteromers is non\u2010selective between Na+ and K+ [http://www.ncbi.nlm.nih.gov/pubmed/9744806?dopt=AbstractPlus]. The reducing agents dithiothreitol (DTT) and glutathione (GSH) increase ASIC1a currents expressed in CHO cells and ASIC\u2010like currents in sensory ganglia and central neurons whereas oxidation, through the formation of intersubunit disulphide bonds, reduces currents mediated by ASIC1a [http://www.ncbi.nlm.nih.gov/pubmed/19218436?dopt=AbstractPlus]. ASIC1a is also irreversibly modulated by extracellular serine proteases, such as trypsin, through proteolytic cleavage [http://www.ncbi.nlm.nih.gov/pubmed/16282326?dopt=AbstractPlus]. Non\u2010steroidal anti\u2010inflammatory drugs (NSAIDs) are direct inhibitors of ASIC currents (reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/25613302?dopt=AbstractPlus]). Extracellular Zn2+ potentiates proton activation of homomeric and heteromeric channels incorporating ASIC2a, but not homomeric ASIC1a or ASIC3 channels [http://www.ncbi.nlm.nih.gov/pubmed/11457851?dopt=AbstractPlus]. However, removal of contaminating Zn2+ by chelation reveals a high affinity block of homomeric ASIC1a and heteromeric ASIC1a+ASIC2 channels by Zn2+ indicating complex biphasic actions of the divalent [http://www.ncbi.nlm.nih.gov/pubmed/15470133?dopt=AbstractPlus]. Nitric oxide potentiates submaximal currents activated by H+ mediated by ASIC1a, ASIC1b, ASIC2a and ASIC3 [http://www.ncbi.nlm.nih.gov/pubmed/18045919?dopt=AbstractPlus]. Ammonium ions activate ASIC channels (most likely ASIC1a) in midbrain dopaminergic neurones: that may be relevant to neuronal disorders associated with hyperammonemia [http://www.ncbi.nlm.nih.gov/pubmed/16847263?dopt=AbstractPlus]. The positive modulation of homomeric, heteromeric and native ASIC channels by the peptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4195 and related substances, such as neuropeptides FF and SF, is reviewed in detail in [http://www.ncbi.nlm.nih.gov/pubmed/25592215?dopt=AbstractPlus]. Inflammatory conditions and particular pro\u2010inflammatory mediators such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391 induce overexpression of ASIC\u2010encoding genes and enhance ASIC currents . The sustained current component mediated by ASIC3 is potentiated by hypertonic solutions in a manner that is synergistic with the effect of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391 [http://www.ncbi.nlm.nih.gov/pubmed/18923424?dopt=AbstractPlus]. ASIC3 is partially activated by the lipids lysophosphatidylcholine (LPC) and arachidonic acid [http://www.ncbi.nlm.nih.gov/pubmed/26772186?dopt=AbstractPlus]. Mit\u2010Toxin, which is contained in the venom of the Texas coral snake, activates several ASIC subtypes [http://www.ncbi.nlm.nih.gov/pubmed/22094702?dopt=AbstractPlus]. Selective activation of ASIC3 by GMQ at a site separate from the proton binding site is potentiated by mild acidosis and reduced extracellular Ca2+ [http://www.ncbi.nlm.nih.gov/pubmed/20920791?dopt=AbstractPlus].et al. (2015) Pharmacology of acid\u2010sensing ion channels \u2010 Physiological and therapeutical perspectives. Neuropharmacology94: 19\u201035 https://www.ncbi.nlm.nih.gov/pubmed/25613302?dopt=AbstractPlusBaron A et al. (2016) The function and regulation of acid\u2010sensing ion channels (ASICs) and the epithelial Na(+) channel (ENaC): IUPHAR Review 19. Br. J. Pharmacol.173: 2671\u2010701 https://www.ncbi.nlm.nih.gov/pubmed/27278329?dopt=AbstractPlusBoscardin E et al. (2017) Acid\u2010sensing ion channel (ASIC) structure and function: Insights from spider, snake and sea anemone venoms. Neuropharmacology127: 173\u2010184 https://www.ncbi.nlm.nih.gov/pubmed/28457973?dopt=AbstractPlusCristofori\u2010Armstrong B et al. (2015) Biophysical properties of acid\u2010sensing ion channels (ASICs). Neuropharmacology94: 9\u201018 https://www.ncbi.nlm.nih.gov/pubmed/25585135?dopt=AbstractPlusGr\u00fcnder S FEBS J.284: 525\u2010545 https://www.ncbi.nlm.nih.gov/pubmed/27580245?dopt=AbstractPlusHanukoglu I. (2017) ASIC and ENaC type sodium channels: conformational states and the structures of the ion selectivity filters. et al. (2015) International Union of Basic and Clinical Pharmacology. XCI. structure, function, and pharmacology of acid\u2010sensing ion channels and the epithelial Na+ channel. Pharmacol. Rev.67: 1\u201035 https://www.ncbi.nlm.nih.gov/pubmed/25287517?dopt=AbstractPlusKellenberger S Adv. Pharmacol.79: 35\u201066 https://www.ncbi.nlm.nih.gov/pubmed/28528673?dopt=AbstractPlusRash LD. (2017) Acid\u2010Sensing Ion Channel Pharmacology, Past, Present, and Future \u2026. http://www.ncbi.nlm.nih.gov/pubmed/7810611?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/7806569?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/26772908?dopt=AbstractPlus]. In these epithelia, ENaC allows flow of Na+ ions from the extracellular fluid in the lumen into the epithelial cell. Na+ ions are then pumped out of the cytoplasm into the interstitial fluid by the Na+/K+ ATPase located on the basolateral membrane [http://www.ncbi.nlm.nih.gov/pubmed/16139686?dopt=AbstractPlus]. As Na+ is one of the major electrolytes in the extracellular fluid (ECF), osmolarity change initiated by the Na+ flow is accompanied by a flow of water accompanying Na+ ions [http://www.ncbi.nlm.nih.gov/pubmed/18509340?dopt=AbstractPlus]. Thus, ENaC has a central role in the regulation of ECF volume and blood pressure, especially via its function in the kidney . The expression of ENaC subunits, hence its activity, is regulated by the renin\u2010angotensin\u2010aldosterone system, and other factors that are involved in electrolyte homeostasis . In the respiratory tract and female reproductive tract large segments of the tracts are covered by multi\u2010ciliated cells. In these cells ENaC has been shown to be located along the entire length of the cilia [http://www.ncbi.nlm.nih.gov/pubmed/22207244?dopt=AbstractPlus]. Cilial location greatly increases ENaC density per cell surface and allows ENaC to serve as a sensitive regulator of osmolarity of the periciliary fluid throughout the whole depth of the fluid bathing the cilia [http://www.ncbi.nlm.nih.gov/pubmed/22207244?dopt=AbstractPlus]. In contrast to ENaC, CFTR that is defective in cystic fibrosis is not located on non\u2010cilial cell\u2010surface [http://www.ncbi.nlm.nih.gov/pubmed/22207244?dopt=AbstractPlus]. Thus, ENaC function is also essential for the clearance of respiratory airways, transport of germ cells, fertilization, implantation and cell migration . ENaC has beenrecently localized in the germinal epithelium of the testis, Sertoli cells, spermatozoa, along the epididymis ducts, and smooth muscle cells . Evidence has been provided that rare mutations in ENaC are associated with female infertility [http://www.ncbi.nlm.nih.gov/pubmed/29885352?dopt=AbstractPlus].The epithelial sodium channels (ENaC) are located on the apical membrane of epithelial cells in the distal kidney tubules, lung, respiratory tract, male and female reproductive tracts, sweat and salivary glands, placenta, colon and some other organs . GABAA receptors exist as pentamers of 4TM subunits that form an intrinsic anion selective channel. Sequences of six \u03b1, three \u03b2, three \u03b3, one \u03b4, three \u03c1, one\u2208, one \u03c0 and one \u03d1 GABAA receptor subunits have been reported in mammals . The \u03c0\u2010subunit is restricted to reproductive tissue. Alternatively spliced versions of many subunits exist \u03b15\u2010, \u03b22\u2010, \u03b23\u2010 and \u03b32), along with RNA editing of the \u03b13 subunit [http://www.ncbi.nlm.nih.gov/pubmed/19909284?dopt=AbstractPlus]. The three \u03c1\u2010subunits, (\u03c11\u20103) function as either homo\u2010or hetero\u2010oligomeric assemblies . Receptors formed from \u03c1\u2010subunits, because of their distinctive pharmacology that includes insensitivity tobicuculline, benzodiazepines and barbiturates, have sometimes been termed GABAC receptors [http://www.ncbi.nlm.nih.gov/pubmed/11239575?dopt=AbstractPlus], A receptors by NC\u2010IUPHAR on the basis of structural and functional criteriabut they are classified as GABA .The GABAA receptor subtypes contain \u03b1\u2010, \u03b2\u2010 and \u03b3\u2010subunits with the likely stoichiometry 2\u03b1.2\u03b2.1\u03b3. It is thought that the majority of GABAA receptors harbour a single type of \u03b1\u2010 and \u03b2 \u2010subunit variant. The \u03b11\u03b22\u03b32 hetero\u2010oligomer constitutes the largest population of GABAA receptors in the CNS, followed by the \u03b12\u03b23\u03b32 and \u03b13\u03b23\u03b32 isoforms. Receptors that incorporate the \u03b14\u2010 \u03b15\u2010or \u03b16\u2010subunit, or the \u03b21\u2010, \u03b31\u2010, \u03b33\u2010, \u03b4\u2010, \u2208\u2010 and \u03d1\u2010subunits, are less numerous, but they may nonetheless serve important functions. For example, extrasynaptically located receptors that contain \u03b16\u2010 and \u03b4\u2010subunits in cerebellar granule cells, or an \u03b14\u2010 and \u03b4\u2010subunit in dentate gyrus granule cells and thalamic neurones, mediate a tonic current that is important for neuronal excitability in response to ambient concentrations of GABA . GABA binding occurs at the \u03b2+/\u03b1\u2010 subunit interface and the homologous \u03b3+/\u03b1\u2010 subunits interface creates the benzodiazepinesite. A second site for benzodiazepine binding hasrecently been postulated to occur at the \u03b1+/\u03b2\u2010 interface . The particular \u03b1\u2010and \u03b3\u2010subunit isoforms exhibit marked effects on recognition and/or efficacy at the benzodiazepine site. Thus, receptors incorporating either \u03b14\u2010 or \u03b16\u2010subunits are not recognised by \u2018classical\u2019 benzodiazepines, such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4193 (but see [http://www.ncbi.nlm.nih.gov/pubmed/20638393?dopt=AbstractPlus]). The trafficking, cell surface expression, internalisation and function of GABAA receptors and their subunits are discussed in detail in several recent reviews but one point worthy of note is that receptors incorporating the \u03b32 subunit (except when associated with \u03b15) cluster at the postsynaptic membrane , whereas as those incorporating the d subunit appear to be exclusively extrasynaptic.Many GABANC\u2010IUPHAR class the GABAA receptors according to their subunit structure, pharmacology and receptor function. Currently, eleven native GABAA receptors are classed as conclusively identified with further receptor isoforms occurring with high probability, or only tentatively . It is beyond the scope of this Guide to discuss the pharmacology of individual GABAA receptor isoforms in detail; such information can be gleaned in the reviews and . Agents that discriminate between \u03b1\u2010subunit isoforms are noted in the table and additional agents that demonstrate selectivity between receptor isoforms, for example via \u03b2\u2010subunit selectivity, are indicated in the text below. The distinctive agonist and antagonist pharmacology of \u03c1 receptors is summarised in the table and additional aspects are reviewed in .A receptor in lipid nanodiscs is bound to the channel\u2010blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (\u03b3\u2010aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam [http://www.ncbi.nlm.nih.gov/pubmed/30602790?dopt=AbstractPlus].Several high\u2010resolution cryo\u2010electron microscopy structures have been described in which the full\u2010length human \u03b11\u03b23\u03b32L GABAA receptor isoforms . For example, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4322 is a partial agonist at receptors with the subunit composition \u03b14\u03b23\u03b32, but elicits currents in excess of those evoked by GABA at the \u03b14\u03b23\u03b4 receptor where GABA itself is a low efficacy agonist . The antagonists http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2312 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4197 differ in their ability to suppress spontaneous openings of the GABAA receptor, the former being more effective [http://www.ncbi.nlm.nih.gov/pubmed/10455284?dopt=AbstractPlus]. The presence of the \u03b3 subunit within the heterotrimeric complex reduces the potency and efficacy of agonists [http://www.ncbi.nlm.nih.gov/pubmed/16272218?dopt=AbstractPlus]. The GABAA receptor contains distinct allosteric sites that bind barbiturates and endogenous and synthetic neuroactive steroids in a diastereo\u2010 or enantio\u2010selective manner . Picrotoxinin and TBPS act at an allosteric site within the chloride channel pore to negatively regulate channel activity; negative allosteric regulation by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5462 derivatives also involves the http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2291 site, whereas positive allosteric regulation by such compounds is proposed to occur at a distinct locus. Many intravenous and inhalational anaesthetics and alcohols also exert a regulatory influence upon GABAA receptor activity . Specific amino acid residues within GABAA receptor \u03b1\u2010 and \u03b2\u2010subunits that influence allosteric regulation by anaesthetic and non\u2010anaesthetic compounds havebeen identified . Photoaffinity labelling of distinct amino acid residues within purified GABAA receptors by the etomidate derivative, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5404, has also been demonstrated [http://www.ncbi.nlm.nih.gov/pubmed/17093081?dopt=AbstractPlus] and this binding subject to positive allosteric regulation by anaesthetic steroids [http://www.ncbi.nlm.nih.gov/pubmed/19282280?dopt=AbstractPlus]. An array of natural products including flavonoid and terpenoid compounds exert varied actions at GABAA receptors (reviewed in detail in [http://www.ncbi.nlm.nih.gov/pubmed/15974965?dopt=AbstractPlus]).The potency and efficacy of many GABA agonists vary between GABAA receptor activity that exhibit subunit dependent activity include: http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5465 ]; fragrent dioxane derivatives ]; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5466, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5463, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5467, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2593, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5468, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5469, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5470 ]; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5467 ]; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2421 [selective blockade of receptors containing an \u03b16\u2010subunit [http://www.ncbi.nlm.nih.gov/pubmed/12021393?dopt=AbstractPlus]]; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4839 ]; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2434 ]; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2299 , but see also [http://www.ncbi.nlm.nih.gov/pubmed/17591542?dopt=AbstractPlus]]; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4183 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4184 [selectively potentiate responses mediated by \u03b4\u2010subunitcontaining receptors [http://www.ncbi.nlm.nih.gov/pubmed/18762200?dopt=AbstractPlus]]. It should be noted that the apparent selectivity of some positive allosteric modulators may be a consequence of the unusually low efficacy of GABA at this receptor isoform .In addition to the agents listed in the table, modulators of GABACNS Neurosci Ther14: 25\u201035 https://www.ncbi.nlm.nih.gov/pubmed/18482097?dopt=AbstractPlusAtack JR. (2008) GABA(A) receptor subtype\u2010selective efficacy: TPA023, an alpha2/alpha3 selective non\u2010sedating anxiolytic and alpha5IA, an alpha5 selective cognition enhancer. et al. (2015) The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders. Neuron86: 1119\u201030 https://www.ncbi.nlm.nih.gov/pubmed/26050032?dopt=AbstractPlusBraat S et al. (2016) Dynamic Regulation of the GABAA Receptor Function by Redox Mechanisms. Mol. Pharmacol.90: 326\u201033 https://www.ncbi.nlm.nih.gov/pubmed/27439531?dopt=AbstractPlusCalvo DJ et al. (2019) GABA_A receptor signalling mechanisms revealed by structural pharmacology. Nature565: 454\u2010459 https://www.ncbi.nlm.nih.gov/pubmed/30602790?dopt=AbstractPlusMasiulis S et al. (2016) Role of GABA_A R trafficking in the plasticity of inhibitory synapses. J. Neurochem.139: 997\u20101018 https://www.ncbi.nlm.nih.gov/pubmed/27424566?dopt=AbstractPlusMele M NC\u2010IUPHAR Subcommittee on Glycine Receptorsnomenclature as agreed by the ) is a member of the Cys\u2010loop superfamily of transmittergated ion channels that includes the zinc activated channels, GABAA, nicotinic acetylcholine and 5\u2010HT3 receptors [http://www.ncbi.nlm.nih.gov/pubmed/18721822?dopt=AbstractPlus]. The receptor is expressed either as a homo\u2010pentamer of \u03b1 subunits, or a complex now thought to harbour 2\u03b1 and 3\u03b2 subunits , that contain an intrinsic anion channel. Four differentially expressed isoforms of the \u03b1\u2010subunit (\u03b11\u2010\u03b14) and one variant of the \u03b2\u2010subunit have been identified by genomic and cDNA cloning. Further diversity originates from alternative splicing of the primary gene transcripts for \u03b11 (\u03b11INS and \u03b11del), \u03b12 (\u03b12A and \u03b12B), \u03b13 (\u03b13S and \u03b13L) and \u03b2 (\u03b2\u03947) subunits and by mRNA editing of the \u03b12 and \u03b13 subunit . Both \u03b12 splicing and \u03b13 mRNA editing can produce subunits with enhanced agonist sensitivity. Predominantly, the mature form of the receptor contains \u03b11 (or \u03b13) and \u03b2 subunits while the immature form is mostly composed of only \u03b12 subunits. RNA transcripts encoding the \u03b14\u2010subunit have not been detected in adult humans. The N\u2010terminal domain of the \u03b1\u2010subunit contains both the agonist and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=347 binding sites that consist of several discontinuous regions of amino acids. Inclusion of the \u03b2\u2010subunit in the pentameric glycine receptor contributes to agonist binding, reduces single channel conductance and alters pharmacology. The \u03b2\u2010subunit also anchors the receptor, via an amphipathic sequence within the large intracellular loop region, to gephyrin. The latter is a cytoskeletal attachment protein that binds to a number of subsynaptic proteins involved in cytoskeletal structure and thus clusters and anchors hetero\u2010oligomeric receptors to the synapse . G\u2010protein \u03b2\u03b3 subunits enhance the open state probability of native and recombinant glycine receptors by association with domains within the large intracellular loop . Intracellular chloride concentration modulates the kinetics of native and recombinant glycine receptors [http://www.ncbi.nlm.nih.gov/pubmed/18987182?dopt=AbstractPlus]. Intracellular Ca2+ appears to increase native and recombinant glycine receptor affinity, prolonging channel open events, by a mechanism that does not involve phosphorylation [http://www.ncbi.nlm.nih.gov/pubmed/11144365?dopt=AbstractPlus].The inhibitory glycine receptor . http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4290, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=260 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2367, for example, although not selective antagonists of glycine receptors, are included for this purpose. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=347 is a potent and selective competitive glycine receptor antagonist with affinities in the range 5\u201315 nM. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2378 demonstrates comparable potency, but additionally blocks GABAA receptors. There are conflicting reports concerning the ability of cannabinoids to inhibit [http://www.ncbi.nlm.nih.gov/pubmed/16107637?dopt=AbstractPlus], or potentiate and at high concentrations activate glycine receptors. Nonetheless, cannabinoid analogues may hold promise in distinguishing between glycine receptor subtypes [http://www.ncbi.nlm.nih.gov/pubmed/18755158?dopt=AbstractPlus]. In addition, potentiation of glycine receptor activity by cannabinoids has been claimed to contribute to cannabis\u2010induced analgesia relying on Ser296/307 (\u03b11/\u03b13) in M3 [http://www.ncbi.nlm.nih.gov/pubmed/21460829?dopt=AbstractPlus]. Several analogues of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4259 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5477 act as agonists and antagonists of both glycine and GABAA receptors. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4051 acts as an allosteric inhibitor that appears to bind within the pore, and shows strong selectivity towards homomeric receptors. While its components, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2291 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4286, have equal potencies at \u03b11 receptors, their potencies at \u03b12 and \u03b13 receptors differ modestly and may allow some distinction between different receptor types [http://www.ncbi.nlm.nih.gov/pubmed/17714449?dopt=AbstractPlus]. Binding of picrotoxin within the pore has been demonstrated in the crystal structure of the related C. elegans GluCl Cys\u2010loop receptor [http://www.ncbi.nlm.nih.gov/pubmed/21572436?dopt=AbstractPlus]. In addition to the compounds listed in the table, numerous agents act as allosteric regulators of glycine receptors . Zn2+ acts through distinct binding sites of high\u2010 and low\u2010affinity to allosterically enhance channel function at low (<10 \u03bcM) concentrations and inhibits responses at higher concentrations in a subunit selective manner [http://www.ncbi.nlm.nih.gov/pubmed/15905212?dopt=AbstractPlus]. The effect of Zn2+ is somewhat mimicked by Ni2+. Endogenous Zn2+ is essential for normal glycinergic neurotransmission mediated by \u03b11 subunit\u2010containing receptors [http://www.ncbi.nlm.nih.gov/pubmed/17114051?dopt=AbstractPlus]. Elevation of intracellular Ca2+ produces fast potentiation of glycine receptor\u2010mediated responses. Dideoxyforskolin (4 \u03bcM) and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1016 (0.2\u20135 \u03bcM) both potentiate responses to low glycine concentrations (15 \u03bcM), but act as inhibitors at higher glycine concentrations (100 \u03bcM). Additional modulatory agents that enhance glycine receptor function include inhalational, and several intravenous general anaesthetics and certain neurosteroids. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2299 and higher order n\u2010alcohols also enhance glycine receptor function although whether this occurs by a direct allosteric action at the receptor [http://www.ncbi.nlm.nih.gov/pubmed/10908659?dopt=AbstractPlus], or through \u03b2\u03b3 subunits [http://www.ncbi.nlm.nih.gov/pubmed/20647311?dopt=AbstractPlus] is debated. Recent crystal structures of the bacterial homologue, GLIC, have identified transmembrane binding pockets for both anaesthetics [http://www.ncbi.nlm.nih.gov/pubmed/21248852?dopt=AbstractPlus] and alcohols [http://www.ncbi.nlm.nih.gov/pubmed/21730162?dopt=AbstractPlus]. Solvents inhaled as drugs of abuse may act at sites that overlap with those recognising alcohols and volatile anaesthetics to produce potentiation of glycine receptor function. The function of glycine receptors formed as homomeric complexes of \u03b11 or \u03b12 subunits, or hetero\u2010oligomers of \u03b11/\u03b2 or \u03b12/\u03b2 subunits, is differentially affected by the 5\u2010HT3 receptor antagonist tropisetron (ICS 205\u2010930) which may evoke potentiation (which may occur within the femtomolar range at the homomeric glycine \u03b11 receptor), or inhibition, depending upon the subunit composition of the receptor and the concentrations of the modulator and glycine employed. Potentiation and inhibition by tropeines involves different binding modes [http://www.ncbi.nlm.nih.gov/pubmed/19383091?dopt=AbstractPlus]. Additional tropeines, including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=320, modulate glycine receptor activity.Data in the table refer to homo\u2010oligomeric assemblies of the \u03b1\u2010subunit, significant changes introduced by coexpression of the \u03b21 subunit are indicated in parenthesis. Not all glycine receptor ligands are listed within the table, but some that may be useful in distinguishing between glycine receptor isoforms are indicated Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors. Mol. Pharmacol. 90: 318\u201025 https://www.ncbi.nlm.nih.gov/pubmed/27401877?dopt=AbstractPlusBurgos CF et al. (2012) Inhibitory glycine receptors: an update. J. Biol. Chem. 287: 40216\u201023 https://www.ncbi.nlm.nih.gov/pubmed/23038260?dopt=AbstractPlusDutertre S Physiol. Rev.84: 1051\u201095 https://www.ncbi.nlm.nih.gov/pubmed/15383648?dopt=AbstractPlusLynch JW. (2004) Molecular structure and function of the glycine receptor chloride channel. et al. (2010) Molecular targets and mechanisms for ethanol action in glycine receptors. Pharmacol. Ther. 127: 53\u201065 https://www.ncbi.nlm.nih.gov/pubmed/20399807?dopt=AbstractPlusPerkins DI et al. (2011) Allosteric modulation of glycine receptors. Br. J. Pharmacol. 164: 224\u201036 https://www.ncbi.nlm.nih.gov/pubmed/21557733?dopt=AbstractPlusYevenes GE http://www.ncbi.nlm.nih.gov/pubmed/10049997?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18765242?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20716669?dopt=AbstractPlus]. Receptor heterogeneity within each class arises from the homo\u2010oligomeric, or hetero\u2010oligomeric, assembly of distinct subunits into cation\u2010selective tetramers. Each subunit of the tetrameric complex comprises an extracellular amino terminal domain (ATD), an extracellular ligand binding domain (LBD), three transmembrane domains composed of three membrane spans , a channel lining re\u2010entrant \u2018p\u2010loop\u2019 (M2) located between M1 and M3 and an intracellular carboxy\u2010 terminal domain (CTD) . The X\u2010ray structure of a homomeric ionotropic glutamate receptor (GluA2 \u2013 see below) has recently been solved at 3.6\u00c5 resolution [http://www.ncbi.nlm.nih.gov/pubmed/19946266?dopt=AbstractPlus] and although providing the most complete structural information current available may not representative of the subunit arrangement of, for example, the heteromeric NMDA receptors [http://www.ncbi.nlm.nih.gov/pubmed/21677647?dopt=AbstractPlus]. It is beyond the scope of this supplement to discuss the pharmacology of individual ionotropic glutamate receptor isoforms in detail; such information can be gleaned from . Agents that discriminate between subunit isoforms are, where appropriate, noted in the tables and additional compounds that distinguish between receptor isoforms are indicated in the text below.The ionotropic glutamate receptors comprise members of the NMDA (N\u2010methyl\u2010D\u2010aspartate), AMPA (\u03b1\u2010amino3\u2010hydroxy\u20105\u2010methyl\u20104\u2010isoxazoleproprionic acid) and kainate receptor classes, named originally according to their preferred, synthetic, agonist [NC\u2010IUPHARThe classification of glutamate receptor subunits has been re\u2010addressed by [http://www.ncbi.nlm.nih.gov/pubmed/18655795?dopt=AbstractPlus]. The scheme developed recommends a nomenclature for ionotropic glutamate receptor subunits that is adopted here.http://www.ncbi.nlm.nih.gov/pubmed/18026130?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/21521608?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18514334?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/20134027?dopt=AbstractPlus]). Functional kainate receptors can be expressed as homomers of GluK1, GluK2 or GluK3 subunits. GluK1\u20103 subunits are also capable of assembling into heterotetramers . Two additional kainate receptor subunits, GluK4 and GluK5, when expressed individually, form high affinity binding sites for http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4231, but lack function, but can form heteromers when expressed with GluK1\u20103 subunits . Kainate receptors may also exhibit \u2018metabotropic\u2019 functions . As found for AMPA receptors, kainate receptors are modulated by auxiliary subunits . An important function difference between AMPA and kainate receptors is that the latter require extracellular Na+ and Cl\u2010 for their activation . RNA encoding the GluA2 subunit undergoes extensive RNA editing in which the codon encoding a p\u2010loop glutamine residue (Q) is converted to one encoding arginine (R). This Q/R site strongly influences the biophysical properties of the receptor. Recombinant AMPA receptors lacking RNA edited GluA2 subunits are: (1) permeable to Ca2+; (2) blocked by intracellular polyamines at depolarized potentials causing inward rectification (the latter being reduced by TARPs); (3) blocked by extracellular argiotoxin and Joro spider toxins and (4) demonstrate higher channel conductances than receptors containing the edited form of GluA2 . GluK1 and GluK2, but not other kainate receptor subunits, are similarly edited and broadly similar functional characteristics apply to kainate receptors lacking either an RNA edited GluK1, or GluK2, subunit . Native AMPA and kainate receptors displaying differential channel conductances, Ca2+ permeabilites and sensitivity to block by intracellular polyamines have been identified . GluA1\u20104 can exist as two variants generated by alternative splicing (termed \u2018flip\u2019 and \u2018flop\u2019) that differ in their desensitization kinetics and their desensitization in the presence of cyclothiazide which stabilises the nondesensitized state. TARPs also stabilise the non\u2010desensitized conformation of AMPA receptors and facilitate the action of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4167 [http://www.ncbi.nlm.nih.gov/pubmed/18514334?dopt=AbstractPlus]. Splice variants of GluK1\u20103 also exist which affects their trafficking .AMPA receptors assemble as homomers, or heteromers, that may be drawn from GluA1, GluA2, GluA3 and GluA4 subunits. Transmembrane AMPA receptor regulatory proteins (TARPs) of class I act, with variable stoichiometry, as auxiliary subunits to AMPA receptors and influence their trafficking, single channel conductance gating and pharmacology with relatively low potency, (EC50 100 \u03bcM). Inclusion of TARPs within the receptor complex increases the potency and maximal effect of kainate . AMPA is weak partial agonist at GluK1 and at heteromeric assemblies of GluK1/GluK2, GluK1/GluK5 and GluK2/GluK5 [http://www.ncbi.nlm.nih.gov/pubmed/18793656?dopt=AbstractPlus]. Quinoxalinediones such as http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5475 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4264 show limited selectivity between AMPA and kainate receptors. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4245 also has kainate (GluK1) receptor activity as has http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4209 (GluK3 and GluK2/GluK3) [http://www.ncbi.nlm.nih.gov/pubmed/18793656?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4141 is a potent competitive antagonist of AMPA receptors, has a weaker antagonist action at kainate receptors comprising GluK1 subunits, butis devoid of activity at kainate receptors formed from GluK2 or GluK2/GluK5 subunits. The pharmacological activity of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4141 resides with the (S)\u2010enantiomer. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4123 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4334 may block GluK3, in addition to GluK1 . \u20104\u2010methylglutamate (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4317) is equipotent in activating (and desensitising) GluK1 and GluK2 receptor isoforms and, via the induction of desensitisation at low concentrations, has beenused as a functional antagonist of kainate receptors. Both \u20104\u2010methylglutamate and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4246 have agonist activity at NMDA receptors. \u20104\u2010methylglutamate is also an inhibitor of the glutamate transporters EAAT1 and EAAT2.All AMPA receptors are additionally activated by http://www.ncbi.nlm.nih.gov/pubmed/16474411?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15701057?dopt=AbstractPlus]. The minimal requirement for efficient functional expression of NMDA receptors in vitro is a di\u2010heteromeric assembly of GluN1 and at least one GluN2 subunit variant, as a dimer of heterodimers arrangement in the extracellular domain . However, more complex tri\u2010heteromeric assemblies, incorporating multiple subtypes of GluN2 subunit, or GluN3 subunits, can be generatedin vitro and occurin vivo. The NMDA receptor channel commonly has a high relative permeability to Ca2+ and is blocked, in a voltage\u2010dependent manner, by Mg2+ such that at resting potentials the response is substantially inhibited.NMDA receptors assemble as obligate heteromers that may be drawn from GluN1, GluN2A, GluN2B, GluN2C, GluN2D, GluN3A and GluN3B subunits. Alternative splicing can generate eight isoforms of GluN1 with differing pharmacological properties. Various splice variants of GluN2B, 2C, 2D and GluN3A have also been reported. Activation of NMDA receptors containing GluN1 and GluN2 subunits requires the binding of two agonists, glutamate to the S1 and S2 regions of the GluN2 subunit and glycine to S1 and S2 regions of the GluN1 subunit . In addition to the glutamate and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=727 binding sites documented in the table, physiologically important inhibitory modulatory sites exist for Mg2+, Zn2+, and protons . Voltage\u2010independent inhibition by Zn2+ binding with high affinity within the ATD is highly subunit selective . The receptor is also allosterically modulated, in both positive and negative directions, by endogenous neuroactive steroids in a subunit dependent manner . Tonic proton blockade of NMDA receptor function is alleviated by polyamines and the inclusion of exon 5 within GluN1 subunit splice variants, whereas the non\u2010competitive antagonists http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5472 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4163 increase the fraction of receptors blocked by protons at ambient concentration. Inclusion of exon 5 also abolishes potentiation by polyamines and inhibition by Zn2+ that occurs through binding in the ATD [http://www.ncbi.nlm.nih.gov/pubmed/9698310?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5472, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4163, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=86, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5473 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4300 discriminate between recombinant NMDA receptors assembled from GluN1 and either GluN2A, or GluN2B, subunits by acting as selective, non\u2010competitive, antagonists of heterooligomers incorporating GluN2B through a binding site at the ATD GluN1/GluN2B subunit interface [http://www.ncbi.nlm.nih.gov/pubmed/21677647?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4244 is a competitive antagonist that also displays selectivity for GluN2B over GluN2A subunit\u2010containing receptors. Similarly, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5474 is a photoaffinity label that interacts selectively with receptors incorporating GluN2B versus GluN2A, GluN2D and, to a lesser extent, GluN2C subunits. TCN 201 and TCN 213 have recently been shown to block GluN2A NMDA receptors selectively by a mechanism that involves allosteric inhibition of glycine binding to the GluN1 site . In addition to influencing the pharmacological profile of the NMDA receptor, the identity of the GluN2 subunit co\u2010assembled with GluN1 is an important determinant of biophysical properties that include sensitivity to block by Mg2+, single\u2010channel conductance and maximal open probablity and channel deactivation time . Incorporation of the GluN3A subunit into tri\u2010heteromers containing GluN1 and GluN2 subunits is associated with decreased single\u2010channel conductance, reduced permeability to Ca2+ and decreased susceptibility to block by Mg2+ . Reduced permeability to Ca2+ has also been observed following the inclusion of GluN3B in tri\u2010heteromers. The expression of GluN3A, or GluN3B, with GluN1 alone forms, in Xenopus laevis oocytes, a cation channel with unique properties that include activation by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=727 (but not http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4268), lack of permeation by Ca2+ and resistance to blockade by Mg2+ and NMDA receptor antagonists [http://www.ncbi.nlm.nih.gov/pubmed/11823786?dopt=AbstractPlus]. The function of heteromers composed of GluN1 and GluN3A is enhanced by Zn2+, or glycine site antagonists, binding to the GluN1 subunit [http://www.ncbi.nlm.nih.gov/pubmed/18711142?dopt=AbstractPlus]. Zn2+ also directly activates such complexes. The co\u2010expression of GluN1, GluN3A and GluN3B appears to be required to form glycine\u2010activated receptors in mammalian cell hosts [http://www.ncbi.nlm.nih.gov/pubmed/17502428?dopt=AbstractPlus].Potency orders unreferenced in the table are from . All nicotinic receptors are pentamers in which each of the five subunits contains four \u03b1\u2010helical transmembrane domains. Genes encoding a total of 17 subunits have been identified [http://www.ncbi.nlm.nih.gov/pubmed/17651090?dopt=AbstractPlus]. All subunits with the exception of \u03b18 (present in avian species) have been identified in mammals. All \u03b1 subunits possess two tandem cysteine residues near to the site involved in acetylcholine binding, and subunits not named \u03b1 lack these residues [http://www.ncbi.nlm.nih.gov/pubmed/18723036?dopt=AbstractPlus]. The orthosteric ligand binding site is formed by residues within at least three peptide domains on the \u03b1 subunit , and three on the adjacent subunit (complementary component). nAChRs contain several allosteric modulatory sites. One such site, for positive allosteric modulators (PAMs) and allosteric agonists, has been proposed to reside within an intrasubunit cavity between the four transmembrane domains ; see also [http://www.ncbi.nlm.nih.gov/pubmed/21572436?dopt=AbstractPlus]). The high resolution crystal structure of the molluscan acetylcholine binding protein, a structural homologue of the extracellular binding domain of a nicotinic receptor pentamer, in complex with several nicotinic receptor ligands (e.g.[http://www.ncbi.nlm.nih.gov/pubmed/15046723?dopt=AbstractPlus]) and the crystal structure of the extracellular domain of the \u03b11 subunit bound to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3964 at 1.94 \u00c5 resolution [http://www.ncbi.nlm.nih.gov/pubmed/17643119?dopt=AbstractPlus], has revealed the orthosteric binding site in detail . Nicotinic receptors at the somatic neuromuscular junction of adult animals have the stoichiometry (\u03b11)2\u03b21\u03b4\u03f5, whereas an extrajunctional (\u03b11)2\u03b21\u03b3\u03b4 receptor predominates in embryonic and denervated skeletal muscle and other pathological states. Other nicotinic receptors are assembled as combinations of \u03b1(2\u20106) and \u03b2(2\u20104) subunits. For \u03b12, \u03b13, \u03b14 and \u03b22 and \u03b24 subunits, pairwise combinations of \u03b1 and \u03b2 (e.g. \u03b13\u03b24 and \u03b14\u03b22) are sufficient to form a functional receptor in vitro, but far more complex isoforms may exist in vivo . There is strong evidence that the pairwise assembly of some \u03b1 and \u03b2 subunits can occur with variable stoichiometry [e.g. (\u03b14)2(\u03b22)2 or (\u03b14)3(\u03b22)2] which influences the biophysical and pharmacological properties of the receptor [http://www.ncbi.nlm.nih.gov/pubmed/18723036?dopt=AbstractPlus]. \u03b15 and \u03b23 subunits lack function when expressed alone, or pairwise, but participate in the formation of functional hetero\u2010oligomeric receptors when expressed as a third subunit with another \u03b1 and \u03b2 pair for further examples]. The \u03b16 subunit can form a functional receptor when co\u2010expressed with \u03b24 in vitro, but more efficient expression ensues from incorporation of a third partner, such as \u03b23 [http://www.ncbi.nlm.nih.gov/pubmed/19498417?dopt=AbstractPlus]. The \u03b17, \u03b18, and \u03b19 subunits form functional homo\u2010oligomers, but can also combine with a second subunit to constitute a hetero\u2010oligomeric assembly (e.g. \u03b17\u03b22 and \u03b19\u03b110). For functional expression of the \u03b110 subunit, co\u2010assembly with \u03b19 is necessary. The latter, along with the \u03b110 subunit, appears to be largely confined to cochlear and vestibular hair cells. Comprehensive listings of nicotinic receptor subunit combinations identified from recombinant expression systems, or in vivo, are given in [http://www.ncbi.nlm.nih.gov/pubmed/18723036?dopt=AbstractPlus]. In addition, numerous proteins interact with nicotinic ACh receptors modifying their assembly, trafficking to and from the cell surface, and activation by ACh .Nicotinic acetylcholine receptors are members of the Cys\u2010loop family of transmitter\u2010gated ion channels that includes the GABANC\u2010IUPHAR has recommended a nomenclature and classification scheme for nicotinic acetylcholine (nACh) receptors based on the subunit composition of known, naturally\u2010 and/or heterologously\u2010expressed nACh receptor subtypes [http://www.ncbi.nlm.nih.gov/pubmed/10353988?dopt=AbstractPlus]. Headings for this table reflect abbreviations designating nACh receptor subtypes based on the predominant \u03b1 subunit contained in that receptor subtype. An asterisk following the indicated \u03b1 subunit denotes that other subunits are known to, or may, assemble with the indicated \u03b1 subunit to form the designated nACh receptor subtype(s). Where subunit stoichiometries within a specific nACh receptor subtype are known, numbers of a particular subunit larger than 1 are indicated by a subscript following the subunit .The nicotinic receptor Subcommittee of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5460, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5347, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3967, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5348, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2585 and the natural transmitter, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=294 (ACh). A summary of their profile across differing receptors is provided in [http://www.ncbi.nlm.nih.gov/pubmed/16876883?dopt=AbstractPlus] and quantitative data across numerous assay systems are summarized in [http://www.ncbi.nlm.nih.gov/pubmed/16033252?dopt=AbstractPlus]. Quantitative data presented in the table for commonly used antagonists and channel blockers for human receptors studied under voltage\u2010clamp are from . Type I PAMs increase peak agonist\u2010evoked responses but have little, or no, effect on the rate of desensitization of \u03b17 nicotinic ACh receptors whereas type II PAMs also cause a large reduction in desensitization (reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/21575610?dopt=AbstractPlus]).Commonly used agonists of nACh receptors that display limited discrimination in functional assays between receptor subtypes include Neuropharmacology96: 150\u20106 https://www.ncbi.nlm.nih.gov/pubmed/25446670?dopt=AbstractPlusAuerbach A. (2015) Agonist activation of a nicotinic acetylcholine receptor. et al. (2015) Therapeutic Potential of \u03b17 Nicotinic Acetylcholine Receptors. Pharmacol. Rev.67: 1025\u201073 https://www.ncbi.nlm.nih.gov/pubmed/26419447?dopt=AbstractPlusBertrand D et al. (2018) Nicotinic acetylcholine receptors at the single\u2010channel level. Br. J. Pharmacol.175: 1789\u20101804 https://www.ncbi.nlm.nih.gov/pubmed/28261794?dopt=AbstractPlusBouzat C et al. (2015) Allosteric modulation of nicotinic acetylcholine receptors. Biochem. Pharmacol.97: 408\u2010417 https://www.ncbi.nlm.nih.gov/pubmed/26231943?dopt=AbstractPlusChatzidaki A et al. (2016) Understanding the Bases of Function and Modulation of \u03b17 Nicotinic Receptors: Implications for Drug Discovery. Mol. Pharmacol.90: 288\u201099 https://www.ncbi.nlm.nih.gov/pubmed/27190210?dopt=AbstractPlusCorradi J et al. (2018) Proteins and chemical chaperones involved in neuronal nicotinic receptor expression and function: an update. Br. J. Pharmacol.175: 1869\u20101879 https://www.ncbi.nlm.nih.gov/pubmed/28294298?dopt=AbstractPlusCrespi A et al. (2015) Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol. Sci.36: 96\u2010108 https://www.ncbi.nlm.nih.gov/pubmed/25639674?dopt=AbstractPlusDineley KT et al. (1999) International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits. Pharmacol. Rev.51: 397\u2010401 https://www.ncbi.nlm.nih.gov/pubmed/10353988?dopt=AbstractPlusLukas RJ et al. (2015) Looking below the surface of nicotinic acetylcholine receptors. Trends Pharmacol. Sci.36: 514\u201023 https://www.ncbi.nlm.nih.gov/pubmed/26067101?dopt=AbstractPlusStokes C et al. (2018) Orthosteric and allosteric potentiation of heteromeric neuronal nicotinic acetylcholine receptors. Br. J. Pharmacol.175: 1805\u20101821 https://www.ncbi.nlm.nih.gov/pubmed/28199738?dopt=AbstractPlusWang J etal. (2016)Heteromeric \u03b17\u03b22 Nicotinic Acetylcholine Receptors in the Brain. Trends Pharmacol. Sci.37: 562\u2010574 https://www.ncbi.nlm.nih.gov/pubmed/27179601?dopt=AbstractPlusWu J NC\u2010IUPHAR Subcommittee on P2X Receptorsnomenclature as agreed by the ) have a trimeric topology with two putative TM domains, gating primarily Na+, K+ and Ca2+, exceptionally Cl\u2010. The Nomenclature Subcommittee has recommended that for P2X receptors, structural criteria should be the initial criteria for nomenclature where possible. X\u2010ray crystallography indicates that functional P2X receptors are trimeric and three agonist molecules are required to bind to a single receptor in order to activate it . Native receptors may occur as either homotrimers (e.g. P2X1 in smooth muscle) or heterotrimers may be inhibited by desensitisation using stable agonists (e.g. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4093\u2010http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4093); http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1728 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1725 are non\u2010selective antagonists at rat and human P2X1\u20103,5 and hP2X4, but not rP2X4,6,7 [http://www.ncbi.nlm.nih.gov/pubmed/8598206?dopt=AbstractPlus], and can also inhibit ATPase activity [http://www.ncbi.nlm.nih.gov/pubmed/7889301?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4225 is inactive at rP2X2, an antagonist at rP2X3 (pIC50 5.6) and enhances agonist responses at rP2X4 [http://www.ncbi.nlm.nih.gov/pubmed/10556935?dopt=AbstractPlus]. Antagonist potency of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4266 at recombinant P2X2, P2X3 and P2X5 is two orders of magnitude lower than that at P2X1 receptors [http://www.ncbi.nlm.nih.gov/pubmed/10193905?dopt=AbstractPlus]. The P2X7 receptor may be inhibited in a non\u2010competitive manner by the protein kinase inhibitors http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4235 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5953 [http://www.ncbi.nlm.nih.gov/pubmed/15210579?dopt=AbstractPlus], while the p38 MAP kinase inhibitor http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4207 and the cyclic imide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4142 show a species\u2010dependent non\u2010competitive action .Agonists listed show selectivity within recombinant P2X receptors of http://www.ncbi.nlm.nih.gov/pubmed/15778739?dopt=AbstractPlus]. Some recombinant P2X receptors expressed to high density bind http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5406 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5405\u2010http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5405, although the latter can also bind to 5\u2010nucleotidase [http://www.ncbi.nlm.nih.gov/pubmed/8548175?dopt=AbstractPlus]. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5407 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5408 have been used as high affinity antagonist radioligands for P2X3 (and P2X2/3) and P2X7 receptors, respectively [http://www.ncbi.nlm.nih.gov/pubmed/19558545?dopt=AbstractPlus]. Several high affinity radioligands for the P2X7 receptor have been recently synthesized . http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=9540 has shown clinical efficacy in reducing refractory chronic cough [http://www.ncbi.nlm.nih.gov/pubmed/25467586?dopt=AbstractPlus].The pH\u2010sensitive dye used in culture media, phenol red, is also reported to inhibit P2X1 and P2X3 containing channels . The channel is likely to exist as a homopentamer of 4TM subunits that form an intrinsic cation selective channel equipermeable to Na+, K+ and Cs+, but impermeable to Ca2+ and Mg2+ [http://www.ncbi.nlm.nih.gov/pubmed/26872532?dopt=AbstractPlus]. ZAC displays constitutive activity that can be blocked by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2294 and high concentrations of Ca2+ [http://www.ncbi.nlm.nih.gov/pubmed/26872532?dopt=AbstractPlus]. Although denoted ZAC, the channel is more potently activated by protons and copper, with greater and lesser efficacy than zinc, respectively [http://www.ncbi.nlm.nih.gov/pubmed/26872532?dopt=AbstractPlus]. ZAC is present in the human, chimpanzee, dog, cow and opossum genomes, but is functionally absent from mouse, or rat, genomes .The zinc\u2010activated channel by transition metals including Fe2+, Co2+, Ni2+, Cd2+, or Al3+ [http://www.ncbi.nlm.nih.gov/pubmed/26872532?dopt=AbstractPlus]. The concentration response relationship to Cu2+ is biphasic, with concentrations exceeding 30 \u03bcM being associated with reduced activation [http://www.ncbi.nlm.nih.gov/pubmed/26872532?dopt=AbstractPlus].The ZAC subunit does not appear to exist in the mouse or rat genomes [et al. (2009) A nomenclature for ligand\u2010gated ion channels. Neuropharmacology56: 2\u20105 https://www.ncbi.nlm.nih.gov/pubmed/18655795?dopt=AbstractPlusCollingridge GL et al. (2016) Zinc as Allosteric Ion Channel Modulator: Ionotropic Receptors as Metalloproteins. Int J Mol Sci17: https://www.ncbi.nlm.nih.gov/pubmed/27384555?dopt=AbstractPlusPeralta FA et al. (2016) Copper and protons directly activate the zinc\u2010activated channel. Biochem. Pharmacol.103: 109\u201017 https://www.ncbi.nlm.nih.gov/pubmed/26872532?dopt=AbstractPlusTrattnig SM http://www.ncbi.nlm.nih.gov/pubmed/16036917?dopt=AbstractPlus]. In addition to their prominence in signal transduction, these ion channels are also among the most common drug targets. As for other large protein superfamilies, understanding the molecular relationships among family members, developing a unified, rational nomenclature for the ion channel families and subfamilies, and assigning physiological functions and pharmacological significance to each family member has been an important challenge.The voltage\u2010gated ion channels and their structural relatives comprise a superfamily encoded by at least 143 genes in the human genome and are therefore one of the largest superfamilies of signal transduction proteins, following the G proteincoupled receptors and the protein kinases in number [et al. (2005) Introduction to the IUPHAR Compendium of Voltage\u2010Gated Ion Channels 2005 Pharmacological Reviews57: 385Catterall WA NC\u2010IUPHARnomenclature as agreed by [http://www.ncbi.nlm.nih.gov/pubmed/16382101?dopt=AbstractPlus]) are putative 6TM, voltage\u2010gated, alkalinization\u2010activated calcium permeant channels that are presumed to assemble as a tetramer of \u03b1\u2010like subunits and mediate the current ICatSper [http://www.ncbi.nlm.nih.gov/pubmed/16467839?dopt=AbstractPlus]. In mammals, CatSper subunits are structurally most closely related to individual domains of voltageactivated calcium channels (Cav) [http://www.ncbi.nlm.nih.gov/pubmed/11595941?dopt=AbstractPlus]. CatSper1 [http://www.ncbi.nlm.nih.gov/pubmed/11595941?dopt=AbstractPlus], CatSper2 [http://www.ncbi.nlm.nih.gov/pubmed/11675491?dopt=AbstractPlus] and CatSpers 3 and 4 , in common with a putative 2TM auxiliary CatSper\u03b2 protein [http://www.ncbi.nlm.nih.gov/pubmed/17478420?dopt=AbstractPlus] and two putative 1TM associated CatSper\u03b3 and CatSper\u03b4 proteins , are restricted to the testis and localised to the principle piece of sperm tail. The novel cross\u2010species CatSper channel inhibitor, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=10266, has been proposed as a useful tool to aid characterisation of native CatSper channels [http://www.ncbi.nlm.nih.gov/pubmed/29723408?dopt=AbstractPlus].CatSper channels are structurally related to CatSpers, CaVs and NaVs. TPCs have a 2x6TM structure with twice the number of TMs of CatSpers and half that of CaVs. There are three animal TPCs (TPC1\u2010TPC3). Humans have TPC1 and TPC2, but not TPC3. TPC1 and TPC2 are localized in endosomes and lysosomes . The properties of CatSper1 tabulated above are derived from whole cell voltage\u2010clamp recordings comparing currents endogenous to spermatozoa isolated from the corpus epididymis of wild\u2010type and(\u2010/\u2010)Catsper1 mice [http://www.ncbi.nlm.nih.gov/pubmed/16467839?dopt=AbstractPlus] and also mature human sperm . ICatSper is also undetectable in the spermatozoa of (\u2212/\u2212)Catsper2, (\u2212/\u2212)Catsper3, (\u2212/\u2212),Catsper4 or CatSper\u03b4(\u2212/\u2212) mice, and CatSper 1 associates with CatSper 2, 3, 4, \u03b2, \u03b3, and \u03b4 . Moreover, targeted disruption of Catsper1, 2, 3, 4, or \u03b4 genes results in an identical phenotype in which spermatozoa fail to exhibit the hyperactive movement (whip\u2010like flagellar beats) necessary for penetration of the egg cumulus and zona pellucida and subsequent fertilization. Such disruptions are associated with a deficit in alkalinization and depolarization\u2010evoked Ca2+ entry into spermatozoa . Thus, it is likely that the CatSper pore is formed by a heterotetramer of CatSpers1\u20104 [http://www.ncbi.nlm.nih.gov/pubmed/17227845?dopt=AbstractPlus] in association with the auxiliary subunits that are also essential for function [http://www.ncbi.nlm.nih.gov/pubmed/21224844?dopt=AbstractPlus]. CatSper channels are required for the increase in intracellular Ca2+ concentration in sperm evoked by egg zona pellucida glycoproteins [http://www.ncbi.nlm.nih.gov/pubmed/19211808?dopt=AbstractPlus]. Mouse and human sperm swim against the fluid flow and Ca2+ signaling through CatSper is required for the rheotaxis [http://www.ncbi.nlm.nih.gov/pubmed/23453951?dopt=AbstractPlus]. In vivo, CatSper1\u2010null spermatozoa cannot ascend the female reproductive tracts efficiently . It has been shown that CatSper channels form four linear Ca2+ signaling domains along the flagella, which orchestrate capacitation\u2010associated tyrosine phosphorylation [http://www.ncbi.nlm.nih.gov/pubmed/24813608?dopt=AbstractPlus].The driving force for Ca2+ entry is principally determined by a mildly outwardly rectifying K+ channel (KSper) that, like CatSpers, is activated by intracellular alkalinization [http://www.ncbi.nlm.nih.gov/pubmed/17460039?dopt=AbstractPlus]. Mouse KSper is encoded by mSlo3, a protein detected only in testis . In human sperm, such alkalinization may result from the activation of Hv1, a proton channel [http://www.ncbi.nlm.nih.gov/pubmed/20679352?dopt=AbstractPlus]. Mutations in CatSpers are associated with syndromic and non\u2010syndromic male infertility [http://www.ncbi.nlm.nih.gov/pubmed/20648059?dopt=AbstractPlus]. In human ejaculated spermatozoa, progesterone (<50 nM) potentiates the CatSper current by a non\u2010genomic mechanism and acts synergistically with intracellular alkalinisation [http://www.ncbi.nlm.nih.gov/pubmed/21412339?dopt=AbstractPlus]. Spermcells frominfertile patients witha deletion inCatSper2gene lack ICatSper and the progesterone response [http://www.ncbi.nlm.nih.gov/pubmed/23530196?dopt=AbstractPlus]. In addition, certain prostaglandins also potentiate CatSper mediated currents .CatSper channel subunits expressed singly, or in combination, fail to functionally express in heterologous expression systems [http://www.ncbi.nlm.nih.gov/pubmed/22354039?dopt=AbstractPlus].In human sperm, CatSper channels are also activated by various small molecules including endocrine disrupting chemicals (EDC) and proposed as a polymodal sensor (31). The channels are regulated by luminal pH [http://www.ncbi.nlm.nih.gov/pubmed/24776928?dopt=AbstractPlus], PIP2 [http://www.ncbi.nlm.nih.gov/pubmed/23063126?dopt=AbstractPlus], intracellular ATP and extracellular amino acids [http://www.ncbi.nlm.nih.gov/pubmed/23394946?dopt=AbstractPlus]. TPCs are also involved in the NAADP\u2010activated Ca2+ release from lysosomal Ca2+ stores . Mice lacking TPCs are viable but have phenotypes including compromised lysosomal pH stability, reduced physical endurance [http://www.ncbi.nlm.nih.gov/pubmed/23394946?dopt=AbstractPlus], resistance to Ebola viral infection [http://www.ncbi.nlm.nih.gov/pubmed/25722412?dopt=AbstractPlus] and fatty liver [http://www.ncbi.nlm.nih.gov/pubmed/25144390?dopt=AbstractPlus]. No major human diseaseassociated TPC mutation has been reported.TPCs are the major Naet al. (2005) International Union of Pharmacology. L. Nomenclature and structure\u2010Kintzer AF et al. (2018) On the structure and mechanism of two\u2010pore channels. FEBS J.285: 233\u2010243 function relationships of CatSper and two\u2010pore channels. Pharmacol. Rev.57: 451\u20104 [https://www.ncbi.nlm.nih.gov/pubmed/28656706?dopt=AbstractPlus] [https://www.ncbi.nlm.nih.gov/pubmed/16382101?dopt=AbstractPlus]Clapham DE et al. (2017) Two\u2010Pore Channels: Catalyzers of Endolysosomal Transport and Function. Front Pharmacol8: 45 [https://www.ncbi.nlm.nih.gov/pubmed/28223936?dopt=AbstractPlus]Grimm C Cyclic nucleotide\u2010gated (CNG) channels are responsible for signalling in the primary sensory cells of the vertebrate visual and olfactory systems.http://www.ncbi.nlm.nih.gov/pubmed/2578616?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/2481236?dopt=AbstractPlus], where light signals through rhodopsin and transducin to stimulate phosphodiesterase and reduce intracellular http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2347level. This results ina closure ofCNG channels and a reduced \u2018dark current\u2019. Similar channels were found in the cilia of olfactory neurons [http://www.ncbi.nlm.nih.gov/pubmed/3027574?dopt=AbstractPlus] and the pineal gland [http://www.ncbi.nlm.nih.gov/pubmed/1719422?dopt=AbstractPlus]. The cyclic nucleotides bind to a domain in the C terminus of the subunit protein: other channels directly binding cyclic nucleotides include HCN, eag and certain plant potassium channels.CNG channels arevoltage\u2010independent cation channels formed as tetramers. Each subunit has 6TM, with the pore\u2010forming domain between TM5 and TM6. CNG channels were first found in rod photoreceptors [NC\u2010IUPHAR subcommittee on voltage\u2010gated ion channelsA standardised nomenclature for CNG and HCN channels has been proposed by the [http://www.ncbi.nlm.nih.gov/pubmed/16382102?dopt=AbstractPlus].https://www.genenames.org/data/gene\u2010symbol\u2010report/#!/hgnc_id/HGNC:2152 (http://www.uniprot.org/uniprot/Q8IV77), https://www.genenames.org/data/gene\u2010symbol\u2010report/#!/hgnc_id/HGNC:2151 (http://www.uniprot.org/uniprot/Q14028) and https://www.genenames.org/data/gene\u2010symbol\u2010report/#!/hgnc_id/HGNC:2153 (http://www.uniprot.org/uniprot/Q9NQW8) do not, and are referred to as auxiliary subunits. The subunit composition of the native channels is believed to be as follows. Rod: CNGA13/CNGB1a; Cone: CNGA32/CNGB32; Olfactory neurons: CNGA22/CNGA4/CNGB1b .CNGA1, CNGA2 and CNGA3 express functional channels as homomers. Three additional subunits http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2352 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2347 directly activate the channels and shift the activation curves of HCN channels to more positive voltages, thereby enhancing channel activity. HCN channels underlie pacemaker currents found in many excitable cells including cardiac cells and neurons . In native cells, these currents have a variety of names, such as Ih, Iq andIf. The four known HCN channels have six transmembrane domains and form tetramers.The hyperpolarisation\u2010activated, cyclic nucleotide\u2010gated (HCN) channels are cation channels that are activated by hyperpolarisation at voltages negative to \u02dc\u201050 mV. The cyclic nucleotides http://www.ncbi.nlm.nih.gov/pubmed/12702747?dopt=AbstractPlus]. High resolution structural studies of CNG and HCN channels has provided insight into the the gating processes of these channels .It is believed that the channels can form heteromers with each other, as has been shown for HCN1 and HCN4 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2357 [http://www.ncbi.nlm.nih.gov/pubmed/12084770?dopt=AbstractPlus] have proven useful in identifying and studying functional HCN channels in native cells. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2358 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2355 are also useful blocking agents.HCN channels are permeable to both Naet al. (2018) Structural insights into the mechanisms of CNBD channel function. J. Gen. Physiol.150: 225\u2013244 [https://www.ncbi.nlm.nih.gov/pubmed/29233886?dopt=AbstractPlus]James ZM et al. (2018) Retinal Cyclic Nucleotide\u2010Gated Channels: From Pathophysiology to Ther\u2010 apy. Int J Mol Sci19: [https://www.ncbi.nlm.nih.gov/pubmed/29518895?dopt=AbstractPlus]Michalakis S et al. (2014) New perspectives in cyclic nucleotide\u2010mediated functions in the CNS: the emerging role of cyclic nucleotide\u2010gated (CNG) channels. Pflugers Arch.466: 1241\u201057 [https://www.ncbi.nlm.nih.gov/pubmed/24142069?dopt=AbstractPlus]Podda MV et al. (2017) The Hyperpolarization\u2010Activated Cyclic Nucleotide\u2010Gated Channels: from Biophysics to Pharmacology of a Unique Family of Ion Channels. Pharmacol. Rev.69: 354\u2010395 [https://www.ncbi.nlm.nih.gov/pubmed/28878030?dopt=AbstractPlus]Sartiani L et al. (2014) HCN channels: new roles in sinoatrial node function. Curr Opin Pharmacol15: 83\u201090 [https://www.ncbi.nlm.nih.gov/pubmed/24441197?dopt=AbstractPlus]Wahl\u2010Schott C NC\u2010IUPHAR subcommittees on potassium channels , which has placed cloned channels into groups based on gene family and structure of channels that exhibit 6, 4 or 2 transmembrane domains (TM).Activation of potassium channels regulates excitability and can control the shape of the action potential waveform. They are present in all cells within the body and can influence processes asdiverse ascognition, muscle contraction and hormone secretion. Potassium channels aresubdivided into families, based on their structural and functional properties. The largest family consists of potassium channels that activated by membrane depolarization, with other families consisting of channels that are either activated by a riseof intracellular calcium ions orareconstitutively active. A standardised nomenclature for potassium channels has been proposed by the 2+\u2010 activated Slo subfamily and the Ca2+and Na+\u2010activated SK subfamily . As for the 2TM family, the pore\u2010forming a subunits form tetramers and heteromeric channels may be formed within subfamilies .Calcium\u2010 and sodium\u2010 activated potassium channels are members of the 6TM family of K channels which comprises the voltage\u2010gated KV subfamilies, including the KCNQ subfamily, the EAG subfamily (which includes herg channels), the Caet al. (2018) Calcium\u2010 and voltage\u2010gated BK channels in vascular smooth muscle. Pflugers Arch.470: 1271\u20101289 [https://www.ncbi.nlm.nih.gov/pubmed/29748711?dopt=AbstractPlus]Dopico AM et al. (2017) International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium\u2010Activated and Sodium\u2010Activated Potassium Channels. Pharmacol. Rev.69: 1\u201011 [https://www.ncbi.nlm.nih.gov/pubmed/28267675?dopt=AbstractPlus]Kaczmarek LK et al. (2018) Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System. Front Mol Neurosci11: 258 [https://www.ncbi.nlm.nih.gov/pubmed/30104956?dopt=AbstractPlus]Kshatri AS ir2.x) that are constitutively active, the G\u2010protein\u2010activated inward\u2010rectifier K channels (Kir3.x) and the ATP\u2010sensitive K channels ). The pore\u2010forming \u03b1 subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. Kir3.2 with Kir3.3).The 2TM domain family of K channels are also known as the inward\u2010rectifier K channel family. This family includes the strong inward\u2010rectifier K channels (K2P channels (and not two\u2010pore channels). Some of the K2P subunits can form heterodimers across subfamilies (e.g. K2P3.1 with K2P9.1). The nomenclature of 4TM K channels in the literature is still a mixture of IUPHAR and common names. The suggested division into subfamilies, described in the http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=79, is based on similarities in both structural and functional properties within subfamilies and this explains the \u201ccommon abbreviation\u201d nomenclature in the tables below.The 4TM family of K channels mediate many of the background potassium currents observed in native cells. They are open across the physiological voltage\u2010range and are regulated by a wide array of neurotransmitters and biochemical mediators. The pore\u2010forming \u03b1\u2010subunit contains two pore loop (P) domains and two subunits assemble to form one ion conduction pathway lined by four P domains. It is important to note that single channels do not have two pores but that each subunit has two P domains in its primary sequence; hence the name two P domain, or K2P6, K2P7.1, K2P15.1and K2P12.1 subtypes, when expressed in isolation, are nonfunctional. All 4TM channels are insensitive to the classical potassium channel blockers http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2343 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2416, but are blocked to varying degrees by Ba2+ ions.The KV subfamilies, the EAG subfamily (which includes hERG channels), the Ca2+\u2010activated Slo subfamily and the Ca2+\u2010activated SK subfamily. These channels possess a pore\u2010forming \u03b1 subunit that comprise tetramers of identical subunits (homomeric) or of different subunits (heteromeric). Heteromeric channels can only be formed within subfamilies . The pharmacology largely, reflects the subunit composition of the functional channel.The 6TM family of K channels comprises the voltage\u2010gated Ket al. (1998) Toward understanding the assembly and structure of KATP channels. Physiol. Rev.78: 227\u201045 [https://www.ncbi.nlm.nih.gov/pubmed/9457174?dopt=AbstractPlus]Aguilar\u2010Bryan L et al. (2015) Targeting two\u2010pore domain K(+) channels TREK\u20101 and TASK\u20103 for the treatment of depression: a new therapeutic concept. Br. J. Pharmacol.172: 771\u201084 [https://www.ncbi.nlm.nih.gov/pubmed/25263033?dopt=AbstractPlus]Borsotto M et al. (2015) SK channels and ventricular arrhythmias in heart failure. Trends Cardiovasc. Med.25: 508\u201014 [https://www.ncbi.nlm.nih.gov/pubmed/25743622?dopt=AbstractPlus]Chang PC et al. (2017) Stretch\u2010activated potassium currents in the heart: Focus on TREK\u20101 and arrhythmias. Prog. Biophys. Mol. Biol.130: 223\u2010232 [https://www.ncbi.nlm.nih.gov/pubmed/28526352?dopt=AbstractPlus]Decher N et al. (2015) The family of >K2P channels: salient structural and functional properties. J. Physiol. (Lond.)593: 2587\u2010603 [https://www.ncbi.nlm.nih.gov/pubmed/25530075?dopt=AbstractPlus]Feliciangeli S et al. (2016) KATP Channels in the Cardiovascular System. Physiol. Rev.96: 177\u2010252Foster MN https://www.ncbi.nlm.nih.gov/pubmed/26660852?dopt=AbstractPlus][et al. (2019) Two\u2010pore domain potassium channels: emerging targets for novel analgesic drugs: IUPHAR Review 26. Br J Pharmacol176: 256\u2010266 [https://www.ncbi.nlm.nih.gov/pubmed/30325008?dopt=AbstractPlus]Gada K et al. (2005) International Union of Pharmacology. LV. Nomenclature and molecular relationships of two\u2010P potassium channels. Pharmacol. Rev.57: 527\u201040 [https://www.ncbi.nlm.nih.gov/pubmed/16382106?dopt=AbstractPlus]Goldstein SA et al. (2017) Modulation of Kv7 channels and excitability in the brain. Cell. Mol. Life Sci.Greene DL 74: 495\u2010508 [https://www.ncbi.nlm.nih.gov/pubmed/27645822?dopt=AbstractPlus]et al. (2003) International Union of Pharmacology. XLI. Compendium of voltage\u2010gated ion channels: potassium channels. Pharmacol. Rev.55: 583\u20106 [https://www.ncbi.nlm.nih.gov/pubmed/14657415?dopt=AbstractPlus]Gutman GA et al. (2017) International Union of Basic and Clinical Pharmacology. C. Nomenclature and Properties of Calcium\u2010Activated and Sodium\u2010Activated Potassium Channels. Pharmacol. Rev.69: 1\u201011 [https://www.ncbi.nlm.nih.gov/pubmed/28267675?dopt=AbstractPlus]Kaczmarek LK et al. (2005) International Union of Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium channels. Pharmacol. Rev.57: 509\u201026 [https://www.ncbi.nlm.nih.gov/pubmed/16382105?dopt=AbstractPlus]Kubo Y et al. (2017) Molecular Determinants of BK Channel Functional Diversity and Functioning. Physiol. Rev.97: 39\u201087 [https://www.ncbi.nlm.nih.gov/pubmed/27807200?dopt=AbstractPlus]Latorre R et al. (2016) Gating, Regulation, and Structure in >K2P K+ Channels: In Varietate Concordia? Mol. Pharmacol.90: 309\u201017 [https://www.ncbi.nlm.nih.gov/pubmed/27268784?dopt=AbstractPlus]Niemeyer MI et al. (2017) Towards understanding the molecular basis of ion channel modulation by lipids: Mechanistic models and current paradigms. Biochim. Biophys. Acta1859: 1507\u20101516 [https://www.ncbi.nlm.nih.gov/pubmed/28408206?dopt=AbstractPlus]Poveda JA et al. (2017) G Protein\u2010Gated Potassium Channels: A Link to Drug Addiction. Trends Pharmacol. Sci.38: 378\u2010392 [https://www.ncbi.nlm.nih.gov/pubmed/28188005?dopt=AbstractPlus]Rifkin RA et al. (2017) Regulation of KCNQ/Kv7 family voltage\u2010gated K+ channels by lipids. Biochim. Biophys. Acta1859: 586\u2010597 [https://www.ncbi.nlm.nih.gov/pubmed/27818172?dopt=AbstractPlus]Taylor KC et al. (2016) Perspectives on the Two\u2010Pore Domain Potassium Channel TREK\u20101 (TWIKRelated K(+) Channel 1). A Novel Therapeutic Target? J. Med. Chem.59: 5149\u201057 [https://www.ncbi.nlm.nih.gov/pubmed/26588045?dopt=AbstractPlus]Vivier D et al. (2005) International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium\u2010activated potassium channels. Pharmacol. Rev.57: 463\u201072 [https://www.ncbi.nlm.nih.gov/pubmed/16382103?dopt=AbstractPlus]Wei AD et al. (2016) Mechanisms contributing to myocardial potassium channel diversity, regulation and remodeling. Trends Cardiovasc. Med.26: 209\u201018 [https://www.ncbi.nlm.nih.gov/pubmed/26391345?dopt=AbstractPlus]Yang KC 2+ storage/release organelles. The family of RyR genes encodes three highly related Ca2+ release channels: RyR1, RyR2 and RyR3, which assemble as large tetrameric structures. These RyR channels are ubiquitously expressed in many types of cells and participate in a variety of important Ca2+ signaling phenomena . In addition to the three mammalian isoforms described below, various nonmammalian isoforms of the ryanodine receptor have been identified [http://www.ncbi.nlm.nih.gov/pubmed/8874493?dopt=AbstractPlus]. The function of the ryanodine receptor channels may also be influenced by closely associated proteins such as the tacrolimus (FK506)\u2010binding protein, calmodulin [http://www.ncbi.nlm.nih.gov/pubmed/12707260?dopt=AbstractPlus], triadin, calsequestrin, junctin and sorcin, and by protein kinases and phosphatases. Recent studies solving the structure of the ryanodine receptor have shed light on the structural basis of ryanodine receptor function and Meissner (2017) [http://www.ncbi.nlm.nih.gov/pubmed/29122978?dopt=AbstractPlus]].The ryanodine receptors (RyRs) are found on intracellular Ca2+ release pathways. Numerous other modulators of ryanodine receptor/channel function can be found in the reviews listed below. The absence of a modulator of a particular isoform of receptor indicates that the action of that modulator has not been determined, not that it is without effect. The potential role of cyclic ADP ribose as an endogenous regulator of ryanodine receptor channels is controversial. A region of RyR likely to be involved in ion translocation and selection has been identified .The modulators of channel function included in this table are those most commonly used to identify ryanodine\u2010sensitive Caet al. (2017) Physiology and Pharmacology of Ryanodine Receptor Calcium Release Channels. Adv. Pharmacol.79: 287\u2010324 https://www.ncbi.nlm.nih.gov/pubmed/28528672?dopt=AbstractPlusDulhunty AF J. Gen. Physiol.149: 1065\u20101089 https://www.ncbi.nlm.nih.gov/pubmed/29122978?dopt=AbstractPlusMeissner G. (2017) The structural basis of ryanodine receptor ion channel function. et al. (2015) The ryanodine receptor provides high throughput Ca2+\u2010release but is precisely regulated by networks of associated proteins: a focus on proteins relevant to phosphorylation. Biochem. Soc. Trans.43: 426\u201033 https://www.ncbi.nlm.nih.gov/pubmed/26009186?dopt=AbstractPlusO'Brien F Protein Sci.26: 52\u201068 ), whose founder member is the Drosophila Trp channel, exists in mammals as six families; TRPC, TRPM, TRPV, TRPA, TRPP and TRPML based on amino acid homologies. TRP subunits contain six putative transmembrane domains and assemble as homo\u2010 or hetero\u2010tetramers to form cation selective channels with diverse modes of activation and varied permeation properties (reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/16460288?dopt=AbstractPlus]). Established, or potential, physiological functions of the individual members of the TRP families are discussed in detail in the recommended reviews and in a number of books . The established, or potential, involvement of TRP channels in disease is reviewed in and [http://www.ncbi.nlm.nih.gov/pubmed/20127491?dopt=AbstractPlus], together with a special edition of Biochemica et Biophysica Acta on the subject [http://www.ncbi.nlm.nih.gov/pubmed/17368864?dopt=AbstractPlus]. Additional disease related reviews, for pain [http://www.ncbi.nlm.nih.gov/pubmed/28924972?dopt=AbstractPlus], stroke [http://www.ncbi.nlm.nih.gov/pubmed/25502473?dopt=AbstractPlus], sensation and inflammation [http://www.ncbi.nlm.nih.gov/pubmed/25361914?dopt=AbstractPlus], itch [http://www.ncbi.nlm.nih.gov/pubmed/24830011?dopt=AbstractPlus], and airway disease , are available. The pharmacology of most TRP channels has been advanced in recent years. Broad spectrum agents are listed in the tables along with more selective, or recently recognised, ligands that are flagged by the inclusion of a primary reference. See Rubaiy (2019) for a review of pharmacological tools for TRPC1/C4/C5 channels [http://www.ncbi.nlm.nih.gov/pubmed/30656647?dopt=AbstractPlus]. Most TRP channels are regulated by phosphoinostides such as PtInsP2 although the effects reported are often complex, occasionally contradictory, and likely to be dependent upon experimental conditions, such as intracellular ATP levels . Such regulation is generally not included in the tables.When thermosensitivity is mentioned, it refers specifically to a high Q10 of gating, often in the range of 10\u2010 30, but does not necessarily imply that the channel's function is to act as a \u2019hot\u2019 or \u2019cold\u2019 sensor. In general, the search for TRP activators has led to many claims for temperature sensing, mechanosensation, and lipid sensing. All proteins are of course sensitive to energies of binding, mechanical force, and temperature, but the issue is whether the proposed input is within a physiologically relevant range resulting in a response.The TRP superfamily of channels (http://www.ncbi.nlm.nih.gov/pubmed/17217068?dopt=AbstractPlus]). TRPA1 activation of sensory neurons contribute to nociception . Pungent chemicals such as mustard oil (AITC), http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2419, and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2423 activate TRPA1 by modification of free thiol groups of cysteine side chains, especially those located in its amino terminus . Alkenals with \u03b1, \u03b2\u2010unsaturated bonds, such as propenal (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2418), butenal (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6288), and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2417 can react with free thiols via Michael addition and can activate TRPA1. However, potency appears to weaken as carbon chain length increases . Covalent modification leads to sustained activation of TRPA1. Chemicals including http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2497, menthol, and local anesthetics reversibly activate TRPA1 by non\u2010covalent binding . TRPA1 is not mechanosensitive under physiological conditions, but can be activated by cold temperatures . The electron cryo\u2010EM structure of TRPA1 [http://www.ncbi.nlm.nih.gov/pubmed/25855297?dopt=AbstractPlus] indicates that it is a 6\u2010TM homotetramer. Each subunit of the channel contains two short \u2018pore helices\u2019 pointing into the ion selectivity filter, which is big enough to allow permeation of partially hydrated Ca2+ ions.TRPA1 is the sole mammalian member of this group . A gain\u2010of\u2010function mutation in TRPA1 was found to cause familial episodic pain syndrome [http://www.ncbi.nlm.nih.gov/pubmed/20547126?dopt=AbstractPlus].Agents activating TRPA1 in a covalent manner are thiol reactive electrophiles that bind to cysteine and lysine residues within the cytoplasmic domain of the channel ) fall into the subgroups outlined below. TRPC2 is a pseudogene in humans. It is generally accepted that all TRPC channels are activated downstream of Gq/11\u2010coupled receptors, or receptor tyrosine kinases . A comprehensive listing of G\u2010protein coupled receptors that activate TRPC channels is given in [http://www.ncbi.nlm.nih.gov/pubmed/18940894?dopt=AbstractPlus]. Hetero\u2010oligomeric complexes of TRPC channels and their association with proteins to form signalling complexes are detailed in [http://www.ncbi.nlm.nih.gov/pubmed/17486362?dopt=AbstractPlus] and [http://www.ncbi.nlm.nih.gov/pubmed/17217079?dopt=AbstractPlus]. TRPC channels have frequently been proposed to act as store\u2010operated channels (SOCs) (or compenents of mulimeric complexes that form SOCs), activated by depletion of intracellular calcium stores . However, the weight of the evidence is that they are not directly gated by conventional store\u2010operated mechanisms, as established for Stim\u2010gated Orai channels. TRPC channels are not mechanically gated in physiologically relevant ranges of force. All members of the TRPC family are blocked by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2433 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2441 . Activation of TRPC channels by lipids is discussed by [http://www.ncbi.nlm.nih.gov/pubmed/21624095?dopt=AbstractPlus]. Important progress has been recently made in TRPC pharmacology . TRPC channels regulate a variety of physiological functions and are implicated in many human diseases .Members of the TRPC subfamily fall into the five subgroups outlined below.Members of the TRPM subfamily exists as multiple splice variants which differ significantly in their biophysical properties. TRPM3 is expressed in somatosensory neurons and may be important in development of heat hyperalgesia during inflammation (see review [http://www.ncbi.nlm.nih.gov/pubmed/28720517?dopt=AbstractPlus]). TRPM3 is frequently coexpressed with TRPA1 and TRPV1 in these neurons. TRPM3 is expressed in pancreatic beta cells as well as brain, pituitary gland, eye, kidney, and adipose tissue . TRPM3 may contribute to the detection of noxious heat [http://www.ncbi.nlm.nih.gov/pubmed/21555074?dopt=AbstractPlus].In darkness, glutamate released by the photoreceptors and ON\u2010bipolar cells binds to the metabotropic glutamate receptor 6, leading to activation of Go . This results in the closure of TRPM1. When the photoreceptors are stimulated by light, glutamate release is reduced, and TRPM1 channels are more active, resulting in cell membrane depolarization. Human TRPM1 mutations are associated with congenital stationary night blindness (CSNB), whose patients lack rod function. TRPM1 is also found melanocytes. Isoforms of TRPM1 may present in melanocytes, melanoma, brain, and retina. In melanoma cells, TRPM1 is prevalent in highly dynamic intracellular vesicular structures [2 must also be present (reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/20553742?dopt=AbstractPlus]). Numerous splice variants of TRPM2 exist which differ in their activation mechanisms [http://www.ncbi.nlm.nih.gov/pubmed/19372375?dopt=AbstractPlus]. The C\u2010terminal domain contains a TRP motif, a coiled\u2010coil region, and an enzymatic NUDT9 homologous domain. TRPM2 appears not to be activated by NAD, NAAD, or NAADP, but is directly activated by ADPRP (adenosine5\u2032\u2010O\u2010disphosphoribose phosphate) [http://www.ncbi.nlm.nih.gov/pubmed/25918360?dopt=AbstractPlus]. TRPM2 is involved in warmth sensation [http://www.ncbi.nlm.nih.gov/pubmed/2955270?dopt=AbstractPlus], and contributes to neurological diseases [http://www.ncbi.nlm.nih.gov/pubmed/29671419?dopt=AbstractPlus]. Recent study shows that 2\u2032\u2010deoxy\u2010ADPR is an endogenous TRPM2 superagonist [http://www.ncbi.nlm.nih.gov/pubmed/28671679?dopt=AbstractPlus].TRPM2 is activated under conditions of oxidative stress (respiratory burst of phagocytic cells) and ischemic conditions. However, the direct activators are ADPR(P) and calcium. As for many ion channels, PIP2+ [http://www.ncbi.nlm.nih.gov/pubmed/20716668?dopt=AbstractPlus]. A splice variant of TRPM4 (i.e.TRPM4b) and TRPM5 are molecular candidates for endogenous calcium\u2010activated cation (CAN) channels [http://www.ncbi.nlm.nih.gov/pubmed/21290294?dopt=AbstractPlus]. TRPM4 is active in the late phase of repolarization of the cardiac ventricular action potential. TRPM4 deletion or knockout enhances beta adrenergic\u2010mediated inotropy [http://www.ncbi.nlm.nih.gov/pubmed/24226423?dopt=AbstractPlus]. Mutations are associated with conduction defects . TRPM4 has been shown to be an important regulator of Ca2+ entry in to mast cells [http://www.ncbi.nlm.nih.gov/pubmed/17217063?dopt=AbstractPlus] and dendritic cell migration [http://www.ncbi.nlm.nih.gov/pubmed/18758465?dopt=AbstractPlus]. TRPM5 in taste receptor cells of the tongue appears essential for the transduction of sweet, amino acid and bitter stimuli [http://www.ncbi.nlm.nih.gov/pubmed/17217064?dopt=AbstractPlus] TRPM5 contributes to the slow afterdepolarization of layer 5 neurons in mouse prefrontal cortex [http://www.ncbi.nlm.nih.gov/pubmed/25237295?dopt=AbstractPlus]. Both TRPM4 and TRPM5 are required transduction of taste stimuli [http://www.ncbi.nlm.nih.gov/pubmed/29311301?dopt=AbstractPlus].TRPM4 and TRPM5 have the distinction within all TRP channels of being impermeable to Ca2+, Mg2+, Zn2+) and monovalent cations, high single channel conductances, but overall extremely small inward conductance when expressed to the plasma membrane. They are inhibited by internal Mg2+ at 0.6 mM, around the free level of Mg2+ in cells. Whether they contribute to Mg2+ homeostasis is a contentious issue. When either gene is deleted in mice, the result is embryonic lethality. The C\u2010terminal kinase region is cleaved under unknown stimuli, and the kinase phosphorylates nuclear histones. TRPM7 is responsible for oxidant\u2010 induced Zn2+ release from intracellular vesicles [http://www.ncbi.nlm.nih.gov/pubmed/28696294?dopt=AbstractPlus] and contributes to intestinal mineral absorption essential for postnatal survival [http://www.ncbi.nlm.nih.gov/pubmed/30770447?dopt=AbstractPlus].TRPM6 and 7 combine channel and enzymatic activities (\u2019chanzymes\u2019). These channels have the unusual property of permeation by divalent . TRPML channels are probably restricted to intracellular vesicles and mutations in the gene (MCOLN1) encoding TRPML1 (mucolipin\u20101) cause the neurodegenerative disorder mucolipidosis type IV (MLIV) in man. TRPML1 is a cation selective ion channel that is important for sorting/transport of endosomes in the late endocytotic pathway and specifically, fission from late endosome\u2010lysosome hybrid vesicles and lysosomal exocytosis [http://www.ncbi.nlm.nih.gov/pubmed/23993788?dopt=AbstractPlus]. TRPML2 and TRPML3 show increased channel activity in low extracellular sodium and are activated by similar small molecules [http://www.ncbi.nlm.nih.gov/pubmed/22753890?dopt=AbstractPlus]. A naturally occurring gain of function mutation in TRPML3 (i.e. A419P) results in the varitint waddler (Va) mouse phenotype .The TRPML family . Data for wild type TRPML3 are also tabulated . It should be noted that alternative methodologies, particularly in the case of TRPML1, have resulted in channels with differing biophysical characteristics (reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/19158345?dopt=AbstractPlus]). Initial functional characteristics of TRPML channels are performed on their Va mutations of TRPMLs at loci equivalent to TRPML3 A419P. Current pharmacological characterization of channel activators and blockers are conducted on wild\u2010type channel proteins using endolysosomal patch\u2010clamp .Data in the table are for TRPML proteins mutated or PKD2 family is comprised of PKD2 (PC2), PKD2L1 (PC2L1), PKD2L2 (PC2L2), which have been renamed TRPP1, TRPP2 and TRPP3, respectively [http://www.ncbi.nlm.nih.gov/pubmed/20716668?dopt=AbstractPlus]. It should also be noted that the nomenclature of PC2 was TRPP2 in old literature. However, PC2 has been uniformed to be called TRPP2 [http://www.ncbi.nlm.nih.gov/pubmed/29149325?dopt=AbstractPlus]. PKD2 family channels are clearly distinct from the PKD1 family, whose function is unknown. PKD1 and PKD2 form a hetero\u2010oligomeric complex with a 1:3 ratio. [http://www.ncbi.nlm.nih.gov/pubmed/30093605?dopt=AbstractPlus]. Although still being sorted out, TRPP family members appear to be 6TM spanning nonselective cation channels.The TRPP family can broadly be divided into the non\u2010selective cation channels, TRPV1\u20104 and the more calcium selective channels TRPV5 and TRPV6.Members of the TRPV family . Numerous splice variants of TRPV1 have been described, some of which modulate the activity of TRPV1, or act in a dominant negative manner when co\u2010expressed with TRPV1 [http://www.ncbi.nlm.nih.gov/pubmed/20515731?dopt=AbstractPlus]. The pharmacology of TRPV1 channels is discussed in detail in [http://www.ncbi.nlm.nih.gov/pubmed/19063991?dopt=AbstractPlus] and [http://www.ncbi.nlm.nih.gov/pubmed/19297520?dopt=AbstractPlus]. TRPV2 is probably not a thermosensor in man [http://www.ncbi.nlm.nih.gov/pubmed/21832173?dopt=AbstractPlus], but has recently been implicated in innate immunity [http://www.ncbi.nlm.nih.gov/pubmed/20118928?dopt=AbstractPlus]. TRPV3 and TRPV4 are both thermosensitive. There are claims that TRPV4 is also mechanosensitive, but this has not been established to be within a physiological range in a native environment .TRPV1 is involved in the development of thermal hyperalgesia following inflammation and may contribute to the detection of noxius heat .TRPV5 and TRPV6 are highly expressed in placenta, bone, and kidney. Under physiological conditions, TRPV5 and TRPV6 are calcium selective channels involved in the absorption and reabsorption of calcium across intestinal and kidney tubule epithelia . Activation of TRPV4 by cell swelling, but not heat, or phorbol esters, is mediated via the formation of epoxyeicosatrieonic acids. Phorbol esters bind directly to TRPV4. Different TRPV4 mutations load to a broad spectrum of dominant skeletal dysplasias and spinal muscular atrophies and hereditary motor and sensory neuropathies . Similar mutations were also found in patients with Charcot\u2010Marie\u2010Tooth disease type 2C [http://www.ncbi.nlm.nih.gov/pubmed/20037586?dopt=AbstractPlus]. TRPV5 preferentially conducts Ca2+ under physiological conditions, but in the absence of extracellular Ca2+, conducts monovalent cations. Single channel conductances listed for TRPV5 and TRPV6 were determined in divalent cation\u2010free extracellular solution. Ca2+\u2010induced inactivation occurs at hyperpolarized potentials when Ca2+ is present extracellularly. Single channel events cannot be resolved (probably due to greatly reduced conductance) in the presence of extracellular divalent cations. Measurements of PCa/PNa for TRPV5 and TRPV6 are dependent upon ionic conditions due to anomalous mole fraction behaviour. Blockade of TRPV5 and TRPV6 by extracellular Mg2+ is voltage\u2010dependent. Intracellular Mg2+ also exerts a voltage dependent block that is alleviated by hyperpolarization and contributes to the time\u2010dependent activation and deactivation of TRPV6 mediated monovalent cation currents. TRPV5 and TRPV6 differ in their kinetics of Ca2+\u2010dependent inactivation and recovery from inactivation. TRPV5 and TRPV6 function as homo\u2010 and hetero\u2010tetramers.Activation of TRPV1 by depolarisation is strongly temperature\u2010dependent via a channel opening rate that increases with increasing temperature. The Vet al. (2017) Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists. Med Res Rev37: 936\u2010983 https://www.ncbi.nlm.nih.gov/pubmed/27976413?dopt=AbstractPlusAghazadeh Tabrizi M et al. (2017) Transient Receptor Potential Channels in neuropathic pain. Curr Opin Pharmacol32: 9\u201015 https://www.ncbi.nlm.nih.gov/pubmed/27835802?dopt=AbstractPlusBasso L et al. (2017) Lipids as central modulators of sensory TRP channels. Biochim. Biophys. Acta1859: 1615\u20101628 and NC\u2010IUPHAR Subcommittee on Ca2+ channelsapproved by the [http://www.ncbi.nlm.nih.gov/pubmed/16382099?dopt=AbstractPlus]. Ca2+ channels form hetero\u2010oligomeric complexes. The \u03b11 subunit is pore\u2010forming and provides the binding site(s) for practically all agonists and antagonists. The 10 cloned \u03b11\u2010subunits can be grouped into three families: (1) the high\u2010voltage activated dihydropyridine\u2010sensitive channels; (2) the highvoltage activated dihydropyridine\u2010insensitive (CaV2.x) channels and (3) the low\u2010voltage\u2010activated channels. Each \u03b11 subunit has four homologous repeats (I\u2013IV),each repeat having six transmembrane domains and a pore\u2010forming region between transmembrane domains S5 and S6. Gating is thought to be associated with the membrane\u2010spanning S4 segment, which contains highly conserved positive charges. Many of the \u03b11\u2010subunit genes give rise to alternatively spliced products. At least for high\u2010voltage activated channels, it is likely that native channels comprise coassemblies of \u03b11, \u03b2 and \u03b12\u2013\u03b4 subunits. The \u03b3 subunits have not been proven to associate with channels other than the \u03b11s skeletal muscle Cav1.1 channel. The \u03b12\u2013\u03b41 and \u03b12\u2013\u03b42 subunits bind http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5483 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5484.Calcium (Cahttp://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2536) has been approved for the treatment of chronic pain [http://www.ncbi.nlm.nih.gov/pubmed/18518786?dopt=AbstractPlus].In many cell types, P and Q current components cannot be adequately separated and many researchers in the field have adopted the terminology \u2018P/Q\u2010type\u2019 current when referring to either component. Both of these physiologically defined current types are conducted by alternative forms of Cav2.1. Ziconotide International Union of Pharmacology. XLVIII. Nomenclature and structure\u2010function relationships of voltage\u2010gated calcium channels. Pharmacol. Rev.57: 411\u201325 [https://www.ncbi.nlm.nih.gov/pubmed/16382099?dopt=AbstractPlus]Catterall WA et al. (2015) Structural basis for pharmacology of voltage\u2010gated sodium and calcium channels. Mol. Pharmacol.88: 141\u201350 [https://www.ncbi.nlm.nih.gov/pubmed/25848093?dopt=AbstractPlus]Catterall WA et al. (2015) Deciphering voltage\u2010gated Na(+) and Ca(2+) channels by studying prokaryotic ancestors. Trends Biochem. Sci.40: 526\u201334 [https://www.ncbi.nlm.nih.gov/pubmed/26254514?dopt=AbstractPlus]Catterall WA Brain Neurosci Adv2: [https://www.ncbi.nlm.nih.gov/pubmed/30320224?dopt=AbstractPlus]Dolphin AC. (2018) Voltage\u2010gated calcium channels: their discovery, function and importance as drug targets. et al. (2017) How and why are calcium currents curtailed in the skeletal muscle voltagegated calcium channels? J. Physiol. (Lond.)595: 1451\u20131463 [https://www.ncbi.nlm.nih.gov/pubmed/27896815?dopt=AbstractPlus]Flucher BE et al. (2017) Regulation of voltage gated calcium channels by GPCRs and post\u2010translational modification. Curr Opin Pharmacol32: 1\u20138 [https://www.ncbi.nlm.nih.gov/pubmed/27768908?dopt=AbstractPlus]Huang J et al. (2018) Calcium Channels, Synaptic Plasticity, and Neuropsychiatric Disease. Neuron98: 466\u2013481 [https://www.ncbi.nlm.nih.gov/pubmed/29723500?dopt=AbstractPlus]Nanou E et al. (2016) L\u2010type calcium channels as drug targets in CNS disorders. Channels (Austin)10: 7\u201313 [https://www.ncbi.nlm.nih.gov/pubmed/26039257?dopt=AbstractPlus]Ortner NJ et al. (2016) Cardiac voltage\u2010gated calcium channel macromolecular complexes. Biochim. Biophys. Acta1863: 1806\u201312 [https://www.ncbi.nlm.nih.gov/pubmed/26707467?dopt=AbstractPlus]Rougier JS Nat Rev Drug Discov15: 19\u201334 [https://www.ncbi.nlm.nih.gov/pubmed/26542451?dopt=AbstractPlus]Zamponi GW. (2016) Targeting voltage\u2010gated calcium channels in neurological and psychiatric diseases. et al. (2015) The Physiology, Pathology, and Pharmacology of Voltage\u2010Gated Calcium Channels and Their Future Therapeutic Potential. Pharmacol. Rev.67: 821\u201370 [https://www.ncbi.nlm.nih.gov/pubmed/26362469?dopt=AbstractPlus]Zamponi GW http://www.ncbi.nlm.nih.gov/pubmed/20961760?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18463791?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/18801839?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16554753?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/16556803?dopt=AbstractPlus]. The structure of Hv1 is homologous to the voltage sensing domain (VSD) of the superfamily of voltage\u2010gated ion channels (i.e. segments S1 to S4) and contains no discernable pore region . Proton flux through Hv1 is instead most likely mediated by a water wire completed in a crevice of the protein whenthe voltage\u2010sensing S4 helix moves in response to a change in transmembrane potential . Hv1 expresses largely as a dimer mediated by intracellular C\u2010terminal coiled\u2010coil interactions [http://www.ncbi.nlm.nih.gov/pubmed/20147290?dopt=AbstractPlus] but individual promoters nonetheless support gated H+ flux via separate conduction pathways . Within dimeric structures, the two protomers do not function independently, but display co\u2010operative interactions during gating resulting in increased voltage sensitivity, but slower activation, of the dimeric,versus monomeric, complexes .The voltage\u2010gated proton channel is a putative 4TM proton\u2010selective channel gated by membrane depolarization and which is sensitive to the transmembrane pH gradient . Phosphorylation of Hv1 within the N\u2010terminal domain by PKC enhances the gating of the channel [http://www.ncbi.nlm.nih.gov/pubmed/20037153?dopt=AbstractPlus]. Tabulated IC50 values for Zn2+ and Cd2+ are for heterologously expressed human and mouse Hv1 . Zn2+ is not a conventional pore blocker, but is coordinated by two, or more, external protonation sites involving http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1204 residues [http://www.ncbi.nlm.nih.gov/pubmed/16554753?dopt=AbstractPlus]. Zn2+ binding may occur at the dimer interface between pairs of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1204 residues from both monomers where it may interfere with channel opening [http://www.ncbi.nlm.nih.gov/pubmed/20231140?dopt=AbstractPlus]. Mouse knockout studies demonstrate that Hv1 participates in charge compensation in granulocytes during the respiratory burst of NADPH oxidasedependent reactive oxygen species production that assists in the clearance of bacterial pathogens [http://www.ncbi.nlm.nih.gov/pubmed/19372380?dopt=AbstractPlus]. Additional physiological functions of Hv1 are reviewed by [http://www.ncbi.nlm.nih.gov/pubmed/20961760?dopt=AbstractPlus].The voltage threshold Voltage\u2010gated proton (H(v)1) channels, a singular voltage sensing domain. FEBS Lett.589: 3471\u20138 [https://www.ncbi.nlm.nih.gov/pubmed/26296320?dopt=AbstractPlus]Castillo K Proc. Natl. Acad. Sci. U.S.A.115: 9057\u20139059 [https://www.ncbi.nlm.nih.gov/pubmed/30135099?dopt=AbstractPlus]DeCoursey TE. (2018) Gating currents indicate complex gating of voltage\u2010gated proton channels. J R Soc Interface15: [https://www.ncbi.nlm.nih.gov/pubmed/29643227?dopt=AbstractPlus]DeCoursey TE. (2018) Voltage and pH sensing by the voltage\u2010gated proton channel, HV1. et al. (2016) Pharmacological Modulation of Proton Channel Hv1 in Cancer Therapy: Future Perspectives. Mol. Pharmacol.90: 385\u2013402 [https://www.ncbi.nlm.nih.gov/pubmed/27260771?dopt=AbstractPlus]Fern\u00e1ndez A et al. (2015) Gating mechanisms of voltage\u2010gated proton channels. Annu. Rev. Biochem.84: 685\u2013709 [https://www.ncbi.nlm.nih.gov/pubmed/26034892?dopt=AbstractPlus]Okamura Y http://www.ncbi.nlm.nih.gov/pubmed/11486343?dopt=AbstractPlus]. \u03b1\u2010Subunits consist of four homologous domains (I\u2010IV), each containing six transmembrane segments (S1\u2010S6) and a pore\u2010forming loop. The positively charged fourth transmembrane segment (S4) acts as a voltage sensor and is involved in channel gating. The crystal structure of the bacterial NavAb channel has revealed a number of novel structural features compared to earlier potassium channel structures including a short selectivity filter with ion selectivity determined by interactions with glutamate side chains [http://www.ncbi.nlm.nih.gov/pubmed/21743477?dopt=AbstractPlus]. Interestingly, the pore region is penetrated by fatty acyl chains that extend into the central cavity which may allow the entry of small, hydrophobic pore\u2010blocking drugs [http://www.ncbi.nlm.nih.gov/pubmed/21743477?dopt=AbstractPlus]. Auxiliary \u03b21, \u03b22, \u03b23 and \u03b24 subunits consist of a large extracellular N\u2010terminal domain, a single transmembrane segment and a shorter cytoplasmic domain.Sodium channels are voltage\u2010gated sodium\u2010selective ion channels present in the membrane of most excitable cells. Sodium channels comprise of one pore\u2010forming \u03b1 subunit, which may be associated with either one or two \u03b2 subunits NC\u2010IUPHAR Subcommittee on sodium channels .http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2616 and rate of fast inactivation (NaV1.8 and particularly NaV1.9 inactivate more slowly). All sodium channels also have a slow inactivation process that is engaged during long depolarizations (>100 msec) or repetitive trains of stimuli. All sodium channel subtypes are blocked by intracellular http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2405.Sodium channels are also blocked by local anaesthetic agents, antiarrythmic drugs and antiepileptic drugs. In general, these drugs are not highly selective among channel subtypes. There are two clear functional fingerprints for distinguishing different subtypes. These are sensitivity to et al. (2005) International Union of Pharmacology. XLVII. Nomenclature and structure\u2010function relationships of voltage\u2010gated sodium channels. Pharmacol. Rev.57: 397409 [https://www.ncbi.nlm.nih.gov/pubmed/16382098?dopt=AbstractPlus]Catterall WA et al. (2017) The chemical basis for electrical signaling. Nat. Chem. Biol.13: 455\u2013463 [https://www.ncbi.nlm.nih.gov/pubmed/28406893?dopt=AbstractPlus]Catterall WA et al. (2017) The pharmacology of voltage\u2010gated sodium channel activators. Neuropharmacology127: 87\u2013108 [https://www.ncbi.nlm.nih.gov/pubmed/28416444?dopt=AbstractPlus]Deuis JR et al. (2018) Structural basis for gating pore current in periodic paralysis. Nature557: 590\u2013594 [https://www.ncbi.nlm.nih.gov/pubmed/29769724?dopt=AbstractPlus]Jiang D et al. (2016) Voltage\u2010gated sodium channels and pain\u2010related disorders. Clin. Sci.130: 2257\u20132265 [https://www.ncbi.nlm.nih.gov/pubmed/27815510?dopt=AbstractPlus]Kanellopoulos AH et al. (2018) Structural basis for the modulation of voltage\u2010gated sodium channels by animal toxins. Science362: [https://www.ncbi.nlm.nih.gov/pubmed/30049784?dopt=AbstractPlus]Shen H et al. (2018) Post\u2010translational dysfunctions in channelopathies of the nervous system. Neuropharmacology132: 31\u201342 [https://www.ncbi.nlm.nih.gov/pubmed/28571716?dopt=AbstractPlus]Terragni B A number of ion channels in the human genome do not fit readily into the classification of either ligand\u2010gated or voltage\u2010gated ion channels. These are identified below.http://www.ncbi.nlm.nih.gov/pubmed/26342685?dopt=AbstractPlus]. Since the isolation and cloning of the first aquaporin (AQP1)[http://www.ncbi.nlm.nih.gov/pubmed/1373524?dopt=AbstractPlus], 12 additional mammalian membersof thefamily havebeenidentified, although little is known about the functional properties of one of these and it is thus not tabulated. The other 12 aquaporins can be broadly divided into three families: orthodox aquaporins permeable mainly to water, but for some additional solutes [http://www.ncbi.nlm.nih.gov/pubmed/24090884?dopt=AbstractPlus]; aquaglyceroporins , additionally permeableto glycerol and for some isoforms urea [http://www.ncbi.nlm.nih.gov/pubmed/26365508?dopt=AbstractPlus], and superaquaporins (AQP11 and 12) located within cells [http://www.ncbi.nlm.nih.gov/pubmed/24189537?dopt=AbstractPlus]. Some aquaporins also conduct ammonia and/or H2O2 giving rise to the terms \u2019ammoniaporins\u2019 (\u2019aquaammoniaporins\u2019) and \u2019peroxiporins\u2019, respectively. Aquaporins are impermeable to protons and other inorganic and organic cations, with the possible exception of AQP1 [http://www.ncbi.nlm.nih.gov/pubmed/26365508?dopt=AbstractPlus]. One or more members of this family of proteins have been found to be expressed in almost all tissues of the body [reviewed in Yang (2017) [1104]]. AQPs are involved in numerous processes that include systemic water homeostasis, adipocyte metabolism, brain oedema, cell migration and fluid secretion by epithelia and loss of function mutations of some human AQPs, or their disruption by autoantibodies further underscore their importance [reviewed by Verkman et al. (2014) [http://www.ncbi.nlm.nih.gov/pubmed/24625825?dopt=AbstractPlus], Kitchen et al. (2105) [http://www.ncbi.nlm.nih.gov/pubmed/26365508?dopt=AbstractPlus]].Aquaporins and aquaglyceroporins are membrane channels that allow the permeation of water and certain other small solutes across the cell membrane, or in the case of AQP6, AQP11 and AQP12A, intracellular membranes, such as vesicles and the endoplasmic reticulum membrane [http://www.ncbi.nlm.nih.gov/pubmed/26342685?dopt=AbstractPlus]. In addition to the four pores contributed by the protomers, an additional hydrophobic pore exists within the center of the complex [http://www.ncbi.nlm.nih.gov/pubmed/26342685?dopt=AbstractPlus] that may mediate the transport of gases and cations by some AQPs . Although numerous small molecule inhibitors of aquaporins, particularly APQ1, have been reported primarily from Xenopus oocyte swelling assays, the activity of most has subsequently been disputed upon retesting using assays of water transport that are less prone to various artifacts [http://www.ncbi.nlm.nih.gov/pubmed/26993802?dopt=AbstractPlus] and they are therefore excluded from the tables [see Tradtrantip et al. (2017) [http://www.ncbi.nlm.nih.gov/pubmed/28258578?dopt=AbstractPlus] for a review].Functional AQPs exist as homotetramers that are the water conducting units wherein individual AQP subunits (each a protomer) have six transmembrane helices and two half helices that constitute a seventh \u2019pseudotransmembrane domain\u2019 that surrounds a narrow water conducting channel [Proc Am Thorac Soc3: 5\u201313 [https://www.ncbi.nlm.nih.gov/pubmed/16493146?dopt=AbstractPlus]Agre P. (2006) The aquaporin water channels. et al. (2002) Aquaporin water channels\u2013from atomic structure to clinical medicine. J. Physiol. (Lond.)542: 3\u201316 [https://www.ncbi.nlm.nih.gov/pubmed/12096044?dopt=AbstractPlus]Agre P et al. (2015) Challenges and achievements in the therapeutic modulation of aquaporin functionality. Pharmacol. Ther.155: 22\u201335 [https://www.ncbi.nlm.nih.gov/pubmed/26277280?dopt=AbstractPlus]Beitz E et al. (2009) Discovery of the aquaporins and development of the field. Handb Exp Pharmacol 3\u201328 [https://www.ncbi.nlm.nih.gov/pubmed/19096770?dopt=AbstractPlus]Carbrey JM et al. (2017) Transport Characteristics of Aquaporins. Adv. Exp. Med. Biol.969: 51\u201362 [https://www.ncbi.nlm.nih.gov/pubmed/28258565?dopt=AbstractPlus]Geng X et al. (2009) Aquaporin water channels in mammals. Clin. Exp. Nephrol.13: 107\u201317 [https://www.ncbi.nlm.nih.gov/pubmed/19085041?dopt=AbstractPlus]Ishibashi K et al. (2015) Beyond water homeostasis: Diverse functional roles of mammalian aquaporins. Biochim. Biophys. Acta1850: 2410\u201321 [https://www.ncbi.nlm.nih.gov/pubmed/26365508?dopt=AbstractPlus]Kitchen P et al. (2018) Aquaporins as Targets of Dietary Bioactive Phytocompounds. Front Mol Biosci5: 30 [https://www.ncbi.nlm.nih.gov/pubmed/29721498?dopt=AbstractPlus]Tesse A et al. (2017) Aquaporin\u2010Targeted Therapeutics: State\u2010of\u2010the\u2010Field. Adv. Exp. Med. Biol.969: 239\u2013250 [https://www.ncbi.nlm.nih.gov/pubmed/28258578?dopt=AbstractPlus]Tradtrantip L InAdvancesin ExperimentalMedicineandBiology Edited by Yang B:Springer: 1\u2013276 [ISBN: 9789402410570]Yang B.(2017) Aquaporins http://www.ncbi.nlm.nih.gov/pubmed/19827947?dopt=AbstractPlus]). Excluding the transmittergated GABAA and glycine receptors (see separate tables), well characterised chloride channels can be classified as certain members of the voltage\u2010sensitive ClC subfamily, calcium\u2010activated channels, high (maxi) conductance channels, the cystic fibrosis transmembrane conductance regulator (CFTR) and volume regulated channels [http://www.ncbi.nlm.nih.gov/pubmed/19153558?dopt=AbstractPlus]. No official recommendation exists regarding the classification of chloride channels. Functional chloride channels that have been cloned from, or characterised within, mammalian tissues are listed with the exception of several classes of intracellular channels (e.g. CLIC) that are reviewed by in [http://www.ncbi.nlm.nih.gov/pubmed/20100480?dopt=AbstractPlus].Chloride channels are a functionally and structurally diverse group of anion selective channels involved in processes including the regulation of the excitability of neurones, skeletal, cardiac and smooth muscle, cell volume regulation, transepithelial salt transport, the acidification of internal and extracellular compartments, the cell cycle and apoptosis contains 9 members that fall, on the basis of sequence homology, into three groups; ClC\u20101, ClC\u20102, hClC\u2010Ka (rClC\u2010K1) and hClC\u2010Kb (rClC\u2010K2); ClC\u20103 to ClC\u20105, and ClC\u20106 and \u20107. ClC\u20101 and ClC\u20102 are plasma membrane chloride channels. ClC\u2010Ka and ClC\u2010Kb are also plasma membrane channels (largely expressed in the kidney and inner ear) when associated with barttin , a 320 amino acid 2TM protein [http://www.ncbi.nlm.nih.gov/pubmed/11734858?dopt=AbstractPlus]. The localisation of the remaining members of the ClC family is likely to be predominantly intracellular in vivo, although they may traffic to the plasma membrane in overexpression systems. Numerous recent reports indicate that ClC\u20104, ClC\u20105, ClC\u20106 and ClC\u20107 (and by inference ClC\u20103) function as Cl\u2010/H+ antiporters (secondary active transport), rather than classical Cl\u2212 channels ; reviewed in ). It has recently been reported that the activity of ClC\u20105 as a Cl\u2010/H+ exchanger is important for renal endocytosis [http://www.ncbi.nlm.nih.gov/pubmed/20430975?dopt=AbstractPlus]. Alternative splicing increases the structural diversity within the ClC family. The crystal structure of two bacterial ClC proteins has been described [http://www.ncbi.nlm.nih.gov/pubmed/11796999?dopt=AbstractPlus] and a eukaryotic ClC transporter (CmCLC) has recently been described at 3.5 \u00c5 resolution [http://www.ncbi.nlm.nih.gov/pubmed/20929736?dopt=AbstractPlus]. Each ClC subunit, with a complex topology of 18 intramembrane segments, contributes a single pore to a dimeric \u2018double\u2010barrelled\u2019 ClC channel that contains two independently gatedpores, confirming the predictions of previous functional and structural investigations . As found for ClC\u20104, ClC\u20105, ClC\u20106 and ClC\u20107, the prokaryotic ClC homologue (ClC\u2010ec1) and CmCLC function as H+/Cl antiporters, rather than as ion channels . The generation of monomers from dimeric ClC\u2010ec1 has firmly established that each ClC subunit is afunctional unit fortransport and thatcross\u2010subunit interaction is not required for Cl\u2010/H+ exchange in ClC transporters [http://www.ncbi.nlm.nih.gov/pubmed/21048711?dopt=AbstractPlus].The mammalian ClC family . ClC\u20101 has significant opening probability at resting membrane potential, accounting for 75% of the membrane conductance at rest in skeletal muscle, and is important for stabilization of the membrane potential. http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4098, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4113 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2439 act intracellularly and exhibit a strongly voltage\u2010dependent block with strong inhibition at negative voltages and relief of block at depolarized potentials ([http://www.ncbi.nlm.nih.gov/pubmed/17128287?dopt=AbstractPlus] and reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/12512775?dopt=AbstractPlus]). Inhibition of ClC\u20102 by the peptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4199, from Leiurus quinquestriatus herbareus venom, is likely to occur through inhibition of channel gating, rather than direct open channel blockade [http://www.ncbi.nlm.nih.gov/pubmed/19574231?dopt=AbstractPlus]. Although ClC\u20102 can be activated by cell swelling, it does not correspond to the VRAC channel (see below). Alternative potential physiological functions for ClC\u20102 are reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/19708126?dopt=AbstractPlus]. Functional expression of human ClC\u2010Ka and ClC\u2010Kb requires the presence of barttin reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/21423394?dopt=AbstractPlus]. The properties of ClC\u2010Ka/barttin and ClC\u2010Kb/barttin tabulated are those observed in mammalian expression systems: in oocytes the channels display time\u2010 and voltage\u2010dependent gating. The rodent homologue (ClC\u2010K1) of ClC\u2010Ka demonstrates limited expression as a homomer, but its function is enhanced by barttin which increases both channel opening probablility in the physiological range of potentials reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/21423394?dopt=AbstractPlus]). ClC\u2010Ka is approximately 5 to 6\u2010fold more sensitive to block by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4104 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4177 than ClC\u2010Kb, while newly synthesized benzofuran derivatives showed the same blocking affinity (<10 \u03bcM) on both CLC\u2010K isoforms [http://www.ncbi.nlm.nih.gov/pubmed/18216243?dopt=AbstractPlus]. The biophysical and pharmacological properties of ClC\u20103, and the relationship of the protein to the endogenous volume\u2010regulated anion channel(s) VRAC are controversial and further complicated by the possibility that ClC\u20103 may function as both a Cl\u2010/H+ exchanger and an ion channel . The functional properties tabulated are those most consistent with the close structural relationship between ClC\u20103, ClC\u20104 and ClC\u20105. Activation of heterologously expressed ClC\u20103 by cell swelling in response to hypotonic solutions is disputed, as are many other aspects of its regulation. Dependent upon the predominant extracellular anion (e.g. SCN\u2212 versus Cl\u2010), CIC\u20104 can operate in two transport modes: a slippage mode in which behaves as an ion channel and an exchanger mode in which unitary transport rate is 10\u2010fold lower [http://www.ncbi.nlm.nih.gov/pubmed/19364886?dopt=AbstractPlus]. Similar findings have been made for ClC\u20105 [http://www.ncbi.nlm.nih.gov/pubmed/18063579?dopt=AbstractPlus]. ClC\u20107 associates with a \u03b2 subunit, Ostm1, which increases the stability of the former [http://www.ncbi.nlm.nih.gov/pubmed/16525474?dopt=AbstractPlus] and is essential for its function [http://www.ncbi.nlm.nih.gov/pubmed/21527911?dopt=AbstractPlus].ClC channels display the permeability sequence Cl\u2212 channel involved in normal fluid transport across various epithelia. Of the 1700 mutations identified in CFTR, the most common is the deletion mutant F508 (a class 2 mutation) which results in impaired trafficking of CFTR and reduces its incorporation into the plasma membrane causing cystic fibrosis (reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/21108631?dopt=AbstractPlus]). Channels carrying the F508 mutation that do traffic to the plasma membrane demonstrate gating defects. Thus, pharmacological restoration of the function of the \u0394F508 mutant would require a compound that embodies \u2019corrector\u2019 (i.e. facilitates folding and trafficking to the cell surface) and \u2019potentiator\u2019 (i.e. promotes opening of channels at the cell surface) activities [http://www.ncbi.nlm.nih.gov/pubmed/21108631?dopt=AbstractPlus]. In addition to acting as an anion channel per se, CFTR may act as a regulator of several other conductances including inhibition of the epithelial Na channel (ENaC), calcium activated chloride channels (CaCC) and volume regulated anion channel (VRAC), activation of the outwardly rectifying chloride channel (ORCC), and enhancementof the sulphonylurea sensitivity of therenalouter medullary potassium channel (ROMK2), (reviewed in [http://www.ncbi.nlm.nih.gov/pubmed/12558550?dopt=AbstractPlus]). CFTR also regulates TRPV4, which provides the Ca2+ signal for regulatory volume decrease in airway epithelia [http://www.ncbi.nlm.nih.gov/pubmed/15489228?dopt=AbstractPlus]. The activities of CFTR and the chloride\u2010bicarbonate exchangers SLC26A3 (DRA) and SLC26A6 (PAT1) are mutually enhanced by a physical association between the regulatory (R) domain of CFTR and the STAS domain of the SCL26 transporters, an effect facilitated by PKA\u2010mediated phosphorylation of the R domain of CFTR [http://www.ncbi.nlm.nih.gov/pubmed/15048129?dopt=AbstractPlus].CFTR, a 12TM, ABC transporter\u2010type protein, is a cAMP\u2010regulated epithelial cell membrane Clhttp://www.ncbi.nlm.nih.gov/pubmed/20829696?dopt=AbstractPlus]). Corrector compounds that aid the folding of DF508CFTR to increase the amount of protein expressed and potentially delivered to the cell surface include VX\u2010532 , http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4340, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4234, Corr\u20103a and Corr\u20104a see [http://www.ncbi.nlm.nih.gov/pubmed/19153558?dopt=AbstractPlus] for details and structures of Corr3a and Corr\u20104a). Inhibition of CFTR by intracellular application of the peptide http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4198, from Leiurus quinquestriatus herbareus venom, occurs preferentially for the closed state of the channel [http://www.ncbi.nlm.nih.gov/pubmed/17951250?dopt=AbstractPlus]. CFTR contains two cytoplasmic nucleotide binding domains (NBDs) that bind http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713. A single open\u2010closing cycle is hypothesised to involve, in sequence: binding of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 at the Nterminal NBD1, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 binding to the C\u2010terminal NBD2 leading to the formation of an intramolecular NBD1\u2010NBD2 dimer associated with the open state, and subsequent http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 hydrolysis at NBD2 facilitating dissociation of the dimer and channel closing, and the initiation of a new gating cycle . Phosphorylation by PKA at sites within a cytoplasmic regulatory (R) domain facilitates the interaction of the two NBD domains. PKC positively regulate CFTR activity.In addition to the agents listed in the table, the novel small molecule, ataluren, induces translational read through of nonsense mutations in CFTR consisting of 10 members has been identified and there is firm evidence that some of these members form chloride channels . TMEM16A produces Ca2+\u2010activated Cl\u2212 currents with kinetics similar to native CaCC currents recorded from different cell types . Knockdown of TMEM16A greatly reduces currents mediated by calcium\u2010activated chloride channels in submandibular gland cells [http://www.ncbi.nlm.nih.gov/pubmed/18724360?dopt=AbstractPlus] and smooth muscle cells from pulmonary artery [http://www.ncbi.nlm.nih.gov/pubmed/20421283?dopt=AbstractPlus]. In TMEM16A(\u2010/\u2010) mice secretion of Ca2+\u2010dependent Cl\u2212 secretion by several epithelia is reduced . Alternative splicing regulates the voltage\u2010 and Ca2+\u2010 dependence of TMEM16A and such processing may be tissue\u2010specific manner and thus contribute to functional diversity [http://www.ncbi.nlm.nih.gov/pubmed/19819874?dopt=AbstractPlus]. There are also reports that TMEM16B supports CaCC activity (e.g.[http://www.ncbi.nlm.nih.gov/pubmed/19475416?dopt=AbstractPlus]) and in TMEM16B(\u2010/\u2010) mice Ca\u2010activated Cl\u2212 currents in the main olfactory epithelium (MOE) and in the vomeronasal organ are virtually absent [http://www.ncbi.nlm.nih.gov/pubmed/21516098?dopt=AbstractPlus].Chloride channels activated by intracellular calcium (CaCC) are widely expressed in excitable and non\u2010excitable cells where they perform diverse functions . Extracellular http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2439; http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4173 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4113 (but not http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4177) exert a complex effect upon ICl(Ca) in vascular smooth muscle, enhancing and inhibiting inwardly and outwardly directed currents in a manner dependent upon [Ca2+]i (see [http://www.ncbi.nlm.nih.gov/pubmed/16091780?dopt=AbstractPlus] for summary). Considerable crossover in pharmacology with large conductance Ca2+\u2010activated K+ channels also exists (see [http://www.ncbi.nlm.nih.gov/pubmed/17150263?dopt=AbstractPlus] for overview). Two novel compounds, CaCCinh\u2010A01 and CaCCinh\u2010B01 have recently been identified as blockers of calcium\u2010activated chloride channels in T84 human intestinal epithelial cells [http://www.ncbi.nlm.nih.gov/pubmed/18083779?dopt=AbstractPlus] for structures). Significantly, other novel compounds totally block currents mediated by TMEM116A, but have only a modest effect upon total current mediated by CaCC native to T84 cells or human bronchial epithelial cells, suggesting that TMEM16A is not the predominant CaCC in such cells [http://www.ncbi.nlm.nih.gov/pubmed/21084298?dopt=AbstractPlus]. CaMKII modulates CaCC in a tissue dependent manner . CaMKII inhibitors block activation of ICl(Ca) in T84 cells but have no effect in parotid acinar cells. In tracheal and arterial smooth muscle cells, but not portal vein myocytes, inhibition of CaMKII reduces inactivation of ICl(Ca). Intracellular http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4224 may act as an endogenous negative regulator of CaCC channels activated by Ca2+, or CaMKII. Smooth muscle CaCC are also regulated positively by Ca2+\u2010dependent phosphatase, calcineurin (see [http://www.ncbi.nlm.nih.gov/pubmed/16091780?dopt=AbstractPlus] for summary).Blockade of I\u2010 channels are high conductance, anion selective, channels initially characterised in skeletal muscle and subsequently found in many cell types including neurones, glia, cardiac muscle, lymphocytes, secreting and absorbing epithelia, macula densa cells of the kidney and human placenta syncytiotrophoblasts [http://www.ncbi.nlm.nih.gov/pubmed/19340557?dopt=AbstractPlus]. The physiological significance of the maxi Cl\u2010 channel is uncertain, but roles in cell volume regulation and apoptosis have been claimed. Evidence suggests a role for maxi Clchannels as a conductive pathway in the swelling\u2010induced release of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 from mouse mammary C127i cells that may be important for autocrine and paracrine signalling by purines . A similar channel mediates http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 release from macula densa cells within the thick ascending of the loop of Henle in response to changes in luminal NaCl concentration [http://www.ncbi.nlm.nih.gov/pubmed/12655045?dopt=AbstractPlus]. A family of human high conductance Cl\u2010 channels (TTYH1\u20103) that resemble Maxi Cl\u2010 channels has been cloned [http://www.ncbi.nlm.nih.gov/pubmed/15010458?dopt=AbstractPlus], but alternatively, Maxi Cl\u2010 channels have also been suggested to correspond to the voltage\u2010dependent anion channel, VDAC, expressed at the plasma membrane .Maxi Clhttp://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391 (and cis\u2010unsaturated fatty acids) is voltageindependent, occurs at an intracellular site, and involves both channel shut down (Kd = 4\u20105 \u03bcM) and a reduction of \u03b3 (Kd = 1314 \u03bcM). Blockade of channel activity by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4314, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4177, Gd3+ and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2391 is paralleled by decreased swelling\u2010induced release of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1713 . Channel activation by anti\u2010oestrogens in whole cell recordings requires the presence of intracellular nucleotides and is prevented by pre\u2010treatment with http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1013, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5485, or intracellular dialysis with GDP\u03b2S [http://www.ncbi.nlm.nih.gov/pubmed/11579158?dopt=AbstractPlus]. Activation by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1016 is suppressed by low concentrations of http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5349, suggesting that a dephosphorylation event by protein phosphatase PP2A occurs in the activation pathway [http://www.ncbi.nlm.nih.gov/pubmed/11579158?dopt=AbstractPlus]. In contrast, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1013 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1016 appear to directly inhibit the maxi Cl\u2010 channel of human placenta reconstituted into giant liposomes and recorded in excised patches [http://www.ncbi.nlm.nih.gov/pubmed/19604577?dopt=AbstractPlus].Differing ionic conditions may contribute to variable estimates of \u03b3 reported in the literature. Inhibition by \u2010 transport, angiogenesis, cell proliferation, necrosis, apoptosis, glutamate release from astrocytes, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5012 release from pancreatic \u03b2 cells and resistance to the anti\u2010cancer drug, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5343 . VRAC may not be a single entity, but may instead represent a number of different channels that are expressed to a variable extent in different tissues and are differentially activated by cell swelling. In addition to ClC\u20103 expression products (see above) several former VRAC candidates including MDR1 (ABCB1 P\u2010glycoprotein), Icln, Band 3 anion exchanger and phospholemman are also no longer considered likely to fulfil this function .Volume activated chloride channels participate in regulatory volumedecrease(RVD) inresponse tocell swelling. VRAC may also be important for several other processes including the regulation of membrane excitability, transcellular ClIn addition to conducting monovalent anions, in many cell types the activation of VRAC by a hypotonic stimulus can allow the efflux of organic osmolytes such as amino acids and polyols that may contribute to RVD.http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2352\u2010activated Cl\u2010 channel that does not correspond to CFTR has been described in intestinal Paneth cells [http://www.ncbi.nlm.nih.gov/pubmed/9769420?dopt=AbstractPlus]. A Cl channel activated by http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2347 with a dependence on raised intracellular Ca2+ has been recorded in various vascular smooth muscle cells types, which has a pharmacology and biophysical characteristics very different from the \u2018conventional\u2019 CaCC . It has been proposed that http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=5377 is an essential component of the http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2347\u2010activated channel [http://www.ncbi.nlm.nih.gov/pubmed/18776041?dopt=AbstractPlus]. A proton\u2010activated, outwardly rectifying anion channel has also been described [http://www.ncbi.nlm.nih.gov/pubmed/15961423?dopt=AbstractPlus].In addition to some intracellular chloride channels that are not considered here, plasma membrane channels other than those listed have been functionally described. Many cells and tissues contain outwardly rectifying chloride channels (ORCC) that may correspond to VRAC active under isotonic conditions. A et al. (2015) Potential role of cardiac chloride channels and transporters as novel therapeutic targets. Pharmacol. Ther.145: 67\u201375 [https://www.ncbi.nlm.nih.gov/pubmed/25160469?dopt=AbstractPlus]Adkins GB et al. (2012) International Union of Basic and Clinical Pharmacology. LXXXV: calciumactivated chloride channels. Pharmacol. Rev.64: 1\u201315 [https://www.ncbi.nlm.nih.gov/pubmed/22090471?dopt=AbstractPlus]Huang F J. Cell. Physiol.233: 787\u2013798 [https://www.ncbi.nlm.nih.gov/pubmed/28121009?dopt=AbstractPlus]KamaleddinMA.(2018)Molecular, biophysical, and pharmacological properties of calcium\u2010activated chloride channels. Trends Biochem. Sci.40: 535\u201343 [https://www.ncbi.nlm.nih.gov/pubmed/26254230?dopt=AbstractPlus]Kunzelmann K. (2015) TMEM16, LRRC8A, bestrophin: chloride channels controlled by Ca(2+) and cell volume. et al. (2016) Biophysics and Physiology of the Volume\u2010Regulated Anion Channel (VRAC)/Volume\u2010Sensitive Outwardly Rectifying Anion Channel (VSOR). Pflugers Arch.468: 371\u201383 [https://www.ncbi.nlm.nih.gov/pubmed/26739710?dopt=AbstractPlus]Pedersen SF et al. (2015) Chloride channels in cancer: Focus on chloride intracellular channel 1 and 4 (CLIC1 AND CLIC4) proteins in tumor development and as novel therapeutic targets. Biochim. Biophys. Acta1848: 2523\u201331 [https://www.ncbi.nlm.nih.gov/pubmed/25546839?dopt=AbstractPlus]Peretti M et al. (2016) The properties, functions, and pathophysiology of maxi\u2010anion channels. Pflugers Arch.468: 405\u201320 [https://www.ncbi.nlm.nih.gov/pubmed/26733413?dopt=AbstractPlus]Sabirov RZ et al. (2017) CFTR pharmacology. Cell. Mol. Life Sci.74: 117\u2013128 [https://www.ncbi.nlm.nih.gov/pubmed/27704174?dopt=AbstractPlus]Zegarra\u2010Moran O http://www.ncbi.nlm.nih.gov/pubmed/14597722?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/15217338?dopt=AbstractPlus, http://www.ncbi.nlm.nih.gov/pubmed/12126230?dopt=AbstractPlus]. Gap junction channels allow the passive diffusion of molecules of up to 1,000 Daltons which can include nutrients, metabolites and second messengers (such as IP3) as well as cations and anions. 21 connexin genes and 3 pannexin genes which are structurally related to the invertebrate innexin genes) code for gap junction proteins in humans. Each connexin gap junction comprises 2 hemichannels or \u2019connexons\u2019 which are themselves formed from 6 connexin molecules. The various connexins have been observed to combine into both homomeric and heteromeric combinations, each of which may exhibit different functional properties. Itis also suggested that individual hemichannels formed by a number of different connexins might be functional in at least some cells [http://www.ncbi.nlm.nih.gov/pubmed/17507078?dopt=AbstractPlus]. Connexins have a common topology, with four \u03b1\u2010helical transmembrane domains, two extracellular loops, a cytoplasmic loop, and N\u2010 and C\u2010termini located on the cytoplasmic membrane face. In mice, the most abundant connexins in electrical synapses in the brain seem to be Cx36, Cx45 and Cx57 [http://www.ncbi.nlm.nih.gov/pubmed/15738956?dopt=AbstractPlus]. Mutations in connexin genes are associated with the occurrence of a number of pathologies, such as peripheral neuropathies, cardiovascular diseases and hereditary deafness. The pannexin genes Px1 and Px2 are widely expressed in the mammalian brain [http://www.ncbi.nlm.nih.gov/pubmed/16143426?dopt=AbstractPlus]. Like the connexins, at least some of the pannexins can form hemichannels .Gap junctions are essential for many physiological processes including cardiac and smooth muscle contraction, regulation of neuronal excitability and epithelial electrolyte transport [http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4151 and http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2447 [http://www.ncbi.nlm.nih.gov/pubmed/16216217?dopt=AbstractPlus]. At least some pannexin hemichannels are more sensitive to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=4151 than connexins but much less sensitive to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2447 [http://www.ncbi.nlm.nih.gov/pubmed/15715654?dopt=AbstractPlus]. It has been suggested that 2\u2010aminoethoxydiphenyl borate (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2433) may be a more effective blocker of some connexin channel subtypes compared to others .Connexins are most commonly named according to their molecular weights, so, for example, Cx23 is the connexin protein of 23 kDa. This can cause confusion when comparing between species \u2013 for example, the mouse connexin Cx57 is orthologous to the human connexin Cx62. No natural toxin or specific inhibitor of junctional channels has been identified yet however two compounds often used experimentally to block connexins are et al. (2015) Connexin and pannexin signaling pathways, an architectural blueprint for CNS physiology and pathology? Cell. Mol. Life Sci.72: 2823\u201351 [https://www.ncbi.nlm.nih.gov/pubmed/26118660?dopt=AbstractPlus]Decrock E et al. (2016) Next\u2010Generation Connexin and Pannexin Cell Biology. Trends Cell Biol.26: 944\u2013955 [https://www.ncbi.nlm.nih.gov/pubmed/27339936?dopt=AbstractPlus]Esseltine JL et al. (2016) Expression and role of connexin\u2010based gap junctions in pulmonary inflammatory diseases. Pharmacol. Ther.164: 105\u201319 [https://www.ncbi.nlm.nih.gov/pubmed/27126473?dopt=AbstractPlus]Freund\u2010Michel V J. Gen. Physiol.150: 1606\u20131639 [https://www.ncbi.nlm.nih.gov/pubmed/30389716?dopt=AbstractPlus]Harris AL. (2018) Electrical coupling and its channels. et al. (2015) Regulation of pannexin and connexin channels and their functional role in skeletal muscles. Cell. Mol. Life Sci.72: 2929\u201335 [https://www.ncbi.nlm.nih.gov/pubmed/26084874?dopt=AbstractPlus]S\u00e1ez JC et al. (2017) Inhibitors of connexin and pannexin channels as potential therapeutics. Pharmacol. Ther.180: 144\u2013160 [https://www.ncbi.nlm.nih.gov/pubmed/28720428?dopt=AbstractPlus]Willebrords J http://www.ncbi.nlm.nih.gov/pubmed/27743844?dopt=AbstractPlus]. Piezo channels play a critical role in sensory neuron transduction Piezo proteins are the pore\u2010forming subunits of trimeric mechanosensitive ion channels that open in response to mechanical stimuli such as shear stress and membrane stretch, allowing positively charged ions, including calcium, to flow into the cell. Piezo orthologs have thus far been identified in numerous eukaryotes. Most vertebrates have two channel isoforms, Piezol and Piezo2. Across species, Piezos are very large proteins with numerous (>14) predicted transmembrane (TM) domains per subunit and, strikingly, no homology to other known proteins .et al. (2018) Portraits of a pressure sensor. Elife7: [https://www.ncbi.nlm.nih.gov/pubmed/29376828?dopt=AbstractPlus]Chesler AT Science362: 398\u2013399 [https://www.ncbi.nlm.nih.gov/pubmed/30361358?dopt=AbstractPlus]Ehmke H. (2018) The mechanotransduction of blood pressure. etal. (2012)Piezo1: propertiesof a cation selective mechanical channel. Channels(Austin)6: 214\u20139 [https://www.ncbi.nlm.nih.gov/pubmed/22790400?dopt=AbstractPlus]Gottlieb PAet al. (2017) Piezo channels. Curr. Biol.27: R250\u2010R252 [https://www.ncbi.nlm.nih.gov/pubmed/28376327?dopt=AbstractPlus]Parpaite T et al. (2015) Piezo channels: from structure to function. Pflugers Arch.467: 95\u20139 [https://www.ncbi.nlm.nih.gov/pubmed/25037583?dopt=AbstractPlus]Volkers L et al. (2017) Touch, Tension, and Transduction \u2010 The Function and Regulation of Piezo Ion Channels. Trends Biochem. Sci.42: 57\u201371 [https://www.ncbi.nlm.nih.gov/pubmed/27743844?dopt=AbstractPlus]Wu J etal. (2018)PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science362: 464\u2013467 [https://www.ncbi.nlm.nih.gov/pubmed/30361375?dopt=AbstractPlus]Zeng WZ NC\u2010IUPHAR tentatively recommends the nomenclature NaVi2.1, W.A. Catterall, personal communication) is structurally a member of the family of voltage\u2010gated sodium channel family (Nav1.1\u2010Nav1.9) . In contrast to the latter, NaVi2.1, is voltage\u2010insensitive (denoted in the subscript \u2019vi\u2019 in the tentative nomenclature) and possesses distinctive ion selectivity and pharmacological properties. NaVi2.1, which is insensitive to http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2616 (10 \u03bcM), has been proposed to mediate the http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2616\u2010resistant and voltage\u2010insensitive Na+ leak current (IL\u2010Na) observed in many types of neurone [http://www.ncbi.nlm.nih.gov/pubmed/17448995?dopt=AbstractPlus]. However, whether NaVi2.1 is constitutively active has been challenged [http://www.ncbi.nlm.nih.gov/pubmed/19575010?dopt=AbstractPlus]. NaVi2.1 is widely distributed within the central nervous system and is also expressed in the heart and pancreas specifically, in rodents, within the islets of Langerhans . Recently, NaVi2.1 has been proposed to be a core effector for the action of inhibitory G proteins [http://www.ncbi.nlm.nih.gov/pubmed/30556810?dopt=AbstractPlus].The sodium leak channel, non selective , neurotensin and M3 muscarinic acetylcholine receptors (in MIN6 pancreatic \u03b2\u2010cells) and in a manner that is independent of signalling through G proteins . Pharmacological and molecular biological evidence indicates such modulation to occur though a pathway that involves the activation of Src family tyrosine kinases. It is suggested that NaVi2.1 exists as a macromolecular complex with M3 receptors [http://www.ncbi.nlm.nih.gov/pubmed/19575010?dopt=AbstractPlus] and peptide receptors [http://www.ncbi.nlm.nih.gov/pubmed/19092807?dopt=AbstractPlus], in the latter instance in association with the protein UNC\u201080, which recruits Src to the channel complex . By contrast, stimulation of NaVi2.1 by decreased extracellular Ca2+ concentration is G protein dependent and involves a Ca2+\u2010sensing G protein\u2010coupled receptor and UNC80 which links NaVi2.1 to the protein UNC79 in the same complex [http://www.ncbi.nlm.nih.gov/pubmed/21040849?dopt=AbstractPlus]. NaVi2.1 null mutant mice have severe disturbances in respiratory rhythm and die within 24 hours of birth [http://www.ncbi.nlm.nih.gov/pubmed/17448995?dopt=AbstractPlus]. NaVi2.1 heterozygous knockout mice display increased serum sodium concentrations in comparison to wildtype littermates and a role for the channel in osmoregulation has been postulated [http://www.ncbi.nlm.nih.gov/pubmed/21177381?dopt=AbstractPlus].In native and recombinant expression systems Naet al. (2014) The sodium leak channel, NALCN, in health and disease. Front Cell Neurosci8: 132 [https://www.ncbi.nlm.nih.gov/pubmed/24904279?dopt=AbstractPlus]Cochet\u2010Bissuel M et al. (2012) NALCN: a regulator of pacemaker activity. Mol. Neurobiol. 45: 415\u201023 [https://www.ncbi.nlm.nih.gov/pubmed/22476981?dopt=AbstractPlus]Lu TZ et al. (2018) G_i/o protein\u2010coupled receptors in dopamine neurons inhibit the sodium leak channel NALCN. Elife7: [https://www.ncbi.nlm.nih.gov/pubmed/30556810?dopt=AbstractPlus]Philippart F et al. (2014) Regulating excitability of peripheral afferents: emerging ion channel targets. Nat. Neurosci. 17: 153\u201063 [https://www.ncbi.nlm.nih.gov/pubmed/24473263?dopt=AbstractPlus]Waxman SG"} +{"text": "Cell Death & Disease; 10.1038/cddis.2017.495; published online 12 Oct 2017.Correction to: The PDF and HTML versions of the article have been updated to include the Creative Commons Attribution 4.0 International License information."} +{"text": "Escherichia coli phage CMSTMSU was isolated from shrimp farm effluent water in Ramanathapuram, India. The phage exhibited lytic activity against both E. coli and the fish pathogen Pseudomonas aeruginosa.The Escherichia coli phage CMSTMSU was isolated from shrimp farm effluent water in Ramanathapuram, India. The phage exhibited lytic activity against both E. coli and the fish pathogen Pseudomonas aeruginosa. Here we report the draft genome sequence, assembly, and annotation of the isolated CMSTMSU phage. This genome resource can be used to utilize the phage as a crucial biocontrol agent in the fish aquaculture sector.The Escherichia coli phage CMSTMSU. The phage was isolated from a wastewater sample obtained from a shrimp farm located in Ramanathapuram, India. It was detected with the soft agar overlay method using log-phase E. coli cells as the host. The isolated CMSTMSU phage also exhibited lytic activity against the fish pathogen Pseudomonas aeruginosa.Bacteriophages are viruses that infect bacteria. They are abundant in natural systems and are considered crucial factors in controlling bacterial populations . Phages E. coli phage CMSTMSU was purified following the protocol reported by Mullan (see https://www.dairyscience.info/index.php/isolation-and-purification-of-bacteriophages.html). Then, the genomic DNA was extracted with the phenol-chloroform extraction method (http://exon.gatech.edu/GeneMark/genemarks.cgi) (https://ccb.jhu.edu/software/glimmer/) (https://www.blast2go.com/) functional annotation software (The draft genome of pdr.org) , GeneMarrks.cgi) , and GLIlimmer/) gene presoftware . Of the software . This geSRP158495, and the draft genome sequence of Escherichia coli phage CMSTMSU has been deposited in NCBI GenBank under the accession number MH494197.The raw sequence reads have been submitted to the NCBI SRA under the accession number"} +{"text": "London Journal of Primary Care, pp. 1\u20132. https://doi.org/10.1080/17571472.2018.1485262Carelli, F. 2018. One hundred years ago \u2026 there was a jigsaw puzzle of a farmer: teaching and learning with Kasimir Malevich. When the above article was first published online, the author was incorrectly listed as Francesco Carelli Matteo. This has now been corrected in the online version to Francesco Carelli (and Matteo).Taylor & Francis apologizes for this error."} +{"text": "Correction to: Breast Cancer Reshttps://doi.org/10.1186/bcr1323After the publication of this work errors w"} +{"text": "The authors wish to make a change to their published paper . Figure http://www.mdpi.com/2073-4360/9/4/137.The change does not affect the scientific results. The manuscript will be updated and the original will remain online on the article webpage"} +{"text": "Journal of Experimental Botany, Advance Access publication: June 8, 2018. doi:10.1093/jxb/ery214The original online version of this article contained an outdated figure . This figure has now been corrected.The authors would like to apologise for this error."} +{"text": "Picocystis sp. strain ML is responsible for recurrent algal blooms in Mono Lake, CA. This organism was characterized by only very little molecular data, despite its prominence as a primary producer in saline environments.The microscopic alga Picocystis sp. strain ML is responsible for recurrent algal blooms in Mono Lake, CA. This organism was characterized by only very little molecular data, despite its prominence as a primary producer in saline environments. Here, we report the draft genome sequence for Picocystis sp. strain ML based on long-read sequencing.The microscopic alga Picocystis sp. strain ML. Previous studies have described this strain, a close relative to Picocystis salinarum or matching (99%) the chloroplast of P. salinarum CCMP:1897 (GenBank accession number KJ746599) based on BLAST alignment rRNA regions were found using RNAmmer version 1.2, closely matching (99.7% \u00b1 0.67%) that of lignment , 13. Repal model . The finPicocystis sp. strain ML was assimilating these compounds , unlike in previous years , and it ompounds . This geQYZS00000000. The version described in this paper is version QYZS01000000. Raw sequence reads have been deposited in the SRA database under BioProject number PRJNA490491. Custom scripts and software settings are available on GitHub at https://github.com/emilyjunkins/PicoML/tree/v1.0 and https://doi.org/10.5281/zenodo.2366252.This whole-genome shotgun project has been deposited in DDBJ/ENA/GenBank under the accession number"} +{"text": "After publication of this article , concernThe authors acknowledge that an error was made during figure preparation for 10.6084/m9.figshare.7804301 for 10.6084/m9.figshare.7804409 for The primary data underlying Figs The authors apologize for the errors in the published article."} +{"text": "Light out of Deep Darkness. A biography of Arthur Ferguson MacCallan, the trachoma pioneer (2nd edition).Ophthalmic surgeon Arthur Ferguson MacCallan (1872\u20131955) worked in Egypt between 1903 and 1923. The MacCallan Classification of Trachoma (now replaced by the WHO grading system) was the first grading system used to standardise the diagnosis of the disease. Grandson Michael MacCallan has now published the second edition of his book about Arthur: Reader offer.Community Eye Health Journal readers can order the book for the reduced price of \u00a330 plus postage and packing . Contact The Choir Press at enquiries@thechoirpress.co.uk or by telephone on +44 (0) 1452 500 016, quoting reference CEHJ09. Offer valid until 30 September 2018.Community Eye Health Journal Nursing Advisor, Janet Marsden, has passed away on the 31st of May 2018. Janet was Professor of Ophthalmology and Emergency Care at Manchester Metropolitan University and has authored several nursing articles in this journal. She was the editor of Ophthalmic Care (Wiley) and later made a significant contribution to the International Centre for Eye Health's Ophthalmic Operating Theatre Practice: a Manual for Lower-resource Settings . Janet's insight, experience and kindness will be missed very much, and we extend our deepest condolences to her family.Former Fully funded scholarships are available for Commonwealth country nationals. The course aims to provide eye health professionals with the public health knowledge and skills required to reduce blindness and visual disability.www.lshtm.ac.uk/study/masters/mscphec.html or email romulo.fabunan@lsthm.ac.ukFor more information visit The ICEH Open Education for eye care programme offers a series of online courses in key topics in public health eye care. All the courses are free to access and include: Global Blindness, Eliminating Trachoma, Ophthalmic Epidemiology: Basic Principles and Application to Eye Disease.More free courses coming! Certification also available.http://iceh.lshtm.ac.uk/oer/For more information visit Contact Anita Shahadmin@cehjournal.orgweb@cehjournal.org or visit www.cehjournal.org/subscribewww.cehjournal.orgwww.facebook.com/CEHJournalhttps://twitter.com/CEHJournal"} +{"text": "Major genera identified were https://link.springer.com/article/10.1007/s12257-013-0517-8Bacillus, Serratia, Lactococcus, Enterococcus, Stenotrophomonas, Klebsiella and Escherichia.Diary wastewater is rich in fat and proteins and so is ideally composed of different members than a chemical or municipal water treatment system. Major genera of bacteria are https://www.hindawi.com/journals/archaea/2017/2170535/This study examined a highly specific microbial consortia using a 16S rRNA gene sequencing and proteomics approach.https://patents.google.com/patent/US7520990This patent describes an anaerobic wastewater treatment with a recycling system designed to recapture anaerobic microbial consortia particles escaping from the bioreactor tank.http://edepot.wur.nl/40320This Ph.D. thesis describes studies on effects of metals on anaerobic methanogenic consortia.http://www.climatetechwiki.org/technology/jiqweb-anbtThis webpage offers a useful primer on anaerobic digestion processes and systems.http://www.onsiteconsortium.org/Glossary2009.pdfThis site provides a useful guide for common and specialized terminology relevant to wastewater treatment and anaerobic consortia.https://www.omicsonline.org/open-access/a-new-perspective-on-microbiome-and-resource-management-in-wastewater-systems-2155-952X-1000184.php?aid=54389This review provides a good overview of microbial wastewater treatment and describes how microbiome research is beginning to impact the field.https://microbedetectives.com/wastewater-treatment/This company website describes their service of analyzing water systems for their microbial contents, with the goal of aiding in process optimization.http://gwmc.ou.eduThe overall goal of the global water microbiome consortium is to provide insights into the diversity and stability of wastewater microbiomes through a global collaboration with different groups working on these microbiomes.https://www.epa.gov/npdes/municipal-wastewaterThis page put out by the United States Environmental Protection Agency contains numerous useful documents for information and standards.http://microbiomewatersummit.com/wastewater-microbiome/The microbiome water summit is one of many conferences on this emerging theme emphasizing the importance of microbiome composition of water treatment processes.https://pubs.acs.org/doi/abs/10.1021/acs.est.5b04847The goal of this study was to drive chain elongation of fatty acids with ethanol as the electron donor. The overall goal is to convert organic waste into process chemicals."} +{"text": "The authors wish to make a change to the published paper . Scheme http://www.mdpi.com/2073-4360/8/6/207.The change does not affect the scientific results. The manuscript will be updated and the original will remain online on the article webpage"} +{"text": "This article has been corrected: The correct Acknowledgments information is given below:ACKNOWLEDGMENTShttp://cancergenome.nih.gov/.We thank Leo Zeef and Andy Hayes of the Bioinformatics and Genomic Technologies Core Facilities at the University of Manchester for providing support with regard to RNAseq. This work was funded by a Cancer Research UK Major Centre award [C147/A18083]; Sarcoma UK (SUK205.2016); and the NIHR Manchester Biomedical Research Centre. The results here are partly based upon data generated by the TCGA Research Network: 3946-3955. https://doi.org/10.18632/oncotarget.23280Original article: Oncotarget. 2018; 9:"} +{"text": "This article has been corrected: During production, the ending page number for this article was listed incorrectly. The page count has now been adjusted to show the proper pagination.936-947. https://doi.org/10.18632/oncotarget.1108Original article: Oncotarget. 2013; 4:"} +{"text": "These articles have been corrected: The proper images for Figure 3 and Figure 4 are shown below. The authors declare that these corrections do not change the results or conclusions of this paper.298-308. https://doi.org/10.18632/oncotarget.1628Original article: Oncotarget. 2014; 5:298\u2013308."} +{"text": "MMWR is a public-private partnership building a nationwide system to deliver an affordable, evidence-based lifestyle change program to prevent or delay type 2 diabetes. In 2018, the National DPP lifestyle change program became a covered service for Medicare beneficiaries with prediabetes. The first national prediabetes awareness campaign, DoIHavePrediabetes.org, done in collaboration with partners, encourages persons to learn their prediabetes risk. CDC also works to increase access to diabetes self-management education and support services to help persons with diabetes manage their daily diabetes care (https://www.cdc.gov/diabetes/dsmes-toolkit/index.html). More information is available at https://www.cdc.gov/diabetes.CDC plays a crucial role in preventing type 2 diabetes and diabetes complications. The National Diabetes Prevention Program ("} +{"text": "Nature Communications 10.1038/ncomms12879, published online 15 September 2016.Correction to: The Supplementary Information associated with this Article contains an error in Supplementary Fig. Supplementary Information"} +{"text": "Health Policy and Planning, doi: 10.1093/heapol/czx183.The authors wish to inform readers that one source of funding (Wellcome Trust grant number 102919/Z/13/Z) was originally omitted from this article\u2019s funding statement. This has now been corrected online."} +{"text": "Environmental Protection Agency. It contains numerous links to information on different remediation projects, involving nanotechnology, phyto\u2010technology and chemical oxidation.https://onlinelibrary.wiley.com/doi/full/10.1111/1751-7915.12837This review is based on the process that biological drinking water treatment processes for removing chemical contaminants are generally less expensive and less energy intensive than other methods.https://tifac.org.in/index.php/8-publication/154-application-of-biotechnology-for-water-treatmentThis site provides a link to a report on biotechnology for advanced water treatment.https://www.nae.edu/7700/BiologicalTreatmentsofDrinkingWaterThis treatise on biological water treatment is put out by the U.S. National Academy of Engineering.https://www.drylet.comDrylet technology combines specific bacteria and porous materials for bioremediation of chemical contaminants in water.http://minnepura.comMinnepura Technologies focuses on using encapsulated bacteria to remove chemicals from water, using silica\u2010based materials for the encapsulation.https://www.nature.com/articles/srep44350Dark matter refers to the sequences in waters that are detected in broad\u2010based genome sequencing and attributed to poorly studied bacterial diversity. This study was devised to help fill gaps in that knowledge.https://aem.asm.org/content/84/5/e02168-17This study examines the impact of wastewater treatment effluents on nearby water systems. In this case, discharge into Lake Michigan was investigated.https://www.frontiersin.org/articles/10.3389/fmicb.2017.01382/fullThis investigation describes the microbial populations found in a pre\u2010treated raw sludge and a post\u2010treated dried sludge from wastewater treatment.https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-017-0298-yThis paper describes research in which wastewater was sampled from around China and examined for antibiotic resistance genes. Correlations were sought, and found, for resistance genes with other markers.https://pubs.rsc.org/en/content/articlelanding/2018/ew/c8ew00395e#!divAbstractThere have been many studies of wastewater metagenomes, but this study focused on treated water post\u2010chlorination, where microbial populations are much lower.https://microbedetectives.comThis is a colorful commercial website. The company seeks to use metagenomic analysis to advise on enhancing performance for wastewater treatment, biogas production, and increasing drinking water safety.https://www.wateronline.com/doc/high-throughput-dna-sequencing-to-profile-microbial-water-quality-of-potable-reuse-0001This webpage provides a good primer on the use of metagenomics for analyzing and improving wastewater treatment.https://f1000research.com/articles/5-1881/v1This web article focuses on the ability of microbial communities to biodegrade personal care products, particularly pharmaceuticals."} +{"text": "Goals also include providing information about risk for overdose and community services and preventing drug-related harm through evidence-based policy and practice increased (https://www.cdc.gov/drugoverdose/index.html.A report in this issue of"} +{"text": "National HIV Testing Day, June 27, highlights the importance of testing in detecting, treating, and preventing human immunodeficiency virus (HIV) infection. Awareness of HIV infection through HIV testing is the first step to prevention, health care, and social services that improve life quality and length of survival (Health care providers and others providing HIV testing can reduce HIV-related adverse health outcomes and risk for HIV transmission by implementing routine and targeted testing to decrease diagnosis delays (https://www.cdc.gov/features/HIVtesting. Basic testing information for the public is available at https://www.cdc.gov/hiv/basics/testing.html. Additional information on HIV testing for health professionals is available at https://www.cdc.gov/hiv/testing. CDC\u2019s guidelines for HIV testing of serum and plasma specimens are available at https://www.cdc.gov/hiv/guidelines/testing.html.Additional information on National HIV Testing Day is available at"} +{"text": "Holm-Bonferroni Sequential Correction: An Excel Calculator Microsoft Excel Workbook. Available online at: www.staff.amu.edu.pl/~leka/_uploads/Holms-correction-calculator.xlsx. It should be Gaetano, J. (2018). Holm-Bonferroni Sequential Correction: An Excel Calculator (v. 1.3) Microsoft Excel Workbook. Available online at: https://www.researchgate.net/publication/322569220_Holm-Bonferroni_sequential_correction_An_Excel_calculator_13. The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way.In the original article, the reference for Gaetano, 2018 was incorrectly written as Gaetano, J. (2018). The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest."} diff --git a/PMC_clustering_689.jsonl b/PMC_clustering_689.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..3a3557a6d0d76fd0f9b905e760333129bfb97ea8 --- /dev/null +++ b/PMC_clustering_689.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:a8c4f4f6c3890dd73db9ed16470a9be3a1bec162e8e883ef0f42a352305c7660 +size 47840961 diff --git a/PMC_clustering_690.jsonl b/PMC_clustering_690.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..489041a940e6252d00f60680fe1cfd8c48bd91e7 --- /dev/null +++ b/PMC_clustering_690.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:ff2d8c71f72d1f6ac954d390b2c6c69b17f5fbb654b6d26b37d5371fbe7684fb +size 98931978 diff --git a/PMC_clustering_691.jsonl b/PMC_clustering_691.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..8ca6b96d5c5b9bdf07fa2f05f9b1cb5428038e8f --- /dev/null +++ b/PMC_clustering_691.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:e96aa78ffd90c25023d47cb1a404ee8509f422ad22bd0dbfbf9c33bb82bb6514 +size 72722235 diff --git a/PMC_clustering_692.jsonl b/PMC_clustering_692.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..117c6b16825cbce75bfc544df8c18057ad975707 --- /dev/null +++ b/PMC_clustering_692.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:2cc388ab6e63279611620d219a171c0fa68b8e3df1055b0435e43fa09aa81cff +size 13724579 diff --git a/PMC_clustering_693.jsonl b/PMC_clustering_693.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..41415dda71de8baceb38b97bc8939be6c6be5edc --- /dev/null +++ b/PMC_clustering_693.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:bfa5ee517018061fdaa7326c1bcd6be46dce3d952ca7ea758f65cce8a8a164d0 +size 43217477 diff --git a/PMC_clustering_694.jsonl b/PMC_clustering_694.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..e000bc02d7cd3480114c5597863d785cc73e0f20 --- /dev/null +++ b/PMC_clustering_694.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:e509f6954d576d7c39dd45c3246f75b714d130b39060959e10bf9b94deb413f2 +size 14908849 diff --git a/PMC_clustering_695.jsonl b/PMC_clustering_695.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..a5df71df522da81cd1f8dece939ed0a0b4dec564 --- /dev/null +++ b/PMC_clustering_695.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:9edbec5d7fcd796916fc5a62b29557423e3e03a74d1128fa791cbfebe98cb5fb +size 41483661 diff --git a/PMC_clustering_696.jsonl b/PMC_clustering_696.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..633de9be0b6d3418f7795a67b160558f5b8867b6 --- /dev/null +++ b/PMC_clustering_696.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:991b31a7981186a1248f522e7a110529edab1ceae3ebcc0b9548ca8159af073f +size 39046289 diff --git a/PMC_clustering_697.jsonl b/PMC_clustering_697.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..6867831697681b55ab6385a2248b86198833a595 --- /dev/null +++ b/PMC_clustering_697.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:926dba0a85d261c81abfcb65045d86e0c3289c89e59d92391092444b32bb14ee +size 39902982 diff --git a/PMC_clustering_698.jsonl b/PMC_clustering_698.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..fa9ba0d00d6ab1f75a3a8130d8fe77f69d31a266 --- /dev/null +++ b/PMC_clustering_698.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:b6a684252d204fc4a9b445215a4e7b6b7ebe0ae23c7ec134794e036ed9d46189 +size 10568622 diff --git a/PMC_clustering_699.jsonl b/PMC_clustering_699.jsonl new file mode 100644 index 0000000000000000000000000000000000000000..54cc665cdb6e6458b8fb8510f476850adc9fec19 --- /dev/null +++ b/PMC_clustering_699.jsonl @@ -0,0 +1,3 @@ +version https://git-lfs.github.com/spec/v1 +oid sha256:4d3cbb5a18e90797022f7971353c3ab2a36b8e1cd916e9db76e4b808120d8561 +size 53181961